PMID- 20191333 TI - Safe switching from dasatinib to nilotinib after a 1-month off-drug period for persistent pleural effusion in patients with chronic myelogenous leukemia in chronic phase. AB - The approval of two new tyrosine kinase (TK) inhibitors, nilotinib and dasatinib, has raised the issue of cross-intolerance. Evaluating the safety of interchanging TK inhibitors is particularly important for patients who are intolerant to one medication but are considered to be sensitive to the other. Available data are limited and it is unclear whether switching between TK inhibitors is possible without an off-drug period. We present two patients with chronic myelogenous leukemia in whom, following the development of symptomatic pleural effusion, medications were safely switched from dasatinib to nilotinib after a 1-month off drug period. The lymphocytosis and increased large granular lymphocyte count observed during dasatinib treatment also subsided after switching medications. PMID- 20191334 TI - Relevance of HBV/HBcAb screening in lymphoma patients treated in the Rituximab era. PMID- 20191335 TI - Inhibition of Staphylococcus epidermidis biofilms using polymerizable vancomycin derivatives. AB - BACKGROUND: Biofilm formation on indwelling medical devices is a ubiquitous problem causing considerable patient morbidity and mortality. In orthopaedic surgery, this problem is exacerbated by the large number and variety of material types that are implanted. Metallic hardware in conjunction with polymethylmethacrylate (PMMA) bone cement is commonly used. QUESTIONS/PURPOSES: We asked whether polymerizable derivatives of vancomycin might be useful to (1) surface modify Ti-6Al-4V alloy and to surface/bulk modify PMMA bone cement to prevent Staphylococcus epidermidis biofilm formation and (2) whether the process altered the compressive modulus, yield strength, resilience, and/or fracture strength of cement copolymers. METHODS: A Ti-6Al-4V alloy was silanized with methacryloxypropyltrimethoxysilane in preparation for subsequent polymer attachment. Surfaces were then coated with polymers formed from PEG(375)-acrylate or a vancomycin-PEG(3400)-PEG(375)-acrylate copolymer. PMMA was loaded with various species, including vancomycin and several polymerizable vancomycin derivatives. To assess antibiofilm properties of these materials, initial bacterial adherence to coated Ti-6Al-4V was determined by scanning electron microscopy (SEM). Biofilm dry mass was determined on PMMA coupons; the compressive mechanical properties were also determined. RESULTS: SEM showed the vancomycin-PEG(3400)-acrylate-type surface reduced adherent bacteria numbers by approximately fourfold when compared with PEG(375)-acrylate alone. Vancomycin loading reduced all mechanical properties tested; in contrast, loading a vancomycin-acrylamide derivative restored these deficits but demonstrated no antibiofilm properties. A polymerizable, PEGylated vancomycin derivative reduced biofilm attachment but resulted in inferior cement mechanical properties. CLINICAL RELEVANCE: The approaches presented here may offer new strategies for developing biofilm-resistant orthopaedic materials. Specifically, polymerizable derivatives of traditional antibiotics may allow for direct polymerization into existing materials such as PMMA bone cement while minimizing mechanical property compromise. Questions remain regarding ideal monomer structure(s) that confer biologic and mechanical benefits. PMID- 20191336 TI - Reduced anisotropy in the middle cerebellar peduncle in Chiari-II malformation. AB - Besides supratentorial abnormalities, spina bifida menigomyelocele (SBM) is typically associated with Chiari-II malformation comprising a small cerebellum, which herniates downward due to a shallow posterior fossa. We used diffusion tensor imaging to probe additional microstructural alterations of the major cerebellar white matter tracts, the cerebellar peduncles. A region-of-interest approach was employed in six SBM patients and six matched controls to compare the fractional anisotropy (FA) within the superior, middle, and inferior cerebellar peduncle (SCP, MCP, and ICP, respectively). The FA in the MCP was significantly reduced in the SBM patients (0.44 vs. 0.65, p = 0.002), while there was no significant difference in the other cerebellar peduncles. In the context of numerous supratentorial white matter abnormalities in SBM such as callosal dysplasia, the most likely explanation of reduced FA in the MCP is a reduced fiber density. PMID- 20191338 TI - Enhanced oral bioavailability of flurbiprofen by combined use of micelle solution and inclusion compound. PMID- 20191339 TI - An efficient synthesis and antioxidant properties of novel imino and amino derivatives of 4-hydroxy coumarins. AB - Series of imino and amino derivatives of 4-hydroxy coumarins were synthesized via conventional and microwave promoted procedure and evaluated for antioxidant potential through different in vitro models such as (DPPH) free radical scavenging activity, linoleic acid emulsion model system, reducing power assay and phosphomolybdenum method. All prepared compounds possess good antioxidant activity and among them p-nitro-phenyl derivative 6c with IC50 at 25.9 microM possesses radical scavenging activity which is comparable to standard BHT, while the best reducing power was observed in a case of benzyl amino compound 8c (RP50 255.6 microM). Also, observed data indicated that compounds may serve as inhibitors of lipid peroxidation process. PMID- 20191340 TI - Synthesis and antimicrobial evaluation of new 3-alkyl/aryl-2-[((alpha,alpha diphenyl-alpha-hydroxy)acetyl)hydrazono]-5-methyl-4-thiazolidinones. AB - New 4-thiazolidinone derivatives of benzilic acid (alpha,alpha-diphenyl-alpha hydroxyacetic acid) have been synthesized and evaluated for antibacterial and antifungal activities. The reaction of 1- (alpha,alpha-diphenyl-alpha hydroxy)acetyl-4-alkyl/arylthiosemicarbazides with ethyl 2-bromopropionate gave 3 alkyl/aryl-2-[((alpha,alpha-diphenyl-alpha-hydroxy)acetyl)hydrazono]-5-methyl-4 thiazolidinone derivatives. Their antibacterial and antifungal activities were evaluated against S. aureus ATCC 29213, P. aeruginosa ATCC 27853, E. coli ATCC 25922, C. albicans ATCC 10231, C. parapsilosis ATCC 22019, C. krusei ATCC 6258, T. mentagrophytes var. erinacei NCPF 375, M. gypseum NCPF 580 and T. tonsurans NCPF 245. 3e, 3f, 3g and 3h showed the highest antibacterial activity. Particularly 3a and 3e showed the highest antifungal activities against C. parapsilosis ATCC 22019, T. tonsurans NCPF 245 and M. gypseum NCPF 580. PMID- 20191341 TI - Synthesis of new 4,5-3(2H)pyridazinone derivatives and their cardiotonic, hypotensive, and platelet aggregation inhibition activities. AB - 4,5-dihydro-3(2H)pyridazinones such as CI-914, CI-930 and pimobendan along with tetrahydropyridopyridazine (endralazine) and perhydropyridazinodiazepine (cilazopril) have been used as potent positive inotropes, antihypertensives as well as platelet aggregation inhibitors. Accordingly, the present work involves the synthesis of 24 target compounds; 4,5-dihydro-3(2H)pyridazinones in addition to seven reported intermediates. The chemical structures of the new compounds were assigned by microanalysis, IR, 1H-NMR spectral analysis and some representatives by mass spectrometry. The positive inotropic effect of the final compounds and the intermediates 12a-12d as well as the reported intermediate compound 10 was determined in-vitro on isolated rabbit heart in comparison to digoxin. Data obtained revealed that twelve of the test compounds exhibited higher effective response than digoxin, nine compounds elicited comparable effects to digoxin and eight compounds were less active than digoxin. In addition, four compounds approved marked significant hypotensive effect better than that of the previously reported compound 10. Moreover, two compounds induced complete platelet aggregation inhibition. The last two compounds were also subjected to determination of their LD50 and they showed no signs of toxicity up to the dose level 300 mg/kg (i.p.), while the reported oral LD50 of digoxin is 17.78 mg/kg. Correlation of cardiotonic and hypotensive activities with structures of compounds was tried and pharmacophore models were computed to get useful insight onto the essential structural features required for inhibiting phosphodiesterase-III in the heart muscles and blood vessels. PMID- 20191342 TI - Synthesis and microbiological activity of thiourea derivatives of 4 azatricyclo[5.2.2.0(2,6)]undec-8-ene-3,5-dione. AB - A series of thiourea derivatives of 4-azatricyclo[5.2.2.0(2,6)]undec-8-ene-3,5 dione were synthesized. The compounds were investigated for antibacterial activity, including Gram-positive cocci, Gram-negative rods, and antifungal activity. Compounds 1b, 2b, 4b showed significant inhibition against Gram positive cocci. Research was carried out over 10 standard strains and 20 hospital strains. Synthesized compounds were evaluated for their cytotoxicity and anti-HIV 1 activity in MT-4 cells. PMID- 20191343 TI - Synthesis and antitumor screening of new 1,7-diphenyl-3-(1,3-disubstituted-1H pyrazole-4-carbonyl)-[1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-ones. AB - A new series of 3-(1,3-disubstituted-1H-pyrazole-4-carbonyl)-1,7-diphenyl [1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-ones 4 was prepared by reaction of the enaminone 2 with hydrazonoyl halides 3. The preliminary screening for antitumor activity of the synthesized compounds was carried out against Ehrlich Ascites Carcinoma tumor cells. The results revealed that the studied compounds 4 have low or no antitumor activity towards EAC tumor cells. PMID- 20191344 TI - Synthesis and microbiological evaluation of honokiol derivatives as new antimicrobial agents. AB - Honokiol, a major phenolic constituent of Magnolia sp., has various pharmacological activities. To improve the solubility and antibacterial activity of honokiol against E. coli and P. aeruginosa, new honokiol-derivatives (honokiol acetate, honokiol-succinic acid, honokiol-glycerol, honokiol-glycine, honokiol glucose and honokiol-mannose) were synthesized and their solubility and antimicrobial activities were investigated. Among the tested compounds, honokiol glycine showed improved water solubility and antibacterial activities against E. coli and P. aeruginosa when compared to honokiol. PMID- 20191345 TI - Tribuli fructus constituents protect against tacrine-induced cytotoxicity in HepG2 cells. AB - A new phenolic amide, tribulusimide D (4-hydroxy-N-[3-(4-hydroxy-3-methoxyphenyl) 1-oxo-2-propen-1-yl]-3-methoxybenzamide) (1), together with a known phenolic amide, terrestriamide ((E)-3-(4-hydroxy-3-methoxyphenyl)-N-[2-(4-hydroxyphenyl)-2 oxoethyl]-prop-2-enamide) (2) and a flavonol glycoside, quercetin-3-O-beta-D glucopyranosyl-(1-->6)-beta-D-glucopyranoside (3) were isolated from the H2O extract of Tribuli Fructus. Compounds 1 and 3 showed significant hepatoprotective activities, with EC50 values of 13.46 +/- 0.2 and 7.06 +/- 0.7 microM, respectively, against tacrine-induced cytotoxicity in HepG2 cells. PMID- 20191346 TI - Cytotoxic germacranolide sesquiterpenes from the bark of Magnolia kobus. AB - A new (3) and three known germacrane-type sesquiterpenoids were isolated from the chloroform-soluble fraction of the methanolic extract of the bark of Magnolia kobus (Magnoliaceae) through repeated silica gel and Sephadex LH-20 column chromatography. Their chemical structures were elucidated as costunolide (1), parthenolide (2), isobisparthenolidine (3), and bisparthenolidine (4) by spectroscopic analysis. Compounds 1-4 exhibited cytotoxicity against human A549, SK-OV-3, SK-MEL-2, and HCT15 tumor cells. PMID- 20191347 TI - A new norlupane triterpene from the leaves of Acanthopanax koreanum increases the differentiation of osteoblastic MC3T3-e1 cells. AB - A new norlupane-triterpene, 3alpha,11alpha-dihydroxy-20,23-dioxo-30-norlupane-28 oic acid (1), and four known compounds; 3alpha,11alpha-dihydroxy-23-oxo-lup 20(29)-en-28-oic acid (2), 3alpha,11alpha-dihydroxylup-20(29)-en-28-oic acid (3), ent-kaur-16-en-19-oic acid (4), and betulabuside B (5) were isolated from the methanolic extract of the leaves of Acanthopanax koreanum. Their chemical structures were elucidated by mass, 1D- and 2D-NMR spectroscopy. To investigate the bioactivities of these compounds, their effects on the differentiation of osteoblastic MC3T3-E1 cells were tested. Compounds 3 and 4 significantly increased osteoblastic cell growth and differentiation as assessed by the MTT assay and collagen content, respectively (p < 0.05). Compounds 1 and 5 significantly increased the growth of MC3T3-E1 cells and caused a significant elevation of osteoblastic cell differentiation as assessed by the alkaline phosphatase activity. These results suggest that the compounds isolated from A. koreanum leaves have a direct stimulatory effect on bone formation in vitro and may contribute to the prevention for osteoporosis. PMID- 20191348 TI - Improvement of the extraction efficiency of D-amygdalin from Armeniacae Semen powder through inactivating emulsin and suppressing the epimerization of D amygdalin. AB - Armeniacae Semen contains not only amygdalin but also emulsin, which is an enzyme that hydrolyzes amygdalin. This hydrolysis reaction has been a major problem associated with the water extraction of Armeniacae Semen powder. In this study, the emulsin was inactivated by extracting Armeniacae Semen powder at a constant temperature of 90 degrees C. In addition, in order to suppress the epimerization of D-amygdalin, the extraction time was kept to less than 8 min. The use of a 10 mM sodium phosphate buffer (pH 2.3) containing 13.5% acetonitrile as a mobile phase in reversed-phase HPLC was effective in separating and analyzing the D amygdalin and neoamygdalin. The linearity between the concentrations and detector responses was obtained in the range of 0.05 to 0.5 mM. The detection limits for D amygdalin and neoamygdalin were approximately 5 microM per amount injected. PMID- 20191349 TI - Attenuation of experimental murine colitis by acanthoic acid from Acanthopanax koreanum. AB - Acanthoic acid (AA) is a pimaradiene diterpene isolated from Acanthopanax koreanum. We examined the effect of AA in dextran sulfate sodium (DSS)-induced colitis. AA (100 mg/kg or 300 mg/kg) was administered p.o. daily for 7 days. AA significantly inhibited Disease Activity Index, histological score, and myeloperoxidase activity. Furthermore, AA markedly suppressed the protein expression of TNF-alpha, COX-2, NF-kappaB and chymase as well as the mRNA expression of TNF-alpha and COX-2. These results suggest that AA exerts beneficial effects in experimental colitis, and therefore we propose that this compound may have therapeutic implications for ulcerative colitis. PMID- 20191350 TI - Enhanced oral bioavailability of flurbiprofen by combined use of micelle solution and inclusion compound. AB - The main purpose of this study was to evaluate the effect of a mixed drug solution containing a surfactant and beta-cyclodextrin (beta-CD) on the solubility and bioavailability of a poorly water soluble drug, flurbiprofen. Solubility, dissolution and in vivo pharmacokinetics of flurbiprofen in the presence of surfactant, beta-CD or mixture of surfactant and beta-CD were investigated. Among the surfactants tested, Tween 80 produced the highest improvement in the aqueous solubility of flurbiprofen. The solubility of flurbiprofen increased linearly as a function of beta-CD, resulting in B8 type that suggested a formation of inclusion complex in a molar ratio of 1:1. The solubility of flurbiprofen increased further when Tween 80 was included in addition to beta-CD, suggesting that a micelle formation in the presence of Tween 80 was the likely reason for additional increase. Furthermore, the data suggested that Tween 80 did not interfere with the inclusion interaction between flurbiprofen and beta-CD. The solubility of flurbiprofen was the highest in the mixed system containing 1.3 mM beta-CD and 0.3% w/v Tween 80, and the maximum solubility of 160 microg/mL was achieved. Consistent with the enhanced solubility, the plasma exposure (both AUC and Cmax) of flurbiprofen when dosed as the mixed system was significantly higher (as much as 2 to 3-fold) than that without surfactant or beta-CD, with surfactant alone, or with beta-CD alone. Therefore, the mixed system consists of surfactant and beta-CD could be used as an effective oral dosage form to improve bioavailability of poorly water soluble drugs such as flurbiprofen. PMID- 20191351 TI - Optimization of drug release from compressed multi unit particle system (MUPS) using generalized regression neural network (GRNN). AB - The purpose of this study was development of diclofenac sodium extended release compressed matrix pellets and optimization using Generalized Regression Neural Network (GRNN). According to Central Composite Design (CCD), ten formulations of diclofenac sodium matrix tablets were prepared. Extended release of diclofenac sodium was accomplished using Carbopol 71G as matrix substance. The process of direct pelletisation and subsequently compression of the pellets into MUPS tablets was applied in order to investigate a different approach in formulation of matrix systems and to achieve more control of the process factors over the principal response--the release of the drug. The investigated factors were X1-the percentage of polymer Carbopol 71 G and X2-crushing strength of the MUPS tablet. In vitro dissolution time profiles at 5 different sampling times were chosen as responses. Results of drug release studies indicate that drug release rates vary between different formulations, with a range of 1 hour to 8 hours of dissolution. The most important impact on the drug release has factor X1the percentage of polymer Carbopol 71 G. The purpose of the applied GRNN was to model the effects of these two causal factors on the in vitro release profile of the diclofenac sodium from compressed matrix pellets. The aim of the study was to optimize drug release in manner which enables following in vitro release of diclofenac sodium during 8 hours in phosphate buffer: 1 h: 15-40%, 2 h: 25-60%, 4 h: 35-75%, 8 h: >70%. PMID- 20191352 TI - Simple preparation of coated resin complexes and their incorporation into fast disintegrating tablets. AB - Even though ion-exchange resins are good drug carriers to get sustained release properties, it may not be good enough only with themselves. For further sustained release effect, a diffusion barrier or coating on the resins' surface can be utilized. Initially, microencapsulation using a w/o/w double emulsion method was used to apply ethylcellulose (EC) onto the drug/resin complexes. Typical pharmaceutical waxes can be alternative materials to delay the drug release from the complex. After the coating, the coated resin particles were incorporated into fast-disintegrating tablets to get an idea regarding the effects of wet granulation and compression on the release. Among the different grades of ECs tested (Ethocel 20, 45, and 100), more viscous EC resulted in better morphologies and sustained release effects. Because the drug release rate was significantly dependent on the coating level, the release rate can be modified easily by changing different levels of the coating. The drug release rate was also strongly dependent on the granulation and compaction process as the coated particles were incorporated into the tablet dosage form. Among the tested waxes, stearic acid had an effect on the sustained release together with lubrication and wetting properties. Even though microencapsulation or wax coating may not be practical for real manufacturing, the results may give valuable information how to formulate sustained release dosage forms and their properties on the tablet preparation. PMID- 20191353 TI - Anticoagulating activities of low-molecular weight fuco-oligosaccharides prepared by enzymatic digestion of fucoidan from the sporophyll of Korean Undaria pinnatifida. AB - In spite of their potential as biologically active compounds, the high molecular mass and viscous natures of fucoidans have hampered their applications especially as a therapeutic agent. Herein the fucoidan-degrading enzyme activities were partially purified from the cultured cells of Sphingomonas paucimobilis PF-1 mainly by ammonium sulfate precipitation. This enzyme preparation degraded fucoidans from the Korean Undaria pinnatifida sporophyll into several low molecular weight fuco-oligosaccharides (LMFOs) with less than 3,749 Da. The FTIR spectra of intact fucoidan and mixture of LMFOs (1,389-3,749 Da) showed no significant structural difference except for about 10% reduced level of sulfate esters in LMFOs. The LMFOs have exerted strong anticoagulating activities at which the activated partial thromboplastin time (APTT) and thrombin time (TT) were significantly prolonged, although 3 approximately 20 times weaker activities were observed than those of intact fucoidan. In addition, unlike intact fucoidan, LMFOs did not affect significantly to the prothrombin time (PT). These results suggest that the partially purified fucoidan-degrading enzyme preparation is valuable for the production of fuco-oligosaccharides having anticoagulating activities, and that the molecular weight and/or sulfate content of the fucoidan from the Korean Undaria pinnatifida sporophyll could be important factors for its anticoagulating activity. PMID- 20191354 TI - N-nitroso-N-methylurea and N-nitroso-N-ethylurea induce upregulation of cellular NF-kappa B activity through protein kinase C-dependent pathway in human malignant keratinocytes. AB - The upregulatory mechanism of cellular NF-kappaB activity by carcinogens, N nitroso-N-methylurea (NMU) and N-nitroso-N-ethylurea (NEU) in human malignant keratinocytes was investigated. To elucidate the role of protein kinase C (PKC) in the upregulation of NF-kappaB by NMU and NEU, two known PKC inhibitors, staurosporine and H-7 were studied. Treatment of cells with PKC inhibitors decreased NF-kappaB activity in a dose responsive manner at concentrations of 20 approximately 200 nM. Staurosporine (160 nM) and H-7 (200 nM) downregulated the cellular NF-kappaB activation up to 20 and 60% compared to the NF-kappaB activity that was upregulated by NMU (5 microM) and NEU (5 microM), respectively. These results indicated that the PKC activity was responsible for the upregulation of NF-kappaB activity. The level of phosphorylation of I-kappaBalpha, the predominant form of the I-kappaB family represented by NMU and NEU, was quantified. The relative amount of I-kappaBalpha phosphorylation (serines-32 and 36) determined using the cellular activation of signaling ELISA assay method showed that NMU (5 microM) and NEU (5 microM) increased the amount of I kappaBalpha phosphorylation up to 17 and 10% compared to the control, respectively. The results demonstrate the upregulatory effect of NMU and NEU on cellular NF-kappaB activity in human keratinocytes via the protein kinase C mediated pathway. PMID- 20191355 TI - Rheological evaluation of petroleum jelly as a base material in ointment and cream formulations: steady shear flow behavior. AB - The objective of the present study is to systematically characterize a nonlinear rheological behavior of petroleum jelly (petrolatum) in steady shear flow fields correspondent to the spreading condition onto the human body. With this aim, using a strain-controlled rheometer, the steady shear flow properties of commercially available petroleum jelly have been measured at 37 degrees C (body temperature) over a wide range of shear rates. In this article, the shear rate dependence of steady shear flow behavior was reported from the experimentally obtained data. In particular, the existence of a yield stress and a non-Newtonian flow behavior were discussed in depth with a special emphasis on their importance in actual application onto the human body. In addition, several inelastic viscoplastic flow models including a yield stress parameter were employed to make a quantitative description of the steady shear flow behavior, and then the applicability of these models was examined in detail. Main findings obtained from this study can be summarized as follows: (1) Petroleum jelly exhibits a finite magnitude of yield stress. The appearance of a yield stress is attributed to its three-dimensional network structure that can show a resistance to flow and plays an important role in determining a storage stability and sensory feature of the product. (2) Petroleum jelly demonstrates a pronounced non-Newtonian shear thinning flow behavior which is well described by a power-law equation and may be interpreted by the disruption of a crystalline network under the influence of mechanical shear deformation. This rheological feature enhances sensory qualities of pharmaceutical and cosmetic products in which petroleum jelly is used as a base material during their actual usage. (3) The Casson, Mizrahi-Berk, Heinz Casson and Herschel-Bulkley models are all applicable and have almost an equivalent ability to quantitatively describe the steady shear flow behavior of petroleum jelly whereas the Bingham model does not give a good validity. Among these flow models, the Herschel-Bulkley model provides the best applicability. PMID- 20191356 TI - Effect of protopanaxadiol derivatives in high glucose-induced fibronectin expression in primary cultured rat mesangial cells: role of mitogen-activated protein kinases and Akt. AB - A lot of anti-diabetic agents using natural plants have been extensively studied. Ginsenosides are known to be used as a remedy for diabetes in Asian countries and American Societies. Diabetic nephropathy is a major complication of diabetes mellitus. Extracellular matrix in mesangial cells is mainly composed of fibronectin and the increase of fibronectin is a hallmark of diabetic nephropathy. Protopenaxadiol (PPD) is a major component of total ginseng. Thus, we examined the regulatory mechanism of PPD derivatives-induced preventive effect of fibronectin expression in mesangial cells cultivated under diabetic condition. In present study, ginsenoside Rb1 prevented the high glucose-induced increase of fibronectin expression in mesangial cells. Ginsenoside Rb2 and Rg3 also mildly inhibited it. However, ginsenoside Rc and Rd did not prevent the high glucose induced increase of fibronectin expression in mesangial cells. In addition, ginsenoside Rb1 prevented high glucose-induced phosphorylation of p44/42 mitogen activated protein kinase (MAPK), p38 MAPK, JNK/SAPK, and Akt. These results suggest that ginsenoside Rb1 is the most powerful component of PPD derivatives. In conclusion, ginsenoside Rb1 prevented high glucose-induced increase of fibronectin expression via the inhibition of MAPK-Akt signaling cascade. PMID- 20191357 TI - Characteristics of spontaneous contraction in the circular smooth muscles of cat ileum. AB - We investigated the characteristics of spontaneous contraction in feline ileal circular smooth. Smooth muscle contractions were recorded by an isometric force transducer. The neurotoxin tetrodotoxin did not alter the spontaneous contraction of the circular muscles. Atropine or guanethidine also did not affect on the contraction. In Ca2+-free Krebs, the spontaneous contraction completely disappeared in the muscles. An L-type Ca2+ channel blockade with nimodipine decreased the amplitude of spontaneous contraction. A selective inhibitor of the sarcoplasmic reticulum Ca2+-ATPase, thapsigargin, had not no effect on spontaneous contraction within incubation time for 10 min. However, phosphoinositide-specific phospholipase C inhibitor, U-73122, decreased the frequency of the contraction in circular smooth muscle These results suggest that the neuronal component, adrenergic or cholinergic innervation was not involved in spontaneous activity and that extracellular Ca2+ influx via an L-type Ca2+ channel may mediate the contractile amplitude in circular smooth muscles of cat ileum. PMID- 20191358 TI - The proanthocyanidins inhibit dimethylnitrosamine-induced liver damage in rats. AB - Proanthocyanidins are naturally occurring compounds widely available in fruits, vegetables, nuts and seeds. They are a class of phenolic compounds and have been reported to exhibit a wide range of biological effects. In this study, we investigated the protective effect of grape seed proanthocyanidins on hepatic injury induced by dimethylnitrosamine (DMN) in rats. Treatment with DMN caused a significant increase in levels of serum alanine transaminase, aspartate transaminase, alkaline phosphatase, and bilirubin. Oral administration of proanthocyanidins (20 mg/kg daily for 4 weeks) remarkably prevented these elevations. Proanthocyanidins also restored serum albumin and total protein levels, and reduced the hepatic level of malondialdehyde. Furthermore, DMN induced collagen accumulation, as estimated by histological analysis of liver tissue stained with Sirius red, was reduced in the proanthocyanidins-treated rats. A reduction in hepatic stellate cell activation, as assessed by alpha smooth muscle actin staining, was associated with proanthocyanidins treatment. In conclusion, these results demonstrate that proanthocyanidins exhibited in vivo hepatoprotective and anti-fibrogenic effects against DMN-induced liver injury. It suggests that grape seed proanthocyanidins may be useful in preventing the development of hepatic fibrosis. PMID- 20191360 TI - Randomized, controlled, double-blind trial of taranabant for smoking cessation. AB - RATIONALE: It has been proposed that cannabinoid-1 receptor inverse agonists might be effective for smoking cessation. We evaluated this hypothesis with the cannabinoid-1 receptor inverse agonist taranabant. METHODS: Adults who smoked > or =10 cigarettes a day for >1 year and had an expired CO level of > or =10 ppm participated in a randomized, double-blind, 8-week, study of taranabant (N = 159) or placebo (N = 158). Taranabant was titrated from 2 mg once daily to 8 mg once daily. Patients received smoking cessation counseling. The primary efficacy endpoint was continuous abstinence, defined as no cigarettes assessed by daily patient self-report and verified by breath CO level (<10 ppm) and plasma cotinine test (<10 ng/ml), during the last 4 weeks of the 8-week treatment period. RESULTS: The percentage of patients achieving continuous abstinence was 7.5% for taranabant 2-8 mg and 6.3% for placebo (odds ratio = 1.2 [90% confidence interval (CI), 0.6, 2.5], P = 0.678). Change from baseline in body weight in the taranabant 2-8-mg group was -1.5 (90% CI, -1.8, -1.3) versus 0.6 kg (90% CI, 0.4, 0.9) in the placebo group. Compared to placebo, taranabant 2-8 mg was associated with an increased incidence of psychiatric-related adverse events (e.g., depression, 8.2% versus 2.5%, P = 0.048), gastrointestinal-related adverse events (e.g., nausea, 49.7% versus 19.0%, P < 0.001), and flushing/hot flash adverse events (10.7% versus 1.9%, P = 0.002). CONCLUSIONS: Taranabant 2-8 mg did not improve smoking cessation and was associated with increased incidences of psychiatric-related, gastrointestinal-related, and flushing adverse events (ClinicalTrials.gov NCT00109135). PMID- 20191362 TI - Comment on: Jeserich M, Konstantinides S, Pavlik G, Bode C, Geibel A (2009) Non invasive imaging in the diagnosis of acute viral myocarditis. Clin Res Cardiol 98:753-763. PMID- 20191363 TI - Measurement of retinal nerve fiber layer thickness in optic atrophy eyes of patients with optic neuritis using optical coherence tomography. AB - OBJECTIVE: To measure the retinal nerve fiber layer (RNFL) thickness using optical coherence tomography (OCT) in optic atrophy eyes of patients with optic neuritis and investigate the correlation between the RNFL thickness and the visual function. METHODS: To compare the RNFL thickness using StratusOCT, three groups of the subjects were enrolled, including 72 patients with optic atrophy with definite demyelinating optic neuritis history (the neuritis group), 47 patients with advanced POAG atrophic neuropathy (the POAG group), and 47 healthy subjects (the control group). The correlation between the RNFL thickness and visual function parameters were investigated in the neuritis group, including the best-corrected visual acuity (BCVA), the visual field mean deviation (MD), pattern standard deviation (PSD), and P(100) latency of visual evoked potentials (VEP). RESULTS: The average RNFL thickness, superior, nasal and inferior thicknesses were significantly thinner in both the neuritis group and the POAG group than those in the control group (p < 0.05), while they were higher in the neuritis group than the POAG group (p < 0.05). The significant correlations were found both between the average RNFL thickness and BCVA (r = 0.35, p < 0.05), MD (r = 0.43, p < 0.05), and PSD (r = 0.39, p < 0.05). CONCLUSION: In comparison to the advanced POAG and normal eyes, the RNFL thickness was decreased moderately in the optic atrophy eyes resulting from demyelinating optic neuritis and was quantitatively correlated with the visual function parameters. PMID- 20191364 TI - The low phytic acid1-241 (lpa1-241) maize mutation alters the accumulation of anthocyanin pigment in the kernel. AB - The lpa1 mutations in maize are caused by lesions in the ZmMRP4 (multidrug resistance-associated proteins 4) gene. In previous studies (Raboy et al. in Plant Physiol 124:355-368, 2000; Pilu et al. in Theor Appl Genet 107:980-987, 2003a; Shi et al. Nat Biotechnol 25:930-937, 2007), several mutations have been isolated in this locus causing a reduction of phytic acid (myo-inositol 1,2,3,4,5,6-hexakisphosphate, or InsP(6)) content and an equivalent increasing of free phosphate. In particular, the lpa1-241 mutation causes a reduction of up to 90% of phytic acid, associated with strong pleiotropic effects on the whole plant. In this work, we show, for the first time to our knowledge, an interaction between the accumulation of anthocyanin pigments in the kernel and the lpa mutations. In fact the lpa1-241 mutant accumulates a higher level of anthocyanins as compared to wild type either in the embryo (about 3.8-fold) or in the aleurone layer (about 0.3-fold) in a genotype able to accumulate anthocyanin. Furthermore, we demonstrate that these pigments are mislocalised in the cytoplasm, conferring a blue pigmentation of the scutellum, because of the neutral/basic pH of this cellular compartment. As a matter of fact, the propionate treatment, causing a specific acidification of the cytoplasm, restored the red pigmentation of the scutellum in the mutant and expression analysis showed a reduction of ZmMRP3 anthocyanins' transporter gene expression. On the whole, these data strongly suggest a possible interaction between the lpa mutation and anthocyanin accumulation and compartmentalisation in the kernel. PMID- 20191365 TI - Effects of shear stress on the microalgae Chaetoceros muelleri. AB - The effect of shear stress on the viability of Chaetoceros muelleri was studied using a combination of a rheometer and dedicated shearing devices. Different levels of shear stress were applied by varying the shear rates and the medium viscosities. It was possible to quantify the effect of shear stress over a wide range, whilst preserving laminar flow conditions through the use of a thickening agent. The threshold value at which the viability of algae was negatively influenced was between 1 and 1.3 Pa. Beyond the threshold value the viability decreased suddenly to values between 52 and 66%. The effect of shear stress was almost time independent compared to normal microalgae cultivation times. The main shear stress effect was obtained within 1 min, with a secondary effect of up to 8 min. PMID- 20191366 TI - Cause of uric acid stones in rotavirus-associated gastroenteritis. PMID- 20191367 TI - Focal segmental glomerulosclerosis, Coats'-like retinopathy, sensorineural deafness and chromosome 4 duplication: a new association. AB - We describe the novel association in a girl of nephrotic syndrome due to focal segmental glomerulosclerosis, bilateral sensorineural deafness, basal ganglia calcification, bilateral retinopathy similar to that seen in Coats' disease, with de novo duplication of a subtelomeric region of chromosome 4q35. The chromosomal duplication was identified during investigation of a possible association with features of fascio-scapulo-humeral dystrophy (FSHD). This duplication has not previously been reported with FSGS and adds to the expanding number of genetic associations with steroid-resistant nephrotic syndrome. PMID- 20191368 TI - Cystinosis and lupus erythematosus: coincidence or causation. AB - A 14-year-old boy with known stable cystinosis, treated with cysteamine since infancy, presented with a deterioration of renal function with haematuria in conjunction with a nodular rash, arthralgia, leucopenia, hypocomplementaemia and raised antinuclear antibodies. He was diagnosed with spontaneous onset of systemic lupus erythematosus (SLE), and his renal biopsy was consistent with lupus nephritis. It is unusual for patients with one severe disease to develop another disease process completely unrelated to their original condition, but it can occur. However, other distinct variants of lupus have been described, including drug-induced lupus (DIL), which have features that over-lap with SLE. The potential differential diagnosis of the SLE as a form of DIL in association with cysteamine is discussed. PMID- 20191369 TI - Successful treatment of steroid-resistant nephrotic syndrome associated with WT1 mutations. AB - The Wilms' tumor suppressor gene 1 (WT1) encodes a transcription factor involved in kidney and gonadal development. WT1 is also a key regulator of podocyte functions and mutations have been found in a small percentage of children with isolated or syndromal steroid-resistant nephrotic syndrome. It is commonly assumed that the nephrotic syndrome (NS) in patients with WT1 mutations is unresponsive to therapy and characterized by rapid progression to end-stage renal disease. We report long-term observations in 3 children with focal-segmental glomerulosclerosis associated with WT1 mutations and NS (2 cases) or nephrotic range proteinuria (1 case). All patients showed a favorable response to an intensified therapy consisting of cyclosporin A (CyA) in combination with induction therapy with intravenous and oral prednisone. Treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers was added to the regimen at various times. As shown both by the short-term response and during long-term follow-up, this treatment resulted in clinical remission of the NS and/or significant reduction of proteinuria, while normal renal function could be maintained over many years. Thus, glomerular diseases in selected patients with mutations in genes regulating renal development and podocyte function may respond to combination therapy with CyA and corticosteroids. PMID- 20191370 TI - Predictors and consequences of higher estimated glomerular filtration rate at dialysis initiation. AB - There have been no studies in pediatric dialysis patients to evaluate the impact of higher estimated glomerular filtration rate (eGFR) at dialysis initiation on clinical outcomes. Baseline clinical and demographic information was collected for children aged 1-18 years undergoing incident dialysis from 1995-2002 within the United States Renal Data System. Baseline eGFRs calculated by the Schwartz formula were categorized as high (>15 ml/min/1.73 m(2)) or low (< or = 15 ml/min/1.73 m(2)). We determined predictors of eGFR at baseline, and associations between baseline eGFR and subsequent hospitalization for hypertension (HTN) or pulmonary edema (PE) in a longitudinal nonconcurrent pediatric end-stage renal disease (ESRD) cohort. Twenty percent of children had a high eGFR at initiation. Black children were less likely to initiate dialysis with a high eGFR [adjusted odds ratio (adjOR) 0.71, p < 0.001]. Girls were less likely to have a high eGFR at baseline (adjOR 0.71, p < 0.001). Children who received predialysis erythropoietin therapy were more likely to start dialysis with a high eGFR (adjOR 6.67, p < 0.001). Children with higher baseline eGFR were found to have a 21% decreased risk of hospitalization [adjusted hazard ratio (HR) 0.79, 95% confidence interval (CI) 0.65-0.96, p = 0.02]. It is not known whether this clinical benefit will result in decreased mortality and complication rates from cardiovascular disease. PMID- 20191371 TI - Ectomycorrhizal lifestyle in fungi: global diversity, distribution, and evolution of phylogenetic lineages. AB - The ectomycorrhizal (EcM) symbiosis involves a large number of plant and fungal taxa worldwide. During studies on EcM diversity, numerous misidentifications, and contradictory reports on EcM status have been published. This review aims to: (1) critically assess the current knowledge of the fungi involved in the EcM by integrating data from axenic synthesis trials, anatomical, molecular, and isotope studies; (2) group these taxa into monophyletic lineages based on molecular sequence data and published phylogenies; (3) investigate the trophic status of sister taxa to EcM lineages; (4) highlight other potentially EcM taxa that lack both information on EcM status and DNA sequence data; (5) recover the main distribution patterns of the EcM fungal lineages in the world. Based on critically examining original reports, EcM lifestyle is proven in 162 fungal genera that are supplemented by two genera based on isotopic evidence and 52 genera based on phylogenetic data. Additionally, 33 genera are highlighted as potentially EcM based on habitat, although their EcM records and DNA sequence data are lacking. Molecular phylogenetic and identification studies suggest that EcM symbiosis has arisen independently and persisted at least 66 times in fungi, in the Basidiomycota, Ascomycota, and Zygomycota. The orders Pezizales, Agaricales, Helotiales, Boletales, and Cantharellales include the largest number of EcM fungal lineages. Regular updates of the EcM lineages and genera therein can be found at the UNITE homepage http://unite.ut.ee/EcM_lineages . The vast majority of EcM fungi evolved from humus and wood saprotrophic ancestors without any obvious reversals. Herbarium records from 11 major biogeographic regions revealed three main patterns in distribution of EcM lineages: (1) Austral; (2) Panglobal; (3) Holarctic (with or without some reports from the Austral or tropical realms). The holarctic regions host the largest number of EcM lineages; none are restricted to a tropical distribution with Dipterocarpaceae and Caesalpiniaceae hosts. We caution that EcM-dominated habitats and hosts in South America, Southeast Asia, Africa, and Australia remain undersampled relative to the north temperate regions. In conclusion, EcM fungi are phylogenetically highly diverse, and molecular surveys particularly in tropical and south temperate habitats are likely to supplement to the present figures. Due to great risk of contamination, future reports on EcM status of previously unstudied taxa should integrate molecular identification tools with axenic synthesis experiments, detailed morphological descriptions, and/or stable isotope investigations. We believe that the introduced lineage concept facilitates design of biogeographical studies and improves our understanding about phylogenetic structure of EcM fungal communities. PMID- 20191372 TI - Platination of telomeric DNA by cisplatin disrupts recognition by TRF2 and TRF1. AB - Telomeres, the nucleoprotein complexes located at the ends of chromosomes, are involved in chromosome protection and genome stability. Telomeric repeat binding factor 1 (TRF1) and telomeric repeat binding factor 2 (TRF2) are the two telomeric proteins that bind to duplex telomeric DNA through interactions between their C-terminal domain and several guanines of the telomeric tract. Since the antitumour drug cisplatin binds preferentially to two adjacent guanines, we have investigated whether cisplatin adducts could affect the binding of TRF1 and TRF2 to telomeric DNA and the property of TRF2 to stimulate telomeric invasion, a process that is thought to participate in the formation of the t-loop. We show that the binding of TRF1 and TRF2 to telomeric sequences selectively modified by one GG chelate of cisplatin is markedly affected by cisplatin but that the effect is more drastic for TRF2 than for TRF1 (3-5-fold more sensitivity for TRF2 than for TRF1). We also report that platinum adducts cause a decrease in TRF2 dependent stimulation of telomeric invasion in vitro. Finally, in accordance with in vitro data, analysis of telomeric composition after cisplatin treatment reveals that 60% of TRF2 dissociate from telomeres. PMID- 20191374 TI - Clinical features of pediatric Graves' orbitopathy. AB - Pediatric Graves' orbitopathy is rare, thus its clinical picture is less well defined in comparison with the adult population. Therefore it is our aim to describe the clinical spectrum at our tertiary referral center. We identified 11 patients under the age of 18 years (3?, 8?; range 3-16 years, mean age 14.5 years) with Graves' disease and signs of orbitopathy. Seven of them where reevaluated (mean follow-up 25 months, range 3-66 months). Eyelid retraction and proptosis were the predominant signs in 10/11 of our patients. In six patients, Hertel readings ranged from 22 mm or above. Mild ocular motility impairment was seen in four children. Active orbitopathy or severe impairment of visual acuity/ocular motility, corneal or optic nerve involvement was not observed in our study. Our series confirms that pediatric Graves' orbitopathy lacks significant inflammatory features; however, proptosis is common and may be marked. All seven patients who were reevaluated did not show any clinically significant change of ocular signs during the observation period. In particular, there was no improvement of proptosis despite restoration of euthyroidism. PMID- 20191375 TI - Missed intraocular foreign body masquerading as intraocular inflammation: two cases. AB - To report two cases with missed intraocular foreign body masquerading as intraocular inflammation. The first patient was referred to our clinic with a diagnosis of a traumatic cataract. She had a history of ocular trauma. The clinical examination revealed intraocular inflammation and a mature cataract. Plain X-ray did not reveal a foreign body. She underwent a successful cataract surgery and intraocular lens implantation 1 month after the initial examination. Two months after the surgery she returned with visual impairment and intraocular inflammation. The foreign body was discovered on the surface of the iris during the follow-up. The second patient was referred to us for endophthalmitis. He denied ocular trauma. Plain X-ray, computerized tomography, and ultrasonography did not show a foreign body, but because of clinical suspicion, surgery was scheduled. In both patients the intraocular foreign bodies in the anterior chamber were removed successfully by a limbal approach. The patients remained symptom free after the foreign bodies were removed. The intraocular inflammation did not persist. A history of ocular trauma, unexplained intraocular inflammation, or intraocular inflammation unresponsive to the standard therapies should alert the physician to the presence of an intraocular foreign body. Further investigations should be performed in these cases to detect the foreign body. PMID- 20191376 TI - Chronic obstructive pulmonary disease and the risk of cardiovascular diseases. AB - Previous large epidemiological studies reporting on the association between chronic obstructive pulmonary disease (COPD) and cardiovascular diseases mainly focussed on prevalent diseases rather than on the incidence of newly diagnosed cardiovascular outcomes. We used the UK-based General Practice Research Database (GPRD) to assess the prevalence and incidence of cardiovascular diseases in COPD patients aged 40-79 between 1995 and 2005, and we randomly matched COPD-free comparison patients to COPD patients. In nested-case control analyses, we compared the risks of developing an incident diagnosis of cardiac arrhythmias, venous thromboembolism, myocardial infarction, or stroke between patients with and without COPD, stratifying the analyses by COPD-severity, using COPD-treatment as proxy for disease severity. We identified 35,772 patients with COPD and the same number of COPD-free patients. Most cardiovascular diseases were more prevalent among COPD patients than among the comparison group of COPD-free patients. The relative risk estimates of developing an incident diagnosis of cardiac arrhythmia (OR 1.19, 95% CI 0.98-1.43), deep vein thrombosis (OR 1.35, 95% CI 0.97-1.89), pulmonary embolism (OR 2.51, 95% CI 1.62-3.87), myocardial infarction (OR 1.40, 95% CI 1.13-1.73), or stroke (OR 1.13, 95% CI 0.92-1.38), tended to be increased for patients with COPD as compared to COPD-free controls. The findings of this large observational study provide further evidence that patients with COPD are at increased risk for most cardiovascular diseases. PMID- 20191377 TI - Comparison between web-based and paper versions of a self-administered anthropometric questionnaire. AB - Online data collection could advantageously replace paper-and-pencil questionnaires in epidemiological studies by reducing the logistic burden, the cost and the duration of data processing. However, there is a need for studies comparing these new instruments to traditional ones. Our objective was to compare the web-based version of the NutriNet-Sante self-administered anthropometric questionnaire to the paper-based version. The questionnaire included 17 questions divided into subquestions (55 variables in all) dealing with height, weight, hip and waist circumferences, weight history, restrictive diet and weight self perception. Both versions of the questionnaire were filled out by 147 volunteers (paper version first, N = 76, or web-based version first, N = 71) participating in the SU.VI.MAX ("Supplementation en VItamines Mineraux et AntioXydants") cohort (age-range: 49-75 years; men: 46.3%). At the end of the test, subjects filled in a "satisfaction" questionnaire giving their opinions and feelings about each version. Agreement was assessed by intraclass correlation coefficients (ICCs) and kappas. We also quantified the number of errors inherent in the paper version. Agreement between the two versions was high. ICCs ranged from 0.86 to 1.00. Kappas ranged from 0.69 to 1.00 for comparable variables. A total of 82 data entry mistakes (1.5% of total entries), 60 missing values (1.1%), 57 inconsistent values (1.1%) and 3 abnormal values (0.1%) were counted in the paper version (non existent in the web-based version due to integrated controls). The web-based version was preferred by 92.2% of users. In conclusion, the quality of information provided by the web-based anthropometric questionnaire used in the NutriNet-Sante Study was equal to, or better than, that of the paper version, with substantial logistic and cost advantages. PMID- 20191378 TI - Sensitive spectrofluorimetric method of analysis for venlafaxine in spiked rat plasma and formulations. AB - A simple, sensitive, accurate and affordable spectrofluorimetric method was developed and validated for the determination of venlafaxine, both in marketed preparations as well as in spiked rat plasma. Venlafaxine depicted strong native fluorescence property in freshly prepared 0.05 M sulphuric acid. The excitation and emission wavelengths were found to be 237.0 nm and 301.0 respectively. Effect of variations in pH, temperature, concentration, change in molarities of different solvents, and effect of excipients were studied. The calibration graph in case of dosage forms and in spiked plasma was found to be rectilinear in the concentrations of 15-600 ng/ml and 20-650 ng/ml respectively. The intra- day and inter-day accuracy measurements of VEN in formulations ranged from 0.29 to 0.44% and 0.27 to 0.49%, respectively. The intra-day and inter-day accuracy in measurement of VEN in plasma ranged from 0.062 to 2.26% and 0.52 to 2.32%, respectively. The limit of detection (LOD) was found to be 6.0 ng/mL and 4.0 ng/mL in plasma and formulations respectively. The mean recovery of VEN from plasma was 97.46. PMID- 20191373 TI - A review of FMRFamide- and RFamide-like peptides in metazoa. AB - Neuropeptides are a diverse class of signalling molecules that are widely employed as neurotransmitters and neuromodulators in animals, both invertebrate and vertebrate. However, despite their fundamental importance to animal physiology and behaviour, they are much less well understood than the small molecule neurotransmitters. The neuropeptides are classified into families according to similarities in their peptide sequence; and on this basis, the FMRFamide and RFamide-like peptides, first discovered in molluscs, are an example of a family that is conserved throughout the animal phyla. In this review, the literature on these neuropeptides has been consolidated with a particular emphasis on allowing a comparison between data sets in phyla as diverse as coelenterates and mammals. The intention is that this focus on the structure and functional aspects of FMRFamide and RFamide-like neuropeptides will inform understanding of conserved principles and distinct properties of signalling across the animal phyla. PMID- 20191379 TI - Targeting Id1 and Id3 by a specific peptide aptamer induces E-box promoter activity, cell cycle arrest, and apoptosis in breast cancer cells. AB - Inhibitors of differentiation or DNA binding (Id) proteins have been shown to be involved in tumor growth, invasiveness, metastasis, and angiogenesis. Overexpression of Id proteins, especially Id1, correlates with unfavorable clinical prognosis. Thus, they are attractive molecular targets for anticancer therapy. Overexpression of Id proteins mediates breast cancer metastasis to lung. Targeting Id1 and Id3 expression in breast cancer cells reduces breast cancer metastasis in animal models. Different breast tumors failed to grow and/or metastasize in Id1 (+/-) Id3 (-/-) mice. Id1 and Id3 preferentially dimerize with the key regulatory E-proteins which inhibit the expression of different tumor suppressor genes. Nevertheless, the inhibition of tumorigenic activities of Id1 and Id3 at protein level has never been studied. Here, we isolated a novel peptide aptamer, Id1/3-PA7, specifically interacting with Id1 and Id3 from randomized combinatorial expression library using yeast and mammalian two-hybrid systems. Intracellular delivered Id1/3-PA7 co-localized to Id1 and Id3 and interfered with their functions. It repressed E47 protein sequestration by Id1 and Id3, activated the E-box promoter and increased the expression level of cyclin-dependent kinase inhibitors (CDKN1A and CDKN1B) in a dose-dependent fashion, paralleled by the cleavage of poly ADP ribose polymerase (PARP). These effects were counteracted by ectopically overexpressed Id1 and Id3. Peptide aptamer Id1/3-PA7 induced cell cycle arrest and apoptosis in breast cancer cells MCF7 and MDA-MB-231. In conclusion, Id1/3-PA7 could represent a nontoxic exogenous agent that can significantly provoke antiproliferative and apoptotic effects in breast cancer cells, which are associated with deregulated expression of Id1 and Id3. PMID- 20191380 TI - Treatment of breast cancer through the application of irreversible electroporation using a novel minimally invasive single needle electrode. AB - Irreversible electroporation (IRE) is a therapeutic technology for the ablation of soft tissues using electrodes to deliver intense but short electric pulses across a cell membrane, creating nanopores that lead to cell death. This phenomenon only affects the cell membrane, leaving the extracellular matrix and sensitive structures intact, making it a promising technique for the treatment many types of tumors. In this paper, we present the first in vivo study to achieve tumor regression using a translatable, clinically relevant single needle electrode for treatment administration. Numerical models of the electric field distribution for the protocol used suggest that a 1000 V/cm field threshold is sufficient to treat a tumor, and that the electric field distribution will slightly decrease if the same protocol were used on a tumor deep seated within a human breast. Tumor regression was observed in 5 out of 7 MDA-MB231 human mammary tumors orthotopically implanted in female Nu/Nu mice, with continued growth in controls. PMID- 20191381 TI - Increased MUTYH mutation frequency among Dutch families with breast cancer and colorectal cancer. AB - Homozygous and compound heterozygous MUTYH mutations predispose for MUTYH associated polyposis (MAP). The clinical phenotype of MAP is characterised by the multiple colorectal adenomas and colorectal carcinoma. We previously found that female MAP patients may also have an increased risk for breast cancer. Yet, the involvement of MUTYH mutations in families with both breast cancer and colorectal cancer is unclear. Here, we have genotyped the MUTYH p.Tyr179Cys, p.Gly396Asp and p.Pro405Leu founder mutations in 153 Dutch families with breast cancer patients and colorectal cancer patients. Families were classified as polyposis, revised Amsterdam criteria positive (FCRC-AMS positive), revised Amsterdam criteria negative (FCRC-AMS negative), hereditary breast and colorectal cancer (HBCC) and non-HBCC breast cancer families. As anticipated, biallelic MUTYH mutations were identified among 13% of 15 polyposis families, which was significantly increased compared to the absence of biallelic MUTYH mutations in the population (P = 0.0001). Importantly, six heterozygous MUTYH mutations were identified among non polyposis families with breast and colorectal cancer. These mutations were identified specifically in FCRC-AMS negative and in HBCC breast cancer families (11% of 28 families and 4% of 74 families, respectively; P = 0.02 for both groups combined vs. controls). Importantly, the 11% MUTYH frequency among FCRC-AMS negative families was almost fivefold higher than the reported frequencies for FCRC-AMS negative families unselected for the presence of breast cancer patients (P = 0.03). Together, our results indicate that heterozygous MUTYH mutations are associated with families that include both breast cancer patients and colorectal cancer patients, independent of which tumour type is more prevalent in the family. PMID- 20191383 TI - Necessity, futility and the possibility of defining life are all embedded in its origin as a punctuated-gradualism. AB - The criteria used for defining life are influenced by various philosophical visions about life, ranging from holism to reductionism and from mechanistic reductionism to vitalism. Using different scenarios about the origin and evolution of life as well as properties of energy-dissipative systems, artificial life simulations and basic tenets of xenobiology, guidelines can be established for formulating a definition of life. A definition of life is proposed that is parametric, non-Earth-centric, quantitative and capable of discriminating 'living entities' from 'life'. Living entities are defined as self-maintained systems, capable of adaptive evolution individually, collectively or as a line of descend. Life is a broader concept indicating that the capacity to express these attributes is either virtual or actual. At least four major phase transitions can be recognized during the origin of life (reflexive activity; self-regulated homeostasis; the advent of informatons and the origin of adaptive evolution); these make the origin and evolution of early life an example of 'punctuated gradualism'. Such phase transitions can be used to identify a boundary in early evolution where life began. This contribution identifies the step in the evolution of a dynamic system when digital control of the system's state becomes dominant over analogical control, and genetic information is irreversibly used for adaptive evolution, as the boundary between non-living and living systems. PMID- 20191384 TI - Analysis of the genetic variation of vascular endothelial growth factor gene in three Chinese indigenous cattle breeds. AB - PCR-SSCP and DNA sequencing methods were employed to screen the genetic variation of vascular endothelial growth factor (VEGF) gene in 675 individuals belonging to three Chinese indigenous cattle breeds including Qinchuan (QC), Jiaxian Red (JX) and Nanyang (NY) breed. Three new single nucleotide polymorphisms (SNPs) (g.6765T > C ss130456744, g.6860A > G ss130456745, g.6893T > C ss130456746) were found. One SNP (g.6765T > C) was detected in intron II of VEGF gene in all three breeds and the other two SNPs (g.6860A > G, g.6893T > C) were in exon III of VEGF gene only in NY breed. Among them, two synonymous mutations of exon III were identified: CCA (Pro) > CCG (Pro) at position 65th amino acid (aa) and TGT (Cys) > TGC (Cys) at position 76th aa of VEGF(190aa) in NY breed. Our study revealed that NY breed exhibited the most abundant genetic diversity in VEGF gene within the three cattle breeds. Furthermore, JX cattle breed was more similar to QC breed than to NY breed. Our genetic data in the present study supported the hypothesis that the distribution pattern of Chinese indigenous cattle breeds was closely related to the geographical and climatic background again. PMID- 20191385 TI - Gene expression profiles of adipose tissue of high-fat diet-induced obese rats by cDNA microarrays. AB - To better understand the molecular basis of dietary obesity, we examined adipose tissue genes differentially expressed in a well-characterized rat model of high fat diet (HFD)-induced obesity using cDNA microarrays. Male Sprague-Dawley rats were fed either the HFD or the normal diet. Seven weeks later, the weights of obese models (362.92 +/- 39.65 g) were significantly higher than those of normal control rats (315.22 +/- 42.30 g, P < 0.01) and the wet weights of adipose tissue of rats fed with HFD (9.29 +/- 5.14 g) were significantly higher than those of normal control rats (4.09 +/- 2.69 g, P < 0.01), which confirmed the successful preparation of obese models. cDNA microarrays containing 9 216 genes/Ests were used to investigate gene expression of adipose tissue. Autoradiographic analysis showed that 532, 154, and 22 genes were differently expressed over 2-, 3-, and 5 fold, respectively. The analysis of gene expression profiles indicated that 276 genes were up-regulated and 432 genes were down-regulated in response to HFD induced obesity. Different clusters of genes associated with lipid metabolism, extracellular matrix, signal transduction, cytoskeleton, cell apoptosis, etc., such as VLCS-H2, DGAT, ACADVL, PHYH, SCD, ACACA, ACS, MMP-2, MMP-15, CD38, CAMK2D, CACNA1F, CAPZA2, TMOD3, ARPC2, KNS2, TPM1, MAPK8, GADD45B, DAXX, TOK-1, PRKACA, STAT6, were concerned. PMID- 20191387 TI - Abstracts of the Sylvester O'Halloran Meeting. March 5-6, 2010. Limerick, Ireland. PMID- 20191386 TI - Analyses of functional IL10 and TNF-alpha genotypes in Behcet's syndrome. AB - We aim to ascertain the possible involvement of functional IL10 and TNF-alpha promoter polymorphisms on the susceptibility to Behcet's syndrome (BS), to examine whether IL10 and TNF-alpha genotypes might work synergistically influencing susceptibility to BS. IL10 -1082G/A, -819C/T and -592C/A and TNF 308G/A polymorphisms were analyzed in 102 Turkish patients with BS and 102 healthy subjects by using amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). We have found no significant associations between IL10 -1082G/A, -819C/T, -592C/A, TNF-alpha -308G/A polymorphisms and BS. Also, no significant correlation was found between IL10 GCC, ACC, ATA haplotypes, GCC(+)/GCC(+), GCC(+)/GCC(-), GCC(-)/GCC(-) genotypes. There was no significant association between combined TNF-alpha/IL10 genotypes and BS. Our study indicates that functional TNF-alpha, IL10 genotypes or combined TNF-alpha, IL10 genotypes do not play a role in BS susceptibility in Turkish BS patients. PMID- 20191388 TI - Comparison of the antioxidant properties and the toxicity of p,p' dichlorodiphenyl ditelluride with the parent compound, diphenyl ditelluride. AB - The hypothesis to be tested in this study is whether the introduction of the chloro group into diphenyl ditelluride molecule (p,p'-dichlorodiphenyl ditelluride, compound 1b) alters the antioxidant and scavenging activity of diphenyl ditelluride (compound 1a) in vitro. The results revealed that 1a and 1b had a potent antioxidant activity in vitro. However, the introduction of a functional group, chloro, into diphenyl ditelluride molecule (1b) did not cause great alterations in the antioxidant action of diphenyl ditelluride against lipid peroxidation, protein carbonyl, and scavenging of 2,2'-azinobis-(3 ethylbenzothiazoline-6-sulfonate) and 2,2'-diphenyl-1-picrylhydrazyl radicals. Based on the in vitro results, different doses (0.25 and 0.75 umol/kg) of 1a and 1b or vehicle (canola oil, 1 ml/kg) were administered to rats to investigate if the presence of chloro into diphenyl ditelluride molecule reduces its toxicity. The data demonstrate that the chloro group introduced into diphenyl ditelluride molecule did not alter the acute oral toxicity in rats. The administration of compound 1a in rats only altered the urea level, while compound 1b caused alterations in all toxicological parameters analyzed (alanine aminotransferase and aspartate aminotransferase activities, urea and creatinine levels) in plasma of rats. The results of the present investigation support similar antioxidant and scavenging activities of 1a and 1b in rat liver homogenate in vitro. Furthermore, the presence of chloro into diphenyl ditelluride molecule did not alter the mortality index but increased toxicity of diphenyl ditelluride in rats. PMID- 20191389 TI - Oxidative stress in the liver of mice caused by intraperitoneal injection with lanthanoides. AB - In order to study the mechanisms underlying the effects of lanthanoid (Ln) on the liver, ICR mice were injected with LaCl3, CeCl3, and NdCl3 at a dose of 20 mg/kg BW into the abdominal cavity daily for 14 days. We then examined oxidative stress mediated responses in the liver. The increase of lipid peroxide in the liver produced by Ln suggested an oxidative attack that was activated by a reduction of antioxidative defense mechanisms as measured by analyzing the activities of superoxide dismutase, catalase, and ascorbate peroxidase, as well as antioxidant levels such as glutathione and ascorbic acid, which were greatest in Ce(3+) treatment, medium in Nd(3+), and least in La(3+). Our results also implied that the oxidative stress in the liver caused by Ln likely is Ce(3+) > Nd(3+) >La(3+), but the mechanisms need to be further studied in future. PMID- 20191390 TI - Effect of chronic fenvalerate intoxication on tissue concentration of copper in goats and further exploration of its mechanism. AB - This experiment was designed to assess the effect of chronic fenvalerate toxicity on tissue Cu concentration in goats and to explore the pathways responsible for it. A significant decrease in tissue Cu concentration of kidney, heart, and brain while an increase in the liver were recorded in fenvalerate intoxicated goats at 15 mg/kg b.w. orally daily for 270 days. Concentration of total Cu, protein-free Cu, and protein-bound Cu in the wet intestine of fenvalerate-treated goats revealed a significant decrease in Cu concentration of the intestine due to the decrease in trichloroacetic acid (TCA)-insoluble Cu, while TCA-soluble Cu remained almost unaffected. Rabbit duodenal loop technique was used to assess the relative absorption of nonisotopic copper in a living animal. This technique enabled to compare Cu absorption from the lumen of three closely associated loops, each receiving 100 ug of copper along with different doses (0, 15, and 30 ug) of fenvalerate. A significant dose-dependent decrease in Cu absorption from the lumen due to fenvalerate treatment was recorded. A decrease in total copper (TCA-insoluble fraction) suggested an interference in active transport of copper due to the inhibition of absorption of protein-bound copper. It was concluded that fenvalerate interfered in copper absorption mostly by inhibiting its active or mediated transport. PMID- 20191392 TI - Sleep habits and sleep disturbances in Dutch children: a population-based study. AB - Sleep disorders can lead to significant morbidity. Information on sleep in healthy children is necessary to evaluate sleep disorders in clinical practice, but data from different societies cannot be simply generalized. The aims of this study were to (1) assess the prevalence of sleep disturbances in Dutch healthy children, (2) describe sleep habits and problems in this population, (3) collect Dutch norm data for future reference, and (4) compare sleep in children from different cultural backgrounds. A population-based descriptive study was conducted using the Children's sleep habits questionnaire and the sleep self report. One thousand five hundred seven proxy-reports and 262 self-reports were analyzed. Mean age was 8.5 years (95% confidence interval, 8.4-8.6), 52% were boys. Sleep problems in Dutch children were present in 25%, i.e., comparable to other populations. Sleep habits were age-related. Problem sleepers scored significantly higher on all scales. Correlations between parental and self assessments were low to moderate. Dutch children had significantly more sleep disturbances than children from the USA and less than Chinese children. Cognitions and attitudes towards what is considered normal sleep seem to affect the appraisal of sleep, this probably accounts partly for cultural differences. For a better understanding of cultural influences on sleep, more information on these determinants and the establishment of cultural norms are mandatory. PMID- 20191393 TI - Vertebral body stenting: a new method for vertebral augmentation versus kyphoplasty. AB - Vertebroplasty and kyphoplasty are well-established minimally invasive treatment options for compression fractures of osteoporotic vertebral bodies. Possible procedural disadvantages, however, include incomplete fracture reduction or a significant loss of reduction after balloon tamp deflation, prior to cement injection. A new procedure called "vertebral body stenting" (VBS) was tested in vitro and compared to kyphoplasty. VBS uses a specially designed catheter-mounted stent which can be implanted and expanded inside the vertebral body. As much as 24 fresh frozen human cadaveric vertebral bodies (T11-L5) were utilized. After creating typical compression fractures, the vertebral bodies were reduced by kyphoplasty (n = 12) or by VBS (n = 12) and then stabilized with PMMA bone cement. Each step of the procedure was performed under fluoroscopic control and analysed quantitatively. Finally, static and dynamic biomechanical tests were performed. A complete initial reduction of the fractured vertebral body height was achieved by both systems. There was a significant loss of reduction after balloon deflation in kyphoplasty compared to VBS, and a significant total height gain by VBS (mean +/- SD in %, p < 0.05, demonstrated by: anterior height loss after deflation in relation to preoperative height [kyphoplasty: 11.7 +/- 6.2; VBS: 3.7 +/- 3.8], and total anterior height gain [kyphoplasty: 8.0 +/- 9.4; VBS: 13.3 +/- 7.6]). Biomechanical tests showed no significant stiffness and failure load differences between systems. VBS is an innovative technique which allows for the possibly complete reduction of vertebral compression fractures and helps maintain the restored height by means of a stent. The height loss after balloon deflation is significantly decreased by using VBS compared to kyphoplasty, thus offering a new promising option for vertebral augmentation. PMID- 20191394 TI - The need for standardised animal models and scoring systems in assessing mesh biocompatibility. PMID- 20191395 TI - Knockdown of a mosquito odorant-binding protein involved in the sensitive detection of oviposition attractants. AB - Odorant-binding proteins (OBPs) were discovered almost three decades ago, but there is still considerable debate regarding their role(s) in insect olfaction, particularly due to our inability to knockdown OBPs and demonstrate their direct phenotypic effects. By using RNA interference (RNAi), we reduced transcription of a major OBP gene, CquiOBP1, in the antennae of the Southern house mosquito, Culex quinquefasciatus. Previously, we had demonstrated that the mosquito oviposition pheromone (MOP) binds to CquiOBP1, which is expressed in MOP-sensitive sensilla. Antennae of RNAi-treated mosquitoes showed significantly lower electrophysiological responses to known mosquito oviposition attractants than the antennae of water-injected, control mosquitoes. While electroantennogram (EAG) responses to MOP, skatole, and indole were reduced in the knockdowns, there was no significant difference in the EAG responses from RNAi-treated and water injected mosquito antennae to nonanal at all doses tested. These data suggest that CquiOBP1 is involved in the reception of some oviposition attractants, and that high levels of OBPs expression are essential for the sensitivity of the insect's olfactory system. PMID- 20191396 TI - AMEG: the new SETAC advisory group on aquatic macrophyte ecotoxicology. AB - INTRODUCTION AND BACKGROUND: Primary producers play critical structural and functional roles in aquatic ecosystems; therefore, it is imperative that the potential risks of toxicants to aquatic plants are adequately assessed in the risk assessment of chemicals. The standard required macrophyte test species is the floating (non-sediment-rooted) duckweed Lemna spp. This macrophyte species might not be representative of all floating, rooted, emergent, and submerged macrophyte species because of differences in the duration and mode of exposure; sensitivity to the specific toxic mode of action of the chemical; and species specific traits (e.g., duckweed's very short generation time). DISCUSSION AND PERSPECTIVES: These topics were addressed during the workshop entitled "Aquatic Macrophyte Risk Assessment for Pesticides" (AMRAP) where a risk assessment scheme for aquatic macrophytes was proposed. Four working groups evolved from this workshop and were charged with the task of developing Tier 1 and higher-tier aquatic macrophyte risk assessment procedures. Subsequently, a SETAC Advisory Group, the Macrophyte Ecotoxicology Group (AMEG) was formed as an umbrella organization for various macrophyte working groups. The purpose of AMEG is to provide scientifically based guidance in all aspects of aquatic macrophyte testing in the laboratory and field, including prospective as well as retrospective risk assessments for chemicals. As AMEG expands, it will begin to address new topics including bioremediation and sustainable management of aquatic macrophytes in the context of ecosystem services. PMID- 20191397 TI - A seven-year prospective study on spondylodiscitis: epidemiological and microbiological features. AB - BACKGROUND: The aim of this paper was to enlarge the available knowledge on clinical and etiological aspects of patients affected by spondylodiscitis. PATIENTS AND METHODS: All patients with spondylodiscitis admitted between January 2001 and December 2007 at the 1,300-bed University Hospital "Policlinico Umberto I" of Rome, Italy, were followed. Demographic characteristics, underlying diseases, invasive procedures, imaging studies, isolated microorganisms, treatment, complications, and outcome were recorded. RESULTS: Eighty-one patients of mean age 57.7 +/- 14.7 years with lumbosacral (72.8%), thoracic (14.8%), and cervical tract (12.3%) site of infection were included, of which 38 developed community-acquired (CA) spondylodiscitis and 43 developed hospital-acquired (HA) spondylodiscitis. Underlying disease was present in 49.4% of patients. HA spondylodiscitis was diagnosed earlier (46.8 +/- 49.7 days) than CA spondylodiscitis (65.0 +/- 55.4 days) (P < 0.05). The most frequently isolated microorganisms were Staphylococcus aureus (28 strains, 43.1%), coagulase-negative staphylococci (CNS) (eight strains, 12.3%), Pseudomonas aeruginosa (eight strains, 12.3%), and three methicillin-resistant S. aureus (MRSA) strains were isolated in CA spondylodiscitis. Fungi and yeasts, isolated in six patients, represented 9.2% of all strains but 17.6% when considering only HA spondylodiscitis. Over 85% of patients were managed by conservative treatment alone, and the treatment time depended on clinical and laboratory evidence. Poor outcome was recorded in 12 (14.8%) patients, and was associated with neurological deficit symptoms (relative risk [RR] 2.87; 95% confidence interval [CI] 1.02 8.07; P < 0.05) and the time between diagnosis and the onset of symptoms > or = 60 days (RR 2.65; 95% CI 0.92-7.59; P < 0.05). CONCLUSIONS: Infectious spondylodiscitis affects most frequently the elderly population, who are more exposed to healthcare contacts. Consequently, the infection etiology includes a growing proportion of multi-resistant bacteria and fungi. PMID- 20191398 TI - Inhaled anti-infective agents: emphasis on colistin. AB - The administration of antibiotics by the inhaled route is a widely recognized treatment in patients with cystic fibrosis (CF) and bronchiectasis. Tobramycin solution for inhalation (TOBI) has been available for many years and is licensed in the USA and Europe. While strong data support the use of aerosolized antibiotics for the treatment of respiratory infections in patients with CF or bronchiectasis, only a few clinical studies have examined the role of aerosolized antibiotics in the treatment of pneumonia, including ventilator-associated pneumonia (VAP) in these patients. During the last decade increasing interest has been directed towards alternative treatments to the systemic administration of antimicrobial agents for the treatment of patients with hospital-acquired pneumonia or VAP due to multidrug-resistant (MDR) Gram-negative bacteria. Recent publications demonstrate the clinical benefits from administering inhaled aminoglycosides or polymyxins in patients with hospital-acquired pneumonia or VAP. In addition to antibiotics, antifungals, and antivirals have been administered by inhalation to specific groups of critically ill patients. However, randomized controlled trials dealing with the administration of anti infective agents via the respiratory tract are necessary in order to validate the efficacy, safety, advantages, and disadvantages of this therapeutic approach for the treatment of nosocomial pneumonia. PMID- 20191399 TI - Contribution of two molecular assays as compared to selective culture for MRSA screening in a low MRSA prevalence population. AB - BACKGROUND: As the prompt detection of methicillin-resistant Staphylococcus aureus (MRSA) carriers upon admission is fundamental in the MRSA prevention strategy of our hospital, the infection control team is eagerly seeking the most sensitive and rapid screening method. The aim of this study was to compare the performance of two molecular techniques with a conventional MRSA-selective culture test (Bio-Rad chromogenic MRSASelect) in order to elucidate the suitability of the assays specifically in an expected low MRSA prevalence population. PATIENTS AND METHODS: The anterior nares and throat of 500 patients and visitors attending the emergency department of Sint-Jan General Hospital between May and June 2007 were sampled, and MRSA carriage was determined by selective culture after enrichment and the BD GeneOhm StaphSR and the Cepheid Xpert MRSA assays. RESULTS: Eight MRSA carriers were detected by selective culture (1.6% prevalence). The sensitivity, specificity, positive [corrected] predictive value, and negative [corrected] predictive value were 62.5, 99.0, 50.0, and 99.4% for BD GeneOhm StaphSR and 62.5, 97.7, 31.3, and 99.4% for Cepheid Xpert MRSA, respectively. CONCLUSIONS: We conclude that MRSA rapid screening techniques must be interpreted cautiously in a low-prevalence population, as the sensitivity is lower than in selected high-risk populations. MRSA carriers detected with molecular techniques must be confirmed by conventional culture methods for follow-up. The specificity and negative predictive value indicate that molecular rapid methods are worthwhile to be considered in MRSA-preventive strategies. PMID- 20191400 TI - Cortisol, stress, and attentional bias toward threat. AB - Attentional bias toward threatening stimuli is a central characteristic of anxiety and acute stress. Recent small-scale studies have provided divergent perspectives on the association between the stress hormone cortisol and attentional bias toward threat cues. In a larger sample size than previous studies, we examined this association by investigating the impact of cortisol on attentional bias in two studies using a psychological stressor (N=35) and a physical stressor (N=65), respectively. Attentional bias and salivary cortisol were measured prior to and following the administration of a stressful task designed to increase cortisol levels. Results across these studies were equivocal relative to the association between baseline cortisol and baseline attentional bias. In addition, the association between acute change in cortisol and change in attentional bias appeared to differ as a function of the presence or absence of psychological stress. There was a trend toward a stronger negative association between acute cortisol change and attentional bias change among women relative to men. These results imply that the association between cortisol and attentional bias may be moderated by additional factors, such as gender or presence of stress. PMID- 20191401 TI - A model that predicts the attachment behavior of Ulva linza zoospores on surface topography. AB - A predictive model for the attachment of spores of the green alga Ulva on patterned topographical surfaces was developed using a constant refinement approach. This 'attachment model' incorporated two historical data sets and a modified version of the previously-described Engineered Roughness Index. Two sets of newly-designed surfaces were used to evaluate the effect of two components of the model on spore settlement. Spores attached in fewer numbers when the area fraction of feature tops increased or when the number of distinct features in the design increased, as predicted by the model. The model correctly predicted the spore attachment density on three previously-untested surfaces relative to a smooth surface. The two historical data sets and two new data sets showed high correlation (R(2) = 0.88) with the model. This model may be useful for designing new antifouling topographies. PMID- 20191404 TI - Normal social cognition in developmental prosopagnosia. AB - Face perception provides information critical to cognitive computations about the social world. This raises the possibility that the development of mechanisms used for social cognition may depend on the presence of normal face perception mechanisms, and this notion partly motivates an aetiological model of autism spectrum disorder (ASD) that suggests that deficits in face perception lead to the social cognition impairments that characterize ASD. To investigate these issues, we examined social cognition in participants with developmental prosopagnosia (DP). A total of 2 male DPs with severe facial identity and facial expression deficits showed no signs of impaired social cognition on three measures. A total of 10 other DPs responded to an inventory measuring autistic traits, and all except one performed normally. These results indicate that social cognition mechanisms can develop normally in the context of developmental face processing impairments. PMID- 20191405 TI - Occupational stress in submariners: the impact of isolated and confined work on psychological well-being. AB - This study aimed to identify work-related and personal factors associated with occupational stress in submariners. Work and well-being questionnaires were distributed to 219 male submariners (mean age 34 years), as part of a larger cohort study involving a stratified sample of 4951 Royal Navy (RN) personnel. The stress rate in submariners was 40%; significantly higher than the stress rate in the general RN, although once demographic factors were controlled for in a matched control sample, this difference was no longer significant. A summary model accounted for 49% of the variance in submariner stress, with key differences emerging between the occupational factors associated with stress in submariners and in the general RN. The longitudinal nature of this study permits stress in submariners to be monitored over 5 years, which will provide valuable insights into the chronicity of stress in this specialised occupational group. STATEMENT OF RELEVANCE: This paper contributes to the current literature on the negative impact of working in isolated conditions. It is demonstrated that occupational stress in submarines can be partially explained using current theories of stress in the workplace. However, the constraints of a restricted environment introduce additional factors which can also be associated with occupational stress. PMID- 20191406 TI - Task selection for increased mechanical exposure variation: relevance to job rotation. AB - It is generally considered that variation in mechanical exposure is beneficial from the viewpoint of preventing musculoskeletal disorders. An approach to quantifying the functional similarity of manual tasks was developed and tested by using three handgrips: power grip (PG); pulp pinch (PP); lateral pinch (LP). Changes in maximal voluntary contraction (MVC) forces were measured during 15 combinations of 2-min duration, 30% MVC isometric contraction in 25 participants. Strength changes in PG were found to be substantially different from LP; when the two grips were alternated, strength dropped to 85.1% MVC whereas after PG alone, strength dropped to 59.3% MVC. The findings suggest that PG and LP are functionally different enough for their alternating use to contribute to increased exposure variation during manual activities. STATEMENT OF RELEVANCE: The paper describes how to determine if two tasks, when performed alternately, are different enough to reduce fatigue, increase work capacity and potentially prevent musculoskeletal disorders. Better understanding of the differences between tasks has the potential to improve job design by allowing better choice of tasks that combine to define a job. PMID- 20191407 TI - Can personal control over the physical environment ease distractions in office workplaces? AB - The purpose of this study was to investigate whether perception of control over aspects of the physical environment reduces the previously documented negative effects of distraction in office workplaces on perceived job performance. This study analysed 384 questionnaires collected from employees in the corporate offices of three manufacturing companies in Michigan, USA. The role of a sense of personal control over physical environment features as a mediating influence between work attitudes and work outcomes was explored using structural equations modelling. The results showed that workers' sense of control over physical aspects of their work environment mediated the relationship between perceived distractions and perceived job performance. These results suggest that increasing perceptions of personal control over features of the physical work environment may serve to link work attitudes and work outcomes. STATEMENT OF RELEVANCE: Open plan offices are common throughout the world, making this study relevant for researchers and practitioners alike. These results suggest that if employees can adjust aspects of their office work environment, this may increase their sense of personal control, reducing the effects of distractions, a frequent complaint in open offices. PMID- 20191408 TI - Forearm posture and grip effects during push and pull tasks. AB - Direction of loading and performance of multiple tasks have been shown to elevate muscle activity in the upper extremity. The purpose of this study was to evaluate the effects of gripping on muscle activity and applied force during pushing and pulling tasks with three forearm postures. Twelve volunteers performed five hand based tasks in supinated, neutral and pronated forearm postures with the elbow at 90 degrees and upper arm vertical. All tasks were performed with the right (dominant) hand and included hand grip alone, push and pull with and without hand grip. Surface EMG from eight upper extremity muscles, hand grip force, tri-axial push and pull forces and wrist angles were recorded during the 10 s trials. The addition of a pull force to hand grip elevated activity in all forearm muscles (all p < 0.017). During all push with grip tasks, forearm extensor muscle activity tended to increase when compared with grip only while flexor activity tended to decrease. Forearm extensor muscle activity was higher with the forearm pronated compared with neutral and supinated postures during most isolated grip tasks and push or pull with grip tasks (all p < 0.017). When the grip dynamometer was rotated so that the push and pull forces could act to assist in creating grip force, forearm muscle activity generally decreased. These results provide strategies for reducing forearm muscle loading in the workplace. STATEMENT OF RELEVANCE: Tools and tasks designed to take advantage of coupling grip with push or pull actions may be beneficial in reducing stress and injury in the muscles of the forearm. These factors should be considered in assessing the workplace in terms of acute and cumulative loading. PMID- 20191409 TI - School furniture match to students' anthropometry in the Gaza Strip. AB - This study aimed at comparing primary school students' anthropometry to the dimensions of school furniture and determining whether the furniture used matches the students' anthropometry. A sample of 600 male students, whose ages were between 6 and 11 years, from five primary schools in the Gaza Strip governorates participated in the study. Several students' body dimensions were measured. The dimensions measured included elbow-seat height, shoulder height, knee height, popliteal height and buttock-popliteal length. Measurements of the dimensions of the classroom furniture indicated that there was a considerable mismatch between the students' body dimensions and the classroom furniture. The mismatches in seat height, seat depth and desk height occurred for 99% of the students, while the mismatch for the back rest height was only 35%. Two design specifications were proposed in order to decrease the mismatch percentage based on the data obtained. The two proposed designs showed a considerable improvement in the match percentages as compared to the existing design. STATEMENT OF RELEVANCE: Having identified mismatches between the dimensions of the school furniture used in primary schools in the Gaza Strip, two new design specifications are proposed and shown to improve match with the students' anthropometric dimensions. The findings of the study are also an important addition to local knowledge on school children's anthropometry. PMID- 20191410 TI - The effects of age and type of carrying task on lower extremity kinematics. AB - The purpose of this study was to determine the effects of age, load amount and load symmetry on lower extremity kinematics during carrying tasks. Forty-two participants in four age groups (8-10 years, 12-14 years, 15-17 years and adults) carried loads of 0%, 10% and 20% body weight (BW) in large or small buckets unilaterally and bilaterally. Reflective markers were tracked to determine total joint range of motion and maximum joint angles during the stance phase of walking. Maximum hip extension, hip adduction and hip internal rotation angles were significantly greater for each of the child/adolescent age groups as compared with adults. In addition, maximum hip internal rotation angles significantly increased when carrying a 20% BW load. The observation that the 8 10-year-old age group carried the lightest absolute loads and still displayed the highest maximum hip internal rotation angles suggests a particular necessity in setting carrying guidelines for the youngest children. STATEMENT OF RELEVANCE: Bucket-carrying tasks were analysed as a function of age group, load amount and load symmetry. Hip joint rotations significantly increased when carrying 20% BW loads and in children as compared to adults, which suggests a particular necessity in setting carrying guidelines for the youngest age group (8-10 year olds). PMID- 20191411 TI - Effects of horizontal whole-body vibration and standing posture on activity interference. AB - Standing people are exposed to whole-body vibration in many environments. This paper investigates the effects of horizontal whole-body vibration and standing posture on task performance. Sixteen participants were exposed to random vibration (up to 4 Hz) whilst performing a timed pegboard task in two standing postures. Objective and subjective indicators of performance were used. Time taken to complete the task increased progressively with increases in vibration magnitude. The fore-and-aft posture generally showed greater performance decrements and postural interruptions (>1.0 ms(-2) root mean square) than the lateral. For both postures, performance was better during y-axis vibration than during x-axis vibration. Subjective ratings showed similar trends to time data. Impairments due to dual axis exposure were well predicted using root sum of squares calculations based on single axis components. These results indicate that best performance for those standing in moving environments will be achieved if individuals adopt a lateral posture with the most severe vibration in the y-axis. STATEMENT OF RELEVANCE: People have a need to work during transportation, either working for the transport provider or as a passenger. All modes of transport result in travellers being exposed to horizontal motion. This study demonstrates that task disturbance is affected by the orientation of the standing person to the vibration and, therefore, vehicle layouts can be optimised. PMID- 20191412 TI - Enhancing digital driver models: identification of distinct postural strategies used by drivers. AB - Driver workspace design and evaluation is, in part, based on assumed driving postures of users and determines several ergonomic aspects of a vehicle, such as reach, visibility and postural comfort. Accurately predicting and specifying standard driving postures, hence, are necessary to improve the ergonomic quality of the driver workspace. In this study, a statistical clustering approach was employed to reduce driving posture simulation/prediction errors, assuming that drivers use several distinct postural strategies when interacting with automobiles. 2-D driving postures, described by 16 joint angles, were obtained from 38 participants with diverse demographics (age, gender) and anthropometrics (stature, body mass) and in two vehicle classes (sedans and SUVs). Based on the proximity of joint angle sets, cluster analysis yielded three predominant postural strategies in each vehicle class (i.e. 'lower limb flexed', 'upper limb flexed' and 'extended'). Mean angular differences between clusters ranged from 3.8 to 52.4 degrees for the majority of joints, supporting the practical relevance of the distinct clusters. The existence of such postural strategies should be considered when utilising digital human models (DHMs) to enhance and evaluate driver workspace design ergonomically and proactively. STATEMENT OF RELEVANCE: This study identified drivers' distinct postural strategies, based on actual drivers' behaviours. Such strategies can facilitate accurate positioning of DHMs and hence help design ergonomic driver workspaces. PMID- 20191414 TI - Determinants of intention to deviate from clinical practice guidelines. AB - The volitional nature of procedural violations in work systems creates a challenge for human factors research and practice. In order to understand how violations are caused and what can be done to mitigate them, there is a need to determine the influence of workers' beliefs about rules and guidelines. This study demonstrates the use of a social psychological approach to investigate the beliefs of anaesthetists about clinical practice guidelines. A survey was completed by 629 consultant anaesthetists, who rated their beliefs about deviation from three guidelines (performing pre-operative visits; checking anaesthetic equipment; handling intravenous fluid bags). Regression analysis indicated that the belief ratings predicted self-rated intention to deviate from the guidelines. Implications for understanding anaesthetists' adherence to guidelines are discussed. STATEMENT OF RELEVANCE: This study builds upon previous work by the authors, presenting a more detailed insight into potential causes of procedural violations in healthcare. The study also demonstrates the use of a social psychological method to the investigation of violations. Hence, it is of interest to researchers and practitioners interested in human reliability, especially in healthcare. PMID- 20191413 TI - Breath control during manual free-style lifting of a maximally tolerated load. AB - Clear evidence links voluntary breath control, intra-abdominal pressure and lumbar stability. However, little is known regarding optimal breath control during manual materials handling. No studies have examined natural breath control while lifting a maximal load. Fourteen healthy subjects lifted a loaded crate from the floor to a table while respiratory flow data were collected. The loads lifted began at 10% of body weight and increased up to 50% (if tolerated) by 5% increments. Data from the minimum, moderate and maximum loads were analysed. Uniform and consistent breath holding during lifting of a maximally tolerated load did not occur. Across all three loads, frequency of inspiration was highest immediately prior to lift-off and significantly higher inspired volume occurred at lift-off of the load compared with preparation for lifting. Holding the breath does not appear to be related to lifting of a maximally tolerated load from floor to table. STATEMENT OF RELEVANCE: The findings demonstrate that consistent patterns of naturally occurring breath control during lifting of a maximal load can be identified and do not include uniform breath holding. The findings may assist in creating models for optimal breath control, which will minimise risk of injury during manual material handling tasks. PMID- 20191415 TI - The validity of driving simulation for assessing differences between in-vehicle informational interfaces: A comparison with field testing. AB - Data from on-road and simulation studies were compared to assess the validity of measures generated in the simulator. In the on-road study, driver interaction with three manual address entry methods (keypad, touch screen and rotational controller) was assessed in an instrumented vehicle to evaluate relative usability and safety implications. A separate group of participants drove a similar protocol in a medium fidelity, fixed-base driving simulator to assess the extent to which simulator measures mirrored those obtained in the field. Visual attention and task measures mapped very closely between the two environments. In general, however, driving performance measures did not differentiate among devices at the level of demand employed in this study. The findings obtained for visual attention and task engagement suggest that medium fidelity simulation provides a safe and effective means to evaluate the effects of in-vehicle information systems (IVIS) designs on these categories of driver behaviour. STATEMENT OF RELEVANCE: Realistic evaluation of the user interface of IVIS has significant implications for both user acceptance and safety. This study addresses the validity of driving simulation for accurately modelling differences between interface methodologies by comparing results from the field with those from a medium fidelity, fixed-base simulator. PMID- 20191416 TI - Visual conspicuity: a new simple standard, its reliability, validity and applicability. AB - A general standard for quantifying conspicuity is described. It derives from a simple and easy method to quantitatively measure the visual conspicuity of an object. The method stems from the theoretical view that the conspicuity of an object is not a property of that object, but describes the degree to which the object is perceptually embedded in, i.e. laterally masked by, its visual environment. First, three variations of a simple method to measure the strength of such lateral masking are described and empirical evidence for its reliability and its validity is presented, as are several tests of predictions concerning the effects of viewing distance and ambient light. It is then shown how this method yields a conspicuity standard, expressed as a number, which can be made part of a rule of law, and which can be used to test whether or not, and to what extent, the conspicuity of a particular object, e.g. a traffic sign, meets a predetermined criterion. An additional feature is that, when used under different ambient light conditions, the method may also yield an index of the amount of visual clutter in the environment. Taken together the evidence illustrates the methods' applicability in both the laboratory and in real-life situations. STATEMENT OF RELEVANCE: This paper concerns a proposal for a new method to measure visual conspicuity, yielding a numerical index that can be used in a rule of law. It is of importance to ergonomists and human factor specialists who are asked to measure the conspicuity of an object, such as a traffic or rail-road sign, or any other object. The new method is simple and circumvents the need to perform elaborate (search) experiments and thus has great relevance as a simple tool for applied research. PMID- 20191419 TI - Geo-climate effects on asthma and allergic diseases in adults in Turkey: results of PARFAIT study. AB - The aim of the study was to evaluate the role of geo-climatic factors on the prevalence of allergic diseases in the adult population in Turkey. A total of 25,843 questionnaires using data from parents of 25,843 primary schoolchildren from 14 cities were evaluated. Mean annual temperature was significantly associated with the prevalence of asthma and wheezing in both sexes [respectively; OR: 1.008 (95% CI: 1.003-1.011) and OR: 1.012 (1.006-1.018 in males), OR: 1.007 (1.003-1.012) and OR: 1.01 (1.002-1.018) in females]. In addition, it was associated with eczema in females [OR: 1.007 (1.001-1.012)]. Asthma in females was associated with mean annual humidity in the air [OR: 1.001 (1.000-1.002)]. Annual number of days with snow is associated with wheezing in both sexes [respectively, OR: 1.001 (1.000-1.002) in males and OR: 1.002 (1.000 1.003) in females]. Protective measures could come into priority in certain areas of the country. Allergic diseases may increase as a cause of climate change in the future. PMID- 20191420 TI - Examining sexual health differences between lesbian, gay, bisexual, and heterosexual adults: the role of sociodemographics, sexual behavior characteristics, and minority stress. AB - Many studies focus on the differences in mental health between lesbian, gay, bisexual (LGB), and heterosexual individuals. Less attention has been paid to the differences in various aspects of sexual health and the potential explanations for these differences. Data from a Dutch population study on sexual health (aged 19-70 years; N = 4,333) were used to examine the potential differences in sexual satisfaction, sexual victimization, sexual dysfunction, and sexual health care need. At the same time, this study examined whether the differences could be attributed to differences in general factors influencing sexual health (sociodemographic variables and sexual behavior characteristics) or to LGB specific factors (minority stress). The results showed that bisexual women and bi and homosexual men had more often experienced sexual coercion and reported a higher need for sexual health care than their heterosexual counterparts. Both general determinants (e.g., a higher number of sexual partners or being single) and LGB-specific factors (e.g., internalized homonegativity or negative social reactions related to sexual orientation) were associated with different aspects of sexual health. Interventions aimed at improving the sexual health of LGB individuals should focus on general risk factors, as well as on LGB-specific stressors. Methodological limitations of the study and implications for further research are discussed. PMID- 20191421 TI - Predictors of men's sexual desire: the role of psychological, cognitive emotional, relational, and medical factors. AB - The aim of this study was to evaluate the main predictive factors of male sexual desire, considering medical, psychological, and relationship factors. The study assessed 205 men from the general population on the following variables: psychological adjustment, dysfunctional sexual beliefs, automatic thoughts and emotions during sexual activity, dyadic adjustment, and the presence of medical conditions. Regarding cognitive and emotional factors, restrictive attitudes toward sexuality (beta = -.27), lack of erotic thoughts during sexual activity (beta = -.35), concerns about erection (beta = -.26), emotions of sadness (beta = -.23), and shame (beta = -.23) in a sexual context were significant predictors of sexual desire. Dyadic adjustment and the presence of medical conditions were not significant predictors of male sexual desire. A multiple regression analysis including all these variables, in addition to age, indicated that lack of erotic thoughts during sexual activity was the only significant predictor of sexual desire (beta = -.28). These findings suggest the importance of cognitive dimensions in sexual desire, particularly the role of attentional focus and lack of erotic thoughts during sexual activity. PMID- 20191422 TI - The bias for a recognition judgement depends on the response emitted in a prior recognition judgement. AB - On each trial of the experimental procedure the participant read a list of words and made successive recognition judgements to multiple test words. The bias for a given recognition judgement was more conservative if the judgement followed a correct positive response to a target than if it followed a correct negative response to a lure. Similar results were not observed for successive semantic recognition judgements. The bias shift was greater when the study list was short than when the list was long. The results suggest that participants in a recognition task have a sense of the size of the set of targets that might possibly be presented on the next trial and that, under conditions in which a word can only be presented once during the test phase, their bias becomes more conservative after a positive response to a target because the set is depleted. PMID- 20191423 TI - 28th Annual JPMorgan Healthcare Conference--Human Genome Sciences and Celgene. AB - The JPMorgan Healthcare Conference, held in San Francisco, included presentations by various pharmaceutical companies summarizing their achievements in 2009 and expectations for 2010. This conference report highlights presentations from Human Genome Sciences Inc and Celgene Corp. Investigational drugs from Human Genome Sciences, including belimumab (in collaboration with GlaxoSmithKline plc), albinterferon alfa-2b (with Novartis AG), mapatumumab (with Takeda Pharmaceutical Co Ltd) and HGS-1029, and from Celgene, including romidepsin, pomalidomide, apremilast and PDA-001 (Celgene Cellular Therapeutics), are discussed. PMID- 20191424 TI - 28th Annual JPMorgan Healthcare Conference--Exelixis and Nektar Therapeutics. AB - The JPMorgan Healthcare Conference, held in San Francisco, included presentations by various pharmaceutical companies summarizing their achievements in 2009 and expectations for 2010. This conference report highlights presentations from Exelixis Inc and Nektar Therapeutics. Investigational drugs from Exelixis, including XL-184 (in collaboration with Bristol-Myers Squibb Co), XL-147 and XL 765 (both in collaboration with sanofi-aventis), and from Nektar, including NKTR 118 and NKTR-119 (both now licensed to AstraZeneca plc), NKTR-171, NKTR-181, NKTR 194, NKTR-102, and NKTR-105, are discussed. PMID- 20191425 TI - 28th Annual JPMorgan Healthcare Conference--Affymax and Infinity Pharmaceuticals. AB - The JP Morgan Healthcare Conference, held in San Francisco, included presentations by various pharmaceutical companies summarizing their achievements in 2009 and expectations for 2010. This conference report highlights presentations from Affymax Inc and Infinity Pharmaceuticals Inc. Investigational drugs from Affymax, including Hematide (in collaboration with Takeda Pharmaceutical Co Ltd), and from Infinity Pharmaceuticals, including IPI-926, retaspimycin hydrochloride, IPI-493 and IPI-940, are discussed. PMID- 20191426 TI - 28th Annual JPMorgan Healthcare Conference--Forest Laboratories and Icagen. AB - The JPMorgan Healthcare conference, held in San Francisco, included presentations by various pharmaceutical companies summarizing their achievements in 2009 and expectations for 2010. This conference report highlights presentations from Forest Laboratories Inc and Icagen Inc. Investigational drugs from Forest Laboratories, including roflumilast (in collaboration with Nycomed Inc/Mitsubishi Tanabe Pharma Corp), ceftaroline fosamil (with AstraZeneca plc), linaclotide (with Ironwood Pharmaceuticals Inc/Astellas Pharma Inc/Almirall Prodesfarma SA), cariprazine (with Gedeon Richter Ltd/Mitsubishi Tanabe Pharma Corp), aclidinium bromide (with Almirall), dutogliptin (with Phenomix Corp/Chiesi Farmaceutici SpA) and levomilnacipran (with Pierre Fabre SA), and from Icagen, including ICA 105665, are discussed. PMID- 20191427 TI - High-Content Analysis--CHI's Seventh Annual Conference--Developments in HCA and Pathway Analysis. AB - CHI's Seventh Annual Conference on High-Content Analysis (HCA), held in San Francisco, incorporated topics covering new developments in the field of HCA, including hardware and software updates, new biological models for HCA and pathway analysis. This conference report highlights selected presentations on the use of HCA for the characterization of stem cells, cell-colony analysis, the validation of disease models and the identification of antiparasitic compounds. PMID- 20191428 TI - High-Content Analysis--CHI's Seventh Annual Conference--Flow Cytometry in Drug Discovery and Development. AB - CHI's Seventh Annual Conference on High-Content Analysis, held in San Francisco, included topics covering new developments in the field, including advances in flow cytometry. This conference report highlights selected presentations on strategies to use higher content in flow cytometry as well as tools to enable high content, including mass spectrometry, surface-enhanced Raman scattering (SERS) and hyperspectral analysis. Very high-throughput systems are also discussed. PMID- 20191429 TI - PepTalk--CHI's Ninth Annual Meeting--Engineering Protein & Peptide Therapeutics: Peptides. AB - The PepTalk conference, held in San Diego, included topics covering new developments in the field of protein and peptide therapeutics. This conference report highlights selected presentations on peptidic tumor-targeting agents, phylomer libraries for identifying potent peptides, li-Key-modified peptides, identifying binding sequences for antibody replacement molecules, sequencing non ribosomal peptides, addressing the siRNA delivery problem, non-invasive systemic peptide delivery and cyclic antimicrobial peptide therapeutics for onychomycosis. PMID- 20191430 TI - BioPartnering North America--Spotlight on Canada. AB - The BioPartnering North America conference, held in Vancouver, included presentations covering drug pipeline developments from both large and small pharmaceutical companies. This conference report highlights selected presentations from drug developers from Canada. Investigational drugs discussed include davunetide (Allon Therapeutics Inc), ANG-1005 (Angiochem Inc), AQX-1125 (Aquinox Pharmaceuticals Inc), and Sertolin (Sernova Corp), APG-2305 (Allostera Pharma Inc). The DepoVax liposomal vaccine delivery platform from Immunovaccine Inc is also highlighted. PMID- 20191431 TI - BioPartnering North America--Programs from Pharma in Europe and the Middle East. AB - The BioPartnering North America conference, held in Vancouver, included presentations covering drug pipeline developments from both large and small pharmaceutical companies. This conference report highlights selected presentations from drug developers from Europe and the Middle East, specifically France, Spain, Denmark, Ireland, Sweden, Switzerland, Germany and Israel. Investigational drugs discussed include naproxcinod and NCX-116 (both NicOx SA), beta-amyloid (Abeta)40- and Abeta42-targeting vaccines (Araclon Biotech SI), ROSE 010 (Rose Pharma A/S), ADC-1004 (Alligator Bioscience AB), and VPM-4-001 (Vakzine Projekt Management GmbH). PMID- 20191432 TI - Phosphodiesterase Targets for Cognitive Dysfunction and Schizophrenia--a New York Academy of Sciences Meeting. AB - The Phosphodiesterase Targets for Cognitive Dysfunction and Schizophrenia meeting, held in New York, included topics covering new therapeutic developments in the field of PDE inhibitors for the treatment of cognitive dysfunction. This conference report highlights selected presentations on inhibitors of PDE1, PDE4, PDE5, PDE8, PDE9 and PDE10 for schizophrenia-related cognitive disorders. Investigational drugs discussed include PF-2545920 (Pfizer Inc). PMID- 20191433 TI - Using ChIP-based technologies to identify epigenetic modifications in disease relevant cells. AB - The effect of epigenetic modifications on the regulation of gene expression and the concomitant relationship to human diseases has become a key area of biological research in recent years. Studies have suggested that there is direct correlation between epigenetic modifications, such as histone methylation, histone acetylation and DNA methylation, and gene expression in disease-relevant cells, including cancer cells. The development of chromatin immunoprecipitation (ChIP)-based technologies, such as ChIP-chip and ChIP-Seq, has facilitated the high-throughput genome-wide mapping of epigenetic modifications that enable researchers to define the epigenome in disease-relevant cells and use comparative ChIP-based epigenetic mapping to correlate changes in epigenetic modifications with key physiological changes in disease-relevant tissues, including cancer cells, stem cells and T-cells. This feature review article provides insight into the nature of epigenetic modifications, the ChIP-based technologies that are available, and how such methods are being used to identify key epigenetic regulatory activities in medically relevant areas such as cancer and immunology. PMID- 20191434 TI - Open-access public-private partnerships to enable drug discovery--new approaches. AB - The productivity of the pharmaceutical industry, as assessed by the number of NMEs produced per US dollar spent in R&D, has been in steady decline during the past 40 years. This decline in productivity not only poses a significant challenge to the pharmaceutical industry, but also to society because of the importance of developing drugs for the treatment of unmet medical needs. The major challenge in progressing a new drug to the market is the successful completion of clinical trials. However, the failure rate of drugs entering trials has not decreased, despite various technological and scientific breakthroughs in recent decades, and despite intense target validation efforts. This lack of success suggests limitations in the fundamental understanding of target biology and human pharmacology. One contributing factor may be the traditional secrecy of the pharmaceutical sector, a characteristic that does not promote scientific discovery in an optimal manner. Access to broader knowledge relating to target biology and human pharmacology is difficult to obtain because interactions between researchers in industry and academia are typically restricted to closed collaborations in which the knowledge gained is confidential.However, open-access collaborative partnerships are gaining momentum in industry, and are also favored by funding agencies. Such open-access collaborations may be a powerful alternative to closed collaborations; the sharing of early-stage research data is expected to enable scientific discovery by engaging a broader section of the scientific community in the exploration of new findings. Potentially, the sharing of data could contribute to an increased understanding of biological processes and a decrease in the attrition of clinical programs. PMID- 20191435 TI - Tecovirimat, a p37 envelope protein inhibitor for the treatment of smallpox infection. AB - Since the eradication of naturally occurring smallpox in 1980, the fear that variola virus could be used as a biological weapon has become real. Over the last 10 years, emergency preparedness programs have been launched to protect populations against a smallpox outbreak or the possible emergence in humans of other orthopoxvirus infections, such as monkeypox. Vaccination against smallpox was responsible for its eradication, but was linked with high rates of adverse events and contraindications. In this context, intensive research in the poxvirus field has led to the development of safer vaccines and to an increase in the number of anti-poxvirus agents in the pipeline. SIGA Technologies Inc, under license from ViroPharma Inc, is developing tecovirimat (ST-246). Tecovirimat is a novel antiviral that inhibits the egress of orthopoxviruses by targeting viral p37 protein orthologs. The development of tecovirimat during the last 5 years for the treatment of smallpox and for its potential use as adjunct to smallpox vaccine is reviewed here. PMID- 20191436 TI - Polish forum for prevention guidelines on metabolic syndrome. PMID- 20191437 TI - Analysis of correlation between the process of thyroid fibrosis and TGFB1 gene expression level in fine-needle aspiration biopsy (FNAB) thyroid specimens collected from patients with Hashimoto's thyroiditis and non-toxic goitre. AB - Transforming growth factor beta 1 (TGFB1) stimulates the production of various extracellular matrix components; at the same time, it inhibits matrix degradation. These actions of TGFB1 contribute to tissue repair, however, an altered expression of TGFB1 can be a causative factor of fibrosis processes, including thyroid fibrosis which follows chronic thyroiditis. The aim of our study was to examine a potential correlation between TGFB1 gene expression level in fine-needle aspiration biopsy (FNAB) thyroid specimens and fibrosis of the thyroid gland in two types of thyroid lesions. Fibrosis of the thyroid tissue was assessed, based on the expression levels of fibrosis-associated genes (COL1A1 and COL3A1) in thyroid FNAB samples, on the FNAB specimen cellularity and other features of the tissue fibrosis assessed during cytological examination, as well as on the size of thyroid gland and its function. Following routine cytological examination, 63 thyroid FNAB specimens, received from patients with Hashimoto's thyroiditis (HT, n=30) and non-toxic goitre (NTG, n=33), were quantitatively evaluated regarding TGFB1, COL1A1 and COL3A1 expression level by real-time PCR in the ABI PRISM 7500 Sequence Detection System. The obtained results showed statistically significant differences regarding the expression level (RQ) of TGFB1 and of COL1A1 genes between the groups with HT and with NTG (higher expression in HT group). No significant differences, concerning the expression level of COL3A1 gene, were observed for the studied groups (HT vs. NTG). In HT group statistically significant correlation was found between TGFB1 gene and COL3A1 gene expression levels (p<0.05). The correlation in question might suggest excessive extracellular matrix deposition and could--possibly--contribute to thyroid fibrosis mechanism in the course of chronic thyroiditis. PMID- 20191438 TI - [Municipal health conferences in North Rhine-westphalia. Experience and perspectives]. AB - Health conferences are established structural elements in the field of health prevention and health-care in North Rhine-Westphalia. This applies to the state level (state health conferences) as well as to the municipal and city levels of government (local health conferences). After being tested in a pilot project in the period 1995-1998, the foundation of local conferences became obligatory in all municipalities when the public health service act of 1998 came into effect. The present article describes the relevant structures, developments and results. PMID- 20191439 TI - [Transnational solidarity? Cross-border heath-care in the European Union]. AB - The responsibilities of the European Union surrounding public health are concentrated on co-ordinating and complementary practices. A mandatory European harmonization of standards and policies is in effect in only a few areas such as pharmaceutical authorization and health protection at the workplace. The implementation of single market rights over the national health-care systems (negative integration) is growing at the European level. This has ambivalent repercussions. Whilst the rights of patients on the basis of the four fundamental freedoms in the context of cross-border health-care have got stronger, national governments see themselves confronted with a limitation of scope for their health care policies. The basic principles of the integration project place European pressure on national governments. They are subject to sanctions if their policies are not directly in accordance with the single market concept. PMID- 20191440 TI - [Everyday life and solidarity in north-east German rural communities - first qualitative results of the Rural Health Study]. AB - There have been increasing discussions in the health sciences in recent years about socio-spatial influences on health activities. The starting point has been the growing territorial inequality in spatial development resources, which has an effect on the participatory chances of people in structurally weak regions. The concept of "peripherisation" is used to describe this change. Empirical investigations of socio-spatial resources at the local level are rare, because the theoretical preconditions have not been elaborated sufficiently for the theoretical modelling to be recognised for hypothesis-based empirical investigations. At the centre of this theorisation are analyses of the "social capital" of every-day actions. As part of the Rural Health Study 2008 at the University of Applied Science Neubrandenburg (involving a longitudinal analysis with quantitative surveys in 14 rural communities in north-eastern Germany 1973, 1994, 2008), a qualitative approach was also adopted with case and community studies. The first results are compared with the state of the literature. Case studies are presented showing strategies for adaptation and improvement of the individual's situation, and also the daily solidarity of people in villages. Development potentials are outlined. PMID- 20191441 TI - [Association between health-related quality of life and selected indicators for 10- to 15-year-old girls in Berlin]. AB - OBJECTIVE: The state of knowledge on health-related quality of life (HRQOL) is incomplete. The influence of social and behavioural factors on HRQOL of 10- to 15 year-old girls was investigated. METHOD: The Berlin School Children's Cohort (BSCOC-cross-sectional study 2006-2007) included 1 842 girls and their parents (n=1 683) in Berlin. Height and body weight were measured. A standardised questionnaire to capture the HRQOL of the girls (KINDL((r)) questionnaire) and possible influencing factors was used. The association of the variables age, social situation, migration background, family situation, weight status, menarche status, eating behaviour and illness in the last weeks with the HRQOL and its partial scales were controlled for using the Kruskal-Wallis test. Variables which showed a statistically significant relationship with HRQOL were included as independent variables in a linear regression model with the outcome variable HRQOL to test their influence and quantify it. RESULTS: In comparison to the KINDL reference values (KiGGS), the HRQOL values of the assessed girls are lower. Quality of life is unfavourably swayed by age, low social status, two-sided migration background, sickness in the last few weeks, little physical activity, unfavourable eating behaviour, overweight and obesity and when post-menarche. With the exception of migration background and menarche status, all results were confirmed in the multivariate model. CONCLUSION: The results of the linear regression model demonstrate a higher importance of body and behaviour-related factors and places and confirm the relevance of past prevention and health promotion in the named areas also for the HRQOL of the girls. PMID- 20191442 TI - The effects of cannabis on heart rate variability and well-being in young men. AB - INTRODUCTION: The effects of cannabis use on the autonomic regulation of the heart had been identified in tests with volunteers. We studied these effects of cannabis use on young adults in everyday life. METHODS: We measured heart rate variability (HRV) and well-being (WHO-5 score) in young men during a routine medical examination. Seventy-two men were identified with a positive drug screening test solely for tetrahydrocannabinol. The comparison group consisted of 72 men, matched according to age and body mass index, who used no illicit drugs or pharmaceuticals. RESULTS: In the cannabis group, HRV was significantly increased compared to the control group. The median value of root mean square of successive differences (RMSSD) at rest was 56.2 ms in the drug users and 48.6 ms in the controls (p<0.05). The ratio of low-to-high frequency was higher in the controls (median 1.87 vs. 1.62; p<0.05). Psychological well-being, measured by WHO-5 score was significantly lower in cannabis users. DISCUSSION: Our data support the hypothesis that the use of cannabis leads to a change in cardiovascular sympathovagal balance. PMID- 20191443 TI - Does night-time cortisol excretion normalize in the long-term course of depression? AB - INTRODUCTION: While there is extensive literature on HPA system activity in acutely depressed patients, there is only limited information about the presence of hypercortisolemia during the interepisode interval of affective disorders. We hypothesized an increase in HPA system activity in depressed patients compared to controls, and proposed that night-time cortisol excretion during follow-up will depend on clinical outcome. METHODS: We measured night-time cortisol excretion in 27 patients during an acute episode of major depression as well as a 20-week follow-up. 40 healthy subjects served as control group. RESULTS: During the acute episode depressed patients showed increased levels of night-time cortisol excretion compared to healthy controls. Both, patients with full and sustained remission (n=8) as well as patients with incomplete remission or relapse (n=19) showed declining cortisol excretion in night-time urine during follow-up. At the end of follow-up cortisol excretion did not differ between patients with affective disorder and healthy controls. DISCUSSION: Irrespective of residual depressive symptoms, HPA system activity declines after the generally investigated acute depressive episode. PMID- 20191444 TI - Familial differential treatment response in schizophrenia--lessons from a case of three affected siblings. PMID- 20191447 TI - [Low level laser therapy: treatment option in neck pain]. PMID- 20191449 TI - [The results of the TREAT study: lessons and limitations]. PMID- 20191450 TI - [PPAR agonists: elixir of eternal youth for the kidney?]. PMID- 20191451 TI - [Cardiovascular risk in kidney transplant recipients with diabetes]. PMID- 20191452 TI - [Neutrophil gelatinase-associated lipocalin (NGAL): a biomarker beyond the confines of nephrology]. PMID- 20191453 TI - [Adiponectin: an adipocyte hormone serving the podocyte]. PMID- 20191454 TI - [Can complement blocking arrest peritoneal fibrosis?]. PMID- 20191455 TI - [Are there differences in the treatment of kidney patients if they are admitted to general medicine vs nephrology units? Yes, and they are significant]. AB - The care provided by a nephrologist is fundamental because the nephrologist is able to prevent, recognize and treat the many and complex factors of comorbidity inherent in chronic kidney disease at its various stages. The nephrologist also has the important task of delaying the start of dialysis for as long as possible. Delaying dialysis slightly, even just one year for each patient, will have ethical, social and economic advantages that should be duly weighed and carefully evaluated when adopting organizational models of care involving nephrology. The nephrologist bases his work on the clinical competence acquired and maintained through appropriate training programs based on CME courses and, above all, daily clinical practice that, in order to be truly educational, must reach a sufficient volume of activity to guarantee the best possible outcome to the patient. PMID- 20191456 TI - [Are there differences in the treatment of kidney patients if they are admitted to general medicine vs nephrology units? No, provided the departmental system is well organized]. AB - Patients with acute renal disease are mostly admitted to the units of internal medicine and nephrology present in the medium-sized hospitals that constitute the bulk of the Italian hospital network. The needs of increasingly elderly patients with chronic conditions and comorbidities warrant a comprehensive approach and continuity of health care along with a high level of specialist expertise. The new models that integrate the specialties within the department of medicine and the new organizational structure of the hospital based on progressive patient care can achieve these objectives by ensuring both the development of the specialties and the overall effectiveness of the system. PMID- 20191457 TI - [The best place for the hospitalized kidney patient: internal medicine or nephrology? Comment]. AB - Proposals of new organizational models and awareness of the limits of the available resources are leading to certain changes in the hospital organization in some Italian regions. These changes consist mainly of the creation of large departments of internal medicine divided into sections according to the different levels of care, and the abolishment of specialty divisions like nephrology. When this happens, it can be hypothesized that specialists will become mere consultants and will no longer take direct care of the patient. This already happens in many countries but is a novelty in the Italian medical system. This paper comments on the pros and cons of the new model as seen by an internist and a nephrologist in two papers in this issue of the journal. When addressing this subject, the main factors to be taken into consideration should be 1) long-term care for patients with chronic disease; 2) coordination of admissions for acute and chronic disease; 3) hospital size. It is to be hoped that the efficacy of the new models will be judged not only by managerial and economic criteria, but also using indicators of clinical outcome. PMID- 20191458 TI - [Cystinuria]. AB - Cystinuria is an autosomal recessive disorder characterized by impairment of the proximal renal tubules which are unable to reabsorb cystine and dibasic amino acids, leading to the formation of recurrent kidney stones. According to the most recent genetic knowledge, there are two types of cystinuria. The disease is more severe in men than in women in terms of early appearance and number of produced stones. Renal function is generally maintained even after long-lasting disease. Type A heterozygotes are generally asymptomatic while type B heterozygotes usually have a three-fold increased incidence of kidney stones compared to the general population. Medical treatment of cystinuria with cystine-binding drugs and alkali is feasible and effective but requires continuous monitoring of free cystine urine levels and urine pH and careful surveillance of side effects, with particular attention to the onset of proteinuria. PMID- 20191459 TI - [Restless legs syndrome in kidney patients]. AB - Restless legs syndrome (RLS) is a sensorimotor disorder characterized by a strong urge to move the legs associated with paresthesias, motor restlessness, worsening of symptoms at night, and at least partial relief by activity. RLS has a negative impact on sleep, may cause depressive and anxious states, result in poor quality of life, and be a risk factor for cardiovascular disease. RLS is frequent in patients with end-stage renal disease; in this patient population it is consistently associated with severe comorbidities. It remains an underdiagnosed clinical condition. Appropriate diagnosis and management of RLS and sleep disorders is necessary to improve the quality of life and survival of kidney patients. PMID- 20191460 TI - [Clinical impact of hypercalcemia after kidney transplant]. AB - Hypercalcemia is a relatively common finding after kidney transplant, and when correctly evaluated has been reported to be present in around 5-15% of patients. The peak of its incidence can be found after the third month from transplantation and it usually maintains relatively constant levels, even though a moderate attenuation of the phenomenon can be expected in the long term. Many factors have been claimed to cause hypercalcemia after kidney transplant. However, the main recognized factor is the degree of persistent hyperparathyroidism deriving from a long previous history of uremia. It has been suggested that hypercalcemia can be damaging to both graft (induction of nephrocalcinosis, reduction of graft survival) and other organ or system functions (vascular calcification, erythrocytosis, pancreatitis, etc.). However, there is no definitive demonstration of a cause-effect relationship between hypercalcemia and the above mentioned clinical events. Furthermore, it is not possible to establish to what extent these effects are due to hypercalcemia per se or also to increased PTH levels, which are often associated with hypercalcemia. In addition, there is no definitive evidence that correction of hypercalcemia might solve the above mentioned clinical events. The best way to reduce the incidence of hypercalcemia is considered to be the optimization of therapy for secondary hyperparathyroidism during the pretransplant period. It has long been thought that parathyroidectomy was the only way to solve the problem of stabilized hypercalcemia associated with moderate-severe persistent hyperparathyroidism after kidney transplant. The introduction of calcimimetics, which have substantially changed the therapeutic approach to secondary hyperparathyroidism in dialysis patients, seems to be promising also in this field. However, many issues need to be clarified before its definitive inclusion into the therapeutic armamentarium of the transplant patient who is already burdened by so many medications. PMID- 20191461 TI - [Non-heart-beating-donor transplant: the first experience in Italy]. AB - A promising way to increase the number of kidneys for transplantation is to expand the donor pool by including non-heart-beating donors (NHBDs). The centers involved in NHBD transplantation programs have reported a 16-40% increase in kidney transplants. A key issue with NHBD is the significantly higher rate of delayed graft function (DGF) and primary non-function (PNF) compared with that associated with heart-beating donor (HBD) transplants. However, although transplants from NHBD are associated with a greater incidence of early adverse events, long-term graft survival appears to be similar to that observed after transplants from HBDs. In addition, the use of extracorporeal membrane oxygenation and mechanical perfusion, the careful selection of recipients and donors, and an adequate therapeutic strategy may at least partially reduce the risk of PNF and DGF and improve transplant outcome. PMID- 20191462 TI - [Multislice computed tomographic angiography in the assessment of central veins for endovascular treatment planning: comparison with phlebography]. AB - The dysfunction of a vascular access for hemodialysis and its loss may depend on drainage difficulties of the superficial or deep venation due to hemodynamically significant stenosis or obstruction of a central vein, which generally involve the innominate-subclavian veins or superior vena cava. These alterations are often neglected due to their central and deep location; when there is hemodynamic compensation, they may remain asymptomatic. For these reasons every suspect clinical sign for central vein stenosis (gross arm syndrome or venous hypertension in an arteriovenous fistula) must not be ignored, as timely intervention is essential for functional recovery of the vessel and for the protection of the arteriovenous fistula. The modern imaging techniques ensure thorough diagnostic assessment, while the possibilities of endovascular treatment with interventional radiology allow, in a large proportion of cases, optimal minimally invasive treatment, but above all the recovery of venation in a hemodialyzed patient. We report our experience with multislice computed tomographic angiography (MS-CTA) and reconstruction software for treatment planning of central vein stenosis or obstruction. Forty-nine patients were studied with MS-CTA (GE 16). Images were acquired in the venous phase (120-180 seconds after contrast medium injection) followed by digital vascular reconstruction (AutoBone for bone removal, vessel analysis for caliber and length measurements, thin and curved MIP, MPR). Within a week control phlebography was performed. The venous tree was divided into seven segments and analyzed in a double-blind fashion with a distinction between patent segments, 50-70% stenosis, >70% stenosis, occlusion, and collateral vascular beds. There was excellent correspondence in all the examined segments for patency, >70% stenosis, and occlusion, with high sensitivity (98%), specificity (99.3%), and diagnostic accuracy (99.1%). The binomial test demonstrated a highly significant concordance (alpha=0.99) for all patients and in all vascular segments with the exception of 70% stenoses, in which MS-CTA gave a slight overestimate. In the central venous district, color Doppler ultrasonography may not be as effective as for the peripheral study of arteriovenous fistulae, and second-level imaging techniques such as MS-CTA are more useful. We suggest that endovascular treatment must be preceded by MS-CTA. This examination shows the lesions that may benefit from endovascular treatment and recognizes ''uncrossable'' lesions, ie, the ones that will not benefit from treatment. Moreover, it allows accurate planning of endovascular treatment by showing the lesion type (stenosis or obstruction), the position and extension of the involved vessels, the vessel caliber above and below the lesion, and the possible presence of a collateral vascular bed. MS-CTA with dedicated reconstruction software, if correctly performed and accurately reconstructed, is a precious tool for diagnosis and treatment planning. PMID- 20191463 TI - [Measures of frequency in epidemiology studies: incidence and prevalence]. PMID- 20191464 TI - [A case of apparently trivial flank pain]. AB - We describe the case of an 80-year-old man who came to our observation with pain in his left side and iliac region. Ultrasonography showed an incidentaloma with a largest diameter of 10 cm in the left suprarenal fossa. It extended downward and anteriorly from the apex of the left kidney; the picture was suggestive of a saccate hematoma. Further examination resulted in a diagnosis of an adrenally located extranodal non-Hodgkin's lymphoma and the patient was treated accordingly. PMID- 20191465 TI - [Organ transplantation: training and prospects for a young surgeon]. PMID- 20191466 TI - Predictors of rheumatoid arthritis patient-physician communication about medication costs during visits to rheumatologists. AB - OBJECTIVE: To examine the frequency with which medication costs are discussed, and the predictors of these discussions, during visits between rheumatologists and their patients with rheumatoid arthritis (RA). METHODS: Audiotapes of medical visits, patient questionnaires, medical records, and physician questionnaires were collected from March 2003 to December 2005. Data were collected from 200 RA patients from 4 rheumatology clinics. Audiotapes were coded for the presence of communication about medication costs using a detailed coding instrument. The final analysis sample included 193 patients and 8 rheumatologists. Stepwise multivariable logistic regression was used to examine the role of patient, physician, medication, and relationship characteristics on discussions of medication costs. RESULTS: Despite medication changes being made in more than 50% of the visits, only 34% of those visits included discussions of medication related costs; 48% of these discussions were initiated by patients. In multivariable logistic regression models, communication about medication costs occurred more often when patients were white (compared with nonwhite) and reported an annual income of $20,000-$59,999 (compared with those earning > or =$60,000). Discussions about medication costs also were more common when physicians were white. CONCLUSION: Although medication changes were common, medication costs were only discussed in one-third of the visits. Communication about medication costs was more common among patients who were white and in a middle income category. Disparities in communication about medication costs have the potential to negatively impact prescribing and subsequent medication use. Further research should examine potential disparities in communication about medication costs. PMID- 20191467 TI - Measurement of varus/valgus alignment in obese individuals with knee osteoarthritis. AB - OBJECTIVE: Frontal plane knee malalignment may increase progression of knee osteoarthritis (OA) and hasten functional decline. An accurate nonradiographic measure of knee alignment is necessary because the gold standard measure, the long-leg radiograph, is costly and often unavailable. Moreover, nonradiographic measures of knee alignment have not been validated in an obese population, where knee OA is common. The purpose of this study was to develop and assess the concurrent validity and reliability of a nonradiographic measure of frontal plane knee alignment and demonstrate the accuracy of the measure in an obese population. METHODS: Fifty-five subjects (41 women, 14 men; mean +/- SD age 62.9 +/- 10.3 years) with knee OA were examined. A nonradiographic measure (umbilical method) of frontal plane alignment, using the landmarks of the umbilicus, knee, and ankle, was compared with the radiograph gold standard. Statistical significance was accepted at P < 0.05. RESULTS: Eighty-nine percent of the participants had a body mass index (BMI) placing them in the overweight or obese category (mean +/- SD BMI for all subjects 31.3 +/- 6.1 kg/m(2)). Radiographic measures of alignment ranged from 9.1 degrees valgus to 14.3 degrees varus (76% of the participants had varus alignment, 12% had valgus alignment, and 2% had neutral alignment). Umbilical measures ranged from 1 degrees valgus to 21 degrees varus. The umbilical measure was significantly correlated with the radiographic method (r = 0.75, P < 0.001). The error of the umbilical measure was not significantly correlated with the BMI (r = -0.21, P = 0.13). CONCLUSION: The umbilical method of assessing frontal plane knee alignment is a valid surrogate for the radiographic gold standard and retains its accuracy in an obese population. PMID- 20191468 TI - Promoting physical activity in children with juvenile idiopathic arthritis through an internet-based program: results of a pilot randomized controlled trial. AB - OBJECTIVE: Patients with juvenile idiopathic arthritis (JIA) are less physically active than healthy peers. Therefore, we developed an Internet-based intervention to improve physical activity (PA). The aim of this study was to examine the effectiveness of the program in improving PA. METHODS: PA was determined by activity-related energy expenditure, PA level, time spent on moderate to vigorous PA, and the number of days with > or =1 hour of moderate to vigorous activity, and was assessed with a 7-day activity diary. Aerobic exercise capacity was assessed by means of a Bruce treadmill test and was recorded as maximum endurance time. Disease activity was assessed by using the JIA core set. Adherence was electronically monitored. RESULTS: Of 59 patients, 33 eligible patients were included and randomized in an intervention (n = 17, mean +/- SD age 10.6 +/- 1.5 years) or control waiting-list group (n = 16, mean +/- SD age 10.8 +/- 1.4 years). All patients completed baseline and T1 testing. PA significantly improved in both groups. Maximum endurance time significantly improved in the intervention group but not in the control group. In a subgroup analysis for patients with low PA (intervention: n = 7, control: n = 5), PA improved in the intervention group but not in the control group. The intervention was safe, feasible, and showed a good adherence. CONCLUSION: An Internet-based program for children with JIA ages 8-12 years directed at promoting PA in daily life effectively improves PA in those patients with low PA levels. It is also able to improve endurance and it is safe, feasible, and has good adherence. PMID- 20191469 TI - Interleukin-6 as a therapeutic target in spondylarthritis: comment on the article by Tanaka et al. PMID- 20191470 TI - Adherence to disease-modifying antirheumatic drugs and the effects of exposure misclassification on the risk of hospital admission. AB - OBJECTIVE: To describe the effect of different exposure classification strategies for disease-modifying antirheumatic drugs (DMARDs) on drug-outcome associations. METHODS: We studied the association between DMARD initiation and all-cause hospitalizations in patients with rheumatoid arthritis (RA), 1995-2005. Initiators of DMARDs and oral glucocorticoids were followed for < or =180 days. We compared 2 strategies for exposure classification: a persistent exposure required (PER) approach, in which followup stopped when the regimen changed; and a persistent exposure ignored (PEI) approach, in which followup continued despite regimen changes. For PEI, adherence was assessed using the medication possession ratio. All-cause hospitalization risk was compared among RA regimen initiators using Cox models and methotrexate as the reference. RESULTS: We identified 28,906 episodes of medication initiation. In PER analyses, tumor necrosis factor alpha antagonists did not increase hospitalization risk compared with methotrexate, whereas leflunomide did (hazard ratio [HR] 1.36, 95% confidence interval [95% CI] 1.1-1.67). Glucocorticoids increased hospitalization risk (HR 1.29, 1.54, and 2.03 for low, medium, and high doses, respectively). PEI results were similar to PER except that infliximab initiation increased the risk of hospitalization compared with methotrexate (HR 1.46, 95% CI 1.19-1.8), and most other effects were closer to the null. In PEI, adherence ranged from 73% for etanercept to 6% for glucocorticoids and adherence to methotrexate was 59%. CONCLUSION: Compared with methotrexate initiation, leflunomide or glucocorticoid initiation consistently increased all-cause hospitalizations in the first 180 days of use. Most PER and PEI estimates were similar; observed differences in risk between these methods were likely due to differences in adherence. PMID- 20191472 TI - Change of synovial vascularity in a single finger joint assessed by power doppler sonography correlated with radiographic change in rheumatoid arthritis: comparative study of a novel quantitative score with a semiquantitative score. AB - OBJECTIVE: To investigate the relationship between synovial vascularity assessed by quantitative power Doppler sonography (PDS) and progression of structural bone damage in a single finger joint in patients with rheumatoid arthritis (RA). METHODS: We studied 190 metacarpophalangeal (MCP) joints and 190 proximal interphalangeal (PIP) joints of 19 patients with active RA who had initial treatment with disease-modifying antirheumatic drugs (DMARDs). Patients were examined by clinical and laboratory assessments throughout the study. Hand and foot radiography was performed at baseline and the twentieth week. Magnetic resonance imaging (MRI) was performed at baseline. PDS was performed at baseline and the eighth week. Synovial vascularity was evaluated according to both quantitative and semiquantitative methods. RESULTS: Quantitative PDS was significantly correlated with the enhancement rate of MRI in each single finger joint. Comparing quantitative synovial vascularity and radiographic change in single MCP or PIP joints, the level of vascularity at baseline showed a significant positive correlation with radiographic progression at the twentieth week. The change of vascularity in response to DMARDs, defined as the percentage change in vascularity by the eighth week from baseline, was inversely correlated with radiographic progression in each MCP joint. The quantitative PDS method was more useful than the semiquantitative method for the evaluation of synovial vascularity in a single finger joint. CONCLUSION: The change of synovial vascularity in a single finger joint determined by quantitative PDS could numerically predict its radiographic progression. Using vascularity as a guide to consider a therapeutic approach would have benefits for patients with active RA. PMID- 20191473 TI - Accuracy of self-reported diagnosis of hip replacement. AB - OBJECTIVE: To examine the accuracy and validity of self-report of hip replacement for osteoarthritis (OA). METHODS: We compared self-reported hip replacement and the reason for surgery in elderly, white women age > or =65 years from the Study for Osteoporotic Fractures cohort with medical records and pelvis radiographs. Women, followed for an average of 8 years at the fifth clinic visit, were asked about any hip replacements since baseline. RESULTS: Among 7,421 women attending the fifth clinic visit, 347 reported 387 hip replacements. Radiographs and/or medical records were available for 316 self-reported hip replacements. Participants accurately reported that hip replacements were for arthritis or fracture, with 94.5% and 97.2% of these self-reported diagnoses, respectively, confirmed from medical records. However, 1 in 8 self-reported hip replacements were not attributed by participants to either arthritis or a fracture; of these, medical records indicated that 88% were for OA. Overall, 302 self-reported hip replacements (95.6%) were confirmed as hip replacements (for agreement with self report, kappa = 0.95 [95% confidence interval 0.92-0.96]). Under-reporting of hip replacements compared with hip replacements seen on radiographs was minimal (0.28%). CONCLUSION: Elderly women accurately reported hip replacements and whether the surgery was for arthritis or a hip fracture, although a small number of hip replacements for arthritis were not attributed to this diagnosis by the women. Because hip OA and hip fracture have very different determinants, epidemiologic studies that use self-reported hip replacement as an indicator for the presence of hip OA or as an outcome of hip OA should verify the underlying cause by asking about the reason for surgery. PMID- 20191474 TI - Work participation and health status in early osteoarthritis of the hip and/or knee: a comparison between the Cohort Hip and Cohort Knee and the Osteoarthritis Initiative. AB - OBJECTIVE: To examine the work participation of Dutch people with early osteoarthritis (OA) in hips or knees and compare this with data from the American Osteoarthritis Initiative (OAI) cohort. The influence of health status and personal factors on work participation was analyzed. METHODS: In the Cohort Hip and Cohort Knee (CHECK) study, 1,002 subjects were included. Baseline questionnaire data from 970 subjects were analyzed. Rate ratios were calculated to compare work participation with the general Dutch population, after correcting (by stratifying) for age, sex, and education. Health status was measured using the Short Form 36 health survey and the Western Ontario and McMaster Universities Osteoarthritis Index. Groups were compared (CHECK versus OAI, workers versus nonworkers) using t-tests. RESULTS: The mean age of the subjects was 56 years and 79% were women. Overall participation was 51%, similar to the general Dutch population and lower than in the OAI (76%). Point prevalence of sick leave because of hip/knee symptoms was 2%, and year prevalence was 12%. Of the subjects, 14% had made work adaptations. Workers reported significantly better health status (corrected for age, sex, and education) than nonworkers. CONCLUSION: Work participation of Dutch people with early OA is similar to the general population and significantly lower than American subjects. Increasing age, female sex, and lower education level were related to lower participation. Societal factors appear to have had more effect on work participation than health status in this stage of OA. The better health status of workers could not be explained solely by selection bias, but may be a result of work. PMID- 20191475 TI - Systematic review of shoulder function questionnaires: comment on the article by Roy et al. PMID- 20191476 TI - An unusual case of cerebellar hemorrhage in a patient with systemic lupus erythematosus. PMID- 20191477 TI - Abatacept for severe anti-tumor necrosis factor alpha refractory juvenile idiopathic arthritis-related uveitis. AB - OBJECTIVE: To evaluate the safety and efficacy of abatacept in patients with severe juvenile idiopathic arthritis (JIA)-related uveitis refractory or intolerant to immunosuppressive and anti-tumor necrosis factor alpha (anti TNFalpha) agents. METHODS: Patients with JIA-related uveitis refractory to immunosuppressive and anti-TNFalpha agents were treated with intravenous abatacept (10 mg/kg monthly). Side effects, frequency of uveitis flares, and ocular complications before and after treatment were reported. RESULTS: Seven patients (6 females and 1 male) with a mean uveitis duration of 11.6 years entered the study. All patients had failed previous immunosuppressive therapy and >or=2 anti-TNFalpha treatments. All patients responded to abatacept and 6 maintained a clinical remission after a mean of 9.2 months of treatment. One patient withdrew from the study with oral mycosis and arthritis flare; no other patients had side effects. The mean frequency of uveitis flares during the 6 months before and after treatment decreased from 3.7 to 0.7 episodes. No new ocular complications or worsening of preexisting ones were reported. CONCLUSION: Abatacept treatment led to sustained improvement in severe anti-TNFalpha resistant JIA-related uveitis and was well tolerated in all but 1 patient. These results provide new insights into a possible indication of abatacept for the treatment of uveitis. PMID- 20191478 TI - Long-term mortality and renal outcome in a cohort of 100 patients with lupus nephritis. AB - OBJECTIVE: To evaluate the long-term mortality and renal outcome in a cohort of Danish patients with lupus nephritis (LN) and to identify outcome predictors among findings registered at the time of the first renal biopsy. METHODS: The cohort consisted of 100 patients diagnosed with LN (World Health Organization classes I-VI) between 1971 and 1995 and followed for a median duration of 14.7 years (range 0.01-36.9 years). Standardized mortality ratios (SMRs) were calculated on the basis of national age-, sex-, and calendar-year period-specific death rates. RESULTS: Thirty-seven deaths occurred in the cohort, corresponding to an overall SMR of 6.8 (95% confidence interval [95% CI] 4.9-9.4). Excess mortality was observed throughout followup. The SMR estimates were 9.0 (95% CI 4.7-17.1), 6.2 (95% CI 4.0-9.5), and 6.6 (95% CI 3.1-13.8) for patients diagnosed during the calendar-year periods 1971-1979, 1980-1989, and 1990-1995, respectively. The cumulative renal survival after 5, 10, and 20 years of followup was 87%, 83%, and 73%, respectively. The risk of end-stage renal disease (ESRD) did not decrease significantly across calendar-year periods. Systolic blood pressure >or=180 mm Hg, focal segmental nephritis, and advanced sclerosing nephritis were identified as baseline predictors of death in multivariate regression analyses, while systolic blood pressure >or=180 mm Hg, serum creatinine level >or=140 mumoles/liter, and diagnostic delay predicted progression to ESRD. CONCLUSION: LN is associated with excess long-term mortality, and patients may progress to ESRD even after prolonged followup. Our analyses indicate that focal segmental histopathology at disease onset constitutes an important risk factor for death among LN patients. Moreover, our data underscore the importance of early intervention, blood pressure control, and long-term followup in LN. PMID- 20191479 TI - Functional impairment of the arterial wall in primary Sjogren's syndrome: combined action of immunologic and inflammatory factors. AB - OBJECTIVE: Primary Sjogren's syndrome (SS) shares clinical and serologic features with rheumatoid arthritis and systemic lupus erythematosus, 2 diseases characterized by acceleration of atherosclerosis. Signs of precocious atherosclerosis have also been shown in SS, although the pathogenic basis of early arterial damage is unclear. The arterial wall was functionally evaluated in SS subjects with analysis of the role played by disease-related factors. METHODS: Endothelium-dependent flow-mediated vasodilation (FMV) and endothelium independent nitrate-mediated vasodilation (NMV) were evaluated in 45 women with SS and 59 age-matched female controls. In addition, serum soluble intercellular adhesion molecule 1, soluble vascular cell adhesion molecule 1 (VCAM-1), and nitrotyrosine were detected. RESULTS: Although patient FMV values did not differ from those of control subjects (mean +/- SD 7.4 +/- 3.6 versus 7.7 +/- 1.9; not significant), NMV was lower in SS patients than in controls (mean +/- SD 8.1 +/- 3.5 versus 10.3 +/- 2.1; P or =25.0 kg/m(2)) had a 60-70% higher risk compared with women with normal weight (BMI 18.5-24.9 kg/m(2)). Overweight or obese women who exercised > or =1 hour per week had an RR of 1.72 (95% CI 1.07-2.76) compared with normal-weight women with a similar activity level, whereas the risk was >2-fold higher for overweight or obese women who were either inactive (RR 2.09, 95% CI 1.36-3.21) or exercised <1 hour per week (RR 2.19, 95% CI 1.39-3.46). CONCLUSION: Being overweight or obese was associated with an increased risk of FM, especially among women who also reported low levels of physical exercise. Community-based measures aimed at reducing the incidence of FM should emphasize the importance of regular exercise and the maintenance of normal body weight. PMID- 20191481 TI - Cognitive-behavioral therapy attenuates nociceptive responding in patients with fibromyalgia: a pilot study. AB - OBJECTIVE: To explore the possibility that cognitive-behavioral therapy (CBT) influences fibromyalgia symptoms via descending inhibition of nociception, we evaluated the effects of CBT on the nociceptive flexion reflex (NFR) threshold, an objective measure of spinal nociceptive transmission. METHODS: Female fibromyalgia patients (n = 32) were randomized to 6 weekly sessions of telephone delivered CBT or usual care (UC). Assessments of the NFR threshold and clinical outcomes were conducted at baseline, week 6 (post-CBT), and week 12. RESULTS: From baseline to week 6, the NFR threshold increased in the CBT group and decreased in the UC group (mean +/- SD 4.4 +/- 13.7 mA versus -10.2 +/- 9.9 mA; P = 0.005). This difference was also apparent at week 12 (mean +/- SD 7.3 +/- 9.2 mA for CBT versus -5.4 +/- 13.5 mA for UC; P = 0.01). The groups reported similar reductions in NFR pain ratings at week 6 (mean +/- SD -20.2 +/- 23.9 for CBT versus -14.9 +/- 16.4 for UC; P = 0.8) and week 12 (mean +/- SD -8.9 +/- 25.3 for CBT versus -10.8 +/- 24.1 for UC; P = 0.4). CONCLUSION: Compared with UC, CBT reduced nociceptive responding in fibromyalgia patients. Moreover, while the UC group exhibited longitudinal decreases in both the stimulation level and pain associated with the NFR threshold, those receiving CBT required more intense stimulation to elicit the NFR as well as rated that stimulation as less painful than at baseline. These data indicate the need for a larger study to confirm that changes in nociceptive responsivity may underlie the benefits of CBT in fibromyalgia patients. PMID- 20191483 TI - Metacognitions about smoking: a preliminary investigation. AB - Preliminary research has indicated that metacognitions are involved in smoking. In the present study, we aimed to investigate whether specific facets of metacognition play a role in explaining smoking initiation and perseveration. Twelve individuals, self-identified as regular smokers and scoring a positive value on the Fagerstrom Test of Nicotine Dependence, were assessed using a semi structured interview to investigate the following: (1) whether they held positive and/or negative metacognitive beliefs about smoking; (2) what their main goal in smoking was, and how they knew if they had achieved their goal; (3) how they directed their focus of attention when smoking; and (4) what they perceived the advantages and disadvantages of these attentional strategies to be. Results indicated that participants endorsed both positive and negative metacognitive beliefs about smoking and that the goal of smoking was to regulate negative emotion and/or to enhance cognitive functioning. Participants reported that they relied either on an internal signal, such as improvement in the emotional/cognitive state, or on a physical sign, in the form of a finished cigarette, to determine if they had achieved their goal. During an episode of smoking, half of the participants reported focusing their attention internally on thoughts and feelings or the sensations of smoking. The remainder of participants reported either an exclusively external focus of attention (e.g., the environment) or a varied focus of attention. Most participants were able to identify advantages to their attentional strategies, whereas two reported perceived disadvantages. The implications of the findings are discussed. PMID- 20191484 TI - Physician preference: filling the evidence gap. PMID- 20191485 TI - Systematic assessment of inflammation by magnetic resonance imaging in the posterior elements of the spine in ankylosing spondylitis. AB - OBJECTIVE: Magnetic resonance imaging (MRI) is sensitive for scoring inflammatory lesions in the spine, but attention has primarily focused on vertebral bodies, and no study has systematically examined the posterior elements. We aimed to systematically determine the frequency and distribution of inflammatory changes in the posterior elements of the spine using MRI, and to assess the reliability of their detection and their impact on discrimination of spinal MRI. METHODS: We scanned 32 patients recruited to placebo-controlled trials of anti-tumor necrosis factor therapy. Inflammatory lesions were detected by systematic review of consecutive sagittal STIR slices of the entire spine. Two readers evaluated pretreatment and posttreatment scans, blinded to treatment and time point. Inflammation was scored dichotomously (present/absent) in each posterior structure. Reproducibility was assessed by calculating random model variance components and generalizability coefficients, and discrimination by using Guyatt's effect size. RESULTS: Most patients (87.5%) had > or =1 lesion in the posterior elements (mean +/- SD number of affected spinal levels per patient 6.7 +/- 5.3), and they were detected most frequently in the thoracic spine. Interobserver reproducibility for total lesion count was very good to excellent for lesions in the thoracic spine and transverse and spinous processes. The addition of a simple dichotomous method for scoring posterior element inflammation substantially enhanced the discrimination observed using established MRI methods for scoring vertebral body inflammation. CONCLUSION: Inflammatory lesions in the posterior elements were present in the majority of patients with AS, and standard MRI protocols of the spine should be modified to ensure adequate visualization of posterolateral structures. PMID- 20191486 TI - Magnetic resonance imaging grading system for active and chronic spondylarthritis changes in the sacroiliac joint. AB - OBJECTIVE: To develop a new grading method to quantify activity and chronic spondylarthritis (SpA) changes in the sacroiliac (SI) joints identified by magnetic resonance imaging (MRI), taking into account the complex joint anatomy, and to compare the findings with radiographic changes. METHODS: A total of 37 patients (15 men, 22 women) fulfilling the European Spondylarthropathy Study Group criteria for SpA were examined by MRI of the SI joint using a semicoronal T1-weighted and T1-weighted fat-saturated (T1FS) sequence, a semiaxial STIR sequence, and postcontrast semicoronal and semiaxial T1FS sequences. The images were assessed independently by 2 radiologists for presence of bone marrow edema and enhancement, fatty marrow deposition, and joint erosion at both the cartilaginous and the ligamentous joint portion. Conventional radiographs were scored in accordance with the modified New York criteria. RESULTS: Inter- and intraobserver agreements for grading activity and chronic changes were good, with kappa values between 0.72 and 0.86 and between 0.83 and 0.90, respectively. Nearly half of the disease activity changes were due to inflammation in the ligamentous joint portion, which was significantly related to ankylosing spondylitis (AS). Patients with AS had significantly higher erosion and fatty marrow deposition scores than patients with nonprimary AS forms of SpA. The degree of erosion by MRI was significantly related to radiographic stages. CONCLUSION: Separate assessment of the ligamentous joint portion by MRI may be valuable for differentiating AS from nonprimary AS forms of SpA. Erosive changes on MRI were significantly related to radiographic changes, implying a possibility for substituting radiography with MRI. PMID- 20191487 TI - Development and validation of a case ascertainment tool for ankylosing spondylitis. AB - OBJECTIVE: Ankylosing spondylitis (AS) diagnosis is often delayed. The availability of effective biologic agents for treating AS has increased the importance of early diagnosis. We tested questions derived from a comprehensive literature review and an advisory board in a case-control study designed to identify patients with AS from among patients with chronic back pain (CBP). METHODS: Question items were cognitively tested among patients with AS, and then in case-control studies for validation and creation of a scoring algorithm and question item reduction. AS cases were recruited from a known database, and CBP subjects (controls) were recruited from clinics, employers, and from the SpineUniverse Web site. We used individual question items in a multivariate framework to discriminate between people with and without AS. RESULTS: Forty three questions yielded 24 items for analyses; 12 of these were entered into a multivariate regression model. Individual items yielded odds ratios ranging from 0.07 to 30.31. Question items with a significant positive relationship to AS included male sex, neck or hip pain/stiffness, longer pain duration, decreased pain/stiffness with daily physical activity, pain relief within 48 hours of nonsteroidal antiinflammatory drugs, and diagnosis of iritis. The tool demonstrated a sensitivity of 67.4 and a specificity of 94.6. The tool was developed from clinically and radiologically diagnosed AS cases and therefore is designed to distinguish AS cases among CBP subjects. In addition, approximately 54% of the AS cases in the study were treated with biologic agents, which may impact questionnaire responses. CONCLUSION: This tool can identify undiagnosed patients with AS and, potentially, those at an earlier stage in their disease course. PMID- 20191488 TI - Reliability, validity, and responsiveness of five at-work productivity measures in patients with rheumatoid arthritis or osteoarthritis. AB - OBJECTIVE: Arthritis often impacts a worker's ability to be productive while at work. However, the ideal approach to measuring arthritis-attributable at-work productivity loss remains unclear. Our objective was to evaluate the relative strengths and weaknesses of 5 measures aimed at quantifying health-related at work productivity loss and to determine the best available instrument for this population. METHODS: In a 12-month longitudinal design, the psychometric properties (reliability, validity, and responsiveness) of 5 self-reported measures of at-work productivity were compared in workers with either rheumatoid arthritis (RA) or osteoarthritis (OA). We tested the Workplace Activity Limitations Scale (WALS), 6-item Stanford Presenteeism Scale (SPS-6), Endicott Work Productivity Scale (EWPS), RA Work Instability Scale (WIS), and Work Limitations Questionnaire (WLQ). RESULTS: Across all measures, participants (n = 250, 120 with RA and 130 with OA) consistently reported mild losses of at-work productivity. The Cronbach's alpha of the scales ranged from 0.71 (for SPS-6) to 0.94 (for EWPS), indicating some concerns over the internal consistency of the SPS-6. The RA WIS demonstrated the strongest construct validity (|r| = 0.54 0.74), whereas the WALS was most responsive to perceived changes in work ability. Despite its increasing popularity and potential application for costing analysis, the WLQ did not compare favorably with the other scales, possibly due to psychometric concerns with its physical demands subscale. CONCLUSION: Measures revealed unique conceptualization of at-work disability, but no single scale emerged as clearly superior. However, current results slightly favor the WALS and RA WIS as superior instruments for measuring at-work productivity loss in workers with arthritis. PMID- 20191489 TI - Knee joint stiffness during walking in knee osteoarthritis. AB - OBJECTIVE: To investigate the construct validity of walking knee stiffness as a measure to differentiate between individuals with and without knee osteoarthritis (OA) and the construct validity of walking knee stiffness as related to self reported knee stiffness. The contributors to walking stiffness and its relationship with loading rate and adduction moment are also investigated. METHODS: Thirty-seven individuals with knee OA and 11 asymptomatic controls participated. Knee stiffness was calculated during walking as the change in knee flexion-extension moment divided by the change in knee flexion angle. Forward stepwise regression models and Pearson's correlation coefficients were used to evaluate the relationships between variables. RESULTS: Knee stiffness in walking was significantly greater in the OA group (mean +/- SD 10.1 +/- 4.4 Nm/ degrees /kg x 100) compared with the controls (mean +/- SD 5.6 +/- 1.5 Nm/degrees/kg x 100) (P < 0.001). Knee excursion range explained 39% of the variance in walking knee stiffness (B = -0.736, P < 0.001) and knee extensor moment a further 7% (B = 6.974, P = 0.045). In the OA group, walking knee stiffness was not associated with self-reported stiffness (r = 0.029; P = 0.863). For the OA group, greater self-reported stiffness was associated with lower peak knee adduction moment (B = -0.354, P < 0.001). CONCLUSION: The construct validity of walking knee stiffness is supported. The poor correlation between walking stiffness and self-reported stiffness suggests the 2 measures evaluate different aspects of knee stiffness. Since a measure of walking stiffness is likely to provide valuable information, future research evaluating its clinical significance is merited. PMID- 20191490 TI - A comparison of strength training, self-management, and the combination for early osteoarthritis of the knee. AB - OBJECTIVE: To assess the relative effectiveness of combining self-management and strength training for improving functional outcomes in patients with early knee osteoarthritis. METHODS: We conducted a randomized intervention trial lasting 24 months at an academic medical center. Community-dwelling middle-aged adults (n = 273) ages 35-64 years with knee osteoarthritis, pain, and self-reported physical disability completed a strength training program, a self-management program, or a combined program. Outcomes included 5 physical function tests (leg press, range of motion, work capacity, balance, and stair climbing) and 2 self-reported measures of pain and disability. RESULTS: A total of 201 participants (73.6%) completed the 2-year trial. Overall, compliance was modest for the strength training (55.8%), self-management (69.1%), and combined (59.6%) programs. The 3 groups showed a significant and large increase from pre- to posttreatment in all of the physical functioning measures, including leg press (d = 0.85), range of motion (d = 1.00), work capacity (d = 0.60), balance (d = 0.59), and stair climbing (d = 0.59). Additionally, all 3 groups showed decreased self-reported pain (d = -0.51) and disability (d = -0.55). There were no significant differences among the groups. CONCLUSION: Middle-aged, sedentary persons with mild early knee osteoarthritis benefited from strength training, self-management, and the combination program. These results suggest that both strength training and self-management are suitable treatments for the early onset of knee osteoarthritis in middle-aged adults. Self-management alone may offer the least burdensome treatment for early osteoarthritis. PMID- 20191491 TI - Total hip or knee replacement for osteoarthritis: mid- and long-term quality of life. AB - OBJECTIVE: To compare quality of life (QOL) scores 3 and 10 years after total hip arthroplasty (THA) or total knee arthroplasty (TKA) for osteoarthritis with QOL scores in a general population, and to determine factors associated with QOL after surgery. METHODS: Data were obtained from 2 multicenter cohorts of patients with THA or TKA: 232 patients were recruited during 2003 (3-year cohort) and 221 patients were recruited during 1994 (10-year cohort). Preoperative data (QOL, radiograph results) and followup data (demographics, comorbidities, pain locations, environmental factors, and QOL) were collected. QOL data for the general population were obtained from a 2003 population-based survey. RESULTS: A total of 195 and 89 patients for the 3- and 10-year cohorts, respectively, were followed up; the mean age at followup was 73 years. For both of the cohorts, physical functioning and role-physical or role-emotional QOL scores were lower than those for a general population with comparable age. Scores for pain, mental health, and social dimensions were lower than those for the reference population for only the 10-year cohort. For both cohorts, increased number of comorbidities, painful locations other than THA or TKA location, and unfavorable environmental factors were associated with impaired QOL. Low preoperative QOL scores were predictive of impaired QOL at followup for only the 3-year cohort. CONCLUSION: THA or TKA can improve QOL, but the benefits may be time limited. Addressing environmental factors and treating comorbidities and pain in locations other than the arthroplasty location could have mid- and long-term effects on the QOL of patients with THA or TKA. PMID- 20191492 TI - Long-term outcome and prognostic factors of juvenile dermatomyositis: a multinational, multicenter study of 490 patients. AB - OBJECTIVE: To investigate the long-term outcome and prognostic factors of juvenile dermatomyositis (DM) through a multinational, multicenter study. METHODS: Patients consisted of inception cohorts seen between 1980 and 2004 in 27 centers in Europe and Latin America. Predictor variables were sex, continent, ethnicity, onset year, onset age, onset type, onset manifestations, course type, disease duration, and active disease duration. Outcomes were muscle strength/endurance, continued disease activity, cumulative damage, muscle damage, cutaneous damage, calcinosis, lipodystrophy, physical function, and health related quality of life (HRQOL). RESULTS: A total of 490 patients with a mean disease duration of 7.7 years were included. At the cross-sectional visit, 41.2 52.8% of patients, depending on the instrument used, had reduced muscle strength/endurance, but less than 10% had severe impairment. Persistently active disease was recorded in 41.2-60.5% of the patients, depending on the activity measure used. Sixty-nine percent of the patients had cumulative damage. The frequency of calcinosis and lipodystrophy was 23.6% and 9.7%, respectively. A total of 40.7% of the patients had decreased functional ability, but only 6.5% had major impairment. Only a small fraction had decreased HRQOL. A chronic course, either polycyclic or continuous, consistently predicted a poorer outcome. Mortality rate was 3.1%. CONCLUSION: This study confirms the marked improvement in functional outcome of juvenile DM when compared with earlier literature. However, many patients had continued disease activity and cumulative damage at followup. A chronic course was the strongest predictor of poor prognosis. These findings highlight the need for treatment strategies that enable a better control of disease activity over time and the reduction of nonreversible damage. PMID- 20191493 TI - Genotoxicity of anti-tumor necrosis factor therapy in patients with juvenile idiopathic arthritis. AB - OBJECTIVE: To assess the possible effects of both inflammation and the anti-tumor necrosis factor agents (anti-TNF) on DNA damage with a specific assay, and their effects on the repair capacity of DNA. METHODS: From a group of 20 children with juvenile idiopathic arthritis (JIA), 16 patients who completed the study and 16 control subjects were evaluated. DNA damage and repair capacity were analyzed by the comet assay at the level of peripheral lymphocytes before anti-TNF (etanercept) injections and on the 15th, 90th, and 180th days after the first injection. RESULTS: The amount of damage as detected by the aforementioned assay was higher in patients with JIA compared with controls. On the 15th day after the initial anti-TNF injection, there was a decrease in the mean DNA tail length of JIA patients, however on the 90th day an increase was observed; thereafter, an upward trend was observed until the end of the study. JIA patients had a DNA repair capacity that was significantly less than that of controls. CONCLUSION: The results of the comet technique suggests that JIA patients already have increased basal DNA damage before anti-TNF therapy; they are more sensitive to the DNA damage produced by H(2)O(2), and have a less efficient DNA repair system in comparison with control cells. After an initial improvement at 2 weeks, parameters of genotoxicity worsened, and DNA repair was further impaired 6 months after the addition of an anti-TNF agent to treatment. PMID- 20191494 TI - Validity of the bath ankylosing spondylitis disease activity index for the evaluation of disease activity in axial psoriatic arthritis. AB - OBJECTIVE: To assess the validity of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for the evaluation and definition of disease activity of axial psoriatic arthritis (PsA). METHODS: Fifty-four peripheral PsA, 46 axial PsA, and 103 primary ankylosing spondylitis (AS) patients were assessed. Patients were classified as having axial PsA if they had grade 2 or higher unilateral sacroiliitis in the presence of spinal symptoms. The 3 groups of patients were evaluated using several measurements for AS. Assessments of acceptability, data quality, internal consistency, construct validity, and responsiveness of the BASDAI were undertaken. Disease activity of the disease was assessed in peripheral PsA and axial PsA patients using the BASDAI, and compared with those with AS. RESULTS: For peripheral PsA patients, the Cronbach's alpha for the BASDAI was 0.783, for axial PSA patients it was 0.647, and for AS patients it was 0.786. The analysis of convergent validity showed that in peripheral PsA and axial PsA patients, the BASDAI was significantly correlated with other subjective disease activity parameters. For responsiveness, no association was found between changes in the BASDAI and changes in disease activity either in peripheral PsA or in axial PsA. BASDAI scores were similar in axial PsA and AS. Axial PsA patients with a BASDAI score >4 cm showed significant differences with peripheral PsA in terms of disease activity and were very similar to patients with AS. CONCLUSION: The BASDAI performed similarly in evaluating disease activity in both axial and peripheral PsA. The BASDAI does not seem to be a good index for evaluating disease activity in axial PsA. PMID- 20191495 TI - A modified Sharp score demonstrates disease progression in established psoriatic arthritis. AB - OBJECTIVE: To use a modified Sharp score (MSS) to measure radiologic progression and to assess its relationship to other radiologic features, peripheral joint disease, and physical function in psoriatic arthritis (PsA). METHODS: Two sets of hand radiographs (median interval 5.75 years) in 139 patients with established PsA were scored using an MSS. Seventy-four patients had standardized clinical joint and Health Assessment Questionnaire (HAQ) scores and other radiologic features of PsA documented at baseline and followup (median interval 5 years). RESULTS: Radiologic damage was present in 58% of patients at baseline and 74% at followup. The median MSS and its components, erosion score and joint space abnormality score, were significantly greater at followup (P < 0.001). The median MSS progression was +1.08 units/year. There was strong correlation between MSS and clinical joint scores at baseline and followup (r = 0.72 and r = 0.81, respectively). There was weak correlation between MSS and HAQ at baseline (r = 0.29), but stronger correlation at followup (r = 0.48). There was a strong association between MSS and other characteristic radiologic features of PsA (bony proliferation, periostitis, bony ankylosis) at baseline and followup (P < 0.001). However, the presence of soft-tissue swelling on radiographs at baseline was the only radiologic parameter associated with an increased rate of change of MSS (corrected P < 0.006). CONCLUSION: The MSS shows good construct validity with measures of peripheral joint involvement such as clinical joint scores and other radiologic features of PsA, and is able to demonstrate that radiologic damage is progressive beyond early disease. PMID- 20191496 TI - Mutuality's prospective beneficial effects on inflammation in female patients with rheumatoid arthritis. AB - OBJECTIVE: Supportive close relationships are important for health. Mutuality, the reciprocal sharing of thoughts and feelings in close relationships, is linked with better outcomes for patients with rheumatoid arthritis (RA) in cross sectional data. Hypothesizing that mutuality has a beneficial impact on inflammation, we tested potentially causal relations of couple mutuality with erythrocyte sedimentation rate (ESR) in prospective data. METHODS: Female patients with RA (n = 70; mean age 57 years, mean RA disease duration 5 years) completed questionnaires at baseline, 6 months, and 12 months, including measures of mutuality, RA flares, and negative affect. ESR laboratory values available near questionnaire dates were collected from medical charts. Using regression, we examined cross-lagged effects of mutuality and ESR over the two 6-month time spans (baseline to 6 months, 6 months to 12 months). We anticipated that mutuality would exert lagged inverse effects on subsequent ESR levels, and that ESR would have no effect on subsequent mutuality levels. RESULTS: After controlling for lagged effects of earlier inflammation, disease-modifying antirheumatic drugs, antiinflammatory drugs, RA flares, and negative affect, mutuality's lagged inverse effects over both time spans accounted for unique variance in subsequent levels of ESR, explaining 9% at 6 months and 12.5% at 12 months. Concomitantly, earlier ESR had no effect on subsequent mutuality. CONCLUSION: Patients with RA reporting more mutuality had less inflammation at subsequent time points, but inflammation had no effect on subsequent reports of mutuality. This suggests that mutuality exerts a beneficial effect on inflammation. Clinical implications and potential applications are discussed. PMID- 20191497 TI - Physician preference motivates the use of anti-tumor necrosis factor therapy independent of clinical disease activity. AB - OBJECTIVE: Physician preference has previously been shown to be an important determinant of prescription patterns, independent of patient-specific factors. We evaluated whether physician preference was important in the decision to select anti-tumor necrosis factor (anti-TNF) therapy rather than nonbiologic disease modifying antirheumatic drugs (DMARDs) among rheumatoid arthritis (RA) patients initiating a new RA medication. METHODS: Using data from the Consortium of Rheumatology Researchers of North America, we identified RA patients who had never taken biologics initiating either anti-TNF therapy or a DMARD in 2001-2008. Physician preference for the use of anti-TNF agents was calculated using data from the preceding calendar year for each physician's other RA patients. Multivariable logistic regression with generalized estimating equations accounted for clustering of patients within the physician practice and evaluated the relationship between physician preference and receipt of anti-TNF therapy, controlling for patient-related factors and disease activity using the Clinical Disease Activity Index. RESULTS: We identified 1,532 RA patients initiating anti TNF therapy or a DMARD. In models adjusting for tender and swollen joint counts and global disease activity, physician preference for the use of anti-TNF therapy was an independent predictor of receipt of these agents. Patients of physicians in the highest and middle tertiles of physician preference had a 2.50 (95% confidence interval [95% CI] 1.76-3.56) and 1.70 (95% CI 1.22-2.39) greater likelihood of receiving anti-TNF medications, respectively. CONCLUSION: Physician preference is an important determinant of patients' receipt of anti-TNF therapy and may be useful to examine in future studies of RA treatment patterns, costs, and medication safety. PMID- 20191498 TI - Evidence for predictive validity of remission on long-term outcome in rheumatoid arthritis: a systematic review. AB - OBJECTIVE: Remission is rapidly becoming a key end point in rheumatoid arthritis (RA) clinical trials, but its definition is not satisfactory. Although it is generally believed that achieving a state of remission will lead to better structural outcome, this has not been studied systematically. As part of an undertaking to redefine remission, the current review describes the relationship between remission and long-term structural outcome. METHODS: A systematic literature search of PubMed, EMBase, and The Cochrane Library intersected 3 groups of terms: RA, remission, and long-term outcome. The search identified 1,138 records, of which 14 were relevant to the research question. RESULTS: All of the studies included in this review showed a relationship between remission and long-term structural damage or disability. Patients that achieved a state of remission, defined in various ways, showed less deterioration of function and radiographic progression compared with patients who did not reach a state of remission. CONCLUSION: Patients who achieved a state of remission were less likely to show deterioration of function and radiographic progression compared with patients who did not reach a state of remission. PMID- 20191499 TI - Dehydroepiandrosterone (DHEA) substitution treatment for severe fatigue in DHEA deficient patients with primary Sjogren's syndrome. AB - OBJECTIVE: Primary Sjogren's syndrome (SS) is characterized by fatigue and low levels of serum dehydroepiandrosterone/dehydroepiandrosterone sulfate (DHEA/DHEAS). Our aim was to study whether SS patients with severe fatigue and low serum DHEAS values benefit from DHEA substitution (50 mg/day). METHODS: A multicenter, investigator-based, powered, randomized controlled clinical trial (crossover, washout design) using fatigue as the primary outcome measure was performed on patients with primary SS (n = 107) who had a general fatigue score > or =14 on the 20-item Multiple Fatigue Inventory (MFI-20), combined with age- and sex-adjusted serum DHEAS values below the mean. Fatigue was assessed using MFI-20 subscales, i.e., general fatigue, physical fatigue, mental fatigue, reduced motivation, and activity (scale 4-20), and with a visual analog scale (VAS; scale 0-100). RESULTS: In an intent-to-treat analysis, a 50-mg DHEA substitution dose and placebo similarly improved fatigue. All of the MFI-20 subscales and the fatigue VAS improved from the baseline levels as a result of treatment (P < 0.001), but with negligible differences between these 2 treatments. The mean between-treatment difference was -0.1 for general fatigue (the primary outcome measure), 0.0 for physical fatigue, 0.0 for mental fatigue, 0.0 for reduced motivation, 0.3 for reduced activity, and 2.2 for the fatigue VAS. None of these differences was statistically significant. CONCLUSION: Similar to earlier results using pharmacologic doses, substitution treatment with 50 mg of DHEA in DHEA deficient and severely tired primary SS patients does not help against fatigue better than placebo. This may relate to the prohormone nature of DHEA and its recently described defective intracrine tissue-specific conversion to active sex steroids in SS. PMID- 20191500 TI - Are tall people at higher risk of low back pain surgery? A discussion on the results of a multipurpose cohort. AB - OBJECTIVE: To investigate whether height is associated with low back pain (LBP) and surgery, taking into account personal and socioeconomic risk factors in a general population. METHODS: In 2001, 13,680 participants of the Gazel cohort completed a self-reported questionnaire on LBP and surgery interventions. Three groups were compared according to their body height: no LBP (reference group, participants who declared they never had LBP), LBP without surgery (participants who ever had LBP but without surgery), and back surgery (participants who ever had surgery for LBP). Adjusted variables were sex, age, educational level, marital status, height, and body mass index. RESULTS: Mean height was significantly higher in men in the back surgery group than in the reference group and the LBP group. The proportion of surgically-treated LBP was higher for people whose height was > or =4th quartile (P < 0.0001). Being in the highest quartile for height was a stronger risk factor for surgery (adjusted odds ratio [OR(adj)] = 2.01, 95% confidence interval [95% CI] 1.61-2.51) than for LBP without surgery (OR(adj) = 1.29, 95% CI 1.18-1.40). CONCLUSION: The results suggest that being tall is a predictor for back surgery. PMID- 20191502 TI - A 36-year-old woman with recurrent high-grade fevers, hypotension, and hypertriglyceridemia. PMID- 20191503 TI - Ultrasound of metatarsophalangeal joints in an early inflammatory arthritis cohort: comment on the article by Sheane et al. PMID- 20191504 TI - Value of assessing the fifth metatarsophalangeal joint in patients with early rheumatoid arthritis: comment on the article by Sheane et al. PMID- 20191506 TI - Efficacy of Tai Chi for chronic musculoskeletal pain conditions: is the evidence ready for meta-analysis? Comment on the article by Hall et al. PMID- 20191507 TI - Measures of psychological distress in patients with arthritis: comment on the article by Fuller-Thomson and Shaked. PMID- 20191511 TI - Pregnancy outcomes in women with familial Mediterranean fever receiving colchicine: is amniocentesis justified? AB - OBJECTIVE: To evaluate the outcome of pregnancies in women with familial Mediterranean fever (FMF) who are taking colchicine, and to reconsider the justification for amniocentesis in these women. METHODS: The outcome of 179 pregnancies in a group of women with FMF taking colchicine was compared with the outcome of 197 pregnancies in women with FMF who did not take colchicine during pregnancy and with 312 pregnancies in another cohort of healthy pregnant women of similar age and ethnicity. RESULTS: There was no difference in the 3 groups regarding early abortions, late abortions, or congenital malformations. There was a mild trend towards a better outcome for the colchicine-treated group but these results did not reach statistical significance. CONCLUSION: Treatment with colchicine during pregnancy in patients with FMF is beneficial in controlling the disease while not affecting the outcome of the pregnancy; therefore there is no justification for recommending amniocentesis in women taking colchicine solely because of this treatment. PMID- 20191512 TI - Malignancy risk in patients with giant cell arteritis: a population-based cohort study. AB - OBJECTIVE: To determine the incidence of cancer in a population-based cohort of patients with giant cell arteritis (GCA) compared with age- and sex-matched referent subjects. METHODS: Using the resources of the Rochester Epidemiology Project, all incident cases of GCA diagnosed between January 1, 1950 and December 31, 2004 were identified. For each GCA patient, 2 subjects without GCA of the same sex and similar age and length of medical history were selected. Diagnosis of malignancy was made by histopathology. Patients were followed until death, last contact, or December 31, 2006. RESULTS: Our study included 204 GCA patients and 407 non-GCA subjects. The GCA cohort had 163 (79%) women and 41 (21%) men, a mean +/- SD age of 76.0 +/- 8.2 years, and a median followup of 7.7 years. The non-GCA cohort consisted of 325 (80%) women and 82 (20%) men, a mean +/- SD age of 75.6 +/- 8.4 years, and a median followup of 8.1 years. During followup, 46 GCA patients and 76 non-GCA subjects developed cancer (hazard ratio [HR] 1.26, 95% confidence interval [95% CI] 0.87-1.83). Adjustment for smoking did not alter the results. The 1-, 10-, and 20-year cumulative incidences of any malignancy were 5.9%, 33.6%, and 50.0% among GCA patients and 2.6%, 27.0%, and 47.0% among non-GCA patients, respectively. There were no differences in hematologic or solid malignancies between both groups. Colon cancer appeared more commonly in the GCA group (P = 0.07). Mortality following cancer was similar in both cohorts (HR 0.80, 95% CI 0.52-1.24). CONCLUSION: GCA patients are not at an increased risk of first cancer after diagnosis. PMID- 20191513 TI - Self-directed learning of basic musculoskeletal ultrasound among rheumatologists in the United States. AB - OBJECTIVE: Because musculoskeletal ultrasound (MSUS) is highly user dependent, we aimed to establish whether non-mentored learning of MSUS is sufficient to achieve the same level of diagnostic accuracy and scanning reliability as has been achieved by rheumatologists recognized as international experts in MSUS. METHODS: A group of 8 rheumatologists with more experience in MSUS and 8 rheumatologists with less experience in MSUS participated in an MSUS exercise to assess patients with musculoskeletal abnormalities commonly seen in a rheumatology practice. Patients' established diagnoses were obtained from chart review (gout, osteoarthritis, rotator cuff syndrome, rheumatoid arthritis, and seronegative arthritis). Two examining groups were formed, each composed of 4 less experienced and 4 more experienced examiners. Each group scanned 1 predefined body region (hand, wrist, elbow, shoulder, knee, or ankle) in each of 8 patients, blinded to medical history and physical examination. Structural abnormalities were noted with dichotomous answers, and an open-ended answer was used for the final diagnosis. RESULTS: Less experienced and more experienced examiners achieved the same diagnostic accuracy (US-established diagnosis versus chart review diagnosis). The interrater reliability for tissue pathology was slightly higher for more experienced versus less experienced examiners (kappa = 0.43 versus kappa = 0.34; P = 0.001). CONCLUSION: Non-mentored training in MSUS can lead to the achievement of diagnostic accuracy in MSUS comparable to that achieved by highly experienced international experts. Reliability may increase slightly with additional experience. Further study is needed to determine the minimal training requirement to achieve proficiency in MSUS. PMID- 20191514 TI - Health care utilization for musculoskeletal disorders. AB - OBJECTIVE: To examine patterns of ambulatory care and hospital utilization for people with musculoskeletal disorders (MSDs), including arthritis and related conditions, bone and spinal conditions, trauma and related conditions, and unspecified MSDs. METHODS: Administrative data from the Ontario Health Insurance Plan database for ambulatory care physician visits, the National Ambulatory Care Reporting System database for day (outpatient) surgeries and emergency department visits, and the Discharge Abstract Database for hospital discharges were used to examine health care utilization for MSDs in fiscal year 2006-2007. Person visit rates (number of people with physician visits or hospital encounters per population) were calculated. RESULTS: Overall, 22.3% of Ontario's population (2.8 million persons) saw a physician for an MSD in ambulatory settings. Person visit rates were highest for arthritis and related conditions (107.7 per 1,000 population), followed by trauma and related conditions (89.6 per 1,000 population), unspecified MSDs (71.0 per 1,000 population), and bone and spinal conditions (62.4 per 1,000 population). The majority of visits were to primary care physicians, with 83.2% of those with visits for all MSDs seeing a primary care physician at least once. Overall, 33.0% of people with a physician visit for an MSD saw a specialist, with orthopedic surgeons being the most commonly consulted type of specialist. In hospital settings, person visit rates for MSDs were highest in the emergency department, followed by day surgeries and inpatient hospitalizations. CONCLUSION: The findings of our study highlight the magnitude of health care utilization for MSDs and the central role of primary care physicians in the management of these conditions. PMID- 20191516 TI - RAPID3 (Routine Assessment of Patient Index Data) on an MDHAQ (Multidimensional Health Assessment Questionnaire): agreement with DAS28 (Disease Activity Score) and CDAI (Clinical Disease Activity Index) activity categories, scored in five versus more than ninety seconds. AB - OBJECTIVE: To compare the Routine Assessment of Patient Index Data 3 (RAPID3) on a Multidimensional Health Assessment Questionnaire (MDHAQ) with the Disease Activity Score (DAS28), Clinical Disease Activity Index (CDAI), and individual core data set measures for correlations, agreement of activity levels, and time to score. METHODS: Four rheumatologists each assessed 50 patients with rheumatoid arthritis in "real-time" clinical care. Patients completed an MDHAQ. The rheumatologist then calculated RAPID3 (physical function, pain, patient global estimate), performed a 28-joint count, assigned a physician global estimate, and scored a CDAI, each timed by an observer. Erythrocyte sedimentation rate (ESR) was tested on the same date, and the DAS28-ESR was computed later, again timed by an observer. Spearman's rank-order correlations and comparisons of patients classified as high activity, moderate activity, low activity, and remission according to the DAS28, CDAI, and RAPID3 were computed and compared with kappa statistics. A second study of 25 "paper patients" was also performed to compare time to score the DAS28, CDAI, and RAPID3 on a 0-10 versus 0-30 scale. Mean and median times to score each index were computed. RESULTS: The 3 indices were correlated significantly, including agreement for >80% of patients for high/moderate activity. The mean time to perform a 28-joint count was 94 seconds, and the mean times to score the DAS28, CDAI, RAPID3 on a 0-10 scale, and RAPID3 on a 0-30 scale were 114, 106, 9.6, and 4.6 seconds, respectively. CONCLUSION: RAPID3 scores provide similar quantitative information to DAS28 and CDAI, while calculated on a 0-30 scale in about 5% of the time. PMID- 20191515 TI - Hyperuricemia and coronary heart disease: a systematic review and meta-analysis. AB - OBJECTIVE: The role of serum uric acid as an independent risk factor for cardiovascular disease remains unclear, although hyperuricemia is associated with cardiovascular disease such as coronary heart disease (CHD), stroke, and hypertension. METHODS: A systematic review and meta-analysis using a random effects model was conducted to determine the risk of CHD associated with hyperuricemia in adults. Studies of hyperuricemia and CHD were identified by searching major electronic databases using the medical subject headings and keywords without language restriction (through February 2009). Only prospective cohort studies were included if they had data on CHD incidences or mortalities related to serum uric acid levels in adults. RESULTS: Twenty-six eligible studies of 402,997 adults were identified. Hyperuricemia was associated with an increased risk of CHD incidence (unadjusted risk ratio [RR] 1.34, 95% confidence interval [95% CI] 1.19-1.49) and mortality (unadjusted RR 1.46, 95% CI 1.20-1.73). When adjusted for potential confounding, the pooled RR was 1.09 (95% CI 1.03-1.16) for CHD incidence and 1.16 (95% CI 1.01-1.30) for CHD mortality. For each increase of 1 mg/dl in uric acid level, the pooled multivariate RR for CHD mortality was 1.12 (95% CI 1.05-1.19). Subgroup analyses showed no significant association between hyperuricemia and CHD incidence/mortality in men, but an increased risk for CHD mortality in women (RR 1.67, 95% CI 1.30-2.04). CONCLUSION: Hyperuricemia may marginally increase the risk of CHD events, independently of traditional CHD risk factors. A more pronounced increased risk for CHD mortality in women should be investigated in future research. PMID- 20191517 TI - Characterization of individual radiographic features of hip osteoarthritis in African American and White women and men: the Johnston County Osteoarthritis Project. AB - OBJECTIVE: To describe differences in radiographic features of hip osteoarthritis (OA) between African American and white men and women. METHODS: We conducted a cross-sectional analysis of radiographic hip OA using baseline data from the Johnston County Osteoarthritis Project, using Kellgren/Lawrence (K/L) grade, and the presence, location, and severity of 4 individual radiographic features (joint space narrowing [JSN], subchondral cysts, sclerosis, and osteophytes). Sex specific logistic regression was used to evaluate associations between race and individual radiographic features, adjusting for age, body mass index, education, and prior hip injury. Robust variance estimators via generalized estimating equations were used to account for correlation between hips from the same individual. RESULTS: The sample (n = 2,739) comprised 57% women and 31% African American participants. Among women, African Americans and whites had a similar prevalence of hip OA, defined as K/L grade > or =2 (23% versus 22%), but African American women were significantly more likely to have superior or medial JSN, moderate or severe axial JSN, medial or lateral osteophytes, and subchondral cysts. Among men, 21% of African Americans and 17% of whites had hip OA; African American men were more likely to have superior or medial JSN and lateral osteophytes, but were less likely to have axial JSN. CONCLUSION: Individual radiographic features and patterns of hip OA differed by race among women and men, suggesting the possibility of anatomic and/or developmental variation in the hip joint. African Americans have an increased frequency of features that have been predictive of hip replacement in other populations, a finding worthy of further study. PMID- 20191518 TI - Within-subregion relationship between bone marrow lesions and subsequent cartilage loss in knee osteoarthritis. AB - OBJECTIVE: Bone marrow lesions are believed to increase risk of knee osteoarthritis (OA) progression. Whether their effect is local and whether it can be explained by other types of bone lesions concomitantly present in the same subregion is unclear. We evaluated bone lesion frequency in subregions without cartilage lesions and cartilage lesion frequency in subregions without bone lesions, and investigated the within-subregion bone marrow lesion/subsequent cartilage loss relationship after adjusting for other types of bone lesions at baseline. METHODS: Individuals with knee OA had magnetic resonance imaging at baseline and 2 years later. Cartilage integrity and bone marrow lesions, cysts, and attrition were scored within tibiofemoral subregions. Logistic regression, with generalized estimating equations to account for correlation among multiple subregions within a knee, was used to estimate odds ratios (ORs) for cartilage loss associated with bone marrow lesions, adjusting for age, sex, body mass index, and bone attrition and cysts in the same subregion. RESULTS: Analyzing 1,953 subregions among 177 knees, 90% of subregions had no bone lesions at baseline. Only 0-3% of subregions without cartilage lesions had bone lesions in the same subregion; in contrast, 5-33% of subregions without bone lesions had cartilage lesions. Bone marrow lesions at baseline were associated with cartilage loss in the same subregion at 2 years, adjusting for other types of bone lesions at baseline (adjusted OR 3.74, 95% confidence interval 1.59-8.82). CONCLUSION: In subjects with knee OA, bone marrow lesions were rare at early disease stages but predicted subregional cartilage loss after accounting for the presence of other types of bone lesions in the same subregion. PMID- 20191519 TI - Clinical course and prognostic value of disease activity in the first two years in different subtypes of juvenile idiopathic arthritis. AB - OBJECTIVE: Juvenile idiopathic arthritis (JIA) is a heterogeneous disease involving chronic arthritis. The clinical course is characterized by a fluctuating pattern of active and inactive disease. We have described in detail the clinical course in different JIA subtypes during the first 2 years after diagnosis and studied its relationship to disease activity in the following years. METHODS: Detailed clinical data on different parameters describing the disease activity in sequential time periods covering the first 2 years after diagnosis were retrieved from the charts of 311 patients with JIA and compared between subtypes. In a cohort of 146 patients, the relation of these different clinical variables to the course of disease in the following 3 years was evaluated. RESULTS: The percentage of time with active disease in the first 2 years differed significantly between subtypes. In all subtypes, a broad spectrum of activity was observed. The time with active disease in the first 2 years was the most significant factor associated with the duration of active disease in the following years. CONCLUSION: Different percentages of time with active disease have been observed between JIA subtypes in the first 2 years. The cumulative duration of activity varied widely within each subtype. Regarding the prognosis of the individual patient, the clinical course in the first 2 years appears to be predictive of the clinical course in the following years. Patients that have less time with active disease in the first 2 years are not likely to develop an unremitting clinical course later on. PMID- 20191520 TI - Incidence of childhood linear scleroderma and systemic sclerosis in the UK and Ireland. AB - OBJECTIVE: Childhood scleroderma encompasses a rare, poorly understood spectrum of conditions. Our aim was to ascertain the incidence of childhood scleroderma in its different forms in the UK and Ireland, and to describe the age, sex, and ethnicity of the cases. METHODS: The members of 5 specialist medical associations including pediatricians, dermatologists, and rheumatologists were asked to report all cases of abnormal skin thickening suspected to be localized (including linear) scleroderma or systemic sclerosis (SSc) in children <16 years of age first seen between July 2005 and July 2007. RESULTS: We received notification of 185 potential cases, and 94 valid cases were confirmed: 87 (93%) with localized scleroderma and 7 (7%) with SSc. This gave an incidence rate per million children per year of 3.4 (95% confidence interval [95% CI] 2.7-4.1) for localized scleroderma, including an incidence rate of 2.5 (95% CI 1.8-3.1) for linear scleroderma, and 0.27 (95% CI 0.1-0.5) for SSc. Of the 87 localized cases, 62 (71%) had linear disease. Of localized disease cases, 55 (63%) were female, 71 (82%) were classified as white British, and the patients' mean age when first seen in secondary care was 10.4 years. Of the 7 SSc cases, all were female, 6 (86%) were white British, and the mean age when first seen was 12.1 years. The median delay between onset and being first seen was 13.1 months for localized scleroderma and 7.2 months for SSc. CONCLUSION: These data provide additional estimates of the incidence of this rare disorder and its subforms. PMID- 20191521 TI - Protocols for the initial treatment of moderately severe juvenile dermatomyositis: results of a Children's Arthritis and Rheumatology Research Alliance Consensus Conference. AB - OBJECTIVE: To use juvenile dermatomyositis (DM) survey data and expert opinion to develop a small number of consensus treatment protocols, which reflect current initial treatment of moderately severe juvenile DM. METHODS: A consensus meeting was held in Toronto, Ontario, Canada on December 1-2, 2007. Nominal group technique was used to achieve consensus on treatment protocols, which represented typical management of moderately severe juvenile DM. Consensus was also reached as to which patients these protocols would be applicable (inclusion and exclusion criteria), which initial investigations should be done prior to initiating one of these protocols, which data should be collected to evaluate these protocols, and the concomitant interventions required or recommended. RESULTS: Three protocols that described the first 2 months of treatment were developed. All protocols included corticosteroids and methotrexate. One protocol also included intravenous gamma globulin. Consensus was achieved for all issues that were addressed by conference participants, although there were some areas of controversy. CONCLUSION: Despite considerable variation in clinical practice, it is possible to achieve consensus on the initial treatment of juvenile DM. Once these protocols are extended beyond 2 months, these protocols will be available for clinical use. By using methods that account for differences between patients (confounding by indication), the comparative effectiveness of the protocols will be evaluated. In the future, the goal will be to identify the optimal treatment of moderately severe juvenile DM. PMID- 20191522 TI - Improvement in work place and household productivity for patients with early rheumatoid arthritis treated with adalimumab plus methotrexate: work outcomes and their correlations with clinical and radiographic measures from a randomized controlled trial companion study. AB - OBJECTIVE: To evaluate household and work place outcomes for patients with rheumatoid arthritis (RA) who were homemakers or employed workers, respectively, and who were treated with adalimumab plus methotrexate versus methotrexate monotherapy. We also determined baseline predictors of household and work place outcomes. METHODS: Data were from a health economic companion study to PREMIER, a 2-year, randomized controlled trial of methotrexate-naive patients with early RA (<3 years) who received treatment with adalimumab plus methotrexate, adalimumab, or methotrexate. Absenteeism (number of days missed or unfit to work), presenteeism (self-judgment of the effects of RA on job or household performance), and employment status were collected from self-reports at baseline and varying time points during the study. RESULTS: Household and work place outcomes were generally similar for homemakers and employed workers. Over 2 years, patients who received combination therapy missed approximately half as many days as patients who received methotrexate (17.4 versus 36.9 days for employed workers; 7.9 versus 18.6 days for homemakers). Presenteeism was lower (reflecting better productivity) for combination therapy than methotrexate monotherapy. The likelihood of gaining/retaining employment over 2 years was greater for combination therapy than methotrexate monotherapy (odds ratio 1.530, 95% confidence interval 1.038-2.255; P = 0.0318). Baseline radiographic progression was an independent predictor for retaining/gaining employment at 2 years. CONCLUSION: Compared with methotrexate monotherapy, combination therapy was associated with more positive work outcomes: less absenteeism, less presenteeism, and greater likelihood of gaining/retaining employment. Radiographic progression at baseline was predictive of the ability to retain or gain employment. PMID- 20191523 TI - Validity of self-reported rheumatoid arthritis in a large cohort: results from the Black Women's Health Study. AB - OBJECTIVE: To evaluate the positive predictive value (PPV) of 3 case definitions of rheumatoid arthritis (RA) based on self-reported data on RA diagnosis and use of arthritis medications, and to determine whether a validated screening survey would increase the PPVs in the 3 groups. METHODS: Medical records and physician checklists were reviewed for confirmation of an RA diagnosis among a sample of Black Women's Health Study participants who reported incident RA and were categorized according to reported medications: disease-modifying antirheumatic drugs (DMARDs) (n = 102), nonsteroidal antiinflammatory drugs (NSAIDs) (n = 100), and no arthritis medications (no meds) (n = 101). PPVs for confirmed RA were calculated for each of the medication groups, both overall and according to the results of the screening survey. RESULTS: The PPVs of confirmed RA were 76%, 61%, and 29% in the DMARDs, NSAIDs, and no meds groups, respectively. After exclusion of women who reported other rheumatic conditions or who reported taking only prednisone, the PPV increased in the DMARDs group to 88%, but little improvement was seen in the other groups. The PPVs increased somewhat according to results of the screening survey for the DMARDs group (92% for positive screen versus 85% for negative screen; P = 1.00), and increased substantially for the NSAIDs group (89% versus 38%, respectively; P = 0.03), but only 43% of participants completed the survey. CONCLUSION: We found that self-report of RA, along with self-reported DMARDs, is a useful case definition for identifying confirmed RA. The validated screening survey could be useful for identifying cases of confirmed RA in some, but not all, medication groups. PMID- 20191524 TI - Association between computer use speed and age, impairments in function, and touch typing training in people with rheumatoid arthritis. AB - OBJECTIVE: To explore the associations between impairments in hand function associated with rheumatoid arthritis (RA) and limitations in computer peripheral use. METHODS: A total of 45 computer users with RA were recruited from the Arthritis Network Research Registry. Impairments in hand function were measured using the Keitel Hand Function Index, and the Arthritis Hand Function Test, while general activity limitations were measured with the Health Assessment Questionnaire. Speed of computer peripheral device use was obtained at a laboratory work station using the Assessment of Computer Task Performance (ACTP). RESULTS: Multiple regression models suggested that keyboarding speed was significantly associated with touch typing training and age, while mouse speed was significantly associated with age. Impairments in hand function were significantly associated with only 2 of 7 keyboarding tasks and no mouse tasks. General activity limitations were associated with 2 of 7 keyboarding tasks and 2 of 5 significant mouse tasks. A comparison of this study's sample with a normative sample reported for the ACTP suggested that this sample's keyboarding speed was similar to a nonimpaired sample, while mouse speed was much slower. CONCLUSION: Reduced keyboarding speed is most strongly associated with touch typing skill. General activity limitations appear to be the strongest arthritis related predictor of decreased computer use speeds. Many computer users with RA will not experience reduced productivity in typing speeds, although many may be slower than their nonimpaired counterparts for mouse use. PMID- 20191525 TI - Diagnostic delay in sternocostoclavicular hyperostosis: impact on various aspects of quality of life. AB - OBJECTIVE: Sternocostoclavicular hyperostosis (SCCH) is a rare, debilitating, chronic inflammatory disorder of the anterior chest wall due to a chronic sterile osteomyelitis of unknown origin, often associated with characteristic skin lesions of palms and soles: pustulosis palmoplantaris. SCCH goes often unrecognized for years before the diagnosis is established and treatment instituted. The objective of this study was to trace the diagnostic paths of patients with SCCH and to investigate the consequences associated with diagnostic delay. METHODS: Data were collected through structured interviews of 52 patients with a clinically, scintigraphically, and radiologically established diagnosis of SCCH. RESULTS: The majority of patients presented with swelling and/or pain in the sternocostoclavicular region and/or limited movement of the shoulder girdle. Pustulosis palmoplantaris was present in approximately 30% of patients. The disease went unrecognized for a median of 3.5 years. Patients were often seen by at least 3 members of the medical profession before the diagnosis was suspected and eventually established. Lack of recognition of the clinical manifestations of the disease and delay in diagnosis were associated with important physical, psychological, and socioeconomic consequences affecting quality of life. CONCLUSION: SCCH remains an ill-recognized disease despite its characteristic clinical features. A low level of awareness of the disorder leads to a delay in diagnosis, which has a significant impact on various aspects of quality of life. Awareness should be raised for this disorder, enabling timely diagnosis and initiation of treatment to prevent the irreversible physical and psychological sequelae associated with the protracted untreated state. PMID- 20191526 TI - Low physical activity is associated with proinflammatory high-density lipoprotein and increased subclinical atherosclerosis in women with systemic lupus erythematosus. AB - OBJECTIVE: To investigate the association between physical activity, functional activity of high-density lipoprotein (HDL), and subclinical cardiovascular disease in patients with systemic lupus erythematosus (SLE). METHODS: A total of 242 SLE patients (all women) participated in this cross-sectional study from February 2004 to February 2008. Carotid plaque and intima-media thickness (IMT), antioxidant function of HDL, and traditional cardiac risk factors were measured. Physical activity was assessed from self-reports by calculating the metabolic equivalents (METS) per week and by the physical function domain of the Medical Outcomes Study Short Form 36 (SF-36). Data were analyzed using bivariate and multivariate regression analyses. RESULTS: Number of METS per week spent performing strenuous exercise was negatively correlated with IMT (r = -0.4, P = 0.002) and number of plaques (r = -0.30, P = 0.0001). Physical function as assessed by the SF-36 was also negatively correlated with IMT (r = -0.14, P = 0.03) and number of plaques (r = -0.14, P = 0.04). In multivariate analyses, number of strenuous exercise METS was significantly associated with IMT (t = 2.2, P = 0.028) and number of plaques (t = -2.5, P = 0.014) when controlling for markers of SLE disease activity and damage, but not after controlling for traditional cardiac risk factors. Low physical activity, defined as <225 total METS per week, was associated with the presence of proinflammatory HDL (P = 0.03). CONCLUSION: Low physical activity is associated with increased subclinical atherosclerosis and proinflammatory HDL in patients with SLE. Increased strenuous exercise may reduce the risk of atherosclerosis in SLE. PMID- 20191527 TI - Impact of systemic lupus erythematosus on health, family, and work: the patient perspective. AB - OBJECTIVE: Qualitative research among patients with systemic lupus erythematosus (SLE) can identify aspects of the disease relevant to clinical research and practice. A phenomenological, mixed-method approach was used to investigate these disease-driven health issues. METHODS: A convenience sample of patients with SLE from Los Angeles County, California was recruited from a private, community-based rheumatology practice for participation in focus groups and interviews. Semistructured discussions explored disease manifestations and impact. A self administered questionnaire evaluated the occurrence and importance of disease issues previously identified from literature. Patient health issues were identified through convergence using 1) qualitative analysis of focus group transcripts and 2) quantitative analysis of the questionnaire. Patients were also asked about their ability to accurately recall disease experiences. RESULTS: Focus group participants (n = 23) had a mean age of 43 years and a mean disease duration of 8 years; 19 (83%) were women and 14 (61%) were white. The most frequent health issues identified by focus group transcript analysis were pain (83%), fatigue (61%), work or school impairment (48%), skin manifestations (43%), and skin sensitivity (43%). Questionnaire findings were similar: the most frequent health issues were inability to do previous activities (87%), fatigue (87%), pain (87%), and work or school impairment (83%). Most interviewed patients (7 of 10) reported an ability to accurately recall disease issues between 24 hours and 7 days. CONCLUSION: SLE patients reported signs and symptoms that could significantly impact their functioning in daily life. Treatments that substantially improve these disease manifestations would offer considerable benefit to patients, treating physicians, and general society. PMID- 20191528 TI - Responsiveness of self-report and therapist-rated upper extremity structural impairment and functional outcome measures in early rheumatoid arthritis. AB - OBJECTIVE: To provide a responsiveness analysis of the self-report and therapist rated upper extremity functional outcome measures used in a rehabilitation trial. METHODS: A variety of commonly used therapist-assessed and self-report structural impairment and functional outcome measures were compared for the ability to detect and measure change in wrist and hand status in an early rheumatoid arthritis population over 12 months. Responsiveness was measured using the standardized response mean (SRM) and effect size (ES). RESULTS: The most responsive measures were the Michigan Hand Outcomes Questionnaire (SRM 0.49 [95% confidence interval (95% CI) 0.27, 0.72], ES = 0.37 [95% CI 0.21, 0.54]), dominant metacarpophalangeal joint ulnar deviation (SRM 0.46 [95% CI 0.27, 0.65], ES = 0.58 [95% CI 0.34, 0.82]), and mean power handgrip test (SRM 0.45 [95% CI 0.26, 0.64], ES = 0.32 [95% CI 0.18, 0.45]) The least responsive measure was the Health Assessment Questionnaire (SRM -0.12 [95% CI -0.31, 0.08], ES = -0.08 [95% CI -0.21, 0.05]). CONCLUSION: Over 12 months, there was substantial variation in wrist and hand outcome measures to detect change over time in an early RA population. Careful consideration is required to choose the most appropriate measure that can detect change. PMID- 20191529 TI - Incidence of chronic cutaneous lupus erythematosus in French Guiana: a retrospective population-based study. AB - OBJECTIVE: To retrospectively study the incidence of chronic cutaneous lupus erythematosus (CCLE) in French Guiana (FG), South America, during the period 1995 1999. METHODS: Private and public physicians specializing in dermatology, rheumatology, and internal medicine were asked during the year 2000 about lupus cases. We reviewed hospitals' files in data-processing departments. RESULTS: Twenty new cases of CCLE, mostly discoid form, were identified during this 5-year period in this population of predominantly African descent. The average annual incidence of the disease was 2.59 per 100,000 inhabitants (95% confidence interval 1.5-4). However, our methodology could introduce underestimation of the incidence of the disease. CONCLUSION: The average annual incidence of CCLE in FG appears to be low in this retrospective study, but is very similar to the only previously published data in the US. PMID- 20191530 TI - A 29-year-old woman with headache, fever, right leg numbness, and dysphagia. PMID- 20191533 TI - Efficacy of intraarticular infliximab administration in patients with recurrent gonarthritis: comment on the article by van der Bijl et al. PMID- 20191535 TI - Fear of recurrence: a case report of a woman breast cancer survivor with GAD treated successfully by CBT. AB - General anxiety disorder (GAD) characterized by persistent, excessive and unrealistic worry about everyday things can affect everybody, including cancer patient survivor.In this paper, we present a case report of a breast cancer survivor with GAD treated by cognitive-behavioural therapy (CBT), who was excessively worried about recurrence of the disease 2 years after the end of any treatment. Cognitive reframing, associated to behavioural exposure and relaxation, were used in order to treat this woman. We describe precisely how the therapy was conducted. Results showed a substantial improvement of the fear of recurrence which 'naturally' extended to other stressful situations not worked during the therapy. Actually, these results are encouraging since it showed that CBT can be efficient in complicated situation involving survivor of a serious disease like cancer who additionally suffers from an anxiety disorder. It also underlines how it is important to be concerned by the distress of cancer survivors. PMID- 20191536 TI - How do social firms contribute to recovery from mental illness? A qualitative study. AB - BACKGROUND: A definition of recovery drawn from qualitative literature and the 'consumer/survivor' movement suggests that recovery should be seen as a way of developing satisfaction and purpose in life, whether or not symptoms of mental illness are present. A qualitative review suggested that meaningful activity may facilitate recovery by providing a sense of purpose in life. Social firms may be well placed to offer this activity due to their ethos of empowerment, their community integration and their similarity to 'recovery-oriented services'. AIMS: The aim of this study was to explore experiences of recovery from mental illness in the context of two emerging social firms. METHOD: A social constructionist version of grounded theory was used to develop a model of recovery through participation in the emerging social firms. Multiple coding, triangulation and respondent validation were used to increase the rigour of study findings. FINDINGS: A model of recovery in the context of the emerging social firms was constructed. This was influenced by characteristics such as a flexible structure, a meaningful and diverse activity, an accepting social group and an inclusive leadership. CONCLUSION: Social firms may provide an important model for 'recovery oriented services'. Clinical, research and policy implications of findings are discussed. PMID- 20191538 TI - Advances in the theory and application of MEEKC. AB - MEEKC is an electrodriven separation technique, which utilises the unique properties of a microemulsion (ME) as a background electrolyte to achieve separation of a diverse range of solutes. MEs are composed of nanometre-sized oil droplets suspended in aqueous buffer, which is commonly referred to as an oil-in water ME. The droplets are stabilised by the presence of a surfactant and co surfactant. The use of water-in-oil MEs in MEEKC has also been investigated. This review details the advances in MEEKC-based separations from the period 2008 to 2009. Areas covered include online sample concentration, suppressed electroosmosis MEEKC, chiral separation, MEEKC-MS, and structure-migration relationships. The review also includes a fundamental introduction to MEEKC, along with the presentation of recent applications. PMID- 20191540 TI - Fundamentals of electrophoresis. PMID- 20191541 TI - Dynamic computer simulations of electrophoresis: a versatile research and teaching tool. AB - Software is available, which simulates all basic electrophoretic systems, including moving boundary electrophoresis, zone electrophoresis, ITP, IEF and EKC, and their combinations under almost exactly the same conditions used in the laboratory. These dynamic models are based upon equations derived from the transport concepts such as electromigration, diffusion, electroosmosis and imposed hydrodynamic buffer flow that are applied to user-specified initial distributions of analytes and electrolytes. They are able to predict the evolution of electrolyte systems together with associated properties such as pH and conductivity profiles and are as such the most versatile tool to explore the fundamentals of electrokinetic separations and analyses. In addition to revealing the detailed mechanisms of fundamental phenomena that occur in electrophoretic separations, dynamic simulations are useful for educational purposes. This review includes a list of current high-resolution simulators, information on how a simulation is performed, simulation examples for zone electrophoresis, ITP, IEF and EKC and a comprehensive discussion of the applications and achievements. PMID- 20191542 TI - Electric field-enhanced transport across phase boundaries and membranes and its potential use in sample pretreatment for bioanalysis. AB - Separation techniques, such as electrodialysis, electroextraction, electro membrane extraction and extraction across phase interfaces, are reviewed and discussed as methods for sample cleanup and preconcentration. This survey clearly shows that electromigration of ionic species across phase interfaces, especially across supported liquid membranes, may be very selective and is strongly dependent on the chemical composition of these interfaces. Thus, electric field enhanced transport across chemically tailored liquid membranes may open new perspectives in preparative analytical chemistry. This review offers comprehensive survey of related literature and discussion of the topic, which may stimulate interest of experts and practitioners in bioanalysis. PMID- 20191543 TI - Investigation of the stereodynamics of molecules and catalyzed reactions by CE. AB - The investigation of the molecular dynamics of stereoisomers and the study of the kinetics of reactions, in particular of catalyzed reactions, is of fundamental interest in chemistry, biochemistry, and medicine. Understanding how to control the transition state of a reaction allows for a directed design of new catalysts and benign processes. The integration of reactions and capillary or microchip based electrophoretic separations is highly attractive to perform on-column derivatizations or enzymatic on-column digests of peptides and proteins for further characterization. The present review article focuses on the recent advances to study the stereodynamics of molecules and reaction kinetics of catalyzed processes by means of CE. Models and algorithms to evaluate interconversion profiles obtained by electrophoretic separation techniques are discussed with respect to the challenging demands of high separation efficiencies typical for electrophoretic techniques. Models used for evaluation are based on iterative computer simulation algorithms using the theoretical plate model or stochastic model of chromatography, empirical calculation methods, derived from equations used in chemical engineering, namely Damkohler analysis, and direct access with the approximation function and more recently with the unified equation, which can be applied to all kinds of first-order reactions taking place during a chromatographic or a electrophoretic separation. Furthermore, areas of applications are presented and discussed to give a guideline for using dynamic CE and on-column reaction electrophoresis to study kinetics of reactions and dynamic processes. PMID- 20191544 TI - Characterization of nanoparticles by capillary electromigration separation techniques. AB - Considering the large number of papers presented in the last years in the field of CE and plate gel electrophoresis (PGE) of nanoparticles and nanoparticle biomolecule conjugates, this review article gives an overview on the application of capillary electromigration separation techniques for the separation of nanoparticles and nanoparticle-biomolecule conjugates according to differences in size and/or zeta potential and for the determination of several physicochemical parameters characterizing a population of nanoparticles. A brief introduction is given into the theoretical background of the size-selective electrophoretic separation of nanospheres in free-solution and sieving media including involvement of interparticle interactions. Some aspects of colloidal system stability are discussed. Applications of capillary electromigration techniques in the field of size-selective and/or surface charge density-selective separation of nanoparticles and nanoparticle-biomolecule conjugates are described, including free-solution CE, CGE, IEF, and ITP, complemented by an overview on the application of (semipreparative) PGE in the field of nanotechnology and nanobiotechnology. The review also includes actual developments regarding the coupling of capillary electromigration techniques to (wavelength-resolved) LIF and other selective detection methods and studies concerning individual-particle CE. PMID- 20191545 TI - Optimization of charged species separation by autogenous electric field-flow fractionation in nano-scale channels. AB - Numerical methods are employed to examine the resolution and optimization of a relatively new technique for charged species separation that is based on flow along nano-scale channels having an electric double-layer thickness comparable to the channel size. In such channels, the electric field inherent to the double layer produces transverse species distributions that depend on the species charge. Flow along the channel thus yields mean axial species speeds that also depend on the species charge, enabling species separation and identification. Building on earlier work describing retention and plate heights, here we characterize this new type of field-flow fractionation via the classic metric of resolution. Sample results are presented and discussed for a wide range of conditions for both pressure-driven and electroosmotic flows. Optimum design and operating conditions are also examined. We find that resolution is maximized for optimum values of the zeta potential and Debye layer thickness and that these optima depend strongly on the species charge or range of charges of interest. Under optimum conditions, acceptable resolution can be obtained over a wide range of species charges for pressure-driven flows. This separable range of charges is much smaller for electroosmotic flows. Finally, sample calculations are presented showing that all species in the range of charge between -8 to 10 can be separated simultaneously with resolutions above unity, and this is possible in less than 6 s under optimum conditions that are readily achievable. PMID- 20191546 TI - Steric effect and slip-modulated energy transfer in narrow fluidic channels with finite aspect ratios. AB - In this study, we delineate the combined consequences of finite channel aspect ratios, wall slip effects and steric interactions on the energy transfer mechanisms in narrow fluidic confinements. By considering the details of ionic interactions within the electrical double layer, we demonstrate that considerations of finite aspect ratios and steric effects may result in dramatic alterations in the predictions of effective viscosity as well as the energy transfer efficiency, particularly for high magnitudes of the surface charge density, as compared with the predictions based on parallel plate channel considerations. We also illustrate the possibilities of obtaining very high energy transfer efficiencies by employing channels of aspect ratios close to unity, with a judicious exploitation of steric interactions and wall slippage effects in highly confined geometries. PMID- 20191547 TI - Destabilization of Pickering emulsions using external electric fields. AB - It is known that emulsions can be stabilized by the presence of particles that get trapped at fluid-fluid interfaces and prevent adjacent drops from coalescing with one another. We show here that such emulsions, or Pickering emulsions, can be destabilized by applying external electric fields. This is demonstrated experimentally by studying water drops in decane and silicone oil drops in corn oil in the presence of micro-sized particles. It is shown that the primary phenomenon responsible for the destabilization is the motion of particles on the surface of drops in the presence of a uniform electric field. Although there should be no electrostatic forces acting on neutral particles in a uniform electric field, the presence of the drop itself introduces nonuniformity, which leads to dielectrophoretic forces acting on the particles and is thus responsible for particle motions along the drop surface. Particles translate to either the poles or the equator of the drop, depending on the relative dielectric constants of the particles, the surrounding fluid and the fluid within the drop. Such motions break the particle barrier, thus allowing for drops to merge with one another and therefore destabilizing the emulsion. PMID- 20191548 TI - Numerical studies of electrokinetic control of DNA concentration in a closed-end microchannel. AB - A major challenge in lab-on-a-chip devices is how to concentrate sample molecules from a dilute solution, which is critical to the effectiveness and the detection limit of on-chip bio-chemical reactions. A numerical study of sample concentration control by electrokinetic microfluidic means in a closed-end microchannel is presented in this paper. The present method provides a simple and efficient way of concentration control by using electrokinetic trapping of a charged species of interest, controlling liquid flow and separating different sample molecules in the microchannel. The electrokinetic-concentration process and the controlled transport of the sample molecules are numerically studied. In this system, in addition to the electroosmotic flow and the electrophoresis, the closed-end of the chamber causes velocity variation at both ends of the channel and induces a pressure gradient and the associated fluid movement in the channel. The combined effects determine the final concentration field of the sample molecules. The influences of a number of parameters such as the channel dimensions, electrode size and the applied electric field are investigated. PMID- 20191549 TI - Analyte transport in liquid junction nano-electrospray interface between capillary electrophoresis and mass spectrometry. AB - The optimization of working parameters controlling the transfer of an analyte from the separation into the spray capillary at the liquid junction interface is a complex problem. The numerical models of hydrodynamic flow, electric field strength and the consequential mass transfer provide a valuable insight into the function of the miniaturized device. The results revealed that the most important parameter is the electric field strength inside the gap between the separation and spray capillaries. In a strong electric field, the analyte leaving the separation capillary is immediately transferred into the spray capillary at its maximum concentration. Although the losses of analyte outside the interface are dominant in this case, the sprayed concentration determines the detection sensitivity. Since only a small amount of the sprayed material enters mass spectrometer, the losses at the interface do not influence the sensitivity. At low electric field strength the total amount of analytes is transferred into the spray capillary. In this case, however, the analytes enter the capillary slowly and, as a result, are significantly diluted. The electric field strength, pressure and dimensions determine the mass transfer in the interface and must be considered when the optimum conditions of an analysis are chosen. Several fold improvement in sensitivity and efficiency of the method can be expected when working under the optimum conditions. PMID- 20191550 TI - A new electrophoretic focusing principle: focusing of nonamphoteric weak ionogenic analytes using inverse electromigration dispersion profiles. AB - This contribution introduces a new separation principle in CE which offers focusing of weak nonamphoteric ionogenic species and their inherent transport to the detector. The prerequisite condition for application of this principle is the existence of an inverse electromigration dispersion profile, i.e. a profile where pH is decreasing toward the anode or cathode for focusing of anionic or cationic weak analytes, respectively. The theory presented defines the principal conditions under which an analyte is focused on a profile of this type. Since electromigration dispersion profiles are migrating ones, the new principle offers inherent transport of focused analytes into the detection cell. The focusing principle described utilizes a mechanism different from both CZE (where separation is based on the difference in mobilities) and IEF (where separation is based on difference in pI), and hence, offers another separation dimension in CE. The new principle and its theory presented here are supplemented by convincing experiments as their proof. PMID- 20191551 TI - Electrophoretic collision of a DNA molecule with a small elliptical obstacle. AB - We present a Brownian dynamics study of the collision and unhooking of a lambda DNA molecule with an elliptical obstacle. The semi-major and semi-minor axes of the obstacle are comparable to the radius of gyration of the DNA, and the field is sufficiently strong to cause frequent hairpin formation upon collision. We focus on how the dynamics of a head-on collision (impact parameter of zero) are affected by the angle between the major axis of the ellipse and the direction of the electric field far from the elliptical surface. When this orientation angle breaks the symmetry of the system, we find that the collision dynamics are considerably more complicated than the cylindrical obstacle case. In particular, a higher strain rate at the stagnation point on an elliptical surface does not always lead to a higher hooking probability. As a result, elliptical obstacles should be less effective than cylindrical obstacles for DNA separations based on hairpin formation. PMID- 20191552 TI - Influence of the semi-permeable membrane on the performance of dynamic field gradient focusing. AB - This paper is part of our continued effort to understand the underlying principles of dynamic field gradient focusing. In this investigation, we examined three problems associated with the use of a semi-permeable membrane. First, the influence of steric and ionic exclusion of current carrying ions through the membrane was examined. It was found that resistance to the transport of ions across the membrane resulted in a shallowing of the electric field profile and an increase in the size of the defocusing zone, which is where the slope of the electric field is reversed so that it disperses rather than concentrates solutes. These problems could be reduced by using a membrane with large pores relative to the size of the buffering ions and completely void of fixed charges. Next, a numerical simulation was used to investigate concentration polarization of protein onto the surface of the membrane. Due to the presence of a transverse electric field, species were pulled toward the membrane. If the membrane is restrictive to those species, a concentrated, polarized layer will form on the surface. The simulation showed that by decreasing the channel to a depth of 20 microm, the concentrated region next to the membrane could be reduced. Finally, it was found that changes in column volume due to loss of membrane structural integrity could be mitigated by including a porous ceramic support. The variation in peak elution times was decreased from greater than 20% to less than 3%. PMID- 20191554 TI - Ionic strength effects on electrophoretic focusing and separations. AB - We present a numerical and experimental study of the effects of ionic strength on electrophoretic focusing and separations. We review the development of ionic strength models for electrophoretic mobility and chemical activity and highlight their differences in the context of electrophoretic separation and focusing simulations. We couple a fast numerical solver for electrophoretic transport with the Onsager-Fuoss model for actual ionic mobility and the extended Debye-Huckle theory for correction of ionic activity. Model predictions for fluorescein mobility as a function of ionic strength and pH compare well with data from CZE experiments. Simulation predictions of preconcentration factors in peak mode ITP also compare well with the published experimental data. We performed ITP experiments to study the effect of ionic strength on the simultaneous focusing and separation. Our comparisons of the latter data with simulation results at 10 and 250 mM ionic strength show the model is able to capture the observed qualitative differences in ITP analyte zone shape and order. Finally, we present simulations of CZE experiments where changes in the ionic strength result in significant change in selectivity and order of analyte peaks. Our simulations of ionic strength effects in capillary electrophoresis compare well with the published experimental data. PMID- 20191553 TI - Development of a membrane-less dynamic field gradient focusing device for the separation of low-molecular-weight molecules. AB - Dynamic field gradient focusing uses an electric field gradient generated by controlling the voltage profile of an electrode array to separate and concentrate charged analytes according to their individual electrophoretic mobilities. This study describes a new instrument in which the electrodes have been placed within the separation channel. The major challenge faced with this device is that when applied voltages to the electrodes are larger than the redox potential of water, electrolysis will occur, producing hydrogen ions (H+) plus oxygen gas on the anodes and hydroxide (OH(-)) plus hydrogen gas on the cathodes. The resulting gas bubbles and pH excursions can cause problems with system performance and reproducibility. An on-column, degassing system that can remove gas bubbles "on the-fly" is described. In addition, the use of a high capacity, low-conductivity buffer to address the problem of the pH shift that occurs due to the production of H+ on the anodes is illustrated. Finally, the successful separation of three, low-molecular-weight dyes (amaranth, bromophenol blue and methyl red) is described. PMID- 20191555 TI - The dependence of the electrophoretic mobility of small organic ions on ionic strength and complex formation. AB - The ionic strength dependence of the electrophoretic mobility of small organic anions with valencies up to -3 is investigated in this study. Provided the anions are not too aspherical, it is argued that shape and charge distribution have little influence on mobility. To a good approximation, the electrophoretic mobility of a small particle should be equal to that of a model sphere with the same hydrodynamic radius and same net charge. For small ions, the relaxation effect (distortion of the ion atmosphere from equilibrium due to external electric and flow fields) is significant even for monovalent ions. Alternative procedures of accounting for the relaxation effect are examined. In order to account for the ionic strength dependence of a specific set of nonaromatic and aromatic anions in aqueous solution, it is necessary to include complex formation between the anion with species in the BGE. A number of possible complexes are considered. When the BGE is Tris-acetate, the most important of these involves the complex formed between anion and Tris, the principle cation in the BGE. When the BGE is sodium borate, an anion-anion (borate) complex appears to be important, at least when the organic anion is monovalent. An algorithm is developed to analyze the ionic strength dependence of the electrophoretic mobility. This algorithm is applied to two sets of organic anions from two independent research groups. PMID- 20191556 TI - Protein adsorption-dependent electro-kinetic pore flow: modeling of ion-exchange electrochromatography with an oscillatory transverse electric field. AB - Electro-kinetic acceleration of protein mass transfer was studied by dynamic chromatographic experiments and computer simulations on IEC with an oscillatory transverse electric field (EF) perpendicular to the mobile-phase flow (pIEEC). The breakthrough behavior of BSA was investigated at different electric current densities. A two-dimensional mathematical model has been established to describe the electro-kinetic convection-diffusion behavior of protein adsorption in a single adsorbent particle. The equation was coupled with the axial dispersion model to simulate the dynamic adsorption process in the pIEEC. The model parameters were determined by independent experiments or calculations. It was found that protein adsorption led to an exponential decrease of intraparticle electro-kinetic flow with increasing protein adsorption. Taking this effect into consideration, the model calculations could well describe dynamic breakthrough curves. Moreover, protein distribution in adsorbents was observed to present excursion along the periodical oscillatory EF direction. At the beginning of pIEEC, intraparticle convection caused by the EF contributed more to the enhancement of dynamic binding capacity. Finally, it was confirmed that both the EOF and electrophoresis contributed to the acceleration of mass transfer. PMID- 20191557 TI - High-throughput log P determination by MEEKC coupled with UV and MS detections. AB - A high-throughput screening method using MEEKC was developed for the determination of 1-octanol-water partition coefficients (log P(oct)). Two approaches were carried out to decrease determination times to about 20 min per compound: (i) a dynamically coated capillary was used to increase the EOF at low pH, allowing the measurement of log P(oct) of acidic compounds and (ii) a short end injection was performed to reduce the capillary effective length. The analytical conditions were optimized to determine the lipophilicity of neutral, basic, and acidic compounds with log P(oct) ranging from 0 to 5. The developed method was first applied to a well-balanced set of 35 reference compounds, and second to a set of 21 acidic and 29 basic pharmaceutical compounds. Finally, determinations were achieved with MS detection, allowing a 20-fold throughput increase thanks to sample pooling. An atmospheric pressure photoionization source was selected to advantageously replace ESI as it was less affected by the non volatile BGE additives used in MEEKC. PMID- 20191558 TI - Modeling the electrophoretic behavior of quinolones in aqueous and hydroorganic media. AB - The applicability of the classical semiempirical relationships between the electrophoretic mobility and charge-to-mass ratio (m(e) versus q/M(alpha)) has been investigated to describe migration behavior of a series of quinolones in aqueous and hydroorganic media. The Stoke's law (alpha=1/3), the classical polymer model (alpha=1/2) and the Offord's surface law (alpha=2/3) were evaluated in the pH range comprised between 2 and 11 in ACN-water mixtures of 0, 10 and 30% m/m ACN. As accurate acidity constant values were available for charge calculations, correlations were excellent. The results obtained using the Offord's surface law were slightly better and the plots of q/M(2/3) against the separation electrolyte pH were used to select the optimum pH values for separation of a quinolone mixture. The electropherograms simulated considering the accurate charge-to-mass ratio of each quinolone at the selected pH values were in good agreement with the experimental results. The ability of these relationships to predict the separation of the studied quinolones at a certain pH value in methanol-water and THF-water mixtures was also demonstrated. PMID- 20191559 TI - Nonlinear Smoluchowski velocity for electroosmosis of Power-law fluids over a surface with arbitrary zeta potentials. AB - Electroosmotic flow of Power-law fluids over a surface with arbitrary zeta potentials is analyzed. The governing equations including the nonlinear Poisson Boltzmann equation, the Cauchy momentum equation and the continuity equation are solved to seek exact solutions for the electroosmotic velocity, shear stress, and dynamic viscosity distributions inside the electric double layer. Specifically, an expression for the general Smoluchowski velocity is obtained for electroosmosis of Power-law fluids in a fashion similar to the classic Smoluchowski velocity for Newtonian fluids. The existing Smoluchowski slip velocities under two special cases, (i) for Newtonian fluids with arbitrary zeta potentials and (ii) for Power-law fluids with small zeta potentials, can be recovered from our derived formula. It is interesting to note that the general Smoluchowski velocity for non-Newtonian Power-law fluids is a nonlinear function of the electric field strength and surface zeta potentials; this is due to the coupling electrostatics and non-Newtonian fluid behavior, which is different from its counterpart for Newtonian fluids. This general Smoluchowski velocity is of practical significance in determining the flow rates in microfluidic devices involving non-Newtonian Power-law fluids. PMID- 20191560 TI - Electrochromatographic retention of peptides on strong cation-exchange stationary phases. AB - We analyze the systematic and substantial electrical field-dependence of electrochromatographic retention for four counterionic peptides ([Met5]enkephalin, oxytocin, [Arg8]vasopressin, and luteinizing hormone releasing hormone (LHRH) ) on a strong cation-exchange (SCX) stationary phase. Our experiments show that retention behavior in the studied system depends on the charge-selectivity of the stationary phase particles, the applied voltage, and the peptides' net charge. Retention factors of twice positively charged peptides ([Arg8]vasopressin and LHRH at pH 2.7) decrease with increasing applied voltage, whereas lower charged peptides (oxytocin and [Met5]enkephalin at pH 2.7, [Arg8]vasopressin and LHRH at pH 7.0) show a concomitant increase in their retention factors. The observed behavior is explained on the basis of electrical field-induced concentration polarization (CP) that develops around the SCX particles of the packing. The intraparticle concentration of charged species (buffer ions, peptides) increases with increasing applied voltage due to diffusive backflux from the enriched CP zone associated with each SCX particle. For twice charged and on the SCX phase strongly retained peptides the local increase in mobile phase ionic strength reduces the electrostatic interactions with the stationary phase, which explains the decrease of retention factors with increasing applied voltage and CP intensity. Lower charged and weaker retained peptides experience a much stronger relative intraparticle enrichment than the twice-charged peptides, which results in a net increase of retention factors with increasing applied voltage. The CP-related contribution to electrochromatographic retention of peptides on the SCX stationary phase is modulated by the applied voltage, the mobile phase ionic strength, and the peptides' net charge and could be used for selectivity tuning in difficult separations. PMID- 20191561 TI - Transmission of swine influenza through organ transplantation. PMID- 20191563 TI - Identification of focal adhesion kinase (FAK) and phosphatidylinositol 3-kinase (PI3-kinase) as Par3 partners by proteomic analysis. AB - Partition defective 3 (Par3) is involved in a variety of polarity events including establishment of apico-basal polarity of epithelial cell, axon/dendrite specification of neurons and directional migration of cells with front-rear polarity. Par3 is thought to regulate cell polarity as a scaffold protein by interacting with various partner proteins such as Par6, aPKC, Tiam1/2 and Numb. However, the mode of actions of Par3 in polarized migration remains largely unknown. To explore Par3 functions, we screened Par3-interacting proteins by combining Par3 affinity column chromatography and shotgun analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS). We obtained about two hundred Par3-interacting proteins from the rat brain cytosol fraction. Among them, we focused on FAK and PI3-kinase, as both of them participate in directional cell migration. FAK associated with the PDZ domain and the coiled-coil region of Par3 and p110 of PI3-kinase associated with the coiled-coil region of Par3. Par3 was partially colocalized with FAK in spreading cells. Depletion of Par3 by RNA interference inhibited adhesion-induced activation of FAK and PI3-kinase, and RNA interference-resistant Par3 restored the inhibitory effects. In addition, Par3 was required for the adhesion-induced cell spreading as well as for directional cell migration toward collagen. These results suggest that Par3 directly interacts with FAK and PI3-kinase, enhancing their activities for polarized cell migration. PMID- 20191564 TI - Tumoral and tissue-specific expression of the major human beta-tubulin isotypes. AB - The beta-tubulins are microtubule components encoded by a multigene family, which produces slightly different proteins with complex expression patterns. Several widely used anticancer drugs base their activity on beta-tubulin binding, microtubule dynamics alteration, and cell division blockage. The expression of these drug targets in tumoral and normal cells could be of crucial importance for therapy outcome, unfortunately, the complex beta-tubulin expression patterns have been poorly characterized in human. In this study, we developed a quantitative RT PCR technique that accurately determines the mRNA expression of the eight human beta-tubulin isotypes, encoding class I, IIa, IIb, III, IVa, IVb, V, and VI and applied it to 21 nontumoral tissues and 79 tumor samples belonging to seven cancer types. In the nontumoral tissues, we found that, overall, TUBB (I), TUBB2C (IVb), and TUBB6 (V) were ubiquitous, TUBB1(VI) was hematopoietic cell-specific, and TUBB2A (IIa), TUBB2B (IIb), TUBB3 (III), and TUBB4 (IVa) had high expression in brain; however, the contribution of the different isotypes to the total beta tubulin content varied for each tissue and had a complex pattern. In tumoral tissues, most isotypes exhibited an altered expression in specific tumor types or related to tumoral characteristics. In general, TUBB3 showed a great increase in expression while TUBB6 expression was largely decreased in most tumors. Thus, normal tissues showed a complex beta-tubulin isotype distribution, which could contribute to the toxicity profile of the microtubule-binding drugs. In addition, the specific isotypes significantly altered in tumors might represent markers for drug response. PMID- 20191565 TI - The kinetics of force-induced cell reorganization depend on microtubules and actin. AB - The cytoskeleton is an important factor in the functional and structural adaption of cells to mechanical forces. In this study we investigated the impact of microtubules and the acto-myosin machinery on the kinetics of force-induced reorientation of NIH3T3 fibroblasts. These cells were subjected to uniaxial stretching forces that are known to induce cellular reorientation perpendicular to the stretch direction. We found that disruption of filamentous actin using cytochalasin D and latrunculin B as well as an induction of a massive unpolarized actin polymerization by jasplakinolide, inhibited the stretch-induced reorientation. Similarly, blocking of myosin II activity abolished the stretch induced reorientation of cells but, interestingly, increased their motility under stretching conditions in comparison to myosin-inhibited nonstretched cells. Investigating the contribution of microtubules to the cellular reorientation, we found that, although not playing a significant role in reorientation itself, microtubule stability had a significant impact on the kinetics of this event. Overall, we conclude that acto-myosin, together with microtubules, regulate the kinetics of force-induced cell reorientation. PMID- 20191566 TI - The molecular basis of frictional loads in the in vitro motility assay with applications to the study of the loaded mechanochemistry of molecular motors. AB - Molecular motors convert chemical energy into mechanical movement, generating forces necessary to accomplish an array of cellular functions. Since molecular motors generate force, they typically work under loaded conditions where the motor mechanochemistry is altered by the presence of a load. Several biophysical techniques have been developed to study the loaded behavior and force generating capabilities of molecular motors yet most of these techniques require specialized equipment. The frictional loading assay is a modification to the in vitro motility assay that can be performed on a standard epifluorescence microscope, permitting the high-throughput measurement of the loaded mechanochemistry of molecular motors. Here, we describe a model for the molecular basis of the frictional loading assay by modeling the load as a series of either elastic or viscoelastic elements. The model, which calculates the frictional loads imposed by different binding proteins, permits the measurement of isotonic kinetics, force-velocity relationships, and power curves in the motility assay. We show computationally and experimentally that the frictional load imposed by alpha actinin, the most widely employed actin binding protein in frictional loading experiments, behaves as a viscoelastic rather than purely elastic load. As a test of the model, we examined the frictional loading behavior of rabbit skeletal muscle myosin under normal and fatigue-like conditions using alpha-actinin as a load. We found that, consistent with fiber studies, fatigue-like conditions cause reductions in myosin isometric force, unloaded sliding velocity, maximal power output, and shift the load at which peak power output occurs. PMID- 20191568 TI - Measuring joint involvement in polyarticular psoriatic arthritis: an introduction of alternatives. AB - OBJECTIVE: To compare the reliability of 3 different simplified joint counts with the gold standard 66 swollen/68 tender joint count (JC66/68) for assessing clinical response in patients with polyarticular psoriatic arthritis (PsA). METHODS: The 28-joint count (JC28), in the same way that it is used in rheumatoid arthritis, and 2 measures including distal interphalangeal (DIP) joints (the 32 joint count [JC32], including all finger joints as well as wrists and knees, and 36-joint count [JC36], which additionally included elbows and ankles), were compared with the JC66/68 in 182 patients using data from the Infliximab Multinational Psoriatic Arthritis Controlled Trial 2 trial database. Pearson's correlation coefficients were calculated to compare the swollen and tender JC28, JC32, and JC36 with the corresponding results of the total JC66/68. American College of Rheumatology (ACR) responses based on the individual measures were compared, and their ability in predicting a clinical response of ACR 20% improvement (ACR20) based on the JC66/68 was assessed by calculating the area under the receiver operating characteristic curve via logistic regression and the maximum Youden indices at weeks 14 and 24. RESULTS: All simplified joint counts were highly correlated to the standard JC66/68 both for tenderness and swelling at each individual visit (Pearson's correlation coefficients consistently >0.8, n = 182-200; P < 0.0001). Logistic regression for ACR20 response showed that area under the curve was constantly >0.91, with comparable results for Youden indices of the simplified joint counts. CONCLUSION: All simplified joint counts considered seemed sufficiently sensitive and specific to measure clinical response in trial patients with polyarticular PsA when compared with the JC66/68, no matter whether DIP joints were included (the JC36 and JC32) or excluded (the JC28). Further research will be needed to clarify this issue. PMID- 20191567 TI - Functional roles of VASP phosphorylation in the regulation of chemotaxis and osmotic stress response. AB - Vasodilator-stimulated phosphoprotein (VASP) plays crucial roles in controlling F actin-driven processes and growing evidence indicates that VASP function is modulated by phosphorylation at multiple sites. However, the complexity of mammalian system prevents the clear understanding of the role of VASP phosphorylation. In this study, we took advantage of Dictyostelium which possesses only one member of the Ena/VASP family to investigate the functional roles of VASP phosphorylation. Our results demonstrated that hyperosmotic stress and cAMP stimulation cause VASP phosphorylation. VASP phosphorylation plays a negative role for the early steps of filopodia/microspikes formation. VASP phosphorylation appears to modulate VASP localization at the membrane cortex and its interactions with WASP and WIPa. Analysis of chemotaxis of cells expressing VASP mutants showed that VASP phosphorylation is required for the establishment of cell polarity under a cAMP gradient. PMID- 20191569 TI - Frequency, predictors, and prognosis of sustained minimal disease activity in an observational psoriatic arthritis cohort. AB - OBJECTIVE: To establish the frequency and predictors of minimal disease activity in psoriatic arthritis (PsA) and to investigate the prognostic ability of minimal disease activity criteria to predict future joint damage. METHODS: The study was conducted using an observational PsA cohort. Patients were classified as being in minimal disease activity if they fulfilled the criteria on consecutive visits for >12 months. Predictive factors for minimal disease activity and joint damage were investigated using regression models. Joint damage progression was based on clinically damaged joint counts. RESULTS: Of the 344 patients, 208 (60%) achieved minimal disease activity at > or = 1 visit and 116 (34%) achieved minimal disease activity for > or = 12 months (sustained minimal disease activity). The average duration of minimal disease activity was 28 months (range 12-48 months). Twelve patients (10%) experienced a flare of disease after 34 months in minimal disease activity. Low erythrocyte sedimentation rate (ESR) and oligoarthritis were predictors of achieving sustained minimal disease activity (P < 0.03). The mean change in damaged joint counts was 0.931 (range 0-12) in the sustained minimal disease activity group and 2.245 (range 0-17) in the controls (P < 0.001). Of the sustained minimal disease activity group, 69% showed no progression of joint damage, compared with 51% in the control group. Elevated ESR, baseline joint damage, and use of biologic therapies increased the likelihood of damage progression (P < 0.05). CONCLUSION: Minimal disease activity was achieved by a significant proportion of patients and was sustained in one-third of the population studied. Patients achieving sustained minimal disease activity had a significant reduction in joint damage progression. Other factors, representing disease activity and disease severity, impact on the likelihood of achieving sustained minimal disease activity and on damage progression. PMID- 20191570 TI - Lupus nephritis associated with complete C1s deficiency efficiently treated with rituximab: a case report. PMID- 20191571 TI - Effects of common footwear on joint loading in osteoarthritis of the knee. AB - OBJECTIVE: Elevated joint loads during walking have been associated with the severity and progression of osteoarthritis (OA) of the knee. Footwear may have the potential to alter these loads. This study compares the effects of several common shoe types on knee loading in subjects with OA of the knee. METHODS: Thirty-one subjects (10 men, 21 women) with radiographic and symptomatic knee OA underwent gait analyses using an optoelectronic camera system and multicomponent force plate. In each case, gait was evaluated during barefoot walking and while wearing 4 different shoe types: 1) clogs, 2) stability shoes, 3) flat walking shoes, and 4) flip-flops. Peak knee loads were compared between the different footwear conditions. RESULTS: Overall, the clogs and stability shoes resulted in a significantly higher (approximately 15% higher) peak knee adduction moment (mean +/- SD 3.1 +/- 0.7 and 3.0 +/- 0.7 divided by body weight [BW] x height [H] multiplied by 100, respectively; P < 0.05) compared with that of flat walking shoes (mean +/- SD 2.8 +/- 0.7 %BW x H), flip-flops (mean +/- SD 2.7 +/- 0.8 %BW x H), and barefoot walking (mean +/- SD 2.7 +/- 0.7 %BW x H). There were no statistically significant differences in knee loads with the flat walking shoes and flip-flops compared with barefoot walking. CONCLUSION: These data confirm that footwear may have significant effects on knee loads during walking in subjects with OA of the knee. Flexibility and heel height may be important differentiating characteristics of shoes that affect knee loads. In light of the strong relationship between knee loading and OA, the design and biomechanical effects of modern footwear should be more closely evaluated in terms of their effects on the disease. PMID- 20191572 TI - The independent effect of pain in one versus two knees on the presence of low physical function in a multicenter knee osteoarthritis study. AB - OBJECTIVE: Although knee pain severity is thought to greatly impact function, the additional contribution of pain in 1 versus 2 knees is not known. We examined the relationship between unilateral versus bilateral pain with low physical functioning at baseline and 30 months while accounting for knee pain severity. METHODS: The Multicenter Osteoarthritis Study is a cohort study of people who have or are at high risk for knee osteoarthritis. We defined low physical function as Western Ontario and McMaster Universities Osteoarthritis Index physical functioning scores > or = 28 of 68, consistent with poor functional outcome. Incidence and improvement from low physical function were defined as scores that declined below and improved above this threshold at 30 months. We examined the association between pain in 1 or 2 knees with low physical function with risk ratios (RRs) adjusting for known confounders. RESULTS: Of the 2,069 subjects (mean +/- SD age 63 +/- 8 years, mean +/- SD body mass index 31 +/- 6 kg/m(2), 63% women), the prevalence of low physical functioning was 50% lower among persons with unilateral pain compared with those with bilateral pain (adjusted prevalence ratio 0.5 [95% confidence interval (95% CI) 0.3-0.7]). Of those without low physical functioning at baseline, the risk of incidence at 30 months was 30% less for unilateral compared with bilateral pain (adjusted RR 0.7 [95% CI 0.5-1.0]). Of those with low physical functioning at baseline, improvement was 1.7 times more likely for those with unilateral compared with bilateral pain (adjusted RR 1.7 [95% CI 1.3-2.2]). CONCLUSION: The presence of pain in 1 versus 2 knees provides important information regarding present and future physical functioning. PMID- 20191573 TI - Preventing hepatitis B reactivation in immunosuppressed patients: is it time to revisit the guidelines? PMID- 20191574 TI - Prediction of nonspecific side effects in rheumatoid arthritis patients by beliefs about medicines. AB - OBJECTIVE: This study examines the determinants of patients' side effects from arthritis medication. Proposed predictors were patients' beliefs about medications, objective disease activity, treatment regimen, and psychiatric and rheumatoid arthritis symptoms. METHODS: In a longitudinal design, 100 rheumatoid arthritis outpatients were investigated at baseline and again at 6 months after receiving both pharmacologic and psychosocial treatment. RESULTS: Multivariate analyses showed no influence of disease status, type of treatment, or psychiatric or arthritis symptoms on side effects. Heightened concerns about arthritis medication at baseline predicted side effects at baseline (partial correlation r = 0.37, P < 0.001) and at 6 months (partial correlation r = 0.25, P < 0.001) after controlling for relevant disease- and treatment-related variables. In a cross-lagged panel analysis, prior experience with side effects from arthritis medication was ruled out as a cause of heightened concerns, indicating that negative beliefs genuinely contribute to side effects. A comparison of patients who did and did not start new medications showed no difference in side effects in patients with positive beliefs about medications, but led to significantly more side effects in patients with negative beliefs. CONCLUSION: Patients' beliefs about arthritis medications were stable and consistently associated with side effects. Patients with greater concerns about their arthritis medications are at higher risk for developing side effects, especially when starting new drugs. Identifying those patients is important to avoid premature drug discontinuation. Research into cause and preventability of negative attitudes to prescribed medicines is needed. PMID- 20191575 TI - Night pain in hip and knee osteoarthritis: a focus group study. AB - OBJECTIVE: To explore the experience of night pain in people with hip or knee osteoarthritis (OA). METHODS: Twenty-eight focus groups were conducted in 6 centers in 4 countries, with a total of 130 men and women with hip or knee OA. Two focus groups were excluded from the analysis, leaving 26 groups comprising 123 participants. Sampling was performed to ensure approximately equal representation of individuals with mild, moderate, and severe pain, hip OA, and knee OA. Format and methodology were standardized across centers, and participants described and discussed their experience of night pain. The focus groups were audio-recorded and transcribed. Data were analyzed by identifying emergent codes that were grouped and compared, resulting in the identification of key themes. RESULTS: The majority of participants (81%) experienced night pain; the remaining 19%, who reported no night pain, were from the moderate or severe pain focus groups. Similar night pain experiences were expressed by the hip and knee OA participants. Night pain was also present regardless of the stage of OA, but severity increased as the disease progressed. Night pain was variable and intermittent. Three key themes were identified: prediction of night pain, sleep disturbance, and adaptations and treatment regimens. CONCLUSION: Due to its variability and complexity, the assessment of night pain should take into account the importance of the patient narrative. Also, night pain may not be a distinct marker of disease severity, and this may have implications for its use as a priority indicator for total joint replacement. PMID- 20191576 TI - Rituximab therapy leads to rapid decline of serum IgG4 levels and prompt clinical improvement in IgG4-related systemic disease. AB - OBJECTIVE: Patients with IgG4-related systemic disease (IgG4-RSD) frequently show an incomplete response to treatment with glucocorticoids and traditional disease modifying antirheumatic drugs (DMARDs). B lymphocyte depletion is a therapeutic strategy known to be effective for pemphigus vulgaris, an autoimmune condition mediated by IgG4 autoantibodies. This study was performed to assess the clinical and serologic responses to B lymphocyte depletion therapy with rituximab in patients with IgG4-RSD. METHODS: Four patients with IgG4-RSD were treated with 2 intravenous doses (1 gram each) of rituximab. Clinical improvement was assessed by monitoring the tapering/discontinuation of prednisone and DMARDs, and by measuring the serum concentrations of B lymphocytes, immunoglobulins, and IgG subclasses before and after therapy. RESULTS: Clinical features of IgG4-RSD in these 4 patients included autoimmune pancreatitis, sclerosing cholangitis, lymphoplasmacytic aortitis, salivary gland involvement, orbital pseudotumor, and lacrimal gland enlargement. The 3 patients with elevated serum IgG and IgG4 levels at baseline had a mean IgG concentration of 2,003 mg/dl (normal range 600 1,500 mg/dl) and a mean IgG4 concentration of 2,160 mg/dl (normal range 8-140 mg/dl). Among these patients, the serum IgG4 concentrations declined by a mean of 65% within 2 months of rituximab administration. All 4 patients demonstrated striking clinical improvement within 1 month of the initiation of rituximab therapy, and tapering or discontinuation of their treatment with prednisone and DMARDs was achieved in all 4 patients. A decrease in IgG concentration was observed for the IgG4 subclass only. CONCLUSION: Treatment with rituximab led to prompt clinical and serologic improvement in these patients with refractory IgG4 RSD, and is a viable treatment option for this condition. The decline in serum IgG4 concentrations was substantially steeper than that of the autoantibody concentrations in immune-mediated conditions in which rituximab is effective, such as in rheumatoid arthritis. In addition, the reduction in IgG-subclass levels appeared to be specific for IgG4. The swift improvement of IgG4-RSD suggests that rituximab achieves its effects in IgG4-RSD by depleting the pool of B lymphocytes that replenish short-lived IgG4-secreting plasma cells. PMID- 20191577 TI - Rheumatoid arthritis incidence: what goes down must go up? PMID- 20191578 TI - Increased glutamate/glutamine compounds in the brains of patients with fibromyalgia: a magnetic resonance spectroscopy study. AB - OBJECTIVE: Fibromyalgia (FM) has been defined as a systemic disorder that is clinically characterized by pain, cognitive deficit, and the presence of associated psychopathology, all of which are suggestive of a primary brain dysfunction. This study was undertaken to identify the nature of this cerebral dysfunction by assessing the brain metabolite patterns in patients with FM through magnetic resonance spectroscopy (MRS) techniques. METHODS: A cohort of 28 female patients with FM and a control group of 24 healthy women of the same age were studied. MRS techniques were used to study brain metabolites in the amygdala, thalami, and prefrontal cortex of these women. RESULTS: In comparison with healthy controls, patients with FM showed higher levels of glutamate/glutamine (Glx) compounds (mean +/- SD 11.9 +/- 1.6 arbitrary units [AU] versus 13.4 +/- 1.7 AU in controls and patients, respectively; t = 2.517, 35 df, corrected P = 0.03) and a higher Glx:creatine ratio (mean +/- SD 2.1 +/- 0.4 versus 2.4 +/- 1.4, respectively; t = 2.373, 35 df, corrected P = 0.04) in the right amygdala. In FM patients with increased levels of pain intensity, greater fatigue, and more symptoms of depression, inositol levels in the right amygdala and right thalamus were significantly higher. CONCLUSION: The distinctive metabolic features found in the right amygdala of patients with FM suggest the possible existence of a neural dysfunction in emotional processing. The results appear to extend previous findings regarding the dysfunction in pain processing observed in patients with FM. PMID- 20191579 TI - Is the incidence of rheumatoid arthritis rising?: results from Olmsted County, Minnesota, 1955-2007. AB - OBJECTIVE: To examine trends in the incidence and prevalence of rheumatoid arthritis (RA) from 1995 to 2007. METHODS: To augment our preexisting inception cohort of patients with RA (1955-1994), we assembled a population-based incidence cohort of individuals >or=18 years of age who first fulfilled the American College of Rheumatology 1987 criteria for the classification of RA between January 1, 1995 and December 31, 2007 and a cohort of patients with prevalent RA on January 1, 2005. Incidence and prevalence rates were estimated and were age and sex-adjusted to the white population in the US in 2000. Trends in incidence rates were examined using Poisson regression methods. RESULTS: The 1995-2007 incidence cohort comprised 466 patients (mean age 55.6 years), 69% of whom were female and 66% of whom were rheumatoid factor positive. The overall age- and sex adjusted annual RA incidence was 40.9/100,000 population. The age-adjusted incidence in women was 53.1/100,000 population (versus 27.7/100,000 population in men). During the period of time from 1995 to 2007, the incidence of RA increased moderately in women (P = 0.02) but not in men (P = 0.74). The increase was similar among all age groups. The overall age- and sex-adjusted prevalence on January 1, 2005 was 0.72% (95% confidence interval [95% CI] 0.66, 0.77), which is an increase when compared with a prevalence of 0.62% (95% CI 0.55, 0.69) in 1995 (P < 0.001). Applying the prevalence on January 1, 2005 to the US population in 2005 showed that an estimated 1.5 million US adults were affected by RA. This is an increase from the previously reported 1.3 million adults with RA in the US. CONCLUSION: The incidence of RA in women appears to have increased during the period of time from 1995 to 2007. The reasons for this recent increase are unknown, but environmental factors may play a role. A corresponding increase in the prevalence of RA was also observed. PMID- 20191581 TI - Analysis of intracellular methotrexate polyglutamates in patients with juvenile idiopathic arthritis: effect of route of administration on variability in intracellular methotrexate polyglutamate concentrations. AB - OBJECTIVE: Intracellular methotrexate (MTX) polyglutamates (MTXGlu) have been shown to be potentially useful biomarkers of clinical response in adult patients with rheumatoid arthritis. The present study was undertaken to measure intracellular MTXGlu concentrations in a cohort of patients with juvenile idiopathic arthritis (JIA) to determine the predictors of MTXGlu variability in these patients. METHODS: Blood samples were obtained from patients with JIA who were being treated with a stable dose of MTX for >or=3 months. Clinical data were collected by chart review. Concentrations of MTXGlu(1-7) in red blood cell lysates were quantitated using an innovative ion-pairing chromatography procedure, with detection by mass spectrometry. RESULTS: Patients with JIA from a single center (n = 99; mean +/- SD age 117.8 +/- 56.5 months, 69 female) were included in the analysis. The mean +/- SD dose of MTX was 0.51 +/- 0.25 mg/kg per week, with a median treatment duration of 18 months (interquartile range 3-156 months). MTX was administered subcutaneously in 66 patients (67%). Fifty-six patients (57%) had active arthritis at the time of the clinic visit. Total intracellular MTXGlu (MTXGlu(TOT)) concentrations varied 40-fold, with a mean +/- SD total concentration of 85.8 +/- 48.4 nmoles/liter. Concentrations of each MTXGlu subtype (MTXGlu(1-7)) were measured individually and as a percentage of MTXGlu(TOT) in each patient. MTXGlu(3) was the most prominent subtype identified, comprising 42% of MTXGlu(TOT), and the interindividual variability in the concentration of MTXGlu(3) was the most highly correlated with that of MTXGlu(TOT) (r = 0.96). The route of MTX administration was significantly associated with MTXGlu(1-5) subtypes; higher concentrations of MTXGlu(1 + 2) were observed in patients receiving oral doses of MTX, whereas higher concentrations of MTXGlu(3-5) were observed in patients receiving subcutaneous doses of MTX (P < 0.0001). CONCLUSION: In this cohort of patients with JIA, the MTXGlu(TOT) concentration varied 40-fold. Individual MTXGlu metabolites (MTXGlu(1-7)), which have, until now, not been previously reported in patients with JIA, were detected. The route of MTX administration contributed to the variability in concentrations of MTXGlu(1-5). PMID- 20191580 TI - Loss of cartilage structure, stiffness, and frictional properties in mice lacking PRG4. AB - OBJECTIVE: To assess the role of the glycoprotein PRG4 in joint lubrication and chondroprotection by measuring friction, stiffness, surface topography, and subsurface histology of the hip joints of Prg4(-/-) and wild-type (WT) mice. METHODS: Friction and elastic modulus were measured in cartilage from the femoral heads of Prg4(-/-) and WT mice ages 2, 4, 10, and 16 weeks using atomic force microscopy, and the surface microstructure was imaged. Histologic sections of each femoral head were stained and graded. RESULTS: Histologic analysis of the joints of Prg4(-/-) mice showed an enlarged, fragmented surface layer of variable thickness with Safranin O-positive formations sometimes present, a roughened underlying articular cartilage surface, and a progressive loss of pericellular proteoglycans. Friction was significantly higher on cartilage of Prg4(-/-) mice at age 16 weeks, but statistically significant differences in friction were not detected at younger ages. The elastic modulus of the cartilage was similar between cartilage surfaces of Prg4(-/-) and WT mice at young ages, but cartilage of WT mice showed increasing stiffness with age, with significantly higher moduli than cartilage of Prg4(-/-) mice at older ages. CONCLUSION: Deletion of the gene Prg4 results in significant structural and biomechanical changes in the articular cartilage with age, some of which are consistent with osteoarthritic degeneration. These findings suggest that PRG4 plays a significant role in preserving normal joint structure and function. PMID- 20191582 TI - Long-term safety and efficacy of abatacept in children with juvenile idiopathic arthritis. AB - OBJECTIVE: We previously documented that abatacept was effective and safe in patients with juvenile idiopathic arthritis (JIA) who had not previously achieved a satisfactory clinical response with disease-modifying antirheumatic drugs or tumor necrosis factor blockade. Here, we report results from the long-term extension (LTE) phase of that study. METHODS: This report describes the long term, open-label extension phase of a double-blind, randomized, controlled withdrawal trial in 190 patients with JIA ages 6-17 years. Children were treated with 10 mg/kg abatacept administered intravenously every 4 weeks, with or without methotrexate. Efficacy results were based on data derived from the 153 patients who entered the open-label LTE phase and reflect >or=21 months (589 days) of treatment. Safety results include all available open-label data as of May 7, 2008. RESULTS: Of the 190 enrolled patients, 153 entered the LTE. By day 589, 90%, 88%, 75%, 57%, and 39% of patients treated with abatacept during the double blind and LTE phases achieved responses according to the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30), Pedi 50, Pedi 70, Pedi 90, and Pedi 100 criteria for improvement, respectively. Similar response rates were observed by day 589 among patients previously treated with placebo. Among patients who had not achieved an ACR Pedi 30 response at the end of the open-label lead-in phase and who proceeded directly into the LTE, 73%, 64%, 46%, 18%, and 5% achieved ACR Pedi 30, Pedi 50, Pedi 70, Pedi 90, and Pedi 100 responses, respectively, by day 589 of the LTE. No cases of tuberculosis and no malignancies were reported during the LTE. Pneumonia developed in 3 patients, and multiple sclerosis developed in 1 patient. CONCLUSION: Abatacept provided clinically significant and durable efficacy in patients with JIA, including those who did not initially achieve an ACR Pedi 30 response during the initial 4-month open-label lead-in phase. PMID- 20191583 TI - Cancer preceding giant cell arteritis: a case-control study. AB - OBJECTIVE: To study the association between previous cancer and giant cell arteritis (GCA). METHODS: Using the resources of the Rochester Epidemiology Project, we identified incident cases of GCA diagnosed between January 1, 1950 and December 31, 2004. Each GCA patient was matched for age, sex, and length of medical history to 2 subjects without GCA from the same population. Medical records were reviewed. Diagnosis of cancer was confirmed by histopathologic analysis. RESULTS: We identified 204 GCA cases and 407 controls. The GCA group included 163 women (80%) and 41 men (20%). Their mean +/- SD age was 76.0 +/- 8.2 years. The non-GCA group consisted of 325 women (80%) and 82 men (20%). Their mean +/- SD age was 75.6 +/- 8.4 years. At the index date, 45 GCA patients (22%) and 125 non-GCA patients (31%) had had a previous cancer. The odds ratio (OR) for previous cancer in cases compared with controls, adjusted for age, sex, and calendar year, was 0.63, and the 95% confidence interval (95% CI) was 0.42-0.94 (P = 0.022). The mean age at diagnosis of the first cancer before the index date was similar in the cases (67.5 +/- 11.9 years) and the controls (64.9 +/- 13.2 years) (P = 0.32). The mean +/- SD duration from the first cancer to the index date was 9.8 +/- 9.9 years in the cases and 11.7 +/- 10.8 years in the controls (P = 0.31). Cancer types were similar in both groups, but fewer gynecologic malignancies were noted in GCA patients (OR 0.39 [95% CI 0.13-1.15], P = 0.09). Colon cancer also appeared less commonly in the cases compared with the controls (OR 0.22 [95% CI 0.03-1.74], P = 0.15). CONCLUSION: The findings of this population-based case-control study indicate that GCA patients had significantly fewer malignancies prior to the index date as compared with controls. PMID- 20191584 TI - Inducible costimulator ligand regulates bleomycin-induced lung and skin fibrosis in a mouse model independently of the inducible costimulator/inducible costimulator ligand pathway. AB - OBJECTIVE: Systemic sclerosis is a connective tissue disease characterized by fibrosis of the skin and internal organs, including the lungs. Inducible costimulator (ICOS), which is expressed on activated T cells, and its ligand ICOSL, which is expressed on antigen-presenting cells, have been considered a single receptor-ligand pair. Although the ICOS/ICOSL pathway is known to play various roles in adaptive immunity, its roles in innate immunity and tissue fibrosis remain unknown. METHODS: We assessed the roles of ICOS and ICOSL in tissue fibrosis by administering bleomycin intratracheally or intradermally into mice deficient in ICOS and/or ICOSL. Tissue fibrosis was evaluated by histologic or biochemical examination. RESULTS: ICOS deficiency attenuated the lung and skin fibrosis, whereas ICOSL deficiency aggravated it. Mice deficient in both ICOS and ICOSL exhibited accelerated fibrosis, reflecting a dominant role of ICOSL over ICOS in this model. Interestingly, ICOSL expression on macrophages and B cells derived from bronchoalveolar lavage fluid was significantly elevated in ICOS deficient mice as compared with wild-type mice during this process. Thus, the levels of ICOSL expression on B cells and macrophages were inversely associated with the severity of tissue fibrosis. CONCLUSION: Our results indicate that ICOSL expression on antigen-presenting cells plays a previously unknown regulatory role during the development of bleomycin-induced tissue fibrosis that is independent of the ICOS/ICOSL pathway. Further studies will be needed to clarify the roles of ICOS and ICOSL in the development of systemic sclerosis. PMID- 20191585 TI - Simvastatin inhibits cytokine-stimulated Cyr61 expression in osteoblastic cells: a therapeutic benefit for arthritis. AB - OBJECTIVE: To examine the effects of proinflammatory cytokines on Cyr61 expression in osteoblastic cells and the modulatory action of simvastatin, to assess the role of CREB in Cyr61 induction, and to investigate the relationship of osteoblastic expression of Cyr61 to disease progression in experimental arthritis. METHODS: Cyr61 expression and CREB phosphorylation at serine 133 were examined by Western blotting. Promoter activity of Cyr61 was assessed by luciferase assay with promoter deletion/mutagenesis and forced expression/gene silencing of CREB. Interaction between CREB and the Cyr61 promoter was evaluated by electrophoretic mobility shift assay and chromatin immunoprecipitation. CCL2 expression was examined by Northern blotting and enzyme-linked immunosorbent assay. In rats with collagen-induced arthritis (CIA), osteoblastic expression of Cyr61 was examined by immunohistochemistry, and disease progression was assessed by clinical, radiographic, and histologic examination. RESULTS: In primary human osteoblasts and U2OS cells, Cyr61 expression stimulated by tumor necrosis factor alpha, interleukin-1beta (IL-1beta), oncostatin M (OSM), and other IL-6-family cytokines was suppressed by simvastatin. In U2OS cells, simvastatin inhibited OSM induced CREB phosphorylation and CREB-DNA binding. Knockdown of CREB by short hairpin RNA reduced Cyr61 synthesis. OSM-induced Cyr61 promoter activation was dependent on CRE-CREB interaction and inhibited by simvastatin. Cyr61 enhanced CCL2 expression by U2OS cells. Intraarticular injection of simvastatin inhibited CIA progression and diminished the number of Cyr61+ osteoblasts and infiltrating macrophages. CONCLUSION: Simvastatin inhibited cytokine-stimulated Cyr61 expression in osteoblastic cells and suppressed disease progression and osteoblastic expression of Cyr61 in inflammatory arthritis. This finding indicates that simvastatin may have potential as a therapeutic agent for inflammatory arthritis. PMID- 20191586 TI - Probable osteosarcoma risk after prolonged teriparatide treatment: comment on the article by Saag et al. PMID- 20191587 TI - Analysis of maternal-offspring HLA compatibility, parent-of-origin effects, and noninherited maternal antigen effects for HLA-DRB1 in systemic lupus erythematosus. AB - OBJECTIVE: Genetic susceptibility to systemic lupus erythematosus (SLE) is well established, with the HLA class II DRB1 and DQB1 loci demonstrating the strongest association. However, HLA may also influence SLE through novel biologic mechanisms in addition to genetic transmission of risk alleles. Evidence for increased maternal-offspring HLA class II compatibility in SLE and differences in maternal versus paternal transmission rates (parent-of-origin effects) and nontransmission rates (noninherited maternal antigen [NIMA] effects) in other autoimmune diseases have been reported. Thus, we investigated maternal-offspring HLA compatibility, parent-of-origin effects, and NIMA effects at DRB1 in SLE. METHODS: The cohort comprised 707 SLE families and 188 independent healthy maternal-offspring pairs (total of 2,497 individuals). Family-based association tests were conducted to compare transmitted versus nontransmitted alleles (transmission disequilibrium test) and both maternally versus paternally transmitted (parent-of-origin) and nontransmitted alleles (using the chi-square test of heterogeneity). Analyses were stratified according to the sex of the offspring. Maternally affected offspring DRB1 compatibility in SLE families was compared with paternally affected offspring compatibility and with independent control maternal-offspring pairs (using Fisher's test) and was restricted to male and nulligravid female offspring with SLE. RESULTS: As expected, DRB1 was associated with SLE (P < 1 x 10(-4)). However, mothers of children with SLE had similar transmission and nontransmission frequencies for DRB1 alleles when compared with fathers, including those for the known SLE risk alleles HLA DRB1*0301, *1501, and *0801. No association between maternal-offspring compatibility and SLE was observed. CONCLUSION: Maternal-offspring HLA compatibility, parent-of-origin effects, and NIMA effects at DRB1 are unlikely to play a role in SLE. PMID- 20191588 TI - Juvenile idiopathic arthritis and HLA class I and class II interactions and age at-onset effects. AB - OBJECTIVE: The aim of this study was to quantitate risk and to examine heterogeneity for HLA at high resolution in patients with the most common subtypes of juvenile idiopathic arthritis (JIA), IgM rheumatoid factor-negative polyarticular JIA and oligoarticular JIA. Use of 4-digit comprehensive HLA typing enabled great precision, and a large cohort allowed for consideration of both age at disease onset and disease subtype. METHODS: Polymerase chain reaction-based high-resolution HLA typing for class I and class II loci was accomplished for 820 patients with JIA and 273 control subjects. Specific HLA epitopes, potential interactions of alleles at specific loci and between loci (accounting for linkage disequilibrium and haplotypic associations), and an assessment of the current International League of Associations for Rheumatology classification criteria were considered. RESULTS: An HLA-DRB1/DQB1 effect was shown to be exclusively attributable to DRB1 and was similar between patients with oligoarticular JIA and a younger subgroup of patients with polyarticular JIA. Furthermore, patients with polyarticular JIA showed age-specific related effects, with disease susceptibility in the group older than age 6 years limited to an effect of the HLA-DRB1*08 haplotype, which is markedly different from the additional susceptibility haplotypes, HLA-DRB1*1103/1104, found in the group with oligoarticular JIA and the group of younger patients with polyarticular JIA. Also in contrast to findings for oligoarticular JIA, patients with polyarticular arthritis had no evidence of an HLA class I effect. Markers associated with a reduced risk of disease included DRB1*1501, DRB1*0401, and DRB1*0701. DRB1*1501 was shown to reduce risk across the whole cohort, whereas DRB1*0401 and DRB1*0701 were protective for selected JIA subtypes. Surprisingly, the disease predisposition mediated by DPB1*0201 in individuals without any disease predisposing DRB1 alleles was great enough to overcome even the very strong protective effect observed for DRB1*1501. CONCLUSION: Inherited HLA factors in JIA show similarities overall as well as differences between JIA subtypes. PMID- 20191590 TI - DNA polyplexes formed using PEGylated biodegradable hyperbranched polymers. AB - A novel PEGylated biodegradable hyperbranched PEG-b-PDMAEMA has been synthesized. The low toxicity, small molecular weight PDMAEMA chains were crosslinked using a biodegradable disulfide-based dimethacrylate (DSDMA) agent to yield higher molecular weight hyperbranched polymers. PEG chains were linked onto the polymer surface, masking the positive charge (as shown by Zeta potential measurements) and reducing the toxicity of the polymer. The hyperbranched structures were also cleaved under reducing conditions and analyzed, confirming the expected component structures. The hyperbranched polymer was mixed with DNA and efficient binding was shown to occur through electrostatic interactions. The hyperbranched structures could be reduced easily, generating lower toxicity oligomer chains. PMID- 20191591 TI - Orientation control of photo-immobilized antibodies on the surface of azobenzene containing polymers by the introduction of functional groups. AB - In our photo-induced immobilization technique for an antibody (IgG) using azopolymers, the introduction of COOH and NMe(2) into the azopolymers, which can introduce surface charges, strongly affected the immobilization properties such as the efficiency of immobilization and the activity of the immobilized IgG (i.e., the orientation of the immobilized IgG). The introduction of COOH promoted a more active orientation of the immobilized IgG. The orientation was determined during the adsorption process onto the azopolymer surface in solution before photo-immobilization, and was maintained during the photo-immobilization. The surface charge of the azopolymer appears to be an important factor for IgG orientation, which involves electrostatic interactions between its Fab and the azopolymer surface. PMID- 20191592 TI - Pharmaceutical policy, policy for (and management of) human resources and the link between the two. PMID- 20191594 TI - Designing a balanced scorecard for a tertiary care hospital in Pakistan: a modified Delphi group exercise. AB - Balanced Scorecards (BSC) are being implemented in high income health settings linking organizational strategies with performance data. At this private university hospital in Pakistan an elaborate information system exists. This study aimed to make best use of available data for better performance management. Applying the modified Delphi technique an expert panel of clinicians and hospital managers reduced a long list of indicators to a manageable size. Indicators from existing documents were evaluated for their importance, scientific soundness, appropriateness to hospital's strategic plan, feasibility and modifiability. Panel members individually rated each indicator on a scale of 1-9 for the above criteria. Median scores were assigned. Of an initial set of 50 indicators, 20 were finally selected to be assigned to the four BSC quadrants. These were financial (n = 4), customer or patient (n = 4), internal business or quality of care (n = 7) and innovation/learning or employee perspectives (n = 5). A need for stringent definitions, international benchmarking and standardized measurement methods was identified. BSC compels individual clinicians and managers to jointly work towards improving performance. This scorecard is now ready to be implemented by this hospital as a performance management tool for monitoring indicators, addressing measurement issues and enabling comparisons with hospitals in other settings. PMID- 20191595 TI - Noninferiority trial designs for odds ratios and risk differences. AB - This study presents constrained maximum likelihood derivations of the design parameters of noninferiority trials for binary outcomes with the margin defined on the odds ratio (psi) or risk-difference (delta) scale. The derivations show that, for trials in which the group-specific response rates are equal under the point-alternative hypothesis, the common response rate, pi(N), is a fixed design parameter whose value lies between the control and experimental rates hypothesized at the point-null, {pi(C), pi(E)}. We show that setting pi(N) equal to the value of pi(C) that holds under H(0) underestimates the overall sample size requirement. Given {pi(C), psi} or {pi(C), delta} and the type I and II error rates, or algorithm finds clinically meaningful design values of pi(N), and the corresponding minimum asymptotic sample size, N=n(E)+n(C), and optimal allocation ratio, gamma=n(E)/n(C). We find that optimal allocations are increasingly imbalanced as psi increases, with gamma(psi)<1 and gamma(delta)~1/gamma(psi), and that ranges of allocation ratios map to the minimum sample size. The latter characteristic allows trialists to consider trade offs between optimal allocation at a smaller N and a preferred allocation at a larger N. For designs with relatively large margins (e.g. psi>2.5), trial results that are presented on both scales will differ in power, with more power lost if the study is designed on the risk-difference scale and reported on the odds ratio scale than vice versa. PMID- 20191596 TI - Assessment of regional variation in polypharmacy. AB - PURPOSE: To assess polypharmacy in a population with emphasis on regions. METHODS: We studied the individual-based data of all dispensed prescription drugs (DP) during a 3-month study period in Sweden 2006. As an indicator of polypharmacy, five or more (DP > or = 5) different drugs (substances) dispensed were applied. For analysis, we used comparisons of prevalence, correlation of prevalence of polypharmacy with different socioeconomic variables, and a novel weighted polypharmacy index. RESULTS: The national prevalence of polypharmacy, DP > or = 5, was 10.5% (inter-regional variation 9.1-12.1%). The regional variation in the prevalence of polypharmacy was largest for the age groups > or =90 (45.6 59.1%), 80-89 (46.1-53.4%) and 70-79 years (33.1-38.0%). The national prevalence of excessive polypharmacy, DP > or = 10, was 2.2% (inter-regional variation 1.9 2.6%). The regional variation in prevalence of excessive polypharmacy was largest for the age groups > or =90 (9.8-22.3%), 80-89 (11.4-17.1%) and 70-79 years (7.0 9.4%). We found a fairly strong positive correlation between polypharmacy and the age group > or =70 years (r = 0.84 for men and 0.71 for women). The novel weighted polypharmacy index indicated regional differences in the internal distribution of the prevalence of dispensed drugs for individuals with polypharmacy. CONCLUSION: Our findings indicate that the observed regional differences in the prevalence of polypharmacy partly can be explained by the regional age distribution in Sweden. The use of the novel weighted polypharmacy index indicated regional differences in drug therapy for individuals with polypharmacy. PMID- 20191597 TI - Safety walkarounds predict injury risk and reduce injury rates in the construction industry. AB - BACKGROUND: "Safe Workplace"-a simplified and educational version of the Finnish building construction methodology involving safety walkarounds where a number of safety indicators are inspected and evaluated-is in widespread use in the Danish construction sector to evaluate physical safety standards proactively at construction work sites. METHODS: Data from the construction of the Copenhagen Metro were analyzed to determine the method's ability to predict injury risk related to joint responsibilities and individual worker responsibilities. RESULTS: A statistically significant association between the risk level as measured by the Safe Workplace methodology and injury risk was found. The relative risk of injury increased with the number of safety indicators violated and was elevated for safety indicators reflecting both individual and joint safety responsibility. The observed injury risk was not elevated in the post safety walkaround period for safety indicators of individual responsibility, but the joint responsibility indicators retained an elevated injury risk level. CONCLUSIONS: The data support the hypothesis that safety walkarounds both predict and prevent injuries. Safety indicators of individual responsibility are more likely to be corrected than those of joint responsibility. PMID- 20191598 TI - Alcohol consumption and work-related injuries among farmers in Heilongjiang Province, People's Republic of China. AB - BACKGROUND: Alcohol consumption has been found to be associated with work-related injuries among workers around the world, but this association has not well been studied among agricultural workers in China. METHODS: This population-based survey aimed to study the association between alcohol use and work-related agricultural injury. Farmers in a northeastern province of China were questioned about work-related injury in the past year (May 2007-April 2008), alcohol use, farming practices, and sociodemographic factors. The Chi-square test and logistic regression analyses were used to investigate the role of alcohol drinking in agricultural injuries. RESULTS: Among 2,050 farmers who completed the survey, the 12-month prevalence of work-related injury was 12.2%. The leading external cause of injury was exposure to mechanical force. The odds of injury among farmers with past month drinking, who drank distilled spirits, and reported intoxication were respectively 1.77 (95% CI = 1.27-2.47), 1.89 (95% CI = 1.35-2.66), 2.12 (95% CI = 1.42-3.11). The odds of injury also significantly increased with greater average amounts of pure alcohol per day, with increased frequency of drinking per week, and with greater reported years of drinking. Each alcohol use variable was associated with injury in logistic regression models while controlling for sex, age, years of farm work, months of farm work in the past 12 months, driving a motor vehicle, and agricultural machinery use. CONCLUSIONS: We found a significant association between alcohol consumption and work-related injuries among farmers. Our findings stress the need for culturally appropriate interventions which affect alcohol use and prevent injuries among Chinese farmers. PMID- 20191599 TI - Controlling ecological bias in evidence synthesis of trials reporting on collapsed and overlapping covariate categories. AB - Meta-analysis of randomized controlled trials based on aggregated data is vulnerable to ecological bias if trial results are pooled over covariates that influence the outcome variable, even when the covariate does not modify the treatment effect, or is not associated with the treatment. This paper shows how, when trial results are aggregated over different levels of covariates, the within study covariate distribution, and the effects of both covariates and treatments can be simultaneously estimated, and ecological bias reduced. Bayesian Markov chain Monte Carlo methods are used. The method is applied to a mixed treatment comparison evidence synthesis of six alternative approaches to post-stroke inpatient care. Results are compared with a model using only the stratified covariate data available, where each stratum is treated as a separate trial, and a model using fully aggregated data, where no covariate data are used. PMID- 20191600 TI - The health of California's immigrant hired farmworkers. AB - BACKGROUND: Hispanic immigrant workers dominate California's hired farm workforce. Little is known about their health status; even less is known about those lacking employment authorization. METHODS: The California Agricultural Workers Health Survey (CAWHS) was a statewide cross-sectional household survey conducted in 1999. Six hundred fifty-four workers completed in-person interviews, comprehensive physical examinations, and personal risk behavior interviews. RESULTS: The CAWHS PE Sample is comprised mostly of young Mexican men who lack health insurance and present elevated prevalence of indicators of chronic disease: overweight, obesity, high blood pressure, and high serum cholesterol. The self-reported, cumulative, farm work career incidence of paid claims for occupational injury under workers compensation was 27% for males and 11% for females. CONCLUSIONS: The survey finds elevated prevalence of indicators of chronic disease but lack of health care access. Participants without employment authorization reported a greater prevalence of high-risk behaviors, such as binge drinking, and were less knowledgeable about workplace protections. PMID- 20191601 TI - Modelling continuous exposures with a 'spike' at zero: a new procedure based on fractional polynomials. AB - A common task in epidemiology is to estimate the dose-response function for a continuous exposure. Often a proportion of subjects is unexposed. Typical examples are cigarette consumption, alcohol intake, or occupational exposures. The question arises as to how to model such variables statistically. The fractional polynomial method of modelling continuous exposure variables is extended to allow for a proportion unexposed. A binary variable for the unexposed fraction is added to the model. In a two-stage procedure, we assess whether the binary variable and/or the continuous function for the exposed individuals is required for a good fit to the data. Extension to the multivariable situation is described. Three data sets with different characteristics are used as illustrations. The analyses of the three studies using the proposed procedure give differing results. In one example, only the binary variable seems to be required. In the other two examples, the binary variable and fractional polynomial functions of the exposure variable are needed. One function is monotonic and the other has a minimum. In the third example, adjusting for confounders has almost no effect on the function selected. In conclusion, the new procedure offers a worthwhile extension of dose-response modelling with an unexposed fraction. It is simple to carry out with standard software. PMID- 20191602 TI - Neurological mortality among Gulf War veterans. PMID- 20191603 TI - Intraoperative magnetic resonance imaging in the surgical treatment of cerebral metastases. AB - BACKGROUND AND OBJECTIVES: To report on the value of intraoperative magnetic resonance imaging (iMRI) in the neurosurgical treatment of cerebral metastases (CM). METHODS: We performed a total of 204 surgical procedures with the use of a mobile ultra-low-field iMRI-unit. Of these, there were 12 craniotomies and 2 minimal-invasive procedures for CM, and 63 craniotomies for glioblastoma (GBM). RESULTS: On intraoperative imaging, all tumors could be localized and targeted with the help of the integrated neuronavigation system. Intraoperative imaging resulted in continued tumor resection due to unexpected residual tumor tissue in 13 patients harboring GBM (20.6%), but no patient with a CM (0%). In two patients with cystic CM, iMRI helped to achieve complete collapse of cysts by means of stereotactic aspiration, relieving mass effect and allowing for adjuvant radiotherapy. All patients subsequently received adjuvant treatment according to clinical protocols. CONCLUSION: Surgical resection represents one of several treatment modalities in metastatic brain disease. iMRI is useful for neuronavigation and resection control and as an adjunct in minimal-invasive procedures in patients with CM; however, its exact value is yet to be determined by prospective randomized trials. PMID- 20191604 TI - Non-small cell lung carcinoma of the superior sulcus: The evolution of treatment outcomes with multimodality treatment at a single institution. AB - OBJECTIVES: We evaluated the efficacy of the multimodality approach in treating superior sulcus non-small cell lung carcinoma (SS NSCLC). METHODS: We retrospectively analyzed the records of 57 patients with SS NSCLC who were treated at our institution between 1982 and 2007. RESULTS: During the study period, 3- and 5-year survival increased significantly from 42.6% and 42.6% in the first half of the study period (1982-1994) to 72.7% and 65.4% in the second half (1995-2007), respectively. Methods of clinical staging were unchanged between the two time periods, although the ratio of adenocarcinoma was increased, and multimodality treatment, particularly concurrent chemoradiotherapy followed by surgical resection, was used more frequently in the second half of the study period. The 5-year survival of patients who received preoperative chemoradiotherapy followed by surgery (n = 27) was better than that of those who received other treatment regimen with surgery (n = 22, 64.6% vs. 49.6%; P = 0.044). Five-year survival in patients with complete resection after chemoradiotherapy was 70.4%. Thirteen patients (48%) achieved a pathologic complete response or minimal microscopic disease. CONCLUSIONS: Multimodality treatment with concurrent chemoradiotherapy followed by surgery appears to contribute to improved outcomes over time in patients with SS NSCLC. PMID- 20191605 TI - A confirmatory seamless phase II/III clinical trial design incorporating short term endpoint information. AB - Seamless phase II/III designs allow strong control of the familywise type I error rate when the most promising of a number of experimental treatments is selected at an interim analysis to continue along with the control treatment. If the primary endpoint is observed only after long-term follow-up it may be desirable to use correlated short-term endpoint data available at the interim analysis to inform the treatment selection. If short-term data are available for some patients for whom the primary endpoint is not available, basing treatment selection on these data may, however, lead to inflation of the type I error rate. This paper proposes a method for the adjustment of the usual group-sequential boundaries to maintain strong control of the familywise error rate even when short-term endpoint data are used for the treatment selection at the first interim analysis. This method allows the use of the short-term data, leading to an increase in power when these data are correlated with the primary endpoint data. PMID- 20191606 TI - Studies of insect peptides alloferon, Any-GS and their analogues. Synthesis and antiherpes activity. AB - The subject of these studies was synthesis and determination of biological properties of a series of insect peptides, such as alloferon, Any-GS and their analogues. The synthesis of 14 peptides was performed by the solid-phase method. Biological effect of these peptides was evaluated by the antiviral test against Human Herpes Virus type 1 (HHV-1) in vitro using a Vero cell line. It was found that the investigated peptides inhibit the replication of HHV-1 in Vero cells. PMID- 20191607 TI - An optimized chemical synthesis of human relaxin-2. AB - Human gene 2 relaxin (RLX) is a member of the insulin superfamily and is a multi functional factor playing a vital role in pregnancy, aging, fibrosis, cardioprotection, vasodilation, inflammation, and angiogenesis. RLX is currently applied in clinical trials to cure among others acute heart failure, fibrosis, and preeclampsia. The synthesis of RLX by chemical methods is difficult because of the insolubility of its B-chain and the required laborious and low yielding site-directed combination of its A (RLXA) and B (RLXB) chains. We report here that oxidation of the Met(25) residue of RLXB improves its solubility, allowing its effective solid-phase synthesis and application in random interchain combination reactions with RLXA. Linear Met(O)(25)-RLX B-chain (RLXBO) reacts with a mixture of isomers of bicyclic A-chain (bcRLXA) giving exclusively the native interchain combination. Applying this method Met(O)(25)-RLX (RLXO) was obtained in 62% yield and was easily converted to RLX in 78% yield, by reduction with ammonium iodide. PMID- 20191608 TI - The neural cell adhesion molecule is involved in the metastatic capacity in a murine model of lung cancer. AB - Neural cell adhesion molecule (NCAM) is involved in cell growth, migration, and differentiation. Its expression and/or polysialylation appear to be deregulated in many different cancer types. We employed the lung tumor cell line LP07, syngeneic in BALB/c mice to investigate the role of NCAM in malignant progression. LP07 cells express the three main NCAM isoforms, all of them polysialylated. This cells line, pretreated with an anti-NCAM antibody and inoculated intravenously (i.v.) into syngeneic mice, developed less and smaller lung metastases. In vitro studies showed that NCAM bound antibody inhibited cell growth, mainly due to an increase in apoptosis, associated with a decrease of cyclin D1 and enhanced expression of active caspase 3 and caspase 9. Anti-NCAM treated LP07 cells showed impairment in their ability to migrate and adhere to several extracellular matrix components. Secreted uPA activity was also reduced. NCAM-140 knocked-down by siRNA in LP07 cells pretreated or not with anti-NCAM showed an impaired metastasizing ability upon i.v. inoculation into mice. These results suggest that anti-NCAM treatment could be mimicking homophilic trans interactions and NCAM-140 knocked-down impairs heterophilic interactions, both leading to inhibition of metastatic dissemination. The involvement of NCAM in lung tumor progression was confirmed in human NSCLC tumors. Sixty percent of the cases expressed NCAM at tumor cell level. A multivariate analysis indicated that NCAM expression was associated with a shorter overall survival in this homogeneous series of Stages I and II NSCLC patients. NCAM may be able to modulate mechanisms involved in lung carcinoma progression and represents an attractive target to control metastatic progression. PMID- 20191609 TI - PIM-1 gene RNA interference induces growth inhibition and apoptosis of prostate cancer cells and suppresses tumor progression in vivo. AB - BACKGROUND: The goal of this study was to investigate the roles of PIM-1 in prostate cancer (CaP) cell proliferation and apoptosis, and to assess the potential of PIM-1 as a target for CaP therapy. METHODS: Using RNAi technology, we knocked down the expression of PIM-1 in PC-3 cell. After siRNA transfection, cell morphology, cell proliferation, cell cycle, and apoptosis rate were analyzed. PIM-1 siRNA with Lipofectamine were injected into xenograft models to evaluate its therapeutic effect. RESULTS: PIM-1 siRNA significantly inhibited PIM 1 expression. In vitro, silencing of the PIM-1 gene resulted in irregular cell morphology, decreased cell proliferation, inhibition of cell-cycle progression, and induction of apoptosis. Compared with control groups, intratumoral injection of PIM-1 siRNA with Lipofectamine in nude mice dramatically suppressed PC-3 tumor progression. CONCLUSIONS: PIM-1 could play important roles in the progression of CaP and may be an interesting target for CaP therapy. PMID- 20191610 TI - Angiosarcoma developing in a non-functioning arteriovenous fistula post-renal transplant. AB - BACKGROUND: Angiosarcomas comprise less than 1% of all sarcomas, arising from endothelial cells of blood or lymph vessels. Chronic immunosuppression increases the risk of many malignancies and an association between the development of angiosarcoma with an immunosuppressed state is established. A few cases have been reported of angiosarcomas arising in the post-renal transplant patient. Specifically, there have been six cases of an angiosarcoma arising in arteriovenous (AV) fistulae in this patient population. We describe a further case and review the relevant literature with specific emphasis on a possible mechanism for the development of angiosarcoma in the post-transplant patient. CASE PRESENTATION: We report the case of a 48-year-old male who developed an angiosarcoma in a ligated native AV fistula. The lesion arose on the background of immunosuppression following a successful ABO-incompatible renal transplant for chronic renal failure. CONCLUSION: Angiosarcomas are extremely rare tumours but should be considered as a differential diagnosis for an evolving mass near the site of an AV fistula. Diagnosis relies on an index of suspicion and obtaining a definitive histological diagnosis. Both clinicians and patients should be aware that an evolving mass within or around an AV fistula should prompt urgent biopsy. PMID- 20191611 TI - Selecting treatment for hepatocellular carcinoma based on the results of hepatic resection and local ablation therapy. AB - BACKGROUND: First-line treatment for 24 hours, who developed agitation and/or delirium upon weaning from sedation and failed to achieve successful extubation with conventional management. Patients were ventilated for a median (interquartile range) of 115 [87 to 263] hours prior to enrolment. Dexmedetomidine infusion was commenced at 0.4 microg/kg/hour for two hours, after which concurrent sedative therapy was preferentially weaned and titrated to obtain target Motor Activity Assessment Score score of 2 to 4. The median (range) maximum dose and infusion time of dexmedetomidine was 0.7 microg/kg/hour (0.4 to 1.0) and 62 hours (24 to 252) respectively. The number of episodes at target Motor Activity Assessment Score score at zero, six and 12 hours after commencement of dexmedetomidine were 7/30 (23.3%), 28/30 (93.3%) and 26/30 (86.7%), respectively (P < 0.001 for 6 and 12 vs. 0 hours). Excluding unrelated clinical deterioration, 22 episodes (73.3%) achieved successful weaning from ventilation with a median (interquartile range) ventilation time of 70 (28 to 96) hours after dexmedetomidine infusion. Dexmedetomidine achieved rapid resolution of agitation and facilitated ventilatory weaning after failure of conventional therapy. Its role as first-line therapy in ventilated, agitated patients warrants further investigation. PMID- 20191783 TI - Incidence of residual neuromuscular blockade in a post-anaesthetic care unit. AB - We conducted a prospective observational study to assess the incidence of residual neuromuscular blockade (RNMB) in a post-anaesthetic care unit (PACU) of a tertiary hospital. The subjects were 102 patients undergoing general anaesthesia with neuromuscular blockade (NMB). The procedural anaesthetists were unaware of their patients' inclusion in the study, and the choice of muscle relaxant and use of reversal agents were at the anaesthetists' discretion. On arrival to the PACU, the train-of-four ratio was assessed using electromyography, repeated every five minutes until the train-of-four ratio exceeded 0.9. RNMB was defined as a train-of-four ratio < 0.9. The requirement for airway support, incidence of desaturation while in the PACU and time to eligibility for PACU discharge were recorded. The mean interval between the last dose of relaxant and arrival in the PACU for patients with RNMB was 81 minutes. An intermediate-acting muscle relaxant had been used for most patients. Despite this, RNMB was observed in 31% (95% confidence interval 25 to 47%) of patients. Our findings suggest that RNMB in the PACU is common. As RNMB may predispose to postoperative complications, anaesthetists should utilise quantitative monitoring to assess neuromuscular blockade and optimise reversal use. Anaesthetists should be aware that intervals between the last dose of relaxant of well over one hour do not exclude the possibility of RNMB, even when using intermediate-acting neuromuscular blockade agents. PMID- 20191784 TI - Monitoring of extubated patients: are routine arterial blood gas measurements useful and how long should patients be monitored in the intensive care unit? AB - Restitution of respiratory support, which may include continuous positive airway pressure, non-invasive ventilation or reintubation, is needed in some patients post-extubation. We aimed to investigate whether serial arterial blood gas measurements done in the post-extubation period would help to identify such patients and to delineate the optimal post-extubation duration for close monitoring. We retrospectively analysed 115 consecutive adult patients who were extubated following successful spontaneous breathing trials in the medical intensive care unit, excluding patients who were extubated to immediate non invasive ventilation. Arterial blood gases were measured at one and three hours post-extubation and patients were followed for any restitution of respiratory support for the remainder of their hospital stay. Restitution of respiratory support was required for 22 of 115 (19.1%) patients, of whom 20 were originally intubated for pneumonia. These patients could all be detected clinically from deteriorating pulse oximetry or increasing drowsiness. Performing serial arterial blood gas measurements following extubation did not improve the detection rate or allow earlier detection of patient deterioration. Among the patients with pneumonia, restitution of respiratory support was required within 24 hours of extubation for 16 patients (80%) and after more than 49 hours for four patients. Serial arterial blood gas measurements at one and three hours after a planned extubation are not useful and patients originally intubated for pneumonia should be monitored post-extubation for at least 24 hours in the intensive care unit. PMID- 20191785 TI - Episodic waveforms in the electroencephalogram during general anaesthesia: a study of patterns of response to noxious stimuli. AB - Previous studies of the electroencephalogram (EEG) during anaesthesia have identified two distinct patterns of change in response to a noxious stimulus, a classical arousal pattern and a paradoxical arousal pattern. We developed methods of EEG analysis to quantify episodic EEG patterns--namely sleep spindle-like ('10 Hz-score') and burst-suppression-like fluctuations in high frequencies ('high frequency variation index')--and used traditional power spectral quantification of non-episodic delta waves. We studied 30 healthy adult patients undergoing elective surgery under general anaesthesia with propofol, fentanyl (1.0, 2.5 or 4.0 microg/kg, n=10 for each group), muscle relaxant and sevoflurane. Prefrontal EEG data were recorded during the operation and analysed for changes in episodic patterns before and after noxious stimuli (intubation and incision). Before noxious stimuli, the EEG patterns varied markedly between patients and were not strongly correlated to calculated effect-site concentrations of fentanyl, propofol or sevoflurane. Noxious stimuli reduced the 10 Hz-score from 0.25 to 0.20 (P = 0.01) after intubation and from 0.33 to 0.27 (P = 0.01) after incision; and high frequency variation index from 2.8 to 2.0 (P=0.02) after incision--the classical arousal pattern. The nociception-induced reduction in spindles was greater in the low-dose fentanyl group (P = 0.01). There was less tachycardia in the high-dose fentanyl group (P = 0.002). It is possible to quantify such episodic EEG patterns during general anaesthesia and in this study noxious stimulation tended to reduce the prevalence of these patterns. PMID- 20191786 TI - Preoperative estimated glomerular filtration rate and RIFLE-classified postoperative acute kidney injury predict length of stay post-coronary bypass surgery in an Australian setting. AB - We investigated the influence of preoperative estimated glomerular filtration rate and postoperative acute kidney injury on outcomes after coronary bypass surgery in a local setting, with the focus on length of stay. A retrospective analysis of prospectively collected data for 3302 consecutive patients who underwent coronary artery bypass graft surgery (June 1997 through to January 2007) at St. Vincent's Public Hospital, Melbourne, was undertaken. Preoperative estimated glomerular filtration rate was calculated and categorised using US National Kidney Foundation cut-offs for chronic kidney disease (normal function; mild, moderate and severe dysfunction). Postoperative acute kidney injury was categorised using serum creatinine RIFLE criteria (no acute kidney injury, risk, injury and failure). Postoperative intensive care and hospital length of stay was determined. The hazard ratios for time to hospital discharge up to one month decreased (indicating a longer length of stay) as severity of preoperative renal dysfunction category increased when compared to those with normal renal function: mild hazard ratio = 1.02 (95% confidence interval: 0.91 to 1.15, P = 0.70), moderate 0.87 (0.76 to 1.00, P = 0.047), severe 0.47 (0.35 to 0.64, P < 0.001). Hazard ratios also decreased as severity of postoperative acute kidney injury category increased, when compared to those with no acute kidney injury: risk 0.67 (0.58 to 0.77, P < 0.001), injury 0.52 (0.41 to 0.65, P < 0.001), failure 0.35 (0.20 to 0.60, P < 0.001). The increasing severity of preoperative renal dysfunction and postoperative acute kidney injury were associated with increased hospital length of stay. This has implications for resource use, informed consent and case selection. PMID- 20191787 TI - An evaluation of P wave dispersion, QT, corrected QT and corrected QT dispersion intervals on the electrocardiograms of malnourished adults. AB - The aim of our study was to investigate P wave dispersion (Pwd), QT corrected QT (QTc), QT dispersion (QTd) and corrected QT dispersion (QTcd) intervals in subjects with malnutrition diagnosed in the pre-anaesthetic assessment, compared to those without malnutrition. A total of 76 adult patients were included. Main diagnoses, anthropometric measurement, body mass index, electrocardiogram and serum sodium, potassium, chloride, magnesium and calcium levels were recorded for all patients. Pwd, QT and QTd intervals were measured on all electrocardiogram records and QTc and QTcd intervals determined with the Bazett formula. Protein energy malnutrition was diagnosed with the nutritional risk index. No statistically significant difference was found between the age, gender and malignant cancer diagnosis rates between patients with malnutrition (group M) and those not suffering from malnutrition (group N) (P > 0.05). Serum albumin, total protein, potassium, calcium, magnesium and chloride values of group M were found to be significantly lower than group N (P < 0.05). In group M, Pwd, QT, QTc, QTd and QTcd intervals were significantly longer than in group N (P < 0.001). Patients diagnosed with malnutrition during pre-anaesthetic assessment had significantly longer Pwd, QTc and QTcd interval durations than the control group. We attribute such extended Pwd, QTc and QTcd durations in these patients to malnutrition and malnutrition-related electrolyte imbalance. PMID- 20191788 TI - Evaluation of P wave and corrected QT dispersion in subarachnoid haemorrhage. AB - The aim of our study was to investigate P wave dispersion (Pwd), QT corrected QT (QTc), QT dispersion (QTd) and corrected QT dispersion (QTcd) intervals in subarachnoid haemorrhage. Thirty-five subarachnoid haemorrhage patients (Group S) and 35 neurologically normal patients (Group C) were included in this retrospective study. The standard 12 derivations of the electrocardiograms of all patients were analysed and Pwd, QT and QTd intervals were measured. QTc and QTcd intervals were determined with the Bazett formula. There was no significant difference between the study groups according to demographic characteristics, hypertension and diabetes mellutus incidences (P > 0.05). The Pwd, QT, QTc, QTd and QTcd durations of Group S were significantly longer than those of Group C (P < 0.001). Subarachnoid haemorrhage patients may have a higher likelihood of arrhythmia during anaesthesia and in intensive care due to extended QTcd and Pwd durations. PMID- 20191789 TI - Decreased cytosolic glucocorticoid receptor levels in critically ill patients. AB - The immune system and the hypothalamic-pituitary-adrenal axis are linked by several mechanisms. Intracellular glucocorticoid receptors represent one important connection. The aim of this study was to examine the coherence between the number of glucocorticoid receptors, activation of the hypothalamic-pituitary adrenal axis, inflammatory cytokine levels and the severity of illness in critically ill patients. In a prospective study, blood was collected from 20 healthy members of the hospital staff (control group) and 50 ventilated patients (sample group) within the first 24 hours after intubation and within three days of extubation. 3H-dexamethasone-binding assay was used to assess cytoplasmatic free glucocorticoid receptors levels. ACTH, cortisol, IL-6 and TNFa levels were measured by ELISA. In the sample group, specific binding of 3H-dexamethasone was significantly decreased compared to the control group. Glucocorticoid receptor levels tended to be lower in more severely ill patients. Plasma cortisol and ACTH levels were significantly different from the control group after extubation but not at intubation. Severe illness is associated with rapid down-regulation of 3H dexamethasone binding. This decrease occurs before elevation of plasma cortisol. Therefore, down-regulation of cortisol binding may be directly associated with the stress response and not due to feedback regulation following increase in plasma cortisol levels. PMID- 20191791 TI - A unique snapshot of intensive care resources in Australia and New Zealand. AB - The objective of this study was to analyse and report on the distribution and attributes of intensive care services in Australia and New Zealand for the 2005/2006 financial year A survey was mailed to 155 Australian and 26 New Zealand intensive care units (ICU) listed on the database of the Australian and New Zealand Intensive Care Society. A descriptive analytical approach was used. Of the 181 ICUs, 177 provided data. In Australia there were 100 public sector and 51 private sector ICUs and in New Zealand, 24 public sector and two private sector ICUs. These units contain 1485 available beds in the public sector and 538 available beds in the private sector Calculations to determine beds per 100,000 population, medical specialists per 1000 patient days and registered nurses per 1000 patient days showed wide variation. International comparisons are limited by lack of data; however it does appear that intensive care patients in Australia and New Zealand have very good outcomes. PMID- 20191790 TI - A randomised comparison of parecoxib versus placebo for pain management following minor day stay gynaecological surgery. AB - At therapeutic concentrations, parecoxib selectively inhibits the cyclo-oxygenase 2 enzyme. We investigated the impact of a single preoperative dose of parecoxib on pain relief following minor gynaecological surgery. Ninety women undergoing uterine dilatation and curettage, with or without hysteroscopy, were randomised to receive either 40 mg of parecoxib intravenously or a saline placebo prior to induction of standardised general anaesthesia. Exclusion criteria included a preoperative history of renal dysfunction or hypertension and the preoperative use of anti-inflammatory or opioid medication. The primary endpoint was the pain score during recovery. There was no difference in global pain scores or area under the curve for pain scores in the recovery area. Pain scores with coughing one hour after surgery were low in both groups but significantly lower after parecoxib (median 2 [interquartile range 0 to 4] parecoxib group vs. 2 [interquartile range 0 to 6] placebo group, P = 0.037). The 24 hour Quality of Recovery score did not differ significantly between groups but the parecoxib group was less likely to experience headache at 24 hours postoperatively (12 vs. 38%, P = 0.007) and reported complete satisfaction more frequently (78 vs. 57%, P = 0.042). The preoperative administration of parecoxib was associated with a significant but small decrease in dynamic pain scores one hour postoperatively. Women who received preoperative parecoxib had a lower incidence of postoperative headache and higher satisfaction. PMID- 20191792 TI - The Entropy Module and Bispectral Index as guidance for propofol-remifentanil anaesthesia in combination with regional anaesthesia compared with a standard clinical practice group. AB - This study was designed to investigate the impact of the Entropy Module and Bispectral Index (BIS) monitoring on drug consumption and recovery times compared with standard anaesthetic practice in patients undergoing orthopaedic surgery using a combination of regional and general anaesthesia as performed by an experienced anaesthesiologist. We hypothesised that electroencephalogram monitoring would lead to a lower drug consumption as well as shorter recovery times. With institutional review board approval and written informed consent, 90 adult patients undergoing surgery to the upper or lower extremity received regional anaesthesia for post- and intraoperative pain control and were randomised to receive general anaesthesia by propofol/remifentanil infusion controlled either solely by clinical parameters or by targeting Entropy or BIS values of 50. Recovery times and drug consumption were recorded. Data from 79 patients were analysed. Compared with standard practice, patients with Entropy or BIS monitoring showed a similar propofol consumption (standard practice 101 +/- 22 microg/kg/minute, Entropy 106 +/- 24 microg/kg/minute, BIS 104 +/- 20 microg/kg/minute) and showed similar Aldrete scores (10/10) one minute after extubation: 9.1 +/- 0.3, 9.2 +/- 0.6 and 9.3 +/- 0.5, respectively. Time points of extubation were 7.3 +/- 2.9 minutes, 9.2 +/- 3.9 minutes and 6.8 +/- 2.9 minutes, respectively, demonstrating a significant difference between Entropy and BIS (P = 0.023). Compared with standard practice, targeting an Entropy or BIS value of 50 did not result in a reduction of propofol consumption during general anaesthesia combined with regional anaesthesia as performed by an experienced anaesthesiologist in orthopaedic patients. PMID- 20191793 TI - An overview of evidence from systematic reviews evaluating early enteral nutrition in critically ill patients: more convincing evidence is needed. AB - International quality improvement initiatives such as Fast-Hug bring a focus on improving the delivery of early enteral nutrition to critically ill patients, however surveys demonstrate current practice remains variable. One way to reduce variability in practice is to provide strong evidence to convince clinicians to change. The purpose of this overview was to identify current best evidence supporting the delivery of early enteral nutrition in critical illness. We sought high-quality evidence in the form of systematic reviews containing meta-analyses of randomised controlled trials. Two authors independently identified studies and assessed methodological quality. Data sources included Medline, EMBASE and hand searching of guideline reference lists. The literature search identified five systematic reviews that summarised 30 clinical trials. These systematic reviews focused on acutely hospitalised patients, critical illness, burns, elective intestinal surgery and pancreatitis. Early enteral nutrition significantly reduced mortality in elective intestinal surgery patients (relative risk 0.41, 95% confidence interval 0.18 to 0.93, P = 0.03, I2 = 0.0%) and significantly reduced infectious complications in acutely ill hospitalised patients (relative risk 0.45, 95% confidence interval 0.3 to 0.66, P = 0.00006, heterogeneity P = 0.049). Four of five identified systematic reviews had key methodological quality deficiencies. The results of this overview highlight the variability in the evidence regarding the benefits of early enteral nutrition in critically ill patient populations. The inconsistent delivery to critically ill patients may be explained by the lack of convincing evidence. Better evidence may be needed to reduce the irregularity in the provision of early enteral nutrition to critically ill patients. PMID- 20191794 TI - Hyperbaric oxygen therapy in the treatment of post cardiac surgical strokes--a case series and review of the literature. AB - Strokes remain an uncommon but significant complication of cardiac surgery. Cerebral air embolism is the likely aetiology in the majority of cases. Hyperbaric oxygen therapy is the recognised treatment for cerebral air embolism associated with compressed air (SCUBA) diving accidents and is therefore also the standard of care for iatrogenic causes of air embolism. It follows that there is a logic in treating post-cardiac surgical stroke patients with hyperbaric oxygen. The aim of this retrospective review was to examine the outcomes of 12 such patients treated in the Christchurch Hospital hyperbaric unit and to appraise the evidence base for the use of hyperbaric oxygen therapy in this setting. Despite delays of up to 48 hours following surgery before the institution of hyperbaric oxygen therapy, 10 of the 12 patients made a full neurological recovery or were left with mild residual symptoms, with nine returning to their previous level of care. One patient remained hemiplegic and there was one early neurological death. There is a paucity of prospective data in this area, but based on sound pathophysiological principles and clinical experience, we believe that patients suffering a stroke following open cardiac surgery should be considered for hyperbaric oxygen therapy. PMID- 20191795 TI - Magnesium sulphate for treatment of tetanus in adults. AB - There are reports that suggest that magnesium sulphate alone may control muscle spasms thereby avoiding sedation and mechanical ventilation in tetanus, but this has not been confirmed. We examined the efficacy and safety of intravenous magnesium sulphate for control of rigidity and spasms in adults with tetanus. A prospective clinical study of intravenous magnesium sulphate was carried out over a period of two years in a tertiary care teaching hospital. In addition to human tetanus immunoglobulin and parenteral antibiotics, patients with tetanus received magnesium sulphate 70 mg/kg intravenously followed by infusion. The infusion was increased by 0.5 g/hour every six hours until cessation of spasms or abolishment of patellar tendon jerk. The primary outcome measure was efficacy determined by control of spasms. Secondary outcomes included frequency of autonomic instability, duration of ventilatory support, hospital stay and mortality. Thirty three patients were enrolled. At presentation, the incidence of severity of tetanus was as follows: Grade I: 5 (15%), Grade II: 13 (39%), Grade III: 14 (42%) and Grade IV: 1 (3%). Rigidity and mild spasms were controlled with magnesium therapy alone in six patients; all were Grades I or II. Additional sedatives were required in severe forms of tetanus. The average duration of ventilatory support was 18.3 +/- 16.0 days and the overall mortality was 22.9%. Asymptomatic hypocalcaemia was a universal finding. Magnesium sulphate therapy alone may not be efficacious for the treatment of severe tetanus. PMID- 20191796 TI - Ocular surface bacterial colonisation in sedated intensive care unit patients. AB - We investigated the time-dependent ocular surface bacterial colonisation of sedated patients hospitalised in an intensive care unit and aimed to evaluate whether proper topical antibiotic prophylaxis could prohibit corneal infection. The study lasted 12 months and included 134 patients undergoing sedation and mechanical respiratory support for various medical reasons. Patients hospitalised for less than seven days and those with pre-existing ocular surface pathology were excluded. All patients were examined on admission by inspecting the cornea for erosions. Followup examinations were performed each subsequent day. Cultures were also obtained from the conjunctival sac of both eyes on admission and every seventh day until the end of sedation. Standard laboratory techniques were used for isolation, identification and antibiotic susceptibility testing of bacteria. Antibiotic treatment for prophylaxis was administered accordingly. Analysis was carried out for 70 patients. Duration of sedation ranged from seven to 122 days. Fifty-four (77%) patients were colonised by at least one bacterial species other than normal flora within seven to 42 days. Multiple bacteria were isolated from 28 patients undergoing prolonged sedation. Prevalent isolates were Pseudomonas aeruginosa, Acinetobacter spp. and Staphylococcus epidermidis. Infectious keratitis was prohibited in all cases. Ocular surface of long-term sedated patients was found to be colonised by various bacterial species and their isolation was closely associated with the time period of hospitalisation. The results of this study suggest that the early identification of ocular surface bacteria colonisation and the administration of topical antibiotics for prophylaxis can prohibit corneal infection in these patients. PMID- 20191797 TI - Difficult double-lumen tube placement due to laryngeal web. AB - We present a case of difficult intubation in a patient with a laryngeal web. A 33 year-old male patient presented for open thoracotomy and had a previously undiagnosed laryngeal web, which complicated the placement of a double-lumen tube. A single-lumen tube was placed with the use of a bougie through the narrowed airway. With the subsequent use of an airway exchange catheter a double lumen tube was positioned. Techniques for managing narrowing of the supraglottic airway are presented and the literature dealing with laryngeal webs is reviewed. In the setting of an unusual airway and thoracic surgery, ventilation via simpler techniques takes precedence over insertion of more complex tubes. PMID- 20191798 TI - 'Speaking valve' aspiration in a laryngectomy patient. AB - Tracheo-oesophageal speech using a one-way speaking valve is a common mode of speech rehabilitation for laryngectomy patients. Aspiration of this device can cause significant airway obstruction and pose anaesthetic and surgical challenges during its retrieval. In this case report, we describe our management of a patient who had had a laryngectomy who aspirated his speaking valve through his stoma. Emergency retrieval of the valve was performed, during which difficulties were encountered, first in obtaining an adequate seal for pre-oxygenation, and second in maintaining adequate oxygen saturation. We discuss some innovative techniques that could be used to address these issues. PMID- 20191799 TI - Duropleural fistula revealed by neurological manifestations: an unusual cause of pleural effusion. AB - Symptomatic pleural collection of cerebrospinal fluid is a rare but accepted complication in hydrocephalic paediatric patients treated with ventriculopleural shunts. Few cases have been described in adults, usually as complication of trauma, tumours or spinal surgery, particularly post-laminectomy. It should be considered in the differential diagnosis of pleural effusion after neurosurgical procedures involving the spine. We describe two patients with large cerebrospinal fluid collections in the pleural cavity caused by postoperative duropleural fistula, who presented with neurological symptoms, cerebrospinal fluid pressure headache and meningitis. PMID- 20191800 TI - Anaesthesia for acute intestinal obstruction associated with cerebral arteriovenous malformation in a child. AB - This case report describes the perioperative management of a child presenting with acute intestinal obstruction secondary to bowel malrotation after a recent intracranial haemorrhage associated with an intracranial arteriovenous malformation. We discuss the anaesthesia planning for this case, where the 'optimal' management strategies for the two conditions present are potentially conflicting. Issues include rapid sequence induction in the presence of a ruptured arteriovenous malformation, maintenance of cerebral perfusion pressure in the face of bowel ischaemia, and the use of epidural anaesthesia in a child with recent intracranial haemorrhage. Written consent was obtained from the patient and parents to publish this case. PMID- 20191801 TI - The ethics of anaesthesia learning curves (comment). PMID- 20191802 TI - The Blease Datum anaesthesia vaporiser and the backbar. PMID- 20191803 TI - Preoperative screening for obstructive sleep apnoea--are we losing sleep over nothing? PMID- 20191805 TI - Preparation of Supreme laryngeal mask airway affects insertion. PMID- 20191804 TI - Use of an i-gel in a 'can't intubate/can't ventilate' situation. PMID- 20191806 TI - A modified posterior approach to lumbar plexus block using a transverse ultrasound image and an approach from the lateral border of the transducer. PMID- 20191807 TI - Waterhouse-friderichsen syndrome caused by invasive haemophilus influenzae type B infection in a previously healthy young man. PMID- 20191808 TI - An unusual phenomenon with entropy during induction of general anaesthesia. PMID- 20191809 TI - [Modern epidemiologic implications in occupational medicine]. PMID- 20191810 TI - Zinc--essential micronutrient for child health and nutrition. AB - Ubicuity of zinc in nature has generally lead to the idea that human zinc deficiency is hardly to appear; however, the last 40 years of research studies showed clear correlation between zinc deficiency and several clinic manifestations: growth retardation, predisposal to infections, delay of wound healing, hypogonadism in boys. Zinc plays multiple roles, especially in pregnant women and children. Although the issue of micronutrient malnutrition has been pointed out in developing countries, it has been remarked also in developed ones, due to unbalanced nutrition and diets. The article aims pointing out important aspects related to zinc micronutrient: metabolic pathway, daily dosage, health benefits as prophylaxis and therapy of respiratory and digestive infections in children. PMID- 20191811 TI - [Attention-deficit/hyperactivity disorder. Clinical and treatment aspects]. AB - Attention-Deficit / Hyperactivity Disorder (ADHD) is a complex disorder. The onset of the disease is in childhood. The most important symptoms of ADHD are hyperactive, impulsive and inattention symptoms. In addition, children with this syndrome often have difficulties with other aspects of their learning, emotional modulation, organization, motivation, memory and other functions of the brain's management system. Drug medications, behavioral treatment and behavioral interventions at school are the most important aspects of treatment for ADHD syndrome. PMID- 20191813 TI - [A model for studying arterial stiffness in essential arterial hypertension]. AB - Arterial stiffness (AS) is a complex parameter, which can be assessed by non invasive methods. Our study demonstrates the usefulness of an integrative model for measuring the components of the AS. MATERIAL AND METHOD: The AS was prospectively studied before and after 6 and 12 months of antihypertensive treatment in 92 hypertensive patients and 50 matched normotensives. The studied parameters were pulse wave velocity (PWV), pulse pressure, indices of vascular compliance assessed by vascular ultrasound (b index and strain) and the systolic volume index/PP ratio (SVI/PP). RESULTS: All parameters of AS have a favourable evolution after 12 months of antihypertensive treatment and the normalization of the blood pressure. The central parameters have a different behavior compared with the peripheral AS, probably in relation with the arterial structure. The ratio SVI/PP is useful for studying the ventricular-arterial coupling. CONCLUSION: An integrative model for studying AS and a prospective follow-up is useful and necessary in essential arterial hypertension. PMID- 20191812 TI - [Euthanasia/assisted suicide. Ethical and socio-religious aspects]. AB - Euthanasia/Assisted Suicide are viewed differently by moral and religious references. In a religious way, cardinal confessions (Christianity, Judaism, Islamism, Buddhism) condemn euthanasia/assisted suicide and, in the same time have a more relaxed attitude regarding passive euthanasia. Other aspects of euthanasia regard financial/economic and ethical-medical considerations. All these contradictory standpoints are expressed in some legal acts that make specifications on the concept of "euthanasia"--Oregon's Death with Dignity Act (1994) and Netherlands's Euthanasia Law (2001). PMID- 20191814 TI - [Assessment of left atrial remodeling in atrial fibrillation]. AB - Left atrial size, most frequently assessed for practical reasons by echocardiography, is important in clinical decision-making. Left atrium volume measurements allow an accurate assessment of asymmetric remodeling and reverse remodeling in atrial fibrillation (AF) patients. AIM: To assess a new method (CTEL2) derived from CT scan by ellipsoid formula (CTEL1) to measure LA volume, we compared the conventional echocardiography-ellipsoid method (EEL), as a reference, with CTEL1 and with the new method-CTEL2. MATERIAL AND METHOD: Left atrium volume was measured by EEL and CTEL2 in 40 consecutive pts (group 1, 56 +/ 12 years, 80% men) and by EEL and CTEL1, in another 46 consecutive patients (group 2, 58 +/- 11 years, 80% men) with AF. For measurements by CTEL2 we used the same formula as the ellipsoid method but as optimal view for the orthogonal dimensions were taken every time the last axial section just under the superior veins (atrialized in dilated left atrium). Usual, the dimensions are taken on the largest axial left atrium area. The correlation coefficients were compared by Z test with Fisher inverse tank transformation. RESULTS: Mean left atrium volume irrespective of methods was > 50 mL. We found a good and significant correlation between CTEL1 and EEL (r1 = 0.769; p < 0.001) but a much better between CTEL2 and EEL (r1 = 0.915; p < 0.001). Both r1 and r2 coefficients were significantly stronger for the correlation with CTEL2 and with CTEL1 (p = 0.016). CONCLUSIONS: This new technique evaluation for left atrium volume is adequacy and could avoid an overestimation or underestimation of LA remodelation assessment, as standard ellipsoid method, in specific situations as cardioversion or AF ablation. PMID- 20191815 TI - [Identification of cardiovascular risk factors in patients with occupational diseases]. AB - The objective of this paper is to study the hospitalized morbidity for cardiovascular diseases in connection with risk factors in a clinic of occupational diseases from Rehabilitation University Hospital, Iasi, Romania. MATERIAL AND METHODS: The survey represents a descriptive analysis of 2003-2007 data regarding the 1771 first admitted and new diagnosed inpatients. The association between risk factors and cardiovascular diseases was assessed using odds ratio (point estimate and 95% confidence interval). RESULTS: Blood hypertension has been diagnosed in 9.20 cases per 100 inpatients and ischemic heart disease in 1.98 cases per 100 inpatients. The prevalence increased with age for both diseases. One in five cases was smoker and had vascular family records. In blood hypertension the odds ratio revealed an increased risk with the exposure for following factors: male gender, smoker status, vascular family records, obesity assessed through body mass index > 30 kg/m2, age > 45 years in male, age > 55 years in female (p < 0.05). The ischemic heart disease was significant associated only with family records and age > 55 years in female. Most of these cases diagnosed in the occupational diseases clinic represent active workforce (47.96 +/- 8.82 years). CONCLUSION: Early diagnosis of cardiovascular diseases in connection with risk factors may prevent a premature death, affecting workforce, with medical and socio-economical consequences. Cooperation between general practitioner-occupational diseases specialist-cardiologist may improve the efficiency of prevention programs. PMID- 20191816 TI - [Chronic miocardial infarction among patients with diabetes mellitus or impaired glucose tolerance]. AB - Chronic myocardial infarction represents one of the most important problems of actual clinical medicine because their incidence is growing especially at young adults (< 45 years) and their mortality with no treatment is high in first month after acute myocardial infarction (50%). When cardiovascular disease is associated with diabetes mellitus, evolution of patients is more serious. AIM: To compare the disease evolution for two groups of patients--one with patients who have purely chronic myocardial infarction and other with patients who have chronic myocardial infarction associated with glycoregulation disturbances (diabetes mellitus, impaired glucose tolerance or impaired fasting glucose). MATERIAL AND METHOD: The study group included 205 patients with chronic myocardial infarction; the study was a retrospective analysis of the clinical and biochemical parameters of patients. RESULTS: The patient age was between 37-89 years (the middle age was 65 years) and the predominant environment was urban. All of the patients have chronic myocardial infarction and 60% of them have associated glycoregulation disturbance. The majority of hospitalised patient was symptomatic and the major symptoms where chest pain and dyspnoea. Most patients had abdominal obesity associated with hypertension and tachycardia. The most frequent component of metabolic syndrome was hypertension. More patients had abnormal value of glycaemia, the expression of an inefficient control of the diabetic disease. High level of the serum cholesterol and triglycerides was found more frequently. Hypercholesterolemia was a predominant expression of dyslipidemia in discordance with literature dates for diabetic patient. A different degree of renal failure was found, frequently in patients with glycoregulation disturbances. The electrocardiograms revealed that the majority of patients have a complete (transmural) myocardial infarction and the most frequently localisation was the previous one. The clinical manifestation breathing and ecocardiographical aspects (law value of EjF and abnormal parietal kinetic) expression of the cardiac failure was found in 46% patients more frequently in diabetic disease. The complication of myocardial infarction -post infarction angina, ventricular aneurism, and arrhythmia -appears more frequently among patient with glycoreglation disturbance. The other vascular territories affected by ATS where cerebral arteries and peripheral arteries. CONCLUSION: This study confirms the unfavourable evolution of myocardial infarction in diabetic patient. PMID- 20191817 TI - Cardiodepressive effects of alcohol. AB - The toxic effect of alcohol on the heart was recognized long time ago. The aim of our study was to evaluate the cardiodepressive effect of alcohol in our in patients and compare the obtained results with those in the literature. MATERIAL AND METHOD: The study included 187 patients (184 men and 3 women) aged 30 to 75 years and followed-up for 8 years. All patients underwent a series of biochemical and hematological test and paraclinical investigations. RESULTS: Our study demonstrates the toxic effects of alcohol on the contractile function of the myocardium, and the deterioration of the global left-ventricular contractile function in all patients. In all our patients the following were found: enlarged cardiac chambers, increased left ventricular mass, systolic dysfunction (reduced left ventricular ejection fraction and shortening fraction), diffuse left ventricular hypokinesis, normal or thickened wall, and signs and symptoms of heart failure. CONCLUSION: The severity of the clinical symptoms and the results of the performed examinations were directly related to the amount and duration of alcohol consumption. PMID- 20191818 TI - [The relationship between bile reflux and symptoms in patients with gallstones before and after cholecystectomy]. AB - Many hypotheses affirm that postcholecystectomy syndrome is caused by alterations in bile flow due to the loss of the reservoir function of the gallbladder. We aimed to establish the relationship between postcholecystectomy symptoms and bile reflux. MATERIAL AND METHOD: Thirty patients with gallstones were included in the study. All patients underwent combined ambulatory pH and bile monitoring (Bilitec). Three months after cholecystectomy, the tests were repeated. RESULTS: Before surgery, the median (interquartile range) total time pH < 4 was 2.8% (0.2 14%) and bilirubin absorbance > 0.14 was 4.1% (0-17%). After cholecystectomy, the median total time pH < 4 was 3.7% (1.5 %-11.4%) and bilirubin absorbance > 0 14 was 13.25% (5.30%-26.5%). The correlation between total time pH < 4 and total time bilirubin absorbance > 0.14 for all patients was good: r = 0.55, p < 0.001. Before surgery 65.03% of symptoms were not associated with neither acid nor bile reflux and postcholecystectomy 37.87% of symptoms were associated with bile reflux and 36.95% without any reflux. Cholecystectomy determines increased biliary reflux compared to the patients with gallstones. Related to gallstones, after cholecystectomy dyspeptic complains are more often related to bile reflux. CONCLUSION: Although cholecystectomy itself does cause increased biliary reflux, in most patients with significant duodenogastric reflux symptoms were not correlated with biliary reflux. PMID- 20191819 TI - 13C-urea breath test for the diagnosis of Helicobacter pylori infection in bleeding duodenal ulcer. AB - Helicobacter pylori (H. pylori) is the main etiologic factor for duodenal ulcer (DU). Bleeding is still a frequent and sometimes severe complication, with unacceptable mortality despite modern therapeutic modalities. The importance of diagnosing and treating H. pylori infection in bleeding DU is underlined by the fact that eradication therapy is effective in preventing recurrent bleeding. The aim of this study was to evaluate the prevalence of H. pylori infection by means of 13C urea breath test (13C-UBT) in patients with bleeding DU. MATERIAL AND METHOD: Thirty-nine patients (25 men, 14 women) hospitalized with bleeding DU underwent emergency endoscopy and treated with intravenous proton pump inhibitors (PPIs), and a 13C-UBT was performed the day after the resuming oral feeding. RESULTS: Twenty-seven patients (19 men, 8 women) (69.3%) had a positive 13C-UBT. All patients received intravenous PPIs (22 pantoprazole, 17 esomeprazole) after emergency endoscopy (80 mg bolus + 8 mg/hour infusion/day) for 3-4 days. The time elapsed between admission and performance of 13C-UBT did not differ significantly between patients having a positive or negative 3C-UBT (5.6 vs 6.1 days). Eight of the twelve patients (66.6%) with a negative 13C-UBT had a repeated test two month later, and five of them became positive; therefore, H. pylori infection was finally detected in 32 (82%) out of 39 patients with bleeding DU. CONCLUSION: Most patients with bleeding DU have a positive 13C-UBT although they were taking PPIs. PMID- 20191820 TI - Adalimumab therapy in patients with active rheumatoid arthritis. AB - AIM: To evaluate efficacy and safety of adalimumab (ADA), a monoclonal anti TNFalpha antibody, in rheumatoid arthritis (RA). MATERIAL AND METHOD: 5 years retrospective observational study on 70 active RA (ARA 1987 modified criteria; 48 women; mean age 52.6 +/- 11.7 years; mean disease duration 6.7 +/- 3.2 years, mean DAS28 6.5 +/- 1.3) treated with ADA (classic regimen). All patients have been assessed according to a standard protocol: (i) clinical (tender and swollen joints; pain; global disease evaluation), (ii) inflammatory and (iii) immune parameters (total antinuclear and anti-double stranded DNA antibodies), (iv) activity and functional scores, (v) response to therapy (EULAR), (vi) adverse events. Evaluation was performed at baseline and every 3 months. Statistical analysis was done in SPSS-13, p < 0.05. RESULTS: Statistical significant improve in RA activity (mean final DAS28 3.6 +/- 0.8, p < 0.05), functional scores (mean HAQ 1.3 +/- 0.3, p < 0.05) and decreased X-ray progression (Sharp score) have been reported; 60% RA were responders (mean EULAR 2.7 +/- 1.2), 35.7% in remission, while switching to another biological agent (14.28% ADA failure) was done in 20% cases, clinical, biological and radiological efficacy and favorable safety profile of ADA have been demonstrated in real life long-term administration in active RA. PMID- 20191821 TI - [Some observations on therapy efficacy in a sample of 111 patients suffering from ankylosing spondylarthritis, assisted in the Clinic of Rheumatology and Rehabilitation Iasi]. AB - The authors present the results of some evaluations on the efficiency of pharmacologic therapy for 111 pacients suffering from ankylosing spondylarthritis (AS). RESULTS: The pacients have been assisted for five years in a specialized hospital. 63.9% out of all were over 30 years old and 46.8% were workers in industry and agriculture. Regarding the frequency of usage, the therapy included the following medicine: movalis, salasopyrine, diclophenac, flamezin, aulin, tilcotil, almiral, and others. After the therapy, during the study period, cumulative, the condition of 62.2% of the pacients improved. The condition of 22.5% remained stationary, and 6.3% got worse. PMID- 20191822 TI - [Study of nosocomial bacillary meningitis admitted in the Clinic of Infectious Diseases Iasi on a 20 years period]. AB - AIM: To analyze the clinical features, etiology and evolution of nosocomial bacillary meningitis admitted to the Clinic of Infectious Diseases Iasi between 1988 and 2007. MATERIAL AND METHOD: The data were gathered from the archive of the Clinic of Infectious Diseases Iasi. We studied the clinical and laboratory features of 28 cases of nosocomial bacillary meningitis admitted in the study period. RESULTS: The development of nosocomial meningitis was subsequent to interventions on the central nervous system for hematoma, ventriculo-peritoneal shunts, tumors, rah anesthesia. The symptoms were fever, headache, stiff neck and vomiting. The etiological agents were: Acinetobacter spp--35.71%, Pseudomonas spp.--25%, Klebsiella pneumoniae--17.85%, Escherichia coli--14.28%, and mixed etiology, in 3.57% of the cases each. The treatment was according to their susceptibility, using systemic quinolones and ceftazidime or colymicin. The evolution was favorable in 13 patients and unfavorable in another 15. CONCLUSION: Nosocomial meningitis caused by Gram negative bacilli is a severe infection, with diverse etiology, which raises therapeutical problems due to antibiotic resistance and a high mortality rate. PMID- 20191823 TI - [The profile of the autolytic critical patient compared to proper suicider]. AB - Out of all the patients with nonlethal self-injuries, only a low percentage inflict on themselves lesions that are severe enough to endanger their lives. The purpose of the paper is to analyze whether this smaller category of patients comes close to the profile of the genuine suicide or it remains within the pattern of the patients with non-lethal self-injurious behaviour. MATERIAL AND METHOD: Between January 1, 2005 and December 31, 2006, 656 patients with non lethal autolytic acts came to the Emergency Hospital (UPU). Only 39 (5.94%) of them had lesions that were so severe as to require their hospitalization in the reanimation unit. During the same period of time, 188 suicial attempts were recorded in Iasi County. The parameters studied were: sex, age, living background and the autolytic method used, since these were the only data to be wholly collected from all the subjects. The information was introduced in the SPSS 8.0 software for Windows. RESULTS: The proportion women: men was higher in the case of sucide attempts (58.8% vs. 38.4%) in comparison to proper suicides (52.7% vs. 46.8%). The division according to age groups shows an almost Gaussian distribution of the suicides, with a peak at the 45-54 years old group whereas, in the case of suicidal attempts, there is a more uniform representation with a peak at the 25-34 years old group. As far as the background and living conditions are concerned, the suicides came mainly from the rural areas in comparison to the others belonging to the urban areas, and, in the case of the methods employed, the former preferred physical methods (87%), while the latter appealed mostly to intoxications (92.3%). CONCLUSIONS: The profile of critical patients hospitalized in the reanimation unit from autolytic lesions partially coincides with that of the subjects who committed suicide. There are similarities concerning their sex or age distribution. There is also a congruence between our data and the specialized literature regarding their distribution according to living areas, but not betweent:he two lots under study. There are major differences in the methods used by the subjects of the two groups we studied. PMID- 20191824 TI - [Disorders of the acid-basic balance in the post-hypoxic suffering at newborn babies]. AB - The study aims to asses the acid-basic disorders and the blood gasses in the blood of the umbilical cord and their correlation with the evolution of the newborn baby in the maternity hospital. MATERIAL AND METHOD: 157 newborns with perinatal asphyxia hospitalized (2002-2005) in the Maternity of "Sf. Apostol Andrei" Clinical Emergency Hospital of Galati, following-up the gestation age, the Apgar score, the risk factors of perinatal asphyxia, the pH in the cord and the evolution of the blood gasses in the cord, the start and evolution of neurologic disorders. RESULTS: The main risk factors for the asphyxia production: prematurity (64% of the cases and 25% of the cases with gestation age below 30 weeks), HTA induced in pregnancy, IUGR 39.4%. The Apgar score at one minute: values between 0-3 (40.8% cases), progressively decreasing to 20 minutes in 1.3%. 50% of the new born babies showed severe acidosis in the cord: pH > 6, 9, hypoxia in the cord blood was of 75%. The neurologic disorders started from the birth in all cases, with evolution to decease in 25.5% of the cases, higher incidence in prematures and a significant correlation with the pH in the cord. PMID- 20191825 TI - [Assessment of complications of excess weight in school-age children and adolescents]. AB - Due to the higher incidence of children obesity, in the last decade, the scientific community as well as mass media have increased their interest towards obesity and eating habits. MATERIAL AND METHOD: The study has been made on a number of 108 pediatric patients with intercurrent affections that has been diagnosed with obesity or weight excess between 2005 and 2008. The evaluation of the pacients has been done with the use of anamnesis, full clinical examination and biochemical investigations. RESULTS: The case repartition based on body mass index has revealed that 46.29% of the pacients have excess weight and 53.70% suffer from obesity. The biochemical alterations have shown the following: regarding the glucidic metabolism--21 cases with impaired basal glycaemia, 5 cases with low glucose tolerance and 2 cases with diabetes mellitus type 1; regarding the lipidic metabolism--39 cases with modifications of triglycerides, of cholesterol fractions or of both categories. Also, we found the X metabolic syndrome in 20 of the studied cases, hyperuricaemia in 13 cases, hepatic steatosis in 10 cases and arterial hypertension in 34 of the cases. Almost half of the interviewed subjects have accused different types of psycho-behaviour changes. CONCLUSIONS: From the investigated complications, the dislipidemic syndrome, arterial hypertension and glucidic metabolism disorders have had an important place and have completed the metabolic syndrome picture in an important number of cases. PMID- 20191826 TI - [Evaluation of quality of life in children with chronic hepatitis]. AB - The evolution of chronic viral and non-viral hepatitis in children, and the response to therapy influence the quality of life and the outcome of these patients and tehir family. MATERIAL AND METHOD: This study analyzes the quality of life in children with chronic liver disease, using the records of 45 patients hospitalised in the Hepatology Department of "Sf. Maria" Hospital of Children in Iasi. Data were customised using Kindle questionnaire, measuring the scores for quality of life in children and adolescents with chronic disease. Patients with chronic viral and autoimmune hepatitis hospitalised in the clinic were interrogated during three months (May-July 2008). All ethical aspects of clinical research were aproved and no child was harmed during the study. The questionnaire for children with chronic viral hepatitis, mostly with B virus, had a good aplicability, being simple and easy to respond. RESULTS: The results showed a positive perception of the disease, probably because of the young age (under 17) and the fact that the liver disfunction was at low rates. The study of quality of life in children with chronic disease can be an efficient method for treatment efficiency evaluation. PMID- 20191827 TI - [Comorbidities in psoriatic patients of Iasi Dermatological Clinic from 2004 2008]. AB - Psoriasis is a chronic inflammatory disease of the skin, relatively frequent in the population. Recent studies have shown that psoriasis can have a great impact on quality of life, even in patients with limited disease. Although the cause of this disease remains unknown, research suggests that psoriasis is a complex disease caused by the interaction of many genes, the immune system and environmental factors. In principle, any disease can coexist with psoriasis. MATERIAL AND METHOD: We conducted a retrospectiv study based on observation files of hospitalized patients with psoriasis admitted in the Dermatology Clinic Iasi during January 2004 - December 2008. RESULTS: Current data suggests that smoking and obesity increase the risk of developing psoriasis. Psoriasis may be an independent risk factor for developing diabetes, atherosclerosis and myocardial infarction. Therefore the patients with psoriasis die 3-4 years earlier than the rest of the population. Patients should be advised to stop excessive alcohol consumption and smoking. CONCLUSION: Further studies are needed to clarify the link between severity of skin lesions, treatments and the evolution of associated diseases. PMID- 20191828 TI - Considerations associated with computer forensic facial reconstructions the limits of soft tissues' thickness determination. AB - Revolutionary progresses in computer technology are of great use during forensic investigations in terms of facial identification based on reconstructions. AIM: The purpose of the current study is to evaluate the use and limits of facial reconstruction by considering soft tissues' thickness determination. MATERIAL AND METHOD: The authors investigated the limits of three methods used for soft tissues' thickness determination on a sample group consisting of 9 cadavers, 30 ultrasound investigations and 27 cranial X-rays. The measurements were performed at standard anthropological landmarks following methods previously described in literature. RESULTS: Measurement values for each soft tissue landmark overlapped between sexes, females having greater soft tissue thickness at two sites: infraorbital and supraorbital notches. US measurements demonstrate a much larger dependence of the soft tissue thickness according to different body posture and imply compressing soft tissues with the transducer. X-rays determinations revealed more accurate values than US, but are nocive to the subjects and can only be performed in standard radiographic positions. For cadavers, different postmortem stages and supine position generated inadequate results. CONCLUSION: In order to increase the degree of accuracy of craniofacial approximation it is necessary to obtain a validated data set specific for the Romanian population. This will allow a better determination of facial measurements opening new perspectives in understanding the relation between physical properties and facial soft tissue. PMID- 20191829 TI - Infective endocarditis--a forgotten cause for heart insufficiency in elderly. Case report. AB - Right heart infective endocarditis in an elderly patient with no previous known risk factors is a very rare situation (even if subacute infective endocarditis has the same chance of occurrence at either a young person, or an elderly patient). We present the case of a 75-years old patient, with no previous cardiac history, addressed to our clinic with nonspecific septic symptoms associated with an edematous syndrome. The patient was treated for right heart valve infective endocarditis; a particularity may be the fact not all Duke criteria were respected. Iatrogeny was involved, our patient having administered a 7-day antibiotic treatment before hospital addressing. The therapeutic probe was positive: excellent evolution under treatment. Few cases of infective endocarditis of the tricuspid valve were reported worldwide, in which the source of infection was unknown in about 80% of cases. In two pediatric cases reported, tricuspid endocarditis was caused by Staphylococcus aureus septicemia following upper respiratory infection. This may also occur in adult cases. Further investigations should be carried out in the future to elucidate the source of infection. Isolated right-sided endocarditis should be included in the differential diagnosis of patients with febrile syndrome, respiratory symptoms and predisposing disease, even when they do not have a pacemaker and are not intravenous-drug users (IVDU). PMID- 20191830 TI - [Hepatic tuberculosis presenting as prolonged fever]. AB - In our country prolonged fever is frequently caused by tuberculosis infection, that is recrudescent. Localized hepatic tuberculosis is a rare clinical form of this specific infection. The authors present the case of a 26 year old man who developed prolonged fever, highly elevated liver enzymes and meningitis syndrome and was admitted to Clinical Hospital of Infectious Diseases and Pneumophtisiology Dr. V. Babes Timisoara during 24.03 - 16.05.2008. Diagnosis of hepatobiliary tuberculosis, acute bacillary meningitis and miliary tuberculosis were established by clinical, laboratory criteria and sustained by imaging techniques. Dynamics of biological features, diagnostic pitfalls, differential diagnosis difficulties, therapeutic schedules and peculiar aspects of evolution are presented. Liver involvement can be the only manifest form of miliary tuberculosis and when it is associated with prolonged fever obligates to begin quadruple specific therapy, especially in communities where tuberculosis is prevalent. Bacteriological findings are belated and antituberculous therapy can not be started early. Quadruple association of antituberculous drugs with corticotherapy and liver protective medication showed utility in favorable resolving of this case. PMID- 20191831 TI - [Frozen section exam value in breast cancer]. AB - Frozen section exam is a peroperative analysis that allows an immediate histopathological diagnosis. Its result influences the extent of surgery. First used only for intraoperative histologic diagnosis, frozen section exam has modified its place nowadays due to the progress in screening methods and preoperative histologic diagnosis. Conservative treatment and sentinel lymph node biopsy technique has orientated frozen section exam towards the evaluation of the sentinel lymph node metastasis and the specimen margins. Sentinel lymph node method remains open to new persectives, influencing therapy decisions, enlarging its indications and improving continuously. PMID- 20191832 TI - Training on a virtual reality simulator--is it really possible a correct evaluation of the surgeons' experience? AB - Laparoscopic simulators provide a safe and efficient means of acquiring surgical skills. It is well known that virtual reality training improves the performance of young surgeons. Most of the virtual reality simulators have construct validity and can differentiate between novice and expert surgeons. However, for some training modules and trainees categories the possibility to distinguish the real surgeon's experience is still discussed. METHODS: A total of 14 young surgeons were evaluated during a 5 days postgraduate laparoscopic course using a LapSim Basic Skills, v. 3.0 simulator and a Virtual Laparoscopic Interface (VLI) hardware. The best performances of the surgeons were included in a MS Access database and statistical analyzed. RESULTS: There were 6 males and 8 women with a mean age of 30.21 +/- 1.01 years old (range 26-38). Nine surgeons (64.28%) were young residents without any laparoscopic surgical experience (group I), and the other 5, had some laparoscopic surgical experience (10 to 30 laparoscopic procedures) (group II). During the instrument navigation task we found that both hands performances were significant better in group II--the navigation time was 12.43 +/- 1.31 vs 19.01 +/- 1.40 seconds for the left hand--p = 0.006 and 13.57 +/- 1.47 vs 22.18 +/- 3.16 seconds for the right hand--p = 0.032); the right instrument angular path degree was also shorter for experienced surgeons (153.17 +/- 16.72 vs 230.88 +/- 22.6 - p = 0.017). The same data were noted for the lifting and grasping module. However, the suturing module tasks revealed contradictory results: the group I residents recorded better performances then the group II surgeons: total time--677.06 +/- 111.48 vs 1122.65 +/- 166.62 seconds; p = 0.043; right instrument path (m)--15.62 +/- 2.47 vs 25.73 +/- 3.13; p = 0.028; right instrument angular path (degree)--3940.43 +/- 572.54 vs 6595.5597 +/- 753.26; p = 0.017. CONCLUSIONS: Laparoscopic simulators are useful to evaluate the surgeons' experience; the parameters of the instrument navigation and lifting and grasping modules, which require a higher degree of eye-hand coordination, were better for residents with previous surgical experience and revealed a good transfer of training (TOT). The suturing module is less influenced by surgeons' experience. This result is probably explained by a lack of TOT. PMID- 20191833 TI - [The electroacupuncture in patients recently operated for peripheral arterial disease. A comparative study of the two electrostimulation techniques]. AB - Possible hemodynamic effects of electro acupuncture (A), by two electro stimulation techniques, were studied at patients with femuro - popliteal bypass revascularization. MMATERIAL AND METHOD:In a prospective study, we evaluated two EA techniques, by calculating the ankle-brachial index (ABI) and by estimating the pain with Numeric Rating Scale (NRS: 0 - 10). The patients were grouped in lot A (30 patients) and B (50 patients) according with the EA technique used. In both lots were used the same acupuncture points (acupoint): Pc6, P9, St36 and Sp6. These acupoints are adjacent to peripheral nerves median, radial, peroneal and safenous nerve. Needles, after insertion, were kept in place for 30 minutes. The electro stimulation (2 Hz) was only for 2 minutes in the lot A and for 30 minutes in the lot B. RESULTS: The blood pressure data and ABI shows a significant increase of ABI (between 0.033 and 0.052) after EA at 5 minutes in the both lots (p < 0.05). At 30 minutes, ABI is increased in lot B, but in the lot A the ABI is elevated only at the non surgical leg (p < 0.05). The decrease of pain post EA is better in the lot B (NRS: initially 2.48--post EA pain decreased to 1.46 and remained 1.66 at 2 hours; p < 0.001), than lot A. CONCLUSIONS: The electro stimulation of certain acupoints, at the operated peripheral arterial disease patients, interfere with tissular perfusion and increase temporally ABI. The pain is diminished more significantly by the 30 minutes electro stimulating technique. PMID- 20191834 TI - Compression and walking compared with bed rest in the treatment of proximal deep venous thrombosis during pregnancy. AB - The purpose was to evaluate the benefits of compression and early mobilization in comparison with compression and bed rest in the acute stage of proximal deep venous thrombosis (DVT) in pregnant women. METHOD: Thirty-two consecutive pregnant women with proximal DVT diagnosed by color duplex ultrasound were divided into two groups. Group A consisted of 15 patients who received elastic compression bandages and early mobilization, and group B including 17 patients with compression bandages and bed rest. All patients received heparin therapy. The clinical characteristics of the two groups were comparable. We assessed the reduction of subjective pain daily with a Visual Analogue Scale (VAS) and the objective pain using Lowenberg test, the reduction of edema was recorded initially and on day 2, 4 and 7. Ultrasound was repeated after seven days. RESULTS: Resolution of subjective pain was faster during the first three days and near absent at the end of the study period in group A (p < 0.001). Objective pain seriously reduced in group A during the observation period while in group B decreased during the first three days almost by half but remained constantly present over the remaining days (p < 0.001). The same was true for the measurement of leg circumference (p < 0.05). There was no pulmonary embolism and progression of thrombus diameter. CONCLUSION: Pregnant women with proximal deep vein thrombosis may benefit from leg compression and early mobilization for a faster resolution of the signs and symptoms and this method does not seem to be an additional risk factor for pulmonary embolism. PMID- 20191835 TI - [Clinical and paraclinical diagnosis of pelvic endometriosis. Clinical study]. AB - Pelvic endometriosis is a difficult diagnosis in gynecological practice, due to different symptoms and advanced stages in which the patients arrive to us. MATERIAL AND METHOD: This study retrospectively analyses 73 cases of confirmed endometriosis admitted in our service during 5 years. We gathered information about their clinical data and diagnosis, and intraoperative laparoscopic or laparotomic findings. RESULTS: The majority of our cases were in the 3rd age decade (52%). The clinical symptoms were: infertility (34%), pelvic or abdominal pain (71%), vaginal bleeding (14%), or an accidental finding after laparotomy or laparoscopy for other reasons (7%). The intraoperative evaluation of the cases showed: endometrial genital foci in 59%, with half of them located at the ovary; extragenital sites in 30 cases (bladder--4 cases, Douglas pouch 19 cases, abdominal wall 5 cases, para-cervix 2 cases). Associated pathology included: adhesions in 46%, retroverted uterus in 15%, ovarian non endometriotic cysts (18%), polycystic ovaries (12%) and tubal pathology (6%). CONCLUSION: Our study confirm the difficulty of a clinical diagnostic of endometriosis, but the main symptoms remain infertility and pelvic-abdominal pain. The laparoscopy or laparotomy were the main tools for the diagnostic and management of our cases. PMID- 20191836 TI - [Sonohysterosalpingography versus hysterosalpingography in the evaluation of uterine and tubal infertility]. AB - OBJECTIVE: The evaluation of the role of sonohysterosalpingography with saline with air as a contrast solution (HYCOSY), in the assessment of uterine cavity and tubal patency, versus hysterosalpingography (HSG) and laparoscopy with dye test combined with hysteroscopy. MATERIAL AND METHOD: Prospective study of 95 infertility patients, with ages 25-40 years (median 31), in which HYCOSY was compared with HSG regarding the diagnostic acuracy for uterine cavity pathology and tubal patency, and compared to laparoscopy with dye test combined with hysteroscopy as gold standard. RESULTS: The sensibility, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the diagnostic of uterine cavity pathology was: HYCOSY versus hysteroscopy of 72.1%, 96.15%, 93.93% and 80.64% respectively; HSG versus hysteroscopy was 83.3%, 60.7%, 63.6% and 81.6%; both methods combined versus hysteroscopy 95.34%, 61.53%, 67.21% and 94.11%. The same parameters for the tubal patency were: HYCOSY versus dye test laparoscopy 81.39%, 87.69%, 67.30% and 97.79%; HSG versus dye test laparoscopy 61.9%, 85.3%, 56.5% and 87.9%; both methods combined versus dye test 86%, 76%, 52.9% and 94.6%. CONCLUSION: HYCOSY can be used in combination with HSG for selecting the patients that need further more invasive investigations, in order to describe uterine and tubal pathology. PMID- 20191837 TI - [Lymph node dissection in endometrial cancer]. AB - Total abdominal hysterectomy(TAH) and bilateral salpingo-oophorectomy (BSO) have been the hallmarks of therapy for endometrial cancer. However, in the last years the significance of surgical staging is increasing; pelvic lymph node dissection is an important part of surgical staging. MATERIAL AND METHOD: We have studied a cohort of 76 patients with endometrial cancer who underwent surgery in the 4th Gynecology Clinic of "Cuza Voda" Hospital, Iasi, between 1997-2008. Our purpose was to determinate the risk factors for lymph node invasion and the value of pelvic lymphadenectomy regarding both prognosis and therapeutic significance. RESULTS: From the 76 cases, 39 underwent selective pelvine lymphadenectomy (51.31%). 48.86% of cases are in the first stage of neoplasia. Invazia cervicala este mai des intalnita in cazul tumorilor slab diferentiate, voluminoase, cu invazie miometriala profunda. 9.21% of cases had endocervical glands invasion and 18.42% presented glandular and stromal invasion. CONCLUSION: Lymphadenectomy is beneficial for prognosis and in some cases for therapy. PMID- 20191838 TI - [The implications of cervical spine degenerative and traumatic diseases in the pathogenesis of cervical vertigo and hearing loss]. AB - AIM: Cervical spine together with vestibular system,visual system and proprioceptive afferents plays an important role in mentaining balance. Spine damage causes distortions in transmitting informations to the brain,favoring vertigo. MATERIAL AND METHOD: The authors point out the occurrence of positional vertigo on 23 patients (20 patients with cervical spondylosis and 3 patients with cervical spine injury) due to blood flow disturbance through vertebral artery. RESULTS: The mechano-receptors located in intervertebral disks and cervical spine muscles are activated by column movement. Changes of blood flow in the vertebral and basilar arteries are showed up by cervical X-Rays, intracranial Doppler ultrasound or angio-MRI, an audiogram marking out the degree of hearing loss or tinnitus occurence. ENT complex treatment outcomes are analyzed and balneo-physio therapy performed in order to improve vertigo and hearing loss. CONCLUSIONS: Stress beside muscle overload and cervical spine injures causes alteration in the ear blood-flow circulation that leads to hearing loss, vertigo and tinnitus. It emphasies the need for collaboration between balneologist and ENT specialist in solving balance and hearing disorders with cervicogenic cause. PMID- 20191839 TI - [Immunohistochemical evaluation of inflammatory reaction in a case of pilomatrixoma]. AB - OBJECTIVES: To identify the types of the cells in a case of pilomatricoma and to evaluate the lesion's stage, the cells' proliferating rate and the associated inflammatory reaction. MATERIAL AND METHODS: The paraffin-embedded tissue was investigated by histological examination and by immunohistochemistry for the expression of some markers such as: cytokeratins, CD3, CD20, CD68, PCNA, CD34 II. RESULTS: The lesion presented the characteristic epithelial cells of a classical pilomatricoma: bazaloid cells, ghost cells and transitional cells. 10-15% of the bazaloid cells were PCNA+. The MNF 116 antibody labeled only some of the transitional and of the ghost cells. We found no CD3-positive cells and few CD20 positive cells. A marked inflammatory reaction was noticed, dominated by giant multinucleated cells, positive for CD68 and PCNA and a rich network of blood vessels with a high vascular density. CONCLUSION: The histological pilomatricoma diagnosis was straightforward on the basis of the bazaloid and ghost cells presence. Immunohistochemistry brought additional data regarding the cells proliferation rate, the stage of the lesion and the intensity of the associated inflammation. PMID- 20191840 TI - [Nutritional antioxidant effects on endotelial dysfunctions in experimental atherosclerosis by ovariectomy]. AB - Endothelial dysfunction and atherogenesis involves a general alteration of unicellular layer of the vascular wall structure. Nutritional antioxidants can improve endothelial dysfunction through dietary supplementation with polyunsaturated fatty acids (PUFA N3 and lignans) from flaxseed. The mechanisms by which these nutritional antioxidants have beneficial effects on endothelial function are less known. AIM: The present study examined the effects of the flaxseed supplemented diet, a rich source in PUFA N3 and lignans on the ovariectomy-induced endothelial dysfunction and atherosclerosis. MATERIAL AND METHOD: Forty-two ovariectomized and non-ovariectomized (control) female Wistar rats were used, each one divided in 3 subgroups depending on diet: standard, fat rich or flaxseed supplemented fat rich diet, for 36 weeks. The circulating soluble adhesion molecules of endothelial origin and von Willebrand factor (sVCAM 1, vWF), were measured to assess the endothelial dysfunction. RESULTS: Presence of endothelial dysfunction in ovariectomized animals fed with standard diet associated with a rich PUFA N6 and saturated lipid was proven by the increased plasma concentration of sVCAM-1 and vWE Dietary supplementation with PUFA N3 and lignans (flaxseed) in these animals led to modest decreases of these parameters. CONCLUSION: The results indicate that dietary supplementation with antioxidant activity substances, in presence of estrogen deficiency, especially when it is associated with increased fat intake, may become a mean of prevention and delay of endothelial dysfunction, via anti-inflammatory actions through a reduction of sVCAM-1. PMID- 20191841 TI - [The effects of some cholinergic drugs on cognitive processes and oxidative stress in rat]. AB - Reactive oxygen species (ROS) are produced within the body during oxygen metabolism and living organisms have developed several defense mechanisms to protect themselves from oxidative stress. Under normal conditions, ROS and antioxidant systems are in balance. Oxidative stress is caused by the imbalance between production of pro-oxidants and the antioxidant defenses. The defense mechanisms include antioxidant enzymes like superoxide dismutase (SOD) or glutathione peroxidase (GPX) and several no enzymatic free radical scavengers. It has been proposed that the progressive increase in ROS and consequent oxidative damage play the major role in neurodegenerative disorders. Learning and memory show an age-related decline and this age-associated impairment extends to spatial memory tasks. Furthermore, the neural circuits between the prefrontal cortex and striatum are also involved in spatial memory. In our previous studies, we have shown the facilitatory role of nicotine and cholinergic system in learning and memory processes. In the present study, we examined whether oxidative stress contributes to the memory deficits induced by muscarinic acetylcholine receptors (mAchRS) blocked by scopolamine. We also examined the effect of nicotine on oxidative stress, and also if nicotine could attenuated the learning and memory deficits induced by blocked of mAchRS. We observed that the levels of SOD and GPX decrease in rats mAchRS blockade by scopolamine (0.75 mg/kg body weight i.p.), and the level of malondialdehyde (MDA) increase in same rats, compared with saline-treated rats. Therefore, our results suggest that the oxidative stress contributes to the learning and memory deficits in rats. PMID- 20191842 TI - Beneficial dexa-related effects of natural polyphenols on experimentally-induced diabetes mellitus complications. AB - The benefits of the proanthocyanidins, polyphenols extracted from black grapes seeds, have been shown by using as experimental model, namely streptozotocin induced diabetes mellitus on Wistar white rats. MATERIAL AND METHOD: Streptozotocin was administered in a single intraperitoneal dose of 60 mg/Kg body mass. Vegetal polyphenols were administered as water solution, in a dose of 0.028 mg/Kg body mass, p.o. (through tube feeding), every two days, for a period of 16 weeks. We performed DEXA bone mineral density tests, in order to determine BDM (bone mineral density in g/cm2), BMC (body mass index expressed in g) and fat (%Fat) in control and diabetic animals, before and after polyphenol delivery. RESULTS: The evolution of bone mineral density depending on the area, in diabetic males, measured from the beginning to the end of the experiment, has shown a significant decrease, especially in the femur area. In diabetic males that received polyphenol treatment, these differences are statistically minimum. Bone mineral density depending on the area showed the highest differences in the spine, followed by the cervical spine. In diabetic males that received polyphenol treatment, we noticed a 4-7% decrease of their body fat as compared to the beginning of the experiment, for all the analyzed samples. As for the spine, the highest BMC difference depending on the area was found in diabetic males with polyphenol intake, and the overall highest difference was noticed in diabetic males. The body fat index we studied in the male groups was the lowest in the diabetic males. CONCLUSION: Osteoporosis regression due to polyphenols proves the benefits of proanthoyianidins used treating the chronic complications of diabetes mellitus. PMID- 20191843 TI - [About wine intake and cardiovascular diseases]. AB - There is a (almost) new current understanding of the health effects of alcohol consumption. The alcohol remains a risk factor in certain diseases. Recent population studies and plausible mechanisms suggest a protective effect of alcohol against coronary disease. International comparisons, starting from 1819, suggest that the type of beverage has a main role (the 'French Paradox'). PMID- 20191844 TI - [Comparative analysis of two different methods of nutrition assessment in the institutionalized elderly]. AB - A nutrition assessment is an evaluation of both objective and subjective data connected to an individual's food intake, lifestyle and medical record. In this study we've tried to assess, by two distinct methods, the nutrition of elderly persons, and to reveal some differences that result from the accuracy of each method in part. MATERIAL AND METHOD: The study focused on a group of 195 elderly institutionalized persons from Galati city, living in three different locations (A, B, C), along a period of 5 years. The quality of their nutrition was assessed by 60 standard nutritional inquiries, and by applying an individual questionnaire regarding to their subjective perception of the same aspect. Statistical analysis of the results was performed with programs EpiInfo 3.3 and SPSS 16.0. RESULTS: On a subjective perspective (data collected from questionnaires) there are no significant differences between all these three groups of elderly persons about the quality of their food, the adequacy to their age requirements and about the misbalances observed in structuring the meals. Also, the majorities from every group appreciate that their nutrition registered an improvement since they were accepted in the institution. If we analyze retrospective the quality of the received food, in location A an elderly receives significantly more vegetables with 5% carbohydrates (both p < 0.001) and fruits (both p < 0.001) than in locations B and C. In the second location elderly menus contains significantly more milk (both p < 0.001) and fish (both p < 0.001) than in locations A and C. Comparative with the first two locations, in the third one menus excel in meat (p = 0.004 and p = 0.0026) and potatoes (both p < 0.001). CONCLUSION: Even we've identified significantly differences between the average daily intakes elderly don't perceive them, as a consequence of their age and health status. Summarizing, the assessment of nutrition quality at elderly persons, should be compulsory an objective one. PMID- 20191845 TI - [Correlation of alcohol intake with breast cancer]. AB - Breast cancer is the most common cancer in females. Epidemiological research has shown a dose-dependent association between alcohol consumption and breast cancer incidence in women. AIM: The purpose of the study was to estimate the relationship between alcohol consumption in Romanian women from Transylvania geographic area and breast cancer risk. MATERIAL AND METHOD: We have performed a case-control study on 223 patients with breast cancer, hospitalized in the Oncologic Institute "Lon Chiricuta", Cluj-Napoca and 211 non-cancer controls, apparently healthy women, from the same geographic area. To achieve this aim we have used a validated food-frequency questionnaire, that included questions about alcoholic beverages consumption. RESULTS: The results shows a low mean level of alcohol ingestion at both studied population groups: 5.87 g/day ethanol in breast cancer women and 4.79g/day ethanol to controls. The positive association between alcohol intake and breast cancer risk was observed for a modest level of ingestion of over 6.03 g/day ethanol (OR = 1.74, p = 0.04). The increase of alcohol intake is associated with the breast cancer risk increase (chi squared = 8.25, p for trend 0.04). CONCLUSION: Reducing alcohol consumption is a potential way to reduce breast cancer risk. PMID- 20191846 TI - [Comparative study of the anthropometric parameters in a group of people with dyslipidemias and a control group]. AB - The aim of the article was to study comparatively the variation of the anthropometric indexes (BMI - body mass index, waist circumference) in a group of people with and without dyslipidemias. MATERIAL AND METHOD: The data (age, sex, location, weight, height, waist) was obtained through the inquiry method, within the statistical processing, using the Pearson Chi-Square Test. A group of 678 people, out of which 339 people with dyslipidemias and 339 without dyslipidemias, was included in the study, the two groups being chosen so as to have an equal number of participants, according to age and sex. Each of the two groups was made up of two sub-groups: one from an urban area and one from a rural area. RESULTS: The hypotesis regarding the existence of a higher percentage of people suffering from I degree obesity (24.5%) was confirmed in the case of the group with dyslipidemias as compared to the control group (5%), the percentage of the people with normal weight being much smaller in the case of the dyslipidemic people (20.6%) as compared to the normal ones (45.7%). PMID- 20191848 TI - [Analysis of premature deaths in the Iasi district]. AB - Potential years of life lost (PYLL) represent an indicator of premature or untimely death and take into account the age at which deaths occur by giving greater weight to deaths at younger age and lower weight to death at older age. AIM: This study represents a descriptive analysis of PYLL in district of Iasi compared to country-wide level, during 2006 year. MATERIAL AND METHOD: Premature deaths have been assessed using following indicators: PYLL per 1000 population (male, female, total); male : female PYLL ratio; average PYLL per a premature death; average PYLL per death. Confidence interval CI95 has been used for an accurate comparison district of Iasi - Romania. RESULTS: The recorded number of PYLL was 67.65 per 1000 population at national level and 54.02 per 1000 population in district of Iasi (CI95 = 67.55-67.75). The average number of PYLL per a premature death was 18.21 in Iasi compared to 20.71 for Romania (CI95 = 19.75-21.66), whereas the average number of PYLL per death was 5.6 for both levels. The values of PYLL by gender pointed out 74.59 per 1000 male population and 33.99 per 1000 female population in district of Iasi. CONCLUSION: The analysis of the premature deaths in Iasi revealed a lower loss of potential life years compared to values reported at national level. PYLL were twice more frequent among male than women. The favourable findings in Iasi may be related to a decrease of infant mortality rate, with a significant contribution to PYLL values in this district. PMID- 20191847 TI - [Clinical epidemiologic study of occupational risks in small- and mid-size businesses in Bacau County]. AB - The aim of the study was to identify and quantify the health risk factors in small and middle enterprises (SME) in Bacau, which represent 5.5% of the total number of enterprises, employing about 29% of the total workforce in Bacau. MATERIAL AND METHOD: Two questionnaires have been administered, first asking for general information about the company and second, asking for data about current exposure, according to the reports required by the Ministry of Health. Workplaces were visited and analyzed through direct observation. RESULTS: The most important risk factors, found in 22% of the employees in small enterprises and 31% of employees in middle enterprises, are visual strain, musculoskeletal strain and exposure to textile dust. The measurements showed exposure over the threshold limit for silica dust, wood dust, noise and organic solvents in 35% of cases. CONCLUSION: The study resulted in a useful database for increasing the quality of occupational health services provided to employees in SMEs and offered the possibility to compare data with other geographical areas of our country and worldwide. PMID- 20191849 TI - [The withdrawal syndrome in benzodiazepine dependence and its management]. AB - The authors present the result of an observational study about the withdrawal syndrome in benzodiazepine dependence, and the aspect of identifying withdrawal symptoms, effective communication with the patient and the structure of withdrawal programmes. MATERIAL AND METHOD: The study included a number of 22 pacients hospitalised in the Drug-Dependence Clinic of Iasi between January 2006 December 2008. RESULTS: The present article consists of data covering current issues in the area of withdrawal syndrome in benzodiazepine dependence. The most prescribed benzodiazepines were diazepam (10 cases), followed by alprazolam (5 cases) and nitrazepam (4 cases). The clinical manifestations such as anxiety, insomnia, concentration problems, fatigability were present at all patients. PMID- 20191850 TI - [Oral effects of systemic medication in elderly]. AB - Though less common than those affecting the skin, adverse drug reactions involving the mouth are quite ferquent. Often there's a high index of suspicion in the diagnosis of these reactions, as they can mimic other disease states such as aphtae, swelling, erythema multiforme or xerostomia. The reactions are often non-specific, but they may mimic specific disease states such as erythema multiforme, lichen planus and pemphigus. Other reactions such as gingival hyperplasia secondary to the administration of phenytoins, nifedipine or cyclosporine are well known and quite characteristic. The pathogenic mechanisms of oral rections to drug administration are similar to those causing adverse drug reactions in the skin. To diagnose such a condition, the clinical interview is a helpful aid to the diagnosis of the adverse drug reaction affecting the mouth and a careful drug history, including identification of any prescription, or herbal medicines used, is needed. PMID- 20191851 TI - [Thermal and structural properties of nano- and micro-filled composites]. AB - The thermal and structural properties of nano-filled and micro-filled restorative composites (Filtek Supreme XT and Filtek Z250) are studied in comparison with the ones of teeth. Our results show slightly decreased values of the thermal constants of Filtek Supreme XT with respect of Filtek Z250. Both analyzed composite materials have the values of the thermal conductivity and diffusivity very close to the one of enamel, with the better fitting in the case of Filtek Supreme XT. Comparing the effusivities, a good compatibility with all dental tissues resulted. The thermal expansion coefficient is about two times higher for Filtek Supreme XT than Filtek Z250 which fits better with the one of teeth. The chemical composition is similar for both composites except for zirconium which indicate a lower percent of zirconia particle for Filtek Supreme XT. PMID- 20191852 TI - Research on serum and saliva concentration of some bivalent cations in patient with suppurations of the oro-maxillo-facial area. AB - Bivalent cations, such as calcium, magnesium, zinc, copper and manganese play important roles in some physiological and pathological processes on the human body. AIM: To determine possible modifications in serum and saliva concentration of total-Ca2+, total-Mg2+, Zn2+ and Cu2+ in patients with suppurative infections of the oro-maxillo-facial area and eventually their significance for the mentioned pathology. MATERIAL AND METHOD: Study included 47 patients with suppurative infections of the oro-maxillo-facial area, hospitalised during 2006 2008 in the oro-maxillo-facial clinic of "Sfantul Spiridon" Hospital Iasi and 43 healthy control volunteers. RESULTS: Results revealed decreased serum Zn2+ (0.94 +/- 0.21 vs. 1.39 +/- 0.14 mg/L, p < 0.01), decreased serum Zn2+/Cu2+ ratio and increased serum and saliva total-Mg2+ concentration (27.34 +/- 2.61 mg/mL in patients vs. 23.83 +/- 1.61 mg/L in healthy controls- serum, p < 0.05 and 3.79 +/ 0.41 mg/mL in patients vs. 3.21 +/- 0.40 mg/mL in healthy controls - saliva, p < 0.05) in patients with suppurative infections of the oro-maxillo-facial area vs. healthy controls. There were no statistically significant differences in total Ca2+ concentrations in saliva and serum. Our data are in agreement with medical literature revealing zinc deficiency as a predisposition factor to infection. CONCLUSION: We consider that a significant increase in total-Mg2+ saliva concentration, as well as a decrease in Zn2+/Cu2+ serum ratio could be considered a marker for predisposition to oro-maxillar suppurations. PMID- 20191853 TI - [The contribution of CT imaging in the diagnosis of periodontal disease]. AB - Generally, the routine clinical and radiographic examination in periodontology are nor enough for establishing a global and individual diagnosis that allow to establish the exact location of alveolar bone loss, their type (vertical or horizontal) as well as the presence of furcation involvement. In the six clinical cases explored with the dental CT it was possible to appreciate the alveolar bone quality (in Hounsfield units), the tridimensional morphology of intrabony defects, the number of vertical bone walls, as well as the architecture of the furcation defects. This dental CT examination is very close to the results obtained during periodontal surgery. However, this fact has permitted for four patients, from the beginning and not intraoperatively, the choice of the regenerative therapeutic procedure in the case of eight intrabony lesions as well as the extraction of three molars with Class II furcations associated with deep periodontal pockets. For the last two patients there were not obtained with the CT exam any more data. CONCLUSION: The CT exam that uses the Dental CT program allows the dental practitioner to obtain important data in cases with complexes infrabony pockets. PMID- 20191854 TI - Antibacterial activity of some Artemisia species extract. AB - The antimicrobial activities of ethanol, methanol and hexane extracts from Artemisia absinthium, Artemisia annua and Artemisia vulgaris were studied. Plant extracts were tested against five Gram-positive bacteria, two Gram-negative bacteria and one fungal strain. The results indicated that Artemisia annua alcoholic extracts are more effective against tested microorganisms. However, all plants extracts have moderate or no activity against Gram-negative bacteria. The obtained results confirm the justification of extracts of Artemisia species use in traditional medicine as treatment for microbial infections. PMID- 20191855 TI - The expanded pharmacological profile of histamine H2 receptor (H2R) species isoforms with respect to the interaction with new squaramide H2R ligands, in the GTP-ASE assay. AB - We comprehensively characterized the human (h), guinea pig (gp), canine (c) and rat (r) H2R species isoforms on Spodoptera frugiperda (Sf9) cell membranes expressing H2R-G(Salpha) with respect to the interaction with new ligands derived from squaramide. MATERIAL AND METHOD: Antagonist potencies were determined in the GTPase assay. Non-linear curve fitting was performed using the computer program Prism 4.0 (GraphPad-Prism). RESULTS: An interesting result was obtained for the squaratepentylamine compound in comparison with famotidine. Furthemore, the analysis of the new squaramide ligands, under the same experimental conditions, at the four H2R species isoforms, indicates that the rH2R exhibits increased constitutive activity, compared with hH2R, gpH2R and cH2R. CONCLUSION: The present study validates the notion that quantitative comparison of species isoforms of GPCRs provides unique insights into the molecular mechanisms of GPCR activation. PMID- 20191856 TI - [Thermal stability evaluation of some W/O/W double emulsions containing 1% piroxicam by rheological measurements]. AB - The aim of this work was to evaluate thermal stability of some W/O/W concentrated double emulsions (with 80% dispersed phase) containing 1% piroxicam following their theological behaviour at various temperatures. W/O/W double emulsions containing 1% piroxicam were prepared using the two-step procedure. RESULTS: The variable parameter of formulations was the hydrophilic macromolecule compound dispersed in the internal and external aqueous phases (hydroxyethylcellulose and Carbopol 940). Rheological behaviour and viscosity of the obtained W/O/W double emulsions was measured at 15 degrees C, 20 degrees C, 25 degrees C, 30 degrees C and 35 degrees C respectively, after preparation. The obtained results demonstrated that the studied W1/O/W2 double emulsions containing 1% piroxicam were stable under applied thermal stress, although they exhibited some differences in rheological properties caused by formulation variable. PMID- 20191857 TI - [The use of open source software in graphic anatomic reconstructions and in biomechanic simulations]. AB - The objective of this study was to obtain three-dimensional (3D) images and to perform biomechanical simulations starting from DICOM images obtained by computed tomography (CT). Open source software were used to prepare digitized 2D images of tissue sections and to create 3D reconstruction from the segmented structures. Finally, 3D images were used in open source software in order to perform biomechanic simulations. This study demonstrates the applicability and feasibility of open source software developed in our days for the 3D reconstruction and biomechanic simulation. The use of open source software may improve the efficiency of investments in imaging technologies and in CAD/CAM technologies for implants and prosthesis fabrication which need expensive specialized software. PMID- 20191858 TI - [Analysis of oxygen transfer in bioreactors for fungus broths. 2. Suspensions of P. chrysogenum mycelial associations]. AB - Unlike the P. shermanii and S. cerevisiae cultures, the study on the distribution of oxygen transfer in stirred bioreactor for P. chrysogenum pellets broths indicated that this process is controlled mainly by the deposition tendency of the biomass. Similar to the previously studied systems, the analysis of k(1)a distribution indicated its heterogeneity on the bioreactor height, the oxygen transfer rate increasing from position 1 to 4. Contrary to the bacterial and yeasts cultures, the intensification of aeration promoted the initial reduction of k(1)a, which reached a minimum level, followed by its increase, due to the flooding phenomenon. PMID- 20191859 TI - [Multi-modal treatment in breast cancer. The prognostic role and correlation between relapse and metastasis]. AB - AIM: The main aim of this study is to analyze the prognostic role of the treatment in breast cancer. MATERIAL AND METHODS: Retrospective study of 445 patients with breast cancer with 3 categories of treatments. RESULTS: Statistic correlation between treatment categories and overall survival, high correlation between treatment and disease free survival. PMID- 20191860 TI - [100 years of Nobel Prizes for Medicine]. PMID- 20191861 TI - [Treatment with statins and angiotensin-converting enzyme inhibitors in degenerative aortic stenosis--an up-date]. AB - Degenerative aortic stenosis (AoS) is the most common valvular disease in adults; that's why, the aortic valve replacement is one of the most frequent cardiac surgical procedures. The etiology of degenerative AoS is actually well known, the primary lesion being aortic sclerosis. Aortic sclerosis shares many pathological features and risk factors with atherosclerosis and, because atherosclerosis may be prevented and/or reversed by cholesterol lowering, there has been postulated that cholesterol lowering therapy using statin drugs could modify the course of aortic sclerosis/stenosis. Some studies also demonstrated the implication of renin-angiotensin-aldosterone system in the degenerative aortic disease, and the use of angiotensin-converting enzyme inhibitors could also be used to delayed or even reverse the evolution of Ao sclerosis/stenosis. The paper reviews the latest literature date about the definition and prevalence of aortic sclerosis and stenosis as well as medical treatment of degenerative AoS. CONCLUSIONS: Treatment with statins has not proved effective in preventing the progression of lesions valves but have an important role in patients with associated coronary artery disease. Angiotensin converting enzyme inhibitors does not influence the progression of lesions valves, but may play a role in cardiac remodeling. PMID- 20191862 TI - [Statins and endothelial dysfunction]. AB - Studies carried out to determine the abilities of statins showed that they have multiple cholesterol-independent benefits, named pleiotropic. These effects are highly diverse and assume such properties as the improvement of endothelial dysfunction, damaged by multiple pathologic conditions, with secondary increase in NO bioavailability. Also at endothelial level, statins have the ability of diminishing the adhesion molecules expression, thus having an indirect vasodilatator role. Their antioxidant ability is manifest in various ways: decreases the superoxide radical anion production, fact that theoretically makes them useful in the treatment of other conditions like dyslipidemia or cardiovascular diseases. Their antiinflammatory role is complex and consists, among others, in the increase of antiinflammatory cytokines production, diminution of the action of the proinflammatory ones, and decrease of monocyte recruitment. CONCLUSION: From this perspective, we believe the understanding of the innermost mechanisms through which statins act, their effects, and their use in other therapeutic schemes than the already accepted ones is useful. PMID- 20191863 TI - [Acute renal failure--the present and perspectives]. AB - Acute kidney injury is a common complication in hospitalized patients, and its incidence has risen significantly in the past 15 yr. Despite significant technical advances in therapeutics, the mortality and morbidity rates associated with acute kidney injury remain dismally high and have not appreciably improved during the past four decades. An ideal biomarker for acute kidney injury would help clinicians and scientists diagnose the most common form of acute kidney injury, acute tubular necrosis, early and accurately and may aid to risk stratify patients with acute kidney injury by predicting the need for renal replacement therapy, the duration of acute kidney injury, the length of stay, and mortality. The major types of urinary biomarkers fall into three classes: 1) inflammatory; 2) renal tubular proteins that are excreted into the urine after injury; 3) surrogate markers of tubular injury. There has been increasing interest in the identification and validation of novel biomarkers of acute kidney injury that permit earlier and more accurate diagnosis. PMID- 20191864 TI - [Adverse reactions of different treatments in chronic hepatitis C]. AB - Hepatitis C virus infection is estimated to affect over 170 million people worldwide. Standard treatment for chronic HCV involves an interferon-based preparation and ribavirin for 24 to 48 weeks. These therapeutic regimens are associated with numerous adverse events, among which constitutional and neuropsychiatric symptoms, as well as hematological abnormalities, stand out. Adverse events resulting from the treatment of hepatitis C can jeopardize the quality of life of patients and their response to treatment. The control of those events involves medicinal and non-medicinal interventions. The latter include a reduction in the dosage of IFN or RBV and discontinuation of the treatment. PMID- 20191865 TI - Premenstrual dysphoric disorder: neuroendocrine interferences. AB - Premenstrual dysphoric disorder (PMDD) consists in severe cognitive and mood changes, more aggressive as seen in premenstrual syndrome (PMS). These two syndromes are situated at the border between gynecology and psychiatry but the link between the two domains remains the neuroendocrine underlying mechanisms. In present, there are some molecular systems certainly proved as being involved, like estrogens. The hormonal pattern consists not in different levels of the hormones but different response to normal hormonal levels. The cyclical biochemical triggers are related to neurotransmitters as serotonin, endorphin and gamma-amino butyric acid (GABA). The heritability of the syndrome is sustained by genetic polymorphism in ESR1 gene. Thus, the PMDD is the result of multiple disturbances regarding neuroendocrine systems. PMID- 20191866 TI - [Hyperuricemia and the metabolic syndrome]. AB - Uric acid is the final product of purine metabolism in human beings. Despite the fact that uric acid was first identified approximately 2 centuries ago, certain pathophysiologic aspects of hyperuricemia are still not clearly understood. For years, hyperuricemia has been identified with or thought to be the same as gout, but uric acid has now been identified as a marker for a number of metabolic and hemodynamic abnormalities.The prevalence of the metabolic syndrome is very high in hyperuricemic patients. Recent epidemiologic studies support the view that asymptomatic hyperuricemia in patients at low cardiovascular risk is likely to result from diminished renal uric acid clearance and to be benign in outcome. In contrast, hyperuricemia in patients at high cardiovascular risk may promote or reflect alternative or additional pathogenetic factors promoting inflammatory, ischaemic or oxidative stresses to the heart and vessels. This hypothesis warrants testing, particularly in carefully designed randomized controlled urate lowering interventional trials. PMID- 20191867 TI - [Obesity paradox]. AB - Obesity has reached global epidemic proportions and is associated with major cardiovascular diseases and reduced overall survival. This paper reviews the metabolic and vascular consequences of dysfunctional adipocytokines in obesity as well as the pathological effects on blood pressure, cardiovascular structure and function. Despite this adverse association, numerous studies have documented an obesity paradox in which overweight and obese population with established cardiovascular disease have a better prognosis. There are potential explanations offered by literature for these puzzling data. For obese hypertensive patients the paradox is possibly linked to the lower systemic vascular resistance and plasma renin activity. In heart failure the excess body weight may confer some protective effects on mortality, due to a more metabolic reserve, higher levels of arterial pressure compatible with higher doses of cardioprotective medications, and a specific neuroendocrine profile with lower levels of circulating natriuretic atrial peptides, attenuated sympathetic nervous system and renin-angiotensin responses. For coronary heart disease and peripheral arterial disease the mechanisms are still uncertain. There are discussed a lesser severity of coronary lesions and left ventricular dysfunction, or a reduced prevalence of moderate-severe chronic obstructive pulmonary disease in patients selected for surgery. On the other hand, the constellation of data which supports purposeful weight reduction in the prevention and treatment of cardiovascular diseases, induces a controversial position regarding this new concept. PMID- 20191868 TI - [Comparative efficiency of externally-irrigated cooled-tip catheter vs. 8-mm-tip catheters in radiofrequency (RF) ablation of common atrial flutter]. AB - Cooled-tip and 8-mm-tip catheters have been found to be more effective than conventional 4-mm-tip catheters for radiofrequency (RF) ablation of common atrial flutter. The aim of this study was retrospective comparison between cooled-tip and and 8-mm-tip catheters in terms of efficacy and safety of RF ablation in atrial flutter. MATERIAL AND METHOD: Among 148 consecutive patients (pts) referred for common atrial flutter, cavotricuspid ablation was performed with an externally-irrigated cool tip catheter in 100 pts, and with an 8-mm-tip ablation catheter in 48 patients. RF current was applied for 60 seconds at powers of 50 W with the cooled-tip catheter, and in a temperature-controlled mode (65 degrees C/70 W) with the 8-mm-tip catheter, until bidirectional isthmus block was reached, or a total of 35 unsuccessful RF applications were performed. RESULTS: A higher initial failure rate with 8-mm-tip catheters was significant, compared to the externally-irrigated catheter (18% vs 4% ; p < 0.01). Significant differences were also found in some procedure parameters, such as the number of RF applications (26 +/- 8 vs 35 +/- 10; p < 0.04), fluoroscopy time (11 +/- 15 min vs 27 +/- 10 min; p < 0.01) and total procedure duration (95 +/- 23 min vs 145 +/ 35 min; p < 0.09). No major complications occurred. In a mean follow-up of 30 +/ 11 months atrial flutter recurred only in group treated with 8 mm catheter (10 patients among 48). CONCLUSION: In achieving cavotricuspid isthmus block, RF ablation performed through cooled-tip catheters is more efficient than application through 8-mm-tip catheters. PMID- 20191869 TI - [Non-traumatic rhabdomyolysis in medical practice]. AB - Rhabdomyolysis, meaning "disintegration of striated muscle", is a potentially life-threatening syndrome resulting from release of muscular cell constituents into the circulation. The aim of this study is to determine frequence and causes of rhabomyolysis in internal medicine practice, as well as diagnostic and therapeutic discussions, based on a retrospective study in patients addressed to a medical clinic of an universitary emergency hospital. RESULTS: The most common causes of rhabdomyolysis in general practice are represented by muscular trauma, muscle enzyme deficiencies, electrolyte abnormalities, infections, drugs, toxins and endocrine disorders. Frequent encountered clinical manifestations are weakness, myalgia and tea-colored urine, and the most sensitive laboratory finding of muscle injury is an elevated plasma creatine kinase level. The management of patients with rhabdomyolysis includes early vigorous hydration, together with specific measures (urine alkalinization, mannitol, hemodialysis). PMID- 20191870 TI - [Expression of Ki-67 in bronchial asthma]. AB - In this paper we want to study the changes in the expression of cell proliferation factor Ki67 in the respiratory epithelium of patients diagnosed with bronchial asthma. MATERIAL AND METHODS: Twenty one patients with bronchial asthma having different degrees of severity (according to GINA 2002) have been included in our study. Fragments of bronchial mucosa were obtained through fiberbronchoscopy, prepared for histologic examination in view of immune marking with anti-Ki67 antibodies. RESULTS: Microscopic examination revealed a progressive increase in the number of Ki-67 cells in the respiratory epithelium corresponding to the severity of asthma (following FEV1 parameters). CONCLUSION: The increase in the cell proliferation in the respiratory epithelium represents one of the mechanisms that can help in rebuilding the epithelial structure destroyed by the chronic irritation. PMID- 20191871 TI - [Prevalence of delayed gastric emptying of solids in functional dyspepsia and its relationship to symptoms]. AB - The relationship between functional dyspepsia and delayed gastric emptying of solids is still unclear. This study evaluated the prevalence of delayed gastric emptying of solids in functional dyspepsia patients and its relationship to dyspeptic symptoms. MATERIAL AND METHOD: 142 patients with functional dyspepsia were prospectively assessed, the solid gastric emptying was measured using 13C acid octanoic breath test and the severity of six dyspeptic symptoms (postprandial fullness, early satiety, bloating, abdominal discomfort, nausea and vomiting) was scored. RESULTS: Gastric emptying of solids was delayed in 45 (31.7%) dyspeptic patients. Multivariate analysis showed that the presence and severity of nausea and vomiting were associated with delayed solid gastric emptying (p < 0.05). Female gender was also associated with the risk of delayed gastric emptying (p < 0.05). CONCLUSIONS: A subset of functional dyspepsia patients has delayed gastric emptying of solids. Female sex, the presence and severity of nausea and vomiting are independently associated with delayed gastric emptying of solids in these patients. PMID- 20191872 TI - [Prevalence of Helicobacter pylori infection in patients with diabetes mellitus]. AB - Helicobacter pylori (H. pylori) and diabetes mellitus are the most important causes of dyspepsia. The aim of this study was to evaluate the prevalence of H. pylori infection in patients with diabetes mellitus, and to assess whether the infection was associated with severity of dyspeptic syndrome and metabolic glycemic control. MATERIAL AND METHOD: 100 patients with diabetes mellitus type 1 and 2 (41 men and 59 women, mean age 58.59 ani) were included in our study. Each patient completed a self-report questionnaire to obtain information concerning the presence and severity of upper gastrointestinal tract symptoms. H. pylori status was confirmed by serological test and histophatology study of gastric biopsy or 13C-urea breath test. RESULTS: Prevalence of H. pylori infection was found not to be significantly higher in diabetics than in controls (70% vs 73% ). 49% H. pylori positive diabetics had type 2 insulinonecesitant diabetes mellitus, 27% had type 1 diabetes mellitus and 24% had type 2 diabetes mellitus, with no statistically significant difference (p > 0.05). We found no statistically significant difference in the symptoms score between H. pylori positive and H. pylori negative diabetic patients. The main value of HbA1 levels in H. pylori- infected diabetics was 7.31% and 7.47% in H. pylori non-infected diabetics, without significant difference. CONCLUSION: There was no statistically significant difference in the prevalence of H. pylori infection between diabetics and non-diabetics patients and no difference in the symptoms score between H. pylori positive and H. pylori negative diabetic patients. H. pylori in diabetics appears no influence glycemic status. PMID- 20191873 TI - [Prevalence of Helicobacter pylori in liver cirrhosis complicated with hepatic encephalopathy]. AB - Hepatic encephalopathy (HE) is a frequent complication of liver cirrhosis, and plasma ammonia plays a pivotal role in its pathogenesis. Helicobacter pylori (H. pylori) urease activity is a potential source of ammonia in the stomach of patients with cirrhosis and may contribute to hyperammonemia in these patients, but conflicting data are available in the literature. The aim of our study was to evaluate the prevalence of H. pylori infection in cirrhotic patients with HE admitted in a tertiary medical center from nord-eastern region of Romania. RESULTS: seroprevalence of H. pylori infection in cirrhotic patients with HE did not significantly differ from cirrhotic patients without HE (51.61% vs. 48.39%). Clinical and biochemical parameters were almost similar between patients with HE H. pylori-positive and those H. pylori-negative. CONCLUSIONS: the prevalence of H. pylori infection in cirrhotic patients with HE is almost similar to that found in patients with liver cirrhosis without HE. Our results suggest that H. pylori infection is not an independent risk factor for HE in cirrhotic patients. PMID- 20191874 TI - [Aflatoxin contamination of food: additional risk factor for chronic liver diseases]. AB - Aflatoxins are over all spread toxic metabolites of fungi, able to induce chronic liver damages. AIM: To establish the correlation between the degree of liver disease and risk of chronic intake of aflatoxin contaminated foods. MATERIAL AND METHOD: 123 patients divided in three groups (controls, chronic hepatitis and liver cirrhosis) completed a food frequency questionaire (FFQ) estimating the intake risk of foods with a high potential of contamination with aflatoxins and alcohol consumption. RESULTS: Frequent intake of high risk foodstuff was declared by 37% of the participants, without any differences between the three groups. Foods with a very high risk of contamination were more frequently consumed in rural areas (predominant maize and oily seeds), while in the urban areas spices and coffee prevailed. In countryside, the feeding risk decreased with the gravity of liver disease, but alcohol consumption was significantly greater. CONCLUSION: FFQ revealed a high risk of ingestion of aflatoxin contaminated foodstuff in general population, greater in rural areas. The risk of aflatoxin intake seems unreleated with the gravity of chronic liver disease. PMID- 20191875 TI - [Clinical characteristics of gastritis due to excessive alcohol drinking. Observation of 117 patients at Dorohoi Hospital]. AB - The aim of the study was to assess the symptoms manifested in patients with gastritis (gastropathies) due to excessive alcohol consumption. MATERIAL AND METHOD: The study sample consisted of 117 cases admitted in the Town Hospital Dorohoi, Botosani County, between 2002-2006. RESULTS: Data were collected using special epidemiological questionnaires and statistical records of the hospital and Public Health Office. Anamnesis, clinical examination, following by endoscopy and histological and radiological examination completed the diagnosis. Although interventions regarding prevention methods were permanently applied, their efficiency was suboptimal for most of the patients suffering from chronic gastritis and excessive alcohol consumption. PMID- 20191876 TI - [Clinical epidemiologic assessment of the incidence of chronic kidney diseases registered in Romania, Iasi County, in the years of 2004-2008]. AB - Authors present the results of a study carried out in Iasi County and Romania, comparatively, between 2004-2008, in order to know the incidence of the main chronic kidney diseases (CKDs) (nephritic syndrome and nephrosis, chronic renal failure, kidney and urinary lithiasis) and those with a major role in their etiology (essential arterial hypertension--EAHT and diabetes mellitus--DM). RESULTS: The distribution of cases at the county and national level was assessed both for CKDs and EAHT and DM, respectively, by area, sex and age groups. Clinical epidemiological research highlighted high values of CKDs incidence, taking into account a defficiency in standardized data collecting, processing, and interpretation to allow a database useful for elaboration and implementation of prevention programmes. PMID- 20191877 TI - [Observation on twins of cosmic radiation influence as a risk factor]. AB - During flight, cosmic radiation is capable to penetrate the walls of airplanes and produce mutations in human chromosomes. AIM: To evaluate the correlations between cosmic radiation and the pathology of flying personnel. MATERIAL AND METHOD: Two twin patients, one with 15 years work as a flight crew member, and the other with regular work on the ground. The patients were examined clinically, biochemically and with imaging methods. The genetic and environmental contribution to their pathology was noted. The patient, working in flight, received additional genetic tests to refute or to confirm the presence of chromosome alterations induced by the cosmic radiation. RESULTS: The patient, member of the flight crew, presented hypercholesterolemia, more evident structure modifications of the mammary gland, but chromosome alterations were not present. CONCLUSIONS: Having a first grade relative with dyslipidemia and uterine cancer, the structural or blood homeostasis modifications of the flight crew member can be either due to a high, genetically transmitted, susceptibility to the effects of the plane's microclimate and possibly to effects of lifestyle. PMID- 20191878 TI - [Fungal infections and nail psoriasis]. AB - Onychomycosis and psoriasis are common diseases and it is possible that they coexist in the same patient. Psoriasis is a common cause of disturbance of the nail morphology. Nail disorders was reported in 10-80% of patients with psoriasis and may be associated with all clinical forms of disease. It has been suggested that the nail dystrophy in patients with psoriasis produce the lose of the natural protective barrier and increase vulnerability to fungal infections. But most authors report that in patients with psoriasis the prevalence of onychomycosis is no higher than in the general population. We conducted an observational analytical retrospective study of case report forms of patients with nail psoriasis hospitalized in Iasi Dermatology Clinic, 2004-2008. 360 patients were hospitalized with psoriasis. Of these 32 patients had nail disorders. PMID- 20191879 TI - General aspects of the morbidity in Alzheimer's dementia during 2003-2005 at the Neurology and Psychiatry Clinical Hospital Oradea. AB - This paper proposes to study some general aspects about the morbidity due to Alzheimer's dementia at the Neurology and Psychiatry Clinical Hospital Oradea. MATERIAL AND METHOD: The study was made based on the observation sheets of the patients with Alzheimer disease hospitalised at the Clinical Hospital of Neurology and Psychiatry Oradea, in 2003-2005. RESULTS: From 34 hospitalised cases the most affected age group was that coresponded to 71 - 80 years old with 64.71%; the women are prevalent with 64.71%; 55.88% occurred at the rural population and 52.95% have an elementary level of education. CONCLUSIONS: The percentage of patients with Alzheimer's in the psychiatric section of the Clinical Hospital of Neurology and Psychiatry, in 2003-2005, was of 1%. Alzheimer's dementia is prevalent in women. The frequency of Alzheimer's disease among the rural population is bigger than the urban population and is greater at the people who have an elementary educational level. Most of the patients showed an improved general health condition when leaving the hospital. PMID- 20191880 TI - [Helicobacter pylori infection in children with celiac disease]. AB - The purpose of this study is to evaluate symptomatology, endoscopic and histopathologic changes of Helicobacter pylori infection and gastritis lesions without Helicobacter pylori infection on children diagnosed with celiac disease. MATERIAL AND METHOD: 15 children under gluten-free diet were selected and, because of the recurrence of the dyspeptic syndrome, an upper digestive endoscopy associated with histopathologic exam was performed. Considering the histopathologic result we made two groups: first group (8 children with celiac disease and Helicobacter pylori infection) and second group (7 children with celiac disease without Helicobacter pylori infection, but associated with gastritis lesions). RESULTS: The main symptom was diffuse abdominal pain in both groups. The endoscopic antrum aspects were congestive with striped aspect (first group--12.5%, second group--42.9%) and congestive with nodulation (first group- 25%, second group--14.3%). The histopathologic diagnosis were: moderate active chronic pangastritis (first group--25%, second group--14.3%) moderate active chronic gastritis (first group--25%,second group--14.3%), lymphocytic gastritis (first group--12.5%, second group--14.3%). CONCLUSION: The histopathologic exam remains the gold standard for celiac disease, gastritis lesions and Helicobacter pylori infection. PMID- 20191881 TI - [Toxocariasis respiratory manifestations in cases hospitalized in the Paediatric Diseases Clinic of Iasi, between 2005-2008]. AB - The authors present the results of retrospective epidemiological, clinical and laboratory diagnosis on toxocariasis cases hospitalized in the Pediatric Diseases Clinic of Iasi, between January 2005-June 2008. MATERIAL AND METHOD: The study included a number of 228 children. RESULTS: Respiratory manifestations were present in 184 children: 105 boys (46.05%) and 79 girls (34.64%), with a slight advance of the rural environment (44.29%). The age distribution highlighted a predominance of 1-5 years of age (65.76%). Respiratory manifestations were fever, coughing, wheezing, asthma, infections of respiratory pathways, pneumonia. The distribution of toxocariasis in children patients in Moldavia, Romania, highlighted a predominance in Iasi. The children with respiratory manifestations had hypereosinophilia associated with hyperleucocytosis. All the patients were serologically confirmed with toxocariasis. The children responded well to treatment with albendazole. PMID- 20191882 TI - [Lichen planus-like eruption. Case report]. AB - Cutaneous adverse drug reactions are among the most common adverse drug reactions. Thise reactions to drugs can comprise a broad spectrum of clinical and histopathological features, with an important capacity to mimic numerous dermatological diseases, making the diagnose very difficult. We present the case of a patient, under immunomodulating treatment (TNFalpha antagonist and leflunomide), with a muco-cutaneous lichen planus-like eruption. PMID- 20191883 TI - Nephrotic syndrome from the genetic point of view. AB - Nephrotic syndrome, an entity described at the beginning of the 20th century, has still an unclear pathophysiology, genetic and immunologic factors being incriminated. Here we report three cases of nephrotic syndrome with genetic involvement. The article presented tremendous progress that have been made over the past few years in enhancing our understanding of the slit-diaphragm and podocyte biology and genetics involvement in nephrotic syndrome. PMID- 20191884 TI - Applications of 3-D ultrasound in female infertility. AB - 3D ultrasound is an emerging technology with great promise to further this role. This overview describes and illustrates the applications of three-dimensional transvaginal ultrasound in female infertility. The authors illustrate their cases where 3D ultrasound was beneficial for infertile patients. The obvious advantages are that 3D ultrasound offers more rapid and reproducible image acquisition as well as enhanced visualization and post-processing capabilities. Its main applications include assessment of uterine congenital anomalies, intrauterine pathology, tubal patency, polycystic ovaries, ovarian follicular monitoring and endometrial receptivity. Ongoing research will likely continue to define the clinical role of 3D ultrasound and it is possible in the near future to regard to 3D ultrasound as the Golden Standard for pelvic imaging. PMID- 20191885 TI - [Glaucoma--neurodegenerative disease]. AB - Glaucoma is a specific optical neuropathy, with local nerve damage and pathogenesis incompletely understood. The progressive death of retinal ganglion cells and optical neural loss suggests the following hypothesis: primary destructive event (ischemia, elevated intraocular pressure and genetic risk factors) and secondary degeneration (apoptosis and excitotoxicity). The concept of neuroprotection is a therapeutical paradigm for preventing and delaying neuronal cell death and maintaining the function of neurons. Other additional concept--neurorescue is used to prevent neuronal death by interrupting the biological cascade of secondary events. Most substances that can be found (glutamate, nitric oxide, a.o) in excess in extra cellular spaces induce damage of retinal ganglion cells, while others (memantine, gingko biloba, nicergoline, flavonoids, ascorbic acid) are used to restore these cells and their axons, i.e., neuroreparation and neuroregeneration in various degrees. This paper is an up date of numerous studies which demonstrate that open-angle glaucoma is considered to be a neurodegenerative disease connected with alterations of the cardiovascular, central nervous, immune, endocrine, psychological systems and of sleep, requiring the introduction of glaucoma in general medical context. PMID- 20191886 TI - [Quantification of the acute respiratory insufficiency of laryngo-tracheal origin]. AB - Acute respiratory insufficiency defines that status in which the respiratory system is not able to supply the metabolic requirements of the organism. The laryngo-tracheal segment plays an important role in the respiratory function, an obstruction at this level inducing an important limitation of oxygen intake. Due to the requirement of fast repermeabilisation of this segment, it is necessary to define all criteria (clinical and laboratory examination) required to diagnose and to evaluate the respiratory failure. The present paper depicts the clinical aspects, the acid-base equilibrium impairment induced by high level airway obstruction and the functional investigations available by ventilation tests. PMID- 20191887 TI - [Primary and secondary hepatic cancer--specifics of surgical treatment in correlation with disease stage]. AB - Given the necessity of increasing their resectability, there are evaluated the possibilities of surgical treatment for these types of hepatic cancer, in the context of dominant clinical presence of advanced hepatic tumors. MATERIAL AND METHOD: The study comprises 190 patients during 01.01.2000-31.12.2007, in the IIIrd Surgical Clinic, Iasi, with primary and secondary hepatic tumors. RESULTS: There were made typical and atypical hepatic resections, metastasectomies--36 cases, alcoholisation--11 cases, and radiofrequency ablation--19 cases. Mortality was 4.73%. This study makes a critical analysis of the surgical treatment methods use, given the apparition of radiofrequency thermodistruction and the surgical technology evolution. PMID- 20191888 TI - Preoperative ultrasonography as a mean of predicting the conversion of mini cholecystectomy into classic cholecystectomy. AB - Cholecystectomy is considered to be the treatment of choice in symptomatic biliary lithiasis. Lately, due to medical progress, classic cholecystectomy has been gradually replaced by laparoscopic cholecystectomy and by mini cholecystectomy. Therefore, it is very important to determine certain preoperative factors which might predict the conversion of mini cholecystectomy (MC) into classic cholecystectomy (CC). MATERIAL AND METHOD: The possibility of selecting high-risk conversion patients has important clinical implications, both for the surgeon and for the patient. Differentiating preoperative risk allows the surgeon to inform the patient about a high conversion risk to CC, and about the ensuing consequences: longer hospitalization period, longer postoperative recovery, greater costs. All the patients were examined by ultrasonography. The tests recorded six parameters: the diameter of the biliary duct (mm), the number of calculi, the diameter of the largest calculus (mm), the contracted aspect of the gallbladder, the distance between the tegument and the gallbladder fundus (cm), the distance between the tegument and the cystic duct (cm). All the variables were introduced into an initial model, which was checked using the colinearity method and significant observations, and subsequently reduced by eliminating insignificant predictive factors, revealed by Wald tests. RESULTS: The significant predictive conversion factors to CC, quantified on the basis of regression analysis, are: age > 70, calculus with a diameter > 20 mm, biliary duct with a diameter > 6 mm, contracted gallbladder, distance between the tegument and gallbladder fundus > 7.2 cm, distance between the tegument and cystic duct > 17.1 cm. CONCLUSION: Being a procedure that can be carried out on an outpatient basis and with rather low costs, ultrasonography plays a very important role in the preoperative prediction of converting MC to CC. PMID- 20191889 TI - [Clinical study of sinus grafts and implants integration, in the posterior maxilla]. AB - In this study we have tried to evaluate the degree of integration for endosinusal grafting and implant placement in the posterior maxilla. MATERIAL AND METHOD: We included in our study a number of 136 patients with sinus lift surgery. We have established the stability of the implants using the periotest. RESULTS: The presence of the antral septum favoured the sinus membrane to tear, the results of our study are obvious (23.46%). Aloplastic materials for sinus grafting is our first choice because the results are comparable with the cases in wich we used autografts, and the advantage is that we don't need a second surgery place. Implant insertion after sinus grafting integration, increases the rate of succes in sinus grafting and implant insertion compared with sinus grafting and implant insertion made in the same operative step. PMID- 20191890 TI - [Management of anxiety associated with oral surgery]. AB - General and practical training, knowing of safe methods of preanesthesia, pain and anxiety control and establishing a good relation with the patient are some of the most important methods of patient management in the dental office. The final goals of the methods are to obtain a calm patient, haemodinamic equilibrated and safely prepared for the surgery. MATERIAL AND METHOD: Our study was performed on 448 patients. Different methods of preanesthesia were used by administrating per oral, intravenous, intramuscular, according with DAS score: Midazolam, Diazepam + Algocalmin, Xanax. RESULTS: 58% of our patients declared after surgery that their satisfaction score is 100% positive after one of our methods of preanesthesia. CONCLUSION: When choosing the appropiate premedication, the ability of the analgesic and anxiolytic drug to improve pain tolerance should be one of the most important criteria. Doses must be correlated with the anxiety score DAS, road use and the probable duration of surgery. PMID- 20191891 TI - [Bilateral ureteroceles with bilateral secondary hydronephrosis and pelvic ureteral calculi. Case report]. AB - Bilateral ureterocele is a rare congenital condition that is usually diagnosed antenatally or in childhood. We present the case of a 64 year-old woman who was admitted for incidentally discovered microscopic hematuria. A bilateral ureterocele and secondary pelvic ureteral calculi were diagnosed by clinical examination (vaginal touch), ultrasound, plain radiography and intravenous urography. A transurethral incision of the ureterocele and extraction of calculi was performed by endoscopic approach. The postoperative recovery was uneventfull. Considering the risk for development of vesicoureteral reflux or recurrence of obstruction at the ureterovesical junction, a close long-term follow-up is required. PMID- 20191892 TI - [Py-Desmanet pinning in distal radius fractures]. AB - Internal fixation by pinning is one of the most used methods of surgical treatment in fractures of the distal extremity of the radius. As in stable fractures a styloid pinning is satisfactory, in unstable fractures however we must resort to different patterns of pin insertion, in order to effectively prevent the secondary displacement of the fractured fragments. The elastic pinning described by Py and Desmanet is one of the possibilities of inserting the pins. The principle of this method is to use the bending-induced tension in the pins to counteract the postero-lateral displacing forces. The authors have treated by this technique five patients with distal radius fractures (3 women and 2 men) about 56 years of average age, all with good-quality bone, all with Colles' fracture pattern (2-4 cm above the radio-carpal articulation, no articular involvement, posterior displacement of the distal fragment). The reduction of the fractures was achieved by closed manipulation and controlled intraoperatively with the C-arm. We preferred to reduce the fractures before inserting the pins, although this is not compulsory, according to the authors of the technique. The approach was minimally-invasive, through two 1-cm long incisions. The pins, previously blunted and curved along the last centimeters, were introduced using a "T"-shaped handle. The potential complications, consisting of injuries of the many elements which cross the region, were avoided by sufficiently long incisions and identification and retraction of these elements (tendons, nervous branches) in order not to penetrate them with the pins. The aftertreatment consisted of immediate mobilization of the wrist in one patient, 21-day splinting in other two and 30-day splinting in the last two, depending on the intraoperative assessment of the stability of the fixation. The pins were removed at 45 days postoperatively in all cases. There were no complications such as loss of reduction or pin migration. In all cases, there were good anatomic and functional results. CONCLUSIONS: This method is relatively fast and simple, does not require special or expensive equipment and it gives good results in carefully selected cases. PMID- 20191893 TI - Micro- and nanoparticles--medical applications. AB - It is a long-standing need of the pharmaceutical industry, physicians, and patients to improve pharmaceutical formulations by establishing simpler, less expensive preparations and treatments, while reducing toxicity. This need can be met with the know-how of drug delivery science that has already made advance developments in improved delivery of injectibles, oral formulations, drug device implants, as well as topical and transdermal delivery formulations, especially in the case of drug delivery to the brain, an untouchable region by traditional drug delivery systems. The reason behind the failure of conventional delivery systems in reaching the brain is the blood brain barrier (BBB) composed of tight tissues making it impervious to outside agents. Nanotechnology has the potential to address and resolve this challenge and make brain a reachable target for drug delivery systems, by combining unique elements of size, surface activity and charge of nanostructures. Micro and nanoparticles have opened up unexpected ways in diagnostics and therapeutics in medicine. The previous treatment strategies in the fields of autoimmune diseases and cancer involved non-targeted treatment options with extensive "collateral damage." Nanodelivery of drugs is predicted to reduce this collateral damage, extend the drug's availability and effectiveness at the site, and reduce toxicity and cost with a high pay-off load. In this review we present the role of micro and nanoparticles in drug delivery and some applications in the health care fields. PMID- 20191894 TI - The protective effect of superoxide dismutase on isolated human mammary arteries preincubated with triglyceride-rich remnant lipoproteins. AB - The main changes of the plasma lipid profile in patients with endothelial dysfunction are the increased triglyceride content of the lipoprotein remnant particles, the presence of the small and dense LDL particles and the decreasing of the HDL-cholesterol level. MATERIAL AND METHOD: Considering these observations, we performed "in vitro" experiments using human mammary artery rings, in order to examine the effect of the lipoprotein "remnants" on endothelium-dependent vasodilatation induced by cumulative doses (10(-9) M - 10( 4) M) of adenosine (ADP) and to study the effect on endothelial--independent vasodilatation induced by cumulative doses (10(-9) M-10(-4) M) of sodium nitropruside (NSP), respectively. RESULTS: Our results showed that 1 hour pre incubation with triglyceride--rich lipoprotein remnants diminished the endothelial-dependent vasodilator response to ADP, but it has not modified the endothelial-independent vasodilator response to NSP. Vascular response was expressed as maximal vasodilatation from the 10(-4)M phenilephrine (PE) induced pre-contraction, considered as reference. In the case of ADP, the maximal vasodilatation was ranged in 36.50% +/- 10.81% interval, comparing with the control group that presented a maximal vasodilatation of 66.15% +/- 19.41% (p < 0.005). In the case of NSP the maximal vasodilatation was ranged in 99.78% +/- 10.53% interval, comparing with the control that presented a maximal vasodilatation of 98.99% +/- 12.45% (p = 0.44). One hour co-incubation of the rings with a solution containing lipoprotein remnants (1% oxidized IDL (ox-IDL) and antioxidant factor (150 U/mL 10(-4) M Superoxid dismutase (SOD) significantly reduced the impairment of the vasodilatation response to ADP. Maximal vasodilatation of ox-IDL and SOD coincubated human mammary artery rings was 58.50% +/- 10.63% compared to the control, were the maximal vasodilatation was 66.15% +/- 19.41% (p < 0.01), but has not modified the vasodilatation response to NSP (99% +/- 0.53% vs control 98.99% +/- 12.45%, p = 0.56). CONCLUSION: The endothelial dysfunction induced by the triglyceride-rich lipoprotein "remnants", could contribute to the pathogenesis of atherosclerosis and the treatment with high doses of antioxidants could "protect" the endothelium against the pro atherogenic action of the lipoprotein "remnants". PMID- 20191895 TI - [Prognostic significance of leukemia-associated phenotype in correlation with other biologic markers in acute myeloid leukemia patients]. AB - Leukemic cells have unique aberrant phenotypes, which permit identification of this cells at diagnose and in evolution of the disease. Signaling molecules with other cells and bone marrow stroma are part of the leukemic cells phenotype. Genetic and molecular abnormalities have the main prognostic significance and confer the leukemic cell status. The main aim of the current study is to identify correlation between recognized prognostic factors in acute myeloid leukemia (AML) patients and other phenotypic markers. MATERIAL AND METHOD: Imunophenotypic analysis (BDFACS CantoII, FACSDiva Software) was performed on peripheral blood/bone marrow aspirate samples of 56 patients diagnosed with AML (9 M0, 3 M1, 10 M2, 4 M3, 28 M4/M5, 1 M6, 1 M7) between 2007-2009 in Hematology Department of "Sf. Spiridon" Hospital Iasi. We used an extended panel of monoclonal antibodies and we determined the level of expression of cytokines receptors (IL3Ra, IL7R) and chemokines (CXCR4, CKR5). RESULTS: In our study, IL7R expression on AML blasts was significant correlate with low WBC count at diagnosis (p = 0.04) and with multilinear displasia (p = 0.01), high CXCR4 expression was correlate (p = 0.05) with lack of response at first induction therapy and CD123 (IL3Ra) expression was correlate with M4 FAB phenotype. Survival was negative influenced by presence of IL3R on AML blasts, but flt3 mutations, CXCR4, IL7R expression on leukemic cells, other phenotypic aberrancies did not influenced treatment response and survival in our patients population. CONCLUSION: Complete investigation of leukemic cells phenotype extended with cytokines/chemokines receptors at diagnostic is useful for correct characterization of the disease, for discover new prognostic categories and for better identification of minimal residual disease. PMID- 20191896 TI - Using MLPA for large genomic rearrangements detection in breast cancer predisposition genes. AB - Breast and ovarian cancer are common pathologies in women, with increasing incidences worldwide. In hereditary breast and ovarian cancer (HBOC) families, a large percentage of cases are attributable to hereditary factors compatibles with dominant autosomal transmission of a major tumour suppressor gene with incomplete penetrance. Screening for BRCA1 mutations is now standard practice for HBOC cases in western world, and permits medical follow-up and genetic counselling. Over 300 BRCA1 germinal mutations are stored in the Breast Cancer Information Core (BIC) mutation database. MATERIAL AND METHODS: Estimates in different countries range from 5 to 15% the BRCA1 related cases of hereditary breast cancer due to copy number changes of one or more exons of this gene. Exon deletions and amplifications will usually not be detected by sequence analysis of the complete BRCA1 gene, therefore MLPA screening is needed. RESULTS: Here we describe Multiplex Ligation-dependent Probe Amplification technique (MLPA) implementation for BRCA1 large genomic rearrangements. CONCLUSIONS: We did not detect any BRCA1 mutation by analysis of 15 HBOC recruited patients. PMID- 20191897 TI - [Expression of CA-125 in ovarian cancer]. AB - Ovarian carcinoma is a heterogeneus disease. Pathologists classify it in serous, clear cell, endometrioid and mucinos subtypes. Each of these subtypes is associated with different genetic risk factors and molecular events during oncogenesis and it is characterised by distinct mRNA expression profiles. MATERIAL AND METHOD: We have studied 55 pacients with ovarian tumours who underwent surgery in Clinic "Elena Doamna", Iasi between 2005-2008. CA-125 value was determined pre or postoperator. RESULTS: We have investigated the relationship between tumoral type and CA125 value in all studied cases. CONCLUSIONS: By demonstrating the correlations between biomarker expression with stage or prognosis and by demonstrating the variation in expression rates between subtypes we offer persuasive evidence supporting the view that ovarian carcinoma subtypes are different diseases and the value of the biomarker is not always correlated with malignancy. PMID- 20191898 TI - Biogenic amines determination in some Romanian meat products. AB - AIM: Biogenic amines are compounds synthesized in human body which in high concentration become toxic and lead to a wide range of symptoms as palpitations, nausea and headache. Meat products can contain high levels of biogenic amines. Ingestion of such product can cause severe illness. For these reason it becomes necessary to determine the biogenic amines levels in meat products. In our work we have determined the amount of some biogenic amines and the ration in which they are present in different type of fresh and processed meat products made by several producers. MATERIAL AND METHOD: Meat sample was homogenized with TCA 5%, than centrifuged at 4000 rpm and supernatant collected was eluted on a solid cartridge extraction. The extracted liquid was than analyzed on high performance liquid chromatography (HPLC) system in order to determine histamine, tyramine, cadaverine and putrescine. RESULTS: Concentration of biogenic amines such as histamine, tyramine, cadaverine and putrescine, find in the foodstuffs we have analyzed, showed significant differences. CONCLUSIONS: Our study indicates the presence of biogenic amines in Romanian meat products and signals to the risk of food consumption, for persons which are allergic or for those under classical monoamine-oxidase inhibitor drug therapy. PMID- 20191899 TI - Effects of dietary flaxseed supplementation on renal oxidative stress in experimental diabetes. AB - Previous results demonstrate that experimental diabetes mellitus is accompanied by increased oxidant stress within glomeruli. Evidence are emerging that dietary flaxseed supplementation can have beneficial effects on oxidative stress. MATERIALS AND METHODS: Diabetes was induced by intraperitoneal injection of streptozotocin (STZ) in male Golden Syrian hamsters, and both diabetic and control groups were fed either standard diet, or standard diet supplemented with flaxseed (15 g/100 g diet), for 20 weeks. At the end of the study, blood samples and renal homogenates were used for determination of oxidative stress markers. RESULTS: STZ-induced diabetes in hamsters substantially increased malondialdehyde levels along with corresponding decrease in the antioxidants levels. Supplementation of flaxseed resulted in the decrease in serum and renal homogenate malondialdehyde levels. The activities of antioxidant enzymes, total glutathione (tGSH) and superoxiddismutase (SOD) were also concomitantly raised to near normal levels by flaxseed supplementation diabetic hamsters. CONCLUSION: Dietary flaxseed supplementation in diabetes mellitus may have beneficial effects on diabetic nephropathy evolution by reducing the levels of oxidative stress and increasing the antioxidant defense systems. PMID- 20191900 TI - [Enhanced molecular techniques for the diagnosis of human papillomavirus infections]. AB - OBJECTIVES: optimisation of Real Time PCR technique for quantifying oncogenic types 16 and 18 of Human Papilloma Viruses, genotyped through classic PCR, followed by hybridisation. MATERIAL AND METHOD: DNA/ HPV was purified with High Pure PCR Template Preparation kit (ROCHE DIAGNOSTICS), genotyping was performed with Linear Array HPV Genotyping (ROCHE DIAGNOSTICS) and PCR reaction was realized with ABI 9700 Gold Plate System. Absolute quantification of HPV 16 and 18 was performed with Path-HPV16/18 Real-time PCR detection kit for Human Papillomavirus, 2 x Precision Mastermix kits (PrimerDesign), and the instrument used was MX3000P STRATAGENE. RESULTS: I. HPV genotyping was optimised through testing of 12 cervical samples, collected from patients who have signed the informed consent approved by the local Bioethical Committee. Among the tested samples, 5 were negative for any HPV type, 3 patients had unique infections with oncogenic HPV type, and 2 patients had multiple infections, with oncogenic and non-oncogenic HPV types. Negative and positive controls were validated, identical as the internal control - beta globin gene. II. Absolute quantification for HPV 16 and 18 were performed on two samples tested by the previous method. The number of viral copies was determined using the standard curves procedure, whose parameters values were between the accepted limits. CONCLUSIONS: We fulfilled the quality criteria for both techniques: genotyping assay and viral load quantification by Real Time PCR. This allows us to start the study for monitoring persistent infections with HPV 16 and HPV 18. PMID- 20191901 TI - [Cross-sectional study to evaluate the development and risk factors in premature children]. AB - Prematurity represents an important medical problem due to the increased incidence and complex treatment measures. MATERIAL AND METHOD: We have made a cross-sectional study to evaluate the causes and risk factors of prematurity and after-birth evolution in 652 premature children. RESULTS: Most children had mothers of low socio-economic status (70.1%), from the countryside (70.5%), housewives (82.8%), elementary educational level (67.7%). The age of pregnancy at the beginning of the observation was significantly different in the urban environment in comparison with the rural (p < 0.05). Emergency life support at birth was needed for 63.2% of the premature newborns and hospitalization in Intensive Care for respiratory distress for 77.6%. Intense icterus required phototherapy in 92% of preterm newborns. Epidemiologic survey proved bacterial colonization in 72.6% of the infants, mostly nasal (24.5%). There was an increased number of bottle-fed infants (63.6%), but regardless of the feeding method, the weight increase was proper. CONCLUSION: The improvement of perinatal care allowed the increase of survival rate of premature infants, but a more serious medical surveillance is needed in order to reduce the number of preterm births. PMID- 20191902 TI - [Specifics of individual risks in a group of women with genital neoplasms]. AB - Genital cancers represent an important issue regarding women health, as they produce a large number of cases, invalidities and deaths. AIM: The evaluation of individual risks for a group of women with genital neoplasia. MATERIAL AND METHODS: We conducted a pilot case-control study to validate the questionnaire for the evaluation of risk factors in genital cancers, in a number of 40 female subjects (20 cases and 20 controls). We have realized the data processing using the SPSS 16 and EpiInfo 3.5.1. soft wares. RESULTS: For questionnaire validation we have evaluated the reproducibility, the validity, the acceptability and the practicability of the questionnaire. In order to establish the test reproducibility, we have calculated k factors for inter-investigator (k = 0.34) and intra-investigator (k = 0.72) variation. To evaluate the questionnaire validity we calculated the sensitivity (cases = 94%; controls = 97%), specificity (cases = 67%, controls = 75%), positive predictive value (cases = 94%; controls = 94%), negative predictive value (cases = 67%; controls = 86%). The risk factors most frequently identified were genital infectious in clinical records (75% comparing to 52.5% - p = 0.036), and also the presence of other pathological records in genital area (65% comparing to 22.5% - p = 0.0001). CONCLUSIONS: For an accurate identification of individual risk at women with genital cancers subsequently studies on greater number of subjects is necessary. PMID- 20191903 TI - [Retrospective clinical epidemiology research on a sample of 277 patients with viral hepatitis A, 20-70 aged, from the Suceava County, between 2001-2008]. AB - Authors present some results of clinical epidemiological research carried out on a sample of 277 patients with viral hepatitis A (VHA), hospitalized in Suceava County, during 8 years. MATERIAL AND METHOD: An annual evolution of VHA incidence correlated with the epidemiological territorial situation was highlighted. RESULTS: Incidence of VHA in 20-40 age group represented 70.8%, and 33.5% in 20 25 age group. Diagnosis index was unfavourable with influence for interval of hospitalization over 21 days in 9.7% of cases. The VHA characteristic medium clinical form was kept in 80.1% of total patients. ASAT and ALAT levels were correlated with the clinical forms, age structure and early diagnosis difficulties. PMID- 20191904 TI - [Average vegetable intake in a group of schoolchildren from Iasi]. AB - Nutritional guidance must take into account the existing situation in order to obtain the desired effects. MATERIAL AND METHOD: Vegetable intake was assessed using a questionary for 127 teenagers (49 boys and 78 girls) from two high schools in Iasi. RESULTS: More than 80% of teenagers use vegetables on a daily base and almost 50% in adequate amount. 7.08% admited an excessive intake of vegetables and 3.93% a lack of vegetable intake, with potential harmfull effects on health status. PMID- 20191905 TI - [Management of emergency cases, hospitalized in Romania in 2007]. AB - We evaluated the main aspects of the management of emergency cases, hospitalized in Romania in 2007, by following the frequency of main diagnosis, their distribution by place and hospital and hospital indicators. MATERIAL AND METHOD: We collected our data from the Insurance Houses and National Institute of Statistics. RESULTS: Emergency cases represented in 2007 half of total cases hospitalized in Romania. Women are more frequent hospitalized then man or children. The Romanian South-East area had the highest frequency of emergency cases hospitalized. From all types of deceased cases, the emergency cases had the highest frequency. In emergency, the main category of diagnosis by frequency is "pregnancy, birth and recently given birth", much higher than non-emergency cases registered, also at the Obstretics-Gynecology and Emergency Hospitals. The medium period of days hospitalized for emergency cases was one week time. Most of the emergency cases are healed comparing to non-emergency ones. CONCLUSIONS: The main problem of hospitals in Romania is related to health services financing, costs for health care are still growing but also did the quality of health services and number of cases coming in emergency rooms. PMID- 20191906 TI - [The monitoring of Neisseria gonorrhoeae infection incidence and its resistance in Suceava County]. AB - Neisseria gonorrhoeae infection is one of the most frequent infections transmitted on sexual intercourse. In the last decades, a significant numbers of gonococcus strains were resistant to penicillin, tetracycline, quinolones and, in the last period, resistant to 3rd generation cephalosporines too. The purpose of this study was to monitor the trend of N. gonorrhoeae isolates from 2004-2008, in Suceava County, North-East region of Romania. MATERIAL AND METHOD: Antimicrobial susceptibility of N. gonorrhoeae isolates from clinical cases in 48 males and 12 females to penicillin, tetracycline, amoxicillin, augmentin, clarithromycine, ciprofloxacin, and ceftriaxone, was determine by disc diffusion method, using WHO reference strains and NCCLS criteria of interpretation. The isolation and identification of N. gonorrhoeae strains was carried out using classical microbiological algorithm, and miniAPI galleries. RESULTS: A high proportion of strains were resistant to tetracycline and penicillin (70 and 80% respectively); 95% of strains were sensitive to ceftriaxone, one strains was resistant and 2 of them (3.33%), intermediate resistant. For all other tested antibiotics the level of resistant strains varied from 55 to 65%. CONCLUSION: The present study is the first one regarding the level of antibiotics resistance of N. gonorrhoeae strains in Suceava County. Penicillin, tetracycline, ciprofloxacin, clarithromycine, amoxicillin, and augmentin can not be indicated as treatment of N. gonorrhoeae infection because of high level of resistance. An active and comprehensive studies for monitoring and surveillance of antimicrobial resistance of N. gonorrhoeae needs to be established in all regions of the country, as support of new therapeutical treatment scheme. PMID- 20191907 TI - Contribution towards developing a new semi-selective medium for Streptococcus anginosus group. AB - The aim of this study was to develop a new selective medium for isolation of Streptococcus anginosus group (SAG) strains, by adding sulphamethazine and aztreonam as selective agents at Mitis-Salivarius agar (MSA), the medium commonly used for recovery of oral streptococci from oral samples. MATERIAL AND METHOD: The evaluation of Mitis-Salivarius--sulphamethazine--aztreonam agar (MSSAA) for SAG selectivity was performed by testing the growth of type strains and laboratory-stored clinical isolates of different oral streptococcal species on this medium and also by investigating the SAG recovery on MSSAA in comparison with MSA and the growth inhibition of non-SAG strains from 100 saliva and 11 pus samples (collected from healthy young subjects and from paediatric patients with upper respiratory tract infections, respectively) on MSSAA. RESULTS: The same SAG recovery rate was obtained on both MSSAA and MSA, while non-SAG strains failed to grow on the novel medium, except for enterococci. The results of the present study have indicated that MSSAA is a suitable medium for selecting SAG isolates from clinical specimens. PMID- 20191908 TI - [Microbial involvement in oral abscesses: update]. AB - Perioral abscesses are common manifestations of acute oral infections and microbiological studies has shown that they are polymicrobial infections, most often with the involvement of 3.5 different bacterial species. Microbial virulence, biocoenosis of oral cavity is elements which contribute to the emergence of oral infections. Although it may seem outside interest of dentist or oral surgeon updating related microbiological pathogens identified in perioral abscess, a brief and modest information about the profile of the pathogens involved is particularly beneficial and useful. The fact that this "explosive army" is not in sight, this not mean that it doesn't exist, so we believe that the holding of general notions of microbiological culture is necessary for prevention and treatment measures. PMID- 20191909 TI - [Correlation between the lower first permanent molar axis and the premature loss of temporary molars]. AB - The aim of our study was to determine the impact of premature loss of temporary molars upon the longitudinal axis of the first permanent molar. MATERIAL AND METHOD: The study sample was formed by 94 orthopanthomografies of child patients with premature loss of lower temporary molars (first or second) after clinical eruption of the first permanent molar. All panoramic radiographs have been realized with the same panoramic unit with 1.4% magnification coefficient and were analyzed using a standardized technique of tracing the images of teeth and bone on matte acetate paper. It was evaluated the angle between longitudinal axis of first permanent lower molar and occlusal plane. RESULTS: It was observed that premature loss of lower second deciduous molar modifies greater the vertical axis of first permanent molar (between 61 degrees and 79 degrees) then premature loss of first lower primary molar. This is perhaps because the loss of space in the case of premature exfoliation of first primary molar is due more to distal drift of canine then mesial drift of molars. CONCLUSION: The drift to mesial of first permanent molar is more accentuated proportional with the age at which appeared premature loss and so it is loss of leeway space. PMID- 20191910 TI - [The bony modifications in the periodontal pockets]. AB - The aim of this study was to demonstrate the bony structural changes in deep periodontal pockets. MATERIAL AND METHODS: Bony fragments were taken from the alveolar wall of a group of 24 patients diagnosed with deep periodontal lesions which required the extraction of certain irrecuperable teeth. Fragments were fixed in glutaraldehyde, then decalcified in EDTA 5% and proccesed for electron microscopic examination and a semifinesse sections to microscop "Zeiss Axioscop". RESULTS: Both optic and electron microscopy showed: decreaze of bone mineralization and alterations in cholagen structure; the presence of osteoclasts with intense activity and numerous macrofages; at the level of bone marrow, small, insignificant inflammatory reactions, contrasting with the important surrounding modifications; in certain cases though osteolytic reactions occured, the osteoclasts could not by evidenced, on the contrary, numerous macrophages with intense lysosomal enzymes activity were noticed; all the cases showed an alteration of the alveolar bone cholagen. CONCLUSION: Thus, we can better understand the role of primary factors in this bony structures. PMID- 20191911 TI - [Clinical aspects of therapeutic options in oral rehabilitation of partially edentulous patients]. AB - This study aims at identifying practical ways of approaching social cases, and creating a hierarchy of the final functions of restauration. MATERIAL AND METHOD: In 2008 the Clinical Base for Learning from the School of Dental Medicine, Iasi, recorded for the Partially Stretched Edentation Clinic and Therapy course a prevalence of biterminal partial edentation (Class I Kennedy)-66.39 per cent from the total number of patients, followed by uniterminal edentation (Class II Kennedy), having 40.24 per cent of the clinical cases, whereas INTERCALATE edentation (Class III Kennedy), frontal edentation (Class IV Kennedy), and subtotal edentation have about 20.12.1 per cent each. RESULTS: The clinical form of edentation contributes to the election of a proper therapeutic solution as well as the odonto-parodontal and muco-osseous status of each clinical case, the patient's general condition or the socio economic and technical factors leading to a modern, classical or social prothesing. An important aspect to take into account is the large percentage of social cases diagnosed with partially edentation, pleading for provisional protheses with an established role in therapy, which sometimes may become social prothesing--an outstanding clinical reality. Social cases should be solved with a view to restoring functionality such as lower level redimensioning and cranio-mandibulary repositioning, whereas aesthetic requirements fall into therapies based on metallo-ceramic and hybrid prothesing or implanto-prothetic therapy. PMID- 20191912 TI - [Study on noninvasive paraclinical evaluation methods according to particular aspects in patients diagnosed with partial dentition]. AB - The aim of this study quantifies the contribution of the non invasive and minimally invasive methods of paraclinic evaluation corroborated with the clinical aspects, a particularly important element being represented by the inter relation between the general condition--oral pathology. MATERIAL AND METHOD: The study group was represented by patients with ages between 18 and 35 years, diagnosed with partial edentation, with various problems of the general condition. To the same extent, with concern to the study group a special emphasis was placed on the paraclinical results and the therapeutic trajectories directed by the use of the diagnodent, without ignoring the role the digital radiography has in the diagnostic stage as well as the therapeutic one. RESULTS: The results obtained subsequent to the thermographic evaluation showed the initially hidden character of the general symptomatology, the patient being unaware of the presence of any pathology at the level of the apparatus and systems, factor which could have interfered negatively with the pathology specific to the field of dental medicine. Creating a hierarchy, the link offered by the thermogram between the systems and the dental segment is already known. The pathology under investigation, both at an oral level and at a general one pleads for the correlative aspects of the binomial dental unit--affected organ, the modifications of the thermographic trajectories for the somatic area analyzed after the specific therapy being eloquent. PMID- 20191913 TI - [Contributions to the comparative study of the antioxidant potential of some extracts obtained from chamomile flowers]. AB - Within a complex research regarding the pharmaceutical quality of Chamomillae flos commercialized in the Romanian pharmaceutical network (as well as the food chain), we investigated 9 samples of chamomile "tea" purchased in April/May 2005 in compliance to the European Pharmacopoeia. AIM: Since the vegetal material proved to be very different from the chemical composition point of view we tried to establish the antioxidant activity of some extracts (tinctures and infusions) obtained from the selected plant material. MATERIAL AND METHODS: Therefore we studied the scavenging abilities observed against DPPH and the ferrous binding propreties correlating its to the polyphenolic content previously determined in the chamomile extracts. RESULTS: Surprisingly, the scavenging activity against DPPH indicates similar potential both for the hidro-alcoholic extracts as well as fot the infusions, meanwhile the chelation on the ferrous ion was higher for the tinctures that for infusions and different from one sample to the other. PMID- 20191914 TI - [Contributions to the study of the chemical variability of some Galium album Mill. Populations harvested from wild flora in northern Moldavia]. AB - Within a complex research regarding the chemical intra- and inter-specific variability of some medicinal plants, we compared two species of Galium: Galium verum L. and Galium album Mill. AIM: In the present study, we quantified some secondary metabolites from 7 natural populations of Galium album Mill., harvested from Suceava and Neamt districts, during July 2008. MATERIAL AND METHODS: The chemical investigations used TLC, UV-VIS spectrophotometry and HPLC, in order to analyze the composition in iridoids, flavones and polyphenolic acids. RESULTS: Our study revealed the existence of important chemical variations between the different populations (Rasca, Crucea/ Borca, Runc, Tarzial). Meanwhile the harvesting moment within the vegetative cycle plays a major role for the further quality of the product. PMID- 20191915 TI - [Comparative data regarding two HPLC methods for determination of isoniazid]. AB - For the determination of isoniazide (isonicotinic acid hydrazide - HIN) two different HPLC methods were developed and validated. METHODS: Both experiments were performed using a Waters 2695 liquid chromatograph and a UV - Waters 2489 detector. The first method (I) used a Nucleosil 100-10 C18 column (250 x 4.6 mm), a mobile phase formed by a mixture of acetonitrile/10(-2) M oxalic acid (80/20) and a flow of 1.5 mL/ min; detection was done at 230 nm. The second method (II) used a Luna 100-5 C18 column (250 x 4.6 mm), a mobile phase formed by a mixture of methanol/acetate buffer, pH = 5.0 (20/ 80), a flow of 1 mL/min; detection was done at 270 nm. RESULTS: Both methods were validated, the correlation coefficients were 0.9998 (I) and 0.9999 (II), the detection limits were 0.6 microg/mL (I) and 0.055 microg/mL (II), the quantitation limits were 1.9 microg/mL (I) and 0.2 microg/ mL (II). There were also studied: the system precision (RSD = 0.1692% (I) and 0.2000% (II)), the method precision (RSD = 1.1844% (I) and 0.6170% (II)) and the intermediate precision (RSD = 1.8058% (I) and 0.5970% (II)). The accuracy was good, the calculated recoveries were 102.66% (I) and 101.36 (II). CONCLUSIONS: Both validated methods were applied for HIN determination from tablets with good and comparable results. PMID- 20191916 TI - [Design considerations for clinical data management in an integrated remote medical system]. AB - In this paper, we present a proposal for the design of a telemedicine system. The system (called SIMPA) will be used for noninvasive monitoring of some vital parameters of patients with chronic diseases. MATERIAL AND METHODS: The telemedicine system contains a fixed unit and some mobile units. The mobile unit contains various sensors used to gather data about vital biosignals, a transceiver and a medical processor. On the fixed unit side, the host transceiver must be compatible with the mobile transceiver. On the server side, an application analyzes and processes the data and further stores it in dedicated databases. RESULTS: The database support for the telemedicine application is ensured by open source technologies and already available communication infrastructures (GSM networks). The requirements for the application were thoroughly analyzed and the Entity-Relationship diagram of the system was designed and translated into relational model. SIMPA will be implemented using only free and open source technologies, which will ensure a low cost and improved extensibility and portability. CONCLUSION: We presented some design considerations for a low-cost telemedicine system. The system will help optimize medical decisions and will increase the quality of the medical act and lower the cost, to the ultimate benefit of the patient. PMID- 20191917 TI - [Hip joint force evaluation to patients with hip prosthesis]. AB - Gait biomechanical parameters is essential to establish the loosening of a hip prosthesis and provide important information about gait analyses from different orthopedics pathologies. MATERIAL AND METHODS: A dynamometric platform was used for measuring the total ground reaction force for patients with hip prosthesis, compared with a healthy patient. RESULTS: Using a theoretical model, the hip joint loading was calculated, obtaining a "walking profile". PMID- 20191918 TI - [Changes of spirographic parameters in type 2 diabetes mellitus]. AB - Diabetes mellitus (DM), metabolic disease with chronic evolution, affects various organs through its macro- and micro-angiopathic complications which it causes, one of this target organs for diabetes being the lungs. OBJECTIVES: The aim of the study is to evaluate the relationship between type 2 diabetes mellitus and the pulmonary function. MATERIAL AND METHOD: 50 non-smoking patients diagnosed with type 2 DM, without respiratory problems were included in this study. The control group consisted of 50 healthy volunteers with same age and height as those with diabetes. For all patients there were measured: height, weight, body mass index, plasma glucose, serum cholesterol, trigycerides. Then there were determined by computerized spirometry: forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), peak expiratory flow (PEF), maximal expiratory flow at 50% from vital capacity (MEF50). These patients were re-evaluated after a 3-year period measuring the same parameters. RESULTS: The study has shown a statistically significant decrease of spirographic parameters (FVC, FEV1, PEF, MEF50) in patients with over 5 years of evolution of type 2 DM, by comparison with the control group. The higher the metabolic unbalance, the lower were these parameters. CONCLUSIONS: Type 2 DM has long-term effects and determines disfunctions and deficiencies of various organs. Our study shows that the lung is a target organ for type 2 DM as well. PMID- 20191919 TI - Class of 1908 of Meharry Medical College. PMID- 20191920 TI - Stroke prevention: awareness of risk factors for stroke among African American residents in the Mississippi delta region. AB - BACKGROUND: Compared to whites, African Americans have almost a 2-fold increased risk of first-ever stroke. Our study sought to determine awareness of stroke risk factors and management, symptoms, and risk reduction strategies in African Americans in Mississippi, which is part of the "stroke belt. METHODS: We conducted a cross-sectional survey of African Americans aged 18 to 74. We collected information on awareness, sources of information, stroke risk behavior, diabetes, and hypertension prevalence: and risk reduction relating to nonsmoking, exercise, and knowledge about ideal targets of blood pressure, body mass index, total blood cholesterol, and blood sugar. RESULTS: The percentage of respondents who identified 1, 2, 3, 4, and 5 warning signs were 21.8%, 11.7%, 15.4%, 10.1%, and 23.9%, respectively; and 17% could not identify any sign. The most factors identified were sudden numbness in the face, arm, or leg, and trouble speaking. Lifestyle factors and their role in stroke were not known to respondents. Specifically, 52.7%, 56.4%, 53.2%, 38.3%, and 28.7% failed to mention lack of physical activity, excessive alcohol consumption, diabetes, smoking, and high cholesterol, respectively, as factors that can contribute to stroke. CONCLUSION: There is need to improve knowledge of stroke, risk reduction, and appropriate stroke response. Family, friends, and African Americans churches should be utilized to deliver stroke and other health information. PMID- 20191921 TI - Does coping mediate the relationship between personality and cardiovascular health in African Americans? AB - Few studies have examined traits or behaviors that may predispose some African Americans to poor cardiovascular health outcomes. While several models of personality exist, the 5-factor model (FFM) is arguably the best representation of personality and provides a useful framework for the study of personality and health. Among personality characteristics associated with health risks among African Americans, a high-effort coping style called John Henryism is among the most thoroughly examined. It is not clear if personality coping and health are connected in a meaningful way. The present study utilized data from the Baltimore Study of Black Aging (BSBA) to examine whether personality was linked to John Henryism, how personality might be linked to cardiovascular health, and how John Henryism might mediate the relationship between personality and cardiovascular health. The sample consisted of 234 older African Americans (mean age, 67 years), 28% of which were men. Regressions were used to examine the questions. The results indicated that those who are more neurotic report more cardiovascular health problems, and that openness and conscientiousness were significant predictors of active coping. The mediation analysis results suggest that coping style did not mediate the relationship between personality and reports of cardiovascular health problems. These findings highlight the importance of personality in accounting for cardiovascular health in African Americans. PMID- 20191923 TI - Racial disparities in urologic health care. AB - In the United States, disparities in health care delivery and access are apparent between different racial and ethnic groups. Minorities, including African Americans, often suffer disproportionately from disease compared to Caucasians. In the urologic arena, this is apparent in urologic cancer screening, treatment choices, and survival, as well as in the arena of chronic kidney disease, transplant allocation, and transplant outcomes. Latino men also seem to be affected more often by erectile dysfunction than Caucasian counterparts. Disparities such as these have been identified as a problem in the delivery of health care in the United States, and resources have been allocated to help allay the disparity. Through organizations such as the Cleveland Clinic Minority Men's Health Center, policy initiatives, and increased cultural awareness by physicians, steps can be made to reduce and eliminate health care disparities. PMID- 20191922 TI - Recruitment of rural physicians in a diabetes internet intervention study: overcoming challenges and barriers. AB - PURPOSE: This paper highlights a descriptive study of the challenges and lessons learned in the recruitment of rural primary care physicians into a randomized clinical trial using an Internet-based approach. METHODS: A multidisciplinary/multi-institutional research team used a multilayered recruitment approach, including generalized mailings and personalized strategies such as personal office visits, letters, and faxes to specific contacts. Continuous assessment of recruitment strategies was used throughout study in order to readjust strategies that were not successful. RESULTS: We recruited 205 primary care physicians from 11 states. The 205 lead physicians who enrolled in the study were randomized, and the overall recruitment yield was 1.8% (205/11231). In addition, 8 physicians from the same practices participated and 12 nonphysicians participated. The earlier participants logged on to the study Web site, the greater yield of participation. Most of the study participants had logged on within 10 weeks of the study. CONCLUSION: Despite successful recruitment, the 2 major challenges in recruitment in this study included defining a standardized definition of rurality and the high cost of chart abstractions. Because many of the patients of study recruits were African American, the potential implications of this study on the field of health disparities in diabetes are important. PMID- 20191924 TI - Perception of weight and threat to health. AB - OBJECTIVES: To examine African American women's perception of their risk for obesity-related comorbid illnesses compared to their weight category. METHODS: Participants were recruited from urban health centers in Atlanta, Georgia. Anthropometric measurements and self-reported demographics, medical conditions, and health beliefs about obesity and its related comorbid diseases were recorded. RESULTS: More than 80% of the women (N=323) were either overweight or obese. Among overweight women, 44% reported being a normal weight. Seventy-two percent of the obese women reported being overweight, and 13.6% reported that they were obese. All women reported that each disease was "very serious;" however, overweight women reported having the same risk for each disease as normal weight women. Obese women reported having a higher risk of each disease (p < .05 for all diseases). CONCLUSION: Overweight and obese women underestimate their weight categories. Overweight, but not obese, women reported the same perceived susceptibility for obesity-related comorbid diseases as normal-weight women. An increase in the perceived threat to health may motivate women to increase prevention efforts in the early stage of overweight to prevent or delay morbidity or mortality. PMID- 20191925 TI - Predictors for survival of penetrating trauma using emergency department thoracotomy in an urban trauma center: the Cardiac Instability Score. AB - BACKGROUND: Emergency department thoracotomy (EDT) is a procedure used in an attempt to save lives of patients in extremis. This study aims to determine predictors of survival and futility by proposing a scoring scale that measures cardiac instability and its use in predicting survival of victims of penetrating trauma undergoing EDT. METHODS: This retrospective study analyzes patients who underwent EDT during a 45-month period at Howard University Hospital, Washington, DC. Vital signs and Glasgow Coma scale (GCS) scores were analyzed at the scene and in the emergency department. A cardiac instability score (CIS) was devised to assign values to vital signs, and the GCS was based on scores from the emergency department. RESULTS: Emergency department vital signs, female gender, absence of cardiopulmonary resuscitation (CPR), and high CIS were found to be statistically significant predictors of survival. CONCLUSIONS: The CIS correlated with survival of patients who underwent EDT and was found to be statistically significant in determining the outcome of an EDT. PMID- 20191927 TI - Concomitant anterior and posterior infantile perianal protrusions. AB - Infantile perianal protrusion is characterized by asymptomatic pyramidal protrusion with a rose-red or purplish red surface along the midline, usually anterior to the anus. The protrusion is usually solitary. Two girls are reported with concomitant anterior and posterior infantile perianal pyramidal protrusions and a history of constipation. The occurrence of concomitant anterior and posterior infantile perianal pyramidal protrusions has not been reported previously. PMID- 20191926 TI - Late-onset Fanconi anemia in an African-Caribbean patient. AB - A 38-year-old female of African-Caribbean origin presented with symptomatic anemia and was found to have hypoplastic thumbs and patchy hypopigmentation. Peripheral blood examination revealed pancytopenia and the bone marrow biopsy confirmed marrow hypoplasia. Fanconi anemia was later confirmed by flow cytometry and diepoxybutane testing. Treatment was limited to transfusions after development of toxicity with cyclosporine and androgen therapy. She manifested classical features of transfusion-related hemosiderosis and died 12 years after initial presentation. PMID- 20191928 TI - A woman with back pain. AB - The Editorial Board of JNMA is proud to launch yet another reader-oriented monthly column entitled "Radiology Rounds", which will be orchestrated by Dr. James Collins, longtime NMA member and professor of radiology at UCLA. Dr Collins and his colleagues across the country will endeavor to bring us a variety of interesting cases with both an educational and clinical message that will undoubtedly prove useful to our primary care physicians and many specialists as well. It is anticipated that this will evolve into a continuing medical education initiative going forward. We would like for this to be an interactive column, so please feel free to forward your views and opinions of the cases being presented to Dr Collins for follow-up in JNMA. If you have an interesting case with excellent radiologic images, please feel free to contact Dr Collins directly so that we can share your experience with all of our NMA colleagues and friends. PMID- 20191929 TI - In JNMA 100 years ago: the 1908 annual meeting. PMID- 20191930 TI - Louis W. Sullivan, MD: an interview by George A. Dawson. PMID- 20191931 TI - The DSM-v sleep-wake disorders nosology: an update and an invitation to the sleep community. PMID- 20191932 TI - A twin study of sleep duration and body mass index. AB - STUDY OBJECTIVE: To determine the relative importance of genetic and environmental contributions to the association between sleep duration and body mass index (BMI). METHODS: Twins from the University of Washington Twin Registry, a community-based sample of U.S. twins, provided self-reported height and weight for BMI calculation and habitual sleep duration. A generalized estimating equation model evaluated the overall and within twin pair effects of sleep duration on BMI with and without stratification by twin zygosity. A structural equation model was used to assess genetic and non-genetic contributions to BMI and sleep duration. RESULTS: The study sample included 1,224 twins comprised of 423 monozygotic, 143 dizygotic, and 46 indeterminate pairs. The mean age was 36.9 years; 69% were female. A multivariate adjusted analysis of all twins revealed an elevated mean BMI (26.0 kg/m2) in short sleeping twins (< 7 h/night) compared to twins sleeping 7-8.9 h/night (BMI 24.8 kg/m2; p < 0.01). The within-twin pair analysis revealed similar results, with the short sleeping twins having a mean BMI of 25.8 kg/ m2 compared to 24.9 kg/m2 for the 7-8.9 h/night sleep duration group (p = 0.02). When restricted to monozygotic twins, the within-twin pair analysis continued to reveal an elevated BMI in the short sleeping twins (25.7 kg/m2) compared to the 7-8.9 h/night reference group (24.7 kg/m2; p = 0.02). No differences in mean BMI were observed between the 7-8.9 h/night reference group twins and longer sleeping twins (> or = 9 h/night) in the analysis of all twins, the overall within-twin pair analysis, or the within-twin pair analysis stratified by zygosity. The heritability of sleep duration was 0.31 (p = 0.08) and BMI 0.76 (p < 0.01). Bivariate genetic analysis revealed little evidence of shared genetics between sleep duration and BMI (p = 0.28). CONCLUSIONS: Short sleep was associated with elevated BMI following careful adjustment for genetics and shared environment. These findings point toward an environmental cause of the relationship between sleep duration and BMI. PMID- 20191933 TI - Healthy sleep education--a salve for obesity? PMID- 20191934 TI - Home is where sleep is: an ecological approach to test the validity of actigraphy for the assessment of insomnia. AB - STUDY OBJECTIVES: This study tested the ecological validity of actigraphy (ACT) for estimating objective sleep parameters in participants' homes. We also examined how well ACT and polysomnography (PSG) measures discriminated (1) individuals with and without insomnia; and (2) nights participants rated worse, the same as, or better than average. METHODS: Thirty-one primary insomnia sufferers and 31 normal sleepers completed up to 3 consecutive monitoring nights with wrist ACT and PSG in their homes. They also rated how each night compared to their "average night's" sleep. ACT and PSG measures of sleep onset latency (SOL), wake after sleep onset (WASO), total sleep time (TST), and sleep efficiency (SE) were then compared using Bland and Altman correlational procedures and repeated measures ANOVAs. Differences between groups and among nights assigned distinctive ratings were tested via mixed-model ANOVAs. RESULTS: Medium to large between- and within-subject correlations were observed for all measures in the insomnia sufferers sample and for most measures in the normal sleepers sample. Two (ACT vs. PSG) x 3 (nights) repeated measures ANOVAs showed that, in both samples, SOL derived from ACT was consistently lower than SOL derived from PSG across the 3 nights of recording. By contrast, ACT and PSG produced estimates of WASO, TST, and SE that did not differ from each other across nights. Subsequent 2 (insomnia vs. normal sleeper) x 3 (worse, same, better than average) mixed-model ANOVAs showed only ACT SOL discriminated those with and without insomnia and nights assigned distinctive ratings. Among the PSG-derived measures, only SE showed such a pattern. CONCLUSIONS: ACT provides informative data for insomnia sufferers and normal sleepers in their usual sleep environments. The ACT estimate of SOL seems sensitive to night-to-night differences in subjective sleep ratings. A possible strength of ACT lies in its assessment of nocturnal movement, a parameter different from PSG-based sleep measures. PMID- 20191935 TI - Effect of gaboxadol on patient-reported measures of sleep and waking function in patients with Primary Insomnia: results from two randomized, controlled, 3-month studies. AB - OBJECTIVE: To evaluate the efficacy and safety of gaboxadol in the treatment of Primary Insomnia. METHODS: Two studies were performed in patients 18 to 65 years of age with Primary Insomnia. After a 7-day single-blind placebo run-in, patients were randomized to double-blind treatment with gaboxadol 15 mg (N = 310), 10 mg (N = 308), or placebo (N = 309) over 3 months in Study 1; and gaboxadol 15 mg (N = 304) or placebo (N = 301) over 12 months in Study 2. Treatment was administered at bedtime. The primary efficacy endpoints in each study were change from baseline in patient-reported total sleep time (sTST) and time to sleep onset (sTSO) at month 3. Safety was assessed primarily by adverse event reports. RESULTS: In Study 1, gaboxadol 15 mg significantly improved sTST (difference vs. placebo of 20.4 min, p < 0.01) and sTSO (difference vs. placebo of -9.8 min, p < 0.05) at 3 months, while gaboxadol 10 mg had no significant effects on these measures. In Study 2, gaboxadol 15 mg showed numerical superiority for improvements on sTST (difference vs. placebo of 14.5 min) and sTSO (difference vs. placebo of -4.9 min) at 3 months, but these differences were not significant. In both studies, there was evidence that the efficacy of gaboxadol was more pronounced in women than men. Gaboxadol was generally well tolerated over 3 months in Study 1, and over 12 months in Study 2. CONCLUSION: Gaboxadol 15 mg showed variable efficacy on measures of sleep duration and onset at 3 months in adult patients with Primary Insomnia in these studies and appeared to be more effective in women than men. Gaboxadol 10 mg was not effective in these studies. (Clinical trial registration numbers: NCT00103818, NCT00095069). PMID- 20191936 TI - Sleep quality and motor vehicle crashes in adolescents. AB - STUDY OBJECTIVES: Sleep-related complaints are common in adolescents, but their impact on the rate of motor vehicle crashes accidents is poorly known. We studied subjective sleep quality, driving habits, and self-reported car crashes in high school adolescents. METHODS: Self-administered questionnaires (with items exploring driving habits) were distributed to 339 students who had a driver's license and attended 1 of 7 high schools in Bologna, Italy. Statistical analysis were performed to describe lifestyle habits, sleep quality, sleepiness, and their relationship with the binary dependent variable (presence or absence of car crashes) to identify the factors significantly affecting the probability of car crashes in a multivariate binary logistic regression model. RESULTS: Nineteen percent of the sample reported bad sleep, 64% complained of daytime sleepiness, and 40% reported sleepiness while driving. Eighty students (24%), 76% of which were males, reported that they had already crashed at least once, and 15% considered sleepiness to have been the main cause of their crash. As compared with adolescents who had not had a crash, those who had at least 1 previous crash reported that they more frequently used to drive (79% vs 62%), drove at night (25% vs 9%), drove while sleepy (56% vs 35%), had bad sleep (29% vs 16%), and used stimulants such as caffeinated soft drinks (32% vs 19%), tobacco (54% vs 27%), and drugs (21% vs 7%). The logistic procedure established a significant predictive role of male sex (p < 0.0001; odds ratio = 3.3), tobacco use (p < 0.0001; odds ratio = 3.2), sleepiness while driving (p = 0.010; odds ratio = 2.1), and bad sleep (p = 0.047; odds ratio = 1.9) for the crash risk. CONCLUSIONS: Our results confirm the high prevalence of sleep-related complaints among adolescents and highlight their independent role on self-reported crash risk. PMID- 20191937 TI - Normative heart rate parameters during sleep for children aged 6 to 11 years. AB - OBJECTIVE: Normative values for pediatric heart rates during sleep are not known. The purpose of this study was to describe the average sleeping heart rate of children and to determine if age, sex, body mass index (BMI) or ethnicity is related to sleeping heart rate. METHODS: Electrocardiogram (ECG) data were obtained from healthy children during in-home polysomnography in the Tucson Children's Assessment of Sleep Apnea study (TuCASA) or home cardiorespiratory sleep studies in the Cleveland Children's Sleep and Health Study (CCSHS). Data were described then compared in separate cohort analyses using least square means from analysis of variance models that controlled for age, sex, ethnicity, and BMI. Student t tests were used to compare groups within cohorts for significant differences. RESULTS: In the cohort of 470 TuCASA children, 50.3% were female, 41% were Hispanic; mean age (SD) was 8.7 (1.7) years. Hispanics and Caucasians did not differ significantly on mean sleeping heart rate. The CCSHS cohort consisted of 561 children; 50.2% female and 33% African American, aged 8.9 (0.6) years. African Americans had significantly faster sleeping heart rates than Caucasians in the CCSHS cohort. In both cohorts, younger children demonstrated significantly faster sleeping heart rates than older children; girls had significantly faster sleeping heart rates than boys (TuCASA: girls 77.6 [9.9] vs boys 73.6 [8.2]; CCHS: girls 81.5 [8.4] vs boys 78.4 [8.1]) and obese children (BMI > or = 95th percentile for age) had significantly faster sleeping heart rates than nonobese children (TuCASA: obese children: 79.3 [12.3] vs nonobese children 75.0 [8.7]; CCHS: obese children: 83.3 [8.4] vs nonobese children 79.4 [8.31]). CONCLUSIONS: Children aged 6 to 11 years have sleeping heart rates that decrease significantly with age. African American ethnicity, female sex, and obesity were associated with faster sleeping heart rates. PMID- 20191938 TI - Impact of clinical assessment on use of data from unattended limited monitoring as opposed to full-in lab PSG in sleep disordered breathing. AB - STUDY OBJECTIVES: We examined agreement among multiple sleep clinicians when presented with clinical data plus the full tracings and data obtained from unattended limited monitoring (ULM) or a full polysomnography (PSG). METHODS: Subjects included 66 patients with complaints of sleep disordered breathing (SDB) and 19 volunteers willing to undergo 2 nights of ULM followed by PSG. Two assessment packages were created for each subject with identical clinical history (Hx) and ARES Symptom Questionnaire, plus the electronic record of signals collected on the ARES Unicorder (Hx+ULM) or on the PSG (Hx+PSG). Data were presented to 4 sleep-trained clinicians for diagnosis and treatment recommendation. For agreement on diagnosis and treatment, comparisons were made between clinicians using ULM or PSG, and within clinicians comparing both techniques. RESULTS: For diagnosis, agreement between pairs of clinicians using Hx+PSG ranged from 74% to 86% and 66% to 85% when using Hx+ULM. For treatment, agreement using Hx+PSG ranged from 74% to 86% and 58% to 77% when using Hx+ULM. Agreement between clinicians was highest in the subjects with the highest RDI and fell off markedly at the lowest RDI, irrespective of whether the clinicians used the Hx+PSG or Hx+ULM. This pattern was also seen for the decisions made by an individual clinician using Hx+ULM vs. Hx+PSG. CONCLUSION: Our data show that sleep clinicians have significant disagreements for diagnosis even when presented with the "gold standard" of a PSG and clinical data. Agreement was high when the SDB index was elevated and lower when the SDB index was in the mild-to-moderate range, regardless of the technique used to obtain it. PMID- 20191939 TI - An automated sleep-analysis system operated through a standard hospital monitor. AB - STUDY OBJECTIVES: Sleep disordered breathing (SDB), a cause of clinically important cardiovascular comorbidity, is often not recognized and diagnosed. An automated system that detects SDB using signals from a standard hospital monitor might provide useful information about the presence and severity of SDB without the need to evaluate the patient in a sleep laboratory and without additional hardware. The aim of this study was to examine the feasibility and accuracy of routine overnight sleep testing for SDB detection by an automated analysis system that operates by analyzing signals derived from standard hospital monitors. METHODS: Comparison of SDB detection by simultaneous "gold-standard" polysomnography and by Morpheus Hx (WideMed, Ltd., Herzliya, Israel), a bedside computerized analysis system (CAS) connected to a standard hospital monitor (ECG, respiratory impedance, end-tidal carbon dioxide (ETCO2), and SpO2). A total of 53 subjects were examined, 36 men and 17 women, all with suspected SDB. Each subject underwent an overnight sleep study, scored both by polysomnography and by CAS. The study was conducted in Brigham and Women's Hospital, Newton Center, MA. RESULTS: CAS-derived values for apnea-hypopnea index and total sleep time, were each found to be highly correlated with the corresponding polysomnography results, with linear regression values of r = 0.96 and r = 0.82, respectively. Mean apnea-hypopnea index values were also quite similar (CAS of 15.5 +/- 20.0 vs polysomnography of 15.4 +/- 24.0). CONCLUSIONS: An automated sleep-analysis system utilizing signals derived from a standard hospital monitor can be considered as a feasible and accurate method to detect and quantify SDB. PMID- 20191940 TI - Can a single cephalometric measurement predict obstructive sleep apnea severity? AB - STUDY OBJECTIVES: To look for an association between the vertical position of the hyoid, as measured by the sella-hyoid (S-H) distance and the severity of obstructive sleep apnea (OSA). A previously published study on this subject showed a significant correlation between S-H distances more than 120 mm and severe OSA. DESIGN AND SETTING: A retrospective study of patients who were treated with a mandibular advancement splint (MAS) for sleep disordered breathing during June 2000 to May 2005 at the orthodontic department of Colchester University Hospital. PATIENTS AND PARTICIPANTS: One hundred and six consecutive patients who were treated with MAS during the period. MEASUREMENTS AND RESULTS: Lateral cephalograms were taken and traced prior to the provision of MAS therapy, and the distance S-H was measured. The mean S-H distance was 125.5 mm (103-148 mm) with a median of 126 mm. Four out of 8 patients (50%) with severe OSA had a S H distance more than 120 mm, as did 38 out of 50 (76%) with mild to moderate OSA (AHI 5-30), and 17 out of 22 patients (77.27%) with an AHI of 0 to 4. No significant correlations between the S-H distance and the severity of OSA were found (Pearson correlation coefficient -0.034 and 95% confidence interval: -0.25, 0.18). CONCLUSION: There was no correlation between patients' OSA severity and their cephalometric S-H distance. The utility of the latter as a screening test cannot therefore be recommended as a substitute for existing diagnostic tests. PMID- 20191941 TI - The nightmares of sleep apnea: nightmare frequency declines with increasing apnea hypopnea index. AB - OBJECTIVE: To clarify the association of reported nightmare recall with polysomnographically defined obstructive sleep apnea (OSA) in a sleep laboratory population. METHODS: This study included 393 individuals undergoing clinical polysomnography including a general intake questionnaire with questions on dream and nightmare recall frequency. Mean age was 50.5 and a range of 13 to 82 years, with 33% of the sample female and 67% male. Reported dream and nightmare recall were classified as infrequent when reported at less than once a month, or frequent when reported at a frequency greater than once per week. RESULTS: Mean Apnea-hypopnea Index AHI was 34.9 (std. 32.0) indicating a high frequency of severe (AHI > 30) OSA in this clinical study population. Both AHI and Apnea Index (AI) were significantly higher (p = 0.000) for the grouping reporting infrequent nightmare recall. As the AHI score increased, the percent of participants with frequent nightmare recall decreased linearly. CONCLUSION: Patients with higher AHI report a lower nightmare frequency, indicating that significant OSA suppresses the cognitive experience of nightmare recall. Depressed nightmare recall may occur secondary to the REMS suppression know to occur in patients with significant OSA. PMID- 20191942 TI - A case of narcolepsy with strictly unilateral cataplexy. AB - I report a case of a 50-year-old African American woman who presented for a sleep medicine evaluation complaining of excessive daytime sleepiness of greater than 10 years' duration. She reported falling asleep while driving, talking with friends, and eating. Her Epworth Sleepiness Scale score was 21/24. Her history was positive for the presence of sleep paralysis. She denied visual or auditory hallucinations in the peri-sleep period. PMID- 20191943 TI - A novel approach to treating morning sleep inertia in narcolepsy. AB - We describe an adolescent with narcolepsy who presented with inability to awaken from sleep to attend early morning classes at school. After he did not respond to traditional therapies, a nicotine patch was prescribed with success. We present our experience with this unconventional treatment, which may benefit others with inability to awaken from sleep that is refractory to standard treatments. PMID- 20191944 TI - Pharmacologically induced/exacerbated restless legs syndrome, periodic limb movements of sleep, and REM behavior disorder/REM sleep without atonia: literature review, qualitative scoring, and comparative analysis. AB - BACKGROUND: Pharmacologically induced/exacerbated restless legs syndrome (RLS), periodic limb movements in sleep (PLMS), and REM behavior disorder/REM sleep without atonia (RSWA) are increasingly recognized in clinical sleep medicine. A scoring system to evaluate the literature was created and implemented. The aim was to identify the evidence with the least amount of confound, allowing for more reliable determinations of iatrogenic etiology. METHODS: Points were provided for the following criteria: manuscript type (abstract, peer-reviewed paper); population size studied (large retrospective study, small case series, case report); explicitly stated dosage timing; identification of peak symptoms related to time of medication administration (i.e., medication was ingested in the evening or at bedtime); initiation of a treatment plan; symptoms subsided or ceased with decreased dosage or drug discontinuation (for RLS articles only); negative personal history for RLS prior to use of the medication; exclusion of tobacco/alcohol/excessive caffeine use; exclusion of sleep disordered breathing by polysomnography (PSG); and PSG documentation of presence or absence of PLMS. For RLS and PLMS articles were also given points for the following criteria: each 2003 National Institutes of Health (NIH) RLS criteria met; exclusion of low serum ferritin; and exclusion of peripheral neuropathy by neurological examination. RESULTS: Thirty-two articles on drug-induced RLS, 6 articles on drug-induced PLMS, and 15 articles on drug-induced RBD/ RSWA were analyzed. CONCLUSION: Based on scores < or = 10 and trials of medication reduction/cessation, the strongest evidence available for drug induced RLS are for the following drugs: escitalopram; fluoxetine; L-dopa/carbidopa and pergolide; L-thyroxine; mianserin; mirtazapine; olanzapine; and tramadol. Since none of the PLMS articles assessed PLMI in trials of medication reduction/cessation, the strongest evidence based on scores > or = 10 are for the following drugs: bupropion, citalopram, fluoxetine, paroxetine, sertraline, and venlafaxine. Based on scores > or = 10 and/or trials of medication cessation, the strongest evidence for drug induced RBD/ RSWA is for the following drugs: clomipramine, selegiline, and phenelzine. PMID- 20191946 TI - A child with REM sleep disturbance. PMID- 20191945 TI - Best practice guide for the treatment of REM sleep behavior disorder (RBD). AB - SUMMARY OF RECOMMENDATIONS: Modifying the sleep environment is recommended for the treatment of patients with RBD who have sleep-related injury. Level A Clonazepam is suggested for the treatment of RBD but should be used with caution in patients with dementia, gait disorders, or concomitant OSA. Its use should be monitored carefully over time as RBD appears to be a precursor to neurodegenerative disorders with dementia in some patients. Level B Clonazepam is suggested to decrease the occurrence of sleep-related injury caused by RBD in patients for whom pharmacologic therapy is deemed necessary. It should be used in caution in patients with dementia, gait disorders, or concomitant OSA, and its use should be monitored carefully over time. Level B Melatonin is suggested for the treatment of RBD with the advantage that there are few side effects. Level B Pramipexole may be considered to treat RBD, but efficacy studies have shown contradictory results. There is little evidence to support the use of paroxetine or L-DOPA to treat RBD, and some studies have suggested that these drugs may actually induce or exacerbate RBD. There are limited data regarding the efficacy of acetylcholinesterase inhibitors, but they may be considered to treat RBD in patients with a concomitant synucleinopathy. Level C. PMID- 20191947 TI - Re-examining respect for human research participants. AB - The demands of respect for persons when conducting clinical research are often reduced to respect for autonomy. In this paper, I re-examine the concept of respect for persons in light of important intuitions from our ordinary language usage of respect. I propose that there are many ways to respect persons as persons and that the core elements of respect for persons are: appreciating what is valuable or important about a person, recognizing the constraints or demands that such a valuation places on one's own conduct, and acting in a way that expresses that recognition. On this account, in addition to autonomous agency, respect demands attention to important subjective experiences, persons' existence as part of communities, and considerations of comportment. This account has important implications for the conduct of clinical research with persons who are autonomous as well as with those who are not. Its implications, however, are different for these two populations, particularly with regard to concerns about well-being. PMID- 20191948 TI - Respect for rational autonomy. AB - The standard notion of autonomy in medical ethics does not require that autonomous choices not be irrational. The paper gives three examples of seemingly irrational patient choices and discusses how a rational autonomy analysis differs from the standard view. It then considers whether a switch to the rational autonomy view would lead to overriding more patient decisions but concludes that this should not be the case. Rather, a determination of whether individual patient decisions are autonomous is much less relevant than usually considered in determining whether health care providers must abide by these decisions. Furthermore, respect for rational autonomy entails strong positive requirements of respect for the autonomy of the person as a rational decision maker. The rationality view of autonomy is conceptually stronger than the standard view, allows for a more nuanced understanding of the practical moral calculus involved in respecting patient autonomy, and promotes positive respect for patient autonomy. PMID- 20191949 TI - Mandatory autopsies and organ conscription. AB - Laws requiring autopsies have generated little controversy. Yet it is considered unconscionable to take organs without consent for transplantation. We think an organ draft is justified if mandatory autopsies are. We reject the following five attempts to show why a mandatory autopsy policy is legitimate, but organ conscription is not: (1) The social contract gives the state a greater duty to protect its citizens from each other than from disease. (2) There is a greater moral obligation to prevent murders than disease-caused deaths because killing people is morally worse than allowing people to die. (3) Autopsies do not confiscate body parts, but organ transplants do. (4) The citizenry's knowledge that their organs are very likely to be taken will generate more anxiety than the remote possibility of a mandatory autopsy. (5) A religious conviction that one's organs will be needed in order to be resurrected is threatened by organ transplantation but not by autopsies that "return" body parts. PMID- 20191950 TI - Commentary on "The incoherence of determining death by neurological criteria". AB - This commentary challenges the conclusions reached by Franklin Miller and Robert Truog in their criticism of the President's Council's White Paper, "Controversies in the Determination of Death." I agree with much of Miller and Truog's criticism of the rationale offered by the President's Council for accepting neurological criteria for determining death but argue that they too quickly dismiss the alternative rationale of determining death by neurological criteria-i.e., the destruction of the psychophysical integrity of the human being that occurs when the potential for consciousness and every other mental function is lost due to catastrophic injury to the brain. By focusing on the death of bodies instead of human beings, their view absurdly implies that decapitation would not necessarily result in one's death. Since total brain failure is a form of physiological decapitation, the neurological criterion coheres perfectly well with the ordinary understanding of decapitation as death. PMID- 20191951 TI - What is affordable health insurance? The reasonable tradeoff account of affordability. AB - The reform of the health care system will include a mandate: Individuals are required to purchase health insurance provided that affordable options are available. But what is affordable health insurance? Three accounts of affordability of health coverage have been advanced. The first two accounts are empirical. The third account is needs-based. All three accounts are inadequate. I propose a fourth, the reasonable tradeoff account, according to which individuals should only be required to make reasonable tradeoffs in order to pay for their health coverage. That is, health insurance is affordable if in order to pay for it one does not to have to sacrifice other benefit(s) that are comparable in importance to the benefits of health coverage. PMID- 20191952 TI - [Clinical application of continuous douche and vacuum sealing drainage in refractory tissue, bone and joint infections after debridement]. AB - OBJECTIVE: To explore effect and the application value of continuous douche and vacuum sealing drainage (VSD) in refractory tissue, and joint infections after complete debridement. METHODS: As retrospective analysis of treatment time and restoration or recurrence, from Jan. 2006 to Dec. 2007, 61 cases of refractory tissue, bone and joint infections underwent continuous douche and VSD combined with the treatment of anti-inflammatory and rehabilitation training after debridement in our hospital. The 61 patients included 39 males and 22 females with age ranging from 10 to 58 years with an average of (35 +/- 12) years, among whom 61 identified to have ankle ulcers combined with infections,open fracture combined with infections, sacrococcygeal pressure ulcers combined with infections, infections after hip replacement, infections after open fracture, and infections after skin avulsion postoperation were 11, 15, 9, 3, 5 and 18 cases respectively. The course was from 2 weeks to 11 months with an average of 4 months. RESULTS: In all 61 patients,the mean healing time was 17, 36, 42, 24, 32, 29 and 28 days in ankle ulcers and infections, tibia and fibula open fracture and infections, femoral shaft fracture and infections, sacrococcygeal pressure ulcers and infections, infections after hip replacement, infections after open fracture, and infections after skin avulsion postoperation respectively. The replacement of VSD was 1, 2-4, 3-5, 1-3, 2-4, 2-3 and 1-3 times in each group respectively. There was no wound recurrence except for 2 cases with recurrent in 61 cases with external fixation nail hole semi-pathological fracture in 1 case of femoral shaft fracture and infection and 1 case of tibia and fibula fracture and infection after follow-up at least one year. CONCLUSION: Application of continuous douche and VSD can effectively decrease incidence of complications and promote the refractory tissue, bone and joint infections wound growth, healing and considerably shorten the healing time. PMID- 20191953 TI - [Establishment and analysis of a three-dimensional finite element model of human cervicotnoracic junction (C6-T1)]. AB - OBJECTIVE: To establish the cervicothoracic spine finite element model with three dimensional finite element method, verify the effectiveness of this model and explore the stress distribution. METHODS: DICOM image data of one normal healthy young male volunteer were obtained by spiral CT scan and processed with Mimics software. Datas were imported to ANSYS software to become a 3D entity. Disc structure and the main ligament were added. Disc structure was added using the shell-nuclear unit, representing the annulus fibrosus and nucleus pulposus. Ligament structure was established with 2-node cable element, the beginning and ending points of the ligament and the cross-sectional area were determined in accordance with references. C(6,7) and C7T1 facet joints were definded as the nonliner contact joints with friction coefficient. The lower surface of TI in all the directions was completely fixed in this model. In the model 2.0 Nm pure torque were imposed on C6, and the extension, flexion, axial rotation and lateral bending experiment were conducted. The experimental results were compared with the in vitro biomechanical tests. RESULTS: The cervicothoracic spine finite element model included 169,317 nodes and 106,242 units, and consistent with the in vitro biomechanical tests. The three-dimensional finite element model was in good running under external force. CONCLUSION: It is a convenient and precise method for physicians to establish the finite element model of the cervicothoracic junction. This method facilitates the computer study on the biomechanical behavior of the local structures of the model under various pressure conditions. PMID- 20191954 TI - [Comparison of clinical effects between locking intramedullary nail fixation and skeletal traction in treating tibiofibula fractures]. AB - OBJECTIVE: To compare and evaluate clinical effects between locking intramedullary nail fixation and skeletal traction in order to provide the best therapeutic choice for tibiofibula fractures. METHODS: From November 1989 to December 2000, 108 patients with tibiofibula fractures (group A) were treated with skeletal traction, there was 76 males and 32 females; the age was from 29 to 66 years with an average of (40.3 +/- 9.6) years; according to AO classification standard,48 cases were type A, 46 type B, 14 type C, of which the standard typing Gustio, type I in 15 cases, type II in 13, type III A in 2. And from January 2001 to July 2007, 57 patients with tibiofibula fractures (group B) were treated with locking intramedullary nail fixation,there was 40 males and 17 females,the age was from 21 to 69 years with an average of (38.1 +/- 8.9) years; according to AO classification standard, 27 cases were type A, 22 type B, 8 type C, of which the standard typing Gustio, type I in 7 cases, type II in 6, type III A in 1. Four indexes were compared, including the time of fracture healing, the time of achieved 90 degrees genuflection, the time of off-bed weight-bearing and complication. RESULTS: Comparison of fracture healing time: group A was (19.0 +/- 0.6) weeks and group B was (14.0 +/- 0.5) weeks; the time of achieved 90 degrees genuflection in group A was (92.0 +/- 8.2) d and in group B was (39.0 +/- 6.1) d; the time of off-bed weight-bearing in group A was (96.0 +/- 6.3) d and in group B was (38.0 +/- 6.5) d. Complication occurred in 42 cases in group A and 6 in group B. There was significantly difference in 4 items between two groups (P < 0.01). The method of locking intramedullary nail fixation was better than skeletal traction in treating tibiofibula fractures. CONCLUSION: Treatment of tibiaofibula fractures with locking intramedullary nail fixation can obtain satisfactory effect, which has less complication, the fracture heals and weigh-loading can be achieved early. PMID- 20191956 TI - [Experience on metal foreign body removed with electric magnet of 28 cases]. PMID- 20191955 TI - [Clinical application of extracorporeal shock wave to repair and reconstruct osseous tissue framework in the treatment of avascular necrosis of the femoral head (ANFH)]. AB - OBJECTIVE: To investigate the application value of extracorporeal shock wave to repair and reconstruct osseous tissue for the treatment of avascular necrosis of the femoral head (ANFH). METHODS: A total of 42 hips of 36 patients with ANFH were treated with extracorporeal shock waves included 29 males and 7 females,aged from 21 to 66 during March 2006 to March 2008. The course of disease was 6 months to 3 years (means 1.3 years). According to Ficat classification 8 hips were in stages I, 25 were in stage II, and 9 were in stage III. The energy density of ESWT was from 0.18 to 0.25 mJ/mm2. The treatment focusing points of avascular necrosis of the femoral on the surface projection were marked with X-ray fluoroscopy, and 1 to 2 points were selected for one treatment with 400 to 500 pulses in each point. Generally 3 to 5 treatments were performed, once per 7 days. The CR, CT or MRI and the hip Harris score were obtained to investigate the clinical effects of extracorporeal shock wave for repair and reconstruct osseous tissue framework and improve the hip function before treatment and at 3, 12 months after treatment. RESULTS: The X-ray,CT or MR were performed of 42 hips,35 hips were treated successfully after extracorporeal shock wave therapy, cure occurred in 6 cases, marked effect in 13 cases, effectiveness in 16 cases and ineffectiveness in 7 case. After one years of followed-up, no relapse was found, the femoral head further collapse did not occur. The Harris hip score of stage I, II, III ere respectivey (90.1 +/- .4), (81.2 +/- .5), (66.9 +/- .6) at 3 months and (91.6 +/- .4), (91.1 +/- .5), (79.0 +/- .1) at 12 months after treatment. The scores after treatment were increased significantly than that of before treatment (P < 0.01). CONCLUSION: Extracorporeal shock wave therapy has obviously therapeutic effect in the repairing and reconstructing osseous tissue and improve the hip Harris score and improve the hip function. It is a effect significantly, non-invasion, less complications, simple-accurate therapy method for ischemic necrosis of the femoral head. PMID- 20191957 TI - [Correlation studies between MRI and the symptom scores of patients with LDH before and after manipulative therapy]. AB - OBJECTIVE: To study the correlation between the MRI and some symptom scores of the patients with lumbar disc herniation (LDH), such as VAS (visual analogue scale), JOA (Japanese orthopedic association scale),and SLR (straight leg raising test) before and after manipulative therapy. METHODS: From June to December in 2007, 70 patients with LDH were selected in the study. Among the patients, 40 patients were male and 30 patients were female, ranging in age from 21 to 56 years (averaged 39 years). MRI was used to measure the size and position of the protruded nucleus pulposus (size of disc protrution, the angle between nerve root canal and disc protrution). Correlation study was conducted between the MRI and VAS, JOA, and SLR before and after therapy. The correlation between the changes of MRI and that of the quantified clinical indexes of LDH patients was also analyzed. RESULTS: There were significant differences before and after therapy in some quantified indexes for the clinical manifestation of the patients, such as VAS, JOA,and SLR. There were no significant changes in the shape and size of protrude nucleus pulposus after 20 days' therapy by CT or MR recheck. Correlation study between the quantified indexes of clinical manifestation (JOA) and MRI before and after the treatment showed that there was no significant correlation. CONCLUSION: The study proves again that the shape and size of protrude nucleus pulposus has no paralleled relation with the patient's clinical manifestation,which is demonstrated by the recheck of MRI after a successful spinal manipulative treatment in the study. PMID- 20191958 TI - [The prevention and treatment of cerebrospinal fluid leakage following cervical spine surgery]. AB - OBJECTIVE: To investigate curative effect of the prevention and treatment in cerebrospinal fluid leakage (CFL) after cervical surgery. METHODS: Medical records of 607 patients who underwent cervical surgery at our hospital from Feb. 2004 to Feb. 2008 were retrospectively reviewed. Six patients complicated by CFL after surgery were enrolled, of which 4 males and 2 females, age for 47-75 years with an average of 60 years. Course of disease was from 6 months to 5 years. 4 cases occurred at 1-3 days after operation and 2 cases at 5 days. 2 cases were treated through latero-incision drainage, 2 cases continuous subarachnoid drainage, and 2 cases pressure dressing. Clinical outcomes of surgical management were recorded. RESULTS: CFL of all the cases was stopped within 1-3 days after operation,and subarachnoid drainage lasted 10-14 days with an average volume of 320 ml. Three cases had headache, nausea and vomiting; 1 case suffered from somnolence and hyponatremia, and symptoms subsided after treatment. All patients were followed up with an average of 30 months. No cerebrospinal fluid cyst or wound infection were found. There was no significant effects on neuromuscular function recovery. CONCLUSION: Timely and correct surgical intervention and postoperative management have good results for CFL. If it is severe, latero incision drainage and continuous subarachnoid drainage should be adopted. PMID- 20191959 TI - [In vitro induction studies of YouGui drink on culture of steroid induced necrosis of femoral head rat osteoblast]. AB - OBJECTIVE: On the basis of YouGui drink ([Chinese characters: see text]) to act on the normal rats in vitro osteoblast proliferation and differentiation, further observe YooGui drink ([Chinese characters: see text]) inductive effect for steroid induced necrosis of femoral head rats in vitro on cultivation of osteoblast proliferation and differentiation. METHODS: Prednisolone acetate 49 mg/kg x d were injected into gluteal of 20 male SD rats (body weight in 100-120 g), continuously 6 days for model. After 7 days, under sterile conditions from the model rats bone marrow stromal cells were induced and cultured to osteoblast, and then randomly divided into 4 groups, respectively, add the high, medium and low concentration YouGui drink ([Chinese characters: see text]) containing serum (group R1, R2, R3) and control serum (group R4). After 72 h, osteoblast proliferation, alkaline phosphatase activities (APA) were detected, and expression level of osteoprotegerin (OPG) and osteoclast differentiation factor (RANKL) were detected by real-time fluorescence quantitative PCR. RESULTS: The high and medium concentration YouGui drink ([Chinese characters: see text]) containing serum group compared with the control group (R1, R2 vs. R4), the rate of osteoblast proliferation was significantly high (P < 0.01), APA significantly increased (P < 0.01), relative expression level of osteoblast OPG mRNA significantly increased (P < 0.01), and with the concentration of a certain dose was positively correlated; RANKL mRNA significantly was lower (P < 0.01). The low concentration YouGui drink (t 91 t) containing serum group compared with the control group (R3 vs R4), there was no significantly different in the rate of osteoblast proliferation, ALP and relative expression level of osteoblast OPG mRNA, RANKL mRNA. CONCLUSION: The high concentration of YouGui drink ([Chinese characters: see text]) containing serum can obviously promote the proliferation and differentiation of steroid induced necrosis of femoral head rats in vitro osteoblast, and plays a clear role in promoting and enhance the relative expression of osteoblast OPG mRNA and an inhibitory effect on RANKL mRNA. The effect of YouGui drink ([Chinese characters: see text]) containing serum acting on induced in vitro cultured osteoblasts have relevance with dose, at a certain concentration range it can promote osteoblast differentiation and proliferation. PMID- 20191960 TI - [Experiment of rhBMP-2 in posterolateral spinal fusion in aged rabbits]. AB - OBJECTIVE: Posterolateral intertransverse process fusion was performed in aged and young adult female rabbits lumbar spine using recombinant human bone morphogenetic protein-2 (rhBMP-2) and autograft to reveal the function of rhBMP-2 on spinal fusion on aged animals. METHODS: A total of 24 female New Zealand white rabbits included 12 young adult of 6 months and 12 aged of 2-year-old, was divided into 4 groups: (1) young adult autologous iliac crest bone group [ICBG(Y), n=6); (2) young adult rhBMP-2/absorbable collagen sponge (ACS) group [BMP-2(Y), n=6]; (3) aged autologous iliac crest bone group [ICBG(O), n=6]; aged rhBMP-2/ACS group [BMP-2(O), n=6]. All were underwent posterolateral fusion in same day. rhBMP-2 and autologous iliac crest bone was implant bilateral LS-L6 intertransverse processes, respectively. Half of the rabbits were sacrificed at 3.6 weeks following surgery, respectively. The results were assessed by manual palpation, radiographs, computed tomographic scans (3D) and histology. RESULTS: Six weeks after surgery, radiography, computed tomography and histology indicated the different result in healing in the posterolateral fusion using rhBMP-2 compared to ICBG (P < 0.05). Aged BMP-2 group showed significantly higher fusion rates than Aged ICBG group. CONCLUSION: This study demonstrated rhBMP-2 can increase the posterolateral fusion rate and new bone quality in aged rabbitss than autograft, it may take the place of ICBG. But its role is effected by age. PMID- 20191961 TI - [Analysis of curative effect on different methods for the treatment fracture of calcaneus]. PMID- 20191962 TI - [The influence of rotary manipulation on the internal pressure of cervical nucleus pulposus]. AB - OBJECTIVE: To measure the pressure changes inside the cervical nucleus pulposus in fresh human cervical specimen by imitating different rotary manipulations. METHODS: The load of 100 N was applied for 5 second on the six fresh male cervical samples by using material test system, which imitated the human head weigh and the strength of cervical extensor muscle. After that, traction, rotation and pulling on the samples were performed in different sequence under the force of 150, 200, 300 N respectively. Three states were included in adding the load state A: samples were loaded with traction and then rotation to the biggest angle, pulling backward for 15 degrees; state B: samples were loaded with rotary stress to the biggest angle and then loaded with traction, pulling backward for 15 degrees; state C: samples were loaded simultaneously with traction and rotary stress to the biggest angle, pulling backward for 15 degrees. The internal pressure of cervical nucleus pulposus at segment of C(3,4), C(4,5), C(5,6), and C7 was measurred by micro-pressure sensors for state A, B, C and for the imitation of head weight and the strength of cervical extensor muscle. RESULTS: The pressure inside the cervical nucleus pulposus at segments C(5,6), C(6,7) was higher than that at segments C(3,4) and C(4,5) (P < 0.05) by loading stress with 100 N for 5 seconds. The internal pressure of the nucleus pulposus decreased with the increase of traction (P < 0.05), and increased when traction and rotary force were loaded. State A, the value of increased pressure within the nucleus pulposus became smaller and smaller while increasing of the traction force loaded (P < 0.05). State B, the increase of internal pressure in nucleus pulposus became obvious as loading pressure increased (P < 0.05). State C, the internal pressure in nucleus pulposus was not increased obviously (P > 0.05). There was a transitional pressure raise inside all cervical nucleus pulposus when pulling added after different sepuence traction and rotary strength was applied, however, the internal pressure of state A was significantly higher than that of state B or C (P < 0.05). There was also a transitional pressure raise inside all cervical nucleus pulposus when pulling added in different strength (P < 0.05),the internal pressure by pulling with 150 N was obviously higher than that with 200 N and 300 N (P < 0.05). CONCLUSION: The order of rotation first and traction second should be avoided when practice of rotary manupuplation in case protrusion of the nucleus pulposus. Meanwhile, proper traction should be applied along with rotary manipulation in order to increase its safety. PMID- 20191963 TI - [Exploring the mechanism of children elbow joint injury led to elbow varus]. AB - OBJECTIVE: To explore the causes and mechanisms of children elbow joint injury led to elbow varus. METHODS: One hundred children with elbow varus causded by elbow joint injuries were retrospectively studied during January 2005 to April 2008 in department of child orthopedics involving 54 males and 46 females with an average age of 9.7 years old ranging from 7 to 16 years. The anterior-posterior and lateral position X-ray films of elbow joint continuous 12 to 18 months (means 15 months) of all the cases were collected. The postoperative X-ray films were observed to analyze the cause of elbow varus. RESULTS: There were 81 cases caused by epiphyseal dysplasia, growth imbalance, included 47 cases of humeral supracondylar fractures, 16 cases of entire epiphysis separation of distal humerus, 11 cases of humeral lateral condyle fractures, 7 cases of humeral medial condyle fractures. There were 19 cases caused by ulna drift and rotation of the distal fracture end,the ulnaris cortibal bone crushing and collapse involving 11 of humeral supracondylar fractures, 2 of entire epiphysis separation of distal humerus, 5 of humeral lateral condyle fractures, 1 of humeral medial condyle fractures. CONCLUSION: There are two main factors of formation for the children elbow varus deformity: the main causes is epiphysial dysplasia after fracture and imbalance growth of epiphysis; the secondary reasons is ulnar inclination of the distal fracture, rotation of the distal fracture, fracture shift such as ulnar bone cortical extrusion collapse. PMID- 20191964 TI - [Clinical apprehension on application of metal on metal total hip arthroplasty with large diameter heads]. AB - OBJECTIVE: To approach the short-term result and clinical application of metal on metal total hip arthroplasty with large diameter heads and evaluate its safety and efficacy clinically. METHODS: From January 2007 to March 2008, 39 hips in 37 patients (24 males and 13 females,ranging in age from 43 to 75 years, with an average of 58.5 years) were treated with metal on metal total hip arthroplasty with large diameter heads (ASRTM XL) included 14 cases of osteonecrosis (ON), 2 cases of osteoarthritis (OA), 18 cases of fresh femoral neck fracture, 3 cases of developmental dysplasia of the hip (DDH). All patients were evaluated by self assessment form, hip function examination, radiographs, preoperative and postoperative Harris hip score. Based on the short-term results, its design characteristic and clinical properties were analyzed. RESULTS: All the incision healed well and there were not any complications such as femoral fracture, infection, dislocation and neurovascular injury. All patients obtained the follow up and an average time was 16.5 months (12 to 19 months), all the joints had good or excellent clinical results. Radiographically, the positions of the prostheses were normal, the average limbs length and femoral eccentricity recovered as normal. The average range of motion of the hip improved remarkable, such as flexion improved from (20.1 +/- 8.2) degrees to (85.7 +/- 9.8) (t = 32.86, P < 0.01), abduction improved from (10.2 +/- 4.4) degrees to (41.5 +/- 9.1) degrees (t = 19.34, P < 0.01), adduction improved from (16.3 +/- 8.8) degrees to (40.3 +/ 10.4) (t = 11.00, P < 0.01),external rotation improved from (12.3 +/- 5.2)0 to (42.0 +/- 7.7) degrees (t = 19.96, P < 0.01), internal rotation improved from (3.4 +/- 1.1) degrees to (23.0 +/- 9.8) degrees (t = 12.41, P < 0.01). The Harris score rose from preoperative (39.3 +/- 5.6) to (91.4 +/- 10.3) at the latest follow up (t = 27.75, P < 0.01). CONCLUSION: Short-term results show that metal on metal hip joint prosthesis with large diameter heads has advantages of small deformation of acetabular cup, lower wearing, large range of motion and few dislocation. It offers a newly valuable technology for treatment of osteonecrosis, osteoarthritis, femoral neck fracture and DDH with the higher requirement of movement after the operation. PMID- 20191965 TI - [Minimally invasive surgery to treat severe acromioclavicular dislocation combined with coracoid process fracture]. AB - OBJECTIVE: To discuss the diagnosis and minimally invasive surgical treatment on severe acromioclavicular dislocation combined with coracoid process fracture. METHODS: Using 2 incisions of shoulder to expose and fix coracoid process and acromioclaricular joint and to repair damaged acromioclavicular ligament in 7 cases from March 1998 to March 2009. There was 2 males and 5 females in the patients. The age was from 23 to 57 years with an average of 44 yeas. The time from injury to operation was 3-7 d with an average of 4 days. According to Eyres typing, 2 cases were type 11 B, 5 cases were type III B. RESULTS: Seven patients were followed up from 6 months to 2 years with an average of 1 year. According to Karlsson criteria, 7 cases got grade A. CONCLUSION: Using 2 incisions of shoulder to expose and fix acromioclaricular joint and coracoid process with strong pertinence, reliable fixation and small tissue injury, which is a minimally invasive and effective method for severe acromioclavicular dislocation combined with coracoid process fracture. PMID- 20191966 TI - [Treatment of complex fracture--dislocation of elbow with external fixator with joint and limited internal fixation]. AB - OBJECTIVE: To discuss the method and the effect of external fixator and limited internal fixation with joint applied for complex fracture-dislocation of elbow. METHODS: From Mar. 2005 to Mar. 2008, 17 patients with complex fracture dislocation of elbow were treated with external fixator with joint and limited internal fixation. Nine of them were on the left side and 8 on the right side. There were 11 males and 6 females. The age was from 21 to 57 years with an average of 37 years. The clinical effects were evaluated according to Mayo scoring of elbow joint function (including pain, rang of motion, joint stability and so on). RESULTS: All patients were followed up from 5 to 10 months with an average of 8 months. The mean mayo score was 82 +/- 10 (62-96). The results were excellent in 7 cases, good in 7, fair in 3. CONCLUSION: The technique of external fixator with joint and limited internal fixation for complex fracture-dislocation of elbow can restore anatomical articular surface with advantage of early functional training which can decrease the occurrence of elbow stiff and soft tissue contracture. It is a satisfactory method in treating complex fracture dislocation of elbow. PMID- 20191967 TI - [Clinical analysis of preoperative deep venous thrombosis (DVT) complicated lower extremity close fractures]. AB - OBJECTIVE: To study the instance of deep venous thrombosis(DVT) complicated by preoperative lower extremity close fracture. METHODS: Retrospectively analyzed the clinical data of 54 patients with DVT (through color Doppler to final diagnosis) complicated by preoperative lower extremity close fracture from March 2008 to February 2009, and explored the concomitant reason of DVT. There were 23 males and 31 females with age for 23-95 years old. RESULTS: DVT including thrombus of ilio-venae external, thrombus of femoral vein, thrombus of popliteal vein, thrombus of posterior tibial veins and thrombus of soleus venae. The instance of DVT complicated by preoperative lower extremity close fracture: (1) The age of 23 cases (42.59%) more than 70 years. (2) 11 cases (20.37%) combined with syndrome, 2 cases had hypertension, 3 cases had hypertension and diabetes, 2 cases hypertension and cerbral infarction, 4 cases had hypertension, diabetes and coronary heart disease. (3) 10 cases (18.51%) were multi-fractures. (4) 28 cases (51.85%) occurred DVT at 7-14 days after lower extremity close fracture. CONCLUSION: Advanced age, complicating hypertension, diabetes, coronary heart disease, cerbral infarction, multi-fractures may be lead to DVT. Multitudinous DVT occurred at 7-14 days after fracture, as early as possible operation has important significance on prevention DVT to decrease risk of pulmonary embolism. PMID- 20191968 TI - [Knee within the posterior mini-incision approach for the treatment of posterior cruciate ligament tibial avulsion fracture]. PMID- 20191969 TI - [Analysis of treatment on rotately and vertically unstable pelvic fractures]. PMID- 20191970 TI - [Treatment of acetabular fractures with reconstruction plates and skin traction]. PMID- 20191971 TI - [Clinical study on the treatment of different distal radius fractures without operation]. PMID- 20191972 TI - [Autografting of fibula for treatment of the one-third of distal femoral fracture with long bone defect]. PMID- 20191973 TI - [Subtotal resection of vertebral body, implantation of titanium cage and internal fixation for the treatment of blowout fractures of thoracic-lumbar vertebrae through posterior approach]. PMID- 20191974 TI - [Simultaneous fracture-dislocation of right shoulder and elbow: a case report]. PMID- 20191975 TI - [Clinical application of atlantoaxial pedicle screw system in degree III odontoid fracture]. PMID- 20191976 TI - [Treatment of anterior dislocation of shoulder joint with setting bone manipulation]. PMID- 20191977 TI - [Current situation and progression in the treatment of spinal cord injury]. AB - Spinal cord injuries include original injury and secondary injury. The aim of therapy is to prevent and reduce the secondary injury. The traditional therapy can alleviate the secondary injury of spinal cord through surgery that can both relieve the pressure of spinal cord and maintain the spinal stability with the internal fixation, medicine and hyperbaric oxygen therapy were applied together. But, the effect of neuroprotection and neurotization of traditional therapy is worse and the most of all is the environment in the spinal cord injury that make against the repairing. At present, the treatment of spinal cord injury with cell transplantation and gene therapy have made achievements in the animal experiment and have been simply tested in clinical. Cell transplantation and gene therapy have a great clinical utilization. PMID- 20191978 TI - [Operative treatment of metastatic tumors of spine]. AB - The spine is the most common site of metastatic tumors. The highest incidence of metastatic tumors on the spine is in the lumbar region, followed by the thoracic and cervical levels. Most associated spinal cord lesions, however, are located in the thoracic spine. The goals of surgery is decompression of the neural tissues, prevention of neural injury by stabilization of the unstable spinal column,or pain control. When there is a need to decompress the neurologic tissues,the most direct approach is anterior because the most common site of metastatic tumors is in the vertebral body. Laminectomy alone is not effective in improving neurologic function. Nevertheless,the posterior approach is more accessible, less hazardous, and effective in the correction of deformity if combined with instrumentation. If complete vertebrectomy is feasible in anterior bone strut combined with anterior and posterior stabilization is necessary following the vertebrectomy. PMID- 20191979 TI - [Clinical application of the fragment fixation system for the treatment of patellar fracture]. PMID- 20191980 TI - [Life and work of Carlos Chagas, on its centennial description of Chagas-Mazza disease]. PMID- 20191981 TI - [Comprehensive assessment of psychopathology and other psychosocial issues in patients with heart disease]. PMID- 20191982 TI - [Radioisotopic ventriculography in the evaluation of the ventricular function in Chagas' disease]. PMID- 20191983 TI - [Evaluation of the function and ventricular synchrony in patients with latency stage of Chagas' disease]. AB - OBJECTIVE: To compare the left ventricular function and the ventricular synchrony in patients with Chagas disease in latency stage respect to a control group. METHODS: We analyze a prospective, comparative, transversal and non randomized study of the left ventricular function (LVF) and the ventricular contraction synchronicity (VCS) in 36 subjects with positive serology for Chagas disease (18 males and 18 females), with mean of 15 +/- 5-years-old. The findings were compared with respect to 23 control volunteers (11 males and 12 females) with mean of 28 +/- 5-years-old. LVF and VCS were evaluated using equilibrium radionuclide angiography images (ERNA). The comparison of both Chagas and control populations was carried out by t Student test for independent samples, considering a statistically significant value of p < 0.05. RESULTS: The parameters of the ventricular function and the ventricular synchronicity in subjects with positive serology for Chagas disease were not statistically different with respect to the parameters of the control group. However, although they have a homogeneous contraction, the mean time of contraction for the right and the left ventricle is statistically smaller with respect to the control group. CONCLUSIONS: In clinically incipient stages of Chagas disease we do not found abnormalities in the ventricular function and the ventricular synchronicity. It's necessary to consider the follow up of the studied populations using indices for the identification of abnormalities of the autonomic nervous system. PMID- 20191984 TI - [Effects of the combined treatment with Metformin/Glimepiride on endothelial function of patients with type 2 diabetes mellitus. A positron emission tomography (PET) evaluation study]. AB - The purpose of this study was to determine the effect of treatment, with Metformin alone or with the combination of Glimepiride/Metformin, on coronary endothelial function in asymptomatic patients with recently diagnosed type 2 diabetes mellitus (DM) Methods: 16 asymptomatic patients with type DM2 and 15 healthy controls (HC) were studied. At baseline and after treatment, myocardial blood flow (MBF) was measured with 13N-ammonia Possitron Emission Tomography (PET) at rest, during cold pressor testing (CPT) and during pharmacologic stress with adenosine. The endothelial dependent vasodilation index (EDVI), myocardial flow reserve (MFR) and the percentage of the change between rest MBF and CPT MBF (%deltaMBF) were calculated as markers of endothelial function. MBF was normalized to the rate pressure product (RPP). RESULTS: EDVI and %deltaMBF were significantly lower in diabetic patients before treatment in comparison with HC demonstrating endothelial dysfunction in the former. Treatment with Glimepiride/Metformin significantly increased EDVI and %deltaMBF in diabetic patients from baseline, thus showing an improvement in coronary endothelial function. PMID- 20191985 TI - [Psychopathology and personality of patients with heart disease]. AB - PURPOSE: To know the psychological aspects involved in cardiac ailments and whether there was a distinctive personality profile of each disorder. METHODS: We evaluated 137 patients with congenital heart, acute myocardial infarction (AMI) or awaiting a heart transplant who came to the National Institute of Cardiology Ignacio Chavez. We used multiphase Personality Inventory, which provides information on personality traits and psychopathology. RESULTS: There were significant differences between some cardiac sufferings and the scales that the inventory measures, as well as the existence of differences between sexes. CONCLUSIONS: The diseases associated with the heart involve not only some physical and psychological consequences, but also significant psychological consequences depending on the type of heart disease. Those with a congenital heart had better conditions than other emotional heart diseases studied. For their part, those who have suffered IAM are showing higher depressive Levels (being higher in males), while those more concerned about their health in this study were patients awaiting heart transplantation. That is why it is important to take into account the psychological aspects in the cardiac conditions to achieve a better multidisciplinary management. PMID- 20191986 TI - [Clinical predictors of ventricular arrhythmia storms in Chagas cardiomyopathy patients with implantable defibrillators]. AB - OBJECTIVES: To define the predictive factors of electrical storm (ES) in patients with Chronic Chagas Heart Disease (CCh) with an implantable cardioverter defibrillator (ICD). MATERIAL AND METHODS: We retrospectively studied 21 consecutive patients with CCh in whom an ICD was implanted between April 2005 and December 2008, with a mean follow up of 867 days. Patients were classified into two groups according to the presence of electrical storm episodes. We compared baseline characteristics, medical treatment and determinants of ventricular function. P values less than 0.05 were considered statistically significant. RESULTS: Of the 21 patients with CCh there were eight women (37%), mean age 61 years and an EF of 30%. It was noted at least one episode of arrhythmic storm in 9 cases (incidence of 43%). The total number of episodes of arrhythmic storm was 13 and the number of ventricular arrhythmias in each episode of arrhythmic storm was 15.6 (range 3-61). A trigger was identified in only two cases (pulmonary infectious process and decompensation of chronic heart failure). After analyzing the possible predictors of arrhythmic storm was found that a greater percentage of subjects with this complication had an EF <35% (89% vs. 50%, p = 0.01) and NYHA functional class III (66% vs. 8.3%, p = 0.001). In contrast, a lower percentage of subjects with arrhythmic storm were under beta-blocker treatment (55% vs. 100%, p = 0.01). CONCLUSIONS: In subjects with CCh with an ICD, the following variables are predictive of arrhythmic storm: EF <35%, NYHA functional class III-IV and absence of beta-blocker treatment. PMID- 20191988 TI - Anomalous origin of the left coronary artery from the pulmonary artery. Echocardiographic diagnosis. AB - The experience with echocardiographic diagnosis of five cases of Anomalous Origin of the Left Coronary Artery from the Pulmonary Artery (ALCAPA) is reviewed. MATERIAL AND METHODS: all cases with a diagnosis of ALCAPA during a 10 year period were included. RESULTS: two age groups were clearly identified: infants and older patients. In the former, the echocardiographic findings included a dilated left ventricle with low ejection fraction (19% and 26%), mitral regurgitation, dilated right coronary artery and difficulties in identifying the origin of the left coronary artery. An 11-year-old asymptomatic boy, a 17-year old young woman with dyspnea on effort and a 55-year-old woman with angina formed the older group. In these three cases, an abnormal upward flow was detected within the ventricular septum related to the collaterals and the inverse flow of the anterior descending artery. A reverse flow within the origin of the left coronary artery, probably related to an origin in the pulmonary artery, was observed. In all five cases the diagnosis was corroborated using selective right coronary artery angiography. CONCLUSIONS: In the infants, the dilated left ventricle with impaired systolic function, mitral regurgitation and dilated right coronary artery make it necessary to discard the ALCAPA diagnosis. In the older group, even in asymptomatic patients, an abnormal ascending flow within the ventricular septum, combined with a dilated coronary artery, was the most reliable echocardiographic evidence for a diagnosis of ALCAPA. PMID- 20191987 TI - [Severe myocardial damage caused by leptospirosis. Report of a fatal case in Mexico]. AB - Chagasic cardiomyopathy is a common disease in Latin America, however similar clinical pictures exist that can be confused with this, as they give negative results to the tests that detects T. cruzi, like non Chagasic rural endemic chronic cardiopathy, highly common in Venezuela. Using histopathology techniques, "idiopathic cardiomyopathy" is frequently found as the cause of death when the etiology of this disease is not known. This paper presents the case of a man of 26-years-old who died of dilated cardiomyopathy secondary to leptospirosis. Clinically, in addition to the cardiac failure, jaundice, hyperbilirubinemia, transaminases increase, proteinuria and hematuria were present. Initially it was suspected Chagasic cardiomyopathy but the epidemiologic background and the parasitologic and serologic tests for T. cruzi gave negative results. The dark field microscopy videorecording of blood and urine samples, argentic impregnation and immunohistochemistry tests as well as haemoculture in EMJH medium were positive for L. interrogans serovar Pomona. Postmortem we confirmed the presence of leptospira in different tissues through of histopathology, argentic impregnation, indirect immunofluorescence and immunohistochemistry. PMID- 20191989 TI - [Coronary artery disease and cardiac ischemic disease: two different pathologies with different diagnostic procedures]. AB - Coronary artery disease (CAD) remains the leading cause of death in the Western world, and early detection of CAD allows optimal therapeutic management. The gold standard has always been invasive coronary angiography, but over the years various non-invasive techniques have been developed to detect CAD, including cardiac SPECT and cardiac computed tomography (Cardiac CT). Cardiac SPECT permitted visualization of myocardial perfusion and have focused on the assessment of the hemodynamic consequences of obstructive coronary lesions as a marker of CAD. Cardiac CT focuses on the detection of atherosclerosis rather than ischemia, and permit detection of CAD at an earlier stage. Objectives of this manuscript are to discuss the clinical experience with both modalities and to provide a critical review of the strengths and limitations of Cardiac SPECT and Cardiac CT for the diagnostic and management of patients with suspected CAD or cardiac ischemic disease. PMID- 20191990 TI - The role of European National Journals in education. PMID- 20191991 TI - [In 2010, a war against malpractice!]. PMID- 20191992 TI - [Recommendations from the Society of concerning domestic violence]. PMID- 20191993 TI - [Evaluating pain in aged persons who are not able to communicate]. PMID- 20191994 TI - [Education of nurses caring for patients with dementia in agreement with long term nurses]. PMID- 20191995 TI - [Organization, association and coordination of geriatric networks in Sarthe]. PMID- 20191996 TI - [Principles of good treatment and mobile training for Alzheimer disease]. PMID- 20191997 TI - [Cerebrovascular accident. It is urgent to proceed!]. PMID- 20191998 TI - [Care of cerebrovascular accidents in the aged]. PMID- 20191999 TI - [Benefits from unity of vascular neurology for the aged]. PMID- 20192000 TI - [Vascular cerebral accidents in the acute phase]. PMID- 20192001 TI - [Imagery in cerebral vascular accidents in the aged]. PMID- 20192003 TI - [Return home after a cerebrovascular accident]. PMID- 20192002 TI - [Multidisciplinary care of aged victims of cerebrovascular accidents]. PMID- 20192004 TI - [France Stroke Association, an aid for patients and their neighbors]. PMID- 20192005 TI - [12/12. Medico-psychological help]. PMID- 20192006 TI - You've come a long way, baby. PMID- 20192007 TI - Revealing the health experiences of women. PMID- 20192008 TI - Vitamin D and women's health. PMID- 20192009 TI - Breastfeeding: a woman's health issue. PMID- 20192010 TI - The greatest health divide in the world--half million die in childbirth annually. PMID- 20192011 TI - Thermography: a holistic approach to breast screening. PMID- 20192012 TI - An ancient practice for today's woman. PMID- 20192013 TI - Coping with stress holistically. PMID- 20192014 TI - Providing holistic care for women with chronic pelvic pain. PMID- 20192015 TI - We are all setting an example. PMID- 20192016 TI - Sodium hypochlorite mouthwash. PMID- 20192017 TI - Morphology of the occlusal surface for premolar and molar teeth as an indicator of age in the horse. PMID- 20192018 TI - Type 1 TR and type 2 TR identified to be two significantly different manifestations of TR. PMID- 20192019 TI - Enamel defects in standard poodle dogs in Sweden. AB - Several disturbances can occur in enamel formation. Amelogenesis imperfecta is an inherited enamel malformation that has not previously been reported in dogs. The aims of this study were to investigate amelogenesis imperfecta-like tooth discoloration in standard poodle dogs by histopathological characterization of discolored teeth from affected dogs, investigating whether these dogs have a common genetic background, and assessing how common this problem is in the breed. Histologically, a defect of enamel mineralization was documented. Affected enamel contained a large residual amount of organic matrix, showing that the enamel was not fully mineralized. In some sections, the enamel appeared intact, but with excessively well-defined enamel prisms which is an additional sign of poor mineralization. The abnormal enamel was identical to that seen in humans with amelogenesis imperfecta. Five of 27 standard poodle dogs present at a dog show had discolored teeth. A four-generation pedigree was available containing an example of parents also having discolored teeth one of which had amelogenesis imperfecta confirmed histologically. In all subsequent litters from these dogs, there was at least one dog with discolored teeth, and two histologically confirmed cases of amelogenesis imperfecta four generations later. Histological examination and the apparent familial occurrence indicates that amelogenesis imperfecta is a common cause of discolored teeth in standard poodle dogs in Sweden. PMID- 20192020 TI - Measurement of the Curve of Spee in horses. AB - The Curve of Spee is well known, yet hardly understood in the horse, as there is a striking lack of biometrically related data which could help to explain its biomechanical significance. Older horses display drastic alterations of the Curve of Spee in routine clinical examinations. Since the Curve of Spee is known to be biomechanically related to the masticatory forces in humans, the same may apply to the equine, and masticatory deficits can be expected in the geriatric horse. Quantitative data of the Curve of Spee cannot be obtained directly by means of measurements in the horse's long and narrow oral cavity. Instead, the radiographs of 24 heads and 6 skulls of horses of different age were used to develop a geometrical procedure facilitating a quantitative analysis of the height of the Curve of Spee. The geometrical values gave clear evidence that the height of the Curve of Spee was smaller in groups of older horses compared with those of younger horses. This finding was in accordance with biomechanical studies which reported decreased masticatory forces in older horses. PMID- 20192021 TI - Endodontic treatment of dens invaginatus in a dog. AB - Dens invaginatus or dens in dente is a developmental dental malformation that has the radiographic appearance of a separate tooth inside the pulp chamber or canal of another tooth. This report describes endodontic treatment of a variation of dens invaginatus in the maxillary canine tooth of a dog. PMID- 20192022 TI - Computed tomography and partial coronoidectomy for open-mouth jaw locking in two cats. AB - Open-mouth jaw locking in the cat has traditionally been minimally evaluated with diagnostic imaging. Multiple methods have been described for surgical management of this problem. This report describes the use of computed tomography to diagnose open-mouth jaw locking in 2 cats secondary to ventrolateral displacement of the coronoid process in relation to the zygomatic arch. In these 2 cases, a previously unreported surgical approach whereby the coronoid was not reduced before partial coronoidectomy was used with successful outcomes. PMID- 20192023 TI - Oral malignant squamo-melanocytic tumor in a dog. PMID- 20192024 TI - Oral examination in the canine patient. PMID- 20192025 TI - Symphyseal sparing rostral mandibulectomy. PMID- 20192026 TI - Keeping it simple. PMID- 20192027 TI - Transitioning to ICD-10. PMID- 20192028 TI - Amend medical records with care. PMID- 20192029 TI - A ringside seat. Why one physician supports a violent sport. PMID- 20192030 TI - [Brain-machine interface--current status and future prospects]. AB - Recent advances in brain activity analysis and computational algorithms have enabled people with severe motor disorders to control external devices via brain activity. Brain-machine interface (BMI)/brain-computer interface has gained importance as the ultimate strategy for functional compensation because it improves impaired neuromuscular systems. Invasive BMI performed using needle arrays can best control robotic arms or computer cursors because it records neural activity in the primary motor cortex in detail. The extensive and validated physiological background of recorded signals enables researchers to develop highly accurate BMI systems with needle electrodes. Less invasive neural recording with an electrocorticogram (ECoG)-electrode array provides good temporal and spatial information for use in prosthetic control. ECoG electrodes have wide clinical applications in pain control and epilepsy; therefore, techniques for electrode implantation are well established compared to those for needle arrays. These electrodes may find wide clinical applications if their accuracy level reaches that suitable for practical use. Noninvasive BMI involving neural recording by electroencephalography (EEG) is the most widely used technique because of a convenient experimental setup, although it provides a limited range of decodable motor outputs. In EEG, arc-shaped mu rhythms of 8-12 Hz appear around the sensorimotor area in the resting state and diminish in amplitude during motor imagery. Thus, the mu rhythm amplitude may correlate with cortical excitability of the sensorimotor area, and EEG-BMI may be useful in the neurorehabilitation of patients with stroke-induced hemiplegia. Research on BMI as a therapeutic tool though emergent, may widen the scope of conventional BMI. PMID- 20192031 TI - [Novel functional electrical stimulation for neurorehabilitation]. AB - Our understanding of motor learning, neuroplasticity, and functional recovery after the occurrence of brain lesions has increased considerably. New findings in basic neuroscience have provided an impetus for research in motor rehabilitation. Several prospective studies have shown that repeated motor practice and motor activity in a real world environment have a favorable effect on motor recovery in stroke patients. Electrical stimulation can be applied in a variety of ways to the hemiparetic upper extremity following a stroke. In particular, electromyography (EMG)-triggered electrical muscle stimulation improves the motor function of the hemiparetic arm and hand. Triggered electrical stimulation is reported to be more effective than non-triggered electrical stimulation in facilitating upper extremity motor recovery after stroke. Power-assisted functional electrical stimulation (FES) induces greater muscle contraction by electrical stimulation that is in proportion to voluntary integrated EMG signals. Daily power-assisted FES home-program therapy with novel equipment has been shown to effectively improve wrist, finger extension, and shoulder flexion. Combined modulation of voluntary movement, proprioceptive sensory feedback, and electrical stimulation might play an important role in improving impaired sensory-motor integration by power-assisted FES therapy. A multi-channel near-infrared spectroscopy (NIRS) studies in which the hemoglobin levels in the brain were non invasively and dynamically measured during functional activity found that the cerebral blood flow in the injured sensory-motor cortex area is greater during a power-assisted FES session than during simple active movement or simple electrical stimulation. A novel power-assisted FES sleeve (Cyberhand) has been developed for the rehabilitation of hemiplegic upper extremities. PMID- 20192032 TI - [Clinical application of functional near-infrared spectroscopy in rehabilitation medicine]. AB - Functional near-infrared spectroscopy (fNIRS) is an effective tool to non invasively investigate cerebral oxygenation and hemodynamics. fNIRS as well as other functional neuroimaging techniques including functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) have been used for investigating the neural mechanisms of functional recovery after a stroke or a traumatic brain injury. fNIRS has several advantages over other neuroimaging techniques in terms of clinical application in the field of rehabilitation medicine. In addition to its portability and low equipment cost, fNIRS does not require strict motion restriction during measurement, unlike other functional imaging techniques. Therefore, this technique enables the examination of cortical activation during physically dynamic activities, like gait or balance perturbation. Studies using fNIRS have revealed several implications for gait recovery after stroke. These studies have shown that the medial sensorimotor cortex (SMC) and the supplementary motor area (SMA) are mainly involved in steadying gait and that the prefrontal cortex (PFC) is involved in the adjustment of walking speed. In hemiparetic patients, lateralization of SMC activation during gait is reduced, and additional cortical activations in the premotor cortex and PFC during gait became evident after focused rehabilitation for several months. The cortical activation pattern may be modified after different types of rehabilitative interventions. These results imply that fNIRS data is a potential biomarker for functional recovery and the response to rehabilitative interventions. Although further studies are required, fNIRS might provide useful information for customizing rehabilitation programs in order to enhance functional recovery. PMID- 20192033 TI - [Robot-aided training in rehabilitation]. AB - Recently, new training techniques that involve the use of robots have been used in the rehabilitation of patients with hemiplegia and paraplegia. Robots used for training the arm include the MIT-MANUS, Arm Trainer, mirror-image motion enabler (MIME) robot, and the assisted rehabilitation and measurement (ARM) Guide. Robots that are used for lower-limb training are the Rehabot, Gait Trainer, Lokomat, LOPES Exoskeleton Robot, and Gait Assist Robot. Robot-aided therapy has enabled the functional training of the arm and the lower limbs in an effective, easy, and comfortable manner. Therefore, with this type of therapy, the patients can repeatedly undergo sufficient and accurate training for a prolonged period. However, evidence of the benefits of robot-aided training has not yet been established. PMID- 20192034 TI - [Neuroimaging and neurorehabilitation for aphasia]. AB - With the development of neuroimaging techniques such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), many reports revealing the underlying mechanisms of functional recovery from aphasia have been published. Three types of compensatory mechanisms seem to operate in aphasic patients with left hemisphere damage: (1) functional recovery of the damaged area in the left hemisphere, (2) activation of the perilesional area in the left hemisphere, and (3) activation of the right frontal area (area homologous to the language-relevant area). Although there are some pitfalls in the interpretation of neuroimaging, it is recommended that the areas that compensate for impaired language function should be clarified prior to the initiation of neurorehabilitation for aphasia. The clinical effectiveness of repetitive transcranial magnetic stimulation (rTMS) and pharmacotherapy for aphasia has been recently studied. We administered low-frequency rTMS and language therapy to 4 stroke patients with motor-dominant aphasia for 6 consecutive days. The application site of rTMS was determined on the basis of the findings of pretreatment fMRI during word repetition tasks. Our novel approach resulted in significant improvement in language functions. The results of some double-blind placebo-controlled trials on aphasic patients have indicated that levodopa, dextroamphetamine, and donepezil play a critical role in the recovery from aphasia. We anticipate limitless future possibilities for the intensive neurorehabilitation of aphasic patients, including constraint-induced language therapy, rTMS application, and pharmacotherapy. The application of newly developed neuroimaging techniques may provide additional important information for improving neurorehabilitative intervention for aphasia. PMID- 20192035 TI - [A new system for the quantitative evaluation of motor commands for neurorehabilitation]. AB - In this study, we introduce a new method to analyze the functional significance of motor commands based on the causal relationship between muscle activities and movement kinematics. We asked 4 healthy subjects to perform 2 movement tasks involving movements of the wrist joint with a manipulandum: (1) a step-tracking movement, and (2) a smooth pursuit movement to follow a smoothly moving target with a cursor. We recorded the movements of the wrist joint and the electromyography (EMG) signals from 4 prime movers of the wrist. We then identified the causal relationship between the muscle activities and the movement kinematics in terms of the torque at the wrist joint torque. Correlation coefficients (R) between the muscle activities and the movement kinematics were surprisingly high for both the step-tracking movement (0.88-0.96) and the smooth pursuit movement (0.89-0.98). Nevertheless, the ratio of the viscosity coefficient B and the elastic coefficient K for the of the causal relationship was systematically different for the 2 movement tasks. For the step-tracking movement, the elastic coefficient K was much higher than the viscosity coefficient B (K>>B, B/K ratio = 0-0.25), suggesting that the muscle activities were correlated mainly with position of the wrist joint. In other words, the central nervous system (CNS) mainly controls the target position during the step tracking movement. In contrast, for the smooth pursuit movement, the elastic coefficient K and the viscosity coefficient B were similar (B approximately equal to K, B/K ratio = 1.0-2.1), suggesting that the muscle activities were correlated both with the position and velocity of the wrist joint. In other words, the CNS controls the velocity as well as position of the target during the smooth pursuit movement. Overall, the controller for the wrist movement can switch between the position-control mode and the position/velocity-control mode depending on the requirement of the task. Our new method is a unique noninvasive tool for the bedside evaluation of the condition of motor controllers in the CNS. Thus, it is useful for finding evidence of neurorehabilitation. PMID- 20192036 TI - [The association of age and tracer clearance determined radionuclide cisternography]. AB - We aimed to study tracer kinetics in radioisotope (RI) cisternography. For this purpose, we analyzed the RI images of 36 individuals in whom absence of cerebrospinal fluid (CSF) leakage was confirmed. For the semiquantitative assessment of tracer clearance, the geometric mean of the RI count in the anterior and posterior images was obtained for the entire head as well as for the whole spinal axis. After correcting for the radioactive decay of the tracer, tracer clearance was expressed as a ratio of the count in the range of the whole CSF space at different time points to that at the time of tracer delivery. Tracer clearance from the CSF space was not related to the degree of cranial transport of the tracer in 1 hour, but was significantly related with the age of the patients. At 24 hours after the injection, tracer clearance was significantly faster in the younger patients (Group I: age < 40 years) than in the older patients (Group II: age > or = 40 years). The cranial transport of the tracer appeared to be rapid in group I; however, the difference between these 2 groups was not significant. These results indicate that age should be taken in account while establishing the reference values for tracer kinetics in normal individuals. PMID- 20192037 TI - [A case of common femoral artery occlusion after homeostasis using device at carotid artery stenting]. AB - The hemostatic puncture closure device Angio-Seal is a quick and easy-to-use system, allowing rapid sealing of the vascular access site after interventional procedure. The rate of complications associated with the use of this device has been reported to be low; nonetheless, certain specific complications may arise. In the present study, we describe a case of vascular occlusion that occurred because of the use of the Angio-Seal device. A 59-year-old man with no sign of peripheral arterial occlusive disease underwent carotid artery stenting. The left common femoral artery was closed with the Angio-Seal device. After 7 days, the patient complained of intermittent claudication, especially while climbing up the stairs. Angiography of the left iliac artery at 2 months after carotid artery stenting revealed occlusion of the left common femoral artery. Deep and superficial femoral arteries were fed by the collateral flow from the muscle branch. Because the patient's symptom was mild and his daily life was not affected, he was treated conservatively. In conclusion, arterial closure performed using a hemostatic device is associated with a risk of vascular occlusion. PMID- 20192038 TI - [A case of unilateral thalamic and striatal lesions associated with deep venous thrombosis]. PMID- 20192039 TI - [One hundred books which built up neurology (38)--Charcot "Lecons du Mardi a la Salpetriere" (1887-1889)]. PMID- 20192040 TI - Nurses warn more single rooms may harm patients. PMID- 20192041 TI - Surgery waiting list targets remove choice and penalise services. PMID- 20192042 TI - Using ideas management to identify ways to improve care in the NHS and in organisations. AB - Nurses and midwives have been asked to implement eight high impact actions, announced by the chief nursing officer for England Dame Christine Beasley in November 2009. Here we describe the process of ideas management that led to the actions being selected for the final list, and suggest ways in which nurses can use this process to implement changes in practice. PMID- 20192043 TI - Implementing the eight high impact actions to transform healthcare and boost efficiency. AB - Nurses and midwives could improve care and save billions of pounds a year by implementing the eight high impact actions unveiled by the chief nursing officer for England Dame Christine Beasley in 2009. We explore how staff can implement the actions through leadership and knowledge of change management processes. PMID- 20192044 TI - The effect of patient positioning during lengthy surgery on postoperative health. PMID- 20192045 TI - How to ensure patient observations lead to effective management of tachycardia. AB - Tachycardia is a normal physiological response to exercise but in the healthcare setting it is considered to be an adverse sign, indicating possible serious illness such as shock. The condition can also be associated with a life threatening cardiac arrhythmia. This article aims to help nurses understand how to manage it. PMID- 20192046 TI - Apex and radial pulse: what are they and why is it necessary to measure both? PMID- 20192047 TI - How to use coaching and action learning to support mentors in the workplace. AB - Using the example of mentoring preregistration student nurses, this article explores facilitation of learning in the workplace and examines the use of coaching and action learning to support mentors and the wider clinical team. A case study, where a mentor has difficulties with an underperforming student, is considered. Action learning and coaching are then explored, with the aim of maximising personal and team learning. These strategies can be easily transferred to other work based learning situations. PMID- 20192048 TI - No one wins when they play the blame game. PMID- 20192049 TI - Do you have the emotional intelligence of a Muppet? PMID- 20192050 TI - A statistical segmentation method for measuring age-related macular degeneration in retinal fundus images. AB - Day by day, huge amount of information is collected in medical databases. These databases include quite interesting information that could be exploited in diagnosis of illnesses and medical treatment of patients. Classification of these data is getting harder as the databases are expanded. On the other hand, automated image analysis and processing is one of the most promising areas of computer vision used in medical diagnosis and treatment. In this context, retinal fundus images, offering very high resolutions that are sufficient for most of the clinical cases, provide many indications that could be exploited in diagnosing and screening retinal degenerations or diseases. Consequently, there is a strong demand in developing automated evaluation systems to utilize the information stored in the medical databases. This study proposes an automatic method for segmentation of ARMD in retinal fundus images. The method used in the automated system extracts lesions of the ARMD by employing a statistical method. In order to do this, the statistical segmentation method is first used to extract the healthy area of the macula that is more familiar and regular than the unhealthy parts. Here, characteristic images of the patterns of the macula are extracted and used to segment the healthy textures of an eye. In addition to this, blood vessels are also extracted and then classified as healthy regions. Finally, the inverse image of the segmented image is generated which determines the unhealthy regions of the macula. The performance of the method is examined on various quality retinal fundus images. Segmented images are also compared with consecutive images of the same patient to follow up the changes in the disease. PMID- 20192051 TI - Design and construction of a low cost dsPIC controller based repetitive transcranial magnetic stimulator (rTMS). AB - In this work, a digital signal peripheral interface controller (dsPIC) based repetitive transcranial magnetic stimulator (rTMS) was designed and tested under low voltages. In addition, some limited knowledge of TMS, especially design parameters and notions concerned with it, also were investigated. The reason employing the dsPIC in the design is that design parameters can effectively be controlled. Pulse width modulation and switching output of the control unit, which is necessary to control the rTMS device, were controlled in a more effective way. The other novelty is that developed system can be used for therapeutic or diagnostic purposes in future work provided by digital signal processing performance of dsPIC. Bounded-cylindrical in shape head model made from nonmagnetic material, was used during the tests of the system. Spectrum analyses of clicking sounds were performed with FFT by using MATLAB. The effectiveness of the designed system have been proved by its' measurement results compared with previous works. PMID- 20192052 TI - Web-based multi-center data management system for clinical neuroscience research. AB - Modern clinical research often involves multicenter studies, large and heterogeneous data flux, and intensive demands of collaboration, security and quality assurance. In the absence of commercial or academic management systems, we designed an open-source system to meet these requirements. Based on the Apache PHP-MySQL platform on a Linux server, the system allows multiple users to access the database from any location on the internet using a web browser, and requires no specialized computer skills. Multi-level security system is implemented to safeguard the protected health information and allow partial or full access to the data by individual or class privilege. The system stores and manipulates various types of data including images, scanned documents, laboratory data and clinical ratings. Built-in functionality allows for various search, quality control, analytic data operations, visit scheduling and visit reminders. This approach offers a solution to a growing need for management of large multi-center clinical studies. PMID- 20192054 TI - An optimization model for locating and sizing emergency medical service stations. AB - Emergency medical services (EMS) play a crucial role in the overall quality and performance of health services. The performance of these systems heavily depends on operational success of emergency services in which emergency vehicles, medical personnel and supporting equipment and facilities are the main resources. Optimally locating and sizing of such services is an important task to enhance the responsiveness and the utilization of limited resources. In this study, an integer optimization model is presented to decide locations and types of service stations, regions covered by these stations under service constraints in order to minimize the total cost of the overall system. The model can produce optimal solutions within a reasonable time for large cities having up to 130 districts or regions. This model is tested for the EMS system of Adana metropolitan area in Turkey. Case study and computational findings of the model are discussed in detail in the paper. PMID- 20192053 TI - Application of K- and fuzzy c-means for color segmentation of thermal infrared breast images. AB - Color segmentation of infrared thermal images is an important factor in detecting the tumor region. The cancerous tissue with angiogenesis and inflammation emits temperature pattern different from the healthy one. In this paper, two color segmentation techniques, K-means and fuzzy c-means for color segmentation of infrared (IR) breast images are modeled and compared. Using the K-means algorithm in Matlab, some empty clusters may appear in the results. Fuzzy c-means is preferred because the fuzzy nature of IR breast images helps the fuzzy c-means segmentation to provide more accurate results with no empty cluster. Since breasts with malignant tumors have higher temperature than healthy breasts and even breasts with benign tumors, in this study, we look for detecting the hottest regions of abnormal breasts which are the suspected regions. The effect of IR camera sensitivity on the number of clusters in segmentation is also investigated. When the camera is ultra sensitive the number of clusters being considered may be increased. PMID- 20192055 TI - Improving mental task classification by adding high frequency band information. AB - Features extracted from delta, theta, alpha, beta and gamma bands spanning low frequency range are commonly used to classify scalp-recorded electroencephalogram (EEG) for designing brain-computer interface (BCI) and higher frequencies are often neglected as noise. In this paper, we implemented an experimental validation to demonstrate that high frequency components could provide helpful information for improving the performance of the mental task based BCI. Electromyography (EMG) and electrooculography (EOG) artifacts were removed by using blind source separation (BSS) techniques. Frequency band powers and asymmetry ratios from the high frequency band (40-100 Hz) together with those from the lower frequency bands were used to represent EEG features. Finally, Fisher discriminant analysis (FDA) combining with Mahalanobis distance were used as the classifier. In this study, four types of classifications were performed using EEG signals recorded from four subjects during five mental tasks. We obtained significantly higher classification accuracy by adding the high frequency band features compared to using the low frequency bands alone, which demonstrated that the information in high frequency components from scalp recorded EEG is valuable for the mental task based BCI. PMID- 20192056 TI - Optimal resource allocation model to mitigate the impact of pandemic influenza: a case study for Turkey. AB - Pandemic influenza has been considered as a serious international health risk by many health authorities in the world. In mitigating pandemic influenza, effective allocation of limited health resources also plays a critical role along with effective use of medical prevention and treatment procedures. A national resource allocation program for prevention and treatment must be supported with the right allocation decisions for all regions and population risk groups. In this study, we develop a multi-objective mathematical programming model for optimal resource allocation decisions in a country where a serious risk of pandemic influenza may exist. These resources include monetary budget for antivirals and preventive vaccinations, intensive care unit (ICU) beds, ventilators, and non-intensive care unit (non-ICU) beds. The mathematical model has three objectives: minimization of number of deaths, number of cases and total morbidity days during a pandemic influenza. This model can be used as a decision support tool by decision makers to assess the impact of different scenarios such as attack rates, hospitalization and death ratios. These factors are found to be very influential on the allocation of the total budget among preventive vaccination, antiviral treatment and fixed resources. The data set collected from various sources for Turkey is used and analyzed in detail as a case study. PMID- 20192057 TI - Novel approach to fuzzy-wavelet ECG signal analysis for a mobile device. AB - This paper describes a signal processing technique for ECG signal analysis based upon the combination of wavelet analysis and fuzzy c-means clustering. The signal analysis technique is implemented into a biomedical signal diagnostic unit that is the carry on device for the Wireless Nano-Bios Diagnostic System (WNBDS) developed at National Taiwan University. The WNBDS integrates mobile devices and remote data base servers to conduct online monitoring and remote healthcare applications. The signal analysis and diagnostic algorithms in this paper are implemented in an embedded mobile device to conduct mobile biomedical signal diagnostics. At this stage, the Electrocardiogram (ECG or EKG) is analyzed for patient health monitoring. The ECG signal processing is based on the wavelet analysis, and the diagnosis is based on fuzzy clustering. The embedded system is realized with the Windows CE operating system. PMID- 20192058 TI - Determination of sleep stage separation ability of features extracted from EEG signals using principle component analysis. AB - In this study, a method was proposed in order to determine how well features extracted from the EEG signals for the purpose of sleep stage classification separate the sleep stages. The proposed method is based on the principle component analysis known also as the Karhunen-Loeve transform. Features frequently used in the sleep stage classification studies were divided into three main groups: (i) time-domain features, (ii) frequency-domain features, and (iii) hybrid features. That how well features in each group separate the sleep stages was determined by performing extensive simulations and it was seen that the results obtained are in agreement with those available in the literature. Considering the fact that sleep stage classification algorithms consist of two steps, namely feature extraction and classification, it will be possible to tell a priori whether the classification step will provide successful results or not without carrying out its realization thanks to the proposed method. PMID- 20192059 TI - Comparison of wavelet and short time Fourier transform methods in the analysis of EMG signals. AB - The electromyographic (EMG) signal observed at the surface of the skin is the sum of thousands of small potentials generated in the muscle fiber. There are many approaches to analyzing EMG signals with spectral techniques. In this study, the short time Fourier Transform (STFT) and wavelet transform (WT) were applied to EMG signals and coefficients were obtained. In these studies, MATLAB 7.01 program was used. According to obtained results, it was determined that WT is more useful than STFT in the fields of eliminating of resolution problem and providing of changeable resolution during analyze. PMID- 20192060 TI - Impact of the Japanese diagnosis procedure combination-based payment system in Japan. AB - In the health insurance system of Japan, a fee-for-service system has been applied to individual treatment services since 1958. This system involves a structural problem of causing an increase in examination and drug administration. A flat-fee payment system called DPC was introduced in April 2003 to solve the problems of the fee-for-service system. Based on the data of 2003 and 2004, we assessed the impact of DPC in Japan, and obtained the following conclusions: First, the introduction of DPC in Japan could not decrease the absolute value of medical costs; second, the internal efficiency of the institutions was improved, for example, by reducing the mean length of hospitalizations; third, the DPC based diagnosis classification is considered to be effective for simplifying the medical fee system within the framework of EBM and for providing patients with information; and fourth, after introduction of the DPC, structural problems remain in the flat-fee payment system, such as examination and treatment of low quality, selection of patients and up coding. Its introduction should thus be performed with sufficient caution. We will make greater efforts to establish a better medical fee system by evaluating these problems. PMID- 20192062 TI - Are uninsured traumas at a greater risk? AB - While a new study indicating that uninsured trauma patients are at greater risk of mortality did not point a finger at EDs, experts say there are proactive steps ED managers can take that will help reduced the risk for these patients: Keep your eyes and ears open for any evidence of bias--where people express concerns about whether patients can pay for treatments. If a patient is on one or more medications, ask where they get the meds filled. With the patient's permission, call the pharmacy and get a list of all the meds he or she is taking. If language assistance is needed, ensure it's given. PMID- 20192061 TI - Preparations enable children's EDs to effectively handle H1N1 surge. AB - Tabletop exercises can be an effective strategy preparing for situations that involve numerous hospital departments, such as a pandemic surge. Here are some highlights of the successful tabletop exercises used by the Minneapolis and St. Paul EDs of Children's Hospitals and Clinics of Minnesota to prepare for last fall's H1N1 outbreak. Every unit that interfaces with the ED was involved in the discussions. Participants were given "homework assignments" to outline their role in the overall response process. Department heads made in-person visits to overflow spaces to ensure they had adequate resources should they be required to accommodate patients. PMID- 20192064 TI - Referral program ensures follow-up. PMID- 20192063 TI - Grant helps ED refer patients to health center. AB - With the help of a $2 million grant from the Centers for Medicare & Medicaid Services, the ED at Monmouth (NJ) Medical Center, and the Monmouth Family Health Center have created a referral system that had lightened the burden for the ED and found many more patients a health care "home." Whereas in the past, length of stay (LOS) for those patients who went to the fast track has been as high as 90 minutes, the LOS for these patients has been under 70 minutes. A shared computer system enables the ED to access the center's schedule and arrange for follow-up visits. The ED added 12 hours a day of advanced practice nurses during the busiest hours of the day to treat and refer uninsured patients. A primary care type conditions list is used during triage to help identify referral prospects. PMID- 20192065 TI - 'Split flow' slashes statistics for LWT, LOS. AB - A "split flow" program in the ED at Baptist Medical Center in San Antonio not only has slashed the left-without-treatment (LWT) rate from a high of 9.5% in spring 2009 to 2.2% at present, but it dramatically has improved patient satisfaction rates as well. An Emergency Severity Index (ESI) score determines which of the two areas is most appropriate for the patient. The "intake" area has an additional physician assistant or nurse practitioner for the 12 peak hours of each day. There is always a tech in triage in the event the nurse is required to leave the area. PMID- 20192066 TI - ED was well prepared for no-diversion law. AB - When the state legislature gives you four-months' notice of passage of a no diversion law, it's impossible to get ready in time, unless you've been working for several years on improving flow in your ED. The new triage process at Massachusetts General Hospital hit its stride just in time, and other departments made changes as well. The new triage process includes having an attending out front 12 hours a day, a resident in screening eight to 10 hours a day, and a nurse practitioner working 12 hours a day. A satellite lab operates in the ED on a 24/7 basis. A radiology attending is provided to the ED on a round-the-clock basis. PMID- 20192067 TI - [NK cells, chemokines and chemokine receptors]. AB - NK cells are an important component of natural immunity, which provides a defence response against viruses, bacterial and parasitic intracellular pathogens and tumour cells. NK cells are capable of rapid responses without prior sensitization and cytotoxic response is independent of the presence of the antigens of the major histocompatibility system. NK cells produce a number of cytokines (e.g. INF gamma, GM-CSF and TNF-beta) and chemokines and in this way they regulate both the natural and acquired immune response. By contrast, NK cells are regulated both positively and negatively by cytokines and chemokines produced by other immune cells. Attention is focused on the possibility of influencing the tumour process by using cytokine- and chemokine-activated NK cells. In studies in mice models as well as in several clinical trials, it has been shown that the presence of cytotoxic cells in tumour stroma is associated with a more favourable prognosis of cancer.There is also plenty of evidence that in tumour stroma a number of cytokines and chemokines are produced which may have ambivalent effects. PMID- 20192068 TI - [New views of modern medicine regarding treatment with stem cells, its practical and ethical consequences]. AB - Embryonic stem (ES) cells recently became the Holy Grail for the treatment of multiple diseases including cancer. A recent discovery of Israeli scientists however shows that ES cells can also become one of the causes triggering cancer. They base this hypothesis on a case of an Israeli boy suffering from Ataxia teleangiectasia, who developed cancer 4 years after ES transplantation. DNA analysis of the tumors showed that the malignant cells originated from the transplanted ES cells of the donors and not from the recipient's own cells. Given the fact that the therapeutic application of ES cells is still in the beginning, it is therefore necessary to thoroughly verify and test all the risks of their potential therapeutic use. This article also discusses in detail ethical and other aspects of ES cells applications, in particular the differences in points of view between Christianity and Judaism. Israeli Health to address these issues draws on traditional Judaism. Judaism defines an individual as a man if he cans a separate existence, in comparison with the human embryo, which is still directly dependent on his or her mother. Therefore, in matters of saving lives, including treatment options for improving the living, treatment with ES cells is tolerated Judaism as a clear preference for live and self-sustaining individual, before a cluster of cells. On the other hand, it is clear that all these therapies must have their basic rules and ethical reasons. In Israel, research on ESC and allowed it to those obtained in the course of unsuccessful fertility treatment by artificial insemination. PMID- 20192069 TI - [Angiogenesis as part of the tumor "ecosystem" and possibilities to influence it]. AB - Angiogenesis is a complex process which is critical for the growth, invasion and metastasis of tumors. In the past ten years numerous new agents have been developed as angiogenesis inhibitors. In the review, angiogenesis inhibitors are classified by their targeted area of the angiogenic process. The role of VEGF and its receptors is described in detail, but other antiangiogenic strategies such as inhibition of endothelial proliferation, inhibition of matrix metalloproteinases and use of vascular disrupting agents are also reviewed. PMID- 20192070 TI - [Very small breast cancer, HER2 positive, and trastuzumab in adjuvant treatment]. AB - Breast cancer patients with a tumor size of < or = 1 cm are still rare but their number is increasing as a consequence of mammary screening. It is logical that the best adjuvant treatment in such cancers is often discussed with respect to the risk of relapse of the disease. The number of patients in clinical trials with very small breast cancer is quite low, and a specific clinical trial for such patients is not planned. Retrospective analysis of some clinical trials which included patients with breast cancer and with very small size shows the worse prognosis of patients with HER2 positive tumors. Indirectly, we can assume the application of adjuvant treatment with trastuzumab in such very small breast cancer. However, the decision should be individual with regards to further risk factors for the disease and risk of the treatment itself. This article is more a contemplation in order to provoke discussion on this provocative subject. PMID- 20192071 TI - [Demonstration of the effect of estrogen and progesterone receptors on survival in breast cancer without cytostatic and hormonal treatment in a small set of patients]. AB - BACKGROUND: With respect to diagnostic and therapeutic progress, it may occur that the statistical sets of patients evaluated and treated with uniform methods are small. As a consequence, it is meaningful to check a greater number of statistical approaches. It is suitable to verify whether, for instance, the differences between the results (+) and (++) for estrogen and progesterone receptors (ER and PR) in breast cancer have an effect on the length of survival. This question could be answered with the use of several Kaplan-Meier survival curves. However, it is also profitable to judge the simple graph of survival in dependence on receptor concentration. Nevertheless, traditional regression brings too great an error to this method of assessment. Therefore, the use of orthogonal regression is much more precise. Since it can be assumed that no non-revealable micro-metastases were present at the time of operation in some patients with N0, it is possible to achieve healing ad integrum of them using only simple surgery. Consequently, we concluded that it was necessary to exclude from the evaluation the group of patients in N0 surviving 10 years (in the search for evidence of the post-operative impact of age-based reduction of blood estrogen on survival). DESIGN AND SUBJECTS: We verified these considerations when monitoring the ER and PR influence on overall survival. We performed this analysis in an approximately 2-year sample of 74 female patients who received the described treatment in Pardubice hospital. At the time of operation, 56 were postmenopausal and 21 of these postmenopausal patients were in stage N1. METHODS AND RESULTS: ER and PR in breast tumours were examined in the cytosol of operational biopsies. Adjuvant radiological treatment was used in addition to the surgical treatment of primary tumours and their original and post-operative metastases. In the case of premenopausal patients with ER, (+) therapeutic sterilization was performed. The finding of higher ER in postmenopausal surviving patients (in comparison to dead ones) was below the boundary of statistical significance. Also, longer survival in cases of higher ER concentrations in the group of dead N1 patients was below the boundary of statistical significance in the use of traditional regression. Therefore, we put together evidence from the group of surviving patients with evidence from the group of dead patients. In the case of N1 patients surviving 10 years, we rounded their survival period to 15 years for inclusion in the graph of survival dependence on ER. In the case of the combined (premenopausal with postmenopausal) group, statistical reliability appeared for longer survival of higher ER already in traditional regression. However, for the postmenopausal alone, the difference was statistically insignificant. Nevertheless, if we used orthogonal regression (similar to Deming regression) instead of traditional regression, then the reliability of the dependence of the length of survival on ER increased (in the last cited graph) to such a degree that it was statistically highly significant (at the level of 0.001) even in case of just postmenopausal patients. The same level of statistical reliability was achieved in the Kaplan Meier analysis. Also in the case of PR--the higher concentrations of this receptor in survivors compared to dead patients were not statistically significant. But (in contrast to ER) in the case of PR, we observed a statistically significant increase in survival time depending on the receptor concentration within the group of only the dead patients--hence without putting them together with the surviving patients). CONCLUSIONS: The graph of the Kaplan Meier analysis is more frequently used when solving these problems but the graph of simple dependence of survival on receptor concentration should not be neglected either because, for example, it better shows the difference in survival between ER(+) and (++). Nevertheless, it is necessary to use orthogonal regression in it. The greater suitability of PR and ER for short-term and long term prognosis, respectively, which we identified in our statistical set, is in concordance with the literature. PMID- 20192072 TI - Long-term outcome of treatment for Hodgkin's disease: the University Hospital Sofia experience. AB - BACKGROUND: To establish the efficacy of the combined modality treatment (CMT) including curative extended field radiotherapy (EFRT) and chemotherapy (CHT) by examining the long-term outcome in Hodgkin's disease (HD) patients at the Sofia University Hospital "Queen Giovanna-ISUL", with particular focus on second primary malignancy (SPM), and to establish independent factors correlated with treatment outcome. METHODS AND MATERIALS: Between 1982 and 2007, 170 patients with HD with median age of 12 years (range 3-40), (68 females, 102 males), were included in this retrospective study. The clinical stage (CS) distribution was CS I in 1 patient (0.6%), CS II in 86 (50.5%), CS III in 77 (45.3%) and CS IV in 6 (3.5%) patients. Histologic subtypes included lymphocyte predominance 7.6%, mixed cellularity 47.1%, nodular sclerosis 42.9% and lymphocyte depletion 0.6%. B symptoms were observed in 57.6% of the patients, hepatosplenomegaly--in 30.6%, anemia--in 27.1% and elevated serum lactat dehydrogenase (LDH)--in 41.2%. The overall treatment consisted of both EFRT and CHT. In 115 patients (67%) supradiaphragmatic irradiation of lymphatic nodes was carried out, in 3 (2%) patients subdiaphragmatic irradiation was performed and in 52 (31%)--irradiation of the supra- and infra-diaphragmatic lymph nodes basically by subtotal 35 (20.6%), and total lymphoid irradiation--in 4 (2.4%) patients. The daily dose was 1.5-2 Gy, the total dose for EFRT was 20-40 Gy. From the analyzed 170 patients 150 were assessable for long-term outcome and 120 for SPM analyses. RESULTS: Follow-up extended from a minimum of 0,3 years to maximum 25,7 years, with a median observation time 12 years.The 5-, 10-, 15-, and 25-year overall survival (OS) in the whole group was 93% : 86% : 82% : 82%, respectively. A tendency for better survival was found for patients with age < or = 15 than for those with > 15 years, with 5-, 10-, and 15- year OS of 95% : 87% : 84% vs 84% : 84% : 56%, p = 0.09. There was a trend for better survival in males compared with females with 5-, 10- and 15-year OS of 96%: 93%: 91% vs 88% : 73% : 65%, p = 0.001. The OS difference between CS IIB and IIIA turned out to be significant in favor of the patients in CS IIIA with 5- and 10-year OS of 89%: 76% vs 95%: 90%, respectively, p = 0.03. The following factors were analyzed for their prognostic influence: age, gender, stage, histologic subtype at first diagnosis, sites of involvement, number of involved lymph node areas, B symptoms, hepatosplenomegaly, anemia, elevated serum LDH, daily dose, total dose, boost and technique used in EFRT. In univariate analysis, independent risk factors were gender (p < 0.001), stage (IIB: IIIA) (p = 0.03), mediastinal involvement (p = 0.03), daily dose (p = 0.01) and total dose (p = 0.02). In multivariate analysis, independent risk factors age < or = 15 years (p < 0.001), male gender (p = 0.005), daily dose < or = 1.5 Gy (p = 0.009), and total dose 26-30 Gy (p = 0.048) were found to positively affect OS. We investigated a prognostic model, identifying groups of HD patients with particularly responsive disease, combining prognostic factors as age < or = 15 years (p = 0.001), male gender (p = 0.011), and total dose 26-30 Gy (p = 0.012). In the observed 25-year period SPM development was not established in any of the 120 patients subjected to follow-up. CONCLUSION: The performed first Bulgarian study on CMT including EFRT and CHT exhibited a certain therapeutic potential in the treatment of HD patients, expressed in the achievement of high long term outcome and low SPM frequency. PMID- 20192073 TI - Small-cell carcinoma of the ovary with breast metastases: a case report. AB - BACKGROUNDS: Small cell carcinoma (SCC) is characterised by high metastatic potential and the possibility to metastasize to practically any tissue. Small cell carcinoma of the ovary (SCCO) has a very poor prognosis and patients usually die within one year of the initial diagnosis. Breast metastases from SCCO are extremely rare. CASE: We present a 67-year-old female patient with SCCO who initially presented with bone and bilateral breast metastases. Considering the clinical presentation, the patient's age, the absence of hypercalcemia and histological characteristics, a diagnosis of pulmonary type SCCO was made. There was no tumour present in the lungs at the time of the initial diagnosis and thus we ruled out pulmonary SCC. RESULTS: Initially, the patient was treated with radiotherapy of the bone lesion and systemic chemotherapy (etoposide with carboplatin) with the result of partial remission. Then, radical abdominal surgery was performed. Six months later she was diagnosed with progressive disease in the bone, soft tissue including the breast as well as new lesions in the right kidney, pelvis and lungs. She was treated with 2nd line chemotherapy (topotecan with cisplatin) with the result of progressive disease. Because of mediastinal lymphadenopathy, which was causing tracheobronchial compression, radiotherapy was administered with a good palliative outcome. Nine months later, multiple brain metastases were diagnosed and she was treated with whole brain radiotherapy. Shortly after brain irradiation, her status deteriorated rapidly and she died two years after her initial SCCO diagnosis. CONCLUSION: Extrapulmonary small cell carcinoma is a clinicopathological entity distinct from pulmonary small cell carcinoma. It is very rare and therefore there is very little information available regarding treatment of this disease. In contrast to experience in the treatment of pulmonary small cell cancers, prolonged survival is not common. PMID- 20192074 TI - [Long-term response of liver metastases of breast cancer to capecitabine--case report]. AB - A case report of a patient with HER2-positive liver metastases of breast cancer. Partial regression was reached during chemotherapy, which was further stabilized by trastuzumab. Resection of the metastases was performed after progression. Capecitabine was started after the occurrence of new multiple lesions; complete regression was reached, which has now lasted over three years with continued capecitabine treatment. PMID- 20192075 TI - [Bevacizumab administered along with chemotherapy results in an improvement in the overall survival in women with advanced breast cancer]. PMID- 20192077 TI - ZPICs are the next, most aggressive layer of the CMS audit process. PMID- 20192076 TI - [AVASTIN clinical registry]. PMID- 20192078 TI - Hospital and SNFs collaborate on transitions. PMID- 20192079 TI - Nonadherent patients may not understand. PMID- 20192081 TI - Hospital provides DM to employee groups. PMID- 20192080 TI - Communication ensures patients are safe post-discharge. PMID- 20192082 TI - Revamped documentation program raises CMI. PMID- 20192083 TI - ED decreases 4-hour wait times to 9 minutes. PMID- 20192084 TI - The states go marching in. With an impasse in Washington, some states are taking sides in the reform debate. AB - With reform apparently sitting on the back burner in Washington, some states are cooking up their own healthcare policies-some of which are designed to slice and dice any federal initiatives. "We're different from Washington, D.C.," said Mark Leno, a state senator for California. "There, Congress has the final word. In California, the voters have the final word". PMID- 20192085 TI - Radiation gets extreme close-up. But uncertainty surrounds viability of FDA's initiative to reduce exposure. PMID- 20192086 TI - Getting them onboard. Tort reform, Medicare pay fix will draw patients, doctors to support reform. PMID- 20192087 TI - Melting pot management. Treat diversity at the workplace as boon, not bane. PMID- 20192089 TI - Affairs of the heart. PMID- 20192088 TI - How do they measure up? Quality-reporting efforts advance but still uneven. PMID- 20192090 TI - Surgical care practitioners...why? PMID- 20192091 TI - Fractures of the wrist and hand. PMID- 20192092 TI - Tourniquet failure during total knee replacement due to arterial calcification: case report and review of the literature. AB - Use of a tourniquet for performing surgery in order to create a bloodless surgical field and reduce blood loss has been in use for many years. Tourniquets may fail perioperatively for various reasons, leading to ongoing bleeding. An important cause of tourniquet failure is calcification of the underlying artery. A patient undergoing total knee replacement surgery in whom the tourniquet failed, secondary to femoral artery calcification is reported. The implications of tourniquet use in patients with arterial calcification, including acute distal ischaemia, aneurysm formation and vessel fracture will be discussed. Recommendations include: thorough vascular assessment of all patients preoperatively, awareness of the possibility of tourniquet failure particularly in vasculopaths, and the provision of an alternative perioperative management plan such as use of a cell saver device, should the tourniquet fail. PMID- 20192093 TI - Pain management in recovery. AB - Recovery room practitioners lay the corner stone for postoperative recuperation in patients undergoing surgical procedures. This article highlights how some aspects of the role, such as pain assessment, commencement of the prescribed analgesic regimen and pain control can be very challenging, for a variety of reasons. The aim, therefore, is to follow a typical patient journey in a structured manner, beginning with a demonstration of how provision of information empowers patients during the key phase of postoperative recovery. This is followed by a description of some assessment tools best suited to patients recovering from anaesthesia who are experiencing acute, postoperative pain. Consequences of under-treated pain are discussed and treatment modalities are described. PMID- 20192094 TI - The monitoring of heparin induced thrombocytopenia following surgery: an audit and international survey. AB - Heparin-induced thrombocytopenia (HIT) is a serious postoperative complication of low-molecular-weight heparin (LWMH) prescribed following surgery and recent evidence based guidelines recommend routine platelet count monitoring for all at risk patients. With the implementation of these guidelines this clinical study demonstrated a significant improvement (2-56% p < 0.05) in HIT diagnosis in postoperative patients receiving LMWH. An international survey showed a lack of awareness of heparin-induced thrombocytopenia and its management. PMID- 20192095 TI - Perioperative care planning for a Down's syndrome patient. PMID- 20192096 TI - The early days of cardiac surgery. PMID- 20192097 TI - Advancing nursing science in tobacco control. Preface. PMID- 20192098 TI - Why nursing research in tobacco control? AB - Tobacco use is an epidemic of overwhelming proportions affecting survival, causing millions of deaths every year, causing untold human suffering worldwide, and contributing to escalating health care costs. Nursing research is vital to advancing knowledge in the field and to the translation of science to evidence based practice. As the largest group of health care professionals (17 million worldwide), nurses have the capacity for an enormous impact on this leading cause of preventable death. This chapter thus provides a historical overview of the tobacco epidemic, health risks of smoking and benefits of quitting, nicotine addiction, and recommendations of evidence-based tobacco dependence treatment as a backdrop for understanding the importance and need for nursing scholarship. Also examined are nursing science efforts and leadership in removing two barriers to mounting programs of nursing research in tobacco control: (1) lack of nursing education and training in tobacco control, and (2) limited research funding and mentorship. The chapter also addresses the issue of smoking in the profession as it impacts nurses' health, clinical practice, and, potentially, scholarship efforts. PMID- 20192099 TI - Theories used in nursing research on smoking cessation. AB - Theories tell how and why things work; how and why one variable is related to another. Research findings that are theory based can be placed in a framework that advances science further than findings that are unconnected to formal theory. However, much of the research in smoking cessation is atheoretical. This review of nursing research on smoking cessation published from 1989 through 2008 revealed that nearly half of the studies were based on explicit formal theories. The transtheoretical model and self-efficacy theory were the most frequently used explicit theories with most theories emanating from psychology. Five nursing theories were identified in this review. Studies that used implicit rather than explicit theories dealt with five major concepts: nicotine dependence, social support, high-risk situations, mood-affect, and the influence of clinical diagnosis. Largely missing from this set of studies were investigations based on biobehavioral models, including genetics and neuroscience. The relevance of the theories and concepts identified in this review to current clinical guidelines on smoking cessation is discussed. With their grounding in theory and their expert knowledge of clinical issues, nurses are in an excellent position to develop theories that will help researchers in every discipline make sense of smoking cessation. PMID- 20192100 TI - The social and political context of the tobacco epidemic: nursing research and scholarship on the tobacco industry. AB - Context matters in addressing tobacco as a global nursing issue. The tobacco epidemic and its resulting health consequences are in great measure the result of industrial decisions over the past century that included deliberately enhancing the addictiveness of cigarettes, marketing them aggressively to vulnerable groups, hiding or manipulating knowledge about the products' harmfulness, and undermining public health efforts. The efforts of the tobacco industry to perpetuate the idea that smoking is solely a problem of individual behavior, or even a "right," still creates barriers to understanding the larger social and political context within which individuals use and attempt to quit tobacco. Nurses have been among the researchers worldwide who are studying tobacco industry activities and their role in policy and public health. This chapter reviews data sources, methods, and analytic approaches for conducting research using documents from the tobacco industry, and provides an overview of research conducted by nurses on this topic. Much of the nursing research to date on the tobacco industry focuses in four broad areas: (1) tobacco industry influence on policy; (2) tobacco industry strategic responses to public health efforts, including use of front groups and attempts to divide and conquer public health advocates; (3) tobacco industry targeting of marginalized groups; and (4) tobacco industry influence on science. Implications of this work for nursing practice, research, and policy intervention are discussed. PMID- 20192101 TI - Monitoring the tobacco epidemic with national, regional, and international databases and systematic reviews: evidence for nursing research and clinical decision making. AB - Tobacco use (primarily cigarette smoking) continues to be the most preventable health risk in the United States and the second greatest health threat around the world. In 2020 the global burden is expected to exceed nine million deaths annually. Nursing, with the largest numbers of health care professionals has an opportunity to make a significant reduction in tobacco use through its research and client-focused care. This chapter addresses why and how monitoring the tobacco epidemic with population-based databases and meta-analyses is important for nurse researchers and for evidence-based nursing practice. Population-based surveys permit an examination of trends in tobacco use and the progress in tobacco control with some confidence across time, places (i.e., states, nations, communities, etc.), and large numbers of participants. Included in this review are a description of the numerous national and international databases and other resources that nurse researchers can use to build the science of tobacco use. Additionally, research reviews and meta-analyses are described as other vehicles for providing a basis for making evidence-based decisions about nursing intervention. Nurse scientists have an obligation to use and evaluate these diverse resources to determine the gaps in knowledge, provide a foundation for clinical practice, and identify the needs and directions for future research in the field. PMID- 20192102 TI - Nurses' use of qualitative research approaches to investigate tobacco use and control. AB - Qualitative research methods are increasingly used by nurse scientists to explore a wide variety of topics relevant to practice and/or health policy issues. The purpose of this chapter is to review the contributions of nurse scientists to the field of tobacco control through the use of qualitative research methods. A systematic literature search strategy was used to identify 51 articles published between 1980 and 2008. The majority (84%) of reviewed articles were authored by North American nurse scientists. Cessation was the most commonly (85%) studied aspect of tobacco control. Six qualitative research approaches were used: qualitative descriptive (55%), narrative analysis (8%), phenomenology (6%), grounded theory (14%), ethnography (12%), and case study (6%). Qualitative descriptive methods were primarily one-off studies to address practical problems or issues encountered in practice, and often validated current understandings related to tobacco. Researchers who used other types of qualitative methods and who conducted qualitative studies as part of programs of research were more likely to make more substantive contributions to the evolving field of tobacco control. These contributions related to how smoking intertwines with personal and social identities, the influence of social context on tobacco use, and nurses' involvement in tobacco control (both of their own tobacco use and in assisting others). Nurse scientists interested in exploring tobacco-related issues are encouraged to consider the full range of qualitative research approaches. Qualitative research methods contribute to our understanding of tobacco use arising from nursing practice, health care and policy, along with the field of tobacco control in general. PMID- 20192103 TI - Biological models for studying and assessing tobacco use. AB - The purpose of this chapter on biological models for studying and assessing tobacco use is to provide an introduction to some of the common concepts and biomarkers in this arena to ultimately inform intervention research by nurse scientists. An overview of selected biomarkers of tobacco exposure in individuals includes exhaled carbon monoxide, cotinine (the proximate metabolite of nicotine), and measurement of an individual's puffing pattern termed smoking topography. Common tobacco contents discussed include tobacco specific nitrosamines (TSNA) and polycyclic aromatic hydrocarbons (PAH) some of which increase disease risk including cancer. Exemplars of additives to cigarettes by the tobacco industry will be described including menthol, one additive marketed by the industry. Genetics and tobacco addiction has emerged as a rapidly expanding field. Illustrative of this area are twin studies, nicotinic receptors, CYP2A6 polymorphisms, and genes that impact dopamine receptors. The cadre of nurse scientists conducting research in this much needed area is small. The opportunity for nurse scientists educated in biological inquiry in tobacco related research is great. Nurse scientists actively involved in multidisciplinary translational teams to address nicotine addition are needed. PMID- 20192104 TI - Primary and secondary tobacco prevention in youth. AB - The childhood years represent a critical time for tobacco experimentation and addiction. This chapter presents risk factors for youth smoking, state of the science of nurse-led primary and secondary tobacco prevention research in youth, and implications for future research, policy, and practice. Nursing research on both primary and secondary tobacco prevention efforts that are school-based, family-based, and community-based are presented. Interventions, including both state and community approaches, and media and policy endeavors to prevent tobacco use and foster successful cessation are discussed. The nursing profession has made an impact on primary and secondary prevention in youth regarding tobacco; however, much remains to be accomplished. As one of the largest health care professions, nurses should seize the important opportunity of positively impacting the health of children and youth through comprehensive and effective primary and secondary tobacco prevention efforts. PMID- 20192105 TI - Two decades of nurse-led research on smoking during pregnancy and postpartum: concept development to intervention trials. AB - Tobacco use during pregnancy and postpartum is a leading cause of preventable morbidities for women and their infants. Over the past two decades, nursing research has addressed this recalcitrant clinical problem from a variety of conceptual and methodological perspectives. The 64 published studies (1988-2009) that met inclusion criteria for this systematic review represent the full research trajectory from concept development to intervention testing. Meta analysis demonstrated an overall significant trend in nursing intervention efficacy (OR = 1.14, 95% CI = 1.08-1.2) for studies that examined comparable prenatal and postpartum smoking cessation outcomes. Implications for future nursing research and evidence-based policy are presented. PMID- 20192106 TI - Nursing interventions in tobacco-dependent patients with cardiovascular diseases. AB - Smoking is a well-established risk factor for cardiovascular disease (CVD). This chapter provides an overview of a program of nursing research relevant to tobacco use in patients with CVD. The Women's Initiative for Nonsmoking (WINS) provides a rich demonstration of a key randomized clinical trial (RCT) on the efficacy of smoking cessation in women. The National Institutes of Health priority for data mining of existing RCTs is demonstrated in the numerous presentations of findings from secondary papers from WINS that answer additional research questions relevant to smoking cessation, including the influence of depression on smoking, myths about and underuse of nicotine replacement therapy. The methodological and logistical challenges inherent in tobacco intervention studies are presented, including a discussion of research needed in the measurement of withdrawal symptoms. Additionally, the role and contributions of nurses serving on the federal guideline development process are highlighted. International research activities of the coauthors from Jordan and Korea are also presented, including a discussion of the need for research in waterpipe use. PMID- 20192108 TI - Evidence-based smoking cessation interventions for patients with acute respiratory disorders. AB - Worldwide, tobacco use continues to be the most significant preventable cause of death and hospital admissions, particularly related to respiratory diseases. Acute respiratory illnesses requiring hospitalization provide an opportunity for nurses to intervene and help smokers quit. Of the three top hospital admissions related to respiratory diseases, chronic obstructive pulmonary disease (COPD) is the one that continues to have increased mortality whereas community acquired pneumonia and asthma have decreased over the past 5 years. The course of all three can be caused or exacerbated by continued smoking. This review describes the state of the science of nursing research focused on tobacco cessation interventions for hospitalized patients with COPD, asthma, or community acquired pneumonia. Additionally, we describe two evidence-based, nurse-driven, hospital protocols to treat tobacco dependence that can serve as models of care. Recommendations are made as to how to effectively promote nursing interventions for tobacco cessation in the acute care setting. PMID- 20192107 TI - Smoking cessation interventions in cancer care: opportunities for oncology nurses and nurse scientists. AB - Smoking cessation is essential after the diagnosis of cancer to improve clinical outcomes. The purpose of this chapter is to provide a systematic review of research on smoking cessation in the context of cancer care with an emphasis on nursing contributions to the field. Data sources included research reports of smoking cessation interventions conducted in people with cancer. Nineteen primary studies were reviewed. High intensity interventions, targeting multiple behaviors, and/or using a multicomponent intervention that included pharmacotherapy, behavioral counseling, and social support were characteristics of the most successful treatments for tobacco dependence. The majority of interventions were conducted in adults with smoking-related malignancies during acute phases of illness. The most striking finding was that more than one half of the studies tested the efficacy of nurse-delivered interventions. Conceptual and methodological issues that can be improved in future studies include: using theoretical frameworks to specify how the intervention will affect outcomes, ensuring adequate sample sizes, using biochemical verification to monitor smoking outcomes, and using standardized outcome measures of abstinence. Although effective interventions are available for healthy populations, further research is needed to determine if tailored cessation interventions are needed for patients with cancer. To provide optimal quality care it is imperative that delivery of evidence-based smoking cessation interventions be integrated into the cancer treatment trajectory. Multiple barriers, including patient and nurse attitudes toward smoking and lack of knowledge related to tobacco treatment, prevent translating evidence-based tobacco dependence treatment into clinical practice. Further nursing research is needed to address these barriers. PMID- 20192109 TI - A review of research by nurses regarding tobacco dependence and mental health. AB - The prevalence of tobacco use and dependence among those with psychiatric and/or substance use disorders is exceptionally high, contributing to significant morbidity and mortality. The purpose of this review is to discuss the findings conducted by nurses regarding smoking and mental health. A search of the available literature since 1950 resulted in a review of 17 studies authored or coauthored by nurses. Most study designs were descriptive with only one investigator reporting the results of a small clinical trial. In addition to documenting smoking patterns in this population, investigators found that many psychiatric nurses assessed their clients for tobacco use and advised them to stop smoking but few intervened intensively to aid cessation. Psychiatric nurses reported low efficacy for delivering interventions and considerable doubt about their clients' abilities and motivation to stop smoking. Although some desired additional training in tobacco dependence interventions, nurses reported feeling ethically conflicted about, and were inconsistently supportive of, system level interventions such as tobacco free health care settings. It is likely that these findings, as well as the paucity of tobacco dependence studies, reflect the relatively small number of psychiatric nurses conducting research as well as the inattention, until recently, of mental health leaders, policy makers, and funders to the importance of tobacco dependence research in this clinical population. As tobacco dependence treatment for those with mental illnesses and/or addictive disorders becomes more of a public health priority, opportunities abound for nurse researchers to contribute to the growing evidence in this often neglected area. PMID- 20192110 TI - Nursing research in tobacco use and special populations. AB - Smoking is responsible for approximately one in five deaths in the United States per year. The Surgeon General's 1964 report first linked smoking as a cause of cancer. Since then cigarette smoking has had a steady decline to its current estimate of 19.8%. There are, however, some special populations where smoking continues to occur at a higher prevalence than the general population. This chapter discusses tobacco dependence among the following special populations: low socioeconomic status including Medicaid, hard-core smokers, rural, and homeless; immigrants; and persons living with HIV. For each population, there is an overview of the disparities in tobacco use, special challenges unique to that population, and exploration of current research on tailoring of tobacco dependence treatment. Each of the special populations discussed present unique challenges with tobacco dependence treatment that will require careful examination before disparities will ultimately decrease. Eliminating disparities has been marked as an important research agenda item as noted in Healthy People 2010. Nurse researchers are well positioned to combine their clinical expertise and knowledge of patient psychosocial needs with investigation of patient-focused research questions in each of these special populations. PMID- 20192111 TI - Systems approaches to tobacco dependence treatment. AB - Nurses have been at the forefront of initiatives to improve patient outcomes through systems change. Nursing research addressing systems approaches to treatment of tobacco dependence has demonstrated increased implementation of evidence-based practice guidelines. Existing health system research conducted by nurse scientists has focused on four strategies: tobacco use identification systems, education and training of nursing staff to deliver tobacco intervention, dedicated staff for tobacco dependence treatment in both acute and primary care settings, and institutional policies to support tobacco intervention. Nursing involvement in multidisciplinary health services research focusing on tobacco treatment has lagged behind advances in clinical nursing research of individual focused smoking cessation interventions. Health information technology shows promise as part of an integrated approach to systems changes to support tobacco intervention, particularly in light of the current national emphasis on adoption and meaningful use of electronic health records. Future directions for translational research present unprecedented opportunity for nurse scientists to respond to the call for policy and systems changes to support tobacco treatment. PMID- 20192112 TI - Nursing research in community-based approaches to reduce exposure to secondhand smoke. AB - Secondhand smoke (SHS) is the third leading cause of preventable death in the United States and a major source of indoor air pollution, accounting for an estimated 53,000 deaths per year among nonsmokers. Secondhand smoke exposure varies by gender, race/ethnicity, and socioeconomic status. The most effective public health intervention to reduce SHS exposure is to implement and enforce smoke-free workplace policies that protect entire populations including all workers regardless of occupation, race/ethnicity, gender, age, and socioeconomic status. This chapter summarizes community and population-based nursing research to reduce SHS exposure. Most of the nursing research in this area has been policy outcome studies, documenting improvement in indoor air quality, worker's health, public opinion, and reduction in Emergency Department visits for asthma, acute myocardial infarction among women, and adult smoking prevalence. These findings suggest a differential health effect by strength of law. Further, smoke-free laws do not harm business or employee turnover, nor are revenues from charitable gaming affected. Additionally, smoke-free laws may eventually have a positive effect on cessation among adults. There is emerging nursing science exploring the link between SHS exposure to nicotine and tobacco dependence, suggesting one reason that SHS reduction is a quit smoking strategy. Other nursing research studies address community readiness for smoke-free policy, and examine factors that build capacity for smoke-free policy. Emerging trends in the field include tobacco free health care and college campuses. A growing body of nursing research provides an excellent opportunity to conduct and participate in community and population-based research to reduce SHS exposure for both vulnerable populations and society at large. PMID- 20192113 TI - Opportunities for nursing research in tobacco control. AB - Nurse scientists have made important contributions to evidence-based practice in tobacco control. This chapter will discuss recent tobacco control developments in the United States and globally, such as legislation giving the U.S. Food and Drug Administration regulatory authority over tobacco products manufacturing, marketing and sales, the World Health Organization Framework Convention on Tobacco Control, and a brief review of research that has guided policy advances and nursing research in tobacco control. Suggestions for future research based on the update of the U.S. Public Health Services Treating Tobacco Use and Dependence clinical practice guideline will be explored. These developments offer nursing researchers a wealth of opportunities and challenges to advance nursing and tobacco control knowledge, address research gaps, and bring a unique nursing perspective to tobacco use prevention, reduction of exposure to secondhand smoke, tobacco dependence treatment, and tobacco control policies. Additionally, we will address how nursing scholarship can and should be supported by academic and organizational leadership to support nurses in realizing their full potential in mitigating the global epidemic of tobacco-caused death and disease. PMID- 20192114 TI - Interstitial infusion of erlotinib in the rodent brain. AB - A critical need exists for the development of novel forms of treatment for high grade glioma. Molecular characterization of high-grade glioma has shown overexpression of the epidermal growth factor receptor, antagonists to which, including erlotinib, may prevent tumor growth. Interstitial infusion is a mode of local delivery which bypasses the blood-brain barrier and utilizes a pressure dependent gradient to enhance drug uniformity and volume of distribution. Interstitial infusion of erlotinib was performed to the striatum of 12 rats in increasing, therapeutic doses. No evidence of clinical or histopathologic toxicity was found. In this experimental study we demonstrate that interstitial infusion of erlotinib is safe in the rodent brain, and may have potential applicability for the treatment of high-grade glioma. PMID- 20192115 TI - Vinblastine-induced ultrastructural transition of microtubular scaffoldings in the SV40-transformed 3T3 murine fibroblasts. AB - SV40-transformed 3T3 cells (SV3T3) treated with the antitubulin chemotherapeutic agent vinblastine exhibited ultrastructural alterations in their cellular microtubular scaffolding by electron microscopy. Apparent disappearance of the subcellular microtubules occurred after the cells were incubated with vinblastine at 10 microg/ml at 37 degrees C for 8 hours. Typical cytoplasmic microtubular crystals were found with additional smooth membrane-limited vesicles. These vesicles mimic the differentiation cellular organelle called annulated lamellae. Microtubules were frequently seen associated with the Golgi apparatus and rough endoplasmic reticulum in the SV3T3 cells. These microtubules may contribute to transport of products between the Golgi and the rough endoplasmic reticulum. When treated with vinblastine, microtubular crystals were also observed between the Golgi and the rough endoplasmic reticulum. The size and numbers of cytoplasmic inclusions were increased in vinblastine-treated cells. In the SV3T3 cells, microtubules are determined by image analysis to be 230 A degrees in diameter with a subunit wall of 45 A degrees thick. These microtubules have a center-to center space of 55.6 A degrees between the protofilaments. The skewed heterodimeric microtubular subunits are composed of disk-like structures of 45 A degrees in length, 30 A degrees in width, and 20 A degrees in thickness. The subunit center-to-center skewed angle is 40 degree. After the cells were treated with vinblastine, the microtubules undergo a transitional dissociation, and reassemble into ordered crystals. These transitional microtubules have an increased diameter of 350 A degrees, and a larger protofilament center-to-center space of 85 A degrees. These morphometric measurements indicated that there is a critical microtubule dissociation distance of 30 A degrees, exceeded which the typical microtubular ultrastructure may no longer exist. PMID- 20192116 TI - Study of in vitro and in vivo effect of docosahexaenoic acid on rat C6 glioma. AB - Docosahexaenoic acid (DHA) may have potential anticarcinogenic effect. In the present study, effect of DHA on rat C6 glioma was tested. In vitro, cytotoxic effect of 50-400 microM DHA on C6 cells was evaluated and compared with linoleic acid (LA). In vivo, adult female Wistar rats implanted with C6 tumor, fed 1 ml of DHA oil (containing 73% DHA, 36 rats) or LA oil (containing 72-77% LA, 41 rats) daily, starting one week prior to tumor implantation until death or if survived, until 30 days after implantation. Another group of tumor bearing rats was treated with chloroethyl-cyclohexyl-nitrosourea (CCNU, 30 mg/kg, 31 rats) at day 8 post implantation to show if the result of oil supplementation is comparable to single agent chemotherapy. mRNA expression of p21 and p27 was determined in vitro at 100 and 150 microM of fatty acids and in tumors of rats supplemented with LA or DHA oils. In vitro, DHA, but not LA, had cytotoxic effect on C6 cells at 200 and 400 microM and DHA increased mRNA expression of p21 at 150 microM (p < 0.05). In rat glioma model, although a non-significant trend towards better survival was observed in DHA oil relative to LA oil group, the difference was not significant (p = 0.20). p21 and p27 mRNA expression in tumors of DHA oil group did not differ with LA oil group. Single dose of CCNU increased survival when compared to LA oil group (p < 0.001). In conclusion, intake of DHA at the dose or duration employed in the present study might be insufficient to bring about its cytotoxic action on rat's C6 brain tumor. PMID- 20192117 TI - Anticancer drugs exert differential apoptotic and cytotoxic effects on glioblastoma primary cultures with various EGFR and bcl-2 profiles. AB - The aim of this study was to determine the apoptotic and cytotoxic effects induced on glioblastoma cells by various anticancer agents that possess different mechanisms of action (alkylating drugs, anti-EGFR (Epidermal Growth Factor receptor), proteasome inhibitor). Primary cell cultures were obtained from patients who underwent surgery for their glioblastoma. The cytotoxic effects of drugs were determined by MTT (dimethylthiazolyl diphenyl tetrazolium bromide) assay and apoptosis was evaluated by measuring mitochondrial potential by flow cytometry. Biological markers (EGFR, bcl-2) were studied by a immunoblotting technique to find out predictive markers of response. We found a large interindividual sensitivity, thus confirming the interest of the primary cultures. New proteasome inhibitor bortezomib had considerable cytotoxic and apoptotic potential in glioblastoma, even at very low concentrations. Moreover, the characterization of patients' cells for EGFR and bcl-2 status could constitute an interest, with the evaluation of other markers, in the study of expected chemotherapy response. PMID- 20192118 TI - Therapeutic suppression of constitutive and inducible JAK?STAT activation in head and neck squamous cell carcinoma. AB - The oncogenic role of STAT3 has been elucidated in a number of human malignancies including leukemia, lymphoma, malignant glioma and cancers of the breast, lung, and head and neck (HNSCC). Here we show that WP1066 has profound anti-neoplastic effects in HNSCC, mediated in part by suppression of JAK2-STAT3 signaling. WP1066 inhibited constitutive and inducible STAT3 phosphorylation in both dose- and time dependant manners. Further, the nuclear translocation of STAT3 was completely inhibited, resulting in decreased DNA binding activity. In vivo testing of WP1066 in a nude mouse orthotopic model of HNSCC demonstrated significant anti-tumor effects, with histological evidence of decreased cellular proliferation and angiogenesis. Collectively, these data suggest that WP1066 suppresses squamous cell carcinoma cell growth, in part through its effects on JAK-STAT pathways, and establishes this small molecule as potentially efficacious agent in the treatment of HNSCC. PMID- 20192119 TI - Inhibition of BCL2 expression and activity increases H460 sensitivity to the growth inhibitory effects of polyphenon E. AB - The anti-cancer properties of the green tea-derived mixture Polyphenon E (Poly E) have been demonstrated in a variety of cell culture and animal models. We recently discovered that the H460 lung cancer cell line is markedly resistant to the growth inhibitory effects of Poly E compared with SW480 colon and Flo-1 esophageal cancer cells. We investigated the mechanism of H460 resistance by comparing gene expression profiles of Poly E-sensitive and -resistant cells. Unsupervised hierarchical clustering revealed that Poly E-sensitive cells clustered separately from Poly E-resistant cells, and 6,242 genes were differentially expressed between the two groups at the 0.01 level of significance. We discovered that BCL2 gene and protein expression were significantly higher in H460 cells compared with SW480 and Flo-1 cells (10.60 fold higher gene expression; P < 0.0001). Inhibition of BCL2 expression and activity, using siRNA and the small molecule inhibitor HA14-1 respectively, restored sensitivity to Poly E and induced BCL2-related apoptosis by decreasing mitochondrial membrane potential and inducing PARP cleavage. Our results suggest that increased BCL2 expression may contribute to H460 resistance to the growth inhibitory effects of Poly E. If validated in additional laboratory and clinical models, BCL2 could ultimately be used as a marker of Poly E resistance. PMID- 20192120 TI - Superselective intraarterial cerebral infusion of bevacizumab: a revival of interventional neuro-oncology for malignant glioma. AB - Glioblastoma Multiforme (GBM) is a uniformly fatal disease with a median survival of approximately 15 months. Recent monoclonal antibody therapies such as Bevacizumab (Avastin) have been shown to be active in GBM and to prolong survival in patients with recurrent malignant glioma. Therefore, patients routinely receive intravenous (i.v.) Bevacizumab (10 mg/kg) every two weeks when they have recurred following standard therapy with chemoradiation. I.v Bevacizumab; however, can cause significant systemic side effects including bowel perforation and pulmonary embolism. In addition, the blood brain barrier (BBB) continues to provide an obstacle to the effective delivery of the antibody to the brain tumor bed. In order to overcome the BBB, and to limit the systemic toxicity of i.v. Bevacizumab, we have begun a Phase I clinical trial to test the safety of transient blood brain barrier disruption with intraarterial (IA) Mannitol followed by superselective intraarterial cerebral infusion (SIACI) of Bevacizumab. This case report describes the technical aspects of this procedure and its associated benefits and risks. This novel delivery method, which may herald the revival of Interventional Neuro-oncology, may significantly alter the way therapy is administered to patients with GBM. PMID- 20192121 TI - P-170 peptides with low similarity to the human proteome: tracing an effective and safe biological way towards effective and safe cancer chemotherapy. AB - We propose low-similarity P-170 peptide-based antibodies to neutralize the multidrug resistance phenomenon and, consequently, improve the treatment regimens for cancer chemotherapy. As a first step in the experimental validation of this approach, we report on the similarity analysis of the P-170 primary amino acid structure versus the human proteome and describe peptide motifs uniquely owned by the human P-170 glycoprotein. PMID- 20192122 TI - Reactive oxygen species, especially O2+* in cancer mechanisms. AB - In the nature including the human organism there are 5 reactive oxygen species (ROS): O2, O2-*, O2+*, 1O2, O3 with different electromagnetic characteristics and biological effects. The effects of enrichment of medical oxygen O2 with traces of ROS on various cells were tested in experiments. METHODS: Human embryonic lung fibroblasts WI38 damaged by Radon Rn222 into WI38/ Rn cells and WI38 cells transformed by virus SV40 into VA13 cells were exposed to different ROS gas mixtures, prepared in high - voltage plasma chamber of "Oxygen Ion 3000". Trans membrane resting potential (TMRP) was measured and cells morphology was visually observed using microscopy during 10 days. RESULTS: Exposition of WI38, WI38/Rn and VA13 to medical O2, alone show no effect in TMRP and in cell morphology. But pico-concentration of O2+* in medical O2 increased the TMRP in WI38/Rn cells from -25mV to -35mV (variance 0.5-2mV) (p < 0.001) with improvement of cells morphology and the TMRP of VA13 cells from -15mV to -32mV (2-3mV) (p < 0.001) with a maximum effect on the 5th day. Later the TMRP strongly decreased and the cell membrane ruptured due to water influx. O2, enriched with O2-* alone or together with O2+* had no significant effect in WI38/Rn and VA13 groups (p > 0.05). CONCLUSION: Radon protective effect on WI38/Rn or destructive effect on VA13 of pico-concentrations of O2+* in medical O2 conforms to the theory of hormesis resp. to hypothesis of cancer induction mechanisms, supporting it's further experimental or clinical use. PMID- 20192123 TI - Susceptibility of colorectal cancer cells to Sindbis virus infection. AB - Sindbis virus (SIN), a member of the Togaviridae family, infects a broad range of cells and has been shown to be an effective anti-tumor agent. The infection efficiency of the virus, however, varies greatly among target cells. In this report, we compared the ability of SIN to infect colorectal cancer cells and cells of other cancer origin. While tumor cells from breast, leukemia, and prostate cancers were largely resistant to SIN infection, nine of the ten colorectal cancer cell lines tested were sensitive to SIN infection. Moreover, SIN susceptibility correlated with the metastatic potential of the colorectal cancer cells. Two highly aggressive and invasive cell lines, SW620 and COLO-320DM were the most sensitive to SIN infection. Similarly, SIN preferentially targeted metastatic tumor cells in a mouse xenograft model for colon cancer progression. The higher infection rate was not due to increased expression of the 67kD laminin receptor, a specific receptor for SIN infection, although viral attachment and entry were markedly enhanced in SW620 cells. These results suggest that SIN may employ a novel cell attachment/entry mechanism during infection, allowing selective targeting of colorectal cancer cells. PMID- 20192124 TI - Looking through the Ames window. PMID- 20192125 TI - Preserved striate cortex is not sufficient to support the McCollough effect: evidence from two patients with cerebral achromatopsia. AB - The McCollough effect (ME) is a colour aftereffect contingent on pattern orientation. This effect is generally thought to be mediated by primary visual cortex (V1) although this has remained the subject of some debate. To determine whether V1 is in fact sufficient to subserve the ME, we compared McCollough adaptation in controls to adaptation in two patients with damage to ventrotemporal cortex, resulting in achromatopsia, but who have spared V1. Each of these patients has some residual colour abilities of which he is unaware. Participants performed a 2AFC orientation-discrimination task for pairs of oblique and vertical/horizontal gratings both before and after adaptation to red/green oblique induction gratings. Successful ME induction would manifest itself as an improvement in oblique-orientation discrimination owing to the additional colour cue after adaptation. Indeed, in controls oblique grating discrimination improved post-adaptation. Further, a subdivision of our control group demonstrated successful ME induction despite a lack of conscious awareness of the added colour cue, indicating that conscious colour awareness is not required for ME induction. The patients, however, did not show improvement in oblique-orientation discrimination, indicating a lack of ME induction. This suggests that V1 must be connected to higher cortical colour areas to drive ME induction. PMID- 20192126 TI - Facilitation of responses to degraded targets by non-degraded distractors. AB - It is well-established that distractors interfere with goal-directed responses. Our recent findings indicate that the presence of corners in degraded line drawings of distractor stimuli modulates response times and accuracy to non degraded targets (Kritikos and Pavlis 2007, Experimental Brain Research 183 159 170). In the present study we asked whether non-degraded distractors may facilitate responses to degraded targets (corners or line segments missing). We presented targets at fixation and accompanied by identical, category-congruent, or category-incongruent distractors. Participants responded to two object categories (musical instruments and tools) consisting of four line drawings. Corners-missing targets in particular were associated with greater interference from distractors than non-degraded targets. This interference was modulated when distractor locations were endogenously or exogenously cued. Findings are discussed in the context of additional processing of object features that are crucial to action. PMID- 20192127 TI - Perception of parallelepipeds: Perkins's law. AB - Two experiments were carried out to study the perception of parallelepipeds. In the first, the subjects were shown images of parallelepipeds and were asked to judge the 3-D orientations of the faces of the parallelepipeds, as well as the shapes of the faces. These two types of judgments were found to be inconsistent. Specifically, the parallelepipeds reconstructed from judgments of 3-D orientations of the faces were systematically different from the parallelepipeds reconstructed from judgments of the shape of the faces. In the second experiment, the subjects were asked to choose which reconstruction was closer to their percept. In most trials the subjects chose the 3-D parallelepiped reconstructed from judgments of the shapes of the faces. These results suggest that the percept of the shape of a 3-D object is not based on the judgments of the 3-D orientations of the object's surfaces. Instead, the 3-D shape percept is based on simplicity constraints. A new computational model is presented, which generalizes Perkins's law (Perkins 1972). Instead of orthogonality, the new model uses mirror symmetry and planarity constraints, in conjunction with maximum 3-D compactness and minimum surface-area constraints. The parallelepipeds recovered by the model are very close to the parallelepipeds perceived by the subjects. PMID- 20192128 TI - Big people, little world: the body influences size perception. AB - Previous research has shown that changes to the body can influence the perception of distances in near space (Witt et al, 2005 Journal of Experimental Psychology: Human Perception and Performance 31 880-888). In this paper, we question whether changes to the body can also influence the perception of extents in extrapersonal space, namely the perception of aperture widths. In experiment 1, broad shouldered participants visually estimated the size of apertures to be smaller than narrow-shouldered participants. In experiment 2, we questioned whether changes to the body, which included holding a large object, wearing a large object, or simply holding out the arms would influence perceived width. Surprisingly, we found that only when participants' hands were widened was extrapersonal space rescaled. In experiment 3, we explored the boundaries of the effect observed in experiment 2 by asking participants to hold their arms at four different positions in order to determine the arm width at which apertures appeared smaller. We found that arm positions that were larger than the shoulder width made apertures appear smaller. The results suggest that dimensions of the body play a role in the scaling of environmental parameters in extrapersonal space. PMID- 20192129 TI - Rubber hand illusions and size-weight illusions: self-representation modulates representation of external objects. AB - Bodily illusions offer an experimental method to investigate the origins and functional role of the sense of one's own body. Using the rubber hand illusion (RHI) we show that a representation of one's own body is implicitly used to calibrate perception of external objects. Twelve participants experienced the RHI while watching stimulation of a large or small glove simultaneously with stimulation of their own hand. They then grasped cylinders of identical size but varying weight. RHI with the large glove caused the cylinders to feel heavier. We suggest that an illusory increase in hand size made the subsequently grasped cylinder feel correspondingly small, evoking a size-weight illusion. Self representation thus influenced exteroception. The sense of one's own body provides a fundamental reference for perception in general. PMID- 20192130 TI - Specificity and coherence of body representations. AB - Bodily illusions differently affect body representations underlying perception and action. We investigated whether this task dependence reflects two distinct dimensions of embodiment: the sense of agency and the sense of the body as a coherent whole. In experiment 1 the sense of agency was manipulated by comparing active versus passive movements during the induction phase in a video rubber hand illusion (vRHI) setup. After induction, proprioceptive biases were measured both by perceptual judgments of hand position, as well as by measuring end-point accuracy of subjects' active pointing movements to an external object with the affected hand. The results showed, first, that the vRHI is largely perceptual: passive perceptual localisation judgments were altered, but end-point accuracy of active pointing responses with the affected hand to an external object was unaffected. Second, within the perceptual judgments, there was a novel congruence effect, such that perceptual biases were larger following passive induction of vRHI than following active induction. There was a trend for the converse effect for pointing responses, with larger pointing bias following active induction. In experiment 2, we used the traditional RHI to investigate the coherence of body representation by synchronous stimulation of either matching or mismatching fingers on the rubber hand and the participant's own hand. Stimulation of matching fingers induced a local proprioceptive bias for only the stimulated finger, but did not affect the perceived shape of the hand as a whole. In contrast, stimulation of spatially mismatching fingers eliminated the RHI entirely. The present results show that (i) the sense of agency during illusion induction has specific effects, depending on whether we represent our body for perception or to guide action, and (ii) representations of specific body parts can be altered without affecting perception of the spatial configuration of the body as a whole. PMID- 20192131 TI - Perception of 'best likeness' to highly familiar faces of self and friend. AB - We investigated the idea that our memory for familiar faces involves an accurate representation of their unique spatial configuration and, further, whether this configuration may be caricatured in memory. In separate experimental blocks, thirty-five Irish participants were presented with a series of photographic images of their own face and of the face of a close friend, and were asked to choose the image which looked most like themselves or their friend. Both sets of images included an original full-face colour photograph, and photographic distortions ranging from a highly caricatured (+100%) to a highly anti caricatured (-100%) version of the original, generated with reference to newly created average male and female Irish faces. Contrary to suggestions that we hold a slightly caricatured version of a familiar face in memory, the mean 'best likeness' image, calculated across both self and friend trials, was an anti caricature of -13.88% which was significantly different from 0 (t69 = -5.34, p < 0.0001). The difference in the mean 'best-likeness' image chosen for self ( 12.06%) and friend (-15.7%) was not significant (t34 = 0.715, p = 0.48). These results are discussed with reference to our ability to discriminate facial shape, together with the possibility that we idealise the attractiveness of faces of those close to us. PMID- 20192132 TI - Revisiting the processing of internal and external features of unfamiliar faces: the headscarf effect. AB - Five experiments are reported in which the relative importance of internal and external features for unfamiliar face identification are examined by a matching task. In experiments 1-3, Egyptian adults showed a robust internal-feature advantage for matching photographs of Egyptian faces. In experiment 4, a cross cultural comparison between the ability of Egyptian and British adults to match the internal and external features of unfamiliar Egyptian and British faces was made. Once again, Egyptians showed an internal-feature advantage, for all faces. In contrast, British observers and also Egyptian children in experiment 5--showed external-feature advantages consistent with previous research. We attribute this contrast to the long-term experience of Egyptians in perceiving and recognising faces with headscarves, which might develop more expertise in processing the internal than the external features of unfamiliar faces. PMID- 20192133 TI - Recognition of emotional expressions is affected by inversion and presentation time. AB - It has been repeatedly shown that face inversion affects the recognition of emotional faces. However, previous results are heterogeneous concerning the affected emotions and the influence of presentation time is unclear. We examined the impact of limited presentation time (200 ms) on the face-inversion effect during recognition of basic emotions in 128 healthy young adults. Data analysis revealed differential inversion effects for emotional expressions, further modified by limitation of presentation time: when presentation was limited, we observed inversion effects for angry and neutral faces which were absent in the unlimited trials. In the unlimited condition, inversion particularly affected recognition of disgust and sadness. No general inversion effect occurred for neutral expressions. Error analysis highlighted specific confusions for the inverted condition, except for happy and neutral expressions. Hence, emotion recognition is affected by inversion--an indicator for configural processing, and presentation time--an indicator for cognitive effort of processing. PMID- 20192134 TI - Look before you leap: jumping ability affects distance perception. AB - Previous research has demonstrated that changing perceivers' action capabilities can affect their perception of the extent over which an action is performed. In the current study, we manipulated jumping ability by having participants wear ankle weights and examined the influence of this manipulation on the perception of jumpable and un-jumpable extents. When wearing ankle weights, jumpable gaps appeared longer than when not wearing ankle weights; however, for un-jumpable gaps, there was no difference in the apparent gap extent, regardless of whether the participant was wearing ankle weights. This suggests that the perception of a jumpable extent is affected by one's action boundary for jumping, but only if jumping is an action that can be performed over the extent. PMID- 20192135 TI - Tolerance of stereopsis to conjunctive cyclorotation. AB - Stereopsis is largely unperturbed by various types of eye, head, and target movements. Here, we used a simple setup to investigate the limits of a previously untested type of stimulus motion on stereoscopic depth perception. Clockwise and counterclockwise rotations of an autostereogram were used to describe the limits of stereopsis to roll-tilt. The result showed intact depth perception with stimulus rotation up to approximately 12 degrees, regardless of rotation direction and viewing distance, indicating a tolerant mechanism for stereoscopic processing by the human neural system. PMID- 20192136 TI - Pain control after total knee arthroplasty: a prospective study comparing local infiltration anesthesia and epidural anesthesia. AB - Postoperative pain control after total knee arthroplasty (TKA) is a well-known clinical problem. Efforts to treat it with the use of local anesthesia have been made, but the results have been contradictive. In the late 1990s, an infiltrated solution of ropivacaine/ketorolac/adrenaline was shown to be effective for this purpose, and this technique has since spread over the world. The purpose of this study was to compare the local infiltration anesthesia technique with epidural anesthesia, which has been the most widely used technique in Sweden.Eighty-five patients received either local infiltration anesthesia or epidural anesthesia for postoperative pain relief. Postoperative morphine consumption, range of motion, walking ability, patient satisfaction, hospital stay, and time in the recovery room were measured. The groups were followed equally. The patients in the local infiltration anesthesia group were mobilized 24 hours earlier. On postoperative day one, 22 of 33 patients in the local infiltration anesthesia group could get in and out of bed without assistance. Only 1 of 31 patients in the epidural anesthesia group could manage this. On postoperative day two, 28 of 33 patients in the local infiltration anesthesia group could walk without assistance, compared to 5 of 31 in the epidural anesthesia group. Seventy-six percent of the local infiltration anesthesia patients were "very satisfied" with their postoperative pain control method, compared to 40% of the epidural anesthesia patients.The local infiltration anesthesia technique is better for postoperative pain relief in TKA than epidural anesthesia. It offers equal pain relief, faster mobilization, and more satisfied patients. No negative side effects were seen during the study. PMID- 20192137 TI - Are patients' expectations of hip and knee arthroplasty fulfilled? A prospective study of 130 patients. AB - Total hip arthroplasty (THA) is the most successful procedure in orthopedic and trauma surgery. Patients' expectations of joint replacement surgery prior to and after the procedure are often discounted. This study investigated the expectations of patients before and 3 years after THA or total knee arthroplasty (TKA). A total of 130 patients (70 hips, 60 knees) received a modified FFbH-OA survey with 6 additional questions concerning patients' expectations before and 3 years after joint replacement surgery. The overall response rate was 78.8% (101 patients). Patients who underwent THA had a mean age of 63.7 years, and those who underwent TKA had a mean age of 67.4 years.Sixty-three percent of all respondents reported that their expectations had been fulfilled or exceeded 3 years postoperatively (THA, 65%; TKA, 61%). A high negative correlation in the THA group could be seen between patients' expectations and clinical scores: the lower the clinical score, the less the patient's expectations had been fulfilled. A statistically significant increase of change in personal relationships was found, as well as a statistically significant decrease in worries and less complications than had been expected before joint replacement.Thirty-seven percent of all respondents felt that their expectations regarding joint replacement had not been fulfilled. Looking at the results of this study, the 37% of patients whose expectations had not been fulfilled did not exhibit a lower postoperative functioning than those who were satisfied. PMID- 20192138 TI - Comparison of vacuum-assisted closure to the antibiotic bead pouch for the treatment of blast injury of the extremity. AB - The surgical care of modern combatants involves treatment of massive extremity wounds from blast mechanism. Currently up to 70% of combat wounds are extremity related. Clinical outcomes for these patients are dependent on the care of these wounds. The Vacuum-Assisted Closure (VAC) Therapy system (KCI Inc, San Antonio, Texas) is ubiquitous in theater and is often considered the only way to treat these wounds. However, the VAC Therapy system is not without problems. It is expensive and requires extensive amounts of product and machinery, as well as functioning suction, and therefore a power source at all times. In addition, the VAC Therapy system requires a trained and vigilant nursing staff. We hypothesized that the antibiotic bead pouch would be a viable alternative to the VAC Therapy system for such blast injuries. We retrospectively analyzed 2 matched groups of 12 patients in terms of outcome and cost. We found that the VAC Therapy system produced more late methicillin-resistant Staphylococcus aureus infections (30%), more unanticipated returns to the operating room for wound problems (4:12 vs 0:12), and required more surgeries overall until closure of the wounds. In addition, the VAC Therapy system cost $12,000 more for 12 patients than the antibiotic bead pouch. We recommend the bead pouch be considered as an equivalent option to the VAC Therapy system in the treatment of blast injury. PMID- 20192139 TI - Lateral tibial plateau fracture depression as a predictor of lateral meniscus pathology. AB - The goal of this study was to determine if the degree of lateral tibial plateau fracture depression on computed tomography (CT) images predicted the presence of lateral meniscus tears. The study group comprised 85 patients who sustained a lateral tibial plateau fracture and underwent open reduction and internal fixation by the same surgeon. Degree of plateau depression was measured in millimeters by CT. Operative reports were retrospectively reviewed to determine if the lateral meniscus tear was intact or torn at the time of surgery. Twenty eight patients had a lateral meniscus tear noted at the time of surgery. No significant differences existed in gender, mechanism or energy level of injury, Schatzker classification, or type of fracture among patients with a lateral meniscal tear as compared to those without a tear. Patients with > or =10 mm of plateau depression had an eight-fold increase in risk of having a lateral meniscus tear compared to those with <10 mm of depression. Patients younger than 48 years had a four-fold increase in risk of having a lateral meniscus tear than older patients.This study demonstrated an association between the amount of tibial plateau depression and the likelihood of a lateral meniscus tear. These findings may be used to predict those who have sustained a tear of the lateral meniscus and to advise the surgeon to prepare for a repair. Further prospective studies using magnetic resonance imaging as a tool to evaluate the extent of soft tissue injuries in plateau fractures is needed. PMID- 20192140 TI - A comparative study of screw and helical proximal femoral nails for the treatment of intertrochanteric fractures. AB - The goal of this study was to compare treatment outcomes of screw proximal femoral nails and helical proximal femoral nails and to investigate the effectiveness of helical proximal femoral nails for the treatment of intertrochanteric fractures. Forty patients with intertrochanteric fractures were treated at our institution between January 2005 and January 2007, with a minimum follow-up of 1.5 years. Seventeen patients were treated with screw proximal femoral nails (mean patient age, 67 years; age range, 45-89 years; men:women ratio, 3:14), and 23 were treated with helical proximal femoral nails (mean patient age, 74 years; age range, 64-91 years; men:women ratio, 6:17). We evaluated mean operation time, amount of bleeding, time to ambulation, average union period, changes in neck shaft angle, and complications, and performed radiographic reviews, telephone interviews, and direct contact interviews at an outpatient clinic. We evaluated postoperative function and mobility using social function scores and mobility scores.Helical proximal femoral nails produced better results in terms of social function scores, mobility scores, and complication rates with statistical significance. No significant differences were found between the 2 nails in terms of mean operation time, amount of bleeding, average union period, time to ambulation, or neck shaft angle changes. Screw proximal femoral nails and helical proximal femoral nails are suitable implants for intertrochanteric fractures, but helical proximal femoral nails are better in terms of functional aspects and complication rates. PMID- 20192141 TI - Arthroscopy on anticoagulated patients: a retrospective evaluation of postoperative complications. AB - Anticoagulation is commonly needed for multiple medical conditions. The indications to discontinue anticoagulation for a simple procedure are controversial. Other surgical subspecialties have shown that keeping patients on warfarin during a simple procedure is safe. The purpose of this retrospective study was to evaluate the postoperative complications encountered for patients undergoing simple arthroscopic procedures while on warfarin. We hypothesized that anticoagulated patients undergoing simple arthroscopic procedures would have few surgical bleeding complications.Arthroscopic procedures performed over a 10-year period on warfarin-anticoagulated patients were retrospectively evaluated. Data collected included the procedure and orthopedic problem, the type of anesthesia, the medical condition requiring anticoagulation, the international normalized ratio (INR) at surgery, and all postoperative complications (bleeding, hematoma, delayed healing, prolonged postoperative course, infection, and medical complication). Twenty-four patients met the inclusion criteria. All had abnormal INR levels at time of surgery. Four patients were operated on emergently for septic joints, and 20 patients had elective arthroscopic procedures (10 knees, 10 shoulders). There were no major intraoperative bleeding problems. Seven patients had minor postoperative surgical complications: 2 prolonged effusions and 5 prolonged ecchymosis. No medical complications were seen. Oral warfarin appeared to be a safe alternative to manipulating anticoagulation during the preoperative period for simple arthroscopic procedures. Minor bleeding complications consisting of ecchymosis were seen, but no medical complications were identified. PMID- 20192142 TI - Autologous blood and corticosteroid injection and extracoporeal shock wave therapy in the treatment of lateral epicondylitis. AB - Lateral epicondylitis is a common disorder characterized by pain and tenderness over the lateral epicondyle. It occurs most frequently as a result of minor, unrecognized trauma during sports activities and occupation-related physical activities. The goal of this study was to evaluate the short-, medium-, and long term effects of corticosteroid injection, autologous blood injection, and extracorporeal shock wave therapy in the treatment of lateral epicondylitis.Sixty patients (32 women, 28 men) with lateral epicondylitis were randomly divided into 3 groups: group 1 received a corticosteroid injection; group 2, an autologous blood injection, and group 3, extracorporeal shock wave therapy. Thomsen provocative testing, upper extremity functional scores, and maximal grip strength were used for evaluation. Outcomes were assessed at 4, 12, 26, and 52 weeks. Corticosteroid injection gave significantly better results for all outcome measures at 4 weeks; success rates in the 3 groups were 90%, 16.6%, and 42.1%, respectively. Autologous blood injection and extracorporeal shock wave therapy gave significantly better Thomsen provocative test results and upper extremity functional scores at 52 weeks; the success rate of corticosteroid injection was 50%, which was significantly lower than the success rates for autologous blood injection (83.3%) and extracorporeal shock wave therapy (89.9%). Corticosteroid injection provided a high success rate in the short term. However, autologous blood injection and extracorporeal shock wave therapy gave better long-term results, especially considering the high recurrence rate with corticosteroid injection. We suggest that the treatment of choice for lateral epicondylitis be autologous blood injection. PMID- 20192143 TI - Computer-assisted 3-dimensional anthropometry of the scaphoid. AB - Scaphoid fracture fixation using a cannulated headless compression screw and the Matti-Russe procedure for the treatment of scaphoid nonunions are performed routinely. Surgeons performing these procedures need to be familiar with the anatomy of the scaphoid. A literature review reveals relatively few articles on this subject. The goal of this anatomical study was to measure the scaphoid using current technology and to discuss the findings with respect to the current, relevant literature.Computed tomography scans of 30 wrists were performed using a 64-slice SOMATOM Sensation CT system (resolution 0.6 mm) (Siemens Medical Solutions Inc, Malvern, Pennsylvania). Three-dimensional reconstructions from the raw data were generated by MIMICS software (Materialise, Leuven, Belgium). The scaphoid had a mean length of 26.0 mm (range, 22.3-30.7 mm), and men had a significantly longer (P<.001) scaphoid than women (27.861.6 mm vs 24.561.6 mm, respectively). The width and height were measured at 3 different levels for volume calculations, resulting in a mean volume of 3389.5 mm(3). Men had a significantly larger (P<.001) scaphoid volume than women (4057.86740.7 mm(3) vs 2846.56617.5 mm(3), respectively).We found considerable variation in the length and volume of the scaphoid in our cohort. We also demonstrated a clear correlation between scaphoid size and sex. Surgeons performing operative fixation of scaphoid fractures and corticocancellous bone grafting for nonunions need to be familiar with these anatomical variations. PMID- 20192144 TI - Stringent patient selection in bulk allograft reconstructions. AB - We hypothesized that stringent patient selection in the use of large bulk structural allografts for limb preservation would positively affect outcomes and decrease complication rates by eliminating certain comorbid or social factors known to contribute to the most detrimental sources of allograft failure: infection, fracture, and nonunion.Our selection criteria included patients who were younger than 50 years, nonsmokers, non-obese (body mass index <40), who did not receive radiation therapy to the recipient site perioperatively, and who underwent intercalary allograft reconstruction except in the upper extremity where osteoarticular allografts were permitted. Outcomes were assessed using the Musculoskeletal Tumor Society (MSTS) and Toronto Extremity Salvage Score (TESS) scoring systems. Twenty-three patients fulfilled our cohort inclusion criteria. The overall survival rate for the 23 allografts was 91% (21/23). Average MSTS and TESS scores were 76% and 87%, respectively. Eleven of 23 patients experienced at least 1 complication requiring a second procedure. Musculoskeletal Tumor Society scores among patients experiencing no complications averaged 83% vs 71% for patients experiencing at least 1 complication. Average TESS scores were 89% and 86%, respectively.The results of our early experience indicate there is no appreciable difference in complication rates among our series of patients stringently selected for bulk allograft reconstruction compared to other previously reported studies. PMID- 20192145 TI - The use of expandable cages in patients undergoing multilevel corpectomies for metastatic tumors in the cervical spine. AB - Expandable cages have been used successfully to reconstruct the anterior spinal column in the treatment of traumatic, neoplastic, infectious, and degenerative spine disease. To the best of our knowledge, no studies report the results of the use of expandable cages in patients undergoing multilevel corpectomies for cervical spine metastatic disease. We report our experience with the use of expandable cages in this subgroup of patients.From August 2006 to May 2008, 5 patients presenting with myelopathy, pain, and/or radiculopathy secondary to metastatic disease of the cervical spine underwent multilevel cervical corpectomies and placement of expandable cages in our institution. All procedures were supplemented with an anterior cervical plate and with posterior instrumentation to achieve a 360 degrees fusion. A visual analog scale (VAS), Nurick grade, Frankel grade, American Spinal Injuries Association (ASIA) grade, and Ranawat grade were used to evaluate patients pre- and postoperatively. The mean follow-up period was 13.2 months. Three patients underwent a 2-level corpectomy, 1 a 3-level corpectomy, and 1 a 4-level corpectomy. Postoperative imaging studies showed that all patients had correction of preoperative kyphosis. The mean VAS score was reduced from 6.4 to 1. All other indices of spinal cord injury measured improved postoperatively or were stabilized. Postoperative imaging studies showed stable constructs in 4 patients.The use of expandable cages in multilevel corpectomies for the treatment of metastatic cervical spine disease appears to be a safe and effective way to reconstruct the anterior column of the cervical spine, preventing further neurologic deterioration. PMID- 20192146 TI - Kyphoplasty for the treatment of painful osteoporotic thoracolumbar burst fractures. AB - This study explored the feasibility and clinical outcome of kyphoplasty for the treatment of painful osteoporotic thoracolumbar burst fractures without neurological deficit. A total of 25 consecutive patients with painful type-A3 amyelic thoracolumbar fractures without neurological deficit were treated by kyphoplasty. Pain was measured using the self-reporting visual analog pain scale (VAS) preoperatively, postoperatively, and at 6-month follow-up. Disability was measured using the Oswestry Disability Index (ODI) preoperatively, postoperatively, and at 6-month follow-up. The height of the fractured vertebral body, kyphotic angle, and spinal canal compromise were measured preoperatively, postoperatively, and at 6-month follow-up. Relief of pain was achieved 24 hours postoperatively. Mean VAS score decreased from 8.2+/-1.3 preoperatively to 2.8+/ 0.8 postoperatively (P<.05), and was maintained at 2.9+/-1.1 at 6-month follow up. The ODI score varied from 68.2%+/-6.6% preoperatively to 35.3%+/-2.8% postoperatively (P<.05). Improvement was maintained at 6-month follow-up. Postoperatively, the height of anterior vertebrae (Ha) was restored from 61.5%+/ 13.9% to 85.3%+/-10.6%, the height of midline vertebrae (Hm) restored from 73.0%+/-19.3% to 83.3%+/-7.4%, the kyphotic angle from 21.7 degrees +/-7.8 degrees to 8.6 degrees +/-6.6 degrees, and the spinal canal compromise from 20.1%+/-4.1% to 17.8%+/-1.3%. At 6-month follow-up, maintenance of the height restoration and kyphotic deformity correction was found. No significant difference was noted in pre- and postoperative spinal canal compromise. Kyphoplasty is a relatively safe and effective method for the treatment of painful osteoporotic thoracolumbar burst fractures. PMID- 20192147 TI - Evaluation of biomechanical and histological features of vertebrae following vertebroplasty using hydroxyapatite blocks. AB - Vertebroplasty was performed using hydroxyapatite blocks to examine the course of compressive strength and histological features in a dog model. The vertebral fracture model was prepared by punching a hole in the center of the vertebra and at 4 sites around the vertebra (5 holes in total) from the front side of the vertebra using an air drill and hollowing the holes. Measurements were made on healthy vertebrae, vertebrae from the vertebral fracture model, vertebrae removed from animals immediately after vertebroplasty, vertebrae collected 1 and 2 months after vertebroplasty, and vertebrae untreated for 1 month after vertebral fracture. Histological examinations were also performed 1 and 2 weeks and 1 and 2 months after vertebroplasty with hydroxyapatite blocks. The strength of vertebrae in the fracture model immediately after vertebroplasty was significantly higher than that in the untreated fracture, and the strength of vertebrae 1 month after the procedure was equivalent to that of healthy vertebrae. Histologically, new bone formation was found around hydroxyapatite blocks 2 weeks after the procedure, and strong crosslinking between neighboring hydroxyapatite blocks was found after 1 month.These results suggest that hydroxyapatite blocks may be effective as filling material for vertebral fracture from both biomechanical and histological perspectives. PMID- 20192148 TI - Impact of passive smoking on the bones of rats. AB - Many epidemiological surveys have identified smoking as a risk factor for osteoporosis, but it is unclear whether smoking has a direct effect on bone metabolism and if such an effect could cause osteoporosis. Therefore, we examined whether smoking causes osteoporosis based on the impact of smoke exposure on the bones of rats. A rat model of passive cigarette smoking was prepared by breeding rats in a cigarette-smoking box for 4 or 8 weeks. Histological changes, micro computed tomographic (CT) analysis, mechanical bone strength, and bone mineral density of the femur and lumbar vertebrae were examined in these rats and in control rats that were not exposed to smoke. Lower mechanical bone strength was observed in smoke-exposed rats, but these differences were not significant. Significantly lower bone mineral density was found in the femur (P<.01) and lumbar bones (P<.001) of 8-week smoke-exposed rats compared to controls. In a micro-CT scan of lumbar vertebrae, the bone volume, trabecular thickness, trabecular number, and trabecular separation differed significantly between smoke exposed rats and controls. Histologically, the osteocytes in the smoke-exposed rats were small (approximately 25% of the size in controls), and decreased numbers of marrow cells and osteoblasts (P<.01), as well as a black carbon dust like substance, were found in the bone of smoke-exposed rats. These results indicate that smoking significantly decreases bone mineral density, which causes osteoporosis, and the organizational changes in the bone suggest a direct effect of smoking on bone structure. Fewer marrow cells were present in the smoke exposed rats, and a black carbon dust-like substance was observed. PMID- 20192149 TI - Superior gluteal artery injury during iliosacral screw placement due to aberrant anatomy. AB - Percutaneous iliosacral screws are considered the standard of care for disruptions of the sacroiliac joint. This article describes a case of iatrogenic injury to the superior gluteal artery during iliosacral screw insertion and analyzes the possible reasons for this complication.A 32-year-old man diagnosed with an unstable pelvic ring injury underwent percutaneous fixation of the right sacroiliac joint. A 2-cm skin incision was made, and a straight cannulated awl was placed with the tip directly lateral to the S1 body. A guide wire was inserted and a partially threaded 6.5-mm cannulated screw with a washer was then placed over the guide wire and was found to be in excellent position. At this time, increased bleeding from the incision was observed. The incision was enlarged and dissection was carried down through the muscle. The bleeding vessel could not be visualized. Therefore, the wound was packed with sponges, and coil embolization of the right superficial gluteal artery was successfully performed.Analysis of the angiography reveled that our patient's superficial branch of the superior gluteal artery measured more than twice the average length reported in a previous anatomic study. We believe this is the first case of superior gluteal artery bleeding due to aberrant superior gluteal artery anatomy. When planning iliosacral screw insertion, the possibility of anatomical variance of the superior gluteal artery should be acknowledged and sought after in preoperative angiography, when available. PMID- 20192150 TI - Femoral stem displacement during closed reduction of a dislocated bipolar hemiarthroplasty of the hip. AB - This article describes a case of femoral stem displacement during closed reduction of a redislocated bipolar hemiarthroplasty of the hip in a 72-year-old woman who had undergone bipolar hemiarthroplasty using a polished, tapered cemented femoral stem. The polished, tapered cemented femoral stem is vulnerable to displacement when exposed to traction forces. Six days after bipolar hemiarthroplasty, the patient experienced her first dislocation, and immediate reduction of the dislocated hip was easily achieved. However, on the ninth postoperative day, redislocation occurred, and this time, reduction was not achieved. Subsequent radiographs revealed an unreduced state with posterosuperior dislocation of the hip and dissociation of the femoral stem at the cement-stem interface with proximal migration. Open reduction was then performed, and it was noted that the bipolar prosthesis had dislocated posterosuperiorly, the neck of the femoral stem was incarcerated between the short external rotators, and the femoral stem had migrated proximally by approximately 8 cm. The femoral stem was repositioned by freeing it from the short external rotators and gently tapping it into the cement mantle. Our surgical solution is questionable, because the stability of the stem is likely to be inadequate. According to the established study, no difference in stuffiness was observed before extraction and after reinsertion, which supports the surgical solution we chose. Pre-reduction analysis should be conducted to determine the cause and status of a dislocation, and open reduction should be performed if closed reduction fails when treating dislocated bipolar hemiarthroplasty patients. PMID- 20192151 TI - Intramedullary bone fragment obstructing passage of reaming guide wire with iatrogenic fractured tibia. AB - Reamed interlocking intramedullary fixation is the treatment of choice for displaced tibial shaft fractures in adults. In most cases it can be performed without difficulty; however, technical difficulties may be encountered during nailing in some cases. This article describes a case of closed nailing for a tibial shaft fracture in which intramedullary guide wire was obstructed by a small intramedullary bone fragment in the distal fracture segment. Forceful reaming and insertion of the nail led to a break in the cortex of the distal fragment and bending of guide wire. Finally, open reduction and intramedullary nailing was performed to retrieve the guide wire and intramedullary bone fragment and fix the tibia.A comminuted fracture with multiple close fragments in proximity to the fracture site should be preoperatively scrutinized to look for intramedullary bone fragment or a fragment that could be pushed in the intramedullary canal during the intramedullary nailing. The surgeon can then anticipate the potential operative difficulty that may be encountered during closed nailing of such a fracture; and the patient can be counseled, as open nailing is a safer and viable option. Finally it is pertinent that even if this fracture type is overlooked, catastrophe can be avoided by properly following all the steps of intramedullary nailing. PMID- 20192152 TI - Nonoperative biological treatment approach for partial Achilles tendon lesion. AB - Tendon injuries, especially those of the Achilles tendon, are major concerns in sports medicine. The clinical presentation can be acute or chronic and the pathologic findings can range from peritendonitis to full-thickness tendon rupture. Nonsurgical treatment is not always successful; in particular, significant partial ruptures seem to respond poorly to conservative measures and do not improve with time. Surgery is most often considered the favored treatment option for this kind of lesion to obtain pain relief and full functionality with long-standing effects.This article describes a case of a partial tear of the Achilles tendon in a 34-year-old competitive athlete where surgical treatment was avoided in favor of a new biological approach. We applied autologous platelet growth factors through multiple platelet-rich plasma injections; approximately 6.5 billion platelets were injected into the lesion 3 times, 7 days apart. The treatment with platelet-rich plasma and a progressive rehabilitation program allowed the patient to play for 20 minutes in a basketball game 64 days after the trauma and in a full game 75 days after the trauma. To date, 18 months later, he has participated regularly in all the season's games and received no further treatment for his tendon.The fast tissue repair, confirmed by magnetic resonance and ultrasound imaging, allowed a swift return to full functionality and competitive sports activity, suggesting a possible role of platelet growth factors in promoting rapid tendon healing with high-quality tissue. This biological approach may represent a less-invasive therapeutic option even in cases where severe tendon lesions are candidates for surgical treatment. PMID- 20192153 TI - Simultaneous dorsal dislocations of the carpometacarpal joints of all four fingers. AB - A 57-year-old right-hand-dominant woman was involved in a motor vehicle collision. Upon examination, her right hand was markedly deformed and swollen, with limited range of movement. Plain radiographs revealed dorsal dislocations of the index, long, ring, and small finger carpometacarpal joints and an avulsion fracture of the dorsal aspect of the capitate. Closed reduction was unsuccessful. Closed reduction under general anesthesia was successful on the carpometacarpal joint of the ring and small fingers, however, the long and index fingers remained irreducible. An open approach revealed that a joint capsule was interposed in the carpometacarpal joints of the long and index fingers, preventing reduction. Kirschner wires were placed through the base of the small and ring finger metacarpals into the carpus. Additional K-wires were placed across the base of the index and long finger metacarpals into the carpus, and removed at 6 weeks. The avulsion fracture of the capitate was not addressed. Follow-up at 24 months demonstrated full range of motion in all fingers. Her DASH Outcome Measure score was 1.7. She was pain free, had full grip strength, and returned to work full time. Whether patients are treated closed or open, appropriate treatment of carpometacarpal dislocations usually leads to excellent outcomes. If closed reduction is unsuccessful, open treatment is required to address any soft tissue that is preventing reduction. Although urgent treatment is preferred, delay in reduction of up to 4 weeks has been shown not to compromise results. PMID- 20192154 TI - Pigmented villonodular synovitis of the elbow treated with the Tsuge wide joint exposure technique. AB - Pigmented villonodular synovitis (PVNS) is a benign, locally aggressive disease of the synovium; its cause remains unclear. The most frequently involved joint is the knee, followed by the hip, ankle, wrist, and shoulder. Pigmented villonodular synovitis of the elbow joint is rare. Synovectomy is currently believed to be the best treatment for PVNS. Open or arthroscopic synovectomy is usually selected. During synovectomy for PVNS, the possibility of local recurrence after surgery must be considered. The recurrence rate after synovectomy of any joint for PVNS is approximately 40%. Therefore, surgical treatment for PVNS of the elbow requires sufficient removal of the lesion. For good functional results, prevention of postoperative joint stiffness is also necessary. This article describes a case of a 29-year-old woman with PVNS of the right elbow who was treated by total synovectomy using the Tsuge technique. Tsuge reported a new surgical technique for debridement arthroplasty using a posterolateral approach to the elbow in 1987. He has also reported using this procedure during arthroplasty for posttraumatic stiff elbow and for synovectomy in rheumatoid arthritis. This approach permits easy dislocation of the elbow and provides a good view of the whole joint. Although the recurrence rate of PVNS of the elbow is high, our patient has retained good elbow function with no evidence of local recurrence at 30 months postoperatively. PMID- 20192155 TI - Chronic closed talus dislocation: a rare presentation and treatment dilemma. AB - A chronic presentation of closed dorsolateral dislocation of the talus is a rare injury. A 35-year-old woman presented with pain and deformity of the right foot of 6 months' duration. Her medical history was significant for rheumatoid arthritis, for which she was being treated with steroids. Radiographs and computed tomography of the right foot showed dorsolateral talar dislocation with fracture of the medial malleolus. Dislocation of the talus from the tibiotalar, talocalcaneal, and talonavicular joints was indicative of talus dislocation with a fracture of the medial malleolus rather than a fracture-dislocation of the ankle joint. Because of chronic presentation of the injury and an inability to reduce this talus dislocation by closed methods, open total talectomy was performed. At 2-year follow-up, the patient had an AOFAS score of 78. The patient had an obvious limp on the affected limb but managed her activities of daily living well without a shoe raise or brace. Because of the severe varus inversion deformity of the foot preoperatively, the patient was not able to walk. Postoperatively, the deformity was corrected and the patient was able to stand and walk; she was satisfied with the outcome of the surgery.To our knowledge, this is the first report of chronic closed dorsolateral talus dislocation. We recommend that chronic closed isolated dorsolateral talus dislocation can be effectively managed by total talectomy. PMID- 20192156 TI - Tibial hemimelia and femoral bifurcation. AB - Femoral bifurcation and tibial agenesis are rare anomalies and have been described in both the Gollop-Wolfgang complex and tibial agenesis-ectrodactyly syndrome. This article presents a case of Gollop-Wolfgang complex without hand ectrodactyly. Tibial agenesis-ectrodactyly syndrome and Gollop-Wolfgang complex are variants of tibial field defect, which includes distal femoral duplication, tibial aplasia, oligo-ectrodactylous toe defects, and preaxial polydactyly, occasionally associated with hand ectrodactyly.This article describes the case of a patient with bilateral tibial hemimelia and left femoral bifurcation. The proximal tibial anlage had not been identified in the patient's left leg. After failed fibular transfer procedure, the knee was disarticulated. The other leg was treated with tibiofibular synostosis and centralization of fibula to os calcis. At 7-year follow-up, the patient ambulates with an above-knee prosthesis and uses an orthopedic boot for ankle stability.In patients with a congenital absence of the tibia, accurate diagnosis is of the utmost importance in planning future treatment. In the absence of proximal tibial anlage, especially in patients with femoral bifurcation, the knee should be disarticulated. Tibiofibular synostosis is a good choice in the presence of a proximal tibial anlage and good quadriceps function. PMID- 20192157 TI - Continuous surface functionalization of flame-made TiO2 nanoparticles. AB - Hydrophilic TiO(2) particles made in a flame aerosol reactor were converted in situ to hydrophobic ones by silylation of their surface hydroxyl groups. So the freshly formed titania aerosol was mixed with a fine spray of octyltriethoxysilane (OTES) in water/ethanol solution and functionalized continuously at high temperature. The extent of functionalization and structure of that surface layer were assessed by thermogravimetric analysis (TGA) coupled to mass spectroscopy (MS), differential scanning calorimetry (DSC), Fourier transform infrared (FTIR), and Raman spectroscopy. Product particles were characterized also by transmission electron microscopy (TEM), X-ray diffraction, and nitrogen adsorption. The influence of titania specific surface area (SSA) and OTES solution concentration on the functional group surface density was investigated. The titanium dioxide surface was covered with functional groups (up to 2.9 wt %) that were thermally stable up to 300 degrees C in air at an average density of 2 OTES/nm(2). Such surface-functionalized particle suspensions in 2 ethylhexanoic acid and xylene were stable over several weeks. In contrast, as prepared hydrophilic TiO(2) precipitated within days in these solvents. PMID- 20192158 TI - Highly ordered self-assemblies of submicrometer Cu2O spheres and their hollow chalcogenide derivatives. AB - Highly ordered superlattices assembled from transition metal oxide/sulfide submicrometer particles are difficult to prepare due to lack of monodisperse primary building blocks. In this work, we have successfully synthesized monodisperse Cu(2)O spheres with diameters in the submicrometer regime of 130-135 nm. Using the as-prepared Cu(2)O spheres as solid precursor, uniform hollow CuS and CuSe derivatives have also been synthesized in solution media. More importantly, a range of two-dimensional and three-dimensional superlattices of Cu(2)O, CuS, and CuSe solid/hollow spheres have been assembled for the first time. Without assistance of conventional sacrificing solid templates, the degree of ordering achieved in these superlattices is comparable to those reported for well-studied silica and polystyrene beads. The realization of these self assembled superlattices may provide a new way of thin film design and fabrication for this class of photosensitive semiconducting materials using their prefabricated building blocks. PMID- 20192159 TI - Electrofluidic gating of a chemically reactive surface. AB - We consider the influence of an electric field applied normal to the electric double layer at a chemically reactive surface. Our goal is to elucidate how surface chemistry affects the potential for field-effect control over micro- and nanofluidic systems, which we call electrofluidic gating. The charging of a metal oxide-electrolyte (MOE) capacitor is first modeled analytically. We apply the Poisson-Boltzmann description of the double layer and impose chemical equilibrium between the ionizable surface groups and the solution at the solid-liquid interface. The chemically reactive surface is predicted to behave as a buffer, regulating the charge in the double layer by either protonating or deprotonating in response to the applied field. We present the dependence of the charge density and the electrochemical potential of the double layer on the applied field, the density, and the dissociation constants of ionizable surface groups and the ionic strength and the pH of the electrolyte. We simulate the responses of SiO(2) and Al(2)O(3), two widely used oxide insulators with different surface chemistries. We also consider the limits to electrofluidic gating imposed by the nonlinear behavior of the double layer and the dielectric strength of oxide materials, which were measured for SiO(2) and Al(2)O(3) films in MOE configurations. Our results clarify the response of chemically reactive surfaces to applied fields, which is crucial to understanding electrofluidic effects in real devices. PMID- 20192160 TI - Hydrogen-bond-directed giant vesicles of guanosine derivatives in water: formation, structure, and stability. AB - Hydrogen-bond-directed giant supramolecular vesicles (diameter 1.20 +/- 0.30 microm (SD)) of an alkylsilylated deoxyguanosine derivative, 2a, were prepared faciley by mixing a small volume of a 2a/THF solution with water. The formation of 2-D inter-guanine hydrogen-bond networks of 2a within the vesicles was indicated by IR spectra. The vesicle solution was stable enough for more than 30 days, in a wide range of temperatures, and between pH 4 and 10 without showing lysis, fusion, precipitation, or leakage of the encapsulated fluorescent probe. In a typical micrometer-sized vesicle, a sufficiently large internal water phase for encapsulating water-soluble substances was surrounded by a multilamellar membrane 15-20 nm in thickness, which was composed of 6-9 layers of 2-D hydrogen bond-directed sheet assemblies. AC-mode AFM observation of the vesicle on a silicon substrate further demonstrated the high stability and deformable properties of the vesicle membrane under vacuum or mechanical stress. The formation and properties of the vesicle membrane in water were analyzed from the viewpoint of the 2-D hydrogen-bond-directed sheet assemblies, and the scope of the design principle to use nonpolar soft segments as the shielding units of the hydrogen-bond networks in water is discussed. PMID- 20192161 TI - Supramolecular photochemistry in beta-cyclodextrin hosts: a TREPR, NMR, and CIDNP investigation. AB - A systematic investigation of the photochemistry and ensuing radical chemistry of three guest ketones encapsulated in randomly methylated beta-cyclodextrin (beta CD) hosts is reported. Dibenzyl ketone (DBK), deoxybenzoin (DOB), and benzophenone (BP) triplet states are rapidly formed after photolysis at 308 nm. Time-resolved electron paramagnetic resonance (TREPR) spectroscopy, steady-state NMR spectroscopy, and time-resolved chemically induced nuclear polarization (TR CIDNP) experiments were performed on the ketone/CD complexes and on the ketones in free solution for comparison. The major reactivity pathways available from these excited states are either Norrish I alpha-cleavage or H-atom abstraction from the interior of the CD capsule or the solvent. The DOB triplet state undergoes both reactions, whereas the DBK triplet shows exclusively alpha cleavage and the BP triplet shows exclusively H-atom abstraction. Radical pairs are observed in beta-CDs by TREPR, consisting of either DOB or BP ketyl radicals with sugar radicals from the CD interior. The TREPR spectra acquired in CDs are substantially broadened due to strong spin exchange. The electron spin polarization mechanism is mostly due to S-T(0) radical pair mechanism (RPM) in solution but changes to S-T(-) RPM in the CDs due to the large exchange interaction. The TR-CIDNP results confirm the reactivity patterns of all three ketones, and DOB shows strong nuclear spin polarization from a novel rearrangement product resulting from the alpha-cleavage reaction. PMID- 20192163 TI - Comments on "Degradation of 1,2,3-trichloropropane (TCP): hydrolysis, elimination, and reduction by iron and zinc". PMID- 20192164 TI - Effect of organometallic fuel additives on nanoparticle emissions from a gasoline passenger car. AB - Particle size measurements were performed on the exhaust of a car operating on a chassis dynamometer fueled with standard gasoline and gasoline containing low levels of Pb, Fe, and Mn organometallic additives. When additives were present there was a distinct nucleation mode consisting primarily of sub-10 nm nanoparticles. At equal molar dosing Mn and Fe gave similar nanoparticle concentrations at the tailpipe, whereas Pb gave a considerably lower concentration. A catalytic stripper was used to remove the organic component of these particles and revealed that they were mainly solid and, because of their association with inorganic additives, presumably inorganic. Solid nucleation mode nanoparticles of similar size and concentration to those observed here from a gasoline engine with Mn and Fe additives have also been observed from modern heavy-duty diesel engines without aftertreatment at idle, but these solid particles are a small fraction of the primarily volatile nucleation mode particles emitted. The solid nucleation mode particles emitted by the diesel engines are likely derived from metal compounds in the lubrication oil, although carbonaceous particles cannot be ruled out. Significantly, most of these solid nanoparticles emitted by both engine types fall below the 23 nm cutoff of the PMP number regulation. PMID- 20192165 TI - Versatile intramolecular aza-Prins and Prins cyclization of aryl epoxides: a facile synthesis of diaza-, oxa-aza-, and dioxa-bicycles. AB - Aryl epoxides undergo coupling smoothly with (E)-hex-3-ene-1,6-ditosylamide in the presence of 10 mol % p-TSA in 1,2-dichloroethane at 75 degrees C to produce the corresponding 1,5-ditosyl-octahydro-1H-pyrrolidino[3,2-c]pyridines in good yields with high trans-selectivity, whereas the coupling of (Z)-hex-3-ene-1,6 ditosylamide gave cis-fused octahydro-1H-pyrrolidino[3,2-c]pyridines predominantly. The use of readily available p-TSA makes this method simple, convenient, and practical. PMID- 20192166 TI - Hosted and free-floating metal-bearing atmospheric nanoparticles in Mexico City. AB - Nanoparticles (NPs) are ubiquitous in the atmosphere. Because of their small sizes, they can travel deeply into the lungs and other parts of the body. Many are highly reactive which, combined with their large surface areas, means they can seriously affect human health. Their occurrences in the atmosphere and their biological effects are not well-understood. We focus on NPs that were either free floating or hosted within large aerosol particles (aerodynamic diameter 50-300 nm) and consist of or contain transition or post-transition metals (m-NPs). The samples were collected from ambient air above Mexico City (MC). We used transmission electron microscopy to measure their sizes and compositions. More than half of the 572 m-NPs that we analyzed contain two or more metals, and Fe, Pb, or Zn occurs in more than 60%. Hg occurs in 21% and is especially abundant in free-floating m-NPs. We find that m-NPs are common in polluted air such as in the MC area and, by inference, presumably other megacities. The range and variety of compositions of m-NPs that we encountered, whether free-floating or hosted within larger aerosol particles, indicate the complicated occurrences that should be considered when evaluating the health effects of m-NPs in complex urban areas. PMID- 20192167 TI - VOC removal and deodorization of effluent gases from an industrial plant by photo oxidation, chemical oxidation, and ozonization. AB - The efficiency of photo-oxidation, chemical oxidation by sodium hypochlorite, and ozonization for the industrial-scale removal of volatile organic compounds (VOCs) and odors from gaseous emissions was studied by applying these treatments (in an experimental system) to substances passing through an emission stack of a factory producing maize derivatives. Absorption and ozonization were the most efficient treatment, removing 75% and 98% of VOCs, respectively, while photo-oxidation only removed about 59%. The emitted chemical compounds and odors were identified and quantified by gas chromatography-mass spectrometry (in full-scan mode). In addition to presenting the results, their implications for selecting optimal processes for treating volatile emissions are discussed. PMID- 20192168 TI - Biodegradation in a partially saturated sand matrix: compounding effects of water content, bacterial spatial distribution, and motility. AB - Bacterial pesticide degraders are generally heterogeneously distributed in soils, leaving soil volumes devoid of degradation potential. This is expected to have an impact on degradation rates because the degradation of pollutant molecules in such zones will be contingent either on degraders colonizing these zones or on pollutant mass transfer to neighboring zones containing degraders. In a model system, we quantified the role exerted by water on mineralization rate in the context of a heterogeneously distributed degradation potential. Alginate beads colonized by Pseudomonas putida KT2440 were inserted at prescribed locations in sand microcosms so that the initial spatial distribution of the mineralization potential was controlled. The mineralization rate was strongly affected by the matric potential (decreasing rate with decreasing matric potential) and by the initial distribution of the degraders (more aggregated distributions being associated with lower rates). The mineralization was diffusion-limited, as confirmed with a mathematical model. In wet conditions, extensive cell dispersal was observed for the flagellated wild type and, albeit to a lesser extent, for a nonflagellated mutant, partially relieving the diffusion limitation. Dry conditions, however, sustained low mineralization rates through the combined effects of low pollutant diffusivity and limited degrader dispersal. PMID- 20192169 TI - Reactive organic gas emissions from livestock feed contribute significantly to ozone production in central California. AB - The San Joaquin Valley (SJV) in California currently experiences some of the highest surface ozone (O(3)) concentrations in the United States even though it has a population density that is an order of magnitude lower than many urban areas with similar ozone problems. Previously unrecognized agricultural emissions may explain why O(3) concentrations in the SJV have not responded to traditional emissions control programs. In the present study, the ozone formation potentials (OFP) of livestock feed emissions were measured on representative field samples using a transportable smog chamber. Seven feeds were considered: cereal silage (wheat grain and oat grain), alfalfa silage, corn silage, high moisture ground corn (HMGC), almond shells, almond hulls, and total mixed ration (TMR = 55% corn silage, 16% corn grain, 8% almond hulls, 7% hay, 7% bran + seeds, and 5% protein + vitamins + minerals). The measured short-term OFP for each gram of reactive organic gas (ROG) emissions from all livestock feed was 0.17-0.41 g-O(3) per g ROG. For reference, OFP of exhaust from light duty gasoline powered cars under the same conditions is 0.69 +/- 0.15 g-O(3) per g-ROG. Model calculations were able to reproduce the ozone formation from animal feeds indicating that the measured ROG compounds account for the observed ozone formation (i.e., ozone closure was achieved). Ethanol and other alcohol species accounted for more than 50% of the ozone formation for most types of feed. Aldehydes were also significant contributors for cereal silage, high moisture ground corn, and total mixed ration. Ozone production calculations based on feed consumption rates, ROG emissions rates, and OFP predict that animal feed emissions dominate the ROG contributions to ozone formation in the SJV with total production of 25 +/- 10 t O(3) day(-1). The next most significant ROG source of ozone production in the SJV is estimated to be light duty vehicles with total production of 14.3 +/- 1.4 t O(3) day(-1). The majority of the animal feed ozone formation is attributed to corn silage. Future work should be conducted to reduce the uncertainty of ROG emissions from animal feeds in the SJV and to include this significant source of ozone formation in regional airshed models. PMID- 20192170 TI - Structural and dynamic aspects of hydration of HAsO4(-2): an ab initio QMCF MD simulation. AB - An ab initio quantum mechanical charge field simulation has been carried out in order to obtain molecular level insight into the hydration behavior of HAsO4(-2), one of the major biologically active components of As(V) oxoanion in neutral to slightly alkaline aqueous medium. Moreover, a geometrical definition of hydrogen bonding has been used to probe and characterize both solute-solvent and solvent solvent hydrogen bonding present in the system. The asymmetry of the anion induced by the protonation of one of the oxygens of the arsenate anion causes rather irregular hydration structure. The nonprotonated oxygen atoms preferably form relatively stable hydrogen bonds with two to three water molecules in their vicinity, while the protonated oxygen forms one or two hydrogen bonds, weaker than water-water hydrogen bonds. The two types of As-O distances obtained from the simulation (1.68 and 1.78 A for the protonated and nonprotonated oxygens, respectively) are in good agreement with the experimental data. The two types of As-O stretching frequencies obtained from the simulation (855 and 660 cm(-1) reproduce well the experimental ATR-FTIR results (859 and 680-700 cm(-1)). PMID- 20192171 TI - Effects of pore-scale heterogeneity and transverse mixing on bacterial growth in porous media. AB - Microbial degradation of contaminants in the subsurface requires the availability of nutrients; this is impacted by porous media heterogeneity and the degree of transverse mixing. Two types of microfluidic pore structures etched into silicon wafers (i.e., micromodels), (i) a homogeneous distribution of cylindrical posts and (ii) aggregates of large and small cylindrical posts, were used to evaluate the impact of heterogeneity on growth of a pure culture (Delftia acidovorans) that degrades (R)-2-(2,4-dichlorophenoxy)propionate (R-2,4-DP). Following inoculation, dissolved O2 and R-2,4-DP were introduced as two parallel streams that mixed transverse to the direction of flow. In the homogeneous micromodel, biomass growth was uniform in pore bodies along the center mixing line, while in the aggregate micromodel, preferential growth occurred between aggregates and slower less dense growth occurred throughout aggregates along the center mixing line. The homogeneous micromodel had more rapid growth overall (2 times) and more R-2,4-DP degradation (9.5%) than the aggregate pore structure (5.7%). Simulation results from a pore-scale reactive transport model indicate mass transfer limitations within aggregates along the center mixing line decreased overall reaction; hence, slower biomass growth rates relative to the homogeneous micromodel are expected. Results from this study contribute to a better understanding of the coupling between mass transfer, reaction rates, and biomass growth in complex porous media and suggest successful implementation and analysis of bioremediation systems requires knowledge of subsurface heterogeneity. PMID- 20192172 TI - Thermodynamic properties of aqueous polyatomic ions at extreme temperatures and pressures. AB - Recently a theoretical treatment (J. Phys. Chem. B 2009, 113, 2398-2404) was developed for predicting the standard state thermodynamic properties of electrolytes up to and beyond the critical temperature of water (1273 K and at pressures up to 1000 MPa). In general, the model requires sufficient data at 298.15 K including the Gibbs free energy of hydration and at two higher temperatures to fix two constants for each electrolyte. This communication describes an extension of this "two constant" theory to thermodynamic properties of polyatomic ions for which no accurate data for the Gibbs free energy of hydration exits at 298.15 K. PMID- 20192173 TI - Room temperature cross-coupling of highly functionalized organozinc reagents with thiomethylated N-heterocycles by nickel catalysis. AB - A variety of thiomethyl-substituted N-heterocycles such as pyridines, isoquinolines, pyrimidines, pyrazines, pyridazines, quinazolines, triazines, benzothiazoles, or benzoxazoles undergo smooth Ni-catalyzed cross-coupling reactions with functionalized aryl-, heteroaryl-, alkyl-, and benzylic zinc reagents using an inexpensive Ni(acac)(2)/DPE-Phos catalytic system at 25 degrees C. PMID- 20192174 TI - Ultrafiltration membranes incorporating amphiphilic comb copolymer additives prevent irreversible adhesion of bacteria. AB - We examined the resistance to bacterial adhesion of a novel polyacrylonitrile (PAN) ultrafiltration membrane incorporating the amphiphilic comb copolymer additive, polyacrylonitrile-graft-polyethylene oxide (PAN-g-PEO). The adhesion of bacteria (E. coli K12) and the reversibility of adhered bacteria were tested with the novel membrane, and the behavior was compared to a commercial PAN ultrafiltration membrane. Under static (no flow) bacterial adhesion tests, we observed no bacterial adhesion to the PAN/PAN-g-PEO membrane at all ionic strengths tested, even with the addition of calcium ions. In contrast, significant adhesion of bacterial cells was observed on the commercial PAN membrane, with increased cell adhesion at higher ionic strengths and in the presence of calcium ions. Under crossflow filtration conditions, initial bacterial deposition rate increased with ionic strength and with addition of calcium ions for both membranes, with generally lower bacterial deposition rate with the PAN/PAN-g-PEO membrane. However, deposited bacteria were readily removed (between 97 and 100%) from the surface of the PAN/PAN-g-PEO membrane upon increasing the crossflow and eliminating the permeate flow (i.e., no applied transmembrane pressure), suggesting reversible adhesion of bacteria. In contrast, bacterial adhesion on the commercial PAN membrane was irreversible, with approximately 50% removal of adhered bacteria at moderate ionic strengths (10 and 30 mM) and less than 25% removal at high ionic strength (100 mM). The resistance to bacterial adhesion of the PAN/PAN-g-PEO membrane was further analyzed via measurement of interaction forces with atomic force microscopy (AFM). No adhesion forces were detected between a carboxylated colloid probe and the PAN/PAN-g-PEO membrane, while the probe exhibited strong adhesion to the commercial PAN membrane, consistent with the bacterial adhesion tests. The exceptional resistance of the PAN/PAN-g-PEO membrane to bacterial adhesion is attributable to steric repulsion imparted by the dense brush layer of polyethylene oxide (PEO) chains. PMID- 20192175 TI - Surface structure of Nafion in vapor and liquid. AB - The microstructure of Nafion varies in response to changes in hydration. Thus, it undergoes a transition from tightly packed bundles of inverted micelles with aqueous cores and fused hydrophobic shells ("macaroni bundles") at low hydrations to normal type ("spaghetti") micelles at high hydrations. It was postulated recently that a similar "macaroni-spaghetti" transition, i.e., breakup of surface aligned macaroni to randomly oriented spaghetti, takes place at the polymer surface when the external medium is changed from vapor to liquid water, which can explain some puzzling features of Nafion and similar microphase-separated ionomers. The resulting (nonequilibrium) structures may remain confined to a few nanometers thick surface region. Here, this picture is corroborated using grazing incidence small-angle X-ray scattering (GISAXS), contact angle, and atomic force microscopy (AFM). The enhanced alignment of bundles adjacent to the surface in vapor, similar to the effect of biaxial stretching, is elucidated by GISAXS of spin-cast Nafion films. It is inferred from the characteristic change in relative intensities and position of the ionomer peak in the X-Y (in-plane) and Z (out-of plane) directions with varying X-ray penetration depths into the film. However, contact angle measurements show that the relatively smooth and very hydrophobic surface of Nafion in vapor transforms to a hydrophilic surface, when vapor as the external medium is replaced with liquid water. In addition, AFM indicates that the surface roughness significantly increases in liquid. The results demonstrate that the surface region of Nafion and similar microphase-separated materials may be indeed subject to drastic structural variations, even though the extremely slow relaxation of the solid matrix may preclude propagation of such changes into the bulk. These effects may have a profound effect on the macroscopic characteristics of Nafion membranes, such as hydration and conductivity, as well as their functioning as ion-selective barriers in electrochemical and other applications. PMID- 20192176 TI - Effects of ethanol on the organization of phosphocholine lipid bilayers. AB - We have investigated the consequences of the addition of ethanol to aqueous solutions containing 100 nm diameter phosphocholine unilamellar vesicles. We have studied the effect of ethanol addition on both gel phase and fluid phase phospholipid bilayers of 1,2-dimyristoyl-sn-phosphatidylcholine (DMPC), using time-resolved fluorescence measurements of perylene incorporated into the vesicles. We observe an increase in the perylene rotational diffusion time constants for ethanol concentrations of ca. 0.6 M in both the gel phase (289 K) and the fluid phase (303 K), indicating a change in the bilayer interacyl chain spacing and/or organization. While the change in rotational diffusion behavior of perylene is seen for both phospholipid phases, the details of the change in chromophore dynamics are not the same for the two phases, likely due to the differing extents of disorder in the phospholipid acyl chain region at the two temperatures. These data provide insight into the effects of ethanol on the local environment of the probe in both gel phase and fluid phase lipid bilayers. PMID- 20192177 TI - Sorption and transport of salicylate in a porous heterogeneous medium of silica quartz and goethite. AB - Among transport studies of solutes in porous media, few works have combined microscopic speciation with macroscopic-scale investigations to describe the impact of antecedent sorbed silica on the transport of organic ligands in porous heterogeneous media. In this study, the sorption of salicylate (SA) to goethite coated sand (GCS) was investigated under static and dynamic conditions by combining batch experiments and column tests with infrared spectroscopy. On the basis of infrared spectra, the salicylate adsorption was described by one type of iron site and a mononuclear bidentate surface complex. The intrinsic complexation constant deduced from batch modeling was successfully applied to estimate the sorbed amount under flow through conditions at various water velocities (0.038 0.768 cm/min). The shape of the breakthrough curve of SA was characterized by two fronts in both SA concentration and pH. This behavior could be likely explained by the mobilization of initially adsorbed silica from goethite surface upon SA sorption. The SA breakthrough can be interpreted as retention of SA on available surface sites up to their saturation and then on additional reactive sites, becoming free due to silicate desorption. This present work demonstrated the importance of sorbed silicate on Fe-oxides in the prediction of reactive transport of organic species on natural surfaces. PMID- 20192179 TI - Multiple spiking species-specific isotope dilution analysis by molecular mass spectrometry: simultaneous determination of inorganic mercury and methylmercury in fish tissues. AB - This work demonstrates, for the first time, the applicability of multiple spiking isotope dilution analysis to molecular mass spectrometry exemplified by the speciation analysis of mercury using GC(EI)MS instrumentation. A double spike isotope dilution approach using isotopically enriched mercury isotopes has been applied for the determination of inorganic mercury Hg(II) and methylmercury (MeHg) in fish reference materials. The method is based on the application of isotope pattern deconvolution for the simultaneous determination of degradation corrected concentrations of methylmercury and inorganic mercury. Mass isotopomer distributions are employed instead of isotope ratios to calculate the corrected concentrations of the Hg species as well as the extent of species degradation reactions. The isotope pattern deconvolution equations developed here allow the calculation of the different molar fractions directly from the GC(EI)MS mass isotopomer distribution pattern and take into account possible impurities present in the spike solutions employed. The procedure has been successfully validated with the analysis of two different certified reference materials (BCR-464 and DOLT-4) and with the comparison of the results obtained by GC(ICP)MS. For the tuna fish matrix (BCR-464), no interconversion reactions were observed at the optimized conditions of open focused microwave extraction at 70 degrees C during 8 min. However, significant demethylation was found under the same conditions in the case of the certified dogfish liver DOLT-4. Methylation and demethylation factors were confirmed by GC(ICP)MS. Transformation reactions have been found to depend on the sample matrix and on the derivatization reagent employed. Thus, it is not possible to recommend optimum extraction conditions suitable for all types of matrices demonstrating the need to apply multiple spiking methodologies for the determination of MeHg and Hg(II) in biological samples. Double spike isotope dilution analysis methodologies using widespread GC(EI)MS instrumentation are proposed here for the routine analysis of inorganic mercury and methylmercury in fish samples. The estimated method detection limits were below 10 ng g(-1) for both mercury species. Precision was evaluated for the concentrations present in the certified reference materials (CRMs) which vary from 0.1 to 5 microg g(-1), achieving values of coefficients of variation ranging from 7% to 2%. The concentrations obtained in both CRMs analyzed were in excellent agreement with the certified values, demonstrating the accuracy of the method at these concentration levels. PMID- 20192180 TI - Ultrafast electron transfer dynamics of a Zn(II)porphyrin-viologen complex revisited: S2 vs S1 reactions and survival of excess excitation energy. AB - The photoinduced electron transfer reactions in a self-assembled 1:1 complex of zinc(II)tetrasulphonatophenylporphyrin (ZnTPPS(4-)) and methylviologen (MV(2+)) in aqueous solution were investigated with transient absorption spectroscopy. ZnTPPS(4-) was excited either in the Soret or one of the two Q-bands, corresponding to excitation into the S(2) and S(1) states, respectively. The resulting electron transfer to MV(2+) occurred, surprisingly, with the same time constant of tau(FET) = 180 fs from both electronic states. The subsequent back electron transfer was rapid, and the kinetics was independent of the initially excited state (tau(BET) = 700 fs). However, ground state reactants in a set of vibrationally excited states were observed. The amount of vibrationally excited ground states detected increased with increasing energy of the initial excited state, showing that excess excitation energy survived a two-step electron transfer reaction in solution. Differences in the ZnTPSS(*3-)/MV(*+) spectra suggest that the forward electron transfer from the S(2) state at least partially produces an electronically excited charge transfer state, which effectively suppresses the influence of the inverted regime. Other possible reasons for the similar electron transfer rates for the different excited states are also discussed. PMID- 20192178 TI - High-performance single cell genetic analysis using microfluidic emulsion generator arrays. AB - High-throughput genetic and phenotypic analysis at the single cell level is critical to advance our understanding of the molecular mechanisms underlying cellular function and dysfunction. Here we describe a high-performance single cell genetic analysis (SCGA) technique that combines high-throughput microfluidic emulsion generation with single cell multiplex polymerase chain reaction (PCR). Microfabricated emulsion generator array (MEGA) devices containing 4, 32, and 96 channels are developed to confer a flexible capability of generating up to 3.4 x 10(6) nanoliter-volume droplets per hour. Hybrid glass-polydimethylsiloxane diaphragm micropumps integrated into the MEGA chips afford uniform droplet formation, controlled generation frequency, and effective transportation and encapsulation of primer functionalized microbeads and cells. A multiplex single cell PCR method is developed to detect and quantify both wild type and mutant/pathogenic cells. In this method, microbeads functionalized with multiple forward primers targeting specific genes from different cell types are used for solid-phase PCR in droplets. Following PCR, the droplets are lysed and the beads are pooled and rapidly analyzed by multicolor flow cytometry. Using Escherichia coli bacterial cells as a model, we show that this technique enables digital detection of pathogenic E. coli O157 cells in a high background of normal K12 cells, with a detection limit on the order of 1/10(5). This result demonstrates that multiplex SCGA is a promising tool for high-throughput quantitative digital analysis of genetic variation in complex populations. PMID- 20192181 TI - Concentration-dependent aggregation of CHAPS investigated by NMR spectroscopy. AB - CHAPS (3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate) is a zwitterionic surfactant, which has been extensively used in various biological fields. In the present work, the concentration-dependent aggregation of the surfactant in deuterium oxide solution was investigated by NMR spectroscopy. We have found that two break points exist on the basis of the NMR parameters such as chemical shift difference (Delta delta), self-diffusion coefficient (D), and relaxation rates (R(1), R(2)). The first break point corresponds to the widely accepted normal critical micelle concentration (cmc). The second one is unexpected and ascribed to the second cmc, indicating that there is another type of micelle at higher concentrations. Further analysis using 1D selective NOESY with spin-diffusion quenching reveals that at the concentration above the second cmc CHAPS may form a two-layer spherical structure of micelles, with the aliphatic groups of CHAPS molecules in the inner layer interact with the steroid groups in the outer layer. The existence of two types of micelles has also been supported by our TEM experiment. The dependence of CHAPS micelle size on concentration explains why some proteins are soluble and stable only at concentrations above the second cmc. Therefore, our finding provides a basis for optimizing CHAPS concentration in functional and structural studies of membrane proteins. PMID- 20192182 TI - Ultrasensitive electrochemical immunosensor for oral cancer biomarker IL-6 using carbon nanotube forest electrodes and multilabel amplification. AB - Squamous cell carcinomas of head and neck (HNSCC) are associated with immune, inflammatory, and angiogenic responses involving interleukin-6 (IL-6). This article reports an ultrasensitive electrochemical immunosensor for human IL-6 and proof-of-concept studies of IL-6 detection in HNSCC cells. Single wall carbon nanotube (SWNT) forests with attached capture antibodies (Ab(1)) for IL-6 were used in an electrochemical sandwich immunoassay protocol using enzyme label horseradish peroxidase (HRP) to measure very low (20:1 and up to 99% enantiomeric excesses were observed. Di-, tri-, and tetra-substituted bromoallenes were prepared together with lactone heterocycles efficiently and stereoselectively. Preliminary investigations suggest that the chiral catalyst may serve as a bifunctional reagent by interacting with both a carboxylic acid nucleophile and NBS electrophile. PMID- 20192185 TI - Superoxide ions entrapped in water cages of ionic clathrate hydrates. AB - In the present work, we first described the stable entrapment of the superoxide ions in gamma-irradiated (Me(4)NOH + O(2)) clathrate hydrate. Owing to peculiar direct guest-guest ionic interaction, the lattice structure of gamma-irradiated (Me(4)NOH + O(2)) clathrate hydrate shows significant change of lattice contraction behavior even at relatively high temperature (120 K). Such findings are expected to provide useful information for a better understanding of unrevealed nature (such as icy nanoreactor concept, ice-based functional material synthesis and lattice tuning by specific ionic guests) of clathrate hydrate fields. PMID- 20192184 TI - Direct catalytic asymmetric vinylogous Mannich-type and Michael reactions of an alpha,beta-unsaturated gamma-butyrolactam under dinuclear nickel catalysis. AB - Direct catalytic asymmetric vinylogous reactions of an alpha,beta-unsaturated gamma-butyrolactam as a donor are described. A homodinuclear Ni(2)-Schiff base complex promoted a vinylogous Mannich-type reaction of N-Boc imines as well as a vinylogous Michael reaction to nitroalkenes selectively at the gamma-position under simple proton-transfer conditions. Vinylogous Mannich adducts were obtained in 5:1-->30:1 dr and 99% ee, and vinylogous Michael adducts were obtained in 16:1 ->30:1 dr and 93-99% ee. PMID- 20192186 TI - Functionalized C-glycoside ketohydrazones: carbohydrate derivatives that retain the ring integrity of the terminal reducing sugar. AB - Glycosylation often mediates important biological processes through the interaction of carbohydrates with complementary proteins. Most chemical tools for the functional analysis of glycans are highly dependent upon various linkage chemistries that involve the reducing terminus of carbohydrates. However, because of ring opening, the structural integrity of the reducing sugar ring (pyranose or furanose) is lost during these techniques, resulting in derivatized carboydrates that markedly differ from the parent molecule. This paper describes a new aqueous based, one-pot strategy that involves first converting the sugar to a C-glycoside ketone, followed by conversion to ketohydrazones or oximes. Hence, the C glycoside ketones are tagged with fluorescence, colored, cationic or biotin labeled groups or immobilized onto hydrazine-functionalized beads. No activating or protecting groups are required, and the chemistry is mild enough for a wide range of carbohydrates. We demonstrate the versatility of the approach to diverse glycans, including bead immobilization and lectin analysis of acarbose, an antidiabetic drug, to dabsyl-tagged enzyme substrates to screen cellulases, and for the analysis of plant cell wall hemicellulosics. PMID- 20192187 TI - A chiral wedge molecule inhibits telomerase activity. AB - In addition to the Watson-Crick double helix, secondary DNA structures are thought to play important roles in a variety of biological processes. One important example is the G-quadruplex structure that is formed at the chromosome ends, which inhibits telomerase activity by blocking its access to telomeres. G quadruplex structures represent a new class of molecular targets for DNA interactive compounds that may be useful to target telomeres. Here, we reported the first example of enantioselective recognition of quadruplex DNA by a chiral cyclic helicene. We propose a new ligand-binding cleft between two telomeric human G-quadruplexes linked by a TTA linker. We found that the cyclic helicene M1 exhibited potent inhibitory activity against telomerase. PMID- 20192188 TI - Self-assembly of linear-dendritic diblock copolymers: from nanofibers to polymersomes. AB - We report the formation of cylindrical micelles, sheet-like micelles, tubular micelles, as well as polymer vesicles by a new series of amphiphilic linear dendritic block-copolymers (BCs). The BCs, noted as PEGm-AZOn, are composed of poly(ethylene glycol) (PEG) chains of different molecular weights as hydrophilic blocks and the first four generations of azobenzene-containing dendrons based on 2,2-bis(hydroxymethyl)propionic acid (bis-MPA) as hydrophobic blocks (m represents the degree of polymerization of PEG, and n is the number of azobenzene units at the periphery of dendron). The polymeric aggregates were formed by adding water to solutions of the BCs in dioxane. The micellar dispersions in water were finally obtained by removing dioxane via dialysis against water. The morphology of the micellar self-assemblies was studied by transmission electron microscopy (TEM), cryo-electron microscopy (cryo-TEM), and atomic force microscopy (AFM). A generation-dependent aggregation behavior was found for the series of BCs PEG45-AZOn. Core-shell structured nanofibers with an inner diameter of 8 nm were observed for the copolymer PEG45-AZO2 (hydrophilic/hydrophobic weight ratio equal to 67/33). Lyotropic liquid crystalline behavior was detected for the aqueous solution of the nanofibers. The coexistence of sheet-like aggregates and tubular micelles was detected for the copolymer PEG45-AZO8 in which the number of cyanoazobenzene units is increased to 8 (hydrophilic/hydrophobic weight ratio equal to 33/67). The tubular micelles could be intermediates in the sheet-like aggregate-to-vesicle transition. Polymer vesicles (polymersomes) with a diameter in the range 300-800 nm were observed for the copolymer PEG45-AZO16 (hydrophilic/hydrophobic weight ratio equal to 20/80). The membrane of the sheet-like aggregates, tubular micelles, and polymersomes was shown to have a bilayer structure, as revealed by cryo-TEM. UV illumination of the aqueous polymersome dispersion induced the formation of wrinkles in the vesicle membrane, thus showing that this type of polymeric aggregate is photoresponsive. PMID- 20192189 TI - Just a proton: distinguishing the two electronic states of five-coordinate high spin iron(II) porphyrinates with imidazole/ate coordination. AB - We report detailed studies on two S = 2 electronic states of high-spin iron(II) porphyrinates. These two states are exemplified by the five-coordinate derivatives with either neutral imidazole or anionic imidazolate as the axial ligand. The application of several physical methods all demonstrate distinctive differences between the two states. These include characteristic molecular structure differences, Mossbauer spectra, magnetic circular dichroism spectroscopy, and integer-spin EPR spectral distinctions. These distinctions are supported by DFT calculations. The two states are characterized by very different spatial properties of the doubly occupied orbital of the high-spin that are consonant with the physical properties. PMID- 20192191 TI - Intramolecular cation-pi interactions as the driving force to restrict the conformation of certain nucleosides. AB - Despite the well-established importance of intermolecular cation-pi interactions in molecular recognition, intramolecular cation-pi interactions have been less studied. Here we describe how the simultaneous presence of an aromatic ring at the 5'-position of an inosine derivative and a positively charged imidazolium ring in the purine base drive the conformation of the nucleoside toward a very major conformer in solution that is stabilized by an intramolecular cation-pi interaction. Therefore, the cation-pi interaction between imidazolium ions and aromatic rings can also be proposed in the design of small molecules where this type of interaction is desirable. The imidazolium ion can be obtained by a simple acidification of the pH of the media. So a simple change in pH can shift the conformational equilibrium from a random to a restricted conformation stabilized by an intramolecular cation-pi interaction. Thus the here described nucleosides can be considered as a new class of pH-dependent conformationally switchable molecules. PMID- 20192190 TI - Elucidation of the structure of the membrane anchor of penicillin-binding protein 5 of Escherichia coli. AB - Penicillin-binding protein 5 (PBP 5) of Escherichia coli is a membrane-bound cell wall dd-carboxypeptidase, localized in the outer leaflet of the cytosolic membrane of this Gram-negative bacterium. Not only is it the most abundant PBP of E. coli, but it is as well a target for penicillins and is the most studied of the PBP enzymes. PBP 5, as a representative peripheral membrane protein, is anchored to the cytoplasmic membrane by the 21 amino acids of its C-terminus. Although the importance of this terminus as a membrane anchor is well recognized, the structure of this anchor was previously unknown. Using natural isotope abundance NMR, the structure of the PBP 5 anchor peptide within a micelle was determined. The structure conforms to a helix-bend-helix-turn-helix motif and reveals that the anchor enters the membrane so as to form an amphiphilic structure within the interface of the hydrophilic/hydrophobic boundary regions near the lipid head groups. The bend and the turn within the motif allow the C terminus to exit from the same side of the membrane that is penetrated. The PBP anchor sequences represent extraordinary diversity, encompassing both N-terminal and C-terminal anchoring domains. This study establishes a surface adherence mechanism for the PBP 5 C-terminus anchor peptide, as the structural basis for further study toward understanding the role of these domains in selecting membrane environments and in the assembly of the multienzyme hyperstructures of bacterial cell wall biosynthesis. PMID- 20192192 TI - Organic radicals as spin filters. AB - Molecular spintronics has received extensive interest in recent years. Due to their favorable properties such as long spin coherence lengths and an amenability to fine-tuning via chemical substituents, organic materials play a prominent role in this field. Here we discuss how organic radicals may act as spin filters in the coherent tunneling regime and how they may be tuned to filter either majority or minority-spin electrons by adding electron-donating or -withdrawing substituents. For a set of benzene-based model systems, we identify dips in the spin-resolved transmission, which may be caused by destructive interference, as a desirable feature when aiming for efficient spin filtering. Furthermore, the qualitative predictions made for our model systems are shown to be transferable to larger stable radicals. PMID- 20192193 TI - Critical nuclei size, initial particle size and packing effect on the phase stability of sol-peptization-gel-derived nanostructured titania. AB - The influence of the initial particle size and packing of anatase crystallites on the phase stability of nanostructured titania was investigated. Dried anatase gels with different degrees of particle packing were prepared through the peptization-induced electrostatic stabilization of primary particles in the sol. The initial size of anatase primary particles was varied by precalcination prior to the anatase-rutile phase transformation that occurred during final calcination. In the case of well-packed titania, the initial size of anatase primary particles does not influence the phase-transformation behavior whereas loosely packed titania shows a strong initial anatase primary particle size dependence on the phase-transformation behavior. PMID- 20192194 TI - Two-component dendritic chain reactions: experiment and theory. AB - New analytical diagnostic techniques that are based on signal-amplification mechanisms could significantly improve the sensitivity of detection of various analytes. We have developed a new approach to achieving exponential amplification of a diagnostic signal through a two-component dendritic chain reaction. The chain reaction generated the analyte of interest and thereby initiated additional diagnostic cycles. The system was designed for the detection of hydrogen peroxide and produced significantly larger intensity of diagnostic signal than a classic probe. In addition, a mathematical model that simulates the disassembly kinetics of one-component and two-component reactions was developed and shown to correlate well with the observed experimental data. The modularity and flexibility of a two component detection system should allow extension to the detection of other analytes. PMID- 20192196 TI - Onset of carbon-carbon bonding in Ta(5)C(y) (y = 0-6) clusters: a threshold photoionization and density functional theory study. AB - We have used photoionization efficiency spectroscopy to determine ionization energies (IEs) of the gas-phase tantalum-carbide clusters Ta(5)C(y) (y = 0-6). The structures of the clusters observed in the experiment are assigned by comparing the experimental IEs with those of candidate isomers, calculated by density functional theory. Two competing geometries of the underlying Ta(5) cluster are found to be present in the assigned Ta(5)C(y) structures; either a "prolate" or "distorted oblate" trigonal bipyramid geometry. The onset of carbon carbon bonding in the Ta(5)C(y) series is proposed to occur at y = 6, with the structure of Ta(5)C(6) containing two molecular C(2) units. PMID- 20192195 TI - Computational design and elaboration of a de novo heterotetrameric alpha-helical protein that selectively binds an emissive abiological (porphinato)zinc chromophore. AB - The first example of a computationally de novo designed protein that binds an emissive abiological chromophore is presented, in which a sophisticated level of cofactor discrimination is pre-engineered. This heterotetrameric, C(2)-symmetric bundle, A(His):B(Thr), uniquely binds (5,15-di[(4 carboxymethyleneoxy)phenyl]porphinato)zinc [(DPP)Zn] via histidine coordination and complementary noncovalent interactions. The A(2)B(2) heterotetrameric protein reflects ligand-directed elements of both positive and negative design, including hydrogen bonds to second-shell ligands. Experimental support for the appropriate formulation of [(DPP)Zn:A(His):B(Thr)](2) is provided by UV/visible and circular dichroism spectroscopies, size exclusion chromatography, and analytical ultracentrifugation. Time-resolved transient absorption and fluorescence spectroscopic data reveal classic excited-state singlet and triplet PZn photophysics for the A(His):B(Thr):(DPP)Zn protein (k(fluorescence) = 4 x 10(8) s(-1); tau(triplet) = 5 ms). The A(2)B(2) apoprotein has immeasurably low binding affinities for related [porphinato]metal chromophores that include a (DPP)Fe(III) cofactor and the zinc metal ion hemin derivative [(PPIX)Zn], underscoring the exquisite active-site binding discrimination realized in this computationally designed protein. Importantly, elements of design in the A(His):B(Thr) protein ensure that interactions within the tetra-alpha-helical bundle are such that only the heterotetramer is stable in solution; corresponding homomeric bundles present unfavorable ligand-binding environments and thus preclude protein structural rearrangements that could lead to binding of (porphinato)iron cofactors. PMID- 20192198 TI - Reaction of alpha-ene-vinylcyclopropanes: type II intramolecular [5+2] cycloaddition or [3+2] cycloaddition? AB - Exposure of alpha-ene-VCPs to catalytic [Rh(dppm)]SbF(6) led to the discovery of a novel Rh(I)-catalyzed [3+2] reaction, which was shown to be efficient for the construction of 5/6- and 5/7-bicyclic compounds rather than the anticipated type II [5+2] products. PMID- 20192197 TI - Nickel, manganese, cobalt, and iron-catalyzed deprotonative arene dimerization. AB - A number of first-row transition metal salts catalyze deprotonative dimerization of acidic arenes. Under the atmosphere of oxygen, nickel, manganese, cobalt, and iron chlorides have been shown to dimerize five- and six-membered ring heterocycles as well as electron-poor arenes. Both tetramethylpiperidide and dicyclohexylamide bases can be employed; however, the former afford slightly higher yields. PMID- 20192199 TI - Nanomagnetic competition assay for low-abundance protein biomarker quantification in unprocessed human sera. AB - A novel giant magnetoresistive sensor and uniform high-magnetic-moment FeCo nanoparticles (12.8 nm)-based detecting platform with minimized detecting distance was developed for rapid biomolecule quantification from body fluids. Such a system demonstrates specific, accurate, and quick detection and quantification of interleukin-6, a low-abundance protein and a potential cancer biomarker, directly in 4 muL of unprocessed human sera. This platform is expected to facilitate the identification and validation of disease biomarkers. It may eventually lead to a low-cost personal medical device for chronic disease early detection, diagnosis, and prognosis. PMID- 20192200 TI - Magnetic properties of transition-metal-doped tubular gold clusters: M@Au(24) (M = V, Cr, Mn, Fe, Co, and Ni). AB - The energetic and magnetic properties of the tubular cluster Au(24), doped endohedrally by a 3d transition-metal atom M (M = V, Cr, Mn, Fe, Co, and Ni) have been investigated by the scalar relativistic density functional simulations. It is found that (1) these 3d transition-metal atoms can be encapsulated stably into the tubular Au(24) and do not significantly perturb the atomic and electronic structures of the parent tubular Au(24), (2) the infrared (IR) spectra of the tubular Au(24) cluster are significantly changed by the dopant atoms, inducing a characteristic absorption peak in the IR spectra of all the M@Au(24), and (3) protected by the tubular Au(24), the 3d states of the dopant atoms are largely localized, and the atom-like magnetism is retained for all the doped gold clusters, exhibiting 3, 6, 5, 4, 3, and 2 mu(B) for V-Ni, respectively. PMID- 20192202 TI - Substituent effects on dynamics at conical intersections: cyclopentadienes. AB - Substituent effects on dynamics at conical intersections are investigated by means of femtosecond time-resolved photoelectron spectroscopy for cyclopentadiene and its substituted analogues 1,2,3,4-tetramethylcyclopentadiene, 1,2,3,4,5 pentamethylcyclopentadiene, and 1,2,3,4-tetramethyl-5-propylcyclopentadiene. By UV excitation to the S(2) (1(1)B(2)) state, the influence of these substitutions on dynamics for the initially excited S(2) (1(1)B(2)) surface and the spectroscopically dark S(1) (2(1)A(1)) surface were investigated. We observed that the dynamics depend only on a small number of specific vibrations. Whereas dynamics at the S(2)/S(1)-conical intersection are independent of substitution at the 5-position, internal conversion dynamics on the S(1) (2(1)A(1)) surface slow down as the inertia of the 5-substituent increases. Contrary to the expectations of simple models of radiationless transitions, an increasing density of states does not lead to faster processes, suggesting that a true dynamical picture of vibrational motions at conical intersections will be required. PMID- 20192201 TI - BF3-promoted synthesis of diarylhexahydrobenzo[f]isoquinoline. AB - An easy and straightforward synthesis of 6,10b diarylhexahydrobenzo[f]isoquinoline by the repeated treatment of boron trifluoride etherate (BF(3) x OEt(2)) is reported. The overall transformation from 4-arylpiperidin-3-one to benzo[f]isoquinoline proceeds via ring contraction, chain elongation, and intramolecular electrophilic cyclization in moderate yields. It presents a novel rearrangement reaction catalyzed by boron trifluoride etherate and broadens the scope of application. PMID- 20192203 TI - Z-selective intramolecular Horner-Wadsworth-Emmons reaction for the synthesis of macrocyclic lactones. AB - When the substrates (ArO)(2)P(O)CH(2)CO(2)---CHO (Ar = Ph, o-t-BuPh) were added to a THF solution containing 3 equiv of NaH at 0 degrees C or NaI-DBU at rt over 1-10 h, the intramolecular Horner-Wadsworth-Emmons reaction proceeded efficiently to give the 12-18-membered-ring lactones in 69-93% yields with 89-100% Z selectivity. On the other hand, (EtO)(2)P(O)CH(2)CO(2)---CHO gave the 13-18 membered-ring lactones in 52-82% yields with 89-99% E selectivity using LiCl-DBU in MeCN or THF. PMID- 20192204 TI - Effects of cooking and subcellular distribution on the bioaccessibility of trace elements in two marine fish species. AB - In current human health risk assessment, the maximum acceptable concentrations of contaminants in food are mostly based on the total concentrations. However, the total concentration of contaminants may not always reflect the available amount. Bioaccessibility determination is thus required to improve the risk assessment of contaminants. This study used an in vitro digestion model to assess the bioaccessibility of several trace elements (As, Cd, Cu, Fe, Se, and Zn) in the muscles of two farmed marine fish species (seabass Lateolabrax japonicus and red seabream Pagrosomus major ) of different body sizes. The total concentrations and subcellular distributions of these trace elements in fish muscles were also determined. Bioaccessibility of these trace elements was generally high (>45%), and the lowest bioaccessibility was observed for Fe. Cooking processes, including boiling, steaming, frying, and grilling, generally decreased the bioaccessibility of these trace elements, especially for Cu and Zn. The influences of frying and grilling were greater than those of boiling and steaming. The relationship of bioaccessibility and total concentration varied with the elements. A positive correlation was found for As and Cu and a negative correlation for Fe, whereas no correlation was found for Cd, Se, and Zn. A significant positive relationship was demonstrated between the bioaccessibility and the elemental partitioning in the heat stable protein fraction and in the trophically available fraction, and a negative correlation was observed between the bioaccessibility and the elemental partitioning in metal-rich granule fraction. Subcellular distribution may thus affect the bioaccessibility of metals and should be considered in the risk assessment for seafood safety. PMID- 20192206 TI - Bound volatile precursors in genotypes in the pedigree of 'Marion' blackberry (Rubus sp.). AB - Glycosidically bound volatiles and precursors in genotypes representing the pedigree for 'Marion' blackberry were investigated over two growing seasons. The volatile precursors were isolated using a C18 solid-phase extraction column. After enzymatic hydrolysis, the released volatiles were analyzed using stir bar sorptive extraction gas chromatography-mass spectrometry (GC-MS) and direct microvial insert thermal desorption GC-MS. The most abundant volatile precursors in the genotypes were alcohols, followed by shikimic acid derivatives. High amounts of furanone glycosides were also detected, while norisoprenoids only existed in a small amount in blackberries. The volatile precursor composition in the genotypes in the 'Marion' pedigree was very similar to their free volatile distribution. 'Logan' and 'Olallie' predominantly had bound norisoprenoids. Wild 'Himalaya' predominated with terpene alcohol and furaneol glycosides, whereas 'Santiam' and 'Chehalem' contained a high level of terpene alcohol glycosides. A similar inheritance pattern was also observed for some volatile precursors in the genotypes in the 'Marion' pedigree. A high content of linalool, hydroxylinalool, and alpha-ionol glycosides in 'Olallie' and a low content in 'Chehalem' resulted in a moderate level in their offspring 'Marion', while a low content of (E) linalool oxide precursor in 'Olallie' and a high content in 'Chehalem' also resulted in a moderate level in 'Marion'. However, the concentration of furaneol glycosides in 'Marion' exceeded that of its two parents. PMID- 20192205 TI - Fruiting body of Niuchangchih (Antrodia camphorata) protects livers against chronic alcohol consumption damage. AB - An alcoholic fatty liver disease was induced by drinking water containing 20% (w/w) alcohol. Therapeutic groups were orally administrated dosages of 0.25 g silymarin/kg body weight (BW) and a low dosage of Niuchangchih (Antrodia camphorata) (0.025 g/kg BW) and a high dosage of Niuchangchih (0.1 g/kg BW) per day. Niuchangchih, especially at the high dosage, not only showed a hypercholesterolemic effect (p < 0.05) but also reduced (p < 0.05) hepatic lipids in alcohol-fed rats. Those beneficial effects could be partially attributed to higher (p < 0.05) fecal cholesterol and bile acid outputs, as well as downregulations (p < 0.05) of 3-hydroxy-3-methylglutaryl-CoA reductase, sterol regulatory element-binding protein-1c, acetyl-CoA carboxylase, fatty acid synthase, and malic enzyme gene expressions; meanwhile, there was an upregulation of low-density lipoprotein receptor and peroxisome proliferator-activated alpha gene expression. Besides, Niuchangchih also enhanced (p < 0.05) the liver glutathione, Trolox equivalent antioxidant capacity, and activities of superoxide dismutase, catalase, and glutathione peroxidase and decreased the liver malondialdehyde content, which also partially contributed to the lowered (p < 0.05) serum aspartate aminotransferase levels and no observed lesion in the histological examination of alcohol-fed rats. PMID- 20192207 TI - Conversion of 4,4-difluoro-4-bora-3a,4a-diaza-s-indacenes (F-BODIPYs) to dipyrrins with a microwave-promoted deprotection strategy. AB - 4,4-Difluoro-4-bora-3a,4a-diaza-s-indacenes (F-BODIPYs) have been deprotected to give the corresponding free-base dipyrrins by heating a solution of the F-BODIPY in tert-butanol under 600 W of microwave irradiation in the presence of 6 equiv of potassium tert-butoxide for 40 min at 92 degrees C. Investigations of BODIPY modification at the meso position have also been undertaken and a meso-butyl product has been isolated. PMID- 20192208 TI - 3,4-Propylenedioxypyrrole-based conjugated oligomers via Pd-mediated decarboxylative cross coupling. AB - An effective decarboxylative cross-coupling involving a 3,4-dioxypyrrole is reported. Several conjugated oligomers were synthesized in high yields using various aryl bromides. No copper salt or other transmetalating agent was required. The reaction conditions employed displayed relatively low sensitivity toward the presence of water. PMID- 20192209 TI - Ga(III)-catalyzed cycloisomerization approach to (+/-)-icetexone and (+/-)-epi icetexone. AB - A Ga(III)-catalyzed cycloisomerization reaction provides expedient access to a benzannulated cycloheptadiene bearing a cyano group, which has been applied to the syntheses of several icetexane diterpenoids including icetexone and epi icetexone. Key to the synthesis is a novel in situ generated diazene rearrangement. PMID- 20192210 TI - First report on Cydonia oblonga Miller anticancer potential: differential antiproliferative effect against human kidney and colon cancer cells. AB - The present study reports the phenolic profile and antiproliferative properties of quince (Cydonia oblonga Miller) leaf and fruit (pulp, peel, and seed) against human kidney and colon cancer cells. The phenolic profiles of quince methanolic extracts were determined by high-performance liquid chromatography (HPLC)/diode array detector (DAD). 5-O-Caffeoylquinic acid was always one of the two major phenolic compounds present in all extracts, except for seed. Our results revealed that quince leaf and fruit extracts exhibited distinctive antiproliferative activities. The extracts from quince leaf showed concentration-dependent growth inhibitory activity toward human colon cancer cells (IC(50) = 239.7 +/- 43.2 microg/mL), while no effect was observed in renal adenocarcinoma cells. Concerning the fruit, seed extracts exhibited no effect on colon cancer cell growth, whereas strong antiproliferative efficiency against renal cancer cells was observed for the highest concentration assayed (500 microg/mL). The antiproliferative activity of pulp and peel extracts was low or absent in the selected range of extract concentrations. This is the first report showing that C. oblonga may be useful as a cancer chemopreventive and/or chemotherapeutic agent. PMID- 20192211 TI - Rigid hydrophilic structures for improved properties of conjugated polymers and nitrotyrosine sensing in water. AB - The efficient synthesis of a hydrophilic monomer bearing a three-dimensional noncompliant array of hydroxyl groups is described that prevents water-driven excimer features of hydrophobic poly(p-phenylene ethynylene) backbones. Sensitivity of the polymer to 3-nitrotyrosine is also discussed. PMID- 20192212 TI - Determination of chloramphenicol residues in milk by enzyme-linked immunosorbent assay: improvement by biotin-streptavidin-amplified system. AB - A sensitive biotin-streptavidin amplified enzyme-linked immunosorbent assay (BA ELISA) method was developed for the determination of chloramphenicol residues in milk. The biotin-streptavidin system was applied to enhance the sensitivity. After optimization, the detection limit of the method was found to be 0.042 +/- 0.006 ng mL(-1), which is 8-fold more sensitive than the traditional competitive ELISA using the same antibody and coating antigen. The amplification mechanism of the biotin-streptavidin system and the major factors affecting the sensitivity of detection are discussed. This method was successfully applied to determine the chloramphenicol residues in milk samples with a simple and rapid extraction procedure, and good recoveries (85.66-109.67%) were obtained. The result indicated that the biotin-streptavidin system may be a valuable tool to improve the specific detection of trace veterinary drug residues and could be widely used for routine monitoring of food samples. PMID- 20192213 TI - Two-step total syntheses of canthin-6-one alkaloids: new one-pot sequential Pd catalyzed Suzuki-Miyaura coupling and Cu-catalyzed amidation reaction. AB - Canthin-6-one (1) and nine analogues including the naturally occurring 9 methoxycanthin-6-one (2) and amaroridine (3) are prepared rapidly and in high yields via a convergent "non-classical" strategy that focuses on construction of the central ring B. The strategy relies on concomitant Pd-catalyzed Suzuki Miyaura C-C coupling followed by a Cu-catalyzed C-N coupling that can be achieved either stepwise or in a new one-pot protocol starting from the appropriate 8 bromo-1,5-naphthyridine. PMID- 20192214 TI - Redox-active ligands facilitate bimetallic O2 homolysis at five-coordinate oxorhenium(V) centers. AB - Five-coordinate oxorhenium(V) anions with redox-active catecholate and amidophenolate ligands are shown to effect clean bimetallic cleavage of O(2) to give dioxorhenium(VII) products. A structural homologue with redox-inert oxalate ligands does not react with O(2). Redox-active ligands lower the kinetic barrier to bimetallic O(2) homolysis at five-coordinate oxorhenium(V) by facilitating formation and stabilization of intermediate O(2) adducts. O(2) activation occurs by two sequential Re-O bond forming reactions, which generate mononuclear eta(1) superoxo species, and then binuclear trans-mu-1,2-peroxo-bridged complexes. Formation of both Re-O bonds requires trapping of a triplet radical dioxygen species by a cis-[Re(V)(O)(cat)(2)](-) anion. In each reaction the dioxygen fragment is reduced by 1e(-), so generation of each new Re-O bond requires that an oxometal fragment is oxidized by 1e(-). Complexes containing a redox-active ligand access a lower energy reaction pathway for the 1e(-) Re-O bond forming reaction because the metal fragment can be oxidized without a change in formal rhenium oxidation state. It is also likely that redox-active ligands facilitate O(2) homolysis by lowering the barrier to the formally spin-forbidden reactions of triplet dioxygen with the closed shell oxorhenium(V) anions. By orthogonalizing 1e(-) and 2e(-) redox at oxorhenium(V), the redox-active ligand allows high-valent rhenium to utilize a mechanism for O(2) activation that is atypical of oxorhenium(V) but more typical for oxygenase enzymes and models based on 3d transition metal ions: O(2) cleavage occurs by a net 2e(-) process through a series of 1e(-) steps. The implications for design of new multielectron catalysts for oxygenase-type O(2) activation, as well as the microscopic reverse reaction, O-O bond formation from coupling of two M=O fragments for catalytic water oxidation, are discussed. PMID- 20192215 TI - Adsorption equilibria of water vapor on cork. AB - We report here for the first time a complete thermodynamic study of water vapor adsorption on crude cork powder and plate. Adsorption-desorption isotherms were accurately measured by thermogravimetry at 283, 298, and 313 K in a large range of relative pressure. Adsorption enthalpies were determined by calorimetry as a function of loading. Adsorption-desorption isotherms exhibit a hysteresis due to the swelling of the material. The influence of the presence of lenticels on the adsorption properties of cork is found to be negligible. A detailed analysis and interpretation of adsorption data allow proposal of an adsorption mechanism in two steps. (i) First, water adsorbs on hydrophilic sites constituted by hydroxyl and methoxyl groups. (ii) Then water adsorption continues by clusters formation around the hydrophilic sites. PMID- 20192216 TI - Combined use of thermomechanics and UV spectroscopy to rationalize the kinetics of bioactive compound (caffeine) mobility in a high solids matrix. AB - An investigation of the diffusional mobility of a bioactive compound (caffeine) within a carbohydrate matrix (glucose syrup) at a glassy consistency is reported. The experimental temperature range was from 30 to - 70 degrees C, and the techniques of modulated differential scanning calorimetry, small-deformation dynamic oscillation on shear, and UV spectrometry were employed. It is not a straightforward matter to identify the relaxation dynamics of such a glassy matrix. This makes suggestions of the relationship between the structural properties of the matrix and the diffusional mobility of bioactive compounds reported earlier in the literature rather tenuous. To address this issue, we recorded mechanical spectra over the aforementioned temperature range and utilized the combined framework of the Williams, Landel, and Ferry (WLF) equation with the time-temperature superposition principle to rationalize results. The protocol produced a fundamental definition of the glass transition temperature and free volume parameters of the glucose syrup sample within the glass transition region. Results were related to the kinetic rates of caffeine diffusion derived by UV spectroscopy leading to the conclusion that the diffusional mobility of the chemical substance is independent of the carbohydrate matrix. This conclusion was further supported by the high level of fractional free volume of caffeine, which is congruent with the predictions of the reaction rate theory (modified Arrhenius equation), as compared to the collapsing levels of free volume in the glucose-syrup matrix that make appropriate WLF considerations. PMID- 20192218 TI - Long-chain N-vanillyl-acylamides from Capsicum oleoresin. AB - N-Vanillyl-acylamides (NVAs) naturally occur as capsaicinoids in Capsicum plants. NVAs with a longer chain acyl moiety (LCNVAs) have been developed as attractive tools for medicinal usage because of their capsaicin-like bioactive and physiological properties, without harmful irritancy. In this study, we isolated four LCNVAs from Capsicum oleoresin. Their structures were determined to be N vanillyl-hexadecanamide (palvanil, 2), N-vanillyl-octadecanamide (stevanil, 3), N vanillyl-9E-octadecenamide (olvanil, 4), and N-vanillyl-9E,12E-octadecadienamide (livanil, 5) by spectroscopic analysis and gas chromatography-mass spectrometry analysis of their methanolysis products. Furthermore, the existence of two LCNVAs in oleoresin, N-vanillyl-tetradecanamide (myrvanil, 1) and N-vanillyl-9E,12E,15E octadecatrienamide (linvanil, 6), was suggested. The contents of these LCNVAs and the major capsaicinoids-capsaicin and dihydrocapsaicin-in three Capsicum oleoresins and the fresh fruits of two hot peppers were measured by a liquid chromatography-tandem mass spectrometry system. The content ratios of the total LCNVAs, except for myrvanil, versus the capsaicin in the oleoresins (0.1-41%) was significantly larger than that in fresh fruits (<0.01%). The composition of these LCNVAs in each oleoresin was similar to that of fatty acids in the oil fraction of each oleoresin. We observed no relationship between the composition of these LCNVAs in the fresh fruits. PMID- 20192217 TI - Anti-inflammatory bioactivities of honokiol through inhibition of protein kinase C, mitogen-activated protein kinase, and the NF-kappaB pathway to reduce LPS induced TNFalpha and NO expression. AB - Much recent research has demonstrated that honokiol, a phenolic compound originally isolated from Magnolia officinalis, has potent anticancer activities; however, the detailed molecular mechanism of its anti-inflammatory activity has not yet been fully addressed. In this study we demonstrated that honokiol inhibited lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha secretion in macrophages, without affecting the activity of the tumor necrosis factor-alpha converting enzyme. At the same time, honokiol not only inhibited nitric oxide expression in LPS-stimulated murine macrophages but also inhibited the LPS induced phosphorylation of ERK1/2, JNK1/2, and p38. By means of confocal microscope analysis we demonstrated that phosphorylation and membrane translocation of protein kinase C-alpha, as well as NF-kappaB activation, were inhibited by honokiol in LPS-stimulated macrophages. Furthermore, it was found that honokiol neither antagonizes the binding of LPS to cells nor alters the cell surface expression of toll-like receptor 4 and CD14. Our current results have exhaustively described the anti-inflammatory properties of honokiol, which could lead to the possibility of its future pharmaceutical application in the realm of immunomodulation. PMID- 20192219 TI - Acrolein in wine: importance of 3-hydroxypropionaldehyde and derivatives in production and detection. AB - Certain lactic acid bacteria strains belonging to the genus Lactobacillus have been implicated in the accumulation of 3-hydroxypropionaldehyde (3-HPA) during anaerobic glycerol fermentation. In aqueous solution 3-HPA undergoes reversible dimerization and hydration, resulting in an equilibrium state between different derivatives. Wine quality may be compromised by the presence of 3-HPA due to the potential for spontaneous conversion into acrolein under winemaking conditions. Acrolein is highly toxic and has been implicated in the development of bitterness in wine. Interconversion between 3-HPA derivatives and acrolein is a complex and highly dynamic process driven by hydration and dehydration reactions. Acrolein is furthermore highly reactive and its steady-state concentration in complex systems very low. As a result, analytical detection and quantification in solution is problematic. This paper reviews the biochemical and environmental conditions leading to accumulation of its precursor, 3-HPA. Recent advances in analytical detection are summarized, and the roles played by natural chemical derivatives are highlighted. PMID- 20192220 TI - Bioactive compounds of four hot pepper varieties (Capsicum annuum L.), antioxidant capacity, and intestinal bioaccessibility. AB - Pepper fruits (Capsicum annuum) contain a wide array of phytochemicals with well known antioxidant properties. Since bioactive compounds depend on their bioavailability to exert beneficial effects, it was crucial to estimate the extent of release from the food matrix and thus their bioaccessibility. Accordingly, we determined the individual carotenoid and phenolic content as well as the antioxidant properties of four red hot dried cultivars (Capsicum annuum L.) of high consumption in Mexico and estimated the extent of intestinal bioaccessibility of carotenoids with significance in human health, beta-carotene, beta-cryptoxanthin, and zeaxanthin, using an in vitro gastrointestinal model. Hot dried peppers at ripe stage had a high content of bioactive compounds that exhibited significant antioxidant properties (26-80 micromol trolox equivalents/g of dry matter), such as polyphenols (>2000 mg/100 g of dry matter) and carotenoids (95-437 mg/100 g of dry matter), which were partially bioaccessible. The amount released from the food matrix by the action of digestive enzymes was about 75% for total polyphenols, up to 49% for both beta-carotene and zeaxanthin, and up to 41% for beta-cryptoxanthin. The results suggest that from 50 to 80% of these carotenoids could reach the colon to be potentially fermented or could remain unavailable. PMID- 20192222 TI - Metalla-cope rearrangements: bridging organic and inorganic chemistry. AB - Density functional theory calculations are performed to explore both concerted chairlike and boatlike as well as stepwise mechanisms of the Cope rearrangement of two hypothetical metalladienes. An osma-1,5-hexadiene is designed by substituting CH(2) in 1,5-hexadiene by its isolobal analogue, 16-electron Os(PH(3))(4). The energy of activation corresponding to the rearrangement of osma 1,5-hexadiene involving the chairlike saddle point is computed as 37.4 kcal/mol, 3.9 kcal/mol above the energy barrier of the parent 1,5-hexadiene calculated with the same method and basis set, and is 4.5 kcal/mol below that of the boatlike pathway. In another isolobal replacement, the CH in 1,5-hexadiene is substituted by a 15-electron Re(PH(3))(3) fragment. Now the chairlike rearrangement of the rhenia-1,5-hexadiene has an E(a) value of 23.0 kcal/mol, 10.8 kcal/mol less than the energy barrier of the parent 1,5-hexadiene calculated at the same level of theory. The ring inversion of the chair and osma-chair diradical intermediates of the stepwise reaction pathway is also examined and is found in both cases to proceed through a very flat potential energy surface involving twist intermediates. PMID- 20192221 TI - Highly diastereoselective synthesis of substituted pyrrolidines using a sequence of azomethine ylide cycloaddition and nucleophilic cyclization. AB - Although cycloadditions of azomethine ylides usually give mixtures of endo/exo adducts, we successfully tuned the mechanistic path of a new reaction cascade to afford substituted pyrrolidines in high yields and diastereomeric purity. This was achieved by forcing the demetalation of tin- or silicon-substituted iminium ions, followed by azomethine ylide cycloaddition and nucleophilic cyclization. Structural complexity is thus built rapidly in a fully controlled one-pot reaction cascade. PMID- 20192223 TI - Agonists and antagonists of antennal responses of gypsy moth (Lymantria dispar) to the pheromone (+)-disparlure and other odorants. AB - Insects use the sense of smell to guide many behaviors that are important for their survival. The gypsy moth uses a pheromone to bring females and males together over long distances. Male moth antennae are equipped with innervated sensory hairs that selectively respond to pheromone components and other odors. Host plant odors, in particular, are detected by moths and sometimes cause an enhancement of the antennal and behavioral responses of the moths to their pheromone. Inspired by naturally occurring agonists and antagonists of insect pheromone responses, we have screened, by electroantennogram (EAG) recordings, a collection of compound sets and of individual compounds. We have detected interference of some compounds with the EAG responses of male gypsy moth antennae to the pheromone. We describe three activities: (1) short-term inhibition or enhancement of mixed compound + pheromone plumes, (2) long-term inhibition of pure pheromone plumes following a mixed compound + pheromone plume, and (3) inhibition of the recovery phase of mixed compound + pheromone plumes. Long-term inhibition was robust, decayed within 30 s, and correlated with the inhibition of recovery; for both activities clear structure-activity patterns were detected. The commercial repellent N,N-diethyltoluamide (DEET) was included for comparison. The most active and reproducible short-term inhibitor was a mixture of 1-allyl 2,4-dimethoxybenzene and 2-allyl-1,3-dimethoxybenzene. The most active long-term inhibitors were a set of 1-alkoxy-4-propoxybenzenes, DEET, and 1-ethoxy-4 propoxybenzene. DEET was more specific in the olfactory responses it inhibited than 1-ethoxy-4-propoxybenzene, and DEET did not inhibit recovery, whereas 1 ethoxy-4-propoxybenzene did. Target sites for the three activities are discussed. PMID- 20192224 TI - Fragment-based deconstruction of Bcl-xL inhibitors. AB - Fragment-based drug design consists of screening low-molecular-weight compounds in order to identify low-affinity ligands that are then modified or linked to yield potent inhibitors. The method thus attempts to build bioactive molecules in a modular way and relies on the hypothesis that the fragment binding mode will be conserved upon elaboration of the active molecule. If the inverse process is considered, do the fragments resulting from the deconstruction of high-affinity inhibitors recapitulate their binding mode in the large molecule? Few studies deal with this issue. Here, we report the analysis of 22 fragments resulting from the dissection of 9 inhibitors of the antiapoptotic protein Bcl-x(L). To determine if the fragments retained affinity toward the protein and identify their binding site, ligand-observed and protein-observed NMR experiments were used. The analysis of the fragments behavior illustrates the complexity of low affinity protein-ligand interactions involved in the fragment-based construction of bioactive molecules. PMID- 20192225 TI - Synthesis and QSAR of quinazoline sulfonamides as highly potent human histamine H4 receptor inverse agonists. AB - Hit optimization of the class of quinazoline containing histamine H(4) receptor (H(4)R) ligands resulted in a sulfonamide substituted analogue with high affinity for the H(4)R. This moiety leads to improved physicochemical properties and is believed to probe a distinct H(4)R binding pocket that was previously identified using pharmacophore modeling. By introducing a variety of sulfonamide substituents, the H(4)R affinity was optimized. The interaction of the new ligands, in combination with a set of previously published quinazoline compounds, was described by a QSAR equation. Pharmacological studies revealed that the sulfonamide analogues have excellent H(4)R affinity and behave as inverse agonists at the human H(4)R. In vivo evaluation of the potent 2-(6-chloro-2-(4 methylpiperazin-1-yl)quinazoline-4-amino)-N-phenylethanesulfonamide (54) (pK(i) = 8.31 +/- 0.10) revealed it to have anti-inflammatory activity in an animal model of acute inflammation. PMID- 20192227 TI - A unique nickel system having versatile catalytic activity of biological significance. AB - A new dinuclear nickel(II) complex, [Ni(2)(LH(2))(H(2)O)(2)(OH)(NO(3))](NO(3))(3) (1), of an "end-off" compartmental ligand 2,6-bis(N-ethylpiperazine-iminomethyl) 4-methyl-phenolato, has been synthesized and structurally characterized. The X ray single crystal structure analysis shows that the piperazine moieties assume the expected chair conformation and are protonated. The complex 1 exhibits versatile catalytic activities of biological significance, viz. catecholase, phosphatase, and DNA cleavage activities, etc. The catecholase activity of the complex observed is very dependent on the nature of the solvent. In acetonitrile medium, the complex is inactive to exhibit catecholase activity. On the other hand, in methanol, it catalyzes not only the oxidation of 3,5-di-tert butylcatechol (3,5-DTBC) but also tetrachlorocatechol (TCC), a catechol which is very difficult to oxidize, under aerobic conditions. UV-vis spectroscopic investigation shows that TCC oxidation proceeds through the formation of an intermediate. The intermediate has been characterized by an electron spray ionizaton-mass spectrometry study, which suggests a bidentate rather than a monodentate mode of TCC coordination in that intermediate, and this proposition have been verified by density functional theory calculation. The complex also exhibits phosphatase (with substrate p-nitrophenylphosphate) and DNA cleavage activities. The DNA cleavage activity exhibited by complex 1 most probably proceeds through a hydroxyl radical pathway. The bioactivity study suggests the possible applications of complex 1 as a site specific recognition of DNA and/or as an anticancer agent. PMID- 20192228 TI - Theoretical study on the possibility of using frustrated lewis pairs as bifunctional metal-free dehydrogenation catalysts of ammonia-borane. AB - Density functional theory calculations have been carried out to study the possibility of using "frustrated Lewis pairs" (FLPs) as bifunctional metal-free dehydrogenation catalysts of ammonia-borane, NH(3)BH(3) (AB), according to the following points: (1) some FLPs react with H(2) at low temperature and the hydrogenated products release H(2) at high temperature; (2) some FLPs hydrogenate imines by taking the protic (N-bound) and hydridic (B-bound) H atoms of AB. In this work, the N/B pair (N-PMTN-CH(2)C(6)H(4)B(C(6)F(5))(2)) is chosen to explore the possibility that FLPs release H(2) from AB. Two steps are involved in the proposed mechanism: first, AB is dehydrogenated by the N/B pair to form the NH/BH compound and NH(2)BH(2) at low temperature, and then H(2) is released from the NH/BH compound at 110 degrees C and the N/B pair regenerates. Several competitive reaction channels have been considered. The calculational results show that the dehydrogenation of AB by the N/B pair has the lowest free-energy barrier. On the basis of the experimental N/B pair, a new dehydrogenation catalyst of AB has been designed, which can release H(2) from AB under milder conditions than the former. This work may be helpful for the experimental chemists to broaden the application of FLPs and to design new dehydrogenation catalysts of AB. PMID- 20192226 TI - Partial steps of charge translocation in the nonpumping N139L mutant of Rhodobacter sphaeroides cytochrome c oxidase with a blocked D-channel. AB - The N139L substitution in the D-channel of cytochrome oxidase from Rhodobacter sphaeroides results in an approximately 15-fold decrease in the turnover number and a loss of proton pumping. Time-resolved absorption and electrometric assays of the F --> O transition in the N139L mutant oxidase result in three major findings. (1) Oxidation of the reduced enzyme by O(2) shows approximately 200 fold inhibition of the F --> O step (k approximately 2 s(-1) at pH 8) which is not compatible with enzyme turnover ( approximately 30 s(-1)). Presumably, an abnormal intermediate F(deprotonated) is formed under these conditions, one proton-deficient relative to a normal F state. In contrast, the F --> O transition in N139L oxidase induced by single-electron photoreduction of intermediate F, generated by reaction of the oxidized enzyme with H(2)O(2), decelerates to an extent compatible with enzyme turnover. (2) In the N139L mutant, the protonic phase of Deltapsi generation coupled to the flash-induced F -> O transition greatly decreases in rate and magnitude and can be assigned to the movement of a proton from E286 to the binuclear site, required for reduction of heme a(3) from the Fe(4+) horizontal lineO(2-) state to the Fe(3+)-OH(-) state. Electrogenic reprotonation of E286 from the inner aqueous phase is missing from the F --> O step in the mutant. (3) In the N139L mutant, the KCN-insensitive rapid electrogenic phase may be composed of two components with lifetimes of approximately 10 and approximately 40 mus and a magnitude ratio of approximately 3:2. The 10 mus phase matches vectorial electron transfer from Cu(A) to heme a, whereas the 40 mus component is assigned to intraprotein proton displacement across approximately 20% of the membrane dielectric thickness. This proton displacement might be triggered by rotation of the charged K362 side chain coupled to heme a reduction. The two components of the rapid electrogenic phase have been resolved subsequently with other D-channel mutants as well as with cyanide-inhibited wild-type oxidase. The finding helps to reconcile the unusually high relative contribution of the microsecond electrogenic phase in the bacterial enzyme ( approximately 30%) with the net electrogenicity of the F --> O transition coupled to transmembrane transfer of two charges per electron. PMID- 20192229 TI - Fabrication and characterization of large-area, semiconducting nanoperforated graphene materials. AB - We demonstrate the fabrication of nanoperforated graphene materials with sub-20 nm features using cylinder-forming diblock copolymer templates across >1 mm(2) areas. Hexagonal arrays of holes are etched into graphene membranes, and the remaining constrictions between holes interconnect forming a honeycomb structure. Quantum confinement, disorder, and localization effects modulate the electronic structure, opening an effective energy gap of 100 meV in the nanopatterned material. The field-effect conductivity can be modulated by 40x (200x) at room temperature (T = 105 K) as a result. A room temperature hole mobility of 1 cm(2) V(-1) s(-1) was measured in the fabricated nanoperforated graphene field effect transistors. This scalable strategy for modulating the electronic structure of graphene is expected to facilitate applications of graphene in electronics, optoelectronics, and sensing. PMID- 20192230 TI - Nanoscale memristor device as synapse in neuromorphic systems. AB - A memristor is a two-terminal electronic device whose conductance can be precisely modulated by charge or flux through it. Here we experimentally demonstrate a nanoscale silicon-based memristor device and show that a hybrid system composed of complementary metal-oxide semiconductor neurons and memristor synapses can support important synaptic functions such as spike timing dependent plasticity. Using memristors as synapses in neuromorphic circuits can potentially offer both high connectivity and high density required for efficient computing. PMID- 20192231 TI - Probing strain in bent semiconductor nanowires with Raman spectroscopy. AB - We present a noninvasive optical method to determine the local strain in individual semiconductor nanowires. InP nanowires were intentionally bent with an atomic force microscope and variations in the optical phonon frequency along the wires were mapped using Raman spectroscopy. Sections of the nanowires with a high curvature showed significantly broadened phonon lines. These observations together with deformation potential theory show that compressive and tensile strain inside the nanowires is the physical origin of the observed phonon energy variations. PMID- 20192232 TI - Photovoltaics with piezoelectric core-shell nanowires. AB - We report on a theoretical discovery of a generic piezoelectric field in strained core-shell compound semiconductor nanowires. We show, using both an analytical model and numerical simulations based on fully electroelastically coupled continuum elasticity theory, that lattice-mismatch-induced strain in an epitaxial core-shell nanowire gives rise to an internal electric field along the axis of the nanowire. This piezoelectric field results predominantly from atomic layer displacements along the nanowire axis within both the core and shell materials and can appear in both zinc blende and wurtzite crystalline core-shell nanowires. The effect can be employed to separate photon-generated electron-hole pairs in the core-shell nanowires and thus offers a new device concept for solar energy conversion. PMID- 20192233 TI - Engineering advanced capsosomes: maximizing the number of subcompartments, cargo retention, and temperature-triggered reaction. AB - Advanced mimics of cells require a large yet controllable number of subcompartments encapsulated within a scaffold, equipped with a trigger to initiate, terminate, and potentially restart an enzymatic reaction. Recently introduced capsosomes, polymer capsules containing thousands of liposomes, are a promising platform for the creation of artificial cells. Capsosomes are formed by sequentially layering liposomes and polymers onto particle templates, followed by removal of the template cores. Herein, we engineer advanced capsosomes and demonstrate the ability to control the number of subcompartments and hence the degree of cargo loading. To achieve this, we employ a range of polymer separation layers and liposomes to form functional capsosomes comprising multiple layers of enzyme-loaded liposomes. Differences in conversion rates of an enzymatic assay are used to verify that multilayers of intact enzyme-loaded liposomes are assembled within a polymer hydrogel capsule. The size-dependent retention of the cargo encapsulated within the liposomal subcompartments during capsosome assembly and its dependence on environmental pH changes are also examined. We further show that temperature can be used to trigger an enzymatic reaction at the phase transition temperature of the liposomal subcompartments, and that the encapsulated enzymes can be utilized repeatedly in several subsequent conversions. These engineered capsosomes with tailored properties present new opportunities en route to the development of functional artificial cells. PMID- 20192234 TI - Photoreduction at a distance: facile, nonlocal photoreduction of Ag ions in solution by plasmon-mediated photoemitted electrons. AB - Surface-immobilized, densely packed gold nanoparticles in contact with aqueous silver ions and exposed to red light rapidly photoreduce silver ions in solution producing radially symmetric metal deposits with diameters many times larger than the diameter of the illuminating laser beam. The average particle sizes in the deposit increase with radial distance from the center of the deposit. This reduction-at-a-distance effect arises from surface-plasmon-mediated photoemission, with the photoemitted electrons conducting along percolating silver pathways, reducing silver ions along these conducting channels and especially at their periphery, thereby propagating the effect of the illuminating laser outward. PMID- 20192235 TI - Controlling half-metallicity of graphene nanoribbons by using a ferroelectric polymer. AB - On the basis of first-principles computational approaches, we present a new method to drive zigzag graphene nanoribons (ZGNRs) into the half-metallic state using a ferroelectric material, poly(vinylidene fluoride) (PVDF). Owing to strong dipole moments of PVDFs, the ground state of the ZGNR becomes half-metallic when a critical coverage of PVDFs is achieved on the ZGNR. Since ferroelectric polymers are physisorbed, the direction of the dipole field in PVDFs can be rotated by relatively small external electric fields, and the switching between half-metallic and insulating states may be achieved. Our results suggest that, without excessively large external gate electric fields, half-metallic states of ZGNRs are realizable through the deposition of ferroelectric polymers and their electronic and magnetic properties are controllable via noninvasive mutual interactions. PMID- 20192236 TI - Terpenoids from Daphne aurantiaca and their potential anti-inflammatory activity. AB - Phytochemical examination of the methanolic extract from the stem bark of Daphne aurantiaca led to the isolation of six new sesquiterpenoids, dauca-3,11-dien 2alpha,15-diol (1), 3-oxoguai-4-ene-11,12-diol (2), 4alpha,5alpha,8alpha,11alphaH 3-oxoguai-1(10)-en-12,8-olide-7alpha-diol (3), 4alpha,5alpha,8alpha,11betaH-3 oxoguai-1(10)-en-12,8-olide-7beta-diol (4), 4alpha,5betaH-guai-9,7(11)-dien-12,8 olide-1alpha,8alpha-diol (5), 4alpha,5alphaH-guai-9,7(11)-dien-12,8-olide 1alpha,8alpha-diol (6), and a new diterpenoid, 12-O-benzoylphorbol 13-nonanoate (7), together with 10 known terpenoids. All compounds were tested for inhibitory activity against LPS-induced NO production in RAW 264.7 macrophages. Compounds 7, 8, 9, 10, and 11 showed potent inhibitory activities against NO production with IC(50) values of 0.01, 0.01, 0.06, 0.07, and 0.03 microM, respectively. PMID- 20192237 TI - Hyaluronidase inhibitors from "Cimicifugae Rhizoma" (a mixture of the rhizomes of Cimicifuga dahurica and C. heracleifolia). AB - From the 80% acetone extract of "Cimicifugae Rhizoma" (a mixture of Cimicifuga dahurica and C. heracleifolia used medicinally), seven new fukiic acid derivatives (1-7) and a new phenylethanoid derivative (8) were isolated along with eight known compounds (9-16). Fukinolic acid (9) and cimicifugic acids A-J (10-16, 5-7) showed stronger hyaluronidase inhibitory activities than the positive control, rosmarinic acid. PMID- 20192238 TI - Synergistic effects on second harmonic generation of hybrid CdSe-Au nanoparticles. AB - Hybrid semiconductor-metal nanoparticles exhibit a combination of properties from the disparate components or even, more interestingly, synergetic properties which arise from the coupling between the two materials. In this work, we study the second harmonic generation (SHG) in CdSe-Au hybrid nanoparticles in comparison with their components, using the Hyper-Rayleigh scattering (HRS) method. Possible contribution of symmetry effects was studied by comparing symmetric two-sided gold-tipped CdSe nanodumbbells with asymmetric one-sided quantum dot-Au (QD-Au) hybrids. A simplistic view of a symmetry effect is disproved in this case by the experimental data, which shows an unexpected reduction in the SHG response in both cases, compared to the respective mixtures of Au and CdSe nanoparticles. For CdSe-Au hybrids with a long semiconductor rod segment, we find that the SHG response corresponds to a sum of the contributions from the semiconductor and the metal components. However, for QD-Au and smaller dumbbells, the SHG response is smaller than expected from a simple sum of the contribution from both components. This reduction is assigned to the effects related to the CdSe-Au interfacial region within these hybrids. A first plausible contribution to the reduction is the dephasing induced by the gold, leading to diminished SHG from the CdSe component. This reduced response of the semiconductor component is accompanied by reduced SHG from the gold component which is assigned to a partial change of the surface of the gold once an interface with CdSe is formed. These observations regarding the SHG response manifest the unique properties that arise from the combination of a semiconductor and a metal within one hybrid nanoparticle. PMID- 20192239 TI - Antiangiogenic metabolites from a marine-derived fungus, Hypocrea vinosa. AB - The aims of this study were to investigate the role of tyrosine kinase in intracellular signaling and to search for lead compounds with tyrosine kinase inhibitory activity from metabolites of marine-derived fungi. We initially prepared 400 extracts from 200 species of marine fungi and then subjected them to a tyrosine kinase screening assay using human umbilical vein endothelial cell lysate. Tyrosine kinase inhibitory activity was observed among certain metabolites of Hypocrea vinosa. We isolated one known compound, SC2051 (1), as well as two new compounds, hypochromins A (2) and B (3), which have a bis(naphtho gamma-pyrone) skeleton. Compounds 1-3 showed tyrosine kinase inhibitory activity, with IC(50) values of 42.1, 58.7, and 18.0 microMu, respectively. Furthermore, compounds 1-3 exhibited inhibitory effects on proliferation, migration, and tubule formation. PMID- 20192240 TI - Tetracenoquinocin and 5-iminoaranciamycin from a sponge-derived Streptomyces sp. Sp080513GE-26. AB - Two new anthracyclines, tetracenoquinocin (1) and 5-iminoaranciamycin (2), together with the known compounds aranciamycin (3) and antibiotic SM 173B were isolated from the culture of Streptomyces sp. Sp080513GE-26 associated with a marine sponge, Haliclona sp. The structures of 1 and 2 were established on the basis of extensive NMR and MS analyses along with (13)C-labeling experiments. The compounds 1-3 were evaluated for cytotoxicity against two cancer cell lines. PMID- 20192241 TI - Role of magic-sized clusters in the synthesis of CdSe nanorods. AB - The dynamics of the CdSe nanorod synthesis reaction have been studied, giving attention to the kinetics of magic-sized clusters (MSCs) that form as intermediates in the overall reaction. The MSCs have a distinct absorption peak, and the kinetics of this peak give insight into the overall reaction mechanism. In these studies, the reaction mixture consists primarily of Cd(phosphonate)(2) and trioctyl phosphine selenium in a solution of trioctylphosphine (TOP) and trioctylphosphine oxide (TOPO). We find that the rate at which precursors react to form CdSe monomers and the rates at which monomers react to form nanoparticles can be varied by changing the chemistry of the reaction mixture. Decreasing the TOP concentration decreases the extent to which selenium is bound, both in the precursors and on the particles' surfaces, and thereby increases both the precursor to monomer and monomer to particle reaction rates. Decreasing the phosphonate concentration decreases the extent to which phosphonate binds cadmium in the precursors and on the surface of the nanoparticles, also increasing the rates of both reactions. This is also accomplished by the addition of inorganic acids which protonate the phosphonates. The presence of inorganic acids (impurities) is the primary reason that the overall synthesis reaction is faster in solutions made with technical grade rather than purified TOPO. The TOP and phosphonic acid concentrations are coupled because excess phosphonic acids react with TOP, forming TOPO and less strongly binding species, specifically phosphinic acids, phosphine oxides, and phosphines. PMID- 20192242 TI - Gneyulins A and B, stilbene trimers, and noidesols A and B, dihydroflavonol-C glucosides, from the bark of Gnetum gnemonoides. AB - Gneyulins A (1) and B (2), two new stilbene trimers consisting of oxyresveratrol constituent units, and noidesols A (3) and B (4), two new dihydroflavonol-C glucosides, were isolated from the bark of Gnetum gnemonoides. The structures and configurations of 1-4 were elucidated on the basis of 2D NMR correlations and X ray analysis. Gneyulins A (1) and B (2) showed inhibition of Na(+)-glucose transporters (SGLT-1 and SGLT-2). PMID- 20192243 TI - Toolbox for regioselective lithiations of furo[2,3-c]pyridine. AB - A detailed procedure for successive regioselective lithiations of furo[2,3 c]pyridine is described by using n-BuLi and the [n-BuLi/LiDMAE] superbase. Several polysubstituted furo[2,3-c]pyridines have been efficiently synthesized and some of them were engaged in Pd- or Ni-catalyzed coupling reactions leading to 2,2'- or 7,7'-bifuro[2,3-c]pyridine ligands. PMID- 20192244 TI - Differential metabolomics for quantitative assessment of oxidative stress with strenuous exercise and nutritional intervention: thiol-specific regulation of cellular metabolism with N-acetyl-L-cysteine pretreatment. AB - Despite several decades of active research, the success of large-scale clinical trials involving antioxidants remains equivocal given the complex biological interactions of reactive oxygen/nitrogen species in human health. Herein, we outline a differential metabolomics strategy by capillary electrophoresis electrospray ionization-mass spectrometry (CE-ESI-MS) to assess the efficacy of nutritional intervention to attenuate oxidative stress induced by strenuous exercise. A healthy volunteer was recruited to perform a submaximal prolonged ergometer cycling trial until volitional exhaustion with frequent blood collection over a 6 h time interval, which included pre-, during, and postexercise periods while at rest. A follow-up study was subsequently performed by the same subject after high-dose oral intake of N-acetyl-L-cysteine (NAC) prior to performing the same exercise protocol under standardized conditions. Time-dependent changes in global metabolism of filtered red blood cell lysates by CE-ESI-MS were measured to reveal a significant attenuation of cellular oxidation associated with high-dose oral NAC intake relative to a control. Untargeted metabolite profiling allowed for the identification and quantification of several putative early- and late-stage biomarkers that reflected oxidative stress inhibition due to nutritional intervention, including oxidized glutathione (GSSG), reduced glutathione (GSH), 3-methylhistidine (3-MeHis), L-carnitine (C0), O-acetyl-L-carnitine (C2), and creatine (Cre). Our work demonstrates the proof-of principle that NAC pretreatment is effective at dampening acute episodes of oxidative stress by reversible perturbations in global metabolism that can provide deeper insight into the mechanisms of thiol-specific protein inhibition relevant to its successful translation as a prophylaxis in clinical medicine. PMID- 20192245 TI - Rolling circle amplification combined with gold nanoparticle aggregates for highly sensitive identification of single-nucleotide polymorphisms. AB - A highly sensitive and specific colorimetry-based rolling circle amplification (RCA) assay method for single-nucleotide polymorphism genotyping has been developed. A circular template is generated by ligation upon the recognition of a point mutation on DNA targets. An RCA amplification is then initiated using the circular template in the presence of Phi29 polymerase. The RCA product can be digested by a restricting endonuclease, and the cleaved DNA fragments can mediate the aggregation of gold nanoparticle-tagged DNA probes. This causes a colorimetric change of the solution as the indicator of the mutation occurrence, which can be detected using UV-vis spectroscopy or viewed by naked eyes. On the basis of the high amplification efficiency of Phi29 polymerase, a mutated target of approximately 70 fM can be detected in this assay. In addition, the protection of the circle template using phosphorothioated nucleotides allows the digestion reaction to be performed simultaneously in RCA. Moreover, DNA ligase offers high fidelity in distinguishing the mismatched bases at the ligation site, resulting in positive detection of mutant targets even when the ratio of the wild-type to the mutant is 10,000:1. The developed RCA-based colorimetric detection scheme was demonstrated for SNP typing of beta-thalassemia gene at position -28 in genomic DNA. PMID- 20192246 TI - Electrically controlled giant piezoresistance in silicon nanowires. AB - Herein we demonstrate giant piezoresistance in silicon nanowires (NWs) by the modulation of an electric field-induced with an external electrical bias. Positive bias for a p-type device (negative for an n-type) partially depleted the NWs forming a pinch-off region, which resembled a funnel through which the electrical current squeezed. This region determined the total current flowing through the NWs. In this report, we combined the electrical biasing with the application of mechanical stress, which impacts the charge carriers' concentration, to achieve an electrically controlled giant piezoresistance in nanowires. This phenomenon was used to create a stress-gated field-effect transistor, exhibiting a maximum gauge factor of 5000, 2 orders of magnitude increase over bulk value. Giant piezoresistance can be tailored to create highly sensitive mechanical sensors operating in a discrete mode such as nanoelectromechanical switches. PMID- 20192247 TI - Cytotoxic activities of several geranyl-substituted flavanones. AB - Nine geranylated flavanones isolated from the fruits of Paulownia tomentosa (4 12) and two from the roots of Morus alba (13 and 14) were examined for cytotoxicity to selected human cancer cell lines and normal human fibroblasts. Cytotoxicity was determined in vitro using a calcein AM cytotoxicity assay. Cytotoxicity for the THP-1 monocytic leukemia cell line was tested using erythrosin B cell staining. The geranylated compounds tested were compared with the known simple flavanone standards taxifolin (1), naringenin (2), and hesperetin (3) and with the standard anticancer drugs olomoucine II, diaziquone, and oxaliplatin and the antineoplastic compound camptothecin, and showed different levels of cytotoxicity. The effects of structural changes on cytotoxic activity, including geranyl substitution of the flavanone skeleton and the oxidation pattern of ring B of the flavanones, are discussed. PMID- 20192248 TI - Subcellular localization of a fluorescent artemisinin derivative to endoplasmic reticulum. AB - A cytotoxic artemisinin derivative conjugated with a fluorescent dansyl moiety was synthesized and its subcellular localization in Hep3B cells was examined. Comparison of the localization signals of the fluorescent artemisinin derivative with organelle specific dyes revealed that endoplasmic reticulum (ER) is the main site of its accumulation. PMID- 20192249 TI - A comprehensive approach to the profiling of the cooked meat carcinogens 2-amino 3,8-dimethylimidazo[4,5-f]quinoxaline, 2-amino-1-methyl-6-phenylimidazo[4,5 b]pyridine, and their metabolites in human urine. AB - A targeted liquid chromatography/tandem mass spectrometry-based metabolomics type approach, employing a triple stage quadrupole mass spectrometer in the product ion scan and selected reaction monitoring modes, was established to profile 2 amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-1-methyl-6 phenylimidazo[4,5-b]pyridine (PhIP), and their principal metabolites in the urine of omnivores. A mixed-mode reverse phase cation exchange resin enrichment procedure was employed to isolate MeIQx and its oxidized metabolites, 2-amino-8 (hydroxymethyl)-3-methylimidazo[4,5-f]quinoxaline (8-CH(2)OH-IQx) and 2-amino-3 methylimidazo[4,5-f]quinoxaline-8-carboxylic acid (IQx-8-COOH), which are produced by cytochrome P450 1A2 (P450 1A2). The phase II conjugates N(2)-(beta-1 glucosiduronyl)-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline and N(2)-(3,8 dimethylimidazo[4,5-f]quinoxalin-2-yl)-sulfamic acid were measured indirectly, following acid hydrolysis to form MeIQx. The enrichment procedure permitted the simultaneous analysis of PhIP, N(2)-(beta-1-glucosidurony1)-2-amino-1-methyl-6 phenylimidazo[4,5-b]pyridine, N3-(beta-1-glucosidurony1)-2-amino-1-methyl-6 phenylimidazo[4,5-b]pyridine, 2-amino-1-methyl-6-(4'-hydroxy)-phenylimidazo[4,5 b]pyridine (4'-HO-PhIP), and the isomeric N(2)- and N3-glucuronide conjugates of the carcinogenic metabolite, 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5 b]pyridine (HONH-PhIP), which is formed by P450 1A2. The limit of quantification (LOQ) for MeIQx, PhIP, and 4'-HO-PhIP was approximately 5 pg/mL; the LOQ values for 8-CH(2)OH-IQx and IQx-8-COOH were, respectively, <15 and <25 pg/mL, and the LOQ values for the glucuronide conjugates of PhIP and HONH-PhIP were 50 pg/mL. The metabolism was extensive; less than 9% of the dose was eliminated in urine as unaltered MeIQx, and <1% was eliminated as unaltered PhIP. Phase II conjugates of the parent amines accounted for up to 12% of the dose of MeIQx and up to 2% of the dose of PhIP. 8-CH(2)OH-IQx and IQx-8-COOH accounted for up to 76% of the dose of MeIQx, and the isomeric glucuronide conjugates of HONH-PhIP accounted for up to 33% of the dose of PhIP that were eliminated in urine within 10 h of meat consumption. P450 1A2 significantly contributes to the metabolism of both HAAs but with marked differences in substrate specificity. P450 1A2 primarily catalyzes the detoxification of MeIQx by oxidation of the 8-methyl group, whereas it catalyzes the bioactivation of PhIP by oxidation of the exocyclic amine group. PMID- 20192251 TI - Mitochondrial toxicity of microcystin-LR on cultured cells: application to the analysis of contaminated water samples. AB - Microcystins (MC) are potent hepatic toxins delivered into the cells by organic anion transporting peptides (OATP) where they target protein phosphatases and mitochondria. We analyzed the effects of MC-LR on primary hepatocytes, HepG2, and Jurkat T cells, and isolated rat liver mitochondria by measuring changes in O(2) consumption by optical oxygen sensing technique. Respiration of fresh primary hepatocytes was inhibited by MC-LR with EC50 = 2.74 +/- 0.65 nM, whereas an uncoupling effect on mitochondrial state 2 and state 3 respiration was observed with glutamate/malate as a substrate. HepG2 and Jurkat T cells lacking OATP showed no sensitivity to MC-LR; however, facilitated delivery of MC-LR resulted in a marked enhancement of HepG2 O(2) consumption and inhibition of Jurkat O(2) consumption at >or=0.1 nM. The respiratory response did not coincide with changes in viability, total cellular ATP, extracellular acidification, ROS formation, or protein phosphorylation, which were detectable at higher MC-LR doses. Such prominent effect on cellular respiration was therefore used for the detection of MC-LR in environmental samples. A simple and sensitive screening assay for MC-LR toxicity was developed, which uses Jurkat cells, facilitated delivery of the toxin(s) and measurement on a fluorescent reader. The assay was applied to a panel of environmental samples suspected to contain MC and benchmarked against the ELISA test. It allowed identification of toxic samples and quantification of both nonspecific and MC-LR type of toxicity. PMID- 20192250 TI - Modeling liver-related adverse effects of drugs using knearest neighbor quantitative structure-activity relationship method. AB - Adverse effects of drugs (AEDs) continue to be a major cause of drug withdrawals in both development and postmarketing. While liver-related AEDs are a major concern for drug safety, there are few in silico models for predicting human liver toxicity for drug candidates. We have applied the quantitative structure activity relationship (QSAR) approach to model liver AEDs. In this study, we aimed to construct a QSAR model capable of binary classification (active vs inactive) of drugs for liver AEDs based on chemical structure. To build QSAR models, we have employed an FDA spontaneous reporting database of human liver AEDs (elevations in activity of serum liver enzymes), which contains data on approximately 500 approved drugs. Approximately 200 compounds with wide clinical data coverage, structural similarity, and balanced (40/60) active/inactive ratios were selected for modeling and divided into multiple training/test and external validation sets. QSAR models were developed using the k nearest neighbor method and validated using external data sets. Models with high sensitivity (>73%) and specificity (>94%) for the prediction of liver AEDs in external validation sets were developed. To test applicability of the models, three chemical databases (World Drug Index, Prestwick Chemical Library, and Biowisdom Liver Intelligence Module) were screened in silico, and the validity of predictions was determined, where possible, by comparing model-based classification with assertions in publicly available literature. Validated QSAR models of liver AEDs based on the data from the FDA spontaneous reporting system can be employed as sensitive and specific predictors of AEDs in preclinical screening of drug candidates for potential hepatotoxicity in humans. PMID- 20192252 TI - Hydrothermal fabrication and catalytic properties of La(1-x)Sr(x)M(1-y)Fe(y)O(3) (M = Mn, Co) that are highly active for the removal of toluene. AB - A series of La(1-x)Sr(x)M(1-y)Fe(y)O(3) (M = Mn, Co; x = 0, 0.4; y = 0.1, 1.0) perovskite-type oxide catalysts have been fabricated via a strategy of citric acid complexation coupled with hydrothermal treatment. The materials are characterized by a number of analytical techniques. The oxidation of toluene is used as a probe reaction for the evaluation of catalytic performance. It is found that both La(0.6)Sr(0.4)FeO(3) and LaFeO(3) exhibit high activities. The partial substitution of manganese and cobalt with iron can significantly improve the catalytic performance of La(0.6)Sr(0.4)MnO(3) and La(0.6)Sr(0.4)CoO(3). At toluene/O(2) molar ratio = 1/200 and space velocity = 20,000 h(-1), the catalytic activity decreases in the sequence of La(0.6)Sr(0.4)Co(0.9)Fe(0.1)O(3) > La(0.6)Sr(0.4)FeO(3) > La(0.6)Sr(0.4)Mn(0.9)Fe(0.1)O(3) > LaFeO(3) > La(0.6)Sr(0.4)CoO(3) > La(0.6)Sr(0.4)MnO(3). Compared to the Fe-free counterparts, the La(0.6)Sr(0.4)Mn(0.9)Fe(0.1)O(3) and La(0.6)Sr(0.4)Co(0.9)Fe(0.1)O(3) catalysts are, respectively, 50 and 85 degrees C lower with regard to the temperature required for complete toluene oxidation. Toluene can be completely oxidized at 245 degrees C over La(0.6)Sr(0.4)Co(0.9)Fe(0.1)O(3). The excellent catalytic performance of La(0.6)Sr(0.4)Co(0.9)Fe(0.1)O(3) can be attributed to the presence of (i) Fe(3+) O-Fe(4+) couples, (ii) a transition of electronic structure, and (iii) a trace amount of Co(3)O(4). PMID- 20192253 TI - Phenol groups in northeastern U.S. submicrometer aerosol particles produced from seawater sources. AB - Atmospheric particles collected during the ICARTT 2004 field experiment at ground based sites at Appledore Island (AI), New Hampshire, Chebogue Point (CP), Nova Scotia, and aboard the R/V Ronald Brown (RB) were analyzed using Fourier transform infrared (FTIR) spectroscopy to quantify organic mass (OM) and organic functional groups. Several of these spectra contain a unique absorbance peak at 3500 cm(-1). Laboratory calibrations identify this peak with phenol functional groups. The phenol groups are associated with seawater-derived emissions based on correlations with tracer volatile organic compounds (VOCs) and ions, and potential source contribution function (PSCF) analysis. On the basis of the measured absorptivities, the project average phenol group concentrations are 0.24 +/- 0.18 microg m(-3) (4% of the total OM) at AI, 0.10 +/- 0.6 microg m(-3) (5% of the total OM) at CP, and 0.08 +/- 0.09 microg m(-3) (2% of the total OM) on board the RB, with detection limits typically between 0.06 and 0.11 microg m(-3). The spectra were partitioned into three primary factors using positive matrix factorization (PMF) sufficient to explain more than 95% of the measured OM. The fossil fuel combustion factor contributed 40% (AI), 34% (CP), and 43% (RB) of the total OM; the terrestrial biogenic factor contributed 20% (AI), 30% (CP), and 27% (RB). The seawater-derived factor contributed 40% (AI), 36% (CP) and 29% (RB) of the OM and showed similar correlations to tracers as the phenol group. PMID- 20192254 TI - Polychlorinated biphenyl and low polybrominated diphenyl ether transfer to milk in lactating goats chronically exposed to contaminated soil. AB - This study investigated milk excretion kinetics of PCBs, tetra-BDE (BDE 47), and penta-BDE (BDE 99) in goats exposed to contaminated soil under controlled conditions. The animals were fed (80 days) with feed containing 5% of contaminated soil. During this exposure period, milk was analyzed weekly. At the end of the experiment the PCBs and PBDEs retained in hepatic and adipose tissues were also determined. The soil-milk carry over rates (CORs) of PCBs ranged from 6 to 62%. This result suggests that a large part of ingested soil-bound PCBs was recovered in milk. Significantly different levels between the congeners were reported in the tissues (fat, liver). BDE 47 and 99 excretions in milk achieved a plateau after 2 weeks of exposure, and their corresponding CORs were about 30%. These two congeners showed a significantly (P < 0.05) lower accumulation in the adipose tissue than the major PCB congeners. The concentrations of BDE 47 and 99 in the liver were the same as PCB concentrations. This result suggests that the low brominated congeners are submitted to the metabolism more extensively than the major PCBs. PMID- 20192255 TI - Heterogeneous chemistry of alkylamines with sulfuric acid: implications for atmospheric formation of alkylaminium sulfates. AB - The heterogeneous interaction of alkylamines with sulfuric acid has been investigated to assess the role of amines in aerosol growth through the formation of alkylaminium sulfates. The kinetic experiments were conducted in a low pressure fast flow reactor coupled to an ion drift-chemical ionization mass spectrometer (ID-CIMS). The measurements of heterogeneous uptake of methylamine, dimethylamine, and trimethylamine were performed in the acidity range of 59-82 wt % H(2)SO(4) and between 243 and 283 K. Irreversible reactive uptakes were observed for all three alkylamines, with comparable uptake coefficients (gamma) in the range of 2.0 x 10(-2) to 4.4 x 10(-2). The measured gamma value was slightly higher in more concentrated sulfuric acid and at lower temperatures. The results imply that the heterogeneous reactions of alkylamines contribute effectively to the growth of atmospheric acidic particles and, hence, secondary organic aerosol formation. PMID- 20192256 TI - Lead substitution in synaptotagmin: a case study. AB - Quantum chemistry computations have been used to investigate the possibility of a Pb(2+)/Ca(2+) substitution in the three calcium sites of the synaptotagmin enzyme. Provided explicit cation solvation is taken into account, it is shown that the substitution is energetically feasible and induces a strong reorganization of the Ca(2+)-coordinating sites, which may preclude the enzyme for any efficient role when lead poisoning occurs. PMID- 20192257 TI - Microwave catalysis revisited: an analytical solution. AB - In our previous work [Bren, U., et al. J. Phys. Chem. A 2008, 112, 166] we proposed a novel physical mechanism for microwave catalysis based on rotationally hot reactive species and verified its validity through a Monte Carlo simulation of a realistic chemical reaction: neutral ester hydrolysis. This article represents a continuation of our ongoing effort toward quantitative understanding of the microwave catalytic effect. It provides a derivation of an analytical solution for the microwave catalysis. The obtained expression is compared with the results of the Monte Carlo simulation and is applied to reproduce the microwave catalytic effect experimentally observed in the polyethylene terephthalate solvolysis. Implications for the interactions of microwaves with living organisms in the context of widespread mobile telephony are also discussed. PMID- 20192258 TI - Excited state processes of 2-butylamino-6-methyl-4-nitropyridine N-oxide in nonpolar solvents. A transient absorption spectroscopy study. AB - Earlier steady-state fluorescence studies showed that 2-butylamino-6-methyl-4 nitropyridine N-oxide (2B6M) can undergo fast excited-state intramolecular proton transfer (ESIPT). In a nonpolar solvent such as n-octane, both normal and tautomeric fluorescence was observed. Strikingly, the relative ratio of those two emission bands and the fluorescence quantum yield of the normal emission were found to depend on the excitation wavelength in violation of the Kasha-Vavilov rule. In this work, the system was investigated further by means of transient absorption spectroscopy, followed by global and target analysis. Upon excitation at 420 nm, a normal excited singlet state S(1)(N) is reached, which decays in about 12 ps via fluorescence and ESIPT (minor pathways) and to a long-lived "dark" state (major pathway) that is most probably the triplet T(1)(N). Upon 330 nm excitation, however, a more complex pattern emerges and additional decay channels are opened. A set of four excited-state species is required to model the data, including a hot state S(1)(N)* that decays in about 3 ps to the tautomer, to the long-lived "dark" state and to the relaxed S(1)(N) state. A kinetic scheme is presented that can explain the observed transient absorption results as well as the earlier fluorescence data. PMID- 20192259 TI - An expedient procedure for the oxidative cleavage of olefinic bonds with PhI(OAc)2, NMO, and catalytic OsO4. AB - PhI(OAc)(2) in the presence of OsO(4) (cat.) and 2,6-lutidine cleaves olefinic bonds to yield the corresponding carbonyl compounds, albeit, in some cases, with alpha-hydroxy ketones as byproduct. A more practical and clean protocol to effect oxidative cleavage of olefinic bonds involves NMO, OsO(4) (cat.), 2,6-lutidine, and PhI(OAc)(2). PMID- 20192260 TI - Characterization of the ubiquinone binding site in the alternative NADH-quinone oxidoreductase of Saccharomyces cerevisiae by photoaffinity labeling. AB - The Ndi1 enzyme found in the mitochondrial membrane of Saccharomyces cerevisiae is an NDH-2-type alternative NADH-quinone oxidoreductase. As Ndi1 is expected to be a possible remedy for complex I defects of mammalian mitochondria, a detailed biochemical characterization of the enzyme is needed. To identify the ubiquinone (UQ) binding site in Ndi1, we conducted photoaffinity labeling using a photoreactive biotinylated UQ mimic (compound 2) synthesized following a concept of the least possible modification of the substituents on the quinone ring. Cleavage with CNBr of Ndi1 cross-linked by 2 revealed the UQ ring of 2 to be specifically cross-linked to the Phe281-Met410 region (130 amino acids). Digestion of the CNBr fragment with V8 protease and lysylendopeptidase (Lys-C) gave approximately 8 and approximately 4 kDa peptides, respectively. The approximately 8 kDa V8 digest was identified as the Thr329-Glu399 region (71 amino acids) by an N-terminal sequence analysis. Although the approximately 4 kDa Lys-C digest could not be identified by N-terminal sequence analysis, the band was thought to cover the Gly374-Lys405 region (32 amino acids). Taken together, the binding site of the Q ring of 2 must be located in a common region of the V8 protease, and Lys-C digests Gly374-Glu399 (26 amino acids). Superimposition of the Ndi1 sequence onto a three-dimensional structural model of NDH-2 from Escherichia coli suggested that the C-terminal portion of this region is close to the isoalloxazine ring of FAD. PMID- 20192261 TI - Nuclear field shift effect in isotope fractionation of mercury during abiotic reduction in the absence of light. AB - We investigated the abiotic reduction of inorganic Hg(II) by dissolved organic matter (DOM) and stannous(II) chloride (SnCl(2)) in the absence of light and quantified fractionation of Hg isotopes during these processes. The kinetics of reduction by DOM was characterized using multiple parallel pseudo-first-order reactions, implying different reactive Hg(II) species resulting from Hg-DOM complexation. Significant mass independent isotopic anomalies were observed in reduction by both reducing reagents. Isotopes with odd atomic masses ((199)Hg and (201)Hg) showed less enrichment in reactants Hg(II) than expected for a mass dependent fractionation process. The fractionation factors (alpha) showed an odd even staggering pattern that resembles the variation of nuclear charge radii. We demonstrated that these isotopic anomalies originated from nuclear field shift effect (NFS). The contribution of NFS to the measured fractionation factors was estimated and found to be as significant as the mass dependent effect. The observed Delta(199)Hg/Delta(201)Hg slope was explained by NFS and determined to be between 1.5 and 1.6 in abiotic nonphotochemical reduction, which is distinguishable from slopes determined for photochemical reduction. Therefore, we first demonstrated experimentally the significance of the nuclear field shift effect during reduction of Hg(II) and showed the application of isotope fractionation to distinguish between different reduction pathways. PMID- 20192262 TI - Metal-directed protein self-assembly. AB - Proteins are nature's premier building blocks for constructing sophisticated nanoscale architectures that carry out complex tasks and chemical transformations. Some 70%-80% of all proteins are thought to be permanently oligomeric; that is, they are composed of multiple proteins that are held together in precise spatial organization through noncovalent interactions. Although it is of great fundamental interest to understand the physicochemical basis of protein self-assembly, the mastery of protein-protein interactions (PPIs) would also allow access to novel biomaterials with nature's favorite and most versatile building block. In this Account, we describe a new approach we have developed with this possibility in mind, metal-directed protein self assembly (MDPSA), which utilizes the strength, directionality, and selectivity of metal-ligand interactions to control PPIs. At its core, MDPSA is inspired by supramolecular coordination chemistry, which exploits metal coordination for the self-assembly of small molecules into discrete, more-or-less predictable higher order structures. Proteins, however, are not exactly small molecules or simple metal ligands: they feature extensive, heterogeneous surfaces that can interact with each other and with metal ions in unpredictable ways. We begin by first describing the challenges of using entire proteins as molecular building blocks. We follow with an examination of our work on a model protein (cytochrome cb(562)), highlighting challenges toward establishing ground rules for MDPSA as well as progress in overcoming these challenges. Proteins are also nature's metal ligands of choice. In MDPSA, once metal ions guide proteins into forming large assemblies, they are by definition embedded within extensive interfaces formed between protein surfaces. These complex surfaces make an inorganic chemist's life somewhat difficult, yet they also provide a wide platform to modulate the metal coordination environment through distant, noncovalent interactions, exactly as natural metalloproteins and enzymes do. We describe our computational and experimental efforts toward restructuring the noncovalent interaction network formed between proteins surrounding the interfacial metal centers. This approach, of metal templating followed by the redesign of protein interfaces (metal templated interface redesign, MeTIR), not only provides a route to engineer de novo PPIs and novel metal coordination environments but also suggests possible parallels with the evolution of metalloproteins. PMID- 20192263 TI - CopK from Cupriavidus metallidurans CH34 binds Cu(I) in a tetrathioether site: characterization by X-ray absorption and NMR spectroscopy. AB - Cupriavidus metallidurans CH34 is a bacterium that is resistant to high metal concentrations in the environment. Increased copper resistance is associated with the cop cluster on the large plasmid pMOL30 that is composed of at least 21 genes. The copK gene encodes a 74 residue periplasmic protein whose expression is strongly upregulated in the presence of copper. CopK was previously shown to cooperatively bind Cu(I) and Cu(II) in distinct, specific sites. The solution structure of Cu(I)-CopK and the characterization of the Cu(I) site by X-ray absorption spectroscopy and NMR are reported here. EXAFS spectra are in agreement with a tetrathioether Cu(I) site, providing so far unique spectral information on a 4S-coordinated Cu(I) in a protein. The methionine residues forming the Cu(I) site, M28, M38, M44, and M54, are identified by NMR. We propose the chemical shift of the methionine C(epsilon) as a new and sensitive probe for the detection of Cu(I) bound to thioether groups. The solution structure of Cu(I)-CopK demonstrates that Cu(I) binding induces a complete structural modification with the disruption of the second beta-sheet and a rotation of the C-terminal part of nearly 180 degrees around a hinge formed by asparagine 57. This conformational change is directly related to the loss of the dimer interface and most probably to the formation of the Cu(II) site involving histidine 70. The solution structure of Cu(I)-CopK therefore provides the molecular basis for the understanding of the Cu(I)/Cu(II) binding cooperativity. PMID- 20192264 TI - Protein-protein interactions in ovalbumin solutions studied by small-angle scattering: effect of ionic strength and the chemical nature of cations. AB - The influence of ionic strength and of the chemical nature of cations on the protein-protein interactions in ovalbumin solution was studied using small-angle X-ray and neutron scattering (SAXS/SANS). The globular protein ovalbumin is found in dimeric form in solutions as suggested by SANS/SAXS experiments. Due to the negative charge of the proteins at neutral pH, the protein-protein interactions without any salt addition are dominated by electrostatic repulsion. A structure factor related to screened Coulombic interactions together with an ellipsoid form factor was used to fit the scattering intensity. A monovalent salt (NaCl) and a trivalent salt (YCl(3)) were used to study the effect of the chemical nature of cations on the interaction in protein solutions. Upon addition of NaCl, with ionic strength below that of physiological conditions (150 mM), the effective interactions are still dominated by the surface charge of the proteins and the scattering data can be understood using the same model. When yttrium chloride was used, a reentrant condensation behavior, i.e., aggregation and subsequent redissolution of proteins with increasing salt concentration, was observed. SAXS measurements reveal a transition from effective repulsion to attraction with increasing salt concentration. The solutions in the reentrant regime become unstable after long times (several days). The results are discussed and compared with those from bovine serum albumin (BSA) in solutions. PMID- 20192265 TI - Bioorthogonal chemical reporters for monitoring protein acetylation. AB - Protein acetylation is a key post-translational modification that regulates diverse biological activities in eukaryotes. Here we report bioorthogonal chemical reporters that enable direct in-gel fluorescent visualization and proteome-wide identification of acetylated proteins via Cu(I)-catalyzed azide alkyne cycloaddition, often termed "click chemistry". We demonstrate that two alkynyl-acetyl-CoA analogues, 4-pentynoyl-CoA and 5-hexynoyl-CoA, function as efficient substrates of lysine acetyltransferase p300 and serve as sensitive reagents for monitoring p300-catalyzed protein acetylation in vitro. In addition, we demonstrate that three alkynylacetate analogues, sodium 3-butynoate, sodium 4 pentynoate, and sodium 5-hexynoate, can be metabolically incorporated onto cellular proteins through biosynthetic mechanisms for profiling of acetylated proteins in diverse cell types. Mass spectrometry analysis of the enriched 4 pentynoate-labeled proteins revealed many reported as well as new candidate acetylated proteins from Jurkat T cells and specific sites of lysine acetylation. The bioorthogonal chemical reporters described here should serve as powerful tools for investigating protein acetylation. PMID- 20192266 TI - Application of the lithiation-borylation reaction to the preparation of enantioenriched allylic boron reagents and subsequent in situ conversion into 1,2,4-trisubstituted homoallylic alcohols with complete control over all elements of stereochemistry. AB - The reactions of Hoppe's lithiated carbamates with vinylboranes and boronic esters give allylic boranes/boronic esters, and subsequent addition of aldehydes provides a new route to enantioenriched homoallylic alcohols with high enantiomeric ratios and diastereomeric ratios. Specifically, reactions of sparteine-complexed lithiated carbamates with trans-alkenyl-9-BBN derivatives followed by addition of aldehydes gave (Z)-anti-homoallylic alcohols in greater than 95:5 er and 99:1 dr. However, in the special case of the methyl-substituted lithiated carbamate, diamine-free conditions were required to achieve high selectivity. Reactions of sparteine-complexed lithiated carbamates with (Z) alkenyl pinacol boronic esters and (E)-alkenyl neopentyl boronic esters gave (E) syn- and (E)-anti-homoallylic alcohols, respectively, in greater than 96:4 er and 98:2 dr. In these reactions, a Lewis acid (MgBr(2) or BF(3) x OEt(2)) was required to promote both the 1,2-metalate rearrangement and the addition of the intermediate allylic boronic ester to the aldehyde. This methodology provides a general route to each of the three classes of homoallylic alcohols with high selectivity. PMID- 20192267 TI - [ReCl4(CN)2]2-: a high magnetic anisotropy building unit giving rise to the single-chain magnets (DMF)4MReCl4(CN)2 (M = Mn, Fe, Co, Ni). AB - An S = 3/2, high-anisotropy building unit, trans-[ReCl(4)(CN)(2)](2-), representing the first paramagnetic complex with a mixture of just cyanide and halide ligands, has been synthesized through the reaction of (Bu(4)N)CN with ReCl(4)(THF)(2). This species is characterized in detail and employed in directing the formation of a series of one-dimensional coordination solids of formula (DMF)(4)MReCl(4)(CN)(2) (M = Mn (2), Fe (3), Co (4), Ni (5)). Variable temperature dc magnetic susceptibility measurements demonstrate the presence of intrachain antiferromagnetic (2) and ferromagnetic (3-5) exchange coupling within these solids. In addition, probing the ac magnetic susceptibility as a function of both temperature and frequency reveals that all of the chain compounds exhibit slow relaxation of the magnetization. The relaxation time is shown to be thermally activated, with energy barriers to relaxation of Delta(tau) = 31, 56, 17, and 20 cm(-1) for 2-5, respectively. Notably, the field-dependent magnetization of the iron congener exhibits a significant hysteresis effect at low temperature, with a coercive field of H(C) = 1.0 T, thus demonstrating magnetlike behavior in this one-dimensional system. Finally, the magnetization dynamics of all solids occur within the finite-size regime, where the magnetic domain growth is limited due to physical defects along the chains within the crystals. PMID- 20192268 TI - Oligonucleotide duplexes and multistrand assemblies with 8-aza-2' deoxyisoguanosine: a fluorescent isoG(d) shape mimic expanding the genetic alphabet and forming ionophores. AB - 8-Aza-2'-deoxyisoguanosine (4) is the first fluorescent shape mimic of 2' deoxyisoguanosine (1a); its fluorescence is stronger in alkaline medium than under neutral conditions. Nucleoside 4, which was synthesized from 8-aza-2' deoxyguanosine via a 4,6-diamino intermediate after selective deamination, was incorporated in oligodeoxyribonucleotides using phosphoramidite 11. Duplexes with 4 x m(5)iC(d) (5-methyl-2'-deoxyisocytidine) base pairs are more stable than those incorporating dG-dC pairs, thereby expanding the genetic alphabet by a fluorescent orthogonal base pair. As demonstrated by T(m) measurements, the base pair stability decreases in the order m(5)iC(d) x 4 >> dG x 4 > dT x 4 > or = dC x 4 >> dA x 4. A better base pairing selectivity of 4 against the canonical nucleosides dT, dC, dA, and dG is observed than for the degenerated base pairing of 1a. The base pair stability changes can be monitored by nucleobase anion fluorescence sensing. The fluorescence change correlates to the DNA base pair stability. Oligonucleotide 5'-d(T(4)4(4)T(4)) (22), containing short runs of nucleoside 4, forms stable multistranded assemblies (ionophores) with K(+) in the central cavity. They are quite stable at elevated temperature but are destroyed at high pH value. PMID- 20192269 TI - Modeling relationships among active components in black raspberry (Rubus occidentalis L.) fruit extracts using high-resolution (1)H nuclear magnetic resonance (NMR) spectroscopy and multivariate statistical analysis. AB - A process was developed to ascertain the bioactive components of black raspberry (Rubus occidentalis L.) fruit extracts by relating chemical constituents determined by high-field nuclear magnetic resonance (NMR) spectroscopy to biological responses using partial least-squares regression analysis. To validate our approach, we outlined relationships between phenolic signals in NMR spectra and chemical data for total monomeric anthocyanin (TMA) content and antioxidant capacity by the ferric-reducing antioxidant power (FRAP) and 2,2-diphenyl-1 picrylhydrazyl (DPPH) assays. Anthocyanins, cyanidin 3-O-rutinoside (Cy 3-rut), cyanidin 3-O-(2(G))-xylosylrutinoside (Cy 3-xylrut), and cyanidin 3-O-glucoside (Cy 3-glc), were significant contributors to the variability in assay results, with the two most important NMR bins corresponding to the methyl peaks in Cy 3 rut (6''') and/or Cy 3-xylrut (6(IV)). Many statistically important bins were common among assay models, but differences in structure-activity relationships resulted in changes in bin ranking. The specificity of these results supported the application of the process to investigate relationships among health beneficial natural products and potential biological activity. PMID- 20192270 TI - Structure-activity relationship of (N)-Methanocarba phosphonate analogues of 5' AMP as cardioprotective agents acting through a cardiac P2X receptor. AB - P2X receptor activation protects in heart failure models. MRS2339 3, a 2-chloro AMP derivative containing a (N)-methanocarba (bicyclo[3.1.0]hexane) system, activates this cardioprotective channel. Michaelis-Arbuzov and Wittig reactions provided phosphonate analogues of 3, expected to be stable in vivo due to the C-P bond. After chronic administration via a mini-osmotic pump (Alzet), some analogues significantly increased intact heart contractile function in calsequestrin-overexpressing mice (genetic model of heart failure) compared to vehicle-infused mice (all inactive at the vasodilatory P2Y(1) receptor). Two phosphonates, (1'S,2'R,3'S,4'R,5'S)-4'-(6-amino-2-chloropurin-9-yl)-2',3' (dihydroxy)-1'-(phosphonomethylene)-bicyclo[3.1.0]hexane, 4 (MRS2775), and its homologue 9 (MRS2935), both 5'-saturated, containing a 2-Cl substitution, improved echocardiography-derived fractional shortening (20.25% and 19.26%, respectively, versus 13.78% in controls), while unsaturated 5'-extended phosphonates, all 2-H analogues, and a CH(3)-phosphonate were inactive. Thus, chronic administration of nucleotidase-resistant phosphonates conferred a beneficial effect, likely via cardiac P2X receptor activation. Thus, we have greatly expanded the range of carbocyclic nucleotide analogues that represent potential candidates for the treatment of heart failure. PMID- 20192271 TI - Characterization of recombinant lysyl oxidase propeptide. AB - Lysyl oxidase enzyme activity is critical for the biosynthesis of mature and functional collagens and elastin. In addition, lysyl oxidase has tumor suppressor activity that has been shown to depend on the propeptide region (LOX-PP) derived from pro-lysyl oxidase (Pro-LOX) and not on lysyl oxidase enzyme activity. Pro LOX is secreted as a 50 kDa proenzyme and then undergoes biosynthetic proteolytic processing to active approximately 30 kDa LOX enzyme and LOX-PP. The present study reports the efficient recombinant expression and purification of rat LOX PP. Moreover, using enzymatic deglycosylation and DTT derivatization combined with mass spectrometry technologies, it is shown for the first time that rLOX-PP and naturally occurring LOX-PP contain both N- and O-linked carbohydrates. Structure predictions furthermore suggest that LOX-PP is a mostly disordered protein, which was experimentally confirmed in circular dichroism studies. Due to its high isoelectric point and its disordered structure, we propose that LOX-PP can associate with extracellular and intracellular binding partners to affect its known biological activities as a tumor suppressor and inhibitor of cell proliferation. PMID- 20192273 TI - Theoretical study of the lactic acid-water system: importance of two- and three body interactions. AB - Optimal structures, interaction energies, harmonic and anharmonic vibrational frequencies, and NMR chemical shifts of the dimers LA...H(2)O and trimers LA...(H(2)O)(2) (where LA is lactic acid) have been determined from the second order Moller-Plesset perturbation theory and B3LYP with the aug-cc-pVDZ calculations. The nature of the pairwise and nonadditive three-body interactions was investigated by the SAPT method. As revealed by SAPT analysis, the main two body binding contributions in the LA...H(2)O dimers and LA...(H(2)O)(2) trimers result from a delicate balance of the attractive and repulsive terms. The three body nonadditivity for LA...(H(2)O)(2) is stabilizing and dominated by the exchange and induction effects but small. PMID- 20192272 TI - Chiral discrimination among aminotransferases: inactivation by 4-amino-4,5 dihydrothiophenecarboxylic acid. AB - Mechanism-based inhibitors such as cycloserine and gabaculine can inactivate aminotransferases via reactions of the compounds with the pyridoxal phosphate cofactor forming an irreversible adduct. The reaction is chirally specific in that any one enzyme usually only recognizes one enantiomer of the inactivator. For instance, l-aspartate aminotransferase (l-AspAT) is inactivated by 4-amino 4,5-dihydro-2-thiophenecarboxylic acid (ADTA), however, only by the S-isomer. We have now shown that d-amino acid aminotransferase (d-a-AT) is irreversibly inactivated by the R-isomer of the same compound. The X-ray crystal structure (PDB code: 3LQS ) of the inactivated enzyme shows that in the product the enzyme no longer makes a Schiff base linkage to the pyridoxal 5'-phosphate (PLP) cofactor, and instead the compound has formed a derivative of the cofactor. The adduct is similar to that formed between d-cycloserine and d-a-AT or alanine racemase (Ala-Rac) in that the thiophene ring of R-ADTA is intact and seems to be aromatic. The plane of the ring is rotated by nearly 90 degrees with respect to the plane of the pyridine ring of the cofactor, in comparison with the enzyme inactivated by cycloserine. Based on the structure of the product, the mechanism of inactivation most probably involves a transamination followed by aromatization to form an aromatic thiophene ring. PMID- 20192274 TI - Functional characterization and high-throughput proteomic analysis of interrupted genes in the archaeon Sulfolobus solfataricus. AB - Sequenced genomes often reveal interrupted coding sequences that complicate the annotation process and the subsequent functional characterization of the genes. In the past, interrupted genes were generally considered to be the result of sequencing errors or pseudogenes, that is, gene remnants with little or no biological importance. However, recent lines of evidence support the hypothesis that these coding sequences can be functional; thus, it is crucial to understand whether interrupted genes are expressed in vivo. We addressed this issue by experimentally demonstrating the existence of functional disrupted genes in archaeal genomes. We discovered previously unknown disrupted genes that have interrupted homologues in distantly related species of archaea. The combination of a RT-PCR strategy with shotgun proteomics demonstrates that interrupted genes in the archaeon Sulfolobus solfataricus are expressed in vivo. In addition, the sequence of the peptides determined by LCMSMS and experiments of in vitro translation allows us to identify a gene expressed by programmed -1 frameshifting. Our findings will enable an accurate reinterpretation of archaeal interrupted genes shedding light on their function and on archaeal genome evolution. PMID- 20192275 TI - The synthesis of a c(RGDyK) targeted SN38 prodrug with an indolequinone structure for bioreductive drug release. AB - Preparation of a novel c(RGDyK) targeted SN38 prodrug incorporating an indolequinone structure for bioreductively triggered drug release is described. This design yields a prodrug that targets surface molecules on tumor cells (alpha(v)beta(3) integrins) and releases drug under bioreductive conditions. There are three moieties in the prodrug design, namely a therapeutic drug SN38, an indolequinone structure serving as a drug releasing trigger, and an alpha(v)beta(3) integrin targeting peptide c(RGDyK). Preliminary studies showed that SN38 is released in the presence of a bioreductive enzyme (DT-diaphorase). PMID- 20192276 TI - Effect of phosphorylation in the motor domain of human myosin IIIA on its ATP hydrolysis cycle. AB - Previous findings suggested that the motor activity of human myosin IIIA (HM3A) is influenced by phosphorylation [Kambara, T., et al. (2006) J. Biol. Chem. 281, 37291-37301]; however, how phosphorylation controls the motor activity of HM3A is obscure. In this study, we clarify the kinetic basis of the effect of phosphorylation on the ATP hydrolysis cycle of the motor domain of HM3A (huM3AMD). The affinity of human myosin IIIA for filamentous actin in the presence of ATP is more than 100-fold decreased by phosphorylation, while the maximum rate of ATP turnover is virtually unchanged. The rate of release of ADP from acto-phosphorylated huM3AMD is 6-fold greater than the overall cycle rate, and thus not a rate-determining step. The rate constant of the ATP hydrolysis step of the actin-dissociated form is markedly increased by phosphorylation by 30 fold. The dissociation constant for dissociation of the ATP-bound form of huM3AMD from actin is greatly increased by phosphorylation, and this result agrees well with the significant increase in the K(actin) value of the steady-state ATPase reaction. The rate constant of the P(i) off step is greater than 60 s(-1), suggesting that this step does not limit the overall ATP hydrolysis cycle rate. Our kinetic model indicates that phosphorylation induces the dissociation of huM3AMD from actin during the ATP hydrolysis cycle, and this is due to the phosphorylation-dependent marked decrease in the affinity of huM3AMD.ATP for actin and the increase in the ATP hydrolysis rate of huM3AMD in the actin dissociated state. These results suggest that the phosphorylation of myosin IIIA significantly lowers the duty ratio, which may influence the cargo transporting ability of the native form of myosin IIIA that contains the ATP-independent actin binding site in the tail. PMID- 20192277 TI - Molecular diversification of peptide toxins from the tarantula Haplopelma hainanum (Ornithoctonus hainana) venom based on transcriptomic, peptidomic, and genomic analyses. AB - The tarantula Haplopelma hainanum (Ornithoctonus hainana) is a very venomous spider found widely in the hilly areas of Hainan province in southern China. Its venom contains a variety of toxic components with different pharmacological properties. In the present study, we used a venomic strategy for high-throughput identification of tarantula-venom peptides from H. hainanum. This strategy includes three different approaches: (i) transcriptomics, that is, EST-based cloning and PCR-based cloning plus DNA sequencing; (ii) peptidomics, that is, off line multiple dimensional liquid chromatography coupled with mass spectrometry (MDLC-MS) plus peptide sequencing (direct Edman sequencing and bottom-up mass spectrometric sequencing); (iii) genomics, that is, genomic DNA cloning plus DNA sequencing. About 420 peptide toxins were detected by mass spectrometry, and 272 peptide precursors were deduced from cDNA and genomic DNA sequences. After redundancy removal, 192 mature sequences were identified by three approaches. This is the largest number of peptide toxin sequences identified from a spider species so far. On the basis of precursor sequence identity, peptide toxins from the tarantula H. hainanum venom can be classified into 11 superfamilies (and related families). Our results revealed that gene duplication and focal hypermutation may be responsible for the enormous molecular diversity in spider peptide toxins. The current work is an initial overview for the study of tarantula-venom peptides in parallel transcriptomic, peptidomic, and genomic analyses. It is hoped that this work will also provide an effective guide for high-throughput identification of peptide toxins from other spider species, especially tarantula species. PMID- 20192281 TI - Communications: A nonperturbative quantum master equation approach to charge carrier transport in organic molecular crystals. AB - We present a nonperturbative quantum master equation to investigate charge carrier transport in organic molecular crystals based on the Liouville space hierarchical equations of motion method, which extends the previous stochastic Liouville equation and generalized master equation methods to a full quantum treatment of the electron-phonon coupling. Diffusive motion of charge carriers in a one-dimensional model in the presence of nonlocal electron-phonon coupling was studied, and two different charge carrier diffusion mechanisms are observed for large and small average intermolecular couplings. The new method can also find applications in calculating spectra and energy transfer in various types of quantum aggregates where the perturbative treatments fail. PMID- 20192279 TI - Agomelatine in the treatment of major depressive disorder: potential for clinical effectiveness. AB - To demonstrate the clinical effectiveness of an antidepressant drug requires evidence beyond short- and long-term efficacy, including a favourable adverse effect profile and sustained treatment adherence. Under these conditions, patients should experience enhanced social and functional outcomes. The novel antidepressant agomelatine, a melatonergic MT(1)/MT(2) receptor agonist with serotonin 5-HT(2C) receptor antagonist activity, displays antidepressant efficacy with a favourable adverse-effect profile that is associated with good patient adherence. Specifically, agomelatine has demonstrated significant short-term (6-8 weeks) and sustained (6 months) antidepressant efficacy relative to placebo, as well as evidence of relapse prevention (up to 10 months). In head-to-head comparative studies with venlafaxine and sertraline, there was evidence of early (at 1-2 weeks) and sustained (at 6 months) advantages for agomelatine. In addition to evidence of early efficacy, agomelatine also restored disturbed sleep wake patterns early in treatment. There was no evidence of antidepressant-induced sexual dysfunction, weight gain or discontinuation-emergent symptoms. Agomelatine has demonstrated a range of properties that suggest it could offer advantages over current treatments for major depressive disorder, although further comparative trials are still required, as is evidence from real-world clinical practice. PMID- 20192280 TI - Pharmacokinetics, safety and tolerability of single and multiple oral doses of aliskiren in healthy Chinese subjects: a randomized, single-blind, parallel group, placebo-controlled study. AB - BACKGROUND: Aliskiren is the first oral direct renin inhibitor to be approved for the treatment of hypertension. The pharmacokinetic and pharmacodynamic profile of aliskiren has been extensively characterized in Caucasian individuals; however, drug disposition, treatment response and tolerability can vary among ethnic groups, and these variations are difficult to predict. OBJECTIVE: To evaluate the single- and multiple-dose pharmacokinetics of aliskiren in healthy Chinese subjects. METHODS: This was a randomized, single-blind, parallel-group, placebo controlled study. On day -1, subjects were randomized to one of four cohorts (aliskiren 75, 150, 300 or 600 mg). On day 1, eight individuals in each cohort received a single dose of active treatment and two received placebo. Subjects randomized to aliskiren 300 mg received additional once-daily doses on days 5-11 to establish steady-state pharmacokinetics. Subjects receiving aliskiren 75, 150 or 600 mg (cohorts 1, 2 and 4) completed the study at the end of the 96-hour pharmacokinetic assessment period. Subjects receiving aliskiren 300 mg (cohort 3) had additional pharmacokinetic assessments on days 5-15. The study was carried out at the Peking Union Medical College Hospital, Beijing, China, and included 40 healthy Chinese subjects. The main outcome measures were the pharmacokinetic parameters for aliskiren, including area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) and maximum plasma concentration (C(max)). RESULTS: Aliskiren AUC(infinity) and C(max) increased greater than proportionally across the 8-fold dose range (75-600 mg; mean AUC(infinity) 291 4726 ng x h/mL, mean C(max) 62-699 ng/mL), but a dose-proportional 2-fold increase was observed within the clinically approved dose range (150-300 mg; mean AUC(infinity) 876-1507 ng x h/mL, mean C(max) 137-271 ng/mL). CONCLUSION: At steady state, the mean AUC during the dosage interval (AUC(tau)) for aliskiren 300 mg (1532 +/- 592 ng x h/mL) was similar to the AUC(infinity) observed following a single dose. Aliskiren exhibits similar single-dose and steady-state pharmacokinetics in Chinese subjects compared with those observed in Caucasian individuals in previous studies. PMID- 20192282 TI - Communications: Adsorption of element 112 on the gold surface: many-body wave function versus density functional theory. AB - The applicability of the relativistic density functional theory (RDFT) with conventional generalized gradient and hybrid exchange-correlation functionals to the description of the interactions of element 112 (Cn) and its lighter homolog Hg with a gold surface is assessed. The comparison of Cn-Au (Hg-Au) bond properties for two simple models of adsorption complexes on Au(111) surface obtained by RDFT and accurate many-body calculations indicates a strong underestimation of binding energies by conventional RDFT schemes. This effect provides a possible explanation of the discrepancies between the RDFT-based theoretical and experimental data concerning the thermochromatographic registration of the alpha-decay chain element 114-->Cn. PMID- 20192283 TI - Communications: Development and characterization of a source of rotationally cold, enriched para-H3+. AB - In an effort to develop a source of H(3)(+) that is almost entirely in a single quantum state (J=K=1), we have successfully generated a plasma that is enriched to approximately 83% in para-H(3)(+) at a rotational temperature of 80 K. This enrichment is a result of the nuclear spin selection rules at work in hydrogenic plasmas, which dictate that only para-H(3)(+) will form from para-H(2), and that para-H(3)(+) can be converted to ortho-H(3)(+) by subsequent reaction with H(2). This is the first experimental study in which the H(2) and H(3) (+) nuclear spin selection rules have been observed at cold temperatures. The ions were produced from a pulsed solenoid valve source, cooled by supersonic expansion, and interrogated via continuous-wave cavity ringdown spectroscopy. PMID- 20192284 TI - Efficient computation of free energy of crystal phases due to external potentials by error-biased Bennett acceptance ratio method. AB - Free energy of crystal phases is commonly evaluated by thermodynamic integration along a reversible path that involves an external potential. However, this method suffers from the hysteresis caused by the differences in the center of mass position of the crystal phase in the presence and absence of the external potential. To alleviate this hysteresis, a constraint on the translational degrees of freedom of the crystal phase is imposed along the path and subsequently a correction term is added to the free energy to account for such a constraint. The estimation of the correction term is often computationally expensive. In this work, we propose a new methodology, termed as error-biased Bennett acceptance ratio method, which effectively solves this problem without the need to impose any constraint. This method is simple to implement and it does not require any modification to the path. We show the applicability of this method in the computation of crystal-melt interfacial energy by cleaving wall method [R. L. Davidchack and B. B. Laird, J. Chem. Phys. 118, 7651 (2003)] and bulk crystal-melt free energy difference by constrained fluid lambda-integration method [G. Grochola, J. Chem. Phys. 120, 2122 (2004)] for a model potential of silicon. PMID- 20192285 TI - Electronic excitation energies in solution at equation of motion CCSD level within a state specific polarizable continuum model approach. AB - We present a study of excitation energies in solution at the equation of motion coupled cluster singles and doubles (EOM-CCSD) level of theory. The solvent effect is introduced with a state specific polarizable continuum model (PCM), where the solute-solvent interaction is specific for the state of interest. Three definitions of the excited state one-particle density matrix (1PDM) are tested in order to gain information for the development of an integrated EOM-CCSD/PCM method. The calculations show the accuracy of this approach for the computation of such property in solution. Solvent shifts between nonpolar and polar solvents are in good agreement with experiment for the test cases. The completely unrelaxed 1PDM is shown to be a balanced choice between computational effort and accuracy for vertical excitation energies, whereas the response of the ground state CCSD amplitudes and of the molecular orbitals is important for other properties, as for instance the dipole moment. PMID- 20192286 TI - Quantum dynamics of the H+CH4-->H2+CH3 reaction in curvilinear coordinates: full dimensional and reduced dimensional calculations of reaction rates. AB - Full-dimensional quantum dynamics calculations for the H+CH(4)-->H(2)+CH(3) reaction using curvilinear coordinates are presented. A curvilinear coordinate system to describe reactions of the type X+YCH(3)-->XY+CH(3) is developed which facilitates efficient calculations using the multiconfigurational time-dependent Hartree (MCTDH) approach. To describe the bending motion of the X and Y atoms relative to the axis defined by the CH(3) fragment, coordinates based on stereographic projection are introduced. These coordinates yield a kinetic energy operator free of singularities within the dynamically relevant region. Employing this curvilinear coordinate system, full-dimensional and reduced dimensional MCTDH calculations study the cumulative reaction probability (for J=0) and the thermal rate constant for the H+CH(4) reaction on the Jordan-Gilbert potential energy surface [J. Chem. Phys. 102, 5669 (1995)]. The full-dimensional results agree very well with previous full-dimensional MCTDH results which used transition state based normal coordinates. The results of our eight-dimensional (8D) calculations are in reasonable agreement with the full-dimensional ones. They deviate significantly from older 8D results of Zhang et al. [J. Chem. Phys. 127, 234213 (2007)] but agree well with more recent results from the same group. PMID- 20192287 TI - Identifying and correcting non-Markov states in peptide conformational dynamics. AB - Conformational transitions in proteins define their biological activity and can be investigated in detail using the Markov state model. The fundamental assumption on the transitions between the states, their Markov property, is critical in this framework. We test this assumption by analyzing the transitions obtained directly from the dynamics of a molecular dynamics simulated peptide valine-proline-alanine-leucine and states defined phenomenologically using clustering in dihedral space. We find that the transitions are Markovian at the time scale of approximately 50 ps and longer. However, at the time scale of 30-40 ps the dynamics loses its Markov property. Our methodology reveals the mechanism that leads to non-Markov behavior. It also provides a way of regrouping the conformations into new states that now possess the required Markov property of their dynamics. PMID- 20192288 TI - Size consistency of explicit functionals of the natural orbitals in reduced density matrix functional theory. AB - We report a size-inconsistency problem for several functionals within reduced density matrix functional theory. Being explicit functionals of the natural orbitals and occupation numbers, instead of the one-body reduced density matrix, many of the approximate functionals are not invariant under unitary transformations in the subspace of degenerate occupation numbers. One such transformation mixes the degenerate natural orbitals of identical independent subsystems, delocalizing them. Noninvariance under this transformation results in size inconsistency for some of the approximations while others avoid this pathology by favoring orbital localization. PMID- 20192289 TI - Moller-Plesset perturbation theory gradient in the generalized hybrid orbital quantum mechanical and molecular mechanical method. AB - An analytic gradient expression is formulated and implemented for the second order Moller-Plesset perturbation theory (MP2) based on the generalized hybrid orbital QM/MM method. The method enables us to obtain an accurate geometry at a reasonable computational cost. The performance of the method is assessed for various isomers of alanine dipepetide. We also compare the optimized structures of fumaramide-derived [2]rotaxane and cAMP-dependent protein kinase with experiment. PMID- 20192278 TI - The safety and tolerability of newer antiepileptic drugs in children and adolescents. AB - The newer antiepileptic drugs (AEDs) provide more therapeutic options and overall improved safety and tolerability for patients. To provide the best care, physicians must be familiar with the latest tolerability and safety data. This is particularly true in children, given there are relatively fewer studies examining the effects of AEDs in children compared with adults. Since we now have significant paediatric literature on each of these agents, we provide a comprehensive and current literature review of the newer AEDs, focusing on safety and tolerability data in children and adolescents. Because the safety profiles in children differ from those in adults, familiarity with this literature is important for child neurologists and other paediatric caregivers. We have organized the data by organ system for each AED for easier reference. PMID- 20192290 TI - A smoothing monotonic convergent optimal control algorithm for nuclear magnetic resonance pulse sequence design. AB - The past decade has demonstrated increasing interests in using optimal control based methods within coherent quantum controllable systems. The versatility of such methods has been demonstrated with particular elegance within nuclear magnetic resonance (NMR) where natural separation between coherent and dissipative spin dynamics processes has enabled coherent quantum control over long periods of time to shape the experiment to almost ideal adoption to the spin system and external manipulations. This has led to new design principles as well as powerful new experimental methods within magnetic resonance imaging, liquid state and solid-state NMR spectroscopy. For this development to continue and expand, it is crucially important to constantly improve the underlying numerical algorithms to provide numerical solutions which are optimally compatible with implementation on current instrumentation and at same time are numerically stable and offer fast monotonic convergence toward the target. Addressing such aims, we here present a smoothing monotonically convergent algorithm for pulse sequence design in magnetic resonance which with improved optimization stability lead to smooth pulse sequence easier to implement experimentally and potentially understand within the analytical framework of modern NMR spectroscopy. PMID- 20192291 TI - Statistics of tethered self-avoiding chains under spherical confinement and an external force. AB - We compute the partition function of self-avoiding chains tethered inside a confining sphere using Monte Carlo simulations on a three-dimensional lattice. Two cases are considered: (i) single-tethered chains with one end anchored and one end free and (ii) double-tethered chains where both ends are tethered at a distance equal to the diameter of the sphere. The self-avoidance, confinement, and tethering constraints dramatically decrease the number of allowed configurations when compared with an unconstrained random coil, thereby affecting the sampling method used in the Monte Carlo procedure. The effect of an external applied force and the bias it introduces in the partition function are also investigated. Our method involves a decomposition of the partition function into the product of several terms that can be evaluated independently. For short chains, we demonstrate the validity of our approach through a direct evaluation of the partition function using an exact enumeration of the appropriate paths on the lattice. In the case of long chains, scaling laws for the behavior of the partition function are identified. PMID- 20192292 TI - Gradient-based multiconfiguration Shepard interpolation for generating potential energy surfaces for polyatomic reactions. AB - This paper describes and illustrates a way to construct multidimensional representations of reactive potential energy surfaces (PESs) by a multiconfiguration Shepard interpolation (MCSI) method based only on gradient information, that is, without using any Hessian information from electronic structure calculations. MCSI, which is called multiconfiguration molecular mechanics (MCMM) in previous articles, is a semiautomated method designed for constructing full-dimensional PESs for subsequent dynamics calculations (classical trajectories, full quantum dynamics, or variational transition state theory with multidimensional tunneling). The MCSI method is based on Shepard interpolation of Taylor series expansions of the coupling term of a 2 x 2 electronically diabatic Hamiltonian matrix with the diagonal elements representing nonreactive analytical PESs for reactants and products. In contrast to the previously developed method, these expansions are truncated in the present version at the first order, and, therefore, no input of electronic structure Hessians is required. The accuracy of the interpolated energies is evaluated for two test reactions, namely, the reaction OH+H(2)-->H(2)O+H and the hydrogen atom abstraction from a model of alpha-tocopherol by methyl radical. The latter reaction involves 38 atoms and a 108-dimensional PES. The mean unsigned errors averaged over a wide range of representative nuclear configurations (corresponding to an energy range of 19.5 kcal/mol in the former case and 32 kcal/mol in the latter) are found to be within 1 kcal/mol for both reactions, based on 13 gradients in one case and 11 in the other. The gradient-based MCMM method can be applied for efficient representations of multidimensional PESs in cases where analytical electronic structure Hessians are too expensive or unavailable, and it provides new opportunities to employ high-level electronic structure calculations for dynamics at an affordable cost. PMID- 20192293 TI - Localized Hartree product treatment of multiple protons in the nuclear-electronic orbital framework. AB - An approximation for treating multiple quantum nuclei within the nuclear electronic orbital (NEO) framework for molecular systems is presented. In the approximation to NEO-Hartree-Fock, the nuclear wave function is represented by a Hartree product rather than a Slater determinant, corresponding to the neglect of the nuclear exchange interactions. In the approximation to NEO-density functional theory, the nuclear exchange-correlation functional is chosen to be the diagonal nuclear exchange interaction terms, thereby eliminating the nuclear self interaction terms. To further enhance the simplicity and computational efficiency, the nuclear molecular orbitals or Kohn-Sham orbitals are expanded in terms of localized nuclear basis sets. These approximations are valid because of the inherent localization of the nuclear orbitals and the numerical insignificance of the nuclear exchange interactions in molecular systems. Moreover, these approximations lead to substantial computational savings due to the reduction in both the number of integrals that must be calculated and the size of the matrices that must be diagonalized. These nuclear Hartree product approximation (HPA) methods scale linearly with the number of quantum protons and are highly parallelizable. Applications to a water hexamer, glycine dimer, and 32 water cluster, where all hydrogen nuclei are treated quantum mechanically, illustrate the accuracy and computational efficiency of the nuclear HPA methods. These strategies will facilitate the implementation of explicitly correlated NEO methods for molecular systems with multiple quantum protons. PMID- 20192294 TI - Compatibility between shape equation and boundary conditions of lipid membranes with free edges. AB - Only some special open surfaces satisfying the shape equation of lipid membranes can be compatible with the boundary conditions. As a result of this compatibility, the first integral of the shape equation should vanish for axisymmetric lipid membranes, from which two theorems of nonexistence are verified: (i) there is no axisymmetric open membrane being a part of torus satisfying the shape equation; (ii) there is no axisymmetric open membrane being a part of a biconcave discodal surface satisfying the shape equation. Additionally, the shape equation is reduced to a second-order differential equation while the boundary conditions are reduced to two equations due to this compatibility. Numerical solutions to the reduced shape equation and boundary conditions agree well with the experimental data [A. Saitoh et al., Proc. Natl. Acad. Sci. U.S.A. 95, 1026 (1998)]. PMID- 20192295 TI - Extraction of state-to-state reactive scattering attributes from wave packet in reactant Jacobi coordinates. AB - The S-matrix for a scattering system provides the most detailed information about the dynamics. In this work, we discuss the calculation of S-matrix elements for the A+BC-->AB+C, AC+B type reaction. Two methods for extracting S-matrix elements from a single wave packet in reactant Jacobi coordinates are reviewed and compared. Both methods are capable of extracting the state-to-state attributes for both product channels from a single wave packet propagation. It is shown through the examples of H+HD, Cl+H(2), and H+HCl reactions that such reactant coordinate based methods are easy to implement, numerically efficient, and accurate. Additional efficiency can be gained by the use of a L-shaped grid with two-dimensional fast Fourier transform. PMID- 20192296 TI - Search for Br* production in the D+DBr reaction. AB - Deuterium bromide (DBr) is expanded from a pulsed jet into a vacuum and a synchronized pulsed laser causes photodissociation of some of the DBr molecules to produce primarily (approximately 85%) ground-state bromine atoms ((2)P(3/2)) and fast D atoms. The latter collide with the cold DBr molecules and react to produce molecular deuterium (D(2)) via two possible channels, the adiabatic channel D(2)+Br((2)P(3/2)) and the nonadiabatic channel D(2)+Br*((2)P(1/2)), which are asymptotically separated in energy by the spin-orbit splitting (0.457 eV) of the bromine atom. Ion images are recorded for D(2)(v'=1, J'=16, 18-21), D(2)(v'=2, J'=6,7, 10-12, 14-16), and D(2)(v'=3, J'=2-5) for various collision energies. For the nonadiabatic production of spin-orbit-excited Br* in the D+DBr reaction for the conditions studied we estimate that this channel contributes 1% or less. PMID- 20192297 TI - Valence ionized states of iron pentacarbonyl and eta5-cyclopentadienyl cobalt dicarbonyl studied by symmetry-adapted cluster-configuration interaction calculation and collision-energy resolved Penning ionization electron spectroscopy. AB - Valence ionized states of iron pentacarbonyl Fe(CO)(5) and eta(5) cyclopentadienyl cobalt dicarbonyl Co(eta(5)-C(5)H(5))(CO)(2) have been studied by ultraviolet photoelectron spectroscopy, two-dimensional Penning ionization electron spectroscopy (2D-PIES), and symmetry-adapted cluster-configuration interaction calculations. Theory provided reliable assignments for the complex ionization spectra of these molecules, which have metal-carbonyl bonds. Theoretical ionization energies agreed well with experimental observations and the calculated wave functions could explain the relative intensities of PIES spectra. The collision-energy dependence of partial ionization cross sections (CEDPICS) was obtained by 2D-PIES. To interpret these CEDPICS, the interaction potentials between the molecules and a Li atom were examined in several coordinates by calculations. The relation between the slope of the CEDPICS and the electronic structure of the ionized states, such as molecular symmetry and the spatial distribution of ionizing orbitals, was analyzed. In Fe(CO)(5), an attractive interaction was obtained for the equatorial CO, while the interaction for the axial CO direction was repulsive. For Co(eta(5)-C(5)H(5))(CO)(2), the interaction potential in the direction of both Co-C-O and Co-Cp ring was attractive. These anisotropic interactions and ionizing orbital distributions consistently explain the relative slopes of the CEDPICS. PMID- 20192298 TI - On the nature of B-Ccarbene bonding in a stable neutral diborene. AB - We report the bonding interactions within [R(H)B=B(H)] and [R] (R=:C(NHCH)(2)) as a ligand in a newly synthesized stable neutral diborene. By using theoretical analyses, we have found the nature of the B-C(carbene) bonding, and, more importantly, the key to realize multiple bonds for chemical elements. With character of almost equal covalency and ionicity, the stabilizing orbital interaction term, DeltaE(orb), of B-C(carbene), is mainly given by sigma-symmetry orbital interactions; the donor-acceptor interaction is weak and contributes small to DeltaE(orb). In the weak donor-acceptor interaction, the B-->C(carbene) pi backdonation is stronger than the B<--C(carbene) sigma donation. Thus, in effect, the bond emerges in the B(delta+)-C(carbene)(delta-) dipole. Inspection of the correlation lines of the orbital correlation diagram for the B-C(carbene) bonding indicates that the strength of the bonding orbitals in the central BB unit is weakened due to the coordination of the carbenes, and the center is unstabilized by the carbene ligand. This is contrary to the conventional view on the mechanism of coordination and the Dewar-Chatt-Duncanson model. However this unstabilizing effect should be responsible for the stability of the B=B double bond in the stable neutral diborene. This is because the very short bond lengths arising from multiple bonds will lead to a very strong Pauli repulsion, and, ultimately, destruction of chemical bonds. It can therefore be concluded that, actually, to prevent the very short bond lengths is the true reason for the successful realization of multiple bonds for main-group elements such as boron. PMID- 20192299 TI - The HOOH UV spectrum: importance of the transition dipole moment and torsional motion from semiclassical calculations on an ab initio potential energy surface. AB - The absorption cross section of HOOH, a starting point for larger ROOH, was calculated using the "Wigner method." Calculations use the Wigner transform of ground state wave functions and classical approximations for excited state wave functions. Potential energy and transition dipole moment surfaces were calculated using the equation-of-motion coupled-cluster singles and doubles method over an extended Franck-Condon region. The first two O-O stretches and the first five HOOH torsional levels are included. This study also addresses two fundamental questions about ROOH photodissociation. The long wavelength A(1)A:B(1)B excited state preference has been measured from dynamics experiments, but a Franck-Condon overlap explanation has not been directly verified. A moderate barrier to HOOH torsional motion and excited state dynamics affect the temperature dependence in the UV spectrum. Based on these initial findings for HOOH, photodissociation of large ROOH cannot be eliminated as an important factor for ozone and particulate matter production seen in both ambient and laboratory studies. PMID- 20192300 TI - Seven-degree-of-freedom, quantum scattering dynamics study of the H2D+ + H2 reaction. AB - A quantum scattering dynamics, time-dependent wavepacket propagation method is applied to study the reaction of H(2)D(+)+H(2)-->H(3)(+)+HD on the Xie-Braams Bowman potential energy surface. The reduced-dimensional, seven-degree-of-freedom approach is employed in this calculation by fixing one Jacobi and one torsion angle related to H(2)D(+) at the lowest saddle point geometry of D(2d) on the potential energy surface. Initial state selected reaction probabilities are presented for various initial rovibrational states. The ground state reaction probability shows no threshold for this reaction, in other words, this reaction can occur without an activation barrier. The vibrational excitation shows that the stretching motion of H(+)-HD only has a small effect on the reaction probability; the vibrational excitation of HD in H(2)D(+) hinders the reactivity. By contrast, rotational excitation of H(+)-HD greatly enhances the reactivity with the reaction probability increased double or triple at high rotational states compared to the ground state. Reactive resonances, seen in all the initial state selected reaction probabilities, are also found in the integral cross section for the ground state of H(2)D(+) and H(2). The thermal rate coefficient is also calculated and is found to be in semiquantitative agreement with experiment; however, quantum scattering approaches including more degrees of freedom, especially including all the angles, are necessary to study this reaction in the future. PMID- 20192301 TI - Probing the oxygen environment in UO(2)(2+) by solid-state 17O nuclear magnetic resonance spectroscopy and relativistic density functional calculations. AB - A combined theoretical and solid-state (17)O nuclear magnetic resonance (NMR) study of the electronic structure of the uranyl ion UO(2)(2+) in (NH(4))(4)UO(2)(CO(3))(3) and rutherfordine (UO(2)CO(3)) is presented, the former representing a system with a hydrogen-bonding environment around the uranyl oxygens and the latter exemplifying a uranyl environment without hydrogens. Relativistic density functional calculations reveal unique features of the U-O covalent bond, including the finding of (17)O chemical shift anisotropies that are among the largest for oxygen ever reported (>1200 ppm). Computational results for the oxygen electric field gradient tensor are found to be consistently larger in magnitude than experimental solid-state (17)O NMR measurements in a 7.05 T magnetic field indicate. A modified version of the Solomon theory of the two-spin echo amplitude for a spin-5/2 nucleus is developed and applied to the analysis of the (17)O echo signal of U (17)O(2)(2+). PMID- 20192302 TI - Mesoscopic nonequilibrium thermodynamics approach to non-Debye dielectric relaxation. AB - Mesoscopic nonequilibrium thermodynamics is used to formulate a model describing nonhomogeneous and non-Debye dielectric relaxation. The model is presented in terms of a Fokker-Planck equation for the probability distribution of noninteracting polar molecules in contact with a heat bath and in the presence of an external time-dependent electric field. Memory effects are introduced in the Fokker-Planck description through integral relations containing memory kernels, which in turn are used to establish a connection with fractional Fokker-Planck descriptions. The model is developed in terms of the evolution equations for the first two moments of the distribution function. These equations are solved by following a perturbative method from which the expressions for the complex susceptibilities are obtained as a function of the frequency and the wave number. Different memory kernels are considered and used to compare with experiments of dielectric relaxation in glassy systems. For the case of Cole-Cole relaxation, we infer the distribution of relaxation times and its relation with an effective distribution of dipolar moments that can be attributed to different segmental motions of the polymer chains in a melt. PMID- 20192303 TI - Matrix isolation and computational study of isodifluorodibromomethane (F2CBr-Br): a route to Br2 formation in CF2Br2 photolysis. AB - The photolysis products of dibromodifluoromethane (CF(2)Br(2)) were characterized by matrix isolation infrared and UV/Visible spectroscopy, supported by ab initio calculations. Photolysis at wavelengths of 240 and 266 nm of CF(2)Br(2):Ar samples (approximately 1:5000) held at approximately 5 K yielded iso-CF(2)Br(2) (F(2)CBrBr), a weakly bound isomer of CF(2)Br(2), which is characterized here for the first time. The observed infrared and UV/Visible absorptions of iso CF(2)Br(2) are in excellent agreement with computational predictions at the B3LYP/aug-cc-pVTZ level. Single point energy calculations at the CCSD(T)/aug-cc pVDZ level on the B3LYP optimized geometries suggest that the isoform is a minimum on the CF(2)Br(2) potential energy surface, lying some 55 kcal/mol above the CF(2)Br(2) ground state. The energies of various stationary points on the CF(2)Br(2) potential energy surface were characterized computationally; taken with our experimental results, these show that iso-CF(2)Br(2) is an intermediate in the Br+CF(2)Br-->CF(2)+Br(2) reaction. The photochemistry of the isoform was also investigated; excitation into the intense 359 nm absorption band resulted in isomerization to CF(2)Br(2). Our results are discussed in view of the rich literature on the gas-phase photochemistry of CF(2)Br(2), particularly with respect to the existence of a roaming atom pathway leading to molecular products. PMID- 20192304 TI - Plasticization and antiplasticization of polymer melts diluted by low molar mass species. AB - An analysis of glass formation for polymer melts that are diluted by structured molecular additives is derived by using the generalized entropy theory, which involves a combination of the Adam-Gibbs model and the direct computation of the configurational entropy based on a lattice model of polymer melts that includes monomer structural effects. Our computations indicate that the plasticization and antiplasticization of polymer melts depend on the molecular properties of the additive. Antiplasticization is accompanied by a "toughening" of the glass mixture relative to the pure polymer, and this effect is found to occur when the diluents are small species with strongly attractive interactions with the polymer matrix. Plasticization leads to a decreased glass transition temperature T(g) and a "softening" of the fragile host polymer in the glass state. Plasticization is prompted by small additives with weakly attractive interactions with the polymer matrix. However, the latter situation can lead to phase separation if the attractive interactions are sufficiently strong. The shifts in T(g) of polystyrene diluted by fully flexible short oligomers (up to 20% mass of diluent) are evaluated from the computations, along with the relative changes in the isothermal compressibility at T(g) (a softening or toughening effect) to characterize the extent to which the additives act as antiplasticizers or plasticizers. The theory predicts that a decreased fragility can accompany both antiplasticization and plasticization of the glass by molecular additives. The general reduction in the T(g) of polymers by molecular additives is rationalized by analyzing the influence of the diluent's properties (cohesive energy, chain length, and stiffness) on glass formation in fluid mixtures and the variation of fragility is discussed in relation to changes in the molecular packing in diluted polymer melts. Our description of constant temperature glass formation upon increasing the diluent concentration directly leads to the Angell equation (tau(alpha) approximately A exp{B/(phi(0,p)-phi(p))}) for the structural relaxation time as function of the polymer concentration, where the extrapolated "zero mobility concentration" phi(0,p) calculated from the theory scales linearly with the inverse polymerization index N. PMID- 20192305 TI - Quantum hydrodynamics of electron gases. AB - Electron gases in metals are described as quantum charged Newtonian viscous fluids experiencing Ohmic Darcy friction on the solid lattice ions as well. The dispersion relation of the electron acoustic waves is derived, which shows the existence of new quantum diffusion processes. The electric double layer near a metal surface is studied, which exhibits a new quantum oscillatory-decaying behavior different from the Friedel oscillations. PMID- 20192306 TI - Simulation and reference interaction site model theory of methanol and carbon tetrachloride mixtures. AB - We report molecular dynamics and reference interaction site model (RISM) theory of methanol and carbon tetrachloride mixtures. Our study encompasses the whole concentration range, by including the pure component limits. We majorly focus on an analysis of partial, total, and concentration-concentration structure factors, and examine in detail the k-->0 limits of these functions. Simulation results confirm the tendency of methanol to self-associate with the formation of ring structures in the high dilution regime of this species, in agreement with experimental studies and with previous simulations by other authors. This behavior emerges as strongly related to the high nonideality of the mixture, a quantitative estimate of which is provided in terms of concentration fluctuation correlations, through the structure factors examined. The interaggregate correlation distance is also thereby estimated. Finally, the compressibility of the mixture is found in good agreement with experimental data. The RISM predictions are throughout assessed against simulation; the theory describes better the apolar solvent than the alcohol properties. Self-association of methanol is qualitatively reproduced, though this trend is much less marked in comparison with simulation results. PMID- 20192307 TI - Thermodynamic pressures for hard spheres and closed-virial equation-of-state. AB - Hard-sphere molecular dynamics (MD) simulation results, with six-figure accuracy in the thermodynamic equilibrium pressure, are reported and used to test a closed virial equation-of-state. This latest equation, with no adjustable parameters except known virial coefficients, is comparable in accuracy both to Pade approximants, and to numerical parameterizations of MD data. There is no evidence of nonconvergence at stable fluid densities. The virial pressure begins to deviate significantly from the thermodynamic fluid pressure at or near the freezing density, suggesting that the passage from stable fluid to metastable fluid is associated with a higher-order phase transition; an observation consistent with some previous experimental results. Revised parameters for the crystal equation-of-state [R. J. Speedy, J. Phys.: Condens. Matter 10, 4387 (1998)] are also reported. PMID- 20192308 TI - Two-center potential correlations and its use to determine effective ion-ion interactions and dielectric permittivities in dipolar solvents. AB - General expressions for two-center electrostatic potential correlations and its use to determine (i) the effective interaction between simple ions in a dipolar solvent and (ii) the dielectric permittivity of the solvent are proposed. Such two-center potential correlations were determined from Monte Carlo simulations of spherically confined dipolar particles embedded in a dielectric medium described by using an image charge approximation. The deduced dielectric permittivities increased with increasing dipolar moment, and at large dipole moments the effective interaction displayed an attractive first minimum. PMID- 20192309 TI - Multiscale modeling of interaction of alane clusters on Al(111) surfaces: a reactive force field and infrared absorption spectroscopy approach. AB - We have used reactive force field (ReaxFF) to investigate the mechanism of interaction of alanes on Al(111) surface. Our simulations show that, on the Al(111) surface, alanes oligomerize into larger alanes. In addition, from our simulations, adsorption of atomic hydrogen on Al(111) surface leads to the formation of alanes via H-induced etching of aluminum atoms from the surface. The alanes then agglomerate at the step edges forming stringlike conformations. The identification of these stringlike intermediates as a precursor to the bulk hydride phase allows us to explain the loss of resolution in surface IR experiments with increasing hydrogen coverage on single crystal Al(111) surface. This is in excellent agreement with the experimental works of Go et al. [E. Go, K. Thuermer, and J. E. Reutt-Robey, Surf. Sci. 437, 377 (1999)]. The mobility of alanes molecules has been studied using molecular dynamics and it is found that the migration energy barrier of Al(2)H(6) is 2.99 kcal/mol while the prefactor is D(0)=2.82 x 10(-3) cm(2)/s. We further investigated the interaction between an alane and an aluminum vacancy using classical molecular dynamics simulations. We found that a vacancy acts as a trap for alane, and eventually fractionates/annihilates it. These results show that ReaxFF can be used, in conjunction with ab initio methods, to study complex reactions on surfaces at both ambient and elevated temperature conditions. PMID- 20192310 TI - Analysis of femtosecond stimulated Raman spectroscopy of excited-state evolution in bacteriorhodopsin. AB - The dispersive lines observed in time-resolved femtosecond stimulated Raman spectroscopy (FSRS), using a pair of 809 nm, 3 ps Raman pump, and 840-960 nm ultrashort probe pulse, for the first 500 fs photoisomerization dynamics in the excited state of bacteriorhodopsin, BR* (S(1)), created by a prior 500 nm, 35 fs actinic pump pulse, have previously been attributed to Raman initiated by nonlinear emission (RINE). We used four-wave mixing energy level diagrams to describe the FSRS process, which include RINE as a subset, and a 29-mode harmonic oscillator model for BR(568) in the calculations. Our calculations showed that FSRS of BR* effectively occurs from the ground vibrational state of each of the observed 800-1800 cm(-1) modes of S(1). The lifetime on S(1) determines the linewidth and decay of the dispersive lines, and is estimated to be approximately 600 fs, comparable to the stimulated emission decay time. The FSRS dipole couplings are from the ground vibrational state of S(1) to high energy vibrational states on BR (S(0)), and we place a fast decay lifetime of approximately 100 fs on S(0) which can be attributed to the correlation function from the many unobserved low frequency modes. The FSRS dispersive lines are shown to be due to the inverse Raman scattering term with mid |0><1| vibrational coherence on the S(1) surface, and are not due to RINE with vibrational coherence on the S(0) surface. Our calculations show that the RINE process gives rise to broad featureless spectra. PMID- 20192311 TI - Simulations of heteroaggregation in a suspension of alumina and silica particles: effect of dilution. AB - The influence of dilution on the aggregation process of suspensions composed of two kinds of oxide particles (alumina positively charged particles d(1)=400 nm and silica negatively charged particles d(2)=250 nm) has been studied by computer simulations. Two kinds of simulations have been performed: Brownian dynamics simulations to study the aggregation process and its kinetics and global minimization searches to find the most stable configurations of aggregates. We show that the rate of dilution has a strong influence on the structure and on the shape of aggregates in Brownian dynamics simulations. By confronting these aggregates with the stable aggregates found by global minimization, we demonstrate that they are metastable and their shape is explained by the competition between the kinetics of aggregate coalescence and the kinetics of aggregate reorganization into more stable configurations. PMID- 20192312 TI - Simulation study of the disjoining pressure profile through a three-phase contact line. AB - Computer simulations are performed to measure the disjoining pressure profile Pi(y) across the three-phase contact line formed by a liquid-vapor interface intersecting a planar substrate wall lying in the xy plane. The method makes use of an exact expression for the disjoining pressure in terms of the density profile and the wall-fluid interaction. Pi(y) is reported for three distinct values of the wall-fluid attractive potential, representing differing levels of partial wetting by macroscopic adsorbed drops. Mechanical force-balance normal to the substrate is confirmed by direct evaluation of the required analog to Young's equation. For the model system under study, the disjoining pressure profiles are well-fitted by inverted Gaussians. The fitted results are used with an extension (to large values of Young's contact angle theta) of the interface Hamiltonian theory of Indekeu, thereby enabling us to report the line tension tau(theta). PMID- 20192313 TI - X-ray absorption and photoemission spectroscopy of zinc protoporphyrin adsorbed on rutile TiO2(110) prepared by in situ electrospray deposition. AB - Zinc-protoporphyrin, adsorbed on the rutile TiO(2)(110) surface, has been studied using photoemission spectroscopy and near-edge absorption fine structure spectroscopy to deduce the nature of the molecule-surface bonding and the chemical environment of the central metal atom. To overcome the difficulties associated with sublimation of the porphyrin molecules, samples were prepared in situ using ultrahigh vacuum electrospray deposition, a technique which facilitates the deposition of nonvolatile and fragile molecules. Monolayers of Zn protoporphyrin are found to bond to the surface via the oxygen atoms of the deprotonated carboxyl groups. The molecules initially lie largely parallel to the surface, reorienting to an upright geometry as the coverage is increased up to a monolayer. For those molecules directly chemisorbed to the surface, the interaction is sufficiently strong to pull the central metal atom out of the molecule. PMID- 20192314 TI - Charge regularization in phase separating polyelectrolyte solutions. AB - Theoretical investigations of phase separation in polyelectrolyte solutions have so far assumed that the effective charge of the polyelectrolyte chains is fixed. The ability of the polyelectrolyte chains to self-regulate their effective charge due to the self-consistent coupling between ionization equilibrium and polymer conformations, depending on the dielectric constant, temperature, and polymer concentration, affects the critical phenomena and phase transitions drastically. By considering salt-free polyelectrolyte solutions, we show that the daughter phases have different polymer charges from that of the mother phase. The critical point is also altered significantly by the charge self-regularization of the polymer chains. This work extends the progress made so far in the theory of phase separation of strong polyelectrolyte solutions to a higher level of understanding by considering chains which can self-regulate their charge. PMID- 20192315 TI - Spreading of colloid clusters in a quasi-one-dimensional channel. AB - The effect of hydrodynamic interactions on the spreading of clusters of colloid particles in a quasi-one-dimensional channel is analyzed both experimentally and theoretically. An n-particle cluster spreading diffusion coefficient is defined, in terms of the displacement Deltax(t) in time t, by D(n)[triple bond]<[Sigma(i=1)(n)Deltax(i)(t)](2)>/2nt, where the average is taken over all groups of n adjacent particles. Our study focuses on the n-dependence of D(n) with some attention to the dependence of D(n) on colloid packing fraction. We find that the ratio of D(n) to the infinite dilution self-diffusion coefficient D(S)(0) increases as n increases, eventually saturating for large n. The observed dependence of D(n) on n is in satisfactory agreement with the predictions obtained from both Stokesian dynamics simulations and hydrodynamic calculations using the method of reflections. PMID- 20192316 TI - Empirical model of residue contact probabilities for polypeptides. AB - An empirical theory for the probability of formation of intrachain contacts in denatured polypeptides is presented. Contact probabilities for arbitrary sequences are modeled by composition-weighted averages of the homopolypeptides contact probabilities. Homopolypeptide probabilities are obtained for each one of the 20 amino acids by Monte Carlo simulations. A multipower law model for the homopolypeptides fits very precisely the contact probabilities after optimization. Its asymptotic behavior for large contact loop lengths consist of three different exponents depending on where the contacts are located along the chain in general agreement with other theoretical models. The model for the heteropolypeptide contact probabilities is also able to reproduce the simulated probabilities of a set of denatured proteins but with less accuracy. Contact probabilities for heteropolypeptides are significantly similar, in particular for loop lengths above 20 residues, and the model does not have enough resolution to clearly distinguish between different proteins. Sequence order information seems necessary to increase the precision. Overall, contacts with loop lengths above 33 residues behave as those from random flight chains. One exception are polyproline chains for which this length seems to be much higher. PMID- 20192317 TI - Unique magnetic signatures of mismatched base pairs in DNA. AB - Magnetic properties of DNA containing mispairs, such as different conformations of the GA mispair, or a GT mispair inserted into the DNA chain, have been theoretically investigated. The essential ingredients for these studies, the charge transfer integrals, were evaluated from the DNA sequences containing the mispair and optimized in the solvent. We find that the magnetic susceptibilities of the host DNA chain containing a large number of Watson-Crick base pairs are significantly altered in the presence of the mispairs, and the effects depend on the choice of mispairs. In particular, insertion of even a single GA mispair changes the nature of magnetization (sign of the susceptibility) of the host DNA. We propose that measurement of the magnetic properties of DNA might provide a direct route to detection and identification of those mispairs. PMID- 20192318 TI - Protein elasticity probed with two synchrotron-based techniques. AB - Compressibility characterizes three interconnecting properties of a protein: dynamics, structure, and function. The compressibility values for the electron carrying protein cytochrome c and for other proteins, as well, available in the literature vary considerably. Here, we apply two synchrotron-based techniques- nuclear resonance vibrational spectroscopy and inelastic x-ray scattering--to measure the adiabatic compressibility of this protein. This is the first report of the compressibility of any material measured with this method. Unlike the methods previously used, this novel approach probes the protein globally, at ambient pressure, does not require the separation of protein and solvent contributions to the total compressibility, and uses samples that contain the heme iron, as in the native state. We show, by comparing our results with molecular dynamics predictions, that the compressibility is almost independent of temperature. We discuss potential applications of this method to other materials beyond proteins. PMID- 20192320 TI - The third generation superconducting 28 GHz electron cyclotron resonance ion source VENUS (invited). AB - VENUS is a third generation electron cyclotron resonance (ECR) ion source, which incorporates a high field superconducting NbTi magnet structure, a 28 GHz gryotron microwave source and a state of the art closed cycle cryosystem. During the decade from initial concept to regular operation, it has demonstrated both the feasibility and the performance levels of this new generation of ECR ion sources and required innovation on magnet construction, plasma chamber design, and beam transport. In this paper, the development, performance, and major innovations are described as well as a look to the potential to construct a fourth generation ECR ion source. PMID- 20192321 TI - New development of advanced superconducting electron cyclotron resonance ion source SECRAL (invited). AB - Superconducting electron cyclotron resonance ion source with advance design in Lanzhou (SECRAL) is an 18-28 GHz fully superconducting electron cyclotron resonance (ECR) ion source dedicated for highly charged heavy ion beam production. SECRAL, with an innovative superconducting magnet structure of solenoid-inside-sextupole and at lower frequency and lower rf power operation, may open a new way for developing compact and reliable high performance superconducting ECR ion source. One of the recent highlights achieved at SECRAL is that some new record beam currents for very high charge states were produced by 18 GHz or 18+14.5 GHz double frequency heating, such as 1 e microA of (129)Xe(43+), 22 e microA of (209)Bi(41+), and 1.5 e microA of (209)Bi(50+). To further enhance the performance of SECRAL, a 24 GHz/7 kW gyrotron microwave generator was installed and SECRAL was tested at 24 GHz. Some promising and exciting results at 24 GHz with new record highly charged ion beam intensities were produced, such as 455 e microA of (129)Xe(27+) and 152 e microA of (129)Xe(30+), although the commissioning time was limited within 3-4 weeks and rf power only 3-4 kW. Bremsstrahlung measurements at 24 GHz show that x-ray is much stronger with higher rf frequency, higher rf power. and higher minimum mirror magnetic field (minimum B). Preliminary emittance measurements indicate that SECRAL emittance at 24 GHz is slightly higher that at 18 GHz. SECRAL has been put into routine operation at 18 GHz for heavy ion research facility in Lanzhou (HIRFL) accelerator complex since May 2007. The total operation beam time from SECRAL for HIRFL accelerator has been more than 2000 h, and (129)Xe(27+), (78)Kr(19+), (209)Bi(31+), and (58)Ni(19+) beams were delivered. All of these new developments, the latest results, and long-term operation for the accelerator have again demonstrated that SECRAL is one of the best in the performance of ECR ion source for highly charged heavy ion beam production. Finally the future development of SECRAL will be presented. PMID- 20192322 TI - Simulation of parameter scaling in electron cyclotron resonance ion source plasmas using the GEM code. AB - Although heating power and gas pressure are two of the two of primary experimental "knobs" available to users of electron cyclotron resonance ion sources, there is still no clear understanding of how they interact in order to provide optimal plasma conditions. FAR-TECH, Inc. has performed a series of simulations with its generalized electron cyclotron resonance ion source model in which the power and pressure were varied over a wide range. Analysis of the numerical data produces scaling laws that predict the plasma parameters as a function of the power and pressure. These scaling laws are in general agreement with experimental data. PMID- 20192323 TI - The effect of rf pulse pattern on bremsstrahlung and ion current time evolution of an ECRIS. AB - Time-resolved helium ion production and bremsstrahlung emission from JYFL 14 GHz ECRIS is presented with different radio frequency pulse lengths. rf on times are varied from 5 to 50 ms and rf off times from 10 to 1000 ms between different measurement sets. It is observed that the plasma breakdown occurs a few milliseconds after launching the rf power into the plasma chamber, and in the beginning of the rf pulses a preglow transient is seen. During this transient the ion beam currents are increased by several factors compared to a steady state situation. By adjusting the rf pulse separation the maximum ion beam currents can be maintained during the so-called preglow regime while the amount of bremsstrahlung radiation is significantly decreased. PMID- 20192324 TI - The role of seed electrons on the plasma breakdown and preglow of electron cyclotron resonance ion source. AB - The 14 GHz Electron Cyclotron Resonance Ion Source at University of Jyvaskyla, Department of Physics (JYFL) has been operated in pulsed mode in order to study the plasma breakdown and preglow effect. It was observed that the plasma breakdown time and preglow characteristics are affected by seed electrons provided by a continuous low power microwave signal at secondary frequency. Sustaining low density plasma during the off-period of high power microwave pulses at the primary frequency shifts the charge state distribution of the preglow transient toward higher charge states. This could be exploited for applications requiring fast and efficient ionization of radioactive elements as proposed for the Beta Beam project within the EURISOL design study, for example. In this article we present results measured with helium and neon. PMID- 20192325 TI - Simulation of charge breeding of rubidium using Monte Carlo charge breeding code and generalized ECRIS model. AB - A Monte Carlo charge breeding code (MCBC) is being developed by FAR-TECH, Inc. to model the capture and charge breeding of 1+ ion beam in an electron cyclotron resonance ion source (ECRIS) device. The ECRIS plasma is simulated using the generalized ECRIS model which has two choices of boundary settings, free boundary condition and Bohm condition. The charge state distribution of the extracted beam ions is calculated by solving the steady state ion continuity equations where the profiles of the captured ions are used as source terms. MCBC simulations of the charge breeding of Rb+ showed good agreement with recent charge breeding experiments at Argonne National Laboratory (ANL). MCBC correctly predicted the peak of highly charged ion state outputs under free boundary condition and similar charge state distribution width but a lower peak charge state under the Bohm condition. The comparisons between the simulation results and ANL experimental measurements are presented and discussed. PMID- 20192326 TI - Glow plasma trigger for electron cyclotron resonance ion sources. AB - Electron cyclotron resonance ion sources (ECRISs) are particularly useful for nuclear, atomic, and high energy physics, as unique high current generators of multicharged ion beams. Plasmas of gas discharges in an open magnetic trap heated by pulsed (100 micros and longer) high power (100 kW and higher) high-frequency (greater than 37.5 GHz) microwaves of gyrotrons is promising in the field of research in the development of electron cyclotron resonance sources for high charge state ion beams. Reaching high ion charge states requires a decrease in gas pressure in the magnetic trap, but this method leads to increases in time, in which the microwave discharge develops. The gas breakdown and microwave discharge duration becomes greater than or equal to the microwave pulse duration when the pressure is decreased. This makes reaching the critical plasma density initiate an electron cyclotron resonance (ECR) discharge during pulse of microwave gyrotron radiation with gas pressure lower than a certain threshold. In order to reduce losses of microwave power, it is necessary to shorten the time of development of the ECR discharge. For fast triggering of ECR discharge under low pressure in an ECRIS, we initially propose to fill the magnetic trap with the plasmas of auxiliary pulsed discharges in crossed ExB fields. The glow plasma trigger of ECR based on a Penning or magnetron discharge has made it possible not only to fill the trap with plasma with density of 10(12) cm(-3), required for a rapid increase in plasma density and finally for ECR discharge ignition, but also to initially heat the plasma electrons to T(e) approximately = 20 eV. PMID- 20192327 TI - Bio-Nano ECRIS: an electron cyclotron resonance ion source for new materials production. AB - We developed an electron cyclotron resonance ion source (ECRIS) for new materials production on nanoscale. Our main target is the endohedral fullerenes, which have potential in medical care, biotechnology, and nanotechnology. In particular, iron encapsulated fullerene can be applied as a contrast material for magnetic resonance imaging or microwave heat therapy. Thus, our new ECRIS is named the Bio Nano ECRIS. In this article, the recent progress of the development of the Bio Nano ECRIS is reported: (i) iron ion beam production using induction heating oven and (ii) optimization of singly charged C(60) ion beam production. PMID- 20192328 TI - Three-dimensional simulations of ion dynamics in an Electron Cyclotron Resonance Ion Source. AB - We present a three-dimensional simulation of the ion dynamics in an electron cyclotron resonance ion source. Ion trajectories in the min-B field of the source are calculated taking ion-ion and electron-ion collisions into account. The electrons are not tracked but considered as a neutralizing background with a Maxwell-Boltzmann velocity distribution. Some applications of the code are discussed, e.g., the calculated charge-state and phase-space distributions of extracted ion beams and the ionization dynamics in the plasma. PMID- 20192329 TI - Measurement of radial and axial high energy x-ray spectra in electron cyclotron resonance ion source plasmas. AB - Radial and axial x-ray measurements of electron cyclotron resonance ion sources operating at microwave frequencies of 6.4 and 14 GHz are presented. Results indicate a greater detected photon energy in the radial direction than the axial direction for both the 6.4 GHz source and the 14 GHz source. It is also seen that the 14 GHz source produces x-rays with higher energies, when compared to the 6.4 GHz source, in both radial and axial directions. PMID- 20192330 TI - Nb3Sn superconducting magnets for electron cyclotron resonance ion sources. AB - Electron cyclotron resonance (ECR) ion sources are an essential component of heavy-ion accelerators. Over the past few decades advances in magnet technology and an improved understanding of the ECR ion source plasma physics have led to remarkable performance improvements of ECR ion sources. Currently third generation high field superconducting ECR ion sources operating at frequencies around 28 GHz are the state of the art ion injectors and several devices are either under commissioning or under design around the world. At the same time, the demand for increased intensities of highly charged heavy ions continues to grow, which makes the development of even higher performance ECR ion sources a necessity. To extend ECR ion sources to frequencies well above 28 GHz, new magnet technology will be needed in order to operate at higher field and force levels. The superconducting magnet program at LBNL has been developing high field superconducting magnets for particle accelerators based on Nb(3)Sn superconducting technology for several years. At the moment, Nb(3)Sn is the only practical conductor capable of operating at the 15 T field level in the relevant configurations. Recent design studies have been focused on the possibility of using Nb(3)Sn in the next generation of ECR ion sources. In the past, LBNL has worked on the VENUS ECR, a 28 GHz source with solenoids and a sextupole made with NbTi operating at fields of 6-7 T. VENUS has now been operating since 2004. We present in this paper the design of a Nb(3)Sn ECR ion source optimized to operate at an rf frequency of 56 GHz with conductor peak fields of 13-15 T. Because of the brittleness and strain sensitivity of Nb(3)Sn, particular care is required in the design of the magnet support structure, which must be capable of providing support to the coils without overstressing the conductor. In this paper, we present the main features of the support structure, featuring an external aluminum shell pretensioned with water-pressurized bladders, and we analyze the expected coil stresses with a two-dimensional finite element mechanical model. PMID- 20192331 TI - Plasma potential and energy spread determination using ion beams extracted from an electron cyclotron resonance source. AB - We have obtained estimates of plasma potentials and energy spreads characterizing an electron cyclotron resonance ion source plasma under different source conditions. Our estimates are obtained from analysis of ion beams extracted from the ion source at 10 kV that are subsequently decelerated into a floating surface scattering chamber where their current intensity incident on a solid sample is measured as function of retardation voltage. The deceleration occurs outside the measurement chamber, permitting beam current measurements in a field-free region. Absence of grids in the deceleration section avoids potential issues of field penetration. The behavior of our deceleration optics was modeled with SIMION. The simulation indicated a linear beam attenuation dependence close to full retardation where the beam current goes to zero. Deviations from this linear dependence observed close to zero beam energy give information on the initial energy spread of the ions extracted from the source. Our decelerated beams measurements are compared with recent in situ probe results and external beams results based on magnetic analysis. PMID- 20192332 TI - Progress in ion source injector development at the ion beam therapy center (Heidelberg Ion Beam Therapy Center). AB - Radiotherapy with heavy ions is an upcoming cancer treatment method with to date unachieved precision. It associates higher control rates particularly for radio resistant tumor species with reduced adverse effects compared to conventional photon therapy. At Heidelberg Ion Beam Therapy Center two 14.5 GHz electron cyclotron resonance ion sources are routinely used to produce a variety of ion beams from protons up to oxygen. The operating time is 330 days per year; our experience after 3 yr of continuous operation will be presented, with special emphasis on stability and breakdowns of components. In addition, the latest enhancement and the results for the operation will be shown. PMID- 20192333 TI - Stability study of all-permanent-magnet electron cyclotron resonance ion source. AB - Beam intensity fluctuation was investigated using an electron cyclotron resonance ion source of an all-permanent-magnet type under development for highly stable beam intensity. While the source achieved a stability of better than 3.2% by strict regulation of the coolant temperature change within +/-0.1 degrees C, the intensity varies strongly with intentional changes in the temperature of the plasma chamber coolant. The influence of the temperature on chamber expansion, magnetic field strength, and vacuum was measured or estimated in detail. The result shows that a slight change in vacuum and magnetic field strength has considerable influence on the intensity fluctuation. PMID- 20192334 TI - Production of electron cyclotron resonance plasma by using multifrequencies microwaves and active beam profile control on a large bore electron cyclotron resonance ion source with permanent magnets. AB - A new concept on magnetic field with all magnets on plasma production and confinement has been proposed to enhance efficiency of an electron cyclotron resonance (ECR) plasma for broad and dense ion beam source under the low pressure. The magnetic field configuration is constructed by a pair of magnets assembly, i.e., comb-shaped magnet which cylindrically surrounds the plasma chamber. The resonance zones corresponding to the fundamental ECR for 2.45 GHz and 11-13 GHz frequencies are constructed at different positions. The profiles of the plasma parameters in the ECR ion source are different from each frequency of microwave. Large bore extractor is set at the opposite side against the microwave feeds. It is found that differences of their profiles also appear at those of ion beam profiles. We conducted to launch simultaneously multiplex frequencies microwaves controlled individually, and tried to control the profiles of the plasma parameters and then those of extracted ion beam. PMID- 20192335 TI - Design and construction of a compact microwave proton source for a proton linac. AB - A 100 MeV, 20 mA proton linear accelerator is being developed by the Proton Engineering Frontier Project at the Korea Atomic Energy Research Institute. 20 MeV acceleration system using radio frequency quadrupole and drift tube linac was already developed and has been tested. To operate this acceleration system with a long time, more reliable proton source is needed. A compact microwave proton source was proposed and has been designed and constructed as a prototype ion source for the 100 MeV proton linear accelerator. The design of microwave power injection system is based on the microwave proton injector at LANL and CEA. The wave power from a 2.45 GHz, 2 kW magnetron source is introduced into a compact plasma chamber with 7 cm diameter and 5 cm length through a standard tapered, double-ridged waveguide (WRD250) and a quartz window. The microwave power supply is installed on high voltage platform. Axial magnetic fields up to 1 kG can be provided with a water-cooled solenoid coil. A single-hole three electrode extraction system is designed for an extraction current up to 30 mA at a 50 kV extraction voltage. The design and initial operations of the proton source are presented. PMID- 20192336 TI - First beams from the new electron cyclotron resonance source LEGIS (LEGnaro ecrIS) at INFN-LNL. AB - From April 2008 the PIAVE injector for the ALPI booster was involved in the upgrade of the high voltage platform housing an electron cyclotron resonance (ECR) source. A 14.5 GHz SUPERNANOGAN type ECR replaced the existing source ALICE; at the same time, the whole platform beam line was redesigned and beam shaping and diagnostic system were installed. The source and the platform were ready to be put into operation in January 2009. PIAVE's commissioning was started from late March and completed in May 2009 using an argon beam. A description of the upgrade will be given in the following; beam quality leading to an improved transmission through the injector will be shown. Results on first gaseous and metallic beams produced will also be given. PMID- 20192337 TI - Status report of the heavy ions source research and development for Spiral2. AB - The physics background requiring a very intense multicharged heavy ion source for Spiral2 is explained. The new Spiral2 low energy beam line dedicated to the heavy ions production and equipped with PHOENIX V2 ECRIS is presented. A status of the A-PHOENIX commissioning at 18 GHz is summarized. A new hybrid ECRIS concept with a cryogenic permanent magnet hexapole is proposed as an improvement of A-PHOENIX technology. PMID- 20192338 TI - Fabrication of an optimized hexapole magnet for a 14.5 GHz electron cyclotron resonance ion source. AB - A hexapole magnet for a 14.5 GHz electron cyclotron resonance (ECR) ion source, where the maximum radial field on the wall of the plasma chamber is higher than 1.1 T, has been designed and fabricated. The size of the outer diameter and the number of the sector of the hexapole are optimized for a 14.5 GHz ECR ion source with the help of a three-dimensional field calculation code. Moreover, to make a strong and long-life magnet against the demagnetic field on the hexapole multilayered structure in radial and axial directions is considered in the design. The distributions of the demagnetic fields are estimated by the calculation of the radial field in a hexapole magnet and the axial field from the solenoid coils. Proper grades of magnetic materials depending on the strength of the demagnetic field are applied for the different layers. The magnetic fields of the measured and calculated ones have been compared. PMID- 20192339 TI - Production of highly charged ion beams with SECRAL. AB - Superconducting electron cyclotron resonance ion source with advanced design in Lanzhou (SECRAL) is an all-superconducting-magnet electron cyclotron resonance ion source (ECRIS) for the production of intense highly charged ion beams to meet the requirements of the Heavy Ion Research Facility in Lanzhou (HIRFL). To further enhance the performance of SECRAL, an aluminum chamber has been installed inside a 1.5 mm thick Ta liner used for the reduction of x-ray irradiation at the high voltage insulator. With double-frequency (18+14.5 GHz) heating and at maximum total microwave power of 2.0 kW, SECRAL has successfully produced quite a few very highly charged Xe ion beams, such as 10 e microA of Xe(37+), 1 e microA of Xe(43+), and 0.16 e microA of Ne-like Xe(44+). To further explore the capability of the SECRAL in the production of highly charged heavy metal ion beams, a first test run on bismuth has been carried out recently. The main goal is to produce an intense Bi(31+) beam for HIRFL accelerator and to have a feel how well the SECRAL can do in the production of very highly charged Bi beams. During the test, though at microwave power less than 3 kW, more than 150 e microA of Bi(31+), 22 e microA of Bi(41+), and 1.5 e microA of Bi(50+) have been produced. All of these results have again demonstrated the great capability of the SECRAL source. This article will present the detailed results and brief discussions to the production of highly charged ion beams with SECRAL. PMID- 20192340 TI - Effect of electron cyclotron resonance ion source frequency tuning on ion beam intensity and quality at Department of Physics, University of Jyvaskyla. AB - Ion beam intensity and quality have a crucial effect on the operation efficiency of the accelerator facilities. This paper presents the investigations on the ion beam intensity and quality after the mass separation performed with the Department of Physics, University of Jyvaskyla 14 GHz electron cyclotron resonance ion source by sweeping the microwave in the 14.05-14.13 GHz range. In many cases a clear variation in the ion beam intensity and quality as a function of the frequency was observed. The effect of frequency tuning increased with the charge state. In addition, clear changes in the beam structure seen with the beam viewer were observed. The results confirmed that frequency tuning can have a remarkable effect on ion beam intensity and quality especially in the case of highly charged ion beams. The examples presented here represent the typical charge state behavior observed during the measurements. PMID- 20192341 TI - First results from the new RIKEN superconducting electron cyclotron resonance ion source (invited). AB - The next generation heavy ion accelerator facility, such as the RIKEN radio isotope (RI) beam factory, requires an intense beam of high charged heavy ions. In the past decade, performance of the electron cyclotron resonance (ECR) ion sources has been dramatically improved with increasing the magnetic field and rf frequency to enhance the density and confinement time of plasma. Furthermore, the effects of the key parameters (magnetic field configuration, gas pressure, etc.) on the ECR plasma have been revealed. Such basic studies give us how to optimize the ion source structure. Based on these studies and modern superconducting (SC) technology, we successfully constructed the new 28 GHz SC-ECRIS, which has a flexible magnetic field configuration to enlarge the ECR zone and to optimize the field gradient at ECR point. Using it, we investigated the effect of ECR zone size, magnetic field configuration, and biased disk on the beam intensity of the highly charged heavy ions with 18 GHz microwaves. In this article, we present the structure of the ion source and first experimental results with 18 GHz microwave in detail. PMID- 20192342 TI - Design of a compact, permanent magnet electron cyclotron resonance ion source for proton and H2(+) beam production. AB - A 2.45 GHz microwave ion source was developed at China Institute of Atomic Energy (CIAE) for proton beam production of over 60 mA [B.-Q. Cui, Y.-W. Bao, L.-Q. Li, W.-S. Jiang, and R.-W. Wang, Proceedings of the High Current Electron Cyclotron Resonance (ECR) Ion Source for Proton Accelerator, APAC-2001, 2001 (unpublished)]. For various proton beam applications, another 2.45 GHz microwave ion source with a compact structure is designed and will be built at CIAE as well for high current proton beam production. It is also considered to be used for the test of H(2)(+) beam, which could be injected into the central region model cyclotron at CIAE, and accelerated to 5 MeV before extraction by stripping. The required ECR magnetic field is supplied by all the permanent magnets rather than electrical solenoids and six poles. The magnetic field distribution provided by this permanent magnets configuration is a large and uniformly volume of ECR zone, with central magnetic field of a magnitude of approximately 875 Gs [T. Taylor and J. S. C. Wills, Nucl. Instrum. Methods Phys. Res. A 309, 37 (1991)]. The field adjustment at the extraction end can be implemented by moving the position of the magnet blocks. The results of plasma, coupling with 2.45 GHz microwave in the ECR zone inside the ion source are simulated by particle-in-cell code to optimize the density by adjusting the magnetic field distribution. The design configuration of the ion source will be summarized in the paper. PMID- 20192343 TI - Induction heating pure vapor source of high temperature melting point materials on electron cyclotron resonance ion source. AB - Multicharged ions that are needed are produced from solid pure material with high melting point in an electron cyclotron resonance ion source. We develop an evaporator by using induction heating (IH) with multilayer induction coil, which is made from bare molybdenum or tungsten wire without water cooling and surrounding the pure vaporized material. We optimize the shapes of induction coil and vaporized materials and operation of rf power supply. We conduct experiment to investigate the reproducibility and stability in the operation and heating efficiency. IH evaporator produces pure material vapor because materials directly heated by eddy currents have no contact with insulated materials, which are usually impurity gas sources. The power and the frequency of the induction currents range from 100 to 900 W and from 48 to 23 kHz, respectively. The working pressure is about 10(-4)-10(-3) Pa. We measure the temperature of the vaporized materials with different shapes, and compare them with the result of modeling. We estimate the efficiency of the IH vapor source. We are aiming at the evaporator's higher melting point material than that of iron. PMID- 20192344 TI - The effect of the dc bias voltage on the x-ray bremsstrahlung and beam intensities of medium and highly charged ions of argon. AB - X-ray bremsstrahlung measurements from the 18 GHz High Temperature Superconducting Electron Cyclotron Resonance Ion Source, Pantechnik-Delhi Ion Source were measured as a function of negative dc bias voltage, keeping all other source operating parameters fixed and the extraction voltage in the off condition. The optimization of medium and highly charged ions of argon with similar source operating parameters is described. It is observed that the high temperature component of the electron is altered significantly with the help of bias voltage, and the electron population has to be maximized for obtaining higher current. PMID- 20192345 TI - SEISM: a 60 GHz cusp electron cyclotron resonance ion source. AB - LPSC has been involved for several years in a challenging research and development program on the production of pulsed ions beams with high ionization efficiency primarily dedicated to radioactive ion beams. The generation of the high magnetic field requires the use of helix techniques developed at Laboratoire National des Champs Magnetiques Intenses. As a first approach, a cusp structure has been chosen. 3D simulations were used to define the geometry of the helices. The computer aided design of the mechanical parts of the magnetic structure has been performed at LPSC and was optimized to decrease the total volume of the source. The first 60 GHz magnetic structure (helices coils in their tanks, electrical, and water cooling environment) should be available before the end of 2009. PMID- 20192346 TI - Pulse modulated microwave operation on large bore electron cyclotron resonance ion source with cylindrically comb-shaped magnetic fields configuration. AB - In order to enhance efficiency of an electron cyclotron resonance (ECR) plasma for broad and dense ion beam source under the low pressure, the magnetic field configuration is constructed by a pair of comb-shaped magnet which has opposite polarity each other, and which cylindrically surrounds the plasma chamber. By using the pulse microwave mode operation, we aim at generation of plasma with parameters that cannot be achieved at the continuous microwave (cw) mode. The maximum beam current is obtained in the experimental condition of the pulse width 100-200 micros at the duty ratio 40%-50%. According to probe measurements of the ECR plasma, it is found the electron density in the pulse mode is larger than that in the cw mode, while the electron temperatures in the pulse mode were lower than that in the cw mode. These indirect evidences cause to enhance ion beams in the pulse mode operation, and then suggest a spread of operation windows for plasma parameters suitable to production of molecular or cluster ions. PMID- 20192347 TI - Metal-dielectric structures for high power electron cyclotron resonance ion source. AB - Metal-dielectric (MD)-structures in electron cyclotron resonance ion source (ECRIS) devices (partially) restore the plasma ambipolarity and supply cold electrons to the plasma. Both effects lead to an enhancement of the plasma electron density and temperature and significantly increase the performance of this type of ion source. At the same time, MD-structures are well suited to reduce the heat load on cold masses by Bremsstrahlung radiation. Here, we report on experiments at high microwave powers to test the practical use of MD structures for new, high performance ECRISs with their much higher power densities. The comparatively long conditioning times can be shortened by covering only those parts of the source with MD-structures, which are essential for the improvement. PMID- 20192348 TI - The compact electron cyclotron resonance ion source KeiGM for the carbon ion therapy facility at Gunma University. AB - A high-energy carbon-ion radiotherapy facility is under construction at Gunma University Heavy Ion Medical Centre (GHMC). Its design was based on a study of the heavy ion radiotherapy at the National Institute of Radiological Sciences (NIRS) in order to reduce the size and construction cost of the facility. A compact electron cyclotron resonance ion source (ECRIS) for Gunma University, called KeiGM, was installed in 2008. It is almost a copy of the prototype ECRIS Kei2 which was developed by NIRS; meanwhile this prototype produced over 1 e mA of C(4+) using C(2)H(2) gas (660 W and 40 kV). The beam intensity of C(4+) was 600 e microA with CH(4) gas (250 W and 30 kV). The beam intensity satisfies the required value of 300 e microA. PMID- 20192349 TI - Ion sources for MedAustron. AB - The MedAustron Ion therapy center will be constructed in Wiener Neustadt (Austria) in the vicinity of Vienna. Its accelerator complex consists of four ion sources, a linear accelerator, a synchrotron, and a beam delivery system to the three medical treatment rooms and to the research irradiation room. The ion sources shall deliver beams of H(3)(1+), C(4+), and light ions with utmost reliability and stability. This paper describes the features of the ion sources presently planned for the MedAustron facility, such as ion source main parameters, gas injection, temperature control, and cooling systems. A dedicated beam diagnostics technique is proposed in order to characterize electron cyclotron resonance (ECR) ion beams; in the first drift region after the ion source, a fraction of the mixed beam is selected via moveable aperture. With standard beam diagnostics, we then aim to produce position-dependant observables such as ion-current density, beam energy distribution, and emittance for each charge states to be compared to simulations of ECR e-heating, plasma simulation, beam formation, and transport. PMID- 20192350 TI - MIVOC method with temperature control. AB - The Heavy Ion Medical Accelerator in Chiba at the National Institute of Radiological Sciences has been used for cancer therapy, physics, and biology experiments since 1994. Its ion sources produce carbon ion for cancer therapy. They also produce various ions (H(+)-Xe(21+)) for physics and biology experiments. Most ion species are produced from gases by an 18 GHz electron cyclotron resonance ion source. However, some of ion species is difficult to produce from stable and secure gases. Such ion species are produced by the sputtering method. However, it is necessary to reduce material consumption rate as much as possible in the case of rare and expensive stable isotopes. We have selected "metal ions from volatile compounds method" as a means to solve this problem. We tested a variety of compounds. Since each compound has a suitable temperature to obtain the optimum vapor pressure, we have developed an accurate temperature control system. We have produced ions such as (58)Fe(9+), Co(9+), Mg(5+), Ti(10+), Si(5+), and Ge(12+) with the temperature control. PMID- 20192352 TI - A multicharge ion source (Supernanogan) for the OLIS facility at ISAC/TRIUMF. AB - The Off-Line Ion Source (OLIS) [K. Jayamanna, D. Yuan, T. Kuo, M. MacDonald, P. Schmor, and G. Dutto, Rev. Sci. Instrum. 67, 1061 (1996); K. Jayamanna, Rev. Sci. Instrum. 79, 02711 (2008)] facility consists of a high voltage terminal containing a microwave cusp ion source, either a surface ion source or a hybrid surface-arc discharge ion source [K. Jayamanna and C. Vockenhuber, Rev. Sci. Instrum. 79, 02C712 (2008)], and an electrostatic switch that allows the selection of any one of the sources without mechanical intervention. These sources provide a variety of +1 beams up to mass 30 for Isotope Separator and ACcelerator (ISAC) [R. E. Laxdal, Nucl. Instrum. Methods Phys. Res. B 204, 400 (2003)] experiments, commissioning the accelerators, setting up the radioactive experiments, and for tuning the beam lines. The radio frequency quadrupole (RFQ) [M. Marchetto, Z. T. Ang, K. Jayamanna, R. E. Laxdal, A. Mitra, and V. Zvyagintsev, Eur. Phys. J. Spec. Top. 150, 241 (2005)] injector accelerator is a constant velocity machine designed to accept only 2 keV/u and the source extraction energy is limited to 60 kV. Further stripping is then needed downstream of the RFQ to inject the beam into the drift tube linac [M. Marchetto, Z. T. Ang, K. Jayamanna, R. E. Laxdal, A. Mitra, and V. Zvyagintsev, Eur. Phys. J. Spec. Top. 150, 241 (2005)] accelerator that requires A/q up to 6. Base on this constraints a multicharge ion source capable to deliver beams above mass 30 with A/q up to 6 was needed in order to reach full capability of the ISAC facility. A Supernanogan [C. Bieth et al., Nucleonika 48, S93 (2003)] multicharge ion source was then purchased from Pantechnik and was installed in the OLIS terminal. Commissioning and performance of the Supernanogan with some results such as emittance dependence of the charge states as well as charge state efficiencies are presented. PMID- 20192351 TI - Enhanced confinement in electron cyclotron resonance ion source plasma. AB - Power loss by plasma-wall interactions may become a limitation for the performance of ECR and fusion plasma devices. Based on our research to optimize the performance of electron cyclotron resonance ion source (ECRIS) devices by the use of metal-dielectric (MD) structures, the development of the method presented here, allows to significantly improve the confinement of plasma electrons and hence to reduce losses. Dedicated measurements were performed at the Frankfurt 14 GHz ECRIS using argon and helium as working gas and high temperature resistive material for the MD structures. The analyzed charge state distributions and bremsstrahlung radiation spectra (corrected for background) also clearly verify the anticipated increase in the plasma-electron density and hence demonstrate the advantage by the MD-method. PMID- 20192354 TI - Microwave to plasma coupling in electron cyclotron resonance and microwave ion sources (invited). AB - Coupling improvements between microwaves and plasmas are a key factor to design more powerful electron cyclotron resonance and microwave ion sources. On this purpose different activities have been undertaken by the INFN-LNS ion source team and a new approach was developed. Recent experiments confirmed the simulations, demonstrating that even in presence of a dense plasma, resonant modes are excited inside the cavity and the plasma dynamics depends on their structure. An overview of the coupling issues on microwave ion sources is also given along with a discussion on alternative coupling techniques. PMID- 20192353 TI - Production of highly charged heavy ions by 18 GHz superconducting electron cyclotron resonance at Research Center for Nuclear Physics. AB - An 18 GHz superconducting electron cyclotron resonance ion source has been installed as a subject of the azimuthally varying field cyclotron upgrade project (K. Hatanaka et al., in Proceedings of the 17th International Conference on Cyclotrons and Their Applications, Tokyo, Japan, 18-22 October 2004, pp. 115 117), in order to increase beam currents and to extend the variety of ions. The production development of several ions has been performed since 2006 and some of them have already been used for user experiments [T. Yorita et al., Rev. Sci. Instrum. 79, 02A311 (2008)]. Further optimizations for each component such as the material of plasma electrode, material, and shape of bias probe and mirror field have been continued and more intense ion beams have been obtained for O, N, and Ar. For the purpose of obtaining highly charged Xe with several microamperes, the optimization of position and shape of plasma electrode and bias disk has also been done and highly charged Xe(32+) beam has been obtained successfully. PMID- 20192355 TI - Plasma ion dynamics and beam formation in electron cyclotron resonance ion sources. AB - In electron cyclotron resonance ion sources it has been demonstrated that plasma heating may be improved by means of different microwave to plasma coupling mechanisms, including the "frequency tuning" and the "two frequency heating." These techniques affect evidently the electron dynamics, but the relationship with the ion dynamics has not been investigated in details up to now. Here we will try to outline these relations: through the study of ion dynamics we may try to understand how to optimize the electron cyclotron resonance ion sources brightness. A simple model of the ion confinement and beam formation will be presented, based on particle-in-cell and single particle simulations. PMID- 20192356 TI - Generation of multicomponent ion beams by a vacuum arc ion source with compound cathode. AB - This paper presents the results of time-of-flight mass spectrometry studies of the elemental and mass-to-charge state compositions of metal ion beams produced by a vacuum arc ion source with compound cathode (WC-Co(0.5), Cu-Cr(0.25), Ti Cu(0.1)). We found that the ion beam composition agrees well with the stoichiometric composition of the cathode material from which the beam is derived, and the maximum ion charge state of the different plasma components is determined by the ionization capability of electrons within the cathode spot plasma, which is common to all components. The beam mass-to-charge state spectrum from a compound cathode features a greater fraction of multiply charged ions for those materials with lower electron temperature in the vacuum arc cathode spot, and a smaller fraction for those with higher electron temperature within the spot. We propose a potential diagram method for determination of attainable ion charge states for all components of the compound cathodes. PMID- 20192357 TI - Laser ion source: a direct plasma injection scheme for two-beam type interdigital H radio frequency quadrupole linac. AB - We developed a laser ion source using a direct plasma injection scheme (DPIS) as an injection system for a two-beam type radio frequency quadrupole (RFQ) linac with an interdigital-H (IH) type cavity. The laser ion source in the DPIS is directly connected to the RFQ cavity without the low energy beam transport system. We achieved a high current C(2+) beam above 60 mA per beam channel from the ion source. The beam will be injected to the two-beam type IH-RFQ linac, and the linac will generate a beam current of approximately 44 mA per beam channel. PMID- 20192358 TI - The NSCL electron beam ion trap for the reacceleration of rare isotopes coming to life: first extraction tests with a high-current electron gun. AB - NSCL is currently constructing the ReA3 reaccelerator, which will accelerate rare isotopes obtained from gas stopping of fast-fragment beams to energies of up to 3 MeV/u for uranium and higher for lighter ions. A high-current charge breeder, based on an electron beam ion trap (EBIT), has been chosen as the first step in the acceleration process, as it has the potential to efficiently produce highly charged ions in a single charge state. These ions are fed into a compact linear accelerator consisting of a radio frequency quadrupole structure and superconducting cavities. The NSCL EBIT has been fully designed with most of the parts constructed. The design concept of the EBIT and results from initial commissioning tests of the electron gun and collector with a temporary 0.4 T magnet are presented. PMID- 20192359 TI - Generation of high currents of carbon ions with the use of subnanosecond near infrared laser pulses. AB - Emission of carbon currents reaching values up to 2 A/cm(2) at a distance of 1 m from the laser ion source driven by the subnanosecond Prague Asterix Laser System operated at a fundamental wavelength of 1315 nm is reported. Graphite targets were exposed to intensities up to 5x10(16) W/cm(2) varying both the laser energy and the position of the laser beam focus with respect to the target surface. The maximum energy gain of carbon ions was approximately = 1 MeV/u. At high laser intensities the shape of time-of-flight spectra is also formed by plasma outbursts, whose growth correlates with the oscillatory self-focusing of the laser beam. PMID- 20192360 TI - Time profile of ion pulses produced in a hot-cavity laser ion source. AB - The time spreads of Mn ions produced by three-photon resonant ionization in a hot cavity laser ion source are measured. A one-dimensional ion-transport model is developed to simulate the observed ion time structures. Assuming ions are generated with a Maxwellian velocity distribution and are guided by an axial electric field, the predictions of the model agree reasonably well with the experimental data and suggest that the ions are radially confined in the ion source and a substantial fraction of the ions in the transport tube are extracted. PMID- 20192361 TI - Measurements of the highest acceleration gradient for ions produced with a long laser pulse. AB - Ultrafast plasma light ion streams have been produced using the 300 ps, kJ-class iodine laser, operating at PALS Centre in Prague. Ion detection was performed through standard ion collectors (IC) in time-of-flight configuration (TOF), shielded by thin metallic absorbers. This new diagnostics technique has been theoretically studied and experimentally tested in order to cut the long photopeak contribution and to analyze the ultrafast particle signal. Processing the obtained experimental IC-TOF data, including deconvolution processes of the TOF signals, UV/soft-x-ray photopeak absorption, and ion transmission calculations for different metallic filters, is shown. Mainly amorphous carbon (graphite) targets have been irradiated in order to limit the maximum number of ion charge states and to focus our study on demonstrating the validity of the proposed investigation technique. Maximum ion energy and acceleration gradient estimations as a function of the laser energy and focal spot diameter are reported. PMID- 20192362 TI - Short time ion pulse extraction from the Dresden electron beam ion trap. AB - We present measurements of the extraction of short time pulses of highly charged ions (4 keV, Ar(16+)) from the Dresden electron beam ion trap. Thereby the dependence of the extractable ionic charge on the extraction regime was investigated. The ion extraction time was varied between 20 ns and 1 micros. Furthermore the production of carbon ions and the influence of the extraction regime on the pulse widths was investigated to obtain information about the suitability of the Dresden EBIS-A in synchrotron based particle therapy facilities. PMID- 20192363 TI - Recent results of the laser ion source facility at INFN-LNS and applications to nuclear and applied research. AB - A pulsed neodymium-doped yttrium aluminum garnet laser ion source has been used as proton beams generator. The laser wavelength is 1064 nm, the pulse duration is 9 ns and the intensity reaches 10(10) W/cm(2). Laser irradiates hydrogenated polymers targets located in a chamber at 10(-7) mbar. The ions are post accelerated in a suitable chamber by 30 kV of voltage between the target, positively biased, and the following ground electrode. The extracted beams is characterized through a time-of-flight technique. Possible applications to the field of nuclear physics, such as nuclear excitation and de-excitations, nuclear reactions and nuclear fusion, will be presented and discussed. PMID- 20192364 TI - The Brookhaven National Laboratory electron beam ion source for RHIC. AB - As part of a new heavy ion preinjector that will supply beams for the Relativistic Heavy Ion Collider and the National Aeronautics and Space Administration Space Radiation Laboratory, construction of a new electron beam ion source (EBIS) is now being completed. This source, based on the successful prototype Brookhaven National Laboratory Test EBIS, is designed to produce milliampere level currents of all ion species, with q/m=(1/6)-(1/2). Among the major components of this source are a 5 T, 2-m-long, 204 mm diameter warm bore superconducting solenoid, an electron gun designed to operate at a nominal current of 10 A, and an electron collector designed to dissipate approximately 300 kW of peak power. Careful attention has been paid to the design of the vacuum system, since a pressure of 10(-10) Torr is required in the trap region. The source includes several differential pumping stages, the trap can be baked to 400 C, and there are non-evaporable getter strips in the trap region. Power supplies include a 15 A, 15 kV electron collector power supply, and fast switchable power supplies for most of the 16 electrodes used for varying the trap potential distribution for ion injection, confinement, and extraction. The EBIS source and all EBIS power supplies sit on an isolated platform, which is pulsed up to a maximum of 100 kV during ion extraction. The EBIS is now fully assembled, and operation will be beginning following final vacuum and power supply tests. Details of the EBIS components are presented. PMID- 20192365 TI - Magnetic plasma confinement for laser ion source. AB - A laser ion source (LIS) can easily provide a high current beam. However, it has been difficult to obtain a longer beam pulse while keeping a high current. On occasion, longer beam pulses are required by certain applications. For example, more than 10 micros of beam pulse is required for injecting highly charged beams to a large sized synchrotron. To extend beam pulse width, a solenoid field was applied at the drift space of the LIS at Brookhaven National Laboratory. The solenoid field suppressed the diverging angle of the expanding plasma and the beam pulse was widened. Also, it was observed that the plasma state was conserved after passing through a few hundred gauss of the 480 mm length solenoid field. PMID- 20192366 TI - Design study of primary ion provider for relativistic heavy ion collider electron beam ion source. AB - Brookhaven National Laboratory has developed the new preinjector system, electron beam ion source (EBIS) for relativistic heavy ion collider (RHIC) and National Aeronautics and Space Administration Space Radiation Laboratory. Design of primary ion provider is an essential problem since it is required to supply beams with different ion species to multiple users simultaneously. The laser ion source with a defocused laser can provide a low charge state and low emittance ion beam, and is a candidate for the primary ion source for RHIC-EBIS. We show a suitable design with appropriate drift length and solenoid, which helps to keep sufficient total charge number with longer pulse length. The whole design of primary ion source, as well as optics arrangement, solid targets configuration and heating about target, is presented. PMID- 20192367 TI - Status report of the Dresden EBIS/EBIT developments. AB - We give an overview about latest developments and measurements with the Dresden electron beam ion source family as compact and economically working table-top sources of highly charged ions. The ion sources are potential tools for various applications such as for use in combination with accelerators in medical particle therapy, as charge breeder or ion trap injector, as ion sources for a new generation of focused ion beam devices and for applications together with time-of flight secondary mass spectrometers. PMID- 20192368 TI - Electron beam ion source and electron beam ion trap (invited). AB - The electron beam ion source (EBIS) and its trap variant [electron beam ion trap (EBIT)] celebrated their 40th and 20th anniversary, respectively, at the EBIS/T Symposium 2007 in Heidelberg. These technologically challenging sources of highly charged ions have seen a broad development in many countries over the last decades. In contrast to most other ion sources the recipe of improvement was not "sorcery" but a clear understanding of the physical laws and obeying the technological constraints. This review will report important achievements of the past as well as promising developments in the future. PMID- 20192369 TI - Ion production from solid state laser ion sources. AB - Laser ion sources based on resonant excitation and ionization of atoms are well established tools for selective and efficient production of radioactive ion beams. Recent developments are focused on the use of the state-of-the-art all solid-state laser systems. To date, 35 elements of the periodic table are available from laser ion sources based on tunable Ti:sapphire lasers. Recent progress in this field regarding the establishment of suitable optical excitation schemes for Ti:sapphire lasers are reported. PMID- 20192370 TI - The laser ion source trap for highest isobaric selectivity in online exotic isotope production. AB - The improvement in the performance of a conventional laser ion source in the laser ion source and trap (LIST) project is presented, which envisages installation of a repeller electrode and a linear Paul trap/ion guide structure. This approach promises highest isobaric purity and optimum temporal and spatial control of the radioactive ion beam produced at an online isotope separator facility. The functionality of the LIST was explored at the offline test separators of University of Mainz (UMz) and ISOLDE/CERN, using the UMz solid state laser system. Ionization efficiency and selectivity as well as time structure and transversal emittance of the produced ion beam was determined. Next step after complete characterization is the construction and installation of the radiation-hard final trap structure and its first online application. PMID- 20192371 TI - A high-current light-ion injector for tandem accelerators. AB - A dual-source injector for tandem accelerators to produce negative ion currents of H, D, and He has been developed and built. The system consists of a central vacuum enclosure that accommodates two multicusp ion sources. Beam currents of several mA of H(-) and D(-) have been obtained by direct negative extraction of one of the multicusp ion sources. The yield for He(-) was optimized applying differentially pumped vacuum sections that support space compensation in the He(+) transport section a well as low neutralization loss of He(-) after charge exchange. In addition, an optimized extraction geometry and beam transport system enabled in excess of 10 mA He(+) within the low acceptance of the charge exchange canal. Early measurements yielded approximately 50 microA for He(-) using Li as a charge exchange medium, but currents over 100 microA are anticipated if Na would be used. PMID- 20192372 TI - Enhanced surface production in H- ion sources by introducing a negatively biased secondary electrode. AB - A transformer coupled plasma negative hydrogen ion source with an external rf antenna has been developed at SNU, which is capable of continuous operation with long lifetime. A positively biased plasma electrode (PE) has been successfully used for the optimization of H(-) extraction. With molybdenum-coated stainless steel PE, the enhancement of H(-) production at the electrode surface was observed at the bias voltage lower than the plasma potential. However, the low bias voltage is unfavorable to H(-) beam extraction since the negative ions are repelled. A second electrode is inserted in front of the PE to enhance H(-) production at the electrode surface without impeding beam extraction. By biasing the secondary electrode (SE) more negatively, H(-) production is clearly enhanced although the SE itself reduces H(-) beam currents because of suppressed electron transport in front of the PE. In this configuration enhancement of surface productions is most pronounced in tantalum electrode among various electrode materials. PMID- 20192373 TI - 3D modeling of the electron energy distribution function in negative hydrogen ion sources. AB - For optimization and accurate prediction of the amount of H-ion production in negative ion sources, analysis of electron energy distribution function (EEDF) is necessary. We are developing a numerical code which analyzes EEDF in the tandem type arc-discharge source. It is a three-dimensional Monte Carlo simulation code with realistic geometry and magnetic configuration. Coulomb collision between electrons is treated with the "binary collision" model and collisions with hydrogen species are treated with the "null-collision" method. We applied this code to the analysis of the JAEA 10 A negative ion source. The numerical result shows that the obtained EEDF is in good agreement with experimental results. PMID- 20192374 TI - Study on transport of negative ion plasma using dc laser photodetachment method. AB - Transport of negative ion containing plasma was studied in a hydrogen plasma by injecting a semiconductor laser to make an electron density perturbation by photodetachment of negative ions. Change due to laser irradiation on electron saturation current to a Langmuir probe and that on electron current extracted through an orifice biased at the anode potential were measured phase sensitively by a lock-in-amplifier. The measured transport velocity of the negative ion containing plasma was about 1.4x10(5) cm/s for both cases. The photodetachment signal measured through the orifice had given a larger ratio of negative ion density to electron density. Change in transport of negative ion containing plasma around the Langmuir probe has been also investigated by detecting photodetachment signal onto electron current extracted through an orifice. PMID- 20192375 TI - Experimental study for 15-20 mA dc H- multicusp source. AB - Recently, a new H- source and test stand was developed at CIAE. The design of this new source is based on the experience on our previous 10-15 mA H(-) ion source and the source at TRIUMF. Major efforts include the study of the virtual filter magnetic field, confining magnetic field, filament shape and location, the vacuum improvement on the extracting area, the extraction optics, new control and interlock system of the power supplies. More than 15 mA of H-beam was obtained for 36 h with stability of +/-0.5%. The normalized emittance of 0.48pi mm mrad (4 rms normalized emittance) were measured with approximately 8 mA dc beam. Further experimental studies are proceeding in an effort to reach 20 mA with reasonable emittance at this moment. More study plans are conducted, e.g., building a longer source body and using cesium injection to get better emittance, which will be presented as a separate paper at this conference. PMID- 20192376 TI - Simulation of cesium injection and distribution in rf-driven ion sources for negative hydrogen ion generation. AB - Cesium seeded sources for surface generated negative hydrogen ions are major components of neutral beam injection systems in future large-scale fusion experiments such as ITER. Stability and delivered current density depend highly on the cesium conditions during plasma-on and plasma-off phases of the ion source. The Monte Carlo code CSFLOW3D was used to study the transport of neutral and ionic cesium in both phases. Homogeneous and intense flows were obtained from two cesium sources in the expansion region of the ion source and from a dispenser array, which is located 10 cm in front of the converter surface. PMID- 20192377 TI - Plasma meniscus and extraction electrode studies of the ISIS H- ion source. AB - In order to reduce the emittance and increase the transported beam current from the ISIS Penning-type H(-) ion source, improvements to the extraction system are required. This ion source is currently being commissioned on the front end test stand at the Rutherford Appleton Laboratory, which demands higher extraction energies, higher beam currents, and smaller emittances. To facilitate this, the present geometry requires optimization. This paper details the experimental and simulation studies performed of the plasma meniscus and the possible electrode geometry modifications needed to extract the highest quality beam. PMID- 20192378 TI - Commissioning of the new H- source for Linac4. AB - As part of the CERN accelerator complex upgrade, a new linear accelerator for H( ) (Linac4) will start its operation in 2014. The source for this linac will be a 2 MHz rf driven H(-) source which is a copy of the very successful source from DESY. In this paper the design and the first results of the commissioning are reported. The commissioning has progressed successfully, and no major obstacles have been identified which will prevent reaching the goal of 80 mA H(-) beam current, 45 keV beam energy, 0.4 ms pulse length, and 2 Hz repetition rate. The source is producing up until now a stable beam of 23 mA, 35 keV, and with a repetition rate of 0.83 Hz. PMID- 20192379 TI - Spallation neutron source saddle antenna H- ion source project. AB - In this project we are developing an H(-) source which will synthesize the most important developments in the field of negative ion sources to provide high current, high brightness, good lifetime, high reliability, and high power efficiency. We describe two planned modifications to the present spallation neutron source external antenna source in order to increase the plasma density near the output aperture: (1) replacing the present 2 MHz plasma-forming solenoid antenna with a 13 MHz saddle-type antenna and (2) replacing the permanent multicusp magnetic system with a weaker electromagnet. PMID- 20192380 TI - Emission characteristics of H- ion source with inverse gas magnetron geometry. AB - The work is dedicated to the experimental investigation of the intense volume plasma H(-) ion source. Preliminary experimental researches of two parameters of the upgraded source--emission density of H(-) ions and gas flow--are represented below. In plasma volume of noncesium H(-) ion source, the conditions for obtaining of increased density of H(-) ions in the field of adjoining to the emission aperture were realized. The advancing of electrode system of the emission chamber of a source has allowed receiving the value of an emission density of H(-) ions equal to 600 mA/cm(2). PMID- 20192381 TI - Electrode activation in cesium-free negative ion sources. AB - Features of emission electrode activation leading to enhancement of negative ion emission in cesium-free discharges are discussed. In some ion sources with cesium free discharges, the emission of negative ions has been increased significantly by emission electrode activation using strong heating of the negative biased electrode by discharge plasma. A simple explanation of this enhancement is that it is due to an accumulation on the emission surface of the plasma electrode of impurities with low ionization potential that decreases in surface work function and increases the secondary emission of negative ions similar to "Cesiation." The negative biasing of emission surface is important for accumulation and trapping the impurities on the emission surface. To effectively control the activation process it is important to directly detect the evolution of the work function and the impurity concentration during electrode activation with enhancement of negative ion emission. PMID- 20192382 TI - Emittance improvement efforts on the 15-20 mA dc H- multicusp source. AB - A 15 mA beam from the 15-20 mA dc H(-) multicusp source has been obtained at China Institute of Atomic Energy. In order to improve the emittance of extracted beam from this new multicusp source, some measures have been taken, i.e., increasing the length of the ion source body, improving the vacuum in the extraction area, injecting cesium vapor into the ion source, etc. The hardware, including the lengthened source body, the improved back cover and cesium heating system, and the extraction vacuum box, will be described. Initial results for these efforts aimed at emittance improvement will also be given in the paper. PMID- 20192383 TI - Design of a versatile multiaperture negative ion source. AB - Negative ion sources are a key component of the neutral beam injector to be installed in the International Thermonuclear Experimental Reactor. At present research and development activities address several important issues related to beam extraction, optics, and optimization. Together with the design of real size devices and the accumulation of atomic cross section databases, a relatively small negative ion source [130 mA of H(-) at 60 kV, named Negative Ion Optimization phase 1 (NIO1)] is under construction at Consorzio RFX to contribute to benchmark numerical simulation tools and to test components, such as emittance scanners, beam dumps, and cesium ovens. NIO1 design, magnet configuration, and rf coupling simulations are described. PMID- 20192384 TI - Cesium control and diagnostics in surface plasma negative ion sources. AB - For efficient and reliable negative ion generation it is very important to improve a cesium control and diagnostics. Laser beam attenuation and resonance fluorescence can be used for measurement of cesium distribution and cesium control. Resonant laser excitation and two-photon excitation can be used for improved cesium ionization and cesium trapping in the discharge chamber. Simple and inexpensive diode lasers can be used for cesium diagnostics and control. Cesium migration along the surface is an important mechanism of cesium escaping. It is important to develop a suppression of cesium migration and cesium accumulation on the extraction system. PMID- 20192385 TI - Recent operation status of Japan Proton Accelerator Research Complex H- ion source. AB - A cesium-free H(-) ion source driven with a LaB(6) filament is being operated at the Japan Proton Accelerator Research Complex for approximately three years without any serious trouble. In the beam commissioning or supply runs, the ion source has been operated in two different modes such as low current mode of 5 mA and high current mode of 30 mA. The total interruption time during the runs due to the ion source failure is approximately 50 h, which correspond to the ion source availability of 99%. After a long-term operation, the surface of the filament and the plasma electrode become discolored with dark partially. The result of surface analysis with field emission scanning electron microscope showed that most of the dark material is formed with boron. At the beam test performed in the interval of the run, we demonstrated that the H(-) current increased by miniaturizing the LaB(6) filament. PMID- 20192386 TI - Development of an H- ion source for Japan Proton Accelerator Research Complex upgrade. AB - A cesium (Cs) free H(-) ion source driven with a lanthanum hexaboride (LaB(6)) filament was adopted as an ion source for the first stage of the Japan Proton Accelerator Research Complex (J-PARC). At present, the maximum H(-) ion current produced by the ion source is 38 mA, using which J-PARC can produce a proton beam power of 0.6 MW by accelerating it with the 181 MeV linac and the 3 GeV rapid cycling synchrotron. In order to satisfy the beam power of 1 MW required for the second stage of the J-PARC in the near future, we have to increase the ion current to more than 60 mA. Therefore, we have started to develop a Cs-seeded ion source by adding an external Cs-seeding system to a J-PARC test ion source that has a structure similar to that of the J-PARC ion source except for the fact that the plasma chamber is slightly larger. As a result, a H(-) ion current of more than 70 mA was obtained from the ion source using a tungsten filament instead of a LaB(6) filament with a low arc discharge power of 15 kW (100 V, 150 A). PMID- 20192387 TI - A survey of optimal filament shape in a Japan Proton Accelerator Research Complex H- ion source. AB - Dependence of various shapes of lanthanum hexaboride (LaB(6)) filaments on H(-) ion currents (I_H(-)'s) was examined by using the first Japan Proton Accelerator Research Complex (J-PARC) test ion source. It is almost the same with the J-PARC H(-) ion source (J-PARC-IS) except for the maximum arc current (290 A instead of 400 A). An I_H(-) of 35.2 mA was extracted by using a cylindrical double-spiral LaB(6) filament with a diameter of 29.5 mm and a length of 35.5 mm, which is the same one used in J-PARC-IS. It increased to 43.4 mA with a flat triple-hairpin LaB(6) filament. The I_H(-) is considered to be increased by the enlargement of the high density plasma region near the plasma electrode aperture and the reduction of the LaB(6) filament unemission area located in the high density plasma region. PMID- 20192388 TI - An innovative high-power constant-current pulsed-arc power-supply for a high density pulsed-arc-plasma ion-source using a LaB6-filament. AB - An innovative high-power constant-current (CC) pulsed-arc (PA) power-supply (PS) indispensable for a high-density PA plasma ion-source using a lanthanum hexaboride (LaB(6)) filament was devised by combining a constant-voltage (CV) PA PS, which is composed of an insulated gate bipolar transistor (IGBT) switch, a CV direct-current (dc) PS and a 270 mF capacitor with a CC-PA-PS, which is composed of an IGBT-switch, a CC-dc-PS and a 400 microH inductor, through the inductor. The hybrid-CC-PA-PS succeeded in producing a flat arc-pulse with a peak power of 56 kW (400 A x 140 V) and a duty factor of more than 1.5% (600 micros x 25 Hz) for Japan Proton Accelerator Research Complex (J-PARC) H(-) ion-source stably. It also succeeded in shortening the 99% rising-time of the arc-pulse-current to about 20 micros and tilting up or down the arc-pulse-current arbitrarily and almost linearly by changing the setting voltage of its CV-dc-PS. PMID- 20192389 TI - Interesting experimental results in Japan Proton Accelerator Research Complex H- ion-source development (invited). AB - The following interesting experimental results observed in Japan Proton Accelerator Research Complex (J-PARC) H(-) ion-source developments are reviewed. It was proven that almost all of H(-) ions were produced with surface reactions in cesium (Cs)-free J-PARC H(-) ion-sources. The world's most intense class H(-) ion current of 38 mA in Cs-free ion sources for a high-energy linac was attained by an optimal shape and high temperature of the plasma electrode (PE), usage of a lanthanum hexaboride (LaB(6)) filament, and a newly devised high-power constant current pulsed-arc power supply indispensable for it. It was also proven that the H(-) ion current could be increased to more than 40 mA by optimizing LaB(6) filament shape. The surface elemental analysis of the PE after operation with a LaB(6)-filament showed that it was coated by boron (B) 95.5%, lanthanum (La) 2.5%, and oxygen (O) 1.9%. The H(-) ion current decreased by about 20% when a tungsten (W) filament was used instead of a LaB(6)-filament. The H(-) ion current could not be increased by seeding cesium (Cs) if the LaB(6)-filament was used. On the other hand, it was increased to more than 70 mA with much lower arc current of 150 A if Cs was seeded when a W-filament was used. PMID- 20192390 TI - The front end test stand high performance H- ion source at Rutherford Appleton Laboratory. AB - The aim of the front end test stand (FETS) project is to demonstrate that chopped low energy beams of high quality can be produced. FETS consists of a 60 mA Penning Surface Plasma Ion Source, a three solenoid low energy beam transport, a 3 MeV radio frequency quadrupole, a chopper, and a comprehensive suite of diagnostics. This paper details the design and initial performance of the ion source and the laser profile measurement system. Beam current, profile, and emittance measurements are shown for different operating conditions. PMID- 20192391 TI - Finite element thermal study of the Linac4 plasma generator. AB - The temperature distribution and heat flow at equilibrium of the plasma generator of the rf-powered noncesiated Linac4 H(-) ion source have been studied with a finite element model. It is shown that the equilibrium temperatures obtained in the Linac4 nominal operation mode (100 kW rf power, 2 Hz repetition rate, and 0.4 ms pulse duration) are within material specifications except for the magnet cage, where a redesign may be necessary. To assess the upgrade of the Linac4 source for operation in the high-power operation mode of the Superconducting Proton Linac (SPL), an extrapolation of the heat load toward 100 kW rf power, 50 Hz repetition rate, and 0.4 ms pulse duration has been performed. The results indicate that a significant improvement of the source cooling is required to allow for operation in the high-power mode of SPL. PMID- 20192392 TI - High duty factor plasma generator for CERN's Superconducting Proton Linac. AB - CERN's Linac4 is a 160 MeV linear accelerator currently under construction. It will inject negatively charged hydrogen ions into CERN's PS-Booster. Its ion source is a noncesiated rf driven H(-) volume source directly inspired from the one of DESY and is aimed to deliver pulses of 80 mA of H(-) during 0.4 ms at a 2 Hz repetition rate. The Superconducting Proton Linac (SPL) project is part of the luminosity upgrade of the Large Hadron Collider. It consists of an extension of Linac4 up to 5 GeV and is foreseen to deliver protons to a future 50 GeV synchrotron (PS2). For the SPL high power option (HP-SPL), the ion source would deliver pulses of 80 mA of H(-) during 1.2 ms and operate at a 50 Hz repetition rate. This significant upgrade motivates the design of the new water cooled plasma generator presented in this paper. Its engineering is based on the results of a finite element thermal study of the Linac4 H(-) plasma generator that identified critical components and thermal barriers. A cooling system is proposed which achieves the required heat dissipation and maintains the original functionality. Materials with higher thermal conductivity are selected and, wherever possible, thermal barriers resulting from low pressure contacts are removed by brazing metals on insulators. The AlN plasma chamber cooling circuit is inspired from the approach chosen for the cesiated high duty factor rf H(-) source operating at SNS. PMID- 20192393 TI - Aberration of a negative ion beam caused by space charge effect. AB - Aberrations are inevitable when the charged particle beams are extracted, accelerated, transmitted, and focused with electrostatic and magnetic fields. In this study, we investigate the aberration of a negative ion accelerator for a neutral beam injector theoretically, especially the spherical aberration caused by the negative ion beam expansion due to the space charge effect. The negative ion current density profiles with the spherical aberration are compared with those without the spherical aberration. It is found that the negative ion current density profiles in a log scale are tailed due to the spherical aberration. PMID- 20192394 TI - rf improvements for Spallation Neutron Source H- ion source. AB - The Spallation Neutron Source at Oak Ridge National Laboratory is ramping up the accelerated proton beam power to 1.4 MW and just reached 1 MW. The rf-driven multicusp ion source that originates from the Lawrence Berkeley National Laboratory has been delivering approximately 38 mA H(-) beam in the linac at 60 Hz, 0.9 ms. To improve availability, a rf-driven external antenna multicusp ion source with a water-cooled ceramic aluminum nitride (AlN) plasma chamber is developed. Computer modeling and simulations have been made to analyze and optimize the rf performance of the new ion source. Operational statistics and test runs with up to 56 mA medium energy beam transport beam current identify the 2 MHz rf system as a limiting factor in the system availability and beam production. Plasma ignition system is under development by using a separate 13 MHz system. To improve the availability of the rf power system with easier maintenance, we tested a 70 kV isolation transformer for the 80 kW, 6% duty cycle 2 MHz amplifier to power the ion source from a grounded solid-state amplifier. PMID- 20192395 TI - Computer simulations for rf design of a Spallation Neutron Source external antenna H- ion source. AB - Electromagnetic modeling of the multicusp external antenna H(-) ion source for the Spallation Neutron Source (SNS) has been performed in order to optimize high power performance. During development of the SNS external antenna ion source, antenna failures due to high voltage and multicusp magnet holder rf heating concerns under stressful operating conditions led to rf characteristics analysis. In rf simulations, the plasma was modeled as an equivalent lossy metal by defining conductivity as sigma. Insulation designs along with material selections such as ferrite and Teflon could be included in the computer simulations to compare antenna gap potentials, surface power dissipations, and input impedance at the operating frequencies, 2 and 13.56 MHz. Further modeling and design improvements are outlined in the conclusion. PMID- 20192396 TI - The continued development of the Spallation Neutron Source external antenna H- ion source. AB - The U.S. Spallation Neutron Source (SNS) is an accelerator-based, pulsed neutron scattering facility, currently in the process of ramping up neutron production. In order to ensure that the SNS will meet its operational commitments as well as provide for future facility upgrades with high reliability, we are developing a rf-driven, H(-) ion source based on a water-cooled, ceramic aluminum nitride (AlN) plasma chamber. To date, early versions of this source have delivered up to 42 mA to the SNS front end and unanalyzed beam currents up to approximately 100 mA (60 Hz, 1 ms) to the ion source test stand. This source was operated on the SNS accelerator from February to April 2009 and produced approximately 35 mA (beam current required by the ramp up plan) with availability of approximately 97%. During this run several ion source failures identified reliability issues, which must be addressed before the source re-enters production: plasma ignition, antenna lifetime, magnet cooling, and cooling jacket integrity. This report discusses these issues, details proposed engineering solutions, and notes progress to date. PMID- 20192397 TI - Modeling of the rf discharge initiation in a negative ion source. AB - The maintenance free rf ion source is expected to be one of the most promising candidates for the negative ion sources of plasma heating for future fusion reactors. As an alternative to the arc-discharge sources, the rf negative ion sources have been developed for H(-) production. In order to make clear the condition for the discharge initiation of the rf source, we are developing a numerical model using the finite difference time domain Monte Carlo method to analyze the electron energy distribution function in rf field. The numerical result shows that the discharge is not successfully initiated due to the wall loss unless the wall potential is considered. More self-consistent model including ion dynamics to evaluate the wall potential and the electron loss at the wall will be needed in the future. PMID- 20192398 TI - Ramping up the Spallation Neutron Source beam power with the H- source using 0 mg Cs/day. AB - This paper describes the ramp up of the beam power for the Spallation Neutron Source by ramping up the pulse length, the repetition rate, and the beam current emerging from the H(-) source. Starting out with low repetition rates (< or = 10 Hz) and short pulse lengths (< or = 0.2 ms), the H(-) source and low-energy beam transport delivered from Lawrence Berkeley National Laboratory exceeded the requirements with almost perfect availability. This paper discusses the modifications that were required to exceed 0.2 ms pulse length and 0.2% duty factor with acceptable availability and performance. Currently, the source is supporting neutron production at 1 MW with 38 mA linac beam current at 60 Hz and 0.9 ms pulse length. The pulse length will be increased to approximately 1.1 ms to meet the requirements for neutron production with a power between 1 and 1.4 MW. A medium-energy beam transport (MEBT) beam current of 46 mA with a 5.4% duty factor has been demonstrated for 32 h. A 56 mA MEBT beam current with a 4.1% duty factor has been demonstrated for 20 min at the conclusion of a 12-day production run. This is close to the 59 mA needed for 3 MW neutron productions. Also notable is the Cs(2)CrO(4) cesium system, which dispenses approximately 10 mg of Cs during the startup of the ion source, sufficient for producing the required 38 mA for 4 weeks without significant degradation. PMID- 20192399 TI - First operation of the charge-breeder electron-cyclotron-resonance ion source at the Texas A&M Cyclotron Institute. AB - The 14.5 GHz electron-cyclotron-resonance ion source (ECRIS) designed and fabricated specifically for charge breeding has been installed at the Texas A&M University Cyclotron Institute for use in the institute's ongoing radioactive-ion beam upgrade. The initial testing of the source has just begun with magnetic analysis of the ECRIS beam. The source has only been conditioning for a brief time at low microwave power, and it is continuing to improve. After the source has been conditioned and characterized, charge-breeding trials with stable beams from a singly ionizing source will begin. PMID- 20192400 TI - Development of radioactive ion beam production systems for Tokai Radioactive Ion Acceleration Complex-High temperature ion source for short-lived isotopes. AB - We have developed a new ion source system in the isotope separator on-line at Japan Atomic Energy Agency, for separation of short-lived isotopes produced by proton-induced fission of (238)U. The ion source system is a forced electron beam induced arc discharge version E type ion source with a target container. We successfully operated this system at 2000 degrees C as a result of reductions in volume of the ion source and the target container, introduction of heating method by electron bombardment, and improvement to the heat shield. This new ion source system was tested using (238)U of 640 mg/cm(2) with a proton primary beam of 30 MeV, 350 nA. Release times were measured for Kr, In, and Xe. The values of release times are 2.6 s for Kr, 1.8 s for In, and 4.6 s for Xe. In this work, the ion source system enabled us to mass-separate short-lived isotopes such as (93)Kr(T(1/2)=1.286 s), (129)In(T(1/2)=0.61 s), and (141)Xe(T(1/2)=1.73 s) with intensity of 10(3) ions/s. PMID- 20192401 TI - Charge state breeding for the acceleration of radioactive ions at TRIUMF. AB - A 14.5 GHz electron cyclotron resonance ion source (PHOENIX from Pantechnik) has been set up at the Isotope Separation and ACceleration (ISAC) facility at TRIUMF for the charge state breeding of radioactive ions. After extensive testing and optimization on a test bench it has been moved on-line and put into operation. During a first test in 2008 a beam of (80)Rb(14+) was successfully created from (80)Rb(1+) and accelerated by the ISAC postaccelerator. Further tests with different stable and radioactive isotopes from the ISAC on-line sources and from a test source with stable Cs have been carried out. Until now an efficiency of 1.4% for (124)Cs(20+) has been obtained. PMID- 20192402 TI - Direct 1+ --> N+ conversion of stable alkali ions using an electron cyclotron resonance ion source. AB - The production of radioactive ions using the Isotope Separation On-Line method gives rise, in most cases, to singly charged ions. In order to perform experiments with postaccelerated radioactive ion beams, these ions have to be multicharged. We describe here a new compact design for a charge breeder that will be coupled to the production target of SPIRAL1 at GANIL. We present recent results obtained offline with stable alkali ions (Na, K, Rb, and Cs) on the SIRa test bench. Particularly, 1(+) to N(+) conversion efficiencies and conversion times are presented. Several points have been identified for the improvements of the present performances. PMID- 20192403 TI - Integrated modeling of electron cyclotron resonance ion sources and charge breeders with GEM, MCBC, and IonEx. AB - A numerical toolset to help in understanding physical processes in the electron cyclotron resonance charge breeder (ECRCB) and further to help optimization and design of current and future machines is presented. The toolset consists of three modules (Monte Carlo charge breeding code, generalized electron cyclotron resonance ion source modeling, and ion extraction), each modeling different processes occurring in the ECRCB from beam injection to extraction. The toolset provides qualitative study, such as parameter studies, and scaling of the operation, and physical understanding in the ECRCB. The methodology and a sample integrated modeling are presented. PMID- 20192404 TI - Development of high efficiency Versatile Arc Discharge Ion Source at CERN ISOLDE. AB - We report here recent developments of Forced Electron Beam Induced Arc Discharge (FEBIAD) ion sources at the ISOLDE radioactive ion beam facility, hosted at the European Organization for Nuclear Research (CERN). As a result of the propositions to improve the ionization efficiency, two FEBIAD prototypes have been produced and successfully tested in 2008. Off-line studies showed that the 1+ ionization efficiencies for noble gases are 5-20 times larger than with the standard ISOLDE FEBIAD ion sources and reach 60% for radon, which allowed the identification at ISOLDE of (229)Rn, an isotope that had never previously been observed in the laboratory. A factor of 3 increase is also expected for the ionization efficiency of the other elements. The experimental and theoretical methodology is presented. The theoretical model, which gives precise insights on the processes affecting the ionization, is used to design optimal sources (grouped under the name of VADIS--Versatile Arc Discharge Ion Source) for the different chemical classes of the produced isotopes, as already demonstrated for the noble gases. PMID- 20192405 TI - Results with the electron cyclotron resonance charge breeder for the 252Cf fission source project (Californium Rare Ion Breeder Upgrade) at Argonne Tandem Linac Accelerator System. AB - The construction of the Californium Rare Ion Breeder Upgrade, a new radioactive beam facility for the Argonne Tandem Linac Accelerator System (ATLAS), is nearing completion. The facility will use fission fragments from a 1 Ci (252)Cf source; thermalized and collected into a low-energy particle beam by a helium gas catcher. In order to reaccelerate these beams, an existing ATLAS electron cyclotron resonance (ECR) ion source was redesigned to function as an ECR charge breeder. Thus far, the charge breeder has been tested with stable beams of rubidium and cesium achieving charge breeding efficiencies of 9.7% into (85)Rb(17+) and 2.9% into (133)Cs(20+). PMID- 20192406 TI - Latest developments at GANIL for stable and radioactive ion beam production. AB - In the frame of the SPIRAL II (Systeme de Production d'Ions Radioactifs Acceleres en Ligne Partie II) project, several developments of stable and radioactive ion production systems have been started up. In parallel, GANIL has the ambition to preserve the existing stable and radioactive beams and also to increase its range by offering new ones. In order to identify the best directions for this development, a new group called GANISOL has been formed. Its preliminary conclusions and the latest developments at GANIL are presented. PMID- 20192407 TI - GISELE: a resonant ionization laser ion source for the production of radioactive ions at GANIL. AB - SPIRAL2 is the new project under construction at GANIL to produce radioactive ion beams and in particular neutron rich ion beams. For the past 10 yr SPIRAL1 at GANIL has been delivering accelerated radioactive ion beams of gases. Both facilities now need to extend the range of radioactive ion beams produced to condensable elements. For that purpose, a resonant ionization laser ion source, funded by the French Research National Agency, is under development at GANIL, in collaboration with IPN Orsay, University of Mainz (Germany) and TRIUMF, Vancouver (Canada). A description of this project called GISELE (GANIL Ion Source using Electron Laser Excitation) is presented. PMID- 20192408 TI - Long pulse H- ion beam acceleration in MeV accelerator. AB - A multiaperture multigrid accelerator called "MeV accelerator" has been developed for neutral beam injection system of international thermonuclear experimental reactor. In the present work, long pulse H(-) ion beam acceleration was performed by the MeV accelerator equipped with new water-cooled grids. At present, the pulse length was extended to 5 s for the beams of 750 keV, 221 mA, and 10 s for the beams of 600 keV, 158 mA. Energy density, defined as products of beam energy (keV), current (mA), and pulse (s) divided by aperture area (m(2)), increased more than one order of magnitude higher compared with original MeV accelerator without water cooling in its grids. At higher energy and current, the grid was melted by beam deflection. Due to this grid melting, breakdowns occurred between the grids, and hence, the pulse length was limited. Beam deflection will be compensated by aperture displacement in next experiment. PMID- 20192409 TI - Fundamental experiments on evaporation of cesium in ion sources. AB - Basic experiments are carried out to study the cesium evaporation and desorption from surfaces at different temperatures in an environment, which is very close to the conditions of negative hydrogen ion sources for fusion applications: in a vacuum base pressure of 10(-5) mbar and in a hydrogen plasma in the Pa-range. Several diagnostic techniques such as emission and absorption spectroscopy, a surface ionization detector, and a quartz-microbalance have been utilized to determine the cesium densities, evaporation and desorption rates. The work function of a cesiated surface measured by the photoelectric effect degrades with increasing plasma-off time. Impurities and cesium compounds are detected by a residual mass analyzer. PMID- 20192410 TI - Analysis of secondary particle behavior in multiaperture, multigrid accelerator for the ITER neutral beam injector. AB - Heat load on acceleration grids by secondary particles such as electrons, neutrals, and positive ions, is a key issue for long pulse acceleration of negative ion beams. Complicated behaviors of the secondary particles in multiaperture, multigrid (MAMuG) accelerator have been analyzed using electrostatic accelerator Monte Carlo code. The analytical result is compared to experimental one obtained in a long pulse operation of a MeV accelerator, of which second acceleration grid (A2G) was removed for simplification of structure. The analytical results show that relatively high heat load on the third acceleration grid (A3G) since stripped electrons were deposited mainly on A3G. This heat load on the A3G can be suppressed by installing the A2G. Thus, capability of MAMuG accelerator is demonstrated for suppression of heat load due to secondary particles by the intermediate grids. PMID- 20192411 TI - Operation and upgrade of diagnostic neutral beam injector RUDI at TEXTOR tokamak. AB - The status and the executing modernization of RUssian Diagnostic Injector (RUDI) are described. The ion source consists of arc plasma emitter and multiaperture four-electrode ion optical system. The present ion optical system with round beamlets is to be replaced by new slit apertures system for the reducing beam angular divergence in one direction. Due to enlarged dimensions and transparency of new ion optical system the extracted ion beam current will be by 50% increased. For the extension of beam pulse duration from 4 s to 8-10 s an optimized metal-ceramic arc-discharge channel is introduced. In the paper, the optical measurements results of beam parameters, including the profile of species distribution, scanned by custom-built multichannel spectroscope, are also presented. PMID- 20192412 TI - The study of helicon plasma source. AB - Helicon plasma source is known as efficient generator of uniform and high density plasma. A helicon plasma source was developed for investigation of plasma neutralization and plasma lens in the Institute of Modern Physics in China. In this paper, the characteristics of helicon plasma have been studied by using Langmuir four-probe and a high argon plasma density up to 3.9x10(13) cm(-3) have been achieved with the Nagoya type III antenna at the conditions of the magnetic intensity of 200 G, working gas pressure of 2.8x10(-3) Pa, and rf power of 1200 W with a frequency of 27.12 MHz. In the experiment, the important phenomena have been found: for a given magnetic induction intensity, the plasma density became greater with the increase in rf power and tended to saturation, and the helicon mode appeared at the rf power between 200 and 400 W. PMID- 20192413 TI - Numerical simulation for the accelerator of the KSTAR neutral beam ion source. AB - Recent experiments with a prototype long-pulse, high-current ion source being developed for the neutral beam injection system of the Korea Superconducting Tokamak Advanced Research have shown that the accelerator grid assembly needs a further upgrade to achieve the final goal of 120keV/65A for the deuterium ion beam. The accelerator upgrade concept was determined theoretically by simulations using the IGUN code. The simulation study was focused on finding parameter sets that raise the optimum perveance as large as possible and reduce the beam divergence as low as possible. From the simulation results, it was concluded that it is possible to achieve this goal by sliming the plasma grid (G1), shortening the second gap (G2-G3), and adjusting the G2 voltage ratio. PMID- 20192414 TI - Radio frequency ion source operated with field effect transistor based radio frequency system. AB - Characteristics of radio frequency (RF) plasma production are investigated using a field effect transistor inverter power supply as an RF wave source. With the frequency of around 0.3 MHz, an electron density over 10(18) m(-3) is produced in argon plasma. Although lower densities are obtained in hydrogen plasma, it drastically increased up to 5x10(18) m(-3) with an axial magnetic field of around 100 G applied in the driver region. Effects of the magnetic field and gas pressure are investigated in the RF produced plasma with the frequency of several hundred kilohertz. PMID- 20192415 TI - Characterization of 1 MW, 40 keV, 1 s neutral beam for plasma heating. AB - Neutral beam with geometrical focusing for plasma heating in moderate-size plasma devices has been developed in Budker Institute of Nuclear Physics, Novosibirsk. When operated with hydrogen, the neutral beam power is 1 MW, pulse duration is 1 s, beam energy is 40 keV, and angular divergence is 1.2 degrees. Initial ion beam is extracted and accelerated by triode multiapertures ion-optical system. To produce 1 MW neutral beam, about 40 A proton current is extracted with nominal current density of 320 mA/cm(2). Ion-optical system has 200 mm diameter grids with 44% transparency. The grids have inertia cooling and heat is removed between the pulses by water flowing in channels placed on periphery of the grids. A plasma emitter for ion extraction is produced by rf-plasma box. Ion species mix of rf plasma source amounts to 70%, 20%, and 10% of H(+), H(2)(+), and H(3)(+) ions, respectively, by current. Heavy impurities contribute less than 0.3%. PMID- 20192416 TI - Erosion of accel grids of ion engine due to sputtering. AB - The erosion rates of extraction electrodes of ion sources due to ion beam irradiation are largely affected by amount of projectiles retained in the electrodes. A Monte Carlo simulation code ACAT has been used to calculate sputtering yields and reflection coefficients by simulating the accumulation effect of projectiles in a target material. The results for Xe projectiles-C target combination have indicated that both sputtering yields and reflection coefficients are largely enhanced by Xe retention, particularly at larger incident angle for the surface normal with low incident energy. PMID- 20192417 TI - Long pulse H- beam extraction with a rf driven ion source on a high power level. AB - IPP Garching is investigating the applicability of rf driven negative ion sources for the neutral beam injection of International Thermonuclear Experimental Reactor. The setup of the tested source was improved to enable long pulses up to 100 kW rf power. The efficiency of negative ion production decreases at high power. The extracted H(-) currents as well as the symmetry of the plasma density close to the plasma grid and of the beam divergence depend on the magnetic filter field. The pulse duration is limited by the increase in coextracted electrons, which depends on the rf power and the caesium conditions on the plasma grid. PMID- 20192418 TI - Investigation of fringe plasma parameters on a high power rf driven ion source. AB - It has been observed that there are differences between the uncompensated Langmuir probes installed in the upper and lower areas of the rf driven H(-) sources at IPP Garching. The two probes often had substantially different floating potentials or ion saturation currents. In an effort to understand the reasons for these differences a Langmuir probe analysis system was used on the probes to collect the full current voltage characteristic. The results show what is likely the formation of an ion-ion plasma. The paper shows the effect of beam extraction and the presence of caesium on the probe characteristics. PMID- 20192419 TI - Analyses of high power negative ion accelerators for ITER neutral beam injector (invited). AB - In JAEA, research and developments to realize high power accelerator (1 MeV, 40 AD(-) ion beams for 3600 s) for ITER have been carried out experimentally and numerically utilizing a five stage MAMuG (Multiaperture, Multigrid) accelerator. In this paper, the extension of the gap length, which is required to improve the voltage holding capability, is examined in two dimensional beam optics analyses and also from view point of stripping loss of ions. In order to suppress excess power loadings due to the direct interception of negative ions, which is issued in long pulse tests, the beamlet deflection is analyzed in three dimensional multibeamlet analyses. The necessary modifications shown above are applied to the MAMuG accelerator for coming long pulse tests in JAEA and ITER. PMID- 20192420 TI - Negative ion source development for fusion application (invited). AB - Giant negative ion sources, producing high-current of several tens amps with high energy of several hundreds keV to 1 MeV, are required for a neutral beam injector (NBI) in a fusion device. The giant negative ion sources are cesium-seeded plasma sources, in which the negative ions are produced on the cesium-covered surface. Their characteristic features are discussed with the views of large-volume plasma production, large-area beam acceleration, and high-voltage dc holding. The international thermonuclear experimental reactor NBI employs a 1 MeV-40 A of deuterium negative ion source, and intensive development programs for the rf driven source plasma production and the multistage electrostatic acceleration are in progress, including the long pulse operation for 3600 s. Present status of the development, as well as the achievements of the giant negative ion sources in the working injectors, is also summarized. PMID- 20192421 TI - Fine-structure characteristics in the emittance images of a strongly focusing He+ beam. AB - The phase space distribution of a strongly focused He(+) ion beam source equipped with concave multiaperture electrodes was measured using a pepper-pot plate and a Kapton foil. The substructure of 301 merging He beamlets was clearly observed on a footprint of pepper-pot hole at the beam waist, where the beam density was 500 mA/cm(2). The position and the width of each beamlet substructure show the effect of interference of beamlets with surrounding one. PMID- 20192422 TI - Characteristics of 80 keV positive ion source for Large Helical Device. AB - An additional beamline, BL5, equipped with four positive ion sources will be installed on Large Helical Device (LHD) in 2010. The performance of an ion source which generates 80 keV deuterium and 60 keV hydrogen beams was investigated. The structure of the ion source is based on that of a BL4 ion source on LHD. The main differences between the ion sources for the BL4 and BL5 are the acceleration voltages and the materials of plasma electrodes: copper and molybdenum, respectively. The molybdenum plasma electrode for BL5 has better performance than the copper plasma electrode of BL4. The integrated performance of the ion source for BL5 reached a value equivalent to approximately 58 A in the beam current of hydrogen positive ion at 60 keV in the beam energy. PMID- 20192423 TI - Beamlet characteristics in the accelerator with multislot grounded grid. AB - Characteristics of multibeamlets are investigated by means of beamlet monitoring technique. The beamlets are extracted from an accelerator with multislot grounded grid and the profiles are observed as infrared images of temperature distributions on a cold isostatic pressed graphite plate exposed by H-beamlets. The optimal horizontal and vertical divergence angles of single beamlet are estimated at 4.1 and 6.1 mrad, respectively. PMID- 20192424 TI - General design of the International Fusion Materials Irradiation Facility deuteron injector: source and beam line. AB - In the framework of the International Fusion Materials Irradiation Facility Engineering Validation and Engineering Design Activities (IFMIF-EVEDA) project, CEA/IRFU is in charge of the design and realization of the 140 mA cw deuteron Injector. The electron cyclotron resonance ion source operates at 2.45 GHz and a 4 electrode extraction system has been chosen. A 2 solenoid beam line, together with a high space charge compensation have been optimized for a proper beam injection in the 175 MHz radio frequency quadrupole. The injector will be tested with proton and deuteron beam production either in pulsed mode or in cw mode on the CEA-Saclay site before to be shipped to Japan. Special attention was paid to neutron emission due to (d,D) reaction. In this paper, the general IFMIF Injector design is reported, pointing out beam dynamics, radioprotection, diagnostics, and mechanical aspects. PMID- 20192425 TI - Sources of polyatomic ions of organic liquids. AB - We have developed two types of liquid ion sources, one of which was a polyatomic ion source using liquid organic materials with a high-vapor pressure. Liquid materials such as octane and ethanol could be heated up to a maximum temperature of 100 degrees C, and the vapors were introduced into an ion source. They were ionized by an electron bombardment method and extracted from the ionizer. The ion current obtained at an extraction voltage of 2 kV was 230 microA for octane and several fragment ions such as alkyl ions were produced. On the other hand, another type of polyatomic ion source using alkyl naphthalene mixed with ionic liquid such as imidazolium dicyanamide has been developed. Instead of the electron bombardment method, a high-electric field method was used for the ion emission from a sharp tip, because the vapor pressure of the liquid materials was relatively low. The threshold voltage was approximately 4.5 kV and the ion current of approximately 250 nA was obtained at an extraction voltage of 9.5 kV. PMID- 20192426 TI - Boron ion source based on planar magnetron discharge in self-sputtering mode. AB - An ion source based on a planar magnetron sputtering device with thermally isolated target has been designed and demonstrated. For a boron sputtering target, high target temperature is required because boron has low electrical conductivity at room temperature, increasing with temperature. The target is well insulated thermally and can be heated by an initial low-current, high-voltage discharge mode. A discharge power of 16 W was adequate to attain the required surface temperature (400 degrees C), followed by transition of the discharge to a high-current, low-voltage mode for which the magnetron enters a self-sputtering operational mode. Beam analysis was performed with a time-of-flight system; the maximum boron ion fraction in the beam is greater than 99%, and the mean boron ion fraction, time-integrated over the whole pulse length, is about 95%. We have plans to make the ion source steady state and test with a bending magnet. This kind of boron ion source could be competitive to conventional boron ion sources that utilize compounds such as BF(3), and could be useful for semiconductor industry application. PMID- 20192427 TI - Broad-beam high-current dc ion source based on a two-stage glow discharge plasma. AB - We have designed, made, and demonstrated a broad-beam, dc, ion source based on a two-stage, hollow-cathode, and glow discharges plasma. The first-stage discharge (auxiliary discharge) produces electrons that are injected into the cathode cavity of a second-stage discharge (main discharge). The electron injection causes a decrease in the required operating pressure of the main discharge down to 0.05 mTorr and a decrease in required operating voltage down to about 50 V. The decrease in operating voltage of the main discharge leads to a decrease in the fraction of impurity ions in the ion beam extracted from the main gas discharge plasma to less than 0.2%. Another feature of the source is a single grid accelerating system in which the ion accelerating voltage is applied between the plasma itself and the grid electrode. The source has produced steady-state Ar, O, and N ion beams of about 14 cm diameter and current of more than 2 A at an accelerating voltage of up to 2 kV. PMID- 20192428 TI - Self-heated hollow cathode discharge system for charged particle sources and plasma generators. AB - This paper presents the results of experimental studies of a new design of discharge system using a self-heated hollow cathode. The discharge system offers certain advantages that are attractive for use in high-dose ion implantation, plasma generators, and plasma electron sources. PMID- 20192429 TI - A self-sputtering ion source: a new approach to quiescent metal ion beams. AB - A new metal ion source is presented based on sustained self-sputtering plasma in a magnetron discharge. Metals exhibiting high self-sputtering yield such as Cu, Ag, Zn, and Bi can be used in a high-power impulse magnetron sputtering discharge such that the plasma almost exclusively contains singly charged metal ions of the target material. The plasma and extracted ion beam are quiescent. The ion beams consist mostly of singly charged ions with a space-charge limited current density which reached about 10 mA/cm(2) at an extraction voltage of 45 kV and a first gap spacing of 12 mm. PMID- 20192430 TI - Gridless, very low energy, high-current, gaseous ion source. AB - We have made and tested a very low energy gaseous ion source in which the plasma is established by a gaseous discharge with electron injection in an axially diverging magnetic field. A constricted arc with hidden cathode spot is used as the electron emitter (first stage of the discharge). The electron flux so formed is filtered by a judiciously shaped electrode to remove macroparticles (cathode debris from the cathode spot) from the cathode material as well as atoms and ions. The anode of the emitter discharge is a mesh, which also serves as cathode of the second stage of the discharge, providing a high electron current that is injected into the magnetic field region where the operating gas is efficiently ionized. In this discharge configuration, an electric field is formed in the ion generation region, accelerating gas ions to energy of several eV in a direction away from the source, without the use of a gridded acceleration system. Our measurements indicate that an argon ion beam is formed with an energy of several eV and current up to 2.5 A. The discharge voltage is kept at less than 20 V, to keep below ion sputtering threshold for cathode material, a feature which along with filtering of the injected electron flow, results in extremely low contamination of the generated ion flow. PMID- 20192431 TI - Review of polarized ion sources (invited). AB - Recent progress in polarized ion sources development is reviewed. New techniques for production of polarized H(-) ion (proton), D(-) (D(+)), and (3)He(++) ion beams are discussed. Feasibility studies of these techniques are in progress at BNL and other laboratories. Polarized deuteron beams will be required for the polarization program at the Dubna Nuclotron and at the deuteron electric dipole moment experiment at BNL. Experiments with polarized (3)He(++) ion beams are a part of the experimental program at the future electron ion collider. PMID- 20192432 TI - Enhancement in ion beam current with layered-glows in a constricted dc plasma ion source. AB - High current mode has been discovered and investigated in a constricted dc plasma ion source. As discharge currents exceed a certain threshold, voltage to sustain the constricted dc plasma suddenly falls down to almost half of the value. In this sense, constricted dc plasmas can be sustained at much higher current than in conventional mode operation at a fixed discharge voltage. Phenomenally, several discrete layered-glows are created between an anode glow and a cathode glow. The layers are thin and divided by dark spaces where charged particles can be accelerated. In this high current mode, ion beam current density is about 100 times higher than in conventional mode at the same voltage. It is noteworthy that lower gas pressure is desirable to sustain the layered-glow mode, which is also profitable for ion source in terms of differential pumping. Ion current density exceeds 300 mA/cm(2) at low discharge power of 175 W where ion density of plasma ball is estimated to be over 3.7x10(12) cm(-3). PMID- 20192434 TI - High-intensity ion sources for accelerators with emphasis on H- beam formation and transport (invited). AB - This paper lays out the fundamental working principles of a variety of high current ion sources for accelerators in a tutorial manner, and gives examples of specific source types such as dc discharge-driven and rf-driven multicusp sources, Penning-type, and electron cyclotron resonance-based sources while discussing those principles, pointing out general performance limits as well as the performance parameters of specific sources. Laser-based, two-chamber, and surface-ionization sources are briefly mentioned. Main aspects of this review are particle feed, ionization mechanism, beam formation, and beam transport. Issues seen with beam formation and low-energy transport of negative hydrogen-ion beams are treated in detail. PMID- 20192433 TI - Ion beam oscillation due to fluctuation of a hot filament driven magnetized plasma. AB - Ion beam current extracted from a modified Bernas type ion source occasionally exhibits an oscillation at a frequency of several 100 kHz. Increase in the strength of a linear magnetic field induced to the ion source has either decreased or increased the frequency of this oscillation. The frequency showed an increase in proportion to the ion extraction voltage when the frequency decreased with increasing magnetic field. The change of extraction voltage did not affect the frequency when the frequency increased with the increasing magnetic field. Mechanisms causing these oscillations of an ion beam had been investigated. PMID- 20192435 TI - Radio frequency-driven proton source with a back-streaming electron dump. AB - This article describes an rf ion source with a back-streaming electron dump. A quartz tube, brazed to a metal plug at one end, is fused in the center of a flat quartz plate. rf power (at 13.6 MHz) is coupled to generate hydrogen plasma using a planar external antenna bonded to the window. Bonding the water-cooled rf antenna to the quartz window significantly lowers its temperature. The water cooled metal plug serves as the back-streaming electron dump. At 1800 W, the current density of extracted hydrogen ions reaches approximately 125 mA/cm(2). PMID- 20192436 TI - Review on high current 2.45 GHz electron cyclotron resonance sources (invited). AB - The suitable source for the production of intense beams for high power accelerators must obey to the request of high brightness, stability, and reliability. The 2.45 GHz off-resonance microwave discharge sources are the ideal device to generate the requested beams, as they produce multimilliampere beams of protons, deuterons, and monocharged ions, remaining stable for several weeks without maintenance. A description of different technical designs will be given, analyzing their strength, and weakness, with regard to the extraction system and low energy beam transport line, as the presence of beam halo is detrimental for the accelerator. PMID- 20192437 TI - Ultracompact/ultralow power electron cyclotron resonance ion source for multipurpose applications. AB - In order to drastically reduce the power consumption of a microwave ion source, we have studied some specific discharge cavity geometries in order to reduce the operating point below 1 W of microwave power (at 2.45 GHz). We show that it is possible to drive an electron cyclotron resonance ion source with a transmitter technology similar to those used for cellular phones. By the reduction in the size and of the required microwave power, we have developed a new type of ultralow cost ion sources. This microwave discharge system (called COMIC, for COmpact MIcrowave and Coaxial) can be used as a source of light, plasma or ions. We will show geometries of conductive cavities where it is possible, in a 20 mm diameter chamber, to reduce the ignition of the plasma below 100 mW and define typical operating points around 5 W. Inside a simple vacuum chamber it is easy to place the source and its extraction system anywhere and fully under vacuum. In that case, current densities from 0.1 to 10 mA/cm(2) (Ar, extraction 4 mm, 1 mAe, 20 kV) have been observed. Preliminary measurements and calculations show the possibility, with a two electrodes system, to extract beams within a low emittance. The first application for these ion sources is the ion injection for charge breeding, surface analyzing system and surface treatment. For this purpose, a very small extraction hole is used (typically 3/10 mm for a 3 microA extracted current with 2 W of HF power). Mass spectrum and emittance measurements will be presented. In these conditions, values down to 1 pi mm mrad at 15 kV (1sigma) are observed, thus very close to the ones currently observed for a surface ionization source. A major interest of this approach is the possibility to connect together several COMIC devices. We will introduce some new on-going developments such as sources for high voltage implantation platforms, fully quartz radioactive ion source at ISOLDE or large plasma generators for plasma immersion, broad or ribbon beams generation. PMID- 20192438 TI - Simulations of negative ion plasma sheaths. AB - The need to accurately model beams of negative ions in high current sources makes reasonable to refine the simulation mesh up to fractions of the Debye length lambda(D), which is typically 0.01 mm. Even if simulations were finally possible in two space dimensions, still the role of one-dimensional (1D) model to clarify the physics of sheath and presheath structure and the stability of numerical solvers is fundamental. Here a 1D model with negative ion production from the extraction wall/grid is considered, coupled to a driver plasma which acts as an electron and proton reservoir at a variable plasma potential. A bias voltage between lateral walls and the extraction wall is also included. Particle motion is modeled with diffusion equations, also for protons; electrons are magnetized and Poisson equation is solved everywhere. The inverted sheath formation and the H(-) forward current result sensitive to bias voltage. PMID- 20192439 TI - Isotopic anomaly for carbon ions in an electron cyclotron resonance ion source. AB - In many experiments methods were applied to increase the highly charged ion output from an electron cyclotron resonance ion source; the gas-mixing method is still generally being applied. The dominant role of the masses of the ions in the gas-mixture was apparent. Two basically differing mechanisms could to first order explain most of the observations. A significant mass effect showed up in a mixture of oxygen isotopes, the so-called oxygen anomaly; so far that effect could be explained in zeroth order only. The anomaly was observed later for nitrogen isotopes as well. In the present experiment it is shown that the anomaly also exists for carbon isotopes, where the necessity of feeding the source with carbon-hydrogen compounds brings about an essential different experimental fact. PMID- 20192440 TI - Influence of the electron cross-field diffusion in negative ion sources with the transverse magnetic field and the plasma-electrode bias. AB - The physical mechanisms involved in the extraction of H(-) ions from the negative ion source are studied with a PIC 2D3V code. The effect of a weak magnetic field transverse to the extraction direction is taken into account, along with a variable bias voltage applied on the plasma electrode (PE). In addition to previous modeling works, the electron diffusion across the magnetic field is taken into account as a simple one-dimensional random-walk process. The results show that without PE bias, the value of the diffusion coefficient has a significant influence upon the value of the extracted H(-) current. However, the value of this coefficient does not affect qualitatively the mechanism leading to the peak of extracted H(-) ion current observed for an optimum value of the PE bias. PMID- 20192441 TI - Influence of H- velocity on H- extraction probability from a negative ion source. AB - We investigate influence of H(-) initial transport direction and kinetic energy on H(-) extraction probability with three-dimensional Monte Carlo calculation. As a result, lower energy H(-) ions are strongly trapped by the electrical potential structure, so that initial condition of H(-) transport direction is cancelled by alignment of the electric field; thus, it has lower influence for H(-) extraction probability. Besides, the potential hill induced by the beam extraction voltage more effectively enhances H(-) extraction probability for the lower energy H(-) ions. The correlation between the magnitude of the local plasma potential near the extraction region and the mean velocity of H(-) ions in the region should determine the H(-) extraction probability from the ion source. PMID- 20192442 TI - Development of a laser-focused ion beam combination machine. AB - We have developed a laser and focused ion beam (FIB) compound system to process an optical component device with an ultrafine precision minute surface structure and a micromedical device. This machine consists of an FIB and three types of lasers with an atomic force microscope. This system can fabricate decamicrometer area by laser and submicrometer area by FIB at one chuck. When processing the press mold die of a microlens array (10x10) in a glasslike carbon with a femtosecond laser, a diameter of 3.2 microm and depth of 0.43 microm are obtained. However, the surface roughness is more than Rz=0.5 microm. After this process, we finished this surface with the use of the FIB. As a result, the surface roughness is less than Rz=0.05 microm. PMID- 20192443 TI - IBSIMU: a three-dimensional simulation software for charged particle optics. AB - A general-purpose three-dimensional (3D) simulation code IBSIMU for charged particle optics with space charge is under development at JYFL. The code was originally developed for designing a slit-beam plasma extraction and nanosecond scale chopping for pulsed neutron generator, but has been developed further and has been used for many applications. The code features a nonlinear FDM Poisson's equation solver based on fast stabilized biconjugate gradient method with ILU0 preconditioner for solving electrostatic fields. A generally accepted nonlinear plasma model is used for plasma extraction. Magnetic fields can be imported to the simulations from other programs. The particle trajectories are solved using adaptive Runge-Kutta method. Steady-state and time-dependent problems can be modeled in cylindrical coordinates, two-dimensional (slit) geometry, or full 3D. The code is used via C++ programming language for versatility but it features an interactive easy-to-use postprocessing tool for diagnosing fields and particle trajectories. The open source distribution and public documentation make the code well suited for scientific use. IBSIMU has been used for modeling the 14 GHz ECR ion source extraction and for designing a four-electrode extraction for a 2.45 GHz microwave ion source at Jyvaskyla. A grid extraction has also been designed for producing large uniform beam for creating conditions similar to solar wind. The code has also been used to design a H(-) extraction with electron dumping for the Cyclotron Institute of Texas A&M University. PMID- 20192444 TI - Recent advances in plasma devices based on plasma lens configuration for manipulating high-current heavy ion beams. AB - We describe new results of development of novel generation cylindrical plasma devices based on the electrostatic plasma lens configuration and concept of electrons magnetic insulation. The crossed electric and magnetic fields plasma lens configuration provides us with the attractive and suitable method for establishing a stable plasma discharge at low pressure. Using plasma lens configuration in this way some cost-effective plasma devices were developed for ion treatment and deposition of exotic coatings and the effective lens was first proposed for manipulating high-current beams of negatively charged particles. Here we describe operation and features of these plasma devices, and results of theoretical consideration of mechanisms determining their optimal operation conditions. PMID- 20192445 TI - IONEX: a meshfree ion extraction code based on "particle in cloud of points" concept. AB - Ion Extraction (IONEX) is an ion extraction modeling code, developed at FAR-TECH, Inc., based on the meshless particle-in-cloud-of-points concept. IONEX self consistently solves motion equations for ions and Poisson's equation for the electrostatic field, assuming a Boltzmann distribution for the electrons. IONEX is capable of handling multiple species and is graphical user interface-driven. The two-dimensional version is benchmarked with IGUN. The basic algorithm and sample runs are presented. PMID- 20192446 TI - Study of ion beam extraction and transport from an electron cyclotron resonance ion source. AB - We have started an experimental and theoretical program to better understand the extraction and transport of intense multiply charged ion beams from an electron cyclotron resonance ion source (ECRIS). In this paper we present the first results of this program concerning a simple, monocomponent He(+) beam extracted from an ECRIS. We have calculated the ion trajectories starting from the ECRIS plasma electrode up to the image plane of the analyzing magnet taking into account space-charge effects and fringe fields. The initial phase-space distribution of the He(+) beam at the extraction aperture has been calculated with a particle-in-cell code. To check the simulations we have measured beam profiles with a viewing screen both before and after the analyzing magnet. In addition also measurements with a pepperpot emittance meter located behind the analyzing magnet have been performed. We find good agreement between these measurements and simulations showing that (i) there is a significant compensation of the space charge and that (ii) our analyzing magnet causes a severe increase in effective beam emittance. PMID- 20192447 TI - Measurements of transverse ion beam emittance generated by high current ion sources at the GSI test injector facility HOSTI. AB - The first emittance measurements with a new test injector facility (HOSTI) at GSI, designed for optimization of high current beam injection scheme, are discussed. The emittance of the ion beam (88 kV, Ar(1+) ions) was investigated as a function of various parameters related to the ion source, extraction, and postacceleration systems and the optimum parameters for future low energy beam transport line are concluded. The preliminary results of the emittance measurements with superconducting solenoid are presented. The influence of the focusing strength as well as the longitudinal field shape of the solenoid on the beam emittance is described. PMID- 20192448 TI - Electron cyclotron resonance plasma photos. AB - In order to observe and study systematically the plasma of electron cyclotron resonance (ECR) ion sources (ECRIS) we made a high number of high-resolution visible light plasma photos and movies in the ATOMKI ECRIS Laboratory. This required building the ECR ion source into an open ECR plasma device, temporarily. An 8MP digital camera was used to record photos of plasmas made from Ne, Ar, and Kr gases and from their mixtures. We studied and recorded the effect of ion source setting parameters (gas pressure, gas composition, magnetic field, and microwave power) to the shape, color, and structure of the plasma. The analysis of the photo series gave us many qualitative and numerous valuable physical information on the nature of ECR plasmas. PMID- 20192450 TI - Development of a pepper-pot device to determine the emittance of an ion beam generated by electron cyclotron resonance ion sources. AB - This paper describes the recent development and commissioning of a pepper-pot emittance meter at the Lawrence Berkeley National Laboratory (LBNL). It is based on a potassium bromide (KBr) scintillator screen in combination with a charged coupled device camera. Pepper-pot scanners record the full four-dimensional transverse phase space emittances which are particularly interesting for electron cyclotron resonance ion sources. The strengths and limitations of evaluating emittances using optical pepper-pot scanners are described and systematic errors induced by the optical data acquisition system will be presented. Light yield tests of KBr exposed to different ion species and first emittance measurement data using ion beams extracted from the 6.4 GHz LBNL electron cyclotron resonance ion source are presented and discussed. PMID- 20192449 TI - The injection efficiency measurement and analysis for central region model cyclotron. AB - At the China Institute of Atomic Energy, a central region model cyclotron has been constructed, which is dedicated for various experimental verifications to study beam properties. The design features of the ion source and injection line have already been described in other papers. We shall report here the results of the initial beam tests. A wire scanner is employed in the injection line to measure beam transverse sizes and these data can be used to fit the phase plane parameters after the ion source. Based on the beam tests results, the ion source built in 2003 has been improved recently. The improvement is mainly due to the repair of the multicusp field. From the ion source to the exit of the inflector, a transmission efficiency of 93% has been obtained for a continuous and low current input beam. It is also described here the experimental arrangement and the results. PMID- 20192451 TI - Preliminary studies on space charge compensation by analyzing residual argon gas ion signals. AB - An experimental method is related to research the space charge compensation (SCC) effect in low energy intense proton beams by analyzing residual gas (RG) ion signals. The signal curves were measured with an energy spectrometer under the RG pressure from 1.2x10(-3) to 1.6x10(-2) Pa. Most of the data showed a similar trend with our theoretical predicts. From the RG ion energy spectra the potential distribution in the beam was calculated both with and without the SCC effect. Moreover, as a preliminary result, a best compensating point is achieved for the low energy beam transport transmission of 40 KeV, 60 mA H(+) beam in Peking University. PMID- 20192452 TI - Extraction simulations and emittance measurements of a Holifield Radioactive Ion Beam Facility electron beam plasma source for radioactive ion beams. AB - The Holifield Radioactive Ion Beam Facility (HRIBF) at Oak Ridge National Laboratory has a variety of ion sources used to produce radioactive ion beams (RIBs). Of these, the workhorse is an electron beam plasma (EBP) ion source. The recent addition of a second RIB injector, the Injector for Radioactive Ion Species 2 (IRIS2), for the HRIBF tandem accelerator prompted new studies of the optics of the beam extraction from the EBP source. The source was modeled using SIMION V8.0, and results will be presented, including comparison of the emittances as predicted by simulation and as measured at the HRIBF offline ion source test facilities. Also presented will be the impact on phase space shape resulting from extraction optics modifications implemented at IRIS2. PMID- 20192453 TI - Studies of emittance of multiply charged ions extracted from high temperature superconducting electron cyclotron resonance ion source, PKDELIS. AB - For the high current injector project at Inter University Accelerator Centre, a high temperature superconducting electron cyclotron resonance (ECR) ion source, PKDELIS, would provide the high charge state ions. The emittance of the ECR ion source is an important parameter to design further beam transport system and to match the acceptances of the downstream radio frequency quadrupole and drift tube linac accelerators of the high current injector. The emittance of the analyzed beam of PKDELIS ECR source has been measured utilizing the three beam size technique. A slit and two beam profile monitors positioned at fixed distances from each other were used to measure the beam size. The digitized beam profiles have been analyzed to determine the emittance of various multiply charged ions. The variation of emittance with gas mixing, ultrahigh frequency power, and extraction energy are discussed in this presentation. PMID- 20192454 TI - The deuteron injector progress of the Peking University Neutron Imaging Facility project. AB - A deuteron radio frequency quadrupoles injector h has been developed at Peking University. A permanent magnetic electron cyclotron resonance (ECR) ion source is used in the injector system. A 50 keV 100 mA proton beam has been extracted from the ECR ion source and the measured normalized rms emittance is 0.11-0.14pi mm mrad. A deuteron beam has also been extracted at 50 kV with 83 mA total current and its emittance is less than 0.18pi mm mrad. The proton beam transmission has been investigated on a low energy beam transport test bench, and up to 93% transmission can be reached. The new injector with two solenoids has been designed and is being constructed. All the development results will be presented in this paper. PMID- 20192455 TI - Upgrade of the extraction system of permanent magnet electron cyclotron resonance ion source. AB - A set of new ion extraction electrodes have been designed for the permanent magnetic electron cyclotron resonance ion source at Peking University to improve beam quality and transmission. PBGUNS has been used to optimize the extraction electrodes and simulate the beam behavior at the extraction region. The experiments showed that with the new system, the beam half divergence angle can be less than 40 mrad and the normalized rms emittance is about 0.13pi mm mrad when the extracted current is 100 mA at 50 keV in pulse mode. The voltage of the suppression electrode has great effect on beam divergence. The effect of the microwave power and gas flow is also studied. PMID- 20192456 TI - Laser plasma in a magnetic field. AB - Laser ion source (LIS) is a candidate among various heavy ion sources. A high density plasma produced by Nd:yttrium aluminum garnet laser with drift velocity realizes high current and high charge state ion beams. In order to obtain higher beam current, we made experiments using the LIS with a magnetic field by which a confinement effect can make higher beam current. We measured total current by Faraday cup and analyzed charge distribution by electrostatic ion analyzer. It is shown that the ion beam charge state is higher by a permanent magnet. PMID- 20192457 TI - Gallium ion extraction from a plasma sputter-type ion source. AB - A broad mixed ion beam containing positive ions of gallium (Ga) was produced with a plasma sputter-type ion source. Liquid Ga was suspended on a tungsten reservoir to be sputtered and postionized in argon (Ar) plasma excited by a radio frequency (rf) power at 13.56 MHz. Optical emission spectra from the plasma near the Ga sputtering target had indicated that the release of Ga into plasma increased with increasing negative bias to the sputtering target. The ratio of Ga(+) current to Ar(+) current was measured to be about 1% with a quadrupole mass analyzer at 100 V extraction voltage for incident rf power as low as 30 W. Ions in the plasma were extracted through a pair of multiaperture electrodes. The homogeneity of Ga flux was examined by making a Ga deposition pattern on a glass substrate located behind the extractor electrodes. PMID- 20192458 TI - Diagnostic experiments at a 3 MeV test stand at Rutherford Appleton Laboratory (United Kingdom). AB - A front end is currently under construction consisting of a H(-) Penning ion source (65 keV, 60 mA), low energy beam transport (LEBT), and radio frequency quadrupole (3 MeV output energy) with a medium energy beam transport suitable for high power proton applications. Diagnostics can be divided either in destructive techniques such as beam profile monitor, pepperpot, slit-slit emittance scanner (preferably used during commissioning) or nondestructive, permanently installed devices such as photodetachment-based techniques. Another way to determine beam distributions is a scintillator with charge-coupled device camera. First experiments have been performed to control the beam injection into the LEBT. The influence of beam parameters such as particle energy and space-charge compensation on the two-dimensional distribution and profiles will be presented. PMID- 20192459 TI - Portable emittance measurement device. AB - In Institute for Theoretical and Experimental Physics (ITEP) the portable emittance measurements device is developed. It provides emittance measurements both with "pepper-pot" and "two slits" methods. Depending on the method of measurements, either slits or pepper-pot mask with scintillator are mounted on the two activators and are installed in two standard Balzer's cross chamber with CF-100 flanges. To match the angle resolution for measured beam, the length of the stainless steel pipe between two crosses changes is adjusted. The description of the device and results of emittance measurements at the ITEP ion source test bench are presented. PMID- 20192460 TI - Emittance estimation by an ion optical element with variable focusing strength and a viewing target. AB - The emittance of an extracted ion beam can be estimated to first order by a series of three linear independent profile measurements. This estimation is restricted to the evaluation of an upper limit of the emittance value for a homogeneous, nonfilamented beam. The beam is assumed to be round, respectively elliptical, without any structure of the intensity distribution, no space charge has been assumed for the drifting beam, and the optics is assumed to be linear. Instead of using three different drift sections, a linear focusing element with three different focusing strengths can be used. Plotting the beam radius as function of focusing strength, three independent solutions can be used to calculate the Twiss parameters alpha, beta, and gamma and furthermore the emittance epsilon. Here we describe the measurements which have been performed with the SECRAL ion source at Institute of Modern Physics Lanzhou. PMID- 20192461 TI - Emittance studies of the Spallation Neutron Source external-antenna H- ion source. AB - A new Allison-type emittance scanner has been built to characterize the ion sources and low energy beam transport systems at Spallation Neutron Source. In this work, the emittance characteristics of the H(-) beam produced with the external-antenna rf-driven ion source and transported through the two-lens electrostatic low energy beam transport are studied. The beam emittance dependence on beam intensity, extraction parameters, and the evolution of the emittance and twiss parameters over beam pulse duration are presented. PMID- 20192462 TI - Control system for the Spallation Neutron Source H- source test facility Allison scanner. AB - Spallation Neutron Source is currently in progress of a multiyear plan to ramp ion beam power to the initial design power of 1.4 MW. Key to reaching this goal is understanding and improving the operation of the H(-) ion source. An Allison scanner was installed on the ion source in the test facility to support this improvement. This paper will discuss the hardware and the software control system of the installed Allison scanner. The hardware for the system consists of several parts. The heart of the system is the scanner head, complete with associated bias plates, slits, and signal detector. There are two analog controlled high voltage power supplies to bias the plates in the head, and a motor with associated controller to position the head in the beam. A multifunction data acquisition card reads the signals from the signal detector, as well as supplies the analog voltage control for the power supplies. To synchronize data acquisition with the source, the same timing signal that is used to trigger the source itself is used to trigger data acquisition. Finally, there is an industrial personal computer to control the rest of the hardware. Control software was developed using National Instruments LABVIEW, and consists of two parts: a data acquisition program to control the hardware and a stand alone application for offline user data analysis. PMID- 20192463 TI - Drift distance survey in direct plasma injection scheme for high current beam production. AB - In a laser ion source, plasma drift distance is one of the most important design parameters. Ion current density and beam pulse width are defined by plasma drift distance between a laser target and beam extraction position. In direct plasma injection scheme, which uses a laser ion source and a radio frequency quadrupole linac, we can apply relatively higher electric field at beam extraction due to the unique shape of a positively biased electrode. However, when we aim at very high current acceleration such as several tens of milliamperes, we observed mismatched beam extraction conditions. We tested three different ion current at ion extraction region by changing plasma drift distance to study better extraction condition. In this experiment, C(6+) beam was accelerated. We confirmed that matching condition can be improved by controlling plasma drift distance. PMID- 20192464 TI - Time structure of an accelerated beam using a radio-frequency quadrupole linac with direct plasma injection scheme. AB - In direct plasma injection scheme, the relation between the ion current from a laser ion source and the accelerated beam current by a radio-frequency quadrupole (RFQ) linac was studied by a series of the following analyses. First, ion current at beam extraction was calculated from measured plasma parameters using a scaling law. Second, the beam emittance at the entrance of acceleration electrode region was evaluated by the simulation of the ion extraction out of the ion source plasma using the result of the first calculation. Last, the accelerated beam current could be reproduced by the simulation of beam acceleration using the results of the second. The second calculation revealed the time variation in the injected beam parameter to the RFQ linac. Then it was proved that the time structure of the accelerated beam was different from that of the injection beam because the degree of the matching between the injected beam emittance and the RFQ acceptance varied with time. PMID- 20192465 TI - Model for the description of ion beam extraction from electron cyclotron resonance ion sources. AB - The finite difference method trajectory code KOBRA3-INP has been developed now for 25 years to perform the simulation of ion beam extraction in three dimensions. Meanwhile, the code has been validated for different applications: high current ion beam extraction from plasma sources for ion implantation technology, neutral gas heating in fusion devices, or ion thrusters for space propulsion. One major issue of the development of this code was to improve the flexibility of the applied model for the simulation of different types of particle sources. Fixed emitter sources might be simulated with that code as well as laser ion sources, Penning ion sources, electron cyclotron resonance ion sources (ECRISs), or H(-) sources, which require the simulation of negative ions, negative electrons, and positive charges simultaneously. The model which has been developed for ECRIS has now been used to explore the conditions for the ion beam extraction from a still nonexisting ion source, a so called ARC-ECRIS [P. Suominen and F. Wenander, Rev. Sci. Instrum. 79, 02A305 (2008)]. It has to be shown whether the plasma generator has similar properties like regular ECRIS. However, the emittance of the extracted beam seems to be much better compared to an ECRIS equipped with a hexapole. PMID- 20192466 TI - Particle simulation for direct plasma injection in a radio frequency quadrupole matching section. AB - We have been investigating direct plasma injection scheme (DPIS) for high intensity heavy-ion beam acceleration. In the DPIS, laser-produced plasma is directly injected into a radio frequency quadrupole (RFQ) linac. To study the beam dynamics of the ion injection in the DPIS, we tracked particle motions in the RFQ matching section using three-dimensional particle-in-cell method. As a result of the numerical simulation, we found that the electrostatic field generated by the extraction electrode reduces the transmission efficiency. To avoid the radially defocusing force, the input beam into the RFQ has to be initially convergent. In the DPIS, further optimization of the plasma density is required for better matching. PMID- 20192467 TI - Carborane beam from ITEP Bernas ion source for semiconductor implanters. AB - A joint research and development of steady state intense boron ion sources for hundreds of electron-volt ion implanters has been in progress for the past 5 years. The difficulties of extraction and transportation of low energy boron beams can be solved by implanting clusters of boron atoms. In Institute for Theoretical and Experimental Physics (ITEP) the Bernas ion source successfully generated the beam of decaborane ions. The carborane (C(2)B(10)H(12)) ion beam is more attractive material due to its better thermal stability. The results of carborane ion beam generation are presented. The result of the beam implantation into the silicon wafer is presented as well. PMID- 20192468 TI - Characteristics of liquid cluster ion beam for surface treatment. AB - A liquid cluster ion source, which is an ion source for the cluster beams produced with liquid materials, has been developed for the surface treatment of solid materials. The electrodes were designed for increasing the cluster beam intensity by a computer simulation of beam trajectories. The peaks of the cluster size distributions of the water and ethanol cluster ion beams of 3 atm vapor pressure were approximately at 2.4x10(3) and 1.6x10(3) molecules, respectively. The cluster size distributions of ethanol clusters were not sensitive to the variations of the acceleration voltages (V(e)) and currents (I(e)) of the electrons for ionization when the V(e) and I(e) were larger than approximately 200 V and 200 mA, respectively. PMID- 20192469 TI - Two-stage plasma gun based on a gas discharge with a self-heating hollow emitter. AB - The paper presents the results of tests of a new compact two-stage bulk gas plasma gun. The plasma gun is based on a nonself-sustained gas discharge with an electron emitter based on a discharge with a self-heating hollow cathode. The operating characteristics of the plasma gun are investigated. The discharge system makes it possible to produce uniform and stable gas plasma in the dc mode with a plasma density up to 3x10(9) cm(-3) at an operating gas pressure in the vacuum chamber of less than 2x10(-2) Pa. The device features high power efficiency, design simplicity, and compactness. PMID- 20192470 TI - A tandem-based compact dual-energy gamma generator. AB - A dual-energy tandem-type gamma generator has been developed at E. O. Lawrence Berkeley National Laboratory and Sandia National Laboratories. The tandem accelerator geometry allows higher energy nuclear reactions to be reached, thereby allowing more flexible generation of MeV-energy gammas for active interrogation applications. Both positively charged ions and atoms of hydrogen are created from negative ions via a gas stripper. In this paper, we show first results of the working tandem-based gamma generator and that a gas stripper can be utilized in a compact source design. Preliminary results of monoenergetic gamma production are shown. PMID- 20192471 TI - ITEP MEVVA ion beam for rhenium silicide production. AB - The rhenium silicides are very attractive materials for semiconductor industry. In the Institute for Theoretical and Experimental Physics (ITEP) at the ion source test bench the research program of rhenium silicide production by ion beam implantation are going on. The investigation of silicon wafer after implantation of rhenium ion beam with different energy and with different total dose were carried out by secondary ions mass spectrometry, energy-dispersive x-ray microanalysis, and x-ray diffraction analysis. The first promising results of rhenium silicide film production by high intensity ion beam implantation are presented. PMID- 20192472 TI - ITEP MEVVA ion beam for reactor material investigation. AB - Since 2008 the ion beam irradiation modeling experiments for the testing of reactor materials radiation hardness are under development at the ITEP heavy ion RFQ injector with MEVVA ion source. Ion beam irradiation method has certain advantages for such tests. One of them is high speed of defect formation. Moreover, the irradiated samples can be investigated by traditional investigation methodic because they have not radioactivity induced. The special sample support with electrostatic deflector was constructed and installed at the injector output. The result of ion beam dynamics simulation throughout the deflector as well as the detailed description of the test facility is presented. The first experimental results are presented as well. They have been demonstrated promising results. PMID- 20192473 TI - Current capabilities and future needs for semiconductor ion implantation (invited). AB - For many years the largest commercial application for particle accelerators has been semiconductor ion implantation. These tools differ from other accelerators in many respects. In particular they are automated to a very high degree and, in addition to technical performance requirements their success depends on other key metrics including productivity, availability and cost of ownership. These tools also operate with a large variety of species, four orders of magnitude of energy range and five orders of magnitude of dose range. The ion source is a key component of implanters with its own performance metrics that include beam current, lifetime, and materials cost. In this paper, we describe the primary applications for ion implantation and some of the beam line architectures that are used. We describe the ion source that has evolved for this application. Some key future challenges for implanter ion source development are also discussed. PMID- 20192474 TI - Sealed operation of a rf driven ion source for a compact neutron generator to be used for associated particle imaging. AB - We present the recent development of a prototype compact neutron generator to be used in conjunction with the method of associated particle imaging for the purpose of active neutron interrogation. In this paper, the performance and device specifications of these compact generators that employ rf driven ion sources will be discussed. Initial measurements of the generator performance include a beam spot size of 1 mm in diameter and a neutron yield of 2x10(5) n/s with air cooling. PMID- 20192475 TI - Review on heavy ion radiotherapy facilities and related ion sources (invited). AB - Heavy ion radiotherapy awakens worldwide interest recently. The clinical results obtained by the Heavy Ion Medical Accelerator in Chiba at the National Institute of Radiological Sciences in Japan have clearly demonstrated the advantages of carbon ion radiotherapy. Presently, there are four facilities for heavy ion radiotherapy in operation, and several new facilities are under construction or being planned. The most common requests for ion sources are a long lifetime and good stability and reproducibility. Sufficient intensity has been achieved by electron cyclotron resonance ion sources at the present facilities. PMID- 20192478 TI - Local shear stress transduction. AB - This is a comprehensive review of local direct measurement shear stress transducers. Transducers are first classified by their movement, measuring mode, and mechanism. These categories are then subclassified into active or passive movement, static or dynamic measuring mode, and rotational or translational mechanisms. Over 80 transducers are reviewed and tabulated. Finally, sources of transducer error are analyzed. Primary sources of error are transducer and housing misalignment, material ingress around the active face, active face roughness, and the effects of temperature gradients when making measurements on surfaces where temperature gradients develop. PMID- 20192479 TI - Variable-wavelength frequency-domain terahertz ellipsometry. AB - We report an experimental setup for wavelength-tunable frequency-domain ellipsometric measurements in the terahertz spectral range from 0.2 to 1.5 THz employing a desktop-based backward wave oscillator source. The instrument allows for variable angles of incidence between 30 degrees and 90 degrees and operates in a polarizer-sample-rotating analyzer scheme. The backward wave oscillator source has a tunable base frequency of 107-177 GHz and is augmented with a set of Schottky diode frequency multipliers in order to extend the spectral range to 1.5 THz. We use an odd-bounce image rotation system in combination with a wire grid polarizer to prepare the input polarization state. A highly phosphorous-doped Si substrate serves as a first sample model system. We show that the ellipsometric data obtained with our novel terahertz ellipsometer can be well described within the classical Drude model, which at the same time is in perfect agreement with midinfrared ellipsometry data obtained from the same sample for comparison. The analysis of the terahertz ellipsometric data of a low phosphorous-doped n-type Si substrate demonstrates that ellipsometry in the terahertz spectral range allows the determination of free charge-carrier properties for electron concentrations as low as 8x10(14) cm(-3). PMID- 20192480 TI - Multifunctional integrating sphere setup for luminous flux measurements of light emitting diodes. AB - A multifunctional setup based on the absolute integrating sphere method for measuring luminous flux of light emitting diodes (LEDs) is presented. The total luminous flux in 2pi and 4pi geometries and partial luminous flux with variable cone angle can be measured with the same custom-made integrating sphere. The number and area of ports and baffles of the sphere was minimized. The sphere has three ports: a main port, a detector port, and an auxiliary port, located in the same hemisphere. The other hemisphere is free of ports. The main port is used for the calibration of the sphere as well as for the LED under test. Only one absolute calibration of the integrating sphere photometer is needed for measuring LEDs in all three geometries. The spatial nonuniformity correction is needed only for LEDs with low directivity or having significant minor beams. The expanded uncertainty (k=2) for the measurement setup varies between 1.2% and 4.6% depending on the measurement geometry, color, and the angular spread of the LED light beam. A complete calibration procedure of the constructed integrating sphere photometer is presented as well as comparison measurements with a goniophotometer. PMID- 20192481 TI - Microfluidic refractometer with integrated optical fibers and end-facet transmission gratings. AB - We demonstrated a microfluidic refractometer with an integrated high resolution transmission grating. This grating was fabricated by UV nanoimprinting on the end facet of a multimode optical fiber which was then placed in the plan of the microfluidic device and perpendicular to a microchannel. On the opposite side of the channel, three cleaved optical fibers were added for the light collection of the zeroth and the +/- first diffraction orders. A white light source was used for illumination and the diffraction beams were analyzed with a minispectrometer. The transmission grating was merged in the sample solution of the channel, providing a refractive index-dependent diffraction efficiency. As expected, the diffraction efficiency of the zeroth and the +/- first diffraction orders are different, both being reliable for the refractive index monitoring. Such a white source and multibeam diffraction analysis also allows monitoring the sample absorption or fluorescence, thereby providing a more accurate determination of the sample refraction index. PMID- 20192482 TI - Laser-plasma debris from a rotating cryogenic-solid-Xe target. AB - We investigate the characteristics of laser plasma debris that is responsible for damaging optics. The debris is composed of fast ions, neutral particles, and fragments, and originates from a solid Xe target on a rotating drum that we developed as an extreme ultraviolet (EUV) source. The ice fragments appear to be a problem most notably with solid Xe targets; however, we find that the damage induced by Xe ice fragments can be avoided by simply reducing the laser pulse energy. We find the number of fast neutral particles to be an order of magnitude less than the number of ions, and we clarify that the plasma debris is primarily composed of fast ions. In addition, we find that the number of fast ions having a few dozen keV of energy decreases when using the rotating target compared with the rest target. We attribute this to a gas curtain effect from the Xe gas localized at the rotating target surface. We estimate the sputtering rate of the Mo/Si mirror, which is caused primarily by the fast ions, to be 104 nm/1x10(6) shots at 190 mm from the source plasma and at an 11.25 degree angle from the incident laser beam. Up to the 1x10(6) shots exposure, remarkable degradation of the mirror reflectivity is not observed though the sputtering damages the mirror. Mitigation of the ions by using gas and/or magnetic fields will further improve the mirror lifetime. By comparing with a liquid jet Xe target, we conclude that the sputtering rate per conversion efficiency when using the solid Xe targets on the rotating drum is the same as that when using the liquid Xe targets. The high conversion efficiency of 0.9% in the rotating drum solid Xe target makes this technique useful for developing laser plasma EUV sources. PMID- 20192483 TI - X-ray polarimeter with a transmission multilayer. AB - We fabricated a novel x-ray polarimeter with a transmission multilayer and measured its performance with synchrotron radiation. A self standing multilayer with seven Mo/Si bilayers was installed with an incident angle of 45 degrees in front of a back-illuminated CCD. The multilayer can be rotated around the normal direction of the CCD keeping an incident angle of 45 degrees. This polarimeter can be easily installed along the optical axis of x-ray optics. By using the CCD as a photon counting detector with a moderate energy resolution, the polarization of photons in a designed energy band can be measured along with the image. At high photon energies, where the multilayer is transparent, the polarimeter can be used for imaging and spectroscopic observations. We confirmed a modulation factor of 45% with 45% and 17% transmission for P- and S-polarization, respectively. PMID- 20192484 TI - Improved piezoelectric actuators for use in high-speed pulsed valves. AB - We describe the assembly of piezoelectric actuators suitable for use in Proch Trickl pulsed gas valves employed in pulsed molecular beam experiments. In their simplest form, these actuators have performance equal to and resistance to chemical attack far superior to the recently discontinued commercial actuator around which the valve was originally designed. New actuators have been designed employing several different dual piezo configurations. The dual piezo design reliably produces shorter pulses than the original actuator, resulting in reduced gas consumption and lower average source chamber pressures for a given backing pressure and pulse rate. By electrically isolating the actuator assembly, active adjustment of the closed position may be achieved by simple addition of a continuous voltage bias. PMID- 20192485 TI - Production of a coherent pair of light beams with a microwave frequency difference from a single extended-cavity diode laser. AB - We produced a pair of coherent laser beams with a 3-GHz frequency difference by optically phase locking two modes from a single, multimode extended-cavity diode laser. This method is complementary to either a direct modulation or an optical phase locking of two independent lasers. A large differential frequency shift between the two modes of the laser allows efficient phase locking. We developed a simple theory to account for the large differential frequency shift. Allan deviation of the beat frequency when the two modes are phase-locked drops as an inverse of the measurement time and it reaches 10(-14) when the time is 1 h. Coherent population trapping spectroscopy of Rb atoms using the phase-locked beams resulted in a spectrum as narrow as that of the case using direct modulation by a stable frequency synthesizer. PMID- 20192486 TI - Design and development of a radio frequency quadrupole linac postaccelerator for the Variable Energy Cyclotron Center rare ion beam project. AB - A four-rod type heavy-ion radio frequency quadrupole (RFQ) linac has been designed, constructed, and tested for the rare ion beam (RIB) facility project at VECC. Designed for cw operation, this RFQ is the first postaccelerator in the RIB beam line. It will accelerate A/q < or = 14 heavy ions coming from the ion source to the energy of around 100 keV/u for subsequent acceleration in a number of Interdigital H-Linac. Operating at a resonance frequency of 37.83 MHz, maximum intervane voltage of around 54 kV will be needed to achieve the final energy over a vane length of 3.12 m for a power loss of 35 kW. In the first beam tests, transmission efficiency of about 90% was measured at the QQ focus after the RFQ for O(5+) beam. In this article the design of the RFQ including the effect of vane modulation on the rf characteristics and results of beam tests will be presented. PMID- 20192487 TI - Electron proportional gas counter for linear and elliptical Mossbauer polarimetry. AB - Design, characterization, and selected applications of a novel electron detector dedicated to conventional perpendicular- and low-angle-incidence conversion electron Mossbauer spectroscopy are presented. The setup is suitable for varying the incident angle and external magnetic fields on Mossbauer source and absorber. Test experiments were performed on alpha-(57)Fe films using a conventional single line (57)Co(Rh) and magnetically split, (57)Co(alpha-Fe) Mossbauer sources. The integral "blackness effect" in conversion-electron Mossbauer spectra of (57)Fe isotope-enriched absorbers is demonstrated and shown to be pronounced at shallow angles of incidence. In order to determine the alignment and sign of the hyperfine field in an isotope-enriched absorber, the blackness effect is accounted for in a semiempirical way by using single-line source/absorber experimental relative intensities determined independently. This method works with high accuracy for linear polarimetry; however it is only a rough approximation in the case of nearly circular polarimetry. PMID- 20192488 TI - Investigations of the emittance and brightness of ion beams from an electron beam ion source of the Dresden EBIS type. AB - We have characterized ion beams extracted from the Dresden EBIS-A, a compact room temperature electron beam ion source (EBIS) with a permanent magnet system for electron beam compression, using a pepper-pot emittance meter. The EBIS-A is the precursor to the Dresden EBIS-SC in which the permanent magnets have been replaced by superconducting solenoids for the use of the source in high-ion current applications such as heavy-ion cancer therapy. Beam emittance and brightness values were calculated from data sets acquired for a variety of source parameters, in leaky as well as pulsed ion extraction mode. With box shaped pulses of C(4+) ions at an energy of 39 keV root mean square emittances of 1-4 mm mrad and a brightness of 10 nA mm(-2) mrad(-2) were achieved. The results meet the expectations for high quality ion beams generated by an electron beam ion source. PMID- 20192489 TI - A multichannel time-of-flight system for observation of energetic ions of multispecies generated from relativistic laser plasma. AB - A multichannel time-of-flight (TOF) system was constructed to observe the ions generated from relativistic laser plasma, where the ions have polychromatic energies and multiple species. The TOF system is composed of a ten-channel scintillation detector array and an electromagnet that generates a magnetic field of 0-1.24 T. The magnet field enables us to analyze protons, deuterons, and full stripped carbon ions to 50, 25, and 150 MeV, respectively. The system experimentally identified protons of 0.27-1.6 MeV energy and ions of a half specific charge (deuterons of 0.3-0.8 MeV and full-stripped carbons of 1.8-4.8 MeV). The measured TOF values agree well with the calculated values within the designed accuracy; +/-2.5 ns for protons and +/-5 ns for the others (d or C(6+)) on each detector channel. Comparison of ion numbers detected by a track detector (CR-39) and the TOF system enabled us to obtain the number of ions detected on each scintillation counter with less than 16% error. PMID- 20192490 TI - High speed infrared camera diagnostic for heat flux measurement in NSTX. AB - A new high speed infrared camera has been successfully implemented and produced first set of heat flux measurements on the lower divertor tiles in the NSTX tokamak. High spatial and temporal resolutions, 6.4 mm and 1.6-6.3 kHz, respectively, enable us to investigate detailed structure of heat flux deposition pattern caused by transient events such as edge localized modes. A comparison of the data with a slow infrared camera viewing the same region of interest shows good agreement between the two independent measurements. Data analysis for various plasma conditions is in progress. PMID- 20192491 TI - Miniature shock tube for laser driven shocks. AB - We describe in this paper the design of a miniature shock tube (smaller than 1 cm(3)) that can be placed in a vacuum vessel and allows transverse optical probing and longitudinal backside extreme ultraviolet emission spectroscopy in the 100-500 A range. Typical application is the study of laser launched radiative shocks, in the framework of what is called "laboratory astrophysics." PMID- 20192492 TI - Straightforward correction for the astigmatism of a Czerny-Turner spectrometer. AB - We describe a simple and inexpensive method, which corrects the astigmatism of a Czerny-Turner spectrometer. Initial characterization of the astigmatism for a particular Czerny-Turner spectrometer was performed and the design of the corrective optic is described. The optic is a thin piece of glass, which is used as a one-dimensional waveguide between the light source and the spectrometer such that the sagittal and tangential focal planes are brought to the same position. This method is demonstrated to work well between 360 and 900 nm for an f/4.7 spectrometer. With appropriate materials, corrections for longer and shorter wavelengths should also be possible. When using an inexpensive glass plate, light intensity lost with this method is approximately 12%. Improved surface finish should reduce this loss. PMID- 20192493 TI - A calorimetric probe for plasma diagnostics. AB - A calorimetric probe for plasma diagnostics is presented, which allows measurements of the power taken by a test substrate. The substrate can be biased and used as an electric probe in order to obtain information about the composition of the total heating power. A new calibration technique for calorimetric probes, which uses monoenergetic electrons at low pressure, has been developed for an improved accuracy. The use of the probe is exemplified with an experiment where both energetic neutral atoms and ions heat the test substrate. PMID- 20192494 TI - Simple filtered repetitively pulsed vacuum arc plasma source. AB - A very simple design of cathodic filtered vacuum arc plasma source is proposed. The source without filter has only four components and none of them require precise machining. The source operates in a repetitively pulsed regime, and for laboratory experiments it can be used without water cooling. Despite the simple construction, the source provides high ion current at the filter outlet reaching 2.5% of 400 A arc current, revealing stable operation in a wide pressure range from high vacuum to oxygen pressure up to more than 10(-2) mbar. There is no need in complicated power supply system for this plasma source, only one power supply can be used to ignite the arc, to provide the current for the arc itself, to generate the magnetic field in the filter, and provide its positive electric biasing without any additional high power resistance. PMID- 20192495 TI - Hydrogen atomic pair-ion production on catalyst surface. AB - To generate a hydrogen pair-ion plasma consisting of only hydrogen atomic pair ions, i.e., H(+) and H(-) ions, the efficient production of pair ions is required. When discharged hydrogen plasma is irradiated to a Ni catalyst, pair ions are produced on the catalyst surface. It is clarified that hydrogen chemisorption on the catalyst affects pair-ion production. PMID- 20192496 TI - A new flexible scatterometer for critical dimension metrology. AB - At Physikalisch-Technische Bundesanstalt, the National Metrology Institute of Germany, a new type of deep ultraviolet scatterometer has been developed and set up. The concept of the system is very variable and versatile, so that many different types of measurements, e.g., classical scatterometry, ellipsometric scatterometry, polarization-dependent reflectometry, and ellipsometry can be performed. The main application is the characterization of linewidth/critical dimension (CD), grating period (pitch), and edge profile of periodically nanostructured surfaces mainly, but not only, on photomasks. Different operation wavelength between 840 and 193 nm can be used, giving also access to a variety of different at-wavelength metrology connected with state-of-the-art photolithography. It allows to adapt and to vary the measurand and measurement geometry to optimize the sensitivity and the unambiguity for the measurement problem. In this paper the concept, design, and performance of the system is described in detail. First measurement examples are shown and current and future applications are discussed. PMID- 20192497 TI - Automated coregistered imaging using a hand-held probe-based optical imager. AB - Near-infrared optical imaging holds a promise as a noninvasive technology toward cancer diagnostics and other tissue imaging applications. In recent years, hand held based imagers are of great interest toward the clinical translation of the technology. However hand-held imagers developed to date are typically designed to obtain surface images and not tomography information due to lack of coregistration facilities. Herein, a recently developed hand-held probe-based optical imager in our Optical Imaging Laboratory has been implemented with novel coregistration facilities toward real-time and tomographic imaging of tissue phantoms. Continuous-wave fluorescence-enhanced optical imaging studies were performed using an intensified charge coupled device camera based imaging system in order to demonstrate the feasibility of automated coregistered imaging of flat phantom surfaces, using a flexible probe that can also contour to curvatures. Three-dimensional fluorescence tomographic reconstructions were also demonstrated using coregistered frequency-domain measurements obtained using the hand-held based optical imager. It was also observed from preliminary studies on cubical phantoms that multiple coregistered scans differentiated deeper targets (approximately 3 cm) from artifacts that were not feasible from a single coregistered scan, demonstrating the possibility of improved target depth detectability in the future. PMID- 20192498 TI - A low noise all-fiber interferometer for high resolution frequency modulated atomic force microscopy imaging in liquids. AB - We have developed a low noise all-fiber interferometer for use as the deflection sensor in liquid environment frequency modulated atomic force microscopy (FM AFM). A detailed description and rationale for the choice of the critical components are provided along with the design of a simple alignment assembly. The optimization of the deflection sensor toward achieving the highest possible sensitivity and lowest deflection noise density is discussed in the context of an ideal interference cavity. Based on the provided analysis we have achieved deflection noise densities of 2 fm/square root(Hz) on commercially available cantilevers in both ambient and liquid environments. The low noise interferometer works without the need for differential detection, special focusing lenses, or polarization sensitive optics, dramatically simplifying measurements. True atomic resolution imaging of muscovite mica by FM-AFM in water is demonstrated using the developed deflection sensor. PMID- 20192500 TI - Intermittent contact scanning nonlinear dielectric microscopy. AB - Intermittent contact scanning nonlinear dielectric microscopy (IC-SNDM) was developed as a novel technique for surface topography measurements and observation of domain structures. Domain structures on ferroelectric single crystals were observed with nanoscale resolution using IC-SNDM. The reproducibility of measurements was improved in comparison to a conventional SNDM operated under contact mode, because the tip and/or sample damage are reduced when using intermittent contact mode. The minimum loading force of the probe to provide basic performance was experimentally determined for IC-SNDM. PMID- 20192499 TI - A compact multipurpose nanomanipulator for use inside a scanning electron microscope. AB - A compact, two-stage nanomanipulator was designed and built for use inside a scanning electron microscope. It consists of a fine stage employing piezostacks that provide a 15 microm range in three dimensions and a coarse stage based on commercially available stick-slip motors. Besides the fabrication of enhanced probes for scanning probe microscopy and the enhancement of electron field emitters, other novel manipulation processes were developed, such as locating, picking up, and positioning small nanostructures with an accuracy of approximately 10 nm. In combination with in situ I-V experiments, welding, and etching, this results in a multipurpose nanofactory, enabling a new range of experiments. PMID- 20192501 TI - Permanent magnet desktop magnetic resonance imaging system with microfabricated multiturn gradient coils for microflow imaging in capillary tubes. AB - A prototype for a desktop high-resolution magnetic resonance imaging (MRI) velocimetry instrument to characterize flow fields in a capillary tube is demonstrated. This inexpensive compact system is achieved with a 0.6 T permanent magnetic configuration (Larmor frequency of 25 MHz) and temperature compensation using off-the-shelf NdFeB permanent magnets. A triaxial gradient module with microfabricated copper coils using a lithographic fabrication process has been developed. This gradient module is capable of generating fast-switching gradients (<100 micros) with amplitudes up to 1.7 T/m using custom made current amplifiers, and was optimized for microflow imaging. The radio frequency probe is integrated with the gradient module and is driven by custom electronics. A two-dimensional (2D) cross-sectional static image of the inside of a capillary tube with an inner diameter of 1.67 mm is acquired at an in-plane spatial resolution of better than 40 microm. Time-of-flight flow measurements were also obtained using this MRI system to measure the velocity profile of water flowing at average velocities of above 50 mm/s. The flow profile for slower flow velocities was obtained using phase-encoded techniques, which provides quantitative velocity information in 2D. PMID- 20192502 TI - Development, analysis and control of a high-speed laser-free atomic force microscope. AB - This paper presents the development and control of a laser-free atomic force microscopy (AFM) system for high-speed imaging of micro- and nanostructured materials. The setup uses a self-sensing piezoresistive microcantilever with nanometer accuracy to abolish the need for a bulky and expensive laser measurement system. A basic model for the interaction dynamics of AFM tip and sample in the high-speed open-loop imaging mode is proposed, accounting for their possible separation. The effects of microcantilever and sample stiffness and damping coefficients on the accuracy of imaging are studied through a set of frequency-domain simulations. To improve the speed of operation, a Lyapunov-based robust adaptive control law is used for the AFM XY scanning stage. It is shown that the proposed controller overcomes the frequency limits of the PID (Proportional-Integral-Derivative) controllers typically used in AFM. Finally, the paper presents a set of experiments on a standard calibration sample with 200 nm stepped topography, indicating accurate imaging up to the scanning frequency of 30 Hz. PMID- 20192503 TI - Strain sensing with submicron Al-AlO(x)-Al tunnel junctions. AB - We demonstrate a local strain sensing method for nanostructures based on metallic Al tunnel junctions with AlO(x) barriers. The junctions were fabricated on top of a thin silicon nitride membrane, which was actuated with an atomic force microscope tip attached to a stiff cantilever. A large relative change in the tunneling resistance in response to the applied strain (gauge factor) was observed up to a value of 37. This facilitates local static strain variation measurements down to approximately 10(-7). This type of strain sensor could have applications in nanoelectromechanical systems used in displacement, force, and mass sensing, for example. PMID- 20192504 TI - In situ temperature measurements through i-anvils in diamond anvil cells. AB - This study is devoted to in situ temperature measurement in diamond anvil cells (DACs) with intelligent anvils (i-anvils). I-anvils consist of diamonds implanted with B and/or C ions, situated below the diamond's surface at a depth of 1-3 microm; forming sensors which are placed below the culet at the location of the DAC's sample chamber. I-anvils can be employed as temperature or pressure sensors, exploiting their electrical properties. We have tested the sensor's behavior with temperatures up to 900 degrees C, at ambient pressure and up to 6 GPa in real experimental conditions in two types of DAC. For this purpose, we performed experiments in four different i-anvils at temperatures up to 900 degrees C. We have compared the signal measured by the sensors with the temperature measured by a thermocouple attached to the i-anvil. The temperature gradient between the sample chamber and the thermocouple position was taken into account by phase transition measurements of calibration standards. Reproducible laws of current variation with temperature have been established. We conclude that i-anvils are reliable and sensitive to measure the temperature in-situ in DACs with an accuracy of better than 1 degree C. PMID- 20192505 TI - Development and operation of research-scale III-V nanowire growth reactors. AB - III-V nanowires are useful platforms for studying the electronic and mechanical properties of materials at the nanometer scale. However, the costs associated with commercial nanowire growth reactors are prohibitive for most research groups. We developed hot-wall and cold-wall metal organic vapor phase epitaxy reactors for the growth of InAs nanowires, which both use the same gas handling system. The hot-wall reactor is based on an inexpensive quartz tube furnace and yields InAs nanowires for a narrow range of operating conditions. Improvement of crystal quality and an increase in growth run to growth run reproducibility are obtained using a homebuilt UHV cold-wall reactor with a base pressure of 2x10(-9) Torr. A load lock on the UHV reactor prevents the growth chamber from being exposed to atmospheric conditions during sample transfers. Nanowires grown in the cold-wall system have a low defect density, as determined using transmission electron microscopy, and exhibit field effect gating with mobilities approaching 16,000 cm(2)/(V s). PMID- 20192506 TI - Selection and generation of waveforms for differential mobility spectrometry. AB - Devices based on differential mobility spectrometry (DMS) are used in a number of ways, including applications as ion prefilters for API-MS systems, as detectors or selectors in hybrid instruments (GC-DMS, DMS-IMS), and in standalone systems for chemical detection and identification. DMS ion separation is based on the relative difference between high field and low field ion mobility known as the alpha dependence, and requires the application of an intense asymmetric electric field known as the DMS separation field, typically in the megahertz frequency range. DMS performance depends on the waveform and on the magnitude of this separation field. In this paper, we analyze the relationship between separation waveform and DMS resolution and consider feasible separation field generators. We examine ideal and practical DMS separation field waveforms and discuss separation field generator circuit types and their implementations. To facilitate optimization of the generator designs, we present a set of relations that connect ion alpha dependence to DMS separation fields. Using these relationships we evaluate the DMS separation power of common generator types as a function of their waveform parameters. Optimal waveforms for the major types of DMS separation generators are determined for ions with various alpha dependences. These calculations are validated by comparison with experimental data. PMID- 20192507 TI - Improved pyroelectric detectors for single crystal adsorption calorimetry from 100 to 350 K. AB - The adsorption of atoms and molecules on single crystal surfaces allows one to produce well-characterized atomic, molecular, or dissociated adsorbates. Microcalorimetric measurement of the resulting adsorption energies, i.e., single crystal adsorption calorimetry, allows determination of the standard enthalpies of formation of these adsorbates. Methods are described for making an improved heat detector for such measurements, which greatly improves the signal-to-noise ratio, particularly at low temperatures (down to 100 K). The heat detector is an adaptation of a previously introduced design, based on a metallized pyroelectric polymer (beta-polyvinylidene fluoride), which is pressed against the back of a single crystal during measurement but removed during sample preparation and annealing. The improvement is achieved by selectively etching the metal coating of the polymer, thus reducing the pyro- and piezoelectric noise from all nonessential regions of the polymer. We, furthermore, describe how to achieve a better thermal contact between the sample and the pyroelectric polymer, without increasing the thermal mass of the detector, resulting in significantly improved sensitivities for both 1 and 127 microm thick samples. The result is a detector which, using 1 microm samples, is approximately 40 times more sensitive at 100 K than the traditional polymer-based detector, showing a pulse-to-pulse standard deviation in the heat of adsorption of just 1.3 kJ/mol with gas pulses containing only 1.1% of a monolayer onto Pt(111), for which 1 ML (monolayer) is 1.5x10(15) species/cm(2). For measurements at 300 K, where especially pyroelectric noise is likely of less concern, the new design improves the sensitivity 3.6-fold compared to the traditional detector. These improvements are furthermore used to propose a new detector design that is able to measure heats of adsorption on samples as thick as 127 microm with reasonable sensitivity. PMID- 20192508 TI - Synchronous measurement of even and odd order intermodulation distortion at the resonant frequency of a superconducting resonator. AB - A method has been developed that uses three input tones to measure both even and odd order intermodulation distortions (IMDs) inside the pass band of resonant devices. With this technique the surface current density of both the driving signal and the IMD tones can be quantified. Synchronous, or same frequency, measurement of both even and odd order distortions permits quantitative comparison of the respective nonlinearity currents measured within the same time scale. As an example of this technique, a superconducting resonator is used to generate even and odd order IMDs at the same frequency, resulting in physical conclusions, which are pertinent to current research in high temperature superconductors. While varying the level of only one tone, the expected slope of the IMD current versus the driving signal current for both orders is unity, but that is only observed at high temperature when the superconductor becomes very lossy. An observed smaller slope at lower temperatures gives support to the linear-nonlinear interaction model. Also, a sharp increase in the third order IMD relative to the second order IMD near T(C) gives support to a substantial nonlinear Meissner effect. PMID- 20192509 TI - A cryogenic analog to digital converter operating from 300 K down to 4.4 K. AB - This paper presents a cryogenic successive approximation register (SAR) based analog to digital converter (ADC) implemented in a standard 0.35 microm complementary metal oxide semiconductor (CMOS) process. It operates from room temperature down to 4.4 K, achieving 10.47 effective number of bits (ENOB) at room temperature. At 4.4 K, the ADC achieves 8.53 ENOB at 50 kS/s sampling rate with a current consumption of 90 microA from a 3.3 V supply. The ADC utilizes an improved comparator architecture, which performs offset cancellation by using preamplifiers designed for cryogenic operation. The conventional offset cancellation algorithm is also modified in order to eliminate the effect of cryogenic anomalies below freeze-out temperature. The power efficiency is significantly improved compared to the state of the art semiconductor ADCs operating in the same temperature range. PMID- 20192510 TI - Multichannel, time-resolved picosecond laser ultrasound imaging and spectroscopy with custom complementary metal-oxide-semiconductor detector. AB - This paper presents a multichannel, time-resolved picosecond laser ultrasound system that uses a custom complementary metal-oxide-semiconductor linear array detector. This novel sensor allows parallel phase-sensitive detection of very low contrast modulated signals with performance in each channel comparable to that of a discrete photodiode and a lock-in amplifier. Application of the instrument is demonstrated by parallelizing spatial measurements to produce two-dimensional thickness maps on a layered sample, and spectroscopic parallelization is demonstrated by presenting the measured Brillouin oscillations from a gallium arsenide wafer. This paper demonstrates the significant advantages of our approach to pump probe systems, especially picosecond ultrasonics. PMID- 20192511 TI - A dual-beam photothermal reflection based system for thermal diffusivity measurement of optically dense liquids. AB - A dual-beam photothermal reflection based system capable to measure thermal diffusivities of optically dense liquids has been designed and implemented. The large optical absorption coefficient of these liquids inhibits the possibility to use conventional transmission instruments for direct thermal diffusivity measurements. To overcome this problem, a front heating front detection photothermal reflection system has been proposed. This method expands the range of application and simplifies the experimental procedure of traditional photothermal methods, allowing precise measurement of thermal diffusivity of a variety of liquids. Measurements of the change in thermal diffusivity with the concentration of asphaltene in toluene solutions are described to test the applicability of this technique for reliable measurements of thermal diffusivities of optically dense liquids. PMID- 20192512 TI - A multichamber system for analyzing the outgassing, deposition, and associated optical degradation properties of materials in a vacuum. AB - We report on the camera materials test chamber, a multivessel apparatus that analyzes the outgassing consequences of candidate materials for use in the vacuum cryostat of a new telescope camera. The system measures the outgassing products and rates of samples of materials at different temperatures and collects films of outgassing products to measure the effects on light transmission in six optical bands. The design of the apparatus minimizes potential measurement errors introduced by background contamination. PMID- 20192513 TI - ELISA: a cryocooled 10 GHz oscillator with 10(-15) frequency stability. AB - This article reports the design, the breadboarding, and the validation of an ultrastable cryogenic sapphire oscillator operated in an autonomous cryocooler. The objective of this project was to demonstrate the feasibility of a frequency stability of 3x10(-15) between 1 and 1000 s for the European Space Agency deep space stations. This represents the lowest fractional frequency instability ever achieved with cryocoolers. The preliminary results presented in this paper validate the design we adopted for the sapphire resonator, the cold source, and the oscillator loop. PMID- 20192514 TI - Removal of a hydrogenated amorphous carbon film from the tip of a micropipette electrode using direct current corona discharge. AB - Micropipette electrodes are fabricated by coating glass micropipettes first with metal and then with hydrogenated amorphous carbon (a-C:H) as an electrical insulator. Furthermore, at the tip of the micropipette electrode, the deposited a C:H film needs to be removed to expose the metal-coated surface and hollow for the purposes of electrical measurement and injection. This paper describes a convenient and reliable method for removing the a-C:H film using direct current corona discharge in atmospheric air. The initial film removal occurred at an applied voltage of 1.5-2.0 kV, accompanied by an abrupt increase in the discharge current. The discharge current then became stable at a microampere level in the glow corona mode, and the removed area gradually extended. PMID- 20192515 TI - Calibration of low-temperature ac susceptometers with a copper cylinder standard. AB - A high-quality low-temperature ac susceptometer is calibrated by comparing the measured ac susceptibility of a copper cylinder with its eddy-current ac susceptibility accurately calculated. Different from conventional calibration techniques that compare the measured results with the known property of a standard sample at certain fixed temperature T, field amplitude H(m), and frequency f, to get a magnitude correction factor, here, the electromagnetic properties of the copper cylinder are unknown and are determined during the calibration of the ac susceptometer in the entire T, H(m), and f range. It is shown that the maximum magnitude error and the maximum phase error of the susceptometer are less than 0.7% and 0.3 degrees, respectively, in the region T=5 300 K and f=111-1111 Hz at H(m)=800 A/m, after a magnitude correction by a constant factor as done in a conventional calibration. However, the magnitude and phase errors can reach 2% and 4.3 degrees at 10,000 and 11 Hz, respectively. Since the errors are reproducible, a large portion of them may be further corrected after a calibration, the procedure for which is given. Conceptual discussions concerning the error sources, comparison with other calibration methods, and applications of ac susceptibility techniques are presented. PMID- 20192516 TI - Elimination of drift in a fiber-Bragg-grating-based multiplexed Michelson interferometer measurement system. AB - Random phase drift in single-mode optical fiber interferometers used with measurement systems, which is resulted from various types of environmental disturbances, should be eliminated in order to obtain high measurement precision. We propose an optical fiber interferometric measurement system which has the function of self-eliminating the random phase drift and is stable and robust enough for real-time precision measurement. By employing the characteristics of fiber Bragg gratings, the system interleaves two fiber Michelson interferometers together that share the common-interferometric-optical path. The signal of one of the interferometers is used to stabilize the system while the signal of the other interferometer is used for measurement. An electronic feedback loop for the stabilizing action is designed. The bandwidth of the feedback loop is 5 kHz, sufficiently wide to eliminate random phase drift resulted from various environmental disturbances. The system is endowed with high stability and therefore suitable for real-time precision measurement. By means of an active phase tracking technique to measure displacement, the linear regression coefficient of the displacement measurement results is 0.9998. PMID- 20192517 TI - Highly sensitive passive radio frequency identification based sensor systems. AB - A novel platform for sensor applications based on radio frequency (rf) identification technology, where passive tags are powered by the rf-field of a reader, is presented. The sophisticated energy harvesting system of the tag enables a blanking of the rf-field for a defined period, while supplying the tag electronics with a highly stable voltage and a power of 25 mW for 100 ms. During this time, span measurements can be performed without interferences of the rf field. The presented tags work without batteries and are designed for impedance measurements on microbiological cell cultures under physiological relevant conditions as well as in harsh environments. PMID- 20192518 TI - Note: Large rotation measurement using half shaded square patterns. AB - As the manufacturing technology ranging from micrometer to nanometer scale requires more planar motion devices, the demand for sensor measuring the planar motion is increasing. However, the previous sensors measuring the planar motion had a drawback in the measurement of rotation, especially regarding yaw angle. In this article, we present a novel method to measure large yaw angle with the planar position sensor based on the half shaded square patterns. The measuring range of the yaw angle is restricted to 45 degrees in this article, but it can be expanded to as much as 360 degrees with an improvement of the algorithm. PMID- 20192519 TI - Note: Sensitivity enhancement in continuous-wave electron paramagnetic resonance: adaptive signal averaging versus a moving average. AB - We compare improvements in signal-to-noise in continuous-wave electron paramagnetic resonance (CW EPR) spectra resulting from adaptive signal averaging and a simple moving average. An adaptive filter module that uses a recursive least-squares (RLS) algorithm was incorporated into a CW EPR data acquisition program. After optimization, the RLS filter produces a significant improvement in the signal-to-noise ratio over conventional digital signal (spectral) averaging alone. However, conventional averaging of spectra combined with a central moving average of the data points provided equal or greater signal-to-noise improvement in the CW EPR spectra. PMID- 20192520 TI - Note: Construction of x-ray scattering and x-ray absorption fine structure beamline at the Pohang Light Source. AB - A new hard x-ray beamline, 10B KIST-PAL beamline (BL10B), has been designed and constructed at the Pohang Light Source (PLS) in Korea. The beamline, operated by Pohang Accelerator Laboratory-Korean Institute of Science and Technology consortium, is dedicated to x-ray scattering (XRS) and x-ray absorption fine structure (XAFS) experiments. X rays with photon energies from 4.0 to 16.0 keV are delivered to the experimental station passing a collimating mirror, a fixed exit double-crystal Si(111) monochromator, and a toroidal mirror. Basic experimental equipment for XAFS measurement, a high resolution diffractometry, an image plate detector system, and a hot stage have been prepared for the station. From our initial commissioning and performance testing of the beamline, it is observed that BL10B beamline can perform XRS and XAFS measurements successfully. PMID- 20192521 TI - Note: Lateral force microscope calibration using multiple location pivot loading of rectangular cantilevers. AB - This note outlines a calibration method for atomic force microscope friction measurement that uses the "pivot" method of [Bogdanovic et al., Colloids Surf. B 19, 397 (2000)] to generate optical lever sensitivities for known torque applied to rectangular cantilevers. We demonstrate the key calibration parameter to be a linear function of the position at which it is determined along the length of the cantilevers. In this way the optical lever system can be calibrated for cantilever torque by applying loads at locations along the length of a cantilever, away from the integrated tip, so that issues such as tip damage or interference can be avoided. PMID- 20192522 TI - Note: Probing quadratic magneto-optical Kerr effects with a dual-beam system. AB - In this Note, we present a dual-beam magneto-optical Kerr effect (MOKE) magnetometer for the study of quadratic MOKE in magnetic thin films. The two beams simultaneously probe the sample, located in the middle of a quadrupole magnet, at two angles of incidence (0 degrees and 45 degrees). This combination of two systems allows one to automatically and routinely perform measurements that are sensitive to the combined longitudinal and quadratic MOKE signals (45 degrees), or the quadratic effect alone (0 degrees). Orientation-dependent and automated quantitative analyses of the quadratic effect's amplitude are also implemented. We present representative measurements on Heusler compound thin films to illustrate the newly combined capabilities of this instrument. PMID- 20192523 TI - Note: High-precision microsphere sorting using velocity sedimentation. AB - Monodisperse populations of microspheres are desirable for a variety of research and industrial applications, but many desirable sizes and materials can be difficult to synthesize and have limited commercial availability. In this paper, we present an effective, straightforward, and low cost method for sorting polydisperse microspheres into many separate monodisperse samples. The basic approach is to use velocity sedimentation through a density gradient in a long vertical column, followed by carefully targeted extraction. We demonstrate this technique by reducing the coefficient of variation of melamine microspheres from 13% to 1%-4% and glass microspheres from 35% to 3%-8%. This simple and inexpensive method can be used to sort microspheres of many sizes and materials, and is easily scalable, opening the possibility of cheap, monodisperse microspheres. PMID- 20192524 TI - Note: Application of laser produced plasma K alpha x-ray probe in radiation biology. AB - A dedicated radiation biology x-ray generation and exposure system has been developed. 8.0 keV in energy x-ray pulses generated with a femtosecond-laser pulse was used to irradiate sample cells through a custom-made culture dish with a silicon nitride membrane. The x-ray irradiation resulted in DNA double-strand breaks in the nucleus of a culture cell that were similar to those obtained with a conventional x-ray source, thus demonstrating the feasibility of radiobiological studies utilizing a single burst of x-rays focused on single cell specimens. PMID- 20192525 TI - Note: An ultranarrow bandpass filter system for single-photon experiments in quantum optics. AB - We describe a combined ultranarrow bandpass filtering setup for single-photon experiments in quantum optics. The filter is particularly suitable for single photon electromagnetically induced transparency (EIT) experiments, but can also be used in several similar applications. A multipass planar Fabry-Perot etalon together with polarization filters and spatial filtering allows 114 dB pump beam suppression, while the signal beam is attenuated by just 4 dB, although both wavelengths are only separated by 0.025 nm (9.2 GHz). The multipass etalon alone accounts for 46 dB suppression while it has a peak transmission of 65%. We demonstrate EIT experiments in Cs vapor at room temperature with probe power in the femtowatt regime using this filter. PMID- 20192526 TI - Note: Toward multiple addressable optical trapping. AB - We describe a setup for addressable optical trapping in which a laser source is focused on a digital micromirror device and generates an optical trap in a microfluidic cell. In this paper, we report a proof-of-principle single beam/single micromirror/single three-dimensional trap arrangement that should serve as the basis for a multiple-trap instrument. PMID- 20192529 TI - Retraction: "A new eye-safe lidar design for studying atmospheric aerosol distributions" [Rev. Sci. Instrum. 80, 035109 (2009)]. PMID- 20192530 TI - Uncertainty in category-based induction: when do people integrate across categories? AB - Two experiments investigated how people perform category-based induction for items that have uncertain categorization. Whereas normative considerations suggest that people should consider multiple relevant categories, much past research has argued that people focus on only the most likely category. A new method is introduced in which responses on individual trials can be classified as using single or multiple categories, an improvement on past methods that relied on null effects as evidence for single-category use. Experiment 1 found that people did use multiple categories when the most likely category gave an ambiguous induction but that few people did so when it gave an unambiguous induction. Experiment 2 suggested that the reluctance to use multiple categories arose from a cognitive shortcut, in which only one source of information is consulted. The experiments revealed significant individual differences, suggesting that use of multiple categories is one of a number of strategies that can be used rather than being the basis for most category-based induction. PMID- 20192531 TI - Multiple sources of competence underlying the comprehension of inconsistencies: A developmental investigation. AB - How do children know the sentence "the glass is empty and not empty" is inconsistent? One possibility is that they are sensitive to the formal structure of the sentences and know that a proposition and its negation cannot be jointly true. Alternatively, they could represent the 2 state of affairs referred to and realize that these are incommensurate, that is, that a glass cannot simultaneously be empty and contain something. In 2 studies, the authors investigated how children (N = 186; ages 4-8) acquire competence to notice inconsistencies. The authors found that children could determine that 2 states of affairs were incommensurate before being able to determine that statements of the form p and not-p were inconsistent. The results demonstrate that competence in understanding inconsistent relations depends on (a) the ability to represent 2 states of affairs and (b) the ability to process negation in the context of an inconsistency. The authors discuss these results in relation to sources of competence that may underlie the assessment of such simple inconsistencies. PMID- 20192532 TI - The influence of interactional semantic patterns on the interpretation of noun noun compounds. AB - The CARIN theory (C. L. Gagne & E. J. Shoben, 1997) proposes that people use statistical knowledge about the relations with which modifiers are typically used to facilitate the interpretation of modifier-noun combinations. However, research on semantic patterns in compounding has suggested that regularities tend to be associated with pairings of semantic categories, rather than individual concepts (e.g., P. Maguire, E. J. Wisniewski, & G. Storms, in press; B. Warren, 1978). In the present study, the authors investigated whether people are sensitive to interactional semantic patterns in compounding. Experiment 1 demonstrated that the influence of a given modifier on ease of interpretation varies depending on the semantic category of the head. Experiment 2 demonstrated that the relation preference of the head noun influences ease of interpretation when the semantic category of the modifier is compatible with that preference. In light of these findings, the authors suggest that people are sensitive to how different semantic categories tend to be paired in combination and that this information is used to facilitate the interpretation process. PMID- 20192533 TI - Conditional reasoning in context: a dual-source model of probabilistic inference. AB - A dual-source model of probabilistic conditional inference is proposed. According to the model, inferences are based on 2 sources of evidence: logical form and prior knowledge. Logical form is a decontextualized source of evidence, whereas prior knowledge is activated by the contents of the conditional rule. In Experiments 1 to 3, manipulations of perceived sufficiency and necessity mapped on the parameters quantifying prior knowledge. Emphasizing rule validity increased the weight given to form-based evidence relative to knowledge-based evidence (Experiment 1). Manipulating rule form (only-if vs. if-then) had a focused effect on the parameters quantifying form-based evidence (Experiment 3). The model also provides a parsimonious description of data from the so-called negations paradigm and adequately accounts for polarity bias in that paradigm (Experiment 4). Relationships to alternative conceptualizations of conditional inference are discussed. PMID- 20192534 TI - Dissociating conditional recency in immediate and delayed free recall: a challenge for unitary models of recency. AB - Temporal distinctiveness models of recency in free recall predict that increasing the delay between the end of sequence and attempting recall of items from that sequence will reduce recency. An empirical dissociation is reported here that violates this prediction when the delay is introduced by the act of recall itself. Analysis of data from a number of previously published free recall studies shows that when the assumed availability of final list items is taken into account, recency increases across the first few output positions in immediate recall despite the delay introduced by recalling items; no such change, with a trend to decreasing recency, is observed in delayed recall. Simulations are presented, showing that 2 models accounting for recency in free recall, the temporal context model (M. W. Howard & M. J. Kahana, 2002) and the SIMPLE model (G. D. A. Brown, I. Neath, & N. Chater, 2007), are unable to account for this novel pattern of data. Further simulations show that the results are consistent with a short-term buffer contributing to recency in immediate free recall and that ordered probing of items may also contribute to this effect; both of these are consistent with the formulation of a short-term buffer akin to models of serial recall. PMID- 20192535 TI - Bottom-up influences on voluntary task switching: the elusive homunculus escapes. AB - Voluntary action can be studied by giving participants free choice over which task to perform in response to each presented stimulus. In such experiments, performance costs are observed when participants choose to switch tasks from the previous trial. It has been proposed that these costs primarily index the time consuming operation of top-down control processes that support voluntary action. The present experiments showed, contrary to this view, that greater costs were associated with voluntary switching to the easier task of a pair. These increased switch costs for the easier task were accompanied by a reliable preference of the participants for performing the other, more difficult task. Interference between tasks during response selection was identified as the critical factor driving these effects of task difficulty. Together, the findings suggest that participants' voluntary choices, and the time taken to execute those choices, may not directly index the operation of cognitive control but instead may reflect complex interactions between top-down and bottom-up influences on behavior. PMID- 20192536 TI - The problem state: a cognitive bottleneck in multitasking. AB - The main challenge for theories of multitasking is to predict when and how tasks interfere. Here, we focus on interference related to the problem state, a directly accessible intermediate representation of the current state of a task. On the basis of Salvucci and Taatgen's (2008) threaded cognition theory, we predict interference if 2 or more tasks require a problem state but not when only one task requires one. This prediction was tested in a series of 3 experiments. In Experiment 1, a subtraction task and a text entry task had to be carried out concurrently. Both tasks were presented in 2 versions: one that required maintaining a problem state and one that did not. A significant overadditive interaction effect was observed, showing that the interference between tasks was maximal when both tasks required a problem state. The other 2 experiments tested whether the interference was indeed due to a problem state bottleneck, instead of cognitive load (Experiment 2: an alternative subtraction and text entry experiment) or a phonological loop bottleneck (Experiment 3: a triple-task experiment that added phonological processing). Both experiments supported the problem state hypothesis. To account for the observed behavior, computational cognitive models were developed using threaded cognition within the context of the cognitive architecture ACT-R (Anderson, 2007). The models confirm that a problem state bottleneck can explain the observed interference. PMID- 20192537 TI - Relationship between measures of working memory capacity and the time course of short-term memory retrieval and interference resolution. AB - The response-signal speed-accuracy trade-off (SAT) procedure was used to investigate the relationship between measures of working memory capacity and the time course of short-term item recognition. High- and low-span participants studied sequentially presented 6-item lists, immediately followed by a recognition probe. Analyses of composite list and serial position SAT functions found no differences in retrieval speed between the 2 span groups. Overall accuracy was higher for high spans than low spans, with more pronounced differences for earlier serial positions. Analysis of false alarms to recent negatives (lures from the previous study list) revealed no differences in the timing or magnitude of early false alarms, thought to reflect familiarity-based judgments. However, analyses of false alarms later in retrieval indicated that recollective information accrues more slowly for low spans, which suggests that recollective information may also contribute less to judgments concerning studied items for low-span participants. These findings can provide an explanation for the greater susceptibility of low spans to interference. PMID- 20192538 TI - Source memory for unidentified stimuli. AB - Two experiments were conducted to determine whether participants have source memory for test stimuli that they cannot identify. Using a paradigm developed to investigate the phenomenon of recognition without identification (Peynircioglu, 1990), we found that even when participants could not identify a previously studied item, they nonetheless exhibited above-chance performance on a source discrimination task. Most surprising was that source accuracy for unidentified items was independent of old-new discrimination and not different from that of identified items. These results are interpreted as evidence that source memory is based on a continuous, as opposed to a threshold-like, process and suggest that recollection may, in some circumstances, contribute to the phenomenon of recognition without identification. PMID- 20192539 TI - Attention and facilitation: converging information versus inadvertent reading in Stroop task performance. AB - Disagreement exists about whether color-word Stroop facilitation is caused by converging information (e.g., Cohen et al., 1990; Roelofs, 2003) or inadvertent reading (MacLeod & MacDonald, 2000). Four experiments tested between these hypotheses by examining Stroop effects on response time (RT) both within and between languages. Words cannot be read aloud to produce facilitation between languages. Dutch-English bilingual participants named color patches while trying to ignore Dutch or English color words presented at a wide range of preexposure and postexposure stimulus onset asynchronies. The color patches were named in Dutch (Experiments 1 and 2) or English (Experiments 3 and 4). In all experiments, Stroop facilitation and interference effects were obtained in mean RTs with similar time courses within and between languages. Facilitation was generally present throughout the entire RT distributions. These results suggest that Stroop interference and facilitation have a common locus within and between languages, supporting the converging information hypothesis of Stroop facilitation. PMID- 20192540 TI - On the flexibility of grammatical advance planning during sentence production: Effects of cognitive load on multiple lexical access. AB - Three picture-word interference experiments addressed the question of whether the scope of grammatical advance planning in sentence production corresponds to some fixed unit or rather is flexible. Subjects produced sentences of different formats under varying amounts of cognitive load. When speakers described 2-object displays with simple sentences of the form "the frog is next to the mug," the 2 nouns were found to be lexically-semantically activated to similar degrees at speech onset, as indexed by similarly sized interference effects from semantic distractors related to either the first or the second noun. When speakers used more complex sentences (including prenominal color adjectives; e.g., "the blue frog is next to the blue mug") much larger interference effects were observed for the first than the second noun, suggesting that the second noun was lexically semantically activated before speech onset on only a subset of trials. With increased cognitive load, introduced by an additional conceptual decision task and variable utterance formats, the interference effect for the first noun was increased and the interference effect for second noun disappeared, suggesting that the scope of advance planning had been narrowed. By contrast, if cognitive load was induced by a secondary working memory task to be performed during speech planning, the interference effect for both nouns was increased, suggesting that the scope of advance planning had not been affected. In all, the data suggest that the scope of advance planning during grammatical encoding in sentence production is flexible, rather than structurally fixed. PMID- 20192541 TI - Working memory enhances visual perception: evidence from signal detection analysis. AB - We show that perceptual sensitivity to visual stimuli can be modulated by matches between the contents of working memory (WM) and stimuli in the visual field. Observers were presented with an object cue (to hold in WM or to merely attend) and subsequently had to identify a brief target presented within a colored shape. The cue could be re-presented in the display, where it surrounded either the target (on valid trials) or a distractor (on invalid trials). Perceptual identification of the target, as indexed by A', was enhanced on valid relative to invalid trials but only when the cue was kept in WM. There was minimal effect of the cue when it was merely attended and not kept in WM. Verbal cues were as effective as visual cues at modulating perceptual identification, and the effects were independent of the effects of target saliency. Matches to the contents of WM influenced perceptual sensitivity even under conditions that minimized competition for selecting the target. WM cues were also effective when targets were less likely to fall in a repeated WM stimulus than in other stimuli in the search display. There were no effects of WM on decisional criteria, in contrast to sensitivity. The findings suggest that reentrant feedback from WM can affect early stages of perceptual processing. PMID- 20192542 TI - Visual word recognition during reading is followed by subvocal articulation. AB - Three experiments examined whether the identification of a visual word is followed by its subvocal articulation during reading. An irrelevant spoken word (ISW) that was identical, phonologically similar, or dissimilar to a visual target word was presented when the eyes moved to the target in the course of sentence reading. Sentence reading was further accompanied by either a sequential finger tapping task (Experiment 1) or an articulatory suppression task (Experiment 2). Experiment 1 revealed sound-specific interference from a phonologically similar ISW during posttarget viewing. This interference was absent in Experiment 2, where similar and dissimilar ISWs impeded target and posttarget reading equally. Experiment 3 showed that articulatory suppression left the lexical processing of visual words intact and that it did not diminish the influence of visual word recognition on eye guidance. The presence of sound specific interference during posttarget reading in Experiment 1 is attributed to deleterious effects of a phonologically similar ISW on the subvocal articulation of a target. Its absence in Experiment 2 is attributed to the suppression of a target's subvocal articulation. PMID- 20192543 TI - Similarities and differences between working memory and long-term memory: evidence from the levels-of-processing span task. AB - Two experiments compared the effects of depth of processing on working memory (WM) and long-term memory (LTM) using a levels-of-processing (LOP) span task, a newly developed WM span procedure that involves processing to-be-remembered words based on their visual, phonological, or semantic characteristics. Depth of processing had minimal effect on WM tests, yet subsequent memory for the same items on delayed tests showed the typical benefits of semantic processing. Although the difference in LOP effects demonstrates a dissociation between WM and LTM, we also found that the retrieval practice provided by recalling words on the WM task benefited long-term retention, especially for words initially recalled from supraspan lists. The latter result is consistent with the hypothesis that WM span tasks involve retrieval from secondary memory, but the LOP dissociation suggests the processes engaged by WM and LTM tests may differ. Therefore, similarities and differences between WM and LTM depend on the extent to which retrieval from secondary memory is involved and whether there is a match (or mismatch) between initial processing and subsequent retrieval, consistent with transfer-appropriate-processing theory. PMID- 20192544 TI - Differentiation and response bias in episodic memory: evidence from reaction time distributions. AB - In differentiation models, the processes of encoding and retrieval produce an increase in the distribution of memory strength for targets and a decrease in the distribution of memory strength for foils as the amount of encoding increases. This produces an increase in the hit rate and decrease in the false-alarm rate for a strongly encoded compared with a weakly encoded list, consistent with empirical data. Other models assume that the foil distribution is unaffected by encoding manipulations or the foil distribution increases as a function of target strength. They account for the empirical data by adopting a stricter criterion for strongly encoded lists relative to weakly encoded lists. The differentiation and criterion shift explanations have been difficult to discriminate with accuracy measures alone. In this article, reaction time distributions and accuracy measures are collected in a list-strength paradigm and in a response bias paradigm in which the proportion of test items that are targets is manipulated. Diffusion model analyses showed that encoding strength is primarily accounted for by changes in the rate of accumulation of evidence (i.e., drift rate) for both targets and foils and manipulating the proportion of targets is primarily accounted for by changes in response bias (i.e., starting point). The diffusion model analyses is interpreted in terms of predictions of the differentiation models in which subjective memory strength is mapped directly onto drift rate and criterion placement is mapped onto starting point. Criterion shift models require at least 2 types of shifts to account for these findings. PMID- 20192545 TI - Strategy selection and use during classification skill acquisition. AB - Two experiments examined 3 variables affecting accuracy, response time, and reports of strategy use in a binary classification skill task. In Experiment 1, higher rule cue salience, allowing faster rule application, produced higher aggregate rule use than lower rule cue salience. After participants were pretrained on the relevant classification rule, rule reports were high but generally declined across training trials; after participants were pretrained on an irrelevant rule, reports of the relevant rule increased across training trials. In Experiment 2, no rule pretraining produced a pattern of results like that obtained with irrelevant rule pretraining in Experiment 1. Presenting novel stimuli during training in Experiment 2 elevated aggregate rule reports relative to conditions where they were absent. Two participant subgroups were identified: those persisting in rule reports and those transitioning from rule to memory reports during training. The proportion of persistent rule users was higher after rule discovery than after relevant rule pretraining. Overall, the results indicate that differences among prior experiments can be reconciled. Further, they raise questions about the inevitability of memory-based automaticity in binary classification, favoring instead strategy choice based on the costs and benefits of a particular strategy and of a shift from one strategy to another. PMID- 20192546 TI - The ubiquitous nature of the Hebb repetition effect: error learning mistaken for the absence of sequence learning. AB - Sequence learning is essential in cognition and underpins activities such as language and skill acquisition. One classical demonstration of sequence learning is that of the Hebb repetition effect, whereby serial recall improves over repetitions on a repeated list relative to random lists. When addressing the question of which mechanism underlies the effect, the traditional approach is to prevent the action of processes thought to be responsible for sequence learning: If the typical Hebb repetition effect is reduced, these processes are key to the effect, researchers claim. By reanalyzing the data of F. B. R. Parmentier, M. T. Maybery, M. Huitson, and D. M. Jones (2008)-who reported no Hebb effect for sequences of auditory-spatial stimuli-we revealed that error learning can be mistaken for the absence of sequence learning. Indeed, incorrect responses are reproduced increasingly over repetitions. Our findings suggest that the Hebb repetition effect can be associated with response learning as well as stimulus processing. PMID- 20192547 TI - The time course of name retrieval during multiple-object naming: evidence from extrafoveal-on-foveal effects. AB - The goal of the study was to examine whether speakers naming pairs of objects would retrieve the names of the objects in parallel or in sequence. To this end, we recorded the speakers' eye movements and determined whether the difficulty of retrieving the name of the 2nd object affected the duration of the gazes to the 1st object. Two experiments, which differed in the spatial arrangement of the objects, showed that the speakers looked longer at the 1st object when the name of the 2nd object was easy than when it was more difficult to retrieve. Thus, the easy 2nd-object names interfered more with the processing of the 1st object than the more difficult 2nd-object names. In the 3rd experiment, the processing of the 1st object was rendered more difficult by presenting it upside down. No effect of 2nd-object difficulty on the gaze duration for the 1st object was found. These results suggest that speakers can retrieve the names of a foveated and an extrafoveal object in parallel, provided that the processing of the foveated object is not too demanding. PMID- 20192548 TI - Effects of plausibility on structural priming. AB - We report a replication and extension of Ferreira (2003), in which it was observed that native adult English speakers misinterpret passive sentences that relate implausible but not impossible semantic relationships (e.g., The angler was caught by the fish) significantly more often than they do plausible passives or plausible or implausible active sentences. In the experiment reported here, participants listened to the same plausible and implausible passive and active sentences as in Ferreira (2003), answered comprehension questions, and then orally described line drawings of simple transitive actions. The descriptions were analyzed as a measure of structural priming (Bock, 1986). Question accuracy data replicated Ferreira (2003). Production data yielded an interaction: Passive descriptions were produced more often after plausible passives and implausible actives. We interpret these results as indicative of a language processor that proceeds along differentiated morphosyntactic and semantic routes. The processor may end up adjudicating between conflicting outputs from these routes by settling on a "good enough" representation that is not completely faithful to the input. PMID- 20192549 TI - Higher social intelligence can impair source memory. AB - Source monitoring is made difficult when the similarity between candidate sources increases. The current work examines how individual differences in social intelligence and perspective-taking abilities serve to increase source similarity and thus negatively impact source memory. Strangers first engaged in a cooperative storytelling task. On each trial, a single word was shown to both participants, but only 1 participant was designated to add a story sentence, using this assigned word. As predicted, social intelligence negatively predicted performance in a subsequent source-monitoring task. In a 2nd study, preventing participants from being able to anticipate their partner's next contribution to the story eliminated the effect. PMID- 20192550 TI - Comprehension as a basis for metacognitive judgments: effects of effort after meaning on recall and metacognition. AB - We examined free recall and metacognitive judgments of ambiguous sentences studied with and without clues to facilitate their comprehension. Sentences were either studied without clues, with clues meaningfully embedded, or with clues following a 10-s interval delay. After presentation, subjects made judgments of comprehension (JCOMPs) or judgments of learning (JOLs). Puzzling over the meaning of sentences for several seconds prior to receiving the clue enhanced recall compared with studying sentences without clues or with embedded clues. This benefit of effort after meaning was not reflected in JCOMPs or JOLs. Rather, sentences considered relatively easy to understand received higher JOLs regardless of experimental condition. Although effort after meaning enhanced recall, subjects displayed no awareness of this benefit in their judgments. Our study adds to a growing literature showing students' ignorance of factors affecting their own learning, which have important implications for education. Making learning conditions more difficult, thus requiring students to engage more cognitive effort, often leads to enhanced retention. PMID- 20192551 TI - Remember-Know and source memory instructions can qualitatively change old-new recognition accuracy: the modality-match effect in recognition memory. AB - Remember-Know (RK) and source memory tasks were designed to elucidate processes underlying memory retrieval. As part of more complex judgments, both tests produce a measure of old-new recognition, which is typically treated as equivalent to that derived from a standard recognition task. The present study demonstrates, however, that recognition accuracy can be qualitatively changed by a RK or source-retrieval orientation. Visual and auditory presentations of words were varied at encoding and at test. The memory test was either a standard (old new) recognition test, the RK test, or a source (modality) test. No effect of modality match was found on standard recognition. However, recognition accuracy in the RK and modality tests was greater when study and test modalities matched-a result obtained for both 1-step (e.g., R, K, or new?) and 2-step (e.g., old-new decision followed by RK decision for items judged old) versions of these tests. Thus, the RK and source (modality) memory procedures produced a measure of old new recognition that was qualitatively different than standard recognition, having a greater sensitivity to perceptual information. PMID- 20192552 TI - Do reaction times in the Perruchet effect reflect variations in the strength of an associative link? AB - In 3 experiments, we examined Perruchet, Cleeremans, and Destrebecqz's (2006) double dissociation of cued reaction time (RT) and target expectancy. In this design, participants receive a tone on every trial and are required to respond as quickly as possible to a square presented on 50% of those trials (a partial reinforcement schedule). Participants are faster to respond to the square following many recent tone-square pairings and slower to respond following many tone-alone presentations. Of importance, expectancy of the square is highest when performance on the RT task is poorest-following many tone-alone trials. This finding suggests that RT performance is determined by the strength of a tone square link and that this link is the product of a non-expectancy-based learning mechanism. The present experiments, however, provide evidence that the speeded RTs are not the consequence of the strengthening and weakening of a tone-square link. Thus, the RT Perruchet effect does not provide evidence for a non expectancy-based link-formation mechanism. PMID- 20192554 TI - Much ado about nothing: the misestimation and overinterpretation of violent video game effects in eastern and western nations: comment on Anderson et al. (2010). AB - The issue of violent video game influences on youth violence and aggression remains intensely debated in the scholarly literature and among the general public. Several recent meta-analyses, examining outcome measures most closely related to serious aggressive acts, found little evidence for a relationship between violent video games and aggression or violence. In a new meta-analysis, C. A. Anderson et al. (2010) questioned these findings. However, their analysis has several methodological issues that limit the interpretability of their results. In their analysis, C. A. Anderson et al. included many studies that do not relate well to serious aggression, an apparently biased sample of unpublished studies, and a "best practices" analysis that appears unreliable and does not consider the impact of unstandardized aggression measures on the inflation of effect size estimates. They also focused on bivariate correlations rather than better controlled estimates of effects. Despite a number of methodological flaws that all appear likely to inflate effect size estimates, the final estimate of r = .15 is still indicative of only weak effects. Contrasts between the claims of C. A. Anderson et al. (2010) and real-world data on youth violence are discussed. PMID- 20192553 TI - Violent video game effects on aggression, empathy, and prosocial behavior in eastern and western countries: a meta-analytic review. AB - Meta-analytic procedures were used to test the effects of violent video games on aggressive behavior, aggressive cognition, aggressive affect, physiological arousal, empathy/desensitization, and prosocial behavior. Unique features of this meta-analytic review include (a) more restrictive methodological quality inclusion criteria than in past meta-analyses; (b) cross-cultural comparisons; (c) longitudinal studies for all outcomes except physiological arousal; (d) conservative statistical controls; (e) multiple moderator analyses; and (f) sensitivity analyses. Social-cognitive models and cultural differences between Japan and Western countries were used to generate theory-based predictions. Meta analyses yielded significant effects for all 6 outcome variables. The pattern of results for different outcomes and research designs (experimental, cross sectional, longitudinal) fit theoretical predictions well. The evidence strongly suggests that exposure to violent video games is a causal risk factor for increased aggressive behavior, aggressive cognition, and aggressive affect and for decreased empathy and prosocial behavior. Moderator analyses revealed significant research design effects, weak evidence of cultural differences in susceptibility and type of measurement effects, and no evidence of sex differences in susceptibility. Results of various sensitivity analyses revealed these effects to be robust, with little evidence of selection (publication) bias. PMID- 20192555 TI - Nailing the coffin shut on doubts that violent video games stimulate aggression: comment on Anderson et al. (2010). AB - Over the past half century the mass media, including video games, have become important socializers of children. Observational learning theory has evolved into social-cognitive information processing models that explain that what a child observes in any venue has both short-term and long-term influences on the child's behaviors and cognitions. C. A. Anderson et al.'s (2010) extensive meta-analysis of the effects of violent video games confirms what these theories predict and what prior research about other violent mass media has found: that violent video games stimulate aggression in the players in the short run and increase the risk for aggressive behaviors by the players later in life. The effects occur for males and females and for children growing up in Eastern or Western cultures. The effects are strongest for the best studies. Contrary to some critics' assertions, the meta-analysis of C. A. Anderson et al. is methodologically sound and comprehensive. Yet the results of meta-analyses are unlikely to change the critics' views or the public's perception that the issue is undecided because some studies have yielded null effects, because many people are concerned that the implications of the research threaten freedom of expression, and because many people have their identities or self-interests closely tied to violent video games. PMID- 20192560 TI - Spontaneous repetitive thoughts can be adaptive: postscript on "mind wandering". AB - When researchers use the term mind wandering for task-unrelated thoughts in signal detection tasks, we may fall into the trap of believing that spontaneous thoughts are task unrelated in a deeper sense. Similar negative connotations are attached to common terms like cognitive failures, resting state, rumination, distraction, attentional failures, absent-mindedness, repetitiveness, mind lapses, going AWOL in the brain, cortical idling, and the like. Nevertheless, it seems obvious that mathematicians and scientists often engage in spontaneous repetitive thoughts and that the results of those thoughts are by no means maladaptive. Yet that seems to be implied by the standard use of common terms in the research literature. As humans, we know that spontaneous ideation goes on during all of our waking hours, during dreams and even in slow-wave sleep. It is unlikely that such a great allocation of mental resources has no useful adaptive function. This view of the spontaneous stream is consistent with the perspective of global workspace theory on conscious contents, which suggests that conscious events are not like unconscious cognitive representations. Rather, conscious events trigger widespread adaptive changes in the brain, far beyond their cortical origins. The brain evidence for such "global broadcasting" triggered by conscious (but not matched unconscious) events throughout the cortex is now quite compelling. Spontaneous conscious thoughts, even if they appear to be arbitrary, irrelevant, unwanted, or intrusive, may still play an important adaptive role in life-relevant problem solving and learning. PMID- 20192557 TI - Does mind wandering reflect executive function or executive failure? Comment on Smallwood and Schooler (2006) and Watkins (2008). AB - In this comment, we contrast different conceptions of mind wandering that were presented in 2 recent theoretical reviews: Smallwood and Schooler (2006) and Watkins (2008). We also introduce a new perspective on the role of executive control in mind wandering by integrating empirical evidence presented in Smallwood and Schooler with 2 theoretical frameworks: Watkins's elaborated control theory and Klinger's (1971, 2009) current concerns theory. In contrast to the Smallwood-Schooler claim that mind wandering recruits executive resources, we argue that mind wandering represents a failure of executive control and that it is dually determined by the presence of automatically generated thoughts in response to environmental and mental cues and the ability of the executive control system to deal with this interference. We present empirical support for this view from experimental, neuroimaging, and individual-differences research. PMID- 20192561 TI - Anxiety psychopathology in African American adults: literature review and development of an empirically informed sociocultural model. AB - In this review, the extant literature concerning anxiety psychopathology in African American adults is summarized to develop a testable, explanatory framework with implications for future research. The model was designed to account for purported lower rates of anxiety disorders in African Americans compared to European Americans, along with other ethnoracial differences reported in the literature. Three specific beliefs or attitudes related to the sociocultural experience of African Americans are identified: awareness of racism, stigma of mental illness, and salience of physical illnesses. In our model, we propose that these psychological processes influence interpretations and behaviors relevant to the expression of nonpathological anxiety as well as features of diagnosable anxiety conditions. Moreover, differences in these processes may explain the differential assessed rates of anxiety disorders in African Americans. The model is discussed in the context of existing models of anxiety etiology. Specific follow-up research is also suggested, along with implications for clinical assessment, diagnosis, and treatment. PMID- 20192563 TI - Making sense of the meaning literature: an integrative review of meaning making and its effects on adjustment to stressful life events. AB - Interest in meaning and meaning making in the context of stressful life events continues to grow, but research is hampered by conceptual and methodological limitations. Drawing on current theories, the author first presents an integrated model of meaning making. This model distinguishes between the constructs of global and situational meaning and between "meaning-making efforts" and "meaning made," and it elaborates subconstructs within these constructs. Using this model, the author reviews the empirical research regarding meaning in the context of adjustment to stressful events, outlining what has been established to date and evaluating the strengths and weaknesses of current empirical work. Results suggest that theory on meaning and meaning making has developed apace, but empirical research has failed to keep up with these developments, creating a significant gap between the rich but abstract theories and empirical tests of them. Given current empirical findings, some aspects of the meaning-making model appear to be well supported but others are not, and the quality of meaning-making efforts and meanings made may be at least as important as their quantity. This article concludes with specific suggestions for future research. PMID- 20192565 TI - Auditory imagery: empirical findings. AB - The empirical literature on auditory imagery is reviewed. Data on (a) imagery for auditory features (pitch, timbre, loudness), (b) imagery for complex nonverbal auditory stimuli (musical contour, melody, harmony, tempo, notational audiation, environmental sounds), (c) imagery for verbal stimuli (speech, text, in dreams, interior monologue), (d) auditory imagery's relationship to perception and memory (detection, encoding, recall, mnemonic properties, phonological loop), and (e) individual differences in auditory imagery (in vividness, musical ability and experience, synesthesia, musical hallucinosis, schizophrenia, amusia) are considered. It is concluded that auditory imagery (a) preserves many structural and temporal properties of auditory stimuli, (b) can facilitate auditory discrimination but interfere with auditory detection, (c) involves many of the same brain areas as auditory perception, (d) is often but not necessarily influenced by subvocalization, (e) involves semantically interpreted information and expectancies, (f) involves depictive components and descriptive components, (g) can function as a mnemonic but is distinct from rehearsal, and (h) is related to musical ability and experience (although the mechanisms of that relationship are not clear). PMID- 20192566 TI - Effects of amino acid substitution polymorphisms of two DNA methyltransferases on susceptibility to sporadic colorectal cancer. AB - BACKGROUND AND AIM: The present study was designed to consider whether amino acid substitution polymorphisms in O6-methylguanine-DNA methyltransferase (MGMT) and DNA methyl transferase 1 (DNMT1) genes may be associated with the genetic susceptibility to sporadic colorectal cancer. PATIENTS AND METHODS: We assessed eight non-synonymous polymorphisms of these two genes by PCR/pyrosequencing. Our population consisted of 208 individuals with sporadic colorectal cancer and 213 controls. Allele frequencies and genotypes were compared between the two groups. RESULTS: The calculated odds ratios indicated no association between DNMT1 and colorectal cancer. However, there was a significant association between two polymorphisms in MGMT with sporadic colorectal cancer: Arg128Gln (OR, 5.53; 95% CI) and Gly160Arg (OR, 3.04; 95% CI). CONCLUSIONS: These findings could be indicative of factors contributing to high occurrence of Iranian colorectal cancer patients. PMID- 20192562 TI - The disclosure processes model: understanding disclosure decision making and postdisclosure outcomes among people living with a concealable stigmatized identity. AB - Disclosure is a critical aspect of the experience of people who live with concealable stigmatized identities. This article presents the disclosure processes model (DPM)-a framework with which to examine when and why interpersonal disclosure may be beneficial. The DPM suggests that antecedent goals representing approach and avoidance motivational systems moderate the effect of disclosure on numerous individual, dyadic, and social contextual outcomes and that these effects are mediated by three distinct processes: (a) alleviation of inhibition, (b) social support, and (c) changes in social information. Ultimately, the DPM provides a framework that advances disclosure theory and identifies strategies that can assist disclosers in maximizing the likelihood that disclosure will benefit well-being. PMID- 20192567 TI - Curcumin: from food spice to cancer prevention. AB - Curcumin [1, 7-bis (4-hydroxy-3-methoxyphenyl)-1, 6 heptadiene-3, 5-dione] is an orange-yellow component of turmeric (Curcuma longa), a spice often found in curry powder. It is known to have a variety of biologic and pharmacologic activities, including anti-inflammatory, anti-oxidant, and anticarcinogenic potential. It is a potent inhibitor of cytochrome P450 with capacity to simultaneously induce detoxifying enzymes such as glutathione S-transferase and as such may find application as a chemopreventive agent. Curcumin is a potent inhibitor of cyclooxygenase-2, lipooxygenase, ornithine decarboxylase (ODC), nuclear factor kappaB, c-Jun N-terminal kinase and protein kinase C and has also been demonstrated to play a vital role against pathological conditions such as cancer, atherosclerosis, and neurodegenerative diseases. PMID- 20192568 TI - Cervical cancer and HPV vaccines in developing countries. AB - Cervical cancer is the second most common cancer among women in the world. Despite a decline of up to 70% in its incidence and prevalence through screening programs, it is still the most common gynecological cancer worldwide. Since the human papilloma virus (HPV) was conclusively identified as the etiological factor inducing cervical cancer, investigations during the last two decades have been concentrating on producing a vaccine against HPV virus. Thus prevention of HPV infection has been the main purpose and vaccination is expected to reduce up to 70% of related cervical cancer and prevent precancerous and cancerous lesions of the genitalia. However, screening programs are still essential for those who have already been exposed to the high risk forms of the virus and educational and information programs continue to play important roles to increase the success rate of screening, by whichever of the modalities is most appropriate for the local conditions. PMID- 20192569 TI - Toxicology of engineered nanomaterials - a review of carcinogenic potential. AB - Nanotechnology has considerable socioeconomic potential. Benefits afforded by engineered nanoparticles (NP: defined as being less than 100 nm in diameter) are expected to be significant in fields such as plastics, energy, electronics, aerospace and medicine. However, NPs are being introduced into the market without adequate assessment of their potential toxicities. It is urgently important to conduct risk assessment of commercial NPs and establish a framework enabling risk management which is not subordinate to their commercial production. An overview of currently available carcinogenicity risk evaluation results of NP materials raises serious questions as to their safety. NP sized titanium dioxide (nTiO(2)) and carbon black (nCB) are carcinogenic to the lung of female rats, and the tumors preferentially include squamous cell morphology. Carbon nanotubes (CNT) induce mesotheliomas when applied intraperitoneally in rats and mice. Data for Fullerenes are insufficient to evaluate carcinogenic risk. Sub-chronic toxicity data indicate that, in general, NPs form aggregates and agglomerates and cause foreign body reactions at their applied sites with inflammatory cell, including macrophage, infiltration. These findings are similar to the biological effects of asbestos, a potent carcinogen, and indicate that careful assessment of NPs is indispensable. PMID- 20192570 TI - Diverse influences of dietary factors on cancer in Asia. AB - The major environmental risk factors for cancer are carcinogen and co-carcinogen exposure in tobacco, insufficient exercise and above all an unhealthy diet. What we eat or do not eat is exceedingly important in determining what cancers or other chronic disease we may suffer from. Carcinogens may be integral contaminants of the diet, like nitrosamines in some situations and aflatoxins, or may be generated by cooking processes, as is known to be the case for heterocyclic amine pyrolysis products. Examples of co-carcinogenic agents may include grit in bread products, salt in pickles or betel in chewing quids. Dietary insufficiencies, for example of zinc, may also act to increase sensitivity to genetic damage, for example. Influence on metabolism of carcinogens, like induction of phase II enzymes like glutathione S transferases, further directly impacts on carcinogenicity. Antioxidants in fruits and vegetables are typical examples of protective agents acting in this way. In addition we have dietary fibre which can decrease carcinogen exposure through accelerating passage of faeces through the gut. Other types of fibre, the soluble forms, can act to decrease uptake of glucose and thus suppress insulin exposure, an important factor for colon cancer. Natural anti-inflammatory agents like N-3 fatty acids in fish offer another example of preventive factors in the diet. Individual dietary components, like isoflavones in soy products, can interfere with hormone function to exert a beneficial action, as on the breast. Other compounds may act via stimulation of the immune system like lactoferrin and betaglucans. Perhaps the most important influence of diet on cancer, however, in a world of increasing comfort and ease of access to foodstuffs, is through over eating and consequent obesity. Given the importance of diet to all our lives, we need to focus on all possible interactive effects in providing an evidence base to guide our choices regarding what we should eat in Asia. PMID- 20192571 TI - Chronic disease prevention research in Central Asia, the Urals, Siberia and Mongolia - past, present and future. AB - Central Asia, the Urals, Siberia and Mongolia cover an immense section of Asia and although relatively sparsely populated the total inhabitants number well in excess of 100 million. Furthermore, there is an increasing tendency for urbanization of the populations, which in many cases are growing. The ethnic make up is diverse, with various degrees of admixture of Russians to the Turkish, Mongolian and other indigenous peoples of the region, and there is evidence of major variation in the burden of different cancers among the groups, although oesophageal and gastric neoplasias are relatively prevalent in common. Clearly there is a need for cooperation for cancer and other chronic disease prevention and the presence of Russian as a shared language of science, commerce and industry means that there should be no major communication difficulties. However, collaborative efforts at present are limited and the research output is low, even in the non-English literature. Here we focus on published work from the individual countries, as assessed by PubMed searches using the country name with cancer, cardiovascular, metabolic syndrome and diabetes as search terms, with an especial focus on epidemiology, environmental carcinogenicity and screening. One major aim is to identify active groups with an interest in participation in a regional meeting and collaborative research, so that a coordinated approach to granting agencies can be made to fund such a collective endeavour. PMID- 20192572 TI - Hepatitis B testing and vaccination in immigrants attending English as a second language classes in British Columbia, Canada. AB - BACKGROUND: Hepatitis B virus (HBV) is a growing health issue in Canada, especially given that population growth is now largely the result of immigration. Immigrants from countries with high HBV prevalence and low levels of HBV vaccination have an excess risk of liver disease and there is a need for increased diligence in HBV blood testing and possibly vaccination among these populations. OBJECTIVE: This study describes the sociodemographic characteristics associated with a history of HBV testing and HBV vaccination in immigrants from several countries with high HBV prevalence who are attending English classes. METHODS: 759 adult immigrants attending English as a Second Language classes completed a self-administered questionnaire asking about sociodemographic characteristics and history of HBV testing and HBV vaccination. Descriptive statistics and adjusted ORs were calculated to explore these associations. RESULTS: 71% reported prior HBV testing, 8% reported vaccination without testing, and 21% reported neither testing nor vaccination. Age, education and country of birth all showed significant effects for both testing and vaccination. CONCLUSIONS: Health care practitioners need to be cognizant of HBV testing, and possibly vaccination, in some of their patients, including immigrants from countries with endemic HBV infection. Infected persons need to be identified by blood testing in order receive necessary care to prevent or delay the onset of liver disease as well as to adopt appropriate behaviours to reduce the risk of transmission to others. Close contacts of infected persons also require HBV testing and subsequent vaccination (if not infected) or medical management (if infected). PMID- 20192573 TI - Impact of nutritional status on the quality of life of advanced cancer patients in hospice home care. AB - BACKGROUND: Cancer patients frequently experience malnutrition and this is an important factor in impaired quality of life. OBJECTIVE: This cross-sectional study examined the association between global quality of life and its various subscales with nutritional status among 61 (33 females and 28 males) advanced cancer patients cared for by selected hospices in peninsular Malaysia. METHODS: The Patient Generated-Subjective Global Assessment (PG-SGA) and the Hospice Quality of Life Index (HQLI) were used to assess nutritional status and quality of life, respectively. RESULTS: Nine (14.7%) patients were well-nourished, 32 (52.5%) were moderately or suspected of being malnourished while 20 (32.8%) of them were severely malnourished. The total HQLI mean score for these patients was 189.9-/+51.7, with possible scores ranging from 0 to 280. The most problem areas in these patients were in the domain of functional well-being and the least problems were found in the social/spiritual domain. PG-SGA scores significantly correlated with total quality of life scores (r2= 0.38, p<0.05), psychophysiological well-being (r2= 0.37, p<0.05), functional well-being (r2= 0.42, p<0.05) and social/ spiritual well-being (r2= 0.07, p<0.05). Thus, patients with a higher PG-SGA score or poorer nutritional status exhibited a lower quality of life. CONCLUSION: Advanced cancer patients with poor nutritional status have a diminished quality of life. These findings suggest that there is a need for a comprehensive nutritional intervention for improving nutritional status and quality of life in terminally ill cancer patients under hospice care. PMID- 20192574 TI - Cyclooxygenase-2 expression in cervical squamous cell carcinoma: the significance of expression in neoplastic cells within the lymphovascular space. AB - BACKGROUND: Cyclooxygenase-2 (COX-2) activity is related to the development and progression of cervical cancer. Previous studies have shown that COX-2 expression in early stage (stage IB-IIA) cervical squamous cell carcinoma is associated with lymph node metastasis in tumors with lymphovascular space invasion (LVSI), and that COX-2 expression may facilitate lymph node metastasis after LVSI occurs. In this study, we evaluated whether COX-2 expression of neoplastic cells within lymphovascular spaces (tumor emboli) would provide additional prognostic information. METHODS: Immunohistochemical stained slides for COX-2 on 150 cases of stage IB-IIA cervical squamous cell carcinoma with LVSI were evaluated for expression of COX-2 in tumor emboli. Results were correlated with overall COX-2 expression of tumor and clinicopathologic features using statistical analysis. RESULTS: Expression of COX-2 was detected in 49.3% of cases. Expression of COX-2 in tumor emboli (LV-COX-2 expression) was identified in 61 cases (40.7%). LV-COX 2 expression was associated with high LVSI count (p<0.001) and had a marginal association with tumor COX-2 expression (p= 0.050) and lymph node metastasis (p= 0.063). In tumors showing high LVSI count, LV-COX-2 expression was an independent predictor for lymph node metastasis (p= 0.038, 95% CI= 1.030-2.725) whereas tumor COX-2 expression (p= 0.550) was not. CONCLUSION: Evaluation of COX-2 expression in tumor emboli may provide additional prognostic value for lymph node metastasis in cervical squamous cell carcinomas with a high LVSI count. PMID- 20192575 TI - Risk factors for prostate cancer in Universiti Kebangsaan Malaysia Medical Centre: a case-control study. AB - INTRODUCTION: In Malaysia, prostate cancer is ranked 6th among male cancer and expected to increase in the future. Several factors have shown to be related to prostate cancer such as sociodemographic, lifestyle, diet, occupational exposure, medical and health status. This is the first time a similar study was conducted in Malaysia to recognize the risk factors for prostate cancer patients who came for treatment at University Kebangsaan Malaysia Medical Centre (UKMMC). METHODS: Prostate cancer cases diagnosed between 2003 and 2008 which met with the inclusion criteria were included in the study. One hundred and twelfth (112) pairs of cases and controls matched by age and ethnicity were analysed. McNemar Odds Ratios (OR(M)) were calculated using McNemar Calculator software for univariate analysis while conditional logistic regression was used for multivariate analysis, both using SPSS version 12.0. RESULTS: Most of the prostate cancer patients (68.8%) that came for treatment in UKMMC were above 70 years old. The majority were Chinese (50.0%) followed by Malay (46.4%) and Indian (3.6%). Multivariate analysis showed cases were more likely to have a first degree relative with a history of cancer (OR= 3.77, 95% CI= 1.19-11.85), to have been exposed to pesticides (OR= 5.57, 95% CI= 1.75-17.78) and consumed more meat (OR= 12.23, 95% CI= 3.89-39.01). Significantly reduced risks of prostate cancer were noted among those consuming more vegetables (OR= 0.12, 95% CI= 0.02-0.84), more tomatoes (OR= 0.35, 95% CI= 0.13-0.93) and those who had frequent sexual intercourse (OR= 0.44, 95% CI= 0.19-0.96). CONCLUSION: Some lifestyle and occupation factors are strong predictors of the occurrence of prostate cancer among patients in UKMMC. More importantly, with the identification of the potentially modifiable risk factors, proper public health intervention can be improved. PMID- 20192576 TI - Serum granulocyte macrophage-colony stimulating factor: a tumor marker in colorectal carcinoma? AB - BACKGROUND/AIMS: Granulocyte macrophage colony-stimulating factor (GM-CSF) is a hematopoietic growth factor, 23 kDA molecular weight with a glycoprotein nature, which is also an immune modulator. The levels of GM-CSF and its role in the pathophysiology of several cancers such as ovarian, breast have been investigated. The aim of the present study was to determine the effect of GM-CSF and carcinoembryogenic antigen levels in predicting survival. METHODOLOGY: Plasma levels of GM-CSF were measured in 51 patients with previously untreated colorectal cancer patients and 21 healthy adults as normal controls. The clinicopathological features of colorectal carcinoma were determined at the time of blood collection. Patient staging was done according to tumor-node-metastasis (TNM) by American Joint Commission on Cancer (AJCC). RESULTS: Plasma concentrations of GM-CSF in colorectal cancer patients (42.0 pg/ml) were statistically significant higher than normal controls (23.2 pg/ml) (p= 0.001). Statistically significant correlation was not determined between pretreatment GM CSF levels and overall survival. On the other hand, stage of disease, carcinoembryogenic antigen and peripheral leukocyte counts were not correlated with GM-CSF levels. CONCLUSIONS: This is the first report in which serum levels of GM-CSF, carcinoembriyogenic and peripheral leukocyte counts have been simultaneously evaluated in colorectal cancer patients. We found significantly elevated GM-CSF but the results suggested that serum GM-CSF may not be useful for clinical information in prognosis as a tumor marker in colorectal cancer. PMID- 20192577 TI - Changing trends in incidence of ovarian cancer - the Indian scenario. AB - Ovarian cancer has emerged as one of the most common malignancies affecting women in India. The present communication reports the trends in the incidence rate of ovarian cancer for Indian women. The data published in Cancer Incidence in Five Continents for various Indian registries for different periods and / or publication by the individual registries served as the source material. Mean annual percentage change (MAPC) in rates was computed using relative differences between two time periods. During the period 2001-06, the age-standardized incidence rates (ASR) for ovarian cancer varied from 0.9 to 8.4 per 100,000 person years amongst various registries. The highest incidence was noted in Pune and Delhi registries. The Age Specific Incidence Rate (ASIR) for ovarian cancer revealed that the disease increases from 35 years of age and reaches a peak between the ages 55-64. The trend analysis by period showed an increasing trend in the incidence rate of ovarian cancer in most of the registries, with a mean annual percentage increase in ASR ranged from 0.7% to 2.4 %. Analysis of data by ASIR revealed that the mean annual percentage increase was higher for women in the middle and older age groups in most of the registries. Estimation of annual percent change (EAPC) in ovarian cancer by Poisson regression model through Maximum Likelihood Estimation (MLE) for the data of 3 population-based cancer registries vs. Mumbai, Chennai and Bangalore for the period 1983-2002 revealed that linear regression was found to be satisfactory fit between period and incidence rate. Statistically significant increase in EAPC was noted with the crude rate (CR,) ASR, and ASIR for several age-groups. Efforts should be made to detect ovarian cancer at an early stage by educating population about the risk factors. Most of the ovarian cancers are environmental in origin and consequently, at least in principle avoidable. PMID- 20192578 TI - Punarnavine induces apoptosis in B16F-10 melanoma cells by inhibiting NF-kappaB signaling. AB - The objective of this study was to assess the effect of Punarnavine, an alkaloid isolated from Boerhaavia diffusa, on apoptosis in B16F-10 melanoma cells. Treatment of B16F-10 melanoma cells with nontoxic concentrations of Punarnvine resulted in the presence of apoptotic bodies and DNA fragmentation in a dose dependent manner. Cell cycle analysis and TUNEL assays also confirmed the observation. The apoptotic genes p53 and caspase-3 were found upregulated in Punarnavine treated cells, whereas the antiapoptotic gene Bcl-2 was downregulated. The inhibited nuclear translocation of NF-kappaBp65, NF-kappaBp50, NF-kappaB-c-Rel, c-Fos, ATF-2 and CREB-1 in Punarnavine treated B16 F-10 cells pointed to suppression of NF-kappaB signaling by Punarnavine. All these results demonstrate that Punarnavine induces apoptosis via activation of p53 induced caspase-3 mediated pro-apoptotic signaling and suppression of NF-kappaB induced Bcl-2 mediated survival signaling. PMID- 20192579 TI - Overview of chronic myeloid leukemia patients in Pakistan in the pre-imatanib era. AB - OBJECTIVE: To study the patient characteristics of patients diagnosed with chronic myelogenous leukemia (CML) at a tertiary care cancer hospital in Pakistan. METHODS AND MATERIALS: A retrospective analysis was conducted on CML patients treated between 1996 and 2004 at Shaukat Khanum Memorial Cancer Hospital and Research Center. RESULTS: A total of 461 CML patient charts were reviewed. The mean and median ages at presentation were much younger than in the prior reports in the western literature with a quicker progression of disease. CONCLUSION: The advent of tyrosine kinase inhibitors will likely have more impact on the lifespan of CML patients in Pakistan when compared with patients in the western hemisphere due to younger age at diagnosis. PMID- 20192580 TI - Clinical outcome of the ovarian clear cell carcinoma compared to other epithelial ovarian cancers when treated with paclitaxel and carboplatin. AB - Ovarian clear cell carcinoma (OCCC) has an aggressive histology. Our aim was to evaluate the progression free survival (PFS) of OCCC patients compared to other epithelial histology patients when treated with surgery followed by carboplatin and paclitaxel (PT) regimen. The medical records of them who treated with PT regimen at Chiang Mai University Hospital between January 2004 and December 2008 were reviewed. 67 ovarian clear cell patients were compared to 121 non-clear cell ovarian cancer patients. The mean age of OCCC patients was younger than that of the non-clear cell group (46.7 vs. 51.2 years old, P= 0.001). OCCC patients presented in early stage more often than the non-clear cell group (76.1% vs. 38.0%, P= 0.001). The surgical procedures in both groups were not significantly different. The complete response rates of OCCC patients and other epithelial histology patients were 65.7% and 55.3%, respectively (P= 0.01). With a mean follow-up time of 25 months, the 3-year PFS rates of OCCC and non-clear cell patients in early stages were not significantly different (65.4% vs. 64.2%, P= 0.45). However, in the advanced stage, the 1-year PFS rate of OCCC patients was significantly lower than that of non clear cell patients (6.3% vs. 49.6%, P= 0.001). In conclusion, patients were commonly younger and presented in earlier stages than non-clear cell ovarian cancer patients. In early stages, clear cell ovarian cancer patients had similar outcomes to other epithelial ovarian histology patients, whereas the outcome was very poor in advanced stages. PMID- 20192581 TI - Women's awareness, knowledge and perceived magnitude regarding common female cancers in Yangon, Myanmar. AB - Early detection and diagnosis can greatly increases the chances for successful treatment particularly relevant for common female cancers like cancer breast and cervix. Increased awareness of the possible warning signs of these cancers among general public is a necessity. A community-based, cross-sectional study was conducted with the objectives of assessing the women's awareness and knowledge on common female cancers and estimating the perceived magnitude and survival of these cancers. A total of 400 women were interviewed using a pre-tested, structured questionnaire. Mean age of women was 48.4 years and majority were married, dependent and primary school passed. Almost all (99.3%) were aware of breast cancer and only (69.5%) were aware of cervical cancer. Breast lump was considered as a condition that will later develop into cancer by (38.8%) and (41.5%) mentioned that it was painless in early stage. Abnormal bleeding per vagina and white discharge were mentioned as main symptoms of cervical cancer (76.3%, 63.3%). Regarding the risk of cervical cancer, female hygiene was indicated by (88.5%) and number of sexual partners by (77.0%). Almost all of them said that both diseases can be cured at early stage. Cancer breast, uterus and cervix were mentioned as the most common female cancers according to their perceived magnitude. Although cervical and breast cancer were perceived as common female cancers, health education activities regarding risk factors and early warning signs of these cancer still need to be promoted. PMID- 20192582 TI - Vinorelbine in combination with carboplatin followed by single-agent consolidation therapy for unresectable localized or metastatic non-small-cell lung carcinomas. AB - BACKGROUND: Adding more than four cycles of the combination regimen increase toxicities. The availability of an intravenous (i.v.) and oral form of vinorelbine appeared as a particularly convenient way to provide a consolidation treatment to patients who have achieved an objective response or stable disease. PATIENTS AND METHODS: This study was retrospectively designed to investigate the efficacy in terms of response and safety of i.v. vinorelbine 25 mg/m(2) on day 1 and oral vinorelbine 60 mg/m(2) on day 8 given with carboplatin area under the curve (AUC) 5 once every 3 weeks (q3w) for four cycles followed by consolidation therapy with single-agent vinorelbine in non-progressive patients with advanced non-small-cell lung cancer (NSCLC). RESULTS: Seventy-two patients enrolled into the study from October 2006 to July 2009 received the combination regimen. Thirty seven patients (51.3%) also received the subsequent consolidation treatment. Partial tumor responses were obtained in 25 patients (34.7%) of 72 evaluable patients. Stable disease was observed in 26 (36.1%) of patients. The median progression free-survival was 4 months (95% CI 3.1-4.8). The median overall survival time was 10 months (95% CI 8.2-11.7) and the 1 year survival was 38.1%. The main toxicities recorded were hematological. Grade 3-4 neutropenia were observed in 17 patients (23.6%). Only two patients experienced grade three febrile neutropenia in the induction period, and there was no occurrence of febril neutropenia in the consolidation period. Nausea and vomiting were the major non-hematological toxicities reported. Toxicities occurred primarily during the initial combination phase of the chemotherapy. CONCLUSIONS: Despite the low dose of vinorelbine (25mg/m(2) i.v. on day 1 and only 60 mg/m(2) oral on day 8, every 3 weeks) achieved during the study, the response rate of 34.7%, the disease control of 70.8% and the 10 months median overall survival with tolerable toxicity profile, confirmed that this combination, offers an active and safe regimen for patients with advanced NSCLC. PMID- 20192583 TI - XRCC1399 and hOGG1326 polymorphisms and frequencies of micronuclei, comet and chromosomal aberrations among tobacco chewers: a South Indian population study. AB - DNA repair plays a critical role in protecting the genome of the cell from the insults of cancer-causing agents such as those found in tobacco. Reduced DNA repair capacity may constitute a significant risk factor for cancers. Recently, a number of polymorphisms in several DNA repair genes have been discovered, these polymorphisms may affect DNA repair capacity and thus modulate cancer susceptibility in exposed populations. In the present study, we explored the relationship between polymorphisms in the DNA repair gene XRCC1399 and hOGG1326 genotypes using polymerase chain reaction-restriction fragment length polymorphism (PCR/RFLP) and risk of cancer development. 156 smokeless tobacco users and 70 controls without significant exposure to mutagens were recruited. Questionnaires were completed to obtain detailed occupational, smoking, and medical histories. A standard micronucleus assay, comet assay and chromosomal aberration assays were used as a marker of genetic damage. There were significant differences in the micronucleus (MN), Comet scores and chromosomal aberrations (CA) between smokeless tobacco users and control subjects by Student's t-test (P< 0.05). These findings provide evidence for the view that polymorphisms in DNA repair genes may modify individual susceptibility to tobacco related cancers and justify additional studies to investigate their potential role in development of cancer. PMID- 20192584 TI - Screening of N-ras gene mutations in urothelial cell carcinomas of the urinary bladder in the Kashmiri population. AB - BACKGROUND AND AIMS: The objective of this study was to assess the frequency of specific-point mutations in N-ras of the RAS gene family in a group of Kashmiri patients with bladder cancer and to observe any association with clinicopathological parameters. METHODS: Paired tumor and normal tissue specimens of 55 consecutive patients with urothelial cell carcinoma were screened and DNA was extracted for detection of N-ras activating mutations in exons 1 and 2. In addition, blood was also collected from all the cases to rule out any germ line mutation. RESULTS: Specific point mutations of activated N-ras were detected in 9% (5 of 55) of the bladder cancer patients, all being missense. The base substitutions identified included three transversions (two G toT and one A to T) and two transitions ( A-G). Sixty % of the mutations were detected in codon 61 and 40% in codon 12. No significant correlations were found between the mutations and clinical features. CONCLUSION: Although N-ras gene mutation might be one of the mechanisms underlying oncogenesis of urothelial cancer, it seems to be a relatively rare event in Kasmiris, pointing to involvement of different etiological factors in the induction of bladder tumor in this population. PMID- 20192585 TI - Estrogen receptor, progesterone receptor, HER2/neu, P53 and Ki-67 status of male breast carcinomas in Pakistan. AB - OBJECTIVE: The aim of present study was to assess the status of estrogen and progesterone receptors, HER2/neu, p53 and ki-67 in male breast carcinomas in our institute. STUDY DESIGN: A descriptive study, carried out in the Department of Pathology (Histopathology), Army Medical College, Rawalpindi, Pakistan from June 2008 to January 2009. SUBJECTS AND METHODS: In this study 45 cases of male breast carcinoma, including all the histological subtypes were assessed with original pathology reports of each case investigated for the age, laterality of breast, histological type of tumour and tumour grade. Tumour blocks of each case were retrieved for immunohistochemical staining of estrogen and progesterone receptors and HER2/neu, ki-67 and p53 scoring was accomplished using established protocols. RESULTS: The majority of the cases were above 65 years of age. Histologically, the invasive ductal carcinoma was the predominant lesion. In total 95.5% of the cases were estrogen and progesterone (ER and PR) receptor positive. The HER2/neu staining was positive in 84.4% cases. According to the percentage of nuclear staining, 77.7% of the cases were p53 positive and 35.6% of the cases had strong nuclear staining intensity. A total of 55.5% of the tumours showed proliferation by ki-67. CONCLUSION: The majority of male breast carcinomas in Pakistan are ER and PR positive and demonstrate immunoreactions for prognostic markers. The results point to a relatively aggressive nature of such lesions in our institute. PMID- 20192586 TI - Neoplasia/dysplasia surveillance of oral lichen planus in Malaysia: a preliminary study using topography maps. AB - BACKGROUND: Conventional methods for writing case notes detailing the progress of oral lichen planus (OLP), a precancerous condition that requires long-term surveillance, is both time-consuming and tedious for the busy clinician. OBJECTIVES: To design and perform a simple surveillance on OLP patients based on colour-coded topography mouth maps (TMM). MATERIALS AND METHODS: Three colour coded TMM were employed: red for OLP in high risk oral mucosal sites, yellow for cases showing improvement and green for asymptomatic lesions at each recall visit. In this preliminary study, these were applied on 30 histologically confirmed OLP individuals attending the Oral Medicine Clinic at the Department of Oral Pathology, Oral Medicine and Periodontology, Faculty of Dentistry, University of Malaya. The sites and extent of OLP lesions were charted on either red, yellow or green TMM based on defined criteria. This surveillance evaluated OLP in relation to patientandapos;s age, race, gender, underlying systemic conditions, oral habits, initial onset of OLP, oral manifestations and presence/absence of clinically suspicious areas. RESULTS: Study sample comprised 4 (13.3%) Malays, 9 (30.0%) Chinese and 17 (56.7%) Indians. Most OLP patients belong to the green TMM (n= 14, 46.6%) group followed by red (n= 11, 36.7%) and yellow (n= 5, 16.7%) groups. Of the 11 cases with red TMM, rebiopsy was performed on 4 cases but no dysplasia was detected. Any local confounding factors namely periodontal disease or faulty dental restorations were managed accordingly. CONCLUSIONS: TMM is simple to use and aided the clinicians in terms of time saving and patient management. Hence, follow-up of OLP patients can be carried out more efficiently and appropriately. TMM can be used for surveillance of other oral precancerous lesions and conditions. PMID- 20192587 TI - Eight year survival among breast cancer Malaysian women from University Kebangsaan Malaysia Medical Centre. AB - Survival after diagnosis of cancer is one of the major outcome measurements and a key criterion for assessing quality of cancer control related to both the preventive and the therapeutic level. The purpose of this study was to determine the 8-year survival time in Malaysia based on socio-demographic and clinical characteristics. A retrospective study of 472 Malaysian women with breast cancer from the Medical Record Department at University Kebangsaan Malaysia Medical Centre (UKMMC) was therefore performed with survival analysis carried out using the Kaplan-Meier with log-rank test for univariate analysis and Cox-regression for multivariate analysis. Women who had cancer or family history of cancer had a longer 8-year survival time (p = 0.008) compared with others who did not have such a history. Tamoxifen use, positive oestrogen receptor status, and race were prognostic indicators for 8-year survival time (p = 0.036, p = 0.018, p = 0.053, respectively) in univariate analysis. Multivariate analysis showed that being Malays and having no family history of cancer were independent prognostic factors for shorter survival time (p = 0.008, p = 0.012, respectively). In conclusion, being Chinese and having a family history of cancer are predictors of longer survival among the Malaysian breast cancer women. PMID- 20192588 TI - Breast carcinoma in young women aged 30 or less in Northern Pakistan - the Armed Forces Institute of Pathology experience. AB - OBJECTIVE: The study was carried out to document the occurrence of early onset breast cancer in our population and to assess prognostic variables. METHODS: Records of a total of 1,644 female patients diagnosed with breast carcinoma during the last four years (Jan 2005 - Dec 2008) at the Histopathology Department, Armed Forces Institute of Pathology (AFIP) were retrieved from the AFIP tumour registry. All cases of breast carcinoma diagnosed in young females, 30 years of age or less, were selected and assessed for the type of specimen, tumour type, size and grade, presence or absence of lymph node metastasis, number of lymph nodes recovered and number of lymph nodes involved. Data were entered into SPSS version 11 to calculate mean, median, mode and standard deviation for quantitative variables and frequencies and percentages for qualitative variables. RESULTS: The mean age was 28+/-2.7 years and the mean tumour size was 3.7+/-2.9 cm. Most frequent age group was 26-30 years (78.6%). The most common histological tumour type was invasive ductal carcinoma (88.7%), followed by invasive lobular carcinoma (5.4%). Seven out of 168 (4.2%) tumours were less than 2 cm in size, 69(41.1%) were between 2-5 cm and 39 (23.2%) were greater than 5 cm. Grade 2 (57.1%), followed by grade 3 (29.8%) were the most frequent. Out of 68 cases in which lymph nodes were included, lymph node metastasis was seen in 55(80.8%). CONCLUSION: Breast cancer is much commoner in young women in Pakistan as compared to the rest of the world. It is important to keep this in mind when evaluating even very young females with breast lumps. PMID- 20192589 TI - Complementary and alternative medicine in cancer patients - analysis of influencing factors in Turkey. AB - OBJECTIVE: This cross-sectional and descriptive study analysed complementary and alternative medicine (CAM) practices of patients with cancer diagnoses and influencing factors. METHODS: The subjects consisted of 55 cancer patients hospitalized in Canakkale State Hospital between November 2008 and March 2009 and who were willing to participate in the study. Research data were collected using a sociodemographic characteristics form regarding CAM practices of cancer patients and the Beck Hopelessness Scale (total points 20, rising with the degree of hopelessness). Written consent from the head physician of Canakkale State Hospital and verbal consents of the patients were obtained in order for the research to be performed. The data were analysed using the SPSS 13.0 program (numbers and percentages, chi-squared and Mann Whitney U tests). FINDINGS: Of the patients (49.1% female and 50.9% male) 78.2% had been living with a cancer diagnosis for more than two years. Of the 23.6% of patients with breast cancer and 21.8% with lung cancer, 87.2% uses CAM (72.7% received alternative treatment and 65.5% complementary treatment). Alternative treatments apply herbal treatments concomitantly such as honey, garlic; balsam apple, iscum album, tar oil and 29.1% of them only use stinging nettle. As a complementary treatment; 60% of patients pray for healing and 16.4% of them have massage regularly. Patients explained that they were using the alternative medicine in order to mitigate effects of the disease, to prevent its recurrence, to increase blood values, to feel psychologically relieved; and they were using complementary medicine just to feel psychologically relieved. Of 60% patients chose not to share their CAM practice with doctors and nurses. 36.4% of them use CAM on friend advice, 20% under media influence, 36.4% on their own initiative and 21.8% under family influence. The satisfaction from CAM is 61.1%. The rate of those who find alternative medicine expensive is 21.8%. There is statistically no correlation between CAM practice and age, gender, marital status, location they live for a long time, education and financial status of patients (p>0.05). The average of total hopelessness score of patients is 8.09 +/- 2.59, there is no statistically meaningful correlation between hopelessness score average of patients who use CAM and who do not use (p>0.05). CONCLUSION: The cancer patients in the study who live in Canakkale province and in its districts use CAM. CAM practice does not vary by selected sociodemographic characteristics and the hope level. It is important that the health care professionals (nurses, doctors, etc) should be conscious of CAM-drug interactions and notify the patients about the risk. PMID- 20192591 TI - Screening and perceived severity of cervical cancer among women attending Mahalapye District Hospital, Botswana. AB - OBJECTIVES: The objectives of the study were to describe women's perceived severity to cervical cancer and its associations with socio-demographic characteristics. METHODS: A cross-sectional study was conducted by a questionnaire survey with a total of 300 participants selected by convenience sampling techniques. RESULTS: The participants' mean age was 37 years (SD= 11) and the cervical cancer screening rate was 39%. Most of the women were sure about the severity of cancer as they responded mostly agreeing or strongly agreeing with statements about severity of cervical cancer. The range of average responses was 2.58 to 3.56. When the ever screened and the never screened for cervical cancer was compared, it was observed that both groups equally believed that there is effective treatment for cervical cancer, and that cervical cancer makes a woman's life difficult. Overall, 60% of the never screened had low perceived severity while 33% of the screened had high perceived severity to cervical cancer. There was no significant association between perceived severity and screening for cervical cancer (c2 = 1.0795; p = 0.2988). Monthly income (c2= 13.077; p<0001) and residential area (c2= 15.457; p= 0.004) were significantly associated with perceived severity. CONCLUSION: The screening rate is still far too low compared to the national target of greater than 75%. Therefore, despite awareness of the perceived severity of cervical cancer, the reasons why at risk women fail to participate in cervical cancer screening need to be adequately explored. PMID- 20192590 TI - Anti-tumor activity of Phyllanthus niruri (a medicinal plant) on chemical-induced skin carcinogenesis in mice. AB - Chemoprevention is an important strategy to control the process of carcinogenesis. The potential of using medicinal herbs as cancer chemopreventive nutraceuticals and functional food is promising. Thus, there is a need for exploring drugs/agents which act as chemopreventive agents. Phyllanthus niruri is a well known medicinal plant which has been used in Ayurvedic medicine as hepatoprotective, antiviral, antibacterial, analgesic, antispasmodic and antidiabetic. The present study was carried out to evaluate the anti-tumor activity of a hydro-alcoholic extract of the whole plant, in 7-9 week old male Swiss albino mice, on the two stage process of skin carcinogenesis induced by a single topical application of 7, 12-dimethylbenz (a)anthracene (100 microg/100 microl acetone) and two weeks later promoted by repeated application of croton oil (1% in acetone/three times a week) till the end of experiment (16 weeks). The oral administration of P. niruri at a dose of 1000 mg/kg/b.wt. at peri- (i.e. 7 days before and 7 days after DMBA application) and post- (i.e. starting from the croton oil application) initiational phase of papillomagenesis caused significant reduction in tumor incidence, tumor yield, tumor burden and cumulative number of papillomas as compared to carcinogen-treated controls. Furthermore, the average latent period was significantly increased in the PNE treated group. The results thus suggest that P. niruri extract exhibits significant anti-tumor activity, which supports the traditional medicinal utilization of this plant. PMID- 20192592 TI - Perspectives on strategies for establishing cancer on the global health agenda: possibilities of creating infrastructure for cancer prevention information using school health classes. AB - The Asia Cancer Forum is a body that is committed to strategic analysis in the area of cancer research. The ultimate objective of the Forum is to achieve the inclusion of cancer in the Millennium Development Goals (MDGs) of the United Nations. The MDGs have a tremendous influence on the setting of the global health agenda and the inclusion of cancer within their scope would be greatly beneficial to the global development of cancer research. Although diseases such as HIV/AIDS and malaria remain priority issues for global health, the time has come for policy transformation. Preventive activities and measures require a long period of time before results become apparent and as the cost-benefit effect of allocated funds cannot be measured in the short-term, preventive activities have therefore tended to be given a low priority in terms of national policy. We must take a long-term perspective that looks ahead to the issues that will face future generations. Transcending challenges presented by cultural diversity, we must work to position cancer as a central theme on the global health agenda, even in the face of limited medical resources. Promoting cancer prevention activities through readily available infrastructure in the form of health classes in schools is also of great significance in terms of setting the agenda for global health. As a joint China-Japan research project, in China a questionnaire survey has been implemented through school pupils, with pupils and parents being asked about health classes implemented in schools. From the perspective of formulating strategy for establishing cancer on the global health agenda we will use the data gained from the surveys to analyze and examine the possibilities and significance of creating an infrastructure for a multilateral information network about cancer prevention. PMID- 20192593 TI - Sida rhombifolia ssp. retusa seed extract inhibits DEN induced murine hepatic preneoplasia and carbon tetrachloride hepatotoxicity. AB - Sida rhombifolia ssp. retusa is a well established drug in the Ayurvedic system of medicine used for antirheumatism and antiasthmatism. Inhibitory effects of S. rhombifolia ssp. retusa seed extract on DEN induced hepatocellular preneoplastic foci and carbon tetrachloride (CCl4) induced hepatotoxicity was investigated in rats. Rats received DEN, 1ppm/g b.w. in drinking water for 6 weeks or CCl(4), 0.7 ml/kg i.p. once a week for 4 weeks and seed extract 50 mg, 100 mg/kg b.w. orally prior, during and after exposure to DEN/CCl4 for 20 or 5 weeks, respectively. Treatment with seed extract significantly inhibited the increase in DEN/CCl(4) induced activities of pre-cancerous marker enzymes; gamma-glutamyl transpeptidase, glutathione-S-transferase, hepatotoxicity marker enzymes; glutamate pyruvate transaminase, glutamate oxaloacetate transaminase and alkaline phosphatase as well as lipid peroxidase. Depleted glutathione, protein and albumin levels were restored. Also, histopathological and transmission electron microscopic studies showed prevention of cellular degenerative changes. The chemopreventive and hepatoprotective potentials of seed extract are due to free radical scavenging activity and restoration of cellular structural integrity. PMID- 20192594 TI - Impact of a health education intervention program regarding breast self examination by women in a semi-urban area of Madhya Pradesh, India. AB - BACKGROUND: Breast cancer is the most common carcinoma in the world and the second most prevalent in Indian females. Over 0.7 million new cases of carcinoma breast are detected every year globally, with nearly 0.3 million deaths, affecting 28 per 100,000 females in the age group of 35 to 60 years. Breast self examination (BSE) can detect 40% of breast lesions. The present study aimed to assess the impact of a health education intervention program about breast self examination (BSE) among women in a semi-urban area in Madhya Pradesh, India. METHODOLOGY: The study was carried out in three phases; pre-intervention phase, intervention phase, and post-intervention phase. A total of 1000 women were included. Interventional health education in the form of a lecture, pamphlets, flip charts and demonstration of the five step method of breast self examination using audio-visual aids was administrated. RESULTS: There was a significant improvement in knowledge regarding all aspects of breast self examination of the intervention group from pre- to post-test. After the intervention program, 590 (59%) women had good knowledge and among them 90.7% practiced (BSE) compared to 0% pre-test. An overall increase in the awareness of 43% and 53% of BSE practice was observed in the study group after intervention. Seven cases of breast disease were detected in which two were breast carcinoma and five were fibroadenomas. CONCLUSION: The knowledge and practices of women toward breast self examination for early detection were observed to be inadequate in respondents but there was a significant improvement after the intervention. Health education programs through various channels to increase the awareness and knowledge about BSE are the need of the hour. Mass media cancer education should promote widespread access to information about early detection behavior. PMID- 20192595 TI - Clinical evaluation of parapelvic renal cysts: do these represent latent urological malignant disease? AB - PURPOSE: The parapelvic renal cyst is a relatively common finding on routine urological examination, but only rarely needs treatment. We here examined all parapelvic renal cyst patients who consulted our Department between April 1998 and December 2004 with the focus on potential for malignant development. MATERIALS AND METHODS: A total of 73 patients were diagnosed as having parapelvic renal cysts by ultrasonography, in combination with computed tomography, and/or drip infusion urography in our Department. The background to diagnosis was suspicion of hydronephrosis in 15, flank and/or back pain in 15, and macroscopic hematuria and/or occult blood urine in 12. RESULTS: There were 3 patients with renal pelvic cancer, and one patient with ureteral cancer. Nephro-ureterectomy was performed for all of these 4 cases. There were 10 patients with renal stones, three of which were given extracorporeal shock wave lithotripsy and one pyelonephrolithotomy. A further three underwent parapelvic renal cyst puncture, performed to preserve renal function or obtain release from symptoms. The remaining 3 cases were symptomless, diagnosed after routine examinations, and were simply followed up, as with the other 59 cases with no stones or cancer. CONCLUSIONS: Unless a parapelvic renal cyst causes pyelonephritis, symptomatic renal stones, or back discomfort, treatment is not indicated. However, the possibility that urological malignant disease may be encountered should be borne in mind and appropriate diagnostic measures should be performed. Furthermore, careful follow up of parapelvic renal cyst patients may be required. PMID- 20192596 TI - Histopathological patterns of female breast lesions at secondary level care in Saudi Arabia. AB - OBJECTIVE: The objective of this study was to characterize the histopathological patterns of female breast lesions encountered at a secondary level care centre in Al Hassa, Saudi Arabia, with special emphasis on multiplicity of benign lesions, their proliferative nature and level of risk for progression. METHODS: In this retrospective, hospital record-based descriptive study, all histopathology records of patients attending King Fahd Hospital in Hofuf, Al Hassa between January 2001 and December 2007, were reviewed using a structured compilation form. Nine and hundred-sixty nine histopathology reports were legible and included. Data regarding type of specimens, age, laterality of the lesions and the prominent cellular morphology were analyzed. RESULTS: Out of 969 records reviewed, benign lesions accounted for 60.1%, followed by malignancy (21.4%) and inflammatory lesions (18.5%). Multiple benign lesions were found in 51.1% and more than two lesions in 21.1% of cases. Non-proliferative breast lesions with low risk were reported in 81.4%, intermediate risk lesion without hyperplastic atypia in 14.6%, while high risk lesions with atypia were only 4.0%. Infiltrating ductal carcinoma was the dominant lesion among the latter and 62.1% of cases were diagnosed before the age of 50 years. CONCLUSION: Benign breast lesion multiplicity is frequent among Saudi female patients; with or without atypia these lesions represent a sizable risk of potential progression to breast cancer. Meticulous follow up with frequent screening may be useful for prevention of cancer development and early intervention in affected patients. PMID- 20192597 TI - Influence of matrix metalloproteinase gene polymorphisms in healthy North Indians compared to variations in other ethnic groups worldwide. AB - Matrix metalloproteinases have a range of biological functions, including the liberation of cytokines and membrane-bound receptors, with roles in promotion of tumor invasion and angiogenesis. Several polymorphisms in MMPs have been implicated in the development of cancer as well as other diseases. Since their frequency distributions in the general North Indian population is not known the present study was conducted with the focus on MMP-1(-519) Aandgt; G, MMP-1(-1607) 1Gandgt; 2G, and MMP-7(-181) Aandgt; G gene polymorphisms. PCR-based analysis was conducted for 200 normal healthy individuals of similar ethnicity. Allelic frequencies in wild type of MMP-1(-519) Aandgt; G were 71.2% A; MMP-1(-1607) 1Gandgt; 2G 48.2% 1G; MMP-7(-181) Aandgt; G 60.7% A. The variant allele frequencies were 29% A in MMP-1(-519) Aandgt; G; 52% 2G in MMP-1(-1607) 1Gandgt; 2G; and 39.3% G in MMP-7(-181) Aandgt; G respectively. We further compared frequency distribution for these genes with various published studies in different ethnicity globally. Our results suggest that frequency in these MMP genes exhibit distinctive patterns in India that could perhaps be attributed to ethnic variation. This study is important as it can form a baseline for screening individuals who are at high risk when exposed to environmental carcinogens. More emphasis is needed on evaluating polymorphisms, alone or in combination, as modifiers of risk from relevant environmental/lifestyle exposures. PMID- 20192598 TI - Oral cancer presentation among Malay patients in hospital Universiti Sains Malaysia, Kelantan. AB - OBJECTIVE: The objective of this study was to identify the characteristics of oral cancer among Malay patients in Hospital Universiti Sains Malaysia (HUSM), Kelantan. METHODS: A retrospective record review was conducted from August to December 2006 in HUSM. Of 133 patients with oral cancer diagnosed from 1986 to 2005, 118 were Malay. Data on socio-demographic background, high-risk habits practiced, clinical and histological characteristics, and treatment profile of the patients were obtained. RESULTS: Malay patients with oral cancer were predominantly elderly, aged 60 years old and above (51.7%) at the time of diagnosis, with a mean age of 58.1 years (SD 16.81). Most patients were males (64.4%) and the majority of them were married (83.9%). More than half (58.5%) had been smokers, and of those who smoked, 89.9% were males. Some had a betel quid chewing habit (22.9%) but none ever consumed alcohol. The majority of the patients (77.1%) were diagnosed at stage IV. The tongue was the most usual site involved (37.3%) and squamous cell carcinoma was the most common histological type seen (75.4%). CONCLUSIONS: The prevalence of oral cancer among Malay patients in HUSM is high (88.7%). It is predominantly found in elderly males and the majority of cases present at advanced stage. PMID- 20192599 TI - Induction of apoptosis in the human Leukemic U937 cell line by Kaempferia parviflora Wall.ex.Baker extract and effects of paclitaxel and camptothecin. AB - Kaempferia parviflora Wall.ex.Baker is a Thai medicinal herb that has high antioxidant and anti-inflammatory activities. Apoptotic effects of the herbal extract alone and in combination with chemotherapeutic drugs, paclitaxel and camptothecin, were here studied in the human promonocytic leukemic U937 cell line. K. parviflora extract suppressed cell proliferation and decreased cell viability in a dose- and time-dependent manner as assessed using the trypan blue exclusion assay. Staining of extract-treated cells with propidium iodide and examination under a fluorescence microscope showed condensed nuclei and apoptotic bodies. Mitochondrial transmembrane potential (MTP) decreased after treatment and the number of cells with decreased MTP also increased. Furthermore, activation of caspase-3 was found in herbal extract-treated cells. When the extract was combined with paclitaxel, an additive effect on U937 cell apoptosis was obtained, whereas camptothecin exerted an antagonistic effect. PMID- 20192600 TI - Chemoprevention of 1,2-dimethylhydrazine-induced colon carcinogenesis by a non steroidal anti-inflammatory drug, etoricoxib, in rats: inhibition of nuclear factor kappaB. AB - Etoricoxib, a highly selective cyclooxygenase- 2 (COX-2) inhibitor (a non steroidal anti-inflammatory drug) used for the treatment of rheumatoid arthritis and osteoarthritis, has been newly marketed and studied for the chemopreventive response in the 1,2-dimethylhydrazine dihydrochloride (DMH) induced rat colon cancer model. Male Sprague-Dawley rats were divided into four groups. Group I served as the Control and received the vehicle treatment, while Groups 2 and 3 were administered freshly prepared DMH (30 mg/kg body weight, subcutaneously) in 1mM EDTA-saline (pH 7.0). Groups 3 and 4 received Etoricoxib (0.64 mg/kg body weight, orally) daily prepared in 0.5% carboxymethyl cellulose. After a 6 week treatment period, animals were sacrificed and the colons were subjected to macroscopic and histopathological studies. Well characterized pre-neoplastic features such as multiple plaque lesions (MPLs), aberrant crypts (ACs) and aberrant crypt foci (ACF) were found in the DMH group. The number was reduced in DMH + Etoricoxib group, while very few MPLs and ACFs were recorded in the Etoricoxib only group. Also, histologically well characterized dysplasia and hyperplasia were observed in DMH treated group. The simultaneous administration of DMH and Etoricoxib reduced these features. To study apoptosis, colonocytes were isolated by metal chelation from colonic sacs and studied by fluorescent staining. The DMH treated animals produced much less apoptotic nuclei as compared to the Control. The number of apoptotic nuclei was also found higher in the DMH + Etoricoxib group as well as in Etoricoxib only group. Studies of a nuclear transcription factor (NF-kB) and COX-2 by Western blot analysis and immunohistochemistry demonstrated expression of both to be elevated in the DMH treated group but reduced in the DMH + Etoricoxib group. Expression was also low in the Etoricoxib only group. It may be concluded that the drug, Etoricoxib, has the potential to reduce DMH induced colon cancer development. PMID- 20192601 TI - Weekly paclitaxel/ docetaxel combined with a platinum in the treatment of advanced non-small cell lung cancer: a study on efficacy, safety and pre medication. AB - OBJECTIVES: To evaluate the efficacy and safety of a weekly taxane schedule in the treatment of advanced non small cell lung cancers (NSCLCs) and to generate an optimal pre-medication protocol for weekly taxane. METHODS: From December 2001 to June 2006, 78 patients with advanced NSCLCs were recruited from the Department of Chemotherapy, Jiangsu Cancer Hospital and Research Institute. Paclitaxel was delivered at 80-100mg/m2 on days 1 and 8 (11 cases), or 50-80 mg/m2 on days 1, 8 and 15 (23 cases), while docetaxel was given with the same schedules at 35-45 mg/m2 (30cases), or 25-35 mg/m2 (14 cases). In all cases this was combined with a platinum-based drug (cisplatin, oxaliplatin or carboplatin) , followed by a 1 week rest. Four pre-medications were attempted were also compared. RESULTS: All 78 patients received a total of 202 courses of treatment. Dose limiting toxicity was myelosuppression. Grades 3 and 4 leukopenia occurred in 19.2% (15/78). Of the 56 eligible patients who completed at least 2 courses, none had a complete response, 20 achieved a partial response and 5 showed progression. Toxicity of pre-medications was indicated by: hypersensitivity (1 case), hypopotassemia (8 cases), myasthenia (5 cases), hiccups (1 case) and infection (2 cases). No treatment related deaths occurred. CONCLUSIONS: Weekly administration of paclitaxel /docetaxel is a safe and active protocol for advanced NSCLCs. Our recommendations for weekly pre-medication with taxane are: dexamethasone 2.25mg 7.5mg orally 12h and 2h before, promethazine and cimetidine 30 min before paclitaxel; oral dexamethasone 4.5mg-7.5mg twice daily for three consecutive days (the day before, the day of, and the day after docetaxel), promethazine and cimetidine 30 min before docetaxel. PMID- 20192602 TI - Pre-treatment hemoglobin levels are important for bladder carcinoma patients with extravesical extension undergoing definitive radiotherapy. AB - PURPOSE: To evaluate prognostic factors affecting local control (LC), distant metastases-free survival (DMFS) and overall survival (OS) in bladder carcinoma patients undergoing extravesical extension. PATIENTS AND METHODS: We retrospectively reviewed the charts of 61 consecutive patients with T3 or T4 bladder carcinoma, treated with definitive radiotherapy from 1999 through 2007. RESULTS: Median age was 69 years and follow-up was 29 months. The LC rate was 33% at 4 years and was increased in patients with a Hb< 12 g/dl (p= 0.003) or a LDH< 180 U/L (p= 0.021) and in those who received concurrent chemotherapy (p= 0.022) on univariate analysis. DMFS was affected by anemia (Hb< 12 g/dl) (p= 0.039), the absence of chemotherapy (p= 0.034) and the presence of newly-diagnosed disease (p= 0.01). The OS rate was 19% at 4 years. Non-pure transitional cell carcinoma histological type (p= 0.024), anemia (p= 0.004), elevated LDH (p= 0.003), and newly diagnosed disease (p= 0.011) were poor prognostic factors on univariate analyses for OS. Anemia was the only negative prognostic factor for LC (p= 0.03), DMFS (p= 0.002) and OS (p< 0.0001) on multivariate analysis. CONCLUSION: Pre treatment Hb level is the most important prognostic factor in patients treated with definitive radiotherapy, so that anemia may act as a surrogate biological marker for aggressive disease. PMID- 20192603 TI - Histopathological findings for cervical lesions in Malaysian women. AB - OBJECTIVE: The objective of this study was to determine the histopathological features and cell morphology of various cervical lesions observed among Malaysian women. METHODOLOGY: A retrospective study was conducted to evaluate 77 cervical cases collected from the histopathology laboratory of Ipoh hospital from 1st January, 2005, to 31st December, 2006. RESULTS: Cervical intraepithelial neoplasia (CIN) was found in 33 (42%) cases, CIN III accounting for 27%, and CIN I, CIN II and CIN II-III 5% each. The highest rate for CIN cases was 43% in the 41-50 year age group and the lowest rate was 6% in the group aged 61-70 years. Non-keratinizing and metastatic squamous cell carcinomas (SCCs) accounted for 16% and 13%, respectively, the combination being second in majority (29%), followed by adenocarcinoma (17%). The histopathological results showed CIN I to be characterized by mild papillary projections of the epithelium with some degree of nuclear enlargement, pleomorphism, mild koilocytosis, bionucleated cells and a low nucleo-cytoplasmic ratio. CIN II demonstrated typical squamous epithelium with disorganization of the lower part of the epithelium accompanied by nuclear hyperchromatism, an increased nucleo-cytoplasmic ratio, and scanty mitotic figures. CIN III was characterized by pleomorphic nuclei, atypical cells with mitotic figures, nucleo-cytoplasmic ratio, anisokaryosis and hyperchromasia. CONCLUSION: Lesions related to cervical cancer showed tumor progression correlating with histopathological changes in cell morphology. PMID- 20192604 TI - Colorectal cancer patients in a tertiary referral centre in Malaysia: a five year follow-up review. AB - BACKGROUND: Colorectal cancer (CRC) is one of the major malignancies in the world. In Malaysia, CRC is fast becoming the commonest cause of cancer death. Its etiology is complex, involving both environmental and genetic factors. This study looked at the profile and outcome of five-year follow-up of patients with CRC. MATERIALS AND METHODS: Retrospective case review study done on CRC patients at University Kebangsaan Malaysia Medical Centre (UKMMC), Kuala Lumpur, Malaysia. Patientsandapos; socio-demographic characteristics, modalities of treatment, cancer characteristics and outcome at 5-year follow up were extracted from the case records. RESULTS: A total of 107 case records of patients were analyzed. Peak age of CRC presentation was 40-69 years (71.1%). Male to female ratio was 1.2:1 with Chinese predominance (52.3%). Anaemia and its related symptoms including per rectal bleeding was the commonest clinical presentation. The median duration of clinical presentation was 13 weeks (IQR 21.8). More than two-thirds presented as non-emergency cases (69.2%). Most patients presented with Dukes C stage (40.2%). The overall 5-year survival rate was 40% with local recurrence rate of 19.6%. Metastasis after curative-intend treatment (surgery with adjuvant therapy) developed in 26% of patients. Lower recurrence (p = 0.016, OR = 0.205) and metastatic disease (p = 0.02, OR = 0.24) found among the Chinese patients. Almost half of the patients defaulted follow up care (43%), most often within the first year of treatment (22.4%) and the Chinese were the least likely to default (p= 0.04, OR = 0.45). CONCLUSION: Socio-demographic profile of CRC patients in UKMMC is comparable to Asia pacific region. Apparent delay in seeking treatment gives rise to poor overall survival and local recurrence rates. PMID- 20192605 TI - Prevalence of tobacco use and tobacco-dependent cancers in males in the Rural Cancer Registry population at Barshi, India. AB - BACKGROUND: In the Rural Cancer Registry at Barshi (western Maharashtra, India), it has been found that the incidence of cancer is relatively low. AIM: To explain the low incidence of tobacco related cancers in males on the basis of prevalence of their tobacco habits. SETTING AND DESIGN: Simple random sample of villages from Barshi Rural Cancer Registry. MATERIAL AND METHODS: A tobacco survey was carried out in 5,319 adult males. Site specific incidence data for Barshi and Mumbai Cancer Registries were available from published reports in the National Cancer Registry Programme. Published report of prevalence of tobacco habits in Mumbai males was available. RESULTS: The tobacco survey showed that the prevalence of smoking compared to Mumbai was low (9.9% vs 23.6%) and the incidence of smoking dependent cancers viz., cancers of oropharynx, larynx and lung were significantly low (P< 0.05). However, although the proportion of tobacco chewers is higher in Barshi compared to Mumbai, the incidence rates for cancer of hypopharynx and oral cancer which are predominantly chewing dependent did not show higher rate than in Mumbai. CONCLUSIONS: The low incidence of smoking dependent cancers in males can be explained by the low prevalence of smoking habit but further studies are needed to explain the observed incidence of predominantly chewing dependent cancers. PMID- 20192606 TI - Significance of alanine aminotransferase testing in diagnosis of acute and chronic HBV infection. AB - Hepatitis B is a major public health problem world wide; more than 350 million people have chronic infection. Diagnosis of hepatitis is made by biochemical assessment of liver function. Alanine aminotransferase (ALT), a liver enzyme, is markedly elevated in hepatitis and with other causes of acute liver damage associated with hepatic necrosis, blood levels being elevated even before the clinical signs and symptoms of disease such as jaundice appear. HBsAg can be detected in the serum from several weeks before onset of symptoms to several months after onset of acute HBV infection. The presence of HBsAg indicates that the person is potentially infectious. In our study we found that 80% patients who were HBsAg positive had abnormal ALT levels, while the remaining 20% had normal ALT values. This is despite suffering from acute or chronic liver disease, providing a reason why some patients positive for hepatitis B have a normal ALT. PMID- 20192607 TI - Identification of a hepatitis B virus core promoter mutant by PCR- RFLP in patients suffering from chronic liver disease, Uttar Pradesh, India. AB - OBJECTIVE: The present study was designed to identify a core promotor mutation in the HBV genome in patients suffering from HBV related chronic liver disease. MATERIALS AND METHODS: 154 chronic liver disease patients were selected for study of DNA extracted using a pure viral DNA extraction kit. The core promoter mutation was detected by the polymerase chain reaction- based restriction fragment length polymorphism (PCR-RFLP) method, using the Sau 3AI restriction enzyme to see if cleavage would occur at this specific site. RESULTS: Among the total of 154, 78 patients were found positive for HBsAg and 71 samples were found to be positive for HBV DNA by first round PCR. The over all prevalence of core mutant was 51(71%) in the 71 patients. 11 (68.8%) of 16 patients, excluding 1 patients with mixed type mutation was detected in inactive HBsAg carriers, 39 (81.3%), excluding 2 patients with mixed type was detected in chronic hepatitis B, and 4/7 (57%) in patients with liver cirrhosis were found. CONCLUSION: Our study concluded that the prevalence of the core promoter mutation in the BCP region was higher in the patients with chronic hepatitis B than in liver cirrhosis and HBsAg carriers. The Sau3AI assay, which is much more convenient than sequencing, was shown to be useful for the detection of the core promoter mutant in an extensive number of clinical samples. Monitoring and detection of HBV variants by PCR-RFLP in chronic infection may improve the management of these patients. PMID- 20192608 TI - Lack of effects of single nucleotide polymorphisms of the DNA methyltransferase 1 gene on gastric cancer in Iranian patients: a case control study. AB - BACKGROUND: Gastric cancer is one of the most common malignant tumors in Iran. Hypomethylation and/or hypermethylation of DNA has been described in gastric cancer and is presumed to be an early event in carcinogeneisis. OBJECTIVE: We therefore hypothesized that single nucleotide polymorphisms of the DNMT1 gene may be associated with the genetic susceptibility to gastric cancer. METHODS: Totals of 200 patients and 200 controls, both of Iranian origin, were studied. Three polymorphisms were genotyped by PCR-RFLP and allele frequencies and genotypes were compared between the cases and controls. Odds ratios were calculated and the interactions between the polymorphisms, age and sex were examined. RESULTS: There were no significant associations between the DNMT1 polymorphisms and gastric cancer. CONCLUSION: We could not show any association between DNMT1 polymorphisms and gastric cancer. Larger sets of polymorphisms and sample sizes are required for future testing of possible associations. PMID- 20192609 TI - Colostomy irrigation: an important issue for Muslim individuals. AB - Colostomy irrigation (CI) is a bowel management method in individuals with permanent colostomy, as an alternative to pouch use, which may provide continence. CI helps the individuals with an artificial stoma to adjust to the stoma and may increase their quality of life (QOL). An uncontrolled intestinal gas discharge invalidates ablution, and noisy gas discharge and smell prevents congregational prayers, which cause problems to Muslims with stomas. Therefore, CI may be an appropriate solution for this patient group. Using the example of one affected individual we discuss how the praying problem can be resolved with teaching to self-perform CI and emphasize the beneficial effects on QOL. PMID- 20192610 TI - Proposal for a cooperative study on population-based cancer survival in selected registries in East Asia. AB - Reliable population-based cancer survival data are essential for assessment of the effectiveness of cancer screening programs, distribution of cancer therapy and prevalent cancer cases. International comparisons are useful to allow societies, mass media and health authorities to gain a real appreciation of the cancer problem in their own country and provide an impetus to improve registration and cancer control planning. Since directly comparable survival data among East Asian countries are presently very limited, a comparative study on population-based cancer survival involving China, Indonesia, Japan, Korea, the Philippines and Taiwan, with Nepal as an observer, was proposed. At the 1st Working Group meeting in Tokyo on March 18th, 2009, it was decided to publish the present Commentary as a step towards realization of truly comparable cancer survival statistics in the region. Included are general information and quality of data of cancer registration at each participating registry and five-year relative survival rates of cancer of the stomach, colo-rectum, liver, lung, breast and cervix. PMID- 20192611 TI - Determination of the amount of micelles in alkylphospholipid liposome formulations with electron paramagnetic resonance method. AB - Alkylphospholipids (APLs) are physiologically active derivatives of lipids with high efficiency in the therapy of experimental human breast cancer. Therefore, they are usually used as liposome formulations, since the application of free, micellar APLs results in serious side effects, such as hemolysis. Since only rough upper estimates of micelle proportions were obtained until now, we developed a new method, based on the spectral decomposition of electron paramagnetic resonance (EPR) spectra. The EPR spectra of different spin-labeled mixed liposome-micelle samples were fitted with a fast, automatic fitting procedure. In this way, we achieved more accurate estimates of the relative proportion of micelles, in comparison to the previously used methods. We confirmed findings of previous studies, which showed that the amount of micelles in OPP liposome formulations increases with a decreasing amount of cholesterol. We analyzed liposome formulations with 29, 39, and 46 mol% of cholesterol and determined the relative proportion of micelles to be 20 +/- 9, 11 +/- 4, and 5 +/ 2, respectively. This study confirms that the efficiency of OPP liposome formulations in experimental breast cancer therapy is not solely a consequence of the amount of micelles present in a liposome formulation, but stems from a propensity of liposomes to interact with cells. PMID- 20192612 TI - Outcomes of percutaneous nephrolithotomy stratified by body mass index. AB - BACKGROUND: Obesity places surgical patients at a greater risk of complications. The effects of obesity on outcomes and complications from percutaneous nephrolithotomy (PCNL) are not well defined. OBJECTIVE: The objective of this study was to stratify outcome and morbidity of PCNL with respect to body mass index (BMI) in a large contemporary series. METHODS: The charts of 234 patients who underwent PCNL were reviewed retrospectively. Patients were divided into four groups depending on their BMIs: ideal body weight (IBW) <25 kg/m(2), overweight 25 to 29.9 kg/m(2), obese >or=30 to 34.9 kg/m(2), and morbidly obese >or=35 kg/m(2). Kidney stone diameter was measured on preoperative computerized tomography scans. Hemorrhage was estimated using hematocrit. Univariate analysis was performed with respect to hospital length of stay (HLOS), stone size, complication rate, hemorrhage, and stone-free rate. RESULTS: Of the 234 patients undergoing PCNL (mean age, 54.3 +/- 13.6 years; 54% male), height and weight data were available for 187 (80%) with a mean BMI of 29.3 +/- 8.0 (range 14.1-57.2); 38 (20.3%) were morbidly obese, 43 (23%) obese, 45 (24.1%) overweight, and 61 (32.6%) were within or below their IBW. Mean stone sizes were comparable: 3.9 +/- 2.0 cm (morbidly obese), 3.7 +/- 2.0 cm (obese), 3.1 +/- 1.4 cm (overweight), and 3.6 +/- 1.9 cm (IBW). Mean HLOS (days) was similar between groups: 2.6 +/- 1.7 (morbidly obese), 2.8 +/- 2.0 (obese), 2.5 +/- 1.2 (overweight), and 3.4 +/- 4.7 (IBW). The largest interval decreases in hematocrit (mg/dL) were also comparable: 5.3 +/- 3.8 (morbidly obese), 5.9 +/- 4.3 (obese), 7.2 +/- 4.1 (overweight), and 6.2 +/- 4.3 (IBW). Using strict imaging criteria, the overall stone-free rate was 80%. No statistically significant differences among the three groups were seen with respect to HLOS, stone-free rate, complication rate, or change in hematocrit when stratified by BMI. CONCLUSION: Stone-free rate, complication rate, hemorrhage, and HLOS are independent of BMI in a retrospective review of patients undergoing PCNL. PMID- 20192613 TI - Malfunction of the Da Vinci robotic system during robot-assisted laparoscopic prostatectomy: an international survey. AB - PURPOSE: To determine how urologists manage technical malfunction of the Da Vinci robotic system during robot-assisted radical prostatectomy (RARP). MATERIALS AND METHODS: A web-based survey was sent to urologists performing RARP. The survey questions were related to the stage of operation during which robotic malfunction occurred, management of malfunctions, and most common types of robotic malfunction. In addition, data were collected concerning surgical volume and training. RESULTS: One hundred (56.8%) of the 176 responding surgeons had experienced an irrecoverable intraoperative malfunction. Eighty respondents experienced mechanical failure before starting RARP, of which 46 (57.5%) rescheduled, 15 (18.8%) performed an open radical approach, 12 (15%) performed standard laparoscopic prostatectomy, and 4 (4.9%) docked another robot. Sixty three respondents experienced mechanical failure before starting urethrovesical anastomosis, of which 26 (41.2%) converted to an open procedure, 20 (31.7%) converted to standard laparoscopy, 10 (15.8%) finished with one less arm, and 3 (4.7%) aborted the procedure. Thirty-two respondents experienced malfunction before completion of the anastomosis, of which 20 (62.5%) converted to standard laparoscopy, while 12 (37.5%) converted to open surgery. Fellowship trained surgeons were more likely to complete the prostatectomy using standard laparoscopy (P = 0.05). No significant differences existed between surgeons performing a high volume or low volume of prostatectomies in regard to management of malfunctions. CONCLUSION: Intraoperative breakdown of the Da Vinci robot is uncommon, but patients should be counseled preoperatively and a plan devised on how breakdown will be managed. Intracorporeal suturing skills allow conversion to a pure laparoscopic approach, if necessary. Consequently, standard laparoscopic suturing skills should remain in the residency curriculum. PMID- 20192615 TI - Health behaviors, periodontal conditions, and periodontal pathogens in spontaneous preterm birth: a case-control study in Korea. AB - BACKGROUND: This study aims to determine whether periodontal conditions or dental health behaviors are risk factors for preterm birth (PTB), and whether periodontal pathogens are risk indicators for PTB among Korean mothers. METHODS: This study was designed as a hospital-based case-control study. Examiner masking was ensured for the validity of the examinations. The mothers included those who gave birth between November 2007 and July 2009 at the obstetrics clinic of a general hospital in Seoul, Korea. Information on demographic and health conditions, periodontal conditions, and microbacterial data was collected. RESULTS: A total of 172 women met the inclusion criteria, 59 mothers who delivered a preterm neonate were assigned to the case group while the other 113 were assigned to the control group. There were no significant differences in demographic information, oral health conditions, and obstetric characteristics. Among health-related behaviors, only scaling within 12 months before pregnancy showed a significant difference (P = 0.031). Even in the adjusted logistic model, only the difference in the experience of scaling before pregnancy was significant between the PTB cases and the controls (P = 0.039). Periodontal disease did not exhibit a significant relationship with PTB even after adjustment for potential confounding factors. Among the microbacterial factors, only Porphyromonas gingivalis showed a slight difference (P = 0.060). CONCLUSION: There was a significant difference in scaling experience within 12 months before pregnancy and P. gingivalis showed a marginal difference between the PTB and the control groups but clinical periodontal conditions showed no association with PTB. PMID- 20192616 TI - Immediate placement of implants into infected sites: a systematic review of the literature. AB - BACKGROUND: Immediate implant placement of dental implants into fresh extraction sockets was shown to be a predictable and successful procedure when proper protocols were followed. Placement into infected sites has been considered a relative contraindication. However, data from animal research, human case reports and case series, and prospective studies showed similar success rates for implants placed into infected sites compared to implants placed in non-infected or pristine sites. The focus questions addressed in this review are: Does the presence of infection compromise the osseointegration of immediate placement of implants? Does the presence of infection compromise immediately placed implant success? What protocols have been used to address the infection prior to immediate implant placement? METHODS: A systematic search of MEDLINE/PubMed articles published from 1982 up to and including November 2009 was independently performed by two investigators (JAW and CIE). The search strategy used combinations of the following terms: dental implants, immediate, immediately, extraction, infection, infected, and pathology. The search included data from animal and human studies. The selection criteria excluded animal studies that did not include a pristine control group and human case reports and case series with <1 year of follow-up. All prospective human studies were included. Studies were limited to those published in the English language, and review article data were excluded. RESULTS: The search strategy initially yielded 417 references. After screening the abstracts for those related to the focus questions, 12 publications qualified for inclusion. The majority of studies examined sites with chronic periapical infection; however, the classification of infection was often vague and not categorized to be related to the outcome. The data from animal studies demonstrated high levels of implant survival, although conflicting data showed that the bone-to-implant contact may be impaired. Human studies showed high levels of implant survival consistent with therapy in non-infected sites, but evidence was limited to a small number of studies and patients. Thorough debridement and the use of systemic antibiotics were employed in all studies. CONCLUSIONS: Evidence suggests implants can be placed into sites with periapical and periodontal infections. The sites must be thoroughly debrided prior to placement. Guided bone regeneration is usually performed to fill the bone-implant gap and/or socket deficiencies. Although controversial, systemic antibiotics should be used until further controlled trials prove otherwise. PMID- 20192617 TI - Serum levels of cytokines in subjects with generalized chronic and aggressive periodontitis before and after non-surgical periodontal therapy: a pilot study. AB - BACKGROUND: The emergence of periodontal medicine has increased interest in defining the serologic profiles of inflammatory mediators in subjects with periodontitis. Thus, the aim of this pilot study is to evaluate the serum levels of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma, and interleukin (IL)-4, -17, and -23 in subjects with generalized chronic periodontitis (GCP) and generalized aggressive periodontitis (GAgP) before and after non-surgical periodontal therapy. METHODS: Cytokines were measured by enzyme-linked immunosorbent assay in serum samples taken from 42 systemically healthy subjects divided according to periodontal status into subjects with GAgP (n = 14) and GCP (n = 14) and periodontally healthy (PH) subjects (n = 14). In addition, the levels of cytokines were reassessed at 6 months after periodontal therapy in the periodontitis groups. Clinical parameters were also evaluated at baseline and 6 months post-therapy. RESULTS: After therapy, both periodontitis groups demonstrated a significant improvement in clinical periodontal status (P <0.05). At baseline, concentrations of TNF-alpha (P = 0.0006) and IL-17 (P = 0.02) were significantly higher in the GAgP group compared to the other groups. There was a significant decrease in serum concentrations of TNF-alpha (P = 0.03) and IL-17 (P = 0.04) at 6 months post-therapy in the GAgP group (P <0.05). The concentration of TNF-alpha remained elevated in the GAgP group compared to the PH group at 6 months post-therapy (P = 0.04). CONCLUSIONS: Subjects with GAgP presented higher levels of TNF-alpha and IL-17 than subjects with GCP and PH subjects. In addition, although the serum levels of these cytokines improved significantly as a result of periodontal therapy, the levels of TNF-alpha remained higher in subjects with GAgP compared to PH subjects. PMID- 20192618 TI - Predetermination of root coverage. AB - BACKGROUND: A method to predetermine the maximum root coverage level (MRC) achievable with surgery was recently presented. The present study evaluates the predictability of such a method by comparing the predetermined MRC with that effectively achieved by means of root coverage surgical procedures. METHODS: A total of 50 patients with single and multiple recession defects were enrolled. MRC was predetermined by an independent periodontist by assessing the ideal height of the interdental papilla. The distance from the apical reference point of a stent (StRP) and the MRC was measured 7 days before root coverage surgery. A total of 135 Miller Class I, II, and III gingival recessions were treated with the coronally advanced flap (CAF) or with the subepithelial connective tissue graft (SCTG). The distance from StRP and the gingival margin (GM) was measured by another independent periodontist 15, 30, and 90 days after surgery. RESULTS: In 97 (71.8%) of 135 treated gingival recessions, the StRP-MRC distance coincided exactly with the StRP-GM distance. No statistically significant difference was demonstrated in the cases with exact predetermination between gingival recessions belonging to the maxilla or mandible and between gingival defects treated with CAF or SCTG. The StRP-MRC distance measured before surgery was greater in 24 recession defects (17.7%) and lower in 14 gingival recessions (10.3%) than the StRP-GM distance measured 90 days after surgery. More cases of underestimation and fewer cases with overestimation of the level of root coverage were found in the SCTG group compared to the CAF group. The difference was statistically significant (P <0.01). CONCLUSIONS: The adopted method was effective in predetermining the position of the soft tissue margin 90 days after root coverage surgery. The cases with underestimation of the level of root coverage should be considered clinically and esthetically successful. PMID- 20192619 TI - Comparative evaluation of topical and electronic anesthesia during scaling and root planing. AB - BACKGROUND: Scaling and root planing (SRP) in periodontitis is considered to be painful and thus requires anesthesia. The present study evaluates the effectiveness of a eutectic mixture of 25 mg/g lignocaine plus 25 mg/g prilocaine and thermosetting agents (EMLA), 20% lignocaine patch, and electronic dental anesthesia (EDA) during SRP. METHODS: In a single-center, randomized, controlled study, 25 subjects with probing depth of 5 mm or more and visual analog scale (VAS) score of >or=30 mm on probing were selected and asked to assess the pain by VAS and verbal rating scale (VRS) during SRP after application of the three agents. RESULTS: The difference between VAS values of patch and EDA (P = 0.012) and EMLA and EDA (P = 0.018) is significant, whereas that between patch and EMLA is non-significant (P = 1.000). The difference between VRS values of patch and EDA (P = 0.046) is significant, whereas that between patch and EMLA (P = 0.655) and EMLA and EDA (P = 0.180) is non-significant. According to the VRS scores, 12% of the subjects in the patch group reported no pain, 84% mild pain, and 4% moderate pain. In the EMLA group, 16% reported no pain, 76% mild pain, and 8% moderate pain. In the EDA group, 88% reported mild pain and 12% moderate pain. None reported severe pain. One subject in the patch group had an adverse event of slight redness. CONCLUSIONS: The data suggest the topical agents used, 5% EMLA and 20% lignocaine patch, are more effective and comparable. Both are superior in performance to EDA. PMID- 20192620 TI - Functional outcome after resection of spinal cord hemangioblastomas associated with von Hippel-Lindau disease. AB - OBJECT: Spinal cord hemangioblastomas are a common protean manifestation of von Hippel-Lindau (VHL) disease and can be associated with significant morbidity. To better define expected outcome and optimal management of these tumors in the context of this neoplasia syndrome, the authors analyzed the findings from patients with VHL disease who underwent resection of spinal cord hemangioblastomas. METHODS: Consecutive patients with VHL disease who underwent surgery for spinal cord hemangioblastomas with > 6 months follow-up were included in the study. Serial clinical examinations, functional scores, imaging findings, and operative records were analyzed. RESULTS: One hundred eight patients (57 male, 51 female) underwent 156 operations for resection of 218 spinal cord hemangioblastomas. One hundred forty-six operations (94%) were performed for symptom-producing tumors. The most common presenting symptoms included hypesthesia (64% of resections), hyperreflexia (57%), dysesthesia (43%), and weakness (36%). Mean follow-up was 7.0 +/- 5.0 years (range 0.5-20.9 years). Complete resection was achieved for 217 tumors (99.5%). At 6-months follow-up, patients were stable or improved after 149 operations (96%) and worse after 7 operations (4%). Ventral tumors (OR 15.66, 95% CI 2.54-96.45; p = 0.003) or completely intramedullary tumors (OR 10.74, 95% CI 2.07-55.66; p = 0.005) were associated with an increased risk of postoperative worsening. The proportion of patients remaining functionally stable at 2, 5, 10, and 15 years' follow-up was 93, 86, 78, and 78%. Long-term functional decline was caused by extensive VHL associated CNS disease (6 patients), VHL-associated visceral disease (1 patient), or non-VHL disease (2 patients). CONCLUSIONS: Resection of symptomatic spinal cord hemangioblastomas is a safe and effective means of preserving neurological function in patients with VHL disease. Tumor location (ventral or completely intramedullary) can be used to assess functional risk associated with surgery. Long-term decline in neurological function is usually caused by VHL-associated disease progression. PMID- 20192621 TI - Accuracy and pitfalls of multidetector-row computed tomography in detecting spinal dural arteriovenous fistulas. AB - OBJECT: The purpose of this study was to evaluate the accuracy of multidetector row CT angiography (MDCTA) in demonstrating spinal dural arteriovenous fistulas (SDAVFs). METHODS: The authors studied 10 patients with SDAVFs, including 2 with spinal epidural AVFs, who underwent preoperative MR imaging, MDCTA, and digital subtraction angiography (DSA). In the evaluation of coronal sections of multiplanar reformation MDCTA images, inspection was focused on the presence of the following findings: 1) dilated perimedullary veins in the spinal canal; 2) focal enhancement of the nerve root, suggesting the location of the AVF, around the dural sleeve; and 3) a radicular vein that drains the AVF into perimedullary veins. The utility of MDCTA was assessed by comparing its findings with those of DSA in each case. RESULTS: Digital subtraction angiography confirmed that the AVFs were located in the thoracic spine in 4 patients and in the lumbar spine in 6 patients, and MDCTA detected dilated perimedullary veins in all 10 patients. In 8 patients, there was focal enhancement of the nerve root. The radicular vein that drains the AVF into the perimedullary veins was found in 8 cases. In 8 cases, the MDCTA-derived level and side of the AVF and its feeder corresponded with those shown by DSA. In 2 patients, however, the MDCTA-derived side of the feeder was on the side contralateral to the feeding artery confirmed by DSA. These lesions were interpreted as spinal epidural AVFs with perimedullary drainage. In 2 cases, MDCTA could not detect the multiplicity of their feeders. CONCLUSIONS: The use of MDCTA preceding DSA can be helpful to focus the selective catheter angiography on certain spinal levels. However, one should keep in mind that epidural AVFs with perimedullary drainage may resemble SDAVFs and also that MDCTA cannot exclude the possibility of multiple feeders. Further research should elucidate how broadly selective angiography should explore around the MDCTA suggested target. PMID- 20192622 TI - Coincidence of cervical spondylotic myelopathy and intramedullary ependymoma: a potential diagnostic pitfall. AB - The authors report the case of a 58-year-old man presenting with a 3-year history of clinical signs of progressive cervical spondylotic myelopathy (CSM). Magnetic resonance imaging showed a severe stenosis of the cervical spinal canal at C3-4 and C5-6 levels due to multiple discopathies. High signal intensities on T2 weighted MR images of the spinal cord and low signal intensities on T1-weighted images at the C2-6 levels were noted, as was contrast enhancement at the C3-4 level. The patient underwent a bilateral decompressive laminectomy at C3-6. The patient did not show any clinical improvement. Thus, further cervical MR imaging was performed and the differential diagnosis of an intramedullary tumor was considered in view of the persisting intramedullary enhancement. This diagnosis prompted a second operation involving a posterior midline myelotomy and excision of an intramedullary ependymoma at the C3-4 level. Intramedullary tumors should be considered in the differential diagnosis of CSM with an atypical pattern of MR imaging features. PMID- 20192623 TI - Neurological function after total en bloc spondylectomy for thoracic spinal tumors. AB - OBJECT: Total en bloc spondylectomy (TES) for thoracic spinal tumors may in theory produce neurological dysfunction as a result of ischemic or mechanical damage to the spinal cord. Potential insults include preoperative embolization at 3 levels, intraoperative ligation of segmental arteries, nerve root ligation, and circumferential dural dissection. The purpose of this study was to assess neurological function after thoracic TES. METHODS: The authors performed a retrospective review of 79 patients with thoracic-level spinal tumors that had been treated with TES between 1989 and 2006. Neurological function was retrospectively analyzed according to the Frankel grading system. Of the 79 cases, 26 involved primary tumors and 53 involved metastatic tumors. The number of excised vertebrae was 1 in 60 cases, 2 in 13, and >or= 3 in 6. The Frankel grade before surgery was B in 1 case, C in 16, D in 29, and E in 33. RESULTS: At the follow-up, the Frankel grade was C in 2 cases, D in 24, and E in 53. Of 46 cases with neurological deficits before surgery, neurological improvement of at least 1 Frankel grade was achieved in 25 cases (54.3%). Although the Frankel grade did not change in 21 patients, improvement in neurological symptoms within the same Frankel grade did occur in these patients. There were no cases of neurological deterioration. CONCLUSIONS: There was no neurological deterioration due to preoperative embolization, ligation of segmental arteries, or ligation of thoracic nerve roots. Each of the cases with preoperative neurological deficits showed improvement in neurological symptoms. Data in the current study clinically proved that TES is a safe operation with respect to spinal cord blood flow. In TES, the spinal cord is circumferentially decompressed and the spinal column is shortened. An increase in spinal cord blood flow due to spinal shortening in addition to decompression was considered to have brought about a resolution of neurological symptoms with TES. PMID- 20192624 TI - Atypical spine involvement of Erdheim-Chester disease in an elderly male. AB - Erdheim-Chester disease is a rare form of non-Langerhans histiocytosis presenting in the 5th through 7th decades of life. Osseous manifestations include symmetrical sclerosis of the long bones and, rarely, the spine. Central nervous system disease commonly affects the white matter tracts as well as the orbits, but epidural disease is rare. To the best of the authors' knowledge, simultaneous epidural and skeletal spine disease has not been reported. The MR imaging characteristics of skeletal spine disease have also not been reported. The authors describe the case of an 87-year-old man with both epidural and skeletal spine disease. The clinical characteristics, imaging manifestations, and the histological features are discussed. PMID- 20192625 TI - A clinical analysis of 4- and 6-year follow-up results after cervical disc replacement surgery using the Bryan Cervical Disc Prosthesis. AB - OBJECT: In this study, long-term results are presented from clinical studies of the Bryan Cervical Disc Prosthesis at University Hospital Gasthuisberg in Leuven, Belgium. A total of 98 patients (89 with 1-level and 9 with 2-level implantations) agreed to participate in follow-up studies for up to 10 years postoperatively. This article focuses on the 4- and 6-year results. Patients in one of the clinical studies had either radiculopathy or myelopathy associated with spondylosis and/or disc herniations that did not respond to conservative treatment. Patients from the other clinical study received commercially available Bryan devices and the study protocol did not have specific inclusion/exclusion criteria. More than 90% of the patients were considered to have radiculopathy. METHODS: Clinical measurements discussed in the article include the 36-Item Short Form Health Survey, Neck Disability Index, numerical ratings of neck and arm pain, neurological outcomes, and Odom classification. Angular motion findings from lateral flexion-extension radiographs are also presented. The occurrence of adverse events and second surgeries are examined as an indicator of device safety. RESULTS: The clinical outcomes at 4 and 6 years postoperatively appear consistent with the previously reported results at 1 and 2 years postoperatively. The mean angular motion results at 4 and 6 years postoperatively for 1-level patients were 7.3 and 7.7 degrees, respectively. Two-level patients had slightly less motion at 4 and 6 years postoperatively with mean caudad values of 5.7 and 6.0 degrees, respectively, and cephalad values of 4.2 and 6.2 degrees, respectively. Efforts were made to capture adverse events, regardless of their nature and relatedness to the study surgery. This effort resulted in a relatively high number of recorded events. However, only 6 patients experienced events that were judged by the investigator to be related, either possibly or definitely, to the Bryan device. These events included device migration, device removal, and hoarseness and vocal cord paralysis, as well as 3 cases involving pain and neurological symptoms. Eight patients underwent further neck surgery to treat symptoms. CONCLUSIONS: The favorable clinical and angular motion outcomes that were previously noted at 1- and 2-years' follow-up after cervical disc replacement with the Bryan Cervical Disc Prosthesis appear to persist after 4 and 6 years of follow-up. PMID- 20192626 TI - The anatomy, spatial relationships, and role of uncovertebral articulations as the source of posterolateral cervical cartilage sequestrations. AB - OBJECT: The aim of this study was to investigate the spatial relationships of the uncovertebral articulations (UAs) with the dural origins of the C-5, C-6, and C-7 nerve roots. METHODS: The C3-7 segment of the cervical spine was removed from 18 embalmed cadavers. Spatial relationships between the C-5, C-6, and C-7 nerve roots and the UAs were examined using combinations of standard surgical approaches together with cross-sections at the level of the dural origins of the nerve roots and exposures of the floor of the spinal canal. RESULTS: The cartilaginous interspace that underlies the dural origin of a nerve root is the interspace of a UA. It is interposed between the central core cartilage of the disc and the dural origin of a nerve root. Cervical nerve roots do not come in contact with the interspace of an intervertebral disc at any site from their dural origin to their exit from the spinal canal. A cartilage fragment that originates from the central core cartilage of the disc may compress the intradural segment of the nerve root by migrating to that site within the epidural space, but it is blocked from reaching the dural origin of a nerve root by the interspace of a UA that is filled with fibrocartilage. CONCLUSIONS: Anatomical considerations indicate that the source of posterolateral cervical cartilage sequestrations is the cartilaginous interspace of a UA rather than that of an intervertebral disc. PMID- 20192627 TI - The rationale of postoperative radiographs after cervical anterior discectomy with stand-alone cage for radicular pain. AB - OBJECT: Cervical anterior discectomy with stand-alone cage (CADC) placement is a known treatment for cervical radiculopathy due to a herniated intervertebral disc or an osteophyte. Routine radiographs are obtained at regular postoperative intervals, but the consequences of routinely obtained radiographs are not known. In this study, the authors evaluated whether postoperative plain radiographs influenced the medical or surgical treatment of patients who underwent CADC placement. METHODS: The charts and radiographs of all patients who underwent CADC placement in 2007 were retrieved and reviewed retrospectively. In addition, the charts and radiographs of 50 consecutive patients who were seen after a CADC was placed during a period in 2008 were studied prospectively. Special emphasis was given to any abnormalities seen on the radiographs and especially their influence on further treatment. RESULTS: The charts and radiographs of 82 patients were retrospectively examined. A total of 138 levels were addressed, and in the prospective series 75 levels were surgically treated. The subsidence rate in the retrospective series was 14.5%. In 1 patient a slight anteroposition of the cage was seen. None of the radiographic abnormalities were related to the outcome of the patient or contributed to a change in the patient's treatment. CONCLUSIONS: Routine radiographs after CADC placement are not warranted. Intraoperative verification of the position of the cage is recommended. Obtaining radiographs are only mandatory when signs or symptoms suggesting a postoperative complication are present. The authors propose a new algorithm for the follow-up of patients after CADC placement. PMID- 20192628 TI - Surgery for cervical dystonia: the emergence of denervation and myotomy techniques and the contributions of early surgeons at The Johns Hopkins Hospital. AB - Cervical dystonia is a psychologically and physically disabling disease that has intrigued clinicians since the early history of surgery. Because of its elusive etiology, its operative treatment has had an extended evolutionary voyage. Early surgical approaches involved resection of the sternocleidomastoid muscle. Later recognition of more diffuse involvement of the posterior neck muscles led to the introduction of new techniques with more effective results. A review of available surgical patient records at The Johns Hopkins Hospital from around the turn of the 20th century provided a glimpse of the early history of the operative treatment for torticollis through the work of some of the leaders of surgery, including Halsted, Cushing, and specifically Finney. Here, the authors present a segment of history on the surgical treatment of this disease as it relates to the introduction of myotomy and denervation techniques. PMID- 20192629 TI - A computed tomography-based feasibility study of translaminar screw fixation in the upper thoracic spine. AB - OBJECT: Translaminar screws (TLSs) offer an alternative to pedicle screw (PS) fixation in the upper thoracic spine. Although cadaveric studies have described the anatomy of the laminae and pedicles at T1-2, CT imaging is the modality of choice for presurgical planning. In this study, the goal was to determine the diameter, maximal screw length, and optimal screw trajectory for TLS placement at T1-2, and to compare this information to PS placement in the upper thoracic spine as determined by CT evaluation. METHODS: One hundred patients (50 men and 50 women), whose average age was 41.7 +/- 19.6 years, were selected by retrospective review of a trauma registry database over a 6-month period. Patients were included in the study if they were over the age of 18, had standardized axial bone-window CT imaging at T1-2, and had no evidence of spinal trauma. For each lamina and pedicle, width (outer cortical and cancellous), maximal screw length, and optimal screw trajectory were measured using eFilm Lite software. Statistical analysis was performed using the Student t-test. RESULTS: The T-1 lamina was estimated to accommodate, on average, a 5.8-mm longer screw than the T-2 lamina (p < 0.001). At T-1, the maximal TLS length was similar to PS length (TLS: 33.4 +/- 3.6 mm, PS: 33.9 +/- 3.3 mm [p = 0.148]), whereas at T-2, the maximal PS length was significantly greater than the TLS length (TLS: 27.6 +/- 3.1 mm, PS: 35.3 +/- 3.5 mm [p < 0.001]). When the lamina outer cortical and cancellous width was compared between T-1 and T-2, the lamina at T-2 was, on average, 0.3 mm wider than at T-1 (p = 0.007 and p = 0.003, respectively). In comparison with the corresponding pedicle, the mean outer cortical pedicle width at T-1 was wider than the lamina by an average of 1.0 mm (lamina: 6.6 +/- 1.1 mm, pedicle: 7.6 +/- 1.3 mm [p < 0.001]). At T-2, however, outer cortical lamina width was wider than the corresponding pedicle by an average of 0.6 mm (lamina: 6.9 +/- 1.1 mm, pedicle: 6.3 +/- 1.2 mm [p < 0.001]). At T-1, 97.5% of laminae measured could accept a 4.0-mm screw with 1.0 mm of clearance, compared with 99.5% of T-1 pedicles; whereas at T-2, 99% of laminae met this requirement, compared with 94.5% of pedicles. The ideal screw trajectory was also measured (T-1: 49.2 +/- 3.7 degrees for TLS and 32.8 +/- 3.8 degrees for PS; T-2: 51.1 +/- 3.5 degrees for TLS and 20.5 +/- 4.4 degrees for PS). CONCLUSIONS: Based on CT evaluation, there are no anatomical limitations to the placement of TLSs compared with PSs at T1-2. Differences were noted, however, in lamina length and width between T-1 and T-2 that must be considered when placing TLS at these levels. PMID- 20192630 TI - Simultaneous double-rod rotation technique in posterior instrumentation surgery for correction of adolescent idiopathic scoliosis. AB - The authors present a new posterior correction technique consisting of simultaneous double-rod rotation using 2 contoured rods and polyaxial pedicle screws with or without Nesplon tapes. The purpose of this study is to introduce the basic principles and surgical procedures of this new posterior surgery for correction of adolescent idiopathic scoliosis. Through gradual rotation of the concave-side rod by 2 rod holders, the convex-side rod simultaneously rotates with the the concave-side rod. This procedure does not involve any force pushing down the spinal column around the apex. Since this procedure consists of upward pushing and lateral translation of the spinal column with simultaneous double-rod rotation maneuvers, it is simple and can obtain thoracic kyphosis as well as favorable scoliosis correction. This technique is applicable not only to a thoracic single curve but also to double major curves in cases of adolescent idiopathic scoliosis. PMID- 20192631 TI - Biomechanical study of the effect of degree of static compression of the spinal cord in ossification of the posterior longitudinal ligament. AB - OBJECT: The authors evaluated the biomechanical effect of 3 different degrees of static compression in a model of the spinal cord in order to investigate the effect of cord compression in patients with ossification of the posterior longitudinal ligament (OPLL). METHODS: A 3D finite element spinal cord model consisting of gray matter, white matter, and pia mater was established. As a simulation of OPLL-induced compression, a rigid plate compressed the anterior surface of the cord. The degrees of compression were 10, 20, and 40% of the anteroposterior (AP) diameter of the cord. The cord was supported from behind by the rigid body along its the posterior border, simulating the lamina. Stress distributions inside of the cord were evaluated. RESULTS: The stresses on the cord were very low under 10% compression. At 20% compression, the stresses on the cord increased very slightly. At 40% compression, the stresses on the cord became much higher than with 20% compression, and high stress distributions were observed in gray matter and the lateral and posterior funiculus. The stresses on the compressed layers were much higher than those on the uncompressed layer. CONCLUSIONS: The stress distributions at 10 and 20% compression of the AP diameter of the spinal cord were very low. The stress distribution at 40% compression was much higher. The authors conclude that a critical point may exist between 20 and 40% compression of the AP diameter of the cord such that when the degree of the compression exceeds this point, the stress distribution becomes much higher, and that this may contribute to myelopathy. PMID- 20192632 TI - Accuracy of pedicle screw placement in the lumbosacral spine using conventional technique: computed tomography postoperative assessment in 102 consecutive patients. AB - OBJECT: The goal of this study was to determine the incidence of screw misplacement and complications in a group of 102 patients who underwent transpedicle screw fixation in the lumbosacral spine with conventional open technique and intraoperative fluoroscopy. The results are compared with published data. METHODS: Cases involving 102 consecutive patients (424 inserted screws) were reviewed. Surgery was performed in all cases by the same surgeon's team, using the same implant, and all results were assessed by means of a specific CT protocol. The screw position was assessed by the authors and an independent observer. Screw position was classified as correct when the screw was completely surrounded by the pedicle cortex, as "cortical encroachment" (questionable violation) if the pedicle cortex could not be visualized, and as "frank penetration" when the screw was outside the pedicular boundaries. Frank penetration was further subdivided as minor (when the edge of the screw thread was up to 2.0 mm outside the pedicle cortex), moderate (2.1-4 mm), and severe (> 4 mm). The incidence of intra- and postoperative complications not related to screw position as well as hardware failures were also registered, with a minimum follow-up duration of 8 months. RESULTS: The rate of frank pedicle screw misplacement was 5%. The rate of minimal or questionable pedicle wall violation was 2.8%. Among the frank misplacements, 6 were classified as minor, 12 as moderate, and 3 as severe penetration. Two patients (2%) had radicular pain and neurological deficits (inferomedial and inferolateral minor misplacement at L-4 and L-5, respectively), and 5 patients (4.9%) complained only of radicular pain. At the follow-up examination all patients had completely recovered their neurological function and radicular pain was resolved in all cases. The complications not related to screw malposition were 2 pedicle fractures (2% of patients), 1 nerve root injury (1%), and 1 dural laceration (1%). Five patients (4.8%) had postoperative anemia and required transfusions. Superficial or deep wound infection was noted in 3 patients (2.9%). Late hardware failure occurred in 2 patients (2%). One patient developed adjacent segmental instability and required additional surgery to extend the fusion. CONCLUSIONS: Our rates of screw misplacement and complications compare favorably with the lowest rates of the series in which conventional technique was used and are close to the rates reported for image-guided methods. The risk of malpositioning may be reduced with careful preoperative surgical planning, accurate knowledge of the spinal anatomy, surgical experience, and correct indication for conventional surgery. The conventional technique still remains a practical, safe, and effective surgical method for lumbosacral fixation. PMID- 20192633 TI - Dermatomyotomal supply in patients with variations in the number of lumbar vertebrae. AB - OBJECT: Variation in the number of lumbar vertebrae occurs in a small portion of the population. Either the fifth lumbar vertebra shows assimilation to the sacrum or the first sacral vertebra shows a lumbar configuration, resulting in 4 or 6 lumbar vertebrae, respectively. Etiologically, lumbar nerve root syndrome is diagnosed by comparing the anatomical level of the disc herniation to the compressed nerve root and to the pattern of the peripheral sensory and motor deficit. In case of a variation in the number of lumbar vertebrae, defining the lumbar nerve roots becomes difficult. Variations in the number of lumbar vertebrae make the landmarks (the twelfth rib and the first sacral vertebra) unreliable clues to define the nerve roots. The allocation of the clinically damaged segment to the spinal disorder seen in imaging studies is essential for differential diagnosis and spine surgery. METHODS: A retrospective study was conducted of clinical, electrophysiological, and imaging data among inpatients over a period of 21 months. Eight patients who had isolated monosegmental discogenic nerve root compression and a variation in the number of lumbar vertebrae were selected. RESULTS: Seven patients presented with 6 lumbar vertebrae, and 1 patient presented with 4 lumbar vertebrae and disc herniation on 1 of the 2 caudal levels. Compression of the second-to-last nerve root in patients with 6 lumbar vertebrae resulted either in clinical L-5 or S-1 syndrome, or a combination of both. Compression of the last caudal nerve root resulted in a clinical S-1 nerve root syndrome. CONCLUSIONS: The findings suggest that the dermatomyotomal supply of the lumbosacral nerve roots can vary in patients with a variation in the number of lumbar vertebrae, and a meticulous clinical, radiological, and electrophysiological examination is essential. PMID- 20192634 TI - Intradiscal electrothermal therapy for symptomatic internal disc disruption: 24 month results and predictors of clinical success. AB - OBJECT: Degeneration of the intervertebral disc can be the source of severe low back pain. Intradiscal electrothermal therapy (IDET) is a minimally invasive treatment option for patients with symptomatic internal disc disruption unresponsive to conservative medical care. This study was undertaken in the neurosurgical setting to evaluate 24-month pain and functional outcomes and predictors of clinical success in patients with discogenic back pain treated with IDET. METHODS: Using MR imaging and discography findings, 50 patients with lumbar discogenic pain were identified, underwent IDET treatment, and were followed up for 24 months. Outcomes included assessments of back pain severity based on an 11 point numeric scale and back function based on the Oswestry Disability Index. The Prolo scale was applied to determine economic and functional status at 24 months. RESULTS: There was an average 68 and 66% improvement in back pain and function, respectively, between pretreatment and 24 months after treatment (p < 0.0001 for both comparisons). A maximum score of 5 on the Prolo scale for economic and functional status was achieved in 63 and 22% of patients, respectively. The global clinical success rate was 78% (39 of 50 patients) based on no reoperations at the affected level due to persistent symptoms, with a >or= 2-point improvement in pain severity and a >or= 15-point improvement in back function. Predictors of 24-month clinical success included discographic concordance (p < 0.0001), a high intensity zone on MR imaging (p = 0.0003), low Pfirrmann grade (p = 0.0002), and more extensive anulus coverage (p < 0.0001). There were no procedure-related adverse events. CONCLUSIONS: The findings of this study suggest that durable clinical improvements can be realized after IDET in highly select surgical candidates with mild disc degeneration, confirmatory imaging evidence of anular disruption, and highly concordant pain provocation on low-pressure discography. PMID- 20192635 TI - Doxorubicin for prevention of epineurial fibrosis in a rat sciatic nerve model: outcome based on gross postsurgical, histopathological, and ultrastructural findings. AB - OBJECT: Epineural fibrosis may complicate peripheral nerve surgeries and currently is considered as one of the main factors responsible for failed surgeries. The authors investigated the postoperative antiscarring effects of topically applied doxorubicin (DXR) on rat sciatic nerves. METHODS: The sciatic nerves were dissected from the surrounding tissue and exposed bilaterally in 20 Wistar albino adult male rats. Abrasion trauma was produced on the exposed surface of the biceps femoris muscle in the vicinity of the sciatic nerves and their main branches in all animals. In the DXR Group, cottonoid pads soaked with DXR (0.5 mg/ml) were placed around the nerves for 5 minutes, whereas cotton pads soaked with saline (0.9% NaCl) were applied to nerves of animals in the Control Group for the same duration. Twelve weeks after the procedure, all of the rats were killed and the sciatic nerves were examined. Epineural adhesions were evaluated histopathologically and ultrastructurally. Additionally, quantitative histological parameters, the scar tissue formation index and the scar density, were calculated in histological evaluation. RESULTS: Gross postsurgical evaluation as well as histopathological and electron microscopic examination of involved nerve segments showed significantly less epineurial adhesions in the DXR Group than in the Control Group. Quantitative analysis of the epineurium revealed a statistically significant reduction in the density and amount of epineural scarring in specimens from the DXR Group than in those from the Control Group. CONCLUSIONS: The results of gross postsurgical anatomical evaluation and histopathological and ultrastructural studies suggested that topical application of DXR effectively reduced epineural scar formation on rat sciatic nerves. These promising findings merit further experimental and clinical studies to determine the efficacy and safe applicability of DXR in human subjects. PMID- 20192636 TI - Tethered cord. PMID- 20192637 TI - Multiple-suture nonsyndromic craniosynostosis: early and effective management using endoscopic techniques. AB - OBJECT: The authors present the results of treating infants with multiple-suture nonsyndromic craniosynostosis in whom the authors used minimally invasive endoscopy-assisted techniques and postoperative cranial molding over an 11-year period. METHODS: A total of 21 patients who presented with multiple-suture (nonsyndromic) craniosynostosis were treated using minimally invasive endoscopy assisted craniectomies. Surgery was followed by treatment with custommade cranial orthoses for up to 12 months. A total of 48 sutures were treated. The most common was the coronal suture (38 cases) and this was followed by the sagittal (11 cases), metopic (6 cases), and lambdoid (3 cases) sutures. There were 13 male and 8 female pediatric patients. Their ages ranged between 3 weeks and 9 months (mean 3.2 months, median 2.5 months). The sagittal suture was treated with a wide vertex craniotomy via 2 incisions located behind the anterior fontanel and in front of the lambda. The metopic suture underwent a suturectomy as did the coronal and lambdoid sutures. RESULTS: The mean follow-up duration was 61 months (range 3-135 months). There were no deaths. In patients with bicoronal synostosis, brachycephaly was corrected. Patients presenting with vertical dystopia or nasal deviation had these deformities corrected as well. The mean blood loss was 42 ml (range 10-120 ml). The mean hospital length of stay was 1 day. The intraoperative transfusion rate was 0%. The results indicate that nonsyndromic multiple-suture synostosis can be safely and effectively treated using endoscopic techniques. CONCLUSIONS: Early treatment of complex multiple suture synostosis with endoscopic techniques provides an excellent surgical alternative. The results of the present study indicate marked correction of skull base and craniofacial deformities. Endoscopy provides a safe and effective way to treat these patients. PMID- 20192638 TI - Long-term neuropsychological development in single-suture craniosynostosis treated early. AB - OBJECT: The authors evaluated the results of complete cognitive function examinations in a series of 65 adolescents who had undergone surgery for sagittal or unicoronal craniosynostosis when they were younger than 1 year old. METHODS: Each of the 65 study participants was evaluated individually. The neuropsychological assessment, consisting of a battery of tests tailored to the patient's age, cognitive level, and level of cooperation, was conducted in 2 separate sessions on the same day. The main outcome measures included fine motor skills, language, visual motor spatial and visual perceptual skills, working and visual memory, attention, executive function, and verbal fluency. RESULTS: Thirty five children (mean age 13.4 years) were affected by sagittal synostosis and 30 (mean age 14.9 years) by unicoronal synostosis (16 right-sided, 14 left-sided). The mean age at surgery was 7.2 months. All of the children had begun school at a normal age and attended regular classes. Seven percent of those with sagittal craniosynostosis demonstrated visuospatial and constructional ability defects with associated visual memory recall deficits; 17% also exhibited selective and sustained attention deficits. Approximately one-third (30%) of the children with anterior plagiocephaly had processing and planning speech deficits. CONCLUSIONS: Data in this study support the hypothesis that children with sagittal or unicoronal craniosynostosis, although they undergo early surgical treatment, may still manifest lower than average results at long-term selective neuropsychological evaluations. PMID- 20192639 TI - Synchrotron-microcomputed tomography studies of normal and pathological cranial sutures: further insight. AB - OBJECT: Both CT and high-frequency ultrasound have been shown to be reliable diagnostic tools used to differentiate normal cranial sutures from suture synostosis. In nonsynostotic plagiocephaly, overlapping of the bony plates and the so-called "sticky suture" is still controversial and is believed to represent a pathological fusion process. Synchrotron-microcomputed tomography (SRmCT) studies were undertaken to determine whether positional head deformities can be assumed to be true suture pathologies. METHODS: Morphological features and growth development of 6 normal cranial sutures between the ages of 3 and 12 months were analyzed histologically. Additionally 6 pathological sutures, including sagittal synostosis and nonsynostotic plagiocephaly (NSP), were compared with the group of normal sutures by histological and SRmCT studies. Synchrotron-microcomputed tomography is a special synchrotron radiation source with a high photon flux providing a monochromatic x-ray beam with a very high spatial resolution. Morphological characteristics of the different suture types were evaluated and bone density alongside the sutures was measured to compare the osseous structure of the adjacent bony plates of normal and pathological sutures. RESULTS: Histologically jointlike osseous edges of the normal sutures were seen in the 1st month of life and interlocking at the age of approximately 12 months. During this 1st year, bone thickness increases and suture width decreases. The SRmCT studies showed that: 1) sutures and adjacent bones in NSP are comparable to normal sutures in terms of their morphological aspects; 2) bone densities in the adjacent bony plates of NSP and normal sutures are not different; 3) thickening of the diploe with ridging of the bone in sagittal synostosis is associated with significantly higher bone density; 4) synostotic sutures are only partially fused but vary in their extent; and 5) nonfused sections in sagittal synostosis behave like normal sutures without any signs of pathological bone formation. CONCLUSIONS: Sutures in patients with NSP were found without any morphological irregularities or different osseous structures alongside those compared with normal sutures. Thus, a true suture pathology or osseous change of the adjacent bony plates is highly unlikely in NSP. Even though the number of specimens is limited in this series, cranial suture fusion seems to start at one undetermined point and spread along the suture, whereas other parts of the same suture are not involved according to morphological aspects and bone density measurements of the adjacent bones. This theory may represent a dynamic fusion process completed over time but just starting too early. PMID- 20192640 TI - Waterjet dissection in pediatric cranioplasty. AB - OBJECT: Waterjet dissection has been shown to separate tissues of different resistance, with preservation of blood vessels. In cranioplasty, separation of subcutaneous tissue and dura mater is often difficult to achieve because the various tissue layers strongly adhere to each other after decompressive craniotomy. In the present study, the potential advantages and drawbacks of the waterjet technique in cranioplasty after craniectomy and duraplasty are addressed. METHODS: The waterjet effect on fresh human cadaveric dura mater specimens as well as on several dural repair patches was tested in vitro under standardized conditions, with waterjet pressures up to 80 bar. Subsequently, 8 pediatric patients (5 boys, 3 girls; mean age 9.9 years, range 1.2-16.7 years) who had been subjected to decompressive craniectomy (7 with duraplasty including bovine pericardium as a dural substitute, 1 without duraplasty in congenital craniosynostosis) underwent waterjet cranioplasty. The waterjet was used to separate the galea and the dura mater. The technique was applied tangentially between the dura and the galea, with different pressure levels up to 50 bar. RESULTS: In vitro, fresh cadaveric human dura mater as well as 2 different dural repair substitutes showed a very high resistance to waterjet dissection up to 80 bar. The human dura and the various substitutes were dissected only after long lasting exposure to the waterjet. Human dura was perforated at pressures of 60 bar and higher. Bovine pericardium dural substitute was perforated at pressures of 55 bar and higher. Artificial nonabsorbable polyesterurethane dural substitute was dissected at pressures of 60 bar and higher. In the clinical setting, the waterjet was able to separate galea and dura with minimal bleeding. No blood transfusion was required. Dissection of scarred tissue was possible by a waterjet of 40 bar pressure. Tissue layers were stretched and separated by the waterjet dissection, and a very reliable hemostasis resulted. This resulted in an effective reduction of bleeding, with < 60 ml blood loss in 7 of the 8 cases. Neither a dural tear nor a perforation of any duraplasty occurred during operative preparation. There were no operative or postoperative complications. CONCLUSIONS: The experimental and clinical data show that waterjet separation of dura mater, dural substitute, and galea can be performed with a high level of safety to avoid dural tears. The waterjet dissection stretches tissue layers, which results in a reliable hemostasis effect. This potentially results in an effective reduction of surgical blood loss, which should be the focus of further studies. PMID- 20192641 TI - Endoscopic third ventriculostomy in patients with a diminished prepontine interval. AB - OBJECT: Fenestration of the floor of the third ventricle is vital to the success of endoscopic third ventriculostomy (ETV) in treating patients with noncommunicating hydrocephalus. A generous prepontine interval (PPI) is generally accepted as one anatomical feature that may affect the safety and functionality of ETV. Whether a diminished PPI influences the safety or success of ETV, however, has not been adequately assessed. METHODS: A review was conducted on the last 100 ETV procedures performed by the first author (M.M.S.). From archived preoperative MR imaging studies, the PPI was measured between the dorsum sellae and the basilar artery. For any patient with an interval of /=70 years) tend to be more severe and have a greater impact on health outcomes such as morbidity, disability, quality of life and mortality. However, some of the more common infections such as influenza and pneumococcal infection are vaccine preventable, but the uptake of such preventive strategies in adults has been poor. In this review some of the key clinical findings supporting the benefits of adult immunization are highlighted. Vaccination of the adult population needs to be a key component of a healthy aging strategy, since there is already convincing evidence that this approach can have an important impact on morbidity, mortality and quality of life. PMID- 20192711 TI - Updated vaccine guidelines for aging and aged citizens of Europe. AB - There is a high burden of infectious diseases in the older population, which is associated with increased morbidity and mortality compared with younger age groups. Too many of these diseases are vaccine preventable yet there is a low vaccine coverage rate across Europe. These findings led the European Union Geriatric Medicine Society and the International Association of Gerontology and Geriatrics-European Region to convene an expert Working Group to address the issue of why vaccination programs have failed to provide adequate protection in older European populations and to recommend immunization guidelines to ensure that they contribute to a healthy aging strategy. This review addresses some of the main issues relating to poor vaccine uptake in older adults and presents the recommendations of the joint Working Group regarding the optimal use of the following vaccines: tetanus-diphtheria-pertussis, influenza, pneumococcal (PV23) and herpes zoster. To improve vaccine coverage, communication and awareness of vaccine preventable diseases in the general community is an important starting point, and all healthcare professionals and public health/social workers can play a key role in this regard. PMID- 20192712 TI - Ensuring the willingness to vaccinate and be vaccinated. AB - Vaccination is one of the success stories in modern day medicine and has contributed to a reduced burden of childhood diseases and increased longevity. However, adult vaccination has not achieved the same level of success and it is now thought that more adults die from vaccine-preventable diseases each year than children. Many of the reasons given by adults for not getting vaccinated are based upon ignorance of the true facts, lack of support/notification from the healthcare system or unfounded fears. The key to addressing these issues is improving communication and this needs to involve healthcare professionals and public health/social workers. To effect change we must provide motivating educational material, which ensures that the benefits of vaccination are clearly emphasized and that issues related to inconvenience and adverse events are discussed and put into perspective. Transparency is important and so the information must be complete and accurate. In addition, we need to make the immunization process easy and convenient for the patient (particularly for house bound individuals and those who live some distance from a general practitioner) and it needs to be proactive (e-mails, reminders and recalls). Only through a massive commitment to making it work, with the lead taken by key healthcare managers/personnel, will we improve vaccine coverage and integrate vaccination of older adults into a life-long healthy aging strategy. PMID- 20192713 TI - Vaccination in older adults: development of an educational tool, Vaxisenior, in France. AB - The benefits of vaccination in older adults are well documented yet there is poor uptake of such preventive measures, and one of the main reasons in France is a lack of recommendation and support from healthcare professionals. To address this issue a multidisciplinary group of experts has developed an educational tool, Vaxisenior, to assist in the training of physicians/healthcare workers who can act as advocates for immunization programs. The tool comprises of eight sections (general introduction; immunosenescence; diphtheria-tetanus-poliomyelitis; influenza; pneumococcus; pertussis; herpes zoster; and vaccines for travelers). In addition, it includes national immunization schedules and recommendations, practical information regarding opportunities to expand vaccine coverage that is convenient to the patient and a questions and answers section covering topics relating to particular usage and responsibilities. Implementation of vaccination policies for older adults is a major issue and will require extensive promotional campaigns, as well as active support from healthcare and public health professionals to improve overall vaccine coverage. PMID- 20192714 TI - Herpes zoster and postherpetic neuralgia. AB - Herpes zoster (HZ; shingles) results from reactivation of varicella-zoster virus that has been dormant in the spinal and cranial sensory ganglia following primary infection with varicella (chickenpox), usually during childhood. In developed countries more than 95% of the adult population are seropositive for varicella zoster virus and are therefore at risk of developing HZ. Reactivation can occur at any age, but it is associated with an age-related decline in cell-mediated immunity and therefore occurs more frequently in older adults. Thus, HZ affects up to 25% of individuals during their lifetime, but approximately 50% of those aged 80 years or more. Whilst the disease is rarely life-threatening, it is associated with a number of acute symptoms such as a vesicular rash and pain. Longer-term complications include visual disturbances and postherpetic neuralgia (PHN), which is potentially the most troubling problem of all, and is associated with severe itching and allodynia. These can combine to negatively impact the day to-day functioning and quality of life of the patient. Hospitalization associated with HZ and PHN is frequent in older individuals and a significant cost to healthcare providers. Current management of HZ with antiviral drugs and analgesics produces reasonable results in younger patients, in whom the disease is usually milder, and is effective against acute pain and skin rash. However, it is much less effective against PHN, which occurs more commonly and more severely in older patients. Once PHN has developed, current treatments offer only limited benefit and adverse effects are common. Management is challenging and often unsatisfactory (<50% of patients gain 50% relief of pain). With the older adult population steadily growing in size, the number of patients presenting with HZ is also likely to increase and this will place a greater burden on healthcare systems. Prevention strategies, such as vaccinating those at greatest risk, may offer the best option for the future. PMID- 20192715 TI - Herpes zoster: a common disease that can have a devastating impact on patients' quality of life. AB - Medical advances have markedly increased human longevity, but this longer life comes at a price; older people often suffer from greater morbidities that severely impact their day-to-day ability to function normally. However, there is a growing commitment from the medical community to add 'quality' to the extra years that people live. An important question in this regard is: how do we impact usual aging, with its attendant higher risks of disease and turn it into successful aging and independency? That is the focus of this review, which looks at herpes zoster (HZ), a condition that is both common and causes severe complications in the elderly. Even with appropriate treatment, HZ can have a significant negative impact on the patient's quality of life. A previously active individual can be severely affected by the disease and its complications such as postherpetic neuralgia. Clinical management, at best, produces modest benefit (for a variety of reasons including a delay in providing treatment, ineffective drugs chosen, poor tolerability and drug-drug interactions). We then find ourselves in the position of trying to treat a patient who is losing confidence in the options available to them, and who is slowly becoming less active and, if we are not careful, more frail and with the increasing likelihood of requiring long-term care. Both the personal and societal burden of HZ and postherpetic neuralgia are therefore considerable, and this highlights the need for better preventative and treatment strategies. PMID- 20192716 TI - Vaccination: a new option to reduce the burden of herpes zoster. AB - There is a strong correlation between the incidence of herpes zoster (HZ) and increasing age, with a marked rise in incidence from approximately the age of 50 60 years. The lifetime risk is approximately 25% and the disease is associated with acute and sometimes persistent pain, which substantially reduces the day-to day functioning and quality of life of affected individuals, particularly older adults. The disease most commonly occurs as a result of an age-related decline in cell-mediated immunity. A live attenuated zoster vaccine has been developed to boost the varicella-zoster virus-specific cell-mediated immunity of older adults and, via this mechanism, protect the individual against HZ and its complications. Evidence that the vaccine is effective in older patients comes from the pivotal Shingles Prevention Study. This was a randomized, double-blind, placebo controlled trial involving approximately 40,000 adults aged 60 years or more. The HZ vaccinated group had a 51% lower incidence of HZ, a 67% reduction in postherpetic neuralgia (defined as pain rated at three or more on a scale ranging from zero [no pain] to ten [pain as bad as you can imagine], persisting or occurring 3 months or more after rash onset), and a 61% lower burden of illness (a composite measure of the incidence, severity and duration of pain and discomfort caused by HZ), indicating that the vaccine decreased both the incidence of HZ and the average severity of HZ in vaccinees who developed HZ. Moreover, there was a 73% reduction in the number of cases of HZ with severe and long-lasting pain. Overall, the vaccine was well-tolerated with the most common adverse events being mild injection site reactions and headache. A continuation trial from the Shingles Prevention Study involving over 14,000 patients approximately 7000 in the HZ vaccine and placebo groups) confirmed that the efficacy of vaccination against HZ is durable through 7 years in terms of a significantly reduced incidence of HZ, a reduced incidence of postherpetic neuralgia and a markedly lower burden of illness. Although significant improvements have been made, available treatment options are only partially effective, and once postherpetic neuralgia is established, management is difficult. Therefore, the introduction of the zoster vaccine is a promising strategy to reduce morbidity associated with HZ, a particular concern in older adults. PMID- 20192718 TI - Preclinical analysis of irreversible electroporation on rat liver tissues using a microfabricated electroporator. AB - A microfabricated electroporator (MFE) for the irreversible electroporation (IRE) of tissues has been developed by miniaturizing a clinical electroporator with a two-needle array while keeping the same electric field strength distribution. Since IRE was brought to special attention as one of the local tissue ablation techniques to treat tumors, many preclinical studies have been conducted to investigate the efficacy of IRE on animal tissues. However, some technical difficulties have been frequently encountered due to the macroscale dimension of clinical electroporators, particularly in experiments on small animal models such as the mouse or rat. Here, the MFE was proposed to solve the associated problems, resulting in time- and cost-effective experimental procedures. With the developed MFE, the effect of IRE on rat liver tissues was analyzed with time by immunohistological stainings and electrical measurement, and the experimental results were compared with those operated with the corresponding real-scale clinical electroporator. PMID- 20192719 TI - A new animal model for assessing cartilage repair and regeneration at a nonarticular site. AB - The aim of this study was to establish a critical-sized nonjoint chondral defect animal model and to evaluate its feasibility for testing cartilage regeneration strategies. Dermal biopsy punches 1-4 mm in diameter were used to create cylindrical full-thickness defects in the center of athymic rat xiphoids. The 3 and 4 mm defects remained unhealed 35 days postsurgery, with a large area in the center that had low proteoglycan content based on contrast-enhanced microCT (EPIC microCT), radiographic, and histological analyses. In a second step, tissue engineered cartilage was synthesized by culturing primary bovine articular chondrocytes on poly-L-lactic acid (PLA) scaffolds in a perfusion-shear bioreactor for 28 days. These chondrocyte/PLA constructs or primary bovine chondrocytes were implanted into 3-mm-diameter defects. Empty defects and defects implanted with empty PLA scaffolds were used as controls. Xiphoids were harvested 28 days after surgery and examined with faxitron, microCT, and histology using hematoxylin and eosin and safranin-O staining. Both chondrocyte/PLA constructs and chondrocytes alone formed neocartilage. The results indicate that a 3 mm cylindrical defect in a rat xiphoid is an economic, feasible, and reproductive model to evaluate the potential of various constructs for nonjoint cartilage repair. PMID- 20192720 TI - Correction of lumbar coronal plane deformity using unilateral cage placement. AB - The authors describe a surgical technique for the correction of symptomatic degenerative lumbar scoliosis. Using a single, unilateral, interbody cage placed on the concave side of the coronal deformity, combined with a dorsal decompression and instrumented posterolateral fusion, this technique has resulted in excellent curve correction, fusion results, and clinical outcomes in a series of 4 patients. Each of these patients presented with intractable, axial low-back pain and symptomatic unilateral nerve root compression on the concave side of a lumbar scoliotic deformity. The management is described in detail. PMID- 20192721 TI - Minimally invasive surgery for thoracolumbar spinal deformity: initial clinical experience with clinical and radiographic outcomes. AB - OBJECT: Adult degenerative scoliosis can be a cause of intractable pain, decreased mobility, and reduced quality of life. Surgical correction of this problem frequently leads to substantial clinical improvement, but advanced age, medical comorbidities, osteoporosis, and the rigidity of the spine result in high surgical complication rates. Minimally invasive surgery is being applied to this patient population in an effort to reduce the high complication rates associated with adult deformity surgery. METHODS: A retrospective study of 23 patients was undertaken to assess the clinical and radiographic results with minimally invasive surgery for adult thoracolumbar deformity surgery. All patients underwent a lateral interbody fusion followed by posterior percutaneous screw fixation and possible minimally invasive surgical transforaminal lumbar interbody fusion if fusion near the lumbosacral junction was necessary. A mean of 3.7 intersegmental levels were treated (range 2-7 levels). The mean follow-up was 13.4 months. RESULTS: The mean preoperative Cobb angle was 31.4 degrees , and it was corrected to 11.5 degrees at follow-up. The mean blood loss was 477 ml, and the operative time was 401 minutes. The mean visual analog scale score improvement for axial pain was 3.96. Clear evidence of fusion was seen on radiographs at 84 of 86 treated levels, with no interbody pseudarthroses. Complications included 2 returns to the operating room, one for CSF leakage and the other for hardware pullout. There were no wound infections, pneumonia, deep venous thrombosis, or new neurological deficits. However, of all patients, 30.4% experienced new thigh numbness, dysesthesias, pain, or weakness, and in one patient these new symptoms were persistent. CONCLUSIONS: The minimally invasive surgical treatment of adult deformities is a promising method for reducing surgical morbidity. Numerous challenges exist, as the surgical technique does not yet allow for all correction maneuvers used in open surgery. However, as the techniques are advanced, the applicability of minimally invasive surgery for this population will likely be expanded and will afford the opportunity for reduced complications. PMID- 20192722 TI - Oral cleansing with chlorhexidine to decrease the incidence of nosocomial pneumonia: using the right concentration in the right place. PMID- 20192724 TI - Relationship between HIV/Highly active antiretroviral therapy (HAART)-associated lipodystrophy syndrome and stavudine-triphosphate intracellular levels in patients with stavudine-based antiretroviral regimens. AB - BACKGROUND: The link between human immunodeficiency virus/highly active antiretroviral therapy (HAART)-associated lipodystrophy syndrome (HALS) and the use of thymidine analogues has been well established. However, to our knowledge, no relationship has been proven between intracellular levels of stavudine (d4T) and HALS. METHODS: We measured peripheral blood mononuclear cell intracellular levels of d4T-triphosphate (TP) in patients who were receiving d4T as part of their antiretroviral regimens. d4T-TP levels were determined by a validated liquid chromatography-tandem mass spectrometry assay method. The diagnosis of HALS was made in accordance with the criteria of a lipodystrophy severity grading scale. The Student t test, Pearson correlations, 1-way analysis of variance with Bonferroni correction, and stepwise logistic regression were used for statistic analyses. RESULTS: This was a cross-sectional study. There were 33 patients: 17 with HALS and 16 without HALS. The median concentration of d4T-TP for patients with HALS was 20.60 femtomoles (fmol)/1 x 10(6) cells (interquartile range [IQR], 14.90-26.92 fmol/1 x 10(6) cells) and for patients without HALS was 13.85 fmol/1 x 10(6) cells (IQR, 8.65-20.15 fmol/1 x 10(6) cells) (P=.013). The median d4T-TP intracellular level in patients who had developed an AIDS-defining condition was 22.50 fmol/1 x 10(6) cells (IQR, 15.80-27.37 fmol/1 x 10(6) cells) and in those who had not was 14.40 fmol/1 x 10(6) cells (IQR, 10.80-20.40 fmol/1 x 10(6) cells) (P=.037). There were no statistically significant differences in d4T-TP intracellular levels with respect to the presence of metabolic syndrome, the clinical form of HALS (pure lipoatrophic vs mixed), the degree of facial lipoatrophy, the presence of hepatitis C virus infection, and the pair of nucleosides in HAART. d4T-TP levels correlated only with cumulative d4T exposure in time and dose. d4T-TP intracellular levels were independently associated with HALS (odds ratio, 1.58; 95% confidence interval, 1.08-2.32; P=.019). CONCLUSIONS: Intracellular levels of d4T-TP are strongly associated with the development of HALS. PMID- 20192726 TI - Expanding the role of the microscopic observation drug susceptibility assay in tuberculosis and HIV management. PMID- 20192727 TI - Microscopic observation drug susceptibility assay for tuberculosis screening before isoniazid preventive therapy in HIV-infected persons. AB - BACKGROUND: Active tuberculosis (TB) must be excluded before initiating isoniazid preventive therapy (IPT) in persons infected with human immunodeficiency virus (HIV), but currently used screening strategies have poor sensitivity and specificity and high patient attrition rates. Liquid TB culture is now recommended for the detection of Mycobacterium tuberculosis in individuals suspected of having TB. This study compared the efficacy, effectiveness, and speed of the microscopic observation drug susceptibility (MODS) assay with currently used strategies for TB screening before IPT in HIV-infected persons. METHODS: A total of 471 HIV-infected IPT candidates at 3 hospitals in Lima, Peru, were enrolled in a prospective comparison of TB screening strategies, including laboratory, clinical, and radiographic assessments. RESULTS: Of 435 patients who provided 2 sputum samples, M. tuberculosis was detected in 27 (6.2%) by MODS culture, 22 (5.1%) by Lowenstein-Jensen culture, and 7 (1.6%) by smear. Of patients with any positive microbiological test result, a MODS culture was positive in 96% by 14 days and 100% by 21 days. The MODS culture simultaneously detected multidrug-resistant TB in 2 patients. Screening strategies involving combinations of clinical assessment, chest radiograph, and sputum smear were less effective than 2 liquid TB cultures in accurately diagnosing and excluding TB (P<.01). Screening strategies that included nonculture tests had poor sensitivity and specificity. CONCLUSIONS: MODS culture identified and reliably excluded cases of pulmonary TB more accurately than other screening strategies, while providing results significantly faster than Lowenstein-Jensen culture. Streamlining of the ruling out of TB through the use of liquid culture-based strategies could help facilitate the massive up-scaling of IPT required to reduce HIV and TB morbidity and mortality. PMID- 20192728 TI - Possible neuropsychiatric reaction to high-dose oseltamivir during acute 2009 H1N1 influenza A infection. AB - The safety of high-dose oseltamivir during treatment of 2009 H1N1 influenza A infection for critically ill patients is unknown. Here we report on a case patient with severe, delayed-onset neuropsychiatric symptoms after administration of high-dose oseltamivir. Clinicians should be vigilant to the possible increased risk of complications associated with high-dose oseltamivir therapy for 2009 H1N1 influenza A infection. PMID- 20192725 TI - Comparison of once-daily versus twice-daily combination antiretroviral therapy in treatment-naive patients: results of AIDS clinical trials group (ACTG) A5073, a 48-week randomized controlled trial. AB - BACKGROUND: Dosing frequency is an important determinant of regimen effectiveness. Methods. To compare efficacy of once-daily (QD) versus twice-daily (BID) antiretroviral therapy, we randomized human immunodeficiency virus (HIV) positive, treatment-naive patients to lopinavir-ritonavir (LPV/r) administered at a dosage of 400 mg of lopinavir and 100 mg of ritonavir BID (n = 160) or 800 mg of lopinavir and 200 mg of ritonavir QD (n = 161), plus either emtricitabine 200 mg QD and extended-release stavudine at a dosage of 100 mg QD or tenofovir at a dosage of 300 mg QD. Randomization was stratified by screening HIV RNA level <100,000 copies/mL versus > or = 100,000 copies/mL. The primary efficacy end point was sustained virologic response (SVR; defined as reaching and maintaining an HIV RNA level <200 copies/mL) through week 48. RESULTS: Subjects were 78% male, 33% Hispanic, and 34% black. A total of 82% of subjects completed the study, and 71% continued to receive the initially assigned dosage schedule. The probability of SVR did not differ significantly for the BID versus QD comparison, with an absolute proportional difference of 0.03 (95% confidence interval [CI], 0.07 to 0.12). The comparison depended on the screening RNA stratum (P=.038); in the higher RNA stratum, the probability of SVR was significantly better in the BID arm than in the QD arm: 0.89 (95% CI, 0.79-0.94) versus 0.76 (95% CI, 0.64 0.84), a difference of 0.13 (95% CI, 0.01-0.25). Lopinavir trough plasma concentrations were higher with BID dosing. Adherence to prescribed doses of LPV/r was 90.6% in the QD arm versus 79.9% in the BID arm (P<.001). Conclusions. Although subjects assigned to QD regimens had better adherence, overall treatment outcomes were similar in the QD and BID arms. Subjects with HIV RNA levels > or =100,000 copies/mL had better SVR with BID regimens at 48 weeks, which suggests a possible advantage in this setting for more frequent dosing. Clinical trial registration. ClinicalTrials.gov registration number: NCT00036452. PMID- 20192729 TI - Increased risk of hospitalization for acute lower respiratory tract infection among Australian indigenous infants 5-23 months of age following pneumococcal vaccination: a cohort study. AB - BACKGROUND: Australian Indigenous children are the only population worldwide to receive the 7-valent pneumococcal conjugate vaccine (7vPCV) at 2, 4, and 6 months of age and the 23-valent pneumococcal polysaccharide vaccine (23vPPV) at 18 months of age. We evaluated this program's effectiveness in reducing the risk of hospitalization for acute lower respiratory tract infection (ALRI) in Northern Territory (NT) Indigenous children aged 5-23 months. METHODS: We conducted a retrospective cohort study involving all NT Indigenous children born from 1 April 2000 through 31 October 2004. Person-time at-risk after 0, 1, 2, and 3 doses of 7vPCV and after 0 and 1 dose of 23vPPV and the number of ALRI following each dose were used to calculate dose-specific rates of ALRI for children 5-23 months of age. Rates were compared using Cox proportional hazards models, with the number of doses of each vaccine serving as time-dependent covariates. RESULTS: There were 5482 children and 8315 child-years at risk, with 2174 episodes of ALRI requiring hospitalization (overall incidence, 261 episodes per 1000 child-years at risk). Elevated risk of ALRI requiring hospitalization was observed after each dose of the 7vPCV vaccine, compared with that for children who received no doses, and an even greater elevation in risk was observed after each dose of the 23vPPV (adjusted hazard ratio [HR] vs no dose, 1.39; 95% confidence interval [CI], 1.12 1.71; P=.002). Risk was highest among children vaccinated with the 23vPPV who had received <3 doses of the 7vPCV (adjusted HR, 1.81; 95% CI, 1.32-2.48). CONCLUSIONS: Our results suggest an increased risk of ALRI requiring hospitalization after pneumococcal vaccination, particularly after receipt of the 23vPPV booster. The use of the 23vPPV booster should be reevaluated. PMID- 20192730 TI - ZNRD1 (zinc ribbon domain-containing 1) is a host cellular factor that influences HIV-1 replication and disease progression. AB - BACKGROUND: Human immunodeficiency virus (HIV) takes advantage of multiple host proteins to support its own replication. The gene ZNRD1 (zinc ribbon domain containing 1) has been identified as encoding a potential host factor that influenced disease progression in HIV-positive individuals in a genomewide association study and also significantly affected HIV replication in a large scale in vitro short interfering RNA (siRNA) screen. Genes and polymorphisms identified by large-scale analysis need to be followed up by means of functional assays and resequencing efforts to more precisely map causal genes. METHODS: Genotyping and ZNRD1 gene resequencing for 208 HIV-positive subjects (119 who experienced long-term nonprogression [LTNP] and 89 who experienced normal disease progression) was done by either TaqMan genotyping assays or direct sequencing. Genetic association analysis was performed with the SNPassoc package and Haploview software. siRNA and short hairpin RNA (shRNA) specifically targeting ZNRD1 were used to transiently or stably down-regulate ZNRD1 expression in both lymphoid and nonlymphoid cells. Cells were infected with X4 and R5 HIV strains, and efficiency of infection was assessed by reporter gene assay or p24 assay. RESULTS: Genetic association analysis found a strong statistically significant correlation with the LTNP phenotype (single-nucleotide polymorphism rs1048412; P = .0004), independently of HLA-A10 influence. siRNA-based functional analysis showed that ZNRD1 down-regulation by siRNA or shRNA impaired HIV-1 replication at the transcription level in both lymphoid and nonlymphoid cells. CONCLUSION: Genetic association analysis unequivocally identified ZNRD1 as an independent marker of LTNP to AIDS. Moreover, in vitro experiments pointed to viral transcription as the inhibited step. Thus, our data strongly suggest that ZNRD1 is a host cellular factor that influences HIV-1 replication and disease progression in HIV-positive individuals. PMID- 20192731 TI - Community-associated methicillin-resistant Staphylococcus aureus and HIV: intersecting epidemics. AB - BACKGROUND: Single-site studies have suggested a link between human immunodeficiency virus (HIV) and community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA). METHODS: Population-level incidence of HIV infected patients with CA-MRSA versus community-associated methicillin susceptible S. aureus (CA-MSSA) infection was assessed in the Cook County Health and Hospitals System (CCHHS), a multi-hospital and ambulatory care center. Rates in zip codes, including those with a high density of individuals with prior incarceration (ie, high-risk zip codes), were calculated. We did a nested case control analysis of hospitalized HIV-infected patients with S. aureus skin and soft-tissue infections (SSTIs). RESULTS: In CCHHS, the incidence of CA-MRSA SSTIs was 6-fold higher among HIV-infected patients than it was among HIV-negative patients (996 per 100,000 HIV-infected patients vs 157 per 100,000 other patients; P < .001). The incidence of CA-MRSA SSTIs among HIV-infected patients significantly increased from 2000-2003 (period 1) to 2004-2007 (period 2) (from 411 to 1474 cases per 100,000 HIV-infected patients; relative risk [RR], 3.6; P<.001), with cases in period 1 clustering in an area 6.3 km in diameter (P=.035) that overlapped high-risk zip codes. By period 2, CA-MRSA SSTIs among HIV infected patients were spread throughout Cook County. USA300 was identified as the predominant strain by pulsed-field gel electrophoresis (accounting for 86% of isolates). Among hospitalized HIV-infected patients, the incidence of CA-MRSA increased significantly from period 1 to period 2 (from 190 to 779 cases per 100,000 HIV-infected patients; RR, 4.1; P<.001). Risks for CA-MRSA by multivariate analysis were residence in alternative housing (eg, shelters), residence in high-risk zip codes, younger age, and infection in period 2. CONCLUSIONS: HIV-infected patients are at markedly increased risk for CA-MRSA infection. This risk may be amplified by overlapping community networks of high risk patients that may be targets for prevention efforts. PMID- 20192732 TI - A wandering pathway in plant biology: from wildflowers to phototropins to bacterial virulence. AB - The author describes the somewhat convoluted pathway he followed from amateur taxonomy of Minnesota wildflowers to identification of the phototropin family of blue-light receptors. He also mentions individuals who were important in moving his career first into plant taxonomy, then plant development, and finally plant photobiology (and out of music). He emphasizes the many twists and turns a research career can take, including a few that lead to blind ends. He also emphasizes the oscillatory nature of his career-back and forth between the Atlantic and Pacific oceans (with occasional forays to Freiburg, Germany) and back and forth between red-light receptors and blue-light receptors. There is a short intermission in which he describes his longtime relationship with California's Henry W. Coe State Park. Finally, he relates how he followed the unlikely pathway from plant blue-light receptors to a blue-light receptor required to maximize virulence of a bacterial animal pathogen. PMID- 20192733 TI - Doomed lovers: mechanisms of isolation and incompatibility in plants. AB - Adaptation to local conditions likely plays an important role in plant diversity and speciation. A fuller understanding of the role of adaptation in speciation requires connecting particular molecular events with selection occurring at individual, population, or community levels. Here I discuss five areas in which we understand the molecular basis of adaptation and isolation sufficiently to begin examining patterns. These examples highlight the importance of understanding both biotic and abiotic factors and the potential overlap between them, and demonstrate that understanding molecular mechanisms aids in interpreting pleiotropy and constraint. For example, mutations affecting anthocyanin production can affect both pollinator visitation and parasite attack, while edaphic adaptation can alter parasite susceptibility and reproductive timing. Adaptation is also implicated in postzygotic incompatibility: Potentially adaptive cytoplasmic divergence can lead to sterility or inviability; hybrid sterility genes may have pleiotropic effects in biotic or abiotic stress; and the plant immune system is implicated in hybrid failure. PMID- 20192734 TI - Improving photosynthetic efficiency for greater yield. AB - Increasing the yield potential of the major food grain crops has contributed very significantly to a rising food supply over the past 50 years, which has until recently more than kept pace with rising global demand. Whereas improved photosynthetic efficiency has played only a minor role in the remarkable increases in productivity achieved in the last half century, further increases in yield potential will rely in large part on improved photosynthesis. Here we examine inefficiencies in photosynthetic energy transduction in crops from light interception to carbohydrate synthesis, and how classical breeding, systems biology, and synthetic biology are providing new opportunities to develop more productive germplasm. Near-term opportunities include improving the display of leaves in crop canopies to avoid light saturation of individual leaves and further investigation of a photorespiratory bypass that has already improved the productivity of model species. Longer-term opportunities include engineering into plants carboxylases that are better adapted to current and forthcoming CO(2) concentrations, and the use of modeling to guide molecular optimization of resource investment among the components of the photosynthetic apparatus, to maximize carbon gain without increasing crop inputs. Collectively, these changes have the potential to more than double the yield potential of our major crops. PMID- 20192735 TI - Arsenic as a food chain contaminant: mechanisms of plant uptake and metabolism and mitigation strategies. AB - Arsenic (As) is an environmental and food chain contaminant. Excessive accumulation of As, particularly inorganic arsenic (As(i)), in rice (Oryza sativa) poses a potential health risk to populations with high rice consumption. Rice is efficient at As accumulation owing to flooded paddy cultivation that leads to arsenite mobilization, and the inadvertent yet efficient uptake of arsenite through the silicon transport pathway. Iron, phosphorus, sulfur, and silicon interact strongly with As during its route from soil to plants. Plants take up arsenate through the phosphate transporters, and arsenite and undissociated methylated As species through the nodulin 26-like intrinsic (NIP) aquaporin channels. Arsenate is readily reduced to arsenite in planta, which is detoxified by complexation with thiol-rich peptides such as phytochelatins and/or vacuolar sequestration. A range of mitigation methods, from agronomic measures and plant breeding to genetic modification, may be employed to reduce As uptake by food crops. PMID- 20192736 TI - Auxin biosynthesis and its role in plant development. AB - Indole-3-acetic acid (IAA), the main auxin in higher plants, has profound effects on plant growth and development. Both plants and some plant pathogens can produce IAA to modulate plant growth. Although the genes and biochemical reactions for auxin biosynthesis in some plant pathogens are well understood, elucidation of the mechanisms by which plants produce auxin has proven to be difficult. So far, no single complete pathway of de novo auxin biosynthesis in plants has been firmly established. However, recent studies have led to the discoveries of several genes in tryptophan-dependent auxin biosynthesis pathways. Recent findings have also determined that local auxin biosynthesis plays essential roles in many developmental processes including gametogenesis, embryogenesis, seedling growth, vascular patterning, and flower development. In this review, I summarize the recent advances in dissecting auxin biosynthetic pathways and how the understanding of auxin biosynthesis provides a crucial angle for analyzing the mechanisms of plant development. PMID- 20192737 TI - Starch: its metabolism, evolution, and biotechnological modification in plants. AB - Starch is the most widespread and abundant storage carbohydrate in plants. We depend upon starch for our nutrition, exploit its unique properties in industry, and use it as a feedstock for bioethanol production. Here, we review recent advances in research in three key areas. First, we assess progress in identifying the enzymatic machinery required for the synthesis of amylopectin, the glucose polymer responsible for the insoluble nature of starch. Second, we discuss the pathways of starch degradation, focusing on the emerging role of transient glucan phosphorylation in plastids as a mechanism for solubilizing the surface of the starch granule. We contrast this pathway in leaves with the degradation of starch in the endosperm of germinated cereal seeds. Third, we consider the evolution of starch biosynthesis in plants from the ancestral ability to make glycogen. Finally, we discuss how this basic knowledge has been utilized to improve and diversify starch crops. PMID- 20192738 TI - Female gametophyte development in flowering plants. AB - The multicellular female gametophyte, a unique feature of higher plants, provides us with an excellent experimental system to address fundamental questions in biology. During the past few years, we have gained significant insight into the mechanisms that control embryo sac polarity, gametophytic cell specification, and recognition between male and female gametophytic cells. An auxin gradient has been shown for the first time to function in the female gametophyte to regulate gametic cell fate, and key genes that control gametic cell fate have also been identified. This review provides an overview of these exciting discoveries with a focus on molecular and genetic data. PMID- 20192739 TI - Genetic and molecular bases of rice yield. AB - Grain yield in rice is a complex trait multiplicatively determined by its three component traits: number of panicles, number of grains per panicle, and grain weight; all of which are typical quantitative traits. The developments in genome mapping, sequencing, and functional genomic research have provided powerful tools for investigating the genetic and molecular bases of these quantitative traits. Dissection of the genetic bases of the yield traits based on molecular marker linkage maps resolved hundreds of quantitative trait loci (QTLs) for these traits. Mutant analyses and map-based cloning of QTLs have identified a large number of genes required for the basic processes underlying the initiation and development of tillers and panicles, as well as genes controlling numbers and sizes of grains and panicles. Molecular characterization of these genes has greatly advanced the mechanistic understanding of the regulation of these rice yield traits. These findings have significant implications in crop genetic improvement. PMID- 20192740 TI - Chloroplast RNA metabolism. AB - The chloroplast genome encodes proteins required for photosynthesis, gene expression, and other essential organellar functions. Derived from a cyanobacterial ancestor, the chloroplast combines prokaryotic and eukaryotic features of gene expression and is regulated by many nucleus-encoded proteins. This review covers four major chloroplast posttranscriptional processes: RNA processing, editing, splicing, and turnover. RNA processing includes the generation of transcript 5' and 3' termini, as well as the cleavage of polycistronic transcripts. Editing converts specific C residues to U and often changes the amino acid that is specified by the edited codon. Chloroplasts feature introns of groups I and II, which undergo protein-facilitated cis- or trans-splicing in vivo. Each of these RNA-based processes involves proteins of the pentatricopeptide motif-containing family, which does not occur in prokaryotes. Plant-specific RNA-binding proteins may underpin the adaptation of the chloroplast to the eukaryotic context. PMID- 20192741 TI - Quantitation in mass-spectrometry-based proteomics. AB - Mass-spectrometry-based proteomics, the large-scale analysis of proteins by mass spectrometry, has emerged as a new technology over the last decade and become routine in many plant biology laboratories. While early work consisted merely of listing proteins identified in a given organ or under different conditions of interest, there is a growing need to apply comparative and quantitative proteomics strategies toward gaining novel insights into functional aspects of plant proteins and their dynamics. However, during the transition from qualitative to quantitative protein analysis, the potential and challenges will be tightly coupled. Several strategies for differential proteomics that involve stable isotopes or label-free comparisons and their statistical assessment are possible, each having specific strengths and limitations. Furthermore, incomplete proteome coverage and restricted dynamic range still impose the strongest limitations to data throughput and precise quantitative analysis. This review gives an overview of the current state of the art in differential proteomics and possible strategies in data processing. PMID- 20192742 TI - Hemicelluloses. AB - Hemicelluloses are polysaccharides in plant cell walls that have beta-(1-->4) linked backbones with an equatorial configuration. Hemicelluloses include xyloglucans, xylans, mannans and glucomannans, and beta-(1-->3,1-->4)-glucans. These types of hemicelluloses are present in the cell walls of all terrestrial plants, except for beta-(1-->3,1-->4)-glucans, which are restricted to Poales and a few other groups. The detailed structure of the hemicelluloses and their abundance vary widely between different species and cell types. The most important biological role of hemicelluloses is their contribution to strengthening the cell wall by interaction with cellulose and, in some walls, with lignin. These features are discussed in relation to widely accepted models of the primary wall. Hemicelluloses are synthesized by glycosyltransferases located in the Golgi membranes. Many glycosyltransferases needed for biosynthesis of xyloglucans and mannans are known. In contrast, the biosynthesis of xylans and beta-(1-->3,1-->4)-glucans remains very elusive, and recent studies have led to more questions than answers. PMID- 20192743 TI - Evolution in action: plants resistant to herbicides. AB - Modern herbicides make major contributions to global food production by easily removing weeds and substituting for destructive soil cultivation. However, persistent herbicide selection of huge weed numbers across vast areas can result in the rapid evolution of herbicide resistance. Herbicides target specific enzymes, and mutations are selected that confer resistance-endowing amino acid substitutions, decreasing herbicide binding. Where herbicides bind within an enzyme catalytic site very few mutations give resistance while conserving enzyme functionality. Where herbicides bind away from a catalytic site many resistance endowing mutations may evolve. Increasingly, resistance evolves due to mechanisms limiting herbicide reaching target sites. Especially threatening are herbicide degrading cytochrome P450 enzymes able to detoxify existing, new, and even herbicides yet to be discovered. Global weed species are accumulating resistance mechanisms, displaying multiple resistance across many herbicides and posing a great challenge to herbicide sustainability in world agriculture. Fascinating genetic issues associated with resistance evolution remain to be investigated, especially the possibility of herbicide stress unleashing epigenetic gene expression. Understanding resistance and building sustainable solutions to herbicide resistance evolution are necessary and worthy challenges. PMID- 20192744 TI - Structure and function of plant photoreceptors. AB - Signaling photoreceptors use the information contained in the absorption of a photon to modulate biological activity in plants and a wide range of organisms. The fundamental-and as yet imperfectly answered-question is, how is this achieved at the molecular level? We adopt the perspective of biophysicists interested in light-dependent signal transduction in nature and the three-dimensional structures that underpin signaling. Six classes of photoreceptors are known: light-oxygen-voltage (LOV) sensors, xanthopsins, phytochromes, blue-light sensors using flavin adenine dinucleotide (BLUF), cryptochromes, and rhodopsins. All are water-soluble proteins except rhodopsins, which are integral membrane proteins; all are based on a modular architecture except cryptochromes and rhodopsins; and each displays a distinct, light-dependent chemical process based on the photochemistry of their nonprotein chromophore, such as isomerization about a double bond (xanthopsins, phytochromes, and rhodopsins), formation or rupture of a covalent bond (LOV sensors), or electron transfer (BLUF sensors and cryptochromes). PMID- 20192745 TI - Diversification of P450 genes during land plant evolution. AB - Plant cytochromes P450 (P450s) catalyze a wide variety of monooxygenation/hydroxylation reactions in primary and secondary metabolism. The number of P450 genes in plant genomes is estimated to be up to 1% of total gene annotations of each plant species. This implies that diversification within P450 gene superfamilies has led to the emergence of new metabolic pathways throughout land plant evolution. The conserved P450 families contribute to chemical defense mechanisms under terrestrial conditions and several are involved in hormone biosynthesis and catabolism. Species-specific P450 families are essential for the biosynthetic pathways of species-specialized metabolites. Future genome-wide analyses of P450 gene clusters and coexpression networks should help both in identifying the functions of many orphan P450s and in understanding the evolution of this versatile group of enzymes. PMID- 20192746 TI - Genetic engineering for modern agriculture: challenges and perspectives. AB - Abiotic stress conditions such as drought, heat, or salinity cause extensive losses to agricultural production worldwide. Progress in generating transgenic crops with enhanced tolerance to abiotic stresses has nevertheless been slow. The complex field environment with its heterogenic conditions, abiotic stress combinations, and global climatic changes are but a few of the challenges facing modern agriculture. A combination of approaches will likely be needed to significantly improve the abiotic stress tolerance of crops in the field. These will include mechanistic understanding and subsequent utilization of stress response and stress acclimation networks, with careful attention to field growth conditions, extensive testing in the laboratory, greenhouse, and the field; the use of innovative approaches that take into consideration the genetic background and physiology of different crops; the use of enzymes and proteins from other organisms; and the integration of QTL mapping and other genetic and breeding tools. PMID- 20192747 TI - Histone methylation in higher plants. AB - Histone methylation plays a fundamental role in regulating diverse developmental processes and is also involved in silencing repetitive sequences in order to maintain genome stability. The methylation marks are written on lysine or arginine by distinct enzymes, namely, histone lysine methyltransferases (HKMTs) or protein arginine methyltransferases (PRMTs). Once established, the methylation marks are specifically recognized by the proteins that act as readers and are interpreted into specific biological outcomes. Histone methylation status is dynamic; methylation marks can be removed by eraser enzymes, the histone demethylases (HDMs). The proteins responsible for writing, reading, and erasing the methylation marks are known mostly in animals. During the past several years, a growing body of literature has demonstrated the impact of histone methylation on genome management, transcriptional regulation, and development in plants. The aim of this review is to summarize the biochemical, genetic, and molecular action of histone methylation in two plants, the dicot Arabidopsis and the monocot rice. PMID- 20192748 TI - Protein transport into chloroplasts. AB - Most proteins in chloroplasts are encoded by the nuclear genome and synthesized as precursors with N-terminal targeting signals called transit peptides. Novel machinery has evolved to specifically import these proteins from the cytosol into chloroplasts. This machinery consists of more than a dozen components located in and around the chloroplast envelope, including a pair of GTPase receptors, a beta barrel-type channel across the outer membrane, and an AAA(+)-type motor in the stroma. How individual components assemble into functional subcomplexes and the sequential steps of the translocation process are being mapped out. An increasing number of noncanonical import pathways, including a pathway with initial transport through the endomembrane system, is being revealed. Multiple levels of control on protein transport into chloroplasts have evolved, including the development of two receptor subfamilies, one for photosynthetic proteins and one for housekeeping proteins. The functions or expression levels of some translocon components are further adjusted according to plastid type, developmental stage, and metabolic conditions. PMID- 20192749 TI - Metal hyperaccumulation in plants. AB - During the history of life on Earth, tectonic and climatic change repeatedly generated large territories that were virtually devoid of life and exhibited harsh environmental conditions. The ability of a few specialist pioneer plants to colonize such hostile environments was thus of paramount ecological importance for the continuous maintenance of primary production over time. Yet, we know very little about how extreme traits evolve and function in plants. Recent breakthroughs have given first insights into the molecular basis underlying the complex extreme model trait of metal hyperaccumulation and associated metal hypertolerance. This review gives an introduction into the hyperaccumulator research field and its history; provides an overview of hyperaccumulator germplasm; describes the state of the art of our understanding of the physiological, molecular, and genetic basis underlying metal hyperaccumulation and its evolution; and highlights future research needs and opportunities. PMID- 20192750 TI - High-throughput characterization of plant gene functions by using gain-of function technology. AB - Gain-of-function approaches have been used as an alternative or complementary method to loss-of-function approaches as well as to confer new functions to plants. Gain-of-function is achieved by increasing gene expression levels through the random activation of endogenous genes by transcriptional enhancers or the expression of individual transgenes by transformation. The advantages of gain-of function approaches compared to loss-of-function approaches for the characterization of gene functions include the abilities to (a) analyze individual gene family members, (b) characterize the function of genes from nonmodel plants using a heterologous expression system, and (c) identify genes that confer stress tolerance to plants that result from the introduction of transgenes. In this review, we describe the current status of gain-of-function mutagenesis and provide several examples of how gene functions have been characterized via high-throughput screening using gain-of-function technology. PMID- 20192752 TI - Brassinosteroid signal transduction from receptor kinases to transcription factors. AB - Brassinosteroids (BRs) are growth-promoting steroid hormones in plants. Genetic studies in Arabidopsis illustrated the essential roles of BRs in a wide range of developmental processes and helped identify many genes involved in BR biosynthesis and signal transduction. Recently, proteomic studies identified missing links. Together, these approaches established the BR signal transduction cascade, which includes BR perception by the BRI1 receptor kinase at the cell surface, activation of BRI1/BAK1 kinase complex by transphosphorylation, subsequent phosphorylation of the BSK kinases, activation of the BSU1 phosphatase, dephosphorylation and inactivation of the BIN2 kinase, and accumulation of unphosphorylated BZR transcription factors in the nucleus. Mass spectrometric analyses are providing detailed information on the phosphorylation events involved in each step of signal relay. Thus, the BR signaling pathway provides a paradigm for understanding receptor kinase-mediated signal transduction as well as tools for the genetic improvement of the productivity of crop plants. PMID- 20192753 TI - The regulation of gene expression required for C4 photosynthesis. AB - C(4) photosynthesis is normally associated with the compartmentation of photosynthesis between mesophyll (M) and bundle sheath (BS) cells. The mechanisms regulating the differential accumulation of photosynthesis proteins in these specialized cells are fundamental to our understanding of how C(4) photosynthesis operates. Cell-specific accumulation of proteins in M or BS can be mediated by posttranscriptional processes and translational efficiency as well as by differences in transcription. Individual genes are likely regulated at multiple levels. Although cis-elements have been associated with cell-specific expression in C(4) leaves, there has been little progress in identifying trans-factors. When C(4) photosynthesis genes from C(4) species are placed in closely related C(3) species, they are often expressed in a manner faithful to the C(4) cycle. Next generation sequencing and comprehensive analysis of the extent to which genes from C(4) species are expressed in M or BS cells of C(3) plants should provide insight into how the C(4) pathway is regulated and evolved. PMID- 20192751 TI - Guard cell signal transduction network: advances in understanding abscisic acid, CO2, and Ca2+ signaling. AB - Stomatal pores are formed by pairs of specialized epidermal guard cells and serve as major gateways for both CO(2) influx into plants from the atmosphere and transpirational water loss of plants. Because they regulate stomatal pore apertures via integration of both endogenous hormonal stimuli and environmental signals, guard cells have been highly developed as a model system to dissect the dynamics and mechanisms of plant-cell signaling. The stress hormone ABA and elevated levels of CO(2) activate complex signaling pathways in guard cells that are mediated by kinases/phosphatases, secondary messengers, and ion channel regulation. Recent research in guard cells has led to a new hypothesis for how plants achieve specificity in intracellular calcium signaling: CO(2) and ABA enhance (prime) the calcium sensitivity of downstream calcium-signaling mechanisms. Recent progress in identification of early stomatal signaling components are reviewed here, including ABA receptors and CO(2)-binding response proteins, as well as systems approaches that advance our understanding of guard cell-signaling mechanisms. PMID- 20192754 TI - The language of calcium signaling. AB - Ca(2+) signals are a core regulator of plant cell physiology and cellular responses to the environment. The channels, pumps, and carriers that underlie Ca(2+) homeostasis provide the mechanistic basis for generation of Ca(2+) signals by regulating movement of Ca(2+) ions between subcellular compartments and between the cell and its extracellular environment. The information encoded within the Ca(2+) transients is decoded and transmitted by a toolkit of Ca(2+) binding proteins that regulate transcription via Ca(2+)-responsive promoter elements and that regulate protein phosphorylation. Ca(2+)-signaling networks have architectural structures comparable to scale-free networks and bow tie networks in computing, and these similarities help explain such properties of Ca(2+)-signaling networks as robustness, evolvability, and the ability to process multiple signals simultaneously. PMID- 20192755 TI - Abscisic acid: emergence of a core signaling network. AB - Abscisic acid (ABA) regulates numerous developmental processes and adaptive stress responses in plants. Many ABA signaling components have been identified, but their interconnections and a consensus on the structure of the ABA signaling network have eluded researchers. Recently, several advances have led to the identification of ABA receptors and their three-dimensional structures, and an understanding of how key regulatory phosphatase and kinase activities are controlled by ABA. A new model for ABA action has been proposed and validated, in which the soluble PYR/PYL/RCAR receptors function at the apex of a negative regulatory pathway to directly regulate PP2C phosphatases, which in turn directly regulate SnRK2 kinases. This model unifies many previously defined signaling components and highlights the importance of future work focused on defining the direct targets of SnRK2s and PP2Cs, dissecting the mechanisms of hormone interactions (i.e., cross talk) and defining connections between this new negative regulatory pathway and other factors implicated in ABA signaling. PMID- 20192756 TI - Computational morphodynamics: a modeling framework to understand plant growth. AB - Computational morphodynamics utilizes computer modeling to understand the development of living organisms over space and time. Results from biological experiments are used to construct accurate and predictive models of growth. These models are then used to make novel predictions that provide further insight into the processes involved, which can be tested experimentally to either confirm or rule out the validity of the computational models. This review highlights two fundamental challenges: (a) to understand the feedback between mechanics of growth and chemical or molecular signaling, and (b) to design models that span and integrate single cell behavior with tissue development. We review different approaches to model plant growth and discuss a variety of model types that can be implemented to demonstrate how the interplay between computational modeling and experimentation can be used to explore the morphodynamics of plant development. PMID- 20192757 TI - Induced systemic resistance and plant responses to fungal biocontrol agents. AB - Biocontrol fungi (BCF) are agents that control plant diseases. These include the well-known Trichoderma spp. and the recently described Sebacinales spp. They have the ability to control numerous foliar, root, and fruit pathogens and even invertebrates such as nematodes. However, this is only a subset of their abilities. We now know that they also have the ability to ameliorate a wide range of abiotic stresses, and some of them can also alleviate physiological stresses such as seed aging. They can also enhance nutrient uptake in plants and can substantially increase nitrogen use efficiency in crops. These abilities may be more important to agriculture than disease control. Some strains also have abilities to improve photosynthetic efficiency and probably respiratory activities of plants. All of these capabilities are a consequence of their abilities to reprogram plant gene expression, probably through activation of a limited number of general plant pathways. PMID- 20192758 TI - Functions and regulation of RNA editing by ADAR deaminases. AB - One type of RNA editing converts adenosines to inosines (A-->I editing) in double stranded RNA (dsRNA) substrates. A-->I RNA editing is mediated by adenosine deaminase acting on RNA (ADAR) enzymes. A-->I RNA editing of protein-coding sequences of a limited number of mammalian genes results in recoding and subsequent alterations of their functions. However, A-->I RNA editing most frequently targets repetitive RNA sequences located within introns and 5' and 3' untranslated regions (UTRs). Although the biological significance of noncoding RNA editing remains largely unknown, several possibilities, including its role in the control of endogenous short interfering RNAs (esiRNAs), have been proposed. Furthermore, recent studies have revealed that the biogenesis and functions of certain microRNAs (miRNAs) are regulated by the editing of their precursors. Here, I review the recent findings that indicate new functions for A-->I editing in the regulation of noncoding RNAs and for interactions between RNA editing and RNA interference mechanisms. PMID- 20192760 TI - From virus structure to chromatin: X-ray diffraction to three-dimensional electron microscopy. AB - Early influences led me first to medical school with a view to microbiology, but I felt the lack of a deeper foundation and changed to chemistry, which in turn led me to physics and mathematics. I moved to the University of Cape Town to work on the X-ray crystallography of some small organic compounds. I developed a new method of using molecular structure factors to solve the crystal structure, which won me a research studentship to Trinity College Cambridge and the Cavendish Laboratory. There I worked on the austenite-pearlite transition in steel. This is governed by the dissipation of latent heat, and I ended up numerically solving partial differential equations. I used the idea of nucleation and growth during the phase change, which had its echo when I later tackled the assembly of Tobacco mosaic virus (TMV) from its constituent RNA and protein subunits. I wanted to move on to X-ray structure analysis of large biological molecules and obtained a Nuffield Fellowship to work in J.D. Bernal's department at Birkbeck College, London. There, I met Rosalind Franklin, who had taken up the study of TMV. I was able to interpret some of Franklin's beautiful X-ray diffraction patterns of the virus particle. From then on, my fate was sealed. After Franklin's untimely death in 1958, I moved in 1962 to the newly built MRC Laboratory of Molecular Biology in Cambridge, which, under Max Perutz, housed the original MRC unit from the Cavendish Laboratory. I was thus privileged to join the Laboratory at an early stage in its expansion and consequently able to take advantage of, and to help build up, its then unique environment of intellectual and technological sophistication. There I have remained ever since. PMID- 20192759 TI - The mechanism of double-strand DNA break repair by the nonhomologous DNA end joining pathway. AB - Double-strand DNA breaks are common events in eukaryotic cells, and there are two major pathways for repairing them: homologous recombination (HR) and nonhomologous DNA end joining (NHEJ). The various causes of double-strand breaks (DSBs) result in a diverse chemistry of DNA ends that must be repaired. Across NHEJ evolution, the enzymes of the NHEJ pathway exhibit a remarkable degree of structural tolerance in the range of DNA end substrate configurations upon which they can act. In vertebrate cells, the nuclease, DNA polymerases, and ligase of NHEJ are the most mechanistically flexible and multifunctional enzymes in each of their classes. Unlike repair pathways for more defined lesions, NHEJ repair enzymes act iteratively, act in any order, and can function independently of one another at each of the two DNA ends being joined. NHEJ is critical not only for the repair of pathologic DSBs as in chromosomal translocations, but also for the repair of physiologic DSBs created during variable (diversity) joining [V(D)J] recombination and class switch recombination (CSR). Therefore, patients lacking normal NHEJ are not only sensitive to ionizing radiation (IR), but also severely immunodeficient. PMID- 20192761 TI - The discovery of zinc fingers and their applications in gene regulation and genome manipulation. AB - An account is given of the discovery of the classical Cys(2)His(2) zinc finger, arising from the interpretation of biochemical studies on the interaction of the Xenopus protein transcription factor IIIA with 5S RNA, and of structural studies on its structure and its interaction with DNA. The finger is a self-contained domain stabilized by a zinc ion ligated to a pair of cysteines and a pair of histidines, and by an inner hydrophobic core. This discovery showed not only a new protein fold but also a novel principle of DNA recognition. Whereas other DNA binding proteins generally make use of the two-fold symmetry of the double helix, zinc fingers can be linked linearly in tandem to recognize nucleic acid sequences of varying lengths. This modular design offers a large number of combinatorial possibilities for the specific recognition of DNA (or RNA). It is therefore not surprising that the zinc finger is found widespread in nature, including 3% of the genes of the human genome. The zinc finger design is ideally suited for engineering proteins to target specific genes. In the first example of their application in 1994, a three-finger protein was constructed to block the expression of an oncogene transformed into a mouse cell line. In addition, a reporter gene was activated by targeting an inserted zinc finger promoter. Thus, by fusing zinc finger peptides to repression or activation domains, genes can be selectively switched off or on. It was also suggested that by combining zinc fingers with other effector domains, e.g., from nucleases or integrases, to form chimeric proteins, genomes could be manipulated or modified. Several applications of such engineered zinc finger proteins are described here, including some of therapeutic importance. PMID- 20192762 TI - Bacterial microcompartment organelles: protein shell structure and evolution. AB - Some bacteria contain organelles or microcompartments consisting of a large virion-like protein shell encapsulating sequentially acting enzymes. These organized microcompartments serve to enhance or protect key metabolic pathways inside the cell. The variety of bacterial microcompartments provide diverse metabolic functions, ranging from CO(2) fixation to the degradation of small organic molecules. Yet they share an evolutionarily related shell, which is defined by a conserved protein domain that is widely distributed across the bacterial kingdom. Structural studies on a number of these bacterial microcompartment shell proteins are illuminating the architecture of the shell and highlighting its critical role in controlling molecular transport into and out of microcompartments. Current structural, evolutionary, and mechanistic ideas are discussed, along with genomic studies for exploring the function and diversity of this family of bacterial organelles. PMID- 20192764 TI - Compact intermediates in RNA folding. AB - Large noncoding RNAs fold into their biologically functional structures via compact yet disordered intermediates, which couple the stable secondary structure of the RNA with the emerging tertiary fold. The specificity of the collapse transition, which coincides with the assembly of helical domains, depends on RNA sequence and counterions. It determines the specificity of the folding pathways and the magnitude of the free energy barriers to the ensuing search for the native conformation. By coupling helix assembly with nascent tertiary interactions, compact folding intermediates in RNA also play a crucial role in ligand binding and RNA-protein recognition. PMID- 20192765 TI - Theoretical perspectives on protein folding. AB - Understanding how monomeric proteins fold under in vitro conditions is crucial to describing their functions in the cellular context. Significant advances in theory and experiments have resulted in a conceptual framework for describing the folding mechanisms of globular proteins. The sizes of proteins in the denatured and folded states, cooperativity of the folding transition, dispersions in the melting temperatures at the residue level, and timescales of folding are, to a large extent, determined by N, the number of residues. The intricate details of folding as a function of denaturant concentration can be predicted by using a novel coarse-grained molecular transfer model. By watching one molecule fold at a time, using single-molecule methods, investigators have established the validity of the theoretically anticipated heterogeneity in the folding routes and the N dependent timescales for the three stages in the approach to the native state. Despite the successes of theory, of which only a few examples are documented here, we conclude that much remains to be done to solve the protein folding problem in the broadest sense. PMID- 20192763 TI - Lessons learned from UvrD helicase: mechanism for directional movement. AB - How do molecular motors convert chemical energy to mechanical work? Helicases and nucleic acids offer simple motor systems for extensive biochemical and biophysical analyses. Atomic resolution structures of UvrD-like helicases complexed with DNA in the presence of AMPPNP, ADP.Pi, and Pi reveal several salient points that aid our understanding of mechanochemical coupling. Each ATPase cycle causes two motor domains to rotationally close and open. At a minimum, two motor-track contact points of alternating tight and loose attachment convert domain rotations to unidirectional movement. A motor is poised for action only when fully in contact with its track and, if applicable, working against a load. The orientation of domain rotation relative to the track determines whether the movement is linear, spiral, or circular. Motors powered by ATPases likely deliver each power stroke in two parts, before and after ATP hydrolysis. Implications of these findings for analyzing hexameric helicase, F(1)F(0) ATPase, and kinesin are discussed. PMID- 20192766 TI - Optical control of neuronal activity. AB - Advances in optics, genetics, and chemistry have enabled the investigation of brain function at all levels, from intracellular signals to single synapses, whole cells, circuits, and behavior. Until recent years, these research tools have been utilized in an observational capacity: imaging neural activity with fluorescent reporters, for example, or correlating aberrant neural activity with loss-of-function and gain-of-function pharmacological or genetic manipulations. However, optics, genetics, and chemistry have now combined to yield a new strategy: using light to drive and halt neuronal activity with molecular specificity and millisecond precision. Photostimulation of neurons is noninvasive, has unmatched spatial and temporal resolution, and can be targeted to specific classes of neurons. The optical methods developed to date encompass a broad array of strategies, including photorelease of caged neurotransmitters, engineered light-gated receptors and channels, and naturally light-sensitive ion channels and pumps. In this review, we describe photostimulation methods, their applications, and opportunities for further advancement. PMID- 20192767 TI - Structural and functional insights into the Myosin motor mechanism. AB - The general structural features of the motor region of myosin superfamily members are now well established, as is a subset of the structural and kinetic transitions of the actin-myosin catalytic cycle. Not yet visualized are the structural rearrangements triggered by actin binding that are coupled to force generation and product release. In this review we describe the recent progress in understanding these missing components of the mechanism of chemomechanical transduction by myosin motors. These insights come from a combination of kinetic and single-molecule studies on multiple classes of myosins, with additional insights from contracting muscle fibers. These recent studies have explored the effects of intermediate and high loads on the kinetics of the actin-bound myosin state transitions. We also describe studies that delineate how some classes of myosin motors are adapted for processive movement on actin. PMID- 20192769 TI - Simplified models of biological networks. AB - The function of living cells is controlled by complex regulatory networks that are built of a wide diversity of interacting molecular components. The sheer size and intricacy of molecular networks of even the simplest organisms are obstacles toward understanding network functionality. This review discusses the achievements and promise of a bottom-up approach that uses well-characterized subnetworks as model systems for understanding larger networks. It highlights the interplay between the structure, logic, and function of various types of small regulatory circuits. The bottom-up approach advocates understanding regulatory networks as a collection of entangled motifs. We therefore emphasize the potential of negative and positive feedback, as well as their combinations, to generate robust homeostasis, epigenetics, and oscillations. PMID- 20192770 TI - Structure and activation of the visual pigment rhodopsin. AB - Rhodopsin is a specialized G protein-coupled receptor (GPCR) found in vertebrate rod cells. Absorption of light by its 11-cis retinal chromophore leads to rapid photochemical isomerization and receptor activation. Recent results from protein crystallography and NMR spectroscopy show how structural changes on the extracellular side of rhodopsin induced by retinal isomerization are coupled to the motion of membrane-spanning helices to create a G protein binding pocket on the intracellular side of the receptor. The signaling pathway provides a comprehensive explanation for the conservation of specific amino acids and structural motifs across the class A family of GPCRs, as well as for the conservation of selected residues within the visual receptor subfamily. The emerging model of activation indicates that, rather than being unique, the visual receptors provide a basis for understanding the common structural and dynamic elements in the class A GPCRs. PMID- 20192768 TI - Eukaryotic chemotaxis: a network of signaling pathways controls motility, directional sensing, and polarity. AB - Chemotaxis, the directed migration of cells in chemical gradients, is a vital process in normal physiology and in the pathogenesis of many diseases. Chemotactic cells display motility, directional sensing, and polarity. Motility refers to the random extension of pseudopodia, which may be driven by spontaneous actin waves that propagate through the cytoskeleton. Directional sensing is mediated by a system that detects temporal and spatial stimuli and biases motility toward the gradient. Polarity gives cells morphologically and functionally distinct leading and lagging edges by relocating proteins or their activities selectively to the poles. By exploiting the genetic advantages of Dictyostelium, investigators are working out the complex network of interactions between the proteins that have been implicated in the chemotactic processes of motility, directional sensing, and polarity. PMID- 20192771 TI - Biophysics of knotting. AB - Knots appear in a wide variety of biophysical systems, ranging from biopolymers, such as DNA and proteins, to macroscopic objects, such as umbilical cords and catheters. Although significant advancements have been made in the mathematical theory of knots and some progress has been made in the statistical mechanics of knots in idealized chains, the mechanisms and dynamics of knotting in biophysical systems remain far from fully understood. We report on recent progress in the biophysics of knotting-the formation, characterization, and dynamics of knots in various biophysical contexts. PMID- 20192773 TI - Protein crystallization using microfluidic technologies based on valves, droplets, and SlipChip. AB - To obtain protein crystals, researchers must search for conditions in multidimensional chemical space. Empirically, thousands of crystallization experiments are carried out to screen various precipitants at multiple concentrations. Microfluidics can manipulate fluids on a nanoliter scale, and it affects crystallization twofold. First, it miniaturizes the experiments that can currently be done on a larger scale and enables crystallization of proteins that are available only in small amounts. Second, it offers unique experimental approaches that are difficult or impossible to implement on a larger scale. Ongoing development of microfluidic techniques and their integration with protein production, characterization, and in situ diffraction promises to accelerate the progress of structural biology. PMID- 20192772 TI - Lipids and cholesterol as regulators of traffic in the endomembrane system. AB - The endomembrane system of eukaryotic cells uses membrane-enclosed carriers to move diverse macromolecules among different membrane-bound compartments, a requirement for cells to secrete and take up molecules from their environment. Two recycling pathways-biosynthetic and endocytic, each with specific lipid components-make up this system, with the Golgi apparatus mediating transport between the two. Here, we integrate lipid-based mechanisms into the description of this system. A partitioning model of the Golgi apparatus is discussed as a working hypothesis to explain how membrane lipids and proteins that are segregated based on lateral lipid partitioning support the unique composition of the biosynthetic and endocytic recycling pathways in the face of constant trafficking of molecular constituents. We further discuss how computational modeling can allow for interpretation of experimental findings and provide mechanistic insight into these important cellular pathways. PMID- 20192774 TI - The distribution and function of phosphatidylserine in cellular membranes. AB - Phosphatidylserine (PS) is the most abundant negatively charged phospholipid in eukaryotic membranes. PS directs the binding of proteins that bear C2 or gamma carboxyglutamic domains and contributes to the electrostatic association of polycationic ligands with cellular membranes. Rather than being evenly distributed, PS is found preferentially in the inner leaflet of the plasma membrane and in endocytic membranes. The loss of PS asymmetry is an early indicator of apoptosis and serves as a signal to initiate blood clotting. This review discusses the determinants and functional implications of the subcellular distribution and membrane topology of PS. PMID- 20192776 TI - Ribosome structure and dynamics during translocation and termination. AB - Protein biosynthesis, or translation, occurs on the ribosome, a large RNA-protein assembly universally conserved in all forms of life. Over the last decade, structures of the small and large ribosomal subunits and of the intact ribosome have begun to reveal the molecular details of how the ribosome works. Both cryo electron microscopy and X-ray crystallography continue to provide fresh insights into the mechanism of translation. In this review, we describe the most recent structural models of the bacterial ribosome that shed light on the movement of messenger RNA and transfer RNA on the ribosome after each peptide bond is formed, a process termed translocation. We also discuss recent structures that reveal the molecular basis for stop codon recognition during translation termination. Finally, we review recent advances in understanding how bacteria handle errors in both translocation and termination. PMID- 20192775 TI - Phase separation in biological membranes: integration of theory and experiment. AB - Lipid bilayer model membranes that contain a single lipid species can undergo transitions between ordered and disordered phases, and membranes that contain a mixture of lipid species can undergo phase separations. Studies of these transformations are of interest for what they can tell us about the interaction energies of lipid molecules of different species and conformations. Nanoscopic phases (<200 nm) can provide a model for membrane rafts, specialized membrane domains enriched in cholesterol and sphingomyelin, which are believed to have essential biological functions in cell membranes. Crucial questions are whether lipid nanodomains can exist in stable equilibrium in membranes and what is the distribution of their sizes and lifetimes in membranes of different composition. Theoretical methods have supplied much information on these questions, but better experimental methods are needed to detect and characterize nanodomains under normal membrane conditions. This review summarizes linkages between theoretical and experimental studies of phase separation in lipid bilayer model membranes. PMID- 20192777 TI - Nanopore analysis of nucleic acids bound to exonucleases and polymerases. AB - When a voltage is imposed across a thin membrane containing a nanoscopic pore, the electric field generated within the pore captures linear ionized polymers, such as nucleic acids, that are present in the solution bathing the pore. The nucleic acid molecule transiently blocks ionic current as it is translocated through the pore, and modulations of the current provide information about the structure and dynamic motion of the molecule. Altering the imposed voltage allows movement of the DNA molecule in the pore to be controlled. If a DNA-processing enzyme such as an exonuclease or polymerase is present, the enzyme-DNA complex is also drawn to the pore, and further modulations of the ionic current reflect enzyme function at the single-molecule level on millisecond timescales. The combined enzymatic and voltage control of a DNA molecule in the nanopore can be used to sequence the DNA. PMID- 20192778 TI - Control of actin filament treadmilling in cell motility. AB - Recent advances in structural, biochemical, biophysical, and live cell imaging approaches have furthered our understanding of the molecular mechanisms by which regulated assembly dynamics of actin filaments drive motile processes. Attention is focused on lamellipodium protrusion, powered by the turnover of a branched filament array. ATP hydrolysis on actin is the key reaction that allows filament treadmilling. It regulates barbed-end dynamics and length fluctuations at steady state and specifies the functional interaction of actin with essential regulatory proteins such as profilin and ADF/cofilin. ATP hydrolysis on actin and Arp2/3 acts as a timer, regulating the assembly and disassembly of the branched array to generate tropomyosin-mediated heterogeneity in the structure and dynamics of the lamellipodial network. The detailed molecular mechanisms of ATP hydrolysis/Pi release on F-actin remain elusive, as well as the mechanism of filament branching with Arp2/3 complex or that of the formin-driven processive actin assembly. Novel biophysical methods involving single-molecule measurements should foster progress in these crucial issues. PMID- 20192779 TI - Expanding roles for diverse physical phenomena during the origin of life. AB - Recent synthetic approaches to understanding the origin of life have yielded insights into plausible pathways for the emergence of the first cells. Here we review current experiments with implications for the origin of life, emphasizing the ability of unexpected physical processes to facilitate the self-assembly and self-replication of the first biological systems. These laboratory efforts have uncovered novel physical mechanisms for the emergence of homochirality; the concentration and purification of prebiotic building blocks; and the ability of the first cells to assemble, grow, divide, and acquire greater complexity. In the absence of evolved biochemical capabilities, such physical processes likely played an essential role in early biology. PMID- 20192780 TI - Rewiring cells: synthetic biology as a tool to interrogate the organizational principles of living systems. AB - The living cell is an incredibly complex entity, and the goal of predictively and quantitatively understanding its function is one of the next great challenges in biology. Much of what we know about the cell concerns its constituent parts, but to a great extent we have yet to decode how these parts are organized to yield complex physiological function. Classically, we have learned about the organization of cellular networks by disrupting them through genetic or chemical means. The emerging discipline of synthetic biology offers an additional, powerful approach to study systems. By rearranging the parts that comprise existing networks, we can gain valuable insight into the hierarchical logic of the networks and identify the modular building blocks that evolution uses to generate innovative function. In addition, by building minimal toy networks, one can systematically explore the relationship between network structure and function. Here, we outline recent work that uses synthetic biology approaches to investigate the organization and function of cellular networks, and describe a vision for a synthetic biology toolkit that could be used to interrogate the design principles of diverse systems. PMID- 20192782 TI - Eukaryotic mechanosensitive channels. AB - Mechanosensitive ion channels are gated directly by physical stimuli and transduce these stimuli into electrical signals. Several criteria must apply for a channel to be considered mechanically gated. Mechanosensitive channels from bacterial systems have met these criteria, but few eukaryotic channels have been confirmed by the same standards. Recent work has suggested or confirmed that diverse types of channels, including TRP channels, K(2P) channels, MscS-like proteins, and DEG/ENaC channels, are mechanically gated. Several studies point to the importance of the plasma membrane for channel gating, but intracellular and/or extracellular structures may also be required. PMID- 20192781 TI - Global dynamics of proteins: bridging between structure and function. AB - Biomolecular systems possess unique, structure-encoded dynamic properties that underlie their biological functions. Recent studies indicate that these dynamic properties are determined to a large extent by the topology of native contacts. In recent years, elastic network models used in conjunction with normal mode analyses have proven to be useful for elucidating the collective dynamics intrinsically accessible under native state conditions, including in particular the global modes of motions that are robustly defined by the overall architecture. With increasing availability of structural data for well-studied proteins in different forms (liganded, complexed, or free), there is increasing evidence in support of the correspondence between functional changes in structures observed in experiments and the global motions predicted by these coarse-grained analyses. These observed correlations suggest that computational methods may be advantageously employed for assessing functional changes in structure and allosteric mechanisms intrinsically favored by the native fold. PMID- 20192783 TI - Single ribosome dynamics and the mechanism of translation. AB - Our current understanding of the mechanism of translation is based on nearly fifty years of biochemical and biophysical studies. This mechanism, which requires the ribosome to manipulate tRNA and step repetitively along the mRNA, implies movement. High-resolution structures of the ribosome and its ligands have recently described translation in atomic detail, capturing the endpoints of large scale rearrangements of the ribosome. Direct observation of the dynamic events that underlie the mechanism of translation is challenged by ensemble averaging in bulk solutions. Single-molecule methods, which eliminate these averaging effects, have emerged as powerful tools to probe the mechanism of translation. Single molecule fluorescence experiments have described the dynamic motion of the ribosome and tRNA. Single-molecule force measurements have directly probed the forces stabilizing ribosomal complexes. Recent developments have allowed real time observation of ribosome movement and dynamics during translation. This review covers the contributions of single-molecule studies to our understanding of the dynamic nature of translation. PMID- 20192784 TI - Psychological approaches to origins and treatments of somatoform disorders. AB - Medically unexplained symptoms are the defining feature of somatoform disorders (SFD) as currently included in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and the International Classification of Diseases, Tenth Edition. Cognitive, behavioral, biological, and social variables are important to our understanding of SFD. Research in the past decade has highlighted the central role of (a) prolonged attention allocation to bodily sensations, (b) the dysfunctional role of catastrophizing symptoms as signs of severe illness, (c) neuroendocrine alterations, and (d) the influence of illness behavior (e.g., the avoidance of physical activity) on the maintenance and chronicity of SFD. Additionally, conditioning approaches have demonstrated that perceiving somatic discomfort can easily be learned. In addition to current models of etiology and pathogenesis, the existing evidence on the efficacy and effectiveness of psychotherapy for SFD is reviewed. Finally, future directions and some current blind spots in research on SFD are outlined. PMID- 20192785 TI - Behavioral treatments in autism spectrum disorder: what do we know? AB - Although there are a large and growing number of scientifically questionable treatments available for children with autism spectrum disorder (ASD), intervention programs applying the scientific teaching principles of applied behavior analysis (ABA) have been identified as the treatment of choice. The following article provides a selective review of ABA intervention approaches, some of which are designed as comprehensive programs that aim to address all developmental areas of need, whereas others are skills based or directed toward a more circumscribed, specific set of goals. However, both types of approaches have been shown to be effective in improving communication, social skills, and management of problem behavior for children with ASD. Implications of these findings are discussed in relation to critical areas of research that have yet to be fully explored. PMID- 20192787 TI - Self-injury. AB - People have engaged in self-injury-defined as direct and deliberate bodily harm in the absence of suicidal intent-for thousands of years; however, systematic research on this behavior has been lacking. Recent theoretical and empirical work on self-injury has significantly advanced the understanding of this perplexing behavior. Self-injury is most prevalent among adolescents and young adults, typically involves cutting or carving the skin, and has a consistent presentation cross-nationally. Behavioral, physiological, and self-report data suggest that the behavior serves both an intrapersonal function (i.e., decreases aversive affective/cognitive states or increases desired states) and an interpersonal function (i.e., increases social support or removes undesired social demands). There currently are no evidence-based psychological or pharmacological treatments for self-injury. This review presents an integrated theoretical model of the development and maintenance of self-injury that synthesizes prior empirical findings and proposes several testable hypotheses for future research. PMID- 20192788 TI - Group-based trajectory modeling in clinical research. AB - Group-based trajectory models are increasingly being applied in clinical research to map the developmental course of symptoms and assess heterogeneity in response to clinical interventions. In this review, we provide a nontechnical overview of group-based trajectory and growth mixture modeling alongside a sampling of how these models have been applied in clinical research. We discuss the challenges associated with the application of both types of group-based models and propose a set of preliminary guidelines for applied researchers to follow when reporting model results. Future directions in group-based modeling applications are discussed, including the use of trajectory models to facilitate causal inference when random assignment to treatment condition is not possible. PMID- 20192786 TI - Implicit cognition and addiction: a tool for explaining paradoxical behavior. AB - Research on implicit cognition and addiction has expanded greatly during the past decade. This research area provides new ways to understand why people engage in behaviors that they know are harmful or counterproductive in the long run. Implicit cognition takes a different view from traditional cognitive approaches to addiction by assuming that behavior is often not a result of a reflective decision that takes into account the pros and cons known by the individual. Instead of a cognitive algebra integrating many cognitions relevant to choice, implicit cognition assumes that the influential cognitions are the ones that are spontaneously activated during critical decision points. This selective review highlights many of the consistent findings supporting predictive effects of implicit cognition on substance use and abuse in adolescents and adults; reveals a recent integration with dual-process models; outlines the rapid evolution of different measurement tools; and introduces new routes for intervention. PMID- 20192789 TI - Prevention of major depression. AB - Before the 1980s, no randomized controlled trials had been carried out to test whether major depressive episodes could be prevented. In the past 30 years, several trials have reported success in reducing the incidence (the number of new cases) of major depressive episodes. These studies suggest that major depression can be prevented. Given the large burden of disease caused by major depression, it is time for substantial systematic efforts to replicate these studies, carry out multisite trials, and widely disseminate prevention interventions found to be effective. The present review examines the conceptual and practical differences between treatment and prevention trials and the importance of identifying groups at high short-term risk for major depressive episodes to make prevention trials feasible. We also list the randomized controlled prevention trials that have been carried out to date and discuss the need for prevention interventions that go beyond the limits of traditional face-to-face interventions. PMID- 20192790 TI - Prescriptive authority for psychologists. AB - The proposal that psychologists should pursue prescriptive authority was first put forth 25 years ago, and it has been an official goal of the American Psychological Association for 15 years. Since then some form of prescriptive authority has been approved by three states, the Territory of Guam, and three branches of the military. Psychologists are also eligible to prescribe in the Public Health Service and the Indian Health Service. The movement has generated strong opinions both in favor and in opposition. Supporters focus particularly on increasing access to appropriate care and changing the role of psychologists within the healthcare system, while opponents raise concerns about how prescriptive authority will change professional psychology and whether psychologists will prescribe safely. This review provides a summary of milestones in the movement to date, as well as the arguments that have been raised for and against prescriptive authority. PMID- 20192791 TI - Update on harm-reduction policy and intervention research. AB - Harm reduction is a pragmatic approach to reduce the harmful consequences of alcohol and drug use or other high-risk activities by incorporating several strategies that cut across the spectrum from safer use to managed use to abstinence. The primary goal of most harm-reduction approaches is to meet individuals "where they are at" and not to ignore or condemn the harmful behaviors but rather to work with the individual or community to minimize the harmful effects of a given behavior. The current review addresses some of the newest developments with respect to harm-reduction policy, prevention, and treatment. In particular, this review highlights policies and programs that have been evaluated in peer-reviewed journals and shown to be effective at reducing the harms associated with alcohol and drug use. The overall goal of this review is to present some of the most recent developments in the field of harm reduction. PMID- 20192792 TI - Systematic reviews of categorical versus continuum models in psychosis: evidence for discontinuous subpopulations underlying a psychometric continuum. Implications for DSM-V, DSM-VI, and DSM-VII. AB - Diagnostic systems, phenotype models, and theories of etiology incorporate propositions on the underlying nature of psychosis and schizophrenia phenotypes. These propositions, whether implicit or explicit, are that the distributions of the phenotypes, or the phenotype experiences themselves, are dimensional or categorical. On one hand, evidence on the epidemiology of schizophrenia phenotypes suggests symptom phenotypes may not be bound by conventional diagnostic thresholds but instead may blend imperceptibly with subclinical, statistically frequent experience, supporting continuum viewpoints. On the other hand, evidence on the population structure suggests a latent categorical structure; the population may be composed of two types of people. However, both sets of evidence are beset by methodological limitations that point unequivocally to the need to move beyond current diagnostic conceptualizations, observation, and anamnesis of psychosis, and toward responsive and scientifically refutable formulations of schizophrenia. PMID- 20192793 TI - Violence and women's mental health: the impact of physical, sexual, and psychological aggression. AB - The reach of violence against women (VAW) has been profoundly felt by women across the United States and around the globe. VAW has been documented for decades as a legal and social justice problem, but as illuminated in this review, it is also a substantial mental health concern. A full understanding of the phenomenon must include discussion of how often it occurs, in what forms, and to whom. This review defines violence against women in its variant forms and examines the literature on the mental health effects associated with these abuse experiences. The effectiveness of the mental health system's response to the complex needs of women suffering battering, rape, stalking, and psychological aggression is also examined. The future of research and the important role of the discipline of psychology in the future of this field of study are discussed. PMID- 20192794 TI - Substance use disorders: realizing the promise of pharmacogenomics and personalized medicine. AB - Current pharmacological and psychosocial approaches to the treatment of alcohol dependence may best be described as modestly effective, and it is unlikely that a magic bullet for the treatment of any substance use disorder will ever be developed. Rather, it seems more likely that there will be a number of treatment options, each of which will target different mechanisms. Thus, future treatment gains are likely to depend on the ability to match individuals with the treatment most likely to benefit them, which in turn is contingent on our ability to understand the mechanisms that drive the maintenance of substance use disorders on an individual level. On a more global scale, this type of effort has been described as "personalized medicine" and has focused largely on the human genome as a source of information that can be used to match individuals to treatments. This review enumerates barriers to realizing the potential of personalized medicine for substance use disorders and identifies opportunities to overcome those barriers, which involve the development of translational approaches that focus on the development of brain-based phenotypes that serve as the target of both treatment development and of genetic research. PMID- 20192795 TI - Cognition and depression: current status and future directions. AB - Cognitive theories of depression posit that people's thoughts, inferences, attitudes, and interpretations, and the way in which they attend to and recall information, can increase their risk for depression. Three mechanisms have been implicated in the relation between biased cognitive processing and the dysregulation of emotion in depression: inhibitory processes and deficits in working memory, ruminative responses to negative mood states and negative life events, and the inability to use positive and rewarding stimuli to regulate negative mood. In this review, we present a contemporary characterization of depressive cognition and discuss how different cognitive processes are related not only to each other, but also to emotion dysregulation, the hallmark feature of depression. We conclude that depression is characterized by increased elaboration of negative information, by difficulties disengaging from negative material, and by deficits in cognitive control when processing negative information. We discuss treatment implications of these conclusions and argue that the study of cognitive aspects of depression must be broadened by investigating neural and genetic factors that are related to cognitive dysfunction in this disorder. Such integrative investigations should help us gain a more comprehensive understanding of how cognitive and biological factors interact to affect the onset, maintenance, and course of depression. PMID- 20192796 TI - Advances in analysis of longitudinal data. AB - In this review, we explore recent developments in the area of linear and nonlinear generalized mixed-effects regression models and various alternatives, including generalized estimating equations for analysis of longitudinal data. Methods are described for continuous and normally distributed as well as categorical (binary, ordinal, nominal) and count (Poisson) variables. Extensions of the model to three and four levels of clustering, multivariate outcomes, and incorporation of design weights are also described. Linear and nonlinear models are illustrated using an example involving a study of the relationship between mood and smoking. PMID- 20192798 TI - Successful aging: focus on cognitive and emotional health. AB - We review the definitions, predictors, and biobehavioral determinants of successful aging, as well as the evidence for and mechanisms of underlying selected interventions to enhance cognitive and emotional health in older adults. Defining successful aging has proven difficult, with discrepancies seen among biomedical, psychological, and lay perspectives. Although consensus is lacking, a number of studies have examined the genetic, lifestyle, and social determinants of operationalized determinants of successful aging; qualitative examinations of the meaning of the construct have also been conducted. The determinants coincide with fundamental aspects of aging. Recent clinical trials suggest that caloric restriction, physical activity, cognitive intervention, stress reduction, and social programs may enhance cognitive and emotional health in older people. PMID- 20192799 TI - Clinical implications of traumatic stress from birth to age five. AB - Children aged birth to five years are exposed to a disproportionately increased amount of potentially traumatic events compared to older children. This review examines the prevalence of traumatic exposure in the birth-to-five age range, the indicators and diagnostic criteria of early traumatic stress, and the contextual issues associated with the experience of early trauma. The article also selectively reviews the impact of trauma on the biological, emotional, social, and cognitive functioning of young children's development along with some promising clinical treatment and service interventions that target the parent child relationship as a vehicle of trauma recovery. Despite extensive documentation of the negative impact of trauma on the normal development of young children, research, clinical, and policy efforts to address the psychological repercussions of early victimization remain remarkably limited. Future directions in research and clinical practice as well as implications for policy are discussed. PMID- 20192797 TI - Emotion-related self-regulation and its relation to children's maladjustment. AB - The development of children's emotion-related self-regulation appears to be related to, and likely involved in, many aspects of children's development. In this review, the distinction between effortful self-regulatory processes and those that are somewhat less voluntary is discussed, and literature on the former capacities is reviewed. Emotion-related self-regulation develops rapidly in the early years of life and improves more slowly into adulthood. Individual differences in children's self-regulation are fairly stable after the first year or two of life. Such individual differences are inversely related to at least some types of externalizing problems. Findings for internalizing problems are less consistent and robust, although emotion-related self-regulation appears to be inversely related to internalizing problems after the early years. Self regulatory capacities have been related to both genetic and environmental factors and their interaction. Some interventions designed to foster self-regulation and, hence, reduce maladjustment, have proved to be at least partially effective. PMID- 20192801 TI - Personality assessment from the nineteenth to the early twenty-first century: past achievements and contemporary challenges. AB - The historical basis of personality assessment that led to the development of today's approaches and applications is described. The modern era of personality assessment began in late nineteenth-century Europe. Early twentieth-century highlights included the development of projective techniques like the Rorschach and several early self-report inventories, culminating in the development of the most widely used measure, the Minnesota Multiphasic Personality Inventory (MMPI). The most recent 30-year period showed expansions into personnel screening; clinical assessment, including wide use in forensic settings; and therapeutic assessment. However, contemporary controversies are apparent with two of the most widely used measures, the Rorschach and the MMPI instruments. These controversies are described, including concerns about the Exner Comprehensive System for the Rorschach and the last five years of changes to the MMPI-2, including the introduction of the Restructured Clinical (RC) Scales, the adoption of the Fake Bad Scale (FBS) into the instrument, and the release of the MMPI-2 Restructured Form (MMPI-2-RF). Current challenges facing psychologists in personality assessment are highlighted. PMID- 20192800 TI - Issues and challenges in the design of culturally adapted evidence-based interventions. AB - This article examines issues and challenges in the design of cultural adaptations that are developed from an original evidence-based intervention (EBI). Recently emerging multistep frameworks or stage models are examined, as these can systematically guide the development of culturally adapted EBIs. Critical issues are also presented regarding whether and how such adaptations may be conducted, and empirical evidence is presented regarding the effectiveness of such cultural adaptations. Recent evidence suggests that these cultural adaptations are effective when applied with certain subcultural groups, although they are less effective when applied with other subcultural groups. Generally, current evidence regarding the effectiveness of cultural adaptations is promising but mixed. Further research is needed to obtain more definitive conclusions regarding the efficacy and effectiveness of culturally adapted EBIs. Directions for future research and recommendations are presented to guide the development of a new generation of culturally adapted EBIs. PMID- 20192802 TI - Substance use in adolescence and psychosis: clarifying the relationship. AB - Adolescence is a time of exploration of the self, and this exploration may involve the use of alcohol and drugs. Sadly, for some, adolescence also marks the first signs of a psychosis. The temporal proximity between the onset of substance use and of psychosis has been the cause of much debate. Here we review the association of alcohol, cannabis, stimulants, and other drugs with psychosis, and we conclude that the use of cannabis and the amphetamines significantly contributes to the risk of psychosis. PMID- 20192803 TI - From allergen genes to allergy vaccines. AB - IgE-mediated allergy is a hypersensitivity disease affecting more than 25% of the population. The structures of the most common allergens have been revealed through molecular cloning technology in the past two decades. On the basis of this knowledge of the sequences and three-dimensional structures of culprit allergens, investigators can now analyze the immune recognition of allergens and the mechanisms of allergic inflammation in allergic patients. Allergy vaccines have been constructed that are able to selectively target the aberrant immune responses in allergic patients via different pathways of the immune system. Here we review various types of allergy vaccines that have been developed based on allergen structures, results from their clinical application in allergic patients, and future strategies for allergen-specific immunotherapy and allergy prophylaxis. PMID- 20192804 TI - Early events in B cell activation. AB - B cell activation is initiated by the ligation of the B cell receptor (BCR) with antigen and ultimately results in the production of protective antibodies against potentially pathogenic invaders. Here we review recent literature concerned with the spatiotemporal dynamic characterization of the early molecular events of B cell activation, including the initiation of BCR triggering, the formation of BCR microclusters, and the dynamic regulation of BCR signaling. Because these events involve the considerable reorganization of molecules within the membrane, an important role for the cytoskeleton is emerging in the regulation of B cell activation. At each stage we highlight the role of the cytoskeleton, establishing its pivotal position during the initiation and regulation of B cell activation. PMID- 20192805 TI - Adaptive immune regulation in the gut: T cell-dependent and T cell-independent IgA synthesis. AB - In mammals, the gastrointestinal tract harbors an extraordinarily dense and complex community of microorganisms. The gut microbiota provide strong selective pressure to the host to evolve adaptive immune responses required for the maintenance of local and systemic homeostasis. The continuous antigenic presence in the gut imposes a dynamic remodeling of gut-associated lymphoid tissues (GALT) and the selection of multiple layered strategies for immunoglobulin (Ig) A production. The composite and dynamic gut environment also necessitates heterogeneous, versatile, and convertible T cells, capable of inhibiting (Foxp3(+) T cells) or helping (T(FH) cells) local immune responses. In this review, we describe recent advances in our understanding of dynamic pathways that lead to IgA synthesis, in gut follicular structures and in extrafollicular sites, by T cell-dependent and T cell-independent mechanisms. We discuss the finely tuned regulatory mechanisms for IgA production and emphasize the role of mucosal IgA in the selection and maintenance of the appropriate microbial composition that is necessary for immune homeostasis. PMID- 20192807 TI - Functions of notch signaling in the immune system: consensus and controversies. AB - Mammalian genomes encode up to four Notch receptors (Notch1-4) and five Notch ligands of the DSL (Delta/Serrate/Lag-2) family, and Notch signaling controls a wide spectrum of developmental processes. Intrathymic Notch1 signaling is essential for several distinct aspects of early T cell development. Notch signaling has also been implicated as a key regulator of peripheral T cell activation and effector cell differentiation, but its functions in these processes remain poorly understood. Notch signaling is dispensable for B cell development in the bone marrow, but it is required to generate the innate-like marginal zone B cell subset in the spleen and may also regulate plasma cell functions. Modification of Notch receptors by fringe glycosyltransferases influences many Notch-dependent aspects of hematopoiesis by altering Notch responsiveness to Delta-like versus Jagged DSL ligands. Here we review recent advances in general aspects of Notch signaling, as well as studies probing Notch functions in these immunological processes. PMID- 20192808 TI - HMGB1 and RAGE in inflammation and cancer. AB - The immune system has evolved to respond not only to pathogens, but also to signals released from dying cells. Cell death through necrosis induces inflammation, whereas apoptotic cell death provides an important signal for tolerance induction. High mobility group box 1 (HMGB1) is a DNA-binding nuclear protein, released actively following cytokine stimulation as well as passively during cell death; it is the prototypic damage-associated molecular pattern (DAMP) molecule and has been implicated in several inflammatory disorders. HMGB1 can associate with other molecules, including TLR ligands and cytokines, and activates cells through the differential engagement of multiple surface receptors including TLR2, TLR4, and RAGE. RAGE is a multiligand receptor that binds structurally diverse molecules, including not only HMGB1, but also S100 family members and amyloid-beta. RAGE activation has been implicated in sterile inflammation as well as in cancer, diabetes, and Alzheimer's disease. While HMGB1 through interactions with TLRs may also be important, this review focuses on the role of the HMGB1-RAGE axis in inflammation and cancer. PMID- 20192806 TI - Differentiation of effector CD4 T cell populations (*). AB - CD4 T cells play critical roles in mediating adaptive immunity to a variety of pathogens. They are also involved in autoimmunity, asthma, and allergic responses as well as in tumor immunity. During TCR activation in a particular cytokine milieu, naive CD4 T cells may differentiate into one of several lineages of T helper (Th) cells, including Th1, Th2, Th17, and iTreg, as defined by their pattern of cytokine production and function. In this review, we summarize the discovery, functions, and relationships among Th cells; the cytokine and signaling requirements for their development; the networks of transcription factors involved in their differentiation; the epigenetic regulation of their key cytokines and transcription factors; and human diseases involving defective CD4 T cell differentiation. PMID- 20192810 TI - The role of antibodies in HIV vaccines. AB - Licensed vaccines against viral diseases generate antibodies that neutralize the infecting virus and protect against infection or disease. Similarly, an effective vaccine against HIV-1 will likely need to induce antibodies that prevent initial infection of host cells or that limit early events of viral dissemination. Such antibodies must target the surface envelope glycoproteins of HIV-1, which are highly variable in sequence and structure. The first subunit vaccines to enter clinical trails were safe and immunogenic but unable to elicit antibodies that neutralized most circulating strains of HIV-1. However, potent virus neutralizing antibodies (NAbs) can develop during the course of HIV-1 infection, and this is the type of antibody response that researchers seek to generate with a vaccine. Thus, current vaccine design efforts have focused on a more detailed understanding of these broadly neutralizing antibodies and their epitopes to inform the design of improved vaccines. PMID- 20192809 TI - A genomic approach to human autoimmune diseases. AB - The past decade has seen an explosion in the use of DNA-based microarrays. These techniques permit assessment of RNA abundance on a genome-wide scale. Medical applications emerged in the field of cancer, with studies of both solid tumors and hematological malignancies leading to the development of tests that are now used to personalize therapeutic options. Microarrays have also been used to analyze the blood transcriptome in a wide range of diseases. In human autoimmune diseases, these studies are showing potential for identifying therapeutic targets as well as biomarkers for diagnosis, assessment of disease activity, and response to treatment. More quantitative and sensitive high-throughput RNA profiling methods are starting to be available and will be necessary for transcriptome analyses to become routine tests in the clinical setting. We expect this to crystallize within the coming decade, as these methods become part of the personalized medicine armamentarium. PMID- 20192815 TI - Recent advances in public health systems research in the United States. AB - Recognizing the public's health is the outcome of dynamic, adaptive, and complex systems of agencies; infrastructure, relationships, and interactions that dictate how to improve health outcomes; and reducing health risks in a population is based on systems thinking and evidence. New methods such as network analysis and public health practice-based research networks demonstrate the potential for new insight to our understanding of how systems and infrastructure influence population health. We examine advances in public health systems research since 1988 and discuss the relevance of this type of research to public health practice. We assess the current infrastructure for conducting public health systems research, suggest how the research infrastructure can be improved, and conclude with a discussion of how health reform in the United States will require research focused on understanding the adaptive complexity inherent in public health and health care systems and strengthening the systems research infrastructure. PMID- 20192814 TI - Fluctuations in biological and bioinspired electron-transfer reactions. AB - Central to theories of electron transfer (ET) is the idea that nuclear motion generates a transition state that enables electron flow to proceed, but nuclear motion also induces fluctuations in the donor-acceptor (DA) electronic coupling that is the rate-limiting parameter for nonadiabatic ET. The interplay between the DA energy gap and DA coupling fluctuations is particularly noteworthy in biological ET, where flexible protein and mobile water bridges take center stage. Here, we discuss the critical timescales at play for ET reactions in fluctuating media, highlighting issues of the Condon approximation, average medium versus fluctuation-controlled electron tunneling, gated and solvent relaxation controlled electron transfer, and the influence of inelastic tunneling on electronic coupling pathway interferences. Taken together, one may use this framework to establish principles to describe how macromolecular structure and structural fluctuations influence ET reactions. This framework deepens our understanding of ET chemistry in fluctuating media. Moreover, it provides a unifying perspective for biophysical charge-transfer processes and helps to frame new questions associated with energy harvesting and transduction in fluctuating media. PMID- 20192816 TI - A new vaginal delivery system of amphotericin B: a dispersion of cationic liposomes in a thermosensitive gel. AB - Amphotericin B (AmB) is used in the treatment of fungal infections; however, its clinical use is limited by its toxic side effects. In this study, AmB-loaded cationic liposome gels were formulated with 1,2-dioleoyl-sn-glycero-3 phosphoethanolamine (DOPE), 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), and cholesterol (CH) at a molar ratio of DOPE:DOTAP:CH = 4:5:1 in thermosensitive gel composed of poloxamer 407 (P407) and poloxamer 188 (P188). To enhance the solubility of AmB, 6 mol% of distearoyl phosphatidyl ethanolamine-polyethylene glycol was added prior to encapsulation of the drug into liposomes. Scanning electron microscopy was used to observe the AmB encapsulated cationic liposome gels. In vitro release, stability and cytotoxicity of AmB in cationic liposome gels were evaluated. The particle size and zeta potential of AmB-loaded liposomes were in the range of 400-500 nm and 40-60 mV, respectively. The thermosensitive gel at the ratio of P407:P188 = 15:15 (w/w) gelled at 37 degrees C, approximating body temperature. Encapsulation efficiency of AmB was approximately 50-60%, which was influenced by the ratio of AmB to lipid. Moreover, AmB-loaded cationic liposome gels were more stable and less toxic than free AmB. From these results, cationic liposome gel formulations may be useful for vaginal delivery of AmB. PMID- 20192813 TI - Attention, intention, and priority in the parietal lobe. AB - For many years there has been a debate about the role of the parietal lobe in the generation of behavior. Does it generate movement plans (intention) or choose objects in the environment for further processing? To answer this, we focus on the lateral intraparietal area (LIP), an area that has been shown to play independent roles in target selection for saccades and the generation of visual attention. Based on results from a variety of tasks, we propose that LIP acts as a priority map in which objects are represented by activity proportional to their behavioral priority. We present evidence to show that the priority map combines bottom-up inputs like a rapid visual response with an array of top-down signals like a saccade plan. The spatial location representing the peak of the map is used by the oculomotor system to target saccades and by the visual system to guide visual attention. PMID- 20192817 TI - Laparoendoscopic single-site nephroureterectomy with bladder cuff excision for upper urinary tract transitional-cell carcinoma: technical details based on oncologic principles. AB - PURPOSE: To describe our technical details of laparoendoscopic single-site (LESS) nephroureterectomy with bladder cuff excision for the management of upper urinary tract transitional-cell carcinoma (TCC) based on oncologic principles. PATIENTS AND METHODS: Two patients underwent LESS nephroureterectomy for upper urinary tract TCC. In both cases, we used a homemade single-port device that consisted of a wound retractor and a surgical glove. Using the flexible laparoscopic instruments, nephrectomy was performed using procedures similar to those of conventional laparoscopic nephrectomy. Bladder cuff excision was performed laparoscopically using the same procedure with open technique. RESULTS: All procedures were completed successfully without conversion to conventional laparoscopic or open surgery and without additional extraumbilical trocars or incisions. LESS nephreoureterectomy with bladder cuff excision was performed in 385 and 285 minutes with estimated blood loss of 100 and 350 mL, respectively. Both patients were discharged on postoperative day 3 without perioperative complications. CONCLUSIONS: LESS nephroureterectomy with bladder cuff excision for upper urinary tract TCC is a minimally invasive technique that may reproduce the open surgical technique and adhere to oncologic principles. PMID- 20192818 TI - Can image-based virtual reality help teach anatomy? AB - OBJECTIVE: To assess the utilization of a novel virtual reality robotic surgical simulator (RoSS) in surgical anatomy training and pattern recognition. STUDY DESIGN: Ten surgical trainees (medical students and residents) were recruited to participate in a study that evaluated the efficacy of a robotic simulator in anatomy training. The subjects were divided into two groups of five individuals each. Each participant received a syllabus consisting of line diagrams and color pictures of the human anatomy. All participants were later tested on identifying the same five anatomical landmarks from photographs from actual laparoscopic procedures. Group I studied the syllabus and took the test. Group II similarly studied the syllabus, but were trained on the RoSS system using cognitive skill sets and then took the same test. Group II were asked to complete a posttest survey. RESULTS: Mean time to complete the test was 142.8 seconds for group I and 118.4 seconds for group II. Mean number of errors committed by the group trained on RoSS was 0.4 out of 5, whereas the group that did not undergo training on RoSS committed 1.7 out of 5. The mean number of correct answers given by group I was 2.9 out of 5, whereas group II answered 4.2 out 5 correctly. All results were statistically significant. The subjects rated the anatomy module helpful, with a mean rating of 3.6 out of 5. CONCLUSIONS: RoSS is an effective tool in anatomy training. Further testing is underway to illustrate its important role in medical education and robotic surgical training. PMID- 20192811 TI - Inflammatory bowel disease. AB - Insights into inflammatory bowel disease (IBD) are advancing rapidly owing to immunologic investigations of a plethora of animal models of intestinal inflammation, ground-breaking advances in the interrogation of diseases that are inherited as complex genetic traits, and the development of culture-independent methods to define the composition of the intestinal microbiota. These advances are bringing a deeper understanding to the genetically determined interplay between the commensal microbiota, intestinal epithelial cells, and the immune system and the manner in which this interplay might be modified by relevant environmental factors in the pathogenesis of IBD. This review examines these interactions and, where possible, potential lessons from IBD-directed, biologic therapies that may allow for elucidation of pathways that are central to disease pathogenesis in humans. PMID- 20192819 TI - Antimicrobial susceptibility patterns of KPC-producing or CTX-M-producing Enterobacteriaceae. AB - Enterobacteriaceae clinical isolates harboring KPC-(178 strains) or CTX-M encoding (67 strains) genes were collected during surveillance programs in the 2000-2007 period; and susceptibility was tested by broth microdilution methods. Organisms were dominantly collected in U.S. hospitals (93%). CTX-M-15 and -14 were the most prevalent CTX-M types (97%), all collected from the United States. KPC producers were isolated in the United States (160/178), Israel, China, and Argentina. bla(CTX-M)-carrying isolates were 95.5 and 98.5%, susceptible to Imipenem and meropenem respectively, and were all susceptible to tigecycline, whereas KPC-producing isolates were highly resistant to all antimicrobials tested except polymyxin B and tigecycline (90.6% and 99.4% susceptibility, respectively). The occurrence of KPC-producing and CTX-M-producing isolates has rapidly increased especially in U.S. hospitals, and expanded therapeutic options are needed to treat infections caused by these emerging organisms. PMID- 20192820 TI - Impact of extensively drug-resistant tuberculosis on treatment outcome of multidrug-resistant tuberculosis patients with standardized regimen: report from Iran. AB - The limited experience in treating patients with extensively drug-resistant tuberculosis (XDR-TB) shows a therapeutic success rate under 50-60% and there are no publications regarding the outcome of these patients treated with standardized regimens. All multidrug-resistant tuberculosis (MDR-TB) patients hospitalized at the Masih Daneshvari Hospital in Tehran, Iran, during 2004-2007 were recruited. Drug susceptibility testing to 14 drugs (including eight second-line drugs) was performed and a standardized regimen with ofloxacin, cycloserine, prothionamide, and amikacin was administered for all patients. Outcome of the patients was studied, comparing between the MDR-TB non-XDR-TB and the XDR-TB. Fifty-one patients were included, 12 with XDR-TB criteria. Of 51, 48 were HIV negative and HIV status was unknown in three cases. All 12 were HIV negative. XDR-TB infection was significantly associated only with age (p = 0.039). The success rates for the total 51 MDR-TB, the 39 MDR-TB non-XDR-TB, and the 12 XDR-TB patients were 76.5% (39 patients), 87.2% (34 patients), and 41.7% (5 patients), respectively. Resistance to ofloxacin, ciprofloxacin, and amikacin were found to be significantly associated with unsuccessful outcome. In this setting, a standardized second-line drugs regimen produces high treatment success rates in MDR-TB patients unless XDR-TB is present. PMID- 20192821 TI - Characterization of a novel trimethoprim resistance gene, dfrA28, in class 1 integron of an oligotrophic Acinetobacter johnsonii strain, MB52, isolated from River Mahananda, India. AB - The present work has validated the capability of using diluted Luria broth (10( 3)) and its amendment with antibiotics to quantify proportions of antibiotic resistant oligotrophic bacteria contained in river water. The assay conditions for assessing fractions of antibiotic-resistant oligotrophic bacteria, especially the type and concentration of antibiotic exposure by determining LD(50) concentration for each antibiotic using sensitive oligotrophic strain, have been standardized. The presence of an array of two gene cassettes including a novel dihydrofolate reductase gene, dfrA28, within the variable region of the class 1 integron in an oligotrophic test strain, MB52, in a population of oligotrophic bacteria isolated from Mahananda River water, has been described. The predicted protein consisting of 172 amino acids exhibited 76.4% amino acid identity with DfrA1. A gene for streptomycin resistance, aminoglycoside adenyl transferase aadA1, was located downstream of dfrA28. Phylogenetic analysis of MB52 identified it as a strain of Acinetobacter johnsonii. PMID- 20192812 TI - Intestinal bacteria and the regulation of immune cell homeostasis. AB - The human intestine is colonized by an estimated 100 trillion bacteria. Some of these bacteria are essential for normal physiology, whereas others have been implicated in the pathogenesis of multiple inflammatory diseases including IBD and asthma. This review examines the influence of signals from intestinal bacteria on the homeostasis of the mammalian immune system in the context of health and disease. We review the bacterial composition of the mammalian intestine, known bacterial-derived immunoregulatory molecules, and the mammalian innate immune receptors that recognize them. We discuss the influence of bacterial-derived signals on immune cell function and the mechanisms by which these signals modulate the development and progression of inflammatory disease. We conclude with an examination of successes and future challenges in using bacterial communities or their products in the prevention or treatment of human disease. PMID- 20192822 TI - Prevalence of antimicrobial resistance in fecal Escherichia coli isolates from stray pet dogs and hospitalized pet dogs in Korea. AB - A total of 628 Escherichia coli isolates recovered from 877 intestinal samples of stray pet dogs (n = 565) and hospitalized pet dogs (n = 312) in Korea were analyzed for resistance to 15 antimicrobial agents. Most common resistance observed in E. coli isolated from both groups of dogs was to tetracycline (52.4 53.6%), streptomycin (35.8-41.7%), ampicillin (32.9-47.1%), nalidixic acid (21.6 37.4%), and trimethoprim/sulfamethoxazole (19.7-36.4%). Resistance to chloramphenicol, gentamicin, and ciprofloxacin was observed in 19.4% (17.1 24.3%), 18% (16.1-21.8%), and 16.1% (13.5-21.4%) of the isolates, respectively. No E. coli isolated from hospitalized dogs showed resistance to imipenem and cefepime, whereas three (0.7%) isolates from stray dogs were resistant to cefepime. Some of the isolates from both groups showed resistance to cefotaxime (2.4-3.9%) and amikacin (0.5-1.5%). In general, the frequency of resistance tended to be higher in isolates from hospitalized dogs than isolates from stray dogs against most antimicrobials tested. Around 39% (162/422) and 27% (55/206) of E. coli isolates from stray dogs and hospitalized dogs were susceptible to all antimicrobials tested, respectively. Multiresistance (> or = 3 subclasses of antimicrobials) was observed in 32% and 48% of E. coli isolates from stray dogs and hospitalized dogs, respectively. More attention should be paid to the use of antimicrobials and the occurrence of antimicrobial resistance in companion animals. PMID- 20192824 TI - A homeobox gene is essential for conidiogenesis of the rice blast fungus Magnaporthe oryzae. AB - Magnaporthe oryzae starts its infection by the attachment of pyriform conidia on rice tissues, and severity of the disease epidemic is proportional to the quantity of conidia produced in the rice blast lesions. However, the mechanism of conidial production is not well understood. Homeodomain proteins play critical roles in regulating various growth and developmental processes in fungi and other eukaryotes. Through targeted gene replacement, we find that deletion of HTF1, one of seven homeobox genes in the fungal genome, does not affect mycelial growth but causes total defect of conidial production. Further observation revealed that the Deltahtf1 mutant produces significantly more conidiophores, which curve slightly near the tip but could not develop sterigmata-like structures. Although the Deltahtf1 mutant fails to form conidia, it could still develop melanized appressoria from hyphal tips and infect plants. The expression level of HTF1 is significantly reduced in the Deltamgb1 G-beta and DeltacpkA deletion mutant, and the ACR1 but not CON7 gene that encodes transcription factor required for normal conidiogenesis is significantly downregulated in the Deltahtf1 mutant. These data suggest that the HTF1 gene is essential for conidiogenesis, and may be functionally related to the trimeric G-protein signaling and other transcriptional regulators that are known to be important for conidiation in M. oryzae. PMID- 20192823 TI - Role of the Sinorhizobium meliloti global regulator Hfq in gene regulation and symbiosis. AB - The RNA-binding protein Hfq is a global regulator which controls diverse cellular processes in bacteria. To begin understanding the role of Hfq in the Sinorhizobium meliloti-Medicago truncatula nitrogen-fixing symbiosis, we defined free-living and symbiotic phenotypes of an hfq mutant. Over 500 transcripts were differentially accumulated in the hfq mutant of S. meliloti Rm1021 when grown in a shaking culture. Consistent with transcriptome-wide changes, the hfq mutant displayed dramatic alterations in metabolism of nitrogen-containing compounds, even though its carbon source utilization profiles were nearly identical to the wild type. The hfq mutant had reduced motility and was impaired for growth at alkaline pH. A deletion of hfq resulted in a reduced symbiotic efficiency, although the mutant was still able to initiate nodule development and differentiate into bacteroids. PMID- 20192825 TI - Multiple coat protein mutations abolish recognition of Pepino mosaic potexvirus (PepMV) by the potato rx resistance gene in transgenic tomatoes. AB - Despite the fact that Pepino mosaic virus (PepMV) and Potato virus X (PVX) share less than 40% identity in their coat proteins (CP), the known PVX elicitor of Rx, transgenic tomato (cv. Microtom) plants expressing a functional potato Rx resistance gene showed resistance toward PepMV. However, in a low percentage of plants, PepMV accumulation was observed and back inoculation experiments demonstrated that these plants contained resistance-breaking PepMV variants. Sequencing of the CP gene of these variants showed the accumulation of mutations in the amino acid 41 to 125 region the CP, whereas no mutations were observed in the nonevolved isolates. Agroinfiltration-mediated transient expression of the mutant CP demonstrated that they had a greatly attenuated or abolished ability to induce a hypersensitive reaction in Rx-expressing Nicotiana benthamiana leaves. The transient expression of truncated forms of the PepMV CP allowed the identification of a minimal elicitor domain (amino acids 30 to 136). These results demonstrate that the Rx-based sensing system is able to recognize the PepMV CP but, contrary to the situation with PVX, for which only two closely spaced resistance-breaking mutations are known, many mutations over a significant stretch of the PepMV CP allow escape from recognition by Rx. PMID- 20192826 TI - Complete genome sequence of the fire blight pathogen Erwinia amylovora CFBP 1430 and comparison to other Erwinia spp. AB - Fire blight, caused by the enterobacterium Erwinia amylovora, is a devastating disease of rosaceous plants that has global economic importance for apple and pear production and trade. The complete genome of E. amylovora CFBP 1430 was sequenced, annotated, and compared with the genomes of other Erwinia spp. Several singleton and shared features of the E. amylovora CFBP 1430 genome were identified that offer a first view into evolutionary aspects within the genus Erwinia. Comparative genomics identified or clarified virulence and fitness determinants and secretion systems. Novel insights revealed in the genome of E. amylovora CFBP 1430 hold potential for exploitation to improve the design of more effective fire blight control strategies. PMID- 20192827 TI - Salicylic acid is involved in the Nb-mediated defense responses to Potato virus X in Solanum tuberosum. AB - To evaluate the role of salicylic acid (SA) in Nb-mediated hypersensitive resistance to Potato virus X (PVX) avirulent strain ROTH1 in Solanum tuberosum, we have constructed SA-deficient transgenic potato plant lines by overexpressing the bacterial enzyme salicylate hydroxylase (NahG), which degrades SA. Evaluation of these transgenic lines revealed hydrogen peroxide accumulation and spontaneous lesion formation in an age- and light-dependent manner. In concordance, NahG potato plants were more sensitive to treatment with methyl viologen, a reactive oxygen species-generating compound. In addition, when challenged with PVX ROTH1, NahG transgenic lines showed a decreased disease-resistance response to infection and were unable to induce systemic acquired resistance. However, the avirulent viral effector, the PVX 25-kDa protein, does induce expression of the pathogenesis-related gene PR-1a in NahG potato plants. Taken together, our data indicate that SA is involved in local and systemic defense responses mediated by the Nb gene in Solanum tuberosum. This is the first report to show that basal levels of SA correlate with hypersensitive resistance to PVX. PMID- 20192828 TI - ACTTS3 encoding a polyketide synthase is essential for the biosynthesis of ACT toxin and pathogenicity in the tangerine pathotype of Alternaria alternata. AB - The tangerine pathotype of Alternaria alternata produces host-selective ACT-toxin and causes Alternaria brown spot disease of tangerine and tangerine hybrids. Sequence analysis of a genomic BAC clone identified part of the ACT-toxin TOX (ACTT) gene cluster, and knockout experiments have implicated several open reading frames (ORF) contained within the cluster in the biosynthesis of ACT toxin. One of the ORF, designated ACTTS3, encoding a putative polyketide synthase, was isolated by rapid amplification of cDNA ends and genomic/reverse transcription-polymerase chain reactions using the specific primers designed from the BAC sequences. The 7,374-bp ORF encodes a polyketide synthase with putative beta-ketoacyl synthase, acyltransferase, methyltransferase, beta-ketoacyl reductase, and phosphopantetheine attachment site domains. Genomic Southern blots demonstrated that ACTTS3 is present on the smallest chromosome in the tangerine pathotype of A. alternata, and the presence of ACTTS3 is highly correlated with ACT-toxin production and pathogenicity. Targeted gene disruption of two copies of ACTTS3 led to a complete loss of ACT-toxin production and pathogenicity. These results indicate that ACTTS3 is an essential gene for ACT-toxin biosynthesis in the tangerine pathotype of A. alternata and is required for pathogenicity of this fungus. PMID- 20192829 TI - Molecular and evolutionary analyses of Pseudomonas syringae pv. tomato race 1. AB - Pseudomonas syringae pv. tomato, the causal agent of bacterial speck of tomato, has recently become an increasing problem in California due to the evolution and prevalence of highly aggressive race 1 strains. In resistant plant genotypes, the type III effectors AvrPto and AvrPtoB are recognized by the tomato proteins Pto and Prf. We investigated the prevalence of avrPto and avrPtoB in strains collected over the last 13 years in California. All race 1 strains retained avrPtoB but did not express AvrPtoB protein at detectable levels in vitro. However, deletion of avrPtoB indicated that this effector protein is still expressed at low levels in race 1 during infection. avrPto was detected in four race 1 strains but a key amino acid polymorphism prevents this new protein from interacting with and eliciting Pto-mediated resistance. Growth curve analyses demonstrate that this new avrPto allele is still functional and can enhance P. syringae virulence on tomato. Multilocus sequence typing was used to resolve phylogenetic relationships and revealed that the majority of race 0 and 1 strains were most closely related to P. syringae T1. Collectively, these data support the hypothesis that existing P. syringae populations evolved to overcome genetic resistance by altering the expression and sequence of avrPto and avrPtoB effectors. PMID- 20192830 TI - Different domains of Phytophthora sojae effector Avr4/6 are recognized by soybean resistance genes Rps4 and Rps6. AB - At least 12 avirulence genes have been genetically identified and mapped in Phytophthora sojae, an oomycete pathogen causing root and stem rot of soybean. Previously, the Avr4 and Avr6 genes of P. sojae were genetically mapped within a 24 kb interval of the genome. Here, we identify Avr4 and Avr6 and show that they are actually a single gene, Avr4/6, located near the 24-kb region. Avr4/6 encodes a secreted protein of 123 amino acids with an RXLR-dEER protein translocation motif. Transient expression of Avr4/6 in soybean leaves revealed that its gene product could trigger a hypersensitive response (HR) in the presence of either Rps4 or Rps6. Silencing Avr4/6 in P. sojae stable transformants abolished the avirulence phenotype exhibited on both Rps4 and Rps6 soybean cultivars. The N terminus of Avr4/6, including the dEER motif, is sufficient to trigger Rps4 dependent HR while its C terminus is sufficient to trigger Rps6-mediated HR. Compared with alleles from avirulent races, alleles of Avr4/6 from virulent races possess nucleotide substitutions in the 5' untranslated region of the gene but not in the protein-coding region. PMID- 20192831 TI - Peroxisome biogenesis factor PEX13 is required for appressorium-mediated plant infection by the anthracnose fungus Colletotrichum orbiculare. AB - Peroxisomes are ubiquitous organelles of eukaryotic cells that fulfill a variety of biochemical functions, including beta-oxidation of fatty acids. Here, we report that an ortholog of the Saccharomyces cerevisiae peroxisome biogenesis gene PEX13 is required for pathogenicity of Colletotrichum orbiculare. CoPEX13 was identified by screening random insertional mutants for deficiency in fatty acid utilization. Targeted knockout mutants of CoPEX13 were unable to utilize fatty acids as a carbon source. Expression analysis using green fluorescent protein fused to the peroxisomal targeting signals PTS1 and PTS2 revealed that the import machinery for peroxisomal matrix proteins was impaired in copex13 mutants. Appressoria formed by the copex13 mutants were defective in both melanization and penetration ability on host plants, had thin cell walls, and lacked peroxisomes. Moreover, the concentration of intracellular glycerol was lower in copex13 appressoria than those of the wild type. These findings indicate that fatty acid oxidation in peroxisomes is required not only for appressorium melanization but also for cell wall biogenesis and metabolic processes involved in turgor generation, all of which are essential for appressorium penetration ability. PMID- 20192832 TI - Expression of BvGLP-1 encoding a germin-like protein from sugar beet in Arabidopsis thaliana leads to resistance against phytopathogenic fungi. AB - Nematode (Heterodera schachtii) resistance in sugar beet (Beta vulgaris) is controlled by a single dominant resistance gene, Hs1(pro-1). BvGLP-1 was cloned from resistant sugar beet. The BvGLP-1 messenger (m)RNA is highly upregulated in the resistant plants after nematode infection, suggesting its role in the Hs1(pro 1) mediated resistance. BvGLP-1 exhibits sequence homology to a set of plant germin-like proteins (GLP), from which several have proved to be functional in plant basal or defense resistance against fungal pathogens. To test whether BvGLP 1 is also involved in the plant-fungus interaction, we transferred BvGLP-1 into Arabidopsis and challenged the transgenic plants with the pathogenic fungi Verticillium longisporum and Rhizoctonia solani as well as with the beneficial endophytic fungus Piriformospora indica. The expression of BvGLP-1 in Arabidopsis elevated the H(2)O(2) content and conferred significant resistance to V. longisporum and R. solani but did not affect the beneficial interaction with P. indica in seedlings. Microscopic observations revealed a dramatic reduction in the amount of hyphae of the pathogenic fungi on the root surface as well as of fungal mycelium developed inside the roots of transgenic Arabidopsis compared with wild-type plants. Molecular analysis demonstrated that the BvGLP-1 expression in Arabidopsis constitutively activates the expression of a subset of plant defense-related proteins such as PR-1 to PR-4 and PDF1.2 but not PDF2.1 and PDF2.3. In contrast, the PDF2.1 mRNA level was downregulated. These data suggest an important role of BvGLP-1 in establishment of plant defense responses, which follow specific signaling routes that diverge from those induced by the beneficial fungus. PMID- 20192833 TI - Six new genes required for production of T-toxin, a polyketide determinant of high virulence of Cochliobolus heterostrophus to maize. AB - Southern Corn Leaf Blight, one of the worst plant disease epidemics in modern history, was caused by Cochliobolus heterostrophus race T, which produces T toxin, a determinant of high virulence to maize carrying Texas male sterile cytoplasm. The genetics of T-toxin production is complex and the evolutionary origin of associated genes is uncertain. It is known that ability to produce T toxin requires three genes encoded at two unlinked loci, Tox1A and Tox1B, which map to the breakpoints of a reciprocal translocation. DNA associated with Tox1A and Tox1B sums to about 1.2 Mb of A+T rich, repeated DNA that is not found in less virulent race O or other Cochliobolus species. Here, we describe identification and targeted deletion of six additional genes, three mapping to Tox1A and three to Tox1B. Mutant screens indicate that all six genes are involved in T-toxin production and high virulence to maize. The nine known Tox1 genes encode two polyketide synthases (PKS), one decarboxylase, five dehydrogenases, and one unknown protein. Only two have a similar phylogenetic profile. To trace evolutionary history of one of the core PKS, DNA from more than 100 Dothideomycete species were screened for homologs. An ortholog (60% identity) was confirmed in Didymella zeae-maydis, which produces PM-toxin, a polyketide of similar structure and biological specificity as T-toxin. Only one additional Dothideomycete species, the dung ascomycete Delitschia winteri harbored a paralog. The unresolved evolutionary history and distinctive gene signature of the PKS (fast-evolving, discontinuous taxonomic distribution) leaves open the question of lateral or vertical transmission. PMID- 20192834 TI - Maize leaf epiphytic bacteria diversity patterns are genetically correlated with resistance to fungal pathogen infection. AB - Plant leaves host a specific set of microbial epiphytes. Plant genetic and solar UV-B radiation effects on the diversity of the phyllosphere were examined by measuring epiphytic bacterial ribosomal DNA diversity in a maize recombinant inbred (RI) mapping population. Several chromosomal quantitative trait loci (QTL) with significant effects on bacterial diversity were identified, some of which had effects only in the presence of UV-B radiation and others that had effects both with and without UV-B. Candidate genes with allele-specific effects were mapped to the bacterial diversity chromosomal regions. A glutamate decarboxylase candidate gene was located at a UV-B-specific chromosomal locus, and in a comparison between two RI lines with contrasting bacterial diversity phenotypes, high bacterial diversity was associated with high levels of glutamate decarboxylase enzyme activity, a component of the gamma-aminobutyric acid (GABA) pathway. The bacterial diversity loci exhibited a significant overlap with loci connected with Southern leaf blight (SLB) susceptibility in the field. A SLB resistant inbred genotype had less beta bacterial diversity, and antibiotic treatment of inbreds increased this diversity. These results suggest that the GABA pathway is genetically associated with phyllosphere bacterial diversity. Furthermore, the colocalization of QTL between low bacterial diversity and fungal blight-resistance and the increase in beta diversity in antibiotic-treated leaves suggest that occupation of leaf habitats by a particular set of suppressive bacteria may restrict phyllosphere bacterial variability and increase resistance to fungal infection. PMID- 20192835 TI - Armillaria mellea induces a set of defense genes in grapevine roots and one of them codifies a protein with antifungal activity. AB - Grapevine root rot, caused by Armillaria mellea, is a serious disease in some grape-growing regions. Young grapevines start to show symptoms of Armillaria root rot from the second year after inoculation, suggesting a certain degree of resistance in young roots. We used a suppression subtractive hybridization approach to study grapevine's reactions to the first stages of A. mellea infection. We identified 24 genes that were upregulated in the roots of the rootstock Kober 5BB 24 h after A. mellea challenge. Real-time reverse transcriptase polymerase chain reaction analysis confirmed the induction of genes encoding protease inhibitors, thaumatins, glutathione S-transferase, and aminocyclopropane carboxylate oxidase, as well as phase-change related, tumor related, and proline-rich proteins, and gene markers of the ethylene and jasmonate signaling pathway. Gene modulation was generally stronger in Kober 5BB than in Pinot Noir plants, and in vitro inoculation induced higher modulation than in greenhouse Armillaria spp. treatments. The full-length coding sequences of seven of these genes were obtained and expressed as recombinant proteins. The grapevine homologue of the Quercus spp. phase-change-related protein inhibited the growth of A. mellea mycelia in vitro, suggesting that this protein may play an important role in the defense response against A. mellea. PMID- 20192836 TI - Diversity at the Mla powdery mildew resistance locus from cultivated barley reveals sites of positive selection. AB - The Mla locus in barley (Hordeum vulgare) conditions isolate-specific immunity to the powdery mildew fungus (Blumeria graminis f. sp. hordei) and encodes intracellular coiled-coil (CC) domain, nucleotide-binding (NB) site, and leucine rich repeat (LRR)-containing receptor proteins. Over the last decades, genetic studies in breeding material have identified a large number of functional resistance genes at the Mla locus. To study the structural and functional diversity of this locus at the molecular level, we isolated 23 candidate MLA cDNAs from barley accessions that were previously shown by genetic studies to harbor different Mla resistance specificities. Resistance activity was detected for 13 candidate MLA cDNAs in a transient gene-expression assay. Sequence alignment of the deduced MLA proteins improved secondary structure predictions, revealing four additional, previously overlooked LRR. Analysis of nucleotide diversity of the candidate and validated MLA cDNAs revealed 34 sites of positive selection. Recombination or gene conversion events were frequent in the first half of the gene but positive selection was also found when this region was excluded. The positively selected sites are all, except two, located in the LRR domain and cluster in predicted solvent-exposed residues of the repeats 7 to 15 and adjacent turns on the concave side of the predicted solenoid protein structure. This domain-restricted pattern of positively selected sites, together with the length conservation of individual LRR, suggests direct binding of effectors to MLA receptors. PMID- 20192837 TI - Evolution and regulation of the Lotus japonicus LysM receptor gene family. AB - LysM receptor kinases were identified as receptors of acylated chitin (Nod factors) or chitin produced by plant-interacting microbes. Here, we present the identification and characterization of the LysM receptor kinase gene (Lys) family (17 members) in Lotus japonicus. Comprehensive phylogenetic analysis revealed a correlation between Lys gene structure and phylogeny. Further mapping coupled with sequence-based anchoring on the genome showed that the family has probably expanded by a combination of tandem and segmental duplication events. Using a sliding-window approach, we identified distinct regions in the LysM and kinase domains of recently diverged Lys genes where positive selection may have shaped ligand interaction. Interestingly, in the case of NFR5 and its closest paralog, LYS11, one of these regions coincides with the predicted Nod-factor binding groove and the suggested specificity determining area of the second LysM domain. One hypothesis for the evolutionary diversification of this receptor family in legumes is their unique capacity to decipher various structures of chitin-derived molecules produced by an extended spectrum of interacting organisms: symbiotic, associative, endophytic, and parasitic. In a detailed expression analysis, we found several Lotus Lys genes regulated not only during the symbiotic association with Mesorhizobium loti but also in response to chitin treatment. PMID- 20192838 TI - The cAMP signaling pathway in Fusarium verticillioides is important for conidiation, plant infection, and stress responses but not fumonisin production. AB - Fusarium verticillioides is one of the most important fungal pathogens of maize. Mycotoxin, fumonisins produced by this pathogen pose a threat to human and animal health. Because cAMP signaling has been implicated in regulating diverse developmental and infection processes in fungal pathogens, in this study, we aimed to elucidate the function of the cAMP-protein kinase A (PKA) pathway in toxin production and plant infection in F. verticillioides. Targeted deletion mutants were generated for the CPK1 and FAC1 genes that encode a catalytic subunit of PKA and the adenylate cyclase, respectively. Defects in radial growth and macroconidiation were observed in both the cpk1 and fac1 deletion mutants. The fac1 mutant also was significantly reduced in virulence and microconidiation but increased in tolerance to heat and oxidative stresses. These phenotypes were not observed in the cpk1 mutant, indicating that additional catalytic subunit of PKA must exist and function downstream from FAC1. The fac1 mutant formed microconidia mainly in false heads. The expression levels of the hydrophobin genes HYD1 and HYD2, which are known to be associated with change in formation of microconidia, were significantly reduced in the fac1 mutant. Expression of F. verticillioides GSY2 and HSP26 genes, two other putative downstream targets of FAC1, was increased in the fac1 mutant and may be associated with its enhanced stress tolerance. Although fumonisin production was normal, biosynthesis of bikaverin was increased in the fac1 mutant, suggesting that FAC1 and cAMP signaling may have pathway-or metabolite-specific regulatory roles in secondary metabolism. Overall, the pleiotropic defects of the fac1 deletion mutant indicate that the cAMP-PKA pathway is involved in growth, conidiation, bikaverin production, and plant infection in F. verticillioides. PMID- 20192840 TI - Founder of Pediatric Pathology. AB - Abstract. PMID- 20192839 TI - Functional improvement of focal cerebral ischemia injury by subdural transplantation of induced pluripotent stem cells with fibrin glue. AB - Ischemic stroke is the leading cause of disability in the world. Cell transplantation has emerged in various neurological diseases as a potential therapeutic approach in the postacute stroke phase. Recently, inducible pluripotent stem (iPS) cells showed potential for multilineage differentiation and provide a resource for stem cell-based therapies. However, whether iPS transplantation could improve the function of stroke-like model is still an open question. The aim of this study is to investigate the therapeutic effects of subdural transplantation of iPS mixed with fibrin glue (iPS-FG) on cerebral ischemic rats induced by middle cerebral artery occlusion (MCAO). We demonstrated an efficient method to differentiate iPS into astroglial-like and neuron-like cells which display functional electrophysiological properties. In vivo study firstly showed that the direct injection of iPS into damaged areas of rat cortex significantly decreased the infarct size and improved the motor function in rats with MCAO. Furthermore, we found that the subdural iPS-FG can also effectively reduce the total infarct volume and greatly improve the behavior of rats with MCAO to perform rotarod and grasping tasks. Importantly, analysis of cytokine expression in iPS-FG-treated ischemic brains revealed a significant reduction of pro-inflammatory cytokines and an increase of anti-inflammatory cytokines. Taken together, these results suggest that iPS cells could improve the motor function, reduce infarct size, attenuate inflammation cytokines, and mediate neuroprotection after ischemic stroke. Subdural iPS-FG could be considered as a more safe approach because this method can avoid iatrogenic injury to brain parenchyma and enhance recovering from stoke-induced impairment. PMID- 20192842 TI - Administrative outcomes five years after opening an acute palliative care unit at a comprehensive cancer center. AB - PURPOSE: We examined administrative outcomes after opening an oncology acute palliative care unit (APCU), to determine attainment of administrative targets related to the unit's function of acute palliation. METHODS: We retrospectively reviewed the administrative database for our APCU for the 5 years following its opening in 2003. Data were abstracted on demographic information, as well as source of admission, primary reason for admission, discharge destination, inpatient death rate, and length of stay. Linear regression and the Cochran Armitage trend test were used for analysis. In keeping with targets set at the unit's opening, our primary hypotheses were that outpatient admissions, admissions for symptom control, and discharges home would increase over the study period; secondary hypotheses were that length of stay and inpatient death rate would decrease. RESULTS: There were 1748 admissions during the study period: the median age was 64, 54% were women, and the most common cancer sites were gastrointestinal (24%), lung (20%), and gynecologic (13%). There were significant changes for all primary endpoints: outpatient admissions increased from 47% to 70% (p < 0.0001), admissions for symptom control increased from 42% to 75% (p < 0.0001), and discharges home increased from 18% to 39% (p < 0.0001). The secondary end points of death rate and length of stay decreased from 65% to 40% (p < 0.0001) and 12 to 11 days (p = 0.54), respectively. CONCLUSION: Setting and adhering to administrative targets for an APCU is possible with appropriate admission criteria, adequate community resources, and education of patients, families and health professionals regarding the model of care. PMID- 20192843 TI - Advance directives and do-not-resuscitate orders in patients with cancer with metastatic spinal cord compression: advanced care planning implications. AB - OBJECTIVES: Communication about end-of-life decisions is crucial. Although patients with metastatic spinal cord compression (MSCC) have a median survival time of 3 to 6 months, few data are available concerning the presence of advance directives and do-not-resuscitate (DNR) orders in this population. The objective of this study was to determine presence of advance directives and DNR order among patients with MSCC. METHODS: We retrospectively reviewed data concerning advance directives for 88 consecutive patients with cancer who had MSCC and required rehabilitation consultation at The University of Texas M. D. Anderson Cancer Center from September 20, 2005 to August 29, 2008. We characterized the data using univariate descriptive statistics and used the Fisher exact test to find correlations. RESULTS: The mean age of this patient population was 55 years (range, 24-81). Thirty patients (33%) were female. Twenty patients (23%) had a living will, 27 patients (31%) had health care proxies, and 10 patients (11%) had either out-of-hospital DNR order and/or dictated DNR note. The median survival time for these patients was 4.3 months. CONCLUSION: Despite strong evidence showing short survival times for MSCC patients, it seems many of these patients are not aware of the urgency to have an advance directive. This may be an indicator of delayed end-of-life palliative care and suboptimal doctor-patient communication. Using the catastrophic event of a diagnosis of MSCC to trigger communication and initiate palliative care may be beneficial to patients and their families. PMID- 20192844 TI - Estrogenic activity of glyceollins isolated from soybean elicited with Aspergillus sojae. AB - Glyceollins, which are synthesized from daidzein in soybeans cultured with fungi, have been shown to have antifungal effects and cancer preventive properties. Several studies have proposed that isoflavones and their metabolites act as a mixed agonist/antagonist for estrogen. Although glyceollins were reported to suppress some cancer cells via anti-estrogenic activity, it is not clear whether the compounds possess estrogenic potential. In contrast to the anti-estrogenic action reported thus far, we observed estrogenic effects of glyceollins using E screen assay and pS2 expression, whereas glyceollins showed higher affinity for estrogen receptor (ER) beta than ERalpha. We also found that glyceollins were more efficiently produced de novo in minced than in half-sliced soybean, following infection with Aspergillus sojae. In conclusion, glyceollins may be useful in the prevention or amelioration of postmenopausal complications because they had strong estrogenic activity, and their production could be variable depending upon processing prior to fungal inoculation. PMID- 20192845 TI - Antimicrobial and antioxidant activities of mycelia of 10 wild mushroom species. AB - Antimicrobial and antioxidant activities of mycelia obtained from 10 wild edible mushrooms-Armillaria mellea, Meripilus giganteus, Morchella costata, Morchella elata, Morchella esculenta var. vulgaris, Morchella hortensis, Morchella rotunda, Paxillus involutus, Pleurotus eryngii, and Pleurotus ostreatus-were investigated. For determination of antimicrobial activities of these mushrooms, ethanol extracts were examined with 11 test microorganisms by the agar well diffusion method. P. ostreatus and M. giganteus were the most active species against both bacteria and yeast. Antioxidant properties of ethanol extracts were studied by the 1,1-diphenyl-2-picrylhydrazyl free radical scavenging method. Among the mushroom extracts, M. elata showed the most potent radical scavenging activity. This research has shown that these 10 wild macrofungi have potential as natural antioxidants and antibiotics. PMID- 20192846 TI - Protective effect of Allium neapolitanum Cyr. versus Allium sativum L. on acute ethanol-induced oxidative stress in rat liver. AB - This study investigated the protective effect of Allium neapolitanum Cyr., a spontaneous species of the Italian flora, compared with garlic (Allium sativum L.) on liver injury induced by ethanol in rats. Male albino Wistar rats were orally treated with fresh Allium homogenates (leaves or bulbs, 250 mg/kg) daily for 5 days, whereas controls received vehicle only. At the end of the experimental 5-day period, the animals received an acute ethanol dose (6 mL/kg, i.p.) 2 hours before the last Allium administration and were sacrificed 6 hours after ethanol administration. The activities of catalase (CAT), superoxide dismutase (SOD), and glutathione reductase (GR) and the levels of malondialdehyde (MDA), ascorbic acid (AA), and reduced (GSH) and oxidized glutathione in liver tissue were determined. Administration of both Allium species for 5 days (leaves or bulbs) led to no statistical variation of nonenzymatic parameters versus the control group; otherwise Allium treatment caused an increase of GSH and AA levels compared with the ethanol group and a diminution of MDA levels, showing in addition that A. neapolitanum bulb had the best protective effect. Regarding to enzymatic parameters, GR and CAT activities were enhanced significantly compared with the ethanol group, whereas SOD activity showed a trend different from other parameters estimated. However, the treatment with both Allium species followed by acute ethanol administration reestablished the nonenzymatic parameters similar to control values and enhanced the activities of the enzymes measured. These results suggest that fresh Allium homogenates (leaves or bulbs) possess antioxidant properties and provide protection against ethanol-induced liver injury. PMID- 20192847 TI - Long-term treatment with shengmai san-derived herbal supplement (Wei Kang Su) enhances antioxidant response in various tissues of rats with protection against carbon tetrachloride hepatotoxicity. AB - Wei Kang Su (WKS) is a commercial herbal product based on a Chinese herbal formula, Shengmai San. Here, we investigated the effects of long-term treatment with WKS on mitochondrial antioxidant status and functional ability, as well as heat shock protein (Hsp) 25/70 production, in various tissues of rats. WKS treatment enhanced mitochondrial antioxidant status and ATP generation capacity, as well as Hsp 25/70 production in various rat tissues. WKS treatment suppressed plasma reactive oxygen metabolite levels and protected against carbon tetrachloride hepatotoxicity in rats. Long-term WKS treatment may prevent diseases by enhancing the resistance of mitochondria to oxidative stress. PMID- 20192848 TI - Evaluation of antioxidant and free radical scavenging capacities of some Nigerian indigenous medicinal plants. AB - Methanolic extracts of 10 selected Nigerian medicinal plants-Psidium guajava, Alstonia boonei, Cassia alata, Newbouldia laevis, Spondias mombin, Globimetula cupulatum, Chromolaena odorata, Securidaca longepedunculata, Ocimum gratissimum, and Morinda lucida-widely used in ethnomedicine, were assessed for phytochemical constituents and antioxidant and free radical scavenging activities using seven different antioxidant assay methods. Phytochemical screening gave positive tests for steroids, terpenoids, and cardiac glycosides, alkaloids, saponins, tannins, and flavonoids contained in the extracts. P. guajava contained the highest amount of total phenolics (380.08 +/- 4.40 mg/L gallic acid equivalents), and the highest amounts of total flavonoids were found in the leaf extracts of C. alata (275.16 +/- 1.62 microg/mL quercetin equivalents [QE]), C. odorata (272.12 +/- 2.32 microg/mL QE), and P. guajava (269.72 +/- 2.78 microg/mL QE). Percentage 2,2 diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity was highest in S. mombin (88.58 +/- 3.04%) and P. guajava (82.79 +/- 2.84%) and compared with values obtained for ascorbic acid and gallic acid. All the extracts, generally, had low nitric oxide radical scavenging activities, and G. cupulatum had the highest hydroxyl radical scavenging activity (63.84 +/- 0.97%). The extracts in general demonstrated high lipid peroxidation inhibitory activity, with only M. lucida (38.74 +/- 1.99%) and A. boonei (47.16 +/- 0.59%) being exceptions. The reductive potential was highest in P. guajava (0.79 +/- 0.04) and least in S. longepedunculata (0.26 +/- 0.00). DPPH assay correlated well with total phenolic contents (r(2) = 0.76) and reductive potential (r(2) = 0.81) and fairly with lipid peroxidation inhibitory activity (r(2) = 0.51). There was a good correlation between total phenolic contents and reductive potential (r(2) = 0.79) and a fair correlation between total phenolic contents and lipid peroxidation inhibitory activity (r(2) = 0.55). These results suggest that the methanolic extracts of the studied plant parts possess significant antioxidant and radical scavenging activities that may be due to the phytochemical content of the plants and as such make them potential candidates as natural chemoprophylactic agents. In addition, multiple assay methods should be used in comparing antioxidant capacities of samples to have a reliable result. PMID- 20192849 TI - Biomedical properties of a series of ruthenium-N-heterocyclic carbene complexes based on oxidant activity in vitro and assessment in vivo of biosafety in zebrafish embryos. AB - N-Heterocyclic carbene (NHC) ligands have attracted great interest over the last decade for their use in the design of homogenous catalysts. NHC-based metal complexes have interesting potential biomedical applications, such as in antimicrobial and cancer therapy, which are beginning to be explored more fully. We have studied here the oxidant activities of a series of Ru(II) complexes in vitro and zebrafish (Danio rerio) have been used as a model in vivo to investigate and characterize the toxicity of some of these compounds. Dual behavior was observed for the NHC-based complexes as they behaved as antioxidants at low concentrations but showed pro-oxidant capacity at higher concentrations. Zebrafish embryos were exposed to Ru(II) complexes under several different conditions (0 or 24 h postfertilization, with or without the chorion) and various parameters, such as viability, edema, heart rate, blood coagulation, pigmentation, scoliosis, malformation, and hatching, were tested. In general, zebrafish embryos were not harmed by exposure to Ru(II) complexes whatever the experimental conditions. Several toxicity profiles were observed depending upon the chemical structure of the compound in question. Their characteristics as pro oxidant and/or antioxidant agents together with their biosafety may point to their having biomedical applications as antitumoral or neuroprotective drugs. PMID- 20192850 TI - Dominance hierarchies in zebrafish (Danio rerio) and their relationship with reproductive success. AB - The zebrafish has considerable potential for use as a model in the study of behavior in social systems, particularly dominance hierarchies, which are widespread in nature and can affect the lifelong success of individuals. There is, however, a paucity of information relating to the characterization of social groups and significance of dominance hierarchies in the zebrafish model. This study set out to bridge this knowledge gap and better characterize dominance and its implications for reproductive success in both male and female zebrafish in colonies comprising of two males and two females. Analyses of four aggressive behaviors (chase, bite, repel, spar) were conducted twice daily over a 5-day period, and fertilized eggs were collected for parentage analyses using DNA microsatellite markers. Dominant-subordinate relationships occurred both between males and between females, and in both sexes, dominance was associated with a greater body size and higher levels of aggression. During the spawning period, dominant females were, however, less aggressive toward their subordinates than dominant males to their subordinates. Aggressive behaviors employed for maintaining dominance did not differ between the sexes, but in females, in contrast with males, the level of aggression directed toward the subordinate fish increased over the study period. Overall, dominance resulted in a greater total reproductive success in males but not in females; however, dominant females sired more offspring with the dominant male. The findings illustrate that energy invested in dominance behavior appears beneficial for both sexes in zebrafish. PMID- 20192851 TI - The temporal resolution of in vivo electroporation in zebrafish: a method for time-resolved loss of function. AB - One caveat to current loss-of-function approaches in zebrafish is that they typically disrupt gene function from the beginning of development. This can be problematic when attempting to study later developmental events. In vivo electroporation is a method that has been shown to be effective at incorporating reagents into the developing nervous system at multiple later developmental stages. The temporal and spatial characteristics of in vivo electroporation that have been previously demonstrated suggest that this could be a powerful approach for time-resolved loss-of-function analysis. Here, in an attempt to demonstrate the efficacy of this approach for analysis of a specific developmental timeframe- that of initial development of the zebrafish visual system-we have done a systematic characterization of the efficiency of in vivo electroporation in zebrafish across multiple developmental stages, from 24 to 96 h postfertilization. We show that electroporation is efficient at delivering expression plasmids to large numbers of neurons at multiple developmental steps, including 24, 48, or 96 h postfertilization. Expression from electroporated plasmids is maximal within 24 h, and significant and useful expression is seen within 6 h. Electroporation can be used to deliver two separate expression plasmids (green fluorescent protein and mCherry), resulting in coexpression in 97% of cells. Most importantly, electroporation can be used to incorporate siRNA reagents, resulting in 84% knockdown of a target protein (green fluorescent protein). In conclusion, in vivo electroporation is an effective method for delivering both DNA-based expression plasmids and RNA interference-based loss-of function reagents, and exhibits the appropriate characteristics to be useful as a time-resolved genetic approach to investigate the molecular mechanisms of visual system development. PMID- 20192853 TI - Association of body composition and muscle function with hip geometry and BMD in premenopausal women. AB - BACKGROUND: Muscle mass and function are related to bone mineral density (BMD) but associations with bone geometry and BMD at differently loaded hip regions are less well-known. AIM: To examine associations of muscle strength, maximal impact forces and body composition with hip bone density and geometry. SUBJECTS AND METHODS: In 88 sedentary, premenopausal women (32.6 +/- 8.5 years), fat-free mass (FFM), isometric knee extension strength (IKES), and peak landing ground reaction force (GRF) were measured. BMD at the proximal femur and sub-regions, section modulus (Z), and cross-sectional area (CSA) were estimated using dual X-ray absorptiometry. RESULTS: BMD at hip sites was significantly associated with body mass, IKES, GRF and FFM (r = 0.31-0.50) whilst Z and CSA were correlated with FFM (r = 0.67 and 0.62, respectively). In multivariate models, variables explaining most variance were body mass for lower neck and shaft BMD (25% and 17%, respectively), IKES for upper neck BMD (21%), GRF for trochanter (19%) and total hip BMD (18%) and FFM for femoral neck Z, CSA and BMD (54%, 38% and 20%, respectively). CONCLUSION: BMD at superolateral hip sites was most strongly related to muscle function and maximal impact forces, BMD at inferiomedial hip sites to body mass, and hip geometry to FFM. PMID- 20192852 TI - Chemical screening for hair cell loss and protection in the zebrafish lateral line. AB - In humans, most hearing loss results from death of hair cells, the mechanosensory receptors of the inner ear. Two goals of current hearing research are to protect hair cells from degeneration and to regenerate new hair cells, replacing those that are lost due to aging, disease, or environmental challenges. One limitation of research in the auditory field has been the relative inaccessibility of the mechanosensory systems in the inner ear. Zebrafish possess hair cells in both their inner ear and their lateral line system that are morphologically and functionally similar to human hair cells. The external location of the mechanosensory hair cells in the lateral line and the ease of in vivo labeling and imaging make the zebrafish lateral line a unique system for the study of hair cell toxicity, protection, and regeneration. This review focuses on the lateral line system as a model for understanding loss and protection of mechanosensory hair cells. We discuss chemical screens to identify compounds that induce hair cell loss and others that protect hair cells from known toxins and the potential application of these screens to human medicine. PMID- 20192855 TI - Re: the impact of the stone age diet on gingival conditions in the absence of oral hygiene. Baumgartner S, Imfeld T, Schicht O, Rath C, Persson RE, Persson GR. (J Periodontol 2009;80:759-768.). PMID- 20192857 TI - Re: clinical and histologic evaluation of non-surgical periodontal therapy with enamel matrix derivative: a report of four cases. Mellonig JT, Valderrama P, Gregory HJ, Cochran DL. (J Periodontol 2009;80:1534-1540.). PMID- 20192859 TI - Osteotome sinus floor elevation and simultaneous implant placement in grafted biomaterial sockets: 3 years of follow-up. AB - BACKGROUND: Immediate bone grafting procedures were proposed to preserve bone volume in residual damaged alveolar walls and to prevent the expansion of the sinus floor in the maxillary molar region. The use of an osteotome allows vertical bone augmentation and localized sinus elevation with minimal surgical trauma. The aim of this study is to evaluate the clinical outcome of implants placed in previously grafted alveoli that were expanded at a second-stage surgery by an osteotome technique. METHODS: Twenty patients requiring extraction of one or two upper molar teeth and/or a second premolar were selected. Thirty teeth were extracted, and their fresh sockets immediately received magnesium-enriched hydroxyapatite as a graft material. Three months after bone filling, osteotome sinus floor elevations were performed in grafted sites, and 30 titanium dental implants were placed. Three months after implant placement, temporary restorations were performed. Follow-up examinations and intraoral digital radiographs were taken at baseline and 6, 12, 24, and 36 months after implant placement to evaluate the alveolar bone gain for each implant. Comparisons among mean values of alveolar bone gain over time were performed by the Student two tailed t test. RESULTS: At the 36-month follow-up, a survival rate of 100% was reported for all implants. The alveolar bone gain after 6 months of healing was 2.41 +/- 1.23 mm. Successively, after 12 months, the bone gain increased (3.85 +/ 1.37 mm). At 24 and 36 months after implant placement, the levels were stable (3.86 +/- 1.50 mm and 3.82 +/- 1.57 mm, respectively). Statistical analyses showed a significant difference (P <0.05) only between the 6- and 12-month values. CONCLUSION: At the 36-month follow-up, the use of the osteotome technique for vertical expansion of the grafted tissue was considered a predictable procedure in the implant surgery. PMID- 20192860 TI - Maternal periodontal disease and preterm or extreme preterm birth: an ordinal logistic regression analysis. AB - BACKGROUND: Despite previous studies addressing the link between preterm or low birth weight infants and maternal periodontitis, extreme preterm births have received far less attention. This study is designed to address the possible association between maternal periodontal disease and preterm or extreme preterm birth. METHODS: Immediately after childbirth, 1,207 women underwent an examination in which periodontal disease was assessed according to two alternative definitions: 1) four or more teeth with at least one site showing probing depth (PD) >or=4 mm and clinical attachment loss (AL) >or=3 mm, and 2) at least one site showing PD and clinical AL >or=4 mm. For each of these definitions, two types of multivariate analysis were conducted: a linear regression analysis for the number of gestation weeks, and a more specific ordinal logistic regression analysis for the ordinal variable gestation time categorized as normal (term) (n = 1,046 women) or mild-moderate (n = 146 women) or extreme preterm (n = 15 women). RESULTS: Periodontal disease was associated with fewer weeks of gestation by linear regression (definition 1: P = 0.012; definition 2: P <0.001) and with preterm (n = 161; mild-moderate and extreme) or extreme preterm births (n = 15) by ordinal logistic regression (definition 1: odds ratio [OR] = 1.83, 95% confidence interval [CI]: 1.28 to 2.62; definition 2: OR = 2.37, 95% CI: 1.62 to 3.46). CONCLUSION: Our findings suggest that periodontal disease is associated with a premature or extremely premature birth. PMID- 20192861 TI - Knowledge and orientations of internal medicine trainees toward periodontal disease. AB - BACKGROUND: There is growing evidence that periodontal disease may be a source of systemic inflammation that impacts overall health. As such, periodontal disease is associated with an increased risk of systemic illnesses such as cardiovascular disease and adverse outcomes in diabetes mellitus and pregnancy. With the aim of assessing oral health knowledge and orientations of physicians in training, we surveyed incoming internal medicine trainees about their general knowledge, attitudes, and behaviors/practices about periodontal health and disease. METHODS: A 16-question survey was distributed during orientation to incoming internal medicine trainees at a single urban teaching hospital in New York City in 2007 and 2008. Questions aimed to assess the knowledge levels of the subjects about periodontal disease and their attitudes toward discussing/evaluating the periodontal status of their patients. The study was approved by the Montefiore Institutional Review Board. RESULTS: Of 125 incoming medical trainees queried, 115 responded (92% response rate). Of the 115 responders, 96% were medical interns. The median age of the trainees was 27 years (interquartile range: 26 to 29 years), and 61% were female. Overall, 34% of the trainees answered all five true/false general knowledge questions correctly, 82% reported that they never asked patients if they were diagnosed with periodontal disease, 90% reported not receiving any training about periodontal disease during medical school, 69% reported that they were not comfortable at all performing a simple periodontal examination, 17% agreed that patients expect physicians to discuss/screen for periodontal disease, 46% felt that discussing/evaluating the periodontal status of their patients was peripheral to their role as physicians, 76% reported never screening patients for periodontal disease, and 23% stated that they never referred patients to dentists. CONCLUSIONS: In this study, incoming internal medicine trainees had inadequate knowledge regarding periodontal disease. They were also generally uncomfortable with performing a simple periodontal examination. Oral health training in medical school and the medical postgraduate setting is recommended. PMID- 20192862 TI - Association of periodontal parameters with metabolic level and systemic inflammatory markers in patients with type 2 diabetes. AB - BACKGROUNDS: Although worldwide evidence tends to prove that diabetes adversely affects periodontal health, there are insufficient clues indicating whether periodontitis may aggravate metabolic control and systemic inflammation. This study, as a preliminary part of an ongoing research project, aims to clarify the relationship of periodontal parameters with metabolic levels and systemic inflammatory markers in patients with diabetes. METHODS: A total of 140 qualified, adult patients with type 2 diabetes and periodontitis were recruited into this study. Periodontal examinations, including a full-mouth assessment of probing depths (PDs), bleeding on probing, gingival recession, and clinical attachment level, were determined. Blood analyses were carried out for glycated hemoglobin (HbA1c), fasting glucose, high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor-alpha (TNF-alpha), and lipid profiles. Subjects were divided into three groups according to tertiles of the mean PD and compared. RESULTS: Upon an analysis of covariance, subjects with an increased mean PD had significantly higher levels of HbA1c and hsCRP (P <0.05). No significant difference was found among different groups in the levels of serum TNF-alpha, fasting glucose, and lipid profiles (P >0.05). After controlling for age, gender, body mass index, duration of diabetes mellitus, smoking, regular physical exercise, and alcohol consumption, positive correlations were found between mean PD and HbA1c (r = 0.2272; P = 0.009) and between mean PD and hsCRP (r = 0.2336; P = 0.007). After adjustment for possible confounders, the mean PD emerged as a significant predictor variable for elevated levels of HbA1c and hsCRP (P <0.05). CONCLUSION: Chronic periodontitis was associated with glycemic metabolic and serum hsCRP levels in patients with type 2 diabetes. PMID- 20192863 TI - The significance of the lingual nerve during periodontal/implant surgery. AB - BACKGROUND: Understanding the position of the lingual nerve is important when performing third molar extractions and periodontal and implant surgeries in the mandible. The careless management of the lingual flap can potentially cause damage to the lingual nerve. The location of the lingual nerve in the third molar region was described in the literature; however, to our knowledge, its course mesial to the third molar region was not reported. The aim of this study is to identify and measure the location of lingual nerves in relation to mandibular teeth in fresh cadaver heads. METHODS: Thirty lingual nerves from 18 cadaver heads were dissected, and the vertical distance from the lingual nerve to the mid lingual cemento-enamel junctions of mandibular molars and premolars and the position where the lingual nerve left the lingual plate and moved toward the tongue were determined. Two cadaver heads were randomly selected and exposed to cone-beam computed tomography (CBCT) scans after the insertion of a wrought wire into the nerve. The same vertical distance as the clinical measurement was determined and compared. RESULTS: Seventy-five percent of lingual nerves turned toward the tongue at the first and second molar region. The vertical distance was 9.6, 13, and 14.8 mm at the second molar, first molar, and second premolar, respectively. The difference between clinical and CBCT measurements was 0.57 +/- 2.62 mm. CONCLUSIONS: The course of the lingual nerve in relation to posterior teeth was described. This information can help surgeons gain more understanding of the location of the lingual nerve and perform safe surgeries in the mandible. PMID- 20192864 TI - Fresh-socket implants in periapical infected sites in humans. AB - BACKGROUND: The aim of the present study is to compare the outcome of the immediate placement of implants when used in the replacement of teeth with and without chronic periapical lesions. METHODS: Thirty patients requiring a single tooth extraction of a monoradicular or premolar tooth were selected. The control group (CG) included 15 patients without periapical lesions but with root caries and root fractures. The test group (TG) included 15 patients with periapical lesions, periapical radiolucencies, and no signs of pain, fistulas, or suppuration. Thirty teeth were extracted, and implants were immediately positioned in fresh sockets and loaded after 3 months in both groups. Clinical parameters (probing depth [PD], modified plaque index, modified bleeding index [mBI], marginal gingiva level [MGL], and keratinized mucosa [KM]) and marginal bone levels were evaluated at baseline and 12 and 24 months after implant placement. Comparisons between CG and TG values over time were performed by the Student two-tailed t test. RESULTS: At the 24-month follow-up, a survival rate of 100% was reported for all implants. The mean bone loss was 0.82 +/- 0.52 mm for the CG and 0.86 +/- 0.54 for the TG. Plaque accumulation was 0.74 +/- 0.29 for the CG and 0.69 +/- 0.29 for the TG. The mBI was 0.77 +/- 0.33 for the CG and 0.72 +/- 0.36 for the TG. The soft tissue profile MGL and KM remained stable for up to 24 months for the CG and TG. The mean PD was 2.05 +/- 0.66 mm for the CG and 1.99 +/- 0.57 mm for the TG. Differences that were not statistically significant were reported between the CG and TG over time and between time points. CONCLUSION: At the 24-month follow-up, endosseous implants placed immediately in extraction sites affected by periapical infection rendered an equally favorable soft and hard tissue integration of the implants, revealing a predictable outcome. PMID- 20192866 TI - Polymorphisms and haplotypes in the interleukin-4 gene are associated with chronic periodontitis in a Brazilian population. AB - BACKGROUND: Some haplotypes in the interleukin-4 (IL4) gene were reported to influence IL-4 cytokine production and were associated with inflammatory diseases. Association studies focusing on IL4 gene polymorphisms and periodontal disease provided conflicting results. The aim of this study is to investigate whether IL4 gene polymorphisms and haplotypes were related to chronic periodontitis in a Brazilian population. METHODS: The polymorphisms -590(C/T) and +33(C/T) in the IL4 gene were identified by polymerase chain reaction (PCR) and restriction fragment-length polymorphism methods; the variable number of tandem repeats (VNTR) was identified by PCR. To assess the differences between the periodontitis group (n = 125) and control group (n = 125), the chi(2) test was used to assess genotype and allele distributions of individual polymorphisms. For haplotypes reconstructed by an expectation-maximization algorithm, the CLUMP program and Fisher exact test were used. Multivariate logistic regression modeling was used to assess the association of age, gender, smoking status, and polymorphism/haplotype with periodontitis. RESULTS: The -590(T), +33(C), and insertion (I) of 70-base pair (bp) alleles and genotypes were more prevalent in the periodontitis group, even after adjusting for covariates. The -590, +33, and insertion (TCI) haplotype was associated with a susceptibility to periodontitis (adjusted odds ratio [OR(adjusted)] = 2.68; 95% confidence interval [CI] = 1.50 to 4.80) as was the genotype TCI/CCI (OR(adjusted) = 5.27; 95% CI = 2.28 to 12.18), whereas the TTD (OR(adjusted) = 0.48; 95% CI = 0.26 to 0.91), CTI (OR(adjusted) = 0.28, 95% CI = 0.11 to 0.70), and TTD/CTI (OR(adjusted) = 0.29; 95% CI = 0.08 to 1.13) genotypes were a associated with protection against the development of chronic periodontitis. CONCLUSION: Significant associations between alleles, genotypes, and haplotypes of polymorphisms in the IL4 gene and chronic periodontitis were verified in Brazilian individuals. PMID- 20192865 TI - Salivary interleukin-6, matrix metalloproteinase-8, and osteoprotegerin in patients with periodontitis and diabetes. AB - BACKGROUND: Diabetes and periodontitis produce a protein discharge that can be reflected in saliva. This study evaluates the salivary concentrations of interleukin (IL)-6, matrix metalloproteinase (MMP)-8, and osteoprotegerin (OPG) in patients with periodontitis with type 2 diabetes. METHODS: Whole saliva samples were obtained from 90 subjects who were divided into four groups: healthy (control; n = 22), untreated periodontitis (UPD; n = 24), diabetes mellitus (DM; n = 20), and UPD + DM (n = 24) groups. Clinical and metabolic data were recorded. Salivary IL-6, MMP-8, and OPG concentrations were determined by a standard enzyme linked immunosorbent assay. RESULTS: The UPD and UPD + DM groups exhibited higher salivary IL-6 than the control and DM groups (P <0.01). The salivary MMP-8 concentrations in all diseased groups (UPD, DM, and UPD + DM) were higher than in the control group (P <0.01). The salivary OPG concentrations in the DM group were higher than in the UPD and control groups (P <0.05). In the UPD + DM group, salivary IL-6 was correlated with glycated hemoglobin (HbA1c) levels (r = 0.60; P <0.05). The regression analysis indicated that the number of remaining teeth, clinical attachment level, and IL-6 might have influenced the HbA1c levels in patients with diabetes. CONCLUSIONS: Salivary IL-6 concentrations were elevated in patients with periodontitis with or without diabetes. Salivary MMP-8 and OPG concentrations were elevated regardless of periodontal inflammation in patients with diabetes. Therefore, periodontitis and diabetes are conditions that may interfere with protein expression and should be considered when using saliva for diagnoses. PMID- 20192867 TI - The microbiota associated with implants restored with platform switching: a preliminary report. AB - BACKGROUND: It was demonstrated that implants restored according to a platform switching concept presented less crestal bone loss than implants restored with standard protocols. The aim of this study is to examine differences between the composition of the peri-implant microbiotas associated with implants restored with the platform-switching approach and implants restored with a standard internal connection protocol. METHODS: A total of 48 implants were examined in 18 subjects: 33 implants were restored with platform switching, and 15 implants were restored using the traditional approach. Thirty-six months after prosthetic loading, subgingival plaque samples were taken from the mesio- and disto-buccal aspects of each implant and from one tooth adjacent to one of the implants in each subject. The levels of 40 subgingival species were measured using checkerboard DNA-DNA hybridization. Microbiologic parameters were averaged within each subject and across subjects in each clinical group (platform switching versus control) and site category (implants versus teeth) separately. The significance of differences between clinical groups and site categories was determined using the Mann-Whitney test and the Wilcoxon test, respectively. RESULTS: There were no statistically significant differences between groups for any of the species. The platform-switching group showed a small trend for lower levels of early colonizer members of the Actinomyces, purple and yellow complexes, Campylobacter species, Tannerella forsythia (previously T. forsythensis), and Porphyromonas gingivalis. Teeth and implants presented similar microbial profiles. CONCLUSION: The results of the study suggest that the difference in bone crest resorption between implants restored with platform switching compared to traditionally restored implants is not associated with differences in the peri-implant microbiota. PMID- 20192868 TI - The effect of metformin on alveolar bone in ligature-induced periodontitis in rats: a pilot study. AB - BACKGROUND: The use of metformin, an antidiabetic agent, is associated with a reduced risk of fractures in patients with diabetes, suggesting that metformin exerts a beneficial effect on bone tissues. The objective of this study was to assess the effect of metformin on alveolar bone loss in ligature-induced periodontitis and osteoblast, osteoclast, and adipocyte differentiation. METHODS: Periodontitis was induced by a ligature around the mandibular first molar of each rat. The rats were divided into two groups: 1) rats with ligature receiving a vehicle (n = 5), and 2) rats with ligature receiving metformin (n = 5). On day 10, after the induction of periodontitis, the alveolar bone volume between the first and second molar was determined via microcomputed tomography. The effect of metformin on osteoblast, osteoclast, and adipocyte differentiation was assessed using MC3T3-E1, cocultures of mouse bone marrow cells and calvaria-derived osteoblasts, and 3T3-L1/C3H10T1/2 cells, respectively. Osteoblast, osteoclast, and adipocyte differentiation was estimated by the degree of mineralization, the formation of tartrate-resistant acid phosphatase-positive multinucleated cells, and the accumulation of triglycerides, respectively. RESULTS: In ligature-induced periodontitis, the metformin treatment of rats induced a significant reduction in alveolar bone loss compared to vehicle-treated rats. With regard to osteoblast differentiation, metformin augmented the mineralization of MC3T3-E1 cells approximately two-fold over the non-treated cells. However, metformin was shown to exert no effects on osteoclast formation induced by 1,25-dihydroxyvitamin D(3), lipopolysaccharide, and prostaglandin E(2). Moreover, metformin exerted no effect on adipocyte differentiation. CONCLUSION: Our findings suggest that metformin may exert a beneficial effect on alveolar bone in periodontitis by increasing osteoblast differentiation. PMID- 20192869 TI - Human periosteum-derived cells combined with superporous hydroxyapatite blocks used as an osteogenic bone substitute for periodontal regenerative therapy: an animal implantation study using nude mice. AB - BACKGROUND: A superporous (85%) hydroxyapatite (HA) block was recently developed to improve osteoconductivity, but it was often not clinically successful when used to treat periodontal osseous defects. The primary purpose of this study is to develop a clinically applicable tissue-engineered bone substitute using this HA block and human alveolar periosteum-derived cells. METHODS: Commercially available superporous HA blocks were acid treated and subjected to a three dimensional (3D) culture for periosteal cell cultivation. Cells in the pore regions of the treated HA block were observed on the fracture surface by scanning electron microscopy. After osteogenic induction, the cell-HA complexes were implanted subcutaneously in nude mice. Osteoid formation was histologically evaluated. RESULTS: Acid treatment enlarged the interconnections among pores, resulting in the deep penetration of periosteal cells. Under these conditions, cells were maintained for >2 weeks without appreciable cell death in the deep pore regions of the HA block. The cell-HA complexes that received in vitro osteogenic induction formed osteoids in pore regions of the treated HA blocks in vivo. In contrast, most pore regions in the non-pretreated, cell-free HA blocks that were evaluated in vivo remained cell free. CONCLUSIONS: Our findings suggest that an acid-treated HA block could function as a better scaffold for the 3D high density culture of human periosteal cells in vitro, and this cell-HA complex had significant osteogenic potential at the site of implantation in vivo. Compared with the cell-free HA block, our cell-HA complex using periosteal cells, which are the most accessible for clinical periodontists, showed promising results as a bone substitute in periodontal regenerative therapy. PMID- 20192870 TI - Crestal bone changes around implants with reduced abutment diameter placed non submerged and at subcrestal positions: a 1-year radiographic evaluation. AB - BACKGROUND: There is limited information about two-part implants placed in subcrestal positions. The aim of this study is to retrospectively evaluate the 1 year outcome of implants placed non-submerged and in a subcrestal position. METHODS: Records of 50 consecutive partially edentulous patients restored with dental implants were reviewed. For each implant, radiographs from the surgical appointment were compared to those from the 1-year follow-up visit and evaluated regarding: 1) the degree of subcrestal positioning of the implant, 2) changes of marginal hard tissue height over time, and 3) if the marginal hard tissue could be detected on the implant platform at the follow-up visit. RESULTS: The overall survival rate from baseline to the last recorded follow-up visit was 100%. At the surgery, the implants were placed, on average, 1.37 mm (mesial) and 1.28 mm (distal) subcrestally. The mean marginal loss of hard tissues was 0.11 +/- 0.30 mm. There were no statistical significant differences regarding the loss of marginal hard tissues between mesial and distal surfaces or the maxilla versus the mandible. There was no statistical significant correlation regarding the degree of subcrestal implant position and loss of marginal mineralized hard tissue (r = 0.15; P >0.05). The mineralized hard tissue on the implant shoulder was found in 69% of the implants at the 1-year follow-up visit. CONCLUSIONS: The present study reported a minimal loss of mineralized hard tissue around dental implants placed non-submerged and at subcrestal positions. In addition, these implants had hard tissue healing that extended onto the implant shoulders on most of the observed implants. PMID- 20192871 TI - Prospective assessment of the use of enamel matrix derivative with minimally invasive surgery: 6-year results. AB - BACKGROUND: Minimally invasive surgery (MIS) is a surgical technique using very small incisions indicated for performing regenerative therapy in periodontal defects. The 11-month results from a prospective study of MIS were previously published. This article presents the 6-year results of that prospective study. METHODS: Patients from two private periodontal practices with advanced periodontitis who, after non-surgical therapy, had one or more sites with probing depths >or=6 mm were included in the study. An MIS surgical approach was used for all sites >or=6 mm. After surgical debridement, enamel matrix derivative (EMD) was placed into the bony defect. The surgical sites were reevaluated after >or=6 years. RESULTS: Six-year data were available on 142 sites in 13 patients. No significant differences were noted in the results between the two offices, and the data were combined. Probing depths (mean: 3.18 mm; SD: 0.59 mm) and attachment levels (mean: 3.93 mm; SD: 0.19) at 6 years were unchanged from the 11 month measurements. No recession from preoperative levels was noted. All sites continued to be considered clinically successful. CONCLUSIONS: The combination of MIS and EMD yielded significant reductions in probing depths and improvements in attachment levels while producing no detectable recession. The 11-month results remained stable at 6 years. PMID- 20192872 TI - Buccal bifurcation cyst in a 7-year-old: surgical management and 14-month follow up. AB - BACKGROUND: The buccal bifurcation cyst (BBC) is a paradental cyst that typically presents on the buccal aspect of mandibular permanent first molars in children 6 to 11 years of age. Histopathologic features are non-specific and closely resemble other inflammatory odontogenic cysts. The aim of this article is to report a case of a BBC and to review the management of such lesions. METHODS: A 7 year-old white male, complaining of lower right tooth pain and swelling, presented to the Nationwide Children's Hospital Dental Clinic. A clinical examination revealed no caries and swelling localized to the area approximating tooth #30 with a 15-mm probing depth on the buccal aspect. Radiographs revealed a radiolucency involving the bifurcation and root area of tooth #30, accompanied by the distal displacement of unerupted tooth #31. Therapy consisted of a simple surgical enucleation of the cyst. RESULTS: A microscopic evaluation revealed a chronically inflamed cyst lined by a non-keratinized stratified squamous epithelium. The immediate postoperative course was uneventful. At 14 months postoperatively, the development of teeth #30 and #31 was noted as normal. Probing depths around tooth #30 were 95% of recording time) adaptive noise-reduction benefit for generic implementations is below 1.2 dB, and 96% and 92% is below 2 dB for 16 and 32-band individualized implementations, respectively. A 256-band, individualized implementation showed a majority of benefit between 1-4 dB. We found no extended (> 2 s) continuous periods of significant (> 2 dB) benefit for the generic adaptive implementations. The recordings-having many independent and simultaneously active sources, spatially extended sources, significant reverberation, or combinations thereof-indicate an environment comprising few instances of high direct-to-diffuse energy situations. Combined with results from previous field trials, the evidence suggests that such an environment is common and represents a significant limitation on adaptive benefit. PMID- 20192875 TI - Otoacoustic emissions in a hearing conservation program: general applicability in longitudinal monitoring and the relation to changes in pure-tone thresholds. AB - The hearing status of workers (N = 233) in a printing office was assessed twice within seventeen months by pure-tone audiometry and otoacoustic emissions (OAEs). One of the questions was how a quality criterion of OAE-measurements based on a minimum signal-to-noise-ratio (SNR) would affect the applicability on the entire population. Secondly, effects of noise exposure were investigated in overall changes in audiogram and OAE-measurements. For TEOAEs (transient evoked OAEs) in the frequency band of 4 kHz, only 55% of the data points meet the SNR-inclusion criterion. For DPOAEs (distortion product OAEs) around 6 kHz approximately 80% of the data points satisfy the criterion. Thus OAEs have a limited applicability for monitoring the hearing status of this entire population. Audiometry shows significant deteriorations at 6 and 8 kHz. TEOAEs show a significant decline at all frequency bands (1-4 kHz), DPOAEs between 4 and 8 kHz and less pronounced between 1 and 2 kHz. On group level, OAEs show a decline in a larger frequency region than the audiogram, suggesting an increased sensitivity of OAEs compared to audiometry. PMID- 20192876 TI - Self-assessed auditory symptoms, noise exposure, and measured auditory function among healthy young Swedish men. AB - The aim of the study was to estimate the prevalence of the exposure to ototraumatic factors and auditory symptoms, and to analyse the relations between these factors in a group of young healthy men. A total of 839 men, 19-22 years old, were recruited for the study when reporting for primary military service. A questionnaire was distributed and audiometry was performed. The prevalence of tinnitus, sensitivity to noise, and measured hearing impairment in the study group was 23.2%, 15.5%, and 14.5% respectively. Exposure to occupational noise often was reported by 21.4%, and playing loud music often by 16.5%. The young men who had experienced tinnitus after noise exposure had an elevated risk of high frequency hearing impairment, tinnitus, and sensitivity to noise. Those who played loud music had elevated prevalence values of tinnitus but not of hearing impairment. In this young group we observed high prevalence values of ototraumatic factors and auditory symptoms. We also observed significant correlations between tinnitus after noise exposure, self-assessed hearing symptoms, and hearing impairment. PMID- 20192877 TI - Trends in survival of patients diagnosed with cancers of the brain and nervous system, thyroid, eye, bone, and soft tissues in the Nordic countries 1964-2003 followed up until the end of 2006. AB - BACKGROUND: Diagnoses of cancer of the brain, thyroid, eye, bone, and soft tissues are categorised by heterogeneity in disease frequency, survival, aetiology and prospects for curative therapy. In this paper, temporal trends in patient survival in the Nordic countries are considered. MATERIAL AND METHODS: Age-standardised incidence and mortality rates, 5-year relative survival, and excess mortality rates for varying follow-up periods are presented, as are age specific 5-year relative survival by country, sex and 5-year diagnostic period. RESULTS: Brain cancer incidence rates have been rising but mortality has been relatively stable, with 5-year survival uniformly increasing from the early 1970s, particularly in younger patients. Five-year survival from brain cancer among men varies between 45% and 50% for men and 60% to 70% in women, with excess deaths decreasing with time in each of the Nordic populations. Age-standardised incidence rates of thyroid cancer have been mainly increasing during the 1960s and 1970s, although trends thereafter diverge, with 5-year relative survival increasing 20-30 percentage points over the last 40 years to around 80-90%. Thyroid cancer survival is consistently lower in Denmark, particularly in patients diagnosed aged over 60, while there is less geographic variation in excess deaths three months beyond initial diagnosis. Relative survival from eye cancer increased with time from approximately 60% in 1964-1968 to 80% 1999-2003, while for bone sarcoma, incidence rates remained stable, mortality rates declined, and 5-year survival increased slightly to around 55-65%. Soft tissue sarcoma incidence and survival have been slowly increasing since the 1960s, with little variation in survival (around 65%) for the most recent period. CONCLUSIONS: There have been some notable changes in survival that can be linked to epidemiological and clinical factors in different countries over time. Time varying proportions of the major histological subtypes might however have affected the survival estimates for a number of the cancer forms reviewed here. PMID- 20192879 TI - UGT2B17 and SULT1A1 gene copy number variation (CNV) detection by LabChip microfluidic technology. AB - BACKGROUND: Gene copy number variations (CNVs) are increasingly recognized to play important roles in the expression of genes and hence on their respective enzymatic activities. This has been demonstrated for a number of drug metabolizing genes, such as UDP-glucuronosyltransferases 2B17 (UGT2B17) and sulfotransferase 1A1 (SULT1A1), which are subject to genetic heterogeneity, including CNV. Quantitative assays to assess gene copy number are therefore becoming an integral part of accurate genotype assessment and phenotype prediction. METHODS: In this study, we evaluated a microfluidics-based system, the Bio-Rad Experion system, to determine the power and utility of this platform to detect UGT2B17 and SULT1A1 CNV in DNA samples derived from blood and tissue. UGT2B17 is known to present with 0, 1 or 2 and SULT1A1 with up to 5 gene copies. RESULTS: Distinct clustering (p<0.001) into copy number groups was achieved for both genes. DNA samples derived from blood exhibited less inter-run variability compared to DNA samples obtained from liver tissue. This variability may be caused by tissue-specific PCR inhibitors as it could be overcome by using DNA from another tissue, or after the DNA had undergone whole genome amplification. CONCLUSIONS: This method produced results comparable to those reported for other quantitative test platforms. PMID- 20192878 TI - Datamining approaches for modeling tumor control probability. AB - BACKGROUND: Tumor control probability (TCP) to radiotherapy is determined by complex interactions between tumor biology, tumor microenvironment, radiation dosimetry, and patient-related variables. The complexity of these heterogeneous variable interactions constitutes a challenge for building predictive models for routine clinical practice. We describe a datamining framework that can unravel the higher order relationships among dosimetric dose-volume prognostic variables, interrogate various radiobiological processes, and generalize to unseen data before when applied prospectively. MATERIAL AND METHODS: Several datamining approaches are discussed that include dose-volume metrics, equivalent uniform dose, mechanistic Poisson model, and model building methods using statistical regression and machine learning techniques. Institutional datasets of non-small cell lung cancer (NSCLC) patients are used to demonstrate these methods. The performance of the different methods was evaluated using bivariate Spearman rank correlations (rs). Over-fitting was controlled via resampling methods. RESULTS: Using a dataset of 56 patients with primary NCSLC tumors and 23 candidate variables, we estimated GTV volume and V75 to be the best model parameters for predicting TCP using statistical resampling and a logistic model. Using these variables, the support vector machine (SVM) kernel method provided superior performance for TCP prediction with an rs=0.68 on leave-one-out testing compared to logistic regression (rs=0.4), Poisson-based TCP (rs=0.33), and cell kill equivalent uniform dose model (rs=0.17). CONCLUSIONS: The prediction of treatment response can be improved by utilizing datamining approaches, which are able to unravel important non-linear complex interactions among model variables and have the capacity to predict on unseen data for prospective clinical applications. PMID- 20192880 TI - Intralipid causes falsely increased glucose concentrations with the Hemocue glucose analyzer. PMID- 20192881 TI - Decision criteria for rational selection of homogeneous genotyping platforms for pharmacogenomics testing in clinical diagnostics. AB - BACKGROUND: Genotyping is crucial for the identification of genetic markers underlying the development of neoplastic diseases and for determining individual variations in response to specific drugs. Technologies which can accurately identify genetic polymorphisms will dramatically affect routine diagnostic processes and future therapeutic developments in personalized medicine. However, such methods need to fulfill the principles of analytical validation to determine their suitability to assess nucleotide polymorphisms in target genes. APPROACH: This article reviews recent developments in homogeneous technologies for the genotyping of single nucleotide polymorphisms. Here, homogeneous methods essentially refer to "single-tube" assays performed in a liquid phase. For the appropriate choice of any method, several criteria must be considered: 1) detection of known genetic variations; 2) analytical performance including specificity, sensitivity and robustness of the method; 3) availability of large platforms and required equipment; 4) suitability of platforms and tests for routine diagnostics; 5) suitability for high throughput implementation. CONTENT: This review is intended to provide the reader with an understanding of these various technologies for pharmacogenomic testing in the routine clinical laboratory. A brief overview is provided on the available technologies for the detection of known mutations, a specific description of the homogeneous platforms currently employed in genotyping analysis, and considerations regarding the proper assessment of the analytical performance of these methods. Based on the criteria proposed here, potential users may evaluate advantages and limitations of the various analytical platforms and identify the most appropriate platform according to their specific setting and diagnostic needs. PMID- 20192882 TI - Methodological weakness in using correlation coefficients for assessing the interchangeability of analyte data between samples collected under different sampling conditions--the example of matrix metalloproteinase 9 determined in serum and plasma samples. PMID- 20192884 TI - Quality control of vital capacity as a primary outcome measure during phase III therapeutic clinical trial in amyotrophic lateral sclerosis. AB - Currently, ALS clinical trials require large sample size and the participation of many clinical evaluators to perform the outcome measure. High variability due to testers, instruments, or patients performance errors may result in systematic bias or random error leading to erroneous or uninterpretable results. Consequently, a quality control system that aims to produce high quality data in terms of reproducibility and accuracy to ensure reliability of the primary outcome measure is essential. In this paper we report our experience in preparing and executing a prospective quality control system that was implemented in conjunction with a large multicenter, multinational randomized placebo-controlled phase III clinical trial in ALS. We have shown that a prospective quality control system is highly effective to ensure inter- and intra-rater reliability of vital capacity as a primary outcome measure during the entire trial. PMID- 20192883 TI - Measuring life quality, physical function and psychological well-being in neurological illness. AB - There is little in the literature comparing experiences of patients with disabling and uniformly terminal illness (e.g. amyotrophic lateral sclerosis) and illness characterized by episodic disability and prognostic uncertainty (e.g. multiple sclerosis). This study aimed to compare experiences of disability, quality of life (QoL) and psychological well-being in ALS and MS. One hundred patients with ALS and MS were interviewed at baseline and at six months. Variables measured included function, health related QoL, individualized QoL and psychological distress. Despite the divergent illness experiences of ALS and MS patients, groups did not differ on individualized QoL or mental well-being, and distress was in the normal range. Despite marked deterioration in ALS patients' health, there was no change in mental well-being and QoL. Psychological well being appeared more important in maintaining QoL (individualized QoL and mental aspects of health related QoL) than physical factors. At the individual level, there was evidence of psychological adaptation to deteriorating function, which underlined the role of specific illness related challenges in determining perceived life quality and emotional well-being. In conclusion, the complex interplay between psychosocial and illness specific factors such as certainty with regard to prognosis has considerable implications for well-being and life quality. Recognizing such factors is essential when designing clinical interventions to promote adjustment and self-management among patients with neurological conditions. PMID- 20192885 TI - Roaring in the ears: patulous Eustachian tube in bulbar amyotrophic lateral sclerosis. AB - We report a 64-year-old female with predominantly bulbar amyotrophic lateral sclerosis who experienced 'roaring' in her ears. She was diagnosed with patulous Eustachian tube, which is presumed to occur secondary to bulbar weakness. The roaring adversely affected the management of her ALS by impairing her ability to tolerate BiPaP. A review of the relevant literature is reported. PMID- 20192886 TI - G127R: A novel SOD1 mutation associated with rapidly evolving ALS and severe pain syndrome. AB - We describe a patient with apparently sporadic amyotrophic lateral sclerosis (SALS) with a novel g > c point mutation at position 382 in the SOD1 gene, leading to a substitution of glycine for arginine in amino acid position 127 (G127R). The disease presented with flaccid leg paresis, and progressed rapidly with generalized paresis resulting in respiratory failure after seven months. In addition to a predominating lower motor neuron syndrome, the phenotype was characterized by a severe lower back and leg pain syndrome which was treated successfully with spinal anaesthesia. PMID- 20192887 TI - Detection of ureaplasmas by the polymerase chain reaction in the amniotic fluid of patients with cervical insufficiency. AB - AIMS: The purpose of this study was to determine the clinical significance of detecting microbial footprints of ureaplasmas in amniotic fluid (AF) using specific primers for the polymerase chain reaction (PCR) in patients presenting with cervical insufficiency. METHODS: Amniocentesis was performed in 58 patients with acute cervical insufficiency (cervical dilatation, > or =1.5 cm) and intact membranes, and without regular contractions (gestational age, 16-29 weeks). AF was cultured for aerobic and anaerobic bacteria as well as genital mycoplasmas. Ureaplasmas (Ureaplasma urealyticum and Ureaplasma parvum) were detected by PCR using specific primers. Patients were divided into three groups according to the results of AF culture and PCR for ureaplasmas: those with a negative AF culture and a negative PCR (n=44), those with a negative AF culture and a positive PCR (n=10), and those with a positive AF culture regardless of PCR result (n=4). RESULTS: 1) Ureaplasmas were detected by PCR in 19.0% (11/58) of patients, by culture in 5.2% (3/58), and by culture and/or PCR in 22.4% (13/58); 2) Among the 11 patients with a positive PCR for ureaplasmas, the AF culture was negative in 91% (10/11); 3) Patients with a negative AF culture and a positive PCR for ureaplasmas had a significantly higher median AF matrix metalloproteinase-8 (MMP 8) concentration and white blood cell (WBC) count than those with a negative AF culture and a negative PCR (P<0.001 and P<0.05, respectively); 4) Patients with a positive PCR for ureaplasmas but a negative AF culture had a higher rate of spontaneous preterm birth within two weeks of amniocentesis than those with a negative AF culture and a negative PCR (P<0.05 after adjusting for gestational age at amnio-centesis); 5) Of the patients who delivered within two weeks of amniocentesis, those with a positive PCR for ureaplasmas and a negative AF culture had higher rates of histologic amnionitis and funisitis than those with a negative AF culture and a negative PCR (P<0.05 after adjusting for gestational age at amniocentesis, for each); 6) However, no significant differences in the intensity of the intra-amniotic inflammatory response and perinatal outcome were found between patients with a positive AF culture and those with a negative AF culture and a positive PCR. CONCLUSIONS: 1) Cultivation techniques for ureaplasmas did not detect most cases of intra-amniotic infection caused by these microorganisms (91% of cases with cervical insufficiency and microbial footprints for ureaplasmas in the amniotic cavity had a negative AF culture); 2) Patients with a negative AF culture and a positive PCR assay were at risk for intra amniotic and fetal inflammation as well as spontaneous preterm birth. PMID- 20192888 TI - Establishing a European research agenda on 'gut feelings' in general practice. A qualitative study using the nominal group technique. AB - OBJECTIVE: Although 'gut feelings' are perceived as playing a substantial role in the diagnostic reasoning of the general practitioner (GP), there is little evidence about their diagnostic and prognostic value. Consensus on both types of 'gut feelings' (a 'sense of alarm', a 'sense of reassurance') has enabled us to operationalize the concept. As a next step we wanted to identify research questions that are considered relevant to validate the concept of 'gut feelings' and to estimate its usefulness for daily practice and medical education. Moreover, we were interested in the study designs considered appropriate to study these research questions. METHODS: The nominal group technique (NGT) is a qualitative research method of judgmental decision-making involving four phases: generating ideas, recording them, evaluation and prioritization. Dutch and Belgian academics whose subject is general practice (n = 18), attended one of three meetings during which NGT was used to produce a 'research agenda' on 'gut feelings'. RESULTS: NGT yielded ten research questions and nine corresponding appropriate designs on four topics, i.e. the diagnostic value of 'gut feelings', the validation of its determinants, the opportunities for integrating 'gut feelings' in medical education and a rest group. The study designs respectively included recording and follow-up of 'gut feelings', video recording of consultations with stimulated recall using simulated and real patients respectively, analysing trainees' consultation stories and videos, linguistic analyses, and vignette studies. Furthermore, two experimental designs were proposed. CONCLUSION: A European research agenda on 'gut feelings' in general practice has been established and could be used in collaborative research. PMID- 20192889 TI - False-positive serum and bronchoalveolar lavage Aspergillus galactomannan assays caused by different antibiotics. AB - Our objective was to identify false-positive serum and bronchoalveolar lavage (BAL) fluid galactomannan (GM) tests caused by various antibiotics commonly used in general practice. Serum and BAL samples from patients who did not have the diagnostic criteria of invasive aspergillosis and received different antibiotics were prospectively analyzed for GM. Serum and BAL samples were also collected from patients who did not receive antibiotics. At the cut-off index of >or=0.5, false-positive serum results were found in patients who received amoxicillin clavulanate, piperacillin-tazobactam, cefepime, and cefoperazone-sulbactam (26.7%, 58.3%, 14.3%, and 66.7%, respectively). Fungal colonization in BAL samples had a higher BAL GM than those without fungal colonization. In 71 patients who had a negative BAL culture for fungi, at the cut-off value of >or=1.0, false-positive BAL fluid results were found in patients who received amoxicillin-clavulanate (27.3%), piperacillin-tazobactam (50%), cefepime (16.7%), carbapenem (45.5%), and ceftriaxone (45.5%). False-positive serum and BAL GM assays were also detected in patients who did not receive any antibiotics. In summary, this study demonstrates the false-positive GM levels in serum and BAL caused by beta-lactam antibiotics that are commonly used in general practice. Physicians should be aware of this possible interference. PMID- 20192890 TI - Usefulness of natriuretic peptides in primary health care: an exploratory study in elderly patients. AB - OBJECTIVE: To explore the negative predictive value (NPV), positive predictive value (PPV), sensitivity, and specificity of natriuretic peptides, cut-off levels, and the impact of gender and age in elderly patients with systolic heart failure (HF). DESIGN: Cross-sectional exploratory study. SETTING: One primary healthcare centre. PATIENTS: A total of 109 patients with symptoms of HF were referred for echocardiographic examination with a cardiovascular consultation. Systolic HF was diagnosed (ESC guidelines) in 48 patients (46% men, 54% women, mean age 79 years) while 61 patients (21% men, 79% women, mean age 76 years) had no HF. MAIN OUTCOME MEASURES: NPV, PPV, sensitivity, specificity, and cut-off levels. RESULTS: Including all 109 patients, NPV was 88% for NT-proBNP (200 ng/L) and 87% for BNP (20 pg/ml). PPV was 81% for NT-proBNP (500 ng/L) and 68% for BNP (50 pg/ml). Sensitivity was 96% for NT-proBNP (100 ng/L) and 96% for BNP (10-20 pg/ml). Specificity was 87% for NT-proBNP (500 ng/L) and 71% for BNP (50 pg/ml). Nt-proBNP (beta = 0.035; p < 0.001) and BNP (beta = 0.030; p < 0.001) were associated with age, but not with gender. In a multivariate analysis age (beta = 0.036; p < 0.001) and male gender (beta = 0.270; p = 0.014) were associated with NT-proBNP, but only age for BNP (beta = 0.030; p < 0.001). CONCLUSION: Natriuretic peptides in an elderly population showed high NPVs, but not as high as in younger patients with HF in other studies. Age and male gender were associated with higher levels of NT-proBNP while only age was related to elevated BNP levels. PMID- 20192891 TI - Suicidality among Norwegian youth: review of research on risk factors and interventions. AB - BACKGROUND AND AIM: Published research on suicidality among Norwegian youth and publications describing interventions were summarized in order to access the current status of knowledge building via empirical research. METHOD: A systematic Medline search identified 29 studies on risk factors on the entire spectrum of suicidal phenomena from self-harm without suicidal ideation to completed suicide with the mean age at/under 25 years. A specialist Norwegian journal, Suicidologi, was searched for additional matter, especially interventions. RESULT: Most studies focussed on psychological and psychiatric risk factors of attempted suicide. Other suicidal phenomena, psychosocial and societal risk factors, and impact of interventions were hardly studied. Depression, previous suicidal behaviour, alcohol use and non-intact parental unit were consistent significant risk factors found in suicide and attempted suicide studies. CONCLUSION: Supporting non-intact parental units and the maintenance of intact parental units along with early detection and management of suicide attempts, depression and alcohol use should be targeted as suicide prevention interventions among adolescents. PMID- 20192892 TI - The Autism--Tics, AD/HD and other Comorbidities (A-TAC) telephone interview: convergence with the Child Behavior Checklist (CBCL). AB - OBJECTIVE: To compare telephone interview screening for child psychiatric/neuropsychiatric disorders using the inventory of Autism-Tics, Attention deficit/hyperactivity disorder (AD/HD) and other Comorbidities (A-TAC) with results from the Child Behavior Checklist (CBCL). BACKGROUND: The A-TAC is a parent telephone interview focusing on autism spectrum disorders (ASDs) and co existing problems, developed for lay interviewers. SUBJECTS AND METHODS: A-TAC telephone interviews and CBCL questionnaires were obtained from parents of 106 Swedish twin pairs aged 9 and 12 years. RESULTS: Correlations between A-TAC modules and CBCL scales aimed at measuring similar concepts were generally significant albeit modest, with correlation coefficients ranging from 0.30 through 0.55. CONCLUSION: The A-TAC has convergent validity with the CBCL in several problem areas, but the A-TAC also provides more detailed and specific assessments of ASD symptoms and related neuropsychiatric problems. PMID- 20192893 TI - Contrast medium nephrotoxicity after renal artery and coronary angioplasty. AB - BACKGROUND: Renal dysfunction induced by iodinated contrast medium (CM) administration can minimize the benefit of the interventional procedure in patients undergoing renal angioplasty (PTRA). PURPOSE: To compare the susceptibility to nephrotoxic effect of CM in patients undergoing PTRA with that of patients submitted to percutaneous coronary intervention (PCI). MATERIAL AND METHODS: A total of 33 patients successfully treated with PTRA (PTRA group, mean age 70+/-12 years, 23 female, basal creatinine 1.46+/-0.79, range 0.7-4.9 mg/dl) were compared with 33 patients undergoing successful PCI (PCI group), matched for basal creatinine (1.44+/-0.6, range 0.7-3.4 mg/dl), gender, and age. In both groups postprocedural (48 h) serum creatinine was measured. RESULTS: Postprocedural creatinine level decreased nonsignificantly in the PTRA group (1.46+/-0.8 vs. 1.34+/-0.5 mg/dl, P=NS) and increased significantly in the PCI group (1.44+/-0.6 vs. 1.57+/-0.7 mg/dl, P<0.02). Changes in serum creatinine after intervention (after-before) were significantly different between the PTRA and PCI groups (-0.12+/-0.5 vs. 0.13+/-0.3, P=0.014). This difference was not related to either a different clinical risk profile or to the volume of CM administered. CONCLUSION: In this preliminary study patients submitted to PTRA showed a lower susceptibility to renal damage induced by CM administration than PCI patients. The effectiveness of PTRA on renal function seems to be barely influenced by CM toxicity. PMID- 20192894 TI - Response to article "Proton magnetic resonance spectroscopy in the distinction of high-grade cerebral gliomas from single metastatic brain tumors". PMID- 20192895 TI - Voxel-specific brain arterial input functions from dynamic susceptibility contrast MRI and blind deconvolution in a group of healthy males. AB - BACKGROUND: Arterial input functions may differ between brain regions due to delay and dispersion effects in the vascular supply network. Unless corrected for, these differences may degrade quantitative estimations of cerebral blood flow in dynamic susceptibility contrast magnetic resonance perfusion imaging (DSC MRI). PURPOSE: To investigate in a healthy population (n=44) the properties of voxel-specific arterial input functions that were obtained using a recently published blind estimation approach. MATERIAL AND METHODS: The voxel-specific arterial input functions were qualitatively and quantitatively assessed, through visual inspection or by comparing time-to-peak (delays) and peak amplitude (dispersion) values between eight regions of the brain. Furthermore, they were compared to arterial input functions selected manually in the middle cerebral artery (MCA), where normally no delay or dispersion of the contrast agent was expected. RESULTS: The estimated voxel-specific arterial input functions varied between brain regions. Differences in delays and dispersion were larger within one brain region among all participants than between regions in one participant. A good correlation was typically found between the estimated voxel-specific arterial input functions and the manually selected arterial input functions in the MCA region. CONCLUSION: Given knowledge of neurovascular anatomy, the current blind approach seemingly produced reasonable estimates of voxel-specific arterial input functions. In addition to potentially reducing quantification errors in DSC MRI, these user-independent voxel-specific arterial input functions could be useful for visualizing abnormal blood supply patterns in patients. PMID- 20192896 TI - Effect of sodium thiosulfate on cisplatin removal after intra-arterial embolization with a lipiodol-platinum suspension for hepatocellular carcinoma. AB - BACKGROUND: Cisplatin is one of the most effective chemotherapeutic agents against a variety of human cancers. Its usefulness is limited by its toxicity to normal tissues, including cells of kidney proximal tubules. PURPOSE: To evaluate the effect of sodium thiosulfate (STS) on cisplatin clearance after transcatheter embolization (TAE) with a lipiodol-platinum suspension (LPS) in patients with hepatocellular carcinoma (HCC). MATERIAL AND METHODS: The study was performed prospectively in a randomized manner. HCC patients underwent intra-arterial LPS embolization with (n=17) and without (n=15) an intravenous STS infusion. Renal toxicity was estimated and free and total platinum concentrations were assessed for 7 days after treatment. RESULTS: After treatment without STS, there was a mild elevation of serum creatinine and a decrease in creatinine clearance. With STS, there was no significant difference before and after treatment in mean serum creatinine and creatinine clearance; free platinum disappeared completely within 120 min. In patients treated without STS, free platinum decreased rapidly within 120 min; this was followed by a gradual decrease during the next 7 days. CONCLUSION: STS seems effective against the renal toxicity of cisplatin. However, in the presence of STS, the anticancer effect of cisplatin may be decreased due to the accelerated disappearance of platinum. PMID- 20192897 TI - Response to article: Adolescent idiopathic scoliosis may not be associated with brain abnormalities. PMID- 20192898 TI - Overweight and obesity negatively affect the outcomes of ovarian stimulation and in vitro fertilisation: a cohort study of 2628 Chinese women. AB - OBJECTIVE: To explore the effects of overweight and obesity on the outcomes of in vitro fertilisation (IVF) in Chinese infertile patients. STUDY DESIGN: A retrospective cohort study was carried out in 2222 normal weight (18.5 or= 30) women who underwent their first IVF cycles between 2002 and 2008. Cycle characteristics and IVF outcomes were analysed. RESULTS: Obese women required significantly higher dose of rFSH (3272 IU vs. 2587 IU, p < 0.001) and days of stimulation (11.89 +/- 4.57 vs. 10.42 +/- 2.03, p < 0.001), but exhibited less oocytes retrieved and significantly lower fertilisation rate (54.1% vs. 61.1%, p < 0.001) than normal weight women. Compared with normal weight women, overweight women displayed significantly less oocytes retrieved (12.98 +/- 6.91 vs. 14.49 +/- 7.96, p < 0.001), lower fertilisation rate (60.8 +/- 23.3 vs. 61.1 +/- 23.0, p < 0.001), less cleavaged embryos (7.55 +/- 4.86 vs. 8.67 +/- 5.90, p < 0.001), less high grade embryos (4.65 +/- 3.96 vs. 5.59 +/- 4.81, p < 0.001) and cryopreserved embryos (4.44 +/- 4.55 vs. 5.49 +/- 5.55, p < 0.001). All parameters of pregnancy outcomes, including pregnancy rate, miscarriage rate and live birth rate, were comparable among three groups. CONCLUSIONS: Overweight and obesity are related with impared ovarian response, and negatively affect the outcomes of IVF. PMID- 20192899 TI - Review of clinical experience with the frameless LNG-IUS for contraception and treatment of heavy menstrual bleeding. AB - OBJECTIVE: Review the clinical experience with the frameless FibroPlant levonorgestrel intrauterine system (FP-LNG-IUS). STUDY DESIGN: An open, prospective non-comparative contraceptive 5-year study; a 1-year MBL study in women with heavy menstrual bleeding (HMB), using a PBAC and a 2-year MBL study in women with HMB and with normal menstruation using the quantitative alkaline hematin method. A literature review on perforation rate with the frameless GyneFix and FibroPlant. RESULTS: 304 insertions were performed with the FP-LNG IUS. The total observation period was 11,299 woman-months. Only one pregnancy occurred. There were two expulsions and two uterine perforations at insertion during the first year. In the first 1-year MBL study, the median MBL decreased by more than 90%. In the second 2-year MBL study, MBL reduced drastically and 80% had amenorrhoea after 24 months. The ferritin values increased significantly. On a total of approximately 17,000 insertions, the perforation rate was between 1.2 and 2.0/1000 insertions. CONCLUSION: The frameless FP-LNG-IUS is an effective and well-tolerated long-acting reversible contraceptive and is also highly effective for the treatment of HMB. The perforation rate is similar to traditional copper and levonorgestrel-releasing intrauterine devices and systems. Strict adherence to the manufacturer's insertion instructions is recommended. PMID- 20192901 TI - In situ collagen polymerization of layered cell-seeded electrospun scaffolds for bone tissue engineering applications. AB - Electrospun scaffolds have been studied extensively for their potential use in bone tissue engineering applications. However, inherent issues with the electrospinning approach limit the thickness of these scaffolds and constrain their use for repair of critical-sized bone defects. One method to increase overall scaffold thickness is to bond multiple electrospun scaffolds together with a biocompatible gel. The objective of this study was to determine whether multiple human adipose-derived stem cell (hASC-seeded electrospun, nanofibrous scaffolds could be layered via in situ collagen assembly and whether the addition of laser-ablated micron-sized pores within the electrospun scaffold layers was beneficial to the bonding process. Pores were created by a laser ablation technique. We hypothesized that the addition of micron-sized pores within the electrospun scaffolds would encourage collagen integration between scaffold layers, and promote osteogenic differentiation of hASCs seeded within the layered electrospun scaffolds. To evaluate the benefit of assembled scaffolds with and without engineered pores, hASCs were seeded on individual electrospun scaffolds, hASC-seeded scaffolds were bonded with type I collagen, and the assembled ~3-mm thick constructs were cultured for 3 weeks to examine their potential as bone tissue engineering scaffolds. Assembled electrospun scaffolds/collagen gel constructs using electrospun scaffolds with pores resulted in enhanced hASC viability, proliferation, and mineralization of the scaffolds after 3 weeks in vitro compared to constructs using electrospun scaffolds without pores. Scanning electron microscopy and histological examination revealed that the assembled constructs that included laser-ablated electrospun scaffolds were able to maintain a contracted structure and were not delaminated, unlike assembled constructs containing nonablated electrospun scaffolds. This is the first study to show that the introduction of engineered pores in electrospun scaffolds assists with multilayered scaffold integration, resulting in thick constructs potentially suitable for use as scaffolds for bone tissue engineering or repair of critical bone defects. PMID- 20192902 TI - Oxime K027: novel low-toxic candidate for the universal reactivator of nerve agent- and pesticide-inhibited acetylcholinesterase. AB - Oxime K027 is a low-toxic bisquaternary compound originally developed as a reactivator of acetylcholinesterase (AChE) inhibited by nerve agents. The reactivation potency of K027 has been tested as a potential reactivator of AChE inhibited by tabun, sarin, cyclosarin, soman, VX, Russian VX, paraoxon, methylchlorpyrifos, and DDVP. The results show that oxime K027 reactivated AChE inhibited by almost all tested inhibitors to more than 10%, which is believed to be enough for saving the lives of intoxicated organisms. In the case of cyclosarin- and soman-inhibited AChE, oxime K027 did not reach sufficient reactivation potency. PMID- 20192904 TI - Diiodothyropropionic acid: WO2008106213. AB - The patent application WO2008106213 describes the beneficial effects of thyroid hormone analogue 3,5 diiodothyropropionic acid (DITPA) such as stimulating weight loss in overweight mammals, lowering of triglyceride and treating metabolic syndrome in humans. The human population of the patients selected in the studies mentioned has a body mass index > 25. Two examples of the human clinical studies employing DITPA have been mentioned, namely, the body weight reduction and improvement in metabolic abnormalities in obese adults. PMID- 20192905 TI - Non-erythropoietic tissue-protective peptides derived from erythropoietin: WO2009094172. AB - Erythropoietin (EPO) is a cytokine with erythropoietic and tissue protective activities. Its action as a tissue protective agent requires, however, high dosage that results in limiting side effects associated with abnormally augmented erythropoiesis. Elimination of the erythropoietic activity of EPO while preserving its tissue protective properties was nevertheless achieved in carbamoylated EPO (CEPO), whose therapeutic activity and apparent safety were documented in experimental models of nervous, heart, kidney and other tissue damage, justifying ongoing clinical trials. Here, we review patent application WO2009094172 by Araim Pharmaceuticals, which describes novel EPO-derived peptides having tissue protective but no erythropoietic activity. The preferred peptide, UEQLERALNSS, which mimics the external 3D structure of the helix B of EPO, was shown to exhibit the same spectrum of tissue protective activity as CEPO in several in vivo models. In addition, it could reduce radiation-induced mortality when administered 24 h after irradiation in mice, suggesting its possible utility in emergency situations after mass irradiation casualties. Owing to their low manufacturing cost, high stability and low immunogenicity, such peptides might well offer a superior alternative to CEPO for therapeutic tissue protection in human pathologies and are likely to provide valuable probes to study the molecular mechanisms of EPO-mediated cytoprotection. PMID- 20192906 TI - Our place in nature: reconnecting with the Earth. PMID- 20192903 TI - Overview of extracellular microvesicles in drug metabolism. AB - IMPORTANCE OF THE FIELD: Liver is the major body reservoir for enzymes involved in the metabolism of endogenous and xenobiotic compounds. Recently, it has been shown that hepatocytes release exosome-like vesicles to the extracellular medium, and the proteomic characterization of these hepatocyte-secreted exosomes has revealed the presence of several of these enzymes on them. AREAS COVERED IN THIS REVIEW: A systematic bibliographic search focused on two related aspects: i) xenobiotic-metabolizing enzymes that have been detected in microvesicles (MVs); and ii) MVs that are in the blood stream or secreted by cell types with clear interactions with this fluid. WHAT THE READER WILL GAIN: A discussion of these hepatocyte-secreted vesicles along with other MVs as enzymatic carriers in the context of extrahepatic drug-metabolizing systems. TAKE HOME MESSAGE: The contribution of many tissues including the liver to the MV plasma population is supported by several reports. On the other hand, many enzymes involved in the metabolism of drugs have been detected in MVs. Together, these observations support a role of hepatic-MVs in spreading the liver metabolizing activities through the body contributing in this manner to extrahepatic drug metabolism systems what could be relevant for body homeostasis and pharmaceutical interests. PMID- 20192900 TI - Drug delivery by red blood cells: vascular carriers designed by mother nature. AB - IMPORTANCE OF THE FIELD: Vascular delivery of several classes of therapeutic agents may benefit from carriage by red blood cells (RBC), for example, drugs that require delivery into phagocytic cells and those that must act within the vascular lumen. The fact that several protocols of infusion of RBC-encapsulated drugs are now being explored in patients illustrates a high biomedical importance for the field. AREAS COVERED BY THIS REVIEW: Two strategies for RBC drug delivery are discussed: encapsulation into isolated RBC ex vivo followed by infusion in compatible recipients and coupling therapeutics to the surface of RBC. Studies of pharmacokinetics and effects in animal models and in human studies of diverse therapeutic enzymes, antibiotics and other drugs encapsulated in RBC are described and critically analyzed. Coupling to RBC surface of compounds regulating immune response and complement, affinity ligands, polyethylene glycol alleviating immune response to donor RBC and fibrinolytic plasminogen activators are described. Also described is a new, translation-prone approach for RBC drug delivery by injection of therapeutics conjugated with fragments of antibodies providing safe anchoring of cargoes to circulating RBC, without need for ex vivo modification and infusion of RBC. WHAT THE READER WILL GAIN: Readers will gain historical perspective, current status, challenges and perspectives of medical applications of RBC for drug delivery. TAKE HOME MESSAGE: RBC represent naturally designed carriers for intravascular drug delivery, characterized by unique longevity in the bloodstream, biocompatibility and safe physiological mechanisms for metabolism. New approaches for encapsulating drugs into RBC and coupling to RBC surface provide promising avenues for safe and widely useful improvement of drug delivery in the vascular system. PMID- 20192907 TI - A randomized study of the effects of t'ai chi on muscle strength, bone mineral density, and fear of falling in women with osteoarthritis. AB - PURPOSE: Individuals with osteoarthritis can experience difficulty walking and poor strength, possibly leading to falls and fractures. Exercise has been found to increase strength and bone mineral density. The purpose of this study was to determine the effects of 6 months of t'ai chi on knee muscle strength, bone mineral density, and fear of falling in older women with osteoarthritis. METHODS: Eighty-two (82) women with osteoarthritis, recruited from outpatient clinics and community health centers, were randomly assigned to either a t'ai chi group and took part in a t'ai chi program, or a control group. Of these, 30 subjects (mean age = 63 years) in the t'ai chi group and 35 (mean age = 61 years) in the control group completed post-test measures at 6 months. RESULTS: After the 6-month study period, subjects in the t'ai chi program had significantly greater knee extensor endurance (pre- to post-test mean increase = 36.4 W/kg, versus 1.1 W/kg for the controls), and significantly greater bone mineral density in the neck of the proximal femur (mean change = 0.09, versus -0.10 for the controls), Ward's triangle (mean change = 0.04, versus -0.04 for the controls), and trochanter (mean change = 0.07, versus -0.05 for the controls) than the controls. However, knee extensor and flexor strength did not differ significantly between the groups. The fear of falling during daily activities reduced significantly more in the t'ai chi group (mean change = -2.40, versus 0.66 for the controls). CONCLUSIONS: T'ai chi increased knee extensor muscle endurance and bone mineral density in older women with osteoarthritis, and decreased their fear of falling during daily activities. Further study with long-term follow-up is needed to substantiate the role of t'ai chi exercise in the prevention of fall and its related fracture. PMID- 20192908 TI - Alternative medical interventions used in the treatment and management of myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia. AB - BACKGROUND: There have been several systematic reviews attempting to evaluate the efficacy of possible treatments for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM). However, information regarding the efficacy of complementary and alternative medicine (CAM) has not been comprehensively or systematically covered in these reviews, despite its frequent use in the patient community. PURPOSE: The purpose of this study was to systematically review and evaluate the current literature related to alternative and complementary treatments for ME/CFS and FM. It should be stressed that the treatments evaluated in this review do not reflect the clinical approach used by most practitioners to treat these illnesses, which include a mix of natural and unconventionally used medications and natural hormones tailored to each individual case. However, nearly all clinical research has focused on the utility of single CAM interventions, and thus is the primary focus of this review. METHODS: Several databases (e.g., PubMed, MEDLINE,((R)) PsychInfo) were systematically searched for randomized and nonrandomized controlled trials of alternative treatments and nonpharmacological supplements. Included studies were checked for references and several experts were contacted for referred articles. Two leading subspecialty journals were also searched by hand. Data were then extracted from included studies and quality assessments were conducted using the Jadad scale. RESULTS: Upon completion of the literature search and the exclusion of studies not meeting criterion, a total of 70 controlled clinical trials were included in the review. Sixty (60) of the 70 studies found at least one positive effect of the intervention (86%), and 52 studies also found improvement in an illness-specific symptom (74%). The methodological quality of reporting was generally poor. CONCLUSIONS: Several types of alternative medicine have some potential for future clinical research. However, due to methodological inconsistencies across studies and the small body of evidence, no firm conclusions can be made at this time. Regarding alternative treatments, acupuncture and several types of meditative practice show the most promise for future scientific investigation. Likewise, magnesium, l-carnitine, and S adenosylmethionine are nonpharmacological supplements with the most potential for further research. Individualized treatment plans that involve several pharmacological agents and natural remedies appear promising as well. PMID- 20192909 TI - Perceived treatment effectiveness, medication compliance, and complementary and alternative medicine use among veterans with bipolar disorder. AB - OBJECTIVES: Recent research shows a high rate of complementary and alternative medicine (CAM) use among persons with mental disorders, although correlates and patterns of CAM use are relatively unknown. This study tested whether CAM use is associated with perceived effectiveness of conventional treatment (i.e., psychotropic medication and psychotherapy) and medication compliance among persons with bipolar disorder. DESIGN: Patients with bipolar disorder (n = 435) were included as part of a naturalistic cohort study. Measures of CAM utilization, medication compliance, and perceptions of the effectiveness of psychotropic medications and psychotherapy were based on previously established questionnaires. Associations were tested using bivariate and multivariate analyses. RESULTS: Bivariate analyses showed that patients who did not perceive psychotherapy as effective at improving social, family, or job functioning reported greater CAM use. However, medication compliance was not significantly associated with use of CAM. Patients who used oral (e.g., herbal therapies) or cognitive (e.g., meditation) CAM were more likely to report that their medications were not effective at relieving manic or depressive symptoms. Users of cognitive CAM were more likely to report that their medications did not help with social, job, or family functioning, and that they did not prevent recurrences of manic or depressive episodes. None of the bivariate associations remained significant in multivariate analyses. CONCLUSIONS: Prior research has suggested that persons who are dissatisfied with treatment for medical conditions are more likely to use CAM therapies. However, the results of this study do not show CAM therapies to be associated with perceived effectiveness of treatments for mental health problems among this sample of persons with serious mental illnesses. This suggests that motivations for CAM use may vary by population and condition. Because few correlates of CAM use among persons with serious mental illnesses are known, providers should conduct routine assessments of CAM use. PMID- 20192910 TI - A new bioimpedance research device (BIRD) for measuring the electrical impedance of acupuncture meridians. AB - OBJECTIVES: The aim of this article is to introduce an electrical bioimpedance device that uses an old and little-known impedance measuring technique to study the impedance of the meridian and nonmeridian tissue segments. DESIGN: Three (3) pilot experimental studies involving both a tissue phantom (a cucumber) and 3 human subjects were performed using this BIRD-I (Bioimpedance Research Device) device. This device consists of a Fluke RCL meter, a multiplexer box, a laptop computer, and a medical-grade isolation transformer. Segment and surface sheath (or local) impedances were estimated using formulae first published in the 1930s, in an approach that differs from that of the standard four-electrode technique used in most meridian studies to date. RESULTS: Our study found that, when using a quasilinear four-electrode arrangement, the reference electrodes should be positioned at least 10 cm from the test electrodes to ensure that the segment (or core) impedance estimation is not affected by the proximity of the reference electrodes. A tissue phantom was used to determine the repeatability of segment (core) impedance measurement by the device. An applied frequency of 100 kHz was found to produce the best repeatability among the various frequencies tested. In another preliminary study, with a segment of the triple energizer meridian on the lower arm selected as reference segment, core resistance-based profiles around the lower arm showed three of the other five meridians to exist as local resistance minima relative to neighboring nonmeridian segments. The profiles of the 2 subjects tested were very similar, suggesting that the results are unlikely to be spurious. CONCLUSIONS: In electrical bioimpedance studies, it is recommended that the measuring technique and device be clearly defined and standardized to provide optimal working conditions. In our study using the BIRD I device, we defined our standard experimental conditions as a test frequency of 100 kHz and the position of the reference electrodes of at least 10 cm from the test electrodes. Our device has demonstrated potential for use in quantifying the degree of electrical interconnection between any two surface-defined test meridian or nonmeridian segments. Issues arising from use of this device and the measurement Horton and van Ravenswaay technique were also presented. PMID- 20192912 TI - Methodological considerations for future controlled influenza treatment trials in complementary and alternative medicine. AB - BACKGROUND: The continuous threat of influenza pandemic, as well as the ongoing costs to human life and health care systems from yearly epidemics, create a continual need for progress in this area of public health. The diversity of available complementary and alternative medicine (CAM) treatment options are well known to the CAM profession, but poorly understood and accepted in mainstream medicine. This situation comes as no surprise given conventional medicine's reliance on repeated, large-scale randomized controlled trials of standardized design to support evidence-based clinical use of influenza antiviral drugs. The relatively low volume of well-conducted clinical trials on the treatment of influenza with CAM therapies compared to the high availability of conventional antiviral drug trials magnifies this problem. OBJECTIVES: The aim of this article is to provide structured guidelines for future CAM influenza studies based on a thorough review of consistent and standard design elements present in the controlled-trial design of conventional antiviral influenza therapies. RESULTS: A selection of high-quality, influenza antiviral controlled trials from the published literature is reviewed, and important design elements are extracted and summarized to show both the consistency and the flexibility within study design elements. CONCLUSIONS: The standardized elements from influenza antiviral trials can be considered and mirrored in future CAM studies. In this way, CAM therapies might be looked at on similar grounds as conventional medicines in terms of potential usefulness and benefit in the treatment of influenza. PMID- 20192911 TI - Pilot study on the effect of grounding on delayed-onset muscle soreness. AB - OBJECTIVES: The purpose of this pilot study was to determine whether there are markers that can be used to study the effects of grounding on delayed-onset muscle soreness (DOMS). DESIGN AND SUBJECTS: Eight (8) healthy subjects were exposed to an eccentric exercise that caused DOMS in gastrocnemius muscles of both legs. Four (4) subjects were grounded with electrode patches and patented conductive sheets connected to the earth. Four (4) control subjects were treated identically, except that the grounding systems were not connected to the earth. OUTCOME MEASURES: Complete blood counts, blood chemistry, enzyme chemistry, serum and saliva cortisols, magnetic resonance imaging and spectroscopy and pain levels were taken at the same time of day before the eccentric exercise and 24, 48, and 72 hours afterwards. Parameters consistently differing by 10% or more, normalized to baseline, were considered worthy of further study. RESULTS: Parameters that differed by these criteria included white blood cell counts, bilirubin, creatine kinase, phosphocreatine/inorganic phosphate ratios, glycerolphosphorylcholine, phosphorylcholine, the visual analogue pain scale, and pressure measurements on the right gastrocnemius. CONCLUSIONS: In a pilot study, grounding the body to the earth alters measures of immune system activity and pain. Since this is the first intervention that appears to speed recovery from DOMS, the pilot provides a basis for a larger study. PMID- 20192913 TI - Antifungal activity of propolis extract against yeasts isolated from vaginal exudates. AB - OBJECTIVE: The objective of this study was to evaluate the in vitro antifungal activity of propolis extract against yeasts Candida albicans and Candida non albicans isolated from vaginal exudates, in comparison with nystatin. DESIGN: Ninety-seven (97) vaginal yeasts strains were evaluated. These strains were obtained from different clinical conditions, isolated and stored at the Sector of Medical Mycology of the State University of Maringa (Parana, Brazil). The assays of susceptibility to nystatin and propolis extracts (PE) were conducted through microdilution in broth (National Committee for Clinical Laboratory Standards NCCLS, M-27A Document of 1997). RESULTS: All the yeasts tested were inhibited by low concentrations of PE (maximum of 393.19 mug/mL of the total flavonoid content), including an isolate resistant to nystatin, regardless of the clinical conditions of the women and the species of yeast isolated. CONCLUSIONS: The PE showed an outstanding performance against the tested vaginal yeast strains, and could be included among the novel therapeutic options for the treatment of vulvovaginal candidiasis. PMID- 20192915 TI - Traditional chinese medicine: an update on clinical evidence. AB - BACKGROUND: As an alternative medical system, Traditional Chinese Medicine (TCM) has been increasingly used over the last several decades. Such a consumer-driven development has resulted in introduction of education programs for practitioner training, development of product and practitioner regulation systems, and generation of an increasing interest in research. Significant efforts have been made in validating the quality, effectiveness, and safety of TCM interventions evidenced by a growing number of published trials and systematic reviews. Commonly, the results of these studies were inconclusive due to the lack of quality and quantity of the trials to answer specific and answerable clinical questions. OBJECTIVES: The methodology of a randomized clinical trial (RCT) is not free from bias, and the unique features of TCM (such as individualization and holism) further complicate effective execution of RCTs in TCM therapies. Thus, data from limited RCTs and systematic reviews need to be interpreted with great caution. Nevertheless, until new and specific methodology is developed that can adequately address these methodology challenges for RCTs in TCM, evidence from quality RCTs and systematic reviews still holds the credibility of TCM in the scientific community. CONCLUSIONS: This article summarizes studies on TCM utilization, and regulatory and educational development with a focus on updating the TCM clinical evidence from RCTs and systematic reviews over the last decade. The key issues and challenges associated with evidence-based TCM developments are also explored. PMID- 20192914 TI - A pilot study of chromium picolinate for weight loss. AB - BACKGROUND: Chromium is an essential trace element and nutritional supplement that has garnered interest for use as a weight loss aid. OBJECTIVE: This trial assesses the effects of chromium picolinate supplementation, alone and combined with nutritional education, on weight loss in apparently healthy overweight adults. DESIGN: This was a randomized, double-blind, placebo-controlled trial of 80 otherwise healthy, overweight adults assessed at baseline for central adiposity measured by computerized tomography. Subjects were randomly assigned to daily ingestion of 1000 microg of chromium picolinate or placebo for 24 weeks. All subjects received passive nutritional education at the 12-week point in both the intervention and control groups. Outcomes include weight, height, blood pressure, percent body fat, serum, and urinary biomarkers. RESULTS: At baseline, both the chromium and placebo groups had similar mean body mass index (BMI) (chromium = 36 +/- 6.7 kg/m(2) versus placebo = 36.1 +/- 7.6 kg/m(2); p = 0.98). After 12 weeks, no change was seen in BMI in the intervention as compared to placebo (chromium = 0.3 +/- 0.8 kg/m(2) versus placebo = 0.0 +/- 0.4 kg/m(2); p = 0.07). No change was seen in BMI after 24 weeks in the intervention as compared to placebo (chromium = 0.1 +/- 0.2 kg/m(2) versus placebo = 0.0 +/- 0.5 kg/m(2); p = 0.81). Variation in central adiposity did not affect any outcome measures. CONCLUSIONS: Supplementation of 1000 microg of chromium picolinate alone, and in combination with nutritional education, did not affect weight loss in this population of overweight adults. Response to chromium did not vary with central adiposity. PMID- 20192916 TI - The determination and fidelity level of medicinal plants used to make traditional Turkish salves. AB - OBJECTIVE: This study has been done in order to identify plants that were used to make traditional Turkish salves between 2007 and 2008. MATERIALS AND METHODS: During the step of identification of plants, the informants from different cities of Turkey were asked questions about the salves they have made and which plants and materials they have used. In this study, a total of 105 people from 21 provinces (N = 5 each province) were interviewed. Information was gathered through scientifically guided questionnaires, interviews, and general conversations, and fidelity level (FL) of species was determined. RESULTS: According to the results of the identification, 68 plants are being used to make Traditional Turkish Salves for medicinal purposes in Turkey. Among them, 61 plants are wild and 7 plants are cultivated plants. Most used families were Asteraceae, Apiaceae, Lamiaceae, Liliaceae, and Rosaceae. Urtica dioica (100%) has the highest FL and Lawsonia inermis (33%) has the lowest. CONCLUSIONS: The data provided from our informants and analyzed in the present article clearly show that folk knowledge on medicinal plants and plant uses is still alive in the studied region. PMID- 20192917 TI - Salmonella spp. and hygiene indicator microorganisms in chicken carcasses obtained at different processing stages in two slaughterhouses. AB - Chicken meat is considered an important vehicle of foodborne pathogens such as Salmonella spp., demanding an effective control of its contamination during industrial processing. This study aimed to investigate the presence of Salmonella spp. and microbiological indicators at different stages of processing in two slaughterhouses (Sh1, high-capacity; Sh2, low-capacity). Surface samples of chicken carcasses were collected in the following sequential stages: (A) immediately before evisceration, (B) after evisceration, (C) after showering, and (D) after chiller. All samples were submitted for detection of Salmonella spp. and enumeration of mesophilic aerobes, total coliforms, thermotolerant coliforms, and Escherichia coli. The obtained means and frequencies were compared by analysis of variance and chi-square tests (p < 0.05), considering different slaughterhouses and stages of processing. No significant differences were observed between the frequencies of Salmonella spp. obtained at different steps in Sh1 and Sh2 (p > 0.05). Sh2 showed higher levels of microbiological contamination when compared with Sh1 for mesophilic aerobes (in stages B and D), total coliforms and thermotolerant coliforms (stage D), and E. coli (all stages) (p < 0.05). The variation in the levels of contamination by microbiological indicators over the processing indicated the significance of different control procedures adopted by slaughterhouses for the microbiological quality of chicken carcasses. PMID- 20192918 TI - Recent advances in understanding the roles of transglutaminase 2 in alcoholic steatohepatitis. AB - Tissue TG (transglutaminase) or TG2 is the most ubiquitously expressed member of the large TG family that catalyses deamidation of a glutamine residue, formation of an N epsilon(gamma-glutamyl)-lysine cross-linking between lysine and glutamine residues and/or covalent incorporation of polyamines into a glutamine residue, exerting a number of physiological and/or pathological functions. Extracellular TG2 contributes to wound healing and exacerbation of liver fibrosis through a role in extracellular matrix assembly and cell adhesion. Intracellular TG2 acts as a GTPase in normal cells when the intracellular Ca2+ concentration is as low as 10-20 nM, participating in the transmembrane signalling of phospholipase C delta as a component of alpha1-adrenergic receptor complexes, and thereby supporting the growth of hepatic cells. When cells are injured and the intracellular Ca2+ concentration rises to more than 700-800 nM, TG2 dramatically alters its structure and transforms into a cross-linking enzyme. TG2 primarily exists in the cytosol in normal cells, but is distributed among multiple intracellular milieus during tissue injury or apoptosis. In particular, TG2 has been shown to be abundant in the nuclei of cells undergoing apoptosis, although its role in the nucleus and the underlying mechanisms remain unresolved. Recently, three findings in the study of alcoholic steatohepatitis have shed light on these issues. Omary's group disclosed that TG2-mediated cross-linking of keratin 8 is essential for the formation of Mallory-Denk bodies. We have demonstrated that in both mouse models of alcoholic steatohepatitis and human patients with alcoholic steatohepatitis, TG2 translocates into the nucleus and provokes hepatocyte death via cross-linking and inactivation of a transcription factor, Sp1, leading to down-regulation of the hepatocyte growth factor receptor, c-Met. Furthermore, Giebeler et al. has reported that down-regulation of c-Met is associated with liver fibrosis. In the present review article, we introduce these recent advances in knowledge with regard to the the roles of TG2 in alcoholic steatohepatitis. PMID- 20192919 TI - Cell cycle distribution, cellular viability and mRNA expression of hGCase-gene transfected cells in dairy goat. AB - Nuclear transfer using transgenic donor cells is an efficient way of generating transgenic goats, wherein the preparation of competent transgenic donor cells is the pivotal upstream step. We have measured the efficiency of transfection with a plasmid containing hGCase (human lysosomal acid beta-glucosidase) gene into goat FFC (fetal-derived fibroblast cells), MEC (mammary epithelial cells) and AEFC (adult ear skin-derived fibroblast cells), and the characteristics of cell cycle, apoptosis and chromosome abnormalities after transfection. The expression of genes involved in imprinting [IGF2 (insulin-like growth factor 2), IGF2R (IGF2 receptor)], apoptosis (Bax), stress (heat-shock protein, Hsp70.1), cellular connections [Cx43 (connexin 43)] and DNA methylation [DNMT1 (DNA methyltransferase 1)] in transgenic fetal cells has been investigated. The hGCase transgene was successfully detected in the transfected cell lines, and chromosomal stability remained similar in FFC and transgenic FFC (70.9 compared with 66.8%), whereas a smaller percentage (P<0.05) of cells at G(0)/G(1) in the transgenic FFC, MEC and AEFC (T-FFC, T-MEC and T-AEFC), and higher percentage (P<0.05) of apoptotic cells in T-FFC than the non-transfected controls were detected by flow cytometric analysis. Among the genes tested, the relative expressions of IGF2, IGF2R and transcripts of Cx43 were significantly higher (P<0.05) in T-FFC compared with non-transfected FFC. These novel findings on gene expression in transgenic fetal cells may have certain implications in the biopharming industry and in our understanding the low efficiency of transgenic cloning. PMID- 20192920 TI - The DNA-binding activity of mouse DNA methyltransferase 1 is regulated by phosphorylation with casein kinase 1delta/epsilon. AB - Dnmt1 (DNA methyltansferase 1) is an enzyme that recognizes and methylates hemimethylated DNA during DNA replication to maintain methylation patterns. The N terminal region of Dnmt1 is known to form an independent domain structure that interacts with various regulatory proteins and DNA. In the present study, we investigated protein kinases in the mouse brain that could bind and phosphorylate the N-terminal regulatory domain of Dnmt1. A protein fraction containing protein kinase activity for phosphorylation of Dnmt1(1-290) was prepared using Dnmt1(1 290)-affinity, DNA-cellulose and gel-filtration columns. When the proteins in this fraction were analysed by LC-MS/MS (liquid chromatography tandem MS), CK1delta/epsilon (casein kinase 1delta/epsilon) was the only protein kinase identified. Recombinant CK1delta/epsilon was found to bind to the N-terminal domain of Dnmt1 and significantly phosphorylated this domain, especially in the presence of DNA. Phosphorylation analyses using various truncation and point mutants of Dnmt1 revealed that the major priming site phosphorylated by CK1delta/epsilon was Ser146, and that subsequent phosphorylation at other sites may occur after phosphorylation of the priming site. When the DNA-binding activity of phosphorylated Dnmt1 was compared with that of the non-phosphorylated form, phosphorylation of Dnmt1 was found to decrease the affinity for DNA. These results suggest that CK1delta/epsilon binds to and phosphorylates the N-terminal domain of Dnmt1 and regulates Dnmt1 function by reducing the DNA-binding activity. PMID- 20192921 TI - VDAC1 cysteine residues: topology and function in channel activity and apoptosis. AB - The VDAC (voltage-dependent anion channel) is proposed to control metabolic cross talk between mitochondria and the cytosol, as well as apoptotic cell death. It has been suggested that apoptosis is modulated by the oxidation state of VDAC. Since cysteine residues are the major target for oxidation/reduction, we verified whether one or both VDAC1 cysteine residues are involved in VDAC1-mediated transport or apoptosis activities. To assess the function of VDAC1 cysteine residues in channel activity and to probe cysteine topology with respect to facing the pore or the bilayer, we used thiol-modifying agents, namely membrane permeable NEM (N-ethylmaleimide), bulky charged 5-FM (fluorescein-5-maleimide) and the cross-linking reagent BMOE [bis(maleimido)ethane]. Bilayer-reconstituted VDAC conductance was decreased by 5-FM, but not by NEM, whereas 5-FM had no effect on NEM-labelled VDAC conductance. BMOE caused the formation of dimeric VDAC1, suggesting that one of the two VDAC1 cysteine residues is exposed and available for cross-linking. The results thus suggest that one of the VDAC1 cysteine residues faces the VDAC pore, whereas the second is oriented towards the lipid bilayer. Mutated rat VDAC1 in which the two cysteine residues, Cys127 and Cys232, were replaced by alanine residues showed channel activity like native VDAC1 and, when expressed in cells, was localized to mitochondria. Human VDAC1 shRNA (small hairpin RNA)- or -siRNA (small interfering RNA)-treated cells, expressing low levels of endogenous human VDAC1 together with native or cysteine less rat VDAC1, undergo apoptosis as induced by overexpression of these VDAC1 or upon treatment with reactive oxygen species-producing agents, H2O2, As2O3 or selenite, suggesting that the two cysteine residues are not required for apoptosis or VDAC1 oligomerization. PMID- 20192922 TI - The vasoactive peptides urotensin II and urotensin II-related peptide regulate astrocyte activity through common and distinct mechanisms: involvement in cell proliferation. AB - UII (urotensin II) and its paralogue URP (UII-related peptide) are two vasoactive neuropeptides whose respective central actions are currently unknown. In the present study, we have compared the mechanism of action of URP and UII on cultured astrocytes. Competition experiments performed with [125I]UII showed the presence of very-high- and high-affinity binding sites for UII, and a single high affinity site for URP. Both UII and URP provoked a membrane depolarization accompanied by a decrease in input resistance, stimulated the release of endozepines, neuropeptides specifically produced by astroglial cells, and generated an increase in [Ca2+]c (cytosolic Ca2+ concentration). The UII/URP induced [Ca2+]c elevation was PTX (pertussis toxin)-insensitive, and was blocked by the PLC (phospholipase C) inhibitor U73122 or the InsP3 channel blocker 2-APB (2-aminoethoxydiphenylborane). The addition of the Ca2+ chelator EGTA reduced the peak and abolished the plateau phase, whereas the T-type Ca2+ channel blocker mibefradil totally inhibited the Ca2+ response evoked by both peptides. However, URP and UII induced a mono- and bi-phasic dose-dependent increase in [Ca2+]c and provoked short- and long-lasting Ca2+ mobilization respectively. Similar mono- and bi-phasic dose-dependent increases in [3H]inositol incorporation into polyphosphoinositides in astrocytes was obtained, but the effect of UII was significantly reduced by PTX, although BRET (bioluminescence resonance energy transfer) experiments revealed that both UII and URP recruited Galphao-protein. Finally, UII, but not URP, exerted a dose-dependent mitogenic activity on astrocytes. Therefore we described that URP and UII exert not only similar, but also divergent actions on astrocyte activity, with UII exhibiting a broader range of activities at physiological peptide concentrations. PMID- 20192923 TI - Chromogranin A detection in saliva of type 2 diabetes patients. AB - Chromogranin A is present in secretion granules of nerve, endocrine and immune cells and is a precursor of several peptides with antibacterial and antifungal properties at micromolar concentrations.Our aim in this prospective, double blind study, was to determine the expression of chromogranin A and its peptides at protein level in saliva of type 2 diabetic patients and thereby to obtain a new non-invasive diagnostic means for the future.Saliva was taken from 30 type 2 diabetic patients and 30 healthy individuals at the same time interval in the morning without any oral stimuli. Circadianic periodics in protein productions have been avoided. The presence of chromogranin A and its derived peptides was determined in whole saliva, after centrifugation at 40C for 12 min at 14 000 rpm, by SDS-PAGE electrophoresis and Immunoblotting (Western Blot). To ensure same protein concentrations Bradford protein quantification assay has been performed before.For the first time, we have determined an overexpression of chromogranin A in saliva of diabetic patients in 100% of the individuals. Chromogranin A, a circulating biomarker for epithelial tumours, is also overexpressed in saliva of type 2 diabetic patients. To confirm our results, more studies with a large amount of patients is necessary. PMID- 20192925 TI - Investigation of vascularization of human pancreas using method of selective arteriography with insight into significance to a surgical approach for this organ. AB - This study explored arterial vascularisation of celiac trunk and superior mesenteric artery using method of selective arteriography in series of arteriogram which were done in 39 patients of Institute for Radiology. There were no pathological findings in a single case at pancreas or duodenum. Arteries which arise for vascularization of pancreas had a common spot of arising, flow and ramification. Pancreatic duodenal arteries arcade, which supply blood to the duodenum and the body of the pancreas, were shown in arteriogram. The branches which provide blood supply to the body and the tail of the pancreas were found. There was one case where lower pancreatic artery arose from gastroduodenal artery and in one case a direct anastomosis for celiac trunk and superior mesenteric arteries, better known as Tandler's anastomosis. PMID- 20192924 TI - Correlation between serum biochemical markers and early amniocentesis in diagnosis of congenital fetal anomalies. AB - A combined test performed at the 12th week of gestation enables us to classify the pregnancy as high risk (risk higher than 1:300) or low risk (risk lower than 1:300) for congenital foetal anomalies, with great accuracy of 85 - 90%. According to the available data, the frequency of false positive results is estimated at around 5%. The objective of the study was to examine possible correlation between the serum marker values and amniocentesis results in prenatal diagnostics of congenital foetal anomalies. The study included 745 pregnant women monitored by the Genetic Counselling Service of the Clinic of Gynaecology and Obstetrics of the Clinics Centre Kragujevac. The subjects were included in the study under condition that CRL (embryonic crown-rump length) was from 45 to 84 mm and that the gestational age was at 11-13+6 weeks. Free beta HCG and PAPP-A were determined from venous blood using commercial DPS-USA tests. Tests were based on the analytic principle of the immuno-chemiluminescence technique and were performed by application of the automatic Immulite 2000 analyzer by DPC-USA. The foetal nuchal translucency thickness (NT) and CRL were measured by Colour Doppler. The chromosome identification was performed after a certain number of cell divisions by stopping the cell division in metaphase of mitosis when the chromosomes were the most distinguishable. The foetal karyotype was prepared using G bands. In the total sample of pregnant women (n=745), there were six cases of pathological foetal karyotype. A statistical paradox in the frequency of congenital foetal anomalies in favour of younger population was noticed. A high coefficient of Spearman's rank correlation suggests great importance of the combined test in the detection of congenital foetal anomalies (p<0,05). A high consistency was also proved for components of biochemical screening and ultrasonographic markers. The combined test, as a method of prenatal screening in the first trimester of pregnancy, if used at 11 - 13+6 weeks' gestation and for CRL of 45-84 mm, has a great importance in the detection of congenital foetal anomalies. PMID- 20192926 TI - Lipoprotein (a) as an acute phase reactant in patients on chronic hemodialysis. AB - Lipoprotein (a) [Lp(a)], is an independent risk factor for atherosclerotic cardiovascular disease in patients on chronic hemodialysis. A low concentration of high density lipoprotein cholesterol (HDL-C) and serum albumin are another potential risk factors. The purpose of this study was to explore in patients on chronic hemodialysis, whether Lp(a) elevated levels are influenced by activated acute phase response (APR) and the correlation of Lp(a) with HDL-C and serum albumin. In 69 hemodialysis patients with C-reactive protein (CRP) levels over than 10 mg/L and 101 hemodialysis patients with CRP levels in the normal range, Lp(a), HDL-C and serum albumin were determined in relation to CRP, as a sensitive marker of an APR. Results showed that serum concentration of CRP in 69 hemodialysis patients was significantly higher than in controls (44,62 mg/L versus 8,75 mg/L, p<0,01).Patients with elevated CRP had significantly higher serum levels of Lp(a) and lower serum levels of HDL-C and albumin, than patients with CRP in the normal range ( 35,39 mg/dl versus 28,6 mg/dl, p<0,01, 0,91 mmol/L versus 1,29 mmol/L, p<0,01 and 33,56 g/L versus 35,86 g/L, p<0,01). Lp(a) levels correlated positively with CRP and negatively with HDL-C and serum albumin, in patients with elevated CRP, but not in healthy controls. According to the results Lp(a) reacts as an acute phase protein, in patients with APR. PMID- 20192927 TI - Extra-articular manifestations of seronegative and seropositive rheumatoid arthritis. AB - Although considered a "joint disease," rheumatoid arthritis is associated with the involvement of extra-articular manifestations. The aim of the study is the investigation and comparison of frequency and type of extra-articular manifestations in a well defined community based cohort of patients with seropositive and seronegative rheumatoid arthritis. Using the ACR (1987) criteria for rheumatoid arthritis, patients have been classified into the 2nd and 3rd functional class (ARA). The studied group consisted of 125 seronegative patients with titters lower than 1:64 as defined by Rose-Waaler test, whereas the control group consisted of 125 seropositive patients with titters of 1:64 or higher. All patients were between 25-60 years of age (Xb=49,96), with disease duration between 1-27 years (Xb=6,41). In order to present the findings of the study, the structure, prevalence, arithmetic mean (Xb), standard deviation (SB), variation quotient (QV%) and variation interval (Rmax-Rmin) have been used. Probability level has been expressed by p<0,01 and p<0,05. Correlation between the number of extra-articular manifestations and duration of the disease has been calculated by means of Pearson linear correlation. Higher presence of diffuse lung fibrosis, central and peripheral nervous system damages have been confirmed in the seropositive group, and osteoporosis in the seronegative; however, no statistical difference has been found. In extra-articular manifestations, "rheumatoid core" in the seropositive subset (chi2=4,80, p<0,05) presented significant statistical difference. Rheumatoid nodules were more frequent in seropositive subset (12%:16%), in both sexes; however, they were not of significant statistical difference. Neuropathy and lung diseases were also frequently present in seropositive group, but no statistical difference has been found regarding the statistical difference. Longer duration of the disease resulted in an increase of the number of extra-articular manifestations. Calculated linear correlation by Pearson, resulted as positive and high correlation in total (r=0,36, p<0,01), and for groups [(r=0,52, p<0,01) seronegative, (r=0,25, p<0,01) seropositive], nevertheless no significant statistical difference was found regarding the sero status. In conclusion, extra-articular manifestations are more frequent in the seropositive patients. The longer the duration of the disease the larger the number of extra-articular manifestations. Differences with regard to sero-status and sex, with some exceptions, are not observed. PMID- 20192928 TI - Methicillin-resistant Staphylococcus aureus (MRSA) as a cause of nosocomial wound infections. AB - Postoperative wound infections represent about 16% of hospital-acquired infections. Staphylococcus aureus is the most common cause of nosocomial wound infections. Increased frequency of Methicillin-resistant Staphylococcus aureus (MRSA) in hospitalized patients and possibility of vancomycin resistance requires permanent control of MRSA spread in the hospital.The purpose of this study was to analyse the frequency of Methicillin-resistant Staphylococcus aureus (MRSA) in the swabs taken from the surgical wounds, the presence of MRSA infection in surgical departments and to examine antimicrobial susceptibility of MRSA isolates. Wound swabs were examined from January 2006 to December 2008. The isolates were identified by conventional methods. Antimicrobial susceptibility testing was performed by Kirby-Bauer disc-diffusion method as per NCCLS guidelines.A total of 5755 wound swabs were examined: 938 (16,3%) swabs were sterile and 4817 (83,7%) were positive. Staphylococcus aureus was isolated in 1050 (22,0%) swabs and it was the most common cause of wound infections. MRSA was isolated from 12,4% samples in 2006, from 6,7% samples in 2007 and from 3,7% samples during 2008. Wound infections caused by MRSA dominated in the department of plastic surgery (24,4%) and in the department of orthopaedic surgery (24,1%). Antimicrobial susceptibility testing showed that 73% of MRSA isolates were with the same antibiotic sensitivity pattern (antibiotyp)-sensitive only to vancomycin, tetracycline, fucid acid and trimethoprim/sulfamethoxasole. Our results show decreasing of MRSA infection in the surgical wards. These results appear to be maintained with strategies for preventing nosocomial infection: permanent education, strong application of protocols and urging the implementation of strict infection control policy. PMID- 20192929 TI - Ultrastructural changes in the liver of intravenous heroin addicts. AB - The ultrastructural research has a decisive role in gathering the knowledge on the liver's response to the influence of some drugs. The aim of the study was to perform an ultrastructural analysis of the liver in chronic intravenous heroin addicts.The study involved the autopsy conducted on 40 bodies of intravenous heroin addicts and 10 control autopsies. The liver tissue was fixed in glutaraldehyde and moulded with epon for investigation purposes of ultrastructural changes. The analysis was performed using the method of transmission electron microscopy.In the group of intravenous heroin addicts, the liver autopsy samples showed degenerative vesicular and fat changes, chronic active and persistent hepatitis, cirrhosis, reduction in the amount of glycogen in hepatocytes, as well as the Kupffer cell's dominant hypertrophy. Various changes occur in organelles, plasma membrane of hepatocytes and biliary channels as well as in the nucleus. The most important ultrastructural findings include: hyperplasia and hypertrophy of the smooth endoplasmic reticulum, which is histologically proven vesicular degeneration of hepatocyte occurring as a result of the increased synthesis of enzymes of smooth endoplasmic reticulum due to chronic intravenous heroin intake, and the presence of continuous basal membrane followed by transformation of the sinusoids into capillaries (in the cases of chronic active hepatitis and cirrhosis) which leads to a disorder of microcirculation and further progress of cirrhosis. PMID- 20192930 TI - Aerobic capacity as an indicator in different kinds of sports. AB - Physical capacity of athletes is an important element of success in sports achievements. Aerobic capacity has been accepted as its major component. Maximal oxygen uptake (VO2max) has been regarded by majority of authors as the best indicator of aerobic capacity of an organism, and at the same time, the best indicator of an athlete's physical capacity. The aim of the investigation was to analyze the aerobic capacity as an indicator of physical capacity of athletes, differences in their aerobic capacity with regard to the kind of sport they are practicing, as well as the differences obtained when compared to physically inactive subjects. The investigation included the determination of absolute and relative VO2max in the total of 66 male examinees. The examinees were divided into two groups of active athletes (football players (n=22) and volleyball players (n=18) of different profiles, while the third group of non-athletes served as control group. Maximal oxygen uptake was determined by performing the Astrand 6 minute cycle test. Peak values of VO2 max were recorded in the group of football players (4,25+/-0,27 l/min), and they were statistically significantly higher (p<0,001) compared to other examined groups. In the group of volleyball players the oxygen uptake was 3,95+/-0,18 l/min, while statistically significantly lower values were reported in the group of non-athletes compared to the groups of athletes (p<0,01). A similar ratio of VO2 max values was also shown by the analysis of values expressed in relative units. Our results showed that peak values of VO2 max were obtained in football players, and that football as a sport requires higher degree of endurance compared to volleyball. Having considered the morphological and functional changes which are the consequence of the training process, it can be concluded that VO2 max values are statistically significantly higher in the groups of athletes compared to the group of non athletes. PMID- 20192931 TI - Clinical and laboratory characteristics of acute community-acquired urinary tract infections in adult hospitalised patients. AB - Urinary tract infections (UTI) cause a great number of morbidity and mortality. These infections are serious complications in pregnancy, patients with diabetes, polycystic kidneys disease, sickle cell anaemia, kidney transplant and in patients with functional or structural anomalies of the urinary tract. The aim of this investigation was to determine a dominant causative agents of UTI and some of the clinical and laboratory characteristics of acute community-acquired UTI in adult hospitalised patients. We studied 200 adult patients with acute community acquired UTI hospitalised in the Clinic for Infectious Diseases Tuzla from January 2006 to December 2007. The patients were divided into two groups: a group of patients with E. coli UTI (147) and a group of patients with non-E. coli UTI (53). In these two groups, the symptoms and signs of illness, blood test and urine analysis results were analysed. Our results have shown that the patients with E. coli UTI frequently had fever higher than 38,5 degrees C (p<0,0001), chills (p=0,0349), headache (p=0,0499), cloudy urine (p<0,0001), proteinuria (p=0,0011) and positive nitrite-test (p=0,0002). The patients with non-E. coli UTI frequently had fever lower than 38,5 degrees C (p<0,0001) and urine specific gravity <1015 (p=0,0012). There was no significant difference in blood test results between patients with E. coli and non-E. coli UTI. These clinical and laboratory findings can lead us to early etiological diagnosis of these UTI before urine culture detection of causative agents, which takes several days. Early etiological diagnosis of the E. coli and non-E. coli UTI is necessary for an urgent administration of appropriate empirical antibiotic treatment. This is very important in prevention of irreversible kidney damage, prolonged treatment, complications, as well as recidives and chronicity of the illness. PMID- 20192932 TI - Relevance of uric Acid in progression of type 2 diabetes mellitus. AB - Recent studies have introduced serum uric acid (UA) as a potential risk factor for developing diabetes, hypertension, stroke, and cardiovascular diseases. The value of elevated levels of UA in serum as a risk factor for diabetes development is still under scrutiny. Recent data suggest that clearance of UA is being reduced with increase in insulin resistance and UA as a marker of prediabetes period. However, conflicting data related to UA in serum of patients with Type 2 diabetes prompted us to study the urine/serum ratio of UA levels (USRUA) in these patients and healthy controls. All subjects included in the study were free of evidence of hepatitis B or C viral infection or active liver and kidney damage. Patients receiving drugs known to influence UA levels were also excluded from this study. Analysis of glucose and uric acid were performed on Dade Behring analyzer using standard IFCC protocols. Interestingly, our data demonstrated about 2.5 fold higher USRUA values in diabetic patients as compared to control subjects. Furthermore, there was a trend of correlation of USRUA value with the blood glucose levels in diabetic patients, which was more prominent in diabetic men than in women. With aging, levels of uric acid increased in serum of diabetic patients, and this effect was also more profound in male than in female diabetics. In conclusion, this study showed significantly elevated USRUA levels in patients with Type 2 diabetes, a negative USRUA correlation with the blood glucose levels in diabetic patients, and an effect of sex and age on the uric acid levels. Since literature data suggest a strong genetic effect on UA levels, it would be pertinent to perform further, possibly genetic studies, in order to clarify gender and ethnic differences in UA concentrations. PMID- 20192933 TI - The importance of determining procalcitonin and C reactive protein in different stages of sepsis. AB - Rapid and early diagnosis of systemic infections is very important for acting on time with an adequate therapy. The aim of this study is to determine the diagnostic importance of procalcitonin (PCT) and C-reactive protein (CRP) of bacterial infections in different stages of sepsis.PCT and CRP have been determined in 45 newborns, 1-21 days of age, with different stages of sepsis, in the centre for prematurely born neonates. These parameters have also been determined for control group, in which there were 10 healthy newborns. Procalcitonin values were significantly increased in neonates with septic shock (92,5 ng/mL; 6,06-200 ng/mL) compared to the systemic inflammatory response syndrome- SIRS (41 ng/mL; 0,28-200 ng/mL), neonatal sepsis (10,26 ng/mL; 1,08 111,3 ng/mL), neonatal sepsis and purulent meningitis (9,80 ng/mL; 4,3-18,9 ng/mL). The control group values were lower than 0,5 ng/mL. CRP is increased without statistical differences in all stages of sepsis in newborns with septic shock (93,2 mg/L; 6,0-196 mg/L) in cases with SIRS (45,64 mg/L; 6,0-147 mg/L), neonatal sepsis (70,02 mg/L; 6-177 mg/L), neonatal sepsis and purulent meningitis (61,98 mg/L; 24-192 mg/L). The average values for the control group were 4,7 mg/L. Procalcitonin is increased in all stages of sepsis with higher values in the septic shock. The increase of PCT levels is related to the severity, course of infection and prognosis of disease. PMID- 20192934 TI - Complications following autologous latissimus flap breast reconstruction. AB - Use of an autologous latissimus flap in breast reconstruction accounts for a supple and natural look of reconstructed breast. Most common postoperative complication, seroma, became more of a rule then an exception when it comes to postoperative evaluation of the patients who underwent this reconstructive procedure. A retrospective study analysing and evaluating different complication rates in 20 patients who underwent breast reconstruction by autologous latissimus flap, was conducted. All patients included in the study were operated at the Department of plastic surgery of Hopital Civil in Strasbourg, France, between 1996 and 2008. The complication rates were noted as follows: seroma in 19 of our 20 patients (95%), late hypertrophic scarring in 3 patients (15%), postoperative surgical site hematoma in 3 patients (15%), and 2 patients (10%) presented postoperative chronic back pain. Different options used in seroma treatment and prevention (subcutaneous-fascia anchor sutures of donor site, application of corticosteroids by injection into donor site postoperatively, passive drainage) can reduce seroma formation and thus overall complication rates, leading to much faster patient's recovery time and return to normal daily activities. PMID- 20192935 TI - Transrectal ultrasound-guided prostate biopsy, periprostatic local anesthesia and pain tolerance. AB - We have evaluated objectively pain tolerance in transrectal ultrasound-guided prostate biopsy (TRUS) using local periprostatic per rectal anesthesia as compared to the conventional method. From November 2008 to May 2009, 90 patients underwent transrectal ultrasound-guided prostate biopsy at Department of Urology, Clinical Center University Sarajevo. 90 patients who fulfilled the inclusion criteria were randomized into 3 groups of 30 patients each. Group 1 received periprostatic local anesthesia with 2% lidocaine, group 2 received Voltaren supp placed in rectum an hour before biopsy while group 3 received no local anesthesia. Pain scale responses were analyzed for each aspect of the biopsy procedure with a visual analog scale of 0-none to 10-maximal. There was no difference between the 3 groups in pain scores during digital rectal examination, intrarectal injection and probe insertion. The mean pain scores during needle insertion in group 1 receiving periprostatic nerve block and in group 2 receiving Voltaren supp were 3,10 +/- 2,32 and 5,15 +/- 2,01 respectively. In group 3 (no local anesthesia), mean pain scores were 6,06 +/- 2,95 which was found to be significantly different (p < 0,001). However, morbidity after the biopsy was not statistically different between all 3 groups. TRUS-guided prostate biopsy is a traumatic and painful experience, but the periprostatic blockage use is clearly associated with more tolerance and patient comfort during the exam. It is an easy, safe, acceptable and reproducible technique and should be considered for all patients undergoing TRUS biopsy regardless of age or number of biopsies. PMID- 20192936 TI - Influence of donor age on renal graft function in first seven post transplant days. AB - Increasing gap between demand and availability of human kidneys for transplantation has forced a re-evaluation of the limits on donor age acceptability. The present study included 74 patients who underwent kidney transplantation in University Clinical Centre Tuzla. In an observational cohort study we assessed impact of donor age on post transplant renal function by analyzing following parameters: 24 hour urine output, creatinine clearance (Cr Cl) and glomerular filtration rate (GFR). Depending on donor age recipients were allocated in to two groups. Group I included patients who received renal graft from donors age up to 55 years, and Group II encountered recipients who received renal graft from donors older than 55 years. Our goal was to determine whether donor age over 55 years significantly diminishes renal graft function in first seven post transplant days. No statistically significant difference was found between Group I and II regarding 24 hour urine output. From second to fifth postoperative day creatinine clearance values were higher in the group of patients who received kidney from donors older than 55 years (47+/-19, 1 vs. 44, 4+/-20, 8). On the fifth, sixth and seventh post operative day GFR was significantly higher in patients who received renal graft from donors age up to 55 years (p<0, 0161). Our data showed no significant difference in observed variables between the two groups, thus indicating that utilization of renal grafts from donors' age > 55 years is acceptable and may considerably expand the donor pool. PMID- 20192937 TI - Atrial fibrillation and coronary bypass surgery - what can be risk factors for its' appearance? AB - The main goal of our study was to evaluate possible perioperative risk factors for occurrence of atrial fibrillation in the postoperative period in patients after CABG operations. The study included 140 patients after CABG, divided into two groups - Group I - 64 patients with new onset of POAF and Group II - 76 patients without postoperative atrial fibrillation occurrence. In both groups possible risk factors for atrial fibrillation onset (preoperative and postoperative) were analyzed.Results showed that we can predict new onset of atrial fibrillation after CABG if the following preoperative factors are present low ejection fraction (less than 40%), LAd > 40mm, higher body mass index (BMI over 30), presence of COPD and older age. Important perioperative factors for onset of atrial fibrillation in our study were longer extracorporeal circulation, increased dose/number of inotropic drugs, blood transfusion and elevated WBC count postoperatively. PMID- 20192938 TI - Lactate dehydrogenase and oxidative stress activity in primary open-angle glaucoma aqueous humour. AB - Lactate dehydrogenase (LDH) and lactate are some of the hypoxy biochemical parameters. Extracellular activity of this enzyme increases under the condition of oxidative stress, since the cell integrity can be disrupted during the lipid peroxidation process. Subsequently that leads to the increase level of the lactic acid and lactic acid salts. The objective of this investigation is establishing the level of LDH, LDH1 (HBDH) and the lactate concentration in aqueous humour in patients with primary open-angle glaucoma. Biochemical analysis have been made by enzymatic-colometric method (lactate) and UV-kinetic method (LDH and HBDH) in aqueous humour of 30 patients (42 eyes) with primary open-angle glaucoma (POAG) and 30 patients (40 eyes) with cataract (the control group). The increased values of lactate and the activity of LDH and HBDH enzyme in aqueous humour of POAG patients in correlation with the control group are the results not only of oxidative stress but also of hypoxy and the mitochondry oxidative function (p<0,001). The increased activity of the examined biochemical parameters in the aqueous humour of the POAG patients points to the fact that other mechanisms, besides IOP, have a role in glaucoma pathogenesis. PMID- 20192939 TI - Candida albicans and non-albicans species as etiological agent of vaginitis in pregnant and non-pregnant women. AB - Pregnancy represents a risk factor in the occurrence of vaginal candidosis. The objectives of our study were: to make determination of the microscopic findings of vaginal swab, frequency of Candida species in the culture of pregnant women and patients who are not pregnant, determine the Candida species in all cultures, and to determine the frequency and differences in the frequency of C. albicans and other non-albicans species. In one year study performed during 2006 year, we tested patients of Gynaecology and Obstetrics clinic of the Clinical Centre in Sarajevo and Gynaecology department of the General hospital in Sarajevo. 447 woman included in the study were separated in two groups: 203 pregnant (in the last trimester of pregnancy), and 244 non-pregnant woman in period of fertility. Each vaginal swab was examined microscopically. The yeast, number of colonies, and the species of Candida were determined on Sabouraud dextrose agar with presence of antibiotics. For determination of Candida species, we used germ tube test for detection of C. albicans, and cultivation on the selective medium and assimilation tests for detection of non-albicans species. The results indicated positive microscopic findings in the test group (40,9%), as well as greater number of positive cultures (46,8%). The most commonly detected species for both groups was C. albicans ( test group 40.9% and control group 23,0%). The most commonly detected non-albicans species for the test group were C. glabrata (4,2 %) and C. krusei (3,2%), and for the control group were C. glabrata (3,2%) and C. parapsilosis (3,2%). The microscopic findings correlated with the number of colonies in positive cultures. In the test group, we found an increased number of yeasts (64,3%), and the pseudopyphae and blastopores by microscopic examination as an indication of infection. In the control group, we found a small number of yeasts (64,6%) , in the form of blastopores, as an indication of the candida colonisation. Our results indicate that gravidity, as the risc factor for incidence of infection, has the significant role in the incidence of vaginal candidosis. PMID- 20192941 TI - Importance of patient's education in favouring compliance with sublingual immunotherapy. PMID- 20192940 TI - Association of the interleukin-23 receptor gene variant rs11209026 with Crohn's disease in German children. AB - AIM: Genome-wide association studies have described variants within the interleukin-23 receptor (IL23R) locus to be associated with Crohn's disease (CD) and ulcerative colitis (UC). We investigated the association of rs11209026 (p.Arg381Gln) and rs7517847 (c.799-3588T>G) into German paediatric inflammatory bowel disease (IBD) patients and analysed IL23R transcriptional activity in colonic tissues. METHODS: The rs11209026 and rs7517847 nucleotide substitutions were determined in 353 German children with IBD (221 CD, 132 UC) and 253 controls using pre-designed TaqMan((R)) SNP genotyping assays. In selected IBD patients and controls, IL23R mRNA expression was measured using real-time PCR. RESULTS: The prevalence of the rs11209026 A allele was lower in CD patients, but not in UC patients, when compared with controls (1.8% vs 7.1%, p < 0.01). The rs7517847 variant, in contrast, was associated neither with CD nor with UC. IL23R expression was variable in IBD patients compared with controls without significant overexpression or downregulation. CONCLUSION: Our study provides additional support for the strong protection of the rs11209026 (p.Arg381Gln) variant against paediatric CD. IL23R was expressed in both CD and UC with a great variability. However, expression levels showed no significant association with the disease. PMID- 20192942 TI - IgE in the human placenta: why there? AB - Immunoglobulin E (IgE) antibodies are key effector molecules in the allergic inflammatory response and are also involved in the protection against extracellular parasites. Allergic symptoms often develop early in life, and the intrauterine environment has been proposed to play an important role in affecting the risk of later allergy development. The placenta constitutes a selective barrier between the maternal and foetal circulation. Recently, we reported that maternal IgE antibodies are present on foetal macrophages in the villous tissue of the human placenta irrespective of maternal allergy status. This review discusses the presence of IgE antibodies in the human placenta and its possible roles in normal and pathologic pregnancy. It also deals with the relationship between placental IgE and development of allergy during childhood. A better understanding of the role of IgE in placenta could give us clues on how to prevent allergy development in the future generations. PMID- 20192944 TI - Systemic allergic contact dermatitis from intravenous piritramide. PMID- 20192943 TI - Inflammatory profiles in nasal mucosa of patients with persistent vs intermittent allergic rhinitis. AB - BACKGROUND: To date there is little information on the inflammatory profiles of patients suffering from persistent (PER) and intermittent allergic rhinitis (IAR). Also, it is not clear whether differences exist in eosinophilic inflammation and/or T-helper cell sub-populations and their markers. The aim of this study was to primarily evaluate the inflammatory profiles of patients with moderate/severe PER and IAR. METHODS: Inferior nasal turbinate tissue was obtained from 12 PER, 12 IAR and 12 nonallergic nonrhinitic (control) patients, and symptoms (visual analogue scales, VAS) and impairment of life was monitored. All tissues were assessed for eosinophil and mast cell numbers by immunohistochemistry; IL-5, ECP and IgE concentrations by immunoassay; mRNA for transcription factors GATA-3, T-bet, FOXP3 and RORc by quantitative real-time polymerase chain reaction; and IgE-induced release of LTC(4)/D(4)/E(4) and PGD(2)in vitro. RESULTS: Eosinophils and mast cells were significantly increased in patients with PER and patients with IAR compared to control subjects; by patients with PER demonstrating even significantly greater increase of both cell types than patients with IAR. Similarly, ECP IL-5, GATA-3 mRNA expression and IgE induced release of LTC4/D(4)/E(4) and PGD(2) from mast cells were significantly increased in patients with PER compared to patients with IAR. In contrast, the expression of T-bet, FOXP3 or RORc mRNA was not significantly different in the PER, IAR or control patients. CONCLUSION: The findings from the present study suggest that PER is characterized by a significantly greater eosinophilic and predominantly Th2 cell-mediated nasal inflammatory profile compared to IAR. PMID- 20192945 TI - The neurotrophic factor pleiotrophin modulates amphetamine-seeking behaviour and amphetamine-induced neurotoxic effects: evidence from pleiotrophin knockout mice. AB - Pleiotrophin (PTN), a neurotrophic factor with important roles in survival and differentiation of dopaminergic neurons, is up-regulated in the nucleus accumbens after amphetamine administration suggesting that PTN could modulate amphetamine induced pharmacological or neuroadaptative effects. To test this hypothesis, we have studied the effects of amphetamine administration in PTN genetically deficient (PTN -/-) and wild type (WT, +/+) mice. In conditioning studies, we found that amphetamine induces conditioned place preference in both PTN -/- and WT (+/+) mice. When these mice were re-evaluated after a 5-day period without amphetamine administration, we found that WT (+/+) mice did not exhibit amphetamine-seeking behaviour, whereas, PTN -/- mice still showed a robust drug seeking behaviour. In immunohystochemistry studies, we found that amphetamine (10 mg/kg, four times, every 2 hours) causes a significant increase of glial fibrillary acidic protein positive cells in the striatum of amphetamine-treated PTN -/- mice compared with WT mice 4 days after last administration of the drug, suggesting an enhanced amphetamine-induced astrocytosis in the absence of endogenous PTN. Interestingly, we found in concomitant in vitro studies that PTN (3 uM) limits amphetamine (1 mM)-induced loss of viability of PC12 cell cultures, effect that could be related to the ability of PTN to induce the phosphorylation of Akt and ERK1/2. To test this possibility, we used specific Akt and ERK1/2 inhibitors uncovering for the first time that PTN-induced protective effects against amphetamine-induced toxicity in PC12 cells are mediated by the ERK1/2 signalling pathway. The data suggest an important role of PTN to limit amphetamine-induced neurotoxic and rewarding effects. PMID- 20192946 TI - NMDA receptors in frontal cortex and hippocampus of alcohol consumers. AB - Specific binding of [3H]MK801 to N-methyl-D-aspartate (NMDA) receptors in the frontal cortex and hippocampus (CA1 and gyrus dentatus) was measured by receptor autoradiography in 16 Caucasian chronic alcohol consumers free of clinical manifestations of alcoholism, and compared with 16 Caucasian control subjects. Binding densities were not significantly different between heavy and moderate drinkers, neither between alcohol consumers that were abstinent or non-abstinent before death, nor between ethanol drinkers and controls. Continued alcohol consumption, in the absence of hepatic, neurologic or psychiatric disorders related to alcoholism, does not alter the binding properties of NMDA receptors in the brain areas studied. PMID- 20192947 TI - Residual performance impairments in adult rats trained on an object discrimination task subsequent to cocaine administration during adolescence. AB - The present study was conducted to determine whether cognitive impairments in adult rats treated with cocaine during adolescence demonstrated in previous investigations extend to tests of object discrimination learning. Accordingly, 30 day-old male Long-Evans rats were injected subcutaneously with either 10 or 20 mg/kg cocaine or received control injections of saline for 7-8 consecutive days. An extended abstinence period was then introduced (mean = 70.7 +/- 9.8 days) before subjects, who were now young adults (mean = 106.3 +/- 10.2 days old), were assessed for acquisition of a two-choice object discrimination task. Using a correctional learning procedure conducted in a water maze, subjects were trained (eight trials per day for 10 days) to approach one of two multi-dimentional 'junk' objects. Although all animals acquired the discrimination to a reasonable extent, cocaine-treated subjects exhibited lower percentages of correct choices over the course of training (10 mg/kg = 59.6 +/- 7.2% and 20 mg/kg = 59.4 +/- 4.9%) relative to the saline control group (67.5 +/- 4.9%). Further analyses revealed that saline-treated subjects acquired proficient discrimination performance earlier during the course of training, achieving an approximate 72% performance rate after only 3 days of training. This was in contrast to the two cocaine-treated groups needing 7 days of training to achieve comparable levels of performance. In addition, saline-treated subjects required significantly fewer trials (20.8 +/- 8.9) than either cocaine-treated group (10 mg/kg = 52.2 +/- 11.9 and 20 mg/kg = 63.3 +/- 8.7) to reach an 87.5% correct response criterion (i.e. 7 correct-out-of-8-consecutive-trials) and performed at a higher above-chance level (13.5%) than either cocaine-treated group (3.6% and 5.3% for the 10 and 20 mg/kg cocaine groups, respectively). These findings demonstrate the existence of cognitive impairments in adulthood subsequent to cocaine exposure during adolescence despite a prolonged drug-free interval. Speculation regarding the neurobiological basis for this effect, especially with regard to alterations to prefrontal circuitry, is provided. PMID- 20192948 TI - Naltrexone attenuates amphetamine-induced locomotor sensitization in the rat. AB - Amphetamine, and other stimulants, readily induces behavioral sensitization, an effect hypothesized to reflect neurobiological changes that may underlie certain aspects of drug addiction. Apart from the effects on the dopamine system, previous studies have also shown that amphetamine interacts with other neurotransmitters, including the endogenous opioid system. The unselective opioid receptor antagonist naltrexone (NTX) modulates amphetamine-induced effects in both laboratory animals and humans. To further examine this interaction, the aim of the present study was to investigate the effect of NTX on the expression of locomotor sensitization and conditioned locomotor response in animals previously conditioned with amphetamine. Sensitization was induced by repeated administration of amphetamine (2 mg/kg) for 10 consecutive days. After a 10-day drug-free period, the rats were administered NTX (3 mg/kg) 30 minutes prior to the administration of a challenge dose of either amphetamine (0.5 mg/kg) (test for drug-induced sensitization) or saline (test for conditioned locomotor response). NTX had no effect on acute amphetamine-induced locomotor activity or on general locomotor activity in animals without a history of amphetamine conditioning. However, animals previously conditioned with amphetamine showed a sensitized locomotor response to the amphetamine challenge following the 10-day drug-free period. This sensitized response was significantly inhibited by NTX pre treatment. In addition, NTX pre-treatment blocked the conditioned locomotor response when the amphetamine-conditioned animals were placed in the previously amphetamine-paired context. This study showed that NTX attenuates drug- and cue induced locomotor behavior in amphetamine-conditioned animals, supporting recent clinical findings that indicated a potential role of NTX as a treatment for amphetamine dependence. PMID- 20192949 TI - CNR1 gene polymorphisms in addictive disorders: a systematic review and a meta analysis. AB - The aim of the present work was to systematically review all association studies of cannabis receptor 1 (CNR1) polymorphisms with dependence syndrome and to perform a meta-analysis. Odds ratios (ORs) were estimated by contrasting the ratio of counts of the 'high risk' versus 'low risk' alleles in cases with dependence versus controls. Studies were analyzed by random-effects meta-analysis using pooled OR. Eleven full text articles met our eligibility criteria and nine meta-analyses were performed on three polymorphisms of CNR1: rs1049353, rs806379 and the AAT repeat. Of these, only the AAT polymorphism showed a significant association with illicit substance dependence but only in the Caucasian population samples and using a risk allele definition of >= 16 repeats. Our analysis showed a small effect size (OR = 1.55, P = 0.045), with strong heterogeneity (Q = 19.87, P < 0.01 with I2 = 85%). In line with the polygenic model, our meta-analysis supports a minor implication for CNR1 AAT polymorphism in illicit substance dependence vulnerability. Further studies in well-phenotyped samples and using more polymorphisms are needed to conclude on the actual influence of cannabinoid receptor polymorphisms. PMID- 20192951 TI - Increased effects of 3,4-methylenedioxymethamphetamine (ecstasy) in a rat model of depression. AB - 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is associated with increases in core body temperature (T(C)) and depressive mood states in users. Flinders Sensitive Line (FSL) rats represent a rat model of depression originally bred from Sprague-Dawley (SD) rats. They are more sensitive to both muscarinic and serotonergic agonists and have altered thermoregulatory responses to various drugs. To examine the link between MDMA and depression, eight FSL and eight SD rats were administered saline and 5 and 7.5 mg/kg MDMA. Immediately following administration, rats were confined to an area with an ambient temperature (T(A)) of 30 +/- 1 degrees C for 30 minutes before being allowed access to a thermal gradient for four hours. The brains were removed one week after final dose of MDMA and concentrations of serotonin and dopamine were measured. Treatment with MDMA at both doses led to a higher T(C) in the FSL rats than the SD rats at high T(A) (P < 0.01). Fatalities due to hyperthermia occurred in the FSL rats after both doses, whereas all but one of the SD rats recovered well. Heart rate was also much higher after MDMA in the FSL rats throughout the experiments. The FSL rats showed significant decreases in all transmitters measured (P < 0.05). These differences between strains were not accounted for by altered blood or brain concentrations of MDMA. The results indicate that the FSL rats may be more susceptible to developing MDMA-induced hyperthermia and possible damage to the brain. These findings may be of importance to human users of MDMA who also have depression. PMID- 20192950 TI - Variation in the gene encoding the serotonin transporter is associated with a measure of sociopathy in alcoholics. AB - The present study examined the association between a measure of sociopathy and 5 HTTLPR genotype in a sample of individuals from Project MATCH, a multi-center alcohol treatment trial. 5-HTTLPR, an insertion-deletion polymorphism in SLC6A4, the gene encoding the serotonin transporter protein, results in functionally distinct long (L) and short (S) alleles. The S allele has been associated with a variety of psychiatric disorders and symptoms including alcohol dependence, but it is unknown whether 5-HTTLPR increases the risk for co-morbid sociopathy among those with alcohol dependence. Eight hundred sixty-two subjects diagnosed with alcohol dependence completed the California Psychological Inventory, a psychological assessment that includes a measure of socialization, which was used as a proxy measure of sociopathy. Subjects were genotyped for the insertion deletion polymorphism, as well as a single nucleotide polymorphism (A->G) that is located in the inserted region. Regression analysis revealed that after controlling for age, which was negatively related to socialization score, 5 HTTLPR genotype interacted with sex to determine socialization score (P < 0.001). Males with the L'L' genotype (i.e. those homozygous for the L(A) allele) had lower socialization scores (i.e. greater sociopathy) than males who were carriers of the S' allele (P = 0.03). In contrast, women with the S'S' genotype had lower socialization scores than women with two L' alleles (P = 0.002) and tended to have lower Socialization Index of the California Psychological Inventory scores than women with one copy of the L' allele (P = 0.07). Among individuals with alcohol use disorders, the tri-allelic 5-HTTLPR polymorphism had opposite effects on socialization scores in men than women. The basis for this finding is unknown, but it may have implications for sub-typing alcoholics. PMID- 20192952 TI - Genetic variation in the indoleamine 2,3-dioxygenase gene in pre-eclampsia. AB - PROBLEM: To investigate the contribution of genomic variations in the indoleamine 2,3-dioxygenase (IDO) gene to the onset of pre-eclampsia. METHOD OF STUDY: We examined sequence variations in the IDO1 gene using placental genomic DNA from 35 pre-eclamptic patients and 32 normotensive pregnant women. RESULTS: A case control study revealed that none of the common variants influences the risk of disease. Sequencing of each IDO1 exon in diseased subjects revealed rare variants. This variation, c.-147_150delGAAA, was located within the 5' untranslated region of the IDO1 gene, and its homozygote was identified only in pre-eclamptic subjects. However, despite the low levels of IDO expression and enzyme activity in the c.-147_150delGAAA homozygote, reporter assays indicated that this variation does not affect gene expression. CONCLUSION: Our findings indicate that genetic alteration of fetal IDO gene does not appear to be a primary cause of pre-eclampsia. PMID- 20192953 TI - Chlamydia trachomatis, a hidden epidemic: effects on female reproduction and options for treatment. AB - The number of genital tract Chlamydia trachomatis infections is steadily increasing worldwide, with approximately 50-70% of infections asymptomatic. There is currently no uniform screening practice, current antibiotic treatment has failed to prevent the increased incidence, and there is no vaccine available. We examined studies on the epidemiology of C. trachomatis infections, the effects infections have on the female reproductive tract and subsequent reproductive health and what measures are being taken to reduce these problems. Undetected or multiple infections in women can lead to the development of severe reproductive sequelae, including pelvic inflammatory disease and tubal infertility. There are two possible paradigms of chlamydial pathogenesis, the cellular and immunological paradigms. While many vaccine candidates are being extensively tested in animal models, they are still years from clinical trials. With no vaccine available and antibiotic treatment unable to halt the increased incidence, infection rates will continue to increase and cause a significant burden on health care systems. PMID- 20192954 TI - Interferon-gamma inhibits metalloproteinase activity and cytotrophoblast cell migration. AB - PROBLEM: Establishment of a successful pregnancy relies on a complex fetal-mother communication that starts with the embryo adhering and invading the endometrium. This requires remodeling of extracellular matrix, performed by metalloproteinases. Cytokines, such as interferon-gamma (IFN-gamma), play a role in implantation and could affect the success of pregnancy. METHOD OF STUDY: Using JEG-3 cell line as model, we cultured the cells in the presence or absence of IFN gamma and determined the activities of MMP-2 and MMP-9 using zymography and the secretion of leptin using Western blot. RESULTS: Interferon-gamma inhibits gelatinase activity from MMP-2 and MMP-9 in a dose-dependent manner, reducing the secretion of leptin (not because of a general inhibition on protein synthesis) and impairs cell migration on Matrigel. CONCLUSION: Our results correlate with previous reports from our laboratory indicating that IFN- gamma is deleterious for mouse embryo outgrowth, having an effect on metalloproteinases activity as well as leptin secretion. PMID- 20192955 TI - Visual cues as a surrogate for tactile feedback during robotic-assisted laparoscopic prostatectomy: posterolateral margin rates in 1340 consecutive patients. AB - OBJECTIVE: To analyse consecutive cases of robotic-assisted laparoscopic prostatectomy (RALP), present the incidence of nerve-sparing-related positive surgical margins (SM+), include visual cues that might assist in smoothly changing to the robotic platform, and discuss the scientific rationale for 'intersensory integration' which might explain the 'reverse Braille' phenomenon, i.e. the ability to feel when vision is greatly enhanced, as the lack of tactile feedback during RALP is often cited as a disadvantage of robotic surgery, interfering with a surgeon's ability to make intraoperative oncological decisions. PATIENTS AND METHODS: Data from 1340 consecutive patients undergoing RALP from one institution were analysed and trends for positive posterolateral SM+ (PLSM+) were correlated with oncological variables before and after RALP. A sample of patient slides were reviewed by a extramural pathologist. Multivariate regression modelling was used to compare the projected rates of PLSM+ vs the actual rate, given the effect of a conscious effort to use visual cues. Finally, video recordings of the procedure were systematically reviewed and correlated with anatomical and histopathological images in an integrated session involving the surgeon and the pathology team. RESULTS: The incidence of PLSM+ was 2.1%, which gradually declined to 1.0% in the last 100 patients. The reduction in PLSM+ occurred despite an increased rate of high-risk tumours operated on during this period. Forecasting analysis showed that the actual PLSM+ rate declined by half in the most recent 1000 patients, due to an integrated effort involving the use of visual cues during surgery. The following visual cues were considered important; appreciation of periprostatic (lateral prostatic) fascial compartments; colour and texture of the tissue; periprostatic veins as a landmark for athermal dissection; signs of inflammation; and a freely separating bloodless plane showing loose shiny areolar tissue. CONCLUSION: Adapting to the robotic platform is easy and there is no compromise of the oncological safety of this procedure. Experienced surgeons can use visual cues to assist during nerve sparing RALP and achieve low PLSM+ rates. PMID- 20192956 TI - Differential distribution of haematopoietic and nonhaematopoietic progenitor cells in intralesional and extralesional keloid: do keloid scars provide a niche for nonhaematopoietic mesenchymal stem cells? AB - BACKGROUND: Keloid disease is a benign, quasineoplastic disease with a high recurrence rate. Mesenchymal-like stem cells (MLSC) have previously been demonstrated in keloid scars and may be involved in keloid pathobiology. However, as these cells have only been examined by single colour fluorescence activated cell sorting (FACS) alone, they need to be more comprehensively characterized so that the key cellular contributors to keloid scars can be better understood. OBJECTIVES: To identify and characterize MLSC in intralesional and extralesional keloid, and to distinguish haematopoietic stem cells (HSC) from mesenchymal stem cells (MSC). METHODS AND PATIENTS: Punch biopsies from intralesional (top, middle and margin) and extralesional keloid scar sites were obtained from 17 patients with a keloid. Multicolour FACS analysis using antibodies specific for HSC markers CD34 and CD117 and MSC markers CD13, CD29, CD44 and CD90 was performed on freshly isolated keloid scar cells and on passage 0 and 1 cells. This was complemented by real-time quantitative polymerase chain reaction (PCR) and immunohistological in situ analyses. RESULTS: Keloid scars contain distinct subpopulations of MLSCs. Cells positive for CD13, CD29, CD44 and CD90 were found to be significantly (P<0.05) higher in the top and middle compartments of keloid scars compared with extralesional skin, where cells positive for CD34, CD90 and CD117 (representing HSCs) predominated. A unique population of CD34+ cells (cells positive for CD13, CD29, CD34, CD44 and CD90) were found in keloid scars and in extralesional skin. FACS and quantitative PCR analysis showed that many of the MSC markers were progressively downregulated and all HSC markers were lost during extended keloid fibroblast culture up to passage 1. CONCLUSION: We have found distinct subpopulations of haematopoietic and nonhaematopoietic MSC in keloid scars, whereby HSC accumulate extralesionally, while keloids seem to provide a niche environment for nonhaematopoietic MSC. Future therapy of keloids may have to target differentially both stem cell populations in order to deprive these tumours of their regenerative cell pools. PMID- 20192957 TI - Psoriasis and extra domain A fibronectin loops. AB - We have previously postulated that as well as T-helper (Th) 1 and Th17 cells, the transforming growth factor (TGF)-beta/fibronectin (FN)/alpha5beta1 pathway is central to psoriasis pathogenesis. EDA+ FN refers to an alternatively spliced isoform of FN with an additional domain known as extra domain A. EDA+ FN has two important properties pertinent to psoriasis lesions: it stimulates keratinocyte hyperproliferation, and, through stimulation of Toll-like receptor (TLR) 4, stimulates production of proinflammatory cytokines. EDA+ FN production induced by TGF-beta stimulation can be maintained in psoriasis lesions via two main feedback loops. Firstly, EDA+ FN stimulates proliferation of keratinocytes, which, in an autocrine fashion, will release more EDA+ FN. Secondly, EDA+ FN stimulates TLR4 expressed by antigen-presenting cells resulting in the production of proinflammatory cytokines such as tumour necrosis factor-alpha, interleukin (IL) 1, IL-6 and IL-12. The resultant promotion of cutaneous inflammation results in the recruitment of Th1 cells, which also produce EDA+ FN. We propose that these 'FN loops' contribute to the maintenance and progression of psoriatic lesions. Finally, although the association between psoriasis and heart/thrombotic disease remains unclear one plausible link may be the promotion of atherosclerosis and thrombotic heart disease by EDA+ FN. PMID- 20192958 TI - Neoadjuvant chemotherapy: a new criterion for selection of candidate patients for surgery of low tumour burden metastases from malignant melanoma? AB - BACKGROUND: Surgery of limited metastatic lesions from malignant melanoma can achieve long-term remission and better survival than chemotherapy. Existing criteria for selection of candidate patients for this surgery do not seem sufficient to avoid useless excisions. OBJECTIVES: To test use of neoadjuvant chemotherapy as a new criterion in this setting. METHODS: All patients who underwent thoracic surgery for one or two lung metastases from melanoma during 1999-2007 were included in the study. Demographic and medical data were collected and analysed. Several possible prognostic factors were evaluated based on the overall survival curves. RESULTS: Thirteen patients were included in this retrospective study. All but two patients had no evidence of disease after surgery. Ten patients received neoadjuvant chemotherapy. Six responded (absence of progression) and four had progressive disease. Response to chemotherapy and no evidence of disease after surgery were predictive of long-term survival. CONCLUSIONS: Neoadjuvant chemotherapy can be considered as a new criterion for better selection of candidate patients for lung metastasis surgical resection. This would also avoid useless surgical procedures in rapidly progressive disease and give information on the chemosensibility of the metastatic disease. This study needs further confirmation, particularly with chemotherapy regimens that have demonstrated better objective responses. PMID- 20192959 TI - Trade-off between antibiotic resistance and biological fitness in Acinetobacter sp. strain DR1. AB - Rifampicin, a bactericidal antibiotic drug, is routinely used to make an environmental recipient selective in laboratory-conjugation experiments. We noticed, inadvertently, that the rifampicin-resistant Acinetobacter sp. strain DR1, a recently discovered hexadecane-degrading environmental isolate, exhibited a substantial loss of quorum sensing signalling. The domesticated ampicillin resistant strain, DR1, evidenced more dramatic phenotypic changes than were observed in the rifampicin-resistant cells: a complete loss of quorum sensing, a loss in swimming and swarming motilities, poor fimbrial expression, increased rigidity in membrane fatty acid composition and reduced hexadecane degradation capability. Interestingly, the motility of strain DR1 grown adjacent to a streptomycin-producing Streptomyces griceus was permanently abrogated, where this change was heritable and other phenotypic changes could not be detected. In this study, we have reported for the first time that the in situ acquisition of antibiotic resistance may reduce biological fitness, including losses in the production of quorum sensing signals, motility and substrate utilization, and each antibiotic is associated with different degrees of phenotypic and genetic alterations. Our data also suggested that the domestication of environmental isolates should be approached with caution, as there are phenotypic variations in antibiotic-resistant cells that might not be noticeable unless all possible phenotypic assays are conducted. PMID- 20192960 TI - Relationship between cystic fibrosis respiratory tract bacterial communities and age, genotype, antibiotics and Pseudomonas aeruginosa. AB - Polymicrobial bronchopulmonary infections in cystic fibrosis (CF) cause progressive lung damage and death. Although the arrival of Pseudomonas aeruginosa often heralds a more rapid rate of pulmonary decline, there is significant inter individual variation in the rate of decline, the causes of which remain poorly understood. By coupling culture-independent methods with ecological analyses, we discovered correlations between bacterial community profiles and clinical disease markers in respiratory tracts of 45 children with CF. Bacterial community complexity was inversely correlated with patient age, presence of P. aeruginosa and antibiotic exposure, and was related to CF genotype. Strikingly, bacterial communities lacking P. aeruginosa were much more similar to each other than were those containing P. aeruginosa, regardless of antibiotic exposure. This suggests that community composition might be a better predictor of disease progression than the presence of P. aeruginosa alone and deserves further study. PMID- 20192961 TI - The Pseudomonas aeruginosa patatin-like protein PlpD is the archetype of a novel Type V secretion system. AB - We discovered a novel secreted protein by Pseudomonas aeruginosa, PlpD, as a member of the bacterial lipolytic enzyme family of patatin-like proteins (PLPs). PlpD is synthesized as a single molecule consisting of a secreted domain fused to a transporter domain. The N-terminus of PlpD includes a classical signal peptide followed by the four PLP conserved blocks that account for its lipase activity. The C-terminus consists of a POTRA (polypeptide transport-associated) motif preceding a putative 16-stranded beta-barrel similar to those of TpsB transporters of Type Vb secretion system. We showed that the C-terminus remains inserted into the outer membrane while the patatin moiety is secreted. The association between a TpsB component and a passenger protein is a unique hybrid organization that we propose to classify as Type Vd. More than 200 PlpD orthologues exist among pathogenic and environmental bacteria, which suggests that bacteria secrete numerous PLPs using this newly defined mechanism. PMID- 20192962 TI - Population ecology of nitrifying archaea and bacteria in the Southern California Bight. AB - Marine Crenarchaeota are among the most abundant microbial groups in the ocean, and although relatively little is currently known about their biogeochemical roles in marine ecosystems, recognition that Crenarchaeota posses ammonia monooxygenase (amoA) genes and may act as ammonia-oxidizing archaea (AOA) offers another means of probing the ecology of these microorganisms. Here we use a time series approach combining quantification of archaeal and bacterial ammonia oxidizers with bacterial community fingerprints and biogeochemistry, to explore the population and community ecology of nitrification. At multiple depths (150, 500 and 890 m) in the Southern California Bight sampled monthly from 2003 to 2006, AOA were enumerated via quantitative PCR of archaeal amoA and marine group 1 Crenarchaeota 16S rRNA genes. Based on amoA genes, AOA were highly variable in time - a consistent feature of marine Crenarchaeota- however, average values were similar at different depths and ranged from 2.20 to 2.76 x 10(4) amoA copies ml( 1). Archaeal amoA genes were correlated with Crenarchaeota 16S rRNA genes (r(2) = 0.79) and the slope of this relationship was 1.02, demonstrating that the majority of marine group 1 Crenarchaeota present over the dates and depths sampled possessed amoA. Two AOA clades were specifically quantified and compared with betaproteobacterial ammonia-oxidizing bacteria (beta-AOB) amoA genes at 150 m; these AOA groups were found to strongly co-vary in time (r(2) = 0.70, P < 0.001) whereas AOA : beta-AOB ratios ranged from 13 to 5630. Increases in the AOA : beta-AOB ratio correlated with the accumulation of nitrite (r(2) = 0.87, P < 0.001), and may be indicative of differences in substrate affinities and activities leading to periodic decoupling between ammonia and nitrite oxidation. These data capture a dynamic nitrogen cycle in which multiple microbial groups appear to be active participants. PMID- 20192963 TI - Identification of the trehalose biosynthetic loci of Pseudomonas syringae and their contribution to fitness in the phyllosphere. AB - Surprisingly little is known of the trehalose biosynthetic pathways in pseudomonads, despite the importance of trehalose to protecting cells from environmental stresses such as low water availability. The genome of the foliar pathogen Pseudomonas syringae pv. tomato strain DC3000 contains genes for two trehalose biosynthetic pathways, TreS and TreYZ, and lacks genes for the more common OtsAB pathway. Deletion of either the treS (PSPTO_2760-2762) or treY/treZ (PSPTO_3125-3134) locus eliminated trehalose accumulation and reduced bacterial growth under hyperosmotic conditions. In evaluating the role of trehalose in P. syringae fitness on leaves, we found that a double deletion mutant lacking these loci exhibited poorer survival than the wild type on tomato leaves over a 2-week period in a growth chamber. Similarly, this mutant exhibited reduced survival on leaves of susceptible and resistant cultivars of the host plant tomato and of the non-host plant soybean over a 10-day period in field plots. Thus, the trehalose biosynthetic loci in P. syringae, which are highly conserved among pseudomonads, contributed to DC3000 fitness on leaves, supporting a role for trehalose in P. syringae survival and population maintenance in the phyllosphere. PMID- 20192964 TI - The effects of submerged aquatic vegetation on the persistence of environmental populations of Enterococcus spp. AB - Enterococcus spp. are utilized worldwide as faecal indicator bacteria, but certain strains exhibit extended survival in environmental habitats and the factors influencing their persistence are poorly understood. We used flowing freshwater mesocosms to explore the effect of submerged aquatic vegetation (SAV) on the persistence of natural enterococci populations from a subtropical lake. The highest mean densities of culturable enterococci over 2 weeks occurred in SAV [8.6 x 10(2) colony-forming units (cfu) per 100 g wet weight], followed by sediments (1.3 x 10(2) cfu per 100 g) and water (18 cfu per 100 ml). However, due to relative differences in the total mass of each substrate in the entire system (water > sediments > SAV), SAV-associated enterococci represented only a minor proportion of the total population. Vegetated mesocosms harboured significantly higher mean cfu per mesocosm and cfu densities in sediments compared with their unvegetated counterparts, suggesting that SAV indirectly facilitates persistence in aquatic habitats. Populations were dominated (> 96%) by a single Enterococcus casseliflavus strain according to BOX-PCR genotyping, which did not change over the 10-month study and strongly suggests bacterial replication in the lake. The presence of such strains in the environment may represent highly competitive, naturalized and reproducing indicator bacteria populations that are not directly related to pollution events. PMID- 20192965 TI - Time-resolved genetic responses of Lactococcus lactis to a dairy environment. AB - Lactococcus lactis is one of main bacterial species found in mixed dairy starter cultures for the production of semi-hard cheese. Despite the appreciation that mixed cultures are essential for the eventual properties of the manufactured cheese the vast majority of studies on L. lactis were carried out in laboratory media with a pure culture. In this study we applied an advanced recombinant in vivo expression technology (R-IVET) assay in combination with a high-throughput cheese-manufacturing protocol for the identification and subsequent validation of promoter sequences specifically induced during the manufacturing and ripening of cheese. The system allowed gene expression measurements in an undisturbed product environment without the use of antibiotics and in combination with a mixed strain starter culture. The utilization of bacterial luciferase as reporter enabled the real-time monitoring of gene expression in cheese for up to 200 h after the cheese-manufacturing process was initiated. The results revealed a number of genes that were clearly induced in cheese such as cysD, bcaP, dppA, hisC, gltA, rpsE, purL, amtB as well as a number of hypothetical genes, pseudogenes and notably genetic elements located on the non-coding strand of annotated open reading frames. Furthermore genes that are likely to be involved in interactions with bacteria used in the mixed strain starter culture were identified. PMID- 20192966 TI - Thermophilic anaerobes in Arctic marine sediments induced to mineralize complex organic matter at high temperature. AB - Marine sediments harbour diverse populations of dormant thermophilic bacterial spores that become active in sediment incubation experiments at much higher than in situ temperature. This response was investigated in the presence of natural complex organic matter in sediments of two Arctic fjords, as well as with the addition of freeze-dried Spirulina or individual high-molecular-weight polysaccharides. During 50 degrees C incubation experiments, Arctic thermophiles catalysed extensive mineralization of the organic matter via extracellular enzymatic hydrolysis, fermentation and sulfate reduction. This high temperature induced food chain mirrors sediment microbial processes occurring at cold in situ temperatures (near 0 degrees C), yet it is catalysed by a completely different set of microorganisms. Using sulfate reduction rates (SRR) as a proxy for organic matter mineralization showed that differences in organic matter reactivity determined the extent of the thermophilic response. Fjord sediments with higher in situ SRR also supported higher SRR at 50 degrees C. Amendment with Spirulina significantly increased volatile fatty acids production and SRR relative to unamended sediment in 50 degrees C incubations. Spirulina amendment also revealed temporally distinct sulfate reduction phases, consistent with 16S rRNA clone library detection of multiple thermophilic Desulfotomaculum spp. enriched at 50 degrees C. Incubations with four different fluorescently labelled polysaccharides at 4 degrees C and 50 degrees C showed that the thermophilic population in Arctic sediments produce a different suite of polymer-hydrolysing enzymes than those used in situ by the cold-adapted microbial community. Over time, dormant marine microorganisms like these are buried in marine sediments and might eventually encounter warmer conditions that favour their activation. Distinct enzymatic capacities for organic polymer degradation could allow specific heterotrophic populations like these to play a role in sustaining microbial metabolism in the deep, warm, marine biosphere. PMID- 20192967 TI - Biosynthesis of uronamide sugars in Pseudomonas aeruginosa O6 and Escherichia coli O121 O antigens. AB - The major component of the outer leaflet of the outer membrane of Gram-negative bacteria is lipopolysaccharide (LPS). The outermost domain of LPS is a polysaccharide called O antigen. Pseudomonas aeruginosa establishes biofilms on wet surfaces in a wide range of habitats and mutations in O-antigen biosynthesis genes affect bacterial adhesion and the structure of these biofilms. The P. aeruginosa O6 O antigen contains a 2-acetamido-2-deoxy-d-galacturonamide (d GalNAcAN) residue. O-antigen biosynthesis in this serotype requires the wbpS gene, which encodes a protein with conserved domains of the glutamine-dependent amidotransferase family. Replacement of conserved amino acids in the N-terminal glutaminase conserved domain of WbpS inhibited O-antigen biosynthesis under restricted-ammonia conditions, but not in rich media; suggesting that this domain functions to provide ammonia for O-antigen biosynthesis under restricted-ammonia conditions, by hydrolysis of glutamine. Escherichia coli O121 also produces a d GalNAcAN-containing O antigen, and possesses a homologue of wbpS called wbqG. An E. coli O121 wbqG mutant was cross-complemented by providing wbpS in trans, and vice versa, showing that these two genes are functionally interchangeable. The E. coli O121 wbqG mutant O antigen contains 2-acetamido-2-deoxy-d-galacturonate (d GalNAcA), instead of d-GalNAcAN, demonstrating that wbqG is specifically required for biosynthesis of the carboxamide in this sugar. PMID- 20192968 TI - DNA sequence-based analysis of the Pseudomonas species. AB - Partial sequences of four core 'housekeeping' genes (16S rRNA, gyrB, rpoB and rpoD) of the type strains of 107 Pseudomonas species were analysed in order to obtain a comprehensive view regarding the phylogenetic relationships within the Pseudomonas genus. Gene trees allowed the discrimination of two lineages or intrageneric groups (IG), called IG P. aeruginosa and IG P. fluorescens. The first IG P. aeruginosa, was divided into three main groups, represented by the species P. aeruginosa, P. stutzeri and P. oleovorans. The second IG was divided into six groups, represented by the species P. fluorescens, P. syringae, P. lutea, P. putida, P. anguilliseptica and P. straminea. The P. fluorescens group was the most complex and included nine subgroups, represented by the species P. fluorescens, P. gessardi, P. fragi, P. mandelii, P. jesseni, P. koreensis, P. corrugata, P. chlororaphis and P. asplenii. Pseudomonas rhizospherae was affiliated with the P. fluorescens IG in the phylogenetic analysis but was independent of any group. Some species were located on phylogenetic branches that were distant from defined clusters, such as those represented by the P. oryzihabitans group and the type strains P. pachastrellae, P. pertucinogena and P. luteola. Additionally, 17 strains of P. aeruginosa, 'P. entomophila', P. fluorescens, P. putida, P. syringae and P. stutzeri, for which genome sequences have been determined, have been included to compare the results obtained in the analysis of four housekeeping genes with those obtained from whole genome analyses. PMID- 20192969 TI - Aqueous films limit bacterial cell motility and colony expansion on partially saturated rough surfaces. AB - Bacterial motility is a key mechanism for survival in a patchy environment and is important for ecosystem biodiversity maintenance. Quantitative description of bacterial motility in soils is hindered by inherent heterogeneity, pore-space complexity and dynamics of microhydrological conditions. Unsaturated conditions result in fragmented aquatic habitats often too small to support full bacterial immersion thereby forcing strong interactions with mineral and air interfaces that significantly restrict motility. A new hybrid model was developed to study hydration effects on bacterial motility. Simulation results using literature parameter values illustrate sensitivity of colony expansion rates to hydration conditions and are in general agreement with measured values. Under matric potentials greater than -0.5 kPa (wet), bacterial colonies grew fast at colony expansion rates exceeding 421 +/- 94 microm h(-1); rates dropped significantly to 31 +/- 10 microm h(-1) at -2 kPa; as expected, no significant colony expansion was observed at -5 kPa because of the dominance of capillary pinning forces in the submicrometric water film. Quantification of hydration-related constraints on bacterial motion provides insights into optimal conditions for bacterial dispersion and spatial ranges of resource accessibility important for bioremediation and biogeochemical cycles. Results define surprisingly narrow range of hydration conditions where motility confers ecological advantage on natural surfaces. PMID- 20192970 TI - Persistence of bacterial and archaeal communities in sea ice through an Arctic winter. AB - The structure of bacterial communities in first-year spring and summer sea ice differs from that in source seawaters, suggesting selection during ice formation in autumn or taxon-specific mortality in the ice during winter. We tested these hypotheses by weekly sampling (January-March 2004) of first-year winter sea ice (Franklin Bay, Western Arctic) that experienced temperatures from -9 degrees C to -26 degrees C, generating community fingerprints and clone libraries for Bacteria and Archaea. Despite severe conditions and significant decreases in microbial abundance, no significant changes in richness or community structure were detected in the ice. Communities of Bacteria and Archaea in the ice, as in under ice seawater, were dominated by SAR11 clade Alphaproteobacteria and Marine Group I Crenarchaeota, neither of which is known from later season sea ice. The bacterial ice library contained clones of Gammaproteobacteria from oligotrophic seawater clades (e.g. OM60, OM182) but no clones from gammaproteobacterial genera commonly detected in later season sea ice by similar methods (e.g. Colwellia, Psychrobacter). The only common sea ice bacterial genus detected in winter ice was Polaribacter. Overall, selection during ice formation and mortality during winter appear to play minor roles in the process of microbial succession that leads to distinctive spring and summer sea ice communities. PMID- 20192972 TI - Temperature controls on aquatic bacterial production and community dynamics in arctic lakes and streams. AB - The impact of temperature on bacterial activity and community composition was investigated in arctic lakes and streams in northern Alaska. Aquatic bacterial communities incubated at different temperatures had different rates of production, as measured by (14)C-leucine uptake, indicating that populations within the communities had different temperature optima. Samples from Toolik Lake inlet and outlet were collected at water temperatures of 14.2 degrees C and 15.9 degrees C, respectively, and subsamples incubated at temperatures ranging from 6 degrees C to 20 degrees C. After 5 days, productivity rates varied from 0.5 to approximately 13.7 microg C l(-1) day(-1) and two distinct activity optima appeared at 12 degrees C and 20 degrees C. At these optima, activity was 2- to 11 fold higher than at other incubation temperatures. The presence of two temperature optima indicates psychrophilic and psychrotolerant bacteria dominate under different conditions. Community fingerprinting via denaturant gradient gel electrophoresis (DGGE) of 16S rRNA genes showed strong shifts in the composition of communities driven more by temperature than by differences in dissolved organic matter source; e.g. four and seven unique operational taxonomic units (OTUs) were found only at 2 degrees C and 25 degrees C, respectively, and not found at other incubation temperatures after 5 days. The impact of temperature on bacteria is complex, influencing both bacterial productivity and community composition. Path analysis of measurements of 24 streams and lakes sampled across a catchment 12 times in 4 years indicates variable timing and strength of correlation between temperature and bacterial production, possibly due to bacterial community differences between sites. As indicated by both field and laboratory experiments, shifts in dominant community members can occur on ecologically relevant time scales (days), and have important implications for understanding the relationship of bacterial diversity and function. PMID- 20192973 TI - Quorum sensing-controlled Evr regulates a conserved cryptic pigment biosynthetic cluster and a novel phenomycin-like locus in the plant pathogen, Pectobacterium carotovorum. AB - Pectobacterium carotovorum SCRI193 is a phytopathogenic Gram-negative bacterium. In this study, we have identified a novel cryptic pigment biosynthetic locus in P. carotovorum SCRI193 which we have called the Pectobacterium orange pigment (pop) cluster. The pop cluster is flanked by two tRNA genes and contains genes that encode non-ribosomal peptide synthases and polyketide synthase and produces a negatively charged polar orange pigment. Orange pigment production is activated when an adjacent transcriptional activator sharing sequence similarity with the Erwinia virulence regulator (Evr) is overexpressed. Evr was shown to positively activate its own transcription and that of the pigment biosynthetic genes and an unlinked locus encoding a phenomycin homologue. In addition, the expression of Evr and orange pigment production was shown to be regulated by N-(3-oxohexanoyl) HSL (OHHL) quorum sensing and have a virulence phenotype in potato. Finally, by comparative genomics and Southern blotting we demonstrate that this pigment biosynthetic cluster is present in multiple P. carotovorum spp., Pectobacterium brasiliensis 1692 and a truncated version of the cluster is present in Pectobacterium atrosepticum. The conserved nature of this cluster in P. carotovorum and P. brasiliensis suggests that the pop cluster has an important function in these broad-host-range soft rotting bacteria, which is no longer required in the narrow-host-range P. atrosepticum SCRI1043. PMID- 20192974 TI - Serum procalcitonin, C-reactive protein and white blood cell levels following hypothermia after cardiac arrest: a retrospective cohort study. AB - INTRODUCTION: The aim of this study was to investigate time course of procalcitonin (PCT), C-reactive protein (CRP) and white blood cell (WBC) levels in patients with therapeutic hypothermia after cardiac arrest. METHODS: We retrospectively assessed laboratory and clinical data in a consecutive cohort of patients admitted to the medical intensive-care-unit of the University Hospital in Basel, Switzerland, in whom therapeutic hypothermia was induced because of cardiac arrest between December 2007 and January 2009. Infection was considered based on microbiological evidence (restricted definition) and/or clinical evidence of infection with prescription of antibiotics (extended definition). RESULTS: From 34 included patients, 25 had respiratory tract infection based on the clinical judgment and in 18 microbiological cultures turned positive (restricted definition). PCT concentrations were highest on the first day after hypothermia and showed a steady decrease until day 7 without differences in patients with and without presumed infection. CRP concentrations increased to a peak level at days 3-4 followed by a steady decrease; CRP concentrations were higher in patients with clinical diagnosis of infection on day 4 (P = 0.02); and in patients with evidence of bacterial growth in cultures on days 4 and 5 (P = 0.01 and P = 0.006). WBC remained unchanged after hypothermia without differences between patients with and without infection. CONCLUSION: High initial values of PCT and high peak levels after 3-4 days of CRP were found in patients with induction of hypothermia after cardiac arrest. This increase was unspecific and mirrors rather an inflammatory reaction than true underlying infection, limiting the diagnostic potential for early antibiotic stewardship in these patients. PMID- 20192975 TI - Neurological manifestations of antiphospholipid syndrome. AB - BACKGROUND: Neurologic disorders are among the most common and important clinical manifestations associated with the antiphospholipid syndrome (APS). It is characterized by diverse neurological manifestations. These include stroke, transient ischaemic attack, Sneddon's syndrome, convulsions/epilepsy, dementia, cognitive deficits, headaches/migraine, chorea, multiple sclerosis-like, transverse myelitis, ocular symptoms and Guillain-Barre syndrome. MATERIAL AND METHODS: We review the latest data about neurologic disorders and APS. RESULTS: In patients under 45 years of age, 20% of strokes are potentially associated with APS. Our study group recently reported a correlation between primary APS and peripheral neuropathy. Only one study investigated the occurrence of peripheral neuropathy in patients diagnosed with PAPS through electrophysiological study and showed alterations in 35% of patients. The mechanism of nervous system involvement in APS is considered to be primarily thrombotic. However, other mechanisms have been described, such as antiphospholipid antibodies that bind to the neural tissue, deregulating their functions and having an immediate pathogenic effect. CONCLUSIONS: This review summarizes the latest data regarding the clinical aspects, radiological and therapeutic of major neurologic manifestations associated with antiphospholipid antibodies. PMID- 20192976 TI - Osteopontin as a novel prognostic marker in stable ischaemic heart disease: a 3 year follow-up study. AB - OBJECTIVES: Osteopontin (OPN) is a glycoprotein, which may play a major role in the regulation of biological phenomena. Increased levels of OPN have been linked to the presence and to the severity of atherosclerosis. This study was undertaken to assess the prognostic significance of plasma OPN levels in patients with stable ischaemic heart disease (IHD). METHODS: In 101 patients with stable IHD and angiographically documented significant coronary artery stenosis, plasma OPN levels were measured at baseline (time of coronary arteriography). Patients were prospectively followed for a median time of 3 years (minimum 2.25, maximum 3.9 years). The primary study endpoint was the composite of cardiovascular death, non fatal myocardial infarction, need for revascularization and hospitalization for cardiovascular reasons. RESULTS: Baseline lnOPN levels were directly related to age (r = 0.27, P < 0.001) and inversely to left ventricular ejection fraction (r = -0.32, P < 0.01). Left ventricular ejection fraction was an independent predictor of plasma OPN levels after adjustment for age and gender (beta = 0.013, P = 0.02). Median OPN value was 55 ng mL(-1). In the univariate Cox regression analysis, OPN levels > 55 ng mL(-1) (n = 50) were significantly related to adverse cardiac outcome (HR = 2.40, 95% CI: 1.11-5.23, P = 0.027). In multivariate model, OPN levels > 55 ng mL(-1) remained statistically significant independent predictor of adverse outcome after adjustment for age, gender, left ventricular ejection fraction and the number of diseased coronary arteries (HR = 2.88, 95% CI: 1.09-7.58, P = 0.032). CONCLUSION: OPN may provide significant prognostic information independent of other traditional prognostic markers in patients with stable IHD. PMID- 20192977 TI - Autonomic symptoms in patients and pre-manifest mutation carriers of Huntington's disease. AB - BACKGROUND AND PURPOSE: Although autonomic function tests have revealed abnormalities of the autonomic nervous system in Huntington's disease (HD), autonomic symptoms and their association with other symptoms and signs of HD have not yet been assessed in large groups of patients or pre-manifest mutation carriers. Therefore, we aimed at delineating the characteristics and correlates of autonomic symptoms in HD. METHODS: Using the scales for outcomes in Parkinson's disease-autonomic symptoms (SCOPA-AUT) and Beck Depression Inventory questionnaires, autonomic symptoms and depressed mood were assessed in 63 patients with HD, 21 pre-manifest mutation carriers, and 85 controls. The Unified Huntington's Disease Rating Scale was used to assess other HD symptoms and signs. RESULTS: Relative to controls, patients with HD experienced significantly more gastrointestinal, urinary, cardiovascular and, in men, sexual problems. The most prevalent symptoms were swallowing difficulties, erection and ejaculation problems, dysphagia, sialorrhea, early abdominal fullness, straining for defecation, fecal and urinary incontinence, urgency, incomplete bladder emptying, and light-headedness whilst standing. Pre-manifest mutation carriers experienced significantly more swallowing difficulties and light-headedness on standing up compared with controls. In patients with HD, autonomic symptoms were associated with a greater degree of functional disability, more severe depression, and antidepressant drugs use. However, depression was the only independent predictor of autonomic dysfunction. CONCLUSIONS: Autonomic symptoms are highly prevalent in patients with HD and may even precede the onset of motor signs. Moreover, autonomic dysfunction is related to functional disability and depression in HD. PMID- 20192978 TI - Clinical effects of deep brain stimulation on gait disorders in Parkinson's disease. PMID- 20192971 TI - Microbial diversity and biogeochemistry of the Guaymas Basin deep-sea hydrothermal plume. AB - Hydrothermal plumes are hot spots of microbial biogeochemistry in the deep ocean, yet little is known about the diversity or ecology of microorganisms inhabiting plumes. Recent biogeochemical evidence shows that Mn(II) oxidation in the Guaymas Basin (GB) hydrothermal plume is microbially mediated and suggests that the plume microbial community is distinct from deep-sea communities. Here we use a molecular approach to compare microbial diversity in the GB plume and in background deep seawater communities, and cultivation to identify Mn(II) oxidizing bacteria from plumes and sediments. Despite dramatic differences in Mn(II) oxidation rates between plumes and background seawater, microbial diversity and membership were remarkably similar. All bacterial clone libraries were dominated by Gammaproteobacteria and archaeal clone libraries were dominated by Crenarchaeota. Two lineages, both phylogenetically related to methanotrophs and/or methylotrophs, were consistently over-represented in the plume. Eight Mn(II)-oxidizing bacteria were isolated, but none of these or previously identified Mn(II) oxidizers were abundant in clone libraries. Taken together with Mn(II) oxidation rates measured in laboratory cultures and in the field, these results suggest that Mn(II) oxidation in the GB hydrothermal plume is mediated by genome-level dynamics (gene content and/or expression) of microorganisms that are indigenous and abundant in the deep sea but have yet to be unidentified as Mn(II) oxidizers. PMID- 20192979 TI - Integrin beta-3 L33P: a new insight into the pathogenesis of chronic oxaliplatin induced peripheral neuropathy? AB - AIM: To assess the significance of the ITGB3 polymorphism at residue 33 (ITGB3 L33P) in the development of chronic oxaliplatin-induced peripheral neuropathy (OXLIPN). METHODS: Fifty-five patients with advanced colorectal cancer were genotyped, using allele-specific primers and sybr green in real-time PCR. Patients had received adjuvant oxaliplatin-based chemotherapy. The severity of the OXLIPN was defined by means of the clinical total neuropathy score (TNSc). Following the discontinuation of treatment, 34/55 patients (61.8%) developed OXLIPN. Grade I neurotoxicity was revealed in 13 (38.2%) patients and grade II neurotoxicity in 21 (61.8%) patients. RESULTS: Patients without OXLIPN (n = 21) were 19% homozygous for C, 33.3% were heterozygous, and 47.7% were homozygous for T. The corresponding percentages for patients developing any grade of OXLIPN (n = 34) were similar. About half of patients (46.1%) with grade I OXLIPN were heterozygotes (CT), 23.1% were CC, and 30.8% were TT. The majority of patients with grade II OXLIPN were TT (66.7%) with the remaining 33.3% being CT. The TT genotype was associated with increased severity of OXLIPN compared to the genotypes containing the C allele (P = 0.044). CONCLUSION: The ITGB3 L33P seems to be unrelated to the development of OXLIPN, but it appears to be related to its severity. PMID- 20192980 TI - The interleukin-1 cluster gene region is associated with multiple sclerosis in an Italian Caucasian population. AB - BACKGROUND: Polymorphisms of the interleukin-1 (IL-1) gene family have been proposed as potential variants for different diseases including multiple sclerosis (MS). With respect to MS, IL-1 beta (-511 C/T; rs16944), IL-1 beta (+3954 C/T; rs1143634), IL-1 alpha (-889 C/T; rs1800587), IL-1 alpha (+4845 G/T; rs17561), and the variable number of tandem repeats in intron 2 of the IL-1 receptor antagonist (IL-1RN) gene polymorphisms have been studied in different ethnic groups, leading to conflicting results. METHODS: This study investigates the association between IL-1 genes and MS by means of 70 markers spanning the 1.1 Mb region where the IL-1 genes map and exploring both the linkage disequilibrium (LD) and the haplotype structure in a case-control design including 410 subjects (160 patients and 250 controls). RESULTS: From allelic/genotypic tests, significant association was found for several polymorphisms including the IL-1 beta (-511 C/T) variant (P-adjusted = 4.5 x 10(-4)) and some polymorphisms around the IL-1RN gene. The 'block-step' pattern obtained from both the LD map and pairwise analysis identifies four LD regions. Region 1 showed a significant association with MS for the global test (P < 0.0001) and haplotypes containing the IL-1 beta (-511 C/T) variant still demonstrate highly significant association with disease (P-value range: 9.9 x 10(-5) to 0.02). CONCLUSIONS: Our findings support the existence of a causative variant for MS within this candidate region in a representative Italian Caucasian population and, in particular, the role of the IL-1 beta (-511 C/T) variant warrants further investigation. PMID- 20192981 TI - Alzheimer's disease, Parkinson's disease and essential tremor: three common degenerative diseases with shared mechanisms? PMID- 20192983 TI - TREX1 mutations are not associated with sporadic inclusion body myositis. AB - BACKGROUND: Sporadic inclusion body myositis (sIBM) is the most frequent acquired myopathy above the age of fifty. The exact mechanism causing this disease is not known, but immune-mediated features are prominent and are probably to play a role in its pathogenesis. TREX1 gene mutations are associated with a large range of autoimmune diseases, such as systemic lupus erythematosus. We investigated whether mutations in the TREX1 gene were associated with sIBM. METHODS: Fifty four patients with sIBM were tested for TREX1 mutations by direct sequencing. RESULTS: All 54 patients tested negative for pathogenic mutations in the TREX1 gene. One presumed non-pathogenic polymorphism was found in 42 out of 54 patients. CONCLUSION: TREX1 mutations do not play a role in the pathogenesis of sIBM. PMID- 20192982 TI - Comorbidities amongst patients with multiple sclerosis: a population-based controlled study. AB - BACKGROUND: Data regarding the wide spectrum of comorbidity amongst patients with multiple sclerosis (MS) are still scanty, especially in Asian populations. Our goal was to analyze comorbidity prevalences and risks amongst Chinese patients with MS, compared to matched controls. METHODS: In total, 898 patients with MS and 4490 randomly matched individuals without MS were extracted from the National Health Insurance Research Dataset in Taiwan. We selected 30 comorbid medical conditions for analysis. Conditional logistic regression analyses were used to examine the risks of comorbidity between the two groups. RESULTS: The regression analyses showed that patients with MS were more likely to have systemic lupus erythematosus (OR = 26.9, 95% CI = 10.3-70.3), depression (OR = 6.9, 95% CI = 5.3 8.9), peripheral vascular disorders (OR = 6.6, 95% CI = 4.0-11.0), deficiency anemias (OR = 4.9, 95% CI = 2.8-8.7), rheumatoid arthritis (OR = 4.8, 95% CI = 2.9-8.1) and fluid and electrolyte disorders (OR = 4.8, 95% CI = 2.8-8.3) than the matched controls. CONCLUSIONS: Patients with MS had higher risk of multiple medical comorbidities compared to a matched control group in an ethnic Chinese population. PMID- 20192984 TI - Electrically evoked nociceptive potentials for early detection of diabetic small fiber neuropathy. AB - BACKGROUND AND PURPOSE: This study investigated the utility of pain-related evoked potentials (PREP's) elicited by a nociceptive electrical stimulation of the skin (= electrically evoked nociceptive potentials) in early detection of diabetic small-fiber neuropathy. METHODS: We studied 36 'young' (19-35 years) and 24 'older' (36-65 years) healthy subjects as well as 35 patients (35-64 years) with diabetes and neuropathic symptoms and 22 patients (34-64 years) with diabetes without neuropathic symptoms. Only patients with normal standard nerve conduction testing were included. RESULTS: In patients with neuropathic symptoms, we found a significant increase in PREP latencies and decrease of amplitudes elicited from both, upper and lower limbs. In non-symptomatic diabetic patients, we observed PREP abnormalities from lower limbs only. CONCLUSIONS: These data suggest that the method of pain-related evoked potentials elicited by a nociceptive electrical stimulation of the skin may contribute to the early detection of diabetic sensory neuropathy. PMID- 20192985 TI - The proteasome inhibitor bortezomib inhibits FGF-2-induced reduction of TAZ levels in osteoblast-like cells. AB - OBJECTIVES: Bortezomib (PS-341; Velcade), a proteasome inhibitor, is used as a therapeutic agent for multiple myeloma. Bortezomib has been shown to strongly induce osteoblast differentiation and elevate the levels of osteoblast-related differentiation markers in the serum of patients with myeloma. Bortezomib also reportedly increases the activity of the transcription factor, Runx2. However, the mechanism of action by which bortezomib-elevated Runx2 activity mediates osteoblast differentiation remains unclear. On the other hand, fibroblast growth factor 2 (FGF-2) is found at high levels in patients with multiple myeloma. We previously reported that FGF-2 reduces the levels of the transcriptional coactivator with PDZ-binding motif (TAZ). We therefore investigated the effects of bortezomib on TAZ protein levels in the presence of FGF-2. METHODS: Osteoblastic MC3T3-E1 cells were treated with different concentrations of bortezomib in the presence or absence of FGF-2 and various biologic responses were investigated by immunoblotting, RT-PCR, quantitative PCR, and alizarin red staining. RESULTS: We found that bortezomib inhibited FGF-2-induced reduction of TAZ levels through a pathway other than that used for proteasome inhibition, while maintaining TAZ function, which in turn, enhanced the expression of Runx2 transcribed osteogenic differentiation markers. Bortezomib also suppressed the antimineralization effect of FGF-2. CONCLUSIONS: These findings suggest that bortezomib inhibited FGF-2-induced reduction of TAZ and consequently stimulated osteogenic differentiation independently of proteasome inhibition. These findings may contribute to elucidate the osteolytic mechanism in multiple myeloma, and to the development of new drugs for multiple myeloma and other osteolytic diseases. PMID- 20192986 TI - Thalidomide-dexamethasone as up-front therapy for patients with newly diagnosed multiple myeloma: thrombophilic alterations, thrombotic complications, and thromboprophylaxis with low-dose warfarin. AB - BACKGROUND: Venous thromboembolism (VTE) is a major complication of myeloma therapy recently observed with the increasing use of up-front thalidomide and dexamethasone (thal-dex). The pathogenesis of thal-induced VTE is not well recognized, and the role of prothrombotic factors, especially of thrombophilic abnormalities, is not yet determined. MATERIAL AND METHODS: Two hundred and sixty six patients with newly diagnosed multiple myeloma (MM) were primarily treated with thal-dex in preparation for subsequent high-dose therapy and autologous stem cell transplantation. Out of these 266 patients, 190 were evaluated for thrombophilic alterations at baseline, and 125 of them were also re-assessed after thal-dex therapy. RESULTS: The presence of genetic thrombophilic polymorphisms among patients with MM was superimposable to that of normal controls and was associated with a twofold increase in the relative risk of VTE. aAPCR and elevated factor VIII levels were frequent, albeit transient, alterations and were not associated with a significant increase in the risk of VTE. Two hundred and forty-six patients received a thromboprophylaxis with fixed low-dose warfarin (1.25 mg/day) during thal-dex therapy. Of these patients (or 10.6%), 26 had symptomatic VTE events. Their patients-years rate of VTE (35.5%) was significantly lower in comparison with the 86.2% rate recorded among the first 19 patients who initially entered the study and did not receive any kind of thromboprophylaxis (P = 0.043). CONCLUSIONS: On the basis of these data, a baseline thrombophilic work up is not recommended in patients with receiving up front thal-dex. For these patients, fixed low-dose warfarin may be a valuable prophylaxis against VTE. PMID- 20192987 TI - Epigenetic therapy in myelodysplastic syndromes. AB - The wide spectrum of clonal hematopoietic disorders that fall under the broad diagnostic category of myelodysplastic syndromes (MDS) consist of a family of bone marrow malignancies - with ineffective, inadequate, and dysplastic hematopoiesis, and with an increased risk of life-threatening infections, bleeding, and progression to acute myeloid leukemia (AML) - that are characterized by a deep heterogeneity on the clinical, biologic and prognostic level. The intrinsic complexity of this group of disorders and the frequent association with one or more comorbidities have limited for many years the number of effective treatment options available: most patients are, indeed, still managed by supportive care measures, with just a minority of them being eligible for allogeneic stem cell transplantation, which is still the only potentially curative modality. In the last two decades, the progressively better understanding of MDS biology has shown how an abnormal epigenetic modulation might play a crucial part in the pathogenesis and in the process of biologic evolution of these disorders. Moreover, pharmacological agents that target the so called epigenome have shown a significant clinical activity for diverse hematologic malignancies, including MDS. The aim of this review is to highlight recent developments within the context of current knowledge of MDS and its altered epigenetic regulation and to recall the experimental steps that have brought to the clinical development and application of epigenetic modifiers, such as azacytidine and decitabine, trying to explain the biologic rationale for their use in this setting. PMID- 20192988 TI - Lenalidomide and dexamethasone for the treatment of refractory/relapsed multiple myeloma: dosing of lenalidomide according to renal function and effect on renal impairment. AB - OBJECTIVES: Lenalidomide and dexamethasone (LenDex) is an active regimen for relapsed/refractory multiple myeloma (MM). However, there is limited data for the effect of LenDex on renal impairment (RI) and on renal reversibility. PATIENTS & METHODS: Fifty consecutive patients with relapsed/refractory MM received LenDex in 28-d cycles. Median lines of previous therapies were 2 (range: 1-6). Lenalidomide was administered on days 1-21 according to creatinine clearance (CrCl), while dexamethasone was given at a dose of 40 mg on days 1-4 and 15-18 for the first four cycles and only on days 1-4 thereafter. RESULTS: Twelve patients (24%) had RI at baseline, defined as CrCl < 50 mL/min. Most patients were pretreated with either thalidomide or bortezomib and > 50% of them were refractory to both drugs. At least partial response was documented in 60.5% and 58% of patients with and without RI. Median progression-free survival (PFS) and overall survival (OS) for all patients was 9 and 16 months, respectively. RI was not associated with an inferior PFS or OS. There were no differences in the incidence of adverse events among patients with and without RI. Three of 12 patients with RI (25%) achieved complete renal response and two (16%) achieved minor renal response with LenDex. CONCLUSIONS: We conclude that LenDex is an active treatment even in heavily pretreated MM. With dosing of lenalidomide according to renal function, LenDex can be administered to patients with RI (who may not have other treatment options) without excessive toxicity. Furthermore, LenDex may improve the renal function in approximately 40% of patients with RI. PMID- 20192989 TI - Inflammatory arthritis--an exciting confluence of human and animal research. PMID- 20192990 TI - Antibodies to citrullinated proteins: molecular interactions and arthritogenicity. AB - The discovery of antibodies specific for citrullinated protein epitopes [anti citrullinated protein antibodies (ACPAs)] is a hallmark for the diagnosis and prognosis of rheumatoid arthritis (RA) and will also be a useful tool for understanding the fundamental pathologic processes. There are several essential questions pertaining to ACPA that remain to be explored, such as understanding the early specificity of the underlying T-cell recognition, whether the production of ACPA is a primary or secondary process, and in the event of such antibodies being arthritogenic, whether they could possibly regulate the disease development. To answer these questions, animal models are needed, but unfortunately ACPA is not a prominent feature of any of the classical animal models of RA. However, we showed recently that ACPA can be isolated from animals susceptible to collagen-induced arthritis that are specific for citrullinated type II collagen (CII). The citrulline specificity could be visualized, and the specificity is determined primarily by a direct interaction with citrulline. We also demonstrated that these antibodies are specific for the citrullinated epitopes and are pathogenic in vivo. A new hypothesis to explain how inflammation in RA can be directed to cartilaginous joints and be self-perpetuating is suggested, which involves recognition of post-translational modifications (glycosylation and citrullination) on CII by T and B cells that can have both arthritogenic and regulatory consequences. PMID- 20192991 TI - Autoimmunity to specific citrullinated proteins gives the first clues to the etiology of rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is now clearly a true autoimmune disease with accumulating evidence of pathogenic disease-specific autoimmunity to citrullinated proteins. Citrullination, also termed deimination, is a modification of arginine side chains catalyzed by peptidylarginine deiminase (PAD) enzymes. This post-translational modification has the potential to alter the structure, antigenicity, and function of proteins. In RA, antibodies to cyclic citrullinated peptides are now well established for clinical diagnosis, though we argue that the identification of specific citrullinated antigens, as whole proteins, is necessary for exploring pathogenic mechanisms. Four citrullinated antigens, fibrinogen, vimentin, collagen type II, and alpha enolase, are now well established, with others awaiting further characterization. All four proteins are expressed in the joint, and there is evidence that antibodies to citrullinated fibrinogen and collagen type II mediate inflammation by the formation of immune complexes, both in humans and animal models. Antibodies to citrullinated proteins are associated with HLA 'shared epitope' alleles, and autoimmunity to at least one antigenic sequence, the CEP-1 peptide from citrullinated alpha-enolase (KIHAcitEIFDScitGNPTVE), shows a specific association with HLA-DRB1*0401, *0404, 620W PTPN22, and smoking. Periodontitis, in which Porphyromonas gingivalis is a major pathogenic bacterium, has been linked to RA in epidemiological studies and also shares similar gene/environment associations. This is also the only bacterium identified that expresses endogenous citrullinated proteins and its own bacterial PAD enzyme, though the precise molecular mechanisms of bacterial citrullination have yet to be explored. Thus, both smoking and Porphyromonas gingivalis are attractive etiological agents for further investigation into the gene/environment/autoimmunity triad of RA. PMID- 20192992 TI - Gene discovery in rheumatoid arthritis highlights the CD40/NF-kappaB signaling pathway in disease pathogenesis. AB - During the past several years, substantial progress has been made in the identification of genetic variants that predispose to rheumatoid arthritis (RA) and other autoimmune disorders. Progress in this area has been facilitated by the availability of new technology that allows for a much more comprehensive screen of the genome than was possible before, in conjunction with large samples of RA patients with well-characterized disease. Recent RA genetic studies have identified genes with important functions related to intracellular signaling mechanisms, transcription factors, cytokines, membrane receptors, costimulatory molecules, and enzymes. In particular, recent discoveries highlight the importance of the CD40/NF-kappaB signaling pathway in RA, based on genetic association with several genes relevant to this pathway, including CD40, TRAF1, TNFAIP3, and REL. Progress in the identification of genes that contribute to RA is proceeding at a very rapid pace. These genetic discoveries shed light on underlying disease mechanisms in RA and provide targets for the development of novel diagnostic and therapeutic tools for future use in this chronic inflammatory disorder. PMID- 20192993 TI - Role of HLA class II genes in susceptibility/resistance to inflammatory arthritis: studies with humanized mice. AB - Predisposition to develop rheumatoid arthritis (RA) has been associated with certain human leukocyte antigen (HLA) class II molecules, although the mechanism is still unknown. Various experimental animal models of inflammatory arthritis have been studied to address the role of major histocompatibility complex (MHC) genes in pathogenesis. We have generated transgenic mice expressing HLA class II molecules (DR and DQ) lacking complete endogenous class II molecules to study the interactions involved between class II molecules (DQ and DR) and to define the immunologic mechanisms in inflammatory arthritis. The HLA transgene can positively select CD4(+) T cells expressing various V beta T-cell receptors, and a peripheral tolerance is maintained to transgenic HLA molecules. The expression of HLA molecules on various cells in these mice is similar to that known in humans. In this review, we describe collagen-induced arthritis as a model for human inflammatory arthritis using these transgenic mice. The transgenic mice carrying RA-susceptible haplotype develop gender-biased inflammatory arthritis with clinical and histopathological similarities to RA. Our studies show that polymorphism of HLA class II genes determine the predisposition to rheumatoid/inflammatory arthritis and the epistatic interactions between HLA-DQ and HLA-DR molecules dictate the severity, progression, and modulation of the disease. PMID- 20192995 TI - CD4+CD25+ regulatory T cells in autoimmune arthritis. AB - CD4(+)CD25(+) regulatory T (Treg) cells can play a critical role in the prevention of autoimmunity, as evidenced by the cataclysmic autoimmune disease that develops in mice and humans lacking the key transcription factor forkhead box protein 3 (Foxp3). At present, however, how and whether Treg cells participate in the development of rheumatoid arthritis (RA), which has both systemic manifestations and a joint-targeted pathology that characterizes the disease, remains unclear. In this review, we describe work that has been carried out aimed at determining the role of Treg cells in disease development in RA patients and in mouse models of inflammatory arthritis. We also describe studies in a new model of spontaneous autoimmune arthritis (TS1 x HACII mice), in which disease is caused by CD4(+) T cells recognizing a neo-self-antigen expressed by systemically distributed antigen-presenting cells. We show that TS1 x HACII mice develop arthritis despite the presence of CD4(+)CD25(+)Foxp3(+) Treg cells that recognize this target autoantigen, and we outline steps in the development of arthritis at which Treg cells might potentially act, or fail to act, in the development of inflammatory arthritis. PMID- 20192996 TI - The role of antibodies in inflammatory arthritis. AB - Inflammatory arthritis presents in a variety of diseases, from rheumatoid arthritis to hepatitis. Antibodies to autoantigens or to microbial constituents are commonly associated with these conditions. In some cases, the antibodies have diagnostic and prognostic relevance. It cannot as yet be determined definitively that any of them mediate joint damage, although the evidence from animal models indicates that this mechanism is likely. The purpose of this article is to give an overview of the spectrum of antibodies found in a variety of inflammatory arthritides. The relevant animal models are also discussed. PMID- 20192994 TI - IRF4 and its regulators: evolving insights into the pathogenesis of inflammatory arthritis? AB - Accumulating evidence from murine and human studies supports a key role for interleukin-17 (IL-17) and IL-21 in the pathogenesis of inflammatory arthritis. The pathways and molecular mechanisms that underlie the production of IL-17 and IL-21 are being rapidly elucidated. This review focuses on interferon regulatory factor 4 (IRF4), a member of the IRF family of transcription factors, which has emerged as a crucial controller of both IL-17 and IL-21 production. We first outline the complex role of IRF4 in the function of CD4(+) T cells and then discuss recent studies from our laboratory that have revealed a surprising role for components of Rho GTPase-mediated pathways in controlling the activity of IRF4. A better understanding of these novel pathways will hopefully provide new insights into mechanisms responsible for the development of inflammatory arthritis and potentially guide the design of novel therapeutic approaches. PMID- 20192998 TI - Suppressive functions of activated B cells in autoimmune diseases reveal the dual roles of Toll-like receptors in immunity. AB - B lymphocytes contribute to immunity through production of antibodies, antigen presentation to T cells, and secretion of cytokines. B cells are generally considered in autoimmune diseases as drivers of pathogenesis. This view is certainly justified, given the successful utilization of the B cell-depleting reagent rituximab in patients with rheumatoid arthritis or other autoimmune pathologies. In a number of cases, however, the depletion of B cells led to an exacerbation of symptoms in patients with autoimmune disorders. In a similar manner, mice lacking B cells can develop an aggravated course of disease in several autoimmune models. These paradoxical observations are now explained by the concept that activated B cells can suppress immune responses through the production of cytokines, especially interleukin-10. Here, we review the stimulatory signals that induce interleukin-10 secretion and suppressive functions in B cells and the phenotype of the B cells with such characteristics. Finally, we formulate a model explaining how this process of immune regulation by activated B cells can confer advantageous properties to the immune system in its combat with pathogens. Altogether, this review proposes that B-cell-mediated regulation is a fundamental property of the immune system, with features of great interest for the development of new cell-based therapies for autoimmune diseases. PMID- 20192999 TI - Genetics and genomics of ankylosing spondylitis. AB - Ankylosing spondylitis (AS) is a common, highly heritable arthropathy, the pathogenesis of which is poorly understood. The mechanism by which the main gene for the disease, HLA-B27, leads to AS is unknown. Genetic and genomic studies have demonstrated involvement of the interleukin-23 (IL-23) signaling pathway in AS, a finding which has stimulated much new research into the disease and has led to therapeutic trials. Several other genes and genetic regions, including further major histocompatibility complex (MHC) and non-MHC loci, have been shown to be involved in the disease, but it is not clear yet how they actually induce the condition. These findings have shown that there is a strong genetic overlap between AS and Crohn's disease in particular, although there are also major differences in the genes involved in the two conditions, presumably explaining their different presentations. Genomic and proteomic studies are in an early phase but have potential both as diagnostic/prognostic tools and as a further hypothesis-free tool to investigate AS pathogenesis. Given the slow progress in studying the mechanism of association of HLA-B27 with AS, these may prove to be more fruitful approaches to investigating the pathogenesis of the disease. PMID- 20192997 TI - The U1-snRNP complex: structural properties relating to autoimmune pathogenesis in rheumatic diseases. AB - The U1 small nuclear ribonucleoprotein particle (snRNP) is a target of autoreactive B cells and T cells in several rheumatic diseases including systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD). We propose that inherent structural properties of this autoantigen complex, including common RNA-binding motifs, B and T-cell epitopes, and a unique stimulatory RNA molecule, underlie its susceptibility as a target of the autoimmune response. Immune mechanisms that may contribute to overall U1-snRNP immunogenicity include epitope spreading through B and T-cell interactions, apoptosis-induced modifications, and toll-like receptor (TLR) activation through stimulation by U1-snRNA. We conclude that understanding the interactions between U1-snRNP and the immune system will provide insights into why certain patients develop anti-U1-snRNP autoimmunity, and more importantly how to effectively target therapies against this autoimmune response. PMID- 20193001 TI - Monosodium urate crystals in inflammation and immunity. AB - Uric acid crystals [monosodium urate (MSU)] have emerged as an important factor for both gouty arthritis and immune regulation. This simple crystalline structure appears to activate innate host defense mechanisms in multiple ways and triggers robust inflammation and immune activation. The recognition mechanisms of MSU following its phase change from soluble uric acid are diverse, involving both protein receptors and non-specific plasma membrane attachment. Upon contact with host cells, MSU induces a set of membrane events that trigger Syk and PI3K activation, phagocytosis, and cytokine production. Having entered the cell, MSU further triggers NALP3 inflammasome activation and induces the production of IL-1 beta, likely inducing a full spectrum of inflammation. This review describes the recognition mechanisms and activation pathways involved in MSU-mediated inflammation and adjuvanticity and hypothesizes that direct membrane binding by solid surfaces, such as MSU, may function as a generic mechanism in tissue responses to particulate and crystalline structures. PMID- 20193000 TI - From HLA-B27 to spondyloarthritis: a journey through the ER. AB - Almost four decades of research into the role of human leukocyte antigen-B27 (HLA B27) in susceptibility to spondyloarthritis has yet to yield a convincing answer. New results from an HLA-B27 transgenic rat model now demonstrate quite convincingly that CD8(+) T cells are not required for the inflammatory phenotype. Discoveries that the HLA-B27 heavy chain has a tendency to misfold during the assembly of class I complexes in the endoplasmic reticulum (ER) and to form aberrant disulfide-linked dimers after transport to the cell surface have forced the generation of new ideas about its role in disease pathogenesis. In transgenic rats, HLA-B27 misfolding generates ER stress and leads to activation of the unfolded protein response, which dramatically enhances the production of interleukin-23 (IL-23) in response to pattern recognition receptor agonists. These findings have led to the discovery of striking T-helper 17 cell activation and expansion in this animal model, consistent with results emerging from humans with spondyloarthritis and the discovery of IL23R as an additional susceptibility gene for ankylosing spondylitis. Together, these results suggest a novel link between HLA-B27 and the T-helper 17 axis through the consequences of protein misfolding and open new avenues of investigation as well as identifying new targets for therapeutic intervention in this group of diseases. PMID- 20193002 TI - Mechanisms of uric acid crystal-mediated autoinflammation. AB - Gout is an arthritis characterized by elevated uric acid in the bloodstream. In this condition, crystals of uric acid are formed and accumulate in the synovial fluids. Crystal deposition leads to acute inflammation, which is associated with the spontaneous resolution of the disease. Recent studies have led to significant advances in the understanding of the basic biology of crystal-mediated inflammation. Uric acid has been identified as a danger signal that triggers a cytosolic sensor, the inflammasome. This signaling platform is required for the activation of interleukin-1, a cytokine that is critical to the initiation of acute inflammation in gout. Importantly, both molecular and pathological evidence support the notion that gout is a prototypical member of the growing family of autoinflammatory diseases. This review discusses the role of the inflammasome in gout and the emerging new therapeutic strategies aimed at controlling inflammation in crystal arthritis. PMID- 20193004 TI - Fibroblast-like synoviocytes in inflammatory arthritis pathology: the emerging role of cadherin-11. AB - Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease affecting the joint synovium. The normal synovium consists of a lining layer of fibroblast like synoviocytes (FLS) and macrophages, one to three cells deep that overlies the loose connective tissue of the synovial sublining. During the course of RA, the synovium is the site of inflammation where immune cells are massively infiltrated, and the lining layer becomes hyperplastic and transforms into a pannus tissue that destroys articular cartilage and bone. FLS play an important role in this RA pathogenesis. In this review, we explain that cadherin-11, an adhesion molecule, is selectively expressed on FLS and required for synovial lining formation. In addition, cadherin-11 on FLS contributes to synovial inflammation and mediates cartilage degradation in a mouse model of inflammatory arthritis. Therefore, we suggest that FLS are critical regulators of synovial inflammation and arthritis pathology via mechanisms that are mediated by cadherin 11. PMID- 20193003 TI - Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) remains a significant unmet medical need despite significant therapeutic advances. The pathogenesis of RA is complex and includes many cell types, including T cells, B cells, and macrophages. Fibroblast-like synoviocytes (FLS) in the synovial intimal lining also play a key role by producing cytokines that perpetuate inflammation and proteases that contribute to cartilage destruction. Rheumatoid FLS develop a unique aggressive phenotype that increases invasiveness into the extracellular matrix and further exacerbates joint damage. Recent advances in understanding the biology of FLS, including their regulation regulate innate immune responses and activation of intracellular signaling mechanisms that control their behavior, provide novel insights into disease mechanisms. New agents that target FLS could potentially complement the current therapies without major deleterious effect on adaptive immune responses. PMID- 20193005 TI - Secondary and ectopic lymphoid tissue responses in rheumatoid arthritis: from inflammation to autoimmunity and tissue damage/remodeling. AB - Rheumatoid arthritis is a chronic systemic inflammatory disease primarily affecting the synovium of diarthrodial joints. Despite the currently unknown etiology, overwhelming evidence indicates that both innate and adaptive immunity play a central role in disease pathogenesis. In this review, we consider recent evidence examining the mechanisms of lymphoid tissue reactivity in rheumatoid arthritis with a focus on the dynamics controlling secondary and ectopic lymphoid tissue response. We then examine the cellular and molecular mechanisms regulating the biopathology of these processes with specific emphasis on cell trafficking, contribution to autoimmunity, and joint damage-repair. We finally provide a brief overview of the most recent studies addressing the clinical relevance of synovial lymphoid tissue analysis as a diagnostic and prognostic tool as well as its response to current biological therapies. PMID- 20193007 TI - Bone remodeling in rheumatic disease: a question of balance. AB - The past decade has observed an explosion of new information regarding the impact of inflammation on bone. In rheumatic diseases, several factors that act as both immune modulators and regulators of bone homeostasis have been shown to mediate an imbalance in bone resorption and bone formation resulting in joint degeneration. In rheumatoid arthritis (RA), focal bone loss is due to excess bone resorption by osteoclasts. Resorption is mediated in part by increased local expression of the cytokine receptor activator of nuclear factor-kappaB ligand (RANKL) compared with expression of its decoy receptor osteoprotegerin (OPG). Bone formation by osteoblasts is also impaired at erosion sites in RA, and inhibitors of the canonical Wingless (Wnt) signaling pathway, including DKK1, have been implicated in the suppression of normal osteoblast function at these sites. Inhibition of DKK1 in an animal model of RA attenuated bone erosion by increasing OPG expression as well as promoting bone formation. In contrast to RA, inflammation in the spondyloarthropathies often results in excess periosteal bone formation, highlighting that the net impact of inflammation on bone is specific to the site at which inflammation occurs, and the cell types, cytokines, and factors present within the local bone microenvironment. This fertile area of research bears watching for the identification of novel targets for the prevention of abnormal bone remodeling in inflammatory diseases. PMID- 20193008 TI - Features of the dendritic cell lineage. PMID- 20193006 TI - Transcriptional regulation of bone and joint remodeling by NFAT. AB - Osteoporosis and arthritis are highly prevalent diseases and a significant cause of morbidity and mortality worldwide. These diseases result from aberrant tissue remodeling leading to weak, fracture-prone bones or painful, dysfunctional joints. The nuclear factor of activated T cells (NFAT) transcription factor family controls diverse biologic processes in vertebrates. Here, we review the scientific evidence that links NFAT-regulated gene transcription to bone and joint pathology. A particular emphasis is placed on the role of NFATs in bone resorption and formation by osteoclasts and osteoblasts, respectively. In addition, emerging data that connect NFATs with cartilage biology, angiogenesis, nociception, and neurogenic inflammation are explored. The goal of this article is to highlight the importance of tissue remodeling in musculoskeletal disease and situate NFAT-driven cellular responses within this context to inspire future research endeavors. PMID- 20193009 TI - The CD8+ dendritic cell subset. AB - Mouse lymphoid tissues contain a subset of dendritic cells (DCs) expressing CD8 alpha together with a pattern of other surface molecules that distinguishes them from other DCs. These molecules include particular Toll-like receptor and C-type lectin pattern recognition receptors. A similar DC subset, although lacking CD8 expression, exists in humans. The mouse CD8(+) DCs are non-migrating resident DCs derived from a precursor, distinct from monocytes, that continuously seeds the lymphoid organs from bone marrow. They differ in several key functions from their CD8(-) DC neighbors. They efficiently cross-present exogenous cell-bound and soluble antigens on major histocompatibility complex class I. On activation, they are major producers of interleukin-12 and stimulate inflammatory responses. In steady state, they have immune regulatory properties and help maintain tolerance to self-tissues. During infection with intracellular pathogens, they become major presenters of pathogen antigens, promoting CD8(+) T-cell responses to the invading pathogens. Targeting vaccine antigens to the CD8(+) DCs has proved an effective way to induce cytotoxic T lymphocytes and antibody responses. PMID- 20193010 TI - Instructive cytokine signals in dendritic cell lineage commitment. AB - Clarifying the signals that lead to dendritic cell (DC) development and identifying cellular intermediates on their way to DC differentiation are essential steps to understand the dynamic regulation of number, localization, and functionality of these cells. In the past decade, much knowledge on cytokines, transcription factors, and successive progenitors involved in steady-state and demand-adapted DC development was gained. From the stage of multipotent progenitors, DCs are generated from Flt3(+) intermediates, irrespective of lymphoid or myeloid commitment, making fms-related tyrosine kinase 3 ligand one of the major regulators for DC development. Additional key cytokines involved are granulocyte-macrophage colony-stimulating factor (GM-CSF) and M-CSF, with each being essential for particular DC subsets and leading to specific activation of downstream transcription factors. In this review, we seek to draw an integrative view on how instructive cytokine signals acting on intermediate progenitors might lead to the generation of specific DC subsets in steady-state and during inflammation. We hypothesize that the lineage potential of a progenitor might be determined by the set of cytokine receptors expressed that make it responsive to further receive lineage instructive signals. Commitment to a certain lineage might consequently occur when lineage-relevant cytokine receptors are further upregulated and others for alternative lineages are lost. Along this line, we emphasize the role that diverse microenvironments have in influencing the generation of DC subsets with specific functions throughout the body. PMID- 20193011 TI - Origin and development of dendritic cells. AB - Dendritic cells (DCs) are specialized antigen-presenting cells and essential mediators of immunity and tolerance. This group of cells is heterogeneous in terms of cell-surface markers, anatomic location, and function. Here, we review the development and function of DCs found in lymphoid and non-lymphoid tissues in the steady state. DC and monocyte lineages originate from a common progenitor, the monocyte and dendritic cell progenitor (MDP). The two cell types diverge when MDPs give rise to monocytes and committed DC progenitors (CDPs) in the bone marrow. CDPs give rise to pre-DCs, which migrate from the bone marrow to lymphoid and non-lymphoid tissues to produce the two major subpopulations of lymphoid tissue DCs and non-lymphoid tissue CD103(+) DCs. Within tissues and during development, DC division and homeostasis are regulated by the hormone Flt3L. PMID- 20193012 TI - Origin and functional heterogeneity of non-lymphoid tissue dendritic cells in mice. AB - Dendritic cells (DCs) have been extensively studied in mice lymphoid organs, but less is known about the origin and the mechanisms that regulate DC development and function in non-lymphoid tissues. Here, we discuss recent evidence establishing the contribution of the DC-restricted lineage to the non-lymphoid tissue DC pool and discuss the mechanisms that control the homeostasis of non lymphoid tissue DCs. We also review recent results underlining the functional specialization of tissue DCs and discuss the potential implications of these findings in tissue immunity and in the development of novel vaccine strategies. PMID- 20193013 TI - Defining dendritic cells by conditional and constitutive cell ablation. AB - Recent years have seen a major advance in our understanding of the organization of the dendritic cell (DC) compartment. Particularly rewarding in this respect have been studies investigating DC origins, based on the identification of transcription factor and growth factor requirements, as well as direct demonstrations of precursor/progeny relationships by adoptive cell transfers. However, to fully understand the organization of the DC compartment, functional definitions of DC subsets must be provided and potential task divisions revealed that distinguish DC from other immune cells, including the closely related mononuclear phagocytes, such as macrophages. In fact, functional definitions might eventually replace the current distinction between DC and macrophages, which is in part based on arbitrary historic considerations, i.e. mononuclear phagocytes identified before the advent of DC in the mid 1970s generally termed macrophages. In this article, we review recent insight in the functions of classical DC in the mouse, focusing on our own work involving conditional and constitutive cell ablation. PMID- 20193014 TI - Differentiation and function of mouse monocyte-derived dendritic cells in steady state and inflammation. AB - Although monocytes were originally described as precursors to all the different subpopulations of macrophages found in the steady state and formed under inflammatory and infectious conditions, recent data have demonstrated conclusively that monocytes can also differentiate into dendritic cells (DCs). Monocytes are the precursors to different subsets of DCs, such as Langerhans cells and DCs found in the lamina propria of the gastrointestinal, respiratory, and urogenital tracts. In addition, monocyte-derived DCs (moDCs), newly formed during inflammatory reactions, appear to fulfill an essential role in defense mechanisms against pathogens by participating in the induction of both adaptive and innate immune responses. In this regard, moDCs have the capacity to activate antigen-specific CD4(+) T-cell responses and to cross-prime CD8(+) T cells, during viral, bacterial, and parasitic infections. In addition, monocytes have been recently described as the precursors to a subset of DCs specialized in innate immunity against pathogens, named TipDCs [for TNF-alpha (tumor necrosis factor-alpha)-iNOS (inducible nitric oxide synthase)-producing DCs] that display a remarkable microbicidal activity and also provide iNOS-dependent help for antibody production by B cells. Importantly, in contrast to DCs developing in the steady state, moDCs formed during inflammatory and infectious processes are subjected to diverse soluble mediators that determine the multiple functional specificities displayed by moDCs, as a result of the remarkable developmental plasticity of monocytes. In this review, we discuss recent findings dealing with the differentiation and functional relevance of moDCs that have widened the frontiers of DC immunobiology in relation to innate and adaptive immunity and the etiology of chronic inflammatory diseases. PMID- 20193015 TI - Regulation of dendritic cell differentiation and function by Notch and Wnt pathways. AB - The process of dendritic cell differentiation is governed by a tightly controlled signaling network regulated by cytokines and direct interaction between progenitor cells and bone marrow stroma. Notch signaling represents one of the major pathways activated during direct interaction between hematopoietic progenitor cells and bone marrow stroma. Wnt pathway is activated by soluble proteins produced by bone marrow stroma. Until recently, the role of Notch and Wnt signaling in the development of myeloid cells and dendritic cells in particular remained unclear. In this review, we discuss recent exciting findings that shed light on the critical role of Notch and Wnt pathways, their interaction in differentiation and function of dendritic cells, and their impact on immune responses. PMID- 20193019 TI - Comparative genomics as a tool to reveal functional equivalences between human and mouse dendritic cell subsets. AB - During evolution, vertebrates have developed an adaptive immune system able to cope with a variety of pathogens. Dendritic cells (DCs) are central to this process. DCs integrate information derived from pathogens or endogenous danger signals and convey them to T lymphocytes. Most of the present knowledge on DCs was generated in mice or by using human DCs differentiated in vitro from monocytes. In both species, several DC subsets have been identified in vivo based on differences in their phenotypes, anatomical locations or functions. In mice, protective immunity against intracellular pathogens or tumors can be induced most efficiently by targeting antigens to the CD8 alpha(+) DCs, a subset of DCs which resides in lymphoid tissues and is especially efficient at cross-presenting exogenous antigens to CD8(+) T lymphocytes. In contrary, harnessing human DC subsets for medical purposes is currently hampered by insufficient knowledge about these cells. To overcome this cognitive gap, we are using comparative genomics as a tool for designing hypotheses and experiments to further characterize DC subset functions and their molecular control, including the investigation of the functional equivalences that might exist between human and mouse DC subsets. PMID- 20193017 TI - Unraveling the functions of plasmacytoid dendritic cells during viral infections, autoimmunity, and tolerance. AB - Plasmacytoid dendritic cells (pDCs) are bone marrow-derived cells that secrete large amounts of type I interferon (IFN) in response to viruses. Type I IFNs are pleiotropic cytokines with antiviral activity that also enhance innate and adaptive immune responses. Viruses trigger activation of pDCs and type I IFN responses mainly through the Toll-like receptor pathway. However, a variety of activating and inhibitory pDC receptors fine tune the amplitude of type I IFN responses. Chronic activation and secretion of type I IFN in the absence of infection can promote autoimmune diseases. Furthermore, while activated pDCs promote immunity and autoimmunity, resting or alternatively activated pDCs may be tolerogenic. The various roles of pDCs have been extensively studied in vitro and in vivo with depleting antibodies. However, depleting antibodies cross-react with other cell types that are critical for eliciting protective immunity, potentially yielding ambiguous phenotypes. Here we discuss new approaches to assess pDC functions in vivo and provide preliminary data on their potential roles during viral infections. Such approaches would also prove useful in the more specific evaluation of how pDCs mediate tolerance and autoimmunity. Finally, we discuss the emergent role of pDCs and one of their receptors, tetherin, in human immunodeficiency virus pathogenesis. PMID- 20193016 TI - Langerhans cells and more: langerin-expressing dendritic cell subsets in the skin. AB - Langerhans cells (LCs) are antigen-presenting dendritic cells (DCs) that reside in epithelia. The best studied example is the LC of the epidermis. By electron microscopy, their identifying feature is the unique rod- or tennis racket-shaped Birbeck granule. The phenotypic hallmark is their expression of the C-type lectin receptor langerin/CD207. Langerin, however, is also expressed on a recently discovered population of DC in the dermis and other tissues of the body. These 'dermal langerin(+) dendritic cells' are unrelated to LCs. The complex field of langerin-negative dermal DCs is not dealt with here. In this article, we briefly review the history, ontogeny, and homeostasis of LCs. More emphasis is laid on the discussion of functional properties in vivo. Novel models using genetically engineered mice are contributing tremendously to our understanding of the role of LCs in eliciting adaptive immune responses against pathogens or tumors and in inducing and maintaining tolerance against self antigens and innocuous substances in vivo. Also, innate effector functions are increasingly being recognized. Current activities in this area are reviewed, and possibilities for future exploitation of LC in medicine, e.g. for the improvement of vaccines, are contemplated. PMID- 20193021 TI - Langerhans cell histiocytosis: fascinating dynamics of the dendritic cell macrophage lineage. AB - In its rare occurrence, Langerhans cell histiocytosis (LCH) is a dangerous but intriguing deviation of mononuclear phagocytes, especially dendritic cells (DCs). Clinically, the disease ranges from self-resolving or well manageable to severe and even fatal. LCH lesions in skin, bone, and other sites contain high numbers of cells with phenotypic features resembling LCs admixed with macrophages, T cells, eosinophils, and multinucleated giant cells. Here we review current progress in the LCH field based on two central questions: (i) are LCH cells intrinsically aberrant, and (ii) how does the lesion drive pathogenesis? We argue that LCH cells may originate from different sources, including epidermal LCs, tissue Langerin(+) DCs, or mononuclear phagocyte precursors. Current and prospective in vitro and in vivo models are discussed. Finally, we discuss recent insights into plasticity of T-helper cell subsets in light of the lesion microenvironment. LCH continues to provide urgent clinical questions thereby inspiring innovative DC lineage research. PMID- 20193018 TI - Signaling and ligand interaction of ILT7: receptor-mediated regulatory mechanisms for plasmacytoid dendritic cells. AB - Plasmacytoid dendritic cells (pDCs) are specialized dendritic cells (DCs) that produce large amounts of type I interferon (IFN) after Toll-like receptor (TLR) activation. Human pDCs preferentially express immunoglobulin-like transcript 7 (ILT7; LILRA4), which couples with a signaling adapter to activate a prominent immunoreceptor tyrosine-based activation motif (ITAM)-mediated signaling pathway. ILT7 protein directly binds to and can be activated by bone marrow stromal cell antigen 2 (BST2; CD317) protein, the expression of which is found on cells pre exposed to IFN or on the surface of human cancer cells. The interaction between ILT7 and BST2 functions to assure an appropriate TLR response by pDCs during viral infection and likely participates in pDC-tumor crosstalk. Two opposing modes of receptor-mediated regulatory mechanisms work jointly to fine tune the innate immunity of pDCs. PMID- 20193020 TI - Harnessing human dendritic cell subsets for medicine. AB - Immunity results from a complex interplay between the antigen-non-specific innate immune system and the antigen-specific adaptive immune system. The cells and molecules of the innate system employ non-clonal recognition receptors including lectins, Toll-like receptors, NOD-like receptors, and helicases. B and T lymphocytes of the adaptive immune system employ clonal receptors recognizing antigens or their derived peptides in a highly specific manner. An essential link between innate and adaptive immunity is provided by dendritic cells (DCs). DCs can induce such contrasting states as immunity and tolerance. The recent years have brought a wealth of information on the biology of DCs revealing the complexity of this cell system. Indeed, DC plasticity and subsets are prominent determinants of the type and quality of elicited immune responses. In this article, we summarize our recent studies aimed at a better understanding of the DC system to unravel the pathophysiology of human diseases and design novel human vaccines. PMID- 20193022 TI - Langerin-expressing dendritic cells in gut-associated lymphoid tissues. AB - Dendritic cells (DCs) are key regulators of the immune system. They act as professional antigen-presenting cells and are capable of activating naive T cells and stimulating the growth and differentiation of B cells. According to their molecular expression, DCs can be divided into several subsets with different functions. We focus on DC subsets expressing langerin, a C-type lectin. Langerin expression is predominant in skin DCs, but langerin-expressing DCs also exist in mucosal tissue and can be induced by immunization and sometimes by nutrient deficiency. Topical transcutaneous immunization induces langerin(+)CD8 alpha(-) DCs in mesenteric lymph nodes (MLNs), which mediate the production of antigen specific immunoglobulin A antibody in the intestine. Yet, in one recent study, langerin(+) DCs were generated in gut-associated lymphoid tissue and contributed to the suppressive intestinal immune environment in the absence of retinoic acid. In this review, we focus on the phenotypic and functional characteristics of langerin(+) DCs in the mucosal tissues, especially MLNs. PMID- 20193023 TI - Regulation of intestinal homeostasis by dendritic cells. AB - The healthy gut consists of the commensal flora, the epithelial layer, and the gut-associated lymphoid tissues (GALT). The GALT need to be hyporesponsive to commensal and dietary antigens while possessing the capacity to detect and attack pathogens. Accumulating evidence suggests that dendritic cells (DCs) play integral roles in managing this paradoxical situation and maintaining the complex homeostasis in the gut, which includes the induction of immunoglobulin A (IgA) synthesis. This review outlines the roles of the commensal flora, epithelial layer, and GALT in mucosal homeostasis and inflammatory conditions and highlights recent progress in our understanding of how DCs are involved in IgA synthesis in the gut. PMID- 20193024 TI - Subsets of migrating intestinal dendritic cells. AB - Dendritic cells (DCs) in the intestine are heterogeneous. Phenotypically different populations of conventional DCs have been identified in the intestinal lamina propria, Peyer's patches, and in the draining mesenteric lymph nodes, to which these DCs constitutively migrate. Markers used to identify these populations include major histocompatibility complex class II, CD11c, CD8 alpha, CD11b, and CD103. Extensive studies in rats, summarized here, which involved collection of migrating DCs by thoracic duct cannulation after mesenteric lymphadenectomy, have clearly demonstrated that the subsets of migrating intestinal lymph DCs have different functional properties. The subsets might play different roles in the induction of oral tolerance and in driving systemic immune responses after vaccination or intestinal stimulation with Toll-like receptor ligands. The use of these surgical techniques allows investigation of the functions of purified subsets of migrating DCs. However, in the rat, these studies are limited by the range of available reagents and are difficult to compare with data from other species in this fast-moving field. Recent refinements have enabled the collection of migrating intestinal DCs from mice; our initial results are described here. We believe that these studies will generate exciting data and have the potential to resolve important questions about the functions of migrating intestinal DC subsets. PMID- 20193025 TI - Development and functional specialization of CD103+ dendritic cells. AB - CD103 (alpha(E)) integrin expression distinguishes a population of dendritic cells (DCs) that can be found in many if not all lymphoid and non-lymphoid organs. CD103(+) DCs display distinct functional activities. Migratory CD103(+) DCs derived from skin, lung, and intestine efficiently present exogenous antigens in their corresponding draining lymph nodes to specific CD8(+) T cells through a mechanism known as cross-presentation. On the T cells they prime, intestinal CD103(+) DCs can drive the induction of the chemokine receptor CCR9 and alpha(4)beta(7) integrin, both known as gut-homing receptors. CD103(+) DCs also contribute to control inflammatory responses and intestinal homeostasis by fostering the conversion of naive T cells into induced Foxp3(+) regulatory T cells, a mechanism that relies on transforming growth factor-beta and retinoic acid signaling. This review discusses recent findings that identify murine CD103(+) DCs as important regulators of the immune response. PMID- 20193026 TI - Dendritic cell physiology and function in the eye. AB - The eye and the brain are immunologically privileged sites, a property previously attributed to the lack of a lymphatic circulation. However, recent tracking studies confirm that these organs have good communication through classical site specific lymph nodes, as well as direct connection through the blood circulation with the spleen. In addition, like all tissues, they contain resident myeloid cell populations that play important roles in tissue homeostasis and the response to foreign antigens. Most of the macrophage and dendritic cell (DC) populations in the eye are restricted to the supporting connective tissues, including the cornea, while the neural tissue (the retina) contains almost no DCs, occasional macrophages (perivascularly distributed), and a specialized myeloid cell type, the microglial cell. Resident microglial cells are normally programmed for immunological tolerance. The privileged status of the eye, however, is relative, as it is susceptible to immune-mediated inflammatory disease, both infectious and autoimmune. Intraocular inflammation (uveitis and uveoretinitis) and corneal graft rejection constitute two of the more common inflammatory conditions affecting the eye leading to considerable morbidity (blindness). As corneal graft rejection occurs almost exclusively by indirect allorecognition, host DCs play a major role in this process and are likely to be modified in their behavior by the ocular microenvironment. Ocular surface disease, including allergy and atopy, also comprise a significant group of immune-mediated eye disorders in which DCs participate, while infectious disease such as herpes simplex keratitis is thought to be initiated via corneal DCs. Intriguingly, some more common conditions previously thought to be degenerative (e.g. age-related macular degeneration) may have an autoimmune component in which ocular DCs and macrophages are critically involved. Recently, the possibility of harnessing the tolerizing potential of DCs has been applied to experimental models of autoimmune uveoretinitis with good effect. This approach has considerable potential for use in translational clinical therapy to prevent sight-threatening disease caused by ocular inflammation. PMID- 20193028 TI - DC subsets in positive and negative regulation of immunity. AB - Since their discovery in 1973, dendritic cells (DCs) have gained strong interest from immunologists because of their unique capacity to sensitize naive T cells. There is now strong evidence that cells of the dendritic family not only control immunity but also regulate responses to self and non-self, thereby avoiding immunopathology. These two complementary functions are critical to ensure the integrity of the organism in an environment full of antigens. How DCs display these opposite functions is still intriguing. Here, we review the role of DC subsets in the regulation of T-helper responses in vivo. PMID- 20193029 TI - Syk-coupled C-type lectin receptors that mediate cellular activation via single tyrosine based activation motifs. AB - Different dendritic cell (DC) subsets have distinct specialized functions contributed in part by their differential expression of pattern recognition receptors (PRRs). C-type lectin receptors (CLRs) are a group of PRRs expressed by DCs and other myeloid cells that can recognize endogenous ligands as well as a wide range of exogenous structures present on pathogens. Dual roles in homeostasis and immunity have been demonstrated for some members of this receptor family. Largely due to their endocytic ability and subset specific expression, DC expressed CLRs have been the focus of significant antigen-targeting studies. A number of CLRs function on the basis of signaling via association with immunoreceptor tyrosine-based activation motif (ITAM)-containing adapter proteins. Others contain ITAM-related motifs or immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in their cytoplasmic tails. Here we review CLRs that induce intracellular signaling via a single tyrosine-based ITAM-like motif and highlight their relevance in terms of DC function. PMID- 20193030 TI - Association of mannose-binding lectin polymorphisms and HBV outcome in a South Indian population. AB - Mannose binding lectin (MBL) is an important innate immune system pattern recognition molecule. The MBL gene polymorphisms are reported to play a crucial role in outcome of hepatitis B virus (HBV) infection. In this study, we ascertained the association of MBL genotypes with HBV outcome in a South Indian population. The MBL gene polymorphisms at codons 52, 54 and 57 of exon I, and promoter polymorphisms at -221 were typed by polymerase chain reaction-sequence specific primer in spontaneously recovered and in chronic HBV group. The allele frequency of codon 52 'C' was significantly higher in chronic HBV group than in the recovered group (98.5% vs. 93.6%; P = 0.003) and codon 52 'T' was significantly higher in recovered group than in the chronic group (6.4% vs. 1.5%; P = 0.003). In multivariate analysis, after adjusting for age, sex and state of origin, codon 52 'CC' and 'CT' genotypes were significantly associated with chronicity and recovery respectively [odds ratio (OR), 0.25; 95% confidence interval (CI), 0.08-0.80, P = 0.02] in co-dominant analyzing models. This was re affirmed in analysis performed exclusively on Tamil Nadu subjects (OR, 0.23; 95% CI, 0.06-0.93, P = 0.039). The frequency of low/none haplotype (XY/O) was significantly higher in recovered group than in chronic group (15.6% vs 7.5%) and associated with spontaneous recovery (OR, 2.28; 95% CI, 1.04-4.99, P = 0.035). Our results provide preliminary evidence that inheritance of codon 52 genotypes and XY/O haplotype associated with low MBL level substantially determine the outcome of HBV infection in a sympatrically isolated South Indian population. PMID- 20193027 TI - Microbe-dendritic cell dialog controls regulatory T-cell fate. AB - Each microenvironment is controlled by a specific set of regulatory elements that have to be finely and constantly tuned to maintain local homeostasis. These environments could be site specific, such as the gut environment, or induced by chronic exposure to microbes. Various populations of dendritic cells are central to the orchestration of this control. In this review, we discuss some new findings associating dendritic cells from defined compartments with the induction and control of regulatory T cells in the context of exposure to both commensal and pathogenic microbes. PMID- 20193031 TI - Compound KIR-HLA genotype analyses in the Iranian population by a novel PCR-SSP assay. AB - Natural killer (NK) cells eliminate infected and transformed cells while still are self-tolerant. Interactions of the independently segregating Killer cell immunoglobulin-like receptors (KIR) and human leucocyte antigens (HLA) loci play a critical role in NK cell regulation. Different compound KIR-HLA genotypes can impart different thresholds of activation to the NK-cell repertoire and such genotypic variation has been found to confer altered risk in a number of human diseases including viral infections, autoimmune disorders, reproduction abnormalities and cancers. In this study, we presented a novel combined KIR-HLA polymerase chain reaction-sequence-specific primers genotyping assay for simultaneous determination of KIR genes and their three major HLA class I ligand groups (C1, C2, and Bw4). Moreover, known inhibitory and activating KIR + HLA (iKIR + HLA: 2DL2/3 + C1, 2DL1 + C2, 3DL1 + Bw4; and aKIR + HLA: 2DS2 + C1, 2DS1 + C2, 3DS1 + Bw4) combinations as well as co-inheritance of aKIR genes and iKIR + HLA pairs were analysed in a total of 200 unrelated healthy Iranian individuals. All tested subjects had at least one of the three iKIR + HLA pairs and the frequencies of various inhibitory combinations in the study group were: 31.5%, three iKIR + HLA pairs, 53.5%, two iKIR + HLA pairs, and 15%, 0ne iKIR + HLA pair. Furthermore, we revealed that majority of Iranians (69%) carry compound genotypes with greater number of inhibitory pairings than activating combinations (iKIR + HLA > aKIR + HLA). Conversely, iKIR + HLA < aKIR (45%) was dominant genotype in the study group. We conclude that selective evolutionary pressure has propensity to maintain KIR-HLA genotypes with more inhibitory combinations to guarantee self-tolerance. In contrast, existence of activating KIR genes without normal endogenous ligands, potentially arms the NK population for competent immunosurveillance and stronger defense against infections. PMID- 20193032 TI - Analysis of DEFB1 regulatory SNPs in cystic fibrosis patients from North-Eastern Italy. AB - Cystic fibrosis (CF) transmembrane regulator protein (CFTR) gene is undoubtedly the main genetic factor involved in the modulation of CF phenotype. However, other factors such as human defensins and the genes encoding for these antimicrobial peptides have been hypothesized as possible modifiers influencing airways infection in CF patients, but their role in the pathogenesis of lung disease is still debated. Since DEFB1 gene encoding for human beta-defensin 1 displays features such as antimicrobial or chemotactic activity playing a role in inflammation, it has been considered as a possible candidate CF modifier gene. We analysed three single nucleotide polymorphisms (SNPs) in the 5'-untranslated region of the DEFB1 gene (namely g-52G>A, g-44C>G and g-20G>A) in a group of 62 CF patients from North Eastern Italy, and in 130 healthy controls, with the aim of verifying the possible association of these functional SNPs with the pulmonary phenotype of CF patients. DEFB1 SNPs have been genotyped by using Taqman allele specific fluorescent probes and a real-time PCR platform. No significant differences were found for allele, genotype and haplotype frequencies of DEFB1 g 52G>A, g-44C>G and g-20G>A SNPs in CF patients stratified for Pseudomonas aeruginosa infection, as well as in patients with a severe and mild clinical phenotype or in patients stratified for CFTR genotypes. DEFB1 allele, genotype and haplotype frequencies of CF patients globally considered were similar to those of healthy controls. Our findings are discordant with respect to another recent study performed on CF patients coming from Southern Italy, probably due to different ethnicity of the patients. PMID- 20193033 TI - Highly sensitivity adhesion molecules detection in hereditary haemochromatosis patients reveals altered expression. AB - Several abnormalities in the immune status of patients with hereditary haemochromatosis (HH) have been reported, suggesting an imbalance in their immune function. This may include persistent production of, or exposure to, altered immune signalling contributing to the pathogenesis of this disorder. Adhesion molecules L-, E- and P-Selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) are some of the major regulators of the immune processes and altered levels of these proteins have been found in pathological states including cardiovascular diseases, arthritis and liver cancer. The aim of this study was to assess L-, E- and P-Selectin, ICAM-1 and VCAM-1 expression in patients with HH and correlate these results with HFE mutation status and iron indexes. A total of 139 subjects were diagnosed with HH (C282Y homozygotes = 87, C282Y/H63D = 26 heterozygotes, H63D homozygotes = 26), 27 healthy control subjects with no HFE mutation (N/N), 18 normal subjects heterozygous for the H63D mutation served as age-sex-matched controls. We observed a significant decrease in L-selectin (P = 0.0002) and increased E selectin and ICAM-1 (P = 0.0006 and P = 0.0059) expression in HH patients compared with healthy controls. This study observes for the first time that an altered adhesion molecules profile occurs in patients with HH that is associated with specific HFE genetic component for iron overload, suggesting that differential expression of adhesion molecules may play a role in the pathogenesis of HH. PMID- 20193034 TI - The mutations of Th1 cell-specific T-box transcription factor may be associated with a predominant Th2 phenotype in gastric cancers. AB - Gastric cancer is a serious public health cancer and causes nearly 1 million deaths a year worldwide. Th1 cells play critical roles in orchestrating the adaptive immune responses against gastric cancer. T-bet, a member of the T-box family of transcription factors, is the Th1 master regulator and up-regulated during Th1 differentiation. Polymorphisms have also been shown to exist in T-bet. Some reports indicated that some tumours were associated with the drift of Th1 and Th2. In the present work, we investigated the drift of Th1/Th2 by detecting the expression levels of T-bet, IFN-gamma, IL-4, and GATA-3 in peripheral blood mononuclear cell of gastric cancer patients by real-time PCR, explored the relationship between the polymorphism of T-bet gene and drift of Th1/Th2 by gene sequence, western blot, and gene transfection. Our results indicated that a predominant Th2 phenotype was existence. T-bet gene mutations may be associated with Th2-dominated condition in gastric cancers. PMID- 20193035 TI - BCL10 as a new candidate gene for immune response in pigs: cloning, expression and association analysis. AB - BCL10 is an apoptotic regulatory molecule identified through its direct involvement in t(1; 14)(p22; q32) of mucosa-associated lymphoid tissue lymphoma, and was implicated in the pathogenesis of this and several other tumour types. BCL10 was recognized as an antigen receptor-specific regulator of NF-kappaB, which showed close association with immune responses. In this study, we cloned and characterized BCL10 from the porcine spleen and analysed its genomic structure. BCL10 was mapped to SSC4q21-q23 by the IMpRH panels, it is closely linked to the marker S0161 and SW1461. This gene has three exons and two introns. Reverse transcriptase-polymerase chain reaction analyses showed that BCL10 was widely expressed in all the examined tissues. Transient transfection indicated that porcine BCL10 was located in cytoplasm in Pig Kidney Epithelial cells. BCL10 gene displays the opposite expression trend between the two treatments mimic virus and bacteria of polyriboinosinic-polyribocytidylic acid (Poly I:C) and lipopolysaccharide (LPS). The level of the BCL10 mRNA was up-regulated during 12 24 h and peaking at 48 h when treated with LPS, whereas it was down-regulated during 0-48 h and highest at 0 h (cells without treating with Poly I:C) when treated with Poly I:C. One single nucleotide polymorphism (SNP) site was identified in the 3'-untranslated region of porcine BCL10. Association analysis revealed that this SNP was significantly associated with intermediate cell mass (eosinophile granulocyte, basophile granulocyte and histoleucocyte) percentage, absolute intermediate cell mass count and mean red blood cell volume of 0-day-old pigs, and red blood cell count of 17-day-old pigs (P < 0.05), and also had significant associations with red blood cell count and haemoglobin concentration of 32-day-old pigs (P < 0.01). PMID- 20193038 TI - Drosophila models of human tauopathies indicate that Tau protein toxicity in vivo is mediated by soluble cytosolic phosphorylated forms of the protein. AB - Tau is a neuronal microtubule-associated protein involved in microtubules assembly and stabilization. Tauopathies, including Alzheimer's disease and fronto temporal dementia with parkinsonism linked to chromosome 17, are a group of neurodegenerative disorders characterized by the presence of intraneuronal filamentous inclusions of abnormally and hyperphosphorylated Tau. Currently, the molecular mechanisms underlying Tau-mediated cellular toxicity remain elusive. To address the determinants of Tau neurotoxicity, we used Drosophila models of human tauopathies to study the microtubule-binding properties of human Tau proteins in vivo. We showed that, in contrast to endogenous Drosophila Tau, human Tau proteins bind very poorly to microtubules in Drosophila, and are mostly recovered as soluble cytosolic hyperphosphorylated species. This weak binding of human Tau to microtubules is neither because of microtubules saturation nor competition with endogenous Drosophila Tau, but clearly depends on its phosphorylation degree. We also reported that accumulation of cytosolic hyperphosphorylated forms of human Tau proteins correlates with human Tau-mediated neurodegeneration in flies, supporting the key role of soluble cytosolic hyperphosphorylated Tau proteins as toxic species in vivo. PMID- 20193036 TI - Injectable cardiac tissue engineering for the treatment of myocardial infarction. AB - Future perspectives Heart disease is a leading cause of morbidity and mortality worldwide. Myocardial infarction leads to permanent loss of cardiac tissue and ultimately heart failure. However, current therapies could only stall the progression of the disease. Thus, new therapies are needed to regenerate damaged hearts to overcome poor prognosis of patients with heart failure. The shortage of heart donors is also a factor for innovating new therapies. Although the cardiac performance by cell-based therapy has improved, unsatisfactory cell retention and transplant survival still plague this technique. Because biomaterials can improve the cell retention, survival and differentiation, cardiac tissue engineering is now being explored as an approach to support cell-based therapies and enhance their efficacy for cardiac disease. In the last decade, cardiac tissue engineering has made considerable progress. Among different kinds of approaches in the cardiac tissue engineering, the approach of injectable cardiac tissue engineering is more minimally invasive than that of in vitro engineered tissue or epicardial patch implantation. It is therefore clinically appealing. In this review, we strive to describe the major progress in the filed of injectable cardiac tissue engineering, including seeding cell sources, biomaterials and novel findings in preclinical studies and clinical applications. The remaining problems will also be discussed. PMID- 20193039 TI - Human TrkB gene: novel alternative transcripts, protein isoforms and expression pattern in the prefrontal cerebral cortex during postnatal development. AB - Brain-derived neurotrophic factor and neurotrophin-4 high-affinity receptor tropomyosine related kinase (Trk) B is required for the differentiation and maintenance of specific neuron populations. Misregulation of TrkB has been reported in many human diseases, including cancer, obesity and neurological and psychiatric disorders. Alternative splicing that generates receptor isoforms with different functional properties also regulates TrkB function. Here, we describe numerous novel isoforms of TrkB proteins, including isoforms generated by alternative splicing of cassette exons in the regions encoding both the extracellular and intracellular domain and also N-terminally truncated isoforms encoded by novel 5' exon-containing transcripts. We also characterize the intracellular localization and phosphorylation potential of novel TrkB isoforms and find that these proteins have unique properties. In addition, we describe the expression profiles of all the known human TrkB transcripts in adult tissues and also during postnatal development in the human prefrontal cortex. We show that transcripts encoding the full-length TrkB receptor and the C-terminally truncated TrkB-T1 have different expression profiles as compared to the proteins they encode. Identification of 36 potential TrkB protein isoforms suggests high complexity in the synthesis, regulation and function of this important neurotrophin receptor emphasizing the need for further study of these novel TrkB variants. PMID- 20193037 TI - Apolipoprotein A-I possesses an anti-obesity effect associated with increase of energy expenditure and up-regulation of UCP1 in brown fat. AB - Apolipoprotein A-I (ApoA-I) is the most abundant protein constituent of high density lipoprotein (HDL). Reduced plasma HDL and ApoA-I levels have been found to be associated with obesity and metabolic syndrome in human beings. However, whether or not ApoA-I has a direct effect on obesity is largely unknown. Here we analysed the anti-obesity effect of ApoA-I using two mouse models, a transgenic mouse with overexpression of ApoA-I and the mice administered with an ApoA-I mimetic peptide D-4F. The mice were induced to develop obesity by feeding with high fat diet. Both ApoA-I overexpression and D-4F treatment could significantly reduce white fat mass and slightly improve insulin sensitivity in the mice. Metabolic analyses revealed that ApoA-I overexpression and D-4F treatment enhanced energy expenditure in the mice. The mRNA level of uncoupling protein (UCP)1 in brown fat tissue was elevated by ApoA-I transgenic mice. ApoA-I and D 4F treatment was able to increase UCP1 mRNA and protein levels as well as to stimulate AMP-activated protein kinase (AMPK) phosphorylation in brown adipocytes in culture. Taken together, our results reveal that ApoA-I has an anti-obesity effect in the mouse and such effect is associated with increases in energy expenditure and UCP1 expression in the brown fat tissue. PMID- 20193041 TI - Modulation of bone morphogenic protein signalling alters numbers of astrocytes and oligodendroglia in the subventricular zone during cuprizone-induced demyelination. AB - The adult subventricular zone (SVZ) is a potential source of precursor cells to replace neural cells lost during demyelination. To better understand the molecular events that regulate neural precursor cell responsiveness in this context we undertook a microarray and quantitative PCR based analysis of genes expressed within the SVZ during cuprizone-induced demyelination. We identified an up-regulation of the genes encoding bone morphogenic protein 4 (BMP4) and its receptors. Immunohistochemistry confirmed an increase in BMP4 protein levels and also showed an increase in phosphorylated SMAD 1/5/8, a key component of BMP4 signalling, during demyelination. In vitro analysis revealed that neural precursor cells isolated from demyelinated animals, as well as those treated with BMP4, produce more astrocytes. Similarly, there were increased numbers of astrocytes in vivo within the SVZ during demyelination. Intraventricular infusion of Noggin, an endogenous antagonist of BMP4, during cuprizone-induced demyelination reduced pSMAD1/5/8, decreased astrocyte numbers and increased oligodendrocyte numbers in the SVZ. Our results suggest that lineage commitment of SVZ neural precursor cells is altered during demyelination and that BMP signalling plays a role in this process. PMID- 20193042 TI - Autoregulatory binding sites in the zebrafish six3a promoter region define a new recognition sequence for Six3 proteins. AB - The homeodomain (HD) transcription factor Six3, which is a member of the Six/Sine oculis family, is essential for development of the eyes and forebrain in vertebrates. It has recently been claimed that the HDs of Six3 and other members of the Six family have a common recognition sequence, TGATAC. However, a different recognition sequence including the typical TAAT core motif, which has not yet been fully defined, has also been proposed for the Six3 HD in mice. Our study of the zebrafish orthologue six3a, which has an identical HD, shows that it binds in vitro to multiple TAAT-containing sites within its promoter region. Comparison of the different binding affinities for these sequences identifies three high-affinity sites with a common TAATGTC motif. Notably, this new recognition sequence, which is supported by our analysis of the influence of single-nucleotide substitutions on the DNA-binding affinity, is distinct from all of the DNA-binding specificities previously described in surveys of HDs. In addition, our comparison of Six3a HD binding to the novel TAATGTC motif and the common recognition sequence of Six family HDs (TGATAC) shows very similar affinities, suggesting two distinct DNA-binding modes. Transient reporter assays of the six3a promoter in zebrafish embryos also indicate that the three high affinity sites are involved in autoregulation. In support of this, chromatin immunoprecipitation experiments show enrichment of Six3a binding to a six3a promoter fragment containing two clustered high-affinity sites. These findings provide strong evidence that the TAATGTC motif is an important target sequence for vertebrate Six3 proteins in vivo. PMID- 20193040 TI - Increased expression of cholesterol 24S-hydroxylase results in disruption of glial glutamate transporter EAAT2 association with lipid rafts: a potential role in Alzheimer's disease. AB - The glial glutamate transporter EAAT2 (excitatory amino acid transporter 2) is the major mediator of glutamate clearance that terminates glutamate-mediated neurotransmission. Loss of EAAT2 and associated glutamate uptake function has been reported in the brains of patients with Alzheimer's disease (AD). We previously reported that EAAT2 is associated with lipid raft microdomains of the plasma membrane. In the present study, we demonstrated that association of EAAT2 with lipid rafts is disrupted in AD brains. This abnormality is not a consequence of neuron degeneration, oxidative stress, or amyloid beta toxicity. In AD brains, cholesterol 24S-hydroxylase (CYP46), a key enzyme in maintenance of cholesterol homeostasis in the brain, is markedly increased in astrocytes but decreased in neurons. We demonstrated that increased expression of CYP46 in primary astrocytes results in a reduction of membrane cholesterol levels and leads to the dissociation of EAAT2 from lipid rafts and the loss of EAAT2 and associated glutamate uptake function. These results suggest that a disturbance of cholesterol metabolism may contribute to loss of EAAT2 in AD. PMID- 20193043 TI - 9-Deazaguanine derivatives connected by a linker to difluoromethylene phosphonic acid are slow-binding picomolar inhibitors of trimeric purine nucleoside phosphorylase. AB - Genetic deficiency of purine nucleoside phosphorylase (PNP; EC 2.4.2.1) activity leads to a severe selective disorder of T-cell function. Therefore, potent inhibitors of mammalian PNP are expected to act as selective immunosuppressive agents against, for example, T-cell cancers and some autoimmune diseases. 9 (5',5'-difluoro-5'-phosphonopentyl)-9-deazaguanine (DFPP-DG) was found to be a slow- and tight-binding inhibitor of mammalian PNP. The inhibition constant at equilibrium (1 mm phosphate concentration) with calf spleen PNP was shown to be = 85 +/- 13 pm (pH 7.0, 25 degrees C), whereas the apparent inhibition constant determined by classical methods was two orders of magnitude higher ( = 4.4 +/- 0.6 nm). The rate constant for formation of the enzyme/inhibitor reversible complex is (8.4 +/- 0.5) x 10(5) m(-1).s(-1), which is a value that is too low to be diffusion-controlled. The picomolar binding of DFPP-DG was confirmed by fluorimetric titration, which led to a dissociation constant of 254 pm (68% confidence interval is 147-389 pm). Stopped-flow experiments, together with the above data, are most consistent with a two-step binding mechanism: E + I <--> (EI) <--> (EI)*. The rate constants for reversible enzyme/inhibitor complex formation (EI), and for the conformational change (EI) <--> (EI)*, are k(on1) = (17.46 +/- 0.05) x 10(5) m(-1).s(-1), k(off1) = (0.021 +/- 0.003) s(-1), k(on2) = (1.22 +/- 0.08) s(-1) and k(off2) = (0.024 +/- 0.005) s(-1), respectively. This leads to inhibition constants for the first (EI) and second (EI)* complexes of K(i) = 12.1 nM (68% confidence interval is 8.7-15.5 nm) and = 237 pm (68% confidence interval is 123-401 pm), respectively. At a concentration of 10(-4) m, DFPP-DG exhibits weak, but statistically significant, inhibition of the growth of cell lines sensible to inhibition of PNP activity, such as human adult T-cell leukaemia and lymphoma (Jurkat, HuT78 and CCRF-CEM). Similar inhibitory activities of the tested compound were noted on the growth of lymphocytes collected from patients with Hashimoto's thyroiditis and Graves' disease. The observed weak cytotoxicity may be a result of poor membrane permeability. PMID- 20193044 TI - Inhibition kinetics of catabolic dehydrogenases by elevated moieties of ATP and ADP--implication for a new regulation mechanism in Lactococcus lactis. AB - ATP and ADP inhibit, in varying degrees, several dehydrogenases of the central carbon metabolism of Lactococcus lactis ATCC 19435 in vitro, i.e. glyceraldehyde 3-phosphate dehydrogenase (GAPDH), lactate dehydrogenase (LDH) and alcohol dehydrogenase (ADH). Here we demonstrate mixed inhibition for GAPDH and competitive inhibition for LDH and ADH by adenine nucleotides in single inhibition studies. The nonlinear negative co-operativity was best modelled with Hill-type kinetics, showing greater flexibility than the usual parabolic inhibition equation. Because these natural inhibitors are present simultaneously in the cytoplasm, multiple inhibition kinetics was determined for each dehydrogenase. For ADH and LDH, the inhibitor combinations ATP plus NAD and ADP plus NAD are indifferent to each other. Model discrimination suggested that the weak allosteric inhibition of GAPDH had no relevance when multiple inhibitors are present. Interestingly, with ADH and GAPDH the combination of ATP and ADP exhibits lower dissociation constants than with either inhibitor alone. Moreover, the concerted inhibition of ADH and GAPDH, but not of LDH, shows synergy between the two nucleotides. Similar kinetics, but without synergies, were found for horse liver and yeast ADHs, indicating that dehydrogenases can be modulated by these nucleotides in a nonlinear manner in many organisms. The action of an elevated pool of ATP and ADP may effectively inactivate lactococcal ADH, but not GAPDH and LDH, providing leverage for the observed metabolic shift to homolactic acid formation in lactococcal resting cells on maltose. Therefore, we interpret these results as a regulation mechanism contributing to readjusting the flux of ATP production in L. lactis. PMID- 20193045 TI - Mechanism for the hydrolysis of hyaluronan oligosaccharides by bovine testicular hyaluronidase. AB - Synthetic hyaluronan oligosaccharides with defined structures and their pyridylaminated derivatives were used to investigate the mechanism of hydrolysis of hyaluronan by bovine testicular hyaluronidase. The products of the hydrolysis were analyzed by HPLC and ion-spray mass spectroscopy (MS). It was confirmed that the minimum substrate for bovine testicular hyaluronidase is the hyaluronan hexasaccharide, even though it is a poor substrate that is barely cleaved, even on prolonged incubation. When hyaluronan octasaccharide was the substrate, increasing amounts of tetrasaccharide and hexasaccharide were produced with increasing time of incubation. Whereas disaccharide was not detectable in the reaction mixture by HPLC, MS analysis revealed trace amounts. The data suggest that the enzyme generates a disaccharide intermediate from hyaluronan oligosaccharide, the majority of which is transferred to the nonreducing ends of other oligosaccharides, only traces being released as free disaccharide. When hyaluronan octasaccharide, with an unsaturated glucuronic acid at the nonreducing end, was used as a substrate, only a tetrasaccharide was detected by HPLC. However, MS showed that the product was a mixture of equal amounts of two tetrasaccharides, one with and the other without the unsaturated glucuronic acid. This suggests that, in the case of substrates with a double bond at the nonreducing end, a tetrasaccharide is cleaved off instead of a disaccharide. The results of the experiments with pyridylaminated oligosaccharides were entirely consistent with these conclusions, and in addition showed the importance of the reducing end of the substrate for the enzyme to recognize the length of the saccharide. PMID- 20193046 TI - Using transcriptomics to identify and validate novel biomarkers of human skeletal muscle cancer cachexia. AB - BACKGROUND: Cancer cachexia is a multi-organ tissue wasting syndrome that contributes to morbidity and mortality in many cancer patients. Skeletal muscle loss represents an established key feature yet there is no molecular understanding of the disease process. In fact, the postulated molecular regulators of cancer cachexia originate largely from pre-clinical models and it is unclear how these translate to the clinical environment. METHODS: Rectus abdominis muscle biopsies were obtained from 65 upper gastrointestinal (UGI) cancer patients during open surgery and RNA profiling was performed on a subset of this cohort (n = 21) using the Affymetrix U133+2 platform. Quantitative analysis revealed a gene signature, which underwent technical validation and independent confirmation in a separate clinical cohort. RESULTS: Quantitative significance analysis of microarrays produced an 83-gene signature that was able to identify patients with greater than 5% weight loss, while this molecular profile was unrelated to markers of systemic inflammation. Selected genes correlating with weight loss were validated using quantitative real-time PCR and independently studied as general cachexia biomarkers in diaphragm and vastus lateralis from a second cohort (n = 13; UGI cancer patients). CaMKIIbeta correlated positively with weight loss in all muscle groups and CaMKII protein levels were elevated in rectus abdominis. TIE1 was also positively associated with weight loss in both rectus abdominis and vastus lateralis muscle groups while other biomarkers demonstrated tissue-specific expression patterns. Candidates selected from the pre-clinical literature, including FOXO protein and ubiquitin E3 ligases, were not related to weight loss in this human clinical study. Furthermore, promoter analysis identified that the 83 weight loss associated genes had fewer FOXO binding sites than expected by chance. CONCLUSION: We were able to discover and validate new molecular biomarkers of human cancer cachexia. The exercise activated genes CaMKIIbeta and TIE1 related positively to weight-loss across muscle groups, indicating that this cachexia signature is not simply due to patient inactivity. Indeed, excessive CaMKIIbeta activation is a potential mechanism for reduced muscle protein synthesis. Our genomics analysis also supports the view that the available preclinical models do not accurately reflect the molecular characteristics of human muscle from cancer cachexia patients. PMID- 20193047 TI - Family-based genetic risk prediction of multifactorial disease. AB - Genome-wide association studies have detected dozens of variants underlying complex diseases, although it is uncertain how often these discoveries will translate into clinically useful predictors. Here, to improve genetic risk prediction, we consider including phenotypic and genotypic information from related individuals. We develop and evaluate a family-based liability-threshold prediction model and apply it to a simulation of known Crohn's disease risk variants. We show that genotypes of a relative of known phenotype can be informative for an individual's disease risk, over and above the same locus genotyped in the individual. This approach can lead to better-calibrated estimates of disease risk, although the overall benefit for prediction is typically only very modest. PMID- 20193048 TI - The 1000 Genomes Project: new opportunities for research and social challenges. AB - The 1000 Genomes Project, an international collaboration, is sequencing the whole genome of approximately 2,000 individuals from different worldwide populations. The central goal of this project is to describe most of the genetic variation that occurs at a population frequency greater than 1%. The results of this project will allow scientists to identify genetic variation at an unprecedented degree of resolution and will also help improve the imputation methods for determining unobserved genetic variants that are not represented on current genotyping arrays. By identifying novel or rare functional genetic variants, researchers will be able to pinpoint disease-causing genes in genomic regions initially identified by association studies. This level of detailed sequence information will also improve our knowledge of the evolutionary processes and the genomic patterns that have shaped the human species as we know it today. The new data will also lay the foundation for future clinical applications, such as prediction of disease susceptibility and drug response. However, the forthcoming availability of whole genome sequences at affordable prices will raise ethical concerns and pose potential threats to individual privacy. Nevertheless, we believe that these potential risks are outweighed by the benefits in terms of diagnosis and research, so long as rigorous safeguards are kept in place through legislation that prevents discrimination on the basis of the results of genetic testing. PMID- 20193049 TI - Musings on genome medicine: Hepatitis C. AB - Hepatitis C is a viral disease transmitted principally by blood, which affects millions of people worldwide. A significant proportion of those affected develop severe liver disease as a result. Only a fraction of patients are responsive to interferon treatment, highlighting the need for further research into genetic factors involved in response to therapy in order to optimize treatment. The only current approach for end-stage disease is liver transplant, which ironically does not cure the condition, and thus poses a clinical dilemma in the face of liver donor shortage. PMID- 20193050 TI - Genomic variants associated with primary biliary cirrhosis. AB - Primary biliary cirrhosis (PBC) is an autoimmune hepatobiliary disease characterized by immune-mediated injury of small and medium-sized bile ducts, eventually leading to liver cirrhosis. Several studies have addressed PBC immunopathology, and the data support an immune activation leading to autoantibodies and autoreactive T cells acting against the lipoylated 2-oxoacid dehydrogenase complexes. The causes of the disease remain unknown, but environmental factors and genetic susceptibility both contribute to its onset. Over the past two decades several association studies have addressed the role of genetic polymorphisms in PBC pathogenesis and have reported multiple associations. However, only a few studies had sufficient statistical power, and in most cases results were not independently validated. A genome-wide association study has recently been reported, but this too awaits independent confirmation. The aim of this present work is to critically review the numerous studies dedicated to revealing genetic associations in PBC, and to predict the potential for future studies based on these data. PMID- 20193052 TI - Genome informatics: advances in theory and practice. AB - A report on the 20th International Conference on Genome Informatics, Yokohama, Japan, 14-16 December 2009. PMID- 20193051 TI - Recent advances in the genetics of language impairment. AB - Specific language impairment (SLI) is defined as an unexpected and persistent impairment in language ability despite adequate opportunity and intelligence and in the absence of any explanatory medical conditions. This condition is highly heritable and affects between 5% and 8% of pre-school children. Over the past few years, investigations have begun to uncover genetic factors that may contribute to susceptibility to language impairment. So far, variants in four specific genes have been associated with spoken language disorders - forkhead box P2 (FOXP2) and contactin-associated protein-like 2 (CNTNAP2) on chromosome7 and calcium transporting ATPase 2C2 (ATP2C2) and c-MAF inducing protein (CMIP) on chromosome 16. Here, we describe the different ways in which these genes were identified as candidates for language impairment. We discuss how characterization of these genes, and the pathways in which they are involved, may enhance our understanding of language disorders and improve our understanding of the biological foundations of language acquisition. PMID- 20193053 TI - Hepatotoxicity and effectiveness of a Nevirapine-based antiretroviral therapy in HIV-infected patients with or without viral hepatitis B or C infection in Cameroon. AB - BACKGROUND: Coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV) in HIV-infected patients receiving a commonly used nevirapine-based antiretroviral therapy is a major concern for African clinicians owing to its high prevalence, the infrequent testing and treatment of viral hepatitis, and the impact of liver disease on the tolerability and effectiveness of anti-HIV treatment. We compared the hepatotoxicity and the immunological, virological and clinical effectiveness of a nevirapine-based antiretroviral therapy between patients infected with HIV only and patients coinfected with hepatitis B or C virus in Cameroon. METHODS: A retrospective cohort study was conducted among HIV 1-infected patients. Plasma HBV DNA and HCV RNA were tested in positive or indeterminate samples for HBsAg or HCV antibodies, respectively. All patients received nevirapine and lamivudine plus stavudine or zidovudine. RESULTS: Of 169 HIV-1-infected patients with a median baseline CD4 count of 135 cells/mm3 (interquartile range [IQR] 67-218), 21% were coinfected with HBV or HCV. In coinfected patients, the median viral load was 2.47 x 107 IU/mL for HBV (IQR 3680 1.59 x 108) and 928 000 IU/mL for HCV (IQR 178 400-2.06 x 106). Multivariate analyses showed that the risk of hepatotoxicity was 2-fold higher in coinfected patients (p < 0.01). The response to antiretroviral therapy was however comparable between monoinfected and coinfected patients in terms of CD4 cell count increase (p = 0.8), HIV-1 viral load below 400 copies/mL (p = 0.9), death (p = 0.3) and death or new AIDS-defining event (p = 0.1). Nevirapine was replaced by a protease inhibitor in 4 patients owing to hepatotoxicity. CONCLUSION: This study suggests that the nevirapine-based antiretroviral therapy could be used safely as first-line treatment in patients with low CD4 cell count in Africa despite frequent coinfections with HBV or HCV and infrequent testing of these infections. Although testing for HBV and HCV should be systematically performed before initiating antiretroviral therapy, transaminases elevations at baseline or during treatment should be a decisive argument for testing when hepatitis status is unknown. PMID- 20193054 TI - Demographic and behavioral characteristics of non-sex worker females attending sexually transmitted disease clinics in Japan: a nationwide case-control study. AB - BACKGROUND: Although number of sexually transmitted infections (STIs) reported in STI surveillance increased rapidly for women in Japan during the 1990s, the sexual behavior of women potentially at risk of STI infection remains unknown. METHODS: In order to determine the demographic and behavioral characteristics of non-sex worker (SW) females attending STI clinics, female attendees (n = 145), excluding SW, from nine clinics across Japan and female controls from the general population (n = 956), both aged 18-50 years, were compared using two data sets of nationwide sexual behavior surveys conducted in 1999. RESULTS: Although the occupation-type and education level were unrelated to STI clinic attendance in multivariate analysis, non-SW females attending STI clinics were younger (adjusted odds ratios [AOR] = 0.94, 95%CI: 0.89, 0.99), and more likely to be unmarried (AOR = 4.11, 95% CI: 1.73, 9.77) than the controls from the general population. In the previous year, STI clinic attendees were more likely to have had multiple partnerships (AOR = 3.09, 95% CI: 1.42, 6.71) and unprotected vaginal sex with regular partners (AOR = 3.59, 95% CI: 1.49, 8.64), and tended to have had their first sexual intercourse at a younger age (AOR = 1.77, 95%CI: 0.89, 3.54) and more unprotected vaginal and/or oral sex with casual partners (AOR = 2.08, 95%CI: 0.75, 5.71). Identical sexual behavior patterns were observed between the female attendees with a current diagnosis of STI (n = 72) and those before diagnosis (n = 73) and between those with a past history of STI (n = 66) and those without (n = 79). CONCLUSION: These results indicate that not only multiple partnerships or unprotected sex with casual partners, but also unprotected vaginal sex within a regular partnership is prevalent among non-SW female STI clinic attendees. The identical sexual behavior patterns observed between female attendees with a current STI diagnosis and those without, and between those attendees with a past history of STI diagnosis and those without, indicate that the result are unlikely confounded with the cases of non-STI infection. This sexual behavior pattern may be predictive of STI infection among young Japanese women and could have contributed to the STI epidemic in women in Japan during the 1990s. PMID- 20193055 TI - Clinical measurement of the thoracic kyphosis. A study of the intra-rater reliability in subjects with and without shoulder pain. AB - BACKGROUND: Clinical sagittal plane assessment of the thoracic kyphosis angle is considered an essential component of the postural examination of patients presenting with upper body pain syndromes. Cervical headaches and conditions involving the shoulder, such as subacromial pain syndrome, have all been associated with an increase in the thoracic kyphosis. Concomitantly a decrease in the thoracic kyphosis as a result of a stretching and strengthening rehabilitation programme is believed to be associated with a reduction in symptoms and pain and improvement in function. Clinicians generally measure the sagittal plane kyphosis angle visually. There is no certainty that this method is reliable or is capable of measuring angular changes over time or in response to intervention. As such a simple and reliable clinical method of measuring the thoracic kyphosis would enable clinicians to record this information. The aim of this investigation was to determine the intra-tester reliability of measuring the thoracic kyphosis angle using a clinical method METHODS: Measurements were made in 45 subjects with and 45 subjects without upper body symptoms. Measurements were made with the subjects in relaxed standing. Two gravity dependent inclinometers were used to measure the kyphosis. The first was placed over the region of the 1st and 2nd thoracic spinous processes. The other, over the region of the 12th thoracic and 1st lumbar spinous processes. The angle produced by each inclinometer was measured 3 times in succession. Each set of 3 measurements was made on two occasions (separated by a minimum of 30 minutes and additional data collection involving 46 further measurements of posture and movement on the same and an additional subject before the thoracic kyphosis measurements were re measured) by one rater. The reliability of the measurements was analyzed using 2 way ANOVA intraclass correlation coefficients (ICC), 95% confidence intervals (CI) and standard error of measurement (SEM) for precision, for a single measurement [ICC(single)] and the average of 3 measures [ICC(average)]. The assessor remained 'blinded' to data input and the measurements were staggered to reduce examiner bias. RESULTS: The measurement of the thoracic kyphosis as used in this investigation was found to have excellent intra-rater reliability for both subjects with and without symptoms. The ICC(single) results for the subjects without symptoms were, .95; (95% CI .91-.97). The corresponding ICC(average) results were; .97; (95% CI .95-.99). The results for the subjects with symptoms were; 93; (95% CI .88-.96), for ICC(single) and for ICC(average); .97; (95% CI .94-.98). The SEM results for subjects without and with symptoms were 1.0 degrees and 1.7 degrees , respectively. CONCLUSIONS: The findings of this immediate test retest reliability study suggest that the clinical measurement of the thoracic kyphosis using gravity dependent inclinometers demonstrates excellent intra-rater reliability. Additional research is required to determine the inter-rater reliability of this method. TRIAL REGISTRATION: National Research Register: N0060148286. PMID- 20193056 TI - Genome-wide transcription factor binding site/promoter databases for the analysis of gene sets and co-occurrence of transcription factor binding motifs. AB - BACKGROUND: The use of global gene expression profiling is a well established approach to understand biological processes. One of the major goals of these investigations is to identify sets of genes with similar expression patterns. Such gene signatures may be very informative and reveal new aspects of particular biological processes. A logical and systematic next step is to reduce the identified gene signatures to the regulatory components that induce the relevant gene expression changes. A central issue in this context is to identify transcription factors, or transcription factor binding sites (TFBS), likely to be of importance for the expression of the gene signatures. RESULTS: We develop a strategy that efficiently produces TFBS/promoter databases based on user-defined criteria. The resulting databases constitute all genes in the Santa Cruz database and the positions for all TFBS provided by the user as position weight matrices. These databases are then used for two purposes, to identify significant TFBS in the promoters in sets of genes and to identify clusters of co-occurring TFBS. We use two criteria for significance, significantly enriched TFBS in terms of total number of binding sites for the promoters, and significantly present TFBS in terms of the fraction of promoters with binding sites. Significant TFBS are identified by a re-sampling procedure in which the query gene set is compared with typically 10(5) gene lists of similar size randomly drawn from the TFBS/promoter database. We apply this strategy to a large number of published ChIP-Chip data sets and show that the proposed approach faithfully reproduces ChIP-Chip results. The strategy also identifies relevant TFBS when analyzing gene signatures obtained from the MSigDB database. In addition, we show that several TFBS are highly correlated and that co-occurring TFBS define functionally related sets of genes. CONCLUSIONS: The presented approach of promoter analysis faithfully reproduces the results from several ChIP-Chip and MigDB derived gene sets and hence may prove to be an important method in the analysis of gene signatures obtained through ChIP-Chip or global gene expression experiments. We show that TFBS are organized in clusters of co-occurring TFBS that together define highly coherent sets of genes. PMID- 20193057 TI - Prolonged mechanical ventilation in a respiratory-care setting: a comparison of outcome between tracheostomized and translaryngeal intubated patients. AB - INTRODUCTION: Mechanical ventilation of patients may be accomplished by either translaryngeal intubation or tracheostomy. Although numerous intensive care unit (ICU) studies have compared various outcomes between the two techniques, no definitive consensus indicates that tracheostomy is superior. Comparable studies have not been performed in a respiratory care center (RCC) setting. METHODS: This was a retrospective observational study of 985 tracheostomy and 227 translaryngeal intubated patients who received treatment in a 24-bed RCC between November 1999 and December 2005. Treatment and mortality outcomes were compared between tracheostomized and translaryngeal intubated patients, and the factors associated with positive outcomes in all patients were determined. RESULTS: Duration of RCC (22 vs. 14 days) and total hospital stay (82 vs. 64 days) and total mechanical ventilation days (53 vs. 41 days) were significantly longer in tracheostomized patients (all P < 0.05). The rate of in-hospital mortality was significantly higher in the translaryngeal group (45% vs. 31%;P < 0.05). No significant differences were found in weaning success between the groups (both were >55%) or in RCC mortality. Because of significant baseline between-group heterogeneity, case-match analysis was performed. This analysis confirmed the whole cohort findings, except for the fact that a trend for in-hospital mortality was noted to be higher in the translaryngeal group (P = 0.08). Stepwise logistic regression revealed that patients with a lower median severity of disease (APACHE II score <18) who were properly nourished (albumin >2.5 g/dl) or had normal metabolism (BUN <40 mg/dl) were more likely to be successfully weaned and survive (all P < 0.05). Patients who were tracheostomized were also significantly more likely to survive (P < 0.05). CONCLUSIONS: These findings suggest that the type of mechanical ventilation does not appear to be an important determinant of weaning success in an RCC setting. Focused care administered by experienced providers may be more important for facilitating weaning success than the ventilation method used. However, our findings do suggest that tracheostomy may increase the likelihood of patient survival. PMID- 20193058 TI - MADAM - An open source meta-analysis toolbox for R and Bioconductor. AB - BACKGROUND: Meta-analysis is a major theme in biomedical research. In the present paper we introduce a package for R and Bioconductor that provides useful tools for performing this type of work. One idea behind the development of MADAM was that many meta-analysis methods, which are available in R, are not able to use the capacities of parallel computing yet. In this first version, we implemented one meta-analysis method in such a parallel manner. Additionally, we provide tools for combining the results from a set of methods in an ensemble approach. Functionality for visualization of results is also provided. RESULTS: The presented package enables the carrying out of meta-analysis either by providing functions directly or by wrapping them to existing implementations. Overall, five different meta-analysis methods are now usable through MADAM, along with another three methods for combining the corresponding results. Visualizing the results is eased by three included functions. For developing and testing meta-analysis methods, a mock up data generator is integrated. CONCLUSIONS: The use of MADAM enables a user to focus on one package, in turn enabling them to work with the same data types across a set of methods. By making use of the snow package, MADAM can be made compatible with an existing parallel computing infrastructure. MADAM is open source and freely available within CRAN http://cran.r-project.org. PMID- 20193059 TI - Maternal allergen immunisation to prevent sensitisation in offspring: Th2 polarising adjuvants are more efficient than a Th1-polarising adjuvant in mice. AB - BACKGROUND: Allergy has been an increasing problem in several parts of the world. Prenatal exposure to allergen and microbial components may affect the development of allergies in childhood, as indicated by epidemiological and experimental studies. We investigated the capacity for allergic sensitisation in offspring after induction of a Th1- or a Th2-polarised immune response to the same allergen in mothers during pregnancy. RESULTS: During pregnancy, mice were immunised with ovalbumin (OVA) given with either one of the Th2-adjuvants pertussis toxin (PT) or Al(OH)3 (aluminium hydroxide), or with the Th1 adjuvant CpG. Offspring were immunised with OVA in Al(OH)3 as young adults. Serum and supernatants from ex vivo stimulated or non-stimulated spleen cells from mothers and offspring were analysed for OVA-specific antibodies and cytokines, respectively. Mothers immunised with OVA together with either Al(OH)3 or PT had increased levels of OVA specific IgE and IgG1 compared to naive mothers, whereas mothers immunised with OVA together with CpG had increased levels of OVA-specific IgG2a compared to naive mothers. In general the highest levels of IL-5, IL-10, and IFNgamma were observed in spleen cells from mothers immunised with PT and OVA. Upon immunisation, offspring from mothers immunised with OVA and either PT or Al(OH)3 showed reduced levels of OVA-specific IgE and IgG1 and increased levels of OVA specific IgG2a antibodies compared to offspring from naive mothers. Maternal immunisation with CpG and OVA did not affect antibody responses in offspring. CONCLUSION: Allergic sensitisation in the offspring was affected by the type of adjuvant used for immunisation of the mothers with the same allergen. Th2 polarisation of the immune response in the mothers was found to give reduced IgE levels upon sensitisation of the offspring, whereas no reduction was achieved with Th1 polarisation in the mothers. PMID- 20193060 TI - The IronChip evaluation package: a package of perl modules for robust analysis of custom microarrays. AB - BACKGROUND: Gene expression studies greatly contribute to our understanding of complex relationships in gene regulatory networks. However, the complexity of array design, production and manipulations are limiting factors, affecting data quality. The use of customized DNA microarrays improves overall data quality in many situations, however, only if for these specifically designed microarrays analysis tools are available. RESULTS: The IronChip Evaluation Package (ICEP) is a collection of Perl utilities and an easy to use data evaluation pipeline for the analysis of microarray data with a focus on data quality of custom-designed microarrays. The package has been developed for the statistical and bioinformatical analysis of the custom cDNA microarray IronChip but can be easily adapted for other cDNA or oligonucleotide-based designed microarray platforms. ICEP uses decision tree-based algorithms to assign quality flags and performs robust analysis based on chip design properties regarding multiple repetitions, ratio cut-off, background and negative controls. CONCLUSIONS: ICEP is a stand alone Windows application to obtain optimal data quality from custom-designed microarrays and is freely available here (see "Additional Files" section) and at: http://www.alice-dsl.net/evgeniy.vainshtein/ICEP/ PMID- 20193061 TI - Molecular differentiation of commercial varieties and feral populations of oilseed rape (Brassica napus L.). AB - BACKGROUND: For assessing the risk of escape of transgenes from cultivation, the persistence of feral populations of crop plants is an important aspect. Feral populations of oilseed rape, Brassica napus, are well known, but only scarce information is available on their population dynamics, particularly in Central Europe. To investigate genetic diversity, origin and persistence of feral oilseed rape in Austria, we compared variation at nine polymorphic microsatellite loci in eight feral populations with 19 commercial varieties. RESULTS: Overall, commercial varieties and feral populations showed a similar pattern of genetic variation and a similar level of observed heterozygosity. The two groups, however, shared less than 50% of the alleles and no multilocus genotype. A significant among-group (commercial varieties versus feral populations) component of genetic variation was observed (AMOVA: FCT = 0.132). Pairwise comparisons between varieties and feral populations showed moderate to very high genetic differentiation (FST = 0.209 - 0.900). The software STRUCTURE also demonstrated a clear separation between commercial varieties and feral samples: out of 17 identified genetic clusters, only one comprised plants from both a commercial variety and feral sites. CONCLUSIONS: The results suggest that feral oilseed rape is able to maintain persistent populations. The feral populations may have derived from older cultivars that were not included in our analyses or perhaps have already hybridised with related crops or wild relatives. Feral populations therefore have to be considered in ecological risk assessment and future coexistence measures as a potential hybridisation partner of transgenic oilseed rape. PMID- 20193062 TI - Lack of detectable DNA uptake by transformation of selected recipients in mono associated rats. AB - BACKGROUND: An important concern revealed in the public discussion of the use of genetically modified (GM) plants for human consumption, is the potential transfer of DNA from these plants to bacteria present in the gastrointestinal tract. Especially, there is a concern that antibiotic resistance genes used for the construction of GM plants end up in pathogenic bacteria, eventually leading to untreatable disease. FINDINGS: Three different bacterial species (Escherichia coli, Bacillus subtilis, Streptococcus gordonii), all natural inhabitants of the food and intestinal tract environment were used as recipients for uptake of DNA. As source of DNA both plasmid and genomic DNA from GM plants were used in in vitro and in vivo transformation studies. Mono-associated rats, creating a worst case scenario, did not give rise to any detectable transfer of DNA. CONCLUSION: Although we were unable to detect any transformation events in our experiment, it cannot be ruled out that this could happen in the GI tract. However, since several steps are required before expression of plant-derived DNA in intestinal bacteria, we believe this is unlikely, and antibiotic resistance development in this environment is more in danger by the massive use of antibiotics than the consumption of GM food harbouring antibiotic resistance genes. PMID- 20193063 TI - High-resolution transcription atlas of the mitotic cell cycle in budding yeast. AB - BACKGROUND: Extensive transcription of non-coding RNAs has been detected in eukaryotic genomes and is thought to constitute an additional layer in the regulation of gene expression. Despite this role, their transcription through the cell cycle has not been studied; genome-wide approaches have only focused on protein-coding genes. To explore the complex transcriptome architecture underlying the budding yeast cell cycle, we used 8 bp tiling arrays to generate a 5 minute-resolution, strand-specific expression atlas of the whole genome. RESULTS: We discovered 523 antisense transcripts, of which 80 cycle or are located opposite periodically expressed mRNAs, 135 unannotated intergenic non coding RNAs, of which 11 cycle, and 109 cell-cycle-regulated protein-coding genes that had not previously been shown to cycle. We detected periodic expression coupling of sense and antisense transcript pairs, including antisense transcripts opposite of key cell-cycle regulators, like FAR1 and TAF2. CONCLUSIONS: Our dataset presents the most comprehensive resource to date on gene expression during the budding yeast cell cycle. It reveals periodic expression of both protein-coding and non-coding RNA and profiles the expression of non-annotated RNAs throughout the cell cycle for the first time. This data enables hypothesis driven mechanistic studies concerning the functions of non-coding RNAs. PMID- 20193064 TI - Trends in the incidence and survival of multiple myeloma in South East England 1985-2004. AB - BACKGROUND: Multiple myeloma is an uncommon cancer with a poor prognosis. Its incidence is expected to increase due to ageing populations and better diagnosis, and new treatments have been developed to improve survival. Our objective was to investigate trends in the epidemiology and survival of multiple myeloma for South East England. METHODS: Data on 15,010 patients diagnosed with multiple myeloma between 1985 and 2004 was extracted from the Thames Cancer Registry database. We calculated the yearly age-standardised incidence rates for males and females and age-specific incidence rates in 10-year age groups for both sexes combined. We also explored geographical variation in incidence across primary care trusts. We then used period analysis to calculate trends in 1- and 5-year relative survival over the 15 years 1990-2004, comparing survival by sex and by age group 59 years and below versus 60 years and above. Finally, we investigated 5-year relative survival for the period 2000-2004 by socio-economic deprivation, assigning patients to quintiles of deprivation using the Income Domain of the Index of Multiple Deprivation 2004 based on postcode of residence. RESULTS: The incidence of multiple myeloma was higher in males than in females and in patients over 70, throughout the period 1985-2004. No obvious geographical pattern of incidence by primary care trust emerged. The 1- and 5-year relative survival of male and female patients increased in both age groups and was statistically significant in males aged over 60. There was a tendency for better survival in patients resident in the most affluent areas, but this did not reach statistical significance. CONCLUSIONS: The trends in incidence of multiple myeloma in males and females are similar to that reported from other western populations. Relative survival was higher for younger patients although we found significant improvements in 1-year relative survival for male patients over 60 years old. The improved survival demonstrated for patients of all ages is likely to reflect increased detection, earlier diagnosis and the introduction of new treatments. Future studies should investigate the influence of ethnicity on incidence and survival, and the effect of specific treatments on survival and quality of life. PMID- 20193066 TI - Collaboratively charting the gene-to-phenotype network of human congenital heart defects. AB - BACKGROUND: How to efficiently integrate the daily practice of molecular biologists, geneticists, and clinicians with the emerging computational strategies from systems biology is still much of an open question. DESCRIPTION: We built on the recent advances in Wiki-based technologies to develop a collaborative knowledge base and gene prioritization portal aimed at mapping genes and genomic regions, and untangling their relations with corresponding human phenotypes, congenital heart defects (CHDs). This portal is not only an evolving community repository of current knowledge on the genetic basis of CHDs, but also a collaborative environment for the study of candidate genes potentially implicated in CHDs - in particular by integrating recent strategies for the statistical prioritization of candidate genes. It thus serves and connects the broad community that is facing CHDs, ranging from the pediatric cardiologist and clinical geneticist to the basic investigator of cardiogenesis. CONCLUSIONS: This study describes the first specialized portal to collaboratively annotate and analyze gene-phenotype networks. Of broad interest to the biological community, we argue that such portals will play a significant role in systems biology studies of numerous complex biological processes.CHDWiki is accessible at http://www.esat.kuleuven.be/~bioiuser/chdwiki. PMID- 20193065 TI - Prescriptions for selective cyclooxygenase-2 inhibitors, non-selective non steroidal anti-inflammatory drugs, and risk of breast cancer in a population based case-control study. AB - INTRODUCTION: Non-steroidal anti-inflammatory drugs (NSAIDs) prevent the growth of mammary tumours in animal models. Two population-based case-control studies suggest a reduced risk of breast cancer associated with selective cyclooxygenase 2 (sCox-2) inhibitor use, but data regarding the association between breast cancer occurrence and use of non-selective NSAIDs are conflicting. METHODS: We conducted a population-based case-control study using Danish healthcare databases to examine if use of NSAIDs, including sCox-2 inhibitors, was associated with a reduced risk of breast cancer. We included 8,195 incident breast cancer cases diagnosed in 1991 through 2006 and 81,950 population controls. RESULTS: Overall, we found no reduced breast cancer risk in ever users (>2 prescriptions) of sCox-2 inhibitors (odds ratio (OR) = 1.08, 95% confidence interval (95% CI) = 0.99, 1.18), aspirin (OR = 0.98, 95% CI = 0.90-1.07), or non-selective NSAIDs OR = 1.04, (95% CI = 0.98, 1.10)). Recent use (>2 prescriptions within two years of index date) of sCox-2 inhibitors, aspirin, or non-selective NSAIDs was likewise not associated with breast cancer risk (Ors = 1.06 (95% CI = 0.96, 1.18), 0.96 (95% CI = 0.87, 1.06) and 0.99 (95% CI = 0.85, 1.16), respectively). Risk estimates by duration (<10, 10 to 15, 15+ years) or intensity (low/medium/high) of NSAID use were also close to unity. Regardless of intensity, shorter or long term NSAID use was not significantly associated with breast cancer risk. CONCLUSIONS: Overall, we found no compelling evidence of a reduced risk of breast cancer associated with use of sCox-2 inhibitors, aspirin, or non-selective NSAIDs. PMID- 20193067 TI - Surgical emergencies confounded by H1N1 influenza infection - a plea for concern. AB - The outbreak of the H1N1 influenza pandemic resulted in unprecedented, overwhelming exposure in the medical and lay media, with the obvious focus of healthcare providers being on patients in internal medicine or intensive care settings.Recently, we treated 3 patients with various surgical emergencies who were also diagnosed with active H1N1 influenza. The purpose of this report is to bring the issue of H1N1 flu in association with surgical emergencies to the forefront of the literature, and suggest that surgical diseases might be significantly accentuated in patients with H1N1 influenza. PMID- 20193068 TI - Mathematical model for empirically optimizing large scale production of soluble protein domains. AB - BACKGROUND: Efficient dissection of large proteins into their structural domains is critical for high throughput proteome analysis. So far, no study has focused on mathematically modeling a protein dissection protocol in terms of a production system. Here, we report a mathematical model for empirically optimizing the cost of large-scale domain production in proteomics research. RESULTS: The model computes the expected number of successfully producing soluble domains, using a conditional probability between domain and boundary identification. Typical values for the model's parameters were estimated using the experimental results for identifying soluble domains from the 2,032 Kazusa HUGE protein sequences. Among the 215 fragments corresponding to the 24 domains that were expressed correctly, 111, corresponding to 18 domains, were soluble. Our model indicates that, under the conditions used in our pilot experiment, the probability of correctly predicting the existence of a domain was 81% (175/215) and that of predicting its boundary was 63% (111/175). Under these conditions, the most cost/effort-effective production of soluble domains was to prepare one to seven fragments per predicted domain. CONCLUSIONS: Our mathematical modeling of protein dissection protocols indicates that the optimum number of fragments tested per domain is actually much smaller than expected a priori. The application range of our model is not limited to protein dissection, and it can be utilized for designing various large-scale mutational analyses or screening libraries. PMID- 20193069 TI - Lack of association between dietary fructose and hyperuricemia risk in adults. AB - BACKGROUND: High serum uric acid concentration (hyperuricemia) has been studied for its relationship with multiple adverse health outcomes, such as metabolic syndrome. Intervention studies have produced inconsistent outcomes for the relationship between fructose intake and serum uric acid concentration. METHODS: The association of dietary fructose intake with hyperuricemia risk in adults was examined using logistic regression and U.S. NHANES 1999-2004 databases. A total of 9,384 subjects, between the ages 20 and 80 years, without diabetes, cancer, or heart disease, were included. RESULTS: The highest added or total fructose intake (quartiles by grams or % energy) was not associated with an increase of hyperuricemia risk compared to the lowest intake with or without adjustment (odds ratios = 0.515-0.992). The associations of alcohol and fiber intakes with the risk were also determined. Compared to the lowest intake, the highest alcohol intake was associated with increased mean serum uric acid concentration (up to 16%, P < 0.001) and hyperuricemia risk (odds ratios = 1.658-1.829, P = 0.057- < 0.001); the highest fiber intake was correlated with decreases of uric acid concentration (up to 7.5%, P < 0.002) and lower risk (odds ratios = 0.448-0.478, P = 0.001- < 0.001). Adults who were over 50 y old, male, or obese had significantly greater risk. CONCLUSIONS: The data show that increased dietary fructose intake was not associated with increased hyperuricemia risk; while increased dietary alcohol intake was significantly associated with increased hyperuricemia risk; and increased fiber intake was significantly associated with decreased hyperuricemia risk. These data further suggest a potential effect of fructose consumption in an ordinary diet on serum uric acid differs from results found in some short-term studies using atypical exposure and/or levels of fructose administration. PMID- 20193070 TI - Hyaline vascular-type Castleman's disease in the hilum of liver: a case report. AB - BACKGROUND: Castleman's disease or angiofollicular lymphoid hyperplasia is a rare benign lymph node hyperplasia usually presenting as an asymptomatic mediastinal mass in children. The disease can present at any extra thoracic site with lymphoid tissue such as retroperitoneal, mesentery, axilla, and pelvis. Hepatic localization castleman disease is very rare in children. Herein, we reported a case of Castleman's disease arising from the lymph node in hilum of liver. CASE PRESENTATION: A 5 -year-old girl with chief complaint of abdominal pain for two months which exaggerated in last three days was referred to the hospital. On routine physical examination, only a generalized abdominal pain was noticed. Routine laboratory investigations and Chest X-Ray were normal. Abdominal Sonography revealed a 3.7 x 3.1 cm solid mass in the hilum of the liver. On the MRI images, a lobulated mass in the portal hepatic associated with mass effect on the portal vein was visible. Histological examination revealed expansion of mantle zone in lymphatic nodules accompanied by burnt out germinal centers. This pattern was matched with the diagnosis of the hyaline-vascular type of Castleman disease. The patient underwent a laparotomy. The patient had an uneventful postoperative course. CONCLUSION: This pattern was matched with the diagnosis of the hyaline-vascular type of Castleman disease. PMID- 20193071 TI - International genomic evaluation methods for dairy cattle. AB - BACKGROUND: Genomic evaluations are rapidly replacing traditional evaluation systems used for dairy cattle selection. Higher reliabilities from larger genotype files promote cooperation across country borders. Genomic information can be exchanged across countries using simple conversion equations, by modifying multi-trait across-country evaluation (MACE) to account for correlated residuals originating from the use of foreign evaluations, or by multi-trait analysis of genotypes for countries that use the same reference animals. METHODS: Traditional MACE assumes independent residuals because each daughter is measured in only one country. Genomic MACE could account for residual correlations using daughter equivalents from genomic data as a fraction of the total in each country and proportions of bulls shared. MACE methods developed to combine separate within country genomic evaluations were compared to direct, multi-country analysis of combined genotypes using simulated genomic and phenotypic data for 8,193 bulls in nine countries. RESULTS: Reliabilities for young bulls were much higher for across-country than within-country genomic evaluations as measured by squared correlations of estimated with true breeding values. Gains in reliability from genomic MACE were similar to those of multi-trait evaluation of genotypes but required less computation. Sharing of reference genotypes among countries created large residual correlations, especially for young bulls, that are accounted for in genomic MACE. CONCLUSIONS: International genomic evaluations can be computed either by modifying MACE to account for residual correlations across countries or by multi-trait evaluation of combined genotype files. The gains in reliability justify the increased computation but require more cooperation than in previous breeding programs. PMID- 20193072 TI - Congenital Plasmodium vivax malaria mimicking neonatal sepsis: a case report. AB - Although malaria in pregnancy can cause very significant neonatal morbidity, congenital malaria is a very rare condition in both endemic and non-endemic areas. A case of congenital malaria by Plasmodium vivax, initially mistaken for neonatal sepsis, is described. The correct diagnosis was accidentally done, as congenital malaria had been missed in the initial differential diagnosis.Vivax malaria is the leading species in congenital infections in Europe. This condition should be included in the differential diagnosis of neonatal sepsis even if the mother has no proven malarial episodes during the gestational period. PMID- 20193073 TI - Chaperonin genes on the rise: new divergent classes and intense duplication in human and other vertebrate genomes. AB - BACKGROUND: Chaperonin proteins are well known for the critical role they play in protein folding and in disease. However, the recent identification of three diverged chaperonin paralogs associated with the human Bardet-Biedl and McKusick Kaufman Syndromes (BBS and MKKS, respectively) indicates that the eukaryotic chaperonin-gene family is larger and more differentiated than previously thought. The availability of complete genome sequences makes possible a definitive characterization of the complete set of chaperonin sequences in human and other species. RESULTS: We identified fifty-four chaperonin-like sequences in the human genome and similar numbers in the genomes of the model organisms mouse and rat. In mammal genomes we identified, besides the well-known CCT chaperonin genes and the three genes associated with the MKKS and BBS pathological conditions, a newly defined class of chaperonin genes named CCT8L, represented in human by the two sequences CCT8L1 and CCT8L2. Comparative analyses from several vertebrate genomes established the monophyletic origin of chaperonin-like MKKS and BBS genes from the CCT8 lineage. The CCT8L gene originated from a later duplication also in the CCT8 lineage at the onset of mammal evolution and duplicated in primate genomes. The functionality of CCT8L genes in different species was confirmed by evolutionary analyses and in human by expression data. Detailed sequence analysis and structural predictions of MKKS, BBS and CCT8L proteins strongly suggested that they conserve a typical chaperonin-like core structure but that they are unlikely to form a CCT-like oligomeric complex. The characterization of many newly-discovered chaperonin pseudogenes uncovered the intense duplication activity of eukaryotic chaperonin genes. CONCLUSIONS: In vertebrates, chaperonin genes, driven by intense duplication processes, have diversified into multiple classes and functionalities that extend beyond their well-known protein-folding role as part of the typical oligomeric chaperonin complex, emphasizing previous observations on the involvement of individual CCT monomers in microtubule elongation. The functional characterization of newly identified chaperonin genes will be a challenge for future experimental analyses. PMID- 20193074 TI - Filifactor alocis--involvement in periodontal biofilms. AB - BACKGROUND: Bacteria in periodontal pockets develop complex sessile communities that attach to the tooth surface. These highly dynamic microfloral environments challenge both clinicians and researchers alike. The exploration of structural organisation and bacterial interactions within these biofilms is critically important for a thorough understanding of periodontal disease. In recent years, Filifactor alocis, a fastidious, Gram-positive, obligately anaerobic rod was repeatedly identified in periodontal lesions using DNA-based methods. It has been suggested to be a marker for periodontal deterioration. The present study investigated the epidemiology of F. alocis in periodontal pockets and analysed the spatial arrangement and architectural role of the organism in in vivo grown subgingival biofilms. RESULTS: A species-specific oligonucleotide probe, FIAL, was designed and evaluated. A total of 490 subgingival plaque samples were submitted to PCR and subsequent dot blot hybridization to compare the prevalence of F. alocis in patients suffering from generalized aggressive periodontitis (GAP), chronic periodontitis (CP), and control subjects resistant to periodontitis. Moreover, a specially designed carrier system was used to collect in vivo grown subgingival biofilms from GAP patients. Subsequent topographic analysis was performed using fluorescence in situ hybridization.While the majority of patients suffering from GAP or CP harboured F. alocis, it was rarely detected in the control group. In the examined carrier-borne biofilms the organism predominantly colonized apical parts of the pocket in close proximity to the soft tissues and was involved in numerous structures that constitute characteristic architectural features of subgingival periodontal biofilms. CONCLUSIONS: F. alocis is likely to make a relevant contribution to the pathogenetic structure of biofilms accounting for periodontal inflammation and can be considered an excellent marker organism for periodontal disease. PMID- 20193075 TI - Intermediate filaments of zebrafish retinal and optic nerve astrocytes and Muller glia: differential distribution of cytokeratin and GFAP. AB - BACKGROUND: Optic nerve regeneration (ONR) following injury is a model for central nervous system regeneration. In zebrafish, ONR is rapid - neurites cross the lesion and enter the optic tectum within 7 days; in mammals regeneration does not take place unless astrocytic reactivity is suppressed. Glial fibrillary acidic protein (GFAP) is used as a marker for retinal and optic nerve astrocytes in both fish and mammals, even though it has long been known that astrocytes of optic nerves in many fish, including zebrafish, express cytokeratins and not GFAP. We used immunofluorescence to localize GFAP and cytokeratin in wild-type zebrafish and transgenic zebrafish expressing green fluorescent protein (GFP) under control of a GFAP promoter to determine the pattern of expression of intermediate filaments in retina and optic nerve. FINDINGS: GFAP labeling and GFAP gene expression as indicated by GFP fluorescence was found only in the Muller glial cells of the retina. Within Muller cells, GFP fluorescence filled the entire cell while GFAP labelling was more restricted in distribution. No GFAP expression was observed in optic nerves. Cytokeratin labeling of astrocytes was observed throughout the optic nerve and less intensely in cells in the retinal inner plexiform layer. The retinal inner limiting membrane was strongly labeled by anti-cytokeratin. CONCLUSIONS: Studies of astrocyte function during ONR in zebrafish cannot solely rely on GFAP as an astrocyte marker or indicator of reactivity. Future studies of ONR in zebrafish should include evaluation of changes in cytokeratin expression and localization in the optic nerve. PMID- 20193076 TI - Exophytic benign mixed epithelial stromal tumour of the kidney: case report of a rare tumour entity. AB - BACKGROUND: Mixed epithelial and stromal tumour (MEST) represents a recently described benign composite neoplasm of the kidney, which predominantly affects perimenopausal females. Most tumours are benign, although rare malignant cases have been observed. CASE REPORT: A 47-year-old postmenopausal female presented to the urologist with flank pain. A CT scan of the abdomen showed a 30-mm-in diameter uniform mass adjacent to the pelvis of the left kidney. Surgical exploration showed a tumour arising from the lower anterior hilus of the left kidney. The tumour could be excised by preserving the kidney. By intraoperative frozen section the tumour showed characteristic features of MEST with epithelial covered cysts embedded in an "ovarian-like" stroma. Additional immunohistochemistry investigations showed expression for hormone receptors by the stromal component of the tumour. DISCUSSION: MEST typically presents in perimenopausal women as a primarily cystic mass. Commonly, the tumour arises from the renal parenchyma or pelvis. The tumour is composed of an admixture of cystic and sometimes more solid areas. The stromal cells typically demonstrate an ovarian-type stroma showing expression for the estrogen and progesterone receptors. CONCLUSION: MEST represents a distinctive benign tumour entity of the kidney, which affects perimenopausal woman. The tumour should be distinguished from other cystic renal neoplasms. By imaging studies it is difficult to distinguish between a benign or malignant nature of the tumour. Thus, intraoperative frozen section is necessary for conservative surgery, since the overall prognosis is favourable and renal function can be preserved in most cases. PMID- 20193077 TI - Budd-Chiari syndrome: long term success via hepatic decompression using transjugular intrahepatic porto-systemic shunt. AB - BACKGROUND: Budd-Chiari syndrome (BCS) generally implies thrombosis of the hepatic veins and/or the intrahepatic or suprahepatic inferior vena cava. Treatment depends on the underlying cause, the anatomic location, the extent of the thrombotic process and the functional capacity of the liver. It can be divided into medical treatment including anticoagulation and thrombolysis, radiological procedures such as angioplasty and transjugular intrahepatic porto systemic shunt (TIPS) and surgical interventions including orthotopic liver transplantation (OLT). Controlled trials or reports on larger cohorts are limited due to rare disease frequency. The aim of this study was to report our single centre long term results of patients with BCS receiving one of three treatment options i.e. medication only, TIPS or OLT on an individually based decision of our local expert group. METHODS: 20 patients with acute, subacute or chronic BCS were treated between 1988 and 2008. Clinical records were analysed with respect to underlying disease, therapeutic interventions, complications and overall outcome. RESULTS: 16 women and 4 men with a mean age of 34 +/- 12 years (range: 14-60 years) at time of diagnosis were included. Myeloproliferative disorders or a plasmatic coagulopathy were identified as underlying disease in 13 patients, in the other patients the cause of BCS remained unclear. 12 patients presented with an acute BCS, 8 with a subacute or chronic disease. 13 patients underwent TIPS, 4 patients OLT as initial therapy, 2 patients required only symptomatic therapy, and one patient died from liver failure before any specific treatment could be initiated. Eleven of 13 TIPS patients required 2.5 +/- 2.4 revisions (range: 0 8). One patient died from his underlying hematologic disease. The residual 12 patients still have stable liver function not requiring OLT. All 4 patients who underwent OLT as initial treatment, required re-OLT due to thrombembolic complications of the graft. Survival in the TIPS group was 92.3% and in the OLT group 75% during a median follow-up of 4 and 11.5 years, respectively. CONCLUSION: Our results confirm the role of TIPS in the management of patients with acute, subacute and chronic BCS. The limited number of patients with OLT does not allow to draw a meaningful conclusion. However, the underlying disease may generate major complications, a reason why OLT should be limited to patients who cannot be managed by TIPS. PMID- 20193078 TI - Visual acuity in larval zebrafish: behavior and histology. AB - BACKGROUND: Visual acuity, the ability of the visual system to distinguish two separate objects at a given angular distance, is influenced by the optical and neuronal properties of the visual system. Although many factors may contribute, the ultimate limit is photoreceptor spacing. In general, at least one unstimulated photoreceptor flanked by two stimulated ones is needed to perceive two objects as separate. This critical interval is also referred to as the Nyquist frequency and is according to the Shannon sampling theorem the highest spatial frequency where a pattern can be faithfully transmitted. We measured visual acuity in a behavioral experiment and compared the data to the physical limit given by photoreceptor spacing in zebrafish larvae. RESULTS: We determined visual acuity by using the optokinetic response (OKR), reflexive eye movements in response to whole field movements of the visual scene. By altering the spatial frequency we determined the visual acuity at approximately 0.16 cycles/degree (cpd) (minimum separable angle = 3.1 degrees ). On histological sections we measured the retinal magnification factor and the distance between double cones, that are thought to mediate motion perception. These measurements set the physical limit at 0.24 cpd (2.1 degrees ). CONCLUSION: The maximal spatial information as limited by photoreceptor spacing can not be fully utilized in a motion dependent visual behavior, arguing that the larval zebrafish visual system has not matured enough to optimally translate visual information into behavior. Nevertheless behavioral acuity is remarkable close to its maximal value, given the immature state of young zebrafish larvae. PMID- 20193079 TI - The inhaled phosphodiesterase 4 inhibitor GSK256066 reduces allergen challenge responses in asthma. AB - GSK256066 is a selective phosphodiesterase 4 inhibitor that can be given by inhalation, minimising the potential for side effects. We evaluated the effects of GSK256066 on airway responses to allergen challenge in mild asthmatics. METHODS: In a randomised, double blind, cross-over study, 24 steroid naive atopic asthmatics with both early (EAR) and late (LAR) responses to inhaled allergen received inhaled GSK256066 87.5 mcg once per day and placebo for 7 days, followed by allergen challenge. Methacholine reactivity was measured 24 h post-allergen. Plasma pharmacokinetics were measured. The primary endpoint was the effect on LAR. RESULTS: GSK256066 significantly reduced the LAR, attenuating the fall in minimum and weighted mean FEV1 by 26.2% (p = 0.007) and 34.3% (p = 0.005) respectively compared to placebo. GSK256066 significantly reduced the EAR, inhibiting the fall in minimum and weighted mean FEV1 by 40.9% (p = 0.014) and 57.2% (p = 0.014) respectively compared to placebo. There was no effect on pre allergen FEV1 or methacholine reactivity post allergen. GSK256066 was well tolerated, with low systemic exposure; plasma levels were not measurable after 4 hours in the majority of subjects. CONCLUSIONS: GSK256066 demonstrated a protective effect on the EAR and LAR. This is the first inhaled PDE4 inhibitor to show therapeutic potential in asthma. PMID- 20193081 TI - Solitary metastatic adenocarcinoma of the sternum treated by total sternectomy and chest wall reconstruction using a Gore-Tex patch and myocutaneous flap: a case report. AB - INTRODUCTION: The consequences of bone metastasis are often devastating. Although the exact incidence of bone metastasis is unknown, it is estimated that 350,000 people die of bone metastasis annually in the United States. The incidence of local recurrences after mastectomy and breast-conserving therapy varies between 5% and 40% depending on the risk factors and primary therapy utilized. So far, a standard therapy of local recurrence has not been defined, while indications of resection and reconstruction considerations have been infrequently described. This case report reviews the use of sternectomy for breast cancer recurrence, highlights the need for thorough clinical and radiologic evaluation to ensure the absence of other systemic diseases, and suggests the use of serratus anterior muscle flap as a pedicle graft to cover full-thickness defects of the anterior chest wall. CASE PRESENTATION: We report the case of a 70-year-old Caucasian woman who was referred to our hospital for the management of a retrosternal mediastinal mass. She had undergone radical mastectomy in 1999. Computed tomography and magnetic resonance imaging revealed a 74.23 x 37.7 x 133.6-mm mass in the anterior mediastinum adjacent to the main pulmonary artery, the right ventricle and the ascending aorta. We performed total sternectomy at all layers encompassing the skin, the subcutaneous tissues, the right pectoralis major muscle, all the costal cartilages, and the anterior part of the pericardium. The defect was immediately closed using a 0.6 mm Gore-Tex cardiovascular patch combined with a serratus anterior muscle flap. Our patient had remained asymptomatic during her follow-up examination after 18 months. CONCLUSION: Chest wall resection has become a critical component of the thoracic surgeon's armamentarium. It may be performed to treat either benign conditions (osteoradionecrosis, osteomyelitis) or malignant diseases. There are, however, very few reports on the results of full-thickness complete chest wall resections for locally recurrent breast cancer with sufficient safety margins, and even fewer reports that describe the operative technique of using the serratus anterior muscle as a pedicled flap. PMID- 20193080 TI - Simultaneous down-regulation of tumor suppressor genes RBSP3/CTDSPL, NPRL2/G21 and RASSF1A in primary non-small cell lung cancer. AB - BACKGROUND: The short arm of human chromosome 3 is involved in the development of many cancers including lung cancer. Three bona fide lung cancer tumor suppressor genes namely RBSP3 (AP20 region),NPRL2 and RASSF1A (LUCA region) were identified in the 3p21.3 region. We have shown previously that homozygous deletions in AP20 and LUCA sub-regions often occurred in the same tumor (P < 10-6). METHODS: We estimated the quantity of RBSP3, NPRL2, RASSF1A, GAPDH, RPN1 mRNA and RBSP3 DNA copy number in 59 primary non-small cell lung cancers, including 41 squamous cell and 18 adenocarcinomas by real-time reverse transcription-polymerase chain reaction based on TaqMan technology and relative quantification. RESULTS: We evaluated the relationship between mRNA level and clinicopathologic characteristics in non-small cell lung cancer. A significant expression decrease (> or =2) was found for all three genes early in tumor development: in 85% of cases for RBSP3; 73% for NPRL2 and 67% for RASSF1A (P < 0.001), more strongly pronounced in squamous cell than in adenocarcinomas. Strong suppression of both, NPRL2 and RBSP3 was seen in 100% of cases already at Stage I of squamous cell carcinomas. Deregulation of RASSF1A correlated with tumor progression of squamous cell (P = 0.196) and adenocarcinomas (P < 0.05). Most likely, genetic and epigenetic mechanisms might be responsible for transcriptional inactivation of RBSP3 in non-small cell lung cancers as promoter methylation of RBSP3 according to NotI microarrays data was detected in 80% of squamous cell and in 38% of adenocarcinomas. With NotI microarrays we tested how often LUCA (NPRL2, RASSF1A) and AP20 (RBSP3) regions were deleted or methylated in the same tumor sample and found that this occured in 39% of all studied samples (P < 0.05). CONCLUSION: Our data support the hypothesis that these TSG are involved in tumorigenesis of NSCLC. Both genetic and epigenetic mechanisms contribute to down-regulation of these three genes representing two tumor suppressor clusters in 3p21.3. Most importantly expression of RBSP3, NPRL2 and RASSF1A was simultaneously decreased in the same sample of primary NSCLC: in 39% of cases all these three genes showed reduced expression (P < 0.05). PMID- 20193082 TI - The Boston Puerto Rican Health Study, a longitudinal cohort study on health disparities in Puerto Rican adults: challenges and opportunities. AB - BACKGROUND: The Boston Puerto Rican Health Study is an ongoing longitudinal cohort study designed to examine the role of psychosocial stress on presence and development of allostatic load and health outcomes in Puerto Ricans, and potential modification by nutritional status, genetic variation, and social support. METHODS: Self-identified Puerto Ricans, aged 45-75 years and residing in the Boston, MA metro area, were recruited through door-to-door enumeration and community approaches. Participants completed a comprehensive set of questionnaires and tests. Blood, urine and salivary samples were extracted for biomarker and genetic analysis. Measurements are repeated at a two-year follow up. RESULTS: A total of 1500 eligible participants completed baseline measurements, with nearly 80% two-year follow-up retention. The majority of the cohort is female (70%), and many have less than 8th grade education (48%), and fall below the poverty level (59%). Baseline prevalence of health conditions is high for this age range: considerable physical (26%) and cognitive (7%) impairment, obesity (57%), type 2 diabetes (40%), hypertension (69%), arthritis (50%) and depressive symptomatology (60%). CONCLUSIONS: The enrollment of minority groups presents unique challenges. This report highlights approaches to working with difficult to reach populations, and describes some of the health issues and needs of Puerto Rican older adults. These results may inform future studies and interventions aiming to improve the health of this and similar communities. PMID- 20193083 TI - Tai Chi for osteopenic women: design and rationale of a pragmatic randomized controlled trial. AB - BACKGROUND: Post-menopausal osteopenic women are at increased risk for skeletal fractures. Current osteopenia treatment guidelines include exercise, however, optimal exercise regimens for attenuating bone mineral density (BMD) loss, or for addressing other fracture-related risk factors (e.g. poor balance, decreased muscle strength) are not well-defined. Tai Chi is an increasingly popular weight bearing mind-body exercise that has been reported to positively impact BMD dynamics and improve postural control, however, current evidence is inconclusive. This study will determine the effectiveness of Tai Chi in reducing rates of bone turnover in post-menopausal osteopenic women, compared with standard care, and will preliminarily explore biomechanical processes that might inform how Tai Chi impacts BMD and associated fracture risks. METHODS/DESIGN: A total of 86 post menopausal women, aged 45-70y, T-score of the hip and/or spine -1.0 and -2.5, have been recruited from primary care clinics of a large healthcare system based in Boston. They have been randomized to a group-based 9-month Tai Chi program plus standard care or to standard care only. A unique aspect of this trial is its pragmatic design, which allows participants randomized to Tai Chi to choose from a pre-screened list of community-based Tai Chi programs. Interviewers masked to participants' treatment group assess outcomes at baseline and 3 and 9 months after randomization. Primary outcomes are serum markers of bone resorption (C terminal cross linking telopeptide of type I collagen), bone formation (osteocalcin), and BMD of the lumbar spine and proximal femur (dual-energy X-ray absorptiometry). Secondary outcomes include health-related quality-of-life, exercise behavior, and psychological well-being. In addition, kinetic and kinematic characterization of gait, standing, and rising from a chair are assessed in subset of participants (n = 16) to explore the feasibility of modeling skeletal mechanical loads and postural control as mediators of fracture risk. DISCUSSION: Results of this study will provide preliminary evidence regarding the value of Tai Chi as an intervention for decreasing fracture risk in osteopenic women. They will also inform the feasibility, value and potential limitations related to the use of pragmatic designs for the study of Tai Chi and related mind-body exercise. If the results are positive, this will help focus future, more in-depth, research on the most promising potential mechanisms of action identified by this study. TRIAL REGISTRATION: This trial is registered in ClinicalTrials.gov, with the ID number of NCT01039012. PMID- 20193084 TI - Dual effect of Plasmodium-infected erythrocytes on dendritic cell maturation. AB - BACKGROUND: Infection with Plasmodium is the cause of malaria, a disease characterized by a high inflammatory response in the blood. Dendritic cells (DC) participate in both adaptive and innate immune responses, influencing the generation of inflammatory responses. DC can be activated through different receptors, which recognize specific molecules in microbes and induce the maturation of DC. METHODS: Using Plasmodium yoelii, a rodent malaria model, the effect of Plasmodium-infected erythrocytes on DC maturation and TLR responses have been analysed. RESULTS: It was found that intact erythrocytes infected with P. yoelii do not induce maturation of DC unless they are lysed, suggesting that accessibility of parasite inflammatory molecules to their receptors is a key issue in the activation of DC by P. yoelii. This activation is independent of MyD88. It was also observed that pre-incubation of DC with intact P. yoelii infected erythrocytes inhibits the maturation response of DC to other TLR stimuli. The inhibition of maturation of DC is reversible, parasite-specific and increases with the stage of parasite development, with complete inhibition induced by schizonts (mature infected erythrocytes). Plasmodium yoelii-infected erythrocytes induce a broad inhibitory effect rendering DC non-responsive to ligands for TLR2, TLR3, TLR4, TLR5, TLR7 and TLR9. CONCLUSIONS: Despite the presence of inflammatory molecules within Plasmodium-infected erythrocytes, which are probably responsible for DC maturation induced by lysates, intact Plasmodium infected erythrocytes induce a general inhibition of TLR responsiveness in DC. The observed effect on DC could play an important role in the pathology and suboptimal immune response observed during the disease. These results help to explain why immune functions are altered during malaria, and provide a system for the identification of a parasite-derived broad inhibitor of TLR-mediated signaling pathways. PMID- 20193085 TI - Attracting, trapping and killing disease-transmitting mosquitoes using odor baited stations - The Ifakara Odor-Baited Stations. AB - BACKGROUND: To accelerate efforts towards control and possibly elimination of mosquito-borne diseases such as malaria and lymphatic filariasis, optimally located outdoor interventions could be used to complement existing intradomicilliary vector control methods such as house spraying with insecticides and insecticidal bednets. METHODS: We describe a new odor-baited station for trapping, contaminating and killing disease-transmitting mosquitoes. This device, named the 'Ifakara Odor-baited Station' (Ifakara OBS), is a 4 m3 hut-shaped canvas box with seven openings, two of which may be fitted with interception traps to catch exiting mosquitoes. It is baited with synthetic human odors and may be augmented with contaminants including toxic insecticides or biological agents. RESULTS: In field trials where panels of fabric were soaked in 1% pirimiphos-methyl solution and suspended inside the Ifakara OBS, at least 73.6% of Anopheles arabiensis, 78.7% of Culex and 60% of Mansonia mosquitoes sampled while exiting the OBS, died within 24 hours. When used simply as a trap and evaluated against two existing outdoor traps, Ifakara Tent trap and Mosquito Magnet-X(R), the OBS proved more efficacious than the Ifakara Tent trap in catching all mosquito species found (P < 0.001). Compared to the Mosquito Magnet X(R), it was equally efficacious in catching An. arabiensis (P = 0.969), but was less efficacious against Culex (P < 0.001) or Mansonia species (P < 0.001). CONCLUSION: The Ifakara OBS is efficacious against disease-carrying mosquitoes including the malaria vector, An. arabiensis and Culicine vectors of filarial worms and arboviruses. It can be used simultaneously as a trap and as a contamination or killing station, meaning most mosquitoes which escape trapping would leave when already contaminated and die shortly afterwards. This technique has potential to complement current vector control methods, by targeting mosquitoes in places other than human dwellings, but its effectiveness in the field will require cheap, long-lasting and easy-to-use mosquito lures. PMID- 20193086 TI - Nitric oxide synthase modulates CFA-induced thermal hyperalgesia through cytokine regulation in mice. AB - BACKGROUND: Although it has been largely demonstrated that nitric oxide synthase (NOS), a key enzyme for nitric oxide (NO) production, modulates inflammatory pain, the molecular mechanisms underlying these effects remain to be clarified. Here we asked whether cytokines, which have well-described roles in inflammatory pain, are downstream targets of NO in inflammatory pain and which of the isoforms of NOS are involved in this process. RESULTS: Intraperitoneal (i.p.) pretreatment with 7-nitroindazole sodium salt (7-NINA, a selective neuronal NOS inhibitor), aminoguanidine hydrochloride (AG, a selective inducible NOS inhibitor), L-N(G) nitroarginine methyl ester (L-NAME, a non-selective NOS inhibitor), but not L N(5)-(1-iminoethyl)-ornithine (L-NIO, a selective endothelial NOS inhibitor), significantly attenuated thermal hyperalgesia induced by intraplantar (i.pl.) injection of complete Freund's adjuvant (CFA). Real-time reverse transcription polymerase chain reaction (RT-PCR) revealed a significant increase of nNOS, iNOS, and eNOS gene expression, as well as tumor necrosis factor-alpha (TNF), interleukin-1 beta (IL-1beta), and interleukin-10 (IL-10) gene expression in plantar skin, following CFA. Pretreatment with the NOS inhibitors prevented the CFA-induced increase of the pro-inflammatory cytokines TNF and IL-1beta. The increase of the anti-inflammatory cytokine IL-10 was augmented in mice pretreated with 7-NINA or L-NAME, but reduced in mice receiving AG or L-NIO. NNOS-, iNOS- or eNOS-knockout (KO) mice had lower gene expression of TNF, IL-1beta, and IL-10 following CFA, overall corroborating the inhibitor data. CONCLUSION: These findings lead us to propose that inhibition of NOS modulates inflammatory thermal hyperalgesia by regulating cytokine expression. PMID- 20193088 TI - Palpitations following regular ibuprofen dosing in a 13-year-old girl: a case report. AB - INTRODUCTION: The sensation of palpitations may either be the initial or the only symptom of cardiac arrhythmia. We describe a case of an apparent clear temporal relationship between standard ibuprofen dosing and palpitations. A review of the medical literature revealed this to be, to the best of our knowledge, the first reported case of this type. CASE PRESENTATION: A 13-year-old Caucasian girl initially presented to our clinic with hamstring tendinitis. She was commenced on a medication regimen of paracetamol and ibuprofen. After the third ibuprofen dose, she experienced palpitations. These were associated with lower chest and/or upper abdominal discomfort, and a feeling of being hot and sweaty. Her symptoms ceased upon the cessation of ibuprofen therapy. CONCLUSION: Cardiac arrhythmia is a potentially fatal disorder that may exhibit heart palpitations as its initial (or only) symptom. The prompt recognition of the cause of the symptom can reduce mortality and morbidity associated with any underlying pathological processes. There is a need to investigate cases of recurrent palpitations so as to exclude underlying structural cardiac pathology and/or abnormal cardiac rhythm. PMID- 20193087 TI - An efficient method for developing SNP markers based on EST data combined with high resolution melting (HRM) analysis. AB - BACKGROUND: In order to identify single nucleotide polymorphisms (SNPs) efficiently from a species with a large genome, SNPs were identified from an expressed sequence tag (EST) database combined with High Resolution Melting (HRM) analysis. FINDINGS: A total of 574 sequence tagged sites (STSs) were generated from Cryptomeria japonica and HRM analysis was used to screen for polymorphisms in these STS markers. STSs were designed in two ways: 1) putative SNP sites were identified by comparing ESTs from specific contigs, then 226 primer pairs designed for the purpose to amplify these SNPs; 2) 348 primer pairs were randomly designed using reads from the 3' end of cDNA. HRM analysis revealed that 325 markers among eight individuals were polymorphic, and that STSs, including putative SNP sites, exhibited higher levels of polymorphism. CONCLUSION: Our results indicate that the combination of SNP screening from an EST database combined with HRM analysis is a highly efficient way to develop SNP markers for expressed genes. This method will contribute to both genetic mapping and the identification of SNPs in non-model organisms. PMID- 20193089 TI - Post traumatic stress symptoms and heart rate variability in Bihar flood survivors following yoga: a randomized controlled study. AB - BACKGROUND: An earlier study showed that a week of yoga practice was useful in stress management after a natural calamity. Due to heavy rain and a rift on the banks of the Kosi river, in the state of Bihar in north India, there were floods with loss of life and property. A week of yoga practice was given to the survivors a month after the event and the effect was assessed. METHODS: Twenty two volunteers (group average age +/- S.D, 31.5 +/- 7.5 years; all of them were males) were randomly assigned to two groups, yoga and a non-yoga wait-list control group. The yoga group practiced yoga for an hour daily while the control group continued with their routine activities. Both groups' heart rate variability, breath rate, and four symptoms of emotional distress using visual analog scales, were assessed on the first and eighth day of the program. RESULTS: There was a significant decrease in sadness in the yoga group (p < 0.05, paired t test, post data compared to pre) and an increase in anxiety in the control group (p < 0.05, paired t-test, post data compared to pre). CONCLUSIONS: A week of yoga can reduce feelings of sadness and possibly prevent an increase in anxiety in flood survivors a month after the calamity. TRIAL REGISTRATION: Clinical Trials Registry of India: CTRI/2009/091/000285. PMID- 20193090 TI - Computational analysis of binding between malarial dihydrofolate reductases and anti-folates. AB - BACKGROUND: Plasmodium falciparum readily develops resistance to the anti-folates pyrimethamine and proguanil via a characteristic set of mutations in the dihydrofolate reductase (PfDHFR) gene that leads to reduced competitive drug binding at the enzyme's active site. Analogous mutations can be found in the DHFR gene in isolates of Plasmodium vivax (PvDHFR) although anti-folates have not been widely used for the treatment of this infection. Here the interactions between DHFR inhibitors and modelled structures of the DHFR enzymes of Plasmodium malariae (PmDHFR) and Plasmodium ovale (PoDHFR) are described, along with an investigation of the effect of recently reported mutations within PmDHFR. METHODS: DHFR models for PmDHFR and PoDHFR were constructed using the solved PfDHFR-TS and PvDHFR structures respectively as templates. The modelled structures were docked with three DHFR inhibitors as ligands and more detailed interactions were explored via simulation of molecular dynamics. RESULTS: Highly accurate models were obtained containing sets of residues that mediate ligand binding which are highly comparable to those mediating binding in known crystal structures. Within this set, there were differences in the relative contribution of individual residues to inhibitor binding. Modelling of PmDHFR mutant sequences revealed that PmDHFR I170M was associated with a significant reduction in binding energy to all DHFR inhibitors studied, while the other predicted resistance mutations had lesser or no effects on ligand binding. CONCLUSIONS: Binding of DHFR inhibitors to the active sites of all four Plasmodium enzymes is broadly similar, being determined by an analogous set of seven residues. PmDHFR mutations found in field isolates influenced inhibitor interactions to a varying extent. In the case of the isolated I170M mutation, the loss of interaction with pyrimethamine suggests that DHFR-inhibitor interactions in P. malariae are different to those seen for DHFRs from P. falciparum and P. vivax. PMID- 20193091 TI - Anabolic and catabolic responses of human articular chondrocytes to varying oxygen percentages. AB - INTRODUCTION: Oxygen is a critical parameter proposed to modulate the functions of chondrocytes ex-vivo as well as in damaged joints. This article investigates the effect of low (more physiological) oxygen percentage on the biosynthetic and catabolic activity of human articular chondrocytes (HAC) at different phases of in vitro culture. METHODS: HAC expanded in monolayer were cultured in pellets for two weeks (Phase I) or up to an additional two weeks (Phase II). In each Phase, cells were exposed to 19% or 5% oxygen. Resulting tissues and culture media were assessed to determine amounts of produced/released proteoglycans and collagens, metalloproteinases (MMPs), collagen degradation products and collagen fibril organization using biochemical, (immuno)-histochemical, gene expression and scanning electron microscopy analyses. In specific experiments, the hypoxia inducible factor-1alpha (HIF-1alpha) inhibitor cadmium chloride was supplemented in the culture medium to assess the involvement of this pathway. RESULTS: Independent from the oxygen percentage during expansion, HAC cultured at 5% O(2) (vs 19% O(2)) during Phase I accumulated higher amounts of glycosaminoglycans and type II collagen and expressed reduced levels of MMP-1 and MMP-13 mRNA and protein. Switching to 19% oxygen during Phase II resulted in reduced synthesis of proteoglycan and collagen, increased release of MMPs, accumulation of type II collagen fragments and higher branching of collagen fibrils. In contrast, reducing O(2) during Phase II resulted in increased proteoglycan and type II collagen synthesis and reduced expression and release of MMP-13 mRNA and protein. Supplementation of cadmium chloride during differentiation culture at 5% O(2) drastically reduced the up-regulation of type II collagen and the down-regulation of MMP-1 mRNA. CONCLUSIONS: The application of more physiologic oxygen percentage during specific phases of differentiation culture enhanced the biosynthetic activity and reduced the activity of catabolic enzymes implicated in cartilage breakdown. Modulation of the oxygen percentage during HAC culture may be used to study pathophysiological events occurring in osteoarthritis and to enhance properties of in vitro engineered cartilaginous tissues. PMID- 20193092 TI - An unedited 1.1 kb mitochondrial orfB gene transcript in the wild abortive cytoplasmic male sterility (WA-CMS) system of Oryza sativa L. subsp. indica. AB - BACKGROUND: The application of hybrid rice technology has significantly increased global rice production during the last three decades. Approximately 90% of the commercially cultivated rice hybrids have been derived through three-line breeding involving the use of WA-CMS lines. It is believed that during the 21st century, hybrid rice technology will make significant contributions to ensure global food security. This study examined the poorly understood molecular basis of the WA-CMS system in rice. RESULTS: RFLPs were detected for atp6 and orfB genes in sterile and fertile rice lines, with one copy of each in the mt-genome. The RNA profile was identical in both lines for atp6, but an additional longer orfB transcript was identified in sterile lines. 5' RACE analysis of the long orfB transcript revealed it was 370 bp longer than the normal transcript, with no indication it was chimeric when compared to the genomic DNA sequence. cDNA clones of the longer orfB transcript in sterile lines were sequenced and the transcript was determined unedited. Sterile lines were crossed with the restorer and maintainer lines, and fertile and sterile F1 hybrids were respectively generated. Both hybrids contained two types of orfB transcripts. However, the long transcript underwent editing in the fertile F1 hybrids and remained unedited in the sterile lines. Additionally, the editing of the 1.1 kb orfB transcript co segregated with fertility restoring alleles in a segregating population of F2 progeny; and the presence of unedited long orfB transcripts was detected in the sterile plants from the F2 segregating population. CONCLUSION: This study helped to assign plausible operative factors responsible for male-sterility in the WA cytoplasm of rice. A new point of departure to dissect the mechanisms governing the CMS-WA system in rice has been identified, which can be applied to further harness the opportunities afforded by hybrid vigor in rice. PMID- 20193093 TI - Effects of decontaminated fish oil or a fish and vegetable oil blend on persistent organic pollutant and fatty acid compositions in diet and flesh of Atlantic salmon ( Salmo salar). AB - The health benefits of seafood are well documented and based on the unique supply of n-3 highly unsaturated fatty acids (HUFA). Aquaculture now contributes about 50 % of food-grade seafood globally and Atlantic salmon (Salmo salar) is a rich source of n-3 HUFA. However, salmon and other oily fish can accumulate lipophilic persistent organic pollutants (POP), including dioxins (PCDD/F), polychlorinated biphenyls (PCB) and polybrominated diphenyl ethers (PBDE), derived largely from feed. In the present study, triplicate groups of salmon, of initial weight 0.78 kg, were fed one of three experimental diets for 11 weeks. The diets were coated with either a northern fish oil (FO) with a high POP content (cNFO), the same oil that had been decontaminated (deNFO) or a blend of southern fish oil, rapeseed and soyabean oils (SFO/RO/SO). Dietary PCDD/F+dioxin-like PCB (DL-PCB) concentrations were 17.36, 0.45 and 0.53 ng toxic equivalents (TEQ)/kg, respectively. After 11 weeks, the flesh concentrations in fish fed the cNFO, deNFO and SFO/RO/SO diets were 6.42, 0.34 and 0.41 ng TEQ/kg, respectively. There were no differences in flesh EPA and DHA between fish fed the cNFO or deNFO diets although EPA and DHA were reduced by 50 and 30 %, respectively, in fish fed the SFO/RO/SO diet. Thus, decontaminated FO can be used to produce salmon high in n-3 HUFA and low in POP. Salmon produced using deNFO would be of high nutritional value and very low in POP and would utilise valuable fish oils that would otherwise be destroyed due to their high pollutant concentrations. PMID- 20193094 TI - Validation of population-specific Mini-Nutritional Assessment with its long-term mortality-predicting ability: results of a population-based longitudinal 4-year study in Taiwan. AB - Nutrition is a key element in geriatric health, and nutritional screening/assessment is a key component of comprehensive geriatric evaluation. The study aimed to validate the Mini Nutritional Assessment Taiwan version-1 (MNA T1) which adopted population-specific anthropometric cut-points, and version-2 (MNA-T2) which replaced BMI with mid-arm and calf circumferences in the scale for predicting the nutritional status of elderly Taiwanese. Using data of a population-representative longitudinal study of 2802 Taiwanese aged 65 years or older, the study graded the nutritional status of each subject with the original and both modified versions at baseline, analysed their hospital length of stay, the Activities of Daily Living (ADL), the Center for Epidemiologic Studies Depression Scale (CES-D) and life-satisfaction scores at baseline and end of 4 years, and tracked their survival during the period. Results showed that both modified versions had superior predictive abilities compared with the original MNA, and their graded scores correlated better with hospital length of stay, and ADL, CES-D and life-satisfaction scores. Both modified versions were effective in predicting follow-up mortality risk. The relative mortality risk was about 7 times for those rated malnourished and 2.5 times for those rated at risk of malnutrition compared with those who were rated normal at baseline by the two modified versions. These results suggest that both of the modified versions are effective in predicting the nutrition and health statuses of Taiwanese elderly and would serve to validate the predictive ability of the two modified versions. The MNA-T2, which requires no BMI, can make routine nutritional screening/assessment an easier task. PMID- 20193095 TI - Effect of vitamin D, calcium and multiple micronutrient supplementation on vitamin D and bone status in Bangladeshi premenopausal garment factory workers with hypovitaminosis D: a double-blinded, randomised, placebo-controlled 1-year intervention. AB - Due to little outdoor activity and low dietary intake of vitamin D (VD), Bangladeshi low-income women are at risk for osteoporosis at an early age. The present study assessed the effect of VD, Ca and multiple micronutrient supplementation on VD and bone status in Bangladeshi young female garment factory workers. This placebo-controlled 1-year intervention randomly assigned 200 apparently healthy subjects (aged 16-36 years) to four groups: VD group, daily 10 microg VD; VD and Ca (VD-Ca) group, daily 10 microg VD+600 mg Ca; multiple micronutrient and Ca (MMN-Ca) group, 10 microg VD and other micronutrients+600 mg Ca; a placebo group. Serum 25-hydroxyvitamin D (S-25OHD), intact parathyroid hormone (S-iPTH), Ca, phosphate and alkaline phosphatase were measured. Bone mineral density and bone mineral content were measured by dual-energy X-ray absorptiometry. All measurements were made at baseline and at 12 months. Significantly (P < 0.001) higher S-25OHD concentrations were observed in the supplemented groups than in the placebo group after the intervention. Supplementation had an effect (P < 0.001) on S-iPTH in the VD-Ca and MMN-Ca groups compared with the placebo group. Bone mineral augmentation increased at the femur in the supplemented groups. Supplementation with VD-Ca should be recommended as a strategic option to reduce the risk of osteomalacia and osteoporosis in these subjects. MMN-Ca may have analogous positive health implications with additional non-skeletal benefits. PMID- 20193096 TI - Physiological parameters governing the action of pancreatic lipase. AB - The most widely used pharmacological therapies for obesity and weight management are based on inhibition of gastrointestinal lipases, resulting in a reduced energy yield of ingested foods by reducing dietary lipid absorption. Colipase dependent pancreatic lipase is believed to be the major gastrointestinal enzyme involved in catalysis of lipid ester bonds. There is scant literature on the action of pancreatic lipase under the range of physiological conditions that occur within the human small intestine, and the literature that does exist is often contradictory. Due to the importance of pancreatic lipase activity to nutrition and weight management, the present review aims to assess the current body of knowledge with regards to the physiology behind the action of this unique gastrointestinal enzyme system. Existing data would suggest that pancreatic lipase activity is affected by intestinal pH, the presence of colipase and bile salts, but not by the physiological range of Ca ion concentration (as is commonly assumed). The control of secretion of pancreatic lipase and its associated factors appears to be driven by gastrointestinal luminal content, particularly the presence of acid or digested proteins and fats in the duodenal lumen. Secretion of colipase, bile acids and pancreatic lipase is driven by cholecystokinin and secretin release. PMID- 20193097 TI - Maternal early pregnancy vitamin D status in relation to fetal and neonatal growth: results of the multi-ethnic Amsterdam Born Children and their Development cohort. AB - Low vitamin D levels during pregnancy may account for reduced fetal growth and for altered neonatal development. The present study explored the association between maternal vitamin D status measured early in pregnancy and birth weight, prevalence of small-for-gestational-age (SGA) infants and postnatal growth (weight and length), as well as the potential role of vitamin D status in explaining ethnic disparities in these outcomes. Data were derived from a large multi-ethnic cohort in The Netherlands (Amsterdam Born Children and their Development (ABCD) cohort), and included 3730 women with live-born singleton term deliveries. Maternal serum vitamin D was measured during early pregnancy (median 13 weeks, interquartile range: 12-14), and was labelled 'deficient' ( or= 50 nmol/l). Six ethnic groups were distinguished: Dutch, Surinamese, Turkish, Moroccan, other non Western and other Western. Associations with neonatal outcomes were analysed using multivariate regression analyses. Results showed that compared with women with adequate vitamin D levels, women with deficient vitamin D levels had infants with lower birth weights ( - 114.4 g, 95 % CI - 151.2, - 77.6) and a higher risk of SGA (OR 2.4, 95 % CI 1.9, 3.2). Neonates born to mothers with a deficient vitamin D status showed accelerated growth in weight and length during the first year of life. Although a deficient vitamin D status influenced birth weight, SGA risk and neonatal growth, it played a limited role in explaining ethnic differences. Although vitamin D supplementation might be beneficial to those at risk of a deficient vitamin D status, more research is needed before a nationwide policy on the subject can be justified. PMID- 20193098 TI - The glucose and insulin response to isoenergetic reduction of dietary energy sources in a true carnivore: the domestic cat ( Felis catus). AB - The present study assessed the effect of separate reduction of each energy delivering nutrient - protein, fat and carbohydrate - on glucose tolerance and insulin response in a strict carnivore: the domestic cat (Felis catus). Three isoenergetic, home-made diets with the following energetic distribution, low protein (LP): protein 28 % of metabolisable energy; fat 43 %; nitrogen-free extract 29 %; low fat: 47, 27 and 25 %; low carbohydrate (LC): 45, 48 and 7 %, were tested in a 3 x 3 Latin square design. Nine healthy normal-weight cats were randomly assigned to each of the diets in a random order at intervals of 3 weeks. At the end of each testing period, intravenous glucose tolerance tests were performed. Plasma glucose concentrations and area under the glucose curve showed no differences. Area under the insulin curve was lower when cats were fed the LP diet, and the second insulin peak tended to be delayed when the LC diet was fed. In contrast to other studies, in which energy sources were elevated instead of being reduced, the present trial contradicts the often suggested negative impact of carbohydrates on insulin sensitivity in carnivores, and shows that reducing the dietary carbohydrate content below common amounts for commercial foods evokes an insulin-resistant state, which can be explained by the cats' strict carnivorous nature. It even points to a negative effect of protein on insulin sensitivity, a finding that corresponds with the highly gluconeogenic nature of amino acids in strict carnivores. PMID- 20193099 TI - Oral administration of Lactobacillus acidophilus induces IL-12 production in spleen cell culture of BALB/c mice bearing transplanted breast tumour. AB - Lactic acid bacteria can affect the maturation of immune cells and their products not only in the gut but also on the systemic immune organs such as lymph nodes and spleen. In the present work, we studied the effects of oral administration of Lactobacillus acidophilus on the immune responses of BALB/c mice bearing transplanted breast tumour. Two groups of female inbred BALB/c mice, each containing nine mice as test and control, were used. The L. acidophilus ATCC4356 strain was inoculated in DeMan-Rogosa-Sharpe broth and cultivated for 24 h at 37 degrees C. Then, it was collected by centrifugation, and was washed and suspended in PBS. Afterwards, 0.5 ml/d of this suspension, which contained 2.7 x 108 colony forming units/ml of bacteria, was orally administered to the mice by gavage, 14 d before tumour transplantation and 30 d after that with 3-d intervals. Similar to the test mice, the control mice received an equal volume of PBS. The results showed that oral administration of L. acidophilus increased the production of IL 12 (P < 0.05) and decreased the level of transforming growth factor beta (P = 0.05) in the splenocyte culture. Moreover, the growth rate of tumour in the test mice decreased (P < 0.01), and the results of delayed-type hypersensitivity assay after 48 h were risen (P < 0.05) in comparison with the controls. Results suggest that daily consumption of L. acidophilus can improve the production of immunomodulatory cytokine IL-12 in the splenocyte culture, which was stimulated by tumour antigen in BALB/c mice bearing transplanted breast tumour. But further studies are needed to find out some other possible mechanisms of this effect. PMID- 20193100 TI - Use of N-butyl cyanoacrylate in nasal septoplasty: histopathological evaluation using rabbit nasal septum model. AB - OBJECTIVES: This study was designed to investigate the effects of the tissue adhesive N-butyl cyanoacrylate on nasal septal tissues after septal surgery in a rabbit model. METHODS: Forty-two adult New Zealand rabbits were randomly divided into three groups (14 in each group): septoplasty alone, septoplasty plus N-butyl cyanoacrylate, and controls. The open approach was used to explore the nasal septum. After raising mucoperichondrial and mucoperiosteal flaps on both sides of the septum, the septum was detached from the nasal floor in the septoplasty alone and septoplasty plus N-butyl cyanoacrylate groups. In the septoplasty plus N butyl cyanoacrylate group, the mucoperichondrial and mucoperiosteal flaps were fixed to the septum and the septum was fixed lateral to the nasal spine using N butyl cyanoacrylate; in the septoplasty alone group, the septum was packed with Merocel. In the control group, no further septal surgery was performed after flap elevation. Animals were observed for bleeding and haematoma formation over the first 24 hours. Seven animals in each group were used to evaluate early histopathological effects on the septal tissues, at four weeks post-operatively; the other seven in each group were used to evaluate late effects, at 12 weeks. RESULTS: Haematoma formation was observed in 10 animals in the septoplasty alone group, in four animals in the control group, and in only one animal in the septoplasty plus N-butyl cyanoacrylate group. The difference in haematoma incidence between the septoplasty alone and the septoplasty plus N-butyl cyanoacrylate groups was significant (p = 0.000). Histopathological evaluation revealed no significant difference between the groups as regards granulation tissue formation at week four versus week 12; however, there was a significant difference between the septoplasty plus N-butyl cyanoacrylate group and the control groups as regards inflammation at week 12 (p = 0.038). There was a significant difference between the septoplasty plus N-butyl cyanoacrylate group and the septoplasty alone group as regards the composition of the bone-cartilage junction zone at week four (p = 0.001). There was also a significant difference between the septoplasty plus N-butyl cyanoacrylate group and the control group as regards the cellular structure of new cartilage formation at week 12 (p = 0.004). CONCLUSIONS: In this rabbit septoplasty model, N-butyl cyanoacrylate appeared to be an effective nasal tissue adhesive, with a low complication rate. PMID- 20193101 TI - Anterior spinal artery syndrome: a rare complication of head and neck surgery. AB - OBJECTIVE: We report a case of anterior spinal artery syndrome, an extremely rare complication, following head and neck surgery. METHOD: A case report and literature review concerning anterior spinal artery syndrome is presented. RESULTS: A 64-year-old man developed an anterior spinal artery infarction following total laryngectomy and bilateral neck dissections for post-radiotherapy glottic carcinoma. Anterior spinal artery infarction is a rare syndrome. It typically presents with weakness, loss of pain and temperature sensation below the level of the injury, with relative sparing of position and vibratory sensation. Recovery is variable. CONCLUSION: To the best of our knowledge, this is the first case report in the English language literature of anterior spinal artery syndrome following a head and neck procedure. This case report highlights a rare complication, and also the susceptibility of head and neck surgery patients to different complications. In head and neck cancer patients suffering anterior spinal artery syndrome following primary surgical treatment, we recommend that the management of this complication should be as aggressive as that of the primary cancer. PMID- 20193102 TI - Atypical presentations of malignant otitis externa. AB - INTRODUCTION: Malignant otitis externa is a life-threatening infection of the skull base. Its presentation is not always typical. CASE REPORTS: We report three cases of malignant otitis externa which illustrate the diversity of its clinical manifestations and the difficulties in its diagnosis. DISCUSSION: The perception of malignant otitis externa as an infection caused by Pseudomonas aeruginosa in diabetic patients is not always correct. The adoption of diagnostic criteria could be helpful in identifying atypical cases. PMID- 20193104 TI - Research progression of CD133 as a marker of cancer stem cells. AB - More and more evidences support the cancer stem cell (CSC) hypothesis which postulates that CSCs are responsible for tumor initiation metastasis recurrence and resistance to treatments. Therefore they are the targets of antitumor therapy. Sorting CSCs using specific surface markers is the premise of investigating their biological behaviors. Recently CD133 has been used extensively as a marker for the identification of stem cells from normal and cancerous tissues. Moreover CD133- positive (CD133+) tumor cells associate with the self-renewal differentiation potentials signal pathway drug-resistance recurrence and prognosis of tumors. Therefore CD133+ cells could be potential targets of antitumor therapy in the future. PMID- 20193103 TI - The impact of brain size on pilot performance varies with aviation training and years of education. AB - Previous studies have consistently reported age-related changes in cognitive abilities and brain structure. Previous studies also suggest compensatory roles for specialized training, skill, and years of education in the age-related decline of cognitive function. The Stanford/VA Aviation Study examines the influence of specialized training and skill level (expertise) on age-related changes in cognition and brain structure. This preliminary report examines the effect of aviation expertise, years of education, age, and brain size on flight simulator performance in pilots aged 45-68 years. Fifty-one pilots were studied with structural magnetic resonance imaging, flight simulator, and processing speed tasks. There were significant main effects of age (p < .01) and expertise (p < .01), but not of whole brain size (p > .1) or education (p > .1), on flight simulator performance. However, even though age and brain size were correlated (r = -0.41), age differences in flight simulator performance were not explained by brain size. Both aviation expertise and education were involved in an interaction with brain size in predicting flight simulator performance (p < .05). These results point to the importance of examining measures of expertise and their interactions to assess age-related cognitive changes. PMID- 20193105 TI - The asymmetric division and tumorigenesis of stem cells. AB - Stem cells use asymmetric and symmetric cell division to generate progeny. Symmetric cell division is defined as the generation of daughter cells that are destined to acquire the same fate. Stem cells divide asymmetrically to generate one daughter with a stem-cell fate and one daughter with different fate. Disruption of the machinery that regulates asymmetric division may be a reason for the generation of cancer. The asymmetric mechanism is maintained by cell polarity factors, cell fate determinants, and the spindle apparatus. The mutation or dysregulation of these factors may change stem cells from asymmetric to symmetric cell division, then leading to tumorigenesis. Therefore, further study is needed on the mechanisms of stem cell control between asymmetric and symmetric cell division, as well as the relationships among stem cells, cancer stem cells, and tumor cells. It may bring us a new approach for the resistance, recurrence, and metastasis of tumors. PMID- 20193106 TI - Biologic characteristics of the side population of human small cell lung cancer cell line H446. AB - BACKGROUND AND OBJECTIVE: Recently, the theory of cancer stem cells (CSCs) has presented new targets and orientations for tumor therapy. The major difficulties in researching CSCs include their isolation and purification. The aim of this study is to identify and characterize the side population (SP) cells in small cell lung cancer (SCLC) cell line H446, which lays the foundation for the isolation and purification of CSCs. METHODS: Fluorescence-activated cell sorting (FACS) was used to sort SP and non-SP (NSP) cells from H446. Both subgroups were cultivated to survey the capacity to form into suspended tumor cell spheres. Reverse transcription-polymerase chain reaction (RT-PCR) and real-time PCR were used to evaluate the expression levels of the mRNA of CD133, ABCG2, and nucleostemin in both subgroups. The capacity of proliferation and the differences in drug resistance of both subgroups and unsorted cells were tested by the MTT method. The differentiation ability of both subgroups was determined by FACS. Proliferation was determined by subcutaneous tumor formation in nude mice. RESULTS: The percent of Hoechst 33342 negative cells was about (5.1 +/- 0.2)% in H446 by fluorescence microscopy. The percent of SP cells was (6.3 +/- 0.1)% by flow cytometry. SP cells had a stronger capability of forming into tumor spheres than NSP cells. The mRNA expression levels of ABCG2, CD133, and nucleostemin in SP cells were 21.60 +/- 0.26, 7.10 +/- 0.14, and 1.02 +/- 0.08 folds higher than that in NSP cells (P < 0.01, P < 0.01, and P > 0.05, respectively). In vivo, SP cells showed better proliferative ability and tougher viability when treated with drugs. SP cells can differentiate into NSP cells, but NSP cells cannot differentiate into SP cells. SP cells had a greater ability to form tumors. CONCLUSION: The H446 cell line contained some SP cells with stem cell properties. CD133 and ABCG2 may be cancer stem cell markers of SCLC. PMID- 20193107 TI - Research progress in cancer stem cells and their drug resistance. AB - Traditional theories suggest that tumor growth occurs when all tumor cells work together and result in proliferation, so treatment has been mainly directed against the majority of the cells in tumor tissue, which often relapse, metastasize, and lead to treatment failure. As cancer stem cells have been successfully isolated from different tumor tissues, in-depth study of their function in relation to traditional cancer treatment faces enormous challenges. At the same time, a new theoretical basis has been provided for the in-depth study of tumorigenesis and the evaluation of prognosis of cancer therapy. Also, new ideas have been introduced for cancer therapy. Therefore, radical treatment of cancer can be achieved through killing cancer stem cells. This article reviews the research progress on cancer stem cells and their drug resistance. PMID- 20193108 TI - Technology update for the sorting and identification of breast cancer stem cells. AB - Breast cancer stem cells are a group of undifferentiated cells with self-renewal and multidifferentiation potential. Chemotherapeutic and radiotherapeutic resistance, hypoxic resistance, high tumorigenicity, high cell invasion, and metastatic abilities are characteristics of these cells, which are responsible for breast cancer recurrence. Therefore, the correct sorting and identification of breast cancer stem cells is a primary step for research in this field. This article briefly describes the recent progress on sorting and identification technologies for breast cancer stem cells. Sorting technologies include the side population technique, technologies that depend on cell surface markers, ALDEFLUOR assays, and in situ detection. Identification technologies include mammosphere cultures, limited dilution in vitro, and in-vivo animal models. This review provides an important reference for breast cancer stem cell research, which will explore new methods for the treatment of patients with breast cancer. PMID- 20193109 TI - Effects of heterochromatin in colorectal cancer stem cells on radiosensitivity. AB - BACKGROUND AND OBJECTIVE: Radiotherapy (RT) is a major non-surgical modality in the comprehensive treatment for colorectal adenocarcinoma. The radioresistance of cancer stem cells (CSCs) is a key factor that influences therapeutic effectiveness. This study was to investigate the effects of specific chromosome structure and histone modification in CSCs in colorectal adenocarcinoma radioresistance. METHODS: Samples were collected from resected human colorectal adenocarcinomas. Subcutaneous colorectal cancer model was established in nude mice. Immunohistochemistry showed that xenografts generated from bulk colorectal cancer cells resembled the original tumor specimen. Flow cytometry was performed to sort CSCs (CD133+) and non-CSCs (CD133-) from both resected samples of colorectal adenocarcinoma and xenograft before and after high single-dose radiation. The markers labeling heterochromatin (H3K9me3, HP1-alpha and H3K4me1) and euchromatin (H3K4me3) in CD133+ and CD133- nucleus were detected by immunofluorescence. RESULTS: There was distinct difference in chromatin structure between colorectal CSCs (CD133+) and non-CSCs (CD133-). The chromatin displayed compact patches in CD133+ nucleus, but loosely latticed structure in CD133- nucleus; immunofluorescence verified that the compact patches existing in CSCs was generated from heterochromatin construction. In addition, the vacuole-like defect in heterochromatin regions of CSCs was observed within 24 h after exposure to 10 gray (Gy) single-dose RT. Interestingly, this phenomenon was repaired from 96 h, and recovered to dense plaque structure in heterochromatin regions of CSCs after 144 h. However, no significant difference in non-CSCs was observed after RT exception for a loose chromatin structure. CONCLUSIONS: CSCs play a role in radiosensitivity in colorectal cancer. The mechanism may be related to heterochromatin formation and histone methylation. PMID- 20193110 TI - Effects of ternary complexes of copper with salicylaldehyde-amino acid Schiff base coordination compounds on the proliferation of BGC823 cells. AB - BACKGROUND AND OBJECTIVE: The basic structure of salicylaldehyde-amino acid Schiff base compounds includes a C=N chemical bond. These compounds show significant antitumor activities in vitro when combined with a metal ion. This study investigated the effects and possible mechanisms of four salicylaldehyde amino acid Schiff base copper ternary coordination compounds on the proliferation of human gastric cancer cell line BGC823. METHODS: The BGC823 cells were treated with the four compounds (6B, 7B, 6P, and 7P). Cell proliferation was detected by MTT assay. Apoptosis and changes in the cell cycle were analyzed by flow cytometry. DNA damage was observed using a DNA ladder assay. The expression of p53 protein was determined by immunocytochemistry. RESULTS: The proliferation of BGC823 cells was significantly inhibited by the four compounds and the effect was concentration-dependent. The half maximal inhibitory concentration (IC50) of 6B, 7B, 6P, and 7P for BGC823 cells were 18.10, 27.50, 3.61, and 3.45 micromol/L, respectively. Flow cytometry showed the four drugs induced apoptosis in BGC823 cells, which was confirmed by DNA ladder experiments. Flow cytometry also detected changed phases in the cell cycle from treatment with the compounds. The percent of cells in the G(0)/G(1) phase decreased and that of cells in the G1/S and G(2)/M phases increased, indicating that S-and G2-phase blockages exist. As shown by immunocytochemistry, the expression of p53 decreased in BGC823 cells treated with the four drugs, indicating the involvement of the p53 pathway to BGC823 cell apoptosis. CONCLUSIONS: The four compounds showed significant activities on restraining proliferation of BGC823 cells in vitro, induced apoptosis, and caused changes in the cell cycle. This may be related to the downregulation of p53. PMID- 20193111 TI - Correlation of Fas/FasL expression to cell apoptosis in Epstein-Barr virus associated gastric carcinoma. AB - BACKGROUND AND OBJECTIVE: Epstein-Barr virus (EBV) has been detected in about 10% of gastric carcinomas. However, the pathogenetic role of EBV in gastric carcinoma is uncertain. This study was to explore the correlation of Fas/FasL expression to the apoptosis of tumor cells and tumor-infiltrating lymphocytes (TIL) in EBV associated gastric carcinoma (EBVaGC). METHODS: Fas/FasL expression in 49 specimens of EBVaGC, 20 specimens of EBV-negative gastric carcinoma (EBVnGC) and 12 specimens of normal gastric mucosa was detected by immunohistochemistry. The apoptotic index (AI) of cells was determined by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL). RESULTS: The positive rates of Fas were 91.7% in normal gastric mucosa and 76.8% in gastric carcinoma (P < 0.05); those of FasL were 16.7% in normal gastric mucosa and 58% in gastric carcinoma (P < 0.05). The positive rate of Fas was significantly lower in EBVaGC than in EBVnGC (71.4% vs. 90.0%, P < 0.05). The positive rate of FasL in EBVaGC was significantly higher than that in EBVnGC (63.2% vs. 45%, P < 0.05). The AI of EBVaGC cells was significantly lower than that of EBVnGC cells (P = 0.002). The number and AI of TIL in EBVaGC were higher than those in EBVnGC (P < 0.05). The AI of TIL was positively correlated with the level of FasL expression in tumor cells (r=0.237, P = 0.028). CONCLUSION: Up-regulation of FasL expression and decrease of TIL apoptosis in EBVaGC may facilitate the escape of tumor cells from the host immunosurveillance, and it might contribute to the development and progression of carcinoma. PMID- 20193112 TI - Expression and clinical significance of syndecan-1 mRNA and HPA-1 mRNA in colorectal cancer detected with real-time fluorescent quantitative polymerase chain reaction. AB - BACKGROUND AND OBJECTIVE: Invasion and metastasis are the most common causes of mortality for patients with colorectal neoplasms, and blocking invasion and metastasis in a timely fashion has become a hot research focus. We investigated the expression of the messenger RNA of Syndecan-1 and HPA-1 in colorectal cancer, and their correlation with invasion and metastasis. METHODS: Real-time fluorescent quantitative polymerase chain reaction (PCR) was used to detect the expression of Syndecan-1 and HPA-1 in specimens from 49 patients with colorectal cancer, 49 paired adjacent colorectal neoplasms (2 cm from the carcinoma), and 49 surgical margins of paired normal colorectal mucosa tissue (5 cm from the carcinoma), to analyze their correlation with clinicopathologic characteristics of colorectal neoplasm. RESULTS: The expression of HPA-1 mRNA was significantly higher in colorectal cancer (40.56 +/- 11.75) than that in the paired adjacent colorectal neoplasms (18.28 +/- 11.33) and normal colorectal mucosa tissue (10.80 +/- 10.20) (all P < 0.001). The expression of HPA-1 mRNA was significantly higher in paired adjacent colorectal neoplasms than that in normal colorectal mucosa (P < 0.05). The expression of Syndecan-1 mRNA was significantly higher in normal colorectal mucosa (61.21 +/- 12.96) than in the paired adjacent mucosa (14.35 +/- 11.06) or colorectal cancer (10.12 +/- 8.58) (all P < 0.001). The expression of Syndecan-1 mRNA was significantly higher in the paired adjacent mucosa than that in colorectal cancer (P < 0.05). The decreased expression of Syndecan-1 mRNA and the increased expression of HPA-1 were closely associated with the degree of differentiation, the depth of infiltration, lymph node metastasis, vessel metastasis, and TNM staging of colorectal cancer (all P < 0.05). Spearman rank correlation analysis demonstrated a significant correlation between Syndecan-1 and HPA-1(r = -0.405, P < 0.05). CONCLUSIONS: The expression of Syndecan-1 mRNA was significantly highest in normal colorectal mucosa and the expression of HPA-1 mRNA was significantly highest in colorectal cancer. At the same time, the decreased expression of Syndecan-1 mRNA and the increased expression of HPA-1 mRNA can promote the invasion and metastasis of colorectal cancer. The determination of Syndecan-1 and HPA-1 may be of value in the treatment as well as in the prognosis of patients with colorectal cancer. PMID- 20193113 TI - Effect of celecoxib on proliferation, apoptosis, and survivin expression in human glioma cell line U251. AB - BACKGROUND AND OBJECTIVE: Celecoxib, one of the new generation of non-steroidal anti-inflammatory drugs (NSAIDs), has a specific inhibitory effect on COX-2. Studies have shown that celecoxib can inhibit the proliferation of tumor cells and induce cell apoptosis, which has been confirmed in colorectal tumors and familial adenomatous polyposis. This study explored the effect of celecoxib on the proliferation and apoptosis of human glioma cell line U251 and elucidated the correlation between the effect of celecoxib and the expression of survivin. METHODS: U251 cells were treated with different concentrations of celecoxib. Cell morphologic changes were observed by optical microscopy. MTT assay was used to detect the absorbance value and to calculate inhibition and survival rates. The rates of apoptosis of U251 cells after 48 h of treatment with celecoxib were assessed by flow cytometry. The expression of survivin was analyzed by immunocytochemistry (ICC) and Western blot analysis. The expression of survivin mRNA was determined by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Significant morphologic changes were shown in U251 cells after treatment with celecoxib. The MTT assay results revealed that celecoxib inhibited the proliferation of U251 cells and the inhibitory rates significantly increased in a dose-and time-dependent manner. After 48 h of treatment with celecoxib, the apoptotic cells could be obviously observed, and the apoptosis rate significantly increased with increases in concentrations of celecoxib. The expression of survivin was observed in the control group, however, the expression of survivin was significantly down-regulated as the concentration of celecoxib increased. The level of survivin mRNA expression in U251 cells was significantly down-regulated after treatment with different concentrations of celecoxib (P < 0.05). CONCLUSIONS: The inhibition of proliferation and apoptosis in U251 cells could be induced by celecoxib in a dose-and time-dependent manner, and its mechanism might be the downregulation of the expression of survivin. PMID- 20193114 TI - Expression and significance of tumor drug resistance related proteins and beta catenin in esophageal squamous cell carcinoma. AB - BACKGROUND AND OBJECTIVE: As chemotherapy is generally used in the clinical treatment of cancer, the problem of multidrug resistance (MDR) of tumors against the chemotherapeutic agents becomes more and more serious. It has been the major cause for the failure of the chemotherapy. We detected the expressions of beta catenin and tumor drug resistance related proteins, MRP2, P-gp, and Bcl-2, in esophageal squamous cell carcinoma (ESCC) to explore their function and correlation in the occurrence and development of MDR in ESCC. METHODS: We used the tissue microarray technique, immunohistochemistry, and image analysis methods to detect the expressions of MRP2, P-gp, beta-catenin, and Bcl-2 proteins and analyze their relationships with clinical data in a ESCC tissue microarray consisting of 582 specimens of ESCC, 294 specimens of normal mucosa, 92 specimens of basal cell hyperplasia, and 87 specimens of dysplasia adjacent to cancer tissue. RESULTS: The integral optical density (IOD) of MRP2 and Bcl-2, which was 195.7 +/- 175.9 x 10(3)) and 90.5 +/- 112.5 x 10(3)), respectively, was significantly higher in ESCC than in normal mucosa, which was 104.8 +/- 86.1 x103) and 25.2 +/- 46.6 x 10(3)), respectively (P < 0.01). The IOD of P-gp and beta-catenin, which was 57.7 +/- 75.5 x 10(3)) and 32.0 +/- 47.0 x 10(3)) respectively, was significantly lower in ESCC than in normal mucosa, which was 114.8 +/- 106.6 x 10(3)) and 46.1 +/- 35.7 x 10(3)), respectively (P < 0.01). According to the following order, well differentiated moderately differentiated poorly differentiated, the IOD of MRP2 increased in ESCC (P < 0.01). The IOD of beta-catenin was higher in poorly differentiated ESCC than in well or moderately differentiated ESCC (P < 0.01). The IOD of Bcl-2 was lower in well differentiated ESCC than in poorly and moderately differentiated ESCC (P < 0.01). The IOD of beta-catenin and Bcl-2 was higher in the ESCC of specimens with infiltration depths that were in membrane mucosa than those in the muscular layer or serous coat (P < 0.01). The IOD of Bcl-2 was significantly higher in cases with lymph node metastasis than in cases without (P < 0.01). Positive correlations which were respectively between the expressions of P-gp and MRP2, the expressions of P gp and Bcl-2 were found (r = 0.288 and r = 0.253, respectively, P < 0.01). CONCLUSIONS: MRP2, P-gp, and Bcl-2 may be taken as prognostic factors for MDR of ESCC. beta-catenin may play an important role in carcinogenesis and progression of ESCC. PMID- 20193115 TI - Using 18F-FDG positron emission tomography/computed tomography to judge benign or malignant colorectal hypermetabolic lesions. AB - BACKGROUND AND OBJECTIVE: The colorectum is long and its position is not fixed. The thickness of the colorectal wall is unfixed because it changes following wall contractions. The metabolism of the colorectum is not stable and abnormal metabolism results from smooth muscle movement, gland action, spasm, inflammation, and so on. These anatomic and physiologic factors can bring a few difficulties in correctly judging colorectal information on 18F-FDG positron emission tomography/computed tomography (PET/CT) scans. This study was to discuss the imaging characteristics of colorectal hypermetabolic lesions in 18F-FDG PET/CT and their value to clinical diagnosis. METHODS: According the metabolic characteristics and the shape of the lesion, 118 colorectal hypermetabolic lesions of 74 patients were detected by 18F-FDG PET/CT and separated to 6 groups (localized/CT+, localized/CT-, segmented/CT+, segmented/CT-, diffuse/CT+, diffuse/CT-). To contrast groups and the qualitative data, a RxC Chi2 test was performed to judge statistical differences. RESULTS: In the 118 lesions, 50 were determined to be malignant and 68 nonmalignant. A total of 30 lesions were in the localized/CT+ group (23 malignant, 7 non), 35 to the localized/CT- group (22 malignant, 13 non), 4 to the segmented/CT+ group (4 malignant, 0 non), 35 to the segmented/CT- group (1 malignant, 34 non), 0 to the diffuse/CT+ group, 14 to the diffuse/CT- group (0 malignant, 14 non). The rates of nonmalignant lesions in the segmented/CT- and diffuse/CT- groups (97.1%, 100%) and of malignant lesions in the segmented/CT+ groups (100%) were similar, so these three groups were combined to a nonlocalized group. The group of diffuse/CT+ was deleted. There were significant differences among the three groups of nonlocalized, localized/CT+, and localized/CT-(P < 0.001). The localized/CT+ and localized/CT- groups were combined into one localized group because no significant difference was found between them (P = 0.229). There was a significant difference between the nonlocalized and the localized groups (P < 0.001). CONCLUSIONS: On 18F-FDG PET/CT, colorectal hypermetabolic lesions in the diffuse/CT- or segmented/CT- groups were highly likely to be nonmalignant and those in the segmented/CT+ group were highly likely to be malignant. Lesions in the localized/CT+ or localized/CT- groups had only a normal likelihood of being malignant. To correctly diagnose colorectal hypermetabolic lesions, it is necessary to analyze the PET of the metabolism and the CT of the anatomy together. Especially for the metabolic lesions of the localized/CT- group, we cannot easily make the judgment of malignant or nonmalignant unless we refer to the relevant clinical data. PMID- 20193116 TI - Significance of myeloid antigen expression in precursor T lymphoblastic lymphoma. AB - BACKGROUND AND OBJECTIVE: Precursor T lymphoblastic lymphoma (T-LBL) is a highly aggressive lymphoma. Myeloid antigen expression was found in some of the patients, and its clinical significance is worth studying. This study was to compare the clinical features, short-term efficacy and survival of T-LBL patients with or without myeloid antigen expression so as to evaluate its prognostic significance. METHODS: Forty-five T-LBL patients, with a median age of 14 years, were treated at Sun Yet-sen University Cancer Center between January 2000 and July 2008. These patients were divided into myeloid antigen-positive group (My(+) group) and myeloid antigen-negative group (My(-) group) based on the flow cytometric (FCM) analysis in bone marrow or pleural fluid. Myeloid antigen expression and its correlation with the short-term efficacy and overall survival were assessed in the two groups. RESULTS: There were 18 patients (40.0%) in the My(+) group and 27 (60.0%) in the My(-) group. The myeloid antigen expression was negatively correlated with the initial level of lactate dehydrogenase (LDH), but not with other clinical features. The remission rate was lower in the My(+) group than in the My(-) group (38.8% vs. 70.3%, P = 0.028). The 2-year overall survival rate was lower in the My(+) group than in the My(-) group (51.9% vs. 78.7%, P = 0.036). By age subgroup analysis, there were no differences in response and survival rate among children and adolescents with or without myeloid antigen expression. But the remission rate and the 2-year overall survival rate were significantly lower in adult patients with myeloid antigen expression than in patients without it. Univariate and multivariate analysis demonstrated that age and myeloid antigen expression were adverse prognostic factors. CONCLUSION: Myeloid antigen expression is a predictor of a poor response to chemotherapy, and adverse prognostic factor in adult T-LBL, but not in children with T-LBL. PMID- 20193117 TI - Expression and clinical significance of Ezrin and E-cadherin in esophageal squamous cell carcinoma. AB - BACKGROUND AND OBJECTIVE: It has been proven that Ezrin protein may interact with E-cadherin protein and take part in metastasis of tumor cells. This study was to investigate the expressions of Ezrin and E-cadherin in esophageal squamous cell carcinoma (ESCC) and their relationship with the clinicopathologic factors, and analyze their diagnostic values for ESCC. METHODS: The expression of Ezrin and E cadherin in 72 specimen of ESCC and the paracancer normal squamous epithelium was detected using tissue array with SP immunohistochemistry. Their correlations to the clinicopathologic factors were analyzed statistically. RESULTS: The positive rate of Ezrin was significantly higher in ESCC than in para-cancer normal squamous epithelium (90.7% vs. 46.0%, P < 0.001); the positive rate of E-cadherin was significantly lower in ESCC than in para-cancer normal squamous epithelium (27.6% vs. 97.4%, P < 0.001). Ezrin expression was related to the invasiveness and lymph node metastasis of ESCC (P < 0.05); E-cadherin expression was related to the differentiation and lymph node metastasis of ESCC (P < 0.05). The high expression of Ezrin was related to the low expression of E-cadherin (P < 0.05). CONCLUSION: The activation of Ezrin and the absence of E-cadherin contribute to the tumorigenesis and metastasis of ESCC. PMID- 20193118 TI - A phase II trial of docetaxel plus nedaplatin and 5-fluorouracil in treating advanced esophageal carcinoma. AB - BACKGROUND AND OBJECTIVE: Accumulating data indicate that docetaxel plus cisplatin and 5-fluorouracil has certain effect on advanced gastric or gastro oesophageal junction adenocarcinoma. This study was to evaluate the efficacy and toxicity of docetaxel plus nedaplatin and 5-fluorouracil (DNF regimen) in treating advanced esophageal carcinoma. METHODS: Forty-three patients with pathologically confirmed advanced esophageal carcinoma treated by DNF regimen: intravenous infusion of docetaxel (75 mg/m(2)) over 1 h, intravenous infusion of nedaplatin (100 mg/m(2)) over 3 h, intravenous infusion of leucovorin (CF, 200 mg/m(2)) over 2 h, intravenous injection of 5-fluorouracil (375 mg/m(2)) over 10 min, followed by a 46-hour infusion of 5-fluorouracil (2.6 g/m(2)). The cycle was repeated every three weeks. Treatment efficacy was evaluated every two weeks according to the WHO standards. All patients received at least two cycles of chemotherapy. RESULTS: Patients received a total of 144 cycles of treatment, and all were evaluable for efficacy and toxicity. Of the 43 patients, 2 (4.65%) achieved complete response (CR), 25 (58.14%) achieved partial response (PR), 9 (20.93%) had stable disease (SD), and 7 (16.28%) had progressive disease (PD). The overall response rate was 62.8%. The median time-to-progression (TTP) was 201 days and the median survival time (MST) was 310 days. Grade III/IV adverse events mainly included neutropenia (20.93%), febrile neutropenia (4.65%), thrombocytopenia (6.98%) and vomiting (9.30%). One patient died of grade IV thrombocytopenia. CONCLUSION: DNF regimen is effective for and well tolerated by patients with advanced esophageal carcinoma. PMID- 20193119 TI - TGF-beta1 in serum and induced sputum for predicting radiation pneumonitis in patients with non-small cell lung cancer after radiotherapy. AB - BACKGROUND AND OBJECTIVE: Research has confirmed that transforming growth factor beta1 (TGF-beta1) is one of the cytokines related to radiation pneumonitis. But the level of TGF-beta1 in serum needed to predict radiation pneumonitis is still not clear. This study assessed the value of TGF-beta1 in both serum and induced sputum in predicting radiation pneumonitis, providing a reference for the radiotherapy of patients with non-small cell lung cancer (NSCLC). METHODS: A total of 23 patients with NSCLC treated with three-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) in our department between November 2007 and January 2009 were analyzed and evaluated. TGF-beta1 levels in both serum and sputum were detected before and near the end of radiotherapy for all the patients. The TGF-beta1 level in serum was measured with enzyme-linked immunosorbent assay (ELISA). Immunocytochemistry assays were used to detect TGF-beta1 expression in sputum sediment. Radiation pneumonitis was graded according to Radiation Therapy Oncology Group (RTOG) radiation scoring criteria every 3 weeks from the start to 3 months after the end of treatment. RESULTS: Radiation pneumonitis was noted in 9 patients in this cohort. The total incidence of radiation pneumonitis was 39.1% (9/23) and those with Grade II or worse was 30.4% (7/23). The absolute TGF-beta1 level in serum after radiotherapy was higher than before radiotherapy, but there was no statistical difference (P = 0.139). Patients with increased levels of TGF-beta1 had a higher incidence of radiation pneumonitis (45.5%) than those with decreased TGF-beta1 levels post radiotherapy (40.0%). Though there was a tendency of higher incidence of radiation pneumonitis with increases in TGF-beta1 level, no statistical difference was found (P = 1.000). Patients with tumor response had higher incidence of radiation pneumonitis (50.0%) than patients without when TGF-beta1 levels in serum increased, but there was no statistical difference (P = 0.792). TGF-beta1 was positively expressed (brown yellow) in sputum on immunocytochemistry assays and located in the cytoplasm of either macrophages or epithelial cells. Macrophages were the main cells expressing TGF-beta1. A significantly higher positive expression rate (71.4%) was found in sputum post radiotherapy than pre-radiotherapy (28.6%) (P = 0.015). The higher incidence of radiation pneumonitis (46.7%) was found in patients with positive TGF-beta1 expression in sputum post-radiotherapy than those with negative expression post radiotherapy (14.3%) (P = 0.193). CONCLUSION: It may be more reasonable to predict radiation pneumonitis by combining the change of TGF-beta1 levels in serum with tumor response than just the change of TGF-beta1 levels in serum alone. TGF-beta1 can positively express in the sputum of patients with NSCLC, located in macrophages and epithelial cells, with macrophages as the main areas of expression. Patients with positively expressed TGF-beta1 in sputum after radiotherapy have a higher incidence of radiation pneumonitis than those with negative expressions. The positive expression of TGF-beta1 in sputum is expected to become a factor for predicting radiation pneumonitis. PMID- 20193120 TI - Cancer incidence and mortality of children in urban districts of Guangzhou between 2000 and 2004. AB - BACKGROUND AND OBJECTIVE: Cancer is one of the most primary causes of death for children. The study was to analyze the cancer incidence and mortality of children in urban districts of Guangzhou between 2000 and 2004, to explore the incidence regularity of pediatric cancers and to provide a reference for prevention and treatment of pediatric cancers. METHODS: The data of cancer incidence and mortality of children during 2000-2004 were collected from Guangzhou Population based Cancer Registry, and were calculated and analyzed. RESULTS: The cancer incidence of children between 2000 and 2004 in Guangzhou was 17.91 per 100,000 (18.92 per 100,000 in males, 16.70 per 100,000 in females); the cancer mortality was 4.73 per 100,000 (4.65 per 100,000 in males, 4.83 per 100,000 in females). The incidence of lymphoid leukemia ranked first followed by cancer of central nervous system and non-Hodgkin's lymphoma. Cancer incidence was 77.52 per 100 000 in children of less than one year old, 21.49 per 100,000 in 1-4 years, 9.66 per 100,000 in 5-9 years and 17.11 per 100 000 in 10-14 years, with significant difference among the four groups (Chi(2) = 307.602, P < 0.001). CONCLUSION: Lymphoid leukemia, cancer of central nervous system and non-Hodgkin's lymphoma are the most common cancers in children. The children of 0-4 years old are the population with high cancer incidence. PMID- 20193121 TI - Anticancer clinical utility of the apurinic/apyrimidinic endonuclease/redox factor-1 (APE/Ref-1). AB - Apurinic/apyrimidinic endonuclease/redox factor-1 (APE/Ref-1), as a type of multifunctional protein, plays an essential role in the base excision repair (BER) pathway, which is responsible for the repair of DNA caused by oxidative and alkylation damage. As importantly, APE/Ref-1 also functions as a redox factor maintaining transcription factors in an active reduced state. APE/Ref-1 stimulates the DNA-binding activity of numerous transcription factors that are involved in cancer promotion and progression, such as AP-1 (Fos/Jun), NF-kappaB, HIF-1alpha, p53, and others. Based on the structures and functions of APE1/Ref-1, we will provide an overview of its activities and explore the budding clinical use of this protein as a target in cancer treatment, and propose that APE/Ref-1 has a great potential for application in clinical research. PMID- 20193122 TI - Molecular-targeted therapy for cancer. AB - Molecular-targeted therapy is a newly developed approach for cancer therapy. With the advantages of lower side effects and higher performance, this approach has become a critical focus of cancer research. There are various molecules that can be treated as therapeutic targets for cancer. These molecules are located in different compartments of cancer cells, such as the cell membrane, cytoplasm, nuclei, and extracellular matrix. In this review, we mainly discussed the current progress in molecular-targeted therapy for cancers and the development of new drugs in this field. PMID- 20193123 TI - A case of primary liver carcinosarcoma: CT findings. AB - Primary liver carcinosarcoma is extremely rare. We report a case of liver carcinosarcoma in a 58-year-old man, which was identified by pathologic and immunohistochemical (IHC) examinations. Plain CT scans showed a hypodense mass in the right liver lobe adjacent to the gallbladder fossa. The triple-phase contrast CT scans showed a mixed density mass with inhomogeneous enhancement. Multiple cystic nodules with irregular rim enhancement of the margin located in the tumor. The gallbladder wall and transverse colon were involved. CT presentations of liver carcinosarcoma were unspecific and the pre-operative diagnosis is difficult. PMID- 20193125 TI - Mouse phenogenomics, toolbox for functional annotation of human genome. AB - Mouse models are crucial for the functional annotation of human genome. Gene modification techniques including gene targeting and gene trap in mouse have provided powerful tools in the form of genetically engineered mice (GEM) for understanding the molecular pathogenesis of human diseases. Several international consortium and programs are under way to deliver mutations in every gene in mouse genome. The information from studying these GEM can be shared through international collaboration. However, there are many limitations in utility because not all human genes are knocked out in mouse and they are not yet phenotypically characterized by standardized ways which is required for sharing and evaluating data from GEM. The recent improvement in mouse genetics has now moved the bottleneck in mouse functional genomics from the production of GEM to the systematic mouse phenotype analysis of GEM. Enhanced, reproducible and comprehensive mouse phenotype analysis has thus emerged as a prerequisite for effectively engaging the phenotyping bottleneck. In this review, current information on systematic mouse phenotype analysis and an issue-oriented perspective will be provided. PMID- 20193124 TI - Control of asymmetric cell division in early C. elegans embryogenesis: teaming-up translational repression and protein degradation. AB - Asymmetric cell division is a fundamental mechanism for the generation of body axes and cell diversity during early embryogenesis in many organisms. During intrinsically asymmetric divisions, an axis of polarity is established within the cell and the division plane is oriented to ensure the differential segregation of developmental determinants to the daughter cells. Studies in the nematode Caenorhabditis elegans have contributed greatly to our understanding of the regulatory mechanisms underlying cell polarity and asymmetric division. However, much remains to be elucidated about the molecular machinery controlling the spatiotemporal distribution of key components. In this review we discuss recent findings that reveal intricate interactions between translational control and targeted proteolysis. These two mechanisms of regulation serve to carefully modulate protein levels and reinforce asymmetries, or to eliminate proteins from certain cells. PMID- 20193126 TI - Macrophage inhibitory cytokine-1 transactivates ErbB family receptors via the activation of Src in SK-BR-3 human breast cancer cells. AB - The function of macrophage inhibitory cytokine-1 (MIC-1) in cancer remains controversial, and its signaling pathways remain poorly understood. In this study, we demonstrate that MIC-1 induces the transactivation of EGFR, ErbB2, and ErbB3 through the activation of c-Src in SK-BR-3 breast cells. MIC-1 induced significant phosphorylation of EGFR at Tyr845, ErbB2 at Tyr877, and ErbB3 at Tyr1289 as well as Akt and p38, Erk1/2, and JNK mitogen-activated protein kinases (MAPKs). Treatment of SK-BR-3 cells with MIC-1 increased the phosphorylation level of Src at Tyr416, and induced invasiveness of those cells. Inhibition of c Src activity resulted in the complete abolition of MIC-1-induced phosphorylation of the EGFR, ErbB2, and ErbB3, as well as invasiveness and matrix metalloproteinase (MMP)-9 expression in SK-BR-3 cells. Collectively, these results show that MIC-1 may participate in the malignant progression of certain cancer cells through the activation of c-Src, which in turn may transactivate ErbB-family receptors. PMID- 20193127 TI - Pig large tumor suppressor 2 (Lats2), a novel gene that may regulate the fat reduction in adipocyte. AB - Clenbuterol, a Beta(2)-adrenoceptor agonist, has been proven to be a powerful repartition agent that can decrease fat deposition. Based on results from our previous cDNA microarray experiment of pig clenbuterol administration, a novel up regulated EST was full-length cloned (4859 bp encoding 1041 amino acids) and found to be the pig homolog of large tumor suppressor 2 (Lats2). We mapped pig Lats2 to chromosome 11p13-14 by using FISH, and western blotting demonstrated that pig Lats2 protein was most abundant in adipose. In Drosophila, Lats2 ortholog was reported as a key component of the Hippo pathway which regulates cell differentiation and growth. Here, we show that pig Lats2 exhibit inverted expression to YAP1, another member of the Hippo pathway which positively regulates cell growth and proliferation, during the differentiation of 3T3-L1 preadipocytes. Our results suggested that Lats2 may involve in Hippo pathway regulating the fat reduction by inhibiting adipocyte differentiation and growth. PMID- 20193128 TI - Response and transcriptional regulation of rice SUMOylation system during development and stress conditions. AB - Modification of proteins by the reversible covalent addition of the small ubiquitin like modifier (SUMO) protein has important consequences affecting target protein stability, sub-cellular localization, and protein-protein interactions. SUMOylation involves a cascade of enzymatic reactions, which resembles the process of ubiquitination. In this study, we characterized the SUMOylation system from an important crop plant, rice, and show that it responds to cold, salt and ABA stress conditions on a protein level via the accumulation of SUMOylated proteins. We also characterized the transcriptional regulation of individual SUMOylation cascade components during stress and development. During stress conditions, majority of the SUMO cascade components are transcriptionally down regulated. SUMO conjugate proteins and SUMO cascade component transcripts accumulated differentially in various tissues during plant development with highest levels in reproductive tissues. Taken together, these data suggest a role for SUMOylation in rice development and stress responses. PMID- 20193129 TI - On-off controllable RNA hybrid expression vector for yeast three-hybrid system. AB - The yeast three-hybrid system (Y3H), a powerful method for identifying RNA binding proteins, still suffers from many false positives, due mostly to RNA independent interactions. In this study, we attempted to efficiently identify false positives by introducing a tetracycline operator (tetO) motif into the RPR1 promoter of an RNA hybrid expression vector. We successfully developed a tight tetracycline-regulatable RPR1 promoter variant containing a single tetO motif between the transcription start site and the A-box sequence of the RPR1 promoter. Expression from this tetracycline-regulatable RPR1 promoter in the presence of tetracycline-response transcription activator (tTA) was positively controlled by doxycycline (Dox), a derivative of tetracycline. This on-off control runs opposite to the general knowledge that Dox negatively regulates tTA. This positively controlled RPR1 promoter system can therefore efficiently eliminate RNA-independent false positives commonly observed in the Y3H system by directly monitoring RNA hybrid expression. PMID- 20193130 TI - Transcript profiling of expressed sequence tags from intramuscular fat, longissimus dorsi muscle and liver in Korean cattle (Hanwoo). AB - A large data set of Hanwoo (Korean cattle) ESTs was analyzed to obtain differential gene expression results for the following three libraries: intramuscular fat, longissimus dorsi muscle and liver. To better understand the gene expression profiles, we identified differentially expressed genes (DEGs) via digital gene expression analysis. Hierarchical clustering of genes was performed according to their relative abundance within the six separate groups (Hanwoo fat versus non-Hanwoo fat, Hanwoo muscle versus non-Hanwoo muscle and Hanwoo liver versus non-Hanwoo liver), producing detailed patterns of gene expression. We determined the quantitative traits associated with the highly expressed genes. We also provide the first list of putative regulatory elements associated with differential tissue expression in Hanwoo cattle. In addition, we conducted evolutionary analysis that suggests a subset of genes accelerated in the bovine lineage are strongly correlated with their expression in Hanwoo muscle. PMID- 20193131 TI - Neuronal differentiation and developmental characteristics in the dentate gyrus of staggerer mutant mice. AB - Homozygous staggerer (RORa(sg/sg)) mice showed a severe ataxia caused by cerebellum degeneration. Decreased and dysfunctional Rora is a main cause of this neurologic phenotype. The phenotype of staggerer mice has been well known in cerebellum. However, there has been rarely reported about cerebrum even though of staggerer is expressed in merely cerebellum but hippocampus, thalamus, cortex, and olfactory bulb. The expressions of Ki67, doublecortin (DCX), and NeuN, which are cell proliferation, neuronal differentiation and mature neuron markers, respectively, were measured with immunohistochemistry in dentate gyrus in staggerer mice in order to uncover whether staggerer can affect the change in dentate gyrus. The immunoreactivities of DCX and NeuN were significantly reduced in the dentate gyrus of staggerer mice than normal control, while Ki67 were rarely unchanged in staggerer mice. These results suggest that staggerer mutation has an influence on the neuronal differentiation and development not only in cerebellum but also in dentate gyrus. PMID- 20193132 TI - PI(3,4,5)P3 regulates the interaction between Akt and B23 in the nucleus. AB - Phosphatidylinositol (3,4,5)-triphosphate (PIP(3)) is a lipid second messenger that employs a wide range of downstream effector proteins for the regulation of cellular processes, including cell survival, polarization and proliferation. One of the most well characterized cytoplasmic targets of PIP(3), serine/threonine protein kinase B (PKB)/Akt, promotes cell survival by directly interacting with nucleophosmin (NPM)/B23, the nuclear target of PIP(3). Here, we report that nuclear PIP(3) competes with Akt to preferentially bind B23 in the nucleoplasm. Mutation of Arg23 and Arg25 in the PH domain of Akt prevents binding to PIP(3), but does not disrupt the Akt/B23 interaction. However, treatment with phosphatases PTEN or SHIP abrogates the association between Akt and B23, indicating that nuclear PIP(3) regulates the Akt/B23 interaction by controlling the concentration and subcellular dynamics of these two proteins. PMID- 20193133 TI - Mitochondrial DNA analysis of ancient human bones excavated from Nukdo island, S.Korea. AB - We have performed analyses using ancient DNA extracted from 25 excavated human bones, estimating around the 1(st) century B.C. Ancient human bones were obtained from Nukdo Island, which is located off of the Korean peninsula of East Asia. We made concerted efforts to extract ancient DNA of high quality and to obtain reproducible PCR products, as this was a primary consideration for this extensive kind of undertaking. We performed PCR amplifications for several regions of the mitochondrial DNA, and could determine mitochondrial haplogroups for 21 ancient DNA samples. Genetic information from mitochondrial DNA belonged to super haplogroup M, haplogroup D or its sub-haplogroups (D4 or D4b), which are distinctively found in East Asians, including Koreans or Japanese. The dendrogram and principal component analysis based on haplogroup frequencies revealed that the Nukdo population was close to those of the East Asians and clearly distinguished from populations shown in the other regions. Considering that Nukdo is geologically isolated in the southern part of them Korean peninsula and is a site of commercial importance with neighboring countries, these results may reflect genetic continuity for the habitation and migration of ethnic groups who had lived in a particular area in the past. Therefore, we suggest that phylogenetic analyses of ancient DNA have significant advantages for clarifying the origins and migrations of ethnic groups, or human races. PMID- 20193134 TI - High glucose induces differentiation and adipogenesis in porcine muscle satellite cells via mTOR. AB - The present study investigated whether the mammalian target of rapamycin (mTOR) signal pathway is involved in the regulation of high glucose-induced intramuscular adipogenesis in porcine muscle satellite cells. High glucose (25 mM) dramatically increased intracellular lipid accumulation in cells during the 10-day adipogenic differentiation period. The expressions of CCAAT/enhancer binding protein-alpha (C/EBP-alpha) and fatty acid synthase (FAS) protein were gradually enhanced during the 10-day duration while mTOR phosphorylation and sterol-regulatory-element-binding protein (SREBP)-1c protein were induced on day 4. Moreover, inhibition of mTOR activity by rapamycin resulted in a reduction of SREBP-1c protein expression and adipogenesis in cells. Collectively, our findings suggest that the adipogenic differentiation of porcine muscle satellite cells and a succeeding extensive adipogenesis, which is triggered by high glucose, is initiated by the mTOR signal pathway through the activation of SREBP-1c protein. This process is previously uncharacterized and suggests a cellular mechanism may be involved in ectopic lipid deposition in skeletal muscle during type 2 diabetes. PMID- 20193135 TI - Induction of insulin receptor substrate-2 expression by Fc fusion to exendin-4 overexpressed in E. coli: a potential long-acting glucagon-like peptide-1 mimetic. AB - Exendin-4 (Ex-4), a peptide secreted from the salivary glands of the Gila monster lizard, can increase pancreatic beta-cell growth and insulin secretion by activating glucagon-like peptide-1 receptor. In this study, we expressed a fusion protein consisting of exendin-4 and the human immunoglobulin heavy chain (Ex 4/IgG-Fc) in E. coli and explored its potential therapeutic use for the treatment of insulin-resistant type 2 diabetes. Here, we show that the Ex-4/IgG-Fc fusion protein induces expression of insulin receptor substrate-2 in rat insulinoma INS 1 cells. Our findings therefore suggest that Ex-4/IgG-Fc overexpressed in E. coli could be used as a potential, long-acting glucagon-like peptide-1 mimetic. PMID- 20193137 TI - [Meta-analysis: right application and rational interpretation]. PMID- 20193138 TI - [Striving to raise the level of pediatric clinical research and practice under the guidance of the principles of evidence-based medicine]. PMID- 20193139 TI - [Meta-analysis of the efficacy and safety of fluconazole in prophylaxis of fungal infection in very low birth weight infants]. AB - OBJECTIVE: To evaluate the effect of fluconazole in prophylaxis of fungal infection in very low birth weight infants. METHODS: PubMed, EMBASE, Ovid, China National Knowledge Infrastructure, Vip Chinese Periodical Database, Wanfang Chinese Periodical Database and Chinese Bio-medicine Database were searched for the case-control study on the effect of fluconazole in prophylaxis of fungal infection in very low birth weight infants from Jan. 1994 to Jan. 2009. Articles were evaluated according to inclusion criteria. Poor-quality studies were excluded, and RevMan 4.22 software was applied for investigating the heterogeneity among individual studies and calculating the pooled risk ratio (RR) and 95% confidence interval (CI). RESULTS: Five eligible randomized clinical trials were included. Four studies were graded as "A" and one study was graded "B". Meta-analysis based on the included studies showed that the prophylactic fluconazole could significantly reduce the fungal colonization (RR: 0.32 and 95% CI: 0.23 to 0.44, P < 0.00001); and infections (RR: 0.44 and 95% CI: 0.29 to 0.65, P < 0.0001) in very low birth weight neonates. However, there was no statistically significant difference between the infants treated and not treated with prophylactic fluconazole in the neonatal mortality (RR: 0.68 and 95% CI: 0.43 to 1.07, P = 0.09) and the prophylactic use of fluconazole did not show any side-effects on the liver and bilirubin. None of the studies found any significant changes in the minimal inhibitory concentration of fluconazole in fungal isolates during the study period. There were different results about the emergence of resistance to fluconazole. CONCLUSIONS: Meta-analysis of five randomized controlled trials suggest that prophylactic fluconazole reduces the incidence of fungal colonization and invasive fungal infection in very low birth weight infants. Further trials are needed to provide more precise evaluation on efficacy, and to assess the effect on mortality, neurodevelopment and the emergence of resistance to antifungal agents. Different NICU should have different policy on prophylactic fluconazole and also adjust the policy at different time according to the incidence of fungal infection and antifungal drug resistance. PMID- 20193140 TI - [Efficacy and safety of cyclosporine A in treatment of refractory nephrotic syndrome in children: a systematic review of randomized controlled trials]. AB - OBJECTIVE: To evaluate the efficacy and safety of cyclosporine A(CsA) in the treatment of refractory nephrotic syndrome (RNS) in children. METHODS: The Cochrane library, PubMed, EMBASE, CBMdisk, CNKI and VIP were searched from the time when the databases were established to December 31, 2008. Reports on RCTs on treating RNS in children with CsA were collected. Data were extracted and assessed independently by three reviewers. The methodological quality of included RCTs was assessed by the revised Jadad-scale (including randomization, allocation concealment, blinding method and withdrawal). Meta-analysis of homogenous RCTs was managed by using RevMan4.2.3. RESULT: Nine RCTs involving 293 participants were included. Six RCTs were assessed as high-quality studies with scores from 4 to 7 and 3 RCTs were assessed as low-quality studies with scores from 1 to 3. Sub category meta-analysis was based on different clinical types and interventions of RNS in children. Meta-analysis based on included RCTs showed the following results. (1) In children with steroid-dependent or frequent relapse nephrotic syndrome: the short-term efficacy of CsA plus prednisone was better than that of prednisone alone [OR 0.14, 95% CI (0.03, 0.71)]; the short-term efficacy of CsA, cyclophosphamide (CTX) and mycophenolate mofetil had no significant differences, but compared with chlorambucil, CsA had a worse short-term efficacy [OR 6.93, 95% CI (1.53, 31.38)] and a higher relapse rate [OR 0.06, 95% CI (0.01, 0.58)]; maintaining a blood level of CsA between 60 and 80 microg/L during remission period could reduce the long term relapse rate [OR 6.43, 95% CI (1.21, 34.19)]; the incidence of end-stage renal disease (ESRD) or mortality was zero in both groups. (2) In children with steroid-resistant nephrotic syndrome, the short-term efficacy of CsA was better than that of placebo or supportive treatment and CTX, OR and 95% CI were 0.15 (0.02, 0.96) and 0.41 (0.03, 5.00), respectively, but no significant differences were found in the relapse rate and the incidence of ESRD or mortality. (3) Side effects of CsA: the incidence of nephrotoxicity, hypertrichosis and gum hypertrophy was higher in the CsA group than in that of control group, OR and 95% CI were 0.19 (0.05, 0.79), 0.06 (0.02, 0.19), 0.05 (0.02, 0.18), respectively, but no significant differences were found in the incidence of hypertension and liver toxicity. CONCLUSIONS: Available evidence showed that CsA could improve short term efficacy in RNS in children, but could not improve long term and endpoint efficacy, therefore CsA could be one of the ideal second-line drugs for RNS in children. There was a trend that the effect of CsA on steroid-dependent or frequent relapse nephrotic syndrome was superior to that on steroid-resistant nephrotic syndrome. PMID- 20193141 TI - [Effects of infant formula containing palm oil on the nutrient absorption and defecation in infants: a meta-analysis]. AB - OBJECTIVE: To evaluate the effects of infant formula containing palm oil on the nutrient absorption and defecation in infants. METHODS: A search in Cochrane Library, PubMed, OVID, Springer, China National Knowledge Infrastructure, Vip Chinese Periodical Database, Wanfang Chinese Periodical Database and Chinese Bio medicine Database was performed to identify relevant English and Chinese language articles between January 1990 and March 2009. Two reviewers independently performed data extraction and appraised using Jadad instrument. Double data were input and analyzed by software of Review Manager 4.2 recommended by Cochrane Collaboration. Intestinal nutrient absorption, electrolyte content of fecal excretion, in vivo calcium deposition, and defecation were included as the target outcomes. These outcomes were evaluated as the combined standardized mean difference (SMD) and relative risk (RR) value and 95% CI of them. RESULTS: Thirteen articles were included. Three articles meeting inclusion criteria were analyzed for the effects between infant formula containing palmitic acid at the Sn-2 positions and palmitic acid at the Sn-1, 3 positions; five articles were analyzed for the effects between infant formula containing palmitic acid at the Sn-1, 3 and without palmitic acid; another five articles were analyzed for the effects between infant formula containing palmitic acid at the Sn-2 positions and without palmitic acid. Absorption of fat and calcium was higher, the Ca(2+) of fecal excretion was lower when the infant formula provided palmitic acid at the Sn-2 positions or without palmitic acid than that determined when formula containing palmitic acid at the Sn-1 and Sn-3 positions was given (P < 0.01). The bone mineral content (BMC) and bone mineral density (BMD) increased at 3, 6 months when the infant formula without palmitic acid as compared with using the formula containing palmitic acid at the Sn-1 and Sn-3 positions (P < 0.01). The formation of calcium soaps in stool was reduced, the BMC increased when the infant formula provided palmitic acid at the Sn-2 positions as compared with using the infant formula without palmitic acid (P < 0.01). The incidence of soft stools was higher, and the incidence of hard stools was lower when the infant formula provided palmitic acid at the Sn-2 positions or without palmitic acid than that when formula containing palmitic acid at the Sn-1 and Sn-3 positions was used (P < 0.01). CONCLUSION: Absorption of fat and calcium was lower, the Ca(2+) of fecal excretion was higher, the BMC was reduced, the incidence of hard stools increased when the infant formula provided the palmitic acid at the Sn-1 and Sn-3 positions as compared with using formula contained palmitic acid at the Sn-2 positions or without palmitic acid. However, this conclusion should be used cautiously because of the limited quality of studies included into the analysis. PMID- 20193142 TI - [Evidence-based guidelines on diagnosis and treatment of childhood common renal diseases (II): evidence-based guideline on diagnosis and treatment of Henoch Schonlein purpura nephritis]. PMID- 20193143 TI - [Intensive reading of evidence-based guidelines on diagnosis and treatment of childhood common renal diseases (II)]. PMID- 20193144 TI - [Epidemiology of mild gastrointestinal disorders among infants and young children in Shanghai area]. AB - OBJECTIVE: To determine the prevalence of functional gastrointestinal disorders in children in Shanghai. METHOD: This study was conducted on the infants and young children who were below 24 months of age recruited consecutively from April 2008 to June 2008 from the 12 communities in Minhang district in Shanghai. The questionnaire on gastrointestinal symptoms and growth was sent to 5030 children < 24 months old. The age distribution of the 5030 children was: < 6 months: 1922 infants (38.2%), 6 - < 12 months: 1933 (38.4%) infants; 12 - < 18 months: 811 (16.1%) children; 18 - < 24 months: 364 (7.2%) children. RESULT: Among the 5030 children, 1909 had gastrointestinal disorders (38.0%). There was no significant difference in the rate of the disorders between sexes (P = 0.06). Regurgitation was found in 899 (17.9%) infants/children, constipation in 690 (13.7%), 619 (12.3%) infants/children suffered from diarrhea and only 71 (1.4%) suffered from colic. The incidence of gastrointestinal disorders was significantly different among different age groups. The incidence of constipation and regurgitation decreased and the incidence of diarrhea increased with growth (P < 0.01). Infants growth parameters in the group with gastrointestinal disorders especially in those with regurgitation were lower than those without gastrointestinal disorders, the difference is statistically significant. The hospital visit rate of infants with diarrhea was 62.68%, which was higher than the rate of the other three symptoms (4.45% - 16.90%). CONCLUSION: Gastrointestinal disorders are common in infants and young children in Shanghai and may have a great impact on growth. Early management could relieve the disorders and ensure infants to get normal growth and development. PMID- 20193145 TI - [Molecular epidemiology of human adenovirus diarrhea among infants and young children in Lanzhou from July 2005 to June 2008]. AB - OBJECTIVE: Gastroenteritis is a major cause of childhood morbidity and mortality worldwide. Adenovirus AdV is recognized to be one of the most important pathogens associated with severe dehydrating gastroenteritis. Studies reported elsewhere have shown that about 8%-10% of cases with infantile diarrhea are caused by AdV and in some areas AdV diarrhea even occurred in the form of outbreaks. Studies have confirmed that AdV infections are also very common in infants and young children in China. This study aimed to investigate the molecular epidemiologic characteristics of human adenovirus diarrhea among infants and children with acute diarrhea in Lanzhou, Gansu province, China. METHOD: Stool specimen and case information were collected from both outpatients and inpatients with acute diarrhea in Lanzhou. Polymerase chain reaction was used to detect AdV in stool specimens. The subjects included 709 urban children and 180 rural children, their age ranged from 19 d to 60 months. RESULT: Of the 889 cases, 43 (4.8%) were found positive for AdV. AdV was detected in 14 of 257 (5.4%) cases seen from July 2005 to June 2006, in 4 of 286 cases (1.4%) seen from July 2006 to June 2007. During the period of July 2007 to June 2008, adenovirus was detected in 346 specimens, the positive rate was 7.2% (25/346). AdV detection rates of the three-year period were significantly different. The major AdV subtypes detected were adenovirus (subgenus F) Ad40, Ad41 with a positive rate of 3.8% (34/889), followed by non enteric adenovirus (Ad12, Ad18, Ad31, Ad2, Ad5, Ad6, Ad7) with a positive rate of 1.0% (9/889) in Lanzhou during the 3 years. Most of the AdV-positive specimens showed Ad41 group F (67.4%, 29/43) as the major epidemic strains, and Ade infection mainly occurred in children under one year of age and no seasonal cluster was found. CONCLUSION: Adenovirus was one of the major etiological agent of viral diarrhea among infants and children in Lanzhou between 2005 and 2008. Ad41 was the prodomiment serotype. PMID- 20193147 TI - [Health status and affecting factors of late-preterm infants]. AB - OBJECTIVE: To study the birth rate, mortality, complications, related factors of preterm infants at Beijing Haidian Maternity and Children's Hospital in 2007, so as to establish the foundations for a more systematic and effective program for clinical treatments. METHODS: Data of all the neonates born at Beijing Haidian Maternity and Children's Hospital during the period from January 1, 2007 to December 31, 2007 were recorded for statistical analysis. All near-term infants of 35 - 37 weeks of gestational age were taken into observation group. Within 24 hours after birth, blood routine examination, urine and stool routine examination, blood gas analysis and electrolytes, blood glucose monitoring (at 1st, 3rd, 6th, 12th, and 24th hours), chest radiography examination, skull and heart color Doppler ultrasonographic examination were conducted. Full-term infants who were born on the first day of every month were randomly selected as a comparison group (totally 350 cases) for statistical analysis. Complications of the two groups were recorded in detail. Factors such as the ages of parturients, maternal infections, pregnancy-induced hypertension, diabetes, anaemia, premature rupture of membranes, abnormal aminotic fluid, abnormal umbilical cord, abnormal placenta, and twin were analyzed and compared. RESULTS: Of the 12,286 infants born during the study period, 333 were late-preterm infants; the birth rate of late-preterm infants was 2.71%. Among the complications in late-preterm infants, the hyperbilirubinemia topped at 33.6%, followed by respiratory distress (16.8%), hypoglycemia (9.0%), intracranial hemorrhage (8.1%), anemia or erythrocytosis (5.7%), and digestive system disease (5.4%). Late-preterm infants have higher rate of the hyperbilirubinemia, respiratory distress, hypoglycemia, anemia or erythrocytosis and digestive system disease (P < 0.05). The length of hospital stay of late-preterm infants, which is 5.1 d +/- 3.90 d, was significantly longer than those of full-term infants which was 3.2 d +/- 1.61 d (P < 0.05). CONCLUSION: The proportion of late-preterm infants was 2.71% of all live born infants at Beijing Haidian Maternity and Children's Hospital from January 1, 2007 to December 31, 2007. The occurrence rate of complications and mortality rate were higher than those of full-term infants. Late-preterm infants also have longer hospital stay. Hyperbilirubinemia is a common complication for late preterm infants. Pregnancy-induced hypertension, anemia, premature rupture of membranes and twins are the major causes of higher morbidity and mortality of late-preterm infants. Pediatricians should pay much more attention to late preterm infants, and should accept them for further observation and treatments. PMID- 20193146 TI - [Gene mutation analysis of a Chinese family of congenital long Q-T syndrome type three]. AB - OBJECTIVE: The congenital long QT syndrome (LQTs) is a hereditary disorder in which most affected family members have delayed ventricular repolarization manifested on the electrocardiogram (ECG) as QT interval prolongation. The disorder is associated with an increased propensity to arrhythmogenic syncope, polymorphous ventricular tachycardia (torsade de pointes), and sudden arrhythmic death. LQTs is due to mutations involving principally the myocyte ion-channels, and this monogenetic disorder has an autosomal inheritance pattern. This study investigated the gene mutation of a Chinese family of LQTs with multiple phenotypes including dilated cardiomyopathy (DCM) and cardiac conduction defects, thus to understand the molecular pathogenesis of the diseases. METHODS: A three generation Chinese LQTs family with multiple phenotypes was investigated. Blood sample was collected from the 8 family members and 100 unassociated normal individuals. Polymerase chain reaction (PCR)-DNA direct sequencing was performed to screen all exons and their flanking introns of SCN5A gene for mutation analysis. Polymerase chain reaction-single strand conformation polymorphism (PCR SSCP) was used to exclude polymorphism. RESULTS: PCR amplification and subsequent direct sequencing of SCN5A from proband revealed a heterozygous deletion of nine base pairs (CAGAAGCCC) in exon 26, corresponding to the three amino acid residues Gln1507-Lys1508-Pro1509 (QKP). This mutation is localized in the linker region between DIII-DIV of SCN5A. The same mutation was found in another patient (her grandmother) and excluded in the remaining living subjects in this family. This mutation was confirmed using SSCP in 100 unassociated healthy individuals. Similar analysis excluded possible mutations that would lead to amino acid changes in KCNQ1, KCNH2 and LAMIN A/C commonly associated with LQTs and DCM with conduction disorders, no new mutations that would lead to amino acid changes was found. CONCLUSION: The result of the present study suggests that SCN5A mutation delQKP1507-1509 exists in patients with LQTs. The delQKP1507-1509 of SCN5A is a novel mutation in Chinese people. The same mutation was previously reported in a French family with only a single LQTs phenotype. Further studies on functional expression of SCN5A mutation delQKP1507-1509 will be helpful to understand the mechanism of the multiple phenotypes. PMID- 20193148 TI - [Analysis of 12 children with novel influenza A (H1N1) virus infection]. AB - OBJECTIVE: Since late March 2009, a novel influenza H1N1 strain emerged in humans in Mexico and the United States. It has rapidly spread to many countries on different continents, prompting unprecedented activation of pandemic preparedness plans. The present study aimed to investigate the characteristics of children with the novel influenza A (H1N1) virus infection. METHOD: Twelve cases with influenza A (H1N1) infection were diagnosed according to the criteria of the Center for Disease Control and Prevention (CDC) of China during 1 May to 15 July 2009 in the Pediatric Hospital of Fudan University were analyzed. Influenza A (H1N1) RNA was detected by RT-PCR in CDC Shanghai China. RESULT: All the 12 children with the novel influenza A (H1N1) virus infection were imported cases, aged from 11 months to 14 years 7 months, 7 of whom were boys, 5 were girls. Five cases contacted closely with influenza A (H1N1) patients; 12 cases had fever and no vomiting or diarrhea; 7 had cough or runny nose or anorexia. One had shortness of breath. Of the 11 cases who could tell about symptoms correctly, 6 had sore throat, 3 had stomachache, and none had muscle pain. Two of the 12 cases had pneumonia, and the disease in 1 of them was fatal and needed intensive care. One case was isolated and treated at home. The 11 cases hospitalized were treated according to the guidance of influenza A (H1N1) diagnosis and treatment issued by the Ministry of Health of China. Ten hospitalized cases were treated with oseltamivir. All the cases recovered completely. The median length of hospital stay was 8.1 days (range, 6 to 16), and the time of negative test results of influenza A (H1N1) RNA from illness onset to collection of samples for viral testing was from 5 to 15 days. CONCLUSION: Symptoms among children with the novel influenza A (H1N1) virus infection were classic and the majority of the cases we treated had a mild clinical course if they were isolated and treated promptly. Antivirals appears to have not had any major adverse effects. More data from different regions and large samples are needed to illuminate the characteristics of children with novel influenza A (H1N1) virus infection. PMID- 20193149 TI - [Clinical study on childhood acute lymphoblastic leukemia diagnosed and treated with 04 Protocol in Chongqing, China]. AB - OBJECTIVE: To analyze the clinical and laboratory data from acute lymphoblastic leukemia (ALL) patients and the results of treatment using 04 Protocol (suggested by the Pediatric Hematology Group of Chinese Medical Association in 2004). METHODS: This study included 88 children with ALL below the age of 18 years during the period from October 1, 2004 to June 30, 2007. Minimal inhibitory concentration (MIC) and clinical risk classification were done and the new chemotherapy regimen was used according to the protocol. Patients were stratified into low-risk (LR), medium-risk (MR), and high-risk (HR) groups. Life table method was used to estimate survival rate and statistical analysis was done by using software SPSS for Windows. RESULTS: From October 2004 to June 2007, 88 childhood ALL patients were treated with the 04 Protocol. Sixty-three (91.30%) patients attained complete remission (CR) and 17 patients lost to follow up. The overall 4-year-event-free survival (EFS) rate (+/- SE) was (59.73 +/- 7.22)%. EFS was (75.60 +/- 9.71)% in the LR (n = 30), (65.50 +/- 11.69)% in the MR (n = 20) and (44.03 +/- 12.36)% in the HR. Relapse occurred in 18.18% of patients. Seven (7.95%) of 88 patients with ALL died during he induction therapy. Infection was the most common cause of death. CONCLUSION: The outcome of patients treated with the 04 Protocol was favorable. Clinical risk classification and the leukemia cells of D19 are independent predictors of prognosis of ALL. High dose methotrexate played an important role in prevention and treatment of central nervous system leukemia. The mortality rate of this chemotherapeutic protocol during induction therapy was high. PMID- 20193150 TI - [Survey on knowledge, attitude and practices in asthmatic children's parents in Beijing]. AB - OBJECTIVES: To study the knowledge, attitude and practice (KAP) concerning asthma in parents of children with asthma and the related factors. METHOD: Questionnaire survey was conducted by using the multi-center research methods in twenty hospitals with asthmatic clinic or pediatric clinic in Beijing from August to October in 2008. The investigation focused on Beijing permanent residents with children who have been diagnosed as asthma for more than 6 months. RESULT: Totally 390 parents of asthmatic children were investigated among whom 351 provided valid questionnaires, the response rate reached 90.0%; 75.2% of the parents knew that the nature of asthma is a chronic allergic airway inflammatory disease; 54.4% of parents think that even if the child is in a state of asthma control he/she can participate in only mild exercise; 88.4% of parents consider that the long-term use of inhaled corticosteroid would have a mild effect on growth and development of children. Of the asthmatic children, 32.5% adhered to use inhaled corticosteroid prescription; 47.2% adhered to use leukotriene receptor modulator; 45.3% of parents of children with acute asthma attack will add antibiotics; 18.1% of parents would choose short-acting beta2-agonist. The multi-factors Logistic regression suggested that the parents' educational background and the frequency of referral in children with asthma under control may have an influences on the parents' KAP (P < 0.05, OR > 1). CONCLUSION: The general understanding of asthma in asthmatic children's parents in Beijing area is good, the higher the parents' educational background and revisit frequency of asthmatic children whose disease is under control, the better the Parents' KAP. PMID- 20193151 TI - [Mycoplasma pneumonia associated with cerebral infarction in 3 children]. AB - OBJECTIVE: To study the clinical features and diagnostic methods of mycoplasma pneumonia complicated with cerebral infarction. METHOD: Data of 3 children with mycoplasma pneumonia who developed cerebral infarction, including clinical manifestations and imaging were collected, analyzed and the literature was reviewed. RESULT: All the cases were pre-school or school-aged children, who developed the respiratory infection initially, the neurological symptoms were acute hemiparesis, with or without convulsion. The IgM antibody to Mycoplasma pneumoniae (Mp) was positive. Pulmonary imaging showed unilateral consolidation with atelectasis and pleural exudate. Neuroimaging showed occlusion of middle cerebral artery and infarction of its territory. After giving azithromycin, anti coagulative and thrombolytic treatments, the neurological deficits recovered to some extent. CONCLUSION: Mycoplasma pneumonia were diagnosed based on respiratory symptoms and pulmonary imaging, the accompanied cerebral infarction was confirmed by neurological and neuroimaging findings. PMID- 20193152 TI - [Neonatal diabetes mellitus complicated with ketoacidosis in a case]. PMID- 20193153 TI - [Transient immunosuppression secondary to neonatal disseminated herpes simplex virus infection in a case]. PMID- 20193154 TI - [Recent research progress in Gaucher disease]. PMID- 20193155 TI - [Epstein-Barr virus associated hemophagocytic lymphohistiocytosis in childhood]. PMID- 20193157 TI - [A discussion regarding reconstruction and rehabilitation of patients with deep burn wound]. AB - With the advances in resuscitation, infection control, and metabolic management, the treatment strategies for burn patients have improved remarkably in the last half century. As a result, more patients with deep burn wound survived, and how to optimize the burn wound care aiming at recovery of the normal appearance and physiologic function of patients has been investigated and discussed widely through both the whole treatment strategy making and the new techniques performing. In the present discussion, early tissue reconstruction as well as early wound covering and repair are emphasized by summarizing the improved aesthetic and functional effects obtained by applying the principles of plastic surgery in early burn wound repair, the use of composite skin grafting, the grafting with split-thickness autografts on the preserved denatured dermis or on the preserved healthy fat tissue, etc. Besides these, more attention should be given to the repair and reconstruction in specialized functional parts of the body, such as head and face, neck, hand, female breast, perineum, and joint areas, after a deep burn. The role of rehabilitation during and after the burn wound treatment process is elucidated by demonstrating its potential biophysical mechanism and preventing scar deformity. Adequate treatment of deep burn wound demands a number of important measures including the timing of surgery, adoption of essential techniques, suitable types of wound covering materials, motivated rehabilitation, and necessary psychological therapy. The optimal recovery of damaged part of body after burn should depend on the similarity of rebuild tissue structure to simulate the nature of the original tissue in the cellular, histological, anatomic characteristics, which is the aim of all burn wound care and the basis of the appearance and function repair or reconstruction. PMID- 20193158 TI - [More stress should be laid on the application of microsurgical techniques in the repair of destructive burns and traumas, and intractable wounds]. AB - Destructive burns and traumas which create composite tissue damages, as well as intractable wounds, usually cause the difficulties or inefficacy in the repair and management through ordinary skin grafting or tissue transplantation owing to the complex defects, unhealthy healing condition, or high requirements for the function and appearance reconstruction of the injured local tissues. The advantages of free tissue transplantation with microsurgical techniques in the tissue repair and reconstruction have been demonstrated as meeting the composite tissues restoration, improving blood supply, avoiding further damage to the wound surrounding tissues, and simplifying the distant tissue transplantation procedure, and therefore significantly decreasing the deformities with good functional and morphological outcomes, and dramatically reducing the hospitalization duration with less complications and faster restitution. In the present discussion, basing on the general literature review and the summary of our long-time clinical application of microsurgical techniques in dealing with serious injuries, we put forward the view that the microsurgical techniques should be considered as the first option for the treatment of destructive burns and traumas, and intractable wounds. And in some cases, only microsurgical techniques can be used, otherwise amputation would be unavoidable, or the optimal treatment would be abandoned or delayed. Meanwhile, it should be emphasized that the risk and the failure rate of performing microsurgical operation can be overcome through strictly hard training. PMID- 20193159 TI - [Repair and reconstruction of penile defects due to devastating deep burn]. AB - OBJECTIVE: To summarize the experience of repair and reconstruction of penile defects as a result of devastating deep burn. METHODS: Twenty-four patients with penile defects in early or late (a half year after wound healed, the same below) stage after burn were involved. Their suspensory ligaments of penis were dissected to lengthen the penis after escharotomy with the necrotic distal part removed. The wounds formed after lengthening were covered with lower abdominal skin flap, scrotal or internal pudendal artery flap. Ten patients underwent surgery within 30 days after burn; the other 14 patients underwent surgery in the late stage. The condition of flaps and complications after surgery were observed. The lengths of penis of patients in flaccid and erection state were measured before surgery and at follow-up period. The sensory function of penile skin, the erectile function of the penis, and sexual intercourse activity of patients were followed up. RESULTS: All the flaps survived except two, in whom areas of 1.0 cm x 0.5 cm and 1.5 cm x 1.0 cm of necrosis at distal parts were found, and they healed after dressing changes. Patients were followed up for 2 to 5 years. The length of penis in flaccid state was (7.4 +/- 1.6) cm, which was (5.3 +/- 1.4) cm longer than that before surgery (P < 0.01). The length of penis in erection state was (9.7 +/- 1.2) cm. The sensory function of penis recovered gradually about half year after surgery with well preserved erectile function. Except one who did not try to have sexual intercourse again, all the other married patients and their spouses were satisfied or quite satisfied with sexual intercourse activity. CONCLUSIONS: Penis elongation combined with skin flap grafting is a good method for the treatment of penile defects due to devastating deep burn. Suitable length and erectile function of penis can be preserved with this method. PMID- 20193160 TI - [The treatment of cicatricial alopecia after burn with the technique of synchronously perforating and transplanting hair follicular-units]. AB - OBJECTIVE: To study the effect of the technique of synchronously perforating and transplanting hair follicular-units in the treatment of cicatricial alopecia after burn. METHODS: One hundred and sixty-six patients with 217 bald scar areas after burn were treated with above-mentioned technique from January 2002 to April 2008. Scalp strips, with conforming the necessity for grafting, were harvested from the occipital or temporal region. A series of follicular-units, each composing 1 - 3 hairs, were dissected from the strips under microscope or magnifying glass. Size-matching micro-slots were made in the scarred recipient area with 16 - 20 G needles to accept the grafts. The prepared follicular-unit was synchronously implanted into the bottom of the micro-slot as the needle being withdrawn. Patients who were not satisfactory with the density of hairs after I stage surgery underwent II stage surgery a half year later. Ten recipient areas with clear boundary in 10 patients were optionally chosen to observe the density of follicular-units and hair amount with naked eyes after I stage surgery. Survived transplanted hairs in above-mentioned 10 areas were counted to calculate hair survival rate at follow-up. Patients' postoperative satisfaction ratings were surveyed with questionnaire. RESULTS: In one half of the patients, treatment was finished after I stage surgery, the other one half received 2 stages of surgery. The follicular-unit density reached 15 - 25 grafts/cm(2) with 40 - 70 hairs/cm(2) after I stage surgery. All patients were followed up for over 8 months. Grafted hairs grew well in a natural way. 96.5% mean hair survival rate was observed in the 10 recipient areas. From patients who received only I stage surgery, 61 patients (73.5%) were very satisfactory and 22 patients (26.5%) satisfactory with the results. From the other half of patients, 76 patients (91.6%) were very satisfactory and 7 patients (8.4%) satisfactory with the results. CONCLUSIONS: The technique of perforating and transplanting follicular unit hair synchronously is safe and effective with less surgery-induced injury and less bleeding. Hairs transplanted on cicatricial alopecia area with this technique grow well with high survival rate. PMID- 20193161 TI - [Investigation and analysis of factors influencing rehabilitation of burn patients]. AB - OBJECTIVE: To study the factors influencing health of burn patients in rehabilitation period. METHODS: One hundred and one patients hospitalized in burn department of Xiehe Hospital of Fujian Medical University from February 2008 to October 2008 were investigated by means of General Information Questionnaire, the Eysenck Personality Questionnaire, the Medical Coping Modes Questionnaire, and the Social Support Rating Scale. Their rehabilitation condition was scored according to the Abbreviated Burn-Specific Health Scale. Investigation data were processed by multiple linear regression analysis in order to find out the factors influencing rehabilitation of burn patients. RESULTS: Patients in this group were scored (57 +/- 16) points in physical function, rate [(actual score/possible highest score) x 100%, the same below] 71.1% (the lowest); (97 +/- 19) points in psychological function, rate 80.6%; (53 +/- 8) points in social function, rate 88.4% (the highest); (45 +/- 11) points in general health, rate 74.5%; (251 +/- 44) points in comprehensive health [standard score (314 +/- 55) points], rate 78.5% (upper middle). The factors included in the comprehensive health regression equation (F = 11.602, P < 0.001) were: monthly income, size of burn, number of operations, introverted/extroverted characteristics, living, degree of utilization of support, social support, and resignation. They accounted for 46.6% of the variance of comprehensive health. CONCLUSIONS: Monthly income, size of burn, introverted/extroverted characteristics, living, social support, and resignation are the main factors influencing the rehabilitation level of burn patients. PMID- 20193162 TI - [Repair of nose and adjacent tissue defect deformities after burn]. AB - OBJECTIVE: To look for the best method of repairing nose and adjacent tissue defect after burn and observe the effect. METHODS: Twelve patients with post-burn nose and adjacent tissue defect deformities hospitalized from January 1999 to December 2008 were repaired with expanded forehead flap, pedicled upper-arm flap, axial post-auricular reversed flow island flap, and nasolabial groove flap. Among them, 4 cases with total nasal defect, 8 cases with partial nasal defect; and 3 cases were accompanied with scars on cheek, 5 cases accompanied with scars on forehead, 5 cases accompanied with upper lip ectropion and subtotal upper lip defect. The skin flap size ranged from 3.0 cm x 1.5 cm to 10.0 cm x 8.0 cm. RESULTS: Five cases were repaired with expanded forehead flap, 3 cases with pedicled upper-arm flap, 1 case with axial post-auricular reversed flow island flap, and 3 cases with nasolabial groove flap respectively. All the 12 flaps survived. Patients were followed up for 1 to 7 years, and nasal function and appearance were obviously improved. CONCLUSIONS: Optimal repairing method shall be chosen to repair nasal defect after burn according to its extent, and forehead flap is preferred. Pedicled upper-arm flap and reversed flow axial post-auricular island flap can be employed if local flap and ortho-position skin flap are unavailable when obvious scar is present on face as a result of severe burn. PMID- 20193163 TI - [A cost-effectiveness analysis of comprehensive rehabilitation treatment of hand burn]. AB - OBJECTIVE: To observe the effect of comprehensive rehabilitation treatment on hand burn, and to make a cost-effectiveness analysis. METHODS: Sixty-two patients with ninety-eight affected hands were divided into rehabilitation group (32 cases, 48 hands) and control group (30 cases, 50 hands). Patients in rehabilitation group received comprehensive rehabilitation treatment at early stage after burn; patients in control group were given instructions for function training at the same time. The functions of the hands to be restored including grasp, hold, pinch, nip, forearm pronation and supination, fetching, laying, and writing abilities of patients in both groups were quantitatively evaluated with Carroll's upper extremity function test before treatment and 5 months after. Direct medical costs of patients in both groups within 5 months were respectively added up to make a cost-effectiveness analysis. RESULTS: In rehabilitation group, function of digital opposition, palmar opposition, holding, and pinching of 37 hands recovered well, with which patients could pick food, put on clothes, go to toilet, and self-care etc. independently. Function of digital opposition, palmar opposition, holding, pinching half recovered in 7 hands, accompanied with well recovered of metacarpophalangeal function, but recovery of function of interphalangeal joint was less satisfactory. Although patients could grasp and hold, they were still poor in fine and harmonized activities. Joint ranges of motion of 4 hands were poor with limited function, and this was resulted from not strictly following treatment for remaining granulation wound. In control group, 23 hands received reconstructive surgery, 14 of them recovered with good function, but were poor in most of fine and harmonized activities. Severe claw hands were found in 13 hands. The ratio between total mean cost value and total function increment value in rehabilitation group (181 +/- 11) was obviously lower than that in control group (298 +/- 30, P < 0.01). CONCLUSIONS: Comprehensive rehabilitation treatment at early stage after hand burn has a good effect on prevention and treatment of hand deformity, promoting recovery of hand function and improving hand appearance. It is also less costly. PMID- 20193164 TI - [Preliminary study on the reliability and validity of Chinese version of the Abbreviated Burn Specific Health Scale]. AB - OBJECTIVE: To assess the reliability and validity of Chinese version of the Abbreviated Burn Specific Health Scale (BSHS-A). METHODS: BSHS-A was translated into Chinese and revised. Eighty-two former burn patients discharged from the Second Affiliated Hospital of Kunming Medical College, and now in rehabilitation stage, were surveyed with the Chinese version of BSHS-A according to the simple random sampling. The psychometric properties of the scale, including internal consistency, test-retest reliability, content validity and discriminant validity, were analyzed. RESULTS: One hundred and sixty-seven scales were sent to 82 participants and all of them were completed and returned. The rate of eligible questionnaire was 98.2% after eliminating 3 ineligible questionnaires. The Crobach's alpha coefficient of total score of questionnaire was 0.97, and in all domains and sub-domains ranged from 0.83 to 0.96. The test-retest coefficients from 20 participants retested within one week were between 0.74 and 0.98 (P < 0.05 or P < 0.01). Forty-eight participants surveyed within 6 months after burn were divided into mild/moderate burn group and severe burn group. The total scores of questionnaire, scores in all domains and sub-domains of patients in the latter group were lower than those in the former group (P < 0.05 or P < 0.01). CONCLUSIONS: The Chinese version of BSHS-A shows satisfactory reliability and validity, and it can be used to investigate quality of life of Chinese burn patients in rehabilitation stage. PMID- 20193165 TI - [Influence of advanced glycosylation end products on wound healing of burn rats with diabetes]. AB - OBJECTIVE: To understand the influence of accumulation of advanced glycosylation end products (AGE) on wound healing of burn rats complicated with diabetes. METHODS: Seventy-five SD rats were divided into control, diabetes, and aminoguanidine-interfered groups in completely randomized method, with 25 rats in each group. All rats were subjected to deep partial-thickness scald. Diabetes was reproduced in rats of diabetes and aminoguanidine-interfered groups. Rats in aminoguanidine-interfered group were fed with 100 mg x kg(-1) xd (-1) aminoguanidine. Rats were sacrificed on post-scald day (PSD) 0, 3, 7, 14, and 21, and portrait of the wounds were taken. Full-thickness skin tissue specimens were obtained for determination. Specimens of epidermis from back of SD rats were obtained for KC cultivation and verification. Wound healing rate, glucose content in skin tissue, morphologic change in wound tissue, AGE distribution in skin tissue, influence of AGE on proliferation and apoptosis of KC were observed. RESULTS: Wound healing rate of rats was respectively lower in diabetes group than that in control group on PSD 7, 14, and 21 (P < 0.01), but it was obviously higher in aminoguanidine-interfered group than that in the former 2 groups (P < 0.01). Glucose content of rat skin in diabetes group was (2.62 +/- 0.19) mmol/g, and it was (2.58 +/- 0.07) mmol/g in aminoguanidine-interfered group, both higher than that in control group [(1.04 +/- 0.09) mmol/g, P < 0.01]. In control group, limited intensive infiltration of inflammatory cells was found in the wound with necrotic tissue formation which fell off in time, and with no obvious delay of wound healing. In diabetes group, infiltration of inflammatory cells in wounds of rats appeared slowly, but diffusely and persistently; necrotic tissue formed and fell off late in time, with obvious delay of wound healing. In aminoguanidine interfered group, intensive infiltration of inflammatory cells was observed in time, and the time of necrotic tissue formation and sloughing, and wound healing were respectively earlier than that in diabetes group. Sporadic disposition of small amount of AGE was found in rats in control group. AGE accumulation increased significantly in rats in diabetes group. AGE content decreased significantly in rats in aminoguanidine-interfered group after administration of aminoguanidine. KC proliferation decreased significantly in concentration dependent manner 48 hours after AGE stimulation. Absorbance value of AGE decreased in each AGE-interfered group (P < 0.01). Early Annexin-V positive apoptotic KC rate was obviously higher in 100 ug/mL AGE-interfered group (15.1 +/ 2.3)% than that in control group [(11.2 +/- 1.2)%, P < 0.05]. There was no statistical significance between 100 ug/mL AGE-interfered group (14.3 +/- 3.5)% and control group (15.2 +/- 2.4)% in respect of the rate of double-positive cells apoptosis at final stage (P > 0.05). CONCLUSIONS: Hyperglycemia may inhibit proliferation of repairing cells such as KC through AGE accumulation, thus impedes wound healing. Reduction of AGE accumulation could ameliorate wound healing delay due to diabetes. PMID- 20193166 TI - [Preliminary study on the phenomenon of epidermal stem cell ectopy in expanded skin]. AB - OBJECTIVE: To observe the differentiation and distribution of epidermal stem cell (ESC) after skin soft tissue expansion, and to initially probe into the growth mechanism of expanded skin tissue. METHODS: Samples of normal skin and expanded skin (mean effusion period 45 days) were harvested from head and cervical region in 15 patients who underwent II stage surgery after skin expansion. Samples were divided into scalp adjacent to the center of expander group (expanded scalp, 3 cm from the vertical axis of the expander), scalp from lateral part of the expander group (expanded scalp, 5 - 7 cm lateral to the vertical axis of the expander), cervical skin expansion group, un-expanded scalp control group, and un-expanded cervical skin control group, according to the position of skin harvested. The tissue structure of skin in each group was observed with HE staining, and the differentiation and distribution characteristics of cytokeratin 19 (CK19) positive cells were observed with immunohistochemical staining. RESULTS: Compared with those in the un-expanded control groups, uneven, relatively thickened and obviously folded epidermis with more cell layers and cells with obvious aggregation close to the basal layer were observed in the expanded groups, but those cells were not well-arranged and the transition of polarity was not obvious. The continuity of CK19 positive cells in the basal layer of skin was observed in each of the expanded group with immunohistochemical staining, and positive cells increased obviously and arranged in multilayer in certain parts of basal layer. Clustered or dispersed CK19 positive cells were also observed outside the basal layer. No above-mentioned phenomenon was observed in the un expanded control group. CONCLUSIONS: The proliferation and differentiation of ESC with ectopic distribution may enhance the repair process after skin soft tissue expansion. PMID- 20193167 TI - [Absorption of albumin in subeschar tissue fluid in early stage after burn in rabbit and its pharmacokinetics]. AB - OBJECTIVE: To observe the change in albumin concentration in the subeschar tissue fluid of rabbits in early stage after burn, and to analyze its regular pattern. METHODS: Thirty-four adult male New Zealand rabbits were divided into control group and experiment group according to the random number table, with 17 rabbits in each group. Rabbits in experiment group were subjected to 8% TBSA full thickness scald on the back and were injected with human serum albumin in subeschar tissue serving as tracing albumin. 1.5 mL blood sample was collected at post scald hour (PSH) 2, 4, 8, 16, 24, 48, 72 respectively. Rabbits in control group were dealt with the above-mentioned procedures except for scald. The concentration of tracing albumin was measured with the enzyme-linked immunosorbent assay kit. The concentration of the serum albumin of rabbits were determined with biochemical analyzer. Pharmacokinetics parameters of tracing albumin were calculated with fitting model of 3P97 practical pharmacokinetics calculating program. RESULTS: (1) Concentration of tracing albumin of rabbits in experiment group was respectively higher than that in control group (P < 0.01) at each time point, and it peaked at PSH 8 [(421 +/- 10) microg/L]. (2) The concentration of serum albumin of rabbits in experiment group decreased in the beginning and increased later, while no significant change was observed in control group. (3) The distribution phase half-life of tracing albumin of rabbits in experiment group (4.0271 h) was about 1/3 of that of the control group (12.0907 h); while the area under the curve in the experiment group (22 336.38 microg.h.mL(-1)) was about 4 times of that in the control group (5827.77 microg.h.mL(-1)). CONCLUSIONS: The albumin in the subcutaneous tissue could be absorbed into blood circulation in normal conditions. The resorption occurs earlier and faster and more when obvious inflammation occurs (such as deep burn). Exudation and resorption of albumin co-exist in the early stage after burn. PMID- 20193168 TI - [Repair non-healing wound with artificial dermis and autologous skin graft]. AB - OBJECTIVE: To observe the feasibility of repairing non-healing wound with artificial dermis and autologous skin graft, and to evaluate its efficacy. METHODS: Twenty in-patients with 25 non-healing wounds lasting more than 8 weeks were divided into chronic ulcer group (9 patients with 11 ulcerating scars after trauma and burn), and bone exposing group (11 patients with 14 wounds with exposed bone ranging from 0.8 - 77.0 cm(2) in size, the largest 22.0 cm x 3.5 cm). Wounds were debrided and repaired with artificial dermis in the first stage. Autologous split-thickness skin was grafted in the II stage when the wounds were well vascularized locally and exposed bone and tendon were covered with dermis like tissue within 2 - 6 weeks. RESULTS: In chronic ulcer group, 9 of the 11 wounds healed well, the other 2 healed after routine dressing change. In bone exposing group, 12 of the 14 wounds healed well and the exposed bone was effectively covered; artificial dermis on the other 2 wounds failed to survive due to infection, and they were repaired with skin flap later. Patients were followed up for 5 - 24 months. Wounds healed with satisfactory appearance and no recurrence of wound or obvious hyperplasic scar was observed; no obvious scar was observed in the donor site. CONCLUSIONS: The method of repairing non-healing wound with artificial dermis combining with autologous skin graft is simple; and it results in healing of wounds with high quality and little damage to the donor site. It provides a new choice for repairing non-healing wound. PMID- 20193169 TI - [Comparison between intermingled skin transplantation and microskin grafting in repairing massive deep burn]. AB - OBJECTIVE: To study difference in curative effect between intermingled skin transplantation (IT) and microskin grafting (MG) in repairing massive deep burn. METHODS: Clinical materials of 101 patients with massive deep burn hospitalized from 1992 to 2008 were retrospectively summarized. Patients were divided into IT group (n = 52) and MG group (n = 49). The size of initial donor site for autologous skin, the wound size initially covered with autologous skin, the survival rate of initial autologous skin grafting, the theoretical expansion multiple of the autologous skin, the actual expansion multiple of the autologous skin, the total size of donated autologous skin, the remained wound condition, and the function of large joint of patients in two groups were compared. RESULTS: In IT group and MG group, the size of initial donor site for autologous skin was respectively (3.25 +/- 0.48)%TBSA and (3.01 +/- 0.21)%TBSA, the wound size initially covered by autologous skin was respectively (30.4 +/- 3.6)%TBSA and (41.4 +/- 1.3)%TBSA, the survival rate of autologous skin grafting was respectively (99.9 +/- 1.9)% and (87.5 +/- 6.8)%, the theoretical expansion multiple of the autologous skin was respectively 9.5 +/- 1.3 and 13.9 +/- 1.4, the actual expansion multiple of the autologous skin was respectively 9.5 +/- 1.3 and 12.0 +/- 1.5, the difference between two figures of each index was statistically significant (P < 0.05). There was no statistical significant difference between IT and MG group in respect of the total size of donated autologous skin [respectively (14.2 +/- 1.9) and (14.0 +/- 2.1)%TBSA, P > 0.05]. There were 23 patients (44.2%) with residual wounds over 0.5%TBSA in IT group, and 37 cases (75.5%) in MG group. There were 34 patients (65.4%) with good function of large joints in IT group, and 18 cases (36.7%) in MG group. CONCLUSIONS: Expansion multiple of autologous skin after MG is obviously larger than that after IT, thus limited skin source can be fully used. The wound healing quality and the restoration of large joint function of patients treated with IT are better than those of patients treated with MG. PMID- 20193170 TI - [Observation on the effect of vitamin C in alleviating peroxidative damage in gut of dogs during enteral fluid resuscitation of severe burn shock]. AB - OBJECTIVE: To investigate the effect of vitamin C (VC) on alleviating peroxidative damage in gut of dogs during enteral fluid resuscitation of severe burn shock. METHODS: Eighteen male Beagle dogs were subjected to 50% total body surface area (TBSA) full-thickness burn 24 hours after duodenostomy and cannulation of cervical artery and vein. The dogs were divided into no resuscitation (NR) group (no treatment after burn), enteral resuscitation (ER) group, and ER+VC group according to the random number table, with 6 dogs in each group. Dogs in ER and ER+VC groups were respectively infused with glucose electrolyte solution (GES) and GES containing 250 mg/kg VC through duodenostomy tube 30 minutes after burn. The infusion rate and volume of GES were in accordance with Parkland formula. Venous blood of dogs was drawn before (0) and at 2, 4, 6, and 8 post burn hours (PBH) to determine the activity of diamine oxidase (DAO) in plasma. Dogs were sacrificed at PBH 8 to collect specimens of jejunum tissue for determining the content of malondialdehyde (MDA), and activity of myeloperoxidase (MPO), xanthine oxidase (XOD) and superoxide dismutase (SOD), and assessment of the water ratio of intestinal tissue by dry-wet weight method. RESULTS: 50% TBSA burn injury resulted in significant elevation of DAO in every group. The activity of DAO in ER group was obviously higher than that in NR group at PBH 6 and 8 (P < 0.05), but DAO activity in ER+VC group was significantly lower than those in the other two groups after PBH 2 (P < 0.05 or P < 0.01). MDA content, MPO and XOD activity and the water ratio of intestinal tissue [(5.74 +/- 0.51) nmol/mg, (2.08 +/- 0.46) U/g, (58.4 +/- 3.8) U/mg, (81.5 +/- 1.8)%] in ER group at PBH 8 was respectively significantly higher than that in NR group [(5.43 +/- 0.25) nmol/mg, (1.55 +/- 0.21) U/g, (50.1 +/- 2.8) U/mg, (78.3 +/- 1.5)%, P < 0.05 or P < 0.01]. While the activity of SOD in ER group (72 +/- 12) U/mg was lower than that in NR group (97 +/- 20) U/mg. MDA content, MPO and XOD activity and water ratio of intestinal tissue in ER+VC group was respectively lower than that in ER group, with activity of SOD in the former group higher than that in the latter group (P < 0.01). CONCLUSIONS: Vitamin C can alleviate peroxidative damage and tissue edema in gut induced by ischemia and reperfusion, and intestinal complications during oral rehydration during burn shock can be reduced. PMID- 20193171 TI - [Effects of interferon-gamma on the transforming growth factor beta/Smad pathway in keloid-derived fibroblasts]. AB - OBJECTIVE: To elucidate the effects of interferon-gamma (IFN-gamma) on the transforming growth factor beta (TGF-beta)/Smad pathway in keloid-derived fibroblasts (KFb), and to investigate the underlying mechanism in the treatment of pathologic scar with IFN-gamma. METHODS: Keloid tissue of 3 patients were obtained, and then KFb were separated and cultured in vitro. KFb from passages 3 to 5 were used for the study. (1) KFb were divided into control group (incubated with serum-free DMEM), TGF-beta(1) group (treated with 10 ng/mL TGF-beta(1)), IFN gamma group (treated with 100 ng/mL IFN-gamma), and TGF-beta(1)+IFN-gamma group (incubated with 10 ng/mL TGF-beta(1) combined with 100 ng/mL IFN-gamma). The expression level of mRNA and protein of connective tissue growth factor (CTGF), alpha smooth muscle actin (alpha-SMA) protein and expression of alpha-SMA positive KFb were detected by real-time fluorescent quantitation RT-PCR (FQ-RT PCR), Western blot and immunofluorescence cytochemical staining. (2) Another sample of KFb was obtained and treated with 10 ng/mL IFN-gamma. The expression level of Smad 3 and Smad 7 protein was detected by Western blot before and 1, 2, 4, 6, 8 h post stimulation (PSH). The expression level of Smad 3 and Smad 7 mRNA was assessed by FQ-RT-PCR before stimulation and 30 mins post stimulation and at PSH, 1, 2, 4, 6, 8. (3) Another sample of KFb was obtained and divided into 1, 10 and 100 ng/mL IFN-gamma groups based on the concentration of IFN-gamma, treated for 4 hours; KFb without IFN-gamma treatment was set up as control group. The expression levels of the protein and mRNA of Smad 3 and Smad 7 were measured by FQ-RT-PCR and Western blot. RESULTS: (1) The level of mRNA and protein of CTGF in IFN-gamma group (0.017 +/- 0.009 and 1.198 +/- 0.004) was respectively lower than that in control group (0.024 +/- 0.013 and 1.229 +/- 0.011, P < 0.05). The level of mRNA and protein of CTGF in TGF-beta(1)+IFN-gamma group (0.634 +/- 0.138 and 1.204 +/- 0.010) was respectively lower than that in TGF-beta(1) group (1.331 +/- 0.298 and 1.727 +/- 0.004, P < 0.01). The fluorescence intensity of alpha-SMA positive KFb (0.922 +/- 0.059) and the expression level of alpha-SMA protein (0.3051 +/- 0.0031) in IFN-gamma group decreased significantly than those in control group (1.055 +/- 0.005 and 0.4513 +/- 0.0094, P < 0.01). The fluorescence intensity of alpha-SMA positive KFb (1.129 +/- 0.004) and the expression level of alpha-SMA protein (0.6734 +/- 0.0098) in TGF-beta(1)+IFN-gamma group decreased significantly than those in TGF-beta(1) group (1.270 +/- 0.005 and 1.3842 +/- 0.0024, P < 0.01). (2) The expression level of Smad 3 mRNA and protein at the first time point after IFN-gamma treatment increased temporarily then decreased gradually, and mRNA expression level reached the nadir at PSH 4, it rose gradually later, though it was still lower at PSH 8 than that before treatment (P < 0.01); protein expression level at PSH 8 was significantly lower than that before treatment (P < 0.01). The expression level of Smad 7 mRNA and protein increased gradually to the maximum at PSH 2 and 4 respectively, then decreased but was still higher at PSH 8 than that before treatment (P < 0.05). (3) Compared with those in control group, the expression levels of Smad 3 mRNA and protein in 1, 10 and 100 ng/mL IFN-gamma group were significantly lower, the expression levels of Smad 7 mRNA and protein were significantly higher (P < 0.05 or P < 0.01). The higher concentration of IFN-gamma, the more significant differences were observed. CONCLUSIONS: IFN-gamma can down-regulate the expression of Smad 3 while up-regulate the expression of Smad 7 in a time- and dose-dependent manner, and reduce the expression level of CTGF and alpha-SMA in the basic state or induced by TGF-beta(1), which shows a significant inhibitory effect on the TGF beta/Smad signal pathway. This may be an important mechanism in the treatment of pathologic scar by IFN-gamma. PMID- 20193172 TI - [The current and emerging role of cardiovascular magnetic resonance imaging in hypertrophic cardiomyopathy]. AB - Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy and the leading cause of sudden death in young people and a major cause of heart failure symptoms at any age. Due to its genetic etiology, there is substantial heterogeneity in the phenotypic expression and clinical course of patients with HCM. Traditionally, two-dimensional echocardiography has been the easiest and reliable technique for establishing a diagnosis of HCM. However, cardiovascular magnetic resonance (CMR) has emerged as a novel, 3-dimensional tomographic imaging technique, which provides high spatial and temporal resolution images of the heart (not limited by thoracic or pulmonary parenchyma), in any plane and without ionizing radiation. As a result, CMR is particularly well suited to provide detailed characterization of the HCM phenotype, including a precise assessment of the location and distribution of LV wall thickening (as well as other myocardial structures such as the right ventricle and papillary muscles). In this regard, CMR has been demonstrated to provide a diagnosis of HCM in cases where the echocardiogram was non-diagnostic. Furthermore, CMR provides an accurate assessment of total LV mass which is a more robust marker of hypertrophy, with potential implications for risk stratification. In addition, with the intravenous administration of gadolinium, first-pass perfusion sequences can identify myocardial perfusion abnormalities, while late gadolinium enhancement sequences can identify areas of myocardial fibrosis/scarring. Although the clinical implications of late gadolinium enhancement in HCM are still uncertain this information may, in the near-future, have important implications with regard to identifying HCM patients at high risk of sudden death and progressive heart failure, including evolution into the end-stage phase of HCM. Therefore, at present, CMR provides important information impacting on diagnosis and clinical management strategies in patients with HCM and will likely have an expanding role in the evaluation of patients with this complex disease. PMID- 20193173 TI - [Using molecular genetics to guide the diagnosis and treatment of hypertrophic cardiomyopathy]. AB - Hypertrophy cardiomyopathy (HCM) is an autosomal dominant disorder characterized by increased heart mass that occurs without a defined stimulus (such as hypertension or valvular disease). It is commonly recognized through the widespread use of non-invasive imaging. Epidemiological studies indicate that 1 of 500 individuals has unexplained cardiac hypertrophy, an observation that predicts a considerable role for genetics in this enigmatic disorder. Indeed, to date, more than 500 mutations had been identified in more than 12 genes encoding components of the thick and thin filament of the sarcomere and other myofilament related proteins. Intensive studies of HCM continue to take our understandings about this fascinating disease in new directions. Mechanistic analyses have provided insights into how mutational alterations in these structural proteins may trigger the hypertrophic remodeling processes and other associated clinical features of HCM. Based on these studies, investigations have been initiated to assess whether early pharmacological interventions could prevent or attenuate the development of the disease and its clinical sequelae. By combining pathophysiology with knowledge of genetic cause and molecular responses, HCM has begun to exemplify opportunities for predictive and personalized medicine. With the emergence of newer technologies that enable high-throughput sequencing of DNA, it is timely to review clinical manifestations and genetic causes of this unique disease, and how intertwining these insights can improve contemporary diagnosis and management of HCM and other genetic forms of cardiac hypertrophy. PMID- 20193174 TI - [Myocardial hypoperfusion due to microvascular dysfunction in hypertrophic cardiomyopathy: role of positron emission tomography]. AB - Hypertrophic cardiomyopathy (HCM) is characterized by extreme clinical heterogeneity, ranging from sudden cardiac death to long-term disease progression and heart failure-related complications. Myocardial ischemia, occurring at the microvascular level, is a major determinant of clinical expression and outcome. Accordingly, the severity of this microvascular dysfunction has been shown to represent an early and powerful predictor of unfavorable outcome in HCM. The assessment of microvascular function in vivo is technically challenging, although critical to a truly comprehensive evaluation and risk stratification of HCM patients. Available technologies include positron emission tomography and cardiac magnetic resonance (CMR). Studies of regional myocardial blood flow using positron emission tomography have demonstrated that the vasodilator response to dipyridamole is impaired in most HCM patients, not only in the hypertrophied ventricular septum but also in the less hypertrophied or non-thickened left ventricular free wall. CMR also allows measurement of myocardial flow, although the technique is currently time-consuming and largely limited to research situations. CMR provides further insight into the effects of ischemia in HCM patients, by visualizing the distribution and extent of fibrosis at the intramyocardial level. Late gadolinium enhancement (LGE) is a potential predictor of risk in HCM patients, and is believed to largely reflect replacement fibrosis resulting from recurrent microvascular ischemia. LGE is associated with increased prevalence of ventricular arrhythmias, and associated with microvascular dysfunction. The present review is to provide a concise overview for the available evidence of microvascular ischemia and its consequences in HCM. PMID- 20193175 TI - [Alcohol septal ablation and hypertrophic cardiomyopathy]. AB - Patients with hypertrophic cardiomyopathy who experience refractory symptoms due to left ventricular outflow tract obstruction are often referred for definitive therapy consisting of either surgical myectomy or alcohol septal ablation (ASA). There currently exists clinical equipoise regarding which therapy is the most efficacious in this challenging patient population. ASA utilizes common interventional techniques usually employed to treat atherosclerotic coronary artery disease to inject small aliquots of ethanol into a branch of the appropriate septal vessel to cause necrosis of the obstructing basal septal tissue. Myocardial contrast echocardiography is used to facilitate location of the most appropriate septal branch with success determined by an acute reduction in the resting and/or provoked gradient. Recent comparative data have suggested similar rates of long and short-term mortality in when comparing patients undergoing ASA and surgical myectomy, with ASA patients experiencing a higher rate of requirement for permanent pacemakers. In addition, patients treated by both techniques appear to have similar gradient reductions and improvement in symptomatic status. Comparisons of these two methods of treatment are limited by the non-randomized nature of the studies, retrospective data collection and the allocation of higher-risk patients to ASA treatment. Concern for the wide-spread adoption of ASA to drug-resistant HCM patients is warranted due to the potential for arrhythmogenesis is a patient population already at risk for life-threatening arrhythmias. There have been case reports of such arrhythmias, however, clinical series to date have not suggested an enhanced risk of sudden cardiac death in patients treated with ASA. Definitive answers concerning which patient subsets with drug-refractory hypertrophic cardiomyopathy would benefit from the two competing therapies can only be answered by a randomized clinical trial. However, for a variety of clinical and logistical factors, such a trial is unlikely to ever be performed. For the foreseeable future, patient-specific therapy will depend on local expertise, patient comorbidities and preferences. PMID- 20193176 TI - [A novel hot-spot mutation S236G in the cardiac myosin binding protein C gene in Chinese patient with hypertrophic cardiomyopathy]. AB - OBJECTIVE: To identify the disease-causing gene mutations and to reveal the relationship between the genotype and the phenotype in Chinese patients with hypertrophic cardiomyopathy (HCM). METHODS: One hundred unrelated patients with HCM and 120 controls were enrolled in this study. The full encoding exons and flanking sequences of the cardiac myosin binding protein C gene (MYBPC3) were amplified with PCR and the products were sequenced. RESULTS: A novel missense mutation c.706T > C was identified in exon 6 of MYBPC3 gene in three HCM patients, which resulted a Serine (S) to Glycine (G) exchange at amino acid residue 236 (S236G). The clinical phenotypes of the three patients were different (2 obstructive HCM, 1 non-obstructive HCM). The 120 controls were normal in the genetic test. CONCLUSIONS: The novel S236G mutation in MYBPC3 gene was a hot-spot mutation in Chinese patients with HCM. PMID- 20193177 TI - [Association between expression of chromogranin A and myocardial fibrosis in patients with dilated cardiomyopathy]. AB - OBJECTIVE: To observe the possible correlation between expression of chromogranin A (CGA) and myocardial fibrosis and investigate the potential role of CGA in the development of myocardial fibrosis in patients with dilated cardiomyopathy (DCM). METHODS: Surgical myocardial specimen from 10 DCM patients underwent successful orthotopic cardiac transplantation, and 3 normal myocardial specimen from brain dead organ donors were obtained. CGA-mRNA, COLI-mRNA, COLIII-mRNA and ADAMTS-1 mRNA were analyzed by real-time PCR. The location and expression of CGA were assessed by immunohistochemistry(INH)with anti-CGA antibody. The collagen specific picrosirius red staining was applied on transversal myocardial slides and the collagen volume fraction (CVF) was calculated. The correlation between CGA and CVF was analyzed. RESULTS: Cytoplasmic expression of CGA assessed by INH showed large amount of strong positive granules densely arranged in the epicardial and endocardial myocardiocytes in DCM specimen while there was only few sparse granules in the normal myocardium (P < 0.05). CVF was significantly higher in DCM myocardial specimen than that in normal specimen (P < 0.001). CGA mRNA was significantly correlated with COLI-mRNA (r = 0.729), COLIII-mRNA (r = 0.95) and ADAMTS-1-mRNA (r = 0.665, all P < 0.05). Moreover, collagen deposition location was almost identical with the strong positive expression location of CGA. CONCLUSION: We demonstrated for the first time that the deposition of CGA was related with the myocardial fibrosis in DCM heart, therefore, CGA might play an important role by influencing myocardial remodeling and fibrosis in DCM patients. PMID- 20193178 TI - [Serum troponin I level in patients with hypertrophic cardiomyopathy]. AB - OBJECTIVE: To observe serum troponin I (TNI) level in patients with hypertrophic cardiomyopathy (HCM). METHOD: Six hundreds and twelve HCM patients were analyzed prospectively from January 1990 to November 2007.Ultracardiography were detected for all the patients. The diagnostic criteria of HCM is ventricular wall thickness more than 15 mm. Serum TNI level was measured in 116 patients with HCM. Clinical data including age, gender, history, main symptoms, NYHA grade, coronary angiograph, electrocardiogram and echocardiography were compared between patients with normal and increased TNI levels. RESULTS: In 116 patients who detected TNI, 62 of them (53.4%) had a degree higher than normal. The median TNI value of all these patients is 0.07 ng/ml (0 - 4.38 ng/ml). Sixty-nine patients (59.5%) had undergone coronary angiography. Only 9 of them (13.0%) could be diagnosised as coronary heart disease. The TNI values of HCM patients with or without coronary heart disease were similar. The factors related to a higher TNI value included maximal depth of ventricule (P < 0.05), significant T inversion (P < 0.01) and chest pain (P < 0.05). Compared to all the 612 patients, the ones who detected serum TNI were likely to have chest pain (45.7% vs. 34.5%, P < 0.01) and significant T inversion (75.9% vs. 30.1%, P < 0.01). CONCLUSION: Increased serum TNI could be seen in half of HCM patients, especially in those patients with chest pain or significant T inversion. It is therefore important to different these patients from patients with acute coronary syndrome. PMID- 20193179 TI - [Value of intravascular ultrasound, 64 multi-detector computed tomography and quantitative coronary angiography on lesion of coronary artery in unstable angina pectoris patient]. AB - OBJECTIVE: To compare the value of intravascular ultrasound (IVUS) and assess the value of quantitative coronary angiography (QCA) and 64 multi-detector computed tomography (MDCT) on unstable anginas (UAP) risk stratification. METHOD: A total of 61 UAP patients (low risk: 17, middle risk: 33 and high risk: 11) were recruited, 71 vessels were examined by MDCT, QCA and IVUS. Plaque characteristics (soft, fibrous, calcified and mixed plaques) and plaque burden at minimum area (< or = 50%, 51% - 74% and > or = 75%) were detected, calculated and analyzed. Results derived from various detection methods were compared. RESULTS: Plaque burden detection by QCA was comparable to IVUS results for low and middle risk UAP (r = 0.768 and r = 0.721, respectively; all P < 0.01) but not for high risk UAP (67% + or - 14% vs.75% + or - 16%, P < 0.01) due to significant positive vessel remodeling (remodeling index = 1.21 + or - 0.31). The high negative predict value of MDCT for stenosed coronary vessels (87.8% - 96.3%)was valuable for exclusion of coronary heart disease but MDCT was not able to identify fibrous cap (kappa = 0.235) and lipid core (kappa = 0.245). Extent of remodeling index, external elastic membrane area, minimum lumen area, plaque burden, plaque rupture and thrombosis increased in proportion to increasing risks of UAP patients. CONCLUSIONS: QCA is a suitable tool for assessing UAP patients with low and middle vessel stenosis but underestimated the stenosis degree in UAP patients with high vessel stenosis. MDCT is valuable for exclusion vessel disease but not useful for identifying soft and fibrous plaque. Soft plaque with positive remodeling index and minimum lumen area < 4 mm(2) derived from IVUS could correctly identify UAP patients with high degree of vessel stenosis. PMID- 20193180 TI - [Long-term clinical outcome of patients with diabetes and chronic total occlusion underwent drug-eluting stents implantation]. AB - OBJECTIVE: The aim of this study was to assess the long-term clinical outcome of patients with diabetes mellitus and chronic total occlusion (CTO) underwent drug eluting stents (DES) implantation. METHODS: Data of 143 consecutive eligible patients from January, 2006 to May, 2007 were retrospectively analyzed. The endpoint of the study was the major adverse cardiac events (MACE), including death, myocardial infarction, target lesion revascularization. The patients were divided into two groups, event group and non-event group, according to the result of follow-up. RESULTS: Long-term follow-up was finished in 139 (97.2%) patients. Mean follow-up duration was (19.8 + or - 5.1) months. MACE rate was 10.5% during follow-up: 3 deaths, 1 myocardial infarction and 11 repeated target lesion revascularization with PCI. Compared with the non-event group, the percentage of residual lesion [(17.7 + or - 1.8)% vs. (15.4 + or - 5.0)%, P = 0.001] was significantly higher in the event group, however, the final minimal luminal diameter [(2.14 + or - 0.22)% vs. (2.89 + or - 0.37)%, P = 0.004] was lower. Cox regression analysis showed that final luminal diameter (OR: 0.097, 95%CI: 0.013 - 0.694, P = 0.020) was the only dependent predictor at follow-up. CONCLUSION: Final minimal luminal diameter is an independent predictor of MACE during follow up for patients with diabetes and CTO underwent DES implantation. PMID- 20193181 TI - [The predictive value of Holter recordings to detect moderate-severe obstructive sleep apnea syndrome]. AB - OBJECTIVE: To evaluate the predictive value of Holter ECG recordings for patients with moderate-severe obstructive sleep apnea and hypopnea syndrome (OSAHS). METHODS: Holter recordings was performed in 76 patients who were diagnosed OSAHS by polysomnography (PSG) within one month from Jan. 2008 to July 2009 in our hospital. Twenty-eight patients were identified as mild OSAHS (AHI < or = 20) and forty-eight patients were moderate-to-severe OSAHS (AHI > 20). The indexes of heart rate variability (HRV), total scores of thirteen sleep apnea risk indexes of Holter recordings and BMI were analyzed by bivariate Logistic regression analysis. RESULTS: Clinical features (eg. Gender, age, complicated with hypertension, coronary heart disease, diabetes mellitus, hyperglycemia, and taken beta-blocker), total scores, the sum of thirteen sleep apnea risk scores collected by Holter recordings (5.64 + or - 2.33 vs. 6.42 + or - 2.22, respectively, P > 0.05) were similar between patients with mild OSAHS and moderate-to-severity OSAHS. VLF/Total Power > 70%, the difference of daytime/nighttime LF Power < -70 and BMI were independent predictors of moderate to-severe OSAHS with OR 3.98 (1.087 - 14.596), 3.69 (1.106 - 12.285) and 1.28 (1.062 - 1.544), respectively (all P < 0.05). CONCLUSIONS: VLF/Total Power and the difference of daytime/nighttime LF Power and BMI could be used as screening parameters to recognize patients with moderate-to-severe OSAHS. PMID- 20193182 TI - [Chronic outcome of patients with paroxysmal atrial fibrillation post catheter ablation]. AB - OBJECTIVE: High short-term successful rate was reported for catheter ablation in patients with paroxysmal atrial fibrillation (AF), we analyzed the long-term outcome (success rate, anticoagulation therapy and embolism event, anti arrhythmic therapy and death post procedure) of catheter ablation for paroxysmal AF in this study. METHODS: From January 2000 to December 2004, 106 consecutive patients with drug-refractory paroxysmal AF underwent catheter ablation and were followed-up for (60.7 + or - 11.8) months. Segmental pulmonary vein isolation (SPVI) was routinely performed by radiofrequency energy under the guidance of circular mapping catheter. The patients were followed up with 24 h-holter, ECG, telephone or letter. Data on recurrence of AF, the anticoagulation medication and the incidence of embolism, anti-arrhythmic therapy were obtained. RESULTS: There were 9 patients lost to follow up. In the remaining 97 patients [65 males, (54.8 + or - 11.2) years old], 3 cases died from cancer, sinus rhythm was maintained in 68 patients (Group S, 72.3%) and AF recurrence evidenced in 26 patients (Group R, 27.7%). In Group S, 56 patients (82.4%) discontinued anticoagulation medication, and 12 patients continued to take aspirin. There was no embolism event in Group S during follow-up. In Group R, 1 patient continued to take warfarin; 11 patients continued to take aspirin and 2 patients suffered from cerebral embolism. Anticoagulation medication was discontinued in 14 patients (53.8%) and 1 patient suffered form cerebral embolism. The incidence of embolism event in Group R is significantly higher than in Group S (P < 0.01). More patients discontinued anti arrhythmic medication in Group S than in Group R (80.9% vs. 56.0%, P < 0.05). CONCLUSION: Catheter ablation is associated with satisfactory long-term success rate, reduced anti-arrhythmia medication, improved quality of life in patients with paroxysmal AF. PMID- 20193183 TI - [The relationship between uncoupling protein 2 expression and myocardial high energy phosphates content in abdominal aorta constriction induced heart failure rats]. AB - OBJECTIVE: To explore the changes of expression of uncoupling protein 2 (UCP2) in pressure overload induced failure myocardium in rats. METHODS: Male SD rats were randomized into 3 groups (n = 15 each): abdominal aorta constriction (AC) 20 weeks group (H20w group), sham operation group (SH20w group) and normal control group (N group). Twenty weeks later, myocardial function was evaluated by echocardiography and hemodynamic measurements. Mitochondria in ventricular tissue were isolated by centrifugation. Adenine nucleotide pools (ATP, ADP, AMP, PCr) in myocardium were measured by high performance liquid chromatography. The expression of UCP2 in mitochondria was detected by PT-PCR and Western blot analysis. RESULTS: Myocardial function was significantly decreased 20 weeks post AC compared to SH20w group and N group. Myocardial ATP, ADP, AMP and PCr contents were also significantly decreased in H20w group than the other 2 control groups. The expression of UCP2 in myocardial mitochondria was significantly increased in H20w group and negatively correlated with ATP contents (r = -0.929, P < 0.01). CONCLUSIONS: The expression of UCP2 was upregulated in pressure overload induced failure heart and might be responsible for decreased myocardial adenine nucleotide and energy metabolism disturbance in this model. PMID- 20193185 TI - [Role of liver X receptors on cardiomyocyte hypertrophy]. AB - OBJECTIVE: To investigate the expression of liver X receptors (LXR) in hypertrophic myocardium and the effect of LXR agonist T0901317 on angiotensin II (AngII) induced cardiomyocyte hypertrophy. METHODS: Transverse aortic coarctation (TAC) or sham operation were performed in 2-month-old wide type mice (C57/B6). Two weeks later, the expression of LXR in myocardium was detected by quantitative real-time PCR analysis and Western blot analysis. The effect of LXR agonist T0901317 on AngII-induced hypertrophy in cultured neonatal rat cardiomyocytes was also assessed. RESULTS: Quantitative real-time PCR analysis and Western blot analysis showed that LXRalpha but not LXRbeta expression was upregulated post TAC both at mRNA and protein levels (All P < 0.05). AngII induced increased [(3)H] leucine incorporation and cardiomyocyte hypertrophy were significantly reduced by T0901317 in a dose-dependent manner (P < 0.05). T0901317 also dose-dependently inhibited atrial natriuretic peptide (ANP) gene expression in cardiomyocytes (P < 0.05). CONCLUSION: Our findings strongly suggest that LXR is a potent mediator of cardiomyocyte hypertrophy and LXR activation could attenuate AngII induced cardiomyocyte hypertrophy in vitro. PMID- 20193184 TI - [Effects of tissue factor pathway inhibitor-1 on no-reflow in a rabbit model]. AB - OBJECTIVE: To investigate the role of plasma tissue factor (TF) and tissue factor pathway inhibitor-1 (TFPI-1) level and to observe the effect of extrinsic TFPI-1 on no-reflow (NR) in a rabbit model of ischemia/reperfusion. METHODS: Rabbits were randomized into four groups (n = 10 each): ischemic- reperfusion group (IR, subjected to 120 minutes of coronary artery occlusion and followed by 60 minutes of reperfusion); ischemic- reperfusion TFPI-1 group (100 ng/kg bolus and 1 ng x kg(-1) x min(-1) infusion during reperfusion); ischemic group (subjected to 180 minutes of coronary artery occlusion) and sham group. The NR area and ischemic area were determined by thioflavin S and Evan's blue staining in vivo. Plasma TF and TFPI-1 levels were measured before operation, before and at 120 minutes post coronary artery ligation, 10 and 60 minutes after reperfusion by ELISA. RESULTS: Plasma TF and TFPI-1 levels before and at 120 minutes post coronary artery ligation were similar among the four groups (all P > 0.05). At 10 and 60 minutes after reperfusion, the plasma TF levels in the IR group was significantly higher than those in ischemic group and sham group [10 minutes: (20.7 + or - 4.1) pg/ml vs. (13.9 + or - 2.2) pg/ml (P < 0.001), (20.7 + or - 4.1) pg/ml vs. (13.2 + or - 2.6) pg/ml (P < 0.001); 60 minutes: (15.8 + or - 2.6) pg/ml vs. (13.5 + or - 1.6) pg/ml (P < 0.05), (15.8 + or - 2.6) pg/ml vs. (12.1 + or - 0.7) pg/ml (P < 0.001)] while the plasma TFPI-1 levels were similar among IR, ischemic and sham groups at 10 minutes after reperfusion and at 60 minutes after reperfusion (all P > 0.05). TFPI-1 level [(9.7 + or - 1.6) ng/ml] was significantly lower in the IR group than in the ischemic group [(11.6 + or - 1.6) ng/ml, P < 0.05] and sham group [(10.1 + or - 1.3) ng/ml, P < 0.01]. TF mRNA expression in the NR area in IR group was significantly up-regulated compared to the ischemic group (P < 0.05) and sham group (P < 0.001) while TFPI-1 mRNA expression was similar between IR group and ischemic group (P > 0.05). NR severity in the ischemic-reperfusion TFPI 1 group was significantly attenuated compared to IR group (0.39 + or - 0.11 vs. 0.54 + or - 0.06, P < 0.01). CONCLUSION: Upregulated TF mRNA expression in the NR area and increased plasma TF level during reperfusion period, reduced plasma TFPI 1 level during reperfusion period as well as attenuated NR severity by extrinsic application of human rTFPI-1 in this model suggested an important role in the pathogenesis of the NR phenomenon. PMID- 20193186 TI - [Prevalence of peripheral arterial disease and correlative risk factors among natural population in China]. AB - OBJECTIVE: To investigate the prevalence of peripheral arterial disease (PAD) and correlative risk factors among natural population in China. METHODS: Ankle brachial index (ABI) was measured by trained doctors and related data were collected in residents from Beijing, Shanghai, Changsha, Guangdong, Neimenggu, and Xinjiang selected through cluster multistage and random sampling method. PAD was defined as an ABI < or = 0.9 in either leg. RESULTS: The prevalence of PAD among 21 152 eligible participants was 3.08%, the standardized prevalence was 3.04%. The prevalence in males and females was 2.52% and 3.66% and the standardized prevalence was 1.84% and 4.31% respectively, the prevalence rate was significantly lower in males than that in females (P < 0.01). The prevalence in both males and females increased significantly in proportion to aging (P < 0.01). The prevalence in Han Chinese was significantly higher than that in non-Han Chinese (P < 0.01). Logistic regression analysis showed that older age, female gender, Han Chinese, waist circumference, smoking, lipid disorder, diabetes mellitus, coronary artery disease and a history of ischemic stroke were associated with the increased prevalence of PAD. Incidence of known PAD was 1.38% in this cohort. CONCLUSIONS: Older age, female gender, Han Chinese, waist circumference, smoking, lipid disorder, diabetes mellitus, coronary artery disease and a history of ischemic stroke were associated with the increased prevalence of PAD in natural Chinese population. PMID- 20193187 TI - [Chronic outcome of percutaneous transcatheter patent foramen ovale closure with Left-disk-coated patent foramen ovale occluder]. AB - OBJECTIVE: To investigate the safety and efficacy of patent foramen ovale (PFO) closure with Left-disk-coated PFO occluder. METHODS: The device was implanted in patients with PFO under the guidance of fluoroscopy and transthoracal echocardiography using a 10-12 French delivery sheath via femoral vein approach. Aspirin (100 mg/d for 6 months) was administered post procedure. Patients were followed clinically and echocardiographically at 24 hours, 1 month, 3 months, 6 months, and 12 months after device implantation and yearly thereafter. RESULTS: Permanent device implantation failed in one patient (4%) and succeed in the remaining 24 patients (96%). There were no major in-hospital-adverse events or complications (thromboembolism, occluder dislodgement, infection or myocardial infarction). Seven patients developed transient atrial premature beats or atrial tachycardia during implantation and stopped without medication post procedure. Follow-up [(25 + or - 12) months] results showed that all occluders were in position and there were no residual shunt, arrhythmia and cerebral vessel events post procedure. CONCLUSION: Left-disk-coated PFO occluder is safe and effective for PFO closure. PMID- 20193188 TI - [A case report: the POEMS syndrome related pulmonary hypertension]. PMID- 20193189 TI - [In-stent restenosis after coronary and renal arteries stenting in a patient with Takayasu's arteritis]. PMID- 20193190 TI - [Long-term clinical observation on one patient with skin radiation damage post coronary artery intervention for chronic total occlusion]. PMID- 20193191 TI - [LMNA gene and dilated cardiomyopathy]. PMID- 20193192 TI - [Research advancements on adult cardiac derived stem cells]. PMID- 20193193 TI - [Relationship between dietary soy isoflavones and blood lipid levels in 40 - 65 year-olds in Guangzhou]. AB - OBJECTIVE: To study the relationship between dietary soy isoflavones and blood lipids among residents of 40 - 65 years old, in Guangzhou. METHODS: Dietary soy isoflavones and other nutrients intakes were assessed with quantitative food frequency questionnaire (FFQ). Total cholesterol (TC), triglycerides (TG), HDL cholesterol (HDL-C) and LDL cholesterol (LDL-C) in plasma were measured with colorimetry. RESULTS: Ranges of dietary soy isoflavones intake among 134 males and 261 females were from 0 mg/day to 61.96 mg/day and 0 mg/day to 82.52 mg/day, with means of 11.95 mg/day, 14.90 mg/day, respectively. After adjusted for total energy intake and fat percent energy, differences of TC, LDL-C in total population and TC in women were statistically significant between groups (P value was 0.002, 0.008, 0.004, respectively) and dose-effect relationships (P value was < 0.001, 0.012, 0.001, respectively) were observed between dietary soy isoflavones intake and the upper mentioned three indices. Compared with the low intake group, these three indices lowered 7.06%, 10.13% and 7.48%, respectively in high-intake group. Critical significance of LDL-C was observed both in women and men between groups. Further controlled for age, BMI and WHR, no obvious change of the results was observed. CONCLUSION: Moderate intakes of soy isoflavone as part of a regular diet seemed to be associated with favorable blood lipid levels. PMID- 20193194 TI - [Study on the prevalence of urinary incontinence and its related factors among elderly in rural areas, Jixian county, Tianjin]. AB - OBJECTIVE: To understand the prevalence of urinary incontinence (UI) and its related factors so as to develop a three-tier program for prevention of the disease. METHODS: A cross-sectional study was carried out in two townships of Jixian county, Tianjin, during July to November 2007. A total of 743 people aged 60 years and over were selected under cluster sampling, and all information were collected with a standardized structured questionnaire by face-to-face interview. All the data were analyzed with multivariate logistic regression method to explore the related factors for UI in the elderly. RESULTS: The overall prevalence of UI was 33.38 percent among people aged 60 years and over in two townships. Risk factors for UI in men would include older age (OR = 1.39), occupation (OR = 5.00), awareness of UI (OR = 1.91), having in chronic respiratory diseases (OR = 2.23), prostate (OR = 11.47), neurological (OR = 11.76), or motor systems (OR = 2.48), while protective factors would include high educational level (taking primary school or below as control group), OR for the junior middle school group appeared to be 0.35, for senior middle school group it was 0.77, and of undergraduate group it was 0.53. Risk factors for UI in women would include older age (OR = 1.31), constipation (OR = 1.46), awareness of UI (OR = 1.94), increased body mass index (when normal weight group served as control group, OR in the overweight group was 1.03 and in the obesity group OR was 1.54), suffering from chronic respiratory diseases (OR = 4.84), diabetes mellitus (OR = 2.36), or motor system diseases (OR = 1.37), more gravidity (OR = 1.03), more parity (OR = 1.02), suffering from perinea laceration (OR = 1.72) and wound infection during delivery (OR = 1.65), while protective factors would include physical exercises (OR = 0.64). CONCLUSION: Prevalence of UI was higher among the elderly people in rural areas of Jixian county, Tianjin. UI in the elderly might have been influenced by various factors which suggesting the intervention strategy should be targeted at those related factors as well as focusing on primary prevention. PMID- 20193195 TI - [Prevalence of dementia among rural elderly in Gushan township, Fuzhou]. AB - OBJECTIVE: To study the prevalence of dementia and its related risk factors in people aged 65 years and older in Gushan township. METHODS: People aged 65 years or older in 22 villages of Gushan township were screened, from July 2007 to November 2007. Face to face interview with mini-mental state examination, and followed by clinical assessment. A series of neuropsychological examination was done on selected subjects based on the results of the screening tests. Clinical diagnosis on dementia was made according to the Diagnosis and Statistical Manual of Mental Disorder Fourth Edition. RESULTS: Out of the 2913 people 2696 aged 65 years or older, were enrolled. Among the participants, 197 were confirmed of having dementia, accounting for the overall rate as 7.3%. The prevalence rate of dementia was 5.1% in males and 8.9% in females. Prevalence of dementia in the highly educated intellectuals was 9.2%, followed by 5.2%, 3.9% and 2.5% in those having received primary, junior high or senior high school education. Results from logistic regression analysis showed that the major risk factors which influencing the prevalence of dementia would include age, activies of daily living, marital status, monthly income, frequency in watching TV/movie/field show, poker player or tress and taking care of the family etc. CONCLUSION: The prevalence rate of dementia went up along with age. Factors as watching TV/movie/field show or playing poker/chess more frequently, as well as taking good care on families tend to help reduce or postpone the development of dementia. PMID- 20193196 TI - [Impact on calcification of aortic arch by lifestyle-related, physiologic and biochemical factors]. AB - OBJECTIVE: To explore the impact of lifestyle-related, physiological and biochemical factors on aortic arch calcification (AAC). METHODS: 20 430 subjects aged 50 to 85 years were included in this study from the first and second recruitment phase of the Guangzhou Biobank Cohort Study. All the subjects received face-to-face interviews to collect detailed information on their socio demographic background, occupational exposures, living environment, lifestyle, family and personal disease histories, and received a physical examination and tests including 12-lead ECG, chest radiograph, and pulmonary function testing. Each subject was screened for a range of fasting biochemical parameters. Radiographs were reviewed by two senior radiologists. 300 radiographs were independently read by the two radiologists to assess agreement using Kappa coefficient. Logistic regression was used to assess the association between life style, physiological and biochemical factors and AAC. RESULTS: (1) The rate of agreement on diagnosis for the two radiologists was 85% and Kappa coefficient was 0.68 (P < 0.01) which showed a moderate agreement between the two radiologists. (2) Except hypertension, the subjects were significantly different on their lifestyle, physiological and biochemical factors in both men and women (P < 0.05). (3) AAC was significantly associated with older age, smoking status, LDL C, and hypertension (P < 0.01) in both genders. ORs (95%CI) indicated the following results: age was 1.11 (1.10 - 1.12) in men and 1.12 (1.12 - 1.13) in women;smoking as 1.31 (1.17 - 1.47) in men and 1.31 (1.09 - 1.57) in women; LDL-C as 1.16 (1.06 - 1.27) in men and 1.38 (1.22 - 1.56) in women, hypertension as 1.33 (1.18 - 1.50) in men and 1.27 (1.18 - 1.38) in women. However, diabetes was found to be associated with an increased risk of AAC in women [OR(95%CI)] 1.38 (1.22 - 1.56). CONCLUSION: Age, smoking, hypertension and Low-density lipoprotein level were risk factors to both genders, on AAC, while diabetes increased the risk of AAC, in women. PMID- 20193197 TI - [Incidence and prognosis of intra-and extracranial large-artery stenosis in the rural community of Beijing]. AB - OBJECTIVE: To assess the prevalence rates of intra- and extracranial large-artery stenosis in the rural community population and its related risk to the development of stroke. METHODS: The study subjects included 1337 residents in the rural community of Beijing. Transcranial Doppler was carried our to examine the relation between intra- and extracranial large-artery stenosis and subsequent cerebrovascular events, with a mean follow-up period of 16.7 months. RESULTS: The incidence densities of cerebral infarction and cerebral hemorrhage in persons without cerebral large-artery stenosis were 410.6 and 351.9/100-thousand person years, respectively. In the group with large-artery stenosis, the incidence density of cerebral infarction was 3303.7/100-thousand person-years. Data from The Fisher's Exact test showed a significant difference in the two groups (P = 0.004). Cerebral large-artery stenosis (OR = 6.593, 95%CI: 1.712 - 25.390) and smoking (OR = 8.437, 95%CI: 2.327 - 30.598) appeared to be independent risk factors to cerebral infarction. CONCLUSION: Cerebral large-artery stenosis and smoking were independent risk factors to cerebral infarction. PMID- 20193198 TI - [Study on the etiology of hand-foot-mouth disease outbreaks in Beijing in 2007]. AB - OBJECTIVE: To identify the etiology of 8 human hand-foot-mouth disease (HFMD) outbreaks in Beijing, during May to July 2007. METHODS: Reverse transcription polymerase chain reaction (RT-PCR) method was used to directly type the specimens including fluid from the herpes and throat swabs from the HFMD patients. Using RD cell lines, the collected stool specimens were cultured followed by typing. Partial VP1 region of selected EV positive specimens and cultures were sequenced and both nucleic acid sequence and predicted amino acid sequence were analyzed. RESULTS: The two HFMD outbreaks in Daxing region in Beijing in 2007 were caused by enterovirus 71 type (EV71), and the others were caused by Coxsackie virus A16 (Cox A16). Two EV71 strains caused epidemics in Daxing region in 2007 belonged to C4 subgenotype but on different branches in VP1 gene phylogenetic tree. The differences on nucleic acid sequence and amino acid sequence were 3.7% and 0.8% between the two EV71 stains, respectively. The Cox A16 strain in Shunyi region and the other strains were on different branches in phylogenetic tree, and the difference on nucleic acid and amino acid sequence were 3.7% and 0% respectively between the two Cox A16 stains. CONCLUSION: The HFMD outbreaks occurred in Beijing in 2007 were caused mainly by EV71 and Cox A16, and there were two individual epidemic virus strains. Cox A16 seemed to spread more widely than EV71 in Beijing, 2007. PMID- 20193199 TI - [Development of a presenteeism questionnaire for skilled workers at high technology enterprises]. AB - OBJECTIVE: To develop a presenteeism questionnaire for Chinese high-technology skilled workers. METHODS: Methods being used would include literature review, face-to-face in depth interview, experts' consultation in developing the questionnaire. RESULTS: The presenteeism questionnaire includes two sections;one on employee's general health condition and the second one is a survey on the influences of employees'health conditions on their productivity. The first section includes 55 terms and 8 dimensionalities as below: Ache, Symptoms, Sleeping problem, Attention, Bad emotion, Pressure, Fatigue, Social adapting. These dimensionalities Cronbach's alpha are 0.79, 0.83, 0.75, 0.69, 0.83, 0.86, 0.80, 0.88 respectively and their half Spearman-Browns are 0.78, 0.75, 0.61, 0.62, 0.82, 0.81, 0.77, 0.88, respectively. Goodness of fit test model indices are as below: chi(2)/df -3.68, normed fit index 0.95, non-normed fit index 0.96, compatative fit index 0.96, standardized root mean residual 0.05, root mean square error of approximation 0.05. The relate-coefficient with SF-36 is 0.55. 42.77% of employees having received the survey, claim that their health problem do not influence their productivity, and 55.72% of them claiming that their productivity are reduced to 50%-90% because of their health problems while another 1.51% of them claim that their productivity reduced more than 50%. 84.5% of the interviewees claim that they have never been absent at work because of health problems, and 15.3% of them claim that their total hours of absence are between 0 and 100. Only 0.2% of the workers claim that the total hours of absence are more than 100. CONCLUSION: The developed presenteeism shows good reliability and higher validity, so can be used to measure the presenteeism of skilled workers working at high-technology enterprises. PMID- 20193200 TI - [Analysis on factors affecting the severity of post-traumatic stress disorder in transferred casualty after Earthquake]. AB - OBJECTIVE: To investigated the related factors which affecting the severity degrees of post-traumatic stress disorder (PTSD) in transferred casualty after Wenchuan Earthquake. METHODS: Taking PTSD symptoms self-assessment scale (PCL-C) to involve 386 wounded who suffered 40 days after the earthquake disaster, from 11 hospitals and were transferred to Chongqing city. Multi-stage cluster sampling method was used. 354 valid questionnaires were recovered to explore the relevant factors affecting the severity on the symptoms of PTSD. RESULTS: This survey contains 354 subjects, with male 154 (43.6%), female 200 (56.4%), age 43.76 +/- 21.22, nation alities: Han people 236 (66.7%), Qiang people 114 (32.2%), others 4 (1.1%), and marriage status as unmarried 92 (26.1%), married 253 (71.7%), others 9 (2.2%). The wounded women PTSD have more serious symptoms than men, and there were differences between them in repeated and disturbing dreams of this stressful experience (t = 2.46, P = 0.014), a strong sense of psychological suffering annoyance (t = 2.02, P = 0.044), having difficulty concentrating (t = 2.04, P = 0.042), being "super-alert" (t = 2.465, P = 0.014) etc, also in the total scores (t = 2.489, P = 0.013) (P < 0.05). The PTSD symptoms of wounded degree in who had been buried in Earthquake were more serious than those not been buried. There were significant differences between them in the items as: avoid thinking about or talking about a stressful experience (t = 2.661, P = 0.008), avoid activities or situations that could recall the stressful experience (t = 2.705, P = 0.007), trouble remembering important parts of a stressful experience (t = 2.775, P = 0.006), feeling emotionally numb or being unable to have loving feelings for those close to you (t = 3.017, P = 0.003), feeling as if your future will somehow be cut short (t = 2.979, P = 0.003) and total scores (t = 3.175, P = 0.002). The wounded that witnessed someone be buried or died in earthquake, in PTSD symptoms, were more serious than those without. In the items of feeling distant or cut off from other people, feeling emotionally numb or being unable to have loving feelings for those close to you, feeling irritable or having angry outbursts, there were significant difference (P < 0.05 - 0.01). There were significant differences among the average score of the three core symptoms (F = 3.350, P < 0.001), among the three core symptoms as well as between the three core symptoms and total score respectively. CONCLUSION: There were differences in the severity degrees of PTST in transferred casualty under different exposed conditions. Correlations were also found between each of the symptoms. PMID- 20193201 TI - [Evaluation on the effects of education regarding road safety among middle school students]. AB - OBJECTIVE: To evaluate the intervention effects for road traffic accident prevention among middle school students through understanding their knowledge, attitude and practice (KAP) on road safety. METHODS: Students in Grade 1 and Grade 2 from 7 junior and senior middle schools in Ji'nan city were selected as intervention group and students from a middle school in Hefei city served as control group. Education was provided to the intervention group and all the middle school students in Ji'nan city. Changes of KAP on road safety were measured for both groups during the follow-up period, and comparison on KAP for the two groups was carried statistically. RESULTS: The mean scores of road safety knowledge for intervention group improved significantly during the follow-up period (from 0.9 - 3.8), while these indices did not change much in the control group (from 0 - 0.2). Negative attitude on road safety was found in both groups, but less in the intervention group. More students started to admit that middle school students themselves should be responsible for most of the RTAs. Per week frequency of violating traffic rules did not improve, however during the follow up period on both groups as still 75% to 80% of the students violating the traffic rules less than 2 times per week. Although three kinds and one kind of traffic rules violation seemed to have improved in the intervention group and in the control group, there were still two and three other kinds turned worse in the intervention and in the control group, respectively. CONCLUSION: Program on road safety education significantly improved the relative knowledge for middle school student and it exerted positive effects in road safety attitude to some extent. However, no significant effect was found in the improvement on their behavior. Education on road safety should be carried out in the early stage of childhood with newer and more effective intervention approaches. PMID- 20193202 TI - [Current situation and surveillance on dengue fever in China, 2005 - 2007]. AB - OBJECTIVE: To provide scientific evidence for prevention and control program on dengue fever through analyzing the situation of dengue fever in China, from 2005 to 2007. METHODS: Data was collected from Internet-based National Notifiable Infectious Disease Reporting System, National Enhanced Dengue Fever Surveillance System and field investigation on dengue outbreaks, described and analyzed with descriptively and by SPSS statistical software. RESULTS: There was a total number of 1623 dengue cases (including 1356 laboratory confirmed cases and 267 probable cases) and 1 death case reported in China from 2005 to 2007. Among the identified cases, 151 were imported from foreign countries as the Southeast Asian countries, accounting for 9.3%, while the rest 1472 cases were reported from local infections, identified only in 9 cities from Guangdong and Fujian provinces. Data from the monitoring program on Aedes Mosquitoes indicated that: The indicators of BI from 84.6% of the sentinels were over 5, and BI from 72.2% of the sentinels were over 10. This index was especially at a higher level during summer in the southern areas of China. Aedes albopictus was found in all the sentinel sites while Aedes aegypti was only found in Hainan and in limited counties of Guangdong. No dengue virus was isolated from mosquito vectors collected from national sentinel sites, whereas positive results had been detected by PCR test in Guangdong province. CONCLUSION: It was assumed that a sustainable local circulation of dengue virus had not yet been established successfully in Mainland China according to the surveillance data. However, more local outbreaks reported in Guangdong and Fujian with the wide distribution and high-level density of aedes mosquito, low antibody level in healthy population and the increasing number of imported dengue cases, there is a potential of Dengue outbreaks in southern China. An integrated mosquito vector monitoring and management system is needed in high risk area to reduce the transmission of dengue fever. PMID- 20193204 TI - [Association between ambient temperature and hospital emergency room visits for cardiovascular diseases: a case-crossover study]. AB - OBJECTIVE: To explore the association between ambient average temperature and hospital emergency room visits for cardiovascular diseases (International Classification of Diseases, Tenth Vision ICD-10: I00 - I99) in Beijing, China. METHODS: Data was collected on daily hospital emergency room visits for cardiovascular diseases from Peking University Third Hospital, including meteorological data (daily average temperature, relative humidity, wind speed, and atmospheric pressure) from the China Meteorological Data Sharing Service System, and on air pollution from the Beijing Municipal Environmental Monitoring Center. Time-stratified case-crossover design was used to analyze data on 4 seasons. RESULTS: After adjusting data on air pollution, 1 degree ( degrees C) increase of ambient average temperature would associate with the emergency room visits of odds ratio (ORs) as 1.282 (95%CI: 1.250 - 1.315), 1.027 (95%CI: 1.001 - 1.055), 0.661 (95%CI: 0.637 - 0.687), and 0.960 (95%CI: 0.937 - 0.984) in spring, summer, autumn, and winter respectively. After controlling the influence of relative humidity, wind speed, and atmospheric pressure, 1 degrees C increase in the ambient average temperature would be associated with the emergency room visits on ORs value as 1.423 (95%CI: 1.377 - 1.471), 1.082 (95%CI: 1.041 - 1.124), 0.633 (95%CI: 0.607 - 0.660) and 0.971 (95%CI: 0.944 - 1.000) in spring, summer, autumn, and winter respectively. CONCLUSION: These data on outcomes suggested that the elevated level of ambient temperature would increase the hospital emergency room visits for cardiovascular diseases in spring and summer while the elevated level of ambient temperature would decrease the hospital emergency room visits for the cardiovascular diseases in autumn and winter, suggesting that patients with cardiovascular diseases should pay attention to the climate change. PMID- 20193203 TI - [Characteristics of 57 acute flaccid paralysis cases with polio-virus isolated from stool specimens, in Yunnan province, from 2003 to 2007]. AB - OBJECTIVE: Study on the epidemiological characteristics of poliomyelitis virus in Yunnan, from 2003 to 2007. METHODS: Surveillance data of acute flaccid paralysis (AFP) cases from year 2003 to 2007 was gathered. All the stool specimens were identified to contain polio virus. RESULTS: 1171 AFP cases were reported. Out of the total number of 1138 stool specimens from 2003 to 2007, 57 cases showed polio virus (5.0%), 159 showed NPEV (14.0%), 922 cases showed virus negative. In those virus, polio type II took the lead (31.6%). 57 AFP cases appeared in 37 (28.7%) counties in Yunnan. Most of the cases were under 2 years of age. 29 cases had taken more than 3 OPV (oral poliovaccine) dosages and 41 cases had fever before paralysis occurred. Most of the cases appeared paralysis on single lower limb, but 26 cases leaving deformity. Significant difference was found between the two groups: having received vaccination more than 3 OPV dosages or less than 3 dosages. CONCLUSION: High quality AFP epidemiological and laboratory surveillance program, together with OPV routine and supplemental immunization strategy to cover the poorly immunized area/population appeared to be most effective. PMID- 20193205 TI - [A case-crossover study on the relationship between air pollution and acute onset of cerebral hemorrhage in Hangzhou city]. AB - OBJECTIVE: To explore the relationship between air pollution and acute onset of cerebral hemorrhage in Hangzhou. METHODS: Time-stratified case-crossover study was used to analyze the effect of aerosol optical depth (AOD), PM(10), SO(2) and NO(2) on the acute onset of cerebral hemorrhage. Conditional logistic regression was used to estimate the odds ratios (ORs) and their 95% confidence intervals (CIs) in relation to an increase of one unit of AOD and 10 microg/m(3) of air pollutants. RESULTS: After adjusted temperature and relative humidity, the ORs of acute onset of cerebral hemorrhage by a unit increase in AOD at a 2 day-lag were 1.727 (95%CI: 1.103 - 2.703) in first half year and 2.412 (95%CI: 1.230 - 4.733) at a 2 day-lag in spring. For a 10 microg/m(3) increase in SO(2), the ORs were 1.119 (95%CI: 1.019 - 1.229), 1.230 (95%CI: 1.092 - 1.386), 1.254 (95%CI: 1.076 - 1.460) in the whole year (2 day-lag), in first half year (2 day-lag) and in spring (2 day-lag), respectively. NO(2) exposure in first half year (2 day-lag) was associated with cerebral hemorrhage, with OR as 0.841 (95%CI: 0.734 - 0.964). However, there were no statistical significances for AOD, SO(2), NO(2) in the rest time-periods (P > 0.05). Additionally, no association was found between PM(10) and the acute onset of cerebral hemorrhage in any time-periods (P > 0.05). CONCLUSION: Our data showed that there was association between air pollution and the acute onset of cerebral hemorrhage, especially in spring and in the first half of the year. PMID- 20193206 TI - [Surveillance on Keshan disease from 1990 to 2008 in Sichuan province]. AB - OBJECTIVE: To study the epidemiological characteristics of Keshan disease (KD) and its trend so as to provide evidences for further research, prevention and treatment of the disease in Sichuan province. METHODS: Based on KD related data from 1990 to 2008, descriptive method was used to analyze the epidemiological characteristics of KD. RESULTS: 87 KD cases were identified during the 19 years. All cases were children from the countryside, with majority of them were Yi nationality. Age of the patients ranged from 5 months to 18 years, with majority at 2 - 6 year-olds. The annual incidence rates were from 0/100 000 to 1.73/100 000 with 1999 the highest (1.73/100 000). A total number of 310 preclinical or chronic KD cases were identified and the total detection rates were between 0.28% and 2.8%, with 1992 the highest. As for levels of blood selenium during the 19 years: 1995 appeared the lowest (0.1345 microg/g), followed by 1990 - 2000 (0.1558 microg/g) but all of them fell in to the level in the KD epidemic areas. CONCLUSION: There were 5 stages in the development trend of KD disease in Sichuan province, with 2 ascending and 3 descending. The differences between any of the two stages were statistically significant. The 3 descending stages all appeared right after the selenium supplement intervention was taken. Our data showed that the program of selenium supplement was closely related to the incidence of KD, suggesting that a long term mechanism of Selenium supplement in the epidemic areas should be taking into account. PMID- 20193207 TI - [Complete genome sequencing and analyses of rabies viruses isolated from wild animals (Chinese Ferret-Badger) in Zhejiang province]. AB - OBJECTIVE: Based on sequencing the full-length genomes of two Chinese Ferret Badger, we analyzed the properties of rabies viruses genetic variation in molecular level to get information on prevalence and variation of rabies viruses in Zhejiang, and to enrich the genome database of rabies viruses street strains isolated from Chinese wildlife. METHODS: Overlapped fragments were amplified by RT-PCR and full-length genomes were assembled to analyze the nucleotide and deduced protein similarities and phylogenetic analyses of the N genes from Chinese Ferret-Badger, sika deer, vole, dog. Vaccine strains were then determined. RESULTS: The two full-length genomes were completely sequenced to find out that they had the same genetic structure with 11 923 nts including 58 nts-Leader, 1353 nts-NP, 894 nts-PP, 609 nts-MP, 1575 nts-GP, 6386 nts-LP, and 2, 5, 5 nts- intergenic regions (IGRs), 423 nts-Pseudogene-like sequence (Psi), 70 nts-Trailer. CONCLUSION: The two full-length genomes were in accordance with the properties of Rhabdoviridae Lyssa virus by blast and multi-sequence alignment. The nucleotide and amino acid sequences among Chinese strains had the highest similarity, especially among animals of the same species. Of the two full-length genomes, the similarity in amino acid level was dramatically higher than that in nucleotide level, so that the nucleotide mutations happened in these two genomes were most probably as synonymous mutations. Compared to the referenced rabies viruses, the lengths of the five protein coding regions did not show any changes or recombination, but only with a few-point mutations. It was evident that the five proteins appeared to be stable. The variation sites and types of the two ferret badgers genomes were similar to the referenced vaccine or street strains. The two strains were genotype 1 according to the multi-sequence and phylogenetic analyses, which possessing the distinct geographyphic characteristics of China. All the evidence suggested a cue that these two ferret badgers rabies viruses were likely to be street virus that already circulating in wildlife. PMID- 20193208 TI - [Comparison of Cj1136, Cj1138 and Cj1139 genes among Campylobacter jejuni strains]. AB - OBJECTIVE: By sequenceing the Cj1136, Cj1138 and Cj1139 gene of Campylobacter jejuni (C. jejuni) strains associated with Guillain-Barre Syndrome (GBS), features of Cj1136, Cj1138 and Cj1139 gene were studied. Results were compared with the C. jejuni strain NCTC11168, to find the mutations in sequence of C. jejuni which inducing GBS and their polygenetic relationship was analyzed. METHODS: Three GBS-associated C. jejuni strains were isolated from stools of GBS patients from Hebei province who had been diagnosed as clinical AMAN pattern and electrophysiological tests were performed. After distilling and sequencing Cj1136, Cj1138 and Cj1139 genes, results were spliced and assembled into a complete sequence by the terminals overlapped with each other. Sequences of Cj1136, Cj1138 and Cj1139 genes were compared with NCTC11168, to find the mutations and gene feature. RESULTS: The Cj1136, Cj1138 and Cj1139 gene of the three GBS- associated C. jejuni strains were composed by 1173 base pairs, 1170 base pairs, 912 base pairs respectively. The alignment with the related sequence of NCTC11168 showed that there were two same mutations in the Cj1138 gene of the three C. jejuni stains. Data from phylogenetic analysis demonstrated that the three C. jejuni strains were genetically closed to NCTC11168, with the biggest phylogenetic distance between the three of them as 2.1%. CONCLUSION: When compared with NCTC11168 the Cj1138 gene of the three GBS-associated C. jejuni strains had the same mutations which might be related to the development of GBS. Relation between the variation and GBS-pathogenesis remained to be confirmed. The mutations found in the three C. jejuni strains established the foundation for exploring the biological characteristics of GBS-associated C. jejuni strains and demonstrated that the GBSassociated C. jejuni strains of Hebei province having its regional features. PMID- 20193209 TI - [Study on the molecular characteristics of multidrug-resistant Acinetobacter baumannii]. AB - OBJECTIVE: To investigate antibiotic resistance, carbapenemase genotype and the molecular epidemiology of multidrug-resistant Acinetobacter baumannii (Aba) collected from 3 military hospitals in China. METHODS: The minimum inhibitory concentrations (MIC) were examined by ager dilution method. Genotypes of carbapenemases were amplified by multiplex PCR and its products were sequenced. PCR was used to detect per gene. Homology of the resistant isolates was analyzed by pulse-field gel electrophoresis (PFGE). RESULTS: Among the 64 MDRA strains, 78.1% (50) strains possessed bla(OXA-23) gene, 89.1% (57) carried Class 1 integrase gene, 39.1% (25) with bla(PER-1) gene, and 1 strain with bla(OXA-58 like) gene. PFGE showed that 13 (A, B, C, D, E genotype) different clones were identified in these strains. A, B, and U clones were the predominant clones in three hospitals, respectitively. CONCLUSION: Outbreaks of multidrug-resistant Aba occurred at 3 military hospitals with the most prevalent carbapenemase as OXA-23 enzyme. OXA-58 type of carbapenemase and per-1 in Aba were also isolated. PMID- 20193210 TI - [Isolation and characterization of Shewanella spp. from patients of food poisoning]. AB - OBJECTIVE: To identify the isolates of Shewanella spp. from specimens of food poisoning based on biological and biochemical analysis. METHODS: Strains were obtained from the investigation on two food poisoning episodes in September and October, 2007 in Ma'anshan city, Anhui province. In accordance with the national standard protocol (GB/T 4789), all specimens were enriched and isolated on selective medium, and the suspected strains were identified by the VITEK-32 and API20E systems. For Shewanella spp. identified by the biochemical system, more characteristics were analyzed using auxiliary biochemical, growth, hemolytic and drug-resistance tests. DNAs of Shewanella spp. were extracted, 16S rDNA was PCR amplified and sequenced with universal 16S rDNA primers. Phylogenetic tree was constructed with MEGA 4.0. RESULTS: After enrichment, all specimens were inoculated to selective medium and Shewanella spp. strains were isolated from 8 samples with single colony on both TCBS and BP media. The characteristics of growth in the Triple Sugar Iron (TSI) agar appeared to have had hydrogen sulfide production but no gas production or positive oxidase. No Shewanella spp. strain was detected in WS, SS and EMB media. The 8 strains were identified as Shewanella algae (S. algae) or Shewanella putrefaciens (S. putrefaciens) by VITEK-32, as S. putrefaciens by API20E system. No other enteropathogenic bacteria, including Vibrio cholerae, Salmonella, Vibrio parahaemolyticus, Proteus vulgaris or Staphylococcus aureus, were detected from those 8 samples. From 16S rDNA phylogenetic trees, 7 out of 8 Shewanella spp. were identified as S. algae, 1 as S. putrefaciens. CONCLUSION: Strains of Shewanella spp. were isolated from samples of the food poisoning episodes, providing a possible clue to investigate the role of Shewanella spp. on food poisoning. PMID- 20193211 TI - [Evaluation on the analytical sensitivity of 31 HBsAg enzyme immunoassay kits]. AB - OBJECTIVE: To study the analytical sensitivity on 31 HBsAg enzyme immunoassy (EIA) test kits. METHODS: Thirty one HBsAg EIA kits produced by domestic or overseas manufactories and applied for approval during May 2007 to May 2008, were evaluated using the national reference panels. The hyperbolic curve of the log A value and log concentration for the national sensitivity standards was established. The cut-off value of each kit was substituted into the curvilinear equation to determine the analytical sensitivity which was compared between different HBsAg EIA kits. RESULTS: Twenty seven (351 lots) domestic and 4 (27 lots) overseas kits were compared. Among 378 lots of the 31 HBsAg EIA kits, only 2 lots of the domestic kits had a lower sensitivity when tested with the national HBsAg reference panels, with an average approvalr ate of 99.43% (349/351). The mean analytical sensitivity of the domestic kits for adr, adw, ay serotypes were 0.307, 0.419, 0.513 ng/ml, respectively. There was a significant difference between serotypes (F = 97.30, P < 0.01). The mean analytical sensitivity of the overseas kits for adr, adw, ay serotypes were 0.054, 0.066, 0.050 ng/ml respectively, with no significant difference between serotypes (F = 0.65, P > 0.05). The analytical sensitivity of the overseas kits for all the three serotypes was higher than that of the domestic kits (P < 0.01). There was no significant difference found between the analytical sensitivities of the kits produced by the same manufactory using 30- or 60-minute incubation of detection (P > 0.05). In contrast, there was significant difference noticed between the analytical sensitivities of the kits produced by the same manufactory when tested for 10 or 15-minute coloration of the results (P < 0.01). CONCLUSION: Analytical sensitivity of the HBsAg EIA domestic kits should be further improved, especially for detecting adw and ay serotypes. PMID- 20193212 TI - [Meta-analysis on the association of G894T polymorphism in endothelial nitric oxide synthase gene and essential hypertension in Chinese population]. AB - OBJECTIVE: To evaluate the relationship between G894T (Glu298Asp) polymorphism in the endothelial nitric oxide synthase (eNOS) gene and essential hypertension in Chinese population from different regions. METHODS: Odds ratios (ORs) of G894T genotype and allele distributions in essential hypertension patients against healthy controls were analyzed. All the relevant studies were screened with poor qualified studies eliminated. Meta-analysis software MIX (Meta-analysis with interactive explanations-version 1.71), was applied for investigating and analyzing heterogeneity among individual studies and summarizing the effects across studies, and the risk of publication bias was evaluated. RESULTS: A total of 1900 cases and 1216 controls from 10 studies were included. The heterogeneity between studies was significant (P = 0.013; P = 0.011) and there were substantial sources of publication bias (P = 0.049; P = 0.038). The pooled OR (with 95%CI) of GT + TT vs. GG genotype was 1.79 (1.33 - 2.42) (Z = 3.83, P < 0.001), and the pooled OR (with 95%CI) of T vs. G allele was 1.73 (1.32 - 2.27) (Z = 3.92, P < 0.001). CONCLUSION: In Chinese population, mainly the Hans ethnic group, 894G-->T mutation in the eNOS appeared to be related to essential hypertension. PMID- 20193214 TI - [Current situation of the research for antifungal drug's targets]. PMID- 20193213 TI - [Association between calpain-10 gene polymorphism and risk of type 2 diabetes mellitus: a meta analysis]. AB - OBJECTIVE: The purpose of this study was to approach the relation of SNP43, SNP44 locus, main haplotypes and haplotype combinations with type 2 diabetes mellitus (T2DM). METHODS: According to the theory and principles of systematic review, data from case-control studies regarding the association between calpain-10 (CAPN10) gene and T2DM were derived through electronic search of PubMed and Chinese journals databases. To gain a more precise estimation of the relationship, a stratified Meta-analysis with four subgroups was performed according to the races. Publication bias was also assessed. RESULTS: The association with T2DM in different races was evaluated. In Mongoloid race, SNP43 G allele, G/G genotype and 111/221 haplotype combination showed notable association with T2DM with ORs (95%CI) as 1.368 (1.155 - 1.620), 1.437 (1.186 - 1.741) and 2.762 (1.287 - 5.927) respectively. In Caucasoid race, SNP44-C allele, 111/111 hapotype combination showed strong relationship with T2DM with ORs (95%CI) as 1.144 (1.023 - 1.278), 1.291(1.050 - 1.586) respectively. In Hybrid race, only one positive finding was obtained which was SNP44-C allele with OR (95%CI) as 1.653 (1.025 - 2.665). CONCLUSION: SNP43-G allele, G/G genotype, 111/221 were risk factors to Mongoloid race. And SNP-C allele, 111/111 haplotype combination were risk factors to Caucasoid race, and SNP44-C allele to Hybrid race. PMID- 20193215 TI - [The evolvement of health expectancy]. PMID- 20193216 TI - [Lay Epidemiology--a new term of epidemiology]. PMID- 20193217 TI - [The application of performance assessment in public health system]. PMID- 20193218 TI - [Surveillance on HIV-1 incidence among men who have sex with men in Chongqing, China, 2006 - 2008]. AB - OBJECTIVE: To estimate HIV-1 incidence among men who have sex with men (MSM) in Chongqing and to provide reasonable evidence for intervention strategy. METHODS: Using "snowballing" and convenient sampling, 2989 MSM were recruited during 2006 2008. BED-CEIA was applied to the leftover blood samples to estimate the crude and adjusted HIV-1 incidence rates. Incidence was stratified by venues and age groups. RESULTS: The incidence among MSM in Chongqing were 7.01%, 7.98% and 7.80% from 2006 - 2008 respectively with statistically significant differences by venues. The highest incidence was found among those who frequently visiting public baths/sauna and those MSM who find sex partners through internet, amounting to 17.87% and 12.22% respectively in 2007 and 2008. The 21 - 25 year old group had the highest incidence in 2008, reaching 8.69%. Various adjustments brought down the estimated incidence across the three years. CONCLUSION: HIV-1 incidence among MSM maintained at a high level across the three years but without an increasing trend. PMID- 20193219 TI - [HIV infections and heterosexual behaviors among men who have sex with men in Chongqing municipality, China]. AB - OBJECTIVE: To understand the prevalence and risk factors for both HIV infection and prevalence rates of syphilis infection among men who exclusively have sex with men (MSM/M) or with both men and women (MSM/W) in Chongqing municipality, China. METHODS: Cross-sectional studies were conducted in Chongqing. Structured questionnaire-based interviews were conducted to provide information about demographic characteristics, behavior, HIV related health services and sexual transmitted infections (STIs). Blood samples were tested for HIV and syphilis infections. RESULTS: Of 1691 participants, 21.6% were MSM/W, with HIV prevalence as 16.1% which was significantly higher than that among MSM/M (9.4%, P < 0.001). Factors independently associated with HIV infection among MSM/W included being separated/divorced/widowed (AOR = 14.8, 95%CI: 3.1 - 71.6), having multiple male sex partners (AOR = 5.4, 95%CI: 1.8 - 16.3), unprotected anal sex behaviors (AOR = 4.6, 95%CI: 1.5 - 13.9) and syphilis infection (AOR = 4.4, 95%CI: 1.1 - 17.3). Factors independently associated with HIV infection among MSM/M were as follows: lower education (AOR = 2.6, 95%CI: 1.6 - 4.5), older age (AOR = 2.0, 95%CI: 1.3 - 3.3, 26 - 35 years vs. < 26 years; AOR = 1.9, 95%CI: 1.1 - 3.5, > 35 years vs. < 26 years), being recruited from bath house/sauna (AOR = 2.5, 95%CI: 1.1 approximately 5.6) syphilis infection (AOR = 1.9, 95%CI: 1.0 - 3.4), multiple male sex partners (AOR = 1.8, 95%CI: 1.1 - 2.9), and STIs infection (AOR = 1.7, 95%CI: 1.0 - 2.7). Heterosexual behaviors independently associated with married/cohabiting (AOR = 6.5, 95%CI: 4.4 - 9.8), self-identified as bisexual/heterosexual (AOR = 3.9, 95%CI: 2.8 - 5.5), first lifetime female sex partners (AOR = 2.2, 95%CI: 1.5 - 3.0), lack of HIV related knowledge (AOR = 1.9, 95%CI: 1.1 - 3.2), being recruited from bars/night clubs/tea bars (AOR = 1.6, 95%CI: 1.0 - 2.6), older age at sex debut (AOR = 0.6, 95%CI: 0.4 - 0.8), not offering sex for money for anal intercourses in the past six months (AOR = 0.5, 95%CI: 0.3 - 1.0) and HIV infection (AOR = 1.7, 95%CI: 1.1 - 2.7). CONCLUSION: HIV prevalence had reached a high level among men who have sex with men and women in Chongqing, China. Multiple sex partners and other high risk behaviors when having sex with men or women among MSM/W represented a unique risk group within the population of MSM that might have bridged the HIV transmission between HIV high risk group and general population. More attention need to be specifically paid to prevent HIV transmit from HIV high risk group to general population. PMID- 20193220 TI - [Analysis on the status of antenatal checkup program in certain areas of China, 2005]. AB - OBJECTIVE: To investigate the status and related factors on antenatal checkup program in women from certain parts of China. METHODS: A total number of 13 532 mothers who had children under-3 years of age, from 920 village in 46 counties, were recruited through random sampling methodology. SPSS 11.5, chi(2) test and logistic regression were used for data analysis. RESULTS: The coverage of antennal care was 95.7%, with the average times of antenatal checkup as 4.9. The proportion of women who received five and more times of antenatal checkup was 50.8%. 25.9% of the pregnant women received antenatal checkup before 12 weeks of gestation. There were significant differences among data on antenatal coverage and the proportion of > or = 5 times antenatal checkup as well as having received antenatal checkup before 12 weeks (P < 0.01). Factors including age, education, nationality and economic situation had influenced the rates on antenatal checkup. Women with illiteracy had a lower antenatal checkup rate than those literate. Women under Han nationality and at 25 - 34 years of age had higher rates on antenatal checkup than other minorities or at other age groups. Rates on women having had > or = 5 times of antenatal checkup or having antenatal checkup before 12 weeks of gestation were 52.8% and 26.7% in the families that owned a television set and 56.7%, 28.1% in the families that owned traffic tools. Data from factor analysis revealed that nationality, age, women's education level, properties as owning television set or traffic tools in the families, knowledge on hospital delivery and health education provided during pregnancy were related to the rates of antenatal checkup. CONCLUSION: The quality of antenatal checkup, especially at the first 1 weeks, should be improved. PMID- 20193221 TI - [Association between pregnancy-induced hypertension, cesarean delivery and perinatal mortality: a prospective study]. AB - OBJECTIVE: To examine the relationship between pregnancy-induced hypertension (PIH) and risks of perinatal mortality. METHODS: A population-based, retrospective cohort study was conducted based on 134 858 women registered in a perinatal health care surveillance system and delivered singleton births between 1995 to 2000 in Zhejiang province, China. Multivariate logistic regression models were employed to estimate the relative risk (OR) and 95%CI. RESULTS: The perinatal mortality rate (95%CI) was 7.6 per thousand (7.1 - 8.1) in normotensive women and 9.2 per thousand (7.7 - 10.8) in PIH women. The cesarean delivery rate was 45.7% in normotensive women and 55.7% in groups with PIH. When compared with the normotensive women, the unadjusted OR (95%CI) for perinatal mortality was 1.21(1.01 - 1.46) in groups with PIH; 0.97 (0.77 - 1.22) in groups with mild PIH, 1.73 (1.26 - 2.37) in groups with moderate PIH, and 2.01 (1.18 - 3.43) in groups with severe PIH; 0.99 (0.77 - 1.26) in groups with PIH developed before delivery, 1.39 (1.05 - 1.84) in groups with PIH developed in second trimester, and 2.69 (1.54 - 4.69) in groups with PIH developed in third trimester. After controlling for maternal age, occupation, educational attainment, parity, times of prenatal visit, infant's sex, pregnancy complications and cesarean delivery, the OR (95%CI) for perinatal mortality was 1.09 (0.90 - 1.31) in women with PIH when compared with the normotensive groups. The adjusted OR for perinatal mortality was 0.81 (0.64 - 1.02) in groups with mild PIH, 1.94 (1.41 - 2.67) in groups with moderate PIH, and 3.32 (1.92 - 5.75) in groups with severe PIH; 0.82 (0.63 - 1.05) in groups with PIH developed before delivery, 1.51 (1.14 - 2.00) in groups with PIH in second trimester, and 2.67 (1.52 - 4.70) in groups with PIH in third trimester. CONCLUSION: Moderate and severe PIH early developed during pregnancy could increase the risk of perinatal mortality, while cesarean delivery could decrease the risks in women with PIH. PMID- 20193222 TI - [Study on a breast-disease screening program and related factors among rural married women at reproductive age in Anhui province]. AB - OBJECTIVE: To study the prevalence and its related factors on breast-diseases among women at reproductive age in the rural areas of Anhui province, and to provide data for the development of prevention and healthcare on breast-diseases. METHODS: 54 400 rural fertile women aged 15 - 49 were surveyed by a stratified cluster-random sampling method. Breast examination was conducted in two steps: converging at the clinics, and later visiting their households. Clinical examination and X-ray scanning check up were performed. RESULTS: The rate of the breast-disease among the rural fertile women was 10.69%, and the first three breast-diseases were galactophore hyperplasia, fibroadenoma and intracanalicular papilloma, their prevalence were 9.39%, 0.65% and 0.50% respectively. The results of logistic regression showed in comparison with women and their husbands who were under 29, low education, husbands being farmers, medium menstrual flow, no dysmenorrheal, the total number of deliveries was 0 while no history of abortion, those who aged 30 to 44, high education, husbands were doing other jobs (they were mainly businessmen or teachers), more menstrual flow, dysmenorrheal, the total number of deliveries was 1, they were more likely to got breast diseases. However in comparison with women who earned less than 5000 Yuan per year, those who had 5001 to 8000 Yuan per year were less likely to get breast diseases. CONCLUSION: Breast diseases were prevalent among rural fertile women and were affected by multi-factors. We suggested that screening program on breast cancer should be carried out at regular intervals and at the same time, to intensify second-class prevention of breast cancer, together with actively treating patients with galactophore hyperplasia, to reduce the prevalence of precancerous pathological changes. PMID- 20193223 TI - [Association between age and quality of semen in Chinese males with normal fertility]. AB - OBJECTIVE: To explore the association between age and variables of semen in Chinese males with normal fertility. METHODS: The population size under study would consist of 946 fertile male volunteers from 6 provinces of China, aged between 20 and 59. Semen quality was analyzed by hand on site and background information was obtained through structured questionnaire. Trend chi-square test and multiple linear regression methods were used and 95%CI were calculated to serve as reference value of semen variables of different age group. RESULTS: The normal percent of motility and living sperm declined significantly while the ascending of age, they were 55.7% and 97.3% in age < 30 group when compared to 21.9% and 90.3% in the age 50 - 59 group respectively. Under control of confounding factors as for center and abstinence time, all semen variables except semen volume were significantly different among the age groups. Sperm concentration, percentage of sperm motility and normal morphology sperm decreased significantly after age 40 while percentage of living sperm decreased after age 50 - 59 group. Sperm concentration among the 50 - 59 year-old group appeared to be lower than the 40 - year-old group. CONCLUSION: The influence of age must be taken into account when evaluating the quality of semen. PMID- 20193224 TI - [A case-control study on genetic and environmental factors regarding polydactyly and syndactyly]. AB - OBJECTIVE: To explore the genetic and environmental factors related to the development of polydactyly and syndactyly, and to provide evidence for prevention on birth defects. METHODS: A hospital-based case-control study was conducted. 111 cases and 222 controls were interviewed with standardized questionnaires. Logistic regression models were used to select risk factors. RESULTS: Research data through univariate analysis showed that the occurrence of polydactyly and syndactyly were associated with educational level, annual average income per family member, meat and egg intake during early pregnancy, family heredity history, exposure to hazardous substance before pregnancy, serious pregnant reaction etc. of the pregnant women. As shown in multivariable logistic model, some factors, including annual average income of per family member (OR = 0.240), meat and egg intake during early pregnancy (OR = 0.182), could reduce the risk of the development of polydactyly and syndactyly. Other factors including family heredity history (OR = 10.187), exposure to hazardous substance before pregnancy (OR = 3.029), could increase the risk of developing polydactyly and syndactyly. The attributable risks (%) of family heredity history and exposure to hazardous substance before pregnancy were 90.18% and 66.99% respectively. CONCLUSION: Genetic factor was the leading cause on the development of polydactyly and syndactyly. In addition, environmental factors, such as family economic condition, nutritional status during early pregnancy and working condition before pregnancy were associated with the development of polydactyly and syndactyly. PMID- 20193225 TI - [Study on the relations between smoking and the risk of age-specific lung cancer deaths in urban and rural areas of China]. AB - OBJECTIVE: To study the association between smoking and lung cancer mortality of residents living in the urban and rural areas of China. METHODS: Using the national census data on causes of death and case-control studies, stratified analysis was conducted by parameters as geography and age, to calculate the risk ratios, excess risks, average years lost for life expectancy by smoking in males and females in 103 cities/counties in China. RESULTS: Smoking increased the risks for lung cancer death in all ages older than 35 years of age, in urban and rural areas, through data analysis on 52 193 cases died from lung cancer in 1986 - 1988 and 307 934 matched controls in China. The risk ratio was 3.0 (95%CI: 2.9 - 3.1) with 53.0% excess for lung cancer deaths in the male smokers. The years lost for life expectancy were 18.5 in urban, and 17.7 in rural male smokers aged 35 to 69 years. Similarly, the risk ratio was 3.0 (95%CI: 2.9 - 3.1), with 26.0% excess for lung cancer deaths in female smokers. The life-expectancy lost was 13.0 and 20.4 for female smokers aged 35 to 69 years in urban and rural areas, respectively. CONCLUSION: In both urban and rural areas, risk on lung cancer deaths caused by smoking in all males and females aged at 35 years and older had been significantly increased. Control of smoking prevalence should play a vital role in the prevention of the lung cancer death risks in China. PMID- 20193226 TI - [Study on the risk factors of injuries among children at school age, from the families of migrant workers in Hangzhou city]. AB - OBJECTIVE: To explore the risk factors of injuries among school aged children from migrant workers' families, in Hangzhou. METHODS: A cross-sectional survey on 3582 students from eight separate schools in which, four were set for migrant workers' families and the other four were for families of permanent residents. Stratified cluster random sampling method was used. Data was analyzed by unconditional univariate and multivariate logistic regression methods under SPSS 13.0. RESULTS: The incidence rate of injury did not show statistical difference between children of migrant workers or from the permanent residents. The incidence rate of multiple injuries was higher in children from the migrant workers' families. The incidence rates on electric shock occurred at the primary school, drowning among boys at the secondary school and scald/crash/cutting by knives in girls at secondary schools were seen higher among children from the of migrant workers. Results from multivariate analysis showed that factors as gender (OR = 1.20), age (6 - 9 years: OR = 0.70, 10 - 12 years: OR = 1.45), fond of playing Pingpong (OR = 1.35), history of injuries by pets (OR = 1.41), skills on swimming (OR = 1.22), no history of being threatened (OR = 0.68), having harmonious family relations (OR = 0.69) and owning a house by family (OR = 0.76) appeared to be the major one that related to the occurrence of injury. CONCLUSION: Personal behavior as well as family and social environment seemed to be factors affecting the occurrence of injuries among children from the migrant workers' families. PMID- 20193227 TI - [Prevalence rates of overweight and obesity in Chinese minority students in 2005]. AB - OBJECTIVE: To analyze the prevalence rates of overweight and obesity in Chinese minority students in 2005. METHODS: We analyzed data of 24 minority groups aged 7 - 18 years from Chinese national survey on students' physical fitness and health in 2005. Criterion made by the workgroup of obesity in China (WGOC) was used. RESULTS: The prevalence rates of overweight in 24 minority groups aged 7 - 18 years were 3.71% for boys and 4.72% for girls, while the prevalence rates of obesity were 1.60% for boys and 1.25% for girls. The total prevalence rates of overweight and obesity were 5.32% for boys and 5.96% for girls. The prevalence rates of overweight and obesity were higher in Korean, Mongolian and Kazak but lower in Zhuang and Shui students the Korean students the highest. CONCLUSION: In general, both the prevalence rates of overweight and obesity in Chinese minority students were comparatively low. However, in some minority groups the prevalence had already become higher, which demands early prevention. PMID- 20193228 TI - [Study on the trend of minority students' health status from 1995 to 2005 in China]. AB - OBJECTIVE: To reveal the trend of minority students' health from 1995 to 2005 in China. METHODS: We selected 15 minority groups wtih data pertaining to students' nutritional status, poor vision and decayed tooth in 1995, 2000 and 2005. The minority groups were Mongolian, Hui, Uygur, Zhuang, Korean, Tibetan, Yao, Li, Qiang, Bouyei, Dong, Hmong, Tu, Salar and Kirgiz. RESULTS: The prevalences of underweight and malnutrition in 2005 in Mongolian, Hui, Uygur, Zhuang and Korean students aged 7 - 22 years were lower than that of 1995 and 2000, indicating the nutrition status was improved. The prevalence of malnutrition in city girls was the highest. The mild malnutrition rates in 2005 decreased to 2.69%, 4.67%, 3.68%, 9.62% and 2.65% but the prevalence of overweight and obesity increased. For city boys, the rates were 5.50%, 8.12%, 2.69%, 3.69% and 13.50%. The prevalence of decayed tooth changed but with no significant differences. The prevalence rates of poor vision and myopia kept increasing. The minority students' myopia rates in 2005 were 29.5%, 39.1%, 10.1%, 42.6%, 41.1%, for boys and 45.4%, 50.0%, 15.4%, 49.7%, 46.7% for girls. CONCLUSION: In order to improve the health of students in minority regions, we need to promote health education at schools. PMID- 20193229 TI - [Surveillance and control of Japanese encephalitis in Henan province, 1950 - 2008]. AB - OBJECTIVE: To analyze the characteristics and trend of Japanese encephalitis (JE) in Henan province. METHODS: Adopting descriptive epidemiological method to analyze the data on the epidemic situation of JE from 1950 to 2008, and on mosquitoes and host animals at disease surveillance points. The host serum JE IgG antibody was detected by ELISA. Data was analyzed using SPSS 12.0 and Excel 2003 software. RESULTS: The incidence of JE in Henan province had a fluctuant downward trend. Peak of the incidence fell in July to September, accounting for 88.09% of total cases. The scope of geographical distribution was increasing from northern to southern parts of the province. Cases mainly concentrated in the southern and south-eastern parts of the province. 0 - 14 year-old group had the highest incidence (81.95%). In Luoyang city, there was a significant increase in children at 15-years or older (58.93%). Most patients were farmers (42.33%). The positive times for half of the antibodies of JE in piglets of the surveillance sentinels were different, which might be the reason for the different levels for the incidence rates. The proportion of different kinds of mosquitoes were also different in surveillance sentinel sites, and the time for the density peak of the mosquitoes was in accordance with the incidence peak of JE. CONCLUSION: To develop control strategies, evidence should be based on the characteristics of geographical variance, age, occupation differences, data related to monitoring on animal host and media mosquitoes of JE incidence in Henan province. PMID- 20193230 TI - [Using general growth balance method and synthetic extinct generations methods to evaluate the underreporting of death at disease surveillance points from 1991 to 1998]. AB - OBJECTIVE: Using both general growth balance (GGB) and synthetic extinct generations (SEG) methods to evaluate the underreporting of deaths in disease surveillance points (DSP) from 1991 to 1998. METHODS: We used those two methods to estimate the underreport rate in DSP from 1991-1998. According to GGB method, death rate and the difference between entry rate and growth rate were regarded as independent and dependent variable, respectively, to fit a one-dimensional linear equation n(*)(x) - r(*)(x+) = [ln(k(1)/k(2))]/t + [(k(1)k(2))(0.5)/c]d(*)(x+). About SEG method, it was calculated by life expectancy at age 85 of national census in 2000 and an equation N(x) = integral(x)(infinity)D(a).exp[integral(x)(a)r(u)du]d(a). Then we drew scatter diagram to evaluate underreporting of average intercensal age-specific mortality rates, and made adjustment. RESULTS: By GGB method, the population count in 1998 was 87.29 percent as complete as the count in 1991. For the period of 1991 - 1998, the number of underreporting of deaths was 11.7 percent. The underreporting of average intercensal age-specific mortality rates was not high. However, when SEG method was used, the underreport rate became 48.0 percent. The underreporting of average intercensal age-specific mortality rates decreased significantly from younger to older age groups. CONCLUSION: GGB and SEG could reduce more cost than other underreporting-related survey, and evaluate the underreporting in a defined time period. GGB could also evaluate the underreporting rate of population and death. However, both these two methods had some limitations. There was big difference between the results when using SEG and GGB, suggesting that we should try to combine GGB and SEG methods to get the better results. PMID- 20193231 TI - [Study on the epidemiological characteristics and molecular typing of Salmonella enterica subsp. enterica serovar Senftenberg in Shanghai]. AB - OBJECTIVE: To study the molecular epidemiological characteristics of Salmonella enterica subsp. enterica serovar Senftenberg (Salmonella senftenberg) in Shanghai, from 2006 to 2007. METHODS: A retrospective analysis in 2006 and 2007 was performed to explore the source of food-borne Salmonella senftenberg. The isolates from diarrhea patients between 2006 and 2007 were identified, including biochemical test, hilA and invA gene phenotyping, drug susceptibility, Riboprinter((R)) (RP) and pulsed-field gel electrophoresis (PFGE). RESULTS: Of the diarrhea patients isolates in the monitoring program on non-typhi Salmonella infection in the year of 2006 in Shanghai, number of patients caused by Salmonella senftenberg ranked the third. The stock of Salmonella senftenberg food born isolates were derived from swine and beef products between 2003 and 2005. All of the strains from diarrhea patients were susceptible to antibiotics except tetracylina (75.6%). With RP and PFGE molecular typing, the two groups (with hydrogen sulfide and hilA, invA gene or without) could be divided into two different independent clone cluster in genetics. 34 strains of diarrhea were divided into 16 PFGE typing-pattern, and among them 12 strains including type 4 (4 strains), type 5 (1 strains), type 6 (6 strains), type 7 (1 strains) and 13 strains including type 11 (3 strains), type 17 (5 strains), type 23 (5 strains) were two different dominant clone cluster. CONCLUSION: The epidemic of Salmonella senftenberg within 2006 might have been the result of a long period of case occurrence in Shanghai. This rare outbreak belonged to a cluster of outbreaks caused by two different PFGE clone clusters. Data suggested that the genetic clone of Salmonella senftenberg might have been unstable and the source of contamination were complicated, with the characteristics as the obvious decreasing number of patients, with no food-borne isolates in 2007. PMID- 20193232 TI - [Complete genome sequencing of enterovirus 71 (EV71) HENAN08 strain isolated in Henan province]. AB - OBJECTIVE: To sequence the whole-genome of enterovirus 71 (EV71) srtain isolated from patient with hand, foot and mouth in Henan province in 2008. METHODS: Eight overlapping clones covering the whole viral genome were obtained by RT-PCR and the sequences were determined by Sanger dideoxg-mediated chain termination method. RESULTS: Data it showed that the full length of enterovirus 71 (EV71) HENAN08 genome (not including Poly A tail) is 7405 bp. No deletion or insertion was detected in the coding region. There were several deletions and insertions in 5'UTR and 3'UTR regions. In P1 region, HENAN08 strain shared high homology with AnhuiFY08 strain, Zhejiang08 strain and SHZH strains (SHZH98, SHZH03) but low homology with Cox. A16. In P2 and P3 regions, HENAN08 strain shared higher nucleotide homology with Cox. A16 (81.7% and 83.7%) than that with BrCr and TW2086 strains. The phylogenetic analysis based on P1 region demonstrates that HENAN08 strain had the nearest genetic relationship with AnhuiFY and Zhejiang strains (isolated in 2008). CONCLUSION: The HENAN08 strain might belong to the same genogroup with AnhuiFY08 and Zhejiang08 strains as C4 gene subtypes. PMID- 20193233 TI - [A 1:1 matched case-control study on the interaction between HBV, HCV infection and DNA repair gene XPC Ala499Val, Lys939Gln for primary hepatocellular carcinoma]. AB - OBJECTIVE: To evaluate the interaction between environmental factors, HBV/HCV infections and DNA repair gene XPC exon 8 Ala499Val, exon 15 Lys939Gln on related risks to primary hepatocellular carcinoma (PHC). METHODS: A 1:1 matched case control study was conducted in Shunde city, Guangdong province. The genotypes of Ala499Val and Lys939Gln were detected by polymerase chain reaction restrictive fragment length polymorphism (PCR-RFLP) analysis, and gene-environment interactions were analyzed by conditional logistic regression. RESULTS: Among people infected by HBV with non- or at least one mutant gene of Ala499Val carriers, the risk of PHC significantly increased, with ORs as 3.768 (95%CI: 1.137 - 12.485) and 3.667(95%CI: 1.122 - 11.981) respectively. With non- or at least one mutant gene of Lys939Gln, the risk was increasing with ORs as 6.778 (95%CI: 2.025 - 22.688) and 3.152 (95%CI: 1.062 - 9.351) respectively. In those with HCV infection, non- or at least one mutant gene of Ala499Val might increase the risk with ORs as 2.955 (95%CI: 0.587 - 14.869), 1.085(95%CI: 0.307 - 3.839) respectively. However, when compared to the ones with no mutant gene of Lys939Gln among the same research subjects, those carrying at least one gene may decrease the risk, with OR lowered from 4.197 (95%CI: 0.870 - 20.243) to 0.887 (95%CI: 0.228 - 3.448). But the interactions between HBV infection, HCV infection and XPC genes were not statistically significant. CONCLUSION: Among people infected by HCV, the mutant gene of Ala499Val had the tendency to lower the risk of PHC, and the mutant gene of Lys939Gln also appeared the same in the population with either HBV infection or HCV infection in Shunde, Guangdong. Another study with large samples should be performed to analyze the interactions among environments-genes. PMID- 20193234 TI - [Amplification and clinical significance of hTERC gene in the cervical exfoliated cells from natural population in Shenzhen]. AB - OBJECTIVE: To study the amplification of human telomerase RNA component (hTERC) gene in the cervical exfoliated cells from natural population in Shenzhen and to explore its relationship with human pappiloma-virus (HPV) infection, abnormal cervical cytology and cervical intraepithelial neoplasia (CIN). METHODS: Three hundred and eighty-eight women, 30 - 59 year-old and having normal intelligence in a community of Shenzhen, were examined with liquid-based cytology. Human pappiloma-virus (HR-HPV) was tested by hybrid capture II (HC-II) and hTERC gene detection by fluorescence in situ hybridization (FISH). Patients with ASCUS and above lesion, and/or positive HR-HPV results and/or amplification of hTERC gene were examined by colposcopy, multiple biopsies of cervical quadrant and pathology. RESULTS: The frequencies of CIN I, II, III, cervical cancer were 55 (14.18%), 4 (1.03%), 9 (2.32%) and 1 (0.26%) respectively, with the rate of hTERC gene amplification as 8.76%. There were significantly differences of hTERC amplification among the samples with different cytological and histological lesions as well with HPV infection (P < 0.01). (1) The positive rate of HPV infection was 17.01%; the positive rates of hTERC gene amplification were 19.70% in HPV positive and 6.52% in HPV negative samples and the results were significantly different (P < 0.01). (2) Cytologically, the rates of hTERC gene amplification appeared to be as follows: NILM (5.97%), ASCUS (18.75%), LSIL (10.00%), ASC-H (66.67%), HSIL (100.00%). There was a marked increase of hTERC amplification in patients with HSIL and above lesions (P < 0.01). (3) On histology findings, the rates of hTERC gene amplification were as follows: NILM (0%), CIN I (5.45%), CIN II (50.00%), CIN III (77.78%), and invasive carcinoma (100.00%). There was a marked increase of hTERC amplification in patients with CIN II and above lesions (P < 0.01). CONCLUSION: There was a close correlation between amplification of hTERC and histological as well cytological lesions which increased progressively along with the severity of cytological and histological grade. The evidence of hTERC, with or without amplification, might serve as a prognostic indicator to measure the grade of lesion. PMID- 20193235 TI - [A 1:2 matched case-control study on the interaction of HPV16E6 and HLA-DR9 allele to esophageal cancer in Kazakh ethnicity, Xinjiang]. AB - OBJECTIVE: To evaluate the role and the association between HPV16E6 infection and HLA-DR9 immune-associated gene to esophageal cancer (EC) in Kazakh of Xinjiang, China. METHODS: A 1:2 matched case-control study was conducted with 63 cases of EC and 126 controls involved. The controls were matched by sex, nationality, area of residence and age within 5-year difference. HPV16E6 and HLA-DR9 allele were identified by PCR-SSP. Interaction was performed to identify risk factors. RESULTS: HPV16E6 infection and HLA-DR9 allele positive status were the risk factors for EC, with OR values as 2.67 (95%CI: 1.38 - 5.17) and 3.83 (95%CI: 1.48 - 9.96) respectively. The rate of HPV16E6 infection in individuals with HLA-DR9 allele was different from the ones who were HLA-DR9 allele free (chi(2) = 7.57, P = 0.006), with OR value as 5.79 (95%CI: 1.53 - 21.87). In the controls, the rates of HPV16E6 infection were 22.2% and 16.2% among individuals with HLA-DR9 allele atatus as positive or negative, and without statistically significant difference. Interaction analysis showed there was an interaction of HPV16E6 with HLA-DR9 and were higher than the sum of the two factors presented individually. CONCLUSION: In our study, we found that the HLA-DR9 allele and HPV16E6 infection had a function of synergy in the process of malignant transformation of esophageal epithelial cells, and jointly promoting the occurrence and development of EC. PMID- 20193236 TI - [Impact of gene-environment interaction between the C (-344) T polymorphism of CYP11B2 and drinking index on the risk of hypertension under multifactor dimensionality reduction model in Chinese Mongolian population]. AB - OBJECTIVE: To explore the interaction between C (-344) T polymorphism of CYP11B2 and drinking index (DI) as well as their impact on the risk of hypertension in Chinese Mongolian population. METHODS: A total of 1575 Mongolian people aged 20 and older including 562 hypertensive and 1013 normal-tensive from agricultural and pastoral areas in Tongliao city of Inner Mongolia, were included in this study. A cross-sectional survey was conducted to collect data by personal interview with local residents, using a standard questionnaire. Fasting blood samples were drawn and height, weight and blood pressure were measured. The variant genotypes of CYP11B2, ACE and eNOS were identified by PCR assays. Gene environment interactions were analyzed, using multifactor dimensionality reduction (MDR) model. Based on the result of the best MDR model, a multiple logistic regression model was constructed as the final cause-effect interpretative model. RESULTS: The interaction between CYP11B2 variant genotype and drinking index appeared the best MDR model with statistical significance (chi(2) = 66.35, P < 0.01). Testing balance accuracy of the model was 0.604. The cross-validation consistency was 10/10. Data from the final multiple logistic regression based on the MDR model showed that the main effects of both CYP11B2 variant genotype and the DI were not significantly different but the interaction between the genotype (TC) and the DI (90-) was, with regard to hypertension (OR, 10.25; 95%CI, 2.23 - 47.18; P = 0.003). The combined effects between CYP11B2 variant genotype and the DI showed that following indices as: genotype TT or TC combining non-zero drinking index, including genotype (TT) combining the drinking index (> or = 168), the genotype (TT) combining the drinking index (> or = 40), the genotype (TT) combining the drinking index (> or = 1) and the genotype (TC) combining the drinking index (> or = 90), were all risk factors of hypertension when comparing with genotype (CC) combining the drinking index (0), and the ORs (95%CI) appeared to be 2.07 (1.15 - 3.70), 2.35 (1.22 - 4.56), 2.05 (1.07 - 3.94) and 5.56 (2.54 - 12.18) respectively. CONCLUSION: Essential hypertension might positively be affected by the interaction of the C (-344) T polymorphism of CYP11B2 and the drinking index in Chinese Mongolian population. PMID- 20193237 TI - [Association between incidence of idiopathic ventricular tachycardia and risk factors with short-term effects: a case-crossover study]. AB - OBJECTIVE: To explore the transient risks regarding idiopathic ventricular tachycardia (IVT). METHODS: A symmetric bidirectional case-crossover design was used to estimate the short-term risk of IVT. In the case-crossover design each case served as its own matched control while case-period were compared to two control-periods, 7 days before and after the case-period. Ninety-four subjects were recruited from People's Hospital of Jiangsu Province and Affiliated Hospital of Southeast University from Dec. 2007 to Nov. 2008. Generalized estimating equation, with binomial distributed dependent variable and logit link-function, was used to estimate OR and 95%CI. RESULTS: The risk factors that were associated with IVT would include: physical exertion (OR = 2.20, 95%CI: 1.51 - 3.19), in the state of anger (OR = 1.87, 95%CI: 1.07 - 3.27) sad feelings (OR = 3.58, 95%CI: 2.19 - 5.84), or agitation (OR = 3.06, 95%CI: 1.61 - 5.83) and having infection of some kind (OR = 2.25, 95%CI: 1.44 - 3.50). CONCLUSION: Factors as physical Exertion, in the mood of anger, sadness agitation, having some kind of infection were related to IVT. Case-crossover design seemed to be able to identify the risk factors of IVT and its intensity. PMID- 20193238 TI - [Comparison of predictive effect between the single auto regressive integrated moving average (ARIMA) model and the ARIMA-generalized regression neural network (GRNN) combination model on the incidence of scarlet fever]. AB - Application of the 'single auto regressive integrated moving average (ARIMA) model' and the 'ARIMA-generalized regression neural network (GRNN) combination model' in the research of the incidence of scarlet fever. Establish the auto regressive integrated moving average model based on the data of the monthly incidence on scarlet fever of one city, from 2000 to 2006. The fitting values of the ARIMA model was used as input of the GRNN, and the actual values were used as output of the GRNN. After training the GRNN, the effect of the single ARIMA model and the ARIMA-GRNN combination model was then compared. The mean error rate (MER) of the single ARIMA model and the ARIMA-GRNN combination model were 31.6%, 28.7% respectively and the determination coefficient (R(2)) of the two models were 0.801, 0.872 respectively. The fitting efficacy of the ARIMA-GRNN combination model was better than the single ARIMA, which had practical value in the research on time series data such as the incidence of scarlet fever. PMID- 20193239 TI - [A review on assays for detecting antibodies of West Nile virus infection]. PMID- 20193240 TI - [A review on the advancement of epidemiology on hand-foot-mouth disease]. PMID- 20193241 TI - A novel two-stage complete repair method for pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries. AB - BACKGROUND: Pulmonary atresia with ventricular septal defect (PA-VSD) and major aortopulmonary collateral arteries (MAPCAs) remains a challenging complex congenital heart disease nowadays. In the present study, we aimed to develop a two-stage surgical method and to evaluate outcomes of this method in managing PA VSD and MAPCAs. METHODS: Between December 2003 and December 2008, 7 female and 4 male patients between the age of 5 and 10 years who were suffering from PA-VSD and MAPCAs were selected and recruited. The native pulmonary artery trunks were absent in all patients; the lungs were solely supplied by major aortopulmonary collaterals, and the numbers of supplied lung segments ranged from 15 to 20 (17.9 +/- 1.6). There were a total of 43 MAPCAs in all the patients (3 - 5 (3.9 +/- 0.7) MAPCAs per patient). The accumulated Nakata index was (222.9 +/- 29.9) mm(2)/m(2) (ranged from 182 to 272). All the patients underwent two sequential operations. Stage one included left major aortopulmonary collateral unifocalization and modified Blalock-Taussig shunt from left posterior lateral thoracotomy; stage two comprised right unifocalization, ligation of the shunt, followed by ventricular septal defect closure and right ventricular outflow tract reconstruction assisted with cardiopulmonary bypass from midline sternotomy. RESULTS: All the patients survived the initial surgery, but one of them died of low cardiac output syndrome on the third day after the second operation. Postoperative complications included pneumonia in one case and capillary leak syndrome in another. Postoperative oxygen saturation maintained about 95% - 100%, which was significantly higher than pre-operation (P < 0.01). During the follow up period of 3 - 51 (25.4 +/- 15.2) months, there were no late death and no need for re-intervention. All the patients enjoyed their lives with good conditions. CONCLUSIONS: This two-stage complete repair strategy was well-tolerated and effective with good outcome, thus offering an alternative surgical approach in the treatment of PA-VSD and MAPCAs. PMID- 20193242 TI - Surgical treatment of IIIb-T4 lung cancer invading left atrium and great vessels. AB - BACKGROUND: IIIb-T(4) non-small cell lung cancer (NSCLC) is commonly considered a contraindication to surgery, although chemo-radiotherapy also achieves a poor survival rate. We reviewed our experience with T(4) NSCLC patients who underwent surgery to explore the indications and prognostic factors of surgical treatment of lung cancer invading the left atrium and great vessels. METHODS: We investigated a cohort of 105 patients, 79 men and 26 women, who underwent surgery from May 1996 to July 2008. Their pathological staging was T(4)N(0)-(2)M(0). The median age was 59 years, ranging from 36 to 75 years. Patients were grouped based on invading sites: tumors invading the left atrium (LA group), tumors invading the superior vena cava (SVC group), and tumors invading the intrapericardial pulmonary artery (PA group). Patients were further characterized based upon the type of operation, complete resection and incomplete resection groups, and on the lymph node pathological status, N(0), N(1) and N(2) groups. We calculated the overall five-year survival rate. RESULTS: All patients received resection of primary lesions, with partial resection of the left atrium in the LA group (n = 25), angioplasty of superior vena cava in the SVC group (n = 23) and intrapericardial ligation of the pulmonary artery in the PA group (n = 57). Complete resection was possible in 77 patients (73.3%). The overall survival rate of the 105 patients was 41.0% at 5 years; 36.0% for the LA group, 34.8% for the SVC group and 45.6% for the PA group. Pathological N status significantly influenced the overall 5-year survival rate; 61.5% for N(0), 51.1% for the N(1) and 11.8% for the N(2) groups (N(2) group versus N(0) group, P < 0.0001, N(2) versus N(1) group, P < 0.0001). Surgical resection also influenced survival; 49.4% for the complete resection group and 17.9% for the incomplete resection group (P < 0.0001). Cox regression analysis demonstrated that pathological N status was a significant independent predictor of prognosis. CONCLUSIONS: Pathological N status is a significant independent predictor for survival of patients with IIIb-T(4) lung cancer invading the left atrium and great vessels. The completeness of resection has a significant influence on the overall 5-year survival rate. Surgery for T(4) lung cancer may be effective in patients without mediastinal lymph node involvement. PMID- 20193243 TI - Extracorporeal membrane oxygenation during double-lung transplantation: single center experience. AB - BACKGROUND: For patients with end-stage lung diseases, lung transplantation is the final therapeutic option. Sequential double-lung transplantation is recognized as an established procedure to avoid cardiopulmonary bypass (CPB). But some of the sequential double-lung transplantations require CPB support during the surgical procedure for various reasons. However, conventional CPB may increase the risk of bleeding and early allograft dysfunction. Extracorporeal membrane oxygenation (ECMO) is more advantageous than conventional CPB during the perioperative period of transplantation. Replacing traditional CPB with ECMO is promising for those patients needing cardiopulmonary support during a sequential double-lung transplantation procedure. This study aimed to summarize the preliminary experience of ECMO practice in lung transplantation. METHODS: Between November 2002 and October 2008, twelve patients with end-stage lung diseases undergoing sequential double-lung transplantation were subjected to ECMO during the surgical procedure. Eleven patients were prepared for the procedure via transverse thoracostomy (clamshell) and cannulated through the ascending aorta and right atrium for ECMO. The first patient who underwent bilateral thoracotomy for bilateral sequential lung transplantation required emergency ECMO via the femoral artery and vein during the second lung implantation. The Medtronic centrifugal pump and ECMO package (CB1V97R1, Medtronic, Inc., USA) were used for all of the patients. RESULTS: During ECMO, the blood flow rate was set between 1.8 - 2.0 L x m(-2) x min(-1) to keep hemodynamic and oxygen saturation stable; colloid oncotic pressure was maintained at more than 18 mmHg with albumin and hematocrit (HCT) kept at 28% or more. Two patients died early in this series and the other 10 patients were weaned from ECMO successfully. The duration of ECMO was 1.38 - 67.00 hours, and postoperative intubation was 10.5 - 67.0 hours. CONCLUSIONS: As an established technique of cardiopulmonary support, ECMO is helpful to keep hemodynamics stable, while reducing risk factors such as ischemia reperfusion injury, anticoagulation requirement and systemic inflammatory response for sequential double-lung transplantation compared with conventional CPB. PMID- 20193244 TI - Removal of vestibular schwannoma and facial nerve preservation using small suboccipital retrosigmoid craniotomy. AB - BACKGROUND: Vestibular schwannoma, the commonest form of intracranial schwannoma, arises from the Schwann cells investing the vestibular nerve. At present, the surgery for vestibular schwannoma remains one of the most complicated operations demanding for surgical skills in neurosurgery. And the trend of minimal invasion should also be the major influence on the management of patients with vestibular schwannomas. We summarized the microsurgical removal experience in a recent series of vestibular schwannomas and presented the operative technique and cranial nerve preservation in order to improve the rates of total tumor removal and facial nerve preservation. METHODS: A retrospective analysis was performed in 145 patients over a 7-year period who suffered from vestibular schwannomas that had been microsurgically removed by suboccipital retrosigmoid transmeatus approach with small craniotomy. CT thinner scans revealed the tumor size in the internal auditory meatus and the relationship of the posterior wall of the internal acoustic meatus to the bone labyrinths preoperatively. Brain stem evoked potential was monitored intraoperatively. The posterior wall of the internal acoustic meatus was designedly drilled off. Patient records and operative reports, including data from the electrophysiological monitoring, follow-up audiometric examinations, and neuroradiological findings were analyzed. RESULTS: Total tumor resection was achieved in 140 cases (96.6%) and subtotal resection in 5 cases. The anatomical integrity of the facial nerve was preserved in 91.0% (132/145) of the cases. Intracranial end-to-end anastomosis of the facial nerve was performed in 7 cases. Functional preservation of the facial nerve was achieved in 115 patients (Grade I and Grade II, 79.3%). No patient died in this series. Preservation of nerves and vessels were as important as tumor removal during the operation. CT thinner scan could show the relationship between the posterior wall of the internal acoustic meatus and bone labyrinths, that is helpful for a safe drilling of the posterior wall of the internal acoustic meatus. CONCLUSIONS: The goal of every surgery should be the preservation of function of all cranial nerves. Using the retrosigmoid approach with small craniotomy is possible even for large schwannomas. Knowing the microanatomy of the cerebellopontine angle and internal auditory meatus, intraoperating neurophysiological monitoring of the facial nerve function, and the microsurgical techniques of the surgeons are all important factors for improving total tumor removal and preserving facial nerve function. PMID- 20193245 TI - Anterior and middle skull base reconstruction after tumor resection. AB - BACKGROUND: Surgical management of skull base tumors is still challenging today due to its sophisticated operation procedure. Surgeons who specialize in skull base surgery are making endeavor to promote the outcome of patients with skull base tumor. A reliable skull base reconstruction after tumor resection is of paramount importance in avoiding life-threatening complications, such as cerebrospinal fluid leakage and intracranial infection. This study aimed at investigating the indication, operation approach and operation technique of anterior and middle skull base reconstruction. METHODS: A retrospective analysis was carried out on 44 patients who underwent anterior and middle skull base reconstruction in the Department of Neurosurgery at Beijing Tiantan Hospital between March 2005 and March 2008. Different surgical approaches were selected according to the different regions involved by the tumor. Microsurgery was carried out for tumor resection and combined endoscopic surgery was performed in some cases. According to the different locations and sizes of various defects after tumor resection, an individualized skull base soft tissue reconstruction was carried out for each case with artificial materials, pedicled flaps, free autologous tissue, and free vascularized muscle flaps, separately. A skull base bone reconstruction was carried out in some cases simultaneously. RESULTS: Soft tissue reconstruction was performed in all 44 cases with a fascia lata repair in 9 cases, a free vascularized muscle flap in 1 case, a pedicled muscle flap in 14 cases, and a pedicled periosteal flap in 20 cases. Skull base bone reconstruction was performed on 10 cases simultaneously. The materials for bone reconstruction included titanium mesh, free autogenous bone, and a Medpor implant. The result of skull base reconstruction was satisfactory in all patients. Postoperative early stage complications occurred in 10 cases with full recovery after conventional treatment. CONCLUSIONS: The specific characteristics of skull base defects in various regions require different reconstruction materials and methods. The individualized reconstruction based on different skull base defects can achieve satisfactory results. PMID- 20193246 TI - Cerebral microbleeds - prevalence, distribution and risk factors in northeast population without preceding large-area stroke. AB - BACKGROUND: Cerebral microbleeds (CMBs) occur frequently in patients suspected of cerebrovascular disease and they are the principle radiographic findings in patients with sub-clinical neurological impairment. The objective of this study was to assess the prevalence, distribution, severity and associated clinical features of CMBs in a prospective hospital patient based cohort undergoing brain MRI for suspected cerebrovascular disease, excluding cases with known intracranial hemorrhage or prior large-area stroke. METHODS: The study population consisted of 447 patients who were evaluated with T2*-gradient echo sequences to detect the CMBs lesion number, location, and their association with white matter hyperintensities and clinical parameters, including blood pressure. RESULTS: CMB lesions were presented in 95 of the 447 patients (21.3%). The distribution of CMBs was 43.95% cortical, 19.77% thalamic, 14.41% in the brainstem, 11.58% cerebellar, 6.21% periventricular white matter, 5.64% involving the basal ganglia regions, and 0.28% involving the hippocampus. There was a statistically significant association between the presence of CMBs and advancing age (adjusted OR 2.082, P < 0.01), the severity of hypertension (adjusted OR 2.208, P < 0.01). Also there was a statistically significant (P < 0.01) correlation between the presence of CMBs and the severity of hypertension and white matter lesions. CONCLUSIONS: CMBs occur frequently in patients with no prior large-area stroke who were referred for brain MRI for suspected cerebrovascular disease. The severity of CMBs correlates with the severity of hypertension and the presence of cerebral white matter changes detected by MRI. PMID- 20193247 TI - Otoendoscopic treatment of hidden lesions in otomastoiditis. AB - BACKGROUND: Surgical treatments for chronic suppurative and cholesteatoma otitis media have been discussed for several decades, but recurrences still occur because of the complex dissection required and hidden lesions associated with otomastoiditis. This study investigated the technology and strategy behind the use of otoendoscopic-assisted otosurgery. METHODS: We reported on hidden lesions in 32 ears of patients with otomastoiditis between November 2006 and January 2009. All the patients were treated with the aid of an otoendoscope. The advantages of otoendoscopy, including multi-angle light scattering, aperture illumination, and magnification of the local operative field, were utilized in otologic microsurgery, and otoendoscopic operative techniques were introduced for operative sites such as the epitympanum, aditus of the antrum, facial recess, sinus tympani and the mastoid tip. RESULTS: All patients were followed up from 3 months to 2 years after surgery. All patients recovered well within 3 months following surgery, except for one case of epithelialization of the mastoid cavity occurring 6 months after surgery for cholesteatoma on the cerebellar surface and another case with Bezold's abscess, hyperplastic granulation tissue developed at the antrum. CONCLUSIONS: Otoendoscopy can overcome the technical deficiency of rectilinearity of the visual axis associated with otomicroscopic illumination, which presents a problem when dealing with otomastoiditis lesions in hidden areas. This technique allows such lesions within the complex three-dimensional structure to be visualized and cleaned. Otoendoscopy thus has significant potential for improving the quality of surgery and reducing the risk of postoperative recurrence. PMID- 20193248 TI - Arthroscopic treatment for osteochondral lesions of the talus: analysis of outcome predictors. AB - BACKGROUND: Compared with traditional arthrotomy procedures, arthroscopic treatment for osteochondral lesions of the talus has some advantages. However, there has been considerable debate about the outcome predictors for this surgical technique. This study aimed to investigate the outcomes of arthroscopic treatment for osteochondral lesions of the talus, and analyze its outcome predictors. METHODS: Clinical data of 48 patients with osteochondral lesions of the talus who underwent ankle arthroscopy were studied. Arthroscopic debridement was performed on all patients, and microfracture was also performed in 36 cases. Scores on a subjective satisfaction questionnaire, visual analog scale (VAS) for pain, and the American Orthopedic Foot & Ankle Society (AOFAS) ankle and hindfoot scores were obtained before and after surgery. RESULTS: Five patients lost to follow up. The other forty-three patients, 8 of whom were athletes, were followed up for an average of 23.9 months. The average AOFAS post-operative score was 90.16 +/- 9.96, compared with 70.81 +/- 6.96 before surgery (t = 9.353, P < 0.001). The VAS pain score after the operation (2.51 +/- 2.45) was significantly lower than that before the operation (6.95 +/- 1.40) (t = 8.647, P < 0.001). Of the 43 patients, 35 (81.4%) had good or excellent results. There was no significant difference in outcome between the medial and lateral groups (z = 0.205, P = 0.838), while a better outcome was found with lesions smaller than 10 mm than those with larger lesions (z = 2.199, P = 0.028). Age, sex, athletic profession and location of the lesion did not significantly correlate with outcomes. CONCLUSIONS: Arthroscopic treatment is effective and safe for osteochondral lesions of the talus. A strong correlation was found between the size of the lesion and successful outcome. PMID- 20193249 TI - Perichondrium/cartilage composite graft for repairing large tympanic membrane perforations and hearing improvement. AB - BACKGROUND: The main risk factors for postoperative failure in tympanoplasties are large perforations that are difficult to repair, annular perforations, and a tympanic membrane (TM) with extensive granular myringitis that require middle ear exploration and mastoidectomy. The aim of this study was to investigate a novel technique of perichondrium/cartilage composite graft for repairing the large TM perforation in the patient of otitis media. METHODS: Retrospective chart reviews were conducted for 102 patients with large tympanic membrane perforations, who had undergone tympanoplasty from August 2005 to August 2008. Tympanoplasty or tympanomastoidectomy using a perichondrium/cartilage composite graft was analyzed. The tragal or conchal perichondrium/cartilage was used to replace the tympanic membrane in patients. RESULTS: Patients aged from 13 to 67 years were followed up in average for 24 months (10 - 36 months). Seventy-four ears (72.61%) were used the tragal perichondrium/cartilage as graft material and 27 ears (27.39%) were used the conchal perichondrium/cartilage. Graft take was successful in all patients. Postoperative complications such as wound infection, hematoma, or sensorineural hearing loss were not identified. Nine patients (8.82%) had the partial ossicular replacement prosthesis, 14 patients (13.72%) using the autologous curved incus and 79 patients (77.45%) without prosthesis. Successful closure occurred in 92% of the ears. A total of 85.8% patients achieved a postoperative hearing improvement. CONCLUSIONS: The graft underlay tympanoplasty using perichondrium/cartilage composite is effective for the majority of patients with large perforation. The hearing was improved even if the mastoidectomy was required in the patients with otitis media with extensive granulation. PMID- 20193251 TI - A new diagnostic algorithm for vascular cognitive impairment: the proposed criteria and evaluation of its reliability and validity. AB - BACKGROUND: Vascular cognitive impairment (VCI) is considered to be the most common pattern of cognitive impairment. We aimed to devise a diagnostic algorithm for VCI, and evaluate the reliability and validity of our proposed criteria. METHODS: We based our new algorithm on previous literature, a Delphi consensus method, and preliminary testing. First, successive 100 patients with cerebrovascular disease (CVD) in hospital underwent a structured medical examination. Twenty-five case vignettes fulfilled the proposed criteria of diagnosis for probable or possible VCI were divided into three subtype categories: vascular cognitive impairment, no dementia (VCIND), vascular dementia (VaD) or mixed VCI/Alzheimer's disease (AD). Inter-raters reliability was assessed using a Fleiss kappa analysis. Convergent validity was also evaluated by correlation coefficients (r) between the proposed key points for each subtype and the currently accepted criteria. Forty-five patients with probable VCI were examined to determine the accuracy of identification for each subtype. RESULTS: The proposed criteria showed clinical diagnostic validity for VCI, and were able to define probable, possible and definite VCI, three VCI subtypes, and vascular causes. There was good consensus between experts (Cronbach's alpha = 0.96 for both rounds). Significant moderate to good items-total correlations were found for two questionnaires (50-r range, 0.40 - 0.97 and 0.41 - 0.99, respectively). Significant slight and moderate inter-raters reliability were obtained for VCI (k = 0.13) and three VCI subtypes (k = 0.45). Furthermore, good convergent validity was observed in a comparison of significant correlations between criteria: good (4-r range, 0.75 - 0.92) to perfect (3-r = 1.00) validity for the VCIND subtype, and moderate to good validity for the VaD subtype (1-r = 0.46; 5-r range, 0.76 - 0.92) and for the mixed VCI/AD subtype (r = 0.92 and 1.00; 4-r range, 0.47 - 0.70). Importantly, the area under receiver operating characteristic (ROC) curves for the subtypes of VCIND, VaD and mixed VCI/AD were 0.85, 0.67 and 0.93, respectively. CONCLUSION: Our results suggest that the new VCI diagnostic algorithm might be a suitable clinical approach for assessing stroke patients. PMID- 20193250 TI - Identification of seven novel mutations in the factor VIII gene in 18 unrelated Chinese patients with hemophilia A. AB - BACKGROUND: Hemophilia A (HA) is an X-linked inherited bleeding disorder caused by decreased activity of factor VIII (FVIII) due to heterogenous mutations in the FVIII coding gene (F8). The type of mutation plays an important role in the FVIII inhibitor formation. To date, several studies on the spectra of F8 defects have been performed in Western populations, but similar studies in Asian races are scarce. Here, we reported the distribution of the F8 gene mutations in 18 unrelated Chinese patients with HA. METHODS: Intron 22 and intron 1 inversions in the F8 gene were screened in 158 unrelated patients with HA using a long-distance PCR and multiplex PCR method. Direct sequencing of the coding region of the F8 gene was used to identify the mutations responsible for HA in 18 unrelated Chinese HA patients who were negative for intron 22 and intron 1 inversions; sequences were compared with the HAMSTeRS database. A clotting method was used to assay the FVIII activity level and the Bethesda assay was used to detect the FVIII inhibitor. RESULTS: A total of 18 different HA F8 mutations were identified, seven of which were described for the first time. These novel mutations included five small deletions, one point mutation and one small insertion. One novel mutation (4382-3 AC deletion) was associated with inhibitor development. CONCLUSION: These data extend our insight into the mechanisms by which novel amino acid mutations may lead to HA and how the HA patient genotypes influence the risk of FVIII inhibitor. PMID- 20193253 TI - Pharmacokinetics of aminophylline delivered to the small intestine and colon using remote controlled capsules. AB - BACKGROUND: A patented remote controlled capsule (RCC) has recently been developed to provide noninvasive drug delivery to selected sites in the human gut that allows assessment of regional gastrointestinal (GI) drug absorption under a normal physiological environment. The objective of this study was to investigate the rate and extent of aminophylline absorption after site-specific delivery of the drug in the GI tract using RCC and a magnetic marker monitoring (MMM) technique. METHODS: This study was conducted in twelve healthy male subjects, in a three-treatment, randomized, crossover manner with a 7-day washout. Eligible subjects received a 150 mg aminophylline dose through an oral administration, or via a remote controlled capsule, delivered to the small bowel or ascending colon. MMM was employed to monitor the GI transit of the RCC, and the radio-frequency signal was used to activate capsules at target sites. Blood samples were obtained at regular intervals until 24 hours post dose/activation. Plasma theophylline concentrations were measured by a TDx System Analyzer. A comparison of the PK profile with the oral dosing route of aminophylline was performed after delivery to the small bowel and colon. RESULTS: The RCC was well tolerated in volunteers. The mean capsule activation time for the small bowel and ascending colon was 2.07 hours and 6.08 hours post dose. Aminophylline had similar absorption profiles from the small bowel compared with the stomach, with an area under the curve (AUC(t)) ratio of 92% vs. the stomach, but a lower absorption profile from the ascending colon, with an AUC(t) ratio of 47.2% vs. the stomach. CONCLUSIONS: The proprietary of the RCC and MMM technique offer the opportunity to obtain data on the intestinal absorption of a drug in humans under noninvasive conditions. Aminophylline is rapidly and efficiently absorbed from the small bowel. While colonic absorption was limited by the poor water condition although effective absorption was observed from the ascending colon. This provides an opportunity for rational development of modified-release formulations as well as alternative dosage forms. PMID- 20193254 TI - Development of a real-time PCR method for the detection of bacterial colonization in rat models of severe acute pancreatitis. AB - BACKGROUND: Techniques for the fast and accurate detection of bacterial infection are critical for early diagnosis, prevention and treatment of bacterial translocation in clinical severe acute pancreatitis (SAP). In this study, the availability of a real-time PCR method in detection of bacterial colonization in SAP rat models was investigated. METHODS: Samples of blood, mesenteric lymph nodes (MLN), pancreas and liver from 24 specific pathogen-free rats (8 in a control group, 16 in a SAP group) were detected for bacterial infection rates both by agar plate culture and a real-time PCR method, and the results were made contrast. RESULTS: Bacterial infection rates of the blood, MLN, pancreas and liver in the SAP group and the control group by the two different methods were almost the same, which were 5/16, 12/16, 15/16, 12/16 in the SAP group compared with 0/8, 1/8, 0/8, 0/8 in the control group by agar plate culture, while 5/16, 10/16, 13/16, 12/16 and 0/8, 1/8, 0/8, 0/8 respectively by a real-time PCR method. Bacterial number was estimated by real-time PCR, which showed that in the same mass of tissues, the pancreas contained more bacteria than the other three kinds of organs in SAP rats (P < 0.01), that may be due to the edema, necrosis and hemorrhage existing in the pancreas, making it easier for bacteria to invade and breed. CONCLUSION: Fast and accurate detection of bacterial translocation in SAP rat models could be carried out by a real-time PCR procedure. PMID- 20193255 TI - Bond strength of different adhesives to normal and caries-affected dentins. AB - BACKGROUND: Currently, several systems of dentin substrate-reacting adhesives are available for use in the restorative treatment against caries. However, the bond effectiveness and property of different adhesive systems to caries-affected dentin are not fully understood. The objective of this study was to evaluate the bond strength of different adhesives to both normal dentin (ND) and caries affected dentin (CAD) and to analyze the dentin/adhesive interfacial characteristics. METHODS: Twenty eight extracted human molars with coronal medium carious lesions were randomly assigned to four groups according to adhesives used. ND and CAD were bonded with etch-and-rinse adhesive Adper Single Bond 2 (SB2) or self-etching adhesives Clearfil SE Bond (CSE), Clearfil S(3) Bond (CS3), iBond GI (IB). Rectangular sticks of resin-dentin bonded interfaces 0.9 mm(2) were obtained. The specimens were subjected to microtensile bond strength (microTBS) testing at a crosshead speed of 1 mm/min. Mean microTBS was statistically analyzed with analysis of variance (ANOVA) and Student-Newman-Keuls tests. Interfacial morphologies were analyzed by Scanning Electron Microscopy (SEM). RESULTS: Etch-and-rinse adhesive Adper(TM) Single Bond 2 yielded high bond strength when applied to both normal and caries-affected dentin. The two-step self-etching adhesive Clearfil SE Bond generated the highest bond strength to ND among all adhesives tested but a significantly reduced strength when applied to CAD. For the one-step self-etching adhesives, Clearfil S(3) Bond and iBond GI, the bond strength was relatively low regardless of the dentin type. SEM interfacial analysis revealed that hybrid layers were thicker with poorer resin tag formation and less resin-filled lateral branches in the CAD than in the ND for all the adhesives tested. CONCLUSION: The etch-and-rinse adhesive performed more effectively to caries-affected dentin than the self-etching adhesives. PMID- 20193256 TI - Regulation of estrogen receptors alpha and beta in human breast carcinoma by exogenous leptin in nude mouse xenograft model. AB - BACKGROUND: It is essential to clarify the interactions of hormones during the progression of human breast cancer. This study examined the effects of exogenous human leptin on estrogen receptor (ER) alpha and beta in human breast tumor tissue in a nude mouse xenograft model. METHODS: We created nude mice xenografts of MCF-7 human breast cancer cells, and randomly divided them into an experimental group and a control group. The mice in experimental group were injected subcutaneously around tumors with human leptin, while the control group were injected with the same dose of normal saline. A real-time RT-PCR assay was developed to quantify the mRNA of ERalpha, beta in the tumor tissues. Western blotting analyses were used to assess the relative quantities of the ERalpha, beta proteins. RESULTS: Leptin-treated xenografted nude mice were successfully established. The amount of ERalpha mRNA was significantly higher in the leptin group than in the control group (P < 0.01), while the amount of ERbeta mRNA was significantly lower in the leptin group than in the control group (P < 0.01). Western blotting analyses revealed that the ERalpha protein level was significantly higher in the leptin group than in the control group (P < 0.01), while the ERbeta protein level was significantly lower in the leptin group than in the control group (P < 0.01). CONCLUSIONS: Nude mouse xenograft model can be safely and serviceably treated with human leptin by subcutaneous injections around tumor. ERalpha, beta were both targets of leptin in breast cancer. Leptin can up-regulate the expression of ERalpha and down-regulate the expression of the ERbeta in human breast tumor. PMID- 20193257 TI - Dexamethasone impairs the differentiation and maturation of murine dendritic cells by Toll-like receptor 4-nuclear factor-kappaB pathway. AB - BACKGROUND: Recent studies have demonstrated that dexamethasone (DEX) interferes with immune responses by targeting key functions of dendritic cells (DCs) at the earliest stage. However, the cellular and molecular mechanisms are still incompletely understood. This study aimed to explore the possible mechanisms by investigating the roles of DEX on differentiation, maturation & function of murine DCs and the effects of DEX on DCs via Toll-like receptor 4 (TLR4)-nuclear factor (NF)-kappaB mediated signal pathway. METHODS: Immature DCs (imDCs) were cultured from murine bone marrow (BM) cells. We added DEX into culture medium at different time. The expression of CD11c, CD86 and I-A(b) (mouse MHC class II molecule) was determined by flow cytometry. We determined the expression of NF kappaB and its inhibitory protein I-kappaBalpha by electrophoretic mobility shift assay (EMSA) and Western blotting, respectively. The productions of interleukin (IL)-12p70 and IL-10 in cell culture supernatants were determined by enzyme linked immunosorbent assay (ELISA). RESULTS: DEX impaired differentiation of DCs from murine bone marrow progenitors, and inhibited lipopolysaccharide (LPS) induced maturation of DCs. DEX significantly inhibited NF-kappaB expression of normal DCs, the higher the DEX concentration or the longer the DEX treatment time, the more obvious the effect. However, DEX had little effect on LPS-induced NF-kappaB activation, and partially impaired LPS-induced I-kappaBalpha degradation. DEX significantly decreased LPS induced IL-12p70 production by DCs. Interestingly, our results showed a synergistic effect between DEX and LPS on the production of IL-10 by DCs. CONCLUSIONS: DEX inhibits the differentiation and maturation of murine DCs involved in TLR4-I-kappaB-NF-kappaB pathway, and also indirectly impairs Th1 development and interferes with the Th1-Th2 balance through IL-12 and/or IL-10 secretion by DCs. PMID- 20193258 TI - Neuronal differentiation of PC12 cells induced by sciatic nerve and optic nerve conditioned medium. AB - BACKGROUND: Previous work has shown that optic nerve and sciatic nerve conditional medium had neurotrophic activity on neurons. In order to find if the optic nerve conditioned media (CM) had a similar activity to make PC12 cells differentiate as sciatic nerve CM did, we explored the neurotrophic activity in optic nerve CM in the same in vitro system and compared the neurotrophin expression levels in optic and sciatic nerves under both conditions. METHODS: PC12 cells were used to examine the effects of neurotrophins secreted by the sciatic nerve and optic nerve. RT-PCR and real-time QPCR showed that the sciatic nerve and optic nerve produced a range of neurotrophins including nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3). RESULTS: The effects of sciatic nerve and optic nerve CM on neurite outgrowth were tested against a range of neurotrophins, and they had different neuritogenic activities. Only NGF and sciatic nerve CM had obvious neuritogenic activities, although the concentration of NGF in the sciatic nerve CM was very low. CONCLUSIONS: Our experiment showed that sciatic nerve CM had a higher neurotrophic activity on PC12 cells than optic nerve CM. These results suggested that peripheral nervous system (PNS) and central nervous system (CNS) had different expression levels of neurotrophin, which may in part explain the lack of ability to regenerate the CNS. PMID- 20193259 TI - Rapamycin enhances the susceptibility of both androgen-dependent and -independent prostate carcinoma cells to docetaxel. AB - BACKGROUND: Docetaxel (DOC) therapy is well tolerated and shows high response rates in patients with hormone refractory prostate cancer (HRPC). There are many reports on the effect of rapamycin (RPM) on the treatment of carcinogenesis. The goal of this study was to test whether RPM could enhance the susceptibility of both androgen-dependent and -independent prostate carcinoma cells to DOC. METHODS: Prostate cancer (PC) cell lines (LNCap, PC3 and AILNCap) were cultured and treated with RPM and DOC alone or in combination. The effects of therapeutic agents on cells were determined by the WST-1 assay. Apoptosis induction was confirmed by flow cytometric analysis. The apopcyto caspase colorimetric assay kit was applied to measure the activities of caspases 3 and 9. The antitumor effects of RPM and DOC against PC cells were also assessed in nude mice using four randomized groups: control, RPM, DOC and combination drug therapy by measuring tumor size. All the animals tolerated both RPM and DOC without significant weight loss. RESULTS: RPM and DOC caused dosage-dependent growth suppression of PC cells. RPM could increase the susceptibility of PC cells to DOC significantly, and combined treatment with RPM and DOC caused synergistic growth suppression in all examined PC cell lines by isobolographic analysis. Both RPM and DOC significantly induced apoptosis in a dosage-dependent manner. RPM (10 nmol/L), DOC (1 nmol/L), and combined treatment induced apoptosis rate were 8%, 17% and 38%, respectively (the control was 2%). RPM could promote the apoptosis induced by DOC in PC cell lines. Both RPM and DOC significantly increased the caspase activity in a dosage-dependent manner. The relative activities of caspase 9 in control, RPM, DOC and RPM + DOC groups were 0.22 +/- 0.02, 0.36 +/- 0.06, 0.47 +/- 0.05 and 0.84 +/- 0.08, respectively. The relative activities of caspase 3 were 0.21 +/- 0.02, 0.24 +/- 0.05, 0.42 +/- 0.06 and 0.81 +/- 0.09, respectively. Either RPM or DOC alone significantly inhibited the growth of PC cells in nude mice compared to the control. The combination of RPM and DOC produced a significant reduction in tumor volume when compared to RPM or DOC alone. After 5-week treatment, the tumor sizes of LNCap in control, RPM, DOC and RPM + DOC groups were (570 +/- 56) mm(3), (412 +/- 41) mm(3), (425 +/- 46) mm(3) and (221 +/- 26) mm(3), respectively. CONCLUSIONS: RPM could significantly increase the susceptibility of both androgen-dependent and -independent PC cells to DOC; the synergy of RPM and DOC was demonstrated. RPM enhanced the DOC-induced upregulation of caspase activity, resulting in an increasing number of cells in sub-G1 phases. The synergy of the combined treatment might be observed in both androgen-dependent and -independent PC cell lines. PMID- 20193260 TI - Fluorine-fixing efficiency on calcium-based briquette: pilot experiment, demonstration and promotion. AB - BACKGROUND: The fluorosis derived from coal burning is a very serious problem in China. By using fluorine-fixing technology during coal burning we are able to reduce the release of fluorides in coal at the source in order to reduce pollution to the surrounding environment by coal burning pollutants as well as decrease the intake and accumulating amounts of fluorine in the human body. The aim of this study was to conduct a pilot experiment on calcium-based fluorine fixing material efficiency during coal burning to demonstrate and promote the technology based on laboratory research. METHODS: A proper amount of calcium based fluorine sorbent was added into high-fluorine coal to form briquettes so that the fluorine in high-fluorine coal can be fixed in coal slag and its release into atmosphere reduced. We determined figures on various components in briquettes and fluorine in coal slag as well as the concentrations of indoor air pollutants, including fluoride, sulfur dioxide and respirable particulate matter (RPM), and evaluated the fluorine-fixing efficiency of calcium-based fluorine sorbents and the levels of indoor air pollutants. RESULTS: Pilot experiments on fluorine-fixing efficiency during coal burning as well as its demonstration and promotion were carried out separately in Guiding and Longli Counties of Guizhou Province, two areas with coal burning fluorosis problems. If the calcium-based fluorine sorbent mixed coal was made into honeycomb briquettes the average fluorine-fixing ratio in the pilot experiment was 71.8%. If the burning calcium based fluorine-fixing bitumite was made into a coalball, the average of fluorine fixing ratio was 77.3%. The concentration of fluoride, sulfur dioxide and PM10 of indoor air were decreased significantly. There was a 10% increase in the cost of briquettes due to the addition of calcium-based fluorine sorbent. CONCLUSIONS: The preparation process of calcium-based fluorine-fixing briquette is simple yet highly flammable and it is applicable to regions with abundant bitumite coal. As a small scale application, villagers may make fluorine-fixing coalballs or briquettes by themselves, achieving the optimum fluorine-fixing efficiency and reducing indoor air pollutants providing environmental and social benefits. PMID- 20193261 TI - A comparative study of buccal mucosa graft and penile pedical flap for reconstruction of anterior urethral strictures. PMID- 20193263 TI - Acute myocardial infarction mimicking squamous cell lung cancer with bone metastases due to hypercalcemia: a case report. PMID- 20193264 TI - A giant cystic adenomatoid tumor of the adrenal gland: a case report. PMID- 20193265 TI - Combination regimen of leflunomide plus methylprednisolone in a female patient with reactive arthritis and concomitant IgA nephropathy. PMID- 20193266 TI - Images for diagnosis. CD4+CD56+ hematodermic neoplasm in a child. PMID- 20193267 TI - Images for diagnosis. A vulva mastocytoma having grown for eighteen years. PMID- 20193268 TI - [A novel strategy for anti-angiogenesis in gastric carcinoma: Delta-like ligand 4/Notch signaling pathway]. PMID- 20193269 TI - [The lab diagnosis of Gaucher disease should be pay more attention]. PMID- 20193270 TI - [Mechanisms of apoptosis induced by trichloroethylene in normal human epidermis keratinocytes]. AB - OBJECTIVE: To explore the potential mechanism of trichloroethylene (TCE)-induced apoptosis in normal human epidermis keratinocyte (NHEK) by assaying the Caspase activities, mitochondrial membrane potential (DeltaPsim) and apoptosis in vitro. METHODS: NHEK was exposed to TCE and Caspases-3, 8 and 9 activities were determined using a commercial assay kit. Apoptosis and DeltaPsim were detected by flow cytometry (FCM) after double-stained with annexin-V and PI, Rh123 and PI respectively. NHEK was pretreated with inhibitor of Caspase-3 or 9 to verify the activation of Caspases by TCE treatment. RESULTS: Various dose of TCE exposure could increase the Caspases-3 and 9 activities in dose- and time-dependent way. There was marked difference between TCE-treated group and control at 12 or 24 h. But no significant influence of Caspase-8 activity was evoked. 0.125, 0.25, 0.5, 1.0 and 2.0 mmol/L TCE treated NHEK 4 h then cultured for 12 h. Annexin-V(+)/PI( ) proportion were (20.1 +/- 4.1)%, (30.0 +/- 7.5)%, (42.1 +/- 8.2)%, (56.0 +/- 6.1)% and (79.1 +/- 4.3)% respectively. There was marked difference between TCE treated group except for 0.125 mmol/L and control (9.4 +/- 3.0)% (all P < 0.05). FITC(+)/PI(-) proportion were marked positive correlation with Caspase-3 and 9 activities, r = 0.786, 0.736 (both P < 0.05). Caspase-3 activities had also a marked positive correlation with Caspase-9 activities, r = 0.845 (P < 0.05). There was no correlation with Caspase-8 activities. Pretreatment for 1 h with 100 micromol/L Z-DEVD-FMK decreased the Caspase-3 activities from (0.963 +/- 0.043) to (0.349 +/- 0.045) nmol pNA * min(-1) * ml(-1), annexin-V(+)/PI(-) proportion decreased from (80.0 +/- 5.5)% to (16.3 +/- 3.2)% in 2.0 mmol/L TCE treated NHEK with a significant difference (P < 0.01), but there was no change of Caspase-9 activities. 100 micromol/L Z-LEHD-FMK pretreatment decreased the Caspase-3 activities to (0.338 +/- 0.011) nmol pNA * min(-1) * ml(-1), annexin-V(+)/PI(-) proportion decreased to (16.1 +/- 1.7)% in 2.0 mmol/L TCE treated NHEK. And the Caspase-9 activities decreased from (0.821 +/- 0.031) to (0.240 +/- 0.043) nmol pNA * min(-1) * ml(-1) with a significant difference (P < 0.01). NHEK was cultured for 4, 8, 12, 24 h after a 4-hour treatment with 2.0 mmol/L TCE. Rhod123 fluorescence intensity (FI) were respectively with a marked decrease as compared with 0 h (18.7 +/- 0.5, all P < 0.01). At 0.125, 0.5 and 2.0 mmol/L TCE treated NHEK for 4 h then cultured 8 h, Rh123 FI were 16.1 +/- 0.5, 12.1 +/- 0.6 and 8.1 +/- 0.6 with a marked decrease as compared with control (18.1 +/- 0.5, all P < 0.01). CONCLUSION: TCE-induced NHEK apoptosis is mediated intrinsically through the mitochondrial pathway of the decrease of DeltaPsim and the Caspase-9 dependent activation of Caspase-3. PMID- 20193271 TI - [Influence of Delta-like ligand 4/Notch signal transduction pathway upon the biological behavior of human umbilical vein endothelial cells]. AB - OBJECTIVE: To study the influence of inhibiting Delta-like ligand 4 (Dll4)/Notch signal transduction pathway upon the biological behavior of human umbilical vein endothelial cells (HUVEC). METHODS: Used rAAV vectors expressing an active small interfering RNA (siRNA) (vector 6) targeting the Dll4 (rAAV-Dll4-shRNA) to infect HUVEC. And an empty plasmid (rAAV-EGFP) was infected into the same cell line as control group. The stable transfection and expression of Dll4 mRNA in HUVEC were determined by semi-quantitative RT-PCR. The protein expression of Dll4 was examined by Western blotting. Distribution of cell cycle was assessed by flow cytometry. The cell growth was analyzed by MTT assay. HUVEC were separated by type I collagen and cultured in a three-dimensional culture system for tubule like structure (TLS) formation. RESULTS: Compared with the negative control cells, semi-quantitative RT-PCR and Western blotting showed the expression of Dll4 mRNA (0.636 +/- 0.082, 0.972 +/- 0.022 vs 0.948 +/- 0.046) and protein (0.632 +/- 0.052, 2.016 +/- 0.048 vs 1.946 +/- 0.066) were down-regulated in the stable cell (P = 0.024, 0.033). The rAAV vectors expressing an active small interfering RNA (siRNA) targeting the Dll4 effectively stimulated HUVEC cell growth and proliferation while empty plasmid had no such specific effect. The proliferation index of experimental group was (39.9 +/- 2.2)% versus untreated group (25.7 +/- 4.5)% (P = 0.036). TLS formation was significantly induced by rAAV vector. And the average length of TLS were more than those of control group (12.5 +/- 0.5, 8.7 +/- 7.7, 8.5 +/- 3.0, P = 0.028). CONCLUSION: The inhibiting Dll4/Notch signal transduction pathway stimulates the proliferation of HUVEC and facilitates the angiogenesis. Interference with Dll4/Notch signaling may be particularly desirable in tumors with highly induced Dll4/Notch pathway. PMID- 20193272 TI - [Effect of Abl-interacting protein 1 overexpression upon human gastric cancer cell proliferation in vitro]. AB - OBJECTIVE: To investigate the expression of Abl-interacting protein 1 (ABI1) in normal gastric mucosal cell line GES-1 and gastric cancer cell line AGS, and the effects of ABI1 gene overexpression upon the proliferation of human gastric cancer cell AGS in vitro. METHODS: Firstly the ABI1 expression in GES-1 and AGS cells were identified by immunohistochemistry, immunofluorescence, RT-PCR, real time PCR and Western blot. Secondly human gastric cancer cell line AGS was cultured and transfected with recombinant MSCV-GFP-ABI1 plasmid or blank plasmid MSCV-GPF. Real-time PCR and Western blot were used to detect the mRNA and protein expression of ABI1. And lastly the cell proliferation was detected by CCK-8 assay. RESULTS: ABI1 was expressed both in normal gastric mucosal cell line GES-1 and in gastric cancer cell line AGS. Compared to GES-1 cells, the ABI1 expression in AGS cells was lowered significantly. There were no significant differences in the ABI1 mRNA and protein expression between the AGS and AGS-MSCV-GFP groups. Compared to those of the AGS group, the ABI1 mRNA expression levels of the AGS MSCV-GFP-ABI1 group increased by 1.87 times (P = 0.002). The protein expression levels of the AGS-MSCV-GFP-ABI1 group were remarkably higher than those of the AGS and AGS-MSCV-GFP groups (P = 0.002). CCK-8 assay showed that there were no significant differences in the proliferation rates at different time points between the AGS and AGS-MSCV-GFP groups. However, the proliferation rates at the time points of 24, 48, 72 and 96 hours of the AGS-MSCV-GFP-ABI1 were 1.46 +/- 0.31, 4.75 +/- 0.12, 6.62 +/- 0.32 and 8.96 +/- 0.27 respectively. And they were significantly lower than the proliferation rates of the AGS and AGS-MSCV-GFP groups (P < 0.01). CONCLUSION: ABI1 gene is down-regulated in gastric cancer cells. The ABI1 overexpression effectively inhibits the proliferation in human gastric cancer cell lines. It suggests that ABI1 may be involved in gastric cancer pathogenesis by regulating the proliferation of gastric carcinomas cells. PMID- 20193273 TI - [Effect of ERK/AP-1 signaling pathway on proliferation of hepatoma cells induced by PAR-2 agonists]. AB - OBJECTIVE: To investigate the expression of protease activated receptor-2 (PAR-2) in human HepG2 hepatoma cells and elucidate the effects of trypsin and PAR-2 agonist peptide SLIGKV-NH(2) upon the proliferation of hepatoma cells and its intracellular signaling mechanism. METHODS: PAR-2 protein and mRNA expression were detected by immunofluorescence and RT-PCR. The cells were treated with SLIGKV-NH(2), trypsin, reverse PAR-2 agonist peptide VKGILS-NH(2) or PD98059. The changes of cell cycle distribution were evaluated by flow cytometry. The proliferative potential of HepG2 cells was estimated by MTT. The changes of PAR 2, c-fos and PCNA mRNA expression were detected by RT-PCR. The changes of c-fos and PCNA protein expression were detected by Western blotting. RESULTS: PAR-2 protein and mRNA were expressed in HepG2 cells. PAR-2 mRNA expression (PAR-2/beta actin) were 0.70 +/- 0.04 and 0.99 +/- 0.05 respectively in cells treated with trypsin and SLIGKV-NH(2). They were both significantly higher than that in the control group (0.35 +/- 0.05, F = 135.534, P < 0.01). Percent G(0)/G(1) phase of HepG2 cells treated with trypsin or SLIGKV-NH(2) were significantly lower than those in the control group [(56.11 +/- 0.85)%, (57.85 +/- 0.46)% vs (79.12 +/- 0.67)%, both P < 0.01] Percent S phase, G(2)/M phase and proliferation index (PI) of HepG2 cells treated with trypsin or SLIGKV-NH(2) were significantly elevated (P < 0.01). The proliferation-enhancing effects and the up-regulation of mRNA and protein of c-fos and PCNA induced by trypsin or SLIGKV-NH(2) were significantly blocked by pretreatment with PD98059 (P < 0.01). There was no statistical significance in proliferation of HepG2 cells between the reverse PAR-2 agonist peptide VKGILS-NH(2) and control group (P > 0.05). CONCLUSION: PAR-2 is expressed in HepG2 hepatoma cells. PAR-2 activation induced by trypsin or SLIGKV-NH(2) promotes the proliferation of HepG2 cells partially via the ERK/AP-1 pathway. PMID- 20193274 TI - [Association between genetic polymorphism of UGT1A7 and susceptibility of bladder cancer]. AB - OBJECTIVE: To investigate the association between genetic polymorphism of UGT1A7 and susceptibility of bladder cancer. METHODS: Based upon a case-control study, UGT1A7 polymorphisms were determined by the semi-nested polymerase chain reaction (SN-PCR) and allele-specific polymerase chain reaction (AS-PCR) in 208 cases with bladder cancer and 205 non-tumor controls. Risks were evaluated by unconditional logistic regression analysis. RESULTS: The frequency of variant homozygous genotype in cases (20.7%) was higher than that in controls (12.2%) and the difference was statistically significant [P < 0.05, OR = 2.16 (1.18 - 3.96)]. The frequency of variant allele (*)3 in cases was higher than that in controls (27.9%, 20.5% respectively) and the difference was statistically significant [P = 0.009, OR = 1.56 (95%CI: 1.12 - 2.18)]. The smokers with variant homozygous and heterozygous genotypes showed an increased risk of bladder cancer compared with those with wild genotype [2.16 (95%CI: 1.07 - 4.36), 2.64 (95%CI: 1.02 - 6.80) respectively]. There was no association between the UGT1A7 polymorphisms and the pathological grade and clinical stage of bladder cancer (both P > 0.05). CONCLUSION: The genetic polymorphisms of UGT1A7 are associated with the susceptibility of bladder cancer and have interactions with smoking in bladder carcinogenesis. PMID- 20193275 TI - [Effect of postoperative pregnancy upon prognosis of young breast cancer patients]. AB - OBJECTIVE: To examine the effect of postoperative pregnancy upon the prognosis of young Chinese breast cancer patients. METHODS: Four hundred and thirty-two female unilateral breast cancer patients aged 35 or younger were retrospectively reviewed. Kaplan-Meier analysis and Log Rank test were used for univariate analysis of factors predictive of disease-free survival (DFS) and overall survival (OS). Multivariate analysis was carried out using the Cox proportional hazards model. RESULTS: Eighteen patients were identified to have postoperative pregnancy, including 5 full-term pregnancy and 13 abortions with the earliest pregnancy taking place at Month 17 post-operation. After a median follow-up of 62 months (6 - 237 months), the DFS and OS rates were 72.5% (313/432) and 88.7% (383/432) respectively. On multivariate analysis, postoperative pregnancy, clinical stage and number of pathologically involved axillary lymph node were significantly associated with DFS. And the axillary lymph node status was also predictive of OS. No death occurred in patient with postoperative pregnancy. There was no significant association between postoperative pregnancy and OS. CONCLUSION: Postoperative pregnancy has no adverse effect upon the prognosis of young breast cancer patients. PMID- 20193276 TI - [Treatment of infantile hemangiomas with low-dose propranolol: evaluation of short-term efficacy and safety]. AB - OBJECTIVE: To evaluate the short-term efficacy and safety of propranolol in the treatment of infantile hemangiomas. METHODS: Between October 2008 and May 2009, oral propranolol was applied to 58 infants with hemangiomas at a dose of 1.0 - 1.5 mg per kilogram of body weight per day in Linyi, Shandong and Shanghai. There were 19 males and 39 females 1 to 12 months old with a mean age of 4 months. The primary tumor size was 1.5 cm x 1.0 cm to 18.0 cm x 5.0 cm. Twenty-seven were superficial, nine deep-seated and 22 mixed. The tumors were located in head and neck (n = 41), trunk and extremities (n = 12), labium vulvae (n = 2), perianal region (n = 1), perineum (n = 1) and scrotum (n = 1). The patients were hospitalized for 7 to 10 days, continued medication at home and revisited every 2 weeks. The changes of tumor size, texture and color were monitored and recorded at a regular interval. The adverse effects after medication were observed and managed accordingly. The short-term results were evaluated using a 4-point scale system. RESULTS: At 24 hours post-medication, all the tumors decreased in density, color and size. The changes became conspicuous within 5 to 7 days. Seven patients had medication for 2 months, 22 for 3 months, 21 for 4 months and 8 for 5 months. The follow-up period was 5 to 9 months. The overall response was scale I (poor) in 1 patient (1.7%), scale II (moderate) in 12 patients (20.7%), scale III (good) in 35 patients (60.4%) and scale IV (excellent) in 10 patients (17.2%). Statistical analysis showed that the treatment response for deep-seated hemangiomas was significantly better than that for superficial hemangiomas (P < 0.05), but no significant difference was found among different primary sites (P > 0.05). The main adverse effects were bradycardia (100%), diarrhea (63.8%) and sleep change (30.2%), which resolved after expectant treatment without any significant sequel. No serious adverse effect was observed. CONCLUSIONS: Oral propranolol treatment at a low dose is a safe and effective regimen for infantile proliferating hemangiomas. And it can be used as the first-line therapeutic modality. The short-term efficacy is excellent while the side effects are minimal. PMID- 20193278 TI - [Characteristics of electrophysiology and effects of ouabain on transient outward potassium current and L-type calcium current of left atrium posterior wall in rabbits]. AB - OBJECTIVE: To investigate the properties of electrophysiology and effects of ouabain upon transient outward potassium current (I(to)) and L-type calcium current (I(Ca-L)) of left atrium posterior wall (LAPW) and left atrium appendage tissue (LAA)in rabbit so as to provide the scientific explanations that LAPW and ouabain can enhance atrial fibrillation (AF) vulnerability through increasing electrophysiological heterogeneity and electrical remodeling of different regions of left atrium in rabbits. METHODS: Atrial myocytes from LAPWs and LAAs of rabbits on an in vitro heart perfusion system were obtained by enzymatic dissociation. The whole-cell patch-clamp technique was used to assess the effects of ouabain upon I(to) and I(Ca-L). The current-voltage (I-V) curves of I(to) and I(Ca-L) in LAPW and LAA myocytes were fitted before and after ouabain administration. RESULTS: (1) With holding potential +50 mV and commanding potential +50 mV, the current densities of LAPW I(to) decreased slightly less than that of LAA I(to) in control groups (P > 0.05). After ouabain administration, the current densities of LAPW I(to) were significantly larger than that of LAA I(to) [(10.97 +/- 0.58) pA/pF vs (9.39 +/- 0.83) pA/pF, P < 0.05]. The I-V curve of LAPW I(to) was slightly lowered to I-V curve of LAA I(to) in control groups. But with perfusion of ouabain, the I-V curve of LAPW I(to) opposed to I-V curve of LAA I(to) significantly changed from the bottom to the top with the same upward direction. (2) With the voltage clamp protocol of I(Ca L), the current densities of LAPW I(Ca-L) markedly decreased compared with that of LAA I(Ca-L) in control groups (P < 0.05). With the addition of ouabain, the peak of amplitude of LAPW I(Ca-L) at +20 mV obviously increased to that of LAA I(Ca-L) [(-11.13 +/- 0.99) pA/pF vs (-8.86 +/- 0.51) pA/pF, P < 0.01]. In the control groups, the I-V curve of LAPW I(Ca-L) was shifted to the bottom of all I V curves of I(Ca-L). Through the effects of ouabain, the I-V curve of LAPW I(Ca L) was completely upgraded to the top of other I-V curves of I(Ca-L). However, all shapes and directions of current peak of I-V curves of I(Ca-L) remained unchanged in both groups. CONCLUSION: The distribution properties of I(Ca-L) have significant difference in LAPW. Ouabain can accentuate the electrophysiological heterogeneity and electrical remodeling of I(to) and I(Ca-L) in LAPW of rabbits. It may become the triggering factor and persisting basis of AF vulnerability. PMID- 20193277 TI - [Predictors of occurrence of left atrium and left appendage thrombosis in patients with nonvalvular atrial fibrillation]. AB - OBJECTIVE: To determine the predictors of thrombosis in left atrium (LA) or left atrial appendage (LAA) in patients with nonvalvular atrial fibrillation. METHODS: Two hundred and eight patients under 65 year old with atrial fibrillation (AF) were included and all of them received examination of transesophageal echocardiography (TEE). Thrombus formation in LA/LAA was found in 23 patients (thrombus group) but absent in the remaining 185 patients (nonthrombus group). All patients were analyzed by univariate regression and binary logistic regression to investigate the relationship between the occurrence of LA/LAA thrombosis and these factors (such as case history, smoking/drinking preference, indicators of clinical blood examination and ultrasound imaging study, etc) RESULTS: Univariate analysis revealed that diameter of LA [(34.9 +/- 4.4) mm vs (42.2 +/- 6.5) mm, P = 0.000], ratio of chest and heart (60/185 vs 20/23 P = 0.000), brain infarction/transient ischemic attack (TAI) (7/185 vs 6/23 P = 0.000), smoking (30/185 vs 8/23, P = 0.030), fibrinogen (FIB) [(3.0 +/- 0.7)g/L vs (3.5 +/- 1.0) g/L, P = 0.000], coronary artery disease (CAD) (10/185 vs 6/23, P = 0.000) and LVDd [(45.7 +/- 4.1) mm vs (48.5 +/- 5.7) mm, P = 0.000] and LVEF [(65.1 +/- 6.6) mm vs (59.3 +/- 1.3) mm, P = 0.050] were significant between nonthrombus group and thrombus group (P < 0.05). However binary logistic regression analysis identified that only LAD, ratio of chest and heart, brain infarction/TAI and FIB were the significant and independent predictors of LA/LAA thrombosis. CONCLUSION: Diameter of LA, ratio of chest and heart, brain infarction/TAI and FIB are independent risk factors of thrombosis in patients under 65 year old with nonvalvular atrial fibrillation. These patients need a better anticoagulation. PMID- 20193279 TI - [Effects of LIMK2 RNA interference on the mechanosensitivity of c-fos gene in osteoblast]. AB - OBJECTIVE: To study the effects of cytoskeleton reorganization inhibition with LIMK2 RNAi upon the mechanosensitivity of c-fos gene in osteoblast. METHODS: Mouse primary osteoblast was treated with LIMK2 specific siRNA (RNAi Group), negative control siRNA (NC Group), and then were loaded or unloaded by fluid shear stress. Real-time PCR and immunofluorescence were used to detect the c-fos expression levels and statistics analysis was performed. RESULTS: When the cytoskeleton reorganization was inhibited with RNAi only, the c-fos mRNA (0.0108 +/- 0.0074 and 0.0042 +/- 0.0018, t = -1.86, P > 0.05) and protein (121 +/- 7 and 119 +/- 6, t = -1.272, P > 0.05) expression levels of each unloaded group had no significant difference; Fluid shear stress could up-regulate the c-fos mRNA (0.2203 +/- 0.1532 vs 0.0042 +/- 0.0018, t = -707.35, P < 0.05)and protein (178 +/- 12 vs 119 +/- 6, t = -30.761, P < 0.05) expression; After the cytoskeleton reorganization was inhibited with RNAi, the c-fos mRNA (0.5280 +/- 0.0879 vs 0.2203 +/- 0.1532, t = -1007.00, P < 0.05) and protein (224 +/- 46 vs 178 +/- 12, t = -6.853, P < 0.05) expression induced by fluid shear stress had significant difference. Cytoskeleton reorganization inhibition with RNAi had synergistic effect upon the expression of c-fos mRNA (F = 84.388, P < 0.05) and protein (F = 42.409, P < 0.05) induced by fluid shear stress. CONCLUSION: Using RNAi against LIMK2 to inhibit the cytoskeleton reorganization can promote the expression of c fos gene and thus enhance the mechanosensitivity of c-fos gene in osteoblast. PMID- 20193280 TI - [Effect of lipid-bound apoA-I cysteine mutants upon lipopolysaccharide-induced endotoxemia in mice]. AB - OBJECTIVE: To determine the anti-inflammatory functions of different cysteine mutants of apolipoprotein A-I recombinant HDLs. METHODS: The authors reconstituted recombinant HDLs (namely rHDL74, rHDL129, rHDL195 and rHDL228) by mixing wild type or those mutants with dipalmitoyl phosphatidylcholine and examined their in vivo effects upon LPS-induced endotoxemia in mice. RESULTS: At 24 h post-injection, mice receiving rHDL74 [TNF-alpha: (24 +/- 3) pg/ml; IL 1beta: (45 +/- 5) pg/ml] had a significant decrease of plasma tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta) as compared with control mice receiving either saline or rHDLwt [TNF-alpha: (135 +/- 12) pg/ml; IL 1beta: (82 +/- 8) pg/ml, P < 0.05]. Administration of rHDL74 to mice injected with LPS also led to a protection of lung against acute injury and attenuation of endotoxin-induced clinical symptoms in mice as compared with controls injected with LPS only. CONCLUSION: Compared with rHDLwt, rHDL74 exhibits higher anti inflammation capabilities. And it may be a potential clinical candidate for therapy for endotoxin-induced septic shock. PMID- 20193281 TI - [Effects of silencing transforming growth factor-beta1 by RNAi upon transdifferentiation of renal allograft tubular epithelial cells in rats]. AB - OBJECTIVE: To investigate the effects of shRNA-transforming growth factor (TGF) beta1 plasmid upon epithelial-myofibroblast transdifferentiation of renal allograft in rats. METHODS: Divided the Wistar rats into 4 groups: Group J (sham operated group), T (plasmid group), H (vacant plasmid group) and Y (simply transplantation group). The SD to Wistar rat transplant kidney-sclerosis accelerated model was constructed and transfected with the plasmid based on hydromechanics. Transplanted kidneys were collected at Months 1, 2 and 3 post transplantation. The gene transcriptional levels of TGF-beta1 and E-cadherin were detected by RT-PCR and the protein variation of E-cadherin was examined by Western blotting. The pathological changes and infiltrated inflammatory cells were assessed by HE staining and the immunohistochemical staining of E-cadherin and alpha-SMA used to label epithelial cells and fibroblast in order to exhibit cell transdifferentiation. RESULTS: Compared with Group H and Y, the mRNA transcription of TGF-beta1 was obviously inhibited in the Group T: at Month 3, the TGF-beta1 mRNA of Group T is 0.73 +/- 0.08, significantly lower than Group H and Y (0.92 +/- 0.07 and 0.95 +/- 0.04, both P < 0.01); the expression of E cadherin was maintained at a high level: at the Month 3, the E-cadherin mRNA of Group T is 0.39 +/- 0.11, significantly higher than Group H and Y (0.15 +/- 0.07, and 0.17 +/- 0.06, both P < 0.01); the E-cadherin protein of Group T is 0.38 +/- 0.08, significantly higher than group H and Y (0.15 +/- 0.07 and 0.15 +/- 0.07, both P < 0.01); epithelial cells were much more and fibroblast was much less than that of Group H and Y; there were also less infiltrated chronic inflammatory cells and extracellular matrix deposition in the Group T. CONCLUSION: The shRNA TGF-beta1 plasmid can inhibit the epithelial-myofibroblast transdifferentiation of renal allograft in rats. The mechanisms may be associated with its effects of down-regulating TGF-beta1 and up-regulating E-cadherin. PMID- 20193282 TI - [Effects of high mobility group box-1 silencing upon the invasion and proliferation in human lung cancer cell L9981 by RNA inhibition]. AB - OBJECTIVE: To investigate the effects of high mobility group box-1 (HMGB1) silencing upon the invasion and proliferation in human lung cancer cell L9981 by RNA inhibition. METHODS: L9981 cells were divided into 3 groups. Group 1 was transfected by HMGB1 small interfering RNA (HMGB1-siRNA group). Group 2 was transfected by negative sequence small interfering RNA (negative control group). Group 3 was blank group. The mRNA and protein of HMGB1 were determined by real time PCR and Western blotting assay respectively. The proliferation ability was examined by cell viability assay. The growth status of cells was examined by MTT at 24, 48, 72 and 96 h post-transfection. Invasion ability was evaluated by Boyden chamber model. RESULTS: The relative expression of HMGB1 mRNA of HMGB1 siRNA group (1.0 +/- 0.0) was much lower than the negative control (12.8 +/- 1.3, P < 0.05) and blank groups (12.1 +/- 1.0, P < 0.05). HMGB1 protein expression was also significantly inhibited. Cell viability of HMGB1-siRNA group was much lower than other two groups. MTT indicated the growth of HMGB1-siRNA group was significantly inhibited than other two groups. Boyden chamber model indicated the number of penetrating membrane in HMGB1-siRNA group was less than other two groups. CONCLUSION: Down-regulating HMGB1 gene expression by HMGB1 siRNA can inhibit the invasion and proliferation of human lung cancer cell. PMID- 20193283 TI - [Condylar fracture: challenges and therapeutic strategies]. PMID- 20193284 TI - [Reduction and screw fixation of condyle sagittal fracture]. AB - OBJECTIVE: To investigate the technique and clinical effect in the surgical reduction and screw fixation of sagittal condylar fractures. METHODS: Open treatment was performed on 21 cases (23 condyles) with sagittal condylar fractures. The condylar fracture segment was reduced and fixed by screw (long screw or lag screw). The patients began the mandible movement exercise early after the operation, and follow-up was performed in the first half year after the operation. RESULTS: Favorable results were obtained in all cases. Slight malocclusion was observed in 3 cases accompanied with mandible fracture, but normal occlusion was almost reestablished after one week of intermaxillary traction. The CT examination indicated the ideal condition of reduction and fixation of these condylar fractures. During the follow-up, the mouth opening was normal, and mandible movement and function was satisfactory. CONCLUSIONS: The technique of reduction and screw fixation in condyle sagittal fracture can obtain stable reduction and fixation. PMID- 20193285 TI - [Results of functional management of condylar fracture in 3 to 16 years old children]. AB - OBJECTIVE: To investigate the effect of soft occlusal splint in the treatment of condylar fracture in children and adolescents. METHODS: Twenty-three children with condylar fracture aged from 3 to 16 were included in this study. Impressions of both jaws were taken and stone working models poured. After occlusion was recovered by mounting on a bionic articulator, a soft occlusal splint was fabricated. The occlusal splint was worn for 1 to 3 months accompanied with functional exercise. Follow-up was carried out by clinical observation and panoramic image. RESULTS: Clinical satisfactory results were obtained in all the patients with good occlusion, unimpaired function and normal growth and development of the mandibles. Panoramic image showed reconstruction of the fractured condyles, which were flattened and short. CONCLUSIONS: Soft occlusal splint is a promising approach for treating condylar fracture in children. PMID- 20193286 TI - [Prosthetic replacement of condylar head for management of traumatic temporomandibular joint ankylosis]. AB - OBJECTIVE: To preliminarily evaluate the method of using titanium condylar protheses in management of traumatic temporomandibular joint ankylosis. METHODS: Between August 2006 and April 2008, titanium condylar replacement was performed in 5 male patients. Preoperative CT datum of patient was obtained and a resin model was then produced and used as a reference to select a suitable titanium condyle for reconstruction of the joint. In the operation, the bony ankylosis was removed. According to the preoperation planning, the selected prosthesis was inserted and fixed to the distal mandibular segment. The results were assessed by means of examinations and measurements postoperatively and during follow-up. RESULTS: The 5 patients received alloplastic replacement of 6 condyles. Three patients were under follow-up and follow-up time ranged from 8 months to 2 years and 6 months. The mean mouth opening was 30 mm. Two patients had good occlusion and one patient developed a slight open bite. CONCLUSIONS: Prosthetic condylar replacement can provide a choice for management of traumatic temporomandibular joint ankylosis. PMID- 20193287 TI - [Prevention and treatment of complications of condylar fractures]. PMID- 20193288 TI - [Treatment differences between unilateral and bilateral condylar fractures of the mandible and combined maxillary fractures]. PMID- 20193289 TI - [Condylar fractures, disc injury and development of temporomandibular joint ankylosis: discussion on the related problems]. PMID- 20193290 TI - [Treatment and prognosis analysis of primary parotid squamous cell carcinoma]. AB - OBJECTIVE: To investigate the prognosis-related factors and treatment strategy of primary parotid squamous cell carcinoma. METHODS: Forty-nine primary parotid squamous cell carcinoma treated from 1970 to 2005 were retrospectively analyzed. The follow up data were analyzed by SPSS 13.0 software. RESULTS: Integrated follow up data were obtained from 44 patients with a median follow up time of 38 months (5 - 215 months). Recurrence or distant metastasis of the carcinoma occurred in 21 patients, including 13 local recurrence in parotid or neck and 8 distant metastasis. Local recurrence was the main reason of treatment failure. The 3-year and 5-year survival rate and disease-free survival rate was 52%, 27% and 34%, 16%. Kaplan-Meier and log-rank analysis indicated that age, tumor size, distant metastasis, postoperative radiotherapy, facial nerve dysfunction, neck dissection, skin invasion, and surgical margins were prognosis-related factors. Cox analysis showed that age, facial nerve dysfunction, distant metastasis and surgical margins were the important factors that influenced the prognosis. CONCLUSIONS: Primary parotid gland squamous cell carcinoma is an uncommon tumor, surgery and postoperative radiotherapy are the optimal treatment, which can improve the prognosis of the patients and decrease recurrence of the tumor. PMID- 20193291 TI - [Occlusal contacts in intercuspal position after orthodontic treatment]. AB - OBJECTIVE: To observe the occlusal contacts in intercuspal position(ICP) in adolescent patients after orthodontic treatment. METHODS: Fourteen adolescent patients after orthodontic treatment were selected as experimental group and 17 healthy adolescents and young adults with normal occlusion were selected as control group. The occlusal contact in ICP in the two groups were recorded with T Scan II system and compared. RESULTS: When the total of force (TOF) were 1/10 TOFmax, 1/4 TOFmax, 1/2 TOFmax, 3/4 TOFmax and TOFmax, the number of occlusal contacts in the anterior segment in the experimental group were 1.5(1.0), 3.0(1.3), 4.5(3.3), 5.5(3.0), 5.5(3.3), which were significantly larger than that in control group [0.0(0.3), 0.0(0.6), 0.3(0.5), 0.3(1.0), 0.0(1.8), P < 0.05]. There were no significant difference in the area of occlusal contacts in the posterior segment between experimental group and control group (P > 0.05). The center of force (COF) in the experimental group located significantly more mesially than that in control group. The value of ICP contact time in experimental group was 0.192(0.141) s and no significant difference was found between experimental group and control group [0.163(0.200) s]. CONCLUSIONS: Although the patients achieved normal occlusion after orthodontic treatment, their anterior teeth received more occlusal force than those in healthy adolescents and young adults with normal occlusion. PMID- 20193292 TI - [Protein expression by planktonic and biofilm cells of clinical isolations of Streptococcus mutans]. AB - OBJECTIVE: To investigate the changes in the surface-associated protein expression of planktonic cells and biofilm cells of clinical isolations of Streptococcus mutans (Sm). METHODS: The proteins were extracted by the method of Homer from the nonadhered planktonic and the adhered biofilm cells and separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and two dimensional gel electrophoresis followed by image analysis. Proteins were identified by matrix-assisted laser desorption time of flight mass spectrometry and computer-assisted protein sequence analysis. RESULTS: Image analysis revealed that 30% - 31% of the protein spots in biofilm was modulated. A total of 238 proteins changed 1.3-fold or greater in biofilm cells compared to planktonic cells in Sm18, with 5 only expressed in biofilm cells and 5 not expressed in biofilm cells. A total of 279 proteins changed 1.3-fold or greater in biofilm cells compared to planktonic cells in Sm593, with 12 only expressed in biofilm cells and 2 not expressed in biofilm cells. Two clinical isolations in biofilm cells had three identical protein expressions whose functions were associated with biosynthetic processes. CONCLUSIONS: The two clinical isolations in biofilm status have high expression of some special proteins, which are presumed to be key proteins essential for formation of biofilm. The difference of protein expression in biofilm cells of the two clinical isolations may represent their distinct characters. PMID- 20193293 TI - [Effect of DNA methyltransferases 1 inhibition on proliferation, invasion, and metastasis in ACC-M line]. AB - OBJECTIVE: To investigate the effect of DNA methyltransferases 1 (DNMT-1) inhibition on the ACC-M cells in vitro and in vivo and discuss the role of DNMT-1 in the development, invasion and metastasis of salivary adenoid cystic carcinoma (SACC). METHODS: ACC-M cells of stable DNMT-1 inhibition were established in a previous research. In vitro, the growth and invasion of ACC-M cells which stably inhibited DNMT-1 were detected and analyzed by methyl thiazolyl tetrazolium (MTT) growth curve, flow cytometry, plating efficiency and invasion assay. In vivo, the growth and metastasis of ACC-M cells which persistently inhibited DNMT-1 were observed and analyzed by subcutaneous injection and tail vein injection into the nude mice. RESULTS: In vitro, the doubling time [(34.7 +/- 2.1) h], S phase fraction [(17.4 +/- 1.7)%], plating efficiency [(43.0 +/- 1.3)%] of ACC-M cells was significantly different from those of blank [(26.2 +/- 3.1) h, (31.5 +/- 2.0)%, (71.0 +/- 4.7)%], empty load control [(28.4 +/- 3.9) h, (39.0 +/- 2.0)%, (66.0 +/- 5.2)%], P < 0.05, and the invasion ability was not significantly different among these groups (P > 0.05). In vivo, the subcutaneous tumor forming rate (6/10), volume [(2.18 +/- 0.83) mm(3)], weight [(0.0156 +/- 0.0046) g] of ACC-M cells was also significantly lower than that of blank [10/10, (155.44 +/- 1.67) mm(3), (0.0724 +/- 0.0157) g], empty load control [10/10, (147.46 +/- 1.73) mm(3), (0.0729 +/- 0.0177) g], P < 0.05, but the rate of lung metastasis was not significantly different among these groups (P > 0.05), and the masses (2.0 +/- 0.5), diameter (70.0 +/- 20.3) microm of ACC-M cells was significantly lower than that of blank [(28.0 +/- 5.5), (195 +/- 25.4) microm], empty load control [(27.0 +/- 4.5), (190.0 +/- 19.9) microm], P < 0.05. CONCLUSIONS: Inhibition of DNMT-1 is able to inhibit the proliferation and metastasis of ACC-M cells in vitro and in vivo. PMID- 20193294 TI - [Fabrication of titanium dioxide nanotube array and effects of its osteoblast proliferation and alkaline phosphatase activity]. AB - OBJECTIVE: To investigate preparation parameters of TiO2 nanotube layer with anodization, and to evaluate the osteoblast activity on TiO2 nanotube layer in vitro. METHODS: Titanium dioxide nanotube layer was grown using anodization method. TiO2 nanotube layers with different structure were obtained by controlling the voltage and time of anodization and rinsing process after anodization. Pure titanium without anodization was used as control. Osteoblasts were cultivated on the anodizated TiO2 nanotube, and the growth of osteoblasts was then evaluated and analyzed. RESULTS: The voltage, duration of anodization and rinsing process following anodization were key factors to affect morphology of TiO2 nanotube layer. The area of osteoblast cultured on TiO2 nanotube layer was larger than that on pure titanium. Results from methylthiazol tetrazolium (MTT) test showed that the proliferation of osteoblasts after 96 h cultivation on TiO2 nanotube layer (0.62 +/- 0.02) was significantly higher than that on unanodizated titanium (0.55 +/- 0.03, P < 0.05). Three weeks later, the alkaline phosphatase (ALP) activity on TiO2 nanotube layer [(130.8 +/- 5.1) A(405)/mg] was significantly higher than that on unanodizated titanium [(109.6 +/- 4.5) A(405)/mg, P < 0.05]. CONCLUSIONS: The structure of TiO2 nanotube layer was greatly associated with anodization voltage. The TiO2 nanotube layer had a positive effect on osteoblast behavior. PMID- 20193295 TI - [Effect of Ti bonder on the bond strength between porcelain and titanium]. AB - OBJECTIVE: To investigate the influence of GC Initial Ti Bonder on bond strength between Vita Titankeramik porcelain and titanium. METHODS: Forty titanium samples were prepared and randomly assigned to 4 groups with 10 samples in each group. Samples in each group were subjected to one of the following surface treatments, burnishing (Group B), sandblasting (Group S), firing GC Initial Ti Bonder after burnishing (Group BG) and firing GC Initial Ti Bonder after sandblasting (Group SG). Vita Titankeramik porcelain were fired on the surface of each sample in the middle. Three-point bending tests were conducted on each sample according to the ISO 9693. The fracture patterns of all specimens were recorded using zoom stereo microscope (ZSM) and the fracture surfaces were observed under scanning electron microscope (SEM). RESULTS: With fired GC Initial Ti Bonder, the bond strength of Vita Titankeramik porcelain to titanium in Group BG and Group SG were (32.72 +/- 4.46) and (34.25 +/- 6.52) MPa respectively, which reach the ISO 9693 standard for clinical use and were significantly higher than those in Group B [(20.70 +/- 3.15) MPa] and Group S [(23.92 +/- 5.02) MPa]. CONCLUSIONS: GC Initial Ti Bonder can significantly improve bond strength between Vita Titankeramik porcelain and titanium. PMID- 20193296 TI - [Cooperative development and application of electronic periodontal examination chart]. AB - OBJECTIVE: To develop an electronic system (software) for collecting and analyzing periodontal examination data, and preliminarily evaluate its clinical application. METHODS: The contents and frame of electronic periodontal examination system were designed based on the aim and requirement of periodontal examination, and the software system was developed under the assistance from computer engineers. The electronic system was implemented for entry, storage, retrieval and output of clinical data and data conversion. A questionnaire survey was performed in 23 periodontists and 20 nurses to evaluate the clinical application of this software. RESULTS: An electronic periodontal examination system was developed, which was used for entry, storage, retrieval and output of clinical data, and converting data into chart. Most nurses could handle this software after 15 minutes of training. Thirteen nurses and 17 periodontists recognized that clinical work efficiency could be improved by application of this software. Nineteen nurses and all periodontists agreed that this software could meet clinical requirements. CONCLUSIONS: The electronic periodontal examination system can fulfill clinical requirements and is helpful for clinical treatment and research work. PMID- 20193297 TI - [Electronic surveying of digital partially dentate casts]. AB - OBJECTIVE: To develop a method of surveying the digitalized partially dentate cast in order to accomplish computer aided design (CAD) of removable partial denture (RPD) frameworks. METHODS: The stone cast of a partially dentate patient was scanned using a three-dimensional laser scanner. Points on the surface of the digitalized cast, termed as a "point cloud", were obtained. The point cloud was then imported into self-developed Tanglong software to sample and uniform. New module of identifying the surveying lines was specially written in Tanglong using C++. A straight line was created in the center of the cloud point. Then the cloud point surrounding the straight line was divided into many parts. Local coordinates were established to indicate the information of angle and distance of every point to the straight line. Surveying lines were produced step by step electronically by identifying the closest and farthest points relative to the straight line and then connected together. Different surveying lines were obtained by adjusting the angle of the straight line. After the surveying lines were decided, the undercut areas could be marked and the depth of undercut was calculated automatically. The blockout of the undercuts could also be achieved by moving the location of the point cloud in undercut area. RESULTS: Survey lines of digitalized partially dentate casts were generated in computer. The undercut area and its depth were identified and the undercut could be blocked out. The shape of survey lines on the digitalized casts was similar to that on the physical casts drawn using traditional method. CONCLUSIONS: The new module in Tanglong software was developed specifically for surveying partially dentate casts. It had a user friendly interface with the easy-to-understand menus. The success of surveying dental casts digitally would make it possible to CAD of RPD frameworks. PMID- 20193298 TI - [Right maintenance and self-discipline of practicing dentist: responsibility for quoting proof in lawsuits for medical care dissension]. PMID- 20193299 TI - [Research advances on receptors and transduction in taste cells]. PMID- 20193300 TI - [The components of metabolic syndrome that influencing the prevalence of cardiovascular disease in a follow-up study]. AB - OBJECTIVE: To investigate metabolic syndrome components that influencing the prevalence of cardiovascular disease (CVD). METHODS: Five hundred persons were selected from a unit in Nanning city, Guangxi, based on the cross-sectional study on a distribution of population with metabolic syndrome in 2004 and followed them up for 3.5 more years. Physical examination would include detection on blood pressure, glucose, serum cholesterol and body index etc. When someone suffered from cardiovascular disease would be viewed as an 'end-point event'. Criteria of diagnosis were under the basis of CVD from the WHO-MONICA. RESULTS: (1) The mean value of physical and biochemical index as BMI, waist circumstance, systolic pressure, diastolic pressure. Fast serum glucose, triglyceride in the population with more MS components were higher than the ones with less components. (2) The prevalence rates of CVD in the four groups were 2.97%, 4.19%, 7.97%, 11.88% respectively with significant differences between the groups (P = 0.0008). (3) Data from the logistic analysis manifested that when compared to the 0 group, the risk rate of CVD for groups having 1, 2, 3 components were 1.41, 2.68, 4.00 respectively. After adjusted age and sex, time of occurrences, results from the Cox model showed that the risk rate of CVD for groups with 1, 2, 3 components were 1.29, 2.47, 3.67 (RR 95%CI: 1.02 - 13.14) respectively. (4) Kaplan-Meier analysis showed that the cum hazard of CVD in the 3rd group was higher than in the 0, 1 group, and at the end of follow-up, the cum hazard of CVD was 12.7% in the 3rd group among population with metabolic syndrome. CONCLUSION: When increasing the number of components of metabolic syndrome, the higher risk ratio for population to suffer from CVD was seen. With the natural process of disease, the more components of metabolic syndrome in population, the higher cum hazard would influence the occurrence of CVD in the future. PMID- 20193302 TI - [Incidence and risk factors on HIV infection among injection drug users in Dehong prefecture area of Yunnan province]. AB - OBJECTIVE: To determine the incidence and risk factors on HIV infection among injection drug users (IDU) in Dehong prefecture area of Yunnan province. METHODS: An epidemiological cohort of HIV-negative IDU had been developed and followed since October, 2004. HIV new infections and related behaviors had been investigated every six months. RESULTS: By the end of 2008, 760 HIV-negative IDU had been recruited and followed for a total of 1153.6 person-years. 47 new HIV infections were identified, with an overall incidence of 4.07/100 person-years during the follow-up period. The HIV incidence was 4.45/100 person-years during 2004 - 2006, 4.50/100 person-years in 2007 and 2.54/100 person-years in 2008. Both the behavior of drug injection and the HIV incidence among the cohort had substantially decreased during the follow-up period. Multiple regression analysis using Cox proportional hazard model indicated that people with Jing-po ethnicity (Hazard ratio, HR = 2.56, 95%CI: 1.06 - 6.19) and other minorities except for Dai (HR = 3.26, 95%CI: 0.89 - 11.96) were at higher risk for HIV infection than the people with Han ethnicity. People injecting drugs with (HR = 2.27, 95%CI: 0.98 - 5.25) or without (HR = 5.27, 95%CI: 2.25 - 12.34) needle sharing were at higher risk for HIV infection than those reporting having no drug injection behavior during the follow-up period. CONCLUSION: Both the behavior of drug injection and the HIV incidence among former IDU in Dehong prefecture area of Yunnan province had been decreasing during the four years. However, needle sharing remained the most important risk factor for HIV new infection among IDUs. IDUs with different ethnicities seemed to have different risks towards HIV infection. PMID- 20193301 TI - [Metabolic syndrome and chronic kidney disease in a rural adult population of Hunan province, China]. AB - OBJECTIVE: To explore the relationship between metabolic syndrome and chronic kidney disease (CKD) in a rural adult population of Hunan province. METHODS: 1953 residents (older than 18 years) from the same village were randomly selected, using a stratified, multistage sampling method. All residents were interviewed and tested for albuminuria with morning spot urine albumin to creatinine ratio (abnormal: >/= 30 mg/g), reduced renal function with estimated glomerular filtration rate by modified MDRD equation [abnormal: < 60 ml/min (1.73 m(2))]. The associations of kidney damage indicators with demographic characteristics (age, gender, smoking status), indicators on health (diabetes, hypertension) and metabolic syndrome traits were examined. RESULTS: Eligible data of 1709 subjects were enrolled in the study. After the adjustment of age, gender and other metabolic syndrome traits, participants with metabolic syndrome had a higher prevalence of CKD (19.3% vs. 13.2%, P < 0.001) than those without the syndrome. As the number of metabolic syndrome traits increased, so did the prevalence of CKD. There seemed to be a strong and independent association between metabolic syndrome and chronic kidney disease. For participants without hypertension and diabetes, metabolic syndrome was also associated with CKD (OR value 1.733, 95%CI: 1.20 - 2.41, P = 0.004). CONCLUSION: In these 1709 adults under this study from a village of southern China, metabolic syndrome seemed to be associated with CKD. PMID- 20193303 TI - [Predictors of retention related factors at the initial methadone maintenance treatment clinics in Guangdong province]. AB - OBJECTIVE: To identify predictors of treatment retention problems at the two initial methadone maintenance treatment (MMT) clinics in Guangdong province, and to provide reference in reducing the rate of drop-outs. METHODS: All of the patients were investigated at baseline and followed during the treatment period. Kaplan-Meier method on Survival Analysis was used to analyze retention related factors and predictors. RESULTS: 509 subjects were recruited in this study with median of retention time as 108 days (95%CI: 74 - 142 days). The retention rate at 1-, 3-, 6-, 12-months were 75.9%, 52.7%, 41.6%, 30.1%, respectively. Data from Multivariate Cox Proportional Hazard Model analysis showed predictors of retention would involve factors as HIV infection state at baseline (HR = 1.241, P = 0.047), daily methadone dose (HR = 0.633, P = 0.004) and secretly using drugs during treatment period (HR = 5.345, P = 0.000). CONCLUSION: The retention rates at the two initial MMT clinics in Guangdong province were low. Patients who were HIV negative at baseline but still secretly using heroine during treatment or accepted low daily average dosage of methadone, had the tendency to drop out. The results implied that retention time could be prolonged by increasing daily methadone dosage. PMID- 20193304 TI - [Study on cognition and behavior of methadone maintenance treatment among the community-based drug users in Dongguan, Guangdong province]. AB - OBJECTIVE: To understand the cognition of methadone maintenance treatment (MMT) and to explore the factors associated with the coverage of MMT, among the community-based drug users in Dongguan, Guangdong province. METHODS: In 2008, respondent-driven sampling was applied to recruit community-based drug users in Dongguan. A structured questionnaire was used for a face to face interview. RDSAT was applied to adjust the estimates and the results from bivariate analysis. SPSS was used for multivariate analysis. RESULTS: A total of 303 drug users were recruited within a 15-week period. The coverage of MMT program was 8.4% (95%CI: 3.4 - 16.5). 62.9% of the drug users had heard of MMT, of which 80.8% had not been enrolled at MMT mainly for the following reasons: fear of being arrested (25%), being not familiar with the application process (18.9%), no certification of domiciliary register and or ever being in detoxification center (18.7%) and thinking poorly of MMT (18.3%). Multiple logistic regression model indicated that those who were local residents (OR = 22.5, 95%CI: 6.6 - 75.7) and whose effect of MMT being evaluated as positive (OR = 24.1, 95%CI: 6.3 - 91.6) were more likely to be enrolled at the MMT program. CONCLUSION: Community-based drug users had some irrational cognition on MMT program. Dissemination and sharing of information on MMT should be strengthened through media and existing social network among drug users. More concern should be paid to the people who were on migration when making policy to improve the coverage of MMT. PMID- 20193305 TI - [An epidemiological study of visual disability and visual rehabilitation in Beijing]. AB - OBJECTIVE: To investigate the status of visual disability and the demands for visual rehabilitation services in Beijing. METHODS: Five hundred and fifty-five persons with visual disability in Beijing from the Second National Survey on Disability of China were involved in this study. Their visual disability and demands for rehabilitation were evaluated. RESULTS: About three fourth of the visual disabled persons were over 60 years of age. Cataract, retinal and choroidal diseases, and glaucoma were the three leading causes of the visual impairment. Medical service was the number one (82.0%) demand for the persons with visual disability, although 89.4% of them had previously received some kinds of medial services. People who had received visual aid devices or rehabilitation training were 26.7% and 5.8%, respectively, while more people showed their demand for these service (36.6% and 11.9%, respectively). The demand for visual rehabilitation varied in different groups of age and severity of disability. CONCLUSION: Accessibility of high quality medical services for preventable blindness diseases should be further promoted. Public health education on visual rehabilitation is also needed. PMID- 20193306 TI - [Birth weight distribution among premature infants and related social factors]. AB - OBJECTIVE: To understand the distribution of birth weight among premature infants and the associated social factors. METHODS: The study population consisted of 97 537 women who delivered singleton live birth of 20 to 41 gestational weeks in 4 counties/cities, Jiangsu and Zhejiang provinces, China from 1995 to 2000. Chi square test was employed to test the difference of proportions between respective groups. One- way ANOVA was used to test the differences regarding the mean of gestational weeks at the first prenatal visit and the mean of prenatal visits between the two groups. Multivariate logistic regression was conducted to examine the factors associated with premature birth. RESULTS: Women aged 35 years had higher (8.8%) premature incidence than those aged less than 24 years (5.6%), 25 - 29 years (4.6%), or 30 - 34 years (4.5%, P < 0.001). Women with height less than 149 cm had higher (6.8%) premature incidence than those with height taller than 150 cm (5.0%). Women whose BMI were at least 28 and 24 - 28 had higher (5.5%, 5.5%) premature incidences than those whose BMI were 18.5 - 24.0 (5.0%), < 18.5 (4.6%, P < 0.001). The incidence of premature birth was 6.0% among women without previous pregnancy, higher than that among those women with 4 times of pregnancies (5.7%), 2 times of pregnancies (4.3%), and 3 times of pregnancies (4.0%). Parous women with at least two deliveries had higher (9.3%) premature incidence than the primiparous women (5.2%) and whose women with only one delivery (4.5%, P < 0.001). Women who received early prenatal care had lower 4.7% premature incidence than those who did not receive the service (6.1%). The mean times of prenatal visits among women with premature births was 8.53, less than that of those with full term delivery (10.97). Women with less than four times of prenatal visit had higher (18.9%) premature incidence than those with at least five prenatal visits (4.9%). Multivariate logistic regression showed that premature delivery risk was associated with age, height, BMI, gravidity, parity, early prenatal care, the mean of gestational weeks at first prenatal visit and the mean number of prenatal visits etc. CONCLUSION: Premature delivery risk was associated with factors as age, height, BMI, gravidity, parity, early prenatal care, the mean of gestational weeks at first prenatal visit, the mean number of prenatal visits etc. PMID- 20193307 TI - [A cross-sectional study of congenital heart disease among children aged from 4 to 18 years at different altitudes in Qinghai province, China]. AB - OBJECTIVE: The epidemiological characteristics of congenital heart disease (CHD) in children aged from 4 to 18 years were investigated in Qinghai province. METHODS: Altogether 288 066 children inhabiting at 6 prefectures and 3 counties were examined by the following three steps: pre-screening, re-examination and diagnosis with color Doppler. And the entity distribution was analyzed while the differences were compared by age, gender, altitudes and nationalities respectively. RESULTS: Altogether 1633 cases of CHD were discovered. The total prevalence of CHD was 5.71 per thousand. The prevalence of CHD was found to increase with the increase of altitude by 4.89 per thousand at the altitude of 2535 m, 5.71 per thousand at 3600 m, and 8.74 per thousand at 4200 m respectively. There were significant differences among different altitude (chi(2) = 54.696, P < 0.001). chi(2) trend analysis showed the increase with chi(2) = 41.826(P < 0.001). The total incidence of CHD in females was 6.95 per thousand, which was significantly higher than that in males with 4.54 per thousand (chi(2) = 73.79, P < 0.001). There were significant differences between males and females at the altitude of 3000 m (chi(2) = 84.733, P < 0.001) and 4000 m (chi(2) = 16.313, P < 0.001) except at the altitude of 2000 m (chi(2) = 0.807, P > 0.05). The prevalence of CHD in different age groups was statistically significant at the every altitude of 2000 m (chi(2) = 18.138, P < 0.001), 3000 m (chi(2) = 18.544, P < 0.001) and 4000 m (chi(2) = 27.535 P < 0.001). The prevalence of CHD was increasing with the increase of age groups at the altitude of 3000 m (chi(2) = 19.230, P < 0.001) and 4000 m (chi(2) = 26.894, P < 0.001) except at the altitude of 2000 m. Within the prevalence of CHD of different nationalities, there was a significant difference with chi(2) = 24.456 (P < 0.001). Within the constituent rate of CHD, the prevalence of atrial septal defect (ASD) was as high as 37.42%, followed by the prevalence of patent ductus arteriosus (PDA) as 28.47% and ventricular septal defect (VSD) as 26.01%. Regarding the four categories of CHD, the constituent rate varied at different altitudes. For example, the prevalence rate of ASD constituted 37% at the altitude of 2000 m and 3000 m, and that of PDA accounted for 46.36% at the altitude of 4200 m. CONCLUSION: The epidemiological characteristics of CHD in Qinghai children were possibly associated with altitude levels. PMID- 20193308 TI - [Epidemiological study on alcohol consumption and agricultural profession-related injuries among minority residents from the northern parts of China]. AB - OBJECTIVE: To understand the incidence rates of agricultural profession-related injuries and the relationship to alcohol consumption. METHODS: A multistage sample of 2366 villagers was selected from Minority Nationality Villages, Heilongjiang province. Face-to-face interviews were conducted by trained interviewers during May 2008. 2198 (92.9%) of the eligible questionnaires were available. RESULTS: Incidence rate of agricultural profession-related injury rate was 11.8% (260/2198) from May 2007 to April 2008. Higher proportions of injuries were seen for males, 30 - 49 year olds, farmers and among those people working on farms for 10 years or more, smoking during farm work, with sleeping disorder, using motor vehicles, and those using agricultural machinery. Rate of alcohol drinking was 29.1% (640/2198) in the month prior to the investigation. Results from logistic regression models showed that alcohol consumption patterns and other alcohol-related behavior were examined in separate logistic models because of collinearity by controlling the variables that were associated with agricultural profession-related injury including sex, age, years of farm work, driving a motor vehicle, and agricultural machinery use etc. In each model, the reference group was those villagers who did not drink in the past month. The odds of injury among villagers with history of past month drinking, who drank distilled spirits, and alcohol drinking at breakfast and lunch were 1.80 (95%CI: 1.24 - 2.62), 2.09 (95%CI: 1.38 - 3.15), 2.15(95%CI: 1.43 - 3.22) respectively. The odds of agricultural injury also significantly increased with greater average amounts of pure alcohol per day, with increased frequency of drinking per week, and reported years of drinking. CONCLUSION: Intervention efforts should include increasing awareness about alcohol drinking as a major risk factor causing agricultural injuries as well as controlling alcohol drinking, improving knowledge about driving motor vehicle and using agricultural machinery. PMID- 20193309 TI - [Interaction between exposure to environmental smoke and the family history of chronic bronchitis (CB) on the risk of CB in rural females in Liuyang city, Hunan province]. AB - OBJECTIVE: To explore the relationships and interaction among the exposure to environmental smoke, family history of chronic bronchitis (CB) and CB, in rural women. METHODS: A population-based case-control study chi(2) was used to analyze the relationship between environmental smoke exposure, CB family history and CB. Additive effects model was used to analyze the interaction. RESULTS: In the first stage, 157 CB patients were screened from 24 268 women residents (prevalence rate is 6.47 per thousand), then 92 patients (case group) and 114 healthy women (control group) were investigated in the second stage. Results showed that: coal/firewood for heating (OR = 36.21) and CB family history (OR = 6.41) might serve as the risk factors of CB in rural women (P < 0.05). Factors as frequent cooking and using coal/firewood for heating had a positive interaction with family history of CB in rural women, CB with S as 5.39 and 9.02, attributable proportions of interaction (API) as 72% and 88%, relative excess risk of interaction (RERI) as 6.50 and 225.99, respectively. CONCLUSION: Using coal/firewood for heating and CB family history might be the risk factors of CB for rural women. A positive interaction between cooking frequently, heating model and CB family history was also seen. PMID- 20193310 TI - [Evaluation on the safety and efficacy of lyophilized purified human rabies vaccine (CTN-Vero-RV)]. AB - OBJECTIVE: To observe the safety and efficacy of lyophilized purified human rabies vaccine CTN-Vero RV, CTN strain produced in Vero cells. METHODS: 450 healthy volunteers were divided into two groups, with 300 of them receiving CTN Vero-RV (rabies vaccine for human use made in Vero cells with CTN strain) while 150 of them receiving PVRV to serve as control group. All the subjects were immunized on days 0, 3, 7, 14 and 28 at deltoid muscle respectively. Local and systemic reactions were observed and sera were collected for neutralizing antibody testing using RFFIT. 365 and 730 days after the first dose, sera from the 212 and 176 subjects of the studied group while 97 and 80 subjects from the control group were collected to test for neutralizing antibody. RESULTS: No severe local or systemic reactions were observed after immunization was performed in the two groups. On days 3, 7, 14, 28 and 365 after the first dose, the antibody positive rates appeared to be 2.35%, 80.78%, 100.00%, 100.00%, 98.58% and 73.30% in the study group and 4.00%, 87.20%, 100.00%, 100.00%, 97.94% and 76.25% in the controls respectively. On day 0, 3, 7, 14, 28, 365 and 730, GMT of the neutralizing antibody level were 0.12, 1.01, 9.83, 12.61, 3.68 and 2.81 IU/ml in the study group while 0.13, 1.18, 10.24, 11.61, 4.18 and 1.92 IU/ml were seen in the control group respectively. There were no significant differences in both antibody positive rates and GMT between the two groups on days 3, 7, 14, 28, 365 or 730 (P > 0.05). CONCLUSION: CTN-Vero-RV was safe and effective as well as could generate a persistent immune response. PMID- 20193311 TI - [Association between polymorphism of BDNF and internalizing disorders]. AB - OBJECTIVE: To investigate the genetic association between brain-derived neurotrophic factor (BDNF) gene polymorphism and internalizing disorders, to provide the theoretical basis to explore the etiology of internalizing disorders. METHODS: PCR-based ligase detection reaction (PCR-LDR) was applied to tag single nucleotide lengh polymorphism (SNPs) of BDNF gene among 259 undergraduates affected by internalizing disorders and 269 healthy undergraduates. Haplotype analysis and multiple locus analysis were conducted to analyze the genotyping data. RESULTS: The genotypic frequency of tag SNPs of BDNF gene did not deviate from Hardy-Weinberg equilibrium in both case and control groups. Rs12273539 was not associated with internalizing disorders (P > 0.05), but rs10835210 and rs2030324 were related to internalizing disorders (P < 0.05). The case group had more A allele of rs10835210 and C allele of rs2030324 when compared to the controls while A allele of rs10835210 and C allele of rs2030324 seemed to be the risk factors of internalizing disorder (OR = 1.877, P < 0.001; OR = 1.347, P < 0.05). Results of multiple locus analysis showed that the haplotype composed by the three tag SNPs which was related to internalizing disorders (chi(2) = 23.537, P < 0.001). CONCLUSION: BDNF gene might serve as the susceptible gene for internalizing disorder. PMID- 20193312 TI - [Phylogenetic analysis of sporadic hepatitis E virus in Eastern China]. AB - OBJECTIVE: To understand phylogenetic characteristics of sporadic hepatitis E virus (HEV) in eastern China. METHODS: Four hundred and thirteen sera were collected from sporadic hepatitis E cases in 14 second- or first-class hospitals in Eastern China from 2005 to 2008 and detected with a nested RT-PCR assay. Partial nucleotide sequences of the HEV isolates were determined for phylogenetic analysis with prototype sequences in the GenBank. RESULTS: The male-to-female sex ratio of the patients was 1.75:1 with 61.5% of them aged 40 - 69 years old. HEV RNA was detected in 140 out of 413(34%)serum samples. Phylogenetic analysis revealed that all the 140 HEV isolates belonged to genotype IV, sharing 77.9% - 88.3%, 80.8% - 90.6%, 73.4% - 85.2% and 91.0% - 95.4% nucleotide sequence identities with prototype I, II, III and IV HEV isolates respectively. CONCLUSION: It was evident that genotype IV HEV served as the main causative agent of sporadic HEV infection in Eastern China. However the viral origin and evolution needs further clarification. PMID- 20193313 TI - [HIV-1 drug-resistance profiles of treated AIDS patients in Liaoning: genetic characteristics and prevalence]. AB - OBJECTIVE: Since the advent in 2004 of highly active antiretroviral therapy (HAART) in Liaoning, a dramatic improvement had been seen in the number of patients attaining undetectable viral loads (92/104), but the extent of mutation diversity on human immunodeficiency virus 1 (HIV-1) and the prevalence of drug resistance had remained elusive. This study aimed to analyze both HIV-1 mutation profiles and prevalence related to antiretroviral resistance following therapeutic failure. METHODS: A total of 104 blood samples circling Liaoning from HAART-treated between 2004 and 2008 were studied. Patients' CD(4)(+) T-cell count and viral load were determined. HIV-1 pol (PR and part of RT) gene fragments were amplified from patients' plasma by reverse transcriptase polymerase chain reaction (RT-PCR) and nest-PCR, subsequently sequenced and analyzed. RESULTS: CD(4)(+) T cell numbers and viral replication capacity were assessed. 88.4% (92/104) of the patients were successful after initial non-suppressive NRTI & NNRTI-based HAART regimens. Subjects on non-nucleoside reverse transcriptase inhibitor (NNRTI) regimens developed more (6/104) drug-resistance mutations than those on nucleoside reverse transcriptase inhibitor (NRTI) regimens did (5/104). No protease-inhibitor (PI) drug resistance mutations developed. The whole rate of drug resistance mutations was about 6.73%. Subjects developing NNRTI-resistance (NNRTI-R) seemed more likely to develop drug-resistant viremia than with NRTI based HAART. CONCLUSION: This finding might have implications in which that the prevalence of drug-resistance mutations was low but remained risk of transmission in HIV-infected therapeutic failure. Meanwhile, data from the present study showed that there was a high frequency of primary mutations, which offered resistance to nrti and nnrti. Monitoring patients with treatment failure seems an important tool in helping the physicians to improve their treatment schedule and to carry out epidemiological surveillance programs. PMID- 20193314 TI - [Identification of Anaplasma phagocytophilum in small mammals from Hengduan Mountains of Southwest China]. AB - OBJECTIVE: To investigate the prevalence of Anaplasma phagocytophilum in small mammals from the forest area of Hengduan Mountains in southwestern China. METHODS: Small mammals captured from Gaoligong and Xianggelila mountainous area of Yunnan province were detected by PCR amplification. The sequences of 16S rRNA and Msp4 gene fragments from positive samples were compared with corresponding sequences deposited in GenBank. RESULTS: A total number of 436 small animals, which belongs to 5 orders 18 genera 35 species were tested, 32 (7.34%) were positive in 6 genera 11 species. There were 8.64% (26/301) positive in 25 species at Goligong mountainous areas, and 4.44% (6/135) were positive in 19 species at the Xianggelila mountainous areas. Positive small mammals were most rodents. The nucleotide sequences of A.phagocytophilum 16S rRNA gene amplified from small mammals varied from 99% - 100% and were 99% - 100% similar with the corresponding segments of A. phagocytophilum from Jilin deposited in GeneBank. The sequences of A. phagocytophilum Msp4 gene showed that there was 95% - 97% similarity with the corresponding sequences registered in GenBank. CONCLUSION: A. phagocytophilum was firstly identified in 6 genera 11 species small mammals from a forest area of Hengduan Mountainous areas in southwestern China. Rodents might serve as the primary hosts indicating the potential risk to the domestic animals and human beings in this area. PMID- 20193315 TI - [Evaluation on the effect of implementation regarding the measles surveillance system in Hainan province]. AB - OBJECTIVE: To evaluate the development and operation on measles surveillance system. METHODS: To formulate surveillance program, and then establish surveillance system on measles in Hainan province before the case surveillance was conducted. Descriptive epidemiological method was used to analyze the measles cases reported through the notifiable diseases epidemic situation report system and measles surveillance system during 2004 - 2008 in Hainan province. RESULTS: From 2004 to 2008, through surveillance system, 3040 suspected measles cases were reported which was 96.00% higher than that from the notifiable diseases epidemic situation report system. When the measles surveillance system was first established in 2004, the number of cases reported by the surveillance system was less than that from the epidemic report system, however, the sensitivity of the surveillance system had been increasing since 2005. In 2008, the number of suspected cases reported by surveillance system was 19.12 times more than from the epidemic report system. The proportion of confirmed cases in the total suspected cases was decreasing annually, from 90.34% to 4.48%, along with the increase of the sample collection rate, from 22.73% to 99.12%. The proportion of laboratory confirmed cases in the total confirmed cases increased from 7.55% to 86.97%. With suspected cases, the IgM antibody positive rate on measles and rubella were 31.57% and 34.52%, respectively. In Hainan, the epidemic pattern of measles had been sporadic, except for 2006 as there occurred several outbreaks in that year. The of disease incidence had an obvious seasonal peaks, from March to June. Measles mainly attacked children under 15 years of age, accounted for 86.68% of the age group. Children with no immunity or unknown immune history accounted for 85.67%. CONCLUSION: The sensitivity of surveillance system had been increasing annually since it was developed and the incidence had been dropping to its lowest level. These achievements had built a solid foundation for the eventual elimination of measles. PMID- 20193316 TI - [Research on the association between Borna disease virus infection and the viral encephalitis]. AB - OBJECTIVE: To investigate the infection of Borna disease virus (BDV) in unidentified viral encephalitis patients in Ningxia in order to explore if the nucleotide sequence and amino acid sequence in BDV p24 were homophylic with the overseas standard strain. We also intended to investigate the correlation between BDV infection and the unidentified viral encephalitis patients from Ningxia to lay an experimental basis for etiological diagnosis, prevention and treatment on certain human neuropsychiatric disorders. METHODS: BDV p24 gene fragment was detected by nested reverse transcriptase polymerase chain reaction with fluorescence quantitative PCR (FQ-nRT-PCR) in peripheral blood mononuclear cells (PBMCs). Samples were from 59 unidentified viral encephalitis patients and 60 normal controls. For those positive products, gene sequence and amino acid sequence were then analyzed by BLAST and DNAsist 5.0. RESULTS: The positive rate of the BDV p24 gene fragment in PBMCs from the unidentified viral encephalitis (10.17%) was significantly higher than from the controls (0%) (P < 0.05). Data from the gene sequence on those positive products showed BDV p24 fragment in the patients with unidentified viral encephalitis from Ningxia was homophylic with strain H3915 detected from ill horses (97.67%), as well as with the strain H1766 (96.51%) and strain V (95.35%). However, their amino acid sequences remained the same. CONCLUSION: BDV infection might probably have existed in the unidentified viral encephalitis patients of Ningxia. The gene sequence seemed to be homophylic with that of standard strain H1766 and strain V, especially with strain H3915. PMID- 20193317 TI - [Secretion expression of cholera toxin B subunit in food-grading Lactococcus lactis expression system]. AB - OBJECTIVE: To clone and secretion express cholera toxin B subunit (CTB) in food grading Lactococcus lactis expression systems. METHODS: ctB fragment that encoding CTB was amplified by polymerase chain reaction (PCR) using the genomic DNA of Vibrio cholera strain 569B as template and was inserted into two secretion expression vector pSQZ and pSQ to construct food-grading expression system L.lactis MBP71/pSQZ-ctB and L.lactis MBP71/pSQ-ctB. The expressed CTB was detected by Western-blot assay. RESULTS: The ctB fragment was successfully amplified from Vibrio cholera strain 569B and inserted into two secretion expression vectors pSQZ and pSQ to construct food-grading expression system L. lactis MBP71/pSQZ-ctB and L. lactis MBP71/pSQ-ctB. Western-blot assay demonstrated that CTB was secretion and expressed from L.lactis MBP71 harboring vectors pSQZ-ctB and pSQ-ctB, and the quantity of CTB secreted by L. lactis MBP71/pSQ-ctB was about 2 microg/ml, higher than that of L. lactis MBP71/pSQZ ctB. CONCLUSION: CTB was successfully secreted and expressed by food-grading L. lactis expression systems. PMID- 20193318 TI - [A case-control study on risk factors of type 2 diabetes mellitus related chronic complications in Baoding city]. AB - OBJECTIVE: To recognize the main risk factors and to provide evidence for prevention and intervention of type 2 diabetes chronic complications. METHODS: A hospital-based frequency matched case-control study including 200 type 2 diabetes mellitus (T2DM) chronic complications cases and 200 controls without T2DM chronic complications was carried out in Baoding city. Relationships between factors and T2DM chronic complications were analyzed by non-conditional uni-variate and multivariate logistic regression methodologies. RESULTS: High C-reactive protein (CRP) (OR = 5.568), dyslipidemia (OR = 4.400), high blood urea nitrogen (BUN) (OR = 4.399), high low density lipoprotein-cholesterol (LDL-C) (OR = 3.594), time of hospitalization (OR = 2.612), grease food intake before developing DM (OR = 2.300), high HbA1c% (OR = 1.747), lack of exercise after the development of DM (OR = 1.672), duration of DM (OR = 1.509), mental stress (OR = 1.427), high quality sleep (OR = 0.606), well control of blood glucose (OR = 0.517), well control of blood fat (OR = 0.299), insulin injections (OR = 0.155) etc. were all significantly associated with T2DM chronic complications. CONCLUSION: The main risk factors of T2DM chronic complications seemed to be related to high CRP, dyslipidemia, high BUN and high LDL-C. The main protective factors were insulin injections, well control of blood fat and blood glucose, good-quality of sleep, while the unique risk factors of cardiovascular disease seemed to be high LDL-C and mental stress. The unique risk factors of neuropathy were lack of exercise after developing DM and the amount of sweet food intake. The duration of DM appeared to be the common risk factor and the common protective factor on those three complications was insulin injection. PMID- 20193319 TI - [Comparison of different definitions on metabolic syndrome in obese children]. AB - OBJECTIVE: To compare the prevalence rates of metabolic syndrome (MS) in obese children, according to three commonly used 'Pediatric MS definitions': (1) the International Diabetes Federation (IDF), (2) Cook, et al, and(3)da Silva, et al, in order to choose an appropriate one for the Chinese obese children. It was also intended to assess the variances of American or Chinese cutoff values on MS prevalence. METHODS: A retrospective study was performed in obese children from Obesity Outpatient Service Program from January 2004 to December 2008. Subjects were eligible if they met the following criteria: (1) aged 7 to 18 years, (2) with no following conditions as hereditary endocrine or metabolic diseases, secondary obesity, hepatic or renal disease, using medication that alters blood pressure or glucose or lipid metabolism etc., (3) data were complete on the variables of interest. Height, weight and waist circumference, systolic and diastolic blood pressure, fasting lipid profiles, blood sugar and insulin were measured. Insulin resistance was evaluated by homeostasis model assessment (HOMA). American or Chinese cutoff values were used to identify central obesity and hypertension. The prevalence rates of MS under three definitions were calculated and compared by Kappa test to determine the degree of agreement. RESULTS: 136 patients with 103 males and 33 females were enrolled in the study. According to the American cutoff value, 19.2%, 34.6%, 52.9% of the subjects were classified as MS under definitions of IDF, Cook, et al, da Silva, et al respectively, matching well with 19.2%, 43.4%, 58.1% when the Chinese cutoff value was used (Kappa = 1, 0.79, 0.90). The degrees of agreement according to the Kappa statistics between Cook, et al and da Silva, et al (0.52, American cutoff value/0.51, Chinese cutoff value) were better than the others (0.24 - 0.4). Children who were diagnosed as MS under the definitions of Cook, et al. or da Silva, et al. appeared to have had serious insulin resistance when compared to those without MS. CONCLUSION: Prevalence of the metabolic syndrome appeared to be high among the obese pediatric outpatients, which was probably due to the definition being chosen. The use of definitions provided by Cook, et al and da Silva, et al might be more suitable for MS diagnosis in obese children in the outpatient department, if insulin resistance was under consideration. Both American and Chinese cutoff value could be used for MS diagnosis in the Chinese obese children. PMID- 20193320 TI - [Applying multilevel models in evaluation of bioequivalence (I)]. AB - This study aims to explore the application value of multilevel models for bioequivalence evaluation. Using a real example of 2 x 4 cross-over experimental design in evaluating bioequivalence of antihypertensive drug, this paper explores complex variance components corresponding to criteria statistics in existing methods recommended by FDA but obtained in multilevel models analysis. Results are compared with those from FDA standard Method of Moments, specifically on the feasibility and applicability of multilevel models in directly assessing the bioequivalence (ABE), the population bioequivalence (PBE) and the individual bioequivalence (IBE). When measuring ln (AUC), results from all variance components of the test and reference groups such as total variance (sigma(TT)(2) and sigma(TR)(2)), between-subject variance (sigma(BT)(2) and sigma(BR)(2)) and within-subject variance (sigma(WT)(2) and sigma(WR)(2)) estimated by simple 2 level models are very close to those that using the FDA Method of Moments. In practice, bioequivalence evaluation can be carried out directly by multilevel models, or by FDA criteria, based on variance components estimated from multilevel models. Both approaches produce consistent results. Multilevel models can be used to evaluate bioequivalence in cross-over test design. Compared to FDA methods, this one is more flexible in decomposing total variance into sub components in order to evaluate the ABE, PBE and IBE. Multilevel model provides a new way into the practice of bioequivalence evaluation. PMID- 20193321 TI - [Progress of research on transmission and pathogenesis of hepatitis E virus]. PMID- 20193322 TI - [Drowning and its prevention]. PMID- 20193323 TI - [Great attention should be paid to the adverse drug reactions associated with the use of molecular targeted anticancer drugs]. PMID- 20193324 TI - [Differentiating effect of PPARgamma ligand rosiglitazone and all trans-retinoic acid on myeloma cells and its possible mechanism]. AB - OBJECTIVE: To investigate the effects of PPARgamma ligand (rosiglitazone, RGZ) as well as combined with all trans-retinoic acid (ATRA) on human myeloma cells and try to explore the possible mechanism. METHODS: Human myeloma cell lines U266 and RPMI-8226 cells were treated with RGZ in the presence or absence of ATRA. Cell proliferation was evaluated by [(3)H] thymidine incorporation, cell cycle distribution and CD49e expression were analyzed by flow cytometry, morphology changes were evaluated by Wright-Giemsa staining, and p27(Kip1) and p21(Waf1) expression was detected by Western blotting. RESULTS: The exposure to RGZ induced proliferation inhibition in both cell lines in a dose-dependent manner. After cultured with 5 micromol/L RGZ, the proportion of U266 and RPMI-8226 cells in phase G(0)/G(1) was (45.2 +/- 6.7)% and (40.3 +/- 7.3)%, respectively (P < 0.05). The proportion of the cells in phase G(2)/M and S was (52.2 +/- 7.4)% and (57.4 +/- 9.5)%, respectively (P < 0.05). These changes were more evident when the RGZ concentration was increased to 10 micromol/L. A combination of RGZ with ATRA enhanced the growth inhibition and cell cycle arrest effects of RGZ. The RGZ treated myeloma cells displayed morphological characteristics of cell differentiation, and more evident signs of differentiation were observed when RGZ was combined with ATRA. These changes were confirmed by the detection of CD49e expression. The expression of p27(Kip1) and p21(Waf1) in myeloma cells was up regulated by RGZ and this change was more apparent when RGZ was used in combination with ATRA. CONCLUSION: RGZ can induce cell cycle arrest and cell differentiation in myeloma cells which maybe caused by up-regulation of p27(Kip1) and p21(Waf1) expression. ATRA can enhance these effects of RGZ on multiple myeloma cells and combined use of these two drugs may show a synergistic effect on myeloma cells. PMID- 20193326 TI - [Immunological killing effect of recombicant adenovirus vector rAD-mTERT-m4-1BBL on mouse hepatoma cell line Hepa1-6 cells co-cultured with T lymphocytes]. AB - OBJECTIVE: To study the immunological suppressing effect of recombinant adenovirus vector rAD-mTERT promotor-m4-1BBL (rAD-mTERT) on mouse hepatoma cell line Hepa1-6 cells in co-culture with T lymphocytes. METHODS: Adding recombinant adenovirus rAD, rAD-CMV-m4-1BBL (rAD-CMV) and rAD-mTERT to Hepa1-6 and L929 cells, respectively, to observe the effect of these adenoviruses on growth and apoptosis of these cells in co-culture with T lymphocytes. RESULTS: Adding adenovirus significantly suppressed the growth and slightly increased apoptosis of the two types of cells (P < 0.05). rAD-mTERT promotor-m4-1BBL showed only pro apoptotic effect on Hepa1-6 cells. When co-cultured with T lymphocytes, rAD-CMV m4-1BBL showed promoting effect on apoptosis of the cells. Compared with that of T cells pre-co-culture, CD4(+) and CD8(+) T cells were proliferated, and the ratio of CD4/CD8 was significantly reduced (from 1.27 to 1.08). CONCLUSION: Adding the recombinant adenoviruses only suppresses the cell growth, but not promotes their apoptosis. In co-culture with T lymphocytes, recombinant adenovirus vector rAD-mTERT promotor-m4-1BBL can targetingly suppress the growth and induce apoptosis of Hepa1-6 cells. The apoptosis is induced through the immunological killing effect of T lymphocytes. PMID- 20193325 TI - [Apoptosis in Jurkat cells induced by bortezomib combined with adriamycin]. AB - OBJECTIVE: The aim of this study was to observe the suppressive effect of bortezomib alone and the synergistic suppressive effect of bortezomib and adriamycin on the proliferation of the cell line Jurkat cells, and to discuss the mechanism of apoptosis induced by bortezomib. METHODS: The suppressive effect of bortezomib and adriamycin on the proliferation of Jurkat cells in vitro was detected by MTT colorimetry, and the morphology of the cells was examined by histology. The cell apoptosis was measured by flow cytometry with Annexin V/PI staining and cell cycle analysis. The effect of bortezomib and adriamycin on the expression levels of caspase-3, caspase-8 and PARP were measured by Nestern blot. RESULTS: The proliferation of Jurkat cells was significantly inhibited by bortezomib treatment (between 10 - 320 ng/ml) for 24 h, 48 h and 72 h, and the growing inhibition ratio showed a positive correlation with the drug concentration (r(24 h) = 0.900, P < 0.01; r(48 h) = 0.849, P < 0.01; r(72 h) = 0.679, P < 0.01), in a concentration-dependent manner. The IC(50) of Jurkat cells treated with bortezomib in a dose of 10 - 320 ng/ml was 137.64 +/- 6.82 ng/ml, but the IC(50) of Jurkat cells treated with bortezomib combined with adriamycin (125 ng/ml) for 24 h was significantly decreased to 20.44 +/- 2.85 ng/ml. The apoptosis rate had a positive correlation with the concentration of bortezomib (P < 0.01). After the Jurkat cells were treated with bortezomib, apparent shear bands of caspase-8, caspase-3 and PARP proteins were observed. CONCLUSION: There is an effect of Bortezomib to induce apoptosis in Jurkat cells, and the extrinsic pathway is one of the apoptosis-inducing mechanisms. There is a synergistic suppressive effect of the combination of bortezomib and adriamycin on the proliferation of Jurkat cells and enhances their chemosensitivity. PMID- 20193328 TI - [Mechanism of intravesical instillation of pirarubicin for preventing recurrence of non-muscle invasive bladder cancer]. AB - OBJECTIVE: To evaluate the apoptosis-inducing effect of intravesical instillation of pirarubicin (THP) on bladder cancer and normal bladder tissue, and explore the mechanism of such treatment for preventing recurrence of non-muscle invasive bladder cancer. METHODS: Forty patients with primary non-muscle invasive bladder cancer were treated in our hospital from January 2006 to October 2008. The patients were divided into three groups, including 15 cases treated by intravesical instillation of THP (30 mg/50 ml, 0.5 hours) at 1 hour, 15 cases at 24 hours before transuretheral resection of bladder tumor (TUR-BT), and 10 cases in control group who received TUR-BT only. The THP uptake of the tumor and normal bladder tissues was observed by fluorescence microscopy, the apoptosis was assessed with TUNEL staining, and immunohistochemistry was used to detect the expression of bcl-2 and bax. RESULTS: Seldom fluorescence of THP in normal bladder tissues and some diffuse fluorescence reaching the muscular layer in the tumor area were observed after THP instillation at 1 hour before TUR-BT. The fluorescence of THP could still be observed in the tumor tissues at 24 hours after THP instillation. The apoptosis indexes (AI) of tumors in the chemotherapy groups were significantly higher than that in the control group (P < 0.01). There was a correlation between bcl-2/bax ratio and AI. CONCLUSION: Pirarubicin can be uptaken by bladder cancer tissue selectively and induces apoptosis of tumor cells. The changes of expression of bcl-2 and bax and decreasing of the bcl-2/bax ratio may be an important mechanism of action of the intravesical instillation of THP for preventing recurrence of non-muscle invasive bladder cancer. PMID- 20193327 TI - [Relationship between estrogen-biosynthesis gene (CYP17, CYP19, HSD17beta1) polymorphisms and breast cancer]. AB - OBJECTIVE: To explore the relationship between the polymorphism of estrogen biosynthesis genes (CYP17, CYP19, HSD17beta1) and risk of breast cancer. METHODS: A matched case-control study was designed. From May 2007 to July 2008, 200 pairs of subjects with and without breast cancer were enrolled, who were matched by age and menstruation status. Demographical characteristics, dietary factors and reproductive factors were investigated by questionnaire. CYP17 locus 1931 (T- >C), CYP19 codon 264 (Arg-->Cys) and HSD17beta1 locus 1954 (A-->G) were identified by AS-PCR (allele-specific PCR). The gene-gene interaction were analyzed with the MDR model (multifactor dimensionality reduction). Based on the results of MDR model, an unconditional logistic regression model was simulated to estimate the ORs of interaction factors and other risk factors. RESULTS: The main effect of CYP17, CYP19 and HSD17beta1 susceptible genotypes were not correlated to breast cancer (OR approximately 1, P > 0.05). The positive interaction effect between CYP17 (T 1931C) and HSD17beta1 (A1954G) was discovered by MDR model with a statistically significant difference (Sign test, P = 0.05). The model's testing balance accuracy was 56.00%, and crossing validation consistency was 10/10. Multivariable unconditional logistic regression showed that after adjusting BMI, intake of estrogen, age of first birth, number of abortion and period of breast feeding, the interaction item of CYP17 (T1931C) and HSD17beta1 (A1954G) was strongly and positively correlated to breast cancer (OR = 2.52, 95%CI = 1.54 to 4.11). CONCLUSION: The estrogen-biosynthesis genes CYP17 (T1931C) and HSD17beta1 (A1954G) polymorphism may jointly increase the risk of breast cancer. PMID- 20193329 TI - [Surface detection of thyroid cancer by Fourier transform infrared spectroscopy]. AB - OBJECTIVE: To explore a novel non-invasive method in detection of thyroid cancer by Fourier transform infrared (FTIR) spectroscopy. METHODS: Surface FTIR spectra of 15 cases of thyroid cancer and 51 cases of normal subjects were collected. 22 variables of 11 bands including peak positions and relative intensities were measured and all data were statistically analyzed. RESULTS: In the cancer group: (1) the peak position of 1743 cm(-1) was shifted toward higher wave number (P < 0.05), and that of 1250 cm(-1) to the lower (P < 0.05), when compared to those of normal ones. (2) The relative intensity ratios of I(1546)/I(1460), I(1250)/I(1460), I(1120)/I(1460), I(1080)/I(1460) were significantly increased (P < 0.05). (3) The presence rate of band of 1340 cm(-1) was significantly decreased (P < 0.05). CONCLUSION: FTIR surface spectra may become a novel powerful non invasive approach of detecting thyroid cancer in regular routine check-up. PMID- 20193330 TI - [Relationship of osteolytic biochemical indicators of bone metabolism with the therapeutic effect in breast cancer patients with bone metastases]. AB - OBJECTIVE: The aim of this study was to access the relationship of osteolytic bone metabolic markers such as serum type I collagen carboxy-terminal telopeptide (sICTP), N-terminal cross-linked telopeptides of type I collagen (uNTx), urinary pyridinoline (uPyd) with the therapeutic effect in breast cancer patients with bone metastases. METHODS: 120 patients with breast cancer were included in this study. The levels of sICTP, uNTx and uPYD were measured by ELISA assay. The differences were compared between patients with and without bone metastasis. The patients with bone metastasis were treated and followed up as clinically indicated. RESULTS: The levels of all above mentioned biomarkers in patients with bone metastasis were significantly higher than that in patients without bone metastasis (P < 0.01). A significant correlation was found between each two markers (r > 0.5, P < 0.01). The biomarkers were examined again in 45 patients with bone metastasis after treatment to evaluate the treatment response. The median follow-up was 10 months. Based on clinical evaluation criteria, 25 patients were responders and 20 were non-responders. For responders, after 3 months treatment, the levels of the three bone markers were significantly reduced (P = 0.025, P < 0.001, P < 0.001). But for non-responders, with progression of bone lesions, the levels of the three markers were significantly raised (P = 0.011, P = 0.002, P = 0.002). By means of multiple logistic regression with stepwise selection, the uPyd and uNTx activities were closely correlated with treatment response (OR = 17.0, P = 0.019; OR = 16.7, P = 0.015), however, the sICTP did not show any correlation with treatment response P = 0.841). CONCLUSION: The levels of sICTP, uNTx and uPyd may be used as indicators in assessment of the effect of antiresorptive treatment and evaluation of prognosis in breast cancer patient with bone metastases. PMID- 20193331 TI - [Clinical characteristics and survival of peripheral T-cell lymphoma-not otherwise specified: a report of 57 cases]. AB - OBJECTIVE: To analyze the clinical characteristics and survival data of 57 patients with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS). METHODS: The medical records of 57 patients with PTCL-NOS classified according to the revised REAL-WHO criteria, treated from Jan 1993 to Dec 2007 at the First and the Third affiliated Hospitals of Medical School of Xi'an Jiaotong University, were retrospectively evaluated by K-M univariate and COX multivariate analysis. RESULTS: 39 of the patients (68.4%) were males and 18 (31.6%) were females, aged 44 (3 - 88). Nine of the 57 patients (15.8%) were treated with chemo radiotherapy, 43 (75.4%) with chemotherapy, 3 (5.3%) with radiotherapy, and 2 with supported treatment alone (2.5%). The overall response rate was 87.3%, with a complete remission (CR) rate of 60.0% in 55 evaluable cases. The 1-, 3-, and 5 year overall survival (OS) rates were 67.0%, 48.0% and 24.3%, respectively, with a median follow-up of 30.4 months (ranged 1-100 months). The median survival time (MST) was 36.0 months. Multivariate analysis showed that the prognostic index for T cell lymphoma (PIT) score was an independent prognostic factor for PTCL-NOS (P < 0.05), but bone marrow involvement, performance status, extranodal involvement, stage, B symptom were not independent prognostic factors. CONCLUSION: Although conventional chemotherapy yields a high response rate for PTCL-NOS, the long-term survival is still low and further investigation for optional treatment is needed. PMID- 20193332 TI - [Relationship between CK18 expression in pathologically negative lymph nodes and Tiam 1 mRNA expression in the gastric cancer tissue]. PMID- 20193333 TI - [Comparison of the clip displacement in the operation cavity during external-beam partial breast irradiation depicted by kV-plain film and cone-beam CT under active breathing control assisted with moderate deep inspiration breath hold.]. PMID- 20193334 TI - [Clinical analysis of the peri-operative complications following percutaneous transhepatic biliary drainage or stent implantation]. PMID- 20193335 TI - [Evaluation of the diagnostic value of (18)F-FDG PET-CT and enhanced CT for staging of lymph node metastasis in non-small cell lung cancer]. AB - OBJECTIVE: To evaluate the clinical value of (18)F-FDG PET-CT and enhanced CT imaging for staging of regional lymph node metastasis in non-small cell lung cancer (NSCLC) patients. METHODS: 122 patients with proven or suspected NSCLC underwent integrated PET-CT and enhanced CT scan before surgery. The results of lymph node metastasis diagnosed by PET-CT and CT were compared and analyzed according to the results of histopathological examination. RESULTS: PET-CT showed correctly lymph node staging in 80.3% of cases, overstaged in 13.1%, and understaged in 6.6%, while 55.8%, 26.2% and 18.0% by CT, respectively. The sensitivity, specificity, and accuracy of PET-CT for lymph node staging was 86.3%, 85.0% and 85.3%, respectively, while the corresponding data were 68.6%, 71.0% and 70.4% by CT, respectively (P < 0.01). 81.3% of false-negative and 71.6% false-positive lymph nodes by CT were interpreted correctly by PET-CT, while 57.1% of false-negative and 45.2% of false-positive lymph nodes by PET-CT were correctly diagnosed by CT. 5.9% of PET-CT-diagnosed negative lymph nodes were pathologically proven to be positive with small cancer foci and below 10 mm in diameter, while 8.2% of pathologically proven negative lymph nodes with inflammation, high FDG uptake and exceeding 10 mm (15 mm in subcarnial nodes) in diameter were false-positive on both PET-CT and CT imaging, therefore, these lymph nodes were still in the common blind area of diagnosis by both of PET-CT and CT. CONCLUSION: Compared with enhanced CT, integrated PET-CT improves the accuracy and is helpful to correct some CT-diagnosed false-positive and false negative lymph nodes. But CT is also beneficial supplementation to PET-CT for assessment of regional lymph node metastasis. The combination of PET-CT and CT can make up the shortage of both of them in staging of regional lymph nodes in NSCLC patients. PMID- 20193336 TI - [Value of mediastinoscopy in preoperative staging of non-small cell lung cancer based on survival analysis]. AB - OBJECTIVE: To evaluate the value of mediastinoscopy in preoperative staging of non-small cell lung cancer (NSCLC) based on survival analysis. METHODS: 152 cases of potentially operable NSCLC were enrolled in this study. All cases underwent CT scan and mediastinoscopy for assessment of the mediastinal lymph node status before initial treatment. The definitive treatment was decided on the basis of mediastinoscopy and the survival rate was analyzed with a median follow-up of 30.5 months. Survival analysis was conducted by comparing the lymph node status which was determined by final pathology (groups pN0, pN1, pN2, pN3), CT scan (group cN0-1, cN2-3) and mediastinoscopy (group mN0-1, mN2, mN3). RESULTS: The 5 year survival rates in group pN0, pN1, pN2 and pN3 were 61.7%, 75.0%, 32.4% and 16.1%, respectively. Both groups pN0 and pN1 had significantly higher survival rates than those in groups pN2 and pN3 (P < 0.05). There were not significant differences between survival rates in groups cN0-1 and cN2-3 (P = 0.670), while the survival rate in group mN0-1 was significantly higher than that in groups mN2 and mN3 (P < 0.05). CONCLUSION: Mediastinoscopy is of great value in preoperative staging of NSCLC. Not only does it detect lymph node metastasis more precisely but also better predict the prognosis than CT scan. PMID- 20193337 TI - [Oxaliplatin-based regimen for the treatment of advanced or metastatic gastric/esophagogastric junction cancer]. AB - OBJECTIVE: To evaluate the efficacy and toxicity of oxaliplatin-based regimen in patients with advanced or metastatic gastric/esophagogastric junction cancer (AGC). METHODS: The clinicopathological data of a total of 180 patients with AGC were retrospectively analyzed. Responses was evaluated by RECIST criteria, and toxicity were assessed according to the NCI-CTC AE version 3.0. RESULTS: 155 patients received mFOLFOX regimen, and 25 patients received regimens of mEOF and CapOX, with a total chemotherapy of 717 cycles with a median of 3 cycles. The therapeutic response was evaluated in 150 patients, showing response rate (RR) of 30.0% and disease control rate (DCR) of 74.0%. The response was evaluated in 103 of 124 patients who received the therapy as 1st line, with RR of 34.0%, DCR of 74.8%, and overall survival of 11.3 months. The major grade III/IV adverse events were leucocytopenia (14.4%), neutropenia (17.8%), thrombocytopenia (3.8%), nausea/vomiting (8.9%), and peripheral neuropathy (2.2%), with no treatment related death. CONCLUSION: Oxaliplatin-based regimen is active and well tolerated in patients with advanced or metastatic gastric/esophagogastric junction cancer. PMID- 20193338 TI - [The effect of thalidomide in preventing delayed nausea and vomiting induced by GP regimen of chemotherapy for non-small cell lung cancer]. AB - OBJECTIVE: To observe the effect of thalidomide in preventing nausea and vomiting induced by emetogenic cisplatin (CDDP) chemotherapy in patients with advanced non small cell lung cancer. METHODS: This study was carried out as a prospective, randomized control clinical trial. 61 patients with advanced non-small cell lung cancer were scheduled to receive chemotherapy (gemcitabin 1000 mg/m(2) i.v. gtt d1, 8 and CDDP 75 mg/m(2) i.v. gtt d1, GP regimen). The patients were randomly divided into a treatment and control groups. All patients in both groups received ramosetron 0.3 mg intravenously (i.v.) and metoclopramide 20 mg intramuscularly (i.m.) 30 min prior to chemotherapy to prevent nausea and emesis on day 1. In the treatment group, addition of thalidomide (50 mg p.o. bid) were administered on days 1 to 5 after the start of chemotherapy. RESULTS: Acute nausea was effectively controlled in 74.2% of the patients in the control group and in 90.0% of treatment group. Acute vomiting was effectively controlled in 90.3% of the patients in the control group and in 93.3% of treatment group. No statistically significant differences showed in effective control of acute nausea and vomiting between the 2 groups (P = 0.108; P = 1.000). Delayed nausea was effectively controlled in 19.4% of the patients in control group and in 56.7% in the treatment group. Delayed vomiting was effectively controlled in 48.4% of the patients in control group and 76.7% in treatment group. Statistically there was a significant differences in effective control of delayed nausea and vomiting between the 2 groups (P = 0.003, P = 0.023). Both antiemetic regimens were well tolerated, and no significant difference was observed in adverse events between the 2 groups (P > 0.05). CONCLUSION: Our results demonstrate that thalidomide is highly effective in controlling delayed nausea and vomiting episodes in patients induced by moderately emetogenic chemotherapy. Moreover, no serious toxic effects are induced by this treatment. PMID- 20193339 TI - [Clinical application of intersphincteric resection in the anal-preserving operation for ultra-low rectal carcinoma]. AB - OBJECTIVE: To investigate the clinical application of intersphincter resection (ISR) combined with total mesorectal excision (TME) and colon-anal anastomosis in the treatment for ultra-low rectal carcinoma. METHODS: To review and analyze retrospectively the data of 34 patients with ultra-low rectal carcinoma (without external anal sphincter involvement) who received treatment of ISR, TME and colon anal anastomosis. RESULTS: Partial resection of internal sphincter was performed in the patients with a distal edge of the tumor greater than or equal to 2 cm from the dentate line. Subtotal removal of the rectum was performed between 1 cm and 2 cm. Total resection was performed in less than 1 cm or involvement of dentate line. Reconstruction of digestive tract was done by manual colon-anal anastomosis. The average distance from distal excised margin to the tumor was 2.3 (1.8 - 3.2) cm among 34 patients. The pathological types were as follows: 28 cases of adenocarcinoma (11 were well differentiated, 17 moderately differentiated), 1 case of papillary carcinoma and 5 cases of villous adenoma with malignant change. The postoperative pathological stages were: Dukes stage A in 28 cases, stage B in 1 and stage C in 5 cases. The pTNM staging was 28 cases in phase I, 1 in phase IIa, 4 in phase IIIa and 1 in phase IIIb. The T stages of the patients were as following: 16 Tl, 17 T2 and 1 T3. Postoperative anastomotic stenosis occurred in 3 cases, anastomotic dehiscence in 2 cases and rectovaginal fistula in 2 cases. The ability of controlling feces of patients decreased significantly in the early postoperative period, and restored gradually at 6 to 12 months after operation. Anastomotic recurrence occurred in 1 case at 5 months after operation and liver metastasis in 1 case at 40 months. CONCLUSION: With strictly grasping indications, radical resection can be attained and anal sphincter preserved by ISR combined with TME and colon-anal anastomosis. It is an effective sphincter-preserving operation. PMID- 20193340 TI - [Minimally invasive video-assisted thyroidectomy for thyroid cancer]. PMID- 20193341 TI - [Some problems in gynecologic oncology and training of gynecologic oncologists]. PMID- 20193342 TI - [Controversy and new opinions on classification of idiopathic interstitial pneumonias.]. PMID- 20193343 TI - [The treatment of interstitial lung disease with corticosteroids.]. PMID- 20193344 TI - [Differential diagnosis should be strengthened in patients with diffuse parechymal lung diseases.]. PMID- 20193345 TI - [Tissue biopsy and pathological diagnosis of sarcoidosis.]. PMID- 20193346 TI - [Clinical and radiological features of pulmonary tuberculosis manifested as interstitial lung diseases.]. AB - OBJECTIVE: The purpose of this paper was to investigate the clinical and radiological features of pulmonary tuberculosis presenting as interstitial lung diseases (ILD). METHODS: We analyzed the data of cases suspected of diffuse parenchyma lung diseases at this hospital between October 2003 and October 2007. The diagnosis of active pulmonary tuberculosis was based on epithelioid granuloma or positive acid-fast bacilli in lung biopsy and changes on serial radiographs obtained during treatment. RESULTS: The data of a series of 230 consecutive patients with suspected ILD were retrospectively analyzed. The diagnosis was confirmed by lung biopsy. Twelve patients were confirmed to have pulmonary tuberculosis. There were 5 males and 7 females with a mean age of 38 +/- 11 years (range, 17 - 68). The median course of disease in these patients was 3 months (range, 0.5 - 18 months). Patients with pulmonary tuberculosis presented with fever (11/12), cough (9/12), weight loss (7/12), dyspnea (7/12), lymphadenopathy (4/12), and splenohepatomegaly (2/12). On chest CT scan, ground-glass attenuation was identified in 4, bilateral patchy infiltration in 5, tree-in-bud appearance 1, and centrilobular lesions in 2 of the 12 patients. During the follow-up period (median, 9 month, range from 3 to 12 month), 11 patients improved, but 1 died of diabetic ketoacidosis. CONCLUSION: The diagnosis of pulmonary tuberculosis should be considered in suspected ILD patients presenting with fever, splenohepatomegaly and lymphadenopathy. PMID- 20193347 TI - [A preliminary study on the mechanisms of N-acetylcysteine in the inhibition of proliferation and collagen synthesis of human pulmonary fibroblasts.]. AB - OBJECTIVE: To study the mechanisms of N-acetylcysteine (NAC) in the inhibition of proliferation and collagen synthesis of human pulmonary fibroblasts. METHODS: The human pulmonary fibroblasts (HFB) were primarily cultured in complete medium of DMEM/F12, with the cell line A549 derived from alveolar epithelia as the control. Different concentrations of NAC were administrated, with or without stimulation by TGF-beta(1) for 24 h. The cell proliferations were tested by methylthiazolyltetrazolium (MTT) and cell cycle detected with flow cytometer. The mRNA expression of type I procollagen was tested with RT-PCR. Proteins of cyclin E, alpha-SMA and STAT-3 were detected with Western blotting. RESULTS: The proliferation of HFB was inhibited significantly by NAC at different concentrations (5, 10, 20 and 40 mmol/L). NAC had no effects on proliferation of A549 at a dose of 20 mmol/L. The cell proportion in G(0)/G(1) phase was increased by NAC at different concentrations (10, 20 and 40 mmol/L), while the changes in S phase ratio were decreased significantly. Procollagen type Isynthesis was increased by TGF-beta(1) significantly. NAC showed inhibition on procollagen type I synthesis before or after stimulation with TGF-beta(1). Expression of protein cyclin E and alpha-SMA was significantly induced by TGF-beta(1), the relative indensity being 0.98 +/- 0.09 and 1.56 +/- 0.23 respectively. Induction of cyclin E by TGF-beta(1) was attenuated significantly by NAC 20 mmol/L (0.52 +/- 0.04). But alpha-SMA was not changed by NAC 20 mmol/L (1.63 +/- 0.20). Stimulation with TGF-beta(1) and NAC had no effects on expression of STAT-3. CONCLUSIONS: Inhibition on proliferation of HFB by NAC may be through the attenuation of cyclin E. Differentiation of fibroblasts into myofibroblasts was inhibited by NAC through inhibition on alpha-SMA. NAC directly inhibited collagen synthesis. PMID- 20193348 TI - [The effect of autologous bone marrow-derived cells mobilized by granulocyte colony stimulating factor on bleomycin-induced lung injury in mice.]. AB - OBJECTIVE: To investigate the contribution of mobilized autologous bone marrow derived cells (BMDC) to lung repair after lung injury induced by bleomycin, and the mechanisms of any protective effects conferred by BMDC. METHODS: Sixty marrow reconstructed mice were randomly divided into 2 groups: group A [bleomycin + granulocyte colony stimulating factor (G-CSF)] and group B (bleomycin + saline). Seventy-five normal mice were randomly divided into 3 groups: group C (bleomycin + G-CSF); group D (bleomycin + saline) and group N (saline only). Each group was further divided into 3 subgroups, which were sacrificed respectively on days 3, 7 and 14. Therapeutic evaluations were made by means of HE stain, Masson's trichrome stain, hydroxyproline concentration and pulmonary permeability index. The expressions of TGF-beta(1), IFN-gamma, MMP-9 and TIMP-1 in the lung tissue were detected by immunohistochemistry. Intrapulmonary BMDC was evaluated by flow cytometry and laser scanning confocal microscope. Another 20 mice were randomly divided into 2 groups including group E (bleomycin + G-CSF) and group F (bleomycin + saline). The survival time of each mouse was observed without end point. RESULTS: The alveolitis score (mean rank 15.3), the pulmonary fibrosis score (46 +/- 8), the hydroxyproline concentrations (0.44 +/- 0.09) microg/mg, the TGF-beta(1) level (111 +/- 23), the IFN-gamma level (250 +/- 72) and the MMP 9 level (59 +/- 19) were significantly decreased in reconstructed treatment group on day 7 as compared to reconstructed control group, which was respectively (mean rank 28.0), (73 +/- 10), (0.52 +/- 0.07) microg/mg, (161 +/- 35), (299 +/- 31) and (314 +/- 77). Likewise, the alveolitis (mean rank 22.7), the pulmonary fibrosis (27 +/- 15), the hydroxyproline concentrations (0.41 +/- 0.05) microg/mg, the pulmonary permeability index (43.8 +/- 9.9) x 10(-3), the TGF beta(1) level (132 +/- 55), the IFN-gamma level (178 +/- 23), and the MMP-9 level (101 +/- 54) in non-reconstructed treatment group on day 7 were significantly lower than those in non-reconstructed control group, (mean rank 33.9), (56 +/- 13), (0.49 +/- 0.08) microg/mg, (54 +/- 9) x 10(-3), (320 +/- 98), (409 +/- 61), (288 +/- 75), the differences being statistically significant (P < 0.05). The intrapulmonary BMDC level of reconstructed treatment group (0.65 +/- 0.13) was significantly higher than that in reconstructed control group (0.46 +/- 0.11), P < 0.05. CONCLUSION: Mobilization of BMDC by G-CSF showed a protective effect on lung injury induced by bleomycin in mice, but did not have significant influence on survival time. PMID- 20193349 TI - [Serum retinol and retinol binding protein-4 levels in patients with chronic obstructive pulmonary disease and their relationship to nutritional status.]. AB - OBJECTIVE: To explore the serum retinol and retinol binding protein-4 (RBP(4)) levels in patients with chronic obstructive pulmonary disease (COPD) and to investigate their relationship with the nutritional status. METHODS: The serum retinol level was determined by high-performance liquid chromatography (HPLC) in 110 outpatients with stable COPD during Sept. 2006 to Sept. 2007, and 90 healthy volunteers served as the controls. The serum RBP(4) level in 62 stable COPD outpatients and 20 healthy controls was measured by enzyme-linked immunosorbent assay (ELISA). Associated factors with the serum retinol and RBP(4) levels were analyzed. t-test and one-way ANOVA were used for the statistic analysis. RESULTS: The serum retinol and RBP(4) levels in COPD patients [(275 +/- 11) microg/L and (7.4 +/- 2.6) mg/L respectively] were significantly lower than those in the healthy controls [(338 +/- 13) microg/L and (11.4 +/- 4.1) mg/L respectively, t = 3.650, t = 4.155 and all P < 0.01]. The serum retinol and RBP(4) levels in COPD patients with malnutrition [(246 +/- 18) microg/L and (6.4 +/- 1.0) mg/L individually] were significantly lower than those in COPD patients without malnutrition [(290 +/- 14) microg/L and (8.2 +/- 3.2) mg/L individually, q = 3.35, P < 0.05 and q = 10.22, P < 0.01 respectively], but the levels of serum retinol and RBP(4) in COPD patients without malnutrition were significantly lower than those in the healthy controls [(338 +/- 13) microg/L and (11.4 +/- 4.1) mg/L respectively, q = 2.26, P < 0.05 and q = 4.82, P < 0.01 respectively]. In a multiple stepwise regression analysis, only body mass index and mid arm circumference were independently associated with the serum retinal level. CONCLUSION: In patients with stable COPD, the levels of serum retinol and RBP(4) were significantly decreased, which was associated with the nutritional status. PMID- 20193350 TI - [Clinical significance of serum copeptin in patients with community-acquired pneumonia.]. AB - OBJECTIVE: To study the clinical significance of serum copeptin in patients with community-acquired pneumonia (CAP). METHODS: Sixty-two cases of hospitalized CAP including 32 males and 30 females with a mean age of (45 +/- 25) years were recruited from the respiratory wards in the affiliated Zhongda Hospital of Southeast University from March 2009 to June 2009. Sixteen healthy volunteers including 8 males and 8 females with a mean age of (41 +/- 23) years served as the control. The CAP patients were divided into 3 groups: grade I - III (n = 24), grade IV (n = 20) and grade V (n = 18) according to pneumonia severity index (PSI). Serum copeptin, blood routine, serum high-sensitivity C-reactive protein, arterial partial pressure of oxygen (PaO2) and oxygenation index (PaO2/FiO2) were detected in the patients with CAP before and after the treatment as well as the volunteers in the control group. The difference of related data among 4 groups were compared. q test was adopted in the comparison between the groups, and group paired t test was adopted in the comparison between parameters before and after the treatment. RESULTS: Serum copeptin concentration of the grade V patients [(0.91 +/- 0.16) microg/L] was significantly higher than those of thegrade IV patients [(0.56 +/- 0.11) microg/L], grade I - III patients [(0.34 +/- 0.06) microg/L] and the control group [(0.08 +/- 0.02) microg/L] before the treatment. Serum copeptin concentration of the grade V patients [(0.11 +/- 0.04) microg/L], grade IV patients [(0.13 +/- 0.05) microg/L], and grade I - III patients [(0.07 +/- 0.03) microg/L] after the treatment were significantly lower than those before the treatment. Serum high-sensitivity C-reactive protein and the total number of white blood cells of the patients with CAP were significantly higher than those of the control group before the treatment. Serum high-sensitivity C reactive protein and total number of white blood cells of the patients with CAP were significantly decreased after the treatment. PaO2 and PaO2/FiO2 of the grade V patients were significantly lower than those of the grade IV patients, grade I III patients and the control group before the treatment, and were significantly increased after the treatment. CONCLUSION: Serum copeptin could be used as an inflammatory marker for judging the treatment efficacy in patients with CAP. PMID- 20193352 TI - [Clinical manifestations and radiological features of hepatopulmonary syndrome.]. AB - OBJECTIVE: To investigate the clinical and radiological features of hepatopulmonary syndrome (HPS). METHODS: Twenty two cases diagnosed as HPS in Peking Union Medical College Hospital from Nov, 1996 to Nov, 2008 were reviewed. Their clinical features and radiological findings were analyzed. RESULTS: The study included 12 males and 10 females with a mean age of (44 +/- 17) years and mean course of (54 +/- 52) months. Abnormalities on chest CT scans were found in 12 cases, which included intrapulmonary artery dilatation in 10 cases, with subpleural small nodular, reticular and patchy opacities; bilateral lower basal segmental artery dilatation in 3 cases; main pulmonary artery dilation in 1 case; right ventricular enlargement in 1 case and bilateral pleural effusion in 1 case. The chest CT was normal in 6 cases. CTPA and pulmonary artery angiogram were performed in 15 cases and artery dilatation was found in 4. Diffuse liver diseases were found in 12 cases by CT scans, 10 of them presented as typical hepatic cirrhosis and 2 cases as liver hepatomegaly, while esophagus varix and(or) fundus gastricus varix were found in 12 cases and splenomegaly in 6 cases, hydroperitonia in 3 cases. CONCLUSION: Clinical manifestations combined with CT features were helpful for the diagnosis of HPS. PMID- 20193351 TI - [A comparison of the blind double-lumen plugged telescoping catheter with protected specimen brush for the diagnosis of ventilator-associated pneumonia.]. AB - OBJECTIVE: To compare the diagnostic value of blind double-lumen plugged telescoping catheter (PTC) and protected specimen brush(PSB) in patients requiring mechanical ventilation (MV) for suspected ventilation-associated pneunonia (VAP). METHODS: Sixty-nine patients with a hospital stay of >/= 48 h who required MV for suspicion of VAP were prospectively enrolled in the study during Jan 2008 and Feb 2009 in the medical intensive care unit. The patients all underwent bronchial samplings: a blind PTC and a fiberoptic PSB were performed successively in each case. A positive culture for both sampling procedures was defined as the recovery of >/= 10(6) CFU/L of at least one potential pathogen. RESULTS: The overall specimen were judged by film preparation through the microscopic examination. The positive result of PTC and PSB were 60 (87.0%) and 58(84.1%) respectively. Bacterial culture was performed for all the specimen and PSB was regarded the golden standard. PTC had a sensitivity of 82.1%, a specificity of 92.7%, a positive predictive value of 88.5%, and a negative predictive value of 88.4%. CONCLUSION: PTC may be a reliable alternative to the newly mechanically ventilated patients with suspicion of VAP. PMID- 20193353 TI - [Food-dependent exercise-induced anaphylaxis: case report and review of literature.]. AB - OBJECTIVE: Food-dependent exercise-induced anaphylaxis (FDEIA) is a kind of food allergic disorder induced by physical exercise. Some FDEIA patients presented severe symptoms which were threat to life. The aim of the article was to improve the recognition of FDEIA among physicians. METHODS: The clinical data of a patient with FDEIA in our hospital was collected and analyzed, and current related literatures were reviewed. RESULTS: An eighteen year-old male was admitted to our hospital because of repeated episodes of urticaria, dyspnea and loss of consciousness for eight months. Each episode was induced by exercise after ingestion of wheat-made food. Symptoms were relieved rapidly by treatment with adrenaline, antihistamines, and/or dexamethasone. Assay of food-specific IgE in serum of the patient showed positive result for shrimp and crab. However, no anaphylaxis was related to the suspected food. Wheat-exercise challenge test showed positive result in the patient, which confirmed the diagnosis of FDEIA. Since then, the patient had avoided wheat food for more than one year, during which period no episode of anaphylaxis was observed, until one day the patient exercised after a diet of wheat food. CONCLUSIONS: The incidence of FDEIA was rare. Wheat is the common causative food. Food-exercise challenge test is a reliable method for diagnosis of FDEIA. Avoidance of exercise for 4h after eating causative food might be helpful to prevent the occurrence of symptoms in many FDEIA cases. Dietary elimination of causative food ingredients was a reliable method for prophylaxis of FDEIA. PMID- 20193354 TI - [Lipid frofile and hemorheology in obstructive sleep apnea-hypopnea syndrome.]. AB - OBJECTIVE: To investigate whether there was a correlation between lipid level, hemorheology and the obstructive sleep apnea hypopnea syndrome. METHODS: Two hundred and thirty-one subjects in our sleep respiratory disease center between 2006 and 2009 were included. Eighty nine were obese OSAHS subjects, 62 were non obese OSAHS subjects, 40 were obese subjects without OSAHS (obese group) and 40 were non-obese subjects without OSAHS (control group). We examined and compared the lipid profile and hemorheology in all subjects. RESULTS: In obese OSAHS group, the levels of triglyceride (TG) [(2.74 +/- 2.02) mmol/L], cholesterol (TC) [(5.14 +/- 0.96) mmol/L] were higher and HDL [(1.13 +/- 0.36) mmol/L], apoA-I [(1.20 +/- 0.20) mmol/L] were lower, compared to the non-obese OSAHS group (F = 7.77, 7.99, all P < 0.01). The level of the whole blood viscosity in obese OSAHS group was significantly higher than that in non-obese OSAHS group (F = 8.81 11.99, P < 0.05). There was no significant difference in blood lipid levels among the 2 study groups:non-obese OSAHS and control group, obese OSAHS and obese group (F = 6.42 - 11.99, P > 005). The levels of the whole blood viscosity and HCT were significantly higher in non-obese OSAHS group than in control group (F = 0.41 - 2.23, P < 0.05); obese OSAHS group were higher than obese group (F = 0.12 - 2.10, P < 0.05). No significant difference in blood lipid levels was noted among the 4 non-obese groups with different disease severity; similar result was also observed among obese OSAHS groups. CONCLUSIONS: Obesity is responsible for dyslipidemia in OSAHS. OSAHS has no significant correlation with lipid abnormalities, but it significantly correlates with hemorheology disorder. PMID- 20193356 TI - [The function of nuclear factor-erythroid 2-related factor 2 and its association with I-kappa B kinases alpha/beta in a rat model of chronic obstructive pulmonary disease.]. AB - OBJECTIVE: To study the expression of nuclear factor-erythroid 2-related factor 2 (Nrf2) in the bronchial and lung tissues of chronic obstructive pulmonary disease (COPD) rat models and its association with I-kappa B kinases (IKKs). METHODS: Rat COPD models were established by intratracheal instillation of lipopolysaccharide (LPS) twice and exposure to cigarette smoke daily. The drug intervention group received 15-deoxy-Delta2, 14-prostaglandin J2 (15d-PGJ2) 0.3 mg/kg twice via tail venous injection. Spirometry was conducted and the pathological changes were observed. Antioxidation activities were measured and the expressions of Nrf2, IKKalpha/beta and NF-kappaB p65 were detected by immunohistochemistry and RT-PCR. The differences among groups were calculated by one-way ANOVA, and comparison between groups was made by LSD-t test. RESULTS: FEV(0.3)/FVC, Cdyn values and antioxidation capacity including total anti-oxidation competence and superoxidase dismutase in the COPD group [(58.8 +/- 2.6)%, (0.14 +/- 0.02) ml/cm H2O (1 cm H2O = 0.098 kPa), (0.20 +/- 0.03) U/ml and (19.6 +/- 2.4) U/ml, respectively] were significantly lower than those in the normal control group [(86.3 +/- 2.5)%, (0.38 +/- 0.02) ml/cm H2O, (3.16 +/- 0.31) U/ml and (56.1 +/- 2.2) U/ml, respectively]. RI values (0.69 +/- 0.17) cm H2Oxml(-1)xs(-1) were significantly higher than that of the normal control group (0.34 +/- 0.06) cm H2Oxml(-1)xs(-1). The above measurements of the drug intervention group [(74.5 +/- 3.9)%, (0.30 +/- 0.04) ml/cm H2O, (1.90 +/- 0.24) U/ml, (39.7 +/- 1.9) U/ml and (0.43 +/- 0.05) cm H2Oxml(-1)xs(-1), respectively] were between the COPD and the control groups, with airflow limitation and pulmonary ventilation improved significantly. Immunohistochemistry showed that, the positive coefficient of Nrf2, IKKalpha/beta and NF-kappaB p65 were increased significantly in the COPD models (3.23 +/- 0.31, 3.80 +/- 0.16 and 3.85 +/- 0.18, respectively), as compared with the control group (0.91 +/- 0.45, 1.17 +/- 0.42 and 1.30 +/- 0.34, respectively). The expression of IKKalpha/beta (2.10 +/- 0.46) and NF-kappaB p65 (2.53 +/- 0.36) in the lungs of the intervention group was between the COPD group and the control group, but the expression of Nrf2 (3.78 +/- 0.22) increased as compared to the COPD group. The results of RT-PCR showed that, the mRNA IOD value of Nrf2, IKKbeta and NF-kappaB p65 increased significantly in the COPD group (0.61 +/- 0.08, 0.89 +/- 0.05 and 0.91 +/- 0.02, respectively), as compared with the control group (0.29 +/- 0.07, 0.30 +/- 0.07, 0.30 +/- 0.07, respectively), while the expression of IKKbeta (0.67 +/- 0.04) and NF-kappaB p65 (0.69 +/- 0.04) in the lungs of the drug intervention group were between the above two groups, and the expression of Nrf2 (0.90 +/- 0.05) increased as compared to the COPD group. CONCLUSIONS: 15d-PGJ2 was shown to have anti-oxidation and anti-inflammation effects in this COPD model, which may be related to the increase of Nrf2. Nrf2 inhibited the expression of NF-kappaB p65 possibly through the down-regulation of IKKbeta. PMID- 20193355 TI - [Activator protein-2alpha inhibits activation of Caspase 3 and cell apoptosis induced by cigarette smoke extract in vascular endothelial cells.]. AB - OBJECTIVE: To investigate the effect of activator protein-2alpha (AP-2alpha) on activation of cysteine proteases with aspartate specificity 3 (Caspase 3) and the apoptosis of vascular endothelial cells (ECV304) induced by cigarette smoke extract (CSE). METHODS: ECV304 were cultured in vitro, and those at the exponential growth phase were studied in experiments. The cells were cultured with 0.0%, 2.5%, 5.0%, 10.0%, 15.0%, and 20.0%CSE respectively for 24 h, and in another experiment, the cells were exposed to 5.0%CSE for 0, 6, 12, 18, 24, 36, and 48 h respectively. Then the cells were infected with different virus vectors or treated by 5%CSE alone for 24 h. Cell apoptosis, and proliferation were tested by Hoechst staining and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) respectively, while the expression of cleaved Caspase 3 and AP 2alpha induced by CSE were tested by Western blot. The effects of over-expression of AP-2alpha on ECV304 apoptosis and the expression of cleaved Caspase 3 were investigated by transfection, Hoechst staining and Western blot. RESULTS: Compared with the blank control group (0.630 +/- 0.086), the proliferation was significantly increased in 2.5% CSE group (0.754 +/- 0.109), while that was decreased in the 5.0%, 10.0%, 15.0% and 20.0% CSE groups in a concentration dependent manner. The cell apoptosis rate induced by 5.0%CSE was increased in a time-dependent manner [from (5.0 +/- 1.0)% to (72.6 +/- 12.1)%], and the differences among the groups was significant (chi(2) = 1773.0, P < 0.01). The expressions of AP-2alpha (0.882 +/- 0.014) in 24 h CSE-treatment group was higher than that of the control group (0.635 +/- 0.005, t = 5.21, P < 0.01). Over expression of AP-2alpha inhibited the cell apoptosis [the apoptosis rate was (0.9 +/- 0.4)%, (7.5 +/- 0.9)% respectively] and the expression of cleaved Caspase 3 (the ratio were 0.300 +/- 0.020, 0.484 +/- 0.025) induced by CSE (t = 6.96, 8.75, all P < 0.01). CONCLUSION: AP-2alpha was shown to inhibit the activation of Caspase 3 and the apoptosis of ECV304 induced by CSE. PMID- 20193357 TI - [Recent advances in pathogenesis and molecular targeted therapies of idiopathic pulmonary fibrosis.]. PMID- 20193358 TI - [Application of phage display technique in the research of tuberculosis.]. PMID- 20193359 TI - [Epidemic feature and prevention and control strategy of influenza A H1N1]. PMID- 20193360 TI - [Assessment of life quality in patients with chronic heart failure]. AB - OBJECTIVE: Using Kansas city cardiomyopathy questionnaire (KCCQ) to evaluate the quality of life (QOL) of the patients with chronic heart failure. METHODS: A total of 271 hospitalized patients with heart failure symptoms in cardiology department, Peking Union Medical College Hospital, who undergone coronary angiography from December 2007 to December 2008, were included in this study. QOL of the subjects was measured, and their demographic and clinical data were collected. Patients were divided into 2 groups according to heart function and they were compared by QOL.Multiple linear regression analysis was conducted to identify the variables associated with the quality of life. RESULTS: KCCQ physical limitation scores of the patients of left ventricular elective fraction (LVEF) < 50% (n = 50) and LVEF > or = 50% (n = 221) were (66 +/- 22) points and (73 +/- 22) points (P < 0.05). In the patients of NYHA I/II (n = 227) vs NYHA III/IV (n = 44), KCCQ scores of physical limitation, symptoms and QOL were (74 +/ 20) vs (60 +/- 27) points, (62 +/- 22) vs (49 +/- 25) points and (61 +/- 16) vs (53 +/- 18) points (all P < 0.05). In the patients of heart failure grade A/B (n = 197) vs grade C/D (n = 74), KCCQ scores of physical limitation, symptoms and QOL were (75 +/- 19) vs (61 +/- 26) points, (63 +/- 22) vs (52 +/- 24) points, (61 +/- 16) vs (56 +/- 18) points (all P < 0.05). Multiple linear regression analysis of QOL KCCQ showed that, age, NYHA cardiac function classification, gender and Judkins score were the risk factors of patients' physical limitation (P < 0.01); gender and stages of heart failure were the risk factors of patients'symptoms (P < 0.01); gender was the risk factors of patients'social function (P < 0.01). CONCLUSION: The patients with poor cardiac function have a poor QOL. KCCQ is more sensitive for the evaluation of heart function. Age, NYHA, gender, Judkins score and stages of heart failure can change QOL for the patients with chronic heart failure. PMID- 20193361 TI - [Role of bulbocavernosus reflex to stimulation of prostatic urethra in pathologic mechanism of primary premature ejaculation]. AB - OBJECTIVE: Primary premature ejaculation (PPE) is a prevalent sexual dysfunction among men while its precise pathologic mechanism has remained poorly understood. In current study the correlation between excitability of bulbocavernosus reflex (BCR) to stimulation of prostatic urethra and primary premature ejaculation was studied. METHODS: Forty-two patients with PPE and 20 normal potent male volunteers were studied by inserting a specially designed Foley catheter with two electrodes mounted on its distal surface (intraurethral catheter electrode) into bladder to evoke the BCR to stimulation of prostatic urethra to record the sensory thresholds of BCR to stimulation of prostatic urethra, thresholds to evoke stable BCR and latencies of BCR. Also the sensitivity of glans penis to electrical stimulation was detected by two surface electrodes. RESULTS: The mean sensory thresholds of BCR to stimulation of prostatic urethra, thresholds to evoke stable BCR, latencies of BCR and sensory thresholds of glans penis were (18.2 +/- 2.7) mA (0.2 ms in duration, 1 Hz), (34.8 +/- 4.2) mA (0.2 ms, 1 Hz), (71.2 +/- 5.8) ms and (14.2 +/- 1.9) mA (0.04 ms in duration, 3 Hz) in normal potent men respectively and were (12.4 +/- 3.7) mA (0.2 ms, 1 Hz), (23.8 +/- 5.6) mA (0.2 ms, 1 Hz), (70.5 +/- 6.3) ms and (11.9 +/- 2.3) mA (0.04 ms, 3 Hz) in patients with PPE respectively. Statistically significant differences were seen regarding the sensory thresholds of BCR to stimulation of prostatic urethra, the thresholds to evoke stable BCR and the sensory thresholds of glans penis between two groups (all P < 0.01). No statistically differences were seen regarding the latencies of BCR between two groups (P > 0.05). CONCLUSION: Patients with PPE have hyperexcitable BCR to stimulation of prostatic urethra. It is probably one of the important etiological factors. Moreover the findings may provide new therapeutic modalities of PPE. PMID- 20193362 TI - [Percutaneous balloon valvuloplasty for severe and critical pulmonary valve stenosis in infants under six months]. AB - OBJECTIVE: To assess the effects and potential role of percutaneous balloon valvuloplasty as an alternative therapy of surgery in young infants with severe and critical pulmonary valve stenosis. METHODS: Eighteen patients aged 8 days to 6 months with severe and critical pulmonary valve stenosis admitted to our hospital from June 2006 to August 2008 underwent balloon valvuloplasty. Among them, 11 infants including 2 neonates had critical pulmonary stenosis. Severe tricuspid regurgitation was seen in 5 and moderate in 3. Right ventricular systolic pressure in all patients was greater than systemic pressure with right to-left or bi-directional shunt at atrial level. Dilatation was performed under general anesthesia with intubation in 12 patients and caudal block combined with sedation in 6 patients. Dilatation with 2 balloons sequentially in one procedure was performed in 6 patients and dilatation with 1 balloon in other 10 patients. RESULTS: Of the 18 patients, there was failure to cross the pulmonary valve with balloon catheter in one and cardiac tamponade in one. The dilatation success rate was 88.9%. Immediately after dilatation, the systemic pressure gradient from right ventricle to pulmonary artery decreased from (87 +/- 24) mm Hg to (30 +/- 19) mm Hg (P < 0.01). No complication was found in all patients during or post dilation. During a follow-up of 6 to 32 months, pressure gradient crossing pulmonary valve measured by echocardiography further decreased or remained stable in 16 cases, except one neonate and one infant whose pressure gradient gradually increased and required a second dilatation. Re-dilatation rate was 12.5%. Tricuspid regurgitation was reduced in all patients. Mild pulmonary regurgitation was seen in most of patients post-dilatation, except moderate in one. All patients fared well and stayed asymptomatic. CONCLUSION: Percutaneous balloon valvuloplasty for severe and critical pulmonary stenosis in infants is relatively safe and effective and should be considered a valid alternative to surgical operation. It should be the first choice for such patients based on its excellent outcome, less trauma and fewer complications. PMID- 20193363 TI - [Sealing of tracheoesophageal fistula using Sigma covered mental stents]. AB - OBJECTIVE: To explore the possibilities and efficiency of Sigma covered stents for the treatment of tracheoesophageal fistula (TEF). METHODS: Between 2006 and 2009, 10 Sigma covered mental stents had been placed by guidance of bronchoscopy and/or fluoroscopy in 8 patients with 9 tracheoesophageal fistulas. Among them, 7 fistulas were caused by cancer and 2 by mechanical damage. Seven fistulas were located in lower part of trachea and 1 each in the middle and upper parts. RESULTS: Six Y-shaped, 2 L-shaped and 2 I-shaped stents were placed respectively in 8 patients with 9 TEFs. All the TEFs were effectively sealed by the stents except for 1 massive lower and 1 upper fistulas. One mechanical fistula was cured within 1 year of stent placement. The mean survival period of all patients was 8 months. CONCLUSION: By sealing the fistula with a Sigma covered stent, severe respiratory infection may be successfully controlled in patients with TEFs with a major improvement of quality of life. PMID- 20193364 TI - [Meta-analyses of oxaliplatin-based chemotherapy versus cisplatin-based chemotherapy in advanced gastric cancer]. AB - OBJECTIVE: To analyze whether Oxaliplatin (OXA) is effective in advanced gastric cancer. METHODS: Clinical trials of OXA-based chemotherapy (treatment group) versus DDP-based chemotherapy (control group) in advanced gastric cancer which published in 6 years were retrieved from China National Knowledge Infrastructure (CNKI), Wanfang Data, VIP information database and PubMed of U.S. National Library of Medicine and NIH. Review Manager 4.2 was used for meta-analysis and main outcome measure included objective response rate, survival and toxicities. RESULTS: There were 2121 patients (1062 cases in treatment group and 1059 cases in control group) from 16 controlled clinical trials were enrolled. Response rate increased (46.3% vs 40.6%, OR = 1.28, P = 0.006) and 1-year survival rate increased (44.6% vs 39.3%, OR = 1.25, P = 0.04) in treatment group than that of control group. Peripheral neurotoxicity was more frequently observed in treatment group (70.6% vs 21.9%, OR = 10.76, P < 0.01) while anemia and nausea/vomiting were reversed (58.0% vs 70.1%, 61.4% vs 75.6% respectively, both P < 0.05). CONCLUSION: Oxaliplatin-based chemotherapy is well-tolerated and more effective than cisplatin in advanced gastric cancer. PMID- 20193365 TI - [Effects of positive end expiratory pressure ventilation upon respiratory function and hydrophobic surfactants proteins in rabbit with seawater respiratory distress syndrome]. AB - OBJECTIVE: To investigate the effects of positive end-expiratory pressure (PEEP) ventilation upon respiratory function and lung surfactant protein B (SP-B)/SP-C in seawater respiratory distress syndrome (SW-RDS) rabbit. METHODS: Twenty-four female New Zealand rabbits were randomly equally divided into three groups:conventional mechanical ventilation (CMV) group, PEEP group, and control group. After anesthesia and tracheal intubation followed by 20 minutes of CMV, SW RDS model was established by lung perfusion of artificial seawater through tracheal intubation. Then the CMV group ventilated for 6 hours (each parameter unchanged); PEEP group ventilated with PEEP of 8 cm H2O for 2 hours based on prior parameters and subsequently with CMV for 4 hours; control group without ventilation after modeling. Oxygenation indices and lung compliance were continuously monitored during ventilation. After ventilation, the rabbits in study groups were sacrificed while those dying a natural death in the control group selected. Bronchoalveolar lavage fluid of the left lung was collected to determine the alveolar surface tension and the right lung was harvested to measure the mRNA expression of SP-B/SP-C by real-time PCR as well as SP-B protein by Western blotting. RESULTS: After modeling, the data of lung compliance and oxygenation indices became significantly worse in every group but without statistical difference in three groups. All rabbits in control group died within 15 minutes of ventilator withdrawal. After receiving PEEP ventilation for 30 minutes, these indices significantly improved compared with CMV group in which there was no significant change of the indices (P < 0.05). Minimal alveolar surface tension in CMV group (mN/m, 30.8 +/- 6.3) was greater than in PEEP group (21.1 +/- 4.4, P < 0.05) and control group (23.6 +/- 4.6, P < 0.05); SP-B/SP-C mRNA relative expression (0.37 +/- 0.15/0.60 +/- 0.19) and SP-B relative protein abundance (0.38 +/- 0.17) in CMV group were obviously lower than in PEEP group (0.73 +/- 0.15/0.92 +/- 0.40, 0.52 +/- 0.22, P < 0.05). CONCLUSIONS: PEEP ventilation can improve the oxygenation indices and lung compliance in SW-RDS animals. And such an effect is correlated with both the mRNA expressions of SP B/SP-C and mechanical distension. PMID- 20193366 TI - [Specific expression in brain of exogenous gene by transpassing blood-brain barrier after intravenous injection]. AB - OBJECTIVE: To study the expression of exogenous LacZ gene in brain via a delivery of OX26-pGFAP-IL. METHODS: pCMV-Liposome, OX26-pCMV-IL, OX26-pGFAP-IL and blank liposome were injected into rats via femoral vein. At 24 h post-injection, the method of Q-PCR was adopted to calculate the relative quantities of LacZ gene mRNA in brain and peripheral organs. At 48 h post-injection, the protein expression of LacZ gene was detected by the activity of beta-galactosidase and the method of histochemical stain. RESULTS: The result of Q-PCR showed that, at 24 h post-injection, the relative quantities of LacZ mRNA in OX26-pCMV-IL group (49.2 x 10(-6)) and OX26-pGFAP-IL group (44.9 x 10(-6)) were significantly higher than pCMV-liposome and blank liposome groups (P < 0.05). In peripheral organs, the relative quantity of LacZ mRNA in OX26-pCMV-IL group were significantly higher than that in OX26-pGFAP-IL group (P < 0.05). At 48 h post-injection, the activity of beta-galactosidase in OX26-pCMV-IL (0.67 pg/mg) and OX26-pGFAP-IL groups (0.92 pg/mg) were significantly higher than pCMV-liposome and blank liposome groups (P < 0.05). There was no significant difference between OX26-pCMV IL group and OX26-pGFAP-IL group in terms of the expression of beta galactosidase. The result of histochemical stain showed that OX26-pGFAP-IL achieved a specifically positive expression in brain and had a decreased expression in peripheral organs. CONCLUSION: OX26-pGFAP-IL injected via femoral vein can cross the brain-blood barrier and achieve a specific expression in brain under the control of GFAP promoter. OX26-pGFAP-IL decreases the non-specific expression in peripheral organs and it may be used as an non-viral gene therapy for intra-cranial diseases. PMID- 20193368 TI - [Effect of alpha-zearalanol upon the expression of HO-1 gene and the cytosolic free calcium level in tumor necrosis factor alpha-stimulated human endothelial cell]. AB - OBJECTIVE: To investigate the effects of alpha-zearalanol on the expression of heme oxygenase-1 (HO-1) gene and cytosolic free calcium level in the tumor necrosis factor alpha (TNF-alpha)-stimulated human umbilical vein endothelial cell (HUVEC) and the mechanisms involved. METHODS: The siRNA expression vector for p47(phox) was constructed and used to block the NADPH oxidase in the HUVEC. The intracellular ROS production was detected by using 2, 7-dichlorofluorescin diacetate as probe. The mRNA expression of the HO-1 was determined by semiquantitative RT-PCR and the protein expression was measured by immunocytochemistry analysis. The level of cytosolic free calcium was determined by using Fluo-3/AM as probe with laser confocal microscope. RESULTS: TNF-alpha stimulation caused ROS output increased by 155% of control (228 +/- 51 vs 89 +/- 24, P < 0.05); alpha-zearalanol was able to reduce the production of ROS in a dose-dependent manner. Knock down of the p47(phox) subunit for NADPH oxidase by siRNA abolished the production of ROS. TNF-alpha stimulation caused HO-1 mRNA increased by 145% of control (0.88 +/- 0.10 vs 0.36 +/- 0.11, P < 0.01), and also obviously increased HO-1 protein expression; alpha-zearalanol inhibited the expression of HO-1 mRNA in a dose-dependent manner; Pretreatment with alpha-ZAL and p47(phox) siRNA both attenuated TNFalpha-induced HO-1 protein expression. The treatment of TNF-alpha for 24 hours up-regulated cytosolic free calcium level by 179% (107.3 +/- 4.9 vs 38.5 +/- 0.6, P < 0.01); Pretreatment with alpha-ZAL and p47(phox) siRNA depressed TNFalpha-induced cytosolic free calcium level by 46% (58.5 +/- 0.3 vs 107.3 +/- 4.9, P < 0.01) and 57% (46.3 +/- 2.1 vs 107.3 +/- 4.9, P < 0.01) respectively. CONCLUSION: ROS only partly mediated HO-1; expression in the TNF-alpha-stimulated HUVEC; alpha-ZAL has a potent inhibitory effect on the HO-1 expression and cytosolic free calcium level in the TNF-alpha-stimulated HUVEC, mainly through the inhibition of ROS generation derived from NADPH oxidase. PMID- 20193367 TI - [Agonist-induced down-regulation of hepatic glucocorticoid receptor via peroxisome proliferator-activated receptor in SD rats]. AB - OBJECTIVE: It was reported that a negative feedback loop might exist between peroxisome proliferator-activated receptor alpha (PPARalpha) and glucocorticoid receptor (GR). However, it is unclear whether GR expression is regulated by PPARalpha activation. To further demonstrate this possibility, we conducted the present study to investigate the regulatory effects of the PPARalpha agonist fenofibrate on GR expression in Sprague-Dawley rats. METHODS: GR gene and protein expression levels were determined in liver, visceral and muscle tissues. Adrenal 11beta-hydroxylase (CYP11B1) expression was examined by RT-PCR and circulating corticosterone level was measured by RIA method. RESULTS: GR expression was reduced by fenofibrate in a time- and does-dependent manner. The GR mRNA in the three fenofibrate groups of rats were 55% (FE1), 54% (FE2) and 68% (FE3) lower than that of the control rats. The GR protein were 28%, 77% and 99% lower than the control. The inhibition was observed in liver, but not in fat and muscle. The corticosterone level in the blood was increased significantly by fenofibrate(the levels of corticosterone in control, FE1, FE2, FE3, MK886 groups were (393 +/- 23), (495 +/- 44), (516 +/- 18), (622 +/- 93), (382 +/- 37) ng/ml respectively. These effects of fenofibrate were abolished by PPARalpha inhibitor MK886, suggesting that fenofibrate activated through PPARalpha. CONCLUSION: A new molecular mechanism has been found for a negative feedback regulation of GR activity by PPARalpha in SD rats. PMID- 20193369 TI - [Optimization of extracting method and inhibitory action of recombinant human endostatin in bladder cancer]. AB - OBJECTIVE: To explore the optimal method for protein expression in rhES (recombinant human endostatin) and study the anti-tumor activities of rhES in solid tumor and established cell line. METHODS: Different IPTG concentrations, the timing of adding IPTG into the culture medium and the different time of expression were employed to explore the optimized conditions of protein expression. Activity examination: (1) animal experiment: nude mice bearing subcutaneous cancer in treated group and controlled group were observed. (2) cellular experiment: the inhibitory effect of rhES in T-24 established cell line were observed by MTT assay and cancer cell growth curve. RESULTS: The expression of rhES protein was 58.65%. Of all the E. coli body proteins, the protein purity after purification was 96.22%. Activity examination indicated that rhES could inhibit the growth of solid tumor and the established cell line. In animal experiment, the tumor inhibition rate was 66.8%. Cell experiment: the 50% inhibitory concentration (IC(50)) was 22 microg/ml. The cell population decreased 58.75% than the control group at Day 7 in the tumor cell growth curve. CONCLUSION: A high expression and activity of rhES protein can be obtained by the optimized expression conditions. rhES can inhibit the cellular growth in both solid tumor and established cell line of bladder cancer. PMID- 20193370 TI - [Cross-talk between Notch1 and epidermal growth factor receptor signalling in regulating cell proliferation of human tongue squamous carcinoma cells]. AB - OBJECTIVE: To investigate the cross-talk between Notch1 and epidermal growth factor receptor (EGFR) signaling in regulating the cellular proliferation of human tongue squamous cell carcinoma (SCC). METHODS: Human tongue SCC cell line Tca8113 cells was transiently transfected with the vector encoding exogenous intracellular fragment of Notch1 and the vector encoding the specific short hairpin RNA (shRNA) targeting EGFR respectively and were treated by AG1478, an inhibitor of receptor tyrosine kinases, for elucidating the effects of constitutive activation, EGFR gene silencing and blocking EGFR signaling upon cellular proliferation and expression of Notch1 and EGFR. The mRNA and protein levels of Notch1 and EGFR were detected by reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot, respectively. The cellular proliferation was evaluated by methyl thiazolyl tetrazolium (MTT) assay. RESULTS: Constitutive activation of Notch1 resulted in inhibition of cellular proliferation, and up regulation of Notch1 (1.102 +/- 0.135, 0.243 +/- 0.032, P < 0.05) but down regulation of EGFR (0.083 +/- 0.009, 0.605 +/- 0.075, P < 0.05) at the the mRNA and protein levels. Silencing of EGFR gene resulted in inhibition of cell proliferation, and down-regulation of EGFR (0.148 +/- 0.019, 1.175 +/- 0.132, P < 0.05) but up-regulation of Notch1 (0.978 +/- 0.115, 0.083 +/- 0.009, P < 0.05) at the mRNA and protein levels. Blocking EGFR signaling had no significant effect upon EGFR expression (P > 0.05), but resulted in inhibition of cellular proliferation and up-regulation of Notch1 (P < 0.05) at the mRNA and protein levels. CONCLUSION: There might be a cross-talk of bi-directional control between Notch1 and EGFR signaling in regulating the cellular proliferation of human tongue SCC cells. PMID- 20193371 TI - [Effects of transfected pIRES-p21(waf1)-p27(kip1) gene on the duplication of centrosomes and the proliferation of breast cancer cell line MCF-7]. AB - OBJECTIVE: To explore the role of transfected pIRES-p21(waf1)-p27(kip1) gene on the centrosome duplication and cell proliferation of MCF-7, a breast cancer cell line. METHODS: The pIRES-p21(waf1), pIRES-p27(kip1) and pIRES-p21(waf1)-p27(kip1) genes were transfected into the MCF-7 cells by lipofection. The effect on proliferation was evaluated by MTT assay and cell growth curve was drawn. The cell cycle was analyzed by flow cytometry. The centrosome duplication was detected by using indirect immunofluorescence microscopy. RESULTS: After transfected 24 hours, the p21(waf1) and p27(kip1) protein expressions were significantly increased as compared with untransfected MCF-7 cells (P < 0.01), and cell growth was obviously inhibited and resulted in an accumulation of cells in G(1) (P < 0.01), presenting that the proportion of cells in G(1) phase was obviously increased from(47.28 +/- 2.25)% to (69.52 +/- 3.21)% of p21(waf1) transfected cells, (60.83 +/- 3.02)% of p27(kip1) transfected cells, and (78.37 +/- 2.83)% of p21 (waf1)-p27(kip1) transfected cells. The proportion of cells which contained unnormal centrosomes was obviously decreased, from (13.47 +/- 0.33)% to (5.07 +/- 0.38)%, (6.28 +/- 0.35)%, (3.47 +/- 0.23)%, respectively. CONCLUSION: The transfer of p21(waf1) and p27(kip1) genes could inhibit the growth of human breast carcinoma cells and the unnormal duplication of centrosomes. p21(waf1) had a really synergy with p27(kip1) in these effects, suggesting p21(waf1)-p27(kip1) combined gene can inhibit the genesis and development of breast cancer and might have potential clinical significance as therapeutic agents of breast cancer. PMID- 20193372 TI - [Effect of methylene chloride upon hepatic ischemic reperfusion injury]. AB - OBJECTIVE: To investigate the effects and mechanisms of methylene chloride (MC) in hepatic ischemic reperfusion injury. METHODS: Eighty SD-rats were divided equally into 4 groups: control group (n = 20), donors without any treatment; CoPP group (n = 20), donors injected with CoPP (5 mg/kg, ip) at 24 h; ZnPP group (n = 20), donors injected with ZnPP (20 mg/kg, ip) at 24 h; MC group (n = 20), donors fed with MC (500 mg/kg) per day for 7 days before graft procurement. Syngeneic orthotopic liver transplantation was performed in rats with modified Kamada's two cuff technique. And SD rats were used as donors (n = 10)and recipients respectively. 5 recipients in each group were sacrificed and the grafts were procured at day 3 after transplantation, the post-operative survival time was observed in the remnant. The tests were determined as following: the level of serum ALT, AST in recipients; heme oxygenase-1 (HO-1) expression of graft was tested by immunohistochemistry and Western blot; the index of graft apoptosis examined by TUNEL method; the pathology of graft assessed by Suzuki's criteria. RESULTS: The level of serum ALT [(65 +/- 28) U/L], AST [(187 +/- 43) U/L] in CoPP and ALT [(75 +/- 16) U/L], AST [(185 +/- 42) U/L] in MC group was significantly lower than that ALT [(346 +/- 45) U/L], AST [(474 +/- 90) U/L] in control group and ALT [(578 +/- 75) U/L], AST [(1084 +/- 128) U/L] in ZnPP group (P < 0.01). The median expression of HO-1 in MC group was no significantly different with that in control group (P > 0.05). While the median expression of HO-1 in CoPP group was higher than that in control group (P < 0.05). The index of graft apoptosis in MC group and CoPP group, 4.1% +/- 0.6% and 3.2% +/- 0.8% respectively, was significantly lower than that (12.5% +/- 2.4%) in control group and (25.8% +/- 3.1%) in ZnPP group (P < 0.05). Compared with the other two groups, MC and CoPP groups had lesser neutrophil infiltration and a lower grade of hepatocytic injury in grafts. Suzuki's scores in grafts of MC and CoPP groups were lower than that in control and ZnPP groups (P < 0.05). The median post transplantation survival time of the recipients in MC and CoPP groups was 100 and 93 days respectively while that in control and ZnPP groups was 85 and 12 days (P < 0.05). CONCLUSION: Over-expression of HO-1 and MC both have protective effects in hepatic ischemic reperfusion injury. PMID- 20193373 TI - [Study on the prevalence and genotypes of Bartonella species in rodent hosts from Fujian coastal regions]. AB - OBJECTIVE: To investigate Bartonella infection in rodent hosts from different environments and types of climate in Fujian coastal regions. Genetypes of the Bartonella strains was also studied to provide scientific basis for prevention and control of the correlated diseases. METHODS: By random sampling method, we selected six study sites in Fujian southeastern coastal regions. Rodents were captured by cages to Isolate Bartonella strains. Bartonella-like isolates were confirmed by polymerase chain reaction (PCR). The 379 bp fragment of gltA gene was sequenced and the growth and development tree was constructed to determine Bartonella species. Distribution of Bartonella species in the different area and related hosts was also analysed. RESULTS: Bartonella species were isolated from 188 of 1161 small animals including five rodent species. The infected animals were grouped into 2 genera and 2 orders. They were Suncus murinus, Rattus norvegicus, Rattus flavipectus, Mus musculus and Rattus rattus. The overall prevalence of Bartonella bacteremia was 16.19% in the most prevalent species of rodents in Fujian southeastern coastal regions including 21.43% in Suncus murinus, 13.54% in Rattus norvegicus and 18.27% in Rattus flavipectus. Rodents in every investigated areas were infected by Bartonella species (9.25% in Ningde, 9.52% in Fuzhou, 9.38% in Putian, 28.18% in Quanzhou, 17.42% in Xiamen and 13.33% in Zhangzhou). There were significant differences among infected rates in different annual accumulated temperature districts (chi(2) = 12.93, P < 0.001). Isolates from rodents were clustered in three genotypes (B. elizabethae, B. qeenslandensis and B. tribocorum A, B). CONCLUSION: The local rodents in Fujian southeastern coastal regions were widely infected by Bartonella spp. Differences among the prevalent species of Bartonella in Fujian southeastern coastal region, Yunan and Beijing were noticed. Our findings suggested there was a need to study the prevalence, related vectors and the molecular organism of Bartonella spp. PMID- 20193374 TI - [Epidemiological investigation on natural infection of different canine breeds with Borna disease virus in Ili, China]. AB - OBJECTIVE: To investigate the epidemiological pattern of Borna disease virus (BDV) among different canine breeds in Ili, China, and to analyze its potential phylogeny. METHODS: BDV p24 RNA fragments were detected from peripheral blood mononuclear cells (PBMCs) of canine by modified nested RT-PCR (nRT-PCR). Possible false positives were excluded by determination of both BDV p40 RNA fragments and PMD19 plasmid standards. Analysis were performed on genetic sequence, homologous comparison, amino acid sequence and phylogeny after p24 positive products were validated. RESULTS: BDV p24 RNA fragments were found only in Kazakh Tobet (a shepherd dog) in 8 breeds of 150 cases and their overall positive rate was 11.0% (10/91). Compared with the strain of He/80 from horse and that of S6 from sheep in Germany, the homologous similarities of Kazakh Tobet was 99.2% and 95.7%, and that of amino acid as 100% and 89.3%, respectively. The kinship of Kazakh Tobet was close to He/80 and next to S6. CONCLUSION: There was potential natural BDV infection in Kazakh Tobet in Ili, and its endemic strain was concerned with He/80 infecting Ili horse and S6 of German Merino sheep introduced into the region from Germany. PMID- 20193375 TI - [Investigation on status of HIV-1 infection among blood recipients from 1994 to 1998 in certain areas of China]. AB - OBJECTIVE: To study the infection status of HIV-1 among blood recipients from 1994 to 1998 in certain areas of Hebei province. METHODS: A general investigation was set up among all the people in 15 townships of certain areas from November 2003 to February 2005. An epidemiological investigation was conducted among people who had received blood from donors, during 1994 and 1998. Blood samples were collected. ELISA was used in preliminary screening and Western-blot (WB) was used among people who showed a positive result in the preliminary screening. RESULTS: The infection rate of HIV-1 after blood receipt was 15.54% (92/592), and the infected persons were all appeared in five medical centers of 6 townships which located at the west part of the area. HIV-1 infection happened over the years, and reaching the zenith in the year 1995. Most of the infected persons were young women. Procreation was the main cause of blood transfusion for women and trauma was for men. CONCLUSION: A typical HIV outbreak happened in certain areas after blood transfusion in Hebei. PMID- 20193376 TI - [A respondent-driven sampling survey on HIV and risk factors among men who have sex with men in Chongqing]. AB - OBJECTIVE: To examine HIV prevalence and related risk factors among men who have sex with men (MSM) in Chongqing, and to explore the feasibility of using respondent-driven sampling (RDS) in the survey. METHODS: Based on results from formative research, a RDS survey was designed and conducted to collect demographic, behavioral and serologic data. RDSAT was used to calculate point estimation and confidence intervals. SPSS was used for bi-variate analysis using RDSAT exported weighed data. NETDRAW was used to draw network diagram. RESULTS: Among 617 subjects recruited, the adjusted HIV and syphilis prevalence rates were 16.8% and 10.9%, respectively. 73.0% of the subjects were 20 to 29 years old and 72.9% were officially registered residents of Chongqing. 83.4% were single, with the proportion of students the highest, accounting for 24.6%. During the last six months, 83.4% of them reported ever having anal sex, and 54.0% reported having unprotected anal sex. CONCLUSION: This survey confirmed that Chongqing had a higher reported HIV prevalence among MSM than from other Chinese cities. Comprehensive intervention services were required to address this alarmingly high prevalence, with focus on intervention through internet and those having syphilis infection. RDS seemed one of the effective ways of recruiting hidden MSM populations in Chongqing which had a large population of active MSM who did not frequently visit MSM venues as compared with snowball method. PMID- 20193378 TI - [Influence of retrospective time period on reliability of epidemiological survey to injuries]. AB - OBJECTIVE: To analyze the influence of different recall time periods on epidemiological survey of injuries among children and adolescents. METHODS: A study on injuries for 12 months follow-up period was actively surveyed among 4523 pupils selected by cluster sampling from 12 kindergartens, 1 elementary school, 1 junior high school, 1 senior high school and 1 college in Maanshan city in November, 2007 to November, 2008. Injury events were actively surveyed by school doctors or class health workers simultaneously. Participants were divided into three groups, the first group including self-reported injuries by 3-months interval, the second group with self-recalled injuries by 6-months interval and the third group with self-reported injuries in the past 12 months. Validity and reliability of injuries between surveillance injuries and retrospective injuries were compared. RESULTS: The overall rate of injury events was 74.2% and injury events and rate was higher in boys than that in girls (P < 0.01), In total, 6350 injury events were registered for the survey. Compare with surveillance findings, the injury rate declined 0.02% and the number of injuries had a 19 person/time reduction from the retrospective injuries by 3-months interval. The injury rate declined 0.02% and number of injuries reduced 58 person/times from the survey of retrospective injuries by 6-month interval. The rate of injuries declined 8.8% and frequencies had a 505 reduction from data of self-reported injuries in the past 12 months. The largest declines were found for the 3 to 6 year-old age group and for minor injuries. CONCLUSION: The 12-month recall period on underestimate injury rates was compared to the 3-month recall periods and 6-month recall periods. Recall periods of 6 months were recommended to be used in injury survey in children and adolescents. PMID- 20193379 TI - [Study on 'dating violence' in 697 male university students]. AB - OBJECTIVE: To explore the prevalence of 'dating violence' in male university students. METHODS: Six hundred and ninety-seven male students from a university were surveyed by self-administered questionnaire anonymously. RESULTS: Of the 697 male students, 73.5% (512/697) had a dating relationship or a dating meeting with the females. Among the 512 male students, 29.7% had physically (7.0%), psychologically (27.7%), or sexually (2.1%) aggressive behaviors to their partners while 25.2% of them had experienced aggression by their partners, physically (10.4%), psychologically (21.9%) or sexually (1.6%) in the past 12 months. Students having had physical punishment and emotional abuse during childhood by their parents were more likely to be involved in dating violence, when compared with the students who had no such experiences. CONCLUSION: The problem of male students dating violence is not uncommon, suggesting that program on school and community-based prevention education and health services need to be developed. PMID- 20193377 TI - [Community-based study on disease burden of diarrhea in Zhejiang province]. AB - OBJECTIVE: To study the status on economic burden of diarrhea in Zhejiang province so as to provide evidence for allocation of health resource as well as decision-making on health issues. METHODS: Multi-phases stratified random cluster sampling was used to select samples in the population. Data was collected on the incidence of diarrhea in the last two weeks as well as on the related cost due to medical care etc. RESULTS: The overall incidence (person per year) of diarrhea was 0.26, with 0.29 in the rural and 0.22 in the urban areas respectively. The incidence of diarrhea in children less than 5 was 0.66 (person per year), higher than in any of the age groups. The average direct cost of medical treatment was 69.23 Yuan with average direct cost of non-medical care was 8.29 Yuan for every person, while the indirect cost was 48.43 Yuan. In conclusion, the average disease burden of diarrhea in the province was 1.697 billion Yuan per year, which accounted for 1 per thousand of the GDP, with 1.217 billion Yuan in rural area and 0.480 billion Yuan in the urban areas respectively. The direct cost of medical care was 0.886 billion Yuan (52.21%) and the direct cost due to non medical care was 0.124 billion Yuan (7.31%). The indirect cost appeared to be 0.480 billion Yuan (40.48%). Factors that affecting the cost would relate to: severity of diarrhea, medical insurance, location of residential area, age and education background of the patients, etc. CONCLUSION: Programs on diarrhea prevention and control should be strengthened to reduce the economic burden caused by this disease while special attention should be paid to those children who are under 5 years of age and living in the rural areas. PMID- 20193381 TI - [Study on the incidence of beta-Thalassemia and genotypes among children under 7 year-olds in Nanning, Liuzhou and Baise areas, Guangxi province]. AB - OBJECTIVE: To conduct research of beta-Thalassemia incidence and genotypes on children below 7 years of age in Nanning, Liuzhou and Baise areas, Guangxi province. METHODS: A total of 2261 children aged below 7 in Nanning, Liuzhou and Baise areas were studied. Venous blood was detected by routine blood test, hemoglobin analysis and beta-Thalassemia genotyping. RESULTS: Among 2261 samples, 125 showed high level of HbA2 and were diagnosed as beta-Thalassemia (5.53%). Genotypes of the patients were classified as: 59 cases with beta-globin gene condon (CD) 41-42 mutation, 33 cases CD17 mutation, 18 cases with TA TA box nt-28 mutation, 7 with IVS-II-654 mutation, 3 with CD43 mutation, 3 with HbE mutation, one with CD71-72 and TATA box nt-29 mutation, respectively. The genotyping frequencies of beta-Thalassemia were as follows: 47.20% for CD41-42 mutation, 26.40% for CD17 mutation, 14.40% for TATAbox nt-28 mutation, 5.60% for IVS-II-654 mutation, 2.40% for CD43 mutation, 2.40% for HbE mutation, 0.80% for CD71-72 mutation and TATAbox nt-29 mutation respectively. CONCLUSION: This study on children in the area with high incidence of beta-Thalassemia reflected the incidence and characteristics of genotypes in this area. Our data also provided evidence for the development of a program on genetic counseling and prevention for thalassemia. PMID- 20193380 TI - [Relationship between post-traumatic stress disorder and perceived social support among middle school students in Wenchuan earthquake-stricken]. AB - OBJECTIVE: To explore the relationship between post-traumatic stress disorder (PTSD) and perceived social support (PSS) ability among middle school students in earthquake-stricken areas after the Wenchuan earthquake accident. METHODS: A total of 1966 students from three secondary schools of Wenchuan earthquake stricken areas were evaluated by PTSD Checklist-Civilian Version (PCL-C) and Perceived Social Support Scale (PSSS). RESULTS: The overall incidence rate of PTSD was 78.3%, with severe PTSD as 24.38%. Significant differences on the incidence rates of PTSD were found among the students who were in different PSS levels (P < 0.05) and significant negative correlation existed between the levels of severity on PTSD and PSS (gamma = -0.226, P < 0.05). Significant differences on PTSD incidence rates were found among those students who were from different families or out-family PSS levels (P = 0.009, P < 0.05). Significant negative correlation existed between the severity of PTSD and family or out-family PSS level (gamma = -0.176, P < 0.05, gamma = -0.214, P < 0.05). CONCLUSION: Relationships between the incidence rate, severity of PTSD and PSS levels existed among the middle school students in Wenchuan earthquake-stricken areas, with higher PSS, lower incidence rate and lighter severity of PTSD. Psychological intervention for earthquake-stricken students should be carried out. PMID- 20193382 TI - [Gender analysis on prenatal care in rural areas of Xinjiang and Anhui province]. AB - OBJECTIVE: To introduce the gender-specific view to the prenatal care and analysing the health behavior and its influencing factors. METHODS: Random sampling in cluster was used to select those study population and face to face interview was carried out at their residence in Xinjiang and Anhui province. RESULTS: The overall socioeconomic status of women in rural areas of Xinjiang and Anhui province was low and 93.2% of the women had education level on junior middle school or below. Politically women were less interested in these issues with only 63.1% of them ever participated in the election program or voting. In household daily life, women's status was almost equal to or even higher than men, but men always called the shots when something important in family happened. Men still held the power of decision making. In 47.3% of the families, the husband played a decisive role on decision making. In 37.7% of the families, husbands controlled the money. When getting into expensive expenditure, 35.2% of the families having men made the final approval. When there were different opinions between the couples, husband usually made the final decision in 44.2% of all the families compared to 6.3% of the families that wives made the final decision. 73.9% of women under survey had undergone prenatal examination and the rate on household deliveries reached 30.3%. Both gender consciousness and educational level had influenced the effect on prenatal care. CONCLUSION: It is important to better prenatal health service in rural areas and to improve socioeconomic status on gender consciousness of women. PMID- 20193383 TI - [Secular changes on the morphological development and nutrition status of Tibetan students from 1985 to 2005]. AB - OBJECTIVE: To study the secular changes on both morphological development and nutritional status among Tibetan students, from 1985 to 2005. METHODS: Data from the Chinese national survey on students' physical fitness and health in 1985, 1995, 2000 and 2005 were used to analyze and find out the difference of the morphological development and nutrition status of Tibetan students aged 7 - 18 years in different years. RESULTS: From 1985 to 2005, the height and weight of Tibetan students had a growing trend. The height and weight of schoolboys and schoolgirls aged 7 - 18 years increased 3.94 cm, 5.08 kg, 2.25 cm, and 4.24 kg respectively, while the circumference decreased without significance. The prevalence rates of underweight and malnutrition in Tibetan students further went down along with the improvement of their nutritional status. However, the prevalence rates on both overweight and obesity increased continuously, affecting the health status of Tibetan students. CONCLUSION: From 1985 to 2005, the morphological development of Tibetan students had a growing trend and their nutrition status improved. However, the prevalence of overweight and obesity continuously increased. PMID- 20193384 TI - [Study on the changing status of morphological development among minority students in China, from 1985 to 2005]. AB - OBJECTIVE: To identify the changes of morphological development status on minority students in China from 1985 to 2005. METHODS: We selected a total of 15 groups of the Chinese minority students as subjects of the study, including Mongolian, Hui, Uygur, Zhuang, Korean, Tibetan, Yao, Li, Qiang, Buyi, Dong, Miao, Tu, Salar, Kirgiz, with data from the Chinese national survey on students' physical fitness and health condition in 1985, 1995, 2000 and 2005. Height, weight and waist of the subjects were calculated and analyzed. RESULTS: From 1985 to 2005, the growth and characteristics of height in the Chinese minority students had a similar increase when comparing to the Han students, but with different degrees. However the growth rate was gradually decreasing. The average heights of Kirgiz, Korean, Salar and Mongolian schoolboys aged 18 years old were 170 cm, being 170.91 cm, 170.47 cm, 170.29 cm and 170.27 cm, respectively, which were close to that of the Han students. Some minority students had a substantial increase of body weight. However, the waist of some minority students decreased. Only a few groups of minority students had increasing waist, such as Mongolian and Korean rural boys, Mongolian, Zhuang, and Korean rural girls, with the growth being 0.101 cm, 0.095 cm, 0.126 cm, 0.163 cm and 0.107 cm, respectively. Uygur, Mongolian, Kirgiz and Korean students had the morphological development similar to Han urban students, especially Uighur boys and girls. CONCLUSION: From 1985 to 2005, The height, weight and waist of Chinese minority students had an overall increase at different degrees. In order to improve the physical fitness of minority students, awareness on nutrition and health education of both students and parents should be strengthened. Surveillance and programs on growth, development and health status of the minority children and adolescents should also be carried out continuously. PMID- 20193385 TI - [Changes of physical functions among Chinese minority students from 1985 to 2005]. AB - OBJECTIVE: To study the changes of physical functions among minority students in China from 1985 to 2005, to provide evidence for health promotion to the minority students in the country. METHODS: Using data from the Chinese national survey on students physical fitness and health from 1985 to 2005, we analyzed the physical functions of 15 minority groups from primary and secondary schools, including Mongolian, Hui, Uygur, Zhuang, Korean, Tibetan, Yao, Li, Qiang, Buyi, Dong, Miao, Tu, Salar, Kirgiz, aged 7 - 18 years old. RESULTS: Some of the minority students had the higher levels of physiological functions and athletic ability, but some indicators decreased significantly. In terms of items related to 'speed', most of the minority boys and girls improved, but items related to 'endurance' or'vital capacity', were significantly declining. Part of the minority students had better 'endurance' than students of Han ethnicity in the cities. All the indicators of athletic ability declined in schoolboys and schoolgirls of Korean ethnicity. Kirgiz students were outstanding in vital capacity and speed quality while Uighur students had better physical development and vital capacity, but were poorer in running and jumping, reflecting the weakness of explosive power of lower limbs. On the contrary, Li and Zhuang students had shown a very good quality in running, jumping, male shoulder muscular strength and endurance items, etc. CONCLUSION: The physical functions and the athletic ability of the minority students in China had the advantages and characteristics, which might be related to their living environment and habits. PMID- 20193386 TI - [Epidemiologic study on patients with invasive fungal infections]. AB - OBJECTIVE: To investigate the epidemiological features of patients with nosocomial invasive fungal infection. METHODS: Fungi in blood were identified by BacT ALERT 3D, other clinical samples were cultured by Sabouraud's dextrose agar (SDA) medium. Candidas were isolated and identified by CHRO Magar candida color medium. Fungus-cultured positive cases from Jan. 2004 to Nov. 2007 were analyzed on items as patients' age, underlying disease, sample, strain, and species distribution. All statistical analyses were carried out by SPSS 13.0. RESULTS: The overall incidence rate of invasive fungal infections was 4.12%. The average age of patients was 7 - 96 with most patients were male, with geriatric problems and different kinds of underlying diseases. Lower respiratory tract infection was the most frequent infection site, followed by urinary tract, gastrointestinal tract. The main pathogens of invasive fungal infections were Candidas (93.80%). Strains of Candida albicans were the most frequent organisms which accounted for 67.29% of all the isolates. Mould fungus infections accounted for only 6.20%. During the 4 years of observation, the detection rate of fungi, specimen sources and the distribution of species and compartment were different with significant differences (P < 0.0083). CONCLUSION: The epidemiological properties such as the source of specimen, the distribution of species and composition sections of invasive fungal infections were changing. Candida spp. were still the main pathogens of invasive fungal infections but the sections of fungi changed. The incidence of Aspergillus infections had been increasing recently. PMID- 20193387 TI - [Comparison on the difference of virulence between Hantaan virus and Seoul virus isolated both from Rattus norvegicus]. AB - OBJECTIVE: Comparing the difference of virulence between the strain CGRn5310 (HTNV) and the strain HR54 (SEOV) isolated both from Rattus norvegicus. METHODS: Suckling mice were used to compare the difference of virulence between the two strains. Hantavirus antigens were detected in brain and lung tissues collected from the infected mice. RESULTS: Compared with the control group, all infected mice grew slowly. Furthermore, the mice inoculated intracerebrally with either CGRn5310 or HR45 appeared ruffled fur, and reduced activity, followed by neurological symptoms, such as paralyses and convulsions. The half lethal dose (LD(50)) of CGRn5310 strain was 10(-6.42), whereas the LD(50) of HR54 strain was 10(-4.51). Hantavirus antigens were identified in brain and lung tissues from the mice infected with the strain CGRn5310 and the strain HR54. CONCLUSION: LD(50) of the strain CGRn5310 was significantly higher than that of the strain HR54. Our results suggested that the virulence of the spillover hantavirus might only slightly be influenced by the non-reservoir rodents. PMID- 20193388 TI - [Complete sequence of the M segment of Amur virus in rodent from China]. AB - OBJECTIVE: To study the complete sequence of M segment of Amur virus in rodents and to explore their molecular characteristics. METHODS: Complete M segment of Amur virus in rodent from China was amplified by RT-PCR. The purified PCR product was cloned into pGEM-T Easy vector and then sequenced. Phylogenetic analysis on multiple nucleotide sequences was performed with the Tree PUZZLE and DNAStar software. RESULTS: The full-length of its M gene comprised of 3615 nucleotides with one open reading frame (ORF) including 3408 nucleotides and encoding a protein which comprised 1135 amino acids. The ORF was located at bases 41 to 3448. The phylogenetic analysis of JilinAP06 with other hantaviruses revealed that the complete sequence of M segment of JilinAP06 strain was closely related to those Amur viruses such as B78 strain, Liu strain and H5 strain were all from the patients. The complete sequence of M segment of JilinAP06 had only 79.5% identities with the nucleotide sequence of HTNV strain 76 - 118. CONCLUSION: The complete sequence on M segment of Amur virus in rodent was first time identified in this country. PMID- 20193389 TI - [Possible determinants of the radial augmentation index in 4985 Chinese population]. AB - OBJECTIVE: The augmentation index (AI) derived from central arteries is generally defined as an index of augmentation of central blood pressure in systole derived from the return of pressure waves reflected from the periphery and is an index of arterial stiffness. There is controversy with respect to how to affect AI. METHODS: In a cross-sectional study of 4985 subjects (2417 men and 2568 women) aged 18 - 96 years (50.94 +/- 14.73 years, mean +/- SD), AI was measured in the left radial artery using tonometry Colin HEM-9000AI. RESULTS: Among the subjects, 39.4% were diagnosed as hypertensive, 11.2% as diabetes mellitus, and 48.7% as hyperlipidemia. Stepwise regression analysis revealed that age, diastolic blood pressure, smoking, heart rate, height, waist circumference and fasting blood glucose were independent determinants of radial AI in women;while in men, it was also determined by total cholesterol. Radial AI was significantly higher in women than in men [(83.18 +/- 12.36)% vs. (71.93 +/- 15.22)%, P < 0.01]. CONCLUSION: Our findings indicate that AI is determined by arterial stiffness, distance to the reflection point and reflection coefficient. It is necessary to take into account these confounding factors when assessing AI is used as an index for atherosclerosis. PMID- 20193390 TI - [Study on depression in 212 patients with viral hepatitis]. AB - OBJECTIVE: To investigate the symptoms on depression in patients with viral hepatitis. METHODS: A cross-sectional study was conducted among the patients with viral hepatitis in infectious diseases Hospital of Taiyuan. The questionnaire included a Eysenck Personality Questionnaire, self-rating depression scale (SDS), and a self-designed one related to information regarding general conditions of the disease and social support. RESULTS: (1) Depression symptom prevalence rate among chronic viral hepatitis patients was 54.7% (116/212). (2) Factors as age, occupation, education, confirmed time, number of recurrence and anti-virus treatment, self-confidence on recovery, satisfaction on the surrounding environment etc. that might be associated with depression. (3) The severity of depression was significantly negative correlation with social support scores, objective support scores, subjective support scores (r = -0.262, P = 0.000; r = 0.228, P = 0.001; r = -0.270, P = 0.000). (4) There was positive correlation noticed between severity of the depressive disorder and Eysenck Personality two dimensions scores, while the scores of introversion and extroversion scores were negatively correlated (r = -0.330, P = 0.000) but positively correlated to the emotional stability scores (r = 0.309, P = 0.000). CONCLUSION: (1) Patients with hepatitis showed symptoms of depression to a certain degree. (2) Factors as age, occupation, education, economic situation, confirmed time of diagnosis, number of recurrence and anti-virus treatments, confidence on recovery, satisfaction on the surrounding environment might be associated with symptoms of depression. (3) There was positive correlation between severity of depressive and Eysenck Personality two dimensions scores but the scores of introversion and extroversion scores were negatively correlated. PMID- 20193391 TI - [The use of antiparkinsonism drugs in 92 cases in Xi'an city]. AB - OBJECTIVE: To investigate the treatment status of antiparkinsonism in Xi'an. METHODS: Six general hospitals were randomly chosen in Xi'an and all Parkinson's disease (PD) patients were interviewed by questionnaire from Jan. 2007 to Apr. 2007. RESULTS: 92 PD outpatients were enrolled in, including 48 males and 44 females, from 43 to 86 years old (mean 65.6 +/- 17.1) with duration of the disease from 0.2 to 27.8 years (mean 4.4 +/- 9.4). The preference of the drug use from the patients were: 40 (43.5%) preferred taking levodopa, 25 (27.2%) with amantadine and/or trihexyphenidyl, 14 (15.2%) with levodopa and others, 4 (4.4%) with dopamine agonist and others, 2 (2.2%) with other drugs, 7 (7.6%) with no treatment. There were 69 (75.0%) patients onset with resting tremor, 15 (16.3%) with bradykinesia, 6 (6.5%) with rigidity, and 2 (2.2%) with unknown symptoms. There was no startically significant difference in anti-PD drugs among the patients onset with different symptoms (P > 0.05). 45 patients appeared the onset of disease before 65 years old and with no dementia, 47 onset after 65 with or without dementia. There was no significant difference of anti-PD drugs between the two groups (P > 0.05). Most patients initiated anti-PD treatment with levodopa but few of them chose dopamine agonist. According to the classification of Hoehn & Yahr, 25(27.2%)belonged to Grade I, 53 (57.6%) to Grade II, 8 (8.7%) to Grade III, 3 (3.3%) to Grade IV and 3 (3.3%) to Grade V. There was no significant differences of anti-PD drugs between different grades of the disease (P > 0.05). 55.3% of the patients changed their anti-PD drugs randomly during the therapy, but with no relation to their gender, age, educational level, dementia, the number of family members, course of diseases, or the degree of Hoehn & Yahr, frequency and categories of medicine. CONCLUSION: Anti-PD treatment in Xi'an did not strictly follow the standardized protocol, with few patients using dopamine agonist and over 50% of the patients changed their drugs randomly. PMID- 20193392 TI - [Associations of the genetic polymorphisms in CYP11B2 gene with nonfamilial structural atrial fibrillation]. AB - OBJECTIVE: To investigate whether polymorphisms in CYP11B2 gene are associated with nonfamilial structural atrial fibrillation (AF) in Chinese Han population. METHODS: A fine-designed pair-matched hospital based case-control study was performed in 297 cases and 297 controls. We investigated two tagging single nucleotide polymorphisms (tSNPs)-rs4545, rs3802228 in CYP11B2 gene by using GenomeLab SNPstream technique. RESULTS: Two tSNPs were consistent with Hardy Weinberg expectations in case and control groups. Compared with controls, the left atrial diameter of cases was significantly higher (P < 0.0001). No significant difference in genotype or allele frequencies of tSNPs in CYP11B2 gene was observed. However, at the site of rs3802228 in 3'UTR of the case group, the left atrial diameter in AF patients with GG genotype was significantly higher than others. After adjusted for covariates age, smoking, Body mass index and hypertension, we did not observe the association of rs4545, rs3802228 with AF. CONCLUSION: Our result suggested that polymorphisms of rs4545 in CYP11B2 gene might not be associated with atrial fibrillation but polymorphism of 3'UTR rs3802228 locus in CYP11B2 gene might be associated with atrial structural remodeling. PMID- 20193393 TI - [Models for risk assessment and prediction in breast cancer]. AB - In the areas of prevention and life skills counseling for breast cancer, risk assessment and prediction can assist clinicians to decide if chemoprevention or prophylactic surgery is needed or suggestions on improving the quality of life for their clients. Several mathematical models, namely Gail Model, Claus Model, BRCAPRO Model and Cuzick-Tyrer Model etc. have been developed to make predictions, clinically. This paper has reviewed the development, operation, advantage versus disadvantage and areas of application for the four models. Having family history of breast cancer, one subject was calculated on the risks by the four models and different results were found. Up to 45 years old, the accumulative risks from the four models and population risk were 1.9%, 11.8%, 2.5%, 5.0% and 1.6%, respectively. To 75 years old, they were 20.2%, 32.5%, 13.1%, 25.0% and 8.5%, respectively. The subject had a relatively high breast cancer risk during her lifetime. A new model is supposed to include a variety of important risk factors and to be validated by large scale of case-control samples. Incidence of breast cancer in China had significantly increased during the last ten years, but the research on developing assessment methods of breast cancer risk had never been reported, suggesting that the development of models for Chinese population is necessary. PMID- 20193394 TI - [Emergence of a new branch on epidemiology: Epigenetic epidemiology]. PMID- 20193395 TI - [Rabies prevention strategies and challenges in the United States]. PMID- 20193396 TI - [The surgery of chronic constipation needs comprehensive evaluation and cautious approach]. PMID- 20193397 TI - [Application of pelvic floor dynamic MRI combining defecography with homemade high conformable sacculus in the management of obstructed defecation syndrome]. AB - OBJECTIVE: To evaluate the sensitivity and feasibility of pelvic floor dynamic MRI combining defecography with homemade high conformable sacculus in the management of obstructed defecation syndrome. METHODS: One hundred and nine female with pelvic floor disorders, such as difficult defecation, fecal incontinence or urinary incontinence, pelvic pain, were treated from July 2007 to March 2009. Pelvic floor dynamic MRI and defecography with homemade high conformable sacculus was performed in the patients to evaluate pelvic floor anatomy. RESULTS: Fifty-four cases (49.6%) of cystocele and 11 cases (10.1%) of rectouterine pouch hernia, 29 cases (26.6%) of perineum prolapse and 71 cases (65.2%) of rectocele were found by dynamic MRI. The dynamic MRI also revealed 19 cases (18.2%) of external sphincter trophy and 32 cases (29.4%) of spastic pelvic floor syndrome. Compared with defecography, dynamic MRI was more positive in diagnosing enterocele. Defecography Of the patients, sacrum-rectal separate was found in 33 cases (30.3%) and rectal mucosal prolapse or internal rectal intussusceptions in 41 cases (37.7%) by defecography, while dynamic MRI found none. CONCLUSIONS: As a new noninvasive imaging technique to evaluate the pelvic floor function, dynamic MRI is more sensitive, especially for patients with complicated multi-organs prolapse, and its deficiency could be remedied by defecography. PMID- 20193398 TI - [Application of stapled transanal rectum resection in the treatment of obstructed defecation syndrome]. AB - OBJECTIVE: To evaluate the effectiveness and safety of stapled transanal rectum resection (STARR) in the treatment of obstructed defecation syndrome (ODS). METHODS: Fifty-six patients with ODS who had rectocele and/or intussusception were treated with STARR from January 2007 to August 2008. The incidence of preoperative and postoperative symptoms of ODS was compared. Symptomatic relief was also observed by using scoring system. RESULTS: The average operation time was 28 min, and in the first 3 days after operation the average VAS pain score was 3.2 points. Two patients experienced mild anal incontinence when followed-up to 6 months; 2 patients suffered mild anal pain during defecation due to slight anastomotic inflammation 2 and 4 months after the operation, respectively. No other complications was found. The mean follow-up period was 8 months after surgery, and the rate of symptoms of ODS reduced significantly compared with that before surgery, in particular the incidence of the difficult and obstructive defecation feelings decreased for more than 50 percent (P<0.05). Compared with that before the operation, the sense of no emptying stool decreased for 65 percent and all the other symptoms reduced for more than 72 percent (all P<0.05). CONCLUSION: The stapled transanal rectum resection is simple, less invasive, less painful and with fewer complications and more satisfactory recent effect in treating obstructed defecation syndrome. PMID- 20193399 TI - [Comparison of subtotal colectomy with antiperistaltic cecoproctostomy and total colectomy with ileoproctostomy in treating slow transit constipation]. AB - OBJECTIVE: To compare clinical outcome and quality of life of subtotal colectomy with antiperistaltic cecoproctostomy and total colectomy with ileorectal anastomosis (TAC-IRA) in patients with severe slow transit constipation (STC). METHODS: Of the 56 patients enrolled in this study from January 1999 to June 2008, 32 cases underwent subtotal colectomy with antiperistaltic cecoproctostomy, and 20 patients underwent TAC-IRA. The patients' clinical characteristics, operative data, postoperative outcome, functional result and gastrointestinal quality of life index (GIQLI) survey were compared between the two groups. RESULTS: All patients were followed up for 1-7 years (median, 4 years). The basic clinical characteristics between the two groups was comparable. During the follow up period, the number of daily bowel movements in the subtotal colectomy group was significantly fewer than that in TAC-IRA group (2.5+/-0.8 vs. 3.4+/-0.8; P=0.000). The Wexner continence score was significantly lower in subtotal colectomy group (4.4+/-1.6 vs. 5.8+/-1.9; P=0.011), and the GIQLI score in subtotal colectomy group was significantly higher than that in the TAC-IRA group (120.7+/-7.5 vs. 111.1+/-12.0; P=0.005). CONCLUSION: Subtotal colectomy with antiperistaltic cecoproctostomy appeared to be the superior treatment than the TAC-IRA for selected patients with slow transit constipation for improved functional outcomes and quality of life. PMID- 20193400 TI - [Expression of Survivin protein in extrahepatic cholangiocarcinoma and its relationship with the prognosis]. AB - OBJECTIVES: To investigate the expression of Survivin in patients with extrahepatic cholangiocarcinoma (EHCC) and its relationship with clinicopathological features of EHCC, and the correlation between the expression of Survivin and lymph node micrometastasis, tumor markers, and the prognosis of EHCC. METHODS: The expression of Survivin protein in paraffin-embedded specimens of 59 patients with EHCC and their 20 para-carcinoma tissues were evaluated by S P method of immunohistochemical staining. The correlation between the expression of Survivin and the lymph node micrometastasis, clinicopathological features of EHCC and the prognosis of EHCC were analyzed. RESULTS: The positive expression rate of Survivin protein was 67.8% (40/59) in paraffin-embedded specimens of 59 patients with EHCC and was 20.0% (4/20) in para-carcinoma tissues, and difference between carcinoma tissues and para-carcinoma tissues was significant (P<0.01). Histological differentiation in EHCC had a negative correlation with the expression of Survivin protein, while the expression of Survivin protein in EHCC had a positive correlation with TNM of EHCC, lymphatic vessel infiltration, lymph node metastasis and perineural invasion (P<0.05). The serum CA19-9 levels in the positive group with expression of Survivin protein was (290,300+/-55 500) U/L and was obviously higher than that in the negative group [(113,300+/-31,400) U/L, P<0.05]. The mean survival time of the patients with negative expression of Survivin protein was higher than that of the patients with positive expression (43.5 vs. 21.1 months, P<0.01). Screened to significance univariate, the multivariate analysis through Cox proportional hazard model analysis showed that lymph node metastasis, residual tumor margins, and expression of Survivin protein were independent prognosis factors of the patients with EHCC (P<0.05, P<0.01, P<0.01). CONCLUSIONS: The expression of Survivin protein in EHCC has a negative correlation with histological differentiation, while has a positive correlation with lymphatic vessel infiltration and serum CA19-9 concentrations. The expression of Survivin protein maybe an independent prognosis factor of the patients with EHCC. PMID- 20193401 TI - [Relationship of extrahepatic metastasis of primary hepatocellular carcinoma between circulative tumor cells in the blood of hepatoma patients]. AB - OBJECTIVE: To study the relationship between extrahepatic metastasis of primary hepatocellular carcinoma and circulative tumor cells in the blood of hepatoma patients. METHODS: The immunomagnetic bead technique was employed to enrich and separate the hepatoma cells in the peripheral blood of preoperative and postoperative hepatoma patients. The relationship between postoperative extrahepatic metastasis and hepatoma cells in peripheral blood cancer cells were analyzed. The circulative tumor cells in the peripheral blood of hepatoma patients were enriched and separated by immunomagnetic bead technique. They were identified as hepatoma cells by AFP immunohistochemistry. Among 30 cases of hepatoma patients, the positive rate of hepatoma cells in the peripheral blood of preoperation and postoperation were 53.3% and 83.3% respectively. There was difference significantly in positive cases before operation and after operation (P<0.05). CONCLUSIONS: Extrahepatic metastasis of primary hepatocellular carcinoma is obviously correlated to the positive tumor cells and the concentration in the peripheral blood of preoperative patients. PMID- 20193402 TI - [Study on the clinicopathological characteristics and pattern of lymph node metastasis in patients with gastric remnant cancer]. AB - OBJECTIVE: To investigate clinicopathological characteristics and the pattern of lymph node metastasis of patients with gastric remnant cancer. METHODS: The data of the clinicopathological characteristics and the pattern of lymph node metastasis in 56 patients with gastric remnant cancer treated from March 1994 to December 2008 was investigated and compared with those in 1171 patients with primary gastric cancer treated over the same period. RESULTS: Fifty-six patients (4.6%) with gastric remnant cancer were enrolled in this study during the period. Compared with patients with primary gastric cancer, the age of cancer onset was older [(64.3+/-9.0) vs. (58.3+/-12.6) yrs], lymph node metastasis rate was higher (31.8% vs. 25.5%), Borrmann's classification was later and neighbor organ resection rate was higher (57.1% vs. 26.4%) in patients with gastric remnant cancer; the differences were all significant (chi2=18.800, 11.679, 9.177, 25.190; P<0.05). Patients with gastric remnant cancer who underwent lymph node dissection tended to have a higher incidence of No.10 (splenic hilar lymph node) and No.11 (splenic artery lymph node) group lymph node metastasis than those in primary gastric cancer (chi2=5.558, 6.099; P<0.05). In contrast, patients with primary gastric cancer had a higher incidence of No. 2 (left cardiac lymph node), No.3 (lesser curvature lymph node) and No.8 (common hepatic artery lymph node) group lymph node metastasis than those in gastric remnant cancer (chi2=15.508, 6.003, 4.084; P<0.05). The jejunal mesentery lymph node metastasis was 24.0% (6/25) in patients with gastric remnant cancer and the peripheral connective tissue infiltration rate was 14.3% (8/56). CONCLUSIONS: It suggested that patients with gastric remnant cancer has different clinicopathologic characteristics and the pattern of lymph node metastasis from those with primary gastric cancer. D2 lymph node dissection of proximate gastric cancer and jejunal mesentery lymph node dissection should be the standard operation for these patients; but combined neighboring organ resection should be taken into consideration. PMID- 20193403 TI - [Research on the postoperative complications and its risk factors of breast reconstruction with abdominal flaps]. AB - OBJECTIVE: To study the postoperative complications and its risk factors in patients underwent breast reconstruction with abdominal flaps. METHODS: The clinical data of 115 cases underwent breast reconstructions with abdominal flaps from May 2001 to October 2008 was reviewed. The postoperative complications included total flap necrosis, partial flap necrosis, fat necrosis, hernia, bulge, fat liquefaction and infection. The risk factors of complication rates were also evaluated. RESULTS: The total postoperative complications rate was 17.4% (20/115). No severe complications was found, such as total flap necrosis, hernia and bulge. The most common complications of flap was fat necrosis which occurred in 6 cases (5.2%), partial flap necrosis in 5 cases (4.3%) and infection in 1 case (0.9%). The donor-site complications included fat liquefaction which occurred in 8 cases (7.0%) and infection in 3 cases (2.6%). No significant relation was found between patient's age, body mass index (BMI), timing of surgery and the postoperative complication rate. The postoperative complications occurred more frequently in active smokers, patients with radiotherapy history, or reconstructions with pedicled transverse rectus abdominis myocutaneous (TRAM) flaps. But no significant difference was found in those factors. CONCLUSIONS: Fewer complications happens in patients with a reconstruction with deep inferior epigastric perforator (DIEP) flap. Abdominal flap should be performed with more consideration in active smokers or patients with a radiotherapy history. Age and obesity should not be contraindications to breast reconstruction with abdominal flaps. PMID- 20193404 TI - [Prospective study of coverage of left subclavian artery during thoracic endovascular aortic repair in a single center]. AB - OBJECTIVE: To describe observation of security and availability of covering left subclavian artery during thoracic endovascular aortic repair (TEVAR) in follow up. METHODS: From December 2007 to December 2008, 111 consecutive patients received stent grafts to treat lesions involving thoracic aorta. According to the covering of left subclavian artery, four groups including total covering (TC), less-than 50% covering (LTC), more-than 50% covering (MTC) and non-covering (NC) were formed. Difference of blood pressure between two upper extremities was required before TEVAR and 1st, 3rd, 5th, 30th day after TEVAR. Patients were evaluated postoperatively and at follow-up for stroke as well as symptoms of paraplegia, hemiparalysis or left upper extremity claudication. RESULTS: Fifty five (49.6%), 18 (16.2%), 7 (6.3%) and 31 (27.9%) cases were divided into TC, LTC, MTC and NC groups, respectively. Difference of blood pressure between TC and the 3 latter groups were significantly different (P<0.01). Complications appeared as followed during one week after TEVAR: 13 patients in dizziness, among which 5 patients suffered from amaurosis and spotted vision, and 7 patients in left upper extremity claudication. No stroke, paraplegia or hemiparalysis in TC. Thoracic aortic lesions were successfully excluded in all patients. CONCLUSIONS: Intentional coverage of left subclavian artery to obtain an adequate proximal landing zone during TEVAR is safe and well-tolerated. But it may be managed expectantly with some exceptions for further lasting efficacy. PMID- 20193405 TI - [Catheter-directed foam sclerotherapy of incompetent saphenous reflux: early results]. AB - OBJECTIVE: To describe observation of availability of catheter-directed foam sclerotherapy for the great saphenous vein varicosis. METHODS: A selective series of 30 patients of vein varicosis were treated with foam sclerotherapy using a standard technique for foam delivery from April 2008 to August 2008. Patients were treated with 1% polidocanol foam through a catheter, which was inserted percutaneously over a guidewire in the great saphenous vein (GSV). All successfully treated patients were examined by colour duplex two weeks after the procedure. RESULTS: Thirty patients with an insufficiency reflux of the GSV were treated with the catheter-directed foam sclerotherapy. Primary technical success was achieved in all the patients. The concentrations (1.0%) and doses (6 to 8 ml) of polidocanol was mainly we used. Five patients experienced transient scotomas and developed segmental phlebitis of a collateral vein. The intervention was well tolerated in all patients without the occurrence of serious side effects. In 27 of the 30 treated patients (90%), a closure of the GSV was found at control visits 2 weeks, 3 months after treatment. CONCLUSION: The use of an endovascular catheter inserted percutaneously over a guidewire is feasible in most patients and has resulted in high primary occlusion rates. PMID- 20193406 TI - [The cryosurgery of central lung cancer by rigid bronchoscopy]. AB - OBJECTIVE: To evaluate the method and effectiveness of rigid-bronchoscopic cryosurgery for advanced central lung cancer. METHODS: Forty-eight patients were enrolled in this study from June 2002 to December 2008, including 33 male and 15 female. The average age was 70 years (ranged from 45 to 83 years old). For the 48 patients, 38 cases were patients with advanced central lung cancer who were not suitable for surgery, and the remaining 10 cases were patients with local recurrence in trachea or main bronchus postoperatively. Cryosurgery was performed 120 times for all patients, 2.5 times per patient on average. The trachea or bronchus station, symptom such as dyspnea, hemoptysis, respiratory function and quality of life were observed. RESULTS: The unblocked ratio of trachea and bronchi was 97%. All patients got satisfied improvement ratio of symptoms, 87.5% for dyspnea, 72.9% for cough, 93.8% for hemoptysis and 62.5% for chest pain. Respiratory function tests showed that both the mean forced expiratory volume in first second and forced vital capacity got an improvement from (1.03+/-0.05) L to (1.85+/-0.13) L and from (1.69+/-0.18) L to (2.96+/-0.14) L respectively (P<0.01). Karnofsky score also got no less than 20 scores improvement. The Follow up time was 6 to 62 months. The longest survival was 62 months. The median survival time was 20 months. There was no severe perioperative complications and mortality except for 3 cases of moderate exeduation. CONCLUSIONS: Cryosurgery is easy to perform with minimal complications. Not only could it provide an effective and rapid control of symptoms caused by central lung cancer, it could also unobstructed bronchus promptly and improve patients' quality of life. PMID- 20193407 TI - [Anatomy character of renal artery and treatment of living-donor renal transplantation]. AB - OBJECTIVE: To study the anatomy characters of renal artery and the treatment of multiple arteries in living donor renal grafts. METHODS: Records of 142 living donors were analyzed in our center. We analyzed the anatomic structure of renal arteries by DSA and CTA pre-transplantation. Thirty-one kidneys with multiple arteries were transplanted after reconstruction. Then clinical effects were compared between multiple-renal-arteries group (n=31) and single-renal-artery group (n=111). RESULTS: The incidence of multiple renal artery was 30.99%, and there was no difference between both sides (left kidney 22.54%, right kidney 22.13%). If the multiple artery occurred in left or right kidney, the incidence of the multiple artery occurred in the other side was 56.25% and 60.00%, respectively. The diameter of left main renal artery was more magnanimous (P=0.001) and the first branch was more closed to abdominal aorta (P=0.004). Operation time and warm/cool ischemia time were longer in the multiple-renal arteries group. However, estimated blood loss, delayed graft function, acute rejection and flow rate of arcuate artery were similar in both groups, the same as serum creatinine and serum creatinine clearance rate on day 7, 1 month and 3 month post-operation. It was shown by repeated measures ANOVA that graft with multiple arteries didn't affect the tendency of renal function at early time post operation. CONCLUSION: Comprehending the character of renal artery and accurate treatment of multiple artery anastomosis are critical for the effect of the living kidney transplantation. PMID- 20193408 TI - [Additional screws fixation on fractured vertebrae versus only short-segment posterior instrumentation for thoracolumbar A3 fracture without neurologic deficit]. AB - OBJECTIVE: To compare the clinical results of additional screws fixation on fractured vertebrae versus only short-segment posterior transpedicular instrumentation for A3 thoracolumbar fracture without neurologic deficit. METHODS: Clinical data of 52 cases of thoracolumbar burst fracture without neurologic deficit were retrospectively analyzed. All patients were divided into 2 groups due to different instrumentation and all fractures were classified as type A3 according to AO Classification.From January 2005 to December 2006, 23 cases in group A were treated by short-segment posterior instrumentation combined with additional screws fixation on fractured vertebrae. There were 18 male and 5 female with a mean age of (35.3+/-8.3) years. The fracture segment included 1 in T11, 9 in T12, 11 in L1 and 2 in L2. From January 1999 to December 2004, 29 cases in group B were treated only by conventional short-segment posterior transpedicular instrumentation. There were 20 male and 9 female with a mean age of (37.3+/-6.8) years. The fracture segment included 1 in T11, 7 in T12, 20 in L1 and 1 in L2. The clinical effect and radiographic measurements were respectively compared preoperatively, immediate and 2 years postoperatively. RESULTS: All patients were followed up and the mean follow-up time was (37.4+/-10.9) months (from 24 to 48 months). There was no statistic difference of mean JOA and VAS score between 2 groups preoperatively, immediate and 2 years postoperatively (P>0.05). The average immediate postoperative correction of Cobb's angle was 13.7 degrees+/-7.7 degrees in group A, which was statistically significantly higher than that of 8.8 degrees+/-5.0 degrees in group B (P<0.01). The mean kyphosis correction loss of 2.9 degrees+/-1.5 degrees in group A was statistically significantly lower than that of 5.0 degrees+/-2.9 degrees in group B 2 years postoperatively (P<0.01). The average restoration of anterior height of fractured vertebral body immediate postoperatively was (29.4+/-6.0)% and (21.7+/-6.9)% respectively. The mean correction loss of anterior height 2 years postoperatively was (3.1+/-0.8)% and (6.6+/-3.0)% respectively. The average restoration of posterior height of fractured vertebral body immediate postoperatively was (8.5+/ 3.2)% and (6.1+/-1.8)% respectively. The mean correction loss of posterior height 2 years postoperatively was (2.0+/-0.8)% and (3.4+/-1.0)% respectively. There were significant differences in average restoration of anterior/posterior height immediate postoperatively and correction loss of anterior/posterior height 2 years postoperatively between the 2 groups (P<0.01). According to fracture fragments protruded into the spinal canal on immediate postoperative CT image, there were complete reduction in 11 cases (47.8%) and partial reduction in 12 cases (52.2%) in group A, which was statistically significantly better than those in group B (P<0.01). There was no severe neurologic complications and no other complications related to additional screws fixation postoperatively. Pedicle screw breakage occurred in 2 cases in group B and none in group A. CONCLUSIONS: Better initial kyphosis correction and less loss of correction 2 years after operation can be obtained by using additional screws fixation on fractured vertebra for thoracolumbar A3 fracture without neurologic deficit. PMID- 20193409 TI - [Polyethylene wear and osteolysis in H/G cementless total hip arthroplasty]. AB - OBJECTIVES: To measure the linear polyethylene wear with use of a computer assisted two-dimensional method, and to evaluate the relationship between wear and long-term clinic-radiological findings. METHODS: Between December 1991 and December 1995, the senior author performed 40 primary total hip arthroplasties with use of H/G porous-coated acetabular component. Radiographs of 40 H/G cementless total hip arthroplasties were examined for osteolysis, radiolucent line, cup migration and so on. To measure the linear polyethylene wear, migration in the femoral head center relative to the cup shell center was calculated on digitized consecutive radiographs with special computer software program. RESULTS: The minimum follow-up was 10 years. Total linear wear was 2-8 mm, the mean rate of linear polyethylene wear was (0.32+/-0.31) mm/year. Twelve acetabular components (30%) were revised at an average follow-up point of 12 years. Three types of polyethylene liner failure were identified: wear-through of the polyethylene liner with resultant metallosis (5 hips), excessive wear necessitating revision (5 hips), and polyethylene liner dissociation without gross evidence of wear (2 hips). CONCLUSIONS: High wear rates and femoral and acetabular osteolysis have been and still are the main problems in uncemented total hip replacement. There is clear relationship between wear and acetabular osteolysis or loosening of the prostheses. The poor long-term results with these uncemented total hip arthroplasties illustrate the necessity of regular radiographic evaluation in order to detect osteolysis and liner failure, which are both generally asymptomatic until catastrophic failure appears. PMID- 20193410 TI - [Clinical report of traumatic lumbo-sacro-pelvic injuries]. AB - OBJECTIVE: To study the characteristic and surgical treatment of traumatic lumbo sacro-pelvic injuries. METHODS: A retrospective study was carried out on 8 cases with traumatic lumbo-sacro-pelvic injuries between August 2005 and February 2008, which included 6 male and 2 female, aged from 21 to 52 years with a mean age of 38.4 years. ISS scores were undertaken to evaluate the injury severity of the cases after admission. Measures were taken to treat the emergency that affected the patients' lives. After the patients' conditions were stable, lumbo-iliac fixation was performed to treat traumatic lumbo-sacro-pelvic injuries. Imaging examinations were made to observe the reduction of fracture after operation. Injury of nerve was evaluated with ASIA score, and ASIA scores of preoperation and the last follow-up were analyzed statistically with paired t test. RESULTS: The group was followed up for 9 to 25 months, averaging 16.9 months. Postoperative imaging examinations showed satisfied reduction of fracture. The preoperative ASIA sensory score and motor score were 35.8+/-5.3 and 31.9+/-6.4 respectively, while the sensory score and motor score were 51.8+/-13.8 and 38.2+/ 7.5 at the last follow-up respectively. The sensory and motor functions were improved significantly after operation (P<0.01). The functions of urination and defecation of 6 cases were recovered for different degree after operation. In all of the cases, no aggravated injury of nerve occurred. CONCLUSIONS: Traumatic lumbo-sacro-pelvic injuries is a kind of severe injury of lumbo-sacro-pelvic region. It can be treated with lumbo-iliac internal fixation and fine clinical effect can be gained. PMID- 20193411 TI - [Correct understandings of human papillomavirus infection and its vaccination.]. PMID- 20193412 TI - [Clinical application of telomerase RNA component gene amplification assay in cervical lesions.]. AB - OBJECTIVE: To investigate the significance of genomic amplification of the telomerase RNA component (TERC) gene to serve as a genetic biomarker in the screening of cervical lesions. METHODS: A total of 715 cases were recruited, with liquid-based cytology diagnosis as normal (n = 347), atypical squamous cells of undetermined significance (ASCUS, n = 180), atypical squamous cells cannot exclude a high-grade lesion (ASC-H, n = 13), low-grade squamous intraepithelial lesions (LSIL, n = 115), high-grade squamous intraepithelial lesions (HSIL, n = 59) and atypical glandular cells (AGC, n = 1). The remaining cervical cells in the cytological preserving fluid were analyzed using a two-color fluorescence in situ hybridization (FISH) probe targeted to chromosome 3q26 containing TERC gene. The TERC gene findings were compared to the cytological and histological detected results, as well as high-risk human papillomavirus (HPV) detected results. RESULTS: Genomic amplification of TERC gene was found in 5.8% of normal specimens, 22.2% of ASCUS, 30.8% of ASC-H, 27.8% of LSIL, 86.4% of HSIL and 1/1 of AGC. The positive rate was significantly lower in normal, ASCUS, ASC-H and LSIL compared with HSIL (all P < 0.01). Significantly more cells with genomic amplification of TERC gene were found in cervical intraepithelial lesion (CIN) II III than CINI (77.8% vs. 9.3%), as well as invasive cervical cancer (96.7% vs. 9.3%), both P < 0.01. The rate of TERC gene amplification was higher in HPV positive patients (33.5%) than in HPV negative patients (5.2%, P < 0.01). The sensitivity of TERC gene amplification was significantly higher than that of cytological screening (81.88% vs. 36.96%, P < 0.01) in the differentiation of CINII or higher and CINI or lower diseases, its specificity was higher than high risk HPV test (93.32% vs. 33.93%, P < 0.01) and positive prediction value (81.29%) was similar with cytological method (86.44%, P > 0.05); but its negative prediction value (93.56%) was lower than HPV test (97.06%, P < 0.05). CONCLUSIONS: The positive rates of TERC gene amplification increased as cervical diseases worsened. TERC gene amplification is related to HPV infection. The gain of chromosome 3q26 in cytological specimens is an effective molecular genetic biomarker in screening of CINII or higher and invasive cervical cancer. PMID- 20193413 TI - [Detection of human papillomavirus L1 capsid protein expression in liquid-based cytology samples with abnormal cytology.]. AB - OBJECTIVE: To investigate the possibility of detection of the human papillomavirus (HPV) L1 capsid protein to predict the course of mild or moderate cervical intraepithelial neoplasia (CIN). METHODS: Immunocytochemical analysis using antibody against HPV L1 capsid protein was carried out on 274 samples obtained from women performed TriPath Pap tests, positive for high-risk HPV DNA detected by hybrid capture II (HC-II) or cytologic diagnosed atypical squamous cells of undetermined significance (ASCUS) or more severe. For cytological diagnosed, there were ASCUS 105 cases, low-grade squamous intraepithelial lesions (LSIL) 119 cases, atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion (ASC-H) 9 cases, high-grade squamous intraepithelial lesions (HSIL) 36 cases, and squamous cell carcinoma (SCC) 5 cases. But for the pathologic diagnosed, there were chronic cervicitis 96 cases, CINI 85 cases, CINII 55 cases, CIN III 32 cases, and SCC 6 cases. RESULTS: Of the 274 cases, HPV L1 capsid protein was positive in 69.8% (67/96) of cervicitis, 83.5% (71/85) of CINI, 41.8% (23/55) of CINII, 3.1% (1/32) of CINIII and 0(0/6) of SCC. Cytologic diagnosis revealed a higher expression rate in LSIL (75.6%, 90/119) than that in ASCUS (63.8%, 67/105) or in HSIL + SCC (9.8%, 4/41; all P < 0.01). Of 71 cases with ASCUS and LSIL without treated, none of HPV L1 positive cases (0/55) progressed in cytology, while 19% (3/16) of HPV L1 negative cases progressed to ASC-H, HSIL (P < 0.01). CONCLUSION: The expression rates of HPV L1 protein in liquid-based cell specimen is decreased as the cytopathology diagnosis severe degree, which may imply the histopathology diagnosis of cervix, predict the progression of cervical lesion, and help to treat the cases with ASCUS and LSIL. PMID- 20193414 TI - [Epidemiological study of high risk human papillomavirus infection in 25 to 54 years old married women in Beijing.]. AB - OBJECTIVE: To investigate high risk human papillomavirus (HR-HPV) prevalence among married women in Beijing and to study the high risk factors. METHODS: During March 2007 to September 2008, a total of 6185 married women sampled from 137 communities in 12 districts were screened by HR-HPV DNA test and cytological test. The interview was carried out with unified questionnaires. The database was set up and twice entered in EpiData 3.0. After checked up, the data were analyzed in SPSS 15.0. RESULTS: (1) The HR-HPV infection rate was 9.89%. The HR-HPV infection rate of the city zone, the suburb and the exurb were 9.34%, 10.51% and 9.51% (P > 0.05). The HR-HPV infection rate of the native and the outlander were 9.53%, 11.30% (P < 0.05). (2) The age distribution of HR-HPV infection was that the rate was around 10% among 25 to 44 age groups, which was the highest (11.21%) in 30 to 34 age group; then the rate was descended as the age raising, the rate of 50 to 54 age group was the lowest (7.78%). (3) Multiple logistic regression showed that the related risk factors of HR-HPV infection mainly included 1000 RMB and above of family income per person per month, possessing more than 1 sexual partner of her husband, outlander and high levels of education. (4) The prevalence of cervical intraepithelial neoplasia (CIN) in HR-HPV positive group was significantly higher than that in HR-HPV negative group (29.76% vs 3.32%, P < 0.01). CONCLUSIONS: (1) The HR-HPV infection rate among aged 25 to 54 years was 9.9% and there was no significant difference in area distribution. (2) The high risk population which should strengthen screening was the married bearing-age women with high level of family income, outlander, high levels of education and her husband possessing more than 1 sexual partner. (3) HR-HPV infection is the main risk factor for CIN and cervical cancer, while does not provide a causal relationship with them. The high risk population should be checked regularly to understand the development of HR-HPV infection and CIN incidence. PMID- 20193415 TI - [Prevalence of human papillomavirus infection in women in Tibet Autonomous Region of China.]. AB - OBJECTIVE: To determine the prevalence of cervical type-specific human papillomavirus (HPV) infection as well as risk factors associated in Tibet Autonomous Region of China. METHODS: A cluster sampling study was performed in Lasa, Rikaze and Naqu of Tibet. An epidemiological questionnaire was applied and 3036 cervical specimens were obtained for liquid-based cytology and HPV DNA detection. Statistical analysis included Wald Chi-square and stepwise logistic regression model. RESULTS: The overall HPV prevalence of involved 3036 women was 9.19% (279/3036), of which 7.05% (214/3036) of the women were infected by high risk types (including 14 sorts of types) and 2.14% (65/3036) by low-risk types (including 6 sorts of types). There were no significant differences of HPV prevalence between age groups (P = 0.936), race (P = 0.718) and areas (P = 0.746), respectively. Twenty-one types of HPV were detected, of which HPV16 (1.52%) was the most common type, followed by HPV33 (1.42%), HPV58 (1.22%), HPV52 (1.15%), and HPV31 (1.05%). HPV type distribution was varied by age. Of the 279 HPV infected women, 14.3% (40/279) exhibited multiple HPV infections. Independent risk factors for HPV infection were smoking (P = 0.027), number of sex partners (P = 0.198) and early age of first intercourse (P = 0.237). CONCLUSION: The overall prevalence of HPV infection in Tibet Autonomous Region is lower than that in China or abroad, in which the most common genotype is HPV16 and the independent risk factors for HPV infection included early age of first intercourse, smoking, and number of sex partners. PMID- 20193416 TI - [Preparation of human papillomavirus 16 E7 peptide vaccine and its effectiveness in vitro and in vivo.]. AB - OBJECTIVE: To prepare the human papillomavirus (HPV) 16 peptide vaccine and explore the effect in vitro and in vivo. METHODS: (1) Prediction of the major histocompatibility complex (MHC) class I restricted T cell epitopes by bioinformatics target at transporter associated with antigen processing (TAP) and named by E7Pa, E7Pb, E7Pc separately. (2) In vivo, the C57BL/6 mice were divided into five groups with same amounts randomly after loading with TC-1 cells (HPV 16 positive tumor cells from C57BL/6 mouse), named as E7Pa + CpG, E7Pb + CpG, E7Pc + CpG (as experiment groups, and added 50 microg/ml E7Pa, E7Pb, E7Pc, respectively), CpG (as positive control group and added Con A with 12 mg/L final concentration) and blank control group (without any treatment). The T cell proliferation was detected by methyl thiazolyl tetrazolium (MTT) assay at different time points; the lactate dehydrogenase (LDH) delivery method was used to test the cytolytic T lymphocyte (CTL) activity of mouse splenic lymphocyte in different ratio of effector cells and target cells (E:T); the related cytokines in tumor tissue and mouse peripheral blood were evaluated by real-time PCR and enzyme-linked immunosorbent assay (ELISA), respectively. The tumor volumes were measured to contrast the therapeutic effect in different groups. RESULTS: (1) Three peptide named E7Pa, E7Pb, E7Pc were successfully preparated which had high affinity and specificity. (2) After vaccination of 24, 48, 72, 96 hours, MTT results shown that the proliferation rate in E7Pa + CpG group were (131 +/- 32)%, (302 +/- 15)%, (552 +/- 28)%, (731 +/- 24)% individually, which were much higher than those in blank control [(72 +/- 15)%, (120 +/- 57)%, (176 +/- 41)%, (288 +/- 29)%; P < 0.01], and the other groups i.e. E7Pb + CpG, E7Pc + CpG and CpG groups all proliferated much higher than those in blank control group with statistic signification (P < 0.05), but there was no significant difference between groups (P > 0.05); the LDH delivery assay showed that when the ratio of E:T was 100:1, the activity of CTL in the E7Pa + CpG group was most powerful than the other groups with statistic signification (P < 0.01).Meanwhile, the ratio of E:T was concentration-dependent. Compared E7Pb + CpG, E7Pc + CpG or CpG groups with blank control group, there were significantly difference (P < 0.05), while there was no significant difference between groups (P > 0.05). The mRNA levels of interferon gamma (IFN-gamma), interleukin-2 (IL-2) in tumor tissue and peripheral blood in E7Pa + CpG group were significantly higher than those in blank control group (P < 0.01), which was the similar results when compared E7Pb + CpG, E7Pc + CpG or CpG groups with control group (P < 0.05), and without significant difference between groups (P > 0.05). The tumor volumes were suppressed obviously in all the experiment groups, especially at the 60th days, the volumes in E7Pa + CpG group were much smaller than that in blank control group with statistic signification (P < 0.01), which was the similar results that E7Pb + CpG, E7Pc + CpG or CpG groups had difference than blank control group with statistic signification (P < 0.05), and without significant difference between groups (P > 0.05). CONCLUSION: The HPV16 E7 peptide target at TAP combination with CpG as a vaccine could treat effectively the HPV16 E7 positive tumor in experiment. PMID- 20193417 TI - [Correlation of toll-like receptor 3 and tumor necrosis factor-alpha with idiopathic fetal growth restriction.]. AB - OBJECTIVE: To investigate the expression and the significance of toll-like receptor 3 (TLR-3) in placenta, tumor necrosis factor-alpha(TNF-alpha) in maternal and cord blood of idiopathic fetal growth restriction (IFGR), and their correlation with the pathogenesis of symmetric and asymmetric IFGR. METHODS: From April 2008 to April 2009, 42 primiparae of singleton pregnancy and their IFGR babies, who delivered at term through cesarean section, in the Third Affiliated Hospital of Zhengzhou University were enrolled. All subjectects were divided into symmetric IFGR group (n = 20) and asymmetric IFGR group (n = 22). Another 42 non IFGR pairs were randomly selected as the control group. The polink-2 plus polymerized horseradish peroxidase (HRP) immunohistochemical method and the enzyme linked immunosorbent assay (ELISA) were applied to detect TLR-3 and TNF alpha levels. RESULTS: (1) The expression of TLR-3 protein were observed in all maternal placenta of the three groups. TLR-3 essentially expressed in syncytiotrophoblasts and hofbouer cells in the symmetric IFGR and control group, but expressed mostly in hofbouer cells and less in syncytiotrophoblasts in the asymmetric IFGR group. (2) The expression of TLR-3 in the syncytiotrophoblasts of the symmetric and asymmetric IFGR group was significantly lower than in the control group (111 +/- 14 and 118 +/- 11 vs. 156 +/- 9, P < 0.01). The number of TLR-3 positive in Hofbourer cell in the symmetric IFGR group was lower than the control group (8.9 +/- 2.8 vs 17.5 +/- 2.8, P < 0.01), but the number in the asymmetric IFGR group was higher (23.8 +/- 3.7) compared with the control group (P < 0.01). (3) The TNF-alpha levels in the maternal and cord blood of the symmetric and the asymmetric group were higher than that of the control group [maternal: (90 +/- 10) microg/L and (86 +/- 11) microg/L vs. (73 +/- 9) microg/L; cord blood: (92 +/- 12) microg/L and (96 +/- 8) microg/L vs. (79 +/- 9) microg/L; P < 0.01]. (4) Neither symmetric nor the asymmetric IFGR group showed any correlations between the maternal and cord blood levels of TNF-alpha (P > 0.05). (5) Significant correlation was found between the TNF-alpha level of the cord blood and TLR-3 expression in the placenta in both the symmetric and asymmetric IFGR group (P < 0.05), but no relationship was found between the maternal blood TNF-alpha level and TLR-3 expression in the placenta (P > 0.05). CONCLUSIONS: The variantions of TLR-3 expression in placenta and the increased expression of TNF alpha in cord blood are associated with the genesis IFGR. The reduced expression of TLR-3 may related to symmetric IFGR, while the increased TLR-3 level in hofbouer cells may lead to asymmetric IFGR. PMID- 20193418 TI - [Correlation of retinol binding protein 4 expression in maternal serum and subcutaneous adipose tissue with insulin resistance in gestational diabetes mellitus.]. AB - OBJECTIVE: To investigate the expression of retinol binding protein 4 (RBP-4) in maternal serum and subcutaneous adipose tissue and its relationship with insulin resistance (IR) in gestational diabetes mellitus (GDM). METHODS: From May 2008 to April 2009, 62 pregnant women who underwent elective cesarean section in the Department of Obstetrics, Affiliated Hospital of Qingdao University Medical College, were recruited, including 32 with GDM (GDM group) and 30 with normal glucose tolerance test (control group). Enzyme-linked immunosorbent assay (ELISA) was used to determine the serum concentrations of RBP-4 and radio immunoassay to measure the serum levels of fasting insulin (FINS). Fasting plasma glucose (FPG) was tested by glucose oxidase, and the Home model insulin resistance index (HOMA IR) was calculated. Reverse transcription PCR (RT-PCR) and Western blot were applied to investigate the expression of RBP-4 mRNA and protein in subcutaneous adipose tissue. The correlations between the expression of RBP-4 mRNA and protein in subcutaneous adipose tissue and the serum RBP-4 concentrations and HOMA-IR were analyzed. RESULTS: (1) The serum concentrations of RBP-4, FINS, FPG, HOMA-IR in GDM group were significantly higher compared with the control group [(27.0 +/- 1.2) mg/L vs. (19.4 +/- 1.8) mg/L, (12.1 +/- 1.4) mU/L vs. (8.3 +/- 0.8) mU/L, (5.3 +/- 0.9) mmol/L vs. (4.1 +/- 0.6) mmol/L, 2.5 +/- 0.2 vs. 1.5 +/- 0.1, P < 0.05, respectively]. (2) The expression of RBP-4 mRNA and protein in subcutaneous adipose tissue in the GDM group were significantly higher than that of the control group (0.76 +/- 0.12 vs. 0.53 +/- 0.06, 0.74 +/- 0.09 vs 0.54 +/- 0.06, P < 0.05). (3) In the GDM group, the expression of both RBP-4 mRNA and protein in the subcutaneous adipose tissue were positively correlated with HOMA-IR (r = 0.575 and 0.851, P < 0.05). The serum concentration of RBP-4 were also positively correlated with HOMA-I (r = 0.635, P < 0.05). No correlations was found between the expressions of RBP-4 mRNA and protein in subcutaneous adipose tissue with the serume RBP-4 concentrations. CONCLUSION: High expression of RBP-4 mRNA in subcutaneous adipose tissue and the elevation of serum RBP-4 levels in GDM women may contribute to IR. PMID- 20193419 TI - [Expression of aquaporin 3 and aquaporin 9 in placenta and fetal membrane with idiopathic polyhydramnios.]. AB - OBJECTIVE: To investigate the pathogenesis role of aquaporin 3 and aquaporin 9 in idiopathic polyhydramnios by detecting their expression and distribution in fetal membranes and placenta. METHODS: Twenty-one of term pregnancy women with idiopathic polyhydramnios were enrolled as patient group matched with 30 women with normal term pregnancy as control group. The expression and localization of aquaporin 3 and aquaporin 9 in fetal membranes and placenta were detected by real time polymerase chain reaction and streptavidin peroxidase immunohistochemiscal staining. RESULTS: (1) The mRNA expressions of aquaporin 3 and aquaporin 9 were detected in amnion, chorion and placental tissue in both patient group and control group. Both aquaporin 3 and aquaporin 9 were demonstrated positive staining in the amnion epithelia, chorion cytotrophoblasts and placental trophoblast. (2) The ratio of aquaporin 3 and aquaporin 9 mRNA expressions in amnion in patient group comparing to those in control group were 5.00 and 3.25, while in chorion they were 2.03 and 2.08. When compared with those in amnion and chorion of control group, there was a significant difference (P < 0.01). However, the relative change fold of aquaporin 3 and aquaporin 9 in placental trophoblast in patient group were decreased in comparison of those in control group, which also showed statistical difference (P < 0.01). (3) The expression of aquaporin 3 and aquaporin 9 protein in amnion were 7.5 +/- 2.0 and 11.1 +/- 1.8 in patient group, while they were 5.3 +/- 1.6 and 5.6 +/- 2.3 in control group. In chorion, the expression of aquaporin 3 and aquaporin 9 protein was 7.5 +/- 2.0 and 10.0 +/ 1.6 in patient group, respectively, while in control group, they were 5.4 +/- 2.2 and 5.6 +/- 2.1. When compared with those proteins in control group, it exhibited statistical difference (P < 0.05). However, in placental trophoblast of patient group, the expression of aquaporin 3 and aquaporin 9 protein were 3.5 +/- 1.4 and 4.0 +/- 2.5, respectively, which were significantly decreased than 5.6 +/ 1.3 and 7.1 +/- 2.9 in control group (P < 0.05). CONCLUSIONS: The alterations of aquaporin 3 and aquaporin 9 expressions in fetal membrane and placenta might be an adaptive response to idiopathic polyhydramnios. Further investigation should be needed to clarify the regulatory mechanism of aquaporin 3 and aquaporin 9 expressions. PMID- 20193420 TI - [Clinical study on in vitro maturation of immature oocytes transferred from conventional in vitro fertilization.]. AB - OBJECTIVE: To investigate clinical effect of in vitro maturation (IVM) of immature oocytes transferred from conventional in vitro fertilization embryo transfer (IVF-ET) cycles. METHODS: From January 2008 to June 2009, medical documents of 155 infertile patients underwent IVF-ET in the Reproductive Medical Center of First Affiliated Hospital of Wenzhou Medical College were analyzed retrospectively. If more than 20 oocytes were monitored after 5 - 7 days of ovulation induction or follicular developmental retardation were confirmed after 8 - 13 days of ovulation induction, according to patients' wish, IVM were transferred in 60 cycles (group A). In the mean time, IVF was continued in 95 cycles (group B). The mean dosage of gonadotropin, the cancellation rate of cycles, the mean numbers of oocytes retrieved and maturation, the rate of fertilization and excellent quality embryos, pregnancy outcome and the incidence rate of ovarian hyperstimulation syndrome (OHSS) were compared and analyzed. RESULTS: The rates of embryo transfer were 92% (55/60) in group A and 63% (60/95) in group B, which showed significant differences (P < 0.05). In group A, the mean dosage of the gonadotropin, the mean number of oocytes retrieved, the cleavage rate and OHSS rate were (1030 +/- 468) U, 10 +/- 6, 82.2% (231/281) and 0, and were (1544 +/- 338) U, 14 +/- 4, 94.0% (502/534) and 35% (21/60) in group B, respectively, all data above exhibited statistical difference between two groups (P < 0.05). However, the rates of fertilization and excellent quality embryos had no significant differences between two groups (P > 0.05). In group A, the rate of clinical pregnancy per transfer was 53% (29/55) and multiple pregnancy was 14% (4/29), and were 47% (28/60) and 32% (9/28) in group B, they all had no significant differences (P > 0.05). CONCLUSION: IVM of immature oocytes used in conventional IVF cycles not only obtained a high clinical pregnancy rate, but also reduced gonadotropin using dosage and avoided OHSS completely. PMID- 20193421 TI - [Expression of estrogen receptor, progesterone receptor and integrin alphaVbeta3 in endometrium of patients with luteinized unruptured follicle.]. AB - OBJECTIVE: To investigate endometrium receptivity in patients with luteinized unruptured follicle (LUF) by measuring the expression of estrogen receptor (ER), progesterone receptor (PR) and integrin alphaVbeta3 in the endometrium. METHODS: From May 2007 to Nov. 2007, 17 infertile women with LUF were selected as LUF group matched with 13 infertile cases with normal ovulation as control group. They all underwent frozen-thawed embryo transfer in Reproductive Medicine Center, Renmin Hospital of Wuhan University. Endometrial tissue in anterior and posterior wall of uterus of LUF group and control group were biopsied by a small curettage between 7 and 11 days after luteinizing hormone (LH) surge. The expression of ER, PR and integrin alphaVbeta3 in endometrium were detected by immunohistochemistry staining. The level of estrogen and progesterone were measured by chemiluminescence assay. Then, the relationship between alphaVbeta3 expression in endometrium and the level of estrogen/progesterone were analyzed in LUF patients. RESULTS: (1) There was no remarkable difference in the level of estrogen between LUF [(656 +/- 299) pmol/L] and control group [(727 +/- 275) pmol/L, P > 0.05]. However, the level of progesterone were (23 +/- 8) nmol/L in LUF group and (35 +/ 10) nmol/L in control group, which reached statistical difference (P < 0.01). (2) The expression of ER, PR in endometrium of LUF patients were 183.9 +/- 2.4 and 168 +/- 3, which were significantly higher than 109.4 +/- 6.3 and 106 +/- 4 in control group (P < 0.01). The expression of integrin alphaVbeta3 in endometrium of 115 +/- 11 in LUF group were significantly lower than 191 +/- 9 in control group (P < 0.01). (4) In LUF group, the expression of alphaVbeta3 in endometrium was correlated positively with the level of progesterone (r = 0.77, P < 0.01) and irrelevant with the level of estrogen (r = 0.01, P > 0.05). CONCLUSION: The higher expression of estrogen and progesterone and lower expression of integrin alphaVbeta3 might confer impaired receptivity of endometrium and interfere with embryo implantation. PMID- 20193422 TI - [Regulation of synthesis function of porcine ovarian granulose cells by mitogen activated protein kinase signaling pathway.]. AB - OBJECTIVE: To investigate the role of mitogen-activated protein kinase (MAPK) signaling pathway regulating synthesis function of steroid hormone of porcine ovarian granulose cells. METHODS: Porcine ovarian granulose cells were cultured in medium added with dimethyl sulfoxide (DMSO) at concentration of 50 micromol/L or with MAPK inhibitor PD98059 (PD) for 48 hours. Then, granulose cells in DMSO medium were added with activator of adenylate cyclase (20 micromol/L) or blank agent for next 48 hours incubation, which were defined as observation group 1 and control group 1, similarly, granulose cells in PD medium were also added with activator of adenylate cyclase (20 micromol/L) or blank agent for next 48 hours, which were defined as observation group 2 and control group 2. The level of estradiol (E(2)), progesterone (P) and testosterone (T) were detected by chemoluminescence. The mRNA expression of 17alpha-hydroxylase/17,20-lyase (CYP17) and aromatase P450 (P450 arom) were assessed by RT-PCR. RESULTS: (1) Hormone expression: the level of T, P and E(2) were (29.5 +/- 2.5) nmol/L, (80 +/- 5) nmol/L, (49 +/- 4) pmol/L in control group 1 and (42.3 +/- 3.4) nmol/L, (170 +/- 15) nmol/L, (75 +/- 6) pmol/L in control group 2, which showed significant difference (P < 0.05). In the mean time, the level of T, P and E(2) were (106.2 +/- 7.6) nmol/L, (210 +/- 16) nmol/L, (130 +/- 11) pmol/L in observation group 2 and (47.2 +/- 3.5) nmol/L, (130 +/- 6) nmol/L, (81 +/- 6) pmol/L in observation group 1, which also reach statistical difference (P < 0.05). (2) The expression of enzyme: the expression of CYP17 mRNA was increased by 50% and P450 arom mRNA was decreased by 20% between control group 1 and 2. However, the mRNA expression of P450 arom and CYP17 were upregulated remarkably, especially, the expression of CYP17 mRNA were increased by 125%. CONCLUSION: MAPK signaling pathway plays an inhibitory role in regulating synthesis of steroid hormone of ovarian granulose cell. PMID- 20193423 TI - [Identification and characterization of ovarian cancer stem-like cells from primary tumor.]. AB - OBJECTIVE: To study whether the primary ovarian cancer cells containing cancer stem cells and its characterization in serum-free culture condition. METHODS: The primary cancer cells were isolated from one stage III, grade 2 serous adenocarcinoma tissue. Cells were cultured in serum-free culture system supplemented with epidermal growth factor, basic fibroblast growth factor, leukemia inhibitory factor and insulin, or standard serum-containing system. Methyl thiazolyl tetrazolium assay, quantitative PCR analysis, flow-cytometric analysis and xenograft experiments in vivo were performed. RESULTS: The primary cancer cells could maintain and form cell sphere in serum-free culture system. These cells had the properties of self-renewal, overexpression of stem cell marker genes Nanog, Oct-4, Sox-2, nestin, ABCG2, CD(133) and CD(117). By contrast with the differentiated cells under standard serum-containing culture conditions, these sphere-forming cells were more resistant to cisplatin and paclitaxel after treated 48 and 72 hours (61% vs. 31%, 73% vs. 29%, P < 0.05). With Hoechst 33342 exclusion assay, only 21.83% of sphere-forming cells were positive with the dye, compared with 83.04% positive cells in differentiated cells (P < 0.01). Only 500 sphere-forming cells resulted subcutaneous xenograft tumors. All of these xenografts were categorized as serous adenocarcinomas, overexpression of CA(125) and cytokeratin-7 which were original tumor phenotype of ovarian cancer. CONCLUSION: The sphere-forming cells isolated from primary ovarian cancer tissues have the characterization of cancer stem cell and may be a more reliable model system for understanding the biology of primary human tumors. PMID- 20193424 TI - [Pay attention to application of pupil reaction testing in assessment of neuro ophthalmologic disorders]. AB - The pupillary light reaction represents the functions of either the afferent visual pathway or the pupillary efferent innervations (parasympathetic and sympathetic). Physiologic and pathologic changes of pupil were usually ignored by the physicians. A correct pupil reaction testing will be of benefit to catch the abnormal pupil reaction as well as the early diagnosis of neuro-ophthalmologic disorders. A precise pupil reaction test is hardly performed because of the variation of individual, illumination and the instantaneous change of pupil. The proper pharmacologic testing is helpful for choosing the right neuro electrophysiological and neuro-image examinations, and also may be of instruction value on the diagnosis of neuro-ophthalmologic diseases. PMID- 20193425 TI - [To improve understanding of etiology of optic neuritis in China]. AB - Domestic ophthalmologists have different understandings on the causes of optic neuritis. Some of them consider infection is the main cause, some believe that so called idiopathic optic neuritis caused by central nervous system primary demyelinating disease, such as multiple sclerosis is the most common type of optic neuritis, while others suggest that optic neuritis is attributed to autoimmune disease. Based on the review of literatures, we describe the development of definition and etiology of optic neuritis in Western countries and in China, and then provide some suggestion to a better understanding of etiology of optic neuritis in China. We also expect to have a population-based, multiple center study to provide more extensive and accurate data on the etiology of optic neuritis in China. PMID- 20193426 TI - [Clinical characteristics of non-arteritic anterior ischemic optic neuropathy]. AB - OBJECTIVE: To evaluate the demographic, risk factors and clinical characteristics of non-arteritic anterior ischemic optic neuropathy (NAION) and provide clinical guidance for this blindness disease. METHODS: Retrospective study was used to investigate the data, which consists of 96 NAION consecutive patients in neurology department of our hospital from 2005 to 2008. RESULTS: The average age of NAION patients is 50.90 +/- 8.88 years (range, 34 - 78 years) and the median is 50 y. About 68.8% of patients are male. The prevalence of hypertension, diabetes mellitus and abnormal lipid level is 34.4% (33/96), 29.2% (21/96) and 59.4% (57/93) respectively. The predominant patterns of visual field loss are altitudinal and accurate defects. Visual acuity was improved (change of >/= 3 lines) in 44.4% of patients. CONCLUSIONS: The age of onset in NAION is relatively early in life, compared with cerebral vascular disease, and male seems to have a high incidence. The most common risk factor is metabolic syndrome. Subcortical and periventricular white matter lesions and myocardial ischemia might associate with NAION. Visual acuity showed improvement in some patients, but the long outcome is poor. PMID- 20193427 TI - [Preliminary report of contrast sensitivity in idiopathic optic neuritis patients after recovery]. AB - OBJECTIVE: To explore the changes of contrast sensitivity (CS) in patients recovered from idiopathic optic neuritis (ION). METHODS: It was a case-control study. We screened 22 idiopathic optic neuritis patients who underwent treatment and obtained normal visual acuity. No nervous system abnormalities were found in MRI scan. Twenty four healthy individuals were enrolled as the control group. OPTEC 6500 contrast sensitivity tester was used to examine near- and far-distance CS values on 1.5, 3.0, 6.0, 12 and 18 cycles/degree (c/d), separately. T-test or u-test was used to compare the mean of CS values between these two groups. ANOVA or H-test was adopted on CS values at the different frequencies in each group. Simple linear correlation was used to analyze the correlation between CS values and age, duration and gender, separately. RESULTS: The maximum CS values in both far- and near-distance appeared in 6.0 c/d in these two groups were 70.27 +/- 40.44, 53.32 +/- 29.50, 78.86 +/- 36.37 and 109.39 +/- 44.98, respectively. The minimum CS values in both far- and near-distance appeared in 18 c/d in these two groups were 8.27 +/- 6.11, 12.09 +/- 8.57, 15.67 +/- 9.02 and 22.22 +/- 14.56, respectively. Far- and near-distance CS values in ION group and control group had very significant differences at these five spatial frequencies (From 1.5 to 18.0 c/d, the test values on far-distance were 4.19, 5.59, 3.06, 2.50, 3.13, P values were 0.00, 0.00, 0.00, 0.01, 0.00. The test values on near-distance were 3.54, 3.98, 2.72, 3.20, 3.39, P values were 0.00, 0.00, 0.01, 0.00, 0.00). CS values had no relation to the duration of ION. Significant difference in CS values existed on most frequencies (In far- and near-distance, H values in ION group were 52.38 and 64.96, in control group were 64.77 and 60.53, P values were both less than 0.01). The maximum H value appeared on near-distance in ION group. The maximum H value was 64.96 of near-distance in ION group. Far- and near-distance CS values in ION group itself and control group itself had very significant differences at these 5 spatial frequencies (From low to high frequencies, F values were 6.36, 0.03, 2.52, 1.53, 2.90; P values were 0.02, 0.87, 0.12, 0.22, 0.10 in ION group. In control group, F values were 5.31, 5.69, 6.06, 0.61, 3.14; P values were 0.03, 0.02, 0.02, 0.44, 0.08 respectively). CONCLUSIONS: CS values at different frequencies in ION patients with normal visual acuity descend significantly. Contrast sensitivity examination can be an important technique to evaluate vision quality in patients after ION. PMID- 20193428 TI - [Visual field defects in 169 cases of pituitary adenomas]. AB - OBJECTIVE: To compare static visual field perimetry with Octopus 101 and Goldmann perimetry in patients with pituitary adenomas; To identify the factors of visual field defects and visual field prognosis. METHODS: Retrospective nested case control study. Visual acuity, fundus, computed tomography (CT) or magnetic resonance imaging (MRI) and visual field were pre-operated assessed in 169 patients (338 eyes) diagnosed pituitary adenoma at the Department of Neurosurgery in Huashan Hospital between Feb. 2006 and Feb. 2007. 334 eyes were underwent Goldmann perimetry, while 323 eyes were underwent static visual field perimetry with Octopus 101 perimeter. In the 169 patients, 28 patients (56 eyes) were followed up post-operatively for 3 to 6 months. Statistical analysis was performed using SPSS 15.0 software. T test and rank sum test were used for continuous variables, and chi-square test and Fisher's exact test were used for categorical variables. We also carry out Logistic regression. RESULTS: Of the 169 patients, unilateral or bilateral visual field defects were observed in 133 cases. In these 323 eyes, 231 eyes showed visual field defects with static visual field perimetry, while 196 eyes in 334 eyes showed defects with Goldmann perimetry. Earlier age of onset, larger tumors and poor preoperative corrected visual acuity were more frequent in patients with visual field defects than in patients with normal visual fields (t = 4.802, 7.930; chi(2) = 28.210, P < 0.01). In the 28 followed-up patients (55 eyes), visual acuity was improved in 69.05% eyes and visual field was improved in 85.71% eyes after operation. There were significant differences in age of onset and preoperative visual field defects in upper temporal quadrants between patients with visual field returned to normal after the operation and patients with visual field improvement only (t = 2.525, P = 0.023; chi(2) = 6.218, P = 0.013). CONCLUSIONS: Static visual field perimetry with Octopus 101 perimeter is more sensitive than Goldmann perimetry in the early diagnosis of pituitary adenomas. Patients with visual field abnormalities are significantly with earlier onset age, larger tumors and worse preoperative visual acuity than patients free of visual field defects. The onset age and the degree of impairment in the preoperative visual field in the upper temporal quadrant may be significant factors for visual field prognosis. PMID- 20193429 TI - [Clinical characteristics of ocular ischemic syndrome]. AB - OBJECTIVE: To study clinical characteristics of ocular ischemic syndrome (OIS). METHODS: Retrospective study. Data, including sex, age, systemic diseases, best corrected visual acuity, anterior segment, fundus, fundus fluorescence angiography (FFA), transcranial Doppler (TCD) and digital subtraction angiography (DSA), were collected from 10 patients (12 eyes) with ocular ischemic syndrome from February 2008 to April 2009. RESULTS: The mean age was 59 years. There were six males and four females. All patients were combined with heart and/or cerebrovascular diseases. Best corrected visual acuity ranged from hand movement to 1.0. Neovascularization of the iris appeared in 5 eyes. Intraocular pressure over 21 mm Hg (1 mm Hg = 0.133 kPa) was present in 3 eyes. Fundus examination showed narrow retinal arteries, dilated but not tortuous veins, fleck-shaped hemorrhage of the retina, cotton-wool exudates, optic disc edema, optic disc neovascularization, and atypical macular cherry-red spots. TCD showed stenosis of internal carotid artery at different degrees. FFA was performed in 9 patients which showed artery front, prolonged arm-retinal circulation time, retinal circulation time and choroid circulation time. All patients accepted vasodilation and microcirculation improving treatments. Visual acuity was improved at different degrees. One patient (2 eyes) with iris neovascularization was treated with retinal photocoagulation and the neovascularization disappeared after the treatment. There were 3 patients (3 eyes) had neovascular glaucoma. One patient was treated by ciliary cryotherapy. One patient was treated by retinal photocoagulation and internal carotid artery stent implantation and one were treated by internal carotid artery stent implantation. Four patients were examined by DSA. Internal carotid artery stent implantation was performed in 3 patients, subclavian artery stent implantation was performed in one patient and internal carotid artery intima decollement was performed in one patient. CONCLUSIONS: Clinical manifestations of ocular ischemic syndrome patients are complicated which are depended on the different extents of ischemia. The management of ocular ischemic syndrome requires the collaboration of ophthalmologists, neurophysicians and neurosurgeons. PMID- 20193430 TI - [Comparative assessment of visual quality after combined implantation of multifocal intraocular lens]. AB - OBJECTIVE: To evaluate the visual quality after combined implantation of refractive and diffractive multifocal intraocular lenses (IOL) in both eyes. METHODS: Prospective, nonrandomized study. Age-related cataract patients were divided into multifocal IOL group (MIOL group) and monofocal IOL group (SIOL group) and received phacoemulsification. In MIOL group, a ReZoom NXG1 IOL and a Tecnis Z M900 IOL were implanted into the dominant eye and the fellow eye, respectively. In SIOL group, Sensar AR40e IOLs were implanted into both eyes. Monocular or binocular test was performed one month after surgery, including wavefront aberration, contrast sensitivity with or without glare and near stereoacuity. RESULTS: The root mean square of spherical aberration at pupil diameter of 5 mm was 0.058 +/- 0.159 microm in NXG1 eyes and 0.005 +/- 0.169 microm in ZM900 eyes, both of them were significantly lower than 0.408 +/- 0.160 microm achieved in AR40e eyes (F = 11.734; P = 0.001, 0.000). There was no significant difference in the total ocular aberration, contrast sensitivity and high-order aberration among eyes with these different IOLs. The uncorrected near stereoacuity in MIOL group was (45.60 +/- 35.04) seconds of arc, which was significantly better than (110.00 +/- 41.23) seconds of arc achieved in SIOL group (F = 2.923; P = 0.010). CONCLUSION: Combined implantation of multifocal ReZoom NXG1 IOL and Tecnis ZM900 IOL provides a good visual quality with reduced spherical aberration and satisfactory near stereoacuity. PMID- 20193431 TI - [Study of surgical techniques of divided nevus of eyelids]. AB - OBJECTIVE: To investigate the surgical techniques of divided nevus of the eyelids with different locations and sizes. METHODS: Retrospective observational case series. Thirty cases (30 eyes) of divided nevus of the eyelids in Zhongshan Ophthalmic Center from July 1997 to November 2006 were retrospectively reviewed. There were three different surgical methods. Excision of the nevus and direct suture after excision in 3 cases. Excision of the nevus and free skin graft transplantation in 5 cases. Excision of the nevus and transfer of skin flap, which included a two stages reconstruction, was performed in 22 cases. The upper or lower eyelid was treated first and another eyelid was treated after three months. Lacrimal punctum and lacrimal canaliculus were excised if they were involved in 8 cases among 22 cases. RESULTS: The mean follow-up time was 60 months (ranging from 2 years to 11 years). Only one case recurred after two years during follow-up and was excised after five years. Pathologic examination indicated malignant transformation. Excision with histopathological control was performed and the nevus did not recur during follow-up time. Recurrence or malignant transformation did not occur in other cases. Aesthetical results of skin flap transplantation were better than skin graft transplantation. CONCLUSIONS: The results of two stages reconstruction and transfer of skin flap after excision of the divided nevus are better than free skin graft transplantation. Close observation is required after excision of the divided nevus for early detection of malignant transformation. PMID- 20193433 TI - [Long-term outcomes of laser peripheral iridectomy for primary angle closure glaucoma]. AB - OBJECTIVE: To explore the long-term efficacy and safety of laser peripheral iridectomy for primary angle closure glaucoma (PACG). METHODS: It was a retrospective case series study. Data were collected from those patients who received laser peripheral iridectomy (LPI) for acute or chronic PACG from April 1992 through October 2002 at the Peking Union Medical College Hospital. Only patients who were followed for at least 5 years were included in this study. The control of intraocular pressure (IOP), visual acuity and managements after LPI were analyzed. All of the studied eyes were re-classified into three categories according to the status of anterior chamber angle, optic nerve head and visual field before LPI: primary angle closure suspect (PACS), primary angle closure (PAC) and primary angle closure glaucoma (PACG). Satisfactory control of IOP was defined as the IOP was less than 21 mm Hg (1 mm Hg = 0.133 kPa) without any medications after LPI. No satisfactory control of IOP was defined as the IOP was greater than 21 mm Hg after LPI, yet could be controlled below 21 mm Hg by anti glaucoma medications. A failure in IOP control was defined as an acute attack of angle closure developed or filtering surgery was required to control IOP after LPI. Chi-square analysis was used for comparison of IOP control in different groups. RESULTS: One hundred and thirty one patients (251 eyes) with PACG were eligible for this study. The mean follow-up period was (9.2 +/- 3.7) years. Of the 251 eyes, 18 eyes (7.2%) were identified as PACS, 98 eyes (39.0%) PAC, 129 eyes (51.4%) PACG, and 6 eyes (2.4%) could not be classified owing to the lack of the information on the optic nerve head and visual field before LPI. The rates of satisfactory control of IOP were 27.1% in all eyes, and 88.9% (16/18), 38.8% (38/98) and 10.9% (14/129) in PACS, PAC and PACG eyes respectively. The rates of no satisfactory control of IOP were 59.8% in all eyes, and 5.6% (1/18), 48.0% (47/98) and 75.2% (97/129) in PACS, PAC and PACG eyes respectively. The rates of failure in IOP control were 13.1% in all eyes, and 5.6% (1/18), 13.3% (13/98) and 14.0% (18/129) in PACS, PAC, PACG eyes respectively. The difference in IOP control between PACS, PAC and PACG eyes was statistically significant (chi(2) = 59.08, P = 0.000). Only 8 eyes had an acute attack of angle closure after LPI. No long-term complications after LPI were observed in all eyes. CONCLUSIONS: The IOP control after LPI in PACG eyes is not so good as expected. However, most of PACG eyes after LPI are free of acute attack of angle closure. PACG eyes should be given close and regular follow-up in a long-term to monitor the IOP control and the progression of PACG after LPI. PMID- 20193432 TI - [Diagnosis and treatment of eye diseases associated with HIV infection and AIDS]. AB - OBJECTIVE: To investigate the manifestations and treatment principles of ocular diseases associated with human immunodeficiency virus infection (HIV) and acquired immunodeficiency syndrome (AIDS). METHODS: It was a retrospective case series. One hundred and ten patients were recruited. Two hundred and twenty eyes underwent ophthalmologic examination that included vision acuity, anterior segment and fundus examinations with papillary dilation and fundus fluorescein angiography. CD(4)(+)T-lymphocyte was counted in peripheral blood of 110 patients. Intravitreal injection of ganciclovir 400 microg was performed in 4 eyes (2 patients) with cytomegalovirus (CMV) retinitis associated with AIDS. All statistical analyses were performed using SPSS 13.0 software. The association between the age, duration of HIV infection and HIV/AIDS related ocular manifestations was analyzed by Pearson Correlation Analysis. The association between the gender and HIV/AIDS related ocular manifestations was analyzed by Pearson Chi-Square test. For comparison of the CD(4)(+)T cells counts of the patients with normal fundus, HIV retinopathy, CMV retinitis, Kruskal-Wallis Test for Several Independent Samples was used. RESULTS: Baseline visual acuity: no light perception (NLP) 5 eyes; light perception (LP) to 0.04, 10 eyes; 0.05 to 0.2, 14 eyes; 0.3 to 0.7, 62 eyes and >/= 0.8, 129 eyes. Small grayish keratin precipitates or pigment keratin precipitates were present in 25 eyes, 22 eyes had positive aqueous flare, 4 eyes had posterior synechia of the iris, 28 eyes had cataract. HIV retinopathy was present in 34 eyes. Cotton-wool spots, retinal hemorrhages, and retinal microaneurysms were found in eyes with HIV retinopathy. CMV retinitis was present in 32 eyes. The fundus manifestations of CMV retinitis included retinal vasculitis; dense, full-thickness, yellow-white lesions along vascular distribution with irregular granules at the border, and hemorrhage on the retinal surface in 26 eyes. Late stage retinopathy was demonstrated in 3 eyes characterized as atrophic retina, sclerotic and attenuated vessels, and optic nerve atrophy. Retinal detachment was found in 3 eyes. The median of CD(4)(+)T lymphocyte counts of the patients with normal fundus was 100.0/mm(3). The median of CD(4)(+)T-lymphocyte counts of the patients with HIV retinopathy was 41.0/mm(3). The median of CD(4)(+)T-lymphocyte counts of the patients with CMV retinitis was 18.0/mm(3). The difference of CD(4)(+)T-lymphocyte counts between patients with normal fundus and HIV retinopathy was statistically significant (chi(2) = 4.848, P = 0.028). The difference of CD(4)(+)T-lymphocyte counts between patients with normal fundus and CMV retinitis was statistically significant (chi(2) = 15.696, P = 0.000). The difference of CD(4)(+)T-lymphocyte counts between patients with CMV retinitis and HIV retinopathy was statistically significant (chi(2) = 4.860, P = 0.027). Four eyes (2 patients) with CMV retinitis underwent intravitreal injection of ganciclovir 400 microg. After intravitreal injection of ganciclovir, visual acuity was improved and fundus lesions disappeared in 4 eyes. CONCLUSIONS: HIV retinopathy is a common intraocular complication in HIV-infected patients. CMV retinitis is the severest intraocular complication in patients with AIDS. Highly active anti-retroviral therapy allows immune reconstitution. Intravitreal injection of ganciclovir can effectively control CMV retinitis and save the vision. PMID- 20193434 TI - [Experimental study on effects of Heparin II domain of fibronectin on cultured human trabecular meshwork cells]. AB - OBJECTIVE: To determine the effects of Heparin II (Hep II) domain on cultured human trabecular meshwork (HTM) cells. METHODS: HTM cells were cultured and treated with Hep II domain for 18 and 24 h. The morphological changes in HTM cells were assessed by light and electron microscopy. Changes in cell morphology and the organization of actin cytoskeleton, Vinculin, beta-Catenin were assessed by using immunofluorescence. RESULTS: Treatment of Hep II domains resulted in morphological changes from 10 to 24 h. In light microscopy, cells rounded up, retracted and detached from each other. In high performance liquid chromatography, Hep II domains-treated cells showed that actin fibre bundles were highly concentrated at the periphery of the cells with few actin filaments left in this area; decreased vinculin staining was observed toward the cell periphery; decreased beta-Catenin staining was also observed around the cell sub-membrane. Transmission electron microscopy showed expended intercellular space. After 24 h, changes of HTM cells were recovered. CONCLUSIONS: Hep II domains reversibly blocks actin cytoskeleton and cell-junction of HTM cells. Disorganization of actin cytoskeleton and cell-junction in trabecular meshwork through signal transduction may be a useful strategy for the decrease of intraocular pressure. PMID- 20193435 TI - [TERT-siRNA inhibits oxygen-induced retinal neovascularization in mice]. AB - OBJECTIVE: To investigate the inhibitory effect of small interfering RNA (siRNA) targeting TERT on murine retinal neovascularization and explore the feasibility of potential therapeutic approach in retinal vascular disease. METHODS: Two recombinant plasmids TERT siRNA (pSIREN-mTERT-1) and negative plasmid (pSIREN mTERT-N) were constructed and 80 seven-day-old C57BL/6J mice were divided randomly into therapeutic group (A), negative plasmid group (B), oxygen-induced retinopathy group (C) and normal control group (D), 20 mice in each group. Group A, B and C were exposed to 75% +/- 2% oxygen for 5 days and then to room air, which induced mice retinal neovascularization. Groups A and B were injected two kinds of the above recombinant plasmid into the murine vitreous on the 12th day. The mice of group D were raised in normal oxygen circumstance. On the 19th day, 2% Evens blue angiography was used to observe the pattern of the retinal vascular. Expression of TERT mRNA were confirmed by reverse-transcription polymerase chain reaction (RT-PCR) and Real-time PCR. Histological observation and vascular endothelial cells counting were used to examine the effects of siRNA on the retinal neovascularization. RESULTS: Retinal flat after Evans blue angiography indicated that the vessels of group A formed a fine radial branching pattern, which was similar to normal mice. In group A, the retinal neovascularization reduced and the structure of retina were more regular than group B and C. At the same time the large vessels were distorted, neovascular clusters proliferated and fluorescence leaked in the middle and periphery area in group B and C. RT-PCR and Real-time PCR showed the expression of TERT mRNA was downregulated in group A compared with groups B and C (P < 0.05). Paraffin tissue slice with hematoxylin-eosin staining showed that the average counts of vascular endothelial cells which break through the inner limiting membrane in group A were less than groups B and C, the differences were significant (P < 0.05). CONCLUSION: Pathologic retinal neovascularization can be inhibited by specific TERT siRNA in vivo, which may be a novel efficient strategy against proliferative vasculopathies. PMID- 20193436 TI - [Expression of regulatory T cells and related cytokines in mice allogenic corneal transplantation rejection]. AB - OBJECTIVE: To study the changes of CD4(+)CD25(+) and CD8(+)CD103(+) regulatory T cells and their relevant cytokines in corneal allograft transplantation in mice. METHODS: BABL/c (H-2(d)) mice received corneal allografts from C3H/He (H-2(k)) mice were served as the experimental group. BABL/c (H-2(d)) mice received corneal from BABL/c (H-2(d)) mice were used as the control group. Corneal graft survival time was recorded pre-, 3rd day, 7th day, 4th week, 8th week post-operatively. Infiltration of inflammatory cells and corneal neovascularization were evaluated by histopathologic examination. The percentage of CD4(+)CD25(+) and CD8(+)CD103(+) T cell in peripheral blood and spleen was determined by flow cytometry. The expression of interleukin-10 (IL-10), IL-4, gamma-interferon (IFN gamma) and IL-1beta in serum and aqueous humor was measured by enzyme-linked immunospecific assay (ELISA). RESULTS: The graft rejection in experimental group occurred at 7 days to 4 weeks after the operation, averaged (14.79 +/- 1.02) days. The grafts in the control group remained clear within 8 weeks observation and the survival time is much longer than that of the allografts (chi(2) = 46.934, P = 0.000). Flow cytometry showed that the percentage of CD4(+)CD25(+) T cell in peripheral blood in the control group after surgery was (3.36 +/- 0.29)%, (4.09 +/- 0.44)%, (5.44 +/- 0.35)%, (5.73 +/- 0.53)% at day 3, day 7, 4th week, and 8th week, respectively, which was significantly higher than that in the experimental group [(2.50 +/- 0.39)%, (3.24 +/- 0.25)%, (4.20 +/- 0.45)%, (4.18 +/- 0.14)%; t = 3.828, 2.898, 3.780, 4.892; P < 0.05]. On the other hand, CD8(+)CD103(+) T cell in peripheral blood in the experimental group after surgery was (2.20 +/- 0.33)%, (2.79 +/- 0.57)%, (4.55 +/- 1.03)%, (4.31 +/- 0.07)% at different periods, which was much higher than that in the control group (t = 7.133, 4.876, 5.196, 19.960; P < 0.05). The changes of CD4(+)CD25(+) and CD8(+)CD103(+) T cells in the spleen was earlier than those in peripheral blood. ELISA showed the expression of IL-10 and IL-4 in the serum in experimental group after surgery was much lower than that in the control group (t = 3.203, 3.141, 3.012, 2.869 and 2.340, 6.681, 8.839, 8.574; P = 0.011, 0.012, 0.013, 0.019 and 0.053, 0.000, 0.000, 0.000). The serum levels of IFN-gamma and IL-1beta in experimental group were higher than that in the control group (t = 3.508, 3.265, 4.402, 5.539 and 3.630, 5.796, 1.728, 0.660; P = 0.006, 0.011, 0.002, 0.000 and 0.005, 0.000, 0.115, 0.524). Furthermore, the cytokine levels in the aqueous humor behaved similarly with those in the serum. CONCLUSION: The down-regulation of CD4(+)CD25(+) Treg, IL-10 and IL-4 and the up-regulation of CD8(+)CD103(+) Treg, IFN-gamma and IL-1beta in mice allograft corneal rejection may play an important role in allograft rejection. PMID- 20193437 TI - [Recent studies on the distribution and immune characterization of dendritic cells in the corneal epithelium]. AB - Langerhans cell-type dendritic cells (DCs) present in the corneal epithelium are capable of taking up, processing, and presenting antigens, leading to the initiation of T-lymphocyte responses. These cells are the professional antigen presenting cells (APCs) of the corneal epithelium and serves as the critical sentinel cells of the immune system in the ocular surface. A recent study has demonstrated that normal limbal basal epithelium is in fact endowed with a small number of slow-cycling DCs with expression of a limbal stem cell marker, ABCG2. Furthermore, it has been found that central corneal inflammation induces recruitment of major histocompatibility complex (MHC) class II(+) DCs from limbal basal epithelium. These findings suggest that limbal basal epithelial DCs play an important role in corneal inflammatory reaction. PMID- 20193438 TI - [The rural polyclinic in the early stage of the People's Republic of China.]. AB - The polyclinic is one type of medical organization of mutual assistance and cooperation of a collective nature, which was founded based on the integration of rural original medical and health resources in the early stage of the People's Republic of China. The polyclinic played a particular role in resolving the extreme shortage of rural medical resources and medicines at that time and promoting the sanitary and anti-epidemic situation in rural communities. This laid a foundation for the three-level network of care and medical prevention. However it did not change the traditional mode of healthcare and medical work so that is also failed in solving the problems of shortage of medicines in rural areas. PMID- 20193439 TI - [The Rise and Demise of the Chinese barefoot doctor.]. AB - A novelty-the barefoot doctor appeared in Chinese rural areas during the period of a great proletarian cultural revolution, which used minimum funds to train maximum sub healthcare workers and solved the most difficult healthcare problems of peasants, who accounted for the largest proportion of the population. Barefoot doctors and the system of cooperative health care had embarked on a rural developing path of healthcare with Chinese Characteristics such as a low-cost but high-yield healthcare, which meant a poor country could do major health work. Barefoot doctors providing basic health care service and health protection for the rural residents played a particular role in promoting the formation of international primary health care ideas. As time passed, barefoot doctors have departed the stage of history, but a principle had been established, which is that the function of basic health prevention and health care networks in rural areas should not be weakened, let alone disappear. PMID- 20193440 TI - [Evolution of China's rural cooperative medical care system.]. AB - The rural cooperative medical care system of our country originated from the beginning of the 50s of the 20(th) century, which developed abnormally due to leftist ideology during the period of the Cultural Revolution. An institutional reform of the rural cooperative medical care system had began after the reform and opening up in China, but with the development of rural productivity and rapid transformation of economic structure, the traditional cooperative medical care system declined rapidly due to incompatibility with the new model of economic and social development. At the beginning of the 90s of the 20(th) century, exploring the developmental path of rural cooperative medical service, under the conditions of market economy and adopting the approach of "main individual investment with partial collective and appropriate government support", to try to establish rural cooperative medical funds, so that the rural cooperative medical system could bottom out gradually, but still failed to achieve the expected goal of universal access to health care in 2000. However, the promotion and establishment of a new rural cooperative medical care and aid system could become a major achievement aim in the 21(st) century. PMID- 20193441 TI - [Historical succour of poverty and medical assistance in rural China.]. AB - There was considerable attention paid to the succour of poverty with widespread practice in China's history. Succour of poverty and medical assistance in rural areas were closely connected with famine relief carried out by the rulers. The mutual assistance of emotional and moral support long-term in rural communities is the most important form of medical assistance. A succour of poverty and medical assistance system in the modern sense should inherit and learn from the past consideration of poverty assistance and bring in the fine tradition of multiple forces to participate, in order to establish a succour of poverty and medical assistance system compatible with economic and social development. This is not only an important component of anti-poverty strategy in rural areas but also an inevitable requirement of historical development. PMID- 20193442 TI - [Thoughts on wellbeing in Emperor Kangxi's Tingxungeyan.]. AB - Emperor Kangxi's Tingxungeyan in which he admonished his sons was connected with the thoughts of wellbeing that included temperance, caution, labour and pleasure. Temperance means moderation in food alcohol, vegetables, fresh fruit and not being extravagant. Caution means keeping cautious in daily life. Labour means being diligent in working rather than seeking ease and comfort. Pleasure means paying attention to cultivating one's mind so as to remain pleasant. PMID- 20193443 TI - [The reasons of over-interpretation during the research of TCM academic history.]. AB - Over-interpretation refers to the excessive understanding, translation and explanation of the implications which the research object represents. TCM academic history is a branch of medicine historiography to study the TCM academic development and evolution. Uncertainty of historical materials, incomplete expression of the author's original meaning and deviation of the scholars' interpretation often lead to over-interpretation during the research of TCM academic history. PMID- 20193444 TI - [Evolution of tooth and oral and maxillofacial anatomy.]. AB - People are constantly studying and exploring teeth and oral and maxillofacial anatomy in order to understand and treat dental and oral and maxillofacial diseases. As early as 2000 years age, people were partially aware of oral topography, but not until the Renaissance was a breakthrough made. In 1728, a dental professional book, "Surgical dentist," was published, which marked dentistry as an independent discipline. Thereafter, John Hunter published "The Natural History of Human Teeth" (1771) and the "Actual Dissertation on Dental Disease" which marked the birth of dental anatomy. By modern times, dental and oral and maxillofacial anatomy has developed rapidly due to the use of a variety of science and technology and the progress in medicine. PMID- 20193445 TI - [A brief history of treatment for radial head fracture with radial head prosthesis.]. AB - Since Speed first treated the radial head fracture with a metal prosthesis in 1941, the purpose of the treatment of radial head fracture with a radial head changed from the prevention of heterotopic ossification to the prevention of proximal migration of the radius and instability of the elbow. The optimal indication is gradually determined as a non-reconstructable radial head fracture with associated injuries that would leave the elbow unstable if the radial head were resected. Types of prosthesis changed from mono-block, bipolar to modular prosthesis. Material of prosthesis changed from acrylic resin, silastic to cobalt chrome titanium and pyrocarbon. The 60-year development indicated that the operative technology of radial head prostheses was to be improved so as to reconstruct the flexibility and stability of the elbow to meet the higher functional requirements of patents. PMID- 20193446 TI - [The complete and extant editions of Jinguiyaolue (Synopsis of Prescriptions of the Golder Chamber).]. AB - The extant Jinguiyaolue (Synopsis of Prescriptions of the Golder Chamber) is less likely to originate directly from the section on miscellaneous diseases in the 16 volume Shanghanzabinglun (Treatise on Cold Pathogenic and Miscellaneous Diseases) of ZHANG Zhong-jing which was complied in the early third century. It was, in fact, compiled in the Northern Song dynasty. All the extant editions of Jinguiyaolue, including Japanese editions, were derived from the five editions system complied from the Yuan dynasty to the Ming dynasty, belongs to the large character version. The small character version of Wu Qian's transcript that was recently discovered in the shanghai Library is different from the original system, and this is worthy of attention to. By comparison of Deng Zhen's version with We Qian's version, it was realized that the Northern Song government had not simply converted the large character version into the small character version, but revised it as large-scale for the second time. PMID- 20193447 TI - [Textual research on the author of Caiaibian and Caiaibianyi.]. AB - The compilation and time of publication of Caiaibian and Caiaibianyi were about 100 years apart. The published author of the former book, YE Guang-zuo, and the author Chashancaomuyin (nom de plume) are not the same as the author of the latter book, YE Cha-shan. The name of the latter book reflects the inherited relationship to the former book academically, but also the different contents of the source and flow. Both books are monographs of moxibustion of Traditional Chinese Medicine (TCM), which made great contributions to the development of moxibustion. PMID- 20193448 TI - [On the academic value of Wutingzisujiebashiyinanjing (Wutingzi's Vernacular Explanation of Nanjing).]. AB - Nanjing, one of the four ancient classics of TCM, was followed by later students of TCM, XIONG Zong-li, a famous doctor and publisher in the Ming Dynasty, compiled Wutingzisujiebashiyinanjing (Wutingzi's Vernacular Explanation of Nanjing) which combined visual and legible graphic interpretation with vernacular language to explain, or quoted the classics, combined with his own opinions. This book popularly and vividly displayed the substance of Nanjing to the descendants and made a great contribution to the popularization and propagation of TCM classics. It is a valuable reference book both to students and researchers of Nanjing. PMID- 20193449 TI - [The textual research on FANG Dao's life and Fangshijiacangjiyaofang (Collected prescription of Fang family's).]. AB - Fangshijiacangjiyaofang (Collected prescription of Fang family's) is a prescription book compiled by Fang Dao in Southern Song Dynasty, and most of these prescriptions from experience have important clinical guiding values. However, few recorders about the book and its compiler could be found in relevant literature, it is necessary for them to be further verified. PMID- 20193450 TI - [Permanently engaged in TCM research, 50 years experience in writing - in memory of Dr. Okanisi Tameto's 110th Birthday.]. AB - Okanisi Tameto (1898 - 1973) lived in Northeast China for 34 years after he came to China at the age of 17. During these 34 years, he graduated from a student to a doctor, became an editor, professor and finally became an excellent researcher of TCM, who made monumental contributions to the development of TCM. Okanisi Tameto witnessed the brutality of war, being even in danger of his life several times. The wars made his life even harder, his parents and friends died in the turbulent years, but all of this did not affect his faith as well as his enthusiasm in studying TCM. After returning to his country when middle-aged, he worked for a pharmaceutical company and lived a simple and plain life. However, his research and writing never stopped. In his lifetime he completed 272 articles, as well as books, dissertations and essays etc. his famous book Songyiqianyijikao (Textual Research on Medical Books of the Pre-Song Period)-a famous TCM literary work that was completed in 1931 - 1948. The Beijing People's Medical Publishing House published his book in 1958, which attracted the attention of the Asian and European TCM sectors. PMID- 20193451 TI - [The impact of HER2 in pathology]. PMID- 20193452 TI - [Comments on American Society of Clinical Oncology/College of American Pathologists for HER2 testing in breast cancer]. PMID- 20193453 TI - [Importance of cytopathology]. PMID- 20193454 TI - [Notch1 mRNA and protein expression in human breast cancer and normal mammary gland tissues]. AB - OBJECTIVE: To explore the Notch1 mRNA and protein expression in human breast cancers and normal mammary tissues, and their relationship with the clinical indicators of breast cancers were analyzed. METHODS: Notch1 gene of human breast invasive ductal carcinoma (IDC) and normal mammary gland tissues were amplified by RT-PCR, and the expression of Notch1 protein was detected by immunohistochemical Streptavidin-Biotin Complex (SP) stain in 60 IDC, 30 ductal carcinoma in situ (DCIS) and 60 normal mammary tissues. RESULTS: Notch1 gene of human IDC and normal mammary tissues both could express in a transcription level; the positive rates of Notch1 protein expression in normal mammary tissues and DCIS were 55% and 70%. Respectively, which did not differ statistically (P > 0.05), while the positive rate in IDC was 90%, significantly higher than that of the normal mammary tissues and DCIS (P < 0.05). The high expression of Notch1 protein in IDC correlate significantly with lymph node metastasis, pathological grades and TNM stages. CONCLUSIONS: Notch1 protein was over expressed in breast IDC. A high Notch1 protein expression is considered associating with the evolution and malignant transformation of the breast tumor. The expression of Notch1 gene maybe impact the effect of on the progression of breast cancers. PMID- 20193456 TI - [Correlation between HLA-DRB1*0901 and 1501, HLA-DQB1*0301 and 0602 alleles and esophageal squamous cell carcinoma of Kazakh in Xinjiang, China]. AB - OBJECTIVE: To investigate the polymorphism of HLA-DRB1 and DQB1 allele in esophageal squamous cell carcinomas of Kazakh in Xinjiang, and to characterize susceptible genes for the family of Kazakh esophageal squamous cell carcinoma. METHODS: HLA-DRB1*0901, DRB1*1501, DQB1*0301, DQB1*0602 alleles were genotyped by sequence specific primers using polymerase chain reaction (PCR-SSP) in 200 Kazakh esophageal squamous cell carcinoma and 177 normal esophageal mucosa. RESULTS: The frequency of HLA-DRB1*1501, HLA-DQB1*0301, HLA-DQB1*0602 alleles in 200 Kazakh esophageal squamous cell carcinoma (0.455, 0.760 and 0.690) were significantly higher than that of 177 normal esophageal mucosa (0.232, 0.520, 0.554; OR = 2.78, 2.93, 1.80; P < 0.05). The frequency of HLA-DRB1*0901 between the carcinoma (0.105) and control groups (0.102) had no association (OR = 1.036, P > 0.05); The frequency of HLA-DQB1*0602 was higher in poor-differentiated squamous cell carcinomas (0.742) than that of well-differentiated tumors (0.597, P < 0.05). CONCLUSIONS: HLA-DRB1*1501, HLA-DQB1*0301, HLA-DQB1* 0602 may be susceptible to Kazakh esophageal squamous cell carcinoma. HLA-DQB1*0602 correlates with well differentiated esophageal squamous cell carcinoma. PMID- 20193455 TI - [Lymphoblastic lymphoma and acute lymphoblastic leukemia: a clinicopathologic, immunophenotypic and prognostic study in 153 Chinese patients]. AB - OBJECTIVE: To study the clinicopathologic features, immunohistochemical findings and prognosis of precursor lymphoblastic lymphoma/acute lymphoblastic leukemia (LBL/ALL). METHODS: One hundred and fifty-three cases of LBL/ALL were retrospectively analyzed. Immunohistochemical study was carried out. The pathologic findings were correlated with Ann Arbor tumor stage, Ki-67 index, other clinical parameters (including mediastinum/bone marrow involvement, hepato splenomegaly, age and gender of the patients) and the survival data. RESULTS: Staining for TdT and CD99 was positive in 79.1% (121/153 cases) and 96.3% (131/136 cases), respectively. The cases were categorized into three groups according to the immunohistochemical findings, as follows: precursor T-cell, precursor B-cell and undefined. T-LBL/ALL accounted for 69.3% (106/153 cases) of all of the cases. The male-to-female ratio was 2.4:1 (including 75 males and 31 females). The median age at diagnosis was 17.5 years (ranged from 2 years to 68 years). Ninety-two patients (86.8%) presented with peripheral lymphadenopathy and 59 of them (55.7%) had mediastinal masses. Ninety-one cases (85.8%) were in stage III or IV at diagnosis. The 1-year and 5-year survival rates in patients with T LBL/ALL were 36.1% and 8.1%, respectively. Patients older than 25 years and those presented in stage III or IV suggested a poor prognosis (P = 0.049 and 0.001, respectively). On the other hand, 29 of the 153 cases (19.0%) belonged to B LBL/ALL. The median age of the patients was 14 years (ranged from 9 months to 75 years). The male-to-female ratio was 1.6:1 (including 18 males and 11 females). Seventeen patients (58.6%) presented with peripheral lymphadenopathy and 13 of them (44.8%) had involvement of bone marrow or peripheral blood. Mediastinal involvement was found only in 5 cases (17.2%). Twenty-one patients (72.4%) were in stage III or IV at diagnosis. The 1-year and 5-year survival rates were 53.3% and 36.7%, respectively. The remaining 11.7% cases (18/153 cases) were categorized as undefined type, with a negative staining for the following immuno markers including: CD3epsilon/CD3, CD45RO, CD79a, CD20, MPO, CD5, CD56, cyclin D1, cytokeratin, neuron-specific enolase, chromogranin A and synaptophysin. The median age of the patients was 15.5 years (ranged from 4 to 53 years). The male to-female ratio was 2.6:1 (including 13 males and 5 females). The percentage of T LBL/ALL patients with mediastinal masses were significantly higher than that of B LBL/ALL cases (P = 0.0003). There was no significant difference in prognostic parameters of T-LBL/ALL and B-LBL/ALL (P = 0.07). The difference in median survival time however was statistically significant (6.0 months +/- 1.1 months versus 15.0 months +/- 7.0 months). CONCLUSIONS: Both TdT and CD99 are useful markers for the diagnosis of precursor lymphoblastic malignancy. T-LBL/ALL predominantly affects children or adolescent males and frequently presents with lymphadenopathy and mediastinal masses, whereas B-LBL/ALL are often accompanied by bone marrow and peripheral blood involvement. In general, T-LBL/ALL carries a poor prognosis. The prognostic criteria include age of older than 25 years and a classification of stage III or IV disease. PMID- 20193457 TI - [Clinicopathologic diagnosis of de-differentiated chondrosarcoma]. AB - OBJECTIVE: To study the clinicopathologic and radiologic features of dedifferentiated chondrosarcoma, focusing on its diagnosis and differential diagnosis. METHOD: Clinical, radiological and pathologic findings of 14 cases of dedifferentiated chondrosarcoma (including biopsy and surgical specimens) were analyzed by hematoxylin and eosin stained sections and immunohistochemistry. RESULTS: The mean age of patients was 52 years. The male-to-female ratio was 9:5. The most common sites of involvement were pelvis, femur and humerus, similar to the conventional chondrosarcoma. Radiologically, they were malignant tumors with dimorphic pattern. Grossly, central chondrosarcomas were more common than those of the peripheral. An essential histological feature of dedifferentiated chondrosarcoma was an abrupt interface between the low-grade cartilaginous tumor and high-grade anaplastic sarcoma. The most common dedifferentiated components were osteosarcoma, malignant fibrous histocytoma and fibrosarcoma. False negative diagnosis and erroneous diagnosis were frequent when only one-time biopsy was available. CONCLUSIONS: Dedifferentiated chondrosarcoma is a rare subtype of chondrosarcoma with poor prognosis, which has different features of clinical manifestation, imaging features and pathological characteristics, compared to conventional chondrosarcoma and chondroblastic osteosarcoma. PMID- 20193458 TI - [Pathologic study of expression and significance of matrix metalloproteinases-9, tissue inhibitor of metalloproteinase-1, vascular endothelial growth factor and transforming growth factor beta-1 in papillary carcinoma and follicular carcinoma of thyroid]. AB - OBJECTIVE: To study the roles of matrix metalloproteinases-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), vascular endothelial growth factor (VEGF) and transforming growth factor beta-1 (TGFbeta-1) in differentiation, invasiveness and metastatic potential of papillary carcinoma and follicular carcinoma of thyroid. METHODS: Eighty-five cases of papillary thyroid carcinoma and 59 cases of follicular thyroid carcinoma were enrolled into the study. Immunohistochemistry using EnVision method was carried out for assessment of the expression of MMP-9, TIMP-1, VEGF and TGFbeta-1 in the tumor tissue. RESULTS: MMP 9, TIMP-1, VEGF and TGFbeta-1 were expressed in the cytoplasm of tumor cells. The positivity rates of MMP-9, TIMP-1, VEGF and TGFbeta-1 in papillary thyroid carcinoma (83.5%, 81.2%, 90.6% and 75.3%, respectively) were similar to or lower than those in follicular thyroid carcinoma (93.2%, 86.4%, 89.9% and 78.0%, respectively). The expression rates in papillary thyroid carcinoma with lymph node metastasis were also higher than those in tumors without lymph node metastasis. The expression rates of MMP-9, VEGF and TGFbeta-1 in poorly differentiated follicular thyroid carcinoma were higher than those in well differentiated follicular thyroid carcinoma. The expression of TIMP-1 however showed a negative correlation with the tumor cell differentiation. In general, the expression of VEGF and MMP-9 was higher than that of TIMP-1 and TGFbeta-1 in papillary thyroid carcinoma and follicular thyroid carcinoma. CONCLUSIONS: Immunohistochemical detection of MMP-9, TIMP-1, VEGF and TGFbeta-1 expression may carry clinical significance in evaluating the degree of differentiation, invasiveness, metastatic potential and prognosis of papillary thyroid carcinoma and follicular thyroid carcinoma. PMID- 20193459 TI - [Effects of antisense Bmi-1 RNA on the proliferation of lung cancer cell line A549]. AB - OBJECTIVE: To study the effects of antisense Bmi-1 (B cell-specific moloney murine leukemia virus insertion site 1) RNA on the growth, cell cycle and apoptosis of lung cancer cell line A549. METHODS: Recombinant plasmids carrying antisense Bmi-1 RNA were transfected into A549 cells, which expressed a high level of endogenous Bmi-1. The mRNA level of A549 cell was analyzed by real time quantitative RT-PCR and the protein level was determined using Western blot. MTT growth curve and plate colony forming assay were used to measure the effect of antisense Bmi-1 RNA expression on the growth of A549. Flow cytometry was used to analyze cell cycle and apoptosis. RESULTS: Antisense Bmi-1 RNA reduced the Bmi-1 expression at the protein level, but did not alter the mRNA level in A549 cells. Compared with the control cells, A549 cells transfected with antisense Bmi-1 RNA showed a strong inhibition of the cell growth. The number of plate colony formation of the antisense Bmi-1 transfected cells (0.67 +/- 0.50) was less than those of the control (73.0 +/- 4.1) and cells transfected with empty vector (67.0 +/- 4.0, P < 0.01). Transfection of antisense Bmi-1 RNA arrested the A549 cells at G0/G1 phase of the cell cycle and did not increase the apoptosis. CONCLUSION: Antisense Bmi-1 RNA expression inhibits A549 cells proliferation, likely through the interference of Bmi-1 leading to an arrest of the proliferating cells at the G0/G1 phase. PMID- 20193460 TI - [Changes in expression of synaptic proteins in brains of patients with Alzheimer's disease]. PMID- 20193461 TI - [Roles and applications of liquid-based cytology in sputum samples from lung cancer patients]. PMID- 20193462 TI - [Guidelines for HER2 detection in breast cancer, the 2009 version]. PMID- 20193463 TI - [Synchronous cervical intraepithelial neoplasia and cervical follicular non Hodgkin lymphoma: report of a case]. PMID- 20193464 TI - [Stillbirth due to obliterative endarteritis of chorionic villi: report of a case]. PMID- 20193465 TI - [Cystic solitary fibrous tumor: report of a case]. PMID- 20193466 TI - [Malignant atrophic papulosis: report of a case]. PMID- 20193467 TI - [Cellular angiofibroma of vulva: report of a case]. PMID- 20193468 TI - [Calcium pyrophosphate crystal deposition disease:report of two cases]. PMID- 20193469 TI - [Rosette-forming glioneuronal tumor of fourth ventricle: report of two cases]. PMID- 20193470 TI - [Impacts of tissue fixation and processing in immunohistochemistry and its standardization]. PMID- 20193471 TI - [Recent advances on EZH2 in malignant tumors]. PMID- 20193472 TI - [Updates on biologic function of tumor suppressor gene inhibitor of growth family and related studies]. PMID- 20193473 TI - Challenges facing venous thromboembolism in China: more public awareness and research needed. PMID- 20193474 TI - Effects of single nucleotide polymorphisms 869 T/C and 915 G/C in the exon 1 locus of transforming growth factor-beta1 gene on chronic obstructive pulmonary disease susceptibility in Chinese. AB - BACKGROUND: The main risk factor for chronic obstructive pulmonary disease (COPD) is cigarette smoking. However, only 10% - 20% of chronic heavy smokers develop systematic COPD. We hypothesized that the inheritance of gene polymorphisms could influence the development of COPD, which was investigated by studying two single nucleotide polymorphisms (SNP) in exon 1 of the transforming growth factor-beta1 (TGF-beta1) gene. METHODS: We enrolled 219 patients with COPD as the research group and 148 healthy people as the control group, all of whom were Chinese Han people. The polymorphisms of the TGF-beta1 gene, 869T/C and 915G/C, were analyzed using the method of amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). RESULTS: The occurrence of the TGF-beta1 gene 869T/C polymorphism in patients with COPD was significantly different from the control group (P < 0.05), in which the relative risk of this disease increased in cases who had the C allele (OR: 1.131, 95%CI: 1.101 - 1.539). There was no increased frequency of TGF-beta1 915G/C gene in COPD patients compared with control subjects (P > 0.05). CONCLUSIONS: The polymorphism 869T/C in TGF-beta1 gene has a significant association with disease occurrence in COPD patients and the C allele might be a risk factor. The homozygous wild-type CC of 869T/C on TGFbeta1 could be a predisposing factor in COPD and those who carry the C allele might have particularly susceptibility to developing COPD. PMID- 20193475 TI - Effects of thrombolytic drugs and a selective endothelin-1 receptor antagonist on acute pulmonary thromboembolism in dogs. AB - BACKGROUND: It has been shown that neurohumoral factors other than mechanical obstruction are involved in the pathophysiology of acute pulmonary thromboembolism (APTE). The aim of this study was to investigate the effects of thrombolytic drugs, a selective endothelin-1 receptor (ET-1R) antagonist alone or their combination on APTE in a canine model. METHODS: Twenty dogs were randomly assigned to five groups: sham, model, urokinase (UK), BQ123, and combination (UK plus BQ123). The dogs in the sham group underwent sham surgery. APTE was induced in the other four groups by intravenous injection of autologous blood clots. Dogs in the UK, BQ123 and combination groups received UK, BQ123 (a selective ET-1R antagonist), or UK plus BQ123, respectively. The dogs in the model group were given saline. Mean pulmonary artery pressure (mPAP), serum concentrations of ET 1, thromboxane (TXB2), and tumor necrosis factor (TNF)-alpha were determined at different time points following the induction of APTE. RESULTS: UK and BQ123 alone markedly decreased mPAP in APTE. By comparison, the reduction was more significant in the combination group. Compared with the sham group ((-0.90 +/- 0.61) mmHg), mPAP increased by (7.44 +/- 1.04), (3.42 +/- 1.12) and (1.14 +/- 0.55) mmHg in the model group, UK alone and BQ123 alone groups, respectively, and decreased by (2.24 +/- 0.67) mmHg in the combination group (P < 0.01). Serum ET-1 concentrations in the BQ123 and combination groups were (52.95 +/- 8.53) and (74.42 +/- 10.27) pg/ml, respectively, and were significantly lower than those in the model and UK groups ((84.56 +/- 7.44) and (97.66 +/- 8.31) pg/ml respectively; P < 0.01). Serum TNF-alpha concentrations were significantly lower in the BQ123 group than in the model, UK and combination groups (P < 0.05). CONCLUSIONS: Our results indicate that the selective ET-1R antagonist BQ123 not only reduces the increase of mPAP and serum ET-1 level, but also inhibits the production of TNF-alpha, and attenuates the local inflammatory response induced by APTE. Selective ET-1R antagonists may be beneficial to the treatment of APTE, particularly when used in combination with a thrombolytic agent. PMID- 20193477 TI - Hospitalized patients with novel influenza A (H1N1) virus infection: Shanghai, June - July 2009. AB - BACKGROUND: From late May 2009, sporadic imported cases of novel influenza A (H1N1) were continuously confirmed in Shanghai, but there were few reports on its clinical presentation in China. The aim of the study was to investigate the demographic and clinical features of the laboratory-confirmed cases and the treatment with oseltamivir. METHOD: We performed a retrospective study in the Shanghai Public Health Clinical Center (SHAPHC), reviewing the medical records of the laboratory-confirmed patients derived from June 10 to July 20, 2009. RESULTS: A total of 156 cases were enrolled, of whom 152 had a history of recent travel. The mean age was 22.6 years and 89 cases (57.1%) were males. The most common symptoms were fever, cough, and sore throat, with children more likely to run a temperature above 38.5 degrees C than adults. The mean leucocyte count was 5.4 x 10(9)/L, the mean neutrophil count 3.2 x 10(9)/L and the mean lymphocyte count 1.4 x 10(9)/L. Other findings included a normal range or elevated level of C reactive protein (CRP) and glutamic-pyruvic transaminase and a normal or decreased level of prealbumin; the levels of prealbumin and CRP were significantly lower in the children than in the adults. Fifty-two patients had abnormal chest CT results, with small unilateral or bilateral pulmonary infiltrates, axillary and mediastinal lymphadenopathy and local pleural thickening, while no cases showed symptoms of hypoxia. All the patients received oseltamivir and recovered without complications, but the duration of fever and virus shedding were significantly longer in the children than in the adults. CONCLUSIONS: Travel-related circulation may be an important reason for the H1N1 epidemic in the non-epidemic areas, and the virus caused mild respiratory symptoms. The infection in children was more severe in terms of prealbumin levels, temperature, the duration of fever and virus shedding. Oseltamivir was effective for H1N1, but more effective in the adults than in the children. PMID- 20193478 TI - Alveolar stability under different combinations of positive end-expiratory pressure and tidal volume: alveolar microscopy in isolated injured rat lungs. AB - BACKGROUND: High positive end-expiratory pressure (PEEP) and low tidal volume (VT) ventilation is thought to be a protective ventilation strategy. It is hypothesized that the stabilization of collapsible alveoli during expiration contributes to lung protection. However, this hypothesis came from analysis of indirect indices like the analysis of the pressure-volume curve of the lung. The purpose of this study was to investigate isolated healthy and injured rat lungs by means of alveolar microscopy, in which combination of PEEP and VT is beneficial with respect to alveolar stability (I-E%). METHODS: Alveolar stability was investigated in isolated, non-perfused mechanically ventilated rat lungs. Injured lungs were compared with normal lungs. For both groups three PEEP settings (5, 10, 20 cmH2O) were combined with three VT settings (6, 10, 15 ml/kg) resulting in nine PEEP-VT combinations per group. Analysis was performed by alveolar microscopy. RESULTS: In normal lungs alveolar stability persisted in all PEEP-VT combinations (I-E% (3.2 +/- 11.0)%). There was no significant difference using different settings (P > 0.01). In contrast, alveoli in injured lungs were extremely instable at PEEP levels of 5 cmH2O (mean I-E% 100%) and 10 cmH2O (mean I-E% (30.7 +/- 16.8)%); only at a PEEP of 20 cmH2O were alveoli stabilized (mean I-E% of (0.2 +/- 9.3)%). CONCLUSIONS: In isolated healthy lungs alveolar stability is almost unaffected by different settings of PEEP and VT. In isolated injured lungs only a high PEEP level of 20 cmH2O resulted in stabilized alveoli whereas lower PEEP levels are associated with alveolar instability. PMID- 20193479 TI - Effects of N-acetylcysteine on Clara cells in rats with cigarette smoke exposure. AB - BACKGROUND: The number of Clara cells and the Clara cell 16-kDa protein (CC16) levels of the lung decrease in patients with chronic obstructive pulmonary disease (COPD). N-acetylcysteine (NAC) is a powerful antioxidant and can reduce the frequency of acute exacerbations of COPD. But the exact mechanism is unclear. The present study was designed to investigate the effects of NAC on Clara cells in rats with cigarette smoke exposure. METHODS: Eighteen adult male Wistar rats were randomly divided into 3 groups, 12 exposed to cigarette smoke (CS) thrice a day, 10 cigarettes for 30 minutes each time for 1 week, without (CS group) or with (CS + NAC group) oral intake of NAC 80 mg x kg(-1) x d(-1), and another 6 rats exposed to fresh air (control group). Clara cells were observed by an electron microscope. The mRNA expression of CC16 and CC16 protein in lungs were determined by reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry respectively. The glutathion (GSH) level in plasma and lung tissue were tested by fluorimetry assay. RESULTS: Compared with the controls, the pathologic score of small airways significantly increased in the CS exposed rats (20.3 +/- 14.7 vs. 53.7 +/- 11.5, P < 0.05). The Clara cell particles in cytoplasm decreased in the CS group (P < 0.05). The percentage of CC16-positive cells in bronchioles in the CS group (27.8 +/- 4.3 and 29.5 +/- 2.4 in terminal bronchioles and respiratory bronchioles, respectively) significantly decreased as compared with the control group (37.1 +/- 3.8 and 43.8 +/- 5.8 in terminal bronchioles and respiratory bronchioles, respectively) (P < 0.05). No significant difference was observed in GSH level ((181 +/- 26) nmol/L in the control group vs. (170 +/- 18) nmol/L in the CS group) between the two groups. After treatment with NAC, the pathologic score of small airways (24.1 +/- 17.5) decreased (P < 0.05). Clara cell particles in cytoplasm of Clara cells increased and GSH level in plasma ((213 +/- 40) nmol/L vs. (170 +/- 18) nmol/L in the CS group) increased too (P < 0.05), while the increase in the proportions of CC16 positive cells in bronchioles (30.1 +/- 6.4 and 34.3 +/- 6.3 in terminal bronchioles and respiratory bronchioles, respectively) did not reach the statistical significance (P > 0.05). No significant difference was found in the expression of CC16 mRNA among the three groups. Correlation analysis indicated that the percentage of CC16-positive cells in bronchioles negatively correlated with the pathologic score of small airways (r = -0.592, P < 0.05), but not with GSH level. CONCLUSIONS: One-week CS exposure decreased the number of Clara cells and the expression of CC16 in bronchioles in rats. NAC might provide protection of the Clara cells from oxidative damage and possibly through the elevation of the synthesis and secretion of CC16. These data indicate that NAC decreases airway inflammation induced by CS via induction of CC16. PMID- 20193480 TI - Obstetric outcome of women with uterine anomalies in China. AB - BACKGROUND: Congenital uterine anomalies are associated with the highest incidence of reproductive failure and obstetric complications. This study aimed to summarize the clinical characteristics and prenatal outcome of pregnancy in women with congenital uterine malformations. METHODS: This retrospective study evaluated the fertility and obstetric outcome of 116 inpatients with uterine malformations with pregnancy in Peking University Third Hospital from June 1998 to June 2009. A total of 270 randomly selected pregnant women with a previously confirmed normally shaped uterus as a control group. Student's t test and analysis of variance (ANOVA) were used to compare means for normally distributed variables. The analysis was carried out using the SPSS. RESULTS: Among 21 961 deliveries in Peking University Third Hospital, 116 (0.45%) were in women with uterine anomalies. A septate uterus was present in 43 (37.1%) and the uterus didelphys in 28 (24.2%) of the 116 women identified. Bicornuate uterus, arcuate and unicomate uterus were observed in 12 (10.3%), 18 (15.5%) and 15 (12.9%) patients, respectively. Patients with uterine anomalies had significantly higher rates of malpresentation (38.8%), preterm delivery (19.8%), and cesarean section (78.5%) compared with the group of women with a normal uterus. Patients with uterine anomalies had significantly lower mean birth-weight neonates and a significantly higher incidence of small for gestationalage (SGA) neonates; women with uterus didelphys more frequently required infertility treatment than patients with other uterine anomalies (P < 0.001). The rate of malpresentation was significantly higher in patients with septated uterus in comparison with patients with uterus unicorns (P < 0.05). CONCLUSIONS: Women with congenital uterinemal formation usually have higher incidence of complications during pregnancy and delivery. A septate uterus appears to be associated with poorer obstetric outcomes. PMID- 20193481 TI - Prenatal cytogenetic diagnosis study of 2782 cases of high-risk pregnant women. AB - BACKGROUND: Prenatal diagnoses are extremely advantageous for pregnant women with high-risk indicators and can help prevent the birth of malformed infants. However, no large-scale statistical study analyzing the correlation between fetal chromosome disorders and abnormal indicators during pregnancy has been done in China. The objectives of this study were to diagnose and analyze fetal chromosome abnormalities, determine the feasibility of the various prenatal test methods and establish diagnostic guidelines for the early, middle, and late trimesters. METHODS: From January 2004 to May 2009, 2782 pregnant women at high-risk underwent prenatal diagnoses. Categorized data expressed as either actual counts or percentages were analyzed by the chi-square or Fisher's exact test. Chorionic villus sampling was performed in the early-trimester (10 - 12 weeks of gestation), amniocentesis in mid-trimester (16 - 28 weeks of gestation), and umbilical cord blood collection in mid- or late-trimester (16 - 37 weeks of gestation). In 51 cases either autopsy samples from intrauterine fetal deaths or placental tissues from aborted fetuses were tested. RESULTS: Chromosomal abnormalities were observed in 3.99% (111/2782) of the samples. Overall, the success rate of cytogenetic analysis for high-risk pregnancy groups was 98.17% (2731/2782). It was significantly less successful when used to analyze data from the chorionic villus sampling compared with that from amniocentesis and umbilical cord blood (P = 0.000). Abnormal chromosome carriers had the highest percentage of abnormal chromosomes (67.86%) when compared with chromosomal abnormalities in patients with ultra-sonographic "soft markers" (11.81%), advanced maternal age (4.51%) and those who had positive serum screening results (P = 0.000). CONCLUSIONS: Invasive prenatal diagnostic techniques are feasible tools for confirming fetal chromosomal abnormalities. Abnormal chromosomes detected in one of the parents carrying abnormal chromosome, ultrasound soft markers, advanced maternal age or positive serum screening results were associated with a higher frequency of fetal genetic diseases. PMID- 20193482 TI - Prediction of recurrence risk in early breast cancer using human epidermal growth factor 2 and cyclin A2. AB - BACKGROUND: Human epidermal growth factor 2 (HER2) is one of the most important prediction factors, but only 25% - 30% of breast cancer patients HER2 are positive. It is unknown whether there are other molecular markers that could be used to predict prognosis and recurrence in HER2 negative patients. This study investigated correlations of cyclin A2 and HER2 levels with clinical outcomes in 281 patients with invasive breast cancer in order to identify whether cyclin A2 can serve as a prognostic factor in HER2 negative patients. METHODS: Immunohistochemical staining was used to detect cyclin A2 and HER2 expression in 281 patients. Cyclin A2 and HER2 gene amplifications were analyzed using gene analysis and RT-PCR in 12 patients. Risk and survival estimates were analyzed using Log-rank, Kaplan-Meier, and Cox regression analysis; cyclin A2 and HER2 consistency with survival were analyzed using Kappa analysis. RESULTS: Patients with higher cyclin A2 and HER2 expressions had significantly shorter disease-free survival periods (P = 0.047 and P = 0.05, respectively). Kappa analysis performed that cyclin A2 and HER2 showed a low Kappa index (kappa = 0.37), allowing us to conclude that cyclin A2 and HER2 detect different pathologies. Gene analysis and RT-PCR showed that cyclin A2 was upregulated in patients with early relapse; the average increase was 3.69 - 2.74 fold. CONCLUSIONS: Cyclin A2 and HER2 are associated with proliferation and high recurrence, particularly when combined. Cyclin A2 is easily detected by nuclear staining and might be a useful biomarker for recurrence risk in HER2 negative patients. PMID- 20193483 TI - Use of amniocytes for prenatal diagnosis of 22q11.2 microdeletion syndrome: a feasibility study. AB - BACKGROUND: A study of prenatal genetic diagnosis for 22q11.2 microdeletion, which has a wide phenotypic spectrum that involves almost all organs, is rarely reported in China. This study aimed to explore the prevalence of 22q11.2 microdeletion in congenitally malformed fetuses via the fluorescent in situ hybridization (FISH) technique and to investigate the feasibility of use of amniocytes to diagnose 22q11.2 microdeletion syndrome prenatally. METHODS: The study enrolled 23 cases of fetal cardiac malformation, as indicated by ultrasound in Beijing Anzhen Hospital and 14 cases of non-cardiac malformation, as determined by type-B ultrasound in Beijing Anzhen Hospital and other hospitals. Amniotic fluid was obtained by amniocentesis before odinopoeia, and the stillborn fetuses of the induced labor were preceded to autopsy. The amniotic fluid of 20 cesarean deliveries during the same period of time was used as a control. The TUPLE1 gene in the amniotic fluid of malformed and normal fetuses was assessed by the FISH method. RESULTS: The prevalence rates of the TUPLE1 gene deletion in the amniotic fluid cells from fetuses with cardiac deformations and fetuses without such malformations were 43.5% and 57.1%, respectively. The deletion of TUPLE1 was significantly associated with fetal malformation. CONCLUSION: Chromosome 22q11.2 microdeletion is one of the major factors leading to fetal congenital malformations, and prenatal FISH screening for 22q11.2 microdeletion syndrome is technically feasible using amniocytes. PMID- 20193484 TI - Optimization of magnetic resonance sequences in lymph node staging of nasopharyngeal carcinoma. AB - BACKGROUND: Detection rate of retropharyngeal lymph node metastasis in patients with nasopharyngeal carcinoma (NPC) needs to be improved. The purpose of this study was to compare three magnetic resonance (MR) sequences for detecting lymph nodes in patients with NPC. METHODS: Between July 2007 and March 2008, MR staging of pre-treated tumor was conducted on 120 patients with pathologically confirmed NPC. The outcome of three different sequences for MR NPC staging were compared: coronal short TI inversion recovery (STIR), axial proton density fat-suppressed (PDWI fs), and coronal contrast enhanced fast spin echo T1 weighted fat suppressed (CE FSE T1WI fs). Nodal classification method (1999) was applied to count the number of retropharyngeal and cervical lymph nodes discovered by each MR sequence. Paired t tests were used for statistical analysis. RESULTS: A total of 2575 lymph nodes were found using coronal STIR sequence; 1816 lymph nodes for coronal CE FSE T1WI fs sequence and 2638 lymph nodes for axial PDWI fs sequence. Significant differences existed in the number of lymph nodes detected by axial PDWI fs and coronal CE FSE T1WI fs sequence (paired t test, P < 0.05), with the former sequence getting higher numbers. Statistical differences also existed between coronal STIR and coronal CE FSE T1WI fs sequence (paired t test, P < 0.05), with the former sequence getting higher numbers. No significant difference was found between coronal STIR sequence and axial PDWI fs sequence (paired t test, P > 0.05). CONCLUSIONS: For the detection of retropharyngeal and cervical lymph nodes, coronal STIR sequence and axial PDWI fs sequence have similar performance and both sequences showed better detection than CE FSE T1WI fs sequence. Furthermore, by combining coronal STIR sequence and axial PDWI fs sequence, we can improve the detection of lymph nodes in NPC N-staging before treatment, especially for lymph nodes located in the thoracic entrance. PMID- 20193485 TI - Modification of closed tympanoplasty in middle ear cholesteatoma. AB - BACKGROUND: Classic mastoidectomy and modified mastoidectomy are traditional surgical procedures for middle ear cholesteatoma with goals of eradicating diseases, creating dry ears and preventing severe complications. However, the drawback of these procedures is the lack of hearing improvement. Therefore, our study aimed to investigate the effects and safety of a modification of closed tympanoplasty for middle ear cholesteatoma. METHODS: Eighty-three patients were recruited in this study based on the following two criteria: each patient had middle ear cholesteatoma in one ear; the affected ears had a functional eustachian tube and had neither intracranial nor extracranial complications. All the patients received a modification of closed tympanoplasty which included ossicular reconstruction with total ossicular replacement prosthesis (TORP) or partial ossicular replacement prosthesis (PORP) and membrane repair with conchal cartilage-perichondral complex. RESULTS: All the 83 cases had dry ears with membranes healed within 4 - 6 postoperative weeks. After 6 postoperative months, there were 3 cases with re-perforation at the tympanic membrane center and after 1.5 postoperative years, there were 5 cases with cholesteatoma recurrence (6.02%). Function tests after one postoperative year exhibited an improvement of pure tone audiometry (PTA) in 27 cases that was more than 30 dB, in 33 cases between 20 - 29 dB, 14 cases with improvement between 10 - 19 dB, and in 9 cases there was no improvement. CONCLUSIONS: The modified closed tympanoplasty procedure for middle ear cholesteatoma in the present study has all the advantages of both close-cavity and open-cavity procedures. It has low recurrence rate and good hearing improvement. PMID- 20193486 TI - Quality of life for primary caregivers of muscular dystrophy patients in South Korea. AB - BACKGROUND: Although some studies measured the burden of caregivers and the factors that influenced their feelings of burden, few studies have measured the quality of life (QOL) for primary caregivers of patients with muscular dystrophy (MD). We assessed the QOL for primary caregivers of patients with MD in South Korea and identified factors associated with caregivers' QOL. METHODS: Ninety dyads of patients with MD and their primary caregivers were enrolled in this study. The QOL of caregivers of patients with MD was assessed subjectively using the World Health Organization Quality of Life Assessment, Life Brief Form. Caregivers' emotional status was assessed using the Beck Depression Inventory (BDI) and family function level was evaluated using the Family APGAR scale. Patients reported their emotional status using the BDI or the Children's Depression Inventory. The functional levels of patients were evaluated by the modified Barthel Index. RESULTS: Caregivers' QOL was statistically associated with family income, family function, emotional status of patients, level of education, and emotional status of caregivers (P < 0.05). Caregivers who were employed had a significantly higher QOL than those who were not (P < 0.05). In multiple regression analyses, emotional and employment status of caregivers was strongly associated with caregivers' QOL. CONCLUSION: Rehabilitation teams should consider not only the physical factors of patients but also the psychological and demographic factors of primary caregivers of patients with MD. PMID- 20193487 TI - Treatment of urethral strictures using lingual mucosas urethroplasty: experience of 92 cases. AB - BACKGROUND: Urethroplasty of complex urethral stricture is a difficult procedure, and there is no widely accepted standard approach described in the published literature. We evaluated the efficacy and safety of urethroplasty using lingual mucosa grafts (LMGs) for the repair of urethral strictures. METHODS: Between August 2006 and April 2009, 92 cases of urethral strictures (length ranging from 2.5 cm to 18 cm, mean 6.5 cm) were treated using LMGs. Of the 92 patients, 38 with long-segment urethral strictures (9 - 18 cm) underwent dual LMG or LMG combined with foreskin flap or buccal mucosal graft urethroplasty. RESULTS: Follow-up was obtained for 3 - 33 months (mean 17.2 months) postoperatively. Complications occurred in 8 patients, including urinary fistulas in 4 patients; recurrent strictures developed in 4 patients at 3 - 4 months post-operatively. The remaining patients voided well postoperatively, with peak flows between 14.3 ml/s and 54.6 ml/s (mean 28.4 ml/s). CONCLUSIONS: The tongue is an excellent source of graft material for the repair of anterior mucosal strictures. Dual LMG substitution urethroplasty can successfully treat longer, more complex urethral strictures. PMID- 20193488 TI - Chronic intermittent hypoxia from pedo-stage decreases glucose transporter 4 expression in adipose tissue and causes insulin resistance. AB - BACKGROUND: The persistence of sleep disordered breathing (SDB) symptoms after tonsil and/or adenoid (T&A) surgery are common in children with obstructive sleep apnea (OSA). We tested the hypothesis that disturbances of glucose transporters (GLUTs) in intraabdominal adipose tissue caused by chronic intermittent hypoxia (CIH) from the pedo-period could facilitate the appearance of periphery insulin resistance in Sprague-Dawley (SD) rats. We tested the hypothesis that the changes of GLUTs in adipose tissue may be one of the reasons for persistent SDB among clinical OSA children after T&A surgery. METHODS: Thirty 21-day-old SD rats were randomly divided into a CIH group, a chronic continuous hypoxia (CCH) group, and a normal oxygen group (control group) and exposed for 40 days. The changes of weight, fasting blood glucose and fasting blood insulin levels were measured. Hyperinsulinemic-euglycemic clamp techniques were used to measure insulin resistance in each animal. Real-time quantitative PCR and Western blotting were used to measure GLUT mRNA and proteins in intraabdominal adipose tissue. Additional intraabdomial white adipose tissue (WAT) was also processed into paraffin sections and directly observed for GLUTs1-4 expression. RESULTS: When compared with control group, CIH increased blood fasting insulin levels, (245.07 +/- 53.89) pg/ml vs. (168.63 +/- 38.70) pg/ml, P = 0.038, and decreased the mean glucose infusion rate (GIR), (7.25 +/- 1.29) mg x kg(-1) x min(-1) vs. (13.34 +/- 1.54) mg x kg(-1) x min(-1), P < 0.001. GLUT-4 mRNA and protein expression was significantly reduced after CIH compared with CCH or normal oxygen rats, 0.002 +/ 0.002 vs. 0.039 +/- 0.009, P < 0.001; 0.642 +/- 0.073 vs. 1.000 +/- 0.103, P = 0.035. CONCLUSIONS: CIH in young rats could induce insulin resistance via adverse effects on glycometabolism. These findings emphasize the importance of early detection and treatment of insulin insensitivity in obese childhood OSA. PMID- 20193489 TI - Transplantation of VEGF165-gene-transfected endothelial progenitor cells in the treatment of chronic venous thrombosis in rats. AB - BACKGROUND: The organization and recanalization of thrombi is a dynamic and complex process. The aim of this research was to study the cotherapeutic effect of stem cell transplantation and gene transfection on chronic venous thrombosis. METHODS: We constructed a recombinant adenoviral vector carrying the vascular endothelial growth factor 165 (VEGF165) gene by using the pAdEasy system, which was subsequently identified and amplified. Simultaneously, endothelial progenitor cells (EPCs) were isolated from rat bone marrow using Ficoll, cultured in EBM-2MV medium, and identified. Then, the cells were transfected with the recombinant Ad VEGF165. The EPCs were labeled with 1,1'-dioctadecyl-3,3,3',3' tetramethylindocarbocyanine (Dil) before transplantation. A rat model of chronic vein thrombosis was developed by partial ligation of the inferior vena cava. The rats were randomly divided into 4 groups (n = 25, each): A, Ad-VEGF165/EPC transplantation group received 1 ml (10(6)) of Ad-VEGF165/EPCs; B, EPC transplantation group received 1 ml (10(6)) of EPCs; C, Ad/EPC-transplantation group received 1 ml (10(6)) of Ad/EPCs; D, control group received 1 ml of the transplantation medium. The thrombi and adjacent caval walls were harvested 28 days after transplantation; real-time quantitative polymerase chain reaction was used to detect the expression level of vascular endothelial growth factor (VEGF) mRNA; and western blotting was used to measure changes in VEGF protein expression. Hematoxylin-eosin staining and immunohistochemical staining were performed to detect recanalization. Neovascularization was detected by immunohistochemical staining using the antibody for von Willebrand factor (vWF), which is a component of endothelial cells. The capillary density was quantitatively determined by counting the capillaries under a high-power microscope. RESULTS: The Ad-VEGF165 was constructed, and bone-marrow-derived EPCs were cultivated and successfully identified. We determined the optimum transfection ratio that promoted the growth of EPCs. After transfection, the EPCs secreted the VEGF protein. After transplantation, the in vivo survival of EPCs and their differentiation into endothelial cells were determined by detecting the fluorescence associated with the Dil stain. VEGF mRNA was expressed in groups A, B, C and D after transplantation, and the VEGF mRNA level in group A was significantly higher than those in groups B, C and D (P < 0.05); the VEGF mRNA levels in groups B and C were significantly higher than those in group D (P < 0.05), and there was no statistical significance between the VEGF mRNA levels in groups B and C. The recanalization capillary density in group A was significantly higher than those in groups B, C (P < 0.05) and D (P < 0.01); the recanalization capillary densities in groups B and C were significantly higher than that in group D (P < 0.05). Moreover, there was no statistical significant difference between the values for groups B and C. CONCLUSIONS: The EPCs were successfully transfected by Ad-VEGF165. A suitable transfection ratio can improve the efficiency of EPCs and the possibility of promotion of angiogenesis after transplantation. Transfected EPCs caused accelerated organization and recanalization of vein thrombi. PMID- 20193490 TI - Effect of gingerol on substance P and NK1 receptor expression in a vomiting model of mink. AB - BACKGROUND: Gingerol is the generic term for pungent constituents in ginger, which has been reported to be effective for inhibiting vomiting. We attempted to investigate the antiemetic effect of gingerol and its effective mechanism on substance P and NK(1) receptors in minks. METHODS: The antiemetic effect of gingerol was investigated during a 6-hour observation on a vomiting model in minks induced by cisplatin, (7.5 mg/kg, intraperitoneal). The distribution of substance P and NK(1) receptors in the area postrema and ileum were measured by immunohistochemistry, and the expression of NK(1) receptor in the area postrema and ileum were measured by Western blotting. RESULTS: The frequency of cisplatin induced retching and vomiting was significantly reduced by pretreatment with gingerol in a dose-dependent manner (P < 0.05). Substance P-immunoreactive was mainly situated in the mucosa and submucosa of the ileum as well as in the neurons of the area postrema. The immunoreactive production of NK(1) receptor was mainly situated in the muscular and submucosa of ileum and the neurons of area postrema, gingerol markedly suppressed the increased immunoreactivity of substance P and NK(1)1 receptor induced by cisplatin in a dose-dependent manner (P < 0.05), and exhibited effective inhibition on the increased expression levels of NK(1) receptor in both the ileum and area postrema dose-dependently (P < 0.05). CONCLUSIONS: Gingerol has good activity against cisplatin-induced emesis in minks possibly by inhibiting central or peripheral increase of substance P and NK(1) receptors. PMID- 20193491 TI - Recent research on venous thromboembolism in China: a brief report from China Venous Thromboembolism Study Group. PMID- 20193492 TI - Basic and clinical research into chronic obstructive pulmonary. PMID- 20193493 TI - Uncommon features of pulmonary Langerhans' cell histiocytosis: analysis of 11 cases and a review of the literature. PMID- 20193494 TI - Isoniazid-induced rhabdomyolysis in a patient with chronic heart failure: a case report. PMID- 20193495 TI - Gefitinib-induced disseminated intravascular coagulation in a patient with non small cell lung cancer. PMID- 20193496 TI - Images for diagnosis. Broncholithiasis-induced bronchial artery fistula and pulmonary artery fistula in an aged female: a case report. PMID- 20193497 TI - Images for diagnosis. An unusual case of Carney triad with high level catecholamine-secreting but no existence of extra-adrenal paraganglioma. PMID- 20193498 TI - [The relationship between percentage body fat, waist-hip ratio and cardiovascular function in the adult females of Heilongjiang province]. AB - OBJECTIVE: To analyze the relationship between body fat mass and distribution and cardiovascular function in the adult females of Heilongjiang province. METHODS: Based on the statistic variable random sampling principal, we selected 1903 healthy adult females with ages of 18 - 70 years old in Heilongjiang province to conduct the study. The height, body weight, waist, chest measurement and waist hip ratio (WHR) were measured. Body components quota including fat weight, lean weight, percentage of body fat (PBF) were taken respectively; systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), cardiac output (CO), cardiac index (CI), stroke volume (SV), stroke index (SI), left cardiac work (LCW) and systemic vascular resistance (SVR) were determined. RESULTS: The PBF and WHR increased with aging, and the PBF of those with ages of 18-, 30-, 40 , 50- and 60 - 70 year's old were (16.86 +/- 5.37)%, (18.43 +/- 4.89)%, (20.99 +/ 5.79)%, (23.47 +/- 5.74)% and (25.77 +/- 6.38)%, respectively (F = 154.46, P < 0.01); and the WHR were 0.77 +/- 0.05, 0.80 +/- 0.05, 0.83 +/- 0.05, 0.85 +/- 0.06 and 0.89 +/- 0.07, respectively (F = 229.84, P < 0.01). The HR, CO, CI, SBP, DBP and LCW were (75.45 +/- 0.35) bpm, (4.42 +/- 0.02) L/min, (2.78 +/- 0.01) L * min(-1) * m(-2), (114.94 +/- 0.40) mm Hg (1 mm Hg = 0.133 kPa), (64.90 +/- 0.28) mm Hg, (4.57 +/- 0.03) kg * m/m(2) respectively in normal PBF groups; whereas the HR, CO, CI, SBP, DBP and LCW in the PBF obesity groups were (77.42 +/- 0.88) bpm, (4.54 +/- 0.05) L/min, (2.88 +/- 0.03) L * min(-1) * m(-2), (120.55 +/- 1.00) mm Hg, (66.56 +/- 0.71) mm Hg and (4.86 +/- 0.07) kg * m/m(2), respectively, F values were 3.182, 9.173, 8.478, 13.497, 2.637, and 10.631, respectively (all P values < 0.05) after the adjustment of age, height and weight, PBF was positively correlated with HR, CO, CI, SI, SBP, DBP and LCW (r values were 0.06, 0.11, 0.10, 0.11 and 0.12, respectively, all P values < 0.05); WHR was positively correlated with CI, SI, SBP, DBP, LCW and SVR (r values were 0.14, 014, 0.19, 0.18, 0.10 and 0.12, respectively, all P values < 0.01) after the adjustment of age, height and weight. CONCLUSION: PBF augmentation and abdominal obesity in females can result in cardiac dysfunction such as cardiac overload, CO increasing and blood pressure rising. PMID- 20193499 TI - [Comparison of the dietary phytosterols intake and serum lipids content in elderly women from three cities of China]. AB - OBJECTIVE: To investigate the dietary phytosterol intake of elderly women in three different cities of China, and to compare the main dietary sources, so that to discuss the relationship of dietary phytosterol intake and serum lipids. METHODS: Based on the dietary pattern, women more than 50 years old from Beijing, Hefei and Urumchi were chosen as testers, 80 - 100 people for each city respectively. The dietary survey was done by continues 24 hours review of two days, the plant food were collected and the phytosterol content (include beta sitosterol, campesterol, stigmasterol, sitostanol) were analyzed by GC methods, the total phytosterols content were calculated. The dietary phytosterol intake were calculated and serum lipids were also analyzed in all the testers. RESULTS: Testers from Beijing, Hefei and Urumchi were 100, 101 and 84 respectively. The average dietary phytosterol intake of people in Beijing and Hefei were 340.3 mg/d and 313.5 mg/d, the main sources were plant oil and cereals, while the average dietary phytosterol intake of people in Urumchi were 550.4 mg/d, higher than the other two cities (t values were 9.369, 10.420, respectively, both P values < 0.01), the main source in Urumchi was cereal (provide 53.1% of the total phytosterol intake). The laboratory results showed, testers in Urumchi had significantly lower serum TC content ((4.04 +/- 0.78) mmol/L) than that in Beijing ((4.89 +/- 0.91) mmol/L) and Hefei ((4.71 +/- 0.83) mmol/L) (t value were 6.766 and 5.401 respectively, both P values < 0.01); serum TG content in Urumchi((1.01 +/- 0.48) mmol/L) was also lower than that in Beijing ((1.31 +/- 0.53) mmol/L) and Hefei ((1.66 +/- 0.75) mmol/L) (t values were 3.343 and 7.293 respectively, both P values < 0.01); the serum glucose is also lower in testers in Urumchi ((5.02 +/- 2.18) mmol/L) compared with testers in Beijing ((5.69 +/- 1.53) mmol/L, t = 2.561, P < 0.05) and Hefei ((5.78 +/- 1.53) mmol/L, t = 2.934, P < 0.01). CONCLUSION: Different dietary pattern result in significantly different dietary phytosterol intake in elder women in three cities, higher, phytosterol intake seemed to contribute to lower serum lipids. PMID- 20193500 TI - [Effects of lycopene on blood lipid and red blood cell of rat with hypercholesterolemia]. AB - OBJECTIVE: To study the effect of lycopene on red blood cell and the level of blood lipid. METHODS: According to the level of serum total cholesterol and weight, forty-eight adult male SD rats were divided randomly into six groups: normal control (group A), fed by normal feed; hyperlipidemia group (group B): fed by high fat diet; positive control group (group C): fed by high fat diet plus 10 mg * kg(-1) * d(-1) fluvastatin sodium; lycopene groups: fed by high fat diet plus 11 (group D), 22 (group E), 44 mg * kg(-1) * d(-1) (group F) lycopene through gavage, respectively. For all six groups, the level of serum total cholesterol (TC) and total triglyceride (TG) were measured at the end of 0, 1, 3 weeks of the study by taking samples from tail vein. At the end of the experiment, RBC and HGB were measured. RESULTS: After the rats were fed with high fat feed for a week, models of hyperlipidemia rats were established. At the end of 3 weeks, TC of group A, B, C, D, E and F were (1.31 +/- 0.05), (19.40 +/- 0.54), (4.66 +/- 0.07), (7.18 +/- 0.06), (5.30 +/- 0.28), (4.49 +/- 0.23) mmol/L (F = 4395.72, P = 0.00), respectively;and TG were (0.42 +/- 0.01), (2.29 +/- 0.42), (0.69 +/- 0.03), (1.10 +/- 0.05), (0.63 +/- 0.02), (0.62 +/- 0.04) mmol/L (F = 127.26, P = 0.00), respectively; HGB were (143.13 +/- 6.33), (112.63 +/- 2.56), (124.75 +/- 3.62), (124.63 +/- 7.78), (132.38 +/- 6.41), (142.13 +/- 5.54) g/L (F = 34.14, P = 0.00), respectively; RBC were (6.75 +/- 0.60) x 10(12)/L, (5.08 +/- 0.75) x 10(12)/L, (7.14 +/- 0.82) x 10(12)/L, (5.94 +/- 1.09) x 10(12)/L, (6.18 +/- 0.36) x 10(12)/L and (7.31 +/- 0.58) x 10(12)/L (F = 10.35, P = 0.00), respectively. CONCLUSION: Lycopene have some protective effects on red blood cells of the hyperlipidemic rats by regulating the blood lipid and antioxidant. PMID- 20193501 TI - [The prevalence and onset of age of stroke in Chinese adults]. AB - OBJECTIVE: To analyze the prevalence and onset of age of stroke in Chinese adults aged 35 years old and above. METHODS: Data from the 2002 National Nutrition and Health Survey was used to analyze the prevalence of stroke by age, sex, regions, and the differences of onset of age of stroke among the alive patients. RESULT: Standardized prevalence of stroke in Chinese adults aged 35 years old and above was 1111.5 per 100,000, 1258.9 per 100,000 in male which was higher than female (959.3 per 100,000). The prevalence of stroke in urban (1544.8 per 100.000) was higher than that in rural (758.1 per 100,000). The standardized prevalence of stroke in the north (1479.3 per 100,000) was significantly higher than that in the south (719.6 per 100,000). The standardized prevalence of stroke in eastern, central and western region was 1469.0 per 100,000, 1085.4 per 100,000, 614.9 per 100,000, respectively. It is estimated that there were 5.627 million patients with stroke aged 35 years old and above in China in 2002. The age at onset of stroke in the alive patients was skewed distribution. Median was 60 years old. The first incidence of stroke within 60-age group accounted for 32.4%. The age at onset of stroke was no significantly different between male (60 years old, chi(2) = 0.00, P > 0.05) and female (60 years old). The median of the age at onset of stroke (61 years old) in urban was higher than that in rural (58 years old, chi(2) = 17.34, P < 0.01). The median in eastern region was higher than that in central and western regions (57 years old, chi(2) = 12.92, P < 0.01). CONCLUSION: The prevalence of stroke was significant different by sex and regions. Among the alive patients, more than half of their first incidence of stroke were before the age of sixties. PMID- 20193502 TI - [The trend of national advanced maternal age woman proportion in hospital-based surveillance]. AB - OBJECTIVE: To investigate the secular trend of advanced maternal age woman (>or= 35 year-old) in our country. METHODS: Data on maternal woman at different age were collected at surveillance hospital in Chinese Birth Defects Monitoring Network from 1996 to 2007 and retrospective analysis of the trend of advanced maternal women were carried out. Trend analysis of the advanced maternal age in urban and rural areas of west, middle and east areas was also conducted. Chi square test was applied to test the differences and the fitting model analysis was also applied. RESULTS: A total of 6,308,594 parturient woman were monitored, included 354,511 woman (5.62%) of advanced maternal age. In 1996 and 2007, the proportion of the advanced maternal woman were 2.96% (12,508/422,486) and 8.56% (66,351/775,333), respectively. It showed an increasing trend for the national woman proportion of advanced maternal age from 1996 to 2007 (chi(2) = 45 376.16, P < 0.01). In city, the proportion of advanced maternal age woman were 2.95% (8755/296,975) and 7.69% (40,197/522,596) in 1996 and 2007, respectively. In rural region, the proportion of advanced maternal age woman were 2.99% (3753/125,511) and 10.35% (26,154/252,737) in 1996 and 2007, respectively. It showed increasing both in city and rural areas (chi(2)(city) = 24,152.86, P < 0.01; chi(2)(rural) = 20,809.79, P < 0.01). And the proportions in urban area and rural area were 5.13% (221,655/4,317,533) and 6.67% (132,856/1,991,061), the proportions difference was significant in statistics (chi(2) = 1536.260, P < 0.01). An Exponential model was established, ln(Y) = ln(2.52) + (0.103 x t). In east areas, the proportion were 3.90%and 8.81% in 1996 and 2007, respectively, in middle areas the respective proportions were 2.49% and 8.56%, in west areas were 2.11% and 8.21%. They all showed increasing trend in proportion of advanced maternal age from 1996 to 2007 year in east areas, middle areas and west areas (chi(2)(east) = 11,746.87, P < 0.01; chi(2)(middle) = 17,350.21, P < 0.01; chi(2)(west) = 16,432.68, P < 0.01). But the proportions of city and rural were different in those areas. CONCLUSION: The proportion of advanced maternal woman had secular increasing trend and the rates were lower in city than in rural areas. PMID- 20193503 TI - [The differences in bone mineral content between female dancers and controls aged 15 - 17 years old and its relationship with physical activity level]. AB - OBJECTIVE: To assess bone mineral content (BMC) of 15 - 17 year-old dancers and high school females and analyze the relationship between physical activity status and BMC. METHODS: Sixty dancers and 77 healthy controls aged 15 - 17 years old were enrolled in our study. BMC in the total body and forearm were measured by dual-energy X-ray absorptiometry (DEXA) while body weight and height were also measured. Physical activity information was collected by "one-year physical activity questionnaire". RESULTS: The physical activity level (PAL) and the average daily energy expenditure (EE) of dancers were all higher than controls (PAL: 2.17 +/- 0.34 vs 1.63 +/- 0.34, t = 7.283; EE: (6876.43 +/- 1036.72) kJ vs (5388.43 +/- 920.83) kJ, t = 7.214, both P values < 0.01). The dancers showed lower BMC/height at total body and arms compared with the controls (the total body BMC/height was (13.896 +/- 1.308) vs (14.494 +/- 1.272) g/cm, F = -2.563); and the BMC/height of left and right arm were (0.779 +/- 0.088) vs (0.829 +/- 0.101) g/cm (F = -2.892) and (0.766 +/- 0.093) vs (0.829 +/- 0.097) g/cm (F = 3.650) respectively, all these P values were < 0.01.Yet after adjusting age and BMI, the dancers showed higher BMC/height at total body and legs, the corresponding values were (14.550 +/- 0.146) vs (13.947 +/- 0.131) g/cm (F = 7.868), (2.681 +/- 0.033) vs (2.389 +/- 0.030) g/cm (F = 36.520), (2.821 +/- 0.031) vs (2.450 +/- 0.028) g/cm (F = 65.279), all these P values were < 0.01. While no differences were found with controls at non-weight bearing sites (arms). Daily period (h) of training was significantly related to BMC/height of legs, total body (r value were 0.618, 0.448 and 0.554 respectively, all the P values < 0.01), while the history of training was also correlated with BMC/height of two legs (r value were 0.38 and 0.304 respectively, both P values < 0.05). CONCLUSION: The adolescent dancers showed higher BMC after adjusting age and BMI, which was attributed to the long-term high level weight-bearing physical activity. PMID- 20193504 TI - [Neurotoxicity of beta-amyloid peptide 31-35 and 25-35 to cultured rat cortical neurons]. AB - OBJECTIVE: To compare the toxicity of mechanism beta amyloid peptide (Abeta) 25 35 and 31-35 to cultured rat cortical neurons. METHODS: The primary rat cerebral cortical neurons of rat were cultured 48 hours and randomly divided into control, Abeta25-35 (25 micromol/L)and Abeta31-35 (25 micromol/L) treated groups. After twenty four hours culturing, the cells were collected MTT assay was performed to measure the viability of cultured neurons. The mitochondrial membrane potential was determined to investigate the alteration of mitochondrial structure and function of neurons by laser scanning confocal microscope. The DNA damage of neurons was measured by single cell gel electrophoresis. The expressions of Bcl 2, Bax and p53 gene were measured by reverse transcriptase polymerase chain reaction (RT-PCR). Each experiment was repeated three times. RESULTS: The absorbance (0.746 +/- 0.071, 0.811 +/- 0.083) and fluorescence intensity (3.050 +/- 0.240, 2.806 +/- 0.203) of neurons in Abeta25-35 and 31-35 treated group were significantly lower (t(A) were 4.023 and 5.401, t(fluorescence intensity) were 9.524 and 7.589 respectively, P < 0.01) than those in control group (1.038 +/- 0.125 and 4.280 +/- 0.358 respectively). The percentage of comet cells (59.0%, 48.5%) and tail length (57.3 +/- 4.7, 54.2 +/- 6.8) microm in Abeta25-35 and 31 35 treated group were significantly higher (chi(2)(comet cell) were 99.397 and 137.071, t(tail length) were 19.058 and 29.173 respectively, P < 0.01) than those in control group (4.5% and (5.2 +/- 1.1) microm respectively). Compared with control group (Bax/Bcl-2 ratio 0.2090 +/- 0.0991, p53/beta-actin ratio 1.6560 +/- 0.0853), the Bax/Bcl-2 ratio (t value were 2.429 and 2.356 respectively, P < 0.05) and expressions of p53 (t value were 2.366 and 2.503 respectively, P < 0.05) gene were significantly increased (P < 0.05) in Abeta25-35 (Bax/Bcl-2 ratio 1.2774 +/- 0.0762, p53/beta-actin ratio 2.0284 +/- 0.2223) and Abeta31-35 (Bax/Bcl-2 ratio 1.0330 +/- 0.0683, p53/beta-actin ratio 1.9505 +/- 0.2725) treated group. CONCLUSIONS: Neurotoxicity-induced by Abeta31-35 in cortical neurons is similar to that induced by Abeta25-35, which is possibly related to its direct neurotoxic and apoptotic effects to neurons. PMID- 20193505 TI - [Investigation on arboviruses at Sino-Vietnam border areas in Wenshan of Yunnan province]. AB - OBJECTIVE: To investigate arboviruses in Wenshan and Hekou county which are the Sino-Vietnam frontier regions of Wenshan, Yunnan province, China. METHODS: In September 2007, 6091 Culicines, 1334 Anophelines, 848 Aedes vexans and 53 Armigeres obturbans were collected from 5 field sites. Mosquitoes were collected and stored in liquid nitrogen after classification. The mosquito pools were homogenized, and centrifuged, then the supematant was inoculated onto C6/36 and BHK-21 cells, and the viral isolates were identified by serological and molecular biological methods.Sequence alignment and phylogenetic analysis on the viral isolates were carried out using Clustal X 1.85, GENEDOC and MEGA4 software. RESULTS: A total of 4 pairs of virus isolated with C6/36 cells cytopathic effect were observed, and other mosquito species have not cytopathic effect.Strain WS0704-2 was Banna virus which identified by antibody response and PCR. Strain WS0704-1, WS0708-1, WS0708-2 were Culex pipens pallens densovirus (CppDNV) which identified by PCR. The phylogenetic analysis the 12th segment showed significant difference between the new Banna virus and other strains isolated in China. CONCLUSION: There are many mosquito vectors in frontier regions (China and Vietnam) of Wenshan in Yunnan province of China, and mosquito-borne arbovirus, such as BAV were isolated here. PMID- 20193506 TI - [A retrospective cohort study on reduction of AIDS mortality among patients enrolled in national-free antiretroviral treatment programme in two cities in China]. AB - OBJECTIVE: To determine the effect of national free highly active antiretroviral treatment (HAART) on reduction of mortality and relevant risk factors among adult Acquired immunodeficiency syndrome (AIDS) patients. METHODS: A retrospective cohort study was conducted and all AIDS patients diagnosed before Aug. 30th, 2008 in Zhumadian, Henan province, and Fuyang, Anhui province were enrolled in this study, where HAART initiated in early time. The data and information were collected such as AIDS progress, diagnosis, treatment, death and et al. RESULTS: Among 10,394 AIDS patients, the mean age was (41.7 +/- 9.3) year-old, 50.3% (5233/10,394) were male, 85.0% (8808/10,394) were married, 95.1% (9880/10,394) were farmers, and 81.2% (8438/10,394) were former plasma donors (FPDs). The coverage of HAART increased from 5.2% in 2002 to 66.5% in 2008. Conversely, the overall mortality declined from 35.4/100 person-years in 2002 to 5.9/100 person years in 2008. In a multivariate Cox proportional hazards analysis, the greatest risk factor for mortality was non-HAART, with a hazard ratio (HR) 4.3 (95%CI: 4.0 - 4.7). Among treated patients, compared with higher CD(4)(+) T cell counts (> 200 cells/microl), those initiating therapy with lower CD(4)(+) T cell counts, were at greater risk to death (< 50 cells/microl, HR = 7.9; 50 - 199 cells/microl, HR = 2.8). Number of opportunistic infections (OIs) was risk to mortality (HR = 2.1). In addition, other risk factors included male, age (>or= 50 years old), and other infection way except FPDs (HR were 1.4, 1.6 and 1.8). CONCLUSION: The national free treatment program has significantly reduced the AIDS mortality rate among HIV-infected FPDs through the use of generic antiretroviral drugs in rural clinical settings. The effective reduction of AIDS mortality could be realized through increased coverage of therapy. PMID- 20193507 TI - [Detection of HIV incidence using BED capture enzyme immunoassay at a surveillance sentinel site of injection drug users in Guangxi]. AB - OBJECTIVE: To detect recent HIV incidence of injection drug users (IDU) from a surveillance site of IDU in Guangxi and estimate HIV incidence. METHODS: 787 Samples from a IDU surveillance sentinel site in Guangxi (2005 - 2007) were collected for ELISA and 168 were HIV-1 positive; then 168 HIV-1 positive samples were detected by BED capture enzyme immunoassay (BED-CEIA) and 17 were positive. RESULTS: A total of 787 samples were tested and 168 were HIV-1 positive and 17 were BED-CEIA positive. The prevalence rates of the IDU surveillance sentinel site were 23.06% (92/399), 21.90% (46/210) and 16.85% (30/178), and the incidence rates were 7.41% (10/135), 6.94% (5/72) and 3.12% (2/64) respectively from 2005 to 2007. CONCLUSION: The incidence rate of HIV infections of IDU from a surveillance site of IDU in Guangxi appeared to decline slowly in recent years, and some might have been infected for long time. PMID- 20193508 TI - [Period survival analysis of esophageal cancer in Linzhou city of Henan province]. AB - OBJECTIVE: To analyze the survival level and variation of esophageal cancer in Linzhou city of Henan province from 1988 to 2004, and evaluate the effects of diagnosis and treatments on esophageal cancer in this area. METHODS: All incidence and death records for esophageal cancer during 1988 to 2004 were collected from Linzhou Tumor Registry. Cases with duplicate information or death certificate only were excluded. A total of 12,160 cases of esophageal cancer were collected, of which, 6914 cases were male, and 5246 cases were female. The sex specific and age-specific probabilities of survival in 1992, 1997 and 2002 were calculated and linked to the data of incidence and death on esophageal cancer in this area. Five-year observed survival rate and five-year relative survival rate during 1990 to 1994, 1995 to 1999, 2000 to 2004 were calculated respectively using period survival analysis and cohort survival analysis and Z test. RESULTS: The 5-year relative survival rates among the three-episode were 28.24%, 35.24% and 40.76% respectively during 1988 to 2004. This showed an increasing trend by periods (Z values were 3.94 and 3.07, P < 0.05). The 5-year observed survival rates in men among the three-episode were 13.67%, 18.08% and 22.46% respectively, the 5-year relative survival rates were 29.94%, 36.96% and 38.40%. The 5-year observed survival rates in women among the three-episode were 15.56%, 19.29% and 28.01% respectively, the 5-year relative survival rates were 26.78%, 33.12% and 43.70%. During the two former periods, there was no significant difference in the 5-year observed survival rate and relative survival rate between men and women (Z values of observed survival rate were 1.48 and 0.88, P > 0.05. Z values of relative survival rate were 1.27 and 1.50, P > 0.05). In the third period, the 5 year observed survival rate and relative survival rate in women was higher than that in men (observed survival rate Z = 3.56, P < 0.05; relative survival rate Z = 2.09, P < 0.05). The relative survival rate that calculated using period method (respectively 35.24% and 40.76%) was higher than that using cohort method (respectively 28.77% and 33.35%) from 1995 to 1999, and from 2000 to 2004. CONCLUSION: The survival rate on esophageal cancer in Linzhou city was increasing in the three different periods. This indicated a rising status in the secondary prevention and clinical diagnosis and treatments on esophageal cancer. PMID- 20193510 TI - [Improving the staging of chronic kidney disease for better early prevention.]. PMID- 20193509 TI - [A multilevel cross-sectional study of mental disorder in community settings in Zhejiang Province]. AB - OBJECTIVE: To investigate the prevalence of mental disorder through the 12-item general health questionnaire (GHQ-12) survey and its related factors in community settings in Zhejiang Province. METHODS: A muti-level model was analyzed using data of 14,632 respondents nested in counties (cities), townships (urban districts), villages (urban neighborhoods) from the epidemiological survey of mental illnesses above 15 years old. RESULTS: The mean score measured by GHQ-12 was (1.54 +/- 2.15), which was lower than that of samples from four cities of Guangzhou, Chongqing, Taiyuan and Hangzhou (U = 11.08, P < 0.01). The mental disorder clustered within county (city) level, which represented 4.3% (chi(2) = 3.94, P < 0.05) of the total variance including four levels. After controlling for the county level, the mental disorder was associated with age, marital status, residency patterns, education, occupation and household incoming. In particular, it was reported that higher household incoming was significantly associated with better mental disorder among population in community settings. CONCLUSION: The prevalence of mental disorder clustered at the county (city) level is relatively lower with vulnerable groups including divorced, widowed, unemployed, retired, lower-income ones in community settings in Zhejiang Province. PMID- 20193511 TI - [Why we misdiagnose?]. PMID- 20193512 TI - [Controversies on the current diagnostic standard of chronic kidney disease.]. PMID- 20193513 TI - [Diagnosis and staging of chronic kidney disease: steady evidence-based advancement and prudent critique.]. PMID- 20193514 TI - [The effects of strict dietary salt restriction on blood pressure and proteinuria in chronic glomerulonephritis patients.]. AB - OBJECTIVE: To evaluate the effects of strict dietary salt restriction on blood pressure and proteinuria in chronic glomerulonephritis (CGN) patients. METHODS: From October 2007 to April 2009, 32 CGN inpatients were enrolled. Among them, 15 patients followed a strict dietary salt restriction menu (sodium 100 mmol/d, potassium 50 mmol/d, protein (0.8 - 1.0) gxkg(-1)xd(-1), calorie (105 - 125) kJxkg(-1)xd(-1)) for 7 days, while the other 17 patients were fed freely offered by hospital as controls. 24 h urinary sodium excretion (24h-UNa) was used to monitor the salt intake. No changes of drug therapy were made during the study. Blood pressure was monitored every day. 24-hour urinary protein and serum biochemical parameter were measured before and after the study. RESULTS: There was no significant difference of baseline 24h-UNa between the two groups [(135.1 +/- 50.4) mmol/d vs (137.4 +/- 28.6) mmol/d)]. During the study, the average 24h UNa of patients with strict dietary intervention was (97.2 +/- 8.6) mmol/d. Both SBP [(117.7 +/- 10.0) mm Hg (1 mm Hg = 0.133 kPa) vs (106.2 +/- 9.9) mm Hg] and DBP [(76.3 +/- 6.1) mm Hg vs (67.5 +/- 5.5) mm Hg] decreased significantly (P < 0.001). Proteinuria decreased significantly too [1.57 (0.3 - 3.0) g/d vs 0.57 (0.16 - 2.72) g/d, P = 0.006]. The reduction of SBP was positively correlated with the reduction of 24h-UNa (r = 0.572, P = 0.026), while the reduction of proteinuria correlated with both the reduction of SBP (r = 0.568, P = 0.027) and 24h-UNa (r = 0.525, P = 0.044). In the control group, only SBP decreased significantly [(122.6 +/- 15.5) mm Hg vs (115.8 +/- 10.4) mm Hg, P = 0.02] without significant changes of DBP and proteinuria. When comparing the subgroups who took ACEI/ARB from both groups, the reduction of proteinuria was more prominent of those from the study group than the control group [-0.4(-0.95 - 0.07) vs 0.07(-0.39 - 0.42), P = 0.014]. CONCLUSION: Strict dietary salt restriction is effective in reducing blood pressure and proteinuria in CGN patients. PMID- 20193515 TI - [The relationship between insulin resistance and left ventricular hypertrophy in patients with early chronic kidney disease.]. AB - OBJECTIVE: To analyze the relationship between insulin resistance (IR) and left ventricular hypertrophy (LVH) in patients with early chronic kidney disease (CKD). METHODS: Homeostatic model method was used for detecting insulin resistance index (Homa-IR) in 108 patients with early CKD and 25 normal healthy cases, and the other clinical data such as Hb, creatinine clearance rate (Ccr), parathyroid hormone (PTH), ambulatory blood pressure monitoring (ABPM) data, including day average systolic blood pressure (dSBP), day average diastolic blood pressure (dDBP), night average systolic blood pressure (nSBP), night average diastolic blood pressure (nDBP), 24-hour mean systolic blood pressure (mSBP), 24 hour mean diastolic blood pressure (mDBP), decline in the percentage of diastolic blood pressure at night (nDPD) and decline in the percentage of systolic blood pressure at night (nDPS) were also measured. Echocardiography was used for measuring LVH relevant data, and left ventricular mass index (LVMI) was calculated. Then, the relationship between LVH and IR and other clinical data were analyzed retrospectively. RESULTS: IR existed in early CKD patients. With the decline of Ccr, both the value of Homa-IR and the incidence of IR increased significantly (both P < 0.05). LVH existed in early CKD patients and with the decline of Ccr, both LVMI value and the incidence of LVH increased significantly (both P < 0.01). Compared with the non-IR group, the IR group had higher LVMI value (P < 0.05) and higher incidence of LVH (P < 0.01). Compared with the non LVH group, the LVH group had higher levels of FIns, 2hPG, Homa-IR (all P < 0.05), and higher incidence of IR (P < 0.01). The LVH group had significant lower levels of Ccr, Hb and nDPD (all P < 0.05), higher levels of dSBP, dDBP, nSBP, nDBP, mSBP, mDBP and PTH (all P < 0.05) than the non-LVH group. LVMI had significant positive correlations with 2hPG, FIns, Homa-IR, dSBP, nSBP, mSBP and PTH (r = 0.255, 0.373, 0.376, 0.222, 0.199, 0.225, 0.221, 0.246, respectively; all P < 0.05), but significant negative correlations with Hb and Ccr (r = -0.588, -0.313, respectively; both P < 0.01). Multi-factor regression analysis showed that Hb, Homa-IR, and Ccr entered the regression equation (y = 167.106 - 0.755x(1)+0.250x(2)+0.322x(3), y = LVMI; 167.106 = constant, t = 12.138, P = 0.000; x(1) = Hb, t = -6.800, P = 0.000; x(2) = Homa-IR, t = 3.229, P = 0.002; x(3) = Ccr, t = 2.898, P = 0.005). CONCLUSION: IR existed in early CKD patients and become more severe with the decline of renal function. IR had a significant correlation with LVH, and it may be an important risk factor for the development of LVH. Besides, both anemia and decline of renal function are also associated with LVH. PMID- 20193516 TI - [Epidemiology of Helicobacter pylori infection in Shandong and Beijing areas.]. AB - OBJECTIVES: To study the current prevalence and recent epidemiological changes of Helicobacter pylori (H. pylori) infection among children and adults residing in regions with high (Muping, Shandong) and low (Yanqing, Beijing) incidence of gastric cancer in China. METHODS: A total of 2065 asymptomatic children aged 8 - 15 years and adults aged 40 - 79 years in the above two regions were examined from May to July 2006. The data obtained in early 1990s in the same two areas and those of 11 656 patients undergoing endoscopy in our hospital in 1991 and 2006 were also collected and studied. RESULTS: The prevalence of H. pylori infection in Muping was significantly higher than that in Yanqing among both children (37.69% vs 25.58%, P < 0.001) and adults (50.95% vs 41.35%, P < 0.01). From 1991 to 2006 H. pylori prevalence among children aged 8 - 10 years decreased in Muping (60.00% vs 32.07%, P < 0.001), but not in Yanqing (24.06% vs 19.10%, P > 0.05). A significant decrease in H. pylori prevalence among adults in both regions was observed when the results of 2006 were compared with the data obtained in 1990 in Muping (50.95% vs 73.78%, P < 0.001) and in 1992 in Yanqing (41.35% vs 55.35%, P < 0.01). The detected rate of H. pylori infection in patients undergoing endoscopy in our hospital decreased from 51.88% in 1991 to 33.59% in 2006 (P < 0.001). CONCLUSIONS: The prevalence of H. pylori infection is significantly higher in areas with a high incidence of gastric cancer in China as compared with that in areas with a low incidence of gastric cancer among both children and adults. H. pylori infection may be a risk factor in gastric carcinogenesis. In the past decade or more, H. pylori infection rates have decreased in Chinese population. PMID- 20193517 TI - [The effect of different dosage of aspirin on inflammatory biomarkers and prognosis in acute coronary syndrome.]. AB - OBJECTIVE: To observe and assess the effect of different dosages of aspirin on inflammatory biomarkers, hemorheology (platelet aggregation rate) and clinical prognosis in patients with acute coronary syndrome (ACS). METHODS: ACS patients were randomly assigned to receive different dosages of aspirin treatment orally. Patients in group A, B and C took 100 mg, 500 mg and 1000 mg of aspirin per day respectively. They were treated and followed-up for 1 year. High-sensitivity C reactive protein (hsCRP), IL-6, tumor necrosis TNFalpha and platelet aggregation rate were examined and major adverse cardiac events (MACE) were recorded. RESULTS: A total of 312 patients with ACS were enrolled in the study. The baseline characteristics of the three groups were not different with respect to age, gender, cardiovascular risk profile, level of inflammatory biomarkers and concomitant treatment before and after randomization. The levels of baseline serum hsCRP, IL-6 and TNFalpha were higher in subjects of the study as compared with normal reference value (P < 0.05, < 0.05, < 0.01) and they decreased significantly after therapy with 3 different doses of aspirin (detected at 30 days, 6 months and 12 months, P < 0.001), but there were no significant differences among the three groups (P > 0.05). Rehospitalization, MACE and the change of platelet aggregation ratio were not significantly different among the three groups. The incidence of gastrointestinal complaints was significantly higher in groups B and C than in group A (P < 0.05). CONCLUSIONS: The levels of serum inflammatory biomarker increase in patients with ACS. Aspirin therapy may decrease the level of inflammatory markers significantly, but increasing the dosage of aspirin from 100 mg to 1000 mg daily does not decrease the level of inflammatory markers and the clinical MACEs further. However, the incidence of gastrointestinal complaints increase significantly with the increase of aspirin dosage. PMID- 20193518 TI - [Prognostic value of adenosine triphosphate myocardial perfusion tomography in octogenarians.]. AB - OBJECTIVE: To evaluate the prognostic value of (99m)Tc-MIBI myocardial perfusion single-photon emission computed tomography (MPS) with adenosine triphosphate in patients aged 80 years or older. METHODS: A total of 265 patients [mean age (84.2 +/- 3.6) years old] who underwent adenosine triphosphate and rest (99m)Tc-MIBI myocardial SPECT imaging were followed-up for (36.7 +/- 22.8) months. RESULTS: During the period of follow-up, 57 patients (20.4%) suffered from cardiac events, including 20 major events: 5 cardiac death and 15 acute non-fatal myocardial infarction, 14 unstable angina pectoris, 7 heart failure and 16 cases undergoing PCI. The cardiac event rate in patients with fixed or mixed perfusion defects (n = 54) was 50%, which was significantly higher than that in patients with reversible perfusion defects (n = 67, 31.3%, P < 0.05) and normal perfusion imaging (n = 144, 6.2%, P < 0.01). The major cardiac event rate in patients with fixed or mixed perfusion defects was 27.8%, which was significantly higher than that in those with reversible perfusion defects (6.0%, P < 0.05) and normal perfusion imaging (0.7%, P < 0.01). Cox multivariate analysis revealed that an abnormal MPS was the most important independent predictor of major or total cardiac events. CONCLUSIONS: (99m)Tc-MIBI MPS with ATP is demonstrated to be a powerful tool for the prognostic evaluation in octogenarian population. Octogenarians with a normal MPS have a low risk of major or total cardiac events, but when an abnormal MPS is present, the risk is significantly higher, being highest in patients with fixed or mixed perfusion defects. PMID- 20193519 TI - [The risk factors for malnutrition in post-stroke patients.]. AB - OBJECTIVE: To investigate the detection rate of malnutrition among post-stroke patients in community hospitals and unravel the relevant factors that precipitate malnutrition after stroke. METHODS: Based on 438 post-stroke patients who were admitted in community hospitals, we examined the demographic characteristics, the nutritional indices and the possible malnutrition related factors through a cross sectional study. RESULTS: The detection rate of malnutrition among post-stroke patients was 52.7%. Group comparison through multivariate logistic regression analysis showed that there was a higher malnutrition detection rate in the post stroke patients with multiple stroke attacks (three stroke attackes and above, OR = 11.00, 95%CI 1.14 - 106.34), higher NIHSS scores (group with NIHSS >/= 15, OR = 7.09, 95%CI 2.90 - 17.36), higher modified Rankin scales (group mRS 4 - 5, OR = 15.77, 95%CI 6.61 - 37.59) (trend test P < 0.0001). The risk of malnutrition was also correlated with the post-stroke depression, poorer family care, no early stage rehabilitation, history of malignant tumors and severe alcoholism. CONCLUSIONS: There is a high detection rate of malnutrition among post-stroke patients in community hospitals. There are many factors related to malnutrition among post-stroke patients in the community. More attention to controllable influencing factors would improve the prognosis of post-stroke patients. PMID- 20193520 TI - [Clinical analysis of subcutaneous panniculitis-like T cell lymphoma misdiagnosed as rheumatic diseases: 8 cases report.]. AB - OBJECTIVE: To investigate the characteristics of subcutaneous panniculitis-like T cell lymphoma (SPTCL) in order to facilitate prompt identification and proper treatment of this rare and heterogeneous disease entity. METHODS: For 8 patients who had been misdiagnosed as rheumatic diseases but eventually confirmed as SPTCL though pathology and immunohistochemistry, a retrospective chart review was made with regard to their clinical symptoms, laboratory test results, pathological features, responses to therapy as well as outcomes. RESULTS: These 8 patients with a male to female ratio of 1:1 were initially misdiagnosed as a variety of rheumatic diseases such as erythema nodosa, nodular panniculitis, systemic vasculitis, etc. The period from the onset of symptoms to the confirmation of diagnosis as SPTCL was 28.6 months on average (range, 4 - 84 months). All the cases presented with multiple subcutaneous nodules, plaques or tumors which involved various anatomic sites including the head and neck, the trunk, and the extremities. Fever was the most frequently accompanying symptom (7/8), followed by lymphadenopathy (4/8), hepatomegaly (3/8), splenomegaly (3/8). Hemophagocytic phenomenon was seen in 3 cases. A total of 22 times of biopsy involving multiple anatomic sites were performed on these 8 cases with 2.75 times on average (range, 1 - 5 times). All cases demonstrated a dense lymphoid infiltrate with significant cellular heteromorphism located in the subcutaneous tissue. CD(3) was positive in the majority of the cases. Immunostaining for gammadeltaTCR was positive in one case. The anti-rheumatic therapy including steroids and immunosuppressants administered before the identification of SPTCL attained minimal therapeutic effect. In contrast, 6 cases gained partial response after chemotherapy except that the other 2 cases died of fatal pulmonary infiltration and subsequent infection. CONCLUSIONS: SPTCL is a rare and heterogeneous entity which is unseldomly misdiagnosed as rheumatic disease. The anti-rheumatic therapy including steroids and immunosuppressants can attain minimal therapeutic effect. Early identification by means of histology and immunohistochemistry as well as immunostaining for PCR is critical for proper treatment. PMID- 20193521 TI - [The effect of different intensity aerobic exercise training on blood pressure control in hypertensive patients.]. AB - OBJECTIVE: To compare the therapeutic effect of aerobic exercise training of different intensity on hypertension. METHODS: Sixty hypertensive patients were randomly allocated to 2 groups and treated with aerobic exercise training at 20% or 60% of maximal intensity. Not only were the relevant parameters of exercise capacity measured by the use of treadmill exercise test, but also was ambulatory blood pressure monitored and the quality of life recorded before and after the therapy. RESULTS: There was no significant difference of the decrement in any parameter of ambulatory blood pressure between the two groups (P > 0.05). There was a significant difference of the increment of general health, vitality, emotion and mentality between the two groups after treatment with group A better than group B (P < 0.05). CONCLUSIONS: Aerobic exercise training at 20% and 60% of the maximal intensity has similar ambulatory blood pressure, but the quality of life is significantly better after aerobic exercise training at 20% of the maximal intensity. PMID- 20193522 TI - [The clinical features and risk factors for invasive fungal infection in multiple myeloma.]. AB - OBJECTIVE: To study the clinical features and risk factors of invasive fungal infection (IFI) in multiple myeloma (MM). METHODS: Three hundred and fifty-seven cases of MM were retrospectively analyzed for IFI, clinical features, complicating diseases, treatment of fungus and side effect of anti-fungal drugs. RESULTS: Forty-four cases (12.3%) of IFI were diagnosed. Three of them were diagnosed definitely, 8 clinically and 33 probably. Ten cases incurred IFI in the induction therapy, 4 in platform, 27 in progress and 3 in the treatment with autologous stem cell transplantation. The lung was the commonest site of infection (50.0%). The total effective rates of amphotericin B liposome, voriconazole, itraconazole, caspofungin and fluconazol were 83.3%, 75.0%, 78.9%, 75.0% and 57.1% respectively (P = 0.493). In a multivariate analysis, independent factors significantly associated with IFI were diabetes (P = 0.035, OR 2.527, 95%CI 1.005 - 6.052), dialysis (P = 0.022, OR 2.768, 95%CI 1.161 - 6.600), persistent agranulocytosis (P = 0.019, OR 3.215, 95%CI 1.200 - 7.407), broad spectrum antibiotic therapy (P = 0.009, OR 3.350, 95%CI 1.353 - 8.295) and fludarabine treatment (P = 0.001, OR 4.669, 95%CI 1.813 - 12.023). CONCLUSIONS: Patients with MM are in high risk of IFI. The lung is the commonest site of infection. The therapeutic effect was similar with itraconazole, voriconazole, caspofungin and amphotericin B liposome in MM patients with complicating IFI. The risk factors for IFI in MM were diabetes, dialysis, persistent agranulocytosis and the use of broad-spectrum antibiotics and fludarabine. PMID- 20193523 TI - [A clinical analysis of HLA-identical hematopoietic stem cell transplantation for severe aplastic anemia.]. AB - OBJECTIVE: To study the outcome of HLA-identical hematopoietic stem cell transplantation (HSCT) for severe aplastic anemia (SAA). METHODS: Twenty patients diagnosed with SAA received allogeneic HSCT from HLA-identical donors (17 from siblings and 3 from unrelated donors) between January 2000 and November 2008. Conditioning regimen consisted of cyclophosphamide (Cy) and anti-thymocyte immunoglobulin (ATG). The patients were administrated with G-CSF-primed bone marrow(G-BM) and mobilized peripheral blood (G-PB) as grafts from the sibling donors or only G-PB from the unrelated donors. RESULTS: The median infused number of mononuclear cells and CD(34)(+) cells were 7.89 (4 - 14.21) x 10(8)/kg and 2.60 (0.81 - 4.45) x 10(6)/kg. All the patients got engraftment with 100% donor chimerism. The median time of neutrophil and platelet engraftment were 14 (11 - 20) d and 12 (8 - 108) d respectively. The cumulative incidence rate of acute GVHD at 100 d was 16% (grade I: 3 cases, grade II: 3 cases). Chronic GVHD occurred in 7 of the 19 evaluable cases (4 limited, 3 extensive). Till February 28, 2009, with a median follow-up of 18 months, 17 patients were alive and the overall survival rate was 82.5%. CONCLUSION: The study confirms that using G-PB with or without G-BM as graft after Cy+ATG conditioning results in excellent outcome of HLA-identical HSCT in patients with SAA. PMID- 20193524 TI - [The establishment of an animal model of gut-brain interaction in irritable bowel syndrome for the evaluation of visceral sensation, motility and psychological behavior.]. AB - OBJECTIVE: To develop a gut-brain interaction animal model of IBS which combines multiple factors including behavior, visceral sensation and motility. METHODS: Setting up a multifactor interactional animal model (chronic acute combining stress model, CACS) based on a chronic unpredictable mild stress model of depression (CUMS) while combined with wrap restraint stress (WRS), changes of some indexes were recorded including motility (granules of defecating, time of defecating), visceral sensitivity (spontaneous contraction of abdominal striated muscles) and behavior/mind (sucrose consumption, body weight). G protein subunits were measured by Western blot in both hippocampus and prefrontal cortex simultaneously. RESULTS: (1) Compared with the state before stress given, defecating granules increased, defecating time of glassie from rectum shorten, number of abdominal contraction increased, and sucrose consumption decreased in CACS, however, neither significant change was found on defecating behavior in CUMS nor on sucrose consumption in WRS;(2) Compared with the control group, some G protein submits expression decreased in both CACS and CUMS (P < 0.05), while no significant changes of any G protein subunits were found in WRS. CONCLUSION: The CACS animal model was a new, brain-gut interaction model, which can mimic part of human symptoms of IBS very well. PMID- 20193526 TI - [Strengthening clinical researches to promote China's standard treatment for deep venous thrombosis]. PMID- 20193525 TI - [In vitro induction of allo-T lymphocytes proliferation by myeloid dendritic cells in patients with severe aplastic anemia.]. AB - OBJECTIVE: To investigate the function of myeloid dendritic cells (mDCs) from severe aplastic anemia (SAA) patients in stimulating allogeneic T lymphocytes proliferation in vitro and then explore the immunopathogenesis of SAA. METHODS: Twenty-five SAA patients (15 untreated and 10 recovered after immunosuppressive therapy) and 12 normal controls were enrolled in this study. Their mature mDCs were induced from their bone marrow monocytes with recombined human interleukin-4 (rhIL-4), recombined human granulocyte-macrophage colony-stimulating factor (rhGM CSF) and recombined human tumor necrosis factor (rhTNF) in vitro. Then mDCs were co-cultured with allogeneic lymphocytes (mixture lymphocyte reaction, MLR) at a ratio of 1:100 or 1:50. The growth rate of lymphocyte was measured with methyl thiazolyl tetrazolium (MTT) colorimetry. The concentrations of interleukin (IL) 12 and interferon gamma (IFNgamma) in MLR supernatant were measured with ELISA. The correlation between the growth rate and the concentration of IL-12 or IFNgamma was analyzed. RESULTS: When mDCs and lymphocytes were co-cultured at the ratio of 1:100, the growth rates of lymphocytes stimulated with mDCs from untreated, recovered SAA patients and controls were (219.8 +/- 94.0)%, (159.1 +/- 66.0)% and (160.1 +/- 91.9)% respectively. The concentrations of IL-12 in MLR supernatant were (8.2 +/- 3.6) ng/L, (6.5 +/- 2.8) ng/L and (6.1 +/- 2.6) ng/L and the concentrations of IFNgamma were (21.8 +/- 8.7) ng/L, (25.5 +/- 9.1) ng/L and (22.6 +/- 7.8) ng/L respectively. All of them had no statistical differences among the three groups (P > 0.05). When mDCs and lymphocytes were co-cultured at the ratio of 1:50, the growth rate of lymphocytes stimulated with mDCs from untreated patients was (322.1 +/- 171.1)%, which was higher than that of recovered patients [(180.9 +/- 79.1)% and controls (192.3 +/- 91.9)%]. The concentrations of IL-12 in MLR supernatant in the three groups were (12.6 +/- 4.4) ng/L, (9.4 +/- 3.3) ng/L and (8.5 +/- 3.7) ng/L, and the concentrations of IFNgamma were (32.3 +/- 9.2) ng/L, (27.4 +/- 6.5) ng/L and (24.4 +/- 7.4) ng/L. Both of the values in untreated cases were higher than those of the recovered cases or controls (P < 0.05), but there were no statistical difference between the recovered and control groups (P > 0.05). The concentration of IL-12 in MLR supernatant correlated positively with the growth rate of lymphocyte (r = 0.529, P < 0.01) and so did the concentration of IFNgamma (r = 0.381, P < 0.05). CONCLUSION: The function of mDCs to stimulate T lymphocytes proliferation in SAA was enhanced; it might play an important role in the immunopathogenesis of SAA. PMID- 20193527 TI - [Boosting the diagnostic and therapeutic capacities of general hospitals in tackling Type A H1N1 influenza remains key to control efforts]. PMID- 20193528 TI - [Preliminary study on epidemiology of deep venous thrombosis of lower extremity in patients with high risk]. AB - OBJECTIVE: To make preliminary cross-sectional study on epidemiology of deep vein thrombosis of lower extremity of inpatients with high risk in Zhongshan hospital, and analyze risk factors in these patients. METHODS: From Sep 2008 and Feb 2009, we performed compressed ultrasound to detect deep vein thrombosis of lower extremity of in-patients with high-risk in Zhongshan hospital, including bedrid stroke patients, post-surgery bedrid patients from department of orthopaedics, gynecology, general surgery and vascular surgery and patients of surgical intensive care unit. Prevalence rate of DVT of the whole study group as well as each department were calculated and analyzed. We collected detailed clinical information of each recruited patient. We made statistical single-factor and then Logistic regression multiple-factor analysis of these data with SPSS 16.0, to determine high risks of deep vein thrombosis of in-patients. RESULTS: (1) Totally 372 patients were enrolled in our study with 38 patients detected with DVT of lower extremity, so the prevalence rate of whole series was 10.2% (38/372). (2) High risks of lower extremity deep vein thrombosis for the whole series were bedrid time (30 day boundary) (P = 0.000), thrombin time (P = 0.007) and history of vascular surgery (P = 0.009). (3) The prevalence rate of DVT of lower extremity of department of neurology, orthopaedics and gynecology were 12.7% (13/102), of 10.0% (10/100) and 6.3% (7/111) respectively. (4) High risk for DVT in post-surgery gynecological patients was resection of uterus and both attachments (P = 0.032). CONCLUSION: In our study, the prevalence rate of DVT of lower extremity for high-risk in-patients was high, most of whom were asymptomatic and left-sided. High risk factors were bedrid time (30 day boundary), thrombin time and history of vascular surgery. It is necessary to strengthen prophylactic anticoagulation in these patients. PMID- 20193529 TI - [Multicentre clinical observation of anticoagulation and thrombolysis for the deep venous thrombosis]. AB - OBJECTIVE: Multicentre clinical observation for therapeutic efficacy and clinical safety of anticoagulation and thrombolysis in deep venous thrombosis (DVT). METHODS: 127 patients with DVT in left leg were randomly divided into four groups. Group A: treated with batroxobin. Group B: use Low Molecular Weight Heparin (LMWH). Group C: batroxobin and LMWH. Group D: urokinase and LMWH. Observing the perimeter of thigh and calf periodically, monitoring coagulation function, registering the frequency and degree of the complication. RESULTS: All the treatments in four groups can relieve the swell level of the affected legs (P < 0.05). We got the best efficacy when we use batroxobin together with LMWH (P < 0.05), especially in treating the patients with a long course of treatment. Batroxobin can obviously reduce the level of blood FBG (P < 0.05), and have no significant effect with other index of coagulation function (P > 0.05). Inject ing batroxobin into affected legs with the micro pump got a better efficacy and much safer than intravenously guttae from peripheral vein. CONCLUSION: Treating DVT with batroxobin got a definite efficacy, especially in cases with a long course of treatment; micro pumping can give a better effect and a high safety. PMID- 20193530 TI - [Treatment of severe acute deep venous thrombosis in lower extremity]. AB - OBJECTIVE: To explore the method and effectiveness of treatment for severe acute deep venous thrombosis (DVT) in lower extremity. METHODS: Eighteen patients with severe acute DVT treated in our hospital from January 1, 2002 to December 31, 2008 were retrospectively analysed. All the patients had limb edema and pain, sixteen had limb cyanochroia(one had calf skin ulcer and foot gangrene), two had limb pallor, ten had weakened dorsalis pedis artery pulsation, eight had silent dorsalis pedis artery pulsation. Colour Doppler ultrasonography revealed DVT and superficial venous thrombosis in all diseased limbs. One patient underwent above knee amputation for limb gangrene. Seventeen underwent surgical thrombectomy, of which three were simple thrombectomy, five were supplemented with suprapubic saphenous vein bypass, six with suprapubic PTFE graft bypass, three with iliac vein lysis angioplasty. RESULTS: One patient died (5.6%) on the third day after surgery. Limb edema relieved in seven patients (41.2%), reduced in ten patients (58.8%). All diseased limbs regained normal artery pulsation and skin appearance except for one limb amputated. Sixteen patients (94.1%) were followed up by a mean of 34 months. Limb edema disappeared in five patients (31.3%), reduced in eight patients (50%), recurrent in three patients (18.7%). Among three recurrent patients, one died of malignant tumor 9 months after operation, two had their graft occluded resulting from intimal hyperplasia. CONCLUSIONS: Surgical thrombectomy is an effective method for treating severe acute DVT in lower extremity. PMID- 20193531 TI - [The comparison of operative and non-operative treatment for acute embolism of upper extremity artery]. AB - OBJECTIVE: To compare surgical and non-surgical therapy of the upper extremity after acute arterial occlusion. To analyze the relation between prognosis and relevant factors of different therapeutic methods. METHODS: Sixty patients with acute upper extremity arterial embolism treated between January 1990 and October 2007 were retrospectively studied in The First Hospital of China Medical University. RESULTS: There were 60 patients, 32 men and 28 women, with a mean age of 63 years (21 - 86 years). Among them, 31 underwent thrombembolectomies with the Fogarty catheter and 29 received anti-coagulation and thrombolytic therapy. Therapeutic effects were evaluated by Cooley's standard. Therapeutic efficacy was better in the surgical group than in the non-surgical group (P < 0.05). There was no relationship between post-operative ischemic recovery and pre-operative ischemia severity and the site of embolism in the surgical group, while there were significant relationships in the nonsurgical group. The result of Cox proportional hazard regression model showed that the age and Cooley's standard of the patient was correlated with survival time. CONCLUSIONS: A more active surgical approach is better for the treatment of acute arterial occlusion of the upper extremity. PMID- 20193532 TI - [Follow-up study of patients with chronic motor axonal neuropathy]. AB - OBJECTIVE: To study the characteristic of chronic motor axonal neuropathy and the prognosis of it. METHODS: 16 chronic motor axonal neuropathy (CMAN) patients were diagnosed by clinical manifestation and neurophysiologic manifestation. Follow-up study was done including living state, medicine they taken, change of physical sign and motor unit number estimation. 60 patients with amyotrophic lateral sclerosis were studies at the same time. The prognosis of these patients was compared. RESULTS: After being treated with intravenous immunoglobulin therapy, the patients with CMAN showed a good clinical recovery except 6 patients who had the characteristic of ALS in the 18 months follow-up study, and the MUNE changed from 68 +/- 17 to 154 +/- 25. On the contrary, the patients with ALS had worse clinical manifestation, and the MUNE changed from 64 +/- 6 to 55 +/- 9. CONCLUSIONS: Immunological factor may be involved in the mechanism of chronic motor axonal neuropathy which has a better prognosis and is difficult to differentiate from amyotrophic lateral sclerosis in the earlier stage. PMID- 20193533 TI - [Retrospective study of application of interspinous implants for degenerative lumbar diseases]. AB - OBJECTIVE: To assess the indications, efficacy and safety of applying interspinous implants for degenerative lumbar diseases. METHODS: From September 2007 to September 2008, 68 cases with degenerative lumbar diseases were treated with interspinous implants. The clinical outcome was assessed by VAS of pain in back and lower extremities, lumbar JOA score and Prolo functional score; the radiological results including implant position, segmental lodosis and segment movement degree were assessed by lumbar X ray including dynamic post-operative versus pre-operative X ray. RESULTS: Sixty-four cases had a complete follow-up and the average time was 11.4 months. At the final follow up, lumbar VAS 1.7 +/- 1.5, lower extremity VAS 1.3 +/- 1.0, lumbar JOA score 23.5 +/- 3.1 and Prolo functional score 8.6 +/- 1.4. They were better than those at pre-operation (1.7 +/- 1.5, 1.3 +/- 1.0, 23.5 +/- 3.1, 8.6 +/- 1.4). Segment lodosis angle (15.4 +/- 4.2) degrees was less than (19.6 +/- 4.7) degrees at pre-operation; segment movement degree was (10.3 +/- 4.5) degrees . Two cases with lumbar disc herniation relapsed and received a second operation. CONCLUSION: The application of interspinous implants for degenerative lumbar diseases is still in its infancy and the selection of indication is very important. Its efficacy and safety have been confirmed by a short follow-up. PMID- 20193534 TI - [Dose distributions of proton beam therapy for hepatocellular carcinoma: a comparative study of treatment planning with 3D-conformal radiation therapy or intensity-modulated radiation therapy]. AB - OBJECTIVE: A comparative dose distribution study has been undertaken between proton beam therapy (PBT), 3-dimensional conformal radiation therapy (3D-CRT) and intensity-modulated radiation therapy (IMRT) in the treatment of hepatocellular carcinoma (HCC), so as to assess the potential advantages of PBT. METHODS: Dose volume histograms (DVHs) were compared between PBT and 3D-CRT or IMRT planning at total dose of 66 Gy and 86 Gy in stage I patients (n = 10, diameter < or = 5 cm), 60 Gy and 72 Gy in stage IIA patients (n = 12, diameter = 5.1-10 cm). RESULTS: For patients with stage I, the mean liver dose (Dmean), V10, V20 and V30 were 13.01 Gy, 51.89%, 36.13% and 21.24% for 3D-CRT, whereas they were 6.34 Gy, 30.23%, 17.86% and 10.66%, respectively, for PBT (P < 0.002). With dose escalation to 86 Gy, the Dmean, V10, V20 and V30 were 16.91 Gy, 67.51%, 46.84% and 27.61% for 3D-CRT, whereas they were 8.26 Gy, 39.31%, 23.22% and 13.86%, respectively, for PBT (P < 0.002). Compared with 3D-CRT with dose of 66 Gy, PBT reduced the Dmean, V10, V20 and V30 even with dose escalation to 86 Gy (P < 0.042). For patients with stage IIA, the Dmean, V10, V20 and V30 were 29.18 Gy, 72.25%, 58.17%, 44.01% and 24.92 Gy, 73.32%, 56.15%, 37.75% for 3D-CRT and IMRT, respectively, with dose of 60 Gy, whereas they were 16.28 Gy, 43.93%, 33.54% and 22.78%, respectively, for PBT (P < 0.002). With dose escalation to 72 Gy, the Dmean, V10, V20, V30 were 35.02 Gy, 86.70%, 69.80%, 52.81% and 29.90 Gy, 87.98%, 67.74% and 45.30% for 3D-CRT and IMRT, respectively, whereas they were 19.54 Gy, 52.72%, 40.25% and 27.34%, respectively, for PBT (P < 0.002). Compared with 3D CRT and IMRT with total dose of 60 Gy, PBT reduced the Dmean, V10, V20 and V30 even with dose escalation to 72 Gy (P < 0.05). In all of the 22 cases, compared with 3D-CRT, PBT reduced the doses to the nonliver OARs (organs at risks) including spinal cord, right kidney and stomach (P < 0.002). Compared with IMRT, PBT also reduced the dose to the right kidney and stomach significantly, while no significant difference was found respect to the dose to spinal cord (P > 0.05). CONCLUSION: Compared with 3D-CRT, PBT reduced the dose to the normal liver tissues and nonliver OARs significantly, even with 20 to 30.3 percent of dose escalation. Compared with IMRT, PBT reduced the dose to the normal liver tissues significantly, even with 20 to 30.3 percent of dose escalation. PBT reduced the dose to the right kidney and stomach significantly. No significant difference was observed respect to the dose to spinal cord. PMID- 20193535 TI - [Clinical features, laboratory findings and imaging appearances of venous diethylene glycol poisoning in patients with liver disease]. AB - OBJECTIVE: To summarize and report the clinical features, laboratory findings and imaging appearances of venous diethylene glycol poisoning in patients with liver disease. METHODS: The clinical features of 15 venous diethylene glycol poisoning patients with liver disease were analyzed and summarized, their laboratory findings and imaging appearances were comparative analyzed before and after poisoning. RESULTS: All poisoned patients presented oliguric acute renal failure with anuria after a mean of 6 days. Carbon dioxide combination power of 13 patients was dropped after a mean of 9 days with trough value at the 10th day, and metabolic acidosis was developed. Gastroenteric symptoms or aggravation of gastroenteric symptoms were displayed in 11 patients after a mean of 9 days. Neurological system impairment was observed in 10 patients after a mean of 14 days. Seven patients had low fever after a mean of 6 days. Causes of death of 14 patients included multiple organ dysfunction syndrome, severe lung infection and massive haemorrhage of digestive tract. Blood creatinine and urea nitrogen were abnormal after a mean of 5 days with peak value at the 11th and 14th days respectively. Serum calcium had no obvious change, and phosphorus was increased distinctly. Liver functions did not change significantly. Poisoned patients had higher white blood cell counts, lower red blood cell counts and hemoglobin value. Of the 7 patients exhibited mild, moderate and severe patchy consolidation shadowing in the lung, 2 manifested mild or severe gaseous distention and dilation of gastroenteric tract. CONCLUSION: Main features of venous diethylene glycol poisoning in patients with liver disease include oliguric acute renal failure, metabolic acidosis, gastroenteric symptoms or aggravation of gastroenteric symptoms, neurological system impairment and low fever, with a mortality of 93.33% of poisoned patients; higher white blood cell counts and anemia; patchy consolidation shadowing in the lung; gaseous distention and dilation of gastroenteric tract, which occures later than mild patchy consolidation shadowing and earlier than moderate patchy consolidation shadowing do in the lung. PMID- 20193536 TI - [The deficit of decision-making in Parkinson's disease]. AB - OBJECTIVE: To investigate the characteristics of decision-making impairment in Parkinson's disease (PD) patients. METHODS: A total of 20 individuals with idiopathic PD were compared with matched health controls on the Iowa Gambling Task, A series of battery including the assessment working memory, visual spatial ability and verbal fluency was also administered. The severity of disease was assessed based on the Hohen and Yahr scale. RESULTS: The results showed that PD group impaired on verbal fluency, working memory and decision-making task. In Iowa gambling task, the PD group selected more disadvantageous cards than health controls (51.6 +/- 5.8, 46.8 +/- 8.2 respectively), the difference between two groups is significant (t((38)) = 2.12, P = 0.04). A 2 (group) x 5 (block) ANOVA (analysis of variance) on the scores of advantageous from the gambling task revealed a significant main effect of group (F((1, 38)) = 6.16, P = 0.01). The ANOVA also revealed a significant main effect of block (F((4, 152)) = 2.43, P = 0.04). The results showed that health controls gradually shifted their selections toward the good decks as the game progresses, but the PD group did not exhibit this stable advantageous shift in decision-making. Meanwhile, the study indicated the total number of disadvantageous cards for PD was positive correlation to the degrees of severity to clinical symptom. CONCLUSION: The present study suggests that the decision-making impairment might be in early PD. The deficit of decision making for PD might be attributed to the dysfunction of the orbito-frontal cortex. PMID- 20193537 TI - [Cytoskeleton rearrangements and induced apoptosis in human umbilical venous endothelial cell and WISH cell lines during the invasion of Staphylococcus aureus]. AB - OBJECTIVE: To investigate the changes of cytoskeleton and induced apoptosis in human umbilical venous endothelial cells (HUVEC) and WISH cells during the invasion of Staphylococcus aureus. METHODS: S. aureus suspension was collected routinely and used to infect HUVEC and WISH cells for 10, 30, 60 and 120 min respectively. The cell-invading ability of S. aureus was observed by microscope and the rearrangement of cytoskeleton of these cells observed under fluorescent microscope. DAPI fluorescent staining and DNA agarose electrophoresis were performed to analyze the apoptosis in HUVEC cells induced by S. aureus. RESULTS: There was bacterial invasion after staphylococcus aureus was co-incubated with HUVEC and WISH cells for 10 min. The rates of infection were (54.9 +/- 2.4)% and (56.1 +/- 2.4)% at 60 min respectively. The ratios of F-actin rearrangements at 10 min, 30 min, 60 min and 120 min after the invasion of HUVEC and WISH cells with S. aureus were different at (54.7 +/- 2.8)%, (63.0 +/- 2.9)%, (71.0 +/- 2.6)%, (39.5 +/- 2.7)% and (63.3 +/- 2.6)%, (65.0 +/- 2.9)%, (77.0 +/- 2.4)% and (44.0 +/- 1.8)% respectively. The ratios of F-actin rearrangements at 10 min, 30 min and 60 min were higher than those at 120 min (P < 0.05). There was no change of microtubule observed in both cells at the same time. The apoptotic appearance was observed after the invasion of HUVEC cells with s. aureus at 60 min. CONCLUSION: S. aureus may invade the HUVEC and WISH cells through F-actin rearrangement. Apoptosis is induced in HUVEC cells at 60 min. PMID- 20193538 TI - [Investigation of ion channel mechanism for the regulatory volume decrease in lung adenocarcinoma cells]. AB - OBJECTIVE: This study was designed to observe the regulatory volume decrease (RVD) process in human lung adenocarcinoma cells (A549) and to investigate its ion channel mechanism. METHODS: Electric measurement system of cell volume was used to detect the cell volume changes following exposure to hypotonic solution. Whole-cell patch clamp recordings were applied to investigate the characteristics of the volume-sensitive Cl(-) channel in A549 cells. RESULTS: Extracellular hypotonicity induced cell swelling followed by a typical RVD process, which can be inhibited by Cl(-) channel blocker (NPPB 100 micromol/L) and K(+) channel blocker (CsCl 5 mmol/L). Meanwhile, a outward-rectifying chloride currents which was sensitive to NPPB and DIDs was recorded in A549 using the whole cell patch clamp. CONCLUSIONS: The human lung adenocarcinoma cells has RVD process which is dependent on the parallel activation of Cl(-) channel and K(+) channel. The volume-sensitive Cl(-) channel is involved in volume regulation of lung adenocarcinoma cells. PMID- 20193539 TI - [Effectiveness and significance of prostatic ischemia in rabbit]. AB - OBJECTIVE: To evaluate the effect of prostatic ischemia in rabbit and approach the significance of ischemia in the development of benign prostatic hyperplasia. METHODS: Male rabbits underwent surgical prostatic ischemia for durations of 1, 2, 4, 8 and 12 weeks and sham-operated rabbits served as controls. The weight of prostate was examined and a histological examination conducted. Ki67 immunohistochemical stain for the generation of prostatic cells and TUNEL test for the apoptosis of prostatic cells were used. RESULTS: In sham-operated rabbits, the mean (SD) weight of prostate were 0.831(0.127) g, the mean (SD) positive Ki67 staining prostatic epithelial cells 2.1(0.8) in 100 prostatic epithelial cells and stromal cells 2.6(1.1) in 100, mean (SD) positive TUNEL test prostatic epithelial cells 2.0(1.0) in 100 and stromal cells 2.5(0.7) in 100. In operated rabbits, the generation of prostatic stromal cells increased and the apoptosis of prostatic stromal cells decreased over 1 - 12 weeks. The generation of prostatic epithelial cells increased and the apoptosis of prostatic epithelial cells decreased over 2 - 12 weeks, but in the first week, there were no significantly difference between operated and sham-operated rabbits in the generation and apoptosis of prostatic epithelial cells. The weight of prostate in operated animals increased at Weeks 4, 8 and 12, were significantly heavier than sham-operated rabbits, 1 week post-op and 2 weeks post-op rabbits, there were no significantly difference between the latter 3 groups. CONCLUSION: Ischemia can induce the gain of prostatic weight by improving the generation and inhibiting the apoptosis of prostatic cells. And the effect of ischemia to prostate is correlated with ischemic time. Ischemia may play an important role in the development of benign prostatic hyperplasia. The first response to ischemia is the change of prostatic stromal cells. PMID- 20193540 TI - [The choice of surgical intervention for extracranial carotid artery stenosis]. PMID- 20193541 TI - [A pancreas suture-less type II binding pancreaticogastrostomy]. AB - OBJECTIVE: To explore the feasibility and safety of type II binding pancreaticogastrostomy (BPG) in pancreaticoduodenectomy and mid-segmentectomy of pancreas. METHODS: From November 2008 to May 2009, 26 patients underwent pancreaticoduodenectomy and mid-segmentectomy of pancreas with type II BPG reconstruction, including 13 cases of pancreatic head cancer, 3 cases of duodenal adenocarcinoma, 2 cases of ampullary carcinoma, 4 cases of cholangiocarcinoma, 1 case of bile duct cell severe atypical hyperplasia, and 1 case of stomach cancer. The process of type II BPG was described as the following: after pancreas remnant was mobilized for 2-3 cm, a piece of sero-muscular layer at the posterior gastric wall was excised and then a sero-muscular depth purse-suturing with 3-0 prolene was pre-placed (outer purse-string). Incising anterior gastric wall or opening part of the closed distal gastric stump, the mucosa layer at the sero-muscular defect was incised and then purse-suture at the mucosal tube was pre-placed (inner purse-string). Through the two pre-placed purse-strings, the pancreas remnant was pulled into the gastric lumen and then posterior gastric wall was pushed backward to keep it closely in contact with the retro-peritoneal wall. Thereafter, the outer purse-string was tied (outer binding) and then the inner purse-string was tied (inner binding). RESULTS: All cases underwent BPG of type II. The operative time ranged from 3 to 5.5 hours. The postoperative hospital stay ranged from 6 to 48 days. Postoperative complications included 1 case of ascites, 2 cases of delayed gastric emptying and 1 case of intra-abdominal bleeding. All cases with complications were cured after nonsurgical treatment. No mortality or pancreatic leakage occurred. CONCLUSIONS: Pancreaticogastrostomy is good for accommodating a large pancreas stump. Binding technique is very helpful in minimizing the leak rate of pancreaticogastrostomy. While type I BPG is safe and easy to perform, type II is even safer and easier to be done. PMID- 20193542 TI - [Combined hepatic resection and intraoperative thermal ablation for multifocal hepatocellular carcinoma]. AB - OBJECTIVE: To investigate the safety and efficacy of hepatic resection combined with intraoperative ablation to treat multifocal hepatocellular carcinoma. METHODS: Clinical data of patients diagnosed with multifocal hepatocellular carcinoma and treated with hepatic resection combined with intraoperative ablation from March 1998 to September 2007 were retrospectively reviewed. Treatment response, postoperative complications and survival data were analyzed. RESULTS: Combined treatment modalities were well tolerated except one patient dying of postoperative hepatic functional failure. The postoperative complication rate was 23.5% with a mortality rate of 6.7%. Postoperative complication included wound infection (1 case), bile leakage (1 case), subphrenic and pleural effusion (1 case), ablation-associated liver abscess (1 case), all of which were treated with non-surgical methods. The median survival time was 25.9 months. The 1, 3, 5 year survival rates were 70.6% (12/17), 23.5% (4/17), 17.6% (3/17), respectively. Three patients survived more than 5 years after surgery. Up to April 2008, 4 patients were still alive. CONCLUSION: Hepatectomy combined with intraoperative thermal ablation provides a treatment modality for patients with multifocal hepatocellular carcinoma and may improve the prognosis. PMID- 20193543 TI - [Model for end-stage liver disease-sodium predicts prognosis in patients with chronic severe hepatitis B]. AB - OBJECTIVES: To study the practical use of the serum sodium incorporated model for end-stage liver disease (MELD-Na) on clinic and to assess its validity by the concordance-statistic in predicting the prognosis of the patients with chronic severe hepatitis B. METHODS: Adult patients with a diagnosis of chronic severe hepatitis B between January 2007 and December 2007 in a single center were analyzed. The serum sodium, MELD, MELD-Na, and Delta MELD-Na (Delta MELD=MELD score at 14 days after medical treatment-MELD score at admission) scores of 426 patients with chronic severe hepatitis B were calculated. The 3-month mortality in patients was measured, and the validity of the models was determined by means of the concordance-statistic. RESULTS: The area under the receiver-operating characteristic curves of Na, MELD and MELD-Na for the occurrence of death in 3 month were 0.718, 0.875 and 0.922. The 3-month mortality of the MELD-Na scores group <25, 25-30, >30-35, >35- <40 and > or = 40 were 2.0%, 5.4%, 35.4%, 53.8% and 86.9% respectively. There was a significant difference of 3-month mortality between the five groups (P<0.05). The 3-month mortality of Delta MELD-Na> 0 group was 65.9%, and the Delta MELD-Na < or = 0 group was 15.8%. There was a significant difference of 3-month mortality between the two groups (P<0.05). CONCLUSIONS: MELD-Na score is a valid model to predict 3-month mortality in patients with chronic severe hepatitis B. Delta MELD-Na is clinically useful parameters for predicting the therapeutic effect of chronic severe hepatitis B. PMID- 20193544 TI - [Analysis of the pattern of solitary lymph node metastasis in gastric cancer and its prognosis]. AB - OBJECTIVE: To explore the pattern of solitary lymph node(LN) metastasis in gastric cancer and its prognosis. METHODS: The clinical records of 83 patients with gastric cancer presenting solitary LN metastasis who underwent D2 radical resection from January 1995 to December 2003 were analyzed retrospectively. The precise stations of the metastasis of LN and their correlation with the location of primary tumor were studied. The 5-year survival rates were compared between patients with and without skipping LN metastasis. The prognostic factors were evaluated by using univariate and multivariate analyses. RESULTS: Among the 83 patients with pathologically proven solitary LN metastasis, 64 cases (77%) presented with the perigastric nodes metastasis (N1 area), and 19 cases (23%) in N2 area without N1 involvement (skipping LN metastasis). For tumors in the upper and middle third stomach, the No. 3 station was the most common first metastasized LN station (40% and 42%, respectively). While for tumors in the lower third stomach, the No.6 station was the mostly affected LN (33%). Of the patients, 77 cases were followed up for 5-14 years, the median survival time was 77.0 months, and the overall 5-year survival rate was 63%. The 5-year survival rates of the patients with and without skipping LN metastasis was 52% and 67% respectively, there was no significant difference between the two groups (P>0.05). The serosal invasion and pathological types were influencing factors of the 5-year survival rate on univariate analysis. But with multivariate analysis, only the serosal invasion was an independent factor affecting the survival. CONCLUSIONS: Perigastric nodes are the most common first sites of tumor metastasis, making them the main targets of operative sentinel lymphatic mapping procedures. The patients with serosal invasion have poorer prognosis. PMID- 20193545 TI - [Impact of neoadjuvant therapy on lymph nodes retrieval in locally advanced mid low rectal carcinoma]. AB - OBJECTIVE: To study the impact of neoadjuvant therapy on lymph nodes retrieval in locally advanced mid-low rectal carcinoma. METHODS: Data collected from 120 patients with locally advanced mid-low rectal cancer (T2-4 and/or N1-2M0) treated from January 2005 to June 2008 was investigated. The patients were divided into two groups: the study group (n=54) was treated with neoadjuvant therapy (preoperative radiation with a total dosage of 50 Gy and synchronous 5-Fu-based chemotherapy) followed by radical tumor resection 4-6 weeks after;the control group (n=66) underwent primary surgery without neoadjuvant therapy. The clinical stage was evaluated before and after neoadjuvant therapy. The total lymph nodes yields, as well as the tumor-positive lymph nodes of each resected specimen was compared between the two groups statistically. RESULTS: Clinical downstage was achieved in 30 cases (56%) in study group after neoadjuvant therapy. The number of total lymph nodes and positive lymph nodes harvested from each resected specimen in the control group were 14+/-7 and 2.2+/-3.7, meanwhile those were 9+/ 6 and 0.7+/-2.4 in study group, which were all significantly lower than those in control group (P<0.01). CONCLUSIONS: Preoperative radiotherapy combined with chemotherapy can downstage the tumor and reduce the retrieval rate of total lymph nodes and positive lymph nodes in locally advanced rectal cancer. It is necessary to retrieve as many lymph nodes as possible for it has some prognostic significance for the patients. PMID- 20193546 TI - [The indication and time of treatment of thoracic endovascular aortic repair in acute Stanford B dissection]. AB - OBJECTIVE: To study the indication of thoracic endovascular aortic repair (TEVAR) in acute Stanford B dissection. METHODS: From February 2004 to June 2008, 464 cases of Stanford B dissection (391 males and 73 females, age from 26 to 88 with a mean of 56.6 years) underwent TEVAR. Patients were divided into group A (acute, n=298) and group B (chronic, n=166). Risk factors of rupture were evaluated and results were compared between the two groups. RESULTS: The incidence of persistent or recurrent pain and hemothorax in ruptured patients was 83.3% and 94.4%, greater than 10.4% and 14.1% in the non-ruptured patients (P<0.01). The mean maximal diameter of the descending thoracic aorta in the rupture group was 49.4 mm, greater than 35.1 mm in the non-rupture group (P<0.01). Aortic branch vessel ischemia was greatly alleviated after TEVAR. Resolution of the proximal false lumen was 51.7% in group A, 19.5% in group B, and the rate of patent distal false lumen was 59.2% in group A, 79.3% in group B (P<0.01). Four out of 24 cases of intramural hematoma had recurrent dissection. CONCLUSIONS: Acute dissection with a patent proximal false lumen is an indication for TEVAR. Intramural hematoma could be given medical treatment under close follow-up. Persistent or recurrent pain, hemothorax, descending thoracic aorta greater than 4.5 cm, or aortic branch vessels ischemia warrant prompt TEVAR. PMID- 20193547 TI - [Deep venous thrombosis of lower extremities: effects of different treatment on the incidence of pulmonary embolism]. AB - OBJECTIVE: To investigate the effects of the different treatments of deep venous thrombosis (DVT) of lower extremities on the incidence of the pulmonary embolism (PE). METHODS: 201 patients (97 males and 104 females, mean age 60.4 years ranged from 24 to 83) from August 2002 to June 2008 with DVT were retrospectively reviewed and divided into 3 groups based on different treatment, including anticoagulants plus thrombolytics alone (group 1), thrombectomy plus anticoagulants plus thrombolytics (group 2) and anticoagulants plus thrombolytics after delivery of inferior vena cava (IVC) filter (group 3) respectively. One hundred and seventy-four cases had left lower limb DVT, 24 cases had right lower limb DVT and 3 cases had both sides of lower limb DVT. Different incidence of PE in different period (7-14 d in hospital and follow-up after discharge) were calculated. Effects of the three different treatment methods of DVT on the incidence of PE were studied. RESULTS: For in-patients, the prevalence of symptomatic PE was 2.8% (3/107) in the group of receiving anticoagulants plus thrombolytics alone, but in the other two groups, no symptomatic PE happened. There was no significant difference in incidence of symptomatic PE among the 3 groups (P=0.425). For patients discharged, after 6 to 72-month follow-up (mean 24 month), we found that no PE happened in group 1 and group 2, while in group 3, the incidence of PE was 2.4% (1/42). There was also no significant difference (P=0.656) among 3 groups. CONCLUSIONS: There is no significant difference in relation to the incidence of PE in these 3 groups. Therefore vena cava filter implantation should be restricted to optimal indication. PMID- 20193548 TI - [Studying the influence of age and short or long segments of pedicle screw instrumentation to the clinical efficacy of early single thoracolumbar fracture]. AB - OBJECTIVE: To study the influence of different age and short or long segments of pedicle screw fixation to the clinical efficacy of early single thoracolumbar fracture. METHODS: From June 2005 to June 2008, 27 patients of early single thoracolumbar fracture were treated using short or long segments pedicle screw instrumentation, fracture vertebral (AO classification: type A1 or A2) was between T11 or L2. All patients were divided into A or B group according to age. A group: 12 cases mean age (32.6+/-10.7) years old (range, 16-55 years old). B group: 15 cases mean age (66.8+/-9.2) years old (range, 56-78 years old). All patients were treated with bony autograft by transpedicular of fracture vertebral and internal fixation by pedicle instrumentation. Pedicle screws were inserted in the pedicles of above and lower adjacent vertebral body of fracture vertebral, and others were inserted in the pedicles of above and lower two vertebral bodies of injured vertebral. Recorded operation time, blood loss and occurrence of complications. All patients took X radiograph plane examination (anterior posterior position and lateral position) before operation and during 1 week of post operation and more than 1 year of follow up. Measured percentage of anterior compression vertebral high and kyphosis angle of the fracture vertebral by the same one group doctors. RESULTS: Mean follow up time was (29.6+/-9.1) months (range, 10 - 34 months). The patients using short segments pedicle screw fixation in A and B group, mean operation time were (102+/-16) min and (118+/-24) min (P=0.072), mean volume of loss blood were (315+/-87) ml and (331+/-87) ml (P=0.064) respectively. The patients using long segments pedicle screw fixation in A and B group, Mean operation time were (138+/-22) min and (159+/-31) min (P=0.052), Mean volume of loss blood were (446+/-102) ml and (482+/-148) ml (P=0.055) respectively. There was no statistic different significantly between A and B group. The patients using short segments fixation, preoperative, during one week of post operation, one year of follow up, in A group the percentage of anterior compression vertebral high were 41.3+/-14.0, 5.4+/-1.0, 13.6+/-1.1, and 38.5+/-11.2, 8.3+/-2.1, 21.4+/-5.2 in B group. The patients using long segments fixation, at some time of preoperative, during one week of post operation and one year of follow up the percentage of anterior compression vertebral high were 40.8+/-11.5, 4.6+/-1.2, 8.3+/-1.0 in group A, and 44.3+/-10.2, 9.7+/-2.1, 11.2+/ 3.0 in group B. In group A and B the kyphosis angle of fracture segment was 17.5 degrees+/-1.0 degrees and 16.3 degrees+/-3.1 degrees before operation, 4.2 degrees+/-1.0 degrees and 6.0 degrees+/-1.1 degrees in one week of postoperation and 11.5 degrees+/-1.0 degrees, 13.4 degrees+/-3.0 degrees in one year later postoperation. All the compression vertebral high was recovered and kyphosis was corrected significantly during one week and one year after operation (P<0.05), but there was some loss of kyphosis correction rate in follow up. CONCLUSION: There is better clinical efficacy of short segments pedicle instrumentation for treating early thoracolumbar fracture in the young group, but long segments fixation of pedicle instrumentation is more suitable for the older group. PMID- 20193549 TI - [The treatment of knee joint peripheral fractures and/or dislocations with vascular injury]. AB - OBJECTIVE: To investigate the effect and influence factors on knee joint peripheral fractures and/or dislocations with an associated vascular injury through retrospectively study. METHODS: From March 2002 to November 2007 31 patients with knee joint peripheral fractures and/or dislocations with an associated vascular injury were treated, including 24 males and 7 females with a mean age of 41 years (range from 21 to 62 years). Definite diagnosis of vascular injury by combining colored ultrasonic, CTA, operative exploration with clinical signs, fixing fractures and/or dislocations with fixators, plates and screws, reconstructing blood circulation based on the condition of the vascular injury by vascular repair, homograft vein or artificial vascular grafting separately and analysing the effects of PSI, diagnosis and treatment methods on salvage lower extremities. RESULTS: Successful reconstruction was carried out in 31 cases, however there were 1 death because of mult-fractures and brain injury and 6 amputation, 24 cases successful salvage followed up mean 24.2 months, 6 cases bone nonunion and infected bone defect were cured by delayed bone planting or bone transportation. Ligaments repair reconstruction of 7 cases knee joint dislocation were done in delayed 3 or 4 weeks after first operation, the good functional rate was 71.4%. CONCLUSIONS: The patients of PSI under 10 grades in knee joint peripheral fractures and/or dislocations with an associated vascular injury should been carried out treatment, early definite diagnosis and blood circulation reconstruction are the key factors of successful salvage treatment. PMID- 20193550 TI - [Retrospective analysis of 100 patients managed by extracorporeal membrane oxygenation]. AB - OBJECTIVE: To describe the experience with extracorporeal membrane oxygenation (ECMO) for cardiorespiratory support of 100 patients. METHODS: Retrospective analysis of the medical files of 100 patients submitted to the implant of extracorporeal membrane oxygenation system for cardiorespiratory assistance of acute and refractory cardiogenic shock from December 2004 to September 2008. There were 67 males and 33 females, age ranged from 5 d to 76 years with a mean of (28+/-26) years, body mass ranged from 3.8 to 100.0 kg with a mean of (42+/ 30) kg. The inter-surface of the ECMO equipment system was completely coated by heparin-coating technique. All patients were applied veno-artery ECMO and activated clotting time was maintained between 120 and 180 s and heparin usage dose was 5 to 20 Uxkg(-1)xh(-1). Mean blood flow was 40 to 220 mlxkg(-1)min(-1) during ECMO assistant period. RESULTS: The shortest ECMO time was 12 to 504 h with a mean of (119+/-80) h. Sixty-one patients (61.0%) weaned off successfully from ECMO, 55 of them (90.2%) were discharged and 6 died of post-operative complications. Thirty-nine patients could not weaned off from ECMO. Total survival discharge rate was 55.0%. Mean aortic pressure before ECMO in survived patients was significantly higher than that of dead patients (P=0.038). Lactic acid concentration of artery blood before ECMO in survived patients was significantly lower than that of dead patients (P=0.005). CONCLUSIONS: ECMO is an effective mechanical assistant therapy method for cardiac and pulmonary failure after cardiac surgery. Earlier usage of ECMO for heart lung failure patient and avoiding the main organs from un-recovery trauma are key success. PMID- 20193551 TI - [The effects of pulsatile perfusion during cardiopulmonary bypass procedures by radial artery pressure and waveform: the preliminary evaluation]. AB - OBJECTIVE: To evaluate the possibility of radial artery pressure and waveform as a convenient definition of pulsatile flow and the the effect of pulsatile perfusion during cardiopulmonary bypass (CPB) procedures. METHODS: From March 2008 to December, Eighty patients underwent open heart surgery were randomly divided into a pulsatile group (P, n=45) and a nonpulsatile group (NP, n=35). Monitored by radial artery pressure and waveform, the pulsatile low was applied from the point of the aortic cross-clamp until its release in P group. A P group of patients whose radial artery pressure and waveform revealed "double peak" or "single peak" (>30 mm Hg, 1 mm Hg=0.133 kPa) were compared with NP group. Parameters examined were lactate, urine volume, high sensitivity C reactive protein, blood urea nitrogen, creatinine, blood uric acid, lactate dehydrogenase, glutamic oxalacetic transaminase, ratio of urine for occult blood test, prothrombin time and tracheal intubation time. RESULTS: The waveform with "double peak" or "single peak" (>30 mm Hg) presented in 35 (77.78%) in P group. The urine volume during CPB was significantly higher in P group. The lactate (P<0.01) during CPB, high sensitivity C reactive protein (P<0.05), increasing extend of lactic acid dehydrogenase (P<0.05) and the prothrombin time (P<0.01) after CPB were significantly lower in P group. The blood uric acid after CPB was increased in P group and decreased in NP group. CONCLUSIONS: Effective pulsatile flow can be generated by optimization of equipment and adjustment of pulsatile parameter. The radial artery pressure and waveform is a convenient definition of pulsatile flow. The pulsatile flow is predominant monitored by radial artery pressure and waveform. PMID- 20193552 TI - [The diagnosis and treatment of the Mullerian duct cyst: 48 cases report]. AB - OBJECTIVE: To study the diagnosis and treatment methods of Mullerian duct cyst. METHODS: The records of 48 patients with Mullerian duct cyst were reviewed and the diagnosis and treatment methods were compared. From January 1993 to December 1997, eight patients visited the clinic, most of whom complained of the chronic prostatitis symptom. They all underwent the transrectal ultrasonography (TRUS). Seven patients were treated by transperineal TRUS-guided aspiration therapy. One patient with the large Mullerian duct cyst was extirpated by open operation. From January 2002 to December 2007, we treated forty patients. Most of them visited us complained of the obstructive azoospermia. All patients were diagnosed by the TRUS and twelve patients underwent MRI examine. Thirty-nine patients with smaller Mullerian duct cyst were treated by transurethral cyst incision therapy. One patient with large Mullerian duct cyst was extirpated by laparoscopic operation. RESULTS: One of the eight patients, recurrence was detected at the half-year's follow-up and cured by transurethral cyst incision. All the 40 patients underwent TRUS at three months postoperative follow-up, no cysts recurrence. At the six months postoperative follow-up, ten of thirty-nine patients obstructive azoospermia patients had made their wives pregnant successfully. Nine patients of the other twenty-nine patients had sperms in semen. One 19 years old patient's symptom disappeared. CONCLUSIONS: The patient with Mullerian duct cyst often complained of chronic prostatitis symptom and the obstructive azoospermia. TURS was the preferred examine method in the diagnosis of the Mullerian duct cyst. And MRI could offer more exact informations. Transurethral cyst incision was effective methods for Mullerian duct cyst. Laparoscopic Mullerian duct cyst resection was a good choice for the large cysts. PMID- 20193553 TI - [The expression of P120 catenin in pancreatic carcinoma and the relationship between the T755G polymorphism of P120 catenin gene and pancreatic carcinoma]. AB - OBJECTIVES: To investigate the expression of P120 catenin in pancreatic carcinoma and to explore the association between P120 catenin gene polymorphism at T755G position and pancreatic carcinoma. METHODS: The expression of P120 catenin in 52 cases of pancreatic carcinoma and normal pancreatic tissues on the mRNA and protein levels were evaluated by RT-PCR and Western Blot methods respectively. P120 catenin gene polymorphism at T755G position of in 52 patients and 60 healthy controls were examined by PCR-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS: The mRNA and protein expressions of P120 catenin in pancreatic carcinoma tissues were significantly lower than normal pancreatic tissues (P=0.000, P=0.002). Reduced expression of P120 catenin mRNA was significantly correlated with differentiated (P=0.033), lymph node metastasis (P=0.004), vascular invasion (P=0.022), and pTNM stage (P=0.003). Additionally, there were significant difference of P120 catenin gene polymorphism genotypes and alleles at T755G position between patients and healthy controls (P=0.008, P=0.016). The GG genotype of P120 catenin gene was associated with higher risk of incidence for pancreatic carcinoma compared with the TT genotype (OR=2.765, 95%CI=1.312-3.958). CONCLUSIONS: The reduced expressions of both P120 catenin mRNA and protein in pancreatic carcinoma suggest its association with pancreatic carcinoma development. Polymorphism of P120 catenin gene at T755G situation might be a risk factor for pancreatic carcinoma, and it may be used to diagnosis and prevent pancreatic carcinoma early. PMID- 20193554 TI - [Association between insulin-like growth factor-1 receptor gene polymorphisms and with susceptibility to adolescent idiopathic scoliosis]. AB - OBJECTIVE: To investigate the association of insulin-like growth factor-1 receptor (IGF-1R) gene polymorphisms and with susceptibility to adolescent idiopathic scoliosis (AIS). METHODS: This study included 200 patients with AIS and 200 healthy controls. Height, menarche status, curve pattern, Cobb angle, and Risser sign in female patients were recorded. Blood samples were taken form each subject by venipuncture. Genetic DNA was extract from peripheral blood leukocytes using standard phenol/chloroform extraction. PCR-RFLP (polymerase chain reaction restriction-fragment length polymorphism) was used for the genotyping. RESULT: The genotype and allele frequency distribution were similar between AIS and normal control (P>0.05). The mean maximum Cobb angle, Risser sign, menarche status of different genotypes of IGF-1R gene were similar with each other among female AIS patients (P>0.05). CONCLUSIONS: The IGF-1R gene is neither associated with the occurrence nor the curve severity of AIS. PMID- 20193555 TI - [The repair of acute spinal cord injury in rats by olfactory ensheathing cells graft modified by glia cell line-derived neurotrophic factor gene in combination with the injection of monoclonal antibody IN-1]. AB - OBJECTIVE: To research the repair effect of transplantation of glial cell line derived neurotrophic factor (GDNF) modified olfactory ensheathing cells (OECs) combination with injecting axonal growth inhibiting protein antibody (IN-1) in vivo. METHODS: To construct lentivirus vector with GDNF gene and infect OECs in vitro, use the immunoblotting (Western Blot) to observe the expression of GDNF was detected through Western Blot. Fifty adult female SD rats which to establish thoracic spinal cord transection injury model were randomly divided into A (control group), B (IN-1 antibody group), C (OECs group), D (GDNF-OECs group), and E (GDNF-OECs+IN-1 group) 5 groups of each 10 rats. To observe regeneration of the impaired nerve axon by NF200 immunohistochemistry, Biotinylated dextran amine (BDA) anterograde tracing corticospinal tract. Basso, Beattie and Bresnahan (BBB) score was used to evaluating hindlimb motor function recovery. RESULTS: Add up to 13 rats died post operation. OECs labeled by hoechst still survived and migrated in spinal cord 8 weeks post operation. Lots of confused and disorderly regenerated axons which crossing the injured region of spinal cord were displayed between spinal cord stumps in GDNF-OECs+IN-1 group and GDNF-OECs group; some of axons existed in OECs group, but there is no obviously continue nerve fibers crossing the injured region of spinal cord;in contrast to IN-1 and control groups, few of regenerated axons and atrophy of spinal cord stumps were observed. The results of BBB hindlimb motor rating scale were 7.70+/-0.24, 7.89+/-0.15, 10.50+/-0.25, 11.43+/-0.23 and 12.81+/-0.40 for the control group, IN-1 group, OECs group, GDNF-OECs group and the allied treatment group respectively. CONCLUSIONS: The transplantation of GDNF-OECs combination with IN-1 antibody may benefit the survival and regeneration of the injured axons, and accelerate the repair of the injured spinal cord and functional recover of hindlimb locomotor in rats in a more efficient way than that with OECs or IN-1 alone. PMID- 20193556 TI - [Issues and recommendations in diagnosis & treatment of hepatolenticular degeneration]. PMID- 20193557 TI - [Clinical and pathologic analysis of an autosomal recessive kindred with nemaline myopathy]. AB - OBJECTIVE: To investigate the clinical, pathological and ultrastructural features of nemaline myopathy (NM). METHODS: The clinical manifestations of four patients in a rare autosomal recessive kindred with nemaline myopathy were analyzed retrospectively. Biopsied specimens of left gastrocnemius from the proband were detected and observed through light microscope using enzymatic histochemical methods for histopathological changes and through electron microscope for ultrastructural features. RESULTS: Four affected siblings in this kindred had an onset at birth or fetal stage, among whom two case were respiratory independent with delayed attainment of motor milestones and general muscle atrophy complying with typical form of NM, whereas the other two did not achieve adequate spontaneous movement or breathing, and died at neonatal period according with severe form of NM. Other clinical characteristics of elongated face, tent-shaped mouth and high-arched palate were also found. The proband had normal serum muscle enzymes and the karyotypic analysis showed a normal G band. Brain magnetic resonance image (MRI) indicated no abnormality. Electromyogram (EMG) showed typical muscle-derived damages of biceps, triceps, brachioradial muscle, vastus medialis muscle, anterior tibial muscle and gastrocnemius with normal motor conduction velocity of bilateral tibial nerves and common peroneal nerves. Myofibrillar atrophy was found through light microscopy with fiber type 1 predominance shown by ATP enzyme staining, yet without indication of lipid or glycogen deposition by ORO or PAS staining. Modified gomori trichrome (MGT) treatment resulted in dark-red staining of nemaline bodies in myofibril cytoplasm. And it was also observed as purple-red staining followed by hematoxylin-eosin (HE) treatment. Electron microscopic observation by lead uranium double staining showed widened interstitial myofibrils, focal myofilament disorganization, partial myofilament atrophy, focal dissolution or necrosis, partial myofibrils nucleus pyknosis, numerous subsarcolemmal and perinuclear rod like structures, partial nemaline bodies connected with Z discs, and mitochondria vacuolation or disappearance. CONCLUSION: NM is among congenital myopathies characterized by marked clinical and pathological heterogeneity. The diagnosis of NM should be based upon typical clinical and histopathological features. PMID- 20193558 TI - [Clinical manifestations and detection of pantothenate kinase 2 gene mutation in a patient with Hallervorden-Spatz syndrome]. AB - OBJECTIVE: To investigate the clinical features and detection of pantothenate kinase 2 (PANK2) gene mutation in a Chinese patient with Hallervorden-Spatz syndrome (HSS). METHODS: The clinical features were analyzed in one HSS patient. PANK2 gene mutations were detected by polymerase chain reaction (PCR) and DNA sequence analysis in this patient, her parents and 50 unrelated healthy persons. RESULTS: The main symptoms of this patient were involuntary movements, dysarthria and progressive course. MRI scans showed hypointensity with a central region of hyperintensity in medial globus pallidus on T2 and T2-weighted fluid attenuated inversion recovery (FLAIR) images, i.e. "eye-of-the-tiger" sign. Novel compound heterozygous PANK2 gene mutations, G115T and A803G, were found in this patient, leading to substitution of a glutamic acid for a premature stop codon at amino acid 39 (E39X) and an aspartic acid for glycine codon at amino acid 268 (D268G) respectively. The father was a heterozygote for G115T mutation and the mother a heterozygote for A803G mutation. CONCLUSION: PANK2 gene mutations are present in Chinese HSS patients. And A803G mutation of PANK2 gene is probably a hot spot. PMID- 20193559 TI - [Mutation analysis of MFN2 gene in Chinese patients with Charcot-Marie-Tooth disease]. AB - OBJECTIVE: To analyze MFN2 gene mutation in Chinese patients Charcot-Marie-Tooth disease (CMT) and to establish a quick and effective diagnostic method. METHODS: Through denaturing high-performance liquid chromatography (DHPLC) combined with DNA sequencing, MFN2 gene mutation analysis was carried out in 35 Chinese CMT2 patients including 9 probands of CMT2 pedigree and 26 sporadic CMT2 patients. RESULTS: The investigators found three abnormal sequence variations in MFN2 gene: c.281G-->A, c.395G-->A and c.408A-->T. c.395G-->A (C132T) was a novel causative missense mutation firstly reported while c.281G-->A (R94Q) a hotspot mutation and c.408A-->T (V136V) a single nucleotide polymorphism (SNP). The accuracy and specificity of DHPLC detection reached up to 100%. CONCLUSION: Through DHPLC combined with DNA sequencing, MFN2 mutations are detected in Chinese CMT2 patients. There are two causative missense mutations: c.395G-->A (C132T) and c.281G-->A (R94Q) and one SNP c.408A-->T (V136V). Such a method is an effective and economic diagnostic screening tool of MFN2 gene in CMT patients on a large scale. PMID- 20193560 TI - [Two novel mutations of GJB1 gene associated with typical X-linked Charcot-Marie Tooth disease]. AB - OBJECTIVE: To analyze the relationship between phenotype and genotype and the role of immune cells in the pathogenesis of X-linked Charcot-Marie-Tooth disease (CMT1X). METHODS: The probands of the two families with X-linked dominant inherited peripheral neuropathy were evaluated clinically, electrophysiologically, pathologically and genetically. The available family members were genetic analyzed and the novel mutations were compared with other known ones. RESULTS: (1) In both families, affected members presented progressive weakness and wasting of distal extremities and it seems that males suffered more severely than affected females with onset in the first decade of their life. Proband of family 1 showed moderately elevated CSF protein and marked increase of IgG-syn in CSF.(2) Nerve conduction velocity (NCV) of the peripheral nerves was intermediately slow in both motor and sensory nerves exhibiting the features of demyelination. Brain-stem auditory evoked potentials (BAEPs) was abnormal in the proband of family 1: delayed I-III interpeak intervals were recorded but with normal III-V interpeak intervals. (3) Sural nerve biopsy in the probands of the two families showed a prominent distinguished loss of myelinated fibers and a few clusters of regenerating axons without conspicuous onion-bulb formations. Thinly myelinated fibers was prominent in family 2 but not in family 1. Immunohistochemical staining showed that there were positive CD68 cells in the endoneurial space and lamellar sheath. (4) By genetic testing, we identified two novel missense mutations of GJB1 gene, which resulted in Ile127Phe amino acid substitution in family 1(located in the intracellular loop of connexin 32) and Asp178Gly amino acid substitution in family 2 (located in the 2(nd) extracellular loop of CX32), respectively. Both mutations were highly conserved in low species and were predicted to be possibly damaging through Polyphen prediction tool. CONCLUSION: The two novel GJB1 gene mutations cause a spectrum of clinical manifestations of CMT1X in both families. However, the mutations site of CX32 alone cannot predict these phenotypic variations in CMT1X fully. The immune system may be involved in the pathogenesis of the disease. PMID- 20193561 TI - [Analysis of features for suicide attempters at emergency departments in general hospitals]. AB - OBJECTIVE: To investigate the prevalence of various mental disorders of suicide attempters and analyze the clinical features of suicide attempters with mental disorders. METHODS: The investigators randomly selected four Class III general hospitals from different parts of Shenyang and collected 239 suicide attempters over 15 years old at emergency room. When the conditions of suicide attempters improved after rescue, the investigators studied by suicide general table, self injury questionnaire, Hamilton Depression Rating Scale for Depression-24 and Structure Clinical Interview for DSM-IV Axis I Disorders-Patient Edition. RESULTS: The overall prevalence of mental disorders in attempted suicides was 69.46% while self-injury, one of the highest prevalent mood disorders, accounted for 48.12%. During the year before suicide, only 7.23% of the suicide attempters with mental disorders consulted a psychologist or psychiatrist, and took anti psychosis drugs, anti-depression or anti-anxiety drugs. Suicide attempters with mental disorders often committed suicide less impulsively. And their purpose was to relieve themselves and reduce the burden of others so that the rate of self help was lower after their injuries occurred; suicide attempters with mental disorders had more obvious symptoms. And their degrees of depression were greater (P < 0.05) than ones without mental disorders. CONCLUSION: The prevalence of mental disorders at emergency rooms in general hospitals is high in suicide attempts, but the pre-suicide consulting rate remains so low. The depressive components of mental disorders are most directly related to suicidal behaviors of suicide attempters. PMID- 20193562 TI - [Mediation of cellular immune response by TP5 in pathogenesis of myasthenia gravis]. AB - OBJECTIVE: To evaluate the effects of TP5 upon the production of IFN-gamma and different T cell subsets by human peripheral blood mononuclear cells (PBMCs) from patients with myasthenia gravis (MG) and to provide experimental rationales for TP5 in clinical therapy of MG. METHODS: PBMCs were isolated from peripheral blood of MG individuals and cultured with anti-CD3. The level of IFN-gamma in culture supernatants was examined by ELISA. The subsets and frequency of IFN-gamma producing cells were examined at a single-cell level by flow cytometry. RESULTS: After PBMCs stimulation with anti-CD3 and TP5 (300 microg/ml), the level of IFN gamma expression was significantly inhibited (P(child) = 0.0001, P(adult) = 0.01); and the level of IFN-gamma expression from normal adult and child controls was also significantly inhibited (P(child) = 0.009, P(adult) = 0.0001). In addition, the inhibition of TP5 on the production of IFN-gamma by PBMCs from MG children was lower compared with normal child control. But as compared with normal adult control, the inhibition of TP5 showed no significant difference in MG adults (P(adult) = 0.481). TP5 inhibited the expression of IFN-gamma by CD8+ T cell and CD4+ T cell. CONCLUSION: TP5 can inhibit the response of cellular immune by decreasing the production of IFN-gamma in MG consequence display that the level of IFN-gamma significant decreased with the addition of TP5 and anti-CD3. But after considering the age, the level of IFN-gamma in MG children was no as much inhibited as normal child. TP5 inhibits the expression of IFN-gamma by CD8+ T and CD4+ T cells. PMID- 20193563 TI - [Expression of P53, COX2 and CD44V6 in early-stage squamous carcinoma of cervix with lymph vascular space invasion positive and negative and its relationship with prognosis]. AB - OBJECTIVE: To investigate the relationship between lymph vascular space invasion (LVSI) and various clinicopathologic factors in early-stage cervical squamous carcinoma; to explore the expression of P53, COX2 and CD44V6 in early stage squamous carcinoma of cervix and its relationship with prognosis. METHODS: A case controlled study was conducted to compare LVSI positive group (n = 44) in early stage squamous carcinoma of cervix with LVSI negative group (n = 44). Expression of P53, COX2 and CD44V6 were evaluated by immunohistochemical method to analyze the relationship between LVSI, P53, COX2 and CD44V6 and various clinicopathologic factors and to investigate their prognostic influences. RESULTS: LVSI positive was correlated with lymph node metastasis and deep stromal invasion. The 5-year disease-free survival was 68.9% in LVSI positive group versus 94.7% in LVSI negative group (P < 0.01). And the 5-year overall survival was 70.2% in LVSI positive group versus 100% in LVSI negative group (P < 0.01) with a significant difference. COX2 was correlated with clinical stage and tumor volume while there was no correlation with P53, CD44V6 and clinical factors. The overall survival of P53, COX2 and CD44V6 positive cases were significantly shorter than that of negative ones, especially in constant positive cases of 3 markers (disease-free survival 60.0 months shorter than constant negative cases with an overall survival of 91.3 months, but there was no significant difference). CONCLUSION: LVSI is correlated with lymph node metastasis and deep stromal invasion in the early-stage squamous carcinoma of cervix while it is negatively correlated with disease-free survival and overall survival. COX2 is correlated with clinical stage and tumor volume. Furthermore P53 and CD44V6 are not correlated with clinical factors. The overall survival of P53, COX2 and CD44V6 positive cases are significantly shorter than that of negative ones. PMID- 20193564 TI - [Biomechanical study and clinical application of cannulated compression screws with across solid frame for intertrochanteric fractures]. AB - OBJECTIVE: To evaluate the safety and efficiency of treating the senile intertrochanteric fractures with cannulated compression screws (CCS) with across solid frame in femur head via biomechanical tests and clinical application. METHODS: Biomechanical tests: the fracture model was made in 31-A1.3 style, 6 pairs of flesh and embalmed cadaveric femurs were mechanically tested in a single limb stance configuration. A material testing machine was used to apply vertical loads onto the femoral head. Both stiffness and reverse turn were recorded. Clinical application: from 1998 to 2006, According to damage control orthopedics (DCO) and American Society of Anesthesiologists (ASA) and the Evans classification, 51 patients received treatment with CCS with across solid flame in femur head. All the cases were followed up for 12 to 36 months (mean: 18 months). RESULTS: the differences between two groups in BMD (bone mineral density) were of statistical significance. And tensile rigidity and torsional rigidity of CCS were strong enough to bear weight. The CCS group had a lesser amount of blood loss or transfusion and lower treatment expenses. CONCLUSION: Cannulated compression screw with across solid flame is strong enough to be employed as an effective method to treat aged intertrochanteric hip fractures with the advantages of simple procedure, minimal invasion, stable fixation and weight bearing. PMID- 20193565 TI - [Outcomes of early surgery combined with anti-vasospasm agents treat ruptured cranial aneurysms: an analysis of 127 cases]. AB - OBJECTIVE: Retrospective study on 127 cases of early microsurgery combined with antivasospasm agents for treatment of subarachnoid hemorrhage after the rupture of intracranial aneurysm. To evaluate the microsurgery for early-stage (3 days) of ruptured aneurysm. METHODS: 127 cases of subarachnoid hemorrhage after the rupture of intracranial aneurysm were diagnosed by MRI and CTA. Patients underwent early microsurgical clipping of intracranial aneurysm followed by antivasospasm agents treatment were retrospectively analyzed for their clinical manifestation, characteristics of imaging presentation, the curative effects and experiences of different operative approaches, surgical methods and techniques, pharmaceutical treatment and other integrated management. RESULTS: In all 127 cases, organized blood clot accompanied with subarachnoid hemorrhage and cerebral vasospasm surrounding the ruptured aneurysm was found in the course of surgical probing, among which 21 aneurysms ruptured during the operation; according to the GOS, 109 cases were cured or free of symptom, 23 cases got a transient hemiparalysis or aggravation of hemiparalysis, among which 18 cases were free of symptom, 9 were slight disability, 6 were severe disability, 3 cases die when discharged. CONCLUSIONS: Early operation could prevent second-time rupture effectively, lower the death rate, and at the same time lower the occurrence of cerebral vasospasm and the succeeding damage caused. Cerebral vasospasm is still the serious complication of subarachnoid hemorrhage of ruptured aneurysm and inappropriate management would cause critical consequences. Antivasospasm agents used postoperative could help preventing cerebral vasospasm and maintaining function. PMID- 20193566 TI - [A simple scoring system to evaluate the severity of acute-on-chronic liver failure in hepatitis B]. AB - OBJECTIVE: To establish an objective, simple and sensitive scoring system to evaluate the severity of acute-on-chronic liver failure in hepatitis B. METHODS: The clinical data of patients (194 survivals and 215 deaths) with acute-on chronic liver failure in hepatitis B were collected and analyzed prospectively. 7 clinical indexes, including the hepatic encephalopathy, creatinine, prothrombin activity, serum total bilirubin, infection, the dimension of liver, the maximum depth of ascites, were scored objectively and simply from 0 to 4 points according to their severity. Then we calculated every patient's total score and divided the 409 patients into two groups: the one was 309 patients and the other is 100 patients. The first group was to establish the severity scoring system and define the cut-off-point, the second group was to test the severity scoring system. RESULTS: The total score of the 144 patients in the survival group was 6.9 +/- 3.2, 165 patients in the dead group was 15.8 +/- 4.0, respectively. There were significant differences (P < 0.01) between the two groups. The area under ROC curve was 0.953. The cut-off-point is 9.5. The sensitivity was 0.97, the specificity was 0.82. The second group patients' total score were divided into two groups: the one is > or = 10 score and the other is < or = 9 score. The prognosis of the first group was much worse than the second group, it's mortality rate was 87.5%; the second was 2.3%. There were significant differences between the two groups (P < 0.01). CONCLUSIONS: This scoring system was simple, sensitive and objective to evaluate the severity of acute-on-chronic liver failure in hepatitis B. PMID- 20193567 TI - [Evaluation of SPECT in lymph node staging for lung cancer]. AB - OBJECTIVE: To assess the usefulness of single photon emission computed tomography (SPECT) in detection of mediastinal lymph node metastasis from lung cancer. METHODS: Computed tomography (CT) and SPECT were performed in 110 patients with lung cancer. Surgical staging was performed in all patients, and the results of the two modalities were compared with the pathologic findings. RESULTS: Cancerous nodes were found in 56.4% of the patients. The sensitivity of CT in detecting mediastinal node metastasis was 63.6%; specificity was 69.7%. These rates for SPECT were 83.3% and 67.4%, respectively. Furthermore, the accuracy of CT and SPECT were 67.3% and 70.9%, respectively. However, SPECT had more limited spatial resolution than did CT. CONCLUSION: SPECT is useful in evaluation of mediastinal node metastasis in lung cancer, especially for patients with enlarged nodes at CT. PMID- 20193568 TI - [Clinical application of MSCT in diagnosis of intestinal obstruction]. AB - OBJECTIVE: To investigate the role of various multiple slice computed tomography (MSCT) and its reconstruction techniques in diagnosing intestinal obstruction (IO). METHODS: 419 cases diagnosed as IO by MSCT and proved by operations or follow up were analysed, retrospectively. RESULT: As to the presence diagnosis of IO, in all the patients, CT diagnosis was consistent with the final results, while X-ray plain film had an accuracy of only 60.5% (237/392). The causes of IO included adhesion 88.6% (117/132), neoplasm 98.2% (112/114), external or internal hernia 93.5% (43/46), intussusception 97.4% (37/38), inflammatory disease (including 7 cases paralytic ileus, 83.3%, 30/36), enterolith 88.5% (23/26), bowel torsion 90.9% (10/11), trauma 62.5% (5/8), ischemia 100% (6/6), congenital lesion (100%, 2/2). Total sensitivity of etiology diagnosis with CT was 92.8% (384/419), with accuracy, false positive and false negative to be 91.9% (385/419), 1.0% (4/419) and 7.2% (31/419), respectively. CONCLUSION: MSCT can correctly diagnose the presence of the ileus, as well as can obviously enhance the accurate rate of diagnosis of its causes and characteristics, position, existence of close-loop and strangulation. PMID- 20193569 TI - [Clinical analysis of surgical treatment of odontoid fracture]. AB - OBJECTIVE: To evaluate the therapies and clinical outcome for different types of odontoid process fracture. METHODS: Twenty-one patients with odontoid process fracture were treated with different therapies for different Anderson-D'Alonzo classifications: three cases of type I were treated by traction of occipital-jaw band and fixed with head-neck-chest plaster at 6 weeks; thirteen cases of type II were treated by cannulated screws following skull traction and reduction; and for the cases of type III, one was fixed with screw when the fracture was reduced by skull traction, and four with atlantoaxial pedicle screw. RESULTS: All cases were followed up for a mean of 9 months (range: 3 - 48). All cases achieved bony union. No post-operative complication was found. CONCLUSION: Odontoid process fracture should be treated according to different types. Conservative treatment for type I fracture and cannulated screws for type II and low type III fracture can obtain a satisfactory outcome. Atlantoaxial pedicle screw should be chosen if the superficial type III fracture is not suitable for cannulated screw. PMID- 20193570 TI - [Effects of high thoracic epidural anesthesia on ventricular remodeling and expression of beta(3)-adrenoceptor in rats with heart failure induced by acute myocardial infarction]. AB - OBJECTIVE: To investigate the effect of high thoracic epidural anesthesia on ventricular remodeling and cardiac function in rats with heart failure induced by myocardial infarction, and to investigate their mechanism. METHODS: Rats that had been established successively model were randomly divided into S group (n = 12), HTEA group and CHF group (24/group). 9.0 g/L normal sodium 100 microl/kg was injected to epidural cavity twice a day separately in group S and group CHF. 1.25 g/L bupivacaine 100 microl/kg was injected to epidural cavity twice a day in group HTEA. Epidural injection was started 24 hrs after the epidural surgery and continued 4 weeks. Then the change of cardiac function was observed by using echocardiogram. The ratio of heart weight to body weight (HW/BW) and the ratio of left ventricular weight to body weight (LVW/BW) were measured. Noninfarct ventricular tissue were stained with hematoxylin-eosin (HE) and Masson's trichrome respectively. beta(3)-adrenoceptor levels and eNOS levels were detected with reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. RESULTS: LVEDD and LVESD were significantly decreased in the group HTEA compared with group CHF (P < 0.01), while LVEF% and LVFS% were significantly increased (P < 0.01). The ratios HW/BW and LVW/BW were significantly increase in the group CHF compared with the group S (P < 0.01), but they were limited in the group HTEA (P < 0.01). Hypertrophy and edema, degeneration and necrosis of myocytes can be seen in rats with CHF, as well as muscle fibers disruption and collagen fiber increase, while the pathological amorphous were attenuated in HTEA rats. beta(3)AR and eNOS mRNA levels were significantly decreased in the group THEA compared with the group CHF. CONCLUSIONS: These results indicate that HTEA could ameliorate ventricular remodeling and cardiac function in rats with heart failure induced by myocardial infarction. The mechanism could involve decreases of beta(3)AR expression in rats of heart failure. PMID- 20193571 TI - [Experimental study of protective mechanism of Lipo-PGE(1) on hepatic ischemia reperfusion injury]. AB - OBJECTIVE: To explore protective mechanism of Lipo-PGE(1) on hepatic ischemia reperfusion injury. METHOD: Twenty-one adult dogs were divided into three groups randomly: CON group, IV group and SMA group, each group includes seven dogs. Animals were occluded porta hepatis 45 min and reperfused 60 min to establish I/R injury models. Lipo-PGE(1) administration was conducted once before porta occlusion 5 min and after reperfusion 60 min in IV and SMA group, the dosage of Lipo-PGE(1) was microgxkg(-1) and rate was 0.05 microgxkg(-1)xmin(-1); and 0.9% sodium chloride administration was conducted once at same time, the rate of NS was 2 mlxkg(-1). CT perfusion imaging, free pressure of portal vein, oxygen content of portal vein and hepatic oxygen delivery, index of liver function (ALT, LDH and TB) were performed in succession and compared before and after I/R. Simultaneously, the morphology of liver samples were observed by light microscope and electron microscope. RESULTS: (1) The liver perfusion was markedly decreased in the CON group, and moderately decreased in IV group and mildly in SMA group. (2) There was no significant difference of CpvO(2) in group comparison (P > 0.05) before and after I/R, but there was an increasing tendency in SMA group after I/R. There was significant difference of HDO(2) in group comparison before and after I/R (P < 0.05), but mildly in SMA group. (3) FPP increased obviously after I/R in control group, but there were no significant differences in the other groups. (4) The serious injury of liver in CON group after I/R was detected under light microscope and electron microscope, and moderately improved in IV group and markedly improved in SMA group. CONCLUSION: The protective mechanisms of Lipo PGE(1) on hepatic ischemia-reperfusion injury include: improving microcirculation, releasing FPP, increasing CpvO(2) and HDO(2), as well as alleviating parenchyma injury. PMID- 20193572 TI - [Spatiotemporal characteristics of seasonal influenza in mainland China]. AB - OBJECTIVE: To study the spatiotemporal distribution and seasonal characteristics of influenza and to explore its transmission patterns, in the mainland of China. METHODS: Spatiotemporal cluster methods and spatial trend surface methods were used to analyze the influenza surveillance data. RESULTS: There were a summer peak in the south from June to August (RR(paediatric) = 1.31, P < 0.01; RR(internal) = 1.74, P < 0.01) and a winter peak from December to January (RR(paediatric) = 1.45, P < 0.01; RR(internal) = 1.45, P < 0.01) in the northern part of the country, during every epidemic season. Influenza virus in mainland China seemed to spread from the southern to the northern parts of the country, in a progressing way. CONCLUSION: In the southern part of the country, it is more important to take prevention and control measurements on influenza from June to August but for the northern part, the key period is from December to January. It is more important to timely identify the variation of the influenza virus, in the southern part of the country. PMID- 20193573 TI - [Epidemiological characteristics of 420 influenza A (H1N1) cases confirmed in the early stage of the epidemic in mainland China]. AB - OBJECTIVE: To describe the epidemical characteristics of A (H1N1) influenza identified in the early stage (from May 11 to June 22, 2009) of the epidemic, in mainland China. METHODS: Epidemical characteristics of 420 confirmed A (H1N1) influenza cases reported from May 11 to June 22, 2009 were analyzed descriptively, including the distribution of age, sex, source of infection, main symptoms and incubation period. RESULTS: A total of 77.8% early cases in mainland China were imported from other countries. Three countries including America, Canada and Australia were attributed to 90% of the imported cases. Most of the cases were from 6 months to 73 years old, with 94% of them under 50 years. Most of the symptoms would include fever (81%), cough (40%) and sore throat (35%). The mean incubation period of second-generation cases was 4.3 (4.2 +/- 1.5) days. CONCLUSION: Imported cases dominated the total cases in the early stage of the epidemic had similar gender distribution of those from exporting countries. Fever, cough and sore throat were the three main symptoms manifested in influenza cases. 2.5 +/- 1.9 (1 - 11) days was found in imported cases between the day of off-board and the onset of symptoms. The incubation period was 4.3 +/- 1.7 (1 - 8) days among the secondary cases. PMID- 20193574 TI - [Pattern on the spread of novel influenza A (H1N1) and quantitative assessment of containment in mainland China]. AB - OBJECTIVE: To study the epidemic tendency of emerging influenza A (H1N1) in mainland China, and to explore the different patterns of spread on the disease under the following contexts: (1) To stop the temperature screening program at the border areas of the country; (2) To stop measures of prevention and control on those identified cases and their close contacts; (3) To strengthen programs for the foreign immigrants on 'home quarantine'. METHODS: Under relevant parameters and information on the transmission link from different reference data, the patterns of influenza spread were simulated by Monte Carlo method. RESULTS: The temperature screening on border could inhibit the transmission of influenza A (H1N1) to some extent, so that after 3 months the cumulative number of cases will be reduced by 21.5% (1718 cases) and transmission speed of influenza A (H1N1) in mainland China will be delayed by about 4 days. Furthermore, taking positive measures of prevention and control could efficiently slow down the epidemic, so that after 3 months the cumulative number of cases will be reduced by 93.4% (about 90 thousand cases) and it would be delayed by about 15 days if influenza A (H1N1) spreads to the whole country. In addition, if the immigrants were able to practise quarantine measures consciously by themselves at home the effect of prevention and control against influenza A (H1N1) would be more significant. If 30%, 60% and 90% of immigrants would take quarantine measures home consciously, after 3 months the cumulative number of cases will be reduced by about 15% (about 940 cases), 34% (about 2230 cases) and 64% (about 4180 cases), respectively. Also, influenza A (H1N1) spreads to the whole country will be delayed by about 4 days, 10 days and 25 days, respectively. It is difficult to curb fully the development of the epidemic by taking existing control measures, and influenza A (H1N1) may spread to almost all provinces after about 3 months. CONCLUSION: The effects of existing prevention and control measures were objectively assessed and the results showed the necessity and effectiveness of these measures against the transmission of influenza A (H1N1), in the mainland of China. PMID- 20193575 TI - [Avian influenza virus infection in people occupied in poultry fields in Guangzhou city]. AB - OBJECTIVE: To conduct serological investigation on H5N1/H9N2/H7N7 infection among people occupied in poultry fields. METHODS: Serum samples were collected from people working in live poultry and none-poultry retailing food markets, poultry wholesaling, large-scale poultry breading factories and in small-scale farms, wide birds breeding, swine slaughtering houses and from normal population. Antibodies of H5, H9 and H7 with hemagglutination inhibition and neutralization tests were tested and analyzed. Logistic regression and chi(2) test were used. RESULTS: Among 2881 samples, 4 were positive to H5-Ab (0.14%), 146 were positive to H9-Ab (5.07%) and the prevalence of H9 among people from live poultry retailing (14.96%) was the highest. Prevalence rates of H9 were as follows: 8.90% in people working in the large-scale poultry breading factories, 6.69% in the live poultry wholesaling business, 3.75% in the wide birds breeding, 2.40% in the swine slaughtering, 2.21% in the non-poultry retailing, 1.77% in the rural poultry farmers and 2.30% in normal population. None was positive to H7-Ab among 1926 poultry workers. CONCLUSION: The H5 prevalence among people was much lower than expected, but the H9 prevalence was higher. None of the populations tested was found positive to H7-Ab. There was a higher risk of AIV infection in live poultry retailing, wholesaling and large-scale breading businesses, with the risk of live poultry retailing the highest. The longer the service length was, the higher the risk existed. PMID- 20193576 TI - [Investigation on the source of the first human of avian influenza A (H5N1) case in Beijing]. AB - OBJECTIVE: To investigate the source of the first human case of avian influenza A (H5N1) infection in Beijing. METHODS: Interviewing the relatives of the case and other key persons, collecting and detecting samples of related biological, epidemiological and environmental data of the case were conducted. Later, the infection source was thoroughly investigated. RESULTS: The case ever contacted a slaughtered duck 5 days prior to the onset of illness, and the duck was bought from a stall of a wet market in Yanjiao area of Hebei province. Ten environmental samples were collected in this stall and the neighboring stall of the market. Another 6 samples were tested positive for H5N1 virus by PCR method, with 5 virus strains isolated. The whole-genome sequencing indicated that the amino acid homology between the H5N1 virus strains from the environment and the virus isolated from the case reached 99.8% - 100%. CONCLUSION: From both epidemiological and virological evidence, it was proved that the first human case of avian influenza A (H5N1) infection in Beijing was infected by a duck that carrying H5N1 virus the case contacted 5 days proceeding the onset of illness. PMID- 20193577 TI - [Needs on information related to influenza pandemic by the public]. AB - OBJECTIVE: To understand the information needs on human infection with avian influenza (H5N1), A (H1N1) and influenza pandemic in different time periods and create well-targeted messages by the public, so as to develop communication with the public effectively when human infection with avian influenza (H5N1), A (H1N1) and influenza pandemic occur. METHODS: Data were collected through questionnaire over telephone calls. The questionnaire was self-designed, revised after pilot testing. RESULTS: The effective response rate in this telephone survey was 54.33%, higher than those in Beijing and Shanghai. The respondents felt that government's propaganda during the influenza virus-active period was more helpful and instructive than those in the period when influenza was relatively inactive (chi(2) = 17.41, P = 0.000). Trust to the government by the public was higher in the influenza virus-active than in the relatively inactive period (chi(2) = 8.15, P = 0.004). As to the information needs, the respondents reflected that during the time period of relative influenza inactivity, they viewed the basic knowledge of human infection with avian influenza (H5N1) as their top priority, while in the influenza virus-active period, the feasible preventive measures was their top priority. The pandemic-related information needs in the influenza virus-active period and in the time period of relative influenza inactivity were similar, demonstrating that the respondents had no perceptual knowledge of influenza pandemic and had poor awareness on the pandemic. The respondents were not used to wear a mask to cover their mouths and noses when sneezing, but were quite knowledgeable about the following preventive measures as: avoid going out and at the crowded areas, wash hands frequently etc. Around 2% to 6% of the respondents did not have any information needs. CONCLUSION: The response rate in this telephone survey was fairly high, indicating that telephone survey was well accepted by Guangzhou residents. The public was satisfied with the government's propaganda activities and trusting the government. Public health professionals should develop communication messages closely related to the epidemic situation to target the information needs from the public. PMID- 20193578 TI - [Personal protective and healthcare seeking behaviors urban residents before and during an influenza pandemic in Beijing]. AB - OBJECTIVE: To provide evidence-based recommendations to the government on strategies for reducing the impact of the imminent influenza pandemic, we conducted a survey on the personal protective and healthcare seeking behaviors of Beijing residents in the wake of the worldwide epidemic of the novel 2009 H1N1 influenza virus, and potential changes in these behaviors during a full-blown pandemic. METHODS: We used a two-stage Mitofsky-Waksberg telephone survey to collect information for Beijing residents >/= 18 years of age and weighted the sample by the census estimate of Beijing population for 2008. A structured questionnaire was used to collect information about the respondents' knowledge regarding the novel influenza virus, current personal protective and healthcare seeking behaviors during a full-blown influenza pandemic. RESULTS: 286 Beijing urban residents were interviewed during May 15 to 18 (response rate: 62%). 77% (95%CI: 71% - 82%) of the residents that they would cover their sneezes at home, and 93% (95%CI: 89% - 96%) would do so in a public place. Of the residents would cover their sneezes at home, 66% (95%CI: 57% - 74%) would covered their sneezes by hand, 33% (95%CI: 25% - 42%) by facial tissue, and only 0.4% (95%CI: 0.1% - 2.9%) by sleeves. Similarly, of the residents would cover their sneezes at a public place, 64% (95%CI: 56% - 71%) would cover their sneezes by hand, 33% (95%CI: 26% - 41%) by facial tissue and 0% by sleeves. 46% (95%CI: 32% - 59%) of the residents would wash their hands after covering their sneezes with hand in public places, and 77% (95%CI: 64% - 89%) would do so at home. Higher percentages of residents would wear a mask (63%, 95%CI: 56% - 70%) and get vaccinated (43%, 95%CI: 37% - 50%) during a pandemic than under currently situation (3.5%, 95%CI: 1.7% - 7.0% for wearing a mask; 13%, 95%CI: 9.8% - 18% for getting vaccinated). 86% (95%CI: 81% - 89%) of the residents would visit a doctor for an influenza like illness during a pandemic, similar to the percentage currently seen (76%, 95%CI: 70% - 81%). 71% (95%CI: 63% - 78%) of the residents would visit a doctor for influenza-like illness and would choose a tertiary medical center; with percentage (74%, 95%CI: 66% - 80%) similar to the one during a pandemic. CONCLUSION: Beijing residents need to be aware of the proper ways to cover their noses when sneezing (especially using their sleeves more), and to wash their hands. An effective plan to triage patients should be immediately established to efficiently utilize the limited healthcare resources, which would likely be further strained during a pandemic. PMID- 20193579 TI - [Epidemiological review on novel influenza A (H1N1) virus infection]. PMID- 20193580 TI - [Molecular epidemiological survey on HIV-1 among the injecting drug users population in Shenzhen]. AB - OBJECTIVE: To study the prevalent status of human immunodeficiency virus-1 (HIV 1) subtypes in IDU (injecting drug users) population in Shenzhen and to study their source of infection in order to predict the epidemic trend and evolution. METHODS: 166 HIV-1 positive plasma from the IDUs was collected from 1996 to 2008. HIV-1 env genes were amplified by nested-PCR from RNA. The C2-V3 regions (450 bp) of HIV-1 env were sequenced for analyses. Phylogenetic analyses were performed on the nucleotide sequence data. RESULTS: Among 166 samples, there were 6 HIV-1 strains including CRF01_AE, CRF08_BC, CRF07_BC 3 circulating recombinant forms (CRFs) and B', C, A1 3 subtypes. Data from the genotype analyses showed that 65.06% (108/166) were CRF01_AE, 19.88% (33/166) were CRF07_BC, 6.02% (10/166) were CRF08_BC, 7.23% (9/166) were subtype B', 0.60% (1/166) were subtype C and 1.20% (2/166) were subtype A1. Phylogenetic tree analysis showed that some of HIV 1 clusters defined in CRF01_AE, CRF07_BC and subtype B' in different time groups. Significant increase of gene distance in CRF01_AE and CRF07_BC strains in the three different periods. CONCLUSION: CRF01_AE and CRF07_BC were the major epidemic CRF strains among the IDU population in Shenzhen while the subtype B', C, A1 and CRF08_BC were also circulating in IDU population in this region. The variation of all different subtypes was increasing through these years. PMID- 20193581 TI - [The median survival and the effect of antiretroviral therapy among HIV-positive former blood donors in Anhui province]. AB - OBJECTIVE: To estimate the median survival and the effect of antiretroviral therapy (ART) among HIV-positive former blood donors of Fuyang in Anhui province, China. METHODS: A retrospective survey was conducted among HIV-positive former blood donors, and data was collected on survivors who had received ART. Weibull function was used to calculate median survival of HIV-positive former blood donors. The effect of ART was estimated through comparing the actual number of deaths after ART with the expected number of deaths in those who did not receive ART. RESULTS: The median period of HIV infection was at the end of 1994, with the median survival of HIV-positive former blood donors in Fuyang as 10.8 years. By the end of September 2008, among 159 former blood donors, 74 received ART, with their mean CD(4)(+) T-cell count increased from 247.8/microl to 475.1/microl (P < 0.0001). 76 of the 159 former blood donors died. When comparing the expected number of deaths calculated by Weibull function, 31.7% of the total number of deaths was reduced. CONCLUSION: Result from this study was in consistent to the UNAIDS' figures that in the absence of treatment, the net median survival time after infection with HIV was estimated to be 11 years and ART has reduced about one third of the expected deaths. PMID- 20193582 TI - [Study on herpes simplex virus 2 infection and risky sexual behavior among HIV infected patients in a county of Yunnan province]. AB - OBJECTIVE: To explore the sero-prevalence and risk factors for herpes simplex virus 2 (HSV-2) infection and unprotected sexual behavior in an ethnically diverse population of HIV-infected subjects in a county of Yunnan province. METHODS: HIV-infected individuals attending for routine follow-up by local Center for Disease Control and Prevention (CDC) were recruited to participate in the study under 'informed consent'. A face-to-face questionnaire interview was administered to each participant. Blood was drawn for HSV-2 testing by HerpeSelect HSV-2 ELISA (Focus Diagnostics) and CD(4)(+) T counting. RESULTS: A total of 300 HIV-infected individuals participated in the study. The mean age of the subjects was 37.6 years with 76.7% as males. Ethnically, Han, Dai and Jingpo accounted for 44.3%, 37.3% and 16.0% of the sample, respectively. Half of the subjects reported HIV acquisition through injection drug use. The sero-prevalence of HSV-2 was 35.0%. Results from multiple logistic regression analysis indicated that individuals who acquired HIV through heterosexual contact were more likely to be HSV-2 positive than those who acquired HIV through injection drug use (OR = 4.244, 95%CI: 1.924 - 9.364), whereas Dai (OR = 0.300, 95%CI: 0.152 - 0.593) and Jingpo (OR = 0.376, 95%CI: 0.167 - 0.850) were less likely to be HSV-2 positive than the Hans. Among 105 people who were co-infected with HIV/HSV-2, 60 had sexual intercourses in the past 3 months and 41.7% of them reported no or inconsistent use of condoms. Most unprotected sexual contacts occurred within married couples. CONCLUSION: HSV-2 infection was highly prevalent among HIV infected individuals in this county, and a significant proportion of HIV/HSV-2 co infected subjects engaged in unprotected sex. HSV-2 testing, behavioral and biomedical interventions among HIV-infected individuals and their sexual partners should be involved in the local HIV prevention and control programs. PMID- 20193583 TI - [Association of hemorrhagic fever with renal syndrome and HLA-DRB allele polymorphisms in Han nationality, Hubei province]. AB - OBJECTIVE: To understand the association of human leukocyte antigen (HLA)-DRB polymorphism and patients diagnosed as hemorrhagic fever with renal syndrome (HFRS). METHODS: HLA-DR allele polymorphism was detected by PCR-sequence specific primers (PCR-SSP). Hantavirus (HV) typed as Hantaan virus (HTNV) and Seoul virus (SEOV) in patients were detected by RT-heminested PCR. RESULTS: The gene frequency of DRB1*0401-0411, *1001 and *1101-1105 in HFRS case group were 3.1%, 2.2% and 15.7% respectively. Compared with control group, it was significant higher in HFRS case group (RR = 13.87, 9.72 and 2.00 respectively with Chi-square value as 10.006, 6.324 and 6.472 respectively, P < 0.05). When compared with HFRS case group, the gene frequency of DRB1*1501-1502, DRB4 and DRB5 in control group were 11.0%, 19.0% and 16.9% respectively, markedly lower than in patients (RR = 0.45, 0.58 and 0.23 respectively. Chi-square values were 6.138, 4.583 and 21.076 respectively, P < 0.05). There was no significant difference in other HLA-DR gene frequencies. Mixed infection was found in Hubei, with HTNV slightly more than SEOV. Distinct hantaviruses could coexist in either different or the same geographic or ecological zores in Hubei province. Patients with HLA-DRB1*1101 1105 alleles were 81.8% (27/33) infected by HTNV and only 18.2% infected by SEOV, which had significant difference (P < 0.05). CONCLUSION: DRB1*0401-0411, *1001 and *1101-1105 were possibly associated with increased susceptibility to HV infection. On the other hand there was an inverse correlation among HFRS, DRB1*1501-1502, DRB4 and DRB5. PMID- 20193584 TI - [An epidemiological investigation on overweight and obesity in adults from Tianjin city]. AB - OBJECTIVE: This study aimed to explore the epidemiological characteristics and related factors of overweight and obesity in Tianjin adults. METHODS: With multi stage randomized cluster sampling, 19 271 people aged 18 years and over were selected from both urban and rural areas of six geographical regions of Tianjin in 2006, using a cross-sectional methodology. Data from these residents was collected, using a questionnaire by face-to-face interview conducted by trained interviewers. Demographic, anthropometric data were collected in all participants. Data was analyzed with SPSS 13.0 software. For diagnosis of overweight and obesity, we adopted the standard of overweight and obesity recommended for Chinese adults. Age, gender and area distribution of overweight and obesity in the population of Tianjin were described, and the related factors were analyzed. RESULTS: Prevalence of overweight and obesity in adults from Tianjin were 32.8% (95%CI: 32.1% - 33.5%) and 11.7% (95%CI: 11.2% - 12.2%), with the standardized rates as 33.1% and 12.2%, respectively. Those figures were higher than the national average levels. The prevalence rates of overweight and obesity were increasing with age. The overweight rate in 50 - 59 year olds and the obesity rate in 60 - 69 year olds reached their peak values. The prevalence rate of obesity was higher in rural (13.5%, with 95%CI: 12.8% - 14.2%) than in the urban areas (11.1%, with 95%CI: 10.4% - 11.7%) and in females (12.6%, 95%CI: 11.9% - 13.2%) than in males (10.9%, 95%CI: 10.3% - 11.5%). RESULTS: from logistic regression model analyses indicated that the prevalence of overweight and obesity in Tianjin were statistically associated with age, gender, educational level, smoking, alcohol consumption and exercises. CONCLUSION: As the urbanization progressing, the prevalence of overweight and obesity was much higher in the population of Tianjin city. Many factors were related to adults overweight and obesity. An active community-based public health intervention should be taken. PMID- 20193585 TI - [Study on risk factors and predictive model for lumbar intervertebral disc herniation in the rural population]. AB - OBJECTIVE: To explore the risk factors on the symptoms of lumbar intervertebral disc herniation so as to develop a predictive model for the disease. METHODS: With a population-based case-control study, 303 of 50 123 residents were diagnosed as having lumbar intervertebral disc herniation symptoms. 152 cases and 167 healthy controls, matched by gender and age, were randomly chosen as case and control groups. Questionnaires were used to collect information on the exposure to risk factors and logistic predictive model was then established. RESULTS: Through non-conditional logistic regression analysis, data showed that the positive family history of lumbar vertebra disorder, lumbar treatment or surgery, mental stress, acute low back injury, permanent work pose, and body mass index >/= 23.0 kg/m(2) were the risk factors among residents from the countryside. The area under the receiver operator characteristic curve of logistic predictive model was 0.809. When 0.4 was set as the classification cutoff, the total predictive correct rate, sensitivity, and specificity were 74.0%, 73.7%, and 74.3% respectively. CONCLUSION: The occurrence of lumbar disk herniation can in countryside population was affected by multi-variables including genetic and environmental, and could be predicted with the logistic regression model established by our group. The positive predictive results could be used to alarm the patients and doctors for prevention and treatment of the disease. PMID- 20193586 TI - [Study on the relationship between chronic diseases and falls in the elderly]. AB - OBJECTIVE: To explore the risk factors on chronic diseases related to falls in the urban-community elderly and to provide evidence for developing a three-tier program for prevention. METHODS: A cross-sectional study was conducted in one community of Beijing. People aged 60 years and over were selected, using a stratified cluster sampling method, and data on falls within the past 12 months and falls-related chronic diseases were collected through face-to-face interview. RESULTS: The incidence of falls was 18.0% within one year among the 1512 interviewees. Seven factors showed statistical significances through univariate analysis including diabetes mellitus (OR = 1.62), postural hypotension (OR = 1.84), hypertension (OR = 1.48), cerebral infarction (OR = 1.98), cataract (OR = 1.56), osteoarthritis (OR = 1.50), dementia (OR = 5.34) and depression (OR = 4.61). Data from multivariate logistic regression analysis showed that the risk factors for falls would include dementia (OR = 4.82), depression (OR = 4.27), postural hypotension (OR = 1.92) and suffering from several kinds of chronic diseases etc. CONCLUSION: The incidence of falls in an urban elderly community of Beijing was considered to be high. The risk of falls was higher among persons suffering from dementia and depression and having more than two kinds of chronic disease. The chances of falls would parallel the increase of several kinds of chronic diseases among the elderly, suggesting that measures should be actively taken to prevent from falls. PMID- 20193587 TI - [Application of the Children's Impact of Event Scale (Chinese Version) on a rapid assessment of posttraumatic stress disorder among children from the Wenchuan earthquake area]. AB - OBJECTIVE: To explore the reliability and validity of the Children's Impact of Event Scale (Chinese version, CRIES-13) and to determine the value and the optimal cutoff point of the score of CRIES-13 in screening posttraumatic stress disorder (PTSD), so as to provide evidence for PTSD prevention and identify children at risk in Wenchuan earthquake areas. METHODS: A total of 253 children experienced the Wenchuan earthquake were tested through Stratified random cluster sampling. The authors examined CRIES-13's internal consistency, discriminative validity and predictive value of the cut-off. PTSD was assessed with the DSM-IV criteria. Area under the curve while sensitivity, specificity and Youden index were computed based on the receiver operating characteristic curve analysis. Optimal cutoff point was determined by the maximum of Youden index. RESULTS: 20.9% of the subjects were found to have met the DSM-IV criteria for PTSD 7 months after the Wenchuan earthquake accident. The Cronbach's coefficient of CRIES-13 was 0.903 and the mean inter-item correlation coefficients ranged from 0.283 to 0.689, the correlation coefficient of the three factors with the total scale scores ranged from 0.836 to 0.868 while the correlation coefficient among the three factors ranged from 0.568 to 0.718, PTSD cases indicated much higher scores than non-PTSD cases, the Youden index reached maximum value when the total score approached 18 in CRIES-13 with sensitivity and specificity as 81.1% and 76.5% respectively. Consistency check showed that there were no significant differences between the results of CRIES-13 score >/= 32 and clinical diagnosis (Kappa = 0.529) from the screening program. CONCLUSION: CRIES-13 appeared to be a reliable and valid measure for assessing the posttraumatic stress symptoms among children after the earthquake accident in the Wenchuan area. The CRIES-13 seemed to be a useful self-rating diagnostic instrument for survivors with PTSD symptoms as a clinical concern by using a 18 cut-off in total score. Consistency check showed that there was no significant difference between the screening result of CRIES-13 score >/= 32 and clinical diagnosis. PMID- 20193588 TI - [Study on cancer incidence through the cancer registry program in 11 cities and counties, China]. AB - OBJECTIVE: Aim of this paper was to explore the trend and characteristics of cancer incidence in 11 areas (5 cities and 6 counties) in China. METHODS: Data from cancer registries during 1988 to 2002 collected from the 11 cancer registry points were used to analyze the trends and characteristics of cancer incidence rates. RESULTS: There were 695 050 newly developed cancer cases in this study. The crude rate of incidence and the world age-adjusted incidence were 215.50/10(5) and 170.97/10(5) respectively. The leading cancer sites were lung, stomach, liver, esophagus, breast, colon, rectum, pancreas, bladder and leukemia. The sixteen key cancers accounted for 85.56% of all the cancer cases. The crude incidence rate of all cancers had been significantly increased from 1988 to 2002. Among them, prostate (185.48%) ranked the fastest growing one followed by cancers of the gallbladder, breast, colon, ovarian, lymphoma, bladder, pancreas, rectum, lung, leukemia and liver. The one that had reduced the most was cervix uteri (17.00%), followed by esophagus, stomach and nasopharynx. CONCLUSION: Crude cancer incidence rate increased in the 11 areas in China from 1988 to 2002. The ranking of pancreas cancer, bladder cancer and leukemia came into the top ten. Even though the incidence rates of prostate and gallbladder cancer were relative low but had a fast increase. The results of this study provided a scientific base for the development of a better strategy on cancer prevention and control in China. PMID- 20193589 TI - [Time trend analysis of incidence rate for nasopharyngeal carcinoma in urban Shanghai]. AB - OBJECTIVE: To explore the secular trend of incidence for nasopharyngeal carcinoma (NPC) in urban Shanghai during 1973 - 2005. METHODS: The incidence data from the population-based cancer registries in Shanghai was used in our analysis. We calculated the crude incidence rates, age-adjusted incidence rates, truncated rates and cumulative rates of NPC. The annual percentage change (APC) was used as an estimate of the secular trend. RESULTS: Over 33 years, a total of 7889 incident NPC cases in urban Shanghai were registered for 5555 males and 2334 females, respectively. The incidence of NPC had remained stable in males during the period (APC = -0.250%, P = 0.340), but a decreasing trend was observed in females with an average reduction of -1.577% (P = 0.000) per year. During the period of 1973 - 1976 to 2001 - 2005, the crude incidence rates changed from 4.56 to 6.18 and from 3.96 to 2.41 per 100 000 in males and females, and the age adjusted rates from 4.12 to 3.96 and from 2.18 to 3.42 per 100 000 in males and females, respectively. CONCLUSION: From 1973 to 2005, the incidence of NPC was stable in males while having a decline in females, indicating that further epidemiological study and prevention for NPC should be addressed. PMID- 20193590 TI - [Monitoring the Microtus fuscus plague epidemic in Sichuan province during 2000 2008]. AB - OBJECTIVE: To analyze the epidemic tendency of Microtus fuscus plague during 2000 - 2008 in Sichuan province. METHODS: To investigate the plague each year according to "overall Plan of the Plague in the Whole Nation" and "Surveillance Program of Sichuan Province Plague". RESULTS: There were plague epidemic from 2000 to 2008, with the average density as 312.41/ha. 42.57% of the Microtus fuscus were infected by body Fleas. The Fleas Index was 0.88 and the Index for nest Fleas of Microtus fuscus was 55.89. Six kinds of animals were infected by not only the Microtus fuscus but also herd-dog, sand fox, Tibetan sheep, domestic cats and Cricetulus longicaulatus as well. The positive rate of live Microtus fuscus was 0.32% but 22.99% in the dead Microtus fuscus. The overall positive rate on serological test was 6.70%. There were 4 Sections, 11 species and 19 kinds Fleas identified and carrying 3 kinds of fleas, Callopsylla sparsilis, Amphipsylla tutua tutua and Rhadinopsylla dahurica vicina, with the overall infection rate as 0.054%. CONCLUSION: Plague among Microtus fuscus showed a continuous epidemic in Sichuan province during 2000-2008. PMID- 20193591 TI - [Analysis on VP7 and VP4 genes of human rotavirus G9 identified from children with diarrhea in Beijing, from 2007 to 2008]. AB - OBJECTIVE: To characterize the outer capsid protein VP7 and VP4 encoding genes of human rotavirus G9 strains detected in Beijing, from 2007 to 2008. METHODS: Full length of VP7 genes of G9 rotaviruses from 12 fecal specimens previously detected by dot-blot hybridization assay were amplified by RT-PCR and sequenced after being cloned into T vector. The sequences of these VP7s were compared to VP7 genes of rotavirus G9 prototype strains and recently circulating strains around the world. VP4 genes of these 12 G9 strains were amplified by nested-PCR for P genotyping. RESULTS: Sequence analysis for the full length of VP7 genes from these 12 specimens confirmed that they were G9 rotaviruses. P genotyping for VP4 genes revealed that both P[8]G9 and P[6]G9 were circulating in Beijing in the last 2 years. Sequence and phylogenetic analysis demonstrated that VP7 genes of G9 strains from Beijing in this study were clustered in the lineage III which resembled the G9 strains circulating in other places around the world, indicated by high identities of nucleotide and deduced amino acid sequences and were distant with the first reported G9 strain T203 identified in China in 1994. It was found that there were some consistent amino acid substitutes at the corresponding positions among VP7s from these 12 specimens and from Xinjiang and Wuhan, both in G9P[8] and G9P[6] strains. CONCLUSION: The rotavirus G9 strains both in combination of G9P[8] and G9P[6] were circulating in Beijing in the past years. It seemed that rotavirus G9 should be included in the list of surveillance for rotavirus in China. PMID- 20193592 TI - [Comparison of genotype characteristics between the circulating mumps virus strain in Beijing area and the vaccine strain]. AB - OBJECTIVE: To compare the genetic characteristics of mumps virus strain circulating in Beijing with vaccine strain and to preliminarily analysis the reasons of vaccine ineffectiveness. METHODS: The following methods were used: Isolation and identification of the mumps virus which had been circulating in Beijing, immunization history analysis, SH gene sequence analysis and comparison genotype homology with reference strains and analysis of the key amino acid sites of HN variation. RESULTS: In 38 mumps cases that virus had been isolated from, another seven cases were IgM negative. In 2007 and 2008, the positive rates on virus isolation, RT-PCR and IgM-decreased significantly, while the cases with immunization history had an increase. Cases without histories of vaccination had both higher positive rates on virus isolation and IgM. Thirty-eight strains belonged to F genotype virus, but vaccine strain was A genotype. The circulating viruses showed 5.6% sequence divergence on SH gene nucleotide and 16.0% - 18.1% from vaccine strain. Conservative hydrophobic amino acids on SH protein of some Beijing strains had changed. For example, there were 6 strains, from No.8: L-->F. The circulating viruses showed 2.3% sequence divergence on HN protein amino acid sequences and 4.2% - 5.3% from vaccine strain. Amino acids sites, which deciding the ability of cross-neutralization of the Beijing strains and vaccine strains were different. At the 354 and 356 sites, all the Beijing strains were different from the vaccine strains. The N-glycosylation sites on HN of Beijing strains were also different from those on vaccine strains. Locations 464 - 466 appeared to be NCS on Beijing strain, but locations 464 - 466 were NCR on the vaccine strains. Another 18 unknown function amino acids sites of all Beijing strains were different from those on vaccine strains. CONCLUSION: In recent years, genotype F became the main genotype of circulating strains in Beijing without genotype variation, but larger difference was found between them. There was a big difference between SH and HN protein of Beijing strains and vaccine strain, which might explain the ineffectiveness of the vaccine. PMID- 20193593 TI - [Population-based molecular epidemiologic study of rifampicin-resistant tuberculosis in rural area of eastern China]. AB - OBJECTIVE: To describe the drug resistance-related molecular characterization and clustering feature of rifampicin-resistant (RIFr) M.tuberculosis (M.tb) in rural area of eastern China. METHODS: All patients diagnosed as RIFr M.tb in Deqing and Guanyun county during one year period from 2004 to 2005 were included in the study. By proportion method of drug susceptibility test, 65 isolates were identified resistant to rifampicin and regarded as the studied strains. Hotspots of rpoB gene and katG gene were detected by direct DNA sequencing. Beijing genotype M.tb strains were identified by spoligotyping. IS6110-RFLP (IS6110 restriction fragment length polymorphism) and clustering analysis were performed on all RIFr M.tb isolates available. RESULTS: The mutations in 81 bp rifampicin resistance determination region (RRDR) of the rpoB gene were observed among 60 (92%) RIFr M.tb isolates, with mutation in locus 531 observed in the majority of RIFr isolates (37/65). 49 (82%) of the 60 isolates were multidrug resistant TB (MDR-TB), which were referred to as resistant to both RIF and isoniazid (INH). Through spoligotyping, 54(83%) isolates were identified as Beijing genotype strains. In clustering analysis of IS6110-RFLP, 24 isolates were grouped into 11 clusters, suggesting that the recent transmission of M.tb did exist among patients. Regarding the drug resistance profile in clusters, all the isolates in clusters were also MDR-TB. 7 clusters contained isolates carrying different mutations were related to RIF-resistance. Multivariate analysis showed the proportion of new cases in clustered patients is higher than that in the un clustered patients (new/previously treated: OR = 3.342; 95%CI: 1.081 - 10.32). CONCLUSION: The acquisition of rifampicin resistance in M.tb was more likely to be resulted from the selective growth of RIFr M.tb in the specific drug resistant M.tb such as isoniazid-resistant M.tb. Previous elongated irregular treatment might favor the epidemic of RIFr M.tb. PMID- 20193594 TI - [Study on abnormal glucose and lipid metabolism among 771 in-patients with ischemic stroke]. AB - OBJECTIVE: To study the epidemiological characteristics of abnormal glucose and lipid metabolism in in-patients with ischemic stroke. METHODS: A total number of 771 in-patients with ischemic stroke, hospitalized in the Department of Neurology/Endocrinology from Changzhou No. 2 Hospital from April 2007 to April 2008 were enrolled in this study. After identifying the condition of glucose metabolism, all diagnosis-undetermined patients received oral glucose tolerance test. RESULTS: Among in-patients with ischemic stroke, 41.8% of the patients were finally diagnosed as diabetes, with 23.4% classified as 'impaired glucose tolerance'. The prevalence of 'abnormal glucose metabolism' was 65.2% in total. If diabetes in the in-patients with ischemic stroke was diagnosed only by fast plasma glucose instead of oral glucose tolerance test, 58.5% diabetic patients would have been misdiagnosed. Abnormal lipid metabolism existed in inpatients with cerebral ischemic stroke were noticed. These abnormalities of lipid metabolism were mainly consisting of increased triglyceride and decreased HDL-C cholesterol. CONCLUSION: The majority of in-patients with ischemic stroke appeared to have had abnormal glucose and lipid metabolism. It seemed necessary to promptly and correctly diagnose these patients with abnormal glucose metabolism by oral glucose tolerance test to reduce the chances of developing the recurrence of stroke. PMID- 20193595 TI - [Study on the association of cytochrome P450 polymorphisms and the risk of esophageal cancer: a meta-analysis]. AB - OBJECTIVE: To examine the association between CYP1A1 polymorphisms (MspI and Ile/Val) and esophageal cancer (EC) by systematically reviewing the risk of the original studies. METHODS: Data from 16 papers (8 for MspI, 14 for Ile/Val) regarding case-control studies on the association of cytochrome P450 polymorphisms and risk of esophageal cancer was analyzed by dominant model (variant genotype vs. wild-type genotype) through meta-analysis. Stratified analysis was carried out according to the pathological types. RESULTS: In systematical analysis, CYP1A1 MspI variant genotype (TC + CC) had no association with EC risk (OR = 1.17, 95%CI: 0.82 - 1.66). Similar results were observed in esophageal squamous-cell carcinoma (ESCC) (OR = 1.17, 95%CI: 0.82 - 1.69) and esophageal adenocarcinoma (EAC) (OR = 1.39, 95%CI: 0.67 - 2.09). Individuals with the CYP1A1 Ile/Val variant genotype (Ile/Val + Val/Val) had an increased risk for EC, when comparing with wild type (Ile/Ile), with an OR of 1.39 (95%CI: 1.07 - 1.80). CYP1A1 Ile/Val variant genotype could increase the risk of ESCC (OR = 1.43, 95%CI: 1.07 - 1.91) but no significant association was found with EAC (OR = 1.20, 95%CI: 0.62 - 2.30). CONCLUSION: CYP1A1 gene polymorphism Ile/Val might have played a role in the development of ESCC but CYP1A1 MspI polymorphism might not be associated with the susceptibility of EC. PMID- 20193596 TI - [Influential factors of Hardy-Weinberg equilibrium on the study of association between gene polymorphism and disease]. AB - OBJECTIVE: According to the data collected from gastric cancer families comparative study, the influence factors of Hardy-Weinberg (H-W) equilibrium in the association studies of gene polymorphism and disease were analyzed to reveal the reasons that affecting the equilibrium deviation in the group. METHODS: Varieties of risk genotype for gastric cancer were analyzed and detected with H-W equilibrium, genetic linkage disequilibrium analysis and Cochran-Armitage trend test. RESULTS: (1) Significant deviations from H-W equilibrium were observed in IL-1B-31, IL-1B-511, IL-1RN and TNF-A-308 of the cases and controls (P < 0.01). MIF-173 tended to be equilibrium in the population. (2) Deviations from expectations of phenotypes combination probability were observed in two-site H-W chi(2) tests (P < 0.01). (3) The Cochran-Armitage trend test showed that distribution of IL-1B-511 and IL-1RN were significantly different (P < 0.05), suggesting that population stratification might have existed in the group. CONCLUSIONS: (1) Affected by frequency-dependent selection, under the combination of linkage disequilibrium, mutations and interaction, genotype frequency of IL-1B 31, IL-1B-511, IL-1RN and TNF-A-308 showed deviation from H-W equilibrium in population. (2) Two-site genetic equilibrium test model seemed better to reflect the differences of phenotypic combination fitness. (3) Population stratification was another factor to express the deviation from H-W equilibrium. PMID- 20193597 TI - [A multicenter retrospective analysis of diagnosis and treatment of 72 hemophagocytic syndrome patients.]. AB - OBJECTIVE: To explore early diagnosis of hemophagocytic syndrome (HPS) and effective treatment. METHODS: A multicenter retrospective study was carried out to analyze the causes, clinical features, laboratory findings, treatment and clinical outcomes of 72 patients with HPS. RESULTS: Among the 72 patients, EBV infection and T lymphoma were the most common initiating diseases. The most common clinical features were persistent fever (100%) and splenomegaly (83.3%). The diagnostic sensitivity was persistent fever (100%), peripheral cytopenia in two or more lineages (97.2%), high concentration of serum soluble CD25 (93.1%) and low NK cell activity (94.4%). The median percentage of serum glycosylated ferritin was significantly lower in patients in HPS group ?[(17.4 +/- 16.0)%?] than in control group ?[(53.6 +/- 13.3)%?] (P < 0.01). And the median level of serum TNF-alpha was significantly higher in patients group ?[(143.2 +/- 64.8) microg/L?] than in controls ?[(66.9 +/- 19.4) microg/L?] (P < 0.01). Hepatic dysfunction was seen in most patients (83.6%) mainly manifested as elevated liver enzymes and hypoalbuminemia. The 15-week total survival rate was 46.8% in 47 treated patients, and was 63% in 27 treated with fludarabine in combination with high dose methylprednisolone. The platelet count and fibrinogen level were significantly lower in death group than in survival group. CONCLUSIONS: The diagnostic sensitivities of presistent fever, peripheral cytopenia in two or more lineages, high concentration of serum soluble CD25 and low NK cell activity are relatively high and lacking hemophagocytosis does not exclude the diagnosis. Low percentage of glycosylated ferritin and high concentration of TNF-alpha would be helpful to the diagnosis. High dose methylprednisolone combined with fludarabine is an effective therapy. Platelet count and fibrinogen level are poor prognostic factors for HPS. PMID- 20193598 TI - [Study on Wnt and Notch signalling involves in regulation of hematopoietic microenvironment.]. AB - OBJECTIVE: To explore the mechanism of Wnt and Notch pathway involved modulating time and spatial restricted hematopoiesis. METHODS: Murine hematopoietic stem and progenitor cells (HSPCs) were isolated from bone marrow (BM) by using c-kit microbeads. E10.5 aorta-gonad-mesonephros (AGM), E12.5, E14.5, E16.5 fetal liver (FL) and adult BM derived stromal cells (StroCs) were isolated and co-cultured with c-kit(+)HSPCs. The floating cells in co-culture system were sorted and counted by FACS. Gene expressions of Wnt and Notch pathway were detected by quantitative PCR and protein expressions by immunostaining. RESULTS: Co-culturing HSPCs with AGM and FL-derived StroCs resulted in an expansion of c kit(+)population from 0.4 x 10(5)/well to (19.2 +/- 3.2) x 10(5)/well and (26.8 +/- 5.4) x 10(5)/well, respectively, being greater than that with BM-derived StroCs (P < 0.05). The percentage of c-kit(+)cells detected in AGM- and BM- derived StroCs culture system was (75.2 +/- 7.1)%, (74.1 +/- 6.2)% respectively, being higher than FL- derived StroCs culture system (63.4 +/- 5.3)% (P < 0.05). Wnt and Notch pathway genes expression varied at different phases of hematopoiesis. Wnt was highly expressed in AGM and FL derived StroCs, and, Notch did in AGM and BM derived StroCs. CONCLUSION: Wnt and Notch pathway are important modulators in regulating time and spatial restricted hematopoiesis. PMID- 20193599 TI - [The effects of AML1B and AML1/ETO on the transactivation of TSC genes.]. AB - OBJECTIVE: To investigate the effects of AML1B and AML1/ETO fusion gene on the transcription activity of TSC1 and TSC2 promotor and to explore its role in leukemogenesis. METHODS: The luciferase reporter plasmids of TSCs gene promoter containing a AML1 binding site were constructed, and cotransfected into CV-1 cells with AML1B or AML1/ETO expression plasmids separately. The transactivity of TSCs gene promoter was assayed by luminometer. RESULTS: AML1B exhibited a transactivity to TSC2 gene promoter in a dosage-dependant manner, but showed no significant transactivity to TSC1's. The transactivity to TSC2 gene promoter showed 8.55 fold increase as companed with control group at 75 ng of pCMV5-AML/B. AML1/ETO showed a significant transactivity to TSC1, but no transactivity to TSC2's. However, AML1/ETO antagonized the effect of AMLlB to TSC2 gene promoter. CONCLUSION: AML1B and AML1/ETO can regulate the transcription of TSC genes. PMID- 20193600 TI - [Study on telomerase gene mutation in northern Chinese patients with acquired bone marrow failure syndromes.]. AB - OBJECTIVE: To study the frequency of telomerase gene (TERC and TERT) mutation in Northern Chinese patients with acquired bone marrow failure syndromes (BMFS). METHODS: DNA extracted from blood samples of 90 patients with BMFS (including AA, MDS, and PNH) and 45 normal controls from 4 northern hospitals was collected. TERC and TERT mutation analysis was performed by PCR. RESULTS: Two TERC mutations (n37 A-->G, and n66 G-->C) and two TERT mutations ?[n1870 G-->T (E/*)?]; and ?[n1780 G-->T (S/I)?] were identified in 90 BMFS patients. Among them, 3 mutations were reported for the first time. One patient with TERT mutation, however, was finally diagnosed as DKC instead of acquired AA, making the incidence of telomerase gene mutation in northern Chinese people with acquired BMFS 3.4%, similar to that of the western country people. CONCLUSION: The incidence of telomerase gene mutation in northern Chinese people with acquired bone marrow failure syndromes is 3.4%, similar to that of the western country people. PMID- 20193601 TI - [The influence of Ara-C on anti-CD3/anti-Pgp mediating T-lymphocytes activities against multi-drug resistant leukemia cells.]. AB - OBJECTIVE: To investigate the role of Ara-C in regulating anti-CD3/anti-Pgp mediating T-lymphocytes activities against multi-drug resistant leukemia cells. METHODS: The diabody of anti-CD3/anti-Pgp was purified by E-tag affinity chromatography. K562 and K562/A02 cells were treated with Ara-C. The expressions of B7-1 and B7-2 on K562 and K562/AO2 cells were detected by FACS. The cytotoxicity of T-lymphocytes combined with anti-CD3/anU-Pgp plus Ara-C was analyzed by CytoTox 96 nonradioactive method. RESULTS: The expressions of B7-1 and B7-2 on K562 and K562/A02 cells treated by Ara-C was significantly higher than those untreated. The effect/target ratio was from 0.39:1 to 25:1, and the killing rate of activated T cells to anti-drug-resistant leukemia cells was from (16.44 +/- 1.20)% to (60.49 +/- 2.90)%. The killing rates were increased gradually, with both the effect/target ratio and the antibody concentration increasing (P < 0.05). CONCLUSION: Ara-C may be an important adjuvant for improving anti-CD3/anti-Pgp mediating T-lymphocytes activities against multi-drug resistant leukemia cells. PMID- 20193602 TI - [Correlation between the change in liver enzymology and the severity of acute graft-versus-host disease.]. AB - OBJECTIVE: To investigate the correlation between the change of liver enzymes and the severity of acute graft-versus-host disease (aGVHD). METHODS: The liver enzyme and severity of aGVHD in 82 patients were analyzed retrospectively. RESULTS: Among the 82 aGVHD patients, 7 developed grade I (18.3%), 47 grade II (57.3%), 13 grade III (15.9%) and 7 grade IV (8.5%) aGVHD. The elevation of ALT, AST and ALP was found in 49 (59.8%), 36(43.9%) and 8(9.8%)patients respectively. Among these patients, 34 (69.4%) were ALT > 40 U/L, 18 (50%) AST > 40 U/L and 4 (50%) ALP > 132 U/L before the onset of aGVHD. The elevation of ALT and AST was more common and the peak value was significantly higher in patients with grade III-IV aGVHD than with grade I-II aGVHD, but those of ALP showed no difference between the two groups. Compared with the patients without ALT elevation, the proportion of severe aGVHD was higher in patients with ALT elevation. CONCLUSIONS: The alteration of liver enzymology is common in aGVHD and its level is correlated with the severity of aGVHD. Liver enzymes, especially the ALT, may be used as a predictor of aGVHD. PMID- 20193603 TI - [beta-elemene enhances aclarubicin-induced apoptotic effect in HL-60 cells and its mechanism.]. AB - OBJECTIVE: To explore the effects of beta-elemene combined with aclarubicin on the induction of HL-60 cell apoptosis and its mechanisms in antileukemia therapy. METHODS: HL-60 cells were treated for 20 hours with different dose of aclarubicin (0.05, 0.10, 0.25 microg/ml) or with different concentrations of beta-elemene (10, 20, 40 microg/ml) in the presence or absence of aclarubicin (0.10 microg/m). The apoptotic rate was analyzed by flow cytometry (FCM), the productions of PGE2 in culture supernatants was detected by competitive ELISA and the expressions of COX-2 and NF-kappaB activity in HL-60 cells by Western blot. RESULTS: Lower concentration of aclarubicin (0.05, 0.10 microg/ml) didn't affect apoptotic rate, and COX-2, NF-kappa B and PGE2 expression on HL-60 cells. Combined treatment of beta-elemene and aclarubicin (0.10 microg/ml) enhanced the apoptotic effect and down-regulated COX-2, NF-kappaB and PGE2 expressions. There was a positive correlation between the effects and beta-elemene concentrations. CONCLUSION: beta elemene enhances aclarubicin-mediated apoptotic effect, down-regulation of COX-2 and their inducing products PGE2 in HL-60 cells by suppressing activitation of NF kappaB. PMID- 20193604 TI - [Effect of siRNA targeting VEGF on cell apoptosis and the expression of survivin in K562 cells.]. AB - OBJECTIVE: To study the effect of adenovirus vector-mediated siRNA targeting vascular endothelial growth factor(VEGF) on apoptosis and the expression of survivin in K562 cells. METHODS: K562 cells were infected with recombinant adenovirus Ad5-VEGFsi for 72 hours as experimental group (K562/Ad5-VEGFsi), and empty vector group (K562/Ad5) and blank control group (K562) as controls. VEGF mRNA and survivin mRNA expression were determined by RT-PCR. The protein levels of VEGF and survivin were measured by ELISA and Western blot, respectively. The apoptosis of K562 cells was detected by flow cytometry. RESULTS: The levels of VEGF and survivin mRNA expression in experimental group cells were significantly decreased (P < 0.01). The protein concentration of VEGF in experimental group supernatant was (1121 +/- 15) pg/ml, being lower than that in empty vector group ?[(1290 +/- 28) pg/ml?] and black control group ?[(1303 +/- 28) pg/ml?] (P < 0.01), and the level of survivin protein in experimental group (0.26 +/- 0.11) was significantly reduced compared with that in blank control group (0.74 +/- 0.10) (P < 0.01). The apoptosis rate of K562/Ad5-VEGFsi cells (16.45 +/- 0.14)% was higher than those of K562/Ad5 cells (3.54 +/- 0.17)% and K562 cells (2.56 +/- 0.20)% (P < 0.01). CONCLUSIONS: VEGF can up-regulate the expression of survivin. After inhibition of VEGF by RNAi, the expression of survivin is decreased subsequently and the rates of cell apoptosis are increased. PMID- 20193605 TI - [Surgical treatment and pathological findings of hematological malignancies patients complicated with lung diseases.]. AB - OBJECTIVE: To determine the pulmonary pathological changes in hematological malignancy patients with pulmonary complications. METHODS: 17 hematological malignancy patients underwent surgical treatment were evaluated retrospectively. The pathological changes of all the surgical specimens were examined postoperatively by standard hematoxylin and eosin (HE) staining. RESULTS: Pathological examination confirmed: aspergillus infection in 9 patients, sub acute inflammation (fibrosis and hematoma formation) in 3, and each in 1 of pulmonary infarction with granulomatous tissue in the periphery; granulomatous inflammation with calcified tubercle; alveolar dilation and hemorrhage, interstitial fibrosis and focal vasculitis; intercostal neurilemmoma; and moderate-differentiated adenocarcinoma accompanied by intrapulmonary metastasis. And several operative complications (1 case of fungal implantation, 3 pleural effusion and adhesions and 2 pulmonary hematoma) were occurred. The coincidence rate of pre- and post-operative diagnosis was 9/14 (64.3%). After surgery, 8 patients were received hematopoietic stem cell transplantation (HSCT, allo-gene or autologous), with 7 succeeded. On effective secondary antifungal prophylaxis, 4 of 5 patients of aspergillosis succeeded in transplantation with free from mycotic relapse, one patient died from fungal relapse. CONCLUSION: Hematological malignancies with persistent and/or resistant pulmonary infection, hemoptysis, or unexplained lung diseases, should be treated in time by surgery operation to effectively eliminate residual disease and obtain a definitive diagnosis, so as to create a prerequisite condition for the following treatments. Moreover, the secondary antifungal prophylaxis can provide active roles for patients scheduled for chemotherapy and/or HSCT. PMID- 20193606 TI - [Important issues in the diagnosis and management of allergic rhinitis.]. PMID- 20193607 TI - [Analysis on guidelines for diagnosis and treatment of allergic rhinitis.]. PMID- 20193608 TI - [Guidelines for diagnosis and treatment of allergic rhinitis (2009, Wuyishan).]. PMID- 20193609 TI - [Minutes of the Chinese symposium on infection and allergy of the nose 2009.]. PMID- 20193610 TI - [Psychological characteristics in patients with allergic rhinitis and its associated factors analysis.]. AB - OBJECTIVE: To investigate the psychological characteristics of patients with allergic rhinitis (AR) and its associated factors. METHODS: Three hundred and seventy-seven patients with AR were evaluated by the Symptom Checklist-90 (SCL 90). The results were compared with a standard, obtained from healthy Chinese population, including factors of gender, age, educational level, medical history of AR, presence of complications, type of allergenic sensitizations and nasal symptoms (using logistic regression analysis). RESULTS: An abnormal psychological state was found in 10% of AR patients, 13% with deuto-healthy, and remaining 77% of AR patients were completely healthy. The SCL-90 scores of the 377 patients were significantly higher than those of the normal standard population, including symptoms of somatization, compulsion, anxiety, rivalry and psychosis (t equals 7.128, 3.943, 2.777, 6.423, 7.507, respectively, all P < 0.01). Male patients had worse psychological state than femals, especially in the aspects of compulsion, depression, anxiety, crankiness and psychosis (t equals respectively 2.680, 1.977, 2.539, 2.107, 2.844, all P < 0.05). The SCL-90 scores of compulsion and horror were respectively different in different AR case history (F equals respectively 2.379, 2.255, all P < 0.05). AR complicated with asthma and eczema was the important factors that influenced patient's psychological status including compulsion, interpersonal sensitivity, depression, crankiness and psychosis (t equals respectively 6.835, 8.914, 7.254, 13.358, 6.030, all P < 0.01). There were no statistical differences in different ages, AR types, educational level, allergen types (all P > 0.05). Snuffle, sneeze and snivel had no influence on patient's SCL-90 scores (all P > 0.05). Itchy nose was a major symptom that affect on AR patients' SCL-90 scores of depression (standard regression b = 0.126, t = 2.076, P < 0.05). CONCLUSIONS: AR patients' psychological status was worse than that of the healthy adults. PMID- 20193611 TI - [Effects of cool restrain stress on eosinophils and interleukin 2 and 6 in nasal mucosa of rats with allergic rhinitis.]. AB - OBJECTIVE: To study the effects of cool restrain stress on the accumulation of eosinophils and expression of Th cytokines in rat nasal mucosa with allergic rhinitis model. METHODS: Fifty healthy female rats were randomly divided into 5 groups: control group, allergic rhinitis (AR) group, AR plus stress group, stress plus AR group and simultaneous stress-AR group. Cool restrain stress, AR model and simultaneous stress-AR were made. Nasal mucosa of septum from rats of five groups were stained routinely by haematoxylin eosin (HE) and immunohistochemistry respectively. The density of eosinophils and expression of interleukin (IL)2, IL 6 were observed by using software of image analysis systems under microscope. RESULTS: The density of eosinophiles and IL-6 in the nasal mucosa of stress-AR group were significantly higher than those in AR [(14.1 +/- 3.2) for eosinophiles, and (15.3 +/- 4.8) for IL-6 ] and were also significantly higher than those in control groups [(2.3 +/- 1.4) for eosinophiles, and (4.9 +/- 2.4) for IL-6)], and the differences reached statistical significance. (F were respectively 7.06, 7.14, 8.54, 8.20, P were respectively < 0.05 or < 0.01), but no significant differences of the three groups (AR plus stress, stress plus AR and simultaneous stress-AR groups) were found (F were respectively 2.90 and 3.20, P > 0.05). The expression of IL-2 in nasal mucosa of stress-AR group was significantly reduced compared with AR and control groups (F were respectively 7.27, 7.32, P were respectively < 0.05 or < 0.01). But there were also no significant differences of the three groups (AR plus stress, stress plus AR and simultaneous stress-AR groups, F = 3.12, P > 0.05). CONCLUSIONS: The abnormal infiltration and accumulation of eosinophiles and the differences in expression of IL-2 and IL-6 which represented Th1 and Th2 cytokines in rats nasal mucosa varied in different groups. The eosinophiles and IL-6 were rarely expressed in control group and moderately expressed in AR group, but significantly expressed in cool restrain groups. The IL-2 representing Th1 cytokines were reduced in cool restrain stress gruops. All these results indicated that cool restrain stress might play a role in inducing rat allergic rhinitis. PMID- 20193612 TI - [Influence of carbon monoxide on the expression of inducible nitric oxide synthase mRNA in guinea pigs with allergic rhinitis.]. AB - OBJECTIVE: To study the impact of carbon monoxide (CO) on expression levels of inducible nitric oxide synthase (iNOS) mRNA in guinea pigs with allergic rhinitis (AR). METHODS: Twenty four guinea pigs were divided randomly into four study groups with 6 guinea pigs in each. The guinea pigs in the first group were treated with saline only (Group 1, the healthy controls). The remaing guinea pigs were sensitized by ovalbumin and thus establishing the AR models. After sensitization, the animals in the second group remained untreated (Group 2, AR control group). The third group was treated with Hemin as the induction group, and the fourth group was treated with Zinc protoporphyrin (ZnPP) as the suppression group. The plasma concentration of carboxyhemoglobin (COHb) was measured, which represents the concentration of CO. The expression levels of Heme oxygenase-1 (HO-1) and NOS mRNAs in nasal mucosa were determined by fluorescent quantitative RT-PCR. RESULTS: AR models were established successfully in all study guinea pigs. The concentrations of COHb (x(-) +/- s) in plasma of the second group (2.27% +/- 1.13%) were significantly (q = 4.10, P < 0.01) higher than those of healthy controls (1.08% +/- 0.24%). The plasma concentration of COHb in the third group (3.17% +/- 0.68%) were also significantly higher (q = 3.12, P < 0.05) than those in the second group. The expression levels of HO-1 and iNOS in nasal mucosa of the second group [(7.80 +/- 1.60) x 10(-3) and (5.81 +/- 0.05) x 10(-3), respectively] were also significantly (q equals 5.52 and 7.21, respectively, P < 0.01) higher than those of controls [(1.96 +/- 0.71) x 10(-3) and (0.97 +/- 0.05) x 10(-3), respectively]. The expression levels of HO-1 and iNOS in the nasal mucosa of the third group [(11.89 +/- 4.78) x 10(-3) and (7.42 +/- 0.70) x 10(-3), respectively] were significantly (q equals 3.86 and 2.22, P < 0.05) higher than those of the second group. The expression levels of HO-1 and iNOS in nasal mucosa of the fourth group [(3.82 +/- 0.98) x 10(-3) and (2.34 +/- 0.04) x 10(-3), respectively] were significantly (q equals 3.76 and 5.18, P < 0.05) lower than those in the second group. CONCLUSIONS: Endogenous carbon monoxide influenced the expression levels of iNOS in nasal mocusa in guinea pigs with AR. PMID- 20193613 TI - [Effects of allergen and intranasal glucocorticoid on Th17 and RORgamma t in peripheral blood in patients with allergic rhinitis.]. AB - OBJECTIVE: To study the effect of specific immunotherapy and intranasal glucocorticoid on T help 17 (Th17) cells and RORgammat in peripheral blood in patients with allergic rhinitis (AR). METHODS: Forty patients with allergic rhinitis (group A) were divided randomly into two subgroups (group A1 and A2), and each subgroup had 20 patients. The patients in group A1 were treated with intranasal glucocorticoid (INGS) for one-year. The patients in group A2 were treated with special immunotherapy (SIT) for 4 weeks. Blood samples were respectively taken from 10 healthy individuals (group B), 20 AR patients (group A1) before and after SIT with specific standardized allergen and 20 AR patients (group A2) before and after INGS. The ratio of Th17 cells in peripheral blood monouclear cells (PBMC) were analysed by flow cytometry. The expression of RORgammat mRNA were detected by real-time polymerase chain reaction and the interleukin-23(IL-23), IL-17, IL-6 were detected by enzyme-linked immunosorbent assay. RESULTS: The ratio of Th17 cells in PBMC and the expression of RORgammat mRNA in group A [(18.97 +/- 1.05)% and (0.604 +/- 0.027)] were respectively higher than those in group B [(15.12 +/- 1.09)% and (0.447 +/- 0.024)] and the difference reached statistical significance (t were respectively -10.056 and 17.986, each P < 0.01). The level of IL-6, IL-17 and IL-23 in group A were respectively higher than those in group B and the difference reached statistical significance (t were respectively -41.149, -17.618 and -26.824, all P < 0.01). The ratio of Th17 cells in PBMC, the expression of RORgammat mRNA, the level of IL-6, IL-17 and IL-23 before INGS did not show significant difference from those of after INGS in group A1 (t were respectively 0.298, 0.240, -1.136, 0.283 and 1.670, all P > 0.05). The ratio of Th17 cells in PBMC and the expression of RORgammat mRNA were respectively (18.99 +/- 1.14)% and (0.603 +/- 0.027) before SIT and were respectively (16.30 +/- 1.63)% and (0.429 +/- 0.023) after SIT in group A2, and the difference reached statistical significance (t were respectively 6.035 and 22.015, all P < 0.01). The level of IL-6, IL-17 and IL-23 before SIT were lower respectively than those of after SIT in group A2 and the difference reached statistical significance (t were respectively 9.235, 11.289, 7.267, all P < 0.01). CONCLUSIONS: The ratio of Th17 cells in PBMC, the expression of RORgammat mRNA, the level of IL-6, IL-17 and IL-23 were up regulated in patients with AR. The treatment of SIT could get the 5 items down and the treatment of INGS couldn't. PMID- 20193614 TI - [Serum ECP levels in patients with allergic rhinitis and chronic rhinosinusitis.]. AB - OBJECTIVE: To investigate the serum eosinophil cationic protein (ECP) levels in patients with allergic rhinitis (AR) or chronic rhinosinusitis with polyps(CRSWP), and its relations with allergic symptoms in patients with AR. METHODS: The ECP in serum and Phadiatop tests were detected by UniCAP100 system. Blood sample was taken from 87 patients with inhaled AR, 49 patients with CRSWP and 20 healthy individuals. The serum ECP levels were detected by enzyme-linked immunosorbent assay. The allergic symptoms in patients with inhaled AR were graded. RESULTS: Phadiatop level was 5185.0 [983.0, 14469.0] Fu in inhaled AR, 317.5 [125.0, 526.8] Fu in CRSWP with Phadiatop positive, 30.0 [28.0, 43.0] Fu in CRSWP with Phadiatop negative and 43.5 [29.0, 105.0] Fu in healthy individuals. The level of ECP in patients with inhaled AR was 24.8 [14.6, 49.1] microg/L, higher than that in CRSWP with Phadiatop positive 7.7 [3.3, 25.6] microg/L, CRSWP with Phadiatop negative 12.5 [6.7, 16.7] microg/L and control 8.8 [5.4, 20.2] microg/L. The difference was significant. There were correlations among the allergic symptoms, serum ECP and Phadiatop levels. CONCLUSIONS: Among patients with inhaled AR, there was an up-regulated concentration of serum ECP, which had relations to allergic symptoms. The detection of serum ECP could be used as a convenient screening test for inhaled AR. Its concentration had correlation with the severity and prognosis of the disease. To the contrary, the serum ECP did not significantly increased in patients with CRSWP. PMID- 20193615 TI - [MRI features of olfactory bulb volume in healthy middle and old-aged persons.]. AB - OBJECTIVE: To investigate the differences of olfactory bulb (OB) volumes between younger and older, male and female, left-side and right-side in healthy middle and old-aged persons by MRI. METHODS: Ninety five healthy middle and old-aged volunteers (male:female = 45:50) were divided into 2 groups, group one included persons aged from 50 to 69, group two included persons elder than 70. The left side, right-side and both-side volumes of OB, the volumes of brain and the ratio of OB/brain were measured by MRI. RESULTS: (1) The left-side and both-side volumes of OB (x(-) +/- s), the volumes of brain [(39.89 +/- 8.7) mm(3), (81.70 +/- 16.8) mm(3) and (1281.86 +/- 140.2) cm(3)] in 50 - 69 years old group were respectively larger than those in >/= 70 years old group [(34.45 +/- 10.4) mm(3), (72.10 +/- 19.3) mm(3) and (1165.77 +/- 165.3) cm(3)], and the differences reached statistical significance (t were respectively 2.649, 2.449, 3.516, all P < 0.05). There were no significant differences of right-side OB volumes and the ratio of OB/brain between 50 - 69 years old group and >/= 70 years old group (t were respectively 1.904, 0.616, each P > 0.05). (2) The male's OB volumes of left side, right-side and both-side, the brain volumes and the ratio of OB/brain were respectively larger than females', and the differences reached statistical significance (t were respectively 4.461, 3.630, 4.399, 3.800, 2.400, all P < 0.05). (3) The right-side OB volumes were larger than left-side's and significant differences were found in female group, 50 - 60 years old group and >/= 70 years old group (t were respectively 2.732, 2.117, 3.516, all P < 0.05). There were no significant differences of OB volumes between left-side and right-side in female (t = 2.649, P = 0.110). The ratio of right-side OB/brain were larger than the ratio of left-side's and the differences reached statistical significance (t = 3.183, P = 0.002). CONCLUSIONS: MRI could be used to measure the volume of OB. The older the people, the smaller the OB volumes. There was no influence of age on the ratio OB/brain. The OB volumes of right-side were larger than those of left-side. The OB volumes of male were larger than those of female. PMID- 20193616 TI - [Use of noninvasive ventilation in surgical treatment of obstructive sleep apnea hypopnea syndrome in children.]. AB - OBJECTIVE: To study the efficacy of noninvasive ventilation in the surgical treatment of obstructive sleep apnea hypopnea syndrome (OSAHS) in children. METHODS: Since 2002.5 - 2007.12, eleven children with adenotonsillar hypertrophy and seven children with post-adenoidtonsillectomy were enrolled in the study. All children were confirmed as OSAHS by polysomnography (PSG) or portable oximetry monitor. Male:female ratio was 17:1. The age ranged from 1 to 11 years (median 3.8 years). The noninvasive ventilation treatment was carried out in all children pre- or postoperatively. PSG was the index for therapy effect. SPSS 11.5 was used to analyse the data. The parameters, x(-) +/- s, were normal distribution, and paired t-test for significancy. A P value of < 0.05 was considered statistically significant. RESULTS: Six children after adenotosillectomy, with AHI < 10/h, lowest pulse oxygen saturation (SpO2) > 0.85, did not need nasal continuous positive airway pressure (nCPAP). Eleven patients with preoperative nCPAP, did not have anesthesia comlications. Post-nCPAP, apnea and hypopnea index AHI (4.7 +/- 3.9)/h, the lowest SpO2 0.867 +/- 0.069, and the average time percents SpO2 < 0.90 during sleep (0.3% +/- 0.5%) improved significantly compared to pre-nasal continuous positive airway pressurecn (nCPAP), which were (77.6 +/- 39.8)/h, (0.535 +/- 0.151) and (46.9% +/- 34.5%), t value were 7.77, -11.62, 5.69, P < 0.001. CONCLUSIONS: Noninvasive ventilation is an effective treatment for severe OSAHS children pre- or postoperation. nCPAP could be used to treat children still with OSAHS after adenotonsillectomy, and also an effective treatment to the ones who had surgical contraindication. Regular follow-up should be done for patients with nCPAP at home. PMID- 20193617 TI - [Clinical applications of magnifying laryngoscopy on nasopharyngeal examination.]. AB - OBJECTIVE: To evaluate the usability of magnifying laryngoscopy for the diagnosis of nasopharyngeal diseases. METHODS: An analysis was made on the nasopharyngeal figure and letter data among 6774 cases undergone magnifying laryngoscopy. Among these cases, biopsy would be given to those with suspected lesion in the nasopharynx carried out under magnifying laryngoscopy or endoscope. RESULTS: Compliance of patients to magnifying laryngoscopy at the rate of 98.9% (6700/6774) was superior to indirect nasopharyngoscopy 30.9% (2095/6774). The difference was statistically significant (chi(2) = 6872.75, P < 0.005). Magnifying laryngoscopy could clearly show a variety of diseases in nasopharynx, early detection of suspicious lesions. Among 615 cases, both fiber nasopharyngoscopy (192 cases) and nasal endoscopy (423 cases) with nasopharyngeal uplift were used, magnifying laryngoscopy found 418 cases bilateral symmetry, the surface smooth, no abnormal. The pathological examination confirmed normal tissue. Other 197 cases in the larger laryngoscopy also showed the uplift in nasopharynx by pathologically examination confirmed a variety of benign and maligant lesions. CONCLUSIONS: Magnifying laryngoscopy with strong brightness, high resolution, can early detect the nasopharyngeal lesions, increase the diagnostic accuracy rate and biopsy-positive rate. Therefore, it is valuable for the diagnosis of nasopharyngeal diseases. PMID- 20193618 TI - [Strategy of surgical management of juvenile on-set recurrent respiratory papillomatosis with trachea or bronchia involvement.]. AB - OBJECTIVE: To investigate the strategy of surgical management of juvenile on-set recurrent respiratory papillomatosis (JORRP) with trachea/bronchia involvement so as to decrease the complications of the surgery. METHODS: Twenty four JORRP patients undergone surgery in Beijing Tongren Hospital were studied between January 2006 and February 2009. All of them had JORRP with trachea/bronchia involvement. Suspension laryngoscopic surgeries were performed using rigid bronchoscope and micro-debrider. High frequency jet ventilator was used to maintain the ventilation in general anesthesia. Excision of tumors, suction of the blood and ventilation were preformed alternately. A total of 149 times of surgeries were analyzed. RESULTS: The age of the patients was from 3 to 16 years old (median 6 years old). The age at diagnosis was from eight months to 10 years old (median 1.5 years old). Twenty of them had undergone tracheostomy and the age at tracheostomy was from 1 to 4 years old (median 2 years old). Twenty two of them had been graded as two-degree dyspnea preoperatively, one graded as three degree dyspnea and one four-degree dyspnea. All subjects underwent more than one surgery. Two cases were intubated and sent to intensive care unit because of postoperative hypercapnia. One was sent to intensive care unit postoperatively because of preoperative phypoxemia and hypercapnia. All subjects were discharged without dyspnea. No death and complications occurred. CONCLUSIONS: Suspension laryngoscopic surgery using rigid bronchoscope and micro-debrider was a safe and effective strategy for the treatment of JORRP with trachea/bronchia involvement. PMID- 20193619 TI - [Expression of E-cadherin and uPA and their prognostic value in carcinoma of human larynx.]. AB - OBJECTIVE: To investigate the expression of E-cadherin (ECD) and uPA in laryngeal cancer and evaluate their clinical value in prognosis. METHODS: ECD and uPA were determined by immunohistochemistry of Envision methods in carcinoma tissues of 51 patients of laryngeal carcinoma. All patients were followed and the prognostic factors were analyzed. RESULTS: Among 51 patients' tumor tissues, 24 (47.1%) were negative expression of ECD, and 26 (51.0%) were positive uPA immunoreaction was observed. There were four subgroups of patterns of ECD and uPA expression: 14 (27.1%) ECD-positive/uPA-negative, 13 (25.5%) ECD-negative/uPA-negative, 11 (21.6%) ECD-positive/uPA-positive, and 13 (25.5%) ECD-negative/uPA-positive. The tumor tissues with ECD-negative and uPA-positive expression were significant associated with lymph nodes metastasis (chi(2) = 5.545, 5.79, P = 0.019, 0.016 respectively). Patients with ECD-negative expression had a shorter survival than the patients with ECD positive expression but no statistic difference (chi(2) = 2.534, P > 0.05). Patients with uPA-positive expression had a significantly shorter survival time than those with uPA-negative expression (chi(2) = 6.259, P < 0.05). There was a difference for the median survival time between the patients with uPA-negative/ECD-positive and the patients with uPA-positive/ECD-negative in laryngeal cancer tissue (chi(2) = 6.559, P = 0.01), and the survival curves between these two groups was also statistically significant difference. Multivariate analysis of Cox revealed that clinical stage and ECD/uPA (P = 0.009, 0.007 respectively) were two independent prognostic factors. CONCLUSIONS: The combination analysis of uPA and ECD immunohistochemical expression in the laryngeal cancer tissue may be useful for predicting tumor metastatic risks and patient's prognosis. PMID- 20193620 TI - [Expression of human beta-defensin-2 in laryngeal squamous cell carcinoma and its correlation with CD1a(+) dendritic cells infiltrating in tumor.]. AB - OBJECTIVE: To investigate the expression of human beta-defensin-2 (HBD-2) in laryngeal squamous cell carcinoma (LSCC), and reveal the immune significance of HBD-2 in LSCC. METHODS: The expression of HBD-2 and the infiltration of CD1a(+) dendritic cells were verified by immunohistochemistry strept actividin-biotin complex (SABC) method in thirty-four cases of LSCC's paraffin sections, and the expression of HBD-2 mRNA was detected in eighteen cases of postoperative tumor specimens and five cases of normal paracarcinoma tissue using cDNA probe by in situ hybridization. Based on the type and characteristic of datas, SPSS13.0 program package was used for statistical calculation. RESULTS: (1) The difference of expression of HBD-2 was significant among the grades of malignant cell differentiation (F = 6.809, P < 0.05), the expression of HBD-2 in well differentiated group was significantly increased compared with moderately and poorly differentiated group (P < 0.05), there wasn't significant difference with the clinical type, T status and lymphatic metastasis in the expression of HBD-2. (2) The difference of expression of HBD-2 mRNA among different grades of malignant cell differentiation was significant (F = 16.391, P < 0.05), less or no positive signal was observed in poorly differentiated group. (3) The infiltration of CD1a(+) dendritic cells had positive correlation with the expression of HBD-2 (r = 0.343, P < 0.05). CONCLUSIONS: The expression of HBD-2 was related to the grade of malignant cell differentiation in LSCC, which was regulated at the level of transcription and translation. HBD-2 might play a role in anti-tumor immunity by chemo-attractiving and activating of immature dendritic cells. PMID- 20193621 TI - [Comparison of the antioxidants lipoic acid pharmacokinetics in inner ear between intravenous and intratympanic administration in guinea pigs.]. AB - OBJECTIVE: To study the pharmacokinetics of lipoic acid in guinea pig perilymph and to provide experimental evidence for clinical delivery methods and dose in order to compare of intravenous and intratympanic administration using high performance liquid chromatography (HPLC). METHODS: Fifty-four guinea pigs were randomly divided into two groups of intratympanic and intravenous administration, with 27 ones in each group, and the concentration of lipoic acid was 100 mg/ml. The concentration of lipoic acid in perilymph was detected respectively by HPLC at 0.5, 1, 2, 3, 4, 5, 6, 8 and 10 h after administration. RESULTS: A well linear relation of concentration of lipoic acid in perilymph was shown when the concentration was detected from 0.1 to 200 microg/ml (r(2) = 0.9996). The maximum of concentration of lipoic acid administrated via intratympanic was 171.7 microg/ml, and via intravenous was 33.7 microg/ml; the MRT of intratympanic injection was 3.7 h while intravenous injection was 2.9 h; the half life (t(1/2)) of the former was 1.8 h but the latter was 2.1 h. CONCLUSIONS: The drug concentration could both be detected via intravenous and intratympanic injection in perilymph of guinea pig, But the effect of local administration via intratympanic was obvious superior to systemic administration. PMID- 20193622 TI - [Report of one case of migratory foreign bodies in thyroid gland complicated with abscess.]. PMID- 20193623 TI - [Resection of the pleomorphic adenoma in trachea by tracheotomy (Report of 2 cases).]. PMID- 20193624 TI - [A case about migration of a foreign object in the neck.]. PMID- 20193625 TI - [Primary granulocytic sarcoma in nasal cavity: a case report.]. PMID- 20193627 TI - [New insights into the hygiene hypothesis of allergic disease.]. PMID- 20193626 TI - [Solitary fibrous tumor in neck: one case report.]. PMID- 20193628 TI - [Recent targeted therapeutic approach of thyroid carcinoma.]. PMID- 20193629 TI - [Some new concepts and important advancements in allergic rhinitis.]. PMID- 20193630 TI - [The hotspot of the 28th European Academy of Allergy and Clinical Immunology (EAACI).]. PMID- 20193631 TI - New roles for mast cells in pathogen defense and allergic disease. AB - Mast cells (MC) are specialized exocytic cells that lie beneath the external surfaces of the body. For many decades, MCs were thought to primarily function as effector cells for IgE mediated allergic diseases. However, recent evidence indicates that MCs also function as important cells in immune surveillance. When activated by pathogens, MCs initiate innate and adaptive immune responses thereby resulting in protection against pathogens. The question remains if MC activation may also function in establishing immune responses against allergens and hence allergic disease. New studies suggest that MCs are not only the effector cell of allergy but may also be the initiator of allergy. PMID- 20193632 TI - Perspectives for personalization in chemotherapy of advanced gastric cancer. AB - No chemotherapy regimen showed a survival benefit better than 5-fluorouracil alone in a phase III trial for advanced gastric cancer in 1990s, and several new cytotoxic agents became available in late 1990s. Thereafter, a couple of phase III trials supported the substitution of infusional 5-fluorouracil by orally administered agents and the replacement of cisplatin by oxaliplatin in early 2000s. Furthermore, a substantial amount of information about the heterogeneity and the biological backgrounds of gastric cancer has been obtained from recent trials, and it is suggested that some cytotoxic agents would be well indicated. Trastuzumab has succeeded in showing a survival benefit for patients with Her-2 positive gastric cancer which accounts for about 10-20% of the cancer. This means that the door is opened to the new era of chemotherapy with molecular target agents and with individualization for advanced gastric cancer. The new approach in the development of molecular target agents, e.g., biomarker oriented strategy, for advanced gastric cancer should be studied in clinical trials in the near future. PMID- 20193633 TI - Vaccines and autoimmune diseases of the adult. AB - Infectious agents contribute to the environmental factors involved in the development of autoimmune diseases possibly through molecular mimicry mechanisms. Hence, it is feasible that vaccinations may also contribute to the mosaic of autoimmunity. Evidence for the association of vaccinations and the development of these diseases is presented in this review. Infrequently reported post vaccination autoimmune diseases include systemic lupus erythematosus, rheumatoid arthritis, inflammatory myopathies, multiple sclerosis, Guillain-Barre syndrome, and vasculitis. In addition, we will discuss macrophagic myofasciitis, aluminum containing vaccines, and the recent evidence for autoimmunity following the use of human papillomavirus vaccine. PMID- 20193634 TI - Computed tomography for atherosclerosis and coronary artery disease imaging. AB - Coronary artery calcification (CAC) has long been known to occur as a part of the atherosclerotic process; recently it has been shown to be an active process resembling bone formation within the vessel wall. There is good evidence that the extent of CAC reflects the total coronary atherosclerotic burden and this has generated interest in using CAC as a marker of risk. The current consensus is that large amounts of CAC identify a patient highly vulnerable to future events. The advent of CT angiography added the ability to non-invasively detect critical luminal stenoses that are associated with a more immediate risk of events, and to visualize the non-calcified component of the atherosclerotic plaque. PMID- 20193636 TI - Does emotional stress cause type 2 diabetes mellitus? A review from the European Depression in Diabetes (EDID) Research Consortium. AB - According to the World Health Organization, approximately 220 million people worldwide have type 2 diabetes mellitus. Patients with type 2 diabetes not only have a chronic disease to cope with, they are also at increased risk for coronary heart disease, peripheral vascular disease, retinopathy, nephropathy, and neuropathy. The exact causes of type 2 diabetes are still not clear. Since the 17th century, it has been suggested that emotional stress plays a role in the etiology of type 2 diabetes mellitus. So far, review studies have mainly focused on depression as a risk factor for the development of type 2 diabetes mellitus. Yet, chronic emotional stress is an established risk factor for the development of depression. The present review provides an overview of mainly prospective epidemiological studies that have investigated the associations between different forms of emotional stress and the development of type 2 diabetes mellitus. Results of longitudinal studies suggest that not only depression but also general emotional stress and anxiety, sleeping problems, anger, and hostility are associated with an increased risk for the development of type 2 diabetes. Conflicting results were found regarding childhood neglect, life events, and work stress. It is important to emphasize that publication-bias may have occurred, resulting from "fishing-expeditions," where authors search their data for significant associations. Publication bias may also be caused by the tendency of reviewers and Editors to reject manuscripts with negative results for publication. It is therefore essential that research groups, who aim to conduct a new epidemiological cohort study, prospectively describe and publish the design of their study. Future research should focus on identifying mechanisms linking different forms of stress and incident type 2 diabetes. PMID- 20193635 TI - Two decades of clinical gene therapy--success is finally mounting. AB - Human gene therapy has made substantial progress since the initiation of the first clinical trials 20 years ago. Here, we summarized important applications of gene transfer protocols in the treatment of various human diseases using different viral vectors. Recent successful trials on the treatment of ocular diseases and inherited immune deficiencies are particularly encouraging and have raised hopes that human gene therapy as a standard treatment option will finally become a reality. While immune responses and insertional mutagenesis pose obstacles for this novel form of molecular medicine, continuous progress suggests that a wider range of diseases can be treated with gene therapy in the future. PMID- 20193637 TI - Immunological aspects of local radiotherapy: clinical relevance. AB - Standard anti-cancer therapeutic modalities like chemotherapy and radiotherapy evoke host's reactions that include involvement of the immune system. Elucidation of these mechanisms offers the double advantage of enabling a more rational choice of cytotoxic therapy and exploring the combination with immunotherapy. Radiotherapy, a well established local anti-cancer approach, is a particularly interesting partner for immunotherapy, since it can be harnessed to specifically modify the immunogenicity of the primary tumor and its microenvironment, in the attempt to generate an in situ immunization of the host against a patient's own cancer. PMID- 20193639 TI - Antioxidant drugs for treating beta-cell oxidative stress in type 2 diabetes: glucose-centric versus insulin-centric therapy. AB - Mainstays of therapy for type 2 diabetes involve drugs that are insulin-centric, i.e., they are designed to increase insulin secretion and decrease insulin resistance. The usual clinical course for people so treated is to have initially improved glycemic control but over time a need for intensification of drug-based treatment of hyperglycemia. The mechanism for this unrelenting deterioration of beta-cell function is related to chronic oxidative stress. This suggests that drug discovery should not exclusively focus on insulin-centric targets, but also include glucose-centric strategies, such as antioxidant protection of the beta cell. This may facilitate repair of beta-cells undergoing damage by oxidative stress secondary to chronic hyperglycemia. PMID- 20193638 TI - Glioblastoma genetics: in rapid flux. AB - Glioblastoma is the most common and most lethal primary brain tumor. While small progress has been made in treating this cancer in recent years, glioblastoma remains largely resistant to all existing therapies. It has been hoped that dissection of the genetics of this cancer would lead to more targeted and effective treatments, and new advances may finally be bringing this closer to fruition. Within the last few years, high-throughput efforts such as The Cancer Genome Atlas and a massive sequencing project have yielded novel insights and classifications of this dreaded cancer. The likely impact on care delivery in the clinic may only be a few years away. The rapid and exciting pace of advances in glioblastoma genetics has prompted this up-to-date review. PMID- 20193640 TI - Behavioral and cognitive effects of anti-epileptic drugs. AB - Anti-epileptic drugs (AEDs) have a variety of mechanisms of action which are reflected through different anticonvulsant activities and behavioral effects. Two categories of AEDs are considered based on psychotropic profile. The first group is characterized by potentiation of gamma-aminobutyric acid (GABA) inhibitory neurotransmission, and comprises of agents such as vigabatrin, tiagabine, and gabapentin. These agents are noted to have sedating effects ranging from cognitive slowing to anti-manic effects. On the other hand, the second group is typified by attenuation of glutamate excitatory neurotransmission and has activating effects including anxiogenic and antidepressant actions. Lamotrigine and felbamate feature in this latter group. Mechanisms of action, chief clinical indications, as well as behavioral profile including comment on chief cognitive effects of the newer AEDs are reviewed in accordance with this dual categorization. In clinical practice, assessment of an individual patient alongside consideration of AED behavioral profile primes for appropriate prescription according to patient mood profile, also permitting exposure of AED induced behavioral disturbance. PMID- 20193641 TI - The role of p53 in apoptosis. AB - The dynamic and multiple functions of p53, together with its involvement in the most common non-infectious diseases, underscore the need to elucidate the complexity of the p53 regulatory networks. Pathological conditions such as cancer, neurodegeneration, ischemia, cholestasis, and atherosclerosis are all strongly associated with deregulated levels of apoptosis in which p53 dysfunction has a prominent role. We will highlight recent developments of p53-induced apoptosis in human diseases, with a focus on modulation of liver cell apoptosis. In addition, we will discuss controversies arising from widespread p53 activation as a therapeutic approach to cancer. Recent studies have provided relevant and unprecedented information about mechanistic antiapoptotic functions of the endogenous bile acid, ursodeoxycholic acid (UDCA), suggesting that the finely tuned, complex control of p53 by Mdm-2 (mouse double minute-2, an oncoprotein) is a key step in UDCA modulation of p53-triggered apoptosis. We will also review recent therapeutic strategies and clinical applications of targeted agents, their safety, and efficacy, with particular emphasis on potential benefits of UDCA. PMID- 20193642 TI - New approaches in the management of radioiodine-refractory thyroid cancer: the molecular targeted therapy era. AB - Although thyroid carcinoma usually has an excellent prognosis, the lack of therapeutic options is an issue for patients that develop metastases and are resistant to radioiodine therapy. The development of novel molecular targeted therapies and the characterization of several proteins that have a crucial role in the carcinogenesis process of differentiated thyroid cancer have created an opportunity to design new clinical trials for this setting. Moreover, the encouraging initial results of first clinical trials have accelerated the development of placebo-controlled phase III studies that will assess the role of these new agents in the management of differentiated thyroid cancer. PMID- 20193643 TI - Switching treatments for complicated depression. AB - The majority of depressed patients will not experience remission when treated with a first-line antidepressant. As a next-step strategy for patients who achieve partial response to the initial antidepressant, clinicians may opt to augment the first antidepressant with another medication or combine it with a second antidepressant. For nonresponders or for patients experiencing intolerable side effects, clinicians may choose to switch medications. Switching can be done within the same drug class to obtain different pharmacologic properties, or to another class to obtain a different neurochemical effect. Switching appears to be fairly well tolerated and effective for patients with treatment-resistant depression, but should be tailored to the individual patient's needs and preferences. PMID- 20193644 TI - Course and impact of bipolar disorder in young patients. AB - The presentation of bipolar disorder in children and adolescents may vary from its presentation in adults. Rage, irritability, and long episodes are common manifestations of mania in young people with bipolar disorder. Frequent comorbid disorders in young patients include ADHD and anxiety disorders. Prodromal and subsyndromal states of bipolar disorder, such as bipolar disorder NOS, present opportunities for early intervention and prevention. Early recognition and intervention are crucial, because untreated pediatric bipolar disorder becomes chronic, has a high incidence of relapse, and has a poor prognosis. PMID- 20193645 TI - Efficacy of the novel antidepressant agomelatine on the circadian rest-activity cycle and depressive and anxiety symptoms in patients with major depressive disorder: a randomized, double-blind comparison with sertraline. AB - OBJECTIVE: This study evaluates the efficacy of agomelatine, the first antidepressant to be an agonist at MT(1)/MT(2) receptors and an antagonist at 5 HT(2C) receptors, versus sertraline with regard to the amplitude of the circadian rest-activity cycle and depressive and anxiety symptoms in patients with major depressive disorder (MDD). METHOD: Outpatients with DSM-IV-TR-defined MDD received either agomelatine 25 to 50 mg (n = 154) or sertraline 50 to 100 mg (n = 159) during a 6-week, randomized, double-blind treatment period. The study was conducted from 2005 to 2006. The main outcome measure was the relative amplitude of the individual rest-activity cycles, expressed as change from baseline to week 6 and collected from continuous records using wrist actigraphy and sleep logs. Secondary outcome measures were sleep efficiency and sleep latency, both derived from actigraphy, and efficacy on depression symptoms (17-Item Hamilton Depression Rating Scale total score and Clinical Global Impressions scale scores) and anxiety symptoms (Hamilton Anxiety Rating Scale total score and subscores). RESULTS: A significant difference in favor of agomelatine compared to sertraline on the relative amplitude of the circadian rest-activity cycle was observed at the end of the first week (P = .01). In parallel, a significant improvement of sleep latency (P <.001) and sleep efficiency (P <.001) from week 1 to week 6 was observed with agomelatine as compared to sertraline. Over the 6-week treatment period, depressive symptoms improved significantly more with agomelatine than with sertraline (P <.05), as did anxiety symptoms (P <.05). CONCLUSIONS: The favorable effect of agomelatine on the relative amplitude of the circadian rest activity/sleep-wake cycle in depressed patients at week 1 reflects early improvement in sleep and daytime functioning. Higher efficacy results were observed with agomelatine as compared to sertraline on both depressive and anxiety symptoms over the 6-week treatment period, together with a good tolerability profile. These findings indicate that agomelatine offers promising benefits for MDD patients. TRIAL REGISTRATION: www.isrctn.org: ISRCTN49376288. PMID- 20193646 TI - A randomized controlled trial comparing the memory effects of continuation electroconvulsive therapy versus continuation pharmacotherapy: results from the Consortium for Research in ECT (CORE) study. AB - OBJECTIVE: To compare the memory effects of continuation electroconvulsive therapy (C-ECT) versus continuation pharmacologic intervention (C-PHARM) at 12 and 24 weeks after completion of acute electroconvulsive therapy (ECT). METHOD: Eighty-five patients with Structured Clinical Interview for DSM-IV-diagnosed unipolar major depressive disorder, enrolled in a multisite, randomized, parallel design trial conducted at 5 academic medical centers from 1997 to 2004, who had remitted with an acute course of bilateral ECT and remained unrelapsed through 24 weeks of continuation therapy, were included in this analysis. They were randomly assigned to C-ECT (10 treatments) or nortriptyline plus lithium (monitored by serum blood levels) for 24 weeks. Objective neuropsychological measures of retrograde and anterograde memory and subjective assessment of memory were obtained at baseline, 12 weeks, and 24 weeks. The Rey Auditory-Verbal Learning Test and the Autobiographical Memory Interview were the primary outcome measures. RESULTS: The C-PHARM group showed a greater group difference (P < .01) for baseline to 12-week change for the Autobiographical Memory Interview. No other memory measures showed group differences for change scores from baseline to 12 weeks. Groups showed no baseline to 24-week change-score differences on any of the memory measures. For both groups, 12-week objective anterograde memory scores (eg, Auditory-Verbal Learning Test percent retention P = .0001; Rey-Osterrieth Complex Figure or Taylor Figure percent retention P < .002) and 24-week subjective memory scores were significantly improved (Squire Subjective Memory Questionnaire P < .02) over baseline. This result reflects the apparent resolution of a presumed decrement in anterograde memory associated with acute ECT preceding this study. CONCLUSIONS: The finding of no memory outcome differences between unrelapsed recipients of C-ECT and C-PHARM is consistent with clinical experience. Memory effects have only a small role in the choice between C-ECT and C-PHARM. PMID- 20193647 TI - Benzodiazepine use and risk of recurrence in bipolar disorder: a STEP-BD report. AB - OBJECTIVE: Benzodiazepines are widely prescribed to patients with bipolar disorder, but their impact on relapse and recurrence has not been examined. METHOD: We examined prospective data from a cohort of DSM-IV bipolar I and II patients who achieved remission during evidence-guided naturalistic treatment in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study (conducted in the United States between 1999 and 2005). Risk for recurrence among individuals who did or did not receive benzodiazepine treatment was examined using survival analysis. Cox regression was used to adjust for clinical and sociodemographic covariates. Propensity score analysis was used in a confirmatory analysis to address the possible impact of confounding variables. RESULTS: Of 1,365 subjects, 349 (25.6%) were prescribed a benzodiazepine at time of remission from a mood episode. After adjusting for potential confounding variables, the hazard ratio for mood episode recurrence among benzodiazepine-treated patients was 1.21 (95% CI, 1.01-1.45). The effects of benzodiazepine treatment on relapse remained significant after excluding relapses occurring within 90 days of recovery, or stratifying the sample by propensity score, a summary measure of likelihood of receiving benzodiazepine treatment. In an independent cohort of 721 subjects already in remission at study entry, effects of similar magnitude were observed. CONCLUSION: Benzodiazepine use may be associated with greater risk for recurrence of a mood episode among patients with bipolar I and II disorder. The prescribing of benzodiazepines, at a minimum, appears to be a marker for a more severe course of illness. PMID- 20193648 TI - How to efficiently maintain your own electronic resource library. PMID- 20193649 TI - Impact of burnout syndrome on gastroesophageal reflux disease and irritable bowel syndrome in health care workers. PMID- 20193650 TI - A case of zaleplon-induced amnestic sleep-related eating disorder. PMID- 20193651 TI - Antidepressants in bipolar disorder: caveats in interpreting and applying the findings of Altshuler et al. PMID- 20193654 TI - The FMN-dependent two-component monooxygenase systems. AB - The FMN-dependent two-component monooxygenase systems catalyze a diverse range of reactions. These two-component systems are composed of an FMN reductase enzyme and a monooxygenase enzyme that catalyze the oxidation of various substrates. The role of the reductase is to supply reduced flavin to the monooxygenase enzyme, while the monooxygenase enzyme utilizes the reduced flavin to activate molecular oxygen. Unlike flavoproteins with a tightly or covalently bound prosthetic group, these enzymes catalyze the reductive and oxidative half-reaction on two separate enzymes. An interesting feature of these enzymes is their ability to transfer reduced flavin from the reductase to the monooxygenase enzyme. This review covers the reported mechanistic and structural properties of these enzyme systems, and evaluates the mechanism of flavin transfer. PMID- 20193653 TI - Maximum yields of microsomal-type membranes from small amounts of plant material without requiring ultracentrifugation. AB - Isolation of a microsomal membrane fraction is a common procedure in studies involving membrane proteins. By conventional definition, microsomal membranes are collected by centrifugation of a postmitochondrial fraction at 100,000g in an ultracentrifuge, a method originally developed for large amounts of mammalian tissue. We present a method for isolating microsomal-type membranes from small amounts of Arabidopsis thaliana plant material that does not rely on ultracentrifugation but instead uses the lower relative centrifugal force (21,000g) of a microcentrifuge. We show that the 21,000g pellet is equivalent to that obtained at 100,000g and that it contains all of the membrane fractions expected in a conventional microsomal fraction. Our method incorporates specific manipulation of sample density throughout the procedure, with minimal preclearance, minimal volumes of extraction buffer, and minimal sedimentation pathlength. These features allow maximal membrane yields, enabling membrane isolation from limited amounts of material. We further demonstrate that conventional ultracentrifuge-based protocols give submaximal yields due to losses during early stages of the procedure; that is, extensive amounts of microsomal type membranes can sediment prematurely during the typical preclearance steps. Our protocol avoids such losses, thereby ensuring maximal yield and a representative total membrane fraction. The principles of our method can be adapted for nonplant material. PMID- 20193655 TI - Kinetic behaviour of WT 1's zinc finger domain in binding to the alpha-actinin-1 mRNA. AB - The zinc finger transcription factor Wilms tumour protein (WT 1) is known for its essential involvement in the development of the genitourinary system as well as of other organs and tissues. WT 1 is capable of selectively binding either DNA or mRNA targets. A KTS insertion due to alternative splicing between the zinc fingers 3 and 4 and an unconventional zinc finger 1 are the unique features that distinguish WT 1 from classical DNA-binding C(2)H(2)-type zinc finger proteins. The DNA binding characteristics of WT 1 are well studied. Due to lack of information about its native RNA targets, no extensive research has been directed at how WT 1 binds RNA. Using surface plasmon resonance, this study attempts to understand the binding behaviour of WT 1 zinc fingers with its recently reported and first putative mRNA target, ACT 34, whose stem-loop structure is believed to be critical for the interactions with WT 1. We have analysed the interactions of five WT 1 zinc finger truncations with wild-type ACT 34 and four variants. Our results indicate that WT 1 zinc fingers bind ACT 34 in a specific manner, and that this occurs as interplay of all four zinc fingers. We also report that a sensitive kinetic balance, which is equilibrated by both zinc finger 1 and KTS, regulates the interaction with ACT 34. The stem-loop and the flanking nucleotides are important elements for specific recognition by WT 1 zinc fingers. PMID- 20193657 TI - Roles of nitric oxide in alleviating heavy metal toxicity in plants. AB - Nitric oxide (NO) is involved in the regulation of multiple plant responses to a variety of abiotic and biotic stresses. Recently, an increasing number of articles have reported the effects of exogenous NO on alleviating heavy metal toxicity in plants. However, compared with the current understanding of the relationships between NO and other abiotic stresses, knowledge of the molecular and physiological mechanisms of NO in alleviating heavy metal toxicity is quite limited, and some results contradict one another. Therefore, to help clarify the roles of NO in heavy metal tolerance, it is valuable to review and discuss the recent advances on this research topic. In this mini-review, the latest advances in understanding the effects of heavy metals on endogenous NO content and the mechanisms and signaling pathways of exogenous NO in alleviating heavy metal toxicity in plants are summarized and discussed. A basic scheme for the roles of NO in alleviating heavy metal toxicity is also proposed. PMID- 20193656 TI - Phosphorylation and the Cajal body: modification in search of function. AB - The Cajal body (CB) is a subnuclear domain that contains proteins and factors involved in a diverse range of activities including ribonucleoprotein maturation, histone gene transcription and telomerase assembly. Among these activities, the CBs' role in small nuclear ribonucleoprotein (snRNP) biogenesis is best characterized. Although CBs are found in plants, flies and mammals, not all cell types contain CBs. Rather, CBs are most prominent in transcriptionally active cells, such as cancer and neuronal cells. Many CB components, including the CB marker protein coilin, are phosphorylated in humans. The functional consequence of phosphorylation on CB assembly, activity and disassembly is largely unknown. Also unknown are the signaling pathways, kinases and phosphatases that act upon proteins which localize in the CB. The goal of this review is to demonstrate the need for a concerted effort towards elucidating the functional consequence of phosphorylation on CB formation and activity. PMID- 20193658 TI - ATP-dependent proteases in biogenesis and maintenance of plant mitochondria. AB - ATP-dependent proteases from three families have been identified experimentally in Arabidopsis mitochondria: four FtsH proteases (AtFtsH3, AtFtsH4, AtFtsH10, and AtFtsH11), two Lon proteases (AtLon1 and AtLon4), and one Clp protease (AtClpP2 with regulatory subunit AtClpX). In this review we discuss their submitochondrial localization, expression profiles and proposed functions, with special emphasis on their impact on plant growth and development. The best characterized plant mitochondrial ATP-dependent proteases are AtLon1 and AtFtsH4. It has been proposed that AtLon1 is necessary for proper mitochondrial biogenesis during seedling establishment, whereas AtFtsH4 is involved in maintaining mitochondrial homeostasis late in rosette development under short-day photoperiod. PMID- 20193661 TI - Monomer-dimer transition of the conserved N-terminal domain of the mammalian peroxisomal matrix protein import receptor, Pex14p. AB - Pex14p is a central component of the peroxisomal matrix protein import machinery. In the recently determined crystal structure, a characteristic face consisting of conserved residues was found on a side of the conserved N-terminal domain of the protein. The face is highly hydrophobic, and is also the binding site for the WXXXF/Y motif of Pex5p. We report herein the dimerization of the domain in the isolated state. The homo-dimers are in equilibrium with the monomers. The homo dimers are completely dissociated into monomers by complex formation with the WXXXF/Y motif peptide of Pex5p. A putative dimer model shows the interaction between the conserved face and the PXXP motif of another protomer. The model allows us to discuss the mechanism of the oligomeric transition of the full length Pex14p modulated by the binding of other peroxins. PMID- 20193660 TI - Pontine norepinephrine defects in Mecp2-null mice involve deficient expression of dopamine beta-hydroxylase but not a loss of catecholaminergic neurons. AB - Rett syndrome is a neurodevelopmental disorder caused by Mecp2 gene mutations. In RTT patients and Mecp2-null (Mecp2(-/Y)) mice, norepinephrine (NE) content drops significantly, which may play a role in breathing arrhythmia, sleep disorders and sudden death. However, the underlying mechanisms for the NE defect are not fully understood. The NE defect may result from decreased NE biosynthesis, loss of catecholaminergic neurons or both. Although deficiency in tyrosine hydroxylase (TH) has been demonstrated, it is possible that dopamine beta-hydroxylase (DBH), the critical enzyme converting dopamine to NE, is also affected. To test these possibilities, we studied DBH expressions in pontine catecholaminergic neurons of Mecp2(-/Y) mice identified with breathing abnormalities. In comparison to the wild type, Mecp2(-/Y) mice at 2months of age showed approximately 50% decrease in the expressions of DBH and TH, at both protein and mRNA levels in the locus coeruleus (LC) region. Consistently, DBH and TH immunoreactivity was markedly decreased in LC neurons of Mecp2(-/Y) mice. No evidence was found for selective deficiency in TH- or DBH-containing neurons in Mecp2(-/Y) mice, as almost all TH positive cells expressed DBH. By counting TH-immunoreactive cells in the LC, we found that the Mecp2(-/Y) mice lost only approximately 5% of the catecholaminergic neurons as compared to wild-type, although their LC volume shrank by approximately 15%. These results strongly suggest that the NE defect in Mecp2(-/Y) mice is likely to result from deficient expression of not only TH but also DBH without significant loss of catecholaminergic neurons in the LC. PMID- 20193662 TI - PTEN silencing reverses aging-related impairment of angiogenesis in microvascular endothelial cells. AB - Aging is associated with impaired angiogenesis (new blood vessels formation from the endothelial cells of pre-existing vessels) in a variety of tissues. The precise mechanisms of aging-related impairment of angiogenesis are not known. PTEN is a dual-specificity phosphatase that antagonizes in some cells the PI3K/Akt signaling pathway, important for cell survival, function and angiogenesis. PTEN's role in aging-related impairment of angiogenesis is not known. In this study, we investigated whether expression of PTEN in endothelial cells may play a mechanistic role in aging-related impairment of angiogenesis. We demonstrated that human microvascular endothelial cells (HMVEC) derived from aging individuals (Aged-HMVEC) have: (1) significantly increased PTEN mRNA and protein levels and (2) impaired in vitro angiogenesis vs. neonatal derived HMVEC (Neo-HMVEC), and that (3) downregulation of PTEN using specific siRNA restores angiogenesis in Aged-HMVEC to normal. This is the first demonstration of increased PTEN expression in human microvascular endothelial cells derived from aging tissues and that elevated PTEN is a major factor responsible for aging related impairment of in vitro angiogenesis. PMID- 20193663 TI - Real-time visualization of prion transport in single live cells using quantum dots. AB - Prion diseases are fatal neurodegenerative disorders resulting from structural conversion of the cellular isoform of PrP(C) to the infectious scrapie isoform PrP(Sc). It is believed that such structural alteration may occur within the internalization pathway. However, there is no direct evidence to support this hypothesis. Employing quantum dots (QDs) as a probe, we have recorded a real-time movie demonstrating the process of prion internalization in a living cell for the first time. The entire internalization process can be divided into four discrete but connected stages. In addition, using methyl-beta-cyclodextrin to disrupt cell membrane cholesterol, we show that lipid rafts play an important role in locating cellular PrP(C) to the cell membrane and in initiating PrP(C) endocytosis. PMID- 20193659 TI - F1F0-ATP synthases of alkaliphilic bacteria: lessons from their adaptations. AB - This review focuses on the ATP synthases of alkaliphilic bacteria and, in particular, those that successfully overcome the bioenergetic challenges of achieving robust H+-coupled ATP synthesis at external pH values>10. At such pH values the protonmotive force, which is posited to provide the energetic driving force for ATP synthesis, is too low to account for the ATP synthesis observed. The protonmotive force is lowered at a very high pH by the need to maintain a cytoplasmic pH well below the pH outside, which results in an energetically adverse pH gradient. Several anticipated solutions to this bioenergetic conundrum have been ruled out. Although the transmembrane sodium motive force is high under alkaline conditions, respiratory alkaliphilic bacteria do not use Na+- instead of H+-coupled ATP synthases. Nor do they offset the adverse pH gradient with a compensatory increase in the transmembrane electrical potential component of the protonmotive force. Moreover, studies of ATP synthase rotors indicate that alkaliphiles cannot fully resolve the energetic problem by using an ATP synthase with a large number of c-subunits in the synthase rotor ring. Increased attention now focuses on delocalized gradients near the membrane surface and H+ transfers to ATP synthases via membrane-associated microcircuits between the H+ pumping complexes and synthases. Microcircuits likely depend upon proximity of pumps and synthases, specific membrane properties and specific adaptations of the participating enzyme complexes. ATP synthesis in alkaliphiles depends upon alkaliphile-specific adaptations of the ATP synthase and there is also evidence for alkaliphile-specific adaptations of respiratory chain components. PMID- 20193664 TI - Naofen, a novel WD40-repeat protein, mediates spontaneous and tumor necrosis factor-induced apoptosis. AB - Naofen has recently been identified from the rat brain/spinal cord cDNA library as a substance reactive against an anti-shigatoxin (Stx)-2 antibody. Naofen mRNA is composed of 4620 nucleotides and encodes 1170 amino acids. Naofen contains four WD-repeat domains in its N-terminus and is ubiquitously distributed in many tissues of the rat. Tumor necrosis factor (TNF)-alpha enhanced the expression of naofen mRNA in HEK293 cells in a dose-dependent manner. Furthermore, naofen siRNA, which predominantly knocked down the expression of naofen mRNA, significantly reduced both TNF-alpha-induced caspase-3 activation and apoptosis in HEK293 cells. Overexpression of naofen in HEK293 cells (FLAG-NF) spontaneously induced caspase -3 activation and apoptosis, and showed extremely high susceptibility to TNF-alpha-induced apoptosis. These results indicated that naofen may function as a novel modulator activating caspase-3, and promoting TNF alpha-stimulated apoptosis. PMID- 20193666 TI - Upregulation of albumin expression in focal ischemic rat brain. AB - To gain insight into the early and late changes in protein expression following focal transient cerebral ischemia in rat, proteomic approach was undertaken. Proteomic profiling using two-dimensional gel electrophoresis indicated upregulation of albumin protein after 2h of ischemia and 22h of reperfusion among the other altered proteins. Further, the albumin overexpression was verified by quantitative real time PCR at mRNA level, validated by western blotting and immunohistochemistry. Although, exogenous human albumin therapy is already under clinical trials for cerebral ischemia, its endogenous expression in ischemic rat brain at mRNA and protein levels has not been investigated as yet. Here we report for the first time de novo synthesis of albumin in the ischemic rat brain. This study paves the way for further investigation of signaling mechanisms leading to albumin overexpression, so that it can be exploited as a therapeutic intervention. PMID- 20193665 TI - Regulation of group I metabotropic glutamate receptor expression in the rat striatum and prefrontal cortex in response to amphetamine in vivo. AB - G protein-coupled metabotropic glutamate receptors (mGluRs) are expressed in widespread regions of the mammalian brain and are involved in the regulation of a variety of neuronal and synaptic activities. Group I mGluRs (mGluR1 and mGluR5 subtypes) are expressed in striatal medium spiny output neurons and are believed to play an important role in the modulation of cellular responses to dopamine stimulation with psychostimulants. In this study, we investigated the effect of a single dose of the psychostimulant amphetamine on mGluR1/5 protein expression in the rat forebrain in vivo. We found that acute systemic injection of amphetamine at a behaviorally active dose (5 mg/kg) was able to reduce mGluR5 protein levels in a confined biochemical fraction of synaptosomal plasma membranes enriched from the striatum. In contrast to the striatum, amphetamine increased mGluR5 protein levels in the medial prefrontal cortex. These changes in mGluR5 expression in both the striatum and the medial prefrontal cortex were transient and reversible. In addition, protein levels of mGluR1 in the enriched synaptosomal fraction from both the striatum and the medial prefrontal cortex remained stable in response to acute amphetamine. Similarly, Homer1b/c proteins, which are prominent anchoring proteins of mGluR1/5 and are highly expressed in the striatum and the medial prefrontal cortex, showed no change in their protein abundance in striatal and cortical synaptosomes after amphetamine administration. These data demonstrate differential sensitivity of mGluR1 and mGluR5 expression to amphetamine. Acute amphetamine injection is able to alter mGluR5 protein levels at synaptic sites in a subtype- and region-specific manner. PMID- 20193667 TI - Two morphological sub-systems within the olfactory organs of a terrestrial snail. AB - In the present work, we have re-visited the problem of the olfactory neural system organization in the terrestrial snail. By staining the tentacle's nerves and their intrinsic tracts in different points of the cerebral ganglia-tentacles system we have found that the relatively small part of the primary sensory neurons from the sensory pad (7-8%) send their axons directly to the cerebral ganglia. The axons terminated in the metacerebral neuropil which suggests these receptors being not chemosensory but rather mechanosensory neurons. Majority of the primary sensory neurons are synaptically switching in the areas outside the cerebral ganglia, i.e. digits, glomeruli, tentacular ganglion. No primary sensory neurons of the olfactory pad were projecting directly to the procerebrum - the putative centre of olfactory information processing. The afferent tract innervating the procerebrum neuropil originated from the interneurons located in the tentacle ganglion and its digits. Our results suggest the presence of two different sub-systems within the snail nose - mechanosensory and chemosensory - with two different projection targets. PMID- 20193668 TI - Frequency-dependent changes in synaptic plasticity and brain-derived neurotrophic factor (BDNF) expression in the CA1 to perirhinal cortex projection. AB - The ability of a synapse to be modulated both positively and negatively may be considered as a plausible model for the formation of learning and memory. The CA1 to perirhinal cortex projection is one of the multiple hippocampal-neocortical projections considered to be crucially involved in memory consolidation. We and others have previously demonstrated the ability of this projection to undergo long-term potentiation (LTP), however it is currently unknown whether the CA1 perirhinal projection can also be modified negatively (i.e. demonstrate long-term depression (LTD)). Here we investigate whether the CA1 to perirhinal projection in vivo in the anaesthetised animal shows a frequency-dependent pattern of synaptic plasticity that is coupled with brain-derived neurotrophic factor (BDNF) expression. Five groups of animals were used and each group underwent one of five different stimulation protocols (1 Hz, 5 Hz, 10 Hz, 50 Hz or 100 Hz) followed by post-stimulation recordings at baseline stimulation intensity (0.05 Hz) for 1h. Paired-pulse facilitation (PPF) recordings were taken both during baseline and 1h post-stimulation across six inter-pulse intervals (IPIs). Following all experiments, tissue samples were taken from area CA1 and perirhinal cortex from both the unstimulated and stimulated hemispheres of each brain and analysed for BDNF. Results indicated that LTP was observed following 50 Hz and 100 Hz HFS but LTD was not observed following any low-frequency stimulation. Pre- and post stimulation PPF recordings revealed no difference for any of the stimulation frequencies, suggesting that the plasticity observed may involve a post- rather than a presynaptic mechanism. Finally, changes in BDNF were positively correlated with stimulation frequency in the area CA1 but the same pattern was not observed in the perirhinal cortex. These findings suggest that the CA1 to perirhinal cortex projection is electrophysiologically excitatory in nature and that changes in BDNF levels in this projection may not be predictive of changes in synaptic plasticity. PMID- 20193669 TI - Development of a fluorescent microsphere technique for rapid histological determination of cerebral blood flow. AB - The purpose of this study was to develop a more efficient fluorescent microsphere method to facilitate the rapid use of the histological technique and to enable its use in large tissue regions. Using fluorescent plate/slide imaging technology and automated detection and analysis software, we were able to rapidly image, detect, and count 3 separate microsphere colors in 200 microm thick tissue sections from piglet brain. In resting newborn piglets (n=6) on isoflurane anesthesia, we measured a median total cerebral blood flow (CBF) of 105 ml/min/100g (range 27-206 ml/min/100 g). Compared with other FM analysis methods, our method reduces the time required to determine blood flow, improves accuracy in lipid-rich tissues and large tissue regions and, unlike the radiolabeled microsphere method, can be combined with histological analysis. PMID- 20193671 TI - Effects of exposure to sublethal propiconazole on intestine-related biochemical responses in rainbow trout, Oncorhynchus mykiss. AB - The effect of long-term (30 days) exposure to PCZ (0.2, 50, and 500 microg l(-1)) on intestine-related biochemical markers in rainbow trout was investigated. Multiple biomarkers were measured, including digestive enzymes (proteolytic enzymes and amylase), antioxidant responses (TBARS, CP, SOD, CAT, GR and GPx) and energy metabolic parameters (RNA/DNA ratio, Na(+)-K(+)-ATPase). Exposure to 500 microg l(-1) PCZ led to significantly inhibited (p<0.01) proteolytic enzyme and amylase activity. Activities of the antioxidant enzymes SOD, CAT, and GPx gradually increased at lower PCZ concentrations (0.2 and 50 microg l(-1)). At the highest concentration (500 microg l(-1)), oxidative stress was apparent as significant higher (p<0.05) lipid peroxidation and protein carbonyls, associated with an inhibition of antioxidant enzymes activity. Moreover, energy metabolic parameters (RNA/DNA ratio, Na(+)-K(+)-ATPase) were significantly inhibited (p<0.01) in the intestines of fish exposed to 500 microg l(-1) PCZ, compared with controls. We suggest that long-term exposure to PCZ could result in several responses in intestine-related biochemical markers, which potentially could be used as indicators for monitoring residual PCZ present in the aquatic environment. PMID- 20193670 TI - A new genetic model of activity-induced Ras signaling dependent pre-synaptic plasticity in Drosophila. AB - Techniques to induce activity-dependent neuronal plasticity in vivo allow the underlying signaling pathways to be studied in their biological context. Here, we demonstrate activity-induced plasticity at neuromuscular synapses of Drosophila double mutant for comatose (an NSF mutant) and Kum (a SERCA mutant), and present an analysis of the underlying signaling pathways. comt; Kum (CK) double mutants exhibit increased locomotor activity under normal culture conditions, concomitant with a larger neuromuscular junction synapse and stably elevated evoked transmitter release. The observed enhancements of synaptic size and transmitter release in CK mutants are completely abrogated by: a) reduced activity of motor neurons; b) attenuation of the Ras/ERK signaling cascade; or c) inhibition of the transcription factors Fos and CREB. All of which restrict synaptic properties to near wild type levels. Together, these results document neural activity-dependent plasticity of motor synapses in CK animals that requires Ras/ERK signaling and normal transcriptional activity of Fos and CREB. Further, novel in vivo reporters of neuronal Ras activation and Fos transcription also confirm increased signaling through a Ras/AP-1 pathway in motor neurons of CK animals, consistent with results from our genetic experiments. Thus, this study: a) provides a robust system in which to study activity-induced synaptic plasticity in vivo; b) establishes a causal link between neural activity, Ras signaling, transcriptional regulation and pre-synaptic plasticity in glutamatergic motor neurons of Drosophila larvae; and c) presents novel, genetically encoded reporters for Ras and AP-1 dependent signaling pathways in Drosophila. PMID- 20193672 TI - In vitro anticancer studies of alpha- and beta-D-glucopyranose betulin anomers. AB - Four derivatives of betulin containing a D-glucopyranosyl moiety at C3 position were synthesized and characterized by (1)H and (13)C NMR spectroscopy as well as mass spectrometry. The crystal structure of 28-O-acetylbetulin-3-yl-beta-D (2',3',4',6'-tetra-O-acetyl)glucopyranoside was determined. The compounds were tested against fifteen tumor cell lines of different histogenic origins. The alpha- and beta-anomers of 28-O-acetylbetulin-3-yl-D-glucopyranoside, exerted a dose dependent antiproliferative action towards the tumor cell lines. Treatment of HCT-116 cells for 24h induced apoptosis, which was confirmed by the appearance of a typical ladder pattern in the DNA fragmentation assay and cell cycle analysis. The alpha- and beta-anomers of 28-O-acetylbetulin-3-yl-D glucopyranoside seem to induce apoptosis by activation of different upstream caspases on colon cancer HCT-116 cell line. PMID- 20193673 TI - Genotype polymorphisms of GGCX, NQO1, and VKORC1 genes associated with risk susceptibility in patients with large-artery atherosclerotic stroke. AB - BACKGROUND: Gamma-glutamyl carboxylation, a reaction essential for the biosynthesis of vitamin K-dependent coagulation factors, requires the participation of the gamma-glutamyl carboxylase (GGCX), vitamin K epoxide reductase (VKORC1), and NAD(P)H:quinone oxidoreductase (NQO1). We evaluated the role of these genotype polymorphisms in patients with large-artery atherosclerotic stroke. METHODS: In this hospital-based case-control study, 117 patients who were categorized as having large-artery atherosclerotic stroke and 115 age- and gender-matched controls were recruited. Genotyping determination for the GGCX1 (Gln325Arg), NQO1 (Pro187Ser), and VKORC1 (rs9923231) polymorphisms was performed. The associations of genotype with ischemic stroke (IS) risk were examined. RESULTS: A higher genotypic frequency of NQO1 C609T was found in the controls than in the patients, manifesting a 0.47-fold risk reduction in IS (95% CI=0.25-0.87). A tendency toward a reduced IS risk was statistically significant in those subjects who carried a greater number of the NQO1, GGCX, and VKORC1 polymorphisms (aOR=0.58, P(trend)=0.005). The synergistic effect of multiple genes on risk reduction was more significant in a subset of patients who were not alcoholics and who were non-smokers (P<0.05). CONCLUSIONS: Compartmentation of coagulation factor metabolism may account for the preferential role of NQO1, GGCX, and VKORC1 polymorphisms to lower the risk for large-artery atherosclerotic stroke. PMID- 20193674 TI - Hedgehog signaling induces arterial endothelial cell formation by repressing venous cell fate. AB - In vertebrate embryos, the dorsal aorta and the posterior cardinal vein form in the trunk to comprise the original circulatory loop. Previous studies implicate Hedgehog (Hh) signaling in the development of the dorsal aorta. However, the mechanism controlling specification of artery versus vein remains unclear. Here, we investigated the cell-autonomous mechanism of Hh signaling in angioblasts (endothelial progenitor cells) during arterial-venous specification utilizing zebrafish mutations in Smoothened (Smo), a G protein-coupled receptor essential for Hh signaling. smo mutants exhibit an absence of the dorsal aorta accompanied by a reciprocal expansion of the posterior cardinal vein. The increased number of venous cells is equivalent to the loss of arterial cells in embryos with loss of Smo function. Activation of Hh signaling expands the arterial cell population at the expense of venous cell fate. Time-lapse imaging reveals two sequential waves of migrating progenitor cells that contribute to the dorsal aorta and the posterior cardinal vein, respectively. Angioblasts deficient in Hh signaling fail to contribute to the arterial wave; instead, they all migrate medially as a single population to form the venous wave. Cell transplantation analyses demonstrate that Smo plays a cell-autonomous role in specifying angioblasts to become arterial cells, and Hh signaling-depleted angioblasts differentiate into venous cells instead. Collectively, these studies suggest that arterial endothelial cells are specified and formed via repressing venous cell fate at the lateral plate mesoderm by Hh signaling during vasculogenesis. PMID- 20193675 TI - TGF-beta mediated FGF10 signaling in cranial neural crest cells controls development of myogenic progenitor cells through tissue-tissue interactions during tongue morphogenesis. AB - Skeletal muscles are formed from two cell lineages, myogenic and fibroblastic. Mesoderm-derived myogenic progenitors form muscle cells whereas fibroblastic cells give rise to the supportive connective tissue of skeletal muscles, such as the tendons and perimysium. It remains unknown how myogenic and fibroblastic cell cell interactions affect cell fate determination and the organization of skeletal muscle. In the present study, we investigated the functional significance of cell cell interactions in regulating skeletal muscle development. Our study shows that cranial neural crest (CNC) cells give rise to the fibroblastic cells of the tongue skeletal muscle in mice. Loss of Tgfbr2 in CNC cells (Wnt1 Cre;Tgfbr2(flox/flox)) results in microglossia with reduced Scleraxis and Fgf10 expression as well as decreased myogenic cell proliferation, reduced cell number and disorganized tongue muscles. Furthermore, TGF-beta2 beads induced the expression of Scleraxis in tongue explant cultures. The addition of FGF10 rescued the muscle cell number in Wnt1-Cre;Tgfbr2(flox/flox) mice. Thus, TGF-beta induced FGF10 signaling has a critical function in regulating tissue-tissue interaction during tongue skeletal muscle development. PMID- 20193676 TI - Mutating the dileucine motif of the human beta(2)-adrenoceptor reduces the high initial rate of receptor phosphorylation by GRK without affecting postendocytic sorting. AB - The internalization of beta(2)-adrenoceptors after agonist activation results in a desensitized and phosphorylated receptor that either resensitizes by recycling to the cell surface or becomes degraded by postendocytic sorting to lysosomes. The duration and physiological effects of agonists therefore depend on beta(2) adrenoceptor sorting, highlighting the importance of sorting signals. Dileucine motifs within other membrane proteins act as signals for endocytosis and/or postendocytic sorting, and the beta(2)-adrenoceptor has a dileucine motif within helix 8 that might play a role in efficient receptor recycling and/or downregulation. beta(2)-adrenoceptor internalization and sorting were studied in HEK293 cells stably expressing wild type or mutant dialanine L339A,L340A beta(2) adrenoceptors. The mutant beta(2)-adrenoceptors showed a significantly lower initial rate of phosphorylation at the prominent G-protein coupled receptor kinase (GRK) sites Ser355 and 356 compared to wild type beta(2)-adrenoceptors. Furthermore, the agonist-induced endocytic rate constant for L339A,L340A beta(2) adrenoceptors was reduced to approximately 25% that of wild type beta(2) adrenoceptors, which resulted in a similar reduction in agonist-induced downregulation. Internalized L339A,L340A beta(2)-adrenoceptors recycled to the surface with a rate and extent similar to that of wild type beta(2) adrenoceptors. Therefore, although the role of L339,L340 in beta(2)-adrenoceptor recycling or postendocytic sorting seems minimal, we conclude that L339,L340 is required for the initial high rate of phosphorylation by G-protein coupled receptor kinases at Ser355,356, which in turn is required for efficient beta(2) adrenoceptors endocytosis. PMID- 20193677 TI - Effects of 17beta-estradiol on expression of muscarinic acetylcholine receptor subtypes and estrogen receptor alpha in rat hippocampus. AB - The aim of the present study was to investigate the effects of 17beta-estradiol on expression of muscarinic acetylcholine receptor subtypes (M1 to M5) and estrogen receptor alpha, in the rat hippocampus. Hippocampi were obtained from rats in proestrus, rats ovariectomized for 15 days, rats ovariectomized for 15 days and then treated with 17beta-estradiol for 7 days, and rats ovariectomized and immediately treated with 17beta-estradiol for 21 days. Expression of M1 to M5 was increased in hippocampi of rats ovariectomized for 15 days compared to rats in proestrus. Although this effect was abolished when replacement with 17beta estradiol started immediately after ovariectomy, the increased expression of M1, M3 and M5 receptor subtypes was unchanged when replacement with 17beta-estradiol started only 15 days after ovariectomy. The expression of estrogen receptor alpha in the hippocampus was also upregulated after ovariectomy when compared to rats in proestrus. This effect was abolished when 17beta-estradiol was replaced immediately after ovariectomy, and slightly reduced when the replacement started 15 days after ovariectomy. The replacement with estrogen also had beneficial effects on cognitive function, as suggested by data obtained in the plus-maze discriminative avoidance task. In conclusion, the present results provide evidence that 17beta-estradiol regulates the expression of muscarinic acetylcholine receptor subtypes and estrogen receptor alpha. The immediate replacement with estrogen seems critical to restore the expression of these receptors after hormonal deprivation. The understanding of the regulation of expression and intracellular signaling of the muscarinic acetylcholine receptor subtype M1 and the estrogen receptor alpha may be helpful to elucidate the mechanisms involved in changes of cognitive function in postmenopausal women and in neurodegenerative diseases. PMID- 20193678 TI - Hypericin, the active component of St. John's wort, inhibits glutamate release in the rat cerebrocortical synaptosomes via a mitogen-activated protein kinase dependent pathway. AB - Changes in central glutamate neurotransmission are involved in the pathophysiology of depression and in the mechanism of antidepressants. In this study, the effect of hypericin, a major active constituent of St. John's wort that is widely used in the treatment of depression, on the release of glutamate from nerve terminals purified from rat cerebral cortex was examined. Result showed that hypericin inhibited the release of glutamate evoked by 4 aminopyridine in a concentration-dependent manner. Further experiments revealed that hypericin-mediated inhibition of glutamate release (i) results from a reduction of vesicular exocytosis, not from an inhibition of Ca2+-independent efflux via glutamate transporter; (ii) is not due to an alternation of nerve terminal excitability; (iii) is associated with a decrease in presynaptic N- and P/Q-type voltage-dependent Ca2+ channel activity; and (iv) appears to involve the suppression of mitogen-activated protein kinase pathway. These results are the first to suggest that, in rat cerebrocortical nerve terminals, hypericin suppresses voltage-dependent Ca2+ channel and mitogen-activated protein kinase activity and in so doing inhibits evoked glutamate release. This finding may provide important information regarding the beneficial effects of St. John's wort in the brain. PMID- 20193679 TI - Protective effect of amlodipine against osteoporosis in stroke-prone spontaneously hypertensive rats. AB - Hypertensive patients have an increasing risk of osteoporosis. A recent case controlled study has demonstrated that anti-hypertensive therapy reduced a risk of fracture in these patients. In this study, we investigated whether amlodipine protects against the reduction in bone density in stroke-prone spontaneously hypertensive rats (SHR-sp). Oral dosing of amlodipine (0.5 and 3.0mg/kg/day) was started when SHR-sp were 3 months old, and continued for 3 months. At the end of the experiment, bone density of femur and serum concentrations of calcium, parathyroid hormone (PTH) and C-telopeptide of type I collagen (CTx), reflecting osteoclast activity, were measured. The bone density dose-dependently increased by the treatment with amlodipine. In addition, amlodipine reduced serum concentrations of calcium, PTH and CTx. This study showed that amlodipine prevents the reduction in bone density during the repeated dosing in SHR-sp. Amlodipine might exert its effect through a direct inhibition of osteoclast function and/or suppression of PTH secretion and subsequent inhibition of osteoclast activity. PMID- 20193680 TI - Calpains: markers of tumor aggressiveness? AB - Rhabdomyosarcoma (RMS) are soft-tissue sarcoma commonly encountered in childhood. RMS cells can acquire invasive behavior and form metastases. The metastatic dissemination implicates many proteases among which are mu-calpain and m-calpain. Study of calpain expression and activity underline the deregulation of calpain activity in RMS. Analysis of kinetic characteristics of RMS cells, compared to human myoblasts LHCN-M2 cells, shows an important migration velocity in RMS cells. One of the major results of this study is the positive linear correlation between calpain activity and migration velocity presenting calpains as a marker of tumor aggressiveness. The RMS cytoskeleton is disorganized. Specifying the role of mu- and m-calpain using antisense oligonucleotides led to show that both calpains up-regulate alpha- and beta-actin in ARMS cells. Moreover, the invasive behavior of these cells is higher than that of LHCN-M2 cells. However, it is similar to that of non-treated LHCN-M2 cells, when calpains are inhibited. In summary, calpains may be involved in the anarchic adhesion, migration and invasion of RMS. The direct relationship between calpain activity and migration velocities or invasive behavior indicates that calpains could be considered as markers of tumor aggressiveness and as potential targets for limiting development of RMS tumor as well as their metastatic behavior. PMID- 20193681 TI - Retinal vascular leakage occurring in GABA Rho-1 subunit deficient mice. AB - Recent studies demonstrate that GABAergic activity elicits relaxation of retinal arterioles leading to an increase in blood flow. It has also been found that GABAnergic activity in the retina of mice with diabetic retinopathy is suppressed. In this study, we provide further evidence that lack of GABAergic activity significantly alters vasculature development as well as the hypoxia induced angiogenic response. Using GABA(C) receptor rho(1) subunit-knockout mice (rho-1(-/-)), our results demonstrate that in hypoxia-induced retinas a severe vascular leakage occurred in 2 week-old rho-1(-/-) mice compared with their wildtype counterparts. In addition, our results also showed that all of the rho 1(-/-) mice developed significant retinal vascular leakages by 48 weeks-of-age. Microarray and real-time PCR experiments revealed a unique angiogenesis-related gene expression pattern. This suggests that retinal vascular disorders of rho-1( /-) mice results from significant up-regulation of angiogenic genes and concomitant down-regulation of anti-angiogenic genes. The study results are consistent with the pathological changes of the retinal vascular leakage seen in diabetic retinopathy. Our data indicate that the GABA(C) rho(1) subunit plays a role in maintaining both homeostasis and balance of retinal neurotransmitter function. Knockout of the retinal GABA(C) rho(1)-subunit leads to changes in vascular permeability similar to the pathological changes induced by retinal hypoxic conditions. PMID- 20193682 TI - Pyrimethamine induces oxidative stress in Plasmodium yoelii 17XL-infected mice: a novel immunomodulatory mechanism of action for an old antimalarial drug? AB - Pyrimethamine is an antimalarial drug that has also been used successfully to treat autoimmune diseases such as lymphoproliferative syndrome. In this work, the effect of pyrimethamine (PYR) on the production of free radicals in malaria infected mice was studied to better understand the drug's immunomodulatory properties. BALB/c and CBA/Ca mice were infected with Plasmodium yoelii 17XL. Seven days after infection, mice were treated with PYR or vehicle and sacrificed 24h later. Treatment with PYR increased superoxide dismutase and glutathione peroxidase activities in erythrocytes and the liver, augmented the levels of nitric oxide in the serum, and upregulated mRNA levels of superoxide dismutase, glutathione peroxidase, catalase, and iNOS in the spleen. In addition, PYR increased lipoperoxidation and protein carbonylation in infected mice. Our results indicate that P. yoelii 17XL reduces oxidative stress in infected cells, while PYR induces it, which is associated with increased parasite elimination. Thus, it is possible that oxidative stress generated by pyrimethamine is also involved in its immunomodulatory mechanism of action. PMID- 20193683 TI - Severe pediatric ulcerative colitis: a prospective multicenter study of outcomes and predictors of response. AB - BACKGROUND & AIMS: In a prospective study of children with severe ulcerative colitis (UC), we aimed to assess outcomes and to identify predictors of nonresponse to intravenous corticosteroids. METHODS: A total of 128 children (47% males; 12.9 +/- 3.9 y) hospitalized for severe UC were enrolled from 10 pediatric centers. Clinical and laboratory data and the Pediatric UC Activity Index (PUCAI) were recorded throughout the admission. Patients were followed up for 1 year postdischarge. RESULTS: Thirty-seven (29%; 95% confidence interval [CI], 22%-37%) children failed intravenous corticosteroids and received, within 10.5 +/- 6.4 days, cyclosporine (n = 1; 3%), colectomy (n = 3; 8%), or infliximab (n = 33; 89%). Several predictors were associated with intravenous corticosteroids failure, but the best model included number of stools, amount of blood, age, and new-onset disease (odds ratio [OR], 1.9; 95% CI, 1.1-3.5; OR, 2.5; 95% CI, 1.3 4.6; OR, 1.2; 95% CI, 1.04-1.36; and OR, 0.27; 95% CI, 0.1-0.7, respectively). The PUCAI, followed closely by the Travis rule, strongly predicted response when compared with other measures (Seo and Lindgren indices, C-reactive protein level, and fecal calprotectin level) (P < .001). Aiming for sensitivity on day 3, a PUCAI greater than 45 screened for patients likely to fail intravenous corticosteroids (negative predictive value, 94%; positive predictive value, 43%; P < .001). Aiming for specificity on day 5, a PUCAI score greater than 70 optimally guided implementation of salvage therapy (positive predictive value, 100%; negative predictive value, 79%; P < .001). Twenty-five of 33 children treated with infliximab responded. The overall cumulative colectomy rate was 9% and 19% by discharge and 1-year, respectively. The day 3 PUCAI score predicted response up to 1 year postdischarge (P < .001; time to salvage therapy). CONCLUSIONS: The PUCAI, calculated on days 3 and 5 of steroid therapy, can identify patients requiring salvage therapy. Infliximab is an effective therapy in steroid-refractory pediatric UC. PMID- 20193684 TI - Signal transducer and activator of transcription 3 protects from liver injury and fibrosis in a mouse model of sclerosing cholangitis. AB - BACKGROUND & AIMS: Signal transducer and activator of transcription 3 (Stat3) is the main mediator of interleukin-6-type cytokine signaling required for hepatocyte proliferation and hepatoprotection, but its role in sclerosing cholangitis and other cholestatic liver diseases remains unresolved. METHODS: We investigated the role of Stat3 in inflammation-induced cholestatic liver injury and used mice lacking the multidrug resistance gene 2 (mdr2(-/-)) as a model for SC. RESULTS: We show that conditional inactivation of Stat3 in hepatocytes and cholangiocytes (stat3(Deltahc)) of mdr2(-/-) mice strongly aggravated bile acid induced liver injury and fibrosis. A similar phenotype was observed in mdr2(-/-) mice lacking interleukin-6 production. Biochemical and molecular characterization suggested that Stat3 exerts hepatoprotective functions in both hepatocytes and cholangiocytes. Loss of Stat3 led to increased expression of tumor necrosis factor alpha, which might reduce the barrier function of bile ducts. Moreover, Stat3-deficient hepatocytes displayed up-regulation of bile acid biosynthesis genes and down-regulation of hepatoprotective epidermal growth factor receptor and insulin-like growth factor 1 signaling pathways. Consistently, stat3(Deltahc) mice were more sensitive to cholic acid-induced liver damage than control mice. CONCLUSIONS: Our data suggest that Stat3 prevents cholestasis and liver damage in sclerosing cholangitis via regulation of pivotal functions in hepatocytes and cholangiocytes. PMID- 20193685 TI - Laparoscopy improves short-term outcomes after surgery for diverticular disease. AB - BACKGROUND & AIMS: Observational studies and small randomized controlled trials have shown that the use of laparoscopy in colon resection for diverticular disease is feasible and results in fewer complications. We analyzed data from a large, prospectively maintained, multicenter database (National Surgical Quality Initiative Program) to determine whether the use of laparoscopy in the elective treatment of diverticular disease decreases rates of complications compared with open surgery, independent of preoperative comorbid factors. METHODS: The analysis included data from 6970 patients who underwent elective surgeries for diverticular disease from 2005 to 2008. Patients with diverticular disease were identified by International Classification of Diseases, 9th revision codes and then categorized into open or laparoscopic groups based on Current Procedural Terminology codes. Preoperative, intraoperative, and postoperative data were analyzed to determine factors associated with increased risk for postoperative complications. RESULTS: Data were analyzed from 3468 patients who underwent open surgery and 3502 patients who underwent laparoscopic procedures. After correcting for probability of morbidity, American Society of Anesthesiology class, and ostomy creation, overall complications (including superficial surgical site infections, deep incisional surgical site infections, sepsis, and septic shock) occurred with significantly lower incidence among patients who underwent laparoscopic procedures compared with those who received open operations. CONCLUSIONS: The use of laparoscopy for treating diverticular disease, in the absence of absolute contraindications, results in fewer postoperative complications compared with open surgery. PMID- 20193686 TI - Post-weaning voluntary exercise exerts long-term moderation of adiposity in males but not in females in an animal model of early-onset obesity. AB - Given the alarming increase in childhood, adolescent and adult obesity there is an imperative need for understanding the early factors affecting obesity and for treatments that may help prevent or at least moderate it. Exercise is frequently considered as an effective treatment for obesity however the empirical literature includes many conflicting findings. In the present study, we used the OLETF rat model of early-onset hyperphagia-induced obesity to examine the influence of early exercise on peripheral adiposity-related parameters in both males and females. Rats were provided voluntary access to running wheels from postnatal day (PND) 22 until PND45. We examined fat pad weight (brown, retroperitoneal, inguinal and epididymal); inguinal adipocyte size and number; and leptin, adiponectin, corticosterone and creatinine levels. We also examined body weight, feeding efficiency and spontaneous intake. Early voluntary exercise reduced intake, adiposity and leptin in the OLETF males following a sharp reduction in adipocyte size despite a significant increase in fat cell number. Exercising males from the lean LETO control strain presented stable intake, but reduced body fat, feeding efficiency and increased plasma creatinine, suggesting an increment in muscle mass. OLETF females showed reduced feeding efficiency and liver fat, and a significant increase in brown fat. Exercising LETO control females increased intake, body weight and creatinine, but no changes in body fat. Overall, OLETF rats presented higher adiponectin levels than controls in both basal and post-exercise conditions. The results suggest an effective early time frame, when OLETF males can be successfully "re-programmed" through voluntary exercise; in OLETF females the effect is much more moderate. Findings expose sex dependent peripheral mechanisms in coping with energy challenges. PMID- 20193687 TI - Validation of a miniaturized assay based on IFNg secretion for assessment of specific T cell immunity. AB - A miniaturized method for detection of antigen induced secretion of IFNg by specific T cells cultured in 384 well plates has been recently reported. In order to confidently apply this assay to clinical investigations for monitoring of specific T cell immunity, an intralaboratory validation study has been undertaken. High reproducibility and linearity of reference curves was demonstrated. Consecutive replicate experiments handled by different operators using broad panels of recall antigens were reproducible when tested on individual biological samples. Kinetics of IFNg secretion with different antigens showed a plateau after 24h culture. Similar trends were observed with secretion of TNFa, GM-CSF and IL17, suggesting that the same kinetics can be applied if other cytokines are tested with this assay. It was demonstrated that frozen-thawed cells can be tested by cell-ELISA and that when PBMC are replaced by whole blood similar reactivity profiles were observed even though cytokine concentration was lower. T cell responses were higher in round bottom than in flat bottom wells, but these plates could not be applied to cell-ELISA as clear plates are not available for scanning. In conclusion, the assay proved flexible, since plates can be frozen at different times during the process, fresh or frozen PBMC and PBMC or whole blood could be used, and robust, since reproducibility was remarkable even when different operators performed the procedures. PMID- 20193688 TI - Development and clinical evaluation of a multi-purpose mAb and a sandwich ELISA test for hepatoma-derived growth factor in lung cancer patients. AB - Hepatoma-derived growth factor (HDGF) is closely related to aggressive tumor behavior and could be a broader biomarker for cancer prognosis and diagnosis. The goal of this study is to develop a sandwich ELISA system to test if HDGF can be detected in serum samples. We produced an anti-HDGF monoclonal antibody designated 2F12 using recombinant human HDGF protein. The specificity of 2F12 mAb was characterized by western blotting, immunohistochemistry (IHC), immunofluorescent staining (IF) and immunoprecipitation (IP). The results showed that 2F12 recognized HDGF in both native and denatured form, and can be used for multiple purposes. We have found that HDGF is also expressed in several cancers unreported previously by IHC staining on tumor cell array sections. In addition, we have developed a sandwich ELISA assay using mAb 2F12 and rabbit anti-HDGF polyclonal antibody, and validated the assay using normal serum and non-small cell lung cancer (NSCLC) serum samples. The sensitivity of this assay is 0.5 ng/ml and the linear range is 0.5-32 ng/ml. The HDGF average level in serum samples from lung cancer patients is significantly elevated relative to that from healthy controls, 9.43+/-6.13 ng/ml versus 4.36+/-2.50 ng/ml (p=1.12E-10). PMID- 20193689 TI - Characterization of a trehalose-6-phosphate synthase gene from Spodoptera exigua and its function identification through RNA interference. AB - Trehalose is an important disaccharide and a key regulation factor for the development of many organisms, including plants, bacteria, fungi and insects. In order to study the trehalose synthesis pathway, a cDNA for a trehalose-6 phosphate synthase from Spodoptera exigua (SeTPS) was cloned which contained an open reading frame of 2481 nucleotides encoding a protein of 826 amino acids with a predicted molecular weight of 92.65kDa. The SeTPS genome has 12 exons and 11 introns. Northern blot and RT-PCR analyses showed that SeTPS mRNA was expressed in the fat body and in the ovary. Competitive RT-PCR revealed that SeTPS mRNA was expressed in the fat body at different developmental stages and was present at a high level in day 1 S. exigua pupae. The concentrations of trehalose and glucose in the hemolymph were determined by HPLC and showed that they varied at different developmental stages and were negatively correlated to each other. The survival rates of the insects injected with dsRNA corresponding to SeTPS gene reached 53.95%, 49.06%, 34.86% and 33.24% for 36, 48, 60 and 204h post-injection respectively which were significantly lower than those of the insects in three control groups. These findings provide new data on the tissue distribution, expression patterns and potential function of the trehalose-6-phosphate synthase gene. PMID- 20193690 TI - Hemolytic activity is mediated by the endogenous lectin in the mosquito hemolymph serum. AB - Although cytolysis of invading organisms is an innate form of immunity used by invertebrates, so far the underlying mechanism remains less explored. The pupal hemolymph of the mosquito Armigeres subalbatus induces an activity that causes hemolysis of human red blood cells (HRBC). This hemolytic activity was inhibited by sialic acid (N-acetylneuraminic acid) and serine protease inhibitors. We purified the sialic acid-specific lectin(s) from the pupal hemolymph using formaldehyde-fixed HRBC and determined the sequence of the amino-terminal 19 amino acid residues. A polyclonal antibody produced against this N-terminal peptide clearly inhibited the hemolytic activity of the hemolymph in vitro, thus suggesting that the hemolysis of HRBC is caused by the lectin present in the mosquito hemolymph. We suggest that mosquitoes possess a cytolysis system. PMID- 20193691 TI - Physiological requirements for 20-hydroxyecdysone-induced rectal sac distention in the pupa of the silkworm, Bombyx mori. AB - Successful insect development is achieved via appropriate fluctuation of ecdysteroid levels. When an insect's ecdysteroid level is disrupted, physiological and developmental defects occur. In the pupa of the silkworm, Bombyx mori, the rectal sac is an essential organ that operates as a repository for degraded ecdysteroids, and it can be distended by administration of 20 hydroxyecdysone (20E). Our previous study showed that rectal sac distention appears 4 days after 20E administration. Hemolymph ecdysteroid levels, however, decrease to lower level during this period. Thus, the timing of the rectal sac distention does not match with that of ecdysteroid elevation. Here, we examine how 20E induces rectal sac distention. A ligature experiment and ecdysteroid quantification showed that continuous 20E stimulation induces rectal sac distention. Thorax tissue contributed to the continuous 20E stimulation needed to induce distention. Ecdysteroid released from the thorax tissue may be converted to 20E by ecdysone 20-hydroxylase to produce continuous 20E stimulation. Thus, the ecdysone metabolic pathway plays a critical role in rectal sac distention. PMID- 20193692 TI - Exercise, eNOS and the heart after myocardial infarction. PMID- 20193693 TI - Gi-protein inhibitor, guanosine 5'-O-(2-thiodiphosphate), induces senescence associated beta-galactosidase positive cell formation through CREB phosphorylation. AB - AIMS: We evaluated Gi-protein inhibitor, guanosine 5'-O-(2-thiodiphosphate)(GOT) induced senescence-associated(SA)-beta-galactosidase(Gal) positive cell formation to determine if it occurred through phosphorylation of cyclic AMP-dependent response element binding protein (CREB). MAIN METHODS: IMR-90 human lung fibroblast cells were used. SA-beta-Gal positive cells and senescence-associated heterochromatic foci (SAHF) were determined by assessing blue color formation of substrate, X-gal inside cells and DAPI staining, respectively. Cell cycle and hypodiploid cell formation were assessed by flow cytometry analysis. CREB phosphorylation and molecular changes were analyzed by western blot. KEY FINDINGS: GOT treatment led to SA-beta-Gal positive cell formation and SAHF. CREB phosphorylation increased in response to GOT treatment but then decreased over 24h. SA-beta-Gal positive cell formation increased in response to transient transfection of pS6-RSV-CREB and no changes were detected following CREB knockdown with CREB-siRNA. In addition, CREB phosphorylation was delayed by treatment with the anti-cellular senescence agents, clitocybins which also reduced the number of SA-beta-Gal positive cells. Collectively, our data showed that GOT-induced CREB phosphorylation initiated SA-beta-Gal positive cell formation after which decreased in SA-beta-Gal positive cells. SIGNIFICANCE: These findings suggest for the first time that CREB phosphorylation by GOT could induce cellular senescence as judged by SA-beta-Gal positive cell formation. PMID- 20193694 TI - Isolated spermatozoa as indicators of mutations transmitted to progeny. AB - Spermatozoa comprise a large and homogeneous population of cells that may serve as an alternative to resource-intensive assays of transmissible mutations based on progeny. To evaluate mutagenic responses in spermatozoa derived from germ cells exposed to a mutagen at different stages of spermatogenesis, we compared cII mutant frequencies (MFs) in spermatozoa collected from male lambda transgenic medaka exposed to ethylnitrosourea (ENU) as either post-meiotic or pre-meiotic germ cells. cII MFs in spermatozoa exposed to ENU as spermatogonial stem cells were induced significantly, 9-fold, compared to controls, whereas, cII MFs in spermatozoa exposed as spermatozoa/late spermatids were not elevated. To directly compare responses in spermatozoa with those in progeny, we analyzed cII MFs directly in spermatozoa and in the offspring produced from identical sperm samples of ENU-exposed males. cII MFs in isolated spermatozoa exposed to ENU as post-meiotic germ cells were not significantly elevated, whereas 11-30% of the progeny derived from the identically exposed germ cells exhibited significantly elevated cII MFs, approximately 2-fold to >130-fold, compared to controls. The contradictory responses between spermatozoa and progeny analyses can be attributed to induced pre-mutational lesions that remain intact in spermatozoa but were not detected as mutations. Progeny analyses, by contrast, revealed mutant individuals with elevated cII mutant frequencies because persistent DNA damage in the spermatozoa was fixed as mutations in cells of the early stage embryo. Spermatozoa exposed to a mutagen as spermatogonial stem cells can provide an efficient means to detect the portion of transmissible mutations that were fixed as mutations in spermatozoa. The caveat is that direct analyses of mutations in spermatozoa excludes the contribution of mutations that arise from post-fertilization processes in cells of early stage embryos, and therefore may underestimate the actual frequency of mutant offspring. PMID- 20193695 TI - DNA methylation changes in a human cell model of breast cancer progression. AB - Epigenetic inactivation of genes by DNA hypermethylation plays an important role in carcinogenesis. An in vitro model of human breast epithelial cell transformation was used to study epigenetic changes induced by estradiol during the neoplastic process. Different stages of tumor initiation and progression are represented in this model being MCF-10F the normal stage; trMCF cells, the transformed stage; bsMCF cells, the invasive stage and, caMCF cells, the tumor stage. Global methylation studies by restriction landmark genomic scanning (RLGS) showed an increased DNA methylation during the in the invasive and tumor stages. Expression studies showed that NRG1 (neuregulin 1), CSS3 (chondroitin sulfate synthase 3) and SNIP (SNAP-25-interacting protein) were downregulated in the invasive and tumor cells. The transformed cells showed low expression of STXBP6 (amysin) compared to the parental cells MCF-10F. The treatment of these cells with the demethylating agent 5-aza-dC alone or in combination with the histone deacetylase inhibitor trichostatin increased the expression of NRG1, STXBP6, CSS3 and SNIP confirming that DNA methylation plays an important role in the regulation of the expression of these genes. The NRG1 exon 1 has a region located between -136 and +79 (considering +1, the translational initiation site) rich in CpG sites that was analyzed by methylation specific PCR (MSP). NRG1 exon 1 showed progressive changes in the methylation pattern associated with the progression of the neoplastic process in this model; NRG1 exon 1 was unmethylated in MCF-10F and trMCF cells, becoming hypermethylated in the invasive (bsMCF) and tumor (caMCF) stages. Studies of human breast tissue samples showed that NRG1 exon 1 was partially methylated in 14 out of 17 (82.4%) invasive carcinomas although it was unmethylated in normal tissues (8 out of 10 normal breast tissue samples). Furthermore, NRG1 exon 1 was partially methylated in 9 out of 14 (64.3%) morphologically normal tissue samples adjacent to invasive carcinomas. PMID- 20193696 TI - Effect of amphetamine on extracellular concentrations of amino acids in striatum in neurotensin subtype 1 and 2 receptor null mice: a possible interaction between neurotensin receptors and amino acid systems for study of schizophrenia. AB - Neurotensin (NT) is a tridecapeptide that acts as a neuromodulator in the central nervous system mainly through two NT receptors: NTS1 and NTS2. The present study was done to determine the roles of NTS1 and NTS2 on amino acid release in striatum with the use of NTS1 or NTS2 knockout ((-/-)) mice given d-amphetamine. Both NTS1(-/-) and NTS2(-/-) mice had lower extracellular concentrations of D serine in striatum than did wild type (WT) mice. NTS2(-/-) but not NTS1(-/-) mice also had significantly lower basal concentrations of glutamate in striatum as compared to that for WT mice. Systemic administration of d-amphetamine (4 mg/kg, ip) increased glutamate release by 500% in WT mice, as compared to 300% in NTS2( /-) mice, and 250% in NTS1(-/-) mice. Additionally, d-amphetamine injection caused a 4-fold increase in GABA release in both WT and NTS2(-/-) mice, but only a 2-fold increase in NTS1(-/-) mice. Therefore, NTS1 and NTS2 modulate basal release of D-serine and glutamate, and also d-amphetamine-induced GABA and glutamate release in striatum. These results provide further support for the involvement of NT receptors in the pathogenesis of schizophrenia and provide a better understanding of the imbalance of amino acid systems through investigation of a DA-based animal model. PMID- 20193697 TI - Wheel running eliminates high-fat preference and enhances leptin signaling in the ventral tegmental area. AB - Voluntary wheel running (WR) is a form of physical activity in rodents that influences ingestive behavior. This study examined the effects of WR on dietary preference and the potential role of leptin in mediating these effects. In a two diet choice paradigm in which both palatable high-fat (HF) food and standard laboratory chow were provided ad libitum, rats displayed a strong preference for the former and chose to eat almost exclusively the HF diet over chow in sedentary conditions. With free access to running wheels, however, rats exhibited no preference for the HF food and consumed equal gram amounts of both chow and HF diets. The total daily caloric consumption during WR in the dietary choice protocol was equivalent to the amount of calories consumed daily by WR rats with only chow or only HF diet available, yet significantly less than sedentary chow caloric consumption. Two days after initiating WR, leptin signal transduction was examined in multiple selected brain sites following leptin injection into the third cerebral ventricle. The maximal leptin-stimulated STAT3 phosphorylation was enhanced only in the ventral tegmental area (VTA), but not in the arcuate nucleus, lateral hypothalamus, dorsal medial or ventral medial hypothalamus, or substantia nigra. In conclusion, wheel running appears to act either as an independent reinforcing factor or as a more favored activity to substitute for the consumption of a palatable HF diet, thus eliminating the preference for the HF food. Moreover, WR enhances leptin signaling specifically in the VTA, suggestive of a WR-evoked mechanism of heightened leptin function in the VTA to curb the drive to consume palatable HF foods. PMID- 20193698 TI - Thermoregulation and aggregation in neonatal bearded dragons (Pogona vitticeps). AB - Ectothermic vertebrates, such as reptiles, thermoregulate behaviorally by choosing from available temperatures in their environment. As neonates, bearded dragons (Pogona vitticeps) are often observed to aggregate in vertical strata. A proximate mechanism for this behavior is the thermal advantage of heat storage (i.e., grouped lizards benefit through a decreased surface area to volume ratio), although competition for limited thermal resources, or aggregation for social reasons are alternative explanations. This study was designed to gain an understanding of how aggregation and thermoregulation interact. We observed that both isolated and grouped individuals achieved a similar level of thermoregulation (mean T(b) over trial) within a thermal gradient, but that individuals within a group had lower thermoregulatory precision. An experimental design in which light and ambient temperature (T(a)) (20 versus 30 degrees C) were altered established that a light bulb (source of heat) was a limited and valuable resource to both isolated and grouped neonatal lizards. Lizards aggregated more when the light was on at both temperatures, suggesting that individuals were equally attracted to or repelled from the heat source, depending on the ambient temperature. These data suggest aggregation occurs in neonatal bearded dragons through mutual attraction to a common resource. Further, increased variability in thermal preference occurs in groups, demonstrating the potential for agonistic behaviors to compromise optimal thermoregulation in competitive situations, potentially leading to segregation, rather than aggregation. PMID- 20193699 TI - Meal replacements and energy balance. AB - Induction and maintenance of a period of negative energy balance are required for overweight and obese subjects to lose weight. Meal replacements, particularly in beverage form, have now evolved as part of the "toolbox" used by researchers and clinicians to achieve negative energy balance. This overview traces the historical development of beverage meal replacements, reviews key studies supporting their clinical efficacy, and examines concerns related to their safe use. This collective information supports the view that meal replacements, particularly in beverage form, are now an effective and safe component for use in the clinical setting. Further studies are needed to identify those subjects most likely to benefit from use of meal replacements as part of their comprehensive weight control program. PMID- 20193701 TI - Effects of chronic stress: a comparison between tethered and loose sows. AB - The present study aimed to investigate whether long-lasting, recurrent tethering of sows leads to enduring effects on measures that may be indicative of chronic stress. Sows that had experienced tethering for about 1.5 or 4.5years and age matched sows kept in a social housing system (loose sows) were compared. Immediately after slaughter, blood samples were taken to measure plasma cortisol levels, and the brain, spleen, and adrenals were dissected and weighed. Gene expression in the frontal cortex and hippocampus was analyzed. Plasma cortisol levels were higher in the tethered sows than in the loose sows. The older, but not the younger, tethered sows had heavier adrenal glands than their loose counterparts. The weight of the spleen was not affected by the housing conditions, but the pituitary gland was lighter in tethered sows than in loose sows. Microarray analyses revealed an increased expression of beta-globin mRNA in the hippocampus and to a lesser extent in the frontal cortex of the older tethered sows, compared with the older loose sows. Taken together, the findings indicate that chronically stressed pigs develop depression-like symptoms. However, it can be questioned whether the pig subjected to repeated, long-term stress can be regarded an animal model of major depression. PMID- 20193700 TI - The roles of leptin receptors on POMC neurons in the regulation of sex-specific energy homeostasis. AB - Leptin regulates energy homeostasis and reproduction. One key population of leptin receptors (Lepr) are found on proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus, and evidence links the action of gonadal estrogens to these same POMC neurons. To determine whether Lepr on POMC neurons are critical for reproductive capacity or for sex-specific energy and glucose homeostasis, we studied Cre/loxP mice lacking Lepr specifically on POMC neurons (Pomc-Cre, Lepr(flox/flox) mice) and their controls with normal Lepr (Lepr(flox/flox) mice). Pomc-Cre, Lepr(flox/flox) mice maintained normal reproductive capacity and accumulated more body fat than their same sex controls. Ovariectomy (OVX) was performed to investigate the effects of the estrogens and Lepr on POMC neurons on body fat accumulation and glucose tolerance. OVX Pomc Cre, Lepr(flox/flox) females accumulated more fat than OVX Lepr(flox/flox) females did. Pomc-Cre, Lepr(flox/flox) males were glucose intolerant and insulin insensitive compared with control males. In contrast, control and Pomc-Cre, Lepr(flox/flox) females had similar glucose tolerance before and after OVX. Therefore leptin's action on POMC neurons reduces body fat accumulation, but is not critical for regulation of reproduction. The sex difference in leptin signaling on POMC neurons on glucose tolerance appears independent of ovarian hormones. PMID- 20193702 TI - Size-dependent tissue kinetics of PEG-coated gold nanoparticles. AB - Gold nanoparticles (AuNPs) can be used in various biomedical applications, however, very little is known about their size-dependent in vivo kinetics. Here, we performed a kinetic study in mice with different sizes of PEG-coated AuNPs. Small AuNPs (4 or 13nm) showed high levels in blood for 24h and were cleared by 7days, whereas large (100nm) AuNPs were completely cleared by 24h. All AuNPs in blood re-increased at 3months, which correlated with organ levels. Levels of small AuNPs were peaked at 7days in the liver and spleen and at 1month in the mesenteric lymph node, and remained high until 6months, with slow elimination. In contrast, large AuNPs were taken up rapidly ( approximately 30min) into the liver, spleen, and mesenteric lymph nodes with less elimination phase. TEM showed that AuNPs were entrapped in cytoplasmic vesicles and lysosomes of Kupffer cells and macrophages of spleen and mesenteric lymph node. Small AuNPs transiently activated CYP1A1 and 2B, phase I metabolic enzymes, in liver tissues from 24h to 7days, which mirrored with elevated gold levels in the liver. Large AuNPs did not affect the metabolic enzymes. Thus, propensity to accumulate in the reticuloendothelial organs and activation of phase I metabolic enzymes, suggest that extensive further studies are needed for practical in vivo applications. PMID- 20193703 TI - Signal transduction pathways and transcription factors triggered by arsenic trioxide in leukemia cells. AB - Arsenic trioxide (As(2)O(3)) is widely used to treat acute promyelocytic leukemia (APL). Several lines of evidence have indicated that As(2)O(3) affects signal transduction and transactivation of transcription factors, resulting in the stimulation of apoptosis in leukemia cells, because some transcription factors are reported to associate with the redox condition of the cells, and arsenicals cause oxidative stress. Thus, the disturbance and activation of the cellular signaling pathway and transcription factors due to reactive oxygen species (ROS) generation during arsenic exposure may explain the ability of As(2)O(3) to induce a complete remission in relapsed APL patients. In this report, we review recent findings on ROS generation and alterations in signal transduction and in transactivation of transcription factors during As(2)O(3) exposure in leukemia cells. PMID- 20193704 TI - Interaction of Naja naja atra cardiotoxin 3 with H-trisaccharide modulates its hemolytic activity and membrane-damaging activity. AB - To address whether saccharide moieties of blood groups A, B and O antigens modulate hemolytic activity of Naja naja atra cardiotoxins (CTXs), the present study was carried out. Unlike other CTX isotoxins, hemolytic activity of CTX3 toward blood group O cholesterol-depleted red blood cells (RBCs) was notably lower than that of blood groups A and B cholesterol-depleted RBCs. Conversion of blood group B RBCs into blood group O RBCs by alpha-galactosidase treatment attenuated the susceptibility for hemolytic activity of CTX3, suggesting that H antigen affected hemolytic potency of CTX3. Pre-incubation with H-trisaccharide reduced hemolytic activity and membrane-damaging activity of CTX3. Moreover, CTX3 showed a higher binding capability with H-trisaccharide than other CTXs did. CD spectra showed that the binding with H-trisaccharide induced changes in gross conformation of CTX3. Self-quenching studies revealed that oligomerization of CTX3 was affected in the presence of H-trisaccharide. Taken together, our data suggest that the binding of CTX3 with H-antigen alters its membrane-bound mode, thus reducing its hemolytic activity toward blood group O cholesterol-depleted RBCs. PMID- 20193705 TI - Is coenzyme Q a key factor in aging? AB - Coenzyme Q (Q) is a key component for bioenergetics and antioxidant protection in the cell. During the last years, research on diseases linked to Q-deficiency has highlighted the essential role of this lipid in cell physiology. Q levels are also affected during aging and neurodegenerative diseases. Therefore, therapies based on dietary supplementation with Q must be considered in cases of Q deficiency such as in aging. However, the low bioavailability of dietary Q for muscle and brain obligates to design new mechanisms to increase the uptake of this compound in these tissues. In the present review we show a complete picture of the different functions of Q in cell physiology and their relationship to age and age-related diseases. Furthermore, we describe the problems associated with dietary Q uptake and the mechanisms currently used to increase its uptake or even its biosynthesis in cells. Strategies to increase Q levels in tissues are indicated. PMID- 20193706 TI - Atrial local Ca2+ signaling and inositol 1,4,5-trisphosphate receptors. AB - In atrial myocytes lacking t-tubules, action potential triggers junctional Ca(2+) releases in the cell periphery, which propagates into the cell interior. The present article describes growing evidence on atrial local Ca(2+) signaling and on the functions of inositol 1,4,5-trisphosphate receptors (IP(3)Rs) in atrial myocytes, and show our new findings on the role of IP(3)R subtype in the regulation of spontaneous focal Ca(2+) releases in the compartmentalized areas of atrial myocytes. The Ca(2+) sparks, representing focal Ca(2+) releases from the sarcoplasmic reticulum (SR) through the ryanodine receptor (RyR) clusters, occur most frequently at the peripheral junctions in isolated resting atrial cells. The Ca(2+) sparks that were darker and longer lasting than peripheral and non junctional (central) sparks, were found at peri-nuclear sites in rat atrial myocytes. Peri-nuclear sparks occurred more frequently than central sparks. Atrial cells express larger amounts of IP(3)Rs compared with ventricular cells and possess significant levels of type 1 IP(3)R (IP(3)R1) and type 2 IP(3)R (IP(3)R2). Over the last decade the roles of atrial IP(3)R on the enhancement of Ca(2+)-induced Ca(2+) release and arrhythmic Ca(2+) releases under hormonal stimulations have been well documented. Using protein knock-down method and confocal Ca(2+) imaging in conjunction with immunocytochemistry in the adult atrial cell line HL-1, we could demonstrate a role of IP(3)R1 in the maintenance of peri-nuclear and non-junctional Ca(2+) sparks via stimulating a posttranslational organization of RyR clusters. PMID- 20193707 TI - Pubertal maturation and programming of hypothalamic-pituitary-adrenal reactivity. AB - Modifications in neuroendocrine function are a hallmark of pubertal development. These changes have many short- and long-term implications for the physiological and neurobehavioral function of an individual. The purpose of the present review is to discuss our current understanding of how pubertal development and stress interact to affect the hypothalamic-pituitary-adrenal (HPA) axis, the major neuroendocrine axis that controls the hormonal stress response. A growing body of literature indicates that puberty is marked by dramatic transitions in stress reactivity. Moreover, recent studies indicate that exposure to stressors during pubertal maturation may result in enduring changes in HPA responsiveness in adulthood. As puberty is marked by a substantial increase in many stress-related psychological and physiological disorders (e.g., depression, anxiety, drug abuse), it is essential to understand the factors that regulate and modulate HPA function during this crucial period of development. PMID- 20193708 TI - Does the effect of morphine challenge change on maternal behaviour of dams chronically treated with morphine during gestation and further on during lactation? AB - Opioids impair the maternal behaviour of rats. The effect of morphine on maternal behaviour in dams treated chronically with morphine during the whole pregnancy and lactation has not been analysed systematically. The aim of the present study was to investigate the possible differences in the disruptive effect of morphine on maternal behaviour following morphine challenges between dams treated chronically with saline or morphine during gestation and postpartum. The antinociceptive action of morphine was also studied in dams. The disruptive effect of morphine on maternal behaviour was not changed as the postpartum period passed. The duration of this effect of morphine lasted for about 2h. The dose dependent disruptive effect of acute doses of morphine on maternal behaviour was more marked in the morphine-treated dams, than in the saline-treated ones, indicating a tendency for sensitisation to this effect. A trend for tolerance was observed to the antinociceptive effect of morphine in animals treated daily with morphine during the entire gestational and lactation periods; however, this difference did not reach statistical significance. Our experimental protocol might be a predictive model of human opioid abuse. Sensitisation to the impairing effect of opiates on maternal behaviour may explain why a mother abusing heroin neglects her baby even if she does not experience euphoria. PMID- 20193709 TI - Chemical characterization of Lycium barbarum polysaccharides and its inhibition against liver oxidative injury of high-fat mice. AB - In this study, we investigated chemical structure of Lycium barbarum polysaccharides and its modulatory effect on oxidative stress in high-fat mice. The polysaccharides mainly contained xylose and glucose. Little amount of rhamnose, mannose and galactose was observed. The Lycium barbarum polysaccharides had IR bands at 800-1200 cm(-1), 1450-1800 cm(-1), 2500-3000 cm(-1), and 3200 3600 cm(-1), which were distinctive absorptions of polysaccharides. Rats are fed with high-fat diet for 2 months. Results showed that blood and liver antioxidant enzymes activities and GSH level in model mice significantly decreased, and MDA level significantly increased (P<0.01) compared to normal control mice. Administration of Lycium barbarum polysaccharides significantly increased antioxidant enzymes activities and decreased MDA level in mice (P<0.01) compared to model group. PMID- 20193711 TI - Control of metabolism and signaling of simple bioactive sphingolipids: Implications in disease. AB - Simple bioactive sphingolipids include ceramide, sphingosine and their phosphorylated forms sphingosine 1-phosphate and ceramide 1-phosphate. These molecules are crucial regulators of cell functions. In particular, they play important roles in the regulation of angiogenesis, apoptosis, cell proliferation, differentiation, migration, and inflammation. Decoding the mechanisms by which these cellular functions are regulated requires detailed understanding of the signaling pathways that are implicated in these processes. Most importantly, the development of inhibitors of the enzymes involved in their metabolism may be crucial for establishing new therapeutic strategies for treatment of disease. PMID- 20193710 TI - Chlorpyrifos exposures in Egyptian cotton field workers. AB - Neurobehavioral deficits have been reported in Egyptian pesticide application teams using organophosphorus (OP) pesticides, but whether these effects are related to OP pesticide exposures has yet to be established. In preparation for a comprehensive study of the relationship between OP pesticide dose and neurobehavioral deficits, we assessed exposure within this population. We conducted occupational surveys and workplace observations, and collected air, dermal patch and biological samples from applicators, technicians and engineers involved in chlorpyrifos applications during cotton production to test the hypotheses that: (1) dermal exposure was an important contributor to internal dose and varied across body regions; and (2) substantial differences would be seen across the three job categories. Applicators were substantially younger and had shorter exposure histories than did technicians and engineers. Applicators and technicians were observed to have relatively high levels of skin or clothing contact with pesticide-treated foliage as they walked through the fields. Both dermal patch loadings of chlorpyrifos and measurements of a chlorpyrifos-specific metabolite (TCPy) in urine confirmed substantial exposure to and skin absorption of chlorpyrifos that varied according to job category; and dermal patch loading was significantly higher on the thighs than on the forearms. These findings support our hypotheses and support the need for research to examine neurobehavioral performance and exposures in this population. More importantly, the exposures reported here are sufficiently high to recommend urgent changes in work practices amongst these workers. PMID- 20193712 TI - Topology-corrected segmentation and local intensity estimates for improved partial volume classification of brain cortex in MRI. AB - In magnetic resonance imaging (MRI), accuracy and precision with which brain structures may be quantified are frequently affected by the partial volume (PV) effect. PV is due to the limited spatial resolution of MRI compared to the size of anatomical structures. Accurate classification of mixed voxels and correct estimation of the proportion of each pure tissue (fractional content) may help to increase the precision of cortical thickness estimation in regions where this measure is particularly difficult, such as deep sulci. The contribution of this work is twofold: on the one hand, we propose a new method to label voxels and compute tissue fractional content, integrating a mechanism for detecting sulci with topology preserving operators. On the other hand, we improve the computation of the fractional content of mixed voxels using local estimation of pure tissue intensity means. Accuracy and precision were assessed using simulated and real MR data and comparison with other existing approaches demonstrated the benefits of our method. Significant improvements in gray matter (GM) classification and cortical thickness estimation were brought by the topology correction. The fractional content root mean squared error diminished by 6.3% (p<0.01) on simulated data. The reproducibility error decreased by 8.8% (p<0.001) and the Jaccard similarity measure increased by 3.5% on real data. Furthermore, compared with manually guided expert segmentations, the similarity measure was improved by 12.0% (p<0.001). Thickness estimation with the proposed method showed a higher reproducibility compared with the measure performed after partial volume classification using other methods. PMID- 20193713 TI - Corticotropin-releasing factor mediates the dysphoria-like state associated with alcohol withdrawal in rats. AB - This study investigated the role of CRF in the dysphoria-like state associated with alcohol withdrawal in rats. The intracranial self-stimulation procedure was used to assess brain reward thresholds. Cessation of chronic alcohol administration led to an elevation in brain reward thresholds in the alcohol dependent rats. The CRF receptor antagonist D-Phe CRF((12-41)) dose-dependently prevented the elevations in brain reward thresholds associated with alcohol withdrawal. This indicates that the dysphoria associated with alcohol withdrawal is at least partly mediated by the activation of central CRF receptors. PMID- 20193714 TI - National validation study of a swab protocol for the recovery of Bacillus anthracis spores from surfaces. AB - Twelve Laboratory Response Network (LRN) affiliated laboratories participated in a validation study of a macrofoam swab protocol for the recovery, detection, and quantification of viable B. anthracis (BA) Sterne spores from steel surfaces. CDC personnel inoculated steel coupons (26cm(2)) with 1-4 log(10) BA spores and recovered them by sampling with pre-moistened macrofoam swabs. Phase 1 (P1) of the study evaluated swabs containing BA only, while dust and background organisms were added to swabs in Phase 2 (P2) to mimic environmental conditions. Laboratories processed swabs and enumerated spores by culturing eluted swab suspensions and counting colonies with morphology consistent with BA. Processed swabs were placed in enrichment broth, incubated 24h, and cultured by streaking for isolation. Real-time PCR was performed on selected colonies from P2 samples to confirm the identity of BA. Mean percent recovery (%R) of spores from the surface ranged from 15.8 to 31.0% (P1) and from 27.9 to 55.0% (P2). The highest mean percent recovery was 31.0% (sd 10.9%) for P1 (4 log(10) inoculum) and 55.0% (sd 27.6%) for P2 (1 log(10) inoculum). The overall %R was higher for P2 (44.6%) than P1 (24.1%), but the overall reproducibility (between-lab variability) was lower in P2 than in P1 (25.0 vs 16.5%CV, respectively). The overall precision (within-lab variability) was close to identical for P1 and P2 (44.0 and 44.1, respectively), but varied greatly between inoculum levels. The protocol demonstrated linearity in %R over the three inoculum levels and is able to detect between 26 and 5x10(6)spores/26cm(2). Sensitivity as determined by culture was >98.3% for both phases and all inocula, suggesting that the culture method maintains sensitivity in the presence of contaminants. The enrichment broth method alone was less sensitive for sampled swabs (66.4%) during P2, suggesting that the presence of background organisms inhibited growth or isolation of BA from the broth. The addition of real-time PCR testing to the assay increased specificity from >85.4% to >95.0% in P2. Although the precision was low at the 1 log(10) inoculum level in both phases (59.0 and 50.2%), this swab processing protocol, was sensitive, specific, precise, and reproducible at 2-4 log(10)/26cm(2) spore concentrations. PMID- 20193715 TI - Rapid quantification of itraconazole-resistant Aspergillus fumigatus in air. AB - Solid-phase cytometry (SPC) was used to determine the total number and the number of itraconazole-resistant Aspergillus fumigatus cells in 60 air samples. Of the 570 A. fumigatus cells that were recovered, 10 (1.8%) were resistant. SPC proved more specific and rapid than culture and allowed high-troughput susceptibility testing. PMID- 20193716 TI - Most-probable-number rapid viability PCR method to detect viable spores of Bacillus anthracis in swab samples. AB - A comparison of Most-Probable-Number Rapid Viability (MPN RV) PCR and traditional culture methods for the quantification of Bacillus anthracis Sterne spores in macrofoam swabs from a multi-center validation study was performed. The purpose of the study was to compare environmental swab processing methods for recovery, detection, and quantification of viable B. anthracis spores from surfaces. Results show that spore numbers provided by the MPN RV-PCR method were typically within 1-log of the values from a plate count method for all three levels of spores tested (3.1x10(4), 400, and 40 spores sampled from surfaces with swabs) even in the presence of debris. The MPN method tended to overestimate the expected result, especially at lower spore levels. Blind negative samples were correctly identified using both methods showing a lack of cross contamination. In addition to detecting low levels of spores in environmental conditions, the MPN RV-PCR method is specific, and compatible with automated high-throughput sample processing and analysis protocols, enhancing its utility for characterization and clearance following a biothreat agent release. PMID- 20193717 TI - Autonomic predictors of Stroop performance in young and middle-aged adults. AB - Although changes in autonomic activity have been extensively examined as responses to cognitive challenges, relatively few studies have used individual differences in autonomic parameters to predict executive performance in healthy adults. Here we examined baseline and task-related changes in heart rate and heart rate variability (measured by respiratory sinus arrhythmia (RSA)) to predict performance of a pictorial Stroop task in a group of 81 healthy adults aged 17-55. Greater autonomic reactivity (increased heart rate and reduced RSA for task performance) was associated with faster colour naming of faces in the Stroop task. Dividing the group by median age revealed that middle-aged adults reduced RSA to a greater degree than their younger counterparts in the context of equivalent performance across groups. Findings suggest that performance of executive function tasks that evoke attentional control may depend in part on the responsiveness of autonomic control parameters via age-dependent mechanisms. PMID- 20193718 TI - Rule-dependent anticipatory activity in prefrontal neurons. AB - The flexibility of the behavior of humans and other primates comes from the cognitive capability to use different behavioral modes depending on the contextual information. To investigate the neural mechanism of such a cognitive function, we trained monkeys to participate in a repeated category-outcome reversal. To perform the task efficiently, they had to explore and remember the relevant rule, i.e., which group of stimuli was associated with which outcome, and apply that rule to the visual cue in order to predict an outcome and select a response correctly. We recorded single-unit activity from the prefrontal cortex, including dorsolateral/ventrolateral prefrontal cortex and orbitofrontal cortex, and found that many neurons in these areas showed rule-dependent changes in activity during the trial and during the inter-trial-interval. The time period when a high proportion of neurons started to show rule-dependent activity was the precue period, and the typical activity pattern at that time was sustained and increasing firing towards the onset of the cue ("anticipatory" precue activity). The results indicate that the prefrontal cortex is involved in maintaining rule information in the short-term memory within and between trials and that the rule information is anticipatorily activated towards the onset of the task-relevant cue. PMID- 20193719 TI - Promises, challenges and future directions of microCCAs. AB - Micro-cell culture analogs (microCCAs) are a class of in vitro tissue analogs that combine multiple organ analogs on one microfluidic platform in physiologically correct volume ratios. The microfluidic platform also provides fluid flow rates and substance residence times close to those present in the human body. Several advantages arise from the microfluidic format that can be exploited for realistic simulations of drug absorption, metabolism and action. We envision that, together with theoretical modeling, microCCAs may produce reliable predictions of the efficacy of newly developed drugs. Advantages, challenges, and future directions of microCCAs are discussed and examples of systems are provided. PMID- 20193720 TI - Common importin alpha specificity for papillomavirus E2 proteins. AB - Papillomaviruses infect keratinocytes and their reproduction is tied to differentiation of the skin. The E2 protein of papillomaviruses is a multifunctional early protein that binds specifically to the viral DNA to regulate genome transcription, replication, and segregation. All of these are nuclear events that require specific transport of E2 into the host nucleus. Nuclear localization signal (NLS) sequences have been mapped for several E2 proteins, and these sequences resemble motifs that interact with cellular transport adaptor molecules termed alpha importins. To determine which importins could carry E2 proteins, in vitro binding studies were performed with three different E2 proteins and the five ubiquitous alpha importins. The E2 proteins preferentially interacted with alpha importins 3 and 5, and showed very weak or no interaction with the other three widely expressed alpha importins (alpha1, alpha 4, and alpha 7). While all five alpha importins appear to be constitutively expressed in keratinocytes, during differentiation of a human keratinocyte line (HaCaT) we observed a specific increase in expression of alphas 3 and 5. This differentiation-specific increase in alpha 3 and alpha 5 expression suggests that preferential usage of these two importins by E2 may facilitate E2 nuclear uptake during terminal differentiation. PMID- 20193721 TI - Tumor regression after systemic administration of transferrin-targeted TNFalpha plasmid-dendrimer conjugates. PMID- 20193722 TI - Cell-delivery therapeutics for liver regeneration. AB - For acute, chronic, or hereditary diseases of the liver, cell transplantation therapies can stimulate liver regeneration or serve as a bridge until liver transplantation can be performed. Recently, fetal hepatocytes, stem cells, liver progenitor cells, or other primitive and proliferative cell types have been employed for cell transplantation therapies, in an effort to improve the survival, proliferation, and engraftment of the transplanted cells. Reviewing earlier studies, which achieved success by transplanting mature hepatocytes, we propose that there is a switch-like regulation of liver regeneration that changes state according to a stimulus threshold of extracellular influences such as cytokines, matrices and neighboring cells. Important determinants of a successful clinical outcome include sufficient quantities and functional levels of the transplanted cells (even for short periods to alter the environment), rather than just engraftment levels or survival durations of the exogenously transplanted cells. The relative importance of these determining factors will impact future choices of cell sources, delivery vehicles, and sites of cell transplantation to stimulate liver regeneration for patients with severe liver diseases. PMID- 20193723 TI - Glia: the many ways to modulate synaptic plasticity. AB - Synaptic plasticity consists in a change in synaptic strength that is believed to be the basis of learning and memory. Synaptic plasticity has been for a very long period of time a hallmark of neurons. Recent advances in physiology of glial cells indicate that astrocyte and microglia possess all the features to participate and modulate the various form of synaptic plasticity. Indeed beside their respective supportive and immune functions an increasing number of study demonstrate that astrocytes and microglia express receptors for most neurotransmitters and release neuroactive substances that have been shown to modulate neuronal activity and synaptic plasticity. Because glial cells are all around synapses and release a wide variety of neuroactive molecule during physiological and pathological conditions, glial cells have been reported to modulate synaptic plasticity in many different ways. From change in synaptic coverage, to release of chemokines and cytokines up to dedicated "glio" transmitters release, glia were reported to affect synaptic scaling, homeostatic plasticity, metaplasticity, long-term potentiation and long-term depression. PMID- 20193724 TI - Prolonged withdrawal delirium in concomitant diphenhydramine and nefopam dependence: A case report. PMID- 20193725 TI - No effect of obstetric complications on basal ganglia volumes in schizophrenia. AB - BACKGROUND: Heterogeneous findings have been reported in studies of basal ganglia volumes in schizophrenia patients as compared to healthy controls. The basal ganglia contain dopamine receptors that are known to be involved in schizophrenia pathology and to be vulnerable to pre- and perinatal hypoxic insults. Altered volumes of other brain structures (e.g. hippocampus and lateral ventricles) have been reported in schizophrenia patients with a history of obstetric complications (OCs). This is the first study to explore if there is a relationship between OCs and basal ganglia volume in schizophrenia. METHODS: Thorough clinical investigation (including information on medication) of 54 schizophrenia patients and 54 healthy control subjects was undertaken. MR images were obtained on a 1.5T scanner, and volumes of nucleus caudatus, globus pallidum, putamen, and nucleus accumbens were quantified automatically. Information on OCs was blindly collected from original birth records. RESULTS: Unadjusted estimates demonstrated a relationship between increasing number of OCs and larger volume of nucleus accumbens in schizophrenia patients and healthy controls. No statistically significant relationships were found between OCs and the basal ganglia volumes when controlled for intracranial volume, age, and multiple comparisons. There were no effects of typical versus atypical medication on the basal ganglia volumes. The patients with schizophrenia had larger globus pallidum volumes as compared to healthy controls, but there were no case-control differences for accumbens, putamen, or caudate volumes. CONCLUSION: The present results do not support the hypothesis that OCs are related to alterations in basal ganglia volume in chronic schizophrenia. PMID- 20193726 TI - Microhardness of dentin underneath fluoride-releasing adhesive systems subjected to cariogenic challenge and fluoride therapy. AB - OBJECTIVES: The aim of this study was to evaluate the microhardness of dentin subjacent to the bonding interface of composite restorations using fluoride releasing adhesive systems submitted to pH-cycling regimen associated or not to fluoride therapies. METHODS: Thirty human third molars were prepared with class V cavities with dentin cervical margins. The adhesive systems One-Up Bond F Plus (OU), Prime&Bond NT (NT), Clearfil Protect Bond (CF), Optibond Solo Plus (OP) and also the controls [-] Single Bond 2 (SB) and [+] Ketac Molar (KM) were used previously to composite resin restorations. The restorations were sectioned into four slabs and submitted to different storage media for 15 days: distilled water, pH-cycling, pH-cycling associated to NaF 0.05% and associated to NaF 1.23%. The Knoop microhardness test was performed in dentin at 50, 100, 150 and 300 microm from the adhesive interface. Data was analyzed by three-way ANOVA and Tukey HSD test (p<0.05). RESULTS: KM resulted in significantly higher microhardness when compared to all the adhesive systems at 50 microm, with the exception of OU, that was similar to KM when submitted to pH-cycling alone or associated to 1.23% NaF. Microhardness of dentin was significantly higher with all the tested materials, when pH-cycling was associated to NaF 0.05%, at 50 microm and 100 microm depths. OU resulted in similar dentin hardness at all depths and storage media. CONCLUSIONS: The incorporation of NaF 0.05% fluoride therapy to the cariogenic challenge was capable to recover the original microhardness of dentin at 50 and 100 microm with all the tested materials. PMID- 20193727 TI - Durability of resin composite restorations in high C-factor cavities: a 12-year follow-up. AB - OBJECTIVE: Polymerization shrinkage and shrinkage stress has been considered as one of the main disadvantages of resin composite restorations. Cavities with high C-factors increase the risk for interfacial failures. Several restorative techniques have been suggested to decrease the shrinkage stress. The purpose of this study was to evaluate the durability of techniques as oblique layering, indirect curing and/or a laminate with a poly-acid modified resin composite in direct Class I resin composite restorations in a 12-year follow-up. METHODS: Each of 29 patients received one or two pair(s) rather extensive Class I restorations. The first restoration was a poly-acid modified resin composite/resin composite sandwich restoration and the second a direct resin composite restoration. Both restorations, except for the laminate layer, were placed with oblique layering and two-step curing technique. 90 restorations were evaluated annually with slightly modified USPHS criteria during 12 years. RESULTS: At 12 years, 38 pairs were evaluated. Two cases of slight post-operative sensitivity were observed in one patient. A cumulative failure rate of 2.4% was observed for both the resin composite and the laminate restorations. One laminate restoration showed non acceptable color match, but was not replaced and one resin composite restoration showed a chip fracture. Five restorations were replaced due to primary proximal caries. CONCLUSIONS: The high failure rate expected in the high C-factor Class I cavity, associated with polymerization shrinkage and shrinkage stress, were not observed. The techniques used resulted in an excellent durability for the Class I resin composite restorations. PMID- 20193728 TI - The effect of various dentifrices on surface roughness and gloss of resin composites. AB - OBJECTIVES: The purpose of this study was to evaluate the effect of different levels of abrasiveness (RDA) of dentifrices on the gloss and surface roughness of resin composites after toothbrushing. METHODS: Sixty disk-shaped composite specimens (D=10.0mm, 2-mm thick, n=15 per material) were made of: microfill (Durafill), nanofill (Filtek Supreme), minifill hybrid (Filtek 250), and nanohybrid (Premise). One side of each specimen was finished with a carbide bur and polished with Enhance and Pogo. Five specimens of each composite were randomly assigned to one of the dentifrices, Colgate Total (CT; RDA 70), Colgate baking soda & peroxide whitening (CBS; RDA 145), and Colgate tartar control & whitening (CTW; RDA 200). Surface gloss was measured with a glossmeter and surface roughness with a profilometer before and after toothbrushing with a 1:2 slurry (dentifrice/deionised water) at 5760 strokes in a brushing machine (approximately 1Hz). Results were analyzed by three-way ANOVA/Tukey's (p<0.05). RESULTS: There was a significant reduction in gloss and increase in surface roughness after brushing with all dentifrices. There was no significant difference in gloss when Durafill was brushed with any dentifrice; the other composites showed less gloss reduction when brushed with CT. Durafill, Supreme and Premise did not show significantly different surface roughness results and CBS and CTW did not produce significantly different results. CONCLUSIONS: Dentifrices of lower abrasivity promote less reduction in gloss and surface roughness for composites of different particle sizes after brushing. Composites containing smaller average fillers showed less reduction in gloss and less increase in surface roughness than ones with larger fillers. PMID- 20193729 TI - Device-guided breathing in the home setting: technology, performance and clinical outcomes. AB - Routine practice of slow breathing is a major component of a variety of behavioral treatments of chronic conditions. The present paper addresses the challenge of using device-guided breathing (DGB) as a self-treatment tool in the home setting. The breathing patterns of hypertensive patients treated using DGB over 8 weeks in 15-min daily sessions were analyzed using minute-by-minute stored data. The relationship of breathing pattern with office blood pressure changes over the treatment period was evaluated. The treatment device operated to reduce breathing rate effortlessly while prolonging exhalation: patients were requested to synchronize breathing with the guiding tones, generated in response to the monitored breathing pattern. Breathing modification was highly individualized, repeatable over sessions, and unrelated to clinical or demographic characteristics; it also seemed to reflect behavioral aspects of device-patient interaction. Quality of breathing synchronization with the guiding tones and time spent in slow breathing displayed a relationship with the clinical outcomes. Different DGB methods are believed to share similar features. A possible physiological mechanism underlying the beneficial effect of slow and effortless breathing in chronic conditions is discussed in relation to restoring autonomic balance via lung reflexes. PMID- 20193730 TI - Adiposity, leptin and stress reactivity in humans. AB - Evidence suggests that individuals who are more obese may be more responsive to stress. Stress activates the sympathetic nervous system (SNS) and the adipose tissue cytokine leptin stimulates SNS activity in animals. We examined the relationship between adiposity, leptin and physiological responses to acute laboratory stress in 67 women. We predicted that individuals with greater adiposity and/or higher plasma leptin would be more stress-responsive. Adiposity was unrelated to cardiovascular or neuroendocrine stress reactivity. However, women with larger waists had greater stress-induced increases in plasma leptin and interleukin-1 receptor antagonist (IL-1Ra). Similarly, women with higher basal leptin displayed greater stress-induced increases in heart rate and plasma interleukin-6, and larger decreases in heart rate variability and cardiac pre ejection period. Heightened cardiovascular and inflammatory stress responses are predictive of future cardiovascular risk. Our findings suggest that the cytokines leptin and IL-1Ra may play a role in the association between obesity, stress and cardiovascular health. PMID- 20193732 TI - Cognitive distancing, cognitive restructuring, and cardiovascular recovery from stress. AB - Research suggests that phasic changes in cardiovascular reactivity can increase the risk of heart disease, yet much of this research has focused on the magnitude rather than the duration of reactivity. In recent years, studies have confirmed that recovery time is also a significant predictor of future heart cardiovascular disorders. Here we review these studies, as well as the cognitions and behaviors that have been found to influence recovery. We suggest that a useful distinction is that some utilize cognitive distancing while others seem to be based on cognitive restructuring. These different approaches have implications for the immediacy and permanence of the recovery effects. Finally, we outline the questions that have yet to be answered about recovery and how it could influence long-term health. PMID- 20193731 TI - Sex-related differences in prepulse inhibition of startle in irritable bowel syndrome (IBS). AB - Alterations in central networks involved in the regulation of arousal, attention, and cognition may be critical for irritable bowel syndrome (IBS) symptom maintenance and exacerbation. Differential sensitivities in these networks may underlie sex differences noted in IBS. The current study examined prepulse inhibition (PPI), a measure of sensorimotor gating, in male and female IBS patients. Relationships between PPI and symptom severity were examined, as well as potential menstrual status effects. Compared to healthy controls, male IBS patients had significantly reduced PPI; whereas female IBS patients (particularly naturally cycling women) had significantly enhanced PPI suggesting hypervigilance. Considering previously demonstrated sex-related differences in perceptual and brain imaging findings in IBS patients, the current findings suggest that different neurobiological mechanisms underlie symptom presentation in male and female IBS patients. Compromised filtering of information in male IBS patients may be due to compromised top down (prefrontal, midcingulate) control mechanisms while increased attention to threat due to increased limbic and paralimbic circuits may be characteristic of female IBS patients. PMID- 20193733 TI - Structural and biological properties of erythropoietin in Xenopus laevis. AB - OBJECTIVE: Erythropoietin (EPO) and its receptor (EPOR) are key regulators of red blood cell production in mammals and fish. We aimed to investigate the structural and functional conservation of the EPO-EPOR system in amphibian erythropoiesis, using Xenopus laevis as a model. MATERIALS AND METHODS: X. laevis epo (xlepo) complementary DNA was identified by referring to the Xenopus tropicalis genome database. Biological activity of recombinant xlEPO expressed in COS-1 cells was evaluated using xlEPOR-expressing murine FDC/P2 cells and human EPO-dependent UT 7/EPO cells. Expression of xlepo messenger RNA in adult X. laevis tissues in the normal state and under the condition of phenylhydrazine-induced anemia was evaluated by real-time reverse transcription polymerase chain reaction. RESULTS: In the encoded protein, the positions of four cysteine residues were conserved; however, xlEPO had only 38% identity with human EPO. N-glycosylation sites were absent. Recombinant xlEPO induced proliferation of cell lines expressing xlEPOR and UT-7/EPO, confirming biological activity and cross-species reactivity. Despite little primary amino acid sequence similarity, the evolutionary highly conserved sequence NFLRGK was identified in the EPOR-binding site 1 region as in the human EPO protein. Strong expression of xlepo messenger RNA was detected in the lung and liver, especially in fractionated hepatocytes. No marked increase in xlepo expression was seen in the lung and liver of phenylhydrazine-induced anemic X. laevis. CONCLUSION: We confirmed that xlEPO is the ligand to the previously reported xlEPOR in X. laevis. xlEPO shares structural and functional similarities and differences with mammalian counterparts, and regulation of xlepo expression and its influence on the erythropoietic system appears to be unique. PMID- 20193734 TI - Heterogeneous expression and function of IL-21R and susceptibility to IL-21 mediated apoptosis in follicular lymphoma cells. AB - OBJECTIVE: Interleukin (IL)-21, a member of the IL-2 family, has antitumor activity and is now being tested in non-Hodgkin's lymphoma in combination with anti-CD20 antibodies. IL-21 may either induce apoptosis or promote growth in different lymphoid malignancies. We therefore investigated the IL-21/IL-21R system in follicular lymphoma (FL) cells. MATERIALS AND METHODS: IL-21R expression was studied by reverse transcription polymerase chain reaction, immunofluorescence, and Western blot analyses. Apoptosis was measured by Annexin V-propidium iodide staining. Signaling via IL-21R was studied using antibodies specific for phosphorylated Janus-activating kinase and signal transducers and activators of transcription proteins by Western Blot. RESULTS: IL-21R was found on primary FL cells in 15 of 15 cases at diagnosis and IL-21 increased apoptosis in 10 of 10 FL samples. However, cells from areas of diffuse growth in FL and from two diffuse lymphomas evolved from previous FL, showed low IL-21R expression. The latter were also resistant to IL-21-mediated apoptosis. Among lymphoma cell lines bearing the t(14;18) translocation, only 1 of 7 showed increased apoptosis in response to IL-21 stimulation. This cell line was IL-21R positive, whereas five of six nonresponsive cell lines showed very low IL-21R expression. Intriguingly, one of the IL-21-resistant cell lines (DOHH2) expressed high levels of IL-21R. Treatment with IL-21 or IL-4 upregulated suppressor of cytokine signaling 3 gene expression in the IL-21-responsive cell line, but not in DOHH2 cells, which showed defective Janus-activating kinase/signal transducers and activators of transcription signaling in response to IL-21, in relationship to the lack of Janus-activating kinase 3 gene expression. CONCLUSION: These data indicate that low IL-21R expression or defective signal transduction downstream IL-21R may cause refractoriness to IL-21-mediated effects in some FL cells. PMID- 20193735 TI - Ca2+-PKC-caspase 3-like protease pathway mediates DNA and nuclear fragmentation in ecdysteroid-induced programmed cell death. AB - 20-Hydroxyecdysone (20E) induces programmed cell death in the anterior silk gland of the silkworm. Here, we report the direct interaction between Ca(2+) and protein kinase C (PKC)-caspase 3-like protease pathway in the 20E-induced cell death. The calcium ionophore can mimic 20E effects in inducing DNA and nuclear fragmentation, but such mimicry is only possible in the glands precultured for 18 h with 20E. The simultaneous presence of translation inhibitor with 20E in the preculture showed that de novo protein synthesis was needed to mimic 20E effects by the calcium ionophore. Both a PKC inhibitor and a caspase 3 inhibitor inhibited the mimicking effects. After substitution of the calcium ionophore for 20E, caspase 3-like protease was fully activated 12h later, and DNA and nuclear fragmentation occurred faster than continuous 20E stimuli. The results show the presence of a Ca(2+)-PKC-caspase 3-like protease pathway in 20E signaling, and possible involvement of the pathway up to the mobilization of Ca(2+) in regulating the timing of cell death in vivo. PMID- 20193736 TI - The phytoestrogen genistein promotes wound healing by multiple independent mechanisms. AB - Genistein has been implicated in the beneficial effects of soy on human health, particularly in the context of ageing. In post-menopausal women reduced systemic estrogen leads to a range of age-associated pathologies, including delayed cutaneous wound healing. We have previously shown that this can be reversed by estrogen replacement. However, the effect of genistein on the skin is poorly understood and crucially the influence of genistein on wound healing has not been assessed. 10-week-old ovariectomised mice were systemically treated with 17beta estradiol or genistein. Genistein substantially accelerated wound repair, associated with a dampened inflammatory response. Unexpectedly, co-treatment with the ER antagonist ICI had little impact on the anti-inflammatory, healing promoting effects of genistein. Thus genistein's actions are only partially mediated via classical estrogen receptor-dependent signalling pathways. Indeed, we report that alternative (cell-type specific) signalling mechanisms are activated in the skin in response to genistein treatment. PMID- 20193737 TI - Cortisol reduces paracellular permeability and increases occludin abundance in cultured trout gill epithelia. AB - A role for the tight junction (TJ) protein occludin in the regulation of gill paracellular permeability was investigated using primary cultured "reconstructed" freshwater (FW) rainbow trout gill epithelia composed solely of pavement cells. Cortisol treatment reduced epithelial permeability characteristics, measured as changes in transepithelial resistance (TER) and paracellular [3H]PEG-4000 flux. Cortisol also reduced net Na+ flux rates when epithelia were exposed to apical FW. cDNA encoding for the TJ protein occludin was cloned from rainbow trout and found to be particularly abundant in gill tissue. In cultured gill preparations, occludin immunolocalized to the TJ complex and transcript abundance dose dependently increased in response to cortisol treatment in association with reduced paracellular permeability. Occludin protein abundance also increased in response to cortisol treatment. However, occludin mRNA levels did not change in response to apical FW exposure, and [3H]PEG-4000 permeability did not decrease. These data support a role for occludin in the endocrine regulation of paracellular permeability across gill epithelia of fishes. PMID- 20193738 TI - Multiple roles for the first transmembrane domain of GABAA receptor subunits in neurosteroid modulation and spontaneous channel activity. AB - Neurosteroids exert potent physiological effects by allosterically modulating synaptic and extrasynaptic GABA(A) receptors. Some endogenous neurosteroids, such as 3alpha, 21-dihydroxy-5beta-pregnan-20-one (5alpha, 3alpha-THDOC), potentiate GABA(A) receptor function by interacting with a binding pocket defined by conserved residues in the first and fourth transmembrane (TM) domains of alpha subunits. Others, such as pregnenolone sulfate (PS), inhibit GABA(A) receptor function through as-yet unidentified binding sites. Here we investigate the mechanisms of PS inhibition of mammalian GABA(A) receptors, based on studies of PS inhibition of the UNC-49 GABA receptor, a GABA(A)-like receptor from Caenorhabditis elegans. In UNC-49, a 19 residue segment of TM1 can be mutated to increase or decrease PS sensitivity over a 20-fold range. Surprisingly, substituting these UNC-49 sequences into mammalian alpha(1), beta(2), and gamma(2) subunits did not produce the corresponding effects on PS sensitivity of the resulting chimeric receptors. Therefore, it is unlikely that a conserved PS binding pocket is formed at this site. However we observed several interesting unexpected effects. First, chimeric gamma2 subunits caused increased efficacy of 5alpha, 3alpha-THDOC potentiation; second, spontaneous gating of alpha(6)beta(2)delta receptors was blocked by PS, and reduced by chimeric beta(2) subunits; and third, direct activation of alpha(6)beta(2)delta receptors by 5alpha, 3alpha-THDOC was reduced by chimeric beta(2) subunits. These results reveal novel roles for non-alpha subunits in neurosteroid modulation and direct activation, and show that the beta subunit TM1 domain is important for spontaneous activity of extrasynaptic GABA(A) receptors. PMID- 20193739 TI - Differential brain, but not serum VEGF levels in a genetic rat model of depression. AB - Compared to the classical monoamine hypotheses focus on neuroplasticity is a major new approach in studies of depression and antidepressants. Recent studies have demonstrated that vascular endothelial growth factor (VEGF) is regulated by antidepressant treatment in rodents. However, in depressive patients no significant changes were found in the serum VEGF levels compared to control subjects. To our knowledge, brain and serum VEGF levels have never been reported in parallel for any psychiatric disease model. That prompted us to examine the levels of VEGF in serum, hippocampus, frontal cortex, corpus striatum, and hypothalamus in male Flinders Sensitive Line (FSL) and Flinders Resistant Line (FRL), a genetic rat model of depression. The VEGF levels were identical in the FSL and the FRL rats in serum, corpus striatum, and hypothalamus. In hippocampus and frontal cortex, the VEGF levels were significantly decreased in the FSL rats compared to the FRL rats. The results may add to the hypothesis that altered expression of growth factors/neurotrophic factors are related to the pathophysiology of depression. PMID- 20193740 TI - CSF hypocretin-1 concentrations correlate with the level of fatigue in multiple sclerosis patients. AB - Considering the multiplicity of symptoms associated with multiple sclerosis (MS), there is possibility that hypocretin system function might be involved in the pathogenesis of the disease. The current study aimed to investigate the hypocretin-1 levels in cerebrospinal fluid (CSF) of MS patients in relation to different neurological deficit measures including: Ambulation Index (AI), Expanded Disability Status Scale (EDSS), Fatigue Severity Scale (FSS), and Epworth Sleepiness Scale (ESS) in relapse-onset MS patients. 53 subjects were included into the study: 38 patients with a diagnosis of MS and 15 healthy controls. Among MS patients, 25 had relapsing-remitting and 13 secondary progressive MS. CSF hypocretin-1 levels did not differ between MS patients and healthy controls (p>0.05). A positive correlation between hypocretin-1 level and fatigue level was found in MS patients (p<0.05) and this effect was even stronger in the MS subgroup suffering from fatigue (p=0.01). Hypocretin system seems to be generally unchanged in MS but a positive correlation between hypocretin-1 level and fatigue may indicate involvement of some compensatory mechanisms stimulating the production of the neuropeptide in MS patients. PMID- 20193741 TI - Anticholinesterase-induced epileptiform activity in immature rat piriform cortex slices, in vitro. AB - PURPOSE: Acute in vitro brain slice models are commonly used to study epileptiform seizure generation and to test anti-epileptic drug action. Seizure like activity can be readily induced by manipulating external ionic concentrations or by adding convulsant agents to the bathing medium. We previously showed that epileptiform bursting was induced in slices of immature (P14-28) rat piriform cortex (PC) by applying oxotremorine-M, a potent muscarinic receptor agonist. Here, we examined whether raising levels of endogenous acetylcholine (ACh) by exposure to anticholinesterases, could also induce epileptiform events in immature (P12-14) or early postnatal (P7-9) rat PC brain slices. METHODS: The effects of anticholinesterases were investigated in rat PC neurons using both extracellular MEA (P7-9 slices) and intracellular (P12-14 slices) recording methods. RESULTS: In P7-9 slices, eserine (20 microM) or neostigmine (20 microM) induced low amplitude, low frequency bursting activity in all three PC cell layers (I-III), particularly layer III, where neuronal muscarinic responsiveness is known to predominate. In P12-14 neurons, neostigmine produced a slow depolarization together with an increase in input resistance and evoked cell firing. Depolarizing postsynaptic potentials evoked by intrinsic fibre stimulation were selectively depressed although spontaneous bursting was not observed. Neostigmine effects were blocked by atropine (1 microM), confirming their muscarinic nature. We conclude that elevation of endogenous ACh by anticholinesterases can induce bursting in early postnatal PC brain slices, further highlighting the epileptogenic capacity of this brain region. However, this tendency declines with further development, possibly as local inhibitory circuit mechanisms become more dominant. PMID- 20193742 TI - The hOGG1 Ser326Cys polymorphism is not associated with sporadic Parkinson's disease. AB - Parkinson's disease (PD) is one of the most common neurodegenerative disorders characterized by progressive and profound loss of dopaminergic neurons in the substantia nigra (SN) resulting in resting tremor, rigidity, bradykinesia, and postural instability. The primary cause of the disease is still unknown, but mitochondrial dysfunction and oxidative stress have been implicated in the neurodegenerative process. Oxoguanine DNA glycosylase (OGG1) removes oxidized guanine (8-oxo-G) from the DNA, thus reducing the mutagenic potential of this modified base. Increased 8-oxo-G levels and up-regulation of OGG1 have been detected in the SN of PD brains. Moreover, studies performed in OGG1 knockout mice revealed the importance of this enzyme in protecting dopaminergic neurons against the accumulation of oxidative DNA damage. A common Ser326Cys polymorphism is known in the human gene encoding OGG1 (hOGG1), and the mutant Cys326 variant has been associated with reduced glycosylase activity. In the present study we screened 139 sporadic PD patients and 211 healthy matched controls for the presence of the hOGG1 Ser326Cys polymorphism. The Cys326 allele frequency was similar between the groups (0.20 in PD patients and 0.19 in controls; p=0.817), and no difference in genotype frequencies was observed. Moreover, the hOGG1 Ser326Cys polymorphism was not associated with disease age at onset (p=0.791). Overall, present results suggest that the hOGG1 Ser326Cys polymorphism is not associated with sporadic PD. PMID- 20193743 TI - Expression analysis of suppression of tumorigenicity 13 gene in patients with Parkinson's disease. AB - Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons. Detecting changes in gene expression in untreated de novo patients with PD is important for understanding disease pathogenesis and for identifying biomarkers for preclinical stage of PD. In this study we investigate ST13 gene expression in the peripheral blood of different groups of patients with neurological diseases using reverse transcription reaction and real-time polymerase chain reaction (PCR). Our results suggest that the expression levels of ST13 cannot serve as a biomarker for early stages of PD. PMID- 20193744 TI - Estradiol regulation of lipocalin-type prostaglandin D synthase promoter activity: evidence for direct and indirect mechanisms. AB - In the CNS, lipocalin-type prostaglandin D synthase (L-PGDS) is predominantly a non-neuronal enzyme responsible for the production of PGD(2), an endogenous sleep promoting substance. We have previously demonstrated that estradiol differentially regulates L-PGDS transcript levels in the rodent brain. In hypothalamic nuclei, estradiol increases L-PGDS transcript expression, whereas in the ventrolateral preoptic area L-PGDS gene expression is reduced after estradiol treatment. In the present study, we have used an immortalized glioma cell line transfected with a L-PGDS reporter construct and estrogen receptor (ER) alpha and ERbeta expression plasmids to further elucidate the mechanisms underlying estradiol regulation of L-PGDS gene expression. We found that physiologically relevant concentrations of estradiol evoked an inverted U response in cells expressing ERalpha. The most effective concentration of estradiol (10(-11)M) increased the promoter activity 3-fold over baseline. Expression of ERbeta did not increase activity over control and when ERbeta was co-expressed with ERalpha there was a significant attenuation of the promoter activity. While ERalpha significantly increased L-PGDS promoter activity, our previous in vivo studies demonstrate a greater magnitude of change in L-PGDS gene expression in the presences of estradiol. This led us to ask whether estradiol is signaling via a paracrine factor released by the neighboring neurons. Conditioned media from estradiol treated neurons applied to the glioma cell line resulted in a significant 7-fold increase in L-PGDS promoter activity supporting the possibility that neuronal-glial interactions are involved in estradiol regulation of L-PGDS. PMID- 20193746 TI - Carbon nanotubes in cancer diagnosis and therapy. AB - During the past years, great progress has been made in the field of nanomaterials given their great potential in biomedical applications. Carbon nanotubes (CNTs), due to their unique physicochemical properties, have become a popular tool in cancer diagnosis and therapy. They are considered one of the most promising nanomaterials with the capability of both detecting the cancerous cells and delivering drugs or small therapeutic molecules to these cells. Over the last several years, CNTs have been explored in almost every single cancer treatment modality, including drug delivery, lymphatic targeted chemotherapy, thermal therapy, photodynamic therapy, and gene therapy. In this review, we will show how they have been introduced into the diagnosis and treatment of cancer. Novel SWNT based tumor-targeted drug delivery systems (DDS) will be highlighted. Furthermore, the in vitro and in vivo toxicity of CNTs reported in recent years will be summarized. PMID- 20193747 TI - Effects of visual-haptic asynchronies and loading-unloading movements on compliance perception. AB - Spring compliance is perceived by combining the sensed force exerted by the spring with the displacement caused by the action (sensed through vision and proprioception). We investigated the effect of delay of visual and force information with respect to proprioception to understand how visual-haptic perception of compliance is achieved. First, we confirm an earlier result that force delay increases perceived compliance. Furthermore, we find that perceived compliance decreases with a delay in the visual information. These effects of delay on perceived compliance would not be present if the perceptual system would utilize all force-displacement information available during the interaction. Both delays generate a bias in compliance which is opposite in the loading and unloading phases of the interaction. To explain these findings, we propose that information during the loading phase of the spring displacement is weighted more than information obtained during unloading. We confirm this hypothesis by showing that sensitivity to compliance during loading movements is much higher than during unloading movements. Moreover, we show that visual and proprioceptive information about the hand position are used for compliance perception depending on the sensitivity to compliance. Finally, by analyzing participants' movements we show that these two factors (loading/unloading and reliability) account for the change in perceived compliance due to visual and force delays. PMID- 20193745 TI - Building a better understanding of the intracellular tyrosine kinase PTK6 - BRK by BRK. AB - Protein tyrosine kinase 6 (PTK6), also referred to as breast tumor kinase BRK, is a member of a distinct family of kinases that is evolutionarily related to the SRC family of tyrosine kinases. While not expressed in the normal mammary gland, PTK6 expression is detected in a large proportion of human mammary gland tumors. In breast tumor cells, PTK6 promotes growth factor signaling and cell migration. PTK6 expression is also increased in a number of other epithelial tumors, including ovarian and colon cancer. In contrast, PTK6 is expressed in diverse normal epithelia, including the linings of the gastrointestinal tract, skin and prostate, where its expression correlates with cell cycle exit and differentiation. Disruption of the mouse Ptk6 gene leads to increased growth and impaired differentiation in the small intestine that is accompanied by increased AKT and Wnt signaling. Following total body irradiation, PTK6 expression is induced in proliferating progenitor cells of the intestine, where it plays an essential role in DNA-damage induced apoptosis. A distinguishing feature of PTK6 is its flexibility in intracellular localization, due to a lack of amino-terminal myristoylation/palmitoylation. Recently a number of substrates of PTK6 have been identified, including nuclear RNA-binding proteins and transcription factors. We discuss PTK6 signaling, its apparent conflicting roles in cancer and normal epithelia, and its potential as a therapeutic target in epithelial cancers. PMID- 20193748 TI - Intraspecific variation in the mitochondrial genome among local populations of Medaka Oryzias latipes. AB - The draft genome data of Medaka Oryzias latipes shows that it has distinct intraspecific genetic variation. To survey the genetic variations contributing to environmental adaptation, we focused on the mitochondrial DNA (mtDNA). The complete mtDNA sequences of Medaka were compared among 8 local population stocks and 4 inbred strains established from genetically divergent groups. Inbred strain HSOK, derived from the Eastern Korean group of Medaka, has a mitochondrial gene order that was distinct from other Medaka groups. Phylogenetic trees based on the mitochondrial genome sequences indicated that the mitogenome from the Shanghai stock (China) and HSOK strain were highly diverged from Japanese Medaka, and that the Japanese Medaka mitogenome was diverged into two groups; this result was fully consistent with those of the previous study using mtDNA-encode gene sequences. Among tRNA genes, the most divergent was the tRNA(Thr) gene as reported in humans previously. The number of tandemly repeated 11 nucleotide units in the Medaka mtDNA control region (CR) varied greatly among local populations. The number of repeats was more variable in the Northern Japanese group (10-34) than in the Southern group (7-12), while two other Oryzias species, inhabiting tropical regions, had no repeats. A comprehensive comparison between the number of repeat units and meteorological data indicated that the number of repeats correlated to the index data of a cold environment and seasonal climatic change. In cold (5 degrees C) acclimated fish, the mRNA levels varied among mitochondria coding genes. mRNA of the cytochrome oxidase subunit I gene in some local stocks was induced by cold temperature and seemed to be correlated with the number of repeated sequences in the CR. This study revealed that the repeated sequences in the mtDNA CR might function for mtDNA gene expression and that the number of tandem repeats in Medaka mtDNA is likely related to adaptation to a harsh habitat. PMID- 20193749 TI - The Arabidopsis AP2/ERF transcription factor RAP2.6 participates in ABA, salt and osmotic stress responses. AB - AP2/ERF proteins play crucial roles in various biological processes. RAP2.6, an Arabidopsis AP2/ERF family member, has been reported to function in plant response to biotic stress, but whether it also functions in plant response to abiotic stress is not known. In this work, we demonstrate that in wild-type Arabidopsis, the expression of RAP2.6 is responsive to abscisic acid (ABA) and different stress conditions such as high salt, osmotic stress, and cold. Trans activating ability tests in yeast demonstrate that RAP2.6 could act as a transactivator. RAP2.6 is able to bind to the GCC and CE1 cis-elements, as confirmed by both electrophoretic mobility shift assay (EMSA) and yeast one hybrid assay. Experiments with RAP2.6-YFP fusion protein indicated that RAP2.6 is nuclear localized. Overexpression of RAP2.6 conferred hypersensitivity to exogenous ABA and abiotic stresses during seed germination and early seedling growth in Arabidopsis. The ABA content in RAP2.6 overexpressor lines decreased after being treated with salt. Furthermore, transcripts of AtABI4 and some stress inducible genes increased, and loss of ABI4 function rescues the hypersensitive phenotype of RAP2.6 overexpression lines under ABA and stress treatment. These results suggest that RAP2.6 participates in abiotic stress, possibly through the ABA-dependent pathway. PMID- 20193750 TI - A method for calibration of bone driver transducers to measure the mastoid impedance. AB - When using bone vibrator transducers for clinical measurements, the transfer of energy from the bone driver depends on the impedance match between the driver and the load (human mastoid or otherwise) to which the driver will be applied. Current clinical calibration methods are incapable of quantifying this impedance mismatch, hence they fail to account for inter-subject variations of the energy transferred from the driver to the load. This study proposes a straightforward method for determining an absolute field calibration of a Radio Ear B71 bone driver, found by measuring the electrical input impedance of the transducer loaded by known masses. This absolute calibration is based upon a circuit model of the driver, describing it with three frequency-dependent parameters. Once these three parameters are known, measurements of the driver input voltage and current may be used to determine arbitrary mechanical load impedances (such as the in situ mastoid impedance), and thus the frequency dependence of the transmitted energy. The results of the proposed calibration method are validated by comparison with direct mechanical measurements using specialized equipment not available in the clinic, and a refined bone driver circuit model is proposed to better capture the observed behaviors. PMID- 20193751 TI - Cinobufacini, an aqueous extract from Bufo bufo gargarizans Cantor, induces apoptosis through a mitochondria-mediated pathway in human hepatocellular carcinoma cells. AB - AIM OF THE STUDY: Cinobufacini (Huachansu), an aqueous extract from the skin and parotid venom glands of Bufo bufo gargarizans Cantor, is a traditional Chinese medicine widely used in clinical cancer therapy in China. The present study sought to investigate the possible signaling pathway implicated in cinobufacini induced apoptosis in the hepatocellular carcinoma cell lines HepG(2) and Bel 7402. MATERIALS AND METHODS: The effects of cinobufacini on cell proliferation of HepG(2) and Bel-7402 cells were evaluated by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl-tetrazolium bromide (MTT) assays. Cell apoptosis was detected by Hoechst 33258 staining and flow cytometry analysis. The mitochondrial membrane potential (Deltapsim) and caspase-9 and -3 activity were detected using MitoCapture reagent staining and colorimetric assays, respectively. The expression of apoptosis related proteins and release of cytochrome c were assessed by Western blot analysis. RESULTS: Cinobufacini significantly inhibited cell proliferation of both cell lines in a dose- and time-dependent manner. Marked changes in apoptotic morphology and apoptosis rates were clearly observed after cinobufacini treatment. The protein expression of Bax increased whereas that of Bcl-2 decreased, leading to an increase in the Bax/Bcl-2 ratio. Subsequently, cinobufacini disrupted the mitochondrial membrane potential (Deltapsim) and resulted in the release of cytochrome c, activation of both caspase-9 and -3, and cleavage of poly (ADP-ribose) polymerase (PARP). CONCLUSION: The present study indicated that cinobufacini can induce apoptosis of HepG(2) and Bel-7402 cells through a mitochondria-mediated apoptosis pathway. PMID- 20193752 TI - Antihypertensive and antioxidant effects of Allanblackia floribunda Oliv. (Clusiaceae) aqueous extract in alcohol- and sucrose-induced hypertensive rats. AB - AIM OF THE STUDY: Allanblackia floribunda Oliv. (Clusiaceae), an evergreen tree of the rain-forest has long been used in traditional African medicine to treat hypertension. The aim of this study was to evaluate the protective effect of Allanblackia floribunda aqueous extract on alcohol- and sugar-induced hypertension in rats. MATERIAL AND METHODS: Alcohol-induced hypertensive rats (AHR) were obtained by oral administration of ethanol (3g/kg/day) while sucrose (5, 6 and 7% in drinking water) was used for sucrose-induced hypertensive rat (SuHR). Both models of animals concomitantly received either aqueous extract (200 or 400mg/kg; p.o.) or nifedipine (10mg/kg; p.o.) all along the 8 weeks of experiment. Blood pressure and heart rate were measured using the direct cannulation method. The effects of the plant extract on lipid profile, oxidative stress markers, as well as on kidney and liver functions were evaluated at the end of the treatment by the colorimetric method. RESULTS: At the doses of Allanblackia floribunda (200 and 400mg/kg/day) significantly prevented (21.74; 26.65% and 11.71; 24.58% of reduction) the increase in mean blood pressure on AHR and SuHR, respectively. Administration of the plant extract at the dose of 400mg/kg led to the prevention of total cholesterol (42.82%), HDL-cholesterol (36.59%) and triglycerides (9.67%) increase in serum lipid in AHR as compared to the untreated AHR. In SuHR, the extract significantly prevented the high concentrations of total cholesterol (44.08%) and triglycerides (33.05%) induced by sucrose treatment as compared to the untreated SuHR, without affecting that of HDL-cholesterol. Allanblackia floribunda (200 and 400mg/kg) also prevented the increase in atherogenic index by 54.45 and 42.94% in AHR and by 23.70 and 44.32% in SuHR, respectively. Allanblackia floribunda (400mg/kg) prevented the increase in bilirubine (19.59 and 16.56%), urea (33.36 and 28.2%), ALT (29.55 and 33.09%) and AST (36.28 and 37.12%) of AHR and SuHR, respectively. Treatment with plant extract significantly prevented the increase of superoxide dismutase (SOD), malondialdehyde (MDA) and catalase and the decrease of reduced glutathione (GSH) concentration in aorta, heart, kidney and liver of AHR and SuHR. CONCLUSION: These results demonstrate that the aqueous extract of Allanblackia floribunda can prevent alcohol- and sugar-induced hypertension and oxidative stress in rats. These findings could therefore justify its use in traditional medicine. PMID- 20193753 TI - Scoparia dulcis (SDF7) endowed with glucose uptake properties on L6 myotubes compared insulin. AB - AIM OF THE STUDY: Insulin stimulates glucose uptake and promotes the translocation of glucose transporter 4 (Glut 4) to the plasma membrane on L6 myotubes. The aim of this study is to investigate affect of Scoparia dulcis Linn water extracts on glucose uptake activity and the Glut 4 translocation components (i.e., IRS-1, PI 3-kinase, PKB/Akt2, PKC and TC 10) in L6 myotubes compared to insulin. MATERIALS AND METHODS: Extract from TLC fraction-7 (SDF7) was used in this study. The L6 myotubes were treated by various concentrations of SDF7 (1 to 50 microg/ml) and insulin (1 to 100 nM). The glucose uptake activities of L6 myotubes were evaluated using 2-Deoxy-D-glucose uptake assay in with or without fatty acid-induced medium. The Glut 4 translocation components in SDF7-treated L6 myotubes were detected using immunoblotting and quantified by densitometry compared to insulin. Plasma membrane lawn assay and glycogen colorimetry assay were carried out in SDF7- and insulin-treated L6 myotubes in this study. RESULTS: Here, our data clearly shows that SDF7 possesses glucose uptake properties on L6 myotubes that are dose-dependent, time-dependent and plasma membrane Glut 4 expression-dependent. SDF7 successfully stimulates glucose uptake activity as potent as insulin at a maximum concentration of 50 microg/ml at 480 min on L6 myotubes. Furthermore, SDF7 stimulates increased Glut 4 expression and translocation to plasma membranes at equivalent times. Even in the insulin resistance stage (free fatty acids-induced), SDF7-treated L6 myotubes were found to be more capable at glucose transport than insulin treatment. CONCLUSIONS: Thus, we suggested that Scoparia dulcis has the potential to be categorized as a hypoglycemic medicinal plant based on its good glucose transport properties. PMID- 20193754 TI - Polymorphisms in the human glutathione transferase Kappa (GSTK1) promoter alter gene expression. AB - The level of glutathione transferase Kappa (GSTK1-1) has been correlated with obesity (Liu et.al. 2008 PNAS 105: 18302-7) and a polymorphism in the hGSTK1 promoter has been associated with insulin secretion and fat deposition (Gao et al 2009 Endocr J 56: 487-94). We searched for additional polymorphisms that may influence GSTK1-1 function or expression. Two SNPs were identified in the 5' non coding region. A SNP at -1308 that occurs in Chinese subjects is predicted to eliminate a FXR/RXR transcription factor-binding site and causes a 55% increase in transcription rate in HepG2 cells and a 59% decrease in HEK293 cells. These data suggest that the impact of this polymorphism is complex and tissue specific. A SNP at -1032 alters a methylation site and represses transcription by 38%. These observations provide the first functional insight into genetic factors that regulate hGSTK1 expression and may directly influence insulin secretion and fat deposition. PMID- 20193755 TI - Elevated expression of MCP-1, IL-2 and PTPR-N in basal ganglia of Tourette syndrome cases. AB - BACKGROUND: Post-infectious autoimmunity has been implicated in pathogenesis of Tourette's syndrome (TS) but no evidence of inflammation in central nervous system has been reported yet. We evaluated the expression of genes encoding selected inflammatory factors in post-mortem specimen of adult TS patients: interferon-gamma (a cytokine released from CD8 and Thelper 1 CD4 subset of T lymphocytes), interleukin-2 (IL-2, a growth factor derived from T lymphocytes), interleukin-1 beta (a cytokine involved in initiation of inflammation), monocyte chemotactic factor -1 (MCP-1, a marker of chronic inflammation) and CD45 (pan leukocytic marker). For validation purposes, we determined expression of three genes that were previously reported to be elevated in post-mortem specimen of other TS cases: protein tyrosine phosphatase receptor-N (PTPR-N), PTPR-U and recoverin. METHODS: Total RNA was isolated from formalin fixed brain tissue sections of basal ganglia area from four patients with TS and four control subjects, and real-time reverse transcription-polymerase chain reaction analysis was employed to quantitatively evaluate gene expression of the selected genes. RESULTS: Significantly increased expression of MCP-1, IL-2 and PTPR-N was observed in TS cases (6.5-fold, 2.3-fold and 16.1-fold increase, respectively, p<0.05). CONCLUSIONS: Elevated expression of MCP-1 and IL-2 supports the possibility of chronic inflammatory processes in the basal ganglia. Replication of elevated expression of PTPR-N in TS specimen suggests that pathway(s) involving this molecule may be important in TS pathogenesis. PMID- 20193756 TI - Noradrenaline acting at central beta-adrenoceptors induces interleukin-10 and suppressor of cytokine signaling-3 expression in rat brain: implications for neurodegeneration. AB - Evidence indicates that the monoamine neurotransmitter noradrenaline elicits anti inflammatory actions in the central nervous system (CNS), and consequently may play a neuroprotective role where inflammatory events contribute to CNS pathology. Here we examined the ability of pharmacologically enhancing central noradrenergic tone to induce expression of anti-inflammatory cytokines in rat brain. Administration of the noradrenaline reuptake inhibitor reboxetine (15mg/kg; ip) combined with the alpha(2)-adrenoceptor antagonist idazoxan (1mg/kg; ip) induced interleukin-10 (IL-10) expression in rat cortex and hippocampus. In addition, these drug treatments induced IL-10 signaling as indicated by increased STAT3 phosphorylation and suppressor of cytokine signaling 3 (SOCS-3) mRNA expression. In contrast to the profound increase in IL-10 induced by the reboxetine/idazoxan combination, the other two broad spectrum anti inflammatory cytokines IL-4 and TGF-beta were not induced by this treatment. The ability of combined treatment with reboxetine and idazoxan to induce IL-10 and SOCS3 expression was mediated by beta-adrenoceptor activation, as their induction was blocked by pre-treatment with the beta-adrenoceptor antagonist propranolol. Moreover, administration of the brain penetrant beta(2)-adrenoceptor agonist clenbuterol induced a time- and dose-dependent increase in central IL-10 and SOCS3 expression, and the ability of clenbuterol to induce IL-10 and SOCS-3 expression was blocked by the centrally acting beta-adrenoceptor antagonist, propranolol, and was mimicked by the highly selective beta(2)-adrenoceptor agonist formoterol. In all, these data indicate that increasing central noradrenergic tone induces IL-10 production and signaling in the CNS, which may protect against neurodegeneration. PMID- 20193757 TI - Linking the cytokine and neurocircuitry hypotheses of depression: a translational framework for discovery and development of novel anti-depressants. AB - Recent studies suggest a model of depression that links the cytokine hypothesis from the field of psychoneuroimmunology with the neurocircuitry hypothesis derived from burgeoning insight into neurophysiological changes observed in depressed patients. According to the neurocircuitry hypothesis of depression, failure of homeostatic synaptic plasticity in cortical-striatal-limbic nodes of a distributed network of neural circuits involving the sub-genual anterior cingulate cortex is responsible for core symptoms of depression: loss of interest or pleasure (anhedonia) and depressed mood (sadness). According to the cytokine hypothesis of depression, inflammatory cytokines act on neural circuits to evoke the behavioral and physiological changes observed in depression. Synthesis of these hypotheses implicates cytokines released during injury, infection, illness, or psychological stress as a cause of dysregulated synaptic plasticity in cortical-striatal-limbic circuits implicated in depression. These neural circuits process affective and reward-based information for optimal cost-benefit decision making, a function that may link cytokine-evoked changes in synaptic plasticity to translatable measures of specific behavioral impairments observed in depressed patients. This viewpoint outlines evidence linking the cytokine and neurocircuitry hypotheses of depression to offer a translational model of major depressive disorder suitable for novel drug discovery and development. PMID- 20193758 TI - DNA-PKcs deficiency leads to persistence of oxidatively induced clustered DNA lesions in human tumor cells. AB - DNA-dependent protein kinase (DNA-PK) is a key non-homologous-end-joining (NHEJ) nuclear serine/threonine protein kinase involved in various DNA metabolic and damage signaling pathways contributing to the maintenance of genomic stability and prevention of cancer. To examine the role of DNA-PK in processing of non-DSB clustered DNA damage, we have used three models of DNA-PK deficiency, i.e., chemical inactivation of its kinase activity by the novel inhibitors IC86621 and NU7026, knockdown and complete absence of the protein in human breast cancer (MCF 7) and glioblastoma cell lines (MO59-J/K). A compromised DNA-PK repair pathway led to the accumulation of clustered DNA lesions induced by gamma-rays. Tumor cells lacking protein expression or with inhibited kinase activity showed a marked decrease in their ability to process oxidatively induced non-DSB clustered DNA lesions measured using a modified version of pulsed-field gel electrophoresis or single-cell gel electrophoresis (comet assay). In all cases, DNA-PK inactivation led to a higher level of lesion persistence even after 24-72h of repair. We suggest a model in which DNA-PK deficiency affects the processing of these clusters first by compromising base excision repair and second by the presence of catalytically inactive DNA-PK inhibiting the efficient processing of these lesions owing to the failure of DNA-PK to disassociate from the DNA ends. The information rendered will be important for understanding not only cancer etiology in the presence of an NHEJ deficiency but also cancer treatments based on the induction of oxidative stress and inhibition of cluster repair. PMID- 20193759 TI - An antagonism between the AKT and beta-adrenergic signaling pathways mediated through their reciprocal effects on miR-199a-5p. AB - We have recently reported that downregulation of miR-199a-5p is necessary and sufficient for inducing upregulation of its targets, including hypoxia-inducible factor-1 alpha (Hif-1 alpha) and Sirt1, during hypoxia preconditioning (HPC). Conversely, others and we have reported that miR-199a-5p is upregulated during cardiac hypertrophy. Thus, the objective of this study was to delineate the signaling pathways that regulate the expression of miR-199a-5p and its targets, and their role in myocyte survival during hypoxia. Since HPC is mediated through activation of the AKT pathway, we questioned if AKT is sufficient for inducing downregulation of miR-199a-5p. Our present study shows that overexpression of a constitutively active AKT (caAKT) induced 70% reduction in miR-199a-5p and was associated with a robust increase in HiF-1 alpha (10+/-2 fold) and Sirt1 (4+/-0.8 fold) that was reversed by overexpression of miR-199a-5p. Similarly, insulin receptor-stimulated activation of the AKT pathway induced downregulation of miR 199a-5p and upregulation of its targets. In contrast, beta-adrenergic receptor (beta AR) activation in vitro and in vivo, induced 1.8-3.5-fold increase in miR 199a-5p. Accordingly, we predicted that beta AR would antagonize AKT-induced, miR 199a-5p-dependent, upregulation of Hif-1 alpha and Sirt1. Indeed, pre-treating the myocytes with isoproterenol before applying HPC, caAKT, or insulin resulted in 87+/-3%, 75+/-15%, and 100% reductions in Hif-1 alpha expression, respectively, and sensitized the cells to hypoxic injury. Thus, activation of beta-adrenergic signaling counteracts the survival effects of the AKT pathway via upregulating miR-199a-5p. PMID- 20193760 TI - Intracellular delivery of full length recombinant human mitochondrial L-Sco2 protein into the mitochondria of permanent cell lines and SCO2 deficient patient's primary cells. AB - Mutations in human SCO2 gene, encoding the mitochondrial inner membrane Sco2 protein, have been found to be responsible for fatal infantile cardioencephalomyopathy and cytochrome c oxidase (COX) deficiency. One potentially fruitful therapeutic approach for this mitochondrial disorder should be considered the production of human recombinant full length L-Sco2 protein and its deliberate transduction into the mitochondria. Recombinant L-Sco2 protein, fused with TAT, a Protein Transduction Domain (PTD), was produced in bacteria and purified from inclusion bodies (IBs). Following solubilisation with l-arginine, this fusion L-Sco2 protein was transduced in cultured mammalian cells of different origin (U-87 MG, T24, K-562, and patient's primary fibroblasts) and assessed for stability, transduction into mitochondria, processing and impact on recovery of COX activity. Our results indicate that: a) l-Arg solution was effective in solubilising recombinant fusion L-Sco2 protein, derived from IBs; b) fusion L-Sco2 protein was delivered successfully via a time- and concentration dependent process into the mitochondria of human U-87 MG and T24 cells; c) fusion L-Sco2 protein was also transduced in human K-562 cells, transiently depleted of SCO2 transcripts and thus COX deficient; transduction of this fusion protein led to partial recovery of COX activity in such cells; d) [(35)S]Methionine-labelled fusion L-Sco2 protein, produced in a cell free transcription/translation system and incubated with intact isolated mitochondria derived from K-562 cells, was efficiently processed to yield the corresponding mature Sco2 protein, thus justifying the potential of the transduced fusion L-Sco2 protein to successfully activate COX holoenzyme; and finally, e) recombinant fusion L-Sco2 protein was successfully transduced into the mitochondria of primary fibroblasts derived from SCO2/COX deficient patient and facilitated recovery of COX activity. These findings provide the rationale of delivering recombinant proteins via PTD technology as a model for therapeutic approach of mitochondrial disorders. PMID- 20193761 TI - Glycosaminoglycan mimetics trigger IP3-dependent intracellular calcium release in myoblasts. AB - Glycosaminoglycans (GAG) are sulfated polysaccharides that play an important role in regulating cell functions. GAG mimetics called RGTAs (for ReGeneraTing Agents) have been shown to stimulate tissue repair. In particular they accelerate myogenesis, in part via their heparin-mimetic property towards growth factors. RGTAs also increase activity of calcium-dependent intracellular protease suggesting an effect on calcium cellular homeostasis. This effect was presently investigated on myoblasts in vitro using one member of the RGTA family molecule named OTR4120. We have shown that OTR4120 or heparin induced transient increases of intracellular calcium concentration ([Ca(2+)]i) in pre-fusing myoblasts from both mouse SolD7 cell line and rat skeletal muscle satellite cells grown in primary culture by mobilising sarcoplasmic reticulum store. This [Ca(2+)]i was not mediated by ryanodine receptors but instead resulted from stimulation of the Inositol-3 phosphate-phospholipase C activation pathway. OTR4120-induced calcium transient was not mediated through an ATP, nor a tyrosine kinase, nor an acetylcholine receptor but principally through serotonin 5-HT2A receptor. This original finding shows that the GAG mimetic can induce calcium signal through serotonin receptors and the IP3 pathway may be relevant to its ability to favour myoblast differentiation. It supports a novel and unexpected function of GAGs in the regulation of calcium homeostasis. PMID- 20193762 TI - In vitro effects of 2-methoxyestradiol on morphology, cell cycle progression, cell death and gene expression changes in the tumorigenic MCF-7 breast epithelial cell line. AB - In the present study, the antiproliferative mechanism of action of 1 microM 2 methoxyestradiol (2ME) was investigated in the MCF-7 cell line. Measurement of intracellular cyclin B and cytochrome c protein levels, reactive oxygen species formation, cell cycle progression and apoptosis induction were conducted by means of flow cytometry. Morphological changes were evaluated using transmission electron microscopy and fluorescent microscopy by employing Hoechst 33342 and acridine orange. Gene expression changes were conducted by means of microarrays. 2ME-treated cells demonstrated an increase in cyclin B protein levels, hydrogen peroxide formation, intracellular levels of cytochrome c, as well as an increase in early and late stages of apoptosis. In addition, morphological data revealed the presence of autophagic processes. Fluorescent microscopy showed an increase in acridine orange staining and electron microscopy revealed an increase in vacuolar formation in 2ME-treated cells. The gene expression of several genes associated with mRNA translation, autophagy-related processes and genes involved in microtubule dynamics were affected. The study contributes to the mechanistic understanding of 2ME's growth inhibition in MCF-7 cells and highlights the possibility of both apoptotic and autophagic processes being activated in response to 2ME treatment in this cell line. PMID- 20193763 TI - Metabolism of substrates incorporated into phospholipid vesicles by mouse 25 hydroxyvitamin D3 1alpha-hydroxylase (CYP27B1). AB - CYP27B1 catalyzes the 1alpha-hydroxylation of 25-hydroxyvitamin D3 to 1alpha,25 dihydroxyvitamin D3, the hormonally active form of vitamin D3. To further characterize mouse CYP27B1, it was expressed in Escherichia coli, purified and its activity measured on substrates incorporated into phospholipid vesicles, which served as a model of the inner mitochondrial membrane. 25-Hydroxyvitamin D3 and 25-hydroxyvitamin D2 in vesicles underwent 1alpha-hydroxylation with similar kinetics, the catalytic rate constants (k(cat)) were 41 and 48mol/min/mol P450, respectively, while K(m) values were 5.9 and 4.6mmol/mol phospholipid, respectively. CYP27B1 showed inhibition when substrate concentrations in the membrane were greater than 4 times K(m), more pronounced with 25-hydroxyvitamin D3 than 25-hydroxyvitamin D2. Higher catalytic efficiency was seen in vesicles prepared from dioleoyl phosphatidylcholine and cardiolipin than for dimyristoyl phosphatidylcholine vesicles. CYP27B1 also catalyzed 1alpha-hydroxylation of vesicle-associated 24R,25-dihydroxyvitamin D3 and 20-hydroxyvitamin D3, and 25 hydroxylation of 1alpha-hydroxyvitamin D3 and 1alpha-hydroxyvitamin D2, but with much lower efficiency than for 25(OH)D3. This study shows that CYP27B1 can hydroxylate 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 associated with phospholipid membranes with the highest activity yet reported for the enzyme. The expressed enzyme has low activity at higher concentrations of 25-hydroxyvitamin D in membranes, revealing that substrate inhibition may contribute to the regulation of the activity of this enzyme. PMID- 20193764 TI - Acetylcholinesterase inhibitors and memantine for neuroenhancement in healthy individuals: a systematic review. AB - The term neuroenhancement refers to improvement in the cognitive, emotional and motivational functions of healthy individuals through, inter alia, the use of drugs. Of known interventions, psychopharmacology provides readily available options, such as the anti-dementia drugs, e.g. acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine. Based on a systematic review we found that expectations about the potential of these drugs exceed their actual effects, as has been demonstrated in randomised controlled trials. Both single and repeated dose trials were included in the systematic review, however repeated dose trials have only been conducted for donepezil. In six small trials lasting 14-42 days, the following results emerged: donepezil improved the retention of training on complex aviation tasks and verbal memory for semantically processed words. In one study episodic memory was improved, whereas in others it remained unaffected by donepezil. In a sleep deprivation trial, donepezil reduced the memory and attention deficits resulting from 24h of sleep deprivation. Two studies reported even transient negative effects. Regarding the safety profile of donepezil, these studies found that it was rather well tolerated. In any case, since large longitudinal studies are not available no conclusions can be drawn. Seven small studies about the effects of a single dose of memantine, and one study with a single dose of rivastigmine have been reported. Again, these studies are not adequate to answer our research question. If, as here and elsewhere suggested, the concept of pharmaceutical neuroenhancement is not to be rejected in principle, the decision of healthy individuals to take drugs for the purpose of neuroenhancement should be based on exhaustive information. At the moment, the research that would support or oppose the use of acetylcholinesterase inhibitors and memantine for neuroenhancement by healthy individuals has not yet been performed. PMID- 20193765 TI - Modulating the p53 pathway. AB - p53 is a transcription factor that protects cells against stress, by modulating genes that induce growth arrest, repair, apoptosis, senescence or altered metabolism. Activation of p53 can potentially be used to modulate disease states. We describe here recent developments that attempt to modulate the function of p53 and outline strategies that are being investigated for pharmacological intervention in the p53 pathway. These include interruption of the interactions between p53 and its negative regulators, restabilization of mutant/misfolded p53, activation of p53 dependant transcription and modulation of p53 function systemically to affect the therapeutic profile of existing drugs. In addition the development of new animal models to investigate the above developments, including mice and zebrafish will be highlighted. PMID- 20193766 TI - Thyroid hormone receptor beta mutation causes severe impairment of cerebellar development. AB - Cerebellar development on the postnatal period is mainly characterized by cellular proliferation in the external granular layer (EGL) followed by migration of granular cells in the molecular layer through the Bergmann glia (BG) fibers in order to form the granular layer in the adult. All these events are drastically affected by thyroid hormones (TH), which actions are mainly mediated by alpha (TRalpha) and beta (TRbeta) nuclear receptor isoforms. Here, we analyzed the effects of a natural human mutation (337T) in the TRbeta locus, which impairs T3 binding to its receptor, on the mouse cerebellum ontogenesis. We report that target inactivation of TRbeta-TH binding leads to a smaller cerebellum area characterized by impaired lamination and foliation. Further, TRbeta mutant mice presented severe deficits in proliferation of granular precursors, arborization of Purkinje cells and organization of BG fibers. Together, our data suggest that the action of TH via TRbeta regulates important events of cerebellar ontogenesis contributing to a better understanding of some neuroendocrine disorders. Further, our data correlate TRbeta with cerebellar foliation, and provide, for the first time, evidence of a receptor-mediated mechanism underlying TH actions on this event. PMID- 20193767 TI - Molecular phylogenetic relationships and a revised classification of the subfamily Ericoideae (Ericaceae). AB - Subfamily Ericoideae (Ericaceae) includes 19 genera in five recognized tribes. Relationships involving the deepest nodes have been difficult to resolve, limiting the potential for further cladistic studies within the Ericoideae. The current study analyses six molecular markers using Bayesian, Maximum Likelihood and Maximum Parsimony methods to improve phylogenetic resolution within the Ericoideae. Two large clades were discovered. One clade includes the Phyllodoceae and Bejaria. The sister clade includes the Empetreae+Diplarche, Ericeae, Rhodoreae, and a clade comprised of Bryanthus and Ledothamnus. The current study improves upon the resolution of the phylogeny of the Ericoideae, particularly demonstrating support for the deepest nodes. Based on these results, we propose to retain the Ericeae, expand the Phyllodoceae to include Bejaria, expand the Empetreae to include Diplarche, retain the Rhodoreae (without Diplarche), dismantle the Bejarieae, and construct a new tribe, Bryantheae (Bryanthus and Ledothamnus). PMID- 20193768 TI - Range-wide genetic differentiation among North American great gray owls (Strix nebulosa) reveals a distinct lineage restricted to the Sierra Nevada, California. AB - Investigations of regional genetic differentiation are essential for describing phylogeographic patterns and informing management efforts for species of conservation concern. In this context, we investigated genetic diversity and evolutionary relationships among great gray owl (Strix nebulosa) populations in western North America, which includes an allopatric range in the southern Sierra Nevada in California. Based on a total dataset consisting of 30 nuclear microsatellite DNA loci and 1938-base pairs of mitochondrial DNA, we found that Pacific Northwest sampling groups were recovered by frequency and Bayesian analyses of microsatellite data and each population sampled, except for western Canada, showed evidence of recent population bottlenecks and low effective sizes. Bayesian and maximum likelihood phylogenetic analyses of sequence data indicated that the allopatric Sierra Nevada population is also a distinct lineage with respect to the larger species range in North America; we suggest a subspecies designation for this lineage should be considered (Strix nebulosa yosemitensis). Our study underscores the importance of phylogeographic studies for identifying lineages of conservation concern, as well as the important role of Pleistocene glaciation events in driving genetic differentiation of avian fauna. PMID- 20193769 TI - Use of within-group designs to test anti-tussive drugs in conscious guinea-pigs. AB - INTRODUCTION: Cough is a common medical problem for which there are few effective drug treatments. A limited understanding of the mechanisms of induction and maintenance of cough and a paucity of suitable animal models frustrate drug discovery efforts to find novel anti-tussives. As in humans, guinea-pigs evoke a cough reflex upon exposure to tussive agents such as citric acid and capsaicin; both of which have been widely used to assess novel anti-tussive drugs. However, the potential for using within-group designs in drug development has received little attention and such designs may offer a way of assisting the drug discovery effort in the area of cough as well as other areas. METHODS: Cough can be monitored in conscious guinea-pigs by placing animals in a Perspex chamber, in which air is continually exchanged by use of negative pressure and drug delivery of aerosols to the chamber can be accurately timed. Cough in response to a tussive agent (e.g. 0.2-0.4M citric acid; 10-30 microM capsaicin) is detected by the simultaneous microphonic recording of audible signals characteristic of the cough response as well as by positive pressure changes in the chamber generated by a cough dependent rapid expiration of air from the lungs. Both the sound and pressure signals are recorded using an online analyzer, whilst the number of coughs can be analyzed off-line. The number of coughs over a 15 min period is used to quantitate tussive events. RESULTS: Reproducible cough can be detected in animals using cross-over designs that lend themselves to drug studies. Both the time and concentration dependence of anti-tussive drug action can be evaluated in the same animal. Furthermore, the effect of different anti-tussive drugs can be evaluated thereby reducing between group error and thereby improving the sensitivity of the test. DISCUSSION: Repeated measures design improves the precision with which to evaluate anti-tussive drugs in preclinical models and could be used to make the drug discovery process more efficient. PMID- 20193770 TI - Quantification of five putative periodontal pathogens in female patients with and without chronic periodontitis by real-time polymerase chain reaction. AB - Chronic periodontitis is a highly prevalent endogenous polymicrobial disease. To better understand the etiology of the disease a quantitative approach is mandatory and real-time PCR is the molecular technique currently preferred to achieve this purpose. Taking into account that such a kind of study is still scarce, we aimed to evaluate the association between periodontal microbiota and chronic periodontitis. A total of 60 low-income age-matched female adults, 30 with chronic periodontitis and 30 without periodontal disease, were enrolled. DNA obtained from subgingival specimens was used for quantification of Aggregatibacter actinomycetemcomitans, Eikenella corrodens, Fusobacterium nucleatum, Porphyromonas gingivalis, and Prevotella intermedia by real-time PCR. A. actinomycetemcomitans, E. corrodens, and F. nucleatum were detected in all subjects, P. gingivalis was observed in 70.0% and 46.6% and P. intermedia in 90.0% and 80.0% of chronic periodontitis patients and periodontally healthy subjects, respectively. P. gingivalis mean count was significantly higher in patients with chronic periodontitis than in periodontally healthy individuals. Accurate detection and quantification of five putative periodontal pathogens was feasible using a simple and fast real-time PCR protocol. Although P. gingivalis and P. intermedia have been found more commonly in chronic periodontitis patients, no statistical difference was observed between periodontally diseased and healthy groups. Quantitative data indicated association between P. gingivalis and chronic periodontitis. However, because of its uneven distribution, it should not be solely taken as a marker of periodontal status. PMID- 20193771 TI - Virulence for chickens of Clostridium perfringens isolated from poultry and other sources. AB - Clostridium perfringens type A is the most common cause of poultry necrotic enteritis (NE). Of the four "major" toxins, type A strains produce only alpha toxin (CPA), which has long been considered a major factor in pathogenesis of NE. We investigated the virulence for poultry of type A strains from a variety of enteric sources. Newly-hatched CornishxRock chicks were fed a low protein diet for one week, a high protein diet for a second week, and then challenged with log phase cultures of C. perfringens, mixed 3:4 (v/v) with high protein feed. Strain JGS4143 [genotype A, beta2 positive (cpb2(pos)), from a field case of NE] produced gross lesions compatible with NE in >85% of challenged birds. However, strains JGS1714 (enterotoxigenic genotype A, cpb2(pos), human food poisoning), JGS1936 (genotype A, cpb2(neg), bovine neonatal enteritis), JGS4142 (genotype A, cpb2(pos), bovine jejunal hemorrhage syndrome), JGS1473 (genotype A, cpb2(pos), chicken normal flora), JGS1070 (genotype C, cpb2(pos), porcine hemorrhagic enteritis), JGS1882 (genotype A, cpb2(pos), porcine neonatal enteritis), JGS1120 (ATCC 13124, genotype A, cpb2(neg), gas gangrene), JGS4151 (strain 13, genotype A, cpb2(pos), canine), and JGS4303 (SM101, enterotoxigenic genotype A, cpb2(neg), human food poisoning) failed to produce disease. In vivo passage failed to increase virulence of the non-NE strains. NE strains must have specific poultry associated virulence attributes, such as the recently identified NetB and other factors, which allow for the development of disease. PMID- 20193772 TI - Gonadotropin-regulated expressions of lanosterol 14alpha-demethylase, sterol Delta14-reductase and C-4 sterol methyl oxidase contribute to the accumulation of meiosis-activating sterol in rabbit gonads. AB - Meiosis-activating sterol (MAS), the intermediate of cholesterol biosynthesis, is an important lipophilic molecule mediating gonadotropins' action in inducing oocyte meiotic resumptions in various mammalian species. With respect to MAS's physiological relevance during oocyte maturation in the rabbit, early study has demonstrated that luteinizing hormone (LH), but not follicle stimulating hormone (FSH) can induce FF-MAS accumulation facilitating oocyte maturation in rabbits. However, the potential underlying mechanism for the MAS accumulation in the rabbit gonad remained unclear. We hypothesized that differential expression of MAS synthetic and metabolic enzymes would contribute to the timely MAS accumulation in the rabbit gonad. To address this issue, in the present investigation, we first cloned the cDNAs encoding there pre- and post-MAS enzymes, lanosterol 14alpha-demethylase (CYP51), sterol Delta14-reductase (14-SR) and C-4 sterol methyl oxidase (C4MO), respectively, using rapid amplification of cDNA ends (RACE) cloning, and then performed northern hybridization experiments to explore their expression profiles in the rabbit ovary, testis, and various other tissues. We observed that CYP51 expression was significantly upregulated only by LH/hCG in the antral follicle exhibiting its peak levels in preovulatory follicles; whereas both FSH and LH significantly downregulated 14-SR expression with the progression of antral follicular development. These findings provided here novel evidence that an inverse upregulation of CYP51 and downregulation of 14-SR expression under FSH/LH stimulation functions as the machinery for FF-MAS accumulation in preovulatory follicles prior to ovulation in the rabbit. PMID- 20193773 TI - Formaldehyde-induced chromosomal aberrations and apoptosis in peripheral blood lymphocytes of personnel working in pathology departments. AB - Peripheral blood lymphocytes (PBL) of 37 formaldehyde-exposed women from four pathology departments in Hungary were investigated to collect data on the effects of occupational exposures to formaldehyde and to find a possible relationship between in vivo formaldehyde-induced apoptosis and genotoxic effects. The subjects were divided into two groups: 16 donors exposed to formaldehyde together with various organic solvents, and 21 subjects exposed mainly to formaldehyde. The results were compared with 37 controls (all women) without known occupational exposure. Ambient air concentrations of formaldehyde were measured in three work places, and ranged from 0.23 to 1.21mg/m(3) (mean 0.9mg/m(3)). Measures of genotoxicity included the determination of the frequencies of chromosomal aberrations (CA), sister-chromatid exchange (SCE), HPRT mutations (variant frequency, VF) and the measurement of UV-induced unscheduled DNA-repair synthesis (UDS). The percentages of premature centromere division (PCD) and of cells with a high frequency of SCE (HF/SCE) were also scored. Apoptosis and cell proliferation were determined by flow cytometry. In both formaldehyde-exposed groups, the apoptotic activity and the CA levels in PBLs were significantly higher than in controls. The CA were mostly breaks of the chromatid type. In the second group, which was mainly exposed to formaldehyde, CA were slightly lower in comparison with the group exposed to formaldehyde and solvents, which may be attributed to a different rate of elimination of damaged lymphocytes as a consequence of formaldehyde-induced apoptotic activity. In the second group, a significant decrease of VF and a non-significant increase in HF/SCE were found compared with the control and the other group. In conclusion, the results demonstrate that exposure to formaldehyde induces apoptosis and CA, indicating an excess cancer risk among subjects occupationally exposed to formaldehyde. The results also emphasize the importance of the measurement of occupational air pollutants, such as formaldehyde, in order to avoid genotoxic effects in the workers. PMID- 20193775 TI - Efficacy of exemestane, a new generation of aromatase inhibitor, on sex differentiation in a gonochoristic fish. AB - We report the first use of exemestane (EM), a steroidal aromatase inhibitor (AI) commercially known as aromasin, in studies of sex differentiation in fish. The effectiveness of EM was examined in two different age groups of the gonochoristic fish, Nile tilapia (Oreochromis niloticus). Untreated control fish (all female) showed normal ovarian differentiation through 120 days after hatching (dah), whereas fish treated with EM at 1000 and 2000 microg/g of feed from 9 dah through 35 dah, the critical period for sex differentiation, exhibited complete testicular differentiation; all stages of spermatogenic germ cells were evident and well developed efferent ducts were present. Fish treated with EM at 1000 microg/g of feed from 70 dah through 100 dah significantly suppressed plasma estradiol-17beta level and increased level of 11-ketotestosterone. Furthermore, untreated control fish showed strong gonadal expression of the steroidogenic enzymes P450 cholesterol-side chain-cleavage enzyme (P450scc), 3beta hydroxysteroid dehydrogenase (3beta-HSD), and cytochrome P450 aromatase (P450arom). In contrast, EM-treated fish showed immunopositive reactions against P450scc and 3beta-HSD but not against P450arom in interstitial Leydig cells. These results indicate that treatment of tilapia juveniles with EM during sex differentiation leads to the development of testes, apparently by a complete suppression of aromatase activity. PMID- 20193774 TI - TAP1 and TAP2 gene polymorphisms in childhood cystic echinococcosis. AB - The incidence of cystic echinococcosis (CE) due to Echinococcus granulosus is as high as 2000-2500 patients per year in Turkey. Whether genetic characteristics of the Turkish population cause a tendency to the disease is currently unknown. We aimed at studying the role of TAP gene polymorphisms in Turkish children with cystic echinococcosis. For an overview of allelic distribution of TAP1 and TAP2 genes, genotypes of 85 patients with CE and 100 controls were studied. To determine the genotype-phenotype correlation, 81 of the patients whose clinical data were available were analyzed. For TAP1-637, Asp/Gly heterozygosity was significantly more prevalent in CE patients than in controls (20 vs. 4%, odds ratio 6.0), while Gly/Gly homozygosity was less frequent (5 vs. 14%). For TAP2 379, Ile/Val heterozygosity was significantly more prevalent in CE patients than in controls (14 vs. 1%, odds ratio 16.27), while Ile/Ile homozygosity was less frequent (13 vs. 25%). TAP1-637 and TAP2-379 polymorphisms may have a role in causing genetic tendency for CE in children. The data may reflect the genetic properties of the Turkish population or may reveal the minor role of TAP gene polymorphisms in CE. PMID- 20193776 TI - Catheter ablation of idiopathic left and right ventricular tachycardias in the pediatric population using noncontact mapping. AB - BACKGROUND: Idiopathic ventricular tachycardia (VT) in children with a structurally normal heart can cause significant morbidity, and although rare, mortality. Conventional activation and pace mapping may be limited by nonsustained tachycardia or unstable hemodynamics. OBJECTIVE: The aim of this study was to assess feasibility of catheter ablation of idiopathic VT in the pediatric population guided by noncontact mapping. METHODS: Twenty consecutive pediatric patients with idiopathic VT underwent electrophysiologic study with the intention to use the noncontact mapping system EnSite 3000 (EnSite Array, St. Jude Medical Inc., Minneapolis, Minnesota). The multielectrode balloon array was introduced into the left or right ventricle, respectively, and tachycardia was analyzed using color-coded isopotential maps as well as reconstructed unipolar electrograms on the virtual geometry. The region of origin was identified in all of them, and the site of earliest activation with a QS pattern of the unipolar electrograms was guided for sites of ablation. RESULTS: Idiopathic VT originated from the right ventricular outflow tract in 6 patients, from the left ventricle in 8, and from the aortic sinus cusp in 6 in this cohort with a median age of 14.4 (range: 4.8 to 20.9) years. Ablation was attempted in 18 of 20 children, and was acutely successful in 17 of these 18 (94%). During a mean follow-up of 2.3 +/ 1.7 years, VT recurred in 3, 2 of them have been treated with a second procedure, resulting in an overall intermediate-term success in 16 of 18 (89%) children with idiopathic VT. CONCLUSION: Noncontact mapping can safely and effectively be used to map and guide catheter ablation of the tachycardia substrate of idiopathic VT in pediatric patients. PMID- 20193777 TI - A stroke preparedness RCT in a multi-ethnic cohort: design and methods. AB - BACKGROUND: Tissue plasminogen activator (tPA), the only approved treatment for acute ischemic stroke (IS), is significantly underutilized likely due to poor lay information about stroke as an emergency. In order to improve outcomes in acute IS, it is critical to raise awareness and recognition of stroke symptoms particularly among minority populations. This manuscript describes the application of a stroke preparedness behavioral intervention and includes baseline information in a multi-ethnic population of stroke and transient ischemic attack (TIA) survivors. METHODS: In the Stroke Warning Information and Faster Treatment Study (SWIFT), we prospectively identified, and randomized IS and TIA patients to determine efficacy of a culturally tailored interactive stroke preparedness strategy. Data collected at baseline included acute stroke parameters, stroke knowledge, severity, social resources and vascular risk assessment. RESULTS: Of the 736 enrolled to date, 76% were IS and 24% TIA events. The cohort was 51% female: 45% Hispanic, 26% White and 25% Black. Over 75% reported hypertension, 36% diabetes, and 16% cardiac disease. Mean time from onset to emergency department (ED) arrival was 46h (median 13h) differing significantly between Whites (mean 52h, median 11h) and Blacks (mean 52h, median 17h) versus Hispanics (mean 39h, median 11h). Knowledge that a stroke occurs in the brain differed significantly by between Whites (85%), Blacks (64%), Hispanics (66%, p<0.000). CONCLUSIONS: Disparities remain in both action and knowledge surrounding acute stroke. Use of written information has not proven an effective means of changing health behaviors. We propose an interactive culturally tailored intervention to address behavioral change in acute stroke. PMID- 20193778 TI - Ceftiofur attenuates lipopolysaccharide-induced acute lung injury. AB - Ceftiofur is a new broad-spectrum, third-generation cephalosporin antibiotic for veterinary use. Our laboratory has previously been reported that ceftiofur can modulate early cytokine responses and increase mouse survival in endotoxemia. In the present study, we investigated the effect of ceftiofur on acute lung injury (ALI) induced by lipopolysaccharide (LPS) in vivo. Mice were pretreated with ceftiofur 1h before challenge with a dose of 0.5mg/kg LPS. Mice treated with LPS alone showed marked increased TNF-alpha, IL-6, and IL-8 levels in the bronchoalveolar lavage fluid (BALF). When pretreated with 30mg/kg of ceftiofur, the TNF-alpha, IL-6, and IL-8 levels were significantly decreased. In addition, the W/D ratio of the lung tissue and the number of total cells, neutrophils and macrophages in the BALF significantly decreased at 8h after pretreatment with ceftiofur. Furthermore, ceftiofur markedly attenuated the LPS-induced histological alteration. These studies indicate that ceftiofur significantly decreases the inflammation in a murine model of LPS-mediated ALI and may represent a novel prevention strategy for nonspecific inflammation in the lungs. PMID- 20193780 TI - The role of Cys108 in Trigonopsis variabilis d-amino acid oxidase examined through chemical oxidation studies and point mutations C108S and C108D. AB - Oxidative modification of Trigonopsis variabilis D-amino acid oxidase in vivo is traceable as the conversion of Cys108 into a stable cysteine sulfinic acid, causing substantial loss of activity and thermostability of the enzyme. To simulate native and modified oxidase each as a microheterogeneity-resistant entity, we replaced Cys108 individually by a serine (C108S) and an aspartate (C108D), and characterized the purified variants with regard to their biochemical and kinetic properties, thermostability, and reactivity towards oxidation by hypochlorite. Tandem MS analysis of tryptic peptides derived from a hypochlorite treated inactive preparation of recombinant wild-type oxidase showed that Cys108 was converted into cysteine sulfonic acid, mimicking the oxidative modification of native enzyme as isolated. Colorimetric titration of protein thiol groups revealed that in the presence of ammonium benzoate (0.12 mM), the two muteins were not oxidized at cysteines whereas in the wild-type enzyme, one thiol group was derivatized. Each site-directed replacement caused a conformational change in D-amino acid oxidase, detected with an assortment of probes, and resulted in a turnover number for the O2-dependent reaction with D-Met which in comparison with the corresponding wild-type value was decreased two- and threefold for C108S and C108D, respectively. Kinetic analysis of thermal denaturation at 50 degrees C was used to measure the relative contributions of partial unfolding and cofactor dissociation to the overall inactivation rate in each of the three enzymes. Unlike wild-type, C108S and C108D released the cofactor in a quasi-irreversible manner and were therefore not stabilized by external FAD against loss of activity. The results support a role of the anionic side chain of Cys108 in the fine-tuning of activity and stability of D-amino acid oxidase, explaining why C108S was a surprisingly poor mimic of the native enzyme. PMID- 20193779 TI - A simplified model of airway narrowing due to bronchial mucosal folding. AB - Bronchial mucosal folding during bronchoconstriction can be a significant phenomenon, and a number of previous studies have provided models which examine a number of aspects of this important problem. Previous approaches include finite element analyses, fluid-structure interaction, linear elasticity models, geometrical computer optimisation, and more. These models have focused on changes to the elastic properties of the airways due to mucosal folding, rather than airway narrowing, and suffer from too great a degree of computational complexity for use in multiscale, spatially distributed models of the lung now being developed. We propose a simplified, geometrical model of airway folding under the assumptions of fixed airway wall area, fixed basement membrane perimeter during constriction, specified shape and number of folds, and liquid filling of the mucosal folds, in the context of determining effective airway radius and hence airway impedance. We show that this model generates predictions in good agreement with existing models while being vastly simpler to solve. PMID- 20193781 TI - Synergistic effects of electrospun PLLA fiber dimension and pattern on neonatal mouse cerebellum C17.2 stem cells. AB - Topographical features, including fiber dimensions and pattern, are important aspects in developing fibrous scaffolds for tissue engineering. In this study aligned poly(l-lactide) (PLLA) fibers with diameters of 307+/-47, 500+/-53, 679+/ 72 and 917+/-84 nm and random fibers with diameters of 327+/-40, 545+/-54, 746+/ 82 and 1150+/-109 nm were obtained by optimizing the electrospinning parameters. We cultured neonatal mouse cerebellum C17.2 cells on the PLLA fibers. These neural stem cells (NSCs) exhibited significantly different growth and differentiation depending upon fiber dimension and pattern. On aligned fibers cell viability and proliferation was best on 500 nm fibers, and reduced on smaller or larger fibers. However, on random fibers cell viability and proliferation was best with the smallest (350 nm) and largest (1150 nm) diameter fibers. Polarized and elongated cells were orientated along the fiber direction on the aligned fibers, with focal contacts bridging the cell body and aligned fibers. Cells of spindle and polygonal morphologies were randomly distributed on the random fibers, with no focal contacts observed. Moreover, longer neurites were obtained on the aligned fibers than random fibers within the same diameter range. Thus, the surface topographic morphologies of fibrous scaffolds, including fiber pattern, dimensions and mesh size, play roles in regulating the viability, proliferation and neurite outgrowth of NSCs. Nevertheless, our results indicated that aligned 500 nm fiber are most promising for fine tuning the design of a nerve scaffold. PMID- 20193782 TI - Injectable oxidized hyaluronic acid/adipic acid dihydrazide hydrogel for nucleus pulposus regeneration. AB - Injectable hydrogel allows irregular surgical defects to be completely filled, lessens the risk of implant migration, and minimizes surgical defects due to the solution-gel state transformation. Here, we first propose a method for preparing oxidized hyaluronic acid/adipic acid dihydrazide (oxi-HA/ADH) injectable hydrogel by chemical cross-linking under physiological conditions. Fourier transform infrared spectrometry and trinitrobenzene sulfonate assay were used to confirm the oxidation of hyaluronic acid. Rheological properties were measured to evaluate the working ability of the hydrogel for further clinical application. The oxi-HA/ADH in situ forming hydrogel can transform from liquid form into a gel like matrix within 3-8 min, depending on the operational temperature. Furthermore, hydrogel degradation and cell assessment is also a concern for clinical application. Injectable oxi-HA/ADH8 hydrogel can maintain its gel-like state for at least 5 weeks with a degradation percentage of 40%. Importantly, oxi HA/ADH8 hydrogel can assist in nucleus pulposus cell synthesis of type II collagen and aggrecan mRNA gene expression according to the results of real-time PCR analysis, and shows good biocompatibility based on cell viability and cytotoxicity assays. Based on the results of the current study, oxi-HA/ADH hydrogel may possess several advantages for future application in nucleus pulposus regeneration. PMID- 20193783 TI - Photopolymerizable and injectable polyurethanes for biomedical applications: synthesis and biocompatibility. AB - Two types of photopolymerizable and injectable polyurethane acrylates (PUAs), based on poly(propylene glycol) or poly(caprolactone diol) and hydroxyethyl methacrylate, were synthesized and characterized in order to obtain information regarding their use as an injectable material for biomedical applications. Structural characteristics of the biomaterials, including the degree of phase separation, were evaluated by Fourier transform infrared spectroscopy. The viscosities of the obtained biomaterials make them suitable for injection, molding and photopolymerization using visible light, as demonstrated by the injection test. The cured polymers had mechanical properties comparable to those of certain soft tissues, such as skin. An in vitro cell-polyurethane cytotoxicity study was carried out with mesenchymal stem cells from rat tibias and femurs. The proliferation/viability of the cells in the presence of the synthesized material was assessed by the MTT assay, collagen synthesis analysis and the expression of alkaline phosphatase. The results that were obtained through the in vitro tests indicated that PUAs are cytocompatible. The in vivo experiments were correlated with the in vitro tests and showed low levels of toxicity for the obtained biomaterials. Histology cross-sections showed that the biomaterials induced no significant inflammatory reaction. Our study demonstrates the potential for using synthesized photocurable polyurethanes in biomedical applications. Furthermore, the obtained injectable polymer systems employ minimally invasive procedures and can be molded in situ before photopolymerization with visible light. PMID- 20193784 TI - Optimization, in vitro release and bioavailability of gamma-oryzanol-loaded calcium pectinate microparticles reinforced with chitosan. AB - Response surface methodology was used to optimize coating conditions, including chitosan concentration (X(1)) and coating time (X(2)), for sustained release of chitosan-coated Ca-pectinate (CP) microparticles containing oryzanol (OZ). The optimized values of X(1) and X(2) were found to be 1.48% and 69.92 min, respectively. These optimized values agreed favorably with the predicted results, indicating the utility of predictive models for the release of OZ in simulated intestinal fluid. In vitro release studies revealed that the chitosan-coated CP microparticles were quite stable under acidic conditions, but swell and disintegrate under alkaline conditions. In vivo release study of OZ, physically entrapped within chitosan-coated CP microcapsules, demonstrated the sustained release of OZ and could be used to improve the bioavailability of OZ following oral administration. PMID- 20193785 TI - Prediction and design of DNA and RNA structures. AB - Computational tools for prediction and design of DNA and RNA structures are used for different approaches in nucleic acid research. The prediction tools are used for the identification and modeling of biologically important nucleic acid structures, whereas the design tools aim at constructing novel molecular architectures and devices for nanotechnology and synthetic biology. The recent successes in predicting RNA three-dimensional structure directly from sequence and in designing sequences that self-assemble into predefined DNA and RNA nanostructures show that nucleic acid structure is predictable and controllable. The prediction and design approaches deal with reverse problems of relating sequence and structure, but share the main computational principles, visual representations and modeling approaches. The prediction and design tools are introduced together here to provide an overview of their current capabilities and deficiencies. The tools are listed by input and output to provide a user perspective and an extended tool table is made available at http://www.cdna.dk/tools/. PMID- 20193786 TI - Essential tactics of tissue preparation and matrix nano-spotting for successful compound imaging mass spectrometry. AB - The ultimate goal of MALDI-Imaging Mass Spectrometry (MALDI-IMS) is to achieve spatial localization of analytes in tissue sections down to individual tissue compartments or even at the level of a few cells. With compound tissue imaging, it is possible to track the transportation of an unlabelled, inhaled reference compound within lung tissue, through the application of MALDI-IMS. The procedure for isolation and preparation of lung tissues is found to be crucial in order to preserve the anatomy and structure of the pulmonary compartments. To avoid delocalization of analytes within lung tissue compartments we have applied an in house designed nano-spotter, based on a microdispenser mounted on an XY table, of which movement and spotting functionality were fully computer controlled. We demonstrate the usefulness of this platform in lung tissue sections isolated from rodent in vivo model, applied to compound tissue imaging as exemplified with the determination of the spatial distribution of (1alpha,2beta,4beta,7beta)-7 [(hydroxidi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9 azoniatricyclo[3.3.1.0(2,4)]nonane, also known as tiotropium. We provide details on tissue preparation protocols and sample spotting technology for successful identification of drug in mouse lung tissue by using MALDI-Orbitrap instrumentation. PMID- 20193788 TI - Effects of capsaicin-induced sensory denervation on bone metabolism in adult rats. AB - Bone metabolism has recently been revealed to be under nerve regulation. In this study, the integrity of the sensory innervation contributing to bone metabolism was examined by capsaicin-induced sensory neuron lesions. Eight-week-old male Wistar strain rats in a modeling phase of skeletal growth were divided into four groups (8 rats per group) and treated with capsaicin at one of three different doses (37.5, 75, 150 mg/kg) or vehicle, subcutaneously. Five weeks later, high dose (150 mg/kg) capsaicin treatment had reduced trabecular bone volume (BV/TV) due to increased trabecular separation (Tb.Sp) in the proximal tibia and the modification of mechanical properties such as strength, ductility, and toughness toward increasing bone fragility in the trunk of the sixth lumbar vertebrae (L6). Moderate-dose (75 mg/kg) capsaicin treatment had no significant effect on trabecular BV/TV or bone mechanical properties but increased Tb.Sp as seen high dose capsaicin treatment. Bone histomorphometry showed osteoclast number (Oc.N/BS) and surface (Oc.S/BS) were increased in both the moderate-dose and high dose capsaicin treatment groups. High-dose capsaicin significantly increased the level of tartrate-resistant acid phosphatase form 5b (TRAP 5b) in plasma, a systemic bone resorption marker, but had no influence on plasma osteocalcin concentration, a bone formation marker, suggesting that capsaicin-induced sensory nerve denervation increased bone resorption but had no influence on bone formation. Low-dose (37.5mg/kg) capsaicin had no influence on bone remodeling. These results suggest that sensory nerve innervation contributes to the maintenance of trabecular bone mass and its mechanical properties by inhibiting bone resorption. PMID- 20193789 TI - Abdominal distension in a 79-year-old patient. PMID- 20193787 TI - Characterization of stem and progenitor cells in the dental pulp of erupted and unerupted murine molars. AB - In the past few years there have been significant advances in the identification of putative stem cells also referred to as "mesenchymal stem cells" (MSC) in dental tissues including the dental pulp. It is thought that MSC in dental pulp share certain similarities with MSC isolated from other tissues. However, cells in dental pulp are still poorly characterized. This study focused on the characterization of progenitor and stem cells in dental pulps of erupted and unerupted mice molars. Our study showed that dental pulps from unerupted molars contain a significant number of cells expressing CD90+/CD45-, CD117+/CD45-, Sca 1+/CD45- and little if any CD45+ cells. Our in vitro functional studies showed that dental pulp cells from unerupted molars displayed extensive osteo dentinogenic potential but were unable to differentiate into chondrocytes and adipocytes. Dental pulps from erupted molars displayed a reduced number of cells, contained a higher percentage of CD45+ and a lower percentage of cells expressing CD90+/CD45-, CD117+/CD45- as compared to unerupted molars. In vitro functional assays demonstrated the ability of a small fraction of cells to differentiate into odontoblasts, osteoblasts, adipocytes and chondrocytes. There was a significant reduction in the osteo-dentinogenic potential of the pulp cells derived from erupted molars compared to unerupted molars. Furthermore, the adipogenic and chondrogenic differentiation of pulp cells from erupted molars was dependent on a long induction period and were infrequent. Based on these findings we propose that the dental pulp of the erupted molars contain a small population of multipotent cells, whereas the dental pulp of the unerupted molars does not contain multipotent cells but is enriched in osteo-dentinogenic progenitors engaged in the formation of coronal and radicular odontoblasts. PMID- 20193790 TI - Retro-inversion enhances the adjuvant and CpG co-adjuvant activity of host defence peptide Bac2A. AB - Host defence peptides (HDPs) have a variety of potential therapeutic applications, including as vaccine adjuvants, energizing efforts for modification strategies to address their toxicity and instability. Here we compare l, d and RI Bac2A as vaccine adjuvants. d and RI-Bac2A are equally resistant to proteolytic degradation with no increases in toxicity, however, only RI-Bac2A maintains adjuvant activity of the natural peptide through conserved induction of a Th2 immune response. As HDPs potentiate the adjuvant activity of CpG ODNs, the isomers were also evaluated as co-adjuvants. l-Bac2A has no significant co adjuvant activity while CpG/RI-Bac2A induces antibody titres significantly higher than CpG (P<0.01), CpG/l-Bac2A (P<0.01) or CpG/d-Bac2A (P<0.01). None of the isomers influence ODN duration or distribution but l and RI-Bac2A promote ODN uptake into B cells and antigen presenting cells. The enhanced adjuvant and co adjuvant of RI-Bac2A is hypothesized to result from an undefined combination of increased stability and retained biological activity supporting application of retro-inversion to this, and potentially other HDPs. PMID- 20193791 TI - AF03-adjuvanted and non-adjuvanted pandemic influenza A (H1N1) 2009 vaccines induce strong antibody responses in seasonal influenza vaccine-primed and unprimed mice. AB - Pandemic influenza vaccines have been manufactured using the A/California/07/2009 (H1N1) strain as recommended by the World Health Organization. We evaluated in mice the immunogenicity of pandemic (H1N1) 2009 vaccine and the impact of prior vaccination against seasonal trivalent influenza vaccines (TIV) on antibody responses against pandemic (H1N1) 2009. In naive mice, a single dose of unadjuvanted H1N1 vaccine (3 microg of HA) was shown to elicit hemagglutination inhibition (HI) antibody titers >40, a titer associated with protection in humans against seasonal influenza. A second vaccine dose of pandemic (H1N1) 2009 vaccine strongly increased these titers, which were consistently higher in mice previously primed with TIV than in naive mice. At a low immunization dose (0.3 microg of HA), the AF03-adjuvanted vaccine elicited higher HI antibody titers than the corresponding unadjuvanted vaccines in both naive and TIV-primed animals, suggesting a potential for antigen dose-sparing. These results are in accordance with the use in humans of a split-virion inactivated pandemic (H1N1) 2009 vaccine formulated with or without AF03 adjuvant to protect children and young adults against influenza A (H1N1) 2009 infection. PMID- 20193793 TI - Spatiotemporal and spectral characteristics of atrial fibrillation waves across atrial walls and remodeling. PMID- 20193792 TI - Evaluation of formalin inactivated V3526 virus with adjuvant as a next generation vaccine candidate for Venezuelan equine encephalitis virus. AB - V3526, a genetically modified strain of Venezuelan equine encephalitis virus (VEEV), was formalin inactivated for evaluation as a next generation vaccine candidate for VEEV. In this study, we tested formalin-inactivated V3526 (fV3526) with and without adjuvant for immunogenicity and efficacy in BALB/c mice and results were compared to the existing inactivated VEEV vaccine, C84. Mice were vaccinated intramuscularly (IM) or subcutaneously (SC) with fV3526 formulations and challenged with VEEV IAB Trinidad donkey (VEEV TrD) strain by SC or aerosol exposure. Efficacy following SC or aerosol challenge was not significantly different between the fV3526 formulations or compared to C84 despite C84 being administered in more doses and higher concentration of viral protein per dose. These data support further evaluation of fV3526 formulations as a next generation VEEV vaccine. PMID- 20193794 TI - Circumferential pulmonary vein ablation: does use of a circular mapping catheter improve results? A prospective randomized study. AB - BACKGROUND: The best method for performing atrial fibrillation (AF) ablation is still under debate. The importance of using a circular mapping (CM) catheter for assessing isolation of the pulmonary vein (PV) antrum on the outcome of the procedure has not been clearly established. OBJECTIVE: The purpose of this study was to evaluate whether use of a CM catheter improves the arrhythmia-free proportion after circumferential pulmonary vein ablation (CPVA). METHODS: A series of 146 consecutive patients (83% males, age 53 +/- 10 years, 53% paroxysmal AF) were randomized to two ablation strategies. In both groups, ipsilateral PV encirclement was performed until disappearance or dissociation of the local electrogram within the surrounded area. In the first group, only the radiofrequency catheter was used to both map and ablate (CPVA group, n = 73). In the other group, a CM catheter was added to assess the electrical activity of the PV antrum (CPVA-CM group, n = 73). An ablation line along the left atrial roof was also created in all patients. RESULTS: Procedural and fluoroscopic times were longer in the CPVA-CM group (P <.05). Severe procedure-related complications occurred in 1 (1.4%) patient in the CPVA group and in 3 (4.1%) patients in the CPVA-CM group (P = .317). After mean follow-up of 9 +/- 3 months, 31 (42.5%) patients in the CPVA group and 47 (64.4%) patients in the CPVA-CM group were arrhythmia-free without antiarrhythmic medication (P = .008). CONCLUSION: Use of a CM catheter to ensure isolation of the PV antrum improved the success of CPVA but increased some procedural requirements. PMID- 20193796 TI - Climbing the mountain. PMID- 20193797 TI - Central sterile supply department professionals: a key piece in the OR quality puzzle. PMID- 20193798 TI - The Ilizarov method of external fixation: current intraoperative concepts. AB - The Ilizarov method of external fixation is used to treat fractures, complex lower extremity deformities, osteomyelitis, and soft tissue contractures and to lengthen limbs. Tremendous improvements in the Ilizarov method have occurred during the past 60 years, improving intraoperative care and limb salvage management concepts. Improved instrumentation has increased the quantity and complexity of the tray systems required for these procedures. Perioperative nurses must be well versed in optimal preparation and function of Ilizarov fixation systems to ensure safe patient care during Ilizarov external fixation procedures. PMID- 20193799 TI - An effective process for making decisions about major operating room purchases. AB - In today's economy, it is imperative that nurses exhibit stewardship for their organization's resources and help ensure that purchasing decisions are sound. Regardless of the decision-making method chosen, a formal, consistent review process that evaluates cost, compares products, examines implications, analyzes risk, uses evidence, and includes safety and outcome measures is vital to success. Clinical Quality Value Analysis (CQVA) is a product evaluation platform that can be used to determine whether a proposed product or service will add value to the organization as well as improve patient outcomes. Using CQVA for a proposed product or service is a five-step process: assess, plan, design, implement, and measure/sustain. PMID- 20193800 TI - Common breaks in sterile technique: clinical perspectives and perioperative implications. AB - Prevention of health care-associated infections, specifically surgical site infections, is a fundamental responsibility of the perioperative team. Breaks in sterile technique can and do occur, even for the most conscientious perioperative practitioners. Surgical site infections are associated with unnecessary patient pain and suffering and increased lengths of hospital stay and health care costs. Prevention of surgical site infections, therefore, takes on great significance in today's dynamic health care environment. Key responsibilities of perioperative nurses are to recognize and correct common breaks in sterile technique that are made in preparation for and during a surgical procedure and to implement methods to prevent future occurrences. PMID- 20193802 TI - Patient safety first. Never events in health care. PMID- 20193803 TI - Improving associate degree nursing students' perioperative clinical observation experiences. AB - For associate degree nursing students at Eastern Kentucky University, Richmond, the perioperative nursing clinical experience typically included a one-day observation of a surgical procedure, with students entering the OR suite after the surgery started and having to leave before the surgery was completed. An associate professor of nursing and a perioperative staff education coordinator partnered to address this lack of a complete perioperative experience for students and offer a more formal OR experience. The clinical experience was altered to provide relevant didactic perioperative nursing content in class before the clinical day, a group orientation, and observation in the preoperative, intraoperative, and postoperative areas. Reactions of students and perioperative staff members to these changes were positive. PMID- 20193804 TI - Different but similar. PMID- 20193805 TI - The role of the medical science liaison in industry. AB - Health care vendors (ie, industry) can be credited with developing products and medications that improve perioperative clinician and patient safety. The role of the medical science liaison in industry is to provide education about these products and facilitate research partnerships between clinicians and industry that can result in new products and innovations. PMID- 20193808 TI - Inadvertent castration. PMID- 20193809 TI - Polymyalgia rheumatica with bilateral subclavian artery stenosis. PMID- 20193810 TI - Bromide toxicity from consumption of dead sea salt. PMID- 20193811 TI - Emergence of fluoroquinolone resistance in outpatient urinary Escherichia coli isolates. PMID- 20193812 TI - Program director satisfaction revisited: an alternate view. PMID- 20193814 TI - Influence of Hispanic Ethnicity and Diabetic End-stage Renal Disease. PMID- 20193816 TI - Nocturia: an uncommon presentation of lower-limb lymphedema. PMID- 20193817 TI - Eroded pacemaker in an elderly patient. PMID- 20193818 TI - Relief of chronic neuropathic pain through endothelin antagonism. PMID- 20193819 TI - Transient collateral circulation during coronary vasospasm. PMID- 20193820 TI - We can reduce us health care costs. PMID- 20193821 TI - Reexamining the physician scholar-professional organization relationship. PMID- 20193823 TI - Atrial fibrillation in heart failure: a comprehensive review. AB - Chronic heart failure and atrial fibrillation are 2 major disorders that are closely linked. Their coexistence is associated with adverse prognosis. Both share several common predisposing conditions, but their interaction involves complex ultrastructural, electrophysiologic, and neurohormonal processes that go beyond mere sharing of mutual risk factors. Rate control approach remains the standard therapy for atrial fibrillation in heart failure because current strategies at rhythm control have so far failed to positively impact mortality and morbidity. This is largely because of the shortcomings of current pharmacologic anti-arrhythmic agents. Surgical and catheter-based therapies are promising, but long-term data are lacking. The role of non-anti-arrhythmic therapeutic agents also is being explored. Further progress toward improved understanding the complex relationship between atrial fibrillation and heart failure should improve management strategies. PMID- 20193824 TI - Primary care of the transplant patient. AB - A total of 153,245 patients are living with a solid organ transplant in the US. In addition, patients are experiencing high 5-year survival rates after transplantation. Thus, primary care physicians will be caring for transplanted patients. The aim of this review is to update primary care physicians on chronic diseases, screening for malignancy, immunizations, and contraception in the transplant patient. Several studies on the treatment of hypertension and hyperlipidemia demonstrate that most agents used to treat the general population also can be used to treat transplant recipients. Little information exists on the medical management of diabetes in the transplant population, but experts in the area believe that the treatment of diabetes should be similar. Transplant recipients are at increased risk for all malignancies. Aggressive screening should be employed for all cancers with a proven screening benefit. Killed immunizations are safe for the transplant population, but live virus vaccines should be avoided. Women of childbearing age should be counseled about the impact of immunosuppressants on the efficacy and side effects of contraception. PMID- 20193825 TI - Diabetic retinopathy: An update on treatment. AB - Diabetic retinopathy is a progressive disease that results from vascular injury due to chronic hyperglycemia. It is the leading cause of blindness in working-age adults in the US and is usually asymptomatic until late stages. Treatment with laser photocoagulation is effective at preventing severe vision loss; thus, diabetic patients should be referred for regular screening by an ophthalmologist. New inhibitors of vascular endothelial growth factor may provide targeted nonsurgical treatment to improve vision in diabetic retinopathy. PMID- 20193826 TI - The Improving Continuous Cardiac Care (IC(3)) program and outpatient quality improvement. PMID- 20193827 TI - Exotic origin, familiar culprit. PMID- 20193828 TI - A Post-cure Complication. PMID- 20193829 TI - Computer calls for cardiology consult STAT! PMID- 20193830 TI - Diabetes mellitus and confusion. PMID- 20193831 TI - Analgesic use and the risk of hearing loss in men. AB - BACKGROUND: Hearing loss is a common sensory disorder, yet prospective data on potentially modifiable risk factors are limited. Regularly used analgesics, the most commonly used drugs in the US, may be ototoxic and contribute to hearing loss. METHODS: We examined the independent association between self-reported professionally diagnosed hearing loss and regular use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen in 26,917 men aged 40-74 years at baseline in 1986. Study participants completed detailed questionnaires at baseline and every 2 years thereafter. Incident cases of new-onset hearing loss were defined as those diagnosed after 1986. Cox proportional hazards multivariate regression was used to adjust for potential confounding factors. RESULTS: During 369,079 person-years of follow-up, 3488 incident cases of hearing loss were reported. Regular use of each analgesic was independently associated with an increased risk of hearing loss. Multivariate-adjusted hazard ratios of hearing loss in regular users (2+ times/week) compared with men who used the specified analgesic <2 times/week were 1.12 (95% confidence interval [CI], 1.04 1.20) for aspirin, 1.21 (95% CI, 1.11-1.33) for NSAIDs, and 1.22 (95% CI, 1.07 1.39) for acetaminophen. For NSAIDs and acetaminophen, the risk increased with longer duration of regular use. The magnitude of the association was substantially higher in younger men. For men younger than age 50 years, the hazard ratio for hearing loss was 1.33 for regular aspirin use, 1.61 for NSAIDs, and 1.99 for acetaminophen. CONCLUSIONS: Regular use of aspirin, NSAIDs, or acetaminophen increases the risk of hearing loss in men, and the impact is larger on younger individuals. PMID- 20193832 TI - Notification of abnormal lab test results in an electronic medical record: do any safety concerns remain? AB - BACKGROUND: Follow-up of abnormal outpatient laboratory test results is a major patient safety concern. Electronic medical records can potentially address this concern through automated notification. We examined whether automated notifications of abnormal laboratory results (alerts) in an integrated electronic medical record resulted in timely follow-up actions. METHODS: We studied 4 alerts: hemoglobin A1c > or =15%, positive hepatitis C antibody, prostate specific antigen > or =15 ng/mL, and thyroid-stimulating hormone > or =15 mIU/L. An alert tracking system determined whether the alert was acknowledged (ie, provider clicked on and opened the message) within 2 weeks of transmission; acknowledged alerts were considered read. Within 30 days of result transmission, record review and provider contact determined follow-up actions (eg, patient contact, treatment). Multivariable logistic regression models analyzed predictors for lack of timely follow-up. RESULTS: Between May and December 2008, 78,158 tests (hemoglobin A1c, hepatitis C antibody, thyroid-stimulating hormone, and prostate-specific antigen) were performed, of which 1163 (1.48%) were transmitted as alerts; 10.2% of these (119/1163) were unacknowledged. Timely follow-up was lacking in 79 (6.8%), and was statistically not different for acknowledged and unacknowledged alerts (6.4% vs 10.1%; P =.13). Of 1163 alerts, 202 (17.4%) arose from unnecessarily ordered (redundant) tests. Alerts for a new versus known diagnosis were more likely to lack timely follow-up (odds ratio 7.35; 95% confidence interval, 4.16-12.97), whereas alerts related to redundant tests were less likely to lack timely follow-up (odds ratio 0.24; 95% confidence interval, 0.07-0.84). CONCLUSIONS: Safety concerns related to timely patient follow-up remain despite automated notification of non-life-threatening abnormal laboratory results in the outpatient setting. PMID- 20193833 TI - Orthostatic syndromes differ in syncope frequency. AB - BACKGROUND: There are conflicting opinions on whether postural tachycardia syndrome predisposes to syncope. We investigated this relationship by comparing the frequency of syncope in postural tachycardia syndrome and orthostatic hypotension. METHODS: We queried our autonomic laboratory database of 3700 patients. Orthostatic hypotension and postural tachycardia syndrome were defined in standard fashion, except that postural tachycardia syndrome required the presence of orthostatic symptoms and a further increase in heart rate beyond 10 minutes. Syncope was defined as an abrupt decrease in blood pressure and often, heart rate, requiring termination of the tilt study. Statistical analysis utilized Fisher's exact test and Student's t test, as appropriate. RESULTS: Of 810 patients referred for postural tachycardia syndrome, 185 met criteria while another 328 patients had orthostatic hypotension. Of the postural tachycardia syndrome patients, 38% had syncope on head-up tilt, compared with only 22% of those with orthostatic hypotension (P<.0001). In the postural tachycardia group, syncope on head-up tilt was associated with a clinical history of syncope in 90%, whereas absence of syncope on head-up tilt was associated with a clinical history of syncope in 30% (P<.0001). In contrast, syncope on head-up tilt did not bear any relationship to clinical history of syncope in the orthostatic hypotension group (41% vs 36%; P=.49). CONCLUSION: Our results demonstrate that syncope (both tilt table and clinical) occurs far more commonly in patients who have postural tachycardia syndrome than in patients with orthostatic hypotension. These findings suggest that one should be clinically aware of the high risk of syncope in patients with postural tachycardia syndrome, and the low-pressure baroreceptor system that is implicated in postural tachycardia syndrome might confer more sensitivity to syncope than the high pressure system implicated in orthostatic hypotension. PMID- 20193834 TI - Long-term effect of chronic oral anticoagulation with warfarin after acute myocardial infarction. AB - BACKGROUND: Antiplatelet therapy is the principal component of the antithrombotic regimen after acute myocardial infarction. It remains unclear whether additional chronic oral anticoagulation (OAC) improves outcomes. We set out to evaluate the risk and benefit of long-term OAC after myocardial infarction. METHODS: We pooled 10 randomized clinical trials comparing warfarin-containing regimens (OAC) with or without aspirin with non-OAC regimens with or without aspirin (No OAC) for patients with recent infarction. The primary endpoint was all-cause mortality. Other endpoints included recurrent infarction, stroke, and major bleeding. We calculated the odds ratio (OR) (fixed effect, OR <1 indicates benefit for OAC) for death and other ischemic and hemorrhagic complications at the longest interval of follow-up available. RESULTS: Among 24,542 patients, 14,062 were assigned to OAC and 10,480 to no OAC. The patients were followed for 3-63 months, for 89,562 patient-years. Death occurred in 2424 patients (9.9%), 1279 OAC patients, and 1145 in the no OAC group, OR 0.97 (95% confidence interval [CI], 0.88-1.05), P=.43. Similarly, there was no effect on recurrent infarction. Stroke occurred in 578 patients (2.4%), 271 in the OAC group and 307 in the no OAC group, OR 0.75 (95% CI, 0.63-0.89), P=.001. There was substantially more major bleeding (OR 1.83 [95% CI, 1.50-2.23], P <.001) in the OAC group. Separate analyses, performed for patients (n=11,920) randomized to aspirin versus aspirin and OAC yielded very similar results. CONCLUSION: As compared with placebo or aspirin, OAC with or without aspirin does not reduce mortality or reinfarction, reduces stroke, but is associated with significantly more major bleeding. PMID- 20193835 TI - Acute myocardial infarction hospitalization in the United States, 1979 to 2005. AB - BACKGROUND: We reported earlier that there was no decline of acute myocardial infarction hospitalization from 1988 to 1997. We now extend these observations to document trends in acute myocardial infarction hospitalization rates and in hospital case-fatality rates for 27 years from 1979 to 2005. METHODS: We determined hospitalization rates for acute myocardial infarction by age and gender using data from the National Hospital Discharge Survey and US civilian population from 1979 to 2005, aggregated by 3-year groupings. We also assessed comorbid, complications, cardiac procedure use, and in-hospital case-fatality rates. RESULTS: Age-adjusted hospitalization rate for acute myocardial infarction identified by primary International Classification of Diseases code was 215 per 100,000 people in 1979-1981 and increased to 342 in 1985-1987. Thereafter, the rate stabilized for the next decade and then declined slowly after 1996 to 242 in 2003-2005. Trends were similar for men and women, although rates for men were almost twice that of women. Hospitalization rates increased substantially with age and were the highest among those aged 85 years or more. Although median hospital stay decreased from 12 to 4 days, intensity of hospital care increased, including use of coronary angioplasty, coronary bypass, and thrombolytics therapy. During the period, reported comorbidity from diabetes and hypertension increased. Acute myocardial infarction complicated by heart failure increased, and cardiogenic shock decreased. Altogether, the in-hospital case-fatality rate declined. CONCLUSION: During the past quarter century, hospitalization for acute myocardial infarction increased until the mid-1990s, but has declined since then. At the same time, in-hospital case-fatality rates declined steadily. This decline has been associated with more aggressive therapeutic intervention. PMID- 20193837 TI - Adoption of once-monthly oral bisphosphonates and the impact on adherence. AB - BACKGROUND: The extent of the adoption of once-monthly bisphosphonates into general clinical practice is not known, nor is it known if the novel formulation improves adherence. METHODS: We analyzed administrative claims 2003-2006 from a large employer-based health insurance database for incident use of oral bisphosphonates and stratified users by daily, weekly, and monthly dosing regimen. We measured adherence as the medication possession ratio (MPR) during the first year of therapy. We compared patient characteristics by dosing regimen and evaluated how the dosing regimen influenced the MPR. RESULTS: We identified 61,125 incident users of bisphosphonates (n=1034 daily, n=56,925 weekly, n=3166 monthly). Monthly bisphosphonate users were, on average, slightly older than the other groups (mean age 66 years for monthly users vs 65 years for weekly users or 66 years for daily users, P<.05) and more often lived in the North Central or South United States (76% vs 72% weekly users or 69% daily users, P<.05). There were no detectable differences among the dosing groups in the history of serious gastrointestinal risk, comorbidity burden, or prior osteoporotic fractures. During the first year of bisphosphonate therapy, 49% of monthly users had MPR> or =80% compared with 49% of weekly users (not significant) or 23% of daily users (P<.0001). CONCLUSION: We found little evidence of preferential prescribing of monthly bisphosphonates to certain types of patients. Furthermore, we found no evidence of improved bisphosphonate adherence with monthly dosing relative to weekly dosing, although adherence with either weekly or monthly dosing was significantly better than with daily dosing. PMID- 20193836 TI - Higher incidence of mild cognitive impairment in familial hypercholesterolemia. AB - OBJECTIVE: Hypercholesterolemia is an early risk factor for Alzheimer's disease. Low-density lipoprotein (LDL) receptors might be involved in this disorder. Our objective was to determine the risk of mild cognitive impairment in a population of patients with heterozygous familial hypercholesterolemia, a condition involving LDL receptor dysfunction and lifelong hypercholesterolemia. METHODS: By using a cohort study design, patients with familial hypercholesterolemia (N=47) meeting inclusion criteria and comparison patients without familial hypercholesterolemia (N=70) were consecutively selected from academic specialty and primary care clinics, respectively. All patients were older than 50 years. Those with disorders that could affect cognition, including history of stroke or transient ischemic attacks, were excluded from both groups. Thirteen standardized neuropsychologic tests were performed in all subjects. Mutational analysis was performed in patients with familial hypercholesterolemia, and brain imaging was obtained in those with familial hypercholesterolemia and mild cognitive impairment. RESULTS: Patients with familial hypercholesterolemia showed a high incidence of mild cognitive impairment compared with those without familial hypercholesterolemia (21.3% vs 2.9%; P=.00). This diagnosis was unrelated to structural pathology or white matter disease. There were significant differences, independent of apolipoprotein E4 or E2 status, between those with familial hypercholesterolemia and those with no familial hypercholesterolemia in several cognitive measures, all in the direction of worse performance for those with familial hypercholesterolemia. CONCLUSION: Because prior studies have shown that older patients with sporadic hypercholesterolemia do not show a higher incidence of mild cognitive impairment, the findings presented suggest that early exposure to elevated cholesterol or LDL receptor dysfunction may be risk factors for mild cognitive impairment. PMID- 20193838 TI - Postprandial hypotension. AB - Postprandial hypotension is both common in geriatric patients and an important but under-recognized cause of syncope. Other populations at risk include those with Parkinson disease and autonomic failure. The mechanism is not clearly understood, but appears to be secondary to a blunted sympathetic response to a meal. This review discusses the epidemiology, risk factors, and pathophysiology of postprandial hypotension in the elderly, as well as diagnosis and treatment strategies. Diagnosis can be made based on ambulatory blood pressure monitoring and patient symptoms. Lifestyle modifications such as increased water intake before eating or substituting 6 smaller meals daily for 3 larger meals may be effective treatment options. However, data from randomized, controlled trials are limited. Increased awareness of this disease may lead to improved quality of life, decreased falls and injuries, and the avoidance of unnecessary testing. PMID- 20193839 TI - Physical activity and the risk of community-acquired pneumonia in US women. AB - BACKGROUND: Exercise bolsters the immune system and can prevent various infections in certain populations. However, limited data exist regarding the role of physical activity and the risk of community-acquired pneumonia. METHODS: During a 12-year period, we prospectively examined the association between physical activity and the risk of community-acquired pneumonia among 83,165 women in the Nurses' Health Study II who were between the ages of 27 and 44 years in 1991. We excluded women who had pneumonia before 1991 and those with a history of cancer, cardiovascular disease, or asthma. Biennial self-administered mailed questionnaires were used to determine activity level. Cases of pneumonia required a diagnosis by a physician and confirmation with a chest radiograph. RESULTS: We identified 1265 new cases of community-acquired pneumonia during 965,168 person years of follow up. After adjusting for age, women in the highest quintile of physical activity were less likely to develop pneumonia than women in the lowest quintile (relative risk [RR] = 0.72; 95% confidence interval [CI], 0.60-0.86; P for trend<.001). However, the association was attenuated and only marginally significant after further adjusting for body mass index, smoking, and alcohol use (RR=0.84; 95% CI, 0.70-1.01; P for trend=.06). Women in the highest quintile of walking were less likely to develop pneumonia compared with women who walked the least (multivariate adjusted RR=0.82; 95% CI, 0.69-0.98); however, the trend across quintiles was not significant (P for trend=.25). CONCLUSION: Higher physical activity does not substantially reduce pneumonia risk in well-nourished women. PMID- 20193840 TI - Severe H1N1-Associated acute respiratory distress syndrome: A case series. AB - BACKGROUND: Acute respiratory distress syndrome resulting from novel influenza A virus (H1N1) infection remains uncommon. METHODS: We describe the clinical profiles of adult patients with acute respiratory distress syndrome due to microbiologically confirmed H1N1 admitted to a medical intensive care unit in San Francisco, California over a 2-month period. RESULTS: Between June 1 and July 31, 2009, 7 patients (age range: 25-66 years; 4 patients under the age of 40 years; 6 male; 1 pregnant) were diagnosed with H1N1, with 5 of 6 (83%) having initial false-negative rapid testing. All developed respiratory failure complicated by acute respiratory distress syndrome, with 4 additionally developing multiorgan dysfunction. All were managed with a lung protective ventilator strategy (average number of days on the ventilator: 16), and 4 patients also required additional rescue therapies for refractory hypoxemia, including very high positive end expiratory pressure, inhaled epoprostenol, recruitment maneuvers, and prone positioning. Despite these measures, 3 patients (43%) ultimately died. CONCLUSIONS: Clinicians should be vigilant for the potential of H1N1 infection to progress to severe acute respiratory distress syndrome in a variety of patient demographics, including younger patients without baseline cardiopulmonary disease. A high degree of suspicion is critical, especially with the relative insensitivity of rapid testing, and should prompt empiric antiviral therapy. PMID- 20193841 TI - Measuring resident hours by tracking interactions with the computerized record. PMID- 20193842 TI - Overexpression of the novel human gene, UBE2Q2, in breast cancer. AB - The ubiquitin-proteasome pathway facilitates the degradation of damaged proteins and regulates growth and stress response. This pathway is activated in various cancers, including breast cancer. We have previously reported that the novel human gene, UBE2Q2, is a putative ubiquitin-conjugating enzyme that is located on chromosome 15 and is overexpressed in tumor mass and invasive epithelium in head and neck squamous-cell carcinoma. Here, real-time polymerase chain reaction was used to investigate the expression levels of UBE2Q2 gene in a collection of 21 breast cancer tissues matched with normal adjacent counterparts. Immunohistochemistry and Western blot testing were also performed on formalin fixed, paraffin-embedded tissue sections by using a rabbit polyclonal antibody that we generated against an amino acid sequence predicted from the DNA sequence of UBE2Q2 gene. In the 21 cases investigated, a high increase in the expression of UBE2Q2 mRNA was found in 8 breast cancers (38.1%), a moderately increased UBE2Q2 expression was observed in 7 cases (33.3%), and no significant changes were detected in 6 cases (28.6%) of tumor samples when compared with corresponding normal tissues. Consistently, a higher level of immunoreactivity for UBE2Q2 protein was detected in invasive epithelium of cancerous tissues when compared with that in the normal epithelium. Our data suggest that the novel human gene UBE2Q2 may have implications for pathogenesis of breast cancer and could be used in molecular diagnosis purposes in the future. PMID- 20193843 TI - Fetal colon cell line FHC exhibits tumorigenic phenotype, complex karyotype, and TP53 gene mutation. AB - Stable cell lines obtained by spontaneous immortalization might represent early stages of malignant transformation and be useful experimental models for studies of mechanisms of cancer development. The FHC (fetal human cells) cell line has been established from normal fetal colonic mucosa. Detailed characterization of this cell line and mechanism of spontaneously acquired immortality have not been described yet. Therefore, we characterized the FHC cell line in terms of its tumorigenicity, cytogenetics, and TP53 gene mutation analysis. FHC cells displayed capability for anchorage-independent growth in semisolid media in vitro and formed solid tumors after transplantation into SCID (severe combined immunodeficiency) mice. This tumorigenic phenotype was associated with hypotriploidy and chromosome number ranging from 66 to 69. Results of comparative genetic hybridization arrays showed that most chromosomes included regions of copy number gains or losses. Region 8q23 approximately 8q24.3 (containing, e.g., MYC proto-oncogene) was present in more than 20 copies per nucleus. Moreover, we identified mutation of TP53 gene in codon 273; triplet CGT coding Arg was changed to CAG coding His. Expression of Pro codon 72 polymorphic variant of p53 was also detected. Mutation of TP53 gene was associated with abolished induction of p21(Waf1/Cip1) and MDM-2 proteins and resistance to apoptosis after genotoxic treatment. Because of their origin from normal fetal colon and their relative resistance to the induction of apoptosis, FHC cells can be considered a valuable experimental model for various studies. PMID- 20193845 TI - Array comparative genomic hybridization analysis of adult acute leukemia patients. AB - We have performed a retrospective array-based comparative hybridization (array CGH) study on 41 acute leukemia samples [n=17 acute lymphoblastic leukemia (ALL) patients only at diagnosis, n=3 ALL patients both at diagnosis and relapse; n=20 acute myeloid leukemia (AML) patients only at diagnosis and n=1 AML patient both at diagnosis and relapse] using an Agilent 44K array. In addition to previously detected cytogenetic aberrations, we observed cryptic aberrations in 95% of ALL and 90.5% of AML cases. ALL-specific recurrent abnormalities were RB1 (n=3), PAX5 (n=4), and CDKN2B (n=3) deletions; AML-specific recurrent abnormalities were HOXA9 and HOXA10 (n=2) deletions and NOTCH1 duplication (n=2). Recurrent duplication of the ELK1 oncogene was observed in both ALL (n=2) and AML (n=3) cases. Our results demonstrate that oligo-array CGH (oaCGH) is an effective method for defining copy number alterations and identification of novel recurring unbalanced abnormalities. At least for now, however, the use of oaCGH for routine diagnosis still has some restrictions. PMID- 20193844 TI - Molecular cytogenetic analysis of Korean patients with Waldenstrom macroglobulinemia. AB - To compare the molecular cytogenetic characteristics between Waldenstrom macroglobulinemia (WM) and multiple myeloma (MM), we performed interphase fluorescent in situ hybridization (FISH) in Korean patients with WM and MM. Forty patients with WM and 132 patients with MM were enrolled onto the study. FISH was performed with seven different probes: 6q21, 6q23, CEP4, CEP9, immunoglobulin (IgH) breakapart, RB1 gene, and 1q25. Out of 22 WM patients, 4 (18%) had abnormal karyotypes, mainly structural changes on conventional karyotyping. After performing FISH for the available 29 cases, deletions of 6q23 and 6q21 were newly detected in 3 cases (10%). There was no other anomaly, including trisomy 4 in WM. No 6q deletion was observed in MM patients, but RB1 deletion was the most common change (45%), followed by IgH translocation (42%) and gain of 1q (38%). In conclusion, Korean WM patients had a low rate of 6q deletion (10%) and no trisomy 4. PMID- 20193846 TI - Homozygous deletion of the STK11/LKB1 locus and the generation of novel fusion transcripts in cervical cancer cells. AB - The STK11/LKB1 gene encodes a ubiquitously expressed serine/threonine kinase that is mutated in multiple sporadic cancers including non-small cell lung carcinomas, pancreatic cancers, and melanomas. LKB1 plays a role in multiple cellular functions including cell growth, cell cycle progression, metabolism, cell polarity, and migration. To date, only a limited number of studies have assessed the status of LKB1 in cervical cancers. Herein, we investigate DNA methylation, DNA mutation, and transcription at the LKB1 locus in cervical cancer cell lines. We identified homozygous deletions of 25-85kb in the HeLa and SiHa cell lines. Deletion breakpoint analysis in HeLa cells revealed that the deletion resulted from an Alu-recombination-mediated deletion (ARMD) and generated a novel LKB1 fusion transcript driven by an uncharacterized CpG island promoter located approximately 11kb upstream of LKB1. Although the homozygous deletion in SiHa cells removes the entire LKB1 gene and portions of the neighboring genes SBNO2 and c19orf26, this deletion also generates a fusion transcript driven by the c19orf26 promoter and composed of both c19orf26 and SBNO2 sequences. Further analyses of public gene expression and mutation databases suggest that LKB1 and its neighboring genes are frequently dysregulated in primary cervical cancers. Thus, homozygous deletions affecting LKB1 in cervical cancers may generate multiple fusion transcripts involving LKB1, SBNO2, and c19orf26. PMID- 20193848 TI - Mutations of NFKBIA in biopsy specimens from Hodgkin lymphoma. AB - To determine the possible alteration of the inhibitor kappaBalpha (HUGO-approved symbol, NFKBIA) gene in Chinese Hodgkin lymphoma (HL) patients, NFKBIA mRNA and protein expression in 22 primary HL patients were examined. Individual tumor cells were used for amplification to obtain the NFKBIA gene, and the polymerase chain reaction products were sequenced. Compared with reactive surrounding lymphocytes, inhibitor kappaBalpha protein (IkappaBalpha) expression was weaker in the cytoplasm of H-RS (Hodgkin and Reed-Sternberg) cells. NFKBIA mRNA was strongly expressed in H-RS cells from HL sections, and little was detected in the reactive surrounding lymphocytes. A total of 37.5% of the patients with HL had mutations in the NFKBIA gene. Some mutations possibly resulted in C-terminally truncated form of the IkappaBalpha. These data suggest that the impairment of the IkappaBalpha functions was produced during the pathogenesis of the tumor cell clone in Chinese HL patients. PMID- 20193847 TI - MTHFR C677T and A1298C variant genotypes and the risk of microsatellite instability among Iranian colorectal cancer patients. AB - Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the folate metabolic pathway. We aimed to test the hypothesis that C677T and A1298C variants of MTHFR predispose to microsatellite instable (MSI) colorectal cancer. We determined MTHFR genotypes in 175 sporadic colorectal cancer patients and a total of 231 normal controls in Shiraz, Southern Iran. Among the genotypes found in our samples, MTHFR CT and CT+TT were associated with increased risk for CRC incidence [odds ratio (OR)=2.4, 95% confidence interval (95%CI)=1.8-4.4; OR=2.4, 95%CI=1.6 3.6, respectively]. Double heterozygotes 677CT/1298AC and double homozygote 677TT/1298AA and 677CC/1298CC genotypes also showed a significantly increased risk of developing CRC compared with the wild-type 677CC/1298AA genotypes of the controls. Among the 151 tumors tested, 36 (23.8%) were MSI+. MSI was more common in proximal tumors (OR=10.4; 95%CI=3.9-27.8) and in smokers (OR=2.9; 95%CI=1.3 6.7). In a case-control comparison, the MTHFR 677CT+TT genotype was strongly associated with MSI (OR=2.6; 95%CI=1.3-5.3). Hypermethylation of mismatch repair genes was positively related with MSI incidence in these tumor series (P=0.00). Our data suggest that the MTHFR 677CT+TT variant genotype may be a risk factor for MSI+ cancer. PMID- 20193849 TI - Amplification and deletion of the ACHE and BCHE cholinesterase genes in sporadic breast cancer. AB - Increasing evidence supports the involvement of acetylcholinesterase and butyrylcholinesterase in cell proliferation control and differentiation, reinforcing the hypothesis that these enzymes might have an influence in tumorigenesis. It has already been shown that the cholinesterase genes are structurally altered or aberrantly expressed in a variety of tumor types. In this study, amplifications and deletions in the ACHE and BCHE genes were investigated in sporadic breast tumors using real-time polymerase chain reaction and the relative quantification method. The majority of the tumor tissues showed a notable number of both deletions and amplifications: 65.7% and 22.9%, respectively, in BCHE and 45.7% and 31.4%, respectively, in ACHE. Deletion of the ACHE gene was significantly correlated with amplification of the protooncogene ERBB2. Tumor size was significantly higher when the ACHE gene was amplified, and the total number of alterations (amplifications plus deletions) of the BCHE gene was positively correlated with tumor malignancy grade. PMID- 20193850 TI - High-resolution oligonucleotide array comparative genomic hybridization study and methylation status of the RPS14 gene in de novo myelodysplastic syndromes. AB - In myelodysplastic syndromes (MDS), close to one half of patients do not have any visible karyotypic change. In order to study submicroscopic genomic alterations, we applied high-resolution array comparative genomic hybridization techniques (aCGH) in 37 patients with de novo MDS. Furthermore, we studied the methylation status of the RPS14 gene in 5q deletion (5q21.3q33.1) in 24 patients. In all, 21 of the 37 patients (57%) had copy number alterations. The most frequent copy number losses with minimal common overlapping areas were 5q21.3q33.1 (21%) and 7q22.1q33 (19%); the most frequent copy number gain was gain of the whole chromosome 8 (8%). Recurrent, but less frequent copy number losses were detected in two cases each: 11q14.1q22.1, 11q22.3q24.2, 12p12.2p13.31, 17p13.2, 18q12.1q12.2, 18q12.3q21.3, 18q21.2qter, and 20q11.23q12; the gains 8p23.2pter, 8p22p23.1, 8p12p21.1, and 8p11.21q21.2 were similarly found in two cases each. No homozygous losses or amplifications were observed. The RPS14 gene was not methylated in any of the patients. PMID- 20193851 TI - Association of TP53 codon 72 polymorphism with cervical cancer risk in Chinese women. AB - Polymorphism at codon 72 of TP53, resulting in either the arginine (Arg) or proline (Pro) form of p53 (R72P), has been associated with the susceptibility to different cancers. To better understand the role of this polymorphism in cervical cancer etiology, we investigated the association between p53 R72P and cervical cancer risk in Chinese women from southern Han. Blood samples from 105 women with cervical cancer and from 140 female blood donors were collected. DNA from peripheral blood lymphocytes was extracted, and the exon 4 of TP53 was amplified by polymerase chain reaction and then digested by BstUI. We observed that the Arg/Arg genotype was significantly associated with an increased risk for cervical cancer [odds ratio (OR)=1.465, 95% confidence interval (95%CI)=1.04-2.138, P=0.02]. The relative frequency of each allele was 0.69 for Arg and 0.31 for Pro in patients with cervical cancer, and 0.60 for Arg and 0.40 for Pro in normal controls (P<0.05). Furthermore, we also found that the TP53 R72P polymorphism was not linked to tumor histologic type, histologic grade, lymph node metastases, and tumor size. These findings suggest that the TP53 codon 72 polymorphism may be implicated in cervical carcinogenesis, with the Arg/Arg genotype being associated with an increased susceptibility for this malignancy in the southern Chinese population. PMID- 20193852 TI - Identification of a patient with 7q32 deletion-associated acute myeloid leukemia and an incidental t(8;14). AB - Constitutional activation of the MYC proto-oncogene resulting from a t(8;14) has been demonstrated in approximately 80% of Burkitt lymphoma patients, but only in one case of acute myeloid leukemia (AML). We report on a 59-year-old female diagnosed with minimally differentiated AML (M0). Chromosome analysis demonstrated both a 7q deletion and a t(8;14). Fluorescence in situ hybridization studies confirmed MYC/IGH fusion in 35% of nuclei, but the translocation was atypical due to lack of immunoglobulin heavy chain (IGH) gene disruption. Such an atypical fusion has never been reported, so the effect on MYC regulation due to proximity of IGH regulatory elements is unknown. Real-time polymerase chain reaction analysis demonstrated no increase in MYC expression (P = 0.12). These results suggest that this novel translocation does not result in dysregulation of MYC expression, so this is likely to be a coincidental, benign finding in this patient. This is yet another example of a classic cytogenetic abnormality observed on conventional chromosome analysis which has no functional significance. PMID- 20193853 TI - Two distinct clonal populations in acute promyelocytic leukemia, one involving chromosome 17 and the other involving an isochromosome 17. AB - Acute promyelocytic leukemia (APL) is characterized by a t(15;17)(q22;q21) rearrangement. Additional chromosomal rearrangements have been reported in 25-40% of APL patients. The most common abnormality involving chromosome 17 is ider(17). Here we report the case of a patient with APL with isochromosome 17q combined with ider(17), confirmed by fluorescence in situ hybridization. Cytogenetic data strongly suggest that the involvement of chromosomes 15 and 17 in translocation occurs after formation of the isochromosome 17. The case reported here presents the novel finding of two separate clonal events apparently occurring at the same time in an APL patient. PMID- 20193854 TI - Paraganglioma in a 13-year-old girl: a novel SDHB gene mutation in the family? PMID- 20193855 TI - rs2981582 is associated with FGFR2 expression in normal breast. PMID- 20193856 TI - Publication bias in Kienbock's disease: systematic review. AB - PURPOSE: Kienbock's disease is considered rare and currently affects fewer than 200,000 people in the United States. Given the inherent challenges associated with researching rare diseases, the intense effort in hand surgery to treat this uncommon disorder may be influenced by publication bias in which positive outcomes are preferentially published. The specific aim of this project was to conduct a systematic review of the literature with the hypothesis that publication bias is present for the treatment of Kienbock's disease. METHODS: We conducted a systematic review of all available abstracts associated with published manuscripts (English and non-English) and abstracts accepted to the 1992 to 2004 American Society for Surgery of the Hand (ASSH) annual meetings. Data collection included various study characteristics, direction of outcome (positive, neutral/negative), complication rates, mean follow-up time, time to publication, and length of patient enrollment. RESULTS: Our study included 175 (124 English, 51 non-English) published manuscripts and 14 abstracts from the 1992 to 2004 annual ASSH meetings. Abstracts from published manuscripts were associated with a 53% positive outcome rate, which is lower than the 74% positive outcome rate found among other surgically treated disorders. Over the past 40 years, studies have become more positive (36% to 68%, p=.007) and are more likely to incorporate statistical analysis testing (0% to 55%, p<.001). Of the 14 abstracts accepted to ASSH, 11 were published in peer-reviewed journals. Ten of the 14 accepted abstracts were considered positive, and there was no significant difference in publication rate between studies with positive (n = 10) and negative (n = 4) outcomes (p>.999). CONCLUSIONS: The acceptance rate for negative outcomes studies regarding Kienbock's disease is higher than for other surgical disorders. This may indicate a relative decrease in positive outcome bias among published Kienbock's disease studies compared with other surgical disorders. However, the increasing positive outcome rate for published Kienbock's disease studies over time may suggest a trend of increasing publication bias among journals toward Kienbock's disease studies. PMID- 20193857 TI - The incidence of intrinsic and extrinsic ligament injuries in scaphoid waist fractures. AB - PURPOSE: To determine the incidence of associated intrinsic and extrinsic ligament injuries in patients with a nondisplaced or displaced scaphoid waist fracture. METHODS: During a 3-year period, a study of all scaphoid fractures was performed at our institution. Diagnosis was confirmed by plain radiographs, computed tomography, and magnetic resonance imaging. A 3-part anatomic classification was used to categorize the scaphoid fractures. The study population comprised 40 patients with 41 scaphoid waist fractures who had wrist arthroscopy for treatment and evaluation of the scaphoid fracture and associated carpal injuries. RESULTS: We observed fresh intrinsic ligament injuries in 34 of 41 wrists. In 29 cases, the scapholunate ligament was injured, with complete rupture occurring in 10 wrists. The lunotriquetral ligament was injured in 8 wrists, and the triangular fibrocartilage complex was injured in 11 wrists. Statistically, the number of intrinsic ligament injuries did not differ between nondisplaced and displaced scaphoid fractures (p> .30). CONCLUSIONS: In this study of acute scaphoid waist fractures, the overall incidence of associated ligament injuries was surprisingly high, at 34 of 41 wrists. Complete scapholunate ligament rupture was found in 10 of 41 wrists. This incidence is higher than previously reported and emphasizes the need for careful assessment of the intrinsic and extrinsic ligaments, particularly the scapholunate ligament, before deciding on treatment. PMID- 20193858 TI - A cost-utility analysis of nonsurgical management, total wrist arthroplasty, and total wrist arthrodesis in rheumatoid arthritis. AB - PURPOSE: Management of end-stage rheumatoid wrist disease remains controversial. Total wrist arthrodesis provides reliable pain relief and stability and is the most commonly applied management strategy. Total wrist arthroplasty is a motion preserving alternative that is gaining popularity. The purpose of this study was to perform a cost-utility analysis comparing nonsurgical management, total wrist arthroplasty, and total wrist arthrodesis for the rheumatoid wrist. METHODS: A time trade-off utility survey was developed to investigate patient and physician preferences for the potential outcomes of total wrist arthroplasty and total wrist arthrodesis. The study sample consisted of rheumatoid patients (N = 49) recruited as part of an ongoing prospective study and a national random sample of hand surgeons and rheumatologists (N = 109). A decision tree was created using utility values derived from the survey, and the expected quality-adjusted life years (QALYs) for each procedure were determined. Using the societal perspective, costs were based on the Medicare fee schedules for the Current Procedural Terminology codes associated with total wrist arthroplasty and total wrist arthrodesis and their potential complications. Costs per QALY were calculated and compared. RESULTS: Patients and physicians both showed a preference for surgical management over nonsurgical management. Application of cost data indicated that the incremental cost per additional QALY gained for total wrist arthroplasty over nonsurgical management was $2,281 and the incremental cost per QALY gained with total wrist arthroplasty over total wrist arthrodesis was $2,328, which is substantially less than the national standard of $50,000/QALY deemed acceptable for adoption. CONCLUSIONS: In the absence of rigorous outcome data, cost-utility analysis is a useful tool to guide treatment decisions. Total wrist arthroplasty and total wrist arthrodesis are both extremely cost-effective procedures. This study incorporated patient and physician utilities to demonstrate that total wrist arthroplasty has only a small incremental cost over the traditional total wrist arthrodesis procedure. Based on this economic model, total wrist arthroplasty may be worthy of further consideration, and cost should not be considered prohibitive. TYPE OF STUDY/LEVEL OF EVIDENCE: Decision Analysis II. PMID- 20193859 TI - Rotation in the interphalangeal thumb joint in vivo. AB - PURPOSE: To investigate rotation at the thumb interphalangeal (IP) joint in vivo to optimize the position of fusion of this joint. METHODS: Standardized photographs were taken of 176 thumbs end-on (88 asymptomatic volunteers) placed on a custom-made splint with the IP joint at 40 degrees . Three blinded investigators measured rotation at the IP joint from these photographs as the angle between a line aligning the eponychial folds and a line aligning the proximal phalanx condyles. Gender, age, hand dominance, and type of occupation of the asymptomatic vounteers were recorded. RESULTS: The variable pronation at the IP joint of the thumb (range, 0 degrees to 12 degrees) was significantly greater on the left than right (p=.001), although the actual difference was only 1 degrees . In subjects who performed fine dexterous work, thumb IP joint pronation was significantly less than in subjects who performed administrative or manual work (p=.009), but we found no statistical difference between manual and administrative groups. There was no correlation between thumb IP joint rotation and hand dominance (p=.2), age (p=.4) or gender (p=.5). CONCLUSIONS: There is functional pronation at the IP joint of the thumb. We propose that this should be taken into account when performing arthrodesis on the joint or designing a joint replacement. The degree of rotation may be associated with occupation. PMID- 20193860 TI - Percutaneous carpal tunnel release compared with mini-open release using ultrasonographic guidance for both techniques. AB - PURPOSE: To compare the outcomes of percutaneous carpal tunnel release (PCTR) and mini-open carpal tunnel release (mini-OCTR) using ultrasonographic guidance for both techniques. METHODS: We included 74 hands of 65 women with idiopathic carpal tunnel syndrome (age, 52-71 y; mean, 58 y). Thirty-five hands of 29 women had the PCTR (release with a device consisting of an angled blade, guide, and holder, along a line midway between the median nerve and ulnar artery (safe line) under ultrasonography (incision, 4 mm), and 39 hands of 36 women had the mini-OCTR (release along the safe line, distally under direct vision (incision, 1-1.5 cm) and proximally under ultrasonography, using a device consisting of a basket punch and outer tube. RESULTS: Assessments at 3, 6, 13, 26, 52, and 104 weeks showed no significant differences in neurologic recovery between the groups (p > .05). The PCTR group had significantly less pain, greater grip and key-pinch strengths, and better satisfaction scores at 3 and 6 weeks (p < .05), and less scar sensitivity at 3, 6, and 13 weeks (p < .05). There were no complications. CONCLUSIONS: The PCTR provides the same neurologic recovery as does the mini-OCTR. The former leads to less postoperative morbidity and earlier functional return and achievement of satisfaction. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III. PMID- 20193861 TI - Recurrence of giant cell tumors in the hand: a prospective study. AB - PURPOSE: Giant cell tumors of the hand remain a treatment dilemma: treatment requires a balance between extensive dissections for excision versus risk of recurrence. There is no consensus regarding how best to manage this balance. The purpose of this study was to identify the recurrence rate of giant cell tumors of the hand, as well as the correlation with the specific tissue type involved. METHODS: Two hundred thirteen cases of giant cell tumor of the hand were recorded in a prospectively designed, anatomically based registry that identified tumor location and surgical planes entered and tissues excised during the procedure. Mean follow-up was 51 months. Demographic and follow-up data were also tracked. The primary outcome tracked was tumor recurrence. Statistical analysis was conducted using chi-square analysis and the Fisher exact test to determine which perioperative and intraoperative factors were associated with tumor recurrence. RESULTS: There were 27 recurrences among our cases. Tumors involving the extensor tendon, flexor tendon, or joint capsule had the strongest correlation with recurrence: 12, 8, and 12 cases, respectively. Conversely, there was only one recurrence among the patients who did not have any involvement of either the flexor or extensor tendons or joint capsules. There was no association for involvement of skin, neurovascular bundle, tendon sheath, or bone at the initial excision. No identifiable preoperative or postoperative factors were linked to recurrence. CONCLUSIONS: Our study shows that direct involvement of the extensor tendons, flexor tendons, or joint capsule puts patients in a high-risk category with respect to recurrence. Based on these findings, efforts regarding close monitoring and the role of adjuvant therapy should be directed at the high-risk population. This information may be helpful for hand surgeons developing evidence based treatment algorithms for giant cell tumor in the hand. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic III. PMID- 20193862 TI - Nonsurgically treated terrible triad injuries of the elbow: report of four cases. AB - This case series describes 4 patients with terrible triad injury of the elbow (dislocation with fractures of the radial head and coronoid) who were treated nonsurgically. Following nonsurgical treatment in this select group of patients, the elbow was well aligned, and the patients regained good elbow function. Three of these 4 patients had good results. One patient had surgery for residual stiffness, ulnar neuropathy, and a radial head deformity. We conclude that, in selected terrible triad cases, when the elbow is well aligned and the radial head and coronoid fractures are relatively small and minimally displaced after closed reduction and there is no mechanical block to motion, patients might regain good elbow function without surgery. PMID- 20193863 TI - Low-level laser treatment. PMID- 20193864 TI - More experiments. PMID- 20193865 TI - Chemistry and mechanics of commonly used sutures and needles. PMID- 20193866 TI - Neuromas of the hand and upper extremity. AB - The painful neuroma is an often debilitating sequela of nerve injury about the hand. The exact pathophysiology of this condition is poorly understood. After sharp trauma to a peripheral nerve, as nerve ends try to connect with their end organs and "find" the distal nerve stump, fascicular escape and scarring can lead to the development of a painful neuroma. Painful neuromas can even be associated with blunt trauma or retraction of a nerve when the nerve is not actually divided. Green's definition of a neuroma is "the inevitable, unavoidable, and biologic response of the proximal stump after it has been divided in situations where regenerating axons are impeded from re-entering the distal stump."(1) A number of unknown factors make certain patients more susceptible to neuroma formation. In addition, certain nerves such as the superficial radial nerve are more prone to the development of a painful neuroma. Treatment of neuromas of the hand is important because they can be quite debilitating and painful, often preventing patients from continuing with their normal daily activities. There are a number of approaches to the painful neuroma, and the treatment plan must be tailored to the individual patient. PMID- 20193867 TI - Computer-assisted navigation of volar percutaneous scaphoid placement. PMID- 20193869 TI - Small finger metacarpal neck fractures. PMID- 20193871 TI - Two-dimensional versus three-dimensional computed tomography. PMID- 20193873 TI - Early onset alcohol dependence with high density of family history is not "male limited". AB - OBJECTIVE: Based on classical adoption studies, early onset type II alcoholism was originally described as "male limited." We examined the possible expression of this subtype in present day alcohol-dependent women. Detailed systematic assessment was obtained from 200 treatment-seeking alcohol-dependent women and 189 healthy population controls. Women fulfilling type II alcoholism criteria had higher alcoholism severity as measured by The Alcohol Use Disorders Identification Test and markedly higher use of illicit drugs. Both alcoholism subtypes scored higher than normal on anxiety and impulsivity traits, but type II women scored markedly higher on aggression subscales than either of the other groups. Importantly, density of family history was markedly higher in type II women, suggesting a higher heritability. Despite its original description as male limited, early onset alcoholism with high density of family history is likely to be a valid construct in women. Its recognition has important implications for diagnosis, treatment, and research. PMID- 20193874 TI - Diagnostic testing. Preface. PMID- 20193875 TI - Diagnostic testing: the search for real evidence. AB - A cornerstone in the quest for evidence is the use of diagnostic tests to determine the underlying issue for any symptoms seen in a patient. Clearly, diagnosis is not the final outcome in any patient scenario, but rather the beginning. The purpose of diagnostic testing is to provide evidence that will guide the health care provider in decision-making that will lead to achieving positive patient outcomes. This article provides a process by which a diagnostic test can be evaluated within the parameters of a patient condition. Through a thorough understanding of the test, the critical care nurse can be more effective in educating the patient, preparing the patient, and anticipating postprocedure nursing interventions for the patient undergoing diagnostic testing. PMID- 20193876 TI - Electrodiagnostic studies. AB - This article overviews electrodiagnostic tests that provide evidence-based data in the treatment and management of abnormalities in nerves and muscles. There is a focused review on cardiac tests, nerve-conduction tests, low-back pain tests, seizure and epilepsy tests, and obstructive sleep apnea electrodiagnostic tests. Case reports demonstrate how these electrophysiologic tests can provide specific data about the location and underlying causative factors of abnormalities in the nerves and muscles that routine diagnostic tests cannot differentiate. PMID- 20193877 TI - Endoscopy: a guide for the registered nurse. AB - As an invasive procedure, endoscopic studies require patient care and considerations that are very similar to minor surgical procedures. There are some general guidelines that are applicable to all endoscopic procedures, and there are special considerations that are dictated by the specific endoscopic procedure. It is important for the critical care nurse to understand the procedures because the differences and similarities of each procedure guide nursing actions to effect the best patient outcomes. PMID- 20193878 TI - Bronchoscopy: What critical care nurses need to know. AB - Although bronchoscopies have been performed for over a century and are relatively safe when practice guidelines are followed, they are invasive and a real source of anxiety and fear for the patient. The role of the critical care nurse is essential to a successful outcome. This article provides an overview of the main diagnostic and therapeutic indications, contraindications, and possible complications. Also discussed are patient education; patient and staff safety; and considerations before, during, and after the procedure. PMID- 20193879 TI - Radiographic studies in the critical care environment. AB - Critical care patients present with or develop conditions that require imaging with a variety of radiographic methods. Technological advances such as the introduction of digital imaging instead of screen-film radiography have improved image resolution, readability, management, and portability of results while maintaining confidentiality of patient information. Radiographic imaging in the critical care unit is an integral part of patient management. It is imperative that the critical care nurse be cognizant of radiographic studies and thus be able to collaborate with all health care providers in the administration of quality patient care. PMID- 20193880 TI - Angiography: From a patient's perspective. AB - In critical care, nurses are expected to react quickly to urgent and emergent situations. It is imperative that nurses have the ability to recognize signs and symptoms in patients that require diagnostic intervention. This article begins with a brief description of angiography and its role in the critical care environment. This is followed by a description and comparison of several modalities used to evaluate the cerebral and carotid vessels. A related case study, from a patient's perspective, provides the context for this discussion. PMID- 20193881 TI - Nuclear scan studies in critical care. AB - The field of nuclear cardiology has grown significantly over the past decade. This is a reflection of the value seen by providers in these safe and effective procedures. Nuclear scan studies are noninvasive and versatile in their usefulness. These studies assist in determining the likelihood of future cardiac events, guide approaches to revascularization, and assist in evaluation of the adequacy of revascularization procedures. Critical thinking and decision-making abilities are two key requirements for nurses in the critical care environment. Knowledge and understanding of the nuclear scan studies indicated for patients help nurses advocate for those in their care. PMID- 20193882 TI - Allergy skin testing: what nurses need to know. AB - Skin testing is a common procedure in any clinical setting. Critical care nurses will encounter skin testing in the inpatient and outpatient settings primarily to test for patient allergies to environmental factors, or allergies to certain medications. As there is a great deal of controversy about standard practices surrounding the different tests, information about various allergy tests and testing protocols is vital. Quality assurance standards should be met to ensure adequacy of the skin testing technique. Persons performing skin tests should undergo evaluation of their technique. To improve the predictive values of skin testing, and to ameliorate the incidence or severity of adverse affects, it is important for the critical care nurse to understand the dynamics of the test and the possible risks, along with variables that can confound the results. By doing this, nurses will improve not only patient outcomes related to the testing itself but also the value and reliability of the most effective diagnostic tool available for allergic disease. PMID- 20193883 TI - Ultrasound studies. AB - This article focuses on the clinical use of ultrasound with the obstetric, gynecologic, and trauma patient by reviewing recent case studies of the use of ultrasound for diagnostic purposes. The article also summarizes the American Institute of Ultrasound in Medicine (AIUM) guidelines for use in several types of patients. The AIUM is a multidisciplinary association whose purpose is to "advance the art and science of ultrasound in medicine and research through educational, scientific, literary, and professional activities." The organization provides guidelines in conjunction with many professional organizations, such as the American College of Cardiology and the American College of Obstetrics and Gynecology. AIUM also serves as an accrediting body for ultrasound practices. PMID- 20193884 TI - Centesis studies in critical care. AB - Critical care nurses have a vital role in caring for patients undergoing centesis studies. Any centesis procedure involves puncturing a body cavity, joint, organ, or space with a hollow needle to withdraw fluid. All centesis studies are invasive procedures, typically performed for either therapeutic or diagnostic purposes. Because there are a variety of centesis procedures that the critical care nurse might encounter, the following centesis procedures are discussed in depth: amniocentesis, arthrocentesis, lumbar puncture, paracentesis, pericardiocentesis, and thoracentesis. By becoming more familiar with each of these procedures, the critical care nurse gains confidence in caring for clients when these procedures are indicated. PMID- 20193885 TI - Urodynamics. AB - Voiding dysfunction has profound physical, emotional, and financial ramifications for patients and health care practitioners from all fields. The improvement of diagnostic testing in the area of voiding dysfunction, throughout decades, has resulted in improved patient outcomes. The components of urodynamic studies can allow practitioners an objective measurement to assist in making a correct diagnosis, hence appropriate interventions. An urodynamic study decreases the risk of a patient undergoing unnecessary surgical procedures. Urodynamics is an invasive procedure, though with the maintenance of sterile technique and patient education it is generally well tolerated with few adverse effects. PMID- 20193886 TI - Urinalysis: a review of methods and procedures. AB - There is much value in using urine as a diagnostic aid in the critical care setting. As a noninvasive source of data, urine reveals a wealth of information about the body's biochemical status. It is important for critical care nurses to understand the processes that occur in the renal system and to comprehend the depth of information that can be obtained through an analysis of urine. This discussion provides an overview of common urine tests and provides information for nurses about urine collection methods. The discussion will help the critical care nurse describe various urine test procedures, common urine collection methods, nursing interventions, and patient education important to each study. PMID- 20193887 TI - Stool studies: tried, true, and new. AB - Much information can be obtained about a patient's gastrointestinal and overall nutritional status through stool samples. Important infectious processes and neoplastic processes are initially identified through diagnostic tests and screening of stool samples. Although in some arenas they are a source of embarrassment and distaste, the value of correctly obtained samples is unquestionable. Patient collaboration with a critical care nurse is integral to obtaining stool samples. PMID- 20193888 TI - A community cancer center program: getting to the next level. PMID- 20193889 TI - Low oxygen-affinity hemoglobin solution increases oxygenation of partially ischemic tissue during acute anemia. AB - BACKGROUND: Maintenance of postsurgical tissue oxygenation depends on the ability of the specific tissue to recruit perfusion and oxygen (O(2)) supply. When native O(2)-carrying capacity is lacking, fluids to improve O(2)-carrying capacity based in hemoglobin (Hb) could prevent partially ischemic tissue hypoxia by increasing O(2) release from the remaining red blood cells. STUDY DESIGN: Responses to facilitated O(2) transport after exchange transfusion with polymerized bovine Hb (PBH) were studied in a chronic partially ischemic tissue model, induced by large feeding arteriole ligation during hamster window chamber model implantation. PBH effects in microvascular perfusion and tissue oxygenation were studied after exchange transfusion of 40% of animal's blood volume. Experimental groups were defined by the concentration of PBH used, ie, PBH at 13 g/dL (PBH13); PBH at 4 g/dL in albumin solution to matching colloidal osmotic pressure (COP) (PBH4); and no PBH, only albumin solution at matching COP (PBH0). RESULTS: Restitution of O(2)-carrying capacity with PBH13 increased blood pressure and produced vasoconstriction compared with PBH4 and PBH0. On the other hand, PBH4 maintained blood pressure without substantial vasoconstriction, increased tissue partial pressure of O(2), arteriolar O(2) supply, and extraction to the partially ischemic tissue compared with PBH0 and PBH13. CONCLUSIONS: Results suggest the existence of an optimal concentration of low O(2)-affinity acellular Hb to increase oxygenation of partially ischemic tissue during anemic conditions. PMID- 20193890 TI - Insurance coverage is associated with mortality after gunshot trauma. AB - BACKGROUND: Poor access to adequate health care coverage is associated with poor outcomes for many chronic medical conditions. We hypothesized that insurance coverage is also associated with mortality after gunshot trauma. STUDY DESIGN: The trauma records for gunshot victims and their insurance status were reviewed at our center from January 1998 to December 2007. Patient demographics (age, gender, race, and insurance coverage), injury severity, hospital care (operations and radiographic studies), and in-hospital mortality were analyzed. RESULTS: There were 2,164 gunshot trauma activations reviewed during the study period. One quarter (n = 544) of these patients had insurance and three-quarters (n = 1,620) were uninsured. The in-hospital mortality rate was significantly higher for uninsured patients than for insured patients (9% vs 6%, p = 0.02). After controlling for age, gender, race, and injury severity by logistic regression analysis, the odds ratio for death of uninsured patients was 2.2 (95% CI 1.1 to 4.5). Insured patients did not differ from uninsured patients with respect to mean Injury Severity Score ([ISS] 12.2 +/- 10.7 vs 12.6 +/- 12.4, p = 0.56); similar percentages of patients were severely injured (ISS 16 to 24, 17% vs 15%, p = 0.19) and most severely injured (ISS > 24, 15% vs 16%, p = 0.68). Insured patients did not differ from uninsured patients with respect to use of radiographic imaging (53% vs 50%, p = 0.15) or operative intervention (37% vs 35%, p = 0.35). CONCLUSIONS: Despite similar injury severity, uninsured trauma patients were more likely to die after gunshot injury than insured patients. This difference could not be attributed to demographics or hospital resource use. Insurance coverage may reflect the many social determinants of health. Improving the social determinants of health in patients affected by violent trauma may be a step toward improving outcomes after trauma. PMID- 20193891 TI - Quantitative weighting of postoperative complications based on the accordion severity grading system: demonstration of potential impact using the american college of surgeons national surgical quality improvement program. AB - BACKGROUND: To quantify severity of postoperative complications based on the Accordion Severity Grading System, determine the ability of severity grading to enhance National Surgical Quality Improvement Program (NSQIP) data, and develop an aggregate measure of severity of complications (the postoperative morbidity index). STUDY DESIGN: Forty-three surgical experts rated case vignettes containing postoperative complications on a severity scale. Vignettes were based on the Accordion Severity Grading System derived from the Toronto Severity Grading System. The system was adjusted using the expert severity scale results and applied to 1 year of NSQIP outcomes (1,857 patients, 704 complications) at a large tertiary care center. RESULTS: Experts initially distinguished the 6 grades of severity in a highly significant manner (t-test probabilities all < 0.005), with 1 exception. They rated reoperation and single-system organ failure without reoperation as similar, rather than distinct, in severity. The Accordion System was adjusted to reflect this. Distinction of grades thereafter was highly significant (t-test probabilities all < 0.005). Application to American College of Surgeons NSQIP data provided important novel insights. For example, complications in 6 American College of Surgeons NSQIP categories spanned 4 or more severity grades. Severity-weighted outcomes revealed that quantitatively the greatest burden of outcomes was due to wound infection, shock, and return to the operating room, which is not revealed by unweighted outcomes. Based on this information, an aggregate measure of severity of complications-the postoperative morbidity index-was proposed. CONCLUSIONS: Quantitative severity weighting of complications is feasible. Adjustment of American College of Surgeons NSQIP outcomes using this quantitative severity grading system provides uniquely informative representations of relative burdens of morbidities. PMID- 20193892 TI - Verified centers, nonverified centers, or other facilities: a national analysis of burn patient treatment location. AB - BACKGROUND: Although comprehensive burn care requires significant resources, patients may be treated at verified burn centers, nonverified burn centers, or other facilities due to a variety of factors. The purpose of this study was to evaluate the association between patient and injury characteristics and treatment location using a national database. STUDY DESIGN: We performed an analysis of all burn patients admitted to United States hospitals participating in the Healthcare Cost and Utilization Project over 2 years. Univariate and multivariate analyses were performed to identify patient and injury factors associated with the likelihood of treatment at designated burn care facilities. Definitive care facilities were categorized as American Burn Association-verified centers, nonverified burn centers, or other facilities. RESULTS: During the 2 years of the study, 29,971 burn patients were treated in 1,376 hospitals located in 19 participating states. A total of 6,712 (22%) patients were treated at verified centers, with 26% and 52% treated at nonverified or other facilities, respectively. Patients treated at verified centers were younger than those treated at nonverified or other facilities (33.1 years versus 33.7 years versus 41.9 years; p < 0.001) and had a higher rate of inhalation injury (3.4% versus 3.2% versus 2.2%; p < 0.001). Independent factors associated with treatment at verified centers include burns to the head or neck (relative risk [RR], 2.4; CI, 2.1 to 2.7), hand (RR, 1.8; CI, 1.6 to 1.9), electrical injury (RR, 1.4; CI, 1.2 to 1.7), and fewer comorbidities (RR, 0.55; CI, 0.5 to 0.6). CONCLUSIONS: More than two-thirds of significantly burned patients are treated at nonverified burn centers in the United States. Many patients meeting American Burn Association criteria for transfer to a burn center are being treated at nonburn center facilities. PMID- 20193893 TI - Patients benefit while surgeons suffer: an impending epidemic. AB - BACKGROUND: The widely held belief that laparoscopy causes greater strain on surgeons' bodies than open surgery is not well documented in scope or magnitude. In the largest North American survey to date, we investigated the association of demographics, ergonomics, and environment and equipment with physical symptoms reported by laparoscopic surgeons. STUDY DESIGN: There were 317 surgeons identified as involved in laparoscopic practices who completed the online survey. Data collected from this comprehensive 23-question survey were analyzed using chi square. RESULTS: There were 272 laparoscopic surgeons (86.9%) who reported physical symptoms or discomfort. The strongest predictor of symptoms was high case volume, with the surprising exceptions of eye and back symptoms, which were consistently reported even with low case volumes. High rates of neck, hand, and lower extremity symptoms correlated with fellowship training, which is strongly associated with high case volume. Surprisingly, symptoms were little related to age, height, or practice length. The level of surgeons' awareness of ergonomic guidelines proved to be somewhere between slightly and somewhat aware. A substantial number of respondents requested improvements in regard to both the positioning and resolution of the monitor. CONCLUSIONS: Far beyond previous reports of 20% to 30% incidence of occupational injury, we present evidence that 87% of surgeons who regularly perform minimally invasive surgery suffer such symptoms or injuries, primarily high case load-associated. Additional data accrual and analysis are necessary, as laparoscopic procedures become more prevalent, for improvement of surgeon-patient and surgeon-technology interfaces to reverse this trend and halt the epidemic before it is upon us. PMID- 20193894 TI - Palpable presentation of breast cancer persists in the era of screening mammography. AB - BACKGROUND: The aim was to describe cancer detection method and frequency of screening mammography in women undergoing breast cancer surgery in 2000. STUDY DESIGN: Patients undergoing breast cancer surgery were identified through an institutional database. Charts were reviewed to determine presentation at time of diagnosis. Presentation was coded "palpable" if the woman presented with a breast complaint or if a new mass was detected on examination versus "screening" if detected on screening mammogram. RESULTS: Five hundred ninety-two breast cancers were identified: 57% presenting by screening and 43% palpable. Cancer was more likely to present as palpable in patients with no previous screening mammography compared with those with previous mammography (67% versus 39%; p = 0.0002). Patients with palpable presentation were younger than those with screen-detected cancer (mean age 57 versus 62 years; p < 0.0001). CONCLUSIONS: Despite the frequent use of screening mammography, 43% of breast cancers presented as a palpable mass or otherwise symptomatic presentation. PMID- 20193895 TI - Factors dominating choice of surgical specialty. AB - BACKGROUND: There has been much focus on factors influencing medical students' career choice, prompted by such concerns as a sufficient future surgical workforce, declining applicant pool, changing gender composition, and a cultural shift in values and priorities. Once in a surgical residency, there are little data on factors influencing general surgery (GS) residents' final specialty choice. STUDY DESIGN: A survey instrument was developed and content validated in conjunction with the Association of American Medical Colleges Center for Workforce Studies. The final instrument was distributed electronically between March 24 and May 2, 2008, through 251 GS program directors to all ACGME accredited GS residents (n = 7,508). RESULTS: Response rate was 29% (2,153 residents; 89% programs). Half of GS residents remained undecided about specialty choice through the 2(nd) year, declining to 2% by year 5. Of the two-thirds who decided on a specialty, 16.5% chose to remain in GS, 14.6% chose plastics, 9.3% cardiothoracic, and 8.5% vascular. The specialty choice factors most likely to be very important were type of procedures and techniques, exposure to positive role model, and ability to balance work and personal life. Relative importance of factors in specialty choice varied by gender and chosen specialty. Mentors play a key role in specialty choice (66% decided had mentors versus 47% undecided). Work schedule was the most frequently selected shortcoming in every specialty except plastics. Cardiothoracic surgery followed by GS had the highest shortcomings. CONCLUSIONS: The majority of GS residents plan to subspecialize. Three factors dominate specialty choice. Faculty need to understand their impact potential to modify or change perceptions of their specialty. PMID- 20193896 TI - Influence of double-gloving on manual dexterity and tactile sensation of surgeons. AB - BACKGROUND: Double-gloving in the performance of surgical procedures has been demonstrated to reduce the frequency of blood contact with the hands of members of the surgical team. Concerns persist that double-gloving can compromise the dexterity and tactile sensitivity of the surgeon. STUDY DESIGN: Fifty-three surgeons and surgeons-in-training volunteered at the Clinical Congress of the American College of Surgeons and were studied using the Purdue Pegboard test and a standard 2-point discrimination test to compare no gloves, a single pair of gloves, and double-gloving on manual dexterity and tactile sensitivity. Categorical and continuous variables were identified, general linear prediction models were computed, and the influence of glove status was analyzed as an independent variable. Monte Carlo simulation was employed to validate conclusions. RESULTS: Gender, specialty, and handedness did not affect prediction models. Glove status did not affect dexterity performance scores (p = 0.57) after accounting for the influence of age on score variation (p < 0.001). Comparing ulnar and radial surfaces of the index finger for 2-point discrimination, no difference was detected between trials (p < 0.66), nor was an interaction effect detected with glove status (p = 0.40). Monte Carlo simulations validated the apparent absence of differences. CONCLUSIONS: Double-gloving does not have a substantial impact on manual dexterity or tactile sensitivity when compared with no gloves or single-gloving in this study. PMID- 20193897 TI - High incidence of technical errors involving the EEA circular stapler: a single institution experience. AB - BACKGROUND: The use of stapling devices is now widespread in colorectal resections. However, the incidence and clinical consequence of technical error involving the circular stapler are still poorly characterized. STUDY DESIGN: We reviewed the operative reports and Web-based charts for all colon and rectal resections performed at our institution that used a circular stapler. Technical error was defined as any deviation from the normal technical performance of the circular stapler, including, but not limited to, surgeon misfiring, incomplete anastomosis (inadequate donuts or staple line defects), and primary device failure. The unpaired t- and chi-square tests were used for statistical analysis; p < 0.05. RESULTS: There were 349 colorectal resections performed and 67 (19%) featured a technical error. Thirty-two resections (9%) included an anastomotic error. The control group (n = 282) and the error group (n = 67) were comparable with regard to leaks, reoperation, suture line strictures, and hospital stay. The malfunction group had higher incidences of proximal diversions (34% versus 16%; p = 0.0003), ileus (24% versus 8%; p = 0.002), gastrointestinal bleeding (4% versus 0.4%; p = 0.023), and transfusion requirements (13% versus 4%; p = 0.004). Although proximal diversions in the error cohorts were also less likely to be planned (p < 0.001), reversal rates were similar in both groups (p = 0.28). CONCLUSIONS: The incidence of technical error involving the circular stapler is considerable. Technical error was found to be associated with a significantly higher risk of gastrointestinal bleeding, transfusions, and unplanned proximal diversions. PMID- 20193898 TI - Pre-transplant overweight and obesity do not affect physical quality of life after kidney transplantation. AB - BACKGROUND: Recent studies demonstrate that obesity does not affect survival after kidney transplantation. However, overweight and obesity impair health related quality of life (HRQOL) in patients with chronic illnesses. We wished to examine the effects of pre-transplant overweight and obesity on post-transplant physical HRQOL in kidney transplant recipients. STUDY DESIGN: Patient-reported HRQOL data were systematically collected in kidney transplant recipients receiving post-transplant follow-up at Vanderbilt Transplant Center. Patients who received kidney transplants between 1998 and 2008, had at least 1 post-transplant physical component summary (PCS) measurement, and did not receive other solid organ transplants were included in this retrospective cohort study. Pre transplant body mass index was stratified as normal, overweight, obese class I, and obese class II/extremely obese. HRQOL was measured primarily with the PCS scale of the Medical Outcomes Study Short Form 36 Health Survey. Multivariate linear and logistic regression models were used to test the effects of body mass index and demographic and clinical covariates on post-transplant HRQOL. RESULTS: The study cohort included 464 adults (mean body mass index 27.5 +/- 5.1; range 18.5 to 47.4). After controlling for gender (p = 0.148), pre-transplant dialysis (p = 0.003), previous kidney transplantation (p = 0.255), donor type (p = 0.455), steroid avoidance immunosuppression (p = 0.070), and follow-up time (p = 0.352), there was no effect of pre-transplant overweight or obesity on post-transplant PCS (all p > or = 0.112). Kidney transplant recipients who did not require dialysis pre-transplant and those who were managed with steroid avoidance after transplantation were more likely to achieve post-transplant PCS scores at or above the general population average (both p < or = 0.011). CONCLUSIONS: Pre transplant overweight and obesity do not affect physical quality of life after kidney transplantation. PMID- 20193899 TI - Proximal esophageal pH monitoring: improved definition of normal values and determination of a composite pH score. AB - BACKGROUND: Patients with respiratory and laryngeal symptoms are commonly referred for evaluation of reflux disease as a potential cause. Dual-probe pH monitoring is often performed, although data on normal acid exposure in the proximal esophagus are limited because of the small number of normal subjects and inconsistent placement of the proximal pH sensor in relation to the upper esophageal sphincter. We measured proximal esophageal acid exposure using dual probe pH and calculated a composite pH score in a large number of asymptomatic volunteers to better define normal values. STUDY DESIGN: Eighty-one normal subjects free of reflux, laryngeal, or respiratory symptoms were recruited. All had video esophagraphy to exclude hiatal hernia. Esophageal pH monitoring was performed using 1 of 3 different dual-probe catheters with sensors spaced 10, 15, or 18 cm apart. The standard components of esophageal acid exposure were measured, excluding meal periods. A composite pH score for the proximal esophagus was calculated using these components. RESULTS: The final study population consisted of 59 (49% male) subjects, with a median age of 27 years. All had normal distal esophageal acid exposure and no hiatal hernia. The 95(th) percentile values for the percent time the pH was < 4 for the total, upright, and supine periods were 0.9%, 1.2%, and 0.4%, respectively. The 95(th) percentile for the number of reflux episodes was 24 and for the calculated proximal esophageal composite pH score was 16.4. CONCLUSIONS: In a large population of normal subjects, we have defined the normal values and calculated a composite pH score for proximal esophageal acid exposure. The total percent time pH < 4 was similar to previously published normal values, but the number of reflux episodes was greater. PMID- 20193900 TI - Treatment options for squamous cell cancer of the esophagus: a systematic review of the literature. PMID- 20193901 TI - Primary chest wall tumors. PMID- 20193902 TI - Management of biliary tract disease during pregnancy. PMID- 20193903 TI - Treating recurrent inguinal hernia. PMID- 20193905 TI - Management of recurrent inguinal hernias. PMID- 20193907 TI - Image-guided treatment of breast cancer. PMID- 20193909 TI - Equitation science, rider effects, saddle and back problems in horses: can technology provide the answer? PMID- 20193910 TI - Long-term pain in cats: how much do we know about this important welfare issue? AB - PRACTICAL RELEVANCE: Long-term pain in cats is an important welfare issue but is often overlooked and undertreated. AUDIENCE: All practitioners are faced with cats that require analgesic intervention to improve their quality of life. PATIENT GROUP: Any cat may potentially experience long-term pain and discomfort. Degenerative joint disease and diabetic-related pain is more common in middle aged or older individuals, whereas persistent postsurgical pain can occur at any age and is seen in young cats following onychectomy. EVIDENCE BASE: Robust evidence on long-term pain issues in cats - specifically, relating to prevalence, etiology, and treatment protocols and outcomes - is missing from the veterinary literature. The aim of this review is to summarise the current state of knowledge. In doing so, it takes a practical approach, highlighting the obvious, and some not so obvious, causes of long-term pain in cats; some aspects that warrant closer attention; our ability to recognize pain and monitor how this impacts on quality of life; and today's treatment options. PMID- 20193911 TI - DJD-associated pain in cats: what can we do to promote patient comfort? AB - PRACTICAL RELEVANCE: Degenerative joint disease (DJD) has a high prevalence in domestic cats and can be associated with pain. This pain should be addressed wherever possible. AUDIENCE: All practitioners are faced with cats that are mobility impaired due to DJD-associated pain. PATIENT GROUP: Cats of all ages and breeds, and either sex, can experience DJD-associated discomfort. CLINICAL CHALLENGES: Recognizing DJD and assessing DJD-associated pain in cats is a challenge. Owner observations of activity and behavior, careful observation and a logical and thorough orthopedic evaluation are key. Current understanding of the etiology of feline DJD and the mechanisms of DJD-associated pain is incomplete, making the rational choice of treatments a further challenge. EVIDENCE BASE: Evidence is emerging on the prevalence of feline DJD, and on how to assess the associated pain and mobility impairment. There is a lack of information on the etiology of feline DJD and a relative lack of data on the efficacy of putative treatments. PMID- 20193912 TI - Early detection, aggressive therapy: optimizing the management of feline mammary masses. AB - AIMS: This article reviews the incidence, etiology, diagnosis, treatment and prognosis of mammary tumors in cats. PRACTICAL RELEVANCE: Approximately 80% of feline mammary masses are malignant, with adenocarcinoma being the most common tumor type. Early diagnosis is, therefore, essential to improve the prognosis and quality of life of affected cats. TREATMENT APPROACHES: Surgery is the most widely used treatment for malignant tumors. However, as mammary tumors are often advanced and metastasis has already occurred by the time of diagnosis, surgery routinely does not provide a cure. Ovariohysterectomy or hormonal therapy are the treatments of choice for fibroadenomatous hyperplasia (the most common benign mass) and usually lead to a successful outcome. PMID- 20193913 TI - Acute vomiting in cats: rational treatment selection. AB - PRACTICAL RELEVANCE: The control of nausea and vomiting in cats is important in order to prevent the development of food aversion, anorexia (with its associated complications of weight loss and dehydration), and hepatic lipidosis. CLINICAL CHALLENGES: There are several antiemetic drugs that are clinically effective in cats. Making a rational choice from the available options requires knowledge of the likely cause of the vomiting, and the mechanisms of action and side effects of each drug. For example, a drug such as prochlorperazine, which can cause sedation, may be a useful first-line choice in a hospitalized cat that requires mild sedation to be handled, but would be undesirable in a critically ill cat. AUDIENCE: For companion animal and feline practitioners, the vomiting cat is a common presentation. EVIDENCE BASE: The guidance provided in this review draws on the findings of clinical trials in humans, experimental studies in cats, some clinical trials in cats, and clinical experience. PMID- 20193915 TI - Acquired motor neuron loss causing severe pelvic limb contractures in a young cat. AB - PRESENTATION: This report describes a kitten with paraplegia and extensor rigidity of the pelvic limbs associated with motor neuron loss and chronic denervation of skeletal muscle. Persistent skeletal muscle atrophy and degeneration had resulted in immobile stifle and hock joints and severe pelvic limb rigidity consistent with a neurogenic form of arthrogryposis. Both pelvic limbs were equally affected and the kitten showed no signs of pain. INVESTIGATIONS: Electromyography identified spontaneous activity in the pelvic limbs. Muscle and peripheral nerve biopsies showed pathology consistent with denervation. On necropsy, 3 weeks after admittance, severe degenerative changes including axonal necrosis and myelin degeneration were confirmed in the lumbar spinal cord. CLINICAL RELEVANCE: There are very few descriptions of feline motor neuron degeneration in the literature and obtaining an ante-mortem diagnosis is difficult. Although an inherited disorder cannot be ruled out, a condition acquired congenitally in utero or postnatally was suspected in this case. PMID- 20193914 TI - Localised microsphaeropsis arundinis infection of the subcutis of a cat. AB - CLINICAL PRESENTATION AND DIAGNOSIS: An 11-year-old spayed domestic crossbred cat was presented for two focal lesions affecting the subcutis that developed 3 weeks after a cat fight. Lesions consisted of swelling of the subcutaneous tissues over the bridge of the nose and a focal swelling of the dewclaw pad of the left thoracic limb. Both lesions were attributable to localised infections with the unusual fungal pathogen Microsphaeropsis arundinis, based on direct microscopy of smear cytology, histology, fungal culture, internal transcribed spacer-polymerase chain reaction (ITS-PCR) and sequence analysis of formalin-fixed tissue and colonial material from primary culture. TREATMENT: The dewclaw pad lesion resolved following cytoreductive surgery and a course of itraconazole (50 mg once daily). The nasal bridge lesion was treated in a similar fashion, except that a range of different antifungal agents (itraconazole, fluconazole, posaconazole) were used, administered sequentially. Despite this, the infection recurred on three subsequent occasions, and the cat has been prescribed indefinite azole therapy. PRACTICAL RELEVANCE: This report of a refractory localised infection of the subcutis in an apparently immune-competent cat illustrates the value of using a mycology reference laboratory, and PCR and sequence analysis for organism identification, and the therapeutic potential of new antifungal agents such as posaconazole. PMID- 20193916 TI - Health care legislation: a cautionary tale of unintended consequences. PMID- 20193917 TI - Between a rock and a hard place... PMID- 20193918 TI - Appropriateness Criteria and patient expectations. PMID- 20193919 TI - Rodney Dangerfield, MD, DABR. PMID- 20193920 TI - Extracardiac and extracolonic findings: extra important. PMID- 20193921 TI - Responding to an accusation of malpractice. PMID- 20193922 TI - Why radiologists lose their hospital contracts: is your contract secure? AB - Previously, a hospital contract meant tenure for the incumbent group of radiologists; however, those days are long gone. Exclusive contracts have morphed into exclusive contracts with carve-outs. Turf erosion has become a fact of life for radiology practices. Now radiologists are losing their hospital contracts in record numbers. Group size, though helpful for a variety of reasons, does not ensure that a practice will be secure in its hospital setting. The reasons that groups lose their hospital contracts are varied, and in this paper, the author discusses the most common ones. Suggestions to help practices avoid this unfortunate fate are presented. PMID- 20193923 TI - Trends in PET scanner ownership and leasing by nonradiologist physicians. AB - PURPOSE: The aim of this study was to examine growth trends in ownership or leasing of private-office PET scanners by nonradiologist physicians. MATERIALS AND METHODS: The Medicare Part B Physician/Supplier Procedure Summary Master Files for 2002 through 2007 were used to collect the following data for each PET related Current Procedural Terminology((R)) code: 1) annual procedure volume, 2) places of service for the procedures, and 3) specialties of the physicians filing the claims. To determine ownership or leasing, only technical and global claims that occurred in the nonhospital, private-office setting were included in the study. Professional component-only claims were not included. Procedure volume and growth trends were compared between radiologists and other specialties. RESULTS: Between 2002 and 2007, radiologist-owned Medicare PET scans increased by 259%, whereas nonradiologist-owned or nonradiologist-leased scans grew by 737%. Five specialty groups accounted for 95% of all nonradiologist PET volume in 2007: internal medicine subspecialties (28,324 studies in 2007), medical oncology (14,320 studies), cardiology (13,724 studies), radiation oncology (9,563 studies), and primary care (2,398 studies). In 2002, of all Medicare PET examinations performed on units owned or leased by physicians, the share for nonradiologists was 13%; their share rose to 24% in 2007. CONCLUSION: Although a large percentage of PET scans in private offices are done by radiologists, the growth rate among nonradiologists was far higher between 2002 and 2007 (259% for the former, 737% for the latter). The disproportionately rapid growth of PET scans performed on units owned by nonradiologists raises concern about self referral at a time when policymakers are struggling to contain costs and reduce radiation exposure. PMID- 20193924 TI - Analysis of appropriateness of outpatient CT and MRI referred from primary care clinics at an academic medical center: how critical is the need for improved decision support? AB - PURPOSE: The aim of this study was to retrospectively analyze a large group of CT and MRI examinations for appropriateness using evidence-based guidelines. METHODS: The authors reviewed medical records from 459 elective outpatient CT and MR examinations from primary care physicians. Evidence-based appropriateness criteria from a radiology benefit management company were used to determine if the examination would have met criteria for approval. Submitted clinical history at the time of interpretation and clinic notes and laboratory results preceding the date of the imaging study were examined to simulate a real-time consultation with the referring provider. The radiology reports and subsequent clinic visits were analyzed for outcomes. RESULTS: Of the 459 examinations reviewed, 284 (62%) were CT and 175 (38%) were MRI. Three hundred forty-one (74%) were considered appropriate, and 118 (26%) were not considered appropriate. Examples of inappropriate examinations included brain CT for chronic headache, lumbar spine MR for acute back pain, knee or shoulder MRI in patients with osteoarthritis, and CT for hematuria during a urinary tract infection. Fifty-eight percent of the appropriate studies had positive results and affected subsequent management, whereas only thirteen percent [corrected] of inappropriate studies had positive results and affected management. CONCLUSION: A high percentage of examinations not meeting appropriateness criteria and subsequently yielding negative results suggests a need for tools to help primary care physicians improve the quality of their imaging decision requests. In the current environment, which stresses cost containment and comparative effectiveness, traditional radiology benefit management tools are being challenged by clinical decision support, with an emphasis on provider education coupled with electronic order entry systems. PMID- 20193925 TI - Augmenting the impact of technology adoption with financial incentive to improve radiology report signature times. AB - PURPOSE: Radiology report signature time (ST) can be a substantial component of total report turnaround time. Poor turnaround time resulting from lengthy ST can adversely affect patient care. The combination of technology adoption with financial incentive was evaluated to determine if ST improvement can be augmented and sustained. METHODS: This prospective study was performed at a 751-bed, urban, tertiary care adult teaching hospital. Test-site imaging volume approximated 48,000 examinations per month. The radiology department has 100 trainees and 124 attending radiologists serving multiple institutions. Over a study period of 4 years and 4 months, three interventions focused on radiologist signature performance were implemented: 1) a notification paging application that alerted radiologists when reports were ready for signature, 2) a picture archiving and communications systems (PACS)-integrated speech recognition report generation system, and 3) a departmental financial incentive to reward radiologists semiannually for ST performance. Signature time was compared before and after the interventions. Wilcoxon and linear regression statistical analyses were used to assess the significance of trends. RESULTS: Technology adoption (paging plus speech recognition) reduced median ST from >5 to <1 hour (P < .001) and 80th percentile ST from >24 to 15 to 18 hours (P < .001). Subsequent addition of a financial incentive further improved 80th-percentile ST to 4 to 8 hours (P < .001). The gains in median and 80th-percentile ST were sustained over the final 31 months of the study period. CONCLUSIONS: Technology interventions coupled with financial incentive can result in synergistic and sustainable improvement in radiologist report-signing behavior. The addition of a financial incentive leads to better performance than that achievable through technology alone. PMID- 20193926 TI - Added value of selected images embedded into radiology reports to referring clinicians. AB - PURPOSE: The aim of this study was to evaluate the added utility of embedding images for findings described in radiology text reports to referring clinicians. METHODS: Thirty-five cases referred for abdominal CT scans in 2007 and 2008 were included. Referring physicians were asked to view text-only reports, followed by the same reports with pertinent images embedded. For each pair of reports, a questionnaire was administered. A 5-point, Likert-type scale was used to assess if the clinical query was satisfactorily answered by the text-only report. A "yes or-no" question was used to assess whether the report with images answered the clinical query better; a positive answer to this question generated "yes-or-no" queries to examine whether the report with images helped in making a more confident decision on management, whether it reduced time spent in forming the plan, and whether it altered management. The questionnaire asked whether a radiologist would be contacted with queries on reading the text-only report and the report with images. RESULTS: In 32 of 35 cases, the text-only reports satisfactorily answered the clinical queries. In these 32 cases, the reports with attached images helped in making more confident management decisions and reduced time in planning management. Attached images altered management in 2 cases. Radiologists would have been consulted for clarifications in 21 and 10 cases on reading the text-only reports and the reports with embedded images, respectively. CONCLUSIONS: Providing relevant images with reports saves time, increases physicians' confidence in deciding treatment plans, and can alter management. PMID- 20193927 TI - Supporting the academic mission. AB - The mission of an academic radiology department includes not only high-quality patient care, but also the educating of a broad variety of health care professionals, the conducting of research to advance the field, and volunteering service to the medical center and our professional societies. While funding is available for the research and educational aspects, it is insufficient to cover the actual costs. Furthermore, it is becoming increasingly difficult to make up the deficit by using a portion of the clinical revenues. Development and revenues derived from intellectual property are becoming essential to support the academic mission. PMID- 20193928 TI - Flying in the plane you service: patient-centered radiology. AB - If you were about to undergo a radiologic procedure, what 5 things would you want? The authors propose a construct for patient-centered radiology. Five wishes of a prospective radiology patient are described: 1) the information to choose, 2) the right examination, 3) a safe examination, 4) effective communication of correctly interpreted results, and 5) a fair price. The authors posit that the American practice of radiology would be considerably different if our profession practiced patient-centered radiology. PMID- 20193929 TI - Outsourcing off-hour imaging services. PMID- 20193930 TI - Ruminations from a European chairperson. PMID- 20193931 TI - Creating a new curriculum to prepare for the 2013 ABR testing changes: an academic residency perspective. PMID- 20193934 TI - From novice to expert: obstacles and opportunities for residency programs. PMID- 20193935 TI - (In search of) excellence in physiatry: what can we learn from our patients. PMID- 20193936 TI - Prescriptions for optimal healing. PMID- 20193937 TI - Risk factors for plantar fasciitis among assembly plant workers. AB - OBJECTIVE: The objective of this study was to determine the relative contributions of work activity (time spent standing, walking, or sitting), floor surface characteristics, weight, body mass index, age, foot biomechanics, and other demographic and medical history factors to the prevalence of plantar fasciitis. DESIGN: A cross-sectional observational study design was used. SETTING: The study site was an automobile engine assembly plant. PARTICIPANTS: Full-time employees of the assembly plant who had been working at least 6 months. ASSESSMENT OF RISK FACTORS: The independent variables included baseline demographics, medical history, ergonomic exposures, psychosocial factors, discomfort ratings, shoe characteristics, and foot biomechanics. MAIN OUTCOME MEASUREMENTS: The dependent variable was the finding of plantar fasciitis on physical examination. RESULTS: The study demonstrated that forefoot pronation on physical examination, high metatarsal pressure on the gait assessment, increasing time spent standing on hard surfaces, increased time spent walking, medium tenure at the plant, and an increased number of times getting in and out of the vehicle (for the truck/forklift drivers) increased the risk of presenting with plantar fasciitis. Rotation of shoes during the work week was found to reduce the risk of presenting with plantar fasciitis. Increased supervisor support showed a trend toward reducing the prevalence of plantar fasciitis. CONCLUSIONS: Plantar fasciitis is relatively common in the manufacturing setting. These findings suggest several options for primary and secondary prevention strategies. Shoe rotation may be an effective strategy that may be used as either a primary or secondary strategy. The use of shoe orthoses with a medial longitudinal arch and metatarsal pad may be used as a preventive or treatment strategy. Work stations that decrease the percentage of time walking or standing on hard surfaces (eg, allowing workers to alternate between sitting and standing postures or providing cushioning mats for concrete surfaces) may lower the risk for plantar fasciitis. PMID- 20193938 TI - Implementation of peer review into a physical medicine and rehabilitation program and its effect on professionalism. AB - OBJECTIVE: To examine the effects of implementing a peer review evaluation system on residents' attitudes and perceptions of professionalism, a core competency of the Accreditation Council for Graduate Medical Education (ACGME), in a Physical Medicine and Rehabilitation (PM&R) program. DESIGN: Four classes of residents were divided prospectively into a control and an intervention group. All residents were asked to complete a survey regarding their attitudes and perceptions on both peer review and professionalism. Only 2 of these classes participated in a newly adopted peer review evaluation system, after which time all participants were again asked to fill out the surveys. SETTING: Residents were from a PM&R residency program at an urban tertiary care medical center. PARTICIPANTS: All residents who completed the entire survey preintervention and postintervention were included. METHODS: The intervention was the introduction of peer review into residents' evaluation assessments. All residents filled out a survey with questions relating to peer review and professionalism before and after this intervention. MAIN OUTCOME MEASUREMENTS: Outcomes include understanding how residents perceive various attributes of professionalism, peer review, and the interconnection of the 2. RESULTS: Data analysis using SPSS was performed using survey scores for 46 residents preintroduction and postintroduction of a peer review evaluation system. Analysis revealed that residents who participated in the peer review process were more likely to agree that certain aspects of daily patient care, behaviors, and concepts were components of professionalism. However, they continued to believe that residents are ultimately not responsible for their colleagues' professionalism and that peer review might be harmful to a residency program. CONCLUSION: This study introduces an interesting dichotomy. Peer review clearly influences resident outlook on professionalism and yet there is a high suspicion regarding its implementation. If appropriately implemented, peer review may be a potent method of enhancing the education of this ACGME requirement. PMID- 20193939 TI - Reliability of gait performance tests in individuals with late effects of polio. AB - OBJECTIVE: To assess the reliability of 4 gait performance tests in individuals with late effects of polio. DESIGN: An intrarater (between occasions) test-retest reliability study. SETTINGS: University hospital. PARTICIPANTS: Thirty men and women (mean age 63 +/- 6.4 years) with clinically and electrophysiologically verified late effects of polio. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: The Timed "Up & Go" test, the Comfortable and the Fast Gait Speed tests, and the 6-Minute Walk test were assessed 7 days apart. Reliability was evaluated with the intraclass correlation coefficient (ICC(2,1)), the mean difference between the test sessions (d), and the 95% confidence intervals for d, the standard error of measurement (SEM and SEM%), the smallest real difference (SRD and SRD%) and the Bland & Altman graphs. RESULTS: Test-retest agreements were high (ICC(2,1) 0.82-0.97) and measurement errors generally small. The standard error of measurement (SEM%), representing the smallest change that indicates a real (clinical) improvement for a group of individuals, was small (4% 7%). The smallest real difference (SRD%), representing the smallest change that indicates a real (clinical) improvement for a single individual also was small (12%-21%). CONCLUSION: These commonly used gait performance tests are highly reliable and can be recommended to evaluate improvements in various aspects of gait performance in groups of individuals as well as single individuals with late effects of polio. PMID- 20193940 TI - Electromyographical assessment of passive, active assistive, and active shoulder rehabilitation exercises. AB - OBJECTIVE: To determine the electromyographical (EMG) activation levels of shoulder musculature during early rehabilitation exercises to regain active range of motion. DESIGN: Descriptive. SETTING: University clinical research laboratory. PARTICIPANTS: Ten asymptomatic volunteers (age, 25 +/- 5 years; height, 171 +/- 7 cm; weight, 78 +/- 15 kg). INTERVENTION: Fine-wire (supraspinatus and infraspinatus) and surface (anterior deltoid, upper trapezius, lower trapezius, and serratus anterior) electrodes recorded EMG activity from each muscle during 12 therapeutic exercises completed during a single testing session in random order. MAIN OUTCOME MEASURE: EMG root mean squared amplitude normalized to a percentage of maximum voluntary contraction (% MVC). RESULTS: Passive exercises generated the lowest mean EMG activity (<10%) for all muscles studied. The standing active shoulder elevation exercises generated the greatest mean EMG activity with an upper boundary of 95% CI (40% MVC). Overall the active-assistive exercises generated a small (<10%) increase in muscle activity compared with the passive exercises for the supraspinatus and infraspinatus muscles, which was not a significant increase (P > .05). CONCLUSION: This electrophysiological data in normal volunteers suggest that many exercises used during the early phase of rehabilitation to regain active elevation do not exceed 20% MVC. Progression from passive to active-assisted can potentially be performed without significantly increasing muscular activation levels exercises. Upright active exercises demonstrated a consistent and often a statistically significant increase in muscular activities supporting that these exercises should be prescribed later in a rehabilitation program. PMID- 20193941 TI - The role of the lumbar multifidus in chronic low back pain: a review. AB - Low back pain (LBP), a highly prevalent problem in society, is often a recurrent condition. Recent advances in the understanding of the biomechanics of LBP have highlighted the importance of muscular stabilization of the "neutral zone" range of motion in the low back. The lumbar multifidus muscles (LMM) are important stabilizers of this neutral zone, and dysfunction in these muscles is strongly associated with LBP. The dysfunction is a result of pain inhibition from the spine, and it tends to continue even after the pain has resolved, likely contributing to the high recurrence rate of LBP. Persisting LMM dysfunction is identified by atrophic replacement of multifidus muscle with fat, a condition that is best seen on magnetic resonance imaging. Muscle training directed at teaching patients to activate their LMM is an important feature of any clinical approach to the LBP patient with demonstrated LMM dysfunction or atrophy. PMID- 20193942 TI - Physiatric practice management: lessons from the field. PMID- 20193943 TI - High-intensity exercise for patients in cardiac rehabilitation after myocardial infarction. PMID- 20193944 TI - Metastatic Crohn disease in a spinal cord injury patient without gastrointestinal manifestation. PMID- 20193945 TI - Chronic nonunion in a patient with bilateral supracondylar distal femur fractures treated successfully with twice daily low-intensity pulsed ultrasound. PMID- 20193946 TI - Sacral insufficiency fracture: a masquerader of diskogenic low back pain. PMID- 20193947 TI - A water-soluble ribosyl-based fluorescent sensor for Hg2+ and Cu2+ ions. AB - A water-soluble ribosyl-based fluorescent sensor 5 was prepared. The sensor contains an anthracene as the fluorophore and a set of complex groups as recognition sites, which bears two triazole ring spacers linked to two ribosyl carboxylic acids groups. The association constants of 5 in water are 2.15x10(5)M( 1) and 9.57x10(4)M(-1) for Cu(2+) and Hg(2+) ions, respectively, and both metals formed complexes with 5 at a 1:1 metal to ligand ratio. The binding of 5 to Cu(2+) shows a broad pH range (5-10) and a low detection limit (57ppb) in water, thus indicating it an efficient and promising cation probe. PMID- 20193948 TI - Isolation and fractionation of hemicelluloses by graded ethanol precipitation from Caragana korshinskii. AB - Caragana korshinskii hemicelluloses were isolated with 10% KOH at 25 degrees C for 10h from the delignified materials. The alkali-extractable hemicelluloses were then successively sub-fractionated by graded precipitation at final ethanol concentrations of 10%, 20%, 30%, 45%, 60%, and 80%, respectively. Neutral sugars and molecular weight analyses of the six hemicellulosic subfractions revealed that the molecular weights and the distribution of branches along the xylan backbone are different among the hemicellulosic fractions obtained in various ethanol concentrations. The less branched hemicelluloses with large molecules were precipitated in lower ethanol percentages, while with the increasing ethanol concentrations, more branched hemicelluloses with low molecular weights were obtained. (1)H and (13)C NMR studies revealed that the hemicellulosic subfraction precipitated at an ethanol concentration of 45% had a backbone of D-xylose residues and were branched mainly through 4-O-methyl-alpha-D-glucopyranosyl units. PMID- 20193949 TI - De novo synthesis of differentially protected L-iduronic acid glycosylating agents. AB - A divergent de novo synthesis of six differentially protected l-iduronic acid thioglycosides from a common advanced precursor is described. The key step of this synthetic sequence is the stereoselective elongation of dithioacetal protected C5-dialdehyde 11 via a highly diastereoselective MgBr(2).OEt(2) mediated cyanation. Orthogonally protected l-iduronic acid building blocks obtained by this synthesis are expected to facilitate access to differentially sulfated heparins for microarray-based structure-activity relationship studies. PMID- 20193950 TI - Serum adipocyte fatty acid-binding protein is independently associated with coronary atherosclerotic burden measured by intravascular ultrasound. AB - OBJECTIVES: Adipocyte fatty acid-binding protein (A-FABP) has been shown to have an effect on insulin resistance, lipid metabolism, and atherosclerosis in animals. We therefore investigated the association between the serum A-FABP level and coronary atherosclerosis. METHODS: One hundred twenty-five consecutive patients with coronary artery disease (CAD) were enrolled after coronary angiography. Plaque volume in non-culprit coronary arteries was determined using intravascular ultrasound and expressed as percent plaque volume (%PV). Voluntary blood donors (n=120), matched for age and gender, served as controls. Serum levels of A-FABP, adiponectin, and inflammatory markers were measured by enzyme linked immunosorbent assay. RESULTS: The serum A-FABP level in CAD patients was significantly higher than in control subjects (median [25th-75th percentiles], 27.2 [20.5-37.1] ng/mL vs. 18.9 [14.6-24.5] ng/mL) (p<0.01). Serum A-FABP showed 0.74 of the area under the curve in the receiver operating characteristic curve for the detection of CAD, with 76% specificity and 65% sensitivity with a cut-off value of 20.1 ng/mL. Further, in CAD patients, serum A-FABP had a significant correlation with %PV in all subjects (r=0.33, p<0.01). Serum A-FABP was positively correlated with the body mass index, serum interleukin-6 and high sensitive CRP, and negatively correlated with HDL-cholesterol and serum adiponectin in CAD patients. Stepwise regression analysis revealed that serum A FABP was independently associated with %PV. CONCLUSION: Increased serum A-FABP was significantly associated with a greater coronary plaque burden. Our findings revealed that the measurement of serum A-FABP could be utilized for the evaluation of the extent of coronary atherosclerosis. PMID- 20193951 TI - Approaches to characterise chromatographic column performance based on global parameters accounting for peak broadening and skewness. AB - Peak broadening and skewness are fundamental parameters in chromatography, since they affect the resolution capability of a chromatographic column. A common practice to characterise chromatographic columns is to estimate the efficiency and asymmetry factor for the peaks of one or more solutes eluted at selected experimental conditions. This has the drawback that the extra-column contributions to the peak variance and skewness make the peak shape parameters depend on the retention time. We propose and discuss here the use of several approaches that allow the estimation of global parameters (non-dependent on the retention time) to describe the column performance. The global parameters arise from different linear relationships that can be established between the peak variance, standard deviation, or half-widths with the retention time. Some of them describe exclusively the column contribution to the peak broadening, whereas others consider the extra-column effects also. The estimation of peak skewness was also possible for the approaches based on the half-widths. The proposed approaches were applied to the characterisation of different columns (Spherisorb, Zorbax SB, Zorbax Eclipse, Kromasil, Chromolith, X-Terra and Inertsil), using the chromatographic data obtained for several diuretics and basic drugs (beta blockers). PMID- 20193952 TI - pH Transients in hydroxyapatite chromatography columns-experimental evidence and phenomenological modeling. AB - Hydroxyapatite (HAP) columns, widely used for chromatographic separation of proteins and other biomolecules because of their unique selectivity and ability to resolve complex mixtures, exhibit limited stability at acidic conditions requiring careful control of pH. Even with buffered solutions, however, unintended pH transients can occur when the salt concentration varies. For example, the pH temporarily decreases below the feed value when the salt concentration increases and increases above the feed value when the salt concentration is decreased. The intensity and duration of these transients depend on the particular buffer used and the magnitude of the salt concentration step, but in extreme cases the pH can drop by as much as 1.5 pH units creating conditions where the HAP stability is potentially compromised. This work examines the mechanisms leading to pH transients in HAP columns generated by salt steps. The pH excursions are similar to those observed for weak cation exchange columns, but are accompanied by a transient evolution of phosphate which temporarily decreases below the feed value when the salt concentration is increased and increases sharply when the salt concentration is reduced before returning to the feed value. A phenomenological model is developed to describe this behavior by considering the reversible uptake of sodium ions by the P-sites and binding of phosphate ions by the C-sites. The interplay of these two adsorption mechanisms results in complex pH patterns that are consistent with those observed experimentally. In addition to helping understand the underlying mechanisms, the model also provides a useful tool to predict the effects of different buffers and salt concentration and develop corrective measures that can reduce the intensity and duration of the pH transients such as the addition of unretained co-buffers. PMID- 20193953 TI - Kinetic study of the adsorption of nitroimidazole antibiotics on activated carbons in aqueous phase. AB - The adsorption kinetics of four nitroimidazoles, Dimetridazole (DMZ), Metronidazole (MNZ), Ronidazole (RNZ) and Tinidazole (TNZ), were studied on three activated carbons: two commercial carbons from Sorbo-Norit (S) and Merck (M) and a third prepared by chemical activation of petroleum coke (C). Experimental data of the corresponding adsorption kinetics were analyzed by applying pseudo-first and pseudo-second-order models and a general diffusion model. Application of pseudo-first and pseudo-second-order kinetic models verified the following: (i) The kinetic model used that better predicts the adsorption rates depends of both the adsorbent and adsorbate studied. (ii) Nitroimidazole adsorption rate decreases in the order MNZ>DMZ>RNZ>TNZ; therefore, in the case of MNZ, molecular size does not appear to be a determining factor in the process. (iii) Nitroimidazole adsorption rate on carbons increases in the order C= 30% (HR 1.3, CI: 1.0-1.5, p=0.03), compared to the reference (p-value for interaction<0.001). CONCLUSION: HF due to VHD, DCM and IHD carry a worse prognosis than that of HTN. For the IHD the risk increases progressively with lower values of LVEF. PMID- 20193970 TI - Molecular methods to assess Listeria monocytogenes route of contamination in a dairy processing plant. AB - In this study we investigated the occurrence of Listeria monocytogenes in a dairy processing plant during two sampling campaigns in 2007 and 2008. Samples represented by semifinished and finished cheeses, swabs from the equipment and brines from the salting step, were subjected to analysis by using traditional and molecular methods, represented mainly by quantitative PCR. Comparing the results obtained by the application of the two approaches used, it became evident how traditional microbiological analysis underestimated the presence of L. monocytogenes in the dairy plant. Especially samples of the brines and the equipment swabs were positive only with qPCR. For some equipment swabs it was possible to detect a load of 10(4)-10(5) cfu/cm(2), while the modified ISO method employed gave negative results both before and after the enrichment step. The evidences collected during the first sampling year, highlighting a heavy contamination of the brines and of the equipment, lead to the implementation of specific actions that decreased the contamination in these samples during the 2008 campaign. However, no reduction in the number of L. monocytogenes positive final products was observed, suggesting that a more strict control is necessary to avoid the presence of the pathogen. All the isolates of L. monocytogenes were able to attach to abiotic surfaces, and, interestingly, considering the results obtained from their molecular characterization it became evident how strains present in the brines, were genetically connected with isolates from the equipment and from the final product, suggesting a clear route of contamination of the pathogen in the dairy plant. This study underlines the necessity to use appropriate analytical tools, such as molecular methods, to fully understand the spread and persistence of L. monocytogenes in food producing companies. PMID- 20193971 TI - Anti-infective mechanisms induced by a probiotic Lactobacillus strain against Salmonella enterica serovar Typhimurium infection. AB - The prevention of pathogen infections is one of the most extensively studied effects of probiotics. L. casei CRL 431 is a probiotic bacterium and its effects on the gut immune cells have been extensively studied. The aim of the present study was to determine, using a mouse model, the preventive and therapeutic effect of L. casei CRL 431 to achieve protection against Salmonella enteritidis serovar Typhimurium infection. In both previous and continuous (previous and post infection) probiotic administration, the mechanisms induced by this lactic acid bacteria on the first line of intestinal defense (non-specific barrier and the innate immune cells associated to the gut), as a way to understand some of the mechanisms involved in the protection against Salmonella enteritidis serovar Typhimurium, were analyzed. The results obtained demonstrated that 7 days L. casei CRL 431 administration before infection decreased the severity of the infection with Salmonella enteritidis serovar Typhimurium, demonstrating that the continuous administration (even after infection) had the best effect. This continuous administration diminished the counts of the pathogen in the intestine as well as its spread outside this organ. Several mechanisms and cells are involved in this protective effect against Salmonella enteritidis serovar Typhimurium. L. casei CRL 431 acted on cells of the innate and adaptive immune response. The probiotic administration decreased the neutrophil infiltration with the consequent diminution of intestinal inflammation; activated the macrophage phagocytic activity in different sites such as Peyer's patches, spleen and peritoneum; and increased the number of IgA+cells in the lamina propria of the small intestine which was correlated with increased release of s-IgA specific against the pathogen in the intestinal fluids. The mechanism of the inhibition of cellular apoptosis was not involved. PMID- 20193973 TI - Mechanobiological regulation of the remodelling cycle in trabecular bone and possible biomechanical pathways for osteoporosis. AB - BACKGROUND: The rapid loss of trabeculae as observed during osteoporosis is attributed to pathological changes in the bone remodelling process. In this study, it is proposed that osteoporosis is due to altered signals resulting from either (i) a decrease in the mechanosensitivity of the sensor cells or (ii) an increase in the bone tissue elastic modulus. METHODS: To test these hypotheses, a mechanobiological algorithm was developed and applied to simulate the remodelling cycle in a realistic trabecular strut. The model is based on the supposition that bone resorption is initiated either to remove damaged tissue or when strains fall below a lower threshold; bone formation is triggered when strains exceed an upper threshold. FINDINGS: Applying this algorithm to a realistic trabecula, resorption and subsequent refilling of a cavity was simulated. Results showed that decreases in the mechanosensitivity (simulated by increasing the upper strain threshold) led to under-refilling of cavities. A critical sensitivity was found to exist, above which perforation of the strut due to osteoclastic resorption occurred. It was also found that increases in the bone tissue elastic modulus lead to an increased propensity for trabecular perforation. INTERPRETATION: It may be concluded that if cells become less mechanosensitive, or if increases in the elastic modulus of trabecular bone tissue occurs, the possibility of trabecular perforation and therefore the rapid loss of bone mass increases. If this is true, the preservation of the bone mineral content or maintenance of bone cell mechanosensitivity are potential therapeutic strategies for the prevention of osteoporosis. PMID- 20193972 TI - Foot placement in a body reference frame during walking and its relationship to hemiparetic walking performance. AB - BACKGROUND: Foot placement during walking is closely linked to the body position, yet it is typically quantified relative to the other foot. The purpose of this study was to quantify foot placement patterns relative to body post-stroke and investigate its relationship to hemiparetic walking performance. METHODS: Thirty nine participants with hemiparesis walked on a split-belt treadmill at their self selected speeds and 20 healthy participants walked at matched slow speeds. Anterior-posterior and medial-lateral foot placements (foot center-of-mass) relative to body (pelvis center-of-mass) quantified stepping in body reference frame. Walking performance was quantified using step length asymmetry ratio, percent of paretic propulsion and paretic weight support. FINDINGS: Participants with hemiparesis placed their paretic foot further anterior than posterior during walking compared to controls walking at matched slow speeds (P<.05). Participants also placed their paretic foot further lateral relative to pelvis than non paretic (P<.05). Anterior-posterior asymmetry correlated with step length asymmetry and percent paretic propulsion but some persons revealed differing asymmetry patterns in the translating reference frame. Lateral foot placement asymmetry correlated with paretic weight support (r=.596; P<.001), whereas step widths showed no relation to paretic weight support. INTERPRETATION: Post-stroke gait is asymmetric when quantifying foot placement in a body reference frame and this asymmetry related to the hemiparetic walking performance and explained motor control mechanisms beyond those explained by step lengths and step widths alone. We suggest that biomechanical analyses quantifying stepping performance in impaired populations should investigate foot placement in a body reference frame. PMID- 20193974 TI - Achilles tendon length changes during walking in long-term diabetes patients. AB - BACKGROUND: Diabetes leads to numerous side effects, including an increased density of collagen fibrils and thickening of the Achilles tendon. This may increase tissue stiffness and could affect stretch distribution between muscle and tendinous tissues during walking. The primary aim of this study was to examine stretch distribution between muscle and tendinous tissues in the medial gastrocnemius muscle-tendon unit in long-term diabetes patients and control subjects during walking. METHODS: Achilles tendon length changes were investigated in 13 non-neuropathic diabetes patients and 12 controls, whilst walking at a self selected speed across a 10 m force platform. Electromyographic activity was recorded in the medial gastrocnemius, soleus and tibialis anterior muscles, goniometers were used to detect joint angle changes, and ultrasound was used to estimate tendon length changes. FINDINGS: Achilles tendon length changes were attenuated in diabetes patients compared to controls, and were inversely correlated with diabetes duration (r=-0.628; P<0.05), as was ankle range of motion (r=-0.693; P<0.01). Tendon length changes were also independent of walking speed (r=-0.299; P=0.224) and age (r=0.115; P=0.721) in the diabetic group. INTERPRETATION: Stretch distribution between muscle and tendon during walking is altered in diabetic patients, which could decrease walking efficiency, a factor that may be exacerbated with increasing diabetes duration. Diabetes-induced changes in mechanical tendon properties may be at least partly responsible for attenuated tendon length changes during walking in this patient group. PMID- 20193975 TI - Effects of a chelating resin on metal bioavailability and toxicity to estuarine invertebrates: divergent results of field and laboratory tests. AB - Benthic invertebrates can uptake metals through diffusion of free ion solutes, or ingestion of sediment-bound forms. This study investigated the efficacy of the metal chelating resin SIR 300 in adsorbing porewater metals and isolating pathways of metal exposure. A field experiment (Botany Bay, Sydney, Australia) and a laboratory toxicity test each manipulated the availability of porewater metals within contaminated and uncontaminated sediments. It was predicted that within contaminated sediments, the resin would adsorb porewater metals and reduce toxicity to invertebrates, but in uncontaminated sediments, the resin would not significantly affect these variables. Whereas in the laboratory, the resin produced the predicted results, in the field the resin increased porewater metal concentrations of contaminated sediments for at least 34 days and decreased abundances of four macroinvertebrate groups, and richness in all sediments. These contrasting findings highlight the limits of extrapolating the results of laboratory experiments to the field environment. PMID- 20193976 TI - Exposure to herbal products during pregnancy and the risk of preterm birth. PMID- 20193977 TI - Anterior urethral surgery: current concepts and future directions. PMID- 20193978 TI - Multiple molecular mechanisms underlying trastuzumab and lapatinib resistance in JIMT-1 breast cancer cells. AB - Trastuzumab plays an important role in breast cancer therapy. However, a significant fraction of patients do not respond to therapy or they tend to develop resistance shortly after beginning therapy. Although some resistance mechanisms have been described, it is unclear whether these mechanisms can coexist. In this study, we analyzed the resistance mechanisms in the breast cancer cell line JIMT-1, a model of intrinsic trastuzumab resistance. We compared the JIMT-1 cell line with a panel of eight HER-2 positive breast cancer cell lines. All cell lines were characterized for the phosphatidylinositol 3-kinase (PIK3CA) mutation status, expression levels of the phosphatase and tensin homolog on chromosome 10 (PTEN) and neuregulin-1 (NRG1) mRNA, HER-2 gene copy number, and protein expression. The results were correlated to the sensitivity to trastuzumab and lapatinib as well as the potency of trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC) evoked by trastuzumab. JIMT-1 cells showed several co-existing drug resistance mechanisms, including an activating mutation of the PIK3CA gene, low expression of PTEN, high expression of NRG1, and relatively low expression of HER-2 receptor protein (despite gene amplification). All these features were present at variable levels in other cell lines, whereas JIMT-1 was unique in displaying all these factors at the same time. Unexpectedly, ADCC reaction by normal lymphocytes was equally strong in all HER-2 positive cell lines, without any correlation to molecular markers or direct sensitivity to the drugs. Resistance to trastuzumab and lapatinib is probably caused by several co existing molecular mechanisms. Direct sensitivity to trastuzumab and lapatinib was not correlated with ADCC. PMID- 20193979 TI - Adsorption of tannin from aqueous solution by deacetylated konjac glucomannan. AB - Konjac glucomannan treated by alkali solution through deacetylated reaction was used as a new water insoluble adsorbent to remove tannin from aqueous solution. A comprehensive study on adsorption of tannin by deacetylated konjac glucomannan (DKGM) was conducted regarding the effects of initial pH, adsorbent dosage, contact time, temperature and initial tannin concentration. The adsorption process was much dependent on the pH and temperature and was found to follow pseudo-second-order kinetics. The optimum pH value was at pH ranging from 2 to 6. The maximum removal efficiency of tannin from aqueous solution was 90%. Increasing the adsorption temperature would result in lower adsorption capacity, suggesting that adsorption of tannin onto DKGM was exothermic in nature. The adsorption isotherms were measured at various temperatures and correlated to Freundlich isotherms. Adsorption mechanism was confirmed that the interaction of DKGM and tannin was through hydrogen bonding. It was also observed that DKGM possesses excellent reusability for tannin removal. PMID- 20193980 TI - Efficacy of moxidectin microsphere sustained release formulation for the prevention of subcutaneous filarial (Dirofilaria repens) infection in dogs. AB - A study was carried out to assess the efficacy of a moxidectin microsphere sustained release (SR) injectable formulation (Guardian SR Iniettabile, Fort Dodge) for the prevention of Dirofilaria repens infection in experimentally infected dogs. On day 0, 18 Beagle dogs, 9 male dogs and 9 female dogs, weighing 12-16 kg were ranked in ascending order of body weight (b.w.) and blocked into pairs. Within each pair, dogs were allocated to Group 1 or Group 2 at random. On the same day, dogs in Group 1 were injected with 0.05 ml/kg b.w. of saline solution and dogs in Group 2 were injected with moxidectin SR at the label dose 0.17 mg/kg b.w. (0.05 ml/kg b.w.). Six months after moxidectin SR or saline injection, on day 180, each dog in the two groups was challenged with 50 infective larvae of D. repens collected from laboratory-reared, experimentally infected Aedes aegypti. Dogs were humanely euthanized on day 380 of the study, approximately 7 months from D. repens challenge. At necropsy, no worms were found in dogs treated with moxidectin SR (Group 2) while adult worms were found in saline-treated dogs (total 90; 38 males and 52 females; arithmetic mean 10, standard error 0.96, median 9, range 7-15) (Group 1 vs Group 2 P<0.001). In this experimental study, moxidectin SR injectable showed full efficacy (100%) lasting at least 6 months, and is able to prevent subcutaneous D. repens patent infection throughout the entire transmission season in Europe. PMID- 20193981 TI - Association of Wolbachia with heartworm disease in cats and dogs. AB - Although the presence of adult Dirofilaria immitis in the pulmonary arteries and its associated arteritis and thromboembolic disease can explain some of the manifestations of canine and feline heartworm disease, the cause of other findings remains unclear. Cats with D. immitis antibodies but lacking adult parasites in the pulmonary arteries frequently develop histological lesions of the airways, resulting in a condition termed Heartworm-Associated Respiratory Disease. All D. immitis parasites harbor Wolbachia pipientis bacteria and D. immitis-infected animals can have circulating Wolbachia antibodies and pro inflammatory Wolbachia antigens (WSP) deposited in tissues. Little is known about the role that Wolbachia plays in lung disease of animals naturally infected with D. immitis. The purpose of this study was to determine the contribution of Wolbachia to the pathogenesis of natural heartworm disease in cats and dogs. We hypothesized that animals having sufficient Wolbachia burden to be detected in lung tissue by immunohistochemistry and/or polymerase chain reaction (PCR) would have more severe pulmonary disease than those with bacteria below the limits of detection. We further hypothesized that animals that were immunoreactive to pro inflammatory WSP would have more severe pulmonary lesions than those that were seronegative for WSP antibodies. Blood and lung tissue samples were collected from cats and dogs representing three different D. immitis infection statuses: heartworm-free, heartworm-exposed, heartworm-infected. There was a positive but weak correlation between the magnitude of D. immitis antibody titers and WSP titers in cats (r=0.57, p<0.001) and in dogs (r=0.39, p<0.001). Pulmonary lesions were more common in HW-infected animals than in HW-free animals. Pulmonary arteriolar occlusion was more common in HW-infected cats (57%; p=0.003) than in HW-infected dogs (17%). Although pulmonary lesions were most common in HW infected animals, there was no clear additive effect when either Wolbachia DNA/WSP was detected in lung tissue or when circulating Wolbachia antibodies were detected. There were no significant differences in the magnitude of pulmonary lesion scores within each HW-infection status group regardless of whether Wolbachia DNA/WSP or antibodies were detected. The relationship between Wolbachia and lung pathology in heartworm-infected animals remains to be determined. The lack of clear evidence for a role of Wolbachia in heartworm disease creates a dilemma for veterinarians treating animals in D. immitis-endemic areas. Although the indiscriminant use of antibiotics should be avoided, many clinicians prescribe doxycycline based on the favorable responses observed in human filarial diseases and promising results from the first published studies of doxycycline use in D. immitis-infected dogs. PMID- 20193982 TI - Cryptosporidium genotypes and subtypes in dairy calves in Egypt. AB - Neonatal calves are prone to Cryptosporidium infection resulting in economic loss as well as a significant source for zoonotic infection. This study was devoted to ascertain the prevalence and molecular analysis of Cryptosporidium in dairy calves at Kafr El Sheikh Province, Egypt. Twenty-nine out of 96 faecal specimens collected from calves, less than 6 weeks of ages, microscopically showed cryptosporidia oocysts (prevalence 30.2%). Among 29 positives, 26 samples were clearly sequenced for the SSU rDNA gene and the Cryptosporidium oocyst wall protein gene (COWP). Homology search revealed that 2 samples were C. andersoni and 24 isolates were C. parvum genotype II. By sequence analysis of the high polymorphic 60-kDa glycoprotein gene, 23 samples of C. parvum belonged to the allele IId (subtypes IIdA20G1), and one sample belonged to the allele IIa (subtype IIaA15G2R1). Prevailing of allele family IId is a unique observation, contrasting the conception that IIa has been the most prevailing allele in calves and cattle generally in other countries such as in Europe and the USA. To our knowledge, this is the first molecular report about genotyping and subtyping of Cryptosporidium in Egypt. PMID- 20193983 TI - The contribution of the Epstein-Barr virus to the pathogenesis of childhood lymphomas. AB - The Epstein-Barr virus (EBV) is a lymphotropic herpes virus with oncogenetic properties which can lead to the development of lymphomas such as Burkitt's lymphoma (BL), Hodgkin's lymphoma (HL), or post-transplant lymphoma. This review discusses our current understanding of lymphomagenesis in relation to EBV and the potential for targeted therapies. PMID- 20193984 TI - Male breast cancer. AB - Male breast cancer accounts for around 1% of all breast cancer cases, but the incidence has increased over the past 25 years. The rarity of this entity precludes prospective randomized clinical trials. Although breast carcinoma in both genders share certain characteristics, notable differences have emerged. Familial cases usually have BRCA2 rather than BRCA1 mutations. Klinefelter syndrome is the strongest risk factor for developing male breast carcinoma. Men tend to be diagnosed at an older age than women. Presentation is usually a painless lump, but is often late, with more than 40% of individuals having stage III or IV disease. When survival is adjusted for age at diagnosis and stage of disease, outcomes for male and female patients with breast cancer is similar. Surgery is usually mastectomy with axillary clearance or sentinel node biopsy. Because 90% of tumors are hormonal receptor positive, tamoxifen is standard adjuvant therapy. Indications for radiotherapy and chemotherapy are similar to female breast cancer. For metastatic disease, hormonal therapy is the main treatment, but chemotherapy can also provide palliation. PMID- 20193985 TI - Can time-related patterns in diagnosis for hospital admission help identify common root causes for disease expression? AB - For many years medical admissions to acute hospitals have been increasing at a rate far higher than expected from demographic change. Analysis shows that the admissions tend to increase in a step-like manner at an interval of 3-6 years. This study characterises the specific diagnoses associated with the step-changes and uses the resulting pattern in admissions over time to identify further diagnoses with a far lower incidence which may also conform to this pattern. All of the diagnoses located using this method have a common immune function linkage in the expression of the chronic form of the condition. It is proposed that the wider use of data mining techniques may enable association between diagnoses associated with the need for inpatient care arising from unexpected common causes. PMID- 20193986 TI - Beads but no collar; the significance of an asymptomatic rib bone healing pattern in infants. AB - When a long bone, such as a rib, is broken, the position of the break can be seen in the following weeks by a temporary collar of a collagen based material (callus) which holds the broken ends together during the repair process. However in infants a different pattern is sometimes found at autopsy, in which the repair material occurs as widely spaced "beads" along the shaft of the rib. The consistency of the bead material corresponds to the progress of repair in the normal way, but there is no focal region as would be expected in a clean break or greenstick fracture. It is proposed that this results from micro-fractures in the compact bone forming the outer aspect of the rib when it is bent excessively, during thoracic compression such as required in Cardiopulmonary Resuscitation, (CPR), or when the infant is "grabbed" when about to slip from the hands of a carer. The compact bone surface is covered by a relatively very elastic layer, the periosteum, which carries nerves sensitive to stretch or tearing of this periosteum. It is proposed that the local stretch induced in the periosteum bridging these micro-fractures is insufficient to cause these nerves to signal pain and so the condition is asymptomatic, and may be quite common in infancy. It should not be confused with imposed trauma. PMID- 20193987 TI - Transient ischemic attack may present a target for normobaric hyperoxia treatment. AB - According to the new revised tissue-based definition, transient ischemic attack is a transient episode of neurological dysfunction caused by a focal brain, spinal cord, or retinal ischemia without acute infarction. This review addresses the pathophysiology of transient ischemic attack and the impact of normobaric hyperoxia on the penumbral tissue. Neuroimaging in transient ischemic attack patients and advances in penumbra imaging allow the transient ischemic attack, from pathophysiological viewpoint, to be defined as an ischemic penumbra of varied duration, which could proceed to a cerebral infarction or reduce to a benign oligemia. Persisting perfusion abnormalities are observed, despite resolution of the neurological symptoms. Preclinical and clinical studies have shown that the normobaric hyperoxia treatment is associated with improvement of hemodynamic and metabolic disturbances, particularly in the penumbral tissue. Transient ischemic attack, considered an ischemic penumbra, may present an ideal target for early normobaric hyperoxia therapy, administered as soon as possible after the onset of the neurological deficit. Follow-up perfusion imaging could guide and individualize the treatment. PMID- 20193989 TI - Veterinary Herpesvirus. Editorial. PMID- 20193988 TI - [Physiologic basis for fetal heart rate analysis during labour]. AB - Fetal monitoring during labour aims to identify fetal acidosis responsible for brain lesions or perpartum death. In France, continuous recording of fetal heart rate (FHR) is largely used during labour. However, FHR interpretation remains difficult, as no specific sign for fetal hypoxia or acidosis have been described. Fetal heart rate is regulated by the autonomous nervous system including the chemoreflex, the baroreflex and the central nervous system. Appropriate regulation is conditioned by tissue oxygenation. Therefore, basal FHR physiologic instability is reduced when fetal hypoxia or acidosis occur, leading to reduce variability. FHR decelerations are frequent during labour due to either fetal response to physiologic modification of oxygenation during labour or fetal hypoxia, which should be differentiated in order to avoid inappropriate intervention. Knowledge of physiologic mechanisms involved in FHR regulation and fetal haemodynamic adaptation to hypoxia could help in learning FHR interpretation. This review is exposing the factors regulating FHR and the mechanisms involved in fetal circulatory responses to hypoxia and acidosis. PMID- 20193990 TI - Protein display by bovine herpesvirus type 1 glycoprotein B. AB - Glycoprotein B (gB) of bovine herpesvirus 1 (BHV-1), a major component of the viral envelope, is essential for membrane fusion during entry and cell-to-cell spread. It is cleaved in the trans-Golgi network by the proprotein convertase furin. Integration of the open reading frame (ORF) encoding a mutated gB with a second furin cleavage site and mature boIFN-alpha as intervening peptide between the amino-terminal (NH(2)) and carboxy-terminal (COOH) gB subunits yielded recombinant BHV-1/gB2FuIFN-alpha which, unexpectedly, express gB with an enlarged NH(2)-subunit of 90kDa. Here we show that boIFN-alpha-specific antibodies bind to the 90kDa gB subunit and efficiently neutralize BHV-1/gB2FuIN-alpha infectivity. We also show that inactivated BHV-1/gB2FuIN-alpha virions induce an antiviral state in cells incubated with UV-inactivated particles. These results demonstrate that the 90kDa protein is a NH(2)-subunit/boIFN-alpha fusion protein whose boIFN alpha domain is biologically active. To verify that BHV-1 gB is suitable for the display of (glyco)proteins on the surface of virions we constructed BHV-1 recombinants expressing within gB the first 273 amino acids of the NH(2)-subunit (HA1) of avian influenza haemagglutinin, either flanked by two furin cleavage sites or with only one cleavage site between a gB/NH(2)_HA1 fusion protein and the COOH subunit. The resulting recombinant BHV-1/gB2FuHA1 expressed gB from which 55kDa HA1 was excised and secreted. In contrast, gB from BHV-1/gB_NH(2)HA1 infected cells retained HA1 as fusion protein with the NH(2)-subunit. Immunoblotting and neutralization analyses revealed that HA1 is incorporated into the envelope BHV-1/gB/NH(2)_HA1 particles and exposed to the exterior of virions. Thus, this novel approach enables display of polypeptides and (glyco)proteins of at least 273 amino acids on viral particles which is of particular interest for development of novel diagnostics and vaccines as well as for, e.g. gene therapy applications especially when biologically active ligands need to be presented. PMID- 20193991 TI - Monitoring of neonatal haemodynamics: light shining at the end of the tunnel? PMID- 20193992 TI - Sexual experience and temperament affect the response of Merino ewes to the ram effect during the anoestrous season. AB - In seasonally anoestrous ewes of many breeds, the introduction of rams triggers an increase in gonadotrophin secretion that induces ovulation, a phenomenon known as the 'ram effect'. The ram effect is a practical method for mating ewes outside the natural breeding season, and also can provide synchronised lambing, but the variability of the response, especially in young animals, reduces its potential for widespread application. The aim of our study was to assess two factors that are thought to contribute to the variability in young ewes: temperament and sexual experience. We used anovulatory ewes from a flock that had been genetically selected for 'calm' or 'nervous' temperament and compared the endocrine and ovarian responses to the ram effect in four groups (each n=15): 'calm' and parous (3-6 years old); 'calm' and nulliparous (2 years old); 'nervous' and parous; and 'nervous' and nulliparous. Parous ewes, independently of their temperament, exhibited a faster endocrine response and a higher proportion of females cycling after ram introduction than nulliparous ewes. 'Nervous' ewes exhibited a higher proportion of females cycling after ram introduction than calm ewes, but only in the nulliparous group. We conclude that temperament exerts little influence on the response to the ram effect in sexually experienced ewes, and that females of 'nervous' temperament appear to respond better when sexually 'naive'. Both sexual experience and temperament need to be taken into consideration when flock management involves the ram effect. Finally, some ewes were cyclic at ram introduction, yet exhibited an increase in LH secretion even in the presence of high concentrations of progesterone. The mechanism by which the inhibitory effect of progesterone on LH secretion was bypassed needs to be clarified. PMID- 20193993 TI - Postmortem diagnostics of assumed food anaphylaxis in an unexpected death. AB - Diagnosis of lethal anaphylaxis is known to be difficult to establish in forensic autopsy. Cases of anaphylactic shock have to be dealt with in forensic medicine comparatively frequently as death due to anaphylaxis is likely to occur rapidly and without warning in seemingly healthy subjects. Autopsy findings might hint at allergic reaction, but classic manifestations can also be completely absent. A case of suspected food anaphylaxis in a middle-aged woman is presented. The deceased had been known to suffer from multiple allergies. Death came about after an evening meal with friends. Dyspnoea was reported to have been followed by collapse, unconsciousness and death within minutes. The course of further analysis undertaken (toxicology, biochemistry, immunohistochemistry) is examplarily described. By means of the results presented we discuss problems and possibilities of postmortem diagnostics of food induced anaphylaxis. PMID- 20193994 TI - Fatal renal failure due to the Chinese herb "GuanMu Tong" (Aristolochia manshuriensis): autopsy findings and review of literature. AB - Herbal remedies have been used since ancient times and it is now known that they are not completely free of adverse effects. We present the case of a 41-year-old Chinese man, who died in renal failure because he consumed a herbal preparation called "Fen Qing Wu Lin Wan", having GuanMu Tong as main ingredient, for about 1 month. GuanMu Tong is derived from the plant Aristolochia manshuriensis which contains aristolochic acid. Aristolochic acid is being reported as the causative agent of what is now called aristolochic acid nephropathy (AAN) which includes Chinese herb nephropathy (CHN) and Balkan endemic nephropathy (BEN), all having renal impairment as hallmark for the disease. The gross autopsy showed multiple punctate hemorrhages over the limbs, pleural effusion, and edematous lungs with consolidation, mild myocardial hypertrophy and normal-looking kidneys. Microscopic renal tissue examination showed severe degeneration, necrosis and desquamation of renal tubular epithelial cells, presence of protein cast and a widened, edematous interstitium with interstitial fibrosis. We also provide the clinical presentation of the deceased as reported in the medical records and briefly review the literature pertinent to similar cases. PMID- 20193995 TI - A head phantom study for intraocular dose evaluation of 64-slice multidetector CT examination in patients with suspected cranial trauma. AB - PURPOSE: In cases of suspected cranial trauma, cranial CT examinations should be performed to rule out pathology. There are some methods available for reducing intraocular doses; however, it is difficult for the operators to conduct the necessary measurements because of restrictions in time and patient mobility, especially in high-energy trauma cases. Therefore, we performed a head phantom study for intraocular dose evaluation of 64-slice multidetector CT examination in patients with suspected cranial trauma. MATERIALS AND METHODS: Assuming that the orbitomeatal (OM) line and bed were vertical, a head phantom was tilted from 10 degrees caudally to 25 degrees cranially at 5-degree intervals. At each tilted position, the phantom was examined using a 64-section multidetector CT device using three acquisition protocols. Intraocular doses during each examination were measured using small dosimeters. RESULTS: Assuming that the OM line and bed were vertical, intraocular doses varied between 52 and 140%, 17-138%, and 90-142% during helical, non-helical, and helical CT angiographic examinations, respectively. Intraocular doses increased when the phantom was tilted cranially. CONCLUSION: If possible, the best way to reduce the intraocular dose is by angling the gantry cranially, tilting the head of each patient caudally and adopting a non-helical acquisition method. During procedure, the acquisition angle should be angled cranially more than 0 degrees based on the OM line. The estimation of intraocular dose using the acquisition angle and displayed volumetric CT dose index might be useful to evaluate the deterministic effect risks and to inform patients about the associated risks. PMID- 20193996 TI - Endovascular treatment of dural fistulas with the venous outflow of laterocavernous sinus. AB - OBJECTIVE: To report our findings concerning the laterocavernous sinus (LCS) drainage of dural fistulas, focusing our attention on the important implications in treatment of the LCS, which is one of the principal drainage pathways of the superficial middle cerebral vein (SMCV). METHODS: Consecutive 32 patients with dural fistulas treated endovascularly between 2005 and 2008 were reviewed. Seven patients had angiographic features such as dural fistulas draining with SMCV via LCS. Clinical records for these 7 patients were focused to determine their presenting symptoms, angiographic features, endovascular treatments, and clinical outcomes. RESULTS: Over 3 years, 7 patients had 7 dural fistulas drained with SMCV via LCS were treated. Six-vessel angiography confirmed the presence of the dural fistulas. All fistulas were Cognard Type III featured by leptomeningeal veins drainage. One fistula involving the lesser sphenoid wing and 6 fistulas involving CS were supplied by external carotid artery branches with or without dural branches of the internal carotid artery. LCS was identified as a contiguous to SMCV drainage in these cases. One patient was treated with transvenous coil embolization alone, two with transvenous a combination of Onyx and coil embolization, and 4 with transarterial embolization. An angiographic obliteration and clinical cure was achieved in all patients. Complication was local hair loss due to X-ray radiation in one patient. CONCLUSION: It is very important to diagnose the presence of LCS in dural fistulas during the diagnostic angiography. It is believed that the knowledge of LCS might be relevant for the understanding and treatment of dural fistulas involving the LCS. PMID- 20193997 TI - Tracking of antibody reduction fragments by capillary gel electrophoresis during the coupling to microparticles surface. AB - Due to their high specificity and efficiency, antibodies are ideal ligands for target-specific ultrasound contrast agents. The present study focuses on the chemical stability of antibodies during functionalisation with sulfosuccinimidyl pyridyldithiopropionamidohexanoate (SPDP), a heterobifunctional linker, which exposes free thiol groups upon treatment with a reducing agent. Thiolated antibodies can then react with thiol-reactive group, such as maleimide present on the microbubble surface to form stable covalent complexes. The immunoglobulin structure relies on several intra- and inter-chain disulfide bridges which might be affected by reducing agents. A capillary electrophoresis-sodium dodecyl sulfate (CE-SDS) method with UV detection was applied to address the effect of the functionalisation process on the structural integrity of the antibodies and revealed that antibody disulfide bonds are prone to reduction as function of the reducing agents. Depending on the coupling conditions, various IgG fragments were identified reflecting different combinations between the light and heavy chains. Furthermore, two commonly used reducing agents, namely triscarboxyethylphosphine (TCEP) and 1,4-dithiothreitol (DTT) were compared under various preparation conditions. Results showed that reduction conditions based on DTT as a reducing agent under acidic pH were more appropriate to preserve intra- and inter disulfide bridges of SPDP-modified antibodies. PMID- 20193998 TI - Patient use of weight-management activities: a comparison of patient and physician assessments. AB - OBJECTIVE: Examine concordance between patient and physician assessments of patient self-reported use of weight-management activities. METHODS: Analysis of baseline data from a randomized controlled trial of patient and physician interventions to improve patient-physician communication (41 physicians and 274 of their patients). RESULTS: A majority of patients reported regular exercise (55.6%) and efforts to lose weight, such as eating less (63.1%) while physicians only perceived one-third of patients as engaging in those activities (exercise, 36.6%; weight loss, 33.3%). Kappa scores indicated small agreement between patient and physician assessments of patient self-reported use of exercise, mean kappa 0.28 (range 0.15 to 0.40) and no agreement between patient and physician assessments of patient self-reported efforts to lose weight, mean kappa -0.14 (range -0.26 to -0.01). Obese patients were more likely than non-obese patients to report trying to lose weight or exercising regularly (p<0.05), but physicians were less likely to perceive obese patients as engaging in those activities (p<0.05). CONCLUSIONS: Primary care physicians differed considerably from their patients, especially obese patients, in their assessments of patient use of weight-management activities. PRACTICE IMPLICATIONS: These results highlight the importance of improving patient-provider communication about weight-management activities, particularly among obese patients. PMID- 20193999 TI - Reevaluation of the effect of mandatory interpreter legislation on use of professional interpreters for ED patients with language barriers. AB - OBJECTIVE: We sought to compare emergency department (ED) use of professional interpreters in 2008 to previously reported 2002 data. METHODS: We surveyed consecutive adult patients for two 24-h periods at 4 Boston EDs in 2008. We used identical questions as in our 2002 study to assess English language barriers and to measure use and type of interpreter for those with language barriers. RESULTS: We enrolled 498 patients (66% of eligible). Of these, 8% had a significant English language barrier, but any interpreter was used for only 69% of these patients; the corresponding data for 2002 were 11% and 89%, respectively. In 2008, compared to 2002, professional interpreter use was similar (18% vs. 15%; p = 0.70), but a friend or family member interpreted more often (59% vs. 24%; p<0.001), and hospital staff less often (10% vs. 47%; p<0.001). CONCLUSION: We found that use of professional interpreters by Boston ED patients with language barriers remained low, despite publicity of the state mandatory interpreter law. However, a majority were comfortable with a friend or family member serving as the interpreter for the clinical encounter, a finding that may contribute to the limited usage of professional interpreters. PMID- 20194000 TI - "It helps me see with my heart": how video informs patients' rationale for decisions about future care in advanced dementia. AB - OBJECTIVE: To explore how a video of a patient with advanced dementia impacts the rationale for patients' decisions about future care. METHODS: Participants were read a verbal description of advanced dementia and asked their preferences for future care--either life-prolonging, limited, or comfort care--and the rationale for that choice. Participants then watched a video of a patient with advanced dementia and again stated their preferred level of care and the rationale. Thematic content analysis was utilized to develop common themes among the rationale of participants in each response category. RESULTS: We interviewed 120 participants. The rationale of those who initially chose life-prolonging or limited care (47/120) emphasized lengthening life and cited an inherent good of medical treatment. Those who initially chose comfort care (60/120) focused on avoiding suffering and quality of life. Post-video, 107/120 participants chose comfort care and the rationale focused on the experience of the patient and family rather than treatment-centered considerations. Participants found great value in the video images. CONCLUSIONS: While pre-video reasoning reflects general beliefs about extending life and the inherent good of treatment, the post video reasoning reveals more focus on the experience of the actual patient and family. PRACTICE IMPLICATIONS: Video may serve an important role in advanced care planning by enriching the understanding of the condition and allowing one to imagine a future health state. PMID- 20194001 TI - [Enzyme therapy in Fabry disease: when scarcity of one enzyme illustrates the vulnerability of biotech]. PMID- 20194002 TI - FDG avid supraclavicular neck adenopathy of tubercular etiology masquerading as neck recurrence in differentiated thyroid carcinoma: potential source of false positive FDG-PET study. PMID- 20194003 TI - The repair of critical-size defects with porous hydroxyapatite/polyamide nanocomposite: an experimental study in rabbit mandibles. AB - This study was conducted to evaluate the healing of critical-size surgical defects after implantation of porous nano-hydroxyapatite/polyamide composite (nHA/PA) blocks based on a bilateral mandible model using adult New Zealand white rabbits. 15 rabbits were divided randomly into three groups according to the observation period: 4, 12 and 24 weeks. The defects on one side were implanted with nHA/PA blocks and the contralateral defects were kept empty as blank controls. A combination of macroscopic, radiographic, histological and histomorphometric studies were performed up to 24 weeks postoperatively and compared with normal healing. Large amounts of callus and active osteoblasts were found in the pore structure after 4 weeks of implantation, and the defects were completely occupied by neo-bone with density comparable with that of host bone at 24 weeks. Significant difference was found between nHA/PA groups and blank controls regarding X-ray opacity over the whole period and bone parameters at 4 weeks postoperation (P<0.05). The porous nHA/PA composite promotes bone formation over the extension of the defect, particularly in the early stage. Porous nHA/PA offers interesting potential for maxillofacial reconstructive procedures in load free areas. PMID- 20194004 TI - Deconstructing processing speed deficits in schizophrenia: application of a parametric digit symbol coding test. AB - Cognitive processing inefficiency, often measured using digit symbol coding tasks, is a putative vulnerability marker for schizophrenia and a reliable indicator of illness severity and functional outcome. Indeed, performance on the digit symbol coding task may be the most severe neuropsychological deficit patients with schizophrenia display at the group level. Yet, little is known about the contributions of simpler cognitive processes to coding performance in schizophrenia (e.g. decision making, visual scanning, relational memory, motor ability). We developed an experimental behavioral task, based on a computerized digit symbol coding task, which allows the manipulation of demands placed on visual scanning efficiency and relational memory while holding decisional and motor requirements constant. Although patients (n=85) were impaired on all aspects of the task when compared to demographically matched healthy comparison subjects (n=30), they showed a particularly striking failure to benefit from the presence of predictable target information. These findings are consistent with predicted impairments in cognitive processing speed due to schizophrenia patients' well-known memory impairment, suggesting that this mnemonic deficit may have consequences for critical aspects of information processing that are traditionally considered quite separate from the memory domain. Future investigation into the mechanisms underlying the wide-ranging consequences of mnemonic deficits in schizophrenia should provide additional insight. PMID- 20194005 TI - Age-related changes of p75 neurotrophin receptor-positive adipose-derived stem cells. AB - BACKGROUND: The existence of multipotent stem cells in subcutaneous adipose tissue has been reported. We previously confirmed that p75 neurotrophin receptor (p75NTR; CD271)-positive cells in subcutaneous adipose tissue possessed multipotency, although changes of the characteristics in p75NTR-positive adipose derived stem cells (ASCs) with aging remain unclear. OBJECTIVE: To investigate the effect of aging on p75NTR-positive ASCs. METHODS: The number of p75NTR positive ASCs in subcutaneous adipose tissue of ICR mice aged 3-24 weeks was analyzed by immunostaining and flow cytometry. Subsequently, the cells were isolated and their ability to attach to the cell culture dish, proliferation rate (doubling time) and the expression of senescence-associated beta-galactosidase (SA-beta gal), a cellular senescence marker, were assessed. Age-related changes in the differentiation potential of p75NTR-positive cells in adipogenic, osteogenic, chondrogenic and myogenic lineage were also investigated. RESULTS: The number of ASCs per unit of tissue weight in adipose tissue and the attachment rate of isolated cells decreased with aging. No difference in the cell proliferation rate and the percentage of SA-beta gal-positive cells was detected. Although the efficacy of differentiation into adipogenic and osteogenic lineages slightly decreased with aging, the differentiation potential into chondrogenic and myogenic lineages was not changed. CONCLUSION: The number of ASCs per unit of tissue weight decreased in aged mice. However, the cells possessed proliferation and differentiation potentials almost equal to those of young mice even though the differentiation potentials showed a tendency of decrease. These results raise the possibility that stem cell functions, self-renewal and multipotency, are maintained regardless of aging. PMID- 20194006 TI - Preparation, characterization and in vitro anticoagulation of emodin-eluting controlled biodegradable stent coatings. AB - In this study, emodin-eluting poly(lactide-co-glycolide) (PLGA) coating stents and emodin-loaded PLGA films were prepared to explore the potential application of emodin-eluting stent for treating cardiovascular disease. Fourier transform infrared spectra (FTIR) showed all characteristic adsorption peaks of emodin in emodin-loaded PLGA film in comparison to pure emodin. The balloon expansion experiment and surface morphology observation suggested that the integrated emodin-eluting coatings were successfully obtained on the stainless steel surfaces and the coatings had the ability to withstand the strains imparted during balloon experiment. The drug release profile revealed the nearly linear release curve without obvious burst release for different doses of emodin-eluting stents. As compared with stainless steel and PLGA, in vitro platelet adhesion and APTT (activated partial thromboplastin time) tests revealed better blood compatibility of emodin-eluting stent. In conclusion, the results of the present study showed that the emodin-eluting stent has a potential application for treating cardiovascular disease. PMID- 20194007 TI - Fertilizer efficiency and environmental risk of irrigating Impatiens with composting leachate in decentralized solid waste management. AB - The reduction and reuse of composting leachate is an issue of importance in the field of decentralized solid waste management. In this study, composting leachate from source-separated food waste was treated and subsequently used as liquid fertilizer to irrigate Impatiens (Impatiens balsamina). The leachate was altered by adjusting storage time and dilution, and through addition of microbial inocula. For each test case, the effects of irrigation were monitored by analyzing the Impatiens extension degree, numbers of leaves and flowers, dry weight, and photosynthetic pigment content to assess fertilizer efficiency. The main results obtained revealed that the addition of microbial inocula and lengthening of storage times may lower COD concentrations, adjust pH value and maintain a comparatively high level of nutrient contents. By adding microbial inocula, a COD concentration of 9.6% and BOD(5) concentration of 6.7% were obtained for non-treated leachate with the same storage time. COD concentrations in leachate decreased to 69.4% after 36weeks storage. Moreover, composting leachate promoted growth of Impatiens. The dry weight biomass of Impatiens irrigated using treated diluted leachate was 1.15-2.94 times that obtained for Impatiens irrigated using tap water. Lastly, following the irrigation of Impatiens over a short period, soil did not accumulate VOCs and heavy metals to levels exceeding relative standards. Further research on heavy metal and salinity accumulation in plants should be undertaken to meet the needs of large-scale applications. PMID- 20194008 TI - Overview on LFG projects in China. AB - Since the first landfill gas (LFG) power plant in China was built in 1998, by now more than 10years have passed. In this period the LFG utilization process has progressed greatly in China. An overall review of the process is presented in this paper, which includes the background of policies, the information about the approval procedure of LFG projects, and the theoretical methods used to estimate the amount of LFG's generation. Detailed analysis on the project practice, such as LFG collection techniques, LFG utilization condition in China, is made. According to statistic data, before the end of 2008, 26 LFG power projects have been built and put into operation with total power capacity around 56.8MW, and 2.234 million tons of carbon dioxide equivalent abatement has been achieved annually by all of these LFG projects. The future of LFG industry in China is expected that there is still considerable developing space for LFG utilization in the near coming years, however after 2012, the progress speed may slow down because of some adverse aspects, such as available landfill resource becomes scarce, new laws implemented in China might exclude Chinese landfills from future CDM activities, etc. PMID- 20194009 TI - Treatment of municipal landfill leachate using a combined anaerobic digester and activated sludge system. AB - The main objective of this study was to assess the feasibility of treating sanitary landfill leachate using a combined anaerobic and activated sludge system. A high-strength leachate from Shiraz municipal landfill site was treated using this system. A two-stage laboratory-scale anaerobic digester under mesophilic conditions and an activated sludge unit were used. Landfill leachate composition and characteristics varied considerably during 8 months experiment (COD concentrations of 48,552-62,150 mg/L). It was found that the system could reduce the COD of the leachate by 94% at a loading rate of 2.25g COD/L/d and 93% at loading rate of 3.37g COD/L/d. The anaerobic digester treatment was quite effective in removing Fe, Cu, Mn, and Ni. However, in the case of Zn, removal efficiency was about 50%. For the rest of the HMs the removal efficiencies were in the range 88.8-99.9%. Ammonia reduction did not occur in anaerobic digesters. Anaerobic reactors increased alkalinity about 3.2-4.8% in the 1st digester and 1.8-7.9% in the 2nd digester. In activated sludge unit, alkalinity and ammonia removal efficiency were 49-60% and 48.6-64.7%, respectively. Methane production rate was in the range of 0.02-0.04, 0.04-0.07, and 0.02-0.04 L/g COD(rem) for the 1st digester, the 2nd digester, and combination of both digesters, respectively; the methane content of the biogas varied between 60% and 63%. PMID- 20194010 TI - The use of fibrinogen concentrate to correct hypofibrinogenaemia rapidly during obstetric haemorrhage. AB - Haemorrhage is a common complication of childbirth with 0.65% of deliveries associated with significant (>1500 mL) peripartum blood loss. Hypofibrinogenaemia secondary to dilutional and consumptive coagulopathies can be challenging to correct quickly with conventional blood and plasma therapy. Fibrinogen concentrate offers rapid restoration of fibrinogen levels with a small volume infusion and minimal preparation time. It is effective in treating patients with congenital hypofibrinogenaemia, but there are few reports of its use in association with continuing obstetric haemorrhage. Six cases of obstetric haemorrhage, associated with hypofibrinogenaemia, treated with fibrinogen concentrate in conjunction with platelets, fresh frozen plasma, packed red blood cells, uterotonics and obstetric intervention are described. In all cases, laboratory assessed coagulation was rapidly normalised and severe haemorrhage improved. These cases suggest that fibrinogen concentrate may be an effective addition to conventional treatments for obstetric haemorrhage associated with hypofibrinogenaemia. PMID- 20194011 TI - Anesthetic management of a consecutive cohort of women with heart disease for labor and delivery. AB - BACKGROUND: The cardiovascular changes of pregnancy may place additional stress upon women with pre-existing heart disease, increasing peripartum morbidity and mortality. The purpose of this descriptive study was to report the anesthetic management of a large cohort of pregnant women with heart disease. METHODS: The medical records of 522 consecutive parturients (657 pregnancies) with heart disease who delivered at Toronto General Hospital or Mount Sinai Hospital in Toronto, Ontario, Canada between 1986 and 2004 were reviewed. Obstetric, medical and anesthetic management data were collected and the women were stratified by New York Heart Association (NYHA) functional status at delivery. The main outcome of interest was the method of analgesia or anesthesia administered during labor and delivery. Univariate and multivariate analysis was performed to identify risk factors associated with the administration of general anesthesia. RESULTS: Of 657 pregnant women, 602 were NYHA 1/2 and 55 were NYHA 3/4 at time of delivery. Epidural analgesia was administered to 84% of NYH 1/2 women and 83% of NYH 3/4. The cesarean section rates were 29% and 31% respectively. The rate of general anesthesia for the entire cohort was 9%. Factors associated with the use of general anesthesia for operative delivery included cesarean delivery (adjusted O.R. 74; 95% CI 9.5, 573), delivering at Toronto General Hospital site (adjusted O.R. 5.5; 95% CI 2.3, 13.3), presence of complex congenital heart lesion (adjusted O.R. 2.3; 95% CI 1.0, 5.4) and each week of premature delivery (adjusted O.R. 1.3; 95% CI 1.1, 1.5). Three percent suffered intrapartum cardiac complications; there was one death. CONCLUSIONS: Pregnant women with heart disease managed within an organized program may undergo labor and delivery with acceptable rates of complications. Cesarean section, epidural analgesia/anesthesia and general anesthesia rates are similar to those in the general obstetric population. PMID- 20194012 TI - Neuraxial labor analgesia in an obese parturient with influenza A H1N1. AB - We describe the use of epidural analgesia in a 39-year-old G2P1 parturient presenting at 38(+6) weeks estimated gestation with confirmed influenza A H1N1 and superimposed bilateral pneumonia. Although the patient had an uncomplicated intra- and post-partum course, little is known about the safety of performing neuraxial analgesia or anesthesia in patients with influenza. The prevalence of viremia and possible translocation of blood-borne virus to the central nervous system are discussed. PMID- 20194013 TI - Maternal haemodynamics at elective caesarean section: a randomised comparison of oxytocin 5-unit bolus and placebo infusion with oxytocin 5-unit bolus and 30-unit infusion. AB - BACKGROUND: Rapid intravenous injection of oxytocin is associated with marked hypotension secondary to decreased venous return. Reductions in dose and rate of bolus administration have reduced the incidence of cardiovascular side effects, but no study has yet investigated cardiovascular stability when oxytocin is infused for several hours after delivery. This study compared maternal haemodynamics during a 4-h 30-unit oxytocin infusion and during a placebo infusion following caesarean section. METHODS: Women booked for elective caesarean section were randomised to receive either oxytocin 5-unit bolus and placebo infusion or oxytocin 5-unit bolus and oxytocin 30-unit infusion. Before, during and for 4 h after surgery electrocardiogram, oxygen saturation, systolic and diastolic pressure and heart rate were monitored non-invasively and cardiac index (CI), left ventricular work index (LVWi) and systemic vascular resistance index (SVRi) by thoracic bioimpedance. RESULTS: A total of 74 women agreed to haemodynamic measurements. Heart rate, systolic and diastolic pressure, CI, LCWi and SVRi all fell following the onset of spinal anaesthesia, and, with the exception of SVRi, continued to decrease throughout surgery. After delivery of the baby, slow injection of oxytocin 5 units was associated with a temporary rise in CI, LCWi and heart rate, a decrease in SVRi and no change in systolic or diastolic pressure. Thereafter, haemodynamic measures returned to normal over 60 min with no adverse effects apparent from the additional oxytocin infusion. CONCLUSIONS: An additional oxytocin infusion at elective caesarean section did not adversely affect maternal haemodynamics either during or after surgery. PMID- 20194014 TI - Accounting for conformational changes during protein-protein docking. AB - Three-dimensional structures of only a small fraction of known protein-protein complexes are currently known. Meanwhile, computational methods are of increasing importance to provide structural models for known protein-protein interactions. Current protein-protein docking methods are often successful if experimentally determined partner proteins undergo little conformational changes upon binding. However, the realistic and computationally efficient treatment of conformational changes especially of the protein backbone during docking remains a challenge. New promising approaches of flexible refinement, ensemble docking and explicit inclusion of flexibility during the entire docking process have been developed. A significant fraction of known protein-protein interactions can be modeled based on homology to known protein-protein complexes which in many cases also requires efficient flexible refinement to provide accurate structural models. PMID- 20194015 TI - Are reported increases in incidence of primary CNS tumours real? An analysis of longitudinal trends in England, 1979-2003. AB - Reported increases in the incidence of CNS tumours in the developed world in the 1970s to 1990s have been a cause for concern and debate. It still remains to be adequately answered whether these increases are true or an artefact of changes in diagnostic and registration practices. Using high-quality national cancer registration data, we have analysed incidence trends for each major histological subgroup of CNS tumour (2000 World Health Organisation (WHO) classification) registered in those aged 0-84 years for the whole of England during the period 1979 through 2003. 134,509 primary CNS tumours of malignant, benign and uncertain behaviour located in the brain, meninges, spinal cord, cranial nerves, other parts of the central nervous system and in the pituitary and pineal glands were registered. In summary, we present the single largest nationwide study on the longitudinal incidence trends of CNS tumours. The increase in incidence observed in the 1970s and 1980s was mainly in the young and the elderly and has now plateaued and may even be decreasing. There is however variation in trends by histology. The incidence of some histological sub-groups has continued to increase until the most recent period of analysis. Much of the initial increase can be attributed to the emergence of much more widely available neuroimaging, while the most recent incidence changes for specific sub-groups of CNS tumours appear to be due to greater diagnostic specificity leading to a shift in registered categories. However, the trends for high-grade astrocytomas and other gliomas need further observation and investigation. PMID- 20194016 TI - Loss of expression of TIMP3 in clear cell renal cell carcinoma. AB - AIMS: In clear cell renal cell carcinoma (CCRCC), vascular endothelial growth factor (VEGF) represents the central positive mediator of tumour angiogenesis while VEGF receptor (VEGFR) is the primary target of anti-angiogenic therapies. TIMP3 is a physiological VEGFR-2 antagonist and thus could be considered as an anti-angiogenic factor. We therefore determined the status of this physiological inhibitor in CCRCC. PATIENTS AND METHODS: Archival tumour from 105 patients was studied. TIMP3 expression was analysed using immuno-histochemistry and real-time RT-PCR. Results were correlated with clinicopathological variables. To analyse the mechanisms of gene silencing involved, we performed Multiplex Ligation dependent Probe Amplification (MLPA) and methylation-specific MLPA (MS-MLPA). At last, we evaluated the main upstream pathway described implicating TGFbetaRII, which induces TIMP3 expression. RESULTS: A down-expression of TIMP3, determined by immunohistochemistry, affected 100/105 renal cancers (95.2%). TIMP3 mRNA levels were significantly lower in high-grade tumours. Loss of heterozygosity of the TIMP3 gene was observed in 8 tumours (7.6%) and the 5'CpG island of the TIMP3 promoter was found to be methylated in 25 tumours (23.8%). A down-expression of TGFbetaRII was found in 85/105 CCRCCs (80.9%). A significant correlation was found between TIMP3 expression and TGFbetaRII expression. CONCLUSIONS: This is the first demonstration that the loss of TIMP3 expression is observed in almost all CCRCCs. This loss of expression is a common molecular event in CCRCC. It may be an important initiation step for tumour development in a complex process implicating loss of heterozygosity on chromosome 22q, promoter hyper-methylation and inactivation of the TGFbetaRII pathway. PMID- 20194017 TI - Equilibrium, kinetic and thermodynamic studies of acid Orange 52 dye biosorption by Paulownia tomentosa Steud. leaf powder as a low-cost natural biosorbent. AB - The biosorption of Acid Orange 52 onto the leaf powder of Paulownia tomentosa Steud. was studied in a batch adsorption system to estimate the equilibrium, kinetic and thermodynamic parameters as a function of solution pH, biosorbent concentration, dye concentration, biosorbent size, temperature and contact time. The Langmuir, Freundlich and Temkin isotherm models were used for modeling the biosorption equilibrium. The experimental equilibrium data could be well interpreted by the Temkin and Langmuir isotherms with maximum adsorption capacity of 10.5 mg g(-1). In order to state the sorption kinetics, the fits of pseudo first order, pseudo-second order, Elovich and intraparticle diffusion kinetic models were investigated. It was obtained that the biosorption process followed the pseudo-second order rate kinetics. Thermodynamic studies indicated that this system was exothermic process. The results revealed that P. tomentosa leaf powder could be an efficient biosorbent for the treatment of wastewater containing Acid Orange 52. PMID- 20194018 TI - Effect of nitroethane, dimethyl-2-nitroglutarate and 2-nitro-methyl-propionate on ruminal methane production and hydrogen balance in vitro. AB - Ruminal methanogenesis is considered a digestive inefficiency that results in the loss of 2-12% of the host's gross energy intake and contributes nearly 20% to the United States annual CH(4) emissions. Presently, the effects of the known CH(4) inhibitor, nitroethane, and two synthetic nitrocompounds, dimethyl-2 nitroglutarate and 2-nitro-methyl-propionate, on ruminal CH(4) production and fermentation were evaluated in vitro. After 24 h incubation at 39 degrees C under 100% CO(2), ruminal fluid cultures treated with 2.97 or 11.88 mumol ml(-1) of the respective nitrocompounds produced > 92% less CH(4) (P < 0.05) than non-treated controls. Quantification of fermentation end-products produced and H(2) balance estimates indicate that fermentation efficiencies were not compromised by the nitro-treatments. PMID- 20194019 TI - Hydrogen-rich gas production by steam gasification of char from biomass fast pyrolysis in a fixed-bed reactor: influence of temperature and steam on hydrogen yield and syngas composition. AB - Steam gasification experiments of biomass char were carried out in a fixed-bed reactor. The experiments were completed at bed temperature of 600-850 degrees C, a steam flow rate of 0-0.357 g/min/g of biomass char, and a reaction time of 15min. The aim of this study is to determine the effects of bed temperature and steam flow rate on syngas yield and its compositions. The results showed that both high gasification temperature and introduction of proper steam led to higher yield of dry gas and higher carbon conversion efficiency. However, excessive steam reduced gas yield and carbon conversion efficiency. The maximum dry gas yield was obtained at the gasification temperature of 850 degrees C and steam flow rate of 0.165 g/min/g biomass char. PMID- 20194020 TI - Second generation bioethanol production from Saccharum spontaneum L. ssp. aegyptiacum (Willd.) Hack. AB - Saccharum (Saccharum spontaneum L. ssp. aegyptiacum (Willd.) Hack.), is a rapidly growing, wide ranging high-yield perennial, suitable for second generation bioethanol production. This study evaluated oxalic acid as a pretreatment for bioconversion. Overall sugar yields, sugar degradation products, enzymatic glucan hydrolysis and ethanol production were studied as effects of temperature (150-190 degrees C), reaction time (10-40 min) and oxalic acid concentration 2-8% (w/w). Time and temperature were combined into a single parameter, Severity Factor (SF) [Log(R(0))], and related to oxalic acid using a response surface methodology. Maximum total sugar yield was attained at a SF of 2.93 and 6.79% (w/w) oxalic acid, while maximum formation of sugar degradation products was observed at the highest SF (4.05) and 5% (w/w) oxalic acid. These were also the conditions for maximum simultaneous saccharification and fermentation (SSF) of the residual solids. Commercial cellulases and Saccharomyces cerevisiae attained 89.9% glucan conversion and 17.8 g/l ethanol. Pichia stipitis CBS 6054 fermented hemicellulosic hydrolysates from less severe conditions to ethanol with a yield of 0.35 (g(e)/g(s)). Maximal product yields were 69% of theoretical value and 90% of the SSF conversion efficiency for hydrolysate fermentation and SSF, respectively. PMID- 20194021 TI - Production and use of lignocellulosic bioethanol in Europe: Current situation and perspectives. AB - Contrary to the case of the United States where a systematic management of the RD&D on lignocellulosic ethanol prevails, in Europe the research works remain fragmented despite the efforts made by the European Union and in few member states. In most of the European countries, sustainable lignocellulosic resources may not be widely available in the future for bioethanol production due to the possible competition between several potential usages. Thus the actual deployment of the lignocellulosic bioethanol in Europe will depend on the opportunity costs of biomass on one side and on the prices of ethanol and gasoline on the other side. While the papers on lignocellulosic ethanol often emphasize technology progress, this review paper also addresses policy measures. It is found that, especially in Europe where security of oil supply will be lower in long term, the policy instruments should explicitly reward the higher value of lignocellulosic ethanol compared to first the generation ethanol and gasoline. PMID- 20194022 TI - Stereoselective synthesis of bioactive natural spiroacetals aculeatins A and B. AB - The stereoselective synthesis of two naturally occurring bioactive spiroacetals, aculeatins A and B has been accomplished using 1-tetradecanal as the starting material. The sequence introduces diastereoselective iodine-induced electrophilic cyclization and ring opening of epoxide with 1,3-dithiane as the key steps. PMID- 20194023 TI - Synthesis of a novel tricyclic 1,2,3,4,4a,5,6,10b-octahydro-1,10-phenanthroline ring system and CXCR4 antagonists with potent activity against HIV-1. AB - Stereorandom and diastereoselective syntheses of a novel 1,2,3,4,4a,5,6,10b octahydro-1,10-phenanthroline ring system are described. Derivatives of all four diastereomers were prepared and isolated in >98% ee. The pure enantiomers were compared in order to determine the preferred absolute and relative configuration required for optimal anti-HIV activity. Anti-HIV potency and pharmacokinetic properties of the newly synthesized tricyclic octahydrophenanthroline inhibitors are presented and comparisons are made to previously reported bicyclic (8S)-N methyl-5,6,7,8-tetrahydro-8-quinolinamine analogs. PMID- 20194024 TI - Novel inhibitors of basal glucose transport as potential anticancer agents. AB - Cancer cells commonly show increased levels of glucose uptake and dependence. A potential strategy for the treatment of cancer may be the inhibition of basal glucose transport. We report here the synthesis of a small library of polyphenolic esters that inhibit basal glucose transport in H1299 lung and other cancer cells. These basal glucose transport inhibitors also inhibit cancer cell growth in H1299 cells, and these two activities appear to be correlated. PMID- 20194025 TI - The interface between transcription and mechanisms maintaining genome integrity. AB - Maintaining genome integrity is crucial for correctly regulated gene expression. Conversely, the process of transcription fundamentally impinges on genome stability, necessitating cellular mechanisms that lessen the genome destabilizing effect of reading genes. This review provides an overview of our present knowledge of how eukaryotic RNA polymerase II transcription affects, and is affected by, other DNA-related processes such as chromatin remodeling, DNA repair, recombination and replication. PMID- 20194026 TI - Analysis of biological time-lapse microscopic experiment from the point of view of the information theory. AB - We report objective analysis of information in the microscopic image of the cell monolayer. The process of transfer of information about the cell by the microscope is analyzed in terms of the classical Shannon information transfer scheme. The information source is the biological object, the information transfer channel is the whole microscope including the camera chip. The destination is the model of biological system. The information contribution is analyzed as information carried by a point to overall information in the image. Subsequently we obtain information reflection of the biological object. This is transformed in the biological model which, in information terminology, is the destination. This, we propose, should be constructed as state transitions in individual cells modulated by information bonds between the cells. We show examples of detected cell states in multidimensional state space reflected in space an colour channel intensity phenomenological state space. We have also observed information bonds and show examples of them. PMID- 20194027 TI - Suction or non-suction to the underwater seal drains following pulmonary operation: meta-analysis of randomised controlled trials. AB - OBJECTIVES: The decision to proceed to simple underwater seal drainage or to apply active suction to the underwater seal following pulmonary operation is a controversial one. For the sake of selecting the alternative to reduce postoperative air leakage, we performed a meta-analysis of randomised controlled trials (RCTs) to determine the benefit of suction or non-suction following lung surgery on patient outcomes. METHODS: RCTs published in English from 1999 to 2009 were included. A fixed-effect model was developed for postoperative pneumothorax cases. A random-effects model was developed for quantitative data synthesis, including prolonged air-leak cases, duration of air leakage, time for the removal of chest tubes and hospital stay. RESULTS: Odds ratio (95% confidence interval (CI)), expressed as suction versus non-suction, was 0.11 (0.03-0.49) for postoperative pneumothorax cases; relative risk was 1.48 (0.82-2.70) for prolonged air-leakage cases; weighted mean difference was 1.16 (-0.63 to 2.94) for the duration of air leakage, 0.96 (-0.12 to 2.05) for the time for removal of chest tubes and 2.19 (0.61-4.98) for the hospital stay. CONCLUSION: There is no necessity to use suction in most cases, since it cannot decrease the incidence of prolonged air leak. However, suction can reduce the occurrence of postoperative pneumothorax resulting from early air leak. As a result, the early use of postoperative suction might be crucial to specific patients to whom early elimination of residual space is very important. PMID- 20194028 TI - Left ventricular pseudo-aneurysm after mitral valve replacement: accurate diagnosis enables treatment. PMID- 20194029 TI - The fate of Hancock II porcine valve recipients 25 years after implant. AB - OBJECTIVE: The Hancock II (HII) is a second-generation porcine bioprosthesis introduced into clinical use in 1982. This study aimed to evaluate very long-term outcomes for the HII valve in a large patient population. METHODS: Between May 1983 and November 1993, 517 consecutive patients (pts) (309 male, mean age: 64+/ 9 years) underwent valve replacement (VR) surgery with HII, with 302 (58.4%) in the aortic VR (AVR) and 215 (41.6%) in the mitral VR (MVR) position, respectively. At implant, 106 pts (20.5%) were <60 years of age (G1), while 411 (79.5%) were > or =60 years of age (G2). The 25-year follow-up was complete for all pts at a median of 12 years (range: 0-25). RESULTS: Long-term death occurred in 208 AVR and in 165 MVR pts. Survival at 15 and 20 years was 39.5% and 23.3% in AVR pts and 39.0% and 15.8% in MVR pts. At 25 years the survival of MVR pts was 13.7% (four pts at risk). Late freedom from re-operation was 85.5% and 79.3% at 15 and 20 years in the AVR pts and 73.3% and 52.8% in the MVR pts, respectively. In the AVR population, 20-year freedom from re-operation was 52.2% in G1 pts and 86.8% in G2 pts (p<0.0001), while in the MVR population it was 41.4% in G1 pts and 61.9% in G2 pts (p=0.201), respectively. CONCLUSIONS: These results confirm the excellent long-term performance of the HII bioprosthesis. PMID- 20194030 TI - Chronic pleural empyema: which is the role for surgery? Past and present. PMID- 20194031 TI - Indication of posterior restoration and surgical results in patients with dilated cardiomyopathy. AB - OBJECTIVE: Nontransplant surgery for dilated cardiomyopathy (DCM) has been in the process of development. Anterior restoration for anterior akinesis has shown favourable outcome. Posterior restoration and surgical results are also discussed. METHODS: At the Hayama Heart Center in Japan, between 2005 and 2009, posterior restoration for DCM was performed in 36 patients (10 with ischaemic and 26 with nonischaemic, including muscular dystrophy in three). There were 32 men and four women with a mean age of 53 years. The mean preoperative ejection fraction was 23% and the preoperative New York Heart Association (NYHA) classification was class III in 16 patients and class IV in 20 with eight emergent operations. To identify the posterior lesion before operation, speckle tracking echocardiography was used, with a Vivid 7 ultrasound machine. The short axis images from the middle level of the left ventricle (LV) were obtained to assess myocardial segmental viability. Based on the results of speckle-tracking echocardiography, posterior restoration was performed in patients with postero lateral akinesis and septal kinesis. After the cardioplegic arrest, mitral plasty or coronary artery bypass grafting (CABG) was performed and the posterior LV muscle between bilateral papillary muscles was partially resected under beating heart. The LV apex was preserved and cryoablation was applied between the cut edge and the mitral annulus. All the patients were followed with cardiac echocardiography. RESULTS: In addition to LV restoration, mitral plasty was successfully performed in all the patients. Concomitant CABG was performed in seven, tricuspid surgery in 11 and cardiac resynchronisation therapy (CRT) in eight. Perioperative intra-aortic balloon pumping (IABP) was used in six and there was no hospital mortality, including eight emergent operations. After the operation, 29 patients (80.6%) improved their functional class into class I or II. In the late follow-up, there were two cardiac deaths and one noncardiac death and the 4-year survival rate was 85.8%. CONCLUSIONS: The site selection with speckle-tracking echocardiography demonstrated the accurate akinetic lesion of the posterior LV wall. The posterior restoration with preservation of bilateral papillary muscles and LV apex based on the site selection improved operative and mid-term results in the selected patients with DCM. PMID- 20194033 TI - Interleukin-22 is a negative regulator of the allergic response. AB - A proinflammatory role of T helper (Th)17 cells, producing IL-22 and IL-17A, has been favored although there is evidence for negative immune regulation by IL-17A. Here we show that IL-22 was produced during an allergic response in lungs of mice, immunized and challenged with ovalbumin (OVA), and that IL-22 neutralization further augmented the eosinophil recruitment to the lung. In a second allergy model, transfer of OVA-pulsed dendritic cells (DC) into naive mice conveyed eosinophil recruitment in response to subsequent inhaled OVA challenge, while DC preincubation with recombinant IL-22 abolished this response. Similarly, DC preincubation with IL-17A abolished DC-driven eosinophil recruitment, showing that both Th17 cytokines IL-22 and IL-17A mediate negative regulation of allergy by acting on DCs. Therefore, IL-22 inhibits DC functions and attenuates an allergic response. PMID- 20194034 TI - A novel mass spectrometry cluster for high-throughput quantitative proteomics. AB - We have developed and implemented a novel mass spectrometry (MS) platform combining the advantages of high mass accuracy and resolving power of Fourier transform ion cyclotron resonance (FTICR) with the economy and speed of multiple ion traps for tandem mass spectrometry. The instruments are integrated using novel algorithms and software and work in concert as one system. Using chromatographic time compression, a single expensive FTICR mass spectrometer can match the throughput of multiple relatively inexpensive ion trap instruments. Liquid chromatography (LC)-mass spectrometry data from the two types of spectrometers are aligned and combined to hybrid datasets, from which peptides are identified using accurate mass from the FTICR data and tandem mass spectra from the ion trap data. In addition, the high resolving power and dynamic range of a 12 tesla FTICR also allows precise label-free quantitation. Using two ion traps in parallel with one LC allows simultaneous MS/MS experiments and optimal application of collision induced dissociation and electron-transfer dissociation throughout the chromatographic separation for increased proteome coverage, characterization of post-translational modifications and/or simultaneous measurement in positive and negative ionization mode. An FTICR-ion trap cluster can achieve similar performance and sample throughput as multiple hybrid ion trap FTICR instruments, but at a lower cost. We here describe the first such FTICR-ion trap cluster, its performance and the idea of chromatographic compression. PMID- 20194035 TI - Effect of the contraction of medial rotators of the tibia on the electromyographic activity of vastus medialis and vastus lateralis. AB - PURPOSE: This study attempted to assess if the resisted contraction of medial rotators of the tibia increases the ratio between the activity of vastus medialis (VM) and vastus lateralis (VL) during maximal isometric contractions (MIC) of the quadriceps femoral (QF) muscle at 90 degrees of knee flexion. METHODS: About 24 female subjects participated in this study, performing four series MIC of the QF. In the first series subjects performed only MIC of the QF muscle, whereas in the other three there was MIC of the QF with resisted contraction of medial rotators of the tibia, with the tibia positioned in medial, neutral and lateral rotation. During each contraction, VM and VL electromyographic signal (EMGs) and QF force were collected, being the EMGs root mean square (RMS) used to access the activity level of these muscles. RESULTS: The use of the General Linear Model (GLM) test showed that for alpha=0.05 there was a significant increase in the VM:VL ratio when the resisted contraction of medial rotators of the tibia was performed with the tibia in medial (p=<0.0001), neutral (p=<0.0001) and lateral rotation (p=0.001). The same test showed that during MIC of the QF associated to resisted contraction of medial rotators of the tibia there were no significant differences in the VM:VL ratio between the three tibial rotation positions adopted (p=0.866 [medial-neutral]; p=0.106 [medial-lateral]; p=0.068 [neutral-lateral]). CONCLUSIONS: The resisted contraction of medial rotators of the tibia increases the VM:VL ratio during MIC of the QF and the tibial rotation position does not influence the VM:VL ratio during MIC associated to resisted contraction of medial rotators of the tibia. PMID- 20194036 TI - Anterior striatum with dysmorphic neurons associated with the epileptogenesis of focal cortical dysplasia. AB - The epileptogenesis of the striatum is unknown. We describe the case of a 12-year old girl with intractable epilepsy who was treated by surgical interventions. Magnetic resonance imaging (MRI) showed ambiguous corticomedullary boundary in the left frontal lobe, and magnetoencephalography (MEG) revealed spike dipoles in the vicinity of the left ventral striatum. The epileptic seizures disappeared after partial resection of the frontal lobe, but recurred within 2 months and remained intractable. Neuropathological examination confirmed the presence of focal cortical dysplasia in the resected brain tissue. Ictal single photon emission computed tomography at this period displayed hyperperfusion of the left anterior striatum. At the second surgery, intraoperative electrocorticography exhibited spike discharges from the anterior striatum. After the removal of this structure and adjacent brain tissues, the patient remains seizure-free for 33 months, without any neurological deficits. Histopathological examination of the resected tissue revealed a large number of dysmorphic neurons distributed widely in the cerebral cortex, subcortical white matter, striatum, and insular cortex. These findings suggest that microscopic dysplasia of basal ganglia can accompany certain cases of focal cortical malformations, and may play a critical role in the epileptogenesis through their interaction with cortical structures. PMID- 20194037 TI - Chromatin regulation by RUNX1. AB - The transcription factor RUNX1 is essential for definitive hematopoiesis and is required for the expression of a number of important hematopoietic regulator genes. It was recently shown that RUNX1 acts within a narrow developmental window during which it cannot be replaced by other members of the RUNX transcription factor family. Studies of the molecular basis of this phenomenon revealed that RUNX1 is required for the opening of chromatin of important hematopoietic regulator genes and for the formation, but not the maintenance of stable transcription factor complexes on these genes. However, the chromatin opening activity of RUNX1 is context dependent, indicating that it cooperates with alternate transcription factors at different stages of hematopoietic development. This review summarizes recent results on the regulation of chromatin structure by RUNX1 in developing hematopoietic cells. PMID- 20194038 TI - The association between supra-physiological levels of estradiol and response patterns to experimental pain. AB - The precise mechanism by which gonadal hormones influence pain perception is still obscure. However, no studies have examined experimental pain responses at supra-physiological hormone levels. This study explored the influence of pharmacological estradiol (E2) levels on the stability of pain perception obtained via quantitative sensory testing. A repeated measures design was used with 31 women, treated by a same In Vitro Fertilization (IVF) protocol. Patterns of experimental pain response were assessed in three different sessions (baseline, down regulation, maximal ovarian stimulation). Correlations between hormonal levels (E2, progesterone, luteinizing hormone (LH)) and pain perceptions were assessed at each session. While in the entire sample the pattern of response to pain stimulations remained unchanged regardless of hormonal manipulations, a greater pain sensitivity was associated with supra-physiological levels of E2 during the maximal ovarian stimulation session (for 47 degrees C stimulation: r=.383, p=0.044). Mixed model repeated measures ANOVA indicated that participants who over-responded to the ovarian stimulation session (E2 > 10,500 pmol/l) showed significant enhanced pain responses under this condition (p=0.004). No correlations between progesterone, LH and experimental pain perception were found in any of the study sessions. Although pain perceptions at different E2 levels remained constant, the enhancement of pain scoring at supra-physiological E2 levels, underscore the possible role of sex hormones in pain modulation and experience. PMID- 20194039 TI - Blind separation of electron paramagnetic resonance signals using diversity minimization. AB - This paper presents a method for the blind separation of Electron Paramagnetic Resonance (EPR) spectroscopy signals that can aid in the detection of free radicals in living organisms. Observed EPR signals are often mixtures of source signals that are approximately "sparse", with a small number of narrow segments of the signal much larger than the remaining parts. We develop a method to separate the sources through minimizing a p-norm-like diversity measure under some mild assumptions which are generally valid for EPR signals. Simulations demonstrate that the proposed method performs well on EPR signal separation, with better robustness to noise compared to other techniques. PMID- 20194040 TI - Structural study of the membrane protein MscL using cell-free expression and solid-state NMR. AB - High-resolution structures of membrane proteins have so far been obtained mostly by X-ray crystallography, on samples where the protein is surrounded by detergent. Recent developments of solid-state NMR have opened the way to a new approach for the study of integral membrane proteins inside a membrane. At the same time, the extension of cell-free expression to the production of membrane proteins allows for the production of proteins tailor made for NMR. We present here an in situ solid-state NMR study of a membrane protein selectively labeled through the use of cell-free expression. The sample consists of MscL (mechano sensitive channel of large conductance), a 75kDa pentameric alpha-helical ion channel from Escherichia coli, reconstituted in a hydrated lipid bilayer. Compared to a uniformly labeled protein sample, the spectral crowding is greatly reduced in the cell-free expressed protein sample. This approach may be a decisive step required for spectral assignment and structure determination of membrane proteins by solid-state NMR. PMID- 20194041 TI - Early-onset atypical ischemic maculopathy after bone marrow transplantation. AB - Typical ischemic retinal microvascular changes after bone marrow transplantation is a well-established entity and is seen in up to 7% of allogenic transplant recipients. Such cases are characterized by symmetric presence of cotton wool spots, retinal hemorrhages, and multiple microaneurysms and have a good visual prognosis. In this report we describe a case of atypical ischemic maculopathy with poor visual recovery after bone marrow transplantation. PMID- 20194042 TI - QSAR models for predicting cathepsin B inhibition by small molecules--continuous and binary QSAR models to classify cathepsin B inhibition activities of small molecules. AB - Cathepsin B is a potential target for the development of drugs to treat several important human diseases. A number of inhibitors targeting this protein have been developed in the past several years. Recently, a group of small molecules were identified to have inhibitory activity against cathepsin B through high throughput screening (HTS) tests. In this study, traditional continuous and binary QSAR models were built to classify the biological activities of previously identified compounds and to distinguish active compounds from inactive compounds for drug development based on the calculated molecular and physicochemical properties. Strong correlations were obtained for the continuous QSAR models with regression correlation coefficients (r(2)) and cross-validated correlation coefficients (q(2)) of 0.77 and 0.61 for all compounds, and 0.82 and 0.68 for the compound set excluding 3 outliers, respectively. The models were further validated through the leave-one-out (LOO) method and the training-test set method. The binary models demonstrated a strong level of predictability in distinguishing the active compounds from inactive compounds with accuracies of 0.89 and 0.94 for active and inactive compounds, respectively, in non-cross validated models. Similar results were obtained for the cross-validated models. Collectively, these results demonstrate the models' ability to discriminate between active and inactive compounds, suggesting that the models may be used to pre-screen compounds to facilitate compound optimization and to design novel inhibitors for drug development. PMID- 20194043 TI - Clinical osteoarthritis predicts physical and psychological QoL in acromegaly patients. AB - OBJECTIVE: Quality of life is decreased in patients with long-term control of acromegaly. In addition, these patients suffer from irreversible osteoarthritis. The aim of this study was to assess the impact of joint-specific complaints, clinical and radiological signs of arthropathy on different aspects of quality of life (QoL) in patients with acromegaly after long-term disease control. DESIGN: Cross-sectional study. METHODS: We studied 58 patients (31 males), mean age 60 years (range 32-81 years), with strict biochemical control of acromegaly for a mean duration of 15 years. QoL was assessed by four health-related QoL questionnaires (HADS, MFI-20, NHP, SF-36) and one disease specific QoL questionnaire (AcroQoL). The outcomes of these questionnaires were compared with joint-specific self-reported complaints of pain/stiffness, clinical osteoarthritis based on American College of Rheumatology (ACR) and radiological osteoarthritis based on the Kellgren-Lawrence (KL) scoring method. RESULTS: Long term cured acromegaly patients had high pain scores of the spine, knee, and hip which limited physical functioning (mean difference -27.0, 95%-CI -9.5, -41.0) and psychological well-being (mean difference -44.4, 95%-CI -26.1, -60.9) (SF 36). Clinical osteoarthritis of the spine was associated mostly with impaired QoL scores, on physical, social, and emotional functioning, and on anxiety and depression. Remarkably, radiological osteoarthritis was not associated with impaired QoL. CONCLUSION: These findings accentuate the importance of recognition of the clinical manifestations of arthropathy in patients with acromegaly despite long-term disease control. PMID- 20194044 TI - Treatment of toxoplasmic lymphadenitis with co-trimoxazole: double-blind, randomized clinical trial. AB - BACKGROUND: Lymphadenitis is one of the presenting signs of toxoplasmosis. Co trimoxazole (CTM) has a good therapeutic effect on ocular and cerebral infections caused by Toxoplasma gondii. Since this infection is endemic in Ahvaz and because of the lack of investigations into the therapeutic effects of CTM in toxoplasmic lymphadenitis (TL), this study was performed from 2005 to 2007 to determine the therapeutic effects of CTM on TL in Ahvaz. METHODS: Forty-six patients with TL were enrolled in this randomized, double-blind, placebo-controlled trial study. Diagnosis was based on clinical examination, serological tests (chemiluminescent), and histopathological examinations. Palpable lymph nodes, IgM >8IU, and follicular hyperplasia were defined as positive findings. Patients were randomly assigned to the comparison groups (23 patients in each group). The CTM patients were treated with 48 mg/kg/day CTM divided into two doses, for 1 month. The placebo patients were treated with placebo for 1 month. The primary endpoint for treatment response was 1 month. Follow-up with physical and serological examinations occurred at 6 months. The secondary endpoint was at 6 months. Clinical response was defined as no palpable lymph nodes and serological response as IgM <6IU; a patient was cured if the lymph nodes were no longer palpable and IgM was <6IU. Results were analyzed using SPSS software and the Chi-square test. RESULTS: At the end of treatment, a clinical response was observed in 15 (65.2%) in the CTM group and five (21.7%) in the placebo group. A serological response was seen in 65.2% of the CTM group and 13.0% of the placebo group. The cure rate was 65.2% in the CTM group and 13.1% in the placebo group. There was a significant difference in therapeutic effect between the two groups (52.2%, 95% confidence interval 32.1-72%, p<0.001). There was no difference in the site of infection between the two groups (p>0.05). CONCLUSION: CTM has a good therapeutic effect in TL and may be used in selected patients for whom treatment is required. PMID- 20194045 TI - Multiple fluid-filled bone metastases. AB - Bone metastases are usually seen on imaging studies as lytic lesions and less often as sclerotic or mixed lesions. We report an exceedingly unusual case of breast cancer identified after magnetic resonance imaging showed bone metastases with fluid-fluid levels in the spine and sacrum. Bone images containing fluid fluid levels are usually solitary abnormalities produced by aneurismal bone cysts. The fluid-fluid level is due to bleeding within the tumor followed by layering of the blood components based on density differences. Only two other cases of bone metastases with multiple fluid-fluid levels have been reported. Although fluid-fluid levels are exceedingly rare, clinicians should be aware that they might indicate a malignancy, particularly when they are multiple. PMID- 20194046 TI - Ionic liquid [EMIM]OAc under ultrasonic irradiation towards the first synthesis of trisubstituted imidazoles. AB - The ionic liquid 1-ethyl-3-methylimidazole acetate ([EMIM]OAc) was found to be a mild and effective catalyst for the efficient, one-pot, three-component synthesis of 2-aryl-4,5-diphenyl imidazoles at room temperature under ultrasonic irradiation. This procedure has many obvious advantages compared to those reported in the previous literatures, including avoiding the use of harmful catalysts, reacting at room temperature, high yields, simplicity of the methodology. PMID- 20194047 TI - Third-order nonlinear optical properties and structures of (E)-N-(4 nitrobenzylidene)-2,6-dimethylaniline and (E)-N-(4-nitrobenzylidene)-2,3 dimethylaniline. AB - (E)-N-(4-Nitrobenzylidene)-2,6-dimethylaniline (1) and (E)-N-(4-nitrobenzylidene) 2,3-dimethylaniline (2) have been synthesized. The crystal structures of both compounds have been defined by X-ray diffraction analysis. The maximum one-photon absorption (OPA) wavelengths recorded by quantum mechanical computations using a configuration interaction (CI) method are estimated in the UV region to be shorter than 450nm, showing good optical transparency to the visible light. To provide an insight into the microscopic third-order nonlinear optical (NLO) properties of the investigated molecules, both dispersion-free (static) and also frequency-dependent (dynamic) linear polarizabilities (alpha) and second hyperpolarizabilities (gamma) at lambda=825-1125nm and 1050-1600nm wavelength areas have been computed using time-dependent Hartree-Fock (TDHF) method. According to the ab initio calculation results, the title molecules exhibit second hyperpolarizabilities with non-zero values, implying microscopic third order NLO behavior. PMID- 20194048 TI - Nearest-neighbour-interaction model in the coupled-optical-phonon-mode theory of the infrared dispersion in monoclinic crystals: Application to Tutton salt single crystal. AB - The coupled-optical-phonon-mode theory of Barker and Hopfield of two mode interaction in isotropic crystals has been extended to monoclinic crystals. The analytical expressions for the calculation of the dielectric tensor elements in the ac crystal plane have been derived. It has been shown that the interaction dielectric model is a generalized expression of the dielectric tensor for monoclinic case when no interaction between modes is present. Also, the results of Barker and Hopfield are obtained from this more general theory, when an isotropic case is considered. In order to be able to investigate real crystals, meaning extending the interactions to a large number of pairs of modes, but at the same time to make the fitting procedure possible, a model dielectric function taking into account the interaction between modes with closest frequencies has been derived. The validity of the model obtained has been tested on a Tutton salt single crystal of K(2)Co(SO(4))(2).6H(2)O. The recorded spectra from the ac crystal plane were fitted in order to obtain best fit parameters. The comparison between the experimentally recorded spectra and the model reflectance function give good results and verify this model to be applicable. PMID- 20194049 TI - Involvement of the peripheral nerves in oculopharyngeal muscular dystrophy. PMID- 20194050 TI - Insulin resistance, adipose depots and gut: interactions and pathological implications. AB - This review article focuses on the many metabolic actions of insulin at the level of muscle, liver and adipose tissue. In terms of pathogenetic mechanisms, the condition of insulin resistance is complex, as multiple genetic and environmental factors, among which an increasingly sedentary lifestyle associated with high-fat diet, mutually interact according to variable patterns in time in any given individual. It is well recognized that obesity (in particular abdominal obesity) favours the development of insulin resistance. Here we evaluate the impact of obesity and ectopic fat accumulation (visceral and hepatic) on insulin resistance at the level of different target organs, i.e., muscle, liver and adipose tissue. The roles of the gut and the liver, in particular of bile acids and gut microflora, are also discussed as possible determinants of energy balance and glucose metabolism. PMID- 20194051 TI - Osteogenic capacity of vascularised periosteum: an experimental study on mandibular irradiated bone in rabbits. AB - BACKGROUND: Free flaps are presently the best way to treat advanced mandibular ostonecrosis. Nevertheless, the functional and morphological results can be improved. To avoid a mandibular resection, a free periosteal flap was envisioned. In a preliminary study, the authors opted for a pedicled periosteal flap and evaluated the effect of the latter on regeneration of a rabbit irradiated mandibular bone. METHODS: Two bone fragments were taken from the basilar part of the mandible of 15 rabbits through skin incision. Those fragments were then exposed to a 30-Gy irradiation. One bone fragment was implanted in a pedicled periosteal flap elevated from the medial aspect of the femur while the other was subcutaneously fixed as a control. We retrieved the fragments at day 10, 20, 30 and 90 to make a histological analysis without prior decalcification using histomorphometry technique. RESULTS: In the periosted fragments, an increased osteoblastic and osteoclastic activity as well as neovascularisation evoked intense remodelling. In the subcutaneous fragments, bone resorption was much more important than osteogenesis and vessels were absent. CONCLUSION: We have concluded than periosteum, which has already been proven to be efficient in normal bone regeneration, can be just as such efficient in irradiated bone regeneration. PMID- 20194052 TI - Primary Care Diabetes. Editorial. PMID- 20194053 TI - The impact of surgical specialty on outcomes for carotid endarterectomy. AB - BACKGROUND: Carotid endarterectomy (CEA) is one of the most frequently performed surgical procedures in the United States. Traditionally, this procedure has been performed by surgeons in at least four specialties. The purpose of this study was to examine the effect of surgeon specialty on the long-term outcomes of CEA among patients receiving the procedure in Pennsylvania. MATERIALS AND METHODS: Data included 17,635 patient admissions for CEA performed between 1995 and 1997, and patient readmission data for the 5-y follow-up period ending in 2002. Five-y outcomes for these patients were compared between vascular, cardiothoracic, general, and neurosurgeons. The primary outcome measures were mortality, stroke, combined stroke and mortality, transient ischemic attack (TIA), and re-occlusion of the ipsilateral artery. Secondary outcomes measured were length of stay and total charges. RESULTS: Using general surgeon as the reference group, and controlling for age, race, severity, and admission type, we found no significant difference across surgical specialties in overall mortality at 5 y post-CEA. Patients treated by vascular surgeons were found to have significantly fewer (P=0.012) strokes and significantly lower re-occlusion rate (P=0.021) at 5 y compared with patients of general surgeons. Patients treated by vascular surgeons also had significantly shorter hospital stay (P<0.0001) but significantly higher charges (P<0.0001) relative to general surgeons. CONCLUSIONS: These results suggest that there are significant differences in outcomes following carotid endarterectomy according to surgeon training. Additional research is needed to explore differences across specialties that may be driving outcomes and to explore the role of surgeon volume at the profession level and cross-volume effects on CEA outcomes. PMID- 20194054 TI - Path control: a method for patient-cooperative robot-aided gait rehabilitation. AB - Gait rehabilitation robots are of increasing importance in neurorehabilitation. Conventional devices are often criticized because they are limited to reproducing predefined movement patterns. Research on patient-cooperative control strategies aims at improving robotic behavior. Robots should support patients only as much as needed and stimulate them to produce maximal voluntary efforts. This paper presents a patient-cooperative strategy that allows patients to influence the timing of their leg movements along a physiologically meaningful path. In this "path control" strategy, compliant virtual walls keep the patient's legs within a "tunnel" around the desired spatial path. Additional supportive torques enable patients to move along the path with reduced effort. Graphical feedback provides visual training instructions. The path control strategy was evaluated with 10 healthy subjects and 15 subjects with incomplete spinal cord injury. The spatio temporal characteristics of recorded kinematic data showed that subjects walked with larger temporal variability with the new strategy. Electromyographic data indicated that subjects were training more actively. A majority of iSCI subjects was able to actively control their gait timing. Thus, the strategy allows patients to train walking while being helped rather than controlled by the robot. PMID- 20194055 TI - Margin-maximizing feature elimination methods for linear and nonlinear kernel based discriminant functions. AB - Feature selection for classification in high-dimensional spaces can improve generalization, reduce classifier complexity, and identify important, discriminating feature "markers." For support vector machine (SVM) classification, a widely used technique is recursive feature elimination (RFE). We demonstrate that RFE is not consistent with margin maximization, central to the SVM learning approach. We thus propose explicit margin-based feature elimination (MFE) for SVMs and demonstrate both improved margin and improved generalization, compared with RFE. Moreover, for the case of a nonlinear kernel, we show that RFE assumes that the squared weight vector 2-norm is strictly decreasing as features are eliminated. We demonstrate this is not true for the Gaussian kernel and, consequently, RFE may give poor results in this case. MFE for nonlinear kernels gives better margin and generalization. We also present an extension which achieves further margin gains, by optimizing only two degrees of freedom--the hyperplane's intercept and its squared 2-norm--with the weight vector orientation fixed. We finally introduce an extension that allows margin slackness. We compare against several alternatives, including RFE and a linear programming method that embeds feature selection within the classifier design. On high-dimensional gene microarray data sets, University of California at Irvine (UCI) repository data sets, and Alzheimer's disease brain image data, MFE methods give promising results. PMID- 20194056 TI - Memory-efficient fully coupled filtering approach for observational model building. AB - Generally, training neural networks with the global extended Kalman filter (GEKF) technique exhibits excellent performance at the expense of a large increase in computational costs which can become prohibitive even for networks of moderate size. This drawback was previously addressed by heuristically decoupling some of the weights of the networks. Inevitably, ad hoc decoupling leads to a degradation in the quality (accuracy) of the resultant neural networks. In this paper, we present an algorithm that emulates the accuracy of GEKF, but avoids the construction of the state covariance matrix-the source of the computational bottleneck in GEKF. In the proposed algorithm, all the synaptic weights remain connected while the amount of computer memory required is similar to (or cheaper than) the memory requirements in the decoupling schemes. We also point out that the new method can be extended to derivative-free nonlinear Kalman filters, such as the unscented Kalman filter and ensemble Kalman filters. PMID- 20194057 TI - A game theory approach to target tracking in sensor networks. AB - In this paper, we investigate a moving-target tracking problem with sensor networks. Each sensor node has a sensor to observe the target and a processor to estimate the target position. It also has wireless communication capability but with limited range and can only communicate with neighbors. The moving target is assumed to be an intelligent agent, which is "smart" enough to escape from the detection by maximizing the estimation error. This adversary behavior makes the target tracking problem more difficult. We formulate this target estimation problem as a zero-sum game in this paper and use a minimax filter to estimate the target position. The minimax filter is a robust filter that minimizes the estimation error by considering the worst case noise. Furthermore, we develop a distributed version of the minimax filter for multiple sensor nodes. The distributed computation is implemented via modeling the information received from neighbors as measurements in the minimax filter. The simulation results show that the target tracking algorithm proposed in this paper provides a satisfactory result. PMID- 20194058 TI - Formaldehyde exposure among children: a potential building block of asthma. PMID- 20194059 TI - Particulate soup: identifying the most toxic constituents of PM(2.5). PMID- 20194060 TI - Better burning, better breathing: improving health with cleaner cook stoves. PMID- 20194061 TI - From one womb to another: early estrogenic exposures and later fibroid risk. PMID- 20194062 TI - Synthetic biology: environmental health implications of a new field. PMID- 20194064 TI - Americas' dengue escalation is real--and shifting. PMID- 20194066 TI - Policy: EPA's ground-level ozone standard redux. PMID- 20194067 TI - Association of intrauterine and early-life exposures with diagnosis of uterine leiomyomata by 35 years of age in the Sister Study. AB - BACKGROUND: Early-life exposures to hormonally active compounds and other factors may affect later response to estrogen or progesterone and hence may influence development of uterine leiomyomata (fibroids). OBJECTIVES: We evaluated associations of in utero and early-life exposures, including soy formula, with self-report of physician-diagnosed fibroids by 35 years of age. METHODS: Our study included 19,972 non-Hispanic white women who were 35-59 years of age when they enrolled in the Sister Study in 20032007. We estimated risk ratios (RRs) and 95% confidence intervals (CIs) using log-binomial regression models for fibroid associations with adjustment for participant's age and education, maternal age at participant's birth, birth order, and childhood family income. RESULTS: Greater risk of early fibroid diagnosis was associated with soy formula during infancy (RR = 1.25; 95% CI, 0.971.61), maternal prepregnancy diabetes (RR = 2.05; 95% CI, 1.163.63), low childhood socioeconomic status (RR = 1.28; 95% CI, 1.011.63), and gestational age at birth (RR = 1.64; 95% CI, 1.272.13, for being born at least 1 month early). In utero diethylstilbestrol (DES) exposure was also associated with early fibroid diagnosis (RR = 1.42; 95% CI, 1.131.80), but this association was driven by women reporting probable rather than definite exposure. CONCLUSIONS: There are plausible biological pathways by which these early-life factors could promote fibroid pathogenesis. This is the first epidemiologic study to evaluate such exposures, with the exception of in utero DES, in relation to fibroid risk, and replication of findings in other populations is needed. PMID- 20194068 TI - House dust concentrations of organophosphate flame retardants in relation to hormone levels and semen quality parameters. AB - BACKGROUND: Organophosphate (OP) compounds, such as tris(1,3-dichloro-2-propyl) phosphate (TDCPP) and triphenyl phosphate (TPP), are commonly used as additive flame retardants and plasticizers in a wide range of materials. Although widespread human exposure to OP flame retardants is likely, there is a lack of human and animal data on potential health effects. OBJECTIVE: We explored relationships of TDCPP and TPP concentrations in house dust with hormone levels and semen quality parameters. METHODS: We analyzed house dust from 50 men recruited through a U.S. infertility clinic for TDCPP and TPP. Relationships with reproductive and thyroid hormone levels, as well as semen quality parameters, were assessed using crude and multivariable linear regression. RESULTS: TDCPP and TPP were detected in 96% and 98% of samples, respectively, with widely varying concentrations up to 1.8 mg/g. In models adjusted for age and body mass index, an interquartile range (IQR) increase in TDCPP was associated with a 3% [95% confidence interval (CI), 5% to 1%) decline in free thyroxine and a 17% (95% CI, 432%) increase in prolactin. There was a suggestive inverse association between TDCPP and free androgen index that became less evident in adjusted models. In the adjusted models, an IQR increase in TPP was associated with a 10% (95% CI, 219%) increase in prolactin and a 19% (95% CI, 30% to 5%) decrease in sperm concentration. CONCLUSION: OP flame retardants may be associated with altered hormone levels and decreased semen quality in men. More research on sources and levels of human exposure to OP flame retardants and associated health outcomes are needed. PMID- 20194069 TI - Probabilistic Modeling of Dietary Arsenic Exposure and Dose and Evaluation with 2003-2004 NHANES Data. AB - BACKGROUND: Dietary exposure from food to toxic inorganic arsenic (iAs) in the general U.S. population has not been well studied. OBJECTIVES: The goal of this research was to quantify dietary As exposure and analyze the major contributors to total As (tAs) and iAs. Another objective was to compare model predictions with observed data. METHODS: Probabilistic exposure modeling for dietary As was conducted with the Stochastic Human Exposure and Dose Simulation Dietary (SHEDS Dietary) model, based on data from the National Health and Nutrition Examination Survey. The dose modeling was conducted by combining the SHEDS-Dietary model with the MENTOR-3P (Modeling ENvironment for TOtal Risk with Physiologically Based Pharmacokinetic Modeling for Populations) system. Model evaluation was conducted via comparing exposure and dose-modeling predictions against duplicate diet data and biomarker measurements, respectively, for the same individuals. RESULTS: The mean modeled tAs exposure from food is 0.38 microg/kg/day, which is approximately 14 times higher than the mean As exposures from the drinking water. The mean iAs exposure from food is 0.05 microg/kg/day (1.96 microg/day), which is approximately two times higher than the mean iAs exposures from the drinking water. The modeled exposure and dose estimates matched well with the duplicate diet data and measured As biomarkers. The major food contributors to iAs exposure were the following: vegetables (24%); fruit juices and fruits (18%); rice (17%); beer and wine (12%); and flour, corn, and wheat (11%). Approximately 10% of tAs exposure from foods is the toxic iAs form. CONCLUSIONS: The general U.S. population may be exposed to tAs and iAs more from eating some foods than from drinking water. In addition, this model evaluation effort provides more confidence in the exposure assessment tools used. PMID- 20194070 TI - Three decades of silicosis: disease trends at autopsy in South African gold miners. AB - BACKGROUND: Eliminating silicosis is a priority of the International Labour Organization and the World Health Organization. Prevalence is particularly high in developing countries. OBJECTIVES: We describe trends in silicosis among South African gold miners who had had an autopsy between 1975 and 2007 and quantify the contributions of age at autopsy and employment duration to these trends. METHODS: South African miners and ex-miners are eligible for autopsy examination for occupational lung disease, regardless of the clinical cause of death, and the families of deceased mine workers may receive compensation from the government of South Africa. Miners who died from external causes and who had been employed in the gold mines for > 1 year were stratified by population group because of differences in exposure, patterns of employment, and autopsy referral patterns. We extracted data from PATHAUT (Pathology Automation System) and used Stata 10 to estimate trends in relative proportions of silicosis that were standardized for age and employment duration. RESULTS: The crude proportion of silicosis for white miners was six times that of black miners in 1975. By 2007, it was 1.5 times higher for black miners. The proportion of miners with silicosis increased from 0.03 to 0.32 for black miners and from 0.18 to 0.22 for white miners. The increase can be explained by increasing age and employment duration for white miners. For black miners, it can be only partly explained by these two factors. CONCLUSION: As miners continue to age and work for longer periods, the burden of silicosis will continue to rise. South Africa is committed to global efforts to eliminate silicosis by 2030. The autopsy database allows for disease surveillance, which is necessary to monitor the success of this initiative. PMID- 20194071 TI - Environmental levels of para-nonylphenol are able to affect cytokine secretion in human placenta. AB - BACKGROUND: para-Nonylphenol (p-NP) is a metabolite of alkylphenols widely used in the chemical industry and manufacturing. It accumulates in the environment, where it acts with estrogen-like activity. We previously showed that p-NP acts on human placenta by inducing trophoblast differentiation and apoptosis. OBJECTIVE: The aim of the present study was to investigate the effect of p-NP on cytokine secretion in human placenta. METHODS: In vitro cultures of chorionic villous explants from human placenta in the first trimester of pregnancy were treated with p-NP (10(13), 10(11), and 10(9) M) in 0.1% ethanol as vehicle. Culture medium was collected after 24 hr and assayed by specific immunoassays for the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon gamma (IFN-gamma), interleukin (IL)-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and tumor necrosis factor-alpha (TNF-alpha). RESULTS: p-NP modulated cytokine secretion by inducing the release of GM-CSF, IFN-gamma, IL-1beta, IL-4, and IL 10, with a maximum effect at 10(11) M. It reduced the release of TNF-alpha at 10(13) M, whereas levels of IL-2 and IL-5 remained below the detection limit. IL 6 and IL-8 levels were 1001,000 times higher than those of other cytokines, and they were not affected by p-NP. We observed significant differences from controls (ethanol alone) only for GM-CSF and IL-10. CONCLUSION: An unbalanced cytokine network at the maternal--fetal interface may result in implantation failure, pregnancy loss, or other complications. The effects of extremely low doses of p NP on the placental release of cytokines raise considerable concerns about maternal exposure to this endocrine disruptor during pregnancy. PMID- 20194074 TI - International Environmental Health: new MPH program a first for India. PMID- 20194072 TI - Interaction between GSTM1/GSTT1 polymorphism and blood mercury on birth weight. AB - BACKGROUND: Mercury (Hg) is toxic to both the reproductive and nervous systems. In addition, glutathione S-transferases (GSTs), which conjugate glutathione to a variety of electrophilic compounds, are involved in the detoxification of Hg. OBJECTIVE: In this study we examined the association between prenatal exposure to Hg and birth weight as well as the influence of GST polymorphisms. METHODS: The total Hg concentration in maternal and cord blood was measured from 417 Korean women and newborns in the Mothers and Children's Environmental Health study from 2006 to 2008. Information on birth weight was collected from the patients' medical records. The genotyping of glutathione S-transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1) polymorphisms was carried out using polymerase chain reaction. Regression analysis was performed to determine the association between the blood Hg concentration and birth weight in mothers with GSTM1 and GSTT1 polymorphisms. RESULTS: The geometric mean levels of Hg in the maternal blood during late pregnancy and in cord blood were 3.30 microg/L and 5.53 microg/L, respectively. For mothers with the GSTT1 null genotype, elevated Hg levels in maternal blood during late pregnancy were associated with an increased risk of lower birth weight. For mothers with both GSTM1 and GSTT1 null genotype, both maternal and cord blood Hg levels were associated with lower birth weight. CONCLUSIONS: This study suggests that the interactions of Hg with GSTM1 and GSTT1 polymorphisms play a role in reducing birth weight. PMID- 20194073 TI - An assessment of potential exposure and risk from estrogens in drinking water. AB - BACKGROUND: Detection of estrogens in the environment has raised concerns in recent years because of their potential to affect both wildlife and humans. OBJECTIVES: We compared exposures to prescribed and naturally occurring estrogens in drinking water to exposures to naturally occurring background levels of estrogens in the diet of children and adults and to four independently derived acceptable daily intakes (ADIs) to determine whether drinking water intakes are larger or smaller than dietary intake or ADIs. METHODS: We used the Pharmaceutical Assessment and Transport Evaluation (PhATE) model to predict concentrations of estrogens potentially present in drinking water. Predicted drinking water concentrations were combined with default water intake rates to estimate drinking water exposures. Predicted drinking water intakes were compared to dietary intakes and also to ADIs. We present comparisons for individual estrogens as well as combined estrogens. RESULTS: In the analysis we estimated that a child's exposures to individual prescribed estrogens in drinking water are 730-480,000 times lower (depending upon estrogen type) than exposure to background levels of naturally occurring estrogens in milk. A child's exposure to total estrogens in drinking water (prescribed and naturally occurring) is about 150 times lower than exposure from milk. Adult margins of exposure (MOEs) based on total dietary exposure are about 2 times smaller than those for children. Margins of safety (MOSs) for an adult's exposure to total prescribed estrogens in drinking water vary from about 135 to > 17,000, depending on ADI. MOSs for exposure to total estrogens in drinking water are about 2 times lower than MOSs for prescribed estrogens. Depending on the ADI that is used, MOSs for young children range from 28 to 5,120 for total estrogens (including both prescribed and naturally occurring sources) in drinking water. CONCLUSIONS: The consistently large MOEs and MOSs strongly suggest that prescribed and total estrogens that may potentially be present in drinking water in the United States are not causing adverse effects in U.S. residents, including sensitive subpopulations. PMID- 20194075 TI - Cardiovascular health: exploring a potential link between BPA and heart disease. PMID- 20194076 TI - Endocrine damper? Flame retardants linked to male hormone, sperm count changes. PMID- 20194077 TI - Phosphorylation of p65 is required for zinc oxide nanoparticle-induced interleukin 8 expression in human bronchial epithelial cells. AB - BACKGROUND: Exposure to zinc oxide (ZnO) in environmental and occupational settings causes acute pulmonary responses through the induction of proinflammatory mediators such as interleukin-8 (IL-8). OBJECTIVE: We investigated the effect of ZnO nanoparticles on IL-8 expression and the underlying mechanisms in human bronchial epithelial cells. METHODS: We determined IL-8 mRNA and protein expression in primary human bronchial epithelial cells and the BEAS-2B human bronchial epithelial cell line using reverse-transcriptase polymerase chain reaction and the enzyme-linked immunosorbent assay, respectively. Transcriptional activity of IL-8 promoter and nuclear factor kappa B (NFkappaB) in ZnO-treated BEAS-2B cells was measured using transient gene transfection of the luciferase reporter construct with or without p65 constructs. Phosphorylation and degradation of IkappaBalpha, an inhibitor of NF-kappaB, and phosphorylation of p65 were detected using immunoblotting. Binding of p65 to the IL-8 promoter was examined using the chromatin immunoprecipitation assay. RESULTS: ZnO exposure (2-8 microg/mL) increased IL-8 mRNA and protein expression. Inhibition of transcription with actinomycin D blocked ZnO-induced IL-8 expression, which was consistent with the observation that ZnO exposure increased IL-8 promoter reporter activity. Further study demonstrated that the kappaB binding site in the IL-8 promoter was required for ZnO-induced IL-8 transcriptional activation. ZnO stimulation modestly elevated IkappaBalpha phosphorylation and degradation. Moreover, ZnO exposure also increased the binding of p65 to the IL-8 promoter and p65 phosphorylation at serines 276 and 536. Overexpression of p65 constructs mutated at serines 276 or 536 significantly reduced ZnO-induced increase in IL-8 promoter reporter activity. CONCLUSION: p65 phosphorylation and IkappaBalpha phosphorylation and degradation are the primary mechanisms involved in ZnO nanoparticle-induced IL-8 expression in human bronchial epithelial cells. PMID- 20194078 TI - Relationship between environmental phthalate exposure and the intelligence of school-age children. AB - BACKGROUND: Concern over phthalates has emerged because of their potential toxicity to humans. OBJECTIVE: We investigated the relationship between the urinary concentrations of phthalate metabolites and children's intellectual functioning. METHODS: This study enrolled 667 children at nine elementary schools in five South Korean cities. A cross-sectional examination of urine phthalate concentrations was performed, and scores on neuropsychological tests were obtained from both the children and their mothers. RESULTS: We measured mono-2 ethylhexyl phthalate (MEHP) and mono(2-ethyl-5-oxohexyl)phthalate (MEOHP), both metabolites of di(2-ethylhexyl)phthalate (DEHP), and mono-n-butyl phthalate (MBP), a metabolite of dibutyl phthalate (DBP), in urine samples. The geometric mean (ln) concentrations of MEHP, MEOHP, and MBP were 21.3 microg/L [geometric SD (GSD) = 2.2 microg/L; range, 0.5-445.4], 18.0 microg/L (GSD = 2.4; range, 0.07 291.1), and 48.9 microg/L (GSD = 2.2; range, 2.1-1645.5), respectively. After adjusting for demographic and developmental covariates, the Full Scale IQ and Verbal IQ scores were negatively associated with DEHP metabolites but not with DBP metabolites. We also found a significant negative relationship between the urine concentrations of the metabolites of DEHP and DBP and children's vocabulary subscores. After controlling for maternal IQ, a significant inverse relationship between DEHP metabolites and vocabulary subscale score remained. Among boys, we found a negative association between increasing MEHP phthalate concentrations and the sum of DEHP metabolite concentrations and Wechsler Intelligence Scale for Children vocabulary score; however, among girls, we found no significant association between these variables. CONCLUSION: Controlling for maternal IQ and other covariates, the results show an inverse relationship between phthalate metabolites and IQ scores; however, given the limitations in cross-sectional epidemiology, prospective studies are needed to fully explore these associations. PMID- 20194079 TI - Chronic social stress and susceptibility to concentrated ambient fine particles in rats. AB - BACKGROUND: Epidemiologic evidence suggests that chronic stress may alter susceptibility to air pollution. However, persistent spatial confounding between these exposures may limit the utility of epidemiologic methods to disentangle these effects and cannot identify physiologic mechanisms for potential differential susceptibilities. OBJECTIVES: Using a rat model of social stress, we compared respiratory responses to fine concentrated ambient particles (CAPs) and examined biological markers of inflammation. METHODS: Twenty-four 12-week-old male Sprague-Dawley rats were randomly assigned to four groups [stress/CAPs, stress/filtered air (FA), nonstress/CAPs, nonstress/FA]. Stress-group animals were individually introduced into the home cage of a dominant male twice weekly. Blood drawn at sacrifice was analyzed for immune and inflammatory markers. CAPs were generated using the Harvard ambient particle concentrator, which draws real time urban ambient fine particles, enriching concentrations approximately 30 times. CAPs/FA exposures were delivered in single-animal plethysmographs, 5 hr/day for 10 days, and respiratory function was continuously monitored using a Buxco system. RESULTS: Stressed animals displayed higher average C-reactive protein, tumor necrosis factor-alpha, and white blood cell counts than did nonstressed animals. Only among stressed animals were CAPs exposures associated with increased respiratory frequency, lower flows, and lower volumes, suggesting a rapid, shallow breathing pattern. Conversely, in animals with elevated CAPs exposures alone, we observed increased inspiratory flows and greater minute volumes (volume of air inhaled or exhaled per minute). CONCLUSIONS: CAPs effects on respiratory measures differed significantly, and substantively, by stress group. Higher CAPs exposures were associated with a rapid, shallow breathing pattern only under chronic stress. Blood measures provided evidence of inflammatory responses. Results support epidemiologic findings that chronic stress may alter respiratory response to air pollution and may help elucidate pathways for differential susceptibility. PMID- 20194080 TI - Childhood lead exposure after the phaseout of leaded gasoline: an ecological study of school-age children in Kampala, Uganda. AB - BACKGROUND: Tetraethyl lead was phased out of gasoline in Uganda in 2005. Recent mitigation of an important source of lead exposure suggests examination and re evaluation of the prevalence of childhood lead poisoning in this country. Ongoing concerns persist about exposure from the Kiteezi landfill in Kampala, the country's capital. OBJECTIVES: We determined blood lead distributions among Kampala schoolchildren and identified risk factors for elevated blood lead levels (EBLLs; >or= 10 microg/dL). Analytical approach: Using a stratified, cross sectional design, we obtained blood samples, questionnaire data, and soil and dust samples from the homes and schools of 163 4- to 8-year-old children representing communities with different risks of exposure. RESULTS: The mean blood lead level (BLL) was 7.15 microg/dL; 20.5% of the children were found to have EBLL. Multivariable analysis found participants whose families owned fewer household items, ate canned food, or used the community water supply as their primary water source to have higher BLLs and likelihood of EBLLs. Distance < 0.5 mi from the landfill was the factor most strongly associated with increments in BLL (5.51 microg/dL, p < 0.0001) and likelihood of EBLL (OR = 4.71, p = 0.0093). Dust/soil lead was not significantly predictive of BLL/EBLL. CONCLUSIONS: Lead poisoning remains highly prevalent among school-age children in Kampala. Confirmatory studies are needed, but further efforts are indicated to limit lead exposure from the landfill, whether through water contamination or through another mechanism. Although African nations are to be lauded for the removal of lead from gasoline, this study serves as a reminder that other sources of exposure to this potent neurotoxicant merit ongoing attention. PMID- 20194082 TI - Significance of interictal occipital epileptiform discharges in children. AB - OBJECTIVE: Interictal occipital epileptiform abnormalities have not been well characterized. The objective of this pilot study was to assess their significance in children. METHODS: A search was performed on the EEG database for the keywords "occipital", "spike", "sharp wave" and "epileptiform". Patients were divided into two groups based on the absence of all (group 1) or presence of any (group 2) of the following criteria: mental retardation, cerebral palsy, neurological deficits, abnormal MRI and/or intractable epilepsy. Special attention was given to the spike/sharp wave amplitude/duration and background slowing. RESULTS: A total of 44 children (eight months to 15 years) were studied. Groups 1 and 2 were each composed of 22 children. Background slowing was more frequent in group 2 (10/22, 45%) compared to group 1 (1/22, 4.5%; p = 0.002). In group 2, 8/22 (36%) had spikes or sharp waves with amplitudes below 50 microV or above 150 microV with a positive predictive value of 89%, and a negative predictive value of 39%. Only 1/22 (4.5%) in group 1 had epileptiform activity outside of the 50-150 microV range. CONCLUSIONS: The presence of very high or low-amplitude occipital epileptiform abnormalities or background slowing may be indicative of encephalopathy. PMID- 20194081 TI - Traffic-related air pollution and QT interval: modification by diabetes, obesity, and oxidative stress gene polymorphisms in the normative aging study. AB - BACKGROUND: Acute exposure to ambient air pollution has been associated with acute changes in cardiac outcomes, often within hours of exposure. OBJECTIVES: We examined the effects of air pollutants on heart-rate-corrected QT interval (QTc), an electrocardiographic marker of ventricular repolarization, and whether these associations were modified by participant characteristics and genetic polymorphisms related to oxidative stress. METHODS: We studied repeated measurements of QTc on 580 men from the Veterans Affairs Normative Aging Study (NAS) using mixed-effects models with random intercepts. We fitted a quadratic constrained distributed lag model to estimate the cumulative effect on QTc of ambient air pollutants including fine particulate matter 60%) was in size fractions less than 0.45 microm. The release rates were highest in May and June (15 to 25 nmol L -1 min -1 ) during the Gonyostomum semen (Raphidophyta) bloom and decreased to less than 2 nmol L -1 min -1 in two weeks and remained low throughout the summer and the fall. Fractionation of 32 P-H 3 PO 4 labelled dissolved organic phosphorus showed this fraction to vary considerably through the year. Potential phosphate release declined through the summer and into the fall. Significance of the co-occurrence of phosphomonoesters and acid phosphatase activity maxima and Gonyostomum semen (Raphidophyta) bloom is discussed. PMID- 20194105 TI - Studer unplugged: identifying underlying managerial concepts. AB - There is evidence that the application of Quint Studer's Hardwiring Excellence approach to organizational change is associated with significant accomplishments in hospitals. The authors' review finds the Studer approach to be closely aligned with management-related concepts of motivation and feedback, social networks, human capital, social capital, management by objectives, evidence based management, and organizational learning. The article is intended to familiarize more managers and management researchers with the content of the Studer approach, demonstrate its grounding in management concepts and principles, and stimulate additional discussion around the utility of such human resources-focused interventions in significant organizational change. PMID- 20194106 TI - Evaluation methods for hospital projects. AB - The authors report the findings of a survey of hospital managers on the utilization of various project selection and evaluation methodologies. The focus of the analysis was the empirical relationship between a portfolio of project evaluation(1) methods actually utilized for a given project and several measures of perceived project success. The analysis revealed that cost-benefit analysis and top management support were the two project evaluation methods used most often by the hospital managers. The authors' empirical assessment provides evidence that top management support is associated with overall project success. PMID- 20194107 TI - Adverse medical events: do they influence discharge decisions? AB - The author examined relationships between adverse medical events (AMEs) on discharge decisions. Using secondary data capturing inpatient utilization from Oklahoma hospitals, the author employed logistic regression to estimate the probability of extended hospital stay and the need for postacute care as a function of AMEs, and multiple regression analysis to assess the effect of AMEs on the number of days of care. Findings showed that an AME increased the likelihood of extended hospital stay, number of extended days of care, and needed postacute care. Findings indicated that reducing AME incidence would likely improve quality while reducing healthcare utilization and spending. PMID- 20194108 TI - RFIDs can improve the patient care supply chain. AB - Technologies that increase efficiency, enhance quality, and improve patient safety are essential for all healthcare organizations. Radio frequency identification devices (RFIDs) seem to be right for this challenge. RFIDs can be integrated into all areas of the internal patient supply chain, serving as clearinghouses of information. By providing timely information on patients, processes, and equipment, RFIDs can save time and reduce costs while simultaneously improving quality and patient safety. Healthcare leaders owe it to all constituencies to take a serious look at what RFIDs can offer. PMID- 20194109 TI - Sphingolipidomics of A2780 human ovarian carcinoma cells treated with synthetic retinoids. AB - The dihydroceramide, ceramide, sphingomyelin, lactosylceramide, and ganglioside species of A2780 human ovarian carcinoma cells treated with the synthetic retinoids N-(4-hydroxyphenyl)retinamide (fenretinide, 4-HPR) and 4-oxo-N-(4 hydroxyphenyl)retinamide (4-oxo-4-HPR) in culture were characterized by ESI-MS. We characterized 32 species of ceramide and dihydroceramide, 15 of sphingomyelin, 12 of lactosylceramide, 9 of ganglioside GM2, and 6 of ganglioside GM3 differing for the long-chain base and fatty acid structures. Our results indicated that treatment with both 4-HPR and 4-oxo-4-HPR led to a marked increase in dihydroceramide species, while only 4-oxo-4-HPR led to a minor increase of ceramide species. Dihydroceramides generated in A2780 cells in response to 4-HPR or 4-oxo-4-HPR differed for their fatty acid content, suggesting that the two drugs differentially affect the early steps of sphingolipid synthesis. Dihydroceramides produced upon treatments with the drugs were further used for the synthesis of complex dihydrosphingolipids, whose levels dramatically increased in drug-treated cells. PMID- 20194110 TI - Arterial colony stimulating factor-1 influences atherosclerotic lesions by regulating monocyte migration and apoptosis. AB - Previous studies have shown that colony stimulating factor-1 (CSF-1) deficiency dramatically reduced atherogenesis in mice. In this report we investigate this mechanism and explore a therapeutic avenue based on inhibition of CSF-1 signaling. Lesions from macrophage colony stimulating factor-1 (Csf1)+/- mice showed increased numbers of apoptotic macrophages, decreased overall macrophage content, and inflammation. In vitro studies indicated that CSF-1 is chemotactic for monocytes. Bone marrow transplantation studies suggested that vascular cell derived, rather than macrophage-derived, CSF-1 is responsible for the effect on atherosclerosis. Consistent with previous studies, CSF-1 affected lesion development in a dose-dependent manner, suggesting that pharmacological inhibition of CSF-1 might achieve similar results. Indeed, we observed that treatment of hyperlipidemic mice with a CSF-1 receptor kinase inhibitor inhibited plaque progression. This observation was accompanied by a reduction in the expression of adhesion factors (ICAM-1), macrophage markers (F4/80), inflammatory cytokines (Il-6, Il-1beta), and macrophage matrix degradation enzymes (MMP-9). We conclude that the M-CSF pathway contributes to monocyte recruitment and macrophage survival and that this pathway is a potential target for therapeutic intervention. PMID- 20194111 TI - Regulation of base excision repair: Ntg1 nuclear and mitochondrial dynamic localization in response to genotoxic stress. AB - Numerous human pathologies result from unrepaired oxidative DNA damage. Base excision repair (BER) is responsible for the repair of oxidative DNA damage that occurs in both nuclei and mitochondria. Despite the importance of BER in maintaining genomic stability, knowledge concerning the regulation of this evolutionarily conserved repair pathway is almost nonexistent. The Saccharomyces cerevisiae BER protein, Ntg1, relocalizes to organelles containing elevated oxidative DNA damage, indicating a novel mechanism of regulation for BER. We propose that dynamic localization of BER proteins is modulated by constituents of stress response pathways. In an effort to mechanistically define these regulatory components, the elements necessary for nuclear and mitochondrial localization of Ntg1 were identified, including a bipartite classical nuclear localization signal, a mitochondrial matrix targeting sequence and the classical nuclear protein import machinery. Our results define a major regulatory system for BER which when compromised, confers a mutator phenotype and sensitizes cells to the cytotoxic effects of DNA damage. PMID- 20194112 TI - Spatial, temporal and interindividual epigenetic variation of functionally important DNA methylation patterns. AB - DNA methylation is an epigenetic modification that plays an important role in gene regulation. It can be influenced by stochastic events, environmental factors and developmental programs. However, little is known about the natural variation of gene-specific methylation patterns. In this study, we performed quantitative methylation analyses of six differentially methylated imprinted genes (H19, MEG3, LIT1, NESP55, PEG3 and SNRPN), one hypermethylated pluripotency gene (OCT4) and one hypomethylated tumor suppressor gene (APC) in chorionic villus, fetal and adult cortex, and adult blood samples. Both average methylation level and range of methylation variation depended on the gene locus, tissue type and/or developmental stage. We found considerable variability of functionally important methylation patterns among unrelated healthy individuals and a trend toward more similar methylation levels in monozygotic twins than in dizygotic twins. Imprinted genes showed relatively little methylation changes associated with aging in individuals who are >25 years. The relative differences in methylation among neighboring CpGs in the generally hypomethylated APC promoter may not only reflect stochastic fluctuations but also depend on the tissue type. Our results are consistent with the view that most methylation variation may arise after fertilization, leading to epigenetic mosaicism. PMID- 20194113 TI - The large-scale organization of the bacterial network of ecological co-occurrence interactions. AB - In their natural environments, microorganisms form complex systems of interactions. Understating the structure and organization of bacterial communities is likely to have broad medical and ecological consequences, yet a comprehensive description of the network of environmental interactions is currently lacking. Here, we mine co-occurrences in the scientific literature to construct such a network and demonstrate an expected pattern of association between the species' lifestyle and the recorded number of co-occurring partners. We further focus on the well-annotated gut community and show that most co occurrence interactions of typical gut bacteria occur within this community. The network is then clustered into species-groups that significantly correspond with natural occurring communities. The relationships between resource competition, metabolic yield and growth rate within the clusters correspond with the r/K selection theory. Overall, these results support the constructed clusters as a first approximation of a bacterial ecosystem model. This comprehensive collection of predicted communities forms a new data resource for further systematic characterization of the ecological design principals shaping communities. Here, we demonstrate its utility for predicting cooperation and inhibition within communities. PMID- 20194114 TI - Identification of a structural element of the hepatitis C virus minus strand RNA involved in the initiation of RNA synthesis. AB - The replication of the genomic RNA of the hepatitis C virus (HCV) of positive polarity involves the synthesis of a replication intermediate of negative polarity by the viral RNA-dependent RNA polymerase (NS5B). In vitro and likely in vivo, the NS5B initiates RNA synthesis without primers. This de novo mechanism needs specific interactions between the polymerase and viral RNA elements. Cis acting elements involved in the initiation of (-) RNA synthesis have been identified in the 3' non-coding region and in the NS5B coding region of the HCV RNA. However, the detailed contribution of sequences and/or structures of (-) RNA involved in the initiation of (+) RNA synthesis has been less studied. In this report, we identified an RNA element localized between nucleotides 177 and 222 from the 3'-end of the (-) RNA that is necessary for efficient initiation of RNA synthesis by the recombinant NS5B. By site-directed mutagenesis experiments, we demonstrate that the structure rather than the primary sequence of this domain is important for RNA synthesis. We also demonstrate that the intact structure of this RNA element is also needed for efficient RNA synthesis when the viral NS5B functions in association with other viral and cellular proteins in cultured hepatic cells. PMID- 20194115 TI - Structural basis for the methylation of G1405 in 16S rRNA by aminoglycoside resistance methyltransferase Sgm from an antibiotic producer: a diversity of active sites in m7G methyltransferases. AB - Sgm (Sisomicin-gentamicin methyltransferase) from antibiotic-producing bacterium Micromonospora zionensis is an enzyme that confers resistance to aminoglycosides like gentamicin and sisomicin by specifically methylating G1405 in bacterial 16S rRNA. Sgm belongs to the aminoglycoside resistance methyltransferase (Arm) family of enzymes that have been recently found to spread by horizontal gene transfer among disease-causing bacteria. Structural characterization of Arm enzymes is the key to understand their mechanism of action and to develop inhibitors that would block their activity. Here we report the structure of Sgm in complex with cofactors S-adenosylmethionine (AdoMet) and S-adenosylhomocysteine (AdoHcy) at 2.0 and 2.1 A resolution, respectively, and results of mutagenesis and rRNA footprinting, and protein-substrate docking. We propose the mechanism of methylation of G1405 by Sgm and compare it with other m(7)G methyltransferases, revealing a surprising diversity of active sites and binding modes for the same basic reaction of RNA modification. This analysis can serve as a stepping stone towards developing drugs that would specifically block the activity of Arm methyltransferases and thereby re-sensitize pathogenic bacteria to aminoglycoside antibiotics. PMID- 20194116 TI - Into the unknown: expression profiling without genome sequence information in CHO by next generation sequencing. AB - The arrival of next-generation sequencing (NGS) technologies has led to novel opportunities for expression profiling and genome analysis by utilizing vast amounts of short read sequence data. Here, we demonstrate that expression profiling in organisms lacking any genome or transcriptome sequence information is feasible by combining Illumina's mRNA-seq technology with a novel bioinformatics pipeline that integrates assembled and annotated Chinese hamster ovary (CHO) sequences with information derived from related organisms. We applied this pipeline to the analysis of CHO cells which were chosen as a model system owing to its relevance in the production of therapeutic proteins. Specifically, we analysed CHO cells undergoing butyrate treatment which is known to affect cell cycle regulation and to increase the specific productivity of recombinant proteins. By this means, we identified sequences for >13,000 CHO genes which added sequence information of approximately 5000 novel genes to the CHO model. More than 6000 transcript sequences are predicted to be complete, as they covered >95% of the corresponding mouse orthologs. Detailed analysis of selected biological functions such as DNA replication and cell cycle control, demonstrated the potential of NGS expression profiling in organisms without extended genome sequence to improve both data quantity and quality. PMID- 20194118 TI - Robustness and modularity properties of a non-covalent DNA catalytic reaction. AB - The biophysics of nucleic acid hybridization and strand displacement have been used for the rational design of a number of nanoscale structures and functions. Recently, molecular amplification methods have been developed in the form of non covalent DNA catalytic reactions, in which single-stranded DNA (ssDNA) molecules catalyze the release of ssDNA product molecules from multi-stranded complexes. Here, we characterize the robustness and specificity of one such strand displacement-based catalytic reaction. We show that the designed reaction is simultaneously sensitive to sequence mutations in the catalyst and robust to a variety of impurities and molecular noise. These properties facilitate the incorporation of strand displacement-based DNA components in synthetic chemical and biological reaction networks. PMID- 20194117 TI - Detection of novel recombinases in bacteriophage genomes unveils Rad52, Rad51 and Gp2.5 remote homologs. AB - Homologous recombination is a key in contributing to bacteriophages genome repair, circularization and replication. No less than six kinds of recombinase genes have been reported so far in bacteriophage genomes, two (UvsX and Gp2.5) from virulent, and four (Sak, Red beta, Erf and Sak4) from temperate phages. Using profile-profile comparisons, structure-based modelling and gene-context analyses, we provide new views on the global landscape of recombinases in 465 bacteriophages. We show that Sak, Red beta and Erf belong to a common large superfamily adopting a shortcut Rad52-like fold. Remote homologs of Sak4 are predicted to adopt a shortcut Rad51/RecA fold and are discovered widespread among phage genomes. Unexpectedly, within temperate phages, gene-context analyses also pinpointed the presence of distant Gp2.5 homologs, believed to be restricted to virulent phages. All in all, three major superfamilies of phage recombinases emerged either related to Rad52-like, Rad51-like or Gp2.5-like proteins. For two newly detected recombinases belonging to the Sak4 and Gp2.5 families, we provide experimental evidence of their recombination activity in vivo. Temperate versus virulent lifestyle together with the importance of genome mosaicism is discussed in the light of these novel recombinases. Screening for these recombinases in genomes can be performed at http://biodev.extra.cea.fr/virfam. PMID- 20194119 TI - Pairwise selection assembly for sequence-independent construction of long-length DNA. AB - The engineering of biological components has been facilitated by de novo synthesis of gene-length DNA. Biological engineering at the level of pathways and genomes, however, requires a scalable and cost-effective assembly of DNA molecules that are longer than approximately 10 kb, and this remains a challenge. Here we present the development of pairwise selection assembly (PSA), a process that involves hierarchical construction of long-length DNA through the use of a standard set of components and operations. In PSA, activation tags at the termini of assembly sub-fragments are reused throughout the assembly process to activate vector-encoded selectable markers. Marker activation enables stringent selection for a correctly assembled product in vivo, often obviating the need for clonal isolation. Importantly, construction via PSA is sequence-independent, and does not require primary sequence modification (e.g. the addition or removal of restriction sites). The utility of PSA is demonstrated in the construction of a completely synthetic 91-kb chromosome arm from Saccharomyces cerevisiae. PMID- 20194120 TI - Directed evolution of recombinase specificity by split gene reassembly. AB - The engineering of new enzymes that efficiently and specifically modify DNA sequences is necessary for the development of enhanced gene therapies and genetic studies. To address this need, we developed a robust strategy for evolving site specific recombinases with novel substrate specificities. In this system, recombinase variants are selected for activity on new substrates based on enzyme mediated reassembly of the gene encoding beta-lactamase that confers ampicillin resistance to Escherichia coli. This stringent evolution method was used to alter the specificities of catalytic domains in the context of a modular zinc finger recombinase fusion protein. Gene reassembly was detectable over several orders of magnitude, which allowed for tunable selectivity and exceptional sensitivity. Engineered recombinases were evolved to react with sequences from the human genome with only three rounds of selection. Many of the evolved residues, selected from a randomly-mutated library, were conserved among other members of this family of recombinases. This enhanced evolution system will translate recombinase engineering and genome editing into a practical and expedient endeavor for academic, industrial and clinical applications. PMID- 20194121 TI - Logic integration of mRNA signals by an RNAi-based molecular computer. AB - Synthetic in vivo molecular 'computers' could rewire biological processes by establishing programmable, non-native pathways between molecular signals and biological responses. Multiple molecular computer prototypes have been shown to work in simple buffered solutions. Many of those prototypes were made of DNA strands and performed computations using cycles of annealing-digestion or strand displacement. We have previously introduced RNA interference (RNAi)-based computing as a way of implementing complex molecular logic in vivo. Because it also relies on nucleic acids for its operation, RNAi computing could benefit from the tools developed for DNA systems. However, these tools must be harnessed to produce bioactive components and be adapted for harsh operating environments that reflect in vivo conditions. In a step toward this goal, we report the construction and implementation of biosensors that 'transduce' mRNA levels into bioactive, small interfering RNA molecules via RNA strand exchange in a cell-free Drosophila embryo lysate, a step beyond simple buffered environments. We further integrate the sensors with our RNAi 'computational' module to evaluate two-input logic functions on mRNA concentrations. Our results show how RNA strand exchange can expand the utility of RNAi computing and point toward the possibility of using strand exchange in a native biological setting. PMID- 20194123 TI - The effect of fatigue from exercise on human limb position sense. AB - We have previously shown, in a two-limb position-matching task in human subjects, that exercise of elbow flexors of one arm led the forearm to be perceived as more extended, while exercise of knee extensors of one leg led the lower leg to be perceived as more flexed. These findings led us to propose that exercise disturbs position sense because subjects perceive their exercised muscles as longer than they actually are. In order to obtain further support for this hypothesis, in the first experiment reported here, elbow extensors were exercised, with the prediction that the exercised arm would be perceived as more flexed after exercise. The experiment was carried out under three load conditions, with the exercised arm resting on a support, with it supporting its own weight and with it supporting a load of 10% of its voluntary contraction strength. For each condition, the forearm was perceived as more extended, not more flexed, after exercise. This result was confirmed in a second experiment on elbow flexors. Again, under all three conditions the exercised arm was perceived as more extended. To explore the distribution of the phenomenon, in a third experiment finger flexor muscles were exercised. This had no significant effect on position sense at the elbow. In a fourth experiment, position sense at the knee was measured after knee flexors of one leg were exercised and, as for knee extensors, it led subjects to perceive their exercised leg to be more flexed at the knee than it actually was. Putting all the observations together, it is concluded that while the influences responsible for the effects of exercise may have a peripheral origin, their effect on position sense occurs centrally, perhaps at the level of the sensorimotor cortex. PMID- 20194122 TI - Differences in the control of breathing between Himalayan and sea-level residents. AB - We compared the control of breathing of 12 male Himalayan highlanders with that of 21 male sea-level Caucasian lowlanders using isoxic hyperoxic ( = 150 mmHg) and hypoxic ( = 50 mmHg) Duffin's rebreathing tests. Highlanders had lower mean +/- s.e.m. ventilatory sensitivities to CO(2) than lowlanders at both isoxic tensions (hyperoxic: 2.3 +/- 0.3 vs. 4.2 +/- 0.3 l min(1) mmHg(1), P = 0.021; hypoxic: 2.8 +/- 0.3 vs. 7.1 +/- 0.6 l min(1) mmHg(1), P < 0.001), and the usual increase in ventilatory sensitivity to CO(2) induced by hypoxia in lowlanders was absent in highlanders (P = 0.361). Furthermore, the ventilatory recruitment threshold (VRT) CO(2) tensions in highlanders were lower than in lowlanders (hyperoxic: 33.8 +/- 0.9 vs. 48.9 +/- 0.7 mmHg, P < 0.001; hypoxic: 31.2 +/- 1.1 vs. 44.7 +/- 0.7 mmHg, P < 0.001). Both groups had reduced ventilatory recruitment thresholds with hypoxia (P < 0.001) and there were no differences in the sub-threshold ventilations (non-chemoreflex drives to breathe) between lowlanders and highlanders at both isoxic tensions (P = 0.982), with a trend for higher basal ventilation during hypoxia (P = 0.052). We conclude that control of breathing in Himalayan highlanders is distinctly different from that of sea-level lowlanders. Specifically, Himalayan highlanders have decreased central and absent peripheral sensitivities to CO(2). Their response to hypoxia was heterogeneous, with the majority decreasing their VRT indicating either a CO(2)-independent increase in activity of peripheral chemoreceptor or hypoxia-induced increase in [H(+)] at the central chemoreceptor. In some highlanders, the decrease in VRT was accompanied by an increase in sensitivity to CO(2), while in others VRT remained unchanged and their sub-threshold ventilations increased, although these were not statistically significant. PMID- 20194124 TI - NaV1.1 channels and epilepsy. AB - Voltage-gated sodium channels initiate action potentials in brain neurons, and sodium channel blockers are used in therapy of epilepsy. Mutations in sodium channels are responsible for genetic epilepsy syndromes with a wide range of severity, and the NaV1.1 channel encoded by the SCN1A gene is the most frequent target of mutations. Complete loss-of-function mutations in NaV1.1 cause severe myoclonic epilepsy of infancy (SMEI or Dravet's Syndrome), which includes severe, intractable epilepsy and comorbidities of ataxia and cognitive impairment. Mice with loss-of-function mutations in NaV1.1 channels have severely impaired sodium currents and action potential firing in hippocampal GABAergic inhibitory neurons without detectable effect on the excitatory pyramidal neurons, which would cause hyperexcitability and contribute to seizures in SMEI. Similarly, the sodium currents and action potential firing are also impaired in the GABAergic Purkinje neurons of the cerebellum, which is likely to contribute to ataxia. The imbalance between excitatory and inhibitory transmission in these mice can be partially corrected by compensatory loss-of-function mutations of NaV1.6 channels, and thermally induced seizures in these mice can be prevented by drug combinations that enhance GABAergic neurotransmission. Generalized epilepsy with febrile seizures plus (GEFS+) is caused by missense mutations in NaV1.1 channels, which have variable biophysical effects on sodium channels expressed in non-neuronal cells, but may primarily cause loss of function when expressed in mice. Familial febrile seizures is caused by mild loss-of-function mutations in NaV1.1 channels; mutations in these channels are implicated in febrile seizures associated with vaccination; and impaired alternative splicing of the mRNA encoding these channels may also predispose some children to febrile seizures. We propose a unified loss-of-function hypothesis for the spectrum of epilepsy syndromes caused by genetic changes in NaV1.1 channels, in which mild impairment predisposes to febrile seizures, intermediate impairment leads to GEFS+ epilepsy, and severe or complete loss of function leads to the intractable seizures and comorbidities of SMEI. PMID- 20194125 TI - The calcium-permeable non-selective cation channel TRPM2 is modulated by cellular acidification. AB - TRPM2 is a calcium-permeable non-selective cation channel expressed in the plasma membrane and in lysosomes that is critically involved in aggravating reactive oxygen species (ROS)-induced inflammatory processes and has been implicated in cell death. TRPM2 is gated by ADP-ribose (ADPR) and modulated by physiological processes that produce peroxide, cyclic ADP-ribose (cADPR), nicotinamide adenine dinucleotide phosphate (NAADP) and Ca(2+). We investigated the role of extra- and intracellular acidification on heterologously expressed TRPM2 in HEK293 cells. Our results show that TRPM2 is inhibited by external acidification with an IC(50) of pH 6.5 and is completely suppressed by internal pH of 6. Current inhibition requires channel opening and is strongly voltage dependent, being most effective at negative potentials. In addition, increased cytosolic pH buffering capacity or elevated [Ca(2+)](i) reduces the rate of current inactivation elicited by extracellular acidification, and Na(+) and Ca(2+) influence the efficacy of proton-induced inactivation. Together, these results suggest that external protons permeate TRPM2 channels to gain access to an intracellular site that regulates channel activity. Consistent with this notion, single-channel measurements in HEK293 cells reveal that internal protons induce channel closure without affecting single-channel conductance, whereas external protons affect channel open probability as well as single-channel conductance of native TRPM2 in neutrophils. We conclude that protons compete with Na(+) and Ca(2+) for channel permeation and channel closure results from a competitive antagonism of protons at an intracellular Ca(2+) binding site. PMID- 20194126 TI - Vasoresponsiveness of collateral vessels in the rat hindlimb: influence of training. AB - Exercise training is known to be an effective means of improving functional capacity and quality of life in patients with peripheral arterial insufficiency (PAI). However, the specific training-induced physiological adaptations occurring within collateral vessels remain to be clearly defined. The purpose of this study was to determine the effect of exercise training on vasomotor properties of isolated peripheral collateral arteries. We hypothesized that daily treadmill exercise would improve the poor vasodilatory capacity of collateral arteries isolated from rats exposed to surgical occlusion of the femoral artery. Following femoral artery ligation, animals were either kept sedentary or exercise trained daily for a period of 3 weeks. Hindlimb collateral arteries were then isolated, cannulated and pressurized via hydrostatic reservoirs to an intravascular pressure of either 45 or 120 cmH(2)O. Non-occluded contralateral vessels of the sedentary animals served as normal Control. Vasodilatory responses to acetylcholine (ACh; 1 x 10(9)-1 x 10(5)m) and sodium nitroprusside (SNP; 1 x 10(9)-1 x 10(4)m), constrictor responses to phenylephrine (PE; 1 x 10(9)-1 x 10(4)m), and flow-induced vasodilatation were determined. Endothelium-mediated vasodilatation responses were significantly greater to either ACh (P < 0.02) or intravascular flow (P < 0.001) in collateral arteries of trained rats. Neither blockade of cyclooxygenase with indomethacin (Indo; 5 microm) nor blockade of endothelial nitric oxide synthase with N(G)-nitro-L-arginine methyl ester (L NAME; 300 microm) eliminated this ACh- or flow-induced vasodilatation. The depressed vasodilatory response to SNP caused by vascular occlusion was reversed with training. These data indicate that exercise training improves endothelium mediated vasodilatory capacity of hindlimb collateral arteries, apparently by enhanced production of the putative endothelium-derived hyperpolarizing factor(s). If these findings were applicable to patients with PAI, they could contribute to an improved collateral vessel function and enhance exercise tolerance during routine physical activity. PMID- 20194127 TI - Insights into migraine mechanisms and CaV2.1 calcium channel function from mouse models of familial hemiplegic migraine. AB - Migraine is a very common disabling brain disorder with unclear pathogenesis. A subtype of migraine with aura (familial hemiplegic migraine type 1: FHM1) is caused by mutations in CaV2.1 (P/Q-type) Ca2+ channels. This review describes the functional consequences of FHM1 mutations in knockin mouse models carrying the mild R192Q or severe S218L mutations in the orthologous gene. The FHM1 knockin mice show allele dosage-dependent gain-of-function of neuronal P/Q-type Ca2+ current, reflecting activation of mutant channels at lower voltages, and allele dosage- and sex-dependent facilitation of induction and propagation of cortical spreading depression (CSD), the phenomenon that underlies migraine aura. Gain-of function of neuronal Ca2+ current, facilitation of CSD and post-CSD motor deficits were larger in S218L than R192Q knockin mice, in correlation with the more severe human S218L phenotype. Enhanced cortical excitatory neurotransmission, due to increased action potential-evoked Ca2+ influx and increased probability of glutamate release at pyramidal cell synapses, but unaltered inhibitory neurotransmission at fast-spiking interneuron synapses, were demonstrated in R192Q knockin mice. Evidence for a causative link between enhanced glutamate release and CSD facilitation was obtained. The data from FHM1 mice strengthen the view of CSD as a key player in the pathogenesis of migraine, give insight into CSD mechanisms and point to episodic disruption of excitation inhibition balance and neuronal hyperactivity as the basis for vulnerability to CSD ignition in migraine. PMID- 20194128 TI - Functional interplay between NMDA receptors, SK channels and voltage-gated Ca2+ channels regulates synaptic excitability in the medial prefrontal cortex. AB - Synaptic activity in the medial prefrontal cortex (mPFC) is fundamental for higher cognitive functions such as working memory. The present study shows that small conductance (SK) calcium-activated potassium channels attenuate excitatory synaptic transmission at layer 2/3 and layer 5 inputs to layer 5 pyramidal neurons in the mPFC. SK channels are located postsynaptically at synapses where they are activated during synaptic transmission by calcium influx through NMDA receptors, L-type calcium channels, R-type calcium channels and by calcium release from IP(3)-sensitive stores. Removal of the SK channel-mediated shunt of synaptic transmission reveals significant NMDA receptor-mediated activation during basal synaptic transmission, which is greater at layer 5 inputs (approximately 30%) than at layer 2/3 inputs (approximately 20%). These findings show that interactions between NMDA receptors, SK channels and voltage-gated calcium channels play a critical role in regulating excitatory synaptic transmission in layer 5 pyramidal neurons in the mPFC. PMID- 20194129 TI - Illusory movements of a phantom hand grade with the duration and magnitude of motor commands. AB - The senses of limb movement and position are critical for accurate control of movement. Recent studies show that central signals of motor command contribute to the sense of limb position but it is not clear whether such signals influence the distinctly different sense of limb movement. Nine subjects participated in two experiments in which we inflated a cuff around their upper arm to produce an ischaemic block, paralysing and anaesthetising the forearm, wrist and hand. This produces an experimental phantom wrist and hand. With their arm hidden from view subjects were asked to make voluntary efforts with their blocked wrist. In the first experiment, efforts were 20 and 40% of maximum and were 2 and 4 s in duration. The second experiment used 1 and 5 s efforts of 5 and 50% of maximum. Subjects signalled perceived movements of their phantom wrist using a pointer. All subjects reported clear perceptions of movement of their phantom hand for all levels and durations of effort. On average, subjects perceived their phantom wrist to move between 16.4 +/- 3.3 deg (mean +/- 95% confidence interval (CI)) and 30.2 +/- 5.4 deg in the first experiment and between 10.3 +/- 3.5 and 38.6 +/ 6.7 deg in the second. The velocity of the movements and total displacement of the phantom graded with the level of effort, and the total displacement also graded with duration. Hence, we have shown that motor command signals have a novel proprioceptive role in the perception of movement of human joints. PMID- 20194131 TI - An interview with Eric Kandel by Brian Robertson. PMID- 20194130 TI - A mutation of the epithelial sodium channel associated with atypical cystic fibrosis increases channel open probability and reduces Na+ self inhibition. AB - Increased activity of the epithelial sodium channel (ENaC) in the respiratory airways contributes to the pathophysiology of cystic fibrosis (CF), a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In some patients suffering from atypical CF a mutation can be identified in only one CFTR allele. We recently identified in this group of CF patients a heterozygous mutation (W493R) in the alpha-subunit of ENaC. Here, we investigate the functional effects of this mutation by expressing wild-type alpha beta gamma ENaC or mutant alpha(W493R)beta gamma ENaC in Xenopus oocytes. The alpha W493R mutation stimulated amiloride-sensitive whole-cell currents (Delta I(ami)) by approximately 4-fold without altering the single-channel conductance or surface expression of ENaC. As these data suggest that the open probability (P(o)) of the mutant channel is increased, we investigated the proteolytic activation of ENaC by chymotrypsin. Single-channel recordings revealed that chymotrypsin activated near-silent channels in outside-out membrane patches from oocytes expressing wild-type ENaC, but not in membrane patches from oocytes expressing the mutant channel. In addition, the alpha W493R mutation abolished Na(+) self inhibition of ENaC, which might also contribute to its gain-of function effects. We conclude that the alpha W493R mutation promotes constitutive activation of ENaC by reducing the inhibitory effect of extracellular Na(+) and decreasing the pool of near-silent channels. The resulting gain-of-function phenotype of the mutant channel might contribute to the pathophysiology of CF in patients carrying this mutation. PMID- 20194132 TI - TRPA1 ion channels: a gateway to airway irritation and reflex responses induced by inhaled oxidants. PMID- 20194133 TI - Glucose and the vagus: sensory cells savour sweet substances. PMID- 20194134 TI - Cell-specific contribution to gamma oscillations. PMID- 20194135 TI - All ahead stop! How intestinal motility adapts to cope with inflammation induced ulceration. PMID- 20194136 TI - A SIC' and painful story. PMID- 20194137 TI - How GABA generates depolarization. PMID- 20194139 TI - Free radicals can kill you: Lavoisier's oxygen revolution. PMID- 20194142 TI - Thermal hypoaesthesia differentiates secondary restless legs syndrome associated with small fibre neuropathy from primary restless legs syndrome. AB - This study aimed to assess thermal and mechanical perception and pain thresholds in primary idiopathic restless legs syndrome and secondary restless legs syndrome associated with small fibre neuropathy. Twenty-one patients (age: 53.4 + or - 8.4, n = 3, male) with primary restless legs syndrome and 13 patients (age: 63.0 + or - 8.2, n = 1, male) with secondary restless legs syndrome associated with small fibre neuropathy were compared with 20 healthy subjects (age: 58.0 + or - 7.0; n = 2, male). Differential diagnosis of secondary restless legs syndrome associated with small fibre neuropathy was based on clinical symptoms and confirmed with skin biopsies in all patients. A comprehensive quantitative sensory testing protocol encompassing thermal and mechanical detection and pain thresholds, as devised by the German Research Network on Neuropathic Pain, was performed on the clinically more affected foot between 2 pm and 1 am when restless legs syndrome symptoms were present in all patients. Patients with primary restless legs syndrome showed hyperalgesia to blunt pressure (P < 0.001), pinprick (P < 0.001) and vibratory hyperaesthesia (P < 0.001). Patients with secondary restless legs syndrome associated with small fibre neuropathy showed thermal hypoaesthesia to cold (Adelta-fibre mediated) and warm (C-fibre mediated) (all P < 0.001) and hyperalgesia to pinprick (P < 0.001). Static mechanical hyperalgesia in primary and secondary restless legs syndrome is consistent with the concept of central disinhibition of nociceptive pathways, which might be induced by conditioning afferent input from damaged small fibre neurons in secondary restless legs syndrome. PMID- 20194143 TI - Patients dismissed from the hospital with a diagnosis of noncardiac chest pain: cardiac outcomes and health care utilization. AB - OBJECTIVE: To determine the proportion of patients with noncardiac chest pain (NCCP) who see a gastroenterologist, the type and frequency of gastrointestinal (GI) and cardiac tests performed, and the frequency of cardiac death. PATIENTS AND METHODS: A cohort of Olmsted County, Minnesota, residents presenting to the emergency department (ED) with chest pain between January 1, 1985, and December 31, 1992, was identified through the Rochester Epidemiology Project. We assessed the frequency of ED, cardiology, and gastroenterology visits and corresponding tests after a diagnosis of NCCP (n=320). We also assessed the frequency of cardiac events. RESULTS: During follow-up, 49% of patients sought care in the ED, 42% had repeated cardiology evaluations, and 15% were seen by a gastroenterologist. Thirty-eight percent underwent esophagogastroduodenoscopy, but very few underwent manometry or a pH probe. Patients with NCCP of unknown origin had 3 times the rate of GI consultations as their counterparts with a GI disorder. Survival free of cardiac death in the subset with NCCP with a GI disorder was 90.2% at 10 years and 84.8% at 20 years, compared with 93.7% at 10 years and 88.1% at 20 years for the subset with NCCP of unknown origin. CONCLUSION: The frequency of health care utilization in NCCP patients is high, but relatively few GI consultations and even fewer GI tests are performed. Patients dismissed from the hospital with NCCP continue to experience cardiac events, which may highlight a need for more aggressive cardiovascular risk factor management in this population. PMID- 20194141 TI - The default-mode, ego-functions and free-energy: a neurobiological account of Freudian ideas. AB - This article explores the notion that Freudian constructs may have neurobiological substrates. Specifically, we propose that Freud's descriptions of the primary and secondary processes are consistent with self-organized activity in hierarchical cortical systems and that his descriptions of the ego are consistent with the functions of the default-mode and its reciprocal exchanges with subordinate brain systems. This neurobiological account rests on a view of the brain as a hierarchical inference or Helmholtz machine. In this view, large scale intrinsic networks occupy supraordinate levels of hierarchical brain systems that try to optimize their representation of the sensorium. This optimization has been formulated as minimizing a free-energy; a process that is formally similar to the treatment of energy in Freudian formulations. We substantiate this synthesis by showing that Freud's descriptions of the primary process are consistent with the phenomenology and neurophysiology of rapid eye movement sleep, the early and acute psychotic state, the aura of temporal lobe epilepsy and hallucinogenic drug states. PMID- 20194144 TI - Treatment considerations for patients with neuropathic pain and other medical comorbidities. AB - The efficacy of drugs for neuropathic pain has been established in randomized controlled trials that have excluded patients with comorbid conditions and those taking complex medications. However, patients with neuropathic pain frequently present with complex histories, making direct application of this evidence problematic. Treatment of neuropathic pain needs to be individualized according to the cause of the pain, concomitant diseases, medications, and other individual factors. Tricyclic antidepressants (TCAs), gabapentinoids, selective noradrenergic reuptake inhibitors, and topical lidocaine are the first-line choices; if needed, combination therapy may be used. When a new drug is added, screening for potential drug interactions is recommended. The TCAs have anticholinergic adverse effects and may cause orthostatic hypotension. They should be avoided or used cautiously in patients with cardiac conduction disturbances or arrhythmias. Patients who lack cytochrome P450 2D6 isoenzyme activity are prone to adverse effects of TCAs and venlafaxine and have a weaker analgesic response to tramadol. A combination of several serotoninergic drugs may lead to serotonin syndrome. Risk of gastrointestinal tract bleeding is increased in patients taking selective serotonin reuptake inhibitors or venlafaxine, especially when combined with nonsteroidal anti-inflammatory drugs. Dose adjustment may be needed in patients with renal or hepatic impairment. Depending on the drug, the dose is reduced or the dosage interval lengthened. Slow titration and careful follow-up are needed. No drug is absolutely safe during pregnancy and lactation. Particular care must be exercised during the first trimester when drug dose should be as low as possible. Individual weighing of benefits and risks should guide therapeutic decisions. PMID- 20194145 TI - Treatment considerations for elderly and frail patients with neuropathic pain. AB - Currently, an estimated 38 million individuals 65 years or older live in the United States, and more than 11 million of these individuals are 80 years or older. Older people are at high risk of neuropathic pain because many diseases that cause neuropathic pain increase in incidence with age. Depending on their underlying health, older adults with neuropathic pain may have to cope with multiple coexisting diseases, polypharmacy, and impaired functional ability. The objective of this article is to review how aging and frailty affect the treatment of older adults with neuropathic pain. Specific topics reviewed include the complexity of treatment decisions in older patients due to aged heterogeneity, multimorbidity, and polypharmacy; selection of treatment in an effort to maximize patients' functional abilities in addition to relieving their pain; more careful dosing (usually lower) and monitoring of pharmacotherapy relative to younger patients due to age-related changes in pharmacokinetics and pharmacodynamics; and underrepresentation of older adults in clinical trials of neuropathic pain treatments, which further compromises physicians' ability to make informed treatment decisions. PMID- 20194146 TI - Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. AB - The Neuropathic Pain Special Interest Group of the International Association for the Study of Pain recently sponsored the development of evidence-based guidelines for the pharmacological treatment of neuropathic pain. Tricyclic antidepressants, dual reuptake inhibitors of serotonin and norepinephrine, calcium channel alpha(2)-delta ligands (ie, gabapentin and pregabalin), and topical lidocaine were recommended as first-line treatment options on the basis of the results of randomized clinical trials. Opioid analgesics and tramadol were recommended as second-line treatments that can be considered for first-line use in certain clinical circumstances. Results of several recent clinical trials have become available since the development of these guidelines. These studies have examined botulinum toxin, high-concentration capsaicin patch, lacosamide, selective serotonin reuptake inhibitors, and combination therapies in various neuropathic pain conditions. The increasing number of negative clinical trials of pharmacological treatments for neuropathic pain and ambiguities in the interpretation of these negative trials must also be considered in developing treatment guidelines. The objectives of the current article are to review the Neuropathic Pain Special Interest Group guidelines for the pharmacological management of neuropathic pain and to provide a brief overview of these recent studies. PMID- 20194148 TI - Assessment and treatment of psychosocial comorbidities in patients with neuropathic pain. AB - Chronic neuropathic pain is a prevalent problem that eludes cure and adequate treatment. The persistence of intense and aversive symptoms, inadequacy of available treatments, and impact of such pain on all aspects of functioning underscore the important role of several psychosocial factors in causing, maintaining, and amplifying the perception of pain severity, coping adequacy, adaptation, impaired physical function, and emotional distress responses. Moreover, these factors have an influential role in response to treatment recommendations. In this article, we (1) review the prevalence and nature of emotional distress, (2) describe and propose methods for screening and comprehensive psychosocial assessment, and (3) review evidence supporting the potential complementary role of psychosocial treatments of patients with chronic pain. The cognitive-behavioral perspective and treatment approach are emphasized because the greatest amount of evidence supports their benefits. Published results of psychological treatments are modest; however, the same indictment can be placed on currently available pharmacological, medical, and interventional treatments for patients with chronic pain. We note the limited research on the effectiveness of psychological treatment specifically applied to patients with chronic neuropathic pain but suggest that it is reasonable to extrapolate from successful trials in other types of chronic pain. Furthermore, psychological approaches should not be viewed as alternatives but rather should be integrated as part of a comprehensive approach to the treatment of patients with chronic neuropathic pain. PMID- 20194147 TI - Neuropathic pain in children: Special considerations. AB - Neuropathic pain is relatively uncommon in children. Although some syndromes closely resemble those found in adults, the incidence and course of the condition can vary substantially in children, depending on developmental status and contextual factors. There are some neuropathic pain syndromes that are rare and relatively unique to the pediatric population. This article discusses the array of neuropathic pain conditions in children and available treatment strategies. Data are limited by small numbers and few randomized controlled trials. Research and clinical implications are discussed. PMID- 20194149 TI - 25-year-old woman with anemia. PMID- 20194150 TI - Patterns of multiple myeloma during the past 5 decades: stable incidence rates for all age groups in the population but rapidly changing age distribution in the clinic. AB - OBJECTIVE: To define age-adjusted incidence trends in multiple myeloma (MM) in a well-characterized population during a long period, given that some, but not all, studies have reported increasing MM incidence over time and that clinical experience from some centers suggests an increased incidence mainly in younger age groups. PATIENTS AND METHODS: We identified all patients (N=773) with MM diagnosed in Malmo, Sweden, from January 1, 1950, through December 31, 2005. Using census data for the population of Malmo, we calculated age- and sex specific incidence rates. Incidence rates were also calculated for 10-year birth cohorts. Analyses for trends were performed using the Poisson regression. RESULTS: From 1950 through 2005, the average annual age-adjusted (European standard population) incidence rate remained stable (Poisson regression, P=.07 for men and P=.67 for women). Also, comparisons between 10-year birth cohorts (from 1870-1879 to 1970-1979) failed to detect any increase. Between 1950-1959 and 2000-2005, the median age at diagnosis of MM increased from 70 to 74 years, and the proportion of newly diagnosed patients aged 80 years or older increased from 16% to 31%. CONCLUSION: Our finding of stable MM incidence rates for all age groups during the past 5 decades suggests that recent clinical observations of an increase of MM in the young may reflect an increased referral stream of younger patients with MM, which in turn might be a consequence of improved access to better MM therapies. Importantly, because of the aging population, the proportion of patients with MM aged 80 years or older doubled between 1950-1959 and 2000 2005. PMID- 20194151 TI - Clinical features and treatment response of light chain (AL) amyloidosis diagnosed in patients with previous diagnosis of multiple myeloma. AB - OBJECTIVE: To identify and assess the clinical features and treatment response of light chain (AL) amyloidosis diagnosed in patients with previous diagnosis of multiple myeloma (MM). PATIENTS AND METHODS: From a prospectively maintained database, we identified 47 patients seen between January 1, 1990, and August 31, 2008, with a diagnosis of AL amyloidosis that was made at least 6 months after MM diagnosis; these patients form the study group. RESULTS: Among the 47 patients, 36 developed typical features, 3 had atypical features, and 8 had an incidental finding of amyloidosis. Amyloid deposits were demonstrated in bone marrow, subcutaneous fat aspirate, or organ biopsy in 24, 19, and 12 patients, respectively. One organ was involved in 29 patients (62%), whereas 11 patients (23%) had involvement in more than one organ. At diagnosis of AL amyloidosis, treatment was changed or started in 22 patients, whereas the same treatment was continued in 21 patients, and no treatment data were available for the rest. The best hematologic response included partial response or better in 11 patients (23%) and stable disease in 18 patients (38%). Improvement in an organ was seen in 3 of the 21 evaluable patients. The median overall survival from diagnosis of AL amyloidosis was 9.1 months (95% confidence interval, 4-14). Of the 6 patients still alive, 2 underwent peripheral blood stem cell transplant, and none had cardiac involvement or involvement in more than one organ. CONCLUSION: Delayed onset of AL amyloidosis is rarely seen in patients with MM and requires a high index of suspicion for prompt diagnosis. Outcome of these patients is poor, especially in the presence of cardiac involvement. PMID- 20194152 TI - Informatics infrastructure for syndrome surveillance, decision support, reporting, and modeling of critical illness. AB - OBJECTIVE: To develop and validate an informatics infrastructure for syndrome surveillance, decision support, reporting, and modeling of critical illness. METHODS: Using open-schema data feeds imported from electronic medical records (EMRs), we developed a near-real-time relational database (Multidisciplinary Epidemiology and Translational Research in Intensive Care Data Mart). Imported data domains included physiologic monitoring, medication orders, laboratory and radiologic investigations, and physician and nursing notes. Open database connectivity supported the use of Boolean combinations of data that allowed authorized users to develop syndrome surveillance, decision support, and reporting (data "sniffers") routines. Random samples of database entries in each category were validated against corresponding independent manual reviews. RESULTS: The Multidisciplinary Epidemiology and Translational Research in Intensive Care Data Mart accommodates, on average, 15,000 admissions to the intensive care unit (ICU) per year and 200,000 vital records per day. Agreement between database entries and manual EMR audits was high for sex, mortality, and use of mechanical ventilation (kappa, 1.0 for all) and for age and laboratory and monitored data (Bland-Altman mean difference +/- SD, 1(0) for all). Agreement was lower for interpreted or calculated variables, such as specific syndrome diagnoses (kappa, 0.5 for acute lung injury), duration of ICU stay (mean difference +/- SD, 0.43+/-0.2), or duration of mechanical ventilation (mean difference +/- SD, 0.2+/-0.9). CONCLUSION: Extraction of essential ICU data from a hospital EMR into an open, integrative database facilitates process control, reporting, syndrome surveillance, decision support, and outcome research in the ICU. PMID- 20194153 TI - Clinician's guide to imaging and pathologic findings in benign breast disease. AB - The discussion of abnormal results of breast imaging and abnormal pathologic findings can be challenging for health care professionals and often is stressful for patients. Although most imaging findings and biopsy results are negative and do not infer a substantial increase in breast cancer risk, the subsequent conversation between the patient and her practitioner is more effective and informative with a thorough review of the pathologic results and an appreciation of the importance of radiologic-histologic concordance. This article provides insight into and understanding of breast imaging and biopsy techniques and of histologic findings as a means to timely and appropriate decision making and action by the patient and her health care professional. PMID- 20194154 TI - 52-year-old woman with intractable nausea and vomiting. PMID- 20194156 TI - Plasma cell labeling index in the evaluation of smoldering (asymptomatic) multiple myeloma. PMID- 20194157 TI - Fatigue, countermeasures, and performance enhancement in resident physicians. PMID- 20194155 TI - Emergency department and office-based evaluation of patients with chest pain. AB - The management of patients with chest pain is a common and challenging clinical problem. Although most of these patients do not have a life-threatening condition, the clinician must distinguish between those who require urgent management of a serious problem such as acute coronary syndrome (ACS) and those with more benign entities who do not require admission. Although clinical judgment continues to be paramount in meeting this challenge, new diagnostic modalities have been developed to assist in risk stratification. These include markers of cardiac injury, risk scores, early stress testing, and noninvasive imaging of the heart. The basic clinical tools of history, physical examination, and electrocardiography are currently widely acknowledged to allow early identification of low-risk patients who have less than 5% probability of ACS. These patients are usually initially managed in the emergency department and transitioned to further outpatient evaluation or chest pain units. Multiple imaging strategies have been investigated to accelerate diagnosis and to provide further risk stratification of patients with no initial evidence of ACS. These include rest myocardial perfusion imaging, rest echocardiography, computed tomographic coronary angiography, and cardiac magnetic resonance imaging. All have very high negative predictive values for excluding ACS and have been successful in reducing unnecessary admissions for patients at low to intermediate risk of ACS. As patients with acute chest pain transition from the evaluation in the emergency department to other outpatient settings, it is important that all clinicians involved in the care of these patients understand the tools used for assessment and risk stratification. PMID- 20194158 TI - Wake-promoting therapeutic medications not an appropriate alternative to implementation of safer work schedules for resident physicians. PMID- 20194159 TI - The Src/PI3K/Akt pathway may play a key role in the production of IL-17 in obesity. PMID- 20194161 TI - Editorial: T cells, not "immune" from HIF. PMID- 20194162 TI - Editorial: Lepromatous leprosy, lipids, and lessons in immunology: what we can learn by using modern methods to study an ancient disease. PMID- 20194163 TI - Darwin's Galapagos finches in modern biology. AB - One of the classic examples of adaptive radiation under natural selection is the evolution of 15 closely related species of Darwin's finches (Passeriformes), whose primary diversity lies in the size and shape of their beaks. Since Charles Darwin and other members of the Beagle expedition collected these birds on the Galapagos Islands in 1835 and introduced them to science, they have been the subjects of intense research. Many biology textbooks use Darwin's finches to illustrate a variety of topics of evolutionary theory, such as speciation, natural selection and niche partitioning. Today, as this Theme Issue illustrates, Darwin's finches continue to be a very valuable source of biological discovery. Certain advantages of studying this group allow further breakthroughs in our understanding of changes in recent island biodiversity, mechanisms of speciation and hybridization, evolution of cognitive behaviours, principles of beak/jaw biomechanics as well as the underlying developmental genetic mechanisms in generating morphological diversity. Our objective was to bring together some of the key workers in the field of ecology and evolutionary biology who study Darwin's finches or whose studies were inspired by research on Darwin's finches. Insights provided by papers collected in this Theme Issue will be of interest to a wide audience. PMID- 20194164 TI - Multilocus genotypes from Charles Darwin's finches: biodiversity lost since the voyage of the Beagle. AB - Genetic analysis of museum specimens offers a direct window into a past that can predate the loss of extinct forms. We genotyped 18 Galapagos finches collected by Charles Darwin and companions during the voyage of the Beagle in 1835, and 22 specimens collected in 1901. Our goals were to determine if significant genetic diversity has been lost since the Beagle voyage and to determine the genetic source of specimens for which the collection locale was not recorded. Using 'ancient' DNA techniques, we quantified variation at 14 autosomal microsatellite loci. Assignment tests showed several museum specimens genetically matched recently field-sampled birds from their island of origin. Some were misclassified or were difficult to classify. Darwin's exceptionally large ground finches (Geospiza magnirostris) from Floreana and San Cristobal were genetically distinct from several other currently existing populations. Sharp-beaked ground finches (Geospiza difficilis) from Floreana and Isabela were also genetically distinct. These four populations are currently extinct, yet they were more genetically distinct from congeners than many other species of Darwin's finches are from each other. We conclude that a significant amount of the finch biodiversity observed and collected by Darwin has been lost since the voyage of the Beagle. PMID- 20194165 TI - How to save the rarest Darwin's finch from extinction: the mangrove finch on Isabela Island. AB - Habitat destruction and predation by invasive alien species has led to the disappearance of several island populations of Darwin's finches but to date none of the 13 recognized species have gone extinct. However, driven by rapid economic growth in the Galapagos, the effects of introduced species have accelerated and severely threatened these iconic birds. The critically endangered mangrove finch (Camarhynchus heliobates) is now confined to three small mangroves on Isabela Island. During 2006-2009, we assessed its population status and monitored nesting success, both before and after rat poisoning. Population size was estimated at around only 100 birds for the two main breeding sites, with possibly 5-10 birds surviving at a third mangrove. Before rat control, 54 per cent of nests during incubation phase were predated with only 18 per cent of nests producing fledglings. Post-rat control, nest predation during the incubation phase fell to 30 per cent with 37 per cent of nests producing fledglings. During the nestling phase, infestation by larvae of the introduced parasitic fly (Philornis downsi) caused 14 per cent additional mortality. Using population viability analysis, we simulated the probability of population persistence under various scenarios of control and showed that with effective management of these invasive species, mangrove finch populations should start to recover. PMID- 20194166 TI - Acoustic discrimination of sympatric morphs in Darwin's finches: a behavioural mechanism for assortative mating? AB - Populations with multiple morphological or behavioural types provide unique opportunities for studying the causes and consequences of evolutionary diversification. A population of the medium ground finch (Geospiza fortis) at El Garrapatero on Santa Cruz Island, Galapagos, features two beak size morphs. These morphs produce acoustically distinctive songs, are subject to disruptive selection and mate assortatively by morph. The main goal of the present study was to assess whether finches from this population are able to use song as a cue for morph discrimination. A secondary goal of this study was to evaluate whether birds from this population discriminate songs of their own locality versus another St Cruz locality, Borrero Bay, approximately 24 km to the NW. I presented territorial males with playback of songs of their own morph, of the other morph, and of males from Borrero Bay. Males responded more strongly to same-morph than to other-morph playbacks, showing significantly shorter latencies to flight, higher flight rates and closer approaches to the playback speaker. By contrast, I found only minor effects of locality on responsiveness. Evidence for morph discrimination via acoustic cues supports the hypothesis that song can serve as a behavioural mechanism for assortative mating and sympatric evolutionary divergence. PMID- 20194167 TI - Divergence with gene flow as facilitated by ecological differences: within-island variation in Darwin's finches. AB - Divergence and speciation can sometimes proceed in the face of, and even be enhanced by, ongoing gene flow. We here study divergence with gene flow in Darwin's finches, focusing on the role of ecological/adaptive differences in maintaining/promoting divergence and reproductive isolation. To this end, we survey allelic variation at 10 microsatellite loci for 989 medium ground finches (Geospiza fortis) on Santa Cruz Island, Galapagos. We find only small genetic differences among G. fortis from different sites. We instead find noteworthy genetic differences associated with beak. Moreover, G. fortis at the site with the greatest divergence in beak size also showed the greatest divergence at neutral markers; i.e. the lowest gene flow. Finally, morphological and genetic differentiation between the G. fortis beak-size morphs was intermediate to that between G. fortis and its smaller (Geospiza fuliginosa) and larger (Geospiza magnirostris) congeners. We conclude that ecological differences associated with beak size (i.e. foraging) influence patterns of gene flow within G. fortis on a single island, providing additional support for ecological speciation in the face of gene flow. Patterns of genetic similarity within and between species also suggest that interspecific hybridization might contribute to the formation of beak-size morphs within G. fortis. PMID- 20194168 TI - Evolution of sexual dimorphism in bill size and shape of hermit hummingbirds (Phaethornithinae): a role for ecological causation. AB - Unambiguous examples of ecological causation of sexual dimorphism are rare, and the best evidence involves sexual differences in trophic morphology. We show that moderate female-biased sexual dimorphism in bill curvature is the ancestral condition in hermit hummingbirds (Phaethornithinae), and that it is greatly amplified in species such as Glaucis hirsutus and Phaethornis guy, where bills of females are 60 per cent more curved than bills of males. In contrast, bill curvature dimorphism is lost or reduced in a lineage of short-billed hermit species and in specialist Eutoxeres sicklebill hermits. In the hermits, males tend to be larger than females in the majority of species, although size dimorphism is typically small. Consistent with earlier studies of hummingbird feeding performance, both raw regressions of traits and phylogenetic independent contrasts supported the prediction that dimorphism in bill curvature of hermits is associated with longer bills. Some evidence indicates that differences between sexes of hermit hummingbirds are associated with differences in the use of food plants. We suggest that some hermit hummingbirds provide model organisms for studies of ecological causation of sexual dimorphism because their sexual dimorphism in bill curvature provides a diagnostic clue for the food plants that need to be monitored for studies of sexual differences in resource use. PMID- 20194169 TI - Conspecific versus heterospecific gene exchange between populations of Darwin's finches. AB - This study addresses the extent and consequences of gene exchange between populations of Darwin's finches. Four species of ground finches (Geospiza) inhabit the small island of Daphne Major in the centre of the Galapagos archipelago. We undertook a study of microsatellite DNA variation at 16 loci in order to quantify gene flow within species owing to immigration and between species owing to hybridization. A combination of pedigrees of observed breeders and assignments of individuals to populations by the program Structure enabled us to determine the frequency of gene exchange and the island of origin of immigrants in some cases. The relatively large populations of Geospiza fortis and G. scandens receive conspecific immigrants at a rate of less than one per generation. They exchange genes more frequently by rare but repeated hybridization. Effects of heterospecific gene flow from hybridization are not counteracted by lower fitness of the offspring. As a result, the standing genetic variation of the two main resident populations on Daphne Major is enhanced to a greater extent by introgressive hybridization than through breeding with conspecific immigrants. Immigrant G. fuliginosa also breeds with G. fortis. Conspecific immigration was highest in the fourth species, G. magnirostris. This species is much larger than the other three and perhaps for this reason it has not bred with any of them. The source island of most immigrants is probably the neighbouring island of Santa Cruz. Evolutionary change may be inhibited in G. magnirostris by continuing gene flow, but enhanced in G. fortis and G. scandens by introgressive hybridization. PMID- 20194170 TI - The influence of gene flow and drift on genetic and phenotypic divergence in two species of Zosterops in Vanuatu. AB - Colonization of an archipelago sets the stage for adaptive radiation. However, some archipelagos are home to spectacular radiations, while others have much lower levels of diversification. The amount of gene flow among allopatric populations is one factor proposed to contribute to this variation. In island colonizing birds, selection for reduced dispersal ability is predicted to produce changing patterns of regional population genetic structure as gene flow-dominated systems give way to drift-mediated divergence. If this transition is important in facilitating phenotypic divergence, levels of genetic and phenotypic divergence should be associated. We consider population genetic structure and phenotypic divergence among two co-distributed, congeneric (Genus: Zosterops) bird species inhabiting the Vanuatu archipelago. The more recent colonist, Z. lateralis, exhibits genetic patterns consistent with a strong influence of distance-mediated gene flow. However, complex patterns of asymmetrical gene flow indicate variation in dispersal ability or inclination among populations. The endemic species, Z. flavifrons, shows only a partial transition towards a drift-mediated system, despite a long evolutionary history on the archipelago. We find no strong evidence that gene flow constrains phenotypic divergence in either species, suggesting that levels of inter-island gene flow do not explain the absence of a radiation across this archipelago. PMID- 20194171 TI - Mechanical stress, fracture risk and beak evolution in Darwin's ground finches (Geospiza). AB - Darwin's finches have radiated from a common ancestor into 14 descendent species, each specializing on distinct food resources and evolving divergent beak forms. Beak morphology in the ground finches (Geospiza) has been shown to evolve via natural selection in response to variation in food type, food availability and interspecific competition for food. From a mechanical perspective, however, beak size and shape are only indirectly related to birds' abilities to crack seeds, and beak form is hypothesized to evolve mainly under selection for fracture avoidance. Here, we test the fracture-avoidance hypothesis using finite-element modelling. We find that across species, mechanical loading is similar and approaches reported values of bone strength, thus suggesting pervasive selection on fracture avoidance. Additionally, deep and wide beaks are better suited for dissipating stress than are more elongate beaks when scaled to common sizes and loadings. Our results illustrate that deep and wide beaks in ground finches enable reduction of areas with high stress and peak stress magnitudes, allowing birds to crack hard seeds while limiting the risk of beak failure. These results may explain strong selection on beak depth and width in natural populations of Darwin's finches. PMID- 20194172 TI - The tale of the finch: adaptive radiation and behavioural flexibility. AB - Darwin's finches are a classic example of adaptive radiation. The ecological diversity of the Galapagos in part explains that radiation, but the fact that other founder species did not radiate suggests that other factors are also important. One hypothesis attempting to identify the extra factor is the flexible stem hypothesis, connecting individual adaptability to species richness. According to this hypothesis, the ancestral finches were flexible and therefore able to adapt to the new and harsh environment they encountered by exploiting new food types and developing new foraging techniques. Phenotypic variation was initially mediated by learning, but genetic accommodation entrenched differences and supplemented them with morphological adaptations. This process subsequently led to diversification and speciation of the Darwin's finches. Their current behaviour is consistent with this hypothesis as these birds use unusual resources by extraordinary means. In this paper, we identify cognitive capacities on which flexibility and innovation depend. The flexible stem hypothesis predicts that we will find high levels of these capacities in all species of Darwin's finches (not just those using innovative techniques). Here, we test that prediction, and find that while most of our data are in line with the flexible stem hypothesis, some are in tension with it. PMID- 20194173 TI - The beak of the other finch: coevolution of genetic covariance structure and developmental modularity during adaptive evolution. AB - The link between adaptation and evolutionary change remains the most central and least understood evolutionary problem. Rapid evolution and diversification of avian beaks is a textbook example of such a link, yet the mechanisms that enable beak's precise adaptation and extensive adaptability are poorly understood. Often observed rapid evolutionary change in beaks is particularly puzzling in light of the neo-Darwinian model that necessitates coordinated changes in developmentally distinct precursors and correspondence between functional and genetic modularity, which should preclude evolutionary diversification. I show that during first 19 generations after colonization of a novel environment, house finches (Carpodacus mexicanus) express an array of distinct, but adaptively equivalent beak morphologies-a result of compensatory developmental interactions between beak length and width in accommodating microevolutionary change in beak depth. Directional selection was largely confined to the elimination of extremes formed by these developmental interactions, while long-term stabilizing selection along a single axis-beak depth-was mirrored in the structure of beak's additive genetic covariance. These results emphasize three principal points. First, additive genetic covariance structure may represent a historical record of the most recurrent developmental and functional interactions. Second, adaptive equivalence of beak configurations shields genetic and developmental variation in individual components from depletion by natural selection. Third, compensatory developmental interactions among beak components can generate rapid reorganization of beak morphology under novel conditions and thus greatly facilitate both the evolution of precise adaptation and extensive diversification, thereby linking adaptation and adaptability in this classic example of Darwinian evolution. PMID- 20194174 TI - Differentiation with drift: a spatio-temporal genetic analysis of Galapagos mockingbird populations (Mimus spp.). AB - Small and isolated island populations provide ideal systems to study the effects of limited population size, genetic drift and gene flow on genetic diversity. We assessed genetic diversity within and differentiation among 19 mockingbird populations on 15 Galapagos islands, covering all four endemic species, using 16 microsatellite loci. We tested for signs of drift and gene flow, and used historic specimens to assess genetic change over the last century and to estimate effective population sizes. Within-population genetic diversity and effective population sizes varied substantially among island populations and correlated strongly with island size, suggesting that island size serves as a good predictor for effective population size. Genetic differentiation among populations was pronounced and increased with geographical distance. A century of genetic drift did not change genetic diversity on an archipelago-wide scale, but genetic drift led to loss of genetic diversity in small populations, especially in one of the two remaining populations of the endangered Floreana mockingbird. Unlike in other Galapagos bird species such as the Darwin's finches, gene flow among mockingbird populations was low. The clear pattern of genetically distinct populations reflects the effects of genetic drift and suggests that Galapagos mockingbirds are evolving in relative isolation. PMID- 20194175 TI - Host-pathogen coevolution, secondary sympatry and species diversification. AB - The build-up of species locally within a region by allopatric speciation depends on geographically separated (allopatric) sister populations becoming reproductively incompatible followed by secondary sympatry. Among birds, this has happened frequently in remote archipelagos, spectacular cases including the Darwin's finches (Geospizinae) and Hawaiian honeycreepers (Drepanidinae), but similar examples are lacking in archipelagos nearer to continental landmasses. Of the required steps in the speciation cycle, achievement of secondary sympatry appears to be limiting in near archipelagos and, by extension, in continental regions. Here, I suggest that secondary sympatry might be prevented by apparent competition mediated through pathogens that are locally coevolved with one population of host and are pathogenic in sister populations. The absence of numerous pathogens in remote archipelagos might, therefore, allow sister populations to achieve secondary sympatry more readily and thereby accelerate diversification. By similar reasoning, species should accumulate relatively slowly within continental regions. In this essay, I explore the assumptions and some implications of this model for species diversification. PMID- 20194176 TI - Rhetoric or reality? A systematic review of the impact of participatory approaches by UK public health units on health and social outcomes. AB - BACKGROUND: There has been a philosophical commitment to participation in public health since the 1970s. UK policy rhetoric on participation in public health has been particularly marked since 1997. It is less clear that participatory approaches have been pursued by UK public health units in practice. METHODS: A systematic review was undertaken of all studies using any recognized research methodology from 1974 to 2007 reporting on health and social outcomes of participatory approaches by UK public health units. Seventeen electronic databases were searched and inclusion/exclusion criteria and quality appraisal criteria applied. RESULTS: Five thousand and four hundred and fifty-one references were identified, reduced to 2155 once duplicates were removed. Only eight papers covering seven studies were relevant and included in the analysis. Only two studies met more than half of the relevant quality appraisal criteria. The studies fell into two distinct groups: four used qualitative methods to illustrate the complexities of effective community participation; three claimed success for their participative initiative without providing adequate evidence to substantiate such claims. CONCLUSIONS: This systematic review demonstrates that there is very little evidence in the peer-reviewed literature of participatory approaches by UK public health units or of such approaches having any noteworthy impact on health and social outcomes. PMID- 20194204 TI - Elevated left atrial pressure estimated by Doppler echocardiography is a key determinant of mitral valve tenting in functional mitral regurgitation. AB - BACKGROUND: Functional mitral regurgitation (FMR) may occur in patients with reduced or preserved left ventricular ejection fraction (LVEF) and has been associated with excess valvular tenting only in patients with reduced LVEF. This study aimed at identifying the predictors of FMR and to determine whether or not they are different in patients with reduced versus preserved LVEF. METHODS: 190 consecutive patients free of congenital or primary valvular disease had a comprehensive echocardiographic assessment of LV remodelling and function, diastolic function and FMR severity. RESULTS: 112 patients had depressed LVEF (<50%) and 78 had preserved LVEF. FMR was present in 30 patients with preserved LVEF and in 65 with reduced LVEF. Higher E/Ea, E/A and larger mitral tenting were independent predictors of FMR regardless of LVEF. The mitral tenting area was an independent predictor of FMR severity in patients with reduced or preserved LVEF (p = 0.04 and p = 0.0045) in addition to E/A (p = 0.0007), E/Ea (p = 0.004) in patients with reduced and preserved LVEF, respectively. Higher E/Ea was independently associated with larger mitral tenting in patients with reduced and preserved LVEF. Mitral tenting area was linearly related to E/Ea (r = 0.30, p<0.0001) and E/A (r = 0.43, p<0.0001) and LA enlargement (r = 0.54, p<0.0001) after having paired 96 patients with and without FMR on indices of LV remodelling. CONCLUSIONS: In both patients with preserved and reduced LVEF, mitral tenting that leads to FMR is mainly determined by both mitral tethering forces-that is, displacement of papillary muscles and by pushing forces-that is, increased left atrial pressure. This study underscores that LV preload is a key determinant of FMR. PMID- 20194205 TI - Childhood adversities as predictors of incident coronary heart disease and cerebrovascular disease. AB - BACKGROUND: Studies suggest that childhood adversities are important determinants of various types of later illnesses as well as poor health behaviour. However, few large-scale prospective studies have examined the associations between childhood adversities and cardiovascular disease. OBJECTIVE: To investigate whether childhood adversities are associated with increased risk of incident cardiovascular disease. DESIGN AND SETTING: Participants were 23 916 men and women in four age groups (20-24, 30-34, 40-44, and 50-54 years) from the Health and Social Support study, a longitudinal study on a random sample representative of the Finnish population. Data from national health registers on coronary heart disease and cerebrovascular disease during a mean follow-up of 6.9 years were linked to survey responses on childhood adversities. Cox proportional hazard models were adjusted for age group and potential mediators (education, health risk behaviours, diabetes and depression). RESULTS: There was a significant linear trend between the number of childhood adversities and disease end points in women. The risk of incident cardiovascular disease was threefold among women exposed concurrently to three types of childhood adversities (financial difficulties, interpersonal conflicts and longstanding illness of a family member). Among men, increased risk was observed only among those with longstanding illness of a family member (HR=1.44; 95% CI 1.06 to 1.96). CONCLUSIONS: In this prospective population-based sample, childhood adversities were associated with a significantly increased risk of objectively verified cardiovascular disease, especially among women but to a lesser extent among men. More studies with prospective settings are needed to confirm the association and possible mechanisms. PMID- 20194207 TI - Waist circumference: a waste of time? PMID- 20194209 TI - T2-weighted magnetic resonance imaging to assess myocardial oedema. PMID- 20194211 TI - NICE evaluation of transmyocardial laser revascularisation and percutaneous laser revascularisation for refractory angina. PMID- 20194212 TI - Biomarkers in heart failure. PMID- 20194213 TI - Dynamic volume 320-slice CT in the assessment of patent ductus arteriosus for percutaneous closure. PMID- 20194214 TI - Sinus rhythm with isolated pulmonary vein fibrillation. PMID- 20194215 TI - Understanding changing patterns of survival and hospitalization for heart failure over two decades in New Zealand: utility of 'days alive and out of hospital' from epidemiological data. AB - AIMS: To describe changes in heart failure (HF) epidemiology in New Zealand between 1988 and 2008 using the number of days alive and out of hospital after a first hospitalization for HF, and to use these data to evaluate the overall impact of changing patterns of hospitalization and survival. METHODS AND RESULTS: We performed a population analysis of all HF hospitalization and mortality data from 1 January 1988 to 31 December 2008 in New Zealand. The main outcome measures were: days alive and out of hospital, age standardized hospitalization rates, and mortality after an index hospitalization for HF. The number of days alive and out of hospital at 2 years increased by 2 months over the two decades of the study (from 448.8 to 511.3 days). Age standardized index HF hospitalization rates increased from 1988 to 1999, and declined thereafter, current rates are 106.9/100 000 for women and 174.3/100 000 for men. Patient age at index admission progressively increased, and hospital length of stay decreased. Mortality rates progressively decreased until 2000, but there has been no further decrease since then. Total hospital days have decreased up to 2008. CONCLUSION: There have been major changes in the epidemiology of HF in New Zealand between 1988 and 2008, during which time there have been important changes in HF management. Despite increasing age, hospitalization rates are now declining and patients with HF are surviving longer out of hospital and with fewer hospital days. These results support the need for continued emphasis on delivery of effective community-based care for patients with this long-term condition. PMID- 20194216 TI - Leptin resistance after heart transplantation. PMID- 20194217 TI - Responding to patient safety incidents: the "seven pillars". AB - BACKGROUND: Although acknowledged to be an ethical imperative for providers, disclosure following patient safety incidents remains the exception. The appropriate response to a patient safety incident and the disclosure of medical errors are neither easy nor obvious. An inadequate response to patient harm or an inappropriate disclosure may frustrate practitioners, dent their professional reputation, and alienate patients. METHODS: The authors have presented a descriptive study on the comprehensive process for responding to patient safety incidents, including the disclosure of medical errors adopted at a large, urban tertiary care centre in the United States. RESULTS: In the first two years post implementation, the "seven pillars" process has led to more than 2,000 incident reports annually, prompted more than 100 investigations with root cause analysis, translated into close to 200 system improvements and served as the foundation of almost 106 disclosure conversations and 20 full disclosures of inappropriate or unreasonable care causing harm to patients. CONCLUSIONS: Adopting a policy of transparency represents a major shift in organisational focus and may take several years to implement. In our experience, the ability to rapidly learn from, respond to, and modify practices based on investigation to improve the safety and quality of patient care is grounded in transparency. PMID- 20194218 TI - Prescription data improve the medication history in primary care. AB - BACKGROUND: Incomplete medication lists increase the risk of medication errors and adverse drug effects. In Denmark, dispensing data and pharmacy records are available directly online to treating physicians. We aimed (1) to describe if use of pharmacy records improved the medication history among patients consulting their general practitioner and (2) to characterise inconsistencies between the medication history reported by the patient and the general practitioner's recordings. METHODS: Patients attending a general practitioner clinic were interviewed about their current medication use. Subsequently, the patients were contacted by phone and asked to verify the medication list previously obtained. Half of the patients were randomly selected for further questioning guided by their dispensing data: during the telephone interview, these patients were asked to clarify whether drugs registered in their pharmacy records were still in use. Pharmacy records show all drugs acquired on prescription from any national pharmacy in the preceding 2 years. The medication list was corrected accordingly. In all patients, the medication lists obtained on the in-clinic and telephone interviews were compared to the general practitioner's registrations. RESULTS: The 150 patients included in the study had a median age of 56 years (range 18-93 years), and 90 (60%) were women. Patients reported use of 849 drugs (median 5, range 0-16) at the in-clinic interview. Another 41 drugs (median 0, range 0-4) were added during the telephone interview. In the subgroup of 75 patients interviewed guided by pharmacy records, additionally 53 drugs (10%) were added to the 474 drugs already mentioned. The 27 patients adding more drugs guided by pharmacy records were significantly older and used more drugs (both p<0.05) than the 48 patients not adding drugs. When the medication lists were compared with the general practitioner's lists, specifically use of over-the-counter products and prescription-only medications from Anatomical Therapeutic Chemical Classification System group J, A, D, N and R were not registered by the general practitioner. DISCUSSION: Dispensing data provide further improvement to a medication history based on thorough in-clinic and telephone interviews. Use of pharmacy records as a supplement when recording a medication history seems beneficial, especially among older patients treated with polypharmacy. PMID- 20194219 TI - A comparative analysis of incident reporting lag times in academic medical centres in Japan and the USA. AB - BACKGROUND: Delays in reporting of medical errors may signal deficiencies in the performance of hospital-based incident reporting. We sought to understand the characteristics of hospitals, providers and patient injuries that affect such delays. SETTING AND METHODS: All incident reports filed between May 2004 and August 2005 at the Kyoto University Hospital (KUH) in Japan and the Brigham and Women's Hospital (BWH) in the USA were evaluated. Lag time between each event and the submission of an incident report were computed. Multivariable Poisson regression with overdispersion, to control for previously described confounding factors and identify independent predictors of delays, was used. RESULTS: Unadjusted lag times were significantly longer for physicians than other reporters (3.6 vs 1.8 days, p < 0.0001), longer for major than minor events (4.1 vs 1.9 days, p = 0.0006) and longer at KUH than at BWH (3.1 vs 1.0 days, p < 0.0001). In multivariable analysis, lag times at KUH remained nearly three times longer than at BWH (incidence-rate ratio 2.95, 95% CI 2.84 to 3.06, p < 0.0001). CONCLUSIONS: Lag time provides a novel and useful metric for evaluating the performance of hospital-based incident reporting systems. Across two very different health systems, physicians reported far fewer events, with significant delays compared with other providers. Even after controlling for important confounding factors, lag times at KUH were nearly triple those at BWH, suggesting significant differences in the performance of their reporting systems, potentially attributable to either the ease of online reporting at BWH or to the greater attention to patient safety reporting in that hospital. PMID- 20194220 TI - Readiness for organisational change among general practice staff. AB - BACKGROUND: Increasing demands on general practice to manage chronic disease may warrant organisational change at the practice level. Staff's readiness for organisational change can act as a facilitator or barrier to implementing interventions aimed at organisational change. OBJECTIVES: To explore general practice staff readiness for organisational change and its association with staff and practices characteristics. METHODS: This is a cross-sectional study of practices in three Australian states involved in a randomised control trial on the effectiveness of an intervention to enhance the role of non-general practitioner staff in chronic disease management. Readiness for organisational change, job satisfaction and practice characteristics were assessed using questionnaires. RESULTS: 502 staff from 58 practices completed questionnaires. Practice characteristics were not associated with staff readiness for change. A multilevel regression analysis showed statistically significant associations between staff readiness for organisational change (range 1 to 5) and having a non clinical staff role (vs general practitioner; B=-0.315; 95% CI -0.47 to -0.16; p<0.001), full-time employment (vs part-time; B=0.175, 95% CI 0.06 to 0.29; p<0.01) and lower job satisfaction (B=-0.277, 95% CI -0.40 to -0.15; p<0.001). CONCLUSIONS: The results suggest that different approaches are needed to facilitate change which addresses the mix of practice staff. Moderately low job satisfaction may be an opportunity for organisational change. PMID- 20194221 TI - Analysis of major complications associated with arterial catheterisation. AB - INTRODUCTION: Arterial catheterisation is used for continuous haemodynamic monitoring in patients undergoing surgery and in critical care units. Although it is considered a safe procedure, a major complication such as arterial occlusion and limb gangrene can occur. OBJECTIVE: To determine the incidence, outcome and potential to avoid complications associated with arterial catheterisation. METHODS: The number of arterial catheterisation was determined using an anaesthesiology and critical care medicine billing database over a period of 4 years (1 January 2003 to 31 December 2006). Possible major complications were identified from two hospital databases; all identified charts were screened and then reviewed by an expert panel that determined causation. A major complication was defined as requiring operative intervention and/or resulting in permanent harm. RESULTS: 15 (0.084%) major complications were identified among 17 840 instances of arterial catheterisation insertions. Of 15 arterial catheterisations, nine were performed in the operating room and six in the intensive care unit. Nine patients suffered ischaemic injury, which progressed to gangrene in three patients. Three patients developed haematoma that required surgical evacuation; two of these required vascular repair. One patient had compartment syndrome requiring fasciotomy and two patients had sheared catheter fragments that needed to be removed. All 15 patients had multiple comorbidities, and those in the operating room had an American Society of Anesthesiologists score of >or=3. Seven (46.6%) had arterial catheterisation done under emergent circumstances. Six (40%) died during hospitalisation because of complications unrelated to arterial catheterisation. CONCLUSION: Arterial catheterisation had a very low rate of major complications. They seem associated with high severity of illness and emergency surgery. PMID- 20194223 TI - Transmembrane TNF-alpha: structure, function and interaction with anti-TNF agents. AB - Transmembrane TNF-alpha, a precursor of the soluble form of TNF-alpha, is expressed on activated macrophages and lymphocytes as well as other cell types. After processing by TNF-alpha-converting enzyme (TACE), the soluble form of TNF alpha is cleaved from transmembrane TNF-alpha and mediates its biological activities through binding to Types 1 and 2 TNF receptors (TNF-R1 and -R2) of remote tissues. Accumulating evidence suggests that not only soluble TNF-alpha, but also transmembrane TNF-alpha is involved in the inflammatory response. Transmembrane TNF-alpha acts as a bipolar molecule that transmits signals both as a ligand and as a receptor in a cell-to-cell contact fashion. Transmembrane TNF alpha on TNF-alpha-producing cells binds to TNF-R1 and -R2, and transmits signals to the target cells as a ligand, whereas transmembrane TNF-alpha also acts as a receptor that transmits outside-to-inside (reverse) signals back to the cells after binding to its native receptors. Anti-TNF agents infliximab, adalimumab and etanercept bind to and neutralize soluble TNF-alpha, but exert different effects on transmembrane TNF-alpha-expressing cells (TNF-alpha-producing cells). In the clinical settings, these three anti-TNF agents are equally effective for RA, but etanercept is not effective for granulomatous diseases. Moreover, infliximab induces granulomatous infections more frequently than etanercept. Considering the important role of transmembrane TNF-alpha in granulomatous inflammation, reviewing the biology of transmembrane TNF-alpha and its interaction with anti TNF agents will contribute to understanding the bases of differential clinical efficacy of these promising treatment modalities. PMID- 20194224 TI - Regulatory polymorphisms in EGR2 are associated with susceptibility to systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease induced by the combinations of environmental and genetic factors. Recently, mice in which the early growth response 2 (EGR2) gene, a zinc-finger transcription factor, is conditionally knocked out in CD2(+) T cells have been shown to develop a lupus like autoimmune disease. Here, we evaluated if polymorphisms in the EGR2 gene influence SLE susceptibility in humans. We first analyzed the effect of SNPs in the EGR2 region on EGR2 expression, and a significant positive correlation with expression was identified in an SNP located at the 5' flanking region of EGR2 (rs10761670, R=0.23, P=0.00072). We then performed a case-control association study using three sets of SLE cohorts by genotyping 14 tag SNPs in the EGR2 gene region. A peak of association with SLE susceptibility was observed for rs10761670 [Pooled: OR = 1.23 (95% CI 1.10-1.37), P=0.00023). This SNP was also associated with susceptibility to rheumatoid arthritis (RA) [OR = 1.15 (95% CI 1.05-1.26), P = 0.0019), suggesting that EGR2 is a common risk factor for SLE and RA. Among the SNPs in complete linkage disequilibrium with rs10761670 (r(2) = 1.0), two SNPs (rs1412554 and rs1509957) affected the binding of transcription factors and transcriptional activity in vitro, suggesting that they may be candidates of causal regulatory variants in this region. Therefore, EGR2 is a genetic risk factor for SLE, in which increased gene expression may contribute to SLE pathogenesis. PMID- 20194225 TI - Population strategies to decrease sodium intake and the burden of cardiovascular disease: a cost-effectiveness analysis. AB - BACKGROUND: Sodium consumption raises blood pressure, increasing the risk for heart attack and stroke. Several countries, including the United States, are considering strategies to decrease population sodium intake. OBJECTIVE: To assess the cost-effectiveness of 2 population strategies to reduce sodium intake: government collaboration with food manufacturers to voluntarily cut sodium in processed foods, modeled on the United Kingdom experience, and a sodium tax. DESIGN: A Markov model was constructed with 4 health states: well, acute myocardial infarction (MI), acute stroke, and history of MI or stroke. DATA SOURCES: Medical Panel Expenditure Survey (2006), Framingham Heart Study (1980 to 2003), Dietary Approaches to Stop Hypertension trial, and other published data. TARGET POPULATION: U.S. adults aged 40 to 85 years. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. OUTCOME MEASURES: Incremental costs (2008 U.S. dollars), quality-adjusted life-years (QALYs), and MIs and strokes averted. RESULTS OF BASE CASE ANALYSIS: Collaboration with industry that decreases mean population sodium intake by 9.5% averts 513 885 strokes and 480 358 MIs over the lifetime of adults aged 40 to 85 years who are alive today compared with the status quo, increasing QALYs by 2.1 million and saving $32.1 billion in medical costs. A tax on sodium that decreases population sodium intake by 6% increases QALYs by 1.3 million and saves $22.4 billion over the same period. RESULTS OF SENSITIVITY ANALYSIS: Results are sensitive to the assumption that consumers have no disutility with modest reductions in sodium intake. LIMITATION: Efforts to reduce population sodium intake could result in other dietary changes that are difficult to predict. CONCLUSION: Strategies to reduce sodium intake on a population level in the United States are likely to substantially reduce stroke and MI incidence, which would save billions of dollars in medical expenses. PRIMARY FUNDING SOURCE: Department of Veterans Affairs, Stanford University, and National Science Foundation. PMID- 20194226 TI - We can reduce dietary sodium, save money, and save lives. PMID- 20194227 TI - Summaries for patients. Are there cost-effective ways to help people eat less salt? PMID- 20194228 TI - Summaries for patients. Adding electrocardiography to medical history and physical examination for evaluation before sports participation in college athletes. PMID- 20194229 TI - Summaries for patients. Cost-effectiveness of different types of evaluations before sports participation in young athletes. PMID- 20194230 TI - Summaries for patients. Unequal leg length and knee osteoarthritis. PMID- 20194231 TI - In the clinic. Type 2 diabetes. AB - This issue provides a clinical overview of type 2 diabetes focusing on prevention, diagnosis, treatment, practice improvement, and patient information. Readers can complete the accompanying CME quiz for 1.5 credits. Only ACP members and individual subscribers can access the electronic features of In the Clinic. Non-subscribers who wish to access this issue of In the Clinic can elect "Pay for View." Subscribers can receive 1.5 category 1 CME credits by completing the CME quiz that accompanies this issue of In the Clinic. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including PIER (Physicians' Information and Education Resource) and MKSAP (Medical Knowledge and Self Assessment Program). Annals of Internal Medicine editors develop In the Clinic from these primary sources in collaboration with the ACP's Medical Education and Publishing division and with assistance of science writers and physician writers. Editorial consultants from PIER and MKSAP provide expert review of the content. Readers who are interested in these primary resources for more detail can consult www.acponline.org, http://pier.acponline.org, and other resources referenced within each issue of In the Clinic. PMID- 20194232 TI - Cardiovascular screening in college athletes with and without electrocardiography: A cross-sectional study. AB - BACKGROUND: Although cardiovascular screening is recommended for athletes before participating in sports, the role of 12-lead electrocardiography (ECG) remains uncertain. To date, no prospective data that compare screening with and without ECG have been available. OBJECTIVE: To compare the performance of preparticipation screening limited to medical history and physical examination with a strategy that integrates these with ECG. DESIGN: Cross-sectional comparison of screening strategies. SETTING: University Health Services, Harvard University, Cambridge, Massachusetts. PARTICIPANTS: 510 collegiate athletes who received cardiovascular screening before athletic participation. MEASUREMENTS: Each participant had routine history and examination-limited screening and ECG. They received transthoracic echocardiography (TTE) to detect or exclude cardiac findings with relevance to sports participation. The performance of screening with history and examination only was compared with that of screening that integrated history, examination, and ECG. RESULTS: Cardiac abnormalities with relevance to sports participation risk were observed on TTE in 11 of 510 participants (prevalence, 2.2%). Screening with history and examination alone detected abnormalities in 5 of these 11 athletes (sensitivity, 45.5% [95% CI, 16.8% to 76.2%]; specificity, 94.4% [CI, 92.0% to 96.2%]). Electrocardiography detected 5 additional participants with cardiac abnormalities (for a total of 10 of 11 participants), thereby improving the overall sensitivity of screening to 90.9% (CI, 58.7% to 99.8%). However, including ECG reduced the specificity of screening to 82.7% (CI, 79.1% to 86.0%) and was associated with a false-positive rate of 16.9% (vs. 5.5% for screening with history and examination only). LIMITATION: Definitive conclusions regarding the effect of ECG inclusion on sudden death rates cannot be made. CONCLUSION: Adding ECG to medical history and physical examination improves the overall sensitivity of preparticipation cardiovascular screening in athletes. However, this strategy is associated with an increased rate of false-positive results when current ECG interpretation criteria are used. PRIMARY FUNDING SOURCE: None. PMID- 20194233 TI - Cost-effectiveness of preparticipation screening for prevention of sudden cardiac death in young athletes. AB - BACKGROUND: Inclusion of 12-lead electrocardiography (ECG) in preparticipation screening of young athletes is controversial because of concerns about cost effectiveness. OBJECTIVE: To evaluate the cost-effectiveness of ECG plus cardiovascular-focused history and physical examination compared with cardiovascular-focused history and physical examination alone for preparticipation screening. DESIGN: Decision-analysis, cost-effectiveness model. DATA SOURCES: Published epidemiologic and preparticipation screening data, vital statistics, and other publicly available data. TARGET POPULATION: Competitive athletes in high school and college aged 14 to 22 years. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTION: Nonparticipation in competitive athletic activity and disease-specific treatment for identified athletes with heart disease. OUTCOME MEASURE: Incremental health care cost per life-year gained. RESULTS OF BASE-CASE ANALYSIS: Addition of ECG to preparticipation screening saves 2.06 life-years per 1000 athletes at an incremental total cost of $89 per athlete and yields a cost-effectiveness ratio of $42 900 per life-year saved (95% CI, $21 200 to $71 300 per life-year saved) compared with cardiovascular-focused history and physical examination alone. Compared with no screening, ECG plus cardiovascular-focused history and physical examination saves 2.6 life-years per 1000 athletes screened and costs $199 per athlete, yielding a cost-effectiveness ratio of $76 100 per life-year saved ($62 400 to $130 000). RESULTS OF SENSITIVITY ANALYSIS: Results are sensitive to the relative risk reduction associated with nonparticipation and the cost of initial screening. LIMITATIONS: Effectiveness data are derived from 1 major European study. Patterns of causes of sudden death may vary among countries. CONCLUSION: Screening young athletes with 12-lead ECG plus cardiovascular-focused history and physical examination may be cost-effective. PRIMARY FUNDING SOURCE: Stanford Cardiovascular Institute and the Breetwor Foundation. PMID- 20194234 TI - Association of leg-length inequality with knee osteoarthritis: a cohort study. AB - BACKGROUND: Leg-length inequality is common in the general population and may accelerate development of knee osteoarthritis. OBJECTIVE: To determine whether leg-length inequality is associated with prevalent, incident, and progressive knee osteoarthritis. DESIGN: Prospective observational cohort study. SETTING: Population samples from Birmingham, Alabama, and Iowa City, Iowa. PATIENTS: 3026 participants aged 50 to 79 years with or at high risk for knee osteoarthritis. MEASUREMENTS: The exposure was leg-length inequality, measured by full-limb radiography. The outcomes were prevalent, incident, and progressive knee osteoarthritis. Radiographic osteoarthritis was defined as Kellgren and Lawrence grade 2 or greater, and symptomatic osteoarthritis was defined as radiographic disease in a consistently painful knee. RESULTS: Compared with leg-length inequality less than 1 cm, leg-length inequality of 1 cm or more was associated with prevalent radiographic (53% vs. 36%; odds ratio [OR], 1.9 [95% CI, 1.5 to 2.4]) and symptomatic (30% vs. 17%; OR, 2.0 [CI, 1.6 to 2.6]) osteoarthritis in the shorter leg, incident symptomatic osteoarthritis in the shorter leg (15% vs. 9%; OR, 1.7 [CI, 1.2 to 2.4]) and the longer leg (13% vs. 9%; OR, 1.5 [CI, 1.0 to 2.1]), and increased odds of progressive osteoarthritis in the shorter leg (29% vs. 24%; OR, 1.3 [CI, 1.0 to 1.7]). LIMITATIONS: Duration of follow-up may not be long enough to adequately identify cases of incidence and progression. Measurements of leg length, including radiography, are subject to measurement error, which could result in misclassification. CONCLUSION: Radiographic leg length inequality was associated with prevalent, incident symptomatic, and progressive knee osteoarthritis. Leg-length inequality is a potentially modifiable risk factor for knee osteoarthritis. PRIMARY FUNDING SOURCE: National Institute on Aging. PMID- 20194235 TI - Brief communication: Management of implantable cardioverter-defibrillators in hospice: A nationwide survey. AB - BACKGROUND: Communication about the deactivation of implantable cardioverter defibrillators (ICDs) in patients near the end of life is rare. OBJECTIVE: To determine whether hospices are admitting patients with ICDs, whether such patients are receiving shocks, and how hospices manage ICDs. DESIGN: Cross sectional survey. SETTING: Randomly selected hospice facilities. PARTICIPANTS: 900 hospices, 414 of which responded fully. MEASUREMENTS: Frequency of admission of patients with ICDs, frequency with which patients received shocks, existence of ICD deactivation policies, and frequency of deactivation. RESULTS: 97% of hospices admitted patients with ICDs, and 58% reported that in the past year, a patient had been shocked. Only 10% of hospices had a policy that addressed deactivation. On average, 42% (95% CI, 37% to 48%) of patients with ICDs had the shocking function deactivated. LIMITATION: The study relied on the knowledge of hospice administrators. CONCLUSION: Hospices are admitting patients with ICDs, and patients are being shocked at the end of life. Ensuring that hospices have policies in place to address deactivation may improve the care for patients with these devices. The authors provide a sample deactivation policy. PRIMARY FUNDING SOURCE: National Institute of Aging and National Institute of Nursing Research. PMID- 20194236 TI - Narrative review: Thrombocytosis, polycythemia vera, and JAK2 mutations: The phenotypic mimicry of chronic myeloproliferation. AB - The myeloproliferative disorders polycythemia vera, essential thrombocytosis, and primary myelofibrosis are clonal disorders arising in a pluripotent hematopoietic stem cell, causing an unregulated increase in the number of erythrocytes, leukocytes, or platelets, alone or in combination; eventual marrow dominance by the progeny of the involved stem cell; and a tendency to arterial or venous thrombosis, marrow fibrosis, splenomegaly, or transformation to acute leukemia, albeit at widely varying frequencies. The discovery of an activating mutation (V617F) in the gene for JAK2 (Janus kinase 2), a tyrosine kinase utilized by hematopoietic cell receptors for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor, provided an explanation for the shared clinical features of these 3 disorders. Constitutive JAK2 activation provides a growth and survival advantage to the hematopoietic cells of the affected clone. Because signaling by the mutated kinase utilizes normal pathways, the result is overproduction of morphologically normal blood cells, an often indolent course, and (in essential thrombocytosis) usually a normal life span. Because the erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor receptors are all constitutively activated, polycythemia vera is the potential ultimate clinical phenotype of the JAK2 V617F mutation and, as a corollary, is the most common of the 3 disorders. The number of cells expressing the JAK2 V617F mutation (the allele burden) seems to correlate with the clinical phenotype. Preliminary results of clinical trials with agents that inhibit the mutated kinase indicate a reduction in splenomegaly and alleviation of night sweats, fatigue, and pruritus. PMID- 20194238 TI - Systematic review: Vitamin D and calcium supplementation in prevention of cardiovascular events. AB - BACKGROUND: Vitamin D and calcium may affect the cardiovascular system independently and interactively. PURPOSE: To assess whether vitamin D and calcium supplements reduce the risk for cardiovascular events in adults. DATA SOURCES: Studies published in English from 1966 to July 2009 in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. STUDY SELECTION: Two investigators independently selected 17 prospective studies and randomized trials that examined vitamin D supplementation, calcium supplementation, or both and subsequent cardiovascular events. DATA EXTRACTION: Three investigators extracted and checked data about study designs, participants, exposures or interventions, outcomes, and data quality. DATA SYNTHESIS: Five prospective studies of patients receiving dialysis and 1 study involving a general population showed consistent reductions in cardiovascular disease (CVD) mortality among adults who received vitamin D supplements. Four prospective studies of initially healthy persons found no differences in incidence of CVD between calcium supplement recipients and nonrecipients. Results of secondary analyses in 8 randomized trials showed a slight but statistically nonsignificant reduction in CVD risk (pooled relative risk, 0.90 [95% CI, 0.77 to 1.05]) with vitamin D supplementation at moderate to high doses (approximately 1000 IU/d) but not with calcium supplementation (pooled relative risk, 1.14 [CI, 0.92 to 1.41]), or a combination of vitamin D and calcium supplementation (pooled relative risk, 1.04 [CI, 0.92 to 1.18]) compared with placebo. LIMITATIONS: Only articles published in English that reported cardiovascular event outcomes were included. The small number of studies, the lack of trials designed specifically to assess primary effects on cardiovascular outcomes, and important between-study heterogeneity preclude definitive conclusions. CONCLUSION: Evidence from limited data suggests that vitamin D supplements at moderate to high doses may reduce CVD risk, whereas calcium supplements seem to have minimal cardiovascular effects. Further research is needed to elucidate the role of these supplements in CVD prevention. PRIMARY FUNDING SOURCE: The American Heart Association and the National Heart, Lung, and Blood Institute. PMID- 20194239 TI - National electrocardiography screening for competitive athletes: Feasible in the United States? PMID- 20194237 TI - Systematic review: Vitamin D and cardiometabolic outcomes. AB - BACKGROUND: Vitamin D may modify risk for cardiometabolic outcomes (type 2 diabetes, hypertension, or cardiovascular disease). PURPOSE: To examine the association between vitamin D status, including the effect of vitamin D supplementation, and cardiometabolic outcomes in generally healthy adults. DATA SOURCES: English-language studies in MEDLINE (inception to 4 November 2009) and the Cochrane Central Register of Controlled Trials (fourth quarter of 2009). STUDY SELECTION: 11 reviewers screened citations to identify longitudinal cohort studies that reported associations between vitamin D status and cardiometabolic outcomes, including randomized trials of vitamin D supplementation. DATA EXTRACTION: 5 independent reviewers extracted data about study conduct, participant characteristics, outcomes, and quality. Differences were resolved by consensus. DATA SYNTHESIS: 13 observational studies (14 cohorts) and 18 trials were eligible. Three of 6 analyses (from 4 different cohorts) reported a lower incident diabetes risk in the highest versus the lowest vitamin D status groups. Eight trials found no effect of vitamin D supplementation on glycemia or incident diabetes. In meta-analysis of 3 cohorts, lower 25-hydroxyvitamin D concentration was associated with incident hypertension (relative risk, 1.8 [95% CI, 1.3 to 2.4]). In meta-analyses of 10 trials, supplementation nonsignificantly reduced systolic blood pressure (weighted mean difference, -1.9 mm Hg [CI, -4.2 to 0.4 mm Hg]) and did not affect diastolic blood pressure (weighted mean difference, -0.1 mm Hg [CI, -0.7 to 0.5 mm Hg]). Lower 25-hydroxyvitamin D concentration was associated with incident cardiovascular disease in 5 of 7 analyses (6 cohorts). Four trials found no effect of supplementation on cardiovascular outcomes. LIMITATIONS: Studies included primarily white participants. Observational studies were heterogeneous. Several trials reported post hoc analyses. CONCLUSION: The association between vitamin D status and cardiometabolic outcomes is uncertain. Trials showed no clinically significant effect of vitamin D supplementation at the dosages given. PRIMARY FUNDING SOURCE: National Institute of Diabetes and Digestive and Kidney Disease, the National Institutes of Health Office of Dietary Supplements, U.S. Food and Drug Administration, Agency for Healthcare Research and Quality, and Public Health Agency of Canada. PMID- 20194240 TI - Vitamin D supplementation in the age of lost innocence. PMID- 20194241 TI - In transition. PMID- 20194242 TI - Justifying different levels of palliative sedation. PMID- 20194243 TI - Justifying different levels of palliative sedation. PMID- 20194244 TI - Cost-effectiveness of biologics in early rheumatoid arthritis. PMID- 20194246 TI - Long-term effects of low-carbohydrate versus low-fat diets in obese persons. PMID- 20194248 TI - Varenicline and pheochromocytoma. PMID- 20194249 TI - Report from the working group conference on multisite trial design for cognitive remediation in schizophrenia. AB - The National Institute of Mental Health (NIMH)-Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Project and related efforts have stimulated the initiation of several studies of pharmacologic treatments for cognitive impairment in schizophrenia. Cognitive remediation may provide an excellent platform for the provision of new learning opportunities and the acquisition of new skills for patients who are engaged in pharmacologic trials to improve cognition. However, it is not clear how a cognitive remediation intervention would be employed in multisite clinical trials. A meeting of experts on cognitive remediation and related methodological topics was convened to address the feasibility and study design issues for the development of a multisite trial of cognitive remediation in schizophrenia called the Cognitive Remediation in the Schizophrenia Trials Network study. This report details the findings from this meeting, which included the following 4 conclusions. (1) A multisite trial of a cognitive remediation intervention using a network of diverse research sites would be of great scientific value. (2) Various interventions could be employed for this multisite trial. (3) Programs that do not address key motivational and interpersonal aspects of cognitive remediation may benefit from supplementation with "bridging groups" that allows patients to meet with others and to apply their newly acquired cognitive skills to everyday life. (4) Before a multisite efficacy trial is initiated, a pilot study could demonstrate the feasibility of conducting a trial using a cognitive remediation intervention. PMID- 20194250 TI - Analysis of the effect of serum interleukin-6 (IL-6) and soluble IL-6 receptor levels on survival of patients with colorectal cancer. AB - OBJECTIVE: The correlations of serum interleukin-6 and soluble interleukin-6 receptor concentrations with clinicopathological features and survival of patients with colorectal cancer were studied. METHODS: We measured the serum levels of interleukin-6 and soluble interleukin-6 receptor in 99 colorectal cancer patients at the Chang Gung Memorial Hospital, Taiwan. The interleukin-6 and soluble interleukin-6 receptor levels were tested for their association with each other, and with the clinical parameters and outcomes. RESULTS: Both interleukin-6 and soluble interleukin-6 receptor concentrations were significantly higher in colorectal cancer patients than in normal individuals. Unlike patients with serum interleukin-6 levels >10 pg/ml, who have increased carcinoembryonic antigen levels and shorter survival, serum soluble interleukin-6 receptor levels >800 pg/ml were found in patients with stages I-II and no regional lymph nodal invasion and appeared to be a positive prognostic factor for improved survival. Especially, patients with serum interleukin-6 <10 pg/ml and soluble interleukin-6 receptor >800 pg/ml lived significantly longer. Nonetheless, the multivariate analysis showed that only tumor-node metastasis stage, metastatic status and serum interleukin-6 level were independent prognostic factors, whereas the serum soluble interleukin-6 receptor level became marginally important for survival. CONCLUSIONS: We suggest the clinical relevance of interleukin-6 and soluble interleukin-6 receptor for the survival of colorectal cancer patients. From a practical point of view, detection of the serum interleukin-6 level alone, rather than combined measurement of interleukin 6 and soluble interleukin-6 receptor, may be sufficient to independently predict survival in colorectal cancer patients. PMID- 20194251 TI - Word learning from baby videos. AB - OBJECTIVE: To examine whether children between 12 and 25 months of age learn words from an infant-directed DVD designed for that purpose. DESIGN: Half of the children received a DVD to watch in their home over the course of 6 weeks. SETTING: All participants returned to a laboratory for testing on vocabulary acquisition every 2 weeks. PARTICIPANTS: Ninety-six 12- to 24-month-old children. MAIN EXPOSURE: Baby videos. MAIN OUTCOME MEASURES: Parent report and observational measures of vocabulary acquisition related to words highlighted in the DVD; parent report of general language development; and parent report of children's media use. RESULTS: The age at first viewing of baby DVDs was related to children's general language development. There was no evidence of learning words highlighted in the infant-directed DVD independent of parental intervention. CONCLUSIONS: Researchers should continue to examine whether infant directed media are effective in teaching infants and toddlers content and consider the cognitive factors related to whether very young viewers should be expected to learn from a DVD. PMID- 20194252 TI - No evidence of a trial effect in newly diagnosed pediatric acute lymphoblastic leukemia. AB - OBJECTIVE: To determine whether clinical trial enrollment by itself is associated with improved outcome. DESIGN: Retrospective cohort study. SETTING: Seattle Children's Hospital from 1997 to 2005. PARTICIPANTS: Data were drawn from 322 patients with newly diagnosed acute lymphoblastic leukemia. Main Exposure Enrollment in a Children's Oncology Group or Children's Cancer Group clinical trial. MAIN OUTCOME MEASURES: (1) Demographic variables associated with trial participation. (2) Event-free survival, which was defined as the time from initial diagnosis to either leukemia recurrence or death from any cause. RESULTS: No outcome advantage was found for participants in a clinical trial compared with nonparticipants. Additionally, there were not demographic factors associated with increased clinical trial participation. CONCLUSIONS: Clinical trial participation does not, by itself, lead to improved outcome for pediatric patients with acute lymphoblastic leukemia in the current era. Discussions about participation in a clinical trial should focus on improvement of future therapy, not the direct benefit of the research participant. PMID- 20194253 TI - Differences in non-Hodgkin lymphoma survival between young adults and children. AB - OBJECTIVE: To examine differences in non-Hodgkin lymphoma (NHL) survival between young adults and children/adolescents. DESIGN: Survival analysis using 13 Surveillance, Epidemiology, and End Results registries. SETTING: Cancer survival information from population-based cancer registries from 1992 through 2001. PARTICIPANTS: A total of 2442 cases of NHL among children/adolescents (aged 0-19 years) and young adults (aged 20-29 years). MAIN EXPOSURE: Differences in NHL survival between young adults and children. MAIN OUTCOME MEASURES: Comparison of 5-year survival by constructing Kaplan-Meier survival curves and modeling 5-year survival with multivariate Cox proportional hazards. RESULTS: Young adults were more likely to die compared with children/adolescents (hazard ratio = 2.06; 95% confidence interval, 1.65-2.56) even after accounting for NHL subtype and stage at diagnosis. Persons diagnosed with stage III disease (hazard ratio = 1.71; 95% confidence interval, 1.20-2.46) and stage IV disease (hazard ratio = 3.19; 95% confidence interval, 2.47-4.13) were more likely to die compared with persons diagnosed with stage I disease. CONCLUSIONS: Being a young adult at diagnosis and having a higher stage of disease at diagnosis were associated with higher risk of death from NHL. Increasing survival with NHL is dependent on receiving appropriate cancer therapy. Therefore, efforts to address survival should include improving enrollment in clinical trials as well as increasing access to care. PMID- 20194254 TI - Palliative care of children with brain tumors: a parental perspective. AB - OBJECTIVE: To explore the end-of-life experience of children with brain tumors and their families. DESIGN: Qualitative analysis of focus group interviews. SETTING: Children's Hospital, London Health Sciences Center. PARTICIPANTS: Twenty five parents of 17 children who had died of brain tumors. INTERVENTION: Parents participated in 3 semistructured focus group interviews. MAIN OUTCOME MEASURES: Themes identified through thematic analysis of interview transcripts. RESULTS: Qualitative analysis identified 3 primary themes. (1) Parents described the dying trajectory of their child as characterized by progressive neurologic deterioration, with the loss of the ability to communicate as a turning point. Parental coping mechanisms included striving to maintain normality and finding spiritual strength through maintaining hope and in the resilience of their child. (2) Parental struggles during this phase included balancing competing responsibilities and speaking with their child about death. (3) Barriers to achieving a home death included suboptimal symptom management, financial and practical hardships, and inadequate community support. A fourth, secondary theme concerned the therapeutic benefits of the interview. CONCLUSION: The neurologic deterioration that characterizes the dying trajectory of children with brain tumors may create significant challenges for health care professionals and the children's parents, supporting the need for increased awareness of the distinct issues in the palliative care of children with brain tumors and for early anticipatory guidance provided for families. PMID- 20194255 TI - Considerations about hastening death among parents of children who die of cancer. AB - OBJECTIVES: To estimate the frequency of hastening death discussions, describe current parental endorsement of hastening death and intensive symptom management, and explore whether children's pain influences these views in a sample of parents whose child died of cancer. DESIGN: Cross-sectional survey. SETTING: Two tertiary care US pediatric institutions. PARTICIPANTS: A total of 141 parents of children who died of cancer (response rate, 64%). OUTCOME MEASURES: Proportion of parents who (1) considered or (2) discussed hastening death during the child's end of life and who endorsed (3) hastening death or (4) intensive symptom management in vignettes portraying children with end-stage cancer. RESULTS: A total of 19 of 141 (13%; 95% confidence interval [CI], 8%-19%) parents considered requesting hastened death for their child and 9% (95% CI, 4%-14%) discussed hastening death; consideration of hastening death tended to increase with an increase in the child's suffering from pain. In retrospect, 34% (95% CI, 26%-42%) of parents reported that they would have considered hastening their child's death had the child been in uncontrollable pain, while 15% or less would consider hastening death for nonphysical suffering. In response to vignettes, 50% (95% CI, 42%-58%) of parents endorsed hastening death while 94% (95% CI, 90%-98%) endorsed intensive pain management. Parents were more likely to endorse hastening death if the vignette involved a child in pain compared with coma (odds ratio, 1.4; 95% CI, 1.1-1.8). CONCLUSIONS: More than 10% of parents considered hastening their child's death; this was more likely if the child was in pain. Attention to pain and suffering and education about intensive symptom management may mitigate consideration of hastening death among parents of children with cancer. PMID- 20194256 TI - Trends in childhood violence and abuse exposure: evidence from 2 national surveys. AB - OBJECTIVE: To assess trends in children's exposure to abuse, violence, and crime victimizations. DESIGN: An analysis based on a comparison of 2 cross-sectional national telephone surveys using identical questions conducted in 2003 and 2008. SETTING: Telephone interview. PARTICIPANTS: Experiences of children aged 2 to 17 years (2030 children in 2003 and 4046 children in 2008) were assessed through interviews with their caretakers and the children themselves. Outcome Measure Responses to the Juvenile Victimization Questionnaire. RESULTS: Several types of child victimization were reported significantly less often in 2008 than in 2003: physical assaults, sexual assaults, and peer and sibling victimizations, including physical bullying. There were also significant declines in psychological and emotional abuse by caregivers, exposure to community violence, and the crime of theft. Physical abuse and neglect by caregivers did not decline, and witnessing the abuse of a sibling increased. CONCLUSION: The declines apparent in this analysis parallel evidence from other sources, including police data, child welfare data, and the National Crime Victimization Survey, suggesting reductions in various types of childhood victimization in recent years. PMID- 20194257 TI - Association between child immunization and availability of health infrastructure in slums in India. AB - OBJECTIVE: To examine the association between presence of an urban health center (UHC) in proximity to a slum and immunization status of slum children in a city in India. DESIGN: Cross-sectional study. SETTING: Slums of Agra, India. PARTICIPANTS: Data were obtained from a baseline survey conducted by the US Agency for International Development Environmental Health Project in 2005 in slums in Agra. The study population consisted of 1728 children aged 10 to 23 months. Information about children's immunization was obtained from interviews with mothers aged 15 to 44 years. Main Exposure Availability and proximity to a UHC that provides immunization services. MAIN OUTCOME MEASURES: Immunization status of children, which was measured as "complete" if the child had received 1 dose of BCG vaccine, 3 doses each of diphtheria, pertussis, and tetanus and oral polio vaccines, and 1 dose of measles vaccine; "partial" if any 1 or more vaccines were missing; and "not" if no vaccine was received. Adjusted relative risk ratios compared children receiving complete or partial immunization with those not immunized. RESULTS: Adjusted models showed that presence of a UHC within 2 km of a slum was associated with more than twice the likelihood of children being completely (relative risk ratio, 2.03; 95% confidence interval, 1.12-3.66) or partially (relative risk ratio, 2.33; 95% confidence interval, 1.55 3.50) immunized. CONCLUSIONS: We found that presence of a UHC was positively associated with immunization status of children in slums. These results suggest a need for greater public attention to expand coverage of slums through UHCs. PMID- 20194258 TI - Prevalence of and early-life influences on childhood strabismus: findings from the Millennium Cohort Study. AB - BACKGROUND: Strabismus is a common disorder of largely unknown cause reported to occur more frequently in children with neurodevelopmental conditions and in children born prematurely or of low birth weight. Population-based investigation of other potential early-life influences has been limited. OBJECTIVE: To investigate the prevalence of and the early-life risk factors associated with childhood strabismus. DESIGN: Cross-sectional analytical study of a nationally representative sample of children participating in the Millennium Cohort Study. SETTING: United Kingdom. PARTICIPANTS: A population-based sample of 14 980 children aged 3 years. MAIN OUTCOME MEASURES: Parental report of "isolated" strabismus and "neurodevelopmental" strabismus (ie, in the context of neurologic disorders), considered separately. RESULTS: Three hundred forty-three children had strabismus (of whom 20 [5.8%] had neurodevelopmental/neurologic disorders), giving a total weighted prevalence of 2.1% (95% confidence interval, 1.8%-2.4%). In multivariable analysis, the risk of isolated strabismus was reduced in children of nonwhite maternal ethnicity and was increased in those born after an assisted or cesarean delivery and in those who were of low birth weight and preterm (in particular, late preterm). An increased risk of neurodevelopmental strabismus was independently associated with maternal smoking into later pregnancy, maternal illnesses in pregnancy, and decreasing birth weight for gestational age and sex. Socioeconomic status was associated with isolated (inverse relationship) and neurodevelopmental (U-shaped relationship) strabismus. CONCLUSIONS: Several early-life social and biological factors are associated with strabismus, with differences in patterns between isolated and neurodevelopmental forms. Further collaborative research could explore this hypothesis to identify modifiable risk factors. PMID- 20194259 TI - Adolescent screen time and attachment to parents and peers. AB - OBJECTIVE: To examine associations between screen time (television, video or DVD, gaming, and computer use) and attachment to parents and peers in 2 cohorts of adolescents 16 years apart. DESIGN: Cross-sectional data regarding screen time and attachment to parents and peers were collected for 2 cohorts of adolescents, one in 1987-1988 (the Dunedin Multidisciplinary Health and Development Study [DMHDS] cohort) and the other in 2004 (the Youth Lifestyle Study [YLS] cohort). SETTING: Members of the DMHDS cohort were interviewed as part of a full day of assessment, and members of the YLS cohort completed a self-report questionnaire in a supervised classroom setting. PARTICIPANTS: The DMHDS cohort (n = 976) was aged 15 years in 1987-1988. The YLS cohort (n = 3043) was aged 14 to 15 years in 2004. MAIN OUTCOME MEASURES: Screen time and low attachment to parents and peers as measured by the Inventory of Parent and Peer Attachment. RESULTS: More time spent television viewing and less time spent reading and doing homework were associated with low attachment to parents for both cohorts. Among the YLS cohort, more time spent playing on a computer was also associated with low attachment to parents. Among the DMHDS cohort, more time spent television viewing was associated with low attachment to peers. CONCLUSIONS: Screen time was associated with poor attachment to parents and peers in 2 cohorts of adolescents 16 years apart. Given the importance of attachment to parents and peers in adolescent health and development, concern about high levels of screen time among adolescents is warranted. PMID- 20194261 TI - Editorial policies of pediatric journals: survey of instructions for authors. AB - OBJECTIVE: To study whether specific recommendations aiming to improve publication practice were included in author instructions of pediatric journals. DESIGN: We identified 69 journals in the subject category "pediatrics" of the Journal Citation Report 2007 that publish original research articles. From the journals' online author instructions, we extracted information regarding endorsement of the Uniform Requirements for Manuscripts (URM) of the International Committee of Medical Journal Editors and of 5 major reporting guidelines such as the Consolidated Standards of Reporting Trials (CONSORT) statement, disclosure of conflicts of interest, and trial registration. Two investigators collected data independently. RESULTS: The URM were mentioned in author instructions of 38 of the 69 journals (55%). Endorsement of reporting guidelines was low: CONSORT was referred to most frequently (14 journals; 20%); each of the other 4 reporting guidelines was mentioned in less than 10% of author instructions. Fifty-four journals (78%) explicitly required authors to disclose conflicts of interest, and 16 (23%) either recommended or required trial registration. The odds of endorsing the URM increased by 2.25 (95% confidence interval [CI], 1.17-4.34) per additional impact factor point. Similarly, the odds increased by 2.32 (95% CI, 0.95-5.70) for requiring disclosure of conflicts of interest and by 3.66 (95% CI, 1.74-7.71) for requiring trial registration. CONCLUSIONS: Many pediatric journals do not include recommendations that aim to improve publication practice in their author instructions. About one-fifth of journals do not require authors to disclose conflicts of interest on manuscript submission and more than three-quarters do not require/recommend trial registration. PMID- 20194260 TI - Identifying children at low risk for bacterial conjunctivitis. AB - OBJECTIVE: To identify a population of children at low risk for bacterial conjunctivitis on the basis of history and physical examination findings. DESIGN: Prospective observational cohort study. SETTING: Urban pediatric emergency department. PARTICIPANTS: Children aged 6 months to 17 years with conjunctival erythema, eye discharge, or both. The exclusion criteria were eye trauma, exposure to a noxious chemical, contact lens use, and antibiotic drug use in the past 5 days. INTERVENTIONS: Clinicians completed a checklist of signs and symptoms and collected a conjunctival swab for bacterial culture. MAIN OUTCOME MEASURES: The chi(2) test, the Mann-Whitney test, and logistic regression were used to create a prediction model for a negative bacterial culture. RESULTS: Of 368 patients enrolled, 194 (52.7%) were males. The median patient age was 3 years (interquartile range, 1-5 years). Conjunctival cultures were negative in 130 patients (35.3%). Age 6 years or older, presentation in April through November, no or watery discharge, and no glued eye in the morning were the clinical factors found to be independently associated with a negative conjunctival culture. If 3 factors were present, 76.4% (95% confidence interval, 63.6%-85.6%) of patients had a negative culture. If all 4 factors were present, 92.3% (95% confidence interval, 66.1%-98.2%) of patients had a negative culture. CONCLUSION: The combination of 4 clinical factors may enable clinicians to identify children at low risk for bacterial conjunctivitis and may reduce routine antibiotic drug administration. PMID- 20194262 TI - Identification of HIV-infected 12- to 24-year-old men and women in 15 US cities through venue-based testing. AB - OBJECTIVE: To test whether "venue-based testing" could identify human immunodeficiency virus (HIV) infection in US youth, 12 to 24 years of age, who were otherwise not aware of their infection. Racial and ethnic minority women and men who have sex with men (WSM and MSM) compose the majority of new HIV cases among adolescents and young adults. DESIGN: Cross-sectional study. SETTING: Selected venues in communities surrounding the 15 Adolescent Trials Network for HIV/AIDS Interventions (ATN) clinical sites over a 3-month period. PARTICIPANTS: At each venue, ATN sites recruited 20 to 30 English- or Spanish-speaking at-risk youth (12 to 24 years of age), resulting in a total of 1217 study participants, including 611 MSM and 606 WSM. Intervention Venue-based HIV testing with 2 components: an anonymous audio computer-assisted self-administered interview and an anonymous HIV antibody assay. MAIN OUTCOME MEASURE: The prevalence of HIV infection in MSM and WSM. RESULTS: The prevalence of HIV infection in MSM and WSM was 15.3% and 0.3%, respectively. Sixty percent of the MSM and 100% of the WSM claimed to not know of their infection. CONCLUSION: Venue-based testing may be an important strategy to identify HIV-infected younger MSM; however, other strategies are needed for WSM. PMID- 20194263 TI - Source of admission and outcomes for critically injured children in the mountain states. AB - OBJECTIVE: To determine whether mortality and length of stay at a pediatric trauma center differ between patients admitted by interhospital transfer and those admitted directly from the injury scene. DESIGN: Analysis of prospectively collected data from a pediatric trauma center database. SETTING: A designated regional level I pediatric trauma center. PARTICIPANTS: Injured children from birth to 17 years of age hospitalized between January 1, 2006, and September 30, 2007. MAIN EXPOSURE: Incident in-hospital mortality rates and length of stay at the trauma center were compared between patients admitted directly and those admitted by interhospital transfer, controlling for potential confounders. OUTCOME MEASURES: In-hospital mortality and duration of hospitalization. RESULTS: Of 2192 patients admitted to the trauma center, 1175 (53.6%) were admitted directly from the injury scene. Patients admitted by interhospital transfer had higher injury severity and lower Glasgow Coma Scale scores at admission (P < .01). Of 31 deaths during the study period, 26 (83.9%) were among patients admitted by interhospital transfer. These patients had a 7-fold higher unadjusted incident rate of death (incidence rate ratio, 7.16; 95% confidence interval, 2.49 20.58) compared with those admitted directly. This finding remained (incidence rate ratio, 3.01; 95% confidence interval, 1.01-8.98) after adjustment for injury severity and Glasgow Coma Scale scores, elapsed time from injury until admission at the trauma center, and age. Among survivors, patients admitted by interhospital transfer stayed longer in the hospital than those admitted directly. CONCLUSION: Pediatric trauma center mortality rates are lower among children admitted directly from the injury scene compared with those admitted by interhospital transfer. PMID- 20194264 TI - Child vs adult randomized controlled trials in specialist journals: a citation analysis of trends, 1985-2005. AB - OBJECTIVE: To compare secular trends in the age representation of published randomized controlled trials (RCTs) in specialty journals during a period of 20 years. DATA SOURCE: A validated electronic search strategy using Ovid MEDLINE was conducted to identify RCTs published in the years 1985 through 2005. STUDY SELECTION: The publications retrieved were subdivided into age-specific groups: adults, children, both adults and children, and studies with no age group identified. Within 31 specialties, we chose up to 5 specialty journals and 5 pediatric specialty journals. MAIN OUTCOME MEASURE: Number of RCTs targeting children compared with adults over time. Linear trends were identified using regression modeling, and an interaction term was included to compare rates of increase between age groups. RESULTS: A total of 174 unique journals with 43 326 unique RCTs with age-specific categorization were included. Adult RCTs increased by 90.5 RCTs per year (95% confidence interval [CI], 78-103), which was significantly higher than either pediatric RCTs, which rose by 16.9 RCTs per year (95% CI, 12-22) or RCTs involving both children and adults, which rose by 22.7 RCTs per year (95% CI, 10-35). Twenty-four of 31 specialties (77%) demonstrated a greater rise in the number of published RCTs per year involving adults than those enrolling children. CONCLUSION: Adult RCT publications are increasing at a faster rate than pediatric RCTs in almost all specialties. PMID- 20194265 TI - Picture of the month. Sinusitis complicated by epidural abscess. PMID- 20194266 TI - Framing the benefits of cancer clinical trials. PMID- 20194267 TI - Rethinking hard-to-reach communities in the realm of global pediatrics: the urban poor and community health workers. PMID- 20194268 TI - Randomized controlled trials and pediatric research. PMID- 20194269 TI - Adherence to prophylactic antibiotic guidelines among Medicaid infants with sickle cell disease. PMID- 20194270 TI - Swimming proficiency in a multiethnic sample in a high-risk area for drowning. PMID- 20194271 TI - Advice for patients. Strabismus. PMID- 20194273 TI - Camp jump start: effects of a residential summer weight-loss camp for older children and adolescents. AB - OBJECTIVE: Residential weight-loss camps offer an opportunity for overweight and obese children to lose weight in a medically safe, supervised, supportive environment. The purpose of this report is to describe short-term outcomes in 76 children participating in a 4- or 8-week residential weight-loss camp for children and adolescents. PATIENTS AND METHODS: The camp program enrolled obese 10- to 18-year-old adolescents. The program consisted of structured and nonstructured physical activities and group educational sessions covering nutrition, physical fitness, and self-esteem. A diet plan of 3 balanced meals and 2 snacks per day was prepared under the supervision of a registered dietitian. Participants had height, weight, and blood pressure measured and performed a 1 mile run at maximum effort on an outdoor track. RESULTS: For all campers, statistically significant (P < .0001) reductions were observed for BMI, BMI z score, systolic blood pressure, body weight, and 1-mile run times. Compared with campers in the 4-week session, campers in the 8-week session had greater reductions in BMI, BMI z score, body weight, and systolic blood pressure. Multivariate analysis revealed that gender was a significant predictor for reduction in body weight, BMI, and BMI z score, all of which decreased more in boys than in girls. CONCLUSIONS: This report adds to the evidence that residential weight-loss camps are highly effective in improving measures of health and fitness among overweight and obese children and adolescents. Additional study is needed on the long-term effects of such camps in terms of weight maintenance, behavior change, and metabolic and health outcomes. PMID- 20194272 TI - Multiple markers of inflammation and weight status: cross-sectional analyses throughout childhood. AB - OBJECTIVE: Inflammatory markers such as C-reactive protein (CRP) are related to obesity in adults, but the association is less clear in children. Our objective was to examine relationships between multiple markers of inflammation and children's weight status; we hypothesized that the prevalence of inflammatory markers would increase as weight status increased. METHODS: We conducted a cross sectional analysis of children in the United States aged 1 to 17 years in the National Health and Nutrition Examination Survey, 1999-2006. Children were categorized using weight-for-length when age <2 years and BMI for > or =2 years, as very obese (> or =99th percentile), obese (<99th and > or =95th percentile), overweight (<95th and > or =85th percentile), and healthy weight (>5th to < or =85th percentile) according to expert consensus. Our main outcome measures were high-sensitivity CRP and absolute neutrophil count, in addition to a novel third measure: ferritin controlled for iron status using a ferritin/transferrin ratio. We used Cox proportional hazards models to examine risk of abnormal values of inflammatory markers according to weight. RESULTS: Increased risk of a CRP level of >1.0 mg/L was evident among very obese children from ages 3 to 5 years (hazard ratio [HR]: 2.29; P < .01) through 15 to 17 years (HR: 4.73; P < .01). Increased risk of abnormal neutrophil count among very obese children began at 6 to 8 years (HR: 2.00; P = .049), and increased prevalence of abnormal ferritin/transferrin ratio began at 9 to 11 years (HR: 7.06; P < .001). CONCLUSIONS: Multiple inflammatory markers are strongly and positively associated with increasing weight status in children, and this relationship starts as young as age 3. Elevated inflammatory markers in very young obese children are particularly concerning, because inflammation may cause long-term, cumulative vascular damage. This deserves additional research via longitudinal design. PMID- 20194274 TI - Has leisure time become Medicaid's new competitor? PMID- 20194275 TI - An evidence-based overview of prenatal consultation with a focus on infants born at the limits of viability. AB - Before the delivery of a premature infant, a prenatal consultation between parents and physicians provides the opportunity to establish a trusting relationship and create a supportive environment for decision-making concerning neonatal resuscitation. The ideal consult enables physicians to educate parents about preterm delivery and potential outcomes for their infant while providing parents with the time to ask questions and express their values. The uncertainty that surrounds many decisions in the treatment and resuscitation of infants born at the limits of viability creates a situation in which joint responsibility for decision-making between parents and physicians is vital. In this review we examine ethical considerations regarding the resuscitation of infants born at the limits of viability and present the current policies established by the Neonatal Resuscitation Program and the American Academy of Pediatrics. The parental and physician perspectives regarding the consultation experience are presented also. Finally, a model for the prenatal consultation is introduced with suggestions for the incorporation of morbidity and mortality data as well as the structure and approach to discussion with parents with threatened preterm delivery. PMID- 20194276 TI - A novel missense mutation in MVK associated with MK deficiency and dyserythropoietic anemia. AB - Mevalonate kinase deficiency (MKD) is a rare inborn error of metabolism caused by mutations in the mevalonate kinase (MVK) gene. The clinical phenotype is variable, ranging from the hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) to mevalonic aciduria (MA), a severe metabolic disease. We report here for the first time (to our knowledge) the case of a patient with MKD and congenital dyserythropoietic anemia. Clinical and laboratory characteristics of inflammatory attacks were compatible with HIDS, but mild dysmorphic features and elevated urinary mevalonic acid levels in the absence of an inflammatory attack suggested an intermediate phenotype between HIDS and MA. Genomic sequencing of the MVK gene revealed compound heterozygosity for a missense mutation previously described in MA (V310M) and a novel missense mutation (Y116H). By contrast, sequencing of the novel CDAII (SEC23B) gene revealed no mutations, suggesting that the bone marrow abnormalities were causally related to the MKD. Treatment with corticosteroids and colchicine directed at controlling the autoinflammatory disease resulted in improvement of the anemia. PMID- 20194277 TI - Generalized petechial rashes in children during a parvovirus B19 outbreak. AB - OBJECTIVES: Human parvovirus B19 infection is associated not only with erythema infectiosum (fifth disease) but also, rarely, with purpuric or petechial rashes. Most reports of these atypical rashes describe sporadic cases with skin lesions that have distinctively focal distributions. During a community outbreak of fifth disease, we investigated a cluster of illnesses in children with generalized petechial rashes to determine whether parvovirus was the causative agent and, if so, to describe more fully the clinical spectrum of petechial rashes that are associated with this virus. METHODS: Systematic evaluation was conducted by general pediatricians of children with petechial rashes for evidence of acute parvovirus infection. RESULTS: During the outbreak, acute parvovirus infection was confirmed in 13 (76%) of 17 children who were evaluated for petechial rash. Confirmed case patients typically had mild constitutional symptoms, and most (11 [85%] of 13) had fever. Petechiae were typically dense and widely distributed; sometimes accentuated in the distal extremities, axillae, or groin; and usually absent from the head/neck. Most case patients had leukopenia, and several had thrombocytopenia. Parvovirus immunoglobulin M was detected in 8 (73%) of 11 acute phase serum specimens, and immunoglobulin G was detectable only in convalescent specimens. Parvovirus DNA was detected in all 7 tested serum specimens, including 2 acute-phase specimens that were immunoglobulin M-negative. All case patients had brief, uncomplicated illnesses, but 6 were briefly hospitalized and 1 underwent a bone marrow examination. Two case patients developed erythema infectiosum during convalescence. CONCLUSIONS: During an outbreak of fifth disease, parvovirus proved to be a common cause of petechial rash in children, and this rash was typically more generalized than described in case reports. Associated clinical features, hematologic abnormalities, and serologic test results are consistent with a viremia-associated illness that is distinct from and occasionally followed by erythema infectiosum. PMID- 20194278 TI - Antibiotic-associated hemorrhagic colitis caused by cytotoxin-producing Klebsiella oxytoca. AB - Klebsiella oxytoca was recently described as the causative organism for antibiotic-associated hemorrhagic colitis (AAHC). It is currently not known if this novel gastrointestinal infection exists in children. AAHC is usually preceded by antibiotic treatment with penicillins, which are frequently prescribed for pediatric patients. In contrast to colitis caused by Clostridium difficile, colitis caused by K oxytoca is usually segmental and located predominantly in the right colon. Patients with AAHC typically present with abdominal pain and almost always bloody diarrhea. We present here the case of an adolescent patient who developed acute abdominal pain and bloody diarrhea after antibiotic treatment for acute urinary infection with amoxicillin-clavulanate. Right-sided colitis was verified by abdominal sonography. Stool culture tested negative for common gastrointestinal pathogens but yielded K oxytoca. Toxin production of the isolated strain was verified in a cell-culture assay. Cessation of the causative antibiotic treatment led to rapid improvement and cessation of bloody diarrhea within 3 days. We report here the first (to our knowledge) pediatric case of K oxytoca infection causing AAHC. Establishing the diagnosis of AAHC by culturing K oxytoca and demonstrating right-sided colitis with noninvasive imaging studies might prevent unnecessary invasive procedures in children with bloody diarrhea. PMID- 20194280 TI - Injury patterns in obese versus nonobese children presenting to a pediatric emergency department. AB - BACKGROUND: Two of the most prevalent problems facing youth in the United States are injury and obesity. Obesity increases the risk of injury, prolongs recovery time, and increases morbidity among injured children. OBJECTIVE: The purpose of this study was to compare characteristics of injuries between obese and nonobese children who presented to a pediatric emergency department. METHODS: Electronic medical records for all patients aged 3 to 14 years who sustained a traumatic injury (International Classification of Diseases, Ninth Revision [ICD-9] codes 800-899) and were seen in our hospital emergency department from January 1, 2005, to March 31, 2008, were obtained. Data collected included age, chief complaint, discharge diagnosis, gender, race, disposition, and weight. Patients with a weight at >95th percentile for age were considered obese. chi(2) analysis was used in comparing the groups; odds ratios (ORs) were calculated. RESULTS: During the study period, 24 588 children had ICD-9 codes that met our inclusion criteria. Of these, 1239 had no weights recorded, leaving 23 349 patients in our study population. Of these children, the mean age was 8.2 years (SD: +/-3.6 years), 60.7% were white, and 61.7% were male. Obese children represented 16.5% of the study population (n = 3861). Overall, obese and nonobese children had the same percentage of upper extremity injuries. However, obese children were significantly more likely to have lower extremity injuries compared with upper extremity injuries than were nonobese children (OR: 1.71 [95% confidence interval: 1.56-1.87]; P < .001). In addition, obese children had significantly fewer head and face injuries than nonobese children (OR: 0.54 [95% confidence interval: 0.50- 0.58]; P < .001). CONCLUSIONS: Obese children are significantly more likely to sustain lower extremity injuries than upper extremity injuries and less likely to sustain head and face injuries than nonobese children. Strategies for preventing lower extremity injuries among obese youth should be sought. PMID- 20194279 TI - Auditory late effects of childhood cancer therapy: a report from the Children's Oncology Group. AB - Children treated for malignancies may be at risk for early- or delayed-onset hearing loss that can affect learning, communication, school performance, social interaction, and overall quality of life. Survivors at particular risk include those treated with platinum compounds (cisplatin and/or carboplatin) for neuroblastoma, hepatoblastoma, osteosarcoma, or germ-cell tumors and/or those treated with radiation that affects the ear at doses of >30 Gy for pediatric head and neck tumors. The aims of the Auditory/Hearing Late Effects Task Force of the Children's Oncology Group in this report were to (1) review ototoxicity resulting from childhood cancer therapy including platinum compounds (cisplatin and carboplatin) and radiation, (2) describe briefly cochlear pathophysiology and genetics of cisplatin-related hearing loss, (3) explain the impact of hearing loss resulting from chemotherapy and radiation, and (4) offer recommendations regarding evaluation and management of pediatric patients who are at risk for treatment-related hearing loss. A questionnaire is included as a tool to assist pediatricians in assessment. PMID- 20194281 TI - Health effects of media on children and adolescents. AB - Youth spend an average of >7 hours/day using media, and the vast majority of them have access to a bedroom television, computer, the Internet, a video-game console, and a cell phone. In this article we review the most recent research on the effects of media on the health and well-being of children and adolescents. Studies have shown that media can provide information about safe health practices and can foster social connectedness. However, recent evidence raises concerns about media's effects on aggression, sexual behavior, substance use, disordered eating, and academic difficulties. We provide recommendations for parents, practitioners, the media, and policy makers, among others, for ways to increase the benefits and reduce the harm that media can have for the developing child and for adolescents. PMID- 20194282 TI - Previous antimicrobial exposure is associated with drug-resistant urinary tract infections in children. AB - OBJECTIVE: The aim of this study was to evaluate the impact of previous antimicrobial exposure on the development of antimicrobial resistance in children with their first urinary tract infection (UTI). METHODS: We conducted a retrospective cohort study of children aged 6 months to 6 years and received their first diagnosis of UTI in a network of 27 outpatient pediatric practices between July 1, 2001, and May 31, 2006. We examined the relationship between antimicrobial resistance in UTI isolates and exposure to specific antimicrobial agents (amoxicillin, amoxicillin-clavulanate, cefdinir, trimethoprim sulfamethoxazole, and azithromycin) in the previous 120 days. We developed multivariable logistic regression models for resistance to ampicillin, amoxicillin-clavulanate, trimethoprim-sulfamethoxazole, and first-generation and third-generation cephalosporins, adjusting for potential confounders such as age, number of siblings, recent hospitalizations, and child care exposure. RESULTS: Of the 533 children who had a first UTI, 8%, 14%, and 21% were exposed to antimicrobial agents within 30, 60, and 120 days before the UTI, respectively. Amoxicillin exposure within 30 days (odds ratio [OR]: 3.6 [95% confidence interval (CI): 1.6-8.2]) and 31 to 60 days (OR: 2.8 [95% CI: 1.0-7.5]) before UTI both were associated with ampicillin resistance. Exposure to amoxicillin >60 days before the UTI was not associated with ampicillin resistance. Amoxicillin exposure within 30 days of UTI was also associated with amoxicillin-clavulanate resistance (OR: 3.9 [95% CI: 1.8-8.7]). No association between exposure to other antimicrobial agents and resistance to any of the antimicrobial agents was seen. CONCLUSIONS: Recent antimicrobial exposure is associated with antimicrobial resistant UTIs among pediatric outpatients, and the magnitude of this association decreases with time since exposure. Judicious antimicrobial prescribers should consider this association when selecting empiric antimicrobial agents for a new UTI and should use strategies to reduce unnecessary antimicrobial use to avoid development of resistant bacteria. PMID- 20194283 TI - Predictive value of albuminuria in American Indian youth with or without type 2 diabetes. AB - OBJECTIVE: To examine the prognostic significance of elevated albuminuria in youth with type 2 diabetes. PATIENTS AND METHODS: Cross-sectional and prospective studies were conducted on Pima Indian youth aged 5 to 19 years at baseline who were examined between July 1, 1982, and December 31, 2007. Prevalence and sequential changes in the level of microalbuminuria (30 < or = albumin-to creatinine ratio [ACR] < 300 mg/g) and macroalbuminuria (ACR > or = 300 mg/g) and incidence of macroalbuminuria were computed according to the presence or absence of type 2 diabetes. RESULTS: The prevalence of microalbuminuria and macroalbuminuria was 6.5% and 0.6% in the 3856 nondiabetic youth and 18.5% and 2.9% in the 103 youth with diabetes, respectively. One hundred forty-one of 187 (75.4%) nondiabetic youth, but only 1 of 14 (7.1%) diabetic youth with an elevated ACR (> or =30 mg/g) regressed to an undetectable or normal ACR (<30 mg/g) on subsequent examination. In a subset of 2666 youth with a median follow up of 8.1 years, 36 nondiabetic and 30 diabetic youth with baseline ACRs of <300 mg/g developed macroalbuminuria. For a given ACR, the incidence of macroalbuminuria was 15.9-fold (95% confidence interval: 11.1-22.6) higher in the diabetic than in the nondiabetic youth. CONCLUSIONS: Elevated albuminuria is infrequent and largely transient in nondiabetic youth, but it is relatively frequent and largely persistent in those with diabetes. Microalbuminuria in youth with type 2 diabetes strongly predicts progression to macroalbuminuria, which supports annual screening for albuminuria. PMID- 20194284 TI - Racial/ethnic differences in early-life risk factors for childhood obesity. AB - OBJECTIVE: By the preschool years, racial/ethnic disparities in obesity prevalence are already present. The objective of this study was to examine racial/ethnic differences in early-life risk factors for childhood obesity. METHODS: A total of 1343 white, 355 black, and 128 Hispanic mother-child pairs were studied in a prospective study. Mother's reported child's race/ethnicity. The main outcome measures were risk factors from the prenatal period through 4 years old that are known to be associated with child obesity. RESULTS: In multivariable models, compared with their white counterparts, black and Hispanic children exhibited a range of risk factors related to child obesity. In pregnancy, these included higher rates of maternal depression (odds ratio [OR]: 1.55 for black, 1.89 for Hispanic); in infancy more rapid weight gain (OR: 2.01 for black, 1.75 for Hispanic), more likely to introduce solid foods before 4 months of age (OR: 1.91 for black, 2.04 for Hispanic), and higher rates of maternal restrictive feeding practices (OR: 2.59 for black, 3.35 for Hispanic); and after 2 years old, more televisions in their bedrooms (OR: 7.65 for black, 7.99 for Hispanic), higher intake of sugar-sweetened beverages (OR: 4.11 for black, 2.48 for Hispanic), and higher intake of fast food (OR: 1.65 for black, 3.14 for Hispanic). Black and Hispanic children also had lower rates of exclusive breastfeeding and were less likely to sleep at least 12 hours/day in infancy. CONCLUSIONS: Racial/ethnic differences in risk factors for obesity exist prenatally and in early childhood. Racial/ethnic disparities in childhood obesity may be determined by factors that operate at the earliest stages of life. PMID- 20194285 TI - Rapid detoxification of cereulide in Bacillus cereus food poisoning. AB - Bacillus cereus is recognized as a major pathogenic bacterium that causes food poisoning and produces gastrointestinal diseases of 2 types: emetic and diarrheal. The emetic type, which is often linked to pasta and rice, arises from a preformed toxin, cereulide, in food. Rapid and accurate diagnostic methods for this emetic toxin are important but are limited. Here we describe 3 patients with B cereus food poisoning in which cereulide was detected and measured sequentially. Three family members began to vomit frequently 30 minutes after consuming reheated fried rice. After 6 hours, a 1-year-old brother died of acute encephalopathy. A 2-year-old sister who presented with unconsciousness recovered rapidly after plasma exchange and subsequent hemodialysis. Their mother recovered soon by fluid therapy. From leftover fried rice and the children's stomach contents, B cereus was isolated. Serum cereulide was detected in both children; it decreased to an undetected level in the sister. These cases highlight the importance of measuring the value of cereulide, which would reflect the severity of B cereus emetic food poisoning. The cases also suggest the possible role of blood-purification therapy in severe cases. PMID- 20194286 TI - Parental vaccine safety concerns in 2009. AB - OBJECTIVE: Vaccine safety concerns can diminish parents' willingness to vaccinate their children. The objective of this study was to characterize the current prevalence of parental vaccine refusal and specific vaccine safety concerns and to determine whether such concerns were more common in specific population groups. METHODS: In January 2009, as part of a larger study of parents and nonparents, 2521 online surveys were sent to a nationally representative sample of parents of children who were aged 0.10 for all indices). BNT also increased RR-high-frequency power (0.15 to 0.40 Hz; P=0.01) and RR interval (P<0.001) during cognitive tasks. Among controls, high-frequency power was unchanged (P=0.29), and RR interval decreased (P=0.03). Neither intervention altered spontaneous baroreflex sensitivity (P>0.10). In contrast to relaxation therapy, BNT with heart rate variability biofeedback modestly lowers ambulatory blood pressure during wakefulness, and it augments tonic vagal heart rate modulation. It is unknown whether efficacy of this treatment can be improved with biofeedback of baroreflex gain. BNT, alone or as an adjunct to drug therapy, may represent a promising new intervention for hypertension. PMID- 20194303 TI - Preserved oxygenation despite reduced blood flow in poststenotic kidneys in human atherosclerotic renal artery stenosis. AB - Atherosclerotic renal artery stenosis reduces blood flow and perfusion pressures to the poststenotic kidney producing renovascular hypertension and threatening glomerular filtration rate. Little is known regarding regional tissue oxygenation in human renovascular disease that develops slowly. We compared stenotic and contralateral kidneys regarding volume, tissue perfusion, blood flow measured by multidetector computed tomography, and blood oxygen level-dependent magnetic resonance values in the cortex and medulla in 14 patients with unilateral stenosis (mean: 71% by quantitative computed tomography) and in 14 essential hypertensive patients during 150 mEq/d of sodium intake and renin-angiotensin blockade. Stenotic kidney volume was reduced compared with the contralateral kidney (118.6+/-9.9 versus 155.4+/-13.7 mL; P<0.01), as was total blood flow (269.7+/-42.2 versus 383.7+/-49; P=0.02), mainly because of reduced cortical volume. Tissue perfusion was similar but lower than essential hypertension (1.5 versus 1.2 mL/min per milliliter; P<0.05). Blood oxygen level-dependent MR at 3 T confirmed elevated R2* values (a measure of deoxyhemoglobin) in deep medullary regions in all 3 sets of kidneys (38.9+/-0.7 versus cortex 17.8+/-0.36 s(-1); P<0.0001). Despite reduced blood flow, R2* values did not differ between atherosclerotic and essential hypertensive kidneys, although furosemide suppressible fall in medullary R2* was reduced in stenotic kidneys (5.7+/-1.8 versus 9.4+/-1.9 s(-1); P<0.05). Renal venous oxygen levels from the stenotic kidney were higher than those from essential hypertensives (65.1+/-2.2 versus 58.1+/-1.2; P=0.006). These data indicate that, although stenosis reduced blood flow and volume, cortical and medullary oxygenation was preserved under these conditions. PMID- 20194304 TI - Renal medullary microRNAs in Dahl salt-sensitive rats: miR-29b regulates several collagens and related genes. AB - MicroRNAs are endogenous repressors of gene expression. We examined microRNAs in the renal medulla of Dahl salt-sensitive rats and consomic SS-13(BN) rats. Salt induced hypertension and renal injury in Dahl salt-sensitive rats, particularly medullary interstitial fibrosis, have been shown previously to be substantially attenuated in SS-13(BN) rats. Of 377 microRNAs examined, 5 were found to be differentially expressed between Dahl salt-sensitive rats and consomic SS-13(BN) rats receiving a high-salt diet. Real-time PCR analysis demonstrated that high salt diets induced substantial upregulation of miR-29b in the renal medulla of SS 13(BN) rats but not in SS rats. miR-29b was predicted to regulate 20 collagen genes, matrix metalloproteinase 2 (Mmp2), integrin beta1 (Itgb1), and other genes related to the extracellular matrix. Expression of 9 collagen genes and Mmp2 was upregulated by a high-salt diet in the renal medulla of SS rats, but not in SS 13(BN) rats, an expression pattern opposite to miR-29b. Knockdown of miR-29b in the kidneys of SS-13(BN) rats resulted in upregulation of several collagen genes. miR-29b reduced expression levels of several collagen genes and Itgb1 in cultured rat renal medullary epithelial cells. Moreover, miR-29b suppressed the activity of luciferase when the reporter gene was linked to a 3'-untranslated segment of collagen genes Col1a1, Col3a1, Col4a1, Col5a1, Col5a2, Col5a3, Col7a1, Col8a1, Mmp2, or Itgb1 but not Col12a1. The result demonstrated broad effects of miR-29b on a large number of collagens and genes related to the extracellular matrix and suggested involvement of miR-29b in the protection from renal medullary injury in SS-13(BN) rats. PMID- 20194305 TI - Emergence of ethnic differences in blood pressure in adolescence: the determinants of adolescent social well-being and health study. AB - The cause of ethnic differences in cardiovascular disease remains a scientific challenge. Blood pressure tracks from late childhood to adulthood. We examined ethnic differences in changes in blood pressure between early and late adolescence in the United Kingdom. Longitudinal measures of blood pressure, height, weight, leg length, smoking, and socioeconomic circumstances were obtained from London, United Kingdom, schoolchildren of White British (n=692), Black Caribbean (n=670), Black African (n=772), Indian (n=384), and Pakistani and Bangladeshi (n=402) ethnicity at 11 to 13 years and 14 to 16 years. Predicted age and ethnic-specific means of blood pressure, adjusted for anthropometry and social exposures, were derived using mixed models. Among boys, systolic blood pressure did not differ by ethnicity at 12 years, but the greater increase among Black Africans than Whites led to higher systolic blood pressure at 16 years (+2.9 mm Hg). Among girls, ethnic differences in mean systolic blood pressure were not significant at any age, but while systolic blood pressure hardly changed with age among White girls, it increased among Black Caribbeans and Black Africans. Ethnic differences in diastolic blood pressure were more marked than those for systolic blood pressure. Body mass index, height, and leg length were independent predictors of blood pressure, with few ethnic-specific effects. Socioeconomic disadvantage had a disproportionate effect on blood pressure for girls in minority groups. The findings suggest that ethnic divergences in blood pressure begin in adolescence and are particularly striking for boys. They signal the need for early prevention of adverse cardiovascular disease risks in later life. PMID- 20194306 TI - Exposure to a high-fat diet alters leptin sensitivity and elevates renal sympathetic nerve activity and arterial pressure in rabbits. AB - The activation of the sympathetic nervous system through the central actions of the adipokine leptin has been suggested as a major mechanism by which obesity contributes to the development of hypertension. However, direct evidence for elevated sympathetic activity in obesity has been limited to muscle. The present study examined the renal sympathetic nerve activity and cardiovascular effects of a high-fat diet (HFD), as well as the changes in the sensitivity to intracerebroventricular leptin. New Zealand white rabbits fed a 13.5% HFD for 4 weeks showed modest weight gain but a 2- to 3-fold greater accumulation of visceral fat compared with control rabbits. Mean arterial pressure, heart rate, and plasma norepinephrine concentration increased by 8%, 26%, and 87%, respectively (P<0.05), after 3 weeks of HFD. Renal sympathetic nerve activity was 48% higher (P<0.05) in HFD compared with control diet rabbits and was correlated to plasma leptin (r=0.87; P<0.01). Intracerebroventricular leptin administration (5 to 100 microg) increased mean arterial pressure similarly in both groups, but renal sympathetic nerve activity increased more in HFD-fed rabbits. By contrast, intracerebroventricular leptin produced less neurons expressing c-Fos in HFD compared with control rabbits in regions important for appetite and sympathetic actions of leptin (arcuate: -54%, paraventricular: -69%, and dorsomedial hypothalamus: -65%). These results suggest that visceral fat accumulation through consumption of a HFD leads to marked sympathetic activation, which is related to increased responsiveness to central sympathoexcitatory effects of leptin. The paradoxical reduction in hypothalamic neuronal activation by leptin suggests a marked "selective leptin resistance" in these animals. PMID- 20194307 TI - Endothelial nitric oxide synthase-independent protective action of statin against angiotensin II-induced atrial remodeling via reduced oxidant injury. AB - Activation of the renin-angiotensin system exacerbates atrial remodeling, leading to atrial fibrillation and thrombosis, especially in a condition with decreased NO bioavailability. Recently, it has been reported that statins reduce the incidence of atrial fibrillation through attenuation of atrial remodeling; however, the mechanisms have not been completely elucidated. Therefore, we aimed to clarify the beneficial effect of statin on atrial remodeling in condition with reduced NO bioavailability. Endothelial NO synthase(-/-) mice were sham operated or infused with angiotensin II (Ang II) via an osmotic minipump for 2 weeks, and Ang II-infused mice were divided into 3 treatment groups: pitavastatin, Tempol (a free radical scavenger), or vehicle. Echocardiography and electrocardiography showed that Ang II infusion caused left atrial enlargement and a high incidence of atrial fibrillation, whereas pitavastatin and Tempol prevented these abnormalities. In histological analysis, Ang II-induced atrial interstitial fibrosis, perivascular fibrosis, and cardiomyocyte hypertrophy were all attenuated by pitavastatin and Tempol. Immunohistochemical staining showed that Ang II downregulated thrombomodulin and tissue factor pathway inhibitor and upregulated tissue factor and plasminogen activator inhibitor 1 in the left atrium and that pitavastatin and Tempol corrected the thrombogenic condition. Moreover, pitavastatin and Tempol reduced Ang II-induced atrial superoxide production and atrial transforming growth factor-beta1 expression and Smad 2/3 phosphorylation. Atrial rac1-GTPase activity, known to activate NADPH oxidase, was attenuated by pitavastatin but not by Tempol. In conclusion, pitavastatin exerts endothelial NO synthase-independent protective actions against Ang II induced atrial remodeling and atrial fibrillation with enhanced thrombogenicity through suppression of oxidant injury. PMID- 20194309 TI - Thrombosis prevention after total hip arthroplasty: a prospective, randomized trial comparing a mobile compression device with low-molecular-weight heparin. AB - BACKGROUND: Thromboembolic disease is a common complication of total hip arthroplasty. The purpose of this study was to compare a new mobile compression device with low-molecular-weight heparin with regard to their safety and effectiveness for the prevention of venous thromboembolic disease. METHODS: Patients who had a total hip arthroplasty were randomized to receive prophylaxis with a mobile compression device or low-molecular-weight heparin for ten days. Use of the compression device began intraoperatively, and the patients in this group could receive 81 mg of aspirin daily after the surgery. The first injection of the low-molecular-weight heparin began between twelve and twenty-four hours after the surgery. After ten to twelve days, all patients underwent bilateral lower-extremity duplex ultrasonography to screen for deep venous thrombi in the calf and thigh. Any clinical symptoms of pulmonary embolism were evaluated with spiral computed tomography lung scans. Bleeding events and utilization of (i.e., compliance with) prophylactic treatment in both groups were documented. Clinical evaluation to look for evidence of deep venous thrombi and pulmonary emboli was performed at twelve weeks postoperatively. RESULTS: Four hundred and ten patients (414 hips) were randomized; 392 of these patients (395 of the hips) were evaluable with regard to the safety of the intervention and 386 patients (389 hips) were evaluable with regard to its efficacy. Demographics were similar clinically between the groups. The rate of major bleeding events was 0% in the compression group and 6% in the low-molecular-weight heparin group. The rates of distal and proximal deep venous thrombosis were 3% and 2%, respectively, in the compression group compared with 3% and 1% in the heparin group. The rates of pulmonary embolism were 1% in the compression group and 1% in the heparin group, and there were no fatal pulmonary emboli. Within the twelve-week follow-up period, two events (one deep venous thrombosis and one pulmonary embolus) occurred in one patient in the compression group following negative findings on duplex ultrasonography on the twelfth postoperative day. There was no difference between the groups with regard to the prevalence of venous thromboembolism. CONCLUSIONS: When compared with low-molecular-weight heparin, use of the mobile compression device for prophylaxis against venous thromboembolic events following total hip arthroplasty resulted in a significant decrease in major bleeding events. PMID- 20194310 TI - The influence of femoral cementing on perioperative blood loss in total knee arthroplasty: a prospective randomized study. AB - BACKGROUND: Total knee arthroplasty can involve substantial blood loss. We prospectively studied a consecutive series of patients undergoing primary total knee arthroplasty to assess the influence of femoral cementing on perioperative blood loss. We hypothesized that an uncemented femoral component is a risk factor for bleeding. METHODS: A semiconstrained posterior stabilized prosthesis was used in all patients. Preoperatively, 130 patients were randomly assigned to either the cement group (Group 1) or the hybrid group (Group 2). We selected all patients who underwent a knee replacement through a medial parapatellar approach (n = 107). Group 1 consisted of forty-two women and twelve men ranging in age from fifty-six to eighty-five years. Group 2 consisted of thirty-seven women and sixteen men ranging in age from fifty-six to eighty-five years. The hemoglobin and hematocrit levels were recorded preoperatively and five days postoperatively for each patient. The volumes of postoperative suction drainage and the rate of blood transfusion were recorded. RESULTS: No differences between the two groups were identified with regard to hemoglobin and hematocrit levels, total measured blood loss, postoperative drainage amounts, or transfusion rates. The total measured blood loss was 1758.9 mL for Group 1 and 1759 mL for Group 2. CONCLUSIONS: Cementing the femoral component during a total knee arthroplasty does not appear to influence the amount of perioperative blood loss or the need for postoperative blood transfusion. PMID- 20194308 TI - Cyclooxygenase 1-derived prostaglandin E2 and EP1 receptors are required for the cerebrovascular dysfunction induced by angiotensin II. AB - Prostaglandin E(2) (PGE(2)) EP1 receptors (EP1Rs) may contribute to hypertension and related end-organ damage. Because of the key role of angiotensin II (Ang II) in hypertension, we investigated the role of EP1R in the cerebrovascular alterations induced by Ang II. Mice were equipped with a cranial window, and cerebral blood flow was monitored by laser-Doppler flowmetry. The attenuation in cerebral blood flow responses to whisker stimulation (-46+/-4%) and the endothelium-dependent vasodilator acetylcholine (-40+/-4%) induced by acute administration of Ang II (250 ng/kg per minute; IV for 30 to 40 minutes) were not observed after cyclooxygenase 1 or EP1R inhibition or in cyclooxygenase 1 or EP1 null mice. In contrast, cyclooxygenase 2 inhibition or genetic inactivation did not prevent the attenuation. Ang II-induced oxidative stress was not observed after cyclooxygenase 1 or EP1R inhibition or in EP1R-null mice. Prostaglandin E(2) reinstated the Ang II-induced cerebrovascular dysfunction and oxidative stress after cyclooxygenase 1 inhibition. Brain prostaglandin E(2) levels were not increased by Ang II but were attenuated by cyclooxygenase 1 and not cyclooxygenase 2 inhibition. The cerebrovascular dysfunction induced by 14-day administration of "slow-pressor" doses of Ang II (600 ng/kg per minute) was attenuated by neocortical application of SC51089. Cyclooxygenase 1 immunoreactivity was observed in microglia and EP1R in endothelial cells. We conclude that the cerebrovascular dysfunction induced by Ang II requires activation of EP1R by constitutive production of prostaglandin E(2) derived from cyclooxygenase 1. The findings provide the first evidence that EP1Rs are involved in the deleterious cerebrovascular effects of Ang II and suggest new therapeutic approaches to counteract them. PMID- 20194311 TI - Epidemiology of shoulder dislocations presenting to emergency departments in the United States. AB - BACKGROUND: The epidemiology of traumatic shoulder dislocations is poorly understood. The aim of the current study was to determine the incidence of shoulder dislocations presenting to hospital emergency departments in the United States and define demographic risk factors for these injuries. METHODS: The National Electronic Injury Surveillance System, a probability sample of all injuries presenting to emergency departments in the United States, was queried for shoulder dislocations from 2002 through 2006. Patient and injury characteristics were analyzed. United States Census data were utilized to calculate incidence rates for the United States population and subgroups. Incidence rate ratios were then calculated with respect to age, sex, and race. RESULTS: A total of 8940 shoulder dislocations were identified, resulting in an overall incidence rate in the United States of 23.9 (95% confidence interval, 20.8 to 27.0) per 100,000 person-years. The male incidence rate was 34.90 (95% confidence interval, 30.08 to 39.73) per 100,000 person-years, with an incidence rate ratio of 2.64 (95% confidence interval, 2.39 to 2.88) relative to the female incidence rate. It was found that 71.8% of the dislocations were in males. Stratified by decade, the maximum incidence rate (47.8 [95% confidence interval, 41.0 to 54.5]) occurred in those between the ages of twenty and twenty-nine years; 46.8% of all dislocations were in patients between fifteen and twenty-nine years of age. There were no significant differences based on race. Dislocations most frequently resulted from a fall (58.8%) and occurred at home (47.7%) or at sites of sports or recreation (34.5%). Overall, 48.3% of injuries occurred during sports or recreation. CONCLUSIONS: The estimated incidence rate of shoulder dislocations in the United States is 23.9 per 100,000 person-years, which is approximately twice the previously reported value. A young age and male sex are risk factors for shoulder dislocation in the United States population. PMID- 20194312 TI - The effect of stem design on the prevalence of squeaking following ceramic-on ceramic bearing total hip arthroplasty. AB - BACKGROUND: The ceramic-on-ceramic bearing for total hip arthroplasty has an extremely low wear rate and demonstrates minimal inflammatory response in comparison with other bearing choices. However, acoustic emissions such as squeaking and clicking are being reported as annoying complications related to its use. The cause or causes of this phenomenon have not been determined. The purpose of the present study was to evaluate the possibility that design aspects of the femoral component may be a contributing factor to the etiology of squeaking associated with the ceramic-on-ceramic bearing total hip arthroplasty. METHODS: We retrospectively reviewed 266 consecutive patients (304 hips) who had undergone total hip arthroplasty with use of ceramic-on-ceramic bearings. The first 131 consecutive patients (152 hips) (Group 1) received a hydroxyapatite coated stem composed of titanium-aluminum-vanadium alloy with a C-taper neck geometry and robust midsection with an anteroposterior diameter of 13 mm. The second 135 consecutive patients (152 hips) (Group 2) also received a hydroxyapatite-coated stem, but in that group the stem was composed of titanium molybdenum-zirconium-iron alloy, with a V-40 neck geometry and a midsection with an anteroposterior thickness of only 10 mm. All 304 hips received the same cup, composed of titanium-aluminum-vanadium alloy. Demographic characteristics, such as age, sex, height, weight, and body mass index, were similar in both groups. Data regarding the presence of squeaking were obtained prospectively. Patients who were seen for clinical follow-up either expressed the squeaking phenomenon themselves or were asked about it by the physician. Patients who were not seen at a recent clinical follow-up visit were contacted by telephone and were asked specifically about squeaking that might be associated with the hip replacement. Only patients with confirmed squeaking noise were included in the present study. Postoperative radiographs, the Short Form-36 health survey, the Harris hip score, and office or telephone interviews of the patient were used to determine the overall outcome of the procedure. RESULTS: The prevalence of squeaking was seven times higher for patients who received the titanium-molybdenum-zirconium-iron alloy stem (twenty-seven patients, twenty-eight hips [18.4%]) than in those who received the titanium-aluminum-vanadium-alloy stem (three patients, four hips [2.6%]); this difference was significant (p < 0.0001). CONCLUSIONS: Our study suggests that different stem alloys, stem geometries, or neck geometries can have an impact on the frequency of squeaking following a ceramic-on-ceramic total hip arthroplasty. PMID- 20194313 TI - Long-term results of radial head resection following isolated radial head fractures in patients younger than forty years old. AB - BACKGROUND: In the past, radial head resection was the surgical treatment of choice for radial head fractures that could not be internally fixed. More recently, radial head implant arthroplasty has gained popularity for the treatment of isolated radial head fractures. The purpose of the present study was to review the long-term results of radial head resection after radial head fractures not associated with elbow instability in patients younger than forty years of age. METHODS: Twenty-six patients younger than forty years of age who had sustained an isolated fracture of the radial head (including six patients who had sustained a Mason type-II fracture and twenty who had sustained a Mason type III fracture) that had been treated with primary radial head resection were reviewed retrospectively at a minimum of fifteen years (mean, twenty-five years). Outcomes were evaluated according to the Mayo Elbow Performance Score and the Disabilities of the Arm, Shoulder and Hand score. Radiographic assessment of osteoarthritic changes and the carrying angle was also performed. RESULTS: Twenty one patients (81%) had no elbow pain, three had mild pain, and two had moderate pain. The mean arc of motion was from 9 degrees to 139 degrees of flexion. All but one patient had a functional arc of motion. The mean pronation was 84 degrees, and the mean supination was 85 degrees. Nineteen elbows had normal strength in comparison with the unaffected side. The mean Mayo Elbow Performance Score was 95 points; the score was classified as good or excellent for twenty four elbows (92%) and as fair for two. The mean Disabilities of the Arm, Shoulder and Hand score was 6 points. Three patients complained of wrist pain, which was mild in two patients and moderate in one. In four patients, some degree of elbow instability could be detected on physical examination. The mean carrying angle of the involved elbow was significantly greater than that of the uninjured elbow (21 degrees compared with 10 degrees). Radiographic changes of arthritis were considered mild in seventeen elbows and moderate in nine. We could not detect significant differences in functional outcome on the basis of the degree of radiographic change. CONCLUSIONS: Radial head resection in young patients with isolated fractures without instability yields long-term satisfactory results in >90% of cases. Osteoarthritic changes are uniformly present but typically are not associated with functional impairment. PMID- 20194314 TI - Mortality in elderly patients after cervical spine fractures. AB - BACKGROUND: Despite an increased risk of cervical spine fractures in older patients, little is known about the mortality associated with these fractures and there is no consensus on the optimal treatment. The purposes of this study were to determine the three-month and one-year mortality associated with cervical spine fractures in patients sixty-five years of age or older and to evaluate potential factors that may influence mortality. METHODS: We performed a retrospective review of all cervical spine fractures in patients sixty-five years of age or older from 1991 to 2006 at two institutions. Information regarding age, sex, race, treatment type, neurological involvement, injury mechanism, comorbidity, and mortality were collected. Overall risk of mortality and mortality stratified by the above factors were calculated at three months and one year. Cox proportional-hazard regression was performed to identify independent correlates of mortality. RESULTS: Six hundred and forty patients were included in our analysis. The mean age was eighty years (range, sixty-five to 101 years). Two hundred and ninety-four patients (46%) were male, and 116 (18%) were nonwhite. The risk of mortality was 19% at three months and 28% at one year. The effect of treatment on mortality varied with age at three months (p for interaction = 0.03) but not at one year (p for interaction = 0.08), with operative treatment being associated with less mortality for those between the ages of sixty-five and seventy-four years. A higher Charlson comorbidity score, male sex, and neurological involvement were all associated with increased risk of mortality. CONCLUSIONS: Operative treatment of cervical spine fractures is associated with a lower mortality rate at three months but not at one year postoperatively for patients between sixty-five and seventy-four years old at the time of fracture. PMID- 20194315 TI - A comparison of subvastus and midvastus approaches in minimally invasive total knee arthroplasty. AB - BACKGROUND: The mini-subvastus and the mini-midvastus approaches are among the most common alternatives to the medial parapatellar approach for total knee arthroplasty. The purpose of this study was to compare the early clinical outcomes of these two approaches. METHODS: In this prospective, randomized study of fifty-one patients who underwent bilateral total knee arthroplasty, the mini subvastus approach was used in one knee and the mini-midvastus approach, in the contralateral knee. There were forty-two women and nine men who had a mean age of seventy years at the time of the index arthroplasties, and they were followed for two years postoperatively. Clinical outcome was assessed and compared with use of the Knee Society pain and function scores, the straight-leg-raising test, range of motion, and isokinetic strength testing. Operating time and blood loss for each approach were also compared. In addition, patients were surveyed concerning which knee they preferred. RESULTS: Comparisons of postoperative Knee Society scores between both approaches at the time of the two-year follow-up did not yield a significant difference in outcome. Isokinetic strength testing at twelve weeks postoperatively revealed no significant differences in muscle strength, with a mean extensor peak torque-to-body weight ratio of 0.14 Nm/kg for both groups. No significant difference was found with respect to total blood loss, straight-leg-raising test, range of motion, or patient preference. There was no clinically relevant difference in operative times between the two approaches. CONCLUSIONS: The minimally invasive subvastus and midvastus approaches for total knee arthroplasty were both associated with excellent short-term clinical results. Some surgeons believe that the subvastus approach completely avoids damage to the quadriceps mechanism and therefore would be associated with improved muscle function. This prospective series did not identify a substantive difference between the two approaches. We believe that the decision between these surgical approaches should be based on surgeon preference and experience. PMID- 20194316 TI - Assessment of the posterior ligamentous complex following acute cervical spine trauma. AB - BACKGROUND: Magnetic resonance imaging is commonly used to assess the integrity of the posterior ligamentous complex following cervical trauma, but its accuracy and reliability have not been documented, to our knowledge. The purpose of this study was to determine the diagnostic accuracy of magnetic resonance imaging in detecting injury to specific components of the posterior ligamentous complex of the cervical spine. METHODS: Patients with an acute cervical spine injury that required posterior surgical treatment were prospectively studied. The six components of the posterior ligamentous complex were characterized as intact, incompletely disrupted, or disrupted on preoperative magnetic resonance imaging studies by a radiologist and intraoperatively by two surgeons. Correlation between the magnetic resonance imaging and intraoperative findings was determined. The percent agreement, sensitivity, specificity, negative predictive value, and positive predictive value of magnetic resonance imaging as a tool for characterizing the integrity of the posterior ligamentous complex were calculated. RESULTS: Forty-seven consecutive patients with a total of seventy levels of injury were studied. Overall, there was moderate agreement between the magnetic resonance imaging and intraoperative findings for the supraspinous and interspinous ligaments (kappa scores of 0.46 and 0.43, respectively) and fair agreement between those for the ligamentum flavum, left and right facet capsules, and cervical fascia (kappa scores of 0.32, 0.31, 0.26, and 0.39, respectively). The sensitivity of the magnetic resonance imaging was greatest for the cervical fascia (100%) and the lowest for the facet capsules (80%). Specificity ranged from 56% (for the facet capsules) to 67% (for the interspinous ligament). The positive predictive value ranged from 42% (for the cervical fascia) to 82% (for the interspinous ligament). CONCLUSIONS: Magnetic resonance imaging is sensitive for the evaluation of injury to the posterior ligamentous complex in the setting of acute cervical trauma. However, it has a lower positive predictive value and specificity, suggesting that injury to the posterior ligamentous complex may be "over-read" on magnetic resonance images. If magnetic resonance imaging is used in isolation to guide treatment, the high rate of false-positive findings may lead to unnecessary surgery. Other factors, including the morphology of the injury and the neurological status, should be considered as well when devising a treatment plan. PMID- 20194317 TI - Revision arthroscopic rotator cuff repair: repair integrity and clinical outcome. AB - BACKGROUND: Literature regarding the outcomes of revision rotator cuff repair is limited. The purposes of the present study were to report the tendon repair integrity and clinical outcomes for a cohort of patients following revision arthroscopic rotator cuff repair and to examine factors related to tendon healing and the influence of healing on clinical outcomes. METHODS: Twenty-one of twenty nine consecutive revision arthroscopic rotator cuff repairs with a minimum of two years of postoperative follow-up were retrospectively reviewed. Outcomes were evaluated on the basis of a visual analog pain scale, the range of motion of the shoulder, the Simple Shoulder Test, the American Shoulder and Elbow Surgeons score, and the Constant score. Ultrasonography was used to examine repair integrity at a minimum of one year following surgery. Ten shoulders underwent arthroscopic repair of a recurrent single-tendon posterior rotator cuff tear, whereas eleven shoulders had repair of both the supraspinatus and infraspinatus. RESULTS: The mean age of the twenty-one subjects was 55.6 years; thirteen subjects were male and eight were female. Complete preoperative and postoperative clinical data were available for nineteen subjects after an average duration of follow-up of thirty-three months. Significant improvements were seen in terms of postoperative pain (p < 0.05), the Simple Shoulder Test score (p < 0.05), the American Shoulder and Elbow Surgeons function (p < 0.05) and total scores (p < 0.05), active forward elevation (p < 0.05), and active external rotation (p < 0.05). Postoperative ultrasound data were available for all twenty-one shoulders after a mean duration of follow-up of twenty-five months. Ten (48%) of the twenty one shoulders had an intact repair. Seven (70%) of the ten single-tendon repairs were intact, compared with three (27%) of the eleven supraspinatus/infraspinatus repairs (p = 0.05). Patient age (p < 0.05) and the number of torn tendons (p = 0.05) had significant effects on postoperative tendon repair integrity. Shoulders with an intact repair had better postoperative Constant scores (p < 0.05) and scapular plane elevation strength (p < 0.05) in comparison with those with a recurrent tear. CONCLUSIONS: Revision arthroscopic rotator cuff repair results in reliable pain relief and improvement in shoulder function in selected cases. Approximately half of the revision repairs can be expected to be intact at a minimum of one year following surgery. Patient age and the number of torn tendons are related to postoperative tendon integrity. The postoperative integrity of the rotator cuff can have a significant influence on shoulder abduction strength and the Constant score. PMID- 20194318 TI - In vivo effects of single intra-articular injection of 0.5% bupivacaine on articular cartilage. AB - BACKGROUND: Single intra-articular injections of local anesthetics are commonly used clinically. Recent in vitro studies have demonstrated chondrotoxic effects of local anesthetics, with the greatest emphasis on bupivacaine toxicity. This in vivo study was conducted to determine whether a single intra-articular injection of 0.5% bupivacaine results in chondrocyte morbidity and rapid chondrolysis. METHODS: Forty-eight Sprague-Dawley rats received a 100-microL injection of sterile 0.9% saline solution (negative control) into one stifle joint and 100 microL of either preservative-free 0.5% bupivacaine (experimental group) or 0.6 mg/mL monoiodoacetate (positive control) into the contralateral joint. The rats were killed at one week, four weeks, twelve weeks, or six months. Live and dead cells were quantified with use of three-dimensional confocal reconstructions of fluorescent-stained tissues at standardized locations on the distal part of the femur. Histological findings were graded with use of a modified Mankin score, and cell density was quantified with use of custom image-analysis software. RESULTS: In the specimens injected with bupivacaine, the chondral surfaces remained intact as seen with gross and histological examination. No differences in superficial chondrocyte viability or modified Mankin scores were observed between the saline solution and bupivacaine groups at any location or time point (p > 0.05). Quantitative histological analysis of the bupivacaine-treated knees at six months revealed an up to 50% reduction in chondrocyte density compared with that of the saline-solution-treated knees (p < or = 0.01). Monoiodoacetate injection resulted in death of up to 87% of the superficial chondrocyte cells at one week and chondrolysis at six months. Despite severe histological abnormalities by four weeks after monoiodoacetate injection, cartilage injury was not evident on gross inspection until six months. CONCLUSIONS: This in vivo study showing reduced chondrocyte density without cartilage tissue loss six months after a single intra articular injection of 0.5% bupivacaine suggests bupivacaine toxicity. The effects of bupivacaine were milder than those of an injection of 0.6% monoiodoacetate, which resulted in chondrolysis over the same time period. PMID- 20194319 TI - Apoptosis and mitochondrial dysfunction in human chondrocytes following exposure to lidocaine, bupivacaine, and ropivacaine. AB - BACKGROUND: Several mechanisms have been proposed to explain toxicity of local anesthetics to chondrocytes, including the blockade of potassium channels and mitochondrial injury. The purposes of this investigation were to study the effects of lidocaine, bupivacaine, and ropivacaine on human chondrocyte viability and mitochondrial function in vitro and to characterize the type of cell death elicited following exposure. METHODS: Primary chondrocyte cultures from patients with osteoarthritis undergoing knee replacement were treated with saline solution and the following concentrations of local anesthetics: 2%, 1%, and 0.5% lidocaine, 0.5% and 0.25% bupivacaine, and 0.5% and 0.2% ropivacaine for one hour. Cell viability and apoptosis were measured by flow cytometry at twenty-four hours and 120 hours after treatment. Nuclear staining and caspase 3 and 9 cleavage assays (Western blot) were used to further establish the induction of apoptosis. Mitochondrial dysfunction was evaluated by the accumulation of mitochondrial DNA damage (quantitative Southern blot), changes in adenosine triphosphate production (bioluminescence kit), and mitochondrial protein levels (Western blot analysis). RESULTS: Exposure of primary human chondrocytes to a 2% concentration of lidocaine caused massive necrosis of chondrocytes after twenty four hours, 1% lidocaine and 0.5% bupivacaine caused a detectable, but not significant, decrease in viability after twenty-four hours, while 0.5% lidocaine, 0.25% bupivacaine, and both concentrations of ropivacaine (0.5% and 0.2%) did not affect chondrocyte viability. Flow cytometry analysis of chondrocytes 120 hours after drug treatment revealed a significant decrease in viability (p < 0.05) with a concomitant increase in the number of apoptotic cells at all concentrations of lidocaine, bupivacaine, and ropivacaine analyzed, except 0.2% ropivacaine. Apoptosis was verified by observation of condensed and fragmented nuclei and a decrease in procaspase 3 and 9 levels. Local anesthetics induced mitochondrial DNA damage and a decrease in adenosine triphosphate and mitochondrial protein levels. CONCLUSIONS: Lidocaine, bupivacaine, and ropivacaine cause delayed mitochondrial dysfunction and apoptosis in cultured human chondrocytes. PMID- 20194320 TI - Internal screw fixation compared with bipolar hemiarthroplasty for treatment of displaced femoral neck fractures in elderly patients. AB - BACKGROUND: Internal fixation and arthroplasty are the two main options for the treatment of displaced femoral neck fractures in the elderly. The optimal treatment remains controversial. Using data from the Norwegian Hip Fracture Register, we compared the results of hemiarthroplasty and internal screw fixation in displaced femoral neck fractures. METHODS: Data from 4335 patients over seventy years of age who had internal fixation (1823 patients) or hemiarthroplasty (2512 patients) to treat a displaced femoral neck fracture were compared at a minimum follow-up interval of twelve months. One-year mortality, the number of reoperations, and patient self-assessment of pain, satisfaction, and quality of life at four and twelve months were analyzed. Subanalyses of patients with cognitive impairment and reduced walking ability were done. RESULTS: In the arthroplasty group, only contemporary bipolar prostheses were used and uncemented prostheses with modern stems and hydroxyapatite coating accounted for 20.8% (522) of the implants. There were no differences in one-year mortality (27% in the osteosynthesis group and 25% in the arthroplasty group; p = 0.76). There were 412 reoperations (22.6%) performed in the osteosynthesis group and seventy-two (2.9%) in the hemiarthroplasty group during the follow-up period. After twelve months, the osteosynthesis group reported more pain (mean score, 29.9 compared with 19.2), higher dissatisfaction with the operation result (mean score, 38.9 compared with 25.7), and a lower quality of life (mean score, 0.51 compared with 0.60) than the arthroplasty group. All differences were significant (p < 0.001). For patients with cognitive impairment, hemiarthroplasty provided a better functional outcome (less pain, higher satisfaction with the result of the operation, and higher quality of life as measured on the EuroQol visual analog scale) at twelve months (p < 0.05). CONCLUSIONS: Displaced femoral neck fractures in the elderly should be treated with hemiarthroplasty. PMID- 20194321 TI - Two short-term outcomes after instituting a national regulation regarding minimum procedural volumes for total knee replacement. AB - BACKGROUND: Several studies have demonstrated positive relationships between high hospital volume and improved outcome following total knee replacement. To our knowledge, it has not been demonstrated whether improved outcomes are causally determined by selective referral to high-volume hospitals. We therefore evaluated the effect of a national regulation regarding minimum hospital volume for total knee replacement on two short-term outcome parameters. METHODS: We performed a comparison of the years before (2004, 2005) and after (2006) the implementation of a national regulation on minimum hospital volume for total knee replacement through a secondary analysis of a national database on the quality of inpatient care in Germany as reflected by the number of cases per hospital and the postoperative rates of wound infection and wound hematoma or secondary hemorrhage. RESULTS: We analyzed 110,349 cases from 2004, 118,922 cases from 2005, and 125,322 cases from 2006. Implementation of the regulation had a significant effect on the number of cases per hospital. Of the hospitals that had performed one to forty-nine cases in 2005, 35.6% moved to higher-volume categories and 21.2% dropped out in 2006. Multiple logistic regression analysis adjusting for patient characteristics demonstrated risk reductions of 22.5% (odds ratio, 0.775; 95% confidence interval, 0.700 to 0.857) for postoperative wound infection and of 44% (odds ratio, 0.562; 95% confidence interval, 0.531 to 0.596) for wound hematoma or secondary hemorrhage from 2005 to 2006. For wound infection, approximately half of the improvement was attributable to the effects of the minimum-volume regulation. For wound hematoma and secondary hemorrhage, the improvement could not be explained by the minimum-volume regulation. CONCLUSIONS: Implementation of the minimum-volume regulation for total knee replacement resulted in more patients being managed at higher-volume hospitals than expected. Following the implementation of a minimum-volume regulation, effects on two short-term outcome parameters were observed, but definite conclusions could only be made regarding wound infection, with the minimum-volume regulation resulting in a decreased rate of infection. PMID- 20194322 TI - Primary cementless total hip arthroplasty with an alumina ceramic-on-ceramic bearing: results after a minimum of twenty years of follow-up. AB - BACKGROUND: The biological problems related to wear debris after total hip arthroplasty have stimulated renewed interest in alternatives to metal-on polyethylene bearing surfaces. METHODS: We retrospectively evaluated the clinical and radiographic results of 100 patients who had undergone a total of 109 primary total hip arthroplasties with a cementless alumina ceramic-on-ceramic prosthesis between January 1985 and December 1989. The mean age of the patients at the time of the index arthroplasty was forty-six years. Clinical evaluation was performed with use of the Charnley modification of the Merle d'Aubigne-Postel scale. Seventy-eight patients who had had a total of eighty-five arthroplasties were available for follow-up evaluation at an average of 20.8 years. The patients' average age at the time of the latest follow-up was 66.8 years. RESULTS: Six hips (six acetabular cups and one femoral stem) in six patients underwent revision. Aseptic loosening of the cup combined with focal osteolysis was the cause of all six revisions. In one patient, the stem was also revised because of aseptic loosening. At the time of final follow-up, the result was excellent (according to the Merle d'Aubigne-Postel scale) in 68% of the hips, good in 19%, fair in 9%, and poor in 4%. The mean Merle d'Aubigne-Postel score improved from 7.9 points preoperatively to 16.9 points postoperatively (p < 0.001). The cumulative rate of survival of the prostheses was 84.4% at 20.8 years. CONCLUSIONS: The results of these cementless ceramic-on-ceramic total hip arthroplasties continued to be satisfactory at a minimum of twenty years postoperatively. The improved design of contemporary prostheses and the new generation of ceramic-on-ceramic bearing surfaces may lead to even better long-term results. PMID- 20194323 TI - Serum after traumatic brain injury increases proliferation and supports expression of osteoblast markers in muscle cells. AB - BACKGROUND: Traumatic brain injury is associated with an increased rate of heterotopic ossification within skeletal muscle, possibly as a result of humoral factors. In this study, we investigated whether cells from skeletal muscle adopt an osteoblastic phenotype in response to serum from patients with traumatic brain injury. METHODS: Serum was collected from thirteen patients with severe traumatic brain injury, fourteen patients with a long-bone fracture, and ten control subjects. Primary cultures of skeletal muscle cells isolated from patients undergoing orthopaedic surgery were performed and characterized with use of immunofluorescence microscopy, reverse transcription-polymerase chain reaction, and Western blot analysis. Proliferation and osteoblastic differentiation were assessed with use of commercial cell assays, Western blot analysis (for Osterix protein), and the Villanueva bone stain. RESULTS: All serum-treated cell populations expressed the osteoblast marker Osterix after one week in culture. Cells treated with serum from all study groups in mineralization medium had increased alkaline phosphatase activity and mineralized nodules within the mesenchymal cell subpopulation after three weeks in culture. Serum from patients with traumatic brain injury induced a significant increase (p = 0.02) in the rate of proliferation of primary skeletal muscle cells (1.87 [95% confidence interval, 1.66 to 2.09]) compared with the rate induced by serum from patients with a fracture (1.42 [95% confidence interval, 1.21 to 1.58]) or by serum from controls (1.35 [95% confidence interval, 1.15 to 1.54]). CONCLUSIONS: Human serum supports the osteoblastic differentiation of cells derived from human skeletal muscle, and serum from patients with severe traumatic brain injury accelerates proliferation of these cells. These findings suggest the early presence of humoral factors following traumatic brain injury that stimulate the expansion of mesenchymal cells and osteoprogenitors within skeletal muscle. PMID- 20194324 TI - Detection of periprosthetic infections with use of ribosomal RNA-based polymerase chain reaction. AB - BACKGROUND: Previously described molecular biology techniques used to detect periprosthetic infections have been complicated by false-positive results. We have reported the development of a messenger RNA (mRNA)-based procedure to reduce these false-positive results. The limitations of this procedure are the lack of a universal target and reduced sensitivity due to a low concentration of bacterial mRNAs in test samples. The objective of the present study was to determine whether reverse transcription-quantitative polymerase chain reaction (RT-qPCR) using universal primers can be used to detect the more abundant bacterial ribosomal RNA (rRNA) as an indicator of periprosthetic infection. METHODS: Serial dilutions of simulated synovial fluid infections were analyzed with rRNA RT-qPCR to determine the detection limit of this assay. Escherichia coli cultures treated with gentamicin were analyzed with RT-qPCR over a twenty-day time course to determine the degradation of rRNA as compared with the decrease in the viable cell count as determined by means of cell plating. As a proof of concept, group specific polymerase chain reaction primers were developed for Streptococcus species and were tested against fifteen orthopaedically relevant organisms to show the potential for speciation with this assay. Sixty-four patients with a symptomatic effusion at the site of a total knee arthroplasty were enrolled, and complete patient information was documented in a prospective manner. Synovial fluid analysis with rRNA RT-qPCR was performed in a blind fashion. RESULTS: The rRNA RT-qPCR assay was able to detect as few as 590 colony forming units/mL of Staphylococcus aureus and 2900 colony forming units/mL of Escherichia coli. The rRNA RT-qPCR signal closely followed cell death, pointing to its potential use as a viability marker. Three group-specific primer sets correctly identified their intended targets without amplifying closely related species. Clinically, the test correctly identified all six patients with a confirmed infection and all fifty patients who clearly did not have an infection. Eight patients had some laboratory or clinical signs of infection, but their status could not be confirmed. Infection was indicated by rRNA RT-qPCR in three of these patients who had elevated synovial fluid white blood-cell counts but negative results on culture. For statistical purposes, all patients who were categorized as indeterminate were considered to have an infection for the purpose of analysis, for a prevalence of 22% in this cohort. CONCLUSIONS: With respect to current diagnostic tests, rRNA-based RT-qPCR demonstrated 100% specificity and positive predictive value with a sensitivity equivalent to that of intraoperative culture. The RT-qPCR signal followed bacterial culture trends but exhibited detectable level for seven days after sterilization, allowing for the detection of infection after the antibiotic administration. These findings indicate that rRNA RT-qPCR is a sensitive and reliable test that retains the universal detection and speciation of DNA-based methods while functioning as a viability indicator. PMID- 20194325 TI - Asynchronous muscle and tendon adaptation after surgical tensioning procedures. AB - BACKGROUND: Donor muscles are often highly stretched in tendon transfer surgery. Despite literature reports that showed adaptation of the serial sarcomere number to moderate stretch, little is known regarding adaptation to stretch outside of the physiological range (commonly seen in clinical tendon transfer). This study was performed to evaluate muscle-tendon-unit adaptation to tendon transfer surgery in an animal model. METHODS: Thirty-seven male New Zealand White rabbits were used for muscle analysis, and twenty-five of those rabbits were also used for biological analysis of the tendons after the experiment. The extensor digitorum muscle of the second toe was transferred at a specific sarcomere length of 3.7 microm, chosen to be near the end of the descending limb of the rabbit sarcomere length-tension curve. Animals were killed at five time points, at which complete muscle architectural analysis as well as measurements of tendon dimension, tendon water content, and tendon cytokine transcript levels were performed. RESULTS: As expected, a rapid increase in the serial sarcomere number (mean and standard error of the mean, 4658 +/- 154 in the transferred muscle compared with 3609 +/- 80 in the control muscle) was found one week after the surgery. From this time point until eight weeks, this increased serial sarcomere number paradoxically decreased, while the sarcomere length remained constant. Eventually, at eight weeks, it reached the same value (3749 +/- 83) as that in the control muscle (3767 +/- 61). Tendon adaptation was delayed relative to muscle adaptation, but it was no less dramatic. Tendon length increased by 1.43 +/- 0.74 mm over the eight-week time period, corresponding to a strain of 15.55% +/- 4.08%. CONCLUSIONS: To our knowledge, this is the first report of biphasic adaptation of the serial sarcomere number followed by tendon adaptation, and it indicates that muscle adapts more quickly than tendon does. Taken together, these results illustrate a complex and unique interaction between muscles and tendons that occurs during adaptation to stretching during tendon transfer. PMID- 20194326 TI - Multipotential differentiation of human anulus fibrosus cells: an in vitro study. AB - BACKGROUND: The existence of fibrocartilage, bone-like tissues, nerves, and blood vessels in the anulus fibrosus during intervertebral disc degeneration has been well documented. Migration of differentiated cells from outside the intervertebral disc has been hypothesized as a possible mechanism for the formation of these tissues. We hypothesized that the normal anulus fibrosus tissue contains multipotent progenitor cells, which are able to differentiate into cartilage and/or fibrocartilage cells, osteoblasts, neurons, and blood vessel cells. METHODS: We isolated anulus fibrosus cells from the nondegenerative intervertebral discs of adolescent (thirteen to sixteen-year-old) patients with idiopathic scoliosis and cultured the cells in vitro in induction media containing different stimuli. Immunophenotypic analysis of cell surface markers was performed by flow cytometry. Expression of markers of adipogenesis, osteogenesis, chondrogenesis, neurogenesis, and differentiation into endothelial lineages was determined with use of immunostaining, cytohistological staining, and reverse transcription-polymerase chain reaction. RESULTS: Anulus fibrosus cells expressed several of the cell surface antigens that are sometimes associated with mesenchymal stem cells, including CD29, CD49e, CD51, CD73, CD90, CD105, CD166, CD184, and Stro-1, and two neuronal stem cell markers, nestin and neuron-specific enolase. Furthermore, varying the stimulants added to the induction media determined whether anulus fibrosus cells differentiated into adipocytes, osteoblasts, chondrocytes, neurons, or endothelial cells. CONCLUSIONS: Anulus fibrosus cells isolated from nondegenerative intervertebral discs can differentiate into adipocytes, osteoblasts, chondrocytes, neurons, and endothelial cells in vitro. PMID- 20194327 TI - Early mortality and cardiorespiratory failure in patients with fibrodysplasia ossificans progressiva. AB - BACKGROUND: Fibrodysplasia ossificans progressiva, a rare genetic disorder of progressive extraskeletal ossification, is the most disabling form of heterotopic ossification in humans. However, little is known about the lifespan or causes of mortality in these patients. We undertook this study to determine the lifespan and causes of mortality in individuals who had fibrodysplasia ossificans progressiva. METHODS: We reviewed comprehensive mortality reports from two large registries of patients with fibrodysplasia ossificans progressiva. Together, these registries comprise >90% of all known patients with this condition in the world. We noted the sex, dates of birth and death, and the cause of death for each individual. We verified the cause of death with extensive medical records, when available. We also collected date of birth, current age, and sex information for each living patient member of the International Fibrodysplasia Ossificans Progressiva Association. RESULTS: Sixty deaths (thirty male and thirty female patients) were reported in the fibrodysplasia ossificans progressiva community during a thirty-three-year-period. For all sixty patients, the median age at the time of death was forty years (range, three to seventy-seven years). Data were sufficient to establish the cause of death in forty-eight (80%) of the sixty individuals. The median age at the time of death for the forty-eight patients (twenty-four male and twenty-four female patients) with an established cause of death was also forty years. The median lifespan estimated from the 371 individuals in the international fibrodysplasia ossificans progressiva community who were alive and the sixty who had died was fifty-six years (95% confidence interval, fifty-one to sixty years). The most common causes of death in patients with fibrodysplasia ossificans progressiva were cardiorespiratory failure from thoracic insufficiency syndrome (54%; median age, forty-two years) and pneumonia (15%; median age, forty years). CONCLUSIONS: Fibrodysplasia ossificans progressiva is not only an extremely disabling disease but also a condition of considerably shortened lifespan. The most common cause of death in patients with fibrodysplasia ossificans progressiva is cardiorespiratory failure from thoracic insufficiency syndrome. PMID- 20194328 TI - Two-dimensional glenoid version measurements vary with coronal and sagittal scapular rotation. AB - BACKGROUND: Accurate analysis of osseous glenoid morphology is important in treating glenohumeral arthritis and instability. Two-dimensional computed tomography scans are used to evaluate glenoid alignment. Accuracy of this method is dependent on the angle of axial reconstruction in relation to the position of the scapula. The purpose of this study was to investigate the effect of scapular rotation in the coronal and sagittal planes on glenoid version as measured on two dimensional images. METHODS: Computer-generated three-dimensional models of scapulae from computed tomography scans of thirty-six shoulders in whole-body cadavers were generated. The anatomic geometry of these models had been previously validated. The position of the scapulae relative to the gantry was determined. The three-dimensional models were rotated in 1 degree increments in the coronal and sagittal planes. Glenoid version was measured on two-dimensional images for each of the rotation increments. Version variability at each rotation increment was calculated. RESULTS: The anatomic glenoid version (independent of the resting position of the scapula) was an average (and standard deviation) of 2.0 degrees +/- 3.8 degrees of retroversion. The average difference between anatomic glenoid version and clinical glenoid version (depending on the position of the scapula on the original computed tomography axial images) was 6.9 degrees +/- 5.6 degrees (range, 0.1 degrees to 22.5 degrees). Version variability with coronal or sagittal rotation was significant for all degrees of rotation (p < 0.0001). Scapular abduction had the greatest effect on version variation and resulted in 0.42 degrees of relative anteversion for every 1 degree of abduction in the coronal plane. In the sagittal plane, internal rotation resulted in relative anteversion. CONCLUSIONS: Any malalignment of > or = 1 degree of the scapula in the coronal or sagittal plane will create inaccuracies in measuring glenoid version. The plane of axial reconstruction should be aligned with the scapula when two-dimensional computed tomography images are used to measure glenoid version. These findings support the use of three-dimensional models to evaluate glenoid version. PMID- 20194329 TI - Comparison of bone mineral density between porous tantalum and cemented tibial total knee arthroplasty components. AB - BACKGROUND: Porous tantalum was recently introduced as a metallic implant material for total knee arthroplasty. Its porosity, low modulus of elasticity, and high frictional characteristics were expected to provide physiologic load transfer and relative preservation of bone stock. However, to our knowledge, the effect of a Trabecular Metal tibial component on bone mineral density has not been reported. The purpose of the present study was to compare the periprosthetic bone mineral density between patients managed with uncemented Trabecular Metal and cemented tibial components. METHODS: Twenty-eight knees receiving a Trabecular Metal tibial component and twenty-eight knees receiving a cemented cobalt-chromium tibial component had dual x-ray absorptiometry scans at two weeks preoperatively and at two weeks and six, twelve, eighteen, and twenty-four months postoperatively, to assess periprosthetic bone mineral density. All of the operations were performed by one surgeon through a medial parapatellar approach. RESULTS: None of the differences between the two groups in terms of preoperative bone mineral density in the femoral neck, wrist, lumbar spine, or knee were significant. In both groups, the bone mineral density in the tibia decreased postoperatively. However, the postoperative decrease in bone mineral density in the lateral aspect of the tibia was significantly less in knees with Trabecular Metal components than in knees with cemented tibial components at twenty-four months (mean and standard deviation, -6.7% +/- 22.9% compared with -36.8% +/- 24.2%; p = 0.002). At twenty-four months postoperatively, there was no significant difference between the two groups in terms of the Knee Society score, range of motion of the knee, or bone mineral density in the lumbar spine. No prosthetic migration or periprosthetic fracture was detected in either group. CONCLUSIONS: The decrease in bone mineral density of the lateral tibial plateau was less in knees with a Trabecular Metal tibial component following total knee arthroplasty than in knees with a cemented tibial component. Additional research is needed to determine whether long-term clinical benefits are realized with the use of porous tantalum tibial components for total knee arthroplasty. PMID- 20194330 TI - Histoplasma osteomyelitis simulating giant-cell tumor of the distal part of the radius: a case report. PMID- 20194331 TI - Periarticular neurofibroma of the shoulder: a case report. PMID- 20194332 TI - Symptomatic SLAP tear and paralabral cyst in a pediatric athlete: a case report. PMID- 20194333 TI - Metatarsal osteosarcoma in Rothmund-Thomson syndrome: a case report. PMID- 20194334 TI - Outcomes of single-row and double-row arthroscopic rotator cuff repair: a systematic review. AB - BACKGROUND: Arthroscopic rotator cuff repair is a common procedure that is gaining wide acceptance among orthopaedic surgeons because it is less invasive than open repair techniques. However, there is little consensus on whether to employ single-row or double-row fixation. The purpose of the present study was to systematically review the English-language literature to see if there is a difference between single-row and double-row fixation techniques in terms of clinical outcomes and radiographic healing. METHODS: PubMed, the Cochrane Central Register of Controlled Trials, and EMBASE were reviewed with the terms "arthroscopic rotator cuff," "single row repair," and "double row repair." The inclusion criteria were a level of evidence of III (or better), an in vivo human clinical study on arthroscopic rotator cuff repair, and direct comparison of single-row and double-row fixation. Excluded were technique reports, review articles, biomechanical studies, and studies with no direct comparison of arthroscopic rotator cuff repair techniques. On the basis of these criteria, ten articles were found, and a review of the full-text articles identified six articles for final review. Data regarding demographic characteristics, rotator cuff pathology, surgical techniques, biases, sample sizes, postoperative rehabilitation regimens, American Shoulder and Elbow Surgeons scores, University of California at Los Angeles scores, Constant scores, and the prevalence of recurrent defects noted on radiographic studies were extracted. Confidence intervals were then calculated for the American Shoulder and Elbow Surgeons, University of California at Los Angeles, and Constant scores. Quality appraisal was performed by the two authors to identify biases. RESULTS: There was no significant difference between the single-row and double-row groups within each study in terms of postoperative clinical outcomes. However, one study divided each of the groups into patients with small-to-medium tears (< 3 cm in length) and those with large-to-massive tears (> or = 3 cm in length), and the authors noted that patients with large to massive tears who had double-row fixation performed better in terms of the American Shoulder and Elbow Surgeons scores and Constant scores in comparison with those who had single-row fixation. Two studies demonstrated a significant difference in terms of structural healing of the rotator cuff tendons after surgery, with the double-row method having superior results. There was an overlap in the confidence intervals between the single-row and double-row groups for all of the studies and the American Shoulder and Elbow Surgeons, Constant, and University of California at Los Angeles scoring systems utilized in the studies, indicating that there was no difference in these scores between single-row and double-row fixation. Potential biases included selection, performance, detection, and attrition biases; each study had at least one bias. Two studies had potentially inadequate power to detect differences between the two techniques. CONCLUSIONS: There appears to be a benefit of structural healing when an arthroscopic rotator cuff repair is performed with double-row fixation as opposed to single-row fixation. However, there is little evidence to support any functional differences between the two techniques, except, possibly, for patients with large or massive rotator cuff tears (> or = 3 cm). A risk-reward analysis of a patient's age, functional demands, and other quality-of-life issues should be considered before deciding which surgical method to employ. Double-row fixation may result in improved structural healing at the site of rotator cuff repair in some patients, depending on the size of the tear. PMID- 20194336 TI - Pediatric trauma: getting through the night. PMID- 20194337 TI - Orthopaedic surgeons and the medical device industry: the threat to scientific integrity and the public trust. PMID- 20194338 TI - An analysis of the orthopaedic in-training examination sports section: the importance of reviewing the current orthopaedic subspecialty literature. PMID- 20194335 TI - The assessment of fracture risk. AB - Bone mineral density is considered to be the standard measure for the diagnosis of osteoporosis and the assessment of fracture risk. The majority of fragility fractures occur in patients with bone mineral density in the osteopenic range. The Fracture Risk Assessment Tool (FRAX) can be used as an assessment modality for the prediction of fractures on the basis of clinical risk factors, with or without the use of femoral neck bone mineral density. Treatment of osteoporosis should be considered for patients with low bone mineral density (a T-score of between -1.0 and -2.5) as well as a ten-year risk of hip fracture of > or = 3% or a ten-year risk of a major osteoporosis-related fracture of > or = 20% as assessed with the FRAX. Biochemical bone markers are useful for monitoring the efficacy of antiresorptive or anabolic therapy and may aid in identifying patients who have a high risk of fracture. An approach combining the assessment of bone mineral density, clinical risk factors for fracture with use of the FRAX, and bone turnover markers will improve the prediction of fracture risk and enhance the evaluation of patients with osteoporosis. PMID- 20194339 TI - What's new in hand surgery. PMID- 20194340 TI - Midtarsal arthrodesis in the treatment of Charcot midfoot arthropathy. Surgical technique. AB - BACKGROUND: Fracture-dislocation of the midfoot with collapse of the longitudinal arch is common in patients with neuropathic arthropathy of the foot. In this study, we describe a technique of midfoot arthrodesis with use of intramedullary axial screw fixation and review the results and complications following use of this technique. METHODS: A retrospective study of twenty-two patients who had undergone surgical reconstruction and arthrodesis to treat Charcot midfoot deformity was performed. Bone resection and/or osteotomy were required to reduce deformity. Axially placed intramedullary screws, inserted either antegrade or retrograde across the arthrodesis sites, were used to restore the longitudinal arch. Radiographic measurements were recorded preoperatively, immediately postoperatively, and at the time of the last follow-up and were analyzed in order to assess the amount and maintenance of correction. RESULTS: Patients were evaluated clinically and radiographically at an average of fifty-two months. Complete osseous union was achieved in sixteen of the twenty-two patients, at an average of 5.8 months. There were five partial unions in which a single joint did not unite in an otherwise stable foot. There was one nonunion, with recurrence of deformity. All patients returned to an independent functional ambulatory status within 9.5 months. Weight-bearing radiographs showed the talar-first metatarsal angle, the talar declination angle, and the calcaneal-fifth metatarsal angle to have improved significantly and to have been corrected to nearly normal values by the surgery. All measurements remained significantly improved, as compared with the preoperative values, at the time of final follow-up. There were no recurrent dislocations. Three patients had a recurrent plantar ulcer at the metatarsophalangeal joint that required additional surgery. There were eight cases of hardware failure. CONCLUSIONS: Open reduction and arthrodesis with use of multiple axially placed intramedullary screws for the surgical correction of neuropathic midfoot collapse provides a reliable stable construct to achieve and maintain correction of the deformity. PMID- 20194341 TI - Realignment and extended fusion with use of a medial column screw for midfoot deformities secondary to diabetic neuropathy. Surgical technique. AB - BACKGROUND: The failure of nonsurgical treatment of patients with midfoot and hindfoot deformity secondary to diabetic Charcot arthropathy may lead to a rocker bottom foot deformity with recurrent or persistent plantar ulceration. We report our experience with realignment and extended fusion with primary use of a medial column screw for this midfoot deformity. METHODS: From July 2001 through July 2005, we performed reconstructive surgery on fifteen adults with diabetes mellitus who had a severe neuropathic midfoot deformity consisting of a collapsed plantar arch with a rocker-bottom foot deformity. Thirteen had a nonhealing midfoot plantar ulcer. All underwent realignment and arthrodesis with a medial column screw; some required additional fixation techniques depending on the extent of the deformity. Outcome measures included ulcer and surgical wound healing, radiographic results, complications, and the need for amputation. RESULTS: The mean duration of clinical follow-up was forty-two months. Fourteen patients were able to walk, and there were no recurrent plantar ulcers. Thirteen patients were able to wear custom-made extra-depth, wide-toed shoes with molded inserts. One patient without prior ulceration had development of a deep infection that necessitated an amputation. Four feet had a nonunion, one of which was symptomatic requiring a revision to obtain union. CONCLUSIONS: Surgical reconstruction of a collapsed neuropathic foot deformity is technically demanding, but a successful outcome can result in a plantigrade foot that is free of ulceration and abnormal pressure points and a patient who is able to walk. The procedure described has an acceptable degree of complications although it has a high rate of nonunion. PMID- 20194342 TI - Subtalar fusion after displaced intra-articular calcaneal fractures: does initial operative treatment matter? Surgical technique. AB - BACKGROUND: Many patients with displaced intra-articular calcaneal fractures require subtalar arthrodesis for the treatment of posttraumatic arthritis. We hypothesized that patients who underwent initial operative treatment would have better functional outcomes as compared with those who underwent initial nonoperative treatment before undergoing a subtalar arthrodesis. METHODS: A consecutive series of sixty-nine patients with seventy-five displaced intra articular calcaneal fractures underwent subtalar arthrodesis for the treatment of painful posttraumatic subtalar arthritis. Group A comprised thirty-four patients (thirty-six fractures) who initially were managed with open reduction and internal fixation and subsequently underwent in situ subtalar fusion at an average of 22.6 months later. Group B comprised thirty-five patients (thirty-nine fractures) who initially were managed nonoperatively and had development of a symptomatic painful malunion and subsequently underwent a subtalar distraction arthrodesis. The two groups were similar with respect to age, sex, injury mechanism, and smoking status. All complications were noted and functional outcomes were assessed at a minimum of forty-eight months after fusion. RESULTS: All sixty-nine patients were available for follow-up. The average duration of follow-up was 62.5 months for Group A and 63.5 months for Group B. There were three nonunions of the subtalar fusion requiring revision in each group. Group A had fewer postoperative wound complications and had significantly higher Maryland Foot Scores (90.8 compared with 79.1; p < 0.0001) and American Orthopaedic Foot and Ankle Society ankle-hindfoot scores (87.1 compared with 73.8; p < 0.0001) than did Group B. CONCLUSIONS: In our study population, better functional outcomes and fewer wound complications were associated with subtalar fusion for the treatment of symptomatic posttraumatic subtalar arthritis after initial open reduction and internal fixation of a displaced intra-articular calcaneal fracture as compared with subtalar arthrodesis for the treatment of symptomatic posttraumatic subtalar arthritis secondary to calcaneal malunion following initial nonoperative treatment.Initial open reduction and internal fixation restores calcaneal shape, alignment, and height, which facilitates the fusion procedure and establishes an opportunity to create a better long-term functional result. We recommend open reduction and internal fixation for the treatment of displaced intra-articular calcaneal fractures when appropriately indicated. PMID- 20194343 TI - The role of pantalar arthrodesis in the treatment of paralytic foot deformities. Surgical technique. AB - BACKGROUND: Pantalar arthrodesis is considered by many to be the final operative option before amputation for the treatment of paralytic foot deformities. The aim of the present study was to evaluate the long-term results of pantalar arthrodesis with regard to its impact on the adjacent joints and the walking ability of patients with paralytic foot deformities. METHODS: Twenty-four patients (seventeen men and seven women) who underwent a one-stage pantalar arthrodesis between 1953 and 1973 for the treatment of sequelae of poliomyelitis were reevaluated. All patients underwent a physical and radiographic examination, and all completed the Short Form-36 questionnaire and a pantalar arthrodesis specific questionnaire. RESULTS: The average age of the patients was twenty years at the time of the operation and 57.2 years at the time of the latest evaluation. The average duration of follow-up was 37.2 years. Eleven patients had development of immediate postoperative complications, including wound-healing problems (nine) and infections (two). The long-term results,however, were good (mean Short Form 36 scores, 73 of 100 points [overall], 51.5 points [physical functioning], and >70 points [all other domains]). Sixteen patients experienced repeated episodes of ipsilateral knee pain; most (fifteen) of these patients experienced a gradual onset of this pain, starting at an average of 20.8 years (range, fifteen to thirty years) postoperatively. The position of the fused ankle did not appear to have a significant impact on the development of ipsilateral knee pain or the time interval between the pantalar arthrodesis and the onset of ipsilateral knee pain. CONCLUSIONS: Pantalar arthrodesis effectively stabilizes the ankle, hindfoot, and midfoot in patients with severe paralytic deformities. Even though most patients can be expected to have development of osteoarthritis of the ipsilateral knee, it seems that a successfully performed pantalar arthrodesis in carefully selected cases is a reliable operative option offering a strong and stable foot that will function well for many years. PMID- 20194344 TI - Conversion of painful ankle arthrodesis to total ankle arthroplasty. Surgical technique. AB - BACKGROUND: Pain following an ankle arthrodesis continues to be a challenging clinical problem. Recent reports on semiconstrained two-component ankle implants have demonstrated the feasibility of reversing a problematic ankle fusion and converting it to a total ankle arthroplasty. However, the failure rate is high. The objective of the present prospective study was to evaluate the intermediate term outcome associated with the use of an unconstrained three-component ankle implant after taking down an ankle arthrodesis. METHODS: Thirty painful ankles in twenty-eight patients (average age, 58.2 years) who were managed with takedown of a fusion and total ankle arthroplasty were followed for a minimum of thirty-six months (average, 55.6 months). The outcome was assessed on the basis of clinical and radiographic evaluations. RESULTS: In twenty-nine ankles in twenty-seven patients, the American Orthopaedic Foot and Ankle Society hindfoot score increased from 34.1 preoperatively to 70.6 at the time of the latest follow-up. Twenty-four patients (82.7%) were satisfied with the results. While five ankles were completely pain-free, twenty-one ankles were moderately painful, and three remained painful. The average clinically measured range of motion of 24.3 degrees amounted to 55.1% of that of the contralateral, unaffected ankle. Radiographically, the tibial component was stable in all ankles but one. The talar component was found to have migrated in four ankles but was asymptomatic in two of them. One ankle had to be revised to a tibiocalcaneal arthrodesis because of persistent pain and loosening of the talar component. CONCLUSIONS: For patients with pain at the site of a failed ankle arthrodesis, conversion to total ankle arthroplasty with the use of a three-component ankle implant is a viable treatment option that provides reliable intermediate-term results. Key factors for the success of this procedure may be the intrinsic coronal plane stability provided by the ankle implants and the use of wider talar implants. PMID- 20194345 TI - Thoracolumbar burst fractures treated with posterior decompression and pedicle screw instrumentation supplemented with balloon-assisted vertebroplasty and calcium phosphate reconstruction. Surgical technique. AB - BACKGROUND: The treatment of unstable thoracolumbar burst fractures with short segment posterior spinal instrumentation without anterior column reconstruction is associated with a high rate of screw breakage and progressive loss of reduction. The purpose of the present study was to evaluate the functional, neurologic, and radiographic results following transpedicular, balloon-assisted fracture reduction with anterior column reconstruction with use of calcium phosphate bone cement combined with short-segment posterior instrumentation and a laminectomy. METHODS: A consecutive series of thirty-eight patients with an unstable thoracolumbar burst fracture with or without neurologic deficit were managed with transpedicular, balloon-assisted fracture reduction, calcium phosphate bone cement reconstruction, and short-segment spinal instrumentation from 2002 to 2005. Twenty-eight of the thirty-eight patients were followed for a minimum of two years. Demographic data, neurologic function, segmental kyphosis, the fracture severity score, canal compromise, the Short Form-36 score, the Oswestry Disability Index score, and treatment-related complications were evaluated prospectively. RESULTS: All thirteen patients with incomplete neurologic deficits had improvement by at least one Frankel grade. The mean kyphotic angulation improved from 17 degrees preoperatively to 7 degrees at the time of the latest follow-up, and the loss of vertebral body height improved from a mean of 42% preoperatively to 14% at the time of the latest follow-up. Screw breakage occurred in two patients, and pseudarthrosis occurred in one patient. CONCLUSIONS: The present study demonstrates that excellent reduction of unstable thoracolumbar burst fractures with and without associated neurologic deficits can be maintained with use of short-segment instrumentation and a transpedicular balloon-assisted reduction combined with anterior column reconstruction with calcium phosphate bone cement performed through a single posterior incision. The resultant circumferential stabilization combined with a decompressive laminectomy led to maintained or improved neurologic function in all patients with neurologic deficits, with a low rate of instrumentation failure and loss of correction. PMID- 20194346 TI - Outcome of lumbar arthrodesis in patients sixty-five years of age or older. Surgical technique. AB - BACKGROUND: The value of lumbar spine arthrodesis in older patients is not well documented. As most of the literature regarding lumbar arthrodesis in older patients has focused on the prevalence of complications, the purpose of this study was to determine the clinical outcomes for older compared with younger patients undergoing lumbar arthrodesis. METHODS: We studied 224 patients who underwent a single-level posterolateral lumbar arthrodesis with an iliac crest bone graft. Outcome measures included the Oswestry Disability Index, the Medical Outcomes Study Short Form-36 and numeric rating scales for back and leg pain, as well as a radiographic assessment of fusion. Outcome measures were evaluated on the basis of the mean change and the percentage of patients reaching a minimum clinically important difference threshold. For comparison, the patients were divided into two groups: 174 patients who were younger than sixty-five years and fifty patients who were sixty-five years of age or older. RESULTS: Substantial improvements from baseline were noted in all of the clinical and health-related quality-of-life measures at the six-month, one-year, and two-year intervals. The mean improvements in the Oswestry Disability Index score at two years postoperatively were 28.5 points for the older patients and 24.5 points for the younger patients. For Short Form-36 physical component summary scores, the mean improvement from baseline was 14.2 points for the older group and 11.7 points for the younger group at two years. The older patients also demonstrated a similar or greater improvement in the numeric rating scale back and leg pain scores at all time intervals, with a significant difference in leg pain scores at two years postoperatively (10.4 points for the older patients and 6.4 points for the younger patients; p=0.002). Perioperative complications, although an obvious concern, did not appear to adversely affect clinical and health-related quality of-life outcomes at two years postoperatively. CONCLUSIONS: This study demonstrates a substantial benefit for patients sixty-five years of age or older with degenerative disc disease who are treated with a single-level lumbar decompression and instrumented arthrodesis, and we conclude that lumbar arthrodesis is a viable and reasonable treatment option for appropriately selected patients sixty-five years of age or older. PMID- 20194347 TI - Open reduction and internal fixation of proximal humeral fractures with use of the locking proximal humerus plate. Surgical technique. AB - BACKGROUND: The treatment of unstable displaced proximal humeral fractures, especially in the elderly, remains controversial. The objective of the present prospective, multicenter, observational study was to evaluate the functional outcome and the complication rate after open reduction and internal fixation of proximal humeral fractures with use of a locking proximal humeral plate. METHODS: One hundred and eighty-seven patients (mean age, 62.9 +/- 15.7 years) with an acute proximal humeral fracture were managed with open reduction and internal fixation with a locking proximal humeral plate. At the three-month, six month,and one-year follow-up examinations, 165 (88%), 158 (84%), and 155 (83%) of the 187 patients were assessed with regard to pain, shoulder mobility, and strength. The Constant score was determined at each interval, and the Disabilities of the Arm, Shoulder and Hand (DASH) score was determined for the injured and contralateral extremities at the time of the one-year follow-up. RESULTS: Between three months and one year, the mean range of motion and the mean Constant score for the injured shoulders improved substantially. Twelve months after surgery, the mean Constant score for the injured side was 70.6 +/- 13.7 points, corresponding to 85.1% +/- 14.0% of the score for the contralateral side. The mean DASH score at the time of the one-year follow-up was 15.2 +/- 16.8 points. Sixty-two complications were encountered in fifty-two (34%) of 155 patients at the time of the one-year follow-up. Twenty-five complications (40%) were related to incorrect surgical technique and were present at the end of the operative procedure. The most common complication, noted in twenty-one (14%) of 155 patients, was intraoperative screw perforation of the humeral head. Twenty-nine patients (19%) had an unplanned second operation within twelve months after the fracture. CONCLUSIONS: Surgical treatment of displaced proximal humeral fractures with use of the locking proximal humeral plate that was evaluated in the present study can lead to a good functional outcome provided that the correct surgical technique is used. Because many of the complications were related to incorrect surgical technique, it behooves the treating surgeon to perform the operation correctly to avoid iatrogenic errors. PMID- 20194348 TI - Operative management of distal radial fractures with 2.4-millimeter locking plates: a multicenter prospective case series. Surgical technique. AB - BACKGROUND: In the past decade, there has been a trend toward open reduction and internal fixation of unstable distal radial fractures. There are now more than thirty different implant designs specific for the fixation of distal radial fractures. A multicenter prospective study of a case series was conducted to determine the efficacy of the operative management of distal radial fractures stabilized with 2.4-mm locking plates. METHODS: One hundred and fifty patients were entered into the study over a two-year period. The mean age of these patients was fifty-one years, and the cohort included eighty-eight women and sixty-two men. Eighty-six patients sustained a low-energy injury. Seventy-one percent of the fractures in the series were intra-articular and were Type C according to the Muller-AO Comprehensive Classification. The follow-up evaluations, which were conducted at six weeks, six months, one year, and two years, included assessments of pain, motion, grip strength, and standard radiographs. Gartland and Werley scores were recorded at six months and one and two years, and Disabilities of the Arm, Shoulder and Hand (DASH) scores were recorded at one and two years. RESULTS: One hundred and twenty-five patients (83%) had a complete follow-up at six months; 121 (81%), at one year; and 117 (78%), at two years. Significant improvements in motion, grip strength, and patient satisfaction were observed between six months and one year, but further improvements were not seen at the two-year follow-up examination. The mean DASH score changed from a preinjury baseline of 2 points to 8 points at one year and 7 points at two years (p < 0.0001). The mean Gartland and Werley score improved significantly from 4 points at six months to 2 points at two years. Of the 102 intra-articular fractures examined in the immediate postoperative period, twenty had a step-off of 2 mm. Of the seventy-one intra-articular fractures seen at two years, sixty-one had no step-off, five had a step-off of 2 mm. Twenty-seven percent of the patients showed an increase of at least one grade in radiographic signs of arthritis at two years. There were twenty-eight complications, twenty of which were considered minor. Tendon inflammation occurred in nine patients. There were two tendon ruptures, one of which was due to a prominent dorsal screw tip placed through a volar plate and one of which was due to a prominent volar plate. Loss of reduction occurred in two patients, and screw loosening occurred in two patients. CONCLUSIONS: Internal fixation of displaced distal radial fractures with implants featuring locking screw fixation can result in good-to-excellent outcomes with a limited number of complications. PMID- 20194349 TI - Comparison of arthroscopic and open treatment of septic arthritis of the wrist. Surgical technique. AB - BACKGROUND: Open irrigation and debridement is the standard of treatment for septic arthritis of the wrist. Although isolated cases of arthroscopic irrigation and debridement have been reported, a comparison of arthroscopic and open techniques has not been performed, to our knowledge. The purpose of this study was to compare the two methods of management. METHODS: A retrospective comparison of patients with septic arthritis of the wrist initially treated, over an eleven year period, with open or arthroscopic irrigation and debridement was undertaken at a single institution. The clinical presentation, laboratory and microbiological findings, hospital course, complications, and outcomes were compared between the two groups. RESULTS: Between 1997 and 2007, thirty-six patients with septic arthritis involving a total of forty wrists were identified. Nineteen wrists (seventeen patients) were initially treated with open irrigation and debridement, and twenty-one wrists (nineteen patients) were initially treated arthroscopically. Eleven wrists in the open-treatment cohort required repeat irrigation and debridement, and eight wrists in the arthroscopy cohort required a repeat procedure. If a repeat irrigation and debridement was required, it was performed in an open fashion in all but two cases. When the comparison included all of the patients in the series, no difference between the two cohorts was found with regard to the number of irrigation and debridement procedures required or the length of the hospital stay. However, when the comparison was limited to the patients with isolated septic arthritis of the wrist, it was found that only one of seven wrists in the open-treatment cohort but all eight wrists in the arthroscopy cohort had been successfully managed with a single irrigation and debridement procedure (p = 0.001). No patient in whom isolated septic arthritis of the wrist had been treated with arthroscopic irrigation and debridement required a second operation. The patients in whom isolated septic arthritis of the wrist was treated with the open method stayed in the hospital for an average of sixteen days compared with a six-day stay for those in whom isolated septic arthritis of the wrist was treated with the arthroscopic method (p = 0.04). The ninety-day perioperative mortality rate in the series was substantial (18% [three patients] in the open-treatment cohort and 21% [four patients] in the arthroscopy cohort). CONCLUSIONS: Arthroscopic irrigation and debridement is an effective treatment for patients with isolated septic arthritis of the wrist; these patients had fewer operations and a shorter hospital stay than did patients who had received open treatment. However, these benefits were not seen in patients with multiple sites of infection. PMID- 20194353 TI - Parent initiated prednisolone for acute asthma in children of school age: randomised controlled crossover trial. AB - OBJECTIVE: To evaluate the efficacy of a short course of parent initiated oral prednisolone for acute asthma in children of school age. DESIGN: Double blind, randomised, placebo controlled, crossover trial in which episodes of asthma, rather than participants, were randomised to treatment. SETTING: The Barwon region of Victoria, Australia. PARTICIPANTS: Children aged 5-12 years with a history of recurrent episodes of acute asthma. INTERVENTION: A short course of parent initiated treatment with prednisolone (1 mg/kg a day) or placebo. MAIN OUTCOME MEASURES: The primary outcome measure was the mean daytime symptom score over seven days. Secondary outcome measures were mean night time symptom score over seven days, use of health resources, and school absenteeism. RESULTS: 230 children were enrolled in the study. Over a three year period, 131 (57%) of the participants contributed a total of 308 episodes of asthma that required parent initiated treatment: 155 episodes were treated with parent initiated prednisolone and 153 with placebo. The mean daytime symptom score was 15% lower in episodes treated with prednisolone than in those treated with placebo (geometric mean ratio 0.85, 95% CI 0.74 to 0.98; P=0.023). Treatment with prednisolone was also associated with a 16% reduction in the night time symptom score (geometric mean ratio 0.84, 95% CI 0.70 to 1.00; P=0.050), a reduced risk of health resource use (odds ratio 0.54, 95% CI 0.34 to 0.86; P=0.010), and reduced school absenteeism (mean difference -0.4 days, 95% CI -0.8 to 0.0 days; P=0.045). CONCLUSION: A short course of oral prednisolone initiated by parents when their child experiences an episode of acute asthma may reduce asthma symptoms, health resource use, and school absenteeism. However, the modest benefits of this strategy must be balanced against potential side effects of repeated short courses of an oral corticosteroid. TRIAL REGISTRATION: ISRCTN 26232583. PMID- 20194354 TI - Acute asthma in children of school age. PMID- 20194350 TI - Sodium taurocholate inhibits intestinal adenoma formation in APCMin/+ mice, potentially through activation of the farnesoid X receptor. AB - In light of clinical and biological evidence that bile constituents exert preventive effects against colorectal cancer, we evaluated the influence of oral bilirubin and sodium taurocholate (NaTC) on intestinal tumor formation in APC(Min/+) mice. Mice received bilirubin and/or bovine serum albumin (BSA) and NaTC in the drinking water for 8 weeks, after which the number, size and location of intestinal adenomas were determined. Tissue specimens were analyzed by light microscopy, TUNEL staining, immunohistochemistry for beta-catenin and Ki-67 and quantitative polymerase chain reaction for farnesoid X receptor (FXR)-dependent gene expression. Colon tumor formation also was assessed in azoxymethane (AOM) treated hyperbilirubinemic Gunn (j/j) and wild-type (+/+) rats. Compared with untreated APC(Min/+) mice, the mean number of intestinal adenomas was markedly lower in both bilirubin (10.5 +/- 0.9 versus 37.0 +/- 5.2; +/-SEM; P < 0.001) and NaTC plus BSA (14.3 +/- 5.4; P = 0.01)-treated animals. Both treatment groups exhibited reduced levels of cellular proliferation in the ileum (by Ki-67 staining), but no differences in TUNEL staining or the percentage of beta-catenin positive crypts. Bilirubin feeding reduced intestinal inducible nitric oxide synthase expression, but did not alter adenoma multiplicity in APC(Min/+) mice or in AOM-treated j/j versus +/+ rats. Mice receiving NaTC manifested increased intestinal expression of the FXR-regulated genes, Shp, FGF15 and IBABP, and a concomitant decrease in cyclin D1 message. Administering NaTC to APC(Min/+) mice causes a marked reduction in intestinal adenomas. We postulate that this effect is mediated through activation of FXR, leading to increased Shp expression and consequent downregulation of cyclin D1. PMID- 20194355 TI - Normal glucose enhances neuronal regeneration after lidocaine-induced injury. AB - BACKGROUND: Local anaesthetics exhibit direct neurotoxic effects on neurones. Numerous studies have investigated the factors that may reverse this neuropathology, but the effects of glucose conditions on neuronal regeneration after lidocaine-induced injury have not been examined by observing living neurones. The present study investigated the effects of different glucose conditions on neurite length, growth cone regeneration, and cell death in dorsal root ganglia (DRG) neurones after lidocaine-induced injury in vitro. METHODS: DRG explants were isolated from chick embryos at embryonic day 8 and cultured in media containing low, normal, or high glucose concentrations (10, 25, or 40 mM) for 24 h. Tissues were exposed to lidocaine 8 mM for 1 h, then rinsed and incubated for a further 24 h. Neurite length and growth cone collapse assays were performed to assess neuronal growth and regeneration. Lactate dehydrogenase (LDH) and caspase assays were also performed to detect neuronal cell death. RESULTS: Addition of lidocaine for 1 h resulted in >97% growth cone collapse and neurite destruction under all three glucose conditions. Two hours after rinsing out the lidocaine, significant reversal of growth cone collapse and neurite elongation was observed under all glucose conditions. Growth cone collapse was higher under low-glucose condition (P<0.05). High glucose negatively affected neurite length more than growth cone collapse. At 24 h, LDH release with both low- and high glucose conditions was higher than with normal glucose (P<0.05). Low- and high glucose conditions increased caspase 3/7 activation. CONCLUSIONS: Normal glucose is optimal for neuronal recovery after lidocaine-induced injury in vitro. PMID- 20194357 TI - NIH and FDA start scheme to deliver new treatments faster. PMID- 20194359 TI - The influence of having a quit date on prediction of smoking cessation outcome. AB - The aim of this study was to explore whether factors predicting making a quit attempt are uniform within the preparation stage of the transtheoretical model (TTM). Participants were 283 smokers, all planning to quit in the next 30 days (preparation stage), who used a computer-generated tailored advice programme. Evidence of differences in prediction of making a quit attempt was found between smokers with and without a quit date, with the predictive power of a multivariate model markedly higher among those with a set date. In particular, one aspect of pros of smoking (smoking helps you feel better when things are bad) was predictive of progression among those with a quit date, but not among those without. The results suggest that factors predicting stage progression are not uniform within the preparation stage. The results complement other recent research that has questioned the stage definitions used in the TTM and provide evidence in support of an alternative stage boundary defined by the commitment of setting a quit date. PMID- 20194360 TI - The PsbK subunit is required for the stable assembly and stability of other small subunits in the PSII complex in the thermophilic cyanobacterium Thermosynechococcus elongatus BP-1. AB - PsbK is a small membrane protein of the PSII core complex and is highly conserved from cyanobacteria to plants. Here, we studied its role in the thermophilic cyanobacterium, Thermosynechococcus elongatus BP-1, by focusing on a psbK disruptant with hexahistidine-tagged CP47. The psbK disruptant showed photoautotrophic growth comparable with that of the wild type under a wide range of light conditions. The mutant PSII complex retained the oxygen-evolving activity with a unique modification of the acceptor Q(B) site. N-terminal sequencing revealed that Ycf12 and PsbZ proteins were lost in the PSII complex prepared from the mutant. Immunoblotting detected reduced accumulation of PsbZ in the mutant thylakoid. These results suggest that PsbK is required not only for association of PsbZ and Ycf12 with the isolated PSII complex but also for the stabilization of PsbZ in the thylakoid membrane. PMID- 20194361 TI - Functional differentiation of two analogous coproporphyrinogen III oxidases for heme and chlorophyll biosynthesis pathways in the cyanobacterium Synechocystis sp. PCC 6803. AB - Coproporphyrinogen III oxidase (CPO) catalyzes the oxidative decarboxylation of coproporphyrinogen III to form protoporphyrinogen IX in heme biosynthesis and is shared in chlorophyll biosynthesis in photosynthetic organisms. There are two analogous CPOs, oxygen-dependent (HemF) and oxygen-independent (HemN) CPOs, in various organisms. Little information on cyanobacterial CPOs has been available to date. In the genome of the cyanobacterium Synechocystis sp. PCC 6803 there is one hemF-like gene, sll1185, and two hemN-like genes, sll1876 and sll1917. The three genes were overexpressed in Escherichia coli and purified to homogeneity. Sll1185 showed CPO activity under both aerobic and anaerobic conditions. While Sll1876 and Sll1917 showed absorbance spectra indicative of Fe-S proteins, only Sll1876 showed CPO activity under anaerobic conditions. Three mutants lacking one of these genes were isolated. The Deltasll1185 mutant failed to grow under aerobic conditions, with accumulation of coproporphyrin III. This growth defect was restored by cultivation under micro-oxic conditions. The growth of the Deltasll1876 mutant was significantly slower than that of the wild type under micro-oxic conditions, while it grew normally under aerobic conditions. Coproporphyrin III was accumulated at a low but significant level in the Deltasll1876 mutant grown under micro-oxic conditions. There was no detectable phenotype in Deltasll1917 under the conditions we examined. These results suggested that sll1185 encodes HemF as the sole CPO under aerobic conditions and that sll1876 encodes HemN operating under micro-oxic conditions, together with HemF. Such a differential operation of CPOs would ensure the stable supply of tetrapyrrole pigments under environments where oxygen levels fluctuate greatly. PMID- 20194362 TI - Do sign language videos improve Web navigation for Deaf Signer users? AB - The efficacy of video-based sign language (SL) navigation aids to improve Web search for Deaf Signers was tested by two experiments. Experiment 1 compared 2 navigation aids based on text hyperlinks linked to embedded SL videos, which differed in the spatial contiguity between the text hyperlink and SL video (contiguous vs. distant). Deaf Signers' performance was similar in Web search using both aids, but a positive correlation between their word categorization abilities and search efficiency appeared in the distant condition. In Experiment 2, the contiguous condition was compared with a text-only hyperlink condition. Deaf Signers became less disorientated (used shorter paths to find the target) in the text plus SL condition than in the text-only condition. In addition, the positive correlation between word categorization abilities and search only appeared in the text-only condition. These findings suggest that SL videos added to text hyperlinks improve Web search efficiency for Deaf Signers. PMID- 20194363 TI - The use of rim excision as a treatment for canine acanthomatous ameloblastoma. AB - This study reviews rim excision as a treatment for canine acanthomatous ameloblastomas (CAA) in dogs with <3 mm of bone involvement. Removal of a canine tooth was involved in 47% of the cases; 33% cases involved the caudal dentition. Follow-up ranged from 3 months to 5 years. No evidence of recurrence was seen. Client satisfaction with cosmesis and the animal's ability to masticate was judged to be good. With appropriate case selection, rim excision appears to be a viable option for CAA and results in improved dental occlusion, cosmesis, and no evidence of epulis recurrence. PMID- 20194364 TI - A retrospective study of factors influencing survival following surgery for gastric dilatation-volvulus syndrome in 306 dogs. AB - Gastric dilatation-volvulus (GDV) is a life-threatening condition in dogs that has been associated with high mortality rates in previous studies. Factors were evaluated in this study for their influence on overall and postoperative mortality in 306 confirmed cases of GDV between 2000 and 2004. The overall mortality rate was 10%, and the postoperative mortality rate was 6.1%. The factor that was associated with a significant increase in overall mortality was the presence of preoperative cardiac arrhythmias. Factors that were associated with a significant increase in postoperative mortality were postoperative cardiac arrhythmias, splenectomy, or splenectomy with partial gastric resection. The factor that was associated with a significant decrease in the overall mortality rate was time from presentation to surgery. This study documents that certain factors continue to affect the overall and postoperative mortality rates associated with GDV, but these mortality rates have decreased compared to previously reported rates. PMID- 20194365 TI - Primary prostatic leiomyosarcoma with pulmonary metastases in a dog. AB - A 6-year-old, intact male Jack Russell terrier was diagnosed with a mass in the caudal abdomen, and ultrasound revealed a large prostatic mass. A total-body computed tomography scan was performed for staging, and lung nodules were detected. Histological examination showed a proliferation of spindle cells arranged in interlacing fascicles. Immunohistochemical staining revealed cells were cytokeratin negative and immunoreactive for vimentin and alpha-smooth muscle actin; cells stained with desmin and S-100 were negative. A diagnosis of primary prostatic leiomyosarcoma with pulmonary metastases was made. This is one of the rare cases of primary prostatic mesenchymal tumor in the canine species. PMID- 20194366 TI - Multiple follicular cysts of the ear canal in a dog. AB - An 11-year-old, 18-kg, neutered male standard schnauzer was presented for evaluation of recurrent otitis externa with para-aural swelling and fistulation of the right external ear canal of 6 months' duration. Otoscopic examination was impossible because of the severe stenosis of the ear canal. Right para-aural ultrasound examination and ultrasound-guided fine-needle aspiration of a mass like lesion were performed. Cytology was suggestive of a follicular cyst. Magnetic resonance imaging revealed severe ear canal stenosis with a heterogeneous mass in the horizontal portion of the ear canal and associated otitis media. Total ear canal ablation with lateral bulla osteotomy was performed. Histopathological diagnosis was chronic otitis externa associated with multiple follicular cysts confined to the ear canal. Surgical treatment proved curative. This is the first report of multiple follicular cysts originating from the ear canal in a dog. PMID- 20194367 TI - Phenobarbital-responsive sialadenosis associated with an esophageal foreign body in a dog. AB - A 4-year-old Yorkshire terrier was presented for an esophageal foreign body. After removal of the foreign body, clinical signs of gagging, regurgitation, and vomiting continued unabated for >6 weeks. The dog had enlarged submandibular salivary glands that were histologically normal. Treatment with phenobarbital resulted in a rapid and dramatic resolution of clinical signs. After 3 months, the dog was weaned of phenobarbital and was free of any signs of disease 6 months later. PMID- 20194368 TI - Surgical resection of a mature teratoma on the head of a young cat. AB - A 4-month-old kitten was presented with a large mass over the temporal area involving the base of the left ear. Cytological evaluation of a fine-needle aspirate was not diagnostic. Computed tomography was used to determine tumor extent. Surgical resection was performed, which included parts of the orbital rim, masticatory muscles, the complete ear canal, and the pinna. Reconstruction of the ocular muscles was performed, and the skin defect was reconstructed using a single pedicle advancement flap. Despite unilateral facial paralysis, postoperative clinical function was excellent and aesthetics were good. Histological examination revealed the tumor to be a teratoma. After a follow-up period of 3 years, no signs of recurrence were evident. Extragonadal teratomas should be considered in the differential diagnosis when young animals are presented with a growing mass located outside the abdominal cavity. Surgical excision of a mature teratoma can be considered curative. PMID- 20194369 TI - Nasal rhinosporidiosis in two dogs native to the upper Mississippi river valley region. AB - Two dogs, 4 and 7 years of age, were presented for evaluation and treatment of excessive sneezing. Physical examinations in both cases were within acceptable limits except for the presence of a single mass in the left nasal passage in the first case and left-sided nasal discharge in the second case. Rhinoscopy was used to visualize the nasal masses, and in both cases a single mass was surgically removed. Impression smears and histopathology submitted from each mass revealed lymphoplasmacytic and neutrophilic inflammation with spores typical of Rhinosporidium seeberi. These are the first reported cases of nasal rhinosporidiosis in two dogs native to the Upper Mississippi River Valley area with no travel history outside the region. PMID- 20194370 TI - Intraaxial spinal cord hemorrhage secondary to atlantoaxial subluxation in a dog. AB - A 1-year-old, 3.5-kg, spayed female, toy poodle was presented for acute-onset tetraplegia and neck pain. Neuroanatomical diagnosis was consistent with a first through fifth cervical (C(1) through C(5)) spinal cord lesion. Radiographs of the cervical vertebral column revealed atlantoaxial (AA) subluxation. Magnetic resonance imaging revealed abnormalities consistent with intraaxial spinal cord hemorrhage at the level of the AA articulation. The dog was treated with external coaptation. After 8 days, the dog regained voluntary motor function in all four limbs. Surgical stabilization was pursued. Postoperatively, the dog regained the ability to ambulate. This report details the imaging findings and management of a dog with intraaxial spinal cord hemorrhage secondary to AA subluxation. PMID- 20194371 TI - Spontaneous feline pneumothorax caused by ruptured pulmonary bullae associated with possible bronchopulmonary dysplasia. AB - Spontaneous pneumothorax is rarely reported in the cat. This case report describes the use of computed tomography (CT) to diagnose pulmonary bullae in an adult cat with recurrent spontaneous pneumothorax. A large bulla in the right middle lung lobe and several blebs in other lobes were identified by CT. Partial lobectomy of the right middle and right and left cranial lung lobes was successfully performed to remove the affected portions of lung. Histopathological examination suggested bronchopulmonary dysplasia (BPD) as the underlying cause for development of the pulmonary bulla. This is the first case report in the veterinary literature describing the use of CT to identify pulmonary bullae in the cat with BPD as a possible underlying cause. PMID- 20194372 TI - Follicular dysplasia of the adult doberman pinscher. AB - This paper presents the case of an adult female, red Doberman pinscher affected by permanent hypotrichosis, limited to the dorsolumbar region and sides of the trunk. The hypotrichosis began at approximately the age of 2 years and progressed slowly with no skin hyperpigmentation. The clinical and histopathological characteristics are of an uncommon form of follicular dysplasia. PMID- 20194373 TI - Education and training: two different proficiencies necessary to provide oral health care. PMID- 20194374 TI - Health care reform. PMID- 20194375 TI - Composite restorations. PMID- 20194376 TI - More about composites. PMID- 20194377 TI - Occlusal loading. PMID- 20194380 TI - Noninvasive technique can block conditioned fear in humans, researchers say. PMID- 20194378 TI - More about occlusal loading. PMID- 20194381 TI - Painless plasma jets could replace dentist's drill, research shows. PMID- 20194382 TI - Cortical integrity of the inferior alveolar canal as a predictor of paresthesia after third-molar extraction. AB - BACKGROUND: Paresthesia is a well-known complication of extraction of mandibular third molars (MTMs). The authors evaluated the relationship between paresthesia after MTM extraction and the cortical integrity of the inferior alveolar canal (IAC) by using computed tomography (CT). METHODS: The authors designed a retrospective cohort study involving participants considered, on the basis of panoramic imaging, to be at high risk of experiencing injury of the inferior alveolar nerve who subsequently underwent CT imaging and extraction of the MTMs. The primary predictor variable was the contact relationship between the IAC and the MTM as viewed on a CT image, classified into three groups: group 1, no contact; group 2, contact between the MTM and the intact IAC cortex; group 3, contact between the MTM and the interrupted IAC cortex. The secondary predictor variable was the number of CT image slices showing the cortical interruption around the MTM. The outcome variable was the presence or absence of postoperative paresthesia after MTM extraction. RESULTS: The study sample comprised 179 participants who underwent MTM extraction (a total of 259 MTMs). Their mean age was 23.6 years, and 85 (47.5 percent) were male. The overall prevalence of paresthesia was 4.2 percent (11 of 259 teeth). The prevalence of paresthesia in group 3 (involving an interrupted IAC cortex) was 11.8 percent (10 of 85 cases), while for group 2 (involving an intact IAC cortex) and group 1 (involving no contact) it was 1.0 percent (1 of 98 cases) and 0.0 percent (no cases), respectively. The frequency of nerve damage increased with the number of CT image slices showing loss of cortical integrity (P=.043). CONCLUSIONS: The results of this study indicate that loss of IAC cortical integrity is associated with an increased risk of experiencing paresthesia after MTM extraction. PMID- 20194383 TI - Hyposalivation and xerostomia in dentate older adults. AB - BACKGROUND: Older adults are susceptible to reduced saliva production related to certain medications, radiation and chronic conditions. Many of these people have many physical and oral health problems and limited access to dental care. The use of effective screening tools for xerostomia and hyposalivation would be helpful in identifying those at risk. The authors conducted a study to investigate the association between three measures of oral dryness: hyposalivation (low unstimulated salivary flow), self-reported xerostomia and clinically assessed dry mouth. METHODS: The authors included a convenience sample of 252 nondemented and dentate West Virginia participants 70 years and older who were part of a larger study on oral health and cognition among older adults. Participants completed a self-reported xerostomia index, provided an unstipulated salivary sample and underwent an oral assessment for the study. RESULTS: Twenty-eight participants (11.1 percent) had hyposalivation, eight of whom reported having xerostomia (sensitivity=28.6 percent). Of the 43 participants who reported having xerostomia, only eight had hyposalivation (positive predictive value=18.6 percent). Hyposalivation and self-reported xerostomia were not significantly related. Clinically assessed dry mouth correlated modestly, but significantly, with hyposalivation and self-reported xerostomia. CONCLUSIONS: Obtaining routine unstimulated salivary flow rates in addition to self-reported information and oral evaluations may increase early detection of oral dryness, which would assist in implementing early interventions to improve patients' quality of life. CLINICAL IMPLICATIONS: Visually inspecting oral tissues for dryness and asking a patient if his or her mouth is dry are insufficient measures for clinicians to use to determine if the patient has hyposalivation. The authors recommend that clinicians determine the patient's unstimulated salivary flow rate. PMID- 20194384 TI - The efficacy of three desensitizing agents used to treat dentin hypersensitivity. AB - BACKGROUND: In a single-center, double-masked, split-mouth-designed, clinical short-term trial, the authors assessed the clinical responses of teeth with dentin hypersensitivity (DH) after treating the teeth with one of three desensitizing agents across four weeks. METHODS: The authors selected 131 teeth with DH in 11 participants. The authors assessed DH of the teeth by using tactile stimuli and air stimuli and had the participants record the level of sensitivity by means of a visual analog scale (VAS). The authors then treated the teeth with one of three desensitizing agents (Pain-Free [Parkell, Edgewood, N.Y.], BisBlock [Bisco, Schaumburg, Ill.], Seal & Protect [Dentsply DeTrey, Konstanz, Germany]) that they applied according to the manufacturers' instructions. The authors used a split-mouth-designed study in which the teeth in different quadrants of the participants' mouths received different desensitizing agents. The authors also conducted DH evaluations at 10 minutes after treatment and at one, two, three and four weeks. The authors analyzed data statistically by using Mann-Whitney U and Kruskal-Wallis tests. RESULTS: The results of the statistical analysis showed that all VAS scores at the posttreatment evaluation periods were reduced significantly compared with those at baseline (P<.05). More teeth were sensitive to air stimuli than to tactile stimuli. The mean VAS scores for DH in the mandibular teeth were significantly higher than for those in maxillary teeth immediately after treatment (for tactile stimuli) and two weeks after the first application (for air stimuli) (P<.05) CONCLUSIONS: All three desensitizing agents were effective in relieving DH up to four weeks, independent of their application procedures. There was, however, a significant reduction in mean sensitivity scores of teeth that had been treated with Seal & Protect and Pain-Free compared with those of BisBlock at weeks two, three and four. CLINICAL IMPLICATIONS: The study results should be considered with caution, as it is not clear how many of the pain relief effects were related to the natural desensitization of teeth over time. PMID- 20194385 TI - Transient morning headache: recognizing the role of sleep bruxism and sleep disordered breathing. PMID- 20194386 TI - Influence of in situ postbleaching times on shear bond strength of resin-based composite restorations. AB - BACKGROUND: The authors conducted an in situ study of the influence of various time intervals after tooth bleaching with 35 percent hydrogen peroxide on the bond strength of resin-based composite restorations. METHODS: After selecting 20 participants, the authors randomly fixed enamel and dentin blocks onto the buccal surfaces of posterior maxillary teeth one week before performing tooth bleaching with 35 percent hydrogen peroxide. After the bleaching treatment, they removed one block of dentin or enamel and prepared it for the bond strength tests according to these time intervals: no bleaching treatment (controls), immediately after bleaching, seven days after bleaching, 14 days after bleaching and 21 days after bleaching. RESULTS: The analysis of variance and Tukey test showed significant differences between times (P<.05), and shear bond strength values of resin-based composite to enamel and dentin were lower immediately after the bleaching treatment. CONCLUSIONS: The authors found that 35 percent hydrogen peroxide reduces the bond strength to enamel and dentin and that it is necessary to wait seven days before performing adhesive restorative procedures. CLINICAL IMPLICATIONS: The results of this study suggest that clinicians should allow seven days to elapse after completion of in-office bleaching with 35 percent hydrogen peroxide before placing adhesive restorations. PMID- 20194387 TI - The relationship between methamphetamine use and increased dental disease. AB - BACKGROUND: Methamphetamine (MA) use has been linked anecdotally to rampant dental disease. The authors sought to determine the relative prevalence of dental comorbidities in MA users, verify whether MA users have more quantifiable dental disease and report having more dental problems than nonusers and establish the influence of mode of MA administration on oral health outcomes. METHODS: Participating physicians provided comprehensive medical and oral assessments for adults dependent on MA (n=301). Trained interviewers collected patients' self reports regarding oral health and substance-use behaviors. The authors used propensity score matching to create a matched comparison group of nonusers from participants in the the Third National Health and Nutrition Examination Survey (NHANES III). RESULTS: Dental or oral disease was one of the most prevalent (41.3 percent) medical cormorbidities in MA users who otherwise were generally healthy. On average, MA users had significantly more missing teeth than did matched NHANES III control participants (4.58 versus 1.96, P<.001) and were more likely to report having oral health problems (P<.001). Significant subsets of MA users expressed concerns with their dental appearance (28.6 percent), problems with broken or loose teeth (23.3 percent) and tooth grinding (bruxism) or erosion (22.3 percent). The intravenous use of MA was significantly more likely to be associated with missing teeth than was smoking MA (odds ratio=2.47; 95 percent confidence interval=1.3-4.8). CONCLUSIONS: Overt dental disease is one of the key distinguishing comorbidities in MA users. MA users have demonstrably higher rates of dental disease and report long-term unmet oral health needs. Contrary to common perception, users who smoke or inhale MA have lower rates of dental disease than do those who inject the drug. Many MA users are concerned with the cosmetic aspects of their dental disease, and these concerns could be used as behavioral triggers for targeted interventions. CLINICAL IMPLICATIONS: Dental disease may provide a temporally stable MA-specific medical marker with discriminant utility in identifying MA users. Dentists can play a crucial role in the early detection of MA use and participate in the collaborative care of MA users. PMID- 20194389 TI - Combination treatments for Bell palsy can provide clinical benefit. PMID- 20194391 TI - Creating true customer service. PMID- 20194388 TI - Two-year clinical evaluation of packable and nanostructured resin-based composites placed with two techniques. AB - BACKGROUND: The authors conducted a two-year clinical trial to evaluate the effectiveness of two resin-based composite materials for Class II restorations placed according to two filling techniques. METHODS: Twenty-six patients received 105 Class II restorations, which the authors distributed randomly into three groups of 35 each. The resin-based composite restorations in group A were composed of average-density material (Ceram X mono [CXM], Dentsply DeTrey, Konstanz, Germany) placed according to the oblique incremental technique (OIT). Restorations in group B were composed of average- and high-density materials (CXM and SureFil [SF], Dentsply DeTrey) placed according to the modified incremental technique (MIT). Restorations in group C were composed of the high-density material (SF) placed with the OIT. The authors evaluated the restorations according to modified U.S. Public Health Service criteria. RESULTS: At the two year recall visit, 92 (88 percent) of 105 restorations were available for examination. Restorations in groups A, B and C had success rates of 96.7 percent (29 of 30 restorations), 96.8 percent (30 of 31) and 100 percent (31 of 31), respectively. Esthetic parameters revealed significant (P<.05) cavo-surface marginal discoloration in group B and a rougher surface in group A. With regard to functional parameters, one (3.3 percent) of 30 restorations in group A exhibited reparable changes in marginal integrity. CONCLUSIONS: Restorations in group B performed worse (P<.05) in terms of esthetic (cavosurface marginal discoloration) and functional (marginal integrity) parameters. Clinical effectiveness was highest in group C and lowest in group B. CLINICAL IMPLICATIONS: The two resin-based composite materials are effective in Class II clinical situations when placed with either the OIT or MIT. PMID- 20194392 TI - What are the ethical issues to consider in the design of my web site? PMID- 20194393 TI - For the dental patient...Sealing out tooth decay. PMID- 20194394 TI - Politics local, science global. PMID- 20194395 TI - Mental health care reforms in Latin America: An overview of mental health care reforms in Latin America and the Caribbean. AB - This new column provides an overview of mental health reforms in Latin America and the Caribbean. Progress has been particularly visible in countries that have implemented policies with strong political support (Brazil, Chile, and Belize, among others). However, lessons may be learned from the collective experience of a region that has faced multiple obstacles to reform. Available resources are still insufficient and inequitably distributed, reform implementation is not complete in most countries, and high levels of unmet need exist. Countries face new challenges related to growing psychosocial problems affecting children and adolescents and increasing violence, which require new responses from mental health services. PMID- 20194396 TI - Mental health care reforms in Europe: Rehabilitation and social inclusion of people with mental illness in Russia. AB - Long-established Medico-Social Expert Commissions (MSECs) play a pivotal role in the Russian mental health system. They act as gatekeepers to pensions, rehabilitation, and employment services. This column describes their role in encouraging or impeding the social inclusion of people with mental illness, drawing on findings of a three-year project in Sverdlovsk Oblast. In Russia the emphasis remains on medical aspects of treatment, without adequate consideration of social and occupational rehabilitation. Links with local employment services are weak. To promote social inclusion, steps must be taken to encourage and facilitate cooperation and collaboration between the MSECs, employment services, and medical services. PMID- 20194397 TI - Public-academic partnerships: Improving human resource provision for mental health in Somaliland. AB - Links between health institutions in countries with high incomes and those with incomes in the low-middle range are becoming more common, and benefits from these links are increasingly recognized. One such link is between Kings College Hospital and THET (Tropical Health and Education Trust) and their partners in Somaliland. The mental health part of the link consists of public service providers, educational institutions, and local nongovernmental organizations in Somaliland with mental health volunteers from the United Kingdom, led by the Institute of Psychiatry. The authors describe how careful planning has permitted the collaboration to evolve to allow mental health services to become embedded into activities that strengthen the Somaliland health sector. PMID- 20194398 TI - Mental health and the development agenda in Sub-Saharan Africa. AB - This article synthesizes the views of participants in two roundtables that were convened in Nairobi (March 2007) and London (July 2008) to identify key challenges to the prioritization of mental health in Africa and possible solutions. Participants included leading development experts and policy makers from head and country offices of international donors, national directors of mental health for several African countries, key mental health and public health professionals, epidemiologists, and an international nongovernmental organization. The challenges they identified to mainstreaming mental health include lack of understanding of the contribution of mental disorders to morbidity and mortality, competition for limited resources within health reform efforts, poor distribution of interventions and lack of inclusion of mental health among core generic health indicators, lack of economic research evidence, lack of a strategic approach to human resources planning, lack of partnerships with the social development sector, and mental health professionals' need for public health skills to effectively conduct national advocacy. Potential solutions include further investment in economic research, better strategic identification of the levers and entry points for integrating mental health into health sector reform plans, more vigorous engagement of mental health professionals in general health sector reforms, strengthening the linkage between mental health and social development, and intensive resource mobilization. In summary, partnerships, underpinned by collaborative training, research, and mutual dialogue with other health and nonhealth sectors, are needed. PMID- 20194399 TI - Pathways to inpatient mental health care among people with schizophrenia spectrum disorders in South Africa. AB - OBJECTIVE: This study examined service utilization patterns and pathways to specialist mental health services among individuals with schizophrenia spectrum disorders in the Western Cape, South Africa, an area that has undergone deinstitutionalization since the mid-1990s. METHODS: Individuals who were consecutively admitted to any of the three psychiatric hospitals in the Western Cape from February 2007 to January 2008 were interviewed. Data on demographic characteristics, psychiatric history, service utilization, and pathways to care were gathered from service users, their relatives or associates, and hospital files. Univariate and multivariate analyses examined differences between high- and low-frequency service users. RESULTS: Of the total sample (N=152) most were first seen at the primary care level (62%). However, very few received treatment at this level (26%), and many (22%) were admitted directly to the psychiatric hospital, bypassing other treatment options. These service utilization patterns differ from the requirements listed in the recently adopted Mental Health Care Act (2002), which states that unless a patient has been recently discharged, he or she should be admitted for 72 hours of observation before referral to psychiatric hospitals. Compared with low-frequency service users, high-frequency users were younger, had lower income, tended to rely more on disability benefits, and were more likely to bypass other levels of care and be admitted directly to the psychiatric hospital. Poor medication adherence was the most likely precipitant for the episode of illness among all users. CONCLUSIONS: The study highlights the inadequacy of current community mental health services in providing for the needs of people with severe mental illness. In South Africa, as in many other middle-income countries, there is an urgent need to develop community-based care. PMID- 20194400 TI - Service use for mental disorders and unmet need: results from the Israel Survey on Mental Health Among Adolescents. AB - OBJECTIVE: The first nationwide Israel Survey of Mental Health Among Adolescents was conducted in 2004-2005 with a representative sample of 957 adolescents aged 14-17 and their mothers to assess 12-month mental health service use, unmet needs, and associated factors. METHODS: Need for services was assessed by presence of a psychiatric disorder diagnosed with the Development and Well-Being Assessment inventory, plus clinicians' verification and additional questions on service use. RESULTS: In the past year, 22% of adolescents and 11% of their mothers consulted a service provider. Adolescents' help seeking in school was associated with residing in an Arab locality (odds ratio [OR]=1.6, 95% confidence interval [CI]=1.1-2.4) and with having single, divorced, or widowed parents (OR=2.9, CI=1.8-4.8); an employed father (OR=1.7, CI=1.0-2.8); and an internalizing disorder (OR=2.2, CI=1.2-3.9). Mothers' consultation was associated with residing in a Jewish or mixed locality (OR=18.1, CI=3.4-96.1); being single, divorced, or widowed (OR=3.1, CI=1.6-6.0); and having a child with an internalizing disorder (OR=6.4, CI=3.2-13.0), an externalizing disorder (OR=8.2, CI=2.9-23.0), or a learning disability (OR=4.5, CI=2.4-8.4). Overall, unmet needs were 66% and 60%, according to adolescents' and mothers' reports, respectively. According to mothers' reports, unmet needs were higher in Arab (91%) than in Jewish or mixed localities (54%). CONCLUSIONS: Adolescents and their mothers reported distinct service use patterns with particular implications for policy makers and health service providers. High rates of unmet needs, particularly among Arab-Israeli adolescents, need to be addressed. PMID- 20194401 TI - Reasons and determinants for not receiving treatment for common mental disorders. AB - OBJECTIVES: This study focused on patients in the general population whose anxiety or depressive disorder is untreated. It explored reasons for not receiving treatment and compared four groups of patients-three that did not receive treatment for different reasons (no problem perceived, no perceived need for care, and unmet need for care) and one that received treatment-regarding their predisposing, enabling, and need factors. METHODS: Cross-sectional data were used for 743 primary care patients with current anxiety or depressive disorder from the Netherlands Study of Depression and Anxiety (NESDA). Diagnoses were confirmed with the Composite International Diagnostic Interview. Patients' perception of the presence of a mental problem, perceived need for care, service utilization, and reasons for not receiving treatment were assessed with the Perceived Need for Care Questionnaire. RESULTS: Forty-three percent of the respondents with a six-month anxiety or depression diagnosis did not receive treatment. Twenty-one percent of all respondents with depression or anxiety expressed a need for care but did not receive any. Preferring to manage the problem themselves was the most common reason for respondents to avoid seeking treatment. There were no significant differences in clinical need factors between treated patients and untreated patients with a perceived need for care. Compared with patients in the other two untreated groups, untreated patients with a perceived need for care were more hindered in regard to symptom severity, functional disability, and psychosocial functioning. CONCLUSIONS: General practitioners should pay considerable attention to patients whose need for care is unmet. Furthermore, findings support the implementation of patient empowerment in mental health care in order to contribute to easily accessible and patient centered care. PMID- 20194402 TI - Inequities in medical follow-up for depression: a population-based study in Montreal. AB - OBJECTIVES: The aim of this study was to measure the quality of medical follow-up of depression in a universal-access health care system and identify its main correlates. METHODS: This retrospective cohort study of adult patients who received diagnoses of depression between April 2003 and March 2005 in Montreal used administrative data to measure the quality of medical follow-up within the first three months of diagnosis. Indicators of adequate follow-up care included having at least one outpatient visit to a family physician or a psychiatrist, the first follow-up visit within 30 days of diagnosis, more than half of follow-up visits with the same physician, and at least three follow-up visits. RESULTS: During the study period, 41,375 Montrealers aged 18 and older received a new diagnosis of depression. Among those, 90% (N=37,071) had at least one visit with a physician (family practitioner or psychiatrist) within the first three months of diagnosis, 59% (N=24,295) benefited from continuity with their usual provider, 50% (N=20,846) received a prompt follow-up visit, and 48% (N=19,819) had optimal contacts with practitioners. Medical follow-up was less adequate for older patients, male patients, patients living in very deprived neighborhoods, and patients with high morbidity levels. The quality of medical follow-up was better when both a family physician and a psychiatrist were involved. CONCLUSIONS: The results suggest that universal access facilitates optimal practitioner contacts during the acute treatment phase of depression. However, despite universal access, the findings revealed that some inequities persist. PMID- 20194403 TI - Mental disorders among homeless people admitted to a French psychiatric emergency service. AB - OBJECTIVE: The aim of this study was to identify factors associated with homelessness status among patients admitted to the psychiatric emergency ward of a French public teaching hospital over a six-year study period (2001-2006). METHODS: The study was based on a retrospective review of the psychiatric emergency ward's administrative and medical computer databases. Each emergency care episode had accompanying data that included demographic, financial, clinical, and management information. RESULTS: During this six-year study, the psychiatric service recorded 16,754 care episodes for 8,860 different patients, of which 591 were homeless (6.7%) and 8,269 were nonhomeless (93.3%). The mean+/ SD number of visits to the psychiatric emergency service was higher for homeless patients (4.9+/-12.3) than for nonhomeless patients (1.7+/-2.4) (p<.001). A total of 331 homeless patients (56.0%) had more than one care episode, whereas 2,180 (26.4%) of nonhomeless patients had more than one care episode. Factors associated with homelessness included being male, being single, and receiving financial assistance through government social programs. Schizophrenia (43.7%) and substance use disorders (31.0%) were the most common disorders among homeless patients. Aggressive behavior and violence were reported equally among homeless patients (3.5%) and nonhomeless patients (3.2%). Homeless patients were less likely than nonhomeless patients to be hospitalized after receiving care in the emergency ward (47.8% versus 51.1%) (p=.002). CONCLUSIONS: Although there is near universal access to free mental health care in France, study findings suggest that the quality and adequacy of subsequent care are not guaranteed. Multidisciplinary and collaborative solutions are needed to improve the management of mental health care for homeless patients. PMID- 20194404 TI - Regional differences in five-year mortality after a first episode of schizophrenia in Finland. AB - OBJECTIVE: This study analyzed gender-specific mortality of patients with a first episode of schizophrenic illness, particularly deaths from circulatory system diseases and suicide. METHODS: This was a nationwide register-based five-year follow-up study of all patients with onset of schizophrenia between 1995 and 2001. Standardized mortality ratios (SMRs) were calculated by matching patients' data with the general Finnish population on age, gender, and place of residence. RESULTS: During the five-year follow-up of 7,591 schizophrenia patients, 403 (5%) patients died. They had 4.45-fold higher mortality than the general population, and patients' mortality was significantly elevated in all age groups. The SMRs for all-cause mortality, circulatory system diseases, and suicides were higher for females than males in almost all age groups. The largest single unnatural cause of death was suicide. In natural causes of death, the SMR for ill-defined and unknown causes of death was almost 25. Total mortality, circulatory deaths, and suicides differed among the 20 hospital districts examined. Regional variations in SMRs were not associated with population characteristics or psychiatric health care resources of a hospital district. CONCLUSIONS: In this nationwide register-based study, excess mortality among persons with schizophrenia was clearly observed. Regional differences in mortality were evident, indicating a need for further research to understand the mortality gap and why it might vary regionally. PMID- 20194405 TI - Treatment intensity in child and adolescent mental health services and health care reform in Norway, 1998-2006. AB - OBJECTIVE: The aim of this study was to assess trends in treatment intensity in outpatient child and adolescent mental health services (CAMHS) in Norway from 1998 to 2006. During this period, Norway experienced substantial growth in available CAMHS resources. In 2002 hospital ownership was recentralized and health enterprises were established. METHODS: A nonexperimental, interrupted time series design was used to estimate trends adjusted for patient case mix and CAMHS size. From a panel of 37 CAMHS units, two subsamples were extracted. These patients (N=94,173) were aged 0-17 years and had participated in at least one treatment session with a therapist (direct consultation) during the year of observation. Direct and indirect consultations (appointments with cooperating services) were separately analyzed with multilevel regression analyses. RESULTS: Patient-level factors were the main sources of variation in number of consultations. CAMHS unit size was positively associated with direct consultations in both subsamples. A trend of increased direct consultations was observed in one subsample. Comparing the period 2002-2006 with 1998-2001 revealed a positive shift in treatment intensity for both consultation types in both subsamples. Trends and shifts differed between patient groups according to the main reason for referral and gender. CONCLUSIONS: The main health policy objective during the study period was increased access to mental health treatment. Both access and treatment intensity increased. The study was inconclusive about whether incentives related to CAMHS performance measurement caused treatment intensity to increase, specifically after the 2002 hospital ownership reform. PMID- 20194406 TI - Coercion and treatment satisfaction among involuntary patients. AB - OBJECTIVE: This study aimed to assess involuntary inpatients' satisfaction with treatment and explore how coercion and other factors are associated with satisfaction. METHODS: An observational prospective study was conducted in 67 acute wards in 22 hospitals in England. A total of 778 involuntary inpatients were recruited, and their satisfaction with treatment was assessed a week after admission and at the one-month, three-month, and one-year follow-ups. Perceived and documented coercion at admission and during hospital treatment, sociodemographic and clinical characteristics, and clinical improvement were tested as potential predictors of satisfaction. RESULTS: Mean scores on the Client's Assessment of Treatment Scale measuring satisfaction with treatment ranged from 5.5 to 6.0 (on a scale with possible scores ranging from 0 to 10) at different time points and improved significantly from admission to the follow ups. Patients who perceived less coercion at admission and during hospital treatment were more satisfied overall, whereas coercive measures documented in the medical records were not linked to satisfaction. Patients with more symptom improvement expressed higher levels of treatment satisfaction. CONCLUSIONS: Satisfaction with treatment among involuntary patients was associated with perceptions of coercion during admission and treatment, rather than with the documented extent of coercive measures. Interventions to reduce patients' perceived coercion might increase overall treatment satisfaction. PMID- 20194407 TI - Promoting recovery in long-term institutional mental health care: an international Delphi study. AB - OBJECTIVE: Service provision in psychiatric and social care is increasingly guided by recovery principles. However, little is known about the degree of consensus among stakeholders in diverse contexts on the components of care that most promote recovery. This study aimed to identify specific items of care that key stakeholders regard as most important in promoting recovery for people with longer-term mental health problems in institutional care, to measure consensus between and across stakeholder groups and countries, and to develop a conceptual framework of the most important domains of care. METHODS: Ten European countries in various stages of deinstitutionalization participated in a series of conventional three-round iterative Delphi exercises. In each country individuals in four separate expert groups (service users, mental health professionals, caregivers, and advocates) identified components of care that they considered important to recovery and then rated their group's suggestions in terms of importance. Median and consensus ratings were measured. High-ranking items were grouped into domains. RESULTS: A total of 4,098 separate items of care were proposed by the 40 participating groups. Eleven broad domains of care important for recovery were identified: social policy and human rights, social inclusion, self-management and autonomy, therapeutic interventions, governance, staffing, staff attitudes, institutional environment, postdischarge care, caregivers, and physical health care. Consensus between groups and countries was generally high, but some modest differences in priorities were noted. CONCLUSIONS: The most consistently highly rated consensus domain was therapeutic interventions. Domains and components of care related to recovery principles were also viewed as important across stakeholder groups. PMID- 20194408 TI - Factors associated with success of smoke-free initiatives in Australian psychiatric inpatient units. AB - OBJECTIVE: Smoking is the largest cause of preventable illness in the United States, the United Kingdom, Canada, Australia, and many other countries. Smokers with mental illness smoke significantly more than those without mental illness and therefore experience even greater smoke-related harm. Internationally, there is increasing pressure on psychiatric inpatient settings to adopt smoke-free policies. This study examined smoke-free policies across psychiatric inpatient settings in Australia and thereby identified factors that may contribute to the success or failure of smoke-free initiatives in order to better inform best practice in this important area. METHODS: Semistructured in-depth telephone interviews were conducted with 60 senior administrators and clinical staff with direct day-to-day experience with smoking activities in 99 adult psychiatric inpatient settings across Australia. Quantitative data were analyzed using descriptive statistical analysis and Pearson's chi square correlations measure of association. RESULTS: Factors associated with greater success of smoke-free initiatives were clear, consistent, and visible leadership; cohesive teamwork; extensive training opportunities for clinical staff; fewer staff smokers; adequate planning time; effective use of nicotine replacement therapies; and consistent enforcement of a smoke-free policy. CONCLUSIONS: A smoke-free policy is possible within psychiatric inpatient settings, but a number of core interlinking features are important for success and ongoing sustainability. PMID- 20194409 TI - The power of theater to promote individual recovery and social change. AB - Although theatrical activities are used in a variety of therapeutic settings, little attention has been paid to the ways that theater can enhance the recovery process and community integration for people living with psychiatric disabilities. Community-based theater involving people with psychiatric disabilities offers unique opportunities for personal growth, social connection, and advocacy efforts. This Open Forum posits that theater has the power to both facilitate individual recovery and improve the social conditions of people living with mental illness. Critical elements of theatrical activities that relate to processes of recovery and community integration are examined. Implications for future research and program development are discussed. PMID- 20194410 TI - Competence of interpreters in a South African psychiatric hospital in translating key psychiatric terms. AB - OBJECTIVE: Provision of good-quality interpreting services in mental health practice is essential, but little is known about interpreting psychiatric terms in low-and middle-income countries. This study examined the basic translation competencies of interpreters in a South African psychiatric hospital. METHODS: In the context of a larger study, six individuals who interpreted from English into Xhosa were asked to translate key psychiatric terms into Xhosa. These translations were back-translated by translators unfamiliar with psychiatric terminology, and back-translations were compared with the original English. RESULTS: Some interpreters had a very limited command of English. None had formal training in interpreting. Not all were familiar with core psychiatric concepts. Incorrect translations were often made. CONCLUSIONS: The competence level of the interpreters was not conducive to optimal care. The lack of formally trained interpreters in South Africa's public health services could lead to misdiagnosis and could compromise interventions. PMID- 20194411 TI - Linguistic competence of interpreters. PMID- 20194412 TI - Subjective life satisfaction and objective living conditions of patients with schizophrenia in Nigeria. AB - OBJECTIVE: This study explored life satisfaction among patients with schizophrenia in Nigeria and its relationship with objective living situation. METHODS: Adult outpatients (N=99) were assessed with the brief version of the World Health Organization Quality of Life Scale. They also rated aspects of their objective living situation corresponding to the satisfaction items. RESULTS: In contrast to their poor living conditions, most patients expressed a high level of life satisfaction. Items with the highest scores included satisfaction with self, "life meaningful," "enjoying life," and overall quality of life; items with the lowest scores included personal relationships, transport, money, and capacity to work. Of 12 satisfaction items, only four (sleep, daily living, relationships with individuals of the same gender, and condition of living place) were significantly correlated with objective measures. CONCLUSIONS: The correlation between subjective life satisfaction and objective living conditions of Nigerian patients with schizophrenia was poor. Efforts to enhance their quality of life should focus on improving work opportunities and transportation options. PMID- 20194413 TI - The schizophrenia care management program for family caregivers of Chinese patients with schizophrenia. AB - OBJECTIVES: This study tested the effectiveness of a schizophrenia care management program for family caregivers of Chinese patients with schizophrenia in Hong Kong. METHODS: A multisite controlled trial was conducted with 92 patient caregiver dyads. They were randomly assigned to either the schizophrenia care management program or to usual care. The patients' symptoms, functioning, and length of rehospitalization and their families' perceived social support, expressed emotion, and functioning were measured at recruitment and at one month and 15 months after the intervention. RESULTS: Compared with families in the usual care group, families in the schizophrenia care management program reported significantly greater improvements in families' and patients' functioning and caregivers' perceived social support and decreases in the number and length of patients' rehospitalization. CONCLUSIONS: The findings provide evidence that the multidisciplinary schizophrenia care program can improve the psychosocial functioning of patients and their families and social support of caregivers. PMID- 20194414 TI - CBT and recovery from psychosis in the ISREP trial: mediating effects of hope and positive beliefs on activity. AB - OBJECTIVE: Hope and positive self-concept have been highlighted as important components of recovery from psychosis. This study investigated the impact of a recovery-focused intervention on these dimensions, as well as their role as mediators of functional outcome. METHODS: Seventy-seven participants in recovery from psychosis were recruited into a randomized controlled trial of social recovery-focused cognitive-behavioral therapy (SRCBT). The primary outcome was hours spent weekly in structured activity. Hopelessness and beliefs about self and others were also assessed. RESULTS: SRCBT had a significant effect on improving positive beliefs about self and others. A trend was noted suggesting a main effect of SRCBT on reducing hopelessness among individuals with nonaffective psychosis. Increases in positive beliefs about self were found to mediate improvements in activity in the SRCBT group. CONCLUSIONS: Fostering hope and positive self-concept should be central components of recovery-oriented services and interventions. Modifying these dimensions may have a positive impact on functional outcome. PMID- 20194415 TI - To screen or not to screen for hepatitis C infection? PMID- 20194416 TI - Weighing the evidence for pediatric antipsychotic use. PMID- 20194418 TI - Cervical cancer screening of women with schizophrenia in Taiwan. PMID- 20194419 TI - Use of hospital emergency services by youths in out-of-home care. PMID- 20194420 TI - Structural analysis and predictive value of the rodent in vivo micronucleus assay results. AB - In vivo genotoxicity studies-shortly followed by carcinogenicity-are posing high demand for test-related recourses in terms of animal lives and resources. Among those, the micronucleus test in rodents is the most widely used as a follow-up to positive in vitro mutagenicity results; therefore, the development and extensive use of estimation techniques based on the concept of Structure-Activity Relationships-such as (Quantitative) Structure-Activity Relationships, read across and grouping of chemicals-might have a huge saving potential for this end point. In this paper, we present a newly derived compilation of Structural Alerts for the rodent in vivo micronucleus assay, thus providing a coarse-grain filter for preliminary screening of potentially in vivo mutagens. The compilation has been implemented as computerized rule of the expert system Toxtree and is freely available: http://ecb.jrc.ec.europa.eu/qsar/qsar-tools/index.php?c=TOXTREE. In addition, analyses on the performance of the micronucleus assay as pre-screening tool for carcinogenesis indicate that this assay is prone to give false-negative predictions and point to the need of improving the in vivo component of the present testing schemes. PMID- 20194421 TI - Gender-related differences in response to mutagens and carcinogens. AB - The incidences of many cancers can be very different in men and women. Besides differences in exposures to putative causative agents, it is plausible that both genetic and epigenetic effects play roles in these differences. In addition, gender-specific lifestyle and behavioural factors may modulate the effects of exposure to genotoxins. This commentary focuses on several aspects of gender related differences in responses to mutagens and carcinogens, including sensitivity to chromosome damage, the contribution of genotypic variation and the role of DNA methylation. It is concluded that the reasons for gender differences in cancer susceptibility remain largely unknown in many cases, and the subject deserves more attention and study. PMID- 20194422 TI - Toxic and genotoxic effects of oral administration of furan in mouse liver. AB - In this study, the effects induced in mouse liver by repeated oral exposure to furan were investigated. To this aim, the compound was given for 28 days by daily gavage to male B6C3F1 mice at 2, 4, 8 and 15 mg/kg body weight (b.w.)/day. Twenty four hours after last administration, animals were sacrificed, liver was excised and the following parameters were evaluated: histological alterations, apoptosis, cell proliferation, polyploidy, overall DNA methylation, gene expression and DNA damage by the immunofluorescence detection of foci of phosphorylated histone H2AX (gamma-H2AX) and by alkaline comet assays, using both standard and modified protocols for the detection of DNA cross links. Liver DNA damage by comet assays was also evaluated in mice receiving furan as a single acute oral dose (15, 100 or 250 mg/kg b.w.). Microscopic analysis of liver sections indicated that repeated oral administration of furan was moderately toxic, producing mild histological alterations with necrotic figures, apoptosis and limited regenerative cell proliferation. The flow cytometric analysis of DNA content in single-cell suspensions of liver cells showed a statistically significant increase in polyploid (8N) cells at the highest dose. No treatment-related changes in overall DNA methylation, gamma-H2AX foci, DNA strand breaks and cross links were observed at the end of the 4-week exposure period. However, several genes involved in DNA damage response, beyond stress and liver toxicity, were over-expressed in mice treated with the highest furan dose (15 mg/kg b.w./day). Acute administration of furan induced evident liver toxicity at the highest dose (250 mg/kg b.w.), which was associated with a significant increase of DNA damage in the alkaline comet assay and with a distinct decrease in gamma-ray-induced DNA migration. Overall, the results obtained suggest that the contribution of genotoxicity to the mechanism of furan carcinogenicity in mouse liver should not be dismissed. PMID- 20194424 TI - Bayesian estimation of divergence times from large sequence alignments. AB - Bayesian estimation of divergence times from molecular sequences relies on sophisticated Markov chain Monte Carlo techniques, and Metropolis-Hastings (MH) samplers have been successfully used in that context. This approach involves heavy computational burdens that can hinder the analysis of large phylogenomic data sets. Reliable estimation of divergence times can also be extremely time consuming, if not impossible, for sequence alignments that convey weak or conflicting phylogenetic signals, emphasizing the need for more efficient sampling methods. This article describes a new approach that estimates the posterior density of substitution rates and node times. The prior distribution of rates accounts for their potential autocorrelation along lineages, whereas priors on node ages are modeled with uniform densities. Also, the likelihood function is approximated by a multivariate normal density. The combination of these components leads to convenient mathematical simplifications, allowing the posterior distribution of rates and times to be estimated using a Gibbs sampling algorithm. The analysis of four real-world data sets shows that this sampler outperforms the standard MH approach and demonstrates the suitability of this new method for analyzing large and/or difficult data sets. PMID- 20194423 TI - Gene family size conservation is a good indicator of evolutionary rates. AB - The evolution of duplicate genes has been a topic of broad interest. Here, we propose that the conservation of gene family size is a good indicator of the rate of sequence evolution and some other biological properties. By comparing the human-chimpanzee-macaque orthologous gene families with and without family size conservation, we demonstrate that genes with family size conservation evolve more slowly than those without family size conservation. Our results further demonstrate that both family expansion and contraction events may accelerate gene evolution, resulting in elevated evolutionary rates in the genes without family size conservation. In addition, we show that the duplicate genes with family size conservation evolve significantly more slowly than those without family size conservation. Interestingly, the median evolutionary rate of singletons falls in between those of the above two types of duplicate gene families. Our results thus suggest that the controversy on whether duplicate genes evolve more slowly than singletons can be resolved when family size conservation is taken into consideration. Furthermore, we also observe that duplicate genes with family size conservation have the highest level of gene expression/expression breadth, the highest proportion of essential genes, and the lowest gene compactness, followed by singletons and then by duplicate genes without family size conservation. Such a trend accords well with our observations of evolutionary rates. Our results thus point to the importance of family size conservation in the evolution of duplicate genes. PMID- 20194425 TI - Structural considerations in the fitness landscape of a virus. AB - Viral fitness is determined by replication within hosts and transmission between them. We examine how pleiotropic mutations that have antagonistic effects (i.e., antibody evasion vs. receptor binding) on viral replication within hosts can impact viral immune escape in the host population. When the host population is vaccinated, the virus escapes from passive immunity by mutations in the antibody binding region on the surface of the target protein. However, the reduced ability of the antibody to bind the virus is often accompanied by a reduced ability of the virus to bind the cell receptor because the antibody-binding region overlaps with the receptor-binding domain (RBD). The types of permitted mutations are limited. To investigate the causal relation between a mutation in a viral genome and adaptive evolution of a viral population, we developed a mathematical model that describes the population dynamics of viruses, antibodies, and normal/infected cells within a host. The coefficients describe the binding affinity between the virus and the induced antibody and that between the virus and its receptor. Our knowledge-based index enables us to estimate the effect of a mutation in a binding region on the binding affinity. Using population genetic theory, we evaluated the probability that a mutant is fixed in a host population. The mutations that can be fixed with high probabilities may determine how long a vaccine remains effective. We simulate the adaptive evolution of coronavirus, the etiological agent of severe acute respiratory syndrome, and show that some of mutations in the RBD may have high fixation probabilities in the vaccinated host population. PMID- 20194427 TI - Phylogenomic evidence for separate acquisition of plastids in cryptophytes, haptophytes, and stramenopiles. AB - According to the chromalveolate hypothesis (Cavalier-Smith T. 1999. Principles of protein and lipid targeting in secondary symbiogenesis: euglenoid, dinoflagellate, and sporozoan plastid origins and the eukaryote family tree. J Eukaryot Microbiol 46:347-366), the four eukaryotic groups with chlorophyll c containing plastids originate from a single photosynthetic ancestor, which acquired its plastids by secondary endosymbiosis with a red alga. So far, molecular phylogenies have failed to either support or disprove this view. Here, we devise a phylogenomic falsification of the chromalveolate hypothesis that estimates signal strength across the three genomic compartments: If the four chlorophyll c-containing lineages indeed derive from a single photosynthetic ancestor, then similar amounts of plastid, mitochondrial, and nuclear sequences should allow to recover their monophyly. Our results refute this prediction, with statistical support levels too different to be explained by evolutionary rate variation, phylogenetic artifacts, or endosymbiotic gene transfer. Therefore, we reject the chromalveolate hypothesis as falsified in favor of more complex evolutionary scenarios involving multiple higher order eukaryote-eukaryote endosymbioses. PMID- 20194426 TI - Birth-and-death long-term evolution promotes histone H2B variant diversification in the male germinal cell line. AB - The rich diversity within each of the five histone families (H1, H2A, H2B, H3, and H4) can hardly be reconciled with the notion of homogenizing evolution. The prevalence of birth-and-death long-term evolution over concerted evolution has already been demonstrated in the linker histone H1 family as well as for the H2A, H3, and H4 core histone families. However, information about histone H2B is lacking. In the present work, we have analyzed the diversity of the members of this histone family across different eukaryotic genomes and have characterized the mechanisms involved in their long-term evolution. Our results reveal that, quite in contrast with other histones, H2B variants are subject to a very rapid process of diversification that primarily affects the male germinal cell lineage and involves their functional specialization probably as a consequence of neofunctionalization and subfunctionalization events after gene duplication. The overall parallelism observed between the molecular phylogenies and the relationships among the electrostatic potentials of the different variants suggests that the latter may have played a major structural selective constraint during H2B evolution. It thus seems that the reorganization of chromatin structure during spermiogenesis might have affected the evolutionary constraints driving histone H2B evolution, leading to an increase in diversity. PMID- 20194428 TI - Rooting the ribosomal tree of life. AB - The origin of the genetic code and the rooting of the tree of life (ToL) are two of the most challenging problems in the study of life's early evolution. Although both have been the focus of numerous investigations utilizing a variety of methods, until now, each problem has been addressed independently. Typically, attempts to root the ToL have relied on phylogenies of genes with ancient duplications, which are subject to artifacts of tree reconstruction and horizontal gene transfer, or specific physiological characters believed to be primitive, which are often based on subjective criteria. Here, we demonstrate a unique method for rooting based on the identification of amino acid usage biases comprising the residual signature of a more primitive genetic code. Using a phylogenetic tree of concatenated ribosomal proteins, our analysis of amino acid compositional bias detects a strong and unique signal associated with the early expansion of the genetic code, placing the root of the translation machinery along the bacterial branch. PMID- 20194429 TI - Genome-wide evidence for efficient positive and purifying selection in Capsella grandiflora, a plant species with a large effective population size. AB - Recent studies comparing genome-wide polymorphism and divergence in Drosophila have found evidence for a surprisingly high proportion of adaptive amino acid fixations, but results for other taxa are mixed. In particular, few studies have found convincing evidence for adaptive amino acid substitution in plants. To assess the generality of this finding, we have sequenced 257 loci in the outcrossing crucifer Capsella grandiflora, which has a large effective population size and low population structure. Using a new method that jointly infers selective and demographic effects, we estimate that 40% of amino acid substitutions were fixed by positive selection in this species, and we also infer a low proportion of slightly deleterious amino acid mutations. We contrast these estimates with those for a similar data set from the closely related Arabidopsis thaliana and find significantly higher rates of adaptive evolution and fewer nearly neutral mutations in C. grandiflora. In agreement with results for other taxa, genes involved in reproduction show the strongest evidence for positive selection in C. grandiflora. Taken together, these results imply that both positive and purifying selection are more effective in C. grandiflora than in A. thaliana, consistent with the contrasting demographic history and effective population sizes of these species. PMID- 20194430 TI - Another systemic impact of inhaled diesel exhaust particles. PMID- 20194431 TI - Cancer patients' experiences of using complementary therapies: polarization and integration. AB - OBJECTIVE: The use of complementary therapies by people with cancer is commonplace. In a recent synthesis of 26 qualitative studies of patients' experiences of complementary therapy use after a diagnosis of cancer, the emergent theme of 'polarization' was the most notable barrier to a positive experience of complementary therapies. In this paper, we explore the two synthesis concepts of 'polarization' and 'integration', and their relationship to health service policies and guidelines on integrated services. METHODS: A systematic literature search and a meta-ethnography to synthesize key concepts. RESULTS: The majority of patients who used complementary therapies after a diagnosis of cancer wanted to be certain that the therapies were not interfering with their conventional cancer treatment. They valued the therapies in wider terms including: taking 'a niche of control', relieving symptoms, improving wellbeing, and promoting reconnection and social interaction. The emergent theme of 'polarization' suggested that conventional physicians who are perceived to be poorly informed or negative about complementary approaches induce patient anxiety, safety concerns, and difficulties in access. They may compromise their therapeutic relationship and, rarely, they may trigger patients to abandon conventional medicine altogether. In contrast, integrated advice and/or services were highly valued by patients, although some patients preferred their complementary health care to be provided in a non-medicalized environment. CONCLUSIONS: Our findings suggest that the current polarized situation is unhelpful to patients, detrimental to therapeutic relationships and may occasionally be dangerous. They indicate that complementary therapies, in a supportive role, should be integrated into mainstream cancer care. PMID- 20194432 TI - Impact of devolution of health care in the UK: provider challenge in England and provider capture in Wales, Scotland and Northern Ireland? PMID- 20194433 TI - The homeobox protein Prox1 is a negative modulator of ERR{alpha}/PGC-1{alpha} bioenergetic functions. AB - Estrogen-related receptor alpha (ERRalpha) and proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) play central roles in the transcriptional control of energy homeostasis, but little is known about factors regulating their activity. Here we identified the homeobox protein prospero-related homeobox 1 (Prox1) as one such factor. Prox1 interacts with ERRalpha and PGC-1alpha, occupies promoters of metabolic genes on a genome-wide scale, and inhibits the activity of the ERRalpha/PGC-1alpha complex. DNA motif analysis suggests that Prox1 interacts with the genome through tethering to ERRalpha and other factors. Importantly, ablation of Prox1 and ERRalpha have opposite effects on the respiratory capacity of liver cells, revealing an unexpected role for Prox1 in the control of energy homeostasis. PMID- 20194435 TI - Personal genome sequencing: current approaches and challenges. AB - The revolution in DNA sequencing technologies has now made it feasible to determine the genome sequences of many individuals; i.e., "personal genomes." Genome sequences of cells and tissues from both normal and disease states have been determined. Using current approaches, whole human genome sequences are not typically assembled and determined de novo, but, instead, variations relative to a reference sequence are identified. We discuss the current state of personal genome sequencing, the main steps involved in determining a genome sequence (i.e., identifying single-nucleotide polymorphisms [SNPs] and structural variations [SVs], assembling new sequences, and phasing haplotypes), and the challenges and performance metrics for evaluating the accuracy of the reconstruction. Finally, we consider the possible individual and societal benefits of personal genome sequences. PMID- 20194434 TI - Isoform-specific p73 knockout mice reveal a novel role for delta Np73 in the DNA damage response pathway. AB - Mice with a complete deficiency of p73 have severe neurological and immunological defects due to the absence of all TAp73 and DeltaNp73 isoforms. As part of our ongoing program to distinguish the biological functions of these isoforms, we generated mice that are selectively deficient for the DeltaNp73 isoform. Mice lacking DeltaNp73 (DeltaNp73(-/-) mice) are viable and fertile but display signs of neurodegeneration. Cells from DeltaNp73(-/-) mice are sensitized to DNA damaging agents and show an increase in p53-dependent apoptosis. When analyzing the DNA damage response (DDR) in DeltaNp73(-/-) cells, we discovered a completely new role for DeltaNp73 in inhibiting the molecular signal emanating from a DNA break to the DDR pathway. We found that DeltaNp73 localizes directly to the site of DNA damage, can interact with the DNA damage sensor protein 53BP1, and inhibits ATM activation and subsequent p53 phosphorylation. This novel finding may explain why human tumors with high levels of DeltaNp73 expression show enhanced resistance to chemotherapy. PMID- 20194436 TI - KDM7 is a dual demethylase for histone H3 Lys 9 and Lys 27 and functions in brain development. AB - Methylation of histone H3 Lys 9 and Lys 27 (H3K9 and H3K27) is associated with transcriptional silencing. Here we show that KDM7, a JmjC domain-containing protein, catalyzes demethylation of both mono- or dimethylated H3K9 and H3K27. Inhibition of KDM7 orthologs in zebrafish resulted in developmental brain defects. KDM7 interacts with the follistatin gene locus, and KDM7 depletion in mammalian neuronal cells suppressed follistatin gene transcription in association with increased levels of dimethylated H3K9 and H3K27. Our findings identify KDM7 as a dual demethylase for H3K9 and H3K27 that functions as an eraser of silencing marks on chromatin during brain development. PMID- 20194437 TI - A degron created by SMN2 exon 7 skipping is a principal contributor to spinal muscular atrophy severity. AB - Spinal muscular atrophy (SMA) is caused by homozygous survival of motor neurons 1 (SMN1) gene deletions, leaving a duplicate gene, SMN2, as the sole source of SMN protein. However, most of the mRNA produced from SMN2 pre-mRNA is exon 7-skipped ( approximately 80%), resulting in a highly unstable and almost undetectable protein (SMNDelta7). We show that this splicing defect creates a potent degradation signal (degron; SMNDelta7-DEG) at SMNDelta7's C-terminal 15 amino acids. The S270A mutation inactivates SMNDelta7-DEG, generating a stable SMNDelta7 that rescues viability of SMN-deleted cells. These findings explain a key aspect of the SMA disease mechanism, and suggest new treatment approaches based on interference with SMNDelta7-DEG activity. PMID- 20194438 TI - Histone deacetylases 1 and 2 act in concert to promote the G1-to-S progression. AB - Histone deacetylases (HDACs) regulate gene expression by deacetylating histones and also modulate the acetylation of a number of nonhistone proteins, thus impinging on various cellular processes. Here, we analyzed the major class I enzymes HDAC1 and HDAC2 in primary mouse fibroblasts and in the B-cell lineage. Fibroblasts lacking both enzymes fail to proliferate in culture and exhibit a strong cell cycle block in the G1 phase that is associated with up-regulation of the CDK inhibitors p21(WAF1/CIP1) and p57(Kip2) and of the corresponding mRNAs. This regulation is direct, as in wild-type cells HDAC1 and HDAC2 are bound to the promoter regions of the p21 and p57 genes. Furthermore, analysis of the transcriptome and of histone modifications in mutant cells demonstrated that HDAC1 and HDAC2 have only partly overlapping roles. Next, we eliminated HDAC1 and HDAC2 in the B cells of conditionally targeted mice. We found that B-cell development strictly requires the presence of at least one of these enzymes: When both enzymes are ablated, B-cell development is blocked at an early stage, and the rare remaining pre-B cells show a block in G1 accompanied by the induction of apoptosis. In contrast, elimination of HDAC1 and HDAC2 in mature resting B cells has no negative impact, unless these cells are induced to proliferate. These results indicate that HDAC1 and HDAC2, by normally repressing the expression of p21 and p57, regulate the G1-to-S-phase transition of the cell cycle. PMID- 20194439 TI - Spermatogenesis rescue in a mouse deficient for the ubiquitin ligase SCF{beta} TrCP by single substrate depletion. AB - beta-TrCP, the substrate recognition subunit of a Skp1-Cul1-F-box (SCF) ubiquitin ligase, is ubiquitously expressed from two distinct paralogs, targeting many regulatory proteins for proteasomal degradation. We generated inducible beta-TrCP hypomorphic mice and found that they are surprisingly healthy, yet have a severe testicular defect. We show that the two beta-TrCP paralogs have a nonredundant role in spermatogenesis. The testicular defect is tightly associated with cell adhesion failure within the seminiferous tubules and is fully reversible upon beta-TrCP restoration. Remarkably, testicular depletion of a single beta-TrCP substrate, Snail1, rescued the adhesion defect and restored spermatogenesis. Our studies highlight an unexpected functional reserve of this central E3, as well as a bottleneck in a specific tissue: a single substrate whose stabilization is incompatible with testicular differentiation. PMID- 20194440 TI - miR-125b-2 is a potential oncomiR on human chromosome 21 in megakaryoblastic leukemia. AB - Children with trisomy 21/Down syndrome (DS) are at high risk to develop acute megakaryoblastic leukemia (DS-AMKL) and the related transient leukemia (DS-TL). The factors on human chromosome 21 (Hsa21) that confer this predisposing effect, especially in synergy with consistently mutated transcription factor GATA1 (GATA1s), remain poorly understood. Here, we investigated the role of Hsa21 encoded miR-125b-2, a microRNA (miRNA) overexpressed in DS-AMKL/TL, in hematopoiesis and leukemogenesis. We identified a function of miR-125b-2 in increasing proliferation and self-renewal of human and mouse megakaryocytic progenitors (MPs) and megakaryocytic/erythroid progenitors (MEPs). miR-125b-2 overexpression did not affect megakaryocytic and erythroid differentiation, but severely perturbed myeloid differentiation. The proproliferative effect of miR 125b-2 on MEPs accentuated the Gata1s mutation, whereas growth of DS-AMKL/TL cells was impaired upon miR-125b repression, suggesting synergism during leukemic transformation in GATA1s-mutated DS-AMKL/TL. Integrative transcriptome analysis of hematopoietic cells upon modulation of miR-125b expression levels uncovered a set of miR-125b target genes, including DICER1 and ST18 as direct targets. Gene Set Enrichment Analysis revealed that this target gene set is down-regulated in DS-AMKL patients highly expressing miR-125b. Thus, we propose miR-125b-2 as a positive regulator of megakaryopoiesis and an oncomiR involved in the pathogenesis of trisomy 21-associated megakaryoblastic leukemia. PMID- 20194443 TI - Exercise in ankylosing spondylitis: discrepancies between recommendations and reality. AB - OBJECTIVE: To determine the type and extent of exercise used by an ankylosing spondylitis (AS) cohort and to examine patients' perceptions of exercise. Recommendations for the management of AS identify exercise as the cornerstone of comprehensive management. METHODS: An exercise inventory questionnaire and the Exercise Benefits and Barriers Scale (EBBS) were administered to patients attending the AS clinic of a large teaching hospital. Benefits and barriers subscales of the EBBS were analyzed to identify the perceived benefits of, and barriers to, exercise. Higher benefits scores (range 29-116) indicate a more positive perception of exercise. Higher barriers scores (range 14-56) indicate a greater perception of barriers to exercise. RESULTS: Sixty-one patients with AS completed the questionnaires. Mean age was 38.0 years, and mean disease duration was 14.7 years. Walking (3 times/week) and stretching (3 times/week) were the most commonly reported types of exercise and were reported in 35.0% and 32.8%, respectively. The mean benefits EBBS score was 87.1 +/- 12.5. The most frequently reported benefits of exercise were that it "increases my level of physical fitness" (96.4%) and "improves functioning of my cardiovascular system" (96.4%). The mean barriers EBBS score was 29.2 +/- 5.3, and the most frequently reported barrier to exercise was that it "tires me" (71.4%). CONCLUSION: Patients with AS perceive the benefits of exercise, with average EBBS benefits scores comparable to historical controls with similar conditions. Despite positive perceptions, the majority of patients with AS did not report participating in exercise on a frequent basis. PMID- 20194441 TI - Differential activation and antagonistic function of HIF-{alpha} isoforms in macrophages are essential for NO homeostasis. AB - Hypoxic response and inflammation both involve the action of the hypoxia inducible transcription factors HIF-1alpha and HIF-2alpha. Previous studies have revealed that both HIF-alpha proteins are in a number of aspects similarly regulated post-translationally. However, the functional interrelationship of these two isoforms remains largely unclear. The polarization of macrophages controls functionally divergent processes; one of these is nitric oxide (NO) production, which in turn is controlled in part by HIF factors. We show here that the HIF-alpha isoforms can be differentially activated: HIF-1alpha is induced by Th1 cytokines in M1 macrophage polarization, whereas HIF-2alpha is induced by Th2 cytokines during an M2 response. This differential response was most evident in polarized macrophages through HIF-alpha isoform-specific regulation of the inducible NO synthase gene by HIF-1alpha, and the arginase1 gene by HIF-2alpha. In silico modeling predicted that regulation of overall NO availability is due to differential regulation of HIF-1alpha versus HIF-2alpha, acting to, respectively, either increase or suppress NO synthesis. An in vivo model of endotoxin challenge confirmed this; thus, these studies reveal that the two homologous transcription factors, HIF-1alpha and HIF-2alpha, can have physiologically antagonistic functions, but that their antiphase regulation allows them to coordinately regulate NO production in a cytokine-induced and transcription-dependent fashion. PMID- 20194444 TI - Thumb involvement in Raynaud's phenomenon as an indicator of underlying connective tissue disease. AB - OBJECTIVE: To conduct a retrospective study to assess whether the degree of thumb involvement differs between primary Raynaud's phenomenon (PRP) and secondary Raynaud's phenomenon (SRP). METHODS: Thermography images from all patients attending Salford Royal Hospital and referred for thermography for assessment of RP between 2004 and 2006 were retrospectively reviewed. A distal dorsal difference (DDD) of -1 degrees C or less between the fingertips and dorsum of the hand (fingers cooler) at 23 degrees C was considered clinically relevant. The worse score (the lower score, i.e., the more negative value) from each pair of digits was considered for analysis. RESULTS: One hundred seventy patients fulfilled the study criteria. DDD at 23 degrees C for the thumbs were significantly higher (digital tips warmer) compared with other digits (p < 0.001) in both PRP and SRP. All digits were significantly warmer in PRP compared to SRP with the exception of the thumbs. The proportion of patients with clinically relevant involvement of thumbs was significantly higher in SRP compared to PRP (p = 0.003) and this difference was more pronounced in the thumbs compared with other digits. CONCLUSION: Although the median temperature gradient along the thumb was not significantly different between SRP and PRP, the thumb is more likely to be involved in SRP than in PRP. Thumb involvement is one of a number of clinical indicators that should alert the clinician to the possibility of an underlying connective tissue disease/disorder. PMID- 20194442 TI - De novo telomere formation is suppressed by the Mec1-dependent inhibition of Cdc13 accumulation at DNA breaks. AB - DNA double-strand breaks (DSBs) are a threat to cell survival and genome integrity. In addition to canonical DNA repair systems, DSBs can be converted to telomeres by telomerase. This process, herein termed telomere healing, endangers genome stability, since it usually results in chromosome arm loss. Therefore, cells possess mechanisms that prevent the untimely action of telomerase on DSBs. Here we report that Mec1, the ATR ortholog, couples the detection of DNA ends with the inhibition of telomerase. Mec1 inhibits telomere healing by phosphorylating Cdc13 on its S306 residue, a phosphorylation event that suppresses Cdc13 accumulation at DSBs. Conversely, telomere addition at accidental breaks is promoted by Pph3, the yeast protein phosphatase 4 (PP4). Pph3 is itself modulated by Rrd1, an activator of PP2A family phosphatases. Rrd1 and Pph3 oppose Cdc13 S306 phosphorylation and are necessary for the efficient accumulation of Cdc13 at DNA breaks. These studies therefore identify a mechanism by which the ATR family of kinases enforces genome integrity, and a process that underscores the contribution of Cdc13 to the fate of DNA ends. PMID- 20194445 TI - Comparison of the construct validity and sensitivity to change of the visual analog scale and a modified rating scale as measures of patient global assessment in rheumatoid arthritis. AB - OBJECTIVE: Patient global assessment (PGA) is commonly measured using a visual analog scale (VAS). The VAS asks patients to integrate many dimensions of rheumatoid arthritis (RA) activity, yet its scope is poorly defined and its endpoints are vague. We investigated whether a modified Rating Scale that used marker states and more defined endpoints would provide a more valid measure of PGA. METHODS: In our prospective longitudinal study, 164 patients with active RA rated their global arthritis activity using the VAS and Rating Scale before and after treatment. To compare construct validity, we correlated each score with 2 reference measures of RA activity, the 28-joint count Disease Activity Score (DAS28) and the physician global assessment, and examined how each measure was associated with different aspects of RA activity, including pain, functioning, and depressive symptoms, in multivariate regression analyses. We also examined sensitivity to change. RESULTS: Both measures were correlated with the DAS28 (r = 0.39 for VAS; r = 0.35 for Rating Scale) and physician global assessment (r = 0.41 for VAS; r = 0.26 for Rating Scale) at the baseline visit. Pain and depressive symptoms had the strongest association with the VAS, while functional limitations and depressive symptoms had the strongest association with the Rating Scale. Residual analysis showed no differences in heterogeneity of patients' ratings. VAS was more sensitive to change than the Rating Scale (standardized response means of 0.55 and 0.45). CONCLUSION: As measures of PGA, the VAS and Rating Scale had comparable construct validity, but differed in which aspects of arthritis activity influenced scores. VAS was more sensitive to change. PMID- 20194446 TI - Correlation between serum anti-C1q antibody levels and renal pathological characteristics and prognostic significance of anti-C1q antibody in lupus nephritis. AB - OBJECTIVE: To investigate the relationship between serum anti-C1q antibody levels and renal pathological characteristics in lupus nephritis as well as the prognostic significance of serum anti-C1q antibody. METHODS: Seventy-three patients with biopsy-proven lupus nephritis were enrolled. Anti-C1q antibody was measured in serum samples taken within 7 days before renal biopsy and remeasured at the end of the first and the third month after treatment. All patients were followed at least once a month for 3 months. A cross-sectional study analyzed the relationship between serum anti-C1q antibody levels and renal histopathology and nephritic activity, while a longitudinal study evaluated the prognostic significance of anti-C1q antibody levels in lupus nephritis. RESULTS: Fifty-eight of 73 patients (79.5%) were reported as having positive baseline serum anti-C1q antibody, with a mean level of 95.3 (+/- 55.2) U/ml. Significant differences were found in serum anti-C1q antibody levels between each World Health Organization (WHO) classification of lupus nephritis. The serum anti-C1q antibody level of WHO class IV was the highest. Serum anti-C1q antibody was positively correlated with the active and chronic indices in renal pathology. Patients with persistent high levels or increased titers of serum anti-C1q antibody tended to develop delayed remission in nephropathy. Serum anti-C1q antibody levels before and after treatment were relevant to renal remission, but serum anti-C1q antibody at the end of the third month after treatment was a stronger predictor for the prognosis after adjustment in the Cox's proportional hazards regression model. CONCLUSION: Serum anti-C1q antibody is a valuable noninvasive biological marker for evaluation of renal involvement and lupus prognosis. PMID- 20194447 TI - Familial Mediterranean fever in children presenting with attacks of fever alone. AB - OBJECTIVE: Familial Mediterranean fever (FMF) is an inherited disease characterized by attacks of febrile polyserositis. In children, attacks of fever alone, or with headache and malaise, may precede other forms of attacks. Our objective was clinical and genetic characterization of FMF and its development in pediatric patients who first presented with attacks of fever alone. METHODS: Clinical characterization and MEFV genotype of all FMF patients < 16 years of age at disease onset and first presenting with attacks of fever alone were analyzed and compared for age, sex, and disease duration with matched FMF patients presenting with serositis at the onset of the disease. RESULTS: There were 814 patients with FMF in our registry. Fifty patients formed the study group and 234 patients the control group. In the study group, the first (febrile) attacks appeared at a younger age than in the control group (1.7 +/- 1.6 yrs vs 5.0 +/- 4.1 yrs, respectively; p < 0.0001), diagnosis was made earlier (4.2 +/- 2.7 yrs vs 6.7 +/- 4.1 yrs; p < 0.0001), despite a trend for a longer delay in diagnosis. In the study group, attacks were shorter (1.6 +/- 0.8 days vs 2.1 +/- 1.0 days; p = 0.023) and homozygosity to the M694V mutation was more prevalent (46% vs 31%; p = 0.03). Attack rate, colchicine dose, and the MEFV mutation carrier rates were comparable between the groups. In 40/50 (80%) of the patients with fever alone, serositis had developed over a course of 2.9 +/- 2.2 years after disease onset. CONCLUSION: FMF in young children may begin with attacks of fever alone, but it progresses to typical FMF disease over the next 2.9 +/- 2.2 years. Our study demonstrates that clinical heterogeneity at presentation is more likely to indicate a feature of a disease in development, rather than to mark distinct phenotypes of FMF. PMID- 20194448 TI - Efficacy and safety of retreatment in patients with rheumatoid arthritis with previous inadequate response to tumor necrosis factor inhibitors: results from the SUNRISE trial. AB - OBJECTIVE: To assess the efficacy and safety of 1 versus 2 courses of rituximab over 48 weeks in patients with rheumatoid arthritis (RA). METHODS: Adult patients taking methotrexate with a previous inadequate response to > or = 1 tumor necrosis factor inhibitor received 1 course of open-label rituximab (2 x 1000 mg IV) at baseline. From Week 24, patients were randomized to receive an additional course of retreatment with rituximab or placebo. Efficacy responses at Week 48 relative to baseline were assessed. RESULTS: Of 559 patients who received the open-label first course of rituximab, 475 patients were randomized to a second course (rituximab retreatment: n = 318, placebo retreatment: n = 157). Relative to baseline, patients who took rituximab during retreatment had significantly improved efficacy at Week 48 compared to patients who took a placebo during retreatment [American College of Rheumatology (ACR20) criteria, 54% vs 45%, p = 0.02; change in Disease Activity Score-28 mean -1.9 vs -1.5, p = 0.006]. Differences in efficacy between groups were first observed following Weeks 28-32. Worsening of most components of the ACR core set occurred in the placebo retreated patients with relative maintenance of these measures in rituximab retreated patients. Randomized patients who had achieved week 24 ACR responses following the first course had greater odds of losing response if retreated with placebo (odds ratios for ACR20, ACR50, ACR70: 2.09, 2.03, and 4.09, respectively). Following retreatment, the proportion of patients experiencing any adverse events (AE), serious AE, infections, and serious infections were comparable between the rituximab and placebo retreatment groups. CONCLUSION: Two courses of rituximab about 6 months apart resulted in improved and sustained efficacy at 1 year, compared with 1 course, with a similar safety profile. PMID- 20194449 TI - Effectiveness and toxicity of methotrexate in juvenile idiopathic arthritis: comparison of 2 initial dosing regimens. AB - OBJECTIVE: To compare the incidence of liver toxicity and clinical response between 2 initial dosing regimens of methotrexate (MTX) for treatment of juvenile idiopathic arthritis (JIA). METHODS: Clinical and laboratory data were abstracted from the medical records of 220 children newly prescribed MTX from the same geographic region. One cohort received initial doses of MTX > 0.5 mg/kg/week ("high-dose") and one cohort received initial doses of MTX or= 100) found no association between the TNF-alpha -308 A/G polymorphism and responsiveness to TNF blockers. The overall metaanalysis showed that the TNF-alpha -238 A/G polymorphism was not associated with the responsiveness of RA patients to TNF blockers, and stratification by TNF blocker revealed that the TNF-alpha -238 A/G polymorphism was associated with response of infliximab (OR 0.441, 95% CI 0.203-0.609, p = 0.039). SE status was found not to be associated with response to TNF blockers. CONCLUSION: Metaanalysis of available data revealed an association between treatment response to infliximab and the TNF-alpha -238 A/G polymorphism, but no associations between treatment response and the TNF-alpha -308 A/G polymorphism or SE status. PMID- 20194456 TI - G-less cassette in vitro transcription using HeLa cell nuclear extracts. AB - The G-less cassette is a 365-nucleotide (nt) segment of DNA lacking guanine (G) residues on the nontemplate strand. In principle, a full-length transcript can be generated in an in vitro reaction lacking GTP, an omission that leads to suppression of most random, nonspecific transcription throughout the plasmid. This method, like runoff transcription, generates radiolabeled RNA products, directly bypassing the necessity and extra time required to perform primer extension or other indirect mRNA product measurements. Unlike runoff transcription, which requires a cleaved end, the G-less assay can be performed on a circular, supercoiled plasmid, which in many systems is a more efficient template. In practice, most crude systems, such as HeLa nuclear extracts, contain low amounts of contaminating GTP that lead to small amounts of background transcription and occasionally can cause random upstream transcription to read through the G-less cassette. To minimize these artifacts, the reaction generally contains 3'-O-Me-GTP, a chain-terminating analog of GTP that causes transcription to cease when it is incorporated into a growing transcript, much like the dideoxy analogs used in DNA sequencing. The reaction products are cleaved with T1 RNase, which cleaves RNAs at G residues, further reducing background transcription; the G-less mRNA remains intact, whereas small random RNAs are digested. PMID- 20194455 TI - Clinical activity after 12 weeks of treatment with nonbiologics in early rheumatoid arthritis may predict articular destruction 2 years later. AB - OBJECTIVE: To investigate earlier prediction of future articular destruction in patients with early rheumatoid arthritis (RA). METHODS: We randomly allocated patients with RA with disease duration < 2 years to different nonbiologic disease modifying antirheumatic drug (DMARD) therapies in a double-blind trial. Progression of articular destruction over the 96-week treatment period was assessed using the modified Sharp method. RESULTS: Progression of articular destruction correlated more strongly with the American College of Rheumatology (ACR) core set measures after 12 weeks of treatment than with pretreatment values. Multiple regression analysis of data after 12 weeks yielded a correlation coefficient of 0.711. The sensitivity and specificity to predict articular destruction over the 75th percentile of the cohort were 78.6% and 84.6%, respectively. Patients who showed articular destruction over the 75th percentile of the cohort had low response to treatment at 12 weeks, and continued to have high clinical disease activity thereafter. Contrasting data were found in patients with slow progression of articular destruction. CONCLUSION: In patients with early RA, ACR core set measures after 12 weeks of nonbiologic DMARD treatment may predict articular destruction 2 years later. Low response to treatment at 12 weeks and continuing high disease activity thereafter were found in patients with rapid radiological progression. These data can be used to determine the appropriateness of treatment at 12 weeks and aid the decision to introduce biologic DMARD. PMID- 20194457 TI - Suspended embryo mount for imaging Caenorhabditis elegans. AB - This protocol describes the preparation of Caenorhabditis elegans embryos for four-dimensional (4D) imaging. Embryos are excised from gravid hermaphrodites and allowed to adhere directly to a poly-L-lysine-coated coverslip. The coverslip is then used to create a slide chamber in which the embryos are suspended in buffer. These suspended mounts are better for 4D recordings than agar mounts because, although agar mounts produce more uniformly oriented embryos, evaporation from the agar pads tends to shift the embryos gradually over time. 4D spatial registration with suspended mounts is quite stable, and it is possible to digitally reorient embryos within the recorded volume of the three-dimensional (3D) stack during post-processing of the data. PMID- 20194458 TI - Preparation and orcein staining of mitotic chromosomes from Drosophila larval brain. AB - In this protocol, larval brains from Drosophila are incubated in vitro with colchicine, treated with hypotonic solution, fixed, and squashed in aceto-orcein. This procedure provides a large number of well-spread metaphase figures (200-400 per brain) that can be analyzed for chromosome morphology, the presence of chromosome aberrations, and the degree of ploidy. PMID- 20194459 TI - Chromosome banding of mitotic chromosomes from Drosophila larval brain. AB - The classical chromosome-banding techniques developed for mammalian chromosomes do not differentiate the euchromatic arms of Drosophila mitotic chromosomes. However, some of these techniques produce a sharp and highly reproducible banding of Drosophila heterochromatin. For example, the use of quinacrine-, Hoechst-, and N-banding differentiates Drosophila heterochromatin into 61 cytological entities, allowing precise localization of heterochromatic breakpoints. These banding techniques can also be successfully used to differentiate mitotic heterochromatin of various Drosophila and mosquito species. Here we present protocols routinely used in our laboratories for chromosome banding, including the use of Hoechst, 4',6-diamidino-2-phenylindole (DAPI), quinacrine, and Giemsa stains. PMID- 20194460 TI - Fluorescent in situ hybridization (FISH) of mitotic chromosomes from Drosophila larval brain. AB - The fluorescent in situ hybridization (FISH) technique permits fine mapping of both middle and highly repetitive DNA sequences along Drosophila melanogaster heterochromatin. Best results are obtained when this technique is coupled with DAPI staining and digital recording of fluorescent signals. For example, if digital images of the FISH signals and DAPI fluorescence are detected separately using a charge-coupled device (CCD) camera, they can then be pseudocolored and merged using suitable computer programs. This allows precise overlapping of the DAPI banding (which is identical to the Hoechst 33258 banding) and the FISH signals, facilitating the assignment of the repetitive sequence under study to specific regions of the cytological map of D. melanogaster heterochromatin. This article describes FISH procedures that are routinely used with larval brain squashes, including preparation of slides, preparation of biotin- and digoxigenin labeled probes, hybridization, and detection. PMID- 20194461 TI - Using WebGBrowse to visualize genome annotation on GBrowse. AB - Although GBrowse is popular for visualizing genomic features along a reference sequence, its installation and configuration are difficult for many biologists. WebGBrowse is a web server that takes a user-supplied annotation file, guides users to configure the display of each genomic feature, and allows users to visualize the genome annotation with integrated GBrowse software. This protocol guides the user through each step of using WebGBrowse. PMID- 20194462 TI - Creation of baculovirus display libraries. AB - The baculovirus expression vector system has been used extensively to produce numerous proteins originating from both prokaryotic and eukaryotic sources. In addition to easy cloning techniques and abundant viral propagation, the system's insect cell environment provides eukaryotic post-translational modification machinery. The baculovirus display vector system provides a number of advantages over prokaryotic systems, allowing the combination of genotype with phenotype, enabling presentation of foreign peptides or even complex proteins on the baculoviral envelope or capsid. Baculoviruses permit larger gene insertions, are easily propagated, and can be grown to high titers. Furthermore, surface modifications of the viral capsid enable specific targeting. This strategy can be used to enhance viral binding and entry to a wide variety of both dividing and nondividing mammalian cells as well as to produce antibodies against the displayed antigen. In addition, the technology should enable modifications of intracellular behavior, i.e., trafficking of recombinant "nanoparticles," a highly relevant feature for studies of targeted gene or protein delivery. It is important to note that, although the viruses do not replicate in mammalian cells, they are not entirely transcriptionally silent. They can also be highly antigenic when used in vivo, limiting their therapeutic use. This protocol describes methods for generating display libraries. PMID- 20194463 TI - Determination of recombinant baculovirus display viral titer. AB - The baculovirus expression vector system has been used extensively to produce numerous proteins originating from both prokaryotic and eukaryotic sources. In addition to easy cloning techniques and abundant viral propagation, the system's insect cell environment provides eukaryotic post-translational modification machinery. The baculovirus display vector system provides a number of advantages over prokaryotic systems, allowing the combination of genotype with phenotype, enabling presentation of foreign peptides or even complex proteins on the baculoviral envelope or capsid. Baculoviruses permit larger gene insertions, are easily propagated, and can be grown to high titers. Furthermore, surface modifications of the viral capsid enable specific targeting. This strategy can be used to enhance viral binding and entry to a wide variety of both dividing and nondividing mammalian cells, as well as to produce antibodies against the displayed antigen. In addition, the technology should enable modifications of intracellular behavior, i.e., trafficking of recombinant "nanoparticles," a highly relevant feature for studies of targeted gene or protein delivery. Although baculovirus titer can be determined by standard methods such as classical plaque assays or end-point dilution assays, such methods often are tedious and time-consuming. The protocol described here is rapid and can be performed directly using marker genes such as green fluorescent protein or beta galactosidase regulated by baculovirus-specific promoters, or indirectly as an immunoassay with baculovirus-specific antibodies (e.g., anti-gp64). PMID- 20194464 TI - Immunofluorescence analysis of baculovirus-displayed viral proteins on infected insect cells. AB - The baculovirus expression vector system has been used extensively to produce numerous proteins originating from both prokaryotic and eukaryotic sources. In addition to easy cloning techniques and abundant viral propagation, the system's insect cell environment provides eukaryotic post-translational modification machinery. The baculovirus display vector system provides a number of advantages over prokaryotic systems, allowing the combination of genotype with phenotype, enabling presentation of foreign peptides or even complex proteins on the baculoviral envelope or capsid. Baculoviruses permit larger gene insertions, are easily propagated, and can be grown to high titers. Furthermore, the eukaryotic system allows for post-translational modifications, and surface modifications of the viral capsid enable specific targeting. This strategy can be used to enhance viral binding and entry to a wide variety of both dividing and nondividing mammalian cells, as well as to produce antibodies against the displayed antigen. In addition, the technology should enable modifications of intracellular behavior, i.e., trafficking of recombinant "nanoparticles," a highly relevant feature for studies of targeted gene or protein delivery. After generating the display viral stock, it is important to confirm the presence and functionality of the displayed peptides or proteins on the viral particles before proceeding to further experiments. Accordingly, infected insect cells and budded virions can be analyzed by a variety of methods using appropriate antibodies. This protocol describes a standard immunofluorescence technique in detail. PMID- 20194465 TI - Immunoelectron microscopy analysis of recombinant baculovirus display viruses. AB - The baculovirus expression vector system has been used extensively to produce numerous proteins originating from both prokaryotic and eukaryotic sources. In addition to easy cloning techniques and abundant viral propagation, the system's insect cell environment provides eukaryotic post-translational modification machinery. The baculovirus display vector system provides a number of advantages over prokaryotic systems, allowing the combination of genotype with phenotype, enabling presentation of foreign peptides or even complex proteins on the baculoviral envelope or capsid. Baculoviruses permit larger gene insertions, are easily propagated, and can be grown to high titers. Furthermore, surface modifications of the viral capsid enable specific targeting. This strategy can be used to enhance viral binding and entry to a wide variety of both dividing and nondividing mammalian cells, as well as to produce antibodies against the displayed antigen. In addition, the technology should enable modifications of intracellular behavior, i.e., trafficking of recombinant "nanoparticles," a highly relevant feature for studies of targeted gene or protein delivery. After generating the display viral stock, it is important to confirm the presence and functionality of the displayed peptides or proteins on the viral particles before proceeding to further experiments. Accordingly, infected insect cells and budded virions can be analyzed by a variety of methods using appropriate antibodies. This protocol describes a standard immunoelectron microscopy technique in detail. PMID- 20194466 TI - Monitoring baculovirus-mediated efficiency of gene delivery. AB - The baculovirus expression vector system has been used extensively to produce numerous proteins originating from both prokaryotic and eukaryotic sources. In addition to easy cloning techniques and abundant viral propagation, the system's insect cell environment provides eukaryotic post-translational modification machinery. The baculovirus display vector system provides a number of advantages over prokaryotic systems, allowing the combination of genotype with phenotype, enabling presentation of foreign peptides or even complex proteins on the baculoviral envelope or capsid. Baculoviruses permit larger gene insertions, are easily propagated, and can be grown to high titers. Furthermore, surface modifications of the viral capsid enable specific targeting. This strategy can be used to enhance viral binding and entry to a wide variety of both dividing and nondividing mammalian cells, as well as to produce antibodies against the displayed antigen. In addition, the technology should enable modifications of intracellular behavior, that is, trafficking of recombinant "nanoparticles," a highly relevant feature for studies of targeted gene or protein delivery. Also, the ability to incorporate reporter genes under transcriptional regulation of mammalian promoters enables transduction efficiency to be monitored in mammalian cells in vitro and in tissues in vivo. Luciferase molecules in particular are nontoxic and emit light in direct proportion to their number in mammalian cells. This provides a sensitive and rapid assay for quantification of transgene expression without the need for illumination with an external excitation source. PMID- 20194467 TI - Determining single-molecule intensity as a function of power density. AB - When performing analysis using total internal reflection fluorescence microscopy (TIRFM), fluorescence intensity depends linearly on excitation intensity, until the dye spends most of its time in the excited state (i.e., saturation is reached). How much light is seen by the dyes in the sample depends not only on the amount of light exiting the objective but also on the area over which it is spread out. The parameter of interest is the power density, measured in W/cm(2). The highest signal-to-noise ratios will be reached when the illumination power just approaches saturation. To determine at what power density a dye is saturated, one should measure fluorescence intensity as a function of power density, as described in this protocol. PMID- 20194468 TI - Imaging single molecular motor motility with total internal reflection fluorescence microscopy (TIRFM). AB - Total internal reflection fluorescence microscopy (TIRFM) allows fluorescent molecules on or near the plasma membrane to be visualized with a very high signal to-noise ratio. This strategy has been very successful for imaging molecular machines as they move and do work. We provide here a general protocol for imaging single molecular motors as they move along microtubule tracks. Our protocol is designed for the study of cytoplasmic dynein purified from Saccharomyces cerevisiae, but it represents a general framework for any in vitro single molecule assay. PMID- 20194469 TI - Unbiased identification of protein-bait interactions using biochemical enrichment and quantitative proteomics. AB - The use of recombinant proteins, antibodies, small molecules, or nucleic acids as affinity reagents is a simple yet powerful strategy to study the protein-bait interactions that drive biological processes. However, such experiments are often analyzed by Western blotting, limiting the ability to detect novel protein interactors. Unbiased protein identification by mass spectrometry (MS) extends these experiments beyond the study of pairwise interactions, allowing analyses of whole networks of protein-bait interactions. With the latest advances in MS, it is not uncommon to identify thousands of proteins from complex mixtures. Paradoxically, the improved sensitivity of proteomic analyses can make it more difficult to distinguish bait-specific interactions from the large background of identified proteins. In quantitative proteomics, MS signals from protein populations labeled with stable isotopes such as (13)C and (15)N can be identified and quantified relative to unlabeled counterparts. Using quantitative proteomics to compare biochemical enrichments with the bait of interest against those obtained with control baits allows sensitive detection and discrimination of specific protein-bait interactions among the large number of nonspecific interactions with beads. Ad hoc optimization of enrichment conditions is minimized, and mild purification conditions preserve secondary or high-order protein-protein interactions. The combination of biochemical enrichment and quantitative proteomics allows rapid characterization of molecular baits with their interacting proteins, providing tremendous insight into their biological mechanisms of action. PMID- 20194470 TI - Overexpressing tagged proteins in plants using a modified gateway cloning strategy. AB - In recent years, sequence-specific recombination cloning methods such as the Gateway system have become increasingly popular for (over)expressing tagged proteins in high-throughput investigations in many different organisms, including plants. Because of their versatility and ease of use, these methods have gained favor in low- and medium-throughput investigations as well. However, due to the recombination step, the resulting fusion proteins contain long and often highly charged polylinker sequences that can interfere with their physiological function. Furthermore, in some cases the gene of interest must be cloned twice (once with and once without a stop codon) for N- and C-terminal tagging. Here, we present a hybrid combinatorial cloning strategy that overcomes many of these limitations. In the first step, the gene of interest is cloned into an entry vector containing standardized cloning sites with the desired N- or C-terminal tag and an optimized polylinker sequence. A Gateway recombination reaction is used to transfer the protein-tag fusion from the entry clone to a Gateway destination vector with the desired promoter and selectable marker for the organism of interest. As experimental requirements evolve, constructs for expressing the protein of interest with the desired tag, promoter, and selectable marker or other features can rapidly and easily be created. PMID- 20194474 TI - How calcium indicators work. AB - In the last two decades, imaging of fluorescent indicators specific for Ca(2+) has revealed its often spectacular spatial dynamics, such as rhythmic oscillations or standing gradients, within single groups or individual cells, in unprecedented detail. This short review describes how the more widely used indicators work. The currently used Ca(2+) indicators have a modular design consisting of a metal-binding site (or sensor) coupled in some way to a fluorescent dye. Combining different sensors with different dyes results in numerous indicators suited to a wide range of experiments and equipment. PMID- 20194475 TI - Imaging embryonic development in Caenorhabditis elegans. AB - Embryos are remarkable for their combination of pluripotency, three dimensionality, and swiftness of subcellular and developmental rearrangements. Embryogenesis in the nematode Caenorhabditis elegans is uniquely suited among model systems to high-resolution dynamic imaging. Within a single high magnification, high-numerical aperture (NA) microscope field, at submicrometer resolution, it is possible to observe several entire animals taking form. The full approximately 14-h course of embryonic cleavage and morphogenesis of this transparent, free-living worm is essentially invariant. Observing specific fluorescently labeled components during embryonic development promises to reveal the roles of organelles and molecules in an extremely diverse and reproducible set of contexts. The C. elegans community has created a growing collection of hundreds of transgenic strains expressing green fluorescent protein (GFP)-labeled versions of distinct endogenously expressed genes. The task of correlating the resulting expression and localization patterns in space and time is simultaneously alluring and technically demanding. This article describes the use of four-dimensional (4D) laser-scanning microscopy and subsequent data processing to record, portray, analyze, and compare the expression of fluorescently tagged gene products during development of the nematode embryo. PMID- 20194476 TI - Baculovirus-based display and gene delivery systems. AB - The baculovirus expression vector system has been used extensively to produce numerous proteins originating from both prokaryotic and eukaryotic sources. In addition to easy cloning techniques and abundant viral propagation, the system's insect cell environment provides eukaryotic post-translational modification machinery. The recently established eukaryotic molecular biology tool, the baculovirus display vector system (BDVS), allows the combination of genotype with phenotype, enabling presentation of foreign peptides or even complex proteins on the baculoviral envelope or capsid. This strategy is important because it can be used to enhance viral binding and entry to mammalian cells as well as to produce antibodies against the displayed antigen. In addition, the technology should enable modifications of intracellular behavior, that is, trafficking of recombinant "nanoparticles," a highly relevant feature for studies of targeted gene or protein delivery. This article discusses the design and potential uses of insect-derived baculoviral display vectors. PMID- 20194477 TI - Imaging single molecules using total internal reflection fluorescence microscopy (TIRFM). AB - Total internal reflection fluorescence microscopy (TIRFM) allows fluorescent molecules to be visualized with an unparalleled signal-to-noise ratio. This is achieved by illuminating only the molecules that are within a thin volume near the coverslip surface but not those that are deeper in solution. Using this technique, fluorescent molecules within approximately 100 nm of the coverslip can be visualized, and single molecules that are separated by a distance greater than the diffraction limit (approximately 200 nm) can be individually resolved. The application of centroid-tracking methods allows subdiffraction-limited localization precision as low as 1 nm. Additionally, by combining centroid tracking methods with recent advances in fluorophore technology and imaging methods, even those molecules that are present at high concentrations and closer to one another than the diffraction limit can be individually imaged. TIRF is ideally suited for studying protein dynamics on or near the plasma membrane. Although TIRFM was pioneered in the 1980s, it was not until the mid-1990s that single biological molecules were imaged directly. The explosion of new fluorescent proteins, new organic dyes, and quantum dots (Qdots), along with commercially available TIRFMs, has made this technique increasingly useful and accessible to biologists. In this review, we first describe the theory of TIRFM. We then give a detailed description of important considerations for setting up a TIRFM, based on commercially available systems, and review considerations for purification and labeling of proteins. Finally, we discuss new techniques that allow single molecules to be imaged at cellular concentrations and with super resolution localization. PMID- 20194478 TI - Introduction to linkage disequilibrium, the HapMap, and imputation. AB - Throughout the human genome, a correlation structure exists across genetic variation of different loci. Such a correlation structure means that knowing the genotype at one locus might provide information about the genotype at a second locus. This correlation between variation at different loci is termed linkage disequilibrium (LD). LD has implications in numerous avenues of genetic research. This article discusses the importance of LD in genetics, touching on both population genetics and association studies. It then introduces the seminal collaborative scientific endeavor to map LD in the human genome--the International HapMap Project--and its relevance for imputation. PMID- 20194479 TI - Project among African-Americans to explore risks for schizophrenia (PAARTNERS): evidence for impairment and heritability of neurocognitive functioning in families of schizophrenia patients. AB - OBJECTIVE: Neurocognitive impairments in schizophrenia are well replicated and widely regarded as candidate endophenotypes that may facilitate understanding of schizophrenia genetics and pathophysiology. The Project Among African-Americans to Explore Risks for Schizophrenia (PAARTNERS) aims to identify genes underlying liability to schizophrenia. The unprecedented size of its study group (N=1,872), made possible through use of a computerized neurocognitive battery, can help further investigation of the genetics of neurocognition. The current analysis evaluated two characteristics not fully addressed in prior research: 1) heritability of neurocognition in African American families and 2) relationship between neurocognition and psychopathology in families of African American probands with schizophrenia or schizoaffective disorder. METHOD: Across eight data collection sites, patients with schizophrenia or schizoaffective disorder (N=610), their biological relatives (N=928), and community comparison subjects (N=334) completed a standardized diagnostic evaluation and the computerized neurocognitive battery. Performance accuracy and response time (speed) were measured separately for 10 neurocognitive domains. RESULTS: The patients with schizophrenia or schizoaffective disorder exhibited less accuracy and speed in most neurocognitive domains than their relatives both with and without other psychiatric disorders, who in turn were more impaired than comparison subjects in most domains. Estimated trait heritability after inclusion of the mean effect of diagnostic status, age, and sex revealed significant heritabilities for most neurocognitive domains, with the highest for accuracy of abstraction/flexibility, verbal memory, face memory, spatial processing, and emotion processing and for speed of attention. CONCLUSION: Neurocognitive functions in African American families are heritable and associated with schizophrenia. They show potential for gene-mapping studies. PMID- 20194480 TI - D2 receptor genetic variation and clinical response to antipsychotic drug treatment: a meta-analysis. AB - OBJECTIVE: Several lines of evidence suggest that antipsychotic drug efficacy is mediated by dopamine type 2 (D(2)) receptor blockade. Therefore, it seems plausible that variation in the DRD(2) gene is associated with clinical response to antipsychotic drug treatment. The authors conducted the first meta-analysis to examine the relationship between DRD2 polymorphisms and antipsychotic drug response. METHOD: A MEDLINE search of articles available up to December 31, 2008, yielded 18 prospective studies examining DRD2 gene variation and antipsychotic response in schizophrenia patients; of which, 10 independent studies met criteria for inclusion. Clinical response to antipsychotic treatment was defined as a 50% reduction of either the Brief Psychiatric Rating Scale total score or Positive and Negative Syndrome Scale total score at approximately 8 weeks of follow-up evaluation. Odds ratio was the primary effect-size measure and computed for each polymorphism in each study. Sufficient data were available for two DRD2 polymorphisms: -141C Ins/Del and Taq1A. RESULTS: Six studies reported results for the -141C Ins/Del polymorphism (total sample size: N=687). The Del allele carrier was significantly associated with poorer antipsychotic drug response relative to the Ins/Ins genotype. Eight studies assessed the Taq1A polymorphism and antipsychotic response (total sample size: N=748). There was no significant difference in the response rate among A1 allele carriers relative to individuals with the A2/A2 genotype or A2 allele carriers relative to individuals with the A1/A1 genotype. CONCLUSIONS: The DRD2 genetic variation is associated with clinical response to antipsychotic drug treatment. These data may provide proof of-principle for pharmacogenetic studies in schizophrenia. PMID- 20194481 TI - Association of mu-opioid receptor variants and response to citalopram treatment in major depressive disorder. AB - OBJECTIVE: Because previous preclinical and clinical studies have implicated the endogenous opioid system in major depression and in the neurochemical action of antidepressants, the authors examined how DNA variation in the mu-opioid receptor gene may influence population variation in response to citalopram treatment. METHOD: A total of 1,953 individuals from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study were treated with citalopram and genotyped for 53 single nucleotide polymorphisms (SNPs) in a 100-kb region of the OPRM1 gene. The sample consisted of Non-Hispanic Caucasians, Hispanic Caucasians, and African Americans. Population stratification was corrected using 119 ancestry informative markers and principal components analysis. Markers were tested for association with phenotypes for general and specific citalopram response as well as remission. RESULTS: Association between one SNP and specific citalopram response was observed. After Bonferroni correction, the strongest finding was the association between the rs540825 SNP and specific response. The rs540825 polymorphism is a nonsynonymous SNP in the final exon of the mu-opioid receptor 1X isoform of the OPRM1 gene, resulting in a histidine to glutamine change in the intracellular domain of the receptor. When Hispanic and Non-Hispanic Caucasians were analyzed separately, similar results in the population-corrected analyses were detected. CONCLUSIONS: These results suggest that rates of response to antidepressants and consequent remission from major depressive disorder are influenced by variation in the mu-opioid receptor gene as a result of either an effect on placebo response or true pharmacologic response. PMID- 20194482 TI - Association of enhanced limbic response to threat with decreased cortical facial recognition memory response in schizophrenia. AB - OBJECTIVE: Recognition memory of faces is impaired in patients with schizophrenia, as is the neural processing of threat-related signals, but how these deficits interact to produce symptoms is unclear. The authors used an affective face recognition paradigm to examine possible interactions between cognitive and affective neural systems in schizophrenia. METHOD: Blood-oxygen level-dependent response was examined by means of functional magnetic resonance imaging (3 Tesla) in healthy comparison subjects (N=21) and in patients with schizophrenia (N=12) or schizoaffective disorder, depressed type (N=4), during a two-choice recognition task that used images of human faces. Each target face, previously displayed with a threatening or nonthreatening affect, was displayed with neutral affect. Responses to successful recognition and responses to the effect of previously threatening versus nonthreatening affect were evaluated, and correlations with symptom severity (total Brief Psychiatric Rating Scale score) were examined. Functional connectivity analyses examined the relationship between activation in the amygdala and cortical regions involved in recognition memory. RESULTS: Patients performed the task more slowly than healthy comparison subjects. Comparison subjects recruited the expected cortical regions to a greater degree than patients, and patients with more severe symptoms demonstrated proportionally less recruitment. Increased symptoms were also correlated with augmented amygdala and orbitofrontal cortex response to threatening faces. Comparison subjects exhibited a negative correlation between activity in the amygdala and cortical regions involved in cognition, while patients showed weakening of this relationship. CONCLUSION: Increased symptoms were related to an enhanced threat response in limbic regions and a diminished recognition memory response in cortical regions, supporting a link between these two brain systems that are often examined in isolation. This finding suggests that abnormal processing of threat-related signals in the environment may exacerbate cognitive impairment in schizophrenia. PMID- 20194484 TI - Combining antidepressant medications: a good idea? PMID- 20194483 TI - Psychiatrists' role in the health of the pregnant mother and the risk for schizophrenia in her offspring. PMID- 20194485 TI - Nutrition and psychiatry. PMID- 20194486 TI - Normalizing effects of modafinil on cocaine-induced sleep abnormalities. PMID- 20194487 TI - Assuring that double-blind is blind. PMID- 20194488 TI - Psychiatric assessment of aggressive patients: a violent attack on a resident. AB - Aggressive patients often target psychiatrists and psychiatric residents, yet most clinicians are insufficiently trained in violence risk assessment and management. Consequently, many clinicians are reluctant to diagnose and treat aggressive and assaultive features in psychiatric patients and instead focus attention on other axis I mental disorders with proven pharmacological treatment in the hope that this approach will reduce the aggressive behavior. Unclear or nonexistent reporting policies or feelings of self-blame may impede clinicians from reporting assaults, thus limiting our knowledge of the impact of, and best response to, aggression in psychiatric patients. The authors pre-sent the case of a young adult inpatient with a long history of antisocial and assaultive behavior who struck and injured a psychiatric resident. With this case in mind, the authors discuss the diagnostic complexities related to violent patients, the importance of assessing violence risk when initially evaluating a patient, and the relevance of risk assessment for treatment considerations and future management. This report illustrates common deficiencies in the prevention of violence on inpatient psychiatric units and in the reporting and response to an assault, and has implications for residency and clinician training. PMID- 20194489 TI - The foundation of the first Western mental asylum. PMID- 20194490 TI - Successful clozapine retrial after suspected myocarditis. PMID- 20194491 TI - Oseltamivir-induced mania in a patient with H1N1. PMID- 20194492 TI - Remission of drug-induced hepatitis after switching from risperidone to paliperidone. PMID- 20194493 TI - Subjective adjustment of individuals with psychiatric disorders in the aftermath of the L'Aquila earthquake. PMID- 20194494 TI - Psychosis following excessive ingestion of energy drinks in a patient with schizophrenia. PMID- 20194495 TI - PrP conformational transitions alter species preference of a PrP-specific antibody. AB - The epitope of the 3F4 antibody most commonly used in human prion disease diagnosis is believed to consist of residues Met-Lys-His-Met (MKHM) corresponding to human PrP-(109-112). This assumption is based mainly on the observation that 3F4 reacts with human and hamster PrP but not with PrP from mouse, sheep, and cervids, in which Met at residue 112 is replaced by Val. Here we report that, by brain histoblotting, 3F4 did not react with PrP of uninfected transgenic mice expressing elk PrP; however, it did show distinct immunoreactivity in transgenic mice infected with chronic wasting disease. Compared with human PrP, the 3F4 reactivity with the recombinant elk PrP was 2 orders of magnitude weaker, as indicated by both Western blotting and surface plasmon resonance. To investigate the molecular basis of these species- and conformer-dependent preferences of 3F4, the epitope was probed by peptide membrane array and antigen competition experiments. Remarkably, the 3F4 antibody did not react with MKHM but reacted strongly with KTNMK (corresponding to human PrP-(106-110)), a sequence that is also present in cervids, sheep, and cattle. 3F4 also reacted with elk PrP peptides containing KTNMKHV. We concluded that the minimal sequence for the 3F4 epitope consists of residues KTNMK, and the species- and conformer-dependent preferences of 3F4 arise largely from the interactions between Met(112) (human PrP) or Val(115) (cervid PrP) and adjacent residues. PMID- 20194496 TI - Peroxynitrite is the major species formed from different flux ratios of co generated nitric oxide and superoxide: direct reaction with boronate-based fluorescent probe. AB - There is much interest in the nitration and oxidation reaction mechanisms initiated by superoxide radical anion (O(2)()) and nitric oxide ((*)NO). It is well known that O(2) and (*)NO rapidly react to form a potent oxidant, peroxynitrite anion (ONOO(-)). However, indirect measurements with the existing probes (e.g. dihydrorhodamine) previously revealed a bell-shaped response to co generated (*)NO and O(2) fluxes, with the maximal yield of the oxidation or nitration product occurring at a 1:1 ratio. These results raised doubts on the formation of ONOO(-) per se at various fluxes of (*)NO and O(2). Using a novel fluorogenic probe, coumarin-7-boronic acid, that reacts stoichiometrically and rapidly with ONOO(-) (k = 1.1 x 10(6) m(-1)s(-1)), we report that ONOO(-) formation increased linearly and began to plateau after reaching a 1:1 ratio of co-generated (*)NO and O(2) fluxes. We conclude that ONOO(-) is formed as the primary intermediate during the reaction between (*)NO and O(2) co-generated at different fluxes. PMID- 20194497 TI - TEAD-1 overexpression in the mouse heart promotes an age-dependent heart dysfunction. AB - TEA domain transcription factor-1 (TEAD-1) is essential for proper heart development and is implicated in cardiac specific gene expression and the hypertrophic response of primary cardiomyocytes to hormonal and mechanical stimuli, and its activity increases in the pressure-overloaded hypertrophied rat heart. To investigate whether TEAD-1 is an in vivo modulator of cardiac specific gene expression and hypertrophy, we developed transgenic mice expressing hemagglutinin-tagged TEAD-1 under the control of the muscle creatine kinase promoter. We show that a sustained increase in TEAD-1 protein leads to an age dependent dysfunction. Magnetic resonance imaging revealed decreases in cardiac output, stroke volume, ejection fraction, and fractional shortening. Isolated TEAD-1 hearts revealed decreased left ventricular power output that correlated with increased betaMyHC protein. Histological analysis showed altered alignment of cardiomyocytes, septal wall thickening, and fibrosis, although electrocardiography displayed a left axis shift of mean electrical axis. Transcripts representing most members of the fetal heart gene program remained elevated from fetal to adult life. Western blot analyses revealed decreases in p phospholamban, SERCA2a, p-CX43, p-GSK-3alpha/beta, nuclear beta-catenin, GATA4, NFATc3/c4, and increased NCX1, nuclear DYKR1A, and Pur alpha/beta protein. TEAD-1 mice did not display cardiac hypertrophy. TEAD-1 mice do not tolerate stress as they die over a 4-day period after surgical induction of pressure overload. These data provide the first in vivo evidence that increased TEAD-1 can induce characteristics of cardiac remodeling associated with cardiomyopathy and heart failure. PMID- 20194498 TI - T cell signal regulation by the actin cytoskeleton. AB - T cells form an immunological synapse (IS) that sustains and regulates signals for cell stimulation. Enriched in the IS is the Src family kinase Lck. Conversely, the membrane phosphatase CD45, which activates Src family kinases, is excluded, and this is necessary to avoid quenching of T cell receptor phosphosignals. Data suggest that this arrangement occurs by an enrichment of cholesterol-dependent rafts in the IS. However, the role of rafts in structuring the IS remains unclear. To address this question, we used fluorescence resonance energy transfer (FRET) to interrogate the nanoscopic structure of the IS. The FRET probes consisted of membrane-anchored fluorescent proteins with distinct affinities for rafts. Both the raft and nonraft probes exhibited clustering in the IS. However, co-clustering of raft donor-acceptor pairs was 10-fold greater than co-clustering of raft-nonraft pairs. We measured the effect of disrupting rafts in the IS on CD45 localization and Lck regulation by treating stimulated T cells with filipin. The filipin specifically disrupted co-clustering of the raft FRET pairs in the IS and allowed targeting of CD45 to the IS and dephosphorylation of the regulatory tyrosine of Lck. Clustering of the raft probes was also sensitive to latrunctulin B, which disrupts actin filaments. Strikingly, enriching the cortical cytoskeleton using jasplakinolide maintained raft probe co-clustering, CD45 exclusion, and Lck regulation in the IS following the addition of filipin. These data show the actin cytoskeleton maintains a membrane raft environment in the IS that promotes Lck regulation by excluding CD45. PMID- 20194499 TI - G alpha(q)-mediated activation of GRK2 by mechanical stretch in cardiac myocytes: the role of protein kinase C. AB - G protein-coupled receptor kinase-2 (GRK2) is a critical regulator of beta adrenergic receptor (beta-AR) signaling and cardiac function. We studied the effects of mechanical stretch, a potent stimulus for cardiac myocyte hypertrophy, on GRK2 activity and beta-AR signaling. To eliminate neurohormonal influences, neonatal rat ventricular myocytes were subjected to cyclical equi-biaxial stretch. A hypertrophic response was confirmed by "fetal" gene up-regulation. GRK2 activity in cardiac myocytes was increased 4.2-fold at 48 h of stretch versus unstretched controls. Adenylyl cyclase activity was blunted in sarcolemmal membranes after stretch, demonstrating beta-AR desensitization. The hypertrophic response to mechanical stretch is mediated primarily through the G alpha(q) coupled angiotensin II AT(1) receptor leading to activation of protein kinase C (PKC). PKC is known to phosphorylate GRK2 at the N-terminal serine 29 residue, leading to kinase activation. Overexpression of a mini-gene that inhibits receptor-G alpha(q) coupling blunted stretch-induced hypertrophy and GRK2 activation. Short hairpin RNA-mediated knockdown of PKC alpha also significantly attenuated stretch-induced GRK2 activation. Overexpression of a GRK2 mutant (S29A) in cardiac myocytes inhibited phosphorylation of GRK2 by PKC, abolished stretch-induced GRK2 activation, and restored adenylyl cyclase activity. Cardiac specific activation of PKC alpha in transgenic mice led to impaired beta-agonist stimulated ventricular function, blunted cyclase activity, and increased GRK2 phosphorylation and activity. Phosphorylation of GRK2 by PKC appears to be the primary mechanism of increased GRK2 activity and impaired beta-AR signaling after mechanical stretch. Cross-talk between hypertrophic signaling at the level of PKC and beta-AR signaling regulated by GRK2 may be an important mechanism in the transition from compensatory ventricular hypertrophy to heart failure. PMID- 20194501 TI - Human GLUD2 glutamate dehydrogenase is expressed in neural and testicular supporting cells. AB - Mammalian glutamate dehydrogenase (GDH) is an allosterically regulated enzyme that is expressed widely. Its activity is potently inhibited by GTP and thought to be controlled by the need of the cell for ATP. In addition to this housekeeping human (h) GDH1, humans have acquired (via a duplication event) a highly homologous isoenzyme (hGDH2) that is resistant to GTP. Although transcripts of GLUD2, the gene encoding hGDH2, have been detected in human neural and testicular tissues, data on the endogenous protein are lacking. Here, we developed an antibody specific for hGDH2 and used it to study human tissues. Western blot analyses revealed, to our surprise, that endogenous hGDH2 is more densely expressed in testis than in brain. At the subcellular level, hGDH2 localized to mitochondria. Study of testicular tissue using immunocytochemical and immunofluorescence methods revealed that the Sertoli cells were strongly labeled by our anti-hGDH2 antibody. In human cerebral cortex, a robust labeling of astrocytes was detected, with neurons showing faint hGDH2 immunoreactivity. Astrocytes and Sertoli cells are known to support neurons and germ cells, respectively, providing them with lactate that largely derives from the tricarboxylic acid cycle via conversion of glutamate to alpha-ketoglutarate (GDH reaction). As hGDH2 is not subject to GTP control, the enzyme is able to metabolize glutamate even when the tricarboxylic acid cycle generates GTP amounts sufficient to inactivate the housekeeping hGDH1 protein. Hence, the selective expression of hGDH2 by astrocytes and Sertoli cells may provide a significant biological advantage by facilitating metabolic recycling processes essential to the supportive role of these cells. PMID- 20194500 TI - Functional identification of two nonredundant Arabidopsis alpha(1,2)fucosyltransferases specific to arabinogalactan proteins. AB - Virtually nothing is known about the mechanisms and enzymes responsible for the glycosylation of arabinogalactan proteins (AGPs). The glycosyltransferase 37 family contains plant-specific enzymes, which suggests involvement in plant specific organs such as the cell wall. Our working hypothesis is that AtFUT4 and AtFUT6 genes encode alpha(1,2)fucosyltransferases (FUTs) for AGPs. Multiple lines of evidence support this hypothesis. First, overexpression of the two genes in tobacco BY2 cells, known to contain nonfucosylated AGPs, resulted in a staining of transgenic cells with eel lectin, which specifically binds to terminal alpha linked fucose. Second, monosaccharide analysis by high pH anion exchange chromatography and electrospray ionization mass spectrometry indicated the presence of fucose in AGPs from transgenic cell lines but not in AGPs from wild type cells. Third, detergent extracts from microsomal membranes prepared from transgenic lines were able to fucosylate, in vitro, purified AGPs from BY2 wild type cells. Susceptibility of [(14)C]fucosylated AGPs to alpha(1,2)fucosidase, and not to alpha(1,3/4)fucosidase, indicated that an alpha(1,2) linkage is formed. Furthermore, dearabinosylated AGPs were not substrate acceptors for these enzymes, indicating that arabinosyl residues represent the fucosylation sites on these molecules. Testing of several polysaccharides, oligosaccharides, and glycoproteins as potential substrate acceptors in the fucosyl transfer reactions indicated that the two enzymes are specific for AGPs but are not functionally redundant because they differentially fucosylate certain AGPs. AtFUT4 and AtFUT6 are the first enzymes to be characterized for AGP glycosylation and further our understanding of cell wall biosynthesis. PMID- 20194502 TI - Determinants for stop-transfer and post-import pathways for protein targeting to the chloroplast inner envelope membrane. AB - The inner envelope membrane (IEM) of the chloroplast plays key roles in controlling metabolite transport between the organelle and cytoplasm and is a major site of lipid and membrane synthesis within the organelle. IEM biogenesis requires the import and integration of nucleus-encoded membrane proteins. Previous reports have led to the conclusion that membrane proteins are inserted into the IEM during protein import from the cytoplasm via a stop-transfer mechanism or are completely imported into the stroma and then inserted into the IEM in a post-import mechanism. In this study, we examined the determinants for each pathway by comparing the targeting of APG1 (albino or pale green mutant 1), an example of a stop-transfer substrate, and atTic40, an example of a post-import substrate. We show that the APG1 transmembrane domain is sufficient to direct stop-transfer insertion. The APG1 transmembrane domain also functions as a topology determinant. We also show that the ability of the post-import signals within atTic40 to target proteins to the IEM is dependent upon their context within the full protein sequence. In the incorrect context, the atTic40 signals can behave as stop-transfer signals or fail to target fusion proteins to the IEM. These data suggest that the post-import pathway signals are complex and have evolved to avoid stop-transfer insertion. PMID- 20194503 TI - Mechanisms of activity and inhibition of the hepatitis C virus RNA-dependent RNA polymerase. AB - The RNA-dependent RNA polymerase NS5B is a key enzyme of the replication of hepatitis C virus (HCV) and a major therapeutic target. Applying a novel continuous assay with highly purified protein and a fluorescent RNA-template we provide for the first time a comprehensive mechanistic description of the enzymatic reaction. Using fluorescence spectroscopy, the kinetics of NS5B was confirmed to consist of two half-reactions, namely substrate binding and turnover. Determining the binding constants of the substrates and the rate constants of individual reaction steps, NS5B was shown to bind the template single-stranded RNA with high affinity (nanomolar range) and in a stepwise process that reflects the substrate positioning. As demonstrated by CD, NTP(s) binding caused a tertiary structural change of the enzyme into an active conformation. The second half-reaction was dissected into a sequential polymerization and a subsequent, rate-limiting product release reaction. Taking advantage of these tools, we analyzed the mechanism of action of the NS5B inhibitor HCV-796, which was shown to interfere with the formation of double stranded RNA by blocking the second half-reaction. PMID- 20194504 TI - Origin of the allyl group in FK506 biosynthesis. AB - FK506 (tacrolimus) is a secondary metabolite with a potent immunosuppressive activity, currently registered for use as immunosuppressant after organ transplantation. FK506 and FK520 are biogenetically related natural products that are synthesized by combined polyketide synthase/nonribosomal peptide synthetase systems. The entire gene cluster for biosynthesis of FK520 from Streptomyces hygroscopicus var. ascomyceticus has been cloned and sequenced. On the other hand, the FK506 gene cluster from Streptomyces sp. MA6548 (ATCC55098) was sequenced only partially, and it was reasonable to expect that additional genes would be required for the provision of substrate supply. Here we report the identification of a previously unknown region of the FK506 gene cluster from Streptomyces tsukubaensis NRRL 18488 containing genes encoding the provision of unusual building blocks for FK506 biosynthesis as well as a regulatory gene. Among others, we identified a group of genes encoding biosynthesis of the extender unit that forms the allyl group at carbon 21 of FK506. Interestingly, we have identified a small independent diketide synthase system involved in the biosynthesis of the allyl group. Inactivation of one of these genes, encoding an unusual ketosynthase domain, resulted in an FK506 nonproducing strain, and the production was restored when a synthetic analog of the allylmalonyl-CoA extender unit was added to the cultivation medium. Based on our results, we propose a biosynthetic pathway for the provision of an unusual five-carbon extender unit, which is carried out by a novel diketide synthase complex. PMID- 20194505 TI - Formation of a cyclopropyl epoxide via a leukotriene A synthase-related pathway in an anaerobic reaction of soybean lipoxygenase-1 with 15S hydroperoxyeicosatetraenoic acid: evidence that oxygen access is a determinant of secondary reactions with fatty acid hydroperoxides. AB - The further conversion of an arachidonic acid hydroperoxide to a leukotriene A (LTA) type epoxide by specific lipoxygenase (LOX) enzymes constitutes a key step in inflammatory mediator biosynthesis. Whereas mammalian 5-LOX transforms its primary product (5S-hydroperoxyeicosatetraenoic acid; 5S-HPETE) almost exclusively to LTA(4), the model enzyme, soybean LOX-1, normally produces no detectable leukotrienes and instead further oxygenates its primary product 15S HPETE to 5,15- and 8,15-dihydroperoxides. Mammalian 15-LOX-1 displays both types of activity. We reasoned that availability of molecular oxygen within the LOX active site favors oxygenation, whereas lack of O(2) promotes LTA epoxide synthesis. To test this, we reacted 15S-HPETE with soybean LOX-1 under anaerobic conditions and identified the products by high pressure liquid chromatography, UV, mass spectrometry, and NMR. Among the products, we identified a pair of 8,15 dihydroxy diastereomers with all-trans-conjugated trienes that incorporated (18)O from H(2)(18)O at C-8, indicative of the formation of 14,15-LTA(4). A pair of 5,15-dihydroxy diastereomers containing two trans,trans-conjugated dienes (6E,8E,11E,13E) and that incorporated (18)O from H(2)(18)O at C-5 was deduced to arise from hydrolysis of a novel epoxide containing a cyclopropyl ring, 14,15 epoxy-[9,10,11-cyclopropyl]-eicosa-5Z,7E,13E-trienoic acid. Also identified was the delta-lactone of the 5,15-diol, a derivative that exhibited no (18)O incorporation due to its formation by intramolecular reaction of the carboxyl anion with the proposed epoxide intermediate. Our results support a model in which access to molecular oxygen within the active site directs the outcome from competing pathways in the secondary reactions of lipoxygenases. PMID- 20194506 TI - Targeting the active site gate to yield hyperactive variants of 5-aminolevulinate synthase. AB - The rate of porphyrin biosynthesis in mammals is controlled by the activity of the pyridoxal 5'-phosphate-dependent enzyme 5-aminolevulinate synthase (EC 2.3.1.37). Based on the postulate that turnover in this enzyme is controlled by conformational dynamics associated with a highly conserved active site loop, we constructed a variant library by targeting imperfectly conserved noncatalytic loop residues and examined the effects on product and porphyrin production. Functional loop variants of the enzyme were isolated via genetic complementation in Escherichia coli strain HU227. Colony porphyrin fluorescence varied widely when bacterial cells harboring the loop variants were grown on inductive media; this facilitated identification of clones encoding unusually active enzyme variants. Nine loop variants leading to high in vivo porphyrin production were purified and characterized kinetically. Steady state catalytic efficiencies for the two substrates were increased by up to 100-fold. Presteady state single turnover reaction data indicated that the second step of quinonoid intermediate decay, previously assigned as reaction rate-limiting, was specifically accelerated such that in three of the variants this step was no longer kinetically significant. Overall, our data support the postulate that the active site loop controls the rate of product and porphyrin production in vivo and suggest the possibility of an as yet undiscovered means of allosteric regulation. PMID- 20194507 TI - Ribosomal protein L11 associates with c-Myc at 5 S rRNA and tRNA genes and regulates their expression. AB - The c-Myc oncoprotein promotes cell growth by enhancing ribosomal biogenesis. Overexpression of c-Myc and aberrant ribosomal biogenesis lead to deregulated cell growth and tumorigenesis. Hence, c-Myc activity and ribosomal biogenesis must be tightly coordinated during normal homeostasis. We previously found that ribosomal protein L11 inhibits c-Myc activity by blocking the recruitment of its co-activator transformation/transcription domain-associated protein (TRRAP) to the promoter regions of c-Myc target genes that are transcribed by RNA polymerases I and II. In this study, we extended the role of L11 to the regulation of c-Myc-driven transcription of the 5 S rRNA and tRNA genes by RNA polymerase III. L11 co-resided with c-Myc at the 5 S rRNA and tRNA genes and significantly inhibited the binding of TRRAP to these genes. Knocking down endogenous L11 enhanced c-Myc-dependent transcription of these genes. Interestingly, in response to ribosomal stress induced by the treatment of cells with a low dose of actinomycin D or serum starvation, L11 binding to these genes was increased, and inversely TRRAP binding to these genes was decreased. Consistently, knockdown of L11 rescued the reduction of the expression of these genes by the two treatments. These results demonstrate that L11 suppresses c-Myc dependent and RNA polymerase III-catalyzed transcription of 5 S rRNA and tRNA genes in response to ribosomal stress, ensuring a tight coordination between c Myc activity and ribosomal biogenesis. PMID- 20194508 TI - Experimental intrauterine growth restriction induces alterations in DNA methylation and gene expression in pancreatic islets of rats. AB - Intrauterine growth restriction (IUGR) increases susceptibility to age-related diseases, including type 2 diabetes (T2DM), and is associated with permanent and progressive changes in gene expression. Our study was designed to test whether epigenomic dysregulation mediates the cellular memory of this intrauterine event. To test this hypothesis, we isolated pancreatic islets from control and IUGR (induced by bilateral uterine artery ligation at day 18 of fetal life) animals at 7 weeks of age. Using the HELP (HpaII tiny fragment enrichment by ligation mediated PCR) assay, we generated the first DNA methylation map at almost 1 million unique sites throughout the rat genome in normal pancreatic islet cells, allowing us to identify the changes that occur as a consequence of IUGR. We validated candidate dysregulated loci with quantitative assays of cytosine methylation and gene expression. IUGR changes cytosine methylation at approximately 1,400 loci (false discovery rate of 4.2%) in male rats at 7 weeks of age, preceding the development of diabetes and thus representing candidate loci for mediating the pathogenesis of metabolic disease that occurs later in life. Epigenetic dysregulation occurred preferentially at conserved intergenic sequences, frequently near genes regulating processes known to be abnormal in IUGR islets, such as vascularization, beta-cell proliferation, insulin secretion, and cell death, associated with concordant changes in mRNA expression. These results demonstrate that epigenetic dysregulation is a strong candidate for propagating the cellular memory of intrauterine events, causing changes in expression of nearby genes and long term susceptibility to type 2 diabetes. PMID- 20194509 TI - TAB2 scaffolds TAK1 and NLK in repressing canonical Wnt signaling. AB - The TAK1-NLK cascade is a mitogen-activated protein kinase-related pathway that plays an inhibitory role in canonical Wnt/beta-catenin signaling through regulating the LEF1/TCF family transcriptional factors. TAB2 (TAK1-binding protein 2) is a putative TAK1 interacting protein that is involved in the regulation of TAK1. Here, we found that TAB2 could directly interact with NLK and function as a scaffold protein to facilitate the interaction between TAK1 and NLK. Knocking down TAB2 using small interfering RNA abolished the interaction of TAK1 with NLK in mammalian cells. The intermediate region (residues 292-417) of TAB2 was mapped for its binding to NLK. TAB2-DeltaM, a TAB2 mutant lacking this region, showed a lower affinity for NLK and became defective in its scaffolding function. In addition, TAB2, but not TAB2-DeltaM, mediated TAK1-dependent activation of NLK and LEF1 polyubiquitylation, resulting in the inhibition of canonical Wnt signaling. Moreover, Wnt3a stimulation led to an increase in the interaction of TAB2 with NLK and the formation of a TAK1.TAB2.NLK complex, suggesting that this TAK1-TAB2-NLK pathway may constitute a negative feedback mechanism for canonical Wnt signaling. PMID- 20194510 TI - Evolution and multifarious horizontal transfer of an alternative biosynthetic pathway for the alternative polyamine sym-homospermidine. AB - Polyamines are small flexible organic polycations found in almost all cells. They likely existed in the last universal common ancestor of all extant life, and yet relatively little is understood about their biological function, especially in bacteria and archaea. Unlike eukaryotes, where the predominant polyamine is spermidine, bacteria may contain instead an alternative polyamine, sym homospermidine. We demonstrate that homospermidine synthase (HSS) has evolved vertically, primarily in the alpha-Proteobacteria, but enzymatically active, diverse HSS orthologues have spread by horizontal gene transfer to other bacteria, bacteriophage, archaea, eukaryotes, and viruses. By expressing diverse HSS orthologues in Escherichia coli, we demonstrate in vivo the production of co products diaminopropane and N(1)-aminobutylcadaverine, in addition to sym homospermidine. We show that sym-homospermidine is required for normal growth of the alpha-proteobacterium Rhizobium leguminosarum. However, sym-homospermidine can be replaced, for growth restoration, by the structural analogues spermidine and sym-norspermidine, suggesting that the symmetrical or unsymmetrical form and carbon backbone length are not critical for polyamine function in growth. We found that the HSS enzyme evolved from the alternative spermidine biosynthetic pathway enzyme carboxyspermidine dehydrogenase. The structure of HSS is related to lysine metabolic enzymes, and HSS and carboxyspermidine dehydrogenase evolved from the aspartate family of pathways. Finally, we show that other bacterial phyla such as Cyanobacteria and some alpha-Proteobacteria synthesize sym homospermidine by an HSS-independent pathway, very probably based on deoxyhypusine synthase orthologues, similar to the alternative homospermidine synthase found in some plants. Thus, bacteria can contain alternative biosynthetic pathways for both spermidine and sym-norspermidine and distinct alternative pathways for sym-homospermidine. PMID- 20194511 TI - Activation of cAMP-dependent signaling induces oxidative modification of the cardiac Na+-K+ pump and inhibits its activity. AB - Cellular signaling can inhibit the membrane Na(+)-K(+) pump via protein kinase C (PKC)-dependent activation of NADPH oxidase and a downstream oxidative modification, glutathionylation, of the beta(1) subunit of the pump alpha/beta heterodimer. It is firmly established that cAMP-dependent signaling also regulates the pump, and we have now examined the hypothesis that such regulation can be mediated by glutathionylation. Exposure of rabbit cardiac myocytes to the adenylyl cyclase activator forskolin increased the co-immunoprecipitation of NADPH oxidase subunits p47(phox) and p22(phox), required for its activation, and increased superoxide-sensitive fluorescence. Forskolin also increased glutathionylation of the Na(+)-K(+) pump beta(1) subunit and decreased its co immunoprecipitation with the alpha(1) subunit, findings similar to those already established for PKC-dependent signaling. The decrease in co-immunoprecipitation indicates a decrease in the alpha(1)/beta(1) subunit interaction known to be critical for pump function. In agreement with this, forskolin decreased ouabain sensitive electrogenic Na(+)-K(+) pump current (arising from the 3:2 Na(+):K(+) exchange ratio) of voltage-clamped, internally perfused myocytes. The decrease was abolished by the inclusion of superoxide dismutase, the inhibitory peptide for the epsilon-isoform of PKC or inhibitory peptide for NADPH oxidase in patch pipette solutions that perfuse the intracellular compartment. Pump inhibition was also abolished by inhibitors of protein kinase A and phospholipase C. We conclude that cAMP- and PKC-dependent inhibition of the cardiac Na(+)-K(+) pump occurs via a shared downstream oxidative signaling pathway involving NADPH oxidase activation and glutathionylation of the pump beta(1) subunit. PMID- 20194512 TI - The changing face of emotion: age-related patterns of amygdala activation to salient faces. AB - The present study investigated age-related differences in the amygdala and other nodes of face-processing networks in response to facial expression and familiarity. fMRI data were analyzed from 31 children (3.5-8.5 years) and 14 young adults (18-33 years) who viewed pictures of familiar (mothers) and unfamiliar emotional faces. Results showed that amygdala activation for faces over a scrambled image baseline increased with age. Children, but not adults, showed greater amygdala activation to happy than angry faces; in addition, amygdala activation for angry faces increased with age. In keeping with growing evidence of a positivity bias in young children, our data suggest that children find happy faces to be more salient or meaningful than angry faces. Both children and adults showed preferential activation to mothers' over strangers' faces in a region of rostral anterior cingulate cortex associated with self-evaluation, suggesting that some nodes in frontal evaluative networks are active early in development. This study presents novel data on neural correlates of face processing in childhood and indicates that preferential amygdala activation for emotional expressions changes with age. PMID- 20194513 TI - Human brain spots emotion in non humanoid robots. AB - The computation by which our brain elaborates fast responses to emotional expressions is currently an active field of brain studies. Previous studies have focused on stimuli taken from everyday life. Here, we investigated event-related potentials in response to happy vs neutral stimuli of human and non-humanoid robots. At the behavioural level, emotion shortened reaction times similarly for robotic and human stimuli. Early P1 wave was enhanced in response to happy compared to neutral expressions for robotic as well as for human stimuli, suggesting that emotion from robots is encoded as early as human emotion expression. Congruent with their lower faceness properties compared to human stimuli, robots elicited a later and lower N170 component than human stimuli. These findings challenge the claim that robots need to present an anthropomorphic aspect to interact with humans. Taken together, such results suggest that the early brain processing of emotional expressions is not bounded to human-like arrangements embodying emotion. PMID- 20194515 TI - From moral to legal judgment: the influence of normative context in lawyers and other academics. AB - Various kinds of normative judgments are an integral part of everyday life. We extended the scrutiny of social cognitive neuroscience into the domain of legal decisions, investigating two groups, lawyers and other academics, during moral and legal decision-making. While we found activation of brain areas comprising the so-called 'moral brain' in both conditions, there was stronger activation in the left dorsolateral prefrontal cortex and middle temporal gyrus particularly when subjects made legal decisions, suggesting that these were made in respect to more explicit rules and demanded more complex semantic processing. Comparing both groups, our data show that behaviorally lawyers conceived themselves as emotionally less involved during normative decision-making in general. A group * condition interaction in the dorsal anterior cingulate cortex suggests a modulation of normative decision-making by attention based on subjects' normative expertise. PMID- 20194514 TI - Neural correlates of recognition memory for emotional faces and scenes. AB - We examined the influence of emotional valence and type of item to be remembered on brain activity during recognition, using faces and scenes. We used multivariate analyses of event-related fMRI data to identify whole-brain patterns, or networks of activity. Participants demonstrated better recognition for scenes vs faces and for negative vs neutral and positive items. Activity was increased in extrastriate cortex and inferior frontal gyri for emotional scenes, relative to neutral scenes and all face types. Increased activity in these regions also was seen for negative faces relative to positive faces. Correct recognition of negative faces and scenes (hits vs correct rejections) was associated with increased activity in amygdala, hippocampus, extrastriate, frontal and parietal cortices. Activity specific to correctly recognized emotional faces, but not scenes, was found in sensorimotor areas and rostral prefrontal cortex. These results suggest that emotional valence and type of visual stimulus both modulate brain activity at recognition, and influence multiple networks mediating visual, memory and emotion processing. The contextual information in emotional scenes may facilitate memory via additional visual processing, whereas memory for emotional faces may rely more on cognitive control mediated by rostrolateral prefrontal regions. PMID- 20194516 TI - Investigating face-property specific processing in the right OFA. AB - Within the neural face-processing network, the right occipital face area (rOFA) plays a prominent role, and it has been suggested that it receives both feed forward and re-entrant feedback from other face sensitive areas. Its functional role is less well understood and whether the rOFA is involved in the initial analysis of a face stimulus or in the detailed integration of different face properties remains an open question. The present study investigated the functional role of the rOFA with regard to different face properties (identity, expression, and gaze) using transcranial magnetic stimulation (TMS). Experiment 1 showed that the rOFA integrates information across different face properties: performance for the combined processing of identity and expression decreased after TMS to the rOFA, while no impairment was seen in gaze processing. In Experiment 2 we examined the temporal dynamics of this effect. We pinpointed the impaired integrative computation to 170 ms post stimulus presentation. Together the results suggest that TMS to the rOFA affects the integrative processing of facial identity and expression at a mid-latency processing stage. PMID- 20194517 TI - Fitness epistasis among 6 biosynthetic loci in the budding yeast Saccharomyces cerevisiae. AB - We generated all possible haploid and homozygous diploid genotypes at 6 biosynthetic loci in yeast and scored their fitness to examine whether there was any pattern of weak synergistic epistasis, which is a requirement of the deterministic mutation model for the evolution of sex. We measured 4 components of fitness: haploid growth rate, haploid mating efficiency, diploid growth rate, and diploid sporulation efficiency. We found that in agreement with previous work in yeast, epistasis tended to be small in magnitude and variable in sign, regardless of the fitness component measured. The number of background mutations had either no effect or no consistent effect on epistasis distributions. For every combination of 2 loci in a mutation-free background, we also generated all heterozygous genotypes so that we could partition diploid epistasis into additive x additive, additive x dominance, and dominance x dominance epistasis. Our main interest was in determining whether dominance by dominance epistasis was large and negative, which is a requirement of diploid models with inbreeding to explain high levels of recombination. Dominance by dominance epistasis estimates obtained by partitioning diploid epistasis for growth rates were both positive and negative. With the caveat that our results are based on only 6 biosynthetic loci, epistasis for fitness is not supported as an explanation for the maintenance of sex or the high rate of meiotic recombination in yeast. PMID- 20194518 TI - Tailoring the switch from IRES-dependent to 5'-end-dependent translation with the RNase P ribozyme. AB - Translation initiation driven by internal ribosome entry site (IRES) elements is dependent on the structural organization of the IRES region. We have previously shown that a structural motif within the foot-and-mouth-disease virus IRES is recognized in vitro as substrate for the Synechocystis sp. RNase P ribozyme. Here we show that this structure-dependent endonuclease recognizes the IRES element in cultured cells, leading to inhibition of translation. Inhibition of IRES activity was dependent on the expression of the active ribozyme RNA subunit. Moreover, expression of the antisense sequence of the ribozyme did not inhibit IRES activity, demonstrating that stable RNA structures located upstream of the IRES element do not interfere with internal initiation. RNAs carrying defective IRES mutants that were substrates of the ribozyme in vivo revealed an increased translation of the reporter in response to the expression of the active ribozyme. In support of RNA cleavage, subsequent analysis of the translation initiation manner indicated a switch from IRES-dependent to 5'-end-dependent translation of RNase P target RNAs. We conclude that the IRES element is inactivated by expression in cis of RNase P in the cytoplasm of cultured cells, providing a promising antiviral tool to combat picornavirus infections. Furthermore, our results reinforce the essential role of the structural motif that serves as RNase P recognition motif for IRES activity. PMID- 20194519 TI - Simple, recurring RNA binding sites for L-arginine. AB - Seven new arginine binding motifs have been selected from a heterogeneous RNA pool containing 17, 25, and 50mer randomized tracts, yielding 131 independently derived binding sites that are multiply isolated. The shortest 17mer random region is sufficient to build varied arginine binding sites using five different conserved motifs (motifs 1a, 1b, 1c, 2, and 4). Dissociation constants are in the fractional millimolar to millimolar range. Binding sites are amino acid side chain specific and discriminate moderately between L- and D-stereoisomers of arginine, suggesting a molecular focus on side-chain guanidinium. An arginine coding triplet (codon/anticodon) is highly conserved within the largest family of Arg sites (72% of all sequences), as has also been found in minimal, most prevalent RNA binding sites for Ile, His, and Trp. PMID- 20194520 TI - Dissecting electrostatic screening, specific ion binding, and ligand binding in an energetic model for glycine riboswitch folding. AB - Riboswitches are gene-regulating RNAs that are usually found in the 5' untranslated regions of messenger RNA. As the sugar-phosphate backbone of RNA is highly negatively charged, the folding and ligand-binding interactions of riboswitches are strongly dependent on the presence of cations. Using small angle X-ray scattering (SAXS) and hydroxyl radical footprinting, we examined the cation dependence of the different folding stages of the glycine-binding riboswitch from Vibrio cholerae. We found that the partial folding of the tandem aptamer of this riboswitch in the absence of glycine is supported by all tested mono- and divalent ions, suggesting that this transition is mediated by nonspecific electrostatic screening. Poisson-Boltzmann calculations using SAXS-derived low resolution structural models allowed us to perform an energetic dissection of this process. The results showed that a model with a constant favorable contribution to folding that is opposed by an unfavorable electrostatic term that varies with ion concentration and valency provides a reasonable quantitative description of the observed folding behavior. Glycine binding, on the other hand, requires specific divalent ions binding based on the observation that Mg(2+), Ca(2+), and Mn(2+) facilitated glycine binding, whereas other divalent cations did not. The results provide a case study of how ion-dependent electrostatic relaxation, specific ion binding, and ligand binding can be coupled to shape the energetic landscape of a riboswitch and can begin to be quantitatively dissected. PMID- 20194521 TI - Predictors of smoking reduction among Blacks. AB - INTRODUCTION: Blacks who smoke have increased tobacco-related health risks. Cessation decreases the likelihood of many health problems. Smoking reduction may be important in the cessation process and potentially reduce health risks. METHODS: Because little is known about specific predictors of smoking reduction, we investigated factors predicting reduction among Black light smokers enrolled in a 26-week cessation trial. Specifically, we compared (a) reducers (reduced cigarettes per day [cpd] >or=50%) with nonreducers and (b) reducers with quitters. Baseline demographic, smoking-related, and psychosocial variables were collected, and Week 26 smoking status was assessed. RESULTS: Among 539 participants, 41.0% (n = 221) reduced their smoking, 17.6% (n = 95) quit, and 41.4% (n = 223) did not reduce their smoking by >or=50%. In comparison with reducers, nonreducers were more likely to have their first cigarette within 30 min of waking (odds ratio [OR] = 2.4, 95% CI = 1.47-3.93), lower baseline cpd (OR = 0.84, 95% CI = 0.77-0.93), higher baseline cotinine levels (OR = 1.002, 95% CI = 1.000-1.003), lower perceived stress (OR = 0.86, 95% CI = 0.78-0.95), and higher Smoking Consequences Questionnaire (SCQ) negative social impression scores (OR = 1.04, 95% CI = 1.01-1.06), after controlling for treatment arm, gender, and age. Significant predictors of smoking cessation versus reduction included lower baseline cpd (OR = 0.85, 95% CI = 0.75-0.95), higher nicotine dependence (OR = 1.47, 95% CI = 1.09-1.98), lower baseline cotinine levels (OR = 0.996, 95% CI = 0.994-0.998), higher body mass index (OR = 1.05, 95% CI = 1.01-1.08), lower perceived stress (OR = 0.82, 95% CI = 0.72-0.95), and higher SCQ negative social impression scores (OR = 1.05, 95% CI = 1.01-1.08). DISCUSSION: Distinct predictors are associated with different trajectories of smoking behavior change (i.e., reduction vs. cessation vs. no change). PMID- 20194522 TI - Effects of bupropion on simulated demand for cigarettes and the subjective effects of smoking. AB - INTRODUCTION: The biobehavioral mechanism(s) mediating bupropion's efficacy are not well understood. Behavioral economic measures such as demand curves have proven useful in investigations of the reinforcing effects of drugs of abuse. Behavioral economic measures may also be used to measure the effect of pharmacotherapies on the reinforcing effects of drugs of abuse. METHODS: The effects of bupropion on simulated demand for cigarettes were investigated in a placebo-controlled double-blind clinical trial. Participants reported the number of cigarettes they would purchase and consume in a single day at a range of prices. The effects of medication on the subjective effects of smoking were also explored. RESULTS: Demand for cigarettes was well described by an exponential demand equation. Bupropion did not significantly decrease the maximum number of cigarettes that participants said they would smoke in a single day nor did it significantly alter the relation between price per cigarette and demand. Baseline demand elasticity did not predict smoking cessation, but changes in elasticity following 1 week of treatment did. Medication group had no effect on any subjective effects of smoking. DISCUSSION: Bupropion had no significant effects on demand for cigarettes. The exponential demand equation, recently introduced in behavioral economics, proved amenable to human simulated demand and might be usefully employed in other pharmacotherapy studies as it provides a potentially useful measure of changes in the essential value of the drug as a reinforcer. Such changes may be useful in predicting the efficacy of medications designed to reduce drug consumption. PMID- 20194524 TI - The role of maternal gut hormones in normal pregnancy: fasting plasma active glucagon-like peptide 1 level is a negative predictor of fetal abdomen circumference and maternal weight change. AB - OBJECTIVE: Maternal weight in pregnancy contributes to a glycemic environment that affects fetal growth. Gut peptides (glucagon-like peptide 1 (GLP1), glucose dependent insulinotropic peptide (GIP), ghrelin, and peptide YY (PYY)) have been related to insulin sensitivity and secretion, weight control, and adipose tissue metabolism. This study aimed at examining the associations of gut hormones during pregnancy with maternal glucose homeostasis, maternal weight, and fetal growth. METHODS: A total of 55 pregnant nonobese, nondiabetic Caucasian women were examined during the three trimesters of pregnancy, and anthropometric measurements, evaluation of fasting maternal plasma GLP1 (active), ghrelin (active), total PYY, total GIP, and a 75-g oral glucose tolerance test were done in them. Homeostasis model assessment (HOMA-R), insulin sensitivity index (ISI), and indices of insulin secretion were calculated. Fetal growth was estimated by ultrasound. RESULTS: Fasting GLP1 increased significantly from the second to the third trimester (P<0.05). Fasting GLP1 correlated positively with high-density lipoprotein cholesterol (r=0.52, P=0.04). At the second trimester, fasting GLP1 levels correlated negatively with fetal abdomen circumference (r=-0.55, P=0.034), birth weight (r=-0.50, P=0.040), HOMA-R (r=-0.65, P=0.001), insulin secretion, and triglycerides. At the first trimester, fasting ghrelin levels correlated negatively with HOMA-R and insulin secretion, and positively with ISI. In backward multiple regression analysis, the first trimester GLP1 levels were the best negative predictors of the second trimester fetal abdomen circumference (beta=-0.96, P=0.009). In longitudinal regression model, maternal fat and HOMA-R were the positive predictors of maternal weight change during pregnancy, and fasting GLP1 levels were the negative predictors of maternal weight change during pregnancy. CONCLUSIONS: During pregnancy, maternal GLP1 might be involved in mechanisms that compensate for the pregnancy-related increase in glycemia and insulin resistance, suggesting a role of this peptide in maternal metabolism and weight and fetal growth. PMID- 20194525 TI - Position paper: Rapid responses to steroids: current status and future prospects. AB - Steroids exert their actions through several pathways. The classical genomic pathway, which involves binding of steroids to receptors and subsequent modulation of gene expression, is well characterized. Besides this, rapid actions of steroids have been shown to exist. Since 30 years, research on rapid actions of steroids is an emerging field of science. Today, rapid effects of steroids are well established, and are shown to exist for every type of steroid. The classical steroid receptors have been shown to be involved in rapid actions, but there is also strong evidence that unrelated structures mediate these rapid effects. Despite increasing knowledge about the mechanisms and structures which mediate these actions, there is still no unanimous acceptance of this category. This article briefly reviews the history of the field including current controversies and challenges. It is not meant as a broad review of literature, but should increase the awareness of the endocrinology society for rapid responses to steroids. As members of the organizing committee of the VI International Meeting on Rapid Responses to Steroid Hormones 2009, we propose a research agenda focusing on the identification of new receptoral structures and the identification of mechanisms of actions at physiological steroid concentrations. Additionally, efforts for the propagation of translational studies, which should finally lead to clinical benefit in the area of rapid steroid action research, should be intensified. PMID- 20194526 TI - Cognition-enhancing properties of Dimebon in a rat novel object recognition task are unlikely to be associated with acetylcholinesterase inhibition or N-methyl-D aspartate receptor antagonism. AB - Dimebon (dimebolin) treatment enhances cognition in patients with Alzheimer's disease (AD) or Huntington's disease. Although Dimebon was originally thought to improve cognition and memory through inhibition of acetylcholinesterase (AChE) and the N-methyl-d-aspartate (NMDA) receptor, the low in vitro affinity for these targets suggests that these mechanisms may not contribute to its clinical effects. To test this hypothesis, we assessed whether Dimebon enhances cognition in rats and if such an action is related to either mechanism or additional candidate mechanisms. Acute oral administration of Dimebon to rats (0.05, 0.5, and 5 mg/kg) enhanced cognition in a novel object recognition task and produced Dimebon brain concentrations of 1.7 +/- 0.43, 14 +/- 5.1, and 172 +/- 94 nM, respectively. At these concentrations, Dimebon did not alter the activity of recombinant human or rat brain AChE. Unlike the AChE inhibitors donepezil and galantamine, Dimebon did not change acetylcholine levels in the hippocampus or prefrontal cortex of freely moving rats. Dimebon displays affinity for the NMDA receptor (K(i) = 105 +/- 18 microM) that is considerably higher than brain concentrations associated with cognition enhancement in the novel object recognition task and 200-fold weaker than that of memantine (K(i) = 0.54 +/- 0.05 microM). Dimebon did not block NMDA-induced calcium influx in primary neuronal cells (IC(50) > 50 microM), consistent with a lack of significant effect on this pathway. The cognition-enhancing effects of Dimebon are unlikely to be mediated by AChE inhibition or NMDA receptor antagonism, and its mechanism of action appears to be distinct from currently approved medications for AD. PMID- 20194527 TI - Extracellular 3',5'-cAMP-adenosine pathway inhibits glomerular mesangial cell growth. AB - Abnormal growth of glomerular mesangial cells (GMCs) contributes to the pathophysiology of many types of nephropathy. Because adenosine is an autocrine/paracrine factor that potentially could regulate GMC proliferation and because the extracellular 3',5'-cAMP-adenosine pathway (i.e., the conversion of extracellular 3',5'-cAMP to 5'-AMP and adenosine on the cell surface) could generate adenosine in the biophase of GMC receptors, we investigated the role of the 3',5'-cAMP-adenosine pathway in modulating growth [cell proliferation, DNA synthesis ([(3)H]thymidine incorporation), collagen synthesis ([(3)H]proline incorporation), and mitogen-activated protein kinase activity] of GMCs. The addition of exogenous 3',5'-cAMP to human GMCs increased extracellular levels of 5'-AMP, adenosine, and inosine, and 3-isobutyl-1-methylxanthine (phosphodiesterase inhibitor), 1,3-dipropyl-8-p-sulfophenylxanthine (ecto phosphodiesterase inhibitor), and alpha,beta-methylene-adenosine-5'-diphosphate (ecto-5'-nucleotidase inhibitor) attenuated the increases in adenosine and inosine. Forskolin augmented extracellular 3',5'-cAMP and adenosine concentrations, and 2',5'-dideoxyadenosine (adenylyl cyclase inhibitor) blocked these increases. Exogenous 3',5'-cAMP and forskolin inhibited all indices of cell growth, and antagonism of A(2) [(E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7 methylxanthine, KF17837] or A(1)/A(2) (1,3-dipropyl-8-p-sulfophenylxanthine, DPSPX), but not A(1) (8-cyclopentyl-1,3-dipropylxanthine), or A(3){N-(2 methoxyphenyl)-N'-[2-(3-pyridinyl)-4-quinazolinyl]-urea, VUF5574}, adenosine receptors blocked the growth-inhibitory actions of exogenous 3',5'-cAMP, but not the effects of 8-bromo-3',5'-cAMP (stable 3',5'-cAMP analog). Erythro-9-(2 hydroxy-3-nonyl)adenine (adenosine deaminase inhibitor) plus 5-iodotubercidin (adenosine kinase inhibitor) enhanced the growth inhibition by exogenous 3',5' cAMP and forskolin, and A(2) receptor antagonism blocked this effect. In rat GMCs, down-regulation of A(2B) receptors with antisense, but not sense or scrambled, oligonucleotides abrogated the inhibitory effects of 3',5'-cAMP and forskolin on cell growth. The extracellular 3',5'-cAMP-adenosine pathway exists in GMCs and attenuates cell growth via A(2B) receptors. Pharmacological augmentation of this pathway could abate pathological glomerular remodeling. PMID- 20194528 TI - Novel anticytomegalovirus activity of immunosuppressant mizoribine and its synergism with ganciclovir. AB - Cytomegalovirus (CMV) infection is a prominent infection in transplant recipients. The immunosuppressive drug mizoribine was shown to have anti-CMV activity in vitro and was reported to have an anti-CMV effect in renal transplantation. This study characterized the anti-CMV activity of mizoribine in vitro and its synergistic activity with ganciclovir. Mizoribine suppressed replication and at the EC(50) for plaque inhibition of 12.0 microg/ml. Mizoribine and ganciclovir exerted a strong synergism in anti-CMV activity. Mizoribine depletes guanosine nucleotides by inhibiting inosine monophosphate dehydrogenase and may increase the ratio of ganciclovir to guanosine in treated cells, resulting in a strong synergistic augmentation of the anti-CMV activity of ganciclovir. Two clinical isolates with UL97 mutations were less susceptible to mizoribine than the Towne strain but were equally susceptible in the presence of guanine. Two mizoribine-resistant strains were isolated after culture for 3 months with 100 microg/ml mizoribine, but they were as sensitive to ganciclovir as the parent Towne strain. The anti-CMV activity of mizoribine was antagonized by 2'-deoxyguanosine. Mizoribine inhibited CMV replication directly, and the sequence of mizoribine-resistant mutants of UL97 and UL54 was identical to that of the parent Towne strain, indicating the different anti-CMV action from ganciclovir, foscarnet, and maribavir. Mizoribine as an immunosuppressive and anti-CMV drug in the clinical regimen was suggested to suppress replication of CMV in vivo and control CMV infection in transplant recipients in combination with ganciclovir. PMID- 20194529 TI - Involvement of multidrug resistance-associated protein 4 in efflux transport of prostaglandin E(2) across mouse blood-brain barrier and its inhibition by intravenous administration of cephalosporins. AB - Prostaglandin E(2) (PGE(2)) acts as a modulator of synaptic signaling and excitability in the brain. Because PGE(2) is barely inactivated enzymatically in adult brain, its brain level is considered to be controlled by efflux transport across the blood-brain barrier (BBB). The purpose of the present study was to clarify the efflux transport of PGE(2) at the BBB and the interaction of various drugs with this process. [(3)H]PGE(2) was eliminated from brain across the BBB with a half-life of 16.3 min, and the elimination was inhibited by 3 mM unlabeled PGE(2). Multidrug resistance-associated protein 4 (MRP4/ABCC4) was reported to be localized at the luminal membrane of the BBB. MRP4-expressing membrane vesicles showed significant uptake of [(3)H]PGE(2) and the uptake was inhibited by cefmetazole with an IC(50) value of 10.2 microM. At the concentration of 20 microM, several drugs, including cefazolin, cefotaxime, ceftriaxone, and ketoprofen, significantly inhibited [(3)H]PGE(2) uptake into MRP4-expressing membrane vesicles. Using the brain efflux index method, preadministration of cefmetazole, cefazolin, ceftriaxone, and cefotaxime was found to inhibit [(3)H]PGE(2) efflux from brain across the BBB. Furthermore, intravenous administration of the cefmetazole dose dependently reduced [(3)H]PGE(2) elimination across the BBB (ID(50) = 120 mg/kg). These results indicate that PGE(2) is eliminated from the brain by MRP4-mediated efflux transport at the BBB, and peripheral administration of cefmetazole decreases the efflux transport of PGE(2) at the BBB; this interaction may influence brain function. PMID- 20194530 TI - Expression and association of TRPC subtypes with Orai1 and STIM1 in human parathyroid. AB - The mechanism behind Ca(2)(+) entry into the parathyroid cells has been widely debated, and the molecular identities of the responsible ion channels have not been established yet. In this study, we show that the parathyroid cells lack voltage-operated Ca(2)(+) channels. Passive store depletion by thapsigargin, on the other hand, induces a large non-voltage-activated non-selective cation current. The increase in intracellular Ca(2)(+) caused by thapsigargin is attenuated by 2-aminoethoxydiphenyl borate, a blocker of store-operated Ca(2)(+) entry (SOCE). Candidate molecules for non-voltage-operated Ca(2)(+) signaling were investigated. These included members of the transient receptor potential canonical (TRPC) ion channel family, as well as Ca(2)(+) release-activated Ca(2)(+) modulator 1 (Orai1) and stromal interaction molecule 1 (STIM1) that are key proteins in the SOCE pathway. Using RT-PCR screening, quantitative real-time PCR, and western blot, we showed expression of TRPC1, TRPC4, and TRPC6; Orai1; and STIM1 genes and proteins in normal and adenomatous human parathyroid tissues. Furthermore, co-immunoprecipitation experiments demonstrated a ternary complex of TRPC1-Orai1-STIM1, supporting a physical interaction between these molecules in human parathyroid. PMID- 20194531 TI - Regulation of copper transporter 2 expression by copper and cisplatin in human ovarian carcinoma cells. AB - Down-regulation of copper transporter 1 (CTR1) reduces uptake and sensitivity, whereas down-regulation of CTR2 enhances both. Cisplatin (DDP) triggers the rapid degradation of CTR1 and thus limits its own accumulation. We sought to determine the effect of DDP and copper on the expression of CTR2. Changes in CTR1 and CTR2 mRNA and protein levels in human ovarian carcinoma 2008 cells and ATOX1(+/+) and ATOX1(-/-) mouse embryo fibroblasts in response to exposure to DDP and copper were measured by quantitative reverse transcriptase-polymerase chain reaction, Western blot analysis, and deconvolution microscopy. DDP triggered rapid degradation of CTR1 in 2008 human ovarian cancer cells. However, it increased the expression of CTR2 mRNA and protein levels. Expression of CTR2 was heavily modulated by changes in intracellular copper concentration; copper depletion produced rapid disappearance of CTR2, whereas excess copper increased the level of CTR2 protein. This increase was associated with an increase in CTR2 mRNA and prolongation of the CTR2 half-life. Consistent with prior observations that short hairpin RNA interference-mediated knockdown of CTR2 enhanced DDP uptake and tumor cell kill, reduction of CTR2 by copper starvation also enhanced DDP uptake and cytotoxicity. Comparison of the ability of copper and DDP to modulate the expression of CTR1 in ATOX1(+/+) and ATOX1(-/-) indicated that ATOX1 participates in the regulation of CTR2 expression. Unlike CTR1, the expression of CTR2 is increased rather than decreased by DDP. Therefore, these two copper transporters have opposite effects on DDP sensitivity. CTR2 expression is regulated by copper availability via the copper-dependent regulator ATOX1. PMID- 20194532 TI - Asymmetric acetylation of the cyclooxygenase-2 homodimer by aspirin and its effects on the oxygenation of arachidonic, eicosapentaenoic, and docosahexaenoic acids. AB - Prostaglandin endoperoxide H synthases (PGHS)-1 and -2, also called cyclooxygenases, convert arachidonic acid (AA) to prostaglandin H(2) (PGH(2)) in the committed step of prostaglandin biosynthesis. Both enzymes are homodimers, but the monomers often behave asymmetrically as conformational heterodimers during catalysis and inhibition. Here we report that aspirin maximally acetylates one monomer of human (hu) PGHS-2. The acetylated monomer of aspirin-treated huPGHS-2 forms 15-hydroperoxyeicosatetraenoic acid from AA, whereas the nonacetylated partner monomer forms mainly PGH(2) but only at 15 to 20% of the rate of native huPGHS-2. These latter conclusions are based on the findings that the nonsteroidal anti-inflammatory drug diclofenac binds a single monomer of native huPGHS-2, having an unmodified Ser530 to inhibit the enzyme, and that diclofenac inhibits PGH(2) but not 15-hydroperoxyeicosatraenoic acid formation by acetylated huPGHS-2. The 18R- and 17R-resolvins putatively involved in resolution of inflammation are reportedly formed via aspirin-acetylated PGHS-2 from eicosapentaenoic acid and docosahexaenoic acid, respectively, so we also characterized the oxygenation of these omega-3 fatty acids by aspirin-treated huPGHS-2. Our in vitro studies suggest that 18R- and 17R-resolvins could be formed only at low rates corresponding to less than 1 and 5%, respectively, of the rates of formation of PGH(2) by native PGHS-2. PMID- 20194533 TI - Up-regulation of human CYP2J2 in HepG2 cells by butylated hydroxyanisole is mediated by c-Jun and Nrf2. AB - Cytochrome P450 2J2 oxidizes arachidonic acid to a series of epoxyeicosatrienoic acid (EET) isomers in human tissues. EETs regulate numerous homeostatic processes, including cytoprotective and proliferative responses against injurious stresses. There is little information currently available on the factors that regulate CYP2J2, but strategies to activate expression could use the beneficial effects of EETs in cells. The basic leucine zipper (bZIP) transcription factor c Jun has been shown previously to maintain CYP2J2 expression in human HepG2 cells; c-Jun forms transcriptionally active dimers with the antioxidant-inducible bZIP factor Nrf2. In the present study, we tested the hypothesis that CYP2J2 expression may be activated in cells by c-Jun/Nrf2 heterodimers. Treatment of HepG2 cells with butylated hydroxyanisole elicited concentration- and time dependent activation of CYP2J2 expression, as well as the bZIP factors Nrf2 and c Jun; chromatin immunoprecipitation assays revealed a pronounced increase in binding of these bZIP factors to the CYP2J2 5'-flank. Transient transfection analysis using deletion constructs and gel-shift assays were consistent with a role for the -105/-88 region of CYP2J2 in c-Jun/Nrf2 responsiveness. Using a series of mutant expression plasmids, we identified c-Jun as the critical partner in CYP2J2 transactivation. Coimmunoprecipitation experiments confirmed the importance of the leucine zipper region of Nrf2 in the enhancement of c-Jun dependent transactivation of CYP2J2. Agents that activate CYP2J2 expression may offer a new approach to using the beneficial effects of EETs in cells. PMID- 20194534 TI - Watching internet pharmacies. AB - The number of illegal internet pharmacies selling prescription-only medicines without a prescription is increasing. Large quantities of drugs are dispensed, making drugs of abuse readily available, and further risks are posed by counterfeit medication. Urgent national and international action is required to stop further proliferation of illegal pharmacies. PMID- 20194535 TI - Electroconvulsive therapy, practice and evidence. AB - This issue includes the findings from the largest randomised controlled trial ever conducted with bilateral, unilateral and bifrontal electroconvulsive therapy (ECT). The background to the study and its findings are discussed. PMID- 20194536 TI - Efficacy of cognitive-behavioural therapy and other psychological treatments for adult depression: meta-analytic study of publication bias. AB - BACKGROUND: It is not clear whether the effects of cognitive-behavioural therapy and other psychotherapies have been overestimated because of publication bias. AIMS: To examine indicators of publication bias in randomised controlled trials of psychotherapy for adult depression. METHOD: We examined effect sizes of 117 trials with 175 comparisons between psychotherapy and control conditions. As indicators of publication bias we examined funnel plots, calculated adjusted effect sizes after publication had been taken into account using Duval & Tweedie's procedure, and tested the symmetry of the funnel plots using the Begg & Mazumdar rank correlation test and Egger's test. RESULTS: The mean effect size was 0.67, which was reduced after adjustment for publication bias to 0.42 (51 imputed studies). Both Begg & Mazumbar's test and Egger's test were highly significant (P<0.001). CONCLUSIONS: The effects of psychotherapy for adult depression seem to be overestimated considerably because of publication bias. PMID- 20194537 TI - Patients' views of involuntary hospital admission after 1 and 3 months: prospective study in 11 European countries. AB - BACKGROUND: Legislation and practice of involuntary hospital admission vary substantially among European countries, but differences in outcomes have not been studied. AIMS: To explore patients' views following involuntary hospitalisation in different European countries. METHOD: In a prospective study in 11 countries, 2326 consecutive involuntary patients admitted to psychiatric hospital departments were interviewed within 1 week of admission; 1809 were followed up 1 month and 1613 3 months later. Patients' views as to whether the admission was right were the outcome criterion. RESULTS: In the different countries, between 39 and 71% felt the admission was right after 1 month, and between 46 and 86% after 3 months. Females, those living alone and those with a diagnosis of schizophrenia had more negative views. Adjusting for confounding factors, differences between countries were significant. CONCLUSIONS: International differences in legislation and practice may be relevant to outcomes and inform improvements in policies, particularly in countries with poorer outcomes. PMID- 20194538 TI - Passages from the diary of a late physician (1837), Samuel Warren. Psychiatrists in 19th-century fiction. PMID- 20194540 TI - Partner alcohol use, violence and women's mental health: population-based survey in India. AB - BACKGROUND: The relationship between partner alcohol use and violence as risk factors for poor mental health in women is unclear. AIMS: To describe partner related and other psychosocial risk factors for common mental disorders in women and examine interrelationships between these factors. METHOD: Data are reported on 821 women aged 18-49 years from a larger population study in north Goa, India. Logistic regression models evaluated the risks for women's common mental disorders and tested for mediation effects in the relationship between partner alcohol use and these disorders. RESULTS: Excessive partner alcohol use increased the risk for common mental disorders two- to threefold. Partner violence and alcohol-related problems each partially mediated the association between partner excessive alcohol use and these mental disorders. Women's own violence-related attitudes were also independently associated with them. CONCLUSIONS: Partner alcohol use, partner violence and women's violence-related attitudes must be addressed to prevent and treat common mental disorders in women. PMID- 20194541 TI - Cognitive style, personality and vulnerability to postnatal depression. AB - BACKGROUND: Only some women with recurrent major depressive disorder experience postnatal episodes. Personality and/or cognitive styles might increase the likelihood of experiencing postnatal depression. AIMS: To establish whether personality and cognitive style predicts vulnerability to postnatal episodes over and above their known relationship to depression in general. METHOD: We compared personality and cognitive style in women with recurrent major depressive disorder who had experienced one or more postnatal episodes (postnatal depression (PND) group, n=143) with healthy female controls (control group, n=173). We also examined parous women with recurrent major depressive disorder who experienced no perinatal episodes (non-postnatal depression (NPND) group, n=131). RESULTS: The PND group had higher levels of neuroticism and dysfunctional beliefs, and lower self-esteem than the control group. However, there were no significant differences between the PND and NPND groups. CONCLUSIONS: Established personality and cognitive vulnerabilities for depression were reported by women with a history of postnatal depression, but there was no evidence that any of these traits or styles confer a specific risk for the postnatal onset of episodes. PMID- 20194539 TI - Family-related adverse childhood experiences as risk factors for psychiatric disorders in Nigeria. AB - BACKGROUND: Adverse childhood experiences have been associated with a variety of mental health problems in adult life. AIMS: To examine whether this reported link between childhood experiences and mental health disorders in adult life applies in a Sub-Saharan African setting where cultural and family attributes may be different. METHOD: A multistage random sampling was used in the Nigerian Survey of Mental Health and Well-Being (NSMHW) to select respondents for face-to-face interviews. Assessments of family-related adverse childhood experiences and lifetime mental health disorders were conducted with the Composite International Diagnostic Interview (CIDI 3.0). RESULTS: Almost half of the respondents had experienced an adverse childhood experience within the context of the family before they were 16 years of age. Associations between adverse childhood experiences and adult mental health disorders were few and were attenuated when clustering of adverse childhood experience and disorder comorbidities were accounted for. There was an elevated likelihood of adult substance use disorders among individuals who had experienced family violence and neglect or abuse. Parental psychopathology was associated with a significantly increased risk for developing mood disorders. CONCLUSIONS: Adverse childhood experiences reflecting violence in the family, parental criminality and parental mental illness and substance misuse were more likely to have significant mental health consequences in adulthood. PMID- 20194543 TI - Superior temporal gyrus volume in antipsychotic-naive people at risk of psychosis. AB - BACKGROUND: Morphological abnormalities of the superior temporal gyrus have been consistently reported in schizophrenia, but the timing of their occurrence remains unclear. AIMS: To determine whether individuals exhibit superior temporal gyral changes before the onset of psychosis. METHOD: We used magnetic resonance imaging to examine grey matter volumes of the superior temporal gyrus and its subregions (planum polare, Heschl's gyrus, planum temporale, and rostral and caudal regions) in 97 antipsychotic-naive individuals at ultra-high risk of psychosis, of whom 31 subsequently developed psychosis and 66 did not, and 42 controls. RESULTS: Those at risk of psychosis had significantly smaller superior temporal gyri at baseline compared with controls bilaterally, without any prominent subregional effect; however, there was no difference between those who did and did not subsequently develop psychosis. CONCLUSIONS: Our findings indicate that grey matter reductions of the superior temporal gyrus are present before psychosis onset, and are not due to medication, but these baseline changes are not predictive of transition to psychosis. PMID- 20194544 TI - Epileptic, organic and genetic vulnerabilities for timing of the development of interictal psychosis. AB - BACKGROUND: Age at the first psychotic episode and an interval between the onset of epilepsy and that of psychosis reflect developmental processes of interictal psychosis. However, factors relating to these indices remain unknown. AIMS: To identify clinical variables that are associated with the timing of the development of interictal psychosis. METHOD: In 285 adults with epilepsy with interictal psychosis, effects of epileptic (epilepsy type), organic (intellectual functioning) and genetic (family history of psychosis) variables on timing of the development of psychosis were examined. RESULTS: The mean interval between the onset of epilepsy and that of psychosis was 14.4 years. Some psychosis occurred within a few years of the first seizure. Generalised epilepsy, normal intellectual function and a positive family history of psychosis were associated with early onset of psychosis. CONCLUSIONS: Early development of interictal psychosis in people with epilepsy may reflect other individual vulnerabilities to psychosis rather than epilepsy-related damage. PMID- 20194545 TI - Rapid-cycling bipolar disorder: cross-national community study. AB - BACKGROUND: The epidemiology of rapid-cycling bipolar disorder in the community is largely unknown. AIMS: To investigate the epidemiological characteristics of rapid-cycling and non-rapid-cycling bipolar disorder in a large cross-national community sample. METHOD: The Composite International Diagnostic Interview (CIDI version 3.0) was used to examine the prevalence, severity, comorbidity, impairment, suicidality, sociodemographics, childhood adversity and treatment of rapid-cycling and non-rapid-cycling bipolar disorder in ten countries (n = 54 257). RESULTS: The 12-month prevalence of rapid-cycling bipolar disorder was 0.3%. Roughly a third and two-fifths of participants with lifetime and 12-month bipolar disorder respectively met criteria for rapid cycling. Compared with the non-rapid-cycling, rapid-cycling bipolar disorder was associated with younger age at onset, higher persistence, more severe depressive symptoms, greater impairment from depressive symptoms, more out-of-role days from mania/hypomania, more anxiety disorders and an increased likelihood of using health services. Associations regarding childhood, family and other sociodemographic correlates were less clear cut. CONCLUSIONS: The community epidemiological profile of rapid cycling bipolar disorder confirms most but not all current clinically based knowledge about the illness. PMID- 20194546 TI - Bifrontal, bitemporal and right unilateral electrode placement in ECT: randomised trial. AB - BACKGROUND: Electroconvulsive therapy (ECT) is an effective treatment for major depression. Optimising efficacy and minimising cognitive impairment are goals of ongoing technical refinements. AIMS: To compare the efficacy and cognitive effects of a novel electrode placement, bifrontal, with two standard electrode placements, bitemporal and right unilateral in ECT. METHOD: This multicentre randomised, double-blind, controlled trial (NCT00069407) was carried out from 2001 to 2006. A total of 230 individuals with major depression, bipolar and unipolar, were randomly assigned to one of three electrode placements during a course of ECT: bifrontal at one and a half times seizure threshold, bitemporal at one and a half times seizure threshold and right unilateral at six times seizure threshold. RESULTS: All three electrode placements resulted in both clinically and statistically significant antidepressant outcomes. Remission rates were 55% (95% CI 43-66%) with right unilateral, 61% with bifrontal (95% CI 50-71%) and 64% (95% CI 53-75%) with bitemporal. Bitemporal resulted in a more rapid decline in symptom ratings over the early course of treatment. Cognitive data revealed few differences between the electrode placements on a variety of neuropsychological instruments. CONCLUSIONS: Each electrode placement is a very effective antidepressant treatment when given with appropriate electrical dosing. Bitemporal leads to more rapid symptom reduction and should be considered the preferred placement for urgent clinical situations. The cognitive profile of bifrontal is not substantially different from that of bitemporal. PMID- 20194547 TI - Adolescent clinical outcomes for young people with attention-deficit hyperactivity disorder. AB - BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is recognised as a common, disabling condition. Little information is available regarding the long term outcomes for individuals with ADHD in the UK. AIMS: To examine the 5-year outcome for a UK cohort of children with diagnosed, treated ADHD and identify whether maternal and social factors predict key outcomes. METHOD: One hundred and twenty-six school-aged children (mean age 9.4 years, s.d. = 1.7) diagnosed with ADHD were reassessed 5 years later during adolescence (mean age 14.5 years, s.d. = 1.7) for ADHD, conduct disorder and other antisocial behaviours. RESULTS: Most adolescents (69.8%) continued to meet full criteria for ADHD, were known to specialist services and exhibited high levels of antisocial behaviour, criminal activity and substance use problems. Maternal childhood conduct disorder predicted offspring ADHD continuity; maternal childhood conduct disorder, lower child IQ and social class predicted offspring conduct disorder symptoms. CONCLUSIONS: The treatment and monitoring of ADHD need to be intensified as outcomes are poor especially in offspring of mothers with childhood conduct disorder symptoms. PMID- 20194548 TI - Restricting the means of suicide by charcoal burning. AB - We conducted an exploratory controlled trial to examine the efficacy of restricting access to charcoal in preventing suicides from carbon monoxide poisoning by charcoal burning in Hong Kong. All charcoal packs were removed from the open shelves of major retail outlets in the intervention region for 12 months; in the control region, charcoal packs were displayed as usual. The suicide rate from charcoal burning was reduced by a statistically significant margin in the intervention region (P<0.05) but not in the control region. We observed no significant change in the suicide rate using other methods in either location. PMID- 20194549 TI - Repeat self-harm: application of hurdle models. AB - Among those who present to the emergency department for self-harm, many will repeat. Self-harm repetition is an outcome of interest in both observational and intervention studies. However, few such studies analyse the number of repeat self harm presentations. Here, hurdle models are introduced as a potentially useful statistical method for these analyses. Emergency department data from the Province of Ontario, Canada, are used to illustrate an example of implementing hurdle models and interpreting their results. PMID- 20194550 TI - Structural brain abnormalities in bipolar disorder: what meta-analyses tell us. PMID- 20194551 TI - Confectionery consumption and violence. PMID- 20194552 TI - Evolution and psychiatry. PMID- 20194553 TI - Evolution and psychiatry. PMID- 20194554 TI - Bringing new life into psychiatry. PMID- 20194556 TI - Seeking a new life in cyberspace. PMID- 20194557 TI - Going gentle. PMID- 20194558 TI - No more dithering on e-health: let's keep patients safe instead. PMID- 20194559 TI - Derivation and validation of an index to predict early death or unplanned readmission after discharge from hospital to the community. AB - BACKGROUND: Readmissions to hospital are common, costly and often preventable. An easy-to-use index to quantify the risk of readmission or death after discharge from hospital would help clinicians identify patients who might benefit from more intensive post-discharge care. We sought to derive and validate an index to predict the risk of death or unplanned readmission within 30 days after discharge from hospital to the community. METHODS: In a prospective cohort study, 48 patient-level and admission-level variables were collected for 4812 medical and surgical patients who were discharged to the community from 11 hospitals in Ontario. We used a split-sample design to derive and validate an index to predict the risk of death or nonelective readmission within 30 days after discharge. This index was externally validated using administrative data in a random selection of 1,000,000 Ontarians discharged from hospital between 2004 and 2008. RESULTS: Of the 4812 participating patients, 385 (8.0%) died or were readmitted on an unplanned basis within 30 days after discharge. Variables independently associated with this outcome (from which we derived the mnemonic "LACE") included length of stay ("L"); acuity of the admission ("A"); comorbidity of the patient (measured with the Charlson comorbidity index score) ("C"); and emergency department use (measured as the number of visits in the six months before admission) ("E"). Scores using the LACE index ranged from 0 (2.0% expected risk of death or urgent readmission within 30 days) to 19 (43.7% expected risk). The LACE index was discriminative (C statistic 0.684) and very accurate (Hosmer Lemeshow goodness-of-fit statistic 14.1, p=0.59) at predicting outcome risk. INTERPRETATION: The LACE index can be used to quantify risk of death or unplanned readmission within 30 days after discharge from hospital. This index can be used with both primary and administrative data. Further research is required to determine whether such quantification changes patient care or outcomes. PMID- 20194560 TI - Lactation associated with a pituitary tumour in a man. PMID- 20194562 TI - Democrats consider playing trump card in effort to pass Obama's health reforms. PMID- 20194561 TI - Office management of a palpable breast lump with aspiration. PMID- 20194563 TI - Accountability key for patient charter. PMID- 20194564 TI - Global shift toward increased biovigilance. PMID- 20194565 TI - Wands and other medical devices. PMID- 20194566 TI - Antibiotics without food. PMID- 20194567 TI - Self-protective strategies are adaptive and increasingly complex: A beginner's look at the DMM and ABCD models of attachment. AB - Clinicians understand the importance of their clients' past relationships on current functioning. The notion of attachment disorganization is especially salient to many clinicians because based on the traditional model of attachment it is the category in which clients with a history of relational trauma are most likely to fall. Unfortunately, lumping together what so many clinicians feel is clinically important may not inform clinical practice and the process by which attachment is assessed is beyond the reach of many clinicians. A different model of attachment, the Dynamic Maturational Model of Attachment and Adaptation offers a new lens through which to view relational trauma and to understand the ways in which danger is processed. This article describes the similarities and differences in the two models of attachment. PMID- 20194568 TI - Playing with Gladys: A case study integrating drama therapy with behavioural interventions for the treatment of selective mutism. AB - This case study examines an integrative approach combining drama therapy and the behavioural skill "shaping", as offered to Gladys, a 5-year-old girl diagnosed with selective mutism. This study found that shaping, when implemented in the context of play, with play as the primary reinforcer, elicited from Gladys vocalization and eventually speech within a very short time. Her vocalizations allowed her to enter dramatic play, which in turn propelled spontaneous speech. This article looks at how the three elements of dramatherapy - the playspace, role-playing and dramatic projection - brought about therapeutic changes for Gladys. Aside from spontaneous speech, Gladys also developed positive self-esteem and a heightened sense of spontaneity. Subsequently, these two qualities helped her generalize her speech to new settings on her own. Gladys's newly harnessed spontaneity further helped her become more sociable and resilient.This study advances the possibility of integrating a behavioural skill with drama therapy for the therapeutic benefits of a child with an anxiety-related condition like selective mutism. PMID- 20194569 TI - Synergistic inhibitory effect of angiotensin II receptor blocker and thiazide diuretic on the tissue renin-angiotensin-aldosterone system. AB - ARBs are conceptually more potent in a high renin state than in a low renin state at blood pressure reduction and cardiovascular protection, whereas the potency of thiazide diuretics in the contrary. However, the additive effect of the agents when used in combination remains unclear. Thus, the goal of the present review was to analyse available data to explain the mechanistic actions of the ARB thiazide diuretic combination. Although the circulating renin-angiotensin aldosterone system (RAAS) has been well characterised in the context of cardiovascular disease, recent attention has also focused on the role of the tissue RAAS. For example, both angiotensin II and aldosterone are produced in small amounts within cardiac tissue, and the angiotensin II type 1 receptor is widely distributed and activated within cardiovascular tissues. Recent reports also suggest that the mineralocorticoid receptor is activated through Rac1 GTP ase in high salt-intake rats. Thus, many components of the RAAS are activated in cardiovascular tissues under high salt-intake conditions, and a low salt diet or use of diuretics likely suppresses the tissue RAAS. Since ARBs can block the effect of both tissue angiotensin II and circulating angiotensin II, it follows that the combination of an ARB and a thiazide diuretic results in synergistic inhibition of the tissue RAAS. PMID- 20194570 TI - Skilled cardiac monitoring at the bedside: an algorithm for success. PMID- 20194571 TI - Alcohol withdrawal: development of a standing order set. PMID- 20194572 TI - Schizophrenia genes, epigenetics and psychoneuroimmunology therapeutics: all make sense now? AB - Genetics, epigenetics, infection as an environmental factor, functional findings for the immune system, and a therapeutic approach with anti-inflammatory therapy provide evidence for a pivotal role of the immune system in schizophrenia. This field, therefore, should focus more on further schizophrenia research. PMID- 20194573 TI - Comparison of antinociceptive and antidiabetic effects of sertraline and amitriptyline on streptozotocin-induced diabetic rats. AB - Antidepressants (ADs) are frequently used for the treatment of persistent pain associated with diabetic neuropathy. The aim of this study is to investigate the antinociceptive effects of sertraline (Ser) and amitriptyline (Ami) in diabetic rats, and additionally monitoring their effects on grip strength, blood glucose and percentage glycosylated hemoglobin (GHb%) levels. Streptozotocin (STZ; 55 mg/kg, intraperitoneal [ip]) was injected in rats to induce diabetes. After 7 days, Ser (30 mg/kg) or Ami (15 mg/kg) was administered in diabetic rats orally. After 28 days drug treatment, the antinociceptive effects were evaluated using hot plate test both in diabetic and non-diabetic rats. The effects of these drugs on grip strength, blood glucose and GHb% were also measured. Ser and Ami showed antinociceptive effects in diabetic and non-diabetic rats. Both the drugs increased the grip strength reduction in STZ-induced diabetic rats. Ser reduces and Ami increases the serum glucose levels in diabetic and normal rats. Administration of Ami per se increased GHb% levels, while Ser per se has no effects. The effects of Ser (30 mg/kg, per os [po]) on glucose, GHb% and antinociceptive action on hot plate test showed an association between improved blood glucose levels and analgesia. However, the results of Ami treatment are controversial and needs further studies. PMID- 20194574 TI - Effect of aqueous extract of Leonotis leonurus (L.) R. Br. leaves in male Wistar rats. AB - The aqueous extract of the leaves of Leonotis leonurus (L.) R. Br. at the doses of 125, 250 and 500 mg/kg body weight was investigated for toxicity in male rats following administration on daily basis for 21 days. The extract did not significantly (p > .05) alter the levels of haemoglobin, packed cell volume, mean corpuscular volume, red cell distribution width, basophils, total protein, phosphorus, calcium and chloride ions of the animals. Whereas the levels of lymphocytes, eosinophils, monocytes, triacylglycerol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, atherogenic index, albumin as well as alkaline phosphatase and gamma glutamyl transferase activity were decreased by the extract, those of neutrophil, magnesium, total and conjugated bilirubin, alanine and aspartate aminotransferase as well as liver and kidney body weight ratios increased. There was decrease in the mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration and cholesterol only at the 500 mg/kg body weight of the extract, whereas the large unstained cells, sodium ions, white blood cells and uric acid increased only at 250 and 500 mg/kg body weight of the extract, respectively. The urea, creatinine and potassium increased only at 125 mg/kg body weight of the extract while the globulin content was elevated only at 500 mg/kg body weight of the extract. The doses did not produce any definite pattern of effect on the red blood cells and platelets. These alterations by the aqueous extract of L. leonurus leaves on the haematological together with the liver and kidney functional indices suggests parameter and dose-selective effects of the extract and will have consequential effects on the normal functioning of the blood system, kidney and liver of the animals. The extract is also unlikely to predispose the animals to cardiovascular risk when repeatedly consumed on daily basis at the doses investigated for 21 days. Therefore, the aqueous extract of L. leonurus leaves may not be 'safe' as oral remedy in male rats. PMID- 20194575 TI - Protection by pentoxifylline of malathion-induced toxic stress and mitochondrial damage in rat brain. AB - OBJECTIVE: The objective of this study was to investigate the possible protective effects of pentoxifylline as a phosphodiesterase-5 inhibitor on malathion-induced oxidative damage to rat brain mitochondria. METHODS: Rats received malathion (200 mg/kg/day) and pentoxifylline (PTX, 50 mg/kg/day) in combination or alone. Alpha tocopherol (AT, 15 mg/kg/day) was used as a positive standard. After 1 week of treatment, blood, whole brain tissue, and brain mitochondria were isolated. The activity of enzymatic scavengers such as glutathione peroxidase (GPx), catalase (CAT), copper-zinc superoxide dismutase (Cu/ZnSOD), and manganese superoxide dismutase (MnSOD) were measured. The extents of cellular lipid peroxidation (LPO), nitrotyrosine (NOx), and the ratio of reduced versus oxidized glutathione (GSH/GSSG) were determined. The protein expression of MnSOD was determined in brain mitochondria. RESULTS: Malathion stimulated activities of CAT, Cu/ZnSOD, GPx, and increased LPO and NOx, and decreased GSH/GSSG in whole brain homogenate. The changes in CAT, LPO, GPx, and GSH/GSSG were restored by PTX and AT. In plasma samples, malathion increased CAT, Cu/ZnSOD, and GPx activities, increased LPO, and decreased GSH/GSSG, while PTX and AT attenuated malathion-induced changes in GPx, Cu/ZnSOD, LPO, and GSH/GSSG. In brain mitochondria, malathion enhanced LPO, NOx, CAT, GPx, and MnSOD and decreased GSH/GSSG as compared to controls, whereas PTX and AT restored malathion-induced changes in GSH/GSSG, NOx, GPx, and CAT. Malathion noticeably enhanced expression of MnSOD protein as compared to controls. Malathion decreased viability of mitochondria that was recovered by AT. It is concluded that oxidative damage is at least in part the mechanism of toxicity of malathion in the mitochondria that can be recovered by PTX comparable to AT. PMID- 20194576 TI - Performance and haematological indices in rats exposed to monocrotophos contamination. AB - Monocrotophos is an organophosphate pesticide used in agriculture to control insect pests. Changes in performance and haematological parameters (such as packed cell volume, white blood cells, neutrophils, eosinophils and lymphocytes) were used to assess the effect of the pesticide on rats chronically exposed to 12.5 parts per million (ppm), 25 ppm, 50 ppm, 100 ppm and 200 ppm for 10 days, while the control rats were placed on borehole water. Administration of the pesticide to the animals resulted in several physical deteriorations including appearance and agility. A significant reduction (p < .05) was observed in the weight gained by rats while the liver-to-body weight ratio increased significantly (p < .05) as the level of exposure to monocrotophos increased. Whereas packed cell volume, white blood cells and lymphocytes increased significantly (p < .05), neutrophils and eosinophils counts reduced significantly (p < .05) as the concentration of monocrotophos in the drinking water increased. Overall, the data indicated that exposure to monocrotophos portends serious consequences on the performance and haematological parameters of rats. PMID- 20194577 TI - 'Flooding' of the lungs and severe dyspnea in a patient with bronchoalveolar carcinoma. AB - In this case report, we describe a patient with bronchoalveolar carcinoma that experienced severe bronchorrhea and dyspnea after inhalation of N-acetylcysteine. The adverse reactions occurred both after oral and nebulized administration of N acetylcysteine, resulting in severe dyspnea and the feeling of 'drowning'. Bronchorrhea has previously been reported as an uncommon but serious complication of bronchoalveolar carcinoma. We strongly suspect the administration of N acetylcysteine to be implicated, as the complications occurred immediately after administration of this drug. As the patient suffered from hyperhomocysteinemia, we speculate that an additive or synergistic interaction with homocysteine may have been involved as well. PMID- 20194578 TI - Early cognitive impairment in multiple sclerosis predicts disability outcome several years later. AB - Cognition is frequently impaired in the early stages of multiple sclerosis (MS). The predictive value of cognitive impairment on disability is unknown. The objective of this study was to correlate cognitive impairment and the progression of disability over 7 years. Forty-five patients, recruited after MS diagnosis, were followed for 7 years by yearly Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) evaluations and were classified as cognitively impaired (CI) or unimpaired (CU) according to neuropsychological testing at baseline. At baseline, 47.8% of patients were CI, with deficits in mainly memory and information processing speed (IPS). The baseline EDSS correlated significantly with one IPS test. The EDSS, but not the MSFC, deteriorated significantly over the 7 years in the whole group and the CI group, but not the CU group. A multivariate analysis showed correlations between the EDSS change over 5 and 7 years and two baseline tests evaluating IPS and verbal memory. The deterioration of the EDSS after 7 years was significantly correlated with verbal memory testing at baseline after adjustment for age and baseline EDSS. In conclusion, in this sample of MS patients early in the disease, the baseline IPS and verbal memory impairments predict the EDSS score 5 and 7 years later. PMID- 20194579 TI - Cerebrospinal fluid ATP metabolites in multiple sclerosis. AB - Increased axonal energy demand and mitochondrial failure have been suggested as possible causes for axonal degeneration and disability in multiple sclerosis. Our objective was to test whether ATP depletion precedes clinical, imaging and biomarker evidence for axonal degeneration in multiple sclerosis. The method consisted of a longitudinal study which included 21 patients with multiple sclerosis. High performance liquid chromatography was used to quantify biomarkers of the ATP metabolism (oxypurines and purines) from the cerebrospinal fluid at baseline. The Expanded Disability Status Scale, MRI brain imaging measures for brain atrophy (ventricular and parenchymal fractions), and cerebrospinal fluid biomarkers for axonal damage (phosphorylated and hyperphosphorylated neurofilaments) were quantified at baseline and 3-year follow-up. Central ATP depletion (sum of ATP metabolites >19.7 micromol/litre) was followed by more severe progression of disability if compared to normal ATP metabolites (median 1.5 versus 0, p< 0.05). Baseline ATP metabolite levels correlated with change of Expanded Disability Status Scale in the pooled cohort (r= 0.66, p= 0.001) and subgroups (relapsing-remitting patients: r= 0.79, p< 0.05 and secondary progressive/primary progressive patients: r= 0.69, p< 0.01). There was no relationship between central ATP metabolites and either biomarker or MRI evidence for axonal degeneration. The data suggests that an increased energy demand in multiple sclerosis may cause a quantifiable degree of central ATP depletion. We speculate that the observed clinical disability may be related to depolarisation associated conduction block. PMID- 20194582 TI - Accuracy of MRI criteria for dissemination in space for the diagnosis of multiple sclerosis in patients with clinically isolated syndromes. AB - The MRI Barkhof-Tintore criteria have proved to be highly specific for predicting conversion to clinically definite multiple sclerosis in patients with clinically isolated syndromes (CIS), but lacked an optimal sensitivity. In order to improve the accuracy of early multiple sclerosis diagnosis, new imaging criteria have been proposed by Swanton et al. We aimed to evaluate the accuracy of both MRI criteria for dissemination in space to predict conversion from CIS to clinically definite multiple sclerosis. We studied 79 CIS patients with baseline MRI performed within the first 3 months after onset. The sensitivity and specificity of both MRI criteria to predict conversion to clinically definite multiple sclerosis were analysed. The time to develop clinically definite multiple sclerosis from CIS onset, according to each imaging criteria, was studied by Kaplan-Meier survival curves. The overall conversion rate was 75.7% with a median follow-up of 57 months. Barkhof- Tintore's criteria showed a sensitivity of 71.9% and a specificity of 77.2%. Swanton's criteria had a sensitivity of 91.2% and a specificity of 68.1%. Both MRI criteria identified CIS patients with higher risk and faster conversion to clinically definite multiple sclerosis. Swanton's criteria are simpler and more sensitive than Barkhof-Tintore's criteria, with a slight decrease in specificity. These results reinforce their use in multiple sclerosis diagnosis. PMID- 20194580 TI - Focal and diffuse cortical degenerative changes in a marmoset model of multiple sclerosis. AB - BACKGROUND: Degenerative features, such as neuronal, glial, synaptic and axonal loss, have been identified in neocortical and other grey matter structures in patients with multiple sclerosis, but mechanisms for neurodegeneration are unclear. Cortical demyelinating lesions are a potential cause of this degeneration, but the pathological and clinical significance of these lesions is uncertain as they remain difficult to identify and study in vivo. In this study we aimed to describe and quantify cellular and subcellular pathology in the cortex of myelin oligodendrocyte glycoprotein-induced marmoset experimental autoimmune encephalomyelitis using quantitative immunohistochemical methods. RESULTS: We found evidence of diffuse axonal damage occurring throughout cortical grey matter with evidence for synaptic loss and gliosis and a 13.6% decrease in neuronal size and occurring in deep cortical layers. Evidence of additional axonal damage and a 29.6-36.5% loss of oligodendrocytes was found in demyelinated cortical lesions. Leucocortical lesions also showed neuronal loss of 22.2% and a 15.8% increase in oligodendrocyte size. CONCLUSIONS: The marmoset experimental autoimmune encephalomyelitis model, therefore, shows both focal and generalized neurodegeneration. The generalized changes cannot be directly related to focal lesions, suggesting that they are either a consequence of diffusible inflammatory factors or secondary to remote lesions acting through trans-synaptic or retrograde degeneration. PMID- 20194581 TI - Interleukin 7 receptor alpha polymorphism rs6897932 and susceptibility to multiple sclerosis in the Western Balkans. AB - The interleukin 7 receptor alpha single nucleotide polymorphism rs6897932 was identified as a multiple sclerosis susceptibility-modifying polymorphism in genome-wide and gene scan studies, mainly in populations in western countries. The aim of this study was to investigate the association of interleukin 7 receptor alpha rs6897932 with multiple sclerosis in populations from the Western Balkans: Serbia, Croatia, and Slovenia. A total of 678 unrelated white patients and 597 unrelated, ethnically matched healthy controls were included in the study. Genotyping was performed by real-time polymerase chain reaction. We found no significant difference in genotype or allele frequencies between controls and patients with multiple sclerosis either separately in Serbian, Croatian, and Slovenian populations or in the whole sample from the Western Balkans. The odds ratio for multiple sclerosis in this study was 1.04 (0.86-1.25) for the C allele. It is known that demographic as well as environmental factors have a substantial role in multiple sclerosis development, as well as population genetic background. The results of this study indicate that other types of genome variants should be required for the development and/or progression of multiple sclerosis, which may vary among populations. PMID- 20194583 TI - The McDonald Criteria for Multiple Sclerosis: time for clarification. AB - The McDonald Criteria for Multiple Sclerosis in general have replaced the Poser criteria. Despite this, many consider that there are still areas of ambiguity. In this study, neurologists completed a questionnaire about familiarity with, usefulness and applicability of the McDonald Criteria for Multiple Sclerosis. Understanding of 'attack'; objective clinical evidence; 'two or more lesions' and their ability to interpret case scenarios was evaluated. Responses were analysed overall and by skill group. Ninety-seven consultants and 30 trainees responded, of whom 37 operated a multiple sclerosis clinic ('experts'). Some (62%) thought the McDonald Criteria for Multiple Sclerosis were useful, and 31% found them confusing or difficult to apply; 38% thought the criteria should be applied universally, others (14-28%) favoured their use for drug trials/research, and 17% rarely used them. Thirty-six (29.1%) thought the McDonald Criteria for Multiple Sclerosis specified two categories: 'MS and not MS', but others considered 'possible' or 'probable' multiple sclerosis were permitted. Experts understood better 'an attack' and 'objective clinical evidence'. All skill groups comprehended poorly what constituted an episode of demyelination, and whether Lhermitte's phenomenon was acceptable as evidence for cervical cord demyelination. A consistent response was given by 44-50% to 'two or more lesions', although this is not well defined. Criteria for primary progressive multiple sclerosis were understood well. We conclude that the McDonald Criteria for Multiple Sclerosis have improved diagnosis but areas of misinterpretation remain, particularly the definition of 'an attack', 'objective clinical evidence' and 'two or more lesions'. There was uncertainty about how many multiple sclerosis categories were permitted and whether the terms 'possible' and 'probable' were allowable. Further clarification might allow the criteria to be applied more consistently. PMID- 20194584 TI - Fatigue, mood and quality of life improve in MS patients after progressive resistance training. AB - Fatigue occurs in the majority of multiple sclerosis patients and therapeutic possibilities are few. Fatigue, mood and quality of life were studied in patients with multiple sclerosis following progressive resistance training leading to improvement of muscular strength and functional capacity. Fatigue (Fatigue Severity Scale, FSS), mood (Major Depression Inventory, MDI) and quality of life (physical and mental component scores, PCS and MCS, of SF36) were scored at start, end and follow-up of a randomized controlled clinical trial of 12 weeks of progressive resistance training in moderately disabled (Expanded Disability Status Scale, EDSS: 3-5.5) multiple sclerosis patients including a Control group (n = 15) and an Exercise group (n = 16). Fatigue (FSS > 4) was present in all patients. Scores of FSS, MDI, PCS-SF36 and MCS-SF36 were comparable at start of study in the two groups. Fatigue improved during exercise by -0.6 (95% confidence interval (CI) -1.4 to 0.4) a.u. vs. 0.1 (95% CI -0.4 to 0.6) a.u. in controls (p = 0.04), mood improved by -2.4 (95% CI -4.1 to 0.7) a.u. vs. 1.1 (-1.2 to 3.4) a.u. in controls (p = 0.01) and quality of life (PCS-SF36) improved by 3.5 (95% CI 1.4-5.7) a.u. vs. -1.0 (95% CI -3.4-1.4) a.u. in controls (p = 0.01). The beneficial effect of progressive resistance training on all scores was maintained at follow-up after further 12 weeks. Fatigue, mood and quality of life all improved following progressive resistance training, the beneficial effect being maintained for at least 12 weeks after end of intervention. PMID- 20194585 TI - Preservation of endothelium nitric oxide release during beating heart surgery with respect to continuous flow cardiopulmonary bypass. AB - A correlation between perfusion modality and vascular dilation induced by endothelial nitric oxide (NO) release has been pointed out in the literature; nevertheless, only a few studies deal with the analysis of patients treated by cardiac surgery. The aim of this work is to analyze endothelial NO release in patients undergoing cardiac surgery under continuous flow cardiopulmonary bypass (CPB) or pulsatile perfusion. Pulsatile devices approved for clinical CPB do not accurately reproduce the physiological flow waveform provided by the left ventricle while, on the other hand, it is important to analyze pulsatile perfusion under both physiological flow waveform and pulsatile flow CPB. Physiological pulsatile perfusion (supplied by the left ventricle) was examined in this study. A total of 16 patients undergoing cardiac surgery were enrolled in the study and divided into two groups: 8 patients were put on continuous flow CPB while the others underwent beating heart surgery. Venous blood samples were withdrawn to quantify endothelial NO release through its bioactive forms in blood. Plasma was used for the chemiluminescent detection of nitrite (NO(2)(-)) and nitrate (NO(3)(-)), and the cellular component for electron spin resonance detection of nitrosylhemoglobin. Significant reduction in the intraoperative concentration with respect to the preoperative was observed only in the continuous group for both NO(2)(-) and NO(x) (NO(2)(-) + NO(3)(-)) concentration (p=0.003 and p=0.016, respectively). A significant difference in the intraoperative nitrite concentration was also observed between the groups (p=0.006). Nitrosylhemoglobin concentration, although not instrumentally detectable, resulted as negligible with respect to the other NO metabolites. Despite the small number of patients belonging to each group, this significant reduction of NO(2)(-) concentration under continuous flow CPB revealed a strong dependence on endothelial NO release and plasma nitrite concentration on perfusion modality. PMID- 20194586 TI - Antigen-presenting dendritic cells rescue CD4-depleted CCR2-/- mice from lethal Histoplasma capsulatum infection. AB - Excessive production of interleukin-4 impairs clearance of the fungal pathogen Histoplasma capsulatum in mice lacking the chemokine receptor CCR2. An increase in the interleukin-4 level is associated with decreased recruitment of dendritic cells to lungs; therefore, we investigated the possibility that these cells influence interleukin-4 production. Adoptive transfer of wild-type or CCR2(-/-) bone marrow-derived dendritic cells loaded with heat-killed yeast cells to infected CCR2(-/-) mice suppressed interleukin-4 transcription. Surprisingly, transfer of cells did not reduce the fungal burden despite the fact that it limited interleukin-4 transcription. Yeast cell-loaded bone marrow-derived dendritic cell-mediated regulation of interleukin-4 transcription was dependent on major histocompatibility complex II antigen presentation to CD4(+) T cells. We previously showed that CD4(+) T cells were a source of interleukin-4 in infected CCR2(-/-) mice, but their contribution to the TH2 phenotype was unclear. Here we demonstrated that these cells were functionally important since elimination of them prior to infection, but not elimination of them at the time of infection, reduced the interleukin-4 level in infected CCR2(-/-) mice. However, the fungal burden was reduced only in CD4-depleted CCR2(-/-) mice that received yeast cell loaded bone marrow-derived dendritic cells. Taken together, the data indicate that generation of excess interleukin-4 in lungs of H. capsulatum-infected CCR2( /-) mice is at least partially a consequence of decreased recruitment of dendritic cells capable of antigen presentation. Furthermore, CD4(+) T cells had a deleterious impact on immunity in infected CCR2(-/-) mice. PMID- 20194587 TI - Identification and characterization of a glycosyltransferase involved in Acinetobacter baumannii lipopolysaccharide core biosynthesis. AB - Although Acinetobacter baumannii has emerged as a significant cause of nosocomial infections worldwide, there have been few investigations describing the factors important for A. baumannii persistence and pathogenesis. This paper describes the first reported identification of a glycosyltransferase, LpsB, involved in lipopolysaccharide (LPS) biosynthesis in A. baumannii. Mutational, structural, and complementation analyses indicated that LpsB is a core oligosaccharide glycosyl transferase. Using a genetic approach, lpsB was compared with the lpsB homologues of several A. baumannii strains. These analyses indicated that LpsB is highly conserved among A. baumannii isolates. Furthermore, we developed a monoclonal antibody, monoclonal antibody 13C11, which reacts to an LPS core epitope expressed by approximately one-third of the A. baumannii clinical isolates evaluated to date. Previous studies describing the heterogeneity of A. baumannii LPS were limited primarily to structural analyses; therefore, studies evaluating the correlation between these surface glycolipids and pathogenesis were warranted. Our data from an evaluation of LpsB mutant 307::TN17, which expresses a deeply truncated LPS glycoform consisting of only two 3-deoxy-d-manno octulosonic acid residues and lipid A, suggest that A. baumannii LPS is important for resistance to normal human serum and confers a competitive advantage for survival in vivo. These results have important implications for the role of LPS in A. baumannii infections. PMID- 20194588 TI - Listeriolysin O-dependent bacterial entry into the cytoplasm is required for calpain activation and interleukin-1 alpha secretion in macrophages infected with Listeria monocytogenes. AB - Listeriolysin O (LLO), an hly-encoded cytolysin of Listeria monocytogenes, plays an essential role in the entry of L. monocytogenes into the host cell cytoplasm. L. monocytogenes-infected macrophages produce various proinflammatory cytokines, including interleukin-1 alpha (IL-1 alpha), that contribute to the host immune response. In this study, we have examined IL-1 alpha production in macrophages infected with wild-type L. monocytogenes or a nonescaping mutant strain deficient for LLO (Delta hly). Expression of IL-1 alpha mRNA and accumulation of pro-IL-1 alpha in the cytoplasm were induced by both strains. In contrast, the secretion of the mature form of IL-1 alpha from infected macrophages was observed in infection with wild-type L. monocytogenes but not with the Delta hly mutant. A recovery of the ability to induce IL-1 alpha secretion was shown in a mutant strain complemented with the hly gene. The Toll-like receptor (TLR)/MyD88 signaling pathway was exclusively required for the expression of pro-IL-1 alpha, independently of LLO-mediated cytoplasmic entry of L. monocytogenes. The LLO dependent secretion of mature IL-1 alpha was abolished by addition of calcium chelators, and only LLO-producing L. monocytogenes strains were able to induce elevation of the intracellular calcium level in infected macrophages. A calcium dependent protease, calpain, was implicated in the maturation and secretion of IL 1 alpha induced by LLO-producing L. monocytogenes strains based on the effect of calpain inhibitor. Functional activation of calpain was detected in macrophages infected with LLO-producing L. monocytogenes strains but not with a mutant strain lacking LLO. These results clearly indicated that LLO-mediated cytoplasmic entry of bacteria could induce the activation of intracellular calcium signaling, which is essential for maturation and secretion of IL-1 alpha in macrophages during L. monocytogenes infection through activation of a calcium-dependent calpain protease. In addition, recombinant LLO, when added to macrophages infected with the Delta hly strain, could induce calcium influx and IL-1 alpha secretion at doses exhibiting cytolytic activity, suggesting that LLO produced by intracellular L. monocytogenes may be implicated in induction of calcium influx through pore formation. PMID- 20194589 TI - CdpA is a Burkholderia pseudomallei cyclic di-GMP phosphodiesterase involved in autoaggregation, flagellum synthesis, motility, biofilm formation, cell invasion, and cytotoxicity. AB - Cyclic diguanylic acid (c-di-GMP) is an intracellular signaling molecule involved in regulation of cellular functions such as motility, biofilm formation and virulence. Intracellular level of c-di-GMP is controlled through opposing diguanylate cyclase (DGC) and phosphodiesterase (PDE) activities of GGDEF and EAL domain proteins, respectively. We report the identification and characterization of cdpA, a gene encoding a protein containing an EAL domain in the Gram-negative soil bacillus and human pathogen Burkholderia pseudomallei KHW. Purified recombinant CdpA protein exhibited PDE activity in vitro. Evidence that CdpA is a major c-di-GMP-specific PDE in B. pseudomallei KHW was shown by an 8-fold-higher c-di-GMP level in the cdpA-null mutant as compared to the wild type and the complemented cdpA mutant. The presence of higher intracellular c-di-GMP levels in the cdpA-null mutant was associated with increased production of exopolysaccharides, increased cell-to-cell aggregation, absence of flagella and swimming motility, and increased biofilm formation. The relevance of CdpA in B. pseudomallei virulence was demonstrated by a 3-fold reduction in invasion of human lung epithelial cells and a 6-fold reduction in cytotoxicity on human macrophage cells infected with the cdpA mutant. PMID- 20194590 TI - Immunization with VAR2CSA-DBL5 recombinant protein elicits broadly cross-reactive antibodies to placental Plasmodium falciparum-infected erythrocytes. AB - Pregnancy-associated malaria is a severe clinical syndrome associated with the sequestration of Plasmodium falciparum-infected erythrocytes in the placenta. Placental binding is mediated by VAR2CSA, a member of the large and diverse P. falciparum erythrocyte membrane 1 (PfEMP1) protein family. To better understand if conserved regions in VAR2CSA can be targeted by antibodies, we immunized rabbits with VAR2CSA-DBL1 and -DBL5 recombinant proteins produced in Pichia pastoris and developed a panel of seven chondroitin sulfate A (CSA)-binding parasites from diverse geographic origins. Overall, no two parasites in the panel expressed the same VAR2CSA sequence. The DBL1 domains averaged 80% amino acid identity (range, 72 to 89%), and the DBL5 domains averaged 86% amino acid identity (range, 83 to 99%), similar to a broader sampling of VAR2CSA sequences from around the world. Whereas antibodies generated against the VAR2CSA-DBL1 recombinant protein had only limited breadth and reacted with three or four parasites in the panel, immunization with DBL5 recombinant proteins elicited broadly cross-reactive antibodies against all or most parasites in the panel, as well as to fresh clinical isolates from pregnant women. These findings demonstrate that the major PfEMP1 variant expressed by placental isolates exposes strain-transcendent epitopes that can be targeted by vaccination and may have application for pregnancy malaria vaccine development. PMID- 20194591 TI - The Brucella abortus phosphoglycerate kinase mutant is highly attenuated and induces protection superior to that of vaccine strain 19 in immunocompromised and immunocompetent mice. AB - Brucella abortus is a facultative intracellular bacterial pathogen that causes abortion in domestic animals and undulant fever in humans. The mechanism of virulence of Brucella spp. is not yet fully understood. Therefore, it is crucial to identify new molecules that can function as virulence factors to better understand the host-pathogen interplay. Herein, we identified the gene encoding the phosphoglycerate kinase (PGK) of B. abortus strain 2308. To test the role of PGK in Brucella pathogenesis, a pgk deletion mutant was constructed. Replacement of the wild-type pgk by recombination was demonstrated by Southern and Western blot analyses. The B. abortus Delta pgk mutant strain exhibited extreme attenuation in bone marrow-derived macrophages and in vivo in BALB/c, C57BL/6, 129/Sv, and interferon regulatory factor-1 knockout (IRF-1 KO) mice. Additionally, at 24 h postinfection the Delta pgk mutant was not found within the same endoplasmic reticulum-derived compartment as the wild-type bacteria, but, instead, over 60% of Brucella-containing vacuoles (BCVs) retained the late endosomal/lysosomal marker LAMP1. Furthermore, the B. abortus Delta pgk deletion mutant was used as a live vaccine. Challenge experiments revealed that the Delta pgk mutant strain induced protective immunity in 129/Sv or IRF-1 KO mice that was superior to the protection conferred by commercial strain 19 or RB51. Finally, the results shown here demonstrated that Brucella PGK is critical for full bacterial virulence and that a Delta pgk mutant may serve as a potential vaccine candidate in future studies. PMID- 20194593 TI - Indispensable role for the eukaryotic-like ankyrin domains of the ankyrin B effector of Legionella pneumophila within macrophages and amoebae. AB - The Dot/Icm-translocated ankyrin B (AnkB) effector of Legionella pneumophila exhibits molecular mimicry of eukaryotic F-box proteins and is essential for intracellular replication in macrophages and protozoa. In addition to two eukaryotic-like ankyrin (ANK) domains, AnkB harbors a conserved eukaryotic F-box domain, which is involved in polyubiquitination of proteins throughout the eukaryotic kingdom. We have recently shown that the F-box domain of the AnkB effector is essential for decoration of the Legionella-containing vacuole (LCV) with polyubiquitinated proteins within macrophages and protozoan hosts. To decipher the role of the two ANK domains in the function of AnkB, we have constructed in-frame deletion of either or both of the ANK domain-encoding regions (ankB Delta A1, ankB Delta A2, and ankB Delta A1A2) to trans-complement the ankB null mutant. Deletion of the ANK domains results in defects in intracellular proliferation and decoration of the LCV with polyubiquitinated proteins. Export of the truncated variants of AnkB was reduced, and this may account for the observed defects. However, while full-length AnkB ectopically expressed in mammalian cells trans-rescues the ankB null mutant for intracellular proliferation, ectopic expression of AnkB Delta A1, AnkB Delta A2, and AnkB Delta A1A2 fails to trans-rescue the ankB null mutant. Importantly, ectopically expressed full-length AnkB is targeted to the host cell plasma membrane, where it recruits polyubiquitinated proteins. In contrast, AnkB Delta A1, AnkB Delta A2, and AnkB Delta A1A2 are diffusely distributed throughout the cytosol and fail to recruit polyubiquitinated proteins. We conclude that the two eukaryotic-like ANK domains of AnkB are essential for intracellular proliferation, for targeting AnkB to the host membranes, and for decoration of the LCV with polyubiquitinated proteins. PMID- 20194592 TI - Salmonella enterica serovar Typhimurium-induced placental inflammation and not bacterial burden correlates with pathology and fatal maternal disease. AB - Food-borne infections caused by Salmonella enterica species are increasing globally, and pregnancy poses a high risk. Pregnant mice rapidly succumb to S. enterica serovar Typhimurium infection. To determine the mechanisms involved, we addressed the role of inflammation and bacterial burden in causing placental and systemic disease. In vitro, choriocarcinoma cells were a highly conducive niche for intracellular S. Typhimurium proliferation. While infection of mice with S. Typhimurium wild-type (WT) and mutant (Delta aroA and Delta invA) strains led to profound pathogen proliferation and massive burden within placental cells, only the virulent WT S. Typhimurium infection evoked total fetal loss and adverse host outcome. This correlated with substantial placental expression of granulocyte colony-stimulating factor (G-CSF), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) and increased serum inflammatory cytokines/chemokines, such as G-CSF, IL-6, CCL1, and KC, evoked by WT S. Typhimurium infection. In contrast, infection with high doses of S. Typhimurium Delta aroA, despite causing massive placental infection, resulted in reduced inflammatory cellular and cytokine response. While S. Typhimurium WT bacteria were dispersed in large numbers across all regions of the placenta, including the deeper labyrinth trophoblast, S. Typhimurium Delta aroA bacteria localized primarily to the decidua. This correlated with the widespread placental necrosis accompanied by neutrophil infiltration evoked by the S. Typhimurium WT bacteria. Thus, the ability of Salmonella to localize to deeper layers of the placenta and the nature of inflammation triggered by the pathogen, rather than bacterial burden, profoundly influenced placental integrity and host survival. PMID- 20194594 TI - CCR7-dependent immunity during acute Toxoplasma gondii infection. AB - The chemokine receptor CCR7 is a well-established homing receptor for dendritic cells and T cells. Interactions with its ligands, CCL19 and CCL21, facilitate priming of immune responses in lymphoid tissue, yet CCR7-independent immune responses can be generated in the presence of sufficient antigen. In these studies, we investigated the role of CCR7 signaling in the generation of protective immune responses to the intracellular protozoan parasite Toxoplasma gondii. The results demonstrated a significant increase in the expression of CCL19, CCL21, and CCR7 in peripheral and central nervous system (CNS) tissues over the course of infection. Unexpectedly, despite the presence of abundant antigen, CCR7 was an absolute requirement for protective immunity to T. gondii, as CCR7(-/-) mice succumbed to the parasite early in the acute phase of infection. Although serum levels of interleukin 12 (IL-12), IL-6, tumor necrosis factor alpha (TNF-alpha), and IL-10 remained unchanged, there was a significant decrease in CCL2/monocyte chemoattractant protein 1 (MCP-1) and inflammatory monocyte recruitment to the site of infection. In addition, CCR7(-/-) mice failed to produce sufficient gamma interferon (IFN-gamma), a critical Th1-associated effector cytokine required to control parasite replication. As a result, there was increased parasite dissemination and a significant increase in parasite burden in the lungs, livers, and brains of infected mice. Adoptive-transfer experiments revealed that expression of CCR7 on the T-cell compartment alone is sufficient to enable T-cell priming, increase IFN-gamma production, and allow the survival of CCR7(-/-) mice. These data demonstrate an absolute requirement for T cell expression of CCR7 for the generation of protective immune responses to Toxoplasma infection. PMID- 20194595 TI - Inactivation of phospholipase D diminishes Acinetobacter baumannii pathogenesis. AB - Acinetobacter baumannii is an emerging bacterial pathogen of considerable health care concern. Nonetheless, relatively little is known about the organism's virulence factors or their regulatory networks. Septicemia and ventilator associated pneumonia are two of the more severe forms of A. baumannii disease. To identify virulence factors that may contribute to these disease processes, genetically diverse A. baumannii clinical isolates were evaluated for the ability to proliferate in human serum. A transposon mutant library was created in a strain background that propagated well in serum and screened for members with decreased serum growth. The results revealed that disruption of A. baumannii phospholipase D (PLD) caused a reduction in the organism's ability to thrive in serum, a deficiency in epithelial cell invasion, and diminished pathogenesis in a murine model of pneumonia. Collectively, these results suggest that PLD is an A. baumannii virulence factor. PMID- 20194596 TI - Role of host sphingosine kinase 1 in the lung response against Cryptococcosis. AB - Cryptococcus neoformans is a fungal pathogen causing pulmonary infection and a life-threatening meningoencephalitis in human hosts. The fungus infects the host through inhalation, and thus, the host response in the lung environment is crucial for containment or dissemination of C. neoformans to other organs. In the lung, alveolar macrophages (AMs) are key players in the host lung immune response, and upon phagocytosis, they can kill C. neoformans by evoking an effective immune response through a variety of signaling molecules. On the other hand, under conditions not yet fully defined, the fungus is able to survive and proliferate within macrophages. Since the host sphingosine kinase 1 (SK1) regulates many signaling functions of immune cells, particularly in macrophages, in this study we determined the role of SK1 in the host response to C. neoformans infection. Using wild-type (SK1/2(+/+)) and SK1-deficient (SK1(-/-)) mice, we found that SK1 is dispensable during infection with a facultative intracellular wild-type C. neoformans strain. However, SK1 is required to form a host lung granuloma and to prevent brain infection by a C. neoformans mutant strain lacking the cell wall-associated glycosphingolipid glucosylceramide (Delta gcs1), previously characterized as a mutant able to replicate only intracellularly. Specifically, in contrast to those from SK1/2(+/+) mice, lungs from SK1(-/-) mice have no collagen deposition upon infection with C. neoformans Delta gcs1, and AMs from these mice contain significantly more C. neoformans cells than AMs from SK1/2(+/+) mice, suggesting that under conditions in which C. neoformans is more internalized by AMs, SK1 may become important to control C. neoformans infection. Indeed, when we induced immunosuppression, a host condition in which wild-type C. neoformans cells are increasingly found intracellularly, SK1(-/-) survived significantly less than SK1/2(+/+) mice infected with a facultative intracellular wild-type strain, suggesting that SK1 has an important role in controlling C. neoformans infection under conditions in which the fungus is predominantly found intracellularly. PMID- 20194598 TI - Cigarette smoke inhibits airway epithelial cell innate immune responses to bacteria. AB - The human upper respiratory tract, including the nasopharynx, is colonized by a diverse array of microorganisms. While the host generally exists in harmony with the commensal microflora, under certain conditions, these organisms may cause local or systemic disease. Respiratory epithelial cells act as local sentinels of the innate immune system, responding to conserved microbial patterns through activation of signal transduction pathways and cytokine production. In addition to colonizing microbes, these cells may also be influenced by environmental agents, including cigarette smoke (CS). Because of the strong relationship among secondhand smoke exposure, bacterial infection, and sinusitis, we hypothesized that components in CS might alter epithelial cell innate immune responses to pathogenic bacteria. We examined the effect of CS condensate (CSC) or extract (CSE) on signal transduction and cytokine production in primary and immortalized epithelial cells of human or murine origin in response to nontypeable Haemophilus influenzae and Staphylococcus aureus. We observed that epithelial production of interleukin-8 (IL-8) and IL-6 in response to bacterial stimulation was significantly inhibited in the presence of CS (P < 0.001 for inhibition by either CSC or CSE). In contrast, epithelial production of beta interferon (IFN-beta) was not inhibited. CSC decreased NF-kappaB activation (P < 0.05) and altered the kinetics of mitogen-activated protein kinase phosphorylation in cells exposed to bacteria. Treatment of CSC with antioxidants abrogated CSC-mediated reduction of epithelial IL-8 responses to bacteria (P > 0.05 compared to cells without CSC treatment). These results identify a novel oxidant-mediated immunosuppressive role for CS in epithelial cells. PMID- 20194597 TI - Disruption of the Rickettsia rickettsii Sca2 autotransporter inhibits actin-based motility. AB - Rickettsii rickettsii, the etiologic agent of Rocky Mountain spotted fever, replicates within the cytosol of infected cells and uses actin-based motility to spread inter- and intracellularly. Although the ultrastructure of the actin tail and host proteins associated with it are distinct from those of Listeria or Shigella, comparatively little is known regarding the rickettsial proteins involved in its organization. Here, we have used random transposon mutagenesis of R. rickettsii to generate a small-plaque mutant that is defective in actin-based motility and does not spread directly from cell to cell as is characteristic of spotted fever group rickettsiae. The transposon insertion site of this mutant strain was within Sca2, a member of a family of large autotransporter proteins. Sca2 exhibits several features suggestive of its apparent role in actin-based motility. It displays an N-terminal secretory signal peptide, a C-terminal predicted autotransporter domain, up to four predicted Wasp homology 2 (WH2) domains, and two proline-rich domains, one with similarity to eukaryotic formins. In a guinea pig model of infection, the Sca2 mutant did not elicit fever, suggesting that Sca2 and actin-based motility are virulence factors of spotted fever group rickettsiae. PMID- 20194599 TI - Interaction of pneumococcal histidine triad proteins with human complement. AB - The pneumococcal histidine triad (Pht) proteins PhtA, PhtB, PhtD, and PhtE form a group of conserved pneumococcal surface proteins. Humans produce antibodies to Pht proteins upon exposure to pneumococcus, and immunization of mice has provided protective immunity against sepsis and pneumonia and reduced nasopharyngeal colonization. Pht proteins are candidates for inclusion in multicomponent pneumococcal protein vaccines. Their biological function in pneumococcal infections is not clear, but a role in complement inhibition has been suggested. We measured complement deposition on wild-type and Pht mutant strains in four genetic backgrounds: Streptococcus pneumoniae D39 (serotype 2) and R36A (unencapsulated derivative of D39) and strains of serotypes 3, 4, and 19F. PspA and PspC single and double mutants were compared to the wild-type and Pht deficient D39 strains. Factor H binding was measured to bacterial cells, lysates, and protein antigens. Deletion of all four Pht proteins (Pht(-)) resulted in increased C3 deposition on the serotype 4 strain but not on the other strains. Pht antigens did not bind factor H, and deletion of Pht proteins did not affect factor H binding by bacterial lysates. The Pht(-) mutant serotype 4 strain bound slightly less factor H than the wild-type strain when binding was measured by flow cytometry. Pht proteins may play a role in immune evasion, but the mechanism of function is unlikely to be mediated by factor H binding. The relative contribution of Pht proteins to the inhibition of complement deposition is likely to be affected by the presence of other pneumococcal proteins and to depend on the genetic background. PMID- 20194600 TI - Minimal role for the circumsporozoite protein in the induction of sterile immunity by vaccination with live rodent malaria sporozoites. AB - Immunization with live Plasmodium sporozoites under chloroquine prophylaxis (Spz plus CQ) induces sterile immunity against sporozoite challenge in rodents and, more importantly, in humans. Full protection is obtained with substantially fewer parasites than with the classic immunization with radiation-attenuated sporozoites. The sterile protection observed comprised a massive reduction in the hepatic parasite load and an additional effect at the blood stage level. Differences in the immune responses induced by the two protocols occur but are as yet little characterized. We have previously demonstrated that in mice immunized with irradiated sporozoites, immune responses against the circumsporozoite protein (CSP), the major component of the sporozoite's surface and the leading malaria vaccine candidate, were not essential for sterile protection. Here, we have employed transgenic Plasmodium berghei parasites in which the endogenous CSP was replaced by that of Plasmodium yoelii, another rodent malaria species, to assess the role of CSP in the sterile protection induced by the Spz-plus-CQ protocol. The data demonstrated that this role was minor because sterile immunity was obtained irrespective of the origin of CSP expressed by the parasites in this model of protection. The immunity was obtained through a single transient exposure of the host to the immunizing parasites (preerythrocytic and erythrocytic), a dose much smaller than that required for immunization with radiation-attenuated sporozoites. PMID- 20194601 TI - The proline-rich region of pneumococcal surface proteins A and C contains surface accessible epitopes common to all pneumococci and elicits antibody-mediated protection against sepsis. AB - Pneumococcal surface protein A (PspA) and PspC of Streptococcus pneumoniae are surface virulence proteins that interfere with complement deposition and elicit protective immune responses. The C-terminal halves of PspA and PspC have some structural similarity and contain highly cross-reactive proline-rich (PR) regions. In many PR regions of PspA and PspC, there exists an almost invariant nonproline block (NPB) of about 33 amino acids. Neither the PR regions nor their NPB exhibit the alpha-helical structure characteristic of much of the protection eliciting N-terminal portions of PspA and PspC. Prior studies of PspA and PspC as immunogens focused primarily on the alpha-helical regions of these molecules that lack the PR and NPB regions. This report shows that immunization with recombinant PR (rPR) molecules and passive immunization with monoclonal antibodies reactive with either NPB or PR epitopes are protective against infection in mice. PR regions of both PspA and PspC were antibody accessible on the pneumococcal surface. Our results indicate that while PspA could serve as a target of these protective antibodies in invasive infections, PspC might not. When antibody responses to rPR immunogens were evaluated by using flow cytometry to measure antibody binding to live pneumococci, it was observed that the mice that survived subsequent challenge produced significantly higher levels of antibodies reactive with exposed PR epitopes than the mice that became moribund. Due to their conservation and cross-reactivity, the PR regions and NPB regions represent potential vaccine targets capable of eliciting cross-protection immunity against pneumococcal infection. PMID- 20194602 TI - Anthrax lethal toxin impairs CD1d-mediated antigen presentation by targeting the extracellular signal-related kinase 1/2 mitogen-activated protein kinase pathway. AB - Lethal toxin (LT) is a critical virulence factor of Bacillus anthracis and an important means by which this bacterium evades the host's immune system. In this study, we demonstrate that CD1d-expressing cells treated with LT have reduced CD1d-mediated antigen presentation. We earlier showed an important role for the mitogen-activated protein kinase extracellular signal-regulated kinase 1/2 (ERK1/2) in the regulation of CD1d-mediated antigen presentation, and we report here that LT impairs antigen presentation by CD1d in an ERK1/2-dependent manner. Similarly, LT and the ERK1/2 pathway-specific inhibitor U0126 caused a decrease in major histocompatibility complex (MHC) class II-mediated antigen presentation. Confocal microscopy analyses revealed altered intracellular distribution of CD1d and LAMP-1 in LT-treated cells, similar to the case for ERK1/2-inhibited cells. These results suggest that Bacillus anthracis has the ability to evade the host's innate immune system by reducing CD1d-mediated antigen presentation through targeting the ERK1/2 pathway. PMID- 20194603 TI - Reduction of CaV channel activities by Ca2+-CaM: inactivation or deactivation? PMID- 20194604 TI - Uncertainties on the frontier: rescue therapy in pandemic influenza. PMID- 20194606 TI - Manufacturers' information is a useful resource for practice. PMID- 20194608 TI - National survey of cardiologists' standard of practice for continuous ST-segment monitoring. AB - BACKGROUND: Continuous ST-segment monitoring can be used to detect early and transient cardiac ischemia. The American Heart Association and American Association of Critical-Care Nurses recommend its use among specific patients, but such monitoring is routine practice in only about half of US hospitals. OBJECTIVE: To determine cardiologists' awareness and practice standards regarding continuous ST-segment monitoring and the physicians' perceptions of appropriate patient selection, benefits and barriers, and usefulness of this technology. METHODS: An electronic survey was sent to a random sample of 915 US cardiologists from a pool of 4985 certified cardiologists. RESULTS: Of 200 responding cardiologists, 55% were unaware of the consensus guidelines. Of hospitals where respondents admitted patients, 49% had a standard of practice for using continuous ST-segment monitoring for cardiac patients. Most cardiologists agreed or strongly agreed that patients in the cardiovascular laboratory (87.5%) and intensive care unit (80.5%) should have such monitoring. Cardiologists routinely ordered ST monitoring for patients with acute coronary syndrome (67%) and after percutaneous coronary intervention (60%). The primary factor associated with higher perceptions for benefits, clinical usefulness, and past use of continuous ST-segment monitoring was whether or not hospitals in which cardiologists practiced had a standard of practice for using this monitoring. A secondary factor was awareness of published consensus guidelines for such monitoring. CONCLUSION: Respondents (55%) were unaware of published monitoring guidelines. Hospital leaders could raise awareness by multidisciplinary review of evidence and possibly incorporating continuous ST-segment monitoring into hospitals' standards of practice. PMID- 20194609 TI - Cardiac surgical nurses' use of atrial electrograms to improve diagnosis of arrhythmia. AB - BACKGROUND: The practice standard for electrocardiographic monitoring in hospitals recommends use of atrial electrograms after cardiac surgery to help diagnose cardiac arrhythmias. OBJECTIVES: To determine whether use of atrial electrograms significantly improves nurses' ability to diagnose cardiac arrhythmias and to assess nurses' perceptions of the ease of obtaining and interpreting electrograms, the frequency of use of atrial electrograms, and the correlation between nurses' experience with the technique and arrhythmia scores. METHODS: In total, 282 nurses completed a test consisting of 5 electrocardiographic rhythms for which use of atrial electrograms might improve interpretation. A standardized educational session on obtaining and interpreting atrial electrograms was given to 165 nurses who had not previously received such education. In a second test, the same rhythms were provided along with atrial electrograms to 261 nurses. Overall changes in total test scores and individual changes in interpreting rhythms were analyzed. Demographic information, perceptions of the ease of obtaining and interpreting atrial electrograms, and the frequency of use were collected. Correlation between scores on the second test and nurses' years of experience in interpreting atrial electrograms was determined. RESULTS: Use of atrial electrograms significantly increased overall arrhythmia interpretation scores. Nurses rated obtaining atrial electrograms as easy and interpreting the findings as moderately easy. Despite this reported ease, 57.1% of nurses obtained atrial electrograms less than monthly and only 3.4% obtained them daily. Correlation between experience with atrial electrograms and arrhythmia test scores was not significant. CONCLUSIONS: Nurses' use of atrial electrograms improves diagnoses of cardiac arrhythmias. PMID- 20194610 TI - Impact of morbidity and mortality conferences on analysis of mortality and critical events in intensive care practice. AB - BACKGROUND: Morbidity and mortality conferences are a tool for evaluating care management, but they lack a precise format for practice in intensive care units. OBJECTIVES: To evaluate the feasibility and usefulness of regular morbidity and mortality conferences specific to intensive care units for improving quality of care and patient safety. METHODS: For 1 year, a prospective study was conducted in an 18-bed intensive care unit. Events analyzed included deaths in the unit and 4 adverse events (unexpected cardiac arrest, unplanned extubation, reintubation within 24-48 hours after planned extubation, and readmission to the unit within 48 hours after discharge) considered potentially preventable in optimal intensive care practice. During conferences, events were collectively analyzed with the help of an external auditor to determine their severity, causality, and preventability. RESULTS: During the study period, 260 deaths and 100 adverse events involving 300 patients were analyzed. The adverse events rate was 16.6 per 1000 patient-days. Adverse events occurred more often between noon and 4 pm (P = .001).The conference consensus was that 6.1% of deaths and 36% of adverse events were preventable. Preventable deaths were associated with iatrogenesis (P = .008), human errors (P < .001), and failure of unit management factors or communication (P = .003). Three major recommendations were made concerning standardization of care or prescription and organizational management, and no similar incidents have recurred. CONCLUSION: In addition to their educational value, regular morbidity and mortality conferences formatted for intensive care units are useful for assessing quality of care and patient safety. PMID- 20194611 TI - Demand for nursing care for patients in intensive care units in Southeast Poland. AB - BACKGROUND: The Therapeutic Intervention Scoring System is widely used in both Western Europe and the United States to assess the level of patients' need for nursing care. Poland currently has 3 types of intensive care according to a territorial division of the country and the scope of medical treatment offered: poviat, voivodeship, and clinical. OBJECTIVE: To determine the need for nursing care for patients in the 3 types of intensive care units in southeastern Poland. METHODS: The investigation was conducted at 6 intensive care units in southeastern Poland in 2005 and 2006. Two units were randomly selected from each type of intensive care unit. A total of 155 patients from the units were categorized according to scores on the Therapeutic Intervention Scoring System 28. RESULTS: Among the 3 types of units, patients varied significantly with respect to age, length of hospitalization, and scores on the Therapeutic Intervention Scoring System 28. Nevertheless, demand for nursing care during night and day shifts was similar in all 3 types. On the basis of the patients' scores, all 3 types of units provided appropriate staffing levels necessary to meet the demands for nursing care. Most patients required category III level of care. CONCLUSION: Need or demand for nursing care in intensive care units in Poland varies according to the type of intensive care unit and can be determined on the basis of scores on the Therapeutic Intervention Scoring System 28. PMID- 20194612 TI - Assessment of family needs in neonatal intensive care units. AB - BACKGROUND: Limited research has been conducted to assess family needs in neonatal intensive care units. Health care providers often make assumptions about what families need, but these assumptions are unfounded and can lead to inappropriate conclusions. When assessed appropriately, family needs can be incorporated into individualized plans of care, enhancing family-centered care. OBJECTIVE: To assess the needs of parents in neonatal intensive care units, we asked the following 3 questions: What are the most and least important needs of families in a level III neonatal intensive care unit? Do parents' needs differ at admission and discharge? Do the needs of mothers and fathers differ? METHODS: Parents were interviewed by using the Neonatal Intensive Care Unit Family Needs Inventory. Participants rated statements as not important (1), slightly important (2), important (3), very important (4), or not applicable (5). RESULTS: Fifty-two (93%) of the 56 items were rated as important or very important, and parents rated assurance-type needs highest. Parents at admission rated support needs higher than parents at discharge rated those needs. Needs of mothers and fathers did not differ significantly. CONCLUSIONS: Identifying the needs of parents in neonatal intensive care units can enhance nursing communication and allow nurses to incorporate parents' needs into families' plans of care. The family needs inventory can help identify those needs and allows the integration of individualized nursing care to fulfill those needs, providing a positive family centered experience in the unit for patients and their families. PMID- 20194613 TI - Clinicians' perception of head-of-bed elevation. AB - BACKGROUND: Head-of-bed elevation of 30 degrees to 45 degrees is important in preventing ventilator-associated pneumonia, but clinicians' perception and determination of head-of-bed elevation are not widely reported. OBJECTIVES: To (1) document the accuracy of clinicians' perception of head-of-bed elevation, (2) document methods clinicians use to determine the head-of-bed angle, and (3) assess knowledge of recommended head-of-bed elevation. METHODS: Clinicians (n = 175) viewed a simulated patient with head of bed elevated 30 degrees and elevation gauge concealed. They answered 3 questions: What is the level of the head of the bed? What head-of-bed elevation is associated with decreased incidence of ventilator-associated pneumonia? When providing care, how do you routinely determine the head-of-bed elevation? RESULTS: Fifty percent of 89 registered nurses and 53% of 39 physicians identified head-of-bed elevation correctly (+/-5 degrees ). Head-of-bed elevation was perceived accurately by 86% of 21 respiratory therapists, 63% of 16 medical assistants, and 50% of 10 physical/occupational therapists. Ninety-five percent of nurses and respiratory therapists, 79% of physicians, 90% of physical/occupational therapists, and 46% of medical assistants correctly identified the head-of-bed angle associated with decreases in occurrence of ventilator-associated pneumonia. Techniques for determining the angle varied; 58% of respondents reported using the gauge. CONCLUSIONS: Head-of-bed angle was perceived correctly by 50% to 86% of clinicians. Nurses tended to underestimate the angle, whereas other clinicians tended to overestimate. Nurses, respiratory therapists, and physical/occupational therapists showed the best understanding of the correct angle for minimizing occurrence of ventilator-associated pneumonia. Elevation gauges were most often used to determine the angle. PMID- 20194614 TI - Oral care practices for orally intubated critically ill adults. AB - BACKGROUND: Ventilator-associated pneumonia is a major threat to patients receiving mechanical ventilation in hospitals. Oral care is a nursing intervention that may help prevent ventilator-associated pneumonia. OBJECTIVES: To describe oral care practices performed by critical care nurses for orally intubated critically ill patients and compare these practices with recommendations for oral care in the 2005 AACN Procedure Manual for Critical Care and the guidelines from the Centers for Disease Control and Prevention. METHODS: A descriptive, cross-sectional design with a 31-item Web-based survey was used to describe oral care practices reported by 347 randomly selected members of the American Association of Critical-Care Nurses. RESULTS: Oral care was performed every 2 (50%) or 4 (42%) hours, usually with foam swabs (97%). Oral care was reported as a high priority (47%). Nurses with 7 years or more of critical care experience performed oral care more often (P=.008) than did less experienced nurses. Nurses with a bachelor's degree in nursing used foam swabs (P=.001), suctioned the mouth before the endotracheal tube (P=.02), and suctioned after oral care (P<.001) more often than other nurses. Nurses whose units had an oral care policy (72%) reported that the policy indicated using a toothbrush (63%), using toothpaste (40%), brushing with a foam swab (90%), using chlorhexidine gluconate oral rinse (49%), suctioning the oral cavity (84%), and assessing the oral cavity (73%). Oral care practices and policies differed for all those items. CONCLUSIONS: Survey results indicate that discrepancies exist between reported practices and policies. Oral care policies appear to be present, but not well used. PMID- 20194615 TI - Preceptor-based orientation programs: Effective for nurses and organizations? PMID- 20194616 TI - Adenosine during arrhythmia. PMID- 20194617 TI - Par1b/MARK2 phosphorylates kinesin-like motor protein GAKIN/KIF13B to regulate axon formation. AB - Here we report that Par1b/MARK2 regulates axon formation via phosphorylation of a kinesin superfamily protein GAKIN/KIF13B. Accumulating evidence indicated the importance of the evolutionarily conserved kinase Par1b in the regulation of cell polarity. Using hippocampal neurons in culture, it has been shown that Par1b regulates axon specification, but the underlying mechanism remains uncharacterized. We identify GAKIN/KIF13B as a novel Par1b-binding protein and reveal that GAKIN/KIF13B is a physiological substrate for Par1b, and the phosphorylation sites are conserved from Drosophila. In hippocampal neurons, GAKIN/KIF13B accumulates at the distal part of the microtubules in the tips of axons, but not of dendrites. Overexpression of GAKIN/KIF13B by itself can induce the formation of extra axons, which is inhibited by the coexpression of Par1b in a manner dependent on its kinase activity. In contrast, small interfering RNA (siRNA)-mediated knockdown of GAKIN/KIF13B severely retards neurite extension and promotes the axonless phenotype. The extra axon phenotype caused by Par1b siRNA is suppressed by cointroduction of GAKIN/KIF13B siRNA, thus placing the GAKIN/KIF13B function downstream of Par1b. We also find that GAKIN/KIF13B acts downstream of the phosphatidylinositol 3-kinase (PI3K) signaling via Par1b phosphorylation. These results reveal that GAKIN/KIF13B is a key intermediate linking Par1b to the regulation of axon formation. PMID- 20194618 TI - HMGA1a trapping of U1 snRNP at an authentic 5' splice site induces aberrant exon skipping in sporadic Alzheimer's disease. AB - Overexpression of high-mobility group A protein 1a (HMGA1a) causes aberrant exon 5 skipping of the Presenilin-2 (PS2) pre-mRNA, which is almost exclusively detected in patients with sporadic Alzheimer's disease. An electrophoretic mobility shift assay confirmed aberrant U1 small nuclear ribonucleoprotein particle (snRNP)-HMGA1a complex formation (via the U1-70K component), with RNA containing a specific HMGA1a-binding site and an adjacent 5' splice site. Psoralen cross-linking analysis demonstrated that the binding of HMGA1a adjacent to the 5' splice site induces unusually extended association of U1 snRNP to the 5' splice site. As a result, spliceosome assembly across either the intron or the exon is arrested at an early ATP-independent stage. We conclude that the HMGA1a induced aberrant exon skipping is caused by impaired dissociation of U1 snRNP from the 5' splice site, leading to a defect in exon definition. The proposed molecular mechanism has profound implications for other known posttranscriptional modulation strategies in various organisms, all of which are triggered by aberrant U1 snRNP binding. PMID- 20194619 TI - The TAL1/SCL transcription factor regulates cell cycle progression and proliferation in differentiating murine bone marrow monocyte precursors. AB - Monocytopoiesis involves the stepwise differentiation in the bone marrow (BM) of common myeloid precursors (CMPs) to monocytes. The basic helix-loop-helix transcription factor TAL1/SCL plays a critical role in other hematopoietic lineages, and while it had been reported to be expressed by BM-derived macrophages, its role in monocytopoiesis had not been elucidated. Using cell explant models of monocyte/macrophage (MM) differentiation, one originating with CMPs and the other from more committed precursors, we characterized the phenotypic and molecular consequences of inactivation of Tal1 expression ex vivo. While Tal1 knockout had minimal effects on cell survival and slightly accelerated terminal differentiation, it profoundly inhibited cell proliferation and decreased entry into and traversal of the G(1) and S phases. In conjunction, steady-state levels of p16(Ink4a) mRNA were increased and those of Gata2 mRNA decreased. Chromatin immunoprecipitation analysis demonstrated the association of Tal1 and E47, one of its E protein DNA-binding partners, with an E box-GATA sequence element in intron 4 of the Gata2 gene and with three E boxes upstream of p16(Ink4a). Finally, wild-type Tal1, but not a DNA binding-defective mutant, rescued the proliferative defect in Tal1-null MM precursors. These results document the importance of this transcription factor in cell cycle progression and proliferation during monocytopoiesis and the requirement for direct DNA binding in these processes. PMID- 20194620 TI - Control of adipogenesis by the SUMO-specific protease SENP2. AB - Here, we demonstrate that SENP2, a desumoylating enzyme, plays a critical role in the control of adipogenesis. SENP2 expression was markedly increased upon the induction of adipocyte differentiation, and this increase was dependent on protein kinase A activation. Remarkably, knockdown of SENP2 led to a dramatic attenuation of adipogenesis with a marked decrease in PPARgamma and C/EBPalpha mRNA levels. Knockdown of SENP2 also caused a marked reduction in the level of C/EBPbeta protein but not in that of C/EBPbeta mRNA. Interestingly, sumoylation of C/EBPbeta dramatically increased its ubiquitination and destabilization, and this increase could be reversed by SENP2. In addition, overexpression of C/EBPbeta could overcome the inhibitory effect of SENP2 knockdown on adipogenesis. Furthermore, SENP2 was absolutely required for adipogenesis of preadipocytes implanted into mice. These results establish a critical role for SENP2 in the regulation of adipogenesis by desumoylation and stabilization of C/EBPbeta and in turn by promoting the expression of its downstream effectors, such as PPARgamma and C/EBPalpha. PMID- 20194621 TI - Human mitochondrial leucyl-tRNA synthetase corrects mitochondrial dysfunctions due to the tRNALeu(UUR) A3243G mutation, associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms and diabetes. AB - Mutations in mitochondrial tRNA genes are associated with a wide spectrum of human diseases. In particular, the tRNA(Leu(UUR)) A3243G mutation causes mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms (MELAS) and 2% of cases of type 2 diabetes. The primary defect in this mutation was an inefficient aminoacylation of the tRNA(Leu(UUR)). In the present study, we have investigated the molecular mechanism of the A3243G mutation and whether the overexpression of human mitochondrial leucyl-tRNA synthetase (LARS2) in the cytoplasmic hybrid (cybrid) cells carrying the A3243G mutation corrects the mitochondrial dysfunctions. Human LARS2 localizes exclusively to mitochondria, and LARS2 is expressed ubiquitously but most abundantly in tissues with high metabolic rates. We showed that the alteration of aminoacylation tRNA(Leu(UUR)) caused by the A3243G mutation led to mitochondrial translational defects and thereby reduced the aminoacylated efficiencies of tRNA(Leu(UUR)) as well as tRNA(Ala) and tRNA(Met). We demonstrated that the transfer of human mitochondrial leucyl-tRNA synthetase into the cybrid cells carrying the A3243G mutation improved the efficiency of aminoacylation and stability of mitochondrial tRNAs and then increased the rates of mitochondrial translation and respiration, consequently correcting the mitochondrial dysfunction. These findings provide new insights into the molecular mechanism of maternally inherited diseases and a step toward therapeutic interventions for these disorders. PMID- 20194622 TI - Molecular basis for lysine specificity in the yeast ubiquitin-conjugating enzyme Cdc34. AB - Ubiquitin (Ub)-conjugating enzymes (E2s) and ubiquitin ligases (E3s) catalyze the attachment of Ub to lysine residues in substrates and Ub during monoubiquitination and polyubiquitination. Lysine selection is important for the generation of diverse substrate-Ub structures, which provides versatility to this pathway in the targeting of proteins to different fates. The mechanisms of lysine selection remain poorly understood, with previous studies suggesting that the ubiquitination site(s) is selected by the E2/E3-mediated positioning of a lysine(s) toward the E2/E3 active site. By studying the polyubiquitination of Sic1 by the E2 protein Cdc34 and the RING E3 Skp1/Cul1/F-box (SCF) protein, we now demonstrate that in addition to E2/E3-mediated positioning, proximal amino acids surrounding the lysine residues in Sic1 and Ub are critical for ubiquitination. This mechanism is linked to key residues composing the catalytic core of Cdc34 and independent of SCF. Changes to these core residues altered the lysine preference of Cdc34 and specified whether this enzyme monoubiquitinated or polyubiquitinated Sic1. These new findings indicate that compatibility between amino acids surrounding acceptor lysine residues and key amino acids in the catalytic core of ubiquitin-conjugating enzymes is an important mechanism for lysine selection during ubiquitination. PMID- 20194623 TI - MED14 tethers mediator to the N-terminal domain of peroxisome proliferator activated receptor gamma and is required for full transcriptional activity and adipogenesis. AB - The Mediator subunit MED1/TRAP220/DRIP205/PBP interacts directly with many nuclear receptors and was long thought to be responsible for tethering Mediator to peroxisome proliferator-activated receptor (PPAR)-responsive promoters. However, it was demonstrated recently that PPARgamma can recruit Mediator by MED1 independent mechanisms. Here, we show that target gene activation by ectopically expressed PPARgamma and PPARalpha is independent of MED1. Consistent with this finding, recruitment of PPARgamma, MED6, MED8, TATA box-binding protein (TBP), and RNA polymerase II (RNAPII) to the enhancer and proximal promoter of the PPARgamma target gene Fabp4 is also independent of MED1. Using a small interfering RNA (siRNA)-based approach, we identify MED14 as a novel critical Mediator component for PPARgamma-dependent transactivation, and we demonstrate that MED14 interacts directly with the N terminus of PPARgamma in a ligand independent manner. Interestingly, MED14 knockdown does not affect the recruitment of PPARgamma, MED6, and MED8 to the Fabp4 enhancer but does reduce their occupancy of the Fabp4 proximal promoter. In agreement with the necessity of MED14 for PPARgamma transcriptional activity, we show that knockdown of MED14 impairs adipogenesis of 3T3-L1 cells. Thus, MED14 constitutes a novel anchoring point between Mediator and the N-terminal domain of PPARgamma that is necessary for functional PPARgamma-mediated recruitment of Mediator and transactivation of PPARgamma subtype-specific target genes. PMID- 20194625 TI - SDOP-DB: a comparative standardized-protocol database for mouse phenotypic analyses. AB - This article reports the development of SDOP-DB, which can provide definite, detailed and easy comparison of experimental protocols used in mouse phenotypic analyses among institutes or laboratories. Because SDOP-DB is fully compliant with international standards, it can act as a practical foundation for international sharing and integration of mouse phenotypic information. AVAILABILITY: SDOP-DB (http://www.brc.riken.jp/lab/bpmp/SDOP/). PMID- 20194624 TI - p27kip1 controls cell morphology and motility by regulating microtubule-dependent lipid raft recycling. AB - p27(kip1) (p27) is an inhibitor of cyclin/cyclin-dependent kinase complexes, whose nuclear loss indicates a poor prognosis in various solid tumors. When located in the cytoplasm, p27 binds Op18/stathmin (stathmin), a microtubule (MT) destabilizing protein, and restrains its activity. This leads to MT stabilization, which negatively affects cell migration. Here, we demonstrate that this p27 function also influences morphology and motility of cells immersed in three-dimensional (3D)matrices. Cells lacking p27 display a decrease in MT stability, a rounded shape when immersed in 3D environments, and a mesenchymal amoeboid conversion in their motility mode. Upon cell contact to extracellular matrix, the decreased MT stability observed in p27 null cells results in accelerated lipid raft trafficking and increased RhoA activity. Importantly, cell morphology, motility, MT network composition, and distribution of p27 null cells were rescued by the concomitant genetic ablation of Stathmin, implicating that the balanced expression of p27 and stathmin represents a crucial determinant for cytoskeletal organization and cellular behavior in 3D contexts. PMID- 20194626 TI - An Ergatis-based prokaryotic genome annotation web server. AB - SUMMARY: Ergatis is a flexible workflow management system for designing and executing complex bioinformatics pipelines. However, its complexity restricts its usage to only highly skilled bioinformaticians. We have developed a web-based prokaryotic genome annotation server, Integrative Services for Genomics Analysis (ISGA), which builds upon the Ergatis workflow system, integrates other dynamic analysis tools and provides intuitive web interfaces for biologists to customize and execute their own annotation pipelines. ISGA is designed to be installed at genomics core facilities and be used directly by biologists. AVAILABILITY: ISGA is accessible at http://isga.cgb.indiana.edu/ and the system is also freely available for local installation. PMID- 20194627 TI - ScripTree: scripting phylogenetic graphics. AB - There is a large amount of tools for interactive display of phylogenetic trees. However, there is a shortage of tools for the automation of tree rendering. Scripting phylogenetic graphics would enable the saving of graphical analyses involving numerous and complex tree handling operations and would allow the automation of repetitive tasks. ScripTree is a tool intended to fill this gap. It is an interpreter to be used in batch mode. Phylogenetic graphics instructions, related to tree rendering as well as tree annotation, are stored in a text file and processed in a sequential way. AVAILABILITY: ScripTree can be used online or downloaded at www.scriptree.org, under the GPL license. IMPLEMENTATION: ScripTree, written in Tcl/Tk, is a cross-platform application available for Windows and Unix-like systems including OS X. It can be used either as a stand alone package or included in a bioinformatic pipeline and linked to a HTTP server. PMID- 20194629 TI - Phosphorylation of MNAR promotes estrogen activation of phosphatidylinositol 3 kinase. Retraction. PMID- 20194630 TI - Essential roles of sphingosine-1-phosphate receptor 2 in human mast cell activation, anaphylaxis, and pulmonary edema. AB - Systemic exacerbation of allergic responses, in which mast cells play a critical role, results in life-threatening anaphylactic shock. Sphingosine-1-phosphate (S1P), a ligand for a family of G protein-coupled receptors, is a new addition to the repertoire of bioactive lipids secreted by activated mast cells. Yet little is known of its role in human mast cell functions and in anaphylaxis. We show that S1P(2) receptors play a critical role in regulating human mast cell functions, including degranulation and cytokine and chemokine release. Immunoglobulin E-triggered anaphylactic responses, including elevation of circulating histamine and associated pulmonary edema in mice, were significantly attenuated by the S1P(2) antagonist JTE-013 and in S1P(2)-deficient mice, in contrast to anaphylaxis induced by administration of histamine or platelet activating factor. Hence, S1P and S1P(2) on mast cells are determinants of systemic anaphylaxis and associated pulmonary edema and might be beneficial targets for anaphylaxis attenuation and prophylaxis. PMID- 20194631 TI - CCR6 is expressed on an IL-10-producing, autoreactive memory T cell population with context-dependent regulatory function. AB - Interleukin (IL)-10 produced by regulatory T cell subsets is important for the prevention of autoimmunity and immunopathology, but little is known about the phenotype and function of IL-10-producing memory T cells. Human CD4(+)CCR6(+) memory T cells contained comparable numbers of IL-17- and IL-10-producing cells, and CCR6 was induced under both Th17-promoting conditions and upon tolerogenic T cell priming with transforming growth factor (TGF)-beta. In normal human spleens, the majority of CCR6(+) memory T cells were in the close vicinity of CCR6(+) myeloid dendritic cells (mDCs), and strikingly, some of them were secreting IL-10 in situ. Furthermore, CCR6(+) memory T cells produced suppressive IL-10 but not IL-2 upon stimulation with autologous immature mDCs ex vivo, and secreted IL-10 efficiently in response to suboptimal T cell receptor (TCR) stimulation with anti CD3 antibodies. However, optimal TCR stimulation of CCR6(+) T cells induced expression of IL-2, interferon-gamma, CCL20, and CD40L, and autoreactive CCR6(+) T cell lines responded to various recall antigens. Notably, we isolated autoreactive CCR6(+) T cell clones with context-dependent behavior that produced IL-10 with autologous mDCs alone, but that secreted IL-2 and proliferated upon stimulation with tetanus toxoid. We propose the novel concept that a population of memory T cells, which is fully equipped to participate in secondary immune responses upon recognition of a relevant recall antigen, contributes to the maintenance of tolerance under steady-state conditions. PMID- 20194632 TI - Evidence that vitamin D(3) promotes mast cell-dependent reduction of chronic UVB induced skin pathology in mice. AB - Mast cell production of interleukin-10 (IL-10) can limit the skin pathology induced by chronic low-dose ultraviolet (UV)-B irradiation. Although the mechanism that promotes mast cell IL-10 production in this setting is unknown, exposure of the skin to UVB irradiation induces increased production of the immune modifying agent 1alpha,25-dihydroxyvitamin D(3) (1alpha,25[OH](2)D(3)). We now show that 1alpha,25(OH)(2)D(3) can up-regulate IL-10 mRNA expression and induce IL-10 secretion in mouse mast cells in vitro. To investigate the roles of 1alpha,25(OH)(2)D(3) and mast cell vitamin D receptor (VDR) expression in chronically UVB-irradiated skin in vivo, we engrafted the skin of genetically mast cell-deficient WBB6F(1)-Kit(W/W-v) mice with bone marrow-derived cultured mast cells derived from C57BL/6 wild-type or VDR(-/-) mice. Optimal mast cell dependent suppression of the inflammation, local production of proinflammatory cytokines, epidermal hyperplasia, and epidermal ulceration associated with chronic UVB irradiation of the skin in Kit(W/W-v) mice required expression of VDR by the adoptively transferred mast cells. Our findings suggest that 1alpha,25(OH)(2)D(3)/VDR-dependent induction of IL-10 production by cutaneous mast cells can contribute to the mast cell's ability to suppress inflammation and skin pathology at sites of chronic UVB irradiation. PMID- 20194634 TI - In vivo detection of vulnerable atherosclerotic plaque by MRI in a rabbit model. AB - BACKGROUND: The ability to identify atherosclerotic plaques with a high risk for sudden disruption before stroke or myocardial infarction would be of great utility. We used a rabbit model of controlled atherothrombosis to test whether in vivo MRI can noninvasively distinguish between plaques that disrupt after pharmacological triggering (vulnerable) and those that do not (stable). METHODS AND RESULTS: Atherosclerosis was induced in male New Zealand White (n=17) rabbits by cholesterol diet and endothelial denudation of the abdominal aorta. After baseline (pretrigger) MRI with and without gadolinium contrast, the rabbits underwent 2 pharmacological triggerings to induce atherothrombosis, followed by another MRI 48 hours later (post-triggering). Atherosclerosis was identified by the pretriggered images in all rabbits, and thrombosis was identified in 9 of 17 animals (53%) by post-trigger MRI. After the animals were euthanized, 95 plaques were analyzed; 28 (29.5%) had thrombi (vulnerable) and 67 did not (stable) (70.5%). Pretriggered MRI revealed comparable stenosis in stable and vulnerable plaques, but vulnerable plaques had a larger plaque area (4.8+/-1.6 versus 3.0+/ 1.0 mm(2); P=0.01), vessel area (9.2+/-3.0 versus. 15.8+/-4.9 mm(2); P=0.01), and higher remodeling ratio (1.16+/-0.2 versus 0.93+/-0.2; P=0.01) compared with stable plaques. Furthermore, vulnerable plaques more frequently exhibited (1) positive remodeling (67.8% versus 22.3%; P=0.01), in which the plaque is hidden within the vessel wall instead of occluding the lumen; and (2) enhanced gadolinium uptake (78.6% versus 20.9%; P=0.01) associated with histological findings of neovascularization, inflammation, and tissue necrosis. CONCLUSIONS: We demonstrate that in vivo MRI at 3.0 T detects features of vulnerable plaques in an animal model of controlled atherothrombosis. These findings suggest that MRI may be used as a noninvasive modality for localization of plaques that are prone to disruption. PMID- 20194635 TI - Effects of mitral valve surgery on myocardial energetics in patients with severe mitral regurgitation. AB - BACKGROUND: Hemodynamically significant mitral regurgitation (MR) may alter left ventricular (LV) myocardial energy requirements. The effects of MR and subsequent corrective mitral valve (MV) surgery on myocardial energetics are not well understood. A better understanding of myocardial energetics and the LV responses to changes in preload and afterload may assist with the understanding of mitral regurgitation and its effect on the LV. We sought to determine the effects of MV surgery on forward stroke work, myocardial oxidative metabolism, and myocardial efficiency. METHODS AND RESULTS: Prospectively enrolled patients with chronic, severe, nonischemic mitral regurgitation underwent echocardiography, radionuclide angiography, and C-11 acetate positron emission tomography to measure LV volumes, ejection fraction, and oxidative metabolism before and 1 year after MV surgery. Forward and total stroke work corrected for oxidative metabolism was used to estimate efficiency using the work metabolic index. Fourteen patients (age, 59+/- 8 years) with myxomatous MV were enrolled. One year after MV surgery, there was a reduction in LV end-diastolic and end-systolic volumes (231+/-86 to 131+/-21 mL; P<0.01 and 98+/-53 to 55+/-17 mL; P<0.01). Forward stroke volume increased (58.1+/-15.0 to 75.5+/-23 mL; P<0.01), LV ejection fraction was preserved without a significant change in oxidative metabolism. Forward work metabolic index improved (4.99+/-1.32 x 10(6) to 6.59+/-2.45 x 10(6) mm Hg x mL/m(2); P=0.02). This was not at the expense of total work metabolic index, which was preserved. CONCLUSIONS: MV surgery has a beneficial effect on forward stroke volume and forward work metabolic index without adverse effects on oxidative metabolism or total work metabolic index. PMID- 20194633 TI - Resistance to antiangiogenic therapy is directed by vascular phenotype, vessel stabilization, and maturation in malignant melanoma. AB - Angiogenesis is not only dependent on endothelial cell invasion and proliferation, it also requires pericyte coverage of vascular sprouts for stabilization of vascular walls. Clinical efficacy of angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signaling pathway is still limited to date. We hypothesized that the level of vessel maturation is critically involved in the response to antiangiogenic therapies. To test this hypothesis, we evaluated the vascular network in spontaneously developing melanomas of MT/ret transgenic mice after using PTK787/ZK222584 for anti-VEGF therapy but also analyzed human melanoma metastases taken at clinical relapse in patients undergoing adjuvant treatment using bevacizumab. Both experimental settings showed that tumor vessels, which are resistant to anti-VEGF therapy, are characterized by enhanced vessel diameter and normalization of the vascular bed by coverage of mature pericytes and immunoreactivity for desmin, NG-2, platelet derived growth factor receptor beta, and the late-stage maturity marker alpha smooth muscle actin. Our findings emphasize that the level of mural cell differentiation and stabilization of the vascular wall significantly contribute to the response toward antiangiogenic therapy in melanoma. This study may be useful in paving the way toward a more rational development of second generation antiangiogenic combination therapies and in providing, for the first time, a murine model to study this. PMID- 20194637 TI - Mitotic chromosomes are constrained by topoisomerase II-sensitive DNA entanglements. AB - We have analyzed the topological organization of chromatin inside mitotic chromosomes. We show that mitotic chromatin is heavily self-entangled through experiments in which topoisomerase (topo) II is observed to reduce mitotic chromosome elastic stiffness. Single chromosomes were relaxed by 35% by exogenously added topo II in a manner that depends on hydrolysable adenosine triphosphate (ATP), whereas an inactive topo II cleavage mutant did not change chromosome stiffness. Moreover, experiments using type I topos produced much smaller relaxation effects than topo II, indicating that chromosome relaxation by topo II is caused by decatenation and/or unknotting of double-stranded DNA. In further experiments in which chromosomes are first exposed to protease to partially release protein constraints on chromatin, ATP alone relaxes mitotic chromosomes. The topo II-specific inhibitor ICRF-187 blocks this effect, indicating that it is caused by endogenous topo II bound to the chromosome. Our experiments show that DNA entanglements act in concert with protein-mediated compaction to fold chromatin into mitotic chromosomes. PMID- 20194639 TI - Integration of contractile forces during tissue invagination. AB - Contractile forces generated by the actomyosin cytoskeleton within individual cells collectively generate tissue-level force during epithelial morphogenesis. During Drosophila mesoderm invagination, pulsed actomyosin meshwork contractions and a ratchet-like stabilization of cell shape drive apical constriction. Here, we investigate how contractile forces are integrated across the tissue. Reducing adherens junction (AJ) levels or ablating actomyosin meshworks causes tissue-wide epithelial tears, which release tension that is predominantly oriented along the anterior-posterior (a-p) embryonic axis. Epithelial tears allow cells normally elongated along the a-p axis to constrict isotropically, which suggests that apical constriction generates anisotropic epithelial tension that feeds back to control cell shape. Epithelial tension requires the transcription factor Twist, which stabilizes apical myosin II, promoting the formation of a supracellular actomyosin meshwork in which radial actomyosin fibers are joined end-to-end at spot AJs. Thus, pulsed actomyosin contractions require a supracellular, tensile meshwork to transmit cellular forces to the tissue level during morphogenesis. PMID- 20194640 TI - The novel endosomal membrane protein Ema interacts with the class C Vps-HOPS complex to promote endosomal maturation. AB - Endosomal maturation is critical for accurate and efficient cargo transport through endosomal compartments. Here we identify a mutation of the novel Drosophila gene, ema (endosomal maturation defective) in a screen for abnormal synaptic overgrowth and defective protein trafficking. Ema is an endosomal membrane protein required for trafficking of fluid-phase and receptor-mediated endocytic cargos. In the ema mutant, enlarged endosomal compartments accumulate as endosomal maturation fails, with early and late endosomes unable to progress into mature degradative late endosomes and lysosomes. Defective endosomal down regulation of BMP signaling is responsible for the abnormal synaptic overgrowth. Ema binds to and genetically interacts with Vps16A, a component of the class C Vps-HOPS complex that promotes endosomal maturation. The human orthologue of ema, Clec16A, is a candidate susceptibility locus for autoimmune disorders, and its expression rescues the Drosophila mutant demonstrating conserved function. Characterizing this novel gene family identifies a new component of the endosomal pathway and provides insights into class C Vps-HOPS complex function. PMID- 20194641 TI - The interphase microtubule aster is a determinant of asymmetric division orientation in Drosophila neuroblasts. AB - The mechanisms that maintain the orientation of cortical polarity and asymmetric division unchanged in consecutive mitoses in Drosophila melanogaster neuroblasts (NBs) are unknown. By studying the effect of transient microtubule depolymerization and centrosome mutant conditions, we have found that such orientation memory requires both the centrosome-organized interphase aster and centrosome-independent functions. We have also found that the span of such memory is limited to the last mitosis. Furthermore, the orientation of the NB axis of polarity can be reset to any angle with respect to the surrounding tissue and is, therefore, cell autonomous. PMID- 20194643 TI - Abstracts of the 5th Annual Perioperative Medicine Summit. March 4 to 6, 2010. Miami Beach, Florida, USA. PMID- 20194642 TI - Regulators of cyclin-dependent kinases are crucial for maintaining genome integrity in S phase. AB - Maintenance of genome integrity is of critical importance to cells. To identify key regulators of genomic integrity, we screened a human cell line with a kinome small interfering RNA library. WEE1, a major regulator of mitotic entry, and CHK1 were among the genes identified. Both kinases are important negative regulators of CDK1 and -2. Strikingly, WEE1 depletion rapidly induced DNA damage in S phase in newly replicated DNA, which was accompanied by a marked increase in single stranded DNA. This DNA damage is dependent on CDK1 and -2 as well as the replication proteins MCM2 and CDT1 but not CDC25A. Conversely, DNA damage after CHK1 inhibition is highly dependent on CDC25A. Furthermore, the inferior proliferation of CHK1-depleted cells is improved substantially by codepletion of CDC25A. We conclude that the mitotic kinase WEE1 and CHK1 jointly maintain balanced cellular control of Cdk activity during normal DNA replication, which is crucial to prevent the generation of harmful DNA lesions during replication. PMID- 20194682 TI - Knowledge of Alzheimer's disease, feelings of shame, and awareness of services among Korean American elders. AB - OBJECTIVE: To explore predictors of knowledge of Alzheimer's disease (AD), feelings of shame if a family member were to have AD, and awareness of AD-related services among Korean American elders. METHOD: Using data from 675 Korean American elders (mean age = 70.2, SD = 6.87), the study estimates hierarchical linear or logistic regression models. RESULTS: Greater knowledge of AD is predicted by higher levels of education and acculturation. Feelings of shame associated with family members having AD are more likely to be reported by individuals with lower levels of education, acculturation, and knowledge of AD. Those who are married have greater levels of education and acculturation, and those who have a family member with AD are more aware of AD-related services. DISCUSSION: The study findings underscore the pivotal role of education and acculturation in predicting knowledge of AD, feelings of shame, and awareness of AD-related services. PMID- 20194683 TI - Physical disability and depression: clarifying racial/ethnic contrasts. AB - OBJECTIVE: This study assesses racial/ethnic disparities in depressive symptoms among persons who are physically disabled and evaluates the extent to which variation in stress exposure, coping resources, and feelings of shame associated with disability account for observed differences. METHOD: Data are drawn from a Miami-Dade County study that oversampled persons with physical disabilities. The sample used in this study includes individuals of Cuban and other Hispanic heritage, African Americans, and non-Hispanic Whites who identify as physically disabled (N = 550). RESULTS: Cubans and other Hispanics report higher levels of depressive symptoms. This elevation in risk is largely explained by variations in stress exposure, available coping resources, and shame. Findings also suggest that feelings of shame may condition the relationships between both stress exposure and coping resources and depressive symptomatology. DISCUSSION: Findings demonstrate racial/ethnic differences in depressive symptoms among persons with physical disabilities and highlight the importance of stress exposure, coping resources, and shame for understanding these differences. PMID- 20194684 TI - Return migration and the health of older aged parents: evidence from rural Thailand. AB - OBJECTIVE: To examine the extent to which an association exists between health of older parents and return migration of children in rural Thailand. METHOD: Data come from the 2006 Migration Impact Survey specifically designed to obtain information on the impact of migration on older adults in rural areas. Associations are examined from both the perspectives of parents (N = 883) and migrating children (N = 2,150) using equations that adjust for demographic characteristics of parents and children and factors that may indicate unmet support needs. RESULTS: A robust association with poor health promoting migration returns from both parent and child perspective exists and remains even with controls that might attenuate the relationship. DISCUSSION: Although media discussions have pointed out dangers of out-migration for older adults, little systematic evidence exists. This study supports the viewpoint that accommodations for older adults can be made despite social changes promoting out-migration and demographic aging of the population. PMID- 20194685 TI - Close companions at church, health, and health care use in late life. AB - OBJECTIVE: This article studies whether there are age variations in the relationships between having a close companion friend at church, health, and outpatient physician visits. METHOD: The data come from two waves of interviews in a nationwide survey of older adults. These data are analyzed with ordinary least squares multiple regression analyses. RESULTS: The findings reveal that older people who have a close companion friend in the place where they worship are more likely to rate their health in a favorable way over time. However, these health-related benefits emerge only among the oldest-old study participants. The data results further indicate that having a close friend at church is associated with fewer outpatient physician visits over time, but once again, the results are observed only among the oldest old. DISCUSSION: The results from this study provide preliminary insight into one way in which spiraling health care costs may eventually be curtailed. PMID- 20194686 TI - Abnormal activation of the primary somatosensory cortex in spasmodic dysphonia: an fMRI study. AB - Spasmodic dysphonia (SD) is a task-specific focal dystonia of unknown pathophysiology, characterized by involuntary spasms in the laryngeal muscles during speaking. Our aim was to identify symptom-specific functional brain activation abnormalities in adductor spasmodic dysphonia (ADSD) and abductor spasmodic dysphonia (ABSD). Both SD groups showed increased activation extent in the primary sensorimotor cortex, insula, and superior temporal gyrus during symptomatic and asymptomatic tasks and decreased activation extent in the basal ganglia, thalamus, and cerebellum during asymptomatic tasks. Increased activation intensity in SD patients was found only in the primary somatosensory cortex during symptomatic voice production, which showed a tendency for correlation with ADSD symptoms. Both SD groups had lower correlation of activation intensities between the primary motor and sensory cortices and additional correlations between the basal ganglia, thalamus, and cerebellum during symptomatic and asymptomatic tasks. Compared with ADSD patients, ABSD patients had larger activation extent in the primary sensorimotor cortex and ventral thalamus during symptomatic task and in the inferior temporal cortex and cerebellum during symptomatic and asymptomatic voice production. The primary somatosensory cortex shows consistent abnormalities in activation extent, intensity, correlation with other brain regions, and symptom severity in SD patients and, therefore, may be involved in the pathophysiology of SD. PMID- 20194687 TI - The emergence of explicit memory during learning. AB - In incidental learning situations, contingencies are extracted from the environment without the intention to learn and can change behavior without awareness for the extracted regularity. The development of explicit access to the learned regularity is an important learning mechanism that is rarely examined. With a series of behavioral, electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) studies, we were able to show that the emergence of awareness for a hidden regularity is accompanied by an increase in neural activity and in high-frequency coupling between distant brain areas as observed with a time-frequency resolved EEG analysis. More importantly, the increase in neural coupling was observed before awareness for the learned material was established behaviorally. In addition, coupling increases were paralleled by an fMRI-signal increase in the ventral striatum and the right ventrolateral prefrontal cortex directly preceding the emergence of awareness. The involvement of this system, which has already been linked to the processing of predictions and prediction errors, indicates the relevance of a reinforcement signal to generate awareness for the learned contingencies. Thus, our data provide direct evidence for the necessity of large-scale coupling and the evaluation of a predictive stimulus value as the basis for a transition from implicit to explicit memory. PMID- 20194688 TI - Improved reversal learning and working memory and enhanced reactivity to novelty in mice with enhanced GABAergic innervation in the dentate gyrus. AB - The balance between excitation and inhibition controls fundamental aspects of the hippocampal function. Here, we report an increase in the ratio of inhibitory to excitatory neurons in the dentate gyrus, accompanied by gamma-aminobutyric acid(A) (GABA(A)) receptor-dependent impairment of synaptic plasticity and enhancement of activity-dependent changes in excitability in anesthetized adult mice deficient for the extracellular matrix glycoprotein tenascin-R (TNR). TNR deficient mice showed faster reversal learning, improved working memory, and enhanced reactivity to novelty than wild-type littermates. Remarkably, in wild type and TNR-deficient mice, faster reversal learning rates correlated at the individual animal level with ratios of parvalbumin-positive interneurons to granule cells and densities of parvalbumin-positive terminals on somata of granule cells. Our data demonstrate that modification of the extracellular matrix by ablation of TNR leads to a new structural and functional design of the dentate gyrus, with enhanced GABAergic innervation, that is, enhanced ratio of inhibitory to excitatory cells, and altered plasticity, promoting working memory and reversal learning. In wild-type mice, the enhanced ratio of inhibitory to excitatory cells in the dentate gyrus also positively correlated with reversal learning, indicating that level of inhibition regulates specific aspects of learning independent of the TNR gene. PMID- 20194689 TI - Decreased in vitro susceptibility of Plasmodium falciparum isolates to artesunate, mefloquine, chloroquine, and quinine in Cambodia from 2001 to 2007. AB - This study describes the results of in vitro antimalarial susceptibility assays and molecular polymorphisms of Plasmodium falciparum isolates from Cambodia. The samples were collected from patients enrolled in therapeutic efficacy studies (TES) conducted by the Cambodian National Malaria Control Program for the routine efficacy monitoring of artemisinin-based combination therapy (ACT) (artesunate mefloquine and artemether-lumefantrine combinations). The isolates (n = 2,041) were obtained from nine sentinel sites during the years 2001 to 2007. Among these, 1,588 were examined for their in vitro susceptibilities to four antimalarials (artesunate, mefloquine, chloroquine, and quinine), and 851 isolates were genotyped for single nucleotide polymorphisms (SNPs). The geometric means of the 50% inhibitory concentrations (GMIC(50)s) of the four drugs tested were significantly higher for isolates from western Cambodia than for those from eastern Cambodia. GMIC(50)s for isolates from participants who failed artesunate mefloquine therapy were significantly higher than those for patients who were cured (P, <0.001). In vitro correlation of artesunate with the other drugs was observed. The distributions of the SNPs differed between eastern and western Cambodia, suggesting different genetic backgrounds of the parasite populations in these two parts of the country. The GMIC(50)s of the four drugs tested increased significantly in eastern Cambodia during 2006 to 2007. These results are worrisome, because they may signal deterioration of the efficacy of artesunate mefloquine beyond the Cambodian-Thai border. PMID- 20194690 TI - Evaluation of nucleoside hydrolase inhibitors for treatment of African trypanosomiasis. AB - In this paper, we present the biochemical and biological evaluation of N arylmethyl-substituted iminoribitol derivatives as potential chemotherapeutic agents against trypanosomiasis. Previously, a library of 52 compounds was designed and synthesized as potent and selective inhibitors of Trypanosoma vivax inosine-adenosine-guanosine nucleoside hydrolase (IAG-NH). However, when the compounds were tested against bloodstream-form Trypanosoma brucei brucei, only one inhibitor, N-(9-deaza-adenin-9-yl)methyl-1,4-dideoxy-1,4-imino-d-ribitol (UAMC-00363), displayed significant activity (mean 50% inhibitory concentration [IC(50)] +/- standard error, 0.49 +/- 0.31 microM). Validation in an in vivo model of African trypanosomiasis showed promising results for this compound. Several experiments were performed to investigate why only UAMC-00363 showed antiparasitic activity. First, the compound library was screened against T. b. brucei IAG-NH and inosine-guanosine nucleoside hydrolase (IG-NH) to confirm the previously demonstrated inhibitory effects of the compounds on T. vivax IAG-NH. Second, to verify the uptake of these compounds by T. b. brucei, their affinities for the nucleoside P1 and nucleoside/nucleobase P2 transporters of T. b. brucei were tested. Only UAMC-00363 displayed significant affinity for the P2 transporter. It was also shown that UAMC-00363 is concentrated in the cell via at least one additional transporter, since P2 knockout mutants of T. b. brucei displayed no resistance to the compound. Consequently, no cross-resistance to the diamidine or the melaminophenyl arsenical classes of trypanocides is expected. Third, three enzymes of the purine salvage pathway of procyclic T. b. brucei (IAG NH, IG-NH, and methylthioadenosine phosphorylase [MTAP]) were investigated using RNA interference. The findings from all these studies showed that it is probably not sufficient to target only the nucleoside hydrolase activity to block the purine salvage pathway of T. b. brucei and that, therefore, it is possible that UAMC-00363 acts on an additional target. PMID- 20194691 TI - 3-hydroxyphthalic anhydride-modified chicken ovalbumin exhibits potent and broad anti-HIV-1 activity: a potential microbicide for preventing sexual transmission of HIV-1. AB - Heterosexual transmission is the primary route by which women acquire human immunodeficiency virus (HIV)/AIDS. Thus, development of woman-controlled topical microbicides for prevention of sexual transmission of HIV is urgently needed. Here we report that 3-hydroxyphthalic anhydride-modified chicken ovalbumin (HP OVA) exhibits potent antiviral activity against a broad spectrum of human immunodeficiency virus type 1 (HIV-1) isolates with different genotypes and biotypes. Its antiviral activity is correlated with the percentages of the chemically modified and unmodified lysines and arginines in OVA. HP-OVA inhibits HIV-1 fusion and entry through multiple mechanisms of action, including (i) blocking gp120 binding to CD4 and (ii) interfering with gp41 six-helix bundle formation. Because of the widespread availability and established safety profile of OVA, HP-OVA has good potential to be developed as an effective, safe, and affordable microbicide for prevention of HIV sexual transmission. PMID- 20194692 TI - Combinations of mutations in the connection domain of human immunodeficiency virus type 1 reverse transcriptase: assessing the impact on nucleoside and nonnucleoside reverse transcriptase inhibitor resistance. AB - Recent reports have described the effect of mutations in the connection and RNase H domains of reverse transcriptase (RT) on nucleoside and nonnucleoside reverse transcriptase inhibitor (NRTI and NNRTI, respectively) resistance in the presence of thymidine analog resistance mutations (TAMs) and NNRTI mutations (J. H. Brehm, D. Koontz, J. D. Meteer, V. Pathak, N. Sluis-Cremer, and J. W. Mellors, J. Virol. 81:7852-7859, 2007; K. A. Delviks-Frankenberry, G. N. Nikolenko, R. Barr, and V. K. Pathak, J. Virol. 81:6837-6845, 2007; G. N. Nikolenko, K. A. Delviks Frankenberry, S. Palmer, F. Maldarelli, M. J. Fivash, Jr., J. M. Coffin, and V. K. Pathak, Proc. Natl. Acad. Sci. U. S. A. 104:317-322, 2007; G. N. Nikolenko, S. Palmer, F. Maldarelli, J. W. Mellors, J. M. Coffin, and V. K. Pathak, Proc. Natl. Acad. Sci. U. S. A. 102:2093-2098, 2005; and S. H. Yap, C. W. Sheen, J. Fahey, M. Zanin, D. Tyssen, V. D. Lima, B. Wynhoven, M. Kuiper, N. Sluis-Cremer, P. R. Harrigan, and G. Tachedjian, PLoS Med. 4:e335, 2007). In the present study, novel mutations in the connection domain of RT (T369I/V), first identified in patient derived viruses, were characterized, and their effects on NNRTI and NNRTI susceptibility were determined. Furthermore, the effect of N348I on NRTI and NNRTI resistance was confirmed. HIV-1 with either N348I or T369I/V demonstrated reduced susceptibility to nevirapine (NVP), efavirenz (EFV), delaviridine (DLV), and zidovudine (ZDV) compared to wild-type HIV-1. However, HIV-1 with T369I and N348I demonstrated 10- to 60-fold resistance to these same drugs. In clinical samples, these two connection domain RT mutations were predominantly observed in viruses containing TAMs and NNRTI mutations and did not alter the susceptible resistant classifications of these samples. Introduction of T369I, N348I, or T369I/N348I also reduced replication capacity (RC). These observations suggest that it may be of scientific interest to test these mutations against new NNRTI candidates. PMID- 20194693 TI - Efflux pumps, OprD porin, AmpC beta-lactamase, and multiresistance in Pseudomonas aeruginosa isolates from cystic fibrosis patients. AB - Expression of ampC, oprD, mexA, mexC, mexE, and mexX was studied in 25 Pseudomonas aeruginosa isolates from cystic fibrosis patients, including 14 isolates of the Liverpool epidemic strain. Overexpressed mexA or ampC and reduced oprD were associated with beta-lactam resistance. A specific combination of mexR, nalC, and nalD mutations occurred in 11 Liverpool strain isolates, including 7 with upregulated mexA. PMID- 20194694 TI - Mechanism of the synergistic effect of amiodarone and fluconazole in Candida albicans. AB - The antiarrhythmic drug amiodarone has been found to have fungicidal activity. In Saccharomyces cerevisiae, its antifungal activity is mediated by calcium overload stress, which leads to a rapid nuclear accumulation of the calcineurin-regulated transcription factor CRZ1. In addition, low doses of amiodarone have been reported to be synergistic with fluconazole in fluconazole-resistant Candida albicans. To establish its mechanism of toxicity in C. albicans, we used expression profiling of key pathway genes to examine cellular responses to amiodarone alone and in combination with fluconazole. Gene expression profiling of 59 genes was done in five C. albicans strains (three fluconazole-susceptible strains and two fluconazole-resistant strains) after amiodarone and/or fluconazole exposure. Of the 59 genes, 27 analyzed showed a significant change (>2-fold) in expression levels after amiodarone exposure. The up- or downregulated genes included genes involved in Ca(2+) homeostasis, cell wall synthesis, vacuolar/lysosomal transport, diverse pathway regulation, stress response, and pseudohyphal morphogenesis. As expected, fluconazole induces an increase in ergosterol pathway genes expression levels. The combination treatment significantly dampened the transcriptional response to either drug, suggesting that synergism was due to an inhibition of compensatory response pathways. This dampening resulted in a decrease in total ergosterol levels and decreased pseudohyphal formation, a finding consistent with decreased virulence in a murine candidiasis model. PMID- 20194695 TI - The 6-aminoquinolone WC5 inhibits human cytomegalovirus replication at an early stage by interfering with the transactivating activity of viral immediate-early 2 protein. AB - WC5 is a 6-aminoquinolone that potently inhibits the replication of human cytomegalovirus (HCMV) but has no activity, or significantly less activity, against other herpesviruses. Here we investigated the nature of its specific anti HCMV activity. Structure-activity relationship studies on a small series of analogues showed that WC5 possesses the most suitable pattern of substitutions around the quinolone scaffold to give potent and selective anti-HCMV activity. Studies performed to identify the possible target of WC5 indicated that it prevents viral DNA synthesis but does not significantly affect DNA polymerase activity. In yield reduction experiments with different multiplicities of infection, the anti-HCMV activity of WC5 appeared to be highly dependent on the viral inoculum, suggesting that WC5 may act at an initial stage of virus replication. Consistently, time-of-addition and time-of-removal studies demonstrated that WC5 affects a phase of the HCMV replicative cycle that precedes viral DNA synthesis. Experiments to monitor the effects of the compound on virus attachment and entry showed that it does not inhibit either process. Evaluation of viral mRNA and protein expression revealed that WC5 targets an event of the HCMV replicative cycle that follows the transcription and translation of immediate-early genes and precedes those of early and late genes. In cell-based assays to test the effects of WC5 on the transactivating activity of the HCMV immediate-early 2 (IE2) protein, WC5 markedly interfered with IE2-mediated transactivation of viral early promoters. Finally, WC5 combined with ganciclovir in checkerboard experiments exhibited highly synergistic activity. These findings suggest that WC5 deserves further investigation as a candidate anti-HCMV drug with a novel mechanism of action. PMID- 20194696 TI - Antiviral properties, metabolism, and pharmacokinetics of a novel azolo-1,2,4 triazine-derived inhibitor of influenza A and B virus replication. AB - Influenza viruses of types A and B cause periodic pandemics in the human population. The antiviral drugs approved to combat influenza virus infections are currently limited. We have investigated an effective novel inhibitor of human influenza A and B viruses, triazavirine [2-methylthio-6-nitro-1,2,4-triazolo[5,1 c]-1,2,4-triazine-7(4I)-one] (TZV). TZV suppressed the replication of influenza virus in cell culture and in chicken chorioallantoic membranes, and it protected mice from death caused by type A and B influenza viruses. TZV was also effective against a rimantadine-resistant influenza virus strain and against avian influenza A virus H5N1 strains. The pharmacokinetic parameters and bioavailability of TZV were calculated after the administration of TZV to rabbits. The TZV metabolite AMTZV [2-methylthio-6-amino-1,2,4-triazolo[5,1-s] 1,2,4-triazin(e)-7(4I)-one] was discovered in IAK 293T and Huh7 cell cultures, a liver homogenate, and rabbit blood after intragastric administration of TZV. AMTZV was nontoxic and inactive as an inhibitor of influenza virus in cell culture. Most likely, this metabolite is a product of TZV elimination. PMID- 20194697 TI - Synergistic activities of three triazoles with caspofungin against Candida glabrata isolates determined by time-kill, Etest, and disk diffusion methods. AB - Combinations of voriconazole, fluconazole, and itraconazole with caspofungin were evaluated against 50 Candida glabrata isolates by the time-kill, disk diffusion, and Etest methods. The majority of antifungal combinations were indifferent. By the time-kill method, synergistic activity was detected with eight (16%) of the caspofungin-voriconazole and seven (14%) of the caspofungin-fluconazole combinations, but synergy was not seen with the caspofungin-itraconazole combination. Further comparisons of the Etest and disk diffusion synergy techniques with the time-kill method are warranted. PMID- 20194698 TI - In Tanzania, hemolysis after a single dose of primaquine coadministered with an artemisinin is not restricted to glucose-6-phosphate dehydrogenase-deficient (G6PD A-) individuals. AB - The current interest in malaria elimination has led to a renewed interest in drugs that can be used for mass administration to minimize malaria transmission. Primaquine (PQ) is the only generally available drug with a strong activity against mature Plasmodium falciparum gametocytes, the parasite stage responsible for transmission. Despite concerns about PQ-induced hemolysis in glucose-6 phosphate dehydrogenase (G6PD)-deficient individuals, a single dose of PQ may be safe and efficacious in clearing gametocytes that persist after conventional treatment. As part of a mass drug intervention, we determined the hemolytic effect of sulfadoxine-pyrimethamine (SP) plus artesunate (AS) plus a single dose of primaquine (PQ; 0.75 mg/kg of body weight) in children aged 1 to 12 years. Children were randomized to receive SP+AS+PQ or placebo; those with a hemoglobin (Hb) level below 8 g/dl were excluded from receiving PQ and received SP+AS. The Hb concentration was significantly reduced 7 days after SP+AS+PQ treatment but not after placebo or SP+AS treatment. This reduction in Hb was most pronounced in G6PD-deficient (G6PD A-) individuals (-2.5 g/dl; 95% confidence interval [95% CI], -1.2 to -3.8 g/dl) but was also observed in heterozygotes (G6PD A) (-1.6 g/dl; 95% CI, -0.9 to -2.2 g/dl) and individuals with the wild-type genotype (G6PD B) (-0.5 g/dl; 95% CI, -0.4 to -0.6 g/dl). Moderate anemia (Hb level of <8 g/dl) was observed in 40% (6/15 individuals) of the G6PD A-, 11.1% (3/27 individuals) of the G6PD A, and 4.5% (18/399 individuals) of the G6PD B individuals; one case of severe anemia (Hb level of <5 g/dl) was observed. PQ may cause moderate anemia when coadministered with artemisinins, and excluding individuals based on G6PD status alone may not be sufficient to prevent PQ induced hemolysis. PMID- 20194699 TI - Use of a high-resolution melt assay to characterize codon 54 of the cyp51A gene of Aspergillus fumigatus on a Rotor-Gene 6000 instrument. AB - A high-resolution melt (HRM) assay using a Rotor-Gene 6000 instrument was developed to characterize the codon for glycine 54 in the cyp51A genes from 13 reference isolates and 12 clinical isolates of Aspergillus fumigatus. Mutations in this codon confer reduced susceptibility to itraconazole and posaconazole. The assay is simple to perform, and a result of "wild type" or "mutant" is available after approximately 1 h following DNA extraction using commercially available reagents and conventional primers. PMID- 20194700 TI - Detection of E119V and E119I mutations in influenza A (H3N2) viruses isolated from an immunocompromised patient: challenges in diagnosis of oseltamivir resistance. AB - The clinical use of the neuraminidase inhibitor (NAI) oseltamivir is associated with the emergence of drug resistance resulting from subtype-specific neuraminidase (NA) mutations. The influenza A/Texas/12/2007 (H3N2) virus isolated from an oseltamivir-treated immunocompromised patient exhibited reduced susceptibility to oseltamivir in the chemiluminescent neuraminidase inhibition (NI) assay (approximately 60-fold increase in its 50% inhibitory concentration [IC(50)] compared to that for a control virus). When further propagated in cell culture, the isolate maintained reduced susceptibility to oseltamivir in both chemiluminescent and fluorescent NI assays (approximately 50- and 350-fold increases in IC(50), respectively). Sequencing analysis of the isolate revealed a mix of nucleotides coding for amino acids at position 119 of the NA [E119(V/I)]. Plaque purification of the isolate yielded E119V and E119I variants, both exhibiting reduced susceptibility to oseltamivir. The E119I variant also showed decreased susceptibility to zanamivir and the investigational NAIs peramivir and A-315675. The emergence of E119V variants in oseltamivir-treated patients has been previously reported; however, the E119I mutation detected here is a novel one which reduces susceptibility to several NAIs. Both mutations were not detected in unpropagated original clinical specimens using either conventional sequencing or pyrosequencing, suggesting that these variants were present in very low proportions (<10%) in clinical specimens and gained dominance after virus propagation in MDCK cells. All virus isolates recovered from the patient were resistant to adamantanes. Our findings highlight the potential for emergence and persistence of multidrug-resistant influenza viruses in oseltamivir-treated immunocompromised subjects and also highlight challenges for drug resistance diagnosis due to the genetic instability of the virus population upon propagation in cell culture. PMID- 20194701 TI - Genetic basis of multidrug resistance in Acinetobacter clinical isolates in Taiwan. AB - Multidrug-resistant (MDR) Acinetobacter spp. have emerged as a threat to public health. We investigated the various genes involved in resistance to fluoroquinolones, aminoglycosides, cephalosporins, and carbapenems in 75 clinical Acinetobacter isolates from a Taiwanese hospital. All isolates were tested for the gyrA mutations, the presence of integrons, bla(AmpC), and carbapenem resistance genes. The Ser83Leu mutation in GyrA accounted for fluoroquinolone resistance. The presence of integrons containing aminoglycoside-modifying enzymes was associated with resistance to gentamicin and tobramycin but not with resistance to amikacin. The presence of an ISAba1 element upstream of bla(AmpC) was correlated with cephalosporin resistance. Although most Acinetobacter baumannii isolates with ISAba1-bla(OXA-51-)(like) were resistant to carbapenems, several isolates remained susceptible to carbapenems. Transformation by the introduction of ISAba1-bla(OXA-23) or ISAba1-bla(OXA-66) into A. baumannii ATCC 15151 (CIP 70.10), resulting in the overexpression of OXA-23 or OXA-66, respectively, suggested the role of the ISAba1 element as a strong promoter. The two transformants showed significantly increased resistance to piperacillin tazobactam, imipenem, and meropenem. The cefepime resistance conferred by ISAba1 bla(OXA-23) and the impact of ISAba1-bla(OXA-66) on carbapenem resistance in A. baumannii are reported here for the first time. Continuous surveillance of antibiotic resistance genes in MDR Acinetobacter spp. and elucidation of their antibiotic resistance mechanisms are crucial for the development of therapy regimens and for the prevention of further dissemination of these antibiotic resistance genes. PMID- 20194702 TI - Skin concentrations and pharmacokinetics of posaconazole after oral administration. AB - A randomized, single-center, open-label study of posaconazole (POS) was performed to determine the concentration of POS in the skin of 30 healthy adult human subjects receiving 400 mg POS oral suspension twice daily for 8 days with a high fat meal. Blood samples for plasma POS level determination were collected at prespecified times on day 1 and day 8. From each subject, two 4-mm skin punch biopsy samples were obtained, one immediately before or after both the first and last doses of POS. A MIC(90) value of 250 ng/ml, which encompasses the majority of common dermatophytes, was used to calculate the time above the MIC(90) in plasma and skin. On days 1 and 8, POS attained peak plasma concentrations at median times of 8 and 5 h, respectively. On days 1 and 8, POS peak skin concentrations were attained at 12 and 3 h, respectively; peak skin concentrations were produced from a single composite profile. On day 8, POS concentrations in skin and plasma for the entire dosing interval were severalfold higher than the MIC(90). POS dosed at 400 mg twice daily per os was well tolerated in healthy subjects. Two subjects reported increased alanine aminotransferase (ALT) levels. The findings of this study demonstrate adequate skin penetration and have certain implications for the treatment of dermatophytic skin and nail infections. PMID- 20194703 TI - Expansion and evolution of the Streptococcus pneumoniae Spain9V-ST156 clonal complex in Poland. AB - In this study, we analyzed 118 penicillin-nonsusceptible Streptococcus pneumoniae (PNSP) isolates (MICs, >or=0.12 microg/ml) recovered in Poland in 2003 to 2005 from patients with respiratory tract diseases and invasive infections. Seven different serotypes (14, 9V, 23F, 19F, 6B, 19A, and 6A, in order of descending frequency), seven alleles of the murM gene (murMA, murMB6, and the new murMB12 to -16 alleles), and 31 multilocus sequence types (STs) were observed. The vast majority of the PNSP isolates (90.7%) belonged to the international multiresistant clones, and among these, the Spain(9V)-ST156 clonal complex was the most prevalent (56 isolates) and was significantly overrepresented in invasive infections. The clone has been evolving rapidly, as demonstrated by the observed number of STs, the diversity in multiple-locus variable-number-tandem repeat analysis (MLVA) types, and the polymorphism of pbp and pspA genes (coding for penicillin-binding proteins and the pneumococcal surface protein A, respectively). The presence and structure of the rlrA islet (encoding the pneumococcal pilus) were very well conserved. The Spain(9V)-ST156 clonal complex has been largely responsible for a decreasing susceptibility to penicillin among pneumococci in Poland in recent years, in spite of a relatively moderate antimicrobial use. PMID- 20194704 TI - Affinity of ceftaroline and other beta-lactams for penicillin-binding proteins from Staphylococcus aureus and Streptococcus pneumoniae. AB - We compared the affinities of ceftaroline for all penicillin-binding proteins (PBPs) with those of ceftriaxone and cefotaxime in 6 Staphylococcus aureus and 7 Streptococcus pneumoniae isolates with various resistance phenotypes. Ceftaroline MICs were PBP1A, -1B, and -2A > PBP2B, and ceftaroline had >or=4-fold higher 50% inhibitory concentrations (IC(50)s) (0.1 to 4 microg/ml) for PBP2X, -2A, -2B, and -3 than those for the other cephalosporins tested. Among 3 penicillin-resistant S. pneumoniae strains, ceftaroline had a high affinity for PBP2X (IC(50), 0.1 to 1 microg/ml), a primary target for cephalosporin PBP binding activity, and high affinities for PBP2B (IC(50), 0.5 to 4 microg/ml) and PBP1A (IC(50), 0.125 to 0.25 microg/ml) as well, both of which are also known as major targets for PBP binding activity of cephalosporins. Ceftaroline PBP affinities in methicillin susceptible S. aureus strains were greater than or equal to those of the 3 other beta-lactams tested. Ceftaroline bound to PBP2a in methicillin-resistant S. aureus (IC(50), 0.01 to 1 microg/ml) with up to 256-fold-higher affinity than those of other agents. Ceftaroline demonstrated very good PBP affinity against all S. aureus and S. pneumoniae strains tested, including resistant isolates. PMID- 20194706 TI - TAC3 and TACR3 defects cause hypothalamic congenital hypogonadotropic hypogonadism in humans. AB - CONTEXT: Missense loss-of-function mutations in TAC3 and TACR3, the genes encoding neurokinin B and its receptor NK3R, respectively, were recently discovered in kindreds with nonsyndromic normosmic congenital hypogonadotropic hypogonadism (CHH), thus identifying a fundamental role of this pathway in the human gonadotrope axis. OBJECTIVE: The objective of the study was to investigate the consequences on gonadotrope axis of TAC3 deletion and TACR3 truncation in adult patients with normosmic complete CHH. RESULTS: We identified three unrelated patients with the same homozygous substitution in the TAC3 intron 3 acceptor splicing site (c.209-1G>C) and three siblings who bore a homozygous mutation in the TACR3 intron 2 acceptor splicing site (c.738-1G>A). We demonstrated that these two mutations, respectively, deleted neurokinin B and truncated its receptor NK3R. We found in three patients with TAC3 mutation originating from Congo and Haiti a founding event in a more distant ancestor by means of haplotype analysis. We calculated that time to this common ancestor was approximately 21 generations. In several patients we observed a dissociation between the very low LH and normal or nearly normal FSH levels, this gonadotropin responding excessively to the GnRH challenge test. This particular hormonal profile, suggests the possibility of a specific neuroendocrine impairment in patients with alteration of neurokinin B signaling. Finally, in these patients, pulsatile GnRH administration normalized circulating sex steroids, LH release, and restored fertility in one subject. CONCLUSION: Our data demonstrate the hypothalamic origin of the gonadotropin deficiency in these genetic forms of normosmic CHH. Neurokinin B and NK3R therefore both play a crucial role in hypothalamic GnRH release in humans. PMID- 20194705 TI - Interaction of Candida albicans biofilms with antifungals: transcriptional response and binding of antifungals to beta-glucans. AB - Candida albicans can form biofilms that exhibit elevated intrinsic resistance to various antifungal agents, in particular azoles and polyenes. The molecular mechanisms involved in the antifungal resistance of biofilms remain poorly understood. We have used transcript profiling to explore the early transcriptional responses of mature C. albicans biofilms exposed to various antifungal agents. Mature C. albicans biofilms grown under continuous flow were exposed for as long as 2 h to concentrations of fluconazole (FLU), amphotericin B (AMB), and caspofungin (CAS) that, while lethal for planktonic cells, were not lethal for biofilms. Interestingly, FLU-exposed biofilms showed no significant changes in gene expression over the course of the experiment. In AMB-exposed biofilms, 2.7% of the genes showed altered expression, while in CAS-exposed biofilms, 13.0% of the genes had their expression modified. In particular, exposure to CAS resulted in the upregulation of hypha-specific genes known to play a role in biofilm formation, such as ALS3 and HWP1. There was little overlap between AMB- or CAS-responsive genes in biofilms and those that have been identified as AMB, FLU, or CAS responsive in C. albicans planktonic cultures. These results suggested that the resistance of C. albicans biofilms to azoles or polyenes was due not to the activation of specific mechanisms in response to exposure to these antifungals but rather to the intrinsic properties of the mature biofilms. In this regard, our study led us to observe that AMB physically bound C. albicans biofilms and beta-glucans, which have been proposed to be major constituents of the biofilm extracellular matrix and to prevent azoles from reaching biofilm cells. Thus, enhanced extracellular matrix or beta-glucan synthesis during biofilm growth might prevent antifungals, such as azoles and polyenes, from reaching biofilm cells, thus limiting their toxicity to these cells and the associated transcriptional responses. PMID- 20194707 TI - Association of lipoprotein-associated phospholipase A2 with coronary artery disease in African-Americans and Caucasians. AB - CONTEXT: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is bound predominately to low-density lipoprotein and has been implicated as a risk factor for coronary artery disease (CAD). OBJECTIVE: We investigated the association between Lp-PLA(2) and CAD in a biethnic African-American and Caucasian population. DESIGN: Lp-PLA(2) mass, activity, and index, an integrated measure of mass and activity, and other cardiovascular risk factors were determined in 224 African-Americans and 336 Caucasians undergoing coronary angiography. MAIN OUTCOME MEASURES: We assessed the distribution of Lp-PLA(2) levels and determined the predictive role of Lp-PLA(2) as a risk factor for CAD. RESULTS: Levels of Lp PLA(2) mass and activity were higher among Caucasians compared with African Americans (293 +/- 75 vs. 232 +/- 76 ng/ml, P < 0.001 for mass and 173 +/- 41 vs. 141 +/- 39 nmol/min/ml, P < 0.001 for activity, respectively). However, Lp-PLA(2) index was similar in the two groups (0.61 +/- 0.17 vs. 0.64 +/- 0.19, P = NS). In both ethnic groups, Lp-PLA(2) activity and index was significantly higher among subjects with CAD. African-American subjects with CAD had significantly higher Lp PLA(2) index than corresponding Caucasian subjects (0.69 +/- 0.20 vs. 0.63 +/- 0.18, P = 0.028). In multivariate regression analyses, after adjusting for other risk factors, Lp-PLA(2) index was independently (odds ratio 6.7, P = 0.047) associated with CAD in African-Americans but not Caucasians. CONCLUSIONS: Lp PLA(2) activity and index was associated with presence of CAD among African Americans and Caucasians undergoing coronary angiography. The findings suggest an independent impact of vascular inflammation among African-Americans as contributory to CAD risk and underscore the importance of Lp-PLA(2) as a cardiovascular risk factor. PMID- 20194708 TI - Comparison of competitive radioimmunoassays and two-site sandwich assays for the measurement and interpretation of plasma ghrelin levels. AB - CONTEXT: Ghrelin, an endogenous ligand for the GH secretagogue receptor, is an orexigenic peptide hormone produced primarily by the stomach. Recent studies suggest significant differences in the specificity of currently available ghrelin assays. OBJECTIVE: The aim of the study was to compare four ghrelin assays (two commercially available and two developed by our group) of differing specificity, each used on the same set of more than 800 plasma samples from a human study. DESIGN: Thirteen volunteers were sampled every 20 min for 6 h after consumption of one of three isocaloric drinks consisting of either 80% fat, 80% carbohydrate, or 80% protein. The samples were assayed by RIA for total and active ghrelin, as well as by sandwich assays for acyl and des-acyl ghrelin. The ghrelin profiles for each individual were smoothed using a statistical algorithm to lessen the effects of pulsatility and noise. RESULTS: The sandwich assays for acyl and des acyl ghrelin yielded ghrelin values that were lower than those from the corresponding RIAs. The ghrelin profiles after nutrient ingestion were similar, yet key differences among the four assays were apparent; in particular, percentage changes were significantly greater in the sandwich assays. CONCLUSIONS: The lower levels and greater relative changes in ghrelin values reported by the sandwich assays are consistent with greater assay specificity. When applied to the nutrient study, the sandwich assays were better able to distinguish the different responses to different nutrients than were the RIAs. PMID- 20194709 TI - Tracking of bone mass and density during childhood and adolescence. AB - CONTEXT: Whether a child with low bone mineral density (BMD) at one point in time will continue to have low BMD, despite continued growth and maturation, is important clinically. The stability of a characteristic during growth is referred to as "tracking." OBJECTIVE: We examined the degree of tracking in bone mineral content (BMC) and BMD during childhood and adolescence and investigated whether tracking varied according to age, sexual maturation, and changes in growth status. DESIGN: We conducted a longitudinal study with measurements at baseline and annually for 3 yr. SETTING: The Bone Mineral Density in Childhood Study was conducted at five clinical centers in the United States. STUDY PARTICIPANTS: A total of 1554 girls and boys, ages 6-16 yr at baseline, participated in the study. MAIN OUTCOME MEASURES: Whole body, spine, hip, and forearm BMC and BMD were measured by dual-energy x-ray absorptiometry, and age-, sex-, and race specific Z-scores were calculated. Deviation from tracking was calculated as the Z-score at yr 3 minus baseline. RESULTS: Correlations between Z-scores at baseline and yr 3 ranged from 0.76-0.88. Among children with a Z-score below -1.5 at baseline, 72-87% still had a Z-score below -1 after 3 yr. Age, sexual maturation, and deviations in growth status (P < 0.01) were associated with deviation from tracking; however, tracking was strongly evident even after adjusting for the effects of age, maturation, and growth. CONCLUSIONS: Bone density showed a high degree of tracking over 3 yr in children and adolescents. Healthy children with low bone density will likely continue to have low bone density unless effective interventions are instituted. PMID- 20194710 TI - Adipokines and cardiometabolic profile in primary hyperaldosteronism. AB - CONTEXT: Primary aldosteronism (PA) has been recently associated with an unfavorable cardiometabolic profile. However, whether pro- and antiinflammatory adipokines levels can vary in PA is unknown. OBJECTIVE: We evaluated the circulating levels of resistin, leptin, and adiponectin, echocardiographic left ventricle (LV) parameters, and the prevalence of metabolic syndrome (SM) in subjects with PA. PATIENTS: Seventy-five subjects with established diagnosis of PA and 232 consecutive individuals with known or suspected hypertension were enrolled. MAIN OUTCOME MEASURES: Plasma adipokine levels and echocardiographic parameters were calculated. Prevalence of SM was also estimated. RESULTS: Among the 75 PA subjects, 37 patients were affected by aldosterone-producing adenoma and 38 by idiopathic hyperaldosteronism; 40 subjects were affected by essential hypertension (EH) and SM (EH SM+); 152 subjects were affected by EH without SM (EH SM-); and 40 subjects were normotensive (NT). Subjects with PA had the highest plasma resistin levels among the four groups (P < 0.01). Plasma resistin concentration was significantly higher in PA subjects when compared with EH SM+ individuals (P < 0.01) and EH SM- subjects (P < 0.01). PA subjects showed the higher LV mass and left atrium than EH individuals, irrespectively of the presence of SM (P < 0.01 for both). Plasma resistin levels was significantly correlated with ejection fraction and LV end-diastolic volume. The prevalence of SM was higher in PA subjects than in those with EH (25.4 vs. 20.3%). CONCLUSIONS: Our data suggest that elevated aldosterone levels is associated with elevated circulating resistin levels and cardiac morphological changes independently of the presence of SM. PMID- 20194711 TI - Do the actions of glucagon-like peptide-1 on gastric emptying, appetite, and food intake involve release of amylin in humans? AB - OBJECTIVE: Amylin, cosecreted with insulin, has like glucagon-like peptide-1 (GLP 1) been reported to inhibit glucagon secretion, delay gastric emptying, and reduce appetite and food intake. We investigated whether the effects of GLP-1 on gastric emptying, appetite, and food intake are mediated directly or indirectly via release of amylin. DESIGN: Eleven C-peptide and amylin-negative patients with type 1 diabetes mellitus (T1DM) and 12 matched healthy controls participated in a placebo-controlled, randomized, single-blinded, crossover study. With glucose clamped between 6 and 9 mm, near-physiological infusions of GLP-1, human amylin, pramlintide, or saline were given for 270 min during and after a fixed meal. Gastric emptying was measured using paracetamol, appetite using visual analog scales, and food intake during a subsequent ad libitum meal (at 240 min). RESULTS: In T1DM, gastric emptying, food intake, and appetite were reduced equally during low GLP-1 and amylin infusion compared with the saline infusion (P < 0.05). The controls showed stronger suppression of gastric emptying (P < 0.0001) and food intake (P < 0.01) with GLP-1 compared to amylin. Postprandial glucagon responses were reduced in controls and T1DM during GLP-1 and amylin infusions (P < 0.05). Amylin and pramlintide infusion had similar effects. CONCLUSIONS: GLP-1 exerts its effect on gastric emptying, appetite, food intake, and glucagon secretion directly, although secretion of amylin may contribute to some of these effects in healthy control subjects. PMID- 20194712 TI - Individualizing therapies in type 2 diabetes mellitus based on patient characteristics: what we know and what we need to know. AB - OBJECTIVE: Type 2 diabetes is heterogeneous in its clinical features, pathogenesis, and predisposing or causal genetic factors. This report examines what is known and what needs to be learned about the potential to individualize glycemic therapies in type 2 diabetes, based on phenotypes and genotypes. PARTICIPANTS: A 29-member international working group with expertise in diabetes epidemiology, physiology, genetics, clinical trials, and clinical care participated in formal presentations and discussions at a conference on April 16 17, 2009. A writing group subsequently prepared this summary and recommendations. The conference was coendorsed by The Endocrine Society and the American Diabetes Association and was supported by an unrestricted educational grant from Novo Nordisk. EVIDENCE: Participants reviewed and discussed published literature, plus their own unpublished data. CONSENSUS PROCESS: The summary and recommendations were supported unanimously by the writing group as representing the majority or unanimous opinions of the working group. CONCLUSIONS: Recent advances in genetics, such as the identification of Kir6.2 mutations and the responsible genes for several forms of maturity onset diabetes of the young (MODY), have established precedents linking specifically effective therapies to defined diabetes subtypes. The recent increase in identified polygenic factors related to type 2 diabetes and our understanding of the pathogenesis of diabetes provide potential opportunities to individualize therapy. To further this process, we recommend expanded analysis of existing data sources and the development of new basic and clinical research studies, including a greater focus on identifying type 2 diabetes subtypes, their response to different therapies, and quantitation of cost-effectiveness. PMID- 20194713 TI - Poor sleep and altered hypothalamic-pituitary-adrenocortical and sympatho-adrenal medullary system activity in children. AB - CONTEXT: Neuroendocrine alterations, with well-known links with health, may offer insight into why poor sleep is associated with poor health. Yet, studies testing associations between sleep and neuroendocrine activity in children are scarce. OBJECTIVE: The aim of this study was to determine whether actigraphy-based sleep pattern is associated with hypothalamic-pituitary-adrenocortical axis and sympatho-adrenal-medullary system activity in children. DESIGN AND SETTING: We conducted a cross-sectional study in a birth cohort in Helsinki, Finland. PARTICIPANTS: We studied 282 8-yr-old children. MAIN OUTCOME MEASURES: We measured diurnal salivary cortisol and salivary cortisol and alpha-amylase (a sympatho-adrenal-medullary system marker) responses to the Trier Social Stress Test for Children (TSST-C). RESULTS: Children with short (77.4%) displayed higher diurnal cortisol levels across the entire day (P < 0.03), higher cortisol levels after the TSST-C stressor (P < 0.04), and higher overall alpha-amylase levels across the entire TSST-C protocol (P < 0.05). The effects were not confounded by factors that may alter sleep or hormonal patterns. CONCLUSIONS: Poor sleep may signal altered neuroendocrine functioning in children. The findings may offer insight into the pathways linking poor sleep with poor health. PMID- 20194714 TI - Blockade of programmed death ligand 1 enhances the therapeutic efficacy of combination immunotherapy against melanoma. AB - Inhibition of antitumor T cell responses can be mediated by the productive interaction between the programmed death-1 (PD-1) receptor on T cells and its ligand PD-L1. PD-L1 is highly expressed on both murine bone marrow-derived dendritic cells (DCs) and B16 melanoma. In this study, in vitro blockade of PD-L1 interaction on DCs led to enhanced IFN-gamma production and cytotoxicity by Ag specific T cells. In vivo, the systemic administration of anti-PD-L1 Ab plus melanoma peptide-pulsed DCs resulted in a higher number of melanoma peptide specific CD8(+) T cells, but this combination was insufficient to delay the growth of established B16 melanoma. Although the addition of 600 rad of total body irradiation delayed tumor growth, further adoptive transfer of Ag-specific CD8(+) T cells was needed to achieve tumor regression and long-term survival of the treated mice. Lymphopenic mice treated with anti-PD-L1 Ab demonstrated increased activation and persistence of adoptively transferred T cells, including a higher number of CD8(+) T cells infiltrating the tumor mass. Together, these studies support the blocking of PD-L1 signaling as a means to enhance combined immunotherapy approaches against melanoma. PMID- 20194715 TI - TLR4 signaling in stromal cells is critical for the initiation of allergic Th2 responses to inhaled antigen. AB - Allergic asthma is an inflammatory lung disease driven by Th2. We have shown that both Th1 and Th2 sensitization to inhaled OVA depend on the presence and concentration of LPS, where high concentrations (LPS(hi)) induce Th1 and low concentrations (LPS(lo)), Th2. Stromal cells (SCs), such as airway SCs, exacerbate established airway disease; however, little is known about their role early during sensitization. In this study, using bone marrow chimeric mice to restrict TLR4 signaling to either the SC compartment (SC(+)HPC(-)) or the hematopoietic cell (HPC) compartment (SC(-)HPC(+)), we report that HPC TLR4 is necessary and sufficient for Th1 sensitization to OVA-LPS(hi), whereas TLR4 in both compartments is required for Th2 sensitization to OVA-LPS(lo). Surprisingly, although SC(+)HPC(-) mice were unable to generate a Th1 response to OVA-LPS(hi), they instead mounted a robust Th2 response, indicating that in the presence of higher concentrations of LPS, SC TLR4 is sufficient for Th2 sensitization. We show that the SC TLR4 response to LPS leads to induction of Th2-inducing dendritic cells that upregulate Notch ligand Jagged-1 but not Delta-4. Furthermore, airway SCs upregulate thymic stromal lymphopoietin in response to exposure to both OVA-LPS(lo) and OVA-LPS(hi). These studies demonstrate that SC TLR4 signaling is critically involved in Th2 but not Th1 sensitization to inhaled Ag. PMID- 20194716 TI - CXC chemokine ligand (CXCL) 9 and CXCL10 are antagonistic costimulation molecules during the priming of alloreactive T cell effectors. AB - Donor Ag-reactive CD4 and CD8 T cell production of IFN-gamma is a principal effector mechanism promoting tissue injury during allograft rejection. The CXCR3 binding chemokines CXCL9 and CXCL10 recruit donor-reactive T cells to the allograft, but their role during the priming of donor-reactive T cells to effector function is unknown. Using a murine model of MHC-mismatched cardiac transplantation, we investigated the influence of CXCL9 and CXCL10 during donor reactive T cell priming. In allograft recipient spleens, CXCL9 and CXCL10 were expressed as early as 24 h posttransplant and increased with similar kinetics, concurrently with CXCR3 expression on T cells. CXCL9, but not CXCL10, expression required NK cell production of IFN-gamma. The absence of CXCL9 in donor allografts, recipients, or both significantly decreased the frequency of donor reactive CD8 T cells producing IFN-gamma and increased the frequency of donor reactive CD8 T cells producing IL-17A. In contrast, the absence of CXCL10 increased the frequency of IFN-gamma-producing CD8 T cells in a CXCL9-dependent manner. These data provide novel evidence that donor-reactive CD8 T cells use the CXCR3 chemokine axis as a costimulation pathway during priming to allografts where CXCL9 promotes the development of IFN-gamma-producing CD8 T cells, and CXCL10 antagonizes this skewing. PMID- 20194717 TI - IL-7 is essential for homeostatic control of T cell metabolism in vivo. AB - It has become apparent that T cells require growth signals to maintain function and viability necessary to maintain proper immune homeostasis. One means by which cell extrinsic signals may mediate these effects is by sustaining sufficient basal cell metabolism to prevent cell atrophy. The role of metabolism and the specific growth factors essential to maintain metabolism of mature T cells in vivo, however, are poorly defined. As IL-7 is a nonredundant cytokine required for T cell development and survival and can regulate T cell metabolism in vitro, we hypothesized it may be essential to sustain metabolism of resting T cells in vivo. Thus, we generated a model for conditional expression of IL-7R in mature T cells. After IL-7R deletion in a generally normal lymphoid environment, T cells had reduced responses to IL-7, including abrogated signaling and maintenance of antiapoptotic Bcl-2 family expression that corresponded to decreased survival in vitro. T cell survival in vivo was also reduced after loss of the IL-7R in a T cell-intrinsic manner. Additionally, IL-7R deletion resulted in delayed growth and proliferation following stimulation. Importantly, in vivo excision of IL-7R led to T cell atrophy that was characterized by delayed mitogenesis and reduced glycolytic flux. These data are the first to identify an in vivo requirement for a specific cell extrinsic signal to sustain lymphocyte metabolism and suggest that control of glycolysis by IL-7R may contribute to the well-described roles of IL-7 in T cell development, homeostatic proliferation, and survival. PMID- 20194718 TI - The actin-bundling protein L-plastin dissociates CCR7 proximal signaling from CCR7-induced motility. AB - Chemokines promote lymphocyte motility by triggering F-actin rearrangements and inducing cellular polarization. Chemokines can also enhance cell-cell adhesion and costimulate T cells. In this study, we establish a requirement for the actin bundling protein L-plastin (LPL) in CCR7- and sphingosine-1-phosphate-mediated T cell chemotaxis using LPL(-/-) mice. Disrupted motility of mature LPL(-/-) thymocytes manifested in vivo as diminished thymic egress. Two-photon microscopy of LPL(-/-) lymphocytes revealed reduced velocity and motility in lymph nodes. Defective migration resulted from defective cellular polarization following CCR7 ligation, as CCR7 did not polarize to the leading edge in chemokine-stimulated LPL(-/-) T cells. However, CCR7 signaling to F-actin polymerization and CCR7 mediated costimulation was intact in LPL(-/-) lymphocytes. The differential requirement for LPL in CCR7-induced cellular adhesion and CCR7-induced motility allowed assessment of the contribution of CCR7-mediated motility to positive selection of thymocytes and lineage commitment. Results suggest that normal motility is not required for CCR7 to function in positive selection and lineage commitment. We thus identify LPL as a molecule critical for CCR7-mediated motility but dispensable for early CCR7 signaling. The requirement for actin bundling by LPL for polarization reveals a novel mechanism of regulating actin dynamics during T cell motility. PMID- 20194719 TI - Effects of MHC class I alleles on licensing of Ly49A+ NK cells. AB - NK cells are innate immune lymphocytes that can react to cells lacking self-MHC class I. However, NK cells that cannot engage self-MHC through an inhibitory receptor are resistant to stimulation through their activation receptors. To become licensed (i.e., functionally competent to be triggered through its activation receptors), an NK cell must engage host MHC class I via a MHC class I specific inhibitory receptor, such as a member of the murine Ly49 family. To explore potential determinants of NK cell licensing on a single Ly49 receptor, we have investigated the relative licensing impacts of the b, d, k, q, r, and s H2 haplotypes on Ly49A(+) NK cells. The results indicate that licensing is essentially analog but is saturated by moderate-binding MHC class I ligands. Interestingly, licensing exhibited a strong inverse correlation with a measure of cis engagement of Ly49A. Finally, licensing of Ly49A(+) NK cells was found to be less sensitive to MHC class I engagement than Ly49A-mediated effector inhibition, suggesting that licensing establishes a margin of safety against NK cell autoreactivity. PMID- 20194720 TI - B cells are required for optimal CD4+ and CD8+ T cell tumor immunity: therapeutic B cell depletion enhances B16 melanoma growth in mice. AB - B lymphocytes can both positively and negatively regulate cellular immune responses. Previous studies have demonstrated augmented T cell-mediated tumor immunity in genetically B cell-deficient mice, suggesting that therapeutic B cell depletion would enhance tumor immunity. To test this hypothesis and quantify B cell contributions to T cell-mediated anti-tumor immune responses, mature B cells were depleted from wild-type adult mice using CD20 mAb prior to syngeneic B16 melanoma tumor transfers. Remarkably, s.c. tumor volume and lung metastasis were increased 2-fold in B cell-depleted mice. Effector-memory and IFN-gamma-or TNF alpha-secreting CD4(+) and CD8(+) T cell induction was significantly impaired in B cell-depleted mice with tumors. Tumor Ag-specific CD8(+) T cell proliferation was also impaired in tumor-bearing mice that lacked B cells. Thus, B cells were required for optimal T cell activation and cellular immunity in this in vivo nonlymphoid tumor model. Although B cells may not have direct effector roles in tumor immunity, impaired T cell activation, and enhanced tumor growth in the absence of B cells argue against previous proposals to augment tumor immunity through B cell depletion. Rather, targeting tumor Ags to B cells in addition to dendritic cells is likely to optimize tumor-directed vaccines and immunotherapies. PMID- 20194721 TI - Swiprosin-1/EFhd2 controls B cell receptor signaling through the assembly of the B cell receptor, Syk, and phospholipase C gamma2 in membrane rafts. AB - Compartmentalization of the BCR in membrane rafts is important for its signaling capacity. Swiprosin-1/EFhd2 (Swip-1) is an EF-hand and coiled-coil-containing adaptor protein with predicted Src homology 3 (SH3) binding sites that we identified in membrane rafts. We showed previously that Swip-1 amplifies BCR induced apoptosis; however, the mechanism of this amplification was unknown. To address this question, we overexpressed Swip-1 and found that Swip-1 amplified the BCR-induced calcium flux in WEHI231, B62.1, and Bal17 cells. Conversely, the BCR-elicited calcium flux was strongly attenuated in Swip-1-silenced WEHI231 cells, and this was due to a decreased calcium mobilization from intracellular stores. Complementation of Swip-1 expression in Swip-1-silenced WEHI231 cells restored the BCR-induced calcium flux and enhanced spleen tyrosine kinase (Syk) tyrosine phosphorylation and activity as well as SLP65/BLNK/BASH and phospholipase C gamma2 (PLCgamma2) tyrosine phosphorylation. Furthermore, Swip-1 induced the constitutive association of the BCR itself, Syk, and PLCgamma2 with membrane rafts. Concomitantly, Swip-1 stabilized the association of BCR with tyrosine-phosphorylated proteins, specifically Syk and PLCgamma2, and enhanced the constitutive interaction of Syk and PLCgamma2 with Lyn. Interestingly, Swip-1 bound to the rSH3 domains of the Src kinases Lyn and Fgr, as well as to that of PLCgamma. Deletion of the predicted SH3-binding region in Swip-1 diminished its association and that of Syk and PLCgamma2 with membrane rafts, reduced its interaction with the SH3 domain of PLCgamma, and diminished the BCR-induced calcium flux. Hence, Swip-1 provides a membrane scaffold that is required for the Syk-, SLP-65-, and PLCgamma2-dependent BCR-induced calcium flux. PMID- 20194722 TI - Hypoxia-mediated expression of 5-lipoxygenase-activating protein involves HIF 1alpha and NF-kappaB and microRNAs 135a and 199a-5p. AB - Hypoxia occurs in a number of pathological states, such as pulmonary, hematological, and cardiovascular disorders. In this study, we examined the molecular mechanism by which hypoxia contributes to increased leukotriene formation. Our studies showed hypoxia augmented the expression of 5-lipoxygenase activating protein (FLAP), a key enzyme in leukotriene formation, in both human pulmonary microvascular endothelial cells and a transformed human brain endothelial cell line. Hypoxia-induced FLAP mRNA expression involved activation of NADPH-oxidase, PI-3 kinase, mitogen-activated protein kinase, NF-kappaB, and hypoxia-inducible factor (HIF)-1alpha. Hypoxia-induced FLAP promoter activity was attenuated on mutation of hypoxia-response elements (HREs) and NF-kappaB binding motif in the FLAP promoter. Hypoxia also augmented binding of HIF-1alpha to HREs in FLAP promoter as demonstrated by EMSA with nuclear extracts. Furthermore, chromain immunoprecipitation analysis showed HIF-1alpha bound to HREs in native chromatin obtained from hypoxia-treated cells. Next, we examined the role of HIF 1alpha regulated microRNAs on FLAP expression. Our studies showed decreased expression of miR-135a and miR-199a-5p in response to hypoxia. However, overexpression of anti-miR-135a and anti-miR-199a-5p oligonucleotides led to a several fold increased FLAP mRNA and protein expression. These studies demonstrate for the first time that hypoxia-mediated FLAP expression is regulated by HREs and NF-kappaB site in its promoter, and negatively regulated by miR-135a and miR-199a-5p, which target the 3'-UTR of FLAP mRNA. An understanding of these regulatory pathways provides new avenues to ameliorate leukotriene formation and hence reactive airway disease, and inflammation in individuals who have sickle cell disease. PMID- 20194723 TI - Proinflammatory cytokine IL-1beta stimulates IL-8 synthesis in mast cells via a leukotriene B4 receptor 2-linked pathway, contributing to angiogenesis. AB - Recent studies have suggested that mast cells have critical roles in angiogenesis. However, the detailed mechanism by which mast cells contribute to angiogenesis is not yet clearly understood, especially in response to proinflammatory cytokines. In this study, we showed that the proinflammatory cytokine IL-1beta induces the synthesis of IL-8, a potent angiogenic factor, in human mast cells via the leukotriene B(4) receptor (BLT)2. We also characterized the BLT2 downstream signaling pathway and determined that BLT2-mediated IL-8 synthesis involves the upregulation of Nox1, a member of the NADPH oxidase family, Nox1-dependent reactive oxygen species generation and the subsequent activation of the redox-sensitive transcription factor NF-kappaB. For instance, knockdown of BLT2 and Nox1 with specific small interfering RNA, treatment with a specific BLT2 antagonist, LY255283, or treatment with a potential Nox inhibitor, diphenylene iodonium, suppressed IL-1beta-induced IL-8 synthesis. We found that the conditioned media collected from IL-1beta-treated human mast cell line HMC-1 had significantly enhanced angiogenic activity that could be dramatically attenuated by either small interfering RNA knockdown of BLT2 or treatment with neutralizing Ab to IL-8. Finally, the experiments were repeated using human primary cord blood-derived mast cells, and the results were clearly reproduced. Taken together, our results suggest that BLT2-Nox1-reactive oxygen species dependent pathway plays a role in promoting the secretion of IL-8 from human mast cells in response to the proinflammatory cytokine IL-1beta, thus contributing to angiogenesis. PMID- 20194724 TI - Triptolide inhibits IL-12/IL-23 expression in APCs via CCAAT/enhancer-binding protein alpha. AB - Triptolide is a biologically active component purified from Chinese herbal plant Tripterygium wilfordii Hook F. It is widely used in East Asia for treatment of systemic lupus erythematosus, rheumatoid arthritis, nephritis, Bechect's disease, psoriasis, atopic dermatitis, and asthma. However, its immunological mechanisms are poorly understood. IL-12 and IL-23 are closely related heterodimeric cytokines that share the common subunit p40. They are produced by APCs and are key factors in the generation and effector functions of Th1 and Th17 cells, respectively. They have been strongly implicated in the pathogenesis of several autoimmune disorders. In this study, we investigated the molecular mechanism whereby triptolide inhibits the expression of the p40 gene in APCs. We demonstrate that triptolide does so at the transcriptional level in part through targeting CCAAT/enhancer-binding protein-alpha (C/EBPalpha), which directly interacts with the p40 promoter and inhibits its transcription in inflammatory macrophages. Triptolide can activate the transcription of C/EBPalpha, and phosphorylation of Ser21 and Thr222/226 critical for C/EBPalpha inhibition of p40. Further, activation of C/EBPalpha by triptolide is dependent on upstream kinases ERK1/2 and Akt-GSK3beta. This study provides mechanistic insights into the immunomodulatory capacity of triptolide and has strong implications for its therapeutic applications in autoimmune diseases. PMID- 20194725 TI - Cleavage of transaldolase by granzyme B causes the loss of enzymatic activity with retention of antigenicity for multiple sclerosis patients. AB - Multiple sclerosis (MS) is an autoimmune demyelinating disease of the CNS resulting from a progressive loss of oligodendrocytes. Transaldolase (TAL) is expressed at selectively high levels in oligodendrocytes of the brain, and postmortem sections show concurrent loss of myelin basic protein and TAL from sites of demyelination. Infiltrating CD8(+) CTLs are thought to play a key role in oligodendrocyte cell death. Cleavage by granzyme B (GrB) is predictive for autoantigenicity of self-proteins, thereby further implicating CTL-induced death in the initiation and propagation of autoimmunity. The precursor frequency and CTL activity of HLA-A2-restricted TAL 168-176-specific CD8(+) T cells is increased in MS patients. In this paper, we show that TAL, but not myelin basic protein, is specifically cleaved by human GrB. The recognition site of GrB that resulted in the cleavage of a dominant TAL fragment was mapped to a VVAD motif at aa residue 27 by N-terminal sequencing and confirmed by site-directed mutagenesis. The major C-terminal GrB cleavage product, residues 28-337, had no enzymatic activity but retained the antigenicity of full-length TAL, effectively stimulating the proliferation and CTL activity of PBMCs and of CD8(+) T cell lines from patients with MS. Sera of MS patients exhibited similar binding affinity to wild-type and GrB-cleaved TAL. Because GrB mediates the killing of target cells and cleavage by GrB is predictive of autoantigen status of self proteins, GrB-cleaved TAL-specific T cell-mediated cytotoxicity may contribute to the progressive destruction of oligodendrocytes in patients with MS. PMID- 20194727 TI - Androgen receptor-dependent activation of endothelial nitric oxide synthase in vascular endothelial cells: role of phosphatidylinositol 3-kinase/akt pathway. AB - The mechanisms of testosterone-induced vasodilatation are not fully understood. This study investigated the effect of testosterone on nitric oxide (NO) synthesis and its molecular mechanism using human aortic endothelial cells (HAEC). Testosterone at physiological concentrations (1-100 nm) induced a rapid (15-30 min) increase in NO production, which was associated with phosphorylation and activation of endothelial NO synthase (eNOS). Then, the involvement of the androgen receptor (AR), which is abundantly expressed in HAEC, was examined. The effect of testosterone on eNOS activation and NO production were abolished by pretreatment with an AR antagonist nilutamide and by transfection with AR small interference RNA. In contrast, testosterone-induced eNOS phosphorylation was unchanged by pretreatment with an aromatase inhibitor or by transfection with ERalpha small interference RNA. 5alpha-Dihydrotestosterone, a nonaromatizable androgen, also stimulated eNOS phosphorylation. Next, the signaling cascade that leads to eNOS phosphorylation was explored. Testosterone stimulated rapid phosphorylation of Akt in a time- and dose-dependent manner, with maximal response at 15-60 min. The rapid phosphorylation of eNOS or NO production induced by testosterone was inhibited by Akt inhibitor SH-5 or by phosphatidylinositol (PI) 3-kinase inhibitor wortmannin. Co-immunoprecipitation assays revealed a testosterone-dependent interaction between AR and the p85alpha subunit of PI3 kinase. In conclusion, testosterone rapidly induces NO production via AR dependent activation of eNOS in HAEC. Activation of PI3-kinase/Akt signaling and the direct interaction of AR with p85alpha are involved, at least in part, in eNOS phosphorylation. PMID- 20194726 TI - Neutrophil transmigration mediated by the neutrophil-specific antigen CD177 is influenced by the endothelial S536N dimorphism of platelet endothelial cell adhesion molecule-1. AB - The human neutrophil-specific adhesion molecule CD177 (also known as the NB1 alloantigen) becomes upregulated on the cell surface in a number of inflammatory settings. We recently showed that CD177 functions as a novel heterophilic counterreceptor for the endothelial junctional protein PECAM-1 (CD31), an interaction that is mediated by membrane-proximal PECAM-1 IgD 6, which is known to harbor an S(536)N single nucleotide polymorphism of two major isoforms V(98)N(536)G(643) and L(98)S(536)R(643) and a yet-to-be-determined region on CD177. In vitro transendothelial migration experiments revealed that CD177(+) neutrophils migrated significantly faster through HUVECs expressing the LSR, compared with the VNG, allelic variant of PECAM-1 and that this correlated with the decreased ability of anti-PECAM-1 Ab of ITIM tyrosine phosphorylation in HUVECs expressing the LSR allelic variant relative to the VNG allelic variant. Moreover, engagement of PECAM-1 with rCD177-Fc (to mimic heterophilic CD177 binding) suppressed Ab-induced tyrosine phosphorylation to a greater extent in cells expressing the LSR isoform compared with the VNG isoform, with a corresponding increased higher level of beta-catenin phosphorylation. These data suggest that heterophilic PECAM-1/CD177 interactions affect the phosphorylation state of PECAM-1 and endothelial cell junctional integrity in such a way as to facilitate neutrophil transmigration in a previously unrecognized allele-specific manner. PMID- 20194728 TI - Aromatase deficiency inhibits the permeability transition in mouse liver mitochondria. AB - Lack of estrogens affects male physiology in a number of ways, including severe changes in liver metabolism that result in lipid accumulation and massive hepatic steatosis. Here we investigated whether estrogen deficiency may alter the functionality and permeability properties of liver mitochondria using, as an experimental model, aromatase knockout (ArKO) male mice, which cannot synthesize endogenous estrogens due to a disruption of the Cyp19 gene. Liver mitochondria isolated from ArKO mice displayed increased activity of the mitochondrial respiratory complex IV compared with wild-type mice and were less prone to undergo cyclosporin A-sensitive mitochondrial permeability transition (MPT) induced by calcium loading. The altered permeability properties of the mitochondrial membranes were not due to changes in reactive oxygen species, ATP levels, or mitochondrial membrane potential but were associated with increased content of the phospholipid cardiolipin, structural component of the mitochondrial membranes and regulator of the MPT pore, and with increased mitochondrial protein levels of Bcl-2 and the adenine nucleotide translocator (ANT), regulator and component of the MPT pore, respectively. Real-time RT-PCR demonstrated increased mRNA levels for Bcl-2 and ANT2 but not for the ANT1 isoform in ArKO livers. Supplementation of 17beta-estradiol retrieved ArKO mice from massive hepatic steatosis and restored mitochondrial permeability properties, cardiolipin, Bcl-2, and ANT2 levels. Overall, our findings demonstrate an important role of estrogens in the modulation of hepatic mitochondrial function and permeability properties in males and suggest that estrogen deficiency may represent a novel positive regulator of Bcl-2 and ANT2 proteins, two inhibitors of MPT occurrence and powerful antiapoptotic molecules. PMID- 20194729 TI - Functional significance of nuclear estrogen receptor subtypes in the liver of goldfish. AB - Estrogens work by binding to and activating specific estrogen receptors (ERs). Although mammals have two major nuclear ER subtypes (ERalpha and ERbeta), three subtypes have been shown in teleost fish (ERalpha, ERbeta-I, and ERbeta-II). 17beta-Estradiol stimulates the production of an egg yolk precursor protein (vitellogenin) in the liver of oviparous species, including the goldfish. However, the functional involvement of the ER subtypes in this process is not fully understood. Here, using primary goldfish hepatocytes, we test the hypothesis that all three ER subtypes are functionally involved in the liver of goldfish by using RNA interference to specifically knock-down the different ER subtypes. The results suggest that ERalpha is induced by estradiol through activation of the ERbeta subtypes. This induction serves to sensitize the liver to further stimulation by estradiol. The knock-down results were supported by use of ER subtype specific antagonists. Sensitization by up-regulation of ERalpha is likely to be important for seasonal spawners such as goldfish, to bring about a change from somatic growth to reproductive development, and vitellogenesis. The novel data presented in this study provide strong support for the hypothesis that the goldfish ER subtypes play functional roles in the regulation of vitellogenin and ERalpha and provide a framework for the better understanding of ER signaling in fish and other vertebrates. PMID- 20194731 TI - Thyroid hormone receptor {alpha} modulates lipopolysaccharide-induced changes in peripheral thyroid hormone metabolism. AB - Acute inflammation is characterized by low serum T(3) and T(4) levels accompanied by changes in liver type 1 deiodinase (D1), liver D3, muscle D2, and muscle D3 expression. It is unknown at present whether thyroid hormone receptor alpha (TRalpha) plays a role in altered peripheral thyroid hormone metabolism during acute illness in vivo. We induced acute illness in TRalpha-deficient (TRalpha(0/0)) mice by administration of a sublethal dose of LPS. Compared with wild-type, TRalpha(0/0) mice have lower basal serum T(4) and lower liver D1 activity and muscle D3 mRNA expression, whereas liver D3 activity is higher. These changes are gender specific. The inflammatory response to LPS was similar in WT and TRalpha(0/0) mice. The decrease in serum thyroid hormones and liver D1 was attenuated in TRalpha(0/0) mice, whereas the LPS induced fall in liver D3 mRNA was more pronounced in TRalpha(0/0) mice. Muscle D2 mRNA increased similarly in both strains, whereas muscle D3 mRNA decreased less pronounced in TRalpha(0/0) mice. We conclude that alterations in peripheral thyroid hormone metabolism induced by LPS administration are partly regulated via TRalpha. PMID- 20194730 TI - Early overnutrition results in early-onset arcuate leptin resistance and increased sensitivity to high-fat diet. AB - Childhood obesity increases the risk of adult obesity and diabetes, suggesting that early overnutrition permanently programs altered energy and glucose homeostasis. In the present studies, we used a mouse model to investigate whether early overnutrition increases susceptibility to obesity and insulin resistance in response to a high-fat diet (HFD). Litters from Swiss Webster dams were culled to three [chronic postnatal overnutrition (CPO)] or 10 (control) pups and then weaned onto standard chow at postnatal day (P) 23. At 6 wk of age, a subset of mice was placed on HFD, and glucose and insulin tolerance were examined at 16-17 wk of age. Leptin sensitivity was determined by hypothalamic phosphorylated signal transducer and activator of transcription-3 immunoreactivity at P16 and adulthood after ip leptin. CPO mice exhibited accelerated body weight gain and hyperleptinemia during the preweaning period but only a slightly heavier body weight and normal glucose tolerance in adulthood on standard chow diet. Importantly, CPO mice exhibited significant leptin resistance in the arcuate nucleus, demonstrated by reduced activation of phospho-signal transducer and activator of transcription-3, as early as P16 and throughout life, despite normalized leptin levels. In response to HFD, CPO but not control mice displayed insulin resistance in response to an insulin tolerance test. In conclusion, CPO mice exhibited early and persistent leptin resistance in the arcuate nucleus and, in response to HFD, rapid development of obesity and insulin resistance. These studies suggest that early overnutrition can permanently alter energy homeostasis and significantly increase susceptibility to obesity and insulin resistance. PMID- 20194732 TI - "Control" laboratory rodents are metabolically morbid: why it matters. AB - Failure to recognize that many standard control rats and mice used in biomedical research are sedentary, obese, glucose intolerant, and on a trajectory to premature death may confound data interpretation and outcomes of human studies. Fundamental aspects of cellular physiology, vulnerability to oxidative stress, inflammation, and associated diseases are among the many biological processes affected by dietary energy intake and exercise. Although overfed sedentary rodents may be reasonable models for the study of obesity in humans, treatments shown to be efficacious in these animal models may prove ineffective or exhibit novel side effects in active, normal-weight subjects. PMID- 20194733 TI - Mutant Ikzf1, KrasG12D, and Notch1 cooperate in T lineage leukemogenesis and modulate responses to targeted agents. AB - Mice that accurately model the genetic diversity found in human cancer are valuable tools for interrogating disease mechanisms and investigating novel therapeutic strategies. We performed insertional mutagenesis with the MOL4070LTR retrovirus in Mx1-Cre, Kras(G12D) mice and generated a large cohort of T lineage acute lymphoblastic leukemias (T-ALLs). Molecular analysis infers that retroviral integration within Ikzf1 is an early event in leukemogenesis that precedes Kras(G12D) expression and later acquisition of somatic Notch1 mutations. Importantly, biochemical analysis uncovered unexpected heterogeneity, which suggests that Ras signaling networks are remodeled during multistep tumorigenesis. We tested tumor-derived cell lines to identify biomarkers of therapeutic response to targeted inhibitors. Whereas all T-ALLs tested were sensitive to a dual-specificity phosphoinosityl 3-kinase/mammalian target of rapamycin inhibitor, biochemical evidence of Notch1 activation correlated with sensitivity to gamma-secretase inhibition. In addition, Kras(G12D) T-ALLs were more responsive to a MAP/ERK kinase inhibitor in vitro and in vivo. Together, these studies identify a genetic pathway involving Ikzf1, Kras(G12D), and Notch1 in T lineage leukemogenesis, reveal unexpected diversity in Ras-regulated signaling networks, and define biomarkers of drug responses that may inform treatment strategies. PMID- 20194734 TI - Allele-specific tumor spectrum in pten knockin mice. AB - Germline mutations in the tumor suppressor gene PTEN (phosphatase and tensin homology deleted on chromosome 10) cause Cowden and Bannayan-Riley-Ruvalcaba (BRR) syndromes, two dominantly inherited disorders characterized by mental retardation, multiple hamartomas, and variable cancer risk. Here, we modeled three sentinel mutant alleles of PTEN identified in patients with Cowden syndrome and show that the nonsense Pten(4-5) and missense Pten(C124R) and Pten(G129E) alleles lacking lipid phosphatase activity cause similar developmental abnormalities but distinct tumor spectra with varying severity and age of onset. Allele-specific differences may be accounted for by loss of function for Pten(4 5), hypomorphic function for Pten(C124R), and gain of function for Pten(G129E). These data demonstrate that the variable tumor phenotypes observed in patients with Cowden and BRR syndromes can be attributed to specific mutations in PTEN that alter protein function through distinct mechanisms. PMID- 20194735 TI - Leptin therapy in insulin-deficient type I diabetes. AB - In nonobese diabetic mice with uncontrolled type 1 diabetes, leptin therapy alone or combined with low-dose insulin reverses the catabolic state through suppression of hyperglucagonemia. Additionally, it mimics the anabolic actions of insulin monotherapy and normalizes hemoglobin A1c with far less glucose variability. We show that leptin therapy, like insulin, normalizes the levels of a wide array of hepatic intermediary metabolites in multiple chemical classes, including acylcarnitines, organic acids (tricarboxylic acid cycle intermediates), amino acids, and acyl CoAs. In contrast to insulin monotherapy, however, leptin lowers both lipogenic and cholesterologenic transcription factors and enzymes and reduces plasma and tissue lipids. The results imply that leptin administration may have multiple short- and long-term advantages over insulin monotherapy for type 1 diabetes. PMID- 20194736 TI - Polygenic and directional regulatory evolution across pathways in Saccharomyces. AB - The search to understand how genomes innovate in response to selection dominates the field of evolutionary biology. Powerful molecular evolution approaches have been developed to test individual loci for signatures of selection. In many cases, however, an organism's response to changes in selective pressure may be mediated by multiple genes, whose products function together in a cellular process or pathway. Here we assess the prevalence of polygenic evolution in pathways in the yeasts Saccharomyces cerevisiae and S. bayanus. We first established short-read sequencing methods to detect cis-regulatory variation in a diploid hybrid between the species. We then tested for the scenario in which selective pressure in one species to increase or decrease the activity of a pathway has driven the accumulation of cis-regulatory variants that act in the same direction on gene expression. Application of this test revealed a variety of yeast pathways with evidence for directional regulatory evolution. In parallel, we also used population genomic sequencing data to compare protein and cis regulatory variation within and between species. We identified pathways with evidence for divergence within S. cerevisiae, and we detected signatures of positive selection between S. cerevisiae and S. bayanus. Our results point to polygenic, pathway-level change as a common evolutionary mechanism among yeasts. We suggest that pathway analyses, including our test for directional regulatory evolution, will prove to be a relevant and powerful strategy in many evolutionary genomic applications. PMID- 20194737 TI - Complete mitochondrial genome of a Pleistocene jawbone unveils the origin of polar bear. AB - The polar bear has become the flagship species in the climate-change discussion. However, little is known about how past climate impacted its evolution and persistence, given an extremely poor fossil record. Although it is undisputed from analyses of mitochondrial (mt) DNA that polar bears constitute a lineage within the genetic diversity of brown bears, timing estimates of their divergence have differed considerably. Using next-generation sequencing technology, we have generated a complete, high-quality mt genome from a stratigraphically validated 130,000- to 110,000-year-old polar bear jawbone. In addition, six mt genomes were generated of extant polar bears from Alaska and brown bears from the Admiralty and Baranof islands of the Alexander Archipelago of southeastern Alaska and Kodiak Island. We show that the phylogenetic position of the ancient polar bear lies almost directly at the branching point between polar bears and brown bears, elucidating a unique morphologically and molecularly documented fossil link between living mammal species. Molecular dating and stable isotope analyses also show that by very early in their evolutionary history, polar bears were already inhabitants of the Artic sea ice and had adapted very rapidly to their current and unique ecology at the top of the Arctic marine food chain. As such, polar bears provide an excellent example of evolutionary opportunism within a widespread mammalian lineage. PMID- 20194739 TI - Ecosystem service bundles for analyzing tradeoffs in diverse landscapes. AB - A key challenge of ecosystem management is determining how to manage multiple ecosystem services across landscapes. Enhancing important provisioning ecosystem services, such as food and timber, often leads to tradeoffs between regulating and cultural ecosystem services, such as nutrient cycling, flood protection, and tourism. We developed a framework for analyzing the provision of multiple ecosystem services across landscapes and present an empirical demonstration of ecosystem service bundles, sets of services that appear together repeatedly. Ecosystem service bundles were identified by analyzing the spatial patterns of 12 ecosystem services in a mixed-use landscape consisting of 137 municipalities in Quebec, Canada. We identified six types of ecosystem service bundles and were able to link these bundles to areas on the landscape characterized by distinct social-ecological dynamics. Our results show landscape-scale tradeoffs between provisioning and almost all regulating and cultural ecosystem services, and they show that a greater diversity of ecosystem services is positively correlated with the provision of regulating ecosystem services. Ecosystem service-bundle analysis can identify areas on a landscape where ecosystem management has produced exceptionally desirable or undesirable sets of ecosystem services. PMID- 20194738 TI - A single mutation in the first transmembrane domain of yeast COX2 enables its allotopic expression. AB - During the course of evolution, a massive reduction of the mitochondrial genome content occurred that was associated with transfer of a large number of genes to the nucleus. To further characterize factors that control the mitochondrial gene transfer/retention process, we have investigated the barriers to transfer of yeast COX2, a mitochondrial gene coding for a subunit of cytochrome c oxidase complex. Nuclear-recoded Saccharomyces cerevisiae COX2 fused at the amino terminus to various alternative mitochondrial targeting sequences (MTS) fails to complement the growth defect of a yeast strain with an inactivated mitochondrial COX2 gene, even though it is expressed in cells. Through random mutagenesis of one such hybrid MTS-COX2, we identified a single mutation in the first Cox2 transmembrane domain (W56 --> R) that (i) results in the cellular expression of a Cox2 variant with a molecular mass indicative of MTS cleavage, which (ii) supports growth of a cox2 mutant on a nonfermentable carbon source, and that (iii) partially restores cytochrome c oxidase-specific respiration by the mutant mitochondria. COX2(W56R) can be allotopically expressed with an MTS derived from S. cerevisiae OXA1 or Neurospora crassa SU9, both coding for hydrophobic mitochondrial proteins, but not with an MTS derived from the hydrophilic protein Cox4. In contrast to some other previously transferred genes, allotopic COX2 expression is not enabled or enhanced by a 3'-UTR that localizes mRNA translation to the mitochondria, such as yeast ATP2(3)('-UTR). Application of in vitro evolution strategies to other mitochondrial genes might ultimately lead to yeast entirely lacking the mitochondrial genome, but still possessing functional respiratory capacity. PMID- 20194740 TI - The making of the Chandra X-Ray Observatory: the project scientist's perspective. AB - The history of the development of the Chandra X-Ray Observatory is reviewed from a personal perspective. This review is necessarily biased and limited by space because it attempts to cover a time span approaching five decades. PMID- 20194741 TI - Loss of high-frequency glucose-induced Ca2+ oscillations in pancreatic islets correlates with impaired glucose tolerance in Trpm5-/- mice. AB - Glucose homeostasis is critically dependent on insulin release from pancreatic beta-cells, which is strictly regulated by glucose-induced oscillations in membrane potential (V(m)) and the cytosolic calcium level ([Ca(2+)](cyt)). We propose that TRPM5, a Ca(2+)-activated monovalent cation channel, is a positive regulator of glucose-induced insulin release. Immunofluorescence revealed expression of TRPM5 in pancreatic islets. A Ca(2+)-activated nonselective cation current with TRPM5-like properties is significantly reduced in Trpm5(-/-) cells. Ca(2+)-imaging and electrophysiological analysis show that glucose-induced oscillations of V(m) and [Ca(2+)](cyt) have on average a reduced frequency in Trpm5(-/-) islets, specifically due to a lack of fast oscillations. As a consequence, glucose-induced insulin release from Trpm5(-/-) pancreatic islets is significantly reduced, resulting in an impaired glucose tolerance in Trpm5(-/-) mice. PMID- 20194742 TI - LRP6 overexpression defines a class of breast cancer subtype and is a target for therapy. AB - The Wnt/beta-catenin signaling pathway is activated in breast cancer, a leading cause of cancer mortality in women. Because mutations in the key intracellular components of this pathway are rare, identifying the molecular mechanisms of aberrant Wnt activation in breast cancer is critical for development of pathway targeted therapy. Here, we show that expression of the Wnt signaling coreceptor LRP6 is up-regulated in a subpopulation of human breast cancers. LRP6 silencing in breast cancer cells reduces Wnt signaling, cell proliferation, and in vivo tumor growth. In vivo administration of an LRP6 antagonist, Mesd, markedly suppressed growth of MMTV-Wnt1 tumors without causing undesirable side effects. These results demonstrate that Wnt activation at the cell surface contributes to breast cancer tumorigenesis. Together, our studies highlight LRP6 as a potential therapeutic target in breast cancer, and introduce Mesd as a promising antitumor agent for treating breast cancer subtypes with Wnt activation at the cell surface. PMID- 20194743 TI - Interaction of natural survival instincts and internalized social norms exploring the Titanic and Lusitania disasters. AB - To understand human behavior, it is important to know under what conditions people deviate from selfish rationality. This study explores the interaction of natural survival instincts and internalized social norms using data on the sinking of the Titanic and the Lusitania. We show that time pressure appears to be crucial when explaining behavior under extreme conditions of life and death. Even though the two vessels and the composition of their passengers were quite similar, the behavior of the individuals on board was dramatically different. On the Lusitania, selfish behavior dominated (which corresponds to the classical homo economicus); on the Titanic, social norms and social status (class) dominated, which contradicts standard economics. This difference could be attributed to the fact that the Lusitania sank in 18 min, creating a situation in which the short-run flight impulse dominated behavior. On the slowly sinking Titanic (2 h, 40 min), there was time for socially determined behavioral patterns to reemerge. Maritime disasters are traditionally not analyzed in a comparative manner with advanced statistical (econometric) techniques using individual data of the passengers and crew. Knowing human behavior under extreme conditions provides insight into how widely human behavior can vary, depending on differing external conditions. PMID- 20194744 TI - Dynamic transcriptomes during neural differentiation of human embryonic stem cells revealed by short, long, and paired-end sequencing. AB - To examine the fundamental mechanisms governing neural differentiation, we analyzed the transcriptome changes that occur during the differentiation of hESCs into the neural lineage. Undifferentiated hESCs as well as cells at three stages of early neural differentiation-N1 (early initiation), N2 (neural progenitor), and N3 (early glial-like)-were analyzed using a combination of single read, paired-end read, and long read RNA sequencing. The results revealed enormous complexity in gene transcription and splicing dynamics during neural cell differentiation. We found previously unannotated transcripts and spliced isoforms specific for each stage of differentiation. Interestingly, splicing isoform diversity is highest in undifferentiated hESCs and decreases upon differentiation, a phenomenon we call isoform specialization. During neural differentiation, we observed differential expression of many types of genes, including those involved in key signaling pathways, and a large number of extracellular receptors exhibit stage-specific regulation. These results provide a valuable resource for studying neural differentiation and reveal insights into the mechanisms underlying in vitro neural differentiation of hESCs, such as neural fate specification, neural progenitor cell identity maintenance, and the transition from a predominantly neuronal state into one with increased gliogenic potential. PMID- 20194745 TI - Polar localization and degradation of Arabidopsis boron transporters through distinct trafficking pathways. AB - Boron (B) is essential for plant growth but is toxic when present in excess. In the roots of Arabidopsis thaliana under B limitation, a boric acid channel, NIP5;1, and a boric acid/borate exporter, BOR1, are required for efficient B uptake and subsequent translocation into the xylem, respectively. However, under high-B conditions, BOR1 activity is repressed through endocytic degradation, presumably to avoid B toxicity. In this study, we investigated the localization of GFP-tagged NIP5;1 and BOR1 expressed under the control of their native promoters. Under B limitation, GFP-NIP5;1 and BOR1-GFP localized preferentially in outer (distal) and inner (proximal) plasma membrane domains, respectively, of various root cells. The polar localization of the boric acid channel and boric acid/borate exporter indicates the radial transport route of B toward the stele. Furthermore, mutational analysis revealed a requirement of tyrosine residues, in a probable cytoplasmic loop region of BOR1, for polar localization in various cells of the meristem and elongation zone. The same tyrosine residues were also required for vacuolar targeting upon high B supply. The present study of BOR1 and NIP5;1 demonstrates the importance of selective endocytic trafficking in polar localization and degradation of plant nutrient transporters for radial transport and homeostasis of plant mineral nutrients. PMID- 20194746 TI - In vivo vomeronasal stimulation reveals sensory encoding of conspecific and allospecific cues by the mouse accessory olfactory bulb. AB - The rodent vomeronasal system plays a critical role in mediating pheromone-evoked social and sexual behaviors. Recent studies of the anatomical and molecular architecture of the vomeronasal organ (VNO) and of its synaptic target, the accessory olfactory bulb (AOB), have suggested that unique features underlie vomeronasal sensory processing. However, the neuronal representation of pheromonal information leading to specific behavioral and endocrine responses has remained largely unexplored due to the experimental difficulty of precise stimulus delivery to the VNO. To determine the basic rules of information processing in the vomeronasal system, we developed a unique preparation that allows controlled and repeated stimulus delivery to the VNO and combined this approach with multisite recordings of neuronal activity in the AOB. We found that urine, a well-characterized pheromone source in mammals, as well as saliva, activates AOB neurons in a manner that reliably encodes the donor animal's sexual and genetic status. We also identified a significant fraction of AOB neurons that respond robustly and selectively to predator cues, suggesting an expanded role for the vomeronasal system in both conspecific and interspecific recognition. Further analysis reveals that mixed stimuli from distinct sources evoke synergistic responses in AOB neurons, thereby supporting the notion of integrative processing of chemosensory information. PMID- 20194747 TI - Dose-dependent induction of distinct phenotypic responses to Notch pathway activation in mammary epithelial cells. AB - Aberrant activation of Notch receptors has been implicated in breast cancer; however, the mechanisms contributing to Notch-dependent transformation remain elusive because Notch displays dichotomous functional activities, promoting both proliferation and growth arrest. We investigated the cellular basis for the heterogeneous responses to Notch pathway activation in 3D cultures of MCF-10A mammary epithelial cells. Expression of a constitutively active Notch-1 intracellular domain (NICD) was found to induce two distinct types of 3D structures: large, hyperproliferative structures and small, growth-arrested structures with reduced cell-to-matrix adhesion. Interestingly, we found that these heterogeneous phenotypes reflect differences in Notch pathway activation levels; high Notch activity caused down-regulation of multiple matrix-adhesion genes and inhibition of proliferation, whereas low Notch activity maintained matrix adhesion and provoked a strong hyperproliferative response. Moreover, microarray analyses implicated NICD-induced p63 down-regulation in loss of matrix adhesion. In addition, a reverse-phase protein array-based analysis and subsequent loss-of-function studies identified STAT3 as a dominant downstream mediator of the NICD-induced outgrowth. These results indicate that the phenotypic responses to Notch are determined by the dose of pathway activation; and this dose affects the balance between growth-stimulative and growth suppressive effects. This unique feature of Notch signaling provides insights into mechanisms that contribute to the dichotomous effects of Notch during development and tumorigenesis. PMID- 20194748 TI - Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease. AB - Understanding the pathogenesis of cancer-related bone disease is crucial to the discovery of new therapies. Here we identify activin A, a TGF-beta family member, as a therapeutically amenable target exploited by multiple myeloma (MM) to alter its microenvironmental niche favoring osteolysis. Increased bone marrow plasma activin A levels were found in MM patients with osteolytic disease. MM cell engagement of marrow stromal cells enhanced activin A secretion via adhesion mediated JNK activation. Activin A, in turn, inhibited osteoblast differentiation via SMAD2-dependent distal-less homeobox-5 down-regulation. Targeting activin A by a soluble decoy receptor reversed osteoblast inhibition, ameliorated MM bone disease, and inhibited tumor growth in an in vivo humanized MM model, setting the stage for testing in human clinical trials. PMID- 20194749 TI - The role of innovative global institutions in linking knowledge and action. AB - It is becoming increasingly recognized that our collective ability to tackle complex problems will require the development of new, adaptive, and innovative institutional arrangements that can deal with rapidly changing knowledge and have effective learning capabilities. In this paper, we applied a knowledge-systems perspective to examine how institutional innovations can affect the generation, sharing, and application of scientific and technical knowledge. We report on a case study that examined the effects that one large innovative organization, The Global Fund to Fight AIDS, Tuberculosis, and Malaria, is having on the knowledge dimensions of decision-making in global health. The case study shows that the organization created demand for new knowledge from a range of actors, but it did not incorporate strategies for meeting this demand into their own rules, incentives, or procedures. This made it difficult for some applicants to meet the organization's dual aims of scientific soundness and national ownership of projects. It also highlighted that scientific knowledge needed to be integrated with managerial and situational knowledge for success. More generally, the study illustrates that institutional change targeting implementation can also significantly affect the dynamics of knowledge creation (learning), access, distribution, and use. Recognizing how action-oriented institutions can affect these dynamics across their knowledge system can help institutional designers build more efficient and effective institutions for sustainable development. PMID- 20194750 TI - A link between the assembly of flagella and lipooligosaccharide of the Gram negative bacterium Campylobacter jejuni. AB - Campylobacter jejuni is the leading cause of acute bacterial diarrhea worldwide and is implicated in development of Guillain-Barre syndrome. Two major surface features, the outer membrane lipooligosaccharide and flagella, are highly variable and are often targets for modification. Presumably, these modifications provide a competitive advantage to the bacterium. In this work, we identify a gene encoding a phosphoethanolamine (pEtN) transferase (Cj0256) that serves a dual role in modifying not only the lipooligosaccharide lipid anchor lipid A with pEtN, but also the flagellar rod protein FlgG. Generation of a mutant in C. jejuni 81-176 by interruption of cj0256 resulted in the absence of pEtN modifications on lipid A as well as FlgG. The cj0256 mutant showed a 20-fold increase in sensitivity to the cationic antimicrobial peptide, polymyxin B, as well as a decrease in motility. Transmission EM of the cj0256 mutant revealed a population (approximately 95%) lacking flagella, indicating that, without pEtN modification of FlgG, flagella production is hindered. Most intriguing, this research identifies a pEtN transferase showing preference for two periplasmic substrates linking membrane biogenesis and flagellar assembly. Cj0256 is a member of a large family of mostly uncharacterized proteins that may play a larger role in the decoration of bacterial surface structures. PMID- 20194751 TI - Interaction of C-type lectin-like receptors NKp65 and KACL facilitates dedicated immune recognition of human keratinocytes. AB - Many well-known immune-related C-type lectin-like receptors (CTLRs) such as NKG2D, CD69, and the Ly49 receptors are encoded in the natural killer gene complex (NKC). Recently, we characterized the orphan NKC gene CLEC2A encoding for KACL, a further member of the human CLEC2 family of CTLRs. In contrast to the other CLEC2 family members AICL, CD69, and LLT1, KACL expression is mostly restricted to skin. Here we show that KACL is a non-disulfide-linked homodimeric surface receptor and stimulates cytotoxicity by human NK92MI cells. We identified the corresponding activating receptor on NK92MI cells that is encoded adjacently to the CLEC2A locus and binds KACL with high affinity. This CTLR, termed NKp65, stimulates NK cytotoxicity and release of proinflammatory cytokines upon engagement of cell-bound KACL. NKp65, a distant relative of the human activating NK receptor NKp80, possesses an amino-terminal hemITAM that is required for NKp65 mediated cytotoxicity. Finally, we show that KACL expression is mainly restricted to keratinocytes. Freshly isolated keratinocytes express KACL and are capable of stimulating NKp65-expressing cells in a KACL-dependent manner. Thus, we report a unique NKC-encoded receptor-ligand system that may fulfill a dedicated function in the immunobiology of human skin. PMID- 20194753 TI - Nanowire platform for mapping neural circuits. PMID- 20194752 TI - Susceptibility of xenotropic murine leukemia virus-related virus (XMRV) to retroviral restriction factors. AB - Xenotropic murine leukemia virus-related virus (XMRV) is a recently discovered gammaretrovirus that has been linked to prostate cancer and chronic fatigue syndrome. This virus is therefore an important potential human pathogen and, as such, it is essential to understand its host cell tropism. Intriguingly, infectious virus has been recovered from patient-derived peripheral blood mononuclear cells. These cells express several antiviral restriction factors that are capable of inhibiting the replication of a wide range of retroviruses, including other gamma retroviruses. This raises the possibility that, similar to HIV, XMRV may have acquired resistance to restriction. We therefore investigated the susceptibility of XMRV to a panel of different restriction factors. We found that both human APOBEC3 and tetherin proteins are able to block XMRV replication. Expression of human TRIM5alpha, however, had no effect on viral infectivity. There was no evidence that XMRV expressed countermeasures to overcome restriction. In addition, the virus was inhibited by factors from nonhuman species, including mouse Apobec3, tetherin, and Fv1 proteins. These results have important implications for predicting the natural target cells for XMRV replication, for relating infection to viral pathogenicity and pathology, and for the design of model systems with which to study XMRV-related diseases. PMID- 20194754 TI - Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin. AB - Loss of the E3 ubiquitin ligase Parkin causes early onset Parkinson's disease, a neurodegenerative disorder of unknown etiology. Parkin has been linked to multiple cellular processes including protein degradation, mitochondrial homeostasis, and autophagy; however, its precise role in pathogenesis is unclear. Recent evidence suggests that Parkin is recruited to damaged mitochondria, possibly affecting mitochondrial fission and/or fusion, to mediate their autophagic turnover. The precise mechanism of recruitment and the ubiquitination target are unclear. Here we show in Drosophila cells that PINK1 is required to recruit Parkin to dysfunctional mitochondria and promote their degradation. Furthermore, PINK1 and Parkin mediate the ubiquitination of the profusion factor Mfn on the outer surface of mitochondria. Loss of Drosophila PINK1 or parkin causes an increase in Mfn abundance in vivo and concomitant elongation of mitochondria. These findings provide a molecular mechanism by which the PINK1/Parkin pathway affects mitochondrial fission/fusion as suggested by previous genetic interaction studies. We hypothesize that Mfn ubiquitination may provide a mechanism by which terminally damaged mitochondria are labeled and sequestered for degradation by autophagy. PMID- 20194755 TI - Evolution of species-specific promoter-associated mechanisms for protecting chromosome ends by Drosophila Het-A telomeric transposons. AB - The non-LTR retrotransposons forming Drosophila telomeres constitute a robust mechanism for telomere maintenance, one which has persisted since before separation of the extant Drosophila species. These elements in D. melanogaster differ from nontelomeric retrotransposons in ways that give insight into general telomere biology. Here, we analyze telomere-specific retrotransposons from D. virilis, separated from D. melanogaster by 40 to 60 million years, to evaluate the evolutionary divergence of their telomeric traits. The telomeric retrotransposon HeT-A from D. melanogaster has an unusual promoter near its 3' terminus that drives not the element in which it resides, but the adjacent downstream element in a head-to-tail array. An obvious benefit of this promoter is that it adds nonessential sequence to the 5' end of each transcript, which is reverse transcribed and added to the chromosome. Because the 5' end of each newly transposed element forms the end of the chromosome until another element transposes onto it, this nonessential sequence can buffer erosion of sequence essential for HeT-A. Surprisingly, we have now found that HeT-A in D. virilis has a promoter typical of non-LTR retrotransposons. This promoter adds no buffering sequence; nevertheless, the complete 5' end of the element persists in telomere arrays, necessitating a more precise processing of the extreme end of the telomere in D. virilis. PMID- 20194757 TI - Atrazine induces complete feminization and chemical castration in male African clawed frogs (Xenopus laevis). AB - The herbicide atrazine is one of the most commonly applied pesticides in the world. As a result, atrazine is the most commonly detected pesticide contaminant of ground, surface, and drinking water. Atrazine is also a potent endocrine disruptor that is active at low, ecologically relevant concentrations. Previous studies showed that atrazine adversely affects amphibian larval development. The present study demonstrates the reproductive consequences of atrazine exposure in adult amphibians. Atrazine-exposed males were both demasculinized (chemically castrated) and completely feminized as adults. Ten percent of the exposed genetic males developed into functional females that copulated with unexposed males and produced viable eggs. Atrazine-exposed males suffered from depressed testosterone, decreased breeding gland size, demasculinized/feminized laryngeal development, suppressed mating behavior, reduced spermatogenesis, and decreased fertility. These data are consistent with effects of atrazine observed in other vertebrate classes. The present findings exemplify the role that atrazine and other endocrine-disrupting pesticides likely play in global amphibian declines. PMID- 20194758 TI - The imprint of China's first emperor on the distant realm of eastern Shandong. AB - Imperial expansion is recurrent in human history. For early empires, such as in ancient China, this process generally is known from texts that glorify and present the perspective of vectors. The legacy of the Qin king, Shihuangdi, who first unified China in 221 BC, remains vital, but we have few details about the consequences of his distant conquests or how they changed the path of local histories. We integrate documentary accounts with the findings of a systematic regional survey of archaeological sites to provide a holistic context for this imperialistic episode and the changes that followed in coastal Shandong. PMID- 20194756 TI - Developmental hyperbilirubinemia and CNS toxicity in mice humanized with the UDP glucuronosyltransferase 1 (UGT1) locus. AB - High levels of unconjugated bilirubin (UCB) in newborn children is associated with a reduction in hepatic UDP glucuronosyltransferase (UGT) 1A1 activity that can lead to CNS toxicity, brain damage, and even death. Little is known regarding those events that lead to UCB accumulation in brain tissue, and therefore, we sought to duplicate this condition in mice. The human UGT1 locus, encoding all 9 UGT1A genes including UGT1A1, was expressed in Ugt1(-/-) mice. Because the most common clinical condition associated with jaundice in adults is Gilbert's syndrome, which is characterized by an allelic polymorphism in the UGT1A1 promoter, hyperbilirubinemia was monitored in humanized UGT1 mice that expressed either the Gilbert's UGT1A1*28 allele [Tg(UGT1(A1*28))Ugt1(-/-) mice] or the normal UGT1A1*1 allele [Tg(UGT1(A1*1))Ugt1(-/-) mice]. Adult Tg(UGT1(A1*28))Ugt1( /-) mice expressed elevated levels of total bilirubin (TB) compared with Tg(UGT1(A1*1))Ugt1(-/-) mice, confirming that the promoter polymorphism associated with the UGT1A1*28 allele contributes to hyperbilirubinemia in mice. However, TB accumulated to near toxic levels during neonatal development, a finding that is independent of the Gilbert's UGT1A1*28 promoter polymorphism. Whereas serum TB levels eventually returned to adult levels, TB clearance in neonatal mice was not associated with hepatic UGT1A1 expression. In approximately 10% of the humanized UGT1 mice, peak TB levels culminated in seizures followed by death. UCB deposition in brain tissue and the ensuing seizures were associated with developmental milestones and can be prevented by enhancing regulation of the UGT1A1 gene in neonatal mice. PMID- 20194759 TI - Phosphoenolpyruvate carboxylase intrinsically located in the chloroplast of rice plays a crucial role in ammonium assimilation. AB - Phosphoenolpyruvate carboxylase (PEPC) is a key enzyme of primary metabolism in bacteria, algae, and vascular plants, and is believed to be cytosolic. Here we show that rice (Oryza sativa L.) has a plant-type PEPC, Osppc4, that is targeted to the chloroplast. Osppc4 was expressed in all organs tested and showed high expression in the leaves. Its expression in the leaves was confined to mesophyll cells, and Osppc4 accounted for approximately one-third of total PEPC protein in the leaf blade. Recombinant Osppc4 was active in the PEPC reaction, showing V(max) comparable to cytosolic isozymes. Knockdown of Osppc4 expression by the RNAi technique resulted in stunting at the vegetative stage, which was much more marked when rice plants were grown with ammonium than with nitrate as the nitrogen source. Comparison of leaf metabolomes of ammonium-grown plants suggested that the knockdown suppressed ammonium assimilation and subsequent amino acid synthesis by reducing levels of organic acids, which are carbon skeleton donors for these processes. We also identified the chloroplastic PEPC gene in other Oryza species, all of which are adapted to waterlogged soil where the major nitrogen source is ammonium. This suggests that, in addition to glycolysis, the genus Oryza has a unique route to provide organic acids for ammonium assimilation that involves a chloroplastic PEPC, and that this route is crucial for growth with ammonium. This work provides evidence for diversity of primary ammonium assimilation in the leaves of vascular plants. PMID- 20194760 TI - Macroecological signals of species interactions in the Danish avifauna. AB - The role of intraspecific and interspecific interactions in structuring biotic communities at fine spatial scales is well documented, but the signature of species interactions at coarser spatial scales is unclear. We present evidence that species interactions may be a significant factor in mediating the regional assembly of the Danish avifauna. Because >95% of breeding species (n = 197) are migratory, we hypothesized that dispersal limitation would not be important and that breeding distributions would largely reflect resource availability and autecological habitat preferences. Instead, we detected a striking pattern of spatial segregation between ecologically similar species at two spatial scales with a suite of null models that factored in the spatial distribution of habitats in Denmark as well as population size and biomass of each species. Habitat utilization analyses indicated that community-wide patterns of spatial segregation could not be attributed to the patchy distribution of habitat or to gross differences in habitat utilization among ecologically similar species. We hypothesize that, when habitat patch size is limited, conspecific attraction in concert with interspecific territoriality may result in spatially segregated distributions of ecologically similar species at larger spatial scales. In the Danish avifauna, the effects of species interactions on community assembly appear pervasive and can be discerned at grain sizes up to four orders of magnitude larger than those of individual territories. These results suggest that species interactions should be incorporated into species distribution modeling algorithms designed to predict species occupancy patterns based on environmental variables. PMID- 20194761 TI - The dimensionality of discourse. AB - The paragraph spaces of five text corpora, of different genres and intended audiences, in four different languages, all show the same two-scale structure, with the dimension at short distances being lower than at long distances. In all five cases the short-distance dimension is approximately eight. Control simulations with randomly permuted word instances do not exhibit a low dimensional structure. The observed topology places important constraints on the way in which authors construct prose, which may be universal. PMID- 20194762 TI - Distal axonopathy with structural persistence in glaucomatous neurodegeneration. AB - An early hallmark of neuronal degeneration is distal transport loss and axon pathology. Glaucoma involves the degeneration of retinal ganglion cell (RGC) neurons and their axons in the optic nerve. Here we show that, like other neurodegenerations, distal axon injury appears early in mouse glaucoma. Where RGC axons terminate in the superior colliculus, reduction of active transport follows a retinotopic pattern resembling glaucomatous vision loss. Like glaucoma, susceptibility to transport deficits increases with age and is not necessarily associated with elevated ocular pressure. Transport deficits progress distal-to proximal, appearing in the colliculus first followed by more proximal secondary targets and then the optic tract. Transport persists through the optic nerve head before finally failing in the retina. Although axon degeneration also progresses distal-to-proximal, myelinated RGC axons and their presynaptic terminals persist in the colliculus well after transport fails. Thus, distal transport loss is predegenerative and may represent a therapeutic target. PMID- 20194764 TI - From the Cover: A Howiesons Poort tradition of engraving ostrich eggshell containers dated to 60,000 years ago at Diepkloof Rock Shelter, South Africa. AB - Ongoing debates about the emergence of modern human behavior, however defined, regularly incorporate observations from the later part of the southern African Middle Stone Age and emphasize the early appearance of artifacts thought to reflect symbolic practice. Here we report a large sample of 270 fragments of intentionally marked ostrich eggshell from the Howiesons Poort at Diepkloof Rock Shelter, Western Cape, South Africa. Dating from approximately 60,000 years ago, these pieces attest to an engraving tradition that is the earliest reliable evidence of what is a widespread modern practice. These abstract linear depictions were made on functional items (eggshell containers), which were curated and involved in daily hunter-gatherer life. The standardized production of repetitive patterns, including a hatched band motif, suggests a system of symbolic representation in which collective identities and individual expressions are clearly communicated, suggesting social, cultural, and cognitive underpinnings that overlap with those of modern people. PMID- 20194763 TI - Reduced voltage sensitivity in a K+-channel voltage sensor by electric field remodeling. AB - Propagation of the nerve impulse relies on the extreme voltage sensitivity of Na(+) and K(+) channels. The transmembrane movement of four arginine residues, located at the fourth transmembrane segment (S4), in each of their four voltage sensing domains is mostly responsible for the translocation of 12 to 13 e(o) across the transmembrane electric field. Inserting additional positively charged residues between the voltage-sensing arginines in S4 would, in principle, increase voltage sensitivity. Here we show that either positively or negatively charged residues added between the two most external sensing arginines of S4 decreased voltage sensitivity of a Shaker voltage-gated K(+)-channel by up to approximately 50%. The replacement of Val363 with a charged residue displaced inwardly the external boundaries of the electric field by at least 6 A, leaving the most external arginine of S4 constitutively exposed to the extracellular space and permanently excluded from the electric field. Both the physical trajectory of S4 and its electromechanical coupling to open the pore gate seemed unchanged. We propose that the separation between the first two sensing charges at resting is comparable to the thickness of the low dielectric transmembrane barrier they must cross. Thus, at most a single sensing arginine side chain could be found within the field. The conserved hydrophobic nature of the residues located between the voltage-sensing arginines in S4 may shape the electric field geometry for optimal voltage sensitivity in voltage-gated ion channels. PMID- 20194765 TI - Seromic profiling of ovarian and pancreatic cancer. AB - Autoantibodies, a hallmark of both autoimmunity and cancer, represent an easily accessible surrogate for measuring adaptive immune responses to cancer. Sera can now be assayed for reactivity against thousands of proteins using microarrays, but there is no agreed-upon standard to analyze results. We developed a set of tailored quality control and normalization procedures based on ELISA validation to allow patient comparisons and determination of individual cutoffs for specificity and sensitivity. Sera from 60 patients with pancreatic cancer, 51 patients with ovarian cancer, and 53 age-matched healthy donors were used to assess the binding of IgG antibodies against a panel of >8000 human antigens using protein microarrays and fluorescence detection. The resulting data interpretation led to the definition and ranking of proteins with preferred recognition by the sera from cancer patients in comparison with healthy donors, both by frequency and strength of signal. We found that 202 proteins were preferentially immunogenic in ovarian cancer sera compared to 29 in pancreatic cancer, with few overlaps. Correlates of autoantibody signatures with known tumor expression of corresponding antigens, functional pathways, clinical stage, and outcome were examined. Serological analysis of arrays displaying the complete human proteome (seromics) represents a new era in cancer immunology, opening the way to defining the repertoire of the humoral immune response to cancer. PMID- 20194766 TI - Axon guidance by growth-rate modulation. AB - Guidance of axons by molecular gradients is crucial for wiring up the developing nervous system. It often is assumed that the unique signature of such guidance is immediate and biased turning of the axon tip toward or away from the gradient. However, here we show that such turning is not required for guidance. Rather, by a combination of experimental and computational analyses, we demonstrate that growth-rate modulation is an alternative mechanism for guidance. Furthermore we show that, although both mechanisms may operate simultaneously, biased turning dominates in steep gradients, whereas growth-rate modulation may dominate in shallow gradients. These results suggest that biased axon turning is not the only method by which guidance can occur. PMID- 20194767 TI - Theta-activity in anterior cingulate cortex predicts task rules and their adjustments following errors. AB - Accomplishing even simple tasks depend on neuronal circuits to configure how incoming sensory stimuli map onto responses. Controlling these stimulus-response (SR) mapping rules relies on a cognitive control network comprising the anterior cingulate cortex (ACC). Single neurons within the ACC convey information about currently relevant SR mapping rules and signal unexpected action outcomes, which can be used to optimize behavioral choices. However, its functional significance and the mechanistic means of interaction with other nodes of the cognitive control network remain elusive and poorly understood. Here, we report that core aspects of cognitive control are encoded by rhythmic theta-band activity within neuronal circuits in the ACC. Throughout task performance, theta-activity predicted which of two SR mapping rules will be established before processing visual target information. Task-selective theta-activity emerged particularly early during those trials, which required the adjustment of SR rules following an erroneous rule representation in the preceding trial. These findings demonstrate a functional correlation of cognitive control processes and oscillatory theta band activity in macaque ACC. Moreover, we report that spike output of a subset of cells in ACC is synchronized to predictive theta-activity, suggesting that the theta-cycle could serve as a temporal reference for coordinating local task selective computations across a larger network of frontal areas and the hippocampus to optimize and adjust the processing routes of sensory and motor circuits to achieve efficient sensory-motor control. PMID- 20194768 TI - Optimal reward harvesting in complex perceptual environments. AB - The ability to choose rapidly among multiple targets embedded in a complex perceptual environment is key to survival. Targets may differ in their reward value as well as in their low-level perceptual properties (e.g., visual saliency). Previous studies investigated separately the impact of either value or saliency on choice; thus, it is not known how the brain combines these two variables during decision making. We addressed this question with three experiments in which human subjects attempted to maximize their monetary earnings by rapidly choosing items from a brief display. Each display contained several worthless items (distractors) as well as two targets, whose value and saliency were varied systematically. We compared the behavioral data with the predictions of three computational models assuming that (i) subjects seek the most valuable item in the display, (ii) subjects seek the most easily detectable item, and (iii) subjects behave as an ideal Bayesian observer who combines both factors to maximize the expected reward within each trial. Regardless of the type of motor response used to express the choices, we find that decisions are influenced by both value and feature-contrast in a way that is consistent with the ideal Bayesian observer, even when the targets' feature-contrast is varied unpredictably between trials. This suggests that individuals are able to harvest rewards optimally and dynamically under time pressure while seeking multiple targets embedded in perceptual clutter. PMID- 20194769 TI - Random cell movement promotes synchronization of the segmentation clock. AB - In vertebrate somitogenesis, the expression of segmentation clock genes oscillates and the oscillation is synchronized over nearby cells. Both experimental and theoretical studies have shown that the synchronization among cells is realized by intercellular interaction via Delta-Notch signaling. However, the following questions emerge: (i) During somitogenesis, dynamic rearrangement of relative cell positions is observed in the posterior presomitic mesoderm. Can a synchronized state be stably sustained under random cell movement? (ii) Experimental studies have reported that the synchronization of cells can be recovered in about 10 or fewer oscillation cycles after the complete loss of synchrony. However, such a quick recovery of synchronization is not possible according to previous theoretical models. In this paper, we first show by numerical modeling that synchronized oscillation can be sustained under random cell movement. We also find that for initial perturbation, the synchronization of cells is recovered much faster and it is for a wider range of reaction parameters than the case without cell movement. When the posterior presomitic mesoderm is rectangular, faster synchronization is achieved if cells exchange their locations more with neighbors located along the longer side of the domain. Finally, we discuss that the enhancement of synchronization by random cell movement occurs in several different models for the oscillation of segmentation clock genes. PMID- 20194770 TI - Atomically detailed simulation of the recovery stroke in myosin by Milestoning. AB - Myosin II is a molecular motor that converts chemical to mechanical energy and enables muscle operations. After a power stroke, a recovery transition completes the cycle and returns the molecular motor to its prestroke state. Atomically detailed simulations in the framework of the Milestoning theory are used to calculate kinetics and mechanisms of the recovery stroke. Milestoning divides the process into transitions between hyper-surfaces (Milestones) along a reaction coordinate. Decorrelation of dynamics between sequential Milestones is assumed, which speeds up the atomically detailed simulations by a factor of millions. Two hundred trajectories of myosin with explicit water solvation are used to sample transitions between sequential pairs of Milestones. Collective motions of hundreds of atoms are described at atomic resolution and at the millisecond time scale. The experimentally measured transition time of about a millisecond is in good agreement with the computed time. The simulations support a sequential mechanism. In the first step the P-loop and switch 2 close on the ATP and in the second step the mechanical relaxation is induced via the relay and the SH1 helices. We propose that the entropy of switch 2 helps to drive the power stroke. Secondary structure elements are progressing through a small number of discrete states in a network of activated transitions and are assisted by side chain flips between rotameric states. The few-state sequential mechanism is likely to enhance the efficiency of the relaxation reducing the probability of off-pathway intermediates. PMID- 20194771 TI - A ratchet mechanism for amplification in low-frequency mammalian hearing. AB - The sensitivity and frequency selectivity of hearing result from tuned amplification by an active process in the mechanoreceptive hair cells. In most vertebrates, the active process stems from the active motility of hair bundles. The mammalian cochlea exhibits an additional form of mechanical activity termed electromotility: its outer hair cells (OHCs) change length upon electrical stimulation. The relative contributions of these two mechanisms to the active process in the mammalian inner ear is the subject of intense current debate. Here, we show that active hair-bundle motility and electromotility can together implement an efficient mechanism for amplification that functions like a ratchet: Sound-evoked forces, acting on the basilar membrane, are transmitted to the hair bundles, whereas electromotility decouples active hair-bundle forces from the basilar membrane. This unidirectional coupling can extend the hearing range well below the resonant frequency of the basilar membrane. It thereby provides a concept for low-frequency hearing that accounts for a variety of unexplained experimental observations from the cochlear apex, including the shape and phase behavior of apical tuning curves, their lack of significant nonlinearities, and the shape changes of threshold tuning curves of auditory-nerve fibers along the cochlea. The ratchet mechanism constitutes a general design principle for implementing mechanical amplification in engineering applications. PMID- 20194772 TI - Tropical cloud forest climate variability and the demise of the Monteverde golden toad. AB - Widespread amphibian extinctions in the mountains of the American tropics have been blamed on the interaction of anthropogenic climate change and a lethal pathogen. However, limited meteorological records make it difficult to conclude whether current climate conditions at these sites are actually exceptional in the context of natural variability. We use stable oxygen isotope measurements from trees without annual rings to reconstruct a century of hydroclimatology in the Monteverde Cloud Forest of Costa Rica. High-resolution measurements reveal coherent isotope cycles that provide annual chronological control and paleoclimate information. Climate variability is dominated by interannual variance in dry season moisture associated with El Nino Southern Oscillation events. There is no evidence of a trend associated with global warming. Rather, the extinction of the Monteverde golden toad (Bufo periglenes) appears to have coincided with an exceptionally dry interval caused by the 1986-1987 El Nino event. PMID- 20194774 TI - An unlocking/relocking barrier in conformational fluctuations of villin headpiece subdomain. AB - A reversible structural unlocking reaction, in which the close-packed van der Waals interactions break cooperatively, has been found for the villin headpiece subdomain (HP35) using triplet-triplet-energy transfer to monitor conformational fluctuations from equilibrium. Unlocking is associated with an unfavorable enthalpy change (DeltaH(0) = 35 +/- 4 kJ/mol) which is nearly compensated in free energy by the entropy change (DeltaS(0) = 112 +/- 20 Jxmol(-1)xK(-1)). The unlocking reaction has a time constant of about 1 mus at 5 degrees C and is enthalpy-limited with an activation energy of 32 +/- 1 kJ/mol and a large Arrhenius preexponential factor of A = 7.5 x 10(11) s(-1). In the unlocked state a fast local conformational fluctuation with a time constant of 170 ns and a low activation barrier of 17 +/- 1 kJ/mol leads to unfolding of the C-terminal helix and to its undocking from the core. On a much slower time scale, global unfolding occurs from the unlocked state. These results suggest that native protein structures are locked into conformations with low amplitude motions. Large scale motions and global unfolding require an initial structural unlocking step leading to a state with properties of a dry molten globule. The experiments additionally yielded information on the dynamics of loop formation between different positions in unfolded HP35. Comparison of the results with dynamics in unstructured model peptides indicates slightly decelerated kinetics of local loop formation in the C terminal region which points at residual, nonrandom structure. Dynamics of long range loop formation, in contrast, are not influenced by residual structure, which argues against unfolded state properties as molecular origin for ultrafast folding of HP35. PMID- 20194775 TI - Analytic index for a family of Dirac-Ramond operators. AB - We derive a cohomological formula for the analytic index of a family of Dirac Ramond operators and exhibit its modular properties. PMID- 20194773 TI - Abundant ribonucleotide incorporation into DNA by yeast replicative polymerases. AB - Measurements of nucleoside triphosphate levels in Saccharomyces cerevisiae reveal that the four rNTPs are in 36- to 190-fold molar excess over their corresponding dNTPs. During DNA synthesis in vitro using the physiological nucleoside triphosphate concentrations, yeast DNA polymerase epsilon, which is implicated in leading strand replication, incorporates one rNMP for every 1,250 dNMPs. Pol delta and Pol alpha, which conduct lagging strand replication, incorporate one rNMP for every 5,000 or 625 dNMPs, respectively. Discrimination against rNMP incorporation varies widely, in some cases by more than 100-fold, depending on the identity of the base and the template sequence context in which it is located. Given estimates of the amount of replication catalyzed by Pols alpha, delta, and epsilon, the results are consistent with the possibility that more than 10,000 rNMPs may be incorporated into the nuclear genome during each round of replication in yeast. Thus, rNMPs may be the most common noncanonical nucleotides introduced into the eukaryotic genome. Potential beneficial and negative consequences of abundant ribonucleotide incorporation into DNA are discussed, including the possibility that unrepaired rNMPs in DNA could be problematic because yeast DNA polymerase epsilon has difficulty bypassing a single rNMP present within a DNA template. PMID- 20194776 TI - Allosteric modulation of Ras positions Q61 for a direct role in catalysis. AB - Ras and its effector Raf are key mediators of the Ras/Raf/MEK/ERK signal transduction pathway. Mutants of residue Q61 impair the GTPase activity of Ras and are found prominently in human cancers. Yet the mechanism through which Q61 contributes to catalysis has been elusive. It is thought to position the catalytic water molecule for nucleophilic attack on the gamma-phosphate of GTP. However, we previously solved the structure of Ras from crystals with symmetry of the space group R32 in which switch II is disordered and found that the catalytic water molecule is present. Here we present a structure of wild-type Ras with calcium acetate from the crystallization mother liquor bound at a site remote from the active site and likely near the membrane. This results in a shift in helix 3/loop 7 and a network of H-bonding interactions that propagates across the molecule, culminating in the ordering of switch II and placement of Q61 in the active site in a previously unobserved conformation. This structure suggests a direct catalytic role for Q61 where it interacts with a water molecule that bridges one of the gamma-phosphate oxygen atoms to the hydroxyl group of Y32 to stabilize the transition state of the hydrolysis reaction. We propose that Raf together with the binding of Ca(2+) and a negatively charged group mimicked in our structure by the acetate molecule induces the ordering of switch I and switch II to complete the active site of Ras. PMID- 20194777 TI - Response of an aerosol mass spectrometer to organonitrates and organosulfates and implications for atmospheric chemistry. AB - Organonitrates (ON) are important products of gas-phase oxidation of volatile organic compounds in the troposphere; some models predict, and laboratory studies show, the formation of large, multifunctional ON with vapor pressures low enough to partition to the particle phase. Organosulfates (OS) have also been recently detected in secondary organic aerosol. Despite their potential importance, ON and OS remain a nearly unexplored aspect of atmospheric chemistry because few studies have quantified particulate ON or OS in ambient air. We report the response of a high-resolution time-of-flight aerosol mass spectrometer (AMS) to aerosol ON and OS standards and mixtures. We quantify the potentially substantial underestimation of organic aerosol O/C, commonly used as a metric for aging, and N/C. Most of the ON-nitrogen appears as NO(x)+ ions in the AMS, which are typically dominated by inorganic nitrate. Minor organonitrogen ions are observed although their identity and intensity vary between standards. We evaluate the potential for using NO(x)+ fragment ratios, organonitrogen ions, HNO(3)+ ions, the ammonium balance of the nominally inorganic ions, and comparison to ion chromatography instruments to constrain the concentrations of ON for ambient datasets, and apply these techniques to a field study in Riverside, CA. OS manifests as separate organic and sulfate components in the AMS with minimal organosulfur fragments and little difference in fragmentation from inorganic sulfate. The low thermal stability of ON and OS likely causes similar detection difficulties for other aerosol mass spectrometers using vaporization and/or ionization techniques with similar or larger energy, which has likely led to an underappreciation of these species. PMID- 20194778 TI - Strong intranucleoid interactions organize the Escherichia coli chromosome into a nucleoid filament. AB - The stochasticity of chromosome organization was investigated by fluorescently labeling genetic loci in live Escherichia coli cells. In spite of the common assumption that the chromosome is well modeled by an unstructured polymer, measurements of the locus distributions reveal that the E. coli chromosome is precisely organized into a nucleoid filament with a linear order. Loci in the body of the nucleoid show a precision of positioning within the cell of better than 10% of the cell length. The precision of interlocus distance of genomically proximate loci was better than 4% of the cell length. The measured dependence of the precision of interlocus distance on genomic distance singles out intranucleoid interactions as the mechanism responsible for chromosome organization. From the magnitude of the variance, we infer the existence of an as yet uncharacterized higher-order DNA organization in bacteria. We demonstrate that both the stochastic and average structure of the nucleoid is captured by a fluctuating elastic filament model. PMID- 20194779 TI - Full-length extracellular region of the var2CSA variant of PfEMP1 is required for specific, high-affinity binding to CSA. AB - Pregnancy-associated malaria (PAM) is a serious consequence of sequestration of Plasmodium falciparum-parasitized erythrocytes (PE) in the placenta through adhesion to chondroitin sulfate A (CSA) present on placental proteoglycans. Recent work implicates var2CSA, a member of the PfEMP1 family, as the mediator of placental sequestration and as a key target for PAM vaccine development. Var2CSA is a 350 kDa transmembrane protein, whose extracellular region includes six Duffy binding-like (DBL) domains. Due to its size and high cysteine content, the full length var2CSA extracellular region has not hitherto been expressed in heterologous systems, thus limiting investigations to individual recombinant domains. Here we report for the first time the expression of the full-length var2CSA extracellular region (domains DBL1X to DBL6epsilon) from the 3D7 parasite strain using the human embryonic kidney 293 cell line. We show that the recombinant extracellular var2CSA region is correctly folded and that, unlike the individual DBL domains, it binds with high affinity and specificity to CSA (K(D) = 61 nM) and efficiently inhibits PE from binding to CSA. Structural characterization by analytical ultracentrifugation and small-angle x-ray scattering reveals a compact organization of the full-length protein, most likely governed by specific interdomain interactions, rather than an extended structure. Collectively, these data suggest that a high-affinity, CSA-specific binding site is formed by the higher-order structure of the var2CSA extracellular region. These results have important consequences for the development of an effective vaccine and therapeutic inhibitors. PMID- 20194780 TI - Geometric cues for directing the differentiation of mesenchymal stem cells. AB - Significant efforts have been directed to understanding the factors that influence the lineage commitment of stem cells. This paper demonstrates that cell shape, independent of soluble factors, has a strong influence on the differentiation of human mesenchymal stem cells (MSCs) from bone marrow. When exposed to competing soluble differentiation signals, cells cultured in rectangles with increasing aspect ratio and in shapes with pentagonal symmetry but with different subcellular curvature-and with each occupying the same area display different adipogenesis and osteogenesis profiles. The results reveal that geometric features that increase actomyosin contractility promote osteogenesis and are consistent with in vivo characteristics of the microenvironment of the differentiated cells. Cytoskeletal-disrupting pharmacological agents modulate shape-based trends in lineage commitment verifying the critical role of focal adhesion and myosin-generated contractility during differentiation. Microarray analysis and pathway inhibition studies suggest that contractile cells promote osteogenesis by enhancing c-Jun N-terminal kinase (JNK) and extracellular related kinase (ERK1/2) activation in conjunction with elevated wingless-type (Wnt) signaling. Taken together, this work points to the role that geometric shape cues can play in orchestrating the mechanochemical signals and paracrine/autocrine factors that can direct MSCs to appropriate fates. PMID- 20194781 TI - Engineering cis-telomerase RNAs that add telomeric repeats to themselves. AB - Telomerase is a ribonucleoprotein complex consisting of a protein reverse transcriptase (TERT) and an RNA subunit (TR). Telomerase normally adds telomeric DNA repeats to chromosome ends. Here, we engineer human and Tetrahymena cis telomerase RNAs, each having a DNA primer covalently linked to its 3' end. We find that cis-telomerase synthesizes DNA with increased repeat addition processivity (RAP) but does not completely rescue the RAP defect of the L14A mutant of Tetrahymena TERT. This supports the conclusion that L14 has a function beyond binding the DNA primer and preventing dissociation during multiple rounds of repeat addition. By comparing cis-telomerases with various linker lengths, we find that a 5 nt linker gives near-optimal activity, indicating that the distance between the 3' end of the telomerase RNA pseudoknot region and the 5' end of the DNA primer is approximately 33 A. Even a 2 nt linker (approximately 14 A) gives some activity, indicating a high degree of conformational flexibility in this ribonucleoprotein complex. More generally, the cis system will allow structure function relationships of each RNA molecule to be read directly through the reaction that it performs on itself. PMID- 20194782 TI - Origins of catalysis by computationally designed retroaldolase enzymes. AB - We have investigated recently reported computationally designed retroaldolase enzymes with the goal of understanding the extent and the origins of their catalytic power. Direct comparison of the designed enzymes to primary amine catalysts in solution revealed a rate acceleration of 10(5)-fold for the most active of the designed retroaldolases. Through pH-rate studies of the designed retroaldolases and evaluation of a Bronsted correlation for a series of amine catalysts, we found that lysine pK(a) values are shifted by 3-4 units in the enzymes but that the catalytic contributions from the shifted pK(a) values are estimated to be modest, about 10-fold. For the most active of the reported enzymes, we evaluated the catalytic contribution of two other design components: a motif intended to stabilize a bound water molecule and hydrophobic substrate binding interactions. Mutational analysis suggested that the bound water motif does not contribute to the rate acceleration. Comparison of the rate acceleration of the designed substrate relative to a minimal substrate suggested that hydrophobic substrate binding interactions contribute around 10(3)-fold to the enzymatic rate acceleration. Altogether, these results suggest that substrate binding interactions and shifting the pK(a) of the catalytic lysine can account for much of the enzyme's rate acceleration. Additional observations suggest that these interactions are limited in the specificity of placement of substrate and active site catalytic groups. Thus, future design efforts may benefit from a focus on achieving precision in binding interactions and placement of catalytic groups. PMID- 20194783 TI - Picomole-scale characterization of protein stability and function by quantitative cysteine reactivity. AB - The Gibbs free energy difference between native and unfolded states ("stability") is one of the fundamental characteristics of a protein. By exploiting the thermodynamic linkage between ligand binding and stability, interactions of a protein with small molecules, nucleic acids, or other proteins can be detected and quantified. Determination of protein stability can therefore provide a universal monitor of biochemical function. Yet, the use of stability measurements as a functional probe is underutilized, because such experiments traditionally require large amounts of protein and special instrumentation. Here we present the quantitative cysteine reactivity (QCR) technique to determine protein stabilities rapidly and accurately using only picomole quantities of material and readily accessible laboratory equipment. We demonstrate that QCR-derived stabilities can be used to measure ligand binding over a wide range of ligand concentrations and affinities. We anticipate that this technique will have broad applications in high-throughput protein engineering experiments and functional genomics. PMID- 20194784 TI - Identification and characterization of the furfural and 5-(hydroxymethyl)furfural degradation pathways of Cupriavidus basilensis HMF14. AB - The toxic fermentation inhibitors in lignocellulosic hydrolysates pose significant problems for the production of second-generation biofuels and biochemicals. Among these inhibitors, 5-(hydroxymethyl)furfural (HMF) and furfural are specifically notorious. In this study, we describe the complete molecular identification and characterization of the pathway by which Cupriavidus basilensis HMF14 metabolizes HMF and furfural. The identification of this pathway enabled the construction of an HMF and furfural-metabolizing Pseudomonas putida. The genetic information obtained furthermore enabled us to predict the HMF and furfural degrading capabilities of sequenced bacterial species that had not previously been connected to furanic aldehyde metabolism. These results pave the way for in situ detoxification of lignocellulosic hydrolysates, which is a major step toward improved efficiency of utilization of lignocellulosic feedstock. PMID- 20194785 TI - Large-scale conformational sampling of proteins using temperature-accelerated molecular dynamics. AB - We show how to apply the method of temperature-accelerated molecular dynamics (TAMD) in collective variables [Maragliano L, Vanden-Eijnden E (2006) Chem Phys Lett 426:168-175] to sample the conformational space of multidomain proteins in all-atom, explicitly solvated molecular dynamics simulations. The method allows the system to hyperthermally explore the free-energy surface in a set of collective variables computed at the physical temperature. As collective variables, we pick Cartesian coordinates of centers of contiguous subdomains. The method is applied to the GroEL subunit, a 55-kDa, three-domain protein, and HIV-1 gp120. For GroEL, the method induces in about 40 ns conformational changes that recapitulate the t --> r('') transition and are not observed in unaccelerated molecular dynamics: The apical domain is displaced by 30 A, with a twist of 90 degrees relative to the equatorial domain, and the root-mean-squared deviation relative to the r('') conformer is reduced from 13 to 5 A, representing fairly high predictive capability. For gp120, the method predicts both counterrotation of inner and outer domains and disruption of the so-called bridging sheet. In particular, TAMD on gp120 initially in the CD4-bound conformation visits conformations that deviate by 3.6 A from the gp120 conformer in complex with antibody F105, again reflecting good predictive capability. TAMD generates plausible all-atom models of the so-far structurally uncharacterized unliganded conformation of HIV-1 gp120, which may prove useful in the development of inhibitors and immunogens. The fictitious temperature employed also gives a rough estimate of 10 kcal/mol for the free-energy barrier between conformers in both cases. PMID- 20194786 TI - Magnetically driven three-dimensional manipulation and inductive heating of magnetic-dispersion containing metal alloys. AB - Fundamental to the development of three-dimensional microelectronic fabrication is a material that enables vertical geometries. Here we show low-melting-point metal alloys containing iron dispersions that can be remotely manipulated by magnetic fields to create vertical geometries and thus enable novel three dimensional assemblies. These iron dispersions enhance the mechanical properties needed for strong, reliable interconnects without significantly altering the electrical properties of the alloys. Additionally, these iron dispersions act as susceptors for magnetic induction heating, allowing the rapid melting of these novel alloys at temperatures lower than those usually reported for conventional metal alloys. By localizing high temperatures and by reducing temperature excursions, the materials and methods described have potential in a variety of device fabrication applications. PMID- 20194787 TI - 4.0-A resolution cryo-EM structure of the mammalian chaperonin TRiC/CCT reveals its unique subunit arrangement. AB - The essential double-ring eukaryotic chaperonin TRiC/CCT (TCP1-ring complex or chaperonin containing TCP1) assists the folding of approximately 5-10% of the cellular proteome. Many TRiC substrates cannot be folded by other chaperonins from prokaryotes or archaea. These unique folding properties are likely linked to TRiC's unique heterooligomeric subunit organization, whereby each ring consists of eight different paralogous subunits in an arrangement that remains uncertain. Using single particle cryo-EM without imposing symmetry, we determined the mammalian TRiC structure at 4.7-A resolution. This revealed the existence of a 2 fold axis between its two rings resulting in two homotypic subunit interactions across the rings. A subsequent 2-fold symmetrized map yielded a 4.0-A resolution structure that evinces the densities of a large fraction of side chains, loops, and insertions. These features permitted unambiguous identification of all eight individual subunits, despite their sequence similarity. Independent biochemical near-neighbor analysis supports our cryo-EM derived TRiC subunit arrangement. We obtained a Calpha backbone model for each subunit from an initial homology model refined against the cryo-EM density. A subsequently optimized atomic model for a subunit showed approximately 95% of the main chain dihedral angles in the allowable regions of the Ramachandran plot. The determination of the TRiC subunit arrangement opens the way to understand its unique function and mechanism. In particular, an unevenly distributed positively charged wall lining the closed folding chamber of TRiC differs strikingly from that of prokaryotic and archaeal chaperonins. These interior surface chemical properties likely play an important role in TRiC's cellular substrate specificity. PMID- 20194788 TI - In vivo gene delivery by cationic tetraamino fullerene. AB - Application of nanotechnology to medical biology has brought remarkable success. Water-soluble fullerenes are molecules with great potential for biological use because they can endow unique characteristics of amphipathic property and form a self-assembled structure by chemical modification. Effective gene delivery in vitro with tetra(piperazino)fullerene epoxide (TPFE) and its superiority to Lipofectin have been described in a previous report. For this study, we evaluated the efficacy of in vivo gene delivery by TPFE. Delivery of enhanced green fluorescent protein gene (EGFP) by TPFE on pregnant female ICR mice showed distinct organ selectivity compared with Lipofectin; moreover, higher gene expression by TPFE was found in liver and spleen, but not in the lung. No acute toxicity of TPFE was found for the liver and kidney, although Lipofectin significantly increased liver enzymes and blood urea nitrogen. In fetal tissues, neither TPFE nor Lipofectin induced EGFP gene expression. Delivery of insulin 2 gene to female C57/BL6 mice increased plasma insulin levels and reduced blood glucose concentrations, indicating the potential of TPFE-based gene delivery for clinical application. In conclusion, this study demonstrated effective gene delivery in vivo for the first time using a water-soluble fullerene. PMID- 20194789 TI - Discovering the flight autostabilizer of fruit flies by inducing aerial stumbles. AB - Just as the Wright brothers implemented controls to achieve stable airplane flight, flying insects have evolved behavioral strategies that ensure recovery from flight disturbances. Pioneering studies performed on tethered and dissected insects demonstrate that the sensory, neurological, and musculoskeletal systems play important roles in flight control. Such studies, however, cannot produce an integrative model of insect flight stability because they do not incorporate the interaction of these systems with free-flight aerodynamics. We directly investigate control and stability through the application of torque impulses to freely flying fruit flies (Drosophila melanogaster) and measurement of their behavioral response. High-speed video and a new motion tracking method capture the aerial "stumble," and we discover that flies respond to gentle disturbances by accurately returning to their original orientation. These insects take advantage of a stabilizing aerodynamic influence and active torque generation to recover their heading to within 2 degrees in < 60 ms. To explain this recovery behavior, we form a feedback control model that includes the fly's ability to sense body rotations, process this information, and actuate the wing motions that generate corrective aerodynamic torque. Thus, like early man-made aircraft and modern fighter jets, the fruit fly employs an automatic stabilization scheme that reacts to short time-scale disturbances. PMID- 20194790 TI - CaV1.2 beta-subunit coordinates CaMKII-triggered cardiomyocyte death and afterdepolarizations. AB - Excessive activation of calmodulin kinase II (CaMKII) causes arrhythmias and heart failure, but the cellular mechanisms for CaMKII-targeted proteins causing disordered cell membrane excitability and myocardial dysfunction remain uncertain. Failing human cardiomyocytes exhibit increased CaMKII and voltage gated Ca(2+) channel (Ca(V)1.2) activity, and enhanced expression of a specific Ca(V)1.2 beta-subunit protein isoform (beta(2a)). We recently identified Ca(V)1.2 beta(2a) residues critical for CaMKII phosphorylation (Thr 498) and binding (Leu 493), suggesting the hypothesis that these amino acids are crucial for cardiomyopathic consequences of CaMKII signaling. Here we show WT beta(2a) expression causes cellular Ca(2+) overload, arrhythmia-triggering cell membrane potential oscillations called early afterdepolarizations (EADs), and premature death in paced adult rabbit ventricular myocytes. Prevention of intracellular Ca(2+) release by ryanodine or global cellular CaMKII inhibition reduced EADs and improved cell survival to control levels in WT beta(2a)-expressing ventricular myocytes. In contrast, expression of beta(2a) T498A or L493A mutants mimicked the protective effects of ryanodine or global cellular CaMKII inhibition by reducing Ca(2+) entry through Ca(V)1.2 and inhibiting EADs. Furthermore, Ca(V)1.2 currents recorded from cells overexpressing CaMKII phosphorylation- or binding-incompetent beta(2a) subunits were incapable of entering a CaMKII-dependent high-activity gating mode (mode 2), indicating that beta(2a) Thr 498 and Leu 493 are required for Ca(V)1.2 activation by CaMKII in native cells. These data show that CaMKII binding and phosphorylation sites on beta(2a) are concise but pivotal components of a molecular and biophysical and mechanism for EADs and impaired survival in adult cardiomyocytes. PMID- 20194791 TI - Molecular basis for the high-affinity binding and stabilization of firefly luciferase by PTC124. AB - Firefly luciferase (FLuc), an ATP-dependent bioluminescent reporter enzyme, is broadly used in chemical biology and drug discovery assays. PTC124 (Ataluren; (3 [5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid) discovered in an FLuc based assay targeting nonsense codon suppression, is an unusually potent FLuc inhibitor. Paradoxically, PTC124 and related analogs increase cellular FLuc activity levels by posttranslational stabilization. In this study, we show that FLuc inhibition and stabilization is the result of an inhibitory product formed during the FLuc-catalyzed reaction between its natural substrate, ATP, and PTC124. A 2.0 A cocrystal structure revealed the inhibitor to be the acyl-AMP mixed-anhydride adduct PTC124-AMP, which was subsequently synthesized and shown to be a high-affinity multisubstrate adduct inhibitor (MAI; K(D) = 120 pM) of FLuc. Biochemical assays, liquid chromatography/mass spectrometry, and near attack conformer modeling demonstrate that formation of this novel MAI is absolutely dependent upon the precise positioning and reactivity of a key meta carboxylate of PTC124 within the FLuc active site. We also demonstrate that the inhibitory activity of PTC124-AMP is relieved by free coenzyme A, a component present at high concentrations in luciferase detection reagents used for cell based assays. This explains why PTC124 can appear to increase, instead of inhibit, FLuc activity in cell-based reporter gene assays. To our knowledge, this is an unusual example in which the "off-target" effect of a small molecule is mediated by an MAI mechanism. PMID- 20194792 TI - Pore architecture of the ORAI1 store-operated calcium channel. AB - ORAI1 is the pore-forming subunit of the calcium release-activated calcium (CRAC) channel, a store-operated channel that is central to Ca(2+) signaling in mammalian cells. Electrophysiological data have shown that the acidic residues E106 in transmembrane helix 1 (TM1) and E190 in TM3 contribute to the high selectivity of ORAI1 channels for Ca(2+). We have examined the pore architecture of the ORAI1 channel using ORAI1 proteins engineered to contain either one or two cysteine residues. Disulfide cross-linking shows that ORAI1 assembles as a tetramer or a higher oligomer with TM1 centrally located. Cysteine side chains projecting from TM1 at position 88, 95, 102, or 106 cross-link efficiently to the corresponding side chain in a second ORAI1 monomer. Cysteine residues at position 190 or at surrounding positions in TM3 do not cross-link. We conclude that E106 residues in wild-type ORAI1 are positioned to form a Ca(2+) binding site in the channel pore and that E190 interacts less directly with ions traversing the pore. The cross-linking data further identify a relatively rigid segment of TM1 adjacent to E106 that is likely to contribute to the selectivity filter. PMID- 20194794 TI - Minute negative superhelicity is sufficient to induce the B-Z transition in the presence of low tension. AB - Left-handed Z-DNA has fascinated biological scientists for decades by its extraordinary structure and potential involvement in biological phenomena. Despite its instability relative to B-DNA, Z-DNA is stabilized in vivo by negative supercoiling. A detailed understanding of Z-DNA formation is, however, still lacking. In this study, we have examined the B-Z transition in a short guanine/cytosine (GC) repeat in the presence of controlled tension and superhelicity via a hybrid technique of single-molecule FRET and magnetic tweezers. The hybrid scheme enabled us to identify the states of the specific GC region under mechanical control and trace conformational changes synchronously at local and global scales. Intriguingly, minute negative superhelicity can facilitate the B-Z transition at low tension, indicating that tension, as well as torsion, plays a pivotal role in the transition. Dynamic interconversions between the states at elevated temperatures yielded thermodynamic and kinetic constants of the transition. Our single-molecule studies shed light on the understanding of Z-DNA formation by highlighting the highly cooperative and dynamic nature of the B-Z transition. PMID- 20194793 TI - Fermentable sugars by chemical hydrolysis of biomass. AB - Abundant plant biomass has the potential to become a sustainable source of fuels and chemicals. Realizing this potential requires the economical conversion of recalcitrant lignocellulose into useful intermediates, such as sugars. We report a high-yielding chemical process for the hydrolysis of biomass into monosaccharides. Adding water gradually to a chloride ionic liquid-containing catalytic acid leads to a nearly 90% yield of glucose from cellulose and 70-80% yield of sugars from untreated corn stover. Ion-exclusion chromatography allows recovery of the ionic liquid and delivers sugar feedstocks that support the vigorous growth of ethanologenic microbes. This simple chemical process, which requires neither an edible plant nor a cellulase, could enable crude biomass to be the sole source of carbon for a scalable biorefinery. PMID- 20194795 TI - Morphology of mixed primary and secondary organic particles and the adsorption of spectator organic gases during aerosol formation. AB - Primary organic aerosol (POA) and associated vapors can play an important role in determining the formation and properties of secondary organic aerosol (SOA). If SOA and POA are miscible, POA will significantly enhance SOA formation and some POA vapor will incorporate into SOA particles. When the two are not miscible, condensation of SOA on POA particles forms particles with complex morphology. In addition, POA vapor can adsorb to the surface of SOA particles increasing their mass and affecting their evaporation rates. To gain insight into SOA/POA interactions we present a detailed experimental investigation of the morphologies of SOA particles formed during ozonolysis of alpha-pinene in the presence of dioctyl phthalate (DOP) particles, serving as a simplified model of hydrophobic POA, using a single-particle mass spectrometer. Ultraviolet laser depth-profiling experiments were used to characterize two different types of mixed SOA/DOP particles: those formed by condensation of the oxidized alpha-pinene products on size-selected DOP particles and by condensation of DOP on size-selected alpha pinene SOA particles. The results show that the hydrophilic SOA and hydrophobic DOP do not mix but instead form layered phases. In addition, an examination of homogeneously nucleated SOA particles formed in the presence of DOP vapor shows them to have an adsorbed DOP coating layer that is approximately 4 nm thick and carries 12% of the particles mass. These results may have implications for SOA formation and behavior in the atmosphere, where numerous organic compounds with various volatilities and different polarities are present. PMID- 20194796 TI - A zinc-binding site by negative selection induces metallodrug susceptibility in an essential chaperonin. AB - GroES is an indispensable chaperonin virtually found throughout all life forms. Consequently, mutations of this protein must be critically scrutinized by natural selection. Nevertheless, the homolog from a potentially virulent gastric pathogen, Helicobacter pylori, strikingly features a histidine/cysteine-rich C terminus that shares no significant homology with other family members. Additionally, three more (H45, C51, and C53) are uniquely present in its apical domain. The statistical analyses show that these residues may have originated from negative selection, presumably driven by either dependent or independent amino acid mutations. In the absence of the C-terminal metal-binding domain, the mutant protein still exhibits a substantial capacity for zinc binding in vivo. The biochemical properties of site-directed mutants indicate that H45, C51, and C53 make up an oxidation-sensitive zinc-binding site that may donate the bound metal to a zinc acceptor. Of interest, bismuth antiulcer drugs strongly bind at this site (K(d) of approximately 7 x 10(-26) M), replacing the bound zinc and consequently inducing the disruption of the quaternary structure. Because biological features by negative selection are usually inert to change during evolution, this study sheds light on a promising field whereby medicines can be designed or improved to specifically target the residues that uniquely evolved in pathogenic proteins so as to retard the emergence of drug resistance. PMID- 20194797 TI - Long-term outcome after ablative therapy of postoperative atrial tachyarrhythmia in patients with congenital heart disease and characteristics of atrial tachyarrhythmia recurrences. AB - BACKGROUND: Catheter ablation has evolved as a possible curative treatment modality for atrial tachyarrhythmia (AT) in patients with congenital heart defects (CHD). However, data on long-term outcome are scarce. We examined characteristics of recurrent AT after ablation of postoperative AT during long term follow-up in CHD patients. METHODS AND RESULTS: CHD patients (n=53; 27 men; age, 38+/-15 years) referred for catheter ablation of AT were studied during a follow-up period of 5+/-3 years. After ablative therapy of the first AT (n=53, 27 atrial flutter, cycle length=288+/-81 ms; 22 intra-atrial reentrant tachycardia, cycle length=309+/-81 ms; 5 focal atrial tachycardia, cycle length=380+/-147 ms; success rate, 65%), AT recurred (59% within the first year) in 29 patients; 15 underwent repetitive ablative therapy. Mechanisms underlying recurrent AT were similar in 7 patients (intra-atrial reentrant tachycardia, 2; atrial flutter, 5). The location of arrhythmogenic substrates of recurrent AT (intra-atrial reentrant tachycardia, focal atrial tachycardia) was different for all but 1 patient. After 5+/-3 years, 5 patients died of heart failure, 3 were lost to follow-up, and the remaining patients had sinus rhythm (n=31), AT (n=5), or atrial flutter (n=14). Antiarrhythmic drugs were used by 18 (57%) sinus rhythm patients. CONCLUSIONS: Successive postoperative AT in CHD patients developing over time may be caused by different mechanisms, including focal and reentrant mechanisms. Recurrent AT originated from different locations, suggesting that these new AT were not caused by arrhythmogenicity of previous ablative lesions. Long-term outcome is often complicated by development of atrial fibrillation. Despite frequent need for repeat ablative therapy, most patients are in sinus rhythm. PMID- 20194798 TI - Amiodarone versus procainamide for the acute treatment of recurrent supraventricular tachycardia in pediatric patients. AB - BACKGROUND: Intravenous amiodarone and procainamide are both used as therapies for refractory supraventricular tachycardia (SVT). However, no studies have compared the efficacy and safety of these agents in pediatric patients. METHODS AND RESULTS: All patients treated with intravenous amiodarone or procainamide during 25 consecutive months for the following mechanisms of SVT were included: orthodromic reciprocating tachycardia, intra-atrial reentrant tachycardia, and ectopic atrial tachycardia; junctional ectopic tachycardia was excluded. Treatment response was categorized as full success, partial success, or failure. Partial success was defined as clinical improvement and/or arrhythmia control but not meeting full success criteria. Adverse events were classified as major (requiring resuscitation) or minor (management changes). There were 40 episodes of SVT in 37 patients (median age, 34 days; 24 with congenital heart disease). Amiodarone was the initial therapy in 26 cases and procainamide in 14 cases. If partial and full success are combined, procainamide was successful in 71% of cases compared with 34% for amiodarone (P=0.046). If partial success is considered a treatment failure, procainamide was successful in 50% compared with 15% for amiodarone (P=0.029). Ten patients received the second medication after the first failed. Success was achieved in 5 of 8 amiodarone-to-procainamide crossovers compared with 1 of 2 procainamide-to-amiodarone crossovers. One major and 10 minor adverse events occurred in amiodarone patients versus 6 minor adverse events in procainamide patients (P=NS). CONCLUSIONS: In this cohort, procainamide achieved greater success compared with amiodarone in the management of recurrent SVT without statistically significant differences in adverse event frequency. PMID- 20194799 TI - Damage to the esophagus after atrial fibrillation ablation: Just the tip of the iceberg? High prevalence of mediastinal changes diagnosed by endosonography. AB - BACKGROUND: Radiofrequency catheter ablation is increasingly used in the treatment of atrial fibrillation. Esophageal wall changes varying from erythema to ulcers have been described by endoscopy in up to 47% of patients following pulmonary vein isolation (PVI). Although esophageal changes are frequently reported, the development of a left atrial (LA)-esophageal fistula is fortunately rare. Nevertheless, mucosal changes may just represent "the tip of the iceberg." The aim of this study was, therefore, to investigate the more subtle changes of and injuries to the posterior wall of the LA, the periesophageal and mediastinal connective tissue, and the whole wall of the esophagus, including mucosal changes by esophagogastroduodenoscopy (EGD) combined with radial endosonography (EUS). METHODS AND RESULTS: Twenty-nine patients (7 females; mean age, 57.7+/-10.5 years [range, 23-75 years]) underwent EGD and EUS before and after PVI within 48 hours. PVI was performed as a circumferential antral isolation of the septal and lateral pulmonary veins guided by a decapolar circular mapping catheter using a 3 dimensional mapping system with the integration of a preprocedurally acquired computed tomography scan of the left atrium. The maximum power applied was 30 W, with an open-irrigated catheter using a maximum flow rate of 30 mL/min. In all patients, the esophagus was reconstructed using the same computed tomography scan and displayed during the ablation procedure. In case of newly detected periesophageal changes, EGD and EUS were repeated 1 week after the PVI. In all patients, a regular contact area between the LA and the esophagus could be demonstrated before PVI. The mean vertical contact length was 4.4+/-1.5 cm (range, 2-10 cm); and the mean distance between the anterior wall of the esophagus and the endocardium was 2.6+/-0.8 mm (range, 1.4-4.0 mm). After PVI, morphological changes of the periesophageal connective tissue and the posterior wall of the LA were diagnosed by endosonography in 8 patients (27%; 95% confidence interval, 12.73-47.24). No mucosal changes of the esophagus in terms of erythema or ulcers were found. In all but one patient (who refused the control), all periesophageal and atrial changes had resolved within 1 week. No atrioesophageal fistula occurred during follow-up (mean follow-up, 294+/-110 days [range, 36-431 days]). CONCLUSIONS: Mucosal changes of the esophagus after PVI like ulcers or erythema could not be demonstrated, yet structural changes of the mediastinum, which were only visible by endosonography, occurred in 27% of patients in the present study. This may indicate a higher than expected periesophageal injury because of PV ablation. Endosonography might prove to be a sensitive and reliable tool in the follow-up after PVI. PMID- 20194800 TI - The problem of revealing how students think: Concept inventories and beyond. PMID- 20194801 TI - Epigenetics online: multimedia teaching resources. PMID- 20194802 TI - Integrated biology and undergraduate science education: a new biology education for the twenty-first century? PMID- 20194804 TI - Maritza Macdonald. Interviewed by Laura L. Mays Hoopes. PMID- 20194805 TI - Educational challenges of molecular life science: Characteristics and implications for education and research. AB - Molecular life science is one of the fastest-growing fields of scientific and technical innovation, and biotechnology has profound effects on many aspects of daily life-often with deep, ethical dimensions. At the same time, the content is inherently complex, highly abstract, and deeply rooted in diverse disciplines ranging from "pure sciences," such as math, chemistry, and physics, through "applied sciences," such as medicine and agriculture, to subjects that are traditionally within the remit of humanities, notably philosophy and ethics. Together, these features pose diverse, important, and exciting challenges for tomorrow's teachers and educational establishments. With backgrounds in molecular life science research and secondary life science teaching, we (Tibell and Rundgren, respectively) bring different experiences, perspectives, concerns, and awareness of these issues. Taking the nature of the discipline as a starting point, we highlight important facets of molecular life science that are both characteristic of the domain and challenging for learning and education. Of these challenges, we focus most detail on content, reasoning difficulties, and communication issues. We also discuss implications for education research and teaching in the molecular life sciences. PMID- 20194806 TI - Different but equal? How nonmajors and majors approach and learn genetics. AB - Introductory biology courses are frequently offered separately to biology majors and nonbiology majors, with the assumption that the two groups of students are different enough to merit different courses. To assess the evidence behind this assumption, we compared students in two different genetics classes at the University of Colorado-Boulder, one class for nonscience majors (nonmajors) and the other class for biology majors and students planning a biology-related career (majors), to see whether these two groups of students were fundamentally different in performance and attitudes. To measure content knowledge, we administered identical assessments to both groups of students during the semester: a validated pre- and postcontent assessment (Genetics Concept Assessment), ungraded quizzes after problem-solving sessions, and questions on each exam. We measured attitudes, study time, and study techniques through online surveys. Majors outperformed nonmajors on content assessments, finishing with significantly higher learning gains. Nonmajors and majors also differed in their motivation, interest, study time, and expert-level of beliefs. We suggest that focusing on the process of science and its connection to students' lives will better engage and motivate nonmajors while still helping them learn the fundamental concepts of genetics. PMID- 20194807 TI - Comparison of views of the nature of science between natural science and nonscience majors. AB - Science educators have the common goal of helping students develop scientific literacy, including understanding of the nature of science (NOS). University faculties are challenged with the need to develop informed NOS views in several major student subpopulations, including science majors and nonscience majors. Research into NOS views of undergraduates, particularly science majors, has been limited. In this study, NOS views of undergraduates in introductory environmental science and upper-level animal behavior courses were measured using Likert items and open-ended prompts. Analysis revealed similarities in students' views between the two courses; both populations held a mix of naive, transitional, and moderately informed views. Comparison of pre- and postcourse mean scores revealed significant changes in NOS views only in select aspects of NOS. Student scores on sections addressing six aspects of NOS were significantly different in most cases, showing notably uninformed views of the distinctions between scientific theories and laws. Evidence-based insight into student NOS views can aid in reforming undergraduate science courses and will add to faculty and researcher understanding of the impressions of science held by undergraduates, helping educators improve scientific literacy in future scientists and diverse college graduates. PMID- 20194809 TI - End-of-life decision making in the intensive care unit. AB - Increasingly in the United States and other countries, medical decisions, including those at the end of life, are made using a shared decision-making model. Under this model, physicians and other clinicians help patients clarify their values and reach consensus about treatment courses consistent with them. Because most critically ill patients are decisionally impaired, family members and other surrogates must make end-of-life decisions for them, ideally in accord with a substituted judgment standard. Physicians generally make decisions for patients who lack families or other surrogates and have no advance directives, based on a best interests standard and occasionally in consultation with other physicians or with review by a hospital ethics committee. End-of-life decisions for patients with surrogates usually are made at family conferences, the functioning of which can be improved by several methods that have been demonstrated to improve communications. Facilitative ethics consultations can be helpful in resolving conflicts when physicians and families disagree in end-of life decisions. Ethics committees actually are allowed to make such decisions in one state when disagreements cannot be resolved otherwise. PMID- 20194808 TI - The genomics education partnership: successful integration of research into laboratory classes at a diverse group of undergraduate institutions. AB - Genomics is not only essential for students to understand biology but also provides unprecedented opportunities for undergraduate research. The goal of the Genomics Education Partnership (GEP), a collaboration between a growing number of colleges and universities around the country and the Department of Biology and Genome Center of Washington University in St. Louis, is to provide such research opportunities. Using a versatile curriculum that has been adapted to many different class settings, GEP undergraduates undertake projects to bring draft quality genomic sequence up to high quality and/or participate in the annotation of these sequences. GEP undergraduates have improved more than 2 million bases of draft genomic sequence from several species of Drosophila and have produced hundreds of gene models using evidence-based manual annotation. Students appreciate their ability to make a contribution to ongoing research, and report increased independence and a more active learning approach after participation in GEP projects. They show knowledge gains on pre- and postcourse quizzes about genes and genomes and in bioinformatic analysis. Participating faculty also report professional gains, increased access to genomics-related technology, and an overall positive experience. We have found that using a genomics research project as the core of a laboratory course is rewarding for both faculty and students. PMID- 20194810 TI - Prognostic significance of sympathetic nervous system activation in pulmonary arterial hypertension. AB - RATIONALE: The sympathetic nervous system has been reported to be activated in pulmonary arterial hypertension (PAH). OBJECTIVES: We investigated the prognostic significance of muscle sympathetic nervous system activity (MSNA) in PAH. METHODS: Thirty-two patients with PAH were included in the study and underwent a measurement of MSNA over a 6-year period of time. They had undergone a concomitant evaluation of New York Heart Association (NYHA) functional class, a 6 minute walk distance (6MWD), an echocardiographic examination, and a right heart catheterization for diagnostic or reevaluation purposes. The median follow-up time was 20.6 months (interquartile range, 45.8 mo). Clinical deterioration was defined by listing for transplantation or death. MEASUREMENTS AND MAIN RESULTS: Seventeen patients presented with clinical deterioration. As compared with the 15 others, they had an increased MSNA (80 +/- 12 vs. 52 +/- 18 bursts/min; P < 0.001) and heart rate (88 +/- 17 vs. 74 +/- 12 bpm; P = 0.01), a lower 6MWD (324 +/- 119 vs. 434 +/- 88 m; P < 0.01) and a deteriorated NYHA functional class (3.6 +/- 0.5 vs. 2.9 +/- 0.8; P < 0.001). The hemodynamic variables were not different. MSNA was directly related to heart rate and inversely to 6MWD. A univariate analysis revealed that increased MSNA and heart rate, NYHA class IV, lower 6MWD, and pericardial effusion were associated with subsequent clinical deterioration. A multivariate analysis showed that MSNA was an independent predictor of clinical deterioration. For every increase of 1 burst/minute, the risk of clinical deterioration during follow-up increased by 6%. CONCLUSIONS: Sympathetic nervous system activation is an independent predictor of clinical deterioration in pulmonary arterial hypertension. PMID- 20194811 TI - Gene set analysis of lung samples provides insight into pathogenesis of progressive, fibrotic pulmonary sarcoidosis. AB - RATIONALE: Approximately 60 to 70% of patients with pulmonary sarcoidosis have disease that resolves spontaneously; the rest follow a chronic course with varying levels of fibrosis. It is unclear why some patients progress and if treatment affects outcome. OBJECTIVES: To determine differential gene expression profile in lungs of patients with self-limiting sarcoidosis compared to those with progressive-fibrotic disease, and to analyze the biological relevance of these differentially expressed genes. METHODS: We examined microarray expression of 26,626 genes in transbronchial biopsies of granulomatous areas in lungs of patients with active but self-limiting (n = 8) versus those with active, progressive (+/- fibrotic) pulmonary disease (n = 7). MEASUREMENTS AND MAIN RESULTS: Three hundred thirty-four genes were differentially expressed between the two groups (P < 0.01, Bayesian moderated t test). Gene Set Enrichment Analysis showed over-representation of gene-sets (defined by Gene Ontology) related to host immune activation, proliferation, and defense, among genes up regulated in the progressive-fibrotic group (FDR q < 0.0001 for the top 43 gene sets), and a marked enrichment of, and similarity in gene expression profiles between, progressive-fibrotic sarcoidosis and hypersensitivity pneumonitis (HP), (q < 0.001), but not idiopathic pulmonary fibrosis (IPF). CONCLUSIONS: The findings suggest that patients with progressive/fibrotic pulmonary sarcoidosis have intense immune activity related to host defense in their lungs, with processes more similar to HP than IPF. The study also demonstrates that transbronchial lung biopsy samples can provide good-quality RNA for gene expression profiling, supporting its potential use as a prognostic classifier for pulmonary sarcoidosis. PMID- 20194812 TI - Noninfectious pneumonitis after everolimus therapy for advanced renal cell carcinoma. AB - RATIONALE: Noninfectious pneumonitis is a known class effect of mammalian target of rapamycin (mTOR) inhibitors. OBJECTIVES: To assess the incidence, radiographic patterns, management, and outcome of pneumonitis in patients with advanced renal cell carcinoma receiving everolimus. METHODS: Clinical study data from 416 patients, randomized to receive everolimus versus placebo, were analyzed for adverse events of pneumonitis. Radiographic studies performed every 8 weeks were subject to a prospective, independent, blinded central review for the presence of findings indicative of pneumonitis. MEASUREMENTS AND MAIN RESULTS: Of 274 patients receiving everolimus, clinical pneumonitis was suspected for 37 patients (13.5%) (none with placebo). Nine cases (3.3%) were grade 1 (asymptomatic), 18 (6.6%) were grade 2 (not interfering with daily living), and 10 (3.6%) were grade 3 (interfering with daily living or oxygen indicated). No grade 4 (life threatening) pneumonitis was observed. Of the 10 patients with grade 3 pneumonitis, 5 had baseline radiological evidence of pneumonitis before everolimus therapy. Twenty of the 37 cases (54.0%) were reversible within the follow-up period; resolution followed dose reduction for 20 patients and treatment discontinuation in 10 patients. Corticosteroid therapy was initiated in 16 cases. Dedicated radiological review of available serial radiographic studies (245 patients receiving everolimus and 132 receiving placebo) found a higher percentage of new radiographic findings even in patients without a diagnosis of clinical pneumonitis who were receiving everolimus versus placebo (38.9 vs. 15.2%). CONCLUSIONS: Early recognition, prompt intervention, and a conservative approach are important in managing the risk associated with noninfectious pneumonitis in association with everolimus. Clinical trial registered with www.clinicaltrials.gov (NCT 00410124). PMID- 20194813 TI - The metalloprotease-disintegrin ADAM8 is essential for the development of experimental asthma. AB - RATIONALE: Expression of the metalloprotease ADAM8 is increased in patients with asthma, but the functional significance of elevated ADAM8 expression in the context of asthma pathogenesis remains elusive. OBJECTIVES: To study development of asthma in ADAM8-deficient mice. METHODS: Ovalbumin-induced asthma was studied in wild-type, ADAM8-deficient, and ADAM8-chimeric mice. Lung inflammation was assessed by histology, analysis of bronchoalveolar lavage, and airway hyperresponsiveness. MEASUREMENTS AND MAIN RESULTS: ADAM8-deficient mice are highly resistant to the development of ovalbumin-induced airway inflammation and hyperresponsiveness. ADAM8 expression was induced in both hematopoietic cells and the nonhematopoietic microenvironment after induction of asthma, and ADAM8 expression in both cell populations was required for the full manifestation of asthma. Interestingly, loss of ADAM8 on T cells alone was sufficient to significantly decrease the asthma response. The attenuated response was not due to an intrinsic defect in antigen presentation or cytokine production but reflected an impaired migration of T cells, eosinophils, CD11b(+) CD11c(-), and CD11c(+) cells from blood vessels to the lung and alveolar space, suggesting a general hematopoietic cell deficiency in the absence of ADAM8. CONCLUSIONS: The results show that ADAM8 plays a proinflammatory role in airway inflammation. The milder disease outcome in the absence of ADAM8 suggests that this protein might be an interesting new target in treatment of this, and potentially other, inflammatory diseases in which recruitment of inflammatory cells is an essential part of pathogenesis. PMID- 20194814 TI - Exposure to mycotoxins increases the allergic immune response in a murine asthma model. AB - RATIONALE: Epidemiological studies have shown that indoor molds are associated with increased prevalence and exacerbation of respiratory symptoms and asthma. Mycotoxins, secondary metabolites of molds, may contribute to these effects. OBJECTIVES: To investigate the adjuvant activity of mycotoxins on allergic airway inflammation. METHODS: Balb/c mice were exposed via the airways to gliotoxin and via the intestine to patulin, sensitized with ovalbumin (OVA), and then analyzed in acute and chronic murine asthma models. In addition, the effect of mycotoxin exposure on dendritic cell (DC) function was investigated using murine bone marrow-derived DCs. MEASUREMENTS AND MAIN RESULTS: Exposure of mice to both mycotoxins enhanced dose-dependently airway hyperreactivity, eosinophilic lung inflammation, and OVA-specific IgE serum levels compared with mice that received only the antigen. These findings correlated with increased Th2 cytokine levels and decreased IFN-gamma production. Long-term mycotoxin exposure exacerbated chronic airway inflammation and airway remodeling. In vitro or in vivo mycotoxin exposure inhibited IL-12 production in maturing DCs and enhanced airway inflammation after adoptive DC transfer into Balb/c mice. Mycotoxin exposure enhanced OVA-induced lung lipid peroxidation and moderately increased isoprostane levels in naive mice. Treatment of mycotoxin-exposed DCs with the antioxidants N acetylcysteine or glutathione ethyl ester restored IL-12 secretion and pretreatment of exposed mice with N-acetylcysteine prevented the mycotoxin induced increase of airway inflammation and AHR. CONCLUSIONS: Our results demonstrate that gliotoxin and patulin increase the allergic immune response in mice by modulating the Th1/Th2 balance via direct effects on IL-12 secretion in DCs and by inducing oxidative stress. PMID- 20194815 TI - Fas/Fas ligand-mediated apoptosis promotes hypersensitivity pneumonitis in mice by enhancing maturation of dendritic cells. AB - RATIONALE: Fas/Fas ligand (FasL)-mediated apoptosis has been implicated in various lung diseases, but whether Fas/FasL-mediated apoptosis in the lungs plays a critical role in the development of hypersensitivity pneumonitis (HP) is unclear. OBJECTIVES: To explore the functional roles of Fas/FasL-mediated apoptosis in HP. METHODS: Fas-deficient (lpr/lpr), FasL-deficient (gld/gld), and B6 mice were challenged with Saccharopolyspora rectivirgula (SR) antigen intranasally. MEASUREMENTS AND MAIN RESULTS: lpr/lpr and gld/gld mice exhibited attenuation of HP in terms of histological alterations, influx of immune cells in bronchoalveolar lavage fluid (BALF), and SR-specific immune responses compared with B6 mice, similar to the effects of SR in B6 mice given a caspase inhibitor. The lungs of lpr/lpr and gld/gld mice showed high IL-4 production and low IFN gamma, IL-8, macrophage inflammatory protein-2, IL-1beta, and tumor necrosis factor-alpha production compared with those of B6 mice. Moreover, mice with chimeric B6 and lpr/lpr bone marrow revealed that apoptosis of nonhematopoietic and BALF immune cells of the lungs enhanced immune responses against SR antigen. Gr-1(+) granulocytes in BALF expressed annexin V and their depletion in B6 mice attenuated HP. Apoptosis of nonhematopoietic cells and Gr-1(+) granulocytes in the lungs enhanced the maturation of pulmonary CD11c(+) dendritic cells and their production of macrophage inflammatory protein-1alpha and monocyte chemoattractant protein-1, resulting in recruitment of immune cells into the lungs during HP. CONCLUSIONS: These results suggest that apoptosis in nonhematopoietic cells and Gr-1(+) granulocytes of the lungs promotes HP by enhancing maturation and chemokine production of CD11c(+) dendritic cells. PMID- 20194816 TI - Systemic sclerosis-associated pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a devastating vascular complication of a number of connective tissue diseases, including systemic sclerosis (SSc), where it has a dramatic impact on the clinical course and overall survival and is the single most common cause of death in patients afflicted with this syndrome. Although remarkable advances have been achieved in elucidating the pathogenesis of PAH over the past 2 decades, leading to the development of disease-targeted therapies for the idiopathic form of this condition (IPAH), the response to therapy is suboptimal in SSc-related PAH (SSc-PAH), and survival remains very poor. Factors accounting for striking clinical and prognostic differences between these two syndromes are unclear but may include a more pronounced autoimmune, cellular, and inflammatory response, and a higher prevalence of comorbidities in SSc-PAH, including cardiac and pulmonary venous and parenchymal involvement. Furthermore, currently available markers of disease severity and clinical tools to assess response to therapy, which may be reliable in IPAH, are either limited or lacking in SSc-PAH. Thus, a more focused approach, including a better understanding of the pathogenesis and genetic factors underlying the development of SSc-PAH, a search for more specific and reliable tools to adequately assess functional impairment and monitor therapy, as well as the design of novel targeted therapies, are all urgently required to alter the dismal course of this syndrome. PMID- 20194817 TI - Thyroid transcription factor-1 influences the early phase of compensatory lung growth in adult mice. AB - RATIONALE: Compensatory lung growth has been well described as a phenomenon in many animal models, but still little is known about the nature, extent, and modulation of such growth. We hypothesized that compensatory lung growth may at least in part recapitulate developmental lung growth, and factors known to be important during normal lung development, such as thyroid transcription factor 1 (TTF-1), may be reactivated during compensatory lung growth. OBJECTIVES: To investigate the role of TTF-1 in correlation with the morphological changes during compensatory lung growth. METHODS: Sequential changes in TTF-1 expression and morphology were examined in the residual right lung after left pneumonectomy in 9-week-old mice. The effect of temporary knockdown of TTF-1 on compensatory lung growth was also evaluated. MEASUREMENTS AND MAIN RESULTS: TTF-1 was transiently but significantly elevated at an early stage in compensatory lung growth. Morphologically, a process resembling septation in lung development may have been initiated during this period in the vicinity of the alveolar duct. furthermore, temporary knockdown of ttf-1 transiently but significantly delayed the early phase of compensatory lung growth. CONCLUSIONS: These results indicate the influential role of TTF-1 in modulating, and possibly initiating, the early phase of compensatory lung growth. Morphologically, compensatory lung growth may at least in part resemble developmental growth. PMID- 20194820 TI - Association between cannabis use and psychosis-related outcomes using sibling pair analysis in a cohort of young adults. AB - CONTEXT: Prospective cohort studies have identified an association between cannabis use and later psychosis-related outcomes, but concerns remain about unmeasured confounding variables. The use of sibling pair analysis reduces the influence of unmeasured residual confounding. OBJECTIVE: To explore the association between cannabis use and psychosis-related outcomes. DESIGN: A sibling pair analysis nested within a prospective birth cohort. SETTING: Births at a Brisbane, Australia, hospital. PARTICIPANTS: Three thousand eight hundred one young adults born between 1981 and 1984 as part of the Mater-University Study of Pregnancy. MAIN OUTCOME MEASURES: Cannabis use and 3 psychosis-related outcomes (nonaffective psychosis, hallucinations, and Peters et al Delusions Inventory score) were assessed at the 21-year follow-up. Associations between duration since first cannabis use and psychosis-related outcomes were examined using logistic regression adjusted for sex, age, parental mental illness, and hallucinations at the 14-year follow-up. Within 228 sibling pairs, the association between within-pair differences in duration since first cannabis use and Peters et al Delusions Inventory score was examined with general linear modeling. The potential impact of attrition was examined. RESULTS: Duration since first cannabis use was associated with all 3 psychosis-related outcomes. For those with duration since first cannabis use of 6 or more years, there was a significantly increased risk of (1) nonaffective psychosis (adjusted odds ratio, 2.2; 95% confidence interval, 1.1-4.5), (2) being in the highest quartile of Peters et al Delusions Inventory score (adjusted odds ratio, 4.2; 95% confidence interval, 4.2-5.8), and (3) hallucinations (adjusted odds ratio, 2.8; 95% confidence interval, 1.9-4.1). Within sibling pairs, duration since first cannabis use and higher scores on the Peters et al Delusions Inventory remained significantly associated. CONCLUSIONS: Early cannabis use is associated with psychosis-related outcomes in young adults. The use of sibling pairs reduces the likelihood that unmeasured confounding explains these findings. This study provides further support for the hypothesis that early cannabis use is a risk modifying factor for psychosis-related outcomes in young adults. PMID- 20194818 TI - Prenatal maternal stress and cord blood innate and adaptive cytokine responses in an inner-city cohort. AB - RATIONALE: Stress-elicited disruption of immunity begins in utero. OBJECTIVES: Associations among prenatal maternal stress and cord blood mononuclear cell (CBMC) cytokine responses were prospectively examined in the Urban Environment and Childhood Asthma Study (n = 557 families). METHODS: Prenatal maternal stress included financial hardship, difficult life circumstances, community violence, and neighborhood/block and housing conditions. Factor analysis produced latent variables representing three contexts: individual stressors and ecological-level strains (housing problems and neighborhood problems), which were combined to create a composite cumulative stress indicator. CBMCs were incubated with innate (lipopolysaccharide, polyinosinic-polycytidylic acid, cytosine-phosphate-guanine dinucleotides, peptidoglycan) and adaptive (tetanus, dust mite, cockroach) stimuli, respiratory syncytial virus, phytohemagglutinin, or medium alone. Cytokines were measured using multiplex ELISAs. Using linear regression, associations among increasing cumulative stress and cytokine responses were examined, adjusting for sociodemographic factors, parity, season of birth, maternal asthma and steroid use, and potential pathway variables (prenatal smoking, birth weight for gestational age). MEASUREMENTS AND MAIN RESULTS: Mothers were primarily minorities (Black [71%], Latino [19%]) with an income less than $15,000 (69%). Mothers with the highest cumulative stress were older and more likely to have asthma and deliver lower birth weight infants. Higher prenatal stress was related to increased IL-8 production after microbial (CpG, PIC, peptidoglycan) stimuli and increased tumor necrosis factor-alpha to microbial stimuli (CpG, PIC). In the adaptive panel, higher stress was associated with increased IL-13 after dust mite stimulation and reduced phytohemagglutinin induced IFN-gamma. CONCLUSIONS: Prenatal stress was associated with altered innate and adaptive immune responses in CBMCs. Stress-induced perinatal immunomodulation may impact the expression of allergic disease in these children. PMID- 20194819 TI - Induction of tissue factor by urokinase in lung epithelial cells and in the lungs. AB - RATIONALE: Urokinase-type plasminogen activator (uPA) regulates extracellular proteolysis in lung injury and repair. Although alveolar expression of uPA increases, procoagulant activity predominates. OBJECTIVES: This study was designed to investigate whether uPA alters the expression of tissue factor (TF), the major initiator of the coagulation cascade, in lung epithelial cells (ECs). METHODS: Bronchial, primary airway ECs and C57B6 wild-type, uPA-deficient (uPA(-/ )) mice were exposed to phosphate-buffered saline, uPA, or LPS. Immunohistochemistry, protein, cellular, and molecular techniques were used to assess TF expression and activity. MEASUREMENTS AND MAIN RESULTS: uPA enhanced TF mRNA and protein expression, and TF-dependent coagulation in lung ECs. uPA induced expression of TF involves both increased synthesis and enhanced stabilization of TF mRNA. uPA catalytic activity had little effect on induction of TF. By contrast, deletion of the uPA receptor binding growth factor domain from uPA markedly attenuated the induction of TF, suggesting that uPA receptor binding is sufficient for TF induction. Lung tissues of uPA-deficient mice expressed less TF protein and mRNA compared with wild-type mice. In addition, intratracheal instillation of mouse uPA increased TF mRNA and protein expression and accelerated coagulation in lung tissues. uPA(-/-) mice exposed to LPS failed to induce TF. CONCLUSIONS: uPA increased TF expression and TF-dependent coagulation in the lungs of mice. We hypothesize that uPA-mediated induction of TF occurs in lung ECs to promote increased fibrin deposition in the airways during acute lung injury. PMID- 20194821 TI - Clark University vicennial conference on psychology and pedagogy. PMID- 20194822 TI - Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies. AB - CONTEXT: Association between obesity and depression has repeatedly been established. For treatment and prevention purposes, it is important to acquire more insight into their longitudinal interaction. OBJECTIVE: To conduct a systematic review and meta-analysis on the longitudinal relationship between depression, overweight, and obesity and to identify possible influencing factors. DATA SOURCES: Studies were found using PubMed, PsycINFO, and EMBASE databases and selected on several criteria. STUDY SELECTION: Studies examining the longitudinal bidirectional relation between depression and overweight (body mass index 25 29.99) or obesity (body mass index > or =30) were selected. DATA EXTRACTION: Unadjusted and adjusted odds ratios (ORs) were extracted or provided by the authors. DATA SYNTHESIS: Overall, unadjusted ORs were calculated and subgroup analyses were performed for the 15 included studies (N = 58 745) to estimate the effect of possible moderators (sex, age, depression severity). Obesity at baseline increased the risk of onset of depression at follow-up (unadjusted OR, 1.55; 95% confidence interval [CI], 1.22-1.98; P < .001). This association was more pronounced among Americans than among Europeans (P = .05) and for depressive disorder than for depressive symptoms (P = .05). Overweight increased the risk of onset of depression at follow-up (unadjusted OR, 1.27; 95% CI, 1.07-1.51; P < .01). This association was statistically significant among adults (aged 20-59 years and > or =60 years) but not among younger persons (aged <20 years). Baseline depression (symptoms and disorder) was not predictive of overweight over time. However, depression increased the odds for developing obesity (OR, 1.58; 95% CI, 1.33-1.87; P < .001). Subgroup analyses did not reveal specific moderators of the association. CONCLUSIONS: This meta-analysis confirms a reciprocal link between depression and obesity. Obesity was found to increase the risk of depression, most pronounced among Americans and for clinically diagnosed depression. In addition, depression was found to be predictive of developing obesity. PMID- 20194823 TI - Increased synaptic dopamine function in associative regions of the striatum in schizophrenia. AB - CONTEXT: A long-standing version of the dopamine hypothesis of schizophrenia postulates that hyperactivity of dopaminergic transmission at D(2) receptors in the limbic striatum is associated with the illness and that blockade of mesolimbic D(2) receptors is responsible for the antipsychotic action of D(2) receptor antagonists. OBJECTIVE: To localize dopaminergic hyperactivity within the striatum in schizophrenia. DESIGN: Case-control study. SETTING: Inpatient research unit. PARTICIPANTS: Eighteen untreated patients with schizophrenia and 18 healthy control subjects matched for age, sex, ethnicity, parental socioeconomic status, cigarette smoking, and weight. MAIN OUTCOME MEASURES: Percentage change in dopamine D(2) receptor availability in striatal subregions within each subject measured by positron emission tomography with carbon 11 labeled raclopride before and during pharmacologically induced dopamine depletion. RESULTS: In the associative striatum, acute dopamine depletion resulted in a larger increase in D(2) receptor availability in patients with schizophrenia (mean [SD], 15% [7%]) than in control subjects (10% [7%], P = .045), suggesting higher synaptic dopamine concentration. Within the associative striatum, this effect was most pronounced in the precommissural dorsal caudate (15% [8%] in patients vs 9% [8%] in controls, P = .03). No between-group differences were observed in the limbic and sensorimotor striatum. CONCLUSIONS: These findings suggest that schizophrenia is associated with elevated dopamine function in associative regions of the striatum. Because the precommissural dorsal caudate processes information from the dorsolateral prefrontal cortex, this observation also suggests that elevated subcortical dopamine function might adversely affect performance of the dorsolateral prefrontal cortex in schizophrenia. On the other hand, the absence of a group difference in the limbic striatum brings into question the therapeutic relevance of the mesolimbic selectivity of second-generation antipsychotic drugs. PMID- 20194824 TI - Prediction of psychosis in adolescents and young adults at high risk: results from the prospective European prediction of psychosis study. AB - CONTEXT: Indicated prevention is currently regarded as the most promising strategy to attenuate, delay, or even avert psychosis. Existing criteria need improvement in terms of specificity and individual risk assessment to allow for better targeted and earlier interventions. OBJECTIVE: To develop a differential predictive clinical model of transition to first-episode psychosis. DESIGN: Prospective multicenter, naturalistic field study with a total follow-up time of 18 months. SETTING: Six early-detection outpatient centers in Germany, Finland, the Netherlands, and England. PARTICIPANTS: Two hundred forty-five help-seeking patients in a putatively prodromal state of psychosis according to either ultra high-risk (UHR) criteria or the basic symptom-based criterion cognitive disturbances (COGDIS). MAIN OUTCOME MEASURE: Incidence of transition to psychosis. RESULTS: At 18-month follow-up, the incidence rate for transition to psychosis was 19%. Combining UHR and COGDIS yielded the best sensitivity. A prediction model was developed and included positive symptoms, bizarre thinking, sleep disturbances, a schizotypal disorder, level of functioning in the past year, and years of education. With a positive likelihood ratio of 19.9, an area under the curve of 80.8%, and a positive predictive value of 83.3%, diagnostic accuracy was excellent. A 4-level prognostic index further classifying the general risk of the whole sample predicted instantaneous incidence rates of up to 85% and allowed for an estimation of time to transition. CONCLUSIONS: The prediction model identified an increased risk of psychosis with appropriate prognostic accuracy in our sample. A 2-step risk assessment is proposed, with UHR and cognitive disturbance criteria serving as first-step criteria for general risk and the prognostic index as a second-step tool for further risk classification of each patient. This strategy will allow clinicians to target preventive measures and will support efforts to unveil the biological and environmental mechanisms underlying progression to psychosis. PMID- 20194825 TI - Severe mental disorders in offspring with 2 psychiatrically ill parents. AB - BACKGROUND: Studies of couples of psychiatric patients with children allow us to calculate the effects of double predispositions on morbid risk in the offspring, which is of interest for molecular genetic research and for genetic counseling. OBJECTIVE: To determine the risks in offspring of receiving a diagnosis of schizophrenia, bipolar disorder, unipolar depressive disorder, or any diagnosis from parents who both have received a diagnosis of schizophrenia or bipolar disorder. DESIGN: National register-based cohort study. SETTING: Denmark. PARTICIPANTS: A population-based cohort of 2.7 million persons born in Denmark, alive in 1968 or born later than 1968, with a register link to their mother and father and aged 10 years or older in 2007. MAIN OUTCOME MEASURE: Risk of schizophrenia or bipolar disorder, calculated as cumulative incidences by age 52 years. RESULTS: The risk of schizophrenia in 270 offspring of 196 parent couples who were both admitted to a psychiatric facility with a diagnosis of schizophrenia was 27.3% (increasing to 39.2% when schizophrenia-related disorders were included) compared with 7.0% in 13 878 offspring from 8006 couples with only 1 parent ever admitted for schizophrenia and 0.86% in 2 239 551 offspring of 1 080 030 couples with neither parent ever admitted. The risk of bipolar disorder was 24.9% in 146 offspring of 83 parent couples who were ever admitted with bipolar disorder (increasing to 36.0% when unipolar depressive disorder was included) compared with 4.4% in 23 152 offspring from 11 995 couples with only 1 parent ever admitted and 0.48% in 2 239 553 offspring of 1 080 030 couples with neither parent ever admitted. Risks of schizophrenia and bipolar disorder in offspring of couples with 1 parent with schizophrenia and the other with bipolar disorder were 15.6% and 11.7%, respectively. The maximal risks of any psychiatric disorders in the offspring of parents both with schizophrenia or both with bipolar disorder were 67.5% and 44.2%, respectively. CONCLUSIONS: Derived risks may be informative for counseling. Patterns of transmission may support evolving assumptions about genetic overlap for traditional categories. PMID- 20194826 TI - Increased BDNF promoter methylation in the Wernicke area of suicide subjects. AB - CONTEXT: Brain-derived neurotrophic factor (BDNF) plays a pivotal role in the pathophysiology of suicidal behavior and BDNF levels are decreased in the brain and plasma of suicide subjects. So far, the mechanisms leading to downregulation of BDNF expression are poorly understood. OBJECTIVES: To test the hypothesis that alterations of DNA methylation could be involved in the dysregulation of BDNF gene expression in the brain of suicide subjects. DESIGN: Three independent quantitative methylation techniques were performed on postmortem samples of brain tissue. BDNF messenger RNA levels were determined by quantitative real-time polymerase chain reaction. SETTING: Academic medical center. PATIENTS OR OTHER PARTICIPANTS: Forty-four suicide completers and 33 nonsuicide control subjects of white ethnicity. MAIN OUTCOME MEASURES: The DNA methylation degree at BDNF promoter IV and the genome-wide DNA methylation levels in the brain's Wernicke area. RESULTS: Postmortem brain samples from suicide subjects showed a statistically significant increase of DNA methylation at specific CpG sites in BDNF promoter/exon IV compared with nonsuicide control subjects (P < .001). Most of the CpG sites lying in the -300/+500 region, on both strands, had low or no methylation, with the exception of a few sites located near the transcriptional start site that had differential methylation, while genome-wide methylation levels were comparable among the subjects. The mean methylation degree at the 4 CpG sites analyzed by pyrosequencing was always less than 12.9% in the 33 nonsuicide control subjects, while in 13 of 44 suicide victims (30%), the mean methylation degree ranged between 13.1% and 34.2%. Higher methylation degree corresponded to lower BDNF messenger RNA levels. CONCLUSIONS: BDNF promoter/exon IV is frequently hypermethylated in the Wernicke area of the postmortem brain of suicide subjects irrespective of genome-wide methylation levels, indicating that a gene-specific increase in DNA methylation could cause or contribute to the downregulation of BDNF expression in suicide subjects. The reported data reveal a novel link between epigenetic alteration in the brain and suicidal behavior. PMID- 20194827 TI - Decreased hippocampal volume in healthy girls at risk of depression. AB - CONTEXT: Researchers have documented that the hippocampus is smaller in individuals with depression than in those without. The temporal or causal association of this reduction in hippocampal volume in depression, however, is not known. OBJECTIVE: To test the hypothesis that reduced hippocampal volume precedes and therefore may be implicated in the onset of depression. DESIGN: We used magnetic resonance imaging to examine brain structure volume in individuals at high and low familial risk of depression. Anatomic images from magnetic resonance imaging were analyzed using both whole-brain voxel-based morphometry and manual tracing of the bilateral hippocampus. SETTING: A research university. PARTICIPANTS: Fifty-five girls aged between 9 and 15 years: 23 daughters of mothers with recurrent episodes of depression in the daughter's lifetime (high risk) and 32 age-matched daughters of mothers with no history of psychopathology (low risk). None of the girls had any past or current Axis I psychopathology. MAIN OUTCOME MEASURES: Group differences in voxel-based morphometry brain matter density estimates and traced hippocampal volume. RESULTS: Voxel-based morphometry analyses indicated that individuals at high risk of depression had significantly less gray matter density in clusters in the bilateral hippocampus (P < .001) than low-risk participants. Tracing yielded a volumetric reduction in the left hippocampus in the high-risk participants (P < .05). CONCLUSIONS: Compared with individuals at low familial risk of the development of depression, high-risk individuals have reduced hippocampal volume, indicating that neuroanatomic anomalies associated with depression may precede the onset of a depressive episode and influence the development and course of this disorder. PMID- 20194828 TI - Support for the vascular depression hypothesis in late-life depression: results of a 2-site, prospective, antidepressant treatment trial. AB - CONTEXT: Research on vascular depression has used 2 approaches to subtype late life depression, based on executive dysfunction or white matter hyperintensity severity. OBJECTIVE: To evaluate the relationship of neuropsychological performance and white matter hyperintensity with clinical response in late-life depression. DESIGN: Two-site, prospective, nonrandomized controlled trial. SETTING: Outpatient clinics at Washington University and Duke University. PARTICIPANTS: A total of 217 subjects aged 60 years or older met DSM-IV criteria for major depression, scored 20 or more on the Montgomery-Asberg Depression Rating Scale (MADRS), and received vascular risk factor scores, neuropsychological testing, and magnetic resonance imaging; they were excluded for cognitive impairment or severe medical disorders. Fazekas rating was conducted to grade white matter hyperintensity lesions. Intervention Twelve weeks of sertraline treatment, titrated by clinical response. Main Outcome Measure Participants' MADRS scores over time. RESULTS: Baseline neuropsychological factor scores correlated negatively with baseline Fazekas scores. A mixed model examined effects of predictor variables on MADRS scores over time. Baseline episodic memory (P = .002), language (P = .007), working memory (P = .01), processing speed (P < .001), executive function factor scores (P = .002), and categorical Fazekas ratings (P = .05) predicted MADRS scores, controlling for age, education, age of onset, and race. Controlling for baseline MADRS scores, these factors remained significant predictors of decrease in MADRS scores, except for working memory and Fazekas ratings. Thirty-three percent of subjects achieved remission (MADRS < or =7). Remitters differed from nonremitters in baseline cognitive processing speed, executive function, language, episodic memory, and vascular risk factor scores. CONCLUSIONS: Comprehensive neuropsychological function and white matter hyperintensity severity predicted MADRS scores prospectively over a 12-week treatment course with selective serotonin reuptake inhibitors in late life depression. Baseline neuropsychological function differentiated remitters from nonremitters and predicted time to remission in a proportional hazards model. Predictor variables correlated highly with vascular risk factor severity. These data support the vascular depression hypothesis and highlight the importance of linking subtypes based on neuropsychological function and white matter integrity. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00045773. PMID- 20194830 TI - Magnetic resonance imaging of hippocampal subfields in posttraumatic stress disorder. AB - CONTEXT: Most neuroimaging studies of posttraumatic stress disorder (PTSD) have focused on potential abnormalities in the whole hippocampus, but the subfields of this structure, which have distinctive histological characteristics and specialized functions, have not been investigated. Studies of individual subfields may clarify the role of the hippocampus in PTSD. OBJECTIVE: To determine if PTSD is associated with structural alterations in specific subfields of the hippocampus. DESIGN: Case-control study. PARTICIPANTS: A total of 17 male veterans with combat trauma and PTSD (mean [SD] age, 41 [12] years) and 19 age matched male veterans without PTSD who were recruited from the outpatient mental health clinic of the San Francisco Veterans Affairs Medical Center and by advertising in the community. INTERVENTIONS: High-resolution magnetic resonance imaging at 4 T. MAIN OUTCOME MEASURE: Volumes of hippocampal subfields. RESULTS: Posttraumatic stress disorder was associated with 11.4% (1.5%) (P = .02) smaller mean (SD) cornu ammonis 3 (CA3)/dentate gyrus subfield volumes, irrespective of age-related alterations, whereas other subfields were spared. Age was associated with reduced volume of the CA1 subfield (P = .03). Total hippocampal volume was also reduced in PTSD by a mean (SD) of 6.5% (0.6%) but, related to both PTSD (P = .05) and age (P = .01), was consistent with the measurements in the subfields. CONCLUSIONS: The findings indicate for the first time in humans that PTSD is associated with selective volume loss of the CA3/dentate gyrus subfields, consistent with animal studies, implying that chronic stress suppresses neurogenesis and dendritic branching in these structures. PMID- 20194829 TI - A placebo-controlled trial of phenelzine, cognitive behavioral group therapy, and their combination for social anxiety disorder. AB - CONTEXT: Medication and cognitive behavioral treatment are the best-established treatments for social anxiety disorder, yet many individuals remain symptomatic after treatment. OBJECTIVE: To determine whether combined medication and cognitive behavioral treatment is superior to either monotherapy or pill placebo. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Research clinics at Columbia University and Temple University. PARTICIPANTS: One hundred twenty-eight individuals with a primary DSM-IV diagnosis of social anxiety disorder. INTERVENTIONS: Cognitive behavioral group therapy (CBGT), phenelzine sulfate, pill placebo, and combined CBGT plus phenelzine. MAIN OUTCOME MEASURES: Liebowitz Social Anxiety Scale and Clinical Global Impression (CGI) scale scores at weeks 12 and 24. RESULTS: Linear mixed-effects models showed a specific order of effects, with steepest reductions in Liebowitz Social Anxiety Scale scores for the combined group, followed by the monotherapies, and the least reduction in the placebo group (Williams test = 4.97, P < .01). The CGI response rates in the intention-to-treat sample at week 12 were 9 of 27 (33.3%) (placebo), 16 of 34 (47.1%) (CBGT), 19 of 35 (54.3%) (phenelzine), and 23 of 32 (71.9%) (combined treatment) (chi(2)(1) = 8.76, P < .01). Corresponding remission rates (CGI = 1) were 2 of 27 (7.4%), 3 of 34 (8.8%), 8 of 35 (22.9%), and 15 of 32 (46.9%) (chi(2)(1) = 15.92, P < .01). At week 24, response rates were 9 of 27 (33.3%), 18 of 34 (52.9%), 17 of 35 (48.6%), and 25 of 32 (78.1%) (chi(2)(1) = 12.02, P = .001). Remission rates were 4 of 27 (14.8%), 8 of 34 (23.5%), 9 of 35 (25.7%), and 17 of 32 (53.1%) (chi(2)(1) = 10.72, P = .001). CONCLUSION: Combined phenelzine and CBGT treatment is superior to either treatment alone and to placebo on dimensional measures and on rates of response and remission. PMID- 20194832 TI - Matters arising. PMID- 20194831 TI - Effect of a purpose in life on risk of incident Alzheimer disease and mild cognitive impairment in community-dwelling older persons. AB - CONTEXT: Emerging data suggest that psychological and experiential factors are associated with risk of Alzheimer disease (AD), but the association of purpose in life with incident AD is unknown. OBJECTIVE: To test the hypothesis that greater purpose in life is associated with a reduced risk of AD. DESIGN: Prospective, longitudinal epidemiologic study of aging. SETTING: Senior housing facilities and residences across the greater Chicago metropolitan area. PARTICIPANTS: More than 900 community-dwelling older persons without dementia from the Rush Memory and Aging Project. MAIN OUTCOME MEASURES: Participants underwent baseline evaluations of purpose in life and up to 7 years of detailed annual follow-up clinical evaluations to document incident AD. In subsequent analyses, we examined the association of purpose in life with the precursor to AD, mild cognitive impairment (MCI), and the rate of change in cognitive function. RESULTS: During up to 7 years of follow-up (mean, 4.0 years), 155 of 951 persons (16.3%) developed AD. In a proportional hazards model adjusted for age, sex, and education, greater purpose in life was associated with a substantially reduced risk of AD (hazard ratio, 0.48; 95% confidence interval, 0.33-0.69; P < .001). Thus, a person with a high score on the purpose in life measure (score = 4.2, 90th percentile) was approximately 2.4 times more likely to remain free of AD than was a person with a low score (score = 3.0, 10th percentile). This association did not vary along demographic lines and persisted after the addition of terms for depressive symptoms, neuroticism, social network size, and number of chronic medical conditions. In subsequent models, purpose in life also was associated with a reduced risk of MCI (hazard ratio, 0.71; 95% confidence interval, 0.53-0.95; P = .02) and a slower rate of cognitive decline (mean [SE] global cognition estimate, 0.03 [0.01], P < .01). CONCLUSION: Greater purpose in life is associated with a reduced risk of AD and MCI in community-dwelling older persons. PMID- 20194833 TI - Our version of normal. PMID- 20194834 TI - Art informs medicine. PMID- 20194835 TI - Molecular predictors of locoregional recurrence in breast cancer: ready for prime time? PMID- 20194836 TI - Improving local control in rectal cancer: radiation sensitizers or radiation dose? PMID- 20194838 TI - Hope and noncurative chemotherapies: which affects the other? PMID- 20194839 TI - What is the right way to administer pegylated liposomal doxorubicin in breast cancer therapy? PMID- 20194840 TI - Critical need for international consensus on ototoxicity assessment criteria. PMID- 20194843 TI - Comparative In vitro cellular data alone are insufficient to predict clinical responses and guide the choice of BCR-ABL inhibitor for treating imatinib resistant chronic myeloid leukemia. PMID- 20194844 TI - Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. AB - PURPOSE: Rituximab, a monoclonal antibody that targets the CD20 cell surface antigen, has clinical activity in patients with non-Hodgkin's lymphoma and other B-lymphocyte disorders when administered alone or in combination with chemotherapy. Promising results have previously been reported in nonrandomized studies in patients with chronic lymphocytic leukemia (CLL). This trial was designed to compare chemoimmunotherapy with chemotherapy alone in patients with previously treated CLL. PATIENTS AND METHODS: This international, multicenter, randomized trial compared six cycles of rituximab plus fludarabine and cyclophosphamide (R-FC) with six cycles of fludarabine and cyclophosphamide alone (FC) in patients with previously treated CLL. A total of 552 patients with Binet stage A (1%), B (59%), or C (31%) disease entered the study and were randomly assigned to receive R-FC (n = 276) or FC (n = 276). RESULTS: After a median follow-up time of 25 months, rituximab significantly improved progression-free survival in patients with previously treated CLL (hazard ratio = 0.65; P < .001; median, 30.6 months for R-FC v 20.6 months for FC). Event-free survival, response rate, complete response rate, duration of response, and time to new CLL treatment or death were also significantly improved. Although the rates of adverse events, grade 3 or 4 events, and serious adverse events were slightly higher in the R-FC arm, R-FC was generally well tolerated, with no new safety findings and no detrimental effect on quality of life. CONCLUSION: R-FC significantly improved the outcome of patients with previously treated CLL. PMID- 20194845 TI - Clinical scoring system to predict hepatocellular carcinoma in chronic hepatitis B carriers. AB - PURPOSE: Hepatitis B virus (HBV) infection is an important etiology for hepatocellular carcinoma (HCC). We aim to develop a simple clinical score in predicting the risk of HCC among HBV carriers. PATIENTS AND METHODS: We first evaluated 1,005 patients and found that the following five factors independently predicted HCC development: age, albumin, bilirubin, HBV DNA, and cirrhosis. These variables were used to construct a prediction score ranging from 0 to 44.5. The score was validated in another prospective cohort of 424 patients. RESULTS: During a median follow-up of 10 years, 105 patients (10.%) in the training cohort and 45 patients (10.6%) in the validation cohort developed HCC. Cutoff values of 5 and 20 best discriminated HCC risk. By applying the cutoff value of 5, the score excluded future HCC development with high accuracy (negative predictive value = 97.8% and 97.3% in the training and validation cohorts, respectively). In the validation cohort, the 5-year HCC-free survival rates were 98.3%, 90.5%, and 78.9% in the low-, medium-, and high-risk groups, respectively. The hazard ratios for HCC in the medium- and high-risk groups were 12.8 and 14.6, respectively. CONCLUSION: A simple prediction score constructed from routine clinical and laboratory parameters is accurate in predicting HCC development in HBV carriers. Future prospective validation is warranted. PMID- 20194846 TI - Accelerated approval and oncology drug development timelines. PMID- 20194847 TI - Translating gene expression into clinical care: sarcomas as a paradigm. AB - Whereas most solid tumors are characterized by considerable genetic instability and molecular heterogeneity, sarcomas include many subtypes with very specific underlying molecular events driving oncogenesis. Gene expression profiling and other modern techniques have consequently had particular success in identifying the critical biologic pathways active in specific sarcomas, yielding insights which can be translated into useful diagnostic biomarkers. Public availability of data sets and new sequencing-based technologies will accelerate this process. Molecular studies have also identified oncogenic pathways of particular importance in sarcomas which can be targeted by investigational drugs. Examples include histone deacetylases in translocation-associated sarcomas of young adults, Akt/mammalian target of rapamycin in pleomorphic sarcomas, and macrophage colony-stimulating factor in tenosynovial giant cell tumor. Despite challenges in organization and accrual, future clinical trials of sarcomas need to be designed that take into account specific molecular subtypes as distinct diseases. PMID- 20194848 TI - Comparable survival between pN0 breast cancer patients undergoing sentinel node biopsy and extensive axillary dissection: a report from the Korean Breast Cancer Society. AB - PURPOSE: Recent studies showing survival benefit of extensive axillary lymph node dissection (ALND) in pN0 breast cancer have challenged the concept of sentinel node biopsy (SNB). In this study, the survival and recurrence after SNB alone and ALND in pN0 Korean breast cancer patients were investigated. PATIENTS AND METHODS: Using information from two large databases, including a Korean nationwide registry, we assessed survival relative to the extent of ALND in pN0 breast cancer patients. We also compared the survival of pN0 patients who underwent SNB alone with survival in those who underwent varying degrees of ALND. RESULTS: In an analysis of 1,607 pN0 patients from a single institution, less extensive ALND significantly increased the risks of breast cancer death and systemic recurrence but not of locoregional recurrence. These findings were validated by an analysis of nationwide registry data on 17,672 pN0 patients; patients with > 20 dissected lymph nodes had significantly better overall survival (OS) and breast cancer-specific survival (BCSS) than those with 10 to 20 or < 10 dissected lymph nodes. Patients who underwent SNB alone showed OS (hazard ratio [HR], 1.03; 9% CI, 0.08 to 1.56) and BCSS (HR, 1.15; 95% CI, 0.75 to 1.78) similar to those of patients who underwent extensive ALND (> 20 dissected lymph nodes), despite the small number of lymph nodes removed. CONCLUSION: Extensive ALND is associated with better survival and less systemic recurrence than less extensive ALND in patients with pN0 breast cancer. However, SNB alone showed excellent survival results, similar to those of extensive ALND, supporting the long-term oncologic safety of SNB. PMID- 20194849 TI - Mixed response in interim positron emission tomography/computed tomography leads to detection of a gastrointestinal stromal tumor in a patient with mediastinal diffuse large B-cell lymphoma. PMID- 20194850 TI - Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2. AB - PURPOSE: Neoadjuvant chemoradiotherapy is considered a standard approach for T3-4 M0 rectal cancer. In this situation, we compared neoadjuvant radiotherapy plus capecitabine with dose-intensified radiotherapy plus capecitabine and oxaliplatin. PATIENTS AND METHODS: We randomly assigned patients to receive 5 weeks of treatment with radiotherapy 45 Gy/25 fractions with concurrent capecitabine 800 mg/m(2) twice daily 5 days per week (Cap 45) or radiotherapy 50 Gy/25 fractions with capecitabine 800 mg/m(2) twice daily 5 days per week and oxaliplatin 50 mg/m(2) once weekly (Capox 50). The primary end point was complete sterilization of the operative specimen (ypCR). RESULTS: Five hundred ninety eight patients were randomly assigned to receive Cap 45 (n = 299) or Capox 50 (n = 299). More preoperative grade 3 to 4 toxicity occurred in the Capox 50 group (25 v 1%; P < .001). Surgery was performed in 98% of patients in both groups. There were no differences between groups in the rate of conservative surgery (75%) or postoperative deaths at 60 days (0.3%). The ypCR rate was 13.9% with Cap 45 and 19.2% with Capox 50 (P = .09). When ypCR was combined with yp few residual cells, the rate was respectively 28.9% with Cap 45 and 39.4% with Capox 50 (P = .008). The rate of positive circumferential rectal margins (between 0 and 2 mm) was 19.3% with Cap 45 and 9.9% with Capox 50 (P = .02). CONCLUSION: The benefit of oxaliplatin was not demonstrated and this drug should not be used with concurrent irradiation. Cap 50 merits investigation for T3-4 rectal cancers. PMID- 20194852 TI - Overall survival and post-progression survival in advanced breast cancer: a review of recent randomized clinical trials. AB - With the availability of several lines of therapy, overall survival (OS) has been progressively substituted by progression-free survival (PFS) and other tumor based assessments as the primary efficacy end point in advanced breast cancer trials. We investigated the frequency and determinants of OS gain in the recent literature and the duration of post-progression survival (PPS) according to treatment type and line. We used PubMed to search for phase III trials on systemic antineoplastic therapies published between January 1998 and December 2007 in 11 leading journals. The primary end point was the one stated explicitly, used for N calculation, or listed first. Significant gain was considered as reported P < .05 for superiority trials or proven non-inferiority or equivalence otherwise. We retrieved 76 trials, and gain in OS was reported in 15 cases (19.7%). The median gain in OS was 4.7 months, and such gain was more frequent when there was significant gain in PFS and in second-line and third-line trials. The average median OS was 20.7 months in trials assessing first-line chemotherapy and 31.1 months with first-line hormone therapy. The median proportion of OS accounted for by PPS was significantly longer in hormone therapy trials than in chemotherapy trials, but varied little across treatment lines. A statistically significant gain in OS has been reported in about one in five recent phase III trials in advanced breast cancer, despite the fact that OS has seldom been used as the primary end point. PPS represents nearly two thirds of patient survival after on-trial disease progression. PMID- 20194851 TI - Imatinib mesylate in advanced dermatofibrosarcoma protuberans: pooled analysis of two phase II clinical trials. AB - PURPOSE: Dermatofibrosarcoma protuberans (DFSP) is a dermal sarcoma typically carrying a translocation between chromosomes 17 and 22 that generates functional platelet-derived growth factor B (PDGFB). PATIENTS AND METHODS: Two distinct phase II trials of imatinib (400 to 800 mg daily) in patients with locally advanced or metastatic DFSP were conducted and closed prematurely, one in Europe (European Organisation for Research and Treatment of Cancer [EORTC]) with 14-week progression-free rate as the primary end point and the other in North America (Southwest Oncology Group [SWOG]) with confirmed objective response rate as the primary end point. In the EORTC trial, confirmation of PDGFB rearrangement was required, and surgery was undertaken after 14 weeks if feasible. The SWOG study confirmed t(17;22) after enrollment. RESULTS: Sixteen and eight patients were enrolled onto the EORTC and SWOG trials, respectively. Tumor size ranged from 1.2 to 49 cm. DFSP was located on head/neck, trunk, and limb in seven, 11, and six patients, respectively, and was classic, pigmented, and fibrosarcomatous DFSP in 13, one, and nine patients, respectively. Metastases were present in seven patients (lung involvement was present six patients). Eleven patients (4%) had partial response as best response, and four patients had progressive disease as best response. Median time to progression (TTP) was 1.7 years. Imatinib was stopped in 11 patients because of progression, one patient because of toxicity, and two patients after complete resection of disease. Median overall survival (OS) time has not been reached; 1-year OS rate was 87.5%. CONCLUSION: Imatinib is active in DFSP harboring t(17;22) including fibrosarcomatous DFSP, with objective response rate approaching 50%. Response rates and TTP did not differ between patients taking 400 mg daily versus 400 mg twice a day. PMID- 20194853 TI - Large randomized study of thymosin alpha 1, interferon alfa, or both in combination with dacarbazine in patients with metastatic melanoma. AB - PURPOSE: Thymosin alpha 1 (Talpha1) is an immunomodulatory polypeptide that enhances effector T-cell responses. In this large randomized study, we evaluated the efficacy and safety of combining Talpha1 with dacarbazine (DTIC) and interferon alfa (IFN-alpha) in patients with metastatic melanoma. PATIENTS AND METHODS: Four hundred eighty-eight patients were randomly assigned to five treatment groups: DTIC+IFN-alpha+Talpha1 (1.6 mg); DTIC+IFN-alpha+Talpha1 (3.2 mg); DTIC+IFN-alpha+Talpha1 (6.4 mg); DTIC+Talpha1 (3.2 mg); DTIC+IFN-alpha (control group). The primary end point was best overall response at study end (12 months). Secondary end points included duration of response, overall survival (OS), and progression-free survival (PFS). Patients were observed for up to 24 months. RESULTS: Ten and 12 tumor responses were observed in the DTIC+IFN alpha+Talpha1 (3.2 mg) and DTIC+Talpha1 (3.2 mg) groups, respectively, versus four in the control group, which was sufficient to reject the null hypothesis that P(0) < or = .05 (expected response rate of standard therapy) in these two arms. Duration of response ranged from 1.9 to 23.2 months in patients given Talpha1 and from 4.4 to 8.4 months in the control group. Median OS was 9.4 months in patients given Talpha1 versus 6.6 months in the control group (hazard ratio = 0.80; 9% CI, 0.63 to 1.02; P = .08). An increase in PFS was observed in patients given Talpha1 versus the control group (hazard ratio = 0.80; 95% CI, 0.63 to 1.01; P = .06). Addition of Talpha1 to DTIC and IFN-alpha did not lead to any additional toxicity. CONCLUSION: These results suggest Talpha1 has activity in patients with metastatic melanoma and provide rationale for further clinical evaluation of this agent. PMID- 20194854 TI - Randomized phase III trial of gemcitabine plus cisplatin compared with single agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. AB - PURPOSE: Single-agent gemcitabine became standard first-line treatment for advanced pancreatic cancer after demonstration of superiority compared with fluorouracil. The Gruppo Italiano Pancreas 1 randomized phase III trial aimed to compare gemcitabine plus cisplatin versus gemcitabine alone (ClinicalTrials.gov ID NCT00813696). PATIENTS AND METHODS: Patients with locally advanced or metastatic pancreatic cancer, age 18 to 75 years, and Karnofsky performance status (KPS) > or = 50, were randomly assigned to receive gemcitabine (arm A) or gemcitabine plus cisplatin (arm B). Arm A: gemcitabine 1,000 mg/m(2) weekly for 7 weeks, and, after a 1-week rest, on days 1, 8, and 15 every 4 weeks. Arm B: cisplatin 25 mg/m(2) added weekly to gemcitabine, except cycle 1 day 22. Primary end point was overall survival. To have 8% power of detecting a 0.74 hazard ratio (HR) of death, with bilateral alpha .05, 355 events were needed and 400 patients planned. RESULTS: Four hundred patients were enrolled (arm A: 199; arm B: 201). Median age was 63, 59% were male, 84% had stage IV, and 83% had KPS > or = 80. Median overall survival was 8.3 months versus 7.2 months in arm A and B, respectively (HR, 1.10; 95% CI, 0.89 to 1.35; P = .38). Median progression-free survival was 3.9 months versus 3.8 months in arm A and B, respectively (HR, 0.97; 95% CI, 0.80 to 1.19; P = .80). The objective response rate was 10.1% in A and 12.9% in B (P = .37). Clinical benefit was experienced by 23.0% in A and 15.1% in B (P = .057). Combination therapy produced more hematologic toxicity, without relevant differences in nonhematologic toxicity. CONCLUSION: The addition of weekly cisplatin to gemcitabine failed to demonstrate any improvement as first line treatment of advanced pancreatic cancer. PMID- 20194855 TI - Potential role of lymphadenectomy in advanced ovarian cancer: a combined exploratory analysis of three prospectively randomized phase III multicenter trials. AB - PURPOSE: Primary surgery followed by platinum/taxane-based chemotherapy is the standard therapy in advanced ovarian cancer. The prognostic role of complete debulking has been well described; however, the impact of systematic pelvic and para-aortic lymphadenectomy and its interaction with biologic factors are still not fully defined. METHODS: This was an exploratory analysis of three prospective randomized trials (Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom trials 3, 5, and 7) investigating platinum/taxane-based chemotherapy regimens in advanced ovarian cancer conducted between 1995 and 2002. RESULTS: One thousand nine hundred twenty-four patients were analyzed. Lymphadenectomy was associated with superior survival in patients without gross residual disease. In patients with and without lymphadenectomy, the median survival time was 103 and 84 months, respectively, and 5-year survival rates were 67.% and 59.2%, respectively (P = .0166); multivariate analysis confirmed a significant impact of lymphadenectomy on overall survival (OS; hazard ratio [HR] = 0.74; 95% CI, 0.59 to 0.94; P = .0123). In patients with small residual tumors up to 1 cm, the effect of lymphadenectomy on OS barely reached significance (HR = 0.85; 95% CI, 0.72 to 1.00; P = .0497). For patients with small residual tumors and clinically suspect nodes, lymphadenectomy resulted in a 16% gain in 5-year OS (log-rank test, P = .0038). CONCLUSION: Lymphadenectomy in advanced ovarian cancer might offer benefit mainly to patients with complete intraperitoneal debulking. However, this hypothesis should be confirmed in the context of a prospectively randomized trial. PMID- 20194856 TI - Serum microRNA signatures identified in a genome-wide serum microRNA expression profiling predict survival of non-small-cell lung cancer. AB - PURPOSE: Recent findings that human serum contains stably expressed microRNA (miRNA) have revealed a great potential of serum miRNA signature as disease fingerprints to predict survival. We used genome-wide serum miRNA expression analysis to investigate the role of serum miRNA in predicting prognosis of non small-cell lung cancer (NSCLC). PATIENTS AND METHODS: To control disease heterogeneity, we used patients with stages I to IIIa lung adenocarcinoma and squamous cell carcinoma, who were treated with both operation and adjuvant chemotherapies. In the discovery stage, Solexa sequencing followed by individual quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assays was used to test the difference in levels of serum miRNAs between 30 patients with longer survival (alive and mean survival time, 49.54 months) and 30 patients with shorter survival matched by age, sex, and stage (dead and mean survival time, 9.54 months). The detected serum miRNAs then were validated in 243 patients (randomly classified into two subgroups: n = 120 for the training set, and n = 123 for the testing set). RESULTS: Eleven serum miRNAs were found to be altered more than five-fold by Solexa sequencing between longer-survival and shorter survival groups, and levels of four miRNAs (ie, miR-486, miR-30d, miR-1 and miR 499) were significantly associated with overall survival. The four-miRNA signature also was consistently an independent predictor of overall survival for both training and testing samples. CONCLUSION: The four-miRNA signature from the serum may serve as a noninvasive predictor for the overall survival of NSCLC. PMID- 20194857 TI - Breast cancer subtypes and the risk of local and regional relapse. AB - PURPOSE: The risk of local and regional relapse associated with each breast cancer molecular subtype was determined in a large cohort of patients with breast cancer. Subtype assignment was accomplished using a validated six-marker immunohistochemical panel applied to tissue microarrays. PATIENTS AND METHODS: Semiquantitative analysis of estrogen receptor (ER), progesterone receptor (PR), Ki-67, human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), and cytokeratin (CK) 5/6 was performed on tissue microarrays constructed from 2,985 patients with early invasive breast cancer. Patients were classified into the following categories: luminal A, luminal B, luminal-HER2, HER2 enriched, basal-like, or triple-negative phenotype-nonbasal. Multivariable Cox analysis was used to determine the risk of local or regional relapse associated the intrinsic subtypes, adjusting for standard clinicopathologic factors. RESULTS: The intrinsic molecular subtype was successfully determined in 2,985 tumors. The median follow-up time was 12 years, and there have been a total of 325 local recurrences and 227 regional lymph node recurrences. Luminal A tumors (ER or PR positive, HER2 negative, Ki-67 < 1%) had the best prognosis and the lowest rate of local or regional relapse. For patients undergoing breast conservation, HER2-enriched and basal subtypes demonstrated an increased risk of regional recurrence, and this was statistically significant on multivariable analysis. After mastectomy, luminal B, luminal-HER2, HER2-enriched, and basal subtypes were all associated with an increased risk of local and regional relapse on multivariable analysis. CONCLUSION: Luminal A tumors are associated with a low risk of local or regional recurrence. Molecular subtyping of breast tumors using a six-marker immunohistochemical panel can identify patients at increased risk of local and regional recurrence. PMID- 20194858 TI - Outcomes of fertility-sparing surgery for stage I epithelial ovarian cancer: a proposal for patient selection. AB - PURPOSE: The objective of this study was to assess clinical outcomes and fertility in patients treated conservatively for unilateral stage I invasive epithelial ovarian cancer (EOC). PATIENTS AND METHODS: A multi-institutional retrospective investigation was undertaken to identify patients with unilateral stage I EOC treated with fertility-sparing surgery. Favorable histology was defined as grade 1 or grade 2 adenocarcinoma, excluding clear cell histology. RESULTS: A total of 211 patients (stage IA, n = 126; stage IC, n = 85) were identified from 30 institutions. Median duration of follow-up was 78 months. Five year overall survival and recurrence-free survival were 100% [corrected] and 97.8% for stage IA and favorable histology (n = 108), 100% and 100% for stage IA and clear cell histology (n = 15), 100% and 33.3% for stage IA and grade 3 (n = 3), 96.9% and 92.1% for stage IC and favorable histology (n = 67), 93.3% and 66.0% for stage IC and clear cell histology (n = 15), and 66.7% and 66.7% for stage IC and grade 3 (n = 3). Forty-five (53.6%) of 84 patients who were nulliparous at fertility-sparing surgery and married at the time of investigation gave birth to 56 healthy children. CONCLUSION: Our data confirm that fertility sparing surgery is a safe treatment for stage IA patients with favorable histology and suggest that stage IA patients with clear cell histology and stage IC patients with favorable histology can be candidates for fertility-sparing surgery followed by adjuvant chemotherapy. PMID- 20194859 TI - Diffuse osteosclerosis complicating hairy cell leukemia. PMID- 20194860 TI - Employment among survivors of lung cancer and colorectal cancer. AB - PURPOSE: To identify the frequency of and factors associated with changes in employment among cancer survivors. METHODS: This prospective cohort study took place in the context of the population-based Cancer Care Outcomes Research and Surveillance Consortium. Patients with nonmetastatic lung or colorectal cancer who survived approximately 15 months after diagnosis without cancer recurrence provided their self-reported employment status, employment experiences, and changes in insurance coverage at 4 and 15 months after diagnosis. Multiple logistic regression was used to relate sociodemographic and disease factors to the probability of labor force departure. RESULTS: Among 2,422 eligible patients, employment declined from 3% to 31% over the 15 months after cancer was diagnosed. Labor force departures attributable to cancer occurred in 17% of those employed at baseline. Factors associated with significantly higher rates of labor force departure were lung versus colon cancer, stage III versus I or II disease, lower educational and income levels, and, among colorectal patients, older age. Married women were significantly more likely than unmarried women to leave the workforce. Only 2% of patients lacked health insurance during the study period. CONCLUSION: Most employed patients with nonmetastatic lung or colorectal cancer return to work, but approximately one sixth of patients leave the workforce, particularly those with worse prognoses or lower socioeconomic status. Potential economic effects must be considered in management decisions about cancer. PMID- 20194861 TI - Practical grading system for evaluating cisplatin ototoxicity in children. AB - PURPOSE: We present a new ototoxicity grading system that has clearly defined and frequency-specific audiometric criteria. The purpose of this study was to validate this grading system by assessing its correspondence to audiology treatment recommendations and comparing it with the currently utilized Common Terminology Criteria for Adverse Events (CTCAE). PATIENTS AND METHODS: A retrospective chart review was conducted using audiologic, demographic, and clinical data from 134 children receiving 149 courses of chemotherapy consisting of cisplatin and/or carboplatin. Pure-tone audiograms were evaluated using both our proposed grading criteria and the CTCAE criteria. The resulting grades were then compared with charted audiologic interventions and a number of clinical parameters to assess the clinical validity of the grading scale. RESULTS: Chang grade 2a or higher predicted audiologic intervention. Although both the Chang and CTCAE ototoxicity grades were significantly related to audiologist recommendations for assistive devices such as hearing aids and/or frequency modulated systems (P < .0001), the Chang scale was more specific, with the CTCAE scale diverging from clinical recommendation at higher grades. As expected, patients receiving cisplatin had more severe hearing loss with concurrent carboplatin administration, radiation therapy exposure, younger age, smaller body surface area, longer treatment exposure, and more severe disease. CONCLUSION: This grading system provides robust and clinically useful criteria to represent clinical hearing loss induced by ototoxicity with regard to the impact on speech and language and the need for assistive hearing devices. It is both more specific and more sensitive than the traditional CTCAE criteria for identifying clinically significant ototoxicity. PMID- 20194863 TI - Prognostic value of changes in health-related quality of life scores during curative treatment for esophagogastric cancer. AB - PURPOSE: Accumulating evidence suggests that health-related quality of life (HRQL) data before treatment predict survival, but the prognostic value of changes in HRQL scores after treatment is unknown. The aim of this study was to explore whether changes in HRQL scores in esophagogastric cancer predict survival. PATIENTS AND METHODS: Consecutive patients undergoing curative treatment completed HRQL questionnaires (EORTC QLQ-C30) at baseline and after six months and were followed up for at least five years. Cox proportional hazard models with adjustments assessed associations between baseline HRQL and survival and between changes in HRQL before and after treatment and survival. RESULTS: Overall, 216 patients initiated curative therapy, of whom 169 completed treatment and survived 6 months. Of these, 132 (7%) had two complete HRQL assessments. Analyses adjusted for age, sex, performance status, tumor stage, and disease site revealed that a 10-point poorer dyspnea score at baseline was significantly associated with an 18% higher risk of death. Additional analyses to adjust for baseline HRQL and treatment showed that a 10-point change in physical function (hazard ratio [HR], 0.85; 95% CI, 0.76 to 0.96; P = .007), pain (HR, 1.20; 95% CI, 1.09 to 1.33; P < .001), and fatigue (HR, 1.16; 95% CI, 1.04 to 1.30; P = .009) scores was associated with better survival. CONCLUSION: This exploratory study found longer survival beyond the 6 months after starting treatment to be associated with fewer problems with dyspnea before treatment and better recovery of physical function, pain, and fatigue after treatment. More research to confirm these findings and understand the results is needed. PMID- 20194862 TI - Neutrophil count in African Americans: lowering the target cutoff to initiate or resume chemotherapy? PMID- 20194864 TI - Psychological distress in adult survivors of childhood cancer: the Swiss Childhood Cancer Survivor study. AB - PURPOSE: To evaluate the degree of psychological distress in adult childhood cancer survivors in Switzerland and to characterize survivors with significant distress. METHODS: Childhood cancer survivors who were age younger than 16 years when diagnosed between 1976 and 2003, had survived more than 5 years, and were currently age 20 years or older received a postal questionnaire. Psychological distress was assessed using the Brief Symptom Inventory (BSI). Raw scores were transformed into T scores according to the German norm sample, and the proportion of participants being at increased risk for psychological distress was calculated (case rule: T > or = 63). t tests and univariable and multivariable logistic regressions were used for statistical analyses. RESULTS: One thousand seventy-six survivors (63.% of eligible survivors, 71.9% of contacted survivors) returned the questionnaire, 987 with complete data on BSI. Comparison with the norm populations showed lower T scores (T < 50) in the Global Severity Index (GSI; T = 46.2), somatization (T = 47.6), obsessive-compulsive tendencies (T = 46.9), and anxiety (T = 48.4). However, more childhood cancer survivors (especially women) had increased distress for GSI (14.4%), interpersonal sensitivity (16.5%), depression (13.4%), aggression (16.9%), and psychotic tendencies (15.6%) than the expected 10% from the norm population. Caseness was associated with female sex, being a single child, older age at study, and self-reported late effects, especially psychological problems. CONCLUSION: Results show that childhood cancer survivors, on average, have less psychological distress than a norm population but that the proportion of survivors at risk for high psychological distress is disproportionally large. Monitoring psychological distress in childhood cancer survivors may be desirable during routine follow-up, and psychological support should be offered as needed. PMID- 20194865 TI - 90Y-edotreotide for metastatic carcinoid refractory to octreotide. AB - PURPOSE: Metastatic carcinoid is an incurable malignancy whose symptoms, such as diarrhea and flushing, can be debilitating and occasionally life-threatening. Although symptom relief is available with octreotide, the disease eventually becomes refractory to octreotide, leaving no proven treatment options. The goal of this study was to evaluate the clinical effect of using (90)Y-edotreotide to treat symptomatic patients with carcinoid tumors. PATIENTS AND METHODS: Patients enrolled had metastatic carcinoid, at least one sign/symptom refractory to octreotide, and at least one measurable lesion. Study treatment consisted of three cycles of 4.4 GBq (120 mCi) (90)Y-edotreotide each, once every 6 weeks. RESULTS: Ninety patients were enrolled in the study. Using Southwest Oncology Group tumor response criteria, 67 (74.%) of 90 patients (95% CI, 65.4% to 83.4%) were objectively stable or responded. A statistically significant linear trend toward improvement was demonstrated across all 12 symptoms assessed. Median progression-free survival was significantly greater (P = .03) for the 38 patients who had durable diarrhea improvement than the 18 patients who did not (18.2 v 7.9 months, respectively). Adverse events (AEs) were reported in 96.7% (87 of 90) of patients. These AEs consisted primarily of reversible GI events (76 of 90), which could be caused in part by concomitant administration of amino acid solution given to reduce radiation exposure to the kidneys. There was one case each of grade 3 oliguria and grade 4 renal failure, each lasting 6 days. CONCLUSION: (90)Y-edotreotide treatment improved symptoms associated with malignant carcinoid among subjects with no treatment alternatives. Treatment was well-tolerated and had an acceptable expected AE profile. PMID- 20194866 TI - Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. AB - PURPOSE: New treatments are needed for patients with fludarabine- and alemtuzumab refractory (FA-ref) chronic lymphocytic leukemia (CLL) or patients with fludarabine-refractory CLL with bulky (> 5 cm) lymphadenopathy (BF-ref) who are less suitable for alemtuzumab treatment; these groups have poor outcomes with available salvage regimens. Ofatumumab (HuMax-CD20) is a human monoclonal antibody targeting a distinct small-loop epitope on the CD20 molecule. We conducted an international clinical study to evaluate the efficacy and safety of ofatumumab in patients with FA-ref and BF-ref CLL. PATIENTS AND METHODS: Patients received eight weekly infusions of ofatumumab followed by four monthly infusions during a 24-week period (dose 1 = 300 mg; doses 2 to 12 = 2,000 mg); response by an independent review committee (1996 National Cancer Institute Working Group criteria) was assessed every 4 weeks until week 24 and then every 3 months until month 24. RESULTS: This planned interim analysis included 138 treated patients with FA-ref (n = 59) and BF-ref (n = 79) CLL. The overall response rates (primary end point) were 58% [corrected] and 47% in the FA-ref and BF-ref groups, respectively. Complete resolution of constitutional symptoms and improved performance status occurred in 57% and 48% of patients, respectively. Median progression-free survival and overall survival times were 5.7 and 13.7 months in the FA-ref group, respectively, and 5.9 and 15.4 months in the BF-ref group, respectively. The most common adverse events during treatment were infusion reactions and infections, which were primarily grade 1 or 2 events. Hematologic events during treatment included anemia and neutropenia. CONCLUSION: Ofatumumab is an active, well-tolerated treatment providing clear clinical improvements for fludarabine-refractory patients with very poor-prognosis CLL. PMID- 20194867 TI - TI-CE high-dose chemotherapy for patients with previously treated germ cell tumors: results and prognostic factor analysis. AB - PURPOSE: We previously reported a dose-finding and phase II trial of the TI-CE regimen (paclitaxel [T] plus ifosfamide [I] followed by high-dose carboplatin [C] plus etoposide [E] with stem-cell support) in germ cell tumor (GCT) patients predicted to have a poor prognosis with conventional-dose salvage therapy. We now report the efficacy of TI-CE with prognostic factors for disease-free survival (DFS) and overall survival (OS) in our full data set of 107 patients. PATIENTS AND METHODS: Eligible patients had advanced GCTs with progressive disease following chemotherapy and unfavorable prognostic features (extragonadal primary site, incomplete response [IR] to first-line therapy, or relapse/IR to ifosfamide cisplatin-based conventional-dose salvage). Univariate and multivariate analyses (MVAs) of prognostic factors were performed. The predictive ability of the Einhorn and Beyer prognostic models was assessed. RESULTS: Most patients were platinum refractory and had an IR to first-line chemotherapy. There were 54 (5%) complete and eight (8%) partial responses with negative markers; 5-year DFS was 47% and OS was 52% (median follow-up, 61 months). No relapses occurred after 2 years. Five (24%) of 21 primary mediastinal nonseminomatous GCTs are continuously disease free. On MVA, primary mediastinal site (P < .001), two or more lines of prior therapy (P < .001), baseline human chorionic gonadotropin > or = 1,000 U/L (P = .01), and lung metastases (P = .02) significantly predicted adverse DFS. Poor-risk patients did worse than good- or intermediate-risk patients according to both Beyer (P < .002) and Einhorn (P < .05) models. CONCLUSION: TI-CE is effective salvage therapy for GCT patients with poor prognostic features. Mediastinal primary site and two or more lines of prior therapy were most predictive of adverse DFS. Beyer and Einhorn models can assist in predicting outcome. PMID- 20194868 TI - Postthrombotic syndrome. Cardiology Patient Page. PMID- 20194869 TI - Coronary embolization of an intramyocardial hematoma after myocardial infarction. PMID- 20194870 TI - Letter by Lown et al regarding article, "Risk of assessing mortality risk in elective cardiac operations: age, creatinine, ejection fraction, and the law of parsimony". PMID- 20194871 TI - Letter by Miceli et al regarding article, "Risk of assessing mortality risk in elective cardiac operations: age, creatinine, ejection fraction, and the law of parsimony". PMID- 20194873 TI - Correction for Circulation 120(11) 964. PMID- 20194876 TI - Nutrition, supplements, and vitamins in platelet function and bleeding. PMID- 20194875 TI - MicroRNAs add a new dimension to cardiovascular disease. PMID- 20194877 TI - High-resolution color-coded sonography in angiolymphoid hyperplasia with eosinophilia presenting as temporal arteritis. PMID- 20194878 TI - Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND study. AB - BACKGROUND: The antiplatelet effects of the Platelet Inhibition and Patient Outcomes (PLATO) trial dose of ticagrelor in patients nonresponsive to clopidogrel and after they switch agents are unknown. METHODS AND RESULTS: Patients with stable coronary artery disease on aspirin therapy received a 300-mg clopidogrel load; nonresponders were identified by light transmittance aggregometry. In a 2-way crossover design, nonresponders (n=41) and responders (n=57) randomly received clopidogrel (600 mg/75 mg once daily) or ticagrelor (180 mg/90 mg twice daily) for 14 days during period 1. In period 2, all nonresponders switched treatment; half of the responders continued the same treatment, whereas the others switched treatment. Inhibition of platelet aggregation was higher in nonresponders treated with ticagrelor compared with clopidogrel (P<0.05). Treatment with ticagrelor among nonresponders resulted in a >10%, >30%, and >50% decrease in platelet aggregation from baseline in 100%, 75%, and 13% of patients, respectively. Platelet aggregation fell from 59+/-9% to 35+/-11% in patients switched from clopidogrel to ticagrelor and increased from 36+/-14% to 56+/-9% in patients switched from ticagrelor to clopidogrel (P<0.0001 for both). Platelet reactivity was below the cut points previously associated with ischemic risk measured by light transmittance aggregometry, VerifyNow P2Y(12) assay, and vasodilator-stimulated phosphoprotein phosphorylation in 98% to 100% of patients after ticagrelor therapy versus 44% to 76% of patients after clopidogrel therapy. CONCLUSIONS: Ticagrelor therapy overcomes nonresponsiveness to clopidogrel, and its antiplatelet effect is the same in responders and nonresponders. Nearly all clopidogrel nonresponders and responders treated with ticagrelor will have platelet reactivity below the cut points associated with ischemic risk. Clinical Trial Registration- http://www.clinicaltrials.gov. Unique Identifier: NCT00642811. PMID- 20194879 TI - High-sensitivity troponin T concentrations in acute chest pain patients evaluated with cardiac computed tomography. AB - BACKGROUND: For evaluation of patients with chest pain and suspected acute coronary syndrome (ACS), consensus guidelines recommend use of a cardiac troponin cut point that corresponds to the 99 th percentile of a healthy population. Most conventional troponin methods lack sufficient precision at this low level. METHODS AND RESULTS: In a cross-sectional study, 377 patients (mean age 53.7 years, 64.2% male) with chest pain and low to intermediate likelihood for ACS were enrolled in the emergency department. Blood was tested with a precommercial high-sensitivity troponin T assay (hsTnT) and compared with a conventional cardiac troponin T method. Patients underwent a 64-slice coronary computed tomography coronary angiogram at the time of phlebotomy, on average 4 hours from initial presentation. Among patients with acute chest pain, 37 (9.8%) had an ACS. Using the 99th percentile cut point for a healthy population (13 pg/mL), hsTnT had 62% sensitivity, 89% specificity, 38% positive predictive value, and 96% negative predictive value for ACS. Compared with the cardiac troponin T method, hsTnT detected 27% more ACS cases (P=.001), and an hsTnT above the 99 th percentile strongly predicted ACS (odds ratio 9.0, 95% confidence interval 3.9 to 20.9, P<0.001). Independent of ACS diagnosis, computed tomography angiography demonstrated that concentrations of hsTnT were determined by numerous factors, including the presence and severity of coronary artery disease, left ventricular mass, left ventricular ejection fraction, and regional left ventricular dysfunction. CONCLUSIONS: Among low- to intermediate-risk patients with chest pain, hsTnT provides good sensitivity and specificity for ACS. Elevation of hsTnT identifies patients with myocardial injury and significant structural heart disease, irrespective of the diagnosis of ACS. PMID- 20194880 TI - Randomized trial of simple versus complex drug-eluting stenting for bifurcation lesions: the British Bifurcation Coronary Study: old, new, and evolving strategies. AB - BACKGROUND: The optimal strategy for treating coronary bifurcation lesions remains a subject of debate. With bare-metal stents, single-stent approaches appear to be superior to systematic 2-stent strategies. Drug-eluting stents, however, have low rates of restenosis and might offer improved outcomes with complex stenting techniques. METHODS AND RESULTS: Patients with significant coronary bifurcation lesions were randomized to either a simple or complex stenting strategy with drug-eluting stents. In the simple strategy, the main vessel was stented, followed by optional kissing balloon dilatation/T-stent. In the complex strategy, both vessels were systematically stented (culotte or crush techniques) with mandatory kissing balloon dilatation. Five hundred patients 64+/ 10 years old were randomized; 77% were male. Eighty-two percent of lesions were true bifurcations (>50% narrowing in both vessels). In the simple group (n=250), 66 patients (26%) had kissing balloons in addition to main-vessel stenting, and 7 (3%) had T stenting. In the complex group (n=250), 89% of culotte (n=75) and 72% of crush (n=169) cases were completed successfully with final kissing balloon inflations. The primary end point (a composite at 9 months of death, myocardial infarction, and target-vessel failure) occurred in 8.0% of the simple group versus 15.2% of the complex group (hazard ratio 2.02, 95% confidence interval 1.17 to 3.47, P=0.009). Myocardial infarction occurred in 3.6% versus 11.2%, respectively (P=0.001), and in-hospital major adverse cardiovascular events occurred in 2.0% versus 8.0% (P=0.002), respectively. Procedure duration and x ray dose favored the simple approach. CONCLUSIONS: When coronary bifurcation lesions are treated, a systematic 2-stent technique results in higher rates of in hospital and 9-month major adverse cardiovascular events. This difference is largely driven by periprocedural myocardial infarction. Procedure duration is longer, and x-ray dose is higher. The provisional technique should remain the preferred strategy in the majority of cases. Clinical Trial Registration Information- URL: http://www.clinicaltrials.gov. Unique identifier: NCT 00351260. PMID- 20194882 TI - Protein aggregates and novel presenilin gene variants in idiopathic dilated cardiomyopathy. AB - BACKGROUND: Heart failure is a debilitating condition resulting in severe disability and death. In a subset of cases, clustered as idiopathic dilated cardiomyopathy (iDCM), the origin of heart failure is unknown. In the brain of patients with dementia, proteinaceous aggregates and abnormal oligomeric assemblies of beta-amyloid impair cell function and lead to cell death. METHODS AND RESULTS: We have similarly characterized fibrillar and oligomeric assemblies in the hearts of iDCM patients, pointing to abnormal protein aggregation as a determinant of iDCM. We also showed that oligomers alter myocyte Ca(2+) homeostasis. Additionally, we have identified 2 new sequence variants in the presenilin-1 (PSEN1) gene promoter leading to reduced gene and protein expression. We also show that presenilin-1 coimmunoprecipitates with SERCA2a. CONCLUSIONS: On the basis of these findings, we propose that 2 mechanisms may link protein aggregation and cardiac function: oligomer-induced changes on Ca(2+) handling and a direct effect of PSEN1 sequence variants on excitation-contraction coupling protein function. PMID- 20194883 TI - Dietary intervention to reverse carotid atherosclerosis. AB - BACKGROUND: It is currently unknown whether dietary weight loss interventions can induce regression of carotid atherosclerosis. METHODS AND RESULTS: In a 2-year Dietary Intervention Randomized Controlled Trial-Carotid (DIRECT-Carotid) study, participants were randomized to low-fat, Mediterranean, or low-carbohydrate diets and were followed for changes in carotid artery intima-media thickness, measured with standard B-mode ultrasound, and carotid vessel wall volume (VWV), measured with carotid 3D ultrasound. Of 140 complete images of participants (aged 51 years; body mass index, 30 kg/m(2); 88% men), higher baseline carotid VWV was associated with increased intima-media thickness, age, male sex, baseline weight, blood pressure, and insulin levels (P<0.05 for all). After 2 years of dietary intervention, we observed a significant 5% regression in mean carotid VWV (-58.1 mm(3;) 95% confidence interval, -81.0 to -35.1 mm(3); P<0.001), with no differences in the low-fat, Mediterranean, or low-carbohydrate groups (-60.69 mm(3), -37.69 mm(3), -84.33 mm(3), respectively; P=0.28). Mean change in intima media thickness was -1.1% (P=0.18). A reduction in the ratio of apolipoprotein B(100) to apolipoprotein A1 was observed in the low-carbohydrate compared with the low-fat group (P=0.001). Participants who exhibited carotid VWV regression (mean decrease, -128.0 mm(3); 95% confidence interval, -148.1 to -107.9 mm(3)) compared with participants who exhibited progression (mean increase, +89.6 mm(3); 95% confidence interval, +66.6 to +112.6 mm(3)) had achieved greater weight loss (-5.3 versus -3.2 kg; P=0.03), greater decreases in systolic blood pressure (-6.8 versus -1.1 mm Hg; P=0.009) and total homocysteine (-0.06 versus +1.44 mumol/L; P=0.04), and a higher increase of apolipoprotein A1 (+0.05 versus -0.00 g/L; P=0.06). In multivariate regression models, only the decrease in systolic blood pressure remained a significant independent modifiable predictor of subsequent greater regression in both carotid VWV (beta=0.23; P=0.01) and intima-media thickness (beta=0.28; P=0.008) levels. CONCLUSIONS: Two-year weight loss diets can induce a significant regression of measurable carotid VWV. The effect is similar in low-fat, Mediterranean, or low-carbohydrate strategies and appears to be mediated mainly by the weight loss-induced decline in blood pressure. Clinical Trial Registration- http://www.clinicaltrials.gov. Unique Identifier: NCT00160108. PMID- 20194884 TI - Relationship between coronary microvascular dysfunction and cardiac energetics impairment in type 1 diabetes mellitus. AB - BACKGROUND: Asymptomatic subjects with diabetes mellitus have an impaired cardiac energetics status that may play a significant role in the development of heart failure. In the present study, we assessed the role of microvascular dysfunction in the development of impaired cardiac energetics in subjects with type 1 diabetes mellitus. METHODS AND RESULTS: Twenty-five asymptomatic subjects with type 1 diabetes mellitus (mean age +/-1 SD 33+/-8 years) and 26 age-, sex-, and body mass index-matched healthy control subjects (32+/-8 years old) were recruited into the study. The type 1 diabetes mellitus subjects were divided into 2 age-matched groups (newly diagnosed [<5 years] and longer-duration [>10 years] diabetes) to assess the impact of microvascular disease. All subjects had an echocardiogram and an exercise ECG performed, followed by magnetic resonance spectroscopy and stress magnetic resonance imaging. Compared with healthy control subjects, the phosphocreatine/gamma-ATP ratio was reduced significantly both in subjects with longer-term (2.1+/-0.5 versus 1.5+/-0.4, P<0.000) and newly diagnosed (2.1+/-0.5 versus 1.6+/-0.2, P<0.000) diabetes. The phosphocreatine/gamma-ATP ratio was similar in newly diagnosed diabetes subjects and those with longer-term disease (1.6+/-0.2 versus 1.5+/-0.4, P=0.32). The mean myocardial perfusion reserve index in the longer-term type 1 diabetes mellitus subjects was significantly lower than in healthy control subjects (1.7+/-0.6 versus 2.3+/-0.4, P=0.005). On univariate analysis, there was no significant correlation of phosphocreatine/gamma-ATP ratio with myocardial perfusion reserve index (r=0.21, P=0.26). CONCLUSIONS: We demonstrate that young subjects with uncomplicated type 1 diabetes mellitus have impaired myocardial energetics irrespective of the duration of diabetes and that the impaired cardiac energetics status is independent of coronary microvascular function. We postulate that impairment of cardiac energetics in these subjects primarily results from metabolic dysfunction rather than microvascular impairment. PMID- 20194886 TI - Seeking alternatives to Hard End Points: is imaging the best APPROACH? PMID- 20194885 TI - Thioredoxin-1 gene therapy enhances angiogenic signaling and reduces ventricular remodeling in infarcted myocardium of diabetic rats. AB - BACKGROUND: The present study evaluated the reversal of diabetes-mediated impairment of angiogenesis in a myocardial infarction model of type 1 diabetic rats by intramyocardial administration of an adenoviral vector encoding thioredoxin-1 (Ad.Trx1). Various studies have linked diabetes-mediated impairment of angiogenesis to dysfunctional antioxidant systems in which thioredoxin-1 plays a central role. METHODS AND RESULTS: Ad.Trx1 was administered intramyocardially in nondiabetic and diabetic rats immediately after myocardial infarction. Ad.LacZ was similarly administered to the respective control groups. The hearts were excised for molecular and immunohistochemical analysis at predetermined time points. Myocardial function was measured by echocardiography 30 days after the intervention. The Ad.Trx1-administered group exhibited reduced fibrosis, oxidative stress, and cardiomyocyte and endothelial cell apoptosis compared with the diabetic myocardial infarction group, along with increased capillary and arteriolar density. Western blot and immunohistochemical analysis demonstrated myocardial overexpression of thioredoxin-1, heme oxygenase-1, vascular endothelial growth factor, and p38 mitogen-activated protein kinase-beta, as well as decreased phosphorylated JNK and p38 mitogen-activated protein kinase-alpha, in the Ad.Trx1-treated diabetic group. Conversely, we observed a significant reduction in the expression of vascular endothelial growth factor in nondiabetic and diabetic animals treated with tin protoporphyrin (SnPP, a heme oxygenase-1 enzyme inhibitor), even after Ad.Trx1 therapy. Echocardiographic analysis after 4 weeks of myocardial infarction revealed significant improvement in myocardial functional parameters such as ejection fraction, fractional shortening, and E/A ratio in the Ad.Trx1-administered group compared with the diabetic myocardial infarction group. CONCLUSIONS: This study demonstrates for the first time that impairment of angiogenesis and myocardial dysfunction can be regulated by Ad.Trx1 gene therapy in streptozotocin-induced diabetic rats subjected to infarction. PMID- 20194887 TI - How would the Reverend Bayes interpret high-sensitivity troponin? PMID- 20194888 TI - Role of ticagrelor in clopidogrel nonresponders: resistance is futile? PMID- 20194890 TI - CYLD regulates angiogenesis by mediating vascular endothelial cell migration. AB - Cylindromatosis (CYLD) is a deubiquitinase that was initially identified as a tumor suppressor and has recently been implicated in diverse normal physiologic processes. In this study, we have investigated the involvement of CYLD in angiogenesis, the formation of new blood vessels from preexisting ones. We find that knockdown of CYLD expression significantly impairs angiogenesis in vitro in both matrigel-based tube formation assay and collagen-based 3-dimensional capillary sprouting assay. Disruption of CYLD also remarkably inhibits angiogenic response in vivo, as evidenced by diminished blood vessel growth into the angioreactors implanted in mice. Mechanistic studies show that CYLD regulates angiogenesis by mediating the spreading and migration of vascular endothelial cells. Silencing of CYLD dramatically decreases microtubule dynamics in endothelial cells and inhibits endothelial cell migration by blocking the polarization process. Furthermore, we identify Rac1 activation as an important factor contributing to the action of CYLD in regulating endothelial cell migration and angiogenesis. Our findings thus uncover a previously unrecognized role for CYLD in the angiogenic process and provide a novel mechanism for Rac1 activation during endothelial cell migration and angiogenesis. PMID- 20194889 TI - Roles of arrest-defective protein 1(225) and hypoxia-inducible factor 1alpha in tumor growth and metastasis. AB - BACKGROUND: Vascular endothelial growth factor A (VEGFA), a critical mediator of tumor angiogenesis, is a well-characterized target of hypoxia-inducible factor 1 (HIF-1). Murine arrest-defective protein 1A (mARD1A(225)) acetylates HIF-1alpha, triggering its degradation, and thus may play a role in decreased expression of VEGFA. METHODS: We generated Apc(Min/+)/mARD1A(225) transgenic mice and quantified growth of intestinal polyps. Human gastric MKN74 and murine melanoma B16F10 cells overexpressing mARD1A(225) were injected into mice, and tumor growth and metastasis were measured. VEGFA expression and microvessel density in tumors were assessed using immunohistochemistry. To evaluate the role of mARD1A(225) acetylation of Lys532 in HIF-1alpha, we injected B16F10-mARD1A(225) cell lines stably expressing mutant HIF-1alpha/K532R into mice and measured metastasis. All statistical tests were two-sided, and P values less than .05 were considered statistically significant. RESULTS: Apc(Min/+)/mARD1A(225) transgenic mice (n = 25) had statistically significantly fewer intestinal polyps than Apc(Min/+) mice (n = 21) (number of intestinal polyps per mouse: Apc(Min/+) mice vs Apc(Min/+)/mARD1A(225) transgenic mice, mean = 83.4 vs 38.0 polyps, difference = 45.4 polyps, 95% confidence interval [CI] = 41.8 to 48.6; P < .001). The growth and metastases of transplanted tumors were also statistically significantly reduced in mice injected with mARD1A(225)-overexpressing cells than in mice injected with control cells (P < .01). Moreover, overexpression of mARD1A(225) decreased VEGFA expression and microvessel density in tumor xenografts (P < .04) and Apc(Min/+) intestinal polyps (P = .001). Mutation of lysine 532 of HIF-1alpha in B16F10-mARD1A(225) cells prevented HIF-1alpha degradation and inhibited the antimetastatic effect of mARD1A(225) (P < .001). CONCLUSION: mARD1A(225) may be a novel upstream target that blocks VEGFA expression and tumor-related angiogenesis. PMID- 20194891 TI - Improved survival of children and adolescents with sickle cell disease. AB - The survival of young children with sickle cell disease (SCD) has improved, but less is known about older children and adolescents. We studied the Dallas Newborn Cohort (DNC) to estimate contemporary 18-year survival for newborns with SCD and document changes in the causes and ages of death over time. We also explored whether improvements in the quality of medical care were temporally associated with survival. The DNC now includes 940 subjects with 8857 patient-years of follow-up. Most children with sickle cell anemia (93.9%) and nearly all children with milder forms of SCD (98.4%) now live to become adults. The incidence of death and the pattern of mortality changed over the duration of the cohort. Sepsis is no longer the leading cause of death. All the recent deaths in the cohort occurred in patients 18 years or older, most shortly after the transition to adult care. Quality of care in the DNC has improved over time, with significantly more timely initial visits and preventive interventions for young children. In summary, most children with SCD now survive the childhood years, but young adults who transition to adult medical care are at high risk for early death. PMID- 20194893 TI - Efficacy of single-agent lenalidomide in patients with JAK2 (V617F) mutated refractory anemia with ring sideroblasts and thrombocytosis. AB - Patients with refractory anemia with ring sideroblasts and thrombocytosis (RARS T) are difficult to treat because the cytoreductive treatment might be beneficial for the thrombocytosis component but harmful for the RARS component. As lenalidomide has shown to be efficacious in both myelodysplastic syndromes and myeloproliferative neoplasms, we have treated 2 RARS-T patients, who were transfusion dependent, with lenalidomide. We report the results of lenalidomide treatment in these patients and show that lenalidomide has clinical activity in this rare disorder. Both patients became transfusion independent, and 1 of the patients attained indeed a complete molecular remission. PMID- 20194892 TI - Promoter choice and translational repression determine cell type-specific cell surface density of the inhibitory receptor CD85j expressed on different hematopoietic lineages. AB - CD85j (ILT2/LILRB1/LIR-1) is an inhibitory receptor that recognizes major histocompatibility complex (MHC) class Ia and Ib alleles that are widely expressed on all cell types. On ligand recognition, CD85j diminishes kinase activity by recruiting phosphatases to motifs within its cytoplasmic domain. Within the hematopoietic system, CD85j is expressed with cell-specific patterns and cell surface densities that reflect the different roles of cell contact mediated inhibition in these lineages. While monocytes ubiquitously have high cell surface expression, B lymphocytes start to express CD85j at intermediate levels during early B-cell maturation and natural killer (NK) cells and T cells exhibit a low level of expression on only a subset of cells. The cell-specific expression pattern is accomplished by 2 complementing but not independent mechanisms. Lymphocytes and monocytes use distinct promoters to drive CD85j expression. The lymphocyte promoter maps 13 kilobases (kb) upstream of the monocyte promoter; its use results in the inclusion of a distant exon into the 5' untranslated region. A short sequence stretch within this exon has the unique function of repressing CD85j protein translation and is responsible for the subdued expression in lymphocytes. These cell-specific mechanisms allow tailoring of CD85j levels to the distinct roles it plays in different hematopoietic lineages. PMID- 20194894 TI - Putative GTPase GIMAP1 is critical for the development of mature B and T lymphocytes. AB - The guanosine triphosphatases (GTPases) of the immunity-associated protein (GIMAP) family of putative GTPases has been implicated in the regulation of T lymphocyte development and survival. A mouse conditional knockout allele was generated for the immune GTPase gene GIMAP1. Homozygous loss of this allele under the influence of the lymphoid-expressed hCD2-iCre recombinase transgene led to severe (> 85%) deficiency of mature T lymphocytes and, unexpectedly, of mature B lymphocytes. By contrast there was little effect of GIMAP1 deletion on immature lymphocytes in either B or T lineages, although in vitro studies showed a shortening of the survival time of both immature and mature CD4(+) single positive thymocytes. These findings show a vital requirement for GIMAP1 in mature lymphocyte development/survival and draw attention to the nonredundant roles of members of the GIMAP GTPase family in these processes. PMID- 20194895 TI - Rational design of a fully active, long-acting PEGylated factor VIII for hemophilia A treatment. AB - A long-acting factor VIII (FVIII) as a replacement therapy for hemophilia A would significantly improve treatment options for patients with hemophilia A. To develop a FVIII with an extended circulating half-life, but without a reduction in activity, we have engineered 23 FVIII variants with introduced surface-exposed cysteines to which a polyethylene glycol (PEG) polymer was specifically conjugated. Screening of variant expression level, PEGylation yield, and functional assay identified several conjugates retaining full in vitro coagulation activity and von Willebrand factor (VWF) binding.PEGylated FVIII variants exhibited improved pharmacokinetics in hemophilic mice and rabbits. In addition, pharmacokinetic studies in VWF knockout mice indicated that larger molecular weight PEG may substitute for VWF in protecting PEGylated FVIII from clearance in vivo. In bleeding models of hemophilic mice, PEGylated FVIII not only exhibited prolonged efficacy that is consistent with the improved pharmacokinetics but also showed efficacy in stopping acute bleeds comparable with that of unmodified rFVIII. In summary site-specifically PEGylated FVIII has the potential to be a long-acting prophylactic treatment while being fully efficacious for on-demand treatment for patients with hemophilia A. PMID- 20194896 TI - The AF4.MLL fusion protein is capable of inducing ALL in mice without requirement of MLL.AF4. AB - The chromosomal translocation t(4;11)(q21;q23) is the most frequent genetic aberration of the human MLL gene, resulting in high-risk acute lymphoblastic leukemia (ALL). To elucidate the leukemogenic potential of the fusion proteins MLL.AF4 and AF4.MLL, Lin(-)/Sca1(+) purified cells (LSPCs) were retrovirally transduced with either both fusion genes or with MLL.AF4 or AF4.MLL alone. Recipients of AF4.MLL- or double-transduced LSPCs developed pro-B ALL, B/T biphenotypic acute leukemia, or mixed lineage leukemia. Transplantation of MLL.AF4- or mock-transduced LSPCs did not result in disease development during an observation period of 13 months. These findings indicate that the expression of the AF4.MLL fusion protein is capable of inducing acute lymphoblastic leukemia even in the absence of the MLL.AF4 fusion protein. In view of recent findings, these results may imply that t(4;11) leukemia is based on 2 oncoproteins, providing an explanation for the very early onset of disease in humans. PMID- 20194897 TI - Ribosomopathies: human disorders of ribosome dysfunction. AB - Ribosomopathies compose a collection of disorders in which genetic abnormalities cause impaired ribosome biogenesis and function, resulting in specific clinical phenotypes. Congenital mutations in RPS19 and other genes encoding ribosomal proteins cause Diamond-Blackfan anemia, a disorder characterized by hypoplastic, macrocytic anemia. Mutations in other genes required for normal ribosome biogenesis have been implicated in other rare congenital syndromes, Schwachman Diamond syndrome, dyskeratosis congenita, cartilage hair hypoplasia, and Treacher Collins syndrome. In addition, the 5q- syndrome, a subtype of myelodysplastic syndrome, is caused by a somatically acquired deletion of chromosome 5q, which leads to haploinsufficiency of the ribosomal protein RPS14 and an erythroid phenotype highly similar to Diamond-Blackfan anemia. Acquired abnormalities in ribosome function have been implicated more broadly in human malignancies. The p53 pathway provides a surveillance mechanism for protein translation as well as genome integrity and is activated by defects in ribosome biogenesis; this pathway appears to be a critical mediator of many of the clinical features of ribosomopathies. Elucidation of the mechanisms whereby selective abnormalities in ribosome biogenesis cause specific clinical syndromes will hopefully lead to novel therapeutic strategies for these diseases. PMID- 20194900 TI - Medical malpractice/expert testimony/disclosure of errors. PMID- 20194898 TI - Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. AB - CD20 is an important target for the treatment of B-cell malignancies, including non-Hodgkin lymphoma as well as autoimmune disorders. B-cell depletion therapy using monoclonal antibodies against CD20, such as rituximab, has revolutionized the treatment of these disorders, greatly improving overall survival in patients. Here, we report the development of GA101 as the first Fc-engineered, type II humanized IgG1 antibody against CD20. Relative to rituximab, GA101 has increased direct and immune effector cell-mediated cytotoxicity and exhibits superior activity in cellular assays and whole blood B-cell depletion assays. In human lymphoma xenograft models, GA101 exhibits superior antitumor activity, resulting in the induction of complete tumor remission and increased overall survival. In nonhuman primates, GA101 demonstrates superior B cell-depleting activity in lymphoid tissue, including in lymph nodes and spleen. Taken together, these results provide compelling evidence for the development of GA101 as a promising new therapy for the treatment of B-cell disorders. PMID- 20194899 TI - Deadly allies: the fatal interplay between platelets and metastasizing cancer cells. AB - The general notion that functional platelets are important for successful hematogenous tumor metastasis has been inaugurated more than 4 decades ago and has since been corroborated in numerous experimental settings. Thorough preclinical investigations have, at least in part, clarified some specifics regarding the involvement of platelet adhesion receptors, such as thrombin receptors or integrins, in the metastasis cascade. Pivotal preclinical experiments have demonstrated that hematogenous tumor spread was dramatically diminished when platelets were depleted from the circulation or when functions of platelet surface receptors were inhibited pharmacologically or genetically. Such insight has inspired researchers to devise novel antitumoral therapies based on targeting platelet receptors. However, several mechanistic aspects underlying the impact of platelet receptors on tumor metastasis are not fully understood, and agents directed against platelet receptors have not yet found their way into the clinic. In addition, recent results suggesting that targeted inhibition of certain platelet surface receptors may even result in enhanced experimental tumor metastasis have demonstrated vividly that the role of platelets in tumor metastasis is more complex than has been anticipated previously. This review gives a comprehensive overview on the most important platelet receptors and their putative involvement in hematogenous metastasis of malignant tumors. PMID- 20194881 TI - Effect of rosiglitazone on progression of coronary atherosclerosis in patients with type 2 diabetes mellitus and coronary artery disease: the assessment on the prevention of progression by rosiglitazone on atherosclerosis in diabetes patients with cardiovascular history trial. AB - BACKGROUND: Rosiglitazone has several properties that may affect progression of atherosclerosis. The Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in Diabetes Patients With Cardiovascular History (APPROACH) study was undertaken to determine the effect of the thiazolidinedione rosiglitazone on coronary atherosclerosis as assessed by intravascular ultrasound compared with the sulfonylurea glipizide. METHODS AND RESULTS: This was a randomized, double-blind, controlled 18-month study in 672 patients aged 30 to 80 years with established type 2 diabetes mellitus treated by lifestyle, 1 oral agent, or submaximal doses of 2 oral agents who had at least 1 atherosclerotic plaque with 10% to 50% luminal narrowing in a coronary artery that had not undergone intervention during a clinically indicated coronary angiography or percutaneous coronary intervention. The primary outcome was change in percent atheroma volume in the longest and least angulated epicardial coronary artery that had not undergone intervention. Secondary outcomes included change in normalized total atheroma volume and change in total atheroma volume in the most diseased baseline 10-mm segment. Rosiglitazone did not significantly reduce the primary outcome of percent atheroma volume compared with glipizide (-0.64%; 95% confidence interval, -1.46 to 0.17; P=0.12). The secondary outcome of normalized total atheroma volume was significantly reduced by rosiglitazone compared with glipizide (-5.1 mm(3); 95% confidence interval, -10.0 to -0.3; P=0.04); however, no significant difference between groups was observed for the change in total atheroma volume within the most diseased baseline 10-mm segment (-1.7 mm(3); 95% confidence interval, -3.9 to 0.5; P=0.13). CONCLUSIONS: Rosiglitazone did not significantly decrease the primary end point of progression of coronary atherosclerosis more than glipizide in patients with type 2 diabetes mellitus and coronary atherosclerosis. Clinical Trial Registration- http://www.clinicaltrials.gov. Unique Identifier: NCT00116831. PMID- 20194902 TI - Otitis media. PMID- 20194901 TI - Pediatric fecal incontinence: a surgeon's perspective. PMID- 20194903 TI - Index of suspicion. PMID- 20194905 TI - Neonatal seizures. PMID- 20194904 TI - Understanding confounding in research. PMID- 20194906 TI - Rubella. PMID- 20194908 TI - Teaching NeuroImages: MRI in Ramsay-Hunt syndrome after trigeminal zoster. PMID- 20194911 TI - Rapid-onset central motor plasticity in multiple sclerosis. AB - OBJECTIVE: To study rapid-onset central motor plasticity, and its relationship to motor impairment and CNS injury in patients with multiple sclerosis (MS). METHODS: In this cross-sectional observational study, motor plasticity was examined neurophysiologically and behaviorally in 22 patients with moderately severe (median Expanded Disability Status Scale score 2.5 [0-6]) stable MS and matched healthy controls. First, plasticity was assessed using paired associative stimulation (PAS), a protocol modeling long-term synaptic potentiation in human cortex. PAS combines repetitive electric nerve stimulation with transcranial magnetic stimulation (TMS) of the contralateral motor cortex. Second, motor learning was tested by a force production task. Motor impairment was assessed by functional tests. CNS injury was evaluated by obtaining normalized N-acetyl aspartate (NAA/Cr) spectra using magnetic resonance spectroscopy and by the corticomuscular latency (CML) to the abductor pollicis brevis muscle as tested by TMS. RESULTS: Patients with MS performed worse than controls in functional motor tests, CMLs were prolonged, and NAA/Cr was decreased. PAS-induced enhancement of corticospinal excitability and training-induced increments of motor performance were comparable between patients with MS and controls. Neither PAS-induced plasticity nor motor learning performance correlated with motor impairment or measures of CNS injury. Patients with high CNS injury and good motor performance did not differ significantly from those with high CNS injury and poor motor performance with respect to PAS-induced plasticity and motor learning success. CONCLUSIONS: Despite motor impairment and CNS injury in patients with multiple sclerosis (MS), rapid-onset motor plasticity is comparable to that in healthy subjects. Compensation of MS-related CNS injury is unlikely to be constrained by insufficient rapid-onset neuroplasticity. PMID- 20194912 TI - Neuromyelitis optica in France: a multicenter study of 125 patients. AB - BACKGROUND: There have been few epidemiologic studies on neuromyelitis optica (NMO) and none used the recent 2006 diagnostic criteria. Here we describe the clinical, laboratory, MRI, and disability course of NMO in a French cohort of 125 patients. METHODS: We performed an observational, retrospective, multicenter study. Data were collected from September 2007 through August 2008, corresponding to the endpoint of the study. We identified 125 patients fulfilling the 2006 NMO criteria. Selection was made using hospital files and a specific clinical questionnaire for NMO. RESULTS: Mean age at onset was 34.5 years (range 4-66) with a mean disease duration of 10 +/- 7.8 years at the endpoint. The patients were mainly (87%) Caucasian, with a female:male ratio of 3:1. In 90% of cases, the association of optic neuritis, longitudinal extensive myelitis, and a Paty negative initial brain MRI was sufficient to fulfill the supportive criteria. Eighty-eight percent of patients were treated with immunosuppressive therapies. Median delay from onset to Expanded Disability Status Scale (EDSS) score 4 was 7 years; score 6, 10 years; and score 7, 21 years. The first episode of myelitis was immediately followed by an EDSS score > or = 4 in 37.3% of cases, and a severe residual visual loss was observed in 22% of patients after the first episode of optic neuritis. Multivariate analysis did not reveal any predictors of a poor evolution other than a high number of MRI brain lesions at diagnosis, which were predictive of a residual visual acuity < or = 1/10. CONCLUSIONS: Our demographic data provide new data on disability in patients with neuromyelitis optica, most of whom were receiving treatment. PMID- 20194913 TI - Effects of STN stimulation on the initiation and inhibition of saccade in Parkinson disease. AB - OBJECTIVES: The basal ganglia (BG) play an important role in controlling saccades. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is widely used as a treatment of Parkinson disease (PD) by altering the function of the BG. Nevertheless, the effects of STN DBS on saccade performance are not fully clarified in a systematic manner. In this study, we examined the effects of bilateral STN DBS on both the initiation and inhibition of saccades in PD. METHODS: Thirty-two patients with PD performed 4 oculomotor tasks. Two tasks (visually guided saccades and gap saccades) were reflexive and 2 (memory-guided saccades [MGS] and antisaccades) were volitional. While taking their regular doses of antiparkinsonian drugs, patients performed these tasks under 2 conditions: during DBS (DBS-on condition) and without DBS (DBS-off condition). Fifty-one age-matched subjects served as controls. RESULTS: In the DBS-on condition, parameters of saccade initiation were improved in all tasks, with shorter latencies and increased amplitudes, except for MGS latency. STN DBS improved the ability to suppress unwanted saccades to the cue stimulus in the MGS task. However, it did not suppress prosaccades during the antisaccade task. CONCLUSIONS: These results suggest that deep brain stimulation (DBS) of the subthalamic nucleus (STN) affects the neural pathway common to both reflexive and volitional saccades, possibly by acting on the STN-substantia nigra pars reticulata-superior colliculi pathway. STN DBS may set the functional level of the superior colliculi appropriate for both saccade initiation and inhibition through this pathway. These findings provide novel insights into the pathophysiology of Parkinson disease and may yield better treatment strategies. PMID- 20194914 TI - Ventromedial prefrontal cortex modulates fatigue after penetrating traumatic brain injury. AB - BACKGROUND: Fatigue is a common and disabling symptom in neurologic disorders including traumatic penetrating brain injury (PBI). Despite fatigue's prevalence and impact on quality of life, its pathophysiology is not understood. Studies on effort perception in healthy subjects, animal behavioral paradigms, and recent evidence in different clinical populations suggest that ventromedial prefrontal cortex could play a significant role in fatigue pathophysiology in neurologic conditions. METHODS: We enrolled 97 PBI patients and 37 control subjects drawn from the Vietnam Head Injury Study registry. Fatigue was assessed with a self report questionnaire and a clinician-rated instrument; lesion location and volume were evaluated on CT scans. PBI patients were divided in 3 groups according to lesion location: a nonfrontal lesion group, a ventromedial prefrontal cortex lesion (vmPFC) group, and a dorso/lateral prefrontal cortex (d/lPFC) group. Fatigue scores were compared among the 3 PBI groups and the healthy controls. RESULTS: Individuals with vmPFC lesions were significantly more fatigued than individuals with d/lPFC lesions, individuals with nonfrontal lesions, and healthy controls, while these 3 latter groups were equally fatigued. VmPFC volume was correlated with fatigue scores, showing that the larger the lesion volume, the higher the fatigue scores. CONCLUSIONS: We demonstrated that ventromedial prefrontal cortex lesion (vmPFC) plays a critical role in penetrating brain injury-related fatigue, providing a rationale to link fatigue to different vmPFC functions such as effort and reward perception. The identification of the anatomic and cognitive basis of fatigue can contribute to developing pathophysiology-based treatments for this disabling symptom. PMID- 20194915 TI - Cognitive effects of pregabalin in healthy volunteers: a double-blind, placebo controlled trial. AB - BACKGROUND: Antiepileptic drugs (AEDs) can be associated with neurotoxic side effects including cognitive dysfunction, a problem of considerable importance given the usual long-term course of treatment. Pregabalin is a relatively new AED widely used for the treatment of seizures and some types of chronic pain including fibromyalgia. We measured the cognitive effects of 12 weeks of pregabalin in healthy volunteers. METHODS: Thirty-two healthy volunteers were randomized in a double-blind parallel study to receive pregabalin or placebo (1:1). Pregabalin was titrated over 8 weeks to 600 mg/d. At baseline, and after 12 weeks of treatment, all subjects underwent cognitive testing. Test-retest changes in all cognitive and subjective measures were Z scored against test retest regressions previously developed from 90 healthy volunteers. Z scores from the placebo and pregabalin groups were compared using Wilcoxon tests. RESULTS: Thirty subjects completed the study (94%). Three of 6 target cognitive measures (Digit Symbol, Stroop, Controlled Oral Word Association) revealed significant test-retest differences between the pregabalin and placebo groups, all showing negative effects with pregabalin (p < 0.05). These cognitive effects were paralleled by complaints on the Portland Neurotoxicity Scale, a subjective measure of neurotoxicity (p < 0.01). CONCLUSION: At conventional doses and titration, pregabalin induced mild negative cognitive effects and neurotoxicity complaints in healthy volunteers. These effects are one factor to be considered in the selection and monitoring of chronic AED therapy. Class of Evidence: This study provides Class I evidence that pregabalin 300 mg BID negatively impacts cognition on some tasks in healthy volunteers. PMID- 20194916 TI - Vitamin E neuroprotection for cisplatin neuropathy: a randomized, placebo controlled trial. AB - OBJECTIVE: The clinical use of cisplatin chemotherapy is limited by severe peripheral neurotoxicity reported in up to 90% of patients receiving a cumulative dose higher than 300 mg/m(2). The present study evaluates the neuroprotective effect of antioxidant supplementation (vitamin E) in patients treated with cisplatin chemotherapy. METHODS: A total of 108 patients treated with cisplatin chemotherapy were randomly assigned to receive vitamin E supplementation (alpha tocopherol 400 mg/day) or placebo. Treatment was started orally before chemotherapy and continued for 3 months after the suspension of cisplatin. RESULTS: Of 108 randomized patients, 68 received at least one clinical and neurophysiologic examination after cisplatin CT; 41 patients received a cumulative dose of cisplatin higher than 300 mg/m(2) and were eligible for statistical analysis: 17 in the vitamin E group (group 1) and 24 in the placebo group (group 2). The incidence of neurotoxicity was significantly lower in group 1 (5.9%) than in group 2 (41.7%) (p < 0.01). The severity of neurotoxicity, measured with a validated neurotoxicity score (Total Neuropathy Score [TNS]), was significantly lower in patients receiving vitamin E than those receiving placebo (mean TNS 1.4 vs 4.1; p < 0.01). CONCLUSIONS: This phase III study confirms the neuroprotective role of vitamin E against cisplatin peripheral neurotoxicity. Vitamin E supplementation should be adopted in patients receiving cisplatin-based chemotherapy. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that vitamin E supplementation significantly reduces the relative risk of developing signs or symptoms of neurotoxicity (relative risk = 0.14) (95% confidence interval = 0.02-1.00, p < 0.05). PMID- 20194917 TI - Differences in stroke outcome based on sex. AB - OBJECTIVE: Stroke thrombolysis may have a differential effect by sex. We sought to examine the relationship between sex and outcome after thrombolysis. METHODS: This is a retrospective cohort study of stroke patients from the Registry of Canadian Stroke Network phase 1 (June 2001-February 2002) and phase 2 (June 2002 December 2002). Variables including demographics, history, clinical data, process measures, and outcome were analyzed. The primary outcomes were the Stroke Impact Scale-16 score (SIS-16) and mortality at 6 months. We compared the outcomes of the thrombolyzed and nonthrombolyzed cohorts and examined the data for a tissue plasminogen activator (tPA)-by-sex interaction on the 2 primary outcomes. RESULTS: The overall proportion of patients who achieved an excellent outcome (SIS-16 >75) was not different by gender. However, the proportion of patients achieving an excellent outcome in the non-tPA cohort was much greater in males, with an absolute risk difference of 11.8%. A multiplicative treatment by sex interaction was evident (p = 0.054). This interaction was not present for stroke case fatality. CONCLUSIONS: Women fared poorly compared to men in the placebo groups, but this negative prognostic sex effect was neutralized by thrombolysis. PMID- 20194918 TI - Neurosarcoidosis with diencephalitis and anti-Ma2 antibodies. PMID- 20194919 TI - Clinical Reasoning: a 34-year-old woman with recurrent bouts of acral paresthesias. PMID- 20194920 TI - Effects of active HCV replication on neurologic status in HIV RNA virally suppressed patients. PMID- 20194921 TI - Chronic daily headache in adolescents: an 8-year follow-up study. PMID- 20194923 TI - Synergic effect of salinity and CO2 enrichment on growth and photosynthetic responses of the invasive cordgrass Spartina densiflora. AB - Spartina densiflora is a C(4) halophytic species that has proved to have a high invasive potential which derives from its clonal growth and its physiological plasticity to environmental factors, such as salinity. A greenhouse experiment was designed to investigate the synergic effect of 380 and 700 ppm CO(2) at 0, 171, and 510 mM NaCl on the growth and the photosynthetic apparatus of S. densiflora by measuring chlorophyll fluorescence parameters, gas exchange and photosynthetic pigment concentrations. PEPC activity and total ash, sodium, potassium, calcium, magnesium, and zinc concentrations were determined, as well as the C/N ratio. Elevated CO(2) stimulated growth of S. densiflora at 0 and 171 mM NaCl external salinity after 90 d of treatment. This growth enhancement was associated with a greater leaf area and improved leaf water relations rather than with variations in net photosynthetic rate (A). Despite the fact that stomatal conductance decreased in response to 700 ppm CO(2) after 30 d of treatment, A was not affected. This response of A to elevated CO(2) concentration might be explained by an enhanced PEPC carboxylation capacity. On the whole, plant nutrient concentrations declined under elevated CO(2), which can be ascribed to the dilution effect caused by an increase in biomass and the higher water content found at 700 ppm CO(2). Finally, CO(2) and salinity had a marked overall effect on the photochemical (PSII) apparatus and the synthesis of photosynthetic pigments. PMID- 20194922 TI - Glyoxylate rather than ascorbate is an efficient precursor for oxalate biosynthesis in rice. AB - Oxalate is widely distributed in the plant kingdom. While excess oxalate in food crops is detrimental to animal and human health, it may play various functional roles in plants, particularly for coping with environmental stresses. Understanding its biosynthetic mechanism in plants, therefore, becomes increasingly important both theoretically and practically. However, it is still a matter of debate as to what precursor and pathway are ultimately used for oxalate biosynthesis in plants. In this study, both physiological and molecular approaches were applied to address these questions. First, it was observed that when glycolate or glyoxylate was fed into detached leaves, both organic acids were equally effective in stimulating oxalate accumulation. In addition, the stimulation could be completely inhibited by cysteine, a glyoxylate scavenger that forms cysteine-glyoxylate adducts. To verify the role of glyoxylate further, various transgenic plants were generated, in which several genes involved in glyoxylate metabolism [i.e. SGAT (serine-glyoxylate aminotransferase), GGAT (glutamate-glyoxylate aminotransferase), HPR (hydroxypyruvate reductase), ICL (isocitrate lyase)], were transcriptionally regulated through RNAi or over expression. Analyses on these transgenic plants consistently revealed that glyoxylate acted as an efficient precursor for oxalate biosynthesis in rice. Unexpectedly, it was found that oxalate accumulation was not correlated with photorespiration, even though this pathway is known to be a major source of glyoxylate. Further, when GLDH (L-galactono-1,4-lactone dehydrogenase), a key enzyme gene for ascorbate biosynthesis, was down-regulated, the oxalate abundance remained constant, despite ascorbate having been largely reduced as expected in these transgenic plants. Taken together, our results strongly suggest that glyoxylate rather than ascorbate is an efficient precursor for oxalate biosynthesis, and that oxalate accumulation and regulation do not necessarily depend on photorespiration, possibly due to the occurrence of the anaplerotic reaction that may compensate for glyoxylate formation in rice. PMID- 20194925 TI - A model for gas transport in pear fruit at multiple scales. AB - A two-dimensional multiscale gas exchange model was developed to evaluate the effect of ambient conditions, fruit size, and maturity on intracellular O(2) and CO(2) concentrations in pear fruit via computational analysis. The model consists of interconnected submodels that describe the gas exchange at the macroscopic scale of the fruit and the microscopic scale of the cells. The multiscale model resulted in a comprehensive description of gas exchange at different scales. The macroscale model was used to describe the gas exchange of the fruit under controlled atmosphere conditions while corresponding intracellular concentrations of microstructure tissue were computed from the microscale. Ripening of the fruit increased the risk of physiological disorders, since increased respiration resulted in anoxia in the fruit centre even under typical storage conditions. PMID- 20194924 TI - A tomato strigolactone-impaired mutant displays aberrant shoot morphology and plant interactions. AB - Strigolactones are considered a new group of plant hormones. Their role as modulators of plant growth and signalling molecules for plant interactions first became evident in Arabidopsis, pea, and rice mutants that were flawed in strigolactone production, release, or perception. The first evidence in tomato (Solanum lycopersicon) of strigolactone deficiency is presented here. Sl-ORT1, previously identified as resistant to the parasitic plant Orobanche, had lower levels of arbuscular mycorrhizal fungus (Glomus intraradices) colonization, possibly as a result of its reduced ability to induce mycorrhizal hyphal branching. Biochemical analysis of mutant root extracts suggested that it produces only minute amounts of two of the tomato strigolactones: solanacol and didehydro-orobanchol. Accordingly, the transcription level of a key enzyme (CCD7) putatively involved in strigolactone synthesis in tomato was reduced in Sl-ORT1 compared with the wild type (WT). Sl-ORT1 shoots exhibited increased lateral shoot branching, whereas exogenous application of the synthetic strigolactone GR24 to the mutant restored the WT phenotype by reducing the number of lateral branches. Reduced lateral shoot branching was also evident in grafted plants which included a WT interstock, which was grafted between the mutant rootstock and the scion. In roots of these grafted plants, the CCD7 transcription level was not significantly induced, nor was mycorrhizal sensitivity restored. Hence, WT interstock grafting, which restores mutant shoot morphology to WT, does not restore mutant root properties to WT. Characterization of the first tomato strigolactone-deficient mutant supports the putative general role of strigolactones as messengers of suppression of lateral shoot branching in a diversity of plant species. PMID- 20194926 TI - cpSecA, a thylakoid protein translocase subunit, is essential for photosynthetic development in Arabidopsis. AB - The endosymbiont-derived Sec-dependent protein sorting pathway is essential for protein import into the thylakoid lumen and is important for the proper functioning of the chloroplast. Two loss-of-function mutants of cpSecA, the ATPase subunit of the chloroplast Sec translocation machinery, were analysed in Arabidopsis. The homozygous mutants were albino and seedling lethal under autotrophic conditions and remained dwarf and infertile with an exogenous carbon supply. They were subject to oxidative stress and accumulated superoxide under normal lighting conditions. Electron microscopy revealed that the chloroplast of the mutants had underdeveloped thylakoid structures. Histochemical GUS assay of the AtcpSecA::GUS transgenic plants confirmed that AtcpSecA was expressed in green organs in a light-inducible way. Real-time RT-PCR and microarray analysis revealed repressed transcription of nucleus- and chloroplast- encoded subunits of photosynthetic complexes, and induced transcription of chloroplast protein translocation machinery and mitochondrion-encoded respiratory complexes in the mutants. It is inferred that AtcpSecA plays an essential role in chloroplast biogenesis, the absence of which triggered a retrograde signal, eventually leading to a reprogramming of chloroplast and mitochondrial gene expression. PMID- 20194927 TI - Modelling temperature-compensated physiological rates, based on the co-ordination of responses to temperature of developmental processes. AB - Temperature fluctuates rapidly and affects all developmental and metabolic processes. This often obscures the effects of developmental trends or of other environmental conditions when temperature fluctuates naturally. A method is proposed for modelling temperature-compensated rates, based on the coordination of temperature responses of developmental processes. In a data set comprising 41 experiments in the greenhouse, growth chamber, or the field, the temperature responses in the range of 6-36 degrees C for different processes were compared in three species, maize, rice, and Arabidopsis thaliana. Germination, cell division, expansive growth rate, leaf initiation, and phenology showed coordinated temperature responses and followed common laws within each species. The activities of 10 enzymes involved in carbon metabolism exhibited monotonous exponential responses across the whole range 10-40 degrees C. Hence, the temperature dependence of developmental processes is not explained by a simple relationship to central metabolism. Temperature-compensated rates of development were calculated from the equations of response curve, by expressing rates per unit equivalent time at 20 degrees C. This resulted in stable rates when temperatures fluctuated over a large range (for which classical thermal time was inefficient), and in time courses of leaf development which were common to several experiments with different temperature scenarios. PMID- 20194928 TI - Why has computed tomography won and ultrasound lost the market share of imaging for acute pelvic conditions in the female patient? PMID- 20194929 TI - A trainee-based randomized comparison of stimulating interscalene perineural catheters with a new technique using ultrasound guidance alone. AB - OBJECTIVE: Compared to the well-established stimulating catheter technique, the use of ultrasound guidance alone for interscalene perineural catheter insertion is a recent development and has not yet been examined in a randomized fashion. We hypothesized that an ultrasound-guided technique would require less time and produce equivalent results compared to electrical stimulation (ES) when trainees attempt interscalene perineural catheter placement. METHODS: Preoperatively, patients receiving an interscalene perineural catheter for shoulder surgery were randomly assigned to an insertion protocol using either ultrasound guidance with a nonstimulating catheter or ES with a stimulating catheter. The primary outcome was the procedural duration (in minutes), starting when the ultrasound probe (ultrasound group) or catheter insertion needle (ES group) first touched the patient and ending when the catheter insertion needle was removed after catheter insertion. RESULTS: All ultrasound-guided catheters (n = 20) were placed successfully and resulted in surgical anesthesia versus 85% of ES-guided catheters (n = 20; P = .231). Perineural catheters placed by ultrasound (n = 20) took a median (10th-90th percentiles) of 8.0 (5.0-15.5) minutes compared to 14.0 (5.0-30.0) minutes for ES (n = 20; P = .022). All catheters placed according to the protocol in both treatment groups resulted in a successful nerve block; however, 1 patient in the ES group had local anesthetic spread to the epidural space. There was 1 vascular puncture using ultrasound guidance compared to 5 in the ES-guided catheter group (P = .182). CONCLUSIONS: Trainees using a new ultrasound-guided technique can place inter-scalene perineural catheters in less time compared to a well-documented technique using ES with a stimulating catheter and can produce equivalent results. PMID- 20194930 TI - Sonography of the coracohumeral interval: a potential technique for diagnosing coracoid impingement. AB - OBJECTIVE: Coracoid impingement has been recognized as an etiology for anterior shoulder pain; however, no imaging reference standard exists. We used sonography to compare the coracohumeral interval (CHI) in asymptomatic volunteers with the CHI in patients with coracoid impingement. METHODS: Bilateral shoulder sonography was performed in 19 asymptomatic volunteers (10 men and 9 women) and in 8 shoulders in 7 patients (6 men and 1 woman) with a clinical diagnosis of coracoid impingement. With the arm adducted across the chest, the interval between the coracoid process and the lesser tuberosity of the humerus was measured using a linear array ultrasound transducer with a peak frequency of 13 MHz. RESULTS: In the asymptomatic volunteers, the mean +/- SD for the CHI was 12.2 +/- 2.5 mm (range, 7.8-17.5 mm). In the symptomatic shoulders, the mean +/- SD for the CHI was 7.9 +/- 1.4 mm (range, 5.9-9.6 mm). Repeated measures analysis of variance revealed the CHI to be significantly narrower in symptomatic shoulders than in asymptomatic volunteers (P < .0001). CONCLUSIONS: These data suggest a role for sonography in diagnosing coracoid impingement. PMID- 20194931 TI - Detecting metastasis of lymph nodes and predicting aggressiveness in patients with breast carcinomas. AB - OBJECTIVE: The purpose of this study was to evaluate the contrast-enhanced ultrasonographic (CEUS) characteristics of metastatic lymph nodes (LNs) and to determine the correlation of CEUS parameters with the tumor aggressiveness in patients with breast cancer. METHODS: Real-time gray scale CEUS of axillary LNs was preoperatively performed in 51 consecutive patients with breast carcinoma who were scheduled for axillary lymph node dissection. The CEUS characteristics assessed by a direct visualization method and quantification software were compared with pathologic findings. Expression of human epidermal growth factor receptor 2 (HER-2/neu) in the primary tumor was detected by immunohistochemical analysis. Correlation analysis of CEUS parameters with HER-2/neu expression and the LN stage was performed. RESULTS: Of the LNs examined, 27 were metastatic, and 25 were diagnosed as reactive hyperplasia. Lymph nodes with metastasis were characterized by centripetal progress (66.7%) and a heterogeneous pattern (55.6%) or no or scarce perfusion (25.9%). However, LNs with nonmetastases were characterized by with centrifugal enhancement (56.0%) and a homogeneous pattern (80.0%). The difference between the hyperintense and hypointense regions was higher in metastatic LNs than nonmetastatic ones (P < .001). No significant differences were found in the arrival time, time to peak intensity, and peak intensity between the two groups. A histopathologic diagnosis could be predicted with sensitivity, specificity, and accuracy of 92.6%, 76.0%, and 84.6% respectively, by a standardized difference between maximum and minimum signal intensity (SI(max)-SI(min)) value of 28. Human epidermal growth factor receptor 2 expression and the LN histopathologic stage were significantly associated with the SI(max)-SI(min). In metastatic LNs, the relationship between the diagnostic sensitivity of CEUS and the transverse diameter of LNs remained statistically significant (P < .05). CONCLUSIONS: Noninvasive CEUS can play a role in discriminating metastatic from nonmetastatic LNs and predicting the aggressiveness in patients with breast cancer. PMID- 20194932 TI - Evaluation of the fetal secondary palate by 3-dimensional ultrasonography. AB - OBJECTIVE: Diagnosis of cleft lip and palate remains a challenge with 2 dimensional ultrasonography, particularly when clefting involves only the secondary palate. The utility of 3-dimensional ultrasonography (3DUS) has enhanced our ability to detect clefts. We report our experience with a modification of the flipped face technique to aid in the diagnosis of clefting of the secondary palate. METHODS: Ninety-two volumes of 92 fetal faces were evaluated. Thirty-six volumes were acquired prospectively. Fifty-six volumes had previously been acquired and included 8 with clefting of the secondary palate. Volumes were obtained on 3DUS systems and reviewed by 4 blinded readers on personal computer workstations. Volumes were manipulated so that an upright profile was visualized. The palate was then rendered using a thin, curved render box. Statistical analysis was performed using the Fisher exact test for categorical data. Intraclass correlations were computed to assess inter-rater agreement. RESULTS: The mean gestational age at image acquisition +/- SD was 22 +/- 5 weeks. Image quality of the secondary palate was obtained and rated as adequate by at least 2 reviewers in 34% (31 of 92) of volumes. The sensitivity of cleft detection ranged from 33% to 63%, and the specificity ranged from 84% to 95%. The low sensitivity was mainly due to artifacts/shadowing. The inter-rater reliability was 0.62 (95% confidence interval, 0.47-0.76). CONCLUSIONS: Three dimensional ultrasonography can be used to diagnose clefts of the secondary palate. This evaluation is limited by the fetal position and artifacts from shadowing of adjoining structures. Pseudoclefts can be created, and optimal imaging cannot be obtained in all fetuses. PMID- 20194933 TI - Detecting degenerative changes in myotonic murine models of Duchenne muscular dystrophy using high-frequency ultrasound. AB - OBJECTIVE: Ultrasound imaging is an economical and noninvasive technique for studying musculoskeletal diseases such as Duchenne muscular dystrophy (DMD). Duchenne muscular dystrophy results from the loss of the cytoskeletal protein dystrophin. This in turn increases muscle susceptibility to injury, resulting in myofiber membrane leakage, inflammation, and degeneration. The purpose of this study was to detect dystrophic changes in muscle noninvasively. High-frequency ultrasound (HFU; 40 MHz) was used to obtain a resolution of 80 microm, which is not achievable with lower-frequency clinical scanners. METHODS: Using HFU, we were able to visualize musculoskeletal abnormalities as hyperechoic lesions within the dystrophic muscle. To validate the imaging findings, fiducial markers were placed in close proximity to lesions under HFU guidance. The nature of the lesion was then investigated histologically. This was repeated in the lower limbs of 10 mdx (mutated dystrophin gene) mice, a transgenic murine model of DMD. RESULTS: The abnormalities in the dystrophic muscle consisted of large influxes of leukocytic infiltrates, fibrotic scars, and calcified lesions. CONCLUSIONS: Although macrophages and fibrosis are commonly noted in DMD, to our knowledge, the presence of intramuscular calcific necrosis in dystrophic muscle has not been reported. This novel dystrophic feature of muscle degeneration may be useful in longitudinal studies of murine DMD and regenerative studies. PMID- 20194934 TI - Doppler sonographic findings in an experimental rabbit model of necrotizing enterocolitis. AB - OBJECTIVE: The purpose of this study was to examine the clinical applicability of Doppler sonography by evaluating Doppler sonographic findings in an experimental rabbit model of necrotizing enterocolitis (NEC). METHODS: Necrotizing enterocolitis was experimentally induced using a combination of endotoxin, hypoxia, and cold stress in 23 rabbits. Doppler sonography was performed to obtain the Doppler spectrum of the superior mesenteric artery. From the flow profile, the peak systolic velocity (PSV) and resistive index (RI) were calculated at 5 time sessions: initial and 1 to 2, 3 to 4, 5 to 6, and 20 to 24 hours. Animals were divided into 2 groups based on pathologic NEC scores (NEC positive [NEC+] group versus NEC-negative [NEC-] group). Differences between the groups with regard to RI and PSV values were evaluated for each time session. RESULTS: Comparison of RI and PSV values between the NEC+ and NEC- groups revealed a significant increase in the PSV in the NEC+ group during the 1- to 2 hour session (P = .0199). Comparison of RI and PSV differences revealed a significant increase in RI and PSV differences in the NEC+ group during the 1- to 2-hour session (P = .0095 and .0013, respectively). In the other time sessions, there was no difference between the groups. CONCLUSIONS: The NEC+ group showed a significant increase in the PSV and RI during the 1- to 2-hour period. PMID- 20194935 TI - A method for characterization of tissue elastic properties combining ultrasonic computed tomography with elastography. AB - OBJECTIVE: The correlation between various diseases and the change in the local mechanical properties of soft tissues has been long known. Over the past 20 years, there have been increasing research efforts to characterize mechanical properties of biological tissues using ultrasonic elastography. However, most of these works were based on characterization of only 1 type of waves (longitudinal or shear). The goal of this work was to devise a comprehensive ultrasound-based imaging method capable of measuring elastic parameters by combining both backscattered elastography and through-transmitted ultrasonic computed tomography. METHODS: Our suggested technique provides measurements of both longitudinal and shear wave velocities. This enables the noninvasive computation of several tissue elasticity parameters such as Young's and shear moduli, Poisson's ratio, and, more importantly, the bulk modulus, the determination of which requires both wave velocities. Four different phantom types were examined: agar-gelatin-based phantoms and porcine fat tissue, turkey breast tissue, and bovine liver tissue in vitro specimens. The values of Young's modulus, the shear modulus, and Poisson's ratio were estimated and were consistent with values published in the literature. RESULTS: The average bulk modulus values of the phantoms +/- SD were 2.83 +/- 0.001, 2.25 +/- 0.01, 2.48 +/- 0.01, and 2.53 +/- 0.02 GPa, respectively. A statistically significant difference (P < .001) in the values of the bulk modulus of the different phantoms was found. CONCLUSIONS: The bulk modulus is suitable for differentiation between different tissue types. The obtained results show the feasibility of using a comprehensive ultrasonic imaging technique for noninvasive quantitative tissue characterization. PMID- 20194936 TI - An integrated approach to computer-based automated tracing and its validation for 200 common carotid arterial wall ultrasound images: a new technique. AB - OBJECTIVE: Most of the algorithms for the segmentation of the common carotid artery (CCA) wall require human interaction to locate the vessel in the ultrasound image. The aim of this article is to show an accurate algorithm for the computer-based automated tracing of the CCA in longitudinal B-mode ultrasound images. METHODS: Two hundred images (100 normal CCAs, 50 CCAs with an increased intima-media thickness, 30 with fibrous plaques, and 20 with anechoic plaques) were processed to delineate the region of interest containing the CCA. The strategy is an integrated approach (carotid artery layer extraction using an integrated approach [CALEXia]) consisting of geometric feature extraction, line fitting, and classification. The output of the algorithm is the tracings of the proximal and distal adventitia layers. Performance of the algorithm was validated against human tracings considered the ground truth. RESULTS: The mean distance errors +/- SD using this integrated approach were 1.05 +/- 1.04 pixels (0.07 +/- 0.07 mm) for proximal or near adventitia and 2.68 +/- 3.94 pixels (0.17 +/- 0.24 mm) for distal or far adventitia. Sixteen of 200 images were not perfectly traced because of the presence of both plaques and blood backscattering. The computational cost ensures the possibility for near real-time detection. Conclusions. Although the CALEXia algorithm automatically detects the CCA, it is also robust and validated over a large database. This can constitute a general basis for a completely automated segmentation procedure widely applicable to other anatomies. PMID- 20194937 TI - Use of color Doppler ultrasonography for the prediction of malignancy in follicular thyroid neoplasms: systematic review and meta-analysis. AB - OBJECTIVE: The purpose of this systematic review was to obtain summary estimates of the diagnostic accuracy of color Doppler ultrasonography (CDU) in predicting malignancy in thyroid follicular neoplasms (FNs). METHODS: We searched Medical Subject Headings together with the search terms "follicular," "thyroid," and "Doppler" in the MEDLINE, Web of Science, and Excerpta Medica databases as well as the Latin American and Caribbean Health Sciences Literature database, after which we performed manual searches of the reference lists to locate additional studies. There were no language restrictions. We included studies that assessed the diagnostic accuracy of CDU in identifying malignancy in thyroid FNs. The assessments of the quality and extraction of data were performed by 3 independent reviewers. RESULTS: We included 4 studies, which collectively evaluated 457 thyroid FNs, 67 of which had been classified as malignant based on the evaluation of surgical biopsy samples. Moderate, rich, predominant, or exclusive internal flow on CDU of thyroid FNs was considered indicative of malignancy. The overall sensitivity of CDU was 85% (95% confidence interval [CI], 74%-93%), with an overall specificity of 86% (95% CI, 82%-89%). The overall prevalence was 14.7%, and the positive and negative predictive values were 51% and 97%, respectively. The positive likelihood ratio was 6.07, and the negative likelihood ratio was 0.18. CONCLUSIONS: Predominant internal flow seen on CDU is associated with malignancy of thyroid FNs. Absence of internal flow or predominantly peripheral flow indicates a low probability of thyroid FN malignancy. PMID- 20194938 TI - The cavum septi pellucidi: why is it important? AB - OBJECTIVE: The cavum septi pellucidi (CSP) is routinely imaged in the fetal brain during obstetric sonography; in fact, for well over a decade, assessment of the CSP has been considered part of the required elements of a standard examination of fetal morphology in guidelines developed by multiple specialty societies. Our objective is to present the 4 reasons why all practicing sonologists and sonographers should be familiar with this anatomic structure. METHODS: Prenatal sonograms and magnetic resonance imaging examinations are used to review the following topics: terminology, embryology, and anatomy of the CSP; pitfalls in its identification; and a wide variety of abnormalities (predominantly relating to nonvisualization) associated with the CSP. RESULTS: Embryologic development of the CSP is intimately associated with the corpus callosum (CC); thus, correct identification of the CSP essentially excludes complete agenesis of the CC. Absence of the CSP is associated with an extremely wide spectrum of neuroanatomic malformations: these range from the lethal entities of hydranencephaly and alobar holoprosencephaly; to the potentially serious but nonlethal entities of schizencephaly, porencephaly, basilar encephaloceles, severe hydrocephalus, and the less severe prosencephalic cleavage disorders (including syntelencephaly); to the normal variant, the rare and somewhat controversial entity of isolated septal deficiency. The value of noting that the absent CSP allows diagnosis of very subtle and easily overlooked abnormalities such as septo-optic dysplasia is presented. CONCLUSIONS: Correct recognition of the CSP provides welcome reassurance of proper development of the central forebrain. PMID- 20194939 TI - Structural anomalies in early embryonic death: a 3-dimensional pictorial essay. AB - OBJECTIVE: The purpose of this pictorial essay was to determine whether 3 dimensional (3D) surface rendering of a dead first-trimester embryo can provide any information for the loss. METHODS: Three-dimensional surface rendering was performed on a collection of dead first-trimester embryos with crown-rump lengths between 12 and 27 mm. These were compared with 2-dimensional (2D) images of the same embryos and with 2D images and 3D surface renderings of normally developing embryos. RESULTS: Surface rendering of dead embryos showed a variety of abnormalities in the contour and limb formation. CONCLUSIONS: The use of 3D sonography may provide insight into the etiology of first-trimester embryonic death. PMID- 20194940 TI - Prenatal diagnosis of spontaneous septostomy in dichorionic diamniotic twins and review of the literature. AB - OBJECTIVE: We present 2 cases of spontaneous septostomy in dichorionic diamniotic twins and review the literature regarding the incidence, etiology, and complications of this condition. METHODS: The following key words were used in the literature search: "rupture dividing membrane twin," "disruption dividing membrane twin," "pseudomonoamniotic twin," "spontaneous septostomy twin," "interfetal membrane disruption," "intertwin membrane rupture," and "intertwin membrane disruption." RESULTS: We present 2 cases in which an intertwin membrane defect was found prenatally in dichorionic diamniotic twins. In both cases, a portion of one twin's body was found traversing the spontaneous septostomy and in the sac of its cotwin. Umbilical cord Doppler studies showed no abnormalities in either case as the cord crossed the membrane disruption. In both cases, the fetuses had no notable sequelae from the ruptured intertwin membrane. The literature review revealed no cases of spontaneous septostomy in dichorionic diamniotic twins but 15 cases in monochorionic diamniotic twins. Possible etiologies include chorioamnionitis, trauma or physical rupture by the fetuses, developmental disturbances represented by amniotic plica, and polyhydramnios. In cases of monozygotic twins, a vascular etiology could explain this rare defect with formation of anastomoses of the outer embryonic vasculature. Complications of the spontaneous septostomy cases identified in the literature included cord entanglement (8 cases), preterm delivery (9 cases), and death (8 cases), although our 2 cases had minimal complications. CONCLUSIONS: Spontaneous septostomy in dichorionic diamniotic twins has not previously been reported. PMID- 20194941 TI - Sonographic evaluation of the abductor mechanism after total hip arthroplasty. AB - OBJECTIVE: The purpose of this series was to determine the frequency of abductor mechanism avulsion by sonography after total hip arthroplasty with the Hardinge approach (J Bone Joint Surg Br 1982; 64:17-19) and its relationship to the presence of insufficiency of this musculature in the postoperative period. METHODS: Thirty-four consecutive patients were prospectively accessed in the postoperative period of hip arthroplasty by the Trendelenburg test, hip sonography, and abductor muscle electromyography. In patients who were found to have clinical insufficiency of the abductor musculature, we also measured the femoral offset in the preoperative and postoperative radiographs. Hip sonography was performed by an experienced musculoskeletal radiologist blinded to the other tests, and the tendons of the gluteus medius and gluteus minimus were visualized on longitudinal and transverse sections with a 7- to 10-MHz linear transducer. RESULTS: Eight patients presented clinical insufficiency of the abductor musculature as detected by the Trendelenburg test. Four of these 8 patients with abductor insufficiency presented tendinous avulsion detected by sonography. One of the 4 patients with abductor insufficiency and normal sonographic findings had a decrease in the femoral offset caused by the arthroplasty itself. Two patients presented electromyographic changes of the abductor musculature, with no tendinous avulsion detected by sonography and no abductor insufficiency. CONCLUSIONS: We concluded that in patients undergoing total hip arthroplasty by the Hardinge approach in whom insufficiency of the abductor musculature develops, sonography is an interesting method of investigation because it identified the cause of this problem in most of our patients. PMID- 20194942 TI - Metatarsal stress fracture diagnosed with high-resolution sonography. PMID- 20194943 TI - Diffuse pulmonary vascular dilatation in a patient with liver cirrhosis. PMID- 20194944 TI - Reversible vasospasm in migrainous infarction: a transcranial Doppler follow-up study. PMID- 20194945 TI - Lymphoepithelioma-like carcinoma of the breast. PMID- 20194946 TI - Metastatic breast cancer from rhabdomyosarcoma mimicking normal breast parenchyma on sonography. PMID- 20194947 TI - Sunray appearance on sonography in Ewing sarcoma of the clavicle. PMID- 20194948 TI - Complex left fetal ovarian cyst with subsequent autoamputation and migration into the right lower quadrant in a neonate: case report and review of the literature. PMID- 20194949 TI - Three-dimensional prenatal diagnosis of monocephalus diprosopus tetraophthalmos. PMID- 20194950 TI - When ultrasound is not enough. PMID- 20194952 TI - Fabrication, falsification et Al. PMID- 20194951 TI - An effective model for natural selection in promoters. AB - We have produced an evolutionary model for promoters, analogous to the commonly used synonymous/nonsynonymous mutation models for protein-coding sequences. Although our model, called Sunflower, relies on some simple assumptions, it captures enough of the biology of transcription factor action to show clear correlation with other biological features. Sunflower predicts a binding profile of transcription factors to DNA sequences, in which different factors compete for the same potential binding sites. The parametrized model simultaneously estimates a continuous measurement of binding occupancy across the genomic sequence for each factor. We can then introduce a localized mutation, rerun the binding model, and record the difference in binding profiles. A single mutation can alter interactions both upstream and downstream of its position due to potential overlapping binding sites, and our statistic captures this domino effect. Over evolutionary time, we observe a clear excess of low-scoring mutations fixed in promoters, consistent with most changes being neutral. However, this is not consistent across all promoters, and some promoters show more rapid divergence. This divergence often occurs in the presence of relatively constant protein coding divergence. Interestingly, different classes of promoters show different sensitivity to mutations, with phosphorylation-related genes having promoters inherently more sensitive to mutations than immune genes. Although there have previously been a number of models attempting to handle transcription factor binding, Sunflower provides a richer biological model, incorporating weak binding sites and the possibility of competition. The results show the first clear correlations between such a model and evolutionary processes. PMID- 20194953 TI - Natural history of concussion in sport: markers of severity and implications for management. AB - BACKGROUND: Evidence-based clinical data are required for safe return to play after concussion in sport. PURPOSE: The objective of this study was to describe the natural history of concussion in sport and identify clinical features associated with more severe concussive injury, using return-to-sport decisions as a surrogate measure of injury severity. STUDY DESIGN: Cohort study (prognosis); Level of evidence, 3. METHODS: Male elite senior, elite junior, and community based Australian Rules football players had preseason baseline cognitive testing (Digit Symbol Substitution Test, Trail-Making Test-Part B, and CogSport computerized test battery). Players were recruited into the study after a concussive injury sustained while playing football. Concussed players were tested serially until all clinical features of their injury had resolved. RESULTS: Of 1015 players, 88 concussions were observed in 78 players. Concussion-associated symptoms lasted an average of 48.6 hours (95% confidence interval, 39.5-57.7 hours) with delayed return to sport correlated with > or = 4 symptoms, headache lasting > or = 60 hours, or self-reported "fatigue/fogginess." Cognitive deficits using the Digit Symbol Substitution Test and Trail-Making Test-part B recovered concomitantly with symptoms, but computerized test results recovered 2 to 3 days later and remained impaired in 35% of concussed players after symptom resolution. CONCLUSION: Delayed return to sport was associated with initially greater symptom load, prolonged headache, or subjective concentration deficits. Cognitive testing recovery varied, taking 2 to 3 days longer for computerized tests, suggesting greater sensitivity to impairment. Therefore, symptom assessment alone may be predictive of but may underestimate time to complete recovery, which may be better estimated with computerized cognitive testing. PMID- 20194954 TI - Shoe-surface friction influences movement strategies during a sidestep cutting task: implications for anterior cruciate ligament injury risk. AB - BACKGROUND: Increasing the coefficient of friction of the shoe-surface interaction has been shown to lead to increased incidence of anterior cruciate ligament (ACL) injuries, but the causes for this increase are unknown. Previous studies indicate that specific biomechanical measures during landing are associated with an increased risk for ACL injury. HYPOTHESIS: At foot contact during a sidestep cutting task, subjects use different movement strategies for shoe-surface conditions with a high coefficient of friction (COF) relative to a low friction condition. Specifically, the study tested for significant differences in knee kinematics, external knee moments, and the position of the center of mass for different COFs. STUDY DESIGN: Controlled laboratory study. METHODS: Twenty-two healthy subjects (11 male) were evaluated performing a 30 degrees sidestep cutting task on a low friction surface (0.38) and a high friction surface (0.87) at a constant speed. An 8-camera markerless motion capture system combined with 2 force plates was used to measure full-body kinematics, kinetics, and center of mass. RESULTS: At foot contact, subjects had a lower knee flexion angle (P = .01), lower external knee flexion moment (P < .001), higher external knee valgus moment (P < .001), and greater medial distance of the center of mass from the support limb (P < .001) on the high friction surface relative to the low friction surface. CONCLUSION: The high COF shoe surface condition was associated with biomechanical conditions that can increase the risk of ACL injury. The higher incidence of ACL injury observed on high friction surfaces could be a result of these biomechanical changes. The differences in the biomechanical variables were the result of an anticipated stimulus due to different surface friction, with other conditions remaining constant. CLINICAL RELEVANCE: The risk analysis of ACL injury should consider the biomechanical movement changes that occur for a shoe-surface condition with high friction. PMID- 20194955 TI - Motion control shoe delays fatigue of shank muscles in runners with overpronating feet. AB - BACKGROUND: The motion control shoe is a well-developed technology in running shoe design for controlling excessive rearfoot pronation and plantar force distribution. However, there is little information on the leg muscle activation with different shoe conditions. HYPOTHESIS: The motion control shoe can prevent excessive shank muscle activation and delay fatigue. STUDY DESIGN: Controlled laboratory study. METHODS: Twenty female recreational runners with excessive rearfoot pronation were tested with running 10 km on a treadmill on 2 days. Participants wore either a motion control running shoe or neutral running shoe on each day. Activities of their right tibialis anterior and peroneus longus were recorded with surface electromyography. The normalized root-mean-square electromyography and median frequency were compared between the 2 shoe conditions. RESULTS: Significant positive correlations were found between the root-mean-square eletromyography and running mileage in both the tibialis anterior and peroneus longus in the neutral shoe condition (P <.001). The median frequency dropped in both shoe conditions with mileage, but paired t tests revealed a significantly larger drop in the neutral shoe (P < .001 for peroneus longus, P = .074 for tibialis anterior). CONCLUSION: The motion control shoe may facilitate a more stable activation pattern and higher fatigue resistance of the tibialis anterior and peroneus longus in individuals with excessive rearfoot pronation during running. CLINICAL RELEVANCE: The motion control shoe may increase the running endurance, thus reduce overuse injuries, in athletes with unstable feet during long-distance running. PMID- 20194956 TI - Early versus late start of isokinetic hamstring-strengthening exercise after anterior cruciate ligament reconstruction with patellar tendon graft. AB - BACKGROUND: Hamstring strengthening after anterior cruciate ligament reconstruction is a vital component of the rehabilitation program. PURPOSE: The objective of this trial was to investigate the effects of hamstring isokinetic training used in the early phase of the rehabilitation program on the stability, strength, symptoms, and functional outcomes of patients throughout 12 months after anterior cruciate ligament surgery. STUDY DESIGN: Randomized controlled clinical trial; Level of evidence, 2. METHODS: Forty-eight men underwent anterior cruciate ligament reconstruction with an ipsilateral bone-patellar tendon-bone autograft. The patients were randomly assigned to perform daily isokinetic hamstring exercises at postoperative 3 weeks (group I) or to perform daily isokinetic hamstring exercises at postoperative 9 weeks (group II). The patients were evaluated monthly for the first 4 months and at the 12th month for postoperative hamstring and quadriceps strength, as well as for knee function via the Cincinnati Knee Rating Scale and International Knee Documentation Committee form. RESULTS: Hamstring isometric strength at 30 degrees of knee flexion (at the first and second months) and concentric isokinetic strength (at 2, 3, 4, and 12 months) at the angular velocity of 60 deg/s were significantly (P <.05-.01) greater in group I compared with group II. Average scores of the Cincinnati Knee Rating Scale for symptoms were significantly (P <.05-.001) higher in group I compared with group II at all evaluation periods. Walking and stair-climbing scores at 1, 2, 3, and 4 months and squatting score at all evaluation periods were also better (P <.05-.01) in group I compared with group II. In addition, group I exhibited better (P <.01-.001) Lachman test results compared with group II for all postoperative evaluation periods. The International Knee Documentation Committee final rating scores were significantly (P <.01) greater at 2, 3, and 4 months in group I compared with group II. CONCLUSION: The results of this study suggest that hamstring as well as quadriceps strength can be increased via early hamstring strengthening after anterior cruciate ligament reconstruction with no negative impact on knee function. PMID- 20194957 TI - Is chemical incompatibility responsible for chondrocyte death induced by local anesthetics? AB - BACKGROUND: Chondrolysis associated with intra-articular administration of local anesthetics has been attributed to chondrocyte death induced by the local anesthetics. The mechanism of how the local anesthetics cause chondrocyte death is not clear. PURPOSE: This study was conducted to determine whether and how the local anesthetics cause chondrocyte death. STUDY DESIGN: Controlled laboratory study. METHODS: Bovine articular chondrocytes in suspension culture were treated for 1 hour with phosphate-buffered saline or phosphate-buffered saline/medium mixture (as controls); 1% lidocaine alone; 0.25% to 0.5% bupivacaine alone; phosphate-buffered saline with pH values of 4.5, 3.8, 3.4, and 2.4; or mixtures of the local anesthetics and cell culture medium or human synovial fluid. Chondrocyte viability was analyzed by flow cytometry using the LIVE/DEAD Viability/Cytotoxicity Kit. RESULTS: In 1% lidocaine-alone or 0.25% to 0.5% bupivacaine-alone groups, the rate of cell death was 11.8% to 13.3% of bovine articular chondrocytes, whereas the phosphate-buffered saline control had 8.4% of cell death. Increased chondrocyte death was only found when the pH value of phosphate-buffered saline dropped to < or = 3.4. In contrast, when bupivacaine was mixed with cell culture medium, needle-like crystals were formed, which was accompanied with 100% death of chondrocytes. Lidocaine did not form visible crystals when it was mixed with culture medium, but the mixtures caused death of over 96% of chondrocytes (P < .001). CONCLUSION: Less than 5% of chondrocyte death was attributable to the anesthetics when applied to the cells alone or in phosphate-buffered saline-diluted solution. Acidity (as low as pH 3.8) or epinephrine in the anesthetic solutions could not account for chondrocyte death. However, chemical incompatibility between the local anesthetics and cell culture medium or human synovial fluid may be the cause of chondrocyte death. CLINICAL RELEVANCE: Intra-articular administration of lidocaine and bupivacaine is not an indicated usage of either anesthetic, although such a usage has become a common practice. Physicians should be aware of the potential incompatibility of the drug and synovial fluid. PMID- 20194958 TI - Effect of humeral head defect size on glenohumeral stability: a cadaveric study of simulated Hill-Sachs defects. AB - BACKGROUND: Hill-Sachs lesions are often present with recurrent shoulder instability and may be a cause of failed Bankart repair. HYPOTHESIS: Glenohumeral joint stability decreases with increasingly larger humeral head defects. STUDY DESIGN: Descriptive laboratory study. METHODS: Humeral head defects, 1/8, 3/8, 5/8, and 7/8 of the humeral head radius, were created in 8 human cadaveric shoulders, simulating Hill-Sachs defects. Testing positions included 45 degrees and 90 degrees of abduction and 40 degrees of internal rotation, neutral, and 40 degrees of external rotation. Testing occurred at each defect size sequentially from smallest to largest for all abduction and rotation combinations. The humeral head was translated at 0.5 mm/s 45 degrees anteroinferiorly to the horizontal glenoid axis until dislocation. Distance to dislocation, defined as humeral head translation until it began to subluxate, was the primary outcome measure. RESULTS: Significant factors by ANOVA were rotation (P < .001) and defect size (P < .001). There was no difference for the 2 abduction angles. External rotation of 40 degrees significantly reduced distance to dislocation compared with neutral and 40 degrees internal rotation (P < .001). Osteotomies of 5/8 and 7/8 radius significantly decreased distance to dislocation over the intact state (P = .009 and P <.001, respectively). Post hoc analysis determined significant differences for the rotational positions. Decreased distance to dislocation occurred at 5/8 radius osteotomy at 40 degrees external rotation with 90 degrees of abduction (P = .008). For the 7/8 radius osteotomy at 90 degrees abduction, there was a decreased distance to dislocation for neutral and 40 degrees external rotation (P < .001); at 45 degrees abduction, there was a decreased distance to dislocation at 40 degrees external rotation (P <.001). With the humerus internally rotated, there was no significant change in distance to dislocation. CONCLUSION: Glenohumeral stability decreases at a 5/8 radius defect in external rotation and abduction. At 7/8 radius, there was a further decrease in stability at neutral and external rotation. CLINICAL RELEVANCE: Defects of 5/8 the humeral head radius may require treatment to decrease the failure rate of shoulder instability repair. PMID- 20194962 TI - Fast transcriptional responses to domestication in the brook charr Salvelinus fontinalis. AB - Domestication has been practiced for centuries yet directed toward relatively few terrestrial crops and animals. While phenotypic and quantitative genetic changes associated with domestication have been amply documented, little is known about the molecular changes underlying the phenotypic evolution during the process. Here, we have investigated the brook charr (Salvelinus fontinalis) responses to artificial selection by means of transcriptional analysis of approximately 32,000 cDNA features performed in both selected and control populations reared under identical environmental conditions during four generations. Our results indicate that selective breeding led to significant changes in the transcription of genes at the juvenile stage, where we observed 4.16% (156/3750) of differentially expressed genes between the two lines. No significant genes were revealed at the earlier life stage. Moreover, when comparing our results to those of previous studies on Atlantic salmon that compared lines that were selected for five to seven generations for similar traits (e.g., growth), genes with similar biological functions were found to be under selection in both studies. These observations indicate that (1) four generations of selection caused substantial changes in regulation of gene transcription between selected and control populations and (2) selective breeding for improving the same phenotypic traits (e.g., rapid growth) in brook charr and Atlantic salmon tended to select for the same changes in transcription profiles as the expression of a small and similar set of genes was affected by selection. PMID- 20194961 TI - Condensins promote coorientation of sister chromatids during meiosis I in budding yeast. AB - The condensin complex is a key determinant of higher-ordered chromosome structure. We show here that the complex is also important for the correct alignment of chromosomes on the meiosis I spindle. Unlike during mitosis and meiosis II, when sister chromatids attach to microtubules emanating from opposite spindle poles (biorientation), accurate meiosis I chromosome segregation requires that sister chromatids attach to microtubules emanating from the same spindle pole (co-orientation). The monopolin complex, consisting of Lrs4, Csm1, and the meiosis-specific component Mam1, brings about meiosis I co-orientation. We find that in the absence of functional condensin complexes, a fraction of sister kinetochores biorient on the meiosis I spindle and association of the monopolin complex subunit Mam1 with kinetochores is decreased. Our studies uncover a new locus-specific effect of the condensin complex. PMID- 20194963 TI - Transformation/transcription domain-associated protein (TRRAP)-mediated regulation of Wee1. AB - The G2 DNA damage checkpoint inhibits Cdc2 and mitotic entry through the dual regulation of Wee1 and Cdc25 by the Chk1 effector kinase. Upregulation of Chk1 by mutation or overexpression bypasses the requirement for upstream regulators or DNA damage to promote a G2 cell cycle arrest. We screened in fission yeast for mutations that rendered cells resistant to overexpressed chk1(+). We identified a mutation in tra1, which encodes one of two homologs of transformation/transcription domain-associated protein (TRRAP), an ATM/R-related pseudokinase that scaffolds several histone acetyltransferase (HAT) complexes. Inhibition of histone deacetylases reverts the resistance to overexpressed chk1(+), suggesting this phenotype is due to a HAT activity, although expression of checkpoint and cell cycle genes is not greatly affected. Cells with mutant or deleted tra1 activate Chk1 normally and are checkpoint proficient. However, these cells are semi-wee even when overexpressing chk1(+) and accumulate inactive Wee1 protein. The changed division response (Cdr) kinases Cdr1 and Cdr2 are negative regulators of Wee1, and we show that they are required for the Tra1-dependent alterations to Wee1 function. This identifies Tra1 as another component controlling the timing of entry into mitosis via Cdc2 activation. PMID- 20194964 TI - Quantitative trait locus mapping of genes under selection across multiple years and sites in Avena barbata: epistasis, pleiotropy, and genotype-by-environment interactions. AB - The genetic architecture of variation in evolutionary fitness determines the trajectory of adaptive change. We identified quantitative trait loci (QTL) affecting fitness in a mapping population of recombinant inbred lines (RILs) derived from a cross between moist- and dry- associated ecotypes of Avena barbata. We estimated fitness in 179 RILs in each of two natural environments in each of 4 years. Two loci account for over half of the variation in geometric mean fitness across environments. These loci are associated in repulsion phase in the wild ecotypes, suggesting the potential for strong transgressive segregation, but also show significant epistasis giving hybrid breakdown. This epistasis is the result of sharply lower fitness in only one of the recombinant genotypes, suggesting that the loci may contain synergistically acting mutations. Within each trial (year/site combination), we can explain less of the variation than for geometric mean fitness, but the two major loci are associated with variation in fitness in most environments. Tests for pleiotropic effects of QTL on fitness in different environments reveal that the same loci are under selection in all trials. Genotype-by-environment interactions are significant for some loci, but this reflects variation in the strength, not the direction of selection. PMID- 20194966 TI - The influence of horizontal gene transfer on the mean fitness of unicellular populations in static environments. AB - Horizontal gene transfer (HGT) is believed to be a major source of genetic variation, particularly for prokaryotes. It is believed that horizontal gene transfer plays a major role in shaping bacterial genomes and is also believed to be responsible for the relatively rapid dissemination and acquisition of new, adaptive traits across bacterial strains. Despite the importance of horizontal gene transfer as a major source of genetic variation, the bulk of research on theoretical evolutionary dynamics and population genetics has focused on point mutations (sometimes coupled with gene duplication events) as the main engine of genomic change. Here, we seek to specifically model HGT processes in bacterial cells, by developing a mathematical model describing the influence that conjugation-mediated HGT has on the mutation-selection balance in an asexually reproducing population of unicellular, prokaryotic organisms. It is assumed that mutation-selection balance is reached in the presence of a fixed background concentration of antibiotic, to which the population must become resistant to survive. We find that HGT has a nontrivial effect on the mean fitness of the population. However, one of the central results that emerge from our analysis is that, at mutation-selection balance, conjugation-mediated HGT has a slightly deleterious effect on the mean fitness of a population. Therefore, we conclude that HGT does not confer a selection advantage in static environments. Rather, its advantage must lie in its ability to promote faster adaptation in dynamic environments, an interpretation that is consistent with the observation that HGT can be promoted by environmental stresses on a population. PMID- 20194965 TI - The nucleosome remodeling factor ISWI functionally interacts with an evolutionarily conserved network of cellular factors. AB - ISWI is an evolutionarily conserved ATP-dependent chromatin remodeling factor playing central roles in DNA replication, RNA transcription, and chromosome organization. The variety of biological functions dependent on ISWI suggests that its activity could be highly regulated. Our group has previously isolated and characterized new cellular activities that positively regulate ISWI in Drosophila melanogaster. To identify factors that antagonize ISWI activity we developed a novel in vivo eye-based assay to screen for genetic suppressors of ISWI. Our screen revealed that ISWI interacts with an evolutionarily conserved network of cellular and nuclear factors that escaped previous genetic and biochemical analyses. PMID- 20194967 TI - SIAMESE cooperates with the CDH1-like protein CCS52A1 to establish endoreplication in Arabidopsis thaliana trichomes. AB - Endoreplication, also known as endoreduplication, is a phyogenetically widespread modified version of the cell cycle in which DNA replication is not followed by cell division. The SIAMESE (SIM) gene of Arabidopsis thaliana encodes the founding member of a novel class of plant-specific cyclin-dependent kinase (CDK) inhibitors and is a key regulator of endoreplication during the development of trichomes (shoot epidermal hairs). Here, we have identified mutations in the CCS52A1 gene as genetic modifiers of the multicellular trichome phenotype of sim mutants. Loss-of-function ccs52A1 mutations dramatically enhance the multicellularity of sim mutants trichomes in double mutants, whereas overexpression of CCS52A1 completely suppresses the sim mutant phenotype. CCS52A1 encodes a CDH1/FZR-like protein, a class of proteins that function as activators of the anaphase-promoting complex. Unicellular ccs52A1 trichomes become multicellular upon overexpression of B-type cyclin, consistent with repression of the accumulation of mitotic cyclins in the developing trichome by CCS52A1. As these M-phase-specific cyclins are known to accumulate in sim mutant trichomes, our data suggest that CCS52A1 and SIM cooperate in repressing accumulation of mitotic cyclins to establish the trichome endocycle. Comparison with endoreplication pathways in Drosophila and mammals indicates that while these organisms all use similar components to initiate endoreplication, the components are deployed differently in each organism. PMID- 20194969 TI - The child abuse we inflict through child obesity. PMID- 20194968 TI - The waved with open eyelids (woe) locus is a hypomorphic mouse mutation in Adam17. AB - The waved with open eyes (woe) locus is a spontaneous recessive mouse mutation that exhibits wavy fur, eyelids open at birth, and enlarged heart and esophagus. In this study, we confirmed the previously identified woe phenotypes and additionally identified anterior eye segment defects, absence of the meibomian glands, and defects in the semilunar cardiac valves. Positional cloning identified a C794T substitution in the Adam17 gene that ablates a putative exonic splicing enhancer (ESE) sequence in exon 7 resulting in aberrant Adam17 splicing. The predominant woe transcript, Adam17(Delta)(exon7), lacks exon 7 resulting in an in-frame deletion of 90 bp and a putative Adam17(Delta252-281) protein lacking residues 252-281 from the metalloprotease domain. Western blot analysis in woe identified only the precursor form of Adam17(Delta252-281) protein. Absence of cleavage of the prodomain renders Adam17(Delta252-281) functionally inactive; however, constitutive and stimulated shedding of Adam17 substrates was detected in woe at significantly reduced levels. This residual Adam17 shedding activity in woe most likely originates from full-length Adam17(T265M) encoded by the Adam17(C794T) transcript identified expressed at severely reduced levels. These results show that even small amounts of functional Adam17 allow woe mice to survive into adulthood. In contrast to Adam17(-/-) mice that die at birth, the viability of woe mice provides an excellent opportunity for studying the role of Adam17 throughout postnatal development and homeostasis. PMID- 20194970 TI - Health centers fill critical gap, enjoy support. PMID- 20194971 TI - Thomas Farley and sugary drinks campaign. PMID- 20194972 TI - National, state, and local disparities in childhood obesity. AB - New data from the 2007 National Survey of Children's Health show that the percentage of children ages 10-17 who are overweight (body mass index in the eighty-fifth to ninety-fourth percentiles) remained stable, while the national prevalence of obesity (BMI in the ninety-fifth percentile and higher) grew significantly, from 14.8 percent in 2003 to 16.4 percent in 2007. This increase in obesity accounted for the entire increase in the combined prevalence of overweight and obesity between 2003 and 2007 (from 30.6 percent to 31.6 percent). An estimated 10.58 million children, or nearly one in three children ages 10-17, were overweight or obese in 2007. Our findings suggest that the obesity epidemic among children may not yet have reached its plateau for some groups of children. The data also reveal persistent and highly variable disparities in childhood overweight and obesity within and among states, associated with socioeconomic status, school outcomes, neighborhoods, type of health insurance, and quality of care. This requires policy makers' attention nationally and within states. PMID- 20194973 TI - Reducing childhood obesity through policy change: acting now to prevent obesity. AB - Childhood obesity is epidemic in the United States, and is expected to increase the rates of many chronic diseases. Increasing physical activity and improving nutrition are keys to obesity prevention and control. But changing individual behavior is difficult. A comprehensive, coordinated strategy is needed. Policy interventions that make healthy dietary and activity choices easier are likely to achieve the greatest benefits. There is emerging evidence on how to address childhood obesity, but we must take action now to begin to reverse the epidemic. PMID- 20194974 TI - The economics of childhood obesity. AB - In the past few decades, obesity rates among American children have skyrocketed. Although many factors have played a part in this unhealthy increase, this paper focuses on how economic policies may be contributing to our children's growing girth and how these policies might be altered to reverse this trend. It examines the economic causes and consequences of obesity, the rationales for government intervention, the cost-effectiveness of various policies, and the need for more research funding. PMID- 20194975 TI - How much should we invest in preventing childhood obesity? AB - Policy makers generally agree that childhood obesity is a national problem. However, it is not always clear whether enough is being spent to combat it. This paper presents nine scenarios that assume three different degrees of reduction in obesity/overweight rates among children in three age groups. A mathematical model was then used to project lifetime health and economic gains. Spending $2 billion a year would be cost-effective if it reduced obesity among twelve-year-olds by one percentage point. The analysis also found that childhood obesity has more profound economic consequences than previously documented. Large investments to reduce this major contributor to adult disability may thus be cost-effective by widely accepted criteria. PMID- 20194976 TI - Personal responsibility and obesity: a constructive approach to a controversial issue. AB - The concept of personal responsibility has been central to social, legal, and political approaches to obesity. It evokes language of blame, weakness, and vice and is a leading basis for inadequate government efforts, given the importance of environmental conditions in explaining high rates of obesity. These environmental conditions can override individual physical and psychological regulatory systems that might otherwise stand in the way of weight gain and obesity, hence undermining personal responsibility, narrowing choices, and eroding personal freedoms. Personal responsibility can be embraced as a value by placing priority on legislative and regulatory actions such as improving school nutrition, menu labeling, altering industry marketing practices, and even such controversial measures as the use of food taxes that create healthier defaults, thus supporting responsible behavior and bridging the divide between views based on individualistic versus collective responsibility. PMID- 20194977 TI - Childhood obesity: the new tobacco. AB - Overcoming the childhood obesity epidemic will require changes on the scale of a social movement similar to the shift in attitudes and regulations toward smoking and tobacco. Tobacco control became a successful public health movement because of shifts in social norms and because cigarette companies came to be perceived by many as a common enemy. In contrast, obesity advocates have not identified a common threat or mobilized grass-roots change, nor have they identified strategies that resonate across diverse settings and constituencies. Framing obesity as a common threat can lead to consensus regarding the interventions needed to achieve healthier children and communities. PMID- 20194978 TI - The science of childhood obesity. AB - As scientists currently understand the phenomenon, widespread obesity represents an interaction of genes and the environment. Throughout human history, the ability to gain weight enabled humans to survive food shortages by tapping energy reserves stored in body fat. Today, an overabundance of calorie-rich foods enables calorie intakes that can overwhelm the body's weight-regulatory system. Genetic variation also makes some people more vulnerable than others to weight gain. Finally, there is a growing understanding of the deleterious biological and physiological consequences of accumulating too much fat. PMID- 20194979 TI - Trends in snacking among U.S. children. AB - Nationally representative surveys of food intake in U.S. children show large increases in snacking between the 1989-91 to 1994-98 and 1994-98 to 2003-06 periods. Childhood snacking trends are moving toward three snacks per day, and more than 27 percent of children's daily calories are coming from snacks. The largest increases have been in salty snacks and candy. Desserts and sweetened beverages remain the major sources of calories from snacks. PMID- 20194980 TI - Agricultural policy and childhood obesity: a food systems and public health commentary. AB - For thirty-five years, U.S. agriculture has operated under a "cheap food" policy that spurred production of a few commodity crops, not fruit or vegetables, and thus of the calories from them. A key driver of childhood obesity is the consumption of excess calories, many from inexpensive, nutrient-poor snacks, sweets, and sweetened beverages made with fats and sugars derived from these policy-supported crops. Limiting or eliminating farm subsidies to commodity farmers is wrongly perceived as a quick fix to a complex agricultural system, evolved over decades, that promotes obesity. Yet this paper does set forth a series of policy recommendations that could help, including managing commodity crop oversupply and supporting farmers who produce more fruit and vegetables to build a healthier, more balanced agricultural policy. PMID- 20194981 TI - Federal food policy and childhood obesity: a solution or part of the problem? AB - Amid growing concern about childhood obesity, the United States spends billions of dollars on food assistance: providing meals and subsidizing food purchases. We examine the relationship between food assistance and body mass index (BMI) for young, low-income children, who are a primary target population for federal food programs and for efforts to prevent childhood obesity. Our findings indicate that food assistance may unintentionally contribute to the childhood obesity problem in cities with high food prices. We also find that subsidized meals at school or day care are beneficial for children's weight status, and we argue that expanding access to subsidized meals may be the most effective tool to use in combating obesity in poor children. PMID- 20194982 TI - Predicting support for restricting food marketing to youth. AB - To address the obesity crisis, public health experts recommend major reductions in the marketing of unhealthy food to youth. However, policies to restrict food marketing are not currently viewed as politically feasible. This paper examines attitudes and knowledge about food marketing and support for restricting unhealthy food marketing [corrected] among one group of constituents: parents. A survey of 807 parents found that those most likely to support food marketing restrictions were also more likely to have negative views of current food practices. [corrected] These findings suggest that increased public education about the harm caused by food marketing may increase public support for policy interventions. PMID- 20194983 TI - Temptations in cyberspace: new battlefields in childhood obesity. AB - Proposed regulations targeting food marketing to children typically focus on traditional media, such as television, radio, and print ads. However, the widespread use of the Internet has promulgated novel food marketing strategies such as "advergaming," or the use of online games incorporating advertisements. In addition, the advent of so-called neuromarketing research is also allowing advertisers to appeal to the subconscious and emotional effects of food and beverage products, to which children may be particularly vulnerable. Current and future regulatory efforts should address the ubiquitous but often subtle marketing to which children are exposed and should measure success in terms of children's consumption of these products. PMID- 20194984 TI - Are 'competitive foods' sold at school making our children fat? AB - Almost one-third of American children and adolescents are now either overweight or obese. One contributing factor may be the foods and beverages sold outside of the U.S. Department of Agriculture (USDA) school meal programs, which are often called "competitive foods." These foods, such as cookies, chips, and sodas, are often available through vending machines, snack bars, and other outlets on school premises. They are not required to conform to the nutritional standards of the USDA school meal programs. This paper looks at the research into whether these competitive foods may be affecting students' dietary intake or contributing to their risk of obesity. PMID- 20194985 TI - 'Competitive' food and beverage policies: are they influencing childhood overweight trends? AB - We examined whether new policies restricting sales in schools of so-called competitive foods and beverages-those that fall outside of what is served through federally reimbursed school meal programs-influenced increasing rates of overweight children in the Los Angeles Unified School District and the rest of California. After these policies, which set stricter nutrition standards for certain food and beverages sold to students, took effect, the rate of increase in overweight children significantly diminished among fifth graders in Los Angeles and among fifth-grade boys and seventh graders in the rest of California. The extent to which the new nutritional policies contributed to the change is unclear. This is one of the first studies examining the postulated population level influence of recently implemented policies aimed at sales of competitive foods and beverages in schools. PMID- 20194986 TI - Lessons from Pennsylvania's mixed response to federal school wellness law. AB - Federal legislation aimed at tackling the nation's soaring childhood obesity rate through changes to school meals and nutrition and wellness programs has met with mixed results. An examination of Pennsylvania's response to the Child Nutrition and Women, Infants, and Children (WIC) Reauthorization Act of 2004, one of the most comprehensive state responses, found improvements to the nutritional quality of foods offered a la carte in conjunction with school meal programs. However, multiple weaknesses remain. Consistent wellness policy implementation steps were not followed, and there was inadequate statewide enforcement. Despite this, Pennsylvania can offer lessons for other states in moving forward with programs to promote good nutrition and wellness. PMID- 20194987 TI - Barriers to obesity prevention in Head Start. AB - Head Start provides early childhood education to nearly one million low-income children, through federal grants to more than 2,000 local programs. About one third of children who enter Head Start are overweight or obese. But program directors face difficulty in implementing policies and practices to address obesity-and in our national survey, they identified the key barriers as lack of time, money, and knowledge. Also, parents and staff sometimes shared cultural beliefs that were inconsistent with preventing obesity, such as the belief that heavier children are healthier. Minimizing those barriers will require federal resources to increase staff training and technical assistance, develop staff wellness programs, and provide healthy meals and snacks. PMID- 20194988 TI - Learning from state surveillance of childhood obesity. AB - Data on childhood obesity collected by the Centers for Disease Control and Prevention helped reveal the nation's epidemic of overweight and obese children. But more information is needed. Collecting body mass index (BMI)-the widely accepted measurement of childhood weight status-at the state and local levels can be instrumental in identifying and tracking obesity trends, designing interventions to help overweight children, and guiding broader policy solutions. Approximately thirty states have enacted or proposed BMI surveillance laws and regulations. Arkansas stands out as the state with the highest-quality surveillance data. Innovative strategies being pursued in a number of other states should be explored for broader dissemination. PMID- 20194989 TI - Policy solutions to the 'grocery gap'. AB - In 2001 the Food Trust, a nonprofit organization committed to ensuring access to affordable, nutritious food, focused attention on the lack of access to healthy foods in Philadelphia by creating food access maps and convening a task force. The campaign led to the creation of a statewide initiative that to date has funded seventy-eight fresh food outlets in Pennsylvania, increasing food access for 500,000 children and adults. This success has led to interest from other states and the federal government in expanding the initiative. Here we present the Food Trust's five-step framework for increasing access to fresh, healthy food in other locales. PMID- 20194990 TI - A statewide strategy to battle child obesity in Delaware. AB - In 2006, approximately 37 percent of Delaware's children were overweight or obese. To combat Delaware's childhood obesity epidemic, Nemours, a leading child health care provider, launched a statewide program to improve child health. The "social-ecological" strategy reaches beyond clinical encounters to promote better health and behavior at multiple levels. Early results show that the initiative halted the increase in the prevalence of overweight and obese children, since no statistically significant change occurred during the two-year span between administrations of the Delaware Survey on Children's Health. The initiative also spurred increased knowledge of healthy eating and awareness of the need for increased physical activity in school, child care, and primary care settings. PMID- 20194991 TI - Youngsters trade bagels and butter for cucumbers and carrots. PMID- 20194992 TI - Mapping data shape community responses to childhood obesity. AB - Geographic information system (GIS) mapping can help communities visualize the health of their neighborhoods and identify opportunities for improvement. In Austin, Texas, Children's Optimal Health, a nonprofit association, used GIS to map the prevalence of obesity among middle school children and to identify contributory factors. The maps indicated that obesity is a problem in all Austin middle schools. Two neighborhoods outside downtown Austin have particularly high concentrations of overweight and obese students. Maps also showed that the neighborhoods have different proportions of fast-food outlets, grocery stores selling fresh produce, green recreation space, and students failing cardiovascular testing. The mapping exercise spurred community groups to propose obesity interventions tailored to each neighborhood. PMID- 20194993 TI - Neighborhood socioeconomic conditions, built environments, and childhood obesity. AB - We examine the impact of neighborhood socioeconomic conditions and "built environments" on obesity and overweight prevalence among U.S. children and adolescents using the 2007 National Survey of Children's Health. The odds of a child's being obese or overweight were 20-60 percent higher among children in neighborhoods with the most unfavorable social conditions such as unsafe surroundings; poor housing; and no access to sidewalks, parks, and recreation centers than among children not facing such conditions. The effects were much greater for females and younger children; for example, girls ages 10-11 were two to four times more likely than their counterparts from more favorable neighborhoods to be overweight or obese. Our findings can contribute to policy decisions aimed at reducing health inequalities and promoting obesity prevention efforts such as community-based physical activity and healthy diet initiatives. PMID- 20194994 TI - Impact of childhood obesity on employers. AB - The impact of childhood obesity on the workplace is not well understood. A study conducted for one large employer indicated that average per capita health insurance claims costs were as high as $2,907 in 2008 for an obese child and $10,789 for a child with type II diabetes. The average claims cost for children with type II diabetes actually exceeded the level of the average claims cost for adults with type II diabetes ($8,844). This paper reviews the evidence on the impact of childhood obesity on employers and discusses opportunities for business engagement-including two current examples of activities involving employers. PMID- 20194995 TI - 'How much does Zozo weigh today'? PMID- 20194996 TI - The elephant in the exam room. PMID- 20194997 TI - Helping States enhance health care quality through technical assistance. AB - For the money spent on health care in the United States, far better quality of care should be expected. The Commonwealth Fund and AcademyHealth have created the State Quality Improvement Institute to assist states in implementing sustainable quality improvement strategies. Lessons have emerged about the role of states in advancing fundamental and systemic changes in the way care is delivered, as well as how providers are organized and compensated. The experiences of states participating in the institute may offer insights for other states seeking to achieve similar goals. PMID- 20194998 TI - Diagnostic imaging in physicians' offices. PMID- 20195000 TI - National initiatives in long-term care. PMID- 20195002 TI - Quality and value in orthopedic surgery. PMID- 20195003 TI - Drug patents in Guatemala. PMID- 20195005 TI - Work expectations, realizations, and depression in older workers. AB - AIMS OF THE STUDY: In this study, we explore whether ex ante work expectations, conditional on work force status at age 62, affect self-reported depressive symptoms at age 62. METHODS: Our sample includes 4,387 participants of the Health and Retirement Study, a national longitudinal survey of individuals born between 1931 and 1941, and their spouses. The sample is composed of workers who were less than 62 years of age at the study baseline (1992), and who had reached age 62 by the current study endpoint (2004). This sample enables comparison of realized work status with prior expectations. We estimate the impact of expected work status on self-reported depressive symptoms using negative binomial and logistic regression methods. Sex-stratified regressions are estimated according to full time work status at age 62. The primary outcome is a summary measure of self reported depressive symptoms based on a short form of the Center for Epidemiologic Studies-Depression (CES-D) scale. The explanatory variable of interest is the subjective probability of working full-time at the age of 62, reported by participants at the 1992 HRS baseline. We control for baseline socioeconomic and demographic variables as well as life events and changes in macroeconomic conditions that occur within the study timeframe. RESULTS: Among participants who were not working full time at age 62, we find that men who provided a higher ex ante likelihood of full-time employment at 62 had significantly worse self-reported depressive symptoms than men who provided a lower ex ante likelihood. A similar effect was not found for women. Among participants who were working full time at age 62, we do not find a statistical relationship between ex ante expectations and age-62 self-reported depressive symptoms, for either men or women. DISCUSSION: The results suggest that an earlier-than-anticipated work exit is detrimental to mental health for men nearing normal retirement age. Previous research has demonstrated that stress is a causal factor in depression, and a premature labor force departure, which is inconsistent with an individual's cognitive judgment of a suitably timed exit from work, is a psychologically stressful transition that could realistically induce depression. This may be especially true of men, who in this cohort, have stronger labor force attachment than women and tend to define their roles by their occupation. The advantages of the study include nationally representative data, a baseline depression control that circumscribes the effect of endogeneity, and a reasonably long follow-up. Despite our efforts to infer causality, unmeasured factors may account for part of the observed relationship. IMPLICATIONS FOR HEALTH POLICY AND RESEARCH: Depression is a disease that, if untreated, may have serious consequences for behavioral, medical, and social well being. Our results suggest that further research should aim to estimate the magnitude of clinically severe and mild depression in populations of those who retire earlier than expected, especially for men. Such information could help health care planners and policy makers to direct resources to the mental health needs of men who retire prematurely. PMID- 20195007 TI - Cost-effectiveness of a psychoeducational relapse prevention program for depression in primary care. AB - BACKGROUND: Major depression is a prevalent mental disorder with a high risk of relapses and recurrences, which are associated with considerable burden for patients and high costs for society. Despite these negative consequences, only few studies have focused on interventions aimed at the prevention of recurrences in primary care patients with depression. AIMS OF THE STUDY: To assess the cost effectiveness of a psychoeducational prevention program (PEP) aimed at improving the long-term outcome of depression in primary care. METHODS: Recruitment took place in the northern part of the Netherlands, patients were referred by general practitioners. In total 267 patients were included in the study and randomly assigned to usual care (UC) or UC with one of three forms of PEP; PEP alone, psychiatric consultation followed by PEP (psychiatrist-enhanced PEP), and cognitive behavioral therapy followed by PEP (CBT-enhanced PEP). Costs and health outcomes were registered at three month intervals during the 36 months follow-up of the study. Primary outcome measure was the proportion of depression-free time. RESULTS: Mean total costs during the 36 months of the study were 8200 euros in the UC group, 9816 euros in the PEP group, 9844 euros in the psychiatrist enhanced PEP group, and 9254 euros in the CBT-enhanced PEP group. Costs of productivity losses, hospital admissions, contacts with regional institutions for mental healthcare, and medication use contributed substantially to the total costs in each group. Results of the primary outcome measure were less positive for PEP than for UC, but slightly better in the enhanced PEP groups. If decision makers are willing to pay up to 300 euros for an additional proportion of depression-free time, UC is most likely to be the optimal intervention. For higher willingness to pay, CBT-enhanced PEP seems most efficient. DISCUSSION: The basic PEP intervention was not cost-effective in comparison with UC. The economic impact of productivity losses associated with depression, and the importance of including these costs in economic studies, was illustrated by the findings of this study. Due to the drop-out of patients during the 36 months follow-up period, economic analyses had to account for missing data, which may complicate the interpretation of the results. Although Quality-Adjusted Life Years (QALYs) could not be assessed for all the patients, the results of analyses focusing on QALYs supported the overall conclusion that PEP is not cost-effective. IMPLICATIONS FOR HEALTH CARE PROVISION AND POLICIES: Results indicated that PEP should not be implemented in the Dutch healthcare system. Furthermore, is seems highly unlikely that PEP could be cost-effective in other (comparable) European healthcare systems. IMPLICATIONS FOR FURTHER RESEARCH: The relatively positive economic results for CBT-enhanced PEP imply that UC enriched with CBT (but without PEP) might be cost-effective in preventing relapses in primary care patients with depression. The actual consequences of CBT for relapse prevention will have to be studied in further detail, both from a clinical and economic point of view. PMID- 20195006 TI - Cost of treating seriously mentally ill persons with HIV following highly active retroviral therapy (HAART). AB - BACKGROUND: Mounting evidence of high HIV prevalence rates among persons with serious mental illness underscores the importance of identifying and treating this population in order to prevent morbidity, mortality and the spread of the disease. Continual monitoring of services and costs is important for public health purposes to insure that persons with serious mental illness receive care for their HIV disorder that is at least comparable to those with HIV only and that the care is considered to be of equal quality. AIM OF STUDY: This current study examines 2003 Medicaid expenditures associated with the treatment of adults with both serious mental illness and HIV, compared to those with HIV and serious mental illness only. The degree to which the occurrences of co-morbid conditions affect overall expenditures is examined, providing the first published co morbidity expenditure ratios showing the additional cost burden associated with having these dual disorders. Also, changes in the composition of service costs for the co-morbid population are examined before and after the advent of newer antiretroviral and atypical antipsychotic medications. METHODS: Study participants were adult Medicaid recipients age 19-64 with serious mental illness and HIV receiving services from a large urban city program in 2003. The expenditures were derived from Medicaid claims records. Differences between groups were compared using Chi-square and ANOVA tests of significance. To determine the relative cost burden of having a co-morbid versus a single disorder, a co-morbidity expenditure ratio was constructed using the total expenditure per person of those with a co-morbid disorder compared to the total expenditures of those with SMI-only and HIV-only. In order to determine the relative change in inpatient, outpatient and pharmacy service costs, the composition of service costs in 1996 is compared to the service cost composition in 2003 using the share of total costs that each service contributes. RESULTS: In 2003, 788 persons with both SMI and HIV had the highest treatment expenditures at $23,842 per person followed by 2984 persons with HIV-only at $13,183, while the SMI-only group of 19,664 individuals was $11,860 per person. The comparison group had expenditures of $4,793 per person. The co-morbidity expenditure ratio in 2003 for the co-morbid population compared to the SMI-only group was 2.0 and 1.8 for the co-morbid population to the HIV-only population. Extensive redistribution of cost occurred between service categories in the co-morbid group between 1996 and 2003. The share of inpatient cost was reduced from 64% of total costs in 1996 to 30% of total cost in 2003. Conversely, the outpatient cost share increased from 17% of total costs in 1996 to 42% of total costs in 2003 as did the pharmacy share, which rose from 19% of total costs in 1996 to 27% of total costs in 2003. DISCUSSION: Consistent with previous studies, the co-morbid group is a costly population with respect to treatment, despite the fact that inpatient care has decreased. The co-morbidity expenditure analysis indicates little cost saving associated with treating individuals with the co-morbid conditions compared to the cost of treating either conditions separately. This may suggest a lack of coordination or effective care management in the current system warranting further investigation. Also, we find no difference in the percent of the co morbid population receiving HIV medication compared to the HIV population alone. This suggests that the co-morbid SMI population was being treated similarly to the HIV only group for their HIV disorders. Finally, though all groups had changes between 1996 and 2003 in the proportion of expenditures allocated to each of the service categories, the redistribution of cost between inpatient and outpatient care was the greatest in the co-morbid group. IMPLICATIONS FOR FUTURE RESEARCH: Although the study data suggests that individuals with both HIV and serious mental illness are receiving similar treatment for their HIV disorder as those with HIV alone, a concern that requires further investigation is the finding that HAART treatment is being used by less than 50% of the co-morbid and HIV only study population. Further investigation is required to determine the reason for the relatively low utilization of HAART medications in both HIV groups. Also, the use of a co-morbidity expenditure ratio offers a promising approach for comparing the cost burden associated with multiple disorders. PMID- 20195008 TI - Cost-effectiveness of integrated care for elderly depressed patients in the PRISM E study. AB - BACKGROUND: One proposed strategy to improve outcomes associated with depression and other behavioral health disorders in primary care settings is to strengthen collaboration between primary care and specialty mental health care through integrated care (IC). AIMS: We compare the cost-effectiveness of IC in primary care to enhanced specialty referral (ESR) for elders with behavioral health disorders from the Primary Care Research in Substance Abuse and Mental Health study, which was a randomized trial conducted between 2000 and 2002, using a societal perspective. METHODS: The IC model had a behavioral health professional co-located in the primary care setting, and the primary care provider continued involvement in the mental health/substance abuse care of the patient. The comparison model, enhanced specialty referral (ESR), required referral to a behavioral health provider outside the primary care setting, and the behavioral health provider had primary responsibility for the mental health/substance abuse needs of the patient. Costs and clinical outcomes for 840 elders with depression were analyzed using incremental cost-effectiveness ratios, the net benefits framework, cost-effectiveness planes, and acceptability curves. Outcomes were measured by the Center for Epidemiologic Studies Depression Scale (CES-D) and converted to depression-free days and Quality Adjusted Life Years (QALY). A variation on depression free days was proposed as an improvement on current methods. Separate analyses were conducted for Veteran's Affairs (n=365; n=175 in IC and n=190 in ESR) and non-Veteran's Affairs (n=475; n=242 in IC and n=233 in ESR) settings. RESULTS: ESR participants in the non-VA sample exhibited lower average CES-D scores (i.e., an improvement in depressive symptoms) than did IC participants (beta = 2.8, p < 0.01), no such difference was noted in the VA sample (p > 0.05). Mean costs were $D6,338 for VA IC participants; $7,007 for VA ESR participants; $3,657 for non-VA IC participants; and $3,673 for non-VA ESR participants. Although the cost-effectiveness planes suggest some uncertainty about the cost-effectiveness of the intervention, more than 75% of the bootstrap draws were considered cost-effective due to a decrease in total costs for IC in the full Veteran's Affairs sample. DISCUSSION: The findings indicate that IC is likely to be a cost-effective intervention in contrast with ESR in the Veteran's Affairs setting. In the non-Veteran's Affairs settings, IC is not a more cost effective intervention in comparison with ESR. In the VA setting, the greater clinical improvement associated with IC coupled with the variation in costs and outcomes were such that IC was determined to be more cost-effective than ESR with a probability of 73-80%. Among non-VA participants, the lower clinical outcomes combined with no discernable differences in costs translated with a low probability that IC was more cost-effective than ESR, at any of the estimated values of clinical improvements. This suggests the importance of clinical setting in determining the clinical and cost effectiveness of IC for mental health. LIMITATIONS: Our analyses were restricted to a six-month period, based on self report, and did not include societal costs related to lost productivity and future costs. IMPLICATIONS: These results suggest that general integration has its advantages and, when such integration exists, further integrating behavioral health care into primary care might be considered as one way to improve depression in elders. The finding that ESR may be cost effective in some settings is also policy relevant. Further research is needed to analyze the components of the costs of ESR in non-VA settings and the effectiveness of IC in VA settings. PMID- 20195009 TI - A study of the memory effects of metallic core-metal oxide shell nanocrystals by a micelle dipping technique. AB - With a simple and conformal metal nanocrystal dipping of synthesized micelles, nonvolatile memory characteristics originating from a metallic cobalt (Co) core nanocrystal (NC) surrounded by a Co-oxide shell are investigated in this study. From transmission electron microscopy (TEM) and x-ray photoelectron spectroscopy (XPS), it was confirmed that Co-oxide was made by oxygen plasma for polymer oxidation and that metallic Co wrapped with a Co-oxide shell was made by hydrogen annealing in order to reduce the Co-oxide. Energy band diagrams considering the extent of the coexistent metallic Co/Co-oxide were also analyzed in terms of how they correspond to each program/erase/retention case. These cases were verified by electrically measured data. These results can provide a guideline for the design and optimization of metal NC embedded memory. PMID- 20195010 TI - The nanostructure effect on the adhesion and growth rates of epithelial cells with well-defined nanoporous alumina substrates. AB - We systematically analyzed the adhesion and the proliferation of cells on various nanoporous alumina surfaces to understand the effects of nanostructured surfaces on cell behavior. Various nanoporous surfaces were fabricated using the anodizing method and characterized by atomic force microscopy and scanning electron microscopy. The adhesion rate and proliferation rate of cells as functions of pore size and depth were statistically investigated using a colorimetric method. The adhesion rate of cells was not affected by the depth of the nanoporous surface whereas the proliferation of cells dramatically increased when the aspect ratio of the nanopore was near unity. This phenomenon was further verified by comparing the change in roughness of the cytoplasmic layer of cells adhered on a nanoporous surface with that of a bare nanoporous surface. The proliferation of cells was also influenced by the pore size of the nanoporous surface because the nanostructure could control the interaction between extracellular matrix (ECM) molecules and the surface. In conclusion, the nanostructured surfaces affected cell adhesion and proliferation by increasing the surface area to which the cells could adhere, and the interactions between small ECM molecules were influenced by the sufficiently small structures of the nanosurface. PMID- 20195011 TI - The bending of single layer graphene sheets: the lattice versus continuum approach. AB - The out-of-plane bending behaviour of single layer graphene sheets (SLGSs) is investigated using a special equivalent atomistic-continuum model, where the C-C bonds are represented by deep shear bending and axial stretching beams and the graphene properties by a homogenization approach. SLGS models represented by circular and rectangular plates are subjected to linear and nonlinear geometric point loading, similar to what is induced by an atomic force microscope (AFM) tip. The graphene models are developed using both a lattice and a continuum finite element discretization of the partial differential equations describing the mechanics of the graphene. The minimization of the potential energy allows us to identify the thickness, elastic parameters and force/displacement histories of the plates, in good agreement with other molecular dynamic (MD) and experimental results. We note a substantial equivalence of the linear elastic mechanical properties exhibited by circular and rectangular sheets, while some differences in the nonlinear geometric elastic regime for the two geometrical configurations are observed. Enhanced flexibility of SLGSs is observed by comparing the nondimensional force versus displacement relations derived in this work and the analogous ones related to equivalent plates with conventional isotropic materials. PMID- 20195012 TI - Bifacial dye-sensitized solar cells based on vertically oriented TiO2 nanotube arrays. AB - In this work we describe a novel bifacial design concept for dye-sensitized solar cells (DSCs). Bifacial DSCs are fabricated with ruthenium complex chemisorbed double-sided TiO(2) nanotube arrays on a Ti metal substrate, in combination with two electron-collecting counter electrodes. Our investigation shows that the present bifacial DSCs have similar conversion efficiencies when illuminated from either their front or rear side, and a summated output power when illuminated on both sides. Furthermore, this type of bifacial DSC is also able to summate the output power of each side when working at an 'unsymmetrical' mode, in which much different output powers are generated by the front and rear sides. Therefore, this bifacial design concept exhibits a promising potential to reduce the cost of solar electricity when DSCs are operated at a location where a high albedo radiation is available. PMID- 20195013 TI - Focused ion beam-assisted manipulation of single and double beta-SiC nanowires and their thermal conductivity measurements by the four-point-probe 3-omega method. AB - Control of one-dimensional (1D) nanostructures is demonstrated in this paper by selectively placing and aligning silicon carbide (beta-SiC) nanowires (NWs). We developed a reliable and highly reproducible way of placing a single or double SiC NW on pre-patterned electrodes by using a focused ion beam and a nanomanipulator. 3-omega signals obtained by the four-point-probe method were used in measuring the thermal conductivity of the NWs. The thermal conductivities of the placed single and double beta-SiC NWs were obtained at 82 +/- 6 W mK( - 1) and 73 +/- 5 W mK( - 1), respectively. The proposed technique offers new possibilities for manipulating and evaluating 1D nanoscale materials. PMID- 20195014 TI - Nanoscale sharpening tips of vapor-liquid-solid grown silicon microwire arrays. AB - We developed out-of-plane, high aspect ratio, nanoscale tip silicon microwire arrays for application to penetrating, multisite, nanoscale biological sensors. Silicon microwire arrays selectively grown by gold-catalyzed vapor-liquid-solid growth of silicon can be formed to create sharpened nanotips with a tip diameter of less than 100 nm by utilizing batch-processed silicon chemical etching for only 1-3 min. The tip angles achieved ranged from 11 degrees to 38 degrees. The nanotip silicon microwires can perform gelatin penetration without wire breakdown, indicating their potential penetrating capability for measurements inside biological tissues. PMID- 20195015 TI - Highly biocompatible and water-dispersible, amine functionalized magnetite nanoparticles, prepared by a low temperature, air-assisted polyol process: a new platform for bio-separation and diagnostics. AB - A low temperature polyol process, based on glycolaldehyde mediated partial reduction of FeCl(3).6H(2)O at 120 degrees C in the presence of sodium acetate as an alkali source and 2, 2(')-(ethylenedioxy)-bis-(ethylamine) as an electrostatic stabilizer has been used for the gram-scale preparation of biocompatible, water dispersible, amine functionalized magnetite nanoparticles (MNPs) with an average diameter of 6 +/- 0.75 nm. With a reasonably high magnetization (37.8 e.m.u.) and amine groups on the outer surface of the nanoparticles, we demonstrated the magnetic separation and concentration implications of these ultrasmall particles in immunoassay. MRI studies indicated that these nanoparticles had the desired relaxivity for T(2) contrast enhancement in vivo. In vitro biocompatibility, cell uptake and MR imaging studies established that these nanoparticles were safe in clinical dosages and by virtue of their ultrasmall sizes and positively charged surfaces could be easily internalized by cancer cells. All these positive attributes make these functional nanoparticles a promising platform for further in vitro and in vivo evaluations. PMID- 20195016 TI - Magnification of photonic crystal fluorescence enhancement via TM resonance excitation and TE resonance extraction on a dielectric nanorod surface. AB - Using a one-dimensional grating surface photonic crystal (PC), we experimentally demonstrate that the detection of fluorescent molecules on a PC surface can be substantially magnified through the combined effects of resonance-enhanced excitation of the fluorescent dye, resonance-enhanced extraction of the fluorescence emission and a dielectric nanorod surface coating increasing the surface area available for fluorophore-PC interaction. Enhanced excitation is obtained by engineering a high-Q TM resonant mode to efficiently couple with an incident TM-polarized lambda = 633 nm laser for exciting Cyanine-5 (Cy5). Enhanced extraction results from a low-Q TE resonance designed to spectrally overlap the Cy5 emission spectrum for channeling TE-polarized emission towards the detection instrument. The entire PC surface is coated with a porous film of TiO(2) nanorods that allows more fluorophores to penetrate into the region of enhanced near-electric fields. Experimental results reveal a 588-fold enhancement in fluorescence intensity relative to an unpatterned glass surface. PMID- 20195017 TI - Crossover behavior in the hydrogen sensing mechanism for palladium ultrathin films. AB - Palladium has been extensively studied as a material for hydrogen sensors because of the simplicity of its reversible resistance change when exposed to hydrogen gas. Various palladium films and nanostructures have been used, and different responses have been observed with these diverse morphologies. In some cases, such as with nanowires, the resistance will decrease, whereas in others, such as with thick films, the resistance will increase. Each of these mechanisms has been explored for several palladium structures, but the crossover between them has not been systematically investigated. Here we report on a study aimed at deciphering the nanostructure-property relationships of ultrathin palladium films used as hydrogen gas sensors. The crossover in these films is observed at a thickness of approximately 5 nm. Ramifications for future sensor developments are discussed. PMID- 20195018 TI - The effect of intertube van der Waals interaction on the stability of pristine and functionalized carbon nanotubes under compression. AB - This paper investigates the effect of intertube van der Waals interaction on the stability of pristine and covalently functionalized carbon nanotubes under axial compression, using molecular mechanics simulations. After regulating the number of inner layers of the armchair four-walled (5, 5)@(10, 10)@(15, 15)@(20, 20) and zigzag four-walled (6, 0)@(15, 0)@(24, 0)@(33, 0) carbon nanotubes, the critical buckling strains of the corresponding tubes are calculated. The results show that each of the three inner layers in the functionalized armchair nanotube noticeably contributes to the stability of the outermost tube, and together increase the critical strain amplitude by 155%. However, the three inner layers in the corresponding pristine nanotube, taken together, increase the critical strain of the outermost tube by only 23%. In addition, for both the pristine and functionalized zigzag nanotubes, only the (24, 0) layer, among the three inner layers, contributes to the critical strain of the corresponding outermost tube, by 11% and 29%, respectively. The underlying mechanism of the enhanced stability related to nanotube chirality and functionalization is analyzed in detail. PMID- 20195020 TI - Three-dimensional scapular and clavicular kinematics and scapular muscle activity during retraction exercises. AB - STUDY DESIGN: Controlled laboratory study. OBJECTIVES: To describe and compare scapular and clavicular kinematics and muscle activity during 6 retraction exercises in young healthy adults (mean +/- SD age, 23.2 +/- 2.4 years). BACKGROUND: Based on the association between shoulder injuries and scapular/clavicular movement, muscle activity during various exercises that target muscles surrounding the scapula have been investigated. However, the scapular and clavicular movements occurring during these exercises remain uninvestigated. Evaluation of the scapular and clavicular kinematics in addition to muscle activity provides additional information that allow clinicians to select exercises that best meet the patient's needs. METHODS: Three-dimensional scapular and clavicular kinematics and scapular muscle activity data were collected while the participants performed 6 scapular retraction exercises. One way repeated-measures ANOVA and post hoc analyses were used to determine differences in scapular/clavicular kinematics and activation levels of the upper, middle, and lower trapezius and serratus anterior muscles occurring during the exercises. RESULTS: The general pattern of the kinematics observed during all retraction exercises was scapular external rotation, scapular upward rotation, scapular posterior tilting, clavicular retraction, and clavicular depression. However, the exercises resulted in varying amounts of scapular movement and muscle activity. CONCLUSION: Clinicians can select appropriate exercises for their patients based on their need to strengthen specific retractor muscles and to improve specific scapular and clavicular movement patterns, pre-existing conditions, and available range of motion. PMID- 20195019 TI - Time line for noncopers to pass return-to-sports criteria after anterior cruciate ligament reconstruction. AB - STUDY DESIGN: Randomized clinical trial. OBJECTIVES: Determine effective interventions for improving readiness to return to sports postoperatively in patients with complete, unilateral, anterior cruciate ligament (ACL) rupture who do not compensate well after the injury (noncopers). Specifically, we compared the effects of 2 preoperative interventions on quadriceps strength and functional outcomes. BACKGROUND: The percentage of athletes who return to sports after ACL reconstruction varies considerably, possibly due to differential responses after acute ACL rupture and different management. Prognostic data for noncopers following ACL reconstruction is absent in the literature. METHODS: Forty noncopers were randomly assigned to receive either progressive quadriceps strength-training exercises (STR group) or perturbation training in conjunction with strength-training exercises (PERT group) for 10 preoperative rehabilitation sessions. Postoperative rehabilitation was similar between groups. Data on quadriceps strength indices [(involved limb/uninvolved limb force) x 100], 4 hop score indices, and 2 self-report questionnaires were collected preoperatively and 3, 6, and 12 months postoperatively. Mann-Whitney U tests were used to compare functional differences between the groups. Chi-square tests were used to compare frequencies of passing functional criteria and reasons for differences in performance between groups postoperatively. RESULTS: Functional outcomes were not different between groups, except a greater number of patients in the PERT group achieved global rating scores (current knee function expressed as a percentage of overall knee function prior to injury) necessary to pass return-to-sports criteria 6 and 12 months after surgery. Mean scores for each functional outcome met return-to-sports criteria 6 and 12 months postoperatively. Frequency counts of individual data, however, indicated that 5% of noncopers passed RTS criteria at 3, 48% at 6, and 78% at 12 months after surgery. CONCLUSION: Functional outcomes suggest that a subgroup of noncopers require additional supervised rehabilitation to pass stringent criteria to return to sports. LEVEL OF EVIDENCE: Therapy, level 2b.Note: If watching the first video, we recommend downloading and referring to the accompanying PowerPoint slides for any text that is not readable. PMID- 20195021 TI - Attentional demands and postural control in athletes with and without functional ankle instability. AB - STUDY DESIGN: Case-control study. OBJECTIVE: To compare the effect of dual tasking on postural and cognitive performance between subjects with functional ankle instability (FAI) and a matched control group without FAI. BACKGROUND: Deficit and expertise in sensorimotor functions have been proposed as factors that can modify the interference between postural control and cognition. To the authors' knowledge, no study has investigated the posture-cognition interaction in individuals with recurrent ankle sprain, an orthopaedic condition with documented sensorimotor deficits. METHODS: Single-limb postural stability was assessed in 15 recreational athletes with FAI and 15 matched healthy athletes without FAI. Each athlete stood on a Biodex Stability System at platform stabilities of 7 and 5, while they performed or did not perform a digits-backward cognitive task. Overall stability index (OSI), anteroposterior stability index (APSI), and mediolateral stability index (MLSI) were used as measures of postural performance. RESULTS: At stability level 5, the individuals in the FAI group had poorer postural stability compared to those in the group without FAI (OSI, P<.01; MLSI, P<.01). A significant increase in OSI (P<.01) and MLSI (P = .02) was also demonstrated by the individuals in the FAI group during dual-task performance compared to the single-task performance. CONCLUSION: Subjects with FAI demonstrated poorer postural stability when tested at level 5 on the Biodex Stability System, but not at level 7. Also, the results indicate that concurrent performance of a cognitive task decreased postural stability in the subjects with FAI, suggesting an increased dependency on attentional demands for maintenance of balance in that group. Such findings highlight the need for the assessment of postural control in patients with ankle sprain to include cognitive loading. PMID- 20195022 TI - The American Society of Shoulder and Elbow Therapists' consensus rehabilitation guideline for arthroscopic anterior capsulolabral repair of the shoulder. AB - SYNOPSIS: This manuscript describes the consensus rehabilitation guideline developed by the American Society of Shoulder and Elbow Therapists. The purpose of this guideline is to facilitate clinical decision making during the rehabilitation of patients following arthroscopic anterior capsulolabral repair of the shoulder. This guideline is centered on the principle of the gradual application of stress to the healing capsulolabral repair through appropriate integration of range of motion, strengthening, and shoulder girdle stabilization exercises during rehabilitation and daily activities. Components of this guideline include a 0- to 4-week period of absolute immobilization, a staged recovery of full range of motion over a 3-month period, a strengthening progression beginning at postoperative week 6, and a functional progression for return to athletic or demanding work activities between postoperative months 4 and 6. This document represents the first consensus rehabilitation guideline developed by a multidisciplinary society of international rehabilitation professionals specifically for the postoperative care of patients following arthroscopic anterior capsulolabral repair of the shoulder. PMID- 20195023 TI - The addition of cervical thrust manipulations to a manual physical therapy approach in patients treated for mechanical neck pain: a secondary analysis. AB - STUDY DESIGN: Secondary analysis of a randomized clinical trial (RCT). OBJECTIVES: To perform a secondary analysis on the treatment arm of a larger RCT to determine differences in treatment outcomes, adverse reactions, and effect sizes between patients who received cervical thrust manipulation and those who received only nonthrust manipulation as part of an impairment-based, multimodal treatment program of manual physical therapy (MPT) and exercise for patients with mechanical neck pain. BACKGROUND: A treatment regimen of MPT and exercise has been effective in patients with mechanical neck pain. Limited research has compared the effectiveness of cervical thrust manipulations and nonthrust mobilizations for this patient population, and no studies have investigated the added benefit of cervical thrust manipulations as part of an overall MPT treatment plan. METHODS: Treatment outcomes from 47 patients in the treatment arm of a larger RCT, with a primary complaint of mechanical neck pain, were analyzed. Twenty-three patients (49%) received cervical thrust manipulations as part of their MPT treatment, and 24 patients (51%) received only cervical nonthrust mobilizations. All patients received up to 6 clinic sessions, twice weekly for 3 weeks, and a home exercise program. Primary outcome measures were the Neck Disability Index (NDI), 2 visual analog scales for cervical and upper extremity pain, and a 15-point global rating of change scale. Blinded outcome measurements were collected at baseline and at 3-, 6- and 52-week follow-ups. RESULTS: Consistent with the larger RCT, both subgroups in this secondary analysis demonstrated improvement in short- and long-term pain and disability scores. Low statistical power (beta< or =.28) and the resultant small effect size indices ( 0.21 to 0.17) preclude the identification of any between-group differences. No serious adverse reactions were reported by patients in either subgroup. CONCLUSIONS: Clinically meaningful and statistically significant improvements in both subgroups of patients over time suggest that cervical thrust manipulation, as part of the MPT treatment plan, did not influence the results of the treatment arm of the larger RCT from which this study was drawn. Although no between-group differences can be identified, the small observed effect sizes in this study may benefit future studies with sample size estimation for larger RCTs and indicate the need to incorporate clinical prediction rule criteria as a means to improve statistical power. LEVEL OF EVIDENCE: Therapy, level 4. PMID- 20195024 TI - Physiotherapist classifiers ensure competitive fair play in para-archery. AB - Over the past 30 years, physiotherapists have played an important role in the continuous refinement of the classification system related to sports participation for athletes with disabilities. This guest editorial is intended to provide a brief history of this evolution, an evolution that in many respects has shifted the focus away from the medical diagnosis to concerns related more to the impact of a disease or condition on the person's function and overall health. PMID- 20195025 TI - Extreme skeletal adaptation to mechanical loading. PMID- 20195026 TI - Diagnostic imaging following cervical spine injury. PMID- 20195028 TI - Patellofemoral pain syndrome: proximal, distal, and local factors, an international retreat, April 30-May 2, 2009, Fells Point, Baltimore, MD. PMID- 20195030 TI - Masters theses from a university medical college: publication in indexed scientific journals. AB - BACKGROUND: The thesis is an integral part of postgraduate medical education in India. Publication of the results of the thesis in an indexed journal is desirable; it validates the research and makes results available to researchers worldwide. AIMS: To determine publication rates in indexed journals, of works derived from theses, and factors affecting publication. SETTINGS AND DESIGN: Postgraduate theses submitted over a five-year period (2001-05) in a university medical college were analyzed in a retrospective, observational study. MATERIALS AND METHODS: Data retrieved included name and gender of postgraduate student, names, department and hierarchy of supervisor and co-supervisor(s), year submitted, study design, sample size, and statistically significant difference between groups. To determine subsequent publication in an indexed journal, Medline search was performed up to December 2007. STATISTICAL ANALYSIS: Chi square test was used to compare publication rates based on categorical variables; Student's t-test was used to compare differences based on continuous variables. RESULTS: One hundred and sixty theses were retrieved, forty-eight (30%) were published. Papers were published 8-74 (33.7+/-17.33) months after thesis submission; the postgraduate student was first author in papers from 26 (54%) of the published theses. Gender of the student, department of origin, year of thesis submission, hierarchy of the supervisor, number and department of co-supervisors, and thesis characteristics did not influence publication rates. CONCLUSIONS: Rate of publication in indexed journals, of papers derived from postgraduate theses is 30%. In this study we were unable to identify factors that promote publication. PMID- 20195031 TI - Peribulbar anesthesia for cataract surgery: effect of lidocaine warming and alkalinization on injection pain, motor and sensory nerve blockade. AB - AIM: To compare self-reported pain and efficacy of warmed, alkalinized, and warmed alkalinized lidocaine with plain 2% lidocaine at room temperature for peribulbar anesthesia in cataract surgery. MATERIALS AND METHODS: Through a prospective, single-blinded, randomized, controlled clinical trial 200 patients were divided into four groups. They received either lidocaine at operating room temperature 18 degrees C, control group (Group C), lidocaine warmed to 37 degrees C (Group W), lidocaine alkalinized to a pH of 7.09+/-0.10 (Group B) or lidocaine at 37 degrees C alkalinized to a pH of 6.94+/-0.05 (Group WB). All solutions contained Inj. Hyaluronidase 50 IU/ml. Pain was assessed using a 10-cm visual analog score scale. Time of onset of sensory and motor blockade and time to onset of postoperative pain were recorded by a blinded observer. RESULTS: Mean pain score was significantly lower in Group B and WB compared with Group C (P<0.001). Onset of analgesia was delayed in Group C compared with Group B (P=0.021) and WB (P<0.001). Mean time taken for the onset of complete akinesia and supplementation required for the block was significantly lower in Group B. Time of onset of pain after operation was significantly earlier in Group W compared with Group C (P=0.036). CONCLUSION: Alkalinized lidocaine with or without warming produced less pain than lidocaine injected at room temperature. Alkalinization enhances the effect of warming for sensory nerve blockade, but warming does not enhance alkalinization, in fact it reduces the efficacy of alkalinized solution for blocking the motor nerves in the eye. PMID- 20195032 TI - Wavefront analysis and modulation transfer function of three multifocal intraocular lenses. AB - PURPOSE: To evaluate wavefront performance and modulation transfer function (MTF) in the human eye after the implantation of diffractive or refractive multifocal intraocular lenses (IOLs). MATERIALS AND METHODS: This was a prospective, interventional, comparative, nonrandomized clinical study. Uncorrected distance and near visual acuity, and wavefront analysis including MTF curves (iTrace aberrometer, Tracey Technologies, Houston, TX, USA) were measured in 60 patients after bilateral IOL implantation with 6 months of follow-up. Forty eyes received the diffractive ReSTOR (Alcon), 40 eyes received the refractive ReZoom (Advanced Medical Optics) and 40 eyes, the Tecnis ZM900 (Advanced Medical Optics). The comparison of MTF and aberration between the intraocular lenses was performed using analysis of variance (ANOVA), followed by the Dunn test when necessary. RESULTS: The mean uncorrected distance visual acuity was similar in all three groups of multifocal IOLs. The ReSTOR group provided better uncorrected near visual acuity than the ReZoom group (P<0.001), but similar to the Tecnis group. Spherical aberration was significantly higher in the ReZoom group (P=0.007). Similar MTF curves were found for the aspheric multifocal IOL Tecnis and the spheric multifocal IOL ReSTOR, and both performed better than the multifocal IOL ReZoom in a 5 mm pupil (P<0.001 at all spatial frequencies). CONCLUSIONS: Diffractive IOLs studied presented similar MTF curves for a 5 mm pupil diameter. Both diffractive IOLs showed similar spherical aberration, which was significantly better with the full-diffractive IOL Tecnis than with the refractive IOL ReZoom. PMID- 20195033 TI - Visual outcome of pars plana vitrectomy with intraocular foreign body removal through sclerocorneal tunnel and sulcus-fixated intraocular lens implantation as a single procedure, in cases of metallic intraocular foreign body with traumatic cataract. AB - AIM: To evaluate visual outcome following pars plana vitrectomy (PPV) and intraocular foreign body (IOFB) removal through the sclerocorneal tunnel combined with simultaneous cataract extraction and sulcus-fixated intraocular lens (IOL) implantation as a single procedure in penetrating ocular trauma with IOFB and traumatic cataract. MATERIALS AND METHODS: Eighteen cases of penetrating ocular trauma with retained IOFB and traumatic cataract who underwent PPV, IOFB body removal and cataract extraction with posterior chamber IOL (PCIOL) implantation in the same sitting, between June '04 and December '05 were retrospectively analyzed. All the foreign bodies were removed through the sclerocorneal tunnel. RESULT: All the 18 patients were young males, with an average follow-up period of 12 months. In 12 cases the foreign body was intravitreal and in six cases it was intraretinal but extramacular. Thirteen cases had a best corrected visual acuity ranging from 20/20 to 20/60 at their last follow-up. Five cases developed retinal detachment due to proliferative vitreoretinopathy (PVR) changes postoperatively and were subsequently managed by surgery. CONCLUSION: Primary IOL implantation with combined cataract and vitreo-retinal surgery is a safe option reducing the need for two separate surgeries in selected patients with retained IOFB and traumatic cataract. This combined procedure provides good visual outcome with early rehabilitation in young working patients. PMID- 20195034 TI - Coats' disease: an Indian perspective. AB - AIM: To describe the clinical features, treatment and outcome patterns in 307 eyes with Coats' disease. MATERIALS AND METHODS: Retrospective chart review of patients diagnosed with Coats' disease between January 1996 and January 2006 from a single referral center in southern India. RESULTS: Two hundred and eighty patients (307 eyes) with mean age of 15.67 years (range: Four months-80 years) were included. Decreased vision (77%), unilateral affection (90%) and male preponderance (83.4%) were chief presenting features. Anterior segment involvement was seen in 67 (21.8%) eyes. Retinal telangiectasia were seen in 302 (99%) eyes, exudation in 274 (89%) eyes and retinal detachment in 158 (51.5%) eyes. Four-quadrant disease was seen in 207 (67.2%) eyes. Visual acuity was <20/200 in 249 (80.9%) eyes. One hundred and nine of 176 treated eyes (61.93%) had favorable anatomical outcome; 207 of 280 eyes (74%) had an optimal structural outcome. Seventeen (5.3%) eyes were enucleated. Complications following treatment included phthisis bulbi (7%), neovascular glaucoma (5%), epiretinal membrane (4.4%) and rubeosis iridis (4.4%). CONCLUSION: Indian patients with Coats' disease have a high male predominance, the majority of whom present with severe visual impairment and extensive four-quadrant exudation. Unusual presentations such as pain, vitreous hemorrhage and a high incidence of anterior segment involvement are distinctive to Indian eyes. PMID- 20195035 TI - Multiple transfused thalassemia major: ocular manifestations in a hospital-based population. AB - PURPOSE: To study the ocular manifestations in multiple transfused beta thalassemia major patients and assess the ocular side-effects of iron chelating agents. MATERIALS AND METHODS: In this prospective observational study, 45 multiple transfused beta-thalassemia major children between six months and 21 years of age were enrolled and assigned groups according to the treatment regimens suggested. Group A received only blood transfusions, Group B blood transfusions with subcutaneous desferrioxamine, Group C blood transfusions with desferrioxamine and oral deferriprone and Group D blood transfusions with deferriprone. Ocular status at the time of enrolment was documented. Subjects were observed quarterly for one year for changes in ocular status arising due to the disease process and due to iron chelation therapy. Children with hemoglobinopathies other than beta-thalassemia major, congenital ocular anomalies and anemia due to other causes were excluded. RESULTS: Ocular involvement was observed in 58% of patients. Lenticular opacities were the most common ocular finding (44%), followed by decreased visual acuity (33%). An increased occurrence of ocular changes was observed with increase of serum ferritin and serum iron levels as well as with higher number of blood transfusions received. Desferrioxamine seemed to have a protective influence on retinal pigment epithelium (RPE) mottling. Occurrence of lenticular opacities and RPE degeneration correlated positively with use of desferrioxamine and deferriprone respectively. Follow-up of patients for one year did not reveal any change in ocular status. CONCLUSION: Regular ocular examinations can aid in preventing, delaying or ameliorating the ocular complications of thalassemia. PMID- 20195036 TI - Quantitative analysis of the Stratus optical coherence tomography fast macular thickness map reports. AB - The cross sectional optical coherence tomography images have an important role in evaluating retinal diseases. The reports generated by the Stratus fast macular thickness scan protocol are useful for both clinical and research purposes. The centerpoint thickness is an important outcome measure for many therapeutic trials related to macular disease. The data is susceptible to artifacts such as decentration and boundary line errors and could be potentially erroneous. An understanding of how the data is generated is essential before utilizing the data. This article describes the interpretation of the fast macular thickness map report, assessment of the quality of an optical coherence tomography image and identification of the artifacts that could influence the numeric data. PMID- 20195037 TI - Community rehabilitation of disabled with a focus on blind persons: Indian perspective. AB - India, the largest democratic country in the world, is marching ahead strongly on the growth and developmental front and is poised to be the leader in the market economy. This role creates and increases far greater responsibilities on us in ensuring that the benefit of the developmental cycle reaches each and every citizen of this country, including the able and the disabled ones. It has been enshrined in the Constitution of India to ensure equality, freedom, justice, and dignity of all individuals and implicitly mandates an inclusive society. With increase in consideration of quality parameters in all spheres of life including availability, access, and provision of comprehensive services to the disabled, it is pertinent to have a look on the contribution of government in keeping the aspiration and commitment towards common people. The article attempts to review the concept of rehabilitation for the disabled keeping a focus on the blind person, and list out the activities, programs/schemes, institutional structure and initiatives taken by the Government of India (GOI) for the same and the incentives/benefits extended to blind persons. The article concludes by reiterating the importance of individual need assessment and mentioning new initiatives proposed on Low Vision services in the approved 11th plan under National Programme for Control of Blindness (NPCB). The source of information has been annual reports, notification and the approved 11th five-year plan of GOI, articles published with key words like rehabilitation, disability, assistive devices, low vision aids, and/or blind person through the mode of Internet. Annexure provides a list of selected institutions in the country offering Low Vision services compiled from various sources through personal communication and an approved list of training institutes under NPCB, GOI offering Low Vision training. PMID- 20195038 TI - Evaluation of retinal nerve fiber layer thickness measurements using optical coherence tomography in patients with tobacco-alcohol-induced toxic optic neuropathy. AB - Three patients with progressive visual loss, chronic alcoholism and tabagism were submitted to a complete neuro-ophthalmic examination and to retinal nerve fiber layer (RNFL) measurements using optical coherence tomography (OCT) scanning. Two patients showed marked RNFL loss in the temporal sector of the optic disc. However, a third patient presented RNFL measurements within or above normal limits, based on the Stratus-OCT normative database. Such findings may be due to possible RNFL edema similar to the one that may occur in the acute phase of toxic optic neuropathies. Stratus-OCT was able to detect RNFL loss in the papillomacular bundle of patients with tobacco-alcohol-induced toxic optic neuropathy. However, interpretation must be careful when OCT does not show abnormality in order to prevent diagnostic confusion, since overestimation of RNFL thickness measurements is possible in such cases. PMID- 20195039 TI - Cystoid macular edema and visual loss as sequelae to interferon alpha treatment of systemic hepatitis C. AB - Hepatitis C virus infection and interferon treatment may be associated with retinopathy but visual function is generally unaffected. This paper reports the rare occurrence of unilateral macular edema with visual loss. We present an interventional case report with fundus photograph and optical coherence tomography (OCT). A 48-year-old white male with hepatitis C, treated with a six month course of pegylated interferon alpha and ribavirin, complained of gradual reduction in the vision of his left eye. Visual acuities were 20/16 right and 20/400 left with clinical examination and OCT confirming cystoid macular edema. This report shows that cystoid macular edema may rarely occur in association with hepatitis C infection and/or interferon therapy. Physicians and ophthalmologists should be alert to this potential but infrequent association as the resultant visual loss is a significant potential complication that should be discussed when obtaining informed consent for interferon treatment. PMID- 20195040 TI - A case of unusual presentation of Takayasu's arteritis. AB - Takayasu's arteritis is a chronic inflammatory disease of the large and medium sized arteries. It commonly involves the aorta with its branches and the pulmonary arteries. The retinal hemodynamics suggest that the carotid artery involvement causes diminished retinal blood flow. This is the pathogenetic mechanism of Takayasu's retinopathy with characteristic features of microaneurysms, arterio-venous anastomosis and non-perfused retinal areas. Our case presented as branch retinal artery occlusion with collaterals and iris neovascularization. The branch retinal artery, a small retinal artery occlusion in our case is an unusual presenting feature of Takayasu's aorto-arteritis. PMID- 20195041 TI - Idiopathic pediatric retinal artery occlusion. AB - We report a case of branch retinal artery occlusion (BRAO) in a healthy young girl. An eight-year-old girl presented with sudden loss of vision in her left eye. She had a pale retina with macular edema consistent with extensive BRAO. A thorough workup was performed to determine any etiologic factor. All test results were within normal limits. Her visual acuity improved from finger counting to 20/40 over two weeks, on immediate treatment with intravenous steroids (methyl prednisolone). This case suggests that BRAO can occur in healthy children without any detectable systemic or ocular disorders and a dramatic improvement may be achieved with prompt treatment with intravenous steroids. PMID- 20195042 TI - Clinical profile of cerebral venous sinus thrombosis and the role of imaging in its diagnosis in patients with presumed idiopathic intracranial hypertension. AB - Retrospective descriptive study reporting the rate of occurrence of cerebral venous sinus thrombosis (CVST), highlighting the role of magnetic resonance imaging (MRI) and magnetic resonance venography (MRV) in patients with presumed idiopathic intracranial hypertension (IIH). Study was conducted in the department of neuro-ophthalmology at a tertiary eye care center in South India. Data from 331 patients diagnosed with IIH from June 2005 to September 2007 was included. Inclusion criteria were: Elevated opening cerebrospinal fluid (CSF) pressure of more than 200 mm of water on lumbar puncture, normal CSF biochemistry and microbiology,and normal neuroimaging as depicted by computed tomography(CT) scan. Exclusion criteria were: Space-occupying lesions, hydrocephalus, meningitis, intracranial pressure within normal range, abnormal CSF biochemistry and microbiology. The remaining patients were evaluated with MRI and MRV. CVST was present in 11.4% of patients who were presumed to have IIH (35/308). MRI alone identified 24 cases (68%) of CVST, while MRI used in combination with MRV revealed an additional 11 cases (32%). Risk factors associated with CVST were identified in nine out of 35 patients (26%). CVST may be misdiagnosed as IIH if prompt neuroimaging by MRI and MRV is not undertaken. Risk factors of CVST may not be apparent in all the cases and these patients are liable to be missed if CT scan alone is used for neuroimaging, hence MRI, combined with MRV should be undertaken to rule out CVST. PMID- 20195043 TI - Retinocytoma associated with bilateral retinoblastoma. AB - A 3-year-old girl presented with left exotropia. Funduscopy demonstrated a retinocytoma associated with five discrete retinoblastomas in the left eye and three discrete retinoblastomas in her right eye. The clinical manifestations and fundus imaging findings are described. PMID- 20195044 TI - Firecracker eye injuries during Deepavali festival: a case series. AB - We report a large series of ocular injuries caused by fire-crackers. This study was a hospital-based, singlecenter, retrospective case series in which the records of 51 patients with ocular injuries were analyzed. Injuries were classified according to Birmingham eye trauma terminology system (BETTS). Visual outcomes before and after the intervention were recorded. Ten patients were admitted for further management. As ocular firecracker injuries result in significant morbidity, public education regarding proper use of firecrackers may help in reducing the incidence of ocular injuries. PMID- 20195045 TI - Intravitreal bevacizumab for choroidal neovascular membrane associated with Best's vitelliform dystrophy. AB - Best's vitelliform macular dystrophy is a hereditary form of progressive macular dystrophy that can be complicated by choroidal neovascularization. Authors report successful treatment of choroidal neovascularization with intravitreal bevacizumab in one such eye in an 'adult' Indian male with visual improvement. A 23-year-old male presented with diminution of vision in the right eye for the past sixteen months. Visual acuity was 20/400 in the that eye. After three consecutive intravitreal injections of bevacizumab (1.25 mg/0.05 ml), vision improved to 20/120. Seven months following the last injection of bevacizumab, fundus appeared stable and visual acuity was maintained. No drug-related ocular or systemic side effects were encountered. To the best of our knowledge (PubMed search), this is the first report of its kind in an adult Indian patient. Intravitreal bevacizumab appears to be a promising and cost-effective modality of treatment in such eyes with potential for improvement in vision. However, a long term follow-up is warranted. PMID- 20195046 TI - Fungal keratitis in lattice dystrophy. AB - We report a case of fungal keratitis occurring in a patient with lattice dystrophy. A 57-year-old farmer presented with a corneal ulcer following probable entry of paddy husk in the right eye, of one month duration. Corneal scraping revealed pigmented fungal filaments while culture grew Alternaria alternata. Treatment with 5% natamycin eye drops and 1% atropine healed the infection in four weeks. We would like to draw attention to the fact that the cornea in lattice dystrophy is prone to frequent erosions and is a compromised epithelial barrier to invasion by microorganisms. Patients must be made aware of this fact and should seek attention at the earliest following any trivial trauma. Management of minor corneal abrasions in them should be directed at healing the epithelium with adequate lubricants and preventing infection with topical antibiotic prophylaxis. PMID- 20195047 TI - Ophthalmoparesis, papillitis and premacular hemorrhage in a case with endocarditis: a rare presentation of Brucellosis. AB - We report a rare presentation of brucellosis as bilateral optic nerve and right abducent nerve involvement, and endocarditis complicated by right premacular hemorrhage in a 28-year-old white female. The patient showed improvement with both medical and surgical therapy. Brucellosis should be considered in the differential diagnosis of papillitis, gaze palsy and endocarditis complicated with premacular hemorrhage in endemic regions. PMID- 20195048 TI - Comments on: Central serous chorioretinopathy after dacryocystorhinostomy operation on the same side. PMID- 20195049 TI - Collagen cross-linkage with riboflavin by Dr. Vinay Agarwal. PMID- 20195050 TI - Is balanced salt solution really superior to ringer lactate for phacoemulsification? PMID- 20195051 TI - Ocular toxicity of Calotropis--missing links. PMID- 20195052 TI - Pneumatic displacement and intravitreal bevacizumab for management of submacular hemorrhage in choroidal neovascular membrane. PMID- 20195053 TI - Gains beyond cosmesis: recovery of fusion and stereopsis in adults with longstanding strabismus following successful surgical realignment. PMID- 20195054 TI - Developing paediatric eye care teams in India. PMID- 20195055 TI - Spectral domain optical coherence tomography predates fluorescein angiography in diagnosing central serous chorioretinopathy. PMID- 20195056 TI - Phrynoderma and night blindness. PMID- 20195057 TI - Fibrin glue in ophthalmology. PMID- 20195058 TI - Development of the body condition score system in Murrah buffaloes: validation through ultrasonic assessment of body fat reserves. AB - The body condition score (BCS) system is a subjective scoring method of evaluating the energy reserves of dairy animals to provide better understanding of biological relationships between body fat, milk production and reproduction. This method helps in adopting the optimum management practices to derive maximum production and maintain optimum health of the livestock. In this study, a new BCS system was developed for Murrah buffaloes. The skeletal check points were identified by studying the anatomical features and amount of fat reserves in slaughtered animals. The scores were assigned from 1 to 5 based on the amount of fat reserves in slaughtered animals. A score of 1 represents least and 5 represents most amount of fat. The skeletal check points identified were ordered based on the amount of carcass fat reserves and scores assigned to prepare a preliminary BCS chart on a 1 to 5 scale at 0.25 increments. The BCS chart was further modified by eliminating the skeletal check points at which the fat reserves were less evident on palpation in most of the buffaloes and a new BCS chart on a 1 to 5 scale at 0.5 increments examining eight skeletal check points was developed. The new BCS system developed was tested for precision in 10 buffaloes for each point of the 1-5 scale by ultrasonographic measurements of body fat reserves. Ultrasonographic measurements showed that as the BCS increased, the amount of fat reserves also increased (p < 0.01), indicating that the BCS adequately reflected the amount of actual fat reserves. BCS was significantly correlated (r = 0.860) with the carcass fat reserves as well as the ultrasonographic fat reserves (r = 0.854). PMID- 20195059 TI - Multidetector row computed tomography evaluation of the micropig kidney as a potential renal donor. AB - Multidetector row computed tomography (MDCT) provides anatomical information about the kidney and other internal organs. Presently, the suitability of 64 channel MDCT to assess the kidney of healthy micropigs was evaluated. Morphological evaluations of the kidney and the major renal vessels of six healthy micropigs were carried out using MDCT, recording kidney volume and the diameter and length of renal arteries and veins. The mean diameters and lengths of the renal artery were 0.44 +/- 0.05 and 4.51 +/- 0.55 cm on the right side and 0.46 +/- 0.06 and 3.36 +/- 0.27 cm on the left side, respectively. The mean diameters and lengths of the renal vein were 1.44 +/- 0.52 and 4.22 +/- 1.29 cm on the right side and 1.38 +/- 0.17 and 5.15 +/- 0.87 cm on the left side, respectively. The mean volume of the right kidney was 79.3 +/- 14.5 mL and of the left kidney was 78.0 +/- 13.9 mL. The data presented in this study suggest that the MDCT offers a noninvasive, rapid, and accurate method for the evaluation of the renal anatomy in living kidney donors. It also provides sufficient information about extra-renal anatomy important for donor surgery and determination of organ suitability. PMID- 20195061 TI - Characterization of canine oral papillomavirus by histopathological and genetic analysis in Korea. AB - In August 2008, forty dogs out of 400 developed oral warts in a breeding farm in Korea. Canine oral papilloma infection is a common disease in dogs. However, there has been no report of an outbreak of canine oral papillomavirus (COPV) in a group of dogs or in dog breeding farms in Korea, and the genetic analysis of COPV in Korea has yet to be performed. This study diagnosed canine oral papilloma from the oral samples of these dogs based on histopathological examination and immunohistochemistry. Polymerase chain reaction was applied to amplify the corresponding products using preexisting primer sets for COPV and a universal human papillomavirus targeting L1 gene. Further genetic analysis of the major viral capsid gene L1 confirms the sequences of Korean COPV, which shows a close relationship to previously reported COPV. This study describes the histopathological and immunohistochemical characteristics of canine oral papilloma in a group of breeding dogs in Korea and discloses the complete L1 gene sequences of Korean COPV. PMID- 20195060 TI - Transcriptional and translational expression of calbindin-D9k in the duodenum, kidney and uterus of a female canine model. AB - Calbindin-D9k (CaBP-9k) is a cytosolic calcium-binding protein expressed in tissues in the intestine, uterus, placenta, kidney, pituitary gland and bone. Its exact function is unknown, but it is considered to regulate intracytoplasmic concentration and transport of free ions (Ca(2+)). CaBP-9k protein is involved in intestinal calcium absorption in the intestine and in the regulation of myometrial activity by intracellular calcium in the uterus. Renal CaBP-9k protein is expressed at the site of calcium re-absorption in the kidney and expressed in distal convoluted tubules, where it is thought to facilitate calcium re absorption. Expression of the CaBP-9k gene has been explored in most mammalians except in a canine model. Presently, we elucidated the expression of CaBP-9k mRNA and protein in the duodenum, kidney and uterus in a canine model involving two adult (2.5-year-old) female beagles. To collect tissues, the dogs were euthanized and then the abdominal cavity was exposed by midline incision. The proximal duodenum, cortex of kidney and uterine horn were collected. Expression of CaBP-9k mRNA was confirmed by reverse transcriptionpolymerase chain reaction (RT-PCR) and real-time PCR. CaBP-9k protein expression and localization were ascertained by Western blot analysis and immunohistochemistry, respectively. CaBP-9k mRNA was detected in the duodenum, but not in the kidney and uterus. Its protein was expressed only in the enterocytes of the duodenum. Taken together, the results indicate that CaBP-9k mRNA and protein are highly expressed in the enterocytes of the duodenum of a canine model, consistent with findings in other mammalian species. PMID- 20195062 TI - Fatal cases of Theileria annulata infection in calves in Portugal associated with neoplastic-like lymphoid cell proliferation. AB - This study was carried out to investigate fifteen cases of acute lethal infection of calves ( CON), resting fatigue ratings (CG < CON), muscle soreness (CG < CON), ultrasound measure swelling (CG < CON), bench press throw (CG > CON), and CK (CG < CON). A whole body compression garment worn during the 24-hour recovery period after an intense heavy resistance training workout enhances various psychological, physiological, and a few performance markers of recovery compared with noncompressive control garment conditions. The use of compression appears to help in the recovery process after an intense heavy resistance training workout in men and women. PMID- 20195086 TI - Mercedes panniculectomy with simultaneous component separation ventral hernia repair. PMID- 20195087 TI - Current status of grafts and implants in rhinoplasty: Part II. Homologous grafts and allogenic implants. AB - LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Understand the challenges in restoring volume and structural integrity in rhinoplasty. 2. Identify the appropriate uses of various homologous grafts and allogenic implants in reconstruction, including: (a) freeze-dried acellular allogenic cadaveric dermis grafts, (b) irradiated cartilage grafts, (c) hydroxyapatite mineral matrix, (d) silicone implants, (e) high-density polyethylene implants, (f) polytetrafluoroethylene implants, and (g) injectable filler materials. 3. Identify the advantages and disadvantages of each of these biomaterials. 4. Understand the specific techniques that may aid in the use these grafts or implants. SUMMARY: This review specifically addresses the use of homologous grafts and allogenic implants in rhinoplasty. It is important to stress that autologous materials remain the preferred graft material for use in rhinoplasty, owing to their high biocompatibility and low risk of infection and extrusion. However, concerns of donor-site morbidity, graft availability, and graft resorption have motivated the development and use of homologous and allogenic implants. PMID- 20195088 TI - Microvascular anastomoses: a series of 200 success stories. PMID- 20195089 TI - A comfortable and practical nasal packing method: tied Merocel in clear glove finger impregnated with lidocaine-prilocaine cream. PMID- 20195090 TI - Optimal timing for nasal cartilage molding in presurgical nasoalveolar molding. PMID- 20195091 TI - Anatomy of a medication error: inadvertent subcutaneous injection of neosynephrine during nasal surgery. PMID- 20195092 TI - Banking a DIEP flap in high-risk patients: a new technique during unilateral DIEP harvest. PMID- 20195093 TI - Laser-assisted indocyanine green angiography and DIEP breast reconstruction. PMID- 20195094 TI - Tissue mummification following exposure to a ruptured hydrogel breast implant. PMID- 20195095 TI - The perforating superficial inferior epigastric vein: a new anatomical variant detected with computed tomographic angiography. PMID- 20195096 TI - Preserved neurologic function following intraneural fascicular dissection and nerve graft for digital and median nerve lipofibromatous hamartoma. PMID- 20195097 TI - A clinically feasible method of surface marking for the superficial palmar arch based on correlation of size-matched angiograms to fixed landmarks in the hand. PMID- 20195098 TI - Salvaging difficult chest and epigastric defects with the intercostal artery perforator flap. PMID- 20195099 TI - Aesthetic correction of postoperative pectoral deformity after minimally invasive funnel chest repair. PMID- 20195100 TI - Salvaging exposed left ventricular assist devices. PMID- 20195101 TI - Pedicled unilateral external pudendal artery perforator flap: a new technique for reconstruction of congenital vagina agenesis. PMID- 20195102 TI - Reconstruction of extensive groin defects with contralateral anterolateral thigh vastus lateralis muscle flaps. PMID- 20195103 TI - The course of anterolateral thigh perforators does not correlate between sides of the body: the role for preoperative imaging. PMID- 20195104 TI - A new surgical technique for lateral ray polydactyly without skin graft: the bell bottom flap. PMID- 20195105 TI - Perforasomes of the DIEP flap: vascular anatomy of the lateral versus medial row perforators and clinical implications. AB - BACKGROUND: Regarding the perfusion of a deep inferior epigastric perforator (DIEP) flap, the classic Hartrampf zones II and III were demonstrated by Holm et al. to be reversed using fluorescent perfusion techniques, implying that blood flow from the pedicle travels to the ipsilateral side before crossing the midline. The authors' hypothesis is that the zones of perfusion and the vascular anatomy differ greatly between lateral row and medial row perforators. METHODS: Three-dimensional and four-dimensional computed tomographic angiography was utilized to reappraise the zones of vascularity. Thirty-six DIEP flaps were simulated for this study (14 lateral row perforators versus 22 medial row perforators). Individual perforators were injected with contrast and each flap was subjected to dynamic computed tomography scanning. Images were viewed using TeraRecon software, allowing analysis of branching patterns and perfusion flow. RESULTS: The mean vascular territory for a medial perforator DIEP flap injected with contrast was 296 cm, compared with 196 cm for a lateral perforator DIEP flap. Zone II perfusion was greater in a medial perforator compared with a lateral perforator. Zone III had greater perfusion in a lateral perforator compared with a medial perforator. The authors found that medial perforators conform to the Hartrampf zones of perfusion and lateral perforators follow the Holm theory of perfusion (zones II and III should be reversed for lateral perforator DIEP flaps). Injection of a lateral row-based perforator flap gave a vascular territory that rarely crossed the midline. CONCLUSION: Medial and lateral row perforators offer distinct and stereotypical zones of perfusion that have a significant effect on flap design and harvesting. PMID- 20195106 TI - Management of the post-breast-conserving therapy defect: extended follow-up and reclassification. AB - BACKGROUND: Suboptimal aesthetic outcomes after conservative therapy for breast cancer are not uncommon, with reported rates up to 30 percent, of which 5 percent may be considered severe. With radiotherapy being an essential component of breast-conserving therapy, surgical correction of deformities is challenging, and guidance as to reparative technique selection is currently limited. METHODS: One hundred forty-one patients have undergone surgical correction of breast conserving therapy-induced deformity since its inception at our institution in 1991. This consecutive series has been analyzed with respect to surgical procedure, complications, revisional surgery, and aesthetic outcome (with a five point scale) to July of 2008. RESULTS: The overall aesthetic result was considered to be at least satisfactory in 94.5 percent at 1 year and in 88.8 percent at 5 years. Secondary surgery was required in 19.1 percent and a third procedure was required in 6.4 percent. Complications were encountered in 14.2 percent. A classification into five grades of deformity was found to be practical and effective for surgical planning. CONCLUSIONS: Reparative surgery for aesthetic deformity in scarred and irradiated breasts is able to produce satisfactory aesthetic results; however, revisional surgery and complications are not inconsiderable, and the authors hope the new classification based on their long-term experience will provide practical guidance for surgical planning to other surgeons encountering such patients. PMID- 20195107 TI - 1000 consecutive venous anastomoses using the microvascular anastomotic coupler in breast reconstruction. AB - BACKGROUND: Microvascular anastomosis is one of the more critical aspects of free flap surgery. A safe, effective, and expedient method for venous anastomosis minimizes flap ischemia time, is easier on the surgical team, and saves costly operating room time. The authors report on their experience using the Synovis microvascular anastomotic coupling device in 1000 consecutive venous anastomoses in free flap breast reconstruction. METHODS: The authors retrospectively reviewed 1000 consecutive venous anastomoses that were performed using the microvascular anastomotic coupler between July of 2002 and July of 2008. Data were obtained on flap type, recipient vessel, coupler size, incidence of venous thrombosis, timing of venous thrombosis, and morbidity as a result of venous thrombosis. RESULTS: All anastomoses were performed in an end-to-end fashion. There were 460 unilateral cases and 270 bilateral cases of breast reconstruction. Flap types included muscle-sparing free transverse rectus abdominis myocutaneous, deep inferior epigastric perforator, superficial inferior epigastric artery, superior gluteal artery perforator, and inferior gluteal artery perforator. The vast majority of the recipient vessels were the internal mammary or thoracodorsal vessels. Most of the couplers that were used were either 3 or 2.5 mm in diameter. Overall, there were six instances of venous thrombosis (rate of 0.6 percent). There were no total flap losses due to venous thrombosis in this series, although two patients had partial flap necrosis. CONCLUSIONS: The patency rate for venous anastomoses performed with the microvascular coupler is excellent when compared with standard suture techniques and has the advantage of overall easier application. PMID- 20195108 TI - Health characteristics of postmenopausal women with breast implants. AB - BACKGROUND: Long-term health characteristics and quality of life in patients with breast implants are important issues in plastic surgery. METHODS: The authors evaluated characteristics of women who had breast implant surgery in the Women's Health Initiative observational study between 1993 and 1998. Most women in this study cohort had breast implant surgery 20 or more years before recruitment into the study. The women who were in the study who had not undergone breast implant surgery served as the comparison group. There were 86,686 women in the study who did not have breast implant surgery and an absent history of breast cancer, and 1257 women who had breast implant surgery and no prior breast cancer. RESULTS: Total mortality rates were substantially lower among women with breast implants, as was the incidence of coronary heart disease. Women with breast implants in this study had a lower body mass index throughout adult life and were more physically active than control subjects. After adjustment for these variables, differences in total mortality were no longer statistically significant. Women who had breast implants reported overall poorer quality of life and emotional well-being. These differences were small, but statistically significant. Among women with breast implant surgery, 7 percent of deaths were due to suicide (n = 3) versus 0.4 percent (n = 20) in controls. CONCLUSIONS: Significant differences in health characteristics and quality-of-life measures are seen in a cohort of women with breast implants decades after implant surgery. Further longitudinal studies need to focus on both physical and psychological health among women undergoing breast implant surgery. PMID- 20195109 TI - Quality-of-life and self-esteem outcomes after oncoplastic breast-conserving surgery. AB - BACKGROUND: This prospective trial was designed to assess the impact of oncoplastic surgery on quality of life and self-esteem of breast cancer patients undergoing breast-conserving treatment. METHODS: Forty-five patients with primary breast cancer to be treated with breast-conserving surgery and immediate partial breast reconstruction were assessed with regard to quality-of-life and self esteem outcomes preoperatively and 6 and 12 months postoperatively. Another 42 breast cancer patients, treated by conservative surgery without breast reconstruction at least 1 year previously, were assessed for the control group. Validated questionnaires (Short Form-36, Brazilian version, and the Rosenberg-EPM Self-Esteem Scale) were used. Data were analyzed by using the Mann-Whitney and Friedman tests. RESULTS: Participation rates at the follow-up assessments were 95.5 percent at the 6-month follow-up and 88.9 percent at the 12-month follow-up. Control and reconstruction groups were matched for age, body mass index, and demographic and oncologic aspects. At postoperative month 12, the breast reconstruction group had significantly better health status than the control group with regard to physical functioning (p < 0.000), health perception (p < 0.002), vitality (p < 0.007), social functioning (p < 0.02), role emotional (p < 0.02), mental health (p < 0.000), and self-esteem (p < 0.02). Compared with preoperatively, breast reconstruction group scores were significantly higher at 12 months postoperatively for seven of the eight dimensions of the Short Form-36: physical functioning (p < 0.01), role physical (p < 0.02), health perception (p < 0.02), vitality (p < 0.01), social functioning (p < 0.02), role emotional (p < 0.05), and mental health (p < 0.02). Self-esteem was also significantly better at 12 months (p < 0.02). CONCLUSION: Oncoplastic surgery had a positive impact on quality of life and self-esteem of patients undergoing breast-conserving treatment. PMID- 20195110 TI - Patient satisfaction following nipple-sparing mastectomy and immediate breast reconstruction: an 8-year outcome study. AB - BACKGROUND: Nipple-sparing mastectomy has become an accepted treatment for appropriately selected breast cancers. No reports have correlated patient satisfaction following nipple-sparing mastectomy with objective observer assessments. METHODS: From 2001 to 2008, nipple-sparing mastectomy and immediate reconstruction were performed on 141 patients. After institutional review board approval, patients completed questionnaires rating their satisfaction with various aspects of their nipple-areola complex using a Likert-type scale. Three independent observers then reviewed the nipple-areola complex in 34 patients and rated the outcome using the same scale. RESULTS: The survey completion rate was 53 percent and the mean follow-up was 50.4 months (range, 9 to 100 months). A majority of patients rated appearance, symmetry, color, position, and texture as good or excellent. A majority of patients rated sensation and arousal as fair or poor. Fifty-seven patients (73.1 percent) stated they would definitely undergo nipple-sparing mastectomy again. Patients with larger volumes of breast tissue removed (p = 0.010), larger preoperative body mass index (p = 0.034), or larger tissue expander volumes (p = 0.007) reported lower satisfaction. Patient assessments for appearance, color, symmetry, and position correlated with those of objective observers. CONCLUSIONS: The authors' study is the largest series to address patient satisfaction with the nipple-areola complex following nipple sparing mastectomy and the only one to correlate patient self-assessment with assessment by independent observers. Overall, patients were very satisfied with appearance of the nipple-areola complex and most would choose nipple-sparing mastectomy again. A majority of patients rated sensation as fair or poor, with sensation constituting the most frequent aspect of the nipple-areola complex that patients would change. Larger body mass index, expander volumes, and volume of breast tissue removed may predict dissatisfaction postoperatively. PMID- 20195111 TI - Repair of the sciatic nerve defect with a direct gradual lengthening of proximal and distal nerve stumps in rabbits. AB - BACKGROUND: The current clinical repair method used for the segmental peripheral nerve defect is autogenous nerve grafting. However, this method has several inherent disadvantages. Therefore, the authors have invented an alternative method for repairing the segmental peripheral nerve defect with a direct gradual lengthening of nerve stumps. In this study, for the clinical application, the authors developed a new external nerve-lengthening device for lengthening peripheral nerve stumps daily without anesthesia. METHODS: In this study, a nerve segment 20 mm in length was resected from the rabbit sciatic nerve. In the nerve lengthening group, direct nerve lengthening was performed in the proximal and distal nerve stumps at a rate of 1 mm/day without anesthesia. After being lengthened for 22 days, both proximal and distal nerve stumps were evaluated by immunohistochemical analysis. When confirming that both nerve stumps were successfully lengthened, a direct end-to-end neurorrhaphy was performed. As a control, 20-mm-long autografting was performed immediately after nerve resection. Nerve regeneration was evaluated by electrophysiologic and histologic examination at 16 weeks after the first operation in both the nerve-lengthening and the control groups. RESULTS: The results of both electrophysiologic evaluation and histologic examination showed that the nerve-lengthening group performed significantly better than the autografting group. CONCLUSION: The gradual nerve lengthening procedure can be used as an alternative therapeutic method for repairing segmental peripheral nerve defects, which proved to be advantageous over widely adopted autogenous nerve grafting. PMID- 20195112 TI - Meshed skin grafts placed upside down can take if desiccation is prevented. AB - BACKGROUND: The role of the wet environment in wound healing has been investigated in various studies. The current study explores the role of the wet wound environment in promoting healing of skin grafts. The authors hypothesized that the survival of skin grafts is dependent not only on the orientation of transplantation but also on the environment into which the skin is transplanted. METHODS: This study included 72 full-thickness (2.5 x 2.5-cm) wounds in six Yorkshire pigs. The wounds were grafted with autologous split-thickness skin grafts (meshed or sheet), placed either regularly (dermal side down) or inverted (dermal side up), and treated in a wet or a dry environment. Behavior of the skin grafts and healing were analyzed in histologic specimens collected on days 4, 6, 9, and 12 after wounding. Wound contraction was quantified by photoplanimetry. RESULTS: In the wet environment, not only did inverted meshed skin grafts survive, but also they proliferated to accelerate reepithelialization. In this environment, wounds transplanted with inverted and regular meshed grafts showed no significant difference in reepithelialization rate and contraction. In contrast, in the dry environment, wounds transplanted with inverted meshed grafts showed a significantly lower reepithelialization rate and a higher contraction rate than wounds transplanted with regular grafts. Inverted meshed grafts in a dry environment and inverted sheet grafts did not survive. CONCLUSION: The wound environment has an important role in the survival and proliferation of skin grafts, as demonstrated by survival of inverted meshed grafts in the wet environment and their contribution to accelerated reepithelialization, equal to the regularly placed grafts. PMID- 20195113 TI - The effect of calcium channel blockers on smoking-induced skin flap necrosis. AB - BACKGROUND: Calcium channel blockers have been shown experimentally to reverse many of the effects of nicotine. The purpose of this study was to assess the effect of calcium channel blockers on smoking-induced skin flap necrosis. METHODS: Forty male albino Wistar rats were divided into four groups. Groups A, B, and C were treated in a controlled smoking chamber for 20 minutes daily for 21 days. On day 14, caudally based dorsal skin flaps (3 x 10 cm) were created. On days 14 through 21, group B animals received verapamil (20 mg/kg/day) by gavage. Group C received nifedipine (10 mg/kg/day). On day 21, standardized photographs were taken and flap survival areas determined. Urine cotinine concentrations were measured on days 14 and 21. RESULTS: The mean cotinine level at surgery was 161 ng/ml in group A (smoking), 149 ng/ml in group B (verapamil), and 168 ng/ml in group C (nifedipine). These differences were not statistically significant. Cotinine concentration at surgery for group D (no smoking) was less than 10 ng/ml. The mean flap survival in group D was 79.1 percent, compared with 63.7 percent in group A (p = 0.003). The mean flap survival in group B (verapamil) was 72.8 percent, compared with 73.7 percent in group C (nifedipine). Both values were significantly greater than in group A (p = 0.04 and p = 0.008, respectively). CONCLUSIONS: In this study, enteral calcium channel blockers were associated with a statistically significant improvement in flap survival compared with untreated animals with an equivalent smoke exposure. Calcium channel blockers may reduce perioperative risk in active smokers who require skin flap surgery. PMID- 20195114 TI - Essays on the facial nerve: Part I. Microanatomy. AB - BACKGROUND: Facial nerve explorations and microstimulation of distal nerve branches during facial reanimation procedures by the senior author (J.K.T.) have yielded various observations. This prompted the authors to quantify the surgical findings with an anatomical study and a subsequent analysis of the electrophysiologic intraoperative data. The present report details the microanatomical observations. METHODS: Ten fresh cadaveric hemiface dissections (five specimens) were performed. The facial nerve branches were traced distally under the operating microscope and mapped with India ink. A number of nerve branches exited the parotid at approximately 9 +/- 0.85 cm from the facial nerve trunk division, and their distribution was noted. Photographic documentation was obtained. RESULTS: The mean number of nerve branches was 7.70 +/- 1.05 at the anterior parotid border and 13.80 +/- 1.81 distally. Differences in the number and configuration of nerve branches existed even between the two sides of the face. The frontal branch had a mean nerve number of 2.80 +/- 0.63; the zygomatic branch, 4.40 +/- 1.34, the buccal branch, 3.20 +/- 0.78; and the marginal mandibular branch, 2.30 +/- 0.48. In 70 percent of specimens, the buccal branches originated from both upper and lower nerve divisions and interconnected with the marginal mandibular branch in 50 percent of specimens. Distally, connectivity was found between buccal branches and the infraorbital nerve, the marginal mandibular branches, and the mental nerve. A constant lower zygomatic or zygomaticobuccal branch reached the procerus and corrugator supercilii muscles. A twig from the frontal branch reached the corrugator muscle in 60 percent of cases. CONCLUSIONS: Diversity of facial nerve anatomy is recognized and documented. Specific anatomical relationships are clarified and demonstrated as a guiding map. PMID- 20195115 TI - Discussion. Essays on the facial nerve: Part I. Microanatomy. PMID- 20195116 TI - Fat graft pedicle stabilization in head and neck microvascular reconstruction. PMID- 20195117 TI - Transoral robotic free flap reconstruction of oropharyngeal defects: a preclinical investigation. PMID- 20195118 TI - Discussion. Construction and clinical application of a human tissue-engineered epidermal membrane. PMID- 20195119 TI - Reconstruction of massive oncologic defects using free fillet flaps. AB - BACKGROUND: Forequarter and hind-limb amputations are used with curative and palliative intent in the setting of proximal limb, thorax, or truncal malignancies. For these large defects that require a free flap, the distal portions of these limbs can be harvested as fillet flaps and represent the "spare parts" concept of surgical reconstruction. METHODS: The authors performed a retrospective review of 27 patients (mean age, 51.4 years) who had undergone immediate reconstruction with free fillet extremity flaps between 1991 and 2008. Seventeen patients received preoperative radiotherapy, and 21 received preoperative chemotherapy. Resections included seven hemipelvectomies, 16 forequarter amputations, and four hindquarter amputations. RESULTS: The mean defect size was 1126 cm (range, 480 to 3500 cm). All 27 flaps survived and all wounds healed. Four patients (15 percent) had complications; three patients developed partial flap necrosis and required operative debridement, and there were two episodes of flap vascular compromise. Mean follow-up time was 14 months. One patient was lost to follow-up. Eight patients (30 percent) were still alive at the end of the study. The remaining 18 patients died within 22 months of resection, for a mean survival of 7 months. There was no cancer recurrence within the flap itself. Phantom pain occurred in 11 patients. At the time of discharge, pain, tissue necrosis, and infection were improved in all patients. CONCLUSION: The use of the fillet flap is oncologically sound, has no associated donor sites, has an acceptable incidence of major complications, and allows for a healed wound with an improvement in the quality of life. PMID- 20195120 TI - The intravascular stenting method for treatment of extremity lymphedema with multiconfiguration lymphaticovenous anastomoses. AB - BACKGROUND: In secondary extremity lymphedema, normal antegrade lymphatic flow is disrupted by the disease state. Attempts to capture aberrant retrograde lymphatic flow by means of microsurgical lymphaticovenous anastomoses have been hindered because of technical limitations. The authors applied the intravascular stenting method to the surgical correction of extremity lymphedema to generate multiconfiguration lymphaticovenous anastomoses capable of decompressing both proximal and distal lymphatic flow. METHODS: Lymphatic channels were detected using indocyanine green injection and infrared scope imaging. Sites felt to be adequate for lymphaticovenous anastomosis were accessed through 2-cm skin incisions under local anesthesia. Using the intravascular stenting method, the authors performed a total of 39 lymphaticovenous anastomoses (15 flow-through, 11 end-to-end, eight end-to-side, two double end-to-end, two end-to-end/end-to-side, and one pi-type) on both the proximal and distal ends of lymphatic channels in 14 female patients with upper (n = 2) and lower (n = 12) extremity lymphedema. RESULTS: At an average follow-up of 8.9 months, average limb girth decreased 3.6 cm (range, 1.5 to 7 cm) or 11.3 percent (range, 4 to 33 percent). There was a greater reduction in cross-sectional area with increasing number of lymphaticovenous anastomoses per limb. CONCLUSIONS: The intravascular stenting method facilitated multiconfiguration lymphaticovenous anastomoses capable of decompressing both antegrade and retrograde lymphatic flow. This approach resulted in durable reduction of both upper and lower extremity lymphedema. As multiconfiguration lymphaticovenous anastomoses are now technically feasible, the influence of the number of lymphaticovenous anastomoses and the effectiveness of specific lymphaticovenous anastomosis configurations for the treatment of lymphedema deserves further study. PMID- 20195121 TI - Treatment of diabetic foot ulcers using a blood bank platelet concentrate. AB - BACKGROUND: Many clinical trials have shown the effectiveness of platelet releasate on chronic wound healing, but large volumes of blood must be aspirated from patients and a platelet separator is required. Moreover, in the case of using homologous platelets, time and effort are needed to locate a suitable donor, and the donor's blood sample must be tested for a history of infectious disease. The current study was undertaken to evaluate the effect of a straightforward method using a blood bank platelet concentrate in treating diabetic foot ulcers. METHODS: Fifty-two patients with diabetic foot ulcers were treated using a blood bank platelet concentrate. A control treatment (i.e., treatment with topical fibrinogen and thrombin) was performed on 48 patients. Twelve weeks after treatment, the percentage of complete healing, mean healing time, percentage of wound shrinkage, and patient satisfaction were compared. RESULTS: Complete wound healing was achieved in 79 percent of the blood bank platelet concentrate-treated group and 46 percent of the control group (p < 0.05). The times required for complete healing were 7.0 +/- 1.9 and 9.2 +/- 2.2 weeks in the blood bank platelet concentrate-treated and control groups, respectively (p < 0.05). The degrees of wound shrinkage were 96.3 +/- 7.8 and 81.6 +/- 19.7 percent for the treated and control groups, respectively (p < 0.05). Patient satisfaction with the blood bank platelet concentrate treatment yielded better results than the control method (mean score, 7.6 +/- 1.6 and 5.3 +/- 1.4, respectively; p < 0.05). No adverse events related to the study treatment occurred. CONCLUSIONS: Treatment of diabetic foot ulcers using a blood bank platelet concentrate showed results superior to control treatment. A blood bank platelet concentrate offers a simple and effective treatment for diabetic foot ulcers. PMID- 20195122 TI - Biomechanical analysis of surgical correction of syndactyly. AB - BACKGROUND: The dorsal rectangular flap technique has been widely used for the correction of syndactyly. In this method, however, the linear scar along the palmar border of the webspace may lead to secondary contracture and web creep. Some modifications have been advocated for breaking these linear scars. In this study, these modifications were evaluated biomechanically with the finite element method. METHODS: Based on computed tomography findings of seven adult hands, three scar models were created: the dorsal rectangular flap, the dorsal flap with palmar-based triangular flap, and the dorsal flap with V-shaped tip. Forced displacements were applied to mimic the hand-opening motion, and scar stresses and web displacement were investigated. RESULTS: The maximal stress of the scar was significantly greater in the dorsal rectangular flap group than in the other groups (dorsal flap with palmar-based triangular flap, p = 0.046; dorsal flap with V-shaped tip, p = 0.018). The web was displaced most distally in the dorsal rectangular flap group compared with the other groups (dorsal flap with palmar based triangular flap, p = 0.043; dorsal flap with V-shaped tip, p = 0.043). There was no significant difference between the dorsal flap with a palmar-based triangular flap group and the dorsal flap with a V-shaped tip group. CONCLUSIONS: The authors' results indicate that both the palmar-based triangular flap and the V-shaped tip flap work well. It is strongly recommended that any break should be made in the palmar edge of the webspace for prevention of web creep. PMID- 20195123 TI - Pedigree and genetic study of a bilateral congenital microtia family. AB - BACKGROUND: Microtia can be defined as a malformation of the auricle; the varying severity that results can range from mild distortion of the anatomic landmarks to the complete absence of the ear. No specific study has been reported analyzing a family of several generations with bilateral congenital concha-type microtia so far. METHODS: The authors obtained medical records and blood samples from a Chinese family with bilateral congenital concha-type microtia that involved 56 members of five generations. There were 20 patients with bilateral congenital concha-type microtia in this pedigree, and 14 patients were still alive. Pedigree analysis and genetic study were carried out to obtain the information in this family. RESULTS: With regard to pedigree, 35.7 percent of the members of this family were affected by bilateral congenital concha-type microtia and showed the possibility of autosomal dominant inheritance model. Missense mutation A deletion on site 76234730 in goosecoid gene exon 3 occurred in eight cases in the family, which resulted in a frame shift mutation. CONCLUSIONS: The goosecoid gene mutation in exon 3 may be involved in the malformation events in this family. The mutation can be accompanied by potential environmental risk factors, such as exposure to poison and hazardous materials, alcohol abuse, and disease during the mother's pregnancy. Further study is needed to clarify the relationship between the genetic and environmental factors associated with the congenital malformation. PMID- 20195124 TI - The effect of electroacustimulation on postoperative nausea, vomiting, and pain in outpatient plastic surgery patients: a prospective, randomized, blinded, clinical trial. AB - BACKGROUND: Current rates of postoperative nausea and vomiting experienced by outpatient surgery patients are as high as 20 to 30 percent. Electroacustimulation therapy has been demonstrated to be effective in controlling these symptoms, but trials identifying its efficacy in the outpatient surgery population are lacking. METHODS: One hundred twenty-two patients undergoing surgical procedures at an outpatient surgery center were randomized to two treatment arms. The first arm received the standardized pharmacologic postoperative nausea and vomiting prevention typical for patients undergoing outpatient surgery, whereas in the second arm, the ReliefBand and pharmacologic measures were used. The ReliefBand is a U.S. Food and Drug Administration approved electroacustimulation device. Electroacustimulation is a derivative of acupuncture therapy that uses a small electrical current to stimulate acupuncture points on the human body and is thought to relieve nausea, vomiting, and pain. Outcomes measured were pain and nausea symptoms, emetic events, the need for rescue medications, and the time to discharge. RESULTS: The electroacustimulation arm reported statistically significant lower nausea scores at 30 minutes and 120 minutes postoperatively (p < 0.05). In addition, subgroup analysis demonstrated significant findings in favor of the experimental group, with anatomical subsets of surgical patients requiring less pain medication and shorter times from surgery to discharge when compared with the standard treatment. However, electroacustimulation did not have a significant effect on the amount of pain experienced by patients in any group. CONCLUSION: The authors' study demonstrates that electroacustimulation offers added protection against symptoms of postoperative nausea and vomiting in an outpatient cosmetic surgery population, representing a safe and cost-effective addition to current pharmacologic preventive measures. PMID- 20195125 TI - Discussion. The effect of electroacustimulation on postoperative nausea, vomiting, and pain in outpatient plastic surgery patients: a prospective, randomized, blinded, clinical trial. PMID- 20195126 TI - A safety and feasibility study of a novel radiofrequency-assisted liposuction technique. AB - BACKGROUND: The feasibility, safety, and efficacy of a novel radiofrequency device for radiofrequency-assisted liposuction were evaluated in various body areas. METHODS: From July to December of 2008, 23 subjects underwent radiofrequency-assisted liposuction using the BodyTite system. Information regarding aesthetic results and local and systemic complications was collected immediately after the procedure and at 6- and 12-week follow-up. RESULTS: The mean age of the patients was 38.8 +/- 12.4 years, and 87 percent were women. Radiofrequency-assisted liposuction was performed successfully in all cases; volume aspirated per patient was 2404 +/- 1290 ml, whereas operative time was 158 +/- 44 minutes. All patients underwent liposuction at the hip and low abdominal areas, bilaterally. Body contour improvement was observed postoperatively in all patients and there were no severe systemic or local complications, although postoperative pain was minimal in all patients. Weight and circumference reductions were significant at both 6-week and 3-month follow-up. Skin tightening was judged optimal by the surgeon in all patients. CONCLUSIONS: The authors' study suggests that the removal of moderate volumes of fat with concurrent subdermal tissue contraction can be performed safely and effectively with radiofrequency-assisted liposuction. Additional benefits of this technique are excellent patient tolerance and fast recovery time. Nonetheless, a larger sample is required to confirm the authors' results and guarantee the efficacy and safety of the procedure. Direct comparison with traditional liposuction or energy assisted liposuction techniques may provide some insights to tailor future indications of this novel technique. PMID- 20195127 TI - Blepharoplasty complications. AB - BACKGROUND: Postoperative complications of blepharoplasty range from cutaneous changes to vision-threatening emergencies. Some of these can be prevented with careful preoperative evaluation and surgical technique. When complications arise, their significance can be diminished by appropriate management. This article addresses blepharoplasty complications based on the typical postoperative timeframe when they are encountered. METHODS: The authors conducted a review article of major blepharoplasty complications and their treatment. RESULTS: Complications within the first postoperative week include corneal abrasions and vision-threatening retrobulbar hemorrhage; the intermediate period (weeks 1 through 6) addresses upper and lower eyelid malpositions, strabismus, corneal exposure, and epiphora; and late complications (>6 weeks) include changes in eyelid height and contour along with asymmetries, scarring, and persistent edema. CONCLUSIONS: A thorough knowledge of potential complications of blepharoplasty surgery is necessary for the practicing aesthetic surgeon. Within this article, current concepts and relevant treatment strategies are reviewed with the use of the most recent and/or appropriate peer-reviewed literature available. PMID- 20195128 TI - A family operation: plastic surgeons who perform aesthetic surgery on spouses or other family members. AB - BACKGROUND: The purpose of this study was to investigate whether plastic surgeons would perform elective cosmetic surgery on spouses or other family members and how many have done so, the type of procedures, the circumstances under which the surgery took place, and the results. METHODS: Participants were 465 members of the American Society for Aesthetic Plastic Surgery, representing 30.7 percent of the overall sample pool of 1513 members recruited through anonymous, voluntary participation in an online survey. Approximately half (51.8 percent) were 51 to 65 years old, most were men (91.2 percent), and most were from large urban areas; respondents had been in practice for 1 to 40 years. RESULTS: The plastic surgeons who returned the survey were comfortable performing elective cosmetic procedures on family members, the majority having already done so. Eighty-eight percent reported they would operate on a spouse or other family member, and 83.9 percent reported they already had. The main motivation (67 percent) was their belief that they were the best surgeon for the procedure. The most commonly listed operations were rhinoplasty, abdominoplasty, eyelidplasty, face lift, breast augmentation, and liposuction. Patients included spouses, children, parents, cousins, and in laws, ranging from teenaged males to women in their 70s. The overwhelming majority (94.2 percent) reported no complications, and 99.5 percent believed the patients were satisfied with their outcome. CONCLUSIONS: Survey participants are comfortable with the idea of performing elective cosmetic procedures on family members. Regardless of the invasiveness of the procedure or their relationship with the patient, respondents reported no complications and a high level of patient satisfaction anomalous for any patient-surgeon sample, suggesting that surgeons who operate on family members hold confident opinions of their surgical skills and results. PMID- 20195129 TI - Use of absorbable running barbed suture and progressive tension technique in abdominoplasty: a novel approach. PMID- 20195130 TI - Recent Canadian plastic surgery graduates: are they prepared for the real world? AB - BACKGROUND: The purpose of this study was to evaluate the correlation between plastic surgery education received through residency in Canadian programs and perceived preparedness for independent clinical practice among recently graduated plastic surgeons. METHODS: All practicing plastic surgeons having graduated from a Canadian program between 1996 and 2006 were surveyed. An itemized Web-based questionnaire was designed and distributed by e-mail with the assistance of all program directors. RESULTS: Eighty (52 percent) of the 155 recent graduates from Canadian plastic surgery programs with valid contact information responded to the survey. The majority of respondents were satisfied with most aspects of their training. Only 22 percent of respondents had done part of their training in a foreign center, but all of them agreed that it was beneficial to their training. Clinical research was encouraged in 92 percent of the respondents' programs, but dedicated time was only allocated in 29 percent of these. At the beginning of their practice, the majority of respondents felt comfortable or very comfortable in all subspecialties with the exception of pediatric plastic surgery and ancillary procedures. CONCLUSIONS: The authors' results describe the tendencies in type and duration of the training that Canadian graduates had over the last 10 years. The majority of respondents were satisfied with most aspects of their residency programs and felt comfortable practicing different subspecialties early in their careers. Expectations during residency and the resources made available to meet these expectations are also revealed. This study will help improve residency programs by identifying existing gaps in the preparedness of surgeons. PMID- 20195131 TI - Discussion. Recent Canadian plastic surgery graduates: are they prepared for the real world? PMID- 20195134 TI - Re: A placebo-controlled surgical trial of the treatment of migraine headaches. PMID- 20195136 TI - Has the time come to change the breast-conserving treatment for skin and nipple areola complex-sparing mastectomy? PMID- 20195138 TI - Re: Arterial and venous anatomies of the deep inferior epigastric artery perforator and superficial inferior epigastric flaps. PMID- 20195139 TI - Comparison of wedge versus straight-line reduction labioplasty. PMID- 20195143 TI - Re: A murine model for studying diffusely injected human fat. PMID- 20195144 TI - What is a leader? Are plastic surgeons leaders? PMID- 20195146 TI - Association of intravesical tumor location with metastases to the pelvic lymph nodes in transitional cell cancer of the bladder. AB - INTRODUCTION: In this study, we aimed to determine those clinical and pathologic features that are associated with pelvic lymph node metastasis in patients with transitional cell cancer of the bladder. Unlike previous studies, we particularly focused on intravesical tumor location. METHODS: We included 173 patients who underwent radical cystectomy and bilateral pelvic lymphadenectomy for muscle invasive or high-risk superficial bladder cancer. Fifty patients (28.9%) presented with lymph node metastases. Tumor-related and personal characteristics were analyzed. RESULTS: Lymph node positive disease occurred in association with an increasing pathologic tumor stage (P < 10(-6)) and with a decreasing differentiation status (P = 0.008). The rate of pelvic lymph node metastasis differed in primary tumors growing on different intravesical locations. Cancers located exclusively on the lateral bladder walls (P < 10(-5)) and tumors involving the lateral walls (P = 0.042) were highly correlated with lymph node positive disease. Posterior wall tumors were least associated with lymph node metastases compared with other tumor locations (P = 0.015). Focal tumor growths located on the lateral bladder wall and an increasing pathologic tumor stage and decreasing differentiation-status were identified as independent risk factors for the pelvic lymph node status. CONCLUSIONS: For the first time we present the association of intravesical tumor location and the rate of lymph node metastasis in transitional cell cancer of the bladder. Our findings may ultimately contribute to a more individualized patient management. PMID- 20195147 TI - Postsplenectomy cytomegalovirus mononucleosis is a distinct clinicopathologic syndrome. AB - Lymphocytosis in response to viral infection, such as infectious mononucleosis, rarely exceeds 20 x 10(9)/L in the adult population. Transfusion-acquired cytomegalovirus (CMV) mononucleosis after trauma-related splenectomy may cause prominent lymphocytosis, but the history and timing usually hint at the diagnosis. We describe a case of severe CMV mononucleosis that was acquired naturally decades after splenectomy. Together with the 2 similar cases that we reported recently, these cases all presented as initial diagnostic challenge because of a remote history of splenectomy, a prolonged febrile illness (approximately 4 weeks), marked lymphocytosis (peak 27.9 x 10(9)/L), and undetectable or weakened anti-CMV IgM antibody response. The diagnosis was eventually established through detection of circulating CMV antigen or DNA and a year or longer follow-up with serial determination of IgM and IgG antibodies. Two similar cases were also identified in the literature and reviewed. Although the impaired IgM response may confuse the diagnosis, it correlates well with recent studies showing that human blood IgM memory B cells are circulating splenic marginal zone B cells; asplenic or splenectomized individuals, irrespective of the underlying cause, have undetectable IgM memory B cells. Together, these findings suggest that distant or recent postsplenectomy CMV mononucleosis represents a distinct clinicopathologic syndrome resulting from poor control of early viremia because of the lack of both splenic filtration and the typical brisk IgM response. For the practicing clinician, recognizing these features may aid timely diagnosis and treatment. PMID- 20195148 TI - Primary hepatic actinomycosis. AB - The clinical and imaging findings of primary hepatic actinomycosis are nonspecific and can mimic other diseases. This condition usually needs to be distinguished from other liver-occupying lesions, including malignancy. Review of the English language literature showed 67 cases of hepatic actinomycosis in immunocompetent, predominantly male patients. Infection was usually (75%) cryptogenic. The results of radiologic imaging showed that the lesion involved the right lobe in half of the cases, mimicked a liver tumor in 45%, and was single in two thirds of the cases. Hepatic actinomycosis coexisted with infections by common bacteria in 32% of cases reported. Diagnosis was usually achieved by microscopic examination of surgical or percutaneous specimens in 84.2% and 78.6%, respectively. Antibiotic therapy alone was used for treatment in approximately one half of cases and combined antibiotic treatment with surgical or percutaneous drainage procedure in the other half. The overall mortality rate was 7.6%. In conclusion, primary hepatic actinomycosis is a rare and usually cryptogenic infection. It is more common in men and immunocompetent subjects. It is well responsive to medical or combined medical and interventional treatment. PMID- 20195149 TI - A 22-year-old woman with abdominal pain. PMID- 20195150 TI - Failure of institutionally derived predictive models of conversion in laparoscopic colorectal surgery to predict conversion outcomes in an independent data set of 998 laparoscopic colorectal procedures. AB - OBJECTIVE: The aim of this study was to perform an external validation of 2 institutionally derived predictive models of laparoscopic conversion in colorectal surgery using the Mayo Clinic, Rochester (MCR) laparoscopic colon and rectal surgery experience. SUMMARY OF BACKGROUND DATA: Two different predictive scoring systems of conversion in laparoscopic colorectal surgery were developed and published based upon single institution experiences. Neither model was validated on an independent data set. Thus, the utility of these models outside of their respective institutions is unknown. METHODS: A prospectively collected data set of 998 laparoscopic colorectal procedures from MCR was analyzed. All patient-, procedure-, and surgeon-related factors used in both models were present in our data set. Logistic regression was used to evaluate their ability to predict conversion in our cohort. Model effectiveness was assessed by area under the curve from the logistic regression model, 95% confidence intervals for the observed number of conversions, and a goodness-of-fit test to compare the observed number of conversions with the predicted conversion rates for each score. RESULTS: The cohort mean age of 552 women was 53, with a median body mass index of 25.2 kg/m. There were 382 right-sided, 251 left-sided, 46 rectal resections, and 151 proctocolectomies. Major diagnoses were inflammatory bowel disease 34%, cancer 18%, polyps 17%, and diverticular disease 13%. The overall MCR conversion rate was 15%. Several variables from the models were statistically significant predictors of conversion in our data set. However, both models performed similarly with an area under the curve of 0.62, suggesting that these models are of limited predictive value in our independent cohort with a performance closer to chance. The numbers of actual conversions were significantly different from the predicted number for both scoring systems. CONCLUSION: Patient and clinical factors associated with laparoscopic conversion in colorectal surgery may be institution dependent. This finding cautions surgeons on the applicability of institution-based surgical predictive models. Independent data set validation is recommended before surgical predictive models are applied to general clinical practice. PMID- 20195151 TI - Sentinel lymph node biopsy in breast cancer: ten-year results of a randomized controlled study. AB - OBJECTIVE: Sentinel node biopsy (SNB) is widely used to stage the axilla in breast cancer. We present 10-year follow-up of our single-institute trial designed to compare outcomes in patients who received no axillary dissection if the sentinel node was negative, with patients who received complete axillary dissection. METHODS: From March 1998 to December 1999, 516 patients with primary breast cancer up to 2 cm in pathologic diameter were randomized either to SNB plus complete axillary dissection (AD arm) or to SNB with axillary dissection only if the sentinel node contained metastases (SN arm). RESULTS: The 2 arms were well-balanced for number of sentinel nodes found, proportion of positive sentinel nodes, and all other tumor and patient characteristics. About 8 patients in the AD arm had false-negative SNs on histologic analysis: a similar number (8, 95% CI: 3-15) of patients with axillary involvement was expected in SN arm patients who did not receive axillary dissection; but only 2 cases of overt axillary metastasis occurred. There were 23 breast cancer-related events in the SN arm and 26 in the AD arm (log-rank, P = 0.52), while overall survival was greater in the SN arm (log-rank, P = 0.15). CONCLUSIONS: Preservation of healthy lymph nodes may have beneficial consequences. Axillary dissection should not be performed in breast cancer patients without first examining the sentinel node. PMID- 20195153 TI - An example to follow. PMID- 20195152 TI - Open pancreatic necrosectomy in the multidisciplinary management of postinflammatory necrosis. AB - OBJECTIVE: To examine clinical outcome in a consecutive cohort of patients undergoing open necrosectomy for postinflammatory necrosis. BACKGROUND INFORMATION: The last decade has witnessed major developments in the surgical management of pancreatic necrosis. Minimally invasive approaches have become established. However, there are limited data from contemporary open necrosectomy, in particular where multidisciplinary care and aggressive interventional radiology are used. This report provides data on outcome from open necrosectomy in a tertiary referral Hepatobiliary unit over the last decade. METHODS: During the period January 1, 2000 to July 31, 2008, 1535 patients were admitted with a final discharge code of acute pancreatitis. Twenty-eight (1.8%) of all admissions underwent open surgical necrosectomy. Twenty-four (86%) were tertiary referral patients. RESULTS: The median APACHE II score on admission was 10.5 (5-26). Median logistic organ dysfunction score on admission was 3 (0-10). Median LODS score after surgery was 2 (0-8). Twenty patients (71%) underwent radiologically guided drainage of collections before surgery. Thirty-day mortality occurred in 2 (7%), 4 further deaths occurred in patients after discharge from intensive care resulting in a total of 6 (22%) episode-related deaths. CONCLUSIONS: Modern open necrosectomy can be performed without the procedure-related deterioration in organ dysfunction associated with major debridement. Multidisciplinary care with an emphasis on aggressive radiologic intervention before and after surgery results in acceptable outcomes in this cohort of critically ill patients. Newer laparoscopic techniques must demonstrate similar outcomes in the setting of stage matched severity before wider acceptance. PMID- 20195154 TI - Evaluation of a cardiovascular disease risk assessment tool for the promotion of healthier lifestyles. AB - BACKGROUND: Although percentage risk formats are commonly used to convey cardiovascular disease (CVD) risk, people find it difficult to understand these representations. AIMS: To compare the impact of providing a CVD risk message in either a traditional format (% risk) or using an analogy of risk (Heart-Age) on participants' risk perceptions and intention to make lifestyle changes. METHODS: Four hundred and thirteen men and women were randomly allocated to one of two conditions; CVD risk as a percentage or as a Heart-Age score (a cardiovascular risk adjusted age). RESULTS: There was a graded relationship between perceived and actual CVD risk only in those participants receiving a Heart-Age message (P<0.05). Heart-Age was more emotionally impactful in younger individuals at higher actual CVD risk (P<0.01). Self-reported emotional reactions further mediated the relationship between risk perception and intention to make lifestyle changes. CONCLUSION: This study found that the Heart-Age message significantly differed from percentage CVD risk score in risk perceptions and was more emotionally impactful in those participants at higher actual CVD risk levels. PMID- 20195155 TI - Evaluation of cardiovascular risk predicted by different SCORE equations: the Netherlands as an example. AB - BACKGROUND: In Europe, for primary prevention of cardiovascular diseases (CVD), the Systematic COronary Risk Evaluation (SCORE) risk charts for high-risk and low risk regions (SCORE-high and SCORE-low, respectively) are used. For the Dutch 'Clinical Practice Guideline for Cardiovascular Risk Management' an adapted SCORE risk chart (SCORE-NL) was developed in collaboration with the SCORE group. We evaluated these three SCORE equations using Dutch risk factor and mortality data. DESIGN: Prospective cohort study with 10-year follow-up. METHODS: Baseline data were collected between 1987 and 1997 in 32 885 persons aged 37.5-62.5 years. Vital status was checked and causes of death were obtained from Statistics Netherlands. On the basis of the level of risk factors, the expected number of CVD deaths was calculated by applying the three SCORE equations and compared with the observed number. RESULTS: The observed CVD mortality was three-fold higher in men (n=242; 1.6%) than in women (n=83; 0.5%). On the basis of SCORE-NL, 8.5% of the men and 0.8% of the women had a CVD mortality risk of 5% or more. The ratio of the observed-to-expected number of CVD deaths was 0.75 for men and 0.55 for women using SCORE-NL, 0.54 and 0.56 using SCORE-high, and 1.11 and 0.95 using SCORE-low. CONCLUSION: At the population level, SCORE-low predicts the number of CVD deaths well, whereas both SCORE-NL and SCORE-high overestimate the number of CVD deaths by a factor 1.5-2. PMID- 20195156 TI - Overcrowding: emergency departments are the canary in the coal mine and overcrowding is the poisonous gas. PMID- 20195157 TI - Acute cardiac effects of carbon monoxide poisoning in children. AB - OBJECTIVE: Carbon monoxide (CO)-induced cardiotoxicity has been investigated infrequently in children and reports of its cardiovascular effects are limited to isolated case reports. Our aims were to describe acute cardiac effects and associated factors with myocardial injury in children with CO poisoning. METHODS: We reviewed the medical records of children below 17 years of age who were diagnosed with CO poisoning at pediatric emergency department between July 2004 and June 2007. Patients who had carboxyhemoglobin level at least 10% were included. Myocardial injury was defined as elevated cardiac biomarkers (creatine kinase-MB or troponin-t). Carboxyhemoglobin level, electrocardiogram (ECG) findings, cardiac biomarkers, and echocardiograph results were recorded for each patient. RESULTS: Cardiac biomarkers were drawn in 107 patients, of which 16 patients (15%) had cardiac biomarkers confirmed diagnosis of myocardial injury. Sinus tachycardia was present in 32% of patients on baseline ECG. None of the patients had ischemic changes on ECG. Echocardiograph was performed in 27 patients (25% of patients with biomarkers drawn), of which nine patients had low ejection fraction and abnormal left ventricular function. Determinators of myocardial injury included a Glasgow Coma Scale (GCS) score or=30% reduction of size and >or=50% reduction of [maximum standardized uptake value] SUVmax and mean TTR, 49.4 months versus 23.5 months, p = 0.022 with criteria of >or=30% reduction of size and >or=25% reduction of SUVmax, respectively). The TTR of radiologic responders (criteria of >or=30% reduction of size) and metabolic responders (criteria of >or=25% reduction of SUVmax) was not different from the TTR of nonresponders (p > 0.05). The accuracy for the prediction of pathologic response was 70% in radiologic responders, 52 to 75% in metabolic responders, and 73 to 82% in radiologic-metabolic responders. CONCLUSIONS: Tumor response evaluation using combined interpretation of [18F] fluorodeoxyglucose-PET and CT was more effective than single interpretation of CT response or PET response alone for the prediction of tumor recurrence and pathologic response. PMID- 20195169 TI - Interactions between cytotoxic chemotherapy and antiretroviral treatment in human immunodeficiency virus-infected patients with lung cancer. AB - Interactions between combination antiretroviral therapy (CART) and lung cancer treatment are emerging clinical concerns. Among the reasons for that, one can observe the longer survival of human immunodeficiency virus (HIV)-infected patients since introduction of CART and the epidemiologic rising of lung cancer, mainly adenocarcinomas, in this population. In addition, the higher relative risk of lung cancer in HIV-infected patients compared with general population has been recently demonstrated. Patients' demography and disease characteristics differ from the general lung cancer population, although most cases occur in patients with a smoking history: HIV-infected subjects are generally younger and diagnosis frequently made at locally advanced or metastatic stages. The choice of cytotoxic chemotherapy and antiretroviral therapy is essential in the context of lung cancer (1) to minimize potential interactions and life-threatening toxicities particularly through cytochrome P450 interaction, (2) to implement adequate prevention of foreseeable toxicity, and (3) to fully reinforce antineoplastic and antiretroviral efficacy. Pharmacokinetics data and clinical cases pinpoint to potential life-threatening interactions between protease inhibitors/ritonavir and taxanes, vinca alkaloids, as well as the anilinoquinazolines erlotinib and gefitinib and irinotecan. Optimal choice of chemotherapy and CART in HIV-infected patients with lung cancer is an individualized multidisciplinary decision, involving clinical and antiretroviral history, and predicting potential adverse events and interactions. PMID- 20195168 TI - Subtyping of undifferentiated non-small cell carcinomas in bronchial biopsy specimens. AB - INTRODUCTION: The emergence of treatments for non-small cell lung carcinoma (NSCLC) with differential efficacy and toxicity between subtypes has highlighted the importance of specific pathologic NSCLC subtyping. Most NSCLCs are inoperable, and pathologic diagnosis is made only on small tissue samples that are prone to diagnostic inaccuracy. In a substantial proportion of cases, standard morphology cannot specifically subtype the tumor, necessitating a diagnosis of NSCLC-not otherwise specified (NOS). Histochemical staining for mucin and immunohistochemical (IHC) identification of NSCLC subtype-associated markers could help predict the final subtype of resected NSCLCs diagnosed as NSCLC-NOS on preoperative bronchial biopsy samples. METHODS: Paraffin sections of 44 bronchial biopsy samples diagnosed as NSCLC-NOS were stained for mucin (Alcian blue/periodic acid Schiff) and thyroid transcription factor 1 by IHC-(markers of adenocarcinoma), and for S100A7, cytokeratin 5/6, high molecular weight cytokeratins, and p63 proteins-markers of squamous cell carcinoma. A predictive staining panel was derived from statistical analysis after comparing staining profiles with the final postsurgical NSCLC subtype. This panel was prospectively applied to 82 small biopsy samples containing NSCLC. RESULTS: True NSCLC subtype of undifferentiated NSCLC samples was best predicted using Alcian blue/periodic acid Schiff plus p63 and thyroid transcription factor 1 IHC, allowing specific subtyping in 73% of NSCLC-NOS cases with 86% accuracy. When applied prospectively, this staining panel showed 100% concordance with specific NSCLC morphologic subtyping in small biopsies. CONCLUSION: This approach can facilitate treatment selection by accurately predicting the subtype in undifferentiated NSCLC biopsies, reducing to 7% the proportion of cases without a definite or probable histologic subtype. PMID- 20195170 TI - Who are less likely to receive subsequent chemotherapy beyond first-line therapy for advanced non-small cell lung cancer? Implications for selection of patients for maintenance therapy. AB - BACKGROUND: Prospective studies have implied that maintenance therapy for non small cell lung cancer (NSCLC) has its effect by giving active drugs earlier to patients who otherwise die without receiving second-line therapy. The purpose of this study was to select patients with NSCLC who could most benefit from maintenance therapy, by evaluating which patients would be less likely to receive second-line therapy. METHODS: Clinicopathologic data of patients with advanced NSCLC who received four cycles of first-line chemotherapy followed by time-off therapy and eventual disease progression or death were reviewed retrospectively. Patients were grouped into ones with first-line therapy only or ones with more than first-line therapy. Clinical characteristics between the two groups were compared. RESULTS: A total of 271 patients were eligible for analysis, and 39 patients (14.4%) received only first-line therapy. Patients significantly more likely to receive only first-line therapy had performance status of two or three after first-line therapy, large volume of initial target lesions (sum of long diameters >or=70 mm), or smaller decrease in target lesions (decrease <20%) after first-line therapy. Median overall survival of the 143 patients (52.8%) with at least one of these characteristics (16.3 months) was significantly shorter than that of patients without any of these characteristics (23.5 months, p = 0.007). CONCLUSION: Maintenance therapy may be of greater benefit to patients with NSCLC who have clinical characteristics including poor performance status after first line therapy, large initial target lesions, or smaller decrease in target lesions after first-line therapy. PMID- 20195171 TI - Osteoblastic reaction in non-small cell lung carcinoma and its association to epidermal growth factor receptor tyrosine kinase inhibitors response and prolonged survival. AB - INTRODUCTION: The aim of this study was to describe the characteristics and epidermal growth factor receptor (EGFR) mutational status of patients with non small cell lung cancer (NSCLC) with osteoblastic reactions diagnosed before or during treatment with EGFR tyrosine kinase inhibitors (TKIs). METHODS: Retrospective study including patients with 36 NSCLC with at least one site of osteoblastic reaction at the time of diagnosis or during treatment with EGFR-TKI. RESULTS: The rate of patients with mutated EGFR tumors with osteoblastic reactions before or after EGFR-TKI treatment was similar. Median progression-free survival (PFS) for the entire group was more than 9 months and median survival was more than 12 months. There was no statistically significant difference in survival between patients with osteoblastic reactions before initiation of TKI and those diagnosed during TKI treatment. Patients with extraosseous metastases when treated with TKI had the lowest survival (P < 0.0001). CONCLUSIONS: In patients with NSCLC treated with TKI, initial or development of an osteoblastic reaction seems to be related to a more favorable outcome. In patients with osteoblastic reactions, tumors present with clinical and biologic characteristics of better survival and response to TKI. The occurrence of osteoblastic reactions during treatment with TKI, while primary tumor and metastases are stable or in response, should not be considered as disease progression. PMID- 20195172 TI - Clinical prescribing (and off-label use) in a second-best world. PMID- 20195173 TI - The rise and fall of gabapentin for bipolar disorder: a case study on off-label pharmaceutical diffusion. AB - CONTEXT: Rising drug costs have increased focus on how new pharmaceuticals diffuse into the marketplace. The case of gabapentin use in bipolar disorder provides an opportunity to study the roles of marketing, clinical evidence, and prior authorization (PA) policy on off-label medication use. DESIGN: Observational study using Medicaid administrative and Verispan marketing data. We examined the association between marketing, clinical trials, and prior authorization on gabapentin use. SETTING AND PATIENTS: Florida Medicaid, bipolar disorder-diagnosed enrollees ages 18 to 64 for fiscal years 1994 to 2004. RESULTS: Gabapentin prescriptions increased from 8/1000 enrollees per quarter in 1994 to a peak of 387/1000 enrollees in 2002. Its uptake tracked marketing efforts towards psychiatrists. The publication of 2 negative clinical trials in 2000 and the discontinuation of marketing expenditures towards psychiatrists were associated with an end to the steep rise in gabapentin prescriptions. After these events gabapentin use remained between 319/1000 and 387/1000 enrollees per quarter until the PA policy, which was associated with a 45% decrease in prescriptions filled. After 1 year, scientific evidence and marketing discontinuation were associated with a 5.4 percentage point decrease in the predicted probability of filling a gabapentin prescription and the PA policy, a 7.1 percentage point decrease. CONCLUSIONS: Pharmaceutical marketing can influence off-label medication prescribing, particularly when pharmacologic options are limited. Evidence of inefficacy and/or the cessation of pharmaceutical marketing, and a restrictive formulary policy can alter prescriber behavior away from targeted pharmacologic treatments. These results suggest that both information and policy are important means in altering physician prescribing behavior. PMID- 20195174 TI - Geographic access and the use of screening mammography. AB - BACKGROUND: Screening mammography rates vary geographically and have recently declined. Inadequate mammography resources in some areas may impair access to this technology. We assessed the relationship between availability of mammography machines and the use of screening. METHODS: The location and number of all mammography machines in the United States were identified from US Food and Drug Administration records of certified facilities. Inadequate capacity was defined as <1.2 mammography machines per 10,000 women age 40 or older, the threshold required to meet the Healthy People 2010 target screening rate. The impact of capacity on utilization was evaluated in 2 cohorts: female respondents age 40 or older to the 2006 Behavioral Risk Factor Surveillance System survey (BRFSS) and a 5% nationwide sample of female Medicare beneficiaries age 65 or older in 2004 2005. RESULTS: About 9% of women in the BRFSS cohort and 13% of women in the Medicare cohort lived in counties with <1.2 mammography machines per 10,000 women age 40 or older. In both cohorts, residence in a county with inadequate mammography capacity was associated with lower odds of a recent mammogram (adjusted odds ratio in BRFSS: 0.89, 95% CI: 0.80-0.98, P < 0.05; adjusted odds ratio in Medicare: 0.86, 95% CI: 0.85-0.87, P < 0.05), controlling for demographic and health care characteristics. CONCLUSION: In counties with few or no mammography machines, limited availability of imaging resources may be a barrier to screening. Efforts to increase the number of machines in low-capacity areas may improve mammography rates and reduce geographic disparities in breast cancer screening. PMID- 20195175 TI - When payment systems collide: the effect of hospitalization on anemia in renal dialysis patients. AB - BACKGROUND: Different types of providers often face differing financial incentives for providing similar types of care. This may have implications for payment systems that target improvements in care requiring multiple types of providers. OBJECTIVES: The objective of this study was to determine how hospitalization influences the anemia of Medicare patients with chronic renal failure, where anemia is treated under a prospective payment system during hospitalizations and under a fee-for-service system during outpatient renal dialysis. METHODS: We examined the effects of time in hospital and reason for hospitalization on levels of anemia among 87,263 Medicare renal dialysis patients with a hospital stay of 3 days or more during 2004. Medicare claims were used to measure changes in hematocrit between the month before and the month after hospital discharge, and to classify admissions with a high risk of anemia. Multilevel models were used to study variation in outcomes across providers. RESULTS: Longer time in the hospital was associated with worsening anemia. As expected, larger declines in hematocrit occurred following admissions for conditions or procedures with a high risk of anemia. However, we observed a similar effect of time in the hospital for admissions both with and without a high risk of anemia. There were relatively large differences in anemia outcomes across both individual hospitals and physicians. CONCLUSIONS: Hospitalization related anemia increases the need for care by outpatient renal dialysis providers. Efforts to improve care through payment system design are more likely to be successful if financial incentives are aligned across care settings. PMID- 20195176 TI - Muscular strength is inversely associated with aortic stiffness in young men. AB - Muscular strength is associated with reduced mortality. Paradoxically, strength training may increase central artery stiffness, a predictor of cardiovascular morbidity and mortality. However, the relationship between muscular strength and central arterial stiffness has yet to be defined. PURPOSE: The purpose of this study was to determine the relationship between muscular strength and central arterial stiffness in young men. METHODS: Central and peripheral pulse wave velocity (PWV), augmentation index, muscular strength, and aerobic capacity (V O2peak) were measured in 79 young men (mean +/- SD, age = 23 +/- 4 yr). Height, weight, and brachial blood pressure were also recorded. Muscular strength was determined using a one-repetition maximum bench press and normalized to bodyweight. Spearman correlations were used to determine the relationships between relative strength, aerobic fitness, and hemodynamic/vascular measures. RESULTS: There was a significant negative correlation between central PWV and strength (r = -0.222, P < 0.05). The relationship remained significant when controlling for aerobic fitness (r = -0.189, P < 0.05). Muscular strength was significantly higher (P < 0.05) in men with low central PWV (5.2 +/- 0.4 m.s) compared with men with high central PWV (6.6 +/- 0.4 m.s). CONCLUSION: These results show that there is a significant inverse association between muscular strength and aortic stiffness independent of aerobic fitness. PMID- 20195177 TI - Greater exercise sweating in obese women with polycystic ovary syndrome compared with obese controls. AB - PURPOSE: We examined estradiol and testosterone effects on thermoregulation in women with and without Polycystic Ovary syndrome (PCOS). We hypothesized that core temperature (Tc) threshold for sweating during exercise is delayed in women with PCOS and that testosterone delays the Tc set point for sweating during exercise. METHODS: For 16 d, we suppressed estrogens, progesterone, and testosterone with a gonadotropin-releasing hormone antagonist (GnRHant) in seven women with and seven women without PCOS (control); we added 17[beta]-estradiol (0.2 mg.d-1, two patches) on days 4-16 (E2) and testosterone (2.5 mg.d-1, orally) on days 13-16 (E2 + T). Under each hormone condition, subjects cycled in a temperature of 35 degrees C at 60% of age-predicted HRmax for 40 min. RESULTS: Tc sweating threshold was lower in women in the PCOS group compared with those in the control during GnRHant (37.21 degrees C +/- 0.51 degrees C vs 37.70 degrees C +/- 0.12 degrees C, P < 0.05); neither E2 nor E2 + T influenced the thermoregulatory responses in PCOS. E2 decreased Tc sweating threshold in control (37.06 degrees C +/- 0.69 degrees C, P < 0.05), but E2 + T attenuated this response (37.53 degrees C +/- 0.19 degrees C). Peak sweating rate was greater in women in the PCOS group compared with those in the control group during GnRHant (1.06 +/- 0.47 vs 0.47 +/- 0.11 mg.cm-2.min-1) and E2 + T (0.85 +/- 0.41 vs 0.44 +/- 0.10 mg.cm-2.min-1, P < 0.05). Compared with the control group, total sweat losses were greater in the PCOS group during GnRHant (0.614 +/- 0.189 vs 0.419 +/ 0.098 L) and during E2 + T (0.696 +/- 0.281 vs 0.434 +/- 0.164 L, P < 0.05) but not during E2 (0.639 +/- 0.231 and 0.505 +/- 0.214 L for PCOS and control groups, respectively, P = 0.09). CONCLUSIONS: Thermoregulation was adequate in women with PCOS; however, the women with PCOS achieved thermoregulation at the expense of producing higher sweat volumes. PMID- 20195178 TI - Glossopharyngeal insufflation and pulmonary hemodynamics in elite breath hold divers. AB - PURPOSE: Acute voluntary lung hyperinflation provoked by glossopharyngeal insufflation (GI) elicits numerous, possibly deleterious, effects on the cardiopulmonary system by increasing intrathoracic pressures far above normal values. This study quantifies acute pulmonary hemodynamics during GI using phase contrast magnetic resonance imaging (MRI). METHODS: Hemodynamic parameters were measured in nine elite male breath hold divers with a mean age of 30 yr (range = 20-43 yr) by velocity-encoding cine (VEC)-MRI of the main pulmonary artery (PA) before, during, and after GI. Simultaneously, GI-lung volume (GIVEC-MRI) was measured by MR-compatible spirometry. RESULTS: Hemodynamic parameters were associated with GIVEC-MRI. Highly significant changes during GI were shown for the mean flow in the PA, which decreased by 45% (P < 0.007), and right ventricular output and cardiac index, which decreased by 41% and 40%, respectively (P < 0.007). Acceleration time also decreased highly significant by 36% during GI (P < 0.007). All hemodynamic parameters except acceleration time returned to baseline after GI. CONCLUSIONS: Acute voluntary lung hyperinflation mimics changes seen in pulmonary arterial hypertension, but unlike the latter, these changes are fully reversible shortly after cessation of voluntary lung hyperinflation. Persistent changes due to repetitive GI could not be detected. PMID- 20195179 TI - Oxygen uptake response to stroke rate manipulation in freestyle swimming. AB - During gait, humans choose a combination of step length and step rate that minimizes VO2. However, little work has been reported on the existence of such optimization in swimming. PURPOSE: The purpose of this study was to examine the manipulation of stroke rate on VO2 in submaximal, constant speed freestyle swimming. METHODS: Preferred stroke rate for swimming freestyle at 1.0 m.s(-1) in a flume was determined for 10 competitive swimmers (mean +/- SD: age = 33.3 +/- 13.6 yr, height = 175.3 +/- 8.6 cm, weight = 74.9 +/- 12.2 kg). Participants then completed flume swims at 1.0 m.s(-1) with stroke rates equal to -20%, -10%, 0%, +10%, and +20% of their preferred stroke rate in a randomized order during which VO2 was continuously monitored. Each trial continued for 1 min after steady-state VO2 was verified (~4-5 min). During the final minute of each trial, VO2 was measured using the Douglas bag technique, HR was recorded, and kick rate (KR) was computed using the time needed to complete 30 kicks. RPE was reported immediately after each trial. RESULTS: VO2 increased 11%-16% (P < 0.05) when stroke rate was reduced but was nominally affected when stroke rate was increased. Likewise, HR increased 4%-6% (P < 0.05), and RPE increased 15%-30% (P < 0.05) when stroke rate was reduced but not affected when stroke rate was increased. CONCLUSIONS: These data suggest that these swimmers preferred to swim freestyle at the lowest stroke rate (or the longest stroke length) that did not require an increase in VO2. PMID- 20195180 TI - Critical power: implications for determination of VO2max and exercise tolerance. AB - For high-intensity muscular exercise, the time-to-exhaustion (t) increases as a predictable and hyperbolic function of decreasing power (P) or velocity (V ). This relationship is highly conserved across diverse species and different modes of exercise and is well described by two parameters: the "critical power" (CP or CV), which is the asymptote for power or velocity, and the curvature constant (W') of the relationship such that t = W'/(P - CP). CP represents the highest rate of energy transduction (oxidative ATP production, VO2) that can be sustained without continuously drawing on the energy store W' (composed in part of anaerobic energy sources and expressed in kilojoules). The limit of tolerance (time t) occurs when W' is depleted. The CP concept constitutes a practical framework in which to explore mechanisms of fatigue and help resolve crucial questions regarding the plasticity of exercise performance and muscular systems physiology. This brief review presents the practical and theoretical foundations for the CP concept, explores rigorous alternative mathematical approaches, and highlights exciting new evidence regarding its mechanistic bases and its broad applicability to human athletic performance. PMID- 20195181 TI - High-intensity training versus traditional exercise interventions for promoting health. AB - PURPOSE: The purpose of this study was to determine the effectiveness of brief intense interval training as exercise intervention for promoting health and to evaluate potential benefits about common interventions, that is, prolonged exercise and strength training. METHODS: Thirty-six untrained men were divided into groups that completed 12 wk of intense interval running (INT; total training time 40 min wk(-1)), prolonged running (approximately 150 min wk(-1)), and strength training (approximately 150 min wk(-1)) or continued their habitual lifestyle without participation in physical training. RESULTS: The improvement in cardiorespiratory fitness was superior in the INT (14% +/- 2% increase in VO2max) compared with the other two exercise interventions (7% +/- 2% and 3% +/- 2% increases). The blood glucose concentration 2 h after oral ingestion of 75 g of glucose was lowered to a similar extent after training in the INT (from 6.1 +/- 0.6 to 5.1 +/- 0.4 mM, P < 0.05) and the prolonged running group (from 5.6 +/- 1.5 to 4.9 +/- 1.1 mM, P < 0.05). In contrast, INT was less efficient than prolonged running for lowering the subjects' resting HR, fat percentage, and reducing the ratio between total and HDL plasma cholesterol. Furthermore, total bone mass and lean body mass remained unchanged in the INT group, whereas both these parameters were increased by the strength-training intervention. CONCLUSIONS: INT for 12 wk is an effective training stimulus for improvement of cardiorespiratory fitness and glucose tolerance, but in relation to the treatment of hyperlipidemia and obesity, it is less effective than prolonged training. Furthermore and in contrast to strength training, 12 wk of INT had no impact on muscle mass or indices of skeletal health. PMID- 20195182 TI - Cruciate ligament forces between short-step and long-step forward lunge. AB - PURPOSE: The purpose of this study was to compare cruciate ligament forces between the forward lunge with a short step (forward lunge short) and the forward lunge with a long step (forward lunge long). METHODS: Eighteen subjects used their 12-repetition maximum weight while performing the forward lunge short and long with and without a stride. EMG, force, and kinematic variables were input into a biomechanical model using optimization, and cruciate ligament forces were calculated as a function of knee angle. A two-factor repeated-measure ANOVA was used with a Bonferroni adjustment (P < 0.0025) to assess differences in cruciate forces between lunging techniques. RESULTS: Mean posterior cruciate ligament (PCL) forces (69-765 N range) were significantly greater (P < 0.001) in the forward lunge long compared with the forward lunge short between 0 degrees and 80 degrees knee flexion angles. Mean PCL forces (86-691 N range) were significantly greater (P < 0.001) without a stride compared with those with a stride between 0 degrees and 20 degrees knee flexion angles. Mean anterior cruciate ligament (ACL) forces were generated (0-50 N range between 0 degrees and 10 degrees knee flexion angles) only in the forward lunge short with stride. CONCLUSIONS: All lunge variations appear appropriate and safe during ACL rehabilitation because of minimal ACL loading. ACL loading occurred only in the forward lunge short with stride. Clinicians should be cautious in prescribing forward lunge exercises during early phases of PCL rehabilitation, especially at higher knee flexion angles and during the forward lunge long, which generated the highest PCL forces. Understanding how varying lunging techniques affect cruciate ligament loading may help clinicians prescribe lunging exercises in a safe manner during ACL and PCL rehabilitation. PMID- 20195183 TI - Early time course of Akt phosphorylation after endurance and resistance exercise. AB - PURPOSE: The aim of this study was to determine the early time course of exercise induced signaling after divergent contractile activity associated with resistance and endurance exercise. METHODS: Sixteen male subjects were randomly assigned to either a cycling (CYC; n = 8, 60 min, 70% VO2peak) or resistance (REX; n = 8, 8 x 5 leg extension, 80% one-repetition maximum, 3-min recovery) exercise group. Serial muscle biopsies were obtained from vastus lateralis at rest before, immediately after, and after 15, 30, and 60 min of passive recovery to determine early signaling responses after exercise. RESULTS: There were comparable increases from rest in Akt(Thr308/Ser473) and mTOR(Ser2448) phosphorylation during the postexercise time course that peaked 30-60 min after both CYC and REX (P < 0.05). There were also similar patterns in p70S6K(Thr389) and 4E BP1(Thr37/46) phosphorylation, but a greater magnitude of effect was observed for REX and CYC, respectively (P < 0.05). However, AMPK(Thr172) phosphorylation was only significantly elevated after CYC (P < 0.05), and we observed divergent responses for glycogen synthase(Ser641) and AS160 phosphorylation that were enhanced after CYC but not REX (P < 0.05). CONCLUSIONS: We show a similar time course for Akt-mTOR-S6K phosphorylation during the initial 60-min recovery period after divergent contractile stimuli. Conversely, enhanced phosphorylation status of proteins that promote glucose transport and glycogen synthesis only occurred after endurance exercise. Our results indicate that endurance and resistance exercise initiate translational signaling, but high-load, low-repetition contractile activity failed to promote phosphorylation of pathways regulating glucose metabolism. PMID- 20195184 TI - Sex differences in fatigue resistance are muscle group dependent. AB - PURPOSE: Women are often reported to be generally more resistant to fatigue than men for relative-intensity tasks. This has been observed repeatedly for elbow flexors, whereas at the ankle, sex differences appear less robust, suggesting localized rather than systemic influences. Thus, the purpose of this study was to examine sex differences in fatigue resistance at muscle groups in a single cohort and which factors, if any, predict endurance time. METHODS: Thirty-two young adults (age = 19-44 yr, 16 women) performed sustained isometric contractions at 50% maximum voluntary isometric contraction to failure for elbow flexion and ankle dorsiflexion. Pain, exertion, and muscle EMG were assessed throughout. Self reported baseline activity was measured using the International Physical Activity Questionnaire. RESULTS: Women were significantly more resistant to fatigue than men at the elbow (112.3 +/- 6.2 vs 80.3 +/- 5.8 s, P = 0.001) but not at the ankle (140.6 +/- 10.7 vs 129.2 +/- 10.5 s, P = 0.45). Peak torque was greater in men than that in women (P < 0.0001) at the ankle (45.0 +/- 1.7 vs 30.1 +/- 1.0 N.m) and at the elbow (75.7 +/- 3.1 vs 34.4 +/- 2.2 N.m). Peak torque was significantly related to endurance time at the elbow (R2= 0.30) but not at the ankle (R2 = 0.03). Peak pain, rate of pain increase, peak exertion, EMG, and baseline physical activity did not differ between sexes. CONCLUSIONS: Sex differences in fatigue resistance are muscle group specific. Women were more fatigue resistant at the elbow but not at the ankle during a sustained isometric contraction. Further, factors that may contribute to fatigue resistance for one muscle group (e.g., sex, peak torque) may not be critical at another. PMID- 20195185 TI - Do we need a universal 'code of ethics' in nuclear medicine? AB - Recent years have seen huge advances in medicine and the science of medicine. Nuclear medicine has been no exception and there has been rapid acceptance of new concepts, new technologies and newer ways of working. Ethical principles have been traditionally considered as generic skills applicable to wide groups of scientists and doctors, with only token refinement at specialty level. Specialist bodies across the world representing wide groups of practitioners frequently have subgroups dealing exclusively with ethical issues. It could easily be argued that the basic principles of ethical practice adopted by specialist bodies closest to nuclear medicine practice, such as radiology and oncology, will also be applicable to nuclear medicine and that time and effort need not be spent on specifying a separate code for nuclear medicine. It could also be argued that nuclear medicine is an independent specialty and some (if not most) practitioners will not be aware of the guidelines adopted by other specialist societies, and that there is a need for re-iteration of ethical principles at the specialty level and on a worldwide scale.In this article we would like to present a brief history of medical ethics, discuss some of the advances in nuclear medicine and their associated ethical aspects, as well as list a framework of principles for consideration, should a specialist body deem it suitable to establish a 'code of ethics' for nuclear medicine. PMID- 20195186 TI - A modified prosthesis head for middle ear titanium implants--experimental and first clinical results. AB - OBJECTIVE: An ossicular chain defect represents a challenging situation for otosurgeons. Despite modern reconstruction techniques, unsatisfying postoperative hearing results regularly occur. These are commonly caused by prosthesis dislocation. Whereas the reasons for prosthesis dysfunction occurring months or years after implantation are related to independent chronic conditions, early events of dislocations are more related to the technical fixation of the prosthesis inside the middle ear cavity. Consequently, a safe coupling between prosthesis head and tympanic membrane is essential for a successful type III tympanoplasty. Our study evaluated the use of a new prosthesis design with the aim to reduce short-term postoperative prosthesis dislocation in mind. STUDY DESIGN: Prospective experimental and clinical study. METHODS: A modified titanium total ossicular replacement prosthesis (TORP), whose head had spikes that extend into the cartilaginous neotympanic membrane, was designed and tested experimentally and then clinically. The lateral holding force of the new prosthesis head against lateral shift was measured and compared with common prosthesis heads without spikes. After proving this design experimentally, the prostheses were used intraoperatively in 35 tympanoplasty type III operations. Results were analyzed prospectively and compared with 35 retrospectively analyzed controls with conventional TORP prostheses. RESULTS: The lateral holding forces for the spike prosthesis heads were significantly higher (134 mN) than those for common prosthesis heads (92 mN) at a contact pressure of 100 mN. Postoperatively, pure-tone audiometry revealed satisfying hearing results. Spiked and conventional titanium TORPs yielded postoperative air-bone gaps (ABGs) of 20.9 and 18.6 dB with 54% and 57% ABG closure, within 20 dB, respectively. The air-bone gap was reduced by an average of 14 and 15 dB, respectively. However, these differences were not statistically significant. Both in the study and in the control group, no signs of prosthesis dislocation were discovered. CONCLUSION: The experimental data show that the new modified prosthesis head has an increased lateral holding force and thus reduces the risk of dislocation at the coupling side of the tympanic membrane. The postoperative hearing results are comparable to those of conventional prostheses. To confirm the advantage of the modified prosthesis plates over conventional prostheses, future studies with larger study populations are necessary. PMID- 20195187 TI - Merlin knockdown in human Schwann cells: clues to vestibular schwannoma tumorigenesis. AB - HYPOTHESIS: To investigate the early events in molecular progression toward schwannoma tumorigenesis, we developed an in vitro model of human Schwann cell tumorigenesis by merlin knockdown. BACKGROUND: Neurofibromatosis 2 (NF2)-related and sporadic vestibular schwannoma (VS) exhibit loss of functional merlin (schwannomin). After loss of merlin expression in the Schwann cell, the initial steps toward VS tumorigenesis are unknown. Merlin, a putative tumor suppressor protein, interacts with many cellular proteins, regulating their function. Among these are receptor tyrosine kinases, including the epidermal growth factor receptor family B (ErbB) family receptors epidermal growth factor receptor and ErbB2. Functional merlin interacts with and internalizes these growth factor receptors, silencing their proliferation and survival signaling. Deregulation of CD44, the cell adhesion/signaling molecule and cancer stem cell marker, has also been implicated in VS tumorigenesis. METHODS: Merlin knockdown was performed using small interfering RNA transfection into human Schwann cell primary cultures. Knockdown was confirmed by real-time quantitative PCR, immunofluorescence, and Western analysis. Expression profiles of ErbB, merlin, and the stem cell markers nestin and CD44 were examined in knockdowns. Proliferation rate was assessed with bromodeoxyuridine incorporation, and radiation sensitivity was assessed using the Annexin assay in knockdowns versus controls. RESULTS: Merlin knockdowns demonstrated increased proliferation rate, upregulation of epidermal growth factor receptor, ErbB2, and ErbB3, CD44, and nestin. Short-term merlin depletion had no effect on gamma irradiation sensitivity compared with controls. CONCLUSION: Merlin depletion results in deregulation of ErbB receptor signaling, promotes a dedifferentiated state, and increases Schwann cell proliferation, suggesting critical steps toward schwannoma tumorigenesis. PMID- 20195188 TI - Cavitating otosclerosis: clinical, radiologic, and histopathologic correlations. AB - BACKGROUND: Despite the high prevalence of otosclerosis and its having long been a subject of scrutiny, cavitary changes in otosclerosis are rare and not well known. Here, we describe and introduce into the literature the unusual histologic and radiologic findings of cavitation and its possible clinical relevance in patients with advanced cochlear otosclerosis. METHODS: Cases with clinical otosclerosis and presence of cavitation were selected from our temporal bone collection and correlated with premortem imaging and clinical manifestations. RESULTS: Two cases of cochlear otosclerosis presented with a clinical syndrome possibly attributed to the existence of a cavity within the otosclerotic foci. CONCLUSION: Cavitating otosclerosis is a not well-known occurrence in patients with advanced cochlear otosclerosis, and it is a possible cause of a "third window" syndrome and surgical complications. PMID- 20195189 TI - Long-term immunity after two doses of inactivated hepatitis A vaccine, in Argentinean children. AB - We examined long-term anti-hepatitis A virus antibody persistence in Argentinean children 10 years after the initial study in which they received 2 doses of inactivated hepatitis A vaccine (Avaxim 80U). Of the 111 children, 48 from the initial trial were enrolled. Of 48, 47 (97.9%) participants had serum anti hepatitis A virus antibody titers > or =20 mIU/mL, with the geometric mean concentration of 390.91 (+/-370.14) mIU/mL; (95% confidence interval, 282.2-499.5 mIU/mL), range, 36 to 1860. PMID- 20195191 TI - Evidence and impact: should these articles change the practice of spine care? An evidence-based medicine process. PMID- 20195192 TI - Athletic performance outcomes following lumbar discectomy in professional basketball players. AB - STUDY DESIGN: Retrospective case-control study. OBJECTIVE: To quantify the athletic performance profiles after lumbar discectomy (LD) in a cohort of National Basketball Association (NBA) players in comparison with a control group of matched NBA players who did not undergo LD during the same study period. SUMMARY OF BACKGROUND DATA: LD provides symptomatic relief and improved functional outcomes in the majority of patients as assessed by validated measures such as Oswestry Disability Index, Visual Analog Scale, and Short Form-36 (SF 36). Among professional athletes, however, the goal of lumbar HNP treated by discectomy is not only to improve functional status but also, ultimately, to return the player to preinjury athletic performance levels. No study to date has compared the athletic performance profiles before and after discectomy in professional athletes. METHODS: An analysis of NBA games summaries, weekly injury reports, player profiles, and press releases was performed to identify 24 NBA players who underwent LD for symptomatic lumbar HNP between 1991 and 2007. A 1:2 case: control study was performed using players without history of lumbar HNP who were matched for age, position, experience, and body mass index as control subjects (n = 48). Paired t tests were conducted on the following parameters: games played, minutes per game, points per 40 minutes, rebounds per 40 minutes, assists per 40 minutes, steals per 40 minutes, blocks per 40 minutes, and shooting percentage. For each athletic performance outcome, between-group comparisons evaluating preindex to postindex season performance were done (index season = season of surgery). RESULTS: In the LD group, 18 of 24 players (75%) returned to play again in the NBA, compared with 42 of 48 players (88%, P = 0.31) in the control group. One year after surgery, between-group comparisons revealed statistically significant increase in blocked shots per 40 minutes in the LD (0.18) versus control group (-0.33; P = 0.008) and a smaller decrease in rebounds per 40 minutes in the LD (-0.25) versus control group (-1.42; P = 0.049). No other performance variable was found to be significantly different between the study and control group. CONCLUSION: Compared with a closely matched control cohort, we found that 75% of surgical patients returned to play again in the NBA, compared with 88% in control subjects who did not undergo surgery. For those players who returned, overall athletic performance was slightly improved or no worse than control subjects. PMID- 20195193 TI - The manubrium as an external guide for centralizing anterior cervical plates: technique tips and initial experience. AB - STUDY DESIGN: Technique tips and retrospective review of prospectively collected data. OBJECTIVE: To describe a technique for centralizing cervical plates using the center of the manubrium as a primary external guide and its alignment with the mandible as a secondary guide. SUMMARY OF BACKGROUND DATA: Proper alignment of cervical plates is desirable to avoid improper placement of screws and possibly altered biomechanical performance. Large body habitus may portend suboptimal exposure, a limited utility of skin surface landmarks for level determination, and may make it difficult to reliably centralize plates in the coronal plane during anterior cervical surgery. METHODS: We describe a technique that uses the center of the manubrium to determine the midline of the cervical spine and align a line drawn through the manubrium with the center of the mandible to provide a central axis for placing cervical plates along the entire cervical spine. We used anteroposterior fluoroscopy to validate that a line from the middle of the manubrium to the mandible bisected the spinous processes and midline of the vertebral bodies. We prospectively collected data on 39 consecutive patients undergoing anterior cervical discectomy and fusion with cervical plates using this technique. RESULTS: The mean amount of angulation and translation about a midline axis were 2.24 degrees +/- 1.49 degrees and 1.04 +/- 0.86 mm, respectively. There were no statistical differences among 1-level, 2 level, and 3-level fusions (P > 0.05). The intraobserver correlation coefficient for the measurement technique was R = 0.90 (P = 0.0016). CONCLUSION: We validated that the midline of the cervical spine is in line with a straight bovie cord connecting the midline of the manubrium to the midline of the mandible using anteroposterior fluoroscopy. Using this line, we prospectively centered cervical plates with no significant difference between levels. These data may also serve as a benchmark for assessing cervical plate alignment. PMID- 20195194 TI - National revision burden for lumbar total disc replacement in the United States: epidemiologic and economic perspectives. AB - STUDY DESIGN: Retrospective cohort study using a nationally representative inpatient database. OBJECTIVE: To quantify the national revision burden for lumbar total disc replacements (TDRs) in the United States following Food and Drug Administration approval, for comparison with lumbar fusion and other common orthopedic procedures, including hip and knee replacement. SUMMARY OF BACKGROUND DATA: Previous studies of revision lumbar TDR surgery have been based on IDE studies. The epidemiology and costs of TDR revision surgery from a national perspective have not yet been reported. METHODS: The Nationwide Inpatient Sample was used to identify primary and revision TDR and anterior fusion procedures in 2005 and 2006. Surgeries were identified in the Nationwide Inpatient Sample using ICD9-CM codes. The prevalence of TDR and fusion surgery was calculated as a function of age, gender, race, census region, primary payer class, and type of hospital. Average length of stay and total hospitalization costs were also computed for each type of procedure. RESULTS: During the study period, there was a national total of 7172 TDR and 62,731 anterior fusion surgeries, including both primary and revisions. Overall, TDR patients were younger and had less comorbidity than fusion surgery patients. The average revision burden for lumbar TDR and anterior fusion was 11.2% and 5.8%, respectively. The average length of stay for primary lumbar TDR was significantly shorter compared to revision TDR, primary anterior fusion, and revision anterior fusion (P < 0.0001). Both the primary and the revision surgery using the TDR surgery involved significantly lower total hospital costs relative to anterior fusion surgery (P < 0.0001). Including revision, the average costs per TDR procedure were lower than anterior and posterior lumbar fusion. CONCLUSION: Although the revision burden for TDR was significantly higher than fusion surgery, the TDR revision burden fell within the revision burden range of hip and knee replacement, which are generally considered successful and cost-effective procedures. Economically, the higher revision burden for TDRs was offset by lower costs for both the primary as well as the revision procedures relative to fusion. PMID- 20195195 TI - Infective spondylitis in Southern Chinese: a descriptive and comparative study of ninety-one cases. AB - STUDY DESIGN: A retrospective review of infective spondylitis patients assessed at a major, tertiary referral centre in Hong Kong. OBJECTIVE: To assess the prevalence, risk factors, clinical features, and prognostic outcomes associated with tuberculous spondylitis to that of pyogenic spondylitis in Southern Chinese treated at a single institution. SUMMARY OF BACKGROUND DATA: Previous studies in Asia suggest that tuberculous spondylitis is the predominant infection unless proven otherwise. Current clinical experiences suggest otherwise; however, the current trend and clinical profile of infective spondylitis among Southern Chinese remains speculative with no published studies examining their prevalence. METHODS: A retrospective review was performed of all infective spondylitis cases presenting from January 2004 to July 2008 to a tertiary referral center. Cases were included on the basis of clinical and microbiological criteria. Radiographic imaging was used for further confirmation. RESULTS: Ninety-one patients were identified. Overall, tuberculous spondylitis and pyogenic spondylitis entailed 22 (24.2%) and 69 (75.8%) cases, respectively. Staphylococcus aureus was the most commonly isolated infective agent associated with pyogenic spondylitis. Individuals with pyogenic spondylitis were significantly much older than those with tuberculous spondylitis (P = 0.001). Intravenous drug addiction was the most commonly noted risk factor followed by diabetes, and found to be more prevalent in pyogenic spondylitis cases. At initial presentation, white cell count and c reactive protein levels were higher in pyogenic spondylitis cases compared with tuberculous spondylitis (P < 0.05). The occurrence of tuberculous spondylitis cases was predominant in the thoracic region (40.9%) (P < 0.05). Surgical intervention was performed in 54.5% of tuberculous spondylitis and in 24.6% of the pyogenic spondylitis cases (P = 0.009). CONCLUSION: In Southern Chinese, compared to previous reports over the past 3 decades, a changing prevalence of decreasing tuberculous spondylitis was observed. Pyogenic spondylitis was found to be more common among patients hospitalized for infective spondylitis. This has important implications on the method of diagnosis and the need for establishing microbiological diagnosis before commencing treatment. "Best guess" therapy should not be targeted at tuberculous spondylitis only. There are clear distinctions in the biologic and clinical profiles between tuberculous and pyogenic spondylitis that would help to direct therapy. PMID- 20195196 TI - Intra-articular meniscoid folds in thoracic zygapophysial joints. AB - STUDY DESIGN: A descriptive morphologic anatomic study was performed. OBJECTIVE: The study aimed to investigate intra-articular meniscoids (folds) and cartilage quality in the thoracic zygapophysial joints (ZAJs), and to discuss them in the context of possible causes of thoracic back pain. SUMMARY OF BACKGROUND DATA: The clinical relevance of the intra-articular meniscoid structures described in the cervical and lumbar spine is unclear, particularly in relation to ZAJ blockades. Corresponding data for the thoracic joints are not available. METHODS: A total of 297 ZAJs between C7 and L1, obtained from 12 human cadavers (7 female, 5 male; mean age 81 years), were studied. The intra-articular folds were described and classified morphologically. The characteristics of the folds and their association with zygapophysial cartilage quality were investigated. Thirteen example folds were studied histologically. RESULTS: In all, 268 intra-articular meniscoid folds were found in 183 joints. Three types were identified: type 1 (90%; mean length 3.1 mm) were thin, solid folds originating from a connective tissue base, with multiple vessels at the joint capsule, extending between the joint surfaces. Type 2 folds (6%) were soft structures of fat and loose connective tissue including multiple vessels, located in the joint recess and not extending between the joint surfaces. The remaining folds (type 3, 4%) were circumscribed thickenings of the joint capsule. Three folds showed chronic hemorrhage, with dilated vessels at the base, and this was associated with severe cartilage lesions. In 16 folds, the base had direct tissue connection to the fat tissue of the epidural space. CONCLUSION: This study for the first time systematically classifies intra-articular meniscoid folds in human thoracic ZAJs. These folds may represent an anatomic correlate for thoracic back pain. The chronic hemorrhage observed may be an important factor leading to arthritis. PMID- 20195197 TI - Efficacy evaluation of a new treatment algorithm for spinal metastases. AB - STUDY DESIGN: A semiprospective clinical study was conducted. OBJECTIVE: To evaluate the efficacy of a new treatment algorithm for spinal metastases. SUMMARY OF BACKGROUND DATA: The surgical treatments in spinal metastatic have been progressing in recent years, while the surgical indications have been controversial. A new treatment algorithm for spinal metastases was developed and prospectively applied clinically in our department since 2002. METHODS: This study included 202 patients with 206 lesions treated in January 1997 to December 2006 and continuously followed-up for more than 6 months or dead within this period. A total of 124 patients with 124 lesions were operated before 2002 were allocated to the control group and 78 patients with 82 lesions prospectively treated after 2002 were allocated to the prospective study group. The primary managements were nonsurgical treatment, palliative surgery, debulking, and en bloc resection. Neurologic evolvement, postoperative survival time, and local recurrence/development rates were statistically compared as the indexes of treatment outcome. RESULTS: Although there was no significant difference of neurologic evolvement immediately after operation (P = 0.24), the prospective study group achieved significantly better neurologic function than the control group long time after operation (P = 0.03). No significant difference (P = 0.26) was shown in local recurrence/development rate comparison. The mean postoperative survival time comparison showed significant difference (P < 0.01). CONCLUSION: The efficacy of the algorithm has been validated preliminarily by the significantly longer survival time and better long-time neurologic function evolvement in the prospectively study group. But the algorithm should continuously be in development and be updated with the latest improvement in metastatic treatment. PMID- 20195198 TI - Anterior instrumentation and correction of congenital spinal deformities under age of four without hemivertebrectomy: a new alternative. AB - STUDY DESIGN: Retrospective clinical and radiologic evaluation of a single-stage partial corpectomy of the hemivertebra with anterior instrumentation and simultaneous posterior noninstrumented fusion. OBJECTIVE: To determine the safety and efficacy of a new technique in the management of progressive congenital spinal deformities due to failure of formation in the very young age. SUMMARY OF BACKGROUND DATA: Several techniques have been reported for the surgical treatment of young children with congenital spinal deformities. There have been concerns regarding epidural bleeding, neurologic complications, pedicle screws placement, implant failure, and prominence of posterior constructs in this very young age group. A single-stage partial corpectomy of the hemivertebra with anterior instrumentation and simultaneous posterior noninstrumented fusion can offer a new alternative which can avoid these concerns. METHODS: Twelve patients with progressive congenital spinal deformities due to failure of formation were retrospectively reviewed after adopting the above mentioned technique. All patients included in the study presented with a single hemivertebra. The mean age at time of surgery was 2 years 7 months (range, 1 year and 9 months to 3 years and 10 months). The average follow-up period was 3 years and 1 month (range, 2 years to 4 years and 5 months). RESULTS: There were no cases of intra or postoperative neurologic or implant related complications. There was 1 superficial infection. All patients showed solid radiologic fusion. The mean scoliosis angle improved from 48.3 degrees (range, 34 degrees -58 degrees ) preoperative to 17.2 degrees (range, 11 degrees -25 degrees ). The mean angle of kyphosis improved from 23.2 degrees (range, 16 degrees -57 degrees ) before surgery to 11.7 degrees (range, 4 degrees -16 degrees ). CONCLUSION: A single stage partial corpectomy of the hemivertebra with anterior instrumentation and simultaneous posterior noninstrumented fusion offers a safe alternative method in treating patients with congenital hemivertebra under the age of 4 years. PMID- 20195199 TI - Biomechanical comparison of iliac screws versus interbody femoral ring allograft on lumbosacral kinematics and sacral screw strain. AB - STUDY DESIGN: This study evaluates the effect of iliac screw fixation versus interbody femoral ring allograft (FRA) on lumbosacral kinematics and sacral screw strain in long segment instrumentations. OBJECTIVE: (1) Quantify kinematic properties of 3 lumbosacral fixation techniques; (2) Evaluate sacral screw strain as instrumented levels extend cephalad; and (3) Determine whether iliac screws or FRA biomechanically protect sacral screws. SUMMARY OF BACKGROUND DATA: High failure rates at the lumbosacral junction have been reported with long posterior instrumentation ending with S1 pedicle screws. Achieving lumbosacral arthrodesis remains a clinical challenge. METHODS: Seven human cadavaric lumbosacral spines were biomechanically evaluated intact and in 3 instrumented conditions: pedicle screw fixation alone (pedicle screw group), pedicle screw fixation supplemented with iliac screws (iliac screw group), and pedicle screw fixation supplemented with FRA (allograft group). Each condition was tested spanning L5-S1, L4-S1, L3 S1, L2-S1, and L1-S1. Testing included pure unconstrained moments (+/-10 Nm) in axial rotation, flexion/extension, and lateral bending, with quantification of S1 screw strain and lumbosacral range of motion (ROM). RESULTS: Testing revealed decreasing lumbosacral ROM as instrumentation extended cephalad (P < 0.05). In axial rotation, ROM was markedly higher for the allograft group compared to pedicle screw and iliac screw groups with instrumentation to L4 (P < 0.05). In flexion/extension, length of instrumentation in each group correlated with ROM. As length of instrumentation increased, ROM decreased, particularly for the iliac screw group. In lateral bending, ROM decreased in all groups as instrumentation lengthened (P < 0.05). Strain on unprotected sacral screws increased in flexion, extension, and lateral bending as instrumentation extended to L3 (P < 0.05). Iliac screws reduced strain in constructs to L3 and above (P < 0.05). Allograft reduced strain when fixation reached L2, but was not as effective as iliac screws overall. Neither iliac screws nor allograft reduced strain in constructs terminating at L5 or L4. (P > 0.05) CONCLUSION.: For instrumented fusions extending above L3, sacral screws should be protected with supplemental iliac screws or FRA at L5-S1. Of the two, iliac screws appear more effective. PMID- 20195200 TI - Spinal metastasis of glioblastoma multiforme: an uncommon suspect? AB - STUDY DESIGN: Case report. OBJECTIVE: To report a case and review the literature on glioblastoma multiforme (GBM) with drop-like metastasis to the spine. SUMMARY OF BACKGROUND DATA: GBM constitutes the most common adult malignant brain tumor with poor prognosis. Spinal metastases of this malignancy are quite rare and dissemination usually occurs late in the course of the disease. However, recent advances in cancer treatment prolongate survival and provide adequate time for these metastases to give clinical symptoms. METHODS: We hereby present a case of a 57-year-old woman with a history of pineal GBM treated by stereotactic biopsy, chemotherapy, and radiotherapy, readmitted 38 months later due to gait disturbance, spastic paraparesis, edema of lower limbs, bilateral positive Babinski response, and loss of bladder control. A contrast-enhanced magnetic resonance imaging demonstrated an intramedullary lesion extending from C7 to T3 level. A T1 and T2 laminectomy was undertaken followed by extensive biopsy. RESULTS: Histologic examination was consistent with GBM. No further treatment was given, and the patient died 2 months after the diagnosis of the spinal metastasis. CONCLUSION: Spinal metastases should be commonly suspected in patients with a history of intracranial GBM who complain about symptoms not explained by the primary lesion.Glioblastoma multiforme (GBM) was first described by Rudolph Virchow in 1863 and represents the most common and most malignant tumor of the cerebral hemispheres, usually arising between the ages of 40 and 60 years. The incidence in Europe and North America is 2 to 3 cases/100,000 per year, and 75% of the patients die within 18 months after diagnosis. It is an infiltrating malignancy that recurs locally and it may spread along compact fiber pathways such as corpus callosum, optic irradiation, anterior commisure, and fornix or via cerebrospinal fluid (CSF) pathways. However, when GBM is under apparent control, spinal metastases are clinically rarely detected. Although involvement of the spinal cord (SC) has been noted with increasing frequency in recent years, literature provides only a few well documented cases. PMID- 20195201 TI - Critical length of fusion requiring additional fixation to prevent nonunion of the lumbosacral junction. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: To determine the critical length of fusion that warrants additional stronger fixation in lumbosacral (L-S) fusion, and to analyze the risk factors of nonunion at the L-S junction. SUMMARY OF BACKGROUND DATA: Long lever arm fusion down to S1 requires stronger fixation than short lever arm fusion. However, no published criteria are available about the critical length of fusion requiring stronger fixation to the ilium or S2 to obtain adequate stability for union at the L-S junction. METHODS: A total of 327 adult patients with degenerative lumbar disease, who were treated with instrumented fusion, including the L-S junction, were included in this study. Mean patient age was 59.7 (20-79) years and the minimum follow-up was 12 months. Union rates were compared using univariate and multivariate logistic regression analysis. Length of fusion, age, sex, lumbar lordosis at preoperative, early postoperative and final follow-ups, BMD, smoking history, associated morbidities, fat content of paraspinal muscle, methods of fusion, and levels of intercristal line were examined as independent variables to identify factors that affect union rate at the L-S junction. RESULTS: Of the 327 patients, 47 (14.4%) had nonunion at the L-S junction. Union rate of the L-S junction at the single level, and at 2, 3, 4, 5, and more than 5 levels were 96.6%, 92.9%, 87.4%, 64.7%, 66.7%, and 58.0%, respectively. A significant difference of union rate was found between less than 4 levels and 4 or more levels of fusion (P < 0.05). The factors found by multivariate analysis to significantly affect union rate at the L-S junction were fusion length and fat content of paraspinal muscle. CONCLUSION: The risk of nonunion at the L-S junction was found to increase significantly for more than 3 levels of fusion. We advise that additional stronger fixation is needed in such cases. PMID- 20195202 TI - The use of indocyanine green videography for intraoperative localization of intradural spinal tumors. AB - STUDY DESIGN: Prospective. OBJECTIVE: To characterize the role of indocyanine green videography in the intraoperative localization of intradural spinal tumors. SUMMARY OF BACKGROUND DATA: Correct intraoperative localization of intradural spinal tumors as well as tailored dural opening is essential in surgery and can be demanding in some instances. We investigated the role of indocyanine green (ICG) videography to correctly localize intradural, spinal tumors. METHODS: We report a series of 30 patients with intradural spinal tumors, in which (hemi )laminectomy or extended laminotomy was followed by ICG videography to determine intradural tumor margins (injection of intravenous ICG, visualization with operating microscope in combination with an additional, fluorescent light source). Tumor projection was verified after dural opening, and surgical resection was continued thereafter. RESULTS: Imaging was conducted without complications in all cases. Identification of the tumor margins before dural opening was achieved in 28 cases (93%), either by tumor enhancement or absence of ICG uptake in relation to the surrounding spinal cord or nerve roots. In 1 case, ICG videography helped to correct the previously determined level of exposure and led to cranial extension of the bony exposure. No significant contrast enhancement was seen in 2 patients who demonstrated a small lesion ventrolaterally to the cervical spinal cord. CONCLUSION: ICG videography represents a helpful tool to localize the position of intraspinal, intradural tumors, which are lateral or dorsal to the spinal cord or nerve roots. Bony exposure can be optimized before dural incision. Positioning and length of dural incision may be tailored to reduce the incidence of complications such as leakage of cerebrospinal fluid and/or accidental fiber damage. PMID- 20195203 TI - Spine adverse events severity system: content validation and interobserver reliability assessment. AB - STUDY DESIGN: A prospective validation study, preliminary single-center report. OBJECTIVE: The purpose of this study was to assess the content validity and interobserver reliability of a simple severity classification system for adverse events (AEs) associated with spinal surgery. SUMMARY OF BACKGROUND DATA: In the surgical literature what is defined as an AE, the severity of an AE, and the reporting of AEs are variable. Consequently, valid comparison of AEs within or among specialties or surgical centers for the same or different procedures is often impossible. METHODS: Since 2002, a Spine Adverse Events Severity system (SAVES) has been locally developed and prospectively used. AEs were graded as I (requires none/minimal treatment, minimal effect [<1-2 days] on length of stay [LOS]), II (requires treatment and/or increases LOS [3-7 days] with no long-term sequelae), III (requires treatment and/or increased LOS [>7 days] with long-term sequelae [>6 months]), and IV (death). Content validity of the grading system was assessed using the hospital chart abstraction (current defacto gold standard) compared with the SAVES from 200 randomly selected patients. Interobserver reliability was assessed in consecutive operative cases for 1 spine surgeon during a 1-year period (2006) using 3 raters (staff surgeon, fellow, and/or resident). RESULTS: The prospectively administered form reported a higher number of surgical AEs (n = 43 vs. n = 30) and a similar number of medical AEs (n = 31 vs. n = 27). Compared with the chart, the AE form displayed substantial agreement for number (70%; weighted Kappa [wK] = 0.60) and type (75%; wK = 0.67) of AE. The interobserver reliability was near perfect (kappa = 0.8) for the actual grade of AE and moderate (kappa = 0.5) for the criteria behind the grading (i.e., clinical effect of the AE or the effect of the AE on LOS or both). CONCLUSION: The result of this study demonstrates improved capture of surgical AEs using SAVES. Excellent interobserver reliability between surgeons at different level of training was demonstrated with minimal education or training regarding the use of SAVES. PMID- 20195204 TI - Migration of laminar hook causing thoracic myelopathy eight years post scoliosis surgery: a case report. AB - STUDY DESIGN: Case report. OBJECTIVE: A case report describing late presentation of neurologic injury with latent infection following scoliosis surgery. SUMMARY OF BACKGROUND DATA: Neurologic injury is a well described complication of scoliosis surgery. Late presentations of neurologic injury are rare but have been reported. To our knowledge, there are no reports of late presenting thoracic cord compression from a Cotrel-Dubousset type hook and rod instrumentation associated with latent indolent infection. METHODS: A 23-year-old man, 8 years status post T3-L3 posterior spinal fusion for scoliosis, presented with approximately a 6 month history of progressive leg numbness and mild weakness. Computed tomography myelogram showed cord compression from a laminar hook at T10 on the left side. RESULTS: The patient's neurologic status improved after device removal. Intraoperative tissue cultures grew coagulase-negative Staphylococci despite having normal preoperative laboratory data for infection. CONCLUSION: We report a case of late presenting neurologic injury from migration of a laminar hook causing thoracic cord compression and myelopathy. Removal of device resulted in discovery of a latent infection and satisfactory neurologic recovery. PMID- 20195205 TI - Acute injury of an intervertebral disc in an elite tennis player: a case report. AB - STUDY DESIGN: A case report. OBJECTIVE: To present a previously not described rare case of intradiscal hematoma due to acute trauma in an elite tennis player. SUMMARY OF BACKGROUND DATA: Several studies have demonstrated a high frequency of radiological changes in the spine of athletes, especially in sports with high loads on the back. Signs of disc degeneration without disc herniation have frequently been found in magnetic resonance imaging (MRI) studies of the spine of athletes. It has also been shown that radiological abnormalities of the spine in young athletes are correlated to back pain. METHODS: An elite male tennis player experienced pain in the right buttock after a backhand stroke. He was successfully treated for hip problems and started to play competitive tennis, 2 weeks later. After few games, a backhand stroke again resulted in intense pain projected in the os coccyx region. At examination, there were no neurologic disturbances. At palpation over the spinal processes (Springing test) of L1-L2, the patient experienced intense pain projected to the os coccyx region. RESULTS: MRI examination showed an injured L1-L2 disc with fluid inside the disc with a signal similar to blood. Four additional MRI examinations were performed 2 weeks and 2 years after the injury until disc degeneration is formed. Radiograph examination before and 2 years after the injury is available. CONCLUSION: In conclusion, trauma in athletes can cause intradiscal hematoma, which probably is a new etiology for disc degeneration. Also that sudden onset of pain in the hip or the gluteal region may be caused by referred pain due to a disc lesion. Intradiscal hematoma can be visualized using MRI. PMID- 20195206 TI - Sitting postures and trunk muscle activity in adolescents with and without nonspecific chronic low back pain: an analysis based on subclassification. AB - STUDY DESIGN: A preliminary cross-sectional comparative study of adolescents with nonspecific chronic low back pain (NSCLBP) and healthy controls. OBJECTIVE: To investigate whether differences in spinal kinematic and trunk muscle activity exist in both usual and slump sitting in adolescents with NSCLBP. SUMMARY OF BACKGROUND: Evidence suggests that low back pain commonly develops in adolescence and increases the risk for low back pain in adulthood. Sitting is an important consideration in adolescents with NSCLBP: currently there are no reports investigating their motor control strategies in sitting. METHODS: Twenty-eight adolescents (14 female) with NSCLBP and 28 matched pain-free controls were recruited from a large cohort study. Pain subjects were subclassified based on O'Sullivan's classification system. Three-dimensional lumbo-pelvic kinematic data and the activation of 3 back and 2 abdominal muscles were recorded during usual and slump sitting. The flexion-relaxation phenomenon in sitting was also investigated. RESULTS: Spinal posture in usual and slump sitting were similar for adolescents with and without NSCLBP. However, differences were identified in both sitting conditions when those with NSCLPB were subclassified and compared with controls. Muscle activation differences were not consistently identified, with only lower levels of internal oblique activation in usual sitting in NSCLBP compared with pain-free controls showing significance. Flexion relaxation was observed in both iliocostalis and thoracic erector spinae in the NSCLBP group but not controls. CONCLUSION: This study provides preliminary results. Differences with sitting posture are only seen when adolescents with NSCLBP are classified. Trunk muscle activation is not a sensitive marker for discriminating subgroups of NSCLBP during adolescence. PMID- 20195207 TI - High mobility group box 1 is upregulated after spinal cord injury and is associated with neuronal cell apoptosis. AB - STUDY DESIGN: Cerebrocortical culture and rat spinal cord injury (SCI) model were used to examine the expression of high mobility group box 1 (HMGB1), TNF-alpha, and Rage by reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemical examination. In addition, relationship between upregulation of HMGB1 and neural cells apoptosis was evaluated after SCI. OBJECTIVE: To evaluate the upregulation of HMGB1, TNF-alpha, and Rage after SCI. SUMMARY OF BACKGROUND DATA: It is known that the mode of delayed neuronal cell death after SCI is apoptosis. Apoptotic cell death is influenced by several injury-promoting factors which include pro-inflammatory cytokines. Inhibition of apoptosis promotes neurologic improvement following SCI. However, the factors which transmit inflammatory signaling following SCI have not yet been clarified in detail. HMGB1 was reported as an important mediator of inflammation. We examined the expression of HMGB1, TNF-alpha and Rage following acute SCI. METHODS: Expression of HMGB1, TNF-alpha and Rage was examined by RT-PCR and immunohistochemical examination. Apoptotic cell death was evaluated by TUNEL methods. RESULTS: HMGB1 was exported from nuclei to cytoplasm in active caspase-3 positive apoptotic cell in vitro. In addition, HMGB1, TNF-alpha, and Rage was expressed in same cell after NMDA treatment. RT-PCR revealed that expression of HMGB1 and TNF-alpha was upregulated following SCI. Immunohistochemical examination revealed that the numbers of HMGB1-, TNF-alpha-, and Rage-positive cells were increased following SCI. The number of TUNEL-positive cells was significantly increased at 12 hours after injury, and was maximal at 72 hours after injury. However, HMGB1- and TNF-alpha-positive cells were maximal in number 48 hours after injury, while Rage-positive cells were maximal in number at 24 hours after injury. These data suggest that HMGB1, TNF-alpha, and Rage were upregulated following SCI but preceding the apoptotic cell death. CONCLUSION: Our findings suggest that HMGB1 play a role in the induction of apoptosis via inflammatory reaction. PMID- 20195208 TI - The effect of posterior distraction on vertebral growth in immature pigs: an experimental simulation of growing rod technique. AB - STUDY DESIGN: Experimental study. OBJECTIVE: The aim of this study is to evaluate the vertebral body growth under distraction forces in immature pigs treated with growing rod (GR) technique. SUMMARY OF BACKGROUND DATA: Distraction forces applied on growth plate of appendicular skeleton stimulate longitudinal growth. However, the effect of distraction forces on axial skeletal growth has not been fully investigated yet. METHODS: Twelve 10-week-old domestic pigs were used in this experimental model to simulate GR technique. Four of them were lost during postoperative period because of deep wound infection. Cranially T12-L1 and caudally L4-L5 vertebrae were instrumented by pedicle screws bilaterally, while L2 and L3 were skipped. Distraction between pedicle screws was applied at index surgery. The rods were then lengthened twice in a month interval. All subjects were evaluated with anteroposterior and lateral spinal radiograph before surgery, after surgery, and at the final follow-up. The vertebral body heights of distracted segments (HD = L2 and L3) and control segments (HC = T9, T10 and T11) were measured. Average vertebral body heights and the increase percentage in the vertebral body heights were compared among control segments and distracted segments. RESULTS: The preoperative vertebral body height was similar in 2 groups (preHC: 10.81 mm, n = 19, preHD: 11.27 mm, n = 16, P > 0.05). At the final follow up, the average vertebral body height in distraction group was significantly higher than the control group (postHC: 17.03 mm, postHD: 18.58 mm, P < 0.05). The increase percentage in vertebral body height was higher in distracted segments, but there was no statistically significant difference between the 2 groups. CONCLUSION: The vertebral growth continues during GR instrumentation. Distraction forces might stimulate also apophyseal growth of axial skeleton. PMID- 20195209 TI - DensiProbe Spine: a novel instrument for intraoperative measurement of bone density in transpedicular screw fixation. AB - STUDY DESIGN: Cadaver study. OBJECTIVE: To determine bone strength in vertebrae by measuring peak breakaway torque or indentation force using custom-made pedicle probes. SUMMARY OF BACKGROUND DATA: Screw performance in dorsal spinal instrumentation is dependent on bone quality of the vertebral body. To date no intraoperative measuring device to validate bone strength is available. Destructive testing may predict bone strength in transpedicular instrumentations in osteoporotic vertebrae. Insertional torque measurements showed varying results. METHODS: Ten human cadaveric vertebrae were evaluated for bone mineral density (BMD) measurements by quantitative computed tomography. Peak torque and indentation force of custom-made probes as a measure for mechanical bone strength were assessed via a transpedicular approach. The results were correlated to regional BMD and to biomechanical load testing after pedicle screw implementation. RESULTS: Both methods generated a positive correlation to failure load of the respective vertebrae. The correlation of peak breakaway torque to failure load was r = 0.959 (P = 0.003), therewith distinctly higher than the correlation of indentation force to failure load, which was r = 0.690 (P = 0.040). In predicting regional BMD, measurement of peak torque also performed better than that of indentation force (r = 0.897 [P = 0.002] vs. r = 0.777 [P = 0.017]). CONCLUSION: Transpedicular measurement of peak breakaway torque is technically feasible and predicts reliable local bone strength and implant failure for dorsal spinal instrumentations in this experimental setting. PMID- 20195210 TI - Does symptom duration correlate negatively with outcome after posterior lumbar interbody fusion for chronic low back pain? AB - STUDY DESIGN: Original report. OBJECTIVE: To investigate the putative negative correlation between the duration of symptoms (DOS) and outcome after surgery for chronic low back pain (CLBP). SUMMARY OF BACKGROUND DATA: Posterior lumbar interbody fusion (PLIF) is a well established treatment for CLBP. Anecdotally, a prolonged DOS is associated with a poor prognosis for recovery of CLBP. In one recent study, a DOS greater than 3 years predicted a poor prognosis for subsequent clinical improvement with CLBP. METHODS: Patients (n = 209) underwent PLIF for CLBP who had proven unresponsive to nonoperative management for at least 6 months. A wide variety of physical and mental outcome scores were simultaneously assessed pre- and after surgery: i.e., the Oswestry Disability Index (ODI), SF-36 body score, SF-36 mental score, Visual Analogue Score (VAS) for back pain, VAS for leg pain, Hospital Anxiety Score (HAS), and Hospital Depression Score. RESULTS: Despite a prolonged mean DOS of 84.3 +/- 6.6 months, there was a significant postoperative improvement in all 7 outcome scores after PLIF. Significant improvement occurred in 181 patients (i.e., 86.6%) and was sustained at 51.6 +/- 12.0 months follow-up. No significant correlation was found between DOS and any outcome score (ODI: rs = 0.013, P = 0.877; SF-36 bodily pain: rs = 0.013, P = 0.87; VAS for back pain: rs = 0.038, P = 0.656; VAS for leg pain: rs = 0.086, P = 0.310; HAS: rs = 0.511, P = 0.056; Hospital Depression Score: rs = 0.056, P = 0.509, or SF-36 mental score rs = 0.007, P = 0.935). No arbitrary DOS "cut-off" was found for which significantly different outcomes were recorded either side of the cut-off; or for which a significant correlation was revealed either side of the cut-off. Finally, no significant partial correlation was found between DOS and any outcome score after controlling for pain severity (VAS(back pain)) before surgery. There were no significant differences in terms of age, sex, or DOS between those with improved ODI scores less than 10 compared with those with improved ODI scores greater than 10. CONCLUSION: The putative negative correlation between DOS and outcome was not observed under any analysis in our study. PLIF procured a rapid and sustained improvement in CLBP, even where the DOS was excessively prolonged; and even after having allowed for pain severity. Symptom chronicity, therefore, does not represent a poor prognostic indicator for CLBP outcome after PLIF: PLIF should be considered irrespective of DOS. Because DOS and pain severity are likely mediators of "central sensitization," the hypothesis that central sensitization may be prevalent in CLBP patients selected for PLIF is therefore questioned. PMID- 20195211 TI - Contralateral approach for far lateral lumbar disc herniations: a modified technique and outcome analysis of nine patients. AB - STUDY DESIGN: A retrospective analysis of 9 patients who underwent a modified surgical procedure for the treatment of far lateral lumbar disc herniations. OBJECTIVES: To illustrate a modified technique for approaching the neural foramen from the contralateral side, minimizing muscle retraction and bone/ligament resection, and to analyze clinical results. SUMMARY OF BACKGROUND DATA: The most commonly used surgical techniques for the removal of far lateral lumbar disc herniations are ipsilateral approaches, that require partial or complete facet resection and/or intertransverse ligament resection, which may result in vertebral instability and/or chronic back pain. METHODS: Nine patients with intraforaminal or intra/extraforaminal lumbar disc herniation underwent surgery using a modified contralateral approach. There was unilateral muscle retraction and no medial facetectomy nor intertransverse/interspinous ligament resection. Preoperative and postoperative Oswestry functional status evaluation and complications were reviewed and Macnab's postoperative categories were assigned to evaluate the efficacy and safety of the surgery. RESULTS: No serious complications were noted. The mean preoperative and postoperative Oswestry scores were 44 and 14 respectively (P < 0.01). Overall excellent-to-good results were 100%. CONCLUSION: This modified contralateral approach offered a wide exposure of intervertebral foramen region and allowed to remove the herniated disc material with minimal resection of osseous and ligamentous structures. Successful results were achieved in all patients treated by this technique. PMID- 20195212 TI - C2 anatomy and dimensions relative to translaminar screw placement in an Asian population. AB - STUDY DESIGN: A cadaveric specimen study. OBJECTIVES: To determine the applicability of a modified C2 translaminar screw placement in the general adult population and to provide pertinent clinical data for screw insertion. SUMMARY OF BACKGROUND DATA: C2 intralaminar screw fixation has recently been popularized, but this technique carries a potential drawback that the screw may breakout ventrally into the spinal canal. For this reason, a modified C2 translaminar screw fixation technique was developed to intraoperatively verify screw position and thereby decrease the risk or canal compromise. To our knowledge, there has been not an anatomic study evaluating this modification of the translaminar screw technique. METHODS: The tips of the modified screws were aimed such that they exited the dorsal cortex of the center of the contralateral lateral mass, achieving bicortical fixation. A total of 120 adult C2 vertebrae were evaluated bilaterally for the following: thickness of the cranial, midportion, and caudal edge of C2 lamina; the heights of the spinous process, lamina, and lateral mass; inclination angle of the laminae, screw projection length, and trajectory angle of cranial and caudal C2 translaminar screw. RESULTS: A total of 83.3% specimens had bilateral laminar thicknesses >=4.0 mm and a spinous process height >=9.0 mm; 5% had a laminar thickness less than 4.0-mm bilaterally; 9.2% had a laminar thickness less than 4.0 mm on one side; 2.5% had a spinous process height lower than 9.0 mm. CONCLUSION: A large percentages of C2 laminae are of sufficient size to safely accommodate a bicortical 3.5-mm diameter screw. The thickness of the lamina and the height of the spinous process are the 2 limiting factors for safe translaminar screws placement. Using a bicortical technique confirms the position of the screw and thereby helps to decrease the risk of neurologic injury from screw penetration of the inner cortex of the lamina. PMID- 20195213 TI - Low back pain history and postural sway in unstable sitting. AB - STUDY DESIGN: A cross-sectional study comparing subjects with self-reported low back pain, recent low back, and no low back pain. OBJECTIVE: To determine differences in trunk postural control between groups. SUMMARY OF BACKGROUND DATA: Poor postural control has been demonstrated in patients with low back pain, but the cause of this is unknown. METHODS: A total of 331 participants of a longitudinal study participated in a seated balancing task. Based on a questionnaire, subjects were subdivided in 3 groups: current-LBP, recent-LBP (last 12 months), no-LBP. Subjects balanced on a seat mounted over a hemisphere during three 30-second trials. Sway amplitudes (RMS), mean power frequency (MPF), short-term diffusion coefficients (DS), and critical point (CP) coordinates of sway were calculated. RESULTS: RMS values differed significantly between groups, with smaller values in recent-LBP than in no-LBP. MPF values were lowest in current-LBP. DS values were highest in no-LBP, with significant differences between this group and recent-LBP only. CP values were generally lower for recent LBP than both other groups. CONCLUSION: In contrast with previous findings, postural sway amplitudes in unstable sitting were not different between LBP and healthy subjects, while subjects with a recent history of LBP showed smaller amplitudes. Higher DS values in subjects without LBP indicated more stochastic sway. These findings may be explained by the disturbing effect of current pain on postural control causing low sway frequencies and by lower effort in balancing in healthy subjects causing high sway amplitudes and diffusion coefficients. PMID- 20195214 TI - Adjacent segment disease after interbody fusion and pedicle screw fixations for isolated L4-L5 spondylolisthesis: a minimum five-year follow-up. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: The purpose of this study are (1) to analyze prevalence of clinical and radiologic adjacent segment diseases (ASD), (2) to find precipitating factor of clinical ASD in each isthmic and degenerative spondylolisthesis groups, and (3) to compare clinical and radiologic change in isthmic and degenerative spondylolisthesis. SUMMARY OF BACKGROUND DATA: There is no clinical report regarding the use of magnetic resonance imaging (MRI) for evaluating ASD in patient who underwent 360 degrees fusion with single-level spondylolisthesis with healthy adjacent segment. METHODS: A total of 69 patients who underwent instrumented single-level interbody fusion at the L4-L5 level and showed no definitive degenerated disc in adjacent segments on preoperative MRI and plain radiographs were evaluated at more than 5 years after surgery. The patients were divided into 2 groups: group I was isthmic spondylolisthesis patients and group II was degenerative spondylolisthesis patients. The radiologic ASD was diagnosed by plain radiographs and MRI. Clinical ASD is defined as symptomatic spinal stenosis, intractable back pain, and subsequent sagittal or coronal imbalance with accompanying radiographic changes. Symptomatic spinal stenosis was defined as stenosis diagnosed by MRI and combined with neurologic claudication. RESULTS: The prevalence of radiologic ASD on group I and group II was 72.7% and 84.0%, respectively. About 7 (15.9%) patients showed clinical ASD in group I and 6 (24.0%) patients showed clinical ASD in group II. MRI showed significant reliability for diagnosis of clinical ASD. Compared with patients with asymptomatic ASD, patients with clinical ASD showed significantly less postoperative lordotic angle at the L4-L5 level (i.e., less than 20 degrees ) in both groups. CONCLUSION: Maintaining postoperative L4-L5 segmental lordotic angle at about 20 degrees or more is important for prevention of clinical ASD in single-level 360 degrees fusion operation. MRI is reliable method for diagnosing clinical ASD. PMID- 20195215 TI - Effect of adverse events on low back surgery outcome: twenty-four-month follow-up results from a Food And Drug Administration investigational device exemptiontrial. AB - STUDY DESIGN: This study was based on a post hoc analysis of data collected from a prospective FDA-regulated trial comparing total disc replacement to fusion surgery. OBJECTIVE: he purpose of this study was to determine if the occurrence of adverse events (AEs) had an impact on outcomes of low back surgery. SUMMARY OF BACKGROUND DATA: AEs are rigorously recorded during clinical trials primarily to evaluate the safety of the investigational device. AEs include a wide variety of events including those that are not typically thought of as complications related to the treatment intervention. During the course of a study, many physical events may happen to a patient including injuries from motor vehicle accidents, falling, various joint injuries, cancer onset, gastrointestinal problems, etc. Although these are generally thought of as having nothing to do with the patient's spine surgery, the potential detrimental impact of these AEs on the patient's overall well being may negatively effect responses to outcome assessments used to evaluated the clinical outcome of the spine surgery. METHODS: Data were collected from an FDA-regulated prospective randomized clinical trial comparing lumbar fusion to total disc replacement. AE and clinical data were analyzed for 155 patients who had reached 24-month follow-up. The number of active AEs, along with event severity (mild, moderate, or severe), and its relationship to surgery (unrelated, possibly related, or causative) were recorded. Clinical outcome was based on VAS, Oswestry, and overall satisfaction at 24-month follow-up. Data were analyzed using ANOVA. RESULTS: There were significant relationships between the presence of active AEs and improvement on VAS pain scores, Oswestry scores, and patient satisfaction (P < 0.05; ANOVA with post hoc Tukey) at 24-month follow-up. Patients with no active adverse events had more than 70% improvement on their VAS and Oswestry scores. Significantly less improvements was seen in the VAS and Oswestry scores for patients with 2 or more active AEs, moderate or severe AEs, and AEs classified as related to the study intervention. Patients with AEs classified as being related to the study intervention were significantly less satisfied than those with no AEs or AEs classified as unrelated to the surgery. CONCLUSION: This study was the first to investigate the impact of active AEs on clinical outcome of spinal surgery. While AEs are recorded to evaluate the safety of new treatments, this study found that AEs also play a role in explaining some of the variation in treatment outcome. PMID- 20195216 TI - Differences in postoperative quality of life between adolescent patients with idiopathic scoliosis residing in urban and rural environments. AB - STUDY DESIGN: A prospective cross-sectional study. OBJECTIVE: To study the effects of living environment, rural and urban, on the postoperative quality of life in adolescent patients with idiopathic scoliosis (AIS) and to explore its causes. SUMMARY OF BACKGROUND DATA: Many factors are capable of influencing the health-related quality of life of AIS patients including degree of the malformation, culture, treatment method, and the living environment of the patient. METHODS: Postoperative AIS patients (n = 117, 16 males and 101 females) were divided into 2 groups (the urban group and the rural group). All patients completed the simplified Chinese version of the SRS-22 scale and the scores on the individual domain, and items were compared between the 2 groups. RESULTS: The score on satisfaction of management domain in the urban group was higher than that in the rural group, but the score on the self-image/appearance in the urban group was significantly lower (P < 0.05). There were no significant differences in function/activity, pain or mental health domain between the 2 groups (P > 0.05). Scores for items 12, 15, and 18 in the function/activity domain, items 4, 6, and 10 in the self-image/appearance domain, and item 22 in the satisfaction of management domain were significantly different between the 2 groups (P < 0.05). CONCLUSION: Living environment may influence the assessment results of the postoperative quality of life in AIS patients. The effects of environment (i.e., rural vs. urban) should be considered when using the SRS-22 scale to evaluate the quality of life of the patients. PMID- 20195217 TI - TDM for mycophenolic acid at no extra cost. PMID- 20195218 TI - Growth enhancement by embryonic fibroblasts upon cotransplantation of noncommitted pig embryonic tissues with fully committed organs. AB - BACKGROUND: We recently defined the optimal gestational time windows for the transplantation of several embryonic tissues. We showed that the liver and kidney obtained from E28 pig embryos can grow and differentiate normally after transplantation, whereas 1 week earlier in gestation, these tissues develop into teratoma-like structures or fibrotic mass. In this study, we investigated whether cotransplantation of E28 with E21 tissue could control its tumorogenic potential, or alternatively whether the stem cells derived from the earlier tissue contribute to the growth of the more committed one. METHODS: Pig embryonic precursors from E21 and E28 gestational age were transplanted alone or together, into nonobese diabetic/severe combined immunodeficiency mice, and their growth and differentiation was evaluated by immunohistology. In situ analysis, based on sex disparity between the E21 and E28 tissues, was used to identify the tissue source. In some experiments, mouse embryonic fibroblasts (MEF) were cotransplanted with E28 liver, and their effect was evaluated. RESULTS: E28 tissues could not abrogate the propensity of the cells within the undifferentiated tissue to form teratoma-like structures. However, E21 kidney or liver tissue markedly enhanced the growth and function of E28 kidney, liver, and heart grafts. Moreover, similar growth enhancement was observed on coimplantation of E28 liver tissue with MEF or on infusion of MEF culture medium, indicating that this enhancement is likely mediated through soluble factors secreted by the fibroblasts. CONCLUSION: Our results suggest a novel approach for the enhancement of growth and differentiation of transplanted embryonic tissues by the use of soluble factors secreted by embryonic fibroblasts. PMID- 20195219 TI - Comparing an early corticosteroid/late calcineurin-free immunosuppression protocol to a sirolimus-, cyclosporine A-, and prednisone-based regimen for pancreas-kidney transplantation. AB - AIM: A prednisone and calcineurin inhibitor (CNI)-free protocol was compared with a sirolimus, cyclosporine A (CsA), and prednisone-based immunosuppressive regimen for simultaneous pancreas-kidney transplantation (SPK). METHODS: A nonrandomized, single-center, sequential study enrolled low-immune responder SPK transplant recipients. The prednisone/CNI-free (minimization) group of 22 patients received thymoglobulin followed by sirolimus and reduced-dose CsA. Prednisone was withdrawn on day 5, and recipients were converted from CsA to mycophenolic acid at 6 months posttransplantation. The sirolimus/CsA group of 20 consecutive recipients transplanted immediately before this series received thymoglobulin followed by sirolimus, reduced-dose CsA, and prednisone. RESULTS: Donor and recipient demographic variables were equivalent between groups. The 24-month actual patient, kidney, and pancreas survivals for the minimization group were 100%, 100%, and 91% vs. 100%, 95%, and 95% for the sirolimus/CsA group (P=not significant [NS] for patient, kidney, and pancreas survivals). One acute rejection occurred in the minimization group and none in the sirolimus/CsA group. After withdrawal of CsA at 6 months, the minimization group showed an increase in mean estimated glomerular filtration rate, resulting in a significant improvement in renal function compared with the sirolimus/CsA group. At 24 months, the mean glomerular filtration rate of the minimization and sirolimus/CsA groups was 71.6+/-11.2 mL/min/1.73 m and 60.1+/-13.4 mL/min/1.73 m, respectively (P<0.05). Mean fasting blood glucose levels were equivalent between groups at all time points studied. CONCLUSION: Low-immune responder SPK recipients receiving a prednisone/CNI-free protocol achieved similar 2-year graft survivals and improved renal function compared with those treated with a sirolimus, CsA, and prednisone regimen. PMID- 20195220 TI - Citalopram enhances cocaine's subjective effects in rats. AB - Serotonin-selective reuptake inhibitors (SSRIs) have been shown to enhance the locomotor stimulatory, discriminative-stimulus, and convulsive effects of cocaine in rodents. A pharmacokinetic mechanism for the interaction is supported by increases in the brain levels of cocaine by fluoxetine treatment. Furthermore, the locomotor-stimulant effects of cocaine in rodents are enhanced by fluoxetine and fluvoxamine, SSRIs known to inhibit cocaine-metabolizing cytochrome P450 enzymes, whereas citalopram, an SSRI that does not inhibit P450 enzymes, does not enhance cocaine's locomotor-stimulant effects. Citalopram, however, attenuated the discriminative-stimulus effects of cocaine in squirrel monkeys trained to discriminate cocaine from saline, though it enhanced the discriminative-stimulus effects of a low dose of cocaine in rats trained to discriminate high and low doses of the drug. This study investigated the effects of citalopram on cocaine's discriminative-stimulus effects in rats trained more simply to discriminate cocaine from saline. Citalopram alone produced predominantly saline-appropriate responding, but when administered before cocaine, citalopram dose-dependently shifted the cocaine dose-response curve leftward. The present findings suggest that enhancement of cocaine's discriminative-stimulus effects may occur through a mechanism different from that underlying enhancement of cocaine's locomotor effects or that another action of citalopram selectively blocks locomotor enhancement. PMID- 20195221 TI - Endobronchial ultrasound-guided transbronchial biopsy using novel thin bronchoscope for diagnosis of peripheral pulmonary lesions. AB - BACKGROUND: The aim of this study was to evaluate the diagnostic utility of endobronchial ultrasound (EBUS)-guided transbronchial biopsy (TBB) using a novel 3.4-mm thin bronchoscope and a 1.4-mm ultrasonic probe for peripheral pulmonary lesions. METHODS: A total of 86 patients with suspected peripheral lesions were included in this prospective study. EBUS-TBBs were performed using a prototype 3.4-mm thin bronchoscope and a 1.4-mm radial ultrasonic probe under fluoroscopic guidance. RESULTS: Twelve patients with endobronchial lesions within the segmental bronchi and three patients who did not return to follow-up were excluded from this analysis. Thus, a total of 71 patients with peripheral pulmonary lesions (mean size, 31.2 +/- 12.7 mm) were included in the final analysis. The mean bronchus level reached with the thin bronchoscope was 4.6 generations. Diagnostic histologic specimens were obtained in 49 of 71 patients (69%:80% for malignant lesions and 52% for benign lesions). A definitive diagnosis of malignancy for lesions > or =20 mm and lesions < 20 mm was made in 82% (31 of 38) and 67% (four of six), respectively. There were no significant complications. CONCLUSION: The EBUS-TBB using a 3.4-mm thin bronchoscope and a 1.4-mm radial probe is feasible, accurate, and safe for the diagnosis of peripheral pulmonary lesions. PMID- 20195222 TI - Thyroid cancer. Rising numbers spotlight uncommon disease. PMID- 20195224 TI - Migraine. A common headache in women. PMID- 20195223 TI - New mammography guidelines go against standard screening recommendations. PMID- 20195225 TI - Mayo Clinic office visit. TNF drugs and rheumatoid arthritis. An interview with Eric Matteson, M.D. PMID- 20195226 TI - Sharing difficult health news. How to stay in touch during a crisis. PMID- 20195227 TI - I've read that the diet drug orlistat may cause liver problems. Should I stop taking it? PMID- 20195228 TI - Lately there's been a small spot that streaks across my vision. Is this normal, or a sign of an eye problem? PMID- 20195230 TI - Depression and the existential domain in the assessment of quality of life in HIV outpatients with the McGill questionnaire. AB - AIM: The aim of the present study was to further test criterion validity and factorial validity of the McGIll Quality Of Life (MQOL) questionnaire, and to assess its reliability and sensitivity to clinical change in outpatients with HIV infection. METHODS: The authors present a longitudinal study on a consecutive sample of 216 adults treated with HAART at the outpatient facility of an hospital based tertiary care center in Italy. Patients completed the MQOL and the Beck Depression Inventory (BDI) both at baseline and follow-up assessments. Patients were classified into subgroups (improved, unchanged, worsened) based on change in BDI scores or CD4 count over time. RESULTS: The pattern of correlation between MQOL subscales and the BDI was as hypothesised. A fairly simple factor structure emerged, with a striking resemblance between the factors and the MQOL subscales. The internal consistency of the MQOL and its subscales was high. The test-retest reliability in clinically unchanged patients was satisfactory. Sensitivity to change, as measured by Guyatt responsiveness statistic, was also satisfactory. CONCLUSIONS: This study contributed to building evidence of reliability and validity for the MQOL questionnaire, which may be particularly useful to assess the so-called "existential" aspects of QOL that are particularly relevant for patients infected with HIV. PMID- 20195229 TI - Altered pattern of circulating matrix metalloproteinases -2,- 9 and tissue inhibitor of metalloproteinase-2 in patients with HCV-related chronic hepatitis. Relationship to histological features. AB - AIM: The aim of this paper was to assess circulating levels of metalloprotease2 (MMP2), metalloprotease9 (MMP9) and tissue inhibitor of metalloprotease2 (TIMP2) in patients with HCV-related chronic hepatitis to verify whether there was a relationship between these molecules and biochemical and histological features. METHODS: Forty-nine neodiagnosed and untreated patients affected by chronic C hepatitis and twenty healthy control subjects were investigated. In overall study series, circulating levels of MMP2, MMP9 and TIMP2 were assessed by ELISA commercial kit (R&D Systems). Patients with chronic hepatitis undergone to liver biopsy and histological features were examined according to Histological Activity Index (HAI). RESULTS: Mean values of MMP2 (1989+/-207 ng/mL. vs 1112+/-120 ng/mL), MMP9 (62.44+/-11.9 ng/mL vs 39.67+/-4.6 ng/mL) and TIMP2 (48.3+/-8.1 ng/mL vs 15.16+/-4.1 ng/mL) were significantly higher (P<0.001) in patients than in controls. Among investigated molecules, only MMP2 was independently related to inflammation and fibrosis according to grading (P=0.036) and staging (P=0.032) score. Moreover, MMP2 but not MMP9 and TIMP2 was related to AST (P=0.015), ALT (P=0.049) and AST/platelet ratio index (P=0.001). No relationship (P>0.05) was found between MMP2 and MMP9 or TIMP2. CONCLUSIONS: Our study confirms an altered pattern of metalloproteases and their tissue inhibitors in subjects with chronic C hepatitis and such alterations can contribute to development of liver fibrosis. In addition MMP2 is related to inflammation and fibrosis as assessed by liver biopsy and laboratory features. The serial detection of MMP2 could help to monitor evolution of disease and to predict onset of cirrhosis. PMID- 20195231 TI - Metabolic syndrome and liver transplantation. AB - Metabolic syndrome comprises a cluster of risk factors that predispose to mainly cardiovascular disease and its complications. It is also closely associated with liver steatosis and fibrosis. Metabolic syndrome and its hepatic manifestation, non-alcoholic fatty liver disease, are very prevalent both in general population and also pre- and post-transplantation setting. Important life-style changes and immunosuppressive treatment after liver transplantation seem to have significant effects for the development of the Metabolic syndrome: increased risks for liver transplant recipients and challenges for successful treatment outcomes. Its association with major vascular events and negative effects on progression of fibrosis in recurrent hepatitis C after transplantation have been major concerns for transplant patients in recent years. There is no standard therapeutic approach to these patients, and well-designed prospective studies are certainly needed to define management strategy. Until such specific data become available, early aggressive risk factor modification should be aimed and each component of the syndrome should be cared separately. PMID- 20195232 TI - Current immunosuppressive approaches in liver transplantation. AB - A significant increase of potent immunosuppressive agents over the last two decades has contributed to improved patient and graft survival after liver transplantation (LT). Numerous ongoing studies aim to determine the most effective immunosuppressive protocols while minimizing drug-related side effects. These protocols often combine several drugs with different mechanisms of action and toxicities allowing dosage adjustment. There is also a trend towards tailored immunosuppressive regimens according to the etiology of liver disease and comorbidities such as renal dysfunction and cardiovascular disease. The introduction of antibody induction therapies and antimetabolites resulted in an increasing number of studies with steroid minimization and calcineurin inhibitor (CNI) reduction protocols. Combined mycophenolate mofetil and minimal dose CNI therapy has shown to be safe and to improve kidney function and cardiovascular risk profile in the majority of studies. Sirolimus (SRL) and everolimus constitute a new class of compounds designated as the mammalian target of rapamycin (mTOR) inhibitors, which exhibit immunosuppressive and antiproliferative effects. There are conflicting results with respect to renal improvement upon switch to mTOR inhibitor therapy with concomitant reduction/elimination of CNI. Further trials will determine whether earlier conversion to mTOR inhibitors enable prevention of CNI-related renal dysfunction. Future results from randomized controlled studies will also show whether SRL can improve recurrence-free survival in patients transplanted for hepatocellular carcinoma. PMID- 20195233 TI - Surgical considerations in liver transplantation: small for size syndrome. AB - The chronic shortage of cadaveric grafts for patients on the liver transplant list has resulted in wide implementation of living donor liver transplant (LDLT) and split cadaveric liver transplantation (SLT). Small for size syndrome (SFSS) is a significant complication that can occur during LDLT or SLT. It is generally defined as the presence of prolonged cholestasis, coagulopathy and ascites within the first week from transplant. Multiple factors contribute to the pathogenesis of SFSS, such as overall graft size, portal hyperperfusion, impaired venous outflow, as well as donor and recipient factors. Strategies utilized to minimize or resolve SFSS include the use of right lobe grafts, modulation of portal flow by splenic artery ligation, splenectomy or porto-systemic bypass, and optimization of venous outflow. Additional surgical techniques to avoid SFSS include the use of auxiliary orthotopic liver grafts and dual liver graft transplantation. Careful consideration of risk to the LDLT donor has to be taken whenever right lobe graft is utilized, especially if the middle hepatic vein (MVH) is going to be included in the graft. PMID- 20195234 TI - Hepatitis C recurrence after liver transplantation. AB - End stage liver disease from hepatitis C is the leading indication for liver transplantation (LT) in the United States. Recurrent hepatitis C after LT is universal and causes substantial morbidity and mortality with up to 30% patients developing cirrhosis by the fifth postoperative year. Once cirrhosis is established, the risk of hepatic decompensation is approximately 40% per year. Risk factors associated with accelerated disease recurrence are elevated high viral load prior to transplantation, older donor age, prolonged ischemic time, cytomegalovirus coinfection, intensity of immunosuppression and HIV coinfection. Although the mechanisms of accelerated HCV-induced liver damage after transplantation are poorly understood, strategies employed to limit severe recurrence include avoidance of older donors, early recognition of cytomegalovirus, minimization of immunosuppression, particularly T-cell depleting therapies and pulsed steroids for acute cellular rejection. Treatment of recurrent hepatitis C post-transplant is also problematic and fraught with controversy. As there is a paucity of evidence on when treatment should be initiated, out of necessity treatment has been empiric and often varies between centers. As prophylactic treatment immediately after transplantation is rarely effective and associated with numerous side effects, most clinicians acknowledge that treatment should be initiated once early fibrosis has developed although sustained viral rates with pegylated interferon and ribavirin are frequently less than 30%. Side effects are common and can lead to dose reduction or discontinuation of treatment. For those patients who develop develop decompensated cirrhosis from recurrent hepatitis C, retransplantation may be considered. PMID- 20195235 TI - The challenge of preserving renal function after liver transplantation. AB - Thanks to new surgical techniques and the use of calcineurin inhibitors for the prevention of allograft rejection, the long-term outcome of liver transplantation has recently improved. In case of liver transplantation, the occurrence of renal failure can impair the outcome. Renal function preservation is, therefore, necessary to improve transplantation outcome. PMID- 20195236 TI - Ethical and social principles in the World Health Days of the WHO. PMID- 20195237 TI - Leucocyte peroxidase and leptin in obese children as early indices of bronchial asthma. PMID- 20195238 TI - Multielectrode array recordings of the vomeronasal epithelium. AB - Understanding neural circuits requires methods to record from many neurons simultaneously. For in vitro studies, one currently available technology is planar multielectrode array (MEA) recording. Here we document the use of MEAs to study the mouse vomeronasal organ (VNO), which plays an essential role in the detection of pheromones and social cues via a diverse population of sensory neurons expressing hundreds of types of receptors. Combining MEA recording with a robotic liquid handler to deliver chemical stimuli, the sensory responses of a large and diverse population of neurons can be recorded. The preparation allows us to remove the intact neuroepithelium of the VNO from the mouse and stimulate with a battery of chemicals or potential ligands while monitoring the electrical activity of the neurons for several hours. Therefore, this technique serves as a useful method for assessing ligand activity as well as exploring the properties of receptor neurons. We present the techniques needed to prepare the vomeronasal epithelium, MEA recording, and chemical stimulation. PMID- 20195239 TI - Involvement of epimorphin in the repair of experimental renal fibrosis in mice. AB - Interaction between epithelial cells and mesenchymal cells is essential in normal organ morphogenesis and in tissue repair after injury. Epimorphin, a mesenchymal protein that regulates epithelial morphogenesis through epithelial-mesenchymal interactions, has recently attracted attention as an important modulator of tissue repair. In this study we analyzed the role of epimorphin in renal fibrosis. We first found a progressive increase in epimorphin expression corresponding to the progression of renal fibrosis in mice with unilateral ureteral obstruction (UUO). To determine whether this expression has a role in the repair or progression of renal fibrosis, we analyzed a model of renal fibrosis repair, the UUO-release (UUO-R) model. Epimorphin expression was increased at 3 and 7 days after the UUO-R rather than on the day of release, but was decreased at 21 days after the release. Inhibition of endogenous epimorphin with anti-epimorphin antibody (MC-1) significantly delayed the repair of fibrosis. When compared with normal-IgG-injected mice, MC-1-injected mice showed significantly decreased renal matrix metalloproteinase (MMP)-2 and MMP-9 expressions by western blotting and increased expression of TGF-beta and collagen I mRNA by real-time RT-PCR. Recombinant epimorphin induced prominent increases in MMP-2 and MMP-9 activities in the culture media of renal interstitial fibroblasts in vitro. These findings indicate that epimorphin has a pivotal role in the repair of renal fibrosis by modulating both extracellular matrix (ECM) degradation and its production. PMID- 20195240 TI - Novel guggulsterone derivative GG-52 inhibits NF-kappaB signaling in intestinal epithelial cells and attenuates acute murine colitis. AB - We already showed that the plant sterol guggulsterone has been reported to inhibit nuclear factor-kappaB (NF-kappaB) signaling in intestinal epithelial cells (IECs) and to attenuate dextran sulfate sodium (DSS)-induced colitis. This study investigates the anti-inflammatory effects of novel guggulsterone derivatives on IEC and preventive and therapeutic murine models of DSS-induced colitis. Novel guggulsterone derivates with high lipophilicity were designed and four derivates, including GG-46, GG-50B, GG-52, and GG-53, were synthesized. Two guggulsterone derivatives, GG-50B and GG-52, significantly inhibited the activated NF-kappaB signals and the upregulated expression of interleukin-8 (IL 8) in COLO 205 cells stimulated with tumor necrosis factor-alpha (TNF-alpha). Pretreatment with GG-50B and GG-52 attenuated the increased IkappaB kinase (IKK) and IkappaBalpha phsophorylation induced by TNF-alpha. In preventive and therapeutic models of murine colitis, administration of GG-52 significantly reduced the severity of DSS-induced colitis, as assessed by disease activity index, colon length, and histology. In contrast, GG-50B did not show a significant reduction in the colitis severity. Moreover, the efficacy on attenuating colitis by GG-52 was comparable to that by sulfasalazine or prednisolone. These results indicate that the novel guggulsterone derivative GG 52 blocks NF-kappaB activation in IEC and ameliorates DSS-induced acute murine colitis, which suggests that GG-52 is a potential therapeutic agent for the treatment of inflammatory bowel diseases. PMID- 20195241 TI - Oxidative stress mediates nephropathy in type Ia glycogen storage disease. AB - Glycogen storage disease type Ia (GSD-Ia) patients, deficient in glucose-6 phosphatase-alpha, manifest disturbed glucose homeostasis with long-term renal disease. We have previously shown that renal fibrosis in GSD-Ia is mediated by the angiotensin/transforming growth factor-beta1 (TGF-beta1) pathway, which also elicits renal damage through oxidative stress. In this study, we further elucidate the mechanism of renal disease by showing that renal expression of Nox 2, p22(phox), and p47(phox), components of NADPH oxidase, are upregulated in GSD Ia mice compared with controls. Akt/protein kinase B, a downstream mediator of angiotensin II and TGF-beta1, is also activated, leading to phosphorylation and inactivation of the Forkhead box O family of transcription factors. This in turn triggers downregulation of superoxide dismutase and catalase (CAT) activities that have essential roles in oxidative detoxification in mammals. Renal oxidative stress in GSD-Ia mice is shown by increased oxidation of dihydroethidium and by oxidative damage of DNA. Importantly, renal dysfunction, reflected by elevated serum levels of blood urea nitrogen, reduced renal CAT activity, and increased renal fibrosis, is improved in GSD-Ia mice treated with the antioxidant drug tempol. These data provide the first evidence that oxidative stress is one mechanism that underlies GSD-Ia nephropathy. PMID- 20195242 TI - Reversal of mouse Acyl-CoA oxidase 1 (ACOX1) null phenotype by human ACOX1b isoform [corrected]. AB - Disruption of the peroxisomal acyl-CoA oxidase 1 (Acox1) gene in the mouse results in the development of severe microvesicular hepatic steatosis and sustained activation of peroxisome proliferator-activated receptor-alpha (PPARalpha). These mice manifest spontaneous massive peroxisome proliferation in regenerating hepatocytes and eventually develop hepatocellular carcinomas. Human ACOX1, the first and rate-limiting enzyme of the peroxisomal beta-oxidation pathway, has two isoforms including ACOX1a and ACOX1b, transcribed from a single gene. As ACOX1a shows reduced activity toward palmitoyl-CoA as compared with ACOX1b, we used adenovirally driven ACOX1a and ACOX1b to investigate their efficacy in the reversal of hepatic phenotype in Acox1(-/-) mice. In this study, we show that human ACOX1b is markedly effective in reversing the ACOX1 null phenotype in the mouse. In addition, expression of human ACOX1b was found to restore the production of nervonic (24:1) acid and had a negative impact on the recruitment of coactivators to the PPARalpha-response unit, which suggests that nervonic acid might well be an endogenous PPARalpha antagonist, with nervonoyl CoA probably being the active form of nervonic acid. In contrast, restoration of docosahexaenoic (22:6) acid level, a retinoid-X-receptor (RXRalpha) agonist, was dependent on the concomitant hepatic expression of both ACOX1a and ACOX1b isoforms. This is accompanied by a specific recruitment of RXRalpha and coactivators to the PPARalpha-response unit. The human ACOX1b isoform is more effective than the ACOX1a isoform in reversing the Acox1 null phenotype in the mouse. Substrate utilization differences between the two ACOX1 isoforms may explain the reason why ACOX1b is more effective in metabolizing PPARalpha ligands. PMID- 20195244 TI - Protein pathway biomarker analysis of human cancer reveals requirement for upfront cellular-enrichment processing. AB - Tissues are complex structures composed of different cell types, each of which present specific functions and characteristics. To better understand and measure the effect of tumor cell enrichment on protein pathway profiling and drug target activation measurements, the signaling activation portraits of laser capture microdissected (LCM) cancer epithelium and tumor stroma were compared with patient-matched whole-tissue specimens from 53 primary colorectal cancer samples. Microdissected material and whole-tissue lysate from contiguous cryostat sections were subjected to reverse-phase protein microarray analysis to determine the level of phopshorylation and expression of 75 different proteins known to be involved in cancer progression. The results revealed distinct differences in the protein activation portraits of cancer epithelium and stroma. Moreover, we found that the signaling activation profiles of the undissected whole-tissue specimens are profoundly different from the matched LCM material. Attempts to rescale the undissected pathway information based on percent endogenous tumor epithelium content were unsuccessful in recapitulating the LCM tumor epithelial signatures. Analysis of epidermal growth factor receptor phosphorylation and COX2 expression in these same sample sets revealed wholesale differences in the rank ordering of patient determination when LCM was compared with undissected samples. On the basis of these data, we conclude that accurate protein pathway activation status, which is under evaluation as a basis for patient selection and stratification for personalized therapy, must include upfront cellular-enrichment techniques such as LCM to generate accurate drug target activation status. PMID- 20195243 TI - Molecular blockade of VEGFR2 in human epithelial ovarian carcinoma cells. AB - Human epithelial ovarian cancer (EOC) is the most lethal neoplasm affecting the female genital tract, and is characterized by overexpression of vascular endothelial growth factor (VEGF) and growth as ascites. Anti-VEGF strategies are currently used in EOC therapy with promising results; however, molecular targeting of specific VEGF receptors on the cancer cells themselves has not been explored to date. We previously showed that activation of a VEGF/VEGFR2 signaling loop in EOC cells supports their survival in suspension, and short-term pharmacological inhibition of this loop increased EOC cell apoptosis in vitro. In this study, we stably knocked down VEGFR2 in OVCAR-3 and SKOV-3 EOC cells using short hairpin RNA (shRNA), an RNA interference strategy that could potentially overcome chemoresistance arising with angiogenic inhibitors. Unexpectedly, we observed an induction of more aggressive cellular behavior in transfected cells, leading to increased growth in mouse xenografts, enhanced accumulation of ascites, increased VEGF and neuropilin-1 (NRP-1) expression, and decreased expression of adhesion proteins, notably cadherins and integrins. Sonic hedgehog (SHH) pathways do not seem to be involved in the upregulation of NRP-1 message in VEGFR2 knockdown cells. Supporting our mouse model, we also found a significant increase in the ratio between NRP-1 and VEGFR2 with increasing tumor grade in 80 cases of human EOC. The change in EOC behavior that we report in this study occurred independent of the angiogenic response and shows the direct effect of VEGF blockade on the cancer cells themselves. Our findings highlight the possible confounding events that may affect the usefulness of RNAi in a therapeutic setting for disrupting EOC cell survival in ascites. PMID- 20195245 TI - Enhanced fibrillin-2 expression is a general feature of wound healing and sclerosis: potential alteration of cell attachment and storage of TGF-beta. AB - Wound healing and sclerosis are characterized by an increase of extracellular matrix proteins, which are characteristically expressed in the embryo-fetal period. We analyzed the expression of fibrillin-2, which is typically found in embryonic tissues, but only scarcely in adult skin. In wound healing and sclerotic skin diseases such as lipodermatosclerosis and scleroderma, a marked increase of fibrillin-2 expression was found by immunohistology. Double labelling of fibrillin-2 and tenascin-C, which is also expressed in wound healing and sclerosis, showed co-localization of both proteins. Solid-phase and slot blot overlay assays showed a dose-dependent binding of the recombinant N-terminal half of fibrillin-2 (rFBN2-N) to tenascin-C. Real-time PCR showed an increase of the fibrillin-2 gene expression in cell culture triggered by typical mediators for fibroblast activation such as serum, IL-4, and TGF-beta. By contrast, prolonged hypoxia is not associated with changes in fibrillin-2 expression. Tenascin-C is an anti-adhesive substrate for fibroblasts, whereas fibrillin-2 stimulates cell attachment. Attachment assays using mixed substrates showed decreased cell attachment when tenascin-C and rFBN2-N were coated together, compared with the attachment to rFBN2-N alone. Fibrillins are involved in storage and activation of TGF-beta. Immunohistology with an antibody against the latency-associated peptide (LAP (TGF-beta1)) showed a marked increase of inactive LAP-bound TGF-beta1 in wound healing and sclerotic skin whereas normal skin showed only a weak expression. Double immunofluorescence confirmed a partial colocalization of both proteins. In conclusion, we show that a stimulation of the fibrillin-2 expression is a characteristic feature of fibroblasts present in wound healing and sclerosis, which may be involved in the alteration of cell attachment and storage of inactive TGF-beta in the matrix. PMID- 20195246 TI - Systematic variation improves reproducibility of animal experiments. PMID- 20195247 TI - Lifeact mice for studying F-actin dynamics. PMID- 20195248 TI - Plasma membrane topography and interpretation of single-particle tracks. PMID- 20195250 TI - Waltz, an exciting new move in amyloid prediction. PMID- 20195251 TI - aMAZe-ing tools for mosaic analysis in zebrafish. PMID- 20195252 TI - The electronic crystal ball: predicting cell fate from time-lapse data. PMID- 20195253 TI - Visualization of multiple alignments, phylogenies and gene family evolution. AB - Software for visualizing sequence alignments and trees are essential tools for life scientists. In this review, we describe the major features and capabilities of a selection of stand-alone and web-based applications useful when investigating the function and evolution of a gene family. These range from simple viewers, to systems that provide sophisticated editing and analysis functions. We conclude with a discussion of the challenges that these tools now face due to the flood of next generation sequence data and the increasingly complex network of bioinformatics information sources. PMID- 20195254 TI - Visualizing biological data-now and in the future. AB - Methods and tools for visualizing biological data have improved considerably over the last decades, but they are still inadequate for some high-throughput data sets. For most users, a key challenge is to benefit from the deluge of data without being overwhelmed by it. This challenge is still largely unfulfilled and will require the development of truly integrated and highly useable tools. PMID- 20195255 TI - Visualization of image data from cells to organisms. AB - Advances in imaging techniques and high-throughput technologies are providing scientists with unprecedented possibilities to visualize internal structures of cells, organs and organisms and to collect systematic image data characterizing genes and proteins on a large scale. To make the best use of these increasingly complex and large image data resources, the scientific community must be provided with methods to query, analyze and crosslink these resources to give an intuitive visual representation of the data. This review gives an overview of existing methods and tools for this purpose and highlights some of their limitations and challenges. PMID- 20195256 TI - Visualization of macromolecular structures. AB - Structural biology is rapidly accumulating a wealth of detailed information about protein function, binding sites, RNA, large assemblies and molecular motions. These data are increasingly of interest to a broader community of life scientists, not just structural experts. Visualization is a primary means for accessing and using these data, yet visualization is also a stumbling block that prevents many life scientists from benefiting from three-dimensional structural data. In this review, we focus on key biological questions where visualizing three-dimensional structures can provide insight and describe available methods and tools. PMID- 20195257 TI - Visualizing genomes: techniques and challenges. AB - As our ability to generate sequencing data continues to increase, data analysis is replacing data generation as the rate-limiting step in genomics studies. Here we provide a guide to genomic data visualization tools that facilitate analysis tasks by enabling researchers to explore, interpret and manipulate their data, and in some cases perform on-the-fly computations. We will discuss graphical methods designed for the analysis of de novo sequencing assemblies and read alignments, genome browsing, and comparative genomics, highlighting the strengths and limitations of these approaches and the challenges ahead. PMID- 20195259 TI - The eyes have it. PMID- 20195262 TI - Immunology and gene therapy: shoulder to shoulder into the fray. PMID- 20195258 TI - Visualization of omics data for systems biology. AB - High-throughput studies of biological systems are rapidly accumulating a wealth of 'omics'-scale data. Visualization is a key aspect of both the analysis and understanding of these data, and users now have many visualization methods and tools to choose from. The challenge is to create clear, meaningful and integrated visualizations that give biological insight, without being overwhelmed by the intrinsic complexity of the data. In this review, we discuss how visualization tools are being used to help interpret protein interaction, gene expression and metabolic profile data, and we highlight emerging new directions. PMID- 20195263 TI - Embryonic stem cells and repair of lung injury. PMID- 20195264 TI - The birth of the American Society of Gene Therapy. PMID- 20195265 TI - LEDGF hybrids efficiently retarget lentiviral integration into heterochromatin. AB - Correction of genetic diseases requires integration of the therapeutic gene copy into the genome of patient cells. Retroviruses are commonly used as delivery vehicles because of their precise integration mechanism, but their use has led to adverse events in which vector integration activated proto-oncogenes and contributed to leukemogenesis. Here, we show that integration by lentiviral vectors can be targeted away from genes using an artificial tethering factor. During normal lentivirus infection, the host cell-encoded transcriptional coactivator lens epithelium-derived growth factor/p75 (LEDGF/p75) binds lentiviral integrase (IN), thereby targeting integration to active transcription units and increasing the efficiency of infection. We replaced the LEDGF/p75 chromatin interaction-binding domain with CBX1. CBX1 binds histone H3 di- or trimethylated on K9, which is associated with pericentric heterochromatin and intergenic regions. The chimeric protein supported efficient transduction of lentiviral vectors and directed the integration outside of genes, near bound CBX1. Despite integration in regions rich in epigenetic marks associated with gene silencing, lentiviral vector expression remained efficient. Thus, engineered LEDGF/p75 chimeras provide technology for controlling integration site selection by lentiviral vectors. PMID- 20195266 TI - Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs. AB - Understanding individual differences in the susceptibility to metabolic side effects as a response to antipsychotic therapy is essential to optimize the treatment of schizophrenia. Here, we perform genomewide association studies (GWAS) to search for genetic variation affecting the susceptibility to metabolic side effects. The analysis sample consisted of 738 schizophrenia patients, successfully genotyped for 492K single nucleotide polymorphisms (SNPs), from the genomic subsample of the Clinical Antipsychotic Trial of Intervention Effectiveness study. Outcomes included 12 indicators of metabolic side effects, quantifying antipsychotic-induced change in weight, blood lipids, glucose and hemoglobin A1c, blood pressure and heart rate. Our criterion for genomewide significance was a pre-specified threshold that ensures, on average, only 10% of the significant findings are false discoveries. A total of 21 SNPs satisfied this criterion. The top finding indicated that a SNP in Meis homeobox 2 (MEIS2) mediated the effects of risperidone on hip circumference (q=0.004). The same SNP was also found to mediate risperidone's effect on waist circumference (q=0.055). Genomewide significant finding were also found for SNPs in PRKAR2B, GPR98, FHOD3, RNF144A, ASTN2, SOX5 and ATF7IP2, as well as in several intergenic markers. PRKAR2B and MEIS2 both have previous research indicating metabolic involvement, and PRKAR2B has previously been shown to mediate antipsychotic response. Although our findings require replication and functional validation, this study shows the potential of GWAS to discover genes and pathways that potentially mediate adverse effects of antipsychotic medication. PMID- 20195267 TI - Mechanisms of stress (Takotsubo) cardiomyopathy. AB - Stress cardiomyopathy, also referred to as Takotsubo cardiomyopathy, transient apical ballooning or broken heart syndrome, is a disorder associated with transient left ventricular dysfunction. Symptoms include acute chest pain and dyspnea accompanied by electrocardiographic changes, such as ST-segment elevation and T-wave inversions, minimal elevation of cardiac enzyme levels and transient wall-motion abnormalities in the absence of substantial coronary artery obstruction. Complete recovery of contractile function has been documented in nearly all cases, but the mechanisms of disease remain unclear and the cause has not been established. Coronary artery vasospasm, microcirculation dysfunction, and transient obstruction of the left ventricular outflow tract have been proposed as possible causes of this disorder. An excessive release of catecholamines also seems to have a pivotal role in the development of stress cardiomyopathy. This Review summarizes published data on stress cardiomyopathy, focusing primarily on the most likely causes of this cardiac entity. PMID- 20195268 TI - New drug-eluting stent concepts. AB - Drug-eluting stents (DES) have revolutionized interventional cardiology. The first bare-metal stents successfully prevented abrupt artery closure and reduced the likelihood of clinical restenosis compared with balloon angioplasty. They were, however, limited by the frequent occurrence of restenosis owing to smooth muscle proliferation, and resultant neointimal hyperplasia and target lesion revascularization. By coating stents with drugs that target smooth muscle cell proliferation, it has been possible to considerably attenuate in-stent restenosis. This innovative technology still has shortcomings, however, and novel approaches are needed to improve the safety and efficacy of DES. The main components that determine the performance of a stent are the stent backbone, active drug, polymer and delivery system, and each of these factors need to be examined to optimize DES platforms. Improvements include the use of new coating technologies, bioabsorbable stents, non-drug-based stent coatings, and tailored lesion therapy. Efforts to develop this technology further will greatly enhance the outcome for patients with coronary artery disease. PMID- 20195269 TI - Transplantation of adipose tissue and stem cells: role in metabolism and disease. AB - Humans and other mammals have three main adipose tissue depots: visceral white adipose tissue, subcutaneous white adipose tissue and brown adipose tissue, each of which possesses unique cell-autonomous properties. In contrast to visceral adipose tissue, which can induce detrimental metabolic effects, subcutaneous white adipose tissue and brown adipose tissue have the potential to benefit metabolism by improving glucose homeostasis and increasing energy consumption. In addition, adipose tissue contains adipose-derived stem cells, which possess the ability to differentiate into multiple lineages, a property that might be of value for the repair or replacement of various damaged cell types. Adipose tissue transplantation has primarily been used as a tool to study physiology and for human reconstructive surgery. Transplantation of adipose tissue is, however, now being explored as a possible tool to promote the beneficial metabolic effects of subcutaneous white adipose tissue and brown adipose tissue, as well as adipose derived stem cells. Ultimately, the clinical applicability of adipose tissue transplantation for the treatment of obesity and metabolic disorders will reside in the achievable level of safety, reliability and efficacy compared with other treatments. PMID- 20195270 TI - SPARC: a key player in the pathologies associated with obesity and diabetes. AB - SPARC (secreted protein acidic and rich in cysteine, also known as osteonectin or BM-40) is a widely expressed profibrotic protein with pleiotropic roles, which have been studied in a variety of conditions. Notably, SPARC is linked to human obesity; SPARC derived from adipose tissue is associated with insulin resistance and secretion of SPARC by adipose tissue is increased by insulin and the adipokine leptin. Furthermore, SPARC is associated with diabetes complications such as diabetic retinopathy and nephropathy, conditions that are ameliorated in the Sparc-knockout mouse model. As a regulator of the extracellular matrix, SPARC also contributes to adipose-tissue fibrosis. Evidence suggests that adipose tissue becomes increasingly fibrotic in obesity. Fibrosis of subcutaneous adipose tissue may restrict accumulation of triglycerides in this type of tissue. These triglycerides are, therefore, diverted and deposited as ectopic lipids in other tissues such as the liver or as intramyocellular lipids in skeletal muscle, which predisposes to insulin resistance. Hence, SPARC may represent a novel and important link between obesity and diabetes mellitus. This Review is focused on whether SPARC could be a key player in the pathology of obesity and its related metabolic complications. PMID- 20195272 TI - In defence of our realm. PMID- 20195271 TI - Pathology of nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is a significant complication of obesity and is recognized as the hepatic manifestation of the metabolic syndrome. The process occurs in adults and children and is characterized by the presence of increased amounts of fat in the liver (steatosis). With inflammation, cell death and scarring (fibrosis), the process may result in end-stage liver disease, or be a precursor for hepatocellular carcinoma. Excess hepatic fat is now recognized as an independent marker for increased cardiovascular risk. Even though imaging studies and laboratory-based tests are accurate at detecting significant steatosis and/or advanced fibrosis, respectively, the diagnosis and characterization of NAFLD ultimately depend on histopathologic evaluation, as the parenchymal alterations that comprise the spectrum of injury in NAFLD include patterns as well as specific lesions. Histologic findings in children may differ from those in adults. In this Review, the histologic features that are diagnostic and discriminatory between steatosis and steatohepatitis, the significance of the distinction between steatosis and steatohepatitis, the types and locations of fibrosis, and the histologic variances between adult and pediatric NAFLD are discussed. Clinical advantages as well as potential drawbacks of liver biopsy are presented. Current pathophysiologic concepts relevant to histologic findings are discussed. PMID- 20195273 TI - Pandemics: is hoping for the best enough? PMID- 20195274 TI - Comment on Steven Rose's opinion article, 'Academic freedom in Israel and Palestine'. PMID- 20195275 TI - It takes two to tango. PMID- 20195277 TI - Comment on 'Big science, little science'. PMID- 20195278 TI - The basis of morality. Psychologists, anthropologists and biologists are uncovering the bigger picture behind the development of empathy and altruism. PMID- 20195279 TI - Women and telomeres. Last year's Nobel Prizes for Carol Greider and Elizabeth Blackburn should be encouraging for all female scientists with children. PMID- 20195280 TI - Lung homing T-cell generation is dependent on strength and timing of antigen delivery to lymph nodes. AB - Inhaled allergens are known for their immediate and ongoing effects in the respiratory tract (RT). In this report, we track inhaled antigen in normal mice for 7 days and find that while it is cleared from the airways, inhaled antigen persists in peripheral lung tissue and the draining lymph nodes (DLNs). The persistence of antigen led to ongoing presentation in the lymph nodes, but not the lungs, that decreased with time in direct proportion with the frequency of antigen-bearing RT dendritic cells (DCs). There was evidence of functional changes among the antigen-bearing DCs in the lymph nodes, as the expression of CD40, CD80 and CD86 were modulated over the course of 7 days. At the same time, there was a decrease in both CD4(+) T-cell proliferation in lymph nodes and the generation of recirculating CD4(+) T cells. However, early presentation of lower doses of inhaled antigen also resulted in a decrease in CD4(+) T-cell proliferation and recirculation. Thus, T-cell recirculation depends on the strength of stimulus in the DLNs and is produced by a combination of the dose of antigen delivered to the RT, DC migration and co-stimulatory molecule expression. These results provide an important insight into the fate of inhaled antigen in vivo and the influence of persistent antigen presentation on T-cell activation in the lymph nodes. PMID- 20195281 TI - Cross-presentation of HCMV chimeric protein enables generation and measurement of polyclonal T cells. AB - CD8(+) T cell immunity has a critical function in controlling human cytomegalovirus (HCMV) infection. In immunocompromized individuals, HCMV reactivation or disease can lead to increased morbidity and mortality, particularly in transplant recipients. In this setting, adoptive transfer of HCMV specific CD8(+) T cells is a promising vaccine strategy to restore viral immunity, with most clinical approaches focussing on the use of peptides for the generation of single epitope-specific CD8(+) T cells. We show that using an IE1 pp65 chimeric protein as the antigen source promotes effective cross presentation, by monocyte-derived dendritic cells (MoDCs), to generate polyclonal CD8(+) T cell epitopes. By exploring human leukocyte antigen (HLA)-restricted immunodominance hierarchies both within and across two immunodominant proteins, we show that HLA-B7 epitopes elicit higher CD8(+) T cell responses compared with HLA-A1, -A2 or -B8. This study provides important evidence highlighting both the efficacy of the IE1-pp65 chimeric protein and the importance of immunodominance in designing future therapeutic vaccines. PMID- 20195282 TI - miR-146a in PBMCs modulates Th1 function in patients with acute coronary syndrome. AB - The upregulation of Th1 cells has been suggested to have an essential function in the development of atherosclerosis (AS). Recent studies indicate that miR-146a is a microRNA specifically and highly expressed in Th1-driven autoimmune disease. The aim of the study was to investigate the possible mechanisms of the miR-146a in the onset of acute coronary syndrome (ACS). The results showed that the expression of miR-146a in peripheral blood mononuclear cells (PBMCs) was significantly increased in patients with ACS. We showed that overexpression of miR-146a in PBMCs could significantly upregulate the function of Th1 cells. Furthermore, we showed that miR-146a treatment could modulate the Th1 differentiation through posttranscriptional enhancing the T-bet pathway in PBMCs. In addition, this study also provided evidence that miR-146a treatment in vitro could induce the protein expression of TNF-alpha, MCP-1, NF-kappaB p65, which are key pro-inflammatory cytokines and critical transcription factor in AS. In contrast, miR-146a inhibitor could attenuate these phenomena significantly. The results support the concept that miR-146a may be a novel regulatory factor in Th1 differentiation and a new therapeutic target for AS and ACS. PMID- 20195283 TI - Effect of a 3-day high-fat feeding period on carbohydrate balance and ad libitum energy intake in humans. AB - OBJECTIVE: A reduction in glycogen after the switch to an isoenergetic high-fat diet (HFD) might promote a compensatory increase in food intake to reestablish carbohydrate balance. We assessed the effect of an isoenergetic switch from a 49% carbohydrate to 50%-fat diet on nutrient balance and ad libitum food intake. We hypothesized that carbohydrate balance would be inversely related to ad libitum energy intake. METHODS: In 47 men and 11 women (22.6+/-0.4 years; 26.1+/-0.5 kg m(-2)), fuel balance was measured in a respiration chamber over 4 days. During the first day, an isoenergetic, high-carbohydrate diet was provided followed by a 3-day isoenergetic, HFD. At the end of this period and after 16 h of fasting, three options of foods (cookies, fruit salad and turkey sandwich) were offered ad libitum for 4 h. The relationships between post-chamber ad libitum intake and macronutrient oxidation and balance measured day-to-day and over the 4-day respiration chamber stay were studied. RESULTS: After switching to a HFD, 24-h respiratory quotient decreased from 0.87+/-0.02 to 0.83+/-0.02 (P<0.0001) resulting in a 4-day cumulative carbohydrate, fat and protein balances of -183+/ 368, 342+/-480 and 65+/-267 kcal, respectively. Cumulative energy balance (224+/ 362 kcal per 4 days) did not influence ad libitum energy intake. However, we detected that 4-day carbohydrate balance was a positive and independent predictor of post-chamber ad libitum energy intake (R (2)=0.10; P=0.01), whereas no significant influence of fat and protein balances was found. CONCLUSION: In response to an isoenergetic change from a high-carbohydrate to HFD, higher carbohydrate balance related to increased energy intake. PMID- 20195285 TI - Parental influence on children's early eating environments and obesity risk: implications for prevention. AB - Most childhood obesity prevention efforts have focused on school-age children and adolescents and have had limited success. We argue that the first years of life, including the prenatal period, the postnatal suckling period and the transition to the modified adult diet, may provide opportunities for preventive interventions. These early periods are characterized by high plasticity and rapid transitions, and parents have a high degree of control over children's environments and experiences. Observational and experimental evidence reveal persistent effects of early environments on eating behavior and obesity risk, suggesting that interventions should be tested during these early periods. The central task parents have in early development points to their potential as key targets and agents of change in early preventive interventions. In this paper, we review evidence of early environmental effects on children's eating and obesity risk, highlighting ways that parental feeding practices and parents' own behaviors impact these outcomes and calling for further experimental research to elucidate whether these factors are indeed promising targets for childhood obesity preventive interventions. PMID- 20195284 TI - Leisure-time physical activity and sedentary behavior clusters and their associations with overweight in middle-aged French adults. AB - OBJECTIVE: To identify leisure-time physical activity (LTPA) and sedentary behavior patterns, as well as to investigate their relationships with overweight. DESIGN: Cross-sectional study. SUBJECTS: Men (n=2206) and women (n=2476) aged >45 years, living in France, enrolled in the SU.VI.MAX (Supplementation en VItamines et Mineraux AntioXydants) study. MEASUREMENTS: LTPA and sedentary behavior were assessed using the Modifiable Activity Questionnaire whereas weight and height were measured from study participants. Clusters were defined, by gender, with multiple correspondence analysis and cluster analysis successively, taking into account the type (walking, gardening, etc.) and duration of each physical activity performed, as well as the time spent watching television (TV) as typical sedentary behavior. Logistic regression models were used to assess associations with overweight. RESULTS: Four physical activity and sedentary behavior clusters were identified among men and three among women. We chose as referent cluster the cluster associating 'walking and gardening-low TV' in men and the cluster associating 'walking and gardening-high TV' in women. Compared with the referent cluster and after adjustment for age, education level, smoking status and place of residence, the likelihood of overweight (defined as body mass index >or=25 kg m(-2)) in women was lower for a 'multiple activity-low TV' cluster (odds ratio (OR)=0.66, 95% confidence interval=0.54-0.81) and for a cluster associating 'endurance physical activity-low TV' (OR=0.42 (0.29-0.60)). Compared with the referent cluster and after adjustment, the likelihood of overweight in men was decreased for the 'endurance physical activity' cluster (OR=0.66, (0.52-0.84)), whereas no significant association was found with the other clusters. CONCLUSIONS: Patterns combining specific types of physical activity and sedentary behavior were identified and differed in their relations to overweight in adults. The identification of global patterns of activity allows us to go beyond a simple decreased activity-increased body weight approach and adds to our understanding of the associations of specific forms and grouping of activity with overweight in adults. PMID- 20195287 TI - Disgust and perceived control in attitudes toward obese people. AB - BACKGROUND: Efforts to explain negative attitudes toward obese people have centered on beliefs about the controllability of body weight, whereas other processes (such as the emotion of disgust) have been largely ignored. This study examined the role of disgust in evaluations of obese people, as well as other social groups (for example smokers, drug addicts, women, homosexuals, politicians). METHOD: In three studies, participants (total N=524) made ratings of how much they believe that obesity is a matter of personal control, indicated how disgusted they are with obese people, and reported their attitudes toward obese people. In Study 1, participants also made similar ratings (perceptions of control over group membership, disgust, and attitudes) for 15 additional social groups. RESULTS: Disgust was the strongest predictor of negative attitudes toward obese people, and disgust fully mediated the association between perceptions of control and attitudes toward obese people. In addition, obese people were rated less favorably, and as more disgusting, than almost all social groups. Across all social groups, perceived control over group membership was positively correlated with disgust ratings, and disgust mediated the link between perceived control and favorability ratings. CONCLUSION: These findings indicate that disgust is an important, yet understudied, component of weight bias. Furthermore, these findings situate representations of obesity in a broader context by establishing similarities with other social groups. PMID- 20195286 TI - Economic implications of obesity among people with atherothrombotic disease. AB - OBJECTIVE: The purpose of this study was to ascertain the impact of obesity on the cost of disease management in people with or at high risk of atherothrombotic disease from a governmental perspective using a bottom-up approach to cost estimation. In addition, the aim was also to explore the causes of any differences found. METHOD: The health-care costs of obesity were estimated from 2819 participants recruited into the nationwide Australian REACH Registry with established atherothrombotic disease or at least three risk factors for atherothrombosis. Enrollment was in 2004, through primary care general practices. Information was collected on the use of cardiovascular drugs, hospitalizations and ambulatory care services. 'Bottom-up' costing was undertaken by assigning unit costs to each health-care item, based on Australian Government-reimbursed figures 2006-2007. Linear-mixed models were used to estimate associations between direct medical costs and body mass index (BMI) categories. RESULTS: Annual pharmaceutical costs per person increased with increasing BMI category, even after adjusting for gender, age, living place, formal education, smoking status, hypertension and diabetes. Adjusted annual pharmaceutical costs of overweight and obese participants were higher ($7 (P=0.004) and $144 (<0.001), respectively) than those of the normal weight participants. This was due to participants in higher BMI categories receiving more pharmaceuticals than normal weight participants. There was no significant change across the BMI categories in annual ambulatory care costs and annual hospital costs. CONCLUSION: In these participants with or at high risk of atherothrombotic disease, annual pharmaceutical costs were greater in participants of higher BMI category, but there was not such a gradient in the annual hospital or ambulatory care costs. The greater cardiovascular pharmaceutical costs for participants of higher BMI categories remained even after adjusting for a range of demographic factors and comorbidities. Our results suggest that these costs are explained by the higher number of drugs used among people with atherothrombotic disease. Further investigation is needed to understand the reasons for this level of drug use. PMID- 20195288 TI - Menopausal transition and changes of body composition: a prospective study in Chinese perimenopausal women. AB - OBJECTIVES: Whether age or menopause per se influences fat distribution remains controversial. This study aimed to investigate the change of body composition, particularly body fat distribution, in relation to menopausal transition in a 30 month prospective study of perimenopausal women. METHODS: A total of 438 community-based healthy women aged 44-55 years participated in the Hong Kong Perimenopausal Women Osteoporosis Study. Data were obtained at baseline, and at 9 , 18- and 30-month during the follow-up. Soft tissue measurements consisting of fat mass and lean muscle mass of the trunk and whole body were obtained by the dual energy X-ray absorptiometry. Percentage change of body measurements over the follow-up period was compared between women who remained premenopausal, those who went through menopausal transition, and those who were menopausal since baseline. RESULTS: A slight decrease in the lean mass but an increase in the total fat mass and trunk fat mass (TFM) over the follow-up period were noted. Multivariate linear regression analysis showed that age was negatively associated with an increase in central obesity. Adjusted for the important predictors--age, age of menarche and education level, menopausal status was a significant and independent predictor of the decrease in lean mass and the increase in percent of body fat, TFM and trunk-leg fat mass ratio. CONCLUSION: Our 30-month longitudinal study showed that menopause has an independent effect on an increase in fat mass, and an increase in central obesity in perimenopausal Chinese women. PMID- 20195289 TI - Genetic variation in carboxylesterase genes and susceptibility to isoniazid induced hepatotoxicity. AB - Treatment of latent tuberculosis infection (LTBI) generally includes isoniazid (INH), a drug that can cause serious hepatotoxicity. Carboxylesterases (CES) are important in the metabolism of a variety of substrates, including xenobiotics. We hypothesized that genetic variation in CES genes expressed in the liver could affect INH-induced hepatotoxicity. Three CES genes are known to be expressed in human liver: CES1, CES2 and CES4. Our aim was to systematically characterize genetic variation in these novel candidate genes and test whether it is associated with this adverse drug reaction. As part of a pilot study, 170 subjects with LTBI who received only INH were recruited, including 23 cases with hepatotoxicity and 147 controls. All exons and the promoters of CES1, CES2 and CES4 were bidirectionally sequenced. A large polymorphic deletion was found to encompass exons 2 to 6 of CES4. No significant association was found. Eleven single-nucleotide polymorphisms (SNPs) in CES1 were in high linkage disequilibrium with each other. One of these SNPs, C(-2)G, alters the translation initiation sequence of CES1 and represents a candidate functional polymorphism. Replication of this possible association in a larger sample set and functional studies will be necessary to determine if this CES1 variant has a role in INH induced hepatotoxicity. PMID- 20195290 TI - Single nucleotide polymorphisms in genes that are associated with a modified response to statin therapy: the Rotterdam Study. AB - The objective of this study was to investigate whether common variation in genes involved in lipid metabolism modify the effect of statins on serum total cholesterol concentration. Statin users were identified in the Rotterdam Study, a prospective population-based cohort study of subjects >55 years of age. We studied the association between single nucleotide polymorphisms (SNPs) in genes involved in lipid metabolism and total cholesterol response to statin therapy, using linear regression analysis and adjusting for potential confounders. Replication was performed in an independent extended cohort of the Rotterdam Study. Genotype data and total cholesterol concentrations after start of statin therapy were available for 554 newly started statin users. Two SNPs were associated with a significantly higher cholesterol concentration under statin therapy: SNP rs1532624 in the CETP gene (beta: 0.141 mmol l(-1), P=0.004 per additional allele) and SNP rs533556 in the APOA1 gene (beta: 0.138 mmol l(-1), P=0.005 per additional allele). In the replication sample, only the CETP rs1532624 SNP again showed a significant association. The SNPs were not related to baseline total cholesterol in non-statin users. In conclusion, we found that the CETP rs1532624 polymorphism is associated with cholesterol response to statin therapy in a cohort of elderly subjects in the general population. PMID- 20195291 TI - BDNF Val66Met genotype and 6-month remission rates in late-life depression. AB - Although not observed in younger adult cohorts, in older individuals the brain derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with major depressive disorder (MDD) risk. It is further associated with subjective social support and magnetic resonance imaging (MRI) hyperintense lesions, clinical features independently related to MDD. We examined the relationship between this polymorphism and antidepressant remission rates in an elderly sample with MDD, while also testing for mediation effects of social support and hyperintensities. A total of 229 elderly Caucasian subjects with MDD completed baseline assessments, 1.5 T MRI, and BDNF genotyping. They received antidepressant medication under a structured treatment algorithm and were evaluated for remission at 3 and 6 months. At the 3-month evaluation, BDNF Val66Met genotype was not associated with remission (Wald's chi2=2.51, P=0.1131). When not controlling for multiple comparisons, Met66 allele carriers were more likely to be remitted at 6 months (chi2=4.32, P=0.0377) with an odds ratio of 1.82 (95% CI: 1.04, 3.22). This effect persisted after controlling for lesion volume and social support, neither of which mediated this relationship. Thus in this exploratory analysis, the Met66 allele may be associated with increased odds of remission in older subjects, but also with increased time to remission as there was no 3-month effect. PMID- 20195292 TI - Association study of MDR1 and 5-HT2C genetic polymorphisms and antipsychotic induced metabolic disturbances in female patients with schizophrenia. AB - The objective of this study was to determine the association of 5-HT2C (serotonin 2C receptor) and MDR1 (multidrug resistant protein) genetic polymorphisms and antipsychotic-induced metabolic abnormalities among female patients with DSM IV schizophrenia spectrum disorders. We have previously reported the associations of -759CT 5-HT2C and G2677T and C3435T MDR1 genetic polymorphisms and olanzapine/risperidone-induced weight gain in a similar sample of patients. Here, we included a total of 101 previously non-medicated female patients treated with olanzapine/risperidone over a 3-month period. The variables analyzed included fasting glucose, total cholesterol, low-density lipoprotein, high-density lipoprotein and triglyceride levels in blood, blood pressure and waist circumferences. We observed significant association of -759T 5-HT2C genetic variant and greater increase in waist circumference (P=0.03), fasting glucose level (P=0.046) and triglyceride level (P=0.045) in blood after a 3-month period. The 2677T and 3435T MDR1 genetic variants were significantly associated with the greater increase in fasting glucose level in blood when patients were using olanzapine (P<0.001 and P=0.028, respectively). Our data indicate a possible influence of -759CT 5-HT2C and MDR1 G2677T and C3435T MDR1 genetic polymorphisms on the development of metabolic abnormalities among female patients treated with olanzapine/risperidone. PMID- 20195293 TI - In vivo assessment of macrophage CNS infiltration during disruption of the blood brain barrier with focused ultrasound: a magnetic resonance imaging study. PMID- 20195294 TI - The influence of hepatic function on prostate cancer outcomes after radical prostatectomy. AB - Prostate growth is dependent on circulating androgens, which can be influenced by hepatic function. Liver disease has been suggested to influence prostate cancer (CaP) incidence. However, the effect of hepatic function on CaP outcomes has not been investigated. A total of 1181 patients who underwent radical prostatectomy (RP) between 1988 and 2008 at four Veterans Affairs hospitals that comprise the Shared Equal Access Regional Cancer Hospital database and had available liver function test (LFT) data were included in the study. Independent associations of LFTs with unfavorable pathological features and biochemical recurrence were determined using logistic and Cox regression analyses. Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) levels were elevated in 8.2 and 4.4% of patients, respectively. After controlling for CaP features, logistic regression revealed a significant association between SGOT levels and pathological Gleason sum > or =7(4+3) cancer (odds ratio=2.12; 95% confidence interval=1.11-4.05; P=0.02). Mild hepatic dysfunction was significantly associated with adverse CaP grade, but was not significantly associated with other adverse pathological features or biochemical recurrence in a cohort of men undergoing RP. The effect of moderate-to-severe liver disease on disease outcomes in CaP patients managed non-surgically remains to be investigated. PMID- 20195295 TI - A de novo originated gene depresses budding yeast mating pathway and is repressed by the protein encoded by its antisense strand. AB - Recent transcription profiling studies have revealed an unexpectedly large proportion of antisense transcripts in eukaryotic genomes. These antisense genes seem to regulate gene expression by interacting with sense genes. Previous studies have focused on the non-coding antisense genes, but the possible regulatory role of the antisense protein is poorly understood. In this study, we found that a protein encoded by the antisense gene ADF1 acts as a transcription suppressor, regulating the expression of sense gene MDF1 in Saccharomyces cerevisiae. Based on the evolutionary, genetic, cytological and biochemical evidence, we show that the protein-coding sense gene MDF1 most likely originated de novo from a previously non-coding sequence and can significantly suppress the mating efficiency of baker's yeast in rich medium by binding MATalpha2 and thus promote vegetative growth. These results shed new light on several important issues, including a new sense-antisense interaction mechanism, the de novo origination of a functional gene, and the regulation of yeast mating pathway. PMID- 20195296 TI - Pure white hybrid light-emitting device with color rendering index higher than 90. AB - The realization of white-light sources with a combination of high color rendering index (CRI), which is the average of the first eight rendering indices, and the deep-red color rendering R9 is an important challenge in the field of solid-state lighting. Herein, we report on a pure white hybrid light-emitting device combining a deep-blue emission from a polymer with blue, green, and red emissions from ternary CdSe/ZnS quantum dots. By carefully designing the device structure and tuning the ratio of QDs with different sizes, high CRI of 94 and R9 of 92 at 525 cd/m(2) were achieved. PMID- 20195297 TI - Multiplexed high temperature sensing with sapphire fiber air gap-based extrinsic Fabry-Perot interferometers. AB - In this Letter we present a high temperature multipoint sensing method using sapphire fiber air gap-based extrinsic Fabry-Perot interferometers. Three sensors are fabricated and tested in a single sensing link. Experimental results show that the air gap-based high temperature sensors have a very high temperature sensitivity (>20 nm/ degrees C) and resolution (<0.3 degrees C) and are capable of operating at temperatures well above 1000 degrees C. The multiplexed sapphire sensors present a significant advancement over traditional single-point sensors for critical high temperature applications. PMID- 20195298 TI - Electromagetically induced transparency with nuclear spin. AB - We report the observation of electromagnetically induced transparency in a sample of cryogenically cooled ground-state atomic ytterbium ((1)S(0)). The transparency is produced due to coherence between the optical field and the nuclear spin state of the (173)Yb nucleus. Because the nuclear spin states interact very weakly with their environment, they are resistant to decoherence due to inelastic collisions and inhomogenous fields. Consequently, atomic ensembles of pure nuclear spin states may be a superior medium for a variety of nonlinear optics and quantum information experiments. PMID- 20195299 TI - Effect of thermal stress slip on microparticle photophoresis in gaseous media. AB - This Letter presents a study on photophoresis of a microparticle in gaseous media with focus on the effect of thermal stress slip, which is deemed as one of factors causing deviations of previous theoretical predictions from measurements. The present modified theory agrees well with the measurements and, combining with 1 order-of-magnitude analysis, demonstrates the significance of the thermal stress slip in photophoresis of a particle, especially, of small radius. With the physical mechanisms addressed, the parametric analysis reveals that this interfacial thermal effect becomes more pronounced with reducing thermal conductivity of the particle and increasing Knudsen number as well. PMID- 20195300 TI - Twin-vortex solitons in nonlocal nonlinear media. AB - We consider soliton formation in thermal nonlinear media bounded by rectangular cross sections and uncover what we believe to be a new class of nonlinear stationary topological state. Specifically, we find that stationary higher-order vortex states in standard shapes do not exist, but rather they take the form of multiple spatially separated single-charge singularities nested in an elliptical beam. Double-charge states are found to be remarkably robust despite their shape asymmetry and phase-singularity splitting. States with higher topological charges are found to be unstable. PMID- 20195301 TI - Using modified Kramers-Kronig relations to test transmission spectra of porous media in THz-TDS. AB - We show that modified Kramers-Kronig relations provide a useful tool to test the validity of the complex refractive index extracted from transmission terahertz spectra of porous matrices containing pharmaceutical materials. The role of scattering of terahertz radiation is qualitatively considered as a reason for the observed discrepancy between experimental data and the values extracted from the inverted complex refractive index. As an example we present an analysis of the terahertz spectra of carbamazepine and lactose alpha-monohydrate. PMID- 20195302 TI - Kalman filtering real-time measurements of H2O isotopologue ratios by laser absorption spectroscopy at 2.73 microm. AB - Kalman adaptive filtering was applied for the first time, to our knowledge, to the real-time simultaneous determination of water isotopic ratios using laser absorption spectroscopy at 2.73 microm. Measurements of the oxygen and hydrogen isotopologue ratios delta(18)O, delta(17)O, and delta(2)H in water showed a 1 sigma precision of 0.72 per thousand for delta(18)O, 0.48 per thousand for delta(17)O, and 0.84 per thousand for delta(2)H, while sampling the output of the tuned Kalman filter at 1 s time intervals. Using a standard running average technique, averaging over approximately 30 s is required to obtain the same level of precision. PMID- 20195303 TI - Polarization-selective grating excitation of plasmons in cylindrical optical fibers. AB - We show that the tilted-grating-assisted excitation of surface plasmon polaritons on gold coated single-mode optical fibers depends strongly on the state of polarization of the core-guided light, even in fibers with cylindrical symmetry. Rotating the linear polarization of the guided light by 90 degrees relative to the grating tilt plane is sufficient to turn the plasmon resonances on and off with more than 17 dB of extinction ratio. By monitoring the amplitude changes of selected individual cladding mode resonances we identify what we believe to be a new refractive index measurement method that is shown to be accurate to better than 5 x 10(-5). PMID- 20195304 TI - Giant enhancement of electric field between two close metallic grains due to plasmonic resonance. AB - We theoretically examine plasmonic resonance between two close metallic grains separated by a gap of width much less than the length of the incident electromagnetic wave. Resonance conditions are established and the electric field enhancement is found. Our general arguments are confirmed by analytic solution of the problem for simplest geometries. We discuss an extension of our results to more complex cases. PMID- 20195305 TI - Single negative birefringence in stacked spoof plasmon metasurfaces by prism experiment. AB - We report negative and positive refraction in a prism made of stacked perforated thin surfaces for s and p polarization, respectively. By corrugating the subwavelength slits of a free-standing periodic arrangement, geometrically induced surface-plasmon-like currents are excited and transmission is allowed under s polarization (electric-field vector parallel to the slit). When several of those corrugated slit arrays are subwavelength stacked, the stack behaves as a negative effective index medium (because of double negativity) under s polarization, whereas it behaves as a positive effective index medium under p polarization. The birefringence has been confirmed by the usual wedge experiment in the millimeter-wave range. PMID- 20195306 TI - In situ 24 kHz coherent imaging of morphology change in laser percussion drilling. AB - We observe sample morphology changes in real time (24 kHz) during and between percussion drilling pulses by integrating a low-coherence microscope into a laser micromachining platform. Nonuniform cut speed and sidewall evolution in stainless steel are observed to strongly depend on assist gas. Interpulse morphology relaxation such as hole refill is directly imaged, showing dramatic differences in the material removal process dependent on pulse duration/peak power (micros/0.1 kW, ps/20 MW) and material (steel, lead zirconate titanate PZT). Blind hole depth precision is improved by over 1 order of magnitude using in situ feedback from the imaging system. PMID- 20195307 TI - Efficient light coupling between dielectric slot waveguide and plasmonic slot waveguide. AB - An efficient coupler between a dielectric waveguide and a plasmonic metal insulator-metal (MIM) waveguide is proposed, modeled, fabricated, and characterized. Based on the platform of a silicon slot waveguide, a quasi-MIM plasmonic junction is formed via e-beam lithography and lift-off process. Coupling efficiency between the silicon slot waveguide and plasmonic waveguide up to 43% is obtained after normalizing to reference waveguides at 1550 nm. This coupling scheme can be potentially used for fast optical switching and small footprint optical modulation. PMID- 20195308 TI - Generation of femtosecond paraxial beams with arbitrary spatial distribution. AB - We present an approach to generate paraxial laser beams with arbitrary spatial distribution in the femtosecond time regime. The proposed technique is based upon a pair of volume phase holographic gratings working in parallel arrangement. It exploits the spatial coherence properties of the incoming laser beam in a compact and robust setup that mitigates angular and spatial chirp. The gratings were recorded in a photopolymerizable glass with a high optical damage threshold and a large optical throughput. Setup performance is studied and experimentally demonstrated by generating Laguerre-Gaussian femtosecond pulses. PMID- 20195309 TI - Rapid phase-shifting fiber interferometer with optical stylus. AB - Optical fiber interferometry holds many advantages for the online measurement of high-precision surfaces. Here, a fiber interferometer with a wavelength-scanning probe is reported. Such an interferometer requires active stabilization against the effects of temperature drift and vibration. A method of multiplexing dual wavelengths into the same fiber, combined with rapid phase shifting and real-time phase calculation, is investigated. Experimental data show the successful stabilization of the interferometer regardless of environmental perturbation. PMID- 20195310 TI - Giant dispersive wave generation through soliton collision. AB - We numerically study long pulse supercontinuum generation in a photonic crystal fiber with two zero-dispersion wavelengths, reporting a dynamical effect where soliton collisions excite dispersive waves with 1 order of magnitude greater peak power than that arising from single-soliton generation. The dispersive wave peak power exhibits extreme-value "rogue" characteristics, with the long tail of the distribution populated by collision-related events. PMID- 20195311 TI - Optical atomic magnetometer at body temperature for magnetic particle imaging and nuclear magnetic resonance. AB - Optical atomic magnetometers are often bulky and operate at elevated temperatures that impose restrictions on studying biological samples. Here we report a miniaturized Cs-based magnetometer, in contrast to conventionally used K- and Rb based ones, with high sensitivity. The magnetic shield employed is more compact, and the optimal operation temperature of 37 degrees C is lower than previous magnetometers and is suitable for biological research. Applications include scanning magnetic imaging of functionalized magnetic particles and nuclear magnetic resonance of water. We reveal that the stability and sensitivity of the apparatus are not significantly affected by the absence of a laser stabilization device. PMID- 20195312 TI - Holographic Fourier transform spectrometer for terahertz region. AB - Because of the development of detector arrays stationary interferometric spectrometers now have many applications in the visible and IR; however, these same array sizes make it impractical to design a single Fourier optics system with the necessary large field angles required for the terahertz region. By dividing the Fourier optics into independent components in each arm of an interferometer we show that the aberrations are dramatically reduced, while the same theoretical throughput as in the scanning Michelson interferometer is maintained. PMID- 20195313 TI - Optical force on a cylindrical cloak under arbitrary wave illumination. AB - The optical force distribution in the cylindrical cloak under arbitrary incident waves is presented. We show that on the inner surface of the cloak both the induced surface currents and polarization charges interact with the waves and give opposite radiation pressure onto the inner surface. The Lorentz force in the cloak can contribute to change the trajectory of the rays, while in some cases it may only reflect the rays having a tendency to decrease the total energy it carries. The force is symmetric and in balance. Therefore the total momentum transfer from the waves to the cylindrical cloak is zero. PMID- 20195314 TI - Propagation of vector fractional charge Laguerre-Gaussian light beams in the thermally nonlinear moving atmosphere. AB - We study numerically the mutual propagation of two fractional topological charge Laguerre-Gaussian (LG) light beams in the moving atmosphere with the thermal nonlinearity. The fractional charge beam is constructed as a weighted superposition of a finite number of the standard LG modes with integer charges. Numerical simulations demonstrate an enhanced stability of the cross-section intensity distribution of the fractional charge LG beams against the thermal blooming, as compared with the case of integer charge beams. The dominant mechanism of such a stability results from the multimodal structure of the fractional charge beams. PMID- 20195315 TI - Subwavelength diffraction control and self-imaging in curved plasmonic waveguide arrays. AB - We study subwavelength light propagation in arrays of coupled metal-dielectric waveguides with a periodically curved axis and show analytically and numerically that subwavelength diffraction management, including self-imaging effects, can be achieved by a suitable engineering of the bending geometry. PMID- 20195316 TI - Design of binary subwavelength multiphase level computer generated holograms. AB - The ability of subwavelength structures to create an artificial effective index opens up new perspectives in designing highly efficient diffractive optical elements. We demonstrate a design approach for binary multi-phase level computer generated holograms based on the effective medium approach. The phase pattern is formed by various subwavelength structures that cause a certain phase delay to an incident light wave. This binary structure approach leads to a significant cost reduction by simplifying the fabrication process. For demonstration, a three phase level element, operating in the visible range, is fabricated and experimentally evaluated. PMID- 20195317 TI - Ge-on-Si laser operating at room temperature. AB - Monolithic lasers on Si are ideal for high-volume and large-scale electronic photonic integration. Ge is an interesting candidate owing to its pseudodirect gap properties and compatibility with Si complementary metal oxide semiconductor technology. Recently we have demonstrated room-temperature photoluminescence, electroluminescence, and optical gain from the direct gap transition of band engineered Ge-on-Si using tensile strain and n-type doping. Here we report what we believe to be the first experimental observation of lasing from the direct gap transition of Ge-on-Si at room temperature using an edge-emitting waveguide device. The emission exhibited a gain spectrum of 1590-1610 nm, line narrowing and polarization evolution from a mixed TE/TM to predominantly TE with increasing gain, and a clear threshold behavior. PMID- 20195318 TI - Efficient 5.3 W cw laser at 559 nm by intracavity frequency summation of fundamental and first-Stokes wavelengths in a self-Raman Nd:GdVO4 laser. AB - We report the generation of 5.3 W cw laser emission at 559 nm by sum-frequency mixing of the fundamental and first-Stokes fields generated within an Nd:GdVO(4) self-Raman laser. A high overall diode-to-visible conversion efficiency of 21% is demonstrated. We discuss the balance that must be maintained between the two nonlinear processes of Raman generation and sum-frequency mixing in order to obtain maximum emission at 559 nm. PMID- 20195320 TI - Hybrid Fourier-real space method for diffuse optical tomography. AB - Optical tomography has recently witnessed a substantial increase in the size of the data sets used, mainly owing to the use of CCD cameras. Larger data sets render 3D reconstructions more robust, quantitative, and reproducible, but also significantly increase the computing time needed to generate the reconstructed data. Approaches working with spatial-frequencies instead of real space variables seem to be the method of choice in this case, and a direct inversion method that can produce three-dimensional images from very large detector numbers (>10(5)) using either very large source numbers (>10(3)) [Phys. Rev. E 64, 035601 (2001)] or structured illumination [Opt. Lett. 34, 983 (2009)] has been presented. However, most small animal imaging setups typically incur a practical upper limit of only approximately 10(2) sources mainly due to imaging time constraints, and currently all relying on point source illumination. In this Letter, what we believe to be a new approach, which combines Fourier and real space functions, is shown, which fills the gap between traditional fiber-based small data sets that are solved in real space and the very large data sets solved entirely in spatial frequency domain. PMID- 20195319 TI - Discrete plasmonic Talbot effect in subwavelength metal waveguide arrays. AB - Discrete plasmonic Talbot effect in the subwavelength metal waveguide arrays (SMWAS) is theoretically analyzed and numerically simulated. Based on the finite difference time-domain technique, we discuss the influence of the structural parameters on the Talbot distance. By carefully choosing the geometry parameters, the Talbot distance decreases to about one third of the incident wavelength. The numerical simulation results agree with the theory of the discrete Talbot effect in the SMWAS. PMID- 20195321 TI - Experimental evidence of enhanced rotation sensing in a slow-light structure. AB - We report the experimental observation of enhanced rotation sensing in a slow light structure. We demonstrate that the differential of the phase difference, introduced by rotation, between the counterpropagating waves is proportional to the group index, and thus we can obtain large rotation sensitivity in the slow light structure with high dispersion (large group index). The results also predict the realization of highly sensitive and compact integrated rotation sensors and gyroscopes by using microwaveguides. PMID- 20195322 TI - Optically pumped semiconductor quantum dot disk laser operating at 1180 nm. AB - We demonstrate an optically pumped semiconductor disk laser using 39 layers of Stranski-Krastanov InGaAs quantum dots self-assembled during epitaxial growth on a monolithic GaAs/AlAs distributed Bragg reflector. The gain structure bonded to an intracavity diamond crystal heat spreader allows 1.75 W single-transverse-mode output (M(2)<1.2) with circular beam shape operating at 1180 nm in a disk laser geometry. PMID- 20195323 TI - Enhancing slow- and fast-light effects in quantum-dot semiconductor waveguides through ultrafast dynamics. AB - We show that ultrafast carrier dynamics plays an important role on slow- and fast light effects based on coherent population oscillations in quantum-dot semiconductor waveguides. Fast light in the gain regime and slow light in the absorption regime are found to be enhanced at frequencies beyond the usual limits of the carrier lifetime. The effects are investigated by a comprehensive model and are shown to originate from nonequilibrium dynamics within the quantum-dot carrier populations. PMID- 20195325 TI - Tuning the aspect ratio of silver nanospheroids embedded in silica. AB - A method is proposed to control the aspect ratio (epsilon) of elongated nanoparticles obtained by ion implantation in a transparent matrix. The procedure was tested for Ag spheroids in silica and we could accurately change epsilon in the range from the maximum value obtained by the ion implantation (around 3.0 in this case) to 1.0 (spherical shape). The values of epsilon were determined in several steps from optical extinction spectroscopy measurements, by fitting the modification and splitting of the surface plasmon resonance peak, using the T matrix method. In the initial (maximum deformation) and final (undeformed) states, transmission electron microscopy images were obtained, showing a good agreement with the T-matrix results in both cases. PMID- 20195326 TI - All-fiber optical isolator based on Faraday rotation in highly terbium-doped fiber. AB - An all-fiber isolator with 17 dB optical isolation is demonstrated. The fiber Faraday rotator uses 56 wt. % terbium (Tb)-doped silicate fiber, and the fiber polarizers are Corning SP1060 single-polarization fiber. The effective Verdet constant of the Tb-doped fiber is measured to be -24.5+/-1.0 rad/(Tm) at 1053 nm, which is 20 times larger than silica fiber and 22% larger than previously reported results. PMID- 20195324 TI - Photothermal optical coherence tomography in ex vivo human breast tissues using gold nanoshells. AB - We demonstrate photothermal optical coherence tomography (OCT) imaging in highly scattering human breast tissue ex vivo. A 120 kHz axial scan rate, swept-source phase-sensitive OCT system at 1300 nm was used to detect phase changes induced by 830 nm photothermal excitation of gold nanoshells. Localized phase modulation was observed 300-600 microm deep in scattering tissue using an excitation power of only 22 mW at modulation frequencies up to 20 kHz. This technique enables integrated structural and molecular-targeted imaging for cancer markers using nanoshells. PMID- 20195327 TI - Dynamically induced double photonic bandgaps in the presence of spontaneously generated coherence. AB - We study a four-level double-Lambda system with spontaneously generated coherence driven by a standing-wave coupling field. It is found that two well-developed photonic bandgaps with reflectivities of about 90% can be generated on the probe resonance in the presence of maximal spontaneously generated coherence. The induced double photonic bandgaps become, however, severely malformed when spontaneously generated coherence vanishes. Dynamic control of the double photonic bandgaps may be exploited to achieve a novel two-port double-channel routing scheme for weak light signals in quantum networks. PMID- 20195328 TI - Phase-shifting point-diffraction interferometry with common-path and in-line configuration for microscopy. AB - A new common-path and in-line point-diffraction interferometer for quantitative phase microscopy is proposed. The interferometer is constructed by introducing a grating pair into the point-diffraction interferometer, thus forming a common path and in-line configuration for object and reference waves. Achromatic phase shifting is implemented by linearly moving one of the two gratings in its grating vector direction. The feasibility of the proposed configuration is demonstrated by theoretical analysis and experiments. PMID- 20195329 TI - Spreading and direction of Gaussian-Schell model beam through a non-Kolmogorov turbulence. AB - We show that the far-field beam spreading and direction of partially coherent Gaussian-Schell model (GSM) beams are independent on the spatial coherence of the source through non-Kolmogorov atmospheric turbulence, which has potential applications in long-distance free-space optical communication. The effects of spatial coherence, exponent value alpha, and inner scale and outer scale of atmospheric turbulence on beam spreading are studied in details. The GSM beam has greater spreading for smaller inner scale or bigger outer scale through non Kolmogorov turbulent atmosphere. PMID- 20195330 TI - Multibeam fluorescence diffuse optical tomography using upconverting nanoparticles. AB - Fluorescence diffuse optical tomography (FDOT) is a biomedical imaging modality that can be used for localization and quantification of fluorescent molecules inside turbid media. In this ill-posed problem, the reconstruction quality is directly determined by the amount and quality of the information obtained from the boundary measurements. Regularly, more information can be obtained by increasing the number of excitation positions in an FDOT system. However, the maximum number of excitation positions is limited by the finite size of the excitation beam. In the present work, we demonstrate a method in FDOT to exploit the unique nonlinear power dependence of upconverting nanoparticles to further increase the amount of information in a raster-scanning setup by including excitation with two beams simultaneously. We show that the additional information can be used to obtain more accurate reconstructions. PMID- 20195331 TI - Heterodyne coherent anti-Stokes Raman scattering for spectral phase retrieval and signal amplification. AB - We study interference between a local oscillator and coherent anti-Stokes Raman scattering signal fields by controlling their relative phase and amplitude. This control allows direct observation of the real and imaginary components of the third-order nonlinear susceptibility (chi((3))) of the sample. In addition, we demonstrate that the heterodyne method can be used to amplify the signal. PMID- 20195332 TI - Aperiodically poled silica fibers for bandwidth control of quasi-phase-matched second-harmonic generation. AB - Precise control of the bandwidth of quasi-phase-matched second-harmonic generation in silica fibers is realized through chirped-period poling. The bandwidth is expanded by a factor of 33 over a uniform-period poled fiber of the same interaction length. PMID- 20195333 TI - Fabrication of transmission phase gratings on porous anodic alumina. AB - The transmission phase grating on anodic alumina membrane (AAM) was fabricated by a lithography and chemical etching method to demonstrate the feasibility of fabricating diffractive optical elements on AAM matrix. The monochromatic light diffraction property of the sample grating was tested using lasers with wavelengths of 532 and 650 nm, respectively. The measured diffraction efficiencies of zeroth and first orders were in good agreement with the calculated results. This method may offer an approach to prepare surface pattern on alumina and could be used in fabricating diffractive optical components such as linear gratings. PMID- 20195334 TI - Record high-speed short-range transmission over 1 mm core diameter POF employing DMT modulation. AB - We report multigigabit/second transmission capacity in 1 mm core diameter graded index plastic optical fiber (POF) exploiting off-the-shelf low-cost components and discrete multitone (DMT) modulation. Transmission capacities of 10.1 Gbits/s x 15 m and 12.7 Gbits/s x 3 m are achieved for average bit-error rates less than 10(-3). PMID- 20195335 TI - Nondestructive analysis of coated periodic nanostructures from optical data. AB - Optical data are essential for the accurate nondestructive determination of profiles of periodic structures in integrated-circuit technology. In rigorous coupled-wave analysis, the sample is generally modeled as layers consisting of a single material and the ambient. We extend present capabilities to the analysis of structures with overlayers and demonstrate our approach by determining quantitatively the thicknesses of top, sidewall, and bottom oxides of deliberately and naturally oxidized structures. PMID- 20195336 TI - Electro-optical effects in strain-compensated InGaAs/InAlAs coupled quantum wells with modified potential. AB - We design and experimentally report strain-compensated InGaAs/InAlAs coupled quantum wells with modified potential. At a lower applied electric field (F=50 kV/cm), the calculated blueshift of the lowest excitonic peak is 40.6 meV. In the room-temperature photocurrent experiments, a maximum upward shift of the apparent peak position of more than 35 meV is observed with an external reverse bias of -4 V. Furthermore, a lower absorption loss (alpha=9.8 cm(-1)) and a large negative refractive index change (Deltan=-0.0095) are obtained at 1.55 mum. This indicates that the strain-compensated InGaAs/InAlAs coupled quantum wells with modified potential have a great potential for application to reflection type electro optical switches. PMID- 20195337 TI - Adjustable adaptive compact fluidic phoropter with no mechanical translation of lenses. AB - We demonstrate a compact optical phoroptor consisting of adjustable astigmatic and defocus lenses. The lenses are fluidically controlled and allow for an arbitrary refractive error to be corrected without mechanically moving lenses. Shack-Hartmann measurements were used to characterize the optical properties of the individual lenses. The lenses were then assembled into the phoropter and controlled with three separate fluid controls. The phoroptor was verified by correcting the vision of a model eye with an induced refraction error. PMID- 20195338 TI - Cavity-enhanced multispectral photodetector using phase-tuned propagation: theory and design. AB - We propose and theoretically analyze what we believe to be a novel design of cavity-enhanced photodetectors capable of sensing multiple wavelengths simultaneously in a single pixel. The design is based on phase-tuned propagation of resonant modes in cascaded planar resonant cavities. We show that this concept can be generalized to detect multiple wavelength combinations covering the entire near to far infrared spectrum. Besides its multispectral detection capability, the design also features minimal spectral cross talk and significantly suppressed noise. The intrinsic design versatility and scalability, as well as process compatibility with planar microfabrication, suggest the design's wide application potential for telecommunications, infrared imaging, and biochemical sensing. PMID- 20195339 TI - Broadband optical serrodyne frequency shifting. AB - We demonstrate serrodyne frequency shifting of light from 200 MHz to 1.2 GHz with an efficiency of better than 60%. The frequency shift is imparted by an electro optic phase modulator driven by a high-frequency high-fidelity sawtooth waveform that is passively generated by a commercially available nonlinear transmission line. We also implement a push-pull configuration using two serrodyne-driven phase modulators, allowing for continuous tuning between -1.6 GHz and +1.6 GHz. Compared with competing technologies, this technique is simple and robust, and it offers the largest available tuning range in this frequency band. PMID- 20195340 TI - Palm-top-size, 1.5 kW peak-power, and femtosecond (160 fs) diode-pumped mode locked Yb+3:KY(WO4)2 solid-state laser with a semiconductor saturable absorber mirror. AB - We report a palm-top-size femtosecond diode-pumped mode-locked Yb(+3):KY(WO(4))(2) solid-state laser with a semiconductor saturable absorber mirror utilizing soliton mode locking for shortening the cavity to 50 mm. An average output power of 680 mW and a pulse width of 162 fs were obtained at 1045 nm with a repetition rate of 2.8 GHz, which led to a peak power of 1.5 kW. Average power fluctuations of a modularized laser source were found to be +/-10% for the free-running 3000 h operation and +/-1% for the power-controlled 2000 h operation. PMID- 20195341 TI - Gratings fabrication in benzildimethylketal doped photosensitive polymer optical fibers using 355 nm nanosecond pulsed laser. AB - We report writing polymer optical fiber (POF) gratings in photosensitive POFs doped with benzildimethylketal (BDK) (BPOF in short) using a 355 nm laser for what we believe to be the first time. Both multimode and single-mode FBGs were fabricated with relatively low writing intensity. The enhanced photosensitivity of the doped POFs is also evident by the observation of obvious change in the UV visible absorption. PMID- 20195342 TI - Double-resonance nanolaser based on coupled slit-hole resonator structures. AB - This work investigates a kind of metallic magnetic cavity based on slit-hole resonators. Two orthogonal hybrid magnetic resonance modes of the cavity with a large spatial overlap are predesigned at the wavelengths of 980 and 1550 nm. The Yb:Er codoped material serving as a gain medium is set in the cavity; this enables the resonator to have a high optical activity. The numerical result shows that the strong lasing at 1550 nm may be achieved when the cavity array is pumped at 980 nm. This double resonance nanolaser array has potential applications in future optical devices and quantum information techniques. PMID- 20195343 TI - Single-shot detection and direct control of carrier phase drift of midinfrared pulses. AB - We introduce a scheme for single-shot detection and correction of the carrier envelope phase (CEP) drift of femtosecond pulses at mid-IR wavelengths. Difference frequency mixing between the mid-IR field and a near-IR gate pulse generates a near-IR frequency-shifted pulse, which is then spectrally interfered with a replica of the gate pulse. The spectral interference pattern contains shot to-shot information of the CEP of the mid-IR field, and it can be used for simultaneous correction of its slow drifts. We apply this technique to detect and compensate long-term phase drifts at 17 microm wavelength, reducing fluctuations to only 110 mrad over hours of operation. PMID- 20195344 TI - Gold nanorings as substrates for surface-enhanced Raman scattering. AB - Surface-enhanced Raman scattering using gold nanoring substrates is studied. The measured enhancement factors of arrays of single nanorings and nanoring dimers are compared with that of an array of nanodisk dimers. The measured average enhancement factor for the single nanorings is 4.2 x 10(6). The experimental enhancement factors are compared with the electromagnetic enhancement factors predicted by simulations. PMID- 20195345 TI - Fast image reconstruction in fluorescence optical tomography using data compression. AB - We present a method for fast reconstruction in fluorescence optical tomography with very large data sets. In recent reports, CCD cameras at multiple positions have been used to collect optical measurements, producing more than 10(7) data samples. This makes storage of the full system Jacobian infeasible, and so data are usually subsampled. The method reported here allows use of the full data set, via image compression methods, and explicit construction of the (small) Jacobian, meaning optimal inversion methods can be applied, and thus leading to very fast reconstruction. PMID- 20195346 TI - Three-dimensional microscopy with single-beam wavefront sensing and reconstruction from speckle fields. AB - Generally, 3D digital holographic microscopy requires the interference of the object wave with a known reference beam under coherent illumination to perform numerical focusing. This configuration may be challenging for some applications, including the use of exotic wavelengths such as x rays, miniaturized instrumentation, etc. Single-beam intensity measurement followed by phase retrieval techniques is attractive for wavefront sensing and reconstruction, including applications with low coherence. We use this method to construct a 3D microscope using volume speckle fields. Transparent phase objects are investigated using this principle. To the best of our knowledge, this is the first report on the application of this principle applied to microscopy. PMID- 20195347 TI - Microwave photonic filter based on circulating a cladding mode in a fiber ring resonator. AB - We propose a microwave photonic filter based on circulating a cladding mode in a fiber ring resonator, where the cladding mode is injected into and extracted from the resonator with a pair of matching long-period fiber gratings (LPFGs). The filter has a compact configuration and allows the frequency spacing and the notch depth to be tuned easily. The use of LPFGs also provides the capability of wavelength selection and tuning. Using a standard single-mode fiber and a pair of CO(2) laser-written LPFGs, we demonstrate a filter with a frequency spacing of approximately 1.3 GHz and a notch depth of approximately 17 dB. Our experimental results agree well with theoretical calculations. PMID- 20195348 TI - Spatial optical memory based on coherent population oscillations. AB - We show that a system characterized by long-lived coherent population oscillations (CPOs), such as a two-level system that decays via a shelving state, can be used to construct a spatial optical memory. In the presence of a cw control field, a field is generated at the four-wave mixing (FWM) frequency with the same spatial profile as the initial probe. When the control field is switched off, these spatial profiles are encoded in the CPOs of the ground and storage states. When the control field is switched on again, the probe and FWM fields are retrieved simultaneously with the same spatial profiles as the initial probe. PMID- 20195349 TI - Concept for phase-to-intensity conversion in SOAs by facet reflections. AB - All-optical conversion from phase-modulated signals to intensity-modulated signals is theoretically demonstrated in semiconductor optical amplifiers (SOAs). Large-signal and small-signal calculations show significant conversion responses appearing as a result of even minute reflections at the end mirrors of the SOA. It is discussed how reflected phase-modulated signals can lead to interference resulting in intensity fluctuations that are amplified by the gain in a SOA. The effect can be utilized for deliberate conversion between optical modulation formats. PMID- 20195350 TI - Origin of the spectral coherence in dynamically broadened Rabi sidebands. AB - We demonstrate the coherent nature of dynamic Rabi-shifted sidebands arising when a picosecond probe laser interacts with a weakly ionized laser-generated microplasma. The coherence is manifested as spectral fringes observed in the sideband spectra. A model is presented that quantitatively predicts both the spectral phase and the spectral interference measured in the sidebands. PMID- 20195351 TI - Wavelength-coded multifocal microscopy. AB - A wavelength-coded multifocal microscope incorporating multiplexed and wavelength coded holographic gratings to generate wavelength-selective multifocal planes is presented. The focal planes are longitudinally spaced on the object plane, and each focal plane is probed by a designated wavelength. The recording of the multiplexed gratings takes place at a single wavelength by utilizing the Bragg degeneracy property; thus the maximum sensitive wavelength of blue 488 nm is used for recording, but the device is operated at a broad wavelength band of interest, all the way to red 633 nm. We present the design, implementation, and experimental image data demonstrating this microscope's ability to obtain biological tissue structures simultaneously at different focal planes using broadband illumination by LEDs. PMID- 20195352 TI - Quantitative infrared imaging of silicon-on-insulator microring resonators. AB - There is considerable research activity in multiresonator optical circuits in silicon photonics, e.g., for higher-order filters, advanced modulation format coding/decoding, or coupled-resonator optical waveguide delay lines. In diagnostics of such structures, it is usually not possible to measure each individual microring resonator without adding separate input and output waveguides to each resonator. We demonstrate a non-invasive diagnostic method of quantitative IR imaging, applied here to a series cascade of rings. The IR images contain information on the otherwise inaccessible individual through ports and the resonators themselves, providing an efficient means to obtain coupling, loss, and intensity-enhancement parameters for the individual rings. PMID- 20195353 TI - Parallel heterodyne detection of dynamic light-scattering spectra from gold nanoparticles diffusing in viscous fluids. AB - We developed a microscope intended to probe, using a parallel heterodyne receiver, the fluctuation spectrum of light quasi-elastically scattered by gold nanoparticles diffusing in viscous fluids. The cutoff frequencies of the recorded spectra scale up linearly with those expected from single-scattering formalism in a wide range of dynamic viscosities (1 to 15 times water viscosity at room temperature). Our scheme enables ensemble-averaged optical fluctuations measurements over multispeckle recordings in low light, at temporal frequencies up to 10 kHz, with a 12 Hz framerate array detector. PMID- 20195354 TI - Modified Fourier transform method for 3D profile measurement without phase unwrapping. AB - An algorithm based on the Fourier transform method without phase unwrapping is proposed to measure the 3D profile of objects. Phase unwrapping is essential and time consuming in conventional fringe projection techniques. To avoid this step, the method utilizes a color fringe pattern to substitute a gray-level fringe pattern. Intensity information can be used to extract the wrapped phase, while color information can be used to calculate the phase shift range. Combining the two parts, real phase value can be obtained without phase unwrapping. Experiments are conducted to verify the feasibility of this method. PMID- 20195355 TI - Ultrafast partial measurement of fourth-order coherence by HBT interferometry of upconversion-based autocorrelation. AB - We introduce, analyze, and experimentally demonstrate a compact semiconductor based scheme for a femtosecond-scale partial fourth-order coherence g((4)) measurements. The scheme is based on a start-stop photon-counting Hanbury Brown and Twiss (HBT) interferometry of an upconversion-based Michelson-interferometer autocorrelation. The experimental realization employs second-harmonic generation in a semiconductor quantum-well structure, which may be further integrated with the HBT setup as a miniature photonic circuit, allowing compact characterization devices for photon-pair statistics in quantum photonics and quantum information processing. PMID- 20195356 TI - A new horned crocodile from the Plio-Pleistocene hominid sites at Olduvai Gorge, Tanzania. AB - BACKGROUND: The fossil record reveals surprising crocodile diversity in the Neogene of Africa, but relationships with their living relatives and the biogeographic origins of the modern African crocodylian fauna are poorly understood. A Plio-Pleistocene crocodile from Olduvai Gorge, Tanzania, represents a new extinct species and shows that high crocodylian diversity in Africa persisted after the Miocene. It had prominent triangular "horns" over the ears and a relatively deep snout, these resemble those of the recently extinct Malagasy crocodile Voay robustus, but the new species lacks features found among osteolaemines and shares derived similarities with living species of Crocodylus. METHODOLOGY/PRINCIPAL FINDINGS: The holotype consists of a partial skull and skeleton and was collected on the surface between two tuffs dated to approximately 1.84 million years (Ma), in the same interval near the type localities for the hominids Homo habilis and Australopithecus boisei. It was compared with previously-collected material from Olduvai Gorge referable to the same species. Phylogenetic analysis places the new form within or adjacent to crown Crocodylus. CONCLUSIONS/SIGNIFICANCE: The new crocodile species was the largest predator encountered by our ancestors at Olduvai Gorge, as indicated by hominid specimens preserving crocodile bite marks from these sites. The new species also reinforces the emerging view of high crocodylian diversity throughout the Neogene, and it represents one of the few extinct species referable to crown genus Crocodylus. PMID- 20195357 TI - A comprehensive resource of interacting protein regions for refining human transcription factor networks. AB - Large-scale data sets of protein-protein interactions (PPIs) are a valuable resource for mapping and analysis of the topological and dynamic features of interactome networks. The currently available large-scale PPI data sets only contain information on interaction partners. The data presented in this study also include the sequences involved in the interactions (i.e., the interacting regions, IRs) suggested to correspond to functional and structural domains. Here we present the first large-scale IR data set obtained using mRNA display for 50 human transcription factors (TFs), including 12 transcription-related proteins. The core data set (966 IRs; 943 PPIs) displays a verification rate of 70%. Analysis of the IR data set revealed the existence of IRs that interact with multiple partners. Furthermore, these IRs were preferentially associated with intrinsic disorder. This finding supports the hypothesis that intrinsically disordered regions play a major role in the dynamics and diversity of TF networks through their ability to structurally adapt to and bind with multiple partners. Accordingly, this domain-based interaction resource represents an important step in refining protein interactions and networks at the domain level and in associating network analysis with biological structure and function. PMID- 20195358 TI - Protective effect of human amniotic fluid stem cells in an immunodeficient mouse model of acute tubular necrosis. AB - Acute Tubular Necrosis (ATN) causes severe damage to the kidney epithelial tubular cells and is often associated with severe renal dysfunction. Stem-cell based therapies may provide alternative approaches to treating of ATN. We have previously shown that clonal c-kit(pos) stem cells, derived from human amniotic fluid (hAFSC) can be induced to a renal fate in an ex-vivo system. Herein, we show for the first time the successful therapeutic application of hAFSC in a mouse model with glycerol-induced rhabdomyolysis and ATN. When injected into the damaged kidney, luciferase-labeled hAFSC can be tracked using bioluminescence. Moreover, we show that hAFSC provide a protective effect, ameliorating ATN in the acute injury phase as reflected by decreased creatinine and BUN blood levels and by a decrease in the number of damaged tubules and apoptosis therein, as well as by promoting proliferation of tubular epithelial cells. We show significant immunomodulatory effects of hAFSC, over the course of ATN. We therefore speculate that AFSC could represent a novel source of stem cells that may function to modulate the kidney immune milieu in renal failure caused by ATN. PMID- 20195359 TI - The chemokine MIP1alpha/CCL3 determines pathology in primary RSV infection by regulating the balance of T cell populations in the murine lung. AB - BACKGROUND: CD8 T cells assist in the clearance of respiratory syncytial virus (RSV) infection from the lungs. However, disease after RSV infection is in part caused by excessive T cell activity, and a balance is therefore needed between beneficial and harmful cellular immune responses. The chemokine CCL3 (MIP1alpha) is produced following RSV infection and is broadly chemotactic for both T cells and natural killer (NK) cells. We therefore investigated its role in RSV disease. METHODOLOGY/PRINCIPAL FINDINGS: CCL3 was produced biphasically, in both the early (day 1) and late (day 6-7) stages of infection. CCL3 depletion did not alter the recruitment of natural killer (NK) cells to the lungs during the early stage, but depletion did affect the later adaptive phase. While fewer T cells were recruited to the lungs of either CCL3 knockout or anti-CCL3 treated RSV infected mice, more RSV-specific pro-inflammatory T cells were recruited to the lung when CCL3 responses were impaired. This increase in RSV-specific pro-inflammatory T cells was accompanied by increased weight loss and illness after RSV infection. CONCLUSIONS/SIGNIFICANCE: CCL3 regulates the balance of T cell populations in the lung and can alter the outcome of RSV infection. Understanding the role of inflammatory mediators in the recruitment of pathogenic T cells to the lungs may lead to novel methods to control RSV disease. PMID- 20195360 TI - Bayesian Markov Random Field analysis for protein function prediction based on network data. AB - Inference of protein functions is one of the most important aims of modern biology. To fully exploit the large volumes of genomic data typically produced in modern-day genomic experiments, automated computational methods for protein function prediction are urgently needed. Established methods use sequence or structure similarity to infer functions but those types of data do not suffice to determine the biological context in which proteins act. Current high-throughput biological experiments produce large amounts of data on the interactions between proteins. Such data can be used to infer interaction networks and to predict the biological process that the protein is involved in. Here, we develop a probabilistic approach for protein function prediction using network data, such as protein-protein interaction measurements. We take a Bayesian approach to an existing Markov Random Field method by performing simultaneous estimation of the model parameters and prediction of protein functions. We use an adaptive Markov Chain Monte Carlo algorithm that leads to more accurate parameter estimates and consequently to improved prediction performance compared to the standard Markov Random Fields method. We tested our method using a high quality S. cereviciae validation network with 1622 proteins against 90 Gene Ontology terms of different levels of abstraction. Compared to three other protein function prediction methods, our approach shows very good prediction performance. Our method can be directly applied to protein-protein interaction or coexpression networks, but also can be extended to use multiple data sources. We apply our method to physical protein interaction data from S. cerevisiae and provide novel predictions, using 340 Gene Ontology terms, for 1170 unannotated proteins and we evaluate the predictions using the available literature. PMID- 20195361 TI - A color hierarchy for automatic target selection. AB - Visual processing of color starts at the cones in the retina and continues through ventral stream visual areas, called the parvocellular pathway. Motion processing also starts in the retina but continues through dorsal stream visual areas, called the magnocellular system. Color and motion processing are functionally and anatomically discrete. Previously, motion processing areas MT and MST have been shown to have no color selectivity to a moving stimulus; the neurons were colorblind whenever color was presented along with motion. This occurs when the stimuli are luminance-defined versus the background and is considered achromatic motion processing. Is motion processing independent of color processing? We find that motion processing is intrinsically modulated by color. Color modulated smooth pursuit eye movements produced upon saccading to an aperture containing a surface of coherently moving dots upon a black background. Furthermore, when two surfaces that differed in color were present, one surface was automatically selected based upon a color hierarchy. The strength of that selection depended upon the distance between the two colors in color space. A quantifiable color hierarchy for automatic target selection has wide-ranging implications from sports to advertising to human-computer interfaces. PMID- 20195362 TI - Sociobiological control of plasmid copy number in bacteria. AB - All genes critical for plasmid replication regulation are located on the plasmid rather than on the host chromosome. It is possible therefore that there can be copy-up "cheater" mutants. In spite of this possibility, low copy number plasmids appear to exist stably in host populations. We examined this paradox using a multilevel selection model. Simulations showed that, a slightly higher copy number mutant could out-compete the wild type. Consequently, another mutant with still higher copy number could invade the first invader. However, the realized benefit of increasing intra-host fitness was saturating whereas that of inter host fitness was exponential. As a result, above a threshold, intra-host selection was overcompensated by inter-host selection and the low copy number wild type plasmid could back invade a very high copy number plasmid. This led to a rock-paper-scissor (RPS) like situation that allowed the coexistence of plasmids with varied copy numbers. Furthermore, another type of cheater that had lost the genes required for conjugation but could hitchhike on a conjugal plasmid, could further reduce the advantage of copy-up mutants. These sociobiological interactions may compliment molecular mechanisms of replication regulation in stabilizing the copy numbers. PMID- 20195363 TI - The octarepeat region of the prion protein is conformationally altered in PrP(Sc). AB - BACKGROUND: Prion diseases are fatal neurodegenerative disorders characterized by misfolding and aggregation of the normal prion protein PrP(C). Little is known about the details of the structural rearrangement of physiological PrP(C) into a still-elusive disease-associated conformation termed PrP(Sc). Increasing evidence suggests that the amino-terminal octapeptide sequences of PrP (huPrP, residues 59 89), though not essential, play a role in modulating prion replication and disease presentation. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report that trypsin digestion of PrP(Sc) from variant and sporadic human CJD results in a disease-specific trypsin-resistant PrP(Sc) fragment including amino acids approximately 49-231, thus preserving important epitopes such as the octapeptide domain for biochemical examination. Our immunodetection analyses reveal that several epitopes buried in this region of PrP(Sc) are exposed in PrP(C). CONCLUSIONS/SIGNIFICANCE: We conclude that the octapeptide region undergoes a previously unrecognized conformational transition in the formation of PrP(Sc). This phenomenon may be relevant to the mechanism by which the amino terminus of PrP(C) participates in PrP(Sc) conversion, and may also be exploited for diagnostic purposes. PMID- 20195364 TI - Modified intracellular-associated phenotypes in a recombinant Salmonella Typhi expressing S. Typhimurium SPI-3 sequences. AB - A bioinformatics comparison of Salmonella Pathogenicity Island 3 sequences from S. Typhi and S. Typhimurium serovars showed that ten genes are highly conserved. However three of them are pseudogenes in S. Typhi. Our aim was to understand what functions are lost in S. Typhi due to pseudogenes by constructing a S. Typhi genetic hybrid carrying the SPI-3 region of S. Typhimurium instead of its own SPI 3. We observed that under stressful conditions the hybrid strain showed a clear impairment in resistance to hydrogen peroxide and decreased survival within U937 culture monocytes. We hypothesized that the marT-fidL operon, encoded in SPI-3, was responsible for the new phenotypes because marT is a pseudogen in S. Typhi and has a demonstrated role as a transcriptional regulator in S. Typhimurium. Therefore we cloned and transferred the S. Typhimurium marT-fidL operon into S. Typhi and confirmed that invasion of monocytes was dramatically decreased. Finally, our findings suggest that the genomic and functional differences between SPI-3 sequences have implications in the host specificity of Typhi and Typhimurium serovars. PMID- 20195365 TI - Oral biofilm architecture on natural teeth. AB - Periodontitis and caries are infectious diseases of the oral cavity in which oral biofilms play a causative role. Moreover, oral biofilms are widely studied as model systems for bacterial adhesion, biofilm development, and biofilm resistance to antibiotics, due to their widespread presence and accessibility. Despite descriptions of initial plaque formation on the tooth surface, studies on mature plaque and plaque structure below the gum are limited to landmark studies from the 1970s, without appreciating the breadth of microbial diversity in the plaque. We used fluorescent in situ hybridization to localize in vivo the most abundant species from different phyla and species associated with periodontitis on seven embedded teeth obtained from four different subjects. The data showed convincingly the dominance of Actinomyces sp., Tannerella forsythia, Fusobacterium nucleatum, Spirochaetes, and Synergistetes in subgingival plaque. The latter proved to be new with a possibly important role in host-pathogen interaction due to its localization in close proximity to immune cells. The present study identified for the first time in vivo that Lactobacillus sp. are the central cells of bacterial aggregates in subgingival plaque, and that Streptococcus sp. and the yeast Candida albicans form corncob structures in supragingival plaque. Finally, periodontal pathogens colonize already formed biofilms and form microcolonies therein. These in vivo observations on oral biofilms provide a clear vision on biofilm architecture and the spatial distribution of predominant species. PMID- 20195366 TI - High resolution niche models of malaria vectors in northern Tanzania: a new capacity to predict malaria risk? AB - BACKGROUND: Malaria transmission rates in Africa can vary dramatically over the space of a few kilometres. This spatial heterogeneity reflects variation in vector mosquito habitat and presents an important obstacle to the efficient allocation of malaria control resources. Malaria control is further complicated by combinations of vector species that respond differently to control interventions. Recent modelling innovations make it possible to predict vector distributions and extrapolate malaria risk continentally, but these risk mapping efforts have not yet bridged the spatial gap to guide on-the-ground control efforts. METHODOLOGY/PRINCIPAL FINDINGS: We used Maximum Entropy with purpose built, high resolution land cover data and other environmental factors to model the spatial distributions of the three dominant malaria vector species in a 94,000 km(2) region of east Africa. Remotely sensed land cover was necessary in each vector's niche model. Seasonality of precipitation and maximum annual temperature also contributed to niche models for Anopheles arabiensis and An. funestus s.l. (AUC 0.989 and 0.991, respectively), but cold season precipitation and elevation were important for An. gambiae s.s. (AUC 0.997). Although these niche models appear highly accurate, the critical test is whether they improve predictions of malaria prevalence in human populations. Vector habitat within 1.5 km of community-based malaria prevalence measurements interacts with elevation to substantially improve predictions of Plasmodium falciparum prevalence in children. The inclusion of the mechanistic link between malaria prevalence and vector habitat greatly improves the precision and accuracy of prevalence predictions (r(2) = 0.83 including vector habitat, or r(2) = 0.50 without vector habitat). Predictions including vector habitat are unbiased (observations vs. model predictions of prevalence: slope = 1.02). Using this model, we generate a high resolution map of predicted malaria prevalence throughout the study region. CONCLUSIONS/SIGNIFICANCE: The interaction between mosquito niche space and microclimate along elevational gradients indicates worrisome potential for climate and land use changes to exacerbate malaria resurgence in the east African highlands. Nevertheless, it is possible to direct interventions precisely to ameliorate potential impacts. PMID- 20195367 TI - Optimal in silico target gene deletion through nonlinear programming for genetic engineering. AB - BACKGROUND: Optimal selection of multiple regulatory genes, known as targets, for deletion to enhance or suppress the activities of downstream genes or metabolites is an important problem in genetic engineering. Such problems become more feasible to address in silico due to the availability of more realistic dynamical system models of gene regulatory and metabolic networks. The goal of the computational problem is to search for a subset of genes to knock out so that the activity of a downstream gene or a metabolite is optimized. METHODOLOGY/PRINCIPAL FINDINGS: Based on discrete dynamical system modeling of gene regulatory networks, an integer programming problem is formulated for the optimal in silico target gene deletion problem. In the first result, the integer programming problem is proved to be NP-hard and equivalent to a nonlinear programming problem. In the second result, a heuristic algorithm, called GKONP, is designed to approximate the optimal solution, involving an approach to prune insignificant terms in the objective function, and the parallel differential evolution algorithm. In the third result, the effectiveness of the GKONP algorithm is demonstrated by applying it to a discrete dynamical system model of the yeast pheromone pathways. The empirical accuracy and time efficiency are assessed in comparison to an optimal, but exhaustive search strategy. SIGNIFICANCE: Although the in silico target gene deletion problem has enormous potential applications in genetic engineering, one must overcome the computational challenge due to its NP hardness. The presented solution, which has been demonstrated to approximate the optimal solution in a practical amount of time, is among the few that address the computational challenge. In the experiment on the yeast pheromone pathways, the identified best subset of genes for deletion showed advantage over genes that were selected empirically. Once validated in vivo, the optimal target genes are expected to achieve higher genetic engineering effectiveness than a trial-and error procedure. PMID- 20195370 TI - Inhibition of in vitro fertilizing capacity of cryopreserved mouse sperm by factors released by damaged sperm, and stimulation by glutathione. AB - BACKGROUND: In vitro fertilization (IVF) of eggs by frozen and thawed C57BL/6J mouse sperm is inhibited by dead sperm and enhanced by preincubation of the sperm in calcium-free medium. In other species, the presence of sperm killed by freezing and thawing has been associated with the generation of hydrogen peroxide. METHODOLOGY/PRINCIPAL FINDINGS: The proportion of eggs fertilized by cryopreserved C57BL/6J mouse sperm was increased significantly by increasing the volume of fertilization medium in which sperm and eggs were coincubated. Enhanced fertilization occurred even though the concentration of potentially fertile sperm was decreased fivefold. This suggested that if a putative soluble factor was inhibiting fertilization, dilution of that factor, but not the sperm, should increase the fertilization rate. This was achieved by coincubation of the gametes in cell culture inserts (Transwells) that during incubation were transferred progressively to wells containing fresh fertilization medium. Fertilization rates using inserts were high (66.6+/-2.4% versus 27.3%+/-2.8% in wells alone). On the assumption that the soluble factor could be H(2)O(2), reduced glutathione was added to the fertilization medium. This enhanced fertilization rate significantly (76.6%+/-2.0% versus 21.2%+/-1.9%), while addition of oxidized glutathione did not (82.7%+/-6.5% with reduced glutathione; 44.5+/-8.8% with oxidized glutathione; 47.8%+/-12.1% with no glutathione). Positive effects of reduced glutathione on IVF were also seen with frozen 129S1, FVB, and C3H sperm, and sperm from two lines of genetically modified C57BL/6J mice. CONCLUSIONS/SIGNIFICANCE: IVF in cell culture inserts and addition of glutathione to fertilization medium significantly increased the proportion of eggs fertilized by cryopreserved mouse sperm from four inbred strains, suggesting that reactive oxygen species generated during fertilization inhibit fertilization. The modified IVF techniques developed here enhance the feasibility and efficiency of using cryopreserved sperm from genetically modified lines of inbred mice. PMID- 20195369 TI - Population hemoglobin mean and anemia prevalence in Papua New Guinea: new metrics for defining malaria endemicity? AB - BACKGROUND: The hypothesis is that hemoglobin-based metrics are useful tools for estimating malaria endemicity and for monitoring malaria control strategies. The aim of this study is to compare population hemoglobin mean and anemia prevalence to established indicators of malaria endemicity, including parasite rates, rates of enlarged spleens in children, and records of (presumptive) malaria diagnosis among populations living with different levels of malaria transmission. METHODOLOGY/PRINCIPAL FINDINGS: Convenience sample, multisite cross-sectional household surveys conducted in Papua New Guinea. Correlations (r(2)) between population Hb mean and anemia prevalence and altitude, parasite rate, and spleen rate were investigated in children ages 2 to 10 years, and in the general population; 21,664 individuals from 156 different communities were surveyed. Altitude ranged from 5 to 2120 meters. In young children, correlations between altitude and parasite rate, population Hb mean, anemia prevalence, and spleen rate were high (r(2): -0.77, 0.73, -0.81, and -0.68; p<0.001). In the general population, correlations between altitude and population Hb mean and anemia prevalence were 0.83 and 0.85, respectively. Among young children, parasite rate correlated highly with anemia prevalence, population Hb mean, and spleen rate (r(2): 0.81, -0.81, and 0.86; p<0.001). Population Hb mean (corrected for direct altitude effects) increased with altitude, from 10.5 g/dl at <500 m to 12.8 g/dl at >1500 m (p<0.001). CONCLUSIONS/SIGNIFICANCE: In PNG, where Plasmodium vivax accounts for an important part of all malaria infections, population hemoglobin mean and anemia prevalence correlate well with altitude, parasite, and spleen rates. Hb measurement is simple and affordable, and may be a useful new tool, alone or in association with other metrics, for estimating malaria endemicity and monitoring effectiveness of malaria control programs. Further prospective studies in areas with different malaria epidemiology and different factors contributing to the burden of anemia are warranted to investigate the usefulness of Hb metrics in monitoring malaria transmission intensity. PMID- 20195371 TI - Structural analysis of biodiversity. AB - Large, recently-available genomic databases cover a wide range of life forms, suggesting opportunity for insights into genetic structure of biodiversity. In this study we refine our recently-described technique using indicator vectors to analyze and visualize nucleotide sequences. The indicator vector approach generates correlation matrices, dubbed Klee diagrams, which represent a novel way of assembling and viewing large genomic datasets. To explore its potential utility, here we apply the improved algorithm to a collection of almost 17,000 DNA barcode sequences covering 12 widely-separated animal taxa, demonstrating that indicator vectors for classification gave correct assignment in all 11,000 test cases. Indicator vector analysis revealed discontinuities corresponding to species- and higher-level taxonomic divisions, suggesting an efficient approach to classification of organisms from poorly-studied groups. As compared to standard distance metrics, indicator vectors preserve diagnostic character probabilities, enable automated classification of test sequences, and generate high-information density single-page displays. These results support application of indicator vectors for comparative analysis of large nucleotide data sets and raise prospect of gaining insight into broad-scale patterns in the genetic structure of biodiversity. PMID- 20195368 TI - Caloric restriction shortens lifespan through an increase in lipid peroxidation, inflammation and apoptosis in the G93A mouse, an animal model of ALS. AB - Caloric restriction (CR) extends lifespan through a reduction in oxidative stress, delays the onset of morbidity and prolongs lifespan. We previously reported that long-term CR hastened clinical onset, disease progression and shortened lifespan, while transiently improving motor performance in G93A mice, a model of amyotrophic lateral sclerosis (ALS) that shows increased free radical production. To investigate the long-term CR-induced pathology in G93A mice, we assessed the mitochondrial bioenergetic efficiency and oxidative capacity (CS- citrate synthase content and activity, cytochrome c oxidase--COX activity and protein content of COX subunit-I and IV and UCP3-uncoupling protein 3), oxidative damage (MDA--malondialdehyde and PC--protein carbonyls), antioxidant enzyme capacity (Mn-SOD, Cu/Zn-SOD and catalase), inflammation (TNF-alpha), stress response (Hsp70) and markers of apoptosis (Bax, Bcl-2, caspase 9, cleaved caspase 9) in their skeletal muscle. At age 40 days, G93A mice were divided into two groups: Ad libitum (AL; n = 14; 7 females) or CR (n = 13; 6 females), with a diet equal to 60% of AL. COX/CS enzyme activity was lower in CR vs. AL male quadriceps (35%), despite a 2.3-fold higher COX-IV/CS protein content. UCP3 was higher in CR vs. AL females only. MnSOD and Cu/Zn-SOD were higher in CR vs. AL mice and CR vs. AL females. MDA was higher (83%) in CR vs. AL red gastrocnemius. Conversely, PC was lower in CR vs. AL red (62%) and white (30%) gastrocnemius. TNF-alpha was higher (52%) in CR vs. AL mice and Hsp70 was lower (62%) in CR vs. AL quadriceps. Bax was higher in CR vs. AL mice (41%) and CR vs. AL females (52%). Catalase, Bcl 2 and caspases did not differ. We conclude that CR increases lipid peroxidation, inflammation and apoptosis, while decreasing mitochondrial bioenergetic efficiency, protein oxidation and stress response in G93A mice. PMID- 20195372 TI - Retrospective analysis for genetic improvement of hip joints of cohort labrador retrievers in the United States: 1970-2007. AB - BACKGROUND: Canine Hip Dysplasia (CHD) is a common inherited disease that affects dog wellbeing and causes a heavy financial and emotional burden to dog owners and breeders due to secondary hip osteoarthritis. The Orthopedic Foundation for Animals (OFA) initiated a program in the 1960's to radiograph hip and elbow joints and release the OFA scores to the public for breeding dogs against CHD. Over last four decades, more than one million radiographic scores have been released. METHODOLOGY/PRINCIPAL FINDINGS: The pedigrees in the OFA database consisted of 258,851 Labrador retrievers, the major breed scored by the OFA (25% of total records). Of these, 154,352 dogs had an OFA hip score reported between 1970 and 2007. The rest of the dogs (104,499) were the ancestors of the 154,352 dogs to link the pedigree relationships. The OFA hip score is based on a 7-point scale with the best ranked as 1 (excellent) and the worst hip dysplasia as 7. A mixed linear model was used to estimate the effects of age, sex, and test year period and to predict the breeding value for each dog. Additive genetic and residual variances were estimated using the average information restricted maximum likelihood procedure. The analysis also provided an inbreeding coefficient for each dog. The hip scores averaged 1.93 (+/-SD = 0.59) and the heritability was 0.21. A steady genetic improvement has accrued over the four decades. The breeding values decreased (improved) linearly. By the end of 2005, the total genetic improvement was 0.1 units, which is equivalent to 17% of the total phenotypic standard deviation. CONCLUSION/SIGNIFICANCE: A steady genetic improvement has been achieved through the selection based on the raw phenotype released by the OFA. As the heritability of the hip score was on the low end (0.21) of reported ranges, we propose that selection based on breeding values will result in more rapid genetic improvement than breeding based on phenotypic selection alone. PMID- 20195373 TI - Multiple motor learning strategies in visuomotor rotation. AB - BACKGROUND: When exposed to a continuous directional discrepancy between movements of a visible hand cursor and the actual hand (visuomotor rotation), subjects adapt their reaching movements so that the cursor is brought to the target. Abrupt removal of the discrepancy after training induces reaching error in the direction opposite to the original discrepancy, which is called an aftereffect. Previous studies have shown that training with gradually increasing visuomotor rotation results in a larger aftereffect than with a suddenly increasing one. Although the aftereffect difference implies a difference in the learning process, it is still unclear whether the learned visuomotor transformations are qualitatively different between the training conditions. METHODOLOGY/PRINCIPAL FINDINGS: We examined the qualitative changes in the visuomotor transformation after the learning of the sudden and gradual visuomotor rotations. The learning of the sudden rotation led to a significant increase of the reaction time for arm movement initiation and then the reaching error decreased, indicating that the learning is associated with an increase of computational load in motor preparation (planning). In contrast, the learning of the gradual rotation did not change the reaction time but resulted in an increase of the gain of feedback control, suggesting that the online adjustment of the reaching contributes to the learning of the gradual rotation. When the online cursor feedback was eliminated during the learning of the gradual rotation, the reaction time increased, indicating that additional computations are involved in the learning of the gradual rotation. CONCLUSIONS/SIGNIFICANCE: The results suggest that the change in the motor planning and online feedback adjustment of the movement are involved in the learning of the visuomotor rotation. The contributions of those computations to the learning are flexibly modulated according to the visual environment. Such multiple learning strategies would be required for reaching adaptation within a short training period. PMID- 20195374 TI - Qualitative analysis of the interdisciplinary interaction between data analysis specialists and novice clinical researchers. AB - BACKGROUND: The inherent complexity of statistical methods and clinical phenomena compel researchers with diverse domains of expertise to work in interdisciplinary teams, where none of them have a complete knowledge in their counterpart's field. As a result, knowledge exchange may often be characterized by miscommunication leading to misinterpretation, ultimately resulting in errors in research and even clinical practice. Though communication has a central role in interdisciplinary collaboration and since miscommunication can have a negative impact on research processes, to the best of our knowledge, no study has yet explored how data analysis specialists and clinical researchers communicate over time. METHODS/PRINCIPAL FINDINGS: We conducted qualitative analysis of encounters between clinical researchers and data analysis specialists (epidemiologist, clinical epidemiologist, and data mining specialist). These encounters were recorded and systematically analyzed using a grounded theory methodology for extraction of emerging themes, followed by data triangulation and analysis of negative cases for validation. A policy analysis was then performed using a system dynamics methodology looking for potential interventions to improve this process. Four major emerging themes were found. Definitions using lay language were frequently employed as a way to bridge the language gap between the specialties. Thought experiments presented a series of "what if" situations that helped clarify how the method or information from the other field would behave, if exposed to alternative situations, ultimately aiding in explaining their main objective. Metaphors and analogies were used to translate concepts across fields, from the unfamiliar to the familiar. Prolepsis was used to anticipate study outcomes, thus helping specialists understand the current context based on an understanding of their final goal. CONCLUSION/SIGNIFICANCE: The communication between clinical researchers and data analysis specialists presents multiple challenges that can lead to errors. PMID- 20195375 TI - Neonatal maternal deprivation response and developmental changes in gene expression revealed by hypothalamic gene expression profiling in mice. AB - Neonatal feeding problems are observed in several genetic diseases including Prader-Willi syndrome (PWS). Later in life, individuals with PWS develop hyperphagia and obesity due to lack of appetite control. We hypothesized that failure to thrive in infancy and later-onset hyperphagia are related and could be due to a defect in the hypothalamus. In this study, we performed gene expression microarray analysis of the hypothalamic response to maternal deprivation in neonatal wild-type and Snord116del mice, a mouse model for PWS in which a cluster of imprinted C/D box snoRNAs is deleted. The neonatal starvation response in both strains was dramatically different from that reported in adult rodents. Genes that are affected by adult starvation showed no expression change in the hypothalamus of 5 day-old pups after 6 hours of maternal deprivation. Unlike in adult rodents, expression levels of Nanos2 and Pdk4 were increased, and those of Pgpep1, Ndp, Brms1l, Mett10d, and Snx1 were decreased after neonatal deprivation. In addition, we compared hypothalamic gene expression profiles at postnatal days 5 and 13 and observed significant developmental changes. Notably, the gene expression profiles of Snord116del deletion mice and wild-type littermates were very similar at all time points and conditions, arguing against a role of Snord116 in feeding regulation in the neonatal period. PMID- 20195376 TI - Gene expression profiles identify inflammatory signatures in dendritic cells. AB - Dendritic cells (DCs) constitute a heterogeneous group of antigen-presenting leukocytes important in activation of both innate and adaptive immunity. We studied the gene expression patterns of DCs incubated with reagents inducing their activation or inhibition. Total RNA was isolated from DCs and gene expression profiling was performed with oligonucleotide microarrays. Using a supervised learning algorithm based on Random Forest, we generated a molecular signature of inflammation from a training set of 77 samples. We then validated this molecular signature in a testing set of 38 samples. Supervised analysis identified a set of 44 genes that distinguished very accurately between inflammatory and non inflammatory samples. The diagnostic performance of the signature genes was assessed against an independent set of samples, by qRT-PCR. Our findings suggest that the gene expression signature of DCs can provide a molecular classification for use in the selection of anti-inflammatory or adjuvant molecules with specific effects on DC activity. PMID- 20195378 TI - Explaining away the body: experiences of supernaturally caused touch and touch on non-hand objects within the rubber hand illusion. AB - BACKGROUND: In rubber hand illusions and full body illusions, touch sensations are projected to non-body objects such as rubber hands, dolls or virtual bodies. The robustness, limits and further perceptual consequences of such illusions are not yet fully explored or understood. A number of experiments are reported that test the limits of a variant of the rubber hand illusion. METHODOLOGY/PRINCIPAL FINDINGS: A variant of the rubber hand illusion is explored, in which the real and foreign hands are aligned in personal space. The presence of the illusion is ascertained with participants' scores and temperature changes of the real arm. This generates a basic illusion of touch projected to a foreign arm. Participants are presented with further, unusual visuotactile stimuli subsequent to onset of the basic illusion. Such further visuotactile stimulation is found to generate very unusual experiences of supernatural touch and touch on a non-hand object. The finding of touch on a non-hand object conflicts with prior findings, and to resolve this conflict a further hypothesis is successfully tested: that without prior onset of the basic illusion this unusual experience does not occur. CONCLUSIONS/SIGNIFICANCE: A rubber hand illusion is found that can arise when the real and the foreign arm are aligned in personal space. This illusion persists through periods of no tactile stimulation and is strong enough to allow very unusual experiences of touch felt on a cardboard box and experiences of touch produced at a distance, as if by supernatural causation. These findings suggest that one's visual body image is explained away during experience of the illusion and they may be of further importance to understanding the role of experience in delusion formation. The findings of touch on non-hand objects may help reconcile conflicting results in this area of research. In addition, new evidence is provided that relates to the recently discovered psychologically induced temperature changes that occur during the illusion. PMID- 20195377 TI - An optimized pentaplex PCR for detecting DNA mismatch repair-deficient colorectal cancers. AB - PURPOSE: Microsatellite instability (MSI) is used to screen colorectal cancers (CRC) for Lynch Syndrome, and to predict outcome and response to treatment. The current technique for measuring MSI requires DNA from normal and neoplastic tissues, and fails to identify tumors with specific DNA mismatch repair (MMR) defects. We tested a panel of five quasi-monomorphic mononucleotide repeat markers amplified in a single multiplex PCR reaction (pentaplex PCR) to detect MSI. EXPERIMENTAL DESIGN: We investigated a cohort of 213 CRC patients, comprised of 114 MMR-deficient and 99 MMR-proficient tumors. Immunohistochemical (IHC) analysis evaluated the expression of MLH1, MSH2, PMS2 and MSH6. MSI status was defined by differences in the quasi-monomorphic variation range (QMVR) from a pool of normal DNA samples, and measuring differences in allele lengths in tumor DNA. RESULTS: Amplification of 426 normal alleles allowed optimization of the QMVR at each marker, and eliminated the requirement for matched reference DNA to define MSI in each sample. Using > or = 2/5 unstable markers as the criteria for MSI resulted in a sensitivity of 95.6% (95% CI = 90.1-98.1%) and a positive predictive value of 100% (95% CI = 96.6%-100%). Detection of MSH6-deficiency was limited using all techniques. Data analysis with a three-marker panel (BAT26, NR21 and NR27) was comparable in sensitivity (97.4%) and positive predictive value (96.5%) to the five marker panel. Both approaches were superior to the standard approach to measuring MSI. CONCLUSIONS: An optimized pentaplex (or triplex) PCR offers a facile, robust, very inexpensive, highly sensitive, and specific assay for the identification of MSI in CRC. PMID- 20195379 TI - The most likely time and place of introduction of BTV8 into Belgian ruminants. AB - BACKGROUND: In northern Europe, bluetongue (BT) caused by the BT virus (BTV), serotype 8, was first notified in August 2006 and numerous ruminant herds were affected in 2007 and 2008. However, the origin and the time and place of the original introduction have not yet been determined. METHODS AND PRINCIPAL FINDINGS: Four retrospective epidemiological surveys have been performed to enable determination of the initial spatiotemporal occurrence of this emerging disease in southern Belgium: investigations of the first recorded outbreaks near to the disease epicenter; a large anonymous, random postal survey of cattle herds and sheep flocks; a random historical milk tank survey of samples tested with an indirect ELISA and a follow-up survey of non-specific health indicators. The original introduction of BTV into the region probably occurred during spring 2006 near to the National Park of Hautes Fagnes and Eifel when Culicoides become active. CONCLUSIONS/SIGNIFICANCE: The determination of the most likely time and place of introduction of BTV8 into a country is of paramount importance to enhance awareness and understanding and, to improve modeling of vector-borne emerging infectious diseases. PMID- 20195380 TI - Molecular model of the microvillar cytoskeleton and organization of the brush border. AB - BACKGROUND: Brush border microvilli are approximately 1-microm long finger-like projections emanating from the apical surfaces of certain, specialized absorptive epithelial cells. A highly symmetric hexagonal array of thousands of these uniformly sized structures form the brush border, which in addition to aiding in nutrient absorption also defends the large surface area against pathogens. Here, we present a molecular model of the protein cytoskeleton responsible for this dramatic cellular morphology. METHODOLOGY/PRINCIPAL FINDINGS: The model is constructed from published crystallographic and microscopic structures reported by several groups over the last 30+ years. Our efforts resulted in a single, unique, self-consistent arrangement of actin, fimbrin, villin, brush border myosin (Myo1A), calmodulin, and brush border spectrin. The central actin core bundle that supports the microvillus is nearly saturated with fimbrin and villin cross-linkers and has a density similar to that found in protein crystals. The proposed model accounts for all major proteinaceous components, reproduces the experimentally determined stoichiometry, and is consistent with the size and morphology of the biological brush border membrane. CONCLUSIONS/SIGNIFICANCE: The model presented here will serve as a structural framework to explain many of the dynamic cellular processes occurring over several time scales, such as protein diffusion, association, and turnover, lipid raft sorting, membrane deformation, cytoskeletal-membrane interactions, and even effacement of the brush border by invading pathogens. In addition, this model provides a structural basis for evaluating the equilibrium processes that result in the uniform size and structure of the highly dynamic microvilli. PMID- 20195381 TI - The Drosophila gene CheB42a is a novel modifier of Deg/ENaC channel function. AB - Degenerin/epithelial Na(+) channels (DEG/ENaC) represent a diverse family of voltage-insensitive cation channels whose functions include Na(+) transport across epithelia, mechanosensation, nociception, salt sensing, modification of neurotransmission, and detecting the neurotransmitter FMRFamide. We previously showed that the Drosophila melanogaster Deg/ENaC gene lounge lizard (llz) is co transcribed in an operon-like locus with another gene of unknown function, CheB42a. Because operons often encode proteins in the same biochemical or physiological pathway, we hypothesized that CHEB42A and LLZ might function together. Consistent with this hypothesis, we found both genes expressed in cells previously implicated in sensory functions during male courtship. Furthermore, when coexpressed, LLZ coprecipitated with CHEB42A, suggesting that the two proteins form a complex. Although LLZ expressed either alone or with CHEB42A did not generate ion channel currents, CHEB42A increased current amplitude of another DEG/ENaC protein whose ligand (protons) is known, acid-sensing ion channel 1a (ASIC1a). We also found that CHEB42A was cleaved to generate a secreted protein, suggesting that CHEB42A may play an important role in the extracellular space. These data suggest that CHEB42A is a modulatory subunit for sensory-related Deg/ENaC signaling. These results are consistent with operon-like transcription of CheB42a and llz and explain the similar contributions of these genes to courtship behavior. PMID- 20195383 TI - Oxidative modification and aggregation of creatine kinase from aged mouse skeletal muscle. AB - Creatine kinase catalyzes the reversible transfer of the gamma phosphate from ATP to creatine forming the high energy compound creatine phosphate. Muscle creatine kinase (CKm) activity maintains energetic homeostasis as variations in energy requirements dictate that ATP be readily available. Recent studies suggest that CKm activity is altered during aging. Proteomic analyses have shown that CKm is 3 nitrotyrosine (3-NT) modified and carbonylated in aged rodent skeletal muscle. However, it remains unknown if these modifications affect its structure and activity. To address this we characterized oxidatively modified CKm from the quadriceps of young, middle-aged, and aged mice. Our data indicate that 3-NT modified and carbonylated CKm are found predominantly in aged muscle and that it exists in high molecular weight oligomers and insoluble protein aggregates. CKm from middle-aged and aged mouse quadriceps also exhibits structural instability that may account for its reduction in function. These structural and functional changes correlate with the differential protein modifications. Interestingly, the majority of the age-related changes in enzyme activity and protein stability occurred by middle age. Our studies indicate that the age-associated oxidative and nitrative modification of CKm results in a decrease in its activity and may cause structural changes that promote oligomerization and aggregation. PMID- 20195382 TI - Immune physiology in tissue regeneration and aging, tumor growth, and regenerative medicine. AB - The immune system plays an important role in immunity (immune surveillance), but also in the regulation of tissue homeostasis (immune physiology). Lessons from the female reproductive tract indicate that immune system related cells, such as intraepithelial T cells and monocyte-derived cells (MDC) in stratified epithelium, interact amongst themselves and degenerate whereas epithelial cells proliferate and differentiate. In adult ovaries, MDC and T cells are present during oocyte renewal from ovarian stem cells. Activated MDC are also associated with follicular development and atresia, and corpus luteum differentiation. Corpus luteum demise resembles rejection of a graft since it is attended by a massive influx of MDC and T cells resulting in parenchymal and vascular regression. Vascular pericytes play important roles in immune physiology, and their activities (including secretion of the Thy-1 differentiation protein) can be regulated by vascular autonomic innervation. In tumors, MDC regulate proliferation of neoplastic cells and angiogenesis. Tumor infiltrating T cells die among malignant cells. Alterations of immune physiology can result in pathology, such as autoimmune, metabolic, and degenerative diseases, but also in infertility and intrauterine growth retardation, fetal morbidity and mortality. Animal experiments indicate that modification of tissue differentiation (retardation or acceleration) during immune adaptation can cause malfunction (persistent immaturity or premature aging) of such tissue during adulthood. Thus successful stem cell therapy will depend on immune physiology in targeted tissues. From this point of view, regenerative medicine is more likely to be successful in acute rather than chronic tissue disorders. PMID- 20195384 TI - The rate of leukocyte telomere shortening predicts mortality from cardiovascular disease in elderly men. AB - Telomere length (TL) has been proposed as a marker of mitotic cell age and as a general index of human organismic aging. Short absolute leukocyte telomere length has been linked to cardiovascular-related morbidity and mortality. Our aim was to test whether the rate of change in leukocyte TL is related to mortality in a healthy elderly cohort. We examined a subsample of 236 randomly selected Caucasian participants from the MacArthur Health Aging Study (aged 70 to 79 years). DNA samples from baseline and 2.5 years later were assayed for mean TL of leukocytes. Percent change in TL was calculated as a measure of TL change (TLC). Associations between TL and TLC with 12-year overall and cardiovascular mortality were assessed. Over the 2.5 year period, 46% of the study participants showed maintenance of mean bulk TL, whereas 30% showed telomere shortening, and, unexpectedly, 24% showed telomere lengthening. For women, short baseline TL was related to greater mortality from cardiovascular disease (OR = 2.3; 95% CI: 1.0 - 5.3). For men, TLC (specifically shortening), but not baseline TL, was related to greater cardiovascular mortality, OR = 3.0 (95% CI: 1.1 - 8.2). This is the first demonstration that rate of telomere length change (TLC) predicts mortality and thus may be a useful prognostic factor for longevity. PMID- 20195386 TI - Modeling of replicative senescence in hematopoietic development. AB - Hematopoietic stem cells (HSC) give rise to an enormous number of blood cells throughout our life. In contrast their number of cell divisions preceding senescence is limited underin vitro culture conditions. Here we consider the question whether HSC can rejuvenate indefinitely or if the number of cell divisions is restricted. We have developed a multi-compartmental model for hematopoietic differentiation based on ordinary differential equations. The model is based on the hypothesis that in each step of maturation, the percentage of self-renewal versus differentiation is regulated by a single external feedback mechanism. We simulate the model under the assumption that hematopoietic differentiation precedes the six steps of maturation and the cells ultimately cease to proliferate after 50 divisions. Our results demonstrate that it is conceivable to maintain hematopoiesis over a life-time if HSC have a slow division rate and a high self-renewal rate. With age, the feedback signal increases and this enhances self-renewal, which results in the increase of the number of stem and progenitor cells. This study demonstrates that replicative senescence is compatible with life-long hematopoiesis and that model predictions are in line with experimental observations. Thus, HSC might not divide indefinitely with potentially important clinical implications. PMID- 20195385 TI - Increased uncoupling protein (UCP) activity in Drosophila insulin-producing neurons attenuates insulin signaling and extends lifespan. AB - To understand the role of mitochondrial uncoupling protein (UCP) in regulating insulin signaling and glucose homeostasis, we created transgenicDrosophila lines with targeted UCP expression in insulin producing cells (IPCs). Increased UCP activity in IPCs results in decreased steady state Ca(2+) levels in IPCs as well as decreased PI3K activity and increased FoxO nuclear localization in periphery. This reduced systemic insulin signaling is accompanied by a mild hyperglycemia and extended life span. To test the hypothesis that ATP-sensitive potassium (K(ATP)) channels may link changes in metabolic activity (e.g., glucose mediated ATP production or UCP-mediated ATP reduction) with insulin secretion, we characterized the effects of glucose and a specific K(ATP) channel blocker, glibenclamide on membrane potential in adult IPCs. Exposure to glucose depolarizes membrane potential of IPCs and this effect is mimicked with glibenclamide, suggesting that K(ATP) channels contribute to the mechanism whereby IPCs sense changes in circulating sugar. Further, as demonstrated in mammalian beta-pancreatic cells, high glucose initiates a robust Ca(2+) influx in adult IPCs. The presence of functional K(ATP) channels in adult IPCs is further substantiated by in situ hybridization detecting the transcript for the sulfonylurea receptor (Sur) subunit of the K(ATP) channel in those cells. Quantitative expression analysis demon-strates a reduction in transcripts for both Sur and the inward rectifying potassium channel (Kir) subunits when IPCs are partially ablated. In summary, we have demonstrated a role for UCP in adult Drosophila IPCs in influencing systemic insulin signaling and longevity by a mechanism that may involve K(ATP) channels. PMID- 20195387 TI - Sex-related differences in length and erosion dynamics of human telomeres favor females. AB - Telomeres are repetitive DNA sequences at chromosomal ends contributing to genomic integrity. In somatic cells, telomeres are shortened during DNA reduplication. Thus, telomere erosion has been regarded as a biological clock. Applying the telomere/centromere (T/C)-FISH technique to human peripheral blood lymphocytes, we showed that pangenomically, telomere shortening is linear in centenarians and that this attrition is delayed in females. Statistics reveal a greater skewness in telomere length distribution in females. As the morphological correlate, we find abnormally long telomeres distributed at random. This "erratic extensive elongation" (EEE) of telomeres is a hitherto unrecognized phenomenon in non-neoplastic cells, and females are more successful in this respect. As evidenced by endoreduplication, EEE is transmitted to the cells' progeny. The mechanism involved is likely to be the alternative pathway of telomere elongation (ALT), counteracting erosion and already known to operate in neoplastic cells. PMID- 20195388 TI - Are epidermal stem cells unique with respect to aging? AB - Epidermal stem cells are a population of somatic stem cells responsible for maintaining and repairing the epidermis of the skin. A malfunctioning epidermal stem cell compartment results in loss of the epidermis and death of the whole organism. Since the epidermis continually renews itself by sloughing a layer of cells every day, it is in a constant state of cellular turnover and requires continual cell replacement for life. Thus, maintaining a pristine epidermal stem cell population is of prime importance, even during aging. Unlike stem cells from internal tissues, epidermal stem cells show little response to aging. They do not appear to decrease in number or functionality with age, and do not show changes in gene expression, developmental responsiveness, or age-associated increases of reactive oxygen species. Thus, epidermal stem cells may be a unique somatic stem cell. PMID- 20195389 TI - Regulation of pro-inflammatory and pro-fibrotic factors by CCN2/CTGF in H9c2 cardiomyocytes. AB - Connective tissue growth factor (CTGF), also known as CCN2, is implicated in fibrosis through both extracellular matrix (ECM) induction and inhibition of ECM degradation. The role of CTGF in inflammation in cardiomyocytes is unknown. In some mesenchymal cell systems, CTGF mediates effects through TGF-beta or tyrosine kinase cell surface receptor, TrkA, signalling. In this study, cellular mechanisms by which CTGF regulates pathways involved in fibrosis and inflammation were explored. Murine H9c2 cardiomyocytes were treated with recombinant human (rh)CTGF and ECM formation gene expression: fibronectin, collagen type -I and III and ECM degradation genes: TIMP-1, TIMP-2 and PAI-1 were found to be induced. CTGF treatment also increased pro-inflammatory cytokines TNF-alpha, IL-6, MCP-1 and IL-8. CTGF upregulated TGF-beta1 mRNA and rapidly induced phosphorylation of TrkA. The CTGF-induced pro-fibrotic and pro-inflammatory effects were blocked by anti-TGF-beta neutralizing antibody and Alk 5 inhibitor (SB431542). A specific blocker of TrkA activation, k252a, also abrogated CTGF-induced effects on fibrosis and gene expresison of MCP-1 and IL-8, but not TNF-alpha or IL-6. Collectively, this data implicates CTGF in effects on pro-fibrotic genes and pro inflammatory genes via TGF-beta pathway signalling and partly through TrkA. PMID- 20195390 TI - The lectin concanavalin-A signals MT1-MMP catalytic independent induction of COX 2 through an IKKgamma/NF-kappaB-dependent pathway. AB - The lectin from Canavalia ensiformis (Concanavalin-A, ConA), one of the most abundant lectins known, enables one to mimic biological lectin/carbohydrate interactions that regulate extracellular matrix protein recognition. As such, ConA is known to induce membrane type-1 matrix metalloproteinase (MT1-MMP) which expression is increased in brain cancer. Given that MT1-MMP correlated to high expression of cyclooxygenase (COX)-2 in gliomas with increasing histological grade, we specifically assessed the early proinflammatory cellular signaling processes triggered by ConA in the regulation of COX-2. We found that treatment with ConA or direct overexpression of a recombinant MT1-MMP resulted in the induction of COX-2 expression. This increase in COX-2 was correlated with a concomitant decrease in phosphorylated AKT suggestive of cell death induction, and was independent of MT1-MMP's catalytic function. ConA- and MT1-MMP-mediated intracellular signaling of COX-2 was also confirmed in wild-type and in Nuclear Factor-kappaB (NF-kappaB) p65(-/-) mutant mouse embryonic fibroblasts (MEF), but was abrogated in NF-kappaB1 (p50)(-/-) and in I kappaB kinase (IKK) gamma(-/-) mutant MEF cells. Collectively, our results highlight an IKK/NF-kappaB-dependent pathway linking MT1-MMP-mediated intracellular signaling to the induction of COX 2. That signaling pathway could account for the inflammatory balance responsible for the therapy resistance phenotype of glioblastoma cells, and prompts for the design of new therapeutic strategies that target cell surface carbohydrate structures and MT1-MMP-mediated signaling. Concise summary Concanavalin-A (ConA) mimics biological lectin/carbohydrate interactions that regulate the proinflammatory phenotype of cancer cells through yet undefined signaling. Here we highlight an IKK/NF-kappaB-dependent pathway linking MT1-MMP-mediated intracellular signaling to the induction of cyclooxygenase-2, and that could be responsible for the therapy resistance phenotype of glioblastoma cells. PMID- 20195391 TI - CCN3/CCN2 regulation and the fibrosis of diabetic renal disease. AB - Prior work in the CCN field, including our own, suggested to us that there might be co-regulatory activity and function as part of the actions of this family of cysteine rich cytokines. CCN2 is now regarded as a major pro-fibrotic molecule acting both down-stream and independent of TGF-beta1, and appears causal in the disease afflicting multiple organs. Since diabetic renal fibrosis is a common complication of diabetes, and a major cause of end stage renal disease (ESRD), we examined the possibility that CCN3 (NOV), might act as an endogenous negative regulator of CCN2 with the capacity to limit the overproduction of extracellular matrix (ECM), and thus prevent, or ameliorate fibrosis. We demonstrate, using an in vitro model of diabetic renal fibrosis, that both exogenous treatment with CCN3 and transfection with the over-expression of the CCN3 gene in mesangial cells markedly down-regulates CCN2 activity and blocks ECM over-accumulation stimulated by TGF-beta1. Conversely, TGF-beta1 treatment reduces endogenous CCN3 expression and increases CCN2 activity and matrix accumulation, indicating an important, novel yin/yang effect. Using the db/db mouse model of diabetic nephropathy, we confirm the expression of CCN3 in the kidney, with temporal localization that supports these in vitro findings. In summary, the results corroborate our hypothesis that one function of CCN3 is to regulate CCN2 activity and at the concentrations and conditions used down-regulates the effects of TGF beta1, acting to limit ECM turnover and fibrosis in vivo. The findings suggest opportunities for novel endogenous-based therapy either by the administration, or the upregulation of CCN3. PMID- 20195397 TI - Description of the efficacy and safety of three new biologics in the treatment of rheumatoid arthritis. AB - English articles on abatacept, golimumab, and tocilizumab in rheumatoid arthritis published between 2002 and 2009 were reviewed systematically. All randomized clinical trials, open-label extensions, meta-analyses, and reviews were examined. There were thirteen articles on abatacept, four on golimumab, and seven on tocilizumab. All three drugs were effective in methotrexate-naive, methotrexate incomplete responders, and tumor-necrosis-factor-failure rheumatoid arthritis patients. Of the three, only abatacept has been tested in a head-to-head trial with infliximab, in which it was found to be equivalent to infliximab. Golimumab resulted in a more modest improvement than the others in methotrexate-naive patients, although no direct comparisons among the three drugs were possible or appropriate. Descriptive analysis of adverse events showed that patients receiving abatacept, golimumab, and tocilizumab were subject to more adverse events than controls overall, as expected. In the abatacept studies, a few cases of tuberculosis, more cardiovascular events and gastrointestinal bleedings and more basal cell carcinoma were seen. Golimumab was associated with more skin rashes and pneumonia, while tocilizumab was associated with increased lipids, more liver-function abnormalities, and neutropenia. These new medications are useful additions to the rheumatologic armamentarium and represent greater convenience (golimumab) or different mechanisms of action (abatacept and tocilizumab) than tumor-necrosis-factor inhibitors for treating rheumatoid arthritis. As expected, some adverse events occur when using these drugs and patients need to be watched carefully. PMID- 20195398 TI - Potential role of uric Acid as a risk factor for cardiovascular disease. PMID- 20195399 TI - Clinical value of serum uric Acid in patients with suspected coronary artery disease. AB - BACKGROUND/AIMS: Although increased serum uric acid (SUA) concentrations are commonly encountered in patients with risk factors for coronary artery disease (CAD), the clinical value of SUA has not been established. METHODS: The study group comprised 687 consecutive patients with suspected CAD who had undergone coronary angiography. CAD was defined as stenosis > or = 50% of the luminal diameter. CAD severity was expressed as 1-, 2-, or 3-vessel disease. Metabolic syndrome (MS) was defined according to National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) criteria, and aortofemoral pulse wave velocity (PWV) was obtained by arterial catheterization invasively. RESULTS: In total, 395 patients had CAD. SUA was higher in patients with CAD as compared to those without CAD (5.5 +/- 1.0 vs. 5.2 +/- 1.0 mg/dL, p = 0.004). In addition, SUA was significantly associated with the severity of CAD (p = 0.002). However, after adjusting for significant confounding factors including age, diabetes, smoking, cholesterol, MS, and PWV, SUA was not an independent risk factor for CAD (p = 0.151). Based on a subgroup analysis, SUA was more closely associated with CAD in women than in men, and in the highest quartile (> or = 6.4 mg/dL) than in the first quartile (< 4.8 mg/dL); however, these results were not significant (p = 0.062, p = 0.075, respectively). In a multivariate regression analysis, the most important determinant of SUA was MS (i.e., insulin resistance syndrome), which is strongly associated with CAD. CONCLUSIONS: In patients with suspected CAD, SUA was not an independent risk factor for CAD and may be merely a marker of insulin resistance. PMID- 20195401 TI - Acceptance and understanding of the informed consent procedure prior to gastrointestinal endoscopy by patients: a single-center experience in Korea. AB - BACKGROUND/AIMS: Only a few reports have examined informed consent for gastrointestinal endoscopy in Korea. The aim of this study was to evaluate the appropriateness of the informed consent procedure in Korea. METHODS: A total of 209 patients who underwent endoscopy were asked to answer a self-administered structured questionnaire on the informed consent procedure for gastrointestinal endoscopy. RESULTS: One hundred thirteen patients completed questionnaires and were enrolled. In the survey, 91.2% answered that they understood the procedure, and the degree of understanding decreased with age; 85.8% were informed of the risks of the procedure, and the proportion was higher for inpatients and for those receiving therapeutic endoscopy or endoscopic retrograde cholangiopancreatography; 60.2% were informed of alternative methods, and the proportion was higher in older patients; 76.1% had the opportunity to ask questions during the informed consent procedure, and the proportion was higher in inpatients. The understanding of the risks of the endoscopic procedure was better in the younger and more highly educated groups. About 80% had sedation before endoscopy, and only 56% were informed of the risks of sedation during endoscopy. CONCLUSIONS: The current informed consent process may be reasonably acceptable and understandable to the patients. However, the understanding of the risks of endoscopy was insufficient especially in the cases of older, poorly educated patients and outpatients. The information about alternatives, the opportunity to ask for additional information, and the information about the risks of sedation during endoscopy were also insufficient in the current consent process. PMID- 20195400 TI - Comparative study of low doses of rosuvastatin and atorvastatin on lipid and glycemic control in patients with metabolic syndrome and hypercholesterolemia. AB - BACKGROUND/AIMS: This multicenter, open-labeled, randomized trial was performed to compare the effects of rosuvastatin 10 mg and atorvastatin 10 mg on lipid and glycemic control in Korean patients with nondiabetic metabolic syndrome. METHODS: In total, 351 patients who met the modified National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria for metabolic syndrome with low-density lipoprotein cholesterol (LDL-C) levels > or = 130 mg/dL were randomized to receive either rosuvastatin 10 mg (n = 173) or atorvastatin 10 mg (n = 178) for over 6 weeks. RESULTS: After 6 weeks of treatment, greater reductions in total cholesterol (- 35.94 +/- 11.38 vs. - 30.07 +/- 10.46%, p < 0.001), LDL-C (48.04 +/- 14.45 vs. 39.52 +/- 14.42%, p < 0.001), non-high-density lipoprotein cholesterol (- 42.93 +/- 13.15 vs. - 35.52 +/- 11.76%, p < 0.001), and apolipoprotein-B (- 38.7 +/- 18.85 vs. - 32.57 +/- 17.56%, p = 0.002) levels were observed in the rosuvastatin group as compared to the atorvastatin group. Overall, the percentage of patients attaining the NCEP ATP III goal was higher with rosuvastatin as compared to atorvastatin (87.64 vs. 69.88%, p < 0.001). Changes in glucose and insulin levels, and homeostasis model assessment of insulin resistance index were not significantly different between the two groups. The safety and tolerability of the two agents were similar. CONCLUSIONS: Rosuvastatin 10 mg was more effective than atorvastatin 10 mg in achieving NCEP ATP III LDL-C goals in patients with nondiabetic metabolic syndrome, especially in those with lower NCEP ATP III target level goals. PMID- 20195402 TI - Relation of anti- to pro-inflammatory cytokine ratios with acute myocardial infarction. AB - BACKGROUND/AIMS: Acute myocardial infarction (AMI) is a leading cause of death. Inflammatory processes play an important role in atherosclerosis, which is intimately related to AMI. The aim of this study was to investigate the association between anti-inflammatory and pro-inflammatory cytokines ratios and AMI. METHODS: A total of 90 AMI patients and 90 age-and sex-matched controls were recruited in this study. Plasma cytokines and conventional risk factors were determined by standard methods. RESULTS: Patients with AMI showed increased interleukin (IL)-6 and tumor necrosis factor-alpha levels and lower anti- to pro inflammatory cytokine ratios as compared with controls. A multivariate logistic regression analysis revealed that IL-10 to IL-6 ratio was independently associated with the occurrence of AMI (odds ratio [OR], 5.39; 95% confidence interval [CI], 2.39 to 12.17; p < 0.0001). In contrast, IL-6 levels were no longer significant in the multivariate model (OR, 1.02; 95% CI, 0.932 to 1.12; p = 0.603). A receiver operating characteristic (ROC) curve analysis indicated that IL-6 levels and IL-10 to IL-6 ratios were a significant predictor of AMI (area under ROC curve, 0.892 and 0.851, respectively). CONCLUSIONS: Our results suggest that the ratio of IL-10 to IL-6 is independently associated with AMI, and reduced levels of this ratio may favor the development of AMI. PMID- 20195403 TI - Prevalence of depression and anxiety in outpatients with chronic airway lung disease. AB - BACKGROUND/AIMS: Patients with chronic airway lung diseases often experience depression and anxiety, but little information is available regarding Koreans with these conditions. We thus assessed depression and anxiety in Korean patients with chronic airway lung diseases. METHODS: The degree of depression and anxiety in 84 outpatients with chronic obstructive pulmonary disease (COPD), 37 with asthma, 33 with bronchiectasis, and 73 healthy controls were evaluated by the Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory (STAI). RESULTS: The patients with COPD and bronchiectasis had higher BDI scores and were more likely than controls to experience depression ([COPD, 17; range, 0 to 42; prevalence, 55%], [bronchiectasis, 16; range, 3 to 51; prevalence, 55%], [controls, 13; range, 0 to 31; prevalence, 30%], p < 0.05). The state-anxiety scores of the patients were higher than those of the controls, but only the bronchiectasis group demonstrated a higher frequency of state-anxiety compared with the controls (39 vs. 16%, patients vs. controls, p = 0.015). Among all patients, 22% presented with concomitant depression and state-anxiety, and 25% demonstrated depression and trait-anxiety. Depression was positively correlated with both state-anxiety (r = 0.644) and trait-anxiety (r = 0.597, p < 0.0001). Irrespective of individual diagnosis, post-bronchodilator FEV(1) (odds ratio [OR], 0.972; p = 0.027) and smoking history (OR, 3.894; p = 0.018) were independent risk factors for depression in patients with chronic airway lung diseases. CONCLUSIONS: Chronic airway lung diseases are associated with depression and/or anxiety, particularly in those with a higher airflow limitation and/or history of smoking. PMID- 20195404 TI - Clinical meaning of early oxygenation improvement in severe acute respiratory distress syndrome under prolonged prone positioning. AB - BACKGROUND/AIMS: Ventilating patients with acute respiratory distress syndrome (ARDS) in the prone position has been shown to improve arterial oxygenation, but prolonged prone positioning frequently requires continuous deep sedation, which may be harmful to patients. We evaluated the meaning of early gas exchange in patients with severe ARDS under prolonged (> or = 12 hours) prone positioning. METHODS: We retrospectively studied 96 patients (mean age, 60.1 +/- 15.6 years; 75% men) with severe ARDS (PaO(2)/FiO2 < or = 150 mmHg) admitted to a medical intensive care unit (MICU). The terms "PaO2 response" and "PaCO2 response" represented responses that resulted in increases in the PaO2/FiO2 ratio of > or = 20 mmHg and decreases in PaCO2 of > or = 1 mmHg, respectively, 8 to 12 hours after first placement in the prone position. RESULTS: The mean duration of prone positioning was 78.5 +/- 61.2 hours, and the 28-day mortality rate after MICU admission was 56.3%. No significant difference in clinical characteristics was observed between PaO2 and PaCO2 responders and non-responders. The PaO2 responders after prone positioning showed an improved 28-day outcome, compared with non-responders by Kaplan-Meier survival estimates (p < 0.05 by the log-rank test), but the PaCO12 responders did not. CONCLUSIONS: Our results suggest that the early oxygenation improvement after prone positioning might be associated with an improved 28-day outcome and may be an indicator to maintain prolonged prone positioning in patients with severe ARDS. PMID- 20195405 TI - Clinical characteristics of pulmonary embolism with underlying malignancy. AB - BACKGROUND/AIMS: The risk of venous thromboembolism (VTE), which encompasses deep vein thrombosis and pulmonary embolism (PE), increases in patients with cancer. Anticancer treatment is also associated with an increased risk for VTE. We conducted this study to investigate the clinical characteristics of patients with cancer and PE related to anticancer treatment in a tertiary care hospital in Korea. METHODS: We retrospectively reviewed the clinical data of patients with an underlying malignancy who were diagnosed with PE by chest computed tomography (CT) with or without lower extremity CT angiography between January 2006 and December 2007 at Seoul National University Hospital. RESULTS: Overall, 95 patients with malignancies among 168 with PE were analyzed. The median age was 64 years. The median time interval from the malignancy diagnosis to the PE diagnosis was 5.5 months. Lung cancer was the most common malignancy (23.0%), followed by pancreatobiliary cancer, stomach cancer, gynecological cancer, breast cancer, and hepatocellular carcinoma. Platinum-containing and pyrimidine analog-containing chemotherapeutic regimens were common. CONCLUSIONS: PE was diagnosed within 1 year after the cancer diagnosis in almost 70% of patients. Lung cancer was the most common underlying malignancy. PMID- 20195406 TI - Ultrasonographic features of papillary thyroid carcinoma in patients with Graves' disease. AB - BACKGROUND/AIMS: To characterize ultrasonographic findings in papillary thyroid carcinoma (PTC) combined with Graves' disease. METHODS: Medical records and ultrasonographic findings of 1,013 patients with Graves' disease and 3,380 patients without Graves' disease were analyzed retrospectively. A diagnosis of PTC was based on a pathologic examination. RESULTS: The frequency of hypoechogenicity was lower in patients with PTC and Graves' disease than in patients with PTC alone (p < 0.05). The frequency of perinodular blood flow in patients with PTC and Graves' disease was significantly higher than in those with PTC alone (p < 0.05). PTC combined with Graves' disease was characterized by more ill-defined borders and less frequency of overall calcification, punctate calcification, and heterogeneous echogenicity, although the difference was not statistically significant. CONCLUSIONS: Our results suggest that patients with Graves' disease more frequently have atypical PTC findings on ultrasonography. PMID- 20195408 TI - Detecting bacterial growth in continuous ambulatory peritoneal dialysis effluent using two culture methods. AB - BACKGROUND/AIMS: The aim of this study was to evaluate the peritonitis-causing bacteria detected in peritoneal fluid using a blood culture bottle in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). METHODS: One-hundred and eleven dialysates from 43 patients suspected of peritonitis related to CAPD were retrospectively evaluated between May 2000 and February 2008. In all cases, 5 to 10 mL of dialysate was inoculated into a pair of BacT/Alert blood culture bottles, and 50 mL of centrifuged dialysate was simultaneously inoculated into a solid culture media for conventional culture. The results were compared to those of the conventional culture method. Isolated microorganisms were compared between the two methods. RESULTS: The blood culture method was positive in 78.6% (88 / 112) of dialysate specimens and the conventional culture method in 50% (56 / 112, p < 0.001). CONCLUSIONS: The blood culture method using the BacT/Alert system is useful for culturing dialysates and improves the positive culture rate in patients with suspected peritonitis compared to the conventional culture method. PMID- 20195407 TI - Application of cystatin C reduction ratio to high-flux hemodialysis as an alternative indicator of the clearance of middle molecules. AB - BACKGROUND/AIMS: Although high-flux (HF) dialyzers with enhanced membrane permeability are widely used in current hemodialysis (HD) practice, urea kinetic modeling is still being applied to indicate the adequacy of both low-flux (LF) and HF HD. In comparison with urea (molecular weight, 60 Da) and beta(2) microglobulin (beta(2)MG, 12 kDa), cystatin C (CyC, 13 kDa) is a larger molecule that has attractive features as a marker for assessing solute clearance. We postulated that CyC might be an alternative for indicating the clearance of middle molecules (MMs), especially with HF HD. METHODS: Eighty-nine patients were divided into LF and HF groups. Using single pool urea kinetic modeling, the urea reduction ratio (URR) and equilibrated Kt/V(urea) (eKt/V(urea)) were calculated. The serum CyC concentrations were measured using particle-enhanced immunonephelometry. As indices of the middle molecular clearance, the reduction ratios of beta(2)MG and CyC were calculated. RESULTS: The beta(2)MG reduction ratio (beta(2)MGRR) and CyC reduction ratio (CyCRR) were higher in the HF group compared to the LF group. However, the URR and eKt/Vurea did not differ between the two groups. The CyCRR was significantly correlated with the eKt/V(urea) and beta(2)MGRR (r = 0.47 and 0.69, respectively, both p < 0.0001). CONCLUSIONS: Compared to the LF dialyzer, the HF dialyzer removed CyC and beta(2)MG more efficiently. Unlike the beta(2)MGRR, the CyCRR was correlated with the eKt/V(urea) and beta(2)MGRR. This study suggests a role for the CyCRR as an alternative indicator of the removal of MMs. PMID- 20195409 TI - Severe pulmonary adverse effects in lymphoma patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen plus rituximab. AB - BACKGROUND/AIMS: The aim of our study was to determine the incidence and clinical features of severe pulmonary complications in patients receiving cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or rituximab plus CHOP (R-CHOP) as the initial treatment for lymphoma. METHODS: A retrospective analysis of pulmonary infection and drug-induced interstitial pneumonitis (DIIP) was performed using lymphoma registry data. R-CHOP was administered in 71 patients and CHOP in 29 patients. RESULTS: The severe pulmonary adverse events tended to occur more frequently with R-CHOP (18.3%) than CHOP alone (13.8%), although the difference was not significant (p = 0.771). DIIP occurred in five patients in the R-CHOP arm (7%) and in one in the CHOP arm (3%). The continuous use of steroids for conditions other than lymphoma significantly increased the risk of pulmonary infection including Pneumocystis jiroveci pneumonia (p = 0.036) in the multivariate analysis. International prognostic index, tumor stage, smoking, previous tuberculosis, chronic obstructive pulmonary disease, and lymphoma involvement of lung parenchyma were not related to pulmonary adverse events. Patients who experienced severe pulmonary events showed shorter survival when compared to those without complications (p = 0.002). CONCLUSIONS: Our experiences with serial cases with DIIP during chemotherapy and the correlation of continuous steroid use with pulmonary infection suggest that the incidence of pulmonary complications might be high during lymphoma treatment, and careful monitoring should be performed. PMID- 20195410 TI - Ethyl acetate fraction from Cudrania tricuspidata inhibits IL-1beta-stimulated osteoclast differentiation through downregulation of MAPKs, c-Fos and NFATc1. AB - BACKGROUND/AIMS: The present study was performed to determine the effects of the ethyl acetate extract of Cudrania tricuspidata (EACT) on interleukin (IL)-1beta stimulated receptor activator of NF-kappaB ligand (RANKL)-mediated osteoclast differentiation. METHODS: Bone marrow cells were harvested from 6-week-old male imprinting control region mice, and the differentiation of osteoclasts from these cells was evaluated by tartrate-resistant acid phosphatase and resorption pit formation assay. Phosphorylated extracellular signal regulated kinase (p-ERK), phosphorylated p38, phosphorylated c-Jun amino-terminal kinase, NF-kappaB (p65), IkappaBalpha, c-Fos, and nuclear factor of activated T-cells c1 (NFATc1) expression was examined by immunoblotting and quantitative reverse transcription polymerase chain reaction. RESULTS: EACT inhibits IL-1beta-stimulated RANKL mediated osteoclast differentiation. EACT also inhibits IL-1beta-stimulated RANKL mediated phosphorylation of ERK 1/2, p38 mitogen activated protein kinase, and expression of c-Fos and NFATc1. CONCLUSIONS: These results suggest that EACT may be involved in the inhibition of bone loss by preventing osteoclast formation and may be used to manage bone destruction in inflammatory diseases, such as rheumatoid arthritis. PMID- 20195411 TI - Myasthenia gravis presenting as isolated respiratory failure: a case report. AB - Myasthenia gravis (MG) is often complicated by respiratory failure, known as a myasthenic crisis. However, most of the patients who develop respiratory symptoms do so during the late course of disease and have other neurological signs and symptoms. However, in some patients respiratory failure is the initial presenting symptom. We report the case of a 68-year-old woman with MG who presented with isolated respiratory failure as her first presenting symptom. As illustrated by this case, it is important to consider neuromuscular disorders in cases of unexplained respiratory failure. PMID- 20195412 TI - A case of rhabdomyolysis associated with use of a pneumatic tourniquet during arthroscopic knee surgery. AB - The common causes of rhabdomyolysis include trauma, hypoxia, drugs, toxins, infections and hyperthermia. Operative insults, including direct trauma and ischemia, have the potential to cause the development of rhabdomyolysis. Pneumatic tourniquets used during arthroscopic knee surgery to prevent blood loss have led to many complications such as nerve paralysis and vascular injuries. Rhabdomyolysis can also be caused by prolonged pneumatic tourniquet application without a midapplication release, and also from an increased application pressure, but the actual incidence of this is low. In order to prevent rhabdomyolysis, the clinicians must be aware of such risks and follow strict guidelines for the application time, the midapplication release and also the inflation pressure. Vigorous hydration and postoperative patient surveillance are helpful to prevent rhabdomyolysis. We have recently experienced a case of rhabdomyolysis after the arthroscopic knee surgery, and the rhabdomyolysis could have been associated with the use of a pneumatic tourniquet. PMID- 20195413 TI - A case report of the second de novo acute myeloid leukemia (AML) following allogeneic stem cell transplantation in a patient with the first AML. AB - Secondary leukemia occurring after hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) is rare. Secondary AML usually follows autologous and not allogeneic transplants. When a new leukemia develops in a patient successfully treated with an allogeneic HSCT, the possibility of a de novo or secondary leukemia from either the donor or recipient should be considered. We present a case initially diagnosed as de novo AML without a cytogenetic abnormality. The patient was successfully treated with an HLA-matched sibling allogeneic HSCT. However, more than six years later, AML developed again and was associated with new complex cytogenetic abnormalities. After a second HSCT, the patient has been followed without serious complications. Considering the allogeneic setting, the newly developed cytogenetic abnormalities, a relatively long latent period, and the good clinical course after the second allogeneic HSCT, this case might represent a second de novo AML following successful treatment of the first AML. PMID- 20195416 TI - CCA Young Investigator Award. PMID- 20195414 TI - Klebsiella pneumoniae orbital cellulitis with extensive vascular occlusions in a patient with type 2 diabetes. AB - A 39-year-old woman visited the emergency room complaining of right eye pain and swelling over the preceding three days. The ophthalmologist's examination revealed orbital cellulitis and diabetic retinopathy in the right eye, although the patient had no prior diagnosis of diabetes. It was therefore suspected that she had diabetes and orbital cellulitis, and she was started on multiple antibiotic therapies initially. She then underwent computed tomography scans of the orbit and neck and magnetic resonance imaging of the brain. These studies showed an aggravated orbital cellulitis with abscess formation, associated with venous thrombophlebitis, thrombosis of the internal carotid artery, and mucosal thickening of maxillary sinus with multiple paranasal abscesses. Three days later, initial blood culture grew Klebsiella pneumoniae. She recovered after incision and drainage and antibiotic therapy for 37 days. PMID- 20195417 TI - CCRF President's Citation Award. PMID- 20195418 TI - Profile. PMID- 20195419 TI - Profile. PMID- 20195420 TI - Chiropractors at McMaster University: The formation and direction of a university based multidisciplinary chiropractic working group. PMID- 20195421 TI - 2010 olympic winter games chiropractic: the making of history. PMID- 20195422 TI - A teaching scholar program in chiropractic education. PMID- 20195423 TI - Chiropractic care for patients with asthma: A systematic review of the literature. AB - OBJECTIVE: To provide a review of the literature and rate the quality of published studies regarding chiropractic care, including spinal manipulation, for asthmatic patients. METHODS: A multimodal search strategy was conducted, including multiple database searches, along with reference and journal hand searching. Studies were limited to those published in English and in peer reviewed journals or conference proceedings between January 1980 and March 2009. All study designs were considered except personal narratives or reviews. Retrieved articles that met the inclusion criteria were rated for quality by using the Downs and Black checklist. A brief summary was also written for each retrieved study. RESULTS: Eight articles met the inclusion criteria of this review in the form of one case series, one case study, one survey, two randomized controlled trials (RCTs), one randomized patient and observer blinded cross-over trial, one single blind cross study design, and one self-reported impairment questionnaire. Their quality scores ranged from 5 to 22 out of 27. CONCLUSION: Results of the eight retrieved studies indicated that chiropractic care showed improvements in subjective measures and, to a lesser degree objective measures, none of which were statistically significant. It is evident that some asthmatic patients may benefit from this treatment approach; however, at this time, the evidence suggests chiropractic care should be used as an adjunct, not a replacement, to traditional medical therapy. PMID- 20195424 TI - Critical sites of entrapment of the posterior division of the obturator nerve: anatomical considerations. AB - IN THE CURRENT ANATOMIC STUDY, SPECIAL ATTENTION WAS GIVEN TO THE RELATIONSHIP OF THE POSTERIOR DIVISION OF THE OBTURATOR NERVE TO SURROUNDING STRUCTURES: the obturator canal and the fibromuscular and vascular structures of the medial thigh region. These intimate relationships may, in certain conditions, constitute critical sites of entrapment of the posterior division of the obturator nerve and may present a diagnostic challenge to the manual practitioner. Knowledge of the potential sites of entrapment of the posterior division of the obturator nerve can aid in differential diagnosis of peripheral neuropathies, provide an anatomic basis for obturator nerve pathology, and guide effective patient management, including the application of modern diagnostic techniques and safe surgical procedures. PMID- 20195426 TI - Jurisprudence and business management course content taught at accredited chiropractic colleges: A comparative audit. AB - INTRODUCTION: the purpose of this study was to conduct a comparative audit of the jurisprudence and business management courses offered at a number of different accredited chiropractic colleges. METHODS: Faculty members responsible for teaching students jurisprudence and/or business management courses at a number of accredited colleges were contacted and asked to electronically submit their course outlines for review. RESULTS: Of the 62 different topics delivered at the 11 chiropractic colleges surveyed, not one topic was taught at all of them. The following topics were taught at 10 of the 11 respondent chiropractic colleges: business plan development; ethics and codes of conduct and; office staff/employees. Several topics were only taught at one accredited chiropractic college. CONCLUSION: While most chiropractic colleges provide some education in the areas of jurisprudence and business management, it would appear that there is no consensus opinion or 'model curriculum' on these topics towards which chiropractic programs may align themselves. Based on a literature search, this study is the first of its kind. A more extensive study is required, as well as a Delphi process to determine what should be taught to chiropractic students with respect to jurisprudence and business management in order to protect the public interest. PMID- 20195425 TI - Statin induced myopathy presenting as mechanical musculoskeletal pain observed in two chiropractic patients. AB - Lipid lowering drugs, such as statins, are commonly used to treat approximately 10 million Canadians affected by hypercholesterolemia. The most commonly experienced side-effect of statin medication is muscle pain. Statin induced myopathy consists of a spectrum of myopathic disorders ranging from mild myalgia to fatal rhabdomyolysis. The following is a presentation of 2 cases of statin induced myopathy in patients presenting in a chiropractic setting. In addition, discussion will surround the mechanism, predisposing risk factors and frequency of statin induced myopathy while highlighting the role that chiropractors and other manual therapists may play in its recognition and management. PMID- 20195427 TI - Restructuring of the jurisprudence course taught at the Canadian Memorial Chiropractic College. AB - INTRODUCTION: The process by which the jurisprudence course was restructured at the Canadian Memorial Chiropractic College is chronicled. METHOD: A Delphi process used to restructure the course is described, and the results of a student satisfaction survey are presented. RESULTS: When asked "I think this material was clinically relevant," over 81% of the 76 students who respondents strongly agreed or agreed with this statement; 100% of students agreed or strongly agreed that scope of practice; marketing, advertising and internal office promotion; record keeping; fee schedules; malpractice issues and; professional malpractice issues and negligence was clinically relevant. When asked "I think this material was taught well," a minimum of 89% of students agreed or strongly agreed with this statement. DISCUSSION: This is the first article published that described the process by which a jurisprudence course was developed and assessed by student survey. SUMMARY: Based on a survey of student perceptions, restructuring of the jurisprudence course was successful in providing students with clinically relevant information in an appropriate manner. This course may serve as an important first step in development a 'model curriculum' for chiropractic practice and the law courses in terms of content, format and assessment strategies. PMID- 20195428 TI - Quality health care in the European Union thanks to competition law. AB - There are many biases concerning the application of competition law in health care. Quality concerns can however be integrated into competition law analysis. The aim of this paper is to identify the links between the application of competition law in the European Union and the right to quality health care and to point out the problems that arise when integrating quality concerns in competition law analysis. Guidelines must be issued and competition authorities must work together with institutions that have expertise in the field of health care quality measurement in order to integrate these dimensions in competition practice. PMID- 20195429 TI - The selection of an appropriate count data model for modelling health insurance and health care demand: case of Indonesia. AB - We apply several estimators to Indonesian household data to estimate the relationship between health insurance and the number of outpatient visits to public and private providers. Once endogeneity of insurance is taken into account, there is a 63 percent increase in the average number of public visits by the beneficiaries of mandatory insurance for civil servants. Individuals' decisions to make first contact with private providers is affected by private insurance membership. However, insurance status does not make any difference for the number of future outpatient visits. PMID- 20195431 TI - Epidemiological methods: about time. AB - Epidemiological studies often produce false positive results due to use of statistical approaches that either ignore or distort time. The three time-related issues of focus in this discussion are: (1) cross-sectional vs. cohort studies, (2) statistical significance vs. public health significance, and (3), how risk factors "work together" to impact public health significance. The issue of time should be central to all thinking in epidemiology research, affecting sampling, measurement, design, analysis and, perhaps most important, the interpretation of results that might influence clinical and public-health decision-making and subsequent clinical research. PMID- 20195432 TI - Challenging the "inoffensiveness" of regular cannabis use by its associations with other current risky substance use--a census of 20-year-old Swiss men. AB - 3,537 men enrolling in 2007 for mandatory army recruitment procedures were assessed for the co-occurrence of risky licit substance use among risky cannabis users. Risky cannabis use was defined as at least twice weekly; risky alcohol use as 6+ drinks more than once/monthly, or more than 20 drinks per week; and risky tobacco use as daily smoking. Ninety-five percent of all risky cannabis users reported other risky use. They began using cannabis earlier than did non-risky users, but age of onset was unrelated to other risky substance use. A pressing public health issue among cannabis users stems from risky licit substance use warranting preventive efforts within this age group. PMID- 20195433 TI - The influence of individual, social and physical environment factors on physical activity in the adult population in Andalusia, Spain. AB - A person's physical and social environment is considered as an influencing factor in terms of rates of engagement in physical activity. This study analyses the influence of socio-demographic, physical and social environmental factors on physical activity reported in the adult population in Andalusia. This is a cross sectional study using data collected in the Andalusia Health Survey in 1999 and 2003. In addition to the influence of the individual's characteristics, if there are no green spaces in the neighbourhood it is less likely that men and women will take exercise (OR = 1.26; 95% CI = 1.13, 1.41). Likewise, a higher local illiteracy rate also has a negative influence on exercise habits in men (OR = 1.39; 95% CI = 1.21, 1.59) and in women (OR = 1.22; 95% CI = 1.07, 1.40). Physical activity is influenced by individuals' characteristics as well as by their social and physical environment, the most disadvantaged groups are less likely to engage in physical activity. PMID- 20195434 TI - What defines an effective anti-tobacco TV advertisement? A pilot study among Greek adolescents. AB - As the Framework Convention on Tobacco Control (FCTC) calls for public health awareness on tobacco use, mass media campaigns should be appropriately designed so as to maximize their effectiveness. In this methodological pilot study, 95 Greek adolescents (mean age 15 +/- 1.8 years), were shown seven different anti tobacco ads, and asked to rate the ad theme, message and emotional context on a 1 7 Likert scale. Health related ads were rated the highest, and as identified through the logistic regression analysis, adolescents who perceived an ad to be emotional or to have a clear message that was relevant to them, were more likely to rate the ad as more effective. The strong agreement between the above findings and the existing literature indicates the applicability of this pilot study's methodological approach. PMID- 20195436 TI - Advances in identifying beryllium sensitization and disease. AB - Beryllium is a lightweight metal with unique qualities related to stiffness, corrosion resistance, and conductivity. While there are many useful applications, researchers in the 1930s and 1940s linked beryllium exposure to a progressive occupational lung disease. Acute beryllium disease is a pulmonary irritant response to high exposure levels, whereas chronic beryllium disease (CBD) typically results from a hypersensitivity response to lower exposure levels. A blood test, the beryllium lymphocyte proliferation test (BeLPT), was an important advance in identifying individuals who are sensitized to beryllium (BeS) and thus at risk for developing CBD. While there is no true "gold standard" for BeS, basic epidemiologic concepts have been used to advance our understanding of the different screening algorithms. PMID- 20195435 TI - Avian colibacillosis and salmonellosis: a closer look at epidemiology, pathogenesis, diagnosis, control and public health concerns. AB - Avian colibacillosis and salmonellosis are considered to be the major bacterial diseases in the poultry industry world-wide. Colibacillosis and salmonellosis are the most common avian diseases that are communicable to humans. This article provides the vital information on the epidemiology, pathogenesis, diagnosis, control and public health concerns of avian colibacillosis and salmonellosis. A better understanding of the information addressed in this review article will assist the poultry researchers and the poultry industry in continuing to make progress in reducing and eliminating avian colibacillosis and salmonellosis from the poultry flocks, thereby reducing potential hazards to the public health posed by these bacterial diseases. PMID- 20195437 TI - Assessing the relationship between socioeconomic conditions and urban environmental quality in Accra, Ghana. AB - The influence of socioeconomic status (SES) on health inequalities is widely known, but there is still poor understanding of the precise relationship between area-based socioeconomic conditions and neighborhood environmental quality. This study aimed to investigate the socioeconomic conditions which predict urban neighbourhood environmental quality. The results showed wide variation in levels of association between the socioeconomic variables and environmental conditions, with strong evidence of a real difference in environmental quality across the five socioeconomic classes with respect to total waste generation (p < 0.001), waste collection rate (p < 0.001), sewer disposal rate (p < 0.001), non-sewer disposal (p < 0.003), the proportion of households using public toilets (p = 0.005). Socioeconomic conditions are therefore important drivers of change in environmental quality and urban environmental interventions aimed at infectious disease prevention and control if they should be effective could benefit from simultaneous implementation with other social interventions. PMID- 20195438 TI - Maternal cigarette smoking during pregnancy and offspring externalizing behavioral problems: a propensity score matching analysis. AB - A body of empirical research has revealed that prenatal exposure to tobacco smoke is related to a host of negative outcomes, including reduced cognitive abilities, later-life health problems, and childhood behavioral problems. While these findings are often interpreted as evidence of the causal role that prenatal exposure to tobacco smoke has on human phenotypes, emerging evidence has suggested that the association between prenatal exposure to tobacco smoke and behavioral phenotypes may be spurious. The current analysis of data from the Early Childhood Longitudinal Study, Birth Cohort (ECLS-B) revealed that the association between prenatal exposure to cigarette smoke and externalizing behavioral problems was fully accounted for by confounding factors. The implications that these findings have for policy and research are discussed. PMID- 20195439 TI - Estimating prevalence of coronary heart disease for small areas using collateral indicators of morbidity. AB - Different indicators of morbidity for chronic disease may not necessarily be available at a disaggregated spatial scale (e.g., for small areas with populations under 10 thousand). Instead certain indicators may only be available at a more highly aggregated spatial scale; for example, deaths may be recorded for small areas, but disease prevalence only at a considerably higher spatial scale. Nevertheless prevalence estimates at small area level are important for assessing health need. An instance is provided by England where deaths and hospital admissions for coronary heart disease are available for small areas known as wards, but prevalence is only available for relatively large health authority areas. To estimate CHD prevalence at small area level in such a situation, a shared random effect method is proposed that pools information regarding spatial morbidity contrasts over different indicators (deaths, hospitalizations, prevalence). The shared random effect approach also incorporates differences between small areas in known risk factors (e.g., income, ethnic structure). A Poisson-multinomial equivalence may be used to ensure small area prevalence estimates sum to the known higher area total. An illustration is provided by data for London using hospital admissions and CHD deaths at ward level, together with CHD prevalence totals for considerably larger local health authority areas. The shared random effect involved a spatially correlated common factor, that accounts for clustering in latent risk factors, and also provides a summary measure of small area CHD morbidity. PMID- 20195440 TI - Aflatoxin contamination in food and body fluids in relation to malnutrition and cancer status in Cameroon. AB - Aflatoxins are food contaminants usually associated with hepatitis, immunodepression, impairment of fertility and cancer. The present work was to determine the presence of aflatoxins in eggs, milk, urine, and blood samples that were collected from various sources and periods; and hepatitis B virus antigen in blood samples. Aflatoxin was found in eggs (45.2%), cow raw milk (15.9%), breast milk (4.8%), urine from kwashiorkor and marasmic kwashiorkor children (45.5%), and sera from primary liver cancer patients (63.9%); HbsAg was also detected in 69.4% of the serum samples, but there was no association between both factors. Both AF and hepatitis B virus seem to be risk factors that could increase the incidence and prevalence rates of malnutrition and cancer in Cameroon. PMID- 20195441 TI - Theoretical models and operational frameworks in public health ethics. AB - The article is divided into three sections: (i) an overview of the main ethical models in public health (theoretical foundations); (ii) a summary of several published frameworks for public health ethics (practical frameworks); and (iii) a few general remarks. Rather than maintaining the superiority of one position over the others, the main aim of the article is to summarize the basic approaches proposed thus far concerning the development of public health ethics by describing and comparing the various ideas in the literature. With this in mind, an extensive list of references is provided. PMID- 20195442 TI - Environmental remediation and conversion of carbon dioxide (CO(2)) into useful green products by accelerated carbonation technology. AB - This paper reviews the application of carbonation technology to the environmental industry as a way of reducing carbon dioxide (CO(2)), a green house gas, including the presentation of related projects of our research group. An alternative technology to very slow natural carbonation is the co-called 'accelerated carbonation', which completes its fast reaction within few hours by using pure CO(2). Carbonation technology is widely applied to solidify or stabilize solid combustion residues from municipal solid wastes, paper mill wastes, etc. and contaminated soils, and to manufacture precipitated calcium carbonate (PCC). Carbonated products can be utilized as aggregates in the concrete industry and as alkaline fillers in the paper (or recycled paper) making industry. The quantity of captured CO(2) in carbonated products can be evaluated by measuring mass loss of heated samples by thermo-gravimetric (TG) analysis. The industrial carbonation technology could contribute to both reduction of CO(2) emissions and environmental remediation. PMID- 20195443 TI - Advancing the selection of neurodevelopmental measures in epidemiological studies of environmental chemical exposure and health effects. AB - With research suggesting increasing incidence of pediatric neurodevelopmental disorders, questions regarding etiology continue to be raised. Neurodevelopmental function tests have been used in epidemiology studies to evaluate relationships between environmental chemical exposures and neurodevelopmental deficits. Limitations of currently used tests and difficulties with their interpretation have been described, but a comprehensive critical examination of tests commonly used in studies of environmental chemicals and pediatric neurodevelopmental disorders has not been conducted. We provide here a listing and critical evaluation of commonly used neurodevelopmental tests in studies exploring effects from chemical exposures and recommend measures that are not often used, but should be considered. We also discuss important considerations in selecting appropriate tests and provide a case study by reviewing the literature on polychlorinated biphenyls. PMID- 20195444 TI - Categorizing US state drinking practices and consumption trends. AB - US state alcohol consumption patterns and trends are examined in order to identify groups of states with similar drinking habits or cultures. Rates of heavy drinking and current abstention and per capita apparent consumption levels are used to categorize states. Six state groupings were identified: North Central and New England with the highest consumption and heavy drinking levels; Middle Atlantic, Pacific and South Coast with moderate drinking levels; and Dry South with the lowest drinking levels. Analyses of relationships between beer and spirits series for states within groups as compared to those in different groups failed to clearly indicate group cohesiveness. PMID- 20195445 TI - Determinants of exposure to Environmental Tobacco Smoke (ETS) among non smoking adolescents (aged 11-17 years old) in Greece: results from the 2004-2005 GYTS Study. AB - The aim of the study is to investigate the determinants of exposure to ETS among Greek adolescents aged 11-17 years old. The GYTS questionnaire was completed by 5,179 adolescents. About 3 in 4 responders (76.8%) were exposed to ETS at home, and 38.5% were exposed to ETS outside of the home. Gender, age group, parental and close friends smoking status were significant determinants of adolescent's exposure to ETS. The results of the study could be valuable for the implementation of public health initiatives in Greece aiming to reduce the burden of adolescent's exposure to passive smoking. PMID- 20195446 TI - Correcting the actual reproduction number: a simple method to estimate R(0) from early epidemic growth data. AB - The basic reproduction number, R(0), a summary measure of the transmission potential of an infectious disease, is estimated from early epidemic growth rate, but a likelihood-based method for the estimation has yet to be developed. The present study corrects the concept of the actual reproduction number, offering a simple framework for estimating R(0) without assuming exponential growth of cases. The proposed method is applied to the HIV epidemic in European countries, yielding R(0) values ranging from 3.60 to 3.74, consistent with those based on the Euler-Lotka equation. The method also permits calculating the expected value of R(0) using a spreadsheet. PMID- 20195447 TI - The toxicity of depleted uranium. AB - Depleted uranium (DU) is an emerging environmental pollutant that is introduced into the environment primarily by military activity. While depleted uranium is less radioactive than natural uranium, it still retains all the chemical toxicity associated with the original element. In large doses the kidney is the target organ for the acute chemical toxicity of this metal, producing potentially lethal tubular necrosis. In contrast, chronic low dose exposure to depleted uranium may not produce a clear and defined set of symptoms. Chronic low-dose, or subacute, exposure to depleted uranium alters the appearance of milestones in developing organisms. Adult animals that were exposed to depleted uranium during development display persistent alterations in behavior, even after cessation of depleted uranium exposure. Adult animals exposed to depleted uranium demonstrate altered behaviors and a variety of alterations to brain chemistry. Despite its reduced level of radioactivity evidence continues to accumulate that depleted uranium, if ingested, may pose a radiologic hazard. The current state of knowledge concerning DU is discussed. PMID- 20195448 TI - Indoor air in beauty salons and occupational health exposure of cosmetologists to chemical substances. AB - The indoor environment in four beauty salons located in Athens (Greece) was examined in order to investigate the occupational health exposure of cosmetologists to various chemical products typically used in their work. Chemical substances chosen for investigation were volatile organic compounds (VOCs), formaldehyde, ozone and carbon dioxide. Total VOCs levels measured showed significant variation (100-1,450 microg m(-3)) depending on the products used and the number of treatments carried out, as well as ventilation. The main VOCs found in the salons were aromatics (toluene, xylene), esters and ketones (ethyl acetate, acetone, etc.) which are used as solvents in various beauty products; terpenes (pinene, limonene, camphor, menthenol) which have a particular odor and others like camphor which have specific properties. Ozone concentrations measured in all salons were quite low (0.1 and 13.3 microg m(-3)) and formaldehyde concentrations detected were lower than the detection limit of the method in all salons (<0.05 ppm). Carbon dioxide levels ranged between 402 and 1,268 ppm, depending on the number of people present in the salons during measurements and ventilation. Cosmetologists may be exposed to high concentrations of a mixture of volatile organic compounds although these levels could be decreased significantly by following certain practices such as good ventilation of the areas, closing the packages of the beauty products when not in use and finally selecting safer beauty products without strong odor. PMID- 20195449 TI - To match or not to match in epidemiological studies--same outcome but less power. AB - This study aimed to analyze the possible resemblance or difference in outcome in a case-control study of quality of life for IBS patients compared to controls free from the disease, when a matching procedure for age and sex was applied for the control group compared to when all participating subjects were included in the control group. The main result was that almost the same and identical results were found irrespective of whether matching or not matching was applied in this epidemiological case-control study. The matching procedure however, slightly diminished the statistical power of the results. PMID- 20195450 TI - Fecundity increase supports adaptive radiation hypothesis in spider web evolution. AB - Identifying the mechanisms driving adaptive radiations is key to explaining the diversity of life. The extreme reliance of spiders upon silk for survival provides an exceptional system in which to link patterns of diversification to adaptive changes in silk use. Most of the world's 41,000 species of spiders belong to two apical lineages of spiders that exhibit quite different silk ecologies, distinct from their ancestors. Orb spiders spin highly stereotyped webs that are suspended in air and utilize a chemical glue to make them adhesive. RTA clade spiders mostly abandoned silk capture webs altogether. We recently proposed that these two clades present very different evolutionary routes of achieving the same key innovation-escape from the constraints imposed by spinning webs that contain a relatively costly type of physically adhesive cribellate silk. Here, we test the prediction that orb and RTA clade spiders are not only more diverse, but also have higher fecundity than other spiders. We show that RTA clade spiders average 23% higher fecundity and orb spiders average 123% higher fecundity than their ancestors. This supports a functional link between the adaptive escape from cribellate silk and increased resource allocation to reproduction in spiders. PMID- 20195451 TI - Geographic variation in the growth of domesticated honey bee stocks: disease or economics? AB - Declines in the stocks of domesticated honey bees in some countries have been attributed to disease, which is at odds with an increasing global trend in the total number of hives. Based on data on annual growth rates in hive numbers and honey production for 87 countries, we tested the hypothesis that geographic heterogeneity in the growth of the domesticated honey bee population can be attributed to disease. In contrast to predictions of this hypothesis, changes in honey production varied in proportion to changes in hive number. Also, growth in honey production was not more spatially heterogeneous than growth in hive numbers, as expected under a scenario of contagious pests. We argue that although disease aggravates production costs, it has less effect on changes in national hive numbers than labor costs, so that geographic variation in the growth of the global honey bee stock reflects the global division of human labor that is a hallmark of economic globalization, rather than persistent and pervasive biological causes. PMID- 20195452 TI - Emergent complexity in simple neural systems. AB - The ornate and diverse patterns of seashells testify to the complexity of living systems. Provocative computational explorations have shown that similarly complex patterns may arise from the collective interaction of a small number of rules. This suggests that, although a system may appear complex, it may still be understood in terms of simple principles. It is still debatable whether shell patterns emerge from some undiscovered simple principles, or are the consequence of an irreducibly complex interaction of many effects. Recent work by Boettiger, Ermentrout and Oster on the biological mechanisms of shell patterning has provided compelling evidence that, at least for this system, simplicity produces diversity and complexity. PMID- 20195453 TI - Potential roles for cellular cofactors in hepatitis C virus replication complex formation. AB - Over 130 million people worldwide are chronically infected with hepatitis C virus (HCV). New antiviral treatment strategies are needed due to limitations with current therapy. The identification of cellular cofactors of infection has the potential to broadly expand our therapeutic targets. We recently reported an RNA interference screen of host membrane trafficking genes in HCV infection and replication and identified several cellular co-factors for viral replication. Phosphatidylinositol 4-kinase III alpha (PI4K-IIIalpha) was found to be essential for HCV replication. PI4K-IIIalpha co-localized with viral replication markers. Silencing of PI4K-IIIalpha by siRNAs prior to HCV infection prevented rearrangement of intracellular membranes associated with viral replication complexes, termed the membranous web. Our data suggest that PI4K-IIIalpha is involved in establishing HCV replication complexes, however the mechanism is unknown. From our analysis, along with several other studies that have identified cellular cofactors for HCV replication, we propose that PI4K-IIIalpha may nucleate replication complex formation by facilitating the interaction of viral and/or cellular proteins with cellular membrane-associated phospholipids. PMID- 20195454 TI - New views on the neural crest epithelial-mesenchymal transition and neuroepithelial interkinetic nuclear migration. AB - By developing a technique for imaging the avian neural crest epithelial mesenchymal transition (EMT), we have discovered cellular behaviors that challenge current thinking on this important developmental event, including the probability that complete disassembly of the adherens junctions may not control whether or not a neural epithelial cell undergoes an EMT. Further, neural crest cells can adopt multiple modes of cell motility in order to emigrate from the neuroepithelium. We also gained insights into interkinetic nuclear migration (INM). For example, the movement of the nucleus from the basal to apical domain may not require microtubule motors nor an intact nuclear envelope, and the nucleus does not always need to reach the apical surface in order for cytokinesis to occur. These studies illustrate the value of live-cell imaging to elucidate cellular processes. PMID- 20195455 TI - Escaping away from and towards a threat: the cockroach's strategy for staying alive. AB - The escape response of the cockroach is a well-studied example of sensorimotor behavior. Cockroaches respond to wind puffs, which may signal a predator attack, by making a swift turn followed by a forward acceleration. We have recently shown that their escape trajectories, measured relative to the position of the threatening stimulus, show preferred directions.1 Previous work has often distinguished between the most common type of escape turn, which begins as a rotation away from the stimulus, and the relatively rare turns initiated towards the stimulus. Here, we analyze these "away" and "towards" responses in light of our recent work on preferred escape trajectories (ETs). We find that the ETs of towards responses show a pattern of frequency distribution similar to that of away responses. The range of the bodyturn angles of towards responses, however, is much smaller than that of away responses, being <30 degrees in most cases, which approximately corresponds to the angular distance between ET peaks. This suggests that cockroaches minimize their turn when making a towards response, which could represent an effective anti-predator behavior that allows cockroaches to reach one of the preferred ETs within a relatively short time. PMID- 20195456 TI - Grip and slip: mechanical interactions between insects and the epidermis of flowers and flower stalks. AB - Flowers interact simultaneously with a variety of insect visitors, including mutualistic pollinators and antagonists such as florivores, nectar robbers and pollinator predators. The plant epidermis produces a range of structures, such as conical or papillate cells, that can help mutualists to grip the flower, while a variety of other structures, such as slippery wax crystals on the flowers or on the stems leading to them, are able to deter non-beneficial insects or behaviors. Modification of the floral surface can also aid pollination in unusual ways in some highly specialized interactions. In the case of the trap-flowers in species of Arisaema, conical cells aid pollination by being present on the spathe surface, but here they are modified in such a way as to decrease the pollinating insect's grip. We discuss a variety of these floral structural features that influence insect stability on the plant. PMID- 20195457 TI - To switch or not to switch?: Phenotypic switching is sensitive to multiple inputs in a pathogenic fungus. AB - Candida albicans is the most commonly isolated human fungal pathogen and uses a diverse repertoire of morphological transitions to aid colonization and infection. In a recent paper we discuss how one of these transitions, the white to-opaque switch, is affected both by cell stress and by several other conditions that change the rate of cell growth. Based on our findings, we propose that the master regulator of the white-to-opaque switch, WOR1, acts as a sensitive monitor of both intrinsic and environmental conditions. PMID- 20195458 TI - Two sides of the same coin no longer: genetic separation of nociceptive sensitization responses. AB - Nociceptive sensitization is a conserved form of neuronal plasticity that serves an important survival function, as it fosters behavior that protects damaged tissue during healing. This sensitization may involve a lowering of the nociceptive threshold (allodynia) or an increased response to normally noxious stimuli (hyperalgesia). Although nociceptive sensitization has been intensively studied in vertebrate models, an open question in the field is the extent to which allodynia and hyperalgesia, which almost always occur in tandem, are truly separate events at the mechanistic level. We recently introduced a genetically tractable model for damage-induced nociceptive sensitization in Drosophila larvae, and identified a conserved cytokine signaling module that mediates development of allodynia following UV irradiation. This pathway includes the Drosophila homolog of Tumor Necrosis Factor-alpha (TNFalpha), Eiger, which is released from damaged epidermal cells and acts directly on its receptor, Wengen, located on nociceptive sensory neurons. Here we show that although Eiger and Wengen are both required for the development of thermal allodynia, they are dispensable for thermal hyperalgesia, suggesting, contrary to what is commonly assumed, that these two forms of hypersensitivity are initiated by separate genetic pathways. PMID- 20195459 TI - Resting state networks and memory consolidation. AB - Despite their name, resting state networks (RSNs) provide a clear indication that the human brain may be hard-working. Unlike the cardiac and respiratory systems, which greatly reduce their rate of function during periods of inactivity, the human brain may have additional responsibilities during rest. One particularly intriguing function performed by the resting brain is the consolidation of recent learned information, which is known to take place over a period of several hours after learning. We recently reported that resting state brain activity is modulated by recent learning. We measured the brain activity using functional MRI during periods of rest that preceded and followed learning of a sensorimotor task, and found a network of brain areas that changed their resting activity. These areas are known to be involved in the acquisition and memory of such sensorimotor tasks. Furthermore, the changes were specific to a task that required learning, and were not found after motor performance without learning. Here we discuss the implications and possible extensions of this work and its relevance to the study of memory consolidation. PMID- 20195460 TI - The expanding roles of caveolin proteins in microbial pathogenesis. AB - Caveolin proteins have been implicated in a wide range of cellular functions including lipid raft mediated endocytosis and regulation of cell signaling cascades. Recent discoveries have shown that these proteins are involved not only in regulating these homeostatic cellular functions, but also in the host response to a wide range of different infections. Both caveolin-1 and 2 have been shown to play important roles in pathogen uptake. While caveolin-1 is the most well studied member of this family, a growing body of evidence has now recognized the role of caveolin-2 in these host pathogen interactions and novel host defense mechanisms. PMID- 20195461 TI - Mosaic, self-similarity logic, and biological attraction principles: three explanatory instruments in biology. AB - From a structural standpoint, living organisms are organized like a nest of Russian matryoshka dolls, in which structures are buried within one another. From a temporal point of view, this type of organization is the result of a history comprised of a set of time backcloths which have accompanied the passage of living matter from its origins up to the present day. The aim of the present paper is to indicate a possible course of this 'passage through time, and suggest how today's complexity has been reached by living organisms. This investigation will employ three conceptual tools, namely the Mosaic, Self-Similarity Logic, and the Biological Attraction principles. Self-Similarity Logic indicates the self consistency by which elements of a living system interact, irrespective of the spatiotemporal level under consideration. The term Mosaic indicates how, from the same set of elements assembled according to different patterns, it is possible to arrive at completely different constructions: hence, each system becomes endowed with different emergent properties. The Biological Attraction principle states that there is an inherent drive for association and merging of compatible elements at all levels of biological complexity. By analogy with the gravitation law in physics, biological attraction is based on the evidence that each living organism creates an attractive field around itself. This field acts as a sphere of influence that actively attracts similar fields of other biological systems, thereby modifying salient features of the interacting organisms. Three specific organizational levels of living matter, namely the molecular, cellular, and supracellular levels, have been considered in order to analyse and illustrate the interpretative as well as the predictive roles of each of these three explanatory principles. PMID- 20195462 TI - Efficacy of the new neuraminidase inhibitor CS-8958 against H5N1 influenza viruses. AB - Currently, two neuraminidase (NA) inhibitors, oseltamivir and zanamivir, which must be administrated twice daily for 5 days for maximum therapeutic effect, are licensed for the treatment of influenza. However, oseltamivir-resistant mutants of seasonal H1N1 and highly pathogenic H5N1 avian influenza A viruses have emerged. Therefore, alternative antiviral agents are needed. Recently, a new neuraminidase inhibitor, R-125489, and its prodrug, CS-8958, have been developed. CS-8958 functions as a long-acting NA inhibitor in vivo (mice) and is efficacious against seasonal influenza strains following a single intranasal dose. Here, we tested the efficacy of this compound against H5N1 influenza viruses, which have spread across several continents and caused epidemics with high morbidity and mortality. We demonstrated that R-125489 interferes with the NA activity of H5N1 viruses, including oseltamivir-resistant and different clade strains. A single dose of CS-8958 (1,500 microg/kg) given to mice 2 h post-infection with H5N1 influenza viruses produced a higher survival rate than did continuous five-day administration of oseltamivir (50 mg/kg twice daily). Virus titers in lungs and brain were substantially lower in infected mice treated with a single dose of CS 8958 than in those treated with the five-day course of oseltamivir. CS-8958 was also highly efficacious against highly pathogenic H5N1 influenza virus and oseltamivir-resistant variants. A single dose of CS-8958 given seven days prior to virus infection also protected mice against H5N1 virus lethal infection. To evaluate the improved efficacy of CS-8958 over oseltamivir, the binding stability of R-125489 to various subtypes of influenza virus was assessed and compared with that of other NA inhibitors. We found that R-125489 bound to NA more tightly than did any other NA inhibitor tested. Our results indicate that CS-8958 is highly effective for the treatment and prophylaxis of infection with H5N1 influenza viruses, including oseltamivir-resistant mutants. PMID- 20195463 TI - Five questions about viruses and microRNAs. PMID- 20195464 TI - Quantitative comparison of HTLV-1 and HIV-1 cell-to-cell infection with new replication dependent vectors. AB - We have developed an efficient method to quantify cell-to-cell infection with single-cycle, replication dependent reporter vectors. This system was used to examine the mechanisms of infection with HTLV-1 and HIV-1 vectors in lymphocyte cell lines. Effector cells transfected with reporter vector, packaging vector, and Env expression plasmid produced virus-like particles that transduced reporter gene activity into cocultured target cells with zero background. Reporter gene expression was detected exclusively in target cells and required an Env expression plasmid and a viral packaging vector, which provided essential structural and enzymatic proteins for virus replication. Cell-cell fusion did not contribute to infection, as reporter protein was rarely detected in syncytia. Coculture of transfected Jurkat T cells and target Raji/CD4 B cells enhanced HIV 1 infection two fold and HTLV-1 infection ten thousand fold in comparison with cell-free infection of Raji/CD4 cells. Agents that interfere with actin and tubulin polymerization strongly inhibited HTLV-1 and modestly decreased HIV-1 cell-to-cell infection, an indication that cytoskeletal remodeling was more important for HTLV-1 transmission. Time course studies showed that HTLV-1 transmission occurred very rapidly after cell mixing, whereas slower kinetics of HIV-1 coculture infection implies a different mechanism of infectious transmission. HTLV-1 Tax was demonstrated to play an important role in altering cell-cell interactions that enhance virus infection and replication. Interestingly, superantigen-induced synapses between Jurkat cells and Raji/CD4 cells did not enhance infection for either HTLV-1 or HIV-1. In general, the dependence on cell-to-cell infection was determined by the virus, the effector and target cell types, and by the nature of the cell-cell interaction. PMID- 20195465 TI - Differentiation, distribution and gammadelta T cell-driven regulation of IL-22 producing T cells in tuberculosis. AB - Differentiation, distribution and immune regulation of human IL-22-producing T cells in infections remain unknown. Here, we demonstrated in a nonhuman primate model that M. tuberculosis infection resulted in apparent increases in numbers of T cells capable of producing IL-22 de novo without in vitro Ag stimulation, and drove distribution of these cells more dramatically in lungs than in blood and lymphoid tissues. Consistently, IL-22-producing T cells were visualized in situ in lung tuberculosis (TB) granulomas by confocal microscopy and immunohistochemistry, indicating that mature IL-22-producing T cells were present in TB granuloma. Surprisingly, phosphoantigen HMBPP activation of Vgamma2Vdelta2 T cells down-regulated the capability of T cells to produce IL-22 de novo in lymphocytes from blood, lung/BAL fluid, spleen and lymph node. Up-regulation of IFNgamma-producing Vgamma2Vdelta2 T effector cells after HMBPP stimulation coincided with the down-regulated capacity of these T cells to produce IL-22 de novo. Importantly, anti-IFNgamma neutralizing Ab treatment reversed the HMBPP mediated down-regulation effect on IL-22-producing T cells, suggesting that Vgamma2Vdelta2 T-cell-driven IFNgamma-networking function was the mechanism underlying the HMBPP-mediated down-regulation of the capability of T cells to produce IL-22. These novel findings raise the possibility to ultimately investigate the function of IL-22 producing T cells and to target Vgamma2Vdelta2 T cells for balancing potentially hyper-activating IL-22-producing T cells in severe TB. PMID- 20195466 TI - Cyr61/CCN1 displays high-affinity binding to the somatomedin B(1-44) domain of vitronectin. AB - BACKGROUND: Cyr61 is a member of the CCN (Cyr61, connective tissue growth, NOV) family of extracellular-associated (matricellular) proteins that present four distinct functional modules, namely insulin-like growth factor binding protein (IGFBP), von Willebrand factor type C (vWF), thrombospondin type 1 (TSP), and C terminal growth factor cysteine knot (CT) domain. While heparin sulphate proteoglycans reportedly mediate the interaction of Cyr61 with the matrix and cell surface, the role of other extracellular associated proteins has not been revealed. METHODS AND FINDINGS: In this report, surface plasmon resonance (SPR) experiments and solid-phase binding assays demonstrate that recombinant Cyr61 interacts with immobilized monomeric or multimeric vitronectin (VTNC) with K(D) in the nanomolar range. Notably, the binding site for Cyr61 was identified as the somatomedin B domain (SMTB(1-44)) of VTNC, which mediates its interaction with PAI-1, uPAR, and integrin alphav beta3. Accordingly, PAI-1 outcompetes Cyr61 for binding to immobilized SMTB(1-44), and Cyr61 attenuates uPAR-mediated U937 adhesion to VTNC. In contrast, isothermal titration calorimetry shows that Cyr61 does not display high-affinity binding for SMTB(1-44) in solution. Nevertheless, competitive ELISA revealed that multimeric VTNC, heat-modified monomeric VTNC, or SMTB(1-44) at high concentrations attenuate Cyr61 binding to immobilized VTNC, while monomeric VTNC was ineffective. Therefore, immobilization of VTNC exposes cryptic epitopes that recognize Cyr61 with high affinity, as reported for a number of antibodies, beta-endorphin, and other molecules. CONCLUSIONS: The finding that Cyr61 interacts with the SMTB(1-44) domain suggests that VTNC represent a point of anchorage for CCN family members to the matrix. Results are discussed in the context of the role of CCN and VTNC in matrix biology and angiogenesis. PMID- 20195467 TI - HLA class I restriction as a possible driving force for Chikungunya evolution. AB - After two decades of quiescence, epidemic resurgence of Chikungunya fever (CHIKF) was reported in Africa, several islands in the Indian Ocean, South-East Asia and the Pacific causing unprecedented morbidity with some cases of fatality. Early phylogenetic analyses based on partial sequences of Chikungunya virus (CHIKV) have led to speculation that the virus behind recent epidemics may result in greater pathogenicity. To understand the reasons for these new epidemics, we first performed extensive analyses of existing CHIKV sequences from its introduction in 1952 to 2009. Our results revealed the existence of a continuous genotypic lineage, suggesting selective pressure is active in CHIKV evolution. We further showed that CHIKV is undergoing mild positive selection, and that site specific mutations may be driven by cell-mediated immune pressure, with occasional changes that resulted in the loss of human leukocyte antigen (HLA) class I-restricting elements. These findings provide a basis to understand Chikungunya virus evolution and reveal the power of post-genomic analyses to understand CHIKV and other viral epidemiology. Such an approach is useful for studying the impact of host immunity on pathogen evolution, and may help identify appropriate antigens suitable for subunit vaccine formulations. PMID- 20195468 TI - The shifting demographic landscape of pandemic influenza. AB - BACKGROUND: As Pandemic (H1N1) 2009 influenza spreads around the globe, it strikes school-age children more often than adults. Although there is some evidence of pre-existing immunity among older adults, this alone may not explain the significant gap in age-specific infection rates. METHODS AND FINDINGS: Based on a retrospective analysis of pandemic strains of influenza from the last century, we show that school-age children typically experience the highest attack rates in primarily naive populations, with the burden shifting to adults during the subsequent season. Using a parsimonious network-based mathematical model which incorporates the changing distribution of contacts in the susceptible population, we demonstrate that new pandemic strains of influenza are expected to shift the epidemiological landscape in exactly this way. CONCLUSIONS: Our analysis provides a simple demographic explanation for the age bias observed for H1N1/09 attack rates, and suggests that this bias may shift in coming months. These results have significant implications for the allocation of public health resources for H1N1/09 and future influenza pandemics. PMID- 20195469 TI - Flagellin-induced corneal antimicrobial peptide production and wound repair involve a novel NF-kappaB-independent and EGFR-dependent pathway. AB - BACKGROUND: The bacterial protein flagellin plays a major role in stimulating mucosal surface innate immune response to bacterial infection and uniquely induces profound cytoprotection against pathogens, chemicals, and radiation. This study sought to determine signaling pathways responsible for the flagellin induced inflammatory and cytoprotective effects on human corneal epithelial cells (HCECs). METHODOLOGY/PRINCIPAL FINDINGS: Flagellin purified from Pseudomonas aeruginosa (strain PAK) or live bacteria were used to challenge cultured HCECs. The activation of signaling pathways was assessed with Western blot, and the secretion of cytokine/chemokine and production of antimicrobial peptides (AMPs) were measured with ELISA and dot blot, respectively. Effects of flagellin on wound healing were assessed in cultured porcine corneas. L94A (a site mutation in TLR5 binding region) flagellin and PAK expressing L94A flagellin were unable to stimulate NF-kappaB activation, but were potent in eliciting EGFR signaling in a TGF-alpha-related pathway in HCECs. Concomitant with the lack of NF-kappaB activation, L94A flagellin was ineffective in inducing IL-6 and IL-8 production in HCECs. Surprisingly, the secretion of two inducible AMPs, LL-37 and hBD2, was not affected by L94A mutation. Similar to wild-type flagellin, L94A induced epithelial wound closure in cultured porcine cornea through maintaining EGFR mediated signaling. CONCLUSIONS/SIGNIFICANCE: Our data suggest that inflammatory response mediated by NF-kappaB can be uncoupled from epithelial innate defense machinery (i.e., AMP expression) and major epithelial proliferation/repair pathways mediated by EGFR, and that flagellin and its derivatives may have broad therapeutic applications in cytoprotection and in controlling infection in the cornea and other mucosal tissues. PMID- 20195470 TI - Evaluation of a prediction protocol to identify potential targets of epigenetic reprogramming by the cancer associated Epstein Barr virus. AB - BACKGROUND: Epstein Barr virus (EBV) infects the majority of the human population, causing fatal diseases in a small proportion in conjunction with environmental factors. Following primary infection, EBV remains latent in the memory B cell population for life. Recurrent reactivation of the virus occurs, probably due to activation of the memory B-lymphocytes, resulting in viral replication and re-infection of B-lymphocytes. Methylation of the viral DNA at CpG motifs leads to silencing of viral gene expression during latency. Zta, the key viral protein that mediates the latency/reactivation balance, interacts with methylated DNA. Zta is a transcription factor for both viral and host genes. A sub-set of its DNA binding sites (ZREs) contains a CpG motif, which is recognised in its methylated form. Detailed analysis of the promoter of the viral gene BRLF1 revealed that interaction with a methylated CpG ZRE (RpZRE3) is key to overturning the epigenetic silencing of the gene. METHODOLOGY AND PRINCIPAL FINDINGS: Here we question whether we can use this information to identify which host genes contain promoters with similar response elements. A computational search of human gene promoters identified 274 targets containing the 7-nucleotide RpZRE3 core element. DNA binding analysis of Zta with 17 of these targets revealed that the flanking context of the core element does not have a profound effect on the ability of Zta to interact with the methylated sites. A second juxtaposed ZRE was observed for one promoter. Zta was able to interact with this site, although co-occupancy with the RpZRE3 core element was not observed. CONCLUSIONS/SIGNIFICANCE: This research demonstrates 274 human promoters have the potential to be regulated by Zta to overturn epigenetic silencing of gene expression during viral reactivation from latency. PMID- 20195471 TI - Angiogenic factors stimulate growth of adult neural stem cells. AB - BACKGROUND: The ability to grow a uniform cell type from the adult central nervous system (CNS) is valuable for developing cell therapies and new strategies for drug discovery. The adult mammalian brain is a source of neural stem cells (NSC) found in both neurogenic and non-neurogenic zones but difficulties in culturing these hinders their use as research tools. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that NSCs can be efficiently grown in adherent cell cultures when angiogenic signals are included in the medium. These signals include both anti-angiogenic factors (the soluble form of the Notch receptor ligand, Dll4) and pro-angiogenic factors (the Tie-2 receptor ligand, Angiopoietin 2). These treatments support the self renewal state of cultured NSCs and expression of the transcription factor Hes3, which also identifies the cancer stem cell population in human tumors. In an organotypic slice model, angiogenic factors maintain vascular structure and increase the density of dopamine neuron processes. CONCLUSIONS/SIGNIFICANCE: We demonstrate new properties of adult NSCs and a method to generate efficient adult NSC cultures from various central nervous system areas. These findings will help establish cellular models relevant to cancer and regeneration. PMID- 20195472 TI - Malaria prevention with IPTp during pregnancy reduces neonatal mortality. AB - BACKGROUND: In the global context of a reduction of under-five mortality, neonatal mortality is an increasingly relevant component of this mortality. Malaria in pregnancy may affect neonatal survival, though no strong evidence exists to support this association. METHODS: In the context of a randomised, placebo-controlled trial of intermittent preventive treatment (IPTp) with sulphadoxine-pyrimethamine (SP) in 1030 Mozambican pregnant women, 997 newborns were followed up until 12 months of age. There were 500 live borns to women who received placebo and 497 to those who received SP. FINDINGS: There were 58 infant deaths; 60.4% occurred in children born to women who received placebo and 39.6% to women who received IPTp (p = 0.136). There were 25 neonatal deaths; 72% occurred in the placebo group and 28% in the IPTp group (p = 0.041). Of the 20 deaths that occurred in the first week of life, 75% were babies born to women in the placebo group and 25% to those in the IPTp group (p = 0.039). IPTp reduced neonatal mortality by 61.3% (95% CI 7.4%, 83.8%); p = 0.024]. CONCLUSIONS: Malaria prevention with SP in pregnancy can reduce neonatal mortality. Mechanisms associated with increased malaria infection at the end of pregnancy may explain the excess mortality in the malaria less protected group. Alternatively, SP may have reduced the risk of neonatal infections. These findings are of relevance to promote the implementation of IPTp with SP, and provide insights into the understanding of the pathophysiological mechanisms through which maternal malaria affects fetal and neonatal health. TRIAL REGISTRATION: ClinicalTrials.gov NCT00209781. PMID- 20195473 TI - Impact of the infection period distribution on the epidemic spread in a metapopulation model. AB - Epidemic models usually rely on the assumption of exponentially distributed sojourn times in infectious states. This is sometimes an acceptable approximation, but it is generally not realistic and it may influence the epidemic dynamics as it has already been shown in one population. Here, we explore the consequences of choosing constant or gamma-distributed infectious periods in a metapopulation context. For two coupled populations, we show that the probability of generating no secondary infections is the largest for most parameter values if the infectious period follows an exponential distribution, and we identify special cases where, inversely, the infection is more prone to extinction in early phases for constant infection durations. The impact of the infection duration distribution on the epidemic dynamics of many connected populations is studied by simulation and sensitivity analysis, taking into account the potential interactions with other factors. The analysis based on the average nonextinct epidemic trajectories shows that their sensitivity to the assumption on the infectious period distribution mostly depends on R0, the mean infection duration and the network structure. This study shows that the effect of assuming exponential distribution for infection periods instead of more realistic distributions varies with respect to the output of interest and to other factors. Ultimately it highlights the risk of misleading recommendations based on modelling results when models including exponential infection durations are used for practical purposes. PMID- 20195474 TI - Antimicrobial resistance, class 1 integrons, and genomic island 1 in Salmonella isolates from Vietnam. AB - BACKGROUND: The objective was to investigate the phenotypic and genotypic resistance and the horizontal transfer of resistance determinants from Salmonella isolates from humans and animals in Vietnam. METHODOLOGY/PRINCIPAL FINDINGS: The susceptibility of 297 epidemiologically unrelated non-typhoid Salmonella isolates was investigated by disk diffusion assay. The isolates were screened for the presence of class 1 integrons and Salmonella genomic island 1 by PCR. The potential for the transfer of resistance determinants was investigated by conjugation experiments. Resistance to gentamicin, kanamycin, chloramphenicol, streptomycin, trimethoprim, ampicillin, nalidixic acid, sulphonamides, and tetracycline was found in 13 to 50% of the isolates. Nine distinct integron types were detected in 28% of the isolates belonging to 11 Salmonella serovars including S. Tallahassee. Gene cassettes identified were aadA1, aadA2, aadA5, bla(PSE-1), bla(OXA-30), dfrA1, dfrA12, dfrA17, and sat, as well as open reading frames with unknown functions. Most integrons were located on conjugative plasmids, which can transfer their antimicrobial resistance determinants to Escherichia coli or Salmonella Enteritidis, or with Salmonella Genomic Island 1 or its variants. The resistance gene cluster in serovar Emek identified by PCR mapping and nucleotide sequencing contained SGI1-J3 which is integrated in SGI1 at another position than the majority of SGI1. This is the second report on the insertion of SGI1 at this position. High-level resistance to fluoroquinolones was found in 3 multiresistant S. Typhimurium isolates and was associated with mutations in the gyrA gene leading to the amino acid changes Ser83Phe and Asp87Asn. CONCLUSIONS: Resistance was common among Vietnamese Salmonella isolates from different sources. Legislation to enforce a more prudent use of antibiotics in both human and veterinary medicine should be implemented by the authorities in Vietnam. PMID- 20195475 TI - Differential associations of early- and late-night sleep with functional brain states promoting insight to abstract task regularity. AB - BACKGROUND: Solving a task with insight has been associated with occipital and right-hemisphere activations. The present study tested the hypothesis if sleep related alterations in functional activation states modulate the probability of insight into a hidden abstract regularity of a task. METHODOLOGY: State-dependent functional activation was measured by beta and alpha electroencephalographic (EEG) activity and spatial synchronization. Task-dependent functional activation was assessed by slow cortical potentials (SPs). EEG parameters during the performance of the Number Reduction Task (NRT) were compared between before sleep and after sleep sessions. In two different groups, the relevant sleep occurred either in the first or in the second half of the night, dominated by slow wave sleep (SWS) or by rapid eye movement (REM) sleep. PRINCIPAL FINDINGS: Changes in EEG parameters only occurred in the early-night group, not in the late-night group and indicated occipital and right-hemisphere functional alterations. These changes were associated with off-line consolidation of implicit task representations and with the amount of SWS but they did not predict subsequent insight. The gain of insight was, however, independently associated with changes of spectral beta and alpha measures only in those subjects from the two sleep groups who would subsequently comprehend the hidden regularity of the task. Insight-related enhancement of right frontal asymmetry after sleep did not depend on sleep stages. SIGNIFICANCE: It is concluded that off-line restructuring of implicit information during sleep is accompanied by alterations of functional activation states after sleep. This mechanism is promoted by SWS but not by REM sleep and may contribute to attaining insight after sleep. Original neurophysiologic evidence is provided for alterations of the functional activation brain states after sleep. These alterations are associated with a decrease in controlled processing within the visual system and with an increase in the functional connectivity of the right hemisphere, and are supported by SWS in the first half of the night. PMID- 20195476 TI - Differentiation of glioma and radiation injury in rats using in vitro produce magnetically labeled cytotoxic T-cells and MRI. AB - BACKGROUND: A limitation with current imaging strategies of recurrent glioma undergoing radiotherapy is that tumor and radiation injury cannot be differentiated with post contrast CT or MRI, or with PET or other more complex parametric analyses of MRI data. We propose to address the imaging limitation building on emerging evidence indicating that effective therapy for recurrent glioma can be attained by sensitized T-cells following vaccination of primed dendritic cells (DCs). The purpose of this study was to determine whether cord blood T-cells can be sensitized against glioma cells (U-251) and if these sensitized cytotoxic T-cells (CTLs) can be used as cellular magnetic resonance imaging probes to identify and differentiate glioma from radiation necrosis in rodent models. METHODOLOGY/PRINCIPAL FINDINGS: Cord blood T and CD14+ cells were collected. Isolated CD14+ cells were then converted to dendritic cells (DCs), primed with glioma cell lysate and used to sensitize T-cells. Phenotypical expression of the generated DCs were analyzed to determine the expression level of CD14, CD86, CD83 and HLA-DR. Cells positive for CD25, CD4, CD8 were determined in generated CTLs. Specificity of cytotoxicity of the generated CTLs was also determined by lactate dehydrogenase (LDH) release assay. Secondary proliferation capacity of magnetically labeled and unlabeled CTLs was also determined. Generated CTLs were magnetically labeled and intravenously injected into glioma bearing animals that underwent MRI on days 3 and 7 post- injection. CTLs were also administered to animals with focal radiation injury to determine whether these CTLs accumulated non-specifically to the injury sites. Multi-echo T2- and T2*-weighted images were acquired and R2 and R2* maps created. Our method produced functional, sensitized CTLs that specifically induced U251 cell death in vitro. Both labeled and unlabeled CTLs proliferated equally after the secondary stimulation. There were significantly higher CD25 positive cells (p = <0.006) in CTLs. In addition, T2- and T2*-weighted MR images showed increased low signal intensity areas in animals that received labeled CTLs as compared to the images from animals that received control cells. Histological analysis confirmed the presence of iron positive cells in sites corresponding to MRI low signal intensity regions. Significant differences (p = <0.001) in tumor R2 and R2* values were observed among the groups of animals. Animals with radiation injury exhibited neither MRI hypointense areas nor presence of iron positive cells. CONCLUSION: Our results indicate that T-cells can be effectively sensitized by in vitro methods and used as cellular probes to identify and differentiate glioma from radiation necrosis. PMID- 20195477 TI - Local membrane deformations activate Ca2+-dependent K+ and anionic currents in intact human red blood cells. AB - BACKGROUND: The mechanical, rheological and shape properties of red blood cells are determined by their cortical cytoskeleton, evolutionarily optimized to provide the dynamic deformability required for flow through capillaries much narrower than the cell's diameter. The shear stress induced by such flow, as well as the local membrane deformations generated in certain pathological conditions, such as sickle cell anemia, have been shown to increase membrane permeability, based largely on experimentation with red cell suspensions. We attempted here the first measurements of membrane currents activated by a local and controlled membrane deformation in single red blood cells under on-cell patch clamp to define the nature of the stretch-activated currents. METHODOLOGY/PRINCIPAL FINDINGS: The cell-attached configuration of the patch-clamp technique was used to allow recordings of single channel activity in intact red blood cells. Gigaohm seal formation was obtained with and without membrane deformation. Deformation was induced by the application of a negative pressure pulse of 10 mmHg for less than 5 s. Currents were only detected when the membrane was seen domed under negative pressure within the patch-pipette. K(+) and Cl(-) currents were strictly dependent on the presence of Ca(2+). The Ca(2+)-dependent currents were transient, with typical decay half-times of about 5-10 min, suggesting the spontaneous inactivation of a stretch-activated Ca(2+) permeability (PCa). These results indicate that local membrane deformations can transiently activate a Ca(2+) permeability pathway leading to increased [Ca(2+)](i), secondary activation of Ca(2+)-sensitive K(+) channels (Gardos channel, IK1, KCa3.1), and hyperpolarization-induced anion currents. CONCLUSIONS/SIGNIFICANCE: The stretch activated transient PCa observed here under local membrane deformation is a likely contributor to the Ca(2+)-mediated effects observed during the normal aging process of red blood cells, and to the increased Ca(2+) content of red cells in certain hereditary anemias such as thalassemia and sickle cell anemia. PMID- 20195478 TI - Co-expression of DevR and DevR(N)-Aph proteins is associated with hypoxic adaptation defect and virulence attenuation of Mycobacterium tuberculosis. AB - BACKGROUND: The DevR response regulator is implicated in both hypoxic adaptation and virulence of Mycobacterium tuberculosis (M. tb). DevR regulon genes are powerfully induced in vivo implicating them in bacterial adaptation to host control strategies. A better understanding of DevR function will illumine the way for new strategies to control and treat tuberculosis. METHODOLOGY/PRINCIPAL FINDINGS: Towards this objective, we used a combination of genetic, microbiological, biochemical, cell biological tools and a guinea pig virulence assay to compare the hypoxic adaptation and virulence properties of two novel M. tb strains, namely, a devR disruption mutant, Mut1, that expresses C-terminal truncated N-terminal domain of DevR (DevR(NTD)) as a fusion protein with AphI (DevR(N)-Kan), and its complemented strain, Comp1, that expresses intact DevR along with DevR(N)-Kan. Comp1 bacteria exhibit a defect in DevR-mediated phosphosignalling, hypoxic induction of HspX and also hypoxic survival. In addition, we find that Comp1 is attenuated in virulence in guinea pigs and shows decreased infectivity of THP-1 cells. While Mut1 bacilli are also defective in hypoxic adaptation and early growth in spleen, they exhibit an overall virulence comparable to that of wild-type bacteria. CONCLUSIONS/SIGNIFICANCE: The hypoxic defect of Comp1 is associated to a defect in DevR expression level. The demonstrated repression of DevR function by DevR(N)-Kan suggests that such a knockdown approach could be useful for evaluating the activity of DevRS and other two-component signaling pathways. Further investigation is necessary to elucidate the mechanism underlying Comp1 attenuation. PMID- 20195479 TI - A tyrosine residue on the TSH receptor stabilizes multimer formation. AB - BACKGROUND: The thyrotropin stimulating hormone receptor (TSHR) is a G protein coupled receptor (GPCR) with a large ectodomain. The ligand, TSH, acting via this receptor regulates thyroid growth and thyroid hormone production and secretion. The TSH receptor (TSHR) undergoes complex post-translational modifications including intramolecular cleavage and receptor multimerization. Since monomeric and multimeric receptors coexist in cells, understanding the functional role of just the TSHR multimers is difficult. Therefore, to help understand the physiological significance of receptor multimerization, it will be necessary to abrogate multimer formation, which requires identifying the ectodomain and endodomain interaction sites on the TSHR. Here, we have examined the contribution of the ectodomain to constitutive multimerization of the TSHR and determined the possible residue(s) that may be involved in this interaction. METHODOLOGY/PRINCIPAL FINDINGS: We studied ectodomain multimer formation by expressing the extracellular domain of the TSHR linked to a glycophosphotidyl (GPI) anchor in both stable and transient expression systems. Using co immunoprecipitation and FRET of tagged receptors, we established that the TSH receptor ectodomain was capable of multimerization even when totally devoid of the transmembrane domain. Further, we studied the effect of two residues that likely made critical contact points in this interaction. We showed that a conserved tyrosine residue (Y116) on the convex surface of the LRR3 was a critical residue in ectodomain multimer formation since mutation of this residue to serine totally abrogated ectodomain multimers. This abrogation was not seen with the mutation of cysteine 176 on the inner side of the LRR5, demonstrating that inter-receptor disulfide bonding was not involved in ectodomain multimer formation. Additionally, the Y116 mutation in the intact wild type receptor enhanced receptor degradation. CONCLUSIONS/SIGNIFICANCE: These data establish the TSH receptor ectodomain as one site of multimerization, independent of the transmembrane region, and that this interaction was primarily via a conserved tyrosine residue in LRR3. PMID- 20195480 TI - The cannabinoid 1 receptor (CNR1) 1359 G/A polymorphism modulates susceptibility to ulcerative colitis and the phenotype in Crohn's disease. AB - BACKGROUND: Recent evidence suggests a crucial role of the endocannabinoid system, including the cannabinoid 1 receptor (CNR1), in intestinal inflammation. We therefore investigated the influence of the CNR1 1359 G/A (p.Thr453Thr; rs1049353) single nucleotide polymorphism (SNP) on disease susceptibility and phenotype in patients with ulcerative colitis (UC) and Crohn's disease (CD). METHODS: Genomic DNA from 579 phenotypically well-characterized individuals was analyzed for the CNR1 1359 G/A SNP. Amongst these were 166 patients with UC, 216 patients with CD, and 197 healthy controls. RESULTS: Compared to healthy controls, subjects A/A homozygous for the CNR1 1359 G/A SNP had a reduced risk to develop UC (p = 0.01, OR 0.30, 95% CI 0.12-0.78). The polymorphism did not modulate CD susceptibility, but carriers of the minor A allele had a lower body mass index than G/G wildtype carriers (p = 0.0005). In addition, homozygous carriers of the G allele were more likely to develop CD before 40 years of age (p = 5.9x10(-7)) than carriers of the A allele. CONCLUSION: The CNR1 p.Thr453Thr polymorphism appears to modulate UC susceptibility and the CD phenotype. The endocannabinoid system may influence the manifestation of inflammatory bowel diseases, suggesting endocannabinoids as potential target for future therapies. PMID- 20195481 TI - Interspecific hybridization as a tool to understand vocal divergence: the example of crowing in quail (Genus Coturnix). AB - Understanding the mechanisms that lead organisms to be separated into distinct species remains a challenge in evolutionary biology. Interspecific hybridization, which results from incomplete reproductive isolation, is a useful tool to investigate such mechanisms. In birds, interspecific hybridization is relatively frequent, despite the fact that closed species exhibit morphological and behavioural differences. Evolution of behaviour is difficult to investigate on a large timescale since it does not 'fossilize'. Here I propose that calls of hybrid non-songbirds that develop without the influence of learning may help in understanding the gradual process that leads to vocal divergence during speciation. I recorded crows produced by the European quail (Coturnix c. coturnix), the domestic Japanese quail (Coturnix c. japonica) and their hybrids (F1, F2 and backcrosses). Most crowing patterns were intermediate to those of the parental species; some were similar to one or the other parental species, or not present in either parental species. I also observed vocal changes in hybrid crows during the breeding season and from one year to the other. This vocal variability resembles those observed during the ontogeny of the crow in quails. It is likely that similar mechanisms involved in vocal changes during ontogeny might have driven vocal divergence in the species of Palearctic quails. I suggest that hybrid crows might have resembled those produced by intermediary forms of quails during speciation. PMID- 20195482 TI - Chronic murine typhoid fever is a natural model of secondary hemophagocytic lymphohistiocytosis. AB - Hemophagocytic lymphohistiocytosis (HLH) is a hyper-inflammatory clinical syndrome associated with neoplastic disorders especially lymphoma, autoimmune conditions, and infectious agents including bacteria, viruses, protozoa and fungi. In both human and veterinary medicine, hemophagocytic histiocytic disorders are clinically important and frequently fatal. HLH in humans can be a primary (familial, autosomal recessive) or secondary (acquired) condition, with both types generally precipitated by an infectious agent. Previously, no mouse model for secondary HLH has been reported. Using Salmonella enterica serotype Typhimurium by oral gavage to mimic naturally-occurring infection in Sv129S6 mice, we characterized the clinical, hematologic and morphologic host responses to disease thereby describing an animal model with the clinico-pathologic features of secondary HLH as set forth by the Histiocyte Society: fever, splenomegaly, cytopenias (anemia, thrombocytopenia), hemophagocytosis in bone marrow and spleen, hyperferritinemia, and hypofibrinogenemia. Disease severity correlates with high splenic and hepatic bacterial load, and we show disease course can be monitored and tracked in live animals. Whereby secondary HLH is known to occur in human patients with typhoid fever and other infectious diseases, our characterization of a viable natural disease model of secondary HLH offers an important means to elucidate pathogenesis of poorly understood mechanisms of secondary HLH and investigation of novel therapies. We characterize previously unreported secondary HLH in a chronic mouse model of typhoid fever, and novel changes in hematology including decreased tissue ferric iron storage that differs from classically described anemia of chronic disease. Our studies demonstrate S. Typhimurium infection of mice is a natural infectious disease model of secondary HLH that may have utility for elucidating disease pathogenesis and developing novel therapies. PMID- 20195487 TI - Chain-breaking antioxidant activity of reduced forms of mitochondria-targeted quinones, a novel type of geroprotectors. AB - The chain-breaking antioxidant activities of reduced form of novel type of geroprotectors, mitochondria-targeted quinones (QH(2)) have quantitatively been measured for the first time. To this end, the chain peroxidation of methyl linoleate (ML) in Triton micelles was used as a kinetic testing model. The studied QH(2) were lipophilic triphenylphosphonium cations conjugated by an aliphatic linker to an antioxidant, i.e. a ubiquinol moiety (MitoQH(2)) or plastoquinol moiety (SkQH(2)). The antioxidant activity was characterized by the rate constant k(1) for the reaction between QH(2) and the lipid peroxyl radical (LO(2) (.)) originated from ML: QH(2) + LO(2) (.) --> HQ(.) + LOOH. All the tested QH(2) displayed a pronounced antioxidant activity. The oxidized forms of the same compounds did not inhibit ML peroxidation. The value of k(1) for SkQH(2) far exceeded k(1) for MitoQH(2). For the biologically active geroprotectors SkQ1H(2), the k(1) value found to be as high as 2.2 x 10(5) M(-) (1)s(-) (1), whereas for MitoQH(2), it was 0.58 x 10(5) M(-) (1)s(-) (1). The kinetic behavior of QH(2) suggested that SkQ1H(2) can rather easily diffuse through lipid-water microheterogeneous systems. PMID- 20195488 TI - Sod2 haploinsufficiency does not accelerate aging of telomere dysfunctional mice. AB - Telomere shortening represents a causal factor of cellular senescence. At the same time, several lines of evidence indicate a pivotal role of oxidative DNA damage for the aging process in vivo. A causal connection between the two observations was suggested by experiments showing accelerated telomere shorting under conditions of oxidative stress in cultured cells, but has never been studied in vivo. We therefore have analysed whether an increase in mitochondrial derived oxidative stress in response to heterozygous deletion of superoxide dismutase (Sod2(+/-)) would exacerbate aging phenotypes in telomere dysfunctional (mTerc(-/-)) mice. Heterozygous deletion of Sod2 resulted in reduced SOD2 protein levels and increased oxidative stress in aging telomere dysfunctional mice, but this did not lead to an increase in basal levels of oxidative nuclear DNA damage, an accumulation of nuclear DNA breaks, or an increased rate of telomere shortening in the mice. Moreover, heterozygous deletion of Sod2 did not accelerate the depletion of stem cells and the impairment in organ maintenance in aging mTerc(-/-) mice. In agreement with these observations, Sod2 haploinsufficiency did not lead to a further reduction in lifespan of mTerc(-/-) mice. Together, these results indicate that a decrease in SOD2-dependent antioxidant defence does not exacerbate aging in the context of telomere dysfunction. PMID- 20195489 TI - Activation of p73 and induction of Noxa by DNA damage requires NF-kappa B. AB - Although the transcription factor NF-kappaB is most clearly linked to the inhibition of extrinsic apoptotic signals such as TNFalpha by upregulating known anti-apoptotic genes, NF-kappaB has also been proposed to be required for p53 induced apoptosis in transformed cells. However, the involvement of NF-kappaB in this process is poorly understood. Here we investigate this mechanism and show that in transformed MEFs lacking NF-kappaB (p65-null cells) genotoxin-induced cytochrome c release is compromised. To further address how NF-kappaB contributes to apoptosis, gene profiling by microarray analysis of MEFs was performed, revealing that NF-kappaB is required for expression of Noxa, a pro-apoptotic BH3 only protein that is induced by genotoxins and that triggers cytochrome c release. Moreover, we find that in the absence of NF-kappaB, genotoxin treatment cannot induce Noxa mRNA expression. Noxa expression had been shown to be regulated directly by genes of the p53 family, like p73 and p63, following genotoxin treatment. Here we show that p73 is activated after genotoxin treatment only in the presence of NF-kappaB and that p73 induces Noxa gene expression through the p53 element in the promoter. Together our data provides an explanation for how loss of NF-kappaB abrogates genotoxin-induced apoptosis. PMID- 20195490 TI - Mitochondria-targeted antioxidant SkQ1 inhibits age-dependent involution of the thymus in normal and senescence-prone rats. AB - One of the most striking changes during mammal aging is a progressive involution of the thymus, associated with an increase in susceptibility to infections, autoimmune diseases and cancer. In order to delay age-related processes, we have developed mitochondria-targeted antioxidant plastoquinonyl decyltriphenyl phosphonium (SkQ1). Here we report that, at low doses, SkQ1 (250 nmol/kg per day) inhibited age-dependent involution of the thymus in normal (Wistar) and senescence-prone (OXYS) rats. SkQ1 preserved total weight and volume of the organ, the volume of thymic cortex and medulla, the thymic cellularity, and the number of CD3+, CD4+, and CD8+ cells in the thymus. Moreover, SkQ1 was especially effective in senescence-prone rats. Thus SkQ1 slows down age-linked decline of the immune system, explaining prevention by this compound of infection-caused death in rodents, previously described in our group. PMID- 20195491 TI - Dual targeting of the antagonistic pathways mediated by Sirt1 and TXNIP as a putative approach to enhance the efficacy of anti-aging interventions. AB - The organism's ability to regulate oxidative stress and metabolism is well recognized as a major determinant of longevity. While much research interest in this area is directed towards the study of genes that inhibit oxidative stress and/or improve metabolism, contribution to the aging process of genes with antagonistic effects on these two pathways is still less understood. The present study investigated the respective roles of the histone deacetylase Sirt1 and the thioredoxin binding protein TXNIP, two genes with opposite effects on oxidative stress and metabolism, in mediating the action of putative anti-aging interventions. Experiments were carried out in vitro and in vivo to determine the effect of proven, limited calorie availability, and unproven, resveratrol and dehydroepiandrosterone (DHEA), on the expression of Sirt1 and TXNIP. The results indicated that limited calorie availability consistently inhibited TXNIP in cancer and in normal cells including stem cells, however, it only slightly induced Sirt1expression in cancer cells. In contrast, resveratrol had a biphasic effect, and DHEA inhibited the expression of these two genes in a tissue specific manner, both in vitro and in vivo. Whereas all the three approaches tested inhibited TXNIP through the glycolytic pathway, DHEA acted by inhibiting G6PD and resveratrol through the activation of AMPK. In light of previous reports that Sirt1 induces AMPK-mediated signaling pathway, our findings point to the possibility of a negative relationship between Sirt1 and TXNIP that, if validated, can be exploited to improve the efficacy of putative anti-aging interventions. PMID- 20195493 TI - Spatial simulations of myxobacterial development. AB - Many bacteria exhibit multicellular behaviour, with individuals within a colony coordinating their actions for communal benefit. One example of complex multicellular phenotypes is myxobacterial fruiting body formation, where thousands of cells aggregate into large three-dimensional structures, within which sporulation occurs. Here we describe a novel theoretical model, which uses Monte Carlo dynamics to simulate and explain multicellular development. The model captures multiple behaviours observed during fruiting, including the spontaneous formation of aggregation centres and the formation and dissolution of fruiting bodies. We show that a small number of physical properties in the model is sufficient to explain the most frequently documented population-level behaviours observed during development in Myxococcus xanthus. PMID- 20195492 TI - Molecular predictors of 3D morphogenesis by breast cancer cell lines in 3D culture. AB - Correlative analysis of molecular markers with phenotypic signatures is the simplest model for hypothesis generation. In this paper, a panel of 24 breast cell lines was grown in 3D culture, their morphology was imaged through phase contrast microscopy, and computational methods were developed to segment and represent each colony at multiple dimensions. Subsequently, subpopulations from these morphological responses were identified through consensus clustering to reveal three clusters of round, grape-like, and stellate phenotypes. In some cases, cell lines with particular pathobiological phenotypes clustered together (e.g., ERBB2 amplified cell lines sharing the same morphometric properties as the grape-like phenotype). Next, associations with molecular features were realized through (i) differential analysis within each morphological cluster, and (ii) regression analysis across the entire panel of cell lines. In both cases, the dominant genes that are predictive of the morphological signatures were identified. Specifically, PPARgamma has been associated with the invasive stellate morphological phenotype, which corresponds to triple-negative pathobiology. PPARgamma has been validated through two supporting biological assays. PMID- 20195494 TI - Stochastic model of integrin-mediated signaling and adhesion dynamics at the leading edges of migrating cells. AB - Productive cell migration requires the spatiotemporal coordination of cell adhesion, membrane protrusion, and actomyosin-mediated contraction. Integrins, engaged by the extracellular matrix (ECM), nucleate the formation of adhesive contacts at the cell's leading edge(s), and maturation of nascent adhesions to form stable focal adhesions constitutes a functional switch between protrusive and contractile activities. To shed additional light on the coupling between integrin-mediated adhesion and membrane protrusion, we have formulated a quantitative model of leading edge dynamics combining mechanistic and phenomenological elements and studied its features through classical bifurcation analysis and stochastic simulation. The model describes in mathematical terms the feedback loops driving, on the one hand, Rac-mediated membrane protrusion and rapid turnover of nascent adhesions, and on the other, myosin-dependent maturation of adhesions that inhibit protrusion at high ECM density. Our results show that the qualitative behavior of the model is most sensitive to parameters characterizing the influence of stable adhesions and myosin. The major predictions of the model, which we subsequently confirmed, are that persistent leading edge protrusion is optimal at an intermediate ECM density, whereas depletion of myosin IIA relieves the repression of protrusion at higher ECM density. PMID- 20195496 TI - Decoupling Environment-Dependent and Independent Genetic Robustness across Bacterial Species. AB - The evolutionary origins of genetic robustness are still under debate: it may arise as a consequence of requirements imposed by varying environmental conditions, due to intrinsic factors such as metabolic requirements, or directly due to an adaptive selection in favor of genes that allow a species to endure genetic perturbations. Stratifying the individual effects of each origin requires one to study the pertaining evolutionary forces across many species under diverse conditions. Here we conduct the first large-scale computational study charting the level of robustness of metabolic networks of hundreds of bacterial species across many simulated growth environments. We provide evidence that variations among species in their level of robustness reflect ecological adaptations. We decouple metabolic robustness into two components and quantify the extents of each: the first, environmental-dependent, is responsible for at least 20% of the non-essential reactions and its extent is associated with the species' lifestyle (specialized/generalist); the second, environmental-independent, is associated (correlation = approximately 0.6) with the intrinsic metabolic capacities of a species-higher robustness is observed in fast growers or in organisms with an extensive production of secondary metabolites. Finally, we identify reactions that are uniquely susceptible to perturbations in human pathogens, potentially serving as novel drug-targets. PMID- 20195495 TI - How to understand the cell by breaking it: network analysis of gene perturbation screens. PMID- 20195497 TI - Unfolding simulations reveal the mechanism of extreme unfolding cooperativity in the kinetically stable alpha-lytic protease. AB - Kinetically stable proteins, those whose stability is derived from their slow unfolding kinetics and not thermodynamics, are examples of evolution's best attempts at suppressing unfolding. Especially in highly proteolytic environments, both partially and fully unfolded proteins face potential inactivation through degradation and/or aggregation, hence, slowing unfolding can greatly extend a protein's functional lifetime. The prokaryotic serine protease alpha-lytic protease (alphaLP) has done just that, as its unfolding is both very slow (t(1/2) approximately 1 year) and so cooperative that partial unfolding is negligible, providing a functional advantage over its thermodynamically stable homologs, such as trypsin. Previous studies have identified regions of the domain interface as critical to alphaLP unfolding, though a complete description of the unfolding pathway is missing. In order to identify the alphaLP unfolding pathway and the mechanism for its extreme cooperativity, we performed high temperature molecular dynamics unfolding simulations of both alphaLP and trypsin. The simulated alphaLP unfolding pathway produces a robust transition state ensemble consistent with prior biochemical experiments and clearly shows that unfolding proceeds through a preferential disruption of the domain interface. Through a novel method of calculating unfolding cooperativity, we show that alphaLP unfolds extremely cooperatively while trypsin unfolds gradually. Finally, by examining the behavior of both domain interfaces, we propose a model for the differential unfolding cooperativity of alphaLP and trypsin involving three key regions that differ between the kinetically stable and thermodynamically stable classes of serine proteases. PMID- 20195498 TI - Temporal sensitivity of protein kinase a activation in late-phase long term potentiation. AB - Protein kinases play critical roles in learning and memory and in long term potentiation (LTP), a form of synaptic plasticity. The induction of late-phase LTP (L-LTP) in the CA1 region of the hippocampus requires several kinases, including CaMKII and PKA, which are activated by calcium-dependent signaling processes and other intracellular signaling pathways. The requirement for PKA is limited to L-LTP induced using spaced stimuli, but not massed stimuli. To investigate this temporal sensitivity of PKA, a computational biochemical model of L-LTP induction in CA1 pyramidal neurons was developed. The model describes the interactions of calcium and cAMP signaling pathways and is based on published biochemical measurements of two key synaptic signaling molecules, PKA and CaMKII. The model is stimulated using four 100 Hz tetani separated by 3 sec (massed) or 300 sec (spaced), identical to experimental L-LTP induction protocols. Simulations show that spaced stimulation activates more PKA than massed stimulation, and makes a key experimental prediction, that L-LTP is PKA-dependent for intervals larger than 60 sec. Experimental measurements of L-LTP demonstrate that intervals of 80 sec, but not 40 sec, produce PKA-dependent L-LTP, thereby confirming the model prediction. Examination of CaMKII reveals that its temporal sensitivity is opposite that of PKA, suggesting that PKA is required after spaced stimulation to compensate for a decrease in CaMKII. In addition to explaining the temporal sensitivity of PKA, these simulations suggest that the use of several kinases for memory storage allows each to respond optimally to different temporal patterns. PMID- 20195499 TI - A primer on metagenomics. AB - Metagenomics is a discipline that enables the genomic study of uncultured microorganisms. Faster, cheaper sequencing technologies and the ability to sequence uncultured microbes sampled directly from their habitats are expanding and transforming our view of the microbial world. Distilling meaningful information from the millions of new genomic sequences presents a serious challenge to bioinformaticians. In cultured microbes, the genomic data come from a single clone, making sequence assembly and annotation tractable. In metagenomics, the data come from heterogeneous microbial communities, sometimes containing more than 10,000 species, with the sequence data being noisy and partial. From sampling, to assembly, to gene calling and function prediction, bioinformatics faces new demands in interpreting voluminous, noisy, and often partial sequence data. Although metagenomics is a relative newcomer to science, the past few years have seen an explosion in computational methods applied to metagenomic-based research. It is therefore not within the scope of this article to provide an exhaustive review. Rather, we provide here a concise yet comprehensive introduction to the current computational requirements presented by metagenomics, and review the recent progress made. We also note whether there is software that implements any of the methods presented here, and briefly review its utility. Nevertheless, it would be useful if readers of this article would avail themselves of the comment section provided by this journal, and relate their own experiences. Finally, the last section of this article provides a few representative studies illustrating different facets of recent scientific discoveries made using metagenomics. PMID- 20195500 TI - Bacterial genes in the aphid genome: absence of functional gene transfer from Buchnera to its host. AB - Genome reduction is typical of obligate symbionts. In cellular organelles, this reduction partly reflects transfer of ancestral bacterial genes to the host genome, but little is known about gene transfer in other obligate symbioses. Aphids harbor anciently acquired obligate mutualists, Buchnera aphidicola (Gammaproteobacteria), which have highly reduced genomes (420-650 kb), raising the possibility of gene transfer from ancestral Buchnera to the aphid genome. In addition, aphids often harbor other bacteria that also are potential sources of transferred genes. Previous limited sampling of genes expressed in bacteriocytes, the specialized cells that harbor Buchnera, revealed that aphids acquired at least two genes from bacteria. The newly sequenced genome of the pea aphid, Acyrthosiphon pisum, presents the first opportunity for a complete inventory of genes transferred from bacteria to the host genome in the context of an ancient obligate symbiosis. Computational screening of the entire A. pisum genome, followed by phylogenetic and experimental analyses, provided strong support for the transfer of 12 genes or gene fragments from bacteria to the aphid genome: three LD-carboxypeptidases (LdcA1, LdcA2,psiLdcA), five rare lipoprotein As (RlpA1-5), N-acetylmuramoyl-L-alanine amidase (AmiD), 1,4-beta-N-acetylmuramidase (bLys), DNA polymerase III alpha chain (psiDnaE), and ATP synthase delta chain (psiAtpH). Buchnera was the apparent source of two highly truncated pseudogenes (psiDnaE and psiAtpH). Most other transferred genes were closely related to genes from relatives of Wolbachia (Alphaproteobacteria). At least eight of the transferred genes (LdcA1, AmiD, RlpA1-5, bLys) appear to be functional, and expression of seven (LdcA1, AmiD, RlpA1-5) are highly upregulated in bacteriocytes. The LdcAs and RlpAs appear to have been duplicated after transfer. Our results excluded the hypothesis that genome reduction in Buchnera has been accompanied by gene transfer to the host nuclear genome, but suggest that aphids utilize a set of duplicated genes acquired from other bacteria in the context of the Buchnera-aphid mutualism. PMID- 20195502 TI - Interpreting metabolomic profiles using unbiased pathway models. AB - Human disease is heterogeneous, with similar disease phenotypes resulting from distinct combinations of genetic and environmental factors. Small-molecule profiling can address disease heterogeneity by evaluating the underlying biologic state of individuals through non-invasive interrogation of plasma metabolite levels. We analyzed metabolite profiles from an oral glucose tolerance test (OGTT) in 50 individuals, 25 with normal (NGT) and 25 with impaired glucose tolerance (IGT). Our focus was to elucidate underlying biologic processes. Although we initially found little overlap between changed metabolites and preconceived definitions of metabolic pathways, the use of unbiased network approaches identified significant concerted changes. Specifically, we derived a metabolic network with edges drawn between reactant and product nodes in individual reactions and between all substrates of individual enzymes and transporters. We searched for "active modules"--regions of the metabolic network enriched for changes in metabolite levels. Active modules identified relationships among changed metabolites and highlighted the importance of specific solute carriers in metabolite profiles. Furthermore, hierarchical clustering and principal component analysis demonstrated that changed metabolites in OGTT naturally grouped according to the activities of the System A and L amino acid transporters, the osmolyte carrier SLC6A12, and the mitochondrial aspartate glutamate transporter SLC25A13. Comparison between NGT and IGT groups supported blunted glucose- and/or insulin-stimulated activities in the IGT group. Using unbiased pathway models, we offer evidence supporting the important role of solute carriers in the physiologic response to glucose challenge and conclude that carrier activities are reflected in individual metabolite profiles of perturbation experiments. Given the involvement of transporters in human disease, metabolite profiling may contribute to improved disease classification via the interrogation of specific transporter activities. PMID- 20195501 TI - Population genomics of parallel adaptation in threespine stickleback using sequenced RAD tags. AB - Next-generation sequencing technology provides novel opportunities for gathering genome-scale sequence data in natural populations, laying the empirical foundation for the evolving field of population genomics. Here we conducted a genome scan of nucleotide diversity and differentiation in natural populations of threespine stickleback (Gasterosteus aculeatus). We used Illumina-sequenced RAD tags to identify and type over 45,000 single nucleotide polymorphisms (SNPs) in each of 100 individuals from two oceanic and three freshwater populations. Overall estimates of genetic diversity and differentiation among populations confirm the biogeographic hypothesis that large panmictic oceanic populations have repeatedly given rise to phenotypically divergent freshwater populations. Genomic regions exhibiting signatures of both balancing and divergent selection were remarkably consistent across multiple, independently derived populations, indicating that replicate parallel phenotypic evolution in stickleback may be occurring through extensive, parallel genetic evolution at a genome-wide scale. Some of these genomic regions co-localize with previously identified QTL for stickleback phenotypic variation identified using laboratory mapping crosses. In addition, we have identified several novel regions showing parallel differentiation across independent populations. Annotation of these regions revealed numerous genes that are candidates for stickleback phenotypic evolution and will form the basis of future genetic analyses in this and other organisms. This study represents the first high-density SNP-based genome scan of genetic diversity and differentiation for populations of threespine stickleback in the wild. These data illustrate the complementary nature of laboratory crosses and population genomic scans by confirming the adaptive significance of previously identified genomic regions, elucidating the particular evolutionary and demographic history of such regions in natural populations, and identifying new genomic regions and candidate genes of evolutionary significance. PMID- 20195503 TI - Genome-wide mRNA expression correlates of viral control in CD4+ T-cells from HIV 1-infected individuals. AB - There is great interindividual variability in HIV-1 viral setpoint after seroconversion, some of which is known to be due to genetic differences among infected individuals. Here, our focus is on determining, genome-wide, the contribution of variable gene expression to viral control, and to relate it to genomic DNA polymorphism. RNA was extracted from purified CD4+ T-cells from 137 HIV-1 seroconverters, 16 elite controllers, and 3 healthy blood donors. Expression levels of more than 48,000 mRNA transcripts were assessed by the Human 6 v3 Expression BeadChips (Illumina). Genome-wide SNP data was generated from genomic DNA using the HumanHap550 Genotyping BeadChip (Illumina). We observed two distinct profiles with 260 genes differentially expressed depending on HIV-1 viral load. There was significant upregulation of expression of interferon stimulated genes with increasing viral load, including genes of the intrinsic antiretroviral defense. Upon successful antiretroviral treatment, the transcriptome profile of previously viremic individuals reverted to a pattern comparable to that of elite controllers and of uninfected individuals. Genome wide evaluation of cis-acting SNPs identified genetic variants modulating expression of 190 genes. Those were compared to the genes whose expression was found associated with viral load: expression of one interferon stimulated gene, OAS1, was found to be regulated by a SNP (rs3177979, p = 4.9E-12); however, we could not detect an independent association of the SNP with viral setpoint. Thus, this study represents an attempt to integrate genome-wide SNP signals with genome wide expression profiles in the search for biological correlates of HIV-1 control. It underscores the paradox of the association between increasing levels of viral load and greater expression of antiviral defense pathways. It also shows that elite controllers do not have a fully distinctive mRNA expression pattern in CD4+ T cells. Overall, changes in global RNA expression reflect responses to viral replication rather than a mechanism that might explain viral control. PMID- 20195504 TI - Mycobacterium tuberculosis peptides presented by HLA-E molecules are targets for human CD8 T-cells with cytotoxic as well as regulatory activity. AB - Tuberculosis (TB) is an escalating global health problem and improved vaccines against TB are urgently needed. HLA-E restricted responses may be of interest for vaccine development since HLA-E displays very limited polymorphism (only 2 coding variants exist), and is not down-regulated by HIV-infection. The peptides from Mycobacterium tuberculosis (Mtb) potentially presented by HLA-E molecules, however, are unknown. Here we describe human T-cell responses to Mtb-derived peptides containing predicted HLA-E binding motifs and binding-affinity for HLA E. We observed CD8(+) T-cell proliferation to the majority of the 69 peptides tested in Mtb responsive adults as well as in BCG-vaccinated infants. CD8(+) T cells were cytotoxic against target-cells transfected with HLA-E only in the presence of specific peptide. These T cells were also able to lyse M. bovis BCG infected, but not control monocytes, suggesting recognition of antigens during mycobacterial infection. In addition, peptide induced CD8(+) T-cells also displayed regulatory activity, since they inhibited T-cell proliferation. This regulatory activity was cell contact-dependent, and at least partly dependent on membrane-bound TGF-beta. Our results significantly increase our understanding of the human immune response to Mtb by identification of CD8(+) T-cell responses to novel HLA-E binding peptides of Mtb, which have cytotoxic as well as immunoregulatory activity. PMID- 20195505 TI - IL-1beta processing in host defense: beyond the inflammasomes. AB - Stimulation and release of proinflammatory cytokines is an essential step for the activation of an effective innate host defense, and subsequently for the modulation of adaptive immune responses. Interleukin-1beta (IL-1beta) and IL-18 are important proinflammatory cytokines that on the one hand activate monocytes, macropages, and neutrophils, and on the other hand induce Th1 and Th17 adaptive cellular responses. They are secreted as inactive precursors, and the processing of pro-IL-1beta and pro-IL-18 depends on cleavage by proteases. One of the most important of these enzymes is caspase-1, which in turn is activated by several protein platforms called the inflammasomes. Inflammasome activation differs in various cell types, and knock-out mice defective in either caspase-1 or inflammasome components have an increased susceptibility to several types of infections. However, in other infections and in models of sterile inflammation, caspase-1 seems to be less important, and alternative mechanisms such as neutrophil-derived serine proteases or proteases released from microbial pathogens can process and activate IL-1beta. In conclusion, IL-1beta/IL-18 processing during infection is a complex process in which the inflammasomes are only one of several activation mechanisms. PMID- 20195506 TI - Cdk2 is required for p53-independent G2/M checkpoint control. AB - The activation of phase-specific cyclin-dependent kinases (Cdks) is associated with ordered cell cycle transitions. Among the mammalian Cdks, only Cdk1 is essential for somatic cell proliferation. Cdk1 can apparently substitute for Cdk2, Cdk4, and Cdk6, which are individually dispensable in mice. It is unclear if all functions of non-essential Cdks are fully redundant with Cdk1. Using a genetic approach, we show that Cdk2, the S-phase Cdk, uniquely controls the G(2)/M checkpoint that prevents cells with damaged DNA from initiating mitosis. CDK2-nullizygous human cells exposed to ionizing radiation failed to exclude Cdk1 from the nucleus and exhibited a marked defect in G(2)/M arrest that was unmasked by the disruption of P53. The DNA replication licensing protein Cdc6, which is normally stabilized by Cdk2, was physically associated with the checkpoint regulator ATR and was required for efficient ATR-Chk1-Cdc25A signaling. These findings demonstrate that Cdk2 maintains a balance of S-phase regulatory proteins and thereby coordinates subsequent p53-independent G(2)/M checkpoint activation. PMID- 20195507 TI - Transit through the flea vector induces a pretransmission innate immunity resistance phenotype in Yersinia pestis. AB - Yersinia pestis, the agent of plague, is transmitted to mammals by infected fleas. Y. pestis exhibits a distinct life stage in the flea, where it grows in the form of a cohesive biofilm that promotes transmission. After transmission, the temperature shift to 37 degrees C induces many known virulence factors of Y. pestis that confer resistance to innate immunity. These factors are not produced in the low-temperature environment of the flea, however, suggesting that Y. pestis is vulnerable to the initial encounter with innate immune cells at the flea bite site. In this study, we used whole-genome microarrays to compare the Y. pestis in vivo transcriptome in infective fleas to in vitro transcriptomes in temperature-matched biofilm and planktonic cultures, and to the previously characterized in vivo gene expression profile in the rat bubo. In addition to genes involved in metabolic adaptation to the flea gut and biofilm formation, several genes with known or predicted roles in resistance to innate immunity and pathogenicity in the mammal were upregulated in the flea. Y. pestis from infected fleas were more resistant to phagocytosis by macrophages than in vitro-grown bacteria, in part attributable to a cluster of insecticidal-like toxin genes that were highly expressed only in the flea. Our results suggest that transit through the flea vector induces a phenotype that enhances survival and dissemination of Y. pestis after transmission to the mammalian host. PMID- 20195508 TI - The genetic interpretation of area under the ROC curve in genomic profiling. AB - Genome-wide association studies in human populations have facilitated the creation of genomic profiles which combine the effects of many associated genetic variants to predict risk of disease. The area under the receiver operator characteristic (ROC) curve is a well established measure for determining the efficacy of tests in correctly classifying diseased and non-diseased individuals. We use quantitative genetics theory to provide insight into the genetic interpretation of the area under the ROC curve (AUC) when the test classifier is a predictor of genetic risk. Even when the proportion of genetic variance explained by the test is 100%, there is a maximum value for AUC that depends on the genetic epidemiology of the disease, i.e. either the sibling recurrence risk or heritability and disease prevalence. We derive an equation relating maximum AUC to heritability and disease prevalence. The expression can be reversed to calculate the proportion of genetic variance explained given AUC, disease prevalence, and heritability. We use published estimates of disease prevalence and sibling recurrence risk for 17 complex genetic diseases to calculate the proportion of genetic variance that a test must explain to achieve AUC = 0.75; this varied from 0.10 to 0.74. We provide a genetic interpretation of AUC for use with predictors of genetic risk based on genomic profiles. We provide a strategy to estimate proportion of genetic variance explained on the liability scale from estimates of AUC, disease prevalence, and heritability (or sibling recurrence risk) available as an online calculator. PMID- 20195509 TI - A major role for the Plasmodium falciparum ApiAP2 protein PfSIP2 in chromosome end biology. AB - The heterochromatic environment and physical clustering of chromosome ends at the nuclear periphery provide a functional and structural framework for antigenic variation and evolution of subtelomeric virulence gene families in the malaria parasite Plasmodium falciparum. While recent studies assigned important roles for reversible histone modifications, silent information regulator 2 and heterochromatin protein 1 (PfHP1) in epigenetic control of variegated expression, factors involved in the recruitment and organization of subtelomeric heterochromatin remain unknown. Here, we describe the purification and characterization of PfSIP2, a member of the ApiAP2 family of putative transcription factors, as the unknown nuclear factor interacting specifically with cis-acting SPE2 motif arrays in subtelomeric domains. Interestingly, SPE2 is not bound by the full-length protein but rather by a 60kDa N-terminal domain, PfSIP2-N, which is released during schizogony. Our experimental re-definition of the SPE2/PfSIP2-N interaction highlights the strict requirement of both adjacent AP2 domains and a conserved bipartite SPE2 consensus motif for high-affinity binding. Genome-wide in silico mapping identified 777 putative binding sites, 94% of which cluster in heterochromatic domains upstream of subtelomeric var genes and in telomere-associated repeat elements. Immunofluorescence and chromatin immunoprecipitation (ChIP) assays revealed co-localization of PfSIP2-N with PfHP1 at chromosome ends. Genome-wide ChIP demonstrated the exclusive binding of PfSIP2 N to subtelomeric SPE2 landmarks in vivo but not to single chromosome-internal sites. Consistent with this specialized distribution pattern, PfSIP2-N over expression has no effect on global gene transcription. Hence, contrary to the previously proposed role for this factor in gene activation, our results provide strong evidence for the first time for the involvement of an ApiAP2 factor in heterochromatin formation and genome integrity. These findings are highly relevant for our understanding of chromosome end biology and variegated expression in P. falciparum and other eukaryotes, and for the future analysis of the role of ApiAP2-DNA interactions in parasite biology. PMID- 20195510 TI - Cheating by exploitation of developmental prestalk patterning in Dictyostelium discoideum. AB - The cooperative developmental system of the social amoeba Dictyostelium discoideum is susceptible to exploitation by cheaters-strains that make more than their fair share of spores in chimerae. Laboratory screens in Dictyostelium have shown that the genetic potential for facultative cheating is high, and field surveys have shown that cheaters are abundant in nature, but the cheating mechanisms are largely unknown. Here we describe cheater C (chtC), a strong facultative cheater mutant that cheats by affecting prestalk differentiation. The chtC gene is developmentally regulated and its mRNA becomes stalk-enriched at the end of development. chtC mutants are defective in maintaining the prestalk cell fate as some of their prestalk cells transdifferentiate into prespore cells, but that defect does not affect gross developmental morphology or sporulation efficiency. In chimerae between wild-type and chtC mutant cells, the wild-type cells preferentially give rise to prestalk cells, and the chtC mutants increase their representation in the spore mass. Mixing chtC mutants with other cell-type proportioning mutants revealed that the cheating is directly related to the prestalk-differentiation propensity of the victim. These findings illustrate that a cheater can victimize cooperative strains by exploiting an established developmental pathway. PMID- 20195511 TI - Ku regulates the non-homologous end joining pathway choice of DNA double-strand break repair in human somatic cells. AB - The repair of DNA double-strand breaks (DSBs) is critical for the maintenance of genomic integrity and viability for all organisms. Mammals have evolved at least two genetically discrete ways to mediate DNA DSB repair: homologous recombination (HR) and non-homologous end joining (NHEJ). In mammalian cells, most DSBs are preferentially repaired by NHEJ. Recent work has demonstrated that NHEJ consists of at least two sub-pathways-the main Ku heterodimer-dependent or "classic" NHEJ (C-NHEJ) pathway and an "alternative" NHEJ (A-NHEJ) pathway, which usually generates microhomology-mediated signatures at repair junctions. In our study, recombinant adeno-associated virus knockout vectors were utilized to construct a series of isogenic human somatic cell lines deficient in the core C-NHEJ factors (Ku, DNA-PK(cs), XLF, and LIGIV), and the resulting cell lines were characterized for their ability to carry out DNA DSB repair. The absence of DNA-PK(cs), XLF, or LIGIV resulted in cell lines that were profoundly impaired in DNA DSB repair activity. Unexpectedly, Ku86-null cells showed wild-type levels of DNA DSB repair activity that was dominated by microhomology joining events indicative of A-NHEJ. Importantly, A-NHEJ DNA DSB repair activity could also be efficiently de repressed in LIGIV-null and DNA-PK(cs)-null cells by subsequently reducing the level of Ku70. These studies demonstrate that in human cells C-NHEJ is the major DNA DSB repair pathway and they show that Ku is the critical C-NHEJ factor that regulates DNA NHEJ DSB pathway choice. PMID- 20195512 TI - Molecular evolution and functional characterization of Drosophila insulin-like peptides. AB - Multicellular animals match costly activities, such as growth and reproduction, to the environment through nutrient-sensing pathways. The insulin/IGF signaling (IIS) pathway plays key roles in growth, metabolism, stress resistance, reproduction, and longevity in diverse organisms including mammals. Invertebrate genomes often contain multiple genes encoding insulin-like ligands, including seven Drosophila insulin-like peptides (DILPs). We investigated the evolution, diversification, redundancy, and functions of the DILPs, combining evolutionary analysis, based on the completed genome sequences of 12 Drosophila species, and functional analysis, based on newly-generated knock-out mutations for all 7 dilp genes in D. melanogaster. Diversification of the 7 DILPs preceded diversification of Drosophila species, with stable gene diversification and family membership, suggesting stabilising selection for gene function. Gene knock-outs demonstrated both synergy and compensation of expression between different DILPs, notably with DILP3 required for normal expression of DILPs 2 and 5 in brain neurosecretory cells and expression of DILP6 in the fat body compensating for loss of brain DILPs. Loss of DILP2 increased lifespan and loss of DILP6 reduced growth, while loss of DILP7 did not affect fertility, contrary to its proposed role as a Drosophila relaxin. Importantly, loss of DILPs produced in the brain greatly extended lifespan but only in the presence of the endosymbiontic bacterium Wolbachia, demonstrating a specific interaction between IIS and Wolbachia in lifespan regulation. Furthermore, loss of brain DILPs blocked the responses of lifespan and fecundity to dietary restriction (DR) and the DR response of these mutants suggests that IIS extends lifespan through mechanisms that both overlap with those of DR and through additional mechanisms that are independent of those at work in DR. Evolutionary conservation has thus been accompanied by synergy, redundancy, and functional differentiation between DILPs, and these features may themselves be of evolutionary advantage. PMID- 20195513 TI - Cdk1 targets Srs2 to complete synthesis-dependent strand annealing and to promote recombinational repair. AB - Cdk1 kinase phosphorylates budding yeast Srs2, a member of UvrD protein family, displays both DNA translocation and DNA unwinding activities in vitro. Srs2 prevents homologous recombination by dismantling Rad51 filaments and is also required for double-strand break (DSB) repair. Here we examine the biological significance of Cdk1-dependent phosphorylation of Srs2, using mutants that constitutively express the phosphorylated or unphosphorylated protein isoforms. We found that Cdk1 targets Srs2 to repair DSB and, in particular, to complete synthesis-dependent strand annealing, likely controlling the disassembly of a D loop intermediate. Cdk1-dependent phosphorylation controls turnover of Srs2 at the invading strand; and, in absence of this modification, the turnover of Rad51 is not affected. Further analysis of the recombination phenotypes of the srs2 phospho-mutants showed that Srs2 phosphorylation is not required for the removal of toxic Rad51 nucleofilaments, although it is essential for cell survival, when DNA breaks are channeled into homologous recombinational repair. Cdk1-targeted Srs2 displays a PCNA-independent role and appears to have an attenuated ability to inhibit recombination. Finally, the recombination defects of unphosphorylatable Srs2 are primarily due to unscheduled accumulation of the Srs2 protein in a sumoylated form. Thus, the Srs2 anti-recombination function in removing toxic Rad51 filaments is genetically separable from its role in promoting recombinational repair, which depends exclusively on Cdk1-dependent phosphorylation. We suggest that Cdk1 kinase counteracts unscheduled sumoylation of Srs2 and targets Srs2 to dismantle specific DNA structures, such as the D loops, in a helicase-dependent manner during homologous recombinational repair. PMID- 20195514 TI - Genome-wide association study reveals multiple loci associated with primary tooth development during infancy. AB - Tooth development is a highly heritable process which relates to other growth and developmental processes, and which interacts with the development of the entire craniofacial complex. Abnormalities of tooth development are common, with tooth agenesis being the most common developmental anomaly in humans. We performed a genome-wide association study of time to first tooth eruption and number of teeth at one year in 4,564 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966) and 1,518 individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC). We identified 5 loci at P<5x10(-8), and 5 with suggestive association (P<5x10(-6)). The loci included several genes with links to tooth and other organ development (KCNJ2, EDA, HOXB2, RAD51L1, IGF2BP1, HMGA2, MSRB3). Genes at four of the identified loci are implicated in the development of cancer. A variant within the HOXB gene cluster associated with occlusion defects requiring orthodontic treatment by age 31 years. PMID- 20195516 TI - Allelic exchange of pheromones and their receptors reprograms sexual identity in Cryptococcus neoformans. AB - Cell type specification is a fundamental process that all cells must carry out to ensure appropriate behaviors in response to environmental stimuli. In fungi, cell identity is critical for defining "sexes" known as mating types and is controlled by components of mating type (MAT) loci. MAT-encoded genes function to define sexes via two distinct paradigms: 1) by controlling transcription of components common to both sexes, or 2) by expressing specially encoded factors (pheromones and their receptors) that differ between mating types. The human fungal pathogen Cryptococcus neoformans has two mating types (a and alpha) that are specified by an extremely unusual MAT locus. The complex architecture of this locus makes it impossible to predict which paradigm governs mating type. To identify the mechanism by which the C. neoformans sexes are determined, we created strains in which the pheromone and pheromone receptor from one mating type (a) replaced the pheromone and pheromone receptor of the other (alpha). We discovered that these "alpha(a)" cells effectively adopt a new mating type (that of a cells); they sense and respond to alpha factor, they elicit a mating response from alpha cells, and they fuse with alpha cells. In addition, alpha(a) cells lose the alpha cell type-specific response to pheromone and do not form germ tubes, instead remaining spherical like a cells. Finally, we discovered that exogenous expression of the diploid/dikaryon-specific transcription factor Sxi2a could then promote complete sexual development in crosses between alpha and alpha(a) strains. These data reveal that cell identity in C. neoformans is controlled fully by three kinds of MAT-encoded proteins: pheromones, pheromone receptors, and homeodomain proteins. Our findings establish the mechanisms for maintenance of distinct cell types and subsequent developmental behaviors in this unusual human fungal pathogen. PMID- 20195517 TI - Nucleoporins and transcription: new connections, new questions. PMID- 20195515 TI - Structure, function, and evolution of the Thiomonas spp. genome. AB - Bacteria of the Thiomonas genus are ubiquitous in extreme environments, such as arsenic-rich acid mine drainage (AMD). The genome of one of these strains, Thiomonas sp. 3As, was sequenced, annotated, and examined, revealing specific adaptations allowing this bacterium to survive and grow in its highly toxic environment. In order to explore genomic diversity as well as genetic evolution in Thiomonas spp., a comparative genomic hybridization (CGH) approach was used on eight different strains of the Thiomonas genus, including five strains of the same species. Our results suggest that the Thiomonas genome has evolved through the gain or loss of genomic islands and that this evolution is influenced by the specific environmental conditions in which the strains live. PMID- 20195518 TI - HIV controller CD4+ T cells respond to minimal amounts of Gag antigen due to high TCR avidity. AB - HIV controllers are rare individuals who spontaneously control HIV replication in the absence of antiretroviral treatment. Emerging evidence indicates that HIV control is mediated through very active cellular immune responses, though how such responses can persist over time without immune exhaustion is not yet understood. To investigate the nature of memory CD4+ T cells responsible for long term anti-HIV responses, we characterized the growth kinetics, Vbeta repertoire, and avidity for antigen of patient-derived primary CD4+ T cell lines. Specific cell lines were obtained at a high rate for both HIV controllers (16/17) and efficiently treated patients (19/20) in response to the immunodominant Gag293 peptide. However, lines from controllers showed faster growth kinetics than those of treated patients. After normalizing for growth rates, IFN-gamma responses directed against the immunodominant Gag293 peptide showed higher functional avidity in HIV controllers, indicating differentiation into highly efficient effector cells. In contrast, responses to Gag161, Gag263, or CMV peptides did not differ between groups. Gag293-specific CD4+ T cells were characterized by a diverse Vbeta repertoire, suggesting that multiple clones contributed to the high avidity CD4+ T cell population in controllers. The high functional avidity of the Gag293-specific response could be explained by a high avidity interaction between the TCR and the peptide-MHC complex, as demonstrated by MHC class II tetramer binding. Thus, HIV controllers harbor a pool of memory CD4+ T cells with the intrinsic ability to recognize minimal amounts of Gag antigen, which may explain how they maintain an active antiviral response in the face of very low viremia. PMID- 20195519 TI - Caspase-1 activation via Rho GTPases: a common theme in mucosal infections? PMID- 20195520 TI - Broadly protective monoclonal antibodies against H3 influenza viruses following sequential immunization with different hemagglutinins. AB - As targets of adaptive immunity, influenza viruses are characterized by the fluidity with which they respond to the selective pressure applied by neutralizing antibodies. This mutability of structural determinants of protective immunity is the obstacle in developing universal influenza vaccines. Towards the development of such vaccines and other immune therapies, our studies are designed to identify regions of influenza viruses that are conserved and that mediate virus neutralization. We have specifically focused on viruses of the H3N2 subtype, which have persisted as a principal source of influenza-related morbidity and mortality in humans since the pandemic of 1968. Three monoclonal antibodies have been identified that are broadly-neutralizing against H3 influenza viruses spanning 40 years. The antibodies react with the hemagglutinin glycoprotein and appear to bind in regions that are refractory to the structural variation required for viral escape from neutralization. The antibodies demonstrate therapeutic efficacy in mice against H3N2 virus infection and have potential for use in the treatment of human influenza disease. By mapping the binding region of one antibody, 12D1, we have identified a continuous region of the hemagglutinin that may act as an immunogen to elicit broadly protective immunity to H3 viruses. The anti-H3 monoclonal antibodies were identified after immunization of mice with the hemagglutinin of four different viruses (A/Hong Kong/1/1968, A/Alabama/1/1981, A/Beijing/47/1992, A/Wyoming/3/2003). This immunization schedule was designed to boost B cells specific for conserved regions of the hemagglutinin from distinct antigenic clusters. Importantly, our antibodies are of naturally occurring specificity rather than selected from cloned libraries, demonstrating that broad-spectrum humoral immunity to influenza viruses can be elicited in vivo. PMID- 20195521 TI - Vaccinia protein F12 has structural similarity to kinesin light chain and contains a motor binding motif required for virion export. AB - Vaccinia virus (VACV) uses microtubules for export of virions to the cell surface and this process requires the viral protein F12. Here we show that F12 has structural similarity to kinesin light chain (KLC), a subunit of the kinesin-1 motor that binds cargo. F12 and KLC share similar size, pI, hydropathy and cargo binding tetratricopeptide repeats (TPRs). Moreover, molecular modeling of F12 TPRs upon the crystal structure of KLC2 TPRs showed a striking conservation of structure. We also identified multiple TPRs in VACV proteins E2 and A36. Data presented demonstrate that F12 is critical for recruitment of kinesin-1 to virions and that a conserved tryptophan and aspartic acid (WD) motif, which is conserved in the kinesin-1-binding sequence (KBS) of the neuronal protein calsyntenin/alcadein and several other cellular kinesin-1 binding proteins, is essential for kinesin-1 recruitment and virion transport. In contrast, mutation of WD motifs in protein A36 revealed they were not required for kinesin-1 recruitment or IEV transport. This report of a viral KLC-like protein containing a KBS that is conserved in several cellular proteins advances our understanding of how VACV recruits the kinesin motor to virions, and exemplifies how viruses use molecular mimicry of cellular components to their advantage. PMID- 20195522 TI - CRY2 is associated with depression. AB - BACKGROUND: Abnormalities in the circadian clockwork often characterize patients with major depressive and bipolar disorders. Circadian clock genes are targets of interest in these patients. CRY2 is a circadian gene that participates in regulation of the evening oscillator. This is of interest in mood disorders where a lack of switch from evening to morning oscillators has been postulated. PRINCIPAL FINDINGS: We observed a marked diurnal variation in human CRY2 mRNA levels from peripheral blood mononuclear cells and a significant up-regulation (P = 0.020) following one-night total sleep deprivation, a known antidepressant. In depressed bipolar patients, levels of CRY2 mRNA were decreased (P = 0.029) and a complete lack of increase was observed following sleep deprivation. To investigate a possible genetic contribution, we undertook SNP genotyping of the CRY2 gene in two independent population-based samples from Sweden (118 cases and 1011 controls) and Finland (86 cases and 1096 controls). The CRY2 gene was significantly associated with winter depression in both samples (haplotype analysis in Swedish and Finnish samples: OR = 1.8, P = 0.0059 and OR = 1.8, P = 0.00044, respectively). CONCLUSIONS: We propose that a CRY2 locus is associated with vulnerability for depression, and that mechanisms of action involve dysregulation of CRY2 expression. PMID- 20195523 TI - In vivo detection of extrapancreatic insulin gene expression in diabetic mice by bioluminescence imaging. AB - BACKGROUND: Extrapancreatic tissues such as liver may serve as potential sources of tissue for generating insulin-producing cells. The dynamics of insulin gene promoter activity in extrapancreatic tissues may be monitored in vivo by bioluminescence-imaging (BLI) of transgenic mice Tg(RIP-luc) expressing the firefly luciferase (luc) under a rat-insulin gene promoter (RIP). METHODS: The Tg(RIP-luc) mice were made diabetic by a single injection of the pancreatic beta cell toxin streptozotocin. Control mice were treated with saline. Mice were subject to serum glucose measurement and bioluminescence imaging daily. On day eight of the treatment, mice were sacrificed and tissues harvested for quantitative luciferase activity measurement, luciferase protein cellular localization, and insulin gene expression analysis. RESULTS: Streptozotocin induced diabetic Tg(RIP-luc) mice demonstrated a dramatic decline in the BLI signal intensity in the pancreas and a concomitant progressive increase in the signal intensity in the liver. An average of 5.7 fold increase in the liver signal intensity was detected in the mice that were exposed to hyperglycemia for 8 days. Ex vivo quantitative assays demonstrated a 34-fold induction of the enzyme activity in the liver of streptozotocin-treated mice compared to that of the buffer-treated controls. Luciferase-positive cells with oval-cell-like morphology were detected by immunohistochemistry in the liver samples of diabetic mice, but not in that of non-treated control transgenic mice. Gene expression analyses of liver RNA confirmed an elevated expression of insulin genes in the liver tissue exposed to hyperglycemia. CONCLUSIONS: BLI is a sensitive method for monitoring insulin gene expression in extrapancreatic tissues in vivo. The BLI system may be used for in vivo screening of biological events or pharmacologic activators that have the potential of stimulating the generation of extrapancreatic insulin-producing cells. PMID- 20195524 TI - Salt stress causes peroxisome proliferation, but inducing peroxisome proliferation does not improve NaCl tolerance in Arabidopsis thaliana. AB - The PEX11 family of peroxisome membrane proteins have been shown to be involved in regulation of peroxisome size and number in plant, animals, and yeast cells. We and others have previously suggested that peroxisome proliferation as a result of abiotic stress may be important in plant stress responses, and recently it was reported that several rice PEX11 genes were up regulated in response to abiotic stress. We sought to test the hypothesis that promoting peroxisome proliferation in Arabidopsis thaliana by over expression of one PEX11 family member, PEX11e, would give increased resistance to salt stress. We could demonstrate up regulation of PEX11e by salt stress and increased peroxisome number by both PEX11e over expression and salt stress, however our experiments failed to find a correlation between PEX11e over expression and increased peroxisome metabolic activity or resistance to salt stress. This suggests that although peroxisome proliferation may be a consequence of salt stress, it does not affect the ability of Arabidopsis plants to tolerate saline conditions. PMID- 20195525 TI - Alpha1A-adrenergic receptor-directed autoimmunity induces left ventricular damage and diastolic dysfunction in rats. AB - BACKGROUND: Agonistic autoantibodies to the alpha(1)-adrenergic receptor occur in nearly half of patients with refractory hypertension; however, their relevance is uncertain. METHODS/PRINCIPAL FINDINGS: We immunized Lewis rats with the second extracellular-loop peptides of the human alpha(1A)-adrenergic receptor and maintained them for one year. Alpha(1A)-adrenergic antibodies (alpha(1A)-AR-AB) were monitored with a neonatal cardiomyocyte contraction assay by ELISA, and by ERK1/2 phosphorylation in human alpha(1A)-adrenergic receptor transfected Chinese hamster ovary cells. The rats were followed with radiotelemetric blood pressure measurements and echocardiography. At 12 months, the left ventricles of immunized rats had greater wall thickness than control rats. The fractional shortening and dp/dt(max) demonstrated preserved systolic function. A decreased E/A ratio in immunized rats indicated a diastolic dysfunction. Invasive hemodynamics revealed increased left ventricular end-diastolic pressures and decreased dp/dt(min). Mean diameter of cardiomyocytes showed hypertrophy in immunized rats. Long-term blood pressure values and heart rates were not different. Genes encoding sarcomeric proteins, collagens, extracellular matrix proteins, calcium regulating proteins, and proteins of energy metabolism in immunized rat hearts were upregulated, compared to controls. Furthermore, fibrosis was present in immunized hearts, but not in control hearts. A subset of immunized and control rats was infused with angiotensin (Ang) II. The stressor raised blood pressure to a greater degree and led to more cardiac fibrosis in immunized, than in control rats. CONCLUSIONS/SIGNIFICANCE: We show that alpha(1A)-AR-AB cause diastolic dysfunction independent of hypertension, and can increase the sensitivity to Ang II. We suggest that alpha(1A)-AR-AB could contribute to cardiovascular endorgan damage. PMID- 20195526 TI - Roles of db-cAMP, IBMX and RA in aspects of neural differentiation of cord blood derived mesenchymal-like stem cells. AB - Mesenchymal stem cells (MSCs) have multilineage differentiation potential which includes cell lineages of the central nervous system; hence MSCs might be useful in the treatment of neurodegenerative diseases such as Parkinson's disease. Although mesenchymal stem cells have been shown to differentiate into the neural lineage, there is still little knowledge about the underlying mechanisms of differentiation particularly towards specialized neurons such as dopaminergic neurons. Here, we show that MSCs derived from human umbilical cord blood (MSC(hUCBs)) are capable of expressing tyrosine hydroxylase (TH) and Nurr1, markers typically associated with DA neurons. We also found differential phosphorylation of TH isoforms indicating the presence of post-translational mechanisms possibly activating and modifying TH in MSC(hUCB). Furthermore, functional dissection of components in the differentiation medium revealed that dibutyryl-cAMP (db-cAMP), 3-isobutyl-1-methylxanthine (IBMX) and retinoic acid (RA) are involved in the regulation of Nurr1 and Neurofilament-L expression as well as in the differential phosphorylation of TH. We also demonstrate a possible inhibitory role of the protein kinase A signaling pathway in the phosphorylation of specific TH isoforms. PMID- 20195527 TI - Hotspots of large rare deletions in the human genome. AB - BACKGROUND: We have examined the genomic distribution of large rare autosomal deletions in a sample of 440 parent-parent-child trios from the Quebec founder population (QFP) which was recruited for a study of Attention Deficit Hyperactivity Disorder. METHODOLOGY/PRINCIPAL FINDINGS: DNA isolated from blood was genotyped on Illumina Hap300 arrays. PennCNV combined with visual evaluation of images generated by the Beadstudio program was used to determine deletion boundary definition of sufficient precision to discern independent events, with near-perfect concordance between parent and child in about 98% of the 399 events detected in the offspring; the remaining 7 deletions were considered de novo. We defined several genomic regions of very high deletion frequency ('hotspots'), usually of 0.4-0.6 Mb in length where independent rare deletions were found at frequencies of up to 100 fold higher than the average for the genome as a whole. Five of the 7 de novo deletions were in these hotspots. The same hotspots were also observed in three other studies on members of the QFP, those with schizophrenia, with endometriosis and those from a longevity cohort. CONCLUSIONS/SIGNIFICANCE: Nine of the 13 hotspots carry one gene (7 of which are very long), while the rest contain no known genes. All nine genes have been implicated in disease. The patterns of exon deletions support the proposed roles for some of these genes in human disease, such as NRXN1 and PARKIN, and suggest limited roles or no role at all, for others, including MACROD2 and CTNNA3. Our results also offer an alternative interpretation for the observations of deletions in tumors which have been proposed as reflecting tumor-suppressive activity of genes in these hotspots. PMID- 20195528 TI - The influence of IS1301 in the capsule biosynthesis locus on meningococcal carriage and disease. AB - Previously we have shown that insertion of IS1301 in the sia/ctr intergenic region (IGR) of serogroup C Neisseria meningitidis (MenC) isolates from Spain confers increased resistance against complement-mediated killing. Here we investigate the significance of IS1301 in the same location in N. meningitidis isolates from the UK. PCR and sequencing was used to screen a collection of more than 1500 meningococcal carriage and disease isolates from the UK for the presence of IS1301 in the IGR. IS1301 was not identified in the IGR among vaccine failure strains but was frequently found in serogroup B isolates (MenB) from clonal complex 269 (cc269). Almost all IS1301 insertions in cc269 were associated with novel polymorphisms, and did not change capsule expression or resistance to human complement. After excluding sequence types (STs) distant from the central genotype within cc269, there was no significant difference for the presence of IS1301 in the IGR of carriage isolates compared to disease isolates. Isolates with insertion of IS1301 in the IGR are not responsible for MenC disease in UK vaccine failures. Novel polymorphisms associated with IS1301 in the IGR of UK MenB isolates do not lead to the resistance phenotype seen for IS1301 in the IGR of MenC isolates. PMID- 20195529 TI - Involvement of transcription factor NR2F2 in human trophoblast differentiation. AB - BACKGROUND: During the in vitro differentiation of human villous cytotrophoblast (CTB) cells to a syncytiotrophoblast (STB) phenotype, mRNA levels for the nuclear hormone receptor NR2F2 (ARP-1, COUP-TFII) increase rapidly, reaching a peak at day 1 of differentiation that is 8.8-fold greater than that in undifferentiated CTB cells. To examine whether NR2F2 is involved in the regulation of villous CTB cell differentiation, studies were performed to determine whether NR2F2 regulates the expression of TFAP2A (AP-2alpha), a transcription factor that is critical for the terminal differentiation of these cells to a STB phenotype. METHODOLOGY/PRIMARY FINDINGS: Overexpression of NR2F2 in primary cultures of human CTB cells and JEG-3 human choriocarcinoma cells induced dose-dependent increases in TFAP2A promoter activity. Conversely, siRNA mediated silencing of the NR2F2 gene in villous CTB undergoing spontaneous differentiation blocked the induction of the mRNAs for TFAP2A and several STB cell specific marker genes, including human placental lactogen (hPL), pregnancy specific glycoprotein 1 (PSG1) and corticotropin releasing hormone (CRH) by 51-59%. The induction of TFAP2A promoter activity by NR2F2 was potentiated by the nuclear hormone receptors retinoic acid receptor alpha (RARA) and retinoid X receptor alpha (RXRA). CONCLUSIONS/SIGNIFICANCE: Taken together, these results strongly suggest that NR2F2 is involved in villous CTB cell differentiation and that NR2F2 acts, at least in part, by directly activating TFAP2A gene expression and by potentiating the transactivation of TFAP2A by RARA and RXRA. PMID- 20195530 TI - Protein aggregation profile of the bacterial cytosol. AB - BACKGROUND: Protein misfolding is usually deleterious for the cell, either as a consequence of the loss of protein function or the buildup of insoluble and toxic aggregates. The aggregation behavior of a given polypeptide is strongly influenced by the intrinsic properties encoded in its sequence. This has allowed the development of effective computational methods to predict protein aggregation propensity. METHODOLOGY/PRINCIPAL FINDINGS: Here, we use the AGGRESCAN algorithm to approximate the aggregation profile of an experimental cytosolic Escherichia coli proteome. The analysis indicates that the aggregation propensity of bacterial proteins is associated with their length, conformation, location, function, and abundance. The data are consistent with the predictions of other algorithms on different theoretical proteomes. CONCLUSIONS/SIGNIFICANCE: Overall, the study suggests that the avoidance of protein aggregation in functional environments acts as a strong evolutionary constraint on polypeptide sequences in both prokaryotic and eukaryotic organisms. PMID- 20195531 TI - Geographic structuring of the Plasmodium falciparum sarco(endo)plasmic reticulum Ca2+ ATPase (PfSERCA) gene diversity. AB - Artemisinin, a thapsigargin-like sesquiterpene has been shown to inhibit the Plasmodium falciparum sarco/endoplasmic reticulum calcium-ATPase PfSERCA. To collect baseline pfserca sequence information before field deployment of Artemisinin-based Combination therapies that may select mutant parasites, we conducted a sequence analysis of 100 isolates from multiple sites in Africa, Asia and South America. Coding sequence diversity was large, with 29 mutated codons, including 32 SNPs (average of one SNP/115 bp), of which 19 were novel mutations. Most SNP detected in this study were clustered within a region in the cytosolic head of the protein. The PfSERCA functional domains were very well conserved, with non synonymous mutations located outside the functional domains, except for the S769N mutation associated in French Guiana with elevated IC(50) for artemether. The S769N mutation is located close to the hinge of the headpiece, which in other species modulates calcium affinity and in consequence efficacy of inhibitors, possibly linking calcium homeostasis to drug resistance. Genetic diversity was highest in Senegal, Brazil and French Guiana, and few mutations were identified in Asia. Population genetic analysis was conducted for a partial fragment of the gene encompassing nucleotide coordinates 87-2862 (unambiguous sequence available for 96 isolates). This supported a geographic clustering, with a separation between Old and New World samples and one dominant ancestral haplotype. Genetic drift alone cannot explain the observed polymorphism, suggesting that other evolutionary mechanisms are operating. One possible contributor could be the frequency of haemoglobinopathies that are associated with calcium dysregulation in the erythrocyte. PMID- 20195532 TI - Blockade of T cell contact-activation of human monocytes by high-density lipoproteins reveals a new pattern of cytokine and inflammatory genes. AB - BACKGROUND: Cellular contact with stimulated T cells is a potent inducer of cytokine production in human monocytes and is likely to play a substantial part in chronic/sterile inflammatory diseases. High-density lipoproteins (HDL) specifically inhibit the production of pro-inflammatory cytokines induced by T cell contact. METHODOLOGY/PRINCIPAL FINDINGS: To further elucidate the pro inflammatory functions of cellular contact with stimulated T cells and its inhibition by HDL, we carried out multiplex and microarray analyses. Multiplex analysis of monocyte supernatant revealed that 12 out of 27 cytokines were induced upon contact with stimulated T cells, which cytokines included IL-1Ra, G CSF, GM-CSF, IFNgamma, CCL2, CCL5, TNF, IL-1beta, IL-6, IL-8, CCL3, and CCL4, but only the latter six were inhibited by HDL. Microarray analysis showed that 437 out of 54,675 probe sets were enhanced in monocytes activated by contact with stimulated T cells, 164 probe sets (i.e., 38%) being inhibited by HDL. These results were validated by qPCR. Interestingly, the cytokines induced by T cell contact in monocytes comprised IL-1beta, IL-6 but not IL-12, suggesting that this mechanism might favor Th17 polarization, which emphasizes the relevance of this mechanism to chronic inflammatory diseases and highlights the contrast with acute inflammatory conditions that usually involve lipopolysaccharides (LPS). In addition, the expression of miR-155 and production of prostaglandin E(2)-both involved in inflammatory response-were triggered by T cell contact and inhibited in the presence of HDL. CONCLUSIONS/SIGNIFICANCE: These results leave no doubt as to the pro-inflammatory nature of T cell contact-activation of human monocytes and the anti-inflammatory functions of HDL. PMID- 20195533 TI - SPARC deficiency results in improved surgical survival in a novel mouse model of glaucoma filtration surgery. AB - Glaucoma is a disease frequently associated with elevated intraocular pressure that can be alleviated by filtration surgery. However, the post-operative subconjunctival scarring response which blocks filtration efficiency is a major hurdle to the achievement of long-term surgical success. Current application of anti-proliferatives to modulate the scarring response is not ideal as these often give rise to sight-threatening complications. SPARC (secreted protein, acidic and rich in cysteine) is a matricellular protein involved in extracellular matrix (ECM) production and organization. In this study, we investigated post-operative surgical wound survival in an experimental glaucoma filtration model in SPARC null mice. Loss of SPARC resulted in a marked (87.5%) surgical wound survival rate compared to 0% in wild-type (WT) counterparts. The larger SPARC-null wounds implied that aqueous filtration through the subconjunctival space was more efficient in comparison to WT wounds. The pronounced increase in both surgical survival and filtration efficiency was associated with a less collagenous ECM, smaller collagen fibril diameter, and a loosely-organized subconjunctival matrix in the SPARC-null wounds. In contrast, WT wounds exhibited a densely packed collagenous ECM with no evidence of filtration capacity. Immunolocalization assays confirmed the accumulation of ECM proteins in the WT but not in the SPARC null wounds. The observations in vivo were corroborated by complementary data performed on WT and SPARC-null conjunctival fibroblasts in vitro. These findings indicate that depletion of SPARC bestows an inherent change in post-operative ECM remodeling to favor wound maintenance. The evidence presented in this report is strongly supportive for the targeting of SPARC to increase the success of glaucoma filtration surgery. PMID- 20195534 TI - IKKalpha and IKKbeta each function to regulate NF-kappaB activation in the TNF induced/canonical pathway. AB - BACKGROUND: Activation of the transcription factor NF-kappaB by cytokines is rapid, mediated through the activation of the IKK complex with subsequent phosphorylation and degradation of the inhibitory IkappaB proteins. The IKK complex is comprised of two catalytic subunits, IKKalpha and IKKbeta, and a regulatory protein known as NEMO. Using cells from mice that are genetically deficient in IKKbeta or IKKalpha, or using a kinase inactive mutant of IKKbeta, it has been proposed that IKKbeta is critical for TNF-induced IkappaB phosphorylation/degradation through the canonical pathway while IKKalpha has been shown to be involved in the non-canonical pathway for NF-kappaB activation. These conclusions have led to a focus on development of IKKbeta inhibitors for potential use in inflammatory disorders and cancer. METHODOLOGY: Analysis of NF kappaB activation in response to TNF in MEFs reveals that IKKbeta is essential for efficient phosphorylation and subsequent degradation of IkappaB alpha, yet IKKalpha contributes to the NF-kappaB activation response in these cells as measured via DNA binding assays. In HeLa cells, both IKKalpha and IKKbeta contribute to IkappaB alpha phosphorylation and NF-kappaB activation. A kinase inactive mutant of IKKbeta, which has been used as evidence for the critical importance of IKKbeta in TNF-induced signaling, blocks activation of NF-kappaB induced by IKKalpha, even in cells that are deficient in IKKbeta. CONCLUSIONS: These results demonstrate the importance of IKKalpha in canonical NF-kappaB activation, downstream of cytokine treatment of cells. The experiments suggest that IKKalpha will be a therapeutic target in inflammatory disorders. PMID- 20195535 TI - Estrogen receptor hormone agonists limit trauma hemorrhage shock-induced gut and lung injury in rats. AB - BACKGROUND: Acute lung injury (ALI) and the development of the multiple organ dysfunction syndrome (MODS) is a major cause of death in trauma patients. Earlier studies in trauma hemorrhagic shock (T/HS) have documented that splanchnic ischemia leading to gut inflammation and loss of barrier function is an initial triggering event that leads to gut-induced ARDS and MODS. Since sex hormones have been shown to modulate the response to T/HS and proestrous (PE) females are more resistant to T/HS-induced gut and distant organ injury, the goal of our study was to determine the contribution of estrogen receptor (ER)alpha and ERbeta in modulating the protective response of female rats to T/HS-induced gut and lung injury. METHODS/PRINCIPAL FINDINGS: The incidence of gut and lung injury was assessed in PE and ovariectomized (OVX) female rats subjected to T/HS or trauma sham shock (T/SS) as well as OVX rats that were administered estradiol (E2) or agonists for ERalpha or ERbeta immediately prior to resuscitation. Marked gut and lung injury was observed in OVX rats subjected to T/HS as compared to PE rats or E2-treated OVX rats subjected to T/HS. Both ERalpha and ERbeta agonists were equally effective in limiting T/HS-induced morphologic villous injury and bacterial translocation, whereas the ERbeta agonist was more effective than the ERalpha agonist in limiting T/HS-induced lung injury as determined by histology, Evan's blue lung permeability, bronchoalevolar fluid/plasma protein ratio and myeloperoxidase levels. Similarly, treatment with either E2 or the ERbeta agonist attenuated the induction of the intestinal iNOS response in OVX rats subjected to T/HS whereas the ERalpha agonist was only partially protective. CONCLUSIONS/SIGNIFICANCE: Our study demonstrates that estrogen attenuates T/HS induced gut and lung injury and that its protective effects are mediated by the activation of ERalpha, ERbeta or both receptors. PMID- 20195536 TI - The genome of Streptococcus mitis B6--what is a commensal? AB - Streptococcus mitis is the closest relative of the major human pathogen S. pneumoniae. The 2,15 Mb sequence of the Streptococcus mitis B6 chromosome, an unusually high-level beta-lactam resistant and multiple antibiotic resistant strain, has now been determined to encode 2100 genes. The accessory genome is estimated to represent over 40%, including 75 mostly novel transposases and IS, the prophage phiB6 and another seven phage related regions. Tetracycline resistance mediated by Tn5801, and an unusual and large gene cluster containing three aminoglycoside resistance determinants have not been described in other Streptococcus spp. Comparative genomic analyses including hybridization experiments on a S. mitis B6 specific microarray reveal that individual S. mitis strains are almost as distantly related to the B6 strain as S. pneumoniae. Both species share a core of over 900 genes. Most proteins described as pneumococcal virulence factors are present in S. mitis B6, but the three choline binding proteins PcpA, PspA and PspC, and three gene clusters containing the hyaluronidase gene, ply and lytA, and the capsular genes are absent in S. mitis B6 and other S. mitis as well and confirm their importance for the pathogenetic potential of S. pneumoniae. Despite the close relatedness between the two species, the S. mitis B6 genome reveals a striking X-alignment when compared with S. pneumoniae. PMID- 20195537 TI - All three subunits of RecBCD enzyme are essential for DNA repair and low temperature growth in the Antarctic Pseudomonas syringae Lz4W. AB - BACKGROUND: The recD mutants of the Antarctic Pseudomonas syringae Lz4W are sensitive to DNA-damaging agents and fail to grow at 4 degrees C. Generally, RecD associates with two other proteins (RecB and RecC) to produce RecBCD enzyme, which is involved in homologous recombination and DNA repair in many bacteria, including Escherichia coli. However, RecD is not essential for DNA repair, nor does its deletion cause any growth defects in E. coli. Hence, the assessment of the P. syringae RecBCD pathway was imperative. METHODOLOGY/PRINCIPAL FINDINGS: Mutational analysis and genetic complementation studies were used to establish that the individual null-mutations of all three genes, recC, recB, and recD, or the deletion of whole recCBD operon of P. syringae, lead to growth inhibition at low temperature, and sensitivity to UV and mitomycin C. Viability of the mutant cells dropped drastically at 4 degrees C, and the mutants accumulated linear chromosomal DNA and shorter DNA fragments in higher amounts compared to 22 degrees C. Additional genetic data using the mutant RecBCD enzymes that were inactivated either in the ATPase active site of RecB (RecB(K29Q)) or RecD (RecD(K229Q)), or in the nuclease center of RecB (RecB(D1118A) and RecB(Delta nuc)) suggested that, while the nuclease activity of RecB is not so critical in vivo, the ATP-dependent functions of both RecB and RecD are essential. Surprisingly, E. coli recBCD or recBC alone on plasmid could complement the defects of the Delta recCBD strain of P. syringae. CONCLUSIONS/SIGNIFICANCE: All three subunits of the RecBCD(Ps) enzyme are essential for DNA repair and growth of P. syringae at low temperatures (4 degrees C). The RecD requirement is only a function of the RecBCD complex in the bacterium. The RecBCD pathway protects the Antarctic bacterium from cold-induced DNA damages, and is critically dependent on the helicase activities of both RecB and RecD subunits, but not on the nuclease of RecBCD(Ps) enzyme. PMID- 20195538 TI - Prevalence of livestock-associated MRSA in communities with high pig-densities in The Netherlands. AB - BACKGROUND: Recently, livestock-associated methicillin-resistant Staphylococcus aureus CC398 has been discovered in animals, livestock farmers and retail meat. This cross-sectional study aimed to determine the spread to persons not in direct contact with livestock in areas with a high density of pig farms. METHODOLOGY/PRINCIPAL FINDINGS: With a random mailing in 3 selected municipalities in The Netherlands, adult persons were asked to fill in a questionnaire and to take a nose swab. In total, complete information was obtained on 583 persons. Of the 534 persons without livestock-contact, one was positive for MRSA (0.2%; 95% confidence interval, <0.01-1.2). Of the 49 persons who did indicate to be working at or living on a livestock farm, 13 were positive for MRSA (26.5%; 95% confidence interval, 16.1-40.4). All spa-types belonged to CC398. CONCLUSIONS/SIGNIFICANCE: Livestock-associated MRSA has a high prevalence in people with direct contact with animals. At this moment it has not spread from the farms into the community. PMID- 20195539 TI - Vertebrate DNA in fecal samples from bonobos and gorillas: evidence for meat consumption or artefact? AB - BACKGROUND: Deciphering the behavioral repertoire of great apes is a challenge for several reasons. First, due to their elusive behavior in dense forest environments, great ape populations are often difficult to observe. Second, members of the genus Pan are known to display a great variety in their behavioral repertoire; thus, observations from one population are not necessarily representative for other populations. For example, bonobos (Pan paniscus) are generally believed to consume almost no vertebrate prey. However, recent observations show that at least some bonobo populations may consume vertebrate prey more commonly than previously believed. We investigated the extent of their meat consumption using PCR amplification of vertebrate mitochondrial DNA (mtDNA) segments from DNA extracted from bonobo feces. As a control we also attempted PCR amplifications from gorilla feces, a species assumed to be strictly herbivorous. PRINCIPAL FINDINGS: We found evidence for consumption of a variety of mammalian species in about 16% of the samples investigated. Moreover, 40% of the positive DNA amplifications originated from arboreal monkeys. However, we also found duiker and monkey mtDNA in the gorilla feces, albeit in somewhat lower percentages. Notably, the DNA sequences isolated from the two ape species fit best to the species living in the respective regions. This result suggests that the sequences are of regional origin and do not represent laboratory contaminants. CONCLUSIONS: Our results allow at least three possible and mutually not exclusive conclusions. First, all results may represent contamination of the feces by vertebrate DNA from the local environment. Thus, studies investigating a species' diet from feces DNA may be unreliable due to the low copy number of DNA originating from diet items. Second, there is some inherent difference between the bonobo and gorilla feces, with only the later ones being contaminated. Third, similar to bonobos, for which the consumption of monkeys has only recently been documented, the gorilla population investigated (for which very little observational data are as yet available) may occasionally consume small vertebrates. Although the last explanation is speculative, it should not be discarded a-priori given that observational studies continue to unravel new behaviors in great ape species. PMID- 20195540 TI - Positive carotenoid balance correlates with greater reproductive performance in a wild bird. AB - BACKGROUND: Carotenoids can confer somatic and reproductive benefits, but most evidence is from captive animal experimentation or single time-point sampling. Another perhaps more informative means by which to assess physiological contributions to animal performance is by tracking an individual's ability to increase or sustain carotenoids or other health-related molecules over time, as these are likely to be temporally variable. METHODOLOGY/PRINCIPAL FINDINGS: In a field study of North American barn swallows (Hirundo rustica erythrogaster), we analyzed within-individual changes in carotenoid concentrations by repeatedly sampling the carotenoid profiles of individuals over the course of the breeding season. Our results demonstrate that carotenoid concentrations of individuals are temporally dynamic and that season-long balance of these molecules, rather than single time-point samples, predict reproductive performance. This was true even when controlling for two important variables associated with reproductive outcomes: (1) timing of breeding and (2) sexually selected plumage coloration, which is itself positively correlated with and concomitantly changes with circulating carotenoid concentrations. CONCLUSIONS/SIGNIFICANCE: While reproduction itself is purported to impose health stress on organisms, these data suggest that free-ranging, high-quality individuals can mitigate such costs, by one or several genetic, environmental (diet), or physiological mechanisms. Moreover, the temporal variations in both health-linked physiological measures and morphological traits we uncover here merit further examination in other species, especially when goals include the estimation of signal information content or the costs of trait expression. PMID- 20195541 TI - Helper T cell epitope-mapping reveals MHC-peptide binding affinities that correlate with T helper cell responses to pneumococcal surface protein A. AB - Understanding the requirements for protection against pneumococcal carriage and pneumonia will greatly benefit efforts in controlling these diseases. Several proteins and polysaccharide capsule have recently been implicated in the virulence of and protective immunity against Streptococcus pneumonia. Pneumococcal surface protein A (PspA) is highly conserved among S. pneumonia strains, inhibits complement activation, binds lactoferrin, elicits protective systemic immunity against pneumococcal infection, and is necessary for full pneumococcal virulence. Identification of PspA peptides that optimally bind human leukocyte antigen (HLA) would greatly contribute to global vaccine efforts, but this is hindered by the multitude of HLA polymorphisms. Here, we have used an experimental data set of 54 PspA peptides and in silico methods to predict peptide binding to HLA and murine major histocompatibility complex (MHC) class II. We also characterized spleen- and cervical lymph node (CLN)-derived helper T lymphocyte (HTL) cytokine responses to these peptides after S. pneumonia strain EF3030-challenge in mice. Individual, yet overlapping peptides, 15 amino acids in length revealed residues 199 to 246 of PspA (PspA(199-246)) consistently caused the greatest IFN-gamma, IL-2, IL-5 and proliferation as well as moderate IL-10 and IL-4 responses by ex vivo stimulated splenic and CLN CD4(+) T cells isolated from S. pneumonia strain EF3030-challeged F(1) (B6xBALB/c) mice. IEDB, RANKPEP, SVMHC, MHCPred, and SYFPEITHI in silico analysis tools revealed peptides in PspA(199-246) also interact with a broad range of HLA-DR, -DQ, and -DP allelles. These data suggest that predicted MHC class II-peptide binding affinities do not always correlate with T helper (Th) cytokine or proliferative responses to PspA peptides, but when used together with in vivo validation can be a useful tool to choose candidate pneumococcal HTL epitopes. PMID- 20195542 TI - An atypical riboflavin pathway is essential for Brucella abortus virulence. AB - Brucellosis is a worldwide zoonosis that affects livestock and humans and is caused by closely related Brucella spp., which are adapted to intracellular life within cells of a large variety of mammals. Brucella can be considered a furtive pathogen that infects professional and non-professional phagocytes. In these cells Brucella survives in a replicative niche, which is characterized for having a very low oxygen tension and being deprived from nutrients such as amino acids and vitamins. Among these vitamins, we have focused on riboflavin (vitamin B2). Flavin metabolism has been barely implicated in bacterial virulence. We have recently described that Brucella and other Rhizobiales bear an atypical riboflavin metabolic pathway. In the present work we analyze the role of the flavin metabolism on Brucella virulence. Mutants on the two lumazine synthases (LS) isoenzymes RibH1 and RibH2 and a double RibH mutant were generated. These mutants and different complemented strains were tested for viability and virulence in cells and in mice. In this fashion we have established that at least one LS must be present for B. abortus survival and that RibH2 and not RibH1 is essential for intracellular survival due to its LS activity in vivo. In summary, we show that riboflavin biosynthesis is essential for Brucella survival inside cells or in mice. These results highlight the potential use of flavin biosynthetic pathway enzymes as targets for the chemotherapy of brucellosis. PMID- 20195543 TI - Increased alpha-defensins 1-3 production by dendritic cells in HIV-infected individuals is associated with slower disease progression. AB - BACKGROUND: Defensins are natural endogenous antimicrobial peptides with potent anti-HIV activity and immuno-modulatory effects. We recently demonstrated that immature dendritic cells (DC) produce alpha-defensins1-3 and that alpha defensins1-3 modulate DC generation and maturation. Since DC-HIV interaction plays a critical role during the first steps of HIV infection, we investigated the possible impact of alpha-defensins1-3 production by DC on disease progression. METHODOLOGY/PRINCIPAL FINDINGS: Monocyte-derived DC (MDDC) were analyzed comparatively in healthy controls (HC) and HIV-infected patients, including untreated "elite" and "viremic" controllers, untreated viremic non controllers and antiretroviral-treated patients. We found that production of alpha-defensins1-3 was significantly increased in MDDC from HIV-infected patients versus HC, and this increase was mainly due to that observed in controllers, while in non-controllers the increase was not statistically significant (controllers vs. HC, p<0.005; controllers vs. non-controllers p<0.05). Secreted alpha-defensins1-3 by immature MDDC positively correlated with CD4 T cell counts in controllers, but not in non-controllers. Moreover, independently of their clinical classification, HIV-infected patients with higher alpha-defensins1-3 secretion by immature MDDC showed slower disease progression, measured as no decrease in the number of CD4+ T-cells below 350 cell/mm(3), lower increase of plasma viral load and no initiation of treatment over time. Plasma alpha defensins1-3 levels lacked any relationship with immunologic and virologic parameters. CONCLUSIONS/SIGNIFICANCE: High production of alpha-defensins1-3 by immature DCs appears as a host protective factor against progression of HIV-1 infection, suggesting potential diagnostic, therapeutic and preventive implications. This protective effect may arise from the activity of alpha defensins1-3 to damage the virions prior and/or after their internalization by immature DC, and hence favoring a more efficient viral processing and presentation to HIV-specific CD4+ T cells, without or with a minor rate of transmission of infectious HIV-1 virions. PMID- 20195544 TI - The core binding factor CBF negatively regulates skeletal muscle terminal differentiation. AB - BACKGROUND: Core Binding Factor or CBF is a transcription factor composed of two subunits, Runx1/AML-1 and CBF beta or CBFbeta. CBF was originally described as a regulator of hematopoiesis. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that CBF is involved in the control of skeletal muscle terminal differentiation. Indeed, downregulation of either Runx1 or CBFbeta protein level accelerates cell cycle exit and muscle terminal differentiation. Conversely, overexpression of CBFbeta in myoblasts slows terminal differentiation. CBF interacts directly with the master myogenic transcription factor MyoD, preferentially in proliferating myoblasts, via Runx1 subunit. In addition, we show a preferential recruitment of Runx1 protein to MyoD target genes in proliferating myoblasts. The MyoD/CBF complex contains several chromatin modifying enzymes that inhibits MyoD activity, such as HDACs, Suv39h1 and HP1beta. When overexpressed, CBFbeta induced an inhibition of activating histone modification marks concomitant with an increase in repressive modifications at MyoD target promoters. CONCLUSIONS/SIGNIFICANCE: Taken together, our data show a new role for Runx1/CBFbeta in the control of the proliferation/differentiation in skeletal myoblasts. PMID- 20195545 TI - MYC overexpression induces prostatic intraepithelial neoplasia and loss of Nkx3.1 in mouse luminal epithelial cells. AB - Lo-MYC and Hi-MYC mice develop prostatic intraepithelial neoplasia (PIN) and prostatic adenocarcinoma as a result of MYC overexpression in the mouse prostate. However, prior studies have not determined precisely when, and in which cell types, MYC is induced. Using immunohistochemistry (IHC) to localize MYC expression in Lo-MYC transgenic mice, we show that morphological and molecular alterations characteristic of high grade PIN arise in luminal epithelial cells as soon as MYC overexpression is detected. These changes include increased nuclear and nucleolar size and large scale chromatin remodeling. Mouse PIN cells retained a columnar architecture and abundant cytoplasm and appeared as either a single layer of neoplastic cells or as pseudo-stratified/multilayered structures with open glandular lumina-features highly analogous to human high grade PIN. Also using IHC, we show that the onset of MYC overexpression and PIN development coincided precisely with decreased expression of the homeodomain transcription factor and tumor suppressor, Nkx3.1. Virtually all normal appearing prostate luminal cells expressed high levels of Nkx3.1, but all cells expressing MYC in PIN lesions showed marked reductions in Nkx3.1, implicating MYC as a key factor that represses Nkx3.1 in PIN lesions. To determine the effects of less pronounced overexpression of MYC we generated a new line of mice expressing MYC in the prostate under the transcriptional control of the mouse Nkx3.1 control region. These "Super-Lo-MYC" mice also developed PIN, albeit a less aggressive form. We also identified a histologically defined intermediate step in the progression of mouse PIN into invasive adenocarcinoma. These lesions are characterized by a loss of cell polarity, multi-layering, and cribriform formation, and by a "paradoxical" increase in Nkx3.1 protein. Similar histopathological changes occurred in Hi-MYC mice, albeit with accelerated kinetics. Our results using IHC provide novel insights that support the contention that MYC overexpression is sufficient to transform prostate luminal epithelial cells into PIN cells in vivo. We also identified a novel histopathologically identifiable intermediate step prior to invasion that should facilitate studies of molecular pathway alterations occurring during early progression of prostatic adenocarcinomas. PMID- 20195546 TI - miR-24 regulates apoptosis by targeting the open reading frame (ORF) region of FAF1 in cancer cells. AB - BACKGROUND: microRNAs (miRNAs) are small noncoding RNAs that regulate cognate mRNAs at the post-transcriptional stage. Several studies have shown that miRNAs modulate gene expression in mammalian cells by base pairing to complementary sites in the 3'-untranslated region (3'-UTR) of the target mRNAs. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, miR-24 was found to target fas associated factor 1(FAF1) by binding to its amino acid coding sequence (CDS) region, thereby regulating apoptosis in DU-145 cells. This result supports an augmented model whereby animal miRNAs can exercise their effects through binding to the CDS region of the target mRNA. Transfection of miR-24 antisense oligonucleotide (miR-24-ASO) also induced apoptosis in HGC-27, MGC-803 and HeLa cells. CONCLUSIONS/SIGNIFICANCE: We found that miR-24 regulates apoptosis by targeting FAF1 in cancer cells. These findings suggest that miR-24 could be an effective drug target for treatment of hormone-insensitive prostate cancer or other types of cancers. Future work may further develop miR-24 for therapeutic applications in cancer biology. PMID- 20195547 TI - Holographic photolysis for multiple cell stimulation in mouse hippocampal slices. AB - BACKGROUND: Advanced light microscopy offers sensitive and non-invasive means to image neural activity and to control signaling with photolysable molecules and, recently, light-gated channels. These approaches require precise and yet flexible light excitation patterns. For synchronous stimulation of subsets of cells, they also require large excitation areas with millisecond and micrometric resolution. We have recently developed a new method for such optical control using a phase holographic modulation of optical wave-fronts, which minimizes power loss, enables rapid switching between excitation patterns, and allows a true 3D sculpting of the excitation volumes. In previous studies we have used holographic photololysis to control glutamate uncaging on single neuronal cells. Here, we extend the use of holographic photolysis for the excitation of multiple neurons and of glial cells. METHODS/PRINCIPAL FINDINGS: The system combines a liquid crystal device for holographic patterned photostimulation, high-resolution optical imaging, the HiLo microscopy, to define the stimulated regions and a conventional Ca(2+) imaging system to detect neural activity. By means of electrophysiological recordings and calcium imaging in acute hippocampal slices, we show that the use of excitation patterns precisely tailored to the shape of multiple neuronal somata represents a very efficient way for the simultaneous excitation of a group of neurons. In addition, we demonstrate that fast shaped illumination patterns also induce reliable responses in single glial cells. CONCLUSIONS/SIGNIFICANCE: We show that the main advantage of holographic illumination is that it allows for an efficient excitation of multiple cells with a spatiotemporal resolution unachievable with other existing approaches. Although this paper focuses on the photoactivation of caged molecules, our approach will surely prove very efficient for other probes, such as light-gated channels, genetically encoded photoactivatable proteins, photoactivatable fluorescent proteins, and voltage-sensitive dyes. PMID- 20195548 TI - Ten simple rules for organizing a virtual conference--anywhere. PMID- 20195550 TI - Will widgets and semantic tagging change computational biology? PMID- 20195551 TI - Computational complementation: a modelling approach to study signalling mechanisms during legume autoregulation of nodulation. AB - Autoregulation of nodulation (AON) is a long-distance signalling regulatory system maintaining the balance of symbiotic nodulation in legume plants. However, the intricacy of internal signalling and absence of flux and biochemical data, are a bottleneck for investigation of AON. To address this, a new computational modelling approach called "Computational Complementation" has been developed. The main idea is to use functional-structural modelling to complement the deficiency of an empirical model of a loss-of-function (non-AON) mutant with hypothetical AON mechanisms. If computational complementation demonstrates a phenotype similar to the wild-type plant, the signalling hypothesis would be suggested as "reasonable". Our initial case for application of this approach was to test whether or not wild-type soybean cotyledons provide the shoot-derived inhibitor (SDI) to regulate nodule progression. We predicted by computational complementation that the cotyledon is part of the shoot in terms of AON and that it produces the SDI signal, a result that was confirmed by reciprocal epicotyl and-hypocotyl grafting in a real-plant experiment. This application demonstrates the feasibility of computational complementation and shows its usefulness for applications where real-plant experimentation is either difficult or impossible. PMID- 20195552 TI - Gordon M Wyant (1914-2009). PMID- 20195553 TI - Patient-controlled oral analgesia for postoperative pain management following total knee replacement. AB - PURPOSE: To investigate whether patient-controlled oral analgesia (PCOA) used by individuals receiving a total knee replacement could reduce pain, increase patient satisfaction, reduce opioid use and/or reduce opioid side effects when compared with traditional nurse (RN)-administered oral analgesia. METHODS: Patients who underwent an elective total knee replacement at a quaternary care centre (Toronto Western Hospital, Toronto, Ontario) were randomly assigned to either PCOA or RN-administered short-acting oral opioids on postoperative day 2. Subjects in the RN group called the RN to receive their prescribed short-acting opioid. Subjects in the PCOA group kept a single dose of their prescribed oral opioid at their bedside and took this dose when they felt they needed it, to a maximum of one dose every 2 h. Study outcomes, collected on postoperative day 2, included pain (measured by the Brief Pain Inventory - Short Form), patient satisfaction (measured by the Pain Outcome Questionnaire Satisfaction subscale - component II), opioid use (oral morphine equivalents), opioid side effects (nausea, pruritus and/or constipation) and knee measures (maximum passive knee flexion and pain at maximum passive knee flexion, performed on the operative knee). RESULTS: Study outcomes were analyzed twice. First, for a subset of 73 subjects who remained in their randomly assigned group (PCOA group, n=36; RN group, n=37), randomized analyses were performed. Second, for the larger sample of 88 subjects who were categorized by their actual method of receiving oral opioids (PCOA group, n=41; RN group, n=47), as-treated analyses were performed. There were no differences in study outcomes between the PCOA and RN groups in either analysis. CONCLUSION: PCOA was not superior to RN administration on study outcomes. However, PCOA did not increase opioid use or pain. PCOA remains an important element in the patient-centred care facility. PMID- 20195554 TI - Analysis of complaints to a tertiary care pain clinic over a nine-year period. AB - BACKGROUND: The present study is the result of an internal audit and examines the profiles of complainants and the sources and nature of complaints toward the staff in a tertiary care pain clinic, the Comprehensive Pain Program of the Toronto Western Hospital in Toronto, Ontario. METHODS: All sources of complaints over a nine-year period were reviewed, which included the following: Toronto Western Hospital Patient Relations (PR) records, with a subset of the files qualitatively analyzed in depth regarding the nature of complaints and complainants; complaints that bypassed PR and were addressed directly to the program director against members of the staff; complaints to the College of Physicians and Surgeons of Ontario; and complaints recorded anonymously at rateMDs.com. RESULTS: Although the prevalence of PR complaints was very low (1.73 complaints per 1000 visits), several other sources of complaints were identified. The typical complainant was a Canadian-born woman acting on her behalf or on behalf of a family member. More than one-half of the complaints were directed against the physicians regarding their opinion of psychological factors augmenting the patient's presentation and/or inappropriate use of opioids. Defensive techniques instituted by the Comprehensive Pain Program staff in reaction to the complaints are discussed, and pertinent literature is reviewed. CONCLUSION: The present study is the first to examine the nature of complaints and complainants from a Canadian pain clinic. Further studies are needed to explore the complex issues of patient and staff interactions, and complaints in the era of 'patient-centred care'. PMID- 20195555 TI - Poststroke pain - but multiple pain mechanisms. AB - A 42-year-old man presented with acute left hemiplegia due to a right frontotemporal hemorrhagic stroke and left-sided pain. While the initial presentation suggested central poststroke pain, subsequent investigations also implicated heterotopic ossification of the left hip and amplification of previous low back pain by the new central pain. While heterotopic ossification has been commonly associated with brain injury, spinal cord injury or osseous injury, it is only rarely associated with stroke. Poststroke pain may be multifactorial, and discovering the pain mechanisms has important implications for treatment. PMID- 20195557 TI - Gender differences in the associations between childhood trauma and parental bonding in panic disorder. AB - OBJECTIVE: The aim of this study is to evaluate the association between childhood trauma and the quality of parental bonding in panic disorder compared to non clinical controls. METHOD: 123 patients and 123 paired controls were evaluated with the Mini International Neuropsychiatric Interview, the Childhood Trauma Questionnaire and the Parental Bonding Instrument. RESULTS: The Parental Bonding Instrument and the Childhood Trauma Questionnaire were highly correlated. Panic disorder patients presented higher rates of emotional abuse (OR = 2.54, p = 0.001), mother overprotection (OR = 1.98, p = 0.024) and father overprotection (OR = 1.84, p = 0.041) as compared to controls. Among men with panic disorder, only mother overprotection remained independently associated with panic disorder (OR = 3.28, p = 0.032). On the other hand, higher father overprotection (OR = 2.2, p = 0.017) and less father warmth (OR = 0.48, p = 0.039) were independently associated with panic disorder among female patients. CONCLUSION: Higher rates of different types of trauma, especially emotional abuse, are described in panic disorder patients as compared to controls. The differences regarding gender and parental bonding could be explained in the light of the psychodynamic theory. PMID- 20195558 TI - [Pathological gambling and computergame-addiction. Current state of research regarding two subtypes of behavioural addiction]. AB - Behavioral addictions, like pathological gambling and computer game addiction (or internet addiction), have become a growing concern in research and public interest. Currently similarities between behavioral addictions and substance dependency are controversially discussed in the scientific community. Unfortunately a mismatch exists between the large number of people seeking treatment and the small number of scientific studies on pathological gambling and computer game addiction. Prevalence of pathological gambling among the German population is estimated to be 0.2-0.5%. These estimations are comparable to prevalence rates reported for drug dependency. Latest research states that about 3% of German adolescents and young adults are believed to suffer from computer game addiction. Therefore, it is important to enhance investigations regarding the clinical and neuroscientific basis of computer game addiction. This review offers a summary of current results of research regarding pathological gambling and internet addiction. The phenomenological description of these two disorders is meant to allow a deeper understanding of behavioral addictions. PMID- 20195559 TI - [Neuroimaging diagnosis of alcohol dependence]. AB - Neuroimaging provides insight into the main biological mechanisms underlying alcohol dependence. This article discusses results from brain imaging studies on neurobiological correlates of alcohol dependence. Cardinal symptoms of alcohol dependence are the development of tolerance, withdrawal symptoms, drug craving, loss of control on alcohol intake, and harmful consequences of alcohol consumption. Brain imaging studies support the hypothesis that tolerance can be understood as a neuroadaptive mechanism to ensure homeostasis during chronic alcohol intake. When alcohol consumption is suddenly interrupted during detoxification, the loss of homeostasis typically manifests as withdrawal syndrome. While tolerance reduces the effects of chronic alcohol intake, sensitization is a neuroadaptive process that increases the effects of alcohol and raises incentive salience. Brain imaging studies indicate that sensitization and drug craving are associated with neuroadaptive processes in the brain reward system. Harmful consequences of alcohol intake also include neurotoxic effects on the central nervous system characterized by local and global atrophy. These findings can be best diagnosed with neuroimaging. PMID- 20195556 TI - Social functioning and peer relationships in children and adolescents with chronic pain: A systematic review. AB - BACKGROUND: Peer relationships during childhood and adolescence are acknowledged to be negatively impacted by chronic pain; however, to date there has been no synthesis of this literature. OBJECTIVE: To systematically review existing literature describing the social functioning and peer relationships in children and adolescents with recurrent or continuous chronic pain. METHODS: Articles on peer relationship factors studied in samples of children and adolescents with chronic pain published in English or French were identified using EMBASE, Medline, CINAHL and PsycINFO. Two independent reviewers performed initial screenings using study titles and abstracts, and reviewed each eligible article in full. RESULTS: Of 1740 published papers yielded by the search, 42 articles met the inclusion criteria and were included in the present review. Nine studies had peer relationship investigation as the primary purpose of the study; the remaining 33 examined peer relationships as part of a broader study. A range of specific and more general measures was used to examine peer relationships. Across studies, children and adolescents with chronic pain were reported to have fewer friends, be subjected to more peer victimization, and were viewed as more isolated and less likeable than healthy peers. CONCLUSIONS: Children and adolescents with chronic pain have peer relationship deficiencies. However, the majority of studies to date measure peer relationships as part of a broader study and, thus, little attention has been paid specifically to peer relationships in this group. Additional research examining the quality of peer relationships of children and adolescents with chronic pain, as well as development of measures specifically designed to assess these relationships, is needed. PMID- 20195560 TI - [Autoimmune sialadenitis]. AB - Using the European-American classification criteria the diagnosis of autoimmune sialadenitis in Sjogren's syndrome can generally be easily established or excluded. In addition, sonography performed by the ENT physician is helpful in diagnosing and especially in follow-up screening for MALT lymphomas, which 5%-10% of patients develop. Therapy of sicca symptoms is primarily symptomatic using substitution with fluids and stimulation with oral cholinergic drugs. Corticosteroids and/or antibiotics may play a role in patients with severe inflammatory episodes of autoimmune sialadenitis. Systemic therapy with immunomodulatory drugs such as azathioprine or cyclophosphamide is reserved for patients with extraglandular manifestations. However, the efficacy of this therapy is not proven by clinical studies. Rituximab, a new monoclonal CD20 antibody, seems to offer the first possibility of a causal therapy, under which the lymphoepithelial lesions in the salivary glands can disappear and saliva production improves. However, larger clinical studies are needed to evaluate the efficacy of this new therapy. Optimal treatment of autoimmune sialadenitis requires interdisciplinary collaboration between ENT physician, oral and maxillofacial surgeon, rheumatologist, ophthalmologist, dentist, and pathologist. PMID- 20195561 TI - [Ophthalmological findings as a hint for systemic disease]. AB - Many eye diseases are associated with systemic diseases. Moreover, ophthalmological findings can be first manifestations of systemic diseases. Therefore internists and ophthalmologists should be familiar with the signs, symptoms, and the management of eye diseases with a possible systemic association. Due to subspecialization in medicine an interdisciplinary approach is mandatory for optimal patient care. In this article examples of eye diseases with a possible association with systemic diseases are presented. PMID- 20195562 TI - [When only the pathologist may help. Limitation and possibilities of biopsies in Internal Medicine]. AB - Histological evaluation after biopsy remains the gold standard for the diagnosis of numerous diseases in Internal Medicine. The gastrointestinal tract (e. g. esophagus, liver and large intestine), the kidneys or bone marrow are organs, where biopsy-driven diagnosis and evaluation of therapeutic regimens are of major relevance. Improvement in blood analysis, endoscopic techniques and radiology could significantly reduce the number of biopsies. Hence under certain circumstances, the risk of biopsy can be avoided and non-invasive markers can sufficiently substitute the histological evaluation. However, histological evaluation derived from biopsies remains the standard of diagnosis in many cases in Internal Medicine. In the present review the current standards and future developments of pathologic diagnosis through biopsy are illustrated. PMID- 20195563 TI - [Indications for magnetic resonance imaging in Internal Medicine. When do we really need this technology?]. AB - Due to further technical developments in recent years, magnet resonance imaging (MRI) is now recognized as one of the primary diagnostic imaging modalities in the field of Internal Medicine. This review describes relevant indications for MRI in the different subspecialties of Internal Medicine and compares the diagnostic yield of MRI to other established modalities such as computed tomography and ultrasound. PMID- 20195564 TI - Occurrence and variation of egg cannibalism in brown trout Salmo trutta. AB - Egg cannibalism is a common behavior among fish taxa and is largely studied in species with parental care. Heterocannibalism and filial cannibalism have both been reported in salmonids, a group with no extended parental care, but the topic remained somewhat under-documented, especially in brown trout (Salmo trutta). In the present study, 83 spawning events were recorded finely with high-resolution video in three natural populations. Redd covering dynamics by females and the timing of cannibalism showed that eggs were vulnerable mainly during the first 120 s after spawning. Cannibalism occurred in 25% of spawnings and was principally perpetrated by peripherals but the sires also cannibalized their brood, especially after multiple mating. The probability of cannibalism increased with operational sex ratio but did not correlate with the date in spawning season. Occurrence of cannibalism also differed between populations. Our results suggest that such behavior is frequent and may reduce the fitness of parents. Its evolutionary implications for population ecology should be considered, since it appeared to be controlled by environmental and spatial factors. PMID- 20195565 TI - [HIV-associated neuropathies]. AB - Human immunodeficiency virus (HIV)-associated polyneuropathy has become the most common neurological complication of HIV infection and is one of the main risk factors for development of a neuropathy worldwide. Therefore HIV should always be considered as an underlying cause in patients with neuropathy. Many types of peripheral neuropathies are seen in HIV infection depending on the stage of infection. The inflammatory demyelinating neuropathies both acute (Guillain-Barre syndrome, GBS) and chronic (chronic inflammatory demyelinating neuropathy, CIDP) occur mainly at the time of seroconversion or early in the course of the disease while syndromes associated with opportunistic infections like CMV (i.e. polyradiculoneuropathy) occur in the late phase of HIV infection and are related to the loss of immune function. Distal symmetrical polyneuropathy (DSP) is the most common neuropathy in HIV-infected patients. We review the clinical manifestations, epidemiology, clinical diagnostics, pathophysiology and management strategies for HIV-associated polyneuropathies. PMID- 20195566 TI - [Treatment of cognitive deficits in schizophrenia. Part 1: Diagnostic and psychological training]. AB - Cognitive dysfunction is a core feature of schizophrenia. Although cognitive deficits in the domains of attention, memory and executive functions have been described for many decades, the focus on therapeutic approaches is new. The recognition that cognitive deficits are the best known predictor of functional outcome in schizophrenic patients explains the increasing interest in the diagnosis and therapy of these impairments. Standards for the reliable evaluation of neurocognitive deficits in schizophrenia have been put forward by the MATRICS initiative (Measurement and Treatment Research to Improve Cognition in Schizophrenia). In German-speaking countries the most popular cognitive training programs for schizophrenic patients are "CogPack" and "Integrated Psychological Therapy (IPT)". Especially in Anglo-Saxon countries cognitive training has become more popular in recent years. Study outcomes can be considered encouraging. They show improvement of cognitive deficits and a positive impact on the functional outcome. Further studies are needed to optimize cognitive training for schizophrenic patients. PMID- 20195568 TI - Genetics and mapping of stem rust resistance to Ug99 in the wheat cultivar Webster. AB - New races of wheat stem rust, namely TTKSK (Ug99) and its variants, pose a threat to wheat production in the regions where they are found. The accession of the wheat cultivar Webster (RL6201) maintained at the Cereal Research Centre in Winnipeg, Canada, shows resistance to TTKSK and other races of stem rust. The purpose of this study was to study the inheritance of seedling resistance to stem rust in RL6201 and genetically map the resistance genes using microsatellite (SSR) markers. A population was produced by crossing the stem rust susceptible line RL6071 with Webster. The F(2) and F(3) were tested with TPMK, a stem rust race native to North America. The F(3) was also tested with TTKSK. Two independently assorting genes were identified in RL6201. Resistance to TPMK was conferred by Sr30, which was mapped with microsatellites on chromosome 5DL. The second gene, temporarily designated SrWeb, conferred resistance to TTKSK. SrWeb was mapped to chromosome 2BL using SSR markers. Comparison with previous genetic maps showed that SrWeb occupies a locus near Sr9. Further analysis will be required to determine if SrWeb is a new gene or an allele of a previously identified gene. PMID- 20195567 TI - [Treatment of cognitive deficits in schizophrenia. Part 2: Pharmacological strategies]. AB - Cognitive deficits in schizophrenia are a clinically relevant symptom dimension and one of the best predictors for functional outcome. Pharmacological treatment of cognitive deficits in schizophrenia is still a challenge. The objective of this article is to present a detailed review of the literature on strategies for the pharmacological treatment of cognitive deficits. It is not clear whether first-generation antipsychotics have a genuine positive influence on cognition. There is only sparse evidence for the positive effect of second-generation antipsychotics on cognitive processes. Furthermore it is not evident that second generation antipsychotics are more beneficial than first-generation antipsychotics in the treatment of cognitive deficits. The add-on use of substances which directly influence cognitive processes, so-called cognition enhancing drugs is more promising. PMID- 20195569 TI - Gender, depression and physical impairment: an epidemiologic perspective from Aleppo, Syria. AB - OBJECTIVE: Examine the association of physical impairment with gender, depression, and socio-demographics in the community in Aleppo, Syria. METHOD: We conducted a cross-sectional, population-based study in Aleppo on adults aged 18 65 (N = 2,038). We used a computerized interviewer-administered structured questionnaire. Physical impairment was measured via an adapted 12-item World Health Organization, Health State Description Individual Questionnaire which includes both physical and emotional items. We used physical impairment items score to classify individuals into low, middle, and high physical impairment category. Self-report of physician-diagnosed depression and chronic diseases active in the past year and their current treatment status were obtained. RESULTS: Sample mean age (SD) was 35.3 (12.1) years, 55% were female, and 4.5% had depression. Female gender, low socioeconomic status (SES), and depression were associated with high physical impairment. Women had more impairment (OR = 3.35, 95% CI: 2.15-5.21) with little change after controlling for depression and chronic diseases, but significantly decreased after controlling for socio demographics (OR = 1.51, 95% CI: 0.84-2.73). The association with low (vs. high) SES was prominent (OR = 2.48, 95% CI: 1.32-4.67) after controlling for all variables. Depression's association (OR = 4.85, 95% CI: 1.93-12.15) lost significance after controlling for chronic diseases (OR = 2.81, 95% CI: 0.96 8.25), but further adjustment for socio-demographics had little effect. CONCLUSION: Women and individuals of low SES appear more vulnerable to physical impairment in the community in Aleppo. Depression's association with physical impairment may be mediated through co-existing chronic diseases. Public health planning regarding physical impairment in Syria should encompass these as putative risk factors. PMID- 20195570 TI - [Negative response bias and assessment of uncooperativeness in independent medical evaluations]. AB - The present article highlights how simple it appears to be to simulate symptoms and how often medical and forensic experts are unable or unwilling to properly identify such attempts at deception. Yet, experts usually lack a critical understanding of the limitations of their own powers of judgement. Although carefully developed and reliable approaches and procedures are available today to verify the validity of symptoms, these are often applied unwillingly. Despite sound base-rate estimates, cooperativeness in forensic evaluations is often accepted without proper critical assessment. In German speaking countries, more empirical research on civil forensic assessment would help to improve the quality of expert opinions. PMID- 20195571 TI - [Medical evaluation of psychological disorders following whiplash injury]. AB - Psychological disorders are not rare following whiplash injury and, when present, determine the further course of symptoms. In addition to an acute stress reaction, adjustment disorders occasionally occur, while posttraumatic stress disorder is rarer; somatoform disorders, however, are frequent, especially persistent somatoform pain disorder and other psychological disorders. Since they defy objective substantiation, chronic complaints following whiplash injury give rise to numerous problems and differences of opinion. Therefore, medical appraisers require expertise not only in somatic, but also in psychological disorders. PMID- 20195572 TI - [Deformities following spinal injury at the thoracolumbar junction]. AB - Due to anatomical characteristics, posttraumatic deformities following spinal injury occur in particular at the transition from the flexible lumbar spine to the rigid thoracic spine. Incorrectly classified vertebral body fractures can lead to the development of posttraumatic kyphosis due to incorrect treatment. It is likewise important to evaluate the integrity of adjacent discs and assess the sagittal index. Management of kyphosis is difficult and requires radiological evaluation following exact planning. Reconstruction of the sagittal anatomical contour is crucial to prevent stress in the compensatory curves. Performing a dorso-ventral or dorso-ventro-dorsal approach, pedicle subtraction osteotomy or an eggshell procedure is also helpful to achieve good correction without anterior reconstructive surgery. The clinical result is not dependent on correct repositioning alone; poor results can be expected in cases with pseudarthrosis, neurological deficits and severe kyphotic deformities. This article gives an overview of pathogenesis, diagnostic steps and therapeutic options for corrective spinal surgery. PMID- 20195573 TI - Site-specific modulation of white adipose tissue lipid metabolism by oleoyl estrone and/or rosiglitazone in overweight rats. AB - In spite of their shared decrease of insulin resistance, oleoyl-estrone [OE], and rosiglitazone show diverging effects on body fat mass and distribution. In this study, we studied whether their effects on white adipose tissue [WAT] were due to a shared or synergistic mechanism of action. Combined effects of OE and rosiglitazone 10-day treatment on WAT lipid, cell mass/number, and the expression of key lipid metabolism and regulatory agents were studied using an adult male overweight rat model. OE decreased WAT cell mass and lipids, parameters not changed by rosiglitazone. The effects of OE and--specially--rosiglitazone were more marked in small-cell WAT (i.e., mesenteric and subcutaneous sites) than in larger cell WAT (retroperitoneal and perigonadal). OE decreased the expressions in WAT of lipogenic enzymes, lipoprotein lipase, PPARs, and SREBP1c, effects symmetrically reversed by rosiglitazone. OE showed no effects on hormone sensitive lipase expression, which was increased by rosiglitazone. OE strongly inhibited WAT lipogenesis, leaving lipolysis unchanged, thus unbalancing (and helping mobilize) WAT lipid stores. Rosiglitazone acted practically only on small cell WAT sites, where it favored lipogenesis, but also stimulated lipolysis, which resulted in limited changes in lipid stores. Combination of OE and rosiglitazone induced less fat loss than OE alone. PMID- 20195574 TI - Blood glucose levels produced by glucose tablets in abstaining smokers. PMID- 20195576 TI - Temporal dynamics of receptor-induced apoptosis in an affinity microdevice. AB - The temporal dynamics of Fas-induced apoptosis is elucidated. Jurkat cells are captured on the affinity surface of a microdevice coated with anti-CD95, an antibody known to induce apoptosis in cells via the extrinsic (caspase 8) pathway. The timing of apoptosis induction is controlled by the binding of the cells to the surface. Once bound, the cells are continuously stained with the caspase probe, L-bisaspartic acid rhodamine 110 (D(2)R), and the fluorescence of the cells was monitored for 6 h by light microscopy. This approach normalizes the temporal dynamics for each cell, as the binding event is also the start of apoptosis. In addition to providing the number of apoptotic cells over time, the fluorescence of individual cells can be monitored, providing information about the timing of caspase activity in each cell. The rate of caspase cleavage of D(2)R in each cell is also measured and shows good agreement between the cells in a given population. The effects of the caspase inhibitor, z-VAD-FMK, on the timing of caspase activity are also investigated and are shown to dramatically slow the apoptotic process. In the future, other caspase probes could be used to provide additional information about the temporal dynamics of caspase activation. Additional techniques, such as fluorescence correlation spectroscopy, can be coupled to these methods to provide faster temporal response and help to elucidate the heterogeneity of the apoptosis process. PMID- 20195575 TI - Interleaved transcranial magnetic stimulation and fMRI suggests that lamotrigine and valproic acid have different effects on corticolimbic activity. AB - RATIONALE: Combined transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) can be used to study anticonvulsant drugs. A previous study showed that lamotrigine (LTG) inhibited brain activation induced when TMS was applied over motor cortex, whereas it increased activation induced by TMS applied over prefrontal cortex. OBJECTIVES: The present double-blind, placebo-controlled, crossover study in 30 healthy subjects again combined TMS and fMRI to test whether the effects seen previously with LTG would be confirmed and to compare these with a second anticonvulsant drug, valproic acid (VPA). RESULTS: Statistical parametric mapping analysis showed that both LTG and VPA, compared to placebo, inhibited TMS-induced activation of the motor cortex. In contrast, when TMS was applied over prefrontal cortex, LTG increased the activation of limbic regions, confirming previous results; VPA had no effect. CONCLUSION: We conclude that LTG and VPA have similar inhibitory effects on motor circuits, but differing effects on the prefrontal corticolimbic system. The study demonstrates that a combination of TMS and fMRI techniques may be useful in the study of the effects of neuroactive drugs on specific brain circuits. PMID- 20195577 TI - A hydrophilic interaction ultraperformance liquid chromatography (HILIC-UPLC) method for genomic DNA methylation assessment by UV detection. AB - A hydrophilic interaction chromatography-based method, in combination with 1.7 microm ethylene bridged hybrid particle packed column (100 mm x 2.1 mm I.D.) and ultraperformance liquid chromatography, has been developed to measure cytosine (C) and methylcytosine (mC) in order to evaluate the extent of DNA methylation. Separation of cytosine and methylcytosine was achieved with good resolution and in fairly short times (5.5 min) by using isocratic elution with a mixture of 97:3 (v/v) acetonitrile/10 mM ammonium acetate as a mobile phase. The determination coefficients of C and mC were high (R(2) > 0.999) within the range tested. The %RSD for intraday and interday were respectively 2.2% and 2.5% for C and 3.5% and 3.8% for mC. The limit of detection was 0.52 microM (0.52 fmol on-column) both for C and mC while the limit of quantification was 1.72 microM (1.72 fmol on column) both for C and mC. The smallest amount of purified DNA that yielded a measurable level of C and mC was 10 microg. On the whole, this method is simple, rapid, sensitive, and precise. PMID- 20195578 TI - Hydrogen exchange mass spectrometry: what is it and what can it tell us? AB - Proteins are undoubtedly some of the most essential molecules of life. While much is known about many proteins, some aspects still remain mysterious. One particularly important aspect of understanding proteins is determining how structure helps dictate function. Continued development and implementation of biophysical techniques that provide information about protein conformation and dynamics is essential. In this review, we discuss hydrogen exchange mass spectrometry and how this method can be used to learn about protein conformation and dynamics. The basic concepts of the method are described, the workflow illustrated, and a few examples of its application are provided. PMID- 20195579 TI - Hydrophilic interaction liquid chromatography/positive ion electrospray ionization mass spectrometry method for the quantification of perindopril and its main metabolite in human plasma. AB - A validated method based on liquid chromatography/positive ion electrospray-mass spectrometry (LC-ESI/MS) is described for the quantification of perindopril and its active metabolite, perindoprilat, in human plasma. The assay was based on 500 microL plasma samples, following solid-phase extraction using Oasis HLB cartridges. All analytes and the internal standard (trandolapril) were separated by hydrophilic interaction liquid chromatography using a SeQuant Zic-HILIC analytical column (150.0 x 2.1 mm i.d., particle size 3.5 microm, 200 A) with isocratic elution. The mobile phase consisted of 10% 5.0 mM ammonium acetate water solution in a binary mixture of acetonitrile/methanol (60:40, v/v) and pumped at a flow rate of 0.10 mL min(-1). Quantitation of the analytes was performed with selected ion monitoring (SIM) in positive ionization mode using electrospray ionization interface. The assay was found to be linear in the concentration range of 5.0-500.0 ng mL(-1) for perindopril and perindoprilat. Intermediate precision were found less than 3.5% over the tested concentration ranges. A run time of less than 6.0 min for each sample made it possible to analyze a large number of human plasma samples per day. The method is the first reported application of HILIC in the analysis of angiotensin-converting enzyme inhibitors and can be used to quantify perindopril and perindoprilat in human plasma covering a variety of pharmacokinetic or bioequivalence studies. PMID- 20195580 TI - Alternative instrumentation for the analysis of total carbon dioxide (TCO(2)) in equine plasma. AB - The analysis of total carbon dioxide (TCO(2)) in equine plasma is conventionally done in Australia and elsewhere using Beckman Synchron EL-ISE(R) analysers. This instrument is no longer being manufactured and has not been supported by the supplier since December 2008. For testing for TCO(2) to continue, it is necessary to evaluate and commission alternative instrumentation. In this paper, we compare the Beckman Synchron EL-ISE, the Beckman Synchron CX5, the Beckman UniCel DxC 600 and the Randox Daytona instruments. Results indicate that all four instruments perform in accordance with the manufacturer's specifications. The Beckman CX 5, DxC 600 and Randox Daytona instruments are therefore all suitable alternatives for routine screening in a laboratory environment. Only the Randox Daytona instrument is sufficiently 'portable', i.e. it can be readily transported and used on-site at a racecourse (typically in a purpose-built modest-size laboratory vehicle). The three Beckman instruments are suitable for 'confirmatory analysis' using the quality-accredited method (Racing Science Centre), but the principle of operation of the Randox Daytona instrument may preclude its use in confirmatory analysis. Instrument costs may affect purchase decisions. PMID- 20195581 TI - Detection of proteases using an immunochemical method with haptenylated-gelatin as a solid-phase substrate. AB - A simplified method for the measurement of proteases utilising solid-phase substrates incorporating an ELISA end-point detection step is described. Gelatin hapten conjugates adsorbed onto polystyrene surfaces were found to be efficient substrates for proteases. Digestion of the solid-phase protein-hapten complexes resulted in proportional desorption of the attached conjugates and decrease in the detectable hapten species. Gelatin-cholic acid conjugates, affinity-purified sheep anti-cholic acid antibody-HRP and a chromogenic substrate were incorporated into a convenient and highly sensitive solid-phase immunochemical method. The detectable signal is inversely proportional to enzyme activity. Bacterial proteases (alpha-chymotrypsin Type II, Type IX from Bacillus polymyxa, Type XIV from Streptomyces griseus, Type XXIV from Bacillus licheniformens) were assayed. Dose-response curves for enzyme activities were measured within ranges of 0-550 microunits mL(-1) for chymotrypsin, 0-12 microunits mL(-1) for type IX, 0-35 microunits mL(-1) for type XIV and 0-100 microunits mL(-1) for type XXIV. The detection limits of the proteases studied were 89 microunits mL(-1) for chymotrypsin, 0.26 microunits mL(-1) for type IX, 5.8 microunits mL(-1) for type XIV and 6.5 microunits mL(-1) for type XXIV. It was demonstrated that the two step immunochemical method combines the simplicity and sensitivity of solid-phase enzyme immunoassays, the broad specificity of gelatin as a protease substrate and the flexibility of the solid-phase format. PMID- 20195583 TI - Certification of reference materials for Cd, Cr, Hg and Pb in polypropylene. AB - Two reference materials, at relatively low and high concentrations (GBW08404 and GBW08405), for analysis of the mass fractions of Cd, Cr, Hg and Pb in polypropylene were developed. The reference materials were prepared by doping blank polypropylene base material with Cd, Cr, Hg and Pb in the form of oxides, salts or pigments. Homogeneity and stability studies were performed by inductively coupled plasma mass spectrometry. The certification of the four analytes was carried out by isotope-dilution mass spectrometry (IDMS) with microwave-assisted digestion. Combined uncertainties were calculated from the IDMS uncertainty evaluation budget and the uncertainty of the homogeneity. The mass fractions of Cd, Cr, Hg and Pb of the two certified reference materials (CRMs) were from 8 to 1,000 mg kg(-1). The two samples were also used in an interlaboratory comparison scheme in which National Institute of Metrology, China, National Metrological Institute of Japan and Korea Research Institute of Standards and Science participated. The agreement of the comparison results proved that the certification procedure of the CRMs is valid and that the certified values of Cd, Cr, Hg and Pb are accurate and reliable. PMID- 20195582 TI - Analysis of hormone antagonists in clinical and municipal wastewater by isotopic dilution liquid chromatography tandem mass spectrometry. AB - A comprehensive method was developed for the simultaneous trace analysis of ten hormone antagonist pharmaceuticals (raloxifene, exemestane, letrozole, anastrozole, mifepristone, finastride, tamoxifen, N-desmethyltamoxifen, clomiphene, and toremifene) in municipal sewage and hospital wastewater samples. The target compounds were firstly extracted using an Oasis HLB cartridge, followed by purification by an aminopropyl cartridge, and were then analyzed by liquid chromatography electrospray ionization tandem mass spectrometry in positive ion mode. The recoveries for the analytes based on internal standard calibration in different test matrices ranged from 67.6 to 118.6% (with the exception of mifepristone in clinical wastewater samples), with relative standard deviations less than 20%. The method quantification limits of the ten pharmaceuticals were in the range 0.10-2.0 ng/L. Excluding exemestane and N desmethyltamoxifen, eight drugs were detected at 0.20-195.0 ng/L in hospital wastewater and municipal wastewater samples from Beijing. PMID- 20195584 TI - Simultaneous quantitation of morphine, 6-acetylmorphine, codeine, 6-acetylcodeine and tramadol in hair using mixed-mode solid-phase extraction and gas chromatography-mass spectrometry. AB - A simple procedure has been developed and validated for the qualitative and quantitative analysis of several opiates (morphine, 6-acetylmorphine, codeine, 6 acetylcodeine) and tramadol in hair. The analytes were extracted from within the matrix via an overnight incubation with methanol at 65 degrees C, and afterwards the samples were cleaned up by mixed-mode solid-phase extraction. The extracts were derivatized with N-methyl-N-(trimethylsilyl) trifluoroacetamide with 5% trimethylchlorosilane and analyzed by gas chromatography-mass spectrometry in the selected ion monitoring mode. The method was linear from 0.05 (lower limit of quantitation) to 50 ng/mg (40 ng/mg for tramadol), with correlation coefficients higher than 0.99 for all compounds, accomplishing the cut-off values proposed by the Society of Hair Testing for the detection of these substances in hair (0.2 ng/mg). Intra- and interday precision and trueness were in conformity with the criteria normally accepted in bioanalytical method validation, and the sample cleanup step presented a mean efficiency higher than 90% for all analytes. Furthermore, using these incubation conditions, 6-acetylmorphine did not significantly hydrolyze to morphine. For these reasons, and because of its simplicity, the proposed method can be successfully applied in the determination of these compounds in hair samples, and is suitable for application in routine analysis with forensic purposes. PMID- 20195585 TI - Holistic visualisation of the multimodal transport and fate of twelve pharmaceuticals in biosolid enriched topsoils. AB - The use of municipal biosolids as agricultural fertilisers has raised significant concerns in recent years. As part of this, the presence of complex mixtures of pharmaceutical residues and their effects on soil ecosystems remains particularly under-researched. This study focuses on the transfer of a selection of pharmaceutical residues from municipal sewage sludge to agricultural topsoils and their fate therein after an accelerated 6-month rainfall event. Twelve pharmaceuticals encompassing antibiotics, analgesics, anti-inflammatories, beta blockers, hyperlipidaemics and stimulants were invesigated by employing a combination of extraction techniques and liquid chromatography-tandem mass spectrometry. Both liquid- and solid-phase pharmaceutical contents were analysed and pharmaceutical and personal care products quantified at defined timepoints to elucidate transport behaviour and transformation potential. Results show the distribution and separation of pharmaceuticals over a 100-mm soil depth following typical biosolid enrichment. Using experimentally determined solid-water partition coefficients (K (d)) and hydrophobicity distribution ratios (D (ow)), mobility and modes of interaction under dynamic conditions are discussed. Finally, a brief study into the susceptibility of soil microbes is also presented. To our knowledge, this is the first investigation of pharmaceutical and personal care products release from amended biosolids to soils to include the factors and mechanisms governing their distribution and transformation even over relatively shallow depths. It applies multicompartmental and mass-balanced chemical analyses as well as microbiological approaches for a holistic view of these complex processes. PMID- 20195586 TI - Novel derivatisation technique for the determination of chlorophenoxy acid type herbicides by gas chromatography-mass spectrometry. AB - The analytical detection of chlorophenoxycarboxylic-acid-type herbicides (2,4-D, dichloprop, MCPA, etc.) in environmental samples is often a problem in instrumental analysis, as these compounds containing free carboxylic groups require chemical derivatisation prior to gas chromatographic (GC) methods. Nine chlorophenoxy-acid-type herbicide active ingredients have been derivatised successfully with trimethylsilyl N,N-dimethyl carbamate and t-butyldimethylsilyl N,N-dimethyl carbamate by forming their trimethylsilyl (TMS) and t butyldimethylsilyl (TBDMS) esters, respectively. The detection and determination of the derivatives were performed by capillary gas chromatography-mass spectrometry. The study included determination of retention indices, mass spectral properties and comparison of derivatives produced. The mass spectra of TBDMS derivatives are usually dominated by very characteristic ions [M-57](+) resulting from the cleavage of t-butyl moiety during electron impact (EI) ionisation in the mass spectrometer. Limits of detection were 5 to 100 pg applying GC with EI-MS detection in full scan mode. The method, using SPE sample preparation, was applied for the analysis of 115 ground water and surface water samples collected in Bekes County, Hungary in 2009. PMID- 20195587 TI - Rationale and conditions for the requirement of chiral bioanalytical methods in bioequivalence studies. AB - PURPOSE: The aim of the present work was to assess the need for chiral bioanalytical methods in bioequivalence studies. METHODS: The samples from a bioequivalence study of two ibuprofen 2% oral suspensions that had shown bioequivalence for AUC and C(max), but not for t(max) (medians of 2.0 and 0.75 h) with a non-chiral method were assayed with a chiral method to investigate whether there was an actual difference in the rate of absorption within the limits of C(max) and AUC bioequivalence. RESULTS: The non-chiral method and the sum of concentrations of both enantiomers obtained with the chiral method gave a similar outcome (90% CI C(max) non-chiral: 82.77-96.09, sum of enantiomers: 82.19-98.23; 90% CI AUC(t) non-chiral: 107.23-115.49, sum of enantiomers: 105.73-121.35). However, the chiral method showed differences in AUC and C(max) that resulted in non-bioequivalence for the individual enantiomers (90% CI C(max) S-ibuprofen: 76.05-91.36, R-ibuprofen: 87.84-113.05; 90% CI AUC(t) S-ibuprofen: 96.67-105.86, R-ibuprofen: 118.86-142.24). The differences in the pharmacokinetics of each enantiomer, and thus in the enantiomer concentration ratio, were dependent on the rate of absorption. CONCLUSIONS: Due to the fact that in bioequivalence studies the rate of absorption of the new product is unknown, chiral bioanalytical methods should be employed for chiral drugs, such as ibuprofen, whose enantiomers exhibit different pharmacodynamic characteristics and whose enantiomer concentration ratio might be modified by the rate of absorption, irrespective of whether the eutomer is the minor enantiomer or the similarity of the pharmacokinetics of the enantiomers at a given rate of absorption. PMID- 20195588 TI - A pilot study to evaluate a community pharmacy-based monitoring system to identify adverse drug reactions associated with paediatric medicines use. AB - INTRODUCTION: Current pharmacovigilance systems are limited by spontaneous reporting of adverse drug reactions (ADRs), lack of a denominator, and lower than expected reporting rates. The aim of our study was to undertake a formal pilot evaluation of a community pharmacy-led ADR monitoring system. METHODS: The setting was community pharmacies in five Health Boards areas of Scotland. Subjects were parents, guardians, or children presenting prescriptions for children 16 years and under prescribed serotonin specific reuptake inhibitors (SSRI), anticonvulsants, or medicines for the treatment of attention deficit hyperactivity disorder (ADHD). All pharmacies (n = 827) were invited to participate. Over a 3-month period they were asked to identify prescriptions for targeted medicines and give out an ADR questionnaire. Questionnaire content included child demography, duration of medicine use, indication, perceived ADRs, and their description and severity. The study was approved by the North of Scotland Research Ethics Committee. RESULTS: Seventy-two community pharmacists (8.7%) agreed to take part. Two hundred and twenty-nine questionnaires were distributed and 55 (24%) completed and returned by parents. Forty-one questionnaires related to ADHD medications, 13 to anticonvulsants, and 1 to an SSRI. Thirty questionnaires reported 44 possible ADRs, 19 of which were related to methylphenidate. CONCLUSIONS: The proposed ADR monitoring system identified expected ADRs thus demonstrating face and content validity for our approach. However the process was limited by low community pharmacist participation rates and low questionnaire return rates. PMID- 20195589 TI - Plasma concentrations of salbutamol in the treatment of acute asthma in a pediatric emergency. Could age be a parameter of influence? AB - OBJECTIVE: The objective was to determine if the plasma concentrations of salbutamol, obtained during inhalation treatment of infantile acute asthma, are influenced by age range and by the aerosol system used. METHOD: A randomized clinical trial was conducted in 46 children (1-5 years of age) with a diagnosis of acute asthma crisis, established in an emergency room pediatric service. Twenty-five children received salbutamol using a pressurized metered-dose inhaler with spacer (50 microg/kg), and 21 children received salbutamol by nebulization (150 microg/kg),three times during a 1-h period. At the end of the treatment, one blood sample was drawn and the plasma was stored for later determination of salbutamol concentration (liquid chromatography). Salbutamol plasma concentrations were compared in two age groups (< or =2 years and >2 years of age). The type of device used (pressurized metered-dose inhaler or nebulizer) and the need of hospitalization were also tested. The Mann-Whitney U test was used with the level of significance set at 5% (P < 0.05). RESULTS: No differences were detected regarding either the aerosol delivery system used or the need for hospitalization in relation to the plasma concentrations of salbutamol. However, higher plasma levels were found in patients >2 years vs patients < or =2 years [median (IQR): 9.40 (6.32-18.22) vs. 4.65 (2.77-10.10) ng/mL], demonstrating a significance difference (P = 0.05). CONCLUSION: Salbutamol plasma concentrations were influenced by age group of the patients submitted to inhalation therapy, even with doses adjusted for body weight. After correcting for the differences in the biovailabilities of the delivery systems, the concentrations were independent of the aerosol delivery device used. PMID- 20195590 TI - Does registration of serial MRI improve diagnosis of dementia? AB - INTRODUCTION: We aimed to assess the value of a second MR scan in the radiological diagnosis of dementia. METHODS: One hundred twenty subjects with clinical follow-up of at least 1 year with two scans were selected from a cognitive disorders clinic. Scans were reviewed as a single first scan (method A), two unregistered scans presented side-by-side (method B) and a registered pair (method C). Scans were presented to two neuroradiologists and a clinician together with approximate scan interval (if applicable) and age. Raters decided on a main and subtype diagnosis. RESULTS: There was no evidence that differences between methods (expressed as relative odds of a correct response) differed between reviewers (p = 0.17 for degenerative condition or not, p = 0.5 for main diagnosis, p = 0.16 for subtype). Accordingly, results were pooled over reviewers. For distinguishing normal/non-progressors from degenerative conditions, the proportions correctly diagnosed were higher with methods B and C than with A (p = 0.001, both tests). The difference between method B and C was not statistically significant (p = 0.18). For main diagnosis, the proportion of correct diagnoses were highest with method C for all three reviewers; however, this was not statistically significant comparing with method A (p = 0.23) or with method B (p = 0.16). For subtype diagnosis, there was some evidence that method C was better than method A (p = 0.01) and B (p = 0.048). CONCLUSIONS: Serial MRI and registration may improve visual diagnosis in dementia. PMID- 20195591 TI - Asexual endophytes in a native grass: tradeoffs in mortality, growth, reproduction, and alkaloid production. AB - Neotyphodium endophytes are asexual, seed-borne fungal symbionts that are thought to interact mutualistically with their grass hosts. Benefits include increased growth, reproduction, and resistance to herbivores via endophytic alkaloids. Although these benefits are well established in infected introduced, agronomic grasses, little is known about the cost and benefits of endophyte infection in native grass populations. These populations exist as mosaics of uninfected and infected plants, with the latter often comprised of plants that vary widely in alkaloid content. We tested the costs and benefits of endophyte infections with varying alkaloids in the native grass Achnatherum robustum (sleepygrass). We conducted a 4-year field experiment, where herbivory and water availability were controlled and survival, growth, and reproduction of three maternal plant genotypes [uninfected plants (E-), infected plants with high levels of ergot alkaloids (E+A+), and infected plants with no alkaloids (E+A-)] were monitored over three growing seasons. Generally, E+A+ plants had reduced growth over the three growing seasons and lower seed production than E- or E+A- plants, suggesting a cost of alkaloid production. The reduction in vegetative biomass in E+A+ plants was most pronounced under supplemented water, contrary to the prediction that additional resources would offset the cost of alkaloid production. Also, E+A+ plants showed no advantage in growth, seed production, or reproductive effort under full herbivory relative to E- or E+A- grasses, contrary to the predictions of the defensive mutualism hypothesis. However, E+A+ plants had higher overwintering survival than E+A- plants in early plant ontogeny, suggesting that alkaloids associated with infection may protect against below ground herbivory or harsh winter conditions. Our results suggest that the mosaic of E-, E+A+, and E+A- plants observed in nature may result from varying biotic and abiotic selective factors that maintain the presence of uninfected plants and infected plants that vary in alkaloid production. PMID- 20195592 TI - SAXS-data-based structural modeling of DNA-gadolinium complexes fixed in particles of cholesteric liquid-crystalline dispersions. AB - Structure of cholesteric liquid-crystalline dispersions (CLCDs) formed by double stranded DNA molecules and treated with gadolinium salts was studied by small angle X-ray scattering (SAXS). The obtained SAXS data open the way for structural modeling of these complexes to obtain a reasonable explanation for the correlated decrease in amplitude of an abnormal negative band in the circular dichroism (CD) spectra and the characteristic Bragg peak in the experimental small-angle X-ray scattering curves observed on treatment of CLCD by gadolinium salts. Model simulations of different kinds of structural organizations of the DNA-gadolinium complex were performed using novel SAXS data analysis methods in combination with several new, complementary modeling techniques, enabling us to build low resolution three-dimensional structural models of DNA-gadolinium complexes fixed in CLCD particles. The obtained models allow us to suggest that a change takes place in the helical twist of quasinematic layers formed by these molecules at high concentrations of gadolinium salt. This change in the twist can be used to explain the experimentally observed increase in amplitude of an abnormal band in the CD spectra of DNA CLCD. PMID- 20195594 TI - Domain architecture evolution of pattern-recognition receptors. AB - In animals, the innate immune system is the first line of defense against invading microorganisms, and the pattern-recognition receptors (PRRs) are the key components of this system, detecting microbial invasion and initiating innate immune defenses. Two families of PRRs, the intracellular NOD-like receptors (NLRs) and the transmembrane Toll-like receptors (TLRs), are of particular interest because of their roles in a number of diseases. Understanding the evolutionary history of these families and their pattern of evolutionary changes may lead to new insights into the functioning of this critical system. We found that the evolution of both NLR and TLR families included massive species-specific expansions and domain shuffling in various lineages, which resulted in the same domain architectures evolving independently within different lineages in a process that fits the definition of parallel evolution. This observation illustrates both the dynamics of the innate immune system and the effects of "combinatorially constrained" evolution, where existence of the limited numbers of functionally relevant domains constrains the choices of domain architectures for new members in the family, resulting in the emergence of independently evolved proteins with identical domain architectures, often mistaken for orthologs. PMID- 20195593 TI - Characterization of rhesus macaque KIR genotypes and haplotypes. AB - Certain combinations of the killer immunoglobulin-like receptors (KIR) and major histocompatibility complex class I ligands in humans predispose carriers to a variety of diseases, requiring sophisticated genotyping of the highly polymorphic and diverse KIR and HLA genes. Particularly, KIR genotyping is challenging due to polymorphisms (allelic substitutions), genomic diversity (presence/absence of genes), and frequent duplications. Rhesus macaques are often used as important animal models of human diseases such as, e.g. AIDS. However, typing of rhesus macaque KIR genes has not been described so far. In this study, we report the identification of additional novel rhesus macaque KIR cDNA sequences and a sequence-specific KIR genotyping assay. From a cohort of four rhesus macaque families with a total of 70 individuals, we identified 25 distinct KIR genotypes. Segregation analyses of KIR genes and of two polymorphic microsatellite markers allowed the identification of 21 distinct KIR haplotypes in these families, with five to 11 segregating KIR genes per haplotype. Our analyses confirmed and extended knowledge on differential gene KIR gene content in macaques and indicate that rhesus macaque and human KIR haplotypes show a comparable level of diversity and complexity. PMID- 20195595 TI - Unique CT imaging findings of liver in Wilson's disease. AB - PURPOSE: To present unique CT imaging findings of the liver in Wilson's disease. MATERIALS AND METHODS: Thirteen consecutive subjects with clinically and/or pathologically proven Wilson's disease underwent abdominal Computer Tomography examination. RESULTS: Hyperdense nodules and a honeycomb appearance were observed on unenhanced CT in 92.31 and 58.33% of our patients, respectively. CONCLUSION: Wilson's disease involving the liver has several unique CT findings in comparison to other types of cirrhosis. These specific features include hyperdense nodules and a honeycomb pattern not only in portal and parenchymal phases, but also in the pre-contrast scan. PMID- 20195596 TI - In vivo experimental study of hat type cervical intervertebral fusion cage (HCIFC). AB - The purpose of this study was to compare the characteristics of interbody fusion achieved using the hat type cervical intervertebral fusion cage (HCIFC) with those of an autologous tricortical iliac crest graft, Harms cage and the carbon cage in a goat cervical spine model. Thirty-two goats underwent C3-4 discectomy and fusion. They were subdivided into four groups of eight goats each: group 1, autologous tricortical iliac crest bone graft; group 2, Harms cage filled with autologous iliac crest graft; group 3, carbon cage filled with autologous iliac bone; and group 4, HCIFC filled with autologous iliac graft. Radiography was performed pre- and postoperatively and after one, two, four, eight and 12 weeks. At the same time points, disc space height, intervertebral angle, and lordosis angle were measured. After 12 weeks, the goats were killed and fusion sites were harvested. Biomechanical testing was performed in flexion, extension, axial rotation, and lateral bending to determine the stiffness and range of motion. All cervical fusion specimens underwent histomorphological analyses. One week after operation, the disc space height (DSH), intervertebral angle (IVA) and lordosis angle (LA) of HCIFC and carbon cage were statistically greater than those of autologous iliac bone graft and Harms cage. Significantly higher values for DSH, IVA and LA were shown in cage-treated goats than in those that received bone graft over a 12-week period. The stiffness of Harms cage in axial rotation and lateral bending were statistically greater than that of other groups. Radiographic and histomorphological evaluation showed better fusion results in the cage groups than in the autologous bone group. HCIFC can provide a good intervertebral distractability and sufficient biomechanical stability for cervical fusion. PMID- 20195597 TI - Two-year migration results of the ReCap hip resurfacing system-a radiostereometric follow-up study of 23 hips. AB - There has been renewed interest for metal-on-metal hip resurfacing due to improved design and manufacturing of implants, better materials, and enhanced implant fixation. In contrast to conventional total hip replacements, only a few clinical hip resurfacing trials using radiostereometry (RSA) have been reported, and solely for the Birmingham hip resurfacing arthroplasty. The purpose of this RSA trial was to describe the migration pattern of a new hip resurfacing system (ReCap) within the first two years after primary surgery. Twenty-six patients underwent total hip replacement. The patients were followed-up for up to 24 months and were evaluated with the use of radiostereometric measurements. The prosthesis showed mean translations and rotation close to zero. Maximum translation was seen along the transverse axis in the medial direction (0.13 mm). No statistically significant translation or rotation was seen at two-years follow up, (t-test, p <0.05, translation or rotation). PMID- 20195598 TI - Allelopathic potential of switchgrass (Panicum virgatum L.) on perennial ryegrass (Lolium perenne L.) and alfalfa (Medicago sativa L.). AB - This study investigated allelopathy and its chemical basis in nine switchgrass (Panicum virgatum L.) accessions. Perennial ryegrass (Lolium perenne L.) and alfalfa (Medicago sativa L.) were used as test species. Undiluted aqueous extracts (5 g plant tissue in 50 ml water) from the shoots and roots of most of the switchgrass accessions inhibited the germination and growth of the test species. However, the allelopathic effect of switchgrass declined when extracts were diluted 5- or 50-fold. Seedling growth was more sensitive than seed germination as an indicator of allelopathic effect. Allelopathic effect was related to switchgrass ecotype but not related to ploidy level. Upland accessions displayed stronger allelopathic potential than lowland accessions. The aqueous extract from one switchgrass accession was separated into phenols, organic acids, neutral chemicals, and alkaloids, and then these fractions were bioassayed to test for allelopathic potential. Alkaloids had the strongest allelopathic effect among the four chemical fractions. In summary, the results indicated that switchgrass has allelopathic potential; however, there is not enough evidence to conclude that allelopathic advantage is the main factor that has contributed to the successful establishment of switchgrass on China's Loess Plateau. PMID- 20195599 TI - A water quality model for regional stream assessment and conservation strategy development. AB - Non-point-source (NPS) pollution remains the primary source of stream impairment in the United States. Many problems such as eutrophication, sedimentation, and hypoxia are linked with NPS pollution which reduces the water quality for aquatic and terrestrial organisms. Increasingly, NPS pollution models have been used for landscape-scale pollution assessment and conservation strategy development. Our modeling approach functions at a scale between simple landscape-level assessments and complex, data-intensive modeling by providing a rapid, landscape-scale geographic information system (GIS) model with minimal data requirements and widespread applicability. Our model relies on curve numbers, literature-derived pollution concentrations, and land status to evaluate total phosphorus (TP), total nitrogen (TN), and suspended solids (SS) at the reach scale. Model testing in the Chesapeake Bay watershed indicated that predicted distributions of water quality classes were realistic at the reach scale, but precise estimates of pollution concentrations at the local scale can have errors. Application of our model in the tributary watersheds along Lake Ontario suggested that it is useful to managers in watershed planning by rapidly providing important information about NPS pollution conditions in areas where large data gaps exist, comparisons among stream reaches across numerous watersheds are required, or regional assessments are sought. PMID- 20195602 TI - Nonsurgical management should be first-line therapy for breast abscess. PMID- 20195600 TI - Management of the retained knife blade. AB - BACKGROUND: The retained knife blade is an unusual and spectacular injury. The aim of this study was to review our experience with the management of such injuries. METHODS: A retrospective chart review of patients with retained knife blades treated at Groote Schuur Hospital Trauma Centre from January 1996 to December 2007 was undertaken. RESULTS: Thirty-three patients with retained knife blades were identified. Site of wound entry was the thorax in 13 patients (40%), the neck and back in 7 patients (21%) each, upper and lower extremities in 4 (12%), and the face and abdomen in 1 patient (3%) each. Thirty patients (91%) were hemodynamically stable on admission; two (6%) presented with wound abscesses, and one patient (3%) with active bleeding required emergency surgery. All 33 blades were extracted after clinical and radiological assessment. Simple withdrawal of the blade was possible in 19 cases (58%) and the likelihood of post extraction bleeding was only 5%. Thirteen patients (40%) required an open surgical approach through dissection of the entry wound, laparotomy, or thoracotomy. Video-assisted thoracoscopic removal was used in one case. Retained thoracic blades were significantly associated with postoperative sepsis (P = 0.0054). There were no deaths. CONCLUSIONS: All impacted knife injuries require careful clinical and radiological assessment. Simple withdrawal can be performed safely in the emergency room provided potential life-threatening vascular and solid organ injuries have been excluded. There should be a low threshold for investigating and treating patients with retained intrathoracic blades for postoperative sepsis. PMID- 20195603 TI - Precise preoperative imaging and adequate oncologic resection is most important in achieving long-term prognosis in gallbladder cancer. PMID- 20195605 TI - Metabolic markers obtained by microdialysis can detect secondary intestinal ischemia: an experimental study of ischemia in porcine intestinal segments. AB - BACKGROUND: The free intestinal flap has become a recognized part of the surgical armamentarium for the reconstruction of the cervical esophagus and in the treatment of severe short bowel syndrome. However, the intestinal flap is difficult to monitor postoperatively and is susceptible to ischemia. Entire avoidance of neglected ischemia and false alarms require a monitoring system with sensitivity and specificity of 100%. The aim of this study was to investigate the value of microdialysis (MD) as a monitoring method for detecting ischemia in intestinal transplants. METHODS: In 12 pigs the entire small intestine was divided into three segments, each isolated on a vascular pedicle consisting of one artery and one vein. For metabolic monitoring of the intestinal segments, one CMA 63 MD catheter was placed in each segment in the mesentery just at the border of the intestinal wall. After 1 h of arterial ischemia followed by 2 h of reperfusion, the three intestinal segments in each pig were allocated to arterial ischemia, venous ischemia, or no ischemia. A total of 10 control segments, 10 segments with arterial ischemia, and nine segments with venous ischemia were provided for evaluation of metabolic changes. RESULTS: One hour of secondary ischemia induced considerable metabolic changes, with a decrease in the concentration of glucose (C (Glucose)) followed by an increase in the concentration of lactate (C (Lactate)) as well as in the lactate:pyruvate (L/P) and lactate:glucose (L/G) ratios. The changes became even more pronounced after 1(1/2) h when the L/P and L/G ratios had increased 9 and 30 times, respectively, in the ischemic segments and without overlap in values between the ischemic and the nonischemic segments. When using C (Glucose) < 0.2 mmol/l or L/G > 50 as cutoff levels for detection of ischemia, a sensitivity and a specificity of 100% could be achieved. An increase in C (Glucose) of more than 2 mmol/l, after the infusion of glucose, could be used as a challenge test to exclude ischemia. CONCLUSIONS: A monitoring system based on the determination of the C (Glucose) and C (Lactate) by using microdialysis can be used for positive differentiation between ischemic and nonischemic intestinal segments. PMID- 20195606 TI - Post-surgical recurrence of ileal Crohn's disease. PMID- 20195607 TI - Gastric mucosa-associated lymphoid tissue lymphoma complicated with hemophagocytic syndrome in an elderly woman. PMID- 20195604 TI - Postsurgical recurrence of ileal Crohn's disease: an update on risk factors and intervention points to a central role for impaired host-microflora homeostasis. AB - BACKGROUND: A pressing need exists to identify factors that predispose to recurrence after terminal ileal resection for Crohn's disease (CD) and to determine effective prophylactic strategies. This review presents an up-to-date summary of the literature in the field and points to a role for bacterial overproliferation in recurrence. METHODS: The literature (Medline, Embase, and the Cochrane Library, 1971-2009) on ileal CD and postoperative recurrence was searched, and 528 relevant articles were identified and reviewed. RESULTS: Smoking is a key independent risk factor for recurrence. NOD2/CARD15 polymorphisms and penetrating phenotype are associated with aggressive disease and higher reoperation rates. Age at diagnosis, disease duration, gender, and family history are inconsistent predictors of recurrence. Prophylactic 5 aminosalicylic acid therapy and nitromidazole antibiotics are beneficial. Combination therapies with immunosuppressants are also effective. Anti-TNFalpha based regimens show benefit but the evidence base is small. Corticosteroid, interleukin-10, and probiotic therapies are not effective. Wider, stapled anastomotic configurations are associated with reduced recurrence rates. Strictureplasty and laparoscopic approaches have similar long-term recurrence rates to open resection techniques. Length of resection and presence of microscopic disease at resection margins do not influence recurrence. A lack of consensus exists regarding whether the presence of granulomas or plexitis affects outcome. CONCLUSIONS: Current evidence points to defects in mucosal immunity and intestinal dysbiosis of either innate (NOD2/CARD15) or induced (smoking) origin in postoperative CD recurrence. Prophylactic strategies should aim to limit dysbiosis (antibiotics, side-to-side anastomoses) or prevent downstream chronic inflammatory sequelae (anti-inflammatory, immunosuppressive, and immunomodulatory therapy). PMID- 20195608 TI - Mutations of the TET2 and CBL genes: novel molecular markers in myeloid malignancies. AB - Despite recent progress in molecular research in myeloid malignancies, in subsets of patients with myelodysplastic syndrome (MDS) so far no underlying mutation was identified. In the myeloproliferative neoplasms (MPNs), the JAK2V617F alone cannot explain the phenotypic heterogeneity. In acute myeloid leukemia (AML), clinical variability exists within distinct subgroups. Thus, the search for novel molecular markers continues. Recently, mutations of the tet oncogene family member 2 (TET2) and Casitas B-cell lymphoma (CBL) genes became the focus of interest. With diverse genetic methods, TET2 on chromosome 4q24 was identified as candidate tumor suppressor gene. Sequencing studies revealed heterogeneous mutations in 10-25% of patients with acute myeloid leukemia (AML), MDS, and MPNs, while the frequency might be higher in chronic myelomonocytic leukemia (CMML). The prognostic impact is being explored. The CBL gene is involved in the degradation of tyrosine kinases. In rare cases of human AML (<2%), CBL mutants were identified, with a higher frequency in core binding factor leukemias. Presence of these mutations was suggested to be involved in aberrant FLT3 expression. In the MPNs, a 2-8% frequency of CBL mutations was reported. These novel mutations deepened insights in the mechanisms of leukemogenesis, might contribute to the identification of new therapeutic targets, and improve diagnostics in the myeloid malignancies. PMID- 20195609 TI - Plasma membrane damage contributes to antifungal activity of silicon against Penicillium digitatum. AB - The antifungal activity of silicon (Si) on Penicillium digitatum, and the possible action mode involved were investigated. Spore germination, germ tube elongation, and mycelial growth of P. digitatum were strongly inhibited by Si in the form of sodium silicate. Using propidium iodide (PI) stain combined with fluorescent microscopy, it was found that the plasma membrane of Si-treated P. digitatum spores was obviously damaged, and the leakage of protein and sugar was significantly higher in Si-treated mycelia than that of control. These findings suggest that the damage on plasma membrane of P. digitatum played a crucial role in the antifungal effect of Si. Moreover, Si was effective in controlling green mold caused by P. digitatum in citrus fruit. These results have a beneficial impact on the application of Si in the control of postharvest diseases. PMID- 20195610 TI - The tissue expression pattern of the AtGRP5 regulatory region is controlled by a combination of positive and negative elements. AB - The AtGRP5 gene from Arabidopsis thaliana encodes a glycine-rich protein which has a major activity in protoderm-derived cells and is expressed in cells that undergo the first anatomical modifications leading to somatic embryo development. It has been previously demonstrated that its minimum promoter is 316 bp long including the 5'UTR and presents three putative TATA-boxes sequences and several regions that are homologous to previous characterized cis-acting elements. In order to better characterize the AtGRP5 expression and to identify the promoter regions involved in its preferential epidermal expression, in situ hybridization and 5' promoter deletions were employed. In situ hybridization and GUS expression assays indicate that, besides being present during somatic embryogenesis, AtGRP5 is also expressed during the zygotic embryo development. The sequential 5' deletions indicate that multiple negative and positive regulatory elements are present in the AtGRP5 promoter and operate in order to confer its distinct expression pattern. A 44-bp region was shown to be essential for the epidermal expression of this gene in leaves, stems, flowers and fruits, and is also responsible for high activity of the AtGRP5 promoter in zygotic embryos. An element responsible for the phloem expression was also identified in a 35-bp region. PMID- 20195612 TI - Fertility restoration by Ifr1 in rice with BT-type cytoplasmic male sterility is associated with a reduced level, but not processing, of atp6-orf79 co-transcribed RNA. AB - BT-type cytoplasmic male sterility (CMS) in rice is associated with accumulation of unprocessed dicistronic RNA containing a duplicated atp6 (B-atp6) and an unusual open reading frame, orf79, encoding a cytotoxic peptide in mitochondria. The male-sterile state of BT-type CMS is stably maintained by backcrossing the plants with line Taichung 65 (T65) that has no restorer gene and is completely suppressed by the presence of the Rf1 gene through the processing of B-atp6-orf79 RNA. A variant of the T65 line, T65(T), has a weak restoration function conferred by the Ifr1 gene, which is genetically independent of the Rf1 gene. However, not much is known about the mechanism(s). In a study to examine whether the mechanism involved in fertility restoration by Ifr1 is analogous to restoration mediated by Rf1, the transcript profile of B-atp6-orf79 in male-sterile plants was compared with that in fertility restored plants obtained by crossing male-sterile plants with T65(T). The cellular level of unprocessed B-atp6-orf79 RNA was reduced in the restored plants, but no change in processing efficiency or the quantity of B atp6-orf79 DNA was detected. These results suggest that Ifr1 restores fertility through reducing either the transcription rate of B-atp6-orf79 or the stability of its primary transcripts, a mechanism distinct from that involved in fertility restoration of BT-type CMS by Rf1. PMID- 20195611 TI - Upregulation of phytosterol and triterpene biosynthesis in Centella asiatica hairy roots overexpressed ginseng farnesyl diphosphate synthase. AB - Farnesyl diphosphate synthase (FPS) plays an essential role in organ development in plants. However, FPS has not previously been identified as a key regulatory enzyme in triterpene biosynthesis. To elucidate the functions of FPS in triterpene biosynthesis, C. asiatica was transformed with a construct harboring Panax ginseng FPS (PgFPS)-encoding cDNA coupled to the cauliflower mosaic virus 35S promoter. Higher levels of CaDDS (C. asiatica dammarenediol synthase) and CaCYS (C. asiatica cycloartenol synthase) mRNA were detected in all hairy root lines overexpressing when compared with the controls. However, no differences were detected in any expression of the CaSQS (C. asiatica squalene synthase) gene. In particular, the upregulation of CaDDS transcripts suggests that FPS may result in alterations in triterpene biosynthesis capacity. Squalene contents in the T17, T24, and T27 lines were increased to 1.1-, 1.3- and 1.5-fold those in the controls, respectively. The total sterol contents in the T24 line were approximately three times higher than those of the controls. Therefore, these results indicated that FPS performs a regulatory function in phytosterol biosynthesis. To evaluate the contribution of FPS to triterpene biosynthesis, we applied methyl jasmonate as an elicitor of hairy roots expressing PgFPS. The results of HPLC analysis revealed that the content of madecassoside and asiaticoside in the T24 line was transiently increased by 1.15-fold after 14 days of MJ treatment. This result may indicate that FPS performs a role not only in phytosterol regulation, but also in triterpene biosynthesis. PMID- 20195613 TI - [Modeling in value-based medicine]. AB - Modeling plays an important role in value-based medicine (VBM). It allows decision support by predicting potential clinical and economic consequences, frequently combining different sources of evidence. Based on relevant publications and examples focusing on ophthalmology the key economic modeling methods are explained and definitions are given. The most frequently applied model types are decision trees, Markov models, and discrete event simulation (DES) models. Model validation includes besides verifying internal validity comparison with other models (external validity) and ideally validation of its predictive properties. The existing uncertainty with any modeling should be clearly stated. This is true for economic modeling in VBM as well as when using disease risk models to support clinical decisions. In economic modeling uni- and multivariate sensitivity analyses are usually applied; the key concepts here are tornado plots and cost-effectiveness acceptability curves. Given the existing uncertainty, modeling helps to make better informed decisions than without this additional information. PMID- 20195614 TI - [Methods for estimating personal costs of disease using retinal diseases as an example]. AB - PURPOSE: Age-related macular degeneration (AMD) and other retinal diseases, such as diabetic retinopathy (DRP) and hereditary retinal dystrophy can not only lead to a loss of visual function but also to a higher psychological and financial burden for the affected persons. Against this background a quantification of personal cost and vision-related quality of life was performed. METHODS: A total of 66 patients (mean age 69 years, SD 13 years) with clinically confirmed diagnoses of AMD, DRP or retinal dystrophy were interviewed regarding costs for medicines, aids and equipment, support in everyday life and social benefits. Vision-related quality of life was recorded using the Impact of Vision Impairment profile (IVI). RESULTS: The average total annual cost was 751 per patient, out of which the largest amount was cost of support in everyday life (506). Costs as well as dependence on other persons or social services increased with decreasing visual acuity (p=0.013). Vision-related quality of life decreased with increasing visual disability especially in the IVI subscales mobility and independence as well as reading and accessing information (p=0.002). CONCLUSIONS: Prevention or delay of visual disability and blindness caused by AMD or other retinal diseases and thus ensuring independence is not only relevant from a medical perspective but also from a health economic perspective. Against the background of a relative shortage of resources, costs should be reduced regardless of whether they are personal or societal costs. PMID- 20195615 TI - An unusual loss of EGFR gene copy in glioblastoma multiforme in a child: a case report and analysis of a successfully derived HGG-02 cell line. AB - PURPOSE: The aim of this study was to perform a detailed cytogenetic and molecular genetic analysis of a tumor taken from a 14.5-year-old boy with glioblastoma multiforme who showed an atypical clinical course. METHODS: Formalin fixed, paraffin embedded tumor tissue and the corresponding HGG-02 cell line derived from this tumor were analyzed using fluorescence in situ hybridization (FISH), G-banding, multiplex ligation-dependent probe amplification (MLPA), functional analysis of separated alleles in yeast (FASAY), immunohistochemistry (IHC), and immunocytochemistry (ICC). RESULTS: Mutation of the p53 gene and hypermethylation of the MLH1 gene were detected by FASAY and MLPA, respectively. Cytogenetic analysis showed a polyploid karyotype with extensive heterogeneity in chromosome number. Using FISH, we identified a very unusual genetic change - a loss of EGFR gene copy in both the tumor tissue and the HGG-02 cell line. In accordance with the cytogenetic findings, IHC and ICC did not demonstrate overexpression of EGFR in the tumor tissue or HGG-02 cells. CONCLUSIONS: Despite his very poor prognosis, the patient experienced 34 months of event-free survival after surgery and adjuvant radiotherapy and chemotherapy. The detected loss of the EGFR gene copy may contribute to the unusual biological features of this tumor, but the forthcoming detailed expression analysis of cancer regulatory pathways is necessary to better understand this tumor phenotype. PMID- 20195616 TI - Pediatric epilepsy surgery and sudden unexpected death epilepsy: the contribution of a Brazilian epilepsy surgery program. AB - BACKGROUND AND PURPOSE: Individuals with epilepsy are at higher risk of death than those from the general population, and sudden unexpected death in epilepsy (SUDEP) is the most important direct epilepsy-related cause of death. Epilepsies in the pediatric group are more frequently associated with known potentially risk factors for SUDEP, and a treatment resulting in an improved seizure control may also decrease mortality. The aim of this study is to identify the incidence of SUDEP in a group of operated-on children and adolescents. METHODS: We analyzed 267 patients up to 18 years old, with medically intractable epilepsy submitted to surgery. We considered the age at surgery, the seizure type, the pathological findings, and the seizure outcome. Data were prospectively collected, according to the protocols of our institution's ethics committee. RESULTS: The percentage of boys was 58.05. A good outcome was achieved in 72.6% of the cases and a bad outcome in 27.4%. Nine patients died during follow-up, six from clinical complications, and one from SUDEP. All patients who died during the long-term follow-up had persisted with refractory postoperative seizures. The patient who died from SUDEP died during a generalized tonic-clonic seizure. CONCLUSIONS: Of the patients, 72.6% had excellent postoperative outcome, and one patient died of SUDEP. All patients who died had had disabling seizures' persistence. The surgical treatment of epilepsy in children and adolescents is an efficient therapy for the medically intractable symptomatic epilepsies and also for the reduction of mortality and SUDEP risks. PMID- 20195617 TI - Subdural hematoma in infants: can it occur spontaneously? Data from a prospective series and critical review of the literature. AB - BACKGROUND: Subdural hematomas (SDH) in infants often result from nonaccidental head injury (NAHI), which is diagnosed based on the absence of history of trauma and the presence of associated lesions. When these are lacking, the possibility of spontaneous SDH in infant (SSDHI) is raised, but this entity is hotly debated; in particular, the lack of positive diagnostic criteria has hampered its recognition. The role of arachnoidomegaly, idiopathic macrocephaly, and dehydration in the pathogenesis of SSDHI is also much discussed. PURPOSE: We decided to analyze apparent cases of SSDHI from our prospective databank. MATERIALS AND METHODS: We selected cases of SDH in infants without systemic disease, history of trauma, and suspicion of NAHI. All cases had fundoscopy and were evaluated for possible NAHI. Head growth curves were reconstructed in order to differentiate idiopathic from symptomatic macrocrania. RESULTS: Sixteen patients, 14 males and two females, were diagnosed with SSDHI. Twelve patients had idiopathic macrocrania, seven of these being previously diagnosed with arachnoidomegaly on imaging. Five had risk factors for dehydration, including two with severe enteritis. Two patients had mild or moderate retinal hemorrhage, considered not indicative of NAHI. Thirteen patients underwent cerebrospinal fluid drainage. The outcome was favorable in almost all cases; one child has sequels, which were attributable to obstetrical difficulties. CONCLUSION: SSDHI exists but is rare and cannot be diagnosed unless NAHI has been questioned thoroughly. The absence of traumatic features is not sufficient, and positive elements like macrocrania, arachnoidomegaly, or severe dehydration are necessary for the diagnosis of SSDHI. PMID- 20195618 TI - Local and regional flap closure in myelomeningocele repair: a 15-year review. AB - PURPOSE: A trend in large myelomeningocele defect repair involves soft tissue closure with muscle and fascial flap techniques to provide a durable, protective, and tension-free soft tissue covering. We propose that composite tissue closure yields superior outcomes regardless of defect size. METHODS: We present a retrospective review of our 15-year, single-institution experience using this approach. Our study includes 45 consecutive patients treated using combinations of muscle and fascia flaps for primary closure of a myelomeningocele defect. RESULTS: Lumbosacral fascia closures were used in 18 cases (40%) with paraspinous muscle closure and 12 cases (27%) without paraspinous closure. Fascial closure with bony pedicle periosteum and gluteal muscle and fascial closure were used in four cases (9%) each. Other techniques included latissimus dorsi flaps and combinations of these techniques. Postoperatively, none of our patients experienced a cerebrospinal fluid leak, and only one patient required reoperation for skin flap necrosis. CONCLUSIONS: Objective measures show that universal application of flap techniques may lead to better outcomes for soft tissue closure during myelomeningocele repair. PMID- 20195619 TI - Vacuum-assisted closure of chronic anorectal fistula. PMID- 20195620 TI - A new sphincter-preserving operation for low rectal cancer: ultralow anterior resection and colorectal/coloanal anastomosis by supporting bundling-up method. AB - PURPOSE: The introductions of total mesorectal excision and double-stapling technique into colorectal surgery have promoted the clinical application of sphincter preservation. However, for the tumors localized on the middle or lower level of rectum, sphincter-preservation approaches might be problematic in some patients. We introduce in this report a new sphincter-preserving technique for low rectal cancer. METHODS: Between August 1999 and May 2004, 310 patients underwent ultralow anterior resection and colorectal/coloanal anastomosis by supporting bundling-up method for low rectal cancer localized in the lower third of rectum. Postoperative evaluation included anal function, anastomotic leakage, anastomotic stenosis, cumulative survival rate, and local recurrence. RESULTS: Three hundred ten patients received the sphincter-preserving operation without severe intraoperative complications. One patient died of lung dysfunction (0.3%). All patients had satisfactory anal function without soiling. The median follow-up was 84 months (9-136 months) and overall survival rate was 97.0% at 1 year, 73.5% at 3 years, and 66% at 5 years. Thirty-six patients (11.6%) patients developed local recurrence. Postoperative complications included anastomotic leakage (1.6%), anastomotic stenosis (2.5%), and local and distant recurrence (11.6% and 18.4%, respectively). CONCLUSIONS: Ultralow anterior resection and colorectal/coloanal anastomosis by supporting bundling-up method may be one of the best choices of sphincter-preserving operation for low rectal cancer. PMID- 20195621 TI - Expression of Lgr5 in human colorectal carcinogenesis and its potential correlation with beta-catenin. AB - BACKGROUNDS AND AIMS: Lgr5 is a member of the G protein receptor super-family and was shown recently to be a stem cell marker for cells with intestinal differentiation. Its over-expression has been demonstrated in hepatocellular, basal cell carcinoma, and ovarian cancers but the underlying mechanisms are poorly understood. The aim of this study was to investigate if Lgr5 over expression was correlated with human colorectal carcinogenesis and its potential correlation with beta-catenin. METHODS: The study was carried out on a tissue microarray that consisted of 102 colorectal carcinomas (CRC; M:F = 55:47), 18 colon adenoma, and 12 colon normal mucosa cases. Immunostains were performed with the standard EnVision method with primary antibodies against Lgr5, beta-catenin, and p53 antigens. Immunoreactivity of neoplastic cells to each antibody was double-blindly semi-quantified by two pathologists and the data were analyzed with the Chi-square and Spearman rank correlation tests. Subsequently, expression of Lgr5 in tissue sections of tumor centre and invasive margins of 21 cases of CRC certified to be immunoreactive of Lgr5 in TMA were evaluated and possible differences of Lgr5 expression between them were analyzed. RESULTS: Lgr5 immunoreactivity was observed only in single cells in the base of normal colon mucosal crypts but high in 28% (five out of 18) adenomas, and significantly higher in 54% (55/102, p = 0.016) CRC cases. In normal mucosa, adenoma, and CRC, beta-catenin expression was seen in 25% (three out of 12), 27% (five out of 18), and 81% (83/102) cases, respectively, in contrast to 0, 0, and 40% (41/102) for p53 expression, respectively. In CRC, Lgr5 expression was more intense in women than men (p < 0.0001), and positively correlated with beta-catenin expression (p < 0.001), but not with patients' ages, tumor sizes, nodal status, TNM stages, and p53 expression. Different expression of Lgr5 between tumor centre and invasive margins was not found (p > 0.05). CONCLUSIONS: The results suggest that up regulation of Lgr5 expression, especially in female patients, may play an important role in colorectal carcinogenesis, probably through the WNT/beta catenin pathway, but not involve the progression of the CRC. PMID- 20195623 TI - Molecular identification of carrion-breeding scuttle flies (Diptera: Phoridae) using COI barcodes. AB - Entomological evidence is often used in forensic cases for post-mortem interval (PMI) calculation. The most dominant species present on a corpse are typically blowflies. However, several cases have been reported where access to a corpse has been restricted for blowflies (e.g., on a buried or wrapped cadavers) but species of the family Phoridae were abundant. It has also been reported that some phorid species that exploit human corpses may also feature in cases of myiasis acquired ante-mortem. In all these cases, they may provide decisive evidence. As for blowflies, the precise identification of a phorid species collected from a corpse is necessary when estimating the PMI. Since morphological determination is often hampered due to similar characteristics especially in the larval and pupal stage, we used DNA-based methods to identify six phorid species (Megaselia scalaris, Megaselia giraudii, Megaselia abdita, Megaselia rufipes, Conicera tibialis, and Puliciphora borinquenensis) on the molecular level. We focused on a 658-bp-long region of the cytochrome oxidase I gene (COI), the most common molecular marker in forensic entomology. The amplified fragment is also used in DNA barcode approaches and was found to be suitable for identification of a wide range of insect taxa. The present study demonstrates that this region is also sufficient to distinguish between several species of scuttle flies. PMID- 20195622 TI - Development and analysis of a germline BAC resource for the sea lamprey, a vertebrate that undergoes substantial chromatin diminution. AB - Over the last several years, the sea lamprey (Petromyzon marinus) has grown substantially as a model for understanding the evolutionary fundaments and capacity of vertebrate developmental and genome biology. Recent work on the lamprey genome has resulted in a preliminary assembly of the lamprey genome and led to the realization that nearly all somatic cell lineages undergo extensive programmed rearrangements. Here we describe the development of a bacterial artificial chromosome (BAC) resource for lamprey germline DNA and use sequence information from this resource to probe the subchromosomal structure of the lamprey genome. The arrayed germline BAC library represents approximately 10x coverage of the lamprey genome. Analyses of BAC-end sequences reveal that the lamprey genome possesses a high content of repetitive sequences (relative to human), which show strong clustering at the subchromosomal level. This pattern is not unexpected given that the sea lamprey genome is dispersed across a large number of chromosomes (n approximately 99) and suggests a low-copy DNA targeting strategy for efficiently generating informative paired-BAC-end linkages from highly repetitive genomes. This library therefore represents a new and biologically informed resource for understanding the structure of the lamprey genome and the biology of programmed genome rearrangement. PMID- 20195624 TI - Transfer of biological stains from different surfaces. AB - Highly sensitive short tandem repeat-based stain analysis of weak biological stains has been improved during the last years. The risk of transfer of cellular material from handled items contaminated with biological stains such as blood and saliva is of forensic relevance. Although the policemen working with crime scene items are very careful, there exists a potential risk of transfer contamination. To obtain estimates for the risk of stain transfer by handling, we have carried out an experimental study on 288 dried blood and saliva stains in two laboratories. DNA quantification showed only small amounts of DNA that could be transferred, especially from stains on paper and cotton. The saliva and especially the blood stains from plastic surface resulted in higher amounts of transferred DNA, depending on the relation of blood volume to included area: Of 192 direct transfers, 17% gave extracts above 10 pg DNA/MUl, and only 3% of 96 secondary transfers resulted in amounts above 10 pg DNA/MUl. PMID- 20195626 TI - Drainage of subretinal fluid in optic disc pit maculopathy using subretinal 42 gauge cannula: a new surgical approach. AB - BACKGROUND: Different surgical approaches have been used for the treatment of optic disc pit associated maculopathy, with increasing emphasis on vitrectomy. METHODS: Case report RESULTS: We report a case of optic disc pit maculopathy where vitrectomy was combined with subretinal fluid drainage using a 42-gauge subretinal cannula connected to a "back-flush" flute handle. No retinopexy was performed at the site of drainage. This technique resulted in almost complete resolution of subretinal fluid by 6 weeks, with visual acuity improving from 1.00 Log MAR preoperatively to 0.40 at 8 months after surgery. CONCLUSION: We describe a novel technique for subretinal fluid drainage using a subretinal 42-G cannula connected to a standard "back flush" flute in optic disc pit-associated maculopathy. PMID- 20195625 TI - Topographic and age-related changes of the retinal epithelium and Bruch's membrane of rhesus monkeys. AB - PURPOSE: To examine structural differences in the retinal pigmented epithelium (RPE) and Bruch's membrane of rhesus monkeys (Macaca mulatta) as a function of topography and age. METHODS: The retinas of two old (24 and 26 years old) and two young (1 and 6 years old) female monkeys were examined by light fluorescence and electron microscopy at the macula, equator, and ora serrata. RESULTS: All monkeys lacked fluorescence and lipofuscin granules in the RPE at the ora serrata where photoreceptors are absent. The equator and macula showed intense fluorescence and many lipofuscin granules in the RPE of the old but not the young monkeys. At the ora, the RPE contained many dense round melanin granules throughout the cell. At the equator and macula, melanin granules were more apical, less frequent, and often elongated. Mitochondria were clustered at the basal side of the RPE cell near infolds of the plasma membrane. Both mitochondria and infolds tended to increase toward the macula. In all regions, the basal lamina of the RPE did not penetrate the extracellular space adjacent to infolds. The elastin layer of Bruch's membrane was wide at the ora and equator and thinner at the macula. In the old monkeys, drusen were found at all retinal regions between the basal lamina and the internal collagen layer of Bruch's membrane. The drusen were often membrane-bound with a basal lamina and contained material resembling structures in the RPE. CONCLUSIONS: Lack of fluorescence and lipofuscin in the RPE at the ora serrata, where photoreceptors are absent, confirms that RPE fluorescence occurs only where outer segments are phagocytized. Mitochondrial clustering indicates that the basal side of the RPE cell uses the most energy and this becomes maximal at the macula. The presence of age-related degenerative changes and drusen at all retinal locations in the older monkeys, even at the ora where RPE lipofuscin was absent, indicates that these processes are not dependent on local lipofuscin accumulation. Therefore lipofuscin toxicity may not be the sole cause of age-related RPE degeneration. PMID- 20195627 TI - Seventy-year-old habitual volleyball players have larger tibial cross-sectional area and may be differentiated from their age-matched peers by the osteogenic index in dynamic performance. AB - The osteogenicity of a given exercise may be estimated by calculating an osteogenic index (OI) consisting of magnitude and rate of strain. Volleyball involves repetitive jumping and requires high power output and thus may be expected to be beneficial to bone and performance. The purpose of the present study was to examine if habitual volleyball playing is reflected in OI. Ten elderly habitual volleyball players [age 69.9 (SD 4.4) years] and ten matched controls volunteered [age 69.7 (4.2) years] as subjects. Distal tibia (d), tibial mid-shaft (50) and femoral neck (FN) bone characteristics were measured using pQCT and DXA. To estimate skeletal rigidity, cross-sectional area (ToA(50)), and compressive (BSI(d)) and bending strength indices (SSImax(50)) were calculated. Maximal performance was assessed with eccentric ankle plantar flexion, isometric leg press and countermovement jump (CMJ). A fast Fourier transform (FFT) was calculated from the acceleration of the center of mass during the CMJ. Maximal acceleration (MAG) and mean magnitude frequency (MMF) were selected to represent the constituents of OI. OI was calculated as the sum of the products of magnitudes and corresponding frequencies. Volleyball players had 7% larger ToA(50) and 37% higher power in CMJ, 15% higher MAG and 36% higher OI (P or= 0.646). In conclusion, habitual volleyball players may be differentiated from their matched peers by their dynamic jumping performance, and the differences are reflected in the magnitude but not rate of loading. PMID- 20195628 TI - Algorithms, modelling and VO2 kinetics. AB - This article summarises the pros and cons of different algorithms developed for estimating breath-by-breath (B-by-B) alveolar O(2) transfer (VO 2A) in humans. VO 2A is the difference between O(2) uptake at the mouth and changes in alveolar O(2) stores (? VO(2s)), which for any given breath, are equal to the alveolar volume change at constant FAO2/FAiO2 ?VAi plus the O(2) alveolar fraction change at constant volume [V Ai-1(F Ai - F Ai-1) O2, where V (Ai-1) is the alveolar volume at the beginning of a breath. Therefore, VO 2A can be determined B-by-B provided that V (Ai-1) is: (a) set equal to the subject's functional residual capacity (algorithm of Auchincloss, A) or to zero; (b) measured (optoelectronic plethysmography, OEP); (c) selected according to a procedure that minimises B-by B variability (algorithm of Busso and Robbins, BR). Alternatively, the respiratory cycle can be redefined as the time between equal FO(2) in two subsequent breaths (algorithm of Gronlund, G), making any assumption of V (Ai-1) unnecessary. All the above methods allow an unbiased estimate of VO2 at steady state, albeit with different precision. Yet the algorithms "per se" affect the parameters describing the B-by-B kinetics during exercise transitions. Among these approaches, BR and G, by increasing the signal-to-noise ratio of the measurements, reduce the number of exercise repetitions necessary to study VO2 kinetics, compared to A approach. OEP and G (though technically challenging and conceptually still debated), thanks to their ability to track ?VO(2s) changes during the early phase of exercise transitions, appear rather promising for investigating B-by-B gas exchange. PMID- 20195629 TI - Redefining surgery and surgical profession. PMID- 20195630 TI - Mercury in pediatric poisoning. PMID- 20195632 TI - Reduced sensitivity of immunodiagnostic tests for active tuberculosis in children. PMID- 20195634 TI - Laboratory evaluation of traditionally used plant-based insect repellent against the malaria vector Anopheles arabiensis Patton (Diptera: Culicidae). AB - A laboratory study was carried out to evaluate the repellent efficacy of a methanol-leaf extract of Ethiopian traditionally used insect repellent plant viz., Lomi sar [vernacular name (local native language, Amharic); Cymbopogon citratus (DC) Stapf. (Poaceae)] against Anopheles arabiensis at four different concentrations viz., 1.0, 1.5, 2.0, and 2.5 mg/cm(2). The percentage protection in relation to the dose method was performed. C. citratus extract has shown various degrees of repellency impact against A. arabiensis. It provided the maximum total percentage protection of 78.83% at 2.5 mg/cm(2) and followed 68.06% at 2.0 mg/cm(2) for 12 h. All four tested concentrations of C. citratus extract offered significant protection and Student's t test results shows statistically significant (p value = 0.001) [1.0 mg/cm(2) (t = 22.89; df = 4); 1.5 mg/cm(2) (t = 24.03; df = 4); 2.0 mg/cm(2) (t = 36.92; df = 4); 2.5 mg/cm(2) (t = 22.31; df = 4)] difference between treated and control groups. The result suggests that it could serve as a potent insect repellent against vectors of disease. Globally, C. citratus is renowned for its therapeutic values. Above and beyond, due to its user- as well as environmental-friendly nature, it should be promoted among the marginalized populations in order to reduce man-vector contact. In addition, this appropriate strategy affords the opportunity to minimize chemical repellent usage and the risks associated with adverse side effects. At the end of the day, traditionally used plant-based insect repellents could be viable safer alternative sources for chemical insect repellents. PMID- 20195633 TI - Effectiveness of neonatal pulse oximetry screening for detection of critical congenital heart disease in daily clinical routine--results from a prospective multicenter study. AB - Pulse oximetry screening (POS) has been proposed as an effective, noninvasive, inexpensive tool allowing earlier diagnosis of critical congenital heart disease (cCHD). Our aim was to test the hypothesis that POS can reduce the diagnostic gap in cCHD in daily clinical routine in the setting of tertiary, secondary and primary care centres. We conducted a prospective multicenter trial in Saxony, Germany. POS was performed in healthy term and post-term newborns at the age of 24-72 h. If an oxygen saturation (SpO(2)) of 0.05). However, Single-Short and Single-Long techniques provided markedly lower construct torsional stiffness than the other three groups (P < 0.05). For lumbo-illiac reconstruction after total sacrectomy, even the use of bilateral single, long iliac screws do not help in restoring the local stability to the intact condition. However, dual iliac screws provide much higher construct stability than single iliac screw techniques. Therefore, dual iliac screw technique should be preferred for treating the unstable situation caused by total sacrectomy. PMID- 20195651 TI - A randomised controlled trial on the effectiveness of bracing patients with idiopathic scoliosis: failure to include patients and lessons to be learnt. AB - Trials often do not succeed in including as many patients as anticipated beforehand. The aim of this paper was to describe why we were not able to include more than a few patients in our randomized controlled treatment trial on the effectiveness of bracing patients with idiopathic scoliosis, and to describe which lessons can be learnt. A pilot study on the willingness to participate in such a trial was conducted amongst 21 patients and their parents. A description of how we prepared and designed this trial, the problems we faced and how we tried to improve the inclusion are given. A total of four patients were included, and 14 refused to participate in an 18-month period. There were a lot less eligible patients than anticipated (40 instead of 100 per year), and the patients' participation rate was much lower than we had found in our pilot study (21% instead of 70%). The trial failed to include more than a few patients because of an overestimation of the number of eligible patients and because a lot less eligible patients were willing to participate compared to our pilot study. One reason for a low participation rate could be that this trial evaluated a frequently used existing treatment instead of a new treatment, and patients and parents might be afraid of not being treated (despite an intensive secure system for the control arm). PMID- 20195652 TI - Idiopathic scoliosis and balance organisation in seated position on a seesaw. AB - The aim was to determine the biomechanical processes involved in postural regulation when self-imposed disturbances occur in the seated position in the antero-posterior direction. Twelve female adolescents with right thoracic scoliosis (SG) (Cobb = 30.4 degrees +/- 9.7) and 15 control adolescents (CG) were included in this study. The ground reaction forces (GRF) were studied whilst the subjects maintained their balance in the sitting position on a seesaw. Six conditions were tested: eyes open and closed; with an additional load placed on the subject's right or left shoulder; and with an additional load on the subject's right or left pelvis. The SG showed significantly higher force amplitudes and variability and fewer oscillations than the CG in all the conditions. In the SG, the time analysis showed that the duration of the GRF was significantly higher in forward and left directions. Whatever the condition tested, the intra-group differences were not significant. The scoliotic patients in seated position were characterised by larger changes of the GRF, especially with a postural control in the forward and left directions, corresponding to that on the concave side of their spinal curvature. No significant differences were found to exist between the various conditions (load and unload, eyes open and eyes closed). Clinical tests and rehabilitation methods should include assessments of seated patients' spatio-temporal adaptation to GRF. PMID- 20195653 TI - 6-Mercaptopurine attenuates adhesive molecules in experimental vasospasm. AB - OBJECTIVE: Adhesion molecules, including intercellular adhesion molecule-1 (ICAM 1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin, are important inflammatory mediators which are elevated in the serum of patients following aneurysmal subarachnoid hemorrhage (SAH). The authors previously found that 6 mercaptopurine (6-mp) was effective in preventing and reversing arterial narrowing in a rodent SAH model. The present study was to examine whether levels of adhesion molecules were altered after treatment with 6-mp in this animal model. MATERIALS AND METHODS: Animals were each injected with autologous blood into the cisterna magna, and intraperitoneal treatment with 6-mp (2 mg/kg) was initiated 1 h before (prevention) or later (treatment). The compound was subsequently administered at 24 and 48 h post-SAH. Blood samples were collected at 72 h post-SAH to measure ICAM-1, VCAM-1, and E-selectin levels. The basilar arteries were harvested and sliced, and their cross-sectional areas were measured. Morphologically, convolution of the internal elastic lamina, distorted endothelial wall, and myonecrosis of the smooth muscle were prominently observed in the SAH only and vehicle-treated SAH groups, but not in the 6-mp-treated SAH group or in healthy controls. No significant differences were found in the levels of VCAM-1 among all groups. However, the levels of E-selectin were increased in all animals subjected to SAH (SAH only and SAH plus vehicle groups) compared with healthy controls (no SAH), but not in the 6-mp group (SAH plus 6-mp treatment and preventive treatment with 6-mp).Likewise, the levels of ICAM-1 in the SAH only and SAH plus vehicle groups were significantly elevated (p < 0.001), and pretreatment and treatment with 6-mp reduced ICAM-1 to control levels. CONCLUSION: These results show that ICAM-1 and E-selectin may play a role in mediating SAH-induced vasospasm and that a reduction of both adhesive molecules after SAH may partly contribute to the antispastic effect of 6-mp. PMID- 20195655 TI - Recombinant mouse beta-defensin 2 inhibits infection by influenza A virus by blocking its entry. AB - Human influenza A virus (IAV) is a major cause of life-threatening respiratory tract disease worldwide. Defensins are small cationic peptides of about 2-6 kDa that are known for their broad-spectrum antimicrobial activity. Here, we focused on the anti-influenza A activity of mouse beta-defensin 2 (mBD2). The prokaryotic expression plasmid pET32a-mBD2 was constructed and introduced into Escherichia coli Rosseta gami (2) to produce recombinant mBD2 (rmBD2). Purified rmBD2 showed strong antiviral activity against IAV in vitro. The protective rate for Madin Darby canine kidney cells was 93.86% at an rmBD2 concentration of 100 microg/ml. Further studies demonstrated that rmBD2 prevents IAV infection by inhibiting viral entry. In addition, both pretreatment and postinfection treatment with rmBD2 provided protection against lethal virus challenge with IAV in experimental mice, with protection rates of 70 and 30%, respectively. These results suggest that the mBD2 might have important effects on influenza A virus invasion. PMID- 20195654 TI - Cross-protection against influenza virus infection by intranasal administration of M2-based vaccine with chitosan as an adjuvant. AB - Influenza vaccines based on conserved antigens could provide cross-protection against infections by multiple subtypes of influenza A virus. Influenza matrix protein 2 (M2) is highly conserved in all influenza A strains. In this study, we deleted the transmembrane domain of the M2 of the avian influenza virus (AIV) A/Chicken/Jiangsu/7/2002 (H9N2) strain to create an M2 without a transmembrane domain, named sM2, which was efficiently expressed in Escherichia coli. The sM2 protein was administered intranasally to mice in combination with chitosan adjuvant three times at an interval of 3 weeks. Three weeks after the last immunization, the mice were challenged with a lethal dose (5 x LD(50)) of A/Chicken/Jiangsu/7/2002 (H9N2) virus, PR8 (H1N1) virus and A/Chicken/Henan/12/2004 (H5N1) virus. The protective immunity of the vaccine was evaluated by determining the survival rates, residual lung virus titers, body weight, and the serum antibody titers of the mice. Nasal administration of 15 microg sM2 in combination with chitosan completely protected mice against the homologous virus and protected 90 and 30% of the mice against the heterologous H1N1 and H5N1 viruses, respectively. The study indicated that the sM2 protein was a candidate antigen for a broad-spectrum influenza virus vaccine and that the adjuvant chitosan improved the efficacy of the sM2 vaccine. PMID- 20195656 TI - Genomic sequences of blackberry chlorotic ringspot virus and strawberry necrotic shock virus and the phylogeny of viruses in subgroup 1 of the genus Ilarvirus. AB - Three members of subgroup 1 of the genus Ilarvirus: blackberry chlorotic ringspot (BCRV), strawberry necrotic shock (SNSV), and tobacco streak viruses (TSV), may infect Rubus and Fragaria species. All cause symptoms similar to those previously attributed to infection by TSV alone. Although similarities exist among the genomic sequences of the three, phylogenetic analysis shows them to be distinct viruses. These viruses and Parietaria mottle virus, the other currently accepted member of subgroup 1, appear to have evolved from a common ancestral virus, share conserved motifs in the products of the genomic RNAs, and constitute a distinct subgroup within the genus. PMID- 20195657 TI - Dynamic morphologies of pollen plastids visualised by vegetative-specific FtsZ1 GFP in Arabidopsis thaliana. AB - The behaviour and multiplication of pollen plastids have remained elusive despite their crucial involvement in cytoplasmic inheritance. Here, we present live images of plastids in pollen grains and growing tubes from transgenic Arabidopsis thaliana lines expressing stroma-localised FtsZ1-green-fluorescent protein fusion in a vegetative cell-specific manner. Vegetative cells in mature pollen contained a morphologically heterogeneous population of round to ellipsoidal plastids, whilst those in late-developing (maturing) pollen included plastids that could have one or two constriction sites. Furthermore, plastids in pollen tubes exhibited remarkable tubulation, stromule (stroma-filled tubule) extension, and back-and-forth movement along the direction of tube growth. Plastid division, which involves the FtsZ1 ring, was rarely observed in mature pollen grains. PMID- 20195658 TI - Thiol dioxygenases: unique families of cupin proteins. AB - Proteins in the cupin superfamily have a wide range of biological functions in archaea, bacteria and eukaryotes. Although proteins in the cupin superfamily show very low overall sequence similarity, they all contain two short but partially conserved cupin sequence motifs separated by a less conserved intermotif region that varies both in length and amino acid sequence. Furthermore, these proteins all share a common architecture described as a six-stranded beta-barrel core, and this canonical cupin or "jelly roll" beta-barrel is formed with cupin motif 1, the intermotif region, and cupin motif 2 each forming two of the core six beta strands in the folded protein structure. The recently obtained crystal structures of cysteine dioxygenase (CDO), with contains conserved cupin motifs, show that it has the predicted canonical cupin beta-barrel fold. Although there had been no reports of CDO activity in prokaryotes, we identified a number of bacterial cupin proteins of unknown function that share low similarity with mammalian CDO and that conserve many residues in the active-site pocket of CDO. Putative bacterial CDOs predicted to have CDO activity were shown to have similar substrate specificity and kinetic parameters as eukaryotic CDOs. Information gleaned from crystal structures of mammalian CDO along with sequence information for homologs shown to have CDO activity facilitated the identification of a CDO family fingerprint motif. One key feature of the CDO fingerprint motif is that the canonical metal-binding glutamate residue in cupin motif 1 is replaced by a cysteine (in mammalian CDOs) or by a glycine (bacterial CDOs). The recent report that some putative bacterial CDO homologs are actually 3-mercaptopropionate dioxygenases suggests that the CDO family may include proteins with specificities for other thiol substrates. A paralog of CDO in mammals was also identified and shown to be the other mammalian thiol dioxygenase, cysteamine dioxygenase (ADO). A tentative fingerprint motif for ADOs, or DUF1637 family members, is proposed. In ADOs, the conserved glutamate residue in cupin motif 1 is replaced by either glycine or valine. Both ADOs and CDOs appear to represent unique clades within the cupin superfamily. PMID- 20195659 TI - The effect of acidic residues and amphipathicity on the lytic activities of mastoparan peptides studied by fluorescence and CD spectroscopy. AB - Some mastoparan peptides extracted from social wasps display antimicrobial activity and some are hemolytic and cytotoxic. Although the cell specificity of these peptides is complex and poorly understood, it is believed that their net charges and their hydrophobicity contribute to modulate their biological activities. We report a study, using fluorescence and circular dichroism spectroscopies, evaluating the influence of these two parameters on the lytic activities of five mastoparans in zwitterionic and anionic phospholipid vesicles. Four of these peptides, extracted from the venom of the social wasp Polybia paulista, present both acidic and basic residues with net charges ranging from +1 to +3 which were compared to Mastoparan-X with three basic residues and net charge +4. Previous studies revealed that these peptides have moderate-to-strong antibacterial activity against Gram-positive and Gram-negative microorganisms and some of them are hemolytic. Their affinity and lytic activity in zwitterionic vesicles decrease with the net electrical charges and the dose response curves are more cooperative for the less charged peptides. Higher charged peptides display higher affinity and lytic activity in anionic vesicles. The present study shows that the acidic residues play an important role in modulating the peptides' lytic and biological activities and influence differently when the peptide is hydrophobic or when the acidic residue is in a hydrophilic peptide. PMID- 20195660 TI - Synthesis and electrochemical behaviour of beta-halodehydroamino acid derivatives. AB - Several new beta,beta-dihalo and beta-halo-beta-substituted dehydroalanines and dehydrodipeptides were synthesized by reacting the corresponding dehydroamino acid derivative with a N-halosuccinimide or in the case of beta,beta-di iododehydroalanines with iodine. The results obtained confirmed that the stereochemical outcome of the halogenation reaction with beta-substituted dehydroamino acids depends on the substrate. Thus, an increase Z stereoselectivity was found when the beta-phenyldehydroalanines were used as substrates and when these compounds were N-protected with 4-tolylsulfonyl or with carbamates. From this study, it is also possible to conclude that when N iodosuccinimide was used as reagent a much higher Z-stereoselectivity is found. The electrochemical behaviour of the halogenated dehydroamino acids was studied by cyclic voltammetry. The results show a shift in the reduction peak to higher potentials of the beta-halogenated dehydroamino acids when compared with the corresponding non-halogenated derivatives. As expected, the beta,beta dihalodehydroalanines exhibit higher peak potentials than beta-halo-beta substituted dehydroalanines and the bromo derivatives have lower peak potentials when compared with the corresponding iododehydroamino acids. Controlled potential electrolysis of several beta-halo-beta-substituted dehydroamino acids afforded the corresponding dehalogenated dehydroamino acids as mixtures of their E and Z isomers. In all cases, the major isomer isolated results from dehalogenation without isomerization. These new results show that electrochemical reduction constitutes a valuable method for the synthesis of the E-isomer of beta substituted dehydroalanines. PMID- 20195661 TI - Study of a structurally similar kappa opioid receptor agonist and antagonist pair by molecular dynamics simulations. AB - Among the structurally similar guanidinonaltrindole (GNTI) compounds, 5'-GNTI is an antagonist while 6'-GNTI is an agonist of the kappaOR opioid receptor. To explore how a subtle alteration of the ligand structure influences the receptor activity, we investigated two concurrent processes: the final steps of ligand binding at the receptor binding site and the initial steps of receptor activation. To trace these early activation steps, the membranous part of the receptor was built on an inactive receptor template while the extracellular loops were built using the ab initio CABS method. We used the simulated annealing procedure for ligand docking and all-atom molecular dynamics simulations to determine the immediate changes in the structure of the ligand-receptor complex. The binding of an agonist, in contrast to an antagonist, induced the breakage of the "3-7 lock" between helices TM3 and TM7. We also observed an action of the extended rotamer toggle switch which suggests that those two switches are interdependent. PMID- 20195662 TI - Effects of the V82A and I54V mutations on the dynamics and ligand binding properties of HIV-1 protease. AB - A major problem in the antiretroviral treatment of HIV-infections with protease inhibitors is the emergence of resistance, resulting from the occurrence of distinct mutations within the protease molecule. In the present work we investigated the structural properties of a triple mutant (I54V-V82A-L90M) and a double mutant (V82A-L90M) that both confer strong resistance to ritonavir (RTV), but not to amprenavir (APV). For the unliganded double mutant protease molecular dynamics simulations revealed a contraction of the ligand binding pocket, which is enhanced by the I54V mutation. The observed displacement of backbone atoms of the 80s loops (residues 80-85 and 80'-85' of the dimer) was found to primarily affect binding of the larger RTV molecule. The pocket contraction detected for the unbound protease upon mutation is also observed in the presence of APV, but not of RTV. As a consequence, the protein-ligand contacts lost upon the V82A mutation are restored by 80s loop motions for the APV-bound, but not for the RTV bound form. RTV binding is therefore both hampered in the initial recognition step due to the poor fit of the bulky inhibitor into the small pocket of the mutant free protease and by the loss of protein-ligand interactions in the RTV bound protease. The synergistic nature of both effects offers an explanation for the high level of resistance observed. These findings demonstrate that large inhibitors, which tightly bind to wild-type protease, may nevertheless be prone to the emergence of resistance in the presence of particular patterns of mutations. This information should be helpful for the design of novel and more effective drugs, e.g., by targeting different residues or by developing allosteric inhibitors that are capable of regulating protease dynamics. PMID- 20195663 TI - Investigation on the micro-mechanisms of Al(3+) interfering the reactivities of aspartic acid and its biological processes with Mg(2+). AB - Density functional theory (DFT) has been applied to study the micro-mechanisms of Al3+ interfering the reactivities of aspartic acid (H2asp) and its biological processes with Mg2+. All the 46 stable conformers of Hasp- and 3 of asp2- have been determined at the B3LYP/6-311++G** level, showing that the 7 most stable conformers of Hasp- all present a very strong and linear O-H...O H-bond between carboxyl and carboxylic acid groups with the bond energy high up to 162 kJ mol( 1). The reaction thermodynamics and micro-mechanism between Al3+ and Hasp- (or asp2-) in aqueous phase have been investigated by the combined application of supramolecular model and polarizable continuum IEFPCM solvent model, firstly revealing Al3+ interfering in the biological processes of aspartic acid. The substitution thermodynamics and mechanisms of Mg2+ by Al3+ in the biological processes between the species of aspartic acid and Mg2+ in aqueous phase were probed, revealing the facile displacement of Mg2+ by Al3+. These results may provide a reasonable mechanism of Al3+ biological toxicity at the microscopic level. PMID- 20195664 TI - Many-body energies during proton transfer in an aqueous system. AB - The energetics of the mechanism of proton transfer from a hydronium ion to one of the water molecules in its first solvation shell are studied using density functional theory and the Moller-Plesset perturbation (MP2) method. The potential energy surface of the proton transfer mechanism is obtained at the B3LYP and MP2 levels with the 6-311++G** basis set. Many-body analysis is applied to the proton transfer mechanism to obtain the change in relaxation energy, two-body, three body and four-body energies when proton transfer occurs from the hydronium ion to one of the water molecules in its first solvation shell. It is observed that the binding energy (BE) of the complex decreases during the proton transfer process at both levels of theory. During the proton transfer process, the % contribution of the total two-body energy to the binding energy of the complex increases from 62.9 to 68.09% (39.9 to 45.95%), and that of the total three-body increases from 25.9 to 27.09% (24.16 to 26.17%) at the B3LYP/6-311++G** (MP2/ 6-311++G**) level. There is almost no change in the water-water-water three-body interaction energy during the proton transfer process at both levels of theory. The contribution of the relaxation energy and the total four-body energy to the binding energy of the complex is greater at the MP2 level than at the B3LYP level. Significant differences are found between the relaxation energies, the hydronium-water interaction energies and the four-body interaction energies at the B3LYP and MP2 levels. PMID- 20195665 TI - Contribution of charged and polar residues for the formation of the E1-E2 heterodimer from Hepatitis C Virus. AB - The transmembrane domains of the envelope glycoprotein E1 and E2 have crucial multifunctional roles in the biogenesis of hepatitis C virus. We have performed molecular dynamics simulations to investigate a structural model of the transmembrane segments of the E1-E2 heterodimer. The simulations support the key role of the Lys370-Asp728 ion pair for mediating the E1-E2 heterodimerization. In comparison to these two residues, the simulation results also reveal the differential effect of the conserved Arg730 residue that has been observed in experimental studies. Furthermore, we discovered the formation of inter-helical hydrogen bonds via Asn367 that stabilize dimer formation. Simulations of single and double mutants further demonstrate the importance of the ion-pair and polar interactions between the interacting helix monomers. The conformation of the E1 fragment in the simulation of the E1-E2 heterodimer is in close agreement with an NMR structure of the E1 transmembrane segment. The proposed model of the E1-E2 heterodimer supports the postulated cooperative insertion of both helices by the translocon complex into the bilayer. PMID- 20195666 TI - Density functional study of oxygen vacancy formation and spin density distribution in octahedral ceria nanoparticles. AB - We report plane wave basis density functional theory (DFT) calculations of the oxygen vacancies formation energy in nanocrystalline CeO2-x in comparison with corresponding results for bulk and (111) CeO2 surface. Effects of strong electronic correlation of Ce4f states are taken into account through the use of an effective on-site Coulomb repulsive interaction within DFT+U approach. Different combinations of exchange-correlation functionals and corresponding U values reported in the literature are tested and the obtained results compared with experimental data. We found that both absolute values and trends in oxygen vacancy formation energy depend on the value of U and associated with degree of localization of Ce4f states. Effect of oxygen vacancy and geometry optimization method on spatial spin distribution in model ceria nanoparticles is also discussed. PMID- 20195667 TI - Docking and 3D-QSAR studies of diverse classes of human aromatase (CYP19) inhibitors. AB - Aromatase (cytochrome 19) inhibitors have emerged as promising candidates for treatment of breast cancer. In search of potent aromatase inhibitors, docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies using molecular shape, spatial, electronic, structural and thermodynamic descriptors have been performed on a diverse set of compounds having human aromatase inhibitory activities. An attempt has also been made to include two dimensional (2D) descriptors in the QSAR studies. The chemometric tools used for model development are genetic function approximation (GFA) and genetic partial least squares (G/PLS). The docking study shows that the important interacting amino acids in the active site cavity are Met374, Arg115, Ile133, Ala306, Thr310, Asp309, Val370 and Ser478. One or more hydrogen bond formation with Met374 is one of the essential requirements for the ligands for optimum aromatase inhibition. The binding is further stabilized by van der Waals interactions with a few non polar amino acid residues in the active site. The developed QSAR models indicate the importance of different shape, Jurs parameters, structural parameters, topological branching index and E-state index for different fragments. The results obtained from the QSAR analysis are supported by our docking observations. There should be one or two hydrogen bond acceptor groups (like NO2, -CN) and optimal hydrophobicity for ideal aromatase inhibitors. A GFA model with spline option obtained using 3D descriptors was found to be the best model based on internal validation (Q2=0.668) while the best (externally) predictive model was a GFA model with spline option using combined set (2D and 3D) descriptors (Rpred2=0.687). Based on rm2(overall) criterion, the best model was a G/PLS model (using 3D descriptors) with spline option (rm2(overall)=0.606). PMID- 20195668 TI - Pharmacophore mapping of arylamino-substituted benzo[b]thiophenes as free radical scavengers. AB - Predictive pharmacophore models have been developed for a series of arylamino substituted benzo[b]thiophenes exhibiting free radical scavenging activity. 3D pharmacophore models were generated using a set of 20 training set compounds and subsequently validated by mapping 6 test set compounds using Discovery Studio 2.1 software. Further model validation was performed by randomizing the data using Fischer's validation technique at the 95% confidence level. The most predictive pharmacophore model developed using the conformers obtained from the BEST method showed a correlation coefficient (r) of 0.942 and consisted of three features: hydrogen bond donor, hydrogen bond acceptor and aromatic ring. Acceptable values of external validation parameters, like R2pred (0.853) and r2m(test) (0.844), also implied that the external predictivity of the model was significant. The development of further pharmacophore models using conformers obtained from the FAST method yielded a few models with good predictivity, with the best one (r=0.904) consisting of two features: hydrogen bond donor and hydrogen bond acceptor. Significant values of external validation parameters, R2pred (0.913) and r2m(test) (0.821), also reflect the high predictive ability of the model. Again, Fischer validation results implied that the models developed were robust enough and their good results were not based on mere chance. These validation approaches indicate the reliability of the predictive abilities of the 3D pharmacophore models developed here, which may thus be further utilized as a 3D query tool in the virtual screening of new chemical entities with potent antioxidant activities. PMID- 20195669 TI - Development of a pulsatile flow-generating circulatory-assist device. AB - We developed a new circulation-assist device that can generate pulsatile assist flow synchronized with the patient's diastolic phase. The device is composed of a drainage tube, a centrifugal pump, an oxygenator, and a sending tube. A portable magnetic valve device composed of a pulse generator and a tamper, which produces intermittent mechanical compression, is attached to the pillow of the sending tube. Preliminary animal experiments were conducted. No changes in the animals' hemodynamics or any device problems were observed during a preliminary 48-h test run. Significant diastolic augmentation was confirmed. This new device may be useful in treating patients with severe heart failure and could be more useful than using percutaneous cardiopulmonary support (PCPS) alone. PMID- 20195670 TI - Distribution of Chlamydia trachomatis ompA genovars and the new variant of C. trachomatis in the Goteborg area, Sweden. AB - The aims of this study were to assess the proportion of the new variant of Chlamydia trachomatis (nvCT) and the distribution of ompA genovars among C. trachomatis-positive patients in the Goteborg area, Sweden. Consecutive urine samples positive for C. trachomatis using BD ProbeTec ET (177 patients, 88 men and 89 women) were collected. An nvCT-specific real-time polymerase chain reaction (PCR) assay was used to investigate the nvCT prevalence. To identify the genovars, a 990-bp ompA DNA segment from 105 specimens was sequenced. Seventeen percent (30/177) of all specimens contained nvCT. Nine different genovars were identified. About 50% were of genovar E, followed by F 16%, G 11%, K 8%, and D 5%, representing about 90% of the specimens in Goteborg. The occurrence of nvCT and the dominance of genovar E in Goteborg is similar to those in other areas of Sweden. To cover about 90% of the C. trachomatis infections in Sweden, the serovars D, E, F, G, and K should be included in future vaccines based on the major outer membrane protein. PMID- 20195671 TI - Seroprevalence of Q fever in a district located in the west Black Sea region of Turkey. AB - Q fever is a worldwide zoonosis caused by Coxiella burnetii. In Turkey, it has been reported from the late 1940s that Q fever is endemic in humans and animals. Our objective was to evaluate the seroprevalence in Samsun Tekkekoy (north Turkey), where an outbreak of Q fever occurred in 2002. In this cross-sectional study, subjects were selected by the random proportional sampling method. All subjects were healthy with no specific symptoms and tested by the microimmunofluorescent antibody test. In total, we tested 407 subjects; 33 (8.1%) of them were identified as past evidence of infection and 22 (5.4%) were considered as evolutive form of Q fever (17 acute and five chronic forms). The seroprevalence was significantly higher among people over 30 years of age, hunters, and slaughters than the others (p = 0.001, p = 0.034, and p = 0.006, respectively). We found 13.5% seropositivity among healthy subjects, confirming that Q fever is prevalent in our region and is often asymptomatic. PMID- 20195672 TI - The rag locus of Porphyromonas gingivalis might arise from Bacteroides via horizontal gene transfer. AB - Porphyromonas gingivalis is regarded as one of the risk factors of periodontitis. P. gingivalis exhibits a wide variety of genotypes. Many insertion sequences (ISs), located in their chromosomes, made P. gingivalis differentiate into virulent and avirulent strains. In this research, we investigated the prevalence of P. gingivalis in the gingival crevicular fluid (GCF) among periodontitis patients from Zhenjiang, China, detected the P. gingivalis rag locus distributions by multiplex polymerase chain reaction (PCR), and analyzed the origin of the P. gingivalis rag locus based on evolution. There were three rag locus variants co-existing in Zhenjiang. The results showed that the rag locus may be associated with severe periodontitis. This work also firstly ascertained that the rag locus might arise, in theory, from Bacteroides sp. via horizontal gene transfer. PMID- 20195673 TI - Low-dose beta-lactam plus amikacin in febrile neutropenia: cefepime vs. piperacillin/tazobactam, a randomized trial. AB - Patients with fever and granulocytopenia are at risk of developing severe infection. We performed a prospective, randomized trial to evaluate the efficacy of low-dose cefepime plus amikacin (C-A) compared to low-dose piperacillin/tazobactam plus amikacin (PT-A). Patients received cefepime (2 g/12 h) plus amikacin (15 mg/kg/day) or piperacillin/tazobactam (4 g/500 mg/8 h) plus amikacin. A total of 317 episodes of febrile granulocytopenia in 190 patients were studied (152 in the C-A group, 165 in the PT-A group). A microbiologically documented infection was present in 53 (35%) episodes in the C-A group and 41 (25%) episodes in the PT-A group (p = ns); a clinically documented infection was observed in 39 (26%) and 47 (28%) episodes, respectively. Toxicity was observed in 6 (4%) episodes in the C-A group and in 5 (3%) episodes in the PT-A group. The antibiotic success rate (no change or addition of antibiotics) was recorded in 89 (59%) and 105 (64%) cases, respectively (p = ns). Mortality related to infection was similar in each arm (3.9% vs. 3.6%). Combination therapy of low-dose beta lactam with an aminoglycoside achieves very good response rates and low rates of toxicity. It might be an attractive option in an environment of increasing resistance among gram-negative bacteria. PMID- 20195674 TI - Magnetic resonance elastography: a general overview of its current and future applications in brain imaging. AB - Magnetic resonance elastography (MRE) has been developed over the last few years as a non-invasive means of evaluating the elasticity of biological tissues. The presence of the skull has always prevented semeiotic palpation of the brain, but MRE now offers the possibility of "palpating by imaging" in order to detect brain consistency under physiological and pathological conditions. The aim of this article is to review the current state-of-the-art of MRE imaging and discuss its possible future diagnostic applications in neuroscience. PMID- 20195675 TI - The striate sign: peritumoural perfusion pattern of infiltrative primary and recurrent gliomas. AB - MR perfusion depicts angiogenesis as a key factor for growth and malignancy in gliomas by means of increased regional cerebral blood volume (rCBV). The rCBV increase is not limited to the tumour area, but may also produce a stripe-like pattern of peritumoural rCBV increase that we defined as the "striate sign". We evaluated if prior radiochemotherapy influences perfusion values and pattern in and adjacent to malignant gliomas comparing rCBV of treated recurrent gliomas with untreated gliomas. Ninety-three patients with primary or recurrent WHO grades II-IV glial tumours underwent T2*-weighted dynamic susceptibility-weighted contrast-enhanced (DSC)-MRI. Differences of normalised rCBV and rCBV(max) were evaluated using Kruskal-Wallis analysis with post hoc tests. The number of cases showing a hot spot of rCBV (rCBV(max)) and/or a peritumoural striate pattern of rCBV increase (striate sign) was assessed and evaluated by Fisher's exact test. Significance level was determined as p < 0.05. Normalised rCBV, rCBV(max) and number of cases with the striate sign were significantly lower in recurrent (rCBV = 3.24 +/- 1.22, rCBV(max) = 5.05 +/- 2.27 and striate sign = 10/24) compared to primary WHO grade IV tumours (rCBV = 4.44 +/- 1.39, rCBV(max) = 7.31 +/- 3.0 and striate sign = 17/21, respectively). There were fewer cases with a striate sign in treated recurrent WHO grade III tumours than in untreated malignant transformed WHO grade II tumours. The pattern and degree of rCBV increase in and around gliomas differ between untreated and previously treated tumours. These differences might be due to post-therapeutic changes of the tumour-associated microvasculature by radiochemotherapy. Spectroscopic and susceptibility-weighted MR imaging may provide further insights into the tumour biology. PMID- 20195676 TI - Endoscopic endonasal skull base reconstruction using a nasal septal flap: surgical results and comparison with previous reconstructions. AB - The objective of this study is to evaluate the usefulness and reliability of endoscopic endonasal skull base reconstructions using a nasal septal flap. This study is designed as a retrospective review. Between April 2005 and November 2009, we performed 32 endoscopic endonasal skull base reconstructions for closure of large dural defects. Eleven patients underwent reconstructions using fat grafts or the fascia lata (non-flap group). Twenty one patients underwent reconstructions using a nasal septal flap with a balloon catheter (flap group). Incidence of postoperative cerebrospinal fluid (CSF) leaks and perioperative insertion rate of external lumbar drain (ELD) were compared between the two groups. Postoperative CSF leaks occurred in two patients (9.5%) in the flap group. Three patients (27.3%) presented CSF leaks in the non-flap group. The rate of insertion of ELD was 81.8% in the non-flap group. In the flap group, one patient (4.8%) should be placed with ELD postoperatively. The incidence of postoperative CSF leaks in the flap group was lower than in the non-flap group, whereas the rate of insertion of ELD in the non-flap group was higher than in the flap group. Endoscopic endonasal skull base reconstruction using a nasal septal flap without ELD seems to be useful and reliable for ventral skull base defects after endoscopic endonasal approaches as compared with our previous single-layer reconstructions using free fat grafts or fascia lata. The long-term effectiveness of nasal septal flaps to prevent intracranial complications should be confirmed. PMID- 20195677 TI - A technical note on endonasal combined microscopic endoscopic with free head navigation technique of removal of pituitary adenomas. AB - Pituitary surgery exemplifies the continuous refinement of surgical techniques. The transsphenoidal approach is the approach of choice to treat most pituitary adenomas. We report here, as a technical note, an operative nuance that represents an encompassment of various technical steps that we utilize in our current surgery, including the corroboration of navigation system on a free head with combined use of endoscope and microscope techniques. PMID- 20195679 TI - Arm port implantation in cancer patients. PMID- 20195678 TI - A pretreatment nomogram predicting recurrence- and progression-free survival for nonmuscle invasive bladder cancer in Japanese patients. AB - PURPOSE: Our aim was to provide nomograms that allow urologists to easily calculate a nonmuscle invasive bladder cancer patient's risk of recurrence and progression. MATERIALS AND METHODS: We retrospectively analyzed 800 nonmuscle invasive bladder cancer patients newly diagnosed between 1991 and 2001 from the Gifu urothelial cancer registry program. We developed the nomogram using the original 500 patients and validated it using the remaining 300 patients. The prognostic factors of recurrence and progression were identified by multivariate analysis in 500 patients. RESULTS: In the multivariate analysis, tumor number, shape, grade, and intravesical instillation were associated with recurrence-free survival. Tumor shape and grade were associated with progression-free survival. Six factors for recurrence and three factors for progression were used to make the nomogram. Using the original 500 patients who were modeled for the nomogram, the areas under the receiver operating characteristic curves (AUCs) were calculated to be 0.61 for recurrence and 0.71 for progression. To validate nomogram performance, we applied an additional 300 patients to the nomograms. The AUCs were 0.57 for recurrence and 0.67 for progression. CONCLUSIONS: The nomograms that have been developed can be used to predict the probability of recurrence and progression of nonmuscle invasive bladder cancer. PMID- 20195680 TI - The duration of functioning of a subcutaneous implantable port for the treatment of hematological tumors: a single institution-based study. AB - BACKGROUND: Although subcutaneous implantable ports have been indicated as venous access for chemotherapy, these devices have not been used routinely for hematological tumors. METHODS: Between May 2006 and April 2009, 39 ports were implanted in 37 patients with hematological tumors and 16 ports were implanted in 14 patients with nonhematological tumors. The patients were treated with standard/first-line and/or salvage/second-line or greater chemotherapy, and were prospectively followed until port removal, death, or the end of the study. RESULTS: Thirty-five (96%) patients with hematological tumors developed grade 4 hematological toxicity, while 1 (7%) patient with nonhematological tumors showed grade 4 neutropenia. The actual duration of the port in situ ranged from 14 to 719 days (mean, 271.4 days) in the hematology group, and from 50 to 955 days (mean, 419.5 days) in the nonhematology group (P = 0.039). The Kaplan-Meier estimated median duration of port in situ in the hematology group was 364 days, which was significantly shorter than that in the nonhematology group (P = 0.009). When patient death and port removal for the end of treatment were censored, the rate of port functioning at 1 year was estimated to be 83% in the hematology group. Bloodstream infection (BSI) occurred in 7 patients with hematological tumors and in 1 patient with metastatic colorectal cancer; however, microbiological confirmation that the implantable port was the source of the BSI was inconclusive. CONCLUSION: The duration of port functioning in patients with hematological tumors was comparable to that in patients with nonhematological tumors. The higher rate of BSI in the hematology group was primarily attributable to profound neutropenia. PMID- 20195681 TI - Complete response of anaplastic pancreatic carcinoma to paclitaxel treatment selected by chemosensitivity testing. AB - A 58-year-old woman was admitted to our institute in June 2007 because of obstructive jaundice. A mass in the pancreatic head and multiple swollen lymph nodes surrounding the common hepatic artery were identified using computed tomography (CT). Subsequently, endoscopic ultrasonography-guided fine-needle aspiration biopsy (EUS-FNA) was done. Histopathologic results revealed anaplastic carcinoma of the pancreas. Using specimens obtained with EUS-FNA, chemosensitivity testing with adenosine triphosphate assay was performed. Testing indicated high chemosensitivity to paclitaxel (PTX). According to this result, chemotherapy using PTX was performed, and the primary lesion and lymph node metastases disappeared completely on CT. The patient has been doing well with no recurrence for 1 year and 11 months since initial chemotherapy. PMID- 20195682 TI - Head and neck sarcoma: report of a case treated by intensity-modulated radiation therapy. AB - We report on a 71-year-old woman with parapharyngeal sarcoma. Surgery could not be performed because of the size and location of the tumor. After failure of four cycles of chemotherapy, intensity-modulated radiation therapy (IMRT) achieved complete clinical response and partial magnetic resonance imaging response (80%) at 24 months of follow-up. The results of radiotherapy, especially IMRT, for nonresectable head and neck soft tissue sarcoma are discussed. PMID- 20195683 TI - Alternate-day treatment with S-1 in patients with gastric cancer: a retrospective study of strategies for reducing toxicity. AB - BACKGROUND: In patients with adverse events of S-1, the dose is generally reduced or the treatment cycle is shortened. Whether the therapeutic effectiveness of modified regimens is similar to that of the standard dosage remains unclear. METHODS: We retrospectively studied patients with gastric cancer who received S-1 on alternate days. RESULTS: A total of 266 patients received S-1 on alternate days. In 116 patients, S-1 was initially given at the standard dosage but was switched to alternate-day treatment because of toxicity within 28 days on average. The other 150 patients initially received alternate-day treatment because of poor general condition. In the adjuvant chemotherapy group (n = 96), the 3-year survival rate was 88% in patients with stage II, 73% in stage IIIA, and 67% in stage IIIB who underwent D2 lymph-node dissection. In the palliative surgery group (n = 96), the response rate was 13%, with a median survival time (MST) of 624 days. In patients with unresectable/recurrent disease (n = 74), the response rate was 25%, with an MST of 338 days. Among the 116 patients who initially received treatment on consecutive days, 100% had grade 1, 53% had grade 2, and 5.2% had grade 3 adverse events. When S-1 was switched to alternate-day treatment, toxicity decreased in all patients. In the 266 patients who received alternate-day treatment, 8% had grade 1, 6% had grade 2, and 0% had grade 3 adverse events. CONCLUSION: Alternate-day treatment with S-1 may have milder adverse events without compromising therapeutic effectiveness. PMID- 20195684 TI - Aspects of TNF inhibitor therapy in rheumatoid arthritis. AB - Treatment outcomes in rheumatoid arthritis (RA) have improved considerably with the use of biological therapies. Since the discovery of the role of tumor necrosis factor (TNF) alpha in the pathogenesis of the disease, three TNF inhibitors, infliximab, etanercept and adalimumab, have become widely used for the treatment of RA. More recently, two newer TNF inhibitors-certolizumab pegol and golimumab-have become available, increasing the armamentarium of therapy. With improved therapies, treatment strategies have also changed, with the aims now being to achieve and maintain remission. This article addresses some of these aspects of treating RA, reviewing the studies on these two newer TNF inhibitors, certolizumab pegol and golimumab, and those addressing the induction of remission or low disease activity with TNF inhibitors and maintenance with less intensive treatment. PMID- 20195685 TI - On the threshold characteristics of the flexoelectric domains arising in a homogeneous electric field: The case of anisotropic elasticity. AB - Precise solutions for the threshold voltage U(c) and wave number q(c) that feature the appearance of longitudinal flexoelectric domains of Vistin'-Pikin Bobylev at strong anchoring have been derived. Based on the formulated expressions, we present and analyze computer calculations for a planar nematic layer with anisotropic elasticity and both negative and positive dielectric anisotropy under the action of a homogeneous flexoelectrically deforming d.c. electric field. The obtained relations allow a selection of particular values of physical parameters, in order to improve the performance of devices exploiting flexoelectrcity in nematics. PMID- 20195686 TI - Leak rate of seals: Effective-medium theory and comparison with experiment. AB - Seals are extremely useful devices to prevent fluid leakage. We present an effective-medium theory of the leak rate of rubber seals, which is based on a recently developed contact mechanics theory. We compare the theory with experimental results for seals consisting of silicon rubber in contact with sandpaper and sand-blasted PMMA surfaces. PMID- 20195687 TI - Nematic liquid crystal in the wedge and edge geometry in the case of homeotropic alignment. AB - Nematic liquid crystal confined to a wedge or edge is studied on the assumption that the confining surfaces provide strong and weak homeotropic anchorings, respectively. Both infinite and finite systems are considered. The model based on the Frank-Oseen and Rapini-Papoular formalisms predicts two textures of opposite rotations of the director as in the case of strong anchoring on both surfaces. However, the presence of weak anchoring results in a length scale lambda which characterizes the crossover between the regions close to the apex and far from it. The ratio lambda/b , where b is the extrapolation length, is a function of the opening angle alpha. Both stable and metastable textures are considered and the mechanism by which a texture loses its stability is found. It is related to the formation of a defect-like structure at the surface of weak anchoring whose distance from the apex is lambda(alpha) and the loss of stability is signalled by the divergence of lambda. Only in the limit alpha --> 2tau, the defect-like structure transforms into a defect of strength -1/2 located at a finite distance from the apex. PMID- 20195688 TI - Why does shear banding behave like first-order phase transitions? Derivation of a potential from a mechanical constitutive model. AB - Numerous numerical and experimental evidence suggest that shear banding behavior looks like first-order phase transitions. In this paper, we demonstrate that this correspondence is actually established in the so-called non-local diffusive Johnson-Segalman model (the DJS model), a typical mechanical constitutive model that has been widely used for describing shear banding phenomena. In the neighborhood of the critical point, we apply the reduction procedure based on the center manifold theory to the governing equations of the DJS model. As a result, we obtain a time evolution equation of the flow field that is equivalent to the time-dependent Ginzburg-Landau (TDGL) equations for modeling thermodynamic first order phase transitions. This result, for the first time, provides a mathematical proof that there is an analogy between the mechanical instability and thermodynamic phase transition at least in the vicinity of the critical point of the shear banding of DJS model. Within this framework, we can clearly distinguish the metastable branch in the stress-strain rate curve around the shear banding region from the globally stable branch. A simple extension of this analysis to a class of more general constitutive models is also discussed. Numerical simulations for the original DJS model and the reduced TDGL equation is performed to confirm the range of validity of our reduction theory. PMID- 20195689 TI - Bubble splitting in oscillatory flows on ground and in reduced gravity. AB - The stability of centimeter scale air bubbles is studied in quiescent suspending liquid under an imposed oscillatory acceleration field. Experiments were performed in reduced- and normal-gravity environments. A strong acceleration resulted in an instability leading to the breakups of the bubbles in both gravity environments. The breakup onset was investigated and found to be characterized by a critical acceleration a (cr). The influence of the liquid viscosity and the gravitational environment was studied. Empirical correlations for the onset are presented and discussed with the intention to reveal splitting mechanism. The inertial mechanism often deemed to cause the breakup of drops subjected to a rapid gas stream is shown to give explanations consistent with the experiments. A breakup criterion for both gravitational environments is proposed through discussions from an energetic point of view. PMID- 20195690 TI - Giant magnetoresistance of coiling polymers. AB - We examine the magnetoresistance (MR) of conducting polymers with interest paid on the role of structural flexibility. Through Monte Carlo simulation and Green function method, we evaluate the electric transmission for a variety of polymer configurations. It is found that for a single polymer the transmission displays a complex oscillation and also a parity-dependent periodicity. For an ensemble of polymers the averaged transmission yields the nonlinear behavior of MR under varying magnetic fields. Interestingly, more flexible polymers are shown to achieve higher MR, depending on the population and the size of the loops. PMID- 20195691 TI - Orientational order in liquid crystals exhibited by some binary mixtures of rod like and bent-core molecules. AB - We report measurements of the temperature variations of the optical birefringence in the nematic (N) and partial bilayer SmA (SmA(d)) phases in 4-n-octyloxy 4(') cyanobiphenyl made of rod-like (R) molecules and five mixtures of this compound with 1,3-phenylene bis[4-(3-methylbenzoyloxy)] 4(')-n-dodecylbiphenyl 4(') carboxylate, made of bent-core (BC) molecules. The birefringence decreases with the concentration x of the BC molecules but the macroscopic order parameter initially decreases upto 11 mol% of BC molecules and subsequently increases with x. This is attributed to the possible formation of polar clusters of BC molecules. Orientation of BC molecules changes between the N and SmA(d) phases and the birefringence data in the two phases imply that the kink angle of the BC molecules is approximately 90 degrees rather than approximately 110 degrees as obtained from calculations which minimize the energy of the molecule. IR spectroscopic measurements on the mixture with 11 mol% of BC molecules have been used to estimate the molecular order parameter S of the R molecules, and to provide additional support for a relatively small kink angle of BC molecules. PMID- 20195692 TI - Metal ion determinants of conantokin dimerization as revealed in the X-ray crystallographic structure of the Cd(2+)/Mg (2+)-con-T[K7gamma] complex. AB - Predatory sea snails from the Conus family produce a variety of venomous small helical peptides called conantokins that are rich in gamma-carboxyglutamic acid (Gla) residues. As potent and selective antagonists of the N-methyl-D: -aspartate receptor, these peptides are potential therapeutic agents for a variety of neurological conditions. The two most studied members of this family of peptides are con-G and con-T. Con-G has Gla residues at sequence positions 3, 4, 7, 10, and 14, and requires divalent cation binding to adopt a helical conformation. Although both Ca(2+) and Mg(2+) can fulfill this role, Ca(2+) induces dimerization of con-G, whereas the Mg(2+)-complexed peptide remains monomeric. A variant of con-T, con-T[K7gamma] (gamma is Gla), contains Gla residues at the same five positions as in con-G and behaves very similarly with respect to metal ion binding and dimerization; each peptide binds two Ca(2+) ions and two Mg(2+) ions per helix. To understand the difference in metal ion selectivity, affinity, and the dependence on Ca(2+) for dimer formation, we report here the structure of the monomeric Cd(2+)/Mg(2+)-con-T[K7gamma] complex, and, by comparison with the previously published con-T[K7gamma]/Ca(2+) dimer structure, we suggest explanations for both metal ion binding site specificity and metal-ion-dependent dimerization. PMID- 20195694 TI - 2010 SIIM Annual meeting. PMID- 20195693 TI - Design, synthesis, and evaluation of cyclofenil derivatives for potential SPECT imaging agents. AB - To develop technetium- and rhenium-labeled nonsteroidal estrogen imaging agents for estrogen receptor (ER) positive breast tumors, two groups of rhenium and technetium cyclofenil derivatives were synthesized and characterized. The binding affinities of the rhenium complexes for ERs were determined. The tricarbonyl rhenium complex showed the highest binding affinity for ERs (81.2 for ERbeta, 16.5 for ERalpha). Tricarbonyl technetium cyclofenil complexes were obtained in high radiochemical purity and radiochemical yields. The results of studies of their octanol/water partition and in vitro stability are presented. These results demonstrate that these radiolabeled cyclofenil derivatives may be considered as potential breast cancer imaging agents. PMID- 20195695 TI - Comparison of image enhancement methods for the effective diagnosis in successive whole-body bone scans. AB - Whole-body bone scan is one of the most frequent diagnostic procedures in nuclear medicine. Especially, it plays a significant role in important procedures such as the diagnosis of osseous metastasis and evaluation of osseous tumor response to chemotherapy and radiation therapy. It can also be used to monitor the possibility of any recurrence of the tumor. However, it is a very time-consuming effort for radiologists to quantify subtle interval changes between successive whole-body bone scans because of many variations such as intensity, geometry, and morphology. In this paper, we present the most effective method of image enhancement based on histograms, which may assist radiologists in interpreting successive whole-body bone scans effectively. Forty-eight successive whole-body bone scans from 10 patients were obtained and evaluated using six methods of image enhancement based on histograms: histogram equalization, brightness preserving bi-histogram equalization, contrast-limited adaptive histogram equalization, end-in search, histogram matching, and exact histogram matching (EHM). Comparison of the results of the different methods was made using three similarity measures peak signal-to-noise ratio, histogram intersection, and structural similarity. Image enhancement of successive bone scans using EHM showed the best results out of the six methods measured for all similarity measures. EHM is the best method of image enhancement based on histograms for diagnosing successive whole-body bone scans. The method for successive whole-body bone scans has the potential to greatly assist radiologists quantify interval changes more accurately and quickly by compensating for the variable nature of intensity information. Consequently, it can improve radiologists' diagnostic accuracy as well as reduce reading time for detecting interval changes. PMID- 20195698 TI - Evidence for a novel cytoplasmic processing event in ribosome maturation in the sea urchin Paracentrotus lividus. AB - In this paper we demonstrate the existence of a cytoplasmic processing step, never before described, involving both the pre-ribosomal subunits in the sea urchin Paracentrotus lividus. Northern-blot hybridization, primer extension, S1 mapping experiments and in situ hybridizations allowed us to demonstrate that cytoplasmic processed particles are successively re-imported into the nucleus where maturation of their RNAs is completed prior to being exported to the cytoplasm. Our findings lead to the proposal of a new model of ribosome maturation and shuttling. PMID- 20195696 TI - Inhibitor of growth tumor suppressors in cancer progression. AB - The inhibitor of growth (ING) family of tumor suppressors has five members and is implicated in the control of apoptosis, senescence, DNA repair, and cancer progression. However, little is known about ING activity in the regulation of cancer progression. ING members and splice variants seem to behave differently with respect to cancer invasion and metastasis. Interaction with histone trimethylated at lysine 4 (H3K4me3), hypoxia inducible factor-1 (HIF-1), p53, and nuclear factor kappa-B (NF-kappaB) are potential mechanisms by which ING members exert effects on invasion and metastasis. Subcellular mislocalization, rapid protein degradation, and to a lesser extent ING gene mutation are among the mechanisms responsible for inappropriate ING levels in cancer cells. The aim of this review is to summarize the different roles of ING family tumor suppressors in cancer progression and the molecular mechanisms involved. PMID- 20195697 TI - Metabolism of the neuromodulator D-serine. AB - Over the past years, accumulating evidence has indicated that D-serine is the endogenous ligand for the glycine-modulatory binding site on the NR1 subunit of N methyl-D-aspartate receptors in various brain areas. D-Serine is synthesized in glial cells and neurons by the pyridoxal-5' phosphate-dependent enzyme serine racemase, and it is released upon activation of glutamate receptors. The cellular concentration of this novel messenger is regulated by both serine racemase isomerization and elimination reactions, as well as by its selective degradation catalyzed by the flavin adenine dinucleotide-containing flavoenzyme D-amino acid oxidase. Here, we present an overview of the current knowledge of the metabolism of D-serine in human brain at the molecular and cellular levels, with a specific emphasis on the brain localization and regulatory pathways of D-serine, serine racemase, and D-amino acid oxidase. Furthermore, we discuss how D-serine is involved with specific pathological conditions related to N-methyl-D-aspartate receptors over- or down-regulation. PMID- 20195699 TI - Thioredoxin reductase inhibitor ethaselen increases the drug sensitivity of the colon cancer cell line LoVo towards cisplatin via regulation of G1 phase and reversal of G2/M phase arrest. AB - We evaluated the combination treatment of ethaselen (BBSKE) as a thioredoxin reductase (TrxR) inhibitor plus cisplatin (CDDP) on the human colon adenocarcinoma cell line LoVo. Therapeutic effects ranging from nearly additive to clearly synergistic demonstrated an effective combination, i.e., the cytostatic dose of CDDP could be reduced without a loss in efficacy. To further investigate the cellular response mechanisms of these favorable outcomes, we analyzed the cell-cycle profiles, mRNA expression patterns, and protein levels of several key genes after incubation with BBSKE or CDDP separately and in combination. In appropriate conditions, CDDP induced arrest at the G2/M phase accompanied by the enhanced inhibitory phosphorylation of Cdk1 and the elevated protein expression of cyclin B1. BBSKE downregulated expression of cyclin D1 by increasing mRNA and protein levels of p21, and thus induced G1 phase arrest. BBSKE returned Cdk1 to an activated state, and reduced the protein level of cyclin B1 after incubation in combination with CDDP, which was consistent with the reduction in the percentage of cells in G2/M identified by flow cytometry. By regulating the G1 phase and reversing CDDP-induced G2/M phase arrest, BBSKE increases drug sensitivity of LoVo cells toward CDDP, and probably provides a meaningful anticancer strategy for further clinical studies. PMID- 20195700 TI - Factors affecting prognosis of patients with intracranial anaplastic oligodendrogliomas: a single institutional review of 70 patients. AB - Anaplastic oligodendroglioma (AO) is an uncommon intracranial tumor and prognosis is poor. In this study, we assessed the factors affecting the prognosis of AO patients. Seventy AO patients were recruited from 2001 to 2006 in Shanghai Huashan Hospital of Fudan University; all were treated surgically. Kaplan-Meier survival analysis and Cox regression analysis were used to analyze the prognostic effects of 14 different factors, which were selected from clinical, radiological, pathological, and treatment variables. The results showed that chemotherapy, age, primary or secondary tumors, preoperative Karnofsky Performance Scale (KPS) scores, the presence of epilepsy at initial presentation, radiological contrast infusion, and neurological parameters all correlated with the prognosis of the patients. Furthermore, Cox multivariate analysis also showed that the age (P < 0.048), primary or secondary tumors (P < 0.010), and chemotherapy (P < 0.010) were significantly correlated with the prognosis of the patients. Age and chemotherapy correlated with the prognosis of AO. The patients younger than 50 years old and who received regular chemotherapy were likely to achieve a good outcome. Moreover, individualized treatment after molecular biological typing of AO may improve the prognosis of AO. PMID- 20195701 TI - Coexistence between meningioma and tuberculosis: case report. AB - Intracranial tuberculoma generally presents as either solitary or multiple lesions in the brain parenchyma. These are characterized by a ring-enhancing area on either computerized tomography scans or magnetic resonance images. A 66 year old female with a history of breast carcinoma at 41 years, treated with radical mastectomy and radio and chemotherapy, and rheumatoid arthritis, treated in the last 10 years, presented two months ago with occipital headache, nausea, cerebellar syndrome, alterations of speech, and memory loss. The TC scan showed occipital enhancement by contrast and surrounded by oedema, suggesting metastasis. Histology showed a benign meningioma with many multinuclear giant cells, granulomas, and central caseating necrosis. In addition, some classic plasma cells, mastocytes, and lymphocytes were also detected. The authors describe the unusual case of coexistence between an occipital meningioma and tuberculosis in the same area that resembled metastasis. PMID- 20195702 TI - The NMR structure of protein-glutaminase from Chryseobacterium proteolyticum. PMID- 20195704 TI - Durability of five native Argentine wood species of the genera Prosopis and Acacia decayed by rot fungi and its relationship with extractive content. AB - The natural durability of four Argentinean species of Prosopis and one of Acacia was evaluated in laboratory tests, according to European standards, using three brown rot and one white rot fungi. These tests were complemented by assessing the wood chemical composition. All the species were from moderately slightly durable to very durable (classes 4-1), and in all cases the heartwood was the most resistant to fungal attack. Chemical extractives content (organic, aqueous, tannic and phenolic) was higher in the heartwood. However, species durability was not related to extractive contents nor with wood density. Instead, it is possible that extractives could contribute to natural durability in different ways, including the effects related to the antioxidant properties of some of them. PMID- 20195703 TI - 15N H/D-SOLEXSY experiment for accurate measurement of amide solvent exchange rates: application to denatured drkN SH3. AB - Amide solvent exchange rates are regarded as a valuable source of information on structure/dynamics of unfolded (disordered) proteins. Proton-based saturation transfer experiments, normally used to measure solvent exchange, are known to meet some serious difficulties. The problems mainly arise from the need to (1) manipulate water magnetization and (2) discriminate between multiple magnetization transfer pathways that occur within the proton pool. Some of these issues are specific to unfolded proteins. For example, the compensation scheme used to cancel the Overhauser effect in the popular CLEANEX experiment is not designed for use with unfolded proteins. In this report we describe an alternative experimental strategy, where amide (15)N is used as a probe of solvent exchange. The experiment is performed in 50% H(2)O-50% D(2)O solvent and is based on the (HACACO)NH pulse sequence. The resulting spectral map is fully equivalent to the conventional HSQC. To fulfill its purpose, the experiment monitors the conversion of deuterated species, (15)N(D), into protonated species, (15)N(H), as effected by the solvent exchange. Conceptually, this experiment is similar to EXSY which prompted the name of (15)N(H/D)-SOLEXSY (SOLvent EXchange SpectroscopY). Of note, our experimental scheme, which relies on nitrogen rather than proton to monitor solvent exchange, is free of the complications described above. The developed pulse sequence was used to measure solvent exchange rates in the chemically denatured state of the drkN SH3 domain. The results were found to correlate well with the CLEANEX-PM data, r = 0.97, thus providing a measure of validation for both techniques. When the experimentally measured exchange rates are converted into protection factors, most of the values fall in the range 0.5 2, consistent with random-coil behavior. However, elevated values, ca. 5, are obtained for residues R38 and A39, as well as the side-chain indole of W36. This is surprising, given that high protection factors imply hydrogen bonding or hydrophobic burial not expected to occur in a chemically denatured state of a protein. We, therefore, hypothesized that elevated protection factors are an artefact arising from the calculation of the reference (random-coil) exchange rates. To confirm this hypothesis, we prepared samples of several short peptides derived from the sequence of the drkN SH3 domain; these samples were used to directly measure the reference exchange rates. The revised protection factors obtained in this manner proved to be close to 1.0. These results also have implications for the more compact unfolded state of drkN SH3, which appears to be fully permeable to water as well, with no manifestations of hydrophobic burial. PMID- 20195705 TI - Alterations in Ca2+ homeostasis in rat erythrocytes with atrazine treatment: positive modulation by vitamin E. AB - A very low level of intra-erythrocytic calcium content is very important for normal physiology of cells. In the present study, our main objective was to investigate the effects of atrazine toxicity on Ca(2+) homeostasis and modulation by vitamin E. Experimental animals were orally administered atrazine (300 mg kg( 1) body weight, daily) and vitamin E (100 mg kg(-1) body weight, daily). All studies were carried out for 7, 14, and 21 days in male Wistar rats. Erythrocyte membranes were prepared and were analyzed for lipid peroxidation (LPO) and membrane bound ATPases. Furthermore, Ca(2+) homeostasis was evaluated in erythrocytes. The present findings indicated that atrazine exposure induced oxidative stress which was associated with significant increase in lipid peroxidation (P < 0.05). Vitamin E treatment on the other hand significantly lowered the atrazine-induced lipid peroxidation. The increased LPO following atrazine exposure was accompanied by significant decrease in ATPases (P < 0.05) and disturbed Ca(2+) homeostasis. Furthermore, vitamin E treatment had a beneficial effect by partially restoring ATPases and Ca(2+) homeostasis. The current findings suggest that atrazine exerts its toxic effect by increasing LPO, altering the activity of membrane bound enzymes and disturbing Ca(2+) homeostasis. Vitamin E treatment ameliorated the toxic effects of atrazine suggesting its role as a potential antioxidant. PMID- 20195706 TI - Intratumoral as well as peritumoral lymphatic vessel invasion correlates with lymph node metastasis and unfavourable outcome in colorectal cancer. AB - The aim of this study was to assess the intratumoral and peritumoral distribution of lymphatic vessel density (LVD) and lymphatic vessel invasion (LVI) in colorectal cancer and their relationships with patients' clinicopathological characteristics and survival. Paraffin sections of 81 primary colorectal cancers were examined by immunohistochemical staining using monoclonal antibody D2-40. Peritumoral LVD was significantly higher than intratumoral LVD (P = 0.000). Both intratumoral LVD and peritumoral LVD were correlated with the presence of LVI (P = 0.006 and P = 0.003, respectively). LVI, intratumoral LVI and peritumoral LVI were identified, respectively in 38, 28 and 32% of the samples investigated. Both intratumoral LVI and peritumoral LVI were correlated with lymph node metastasis (P = 0.030 and P = 0.014, respectively). Lymph node metastasis, the presence of intratumoral LVI and peritumoral LVI were adversely associated with the 5-year overall survival in a univariate analysis (P = 0.001, P = 0.011 and P = 0.017, respectively). Multivariate analysis using Cox proportional hazard model showed that neither intratumoral LVI nor peritumoral LVI was an independent prognostic factor of overall survival. The results of this study demonstrated that intratumoral as well as peritumoral LVI was associated with lymph node metastasis and adverse outcome in colorectal cancer. PMID- 20195707 TI - Influence of preparation methods on solid state supersaturation of amorphous solid dispersions: a case study with itraconazole and eudragit e100. AB - PURPOSE: The present study aims to determine the drug / polymer miscibility level as a function of the preparation method for an amorphous solid dispersion model system containing itraconazole and eudragit E100. This value was compared to the theoretical crystalline drug solubility in the amorphous polymer and the miscibility of the amorphous drug in the amorphous polymer. METHODS: The amorphous solid dispersions were prepared via spray drying and film casting in order to evaluate the influence of the solvent drying rate. The experimental miscibility level was estimated using XRPD, MDSC, FT-IR, HPLC and TGA. The solubility and miscibility were estimated using the Flory-Huggins mixing theory and experimental drug in monomer solubility data. RESULTS: The experimental miscibility level was found to be 27.5% w/w for spray-dried and 15% for film casted solid dispersions. FT-IR measurements confirmed the absence of saturable interactions like hydrogen bonds, and analysis of the mixed glass transition temperatures suggested low adhesion forces in the amorphous mixture. The solubility analysis rendered a positive FH interaction parameter, a crystalline solubility of approximately 0.012% w/w and an amorphous drug-polymer miscibility of approximately 7.07% w/w. CONCLUSION: The solid dispersions are significantly supersaturated with respect to both crystalline solubility and amorphous miscibility demonstrating the influence of manufacturing methodology. PMID- 20195708 TI - In vivo distribution of polymeric nanoparticles at the whole-body, tumor, and cellular levels. AB - PURPOSE: Block copolymer micelles (BCMs) were functionalized with indium-111 and/or epidermal growth factor (EGF), which enabled investigation of the in vivo transport of passively and actively targeted BCMs. The integration of conventional and image-based techniques afforded novel quantitative means to achieve an in-depth insight into the fate of polymeric nanoparticles in vivo. METHODS: Pharmacokinetics and biodistribution studies were performed in athymic mice bearing human breast xenografts to evaluate the whole-body transport of NT BCMs (non-targeted, EGF-) and T-BCMs (targeted, EGF+). The intratumoral distribution of BCMs was investigated using MicroSPECT/CT and autoradiographic imaging, complemented with quantitative MATLAB(r) analyses. Tumors were fractionated for quantifying intracellular uptake of BCMs via gamma-counting. RESULTS: The intratumoral distribution of NT-BCMs and T-BCMs were found to be heterogeneous, and positively correlated with tumor vascularization (r>0.68 +/- 0.04). The enhanced in vivo cell uptake and cell membrane binding of T-BCMs were found to delay their clearance from tumors overexpressing EGFR, and therefore resulted in enhanced tumor accumulation for the T-BCMs in comparison to the NT BCMs. CONCLUSIONS: Adequate passive targeting is required in order to achieve effective active targeting. Tumor physiology has a significant impact on the transvascular and intratumoral transport of passively and actively targeted BCMs. PMID- 20195709 TI - Regulation by scaffolding proteins of canonical transient receptor potential channels in striated muscle. AB - Recent studies proposed a pivotal role of TRPC channels, in particular TRPC1, in the striated muscle tissue and in the development of calcium mishandling observed in dystrophin-deficient skeletal and cardiac muscle cells (Vandebrouck et al. in J Cell Biol 158:1089-1096, 2002; Williams and Allen in Am J Physiol Heart Circ Physiol 292:H846-H855, 2007; Stiber et al. in Mol Cell Biol 28:2637-2647, 2008). In skeletal muscle, TRPCs are proposed to function in a costameric macromolecular complex (Vandebrouck et al. in FASEB J 21:608-617, 2007; Gervasio et al. in J Cell Sci 121:2246-2255, 2008) in which scaffolding proteins and dystrophin are central components maintaining normal calcium entry (Stiber et al. in Mol Cell Biol 28:2637-2647, 2008; Sabourin et al. in J Biol Chem 284:36248-61, 2009). In this review, we shall summarize the roles played by scaffolding proteins in regulating the calcium entry through TRPC channels of skeletal muscle cells and the implications in muscle physiopathology. Interactions of TRPC1 with caveolin 3, Homer-1 and alpha-syntrophin will be addressed and these complexes will be compared with signalplex in other systems. The mechanosensitive function of scaffolding proteins will be discussed as well as interactions with TRPV2 channels regarding to calcium mishandling in Duchenne dystrophy. PMID- 20195711 TI - Fluorescence quenching reaction of polyvinylpyrrolidone-eosin Y system for the determination of polyvinylpyrrolidone. AB - In pH 1.8-2.8 weak acid medium, polyvinylpyrrolidone (PVP) and Eosin Y reacted to form complex that could result in Eosin Y (EY) fluorescence quenching. The maximum quenching wavelength was at 542 nm. The fluorescence quenching (DeltaF) was proportional to the concentration of polyvinylpyrrolidone in a certain range. The linear range, the correlation coefficient and the detection limit were 0.33 2.0 microg x mL(-1), 0.9994 and 99.6 ng x mL(-1), respectively. The influences of the coexistence substances were tested and the results showed that the method had good selectivity. Therefore, a new method based on fluorescence quenching of eosin Y by PVP for the determination of trace PVP was developed. The method was sensitive, simple and rapid, which was applied to the determination of trace PVP in the beer with satisfactory results. The reaction mechanism was also discussed. PMID- 20195712 TI - Dynamics of bacteriophage R17 probed with a long-lifetime Ru(II) metal-ligand complex. AB - The metal-ligand complex, [Ru(2,2'-bipyridine)(2)(4,4'-dicarboxy-2,2' bipyridine)](2+) (RuBDc), was used as a spectroscopic probe for studying macromolecular dynamics. RuBDc is a very photostable probe that possesses favorable photophysical properties including long lifetime, high quantum yield, large Stokes' shift, and highly polarized emission. To further show the usefulness of this luminophore for probing macromolecular dynamics, we examined the intensity and anisotropy decays of RuBDc when conjugated to R17 bacteriophage using frequency-domain fluorometry with a blue light-emitting diode (LED) as the modulated light source. The intensity decays were best fit by a sum of two exponentials, and we obtained a longer mean lifetime at 4 degrees C ( = 491.8 ns) as compared to that at 25 degrees C ( = 435.1 ns). The anisotropy decay data showed a single rotational correlation time, which is typical for a spherical molecule, and the results showed a longer rotational correlation time at 4 degrees C (2,574.9 ns) than at 25 degrees C (2,070.1 ns). The use of RuBDc enabled us to measure the rotational correlation time up to several microseconds. These results indicate that RuBDc has significant potential for studying hydrodynamics of biological macromolecules. PMID- 20195713 TI - Fluorescence studies on new potential antitumoral benzothienopyran-1-ones in solution and in liposomes. AB - Fluorescence properties of four new potential antitumoral compounds, 3 arylbenzothieno[2,3-c]pyran-1-ones, were studied in solution and in lipid membranes of dipalmitoyl phosphatidylcholine (DPPC), egg yolk phosphatidylcholine (Egg-PC) and dioctadecyldimethylammonium bromide (DODAB). The 3-(4 methoxyphenyl)benzothieno[2,3-c]pyran-1-one (1c) exhibits the higher fluorescence quantum yields in all solvents studied. All compounds present a solvent sensitive emission, with significant red shifts in polar solvents for the methoxylated compounds. The results point to an ICT character of the excited state, more pronounced for compound 1c. Fluorescence (steady-state) anisotropy measurements of the compounds incorporated in liposomes of DPPC, DODAB and Egg-PC indicate that all compounds have two different locations, one due to a deep penetration in the lipid membrane and another corresponding to a more hydrated environment. In general, the methoxylated compounds prefer hydrated environments inside the liposomes. The 3-(4-fluorophenyl)benzothieno[2,3-c]pyran-1-one (1a) clearly prefers a hydrated environment, with some molecules located at the outer part of the liposome interface. On the contrary, the preferential location of 3-(2 fluorophenyl)benzothieno[2,3-c]pyran-1-one (1b) is in the region of lipid hydrophobic tails. Compounds with a planar geometry (1a and 1c) have higher mobility in the lipid membranes when phase transition occurs. PMID- 20195710 TI - Cellular mechanisms and local progenitor activation to regulate skeletal muscle mass. AB - Skeletal muscle hypertrophy is a result of increased load, such as functional and stretch-overload. Activation of satellite cells and proliferation, differentiation and fusion are required for hypertrophy of overloaded skeletal muscles. On the contrary, a dramatic loss of skeletal muscle mass determines atrophy settings. The epigenetic changes involved in gene regulation at DNA and chromatin level are critical for the opposing phenomena, muscle growth and atrophy. Physiological properties of skeletal muscle tissue play a fundamental role in health and disease since it is the most abundant tissue in mammals. In fact, protein synthesis and degradation are finely modulated to maintain an appropriate muscle mass. When the molecular signaling is altered muscle wasting and weakness occurred, and this happened in most common inherited and acquired disorders such as muscular dystrophies, cachexia, and age-related wasting. To date, there is no accepted treatment to improve muscle size and strength, and these conditions pose a considerable anxiety to patients as well as to public health. Several molecules, including Magic-F1, myostatin inhibitor, IGF, glucocorticoids and microRNAs are currently investigated to interfere positively in the blueprint of skeletal muscle growth and regeneration. PMID- 20195714 TI - Rotational diffusion of coumarins: a dielectric friction study. AB - The rotational diffusion of three probes: coumarin 522B (C522B), coumarin 307 (C307) and coumarin 138 (C138) with nearly identical size was studied at room temperature employing steady-state and time-resolved fluorescence anisotropy techniques in series of alcohols and alkanes. Experimental observations indicate faster rotation of C138 compared to the other two dyes in alcohols and a faster rotation of C522B than C307 in alkanes. The dielectric friction theories of Nee Zwanzig (NZ) and van der Zwan-Hynes (ZH) were employed to estimate the friction experienced by the probes in alcohols, in addition to the mechanical friction calculated using Stokes-Einstein-Debye (SED) hydrodynamic with slip boundary condition and Dote-Kivelson-Schwartz (DKS) quasihydrodynamic theories. The observed reorientation times for the three probes do not follow the trend predicted by dielectric friction theories of NZ and ZH. The dipole moments determined from solvatochromic techniques were found to be different for the three probes. PMID- 20195715 TI - Origin of fluorescence lifetimes in human serum albumin. Studies on native and denatured protein. AB - Human serum albumin consists of a single polypeptide of 585 amino acid residues with 1 Trp residue. In the present work, we measured fluorescence lifetimes of the protein in both native and denatured states. The results indicate that Trp emission occurs with three lifetimes in both states. Lifetimes values and contribution to the global emission decay differ between the two states. Data are interpreted as the results of an emission occurring from three substructures of the tryptophan formed in the excited state. Two of these substructures are already present for the tryptophan free in solution. The third lifetime is the result of the interaction between the tryptophan residue and surrounding microenvironment. The populations of these substructures characterized by the pre exponential parameters of the fluorescence lifetimes are dependent on the fluorophore microenvironment and on the global protein structure. PMID- 20195716 TI - Investigation of functional IL-10 gene polymorphism and IL-10 levels in acute graft-versus-host disease. AB - BACKGROUND: Graft-versus-host disease (GVHD) represents a major complication in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. Although studies have been conducted concerning the investigation of cytokine polymorphisms in the development of acute GVHD (aGVHD), the contribution of recipients and donors as regards cytokine levels has not yet been thoroughly assessed. OBJECTIVE: The aim of this study was to investigate the impact of IL-10 polymorphisms on cytokine levels in blood and saliva, in addition to the occurrence and severity of aGVHD. METHODS: Fifty-eight consecutive allo-HSCT recipients and their donors were included in this prospective study. Saliva and/or blood samples were obtained from recipients and donors to determine IL10 polymorphisms. The IL-10 levels in the blood and saliva were also assessed. The samples were collected from seven days before transplant (day -7) to 100 days after allo-HSCT (day +100), once a week or until the death of recipient. RESULTS: No association was found between recipient and donor IL10 polymorphism and IL-10 levels in the saliva with aGVHD. In contrast, IL-10 levels in the blood were associated with the occurrence of aGVHD. The high producer phenotype in the recipient was also associated with high levels of IL-10 in the blood and saliva. CONCLUSION: Although IL10 polymorphisms were not associated with the occurrence and severity of aGVHD, the genetic background of the recipient did in fact influence the production of the cytokine. Furthermore, as IL-10 levels in the blood were associated with the disease development, this parameter may well be a useful predictor of aGVHD development. PMID- 20195717 TI - Phosphoinositide 3-kinase gamma has multiple phospholipid binding sites. AB - Phosphoinositide 3-kinase gamma is a multifunctional enzyme with lipid and protein kinase activities that also acts as a scaffold protein in many diverse signalling processes. The enzyme contains five different domains, but their individual contributions to membrane binding are not fully understood. Here, using in vitro liposome binding assays of individual domains and deletion constructs of human phosphoinositide 3-kinase gamma, we show that each domain is capable of binding anionic phospholipids to varying degrees, depending on the charge of the anionic substrate. Moreover, with the exception of the C2-domain, deletion of any single protein domain results in a complete loss of kinase activity toward both lipids and proteins. PMID- 20195718 TI - Neurotoxic, myotoxic and cytolytic activities of the new basic PLA(2) isoforms BmjeTX-I and BmjeTX-II isolated from the Bothrops marajoensis (Marajo Lancehead) snake venom. AB - The BmjeTX-I and BmjeTX-II isoforms of PLA(2) were purified from Bothrops marajoensis venom by ion-exchange chromatography and reverse phase HPLC. Both isoforms showed a molecular mass of 13808.89 Da (BmjeTX-I) and 13863.97 Da (BmjeTX-II) determined by based on the determined primary structures and SDS-PAGE and confirmed experimentally by MALDI-TOF mass spectrometry. Multiple alignment of BmjeTX-I and BmjeTX-II isoforms of PLA(2) show high degree of homology with basic PLA(2) myotoxins from other Bothrops venoms. Ex vivo, both isoforms caused a blockade of the neuromuscular transmission in young chick biventer cervicis preparations in a similar way to other Bothrops species. In chick preparations, contractures to exogenous acetylcholine (55 and 110 microM) or KCl (13.4 mM) were unaltered after complete blockade for the both isoforms BmjeTX-I and BmjeTX-II of PLA(2). These results, which strongly suggested a presynaptic mechanism of action for these toxins. In mice, both isoforms induced myonecrosis and a systemic interleukin-6 response upon intramuscular injection. Both isoforms BmjeTX-I and BmjeTX-II of PLA(2) also induced moderate marked paw edema, evidencing the local increase in vascular permeability. Since both isoforms of PLA(2) exert a strong proinflammatory effect, the enzymatic hydrolysis of phospholipids might be relevant for this phenomenon and produced cytotoxicity in murine skeletal muscle C2C12 myoblasts and myotubes. PMID- 20195720 TI - Parental attitudes, beliefs, and perceptions about genetic testing for FAP and colorectal cancer surveillance in minors. AB - Familial adenomatous polyposis (FAP) is the second most common hereditary colorectal cancer syndrome and confers a nearly 100% lifetime risk of developing colorectal cancer. Understanding factors that facilitate and inhibit genetic testing and cancer surveillance in children who are members of families affected by FAP will better equip clinicians to clarify misunderstandings and facilitate appropriate care. The aims of this study were to examine parental attitudes and beliefs regarding endoscopic surveillance and genetic testing in minors at risk for developing FAP. This cross-sectional study includes analyses of qualitative and quantitative interview data collected from parents of children with or at risk for FAP. This report includes data from 28 parents with a total of 51 biological children between 10-17 years of age. The parents had a clinical and/or genetic diagnosis of FAP. Most commonly reported facilitators included provider recommendation (surveillance) and personalized medical management (genetic testing). Most commonly reported barriers included lack of provider recommendation (surveillance) and cost (genetic testing). PMID- 20195722 TI - Insurance coverage gaps among US children with insured parents: are middle income children more likely to have longer gaps? AB - Millions of US children have unstable health insurance coverage. Some of these uninsured children have parents with stable coverage. We examined whether household income was associated with longer coverage gaps among US children with at least one insured parent. A secondary data analysis of the nationally representative 2004 Medical Expenditure Panel Survey, this study uses logistic regression models to examine the association between income and children's insurance gaps. We focused on children with at least one parent insured all year (n = 6,151; estimated weighted N = 53.5 million). In multivariate models, children from families earning between 125 and 400% of the federal poverty level (FPL) had twice the odds of experiencing coverage gaps >6 months, as compared to those from high income families. Children in the poorest income groups (<125% FPL) did not have significantly greater odds of a gap >6 months. However, the odds of a gap <=6 months were significantly greater for all income groups below 400% FPL, when compared to the highest income group. Among children with continuously insured parents, those from lower middle income families were most vulnerable to experiencing coverage gaps >6 months, as compared to those from the lowest and highest income families. These findings are likely due to middle class earnings being too high to qualify for public insurance but not high enough to afford private coverage. This study highlights the need for new US health care financing models that give everyone in the family the best chance to obtain stable coverage. It also provides valuable information to other countries with employer-sponsored insurance models or those considering privatization of insurance payment systems and how this might disproportionately impact the middle class. PMID- 20195724 TI - Evidence for oxidative/nitrosative stress in the pathogenesis of hepatic encephalopathy. AB - Hepatic encephalopathy (HE) is a serious complication of liver failure. HE manifests as a series of neuropsychiatric and neuromuscular symptoms including personality changes, sleep abnormalities, asterixis and muscle rigidity progressing through stupor to coma. The pathophysiologic basis of HE remains unclear. There is general agreement that ammonia plays a key role. In recent years, it has been suggested that oxidative/nitrosative stress constitutes part of the pathophysiologic cascade in HE. Direct evidence for oxidative/nitrosative stress in the pathogenesis of HE has been demonstrated in experimental animal models of acute or chronic liver failure. However, evidence from studies in HE patients is limited. This review summarizes this evidence for a role of oxidative/nitrosative stress in relation to ammonia toxicity and to the pathogenesis of HE. PMID- 20195725 TI - Portacaval anastomosis-induced hyperammonemia does not lead to oxidative stress. AB - Ammonia is neurotoxic and believed to play a major role in the pathogenesis of hepatic encephalopathy (HE). It has been demonstrated, in vitro and in vivo, that acute and high ammonia treatment induces oxidative stress. Reactive oxygen species (ROS) are highly reactive and can lead to oxidization of proteins resulting in protein damage. The present study was aimed to assess oxidative status of proteins in plasma and brain (frontal cortex) of rats with 4-week portacaval anastomosis (PCA). Markers of oxidative stress, 4-hydroxy-2-nonenal (HNE) and carbonylation were evaluated by immunoblotting in plasma and frontal cortex. Western blot analysis did not demonstrate a significant difference in either HNE-linked or carbonyl derivatives on proteins between PCA and sham operated control rats in both plasma and frontal cortex. The present study suggests PCA-induced hyperammonemia does not lead to systemic or central oxidative stress. PMID- 20195723 TI - Cyclic GMP pathways in hepatic encephalopathy. Neurological and therapeutic implications. AB - Cyclic GMP (cGMP) modulates important cerebral processes including some forms of learning and memory. cGMP pathways are strongly altered in hyperammonemia and hepatic encephalopathy (HE). Patients with liver cirrhosis show reduced intracellular cGMP in lymphocytes, increased cGMP in plasma and increased activation of soluble guanylate cyclase by nitric oxide (NO) in lymphocytes, which correlates with minimal HE assessed by psychometric tests. Activation of soluble guanylate cyclase by NO is also increased in cerebral cortex, but reduced in cerebellum, from patients who died with HE. This opposite alteration is reproduced in vivo in rats with chronic hyperammonemia or HE. A main pathway modulating cGMP levels in brain is the glutamate-NO-cGMP pathway. The function of this pathway is impaired both in cerebellum and cortex of rats with hyperammonemia or HE. Impairment of this pathway is responsible for reduced ability to learn some types of tasks. Restoring the pathway and cGMP levels in brain restores learning ability. This may be achieved by administering phosphodiesterase inhibitors (zaprinast, sildenafil), cGMP, anti-inflammatories (ibuprofen) or antagonists of GABAA receptors (bicuculline). These data support that increasing cGMP by safe pharmacological means may be a new therapeutic approach to improve cognitive function in patients with minimal or clinical HE. PMID- 20195727 TI - Increased extracellular survivin in the synovial fluid of rheumatoid arthritis patients: fibroblast-like synoviocytes as a potential source of extracellular survivin. AB - Survivin belongs to the family of inhibitor of apoptosis proteins and plays an important role in the hyperplastic growth of tissues and tumors. In this study, we assessed the expression of survivin in rheumatoid synovial fluids (SF) and synovial tissues (ST) of rheumatoid arthritis (RA) patients in order to investigate the role of extracellular survivin in the pathogenesis of RA. The survivin level from SF was significantly higher in RA patients (n = 38) than in osteoarthritis patients (n = 18; 10.68 +/- 2.76 vs. 1.0 +/- 0.56 pg/ml, p = 0.02). In addition, SF survivin level was higher in erosive RA patients (n = 23) than in non-erosive RA patients (n = 15; 15.26 +/- 4.26 vs. 4.47 +/- 1.12 pg/ml, p = 0.05). SF survivin level in RA was positively correlated with disease activity score 28, but did not reach statistical significance (r = 0.309, p = 0.07). RA SF survivin level was also positively correlated with peripheral blood leukocyte counts (r = 0.443, p = 0.005). The immunohistochemical staining and Western blot analysis revealed survivin expression in the ST and fibroblast-like synoviocytes of RA patients, respectively. These findings suggest that extracellular survivin may be produced from rheumatoid FLS and may play an important role in the destructive RA process. PMID- 20195726 TI - Organic osmolytes in hyponatremia and ammonia toxicity. AB - Hyperammonemia (HA) is a major and commonly observed feature of hepatic encephalopathy. Furthermore, hyponatremia is an important pathogenetic factor in patients with hepatic encephalopathy. Both conditions have some features in common, such as the release of organic osmolytes, which might be an adaptive mechanism against cell swelling. However, the consequence of a possible relationship between osmoregulatory response in hyperammonemia and hyponatremia is not completely understood. This review gives a short introduction into the pathogenesis of hepatic encephalopathy and hyponatremia. For a comparison of both pathological events, some basics on cellular osmo- and volume regulation are explained, in particular as the mechanisms involved in the adaption of the cell to volume changes can be different under both pathological conditions. The role of brain glutamine and organic osmolytes in hyponatremia and hyperammonemia and their combination are discussed based on findings in experimental animal models, and finally on data obtained from primary astrocytes in culture. The observations that the decrease of brain organic osmolytes in astrocytes not adequately compensate for an increased intracellular osmolarity caused by glutamine are consistent with results obtained after chronic hyponatremia in rats, in which the release of osmolytes does not protect from ammonia-induced brain edema. Furthermore, a decrease in intracellular osmolarity is attributed both to the release and a reduced de novo synthesis of amino acids. PMID- 20195729 TI - Asthma and dehydroepiandrosterone (DHEA): facts and hypotheses. AB - Dehydroepiandrosterone (DHEA) is considered as an important immunomodulating and anti-inflammatory hormone. Despite the continuing interest in DHEA replacement therapy, our knowledge of its effects upon asthma is very limited. DHEA is able to reverse cytokine imbalances associated with asthma, may prevent and attenuate allergic inflammation in airways, and does not possess the undesirable side effects of glucocorticoids; therefore, it may be potentially applied in the treatment of asthma. The steroid-sparing effect observed with DHEA clinically could appear especially favorable in asthmatic patients receiving oral treatment and those inhaling high doses of glucocorticoids. In addition, DHEA and its analogs might prove useful in reversing relative glucocorticoids insensitivity in patients with corticosteroid-resistant asthma. In this review we have focused specifically on DHEA's role in asthma. PMID- 20195728 TI - Prostaglandin I(2) analogues enhance growth-related oncogene-alpha expression in human monocyte-derived dendritic cells. AB - Chemokines for neutrophils such as growth-related oncogene-alpha (GRO-alpha) are important in patients with refractory or severe asthma. Prostaglandin I(2) (PGI(2)) analogues were regarded as potential treatments for asthma. Dendritic cells (DCs) are the professional antigen-presenting cells and play a critical role in regulating immune response. However, it is unknown whether PGI(2) analogues have regulatory effects on GRO-alpha expression in human monocyte derived DCs (MDDCs). The human MDDCs were pretreated with iloprost and treprostinil (two PGI(2) analogues) or forskolin, a cyclic adenosine monophosphate (cAMP) activator, before stimulation with lipopolysaccharide (LPS). In some cases, I prostanoid (IP) receptor and E prostanoid (EP) antagonists were pretreated before PGI(2) analogue treatment. To investigate the intracellular signaling, nuclear factor (NF)-kappaB inhibitor and the mitogen-activated protein kinase (MAPK) inhibitors were pretreated before PGI(2) analogue treatment. GRO alpha was measured by enzyme-linked immunosorbent assay. Intracellular signaling was also investigated by Western blot. Iloprost and treprostinil enhanced LPS induced GRO-alpha expression in MDDCs. This effect could be reversed by an I prostanoid receptor antagonist, CAY10449, but not EP receptor antagonists. Forskolin conferred a similar modulating effect as that noted in iloprost- and treprostinil-treated MDDCs. PGI(2) analogue-enhanced LPS-induced GRO-alpha expression was reduced by MAPK-p38 inhibitor, SB203580. PGI(2) analogues enhanced LPS-induced phospho-p38 expression. PGI(2) analogues enhanced LPS-induced GRO alpha expression via the IP receptor-cAMP and p38-MAPK pathways in human MDDCs, which may further recruit neutrophil accumulation and adversely affect patients with refractory or severe asthma because of airway neutrophilia. These effects should be considered for PGI(2) analogues as candidates for the treatment of asthma. PMID- 20195733 TI - Brief report: telephone administration of the autism diagnostic interview- revised: reliability and suitability for use in research. AB - The Autism Diagnostic Interview--revised is one of the "gold standard" diagnostic tools for autism spectrum disorders. It is traditionally administered face-to face. Cost and geographical concerns constrain the employment of the ADI-R for large-scale research projects. The telephone interview is a reasonable alternative, but has not yet been examined for reliability with face-to-face administration. In this study, participants were interviewed both face-to-face and on the telephone using the complete ADI-R interview. Results indicate that there was no significant difference between the algorithm scores or the diagnoses arrived at for face-to-face and telephone administrations. Reliability statistics across the two modalities were very good and indicate that telephone interviews using the ADI-R are a viable option for researchers. PMID- 20195734 TI - Optimism, social support, and well-being in mothers of children with autism spectrum disorder. AB - This study used structural equation modeling to examine the relationship between multiple sources of social support (e.g., partner, family, and friends), optimism, and well-being among mothers of children with ASD. Social support was examined as a mediator and moderator of the optimism-maternal well-being relationship. Moreover, the role of optimism as a mediator of the social support maternal well-being relationship was also evaluated. Results revealed that family support was associated with increased optimism that, in turn, predicted higher levels of positive maternal outcomes and lower levels of negative maternal outcomes. In addition, partner and friend support were directly associated with maternal outcomes. Implications for the development of interventions directed at increasing the quality of social support networks are discussed. PMID- 20195735 TI - Early language patterns of toddlers on the autism spectrum compared to toddlers with developmental delay. AB - This study characterized early language abilities in toddlers with autism spectrum disorders (n = 257) using multiple measures of language development, compared to toddlers with non-spectrum developmental delay (DD, n = 69). Findings indicated moderate to high degrees of agreement among three assessment measures (one parent report and two direct assessment measures). Performance on two of the three measures revealed a significant difference in the profile of receptive expressive language abilities for toddlers with autism compared to the DD group, such that toddlers with autism had relatively more severe receptive than expressive language delays. Regression analyses examining concurrent predictors of language abilities revealed both similarities in significant predictors (nonverbal cognition) and differences (frequency of vocalization, imitation) across the diagnostic groups. PMID- 20195736 TI - County-level variation in the prevalence of medicaid-enrolled children with autism spectrum disorders. AB - This study examined how county-level resources are associated with the identification of children with autism spectrum disorders (ASD) in Medicaid. Medicaid claims from 2004 were combined with county-level data. There were 61,891 children diagnosed with ASD in the Medicaid system in 2004. Counties with lower per-student education expenditures, more students, a greater proportion of students in special education, higher per capita number of pediatricians and pediatric specialists, and a greater proportion of Medicaid enrollees and white residents had higher Medicaid prevalence. Within states, counties differ in how they implement Medicaid policies. The results suggest the substitution of education and Medicaid-reimbursed services. Our findings highlight the need for geographically targeted outreach to minority groups and clinicians to improve recognition of ASD. PMID- 20195738 TI - Punishment and sympathy judgments: is the quality of mercy strained in Asperger's syndrome? AB - This study examined reasoning about wrongdoing in people with Asperger's syndrome (AS) and matched healthy controls in relation to car accident scenarios. The two groups made similar judgments with respect to degree of driver negligence for both fines imposed and sympathy ratings. They also made similar judgments of fines in relation to the type of justification given for the drivers' actions. However, the AS group differentiated more in sympathy judgments relating to good and poor justifications. The AS group thus appeared to show preserved judgment with respect to compensation and sympathy for the victim and fines for the driver, but expressed less sympathy towards drivers with poor justifications for their actions. PMID- 20195739 TI - Multirater congruence on the social skills assessment of children with asperger syndrome: self, mother, father, and teacher ratings. AB - Children with Asperger Syndrome (AS) who attend mainstream settings face social skills deficits that have not been adequately explored. This study aims to examine social skills through self-reports of children with AS (N = 21) and a matched group of typically developing peers, as well as reports from their mothers, fathers, and teachers. Results showed that children with AS had more social skills deficits according to all raters and that they reported more aggressiveness/antisocial behavior, more conceit/haughtiness, more loneliness/social anxiety, and less assertiveness than controls. The level of agreement between raters varied significantly, suggesting that social skills are best studied with multiple informants. PMID- 20195740 TI - Animacy and word order in individuals with autism spectrum disorders. AB - Individuals with autism or autism spectrum disorders (ASDs) are known to have difficulties discriminating animacy and are less likely to attend to animate stimuli, which may underlie the social deficits of autism. For individuals without ASD, animacy also affects word order choices: speakers choose syntactic structures (active vs. passive) that place animate entities as the grammatical subject, as a result of their conceptual salience. This study tested whether highly verbal adults with ASD would show sensitivity to animacy in a picture description task. Results showed that individuals with ASD were as sensitive to animacy as controls, and overwhelmingly placed animate entities as the grammatical subject. One stimulus proved an exception, where only individuals with ASD placed an inanimate entity (a clock) in subject position in preference to an animate one (a boy), which coincides with previous observations that individuals with autism find clocks highly salient. This study provides converging evidence of the role of conceptual salience in word order choices, and furthermore shows animate entities to be highly salient for individuals with ASD, at least as it pertains to these word order choices. PMID- 20195737 TI - Motor coordination in autism spectrum disorders: a synthesis and meta-analysis. AB - Are motor coordination deficits an underlying cardinal feature of Autism Spectrum Disorders (ASD)? Database searches identified 83 ASD studies focused on motor coordination, arm movements, gait, or postural stability deficits. Data extraction involved between-group comparisons for ASD and typically developing controls (N = 51). Rigorous meta-analysis techniques including random effects models, forest and funnel plots, I (2), publication bias, fail-safe analysis, and moderator variable analyses determined a significant standardized mean difference effect equal to 1.20 (SE = 0.144; p <0.0001; Z = 10.49). This large effect indicated substantial motor coordination deficits in the ASD groups across a wide range of behaviors. The current overall findings portray motor coordination deficits as pervasive across diagnoses, thus, a cardinal feature of ASD. PMID- 20195741 TI - Genomic characterization of a proventriculitis-associated infectious bronchitis coronavirus. AB - Transmissible proventriculitis associated with infectious bronchitis virus (IBV) was at first seen in eastern China in mid-1995, and is now endemic in China. Herein, the complete genome sequence of a proventiculitis-associated infectious bronchitis coronavirus (ZJ971) was sequenced and analyzed. Compared with the genome of the vaccine strain H120, ZJ971 had 54 nucleotide substitutions and a deletion in the 3'-UTR. The substitutions were in the regions of nsp2-nsp5, nsp7, nsp12, nsp13, nsp15, S and N genes, and the untranslating region. The results indicated that ZJ971 could be a variant of IBV strain H120. PMID- 20195742 TI - Early behavioral adherence predicts short and long-term weight loss in the POUNDS LOST study. AB - The primary aim of this study was to test the association of early (first 6 months) adherence related to diet, self-monitoring, and attendance with changes in adiposity and cardiovascular risk factors. This study used data from the 24 month POUNDS LOST trial that tested the efficacy of four dietary macronutrient compositions for short-and long-term weight loss. A computer tracking system was used to record data on eight indicator variables related to adherence. Using canonical correlations at the 6 and 24 month measurement periods, early behavioral adherence was associated with changes in percent weight loss and waist circumference at 6 months (R = 0.52) and 24 months (R = 0.37), but was not associated with cardiovascular disease risk factor levels. Early dietary adherence was associated with changes in insulin at 6 months (R = 0.19), but not at 24 months (R = 0.08, ns). Early dietary adherence was not associated with changes in adiposity. PMID- 20195743 TI - Parent advocates in children's mental health: program implementation processes and considerations. AB - Children's mental health service systems are increasingly utilizing peer support services to support families experiencing serious child mental illness. The literature provides few detailed accounts of such peer-based approaches. This study qualitatively examined the approaches and processes of "parent advocate" programs implemented in two Ohio counties for children served through publicly funded mental health services. Descriptions of each county's program, the background and roles of parent advocates, reasons families decline advocate services, and challenges to advocates' work with families are provided. Implications for the field in developing clear and effective administrative and practice structures for peer support services are discussed. PMID- 20195744 TI - Adjuvant! Online estimation of chemotherapy effectiveness when added to ovarian function suppression plus tamoxifen for premenopausal women with estrogen receptor-positive breast cancer. AB - Adjuvant! Online (Adjuvant!) is a user-friendly, web-based tool that provides estimates of adjuvant therapy outcomes for individual patients. While reliable evidence underpins estimates for most patient cohorts, there is a paucity of data on the effect of adding chemotherapy to complete estrogen blockade for premenopausal women with estrogen-receptor positive breast cancer. International Breast Cancer Study Group (IBCSG) Trial 11-93 enrolled 174 premenopausal women with estrogen-receptor positive, node-positive breast cancer. Among these patients, 55% had one positive axillary lymph node and 97% had three or fewer positive nodes. Patients were randomized to receive ovarian function suppression plus 5 years of tamoxifen with or without anthracycline-based chemotherapy. Estimated hazard rates and corresponding 10-year relapse-free survival percentages obtained from Trial 11-93 data were compared with those predicted using Adjuvant!. The 10-year relapse-free survival percentages predicted from Adjuvant! were 64.4% (95% CI, 61.9-67.2%) for endocrine therapy alone and 74.9% (95% CI, 73.1-76.8%) for chemoendocrine therapy. By contrast, these estimates in Trial 11-93 were 76.4% (95% CI, 65.8-84.0%) for endocrine therapy alone and 74.9% (95% CI, 64.5-82.7%) for chemoendocrine therapy. The Adjuvant! estimate for the endocrine-alone control group is lower than that observed in Trial 11-93 (P = 0.03), while the estimates for the two chemoendocrine therapy groups are similar. Adjuvant! appears to underestimate the effectiveness of adjuvant endocrine therapy alone for premenopausal women with endocrine responsive breast cancer, thus overestimating the added benefit, if any, from chemotherapy for this patient population. PMID- 20195745 TI - The fouling of fish farm cage nets as bioindicator of aquaculture pollution in the Adriatic Sea (Croatia). AB - A fouling assemblage (including density, species richness and diversity, and biomass) growing on netting of fish farm cages was investigated in Stracinska Bay -Location 1 and Peles Bay--Location 2 (Croatia) in order to test the efficiency of fouling as a bioindicator of organic pollution. A total number of 40 algal taxa in Location 1 and total number of 22 algal taxa in Location 2 were identified, with a dominance of opportunistic species (ESG II). We found domination of algal species over animal species and absolute dominance of Rhodophyta which are typical fouler in the Adriatic Sea. Low diversity and species richness with increase in value of the R/P index (occasionally higher than 6) were recorded in Location 2, indicating a certain impact of nutrient enrichment from fish culture facilities on a fouling community structure. PMID- 20195746 TI - Integrated estuary management for diffused sediment pollution in Dapeng Bay and neighboring rivers (Taiwan). AB - This work investigated sediment samples collected from Dapeng Bay and three neighboring rivers (Kaoping River, Tungkang River, and Lingbeng River) in southwestern Taiwan, Republic of China. Multivariate statistical analysis techniques, i.e., factor analysis, cluster analysis, and canonical discriminant analysis were used for the evaluation of spatial variations to determine the types of pollution and to identify pollutant sources from neighboring rivers. Factor analysis results showed that the most important latent factors in Dapeng Bay are soil texture, heavy metals, organic matter, and nutrients factors. Contour maps incorporating the factor scores showed heavy metals accumulate along the lakesides, especially on the southeastern banks of the lakes. A cluster analysis was performed using factor scores computed from these latent factors. We then classified these areas into five distinct classes using sampling stations, and we illustrate that in the three river classes, the sediment properties are influenced by industrial and domestic wastewater and agricultural activities (including livestock rearing and farm activities). However, in Dapeng Bay, the rivers were influenced more by complicated biogeochemical processes; these could be identified as a type of pollution. Canonical discriminant analysis illustrated that two constructed discriminant functions made a marked contribution to most of the discriminant variables, and the significant parameters of porosity and Cd, Cr, Al, and Pb content were combined as the "heavy metal factor". The recognition capacities of the two discriminant functions were 82.6% and 17.4%, respectively. It is also likely that the annual mean of the water exchange rate is insufficient (taking about 7 days to eliminate pollutants) and therefore has significantly influenced the carbon and nutrient biogeochemical processes and budgets in the semi-enclosed ecosystem. Thus, the sediment properties are not similar between the lagoon and the neighboring rivers. Our results yield useful information concerning estuary recovery and water resources management and may be applicable to other basins with similar characteristics that are experiencing similar coastal environmental issues. PMID- 20195747 TI - Assessment of pollution profile in Buyukcekmece Watershed, Turkey. AB - Buyukcekmece Lake located north of the Marmara Sea coast of Turkey is the third largest water resources among the six main reservoirs of a megacity Istanbul, providing 17% water demand. This study aims to investigate the water quality changes in Buyukcekmece Lake and to classify it in accordance to Turkish Water Pollution Control Regulation for inland surface waters, and assess the impacts of the land-use practices, population density, and settlement in the Buyukcekmece watershed. Physical, chemical, and biological quality of Buyukcekmece Lake has been investigated between December 2007 and June 2008 by collecting samples from the Lake and four streams that feed Buyukcekmece Lake. Land use profile maps of the water basin were created by using ARC-GIS to ensure the quality of drinking water. It was determined that the water quality of Buyukcekmece Lake was still of overall second class, implying that it can be used as a safe drinking water resource following a conventional water treatment scheme; however, it is moving toward the third class. Remarkable portion of the pollution in water basin was attributed to domestic wastewater discharges. Agricultural areas that occupy more than half of the water basin have also adversely affected the water quality. PMID- 20195748 TI - Diversity of cyanobacterial phylotypes in a Mediterranean drinking water reservoir (Marathonas, Greece). AB - The structure of the cyanobacterial community in a large drinking water reservoir (Marathonas, Greece) was investigated in October 2007 and September 2008. Cyanobacteria-specific primers were used for the PCR amplification of cyanobacterial 16S rDNAs from three water column sites and the water collection tank. In total, 199 clones were sequenced representing 52 unique cyanobacterial, including chloroplast-related, and 11 non-cyanobacterial phylotypes. All cyanobacterial phylotypes belonged to the order Chroococcales. Cluster analysis showed that the cyanobacterial communities in 2007 in the three water column sites showed high similarity between the stations and low diversity (H=1.17 1.44), due to the occurring common phylotypes, while all sites in 2008 had very low similarities between them and higher diversity (H=1.56-2.40). Some of the most abundant phylotypes were closely related (>98%) to members of the genus Gloeocapsa and a potentially toxin-producing strain of Microcystis aeruginosa. The non-cyanobacterial phylotypes were either unaffiliated or belonged to the Verrucomicrobia, and were related with sequences originating from lake water habitats. PMID- 20195749 TI - Distribution and enrichment of acid-leachable heavy metals in the intertidal sediments from Quanzhou Bay, southeast coast of China. AB - The article presents the distribution and enrichment of acid-leachable heavy metals (ALHMs) Cu, Zn, Pb, Cr, Mn, and Fe in the intertidal sediments collected from Quanzhou Bay, southeast coast of China. The contents of ALHMs along with sediment texture, total organic carbon, S2-, and CaCO3 in surface sediments were analyzed to identify the input of heavy metals from various sources. The enrichment of ALHMs in the sediments is mainly attributed to the intense industrial activities around Quanzhou Bay and to the serried activities of intertidal breed aquatics along the seacoast. The results also illustrate the association between the ALHMs with the finer fractions, organic matter, and Fe oxyhydroxides in the sediments. The above results were very supported by the multivariate statistical analyses, including correlation, principal component analysis, and hierarchical clustering analysis. Comparative results of ALHMs in the intertidal sediments from Quanzhou Bay with those in other domestic bays and estuaries indicate that the study area has been enriched with heavy metals, especially with Zn, Cu, and Pb, during the past few decades. The results of the present study suggest that the authorities should pay attention to the current status and take some measures to control the heavy metal pollution in the study area. PMID- 20195750 TI - Distribution of microbiological indicators of fecal pollution in the riverine substrates. AB - Distribution of fecal microorganisms in water, periphyton, and sediment was studied along the Zrnovnica river (Croatia) over a 1.5-year period. It was found that periphyton was inhabited by the highest number of investigated bacteria, while lower numbers of them were found in sediment and the lowest in surface water of the river. The concentrations of fecal microorganisms in periphyton and partly in sediment were found to be significantly higher in the middle of the river course, near the town of Zrnovnica, while according to the analysis of surface water the highest degree of pollution was reached on its estuary. The results were explained with respect to bacterial-algal associations. Considering the fact that most of the river microorganisms are associated with periphyton and sediment particles and only a small number of them is in the free-living form, microbiological analysis of both periphyton and sediment together with water samples has been suggested when fecal pollution of a river is concerned. PMID- 20195751 TI - Estimation of bacteriological levels in surface water samples to evaluate their contamination profile. AB - The present work deals with the assessment of bacteriological contamination along with some physico-chemical parameters of water samples from Lahore canal. ANOVA showed that the observed p values of log-transformed viable plate counts, total suspended solids, turbidity, and biological oxygen demand are 0.000, 0.000, 0.000, and 0.000, respectively, which are < 0.05, while the p value of total coliforms, total fecal coliforms, and Escherichia coli are 0.728, 0.827, and 0.081, respectively which are > 0.05. Significant correlation was observed between log-transformed viable plate counts (CFU), biological oxygen demand, total suspended solids, and turbidity. Further regression analysis revealed that simple line regression model is fit for log-transformed viable plate counts and total suspended solids, log-transformed viable plate counts and turbidity, turbidity and total suspended solids, biological oxygen demand and total suspended solids, biological oxygen demand and log-transformed viable plate counts, and biological oxygen demand and turbidity. PMID- 20195752 TI - Maternal and cord blood levels of aldrin and dieldrin in Delhi population. AB - Aldrin and dieldrin, structurally similar organochlorine pesticides belong to cyclodiene family and were widely used for agriculture and public health program in India. Although the manufacturing, use and import of aldrin and dieldrin have been banned in India since 2003, these pesticides are still persistent in environment and may be associated with adverse neurological and reproductive effects. The aim of this study is to assess the recent exposure level of aldrin and dieldrin and their placental transfer to fetus in normal healthy full-term pregnant women belonging to north Indian population undergoing normal delivery at Obstetrics and Gynecology department of UCMS and GTB hospital, Delhi. Quantitative analysis of aldrin and dieldrin residues in maternal and cord blood samples were carried out by gas chromatography system equipped with electron capture detector. The results of our study clearly revealed that maternal and cord blood levels of aldrin and dieldrin of pregnant women are age and dietary habit dependent. The aldrin level in maternal blood and dieldrin level in cord blood are higher in women in the age group 25-30 years than in women in age group of 19-24 years. Similarly, aldrin level in maternal blood is significantly higher in women with non-vegetarian dietary habit than in women with vegetarian dietary habit. No significant association is found for maternal and cord blood level. The results of the present study clearly demonstrate prenatal uptake of aldrin and dieldrin and provide recent information on the subsequent transplacental transfer. PMID- 20195753 TI - High-fat feeding and Staphylococcus intermedius infection impair beta cell function and insulin sensitivity in mongrel dogs. AB - As obesity is a state of low-grade inflammation, we aimed to investigate the combined effect of high-fat diet and bacterial infection on beta-cell function and insulin sensitivity in dogs. We used 20 healthy, male, mongrel dogs randomly divided into four groups: control group-healthy, non-obese dogs; infected group non-obese dogs with experimentally induced infection (Staphylococcus intermedius); obese group-obese dogs (after 90 day high-fat diet) and obese infected group-obese dogs with experimentally induced infection (Staphylococcus intermedius). To evaluate insulin sensitivity and beta-cell function an intravenous glucose tolerance test (IVGTT) was performed. Plasma insulin increased in all group after glucose infusion. The lowest values were found in obese-infected group. Blood glucose also increased on 3 min after glucose infusion and then gradually decreased. In obese-infected group glucose concentration on 30 min was still significantly higher than initial levels, while in other groups glucose concentration returned to the initial values. The lowest rate of glucose elimination was found in infected group. In dogs of obese group and obese-infected group AUC(ins 0-60 min) was lower compared to controls. AUC(glucose 0-60 min) values were lowest in infected group, while in obese infected group values were the highest. Levels of I/G in dogs of obese-infected group were significantly lower compared to controls and infected group. In conclusion, these results reveal that infection in obese dogs leads to impaired glucose tolerance, which is result of impairment in both insulin secretion and insulin sensitivity. PMID- 20195754 TI - Ectoparasites are the major causes of various types of skin lesions in small ruminants in Ethiopia. AB - Ectoparasites are the major causes of skin lesions in animals. Clinical, skin scraping examination, and histopathological studies were conducted to identify and characterize skin lesions in small ruminants caused by ectoparasites. Mange mites, lice, sheep keds, and ticks were collected from the skin of affected animals for species identification. Skin biopsies were collected from affected part of the skin and fixed in 10% neutral buffered formalin for histopathology. Of 1,000 sheep and 600 goats examined, 815 (81.50%) sheep and 327 (54.5%) goats were infested with one or more types of ectoparasites. Sarcoptes scabiei var ovis, Demodex ovis, Psoroptes ovis, Bovicola ovis, Melophagus ovinus, and Amblyomma variegatum and other tick species were identified from sheep. S. scabiei var caprae, Demodex caprae, Linognathus stenopsis, and A. variegatum and other tick species were identified from goats. Gross skin lesions or defects observed on the skin include stained and ragged wool, loss of wool/hair, nodules, crusts, lichenification, and fissuring. Microscopic evaluation of H and E stained skin sections revealed lesions in the epidermal layer such as hyperkeratosis, acanthosis, and melanin inconsistency on the basal cells of the epidermis. Follicular keratosis, perifolliculitis, frunculosis, perivasculitis, and aggregates of inflammatory cells (of acute and chronic type) with fibrosis were experiential in the dermal layer of the skin. Most of the skin lesions caused by ectoparasites are overlapping. Thus, ectoparasites control program should be executed to reduce skin lesions as skins are the major export commodity of the country. PMID- 20195755 TI - Non-genetic factors influencing reproductive traits and calving weight in Saudi camels. AB - Reproductive traits and calving weight were assessed in Saudi camels, and non genetic factors influencing them were studied using data collected at Al Jouf centre from 1987 to 2009. Age at first conception, age at first calving, open period, calving interval, gestation length and weight at calving of camels averaged 42.3 months, 54.8 months, 10.6 months, 22.6 months, 377.5 days and 591.9 kg, respectively. A mixed model including the camel as a random effect was used to assess the effect of environmental effects on the traits studied. Age at first conception and age at first calving were affected by camel's birth year. Open period and calving interval were not affected by parity or year of calving. However, camels that calved from October to February had a calving interval of 2.5 months higher than those that calved from March to September. Gestation length was affected by season and year of calving but not by parity or sex of calf. Camels calving from March to September had a gestation length 6.6 days shorter than those calving from October to February. Weight at calving was affected by parity and year of calving but not by season of calving. It was concluded that an improvement in camel reproductive traits is possible both through improving management systems and utilisation of controlled breeding techniques. PMID- 20195756 TI - Biogerontology in Austria. AB - In Austria significant progress in the field of biogerontology has been achieved in the past years. Biogerontological research is performed in academic and extramural institutions. The Institute for Biomedical Aging Research of the Austrian Academy of Science at Innsbruck is the largest institution dealing with biogerontology in Austria. Moreover, gerontologic research is performed at the Universities of Salzburg and Graz, the Medical Universities of Vienna, Innsbruck and Graz, the University of Veterinary Medicine (Vienna) and the University of Natural Resources and Applied Life Sciences (Vienna). This article describes the work of selected research groups involved in biogerontology in a geographic arrangement. PMID- 20195757 TI - Fecal occult blood test in patients on low-dose aspirin, warfarin, clopidogrel, or non-steroidal anti-inflammatory drugs. AB - AIM: To determine the effect of anticoagulants and antiplatelet medications on the positive-predictive-value of fecal occult blood test (FOBT). METHODS: All patients who underwent a colonoscopy at our institution from 1995 to 2006 for a positive FOBT were identified. Medical records were searched, and patients were stratified into five groups selected a priori: low-dose aspirin, NSAIDs, warfarin, clopidogrel, or controls. The positive-predictive-value of FOBT for advanced colonic neoplasia was computed for each group. RESULTS: During the study period, 1,126 patients underwent colonoscopy for a positive FOBT and met entry criteria. The average age of study participants was 69 years and most were men. The positive-predictive-value of FOBT for advanced colon neoplasia was significantly higher in the control group (30.5%) when compared to those on low dose aspirin (20.5%; p = 0.003), NSAIDs (19.7%; p = 0.003), clopidogrel (7.3%; p = 0.002), or warfarin (20%; p = 0.05). The positive-predictive-value of FOBT was significantly lower for those on clopidogrel than those on low-dose aspirin (p = 0.04) and NSAIDs (p = 0.05), but not warfarin (p = 0.08). The positive-predictive value for FOBT was similar for those on aspirin, NSAIDs, and warfarin. There was a linear trend between the number of number of positive FOBT cards and prevalence of advanced colon neoplasia (p = 0.01). CONCLUSION: Anticoagulants and antiplatelet medications lower the positive-predictive-value of FOBT for advance colonic neoplasia and should be stopped if clinically feasible prior to stool collection. PMID- 20195758 TI - Computational hemodynamic analysis in congenital heart disease: simulation of the Norwood procedure. AB - Hypoplastic left heart syndrome (HLHS) is a congenital heart disease which should be treated at neonate. Even now, its operation is one of the greatest challenges. However, currently there are no quantitative standards to evaluate and predict the outcome of the therapy. In this study, computational fluid dynamics (CFD) was used to estimate the performance of first stage HLHS surgery, the Norwood operation. An image data transfer system was developed to convert clinical images into three-dimensional geometry. To confirm software applicability, a validation process was carried out to eliminate any influence of numerical procedures. The velocities derived from echocardiography measurements were used as boundary conditions, and pressure waves measured by a cardiac catheter simultaneous with an electrocardiogram (ECG) were employed to validate the results of CFD simulation. Calculated results were congruent with the in vivo measurement results. The blood flow circulations were successfully simulated and the distribution of blood flow in each vessel was estimated. Time-varying energy losses (EL), local pressure and wall shear stress (WSS) were analyzed to estimate clinical treatment. The results indicated that pulsatile simulation is essential in quantitative evaluation. Computational hemodynamics may be applied in the surgical optimization for the treatment of HLHS. PMID- 20195760 TI - Computational study of proteolysis-driven single cell migration in a three dimensional matrix. AB - Cell migration is a fundamental process that is crucial to a variety of physiological events. While traditional approaches have focused on two dimensional (2D) systems, recent efforts have shifted to studying migration in three-dimensional (3D) matrices. A major distinction that has emerged is the increased importance of cell-matrix interactions in 3D environments. In particular, cell motility in 3D matrices is more dependent on matrix metalloproteinases (MMPs) to degrade steric obstacles than in 2D systems. In this study, we implement the effects of MMP-mediated proteolysis in a force-based computational model of 3D migration, testing two matrix ligand-MMP relationships that have been observed experimentally: linear and log-linear. The model for both scenarios predicts maximal motility at intermediate matrix ligand and MMP levels, with the linear case providing more physiologically compelling results. Recent experimental results suggesting MMP influence on integrin expression are also integrated into the model. While the biphasic behavior is retained, with MMP integrin feedback peak cell speed is observed in a low ligand, high MMP regime instead of at intermediate ligand and MMP levels for both ligand-MMP relationships. The simulation provides insight into the expanding role of cell matrix interactions in cell migration in 3D environments and has implications for cancer research. PMID- 20195762 TI - A stretching device for high-resolution live-cell imaging. AB - Several custom-built and commercially available devices are available to investigate cellular responses to substrate strain. However, analysis of structural dynamics by microscopy in living cells during stretch is not readily feasible. We describe a novel stretch device optimized for high-resolution live cell imaging. The unit assembles onto standard inverted microscopes and applies constant magnitude or cyclic stretch at physiological magnitudes to cultured cells on elastic membranes. Interchangeable modular indenters enable delivery of equibiaxial and uniaxial stretch profiles. Strain analysis performed by tracking fluorescent microspheres adhered onto the substrate demonstrated reproducible application of stretch profiles. In endothelial cells transiently expressing enhanced green fluorescent protein (EGFP)-vimentin and paxillin-DsRed2 and subjected to constant magnitude equibiaxial stretch, the two-dimensional strain tensor demonstrated efficient transmission through the extracellular matrix and focal adhesions. Decreased transmission to the intermediate filament network was measured, and a heterogeneous spatial distribution of maximum stretch magnitude revealed discrete sites of strain focusing. Spatial correlation of vimentin and paxillin displacement vectors provided an estimate of the extent of mechanical coupling between the structures. Interestingly, switching the spatial profile of substrate strain reveals that actin-mediated edge ruffling is not desensitized to repeated mechanostimulation. These initial observations show that the stretch device is compatible with live-cell microscopy and is a novel tool for measuring dynamic structural remodeling under mechanical strain. PMID- 20195763 TI - Evaluating anisotropic properties in the porcine temporomandibular joint disc using nanoindentation. AB - The objective of this study was to determine the viscoelastic properties present within the intermediate zone of the porcine temporomandibular joint (TMJ) disc using nanoindentation. A 50-microm conospherical indenter tip using a displacement-controlled ramp function with a 600 nm/s loading and unloading rate, a 3000-nm peak displacement with a holding period of 30 s was used to indent the samples. Experimental load-relaxation tests were performed on the TMJ disc to determine the response in three different directions; the mediolateral, anteroposterior, and articular surface directions. The experimental data were analyzed using a generalized Maxwell model to obtain values for short- and long time relaxation modulus and of material time constants. The short time relaxation modulus E ( I ) values were 180.92, 64.99, and 487.77 kPa for testing done on the articular surface, mediolateral, and anteroposterior directions, respectively. Corresponding values for the long-time relaxation modulus E (infinity) were 45.9, 14.97, and 133.5 kPa. The method confirmed anisotropy present within the central intermediate zone of the porcine TMJ disc due to the directional orientation of the collagen fibers. PMID- 20195764 TI - Antioxidant activity and phenolic content of betalain extracts from intact plants and hairy root cultures of the red beetroot Beta vulgaris cv. Detroit dark red. AB - Betalains are water-soluble plant pigments that are widely used as food colorants, and have a wide range of desirable biological activities, including antioxidant, anti-inflammatory, hepatoprotective, anti-cancer properties. They can be produced from various plants, notably beetroot, but betalain products obtained in this way also have some undesirable properties and are difficult to standardize. A potentially attractive alternative is to use hairy root cultures. In the study reported here, we found that betalain extracts obtained from hairy root cultures of the red beetroot B. vulgaris cv. Detroit Dark Red also had higher antioxidant activity than extracts obtained from mature beetroots: six fold higher 2,2-dyphenyl-1-picrylhydrazyl radical scavenging ability (90.7% inhibition, EC(50) = 0.11 mg, vs 14.2% inhibition, EC(50) = 0.70 mg) and 3.28 fold higher oxygen radical absorbance capacity (4,100 microM TE/g dry extract, vs 1,250 microM TE/g dry extract). The high antioxidant activity of the hairy root extracts was associated with increased concentrations (more than 20-fold) of total phenolic concomitant compounds, which may have synergistic effects with betalains. The presence of 4-hydroxybenzoic acid, caffeic acid, catechin hydrate, and epicatechin were detected in both types of extract, but at different concentrations. Rutin was only present at high concentration (1.096 mg.g(-1) dry extract) in betalain extracts from the hairy root cultures, whereas chlorogenic acid was only detected at measurable concentrations in extracts from intact plants. PMID- 20195765 TI - Microfluidic devices for characterizing the agonist of formyl peptide receptor in RBL-FPR cells. AB - The human formyl peptide receptor (FPR) plays an important role in inflammation and immunity. Finding of specific agonists and antagonists of FPR may provide potential therapeutic agents for FPR related disorders. The binding of agonist by FPR induces a cascade of G protein-mediated signaling events leading to neutrophil chemotaxis, intracellualr calcium mobilization, FPR ligand uptake and so on. This work proposed a microfluidic-based method to characterize FPR-related cellular events in response to small peptides, N-formyl-Met-Leu-Phe (fMLF), in rat basophilic leukemia cell line RBL-2H3 expressing human FPR (RBL-FPR). The results showed that fMLF triggered chemotaxis, calcium mobilization and FPR ligand uptake in RBL-FPR cells, indicating the potential role of FPR agonist. The chemotaxis index and the calcium mobilization intensity increased but the time course of calcium mobilization decreased, as the rising of fMLF concentration. The basic agreement between the microfluidic results and the previous studies demonstrated good feasibility of the microfluidic method for characterization of FPR agonist. Microfluidic technology displays significant advantages over traditional methods in terms of sample consumption and assay time. It also facilitates experimental process and real-time observation of cellular responses at single cell resolution. PMID- 20195766 TI - Multiphysics modeling of responsive characteristics of ionic-strength-sensitive hydrogel. AB - A multiphysics model is developed in this paper for simulation of the volume transition mechanism of the smart hydrogel in response to the changes in the ionic strength of bathing solution as an important measure of the ionic concentration of that solution, which is termed the multi-effect-coupling ionic strength-stimulus (MECis) model. In the present works, the ionic strength is treated as a main stimulus and incorporated into both the ionic convection diffusion system in the Nernst-Planck flux and the fixed charge density equation characterized by Langmuir isotherm theory. Due to the diffusion and convection, the osmotic pressure is produced by the difference in the ionic concentration between the interior hydrogel and exterior solution, which drives the swelling of the smart hydrogel. The deformation of the ionic-strength-sensitive hydrogel is described by the momentum conservation law, in which the osmotic pressure is a main driving source. Apart from osmotic pressure, however, the repulsive force between the fixed charges is also considered in the mechanical equilibrium equation as another driving source for the swelling of the hydrogel. The simulation is conducted for one-dimensional steady-state problem, and then compared with the experimental data and other theories from open literature. The comparisons demonstrate that the MECis model can simulate well the swelling behavior of the ionic-strength-sensitive hydrogel qualitatively and quantitatively. Probably it is able to predict the responsive characteristics of the bathing solution including the distribution of diffusive ionic concentrations and electrical potential. PMID- 20195761 TI - Adhesive/Dentin interface: the weak link in the composite restoration. AB - Results from clinical studies suggest that more than half of the 166 million dental restorations that were placed in the United States in 2005 were replacements for failed restorations. This emphasis on replacement therapy is expected to grow as dentists use composite as opposed to dental amalgam to restore moderate to large posterior lesions. Composite restorations have higher failure rates, more recurrent caries, and increased frequency of replacement as compared to amalgam. Penetration of bacterial enzymes, oral fluids, and bacteria into the crevices between the tooth and composite undermines the restoration and leads to recurrent decay and premature failure. Under in vivo conditions the bond formed at the adhesive/dentin interface can be the first defense against these noxious, damaging substances. The intent of this article is to review structural aspects of the clinical substrate that impact bond formation at the adhesive/dentin interface; to examine physico-chemical factors that affect the integrity and durability of the adhesive/dentin interfacial bond; and to explore how these factors act synergistically with mechanical forces to undermine the composite restoration. The article will examine the various avenues that have been pursued to address these problems and it will explore how alterations in material chemistry could address the detrimental impact of physico-chemical stresses on the bond formed at the adhesive/dentin interface. PMID- 20195767 TI - Linking the septin expression with carcinogenesis. AB - The septin is a conserved GTP binding protein family which is involved in multiple cellular processes. Many evidences have indicated that some septins were abnormally expressed in certain kinds of tumors and the altered expressions were related to the process of carcinogenesis. To better understand the relationship between septins and cancer, we compared the expression of 14 human septin family members in 35 kinds of tumor types with their normal counterparts using the publicly available ONCOMINE microarray database. We found altered expression of most septin members in many kinds of tumors. Significantly, SEPT2, SEPT8, SEPT9, SEPT11 were consistently up-regulated, and SEPT4, SEPT10 were down-regulated in most cancer types investigated. Furthermore, the abnormal expressions were also in accordance with the tumor malignancies or prognosis of corresponding cancer patients. These findings have contributed to the view that septins may belong to a kind of cancer critical genes. More septins might act as potential oncogenes or tumor suppressor genes in cancer development. PMID- 20195768 TI - Cloning and expression of a cellulase gene in the silkworm, Bombyx mori by improved Bac-to-Bac/BmNPV baculovirus expression system. AB - Cellulases catalyze the hydrolysis of cellulose which are mainly three types: endoglucanases, cellobiohydrolases and beta-glucosidases. It can be used in converting cellulosic biomass to glucose that can be used in different applications such as production of fuel ethanol, animal feed, waste water treatment and in brewing industry. In this paper, we cloned a 1380-bp endoglucanase I (EG I) gene from mycelium of filamentous fungus Trichoderma viride strain AS 3.3711 using PCR-based exon splicing methods, and expressed the recombinant EG I mature peptide protein in both silkworm BmN cell line and silkworm larvae with a newly established Bac-to-Bac/BmNPV mutant baculovirus expression system, which lacks the virus-encoded chitinase (chiA) and cathepsin (v-cath) genes of Bombyx mori nucleopolyhedrovirus (BmNPV). An around 49-kDa protein was visualized after mBacmid/BmNPV/EG I infection, and the maximum expression in silkworm larvae was at 84 h post-infection. The ANOVA showed that the enzymes from recombinant baculoviruses infected silkworms exhibited significant maximum enzyme activity at the environmental condition of pH 7.0 and temperature 50 degrees C. It was stable at pH range from 5.0 to 10.0 and at temperature range from 50 to 60 degrees C, and increased 24.71 and 22.84% compared with that from wild baculoviruses infected silkworms and normal silkworms, respectively. The availability of large quantities of EG I that the silkworm provides maybe greatly facilitate the future research and the potential application in industries. PMID- 20195769 TI - Acylated and des acyl ghrelin in human portal and systemic circulations. AB - Octanoylation of the gastric peptide ghrelin produces an active isoform that regulates appetite and other metabolic functions. Acylated ghrelin is present in the gastrointestinal tract suggesting that octanoylation may occur in these tissues and thereby affect the acylated ghrelin in the systemic circulation. In this study blood samples were collected simultaneously from portal, arterial, peripheral venous and central venous compartments from patients undergoing laparotomy. ELISA and high sensitivity Bioplex was used to measure the concentration of acylated and des acyl ghrelin. We found median (95% confidence interval (CI)) plasma acylated ghrelin (pg/ml) was 35.8 (30.0-59.6) in the portal compartment compared to 51.5 (37.6-74.8; P < 0.05, n = 11) in the arterial, 39.3 (33.3-56.3) in the portal compartment compared to 55.0 (48.5-77.0; P < 0.001, n = 12) in the peripheral venous and 36.0 (33.1-57.4) in the portal compartment compared to 48.9 (43.3-65.6; P < 0.01, n = 15) in the central venous compartment. Median (95% CI) plasma des acyl ghrelin levels (pg/ml) was 173 (125-220) in the portal compartment compared to 136 (99.3-125; P < 0.001, n = 14)in the arterial, 186 (136-233) in the portal compartment compared to 149 (111-190; P < 0.01, n = 15) in the peripheral venous and 171 (140-208) in the portal compartment compared to 152 (119-175; P < 0.01, n = 15) the central venous compartment. We conclude that plasma acylated ghrelin concentration was significantly lower in portal compared with the systemic compartments whilst plasma des acyl ghrelin was significantly higher in portal compared with systemic compartments. These findings suggest that the liver could be involved in the regulation of circulating ghrelin. PMID- 20195770 TI - Expressed sequence tags-based identification of genes in a biocontrol strain Trichoderma asperellum. AB - Trichoderma asperellum, a filamentous soil fungus, is an effective biocontrol agent against many fungal plant pathogenic species. In the present study, we investigated the biological control properties of the strain T. asperellum T4. T. asperellum fermentation products significantly decreased the ability of Rhizoctonia solani and Sclerotinia sclerotiorum to infect rice and soybean, respectively. To further elucidate the biocontrol mechanisms of T. asperellum at the molecular level, a cDNA library was constructed from its mycelium. In total, 3114 expressed sequence tags (ESTs) were generated, which represented 1,554 unigenes, including 354 contigs and 1,200 singletons. Among these unigenes, 731 represented known genes while 823 were novel genes. Forty-six unigenes potentially involved in biocontrol processes were identified from the EST collection. Among them, the expressions of 16 genes were studied, and 15 genes were highly differentially regulated during confrontation with 2 phytopathogens, suggesting that they play roles in the T. asperellum response to phytopathogens. Our study may provide helpful insight in the mechanism of biocontrol by T. asperellum T4 against plant pathogens. PMID- 20195771 TI - Type 2 diabetes mellitus and the risk of sudden cardiac arrest in the community. AB - The reduction of mortality from sudden cardiac arrest (SCA) in the setting of coronary heart disease (CHD) remains a major challenge, especially among patients with type 2 diabetes. Diabetes is associated with an increased risk of SCA, at least in part, from an increased presence and extent of coronary atherosclerosis (macrovascular disease). Diabetes also is associated with microvascular disease and autonomic neuropathy; and, these non-coronary atherosclerotic pathophysiologic processes also have the potential to increase the risk of SCA. In this report, we review the absolute and relative risk of SCA associated with diabetes. We summarize recent evidence that suggests that the increase in risk in patients with diabetes is not specific for SCA, as diabetes also is associated with a similar increase in risk for non-SCA CHD death and non-fatal myocardial infarction. These data are consistent with prior observations that coronary atherosclerosis is a major contributor to the increased SCA risk associated with diabetes. We also present previously published and unpublished data that demonstrates that both clinically-recognized microvascular and autonomic neuropathy also are associated with the risk of SCA among treated patients with diabetes, after taking into account prior clinically-recognized heart disease and other risk factors for SCA. We then discuss how these data might inform research and clinical efforts to prevent SCA. Although the prediction of SCA in this "high" risk population is likely to remain a challenge, as it is in other "high" risk clinical populations, we suggest that current recommendations for the prevention of SCA in the community, related to both lifestyle prescriptions and risk factor reduction, are likely to reduce mortality from SCA among patients with diabetes. PMID- 20195772 TI - Impact of cardiovascular outcomes on the development and approval of medications for the treatment of diabetes mellitus. AB - All medications currently approved by the Food and Drug Administration (FDA) for the treatment of type 2 diabetes mellitus are indicated to improve glycemic control. Since 1995, FDA has used HbA1c as the primary basis for approval of these therapies because a reduction in blood glucose lessens the symptoms of hyperglycemia and lowering of HbA1c has been shown to reduce the risk for some of the chronic complications of diabetes. Despite evidence of clinical benefit with therapies that reduce HbA1c, concerns have been raised that some diabetes medications may increase cardiovascular risk in a patient population that is already vulnerable to cardiovascular disease. Therefore, FDA convened a public advisory committee meeting to discuss the role of cardiovascular assessment in the pre-approval and post-approval settings for medications developed for the treatment of type 2 diabetes. After considering the advisory panel's recommendations and other data, FDA published a guidance document requesting evidence showing that new treatments for type 2 diabetes do not result in an unacceptable increase in cardiovascular risk. This review article begins by summarizing the events leading up to publication of this guidance. Subsequent sections discuss the guidance itself as well as general considerations for implementing the new cardiovascular recommendations. The new approach to developing medications for the treatment of type 2 diabetes will lead to evaluation in patients more representative of those who will use these therapies, if approved, and will help healthcare providers make informed decisions when choosing a medication within the growing treatment armamentarium for type 2 diabetes. PMID- 20195773 TI - Population-based provider engagement in delivery of evidence-based parenting interventions: challenges and solutions. AB - Population-wide interventions do not often address parenting, and relatively little is known about large scale dissemination of evidence-based parenting interventions. Most parenting interventions are not designed to reach the majority of parents in a geographic area or to influence prevalence rates for a problem, nor do they take full advantage of the existing workforce. Implementation of parenting interventions on this scale is a complex process; examination of such efforts can inform both research and policy. The US Triple P System Population Trial, designed to reduce child maltreatment at a population level, affords a unique opportunity to examine the steps involved in launching positive parenting support at a population level via an existing provider workforce. The implementation process is described; challenges and solutions are discussed. PMID- 20195774 TI - The resurrection of life. AB - The question of life was progressively put aside in the second half of the 20th century with the rise of molecular biology, but has recently re-emerged. Many scientists and philosophers consider that there is no place for this question within biology; that the distinction between living and non-living is arbitrary; and that progress in synthetic biology will finally put this question out of people's minds. I will argue that there is something wrong with the arguments supporting these statements. There are no reasons to exclude the question "What is life?" from biology. But the nature of the question has dramatically changed recently. Instead of being a search for the principles of life, the answer is now sought in the description of the historical process that has coupled the now well established characteristics of organisms. PMID- 20195775 TI - Prevalence of BRCA2 and CDKN2a mutations in German familial pancreatic cancer families. AB - Previous small scale studies reported that deleterious BRCA2 and CDKN2a germline mutations contribute to a subset of families with inherited pancreatic cancer. As the prevalence of those mutations in the setting of familial pancreatic cancer is still not well defined for the German population, we evaluated the presence of BRCA2 and CDKN2a germline mutations in a large cohort of familial pancreatic cancer (FPC) families from the German National Case Collection for Familial Pancreatic Cancer (FaPaCa). Fifty-six FPC families with at least two-first-degree relatives with confirmed pancreatic cancer that did not fulfill the criteria of other tumor predisposition syndromes, were analyzed for BRCA2 and CDKN2a germline mutations by DHPLC and/or direct sequencing. No deleterious CDKN2a mutations were identified in our families suggesting that CDKN2a mutations are unlikely to predispose PC in FPC families without melanoma. No deleterious BRCA2 mutations, but 6 unclassified variants, were detected in our FPC collection. Combining the prevalence of deleterious BRCA2 germline mutations from our previous separate study with the data from this study we were able to much more accurately estimate the BRCA2 carrier frequency for FPC families in the German population. A total of two mutations and 6 unclassified variants (mutation range: 2.8-11.4%) were thus identified in 70 German FPC families, indicating that the prevalence of BRCA2 mutations in the German FPC population is less frequent than previously reported. PMID- 20195776 TI - Modifications in tissue kallikrein activity with indomethacin and prednisolone treatment in arthritic rats. AB - This investigation was conducted to evaluate the tissue kallikrein activity in the synovial and paw tissues of control, non-treated adjuvant arthritic and adjuvant arthritic rats treated either with indomethacin or prednisolone. Adjuvant arthritis was induced in male Sprague-Dawley rats in the right knee by injecting 0.05 ml of a fine suspension of heat-killed Mycobacterium tubercle bacilli in liquid paraffin (5 mg/ml). Indomethacin (2.5 mg/kg given orally) and prednisolone (3.0 mg/kg given orally) treatment for 9 days caused a significant reduction (P < 0.001) in knee swelling. In non-treated adjuvant rats, synovial tissue kallikrein levels were raised (P < 0.01) than the synovial tissue kallikrein obtained from control normal rats. Prednisolone treatment resulted in reduction (P < 0.05) and indomethacin treatment produced raise (P < 0.01) in synovial tissue kallikrein levels. In non-treated arthritic rats, the paw tissue kallikrein levels were lower (P < 0.001) than the control rats; whereas, rats treated with prednisolone and indomethacine showed higher levels (P < 0.05) of paw tissue kallikrein. These results may suggest that the prednisone and indomethacin differ in their actions in inflamed synovial tissue kallikrein and have a similar effect in non-inflamed paw tissues. PMID- 20195778 TI - Reducing HIV and AIDS through Prevention (RHAP): a theoretically based approach for teaching HIV prevention to adolescents through an exploration of popular music. AB - Using popular culture to engage students in discussions of HIV prevention is a nontraditional approach that may complement current prevention efforts and enhance the ability to reach youth who are at high risk of contracting HIV and other sexually transmitted infections. Hip-hop or rap music is the dominant genre of music among adolescents, especially Black and Latino youth who are disproportionately impacted by HIV and AIDS. This paper describes the rationale and development of the Reducing HIV and AIDS through Prevention (RHAP) program, a school-based program that uses hip-hop/rap music as a vehicle for raising awareness among adolescents about HIV/AIDS. Constructs from the Social Cognitive Theory and the Sexual Script Theory were used in developing the program. It was piloted and evaluated among 26 middle school students in East Harlem, New York. The lessons learned from a formative evaluation of the program and the implications for developing other programs targeting public health problems are discussed. The RHAP program challenges the traditional pedagogue-student paradigm and provides an alternative approach to teaching about HIV prevention and awareness. PMID- 20195779 TI - Supportive housing approaches in the Collaborative Initiative to Help End Chronic Homelessness (CICH). AB - The Federal Collaborative Initiative to Help End Chronic Homelessness funded 11 sites to expand permanent housing and offer supportive services to persons experiencing chronic homelessness and suffering from mental and substance use disorders. This study examines qualitative data on how the projects used US Department of Housing and Urban Development funding and three housing approaches (scattered units, congregate/clustered, or a combination) for rapid placement of clients. Each housing approach called for adaptations by the services teams and property personnel in order to support clients with independent living skills, prevent housing loss, and promote their overall health in line with Initiative goals. Property personnel reported taking on new roles with clients and forming new collaborative arrangements with services teams. The authors discuss the lessons reported by sites that were associated with housing configuration, type of lease, and role of property personnel. PMID- 20195780 TI - Abstracts of the 16th Annual Society on NeuroImmune Pharmacology (SNIP) Conference. April 13-17, 2010. Manhattan Beach, California, USA. PMID- 20195781 TI - Fatty acyl-CoA reductase and wax synthase from Euglena gracilis in the biosynthesis of medium-chain wax esters. AB - Euglena gracilis, a unicellular phytoflagellate, can accumulate a large amount of medium-chain wax esters under anaerobic growth conditions. Here we report the identification and characterization of two genes involved in the biosynthesis of wax esters in E. gracilis. The first gene encodes a fatty acyl-CoA reductase (EgFAR) involved in the conversion of fatty acyl-CoAs to fatty alcohols and the second gene codes for a wax synthase (EgWS) catalyzing esterification of fatty acyl-CoAs and fatty alcohols, yielding wax esters. When expressed in yeast (Saccharomyces cerevisiae), EgFAR converted myristic acid (14:0) and palmitic acid (16:0) to their corresponding alcohols (14:0Alc and 16:0Alc) with myristic acid as the preferred substrate. EgWS utilized a broad range of fatty acyl-CoAs and fatty alcohols as substrates with the preference towards myristic acid and palmitoleyl alcohol. The wax biosynthetic pathway was reconstituted by co expressing EgFAR and EgWS in yeast. When myristic acid was fed to the yeast, myristyl myristate (14:0-14:0), myristyl palmitoleate (14:0-16:1), myristyl palmitate (14:0-16:0) and palmityl myristate (16:0-14:0) were produced. These results indicate EgFAR and EgWS are likely the two enzymes involved in the biosynthesis of medium-chain wax esters in E. gracilis. PMID- 20195782 TI - Validation of the group-based medical mistrust scale among urban black men. AB - BACKGROUND: Socioculturally relevant measures of medical mistrust are needed to better address health disparities, especially among Black men, a group with lower life expectancy and higher death rates compared to other race/gender groups. OBJECTIVES: The study aim was to investigate the psychometric properties of the Group-Based Medical Mistrust Scale (GBMMS) in a Black male sample. DESIGN: Data were collected as part of a randomized controlled trial testing educational strategies to support Black men's decisions about prostate cancer screening. PARTICIPANTS: Participants included 201 Black men ages 40-75 years recruited in New York City during 2006-2007. MAIN MEASURES: The primary measures included: race-based medical mistrust, health care participation, avoidance of health care, perceived access to health care, health care satisfaction, racial identity, residential racial segregation, attitudes towards prostate cancer screening, and past prostate cancer screening behavior. KEY RESULTS: An exploratory factor analysis suggested a three-factor structure. Confirmatory factor analysis supported the three-factor model. Internal consistency was high for the total GBMMS and the three sub-scales: Suspicion, Discrimination, and Lack of Support. Construct validity was supported by: significant positive correlations between GBMMS and avoidance of health care and racial identity as well as significant negative correlations with health care access, health care satisfaction, and attitudes about prostate cancer screening. ANOVA showed that the GBMMS was associated with greater residential racial segregation. Higher total GBMMS scores were associated with not visiting a physician in the last year and not having a regular physician. CONCLUSIONS: The present findings provide strong additional evidence that the GBMMS is a valid and reliable measure that may be used among urban Black men. PMID- 20195783 TI - Primary non-adherence of medications: lifting the veil on prescription-filling behaviors. PMID- 20195784 TI - Procedures performed by hospitalist and non-hospitalist general internists. AB - BACKGROUND: In caring exclusively for inpatients, hospitalists are expected to perform hospital procedures. The type and frequency of procedures they perform are not well characterized. OBJECTIVES: To determine which procedures hospitalists perform; to compare procedures performed by hospitalists and non hospitalists; and to describe factors associated with hospitalists performing inpatient procedures. DESIGN: Cross-sectional survey. PARTICIPANTS: National sample of general internist members of the American College of Physicians. METHODS: We characterized respondents to a national survey of general internists as hospitalists and non-hospitalists based on time-activity criteria. We compared hospitalists and non-hospitalists in relation to how many SHM core procedures they performed. Analyses explored whether hospitalists' demographic characteristics, practice setting, and income structure influenced the performance of procedures. RESULTS: Of 1,059 respondents, 175 were classified as "hospitalists". Eleven percent of hospitalists performed all 9 core procedures compared with 3% of non-hospitalists. Hospitalists also reported higher procedural volumes in the previous year for 7 of the 9 procedures, including lumbar puncture (median of 5 by hospitalists vs. 2 for non-hospitalists), abdominal paracentesis (5 vs. 2), thoracenteses (5 vs. 2) and central line placement (5.5 vs. 3). Performing a greater variety of core procedures was associated with total time in patient care, but not time in hospital care, year of medical school graduation, practice location, or income structure. Multivariate analysis found no independent association between demographic factors and performing all 9 core procedures. CONCLUSIONS: Hospitalists perform inpatient procedures more often and at higher volumes than non-hospitalists. Yet many do not perform procedures that are designated as hospitalist "core competencies." PMID- 20195785 TI - The association of provider communication with trust among adults with sickle cell disease. AB - BACKGROUND: Adults with sickle cell disease often report poor interpersonal healthcare experiences, including poor communication with providers. However, the effect of these experiences on patient trust is unknown. OBJECTIVE: To determine the association between patient ratings of the previous quality of provider communication and current trust in the medical profession among adults with sickle cell disease. RESEARCH DESIGN: Cross-sectional survey. PARTICIPANTS: A total of 95 adults with sickle cell disease. MEASUREMENTS: The four-item Provider Communication Subscale from the Consumer Assessment of Healthcare Plans and Systems Survey; The five-item Wake Forest Trust in the Medical Profession Scale. MAIN RESULTS: Better ratings of previous provider communication were significantly associated with higher levels of trust toward the medical profession. A 10% increase in provider communication rating was associated with a 3.76% increase in trust scores (p < 0.001, 95% CI [1.76%, 5.76%]), adjusting for patient-level demographic, clinical, and attitudinal characteristics. CONCLUSIONS: Poorer patient ratings of provider communication are associated with lower trust toward the medical profession among adults with sickle cell disease. Future research should examine the impact of low trust in the medical profession on clinical outcomes in this population of patients. PMID- 20195786 TI - The International Stem Cell Banking Initiative (ISCBI): raising standards to bank on. AB - The International Stem Cell Banking Initiative (ISCBI) aims to create a global network of stem cell banks to facilitate best practice in stem cell research and clinical cell delivery, primary objectives of national and local governments worldwide and stem cell organizations such the International Stem Cell Forum and the International Society of Stem Cell Research. This paper is a brief overview of ISCBI, its primary activities, potential network participants, and the challenges for harmonizing stem cell banking on a global level. PMID- 20195787 TI - Wernicke's encephalopathy after laparoscopic Roux-en-Y gastric bypass: a misdiagnosed complication. AB - Malabsorptive syndromes and micronutrient deficiencies represent well-known long term complications of bariatric surgery. Wernicke's encephalopathy (WE), a neurologic manifestation of thiamine deficiency, has been classically associated with alcoholism or severe malnutrition, but rarely reported after bariatric surgery. Herein, we describe the case of a 27-year-old woman that developed WE 10 months after laparoscopic Roux-en-Y gastric bypass for morbid obesity that was initially misdiagnosed with a consequent retard in the appropriate treatment. Although only a few sporadic cases have been reported in the literature, all surgeons and physicians involved in the care of bariatric patients must be aware of this potentially serious complication. PMID- 20195788 TI - Short-term carbohydrate-restricted diet for weight loss in severely obese women. AB - BACKGROUND: Weight loss in bariatric pre-surgery period reduces surgical complications, surgery time, blood loss, and length of hospital stay. Carbohydrate-restricted diets have been used as an alternative for weight loss. We tested the efficacy of a low-calorie carbohydrate-restricted diet (RD) for short-term weight loss in women with severe obesity and evaluate its metabolic effects in relation to a conventional low-calorie diet (CD). METHODS: The subjects received a 1,200-kcal diet with or without carbohydrate restriction for a period of 1 week in the hospital. Nineteen obesity class III women were distributed into two groups: experimental (n = 10) and control (n = 9). The following variables were assessed at the beginning and end of the study: anthropometric measurements, body composition, resting energy expenditure, substrate oxidation, and biochemical tests. RESULTS: Compared with CD, RD led to larger weight loss (2.6 and 4.4 kg, respectively; p = 0.01) and waist circumference reduction (p < 0.01). Among the assessed biochemical indicators, only plasma and urine acetone levels were different (p < 0.01); higher values were found in the experimental group with no symptoms and other diet-related complaints. There was also a significant decrease in triglycerides and carbohydrate oxidation, as well as a significant enhancement in lipid oxidation in the RD group. CONCLUSION: Short-term RD was more efficient than CD regarding quick weight loss and waist circumference reduction, which may favor gastroplasty. Also, RD did not lead adverse metabolic effects. PMID- 20195790 TI - New analytical method using coupled enzymes for determination of polyunsaturated fatty acid content in olive oil. AB - A new, simple, and original method is described for specific measurement of polyunsaturated fatty acid content in olive oil. This analytical system uses coupled enzymes, lipase and lipoxygenase. The system consists of lipase-catalyzed hydrolysis of triacylglycerol and subsequent lipoxygenation of liberated polyunsaturated fatty acids. The hydroperoxy-fatty acids formed were easily monitored by spectrophotometry at 234 nm. After being optimized, the method was validated in terms of linearity, precision sensitivity, and recovery. Linear calibration graph was obtained in the range 50-500 microg mL(-1), with a correlation coefficient higher than 0.921 and a detection limit (S/N = 3) of 15 microg mL(-1). The precision of the method (relative standard deviation) for within and between days is better than 7% and 12%, respectively. The proposed method was successfully applied to the estimation of polyunsaturated fatty acids level in olive oil samples and results obtained were in excellent agreement with those obtained by the classical official method. The proposed method is accurate, simple, cheap, and can be satisfactorily used for routine analysis of edible oils. PMID- 20195791 TI - Influence of ionic strength, pH, and SDS concentration on subunit analysis of phycoerythrins by SDS-PAGE. AB - Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) is often used for subunit analysis of proteins, but it is not efficient to make the alpha- and beta-subunits of phycoerythrins separated by normal SDS-PAGE. In this research, subunit components and subunit molecular weights of four purified phycoerythrins were analyzed by SDS-PAGE. Four factors including Tris concentration, pH, ammonium persulfate (APS), and SDS concentration were studied for their effects on SDS-PAGE of phycoerythrins. It showed that these factors can influence the separation of alpha- and beta-subunits, electrophoresis effect of gamma-subunits, apparent molecular weights of subunits, and mobility of marker proteins. The alpha- and beta-subunits separated better in the case of lower SDS concentration, lower Tris concentration, higher pH, and/or lower APS addition in separating gels. The molecular weights of alpha- and beta-subunits increased when Tris concentration increased in a certain range. It can be concluded that factors critical to subunit analysis by SDS-PAGE are SDS concentration and ionic strength, both of which are related to critical micelle concentration of SDS and ratio of SDS monomer to micelle in SDS-PAGE system. The ratio is postulated to influence SDS-PAGE by influencing the amount of SDS bound to polypeptides and shapes of polypeptide-SDS complexes. PMID- 20195789 TI - The relationships between IGF-1 and CRP, NO, leptin, and adiponectin during weight loss in the morbidly obese. AB - BACKGROUND: The relationship between C-reactive protein (CRP), nitric oxide (NO), leptin, adiponectin, and insulin growth factor 1 (IGF-1) is poorly defined in morbidly obese patients before and after gastric bypass and, in some cases, is controversial. METHODS: We examined the plasma of 34 morbidly obese patients before and 1, 6, and 12 months after Roux-en-Y gastric bypass surgery. RESULTS: Obese people had more CRP (21.3 +/- 1.8 microg/ml) and leptin (36.9 +/- 4.0 ng/ml) than those in the control group (nonobese people: CRP = 6.9 +/- 0.9 microg/ml, p < 0.0001; leptin = 7.5 +/- 0.4 ng/ml, p < 0.0001). However, they had less NO (30.4 +/- 2.7 nmol/ml), IGF-1 (77.5 +/- 6.6 ng/ml), and adiponectin (11.1 +/- 1.0 microg/ml) than those in the control group (NO = 45.8 +/- 3.9 nmol/ml, p = 0.0059; IGF-1 = 202.0 +/- 12.0 ng/ml, p < 0.0001; adiponectin = 18.0 +/- 2.0 microg/ml, p < 0.0001). During weight loss, the amount of CRP and leptin decreased until they reached the nonobese values, but the level of NO remained lower than in nonobese people, even 1 year after surgery. The linear regression slopes were negative and very significant for leptin (p = 0.0005) and CRP (p = 0.0018) but were less significant for NO (p = 0.0221). IGF-1 displayed a very good linear regression (both negative and significant) with some anthropometric parameters, including body mass index (p = 0.0025), total fat (p = 0.0177), and the percentage of fat (p < 0.0001). CONCLUSION: For the first time, we report the relationship between IGF-1 and CRP, NO, leptin, and adiponectin. For all these parameters, the best and most widely demonstrated improvements in comorbidities before and during weight loss in morbid obesity were associated with CRP and leptin. PMID- 20195792 TI - An oxidant- and organic solvent-resistant alkaline metalloprotease from Streptomyces olivochromogenes. AB - Organic solvent- and detergent-resistant proteases are important from an industrial viewpoint. However, they have been less frequently reported and only few of them are from actinomycetes. A metalloprotease from Streptomyces olivochromogenes (SOMP) was purified by ion exchange with Poros HQ and gel filtration with Sepharose CL-6B. Apparent molecular mass of the enzyme was estimated to be 51 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and gelatin zymography. The activity was optimum at pH 7.5 and 50 degrees C and stable between pH 7.0 and 10.0. SOMP was stable below 45 degrees C and Ca(2+) increased its thermostability. Ca(2+) enhanced while Co(2+), Cu(2+), Zn(2+), Mn(2+), and Fe(2+) inhibited the activity. Ethylenediaminetetraacetic acid and ethylene glycol-bis (beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid, but not phenylmethylsulfonyl fluoride, aprotinin, and pefabloc SC, significantly suppressed the activity, suggesting that it might be a metalloprotease. Importantly, it is highly resistant against various detergents, organic solvents, and oxidizing agents, and the activity is enhanced by H(2)O(2). The enzyme could be a novel protease based on its origin and peculiar biochemical properties. It may be useful in biotechnological applications especially for organic solvent based enzymatic synthesis. PMID- 20195794 TI - The expression of neuroepithelial cell fate determinants in rat spinal cord development. AB - Lineage specification is tightly regulated by a unique combination of extrinsic and intrinsic cues, but exactly how these cues coordinate the timing and position of cell differentiation during spinal cord development needs further investigation. Notch signaling has major roles in lineage specification. Recent evidence also indicates that the combination of transcription factors of the basic helix-loop-helix (Hes3, Hes5) and homeodomain (Pax6) families establish molecular codes that determine both the timing and position of neurons and glia. The precise expression patterns of these genes in vivo in the developing spinal cord from E13 to E18 are not fully known. In this study, the spatial and temporal expression patterns of these genes have been investigated. RT-PCR studies reveal the differential expression of these genes. The dynamic changes detected in the expression of these molecules have an important role in spinal cord cell lineage specification. Moreover, this study clarifies their in vivo expression during spinal cord development, and the expression patterns observed shed light on the generation of the rostro-caudal gradient of development. By understanding how neural stem cells are regulated in spinal cord development in vivo, we may gain insight of relevance to cell replacement strategies to treat spinal cord injuries. PMID- 20195795 TI - Run-time interoperability between neuronal network simulators based on the MUSIC framework. AB - MUSIC is a standard API allowing large scale neuron simulators to exchange data within a parallel computer during runtime. A pilot implementation of this API has been released as open source. We provide experiences from the implementation of MUSIC interfaces for two neuronal network simulators of different kinds, NEST and MOOSE. A multi-simulation of a cortico-striatal network model involving both simulators is performed, demonstrating how MUSIC can promote inter-operability between models written for different simulators and how these can be re-used to build a larger model system. Benchmarks show that the MUSIC pilot implementation provides efficient data transfer in a cluster computer with good scaling. We conclude that MUSIC fulfills the design goal that it should be simple to adapt existing simulators to use MUSIC. In addition, since the MUSIC API enforces independence of the applications, the multi-simulation could be built from pluggable component modules without adaptation of the components to each other in terms of simulation time-step or topology of connections between the modules. PMID- 20195798 TI - Inflammatory neurodegeneration and mechanisms of microglial killing of neurons. AB - Inflammatory neurodegeneration contributes to a wide variety of brain pathologies. A number of mechanisms by which inflammatory-activated microglia and astrocytes kill neurons have been identified in culture. These include: (1) acute activation of the phagocyte NADPH oxidase (PHOX) found in microglia, (2) expression of the inducible nitric oxide synthase (iNOS) in glia, and (3) microglial phagocytosis of neurons. Activation of PHOX (by cytokines, beta amyloid, prion protein, lipopolysaccharide, ATP, or arachidonate) causes microglial proliferation and inflammatory activation; thus, PHOX is a key regulator of inflammation. However, activation of PHOX alone causes little or no death, but when combined with iNOS expression results in apparent apoptosis via peroxynitrite production. Nitric oxide (NO) from iNOS expression also strongly synergizes with hypoxia to induce neuronal death because NO inhibits cytochrome oxidase in competition with oxygen, resulting in glutamate release and excitotoxicity. Finally, microglial phagocytosis of these stressed neurons may contribute to their loss. PMID- 20195799 TI - Relatedness of Indian flax genotypes (Linum usitatissimum L.): an inter-simple sequence repeat (ISSR) primer assay. AB - The objective of this study was to analyze the genetic relationships, using PCR based ISSR markers, among 70 Indian flax (Linum usitatissimum L.) genotypes actively utilized in flax breeding programs. Twelve ISSR primers were used for the analysis yielding 136 loci, of which 87 were polymorphic. The average number of amplified loci and the average number of polymorphic loci per primer were 11.3 and 7.25, respectively, while the percent loci polymorphism ranged from 11.1 to 81.8 with an average of 63.9 across all the genotypes. The range of polymorphism information content scores was 0.03-0.49, with an average of 0.18. A dendrogram was generated based on the similarity matrix by the Unweighted Pair Group Method with Arithmetic Mean (UPGMA), wherein the flax genotypes were grouped in five clusters. The Jaccard's similarity coefficient among the genotypes ranged from 0.60 to 0.97. When the omega-3 alpha linolenic acid (ALA) contents of the individual genotypes were correlated with the clusters in the dendrogram, the high ALA containing genotypes were grouped in two clusters. This study identified SLS 50, Ayogi, and Sheetal to be the most diverse genotypes and suggested their use in breeding programs and for developing mapping populations. PMID- 20195797 TI - Microglia activation and anti-inflammatory regulation in Alzheimer's disease. AB - Inflammatory regulators, including endogenous anti-inflammatory systems, can down regulate inflammation thus providing negative feedback. Chronic inflammation can result from imbalance between levels of inflammatory mediators and regulators during immune responses. As a consequence, there are heightened inflammatory responses and irreversible tissue damage associated with many age-related chronic diseases. Alzheimer's disease (AD) brain is marked by prominent inflammatory features, in which microglial activation is the driving force for the elaboration of an inflammatory cascade. How the regulation of inflammation loses its effectiveness during AD pathogenesis remains largely unclear. In this article, we will first review current knowledge of microglial activation and its association with AD pathology. We then discuss four examples of anti-inflammatory systems that could play a role in regulating microglial activation: CD200/CD200 receptor, vitamin D receptor, peroxisome proliferator-activated receptors, and soluble receptor for advanced glycation end products. Through this, we hope to illustrate the diverse aspects of inflammatory regulatory systems in brain and neurodegenerative diseases such as AD. We also propose the importance of neuronal defense systems, because they are part of the integral inflammatory and anti inflammatory systems. Augmenting the anti-inflammatory defenses of neurons can be included in the strategy for restoration of balanced immune responses during aging and neurodegenerative diseases. PMID- 20195796 TI - Targeting NADPH oxidase and phospholipases A2 in Alzheimer's disease. AB - Alzheimer's disease (AD) is marked by an increase in the production of extracellular beta amyloid plaques and intracellular neurofibrillary tangles associated with a decline in brain function. Increases in oxidative stress are regarded as an early sign of AD pathophysiology, although the source of reactive oxygen species (ROS) and the mechanism(s) whereby beta amyloid peptides (Abeta) impact oxidative stress have not been adequately investigated. Recent studies provide strong evidence for the involvement of NADPH oxidase and its downstream oxidative signaling pathways in the toxic effects elicited by Abeta. ROS produced by NADPH oxidase activate multiple signaling pathways leading to neuronal excitotoxicity and glial cell-mediated inflammation. This review describes recent studies demonstrating the neurotoxic effects of Abeta in conjunction with ROS produced by NADPH oxidase and the downstream pathways leading to activation of cytosolic phospholipase A(2) (PLA(2)) and secretory PLA(2). In addition, this review also describes recent studies using botanical antioxidants to protect against oxidative damage associated with AD. Investigating the metabolic and signaling pathways involving Abeta NADPH oxidase and PLA(2) can help understand the mechanisms underlying the neurodegenerative effects of oxidative stress in AD. This information should provide new therapeutic approaches for prevention of this debilitating disease. PMID- 20195800 TI - High-level expression of heme-dependent catalase gene katA from Lactobacillus Sakei protects Lactobacillus rhamnosus from oxidative stress. AB - Lactic acid bacteria (LAB) are generally sensitive to hydrogen peroxide (H(2)O(2)), Lactobacillus sakei YSI8 is one of the very few LAB strains able to degrade H(2)O(2) through the action of a heme-dependent catalase. Lactobacillus rhamnosus strains are very important probiotic starter cultures in meat product fermentation, but they are deficient in catalase. In this study, the effect of heterologous expression of L. sakei catalase gene katA in L. rhamnosus on its oxidative stress resistance was tested. The recombinant L. rhamnosus AS 1.2466 was able to decompose H(2)O(2) and the catalase activity reached 2.85 mumol H(2)O(2)/min/10(8) c.f.u. Furthermore, the expression of the katA gene in L. rhamnosus conferred enhanced oxidative resistance on the host. The survival ratios after short-term H(2)O(2) challenge were increased 600 and 10(4)-fold at exponential and stationary phase, respectively. Further, viable cells were 100 fold higher in long-term aerated cultures. Simulation experiment demonstrated that both growth and catalase activity of recombinant L. rhamnosus displayed high stability under environmental conditions similar to those encountered during sausage fermentation. PMID- 20195801 TI - Should adjuvant trastuzumab be offered in very early-stage (pT1a/bN0M0) HER2-neu positive breast cancer? A current debate. AB - There are many controversies regarding the treatment of very early-stage (pT1a/bN0M0) breast cancer (BC), generally considered to have a very good prognosis. The debate is the benefit of an adjuvant treatment of HER2-neu (namely HER-2)-positive subcentimetric carcinoma with trastuzumab. Current guidelines do not suggest, with the highest level of evidence, whether trastuzumab should be administered after adjuvant chemotherapy in the treatment of high-risk pT1a/bN0M0 breast cancer. The major phase III trials that confirmed the benefit of adjuvant immunotherapy did not include small (<1 cm diameter) node-negative breast cancer. Several retrospective case series of HER-2-positive pT1a/bN0M0 carcinoma seem to demonstrate that they have a higher risk of relapse compared to the HER-2 negative counterpart. HER-2 also seems to confer an independent risk of recurrence and/or death in a multivariate analysis within large node-negative breast cancer populations. In particular, the best way to select higher-risk tumours that may achieve the best results from a trastuzumab-based therapy appears to be the in situ hybridization, which should follow the new recommended algorithm of the ASCO/CAP guidelines in case of doubtful results. According to the evidence that the survival of HER-2-positive BC can be improved with the introduction of trastuzumab respect to the HER-2-negative counterpart, there is today less uncertainty about the curative role of anti-HER-2 therapy in very early disease. PMID- 20195803 TI - CYP2E1 Rsa I/Pst I polymorphism and esophageal cancer risk: a meta-analysis based on 1,088 cases and 2,238 controls. AB - The common functional CYP2E1 Rsa I/Pst I polymorphism may influence the risk of esophageal cancer. However, the published results are conflicting. We therefore conducted a meta-analysis comprised of 11 published case-control studies with 1,088 cases and 2,238 controls. Odds ratios (ORs) with 95% confidence interval (CIs) were used to assess the strength of the association. Overall, the pooled ORs were 0.53 (95% CI = 0.31-0.89, P (heterogeneity) < 0.001) and 0.57 (95% CI = 0.34-0.96, P (heterogeneity) < 0.001), for the heterogeneity c1/c2 and c2 allele carriers (c1/c2 + c2/c2) compared with the homozygous c1/c2, respectively. In subgroup analysis by race, the same significant risks were found among Asians (for c2 vs. c1: OR = 0.64, 95% CI = 0.43-0.95, P (heterogeneity) < 0.001; for c1/c2 vs. c1/c1: OR = 0.48, 95% CI = 0.28-0.82, P (heterogeneity) < 0.001; for c1/c2 + c2/c2 vs. c1/c1: OR = 0.51, 95% CI = 0.30-0.86, P (heterogeneity) < 0.001). In conclusion, our meta-analysis demonstrates that CYP2E1 Rsa I/Pst I c2 allele may be a decreased risk factor for developing esophageal cancer among Asians populations. PMID- 20195802 TI - Relevance of serum estradiol and estrogen receptor beta expression from a high incidence area for esophageal squamous cell carcinoma in China. AB - The striking 3-4:1 male predominance of esophageal squamous cell carcinoma (ESCC) has not yet been well explained. Our hypothesis is that the changes in level of estrogen and/or subtype of estrogen receptor (ER) may exert a protective factor in esophageal carcinogenesis and prognosis of ESCC. Radioimmunoassay (RIA) was used to determine the serum level of estradiol in healthy cohort from high incidence area (HIA) and low-incidence area (LIA) for esophageal cancer as well as patients with ESCC from HIA in Henan, northern China. The ERbeta expression profiling during the multi-stage progression of ESCC pathogenesis was evaluated by immunohistochemistry (IHC). Both males and females from HIA had significant decreases of serum estradiol in high-risk subjects predisposing for ESCC compared to healthy counterparts from LIA (P < 0.01). Furthermore, patients with ESCC from HIA developed the lowest level of estradiol (P < 0.01). ERbeta expressed in precursor lesions of ESCC and changed quantitatively and qualitatively with disease progression during the multi-stages process of esophageal carcinogenesis. High frequency of ERbeta expression was correlated with less aggressive potential of clinical behavior (P = 0.012, 0.015 for lymph node metastasis and tumor stage, respectively). This study indicates that lower serum level of estradiol may represent higher predisposition for development of ESCC, and ERbeta expression and/or nuclear location may predict better outcome for patients with ESCC. The present results provide clues to explain the striking gender difference for ESCC, which warrants further investigations on potential applications of estrogen or analogs in prevention of ESCC. PMID- 20195804 TI - Pediatric radiological diagnostic procedures in cases of suspected child abuse. AB - Advanced and specialized radiological diagnostic procedures are essential in cases of clinically diagnosed injuries to the head, thorax, abdomen or extremities of a child, especially if there is no case history or if the reporting of an inadequate trauma suggests battered child syndrome. In particular, these diagnostic procedures should aim at detecting lesions of the central nervous system (CNS), so that the treatment can be immediately initiated. If the diagnostic imaging reveals findings typically associated with child abuse, accurate documentation constituting evidence, which will stand up in court, is required to prevent any further endangerment of the child's welfare. PMID- 20195805 TI - Development and characterization of enteric-coated immediate-release pellets of aceclofenac by extrusion/spheronization technique using kappa-carrageenan as a pelletizing agent. AB - In the present study, an attempt was made to prepare immediate-release enteric coated pellets of aceclofenac, a poorly soluble nonsteroidal anti-inflammatory drug that has a gastrointestinal intolerance as its serious side effect. Formulation of enteric-coated pellets with improved solubility of aceclofenac could address both of these problems. To achieve these goals, pellets were prepared by extrusion-spheronization method using pelletizing agents that can contribute to the faster disintegration and thereby improve the solubility of the drug. Different disintegrants like beta-cyclodextrin, kollidon CL, Ac-Di-Sol, and sodium starch glycolate were tried in order to further improve disintegration time. The pellets were characterized for drug content, particle size distribution, flow properties, infrared spectroscopy, surface morphology, disintegration rate, and dissolution profile. The formulations, which showed best disintegration and dissolution profiles, were coated with Eudragit L100-55, an enteric-coated polymer which does not dissolve at gastric pH but dissolves at intestinal pH, releasing the drug immediately in the dissolution medium. The optimized enteric-coated formulation containing 20% kappa-carrageenan, lactose, and sodium starch glycolate as a disintegrant did inhibit the release of the drug for 2 h in 0.1 N HCl, whereas 87% of the drug was released within 45 min. The improvement was substantial when it was compared with solubility of pure drug under the same conditions. Thus, dissolution profiles suggested that combination of kappa-carrageenan and sodium starch glycolate resulted into fast disintegrating, immediate-release pellets, overcoming the bioavailability problem of the poorly soluble drug, aceclofenac, and enteric coating of these pellets avoids the exposure of aceclofenac to ulcer-prone areas of the gastrointestinal tract. PMID- 20195806 TI - An Approach for determining antibiotic loading for a physician-directed antibiotic-loaded PMMA bone cement formulation. AB - BACKGROUND: When a physician-directed antibiotic-loaded polymethylmethacrylate (PMMA) bone cement (ALBC) formulation is used in total hip arthroplasties (THAs) and total knee arthroplasties (TKAs), current practice in the United States involves arbitrary choice of the antibiotic loading (herein defined as the ratio of the mass of the antibiotic added to the mass of the cement powder). We suggest there is a need to develop a rational method for determining this loading. QUESTIONS/PURPOSES: We propose a new method for determining the antibiotic loading to use when preparing a physician-directed ALBC formulation and illustrate this method using three in vitro properties of an ALBC in which the antibiotic was daptomycin. MATERIALS AND METHODS: Daptomycin was blended with the powder of the cement using a mechanical mixer. We performed fatigue, elution, and activity tests on three sets of specimens having daptomycin loadings of 2.25, 4.50, and 11.00 wt/wt%. Correlational analyses of the results of these tests were used in conjunction with stated constraints and a nonlinear optimization method to determine the daptomycin loading to use. RESULTS: With an increase in daptomycin loading, the estimated mean fatigue limit of the cement decreased, the estimated elution rate of the antibiotic increased, and the percentage inhibition of staphylococcal growth by the eluate remained unchanged at 100%. For a daptomycin-loaded PMMA bone cement we computed the optimum amount of daptomycin to mechanically blend with 40 g of cement powder is 1.36 g. CONCLUSIONS: We suggest an approach that may be used to determine the amount of antibiotic to blend with the powder of a PMMA bone cement when preparing a physician-directed ALBC formulation, and highlighted the attractions and limitations of this approach. CLINICAL RELEVANCE: When a physician-directed ALBC formulation is selected for use in a TKA or THA, the approach we detail may be employed to determine the antibiotic loading to use rather than the empirical approach that is taken in current clinical practice. PMID- 20195807 TI - Fractures in brief: intertrochanteric hip fractures. PMID- 20195808 TI - Revision hip arthroplasty: infection is the most common cause of failure. AB - BACKGROUND: Revision total hip arthroplasty (THA), although relieving pain and restoring function, fails in some patients. In contrast to failures in primary THA, the frequency of the causes of failure in revision THA has been less well established. QUESTIONS/PURPOSES: We therefore determined the rate of each failure mode and the survivorship of revision THAs. METHODS: We retrospectively reviewed the charts of 1366 revision THAs performed between 2000 and 2007. There were 609 (44.5%) men and 757 (55.5%) women with a mean age of 66 years. The indications for the revision surgery were mainly aseptic loosening (51%), instability (15%), wear (14%), and infection (8%). The minimum followup was 1 day (mean, 5.5 years; range, 1 day to 9 years). RESULTS: Two hundred fifty-six of the revisions (18.7%) failed with an average time to failure of 16.6 months (range, 1 day to 7.5 years). Among 256 failed hips, infection was the most common cause of failure (30.2%) followed by instability (25.1%) and aseptic loosening (19.4%). At 5 years, the survivorships of septic and aseptic groups were 67% and 84.8%, respectively. Revision for infection or instability appears to have a considerably lower survivorship when compared to revision for aseptic causes. CONCLUSIONS: The lower survivorship of revision for infection or instability highlights the importance of implementing better preventative methods that can minimize the impact of these two major causes of failure. LEVEL OF EVIDENCE: Level III, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 20195809 TI - Initial psychological responses to swine flu. AB - BACKGROUND: The emergence of influenza A ("swine flu") in early 2009 led to widespread public concern. However, little research has examined the factors that underlie initial worry about infection and subsequent behavioral responses to such worry. PURPOSE: This study seeks to model some key predictors of worry and behavioral responses in the early stages of the swine flu pandemic (WHO pandemic stage 5). METHOD: A cross-sectional internet questionnaire study (N = 186). RESULTS: Twenty-five percent of respondents rated themselves as worried about being a victim of swine flu, 40% that they were worried of a family member contracting the virus. Twenty percent had bought, or intended to buy, preparatory materials (e.g., face masks), 20% intended to delay or cancel air travel. In a structural equation model, conservation values and family or friends perception of risks predicted worry about infection, while worry correlated with the purchase of preparatory materials, a lesser willingness to travel by public transport, and difficulty in focusing on everyday activities. CONCLUSION: While previous research on pandemic risk perception has focused on cognitive risk judgments, our data suggests that initial "emotional" concerns about infection are also significant predictors of behavioral responses to pandemic threat. Such worry is likely to be influenced by a variety of individual factors, such as personal values, as well as normative pressures. Practitioners can use and expand on such models of pandemic response when tailoring health campaigns to meet newly emergent threats. PMID- 20195810 TI - A longitudinal test of the demand-control model using specific job demands and specific job control. AB - BACKGROUND: Supportive studies of the demand-control (DC) model were more likely to measure specific demands combined with a corresponding aspect of control. PURPOSE: A longitudinal test of Karasek's (Adm Sci Q. 24:285-308, 1) job strain hypothesis including specific measures of job demands and job control, and both self-report and objectively recorded well-being. METHOD: Job strain hypothesis was tested among 267 health care employees from a two-wave Dutch panel survey with a 2-year time lag. RESULTS: Significant demand/control interactions were found for mental and emotional demands, but not for physical demands. The association between job demands and job satisfaction was positive in case of high job control, whereas this association was negative in case of low job control. In addition, the relation between job demands and psychosomatic health symptoms/sickness absence was negative in case of high job control and positive in case of low control. CONCLUSION: Longitudinal support was found for the core assumption of the DC model with specific measures of job demands and job control as well as self-report and objectively recorded well-being. PMID- 20195811 TI - Equivalent annual cost: a method for comparing the cost of multi-use medical devices. PMID- 20195812 TI - Melamine toxicity. AB - Melamine contamination of infant formula in China and its health effects highlight the safety of the global food supply especially as it relates to formula-fed infants. Melamine is a widely used industrial chemical not considered acutely toxic with a high LD(50) in animals. The data available on acute and chronic human exposure to melamine have been limited and extrapolated from animal data. Pet food contamination in 2004 and 2007 showed stone formation and illness in animals when melamine was co-ingested with cyanuric acid. The recent outbreak in infants showed that melamine ingested in large doses may cause stones and illness without significant ingestion of cyanuric acid or other melamine-related chemicals. This may be due to increased uric acid excretion in infants and formation of melamine-uric acid stones. Diagnosis and treatment of infants exposed to melamine requires further study. Clinical signs and symptoms in infants are nonspecific. The stones may be radiolucent and are not consistently seen on ultrasound. The use of alkalinization of the urine for treatment has been proposed, but is of unproven benefit. The FDA and other regulatory agencies have recommended acceptable levels of melamine in foods for consumption. Melamine ingestion has been implicated in stone formation when co-ingested with cyanuric acid, but will cause urinary stones in infants when large amounts of melamine alone are ingested. PMID- 20195813 TI - Cardiac conduction disturbance due to prallethrin (pyrethroid) poisoning. AB - Pyrethroids are common household insecticides. Even though they are less toxic to humans, reports of accidental and suicidal poisoning are not uncommon. Cardiotoxicity due to pyrethroid poisoning is rare. We report a case of cardiac conduction disturbance due to a pyrethroid, prallethrin. A 28-year-old female presented after a suicidal consumption of prallethrin. Her clinical and laboratory parameters were normal during the first 24 h of hospital stay. On the second hospital day, she developed metabolic acidosis and sinus arrest with escape junctional rhythm. Despite correction of metabolic acidosis, the sinus arrest persisted for 3 days. She reverted back to sinus rhythm with bradycardia after this period and was discharged on the seventh hospital day. Her follow-up was uneventful. Pyrethroid poisoning can affect the gastrointestinal, respiratory, and nervous system. Most serious effects of the toxin in humans are seizures and coma. Mechanism of pyrethroid neurotoxicity is believed to be due to its ability to modify sodium, chloride, and calcium channels of the neurons. Our case raises the possibility that cardiac arrhythmia due to pyrethroid poisoning can occur due to its effect on sodium channels in the heart. PMID- 20195814 TI - Conducting drug abuse investigations in natural environments: potential directions for medical toxicology research. AB - Physician-scientists, in the eyes of the National Institutes of Health (NIH), are crucial to the biomedical research enterprise since the development of evidence based practice based on cutting-edge research. At the same time, NIH has heightened the importance of research mentorship by permitting investigators to revise an application a single time. The current NIH approach, therefore, narrows the margin of error allowable in a proposal and requires that investigators fully develop research protocols for initial submission. The purpose of this manuscript, therefore, is to provide medical toxicologists with a proven research methodology that can be applied to substance abuse investigations. A secondary aim is to provide successful grant language that can be used in subsequent applications for research funding. PMID- 20195815 TI - Antiviral fluorinated acyclic nucleosides. PMID- 20195816 TI - Role of cyclophilin a during oncogenesis. AB - Cyclophilins (Cyps) are ubiquitously expressed proteins that are evolutionarily conserved. CypA is the most abundant among the Cyps and is expressed in the cytosol. With its chaperone and PPIase activities, CypA contributes to the maintenance of correct conformation of nascent or denatured proteins and also provides protection against environmental insults. Also, its expression is induced in response to a wide variety of stressors including cancer. Upregulation of CypA in small cell lung cancer, pancreatic cancer, breast cancer, colorectal cancer, squamous cell carcinoma and melanoma has been reported. In some cancers a correlation between CypA overexpression and malignant transformation has been established. While molecular partners of CypA that promote cancer development are yet to be discovered, various mechanisms have been proposed to account for the cytoprotective functions of CypA during cancer development. CypA may promote the survival of cells under the stressful condition of cancer. CypA may well be essential for maintaining the conformation of oncogenic proteins, signalling proteins for cell proliferation, antiapoptotic components, transcription factors, or cell motility regulatory proteins. Antioxidant effects of CypA, which have been suggested by some researchers, may also become critical to reactive oxygen species (ROS) creating an oncogenetic environment. Developing new CypA inhibitors for therapeutics has been surmised from the cytoprotective functions of CypA and its overexpression in many cancer types. Therefore, CypA can be further investigated as a useful tool for early diagnosis, treatment and prevention of human cancers. PMID- 20195817 TI - Synthesis and anticancer activities of new 3-allylthio-6-(mono or disubstituted)aminopyridazines. AB - A new series of 3-allylthio-6-(mono or disubstituted) aminopyridazines was synthesized by reacting 3-allylthio-6-chloropyridazine with several amines to develop new anticancer agents. These new compounds showed antiproliferative activities against lung cancer (A549), hepatoblastoma (Hep3b), prostate cancer (PC3), colon cancer (SW480) and cervical cancer (HeLa) cells in MTT assays, and could be promising candidates for chemotherapy of carcinomas. Compound 5 (3 allylthio-6-homopiperidinylaminopyridazine) showed higher potencies than 5-FU for inhibiting the growth of these cell lines. This suggests the potential anticancer activity of compound 5. PMID- 20195818 TI - Design and synthesis of 3'-fluoropenciclovir analogues as antiviral agents. AB - Based on fluorine switch approach, a series of 3'-fluoropenciclovir analogues with different purine and pyrimidine bases were designed and synthesized. Direct reduction of beta-fluoroester to the corresponding 3-fluoroalcohol provided an easy and new entry pathway towards the synthesis of 3'-fluoropenciclovir analogues. The synthesized 3'-fluoropenciclovir analogues were evaluated for their antiviral activities against the poliovirus, HSV-1, HSV-2 and HIV. PMID- 20195819 TI - Two new C-glucosyl benzoic acids and flavonoids from Mallotus nanus and their antioxidant activity. AB - Two new 2-C-beta-D-glucopyranosyl benzoic acid derivatives named mallonanosides A (1) and B (2) were isolated from the methanolic extract of the leaves of Mallotus nanus along with five known flavonoids, kaempferin (3), juglanin (4), quercitrin (5), myricitrin (6), and rhoifolin (7). Their structures were established on the basis of spectral and chemical evidence. Their antioxidant activities were shown to depend on the number of hydroxyl groups, and the location and species of sugar moiety. PMID- 20195820 TI - Anthraquinones from the roots of Knoxia valerianoides inhibit the formation of advanced glycation end products and rat lens aldose reductase in vitro. AB - Eight known compounds, lucidin (1), lucidin-omega-methyl ether (2), rubiadin (3), damnacanthol (4), 1,3,6-trihydroxy-2-methoxymethylanthraquinone (5), 3,6 dihydroxy-2-hydroxymethyl-9,10-anthraquinone (6), 1,3,6-trihydroxy-2 hydroxymethyl-9,10-anthraquinone 3-O-beta-primeveroside (7), and vanillic acid (8), were isolated from EtOAc- and n-BuOH-soluble fractions of the roots of Knoxia valerianoides. The structures of 1-8 were identified by analysis of spectroscopic data as well as by comparison with published values. All the isolates were subjected to in vitro bioassays to evaluate advanced glycation end products (AGEs) formation and rat lens aldose reductase (RLAR) inhibitory activity. Compound 5 showed the most potent inhibitory activity (IC(50) = 52.72 microM) against AGEs formation. Compounds 1, 2, and 8 also showed potent inhibitory activity on AGEs formation with IC(50) values of 79.28, 62.79, and 93.93 microM, respectively, compared with positive control, aminoguanidine (IC(50) = 962 microM). While, compounds 1 and 5-7 showed strong inhibitory activity against RLAR with IC(50) values of 3.35, 3.04, 6.39, and 2.05 microM, respectively. PMID- 20195821 TI - Bee venom protects hepatocytes from tumor necrosis factor-alpha and actinomycin D. AB - Honeybee (Apis mellifera) venom (BV) has a broad array of therapeutic applications in traditional medicine to treat variety of diseases. It is also known that BV possesses anti-inflammatory and anticancer effect and that it can inhibit proliferation and induces apoptosis in cancer cells, but there is no evidence of information regarding anti-apoptosis of BV on hepatocytes. In the present study, we investigated the anti-apoptotic effect of BV on tumor necrosis factor (TNF)-alpha with actinomycin (Act) D induces apoptosis in hepatocytes. TNF alpha/Act D-treated hepatocytes were exposed to different low concentration (1, 10 and 100 ng/mL) of BV. Our results showed statistically significant inhibition in DNA damage caused by BV treatment compared to corresponding TNF-alpha/Act D treated hepatocytes. BV suppressed TNF-alpha/Act Dtreated activation of bcl-2 family and caspase family, which resulted in inhibition of cytochrome c release and PARP cleavage. These results demonstrate that low concentration BV possess a potent suppressive effect on anti-apoptotic responses of TNF-alpha/Act D-treated hepatocytes and suggest that these compounds may contribute substantial therapeutic potential for the treatment of liver diseases. PMID- 20195822 TI - Pharmacokinetics, tissue distribution and excretion of coumarin components from Psoralea corylifolia L. in rats. AB - Coumarin components from Psoralea corylifolia L. are novel drugs in which psoralen and isopsoralen are the active components. The pharmacokinetics, tissue distribution and excretion of the two compounds were studied by liquid chromatography-tandem mass spectrometry after intravenous administration to Wistar rats. The elimination half-lives of psoralen and isopsoralen were 4.88 and 5.35 h. After dosing, the area under the curves of the tissues decreased in the following order: liver > lung > heart > kidney > spleen > brain for psoralen; and kidney > lung > liver > heart > spleen > brain for isopsoralen. After dosing, 51.27% of psoralen and 56.25% of isopsoralen were excreted as prototype, and urine was the major excretion route. In addition, the pharmacokinetics of psoralen and isopsoralen after oral administration to Wistar rats were also studied. The elimination half-lives of psoralen and isopsoralen were 4.13 and 5.56 h, and their relative bioavailabilities were 61.45% and 70.35%. Overall, the results show that coumarin components from P. corylifolia L. have high oral bioavailability, they are rapidly and widely distributed into tissues after intravenous administration, but they are slowly cleared and excreted. PMID- 20195823 TI - Bioactive metabolites from the sponge-derived fungus Aspergillus versicolor. AB - As part of an ongoing search for bioactive metabolites from the fungus Aspergillus versicolor derived from a marine sponge Petrosia sp., an aromatic polyketide derivative (1), two xanthones (2 and 3), and five anthraquinones (4-8) were isolated by bioactivity-guided fractionation. The gross structures were determined based on the NMR and MS spectroscopic data, and the absolute configurations were defined by comparison of optical rotation data with those of reported. Compounds 2, 4, 5, and 7 exhibited significant cytotoxicity against five human solid tumor cell lines (A-549, SK-OV-3, SK-MEL-2, XF-498, and HCT-15) with IC50 values in the range of 0.41-4.61 microg/mL. Compounds 4 and 7 exhibited antibacterial activity against several clinically isolated Gram-positive strains with MIC values of 0.78-6.25 microg/mL. PMID- 20195825 TI - The effects of puerarin on CYP2D6 and CYP1A2 activities in vivo. AB - Ge-gen (Radix Puerariae) is used in traditional oriental medicine for various medicinal purposes. The drug is the root of a wild leguminous creeper, Pueraria lobata (Willd) Ohwi. It possesses a high content of avonoid derivatives, the most abundant of which is puerarin. Our goal was to find the effect of puerarin on cytochrome P450 enzymes in vivo. The study was conducted in 18 male volunteers of different genotypes (CYP2D6 *1/*1, *1/*10, *10/*10). Plasma was obtained at 6 h after oral administration and urine was collected from 0 to 8 h after probe drug administration. The logarithm value of metabolic rate decrease from -0.0055 +/- 0.1887 to -0.1754 +/- 0.2411 implied puerarin inhibited activity of CYP2D6. There was no significant relationship between the inhibition with the CYP2D6 genotypes. The paraxanthin/caffeine ratio in the plasma sample at 6th hour was increased by 30 +/- 47% (p = 0.003), implied puerarin induced the activity of CYP1A2. While puerarin used together with the substrates of both enzymes, drug interaction worth the attention and at sometimes precautions are needed. PMID- 20195824 TI - Inhibitory activity of diacylglycerol acyltransferase by glabrol isolated from the roots of licorice. AB - Acyl-coenzyme A: diacylglycerol acyltransferase (DGAT, EC 2.3.1.20) catalyzes triglyceride synthesis in the glycerol phosphate pathway. It has relations with the excess supply and accumulation of triglycerides. Therefore, DGAT inhibitors may act as a potential therapy for obesity and type 2 diabetes. Five flavonoids were isolated from the ethanol extracts of licorice roots, using an in vitro DGAT inhibitory assay. One isoprenyl flavonoid showed most potential inhibition of DGAT on five flavonoids (1-5). On the basis of spectral evidences, the compound was identified as glabrol (5). Compound 5 inhibited rat liver microsomal DGAT activity with an IC50 value of 8.0 microM, but the IC50 value for four flavonoids (1-4) was more than 100 microM. In addition, glabrol showed a noncompetitive type of inhibition against DGAT. These data suggest that potential therapy for the treatment in obesity and type 2 diabetes patients by licorice roots might be related with its DGAT inhibitory effect. PMID- 20195826 TI - Evaluation of plasma carcinogenic markers in rat hepatic tumors models induced by rat hepatoma N1-S1 cells and benzo[a]pyrene. AB - Benzo[a]pyrene (BaP) is a known carcinogen. Grilled or smoked meat is the major source of BaP intake for human beings. Previously, we established hepatic tumor animal models by injecting rat hepatoma N1-S1 cells or concomitant injection of N1-S1 cells and BaP into healthy Sprague-Dawley rats. In this study, we performed proteomic analyses of rat plasma collected from a hepatic tumor model and compared them to controls using a 3-10 pI range and large two dimensional gel electrophoreses. Proteomic analyses of rat plasma with hepatic tumors induced by the injection of N1-S1 cells resolved 1295 protein spots. Among them, 10 proteins were identified by ESI-MS-MS; four proteins were up-regulated and six proteins were down-regulated as compared to the controls. In addition, 1295 protein spots were also resolved from rats with hepatic tumors by the injection of N1-S1 cells plus BaP; five proteins were upregulated, and seven proteins were down-regulated. Of these 12 proteins, 10 proteins were identified by ESI-MS-MS. Out of 20 identified proteins, alpha-1-inhibitor 3 and zero beta-1 globin were down regulated in both rats with hepatic tumors by N1-S1 cell-only and rats with hepatic tumors by the injection of N1-S1 cell plus BaP as compared to the controls. In addition, the identities of four proteins, including dermcidin, serum amyloid P-component (SAP), proteasome subunit alpha type-4 and glutathione peroxidase 3 (GPX-3) were confirmed by western blot analysis. Therefore, the importance of those proteins as candidate biomarkers for the development of hepatic tumors should be further elucidated. PMID- 20195827 TI - ATP induced microglial cell migration through non-transcriptional activation of matrix metalloproteinase-9. AB - In response to brain insults, microglia, the resident inflammatory cells in CNS, migrate into injured sites to initiate inflammatory responses in brain. ATP, released from apoptotic or necrotic cells induce chemoattractive responses but the mechanism is not clear yet. In this study, we investigated whether ATP modulates microglial migration by regulating the activity of matrix metalloproteinases (MMPs). ATP induced rapid microglial migration and increased the activity of MMP-9 in the culture supernatants (secreted compartments) in a concentration-dependent manner. The increased activity of secreted MMP-9 is due to the increased protein secretion, but not by the increased MMP-9 mRNA and protein expression. Inhibition of MMP-9 activity by treatment with specific inhibitors including GM6001 and SB-3CT prevented ATP-induced microglial migration. ATP-induced microglial migration was also inhibited by P2Y receptor antagonists including clopidogrel as well as PI3K inhibitor such as wortmanin. Taken together, ATP non-transcriptionally increased MMP-9 activity by activation of P2Y and PI3K. The results from the present investigation may provide further insights into the regulation of the activity of MMP-9 during microglial migration, which may play essential role in the regulation of inflammatory responses in pathological situations such as neurodegenerative disorders. PMID- 20195828 TI - Enantioselective pharmacokinetics of sibutramine in rat. AB - Racemic sibutramine is widely used to treat obesity owing to its inhibition of serotonin and noradrenaline reuptake in synapses. Although the enantioselective effects of sibutramine and its two active desmethyl-metabolites, monodesmethylsibutramine (MDS) and didesmethylsibutramine (DDS), on anorexia and energy expenditure have been elucidated, the enantioselective pharmacokinetics of sibutramine are still unclear. Therefore, we aimed to characterize the enantioselective pharmacokinetics of sibutramine and its metabolites in plasma and urine following an intravenous and a single oral administration of sibutramine in rats. The absolute bioavailability of sibutramine was only about 7%. The pharmacologically less effective S-isomer of DDS was predominant in the plasma: the C ( max ) and the AUC ( inf ) were 28 and 30 times higher than those of the R-isomer, respectively (p<0.001). In the urine, the concentrations of the R-isomers of hydroxylated DDS and hydroxylated and carbamoylglucuronized MDS and DDS appeared to be 11.3-, 5.1-, and 5.3-times the concentrations of the respective S-isomers. Thus, regardless of increased potency than the S enantiomers, the R-enantiomers of the sibutramine metabolites MDS and DDS were present at lower concentrations, owing to their rapid biotransformation to hydroxylated and/or carbamoylglucuronized forms and their faster excretion in the urine. The present study is the first to elucidate the enantioselective pharmacokinetics of sibutramine in rats. PMID- 20195829 TI - LSKL, a peptide antagonist of thrombospondin-1, attenuates renal interstitial fibrosis in rats with unilateral ureteral obstruction. AB - The effects of LSKL, the peptide antagonist of thrombospondin-1 (TSP-1), on renal interstitial fibrosis in rats subjected to unilateral ureteral obstruction (UUO) were investigated. Rats were divided randomly into three groups (n = 20 each): UUO group, sham-operation group and UUO plus LSKL treatment group. Collagen deposition was studied using histopathology and reverse transcription polymerase chain reaction analysis (RT-PCR). TSP-1, transforming growth factor beta 1 (TGF beta1), phosphorylated Smad2 (pSsmad2) and alpha-smooth muscle actin (alpha-SMA) in the kidney were measured using immunocytochemistry, western blotting analysis, RT-PCR and enzyme-linked immunosorbent assay. Biochemical analyses in the serum and urine were made. Histopathology showed severe tubular dilatation and atrophy, interstitial inflammation and collagen accumulation after surgery and LSKL significantly inhibited interstitial fibrosis including tubular injury as well as collagen deposition. The protein and mRNA levels of TSP-1 increased notably at different time point and significantly decreased in the presence of LSKL. The expression of TGF-beta1 and pSmad2 were upregulated in the obstructed kidney and substantially suppressed by LSKL treatment. Myofibroblast accumulation could be alleviated after administration of LSKL. Biochemical parameters did not show differences among the three groups. As TSP-1 is the major activator of TGF-beta1, we demonstrate that LSKL can attenuate renal interstitial fibrosis in vivo by preventing TSP-1-mediated TGF-beta1 activation. PMID- 20195830 TI - Interferon-gamma enhances the apoptosis of macrophages under trophic stress through activation of p53 and the JAK1 pathway. AB - Apoptosis has been implicated as an important mediator of immunosuppression associated with a depleted nutritional state. Since a number of cytokines are likely to influence the rate of apoptosis, we determined the effect of interferon gamma (IFN-gamma) on apoptosis of macrophages in serum/amino acid deprived cell culture conditions. IFN-gamma further increased the rate of apoptosis compared to trophically stressed macrophages. In addition, we showed that enhancement of apoptosis by IFN-gamma is caused by a decrease in mitochondrial membrane potential due to upregulation of p53 and Bax and down-regulation of Bcl-xL. Moreover, we found that IFN-gamma increases caspase-3 activity that had been induced by serum/amino acid depletion, and that JAK1 signaling is involved in capase-3 activation and in the enhancement of apoptosis by IFN-gamma. PMID- 20195832 TI - Increases in serotonergic neuronal activity following intracerebroventricular administration of AF64A in rats. AB - Changes in the serotonergic nervous system after the intracerebroventricular (i.c.v.) administration of ethylcholine aziridinium (AF64A, 3 nmol/each ventricle) were studied in rats. Two weeks after the infusion of AF64A, the levels of 5-HT and 5-HIAA in microdialysed cerebrospinal fluid (CSF), the levels of total 5-HT and 5-HIAA, the density of serotonin uptake sites and the activities of tryptophan hydroxylase (TPH) and monoamine oxidase (MAO) in various brain regions were determined. After AF64A administration, the concentrations of 5-HT in lateral ventricle were increased and the levels of 5-HIAA were decreased. However, the hippocampal levels of total 5-HT were decreased without changes in the levels of 5-HIAA and the hippocampal turnover rates of 5-HT increased. Also, the density of uptake sites of serotonin ([(3)H]citalopram binding sites) was decreased in the various brain. The activities of TPH were increased in striatum and frontal cortex and the activity of MAO was also increased in striatum. These results indicate that AF64A induces an increase in serotonergic neuronal activity and decreased densities of 5-HT uptake sites which may affect the change in the other parameters of serotonergic neuronal activities. Furthermore, these results suggest that the impaired cholinergic neuronal activity induces the alteration in the serotonergic nervous activities. PMID- 20195831 TI - Identification and assessment of permeability enhancing vehicles for transdermal delivery of glucosamine hydrochloride. AB - As an initial step to develop the transdermal delivery system of glucosamine hydrochloride (GL-HCl), the permeation study across the rat skin in vitro was performed to identify the most efficient vehicle with regard to the ability to deliver GL-HCl transdermally. The GL-HCl formulations such as o/w cream, liposome suspension, liposomal gel, and liquid crystalline vehicles were prepared and compared for transdermal flux of GL-HCl. The liquid crystalline vehicles were more effective in increasing the skin permeation of GL-HCl than o/w cream and liposomal vehicles. Of the liquid crystalline vehicles tested, the permeation enhancing ability of the cubic phase was greater than that of the hexagonal phase when the nanoparticle dispersion was used. The skin permeation enhancing ability of the cubic nanoparticles for GL-HCl was further increased by employing both oleic acid and polyethylene glycol 200. Therefore, the cubic liquid crystalline nanodispersion containing oleic acid and PEG 200 can provide a possibility of clinical application of transdermal GL-HCl. PMID- 20195833 TI - Assessment of the anti-angiogenic, anti-inflammatory and antinociceptive properties of ethyl vanillin. AB - The present work aimed to assess novel pharmacological properties of ethyl vanillin (EVA) which is used as a flavoring agent for cakes, dessert, confectionary, etc. EVA exhibited an inhibitory activity in the chorioallantoic membrane angiogenesis. Anti-inflammatory activity of EVA was convinced using the two in vivo models, such as vascular permeability and air pouch models in mice. Antinociceptive activity of EVA was assessed using acetic acid-induced writhing model in mice. EVA suppressed production of nitric oxide and induction of inducible nitric oxide synthase in the lipopolysaccharide (LPS)-activated RAW264.7 macrophage cells. However, EVA could not suppress induction of cyclooxygenase-2 in the LPS-activated macrophages. EVA diminished reactive oxygen species level in the LPS-activated macrophages. EVA also suppressed enhanced matrix metalloproteinase-9 gelatinolytic activity in the LPSactivated RAW264.7 macrophage cells. EVA at the used concentrations couldn't diminish viability of the macrophage cells. Taken together, the anti-angiogenic, anti-inflammatory and anti-nociceptive properties of EVA are based on its suppressive effect on the production of nitric oxide possibly via decreasing the reactive oxygen species level. PMID- 20195834 TI - Determination of pipecolic acid following trimethylsilyl and trifluoroacyl derivatisation on plasma filter paper by stable isotope GC-MS for peroxisomal disorders. AB - If early diagnosis is not made, patients with peroxisomal disorders rapidly progress to sudden death, physical defect or mental retardation resulted in storage of the toxic material into the brain. Therefore, it is necessary to develop the analytical method for rapid screening and/or correct confirmation diagnosis. The method utilizes [2H(9)]pipecolic acid as internal standard. The formation of trimethylsilyl derivative (TMS) of the carboxylic functional group was performed by adding MSTFA. And then 5 microL of methyl orange was added until the color of methyl orange was to yellow. Consecutively, the trifluoroacyl (TFA) derivative of the -NH functional group was produced by adding MBTFA. GC-MS was set with specific ions (m/z 282, m/z 297) of the TMSTFA derivative of pipecolic acid for selected ion monitoring. The linearity of pipecolic acid in pooled plasma spots showed 0.9999 in the range of 10-150 ng investigated. The precision and accuracy was within S.D. of 5% (RSD, within 5%) for intra-day and inter-day assay. Normal control value has been determined in plasma spots of infant and adults aged 0-30 (including newborn). The utility of the method was demonstrated by quantifying various concentration of fortified pipecolic acid on a filter plasma spot. The new method was simple with just two step derivatisation, time and labor saving without SPE or liquid-liquid extraction, and convenience of delivery owing to the use of filter paper. The described method could be used for routine analysis, monitoring, and clinical diagnostic application of peroxisomal disorders on dietary therapy. PMID- 20195835 TI - Antihyperglycemic and antihyperlipidemic action of Cinnamomi Cassiae (Cinnamon bark) extract in C57BL/Ks db/db mice. AB - In previous study, the anti-diabetic effect of Cinnamomi Cassiae extract (Cinnamon bark: Lauraceae) in a type II diabetic animal model (C57BIKsj db/db) has been reported. To explore their mechanism of action, in present study, the effect of cinnamon extract on anti-hyperglycemia and anti-hyperlipidemia was evaluated by measuring the blood glucose levels, serum insulin, and adiponectin levels, serum and hepatic lipids, PPARalpha mRNA expression in liver and PPARgamma mRNA expression in adipose tissue, respectively. Male C57BIKs db/db mice were divided into a diabetic group and cinnamon extract treated group and examined for a period of 12 weeks (200 mg/kg, p.o). The fasting blood glucose and postprandial 2 h blood glucose levels in the cinnamon treated group were significantly lower than those in the control group (p < 0.01), whereas the serum insulin and adiponectin levels were significantly higher in the cinnamon treated group than in the control group (p < 0.05). The serum lipids and hepatic lipids were improved in the cinnamon administered group. Also the PPARalpha mRNA (liver) and PPARgamma mRNA (adipose tissue) expression levels were increased significantly in the cinnamon treated group (p < 0.05). Our results suggest that cinnamon extract significantly increases insulin sensitivity, reduces serum, and hepatic lipids, and improves hyperglycemia and hyperlipidemia possibly by regulating the PPAR-medicated glucose and lipid metabolism. PMID- 20195839 TI - [The surgeon as a patient]. PMID- 20195840 TI - [Fractures of the acetabulum. Diagnostic and therapeutic strategies]. AB - Fractures of the acetabulum are a challenge in terms of orientation and the surgical skills of the orthopedic trauma surgeon. Due to the surrounding soft tissues and because of the indirect reduction control, operative treatment of acetabular fractures can be very demanding. This review includes the anatomical and clinical features, the radiological diagnostic approach, the classification systems, and, in particular, the surgical approaches and treatment principles. The work houses for surgical approaches are the ilioinguinal and the posterior (Kocher-Langenbeck) approach. In view of the high complication rate, the extended approaches are of less relevance. The therapeutic relevance of recent developments including navigation is discussed. PMID- 20195841 TI - [Early functional treatment and full weight-bearing of surgically treated isolated ankle fractures in the elderly]. AB - QUESTION: Fractures of the ankle joint belong to the most often occurring injuries. The aftercare in plaster lasts several weeks and is problematic especially in elderly patients. METHODS: In a retrospective study patients over the age of 50 years who underwent surgical treatment of ankle fractures and early functional mobilization were examined in a follow-up. The range of motion, the circumferential measurements and the radiological course were examined by comparing preoperative and postoperative X-ray images after 13-24 months. The subjective results were collected using the Olerud-Molander score (OMS). RESULTS: A total of 30 out of 42 patients who qualified for the follow-up were included in the study. The distribution of the gender was equal as was the right/left distribution and the mean age was 68 years. The magnitude of movement and comparison between the two sides showed no significant differences. The average score for subjective satisfaction was 90 in the OMS. The radiological results showed few changes and no deviations from the axis. No redislocations or implant fractures could be observed. Early functional full weight-bearing showed satisfactory preliminary results. CONCLUSION: This treatment concept can be recommended because patient comfort is increased and the risk of immobilization is excluded. PMID- 20195842 TI - Activation of the mitogen-activated protein kinase (MAPK) signalling pathway in the liver of mice is related to plasma glucose levels after acute exercise. AB - AIMS/HYPOTHESIS: We aimed to identify, in the liver of mice, signal transduction pathways that show a pronounced regulation by acute exercise. We also aimed to elucidate the role of metabolic stress in this response. METHODS: C57Bl6 mice performed a 60 min run on a treadmill under non-exhaustive conditions. Hepatic RNA and protein lysates were prepared immediately after running and used for whole-genome-expression analysis, quantitative real-time PCR and immunoblotting. A subset of mice recovered for 3 h after the treadmill run. A further group of mice performed the treadmill run after having received a vitamin C- and vitamin E enriched diet over 4 weeks. RESULTS: The highest number of genes differentially regulated by exercise in the liver was found in the mitogen-activated protein kinase (MAPK) signalling pathway, with a pronounced and transient upregulation of the transcription factors encoded by c-Fos (also known as Fos), c-Jun (also known as Jun), FosB (also known as Fosb) and JunB (also known as Junb) and phosphorylation of hepatic MAPK. Acute exercise also activated the p53 signalling pathway. A major role for oxidative stress is unlikely since the antioxidant enriched diet did not prevent the activation of the MAPK pathway. In contrast, lower plasma glucose levels after running were related to enhanced levels of MAPK signalling proteins, similar to the upregulation of Igfbp1 and Pgc-1alpha (also known as Ppargc1a). In the working muscle the activation of the MAPK pathway was weak and not related to plasma glucose concentrations. CONCLUSIONS/INTERPRETATION: Metabolic stress evidenced as low plasma glucose levels appears to be an important determinant for the activation of the MAPK signalling pathway and the transcriptional response of the liver to acute exercise. PMID- 20195843 TI - Severity of vertebral fracture and risk of hip fracture: a nested case-control study. AB - Severe vertebral fractures strongly predicted subsequent hip fracture in this population-based study. Such high-risk patients should be provided with clinical evaluation and care for osteoporosis. INTRODUCTION: Vertebral fractures are commonly osteoporotic and known to predict hip fracture. The aim of this study was to evaluate associations between the severity of vertebral fractures and the risk of subsequent hip fracture. METHODS: Chest radiographs were obtained of 7,095 Finnish men and women aged 30 years or over in the Mini-Finland Health Survey in 1978-1980. Record linkage to the National Hospital Discharge Register identified 182 subjects from the survey who had subsequently been hospitalized for primary treatment of hip fracture by the end of 1994. A nested case-control setting was adopted, where three controls individually matched for age, gender, and place of residence were drawn for 169 subjects with hip fracture from the same cohort. Baseline vertebral fractures were identified at levels T3 to T12, and their morphology was categorized to mild, moderate, or severe according to Genant's classification. RESULTS: Severe vertebral fracture (>40% reduction in vertebral body height) strongly predicted hip fracture. After controlling for education, physical activity, smoking, alcohol consumption, and self-rated general health, the adjusted relative odds was 12.06 (95% confidence interval, 3.80-38.26). Mild to moderate fracture grades and the number of compressed vertebral bodies showed no prediction for hip fracture. CONCLUSIONS: The presence of a severe vertebral fracture in the thoracic spine strongly predicts subsequent hip fracture. Such high-risk patients should be clinically evaluated and provided with care for osteoporosis and measures to reduce the risk of falling as required. PMID- 20195844 TI - Dose-response effect of 40 weeks of resistance training on bone mineral density in older adults. AB - Resistance training is becoming popular for maintaining bone health. Previous studies examined high intensity exercise; we compared high and low intensity resistance training performed 2 or 3 days per week in older adults. We found positive bone density responses for the hip and spine for all types of resistance training. INTRODUCTION: This study determined the dose-response effect of resistance training on lumbar spine, proximal femur, and total body bone mineral density (BMD) in older men and women (55-74 years). METHODS: Subjects included 45 men and 79 women who were assigned to one of the following training groups: 1 high intensity (80% 1RM), 2 days/week (2HI); 2-low intensity (40% 1RM), 2 days/week (2LI); 3-high intensity (80% 1RM), 3 days/week (3HI); and 4-low intensity (40% 1RM), 3 days/week (3LI). Bone scans (dual energy X-ray absorptiometry) were performed at baseline and after 40 weeks of training. Muscular strength (1-repetition maximum) was assessed every 5 weeks. RESULTS: There were significant trial (p < 0.05) effects but no significant trial * training group interactions for the BMD sites. Spine, trochanter, and total hip BMD increased from baseline to 40 weeks; however, the total body BMD site decreased in the 3LI group. Men and women exhibited similar improvements for the trochanter and total hip sites but the percent change in the spine tended (p = 0.054) to be higher for men (1.8%) than women (0.4%). CONCLUSIONS: The resistance training programs, regardless of intensity and frequency, were effective in improving BMD of the proximal femur and lumbar spine but not the total body. Both men and women responded similarly for the hip sites but men show a greater response at the lumbar spine than women. PMID- 20195845 TI - Oral contraceptive use and bone mass in women aged 26-36 years. AB - INTRODUCTION: The association between hormonal contraceptive use and bone mineral density remains controversial. HYPOTHESIS: Hormonal contraceptive use is positively associated with bone mass in young premenopausal women. METHODS: Cross sectional analysis of data collected from women aged 26-36 years (n = 687) in the Childhood Determinants of Adult Health study-a longitudinal study investigating childhood determinants of cardiovascular disease, diabetes, and other chronic diseases in adulthood. Participants were not currently pregnant or breast feeding. Contraceptive use was obtained by self-administered questionnaire. Women were categorized as combined oral contraceptive users (n = 219), progestogen-only contraceptive users (n = 43), and non-users of hormonal contraceptives (n = 425). Bone mass was measured by quantitative ultrasound. RESULTS: Compared with women who were not using any hormonal contraceptives, women using combined oral contraceptives had significantly higher values of broadband ultrasound attenuation (BUA), speed of sound, and quantitative ultrasound index. These associations remained after adjustment for confounders. Progestogen-only contraceptive users had higher BUA than non-users, but the differences were not statistically significant in this small group. CONCLUSION: Combined oral contraceptive use was associated with higher bone mass measured by quantitative ultrasound in this population-based sample of premenopausal women aged 26-36 while progestogen-only contraceptives appeared to have no deleterious effect on bone mass. PMID- 20195846 TI - International comparison of cost of falls in older adults living in the community: a systematic review. AB - SUMMARY: Our objective was to determine international estimates of the economic burden of falls in older people living in the community. Our systematic review emphasized the need for a consensus on methodology for cost of falls studies to enable more accurate comparisons and subgroup-specific estimates among different countries. INTRODUCTION: The purpose of this study was to determine international estimates of the economic burden of falls in older people living in the community. METHODS: This is a systematic review of peer-reviewed journal articles reporting estimates for the cost of falls in people aged > or =60 years living in the community. We searched for papers published between 1945 and December 2008 in MEDLINE, PUBMED, EMBASE, CINAHL, Cochrane Collaboration, and NHS EED databases that identified cost of falls in older adults. We extracted the cost of falls in the reported currency and converted them to US dollars at 2008 prices, cost items measured, perspective, time horizon, and sensitivity analysis. We assessed the quality of the studies using a selection of questions from Drummond's checklist. RESULTS: Seventeen studies met our inclusion criteria. Studies varied with respect to viewpoint of the analysis, definition of falls, identification of important and relevant cost items, and time horizon. Only two studies reported a sensitivity analysis and only four studies identified the viewpoint of their economic analysis. In the USA, non-fatal and fatal falls cost US $23.3 billion (2008 prices) annually and US $1.6 billion in the UK. CONCLUSIONS: The economic cost of falls is likely greater than policy makers appreciate. The mean cost of falls was dependent on the denominator used and ranged from US $3,476 per faller to US $10,749 per injurious fall and US $26,483 per fall requiring hospitalization. A consensus on methodology for cost of falls studies would enable more accurate comparisons and subgroup-specific estimates among different countries. PMID- 20195847 TI - Postural challenge and adaptation to vibration-induced disturbances. AB - The described experiment investigated whether adaptation to successive Achilles tendon vibration depends on the postural challenge. In phase 1, thirty-six participants were divided into three groups, each with a different postural challenge. After being blindfolded, participants received 15 trials of Achilles tendon vibration (10 s-90 Hz) while standing upright in either a free-standing condition (FS group), a light finger touch condition (LFT group), or a restrained standing condition (RS group) in which a dorsal stand prevented body displacement. In phase 2, all participants were freely standing and received 15 additional trials of vibration. Antero-posterior trunk tilt was measured at the level of the trunk (C7). Although there were limited postural readjustments in LFT, adaptation was observed in phase 1 in both FS and LFT groups. In phase 2, the evoked postural displacement was greater in the RS group than in the other two groups. We concluded that although the absence of any postural challenge concomitant to the sensory stimulation prevented adaptation to occur, a minimal challenge was sufficient. PMID- 20195848 TI - Planning and control of hand orientation in grasping movements. AB - Humans grasp objects in a way that facilitates the intended use of the object. We examined how humans grasp a circular control knob in order to turn it in different directions and by different extents. To examine the processes involved in anticipatory planning of grasps, we manipulated advance information about the location of the control knob and the target of the knob-turn. The forearm orientation at the time of grasping depended strongly on the knob-turn, with the direction of the knob-turn having a stronger effect than the extent of the knob turn. However, the variability of the forearm orientations after the knob-turn remained considerable. Anticipatory forearm orientations began early during the grasping movement. Advance information had no influence on the trajectory of the grasp but affected reaction times and the duration of the grasp. From the results, we conclude that (1) grasps are selected in anticipation of the upcoming knob rotation, (2) the desired hand location and forearm orientation at the time of grasping are specified before the onset of the grasp, and (3) an online programming strategy is used to schedule the preparation of the knob-turn during the execution of the grasp. PMID- 20195850 TI - Giant coronary aneurysms caused by Kawasaki disease. PMID- 20195851 TI - Partial anomalous pulmonary venous return to the azygos vein: an unusual case. PMID- 20195849 TI - Hippocampal contribution to early and later stages of implicit motor sequence learning. AB - Implicit motor sequence learning refers to an important human ability to acquire new motor skills through the repeated performance of a motor sequence. This learning process is characterized by slow, incremental gains of motor performance. The present fMRI study was developed to better delineate the areas supporting these temporal dynamics of learning. By using the serial color matching paradigm, our study focused on the motor level of sequence learning and tracked the time course of learning-related neural changes. Imaging results showed a significant contribution of the left anterior hippocampus in an early sequence acquisition stage (first scanning session) as well as during a later stage with stabilized learning effects (second scanning session). Hippocampal activation significantly correlated with the behavioral learning process and was affected by a change of the motor sequence. These results suggest a strong involvement of the hippocampus in implicit motor sequence learning. On the other hand, a very extensive and bilateral neural network of parietal, temporal and frontal cortical areas (including SMA, pre-SMA) together with parts of the cerebellum and striatum were found to play a role during random visuo-motor task performance. PMID- 20195853 TI - Pre and post operative 3D echocardiographic [corrected] appearance of isolated cleft of the anterior mitral valve leaflet. PMID- 20195852 TI - Risk of nephropathy after consumption of nonionic contrast media by children undergoing cardiac angiography: a prospective study. AB - Despite increasing reports on nonionic contrast media-induced nephropathy (CIN) in hospitalized adult patients during cardiac procedures, the studies in pediatrics are limited, with even less focus on possible predisposing factors and preventive measures for patients undergoing cardiac angiography. This prospective study determined the incidence of CIN for two nonionic contrast media (CM), iopromide and iohexol, among 80 patients younger than 18 years and compared the rates for this complication in relation to the type and dosage of CM and the presence of cyanosis. The 80 patients in the study consecutively received either iopromide (group A, n = 40) or iohexol (group B, n = 40). Serum sodium (Na), potassium (K), and creatinine (Cr) were measured 24 h before angiography as baseline values, then measured again at 12-, 24-, and 48-h intervals after CM use. Urine samples for Na and Cr also were checked at the same intervals. Risk of renal failure, Injury to the kidney, Failure of kidney function, Loss of kidney function, and End-stage renal damage (RIFLE criteria) were used to define CIN and its incidence in the study population. Accordingly, among the 15 CIN patients (18.75%), 7.5% of the patients in group A had increased risk and 3.75% had renal injury, whereas 5% of group B had increased risk and 2.5% had renal injury. Whereas 33.3% of the patients with CIN were among those who received the proper dosage of CM, the percentage increased to 66.6% among those who received larger doses, with a significant difference in the incidence of CIN related to the different dosages of CM (p = 0.014). Among the 15 patients with CIN, 6 had cyanotic congenital heart diseases, but the incidence did not differ significantly from that for the noncyanotic patients (p = 0.243). Although clinically silent, CIN is not rare in pediatrics. The incidence depends on dosage but not on the type of consumed nonionic CM, nor on the presence of cyanosis, and although CIN usually is reversible, more concern is needed for the prevention of such a complication in children. PMID- 20195854 TI - A rare case of hypoplastic left heart syndrome and scimitar syndrome: value of neonatal cardiac magnetic resonance imaging. PMID- 20195855 TI - Comparison of endothelial biomarkers according to reversibility of pulmonary hypertension secondary to congenital heart disease. AB - The reversibility of pulmonary arterial hypertension (PAH) in children with congenital heart disease (CHD) is strongly associated with the degree of intimal proliferation, vessel narrowing, and number of circulating endothelial cells (CECs). Circulating endothelial cells may arise from either endothelial damage or accelerated turnover during vessel remodeling, but nothing is known about endothelial microparticles (EMPs) and other biomarkers reflecting endothelial alterations. This study aimed to document endothelial markers further according to the irreversibility of PAH secondary to CHD. The study investigated soluble markers of endothelial damage or activation (thrombomodulin, soluble endothelial protein C receptor, and soluble E-selectin), inflammation (interleukin-6), and angiogenic cytokine levels [vascular endothelial growth factor (VEGF) and placental growth factor (PlGF)] in 26 patients with CHD, 16 with reversible PAH (median age, 2 years) and 10 with irreversible PAH (median age, 9 years). Endothelial activation/apoptosis was evaluated by measuring EMP levels. Plasma procoagulant activity also was measured. The results show that the levels of soluble markers indicating endothelial activation were not predictors of PAH irreversibility. Lower levels of PlGF were observed in reversible compared with irreversible PAH but were not associated with the CEC level, the mean pulmonary artery pressure (mPAP), or age. No significant difference in procoagulant activity or EMP level was found between irreversible and reversible PAH. Among a large panel of biomarkers reflecting endothelial activation, regeneration, and injury, the high CEC levels previously described proved to be the only marker allowing discrimination between reversible and irreversible PAH secondary to CHD. PMID- 20195856 TI - Identification and characterization of genes involved in naphthalene degradation in Rhodococcus opacus R7. AB - Rhodococcus opacus R7 is a naphthalene-degrading microorganism which is also able to grow on o-xylene. This work describes the isolation and analysis of two new genomic regions in which genes involved in naphthalene (nar gene cluster) and salicylate (gen gene cluster) degradation are located. In the nar gene cluster we found: two genes encoding the large (narAa) and the small (narAb) components of the naphthalene dioxygenase, three genes (rub1, rub2, rub1bis) encoding three rubredoxins, an orf (orf7) associated to the complex encoding a protein of unknown function, two regulatory genes (narR1, narR2), a gene (narB) encoding the naphthalene dihydrodiol dehydrogenase and six orfs (orf1, orf2, orf3, orf4, orf5, orf6) encoding proteins of unknown function. In the gen gene cluster, we found the following genes: two genes encoding the salicylate CoA ligase and the salicylate CoA synthetase (genA and genB), respectively, a gene (genC) encoding a salicylate hydroxylase, a gene (genH) encoding a gentisate 1,2-dioxygenase, a gene (genI) encoding a 3-maleylpyruvate isomerase, and a gene (genL) encoding a protein of unknown function. The transcription of some genes of R. opacus R7 strain grown on different substrates was also investigated to evaluate the expression of the two gene clusters after cDNA preparations. PMID- 20195857 TI - Genetic improvement of brewer's yeast: current state, perspectives and limits. AB - Brewer's yeast strain optimisation may lead to a more efficient beer production process, better final quality or healthier beer. However, brewer's yeast genetic improvement is very challenging, especially true when it comes to lager brewer's yeast (Saccharomyces pastorianus) which contributes to 90% of the total beer market. This yeast is a genetic hybrid and allopolyploid. While early studies applying traditional genetic approaches encountered many problems, the development of rational metabolic engineering strategies successfully introduced many desired properties into brewer's yeast. Recently, the first genome sequence of a lager brewer's strain became available. This has opened the door for applying advanced omics technologies and facilitating inverse metabolic engineering strategies. The latter approach takes advantage of natural diversity and aims at identifying and transferring the crucial genetic information for an interesting phenotype. In this way, strains can be optimised by introducing "natural" mutations. However, even when it comes to self-cloned strains, severe concerns about genetically modified organisms used in the food and beverage industry are still a major hurdle for any commercialisation. Therefore, research efforts will aim at developing new sophisticated screening methods for the isolation of natural mutants with the desired properties which are based on the knowledge of genotype-phenotype linkage. PMID- 20195858 TI - Marine yeasts as biocontrol agents and producers of bio-products. AB - As some species of marine yeasts can colonize intestine of marine animals, they can be used as probiotics. It has been reported that beta-glucans from marine yeast cells can be utilized as immuno-stimulants in marine animals. Some siderophores or killer toxins produced by marine yeasts have ability to inhibit growth of pathogenic bacteria or kill pathogenic yeasts in marine animals. The virulent factors from marine pathogens can be genetically displayed on marine yeast cells, and the yeast cells displaying the virulent factors can stimulate marine animals to produce specific antibody against the pathogens. Some marine yeast cells are rich in proteins and essential amino acids and can be used in nutrition for marine animals. The marine yeast cells rich in lipid can be used for biodiesel production. Recently, it has been reported that some strains of Yarrowia lipolytica isolated from marine environments can produce nanoparticles. Because many marine yeasts can remove organic pollutants and heavy metals, they can be applied to remediation of marine environments. It has been shown that the enzymes produced by some marine yeasts have many unique properties and many potential applications. PMID- 20195859 TI - Cyanobactins-ribosomal cyclic peptides produced by cyanobacteria. AB - Cyanobactins are small cyclic peptides that are produced by a diverse selection of cyanobacteria living in symbioses as well as terrestrial, marine, or freshwater environments. They include compounds with antimalarial, antitumor, and multidrug reversing activities and potential as pharmaceutical leads. Cyanobactins are produced through the proteolytic cleavage and cyclization of precursor peptides coupled with further posttranslational modifications such as heterocyclization, oxidation, or prenylation of amino acids. Cyanobactin gene clusters encode two proteases which cleave and cyclisize the precursor peptide as well as proteins participating in posttranslational modifications. The bioinformatic mining of cyanobacterial genomes has led to the discovery of novel cyanobactins. Heterologous expression of these gene clusters provided insights into the role of the genes participating in the biosynthesis of cyanobactins and facilitated the rational design of novel peptides. Enzymes participating in the biosynthesis of cyanobactins may prove useful as catalysts for producing novel cyclic peptides in the future. The recent discovery of the cyanobactin biosynthetic pathway in cyanobacteria extends our knowledge of their potential as producers of interesting metabolites. PMID- 20195860 TI - Reconstructing the clostridial n-butanol metabolic pathway in Lactobacillus brevis. AB - A Lactobacillus brevis strain with the ability to synthesize butanol from glucose was constructed by metabolic engineering. The genes crt, bcd, etfB, etfA, and hbd, composing the bcs-operon, and the thl gene encode the enzymes of the lower part of the clostridial butanol pathway (crotonase, butyryl-CoA-dehydrogenase, two subunits of the electron transfer flavoprotein, 3-hydroxybutyryl-CoA dehydrogenase, and thiolase) of Clostridium acetobutylicum. They were cloned into the Gram-positive/Gram-negative shuttle plasmid vector pHYc. The two resulting plasmids pHYc-thl-bcs and pHYc-bcs (respectively, with and without the clostridial thl gene) were transferred to Escherichia coli and L. brevis. The recombinant L. brevis strains were able to synthesize up to 300 mg l(-1) or 4.1 mM of butanol on a glucose-containing medium. A L. brevis strain carrying the clostridial bcs-operon has the ability to synthesize butanol with participation of its own thiolase, aldehyde dehydrogenase, and alcohol dehydrogenase. The particular role of the enzymes involved in butanol production and the suitability of L. brevis as an n-butanol producer are discussed. PMID- 20195861 TI - Potential roles of anaerobic ammonium and methane oxidation in the nitrogen cycle of wetland ecosystems. AB - Anaerobic ammonium oxidation (anammox) and anaerobic methane oxidation (ANME coupled to denitrification) with nitrite as electron acceptor are two of the most recent discoveries in the microbial nitrogen cycle. Currently the anammox process has been relatively well investigated in a number of natural and man-made ecosystems, while ANME coupled to denitrification has only been observed in a limited number of freshwater ecosystems. The ubiquitous presence of anammox bacteria in marine ecosystems has changed our knowledge of the global nitrogen cycle. Up to 50% of N(2) production in marine sediments and oxygen-depleted zones may be attributed to anammox bacteria. However, there are only few indications of anammox in natural and constructed freshwater wetlands. In this paper, the potential role of anammox and denitrifying methanotrophic bacteria in natural and artificial wetlands is discussed in relation to global warming. The focus of the review is to explore and analyze if suitable environmental conditions exist for anammox and denitrifying methanotrophic bacteria in nitrogen-rich freshwater wetlands. PMID- 20195862 TI - Effects of biotic and abiotic elicitors on cell growth and tanshinone accumulation in Salvia miltiorrhiza cell cultures. AB - This study examined the effects of biotic and abiotic elicitors on the production of diterpenoid tanshinones in Salvia miltiorrhiza cell culture. Four classes of elicitors were tested, heavy metal ions (Co2+, Ag+, Cd2+), polysaccharides (yeast extract and chitosan), plant response-signaling compounds (salicylic acid and methyl jasmonate), and hyperosmotic stress (with sorbitol). Of these, Ag (silver nitrate), Cd (cadmium chloride), and polysaccharide from yeast extract (YE) were most effective to stimulate the tanshinone production, increasing the total tanshinone content of cell by more than ten-fold (2.3 mg g(-1) versus 0.2 mg g( 1) in control). The stimulating effect was concentration-dependent, most significant at 25 microM of Ag and Cd and 100 mg l(-1) (carbohydrate content) of YE. Of the three tanshinones detected, cryptotanshinone was stimulated most dramatically by about 30-fold and tanshinones I and IIA by no more than 5-fold. Meanwhile, most of the elicitors suppressed cell growth, decreasing the biomass yield by about 50% (5.1-5.5 g l(-1) versus 8.9 g l(-1) in control). The elicitors also stimulated the phenylalanine ammonia lyase activity of cells and transient increases in the medium pH and conductivity. The results suggest that the elicitor-stimulated tanshinone accumulation was a stress response of the cells. PMID- 20195863 TI - Weakness after foreign travel in a 40-year-old man. PMID- 20195864 TI - Simple overlay device for determining radial head and neck height. AB - BACKGROUND: The purpose of this study was to test the hypothesis that a simple overlay device can be used on radiographs to measure radial head and neck height. MATERIALS AND METHODS: Thirty anteroposterior elbow radiographs from 30 patients with a clinical diagnosis of lateral epicondylitis were examined to measure radial head and neck height. Three methods using different points along the bicipital tuberosity as a landmark were used. Method 1 used the proximal end of the bicipital tuberosity, method 2 used the most prominent point of the bicipital tuberosity, and method 3 used a simple overlay device (SOD) template that was aligned with anatomic reference points. All measurements were performed three times by three observers to determine interobserver and intraobserver reliability. RESULTS: Intraclass correlation coefficients revealed higher interobserver and intraobserver correlations for the SOD template method than for the other two methods. The 95% limits of agreement between observers were markedly better (-1.8 mm to +1.0 mm) for the SOD template method than for the proximal point method (-3.8 mm to +3.4 mm) or the prominent point method (-5.9 mm to +4.9 mm). CONCLUSIONS: We found that the SOD template method was reliable for assessing radial head and neck height. It had less variability than other methods, its 95% limit of agreement being less than 2 mm. This method could be helpful for assessing whether or not the insertion of a radial head prosthesis has resulted in over-lengthening of the radius. PMID- 20195866 TI - Rhinoplasty using Nacul's suspensor system: a preliminary report. AB - A minimally invasive procedure based on a "suspensory system" is presented for the aesthetic correction of the flat nose. A Goretex monofilament is inserted between the connective tissue and the perichondrium from the septal, upper lateral, and alar cartilages in a quadrangular fashion. When tightened, it shortens the nose and elevates the tip. The procedure is performed on an outpatient basis with the patient under local anesthesia. It offers the patient immediate evaluation of the result. No edema or bruises have been observed. At this writing, 8 months after an application of this procedure, no extrusions or collateral reactions have been found. PMID- 20195865 TI - Longitudinal assessment of bone marrow edema-like lesions and cartilage degeneration in osteoarthritis using 3 T MR T1rho quantification. AB - OBJECTIVE: To quantitatively assess the relationship between bone marrow edema like lesions (BMELs) and the associated cartilage in knee osteoarthritis (OA) using T(1rho) quantification at 3 T MRI. MATERIALS AND METHODS: Twenty-four patients with knee OA and 14 control subjects underwent 3 T MRI. Nineteen patients and all control subjects had 1-year follow-up studies. The volume and signal intensity difference of BMELs were calculated. Cartilage degeneration was graded using the cartilage subscore of Whole-Organ MRI Score (WORMS) analysis. Cartilage T(1rho) values were calculated in each compartment as well as in cartilage overlying BMELs (OC) and surrounding cartilage (SC). RESULTS: At baseline, 25 BMELs were found in 16 out of 24 patients. The overall T(1rho) values were significantly higher in patients with BMELs than in those without BMELs. At baseline and follow-up, both T(1rho) values and WORMS cartilage subscore grading were significantly higher in OC than SC. Cartilage T(1rho) increase from baseline to follow-up in OC was significantly higher than that in SC. An increase in T(1rho) values in OC was correlated with signal intensity of BMEL at both baseline and follow-up, but was not correlated with BMEL volume. CONCLUSIONS: The results of this study suggest a local spatial correlation between BMELs and more advanced and accelerated cartilage degeneration. MRI T(1rho) quantification in cartilage provides a sensitive tool for evaluating such correlations. PMID- 20195867 TI - Th17 cells in autoimmune demyelinating disease. AB - Recently published studies in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) have demonstrated an association between the development of demyelinating plaques and the accumulation of Th17 cells in the central nervous system and periphery. However, a causal relationship has been difficult to establish. In fact, in reports published thus far, interleukin (IL)-17A deficiency or neutralization in vivo attenuates, but does not completely abrogate, EAE. There is growing evidence that clinically similar forms of autoimmune demyelinating disease can be driven by myelin-specific T cells of distinct lineages with different degrees of dependence on IL-17A production to achieve their pathological effects. While such observations cast doubts about the potential therapeutic efficacy of Th17 blocking agents in MS, the collective data suggest that IL-17A expression in peripheral blood mononuclear cells could serve as a surrogate biomarker of neuroinflammation and plaque formation and be a useful outcome measure for future clinical trials. PMID- 20195868 TI - X-inactivation analysis of embryonic lethality in Ocrl wt/-; Inpp5b-/- mice. AB - Mutations in the human OCRL gene, which encodes a phosphatidylinositol(4,5)bisphosphate 5-phosphatase, result in the X-linked oculocerebrorenal syndrome of Lowe. Mice with a targeted disruption of Ocrl have no phenotypic abnormalities. Targeted disruption of its closest paralog, Inpp5b, causes male infertility in the 129S6 background. Mice with disruptions of both genes are lost in utero prior to 9.5-10.5 dpc, indicating that there is a functional overlap between the two paralogs early in development. We analyzed the pattern of X-inactivation in four tissues of distinct embryonic origin from Ocrl (wt/-);Inpp5b (-/-) females to explore the timing and tissue distribution of the functional overlap. X-inactivation was strongly skewed against the disrupted Ocrl (-) allele being on the active X chromosome in all four tissues tested, indicating that there is early selection against cell lineages lacking both Ocrl and Inpp5b. Extraembryonic tissue was also involved in the lethality because there were never any live-born Ocrl (wt/-);Inpp5b (-/-) females when the functional Ocrl (wt ) allele was on the paternal X chromosome, which is preferentially inactivated in trophoblast-derived extraembryonic tissues. Live born Ocrl (wt/-);Inpp5b (-/-) females were found when the functional Ocrl (wt) allele was maternal, although in fewer numbers than expected. The importance of the extraembryonic tissues in the early embryonic lethality of embryos lacking both Ocrl and Inpp5b is reinforced by the successful isolation of a viable 40,XX Ocrl (-/-);Inpp5b (-/-) embryonic stem cell from the inner cell mass of a 3.5-dpc blastocyst prior to implantation. These results indicate a functional overlap of Ocrl and Inpp5b in most cell lineages, especially in extraembryonic tissues. PMID- 20195869 TI - Validity of the definite and semidefinite questionnaire version of the Hamilton Depression Scale, the Hamilton Subscale and the Melancholia Scale. Part I. AB - Instruments for self-rating in depression are available, but their psychometric properties have not been fully explored; discrepancies with clinician ratings have been identified. This study was longitudinal with 85 patients fulfilling the DSM-III-R diagnosis of Seasonal Affective Disorder. Self-reporting versions (definitely and semidefinitely anchored) corresponding to the Hamilton Depression Scale (HAMD), the Hamilton Subscale (HAM6), and the Bech-Rafaelsen Melancholia Scale (MES) were compared to each other and the clinician-rated version. The unidimensional property of the sum score in each scale was tested by the item response theory model ad modum Rasch. The scales were also tested for their sensitivity to discriminate between placebo and citalopram therapy. The sum scores and the sum score variances of the definite self-rating versions did not differ significantly from the sum scores of the corresponding observer scales at any of the five time points. The semidefinite scales significantly over-scored at all time points. The convergent validity between corresponding definite self ratings and observer ratings was very high with correlations exceeding 0.90. Only item responses from the MES, the HAM6, and their corresponding definite versions of the self-rating questionnaires DMQ and DHAM6 were accepted by the Rasch analysis, and only these four valid scales discriminated significantly between the effect of citalopram and placebo treatment. Our results are limited to patients with moderate depression. Two new self-report scales with unparalleled construct validity, reliability, sensitivity, and convergent validity have been identified (DMQ and DHAM6). We have also identified a crucial importance of format for the means and variances of self-rating scales. These findings are of high practical and scientific value. PMID- 20195870 TI - Female carriers of X-chromosomal adrenoleukodystrophy: a major differential diagnosis in progressive myelopathy. AB - Adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN) are allelic X chromosomal disorders of peroxisomal lipid metabolism due to mutations of the ABCD1-gene, leading, respectively, to leukoencephalopathy or myeloneuropathy in male patients. We report a family with two symptomatic carriers in subsequent generations who both suffer from symptoms of an AMN. In both patients, molecular genetic testing revealed a heterozygous c.1552C>T-transition (p.Arg518Trp) in exon 6 of ABCD1. Our observations underline the importance of identifying such symptomatic ALD carriers. PMID- 20195871 TI - Early embryonic development and diapause stage in the band-legged ground cricket Dianemobius nigrofasciatus. AB - The band-legged ground cricket Dianemobius nigrofasciatus enters diapause at an early embryonic stage when adults are reared under short-day conditions or the eggs are exposed to a low temperature. We examined the morphological features of the embryo during early development and determined the exact stage of entry into diapause. In non-diapause eggs, no periplasmic space was observed in the surface region and a small number of nuclei surrounded by cytoplasm (energids) were found among the yolk granules and lipid droplets 12 h after egg laying (AEL) at 25 degrees C. The energids sparsely but evenly populated the surface region at 40 h AEL, but there were some gaps between these energids. A continuous thin layer of nuclei with cytoplasm had completely covered the egg surface at 56 h AEL, suggesting that the blastoderm is formed between 40 and 56 h AEL. At 72 h AEL, we found a germ band at the posterior pole. Electron microscopy revealed clear cell membranes at 40 h AEL. Staining with rhodamine-dextran dye demonstrated that the cell membrane is formed when the nuclei appear on the egg surface at 12-24 h AEL. These results indicate that cellularization occurs before blastoderm formation. In diapause eggs, neither the embryonic rudiment nor germ band was formed, but a continuous layer of cells covered the egg surface. It is concluded that D. nigrofasciatus enters diapause at the cellular blastoderm. PMID- 20195872 TI - Unusual manifestations of bilateral carotid artery dissection: Dysphagia and hoarseness. AB - Dissection of the carotid artery can occur intracranially or extracranially, although dissections tend to affect extracranial segments of the arteries much more commonly than intracranial segments. Carotid artery dissection (CAD) is most common in middle-aged women. Although not completely known, the main risk factors related to carotid artery dissection are genetic and environmental factors, traumatic events, cervical manipulation, migraine, recent infections, hyperhomocysteinemia, and hereditary connective tissue disorders. Although some cases of bilateral internal CAD have been reported, spontaneous bilateral dissections are rare. Prolonged hoarseness is usually due to using the voice either too much, too loudly, or improperly over an extended period of time. Disorders leading to dysphagia may affect the oral, pharyngeal, or esophageal phases of swallowing. In this study we report on a patient with bilateral CAD who presented to our clinic with dysphagia and hoarseness. PMID- 20195873 TI - Circadian and ultradian extrasystole rhythms in healthy individuals at elevated versus lowland altitudes. AB - We defined chronobiologic norms for supraventricular and ventricular single extrasystoles (SV and VE, respectively) in healthy older males in lowland areas. The study was extended to higher altitudes, where hypobaric hypoxia was expected to increase extrasystole frequency, while perhaps not changing rhythmicity. In healthy men (lowland n = 37, altitude n = 22), aged 49-72 years, mean numbers of SVs and VEs were counted over a 24-h period. Cosinor regression was used to test the 24-h rhythm and its 2nd-10th harmonics. The resulting approximating function for either extrasystole type includes its point, 95% confidence interval of the mean, and 95% tolerance for single measurement estimates. Separate hourly differences (delta) between altitude and lowland (n = 59) were also analysed. Hourly means were significantly higher in the mountains versus lowland, by +0.8 beats/h on average for SVs, and by +0.9 beats/h for VEs. A relatively rich chronogram for VEs in mountains versus lowland exists. Delta VEs clearly display a 24-h component and its 2nd, 3rd, 4th and 7th harmonics. This results in significantly higher accumulation of VEs around 8.00 a.m., 11.00 a.m. and 3.00 p.m. in the mountains. The increase in extrasystole occurrence in the mountains is probably caused by higher hypobaric hypoxia and resulting sympathetic drive. Healthy men at elevated altitudes show circadian and several ultradian rhythms of single VEs dependent on the hypoxia level. This new methodological approach- evaluating the differences between two locations using delta values--promises to provide deeper insight into the occurrence of premature beats. PMID- 20195874 TI - Arbuscular mycorrhiza of Arnica montana under field conditions--conventional and molecular studies. AB - Two distinct populations of Arnica montana, an endangered medicinal plant, were studied under field conditions. The material was investigated using microscopic and molecular methods. The analyzed plants were always found to be mycorrhizal. Nineteen arbuscular mycorrhizal fungal DNA sequences were obtained from the roots. They were related to Glomus Group A, but most did not match any known species. Some showed a degree of similarity to fungi colonizing liverworts. Conventional analysis of spores isolated from soil samples allowed to identify different fungal taxa: Glomus macrocarpum, Glomus mosseae, Acaulospora lacunosa, and Scutellospora dipurpurescens. Their spores were also isolated from trap cultures. PMID- 20195875 TI - Correlation of BDNF blood levels with interoceptive awareness and maturity fears in anorexia and bulimia nervosa patients. AB - Association studies and rodent models suggest a major role for BDNF (brain derived neurotrophic factor) in feeding regulation. Altered BDNF blood levels have been associated with eating disorders (ED) and their related psychopathological traits. Since the influence of BDNF on self-reported eating disorder inventory scores (EDI) has not been tested, we investigated the correlation of EDI scales with BDNF plasma levels. BDNF levels were measured by (ELISA), and the EDI questionnaire was administered in a total of 81 ED patients. The relationship between BDNF levels and EDI scores was calculated using a general linear model. After correcting for multiple testing, BDNF plasma levels negatively correlated with the EDI total score (R (2) = 0.26; p = 4.09 x 10(-4)), interoceptive awareness (R (2) = 0.26; p = 1.96 x 10(-4)), and maturity fears (R (2) = 0.13; p = 6.92 x 10(-4)). When subdividing according to the main diagnoses, interoceptive awareness presented significant correlations with BDNF blood levels in both the anorexia nervosa (R (2) = 0.33, p = 0.0026) and bulimia nervosa groups (R (2) = 0.10; p = 0.008). Our data suggest that BDNF levels may influence the severity of the ED by modulating the associated psychopathology, in particular through the impairment of interoceptive awareness. PMID- 20195878 TI - Wegener's granulomatosis: experience from a Brazilian tertiary center. AB - Most epidemiological studies with Wegener's granulomatosis (WG) patients are based on populations from the Northern hemisphere, whereas very few studies have been conducted in Southern hemisphere populations, particularly from South America. The authors performed a large retrospective, demographic study including clinical and laboratory profiles of 134 consecutive WG patients seen at one Brazilian center from 1999 to 2009. Mean age at initial WG diagnosis was 43.4 +/- 15.5 years, and mean disease duration was 8.6 +/- 6.6 years. Sixty-four (47.8%) patients were male and a total of 113 (84.3%) subjects were white. Ear/nose/throat involvement occurred in 85.8%. The classic lung and renal involvement were observed in 77.6% and 75.4%, respectively, followed by ocular (35.8%), musculoskeletal (33.4%), cutaneous (29.1%), neurological (20.1%), cardiac (11.2%), and genitourinary involvement in 2.2% of cases. Cytoplasmic pattern-antineutrophil cytoplasmic antibody was detected in 83 (61.9%) cases. Ten (7.5%) individuals presented limited forms of WG. Classic therapy with corticosteroids and cyclophosphamide was used in 97 cases (72.4%). There were no cases of tuberculosis or Pneumocystis jiroveci pneumonia, but cutaneous herpes zoster occurred in eight (6.0%) individuals. There were 29 deaths (21.6%). Eighteen patients died of septic shock (mainly bacterial pneumonia), whereas four died of alveolar hemorrhage, four of myocardial infarction, and three of other causes. In summary, our data from a very large retrospective and descriptive study mirrored the main clinical features of WG described in other countries, demonstrating that they may serve as a reference for South American populations. PMID- 20195877 TI - Altered expression of cell-cell adhesion molecules beta-catenin/E-cadherin and related Wnt-signaling pathway in sporadic and syndromal keratocystic odontogenic tumors. AB - Differential diagnosis of the keratocystic odontogenic tumor (KCOT) still represents a challenging problem especially if compared with the dentigerous cyst, which is similar in clinical and radiological course. Histological assessment of this entity may therefore draw crucial attention since various radical procedures are recommended for such lesions in contrast to dentigerous cysts. Since recent reports could prove the involvement of wingless(Wnt) signaling pathway and beta-catenin in the pathogenesis of many odontogenic and neoplastic lesions indicating impairment of cell-cell adhesion, we investigated the expression of two Wnt-signaling pathways, Wnt-1 and Wnt-10A as well as beta catenin and E-cadherin along with other related proteins in both lesions. We found a significant down-regulation in the expression of cell adhesion proteins beta-catenin and E-cadherin along with alteration of Wnt-1 and Wnt-10A expression in the epithelium of KCOT. We assessed a specific focal distribution pattern of p63 in the suprabasal cell layer and a significant up-regulation of cyclin D1. Furthermore, laminin alpha-2 was a characteristic marker labelling only the basement membrane of dentigerous cysts. These results provide a new hypothesis explaining a molecular mechanism to understand initiating and development of KCOTs and an alternative therapeutic approach, especially for syndromal patients, where these multilocal lesions may involve and destroy wide orofacial bony structures. PMID- 20195879 TI - The efficacy of low-dose mycophenolate mofetil for treatment of lupus nephritis in Taiwanese patients with systemic lupus erythematosus. AB - Mycophenolate mofetil (MMF) has recently been introduced as an immunosuppressive agent for the treatment of glomerulonephritis with systemic lupus erythematosus (SLE) and the data have been encouraging. However, response to MMF treatment appears to differ ethnically. Therefore, we determined efficacy and safety of low dose MMF for Taiwanese patients with lupus nephritis. We studied 36 lupus nephritis patients who were treated with MMF. The dose started at 0.5 g/day and we collected the data from patients who received up to 1 g/day MMF. Outcome measures were 24 h for proteinuria, serum creatinine, C3/C4 levels, and anti dsDNA titers collected at the baseline and at 3-month treatment intervals. Daily urinary protein significantly decreased from 6.15 +/- 4.28 g to 2.69 +/- 2.36 g at the last visit (P < 0.01) in spite of the significant absence of changes in serum creatinine levels. The response rate was 65.7% including five (14.3%) cases of complete remission and 18 (51.4%) cases of partial remission. The concomitant oral prednisolone dose decreased significantly from 20.07 +/- 11.78 mg/day to 13.93 +/- 6.79 mg/day at 6 months (P < 0.01). The level of C3 increased significantly from 59.46 +/- 32.73 to 71.99 +/- 25.81 (P < 0.01) and the anti dsDNA antibody titer decreased from 161.71 +/- 221.42 to 46.57 +/- 117.47 (P < 0.01). No severe adverse effects were observed in the study. Low-dose MMF (0.5 to 1 g/day) combined with glucocorticoids appears to be a safe and effective therapy for lupus nephritis in Taiwanese patients. Our results suggest that lupus nephritis in Oriental patients might respond to lower doses of MMF than Caucasians. PMID- 20195880 TI - Juvenile idiopathic arthritis among Nigerians: a case study. AB - Juvenile idiopathic arthritis (JIA) has rarely been reported among Black Africans. This retrospective case study was part of an audit of cases presenting to a private practice rheumatology clinic in Lagos, Nigeria. The objective of this study was to determine the clinical, laboratory, and radiographic features of patients with JIA, as well as to highlight their management. A total of 23 cases (F-16:M-7) were seen over an 8.5-year period. Polyarticular presentation was the commonest while systemic onset was the least. The mean age at presentation was 12.7 years. Most of the patients presented late with mean of 3.7 years before presentation. The knees and ankles were most commonly involved. ESR was elevated in most of the cases. Rheumatoid factor and Antinuclear antibodies were invariably negative. Treatments were with standard drugs. Although JIA is uncommonly seen in our population, the clinical and laboratory features are similar as elsewhere, though there are some differences. PMID- 20195881 TI - Spontaneous pneumomediastinum secondary to refractory dermatomyositis successfully treated with rituximab. AB - Spontaneous pneumomediastinum has been described in patients with dermatomyositis (DM) and polymyositis (Korkmaz et al., Rheumatology 40:476-478, 2001; Maruoka et al., Mod Rheumatol 16:55-57, 2006; Kono et al., Ann Rheum Dis 59:372-376, 2000; Neves et al., Clin Rheumatol 26:105-107, 2007). Literature reviews suggest that this complication has a mortality of between 27% and 41% ( Kono et al., Ann Rheum Dis 59:372-376, 2000; Neves et al., Clin Rheumatol 26:105-107, 2007; Goff et al., Arthritis Rheum 61:108-118, 2009). This is the first report of rituximab being used successfully as part of the treatment for DM complicated by pneumomediastinum. PMID- 20195882 TI - Determination of teicoplanin trough concentration target and appropriate total dose during the first 3 days: a retrospective study in patients with MRSA infections. AB - An initial loading procedure has been recommended to enable teicoplanin to promptly reach an effective serum concentration for the treatment of methicillin resistant Staphylococcus aureus (MRSA). This study aimed to retrospectively evaluate the pharmacokinetics and pharmacodynamics of teicoplanin to determine the therapeutic target for the teicoplanin trough concentration and an appropriate dosing method during the first 3 days. The mean trough concentrations were 13.2 mg/L for patients with eradication of MRSA. Moreover, logistic regression analysis showed that the teicoplanin trough concentration was 13 mg/L to achieve MRSA eradication with a probability of 89.0%. The rates of achieving >or=13 mg/L in or=36 mg/kg (total dose during the first 3 days) groups were 9.1, 48.4 and 87.5%, respectively. These results suggest that the administration of >or=36 mg/kg during the first 3 days is appropriate to promptly obtain a trough concentration target of >or=13 mg/L for the initial treatment of MRSA infections. PMID- 20195883 TI - Control of endoreduplication of trichome by RPT2a, a subunit of the 19S proteasome in Arabidopsis. AB - The ubiquitin/26S proteasome pathway plays a central role in the degradation of short-lived regulatory proteins to control many cellular events. The Arabidopsis knockout mutant rpt2a, which contains a defect in the AtRPT2a subunit of the 26S proteasome regulatory particle, showed enlarged leaves caused by increased cell size that correlated with increased ploidy caused by extended endoreduplication. To clarify the role of RPT2a in endoreduplication control, trichome development was genetically examined in further detail. RHL1 and GL3 encode proteins that have a role in the positive regulation of endocycle progression in trichomes. The rhl1 mutants are stalled at 8C and have trichomes with only a single branch. The rpt2a mutation did not alter the rhl1 mutant phenotype, and trichomes of double rpt2a rhl1 mutants resembled that of single rhl1 mutants. On the other hand, the rpt2a mutation suppressed the gl3 phenotype (stalled at 16C, two trichome branches), and trichomes of the double rpt2a gl3 mutant resembled those of the wild type (WT) plants. Together, these data suggest that RPT2a functions to negatively regulate endocycle progression following completion of the third endoreduplication step mediated by RHL1 (8C-16C). PMID- 20195884 TI - Carbon and nitrogen status of litterfall, litter decomposition and soil in even aged larch, red pine and rigitaeda pine plantations. AB - The carbon (C) and nitrogen (N) status in forest ecosystems can change upon establishment of plantations because different tree species have different nutrient cycling mechanisms. This study was carried out to evaluate C and N status of litterfall, litter decomposition and soil in three adjacent plantations consisting of one deciduous (larch: Larix leptolepis) and two evergreen (red pine: Pinus densiflora; rigitaeda pine: P. rigida x P. taeda) species planted in the same year (1963). Both the pine plantations showed comparatively higher C input from needle litter but significantly lower N concentration and input than the larch plantation (P < 0.05). During the decomposition process, the deciduous larch needle litter showed low C concentration and C remaining in soil, but high N concentration and N remaining in soil compared to the two evergreen pine needle litters. However, the soil C and N concentration and their content at a soil depth of 0-10 cm were not affected significantly (P > 0.05) by the plantation type. These results demonstrate the existence of considerable variation in C and N status resulting from needle litter input and litter decomposition in these three plantations grown at sites with similar environmental conditions. PMID- 20195885 TI - Coenzyme Q10 production in a 150-l reactor by a mutant strain of Rhodobacter sphaeroides. AB - For the commercial production of CoQ(10), batch-type fermentations were attempted in a 150-l fermenter using a mutant strain of R. sphaeroides. Optimum temperature and initial aeration rate were found to be 30 degrees C and 2 vvm, respectively. Under optimum fermentation conditions, the maximum value of specific CoQ(10) content was achieved reproducibly as 6.34 mg/g DCW after 24 h, with 3.02 g/l of DCW. During the fermentation, aeration shift (from the adequate aeration at the early growth phase to the limited aeration in active cellular metabolism) was a key factor in CoQ(10) production for scale-up. A higher value of the specific CoQ(10) content (8.12 mg/g DCW) was achieved in fed-batch fermentation and comparable to those produced by the pilot-scale fed-batch fermentations of A. tumefaciens, which indicated that the mutant strain of R. sphaeroides used in this study was a potential high CoQ(10) producer. This is the first detailed study to demonstrate a pilot-scale production of CoQ(10) using a mutant strain of R. sphaeroides. PMID- 20195886 TI - A preliminary approach to creating an overview of lactoferrin multi-functionality utilizing a text mining method. AB - Lactoferrin is a multi-functional metal-binding glycoprotein that exhibits many biological functions of interest to many researchers from the fields of clinical medicine, dentistry, pharmacology, veterinary medicine, nutrition and milk science. To date, a number of academic reports concerning the biological activities of lactoferrin have been published and are easily accessible through public data repositories. However, as the literature is expanding daily, this presents challenges in understanding the larger picture of lactoferrin function and mechanisms. In order to overcome the "analysis paralysis" associated with lactoferrin information, we attempted to apply a text mining method to the accumulated lactoferrin literature. To this end, we used the information extraction system GENPAC (provided by Nalapro Technologies Inc., Tokyo). This information extraction system uses natural language processing and text mining technology. This system analyzes the sentences and titles from abstracts stored in the PubMed database, and can automatically extract binary relations that consist of interactions between genes/proteins, chemicals and diseases/functions. We expect that such information visualization analysis will be useful in determining novel relationships among a multitude of lactoferrin functions and mechanisms. We have demonstrated the utilization of this method to find pathways of lactoferrin participation in neovascularization, Helicobacter pylori attack on gastric mucosa, atopic dermatitis and lipid metabolism. PMID- 20195887 TI - Bactericidal effect of bovine lactoferrin, LFcin, LFampin and LFchimera on antibiotic-resistant Staphylococcus aureus and Escherichia coli. AB - Increased prevalence of antibiotic-resistant bacteria has become a major threat to the health sector worldwide due to their virulence, limited therapeutic options and distribution in both hospital and community settings. Discovery and development of new agents to combat antibiotic-resistant bacteria is thus needed. This study therefore aimed to evaluate the ability of bovine lactoferrin (LF), peptides from two antimicrobial domains lactoferricin B (LFcin17-30) and lactoferrampin (LFampin265-284) and a chimeric construct (LFchimera) containing both peptides, as potential bactericidal agents against clinical isolates of antibiotic-resistant Staphylococcus aureus and Escherichia coli. Results in kinetics of growth show that LF chimera and peptides inhibited the growth of both bacterial species. By confocal microscopy and flow cytometry it was observed that LF and FITC-labeled peptides are able to interact with these bacteria and cause membrane permeabilization, as monitored by propidium iodide staining, these effects were decreased by preincubation with lipopolysaccharide in E. coli. By electron microscopy, a clear cellular damage was observed in bacteria after treatments with LFchimera and peptides, suggesting that interaction and membrane disruption are probably involved as a mechanism of action. In conclusion, results show that LFchimera, LF and peptides have potential as bactericidal agents in the antibiotic-resistant strains of S. aureus and E. coli and also the work strongly suggest that LFcin17-30 and LFampin265-284 acts synergistically with antibiotics against multidrug resistant EPEC and MRSA in vitro. PMID- 20195888 TI - Lens epithelial cell response to atmospheric pressure plasma modified poly(methylmethacrylate) surfaces. AB - Selective control of cellular response to polymeric biomaterials is an important consideration for many ocular implant applications. In particular, there is often a need to have one surface of an ophthalmic implant capable of promoting cell attachment while the other needs to be resistant to this effect. In this study, an atmospheric pressure dielectric barrier discharge (DBD) has been used to modify the surface region of poly(methyl methacrylate) (PMMA), a well established ocular biomaterial, with the aim of promoting a controlled response to human lens epithelial cells (LEC) cultured thereon. The DBD plasma discharge environment has also been employed to chemically graft a layer of poly(ethylene glycol) methyl ether methacrylate (PEGMA) onto the PMMA and the response to LEC likewise determined. Two different molecular weights of PEGMA, namely 1000 and 2000 MW were used in these experiments. The LEC response to DBD treated polystyrene (PS) samples has also been examined as a positive control and to help to further elucidate the nature of the modified surfaces. The LEC adhered and proliferated readily on the DBD treated PMMA and PS surfaces when compared to the pristine polymer samples which showed little or no cell response. The PMMA and PS surfaces that had been DBD grafted with the PEGMA(1000) layer were found to have some adhered cells. However, on closer inspection, these cells were clearly on the verge of detaching. In the case of the PEGMA(2000) grafted surfaces no cells were observed indicating that the higher molecular weight PEGMA has been able to attain a surface conformation that is capable of resisting cell attachment in vitro. PMID- 20195889 TI - Nano iron oxide-hydroxyapatite composite ceramics with enhanced radiopacity. AB - Hydroxyapatite has been widely used for a variety of bone filling and augmentation applications. But the poorly resolved X-ray image of certain hydroxyapatite (HA) based implants such as porous blocks and self setting HA cements is a radiological problem to surgeons for monitoring of the implant and early diagnosis complications. In the present work the practical difficulty related to the reduced X-ray opacity was overcome by exploiting the contrast enhancement property of iron oxide nano particles. Sintered nano iron oxide-HA composite ceramics were prepared from powders produced through a co-precipitation route. The phase purity and bioactivity of the composites were analyzed as a function of percentage iron oxide in the composite. The X-ray attenuation of dense and porous composites was compared with pure HA using a C-arm X-ray imaging system and micro computed tomography. In all the prepared composites, HA retains its phase identity and high X-ray opacity as obtained for a composition containing 40 wt% iron oxide. The increased cell viability and cell adhesion nature depicted by the prepared composite offers considerable interest for the material in bone tissue engineering applications. PMID- 20195890 TI - Sex Pheromone of Agriotes acuminatus (Stephens, 1830) (Coleoptera: Elateridae). AB - The click beetle species Agriotes acuminatus is distributed in open deciduous forests throughout a large area in Europe. In order to identify its sex pheromone, gland extracts of female beetles were investigated by using GC/MS. Neryl butanoate and 2,6-dimethyl-(Z,E)-2,6-octadien-1,8-diol dihexanoate, in a ratio of approximately 1:5, were the only volatile compounds present in the extracts. Structures of both esters were confirmed by synthesis. Field experiments revealed a strong attraction of A. acuminatus males towards neryl butanoate, which could be synergistically enhanced by addition of 2,6-dimethyl (Z,E)-2,6-octadien-1,8-diol dihexanoate. The latter compound alone did not show any attractive effect. While all Agriotes spp. investigated to date use geranyl and/or (E,E)-farnesyl esters as sex pheromones, the nerol derivatives of A. acuminatus are the first (Z)-2-configurated pheromones within this genus. PMID- 20195891 TI - Fatty acid-amino acid conjugates diversification in lepidopteran caterpillars. AB - Fatty acid amino acid conjugates (FACs) have been found in noctuid as well as sphingid caterpillar oral secretions; in particular, volicitin [N-(17 hydroxylinolenoyl)-L-glutamine] and its biochemical precursor, N-linolenoyl-L glutamine, are known elicitors of induced volatile emissions in corn plants. These induced volatiles, in turn, attract natural enemies of the caterpillars. In a previous study, we showed that N-linolenoyl-L-glutamine in larval Spodoptera litura plays an important role in nitrogen assimilation which might be an explanation for caterpillars synthesizing FACs despite an increased risk of attracting natural enemies. However, the presence of FACs in lepidopteran species outside these families of agricultural interest is not well known. We conducted FAC screening of 29 lepidopteran species, and found them in 19 of these species. Thus, FACs are commonly synthesized through a broad range of lepidopteran caterpillars. Since all FAC-containing species had N-linolenoyl-L-glutamine and/or N-linoleoyl-L-glutamine in common, and the evolutionarily earliest species among them had only these two FACs, these glutamine conjugates might be the evolutionarily older FACs. Furthermore, some species had glutamic acid conjugates, and some had hydroxylated FACs. Comparing the diversity of FACs with lepidopteran phylogeny indicates that glutamic acid conjugates can be synthesized by relatively primitive species, while hydroxylation of fatty acids is limited mostly to larger and more developed macrolepidopteran species. PMID- 20195892 TI - Weight change and functional limitations among older adults in North Carolina. AB - There is emerging evidence that weight change during older adulthood is associated with decreased physical function; however, less is known about the association between weight change during middle to older adulthood and physical function. This study assessed the association of weight change between middle and older adulthood and functional limitations among 2,531 older African-American and white participants, ages 65 and older at baseline (1987), from the Piedmont Health Survey of the Elderly. Weight gainers had >=8% increase in weight, weight losers had >8% decrease in weight, and weight maintainers had <8% increase or decrease between age 50 and baseline. Functional limitations were categorized as none (0), mild (1-3), or severe (4 or more) using items from the activities of daily living scale by Katz and the extremity function scale by Nagi. Modified Poisson regression was used to assess these associations in crude and adjusted analyses. Weight gain and weight loss between age 50 and baseline were associated with severe functional limitations (prevalence ratio (PR) = 1.19, 95% CI: 1.04, 1.36 and PR = 1.58, 95% CI: 1.41, 1.78, respectively) compared to weight maintainers after adjustment for age, race, and gender. These associations were attenuated after additional adjustment for health characteristics, while weaker associations were noted for mild functional limitations. In summary, weight gain and weight loss between middle and older adulthood were associated with severe functional limitations among older adults in North Carolina. Additional research is needed to explore weight change across the life course and its possible effects on physical function later in life. PMID- 20195893 TI - Factors associated with healthcare visits by young children for nontoxic poisoning exposures. AB - Poison control centers have been shown to be a cost-effective alternative to healthcare visits for poisoning exposures, yet emergency departments (ED) and urgent care centers (UCC) continue to be frequently accessed for poisoning exposures in young children. We sought to identify predictors of young children who obtain healthcare for a nontoxic poisoning exposure. Poisoning exposure cases for children <=5 years old who sought ED, UCC, or clinic care between 2001 and 2005 from an urban regional pediatric hospital system were identified from poisoning ICD-9 codes in the hospital administrative data and from a poisoning designation in the National Electronic Injury Surveillance System (NEISS) data. Cases (n = 2,494) were reviewed and categorized as either toxic or nontoxic. Toxic exposures were those with more than minimal potential for clinical effects. Most cases were between 1 and 2 years old, male, White, enrolled in Medicaid, sought ED care, had no referring physician, and brought to the facility by a parent/guardian. Logistic regression analysis revealed that the odds of seeking healthcare for a nontoxic poisoning exposure were significantly greater if the child was African American, enrolled in Medicaid, had a non-medication related poisoning, and was brought to the healthcare site by a parent/guardian. Healthcare costs and unnecessary use of healthcare resources for nontoxic poisoning exposures could be reduced by educating parents and providers of children at high risk for inappropriate healthcare visits for nontoxic poisonings to initially contact the poison control center (1-800-222-1222). PMID- 20195894 TI - A national survey of training and smoking cessation services provided in community pharmacies in Thailand. AB - Over the past few years, several training programs have been run in support of smoking cessation services within community pharmacy circles in Thailand. These have included a comprehensive training program offered by the Thai Pharmacy Network for Tobacco Control (TPNTC) and brief training programs run by other agencies. This study provides an estimate of the scale of smoking cessation activities among Thai pharmacies, and examines the impact of both the brief and comprehensive training programs on the provision of smoking cessation services. A self-administered questionnaire was mailed to 3,600 Thai community pharmacists. A total of 1,001 questionnaires were returned (response rate: 27.8%). Smoking cessation services were provided by 71.1% of the respondents, and 47.4% of such services gave only brief advice. Comprehensive services (defined by the 5A's: ask, advise, assess, assist, and arrange follow-up) accounted for 15.3% of the respondents. Only 293 pharmacists (29.6%) said they had received cessation training; 62.5% of whom had received such training from TPNTC. The receipt of brief and comprehensive training was associated with a higher rate of the provision of brief advice, when compared with no training, showing adjusted odds ratios (ORs) of 2.93 (95% CI, 1.66-5.18) and 5.93 (95% CI, 3.18-10.17) respectively, while evidence of differences between these training programs was not observed, having an adjusted OR of 1.94 (95% CI, .89-4.21). TPNTC trained pharmacists were 4.98 times (95% CI, 2.24-11.05) more likely than those who received other brief training to provided the 5A's cessation services. All types of training program help to promote the provision of brief counseling by pharmacists. Comprehensive training is associated with the increased provision of both 4A's and 5A's cessation services. PMID- 20195895 TI - Differential effects of adult court transfer on juvenile offender recidivism. AB - Prior research indicates that adolescent offenders transferred to adult court are more likely to recidivate than those retained in the juvenile system. The studies supporting this conclusion, however, are limited in addressing the issue of heterogeneity among transferred adolescents. This study estimates the effect of transfer on later crime using a sample of 654 serious juvenile offenders, 29% of whom were transferred. We use propensity score matching to reduce potential selection bias, and we partition the sample on legal characteristics to examine subgroup effects. We find an overall null effect of transfer on re-arrest, but evidence of differential effects of transfer for adolescents with different offending histories. These results suggest that evaluating the effects of transfer for all transferred adolescents together may lead to misguided policy conclusions. PMID- 20195896 TI - Exploring intergenerational relations in a multi-cultural context: the example of filial responsibility in Mauritius. AB - The purpose of this study is to explore attitudes towards filial responsibility amongst dyads of parents and young adult children using qualitative data from Mauritius, and to draw on the intergenerational solidarity-conflict and ambivalence frameworks to see whether they provide relevant interpretive tools for understanding these attitudes in a multi-cultural society. The study shows that although both generations agree that younger kin should support parents in later life, their motives vary: parents' attitudes reflect norms of obligation, children those of reciprocity; parents want autonomy and independence, but are ambivalent about expectations of future support. Both generations think providing support will be mediated by past parent-child relationships, socialization experiences, gender expectations and cultural tradition. The study suggests that attitudes towards filial responsibility are influenced by a broad set of mechanisms, which can be equated with concepts of structure, function, association, consensus and norm, as well as conflict and ambivalence. PMID- 20195897 TI - Vacuolated oocytes: fertilization and embryonic arrest following intra cytoplasmic sperm injection in a patient exhibiting persistent oocyte macro vacuolization--case report. AB - PURPOSE: To describe a case of homogeneous macro vacuolar formation in oocytes from a patient undergoing IVF/ICSI over 3 cycles and implications thereof. METHODS: Case report and analysis of cycle outcomes including spindle visualization to determine severity of internal disruption caused. RESULTS: Characteristic macro vacuoles (>25 microm diameter) were identified in the vast majority of oocytes. Spindle visualization identified that macro vacuoles were not associated with spindle displacement. IVF resulted in failed fertilization. Low numbers of fertilized oocytes were obtained through ICSI. The vast majority of embryos exhibited maturation arrest on day 2. CONCLUSIONS: It is likely that persistent Oocyte Macro Vacuolization is the cause of infertility in this patient. It probably has a biological basis and possibly a genetic cause, resulting in either uncontrollable endocytosis or poor exocytosis and consequent vacuolar formation. PMID- 20195898 TI - On chilling oocytes and secrets in sperm. PMID- 20195899 TI - Potential liability of reproductive endocrinologists for high order multiple gestation. AB - BACKGROUND: In light of the recent octuplet birth and the accompanying intensive media coverage, there has been much attention on high order multiple births resulting from assisted reproductive technology. OBJECTIVES: The purpose of this commentary is to review 1) the relative contribution of ART to high order multiple gestation and its impact on infant morbidity, mortality, and health care dollar loss; 2) American Society of Reproductive Medicine's guidelines for the number of embryos transferred in ART; and 3) how reproductive endocrinologists can lessen their exposure to litigation by following the ASRM guidelines for the number of embryos transferred and documenting proper informed consent in the medical records. RECOMMENDATIONS: In situations in which the number of embryos transferred is in excess of the ASRM guidelines, justification for deviating from the ASRM guidelines should be justifiable and documented in the medical records. PMID- 20195900 TI - Shift in oligosaccharide specificities of hemagglutinin and neuraminidase of influenza B viruses resistant to neuraminidase inhibitors. AB - Influenza virus neuraminidase inhibitors (NAIs), currently used as anti-influenza drugs, can lead to the appearance of drug-resistant variants. Resistance to NAIs appears due to mutations in the active site of the neuraminidase (NA) molecule that decrease the NA enzymatic activity and sometimes in the hemagglutinin (HA) that decrease its affinity for cell receptors and, therefore, reduce the requirement for NA activity in releasing mature virions from infected cells. Using a set of sialo-oligosaccharides, we evaluated changes in the receptor binding specificity of the HA and substrate specificity of the NA of influenza B viruses that had acquired resistance to NAIs. The oligosaccharide specificity of two pairs of field influenza B viruses, namely: i) B/Memphis/20/96 and its NAI resistant variant, B/Memphis/20-152K/96, containing mutation R152K in the NA and 5 amino acid substitutions in the HA1, and ii) B/Hong Kong/45/2005 and its NAI resistant variant B/Hong Kong/36/2005, containing a single R371K mutation in the NA, was evaluated. Wild type viruses bound strictly to a "human type" receptor, alpha2-6-sialo-oligosaccharide 6;SLN, but desialylated it is approximately 8 times less efficiently than the alpha2-3 sialosaccharides. Both drug-resistant viruses demonstrated the ability to bind to "avian type" receptors, alpha2-3 sialo-oligosaccharides (such as 3;SLN), whereas their affinity for 6;SLN was noticeably reduced in comparison with corresponding wild type viruses. Thus, the development of the NAI resistance in the studied influenza B viruses was accompanied by a readjustment of HA-NA oligosaccharide specificities. PMID- 20195901 TI - Diversity and identification of methanogenic archaea and sulphate-reducing bacteria in sediments from a pristine tropical mangrove. AB - Mangrove sediments are anaerobic ecosystems rich in organic matter. This environment is optimal for anaerobic microorganisms, such as sulphate-reducing bacteria and methanogenic archaea, which are responsible for nutrient cycling. In this study, the diversity of these two functional guilds was evaluated in a pristine mangrove forest using denaturing gradient gel electrophoresis (DGGE) and clone library sequencing in a 50 cm vertical profile sampled every 5.0 cm. DGGE profiles indicated that both groups presented higher richness in shallow samples (0-30 cm) with a steep decrease in richness beyond that depth. According to redundancy analysis, this alteration significantly correlated with a decrease in the amount of organic matter. Clone library sequencing indicated that depth had a strong effect on the selection of dissimilatory sulphate reductase (dsrB) operational taxonomic units (OTUs), as indicated by the small number of shared OTUs found in shallow (0.0 cm) and deep (40.0 cm) libraries. On the other hand, methyl coenzyme-M reductase (mcrA) libraries indicated that most of the OTUs found in the shallow library were present in the deep library. These results show that these two guilds co-exist in these mangrove sediments and indicate important roles for these organisms in nutrient cycling within this ecosystem. PMID- 20195902 TI - Newborn screening strategies for congenital hypothyroidism: an update. AB - It is the purpose of this article to briefly review the initial development and subsequent evolution of newborn screening programs to detect infants with congenital hypothyroidism (CH) and then to provide an update of the advantages and disadvantages of the main test strategies. Pilot programs began screening newborn populations in North America in the mid-1970s using either primary thyroxine (T4)-follow-up thyroid stimulating hormone (TSH) or primary TSH testing. Many programs in the United States and around the world continue to prefer a primary T4-follow-up TSH test strategy. This approach has the advantage of detecting infants with primary CH, as well as cases of hypopituitary hypothyroidism, by follow-up of infants with a T4 below an absolute cutoff or with a persistently low T4 level, necessitating a higher recall rate. With increasing assay sensitivity and specificity, several programs in the United States and worldwide have elected to switch to a primary TSH test strategy. This test strategy has the advantage of detecting primary CH and subclinical hypothyroidism and at a lower recall rate. Programs considering switching to a primary TSH test strategy need to develop age-related TSH cutoffs to maintain an acceptable recall rate. Both test strategies have the potential to detect infants with CH characterized by "delayed TSH rise," but only if they collect a routine or discretionary second specimen, now recommended in low-birth-weight and acutely ill infants. Lastly, a lower TSH cutoff appears to be one of the explanations for the recently described increased incidence of CH. PMID- 20195904 TI - Phospholipase and esterase production by clinical strains of Fonsecaea pedrosoi and their interactions with epithelial cells. AB - Fonsecaea pedrosoi is the major etiologic agent of chromoblastomycosis. The virulence of F. pedrosoi is a meagerly explored phenomenon. The ability to interact with host cells and the production of hydrolytic enzymes are thought to be important virulence mechanisms of fungal pathogens. Here, we measured the production of two distinct lipolytic enzymes, phospholipase and esterase, by three clinical strains of F. pedrosoi isolated from chromoblastomycosis lesions, as well as their capabilities to interact with epithelial cells. All the strains were excellent esterase producers, generating elevated hydrolytic halos after 5 days of growth. Conversely, phospholipase activity was detected only after 10 days, except for the most recent strain of F. pedrosoi (Mage) in which measurable phospholipase activity was detected on day 5. The ability to interact with epithelial cells was also investigated. Regarding the adhesion capability, an indirect connection was observed in relation to the adaptation time of each strain in axenic culture, in which Mage strain showed the best adhesion ability followed by LDI 11428 and 5VPL strains. Both 5VPL and Mage strains were also detected inside the epithelial cells, while the LDI 11428 strain was rarely detected in cytoplasmatic vacuolar compartments. Moreover, these F. pedrosoi strains were able to cause injury in epithelial cells. PMID- 20195905 TI - Validation of the PAGI-SYM and PAGI-QOL among healing and maintenance of erosive esophagitis clinical trial participants. AB - BACKGROUND AND AIMS: Valid instruments are needed to assess important patient reported outcomes (PROs) in erosive esophagitis (EE). METHODS: Data from 4,092 patients in clinical trials to determine efficacy of dexlansoprazole MR to heal EE and maintain healed EE were used to assess the psychometric properties of the Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life (PAGI-QOL) and the PAGI-Symptoms Severity Index (PAGI-SYM). A daily diary, gastroesophageal reflux disease (GERD) Symptoms Investigator Assessment and endoscopy results were also used in this study. RESULTS: PAGI-QOL and PAGI-SYM subscales and total score internal consistency reliability estimates for both studies were acceptable (Cronbach's alpha coefficient = 0.81-0.97). Most subscale and total scores yielded moderate-to-strong correlations with other measures reflecting signs and symptoms of EE. Some subscales were able to detect differences >1 standard error of measurement (SEM) in change scores among patients with improved heartburn frequency compared to those with stable/worsening heartburn frequency in the healing study. Those with relapsed EE demonstrated differences >1 SEM in some PAGI-QOL and PAGI-SYM subscale or total scores compared to patients who maintained their healing status. CONCLUSION: The findings of this study support the consideration of the PAGI-QOL and PAGI-SYM in future clinical trials and in the general EE population. PMID- 20195903 TI - A general introduction to the biochemistry of mitochondrial fatty acid beta oxidation. AB - Over the years, the mitochondrial fatty acid beta-oxidation (FAO) pathway has been characterised at the biochemical level as well as the molecular biological level. FAO plays a pivotal role in energy homoeostasis, but it competes with glucose as the primary oxidative substrate. The mechanisms behind this so-called glucose-fatty acid cycle operate at the hormonal, transcriptional and biochemical levels. Inherited defects for most of the FAO enzymes have been identified and characterised and are currently included in neonatal screening programmes. Symptoms range from hypoketotic hypoglycaemia to skeletal and cardiac myopathies. The pathophysiology of these diseases is still not completely understood, hampering optimal treatment. Studies of patients and mouse models will contribute to our understanding of the pathogenesis and will ultimately lead to better treatment. PMID- 20195906 TI - Restless legs syndrome and its relationship with anxiety, depression, and quality of life in cancer patients undergoing chemotherapy. AB - OBJECTIVE: Restless legs syndrome (RLS) is a common sensorimotor disorder characterized by uncomfortable and unpleasant sensations in the legs that are relieved by movement. This study evaluated the prevalence of RLS in a consecutive series of cancer patients during chemotherapy and examined the relationship between presence of RLS and quality of life, anxiety, and depressive symptoms in these patients. METHODS: RLS was assessed according to the International RLS Study Group essential diagnostic criteria in two stages: a screening questionnaire first, followed by a sleep specialist-conducted structured diagnostic interview. The following questionnaires were administered: Functional Assessment of Cancer Therapy-General (FACT-G) for Quality-of-life (QoL) assessment; Hospital Anxiety and Depression Scale (HADS) to evaluate the levels of anxiety and depression; and Mini Mental Adjustment to Cancer Scale (Mini-MAC) to assess coping styles. RESULTS: A total of 257 patients were evaluated. Among them 56 were identified by the screening questionnaire to meet the criteria for RLS and 47 of whom were confirmed as affected by RLS after a structured interview, rendering a prevalence rate of 18.3%. RLS was significantly more frequent in women than men (23.7 vs. 11.8%; P = 0.01), and in patients receiving antineoplastic therapies for more than 3 months than their counterpart (21.8 vs. 10.8%; P = 0.03). Compared with those without RLS, patients with RLS had higher levels of anxiety (P = 0.0009) and depression (P = 0.001) and lower quality of life (P = 0.006). Sex-chemotherapy-duration-adjusted odds ratios of anxiety and physical well-being associated with RLS were 1.1 (95% CI 1.00-1.19; P = 0.04) and 0.7 (95% CI 0.43-1.01; P = 0.04), respectively. CONCLUSIONS: The prevalence of RLS in cancer patients undergoing chemotherapy is 18.3%, about double of that expected in the general population. The occurrence of RLS is much more frequent in female patients and with longer-term chemotherapy. Cancer patients afflicted by RLS have significantly higher levels of anxiety and depression, and poorer quality of life especially in the physical well-being dimension. Recognition and treatment of RLS in cancer patients is an important target in clinical management and may improve quality of life and overall health outcomes in these patients. PMID- 20195907 TI - An insertional mutagenesis system for analyzing the Chinese cabbage genome using Agrobacterium T-DNA. AB - In this study, we applied insertional mutagenesis using Agrobacterium transfer DNA to functionally characterize the gene of Brassica rapa L. ssp. pekinensis. The specific objectives were to: (i) develop and apply a gene tagging system using plasmid rescue and inverse PCR, (ii) select and analyze mutant lines, and (iii) analyze the phenotypic characteristics of mutants. A total of 3,400 insertional mutant lines were obtained from the Chinese cabbage cultivar, 'seoul', using optimized condition. Plasmid rescue was performed successfully for transgenic plants with multiple T-DNA insertions, and inverse PCR was performed for plants with a single copy. The isolated flanking DNA sequences were blasted against the NCBI database and mapped to a linkage map. We determined the genetic loci in B. rapa with two methods: RFLP using the rescue clones themselves and sequence homology analysis to the B. rapa sequence database by queries of rescued clones sequences. Compared to wild type, the T(1) progenies of mutant lines showed variable phenotypes, including hairless and wrinkled leaves, rosette-type leaves, and chlorosis symptoms. T-DNA inserted mutant lines were the first population that we developed and will be very useful for functional genomics studies of Chinese cabbage. PMID- 20195908 TI - Characterization of particle number concentrations and PM2.5 in a school: influence of outdoor air pollution on indoor air. AB - BACKGROUND, AIM AND SCOPE: The impact of air pollution on school children's health is currently one of the key foci of international and national agencies. Of particular concern are ultrafine particles which are emitted in large quantities, contain large concentrations of toxins and are deposited deeply in the respiratory tract. MATERIALS AND METHODS: In this study, an intensive sampling campaign of indoor and outdoor airborne particulate matter was carried out in a primary school in February 2006 to investigate indoor and outdoor particle number (PN) and mass concentrations (PM(2.5)), and particle size distribution, and to evaluate the influence of outdoor air pollution on the indoor air. RESULTS: For outdoor PN and PM(2.5), early morning and late afternoon peaks were observed on weekdays, which are consistent with traffic rush hours, indicating the predominant effect of vehicular emissions. However, the temporal variations of outdoor PM(2.5) and PN concentrations occasionally showed extremely high peaks, mainly due to human activities such as cigarette smoking and the operation of mower near the sampling site. The indoor PM(2.5) level was mainly affected by the outdoor PM(2.5) (r = 0.68, p < 0.01), whereas the indoor PN concentration had some association with outdoor PN values (r = 0.66, p < 0.01) even though the indoor PN concentration was occasionally influenced by indoor sources, such as cooking, cleaning and floor polishing activities. Correlation analysis indicated that the outdoor PM(2.5) was inversely correlated with the indoor to outdoor PM(2.5) ratio (I/O ratio; r = -0.49, p < 0.01), while the indoor PN had a weak correlation with the I/O ratio for PN (r = 0.34, p < 0.01). DISCUSSION AND CONCLUSIONS: The results showed that occupancy did not cause any major changes to the modal structure of particle number and size distribution, even though the I/O ratio was different for different size classes. The I/O curves had a maximum value for particles with diameters of 100-400 nm under both occupied and unoccupied scenarios, whereas no significant difference in I/O ratio for PM(2.5) was observed between occupied and unoccupied conditions. Inspection of the size-resolved I/O ratios in the preschool centre and the classroom suggested that the I/O ratio in the preschool centre was the highest for accumulation mode particles at 600 nm after school hours, whereas the average I/O ratios of both nucleation mode and accumulation mode particles in the classroom were much lower than those of Aitken mode particles. RECOMMENDATIONS AND PERSPECTIVES: The findings obtained in this study are useful for epidemiological studies to estimate the total personal exposure of children, and to develop appropriate control strategies for minimising the adverse health effects on school children. PMID- 20195909 TI - Extractable organic matter of standard reference material 1649a influences immunological response induced by pathogen-associated molecular patterns. AB - BACKGROUND, AIM, AND SCOPE: Lungs are permanently and simultaneously challenged by airborne microorganisms and airborne pollutants. Temporal increase of airborne particulate matter (APM), a potential carrier for extractable organic matter (EOM), degrades the situation of pulmonary patients. The Ah receptor (AhR) has been described as an important factor influencing the immunological challenge by viral infections. Molecular mechanisms underlying epidemiological observations are not well understood. Cytokine secretion (IL-6, IL-8, and TGF-beta) from human bronchial epithelial cells (Beas2B) was determined as an indicator for immune responses upon co-stimulation with an artificial analog of viral dsRNA [polyinosinic/polycytidylic acid, (PIC)] and EOM of Standard Reference Material 1649a (SRM). Since polycyclic aromatic hydrocarbons are major components of APM usually acting via the AhR, particular focus was on AhR involvement. MATERIALS AND METHODS: Cytokine secretion was demonstrated by enzyme-linked immunosorbent assay. To mimic the activation of organic matter during contact of particles with the human lung, Soxhlet extraction of SRM was performed. In some experiments, the AhR was blocked by alpha-naphthoflavone. RESULTS: Microbial stimulation (PIC) induced Beas2B cytokine release, whereas isolated exposure to EOM of APM did not. Co-stimulation with EOM and PIC increased IL-8 secretion, whereas neither IL-6 nor TGF-beta was affected. Blocking of the AhR suppressed the release of IL-8. DISCUSSION: Organic compounds adsorbed on airborne particulate matter influence the cytokine secretion of lung epithelial cells induced by pathogen-associated molecular patterns. RECOMMENDATIONS AND PERSPECTIVES: Further investigation of these observations is required to understand the molecular mechanisms underlying adverse health effects of APM reported in epidemiological studies. PMID- 20195910 TI - Estimation of cell proliferation dynamics using CFSE data. AB - Advances in fluorescent labeling of cells as measured by flow cytometry have allowed for quantitative studies of proliferating populations of cells. The investigations (Luzyanina et al. in J. Math. Biol. 54:57-89, 2007; J. Math. Biol., 2009; Theor. Biol. Med. Model. 4:1-26, 2007) contain a mathematical model with fluorescence intensity as a structure variable to describe the evolution in time of proliferating cells labeled by carboxyfluorescein succinimidyl ester (CFSE). Here, this model and several extensions/modifications are discussed. Suggestions for improvements are presented and analyzed with respect to statistical significance for better agreement between model solutions and experimental data. These investigations suggest that the new decay/label loss and time dependent effective proliferation and death rates do indeed provide improved fits of the model to data. Statistical models for the observed variability/noise in the data are discussed with implications for uncertainty quantification. The resulting new cell dynamics model should prove useful in proliferation assay tracking and modeling, with numerous applications in the biomedical sciences. PMID- 20195911 TI - A state space transformation can yield identifiable models for tracer kinetic studies with enrichment data. AB - Tracer studies are analyzed almost universally by multicompartmental models where the state variables are tracer amounts or activities in the different pools. The model parameters are rate constants, defined naturally by expressing fluxes as fractions of the source pools. We consider an alternative state space with tracer enrichments or specific activities as the state variables, with the rate constants redefined by expressing fluxes as fractions of the destination pools. Although the redefinition may seem unphysiological, the commonly computed fractional synthetic rate actually expresses synthetic flux as a fraction of the product mass (destination pool). We show that, for a variety of structures, provided the structure is linear and stationary, the model in the enrichment state space has fewer parameters than that in the activities state space, and is hence better both to study identifiability and to estimate parameters. The superiority of enrichment modeling is shown for structures where activity model unidentifiability is caused by multiple exit pathways; on the other hand, with a single exit pathway but with multiple untraced entry pathways, activity modeling is shown to be superior. With the present-day emphasis on mass isotopes, the tracer in human studies is often of a precursor, labeling most or all entry pathways. It is shown that for these tracer studies, models in the activities state space are always unidentifiable when there are multiple exit pathways, even if the enrichment in every pool is observed; on the other hand, the corresponding models in the enrichment state space have fewer parameters and are more often identifiable. Our results suggest that studies with labeled precursors are modeled best with enrichments. PMID- 20195912 TI - Self-tolerance and autoimmunity in a regulatory T cell model. AB - The class of immunosuppressive lymphocytes known as regulatory T cells (Tregs) has been identified as a key component in preventing autoimmune diseases. Although Tregs have been incorporated previously in mathematical models of autoimmunity, we take a novel approach which emphasizes the importance of professional antigen presenting cells (pAPCs). We examine three possible mechanisms of Treg action (each in isolation) through ordinary differential equation (ODE) models. The immune response against a particular autoantigen is suppressed both by Tregs specific for that antigen and by Tregs of arbitrary specificities, through their action on either maturing or already mature pAPCs or on autoreactive effector T cells. In this deterministic approach, we find that qualitative long-term behaviour is predicted by the basic reproductive ratio R(0) for each system. When R(0)<1, only the trivial equilibrium exists and is stable; when R(0)>1, this equilibrium loses its stability and a stable non-trivial equilibrium appears. We interpret the absence of self-damaging populations at the trivial equilibrium to imply a state of self-tolerance, and their presence at the non-trivial equilibrium to imply a state of chronic autoimmunity. Irrespective of mechanism, our model predicts that Tregs specific for the autoantigen in question play no role in the system's qualitative long-term behaviour, but have quantitative effects that could potentially reduce an autoimmune response to sub clinical levels. Our results also suggest an important role for Tregs of arbitrary specificities in modulating the qualitative outcome. A stochastic treatment of the same model demonstrates that the probability of developing a chronic autoimmune response increases with the initial exposure to self antigen or autoreactive effector T cells. The three different mechanisms we consider, while leading to a number of similar predictions, also exhibit key differences in both transient dynamics (ODE approach) and the probability of chronic autoimmunity (stochastic approach). PMID- 20195913 TI - Conditions for global dynamic stability of a class of resource-bounded model ecosystems. AB - This paper studies a class of dynamical systems that model multi-species ecosystems. These systems are 'resource bounded' in the sense that species compete to utilize an underlying limiting resource or substrate. This boundedness means that the relevant state space can be reduced to a simplex, with coordinates representing the proportions of substrate utilized by the various species. If the vector field is inward pointing on the boundary of the simplex, the state space is forward invariant under the system flow, a requirement that can be interpreted as the presence of non-zero exogenous recruitment. We consider conditions under which these model systems have a unique interior equilibrium that is globally asymptotically stable. The systems we consider generalize classical multi-species Lotka-Volterra systems, the behaviour of which is characterized by properties of the community (or interaction) matrix. However, the more general systems considered here are not characterized by a single matrix, but rather a family of matrices. We develop a set of 'explicit conditions' on the basis of a notion of 'uniform diagonal dominance' for such a family of matrices, that allows us to extract a set of sufficient conditions for global asymptotic stability based on properties of a single, derived matrix. Examples of these explicit conditions are discussed. PMID- 20195914 TI - Autoimmune esophagitis: IgG4-related tumors of the esophagus. AB - We present a case of a 23-year-old gentleman who presented with dysphagia, weight loss, and recurrent esophageal strictures requiring multiple dilatations. An endoscopic ultrasound with esophagogastroduodenoscopy revealed a mass present in the distal esophagus. Fine needle aspiration suggested that the mass in the lower esophagus resembled a gastrointestinal stromal tumor. After surgical resection, final pathologic analysis revealed that the tumor was comprised of benign appearing fibroinflammatory cells with an increase and predominance of IgG4 positive plasma cells. The microscopic appearance was consistent with a benign condition as a result of an IgG4-related process. He did not, however, have any other symptoms indicative of systemic autoimmune disease or connective tissue disorders. We present the pre-operative imaging, operative management, pathologic diagnosis, and literature review of this rare condition and the first known report of autoimmune esophagitis as part of the IgG4 spectrum of diseases. PMID- 20195916 TI - Iodine distribution in the environment as a limiting factor for roe deer antler development. AB - The iodine-containing hormones produced by the thyroid gland play a role in the complex neuro-hormonal regulation of antler development. The proper function of the thyroid depends on the adequate iodine supply of the organism, which is directly related to the iodine content of food and drinking water. The purpose of this study was to explore the connection between the iodine content of the water base, which has a strong correlation with the iodine concentration of environmental components available to animals, and the antler weight of roe deer (Capreolus capreolus) shot in Hungarian hunting areas. Using a general linear model, controlling for the collective effects of other environmental factors (deer population density, harvest rate, land use, and soil fertility information), the iodine content of the water base explained 51.4% of the total variance of antler weights. The results suggest that antler weights increase with increasing iodine concentration regardless of other factors; thus, the environmental iodine distribution can be a limiting factor suppressing roe deer performance assessed here as antler weight. Further experimental studies of controlled iodine uptake are needed to define the exact physiological iodine requirements of roe deer bucks. PMID- 20195915 TI - Conservative and surgical treatment of chronic anal fissure: prospective longer term results. AB - INTRODUCTION: The aim of this prospective study was to assess the efficacy of different medical treatments and surgery in the treatment of chronic anal fissure (CAF). PATIENTS AND METHODS: From January 2004 to March 2009, 311 patients with typical CAF completed the study. All patients were initially treated with 0.2% nitroglycerin ointment (GTN) or anal dilators (DIL) for 8 weeks. If no improvement was observed after 8 weeks, the patients were assigned to the other treatment or a combination of the two. Persisting symptoms after 12 weeks or recurrence were indications for either botulinum toxin injection into the internal sphincter and fissurectomy or lateral internal sphincterotomy (LIS). During the follow-up (29 +/- 16 months), healing rates, symptoms, incontinence scores, and therapy adverse effects were prospectively recorded. RESULTS: Overall healing rates were 64.6% and 94% after GTN/DIL or BTX/LIS. Healing rate after GTN or DIL after 12 weeks course were 54.5% and 61.5%, respectively. Fifty-four patients (17.4%) responded to further medical therapy. One hundred two patients (32.8%) underwent BTX or LIS. Healing rate after BTX was 83.3% and overall healing after LIS group was 98.7% with no definitive incontinence. CONCLUSION: In conclusion, although LIS is far more effective than medical treatments, BTX injection/fissurectomy as first line treatment may significantly increase the healing rate while avoiding any risk of incontinence. PMID- 20195917 TI - Dietary intake and serum and hair concentrations of minerals and their relationship with serum lipids and glucose levels in hypertensive and obese patients with insulin resistance. AB - Inadequate minerals intake, as well as disruption of some metabolic processes in which microelements are cofactors, are suggested to lead to the development of hypertension. The role of minerals in the pathogenesis of hypertension still remains to be explained. In the present study, we sought to determine associations between serum and hair mineral concentrations and serum lipids and glucose levels. Forty obese hypertensive subjects with insulin resistance and 40 healthy volunteers were recruited in the study. Blood pressure, BMI, and insulin resistance were recorded in all subjects. Levels of lipids, glucose, sodium and potassium, iron, copper, zinc, magnesium, and calcium were assessed in serum. Iron, copper, zinc, magnesium, and calcium were assessed in hair. Dietary intake of the analyzed minerals was estimated. We found distinctly higher concentrations of serum iron and serum and hair calcium as well as markedly lower levels of hair zinc in the hypertensive subjects. The study group manifested also significantly lower daily intake of calcium, magnesium, and iron. We observed a relationship between the concentrations of iron, zinc, and copper in serum and hair and high and low range of cholesterol, triglycerides, and glucose serum levels in the studied patients. Moreover, this study demonstrated significant correlation between serum and hair concentrations of selected minerals and their dietary intake and levels of serum lipids and glucose and blood pressure in the study and the control groups. The obtained results seem to indicate the association between lipid and glucose metabolism and iron, copper, zinc, and calcium concentrations in blood and hair of hypertensive and obese patients with insulin resistance. PMID- 20195918 TI - Maternal-fetal distribution of calcium, iron, copper, and zinc in pregnant teenagers and adults. AB - Adolescence is marked by intensive growth and development. When pregnancy occurs during this period of the mother's growth, there is an increase in her nutritional needs. The aim of this study was to determine the levels of calcium, iron, copper, and zinc in maternal plasma, the placenta, and in the cord plasma of pregnant teenagers and adults. A total of 80 sets of maternal plasma, placentas, and cord plasma (40 from teenagers and 40 from adults) were analyzed using synchrotron radiation total reflection X-ray fluorescence. The levels of calcium, copper, and zinc in the maternal and cord plasma from teenagers were not significantly different than those from adults. Iron levels in the teenagers maternal and cord plasma were higher than in the adults. All of the minerals analyzed were present at higher levels in the placentas from adults than those from teenagers. However, the low quantities of placental calcium, iron, copper, and zinc in the teenagers do not compromise the levels of these minerals in the cord plasma. Future research regarding the placental transport of these minerals is recommended to investigate the efficiency of mechanisms of transfer of these minerals in pregnant teenagers. PMID- 20195919 TI - Elements in sera of elite taekwondo athletes: effects of vitamin E supplementation. AB - Many researchers have emphasized the relation between nutrition and development and sustaining performance. Two methods are commonly employed to identify the interaction between physical activity and nutrition. The first consists of administering food with a variety of contents to people engaged in physical activity and observing their performance responses, and the other is concerned with determining the effects of physical activity on nutrition. Therefore, it can be said that there has been a growing interest in the explorations into the relation between exercise and vitamins, minerals, and elements. The present study reports the effects of 6 weeks administration of 300 mg/day vitamin E on the distribution of serum elements in elite taekwondo athletes. Seven male athletes, mean ages 22.1 +/- 0.5 years weighing on average 66.4 +/- 2.4 kg were included in the study. The athletes had been practicing taekwondo for 10-12 years. Resting blood samples were collected in duplicate before and after supplementation for determination of serum levels of cobalt, boron, cadmium, chromium, nickel, manganese, sulfur, copper, iron, zinc, phosphorus, sodium, potassium, and calcium. Supplementation resulted in significant increases of all elements relative to values before supplementation (p < 0.001), with the exception of boron and sulfur, which remained without change. The results of the present study demonstrate that vitamin E supplementation crucially influences the element and mineral metabolism in elite athletes. PMID- 20195920 TI - Low cadmium levels in urine of residents in two prefectures where cadmium levels in locally harvested brown rice are higher than in other prefectures in Japan. AB - Recent publications in Japan suggest that Cd in river beds and locally harvested rice tend to be higher in seven prefectures in the north-eastern part on the coast of the Sea of Japan (the high-Cd zone). The present study was initiated to investigate the current level of exposure to Cd and possible health effects among local populations in the zone. Thus, levels of Cd and three tubular dysfunction markers [i.e., alpha(1)-MG, beta(2)-MG, and N-acetyl-beta-D-glucosaminidase (NAG)] were examined in urine of local residents (700 and 704 adult women, respectively) in two prefectures (prefecture 1 and prefecture 7), which were located in the north-east (prefecture 1) and south-west ends (prefecture 7) of the high-Cd zone. Urinary Cd levels [e.g., 0.99 and 0.78 MUg/l as geometric mean (GM) for observed (non-corrected) values, respectively] in prefecture 1 and prefecture 7 were comparable to the levels in other parts of Japan (All Japan-A; 0.99 MUg/l). Correspondingly, GM values for alpha(1)-MG (2.29 and 1.99 mg/l vs. 2.17 mg/l for All Japan-A) and for beta(2)-MG (87 and 80 MUg/l vs. 99 MUg/l for All Japan-A) were not elevated, and NAG also stayed unchanged (2.89 and 2.87 units/l for prefecture 1 and prefecture 7, respectively). Evaluation in combination with the findings in other five prefectures in the zone suggests that Cd exposure is equal to the national average both in prefecture 1 and in prefecture 7, whereas Cd exposure appeared to be elevated in the central part of the zone. The observation appears to be on line with geographical location of the two prefectures that they are on the two ends of the zone of high natural Cd background. PMID- 20195921 TI - The cell cycle arrest and apoptosis of bursa of Fabricius induced by low selenium in chickens. AB - The purpose of this 42-day study was to investigate the effects of low selenium (Se) on immune function by determining cell cycle and apoptosis of bursa of Fabricius. One hundred twenty 1-day-old avian broilers were randomly assigned to two groups of 60 each and were fed on a low Se diet (0.0342 mg/kg Se) or a control diet (0.2 mg/kg Se), respectively. The relative weight of bursa was significantly decreased in low Se group from 28 days of age in time-dependent manner when compared with that of control group. Cell cycle analysis by flow cytometry showed that low Se caused an increase in G0G1 phase cells that corresponded to a decrease in S phase cells in bursa of Fabricius. Ultrastructurally, mitochondria injury and increased apoptotic cells with condensed nuclei were observed. Low Se increased the percentage of Annexin V positive cells, as measured by flow cytometry, in comparison with that of control group. These data suggested that low Se diet restrained the development of bursa of Fabricius by cell cycle arrest and apoptosis. PMID- 20195922 TI - Spectroscopic studies on the interaction of fluorine containing triazole with bovine serum albumin. AB - The binding of one fluorine including triazole (C(10)H(9)FN(4)S, FTZ) to bovine serum albumin (BSA) was studied by spectroscopic techniques including fluorescence spectroscopy, UV-Vis absorption, and circular dichroism (CD) spectroscopy under simulative physiological conditions. Fluorescence data revealed that the fluorescence quenching of BSA by FTZ was the result of forming a complex of BSA-FTZ, and the binding constants (K (a)) at three different temperatures (298, 304, and 310 K) were 1.516 * 10(4), 1.627 * 10(4), and 1.711 * 10(4) mol L(-1), respectively, according to the modified Stern-Volmer equation. The thermodynamic parameters DeltaH and DeltaS were estimated to be 7.752 kJ mol( 1) and 125.217 J mol(-1) K(-1), respectively, indicating that hydrophobic interaction played a major role in stabilizing the BSA-FTZ complex. It was observed that site I was the main binding site for FTZ to BSA from the competitive experiments. The distance r between donor (BSA) and acceptor (FTZ) was calculated to be 7.42 nm based on the Forster theory of non-radioactive energy transfer. Furthermore, the analysis of fluorescence data and CD data revealed that the conformation of BSA changed upon the interaction with FTZ. PMID- 20195923 TI - Muscle calcium metabolic effects of hypokinesia in physically healthy subjects. AB - The incompleteness of electrolyte deposition during hypokinesia (HK; diminished movement) is the defining factor of electrolyte metabolic changes, yet the effect of prolonged HK upon electrolyte deposition is poorly understood. The objective of this investigation was to determine the effect of muscle calcium (Ca(++)) changes upon Ca(++) losses during prolonged HK. Studies were conducted on 20 physically healthy male volunteers during a pre-experimental period of 30 days and an experimental period of 364 days. Subjects were equally divided in two groups: control subjects (CS) and experimental subjects (ES). The CS group ran average distances of 9.2 +/- 1.2 km day(-l), and the ES group walked average distances of 2.3 +/- 0.2 km day(-l). Muscle Ca(++) contents, plasma Ca(++) concentrations, and Ca(++) losses in urine and feces were measured in the experimental and control groups of subjects. The muscle Ca(++) contents decreased (p < 0.05), and plasma Ca(++) levels and Ca(++) losses in the urine and feces increased (p < 0.05) in the ES group compared with their pre-experimental levels and the values in their respective CS group. Muscle Ca(++) contents and plasma Ca(++) levels and urinary and fecal Ca(++) losses did not change in the CS group compared to their pre-experimental levels. It is concluded that prolonged HK increase plasma Ca(++) concentrations and Ca(++) losses in Ca(++) deficient muscle indicating decreased Ca(++) deposition. PMID- 20195924 TI - Oral administration of the high-chromium yeast improve blood plasma variables and pancreatic islet tissue in diabetic mice. AB - The in vivo effects of oral administration of the high-chromium yeast to healthy and diabetic mice are described. Given that these complexes are proposed to function by potentiating the actions of insulin and activating the insulin receptor kinase, changes in lipid and carbohydrate metabolism would be expected. After 15 weeks administration (500 MUg Cr/kg body mass) to healthy mice, abnormal metabolism and pathological change were not observed. After 15 weeks of treatment (0-1,000 MUg Cr/kg body mass) of diabetic mice, the effect of high-chromium yeast on blood lipids and blood glycosylated hemoglobin (GHb) of diabetes are not consistent. High-chromium yeast results in a lowering (P < 0.05) of GHb and triglyceride, lowering (P < 0.01) of total cholesterol, and restoration (P < 0.01) of insulin; these results are in stark contrast to those of diabetic mice of administration of normal yeast, which have no effect on these parameters and serve as control group. The histopathological analysis of pancreas islet shows that high-chromium yeast could profoundly protect the impaired pancreatic islet and beta-cells from inflammatory infiltration and fibrosis. PMID- 20195925 TI - Lead exposure: a contributing cause of the current breast cancer epidemic in Nigerian women. AB - Breast cancer incidence in Nigerian women has significantly increased during the past three decades in parallel with the rapid industrialization of that country. This suggested that the associated widespread contamination of the soil and of the water supplies by lead (Pb) and other industrial metals was a major contributing cause. Because of its many domestic, industrial, and automotive uses, Pb is of particular concern as it has been shown to promote the development of mammary tumors in murine mammary tumor virus-infected female C3H mice at levels as low of 0.5 ppm Pb in the drinking water. Lead belongs to the group of selenium-antagonistic elements that interact with selenium (Se), abolishing its anti-carcinogenic effect. Lead on chronic, low-level exposure in addition also accelerates tumor growth rates. Higher levels of Pb were found in blood and head hair samples of newly diagnosed patients with breast cancer, all with infiltrating ductal carcinoma, the most common form of breast cancer in Nigeria, seen at Obafemi Awolowo University, than in cancer-free controls from the same area. Evidence for interactions between Pb and Se was obtained from blood, hair, and tumor biopsy tissue analyses. Furthermore, the Pb levels in hair samples of the patients were directly correlated with the volumes of their tumors, in accord with the tumor growth-promoting effects of Pb. Conversely, Se levels in hair and blood were inversely correlated with the tumor volumes, consistent with the anti proliferative effects of Se. Several other elements, e.g., Cd, Hg, Cr, Sn, and As, were detected in the scalp hair of the patients and the controls, although at significantly lower levels than those of Pb. However, correlation calculations revealed them also to interact with Se, suggesting that only a fraction of the Se in organs and tissues is actually present in bioactive forms. In metal-exposed subjects, a state of latent Se deficiency may exist, resulting in depressed immune functions and increased cancer susceptibility. Evidence is presented to show that Pb and other metals also interact with iodine, another vitally important essential trace element believed to protect against breast cancer development. Public health programs aiming at lowering the breast cancer risk of Nigerian women thus will have to include effective measures to protect the population from exposures to Pb and other industrial metals that are presently contaminating the environment and the water supplies. PMID- 20195926 TI - Atypical carcinoid with prominent mucinous stroma: a hitherto unreported variant of pulmonary neuroendocrine tumor. AB - Carcinoid tumors of the lung may show several growth patterns and cell types. We report here a previously undescribed case of primary pulmonary atypical carcinoid with prominent mucinous stroma, an exceedingly rare variant of carcinoid tumor so far reported only in the thymus. The tumor was discovered in a 50-year-old, non smoker woman, and pursued an aggressive behavior. The lack of TTF-1 expression and the positive staining with hormonal receptors made the diagnosis very challenging. Differential diagnosis with other primary and metastatic mucin-rich tumors is also discussed. PMID- 20195927 TI - Fondaparinux in major orthopedic surgical patients. PMID- 20195928 TI - Overcoming the effect of rifampin on the tacrolimus metabolism by itraconazole administration in an allogeneic hematopoietic stem cell transplant recipient. PMID- 20195929 TI - Cystatin C level as a marker of renal function in allogeneic hematopoietic stem cell transplantation. AB - We retrospectively reviewed the medical records of 75 allogeneic hematopoietic transplant recipients and evaluated cystatin C as a potential marker of subsequent renal dysfunction. Acute kidney injury developed in 31 of 75 patients after a median of 46 days post-transplantation (range 1-502 days), while worsening of chronic kidney disease (CKD) was observed in 21 patients during the observational period. Cystatin C level was significantly elevated after allogeneic transplantation (P < 0.001). Multivariate analysis revealed the use of calcineurin inhibitors as a major cause of cystatin C elevation (odds ratio 7.26, P = 0.04). A strong inverse correlation was also noted between cystatin C and estimated glomerular filtration rate (r = -0.682, P < 0.001). Cystatin C measurement could provide a useful clinical tool to identify hematopoietic stem cell transplantation recipients at an increased risk for CKD. PMID- 20195930 TI - Preservation of the immunogenicity of dry-powder influenza H5N1 whole inactivated virus vaccine at elevated storage temperatures. AB - Stockpiling of pre-pandemic influenza vaccines guarantees immediate vaccine availability to counteract an emerging pandemic. Generally, influenza vaccines need to be stored and handled refrigerated to prevent thermal degradation of the antigenic component. Requirement of a cold-chain, however, complicates stockpiling and the logistics of vaccine distribution. We, therefore, investigated the effect of elevated storage temperatures on the immunogenicity of a pre-pandemic influenza A H5N1 whole inactivated virus vaccine. Either suspended in liquid or kept as a freeze-dried powder, vaccines could be stored for 1 year at ambient temperature (20 degrees C) with minimal loss of immunogenicity in mice. Elevation of the storage temperature to 40 degrees C, however, resulted in a significant loss of immunogenic potency within 3 months if vaccines were stored in liquid suspension. In sharp contrast, freeze-dried powder formulations were stable at 40 degrees C for at least 3 months. The presence of inulin or trehalose sugar excipients during freeze-drying of the vaccine proved to be critical to maintain its immunogenic potency during storage, and to preserve the characteristic Th1-type response to whole inactivated virus vaccine. These results indicate that whole inactivated virus vaccines may be stored and handled at room temperature in moderate climate zones for over a year with minimal decline and, if converted to dry-powder, even in hot climate zones for at least 3 months. The increased stability of dry-powder vaccine at 40 degrees C may also point to an extended shelf-life when stored at 4 degrees C. Use of the more stable dry-powder formulation could simplify stockpiling and thereby facilitating successful pandemic intervention. PMID- 20195931 TI - Near-infrared investigations of novel anti-HIV tenofovir liposomes. AB - Near-infrared (NIR) approaches is considered one of the most well-studied process analyzers evolving from the process analytical technology initiatives. The objective of this study was to evaluate NIR spectroscopy and imaging to assess individual components within a novel tenofovir liposomal formulation. By varying stearylamine, as a positive charge imparting agent, five batches were prepared by the thin film method. Each formulation was characterized in terms of drug entrapment efficiency, release characteristics, particle sizing, and zeta potential. Drug excipients compatibility was tested using Fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction. The obtained results showed an increase in drug entrapment and a slower drug release by increasing the incorporated percentage of stearylamine. The compatibility testing revealed a significant interaction between the drug and some of the investigated excipients. The developed NIR calibration model was able to assess drug, phospholipid, and stearylamine levels along the batches. The calibration and prediction plots were linear with correlation coefficients of more than 0.9. The root square standard errors of calibration and prediction did not attain 5% of the measured values confirming the accuracy of the model. In contrast, NIR spectral imaging was capable of clearly distinguishing the different batches, both qualitatively and quantitatively. A linear relationship was obtained correlating the actual drug entrapped and the predicted values obtained from the partial least squares images. PMID- 20195934 TI - [The future of the Parkinson syndrome]. PMID- 20195932 TI - [Prevalence of ketotic hypoglycaemia among schoolchildren in the village of Ahoue in Cote-d'Ivoire]. AB - To determine the prevalence of ketotic hypoglycemia among schoolchildren, a descriptive cross-sectional study was conducted in preschools and schools in rural areas that involved 102 schoolchildren, from 4 to 7 years old, comprised 51 girls and 51 boys. Index WHZ was used to evaluate the children's nutritional status. The sampling was obtained by a drop of capillary blood in the pulp of the finger. The determination of glucose was realized by glucose oxidase method using an ultra sensitive and fast (One Touch Ultra) glucometer, and ketonuria was detected by dipstick "Ketodiastix." The clinical results revealed that most of children had a normal birth weight with an average of 2.885 g, a good Apgar's score superior to 7, and then the nutritional index WHZ revealed 3% of severe malnutrition and 34% of moderate malnutrition. Ten children (9.8%) had a hypoglycemia with a median of 0.51 g/l and extreme values going from 0.42 to 0.59 g/l. Seven children had a hypoglycemia associated with ketonuria. The prevalence of ketotic hypoglycemia was 7% in this study, and more frequent in the children between 4 and 5 years with 57% of cases in this age group. Thus, this condition, found in Western countries is a reality in Cote d'Ivoire, where the diathesis of malnutrition (37% of the population of the study) is a favorable factor. Therefore, it is useful to prevent protein-energy malnutrition by a balanced food by avoiding fasting before school by diet management. PMID- 20195935 TI - [Parkinson's disease - the future of invasive therapy]. AB - For the treatment of Parkinson's disease invasive therapies have a long tradition. Deep brain stimulation is a well-established treatment option for the treatment of advanced Parkinson's disease with fluctuations. Further promising interventions for invasive therapy of Parkinson's disease are transplantation of foetal cells and stem cells, gene therapy and the use of duo-dopa and apomorhine. PMID- 20195936 TI - [Pathophysiology of sporadic Parkinson's disease]. AB - Sporadic Parkinson's disease is a multisystem disorder that involves predisposed nerve cell types in circumscribed regions of the entire human nervous system (peripheral, enteric, and central nervous systems). A recent staging procedure for the pathological process proposes that, in the brain, the formation of intraneuronal Lewy bodies and Lewy neurites begins at two sites and continues in a topographically predictable sequence in 6 stages, during which components of the olfactory, autonomic, limbic, and somatomotor systems become progressively involved. In stages 1 - 2, the Lewy body pathology is confined to the medulla oblongata/pontine tegmentum and anterior olfactory structures. In stages 3 - 4, the substantia nigra, other nuclei of the basal mid- and forebrain, and the mesocortex become the focus of initially subtle and, then, severe changes. During this phase, the illness probably becomes clinically manifest. In the final stages 5 - 6, the lesions appear in the neocortex. PMID- 20195937 TI - [Clinical data of the prolonged-release formulation of ropinirole]. AB - Ropinirole is a non-ergoline dopamine agonist with medium elimination half time, which has been licensed for the therapy of idiopathic Parkinson syndrome in mono- and add-on therapy for more than 10 years. Since 2008 a prolonged-release formulation has been available in Germany, which can be taken once daily. This formulation results in less plasma level fluctuations compared to the thrice daily immediate-release formulation enabling smoother dopaminergic therapy with symptomatic efficacy day and night. Ropinirole PR has shown good efficacy and tolerability in controlled trials in monotherapy in early patients as well as in add-on studies in advanced patients. In a head-to-head comparison of both formulations as add-on therapy in advanced patients higher doses were achieved with ropinirole PR accompanied by a higher mean decrease of L-Dopa dose. Under these conditions significantly higher efficacy was observed. The titration regime of ropinirole PR is faster with significant efficacy versus placebo as early as in week 2. Especially in patients with pre-existing Parkinson-related poor sleep quality positive effects on sleep and nocturnal symptoms were shown. PMID- 20195938 TI - [Transcraniel ultrasound in the differential diagnosis of Parkinson's disease]. AB - Imaging of the brain structure with transcranial ultrasound has become an important tool for the diagnosis and differential diagnosis of Parkinson's Disease. In up to 90 % of parkinsonian patients abnormal echogenity of the substantia nigra could be demonstrated. Particularly in the early diagnosis in subjects with only very mild extrapyramidal features and in the differential diagnosis to other neurodegenerative disorders with parkinsonian features, such as the parkinsonian variant of multisystematrophy (MSA-P) and progressive supranuclear paralysis (PSP) ultrasound has a high diagnostic yield. Because of a prevalence of about 10 % in the normal population, the evidence of an abnormal echogenity of the substantia nigra has to be interpreted carefully in the context of a clinical examination. Although there are a number of studies indicating that in some of these subjects a vulnerability of the nigrostriatal system can be found, the meaning of an abnormal echogenicity of the substantia nigra in the healthy population needs to be further elucidated in already ongoing research projects. PMID- 20195939 TI - [When should we start medical treatment in Parkinson disease]. AB - There is still uncertainty when to start medical treatment in Parkinson disease (PD). Lack of availability of an unambiguous neuroprotective treatment and concern of potential short or long term adverse effects of medication often lead to an "wait and see" policy regarding initiation of medical treatment. This can result in insufficient symptom control and potentially reduced quality of life. There is increasing evidence of negative influence on disease progression by delayed onset of medical drug treatment in PD. It is under discussion whether symptomatic treatment in PD supports compensatory mechanisms of the cortico basalganglionar system which might have been responsible for a physically intact motor function despite considerable and increasing nigro-striatal dopaminergic deficit during the preclinical phase of the disease. Therefore, symptomatic treatment might modify disease progression by supporting compensatory mechanisms within the basal ganglia. In this paper we discuss pro and contra of early medical treatment onset in PD under consideration of hitherto available scientific investigations. PMID- 20195940 TI - [On the role of MAO B inhibitors and NMDA antagonists in the therapy of Parkinson's disease]. AB - In this workshop report, the N-methyl-D-aspartate (NMDA) receptor antagonists and the monoamine oxidase (MAO) type B inhibitors are discussed with respect to their role in the pharmacotherapy of Parkinson's Disease (PD). For the NMDA antagonist amantadine, studies demonstrated beneficial effects in various symptoms of the PD complex, while memantine seems to be beneficial in the treatment of cognitive deficits in PD-associated dementia. The MAO B inhibitors selegiline and rasagiline are in use for PD pharmacotherapy; for rasagiline, studies have demonstrated a possible disease-modifying effect. Although not supported by specific controlled studies, a "triple" early therapy is discussed which consists of a dopamine agonist, a MAO B inhibitor and amantadine, in order to try to delay the start of levodopa therapy. PMID- 20195941 TI - [Early deep brain stimulation for Parkinson's disease]. AB - Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a powerful treatment for advanced Parkinson's disease with levodopa-induced motor complications. Randomized controlled studies have shown that motor fluctuations and quality of life are significantly more improved by STN-DBS than by best medical treatment. The main delay before neurosurgery is currently 14 years after diagnosis. Clinical pilot data suggest that neurosurgery performed already with beginning motor fluctuations and an average disease duration of 7 years may lead to earlier improvement of motor deficits and quality of life, thus preventing disease-related psycho-social decline, and extending the period of beneficial effects of STN-DBS. Results of an ongoing multicenter trial (EARLYSTIM) comparing the effects of STN-DBS and best medical treatment on motor symptoms, quality of life, and psycho-social adaptation will be available in 2 years time and will clarify whether or not early STN-DBS is superior to best medical treatment. PMID- 20195942 TI - [Future standards in diagnosing Parkinson syndrome]. AB - So far, the diagnosis of an idiopathic Parkinson-syndrome was based on the British Brain Bank Criteria, that is the occurrence of bradykinesia together with at least one more of the cardinal symptoms, i. e. resting tremor, rigidity or postural instability. The latter symptom is not useful, since it occurs only in the Hoehn and Yahr stage III which is seen in advanced PD patients. Thus, this symptom is certainly not useful for EARLY diagnosis. Early signs for PD are hyposmia, constipation, REM sleep behaviour disorder and depression. Early diagnosis is still a clinical one, which can be supported by a levodopa test. It can be expected that in the near future gene chips will be available for patients with a positive family history for PD or with an early onset. As long as a blood test for PD is not available, methods such as SPECT and PET are extremely useful in patients with an unclear clinical symptomatology. In my own view, each PD patient should receive once in his career a cranial CT or MRI. PMID- 20195943 TI - [Differential diagnosis of Parkinson's disease: current consensus criteria and outlook]. AB - Parkinsonian-syndrome, clinically based on the combination of cardinal symptoms, could be the clinical manifestation of different, neuropathological defined entities. Because of the different prognostic, therapeutical and scientific implications a reliable differential diagnostic of the entities in early course of disease is desirable. For this purpose standardized clinical diagnostic criteria with sufficient validation against the gold standard of the neuropathological diagnostic are important. In this article, the clinical diagnostic criteria of atypical Parkinsonian-syndrome and their validity were discussed. PMID- 20195944 TI - [Endoscopic-bioptic diagnostics, surveillance of and therapy for gastrointestinal diseases according to guidelines]. AB - The present review summarises the detailed recommendations for an optimal endoscopic-bioptic diagnostic procedure, endoscopic surveillance of and therapy for gastrointestinal diseases. The recommendations are mainly based on the S 3 guidelines and have been developed by histopathologists and gastroenterologists in interdisciplinary work. The material has been arranged according to topographic regions of the gastrointestinal tract and clinical problems. The focus is placed on diagnostic and surveillance of Barrett's oesophagus, therapy and postoperative treatment for early gastrointestinal carcinoma, management of colon polyps and endoscopic surveillance of inflammatory bowel disease. Treatment recommendations for both ulcerative colitis and Crohn's disease as well as low grade and high-grade intraepithelial neoplasia and polypoid neoplasia are currently being intensively discussed. Thus we examine this controversial discussion in detail. Furthermore, the recent guidelines for Helicobacter pylori (H. pylori) and gastric MALT-lymphoma diagnostics are included in this survey. To allow the gastroenterologist a time-sparing overview during practical work, most of the recommendations are presented in itemised form and summarised in tables and figures at the end of the discussion. PMID- 20195945 TI - [PPI for dual therapy with clopidogrel: to use or not to use? ]. PMID- 20195946 TI - High fat programming induces glucose intolerance in weanling Wistar rats. AB - We sought to determine whether maintenance on a high fat diet during defined periods of gestation and lactation induced glucose intolerance in weanling Wistar rats or affected food intake, weight, and glucose concentrations in mothers. Experimental groups comprised mothers and their weanling offspring maintained on a high fat diet during gestation and lactation (HFGL), during gestation only (HFG), or during lactation only (HFL). Maternal food intake, body weight, and fasting blood glucose concentrations were determined during lactation. Glucose tolerance was measured in the three-week-old weanling offspring. After overnight fasting, oral glucose tolerance tests were performed in the weanlings. Glucose was collected at (0), 10, 15, 30 and 60 min. HFGL and HFL weanlings had greater glucose concentrations compared to control weanlings at 10, 15, 30 and 60 min. For HFG weanlings, greater glucose concentrations were only found at 30 min, which normalized at 60 min. In all of the experimental groups, the highest glucose concentrations were demonstrated at 30 min, whereas the peak was achieved at 15 min in the control weanlings. Overt glucose intolerance was induced in weanlings maintained on a high fat diet throughout both gestation and lactation or throughout lactation only. Further, weanlings maintained on a high fat diet solely throughout gestation displayed milder glucose intolerance. Developmental programming with a high fat diet during defined periods of gestation and lactation induces glucose intolerance in weanling rats. PMID- 20195947 TI - Metabolic effects of free fatty acids during endotoxaemia in a porcine model- free fatty acid inhibition of growth hormone secretion as a potential catabolic feedback mechanism. AB - Critical illness and severe inflammation are catabolic states characterised by breakdown of tissue and protein stores, by increased levels of free fatty acids, and by insulin resistance. These metabolic features contribute to morbidity and mortality. Growth hormone and insulin are the two major anabolic hormones. The present study was designed to test whether increased levels of free fatty acids (i) inhibit growth hormone secretion and (ii) induce insulin resistance during acute endotoxin exposure in a porcine model of critical illness. We studied 20 pigs for 6 h during combined anaesthesia and endotoxin infusion and a hyperinsulinaemic glucose clamp to control glucose, insulin, and free fatty acid concentrations. Pigs were randomised to two different continuous infusion rates of Intralipid resulting in different, sustained, and elevated free fatty acid concentrations (1.63 mmol l(-1) vs. 0.58 mmol l(-1), p=0.0002). Concomitantly, we observed reduced growth hormone concentrations in the group with high free fatty acid concentrations (3.5 ng ml(-1) vs. 6.6 ng ml(-1), p<0.003). No difference in insulin sensitivity, measured as the glucose infusion rate necessary to maintain euglycaemia, was observed. We conclude that high levels of free fatty acids reduce circulating growth hormone concentrations in porcine endotoxaemia; this probably constitutes a negative feedback mechanism whereby growth hormone induced stimulation of free fatty acids release inhibit growth hormone secretion. This mechanism may further contribute to protein loss in critical illness. We found no evidence that the increment of plasma free fatty acids between groups contribute to insulin resistance in critical illness. PMID- 20195948 TI - [Dying demented. Concepts of care and palliative medicine]. AB - A third of the elderly population dies with dementia. This poses major and partly unmet needs on relatives, professional carers and medical specialists. Our review summarizes epidemiological risk factors for the increased mortality in demented patients (age, somatic co-morbidity, neuropsychiatric symptoms), current practice (place of death, decision making, complications, medical treatment, course of dying, cause of death, suicide, bereaved relatives), and instruments for the assessment of pain, burden, prognosis and treatment planning in the terminal stage of illness. We describe the current legal situation in Germany and present a brief outline of practical management issues. We also list a number of areas offering leeway for improvement regarding research, training, psycho-education, preparation, diagnosis, treatment and support. PMID- 20195949 TI - [Depressive symptoms in a case of "posterior cortical atrophy"]. AB - Posterior cortical atrophy (PCA) is a neurodegenerative disease which leads to a dementing syndrome that involves an irreversible impairment of higher visual and spatial functions. Memory and language functions generally tend to be preserved better than in other types of dementia including Alzheimer's disease. Here we report a case of PCA, which initially was diagnosed and treated for about a year as a major depressive episode. While most patients initially present with neurologic symptoms, in some PCA cases secondary manifestations, such as e. g. affective symptoms, might appear before the onset of overt cognitive dysfunction. In some cases, this might lead to a diagnostic delay of this neurodegenerative disease. PMID- 20195951 TI - Is it useful to measure C-reactive protein and leukocytes in patients with prelabor rupture of membranes? AB - Neonatal infection is the main complication of prelabor rupture of membranes (PROM). We studied the accuracy of measuring C-reactive protein (CRP) and leukocytes in maternal serum to predict neonatal infection. We performed a retrospective cohort study in two hospitals in the Netherlands between 2003 and 2006. We included consecutive women hospitalized for PROM. In both hospitals, CRP and leukocytes were measured routinely in maternal serum every 2 days until delivery. End points considered were clinical neonatal infection and proven neonatal sepsis. The accuracy of CRP and leukocytes was assessed using receiver operating characteristic (ROC) analysis. We included 299 women with PROM, 12 of whom had a twin pregnancy. Gestational age at inclusion varied between 26 weeks and 0 days and 41 weeks and 5 days with a median of 37 weeks and 3 days. In 47 women (16%), the neonate developed a clinical infection. The areas under the ROC curve of CRP and leukocytes in the prediction of clinical neonatal infection were 0.61 and 0.62, respectively. Of the 47 infected neonates, six neonates (2%) had a proven neonatal sepsis. In the mothers of these septic neonates, maternal CRP did not rise above 50 mg/L and leukocyte values varied between 9.8 and 25.8 x 10 (9)/L. In women with PROM, CRP and leukocytes should not be measured routinely. PMID- 20195953 TI - American College of Obstetricians and Gynecologists Practice Bulletins: original versus revised. AB - We compared the types (A, B, or C) of recommendations and levels (I, II, III, or others) of references in the original versus revised practice bulletins (PBs). American College of Obstetricians and Gynecologists (ACOG) compendiums and Web site were used to obtain the PBs. Chi-square test for trend or Wilcoxon matched pairs tests were used. From December 1998 to December 2008, ACOG published 78 PBs, of which 24% (19) have been revised. Neither the median numbers of recommendations per PB (8 to 10; P = 0.235) nor the type ( P = 0.155) increased significantly. Additionally, the level of references ( P = 0.130) and the type of journals they were published in did not vary significantly ( P = 0.554). In 10 years, approximately one in four PBs has been revised and the number of recommendations per PB has increased, but the types of suggestions and level of references has not improved appreciably. PMID- 20195954 TI - Maternal body mass index does not affect performance of fetal electrocardiography. AB - The obesity epidemic challenges traditional antenatal fetal heart rate (FHR) monitoring technologies. Doppler signals in particular are attenuated. We sought to evaluate whether the performance of a novel transabdominal fetal electrocardiogram (fECG) device (AN24, Monica Healthcare) is influenced by body mass index (BMI). We performed a prospective observational study of singleton pregnancies (gestational age [GA] 20 to 41 weeks) monitored overnight with fECG. Recording quality ([RQ] %) of both the best hour and the total recording time of the FHR record were related to BMI. Two hundred four women were monitored. BMI ranged from 16.0 to 50.7 (median BMI 26.9). The correlation coefficient (with 95% confidence interval [CI]) between BMI and RQ was -0.35 (CI -0.60; -0.03) for the gestational age group 20(+0) to 25(+6) weeks, -0.08 (CI -0.28; 0.13) for GA 26(+0) to 33(+6) weeks, and -0.20 (CI -0.40; 0.03) for GA group > or =34(+0) weeks. Median RQ in obese women (BMI > or =30 kg/m(2)) was 97.4, 98.9, and 100%, respectively. BMI has no clinically significant influence on recording quality of FHR monitored with fECG. It can therefore be considered a good method for monitoring the fetal condition in pregnancies of obese women. PMID- 20195952 TI - Maternal serum interleukin-6, C-reactive protein, and matrix metalloproteinase-9 concentrations as risk factors for preterm birth <32 weeks and adverse neonatal outcomes. AB - Elevated concentrations of interleukin-6 (IL-6), C-reactive protein (CRP), and matrix metalloproteinase-9 (MMP-9) in fetal and neonatal compartments have been associated with an increased risk for preterm birth (PTB) and/or neonatal morbidity. The purpose of this study was to determine if the maternal serum concentration of IL-6, CRP, and MMP-9 in women at risk for PTB, who are not in labor and have intact membranes, are associated with an increased risk for PTB <32 weeks and/or neonatal morbidity. Maternal serum samples collected from 475 patients enrolled in a multicenter randomized controlled trial of single versus weekly corticosteroids for women at increased risk for preterm delivery were assayed. Serum was collected at randomization (24 to 32 weeks' gestation). Maternal serum concentrations of IL-6, CRP, and MMP-9 were subsequently determined using enzyme-linked immunoassays. Multivariate logistic regression analysis was performed to explore the relationship between maternal serum concentrations of IL-6, CRP, and MMP-9 and PTB <32 weeks, respiratory distress syndrome (RDS), chronic lung disease (CLD), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), and any sepsis. Maternal serum concentrations of IL-6 and CRP, but not MMP-9, above the 90th percentile at the time of randomization were associated with PTB <32 weeks. In contrast, there was no significant relationship between RDS and NEC and the maternal serum concentration of IL-6, CRP, or MMP-9 (univariate analysis). The development of CLD was associated with a high (above 90th percentile) IL-6 and CRP in maternal serum, even after adjustment for gestational age (GA) at randomization and treatment group. However, when GA at delivery was added to the model, this finding was nonsignificant. Neonatal sepsis was more frequent in neonates born to mothers with a high maternal serum concentration of CRP (>90th percentile). However, there was no significant association after adjustment for GA at randomization and treatment group. Logistic regression analysis for each analyte indicated that high maternal serum concentrations of IL-6 and CRP, but not MMP-9, were associated with an increased risk of IVH (odds ratio [OR] 4.60, 95% confidence interval [CI] 1.86 to 10.68; OR 4.07, 95% CI 1.63 to 9.50) after adjusting for GA at randomization and treatment group. Most babies (25/30) had grade I IVH. When GA at delivery was included, elevated IL-6 remained significantly associated with IVH (OR 2.77, 95% CI 1.02 to 7.09). An elevated maternal serum concentration of IL-6 and CRP are risk factors for PTB <32 weeks and subsequent development of neonatal IVH. An elevated maternal serum IL-6 appears to confer additional risk for IVH even after adjusting for GA at delivery. PMID- 20195955 TI - [Air embolisation during vitrectomy?]. AB - Life-threatening complications are extremely rare in ophthalmic surgery. If they occur, then mostly because of a pre-existing severe cardiovascular condition of the patient, and only to a much lesser extent because of the operation of the eye itself. One theoretically possible complication is an air embolisation during air tamponade of the vitreous cavity with simultaneously opened choroidal vessels. There are some descriptions of such possible cases of air embolisation in the anaesthesiologic literature. Vitreoretinal surgeons should be aware of the theoretically possible complication of air embolisation during vitrectomy with air tamponade and simultaneously opened choroidal vessels. PMID- 20195956 TI - [Smoking cessation programmes at hospitals with departments for lung diseases]. AB - BACKGROUND AND OBJECTIVES: Tobacco smoking is the main preventable risk factor resulting in multiple diseases and premature death. In particular, the airways and the lungs are affected by the effects of smoking. Hospitals have considerable potential to advance smoking cessation. However, so far there have only been a few data on availability and effectiveness of smoking cessation programs in hospitals. This study aimed to assess such programs in general hospitals with a special department for lung disease in South West Germany. METHODS: 40 hospitals with at least one pulmonary specialist were identified. This doctor was subsequently interviewed by a telephone call. 39 hospitals participated, one could not be reached by telephone. RESULTS: Although most of the interviewed specialists confirmed the importance of smoking cessation in the field of pneumology only 3 hospitals had own activities for promoting smoking cessation. Another 7 hospitals cooperated with other institutions. Accompanying pharmacotherapy was not practised regularly. The main reasons for a lack of smoking cessation activities in the hospitals were due to the lack of personnel, time and money. CONCLUSION: Our study highlights the tremendous difficulties facing general hospitals when trying to implement a smoking cessation program. Changes in the economic frameworks, and further examination of appropriate measures for brief interventions in the hospital setting are necessary. PMID- 20195957 TI - Comparative analysis of Sambucus nigra and Sambucus australis flowers: development and validation of an HPLC method for raw material quantification and preliminary stability study. AB - This work was designed to develop a simple, effective, and reliable LC system to identify a chemical marker and compare Sambucus nigra L. and Sambucus australis Cham. et Schltdl. flower extracts (American and European elder). Rutin was the main constituent of both species. The developed method showed a linear response in the range of 10 to 45 microg x mL(-1) for rutin and 1.75 to 3.25 microg x mL( 1) for samples of the Sambucus species. Precision was determined and the relative standard deviations were 1.75 % for HSN and 1.28 % for HSA for intraday precision and 1.28 % and 1.51 % for inter-day precision, respectively, while accuracy was 97.9 % for HSN and 99.41 % for HSA. Quantification and detection limits as well as robustness were determined, presenting adequate results. The LC method showed an adequate performance for the separation of flavonoid glycosides in S. nigra and S. australis extracts, since the presence of interference had been previously evaluated. The analysis of thirty different samples of S. NIGRA and S. australis of different origins did not show significant variability among them. An accelerated stability study revealed a significant decrease in the first 30 days reaching 57 % in 90 days for S. australis samples and a total decrease of 25 % in 90 days for S. nigra samples, considering rutin as the chemical marker. These results will contribute to quality control analysis routines of these raw materials in pharmaceutical production facilities. PMID- 20195958 TI - Altered expression of genes profiles modulated by a combination of Astragali Radix and Angelicae Sinensis Radix in obstructed rat kidney. AB - The decoction of a combination of two Chinese herbs, Astragali Radix (the roots of Astragalus membranaceus var. mongholicus) and Angelicae Sinensis Radix (the roots of Angelica sinensis), here named as A&A, has been demonstrated to have renoprotective effects in several animal models and may be considered as a complementary therapeutic medicine for chronic kidney disease. In this study, genomic approaches were employed to identify expression signatures in the obstructed kidney, which may be linked to the molecular actions associated with anti-fibrotic effects of A&A. Ninety-six male Wistar rats were divided randomly into sham, SAA (sham + A&A), UUO (unilateral ureteral obstruction), and UAA (UUO + A&A) groups. The rats in the SAA and UAA groups were administered A&A (14 g/kg) by oral gavage once daily; the ones in the sham and UUO groups were given equal volumes of water. Eight rats from each group were sacrificed at days 3, 7, and 10 after the operation, respectively. Changes in gene expression in the kidneys were determined using Affymetrix RAE-230A GeneChips. The differential expression of known genes between UAA and UUO was confirmed by RT-PCR. The results revealed that 40, 65, and 104 genes were upregulated and 30, 36, and 40 genes downregulated in UUO compared with the sham group at days 3, 7, and 10, respectively. Compared to the UUO group, eight genes were upregulated and two genes were downregulated at day 3 in the UAA group, and two genes were upregulated at day 10. These genes included transient receptor protein 3 (TRP3), bone marrow stromal cell antigen 1 (BST-1), peroxisomal biogenesis factor 6 (PEX6), xanthine dehydrogenase (XDH), cytochrome P450 subfamily I member A1 (CYP1A1), serine/cysteine proteinase inhibitor clade E member1 (PAI-1), fibroblast growth factor 23 (FGF23), and five ESTs. Among these genes, differential expression of PAI-1, FGF23, and CYP1A1 were further confirmed by RT PCR. These data provide the evidence that the anti-fibrotic effects of A&A are mediated through multiple pathways in obstructive nephropathy, and novel mechanisms may be involved in the increasing degeneration of ECM, decreasing ROS reaction, and regulation of the calcium-phosphate metabolism. PMID- 20195959 TI - 5,6,3',4'-Tetrahydroxy-7-methoxyflavone as a novel potential proteasome inhibitor. AB - Proteasome inhibition is one of the new pharmaceutical approaches to study antitumor activity. Although the active components are not yet identified for either treating or preventing cancer, the low toxicity plant Anisomeles ovata R. Br. has been used in traditional herbal medicine for more than 1000 years. In this study, the methanol extract from Anisomeles ovata showed potent inhibition of proteasome activity. Twenty compounds, two macrocycylic diterpenoids, six aromatics, seven flavonoids, and five phenylethanoids were isolated from Fang Feng Cao the dried aerial parts of A. ovata. Their structures have been established on the basis of spectral evidence. Using a proteolysis assay for inhibition of 26S proteasome from pig red blood cells, we found that 5,6,3',4' tetrahydroxy-7-methoxyflavone inhibited 90.5 %, 85.4 % and 73.1 % the chymotrypsin-like, caspase-like and trypsin-like activities of 26S proteasome with IC (50) values of 14.0, 5.4 and 24.1 microM, respectively, when Suc-LLVY AMC, Z-LLE-AMC and Ac-RLR-AMC were used as substrates. 5,6,3',4'-Tetrahydroxy-7 methoxyflavone had a higher inhibitory at 15 minutes. A combination of 5,6,3',4' tetrahydroxy-7-methoxyflavone and 5,6,4'-trihydroxy-7,3'-dimethoxyflavone increased the inhibition ability on 26S enzymatic activity. This combination appears to be a potentially attractive chemotherapy approach. We have found that 5,6,3',4'-tetrahydroxy-7-methoxyflavone has the highest inhibitory effects on 26S proteasome activities when compared to the other 11 flavonoids. These results suggest that both the 6-hydroxy and 7-methoxy positions of the flavone may play an important role in targeting 26S proteasome activity. PMID- 20195960 TI - A new cytotoxic trichothecene macrolide from the endophyte Myrothecium roridum. AB - A new cytotoxic roridin-type trichothecene macrolide named roritoxin E(1) was characterized from the solid culture of Myrothecium roridum IFB-E091 (residing originally inside Artemisia annua root), together with the known compounds lumichrome (2), (22 E,24 S)-cerevisterol (3), and (22 E,24 R)-6 beta-methoxy ergosta-7,22-diene-3 beta,5 alpha-diol (4). The structure of the new macrolide (1) was elucidated by a combination of spectroscopic (UV, IR, MS, and 1D and 2D NMR) analyses. Compound 1 was demonstrated to be inhibitory in vitro against the gastric carcinoma SGC-7901 and hepatocarcinoma SMMC-7721 cell lines, with IC (50) values of 0.26 and 10.54 microg/mL, respectively. 5-Fluorouracil co-assayed as a positive control had an IC (50) value of 6.66 microg/mL against SGC-7901 cells, and it demonstrated only a 9.98 % growth inhibition against SMMC-7721 cells at 10 microg/mL. PMID- 20195961 TI - Piper peltatum: biomass and 4-nerolidylcatechol production. AB - Piper peltatum L. is used for the treatment of inflammation, malaria, and other ailments. 4-Nerolidylcatechol (4-NC) is a valuable natural product that has important anti-inflammatory, antimalarial, and antioxidant properties. 4-NC is a component of P. peltatum and P. umbellatum extracts, which are used in cosmetics. The aim of this work was to evaluate the production of plant biomass and the production of 4-NC in roots of cultivated P. peltatum over a full life cycle. Seedlings were produced in a greenhouse and then transplanted. The weight of dry plant parts (leaves, stems, roots, and inflorescences); numbers of stems, leaves, and inflorescences; and the leaf-to-stem ratio were evaluated at intervals of 60 days after transplanting (DAT). Extracts were prepared using 1:1 ethanol chloroform and an ultrasound bath. Roots, leaves, and inflorescences contained 4 NC according to TLC photodensitometry analysis. Quantification of 4-NC in root extracts was performed using HPLC-DAD analysis. Per-hectare production of 4-NC by roots was estimated based on quantitative HPLC analysis and biomass data. Optimal per-hectare yields of 4-NC were obtained by harvesting roots between 350 and 400 DAT. In this period, the average yield was 27 kg 4-NC per hectare. Importantly, at the time of maximal overall production of root biomass (470 DAT), there was a decrease in the production of 4-NC (23.8 kg/ha), probably due to the onset of senescence. PMID- 20195962 TI - Two new phenylpropanoid derivatives and other constituents from Illicium simonsii active against oral microbial organisms. AB - Bioassay-guided fractionation of the ethanol extract of the leaves and stems of Illicium simonsii led to the isolation of two new compounds, simonin A (1) and 1 hydroxyl-2- O- beta- D-6'-acetyl-glucopyranosyl-4-allylbenzene (2), along with eight known compounds. Their structures were elucidated by spectroscopic analysis. The isolates were tested for anti-oral microbial activity using a microdilution method. Compounds 1 and 3- 6 showed significant activities against oral microbial organisms (Actinomyces viscosus, Streptococcus mutans, Streptococcus sanguis, and Actinomyces naeslundii), with minimum inhibitory concentration (MIC) values ranging from 1.95 to 31.25 ug/mL in vitro. PMID- 20195963 TI - Chemical constituents of Alnus firma and their inhibitory activity on lipopolysaccharide-induced nitric oxide production in BV2 microglia. AB - A methanolic extract of ALNUS FIRMA barks (Betulaceae) significantly attenuated nitric oxide production in lipopolysaccharide-stimulated BV2 microglia. Two new compounds, characterized as 4-hydroxy-2,6-dimethoxyphenyl 6'- O-syringoyl- beta- D-glucopyranoside (1) and 4-hydroxy-2,6-dimethoxyphenyl 6'- O-vanilloyl- beta- D glucopyranoside (2), were isolated from the barks of A. FIRMA using bioactivity guided fractionation, together with two known phenolic glycosides (3, 4) and 11 known diarylheptanoids (5- 15). Among these compounds, 1- 4 and 6- 11 showed significant inhibitory effect on lipopolysaccharide-induced nitric oxide production in BV2 microglial cells at concentrations ranging from 10 microM to 100 microM. PMID- 20195965 TI - Breast sensation after breast reconstruction: a systematic review. AB - Studies show some return of breast sensation after breast reconstruction; however, recovery is variable and unpredictable. Efforts are being made to restore innervation by reattaching nerves (neurotization). We sought to systematically review the literature addressing breast sensation after reconstruction. The following databases were searched: EMBASE, Cochrane, and PubMed. Additionally, the PLASTIC AND RECONSTRUCTIVE SURGERY journal was hand searched from 1960 to 2009. Inclusion criteria included breast reconstruction for cancer, return of sensation with objective results, and patients aged 18 to 90 years. Studies with purely cosmetic procedures, case reports, studies with less than 10 patients, and studies involving male patients were excluded. The initial search yielded 109 studies, which was refined to 20 studies with a total pool of 638 patients. Innervated flaps have a greater magnitude of recovery, which occurs at an earlier stage compared with the noninnervated flaps. Overall, sensation to deep inferior epigastric artery perforator flaps may recover better sensation than transverse rectus abdominis myocutaneous flaps, followed by latissimus dorsi flaps, and finally implants. Women's needs and expectations for sensation have led plastic surgeons to investigate ways to facilitate its return. Studies, however, depict conflicting data. Larger series are needed to define the role of neurotization as a modality for improving sensory restoration. PMID- 20195966 TI - Organ-preserving and reconstructive microsurgery of the fallopian tubes in tubal infertility: still an alternative to in vitro fertilization (IVF). AB - Tubal infertility mostly results from infections. Conception only is possible through complex treatments (in vitro fertilization or surgery). Success cannot be guaranteed, even after repeated treatments. Unfortunately, many couples are not informed about the prospect for success of tubal reconstruction. Problems of in vitro fertilization are low pregnancy and birth rates of 28.4% and <20% respectively (Germany) and the high number of multiple pregnancies (21%). In this retrospective study 462 women with acquired tubal infertility and further 127 women after previous sterilization underwent microsurgical treatment (microsurgical adhesiolysis, anastomosis, fimbrioplasty, salpingostomy, and refertilization due to former sterilization). The main outcome measures are the pregnancy and birth rates following the microsurgical procedure. Pregnancy and birth rates of 43.4% and 29.2%, respectively, were higher than the outcomes post single in vitro fertilization (abortion: 6.4%, extrauterine pregnancy: 7.9%). When reversal of sterilization was performed, pregnancy and birth rates were higher at 73% and 50.6%, respectively (abortion: 15.7%, extrauterine pregnancy: 6.7%). The advantages of reconstructive microsurgery over in vitro fertilization include the ideally permanent restoration of woman's ability to conceive naturally (repeated pregnancies are possible without further therapy), a high postoperative birth rate overall, and avoidance of multiple births. It is advisable to inform the patient about the objective possibility of reconstructive tubal surgery. PMID- 20195967 TI - Endoscopic biliary stenting successfully managed mucus obstructive jaundice in intraductal papillary mucinous carcinoma. PMID- 20195968 TI - A case of a peculiarly shaped gastrointestinal stromal tumor. PMID- 20195969 TI - Superior mesenteric artery syndrome diagnosed with linear endoscopic ultrasound. PMID- 20195970 TI - Recurrent borderline ovarian tumor presenting as a pedunculated polyp at colonoscopy. PMID- 20195971 TI - Use of an over-the-scope clip for endoscopic sealing of a gastric fistula after sleeve gastrectomy. PMID- 20195972 TI - Lymphoepithelioma-like gastric carcinoma resected by endoscopic submucosal dissection (ESD). PMID- 20195973 TI - Endoscopic treatment of a transversely impacted perforating fish bone in the esophagus with pneumomediastinum. PMID- 20195974 TI - Clinical experience in the placement of a novel motility capsule by using a capsule delivery device in critical care patients. PMID- 20195975 TI - Hemosuccus pancreaticus after endoscopic ultrasound-guided fine needle aspiration of a pancreatic cyst. PMID- 20195976 TI - Myocardial and cerebral infarction due to massive air embolism following endoscopic retrograde cholangiopancreatography (ERCP). PMID- 20195977 TI - Endoscopic band ligation for the treatment of bleeding colonic and ileal diverticula. PMID- 20195978 TI - Crohn's appendicitis. PMID- 20195979 TI - Perforation with retroperitoneal emphysema after endoscopic submucosal dissection for a rectal carcinoid tumor. PMID- 20195980 TI - Spontaneous resolution of capsule endoscope retention in a normal small bowel after 2.5 years. PMID- 20195981 TI - Management of benign intrahepatic bile duct strictures: initial experience with polydioxanone biodegradable stents. PMID- 20195982 TI - Management of an esophageal metallic stent obstructed by tumor progression: endoscopic alcohol injection therapy instead of restenting. PMID- 20195983 TI - Endoscopic features of short-term progression of esophageal intramural pseudodiverticulosis. PMID- 20195984 TI - Magnifying endoscopic observation of mantle cell lymphoma in the stomach using the narrow-band imaging system. PMID- 20195988 TI - Narrow band imaging for detecting superficial squamous cell carcinoma of the head and neck in patients with esophageal squamous cell carcinoma. AB - BACKGROUND AND STUDY AIMS: Narrow band imaging combined with magnifying endoscopy (NBI-ME) is useful for the detection of superficial squamous cell carcinoma (SCC) within the oropharynx, hypopharynx, and oral cavity. The risk of a second primary SCC of the head and neck is very high in patients with esophageal SCC. This prospective study evaluated the detection rate of superficial SCC within the head and neck region (superficial SCCHN) with NBI-ME in patients with esophageal SCC. PATIENTS AND METHODS: Between March 2006 and February 2008, 112 patients with a current or previous diagnosis of esophageal SCC were enrolled. All patients underwent endoscopic screening of the head and neck by NBI-ME. The primary end point was the detection rate for superficial SCCHN. Secondary end points were to compare demographic characteristics between patients with and without superficial SCCHN and to assess the clinical course of patients with superficial SCCHN. RESULTS: The detection rate for superficial SCCHN was 13 % (15/112). The prevalence of multiple Lugol-voiding lesions, observed endoscopically throughout the esophageal mucosa after application of Lugol dye solution, was significantly higher in patients with superficial SCCHN than in those without (100 % vs. 24 %, P < 0.0001). Minimally invasive curative treatment with organ preservation was feasible without severe complications in patients with superficial SCCHN after curative treatment of esophageal SCC. CONCLUSIONS: In patients with esophageal SCC, NBI-ME is useful for detecting superficial SCCHN, thereby facilitating minimally invasive treatment. PMID- 20195989 TI - Diagnostic value of confocal endomicroscopy in celiac disease. AB - BACKGROUND: Improved endoscopic screening with targeted biopsies might enhance diagnostic yield in celiac disease. Confocal endomicroscopy (CEM) allows high resolution in vivo histological analysis. We compared the endomicroscopic findings during ongoing endoscopy with the histological findings graded according to the Marsh classification. METHODS: Twenty-four patients with celiac disease and six patients with celiac disease that was refractory on a gluten-free diet were examined using CEM. The duodenal mucosa was evaluated by CEM and by conventional histological analysis in respect of villous atrophy, crypt hyperplasia, and increased numbers of intraepithelial lymphocytes (IELs > 40 / 100 enterocytes). The CEM results were assessed as to sensitivity, specificity, and interobserver variability. A Marsh classification score determined by CEM was compared to that obtained by histology. Thirty patients undergoing routine upper gastrointestinal endoscopy were used as controls. RESULTS: Conventional histology showed villous atrophy and crypt hyperplasia in 23 and increased numbers of IELs in 27 of the 30 patients with celiac disease. With CEM, villous atrophy, crypt hyperplasia, and increased IELs were respectively identified in 17, 12, and 22 of the 30 patients. The agreement of the findings on CEM with those of conventional histology was good in relation to villous atrophy (sensitivity 74 %) and increased numbers of IELs (sensitivity 81 %), but inadequate in relation to crypt hyperplasia (sensitivity 52 %). The kappa values for determination of interobserver variability were 0.90 for villous atrophy, 1.00 for crypt hyperplasia, and 0.84 for IEL detection. In the 30 control patients, normal duodenal architecture was found by both histology and endomicroscopy, indicating an overall specificity of 100 %. CONCLUSION: The assessment of duodenal histology by CEM in patients with celiac disease is sensitive and specific in determining increased numbers of IELs and villous atrophy, but insufficient in respect of crypt hyperplasia. For routine use of CEM in patients with celiac disease, the technique would need to be improved. PMID- 20195990 TI - Endoscopic ultrasound-guided fine-needle aspiration for the diagnosis of sarcoidosis. AB - BACKGROUND AND STUDY AIMS: Transesophageal endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) of mediastinal lymph nodes is increasingly used to detect noncaseating granulomas in patients with suspected sarcoidosis. The optimal needle size and tissue processing method for detecting noncaseating granulomas are debated. We assessed the value of cell-block analysis when added to conventional cytological evaluation of EUS aspirates obtained by 22-gauge needles in patients with stage I and II sarcoidosis. PATIENTS AND METHODS: Data from 101 consecutive patients (55 % of whom had previously had a nondiagnostic bronchoscopy) with suspected pulmonary sarcoidosis (stage I and II), who underwent EUS-FNA of mediastinal lymph nodes with 22-gauge needles were retrospectively analyzed. RESULTS: The sensitivity of EUS in detecting granulomas was 87 % (cytology and cell-block analysis together) (stage I, 92 %; stage II, 77 %). In 33 % of cytology negative patients (n = 6), granulomas were present in the cell block. The optimal yield for granuloma detection was reached with four needle passes. One patient developed mediastinitis after EUS-FNA. CONCLUSIONS: Cell-block analysis added to conventional cytological evaluation of 22-gauge EUS aspirates, results in a high yield in detecting granulomas in patients with suspected sarcoidosis and reduces the false-negative rate substantially. EUS has a considerably higher yield in stage I compared with stage II sarcoidosis. For an optimal yield, four needle passes are required. PMID- 20195991 TI - Celiac disease is not yet mainstream in endoscopy. PMID- 20195993 TI - Advances in locating lymph nodes by endoscopic ultrasound-guided fine-needle marking. PMID- 20195992 TI - European Society of Gastrointestinal Endoscopy (ESGE): recommendations (2009) on clinical use of video capsule endoscopy to investigate small-bowel, esophageal and colonic diseases. AB - These recommendations on video capsule endoscopy, an emerging technology with an impact on the practice of endoscopy, were developed by the European Society of Gastrointestinal Endoscopy (ESGE) Guidelines Committee. The first draft of each section was prepared by one or two members of the writing team, who were selected as experts on the content of that section on the basis of their published work. They used evidence-based methodology, performing MEDLINE and PubMed literature searches to identify relevant clinical studies. Abstracts from scientific meetings were included only if there was no published full paper on a particular topic. If there was disagreement, the first author of the Guideline made the final decision. Recommendations were graded according to the strength of the supporting evidence. The draft guideline was critically reviewed by all authors and submitted to the ESGE councillors for their critical review before approval of the final document. The ESGE Guidelines Committee acknowledges that this document is based on a critical review of the data available at the time of preparation and that further studies may be needed to clarify some aspects. Moreover, this Guideline may be revised as necessary to account for changes in technology, new data, or other aspects of clinical practice. This document should be regarded as supplying recommendations only to gastroenterologists in providing care to their patients. It is not a set of rules and should not be construed as establishing a legal standard of care, or as encouraging, advocating, requiring, or discouraging any particular treatment. These recommendations must be interpreted according to the clinician's knowledge, expertise, and clinical judgment in the management of individual patients and, if necessary, a course of action that varies from recommendations must be undertaken. PMID- 20195995 TI - Wire-guided biliary cannulation should be considered to be standard practice. PMID- 20195999 TI - Advocating with one voice for a new world. PMID- 20196001 TI - Basic tools and processes for handling liability claims. PMID- 20196004 TI - Financial responsibility. Mercy Hospital v. Baumgardner, So. 2d, No. 3D02-3095, 3D02-2686 (Ct. App. Fla. (3rd Dist.) Dec. 24, 2003). PMID- 20196003 TI - Tracking level one trauma center staff behaviors on adverse event reporting. PMID- 20196005 TI - World-class health care risk management education and networking. PMID- 20196007 TI - Survey adds to understanding of initiatives and challenges that lie ahead. PMID- 20196009 TI - Optimizing FMEA and RCA efforts in health care. PMID- 20196008 TI - Assessing your organization's potential to become a high reliability organization. PMID- 20196010 TI - Case law update. State law negligence actions against MCOs are pre-empted by ERISA. PMID- 20196012 TI - Meeting the next generation's needs. PMID- 20196013 TI - A call for federal immunity to protect health care employers - and patients. PMID- 20196014 TI - Physician partnerships: the value of clinical effectiveness resource management. AB - Once perceived as a hospital-only process, risk management is now recognized as an important part of clinical decision-making and hospital operations. The greatest opportunities exist where risk management programs can be integrated into the development and implementation of guidelines, protocols and order sets that encourage adherence to valid clinical evidence and reduce unwarranted clinical variation in patient care. The limiting factors in this approach are providing the data needed to demonstrate the need for change and engaging administrators and clinicians in the development and implementation of those changes.This article describes a process for the development of hospital-specific data that can be used to evaluate the cost impact of various decisions about patterns of care - the Clinical Effectiveness Initiative - in this case used to demonstrate the cost impact of a choice between two medications used to prevent and treat a common disorder, venous thrombosis. It also describes how this data can be used to engage clinicians and administrators in a partnership focused on improving outcomes and patient safety by considering the full complement of factors - clinical, operational and risk management-related - that contribute to those costs and outcomes. This process is clinical effectiveness resource management. PMID- 20196015 TI - Special considerations accompany the 'gift of life'. AB - Patient safety practices for organ and tissue donors - as well as recipients - must be understood by health care providers to combat medical error.This article discusses how regulatory and accreditation bodies are doing their part to reassure the public that there are strict rules, criteria and provisions specific to organ donation and transplantation. Additionally, health care risk management concepts as they apply to emerging issues in the organ donation and transplant field are explained. The article also highlights strategies to address particular patient safety issues and concerns. Case studies illustrate risk management applications and lessons learned. PMID- 20196019 TI - Doing something for yourself--and your profession. PMID- 20196017 TI - Case law update. Nolen v. Boca Raton Community Hospital, 373 F. 3d 1151 (11thCir. 2004). PMID- 20196016 TI - The benefits of online policy and procedure management systems. AB - Operational inefficiencies, sub-optimal patient care, financial losses and missing or ineffective sanctions for non-compliance are all potential outcomes that can stem from passive policy and procedure management. Automation can help solve these problems and provide strategic, operational and financial benefits to health care organizations and their professionals.The implementation and use of an online policy and procedure management system can facilitate and support excellence and sound risk management practices in compliance and accreditation, document management, education and risk management/patient safety. PMID- 20196020 TI - Integrating quality with risk financing through a risk retention group. AB - In Philadelphia, one of the nation's judicial battlegrounds, a clinical practice group of 360 physicians responded to the medical malpractice insurance crisis by creating a reciprocal risk retention group that has supported the group's best practices while almost eliminating the number of claims going to trial. This article describes how the insurance crisis helped change the culture of its physician practice group, restore the close physician-patient relationship that lies at the heart of medicine, and shows how elements of this revolutionary program can be adopted by all professional liability insurers. PMID- 20196022 TI - Using technology to facilitate informed consent, manage expectations and improve communication. AB - Rising malpractice rates and damages to finances and reputations caused by litigation are leading risk managers to seek new solutions to reduce the frequency and severity of malpractice. Any effort to meet the challenges of malpractice must consider three areas: the informed consent process, expectation management and physician communication. Technology is emerging as an important tool that can help risk managers better address these critical areas. This article explores the realities of malpractice today - specifically the factors behind the majority of cases and discusses how new tools can help risk managers. PMID- 20196021 TI - Case studies in acute aortic dissection: strategies to avoid a catastrophic outcome. AB - Aortic dissection is a catastrophic illness that is a significant source of liability for hospitals if diagnosis and treatment are not done promptly. The diagnosis is often difficult to make because not all dissections have the typical presentation of sudden severe chest pain radiating to the back. Symptoms often include abdominal pain, flu-like complaints, vomiting and diarrhea, low back pain, stroke syndromes and syncope. Patients at risk include those with Marfan syndrome and other connective tissue diseases, familial aortic disease, age and hypertension. Aortic dissection is a different clinical entity than abdominal aortic aneurysm. Strategies to reduce risk and improve outcome include staff education on various presentations and risk factors, rapid availability of diagnostic testing modalities such as chest CT scan or transesophageal echocardiogram, and protocols to ensure prompt transfer for cardiothoracic surgery. PMID- 20196023 TI - An overview of common provisions and contractual issues for organizations. AB - Although contract review is often seen as a process within the purview of legal counsel, the involvement of risk management professionals can serve to provide valuable insight into potential risks to the organization created by such contracts, particularly where the risk management professional is in a position to take an "enterprise wide" view of the organization and its operations. This insight can extend beyond reviewing standard insurance and indemnification clauses to identifying the risks created by different contractual relationships with other providers or contractors. This article describes a number of contractual issues and offers practical guidance on how the risk management professional can address those issues in order to avoid or limit risk to the organization. It also provides an explanation of the purpose and intent of a number of standard or "boilerplate" terms found in many contracts. PMID- 20196024 TI - Professional liability: hospital's liability for 'bare' physicians in Florida increasingly unclear. Plantation General Hospital Limited Partnership v. Horowitz, _____ So. 2d _____, No. 4D03-3873 (Ct. App. 4th Dist. Fla. February 9, 2005); North Miami Medical Center, Ltd. v. Miller, _____ So. 2d _____, Nos. 3D03 3183, 3D03-3233 (Ct. App. 3rd Dist. Fla. March 2, 2005). PMID- 20196025 TI - Quantitative cell bioimaging using gold-nanoshell conjugates and phage antibodies. AB - The authors describe a quantitative evaluation of the efficacy of cell labeling with plasmon-resonant light-scattering nanoparticles used as contrast agents for dark-field microscopy imaging. The experimental model is based on the biospecific labeling of pig embryo kidney (SPEV) cells with primary phage antibodies, followed by the dark-field microscopic visualization using conjugates of silica/gold nanoshells with secondary rabbit antiphage antibodies. To quantify nanoparticle binding, the authors introduce the labeling-efficacy factor (LEF) which is equal to the ratio of the bound-particle pixels per cell to the total number of pixels occupied by the cell. The LEF is calculated by an imaging analysis algorithm based on the freely available ImageJ Java-based processing code. In terms of the LEF, a distinct difference was found between intact, nonspecifically labeled, and biospecifically labeled cells. PMID- 20196026 TI - Analysis of the alcohol biomarker phosphatidylethanol by NACE with on-line ESI MS. AB - Phosphatidylethanol (Peth), a group of aberrant phospholipids formed in cell membranes in the presence of ethanol, has been recently proposed as biomarker of chronic alcohol abuse. The aim of this study was to develop a new analytical method, based on NACE online coupled with a mass spectrometer for the analysis of Peth in blood. For this purpose an ion-trap mass spectrometer equipped with an orthogonal ESI source operating in negative ion mode was used. An alkaline solution of ammonium acetate 5 mM (pH 9) in water/methanol (MeOH) (80:20 v/v) was delivered as coaxial sheath liquid. All experiments were performed using an uncoated fused-silica capillary (90 cm x 75 microm id). The effects of variable percentages of ACN, MeOH, 2-propanol, dichloromethane, along with variable concentrations of ammonium acetate were investigated for the separation of Peth. Collectively, a separation medium composed of ACN (45% v/v), 2-propanol (20% v/v), dichloromethane (20% v/v), MeOH (10% v/v), water (5% v/v), and ammonium acetate (25 mM) was chosen. The estimated LOD was 0.1 microM, while LOQ was 0.4 microM. Within-run (intra-day) and between-run (inter-day) precision was always lower than 15%. The method proved to be robust and reliable. The MS detector allowed the simultaneous identification of several Peth homologues, and the use of an internal standard (phosphatidylbutanol) with similar electrophoretic properties of that of Peth increased quantitation effectiveness. PMID- 20196027 TI - Decoupling CE and ESI for a more robust interface with MS. AB - An interface for CE-ESI-MS that decouples both the electrical and the solution flow rate requirements of the separation and ionization processes is presented. The interface uses a tapered and beveled stainless steel hollow needle surrounding the separation capillary terminus so that the inside of the electrode acts as the CE outlet vial and the outside tip acts as the electrospray emitter. No capillary pre-treatment is required, enabling the use of capillaries with any type of surface modification. A chemical modifier solution is introduced through a second capillary connected to the needle via a tee junction and can be used to improve the compatibility of the CE BGE with electrospray. The flow rate of modifier solution can be as low as 0.1 microL/min, much less than that in a typical sheath-flow interface, thus minimizing dilution of the CE effluent in order to maximize sensitivity. The presence of the modifier solution also allows the use of neutral-coated capillaries for protein analysis by CE-MS without using an assisting pressure, despite the absence of EOF under these conditions. The interface is easily integrated into a commercial CE instrument, such that all operations can be carried out by the automated controls. Compared with a commercial sheath-flow CE-MS interface operating under optimized conditions, LODs for amino acids were, on average, improved fivefold. PMID- 20196028 TI - Analysis of hemoglobin-based oxygen carriers by CE-UV/Vis and CE-ESI-TOF/MS. AB - Blood doping involves the use of products that enhance the uptake, transport, or delivery of oxygen to the blood. One approach uses artificial oxygen carriers, known as hemoglobin-based oxygen carriers (HBOCs). This study describes an analytical strategy based on CE for detecting intact HBOCs in plasma samples collected for doping control. On-capillary detection was performed by UV/Vis at 415 nm, which offered detection selectivity for hemoproteins (such as hemoglobin and HBOCs). On-line ESI-MS detection with a TOF analyzer was further used to provide accurate masses on CE peaks and to confirm the presence of HBOCs. An immunodepletion sample preparation step was mandatory prior to analysis, in order to remove most abundant proteins that interfered with CE separation and altered the ESI process. This analytical method was successfully applied to plasma samples enriched with Oxyglobin, a commercially available HBOC used for veterinary purposes. Detection limits of 0.20 and 0.45 g/dL were achieved in plasma for CE-UV/Vis at 415 nm and CE-ESI-TOF/MS, respectively. PMID- 20196029 TI - Gold nanorods as new nanochromophores for photothermal therapies. AB - Results and perspectives on the biomedical exploitation of gold nanorods with plasmon resonances in the near infrared window are reported. The authors describe experimental studies of laser-activated nanoparticles in the direct welding of connective tissues, which may become a valuable technology in biomedicine. In particular, colloidal gold nanorods excited by diode laser radiation at 810 nm were used to mediate functional photothermal effects and weld eye's lens capsules and arteries. The preparation of biopolymeric matrices including gold nanorods is also described, as well as preliminary tests for their application in the closure of wounds in vessels and tendons. Finally, the use of these nanoparticles for future applications in the diagnosis, imaging and therapy of cancer is discussed. PMID- 20196030 TI - CE-ESI-MS/MS as a rapid screening tool for the comparison of protein-ligand interactions. AB - In drug development, the combinatorial synthesis of drug libraries is common use, therefore efficient tools for the characterization of drug candidates and the extent of interaction between a drug and its target protein is a central question of analytical interest. While biological activity is tested today by enzyme assays, MS techniques attract more and more attention as an alternative for a rapid comparison of drug-target interactions. CE enables the separation of proteins and drug-enzyme complexes preserving their physiological activity in aqueous media. By hyphenating CE with ESI-MS/MS, the binding strength of enzyme inhibitors can be deduced from MS/MS experiments, which selectively release the inhibitor from the drug-target complex after CID. In this study, alpha chymotrypsin (CT), a serine protease, was chosen as a model compound. Chymostatin is a naturally occurring peptide aldehyde binding to CT through a hemiacetal bond and electrostatic interaction. First, a CE separation was developed, which allows the analysis of alpha-CT and a chymotrypsin-chymostatin complex under MS compatible conditions. The use of neutral-coated CE capillaries was mandatory to reduce analyte-wall interactions. ESI-quadrupole ion trap-MS was worked out to demonstrate the selective drug release after CID. Fragmentation of the drug enzyme complex was monitored in dependence from the excitation energy in the ion trap, leading to the V(50) voltage that enables 50% complex fragmentation as a reference value for chymotrypsin-chymostatin complex. A stable CE-ESI-MS/MS setup was established, which preserves the drug-enzyme complexes during ionization desolvation processes. With this optimized setup, different CT inhibitors could be investigated and compared. PMID- 20196031 TI - Analysis of methylated melamines in reaction mixtures by CZE-MS. AB - A fast and reliable method based on CZE coupled to Q-TOF MS for the analysis of methylated melamines is presented. Experiments with UV detection were performed using BGE containing formic acid and TFA to optimize electrophoretic conditions and to achieve baseline separation. Employing a TFA-based electrolyte containing 80% ACN and MS detection, nine different methyl melamines were determined in real samples, which were produced by catalytic hydrogenation of melamine/formaldehyde reaction mixtures. The use of a Q-TOF MS resulted in LOD better than 0.01 mg/L for all compounds and high mass accuracy with mass errors lower than 2.3 ppm. PMID- 20196032 TI - Thermal model for optimization of vascular laser tissue soldering. AB - Laser tissue soldering (LTS) is a promising technique for tissue fusion based on a heat-denaturation process of proteins. Thermal damage of the fused tissue during the laser procedure has always been an important and challenging problem. Particularly in LTS of arterial blood vessels strong heating of the endothelium should be avoided to minimize the risk of thrombosis. A precise knowledge of the temperature distribution within the vessel wall during laser irradiation is inevitable. The authors developed a finite element model (FEM) to simulate the temperature distribution within blood vessels during LTS. Temperature measurements were used to verify and calibrate the model. Different parameters such as laser power, solder absorption coefficient, thickness of the solder layer, cooling of the vessel and continuous vs. pulsed energy deposition were tested to elucidate their impact on the temperature distribution within the soldering joint in order to reduce the amount of further animal experiments. A pulsed irradiation with high laser power and high absorbing solder yields the best results. PMID- 20196036 TI - [Importance of GLP-1 for glucose homeostasis. Discovery of incretin]. PMID- 20196037 TI - [DPP-IV inhibitors and GLP-1 analogues]. PMID- 20196038 TI - [DPP-4 inhibitors in clinical use. Therapy without the risk of hypoglycaemia]. PMID- 20196040 TI - [GLP-1 mimetics in clinical studies. Treatment by activation of the GLP-1 receptor]. PMID- 20196041 TI - [Gliptin and GLP-1 analogues - aspects of pharmaceutical care. The patient's responsibility]. PMID- 20196042 TI - [New classes of drugs in the pipeline. New in the treatment of diabetes mellitus]. PMID- 20196045 TI - [The unresolved problems of type 2 diabetes. Diabetology practice]. PMID- 20196052 TI - [Obituary: Frau Professor Dr. Elsa Ullmann]. PMID- 20196055 TI - [Dual attack on the gyrase by simocyclinone]. PMID- 20196056 TI - [Antibodies instead of insulin?]. PMID- 20196058 TI - [Editorial: Pharmazie in unserer Zeit 2/2010]. PMID- 20196060 TI - [Amadacyclin - a new tetracycline antibiotic in the pipeline]. PMID- 20196065 TI - Injectable biodegradable hydrogels. AB - Injectable biodegradable copolymer hydrogels, which exhibit a sol-gel phase transition in response to external stimuli, such as temperature changes or both pH and temperature (pH/temperature) alterations, have found a number of uses in biomedical and pharmaceutical applications, such as drug delivery, cell growth, and tissue engineering. These hydrogels can be used in simple pharmaceutical formulations that can be prepared by mixing the hydrogel with drugs, proteins, or cells. Such formulations are administered in a straightforward manner, through site-specific control of release behavior, and the hydrogels are compatible with biological systems. This review will provide a summary of recent progress in biodegradable temperature-sensitive polymers including polyesters, polyphosphazenes, polypeptides, and chitosan, and pH/temperature-sensitive polymers such as sulfamethazine-, poly(beta-amino ester)-, poly(amino urethane)-, and poly(amidoamine)-based polymers. The advantages of pH/temperature-sensitive polymers over simple temperature-sensitive polymers are also discussed. A perspective on the future of injectable biodegradable hydrogels is offered. PMID- 20196066 TI - Incorporation of femur length leads to underestimation of fetal weight in asymmetric preterm growth restriction. AB - OBJECTIVE: To review the performance of a variety of biometry formulae for estimated fetal weight (EFW) in the management of severely growth restricted fetuses with abnormal umbilical artery Doppler at a single perinatal institution. METHODS: Forty-three pregnancies were retrospectively reviewed. Inclusion criteria were: chromosomally/ structurally normal fetus; complete ultrasound biometry at < or = 7 days from delivery; EFW < 10(th) centile; absent/reversed end-diastolic flow in the umbilical arteries; and delivery at < 32 + 6 weeks. EFW accuracy and precision were compared among nine formulae utilizing combinations of head circumference (HC), biparietal diameter (BPD), abdominal circumference (AC) and femur length (FL) measurements. RESULTS: Twenty-six (60.5%) fetuses showed asymmetric growth (HC/AC ratio > 95(th) centile). Analysis of the systematic and random errors associated with each formula showed that the birth weight of asymmetrically-grown fetuses was most closely approximated by the Hadlock equation that utilized BPD and AC measurements only. The birth weight of symmetrically-grown fetuses was most closely approximated by EFW derived from Hadlock equations that utilized > or = three biometry measurements, including FL. Incorporation of FL into Hadlock formulae led to significant underestimation of birth weight in the fetuses with asymmetric growth (mean percentage error +/- SD: EFW(FL-AC), -13.3 +/- 9.8%; EFW(BPD-FL-AC), -10.8 +/- 9.8%; EFW(HC-FL-AC), -11.8 +/- 9.3%; EFW(BPD-HC-FL-AC), -11.7 +/- 9.5%; P < 0.001). The same equations were accurate in fetuses with symmetric growth (EFW(FL-AC), 3.1 +/- 10.0%; EFW(BPD-FL AC), 1.0 +/- 8.9%; EFW(HC-FL-AC), 0.3 +/- 8.7%; EFW(BPD-HC-FL-AC), 0.4 +/- 15.5%). Use of the best performing equation (Hadlock 3), which does not include FL, to estimate weight in asymmetrically-grown fetuses over 28 weeks' gestation, would have reduced the proportion of those with an underestimation of fetal weight of > 100 g from nine (50.0%) to three (16.7%). CONCLUSIONS: Biometry methods that exclude FL should be considered in asymmetric intrauterine growth restriction associated with abnormal umbilical artery Doppler waveforms. PMID- 20196068 TI - Clinical signs of photodamage are associated with basal cell carcinoma multiplicity and site: a 16-year longitudinal study. AB - Although sun exposure is known to be associated with basal cell carcinoma (BCC), it is not known what determines multiple occurrences of BCCs among sporadically affected individuals or why BCCs develop on uncommonly sun-exposed body sites like the trunk. In a prospective community-based skin cancer study in Queensland, Australia, we studied all participants who experienced a histologically confirmed BCC from 1992 to 2007. Sun exposure history was monitored, and dermatologists documented phenotype at baseline and signs of photodamage over the study period. Anatomic sites of all incident BCCs were recorded. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using logistic regression. Of 401 participants who developed a new BCC during the 16 years of follow-up, 232 (58%) developed more than 1. Male sex (OR = 2.5, 95% CI 1.5-5.3) and age 60 or over (OR = 4.2, 95% CI 1.5-11.8) but not skin type were associated with highest BCC counts among those affected. Participants with high numbers of solar keratoses were most likely to experience the highest BCC counts overall (OR = 4.3, 95% CI 1.4-13.5). Moreover, occurrences of BCC on the trunk (OR = 3.3, 95% CI 1.4-7.6) and on the limbs (OR = 3.7, 95% CI 2.0-7.0) were strongly associated with high numbers of solar keratoses on these sites, respectively. Among those newly affected by BCC, chronic cutaneous sun damage predicts those who will be affected by more than 1 BCC, while chronic sun damage on the trunk and limbs predicts BCC occurrence on the trunk and limbs, respectively. PMID- 20196067 TI - Effect of the correction for noncompliance and contamination on the estimated reduction of metastatic prostate cancer within a randomized screening trial (ERSPC section Rotterdam). AB - The European Randomized study of Screening for Prostate Cancer (ERSPC) has recently reported a 20% reduction in death from prostate cancer in a population based prostate cancer screening (core age group: 55-69 years of age). The effect of screening may be diluted by noncompliance in the screening arm and contamination by PSA testing in the control arm. The purpose is to analyze the effect of prostate cancer screening on the incidence of metastatic prostate cancer, both with and without adjustment for noncompliance and contamination. We analyzed the occurrence of metastases in 42,376 men aged 55-75 years who were randomized in the Rotterdam section of the ERSPC between 1993 and 1999. Contamination adjustment was based on follow-up findings and questionnaire data from all men in the control group who developed prostate cancer and from a random sample of 291 men without cancer who had a PSA test. Prostate cancer screening significantly reduced the occurrence of metastatic prostate cancer in the intention-to-screen analysis [RR 0.75, 95% CI 0.59-0.95, p = 0.02] and more so in adjusted analyses; contamination adjusted RR 0.73, 95% CI 0.56-0.96; noncompliance adjusted RR 0.72, 95% CI 0.55-0.95 and fully adjusted analysis RR 0.68, 95% CI 0.49-0.94, p = 0.02. In the population of ERSPC Rotterdam (N = 42,376 men), screening reduces the risk to be diagnosed with metastatic prostate cancer considerably on population level, an effect which is even more pronounced in men who are in fact screened. PMID- 20196070 TI - Effect of vaginal progesterone, administered to prevent preterm birth, on impedance to blood flow in fetal and uterine circulation. AB - OBJECTIVE: To evaluate the effect on the maternal and fetal circulation of progesterone administered to prevent preterm birth. METHODS: We used an observational cohort study design. The study group included 44 women at 18-32 weeks' gestation who presented with an episode of preterm labor, with or without history of delivery before 34 weeks' gestation, or an incidental finding of short cervix (<= 25 mm). Doppler flow assessment of the umbilical artery, fetal middle cerebral artery and uterine arteries was performed before and 24 h after vaginal administration of progesterone. RESULTS: Seventeen (38.6%) women gave birth before term, but only nine (20.4%) did so before 34 weeks' gestation. Following progesterone treatment, there was a statistically significant decrease in the pulsatility index of the fetal middle cerebral artery (mean reduction, 18.2%; mean change in pulsatility index, 0.44 (95% CI, 0.25-0.63), P < 0.001), with no changes in the other vessels. Comparison of the women who gave birth before with those who delivered at term yielded no significant differences in Doppler flow parameters in any vessel examined, either before or after progesterone treatment. CONCLUSION: Treatment with vaginal progesterone is associated with a lower pulsatility index in the fetal middle cerebral artery, suggesting a vasodilatory effect on the fetal circulation. PMID- 20196071 TI - Structures of the OmpF porin crystallized in the presence of foscholine-12. AB - The endogenous Escherichia coli porin OmpF was crystallized as an accidental by product of our efforts to express, purify, and crystallize the E. coli integral membrane protein KdpD in the presence of foscholine-12 (FC12). FC12 is widely used in membrane protein studies, but no crystal structure of a protein that was both purified and crystallized with this detergent has been reported in the Protein Data Bank. Crystallization screening for KdpD yielded two different crystals of contaminating protein OmpF. Here, we report two OmpF structures, the first membrane protein crystal structures for which extraction, purification, and crystallization were done exclusively with FC12. The first structure was refined in space group P21 with cell parameters a = 136.7 A, b = 210.5 A, c = 137 A, and beta = 100.5 degrees , and the resolution of 3.8 A. The second structure was solved at the resolution of 4.4 A and was refined in the P321 space group, with unit cell parameters a = 215.5 A, b = 215.5 A, c = 137.5 A, and gamma = 120 degrees . Both crystal forms show novel crystal packing, in which the building block is a tetrahedral arrangement of four trimers. Additionally, we discuss the use of FC12 for membrane protein crystallization and structure determination, as well as the problem of the OmpF contamination for membrane proteins overexpressed in E. coli. PMID- 20196072 TI - A synergistic approach to protein crystallization: combination of a fixed-arm carrier with surface entropy reduction. AB - Protein crystallographers are often confronted with recalcitrant proteins not readily crystallizable, or which crystallize in problematic forms. A variety of techniques have been used to surmount such obstacles: crystallization using carrier proteins or antibody complexes, chemical modification, surface entropy reduction, proteolytic digestion, and additive screening. Here we present a synergistic approach for successful crystallization of proteins that do not form diffraction quality crystals using conventional methods. This approach combines favorable aspects of carrier-driven crystallization with surface entropy reduction. We have generated a series of maltose binding protein (MBP) fusion constructs containing different surface mutations designed to reduce surface entropy and encourage crystal lattice formation. The MBP advantageously increases protein expression and solubility, and provides a streamlined purification protocol. Using this technique, we have successfully solved the structures of three unrelated proteins that were previously unattainable. This crystallization technique represents a valuable rescue strategy for protein structure solution when conventional methods fail. PMID- 20196073 TI - CTCF terminal segments are unstructured. AB - The human CCCTC-binding factor, CTCF, organizes and regulates transcription of the genome by colocalizing distant DNA elements on the same and even different chromosomes. This protein consists of 11 zinc fingers flanked by polypeptide segments of unknown structure and function. We purified recombinant terminal fragments and observed that both are extended, monomeric, and predominantly consist of unordered content. We thus speculate that the role of the terminal extensions, and perhaps all of CTCF, is to act as a scaffold for the assembly of other proteins on a specific binding site. PMID- 20196074 TI - A flexible docking scheme to explore the binding selectivity of PDZ domains. AB - Modeling of protein binding site flexibility in molecular docking is still a challenging problem due to the large conformational space that needs sampling. Here, we propose a flexible receptor docking scheme: A dihedral restrained replica exchange molecular dynamics (REMD), where we incorporate the normal modes obtained by the Elastic Network Model (ENM) as dihedral restraints to speed up the search towards correct binding site conformations. To our knowledge, this is the first approach that uses ENM modes to bias REMD simulations towards binding induced fluctuations in docking studies. In our docking scheme, we first obtain the deformed structures of the unbound protein as initial conformations by moving along the binding fluctuation mode, and perform REMD using the ENM modes as dihedral restraints. Then, we generate an ensemble of multiple receptor conformations (MRCs) by clustering the lowest replica trajectory. Using ROSETTALIGAND, we dock ligands to the clustered conformations to predict the binding pose and affinity. We apply this method to postsynaptic density-95/Dlg/ZO 1 (PDZ) domains; whose dynamics govern their binding specificity. Our approach produces the lowest energy bound complexes with an average ligand root mean square deviation of 0.36 A. We further test our method on (i) homologs and (ii) mutant structures of PDZ where mutations alter the binding selectivity. In both cases, our approach succeeds to predict the correct pose and the affinity of binding peptides. Overall, with this approach, we generate an ensemble of MRCs that leads to predict the binding poses and specificities of a protein complex accurately. PMID- 20196075 TI - Localization of MglA, an essential gliding motility protein in Myxococcus xanthus. AB - MglA, a 22-kDa protein related to monomeric GTPases, is required for the normal operation of the A (Adventurous) and S (Social) motility and for multicellular development of Myxococcus xanthus. To determine how MglA controls A- and S motility, MglA was assayed biochemically and its cellular location was determined. His-tagged MglA hydrolyzed GTP slowly in vitro at a rate nearly identical to that of Ras showing that MglA has GTPase activity. Immunofluorescence microscopy of fixed cells from liquid showed that MglA was associated with helical track similar to the MreB spiral that spanned the length of the cell. The distribution pattern of MglA depended on the type of surface from which cells were harvested. In cells gliding on 1.5% (w/v) agar, the helical pattern gave way to punctate clusters of MglA-Yfp at the poles and along the long axis (lateral clusters). The lateral clusters emerged near the leading pole as the cell advanced coincident with a decrease in the intensity of the MglA-Yfp cluster at the leading pole. Newly formed lateral clusters remained fixed with regard to the substratum as the cell moved forward, similar to focal adhesion complexes described for AglZ, a protein partner of MglA. Lateral clusters did not form in cells gliding in methylcellulose, a polymer that stimulates S-motility at low cell density; rather MglA-Yfp was diffuse in the cytoplasm and more concentrated at the poles. The results suggest that conditions that favor S motility prevent the formation of lateral clusters of MglA, which are associated with A-motility functions. PMID- 20196076 TI - Bridging the gap: a GFP-based strategy for overexpression and purification of membrane proteins with intra and extracellular C-termini. AB - Low expression and instability during isolation are major obstacles preventing adequate structure-function characterization of membrane proteins (MPs). To increase the likelihood of generating large quantities of protein, C-terminally fused green fluorescent protein (GFP) is commonly used as a reporter for monitoring expression and evaluating purification. This technique has mainly been restricted to MPs with intracellular C-termini (C(in)) due to GFP's inability to fluoresce in the Escherichia coli periplasm. With the aid of Glycophorin A, a single transmembrane spanning protein, we developed a method to convert MPs with extracellular C-termini (C(out)) to C(in) ones providing a conduit for implementing GFP reporting. We tested this method on eleven MPs with predicted C(out) topology resulting in high level expression. For nine of the eleven MPs, a stable, monodisperse protein-detergent complex was identified using an extended fluorescence-detection size exclusion chromatography procedure that monitors protein stability over time, a critical parameter affecting the success of structure-function studies. Five MPs were successfully cleaved from the GFP tag by site-specific proteolysis and purified to homogeneity. To address the challenge of inefficient proteolysis, we explored expression and purification conditions in the absence of the fusion tag. Contrary to previous studies, optimal expression conditions established with the fusion were not directly transferable for overexpression in the absence of the GFP tag. These studies establish a broadly applicable method for GFP screening of MPs with C(out) topology, yielding sufficient protein suitable for structure-function studies and are superior to expression and purification in the absence GFP fusion tagging. PMID- 20196077 TI - Identification of a Van der Woude syndrome mutation in the cleft palate 1 mutant mouse. AB - Mutations in Interferon Regulatory Factor 6 (IRF6) have been identified in two human allelic syndromes with cleft lip and/or palate: Van der Woude (VWS) and Popliteal Pterygium syndromes (PPS). Furthermore, common IRF6 haplotypes and single nucleotide polymorphisms (SNP) alleles are strongly associated with nonsyndromic clefting defects in multiple ethnic populations. Mutations in the mouse often provide good models for the study of human diseases and developmental processes. We identified the cleft palate 1 (clft1) mouse mutant in a forward genetic screen for phenotypes modeling human congenital disease. In the clft1 mutant, we have identified a novel missense point mutation in the mouse Irf6 gene, which confers an amino acid alteration that has been found in a VWS family. Phenotypic comparison of clft1 mutants to previously reported Irf6 mutant alleles demonstrates the Irf6(clft1) allele is a hypomorphic allele. The cleft palate seen in these mutants appears to be due to abnormal adhesion between the palate and tongue. The Irf6(clft1) allele provides the first mouse model for the study of an etiologic IRF6 missense mutation observed in a human VWS family. PMID- 20196078 TI - p89c-Myb is not required for fetal or adult hematopoiesis. AB - The c-myb gene encodes two proteins, termed p75 and p89. Of these, the larger isoform is transcribed from an alternatively spliced message that contains an additional exon, exon 9A. Disruption of the c-myb locus in mice results in embryonic lethality due to defective hematopoiesis and in the adult, tissue specific inactivation of c-myb in hematopoietic tissues blocks differentiation along several lineages. The c-myb knock-out mouse models described thus far result in the disruption of both the p75 and p89 isoforms, making it impossible to assign a definitive role to p89(c-Myb) in development and hematopoiesis. We have therefore generated a null-mutant mouse where exon 9A has been systemically deleted that results in the absence of only the p89-myb transcript and protein. Unlike disruption of both forms of the c-myb gene, loss of only the p89-encoding isoform does not have any deleterious effects on mammalian hematopoiesis and development. PMID- 20196079 TI - Oncogenic KRAS is not necessary for Wnt signalling activation in APC-associated FAP adenomas. AB - Recent studies have suggested that APC loss alone may be insufficient to promote aberrant Wnt/beta-catenin signalling. Our aim was to comprehensively characterize Wnt signalling components in a set of APC-associated familial adenomatous polyposis (FAP) tumours. Sixty adenomas from six FAP patients with known pathogenic APC mutations were included. Somatic APC and KRAS mutations, beta catenin immunostaining, and qRT-PCR of APC, MYC, AXIN2 and SFRP1 were analysed. Array-comparative genomic hybridization (aCGH) was also assessed in 26 FAP adenomas and 24 paired adenoma-carcinoma samples. A somatic APC alteration was present in 15 adenomas (LOH in 11 and four point mutations). KRAS mutations were detected in 10% of the cases. APC mRNA was overexpressed in adenomas. MYC and AXIN2 were also overexpressed, with significant intra-case heterogeneity. Increased cytoplasmic and/or nuclear beta-catenin staining was seen in 94% and 80% of the adenomas. beta-Catenin nuclear staining was strongly associated with MYC levels (p value 0.03) but not with KRAS mutations. Copy number aberrations were rare. However, the recurrent chromosome changes observed more frequently contained Wnt pathway genes (p value 0.012). Based on beta-catenin staining and Wnt pathway target genes alterations the Wnt pathway appears to be constitutively activated in all APC-FAP tumours, with alterations occurring both upstream and downstream of APC. Wnt aberrations are present at both the DNA and the RNA level. Somatic profiling of APC-FAP tumours provides new insights into the role of APC in tumourigenesis. PMID- 20196080 TI - The crystal structure of NGO0477 from Neisseria gonorrhoeae reveals a novel protein fold incorporating a helix-turn-helix motif. PMID- 20196081 TI - Classification of transporters using efficient radial basis function networks with position-specific scoring matrices and biochemical properties. AB - Transporters are proteins that are involved in the movement of ions or molecules across biological membranes. Transporters are generally classified into channels/pores, electrochemical transporters, and active transporters. Discriminating the specific class of transporters and their subfamilies are essential tasks in computational biology for the advancement of structural and functional genomics. We have systematically analyzed the amino acid composition, residue pair preference and amino acid properties in six different families of transporters. Utilizing the information, we have developed a radial basis function (RBF) network method based on profiles obtained with position specific scoring matrices for discriminating transporters belonging to three different classes and six families. Our method showed a fivefold cross validation accuracy of 76%, 73%, and 69% for discriminating transporters and nontransporters, three different classes and six different families of transporters, respectively. Further, the method was tested with independent datasets, which showed similar level of accuracy. A web server has been developed for discriminating transporters based on three classes and six families, and it is available at http://rbf.bioinfo.tw/ approximately sachen/tcrbf.html. We suggest that our method could be effectively used to identify transporters and discriminating them into different classes and families. PMID- 20196082 TI - Impact of freezing on immunology and incorporation of bone allograft. AB - With an increasing clinical use of deep frozen allograft for bone reconstruction, it is important to understand the immunological and biological events of allograft incorporation. In this study, we have investigated the impact of deep freezing on immunology and biopotency for incorporation of bone allografts. Deep frozen bone grafts matched or mismatched for major histoscompatibilty complex (MHC) were implanted in an 8-mm segmental defect in the tibia in rats. The construct was stabilized with intramedullary nailing. The immune response was evaluated by determination of serum antibody against the grafts MHC molecules at day 1 and after 2 and 4 months. Incorporation of the graft was compared with fresh syngeneic grafts and assessed with the use of conventional radiography, biomechanical testing and measurement of bone mineral content and density after 4 months. The analyses revealed no antibody responses in the rats that received grafts from donors differing at histocompatibility loci, and at 4 months the frozen grafts showed an overall reconstruction that was not significantly different from the fresh grafts. This study indicates that in the long run there are no significant consequences; either immunological or biomechanical, of the use of deep frozen allogenous bone as compared to fresh autogenous bone grafts in this animal model. PMID- 20196083 TI - Effect of psoralen on bone formation. AB - To compare the amount of new bone and bone cells produced by psoralen in collagen matrix to that produced by collagen matrix in vivo. Eighteen bone defects, 5 mm by 10 mm were created in the parietal bone of nine New Zealand White rabbits. Six defects were grafted with psoralen mixed with collagen matrix. Six defects were grafted with collagen matrix alone (negative control--collagen) and six were left empty (negative control--empty). Animals were killed on day 14 and the defects were dissected and prepared for histological assessment. Quantitative analysis of new bone formation and bone cells were made on 100 sections (50 sections for each group) using image analysis. A total of 454% more new bone was present in defects grafted with psoralen in collagen matrix than those grafted with collagen matrix. No bone was formed in the negative control--empty group. The amount of bone forming osteoblasts was also significantly greater in the psoralen group than the negative control--collagen group. Psoralen in collagen matrix has the effect of increasing new bone formation locally in vivo. Psoralen in collagen matrix can be developed as a bone graft material. PMID- 20196085 TI - Novel method for the synthesis of urea backbone cyclic peptides using new Alloc protected glycine building units. AB - Cyclization of bioactive peptides, utilizing functional groups serving as natural pharmacophors, is often accompanied with loss of activity. The backbone cyclization approach was developed to overcome this limitation and enhance pharmacological properties. Backbone cyclic peptides are prepared by the incorporation of special building units, capable of forming amide, disulfide and coordinative bonds. Urea bridge is often used for the preparation of cyclic peptides by connecting two amine functionalized side chains. Here we present urea backbone cyclization as an additional method for the preparation of backbone cyclic peptide libraries. A straightforward method for the synthesis of crystalline Fmoc-N(alpha) [omega-amino(Alloc)-alkyl] glycine building units is presented. A set of urea backbone cyclic Glycogen Synthase Kinase 3 analogs was prepared and assessed for protein kinase B inhibition as anticancer leads. PMID- 20196084 TI - In vivo anabolic effect of strontium on trabecular bone was associated with increased osteoblastogenesis of bone marrow stromal cells. AB - In vitro studies have demonstrated that strontium (Sr) could increase osteogenic differentiation of bone marrow stromal cells (BMSCs). We investigated the in vivo effect of Sr on BMSCs. Thirty-six female rats were randomly divided into the following groups: sham operated and treated with either vehicle (Sham + Veh) or Sr compound (Sham + Sr) and ovariectomized and treated with either vehicle (OVX + Veh) or Sr compound (OVX + Sr). Vehicle and Sr were orally administrated daily starting immediately after the surgery and continuing for 12 weeks. The anabolic effect of Sr on trabecular bone was determined at the structural and tissue level by microCT and histomorphometry, respectively. Colony formation assays demonstrated that BMSCs exhibited higher osteogenic colony but lower adipogenic colony in Sr-treated versus Veh-treated OVX rats. The mRNA level of osteogenic genes was higher, while the mRNA level of adipogenic genes was lower in BMSCs from Sr-treated versus Veh-treated Sham and OVX rats. The effect of Sr on rat BMSCs was reproducible in human BMSCs. Taken together, this study suggests that the anabolic effect of Sr on normal or osteoporotic bones is associated with increased osteoblastic differentiation of BMSCs. PMID- 20196086 TI - Integrated genomic profiling identifies candidate genes implicated in glioma genesis and a novel LEO1-SLC12A1 fusion gene. AB - We performed genotyping and exon-level expression profiling on 21 glioblastomas (GBMs) and 19 oligodendrogliomas (ODs) to identify genes involved in glioma initiation and/or progression. Low-copy number amplifications (2.5 < n < 7) and high-copy number amplifications (n > 7) were more frequently observed in GBMs; ODs generally have more heterozygous deletions per tumor. Four high-copy amplicons were identified in more than one sample and resulted in overexpression of the known oncogenes EGFR, MDM2, and CDK4. In the fourth amplicon, RBBP5, a member of the RB pathway, may act as a novel oncogene in GBMs. Not all hCNAs contain known genes, which may suggest that other transcriptional and/or regulatory elements are the target for amplification. Regions with most frequent allelic loss, both in ODs and GBMs, resulted in a reduced expression of known tumor suppressor genes. We identified a homozygous deletion spanning the Pragmin gene in one sample, but direct sequencing of all coding exons in 20 other glioma samples failed to detect additional genetic changes. Finally, we screened for fusion genes by identifying aberrant 5'-3' expression of genes that lie over regions of a copy number change. A fusion gene between exon 11 of LEO1 and exon 10 of SLC12A1 was identified. Our data show that integrated genomic profiling can identify genes involved in tumor initiation, and/or progression and can be used as an approach to identify novel fusion genes. PMID- 20196087 TI - Tunable water channels with carbon nanoscrolls. AB - Molecular dynamics simulations and theoretical analyses are performed to show that the flow rate of water through the core of carbon nanoscrolls (CNSs) can be adjusted over a broad range through the effective surface energy, which in turn can be tuned by an applied DC or AC electric field. The results suggest that the CNSs hold great promise for applications such as tunable water and ion channels, nanofluidic devices, and nanofilters, as well as tunable gene- and drug-delivery systems. PMID- 20196088 TI - Fabrication of tunable spherical colloidal crystals immobilized in soft hydrogels. PMID- 20196089 TI - Sequential reactions directed by core/shell catalytic reactors. AB - Millimeter-sized reactor particles made of permeable polymer doped with catalysts arranged in a core/shell fashion direct sequences of chemical reactions (e.g., alkyne coupling followed by hydrogenation or hydrosilylation followed by hydrogenation). Spatial compartmentalization of catalysts coupled with the diffusion of substrates controls reaction order and avoids formation of byproducts. The experimentally observed yields of reaction sequences are reproduced by a theoretical model, which accounts for the reaction kinetics and the diffusion of the species involved. PMID- 20196091 TI - Selflessness and perfectionism as predictors of pathological eating attitudes and disorders: A longitudinal study. AB - This paper examines the role that selflessness and perfectionism may play as possible predictors of pathological eating attitudes and eating disorders (ED). 1057 schoolgirls (seventh to ninth grade) participated in the initial screening phase. They were administered the Eating Attitudes Test (EAT-26), Selflessness Scale (SS) and Multidimensional Perfectionism Scale (MPS). Based on their EAT-26 scores, 150 girls were invited to a clinical interview 2 years later (second phase). In the third phase 4 years later, 243 girls who completed the questionnaires in the seventh grade were the target of re-administration of these scales. Seventh-grade selflessness scores at initial screening phase predicted ED status determined in clinical interview at the 2-year interval and abnormal eating attitudes at the 4-year interval, above and beyond baseline seventh-grade eating-attitude scores. Perfectionism was not found to predict the development of neither ED nor abnormal eating attitudes. Preventional and therapeutic implications of the role of selflessness as a predisposing factor for ED are discussed. PMID- 20196090 TI - Synthesis of disulfated peptides corresponding to the N-terminus of chemokines receptors CXCR6 (CXCR6 1-20) and DARC (DARC 8-42) using a sulfate-protecting group strategy. AB - Tyrosine sulfation is a post translational modification that occurs on integral membrane and secreted proteins, and is required for mediating crucial biological processes. Until recently the synthesis of sTyr peptides, especially those containing multiple sTyr residues, were among the most challenging peptides to prepare. We recently described an efficient strategy for Fmoc-based solid phase synthesis of sTyr peptides in which the sulfate group in the sTyr residue(s) is protected with a DCV group (FmocTyr(SO(3)DCV)OH, 1). After cleavage of the peptide from the support the DCV group is removed by hydrogenolysis. Here we demonstrate that sTyr peptides containing Met or Trp residues can be prepared using our sulfate-protecting group strategy by preparing peptides corresponding to residues 1-20 of chemokine receptor CXCR6 and 8-42 of chemokine receptor DARC. Removing the DCV groups at the end of the syntheses was readily achieved, without any reduction of the indole ring in Trp, by performing the hydrogenolysis in the presence of triethylamine. These conditions were found to be particularly efficient for removing the DCV group and superiour to our original conditions using H(2), ammonium formate, Pd/C. The presence of Met was found not to interfere with the removal of the DCV group. The use of pseudoproline dipeptides and N-backbone protection with the 2,4-dimethoxybenzyl group were found to be very effective tactics for preventing aggregation and aspartimide formation during the synthesis of these peptides. We also report an alternative and more cost effective synthesis of amino acid 1. PMID- 20196092 TI - French adaptation of the eating disorder recovery self-efficacy questionnaire (EDRSQ): psychometric properties and conceptual overview. AB - High prevalence of Eating Disorders (EDs) and poor treatment outcome rates have urged research in the assessment of EDs. Self-efficacy is a key motivational factor in the recovery from EDs. A self-report measure, the Eating Disorder Recovery Self-Efficacy Questionnaire (EDRSQ), was recently developed to assess confidence in adopting healthy eating behaviours and in maintaining a realistic body image. The objectives of this study were to (a) translate the EDRSQ to French (EDRSQ-F), (b) assess the psychometric properties of this French version, and (c) establish normative data for a non-clinical sample. Participants were 203 undergraduate women. They completed the EDRSQ-F and measures of ED symptoms, depression and self-esteem. A confirmatory factor analysis (CFA) revealed a bi factorial structure. Both scales demonstrated evidence of reliability and theoretically consistent evidence of construct validity. Findings support the validity of the EDRSQ-F and suggest it is a useful instrument for the assessment of EDs. PMID- 20196093 TI - Strategies to recruit and retain college smokers in cessation trials. AB - Techniques to recruit and retain college fraternity and sorority members who reported past 30-day smoking into a cessation trial are described. Recruitment efforts included relationship-building, raffles, and screening survey administration during existing meetings. Surveys were administered to 76% (n = 3,276) of members in 30 chapters, 79% of eligible members agreed to participate, and 76% of those completed assessments and were enrolled in the trial (n = 452). The retention rate was 73%. Retention efforts included cash incentives, flexible scheduling, multiple reminders, chapter incentives, and use of chapter members as study personnel. Retention was not related to demographic, behavioral, or group characteristics. The strategies of partnership, convenience, and flexibility appear effective and may prove useful to investigators recruiting similar samples. PMID- 20196094 TI - Immigrants as crime victims: Experiences of personal nonfatal victimization. AB - BACKGROUND: Immigrants to the United States are disproportionately victims of homicide mortality in and outside the workplace. Examining their experiences with nonfatal victimization may be helpful in understanding immigrant vulnerability to violence. METHODS: We compared the annual prevalence of nonfatal personal victimization experienced by immigrant and US-born adults by sociodemographics, employment, occupation, industry, smoking, alcohol and drug use using data from Wave 1 National Epidemiologic Survey on Alcohol and Related Conditions. RESULTS: The prevalence of victimization among immigrants was comparable to that among US born adults [3.84% (95% CI: 3.18-4.63) vs. 4.10% (95% CI: 3.77-4.44)]. Lower percentages of victimization experienced by immigrants were seen among the unmarried, those age 30-44 years, and among residents of central city areas as compared to those groups among the US-born. For immigrants entering the US as youth, the victimization prevalence declines with greater years of residency in US. Multivariate logistic regression models suggest that, the odds of victimization was significantly associated with age, family income, marital status, central city residency, smoking, and drug use while employment status was not a significant factor. Immigrant workers with farming/forestry occupations might face a higher risk of being victims of violence than their US-born counterparts. CONCLUSIONS: The prevalence of victimization among immigrants was comparable to that among US-born adults. Employment status and industry/occupation overall were not significant risk factors for becoming victims of violence. PMID- 20196095 TI - A global perspective of migration and occupational health. AB - BACKGROUND: Global migration has dramatically increased over the past decade and is at an all-time high, approaching 200 million persons per year. Demographics and economic interdependence suggest that immigration will continue for the near future at record high levels. METHODS: A review of the few studies that have investigated occupational injury and illness rates among immigrant populations. RESULTS: Existing data indicate that higher rates of fatal and non-fatal injuries are common compared to native populations. This increase is in part due to immigrants working in higher risk occupations (e.g., agriculture, construction), but occupational morbidity and mortality is higher among immigrants than native born workers within occupational categories. CONCLUSIONS: Research is needed to identify the causes of increased risk among immigrants and to provide direction to effective public health interventions. Research methods must be adapted to different epidemiologic characteristics of immigrant populations, including lack of standard sampling frames, different language and culture from the dominant culture, and precarious work status. PMID- 20196096 TI - Migration and occupational health: Shining a light on the problem. PMID- 20196097 TI - Working to eat: Vulnerability, food insecurity, and obesity among migrant and seasonal farmworker families. AB - BACKGROUND: Food insecurity and obesity have potential health consequences for migrant and seasonal farm workers (MSFW). METHODS: Thirty-six Latino MSFW working in eastern North Carolina whose children attended Migrant Head Start completed interviews, focus groups and home visits. Content analysis, nutrient analysis, and non-parametric statistical analysis produced results. RESULTS: MSFW (63.8%) families were food insecure; of those, 34.7% experienced hunger. 32% of pre school children were food insecure. Food secure families spent more money on food. Obesity was prevalent in adults and children but the relationship to food insecurity remains unclear. Strategies to reduce risk of foods insecurity were employed by MSFW, but employer and community assistance is needed to reduce their risk. CONCLUSIONS: Food insecurity is rooted in the cultural lifestyle of farmwork, poverty, and dependency. MSFW obesity and food insecurity require further study to determine the relationship with migration and working conditions. Networking and social support are important for MSFW families to improve food security. Policies and community/workplace interventions could reduce risk of food insecurity and improve the health of workers. PMID- 20196098 TI - Antidepressant drug action: a neuropsychological perspective. PMID- 20196099 TI - Tribute to Jerilyn Ross. PMID- 20196100 TI - Distinct electrocortical and behavioral evidence for increased attention to threat in generalized anxiety disorder. AB - BACKGROUND: Neural activity is increasingly used in addition to behavioral measures to study anxiety and attentional biases toward threatening stimuli. Event-related potentials (ERPs) might be particularly useful because of their excellent temporal resolution. In particular, the late positive potential (LPP) reflects increased attention to emotional stimuli-and was recently found to be larger with increasing state anxiety. This study sought to examine the LPP among individuals with generalized anxiety disorder (GAD). METHODS: Fifteen individuals with GAD and 15 healthy controls (HCs) viewed briefly presented pairs of aversive and neutral pictures that were presented to the left and right of, as well as above and below, fixation on each trial; ERP and behavioral measures were recorded as participants indicated whether the horizontal or vertical image pairs were the same or different. RESULTS: Aversive pictures presented in unattended locations were associated with more errors overall, and this effect was larger in GAD than HC participants. Moreover, aversive targets elicited larger LPPs across all participants; this difference was larger in GAD than HC participants when distracters were neutral. CONCLUSIONS: Threatening stimuli presented in both target and distracting spatial locations have a greater impact on GAD than HC participants. Behavioral and ERP measures provide complimentary indices of attention toward threat in GAD. In terms of attentional control theory, behavioral interference indexes impaired processing effectiveness, whereas the LPP might index reduced processing efficiency in GAD. Both measures may provide unique windows onto how increased stimulus-driven attention to threat impacts and characterizes GAD. PMID- 20196102 TI - Biology of Aurora A kinase: implications in cancer manifestation and therapy. AB - The Aurora A kinase belongs to serine/threonine group of kinases, well known for its role in cell cycle, especially in the regulation of mitosis. Numerous substrates of Aurora A kinase have been identified, which are predominantly related to cell cycle progression while some of them are transcription factors. Aurora A-mediated phosphorylation can either directly or indirectly regulate the function of its substrates. There are overwhelming evidences which report overexpression and gene amplification of Aurora A in several human cancers, and suggest that Aurora A could be a bona fide oncogene involved in tumorigenesis. Hence, Aurora A plays wide-ranging roles in both mitosis and its deregulation manifests in cancer progression. These observations have favored the choice of Aurora kinases as a target for cancer therapy. Recently, numerous small molecules have been discovered against Aurora kinases and many have entered clinical trials. Most of these small-molecule modulators designed are specific against either Aurora A or Aurora B, but some are dual inhibitors targeting the ATP binding site which is highly conserved among the three human homologues of Aurora kinase. In this review, we discuss the physiological functions of Aurora A, interactions between Aurora A kinase and its cellular substrates, tumorigenesis mediated by Aurora A kinase upon overexpression, and small-molecule modulators of Aurora kinase as targets for cancer therapy. PMID- 20196103 TI - Selective MMP13 inhibitors. AB - Pharmacology of MMP13 and MMP13 selective inhibitors is reviewed. PMID- 20196101 TI - The serotonin transporter polymorphism (5-HTTLPR): allelic variation and links with depressive symptoms. AB - BACKGROUND: We compare the genotype distribution for the serotonin transporter polymorphism (5-HTTLPR) in a sample of older Taiwanese adults with samples of various racial and ethnic groups collected in other studies. We also explore interactions among sex, stressors, and 5-HTTLPR genotype on depressive symptoms in our sample. METHODS: Using a nationally representative sample of 984 Taiwanese aged 53 and older, we model depressive symptoms as a function of 5-HTTLPR genotype and two classes of stressors: lifetime trauma and recent major life events. We test two- and three-way interactions among stressors, 5-HTTLPR, and sex. RESULTS: This sample exhibits higher frequency of S/S and lower frequency of L/L genotype than Western samples, but the distribution is comparable to those in East Asian populations. Nearly 9% carry an allele (XL) that has rarely been reported in the literature. Although the gene-environment (GxE) interaction with recent major life events is not significant, our results suggest that trauma has a worse effect on depressive symptoms for those with S/S or S/L genotype than for those who do not carry the S allele (P<0.05). We find no evidence that this GxE interaction varies by sex. CONCLUSIONS: Previous studies of this GxE interaction have been inconclusive, perhaps because interactions between genotype and stressful events are more prominent under extreme stressors. Our findings underscore the need to move beyond a bi-allelic parameterization of the 5-HTTLPR polymorphism and raise questions about why East Asian populations exhibit low rates of depression despite a high frequency of the S allele. PMID- 20196104 TI - A scanning electron microscopy specimen holder for viewing different angles of a single specimen. AB - The specimen holder for scanning electron microscopy described herein allows a single specimen to be examined in any possible view and significantly improves object illumination. The specimen is glued to a fine pin and flexibly mounted on a double-sided adhesive conductive pad on a rotatable pivot. A milled pot placed beneath the specimen acts as an electron trap. This provides a homogeneous black image background by minimizing noisy signals from the specimen's surroundings. PMID- 20196105 TI - Low-temperature glycol methacrylate resin embedding method: A protocol suitable for bone marrow immunohistochemistry, PCR, and fish analysis. AB - Molecular analyses such as fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) are demanded to improve diagnostic accuracy in addition to immunohistopathology of bone marrow (BM) trephine specimens. Conventional BM embedding method needs decalcification, and its procedure may impair tissue morphology and DNA quality. Here, we report an undecalcified method by which glycol methacrylate resin is polymerized at low temperature (4 degrees C). Using this method, BM enzyme activity and antigenic determinants are well preserved, and moreover, DNA extracted from plastic embedding sections is suitable for PCR amplification and sequencing, FISH analysis can be well done because of the DNA integrity of BM sections. If working with BM trephine specimen, our protocol offers the possibility to combine superior morphology with modern molecular analysis. PMID- 20196106 TI - Optimization of culture conditions for an efficient xeno-feeder free limbal cell culture system towards ocular surface regeneration. AB - Ex vivo expansion of limbal stem cells from a small biopsy and its subsequent transplantation is the golden choice of treatment for limbal stem cell deficiency. Use of murine 3T3 feeder layer is a prerequisite for this ex vivo expansion. There is an ever-increasing demand for feeder free cultures to avoid xenotoxicity and transmission of xeno-diseases to human system. This study was aimed to establish an efficient xeno-feeder free limbal culture system towards ocular surface regeneration. To study the effect of initial dispase treatment and culture system used, migratory distance of cells from explants was analyzed from phase contrast images using "interactive measurements" of Qwin software (Leica). Expression of p63 in different culture systems was studied by immunofluorescent staining, followed by quantitative confocal microscopy (Carl Zeiss). Results showed dispase treatment was not necessary for establishing limbal explant culture. A combination of Iscove's modified Dulbecco's medium and Panserin 801 resulted in formation of autofeeder layer with maintenance of progenitor characteristics, thus mimicking natural tissue architecture. Further analysis of this culture system showed that cells could be cultured till confluency. Immunofluorescent staining of ABCG2 revealed presence of stem cell marker in the confluent cell layer. Scanning Electron Micrographs demonstrated homogenous population of tightly packed cells in this culture system. Replacement of bovine serum with autologous serum did not affect morphology or growth of cells in this culture system. This study will be a major step in the development of xeno-feeder free epithelial equivalents towards ocular surface reconstruction. PMID- 20196107 TI - Expression and function of phosphodiesterases in nitrofen-induced congenital diaphragmatic hernia in rats. AB - BACKGROUND: Congenital diaphragmatic hernia (CDH) is an anomaly associated with pulmonary hypoplasia and pulmonary hypertension (PH). The limited efficacy of current approaches to treat PH in CDH, including inhaled nitric oxide (NO), drives the search for other therapies. Phosphodiesterases (PDEs) degrade cyclic nucleotide second messenger cAMP and cGMP downstream of NO thereby limiting the vasodilatory response to NO. OBJECTIVE: To identify therapeutic targets by cataloguing the expression and function of PDE isoforms in the pulmonary vasculature in nitrofen-induced CDH in fetal rats. METHODS/RESULTS: Quantitative RT-PCR revealed PDE1-5 and PDE9 mRNA expression in pulmonary arteries (PAs) of control and nitrofen-induced CDH term fetal rats. In this order of potency, the PDE inhibitors Sildenafil (PDE5) > EHNA (PDE2) > Rolipram (PDE4) > Cilostamide (PDE3) all dilated isolated third generation PA after pre-constriction with the thromboxane analog U46619. Hyperoxic pre-incubation of PAs significantly attenuated vasodilatation induced by the PDE5 inhibitor Sildenafil (65% vs. 33%, P < 0.004). CDH PAs dilated significantly less to PDE2 inhibitor EHNA compared to control (51% vs. 72%, P < 0.05). Subsequently PDE2 protein expression was higher in PAs of CDH animals. CONCLUSION: Most PDE isoforms exist in the PAs of fetal rats and their inhibition causes pulmonary vasodilatation. PDE5 inhibition was the most potent vasodilator, however, there were no differences between groups. PDE5-induced vasodilatation was attenuated by hyperoxic pre-incubation. PDE inhibitors might be considered therapeutic targets in combination with iNO in neonates with CDH. PMID- 20196108 TI - Estimation of renal function in patients with eating disorders. AB - BACKGROUND: Renal function could be evaluated with different equations such as Cockcroft-Gault formula (C-G), Mayo Clinic Quadratic (MAYO) and four MDRD variables. Clinical application of different formulae in conditions with severe energy restriction or in obese subjects is still a matter of investigation. METHOD: Renal function of 55 anorexia nervosa (AN) and 44 bulimia nervosa (BN) patients was evaluated with C-G formula for creatinine clearance calculation, and glomerular filtration rate (GFR) was estimated with MAYO and MDRD equations. RESULTS: BN group was older and had higher weight, body mass index (BMI), body surface area than AN subjects; however, their mean BMI was in the normal range. AN group had better renal function than BN one when it was evaluated with MAYO and MDRD; on the contrary, it was worse when it was calculated with C-G. The results obtained from the three formulae were poorly correlated and Bland-Altman analysis confirmed that the results of the three formulae were not in agreement. DISCUSSION: C-G is inaccurate when it is applied to obese or cachectic subjects. MDRD underestimates renal function in normal-high GFR. MAYO seems to be a good alternative to the other equations leading to correct classification of patients; therefore, it should be used to diagnose eating disorder subjects as renal insufficient. PMID- 20196109 TI - Appetite-focused dialectical behavior therapy for the treatment of binge eating with purging: a preliminary trial. AB - OBJECTIVE: This treatment development study investigated the acceptability and efficacy of a modified version of dialectical behavior therapy (DBT) for bulimia nervosa (BN), entitled appetite focused DBT (DBT-AF). METHOD: Thirty-two women with binge/purge episodes at least one time per week were randomly assigned to 12 weekly sessions of DBT-AF (n = 18) or to a 6-week delayed treatment control (n = 14). Participants completed the EDE interview and self-report measures at baseline, 6 weeks, and posttreatment. RESULTS: Treatment attrition was low, and DBT-AF was rated highly acceptable. At 6 weeks, participants who were receiving DBT-AF reported significantly fewer BN symptoms than controls. At posttest, 26.9% of the 26 individuals who entered treatment (18 initially assigned and 8 from the delayed treatment control) were abstinent from binge/purge episodes for the past month; 61.5% no longer met full or subthreshold criteria for BN. Participants demonstrated a rapid rate of response to treatment and achieved clinically significant change. DISCUSSION: Results suggest that DBT-AF warrants further investigation as an alternative to DBT or cognitive behavior therapy for BN. PMID- 20196110 TI - Is home spirometry useful in diagnosing asthma in children with nonspecific respiratory symptoms? AB - BACKGROUND: Variation of lung function is considered to be a hallmark of asthma. Although guidelines recommend measuring it as a diagnostic tool for asthma, the usefulness of this approach has not been studied in children. AIM: To assess the usefulness of home spirometry in children with nonspecific lower respiratory tract symptoms, to diagnose or exclude asthma. METHODS: In school-aged children, referred by their general practitioner because of chronic respiratory symptoms of unknown origin, the diagnosis of asthma was made or excluded by a pediatric pulmonologist (gold standard), based on international guidelines and a standardized protocol. Additionally, children measured peak expiratory flow (PEF) and forced expiratory flow in 1 sec (FEV(1)) twice daily for 2 weeks on a home spirometer, from which diurnal variation was calculated. These results (index test) were not revealed to the pediatric pulmonologist. The value of home spirometry to diagnose asthma was calculated. RESULTS: Sixty-one children (27 boys) were included (mean age: 10.4 years; range: 6-16 years). Between asthma and no asthma, the mean difference in PEF variation was 4.4% (95% CI: 0.9-7.9; P = 0.016) and in FEV(1) variation 4.5% (95% CI: 1.6-7.4; P = 0.003). Sensitivity and specificity, based on the 95th-centile of the reference values for PEF and FEV(1) variation (12.3% and 11.8%, respectively) were 50% and 72% for PEF variation and 45% and 92% for FEV(1) variation. The likelihood ratio was 1.8 for PEF and 5.6 for FEV(1). CONCLUSIONS: The contribution of home spirometry in the diagnostic process for asthma in schoolchildren with nonspecific respiratory symptoms is limited. PMID- 20196111 TI - On a multistable dynamic model of behavioral and perceptual infant development. AB - In this theoretical work, we treat behavioral and perceptual issues on an equal footing and examine the emergence of mutually exclusive behavioral patterns and perceptual variables during infant development from the perspective of multistable competitive dynamic systems. Accordingly, behavioral modes and modes of perception compete with each other for activation. One and only one mode survives the mode-mode competition, which accounts for the incompatibility of modes being considered. However, the winning behavioral or perceptual state is not predefined. Rather, we argue that during particular stages of maturation multiple modes coexist for the same set of developmental, body-scaled, and environmental parameters or constraints. The winning behavioral or perceptual state depends on these parameters as well as on initial conditions as operationalized in terms of previously performed behaviors or utilized perceptual stimuli. We give explicit examples of our approach and address the emergence of two-handed grasping and catching movements and the emergence of monocular and binocular vision during infant development. In particular, we propose that the emergence of midline crossing movements in 3- to 6-month-old infants involves two independent but interaction control parameters: a body-scaled and a developmental one. Likewise, we argue that the onset of binocularity in infants involves two independent but interaction control parameters: a developmental and an environmental one. PMID- 20196112 TI - Putting pubertal timing in developmental context: implications for prevention. AB - This article examines selected findings regarding the consequences of difference in timing of pubertal onset in order to build an explanatory model of puberty in context. We also seek to shed light on possible prevention efforts targeting adolescent risk. To date, there is substantial evidence supporting early onset effects on both internalizing and externalizing problems during the adolescent decade and possibly beyond. However, such effects do not directly speak to preventive intervention. The biological, familial, and broader relationship contexts of puberty are considered along with unique contexts for early maturing girls versus boys. Finally, we identify potential strategies for intervention based on these explanatory models. PMID- 20196113 TI - Contactless passive diagnosis for brain intracranial applications: A study using dielectric matching materials. AB - A prototype system for passive intracranial monitoring using microwave radiometry is proposed. It comprises an ellipsoidal conductive wall cavity to achieve beamforming and focusing, in conjunction with sensitive multiband receivers for detection. The system has already shown the capability to provide temperature and/or conductivity variations in phantoms and biological tissue. In this article, a variant of the initially constructed modality is theoretically and experimentally investigated. Specifically, dielectric matching materials are used in an effort to improve the system's focusing attributes. The theoretical study investigates the effect of dielectric matching materials on the system's detection depth, whereas measurements with phantoms focus on the investigation of the system's detection level and spatial resolution. The combined results suggest that the dielectric matching layers lead to the improvement of the system's detection depth and temperature detection level. Also, the system's spatial resolution is explored at various experimental setups. Theoretical and experimental results conclude that with the appropriate combination of operation frequencies and dielectric layers, it is possible to monitor areas of interest inside human head models with a variety of detection depths and spatial resolutions. PMID- 20196114 TI - A missing link in the puzzle: brown adipose tissue. PMID- 20196115 TI - Epigenetic regulation of cancer stem cell marker CD133 by transforming growth factor-beta. AB - Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. CD133, a transmembrane glycoprotein, is an important cell surface marker for both stem cells and cancer stem cells in various tissues including liver. CD133 expression has been recently linked to poor prognosis in HCC patients. CD133+ liver cancer cells are characterized by resistance to chemotherapy, self-renewal, multilineage potential, increased colony formation, and in vivo cancer initiation at limited dilution. Recent studies demonstrate that CD133 expression is regulated by DNA methylation. In this study, we explored the role of transforming growth factor beta (TGFbeta), a multifunctional cytokine that plays a critical role in chronic liver injury, in the regulation of CD133 expression. TGFbeta1 is capable of up-regulating CD133 expression specifically within the Huh7 HCC cell line in a time- and dose-dependent manner. Most important, TGFbeta1-induced CD133+ Huh7 cells demonstrate increased tumor initiation in vivo. Forced expression of inhibitory Smads, including Smad6 and Smad7, attenuated TGFbeta1-induced CD133 expression. Within CD133- Huh7 cells, TGFbeta1 stimulation inhibited the expression of DNA methyltransferases (DNMT) 1 and DNMT3beta, which are critical in the maintenance of regional DNA methylation, and global DNMT activity in CD133- Huh7 cells was inhibited by TGFbeta1. DNMT3beta inhibition by TGFbeta1 was partially rescued with overexpression of inhibitory Smads. Lastly, TGFbeta1 treatment led to significant demethylation in CD133 promoter-1 in CD133- Huh7 cells. CONCLUSION: TGFbeta1 is able to regulate CD133 expression through inhibition of DNMT1 and DNMT3beta expression and subsequent demethylation of promoter-1. TGFbeta1-induced CD133+ Huh7 cells are tumorigenic. The mechanism by which TGFbeta induces CD133 expression is partially dependent on the Smads pathway. PMID- 20196116 TI - Antituberculosis therapy-induced acute liver failure: magnitude, profile, prognosis, and predictors of outcome. AB - Antituberculosis therapy (ATT)-associated acute liver failure (ATT-ALF) is the commonest drug-induced ALF in South Asia. Prospective studies on ATT-ALF are lacking. The current study prospectively evaluated the magnitude, clinical course, outcome, and prognostic factors in ATT-ALF. From January 1986 to January 2009, 1223 consecutive ALF patients were evaluated: ATT alone was the cause in 70 (5.7%) patients. Another 15 (1.2%) had ATT and simultaneous hepatitis virus infection. In 44 (62.8%) patients, ATT was prescribed empirically without definitive evidence of tuberculosis. ATT-ALF patients were younger (32.87 [+/ 15.8] years), and 49 (70%) of them were women. Most had hyperacute presentation; the median icterus encephalopathy interval was 4.5 (0-30) days. The median duration of ATT before ALF was 30 (7-350) days. At presentation, advanced encephalopathy and cerebral edema were present in 51 (76%) and 29 (41.4%) patients, respectively. Gastrointestinal bleed, seizures, infection, and acute renal failure were documented in seven (10%), five (7.1%), 26 (37.1%), and seven (10%) patients, respectively. Compared with hepatitis E virus (HEV) and non-A non E-induced ALF, ATT-ALF patients had nearly similar presentations except for older age and less elevation of liver enzymes. The mortality rate among patients with ATT-ALF was high (67.1%, n = 47), and only 23 (32.9%) patients recovered with medical treatment. In multivariate analysis, three factors independently predicted mortality: serum bilirubin (>or=10.8 mg/dL), prothrombin time (PT) prolongation (>or=26 seconds), and grade III/IV encephalopathy at presentation. CONCLUSION: ATT-ALF constituted 5.7% of ALF at our center and had a high mortality rate. Because the mortality rate is so high, determining which factors are predictors is less important. A high proportion of patients had consumed ATT empirically, which could have been prevented. PMID- 20196118 TI - Identifying hepatitis C virus genotype 2/3 patients who can receive a 16-week abbreviated course of peginterferon alfa-2a (40KD) plus ribavirin. AB - The objective of this analysis was to compare sustained virological response (SVR) and relapse rates in patients with a rapid virological response (RVR, HCV RNA <50 IU/mL at week 4) randomized to 24 or 16 weeks of treatment with peginterferon alfa-2a (40KD) 180 microg/week plus ribavirin 800 mg/day in the multinational ACCELERATE study. The analysis was restricted to patients who received treatment for 80% or more of the planned duration. Of 1309 eligible patients, 863 individuals (65.9%) achieved an RVR and were included in this analysis (458 assigned to 16 weeks and 405 assigned to 24 weeks). The overall SVR rate was significantly higher in patients randomized to 24 weeks of treatment (91% versus 82%; P = 0.0006) and among patients infected with genotype 2 (92% versus 81%; P = 0.0010) but not genotype 3 (90% versus 84%; P = 0.1308). Relapse rates were significantly lower among all patients randomized to 24 weeks of treatment: overall (6% versus 15%, P < 0.0001); in those infected with genotype 2 (5% versus 17%, P = 0.0001), and genotype 3 (7% versus 14%, P = 0.0489). SVR rates in patients with a viral load of 400,000 IU/mL or less randomized to 24 and 16 weeks of treatment were similar, 95% and 91% (P = 0.2012). Significant pretreatment predictors of SVR included assignment to 24 weeks of treatment (P = 0.0006), absence of advanced fibrosis on liver biopsy (P = 0.0032), lower HCV RNA level (P = 0.0017), and lower body weight (P < 0.0001). CONCLUSION: The standard 24-week regimen of peginterferon alfa-2a (40KD) plus ribavirin is significantly more effective than an abbreviated 16-week regimen in genotype 2/3 patients who achieve an RVR. Abbreviated regimens may be considered in patients with a low baseline viral load who achieve an RVR. PMID- 20196117 TI - Dissociation between liver inflammation and hepatocellular damage induced by carbon tetrachloride in myeloid cell-specific signal transducer and activator of transcription 3 gene knockout mice. AB - Liver injury is associated with inflammation, which is generally believed to accelerate the progression of liver diseases; however, clinical data show that inflammation does not always correlate with hepatocelluar damage in some patients. Investigating the cellular mechanisms underlying these events using an experimental animal model, we show that inflammation may attenuate liver necrosis induced by carbon tetrachloride (CCl(4)) in myeloid-specific signal transducer and activator of transcription 3 (STAT3) knockout mice. As an important anti inflammatory signal, conditional deletion of STAT3 in myeloid cells results in markedly enhanced liver inflammation after CCl(4) injection. However, these effects are also accompanied by reduced liver necrosis, correlating with elevated serum interleukin-6 (IL-6) and hepatic STAT3 activation. An additional deletion of STAT3 in hepatocytes in myeloid-specific STAT3 knockout mice restored hepatic necrosis but decreased liver inflammation. CONCLUSION: Inflammation-mediated STAT3 activation attenuates hepatocellular injury induced by CCl(4) in myeloid specific STAT3 knockout mice, suggesting that inflammation associated with a predominance of hepatoprotective cytokines that activate hepatic STAT3 may reduce rather than accelerate hepatocellular damage in patients with chronic liver diseases. PMID- 20196120 TI - Sustained virologic response prevents the development of esophageal varices in compensated, Child-Pugh class A hepatitis C virus-induced cirrhosis. A 12-year prospective follow-up study. AB - The incidence of de novo development of esophageal varices (EV) in patients with compensated liver cirrhosis has been determined by few studies in the short term and never in the long term. The aims of the present study were to determine the incidence and the risk factors associated with the development of EV and to assess whether antiviral treatment and achievement of sustained virologic response (SVR) may prevent de novo EV development in patients with HCV-induced cirrhosis. We studied 218 patients with compensated EV-free, HCV-induced cirrhosis consecutively enrolled between 1989 and 1992 at three referral centers in Milan, Italy. Endoscopic surveillance was performed at 3-year intervals according to international guidelines. SVR was defined as undetectable serum HCV RNA 24 weeks after treatment discontinuation. During a median follow-up of 11.4 years, 149/218 (68%) patients received antiviral treatment and 34 (22.8%) achieved SVR. None of the SVR patients developed EV compared with 22 (31.8%) of the 69 untreated subjects (P < 0.0001) and 45 (39.1%) of the 115 non-SVR patients (P < 0.0001). On multivariate analysis, HCV genotype 1b (hazard ratio [HR] 2.40; 95% confidence interval [CI] 1.17-4.90) and baseline model for end-stage liver disease (MELD) score (HR 1.20; 95% CI 1.07-1.35 for 1 point increase) were independent predictors of EV. CONCLUSION: In the long term, the achievement of SVR prevents the development of EV in patients with compensated HCV-induced cirrhosis. Therefore, in these patients, endoscopic surveillance can be safely delayed or avoided. Genotype 1b infection and MELD score identify the subset of patients at higher risk of EV development who need tailored endoscopic surveillance. PMID- 20196119 TI - S-adenosylmethionine regulates dual-specificity mitogen-activated protein kinase phosphatase expression in mouse and human hepatocytes. AB - Increased mitogen-activated protein kinase (MAPK) activity correlates with a more malignant hepatocellular carcinoma (HCC) phenotype. There is a reciprocal regulation between p44/42 MAPK (extracellular signal-regulated kinase [ERK]1/2) and the dual-specificity MAPK phosphatase MKP-1/DUSP1. ERK phosphorylates DUSP1, facilitating its proteasomal degradation, whereas DUSP1 inhibits ERK activity. Methionine adenosyltransferase 1a (Mat1a) knockout (KO) mice express hepatic S adenosylmethionine (SAM) deficiency and increased ERK activity and develop HCC. The aim of this study was to examine whether DUSP1 expression is regulated by SAM and if so, elucidate the molecular mechanisms. Studies were conducted using Mat1a KO mice livers, cultured mouse and human hepatocytes, and 20S and 26S proteasomes. DUSP1 messenger RNA (mRNA) and protein levels were reduced markedly in livers of Mat1a KO mice and in cultured mouse and human hepatocytes with protein falling to lower levels than mRNA. SAM treatment protected against the fall in DUSP1 mRNA and protein levels in mouse and human hepatocytes. SAM increased DUSP1 transcription, p53 binding to DUSP1 promoter, and stability of its mRNA and protein. Proteasomal chymotrypsin-like and caspase-like activities were increased in Mat1a KO livers and cultured hepatocytes, which was blocked by SAM treatment. SAM inhibited chymotrypsin-like and caspase-like activities by 40% and 70%, respectively, in 20S proteasomes and caused rapid degradation of some of the 26S proteasomal subunits, which was blocked by the proteasome inhibitor MG132. SAM treatment in Mat1a KO mice for 7 days raised SAM, DUSP1, mRNA and protein levels and lowered proteosomal and ERK activities. CONCLUSION: DUSP1 mRNA and protein levels are lower in Mat1a KO livers and fall rapidly in cultured hepatocytes. SAM treatment increases DUSP1 expression through multiple mechanisms, and this may suppress ERK activity and malignant degeneration. PMID- 20196122 TI - Solution structure of LC5, the CCR5- derived peptide for HIV-1 inhibition. AB - The synthetic peptide fragment (LC5: LRCRNEKKRHRAVRLIFTI) inhibits human immunodeficiency virus type 1 (HIV-1) infection of MT-4 cells. In this study, the solution structure of LC5 in SDS micelles was elucidated by using the standard (1)H two-dimensional NMR spectroscopic method along with circular dichroism and fluorescence quenching. The peptide adopts a helical structure in the C-terminal region (residues 13-16), whereas the N-terminal part remains unstructured. The importance of Phe17 in maintaining the structure of LC5 was demonstrated by replacing Phe17 with Ala, which resulted in the dramatic conformational change of LC5. The solution structure of LC5 elucidated in the present work provides a basis for further study of the mechanism of the inhibition of HIV-1 infection. PMID- 20196121 TI - Rm62, a DEAD-box RNA helicase, complexes with DSP1 in Drosophila embryos. AB - Two main classes of proteins, Polycomb group (PcG) and Trithorax group (TrxG), play a key role in the regulation of homeotic genes. These proteins act in multimeric complexes to remodel chromatin. A third class of proteins named Enhancers of Trithorax and Polycomb (ETP) modulates the activity of TrxG and PcG, but their role remains largely unknown. We previously identified an HMGB-like protein, DSP1 (Dorsal Switch Protein 1), which was classified as an ETP. Preliminary studies have revealed that DSP1 is involved in multimeric complexes. Here we identify a DEAD-box RNA helicase, Rm62, as partner of DSP1 in a 250-kDa complex. Coimmunoprecipitation assays performed on embryo extracts indicate that DSP1 and Rm62 are associated in 3- to 12-h embryos. Furthermore, DSP1 and Rm62 colocalize on polytene chromosomes. Consistent with these results, a mutation in Rm62 enhances a null mutation of dsp1 and also mutations of trxG or PcG, suggesting that Rm62 has characteristics of an ETP. We show here for the first time that an RNA helicase is involved in the maintenance of homeotic genes. PMID- 20196123 TI - Structure-activity relationship of indolicidin, a Trp-rich antibacterial peptide. AB - A series of Trp and Arg analogs of antibacterial indolicidin (Ind) was synthesized and the antimicrobial and hemolytic activities were investigated. [L(9)]Ind, [L(11)]Ind, [K(8),L(9)]Ind and [K(6, 8),L(9)]Ind showed desirable characteristics, exhibiting negligible hemolytic activity while keeping strong antibacterial activity. The results indicated that the Trp residue at position 11 essentially contributes to both activities and one can not be exchanged for the other, whereas the Trp residues at positions 4 and 9 play important roles in antimicrobial and hemolytic activities, respectively. The Trp residues at positions 6 and 8 play no important roles in biological activities. We then found that the retro analog of Ind showed higher antibacterial activity than Ind against both Gram-positive and Gram-negative bacteria but remarkably lower hemolytic activity than that of Ind. PMID- 20196124 TI - Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. AB - Elevated concentrations of unconjugated bilirubin (UCB) are responsible for neonatal jaundice and can eventually lead to kernicterus or death. The molecular mechanism of UCB toxicity is incompletely elucidated. The purpose of this study was to analyze changes in gene regulation mediated by UCB to determine novel pathways that contribute to UCB-mediated toxicity. We employed microarray analysis to determine changes in gene regulation mediated by UCB at both pro- (50 microM) and antioxidant (70 nM) concentrations in Hepa 1c1c7 cells at 1 and 6 h. The changes observed in select genes were validated with qPCR. Using immunoblot analysis, we validated these changes at the protein level for select genes and documented the activation of two proteins involved in the endoplasmic reticulum (ER) stress pathway, eIF2 alpha and PERK. Following treatment with 50 microM UCB, microarray analysis revealed the upregulation of many genes involved in ER stress (ATF3, BiP, CHOP, Dnajb1, and Herp). We demonstrate that upregulation of the proapoptotic transcription factor CHOP results in increased intracellular protein content. It was determined that activation of proteins involved in ER stress was an early event in UCB toxicity as eIF2 alpha and PERK were both phosphorylated and activated by 1 h posttreatment. We also demonstrate that procaspase-12 content, a proposed initiator caspase in ER stress-mediated apoptosis, is decreased by 4 h posttreatment. In conclusion, this study demonstrates that elevated concentrations of UCB (50 microM) are able to activate select components of the ER stress pathway in Hepa 1c1c7 cells, which may contribute to UCB mediated apoptosis. PMID- 20196125 TI - Evaluation of anatomical variation of the crista galli using computed tomography. AB - Pneumatization of the crista galli is a recognized incidental finding on computed tomography (CT), usually with little relevance to the clinical picture. There are, however, notable exceptions: congenital midline nasal defects including nasal dermoids have been seen to track through or near the crista galli. Mucocele development has also been seen. This study aimed to evaluate the variation in crista galli morphology and pneumatization and assess whether specific morphologies occur. A retrospective observational study was undertaken between November 2007 and January 2008. Using coronal and axial reconstructed CT views, images of the head in the region of the paranasal sinuses were assessed. Variations in the crista galli were classified according to their position relative to the cribriform plate and to the degree of pneumatization. Computed tomography findings of the morphology of the crista galli in 99 patients were reviewed and a classification system derived from the findings. Three variations of the position of the base of the crista galli were defined. In 28.3% of subjects the base of the crista galli did not extend below the level of the cribriform plate. In 63.6%, the crista galli extended less than 50% of its height below the cribriform plate and in 8.1% of the scans the crista galli extended more than 50% of its height below the cribriform plate. Pneumatization was noticed in 14.1% of the scans. Our results demonstrate the variation that occurs in the morphology and pneumatization of the crista galli. We hope this knowledge might be of help in preoperative planning of surgical approaches to sites of disease involving the crista galli. PMID- 20196126 TI - Blood supply to the lymphatic vessels in the leg: an incidental finding. AB - There are no reports or images of the blood supply to the lymphatic vessels. One lower limb of an unembalmed human cadaver was studied. Hydrogen peroxide (6%) was applied to find the lymphatic vessels by using a surgical microscope. The vessels were injected with a radio-opaque mixture and dissected. During the dissection, several sites of paralymphatics arteriole nutrient (PAN) vessels were found in close proximity to collecting lymphatic vessels in the medial aspect of the leg. The caliber of the lymphatic vessels was about 1 mm. The caliber of PAN vessels was <0.1 mm. The blood vessels were seen running along the lymphatic vessels. Some of them crossing the lymphatics and supplying the fatty tissue nearby and some running parallel on the lymph vessel walls. Histology sections show different-sized PAN vessels containing blood cells situated close to the lymphatic wall and within the lymphatic vessel wall. PAN vessels have been found and described. It will upgrade our anatomical knowledge and also be of benefit for medical and/or scientific research. PMID- 20196127 TI - Anomalies of the flexor carpi ulnaris: clinical case report and cadaveric study. AB - Flexor carpi ulnaris (FCU) is an ever-present muscle of the anterior flexor compartment of the forearm. Variations of FCU are uncommon, with additional slips or heads of muscles described, and only one reported case of an accessory muscle. We describe a unique clinical case report in which an accessory FCU was identified and describe the findings of 5,000 cadaveric dissections of the forearm, performed as part of an ongoing institutional study of anatomical variations. An aberrant accessory forearm flexor muscle was identified incidentally at the wrist during surgery for an anterior interosseous to ulnar nerve transfer for management of ulnar nerve palsy. This muscle was seen running superficial to the ulnar nerve and radial to the FCU proper, arising from the common flexor origin and inserting at the triquetral carpal bone. This was therefore suitably acknowledged as an "accessory FCU". The anomaly was identified as bilateral using ultrasound imaging, and was found to be anomalously innervated by the median nerve with nerve conduction studies. A subsequent review of 5,000 cadaveric dissections of the forearm did not identify any such variations related to FCU, despite identifying a range of variations of the other forearm flexor musculature. While the scarcity of this anomaly is thus highlighted, consideration of an accessory FCU, and its aberrant innervation is important in a range of surgical approaches. PMID- 20196128 TI - Predicting radial nerve location using palpable landmarks. AB - The purpose of this study is to predict the location of radial nerve (RN) utilizing palpable anatomic landmarks. Thirty-four paired upper limbs were dissected. The RN was localized: (1) at the humeral spiral groove (SG), (2) lateral intermuscular septum (LIS), and (3) at its' division into the posterior interosseous nerve (PIN) and radial sensory nerve (RSN). The PIN was located at the anterior aspect of the radial neck (AN). Humeral and radial lengths were measured. The RN traversed the SG, on average, 48% (36%-63%) of humeral length, distal to the greater tuberosity. The RN pierced the LIS, on average, 38% (29% 56%) of humeral length, proximal to the lateral epicondyle (LE). The PIN/RSN division occurred on average 1.0 cm (-11.4 to 3.5) distal to the LE. The PIN crossed the AN, on average, 10% (5%-14%) of radial length, distal to the radial head articular surface. PMID- 20196129 TI - Right heterotaxy with Hirschsprung's disease - a new association. AB - A baby girl with prenatal diagnosis of complex cardiac anomalies and diaphragmatic hernia was born at 36 weeks of gestation. At 4 hr of life, the baby developed respiratory distress and was intubated. She was found to have right hetetrotaxy with total anomalous pulmonary venous drainage into the portal vein, five hepatic veins draining the liver and intrathoracic herniation of the stomach. The child also developed abdominal distension on the second day of life with passage of scanty meconium. The diagnosis of Hirschsprung's disease (HD) was confirmed by histology. HD in association with right heterotaxy has not been reported earlier. The association of heterotaxy with HD in our patient raises a possible genetic link between the two anomalies that needs further research. PMID- 20196130 TI - Microsurgical and histomorphometric study of the occipital sinus: quantitative measurements using a novel approach of stereology. AB - Quantitative descriptions of the occipital sinus are lacking in the extant medical literature. Posterior fossa duras with the superior sagittal sinus, the inferior and superior petrosal sinuses were dissected and taken out from fresh human cadavers by cutting at the superior sagittal sinus, the marginal sinuses and the petrosal sinuses bilaterally. The length of the occipital sinuses was measured using calipers. A 0.5-cm section of the occipital sinus was cut out at its midpoint and prepared for measurements of the perimeter and diameter using a stereology workstation. The sinuses were also examined qualitatively using a surgical microscope. There was no occipital sinus in 6.6% of total 30 cases. Multiple occipital sinuses were seen in 10%. In one specimen, the sinus seemed incomplete, failing to reach the marginal sinuses. Some specimens gave the impression that more than one occipital sinus was present, nevertheless, careful dissection showed connections. The breadth of the sinus steadily narrowed downward in direction of foramen magnum. The inner wall with many fibrous bridges was tight, except the lateral parts that were easily separated into two dural sheets. The length of the sinus varied from 10 to 37 mm. The inner diameter (feret maximum) varied from 0.33 to 7.06 mm at midpoint. The breadth of the multiple sinuses did not exceed the mean of our series except in one case. The occipital sinus, which is generally ellipsoid in shape, functions in the majority of cases as a thin, single midline sinus. It may have less resistant recesses laterally. PMID- 20196131 TI - Commentary on Sabine Hildebrandt's Anatomy in the Third Reich. PMID- 20196132 TI - Selection of sleeping trees in pileated gibbons (Hylobates pileatus). AB - Selection and use patterns of sleeping sites in nonhuman primates are suggested to have multiple functions, such as predation avoidance, but they might be further affected by range defense as well as foraging constraints or other factors. Here, we investigate sleeping tree selection by the male and female members of one group of pileated gibbons (Hylobates pileatus) at Khao Ang Rue Nai Wildlife Sanctuary, Thailand. Data were collected on 113 nights, between September 2006 and January 2009, yielding data on 201 sleeping tree choices (107 by the female and 94 by the male) and on the characteristics of 71 individual sleeping trees. Each sleeping tree and all trees > or =40 cm diameter at breast height (DBH) in the home range were assessed (height, DBH, canopy structure, liana load) and mapped using a GPS. The gibbons preferentially selected tall (mean=38.5 m), emergent trees without lianas. The majority of the sleeping trees (53.5%) were used only once and consecutive reuse was rare (9.5%). Sleeping trees were closer to the last feeding tree of the evening than to the first feeding tree in the morning, and sleeping trees were located in the overlap areas with neighbors less often than expected based on time spent in these areas. These results suggest avoidance of predators as the main factor influencing sleeping tree selection in pileated gibbons. However, other non-mutually exclusive factors may be involved as well. PMID- 20196134 TI - Poly (ADP-ribose) polymerase-1 deficiency does not affect ethylnitrosourea mutagenicity in liver and testis of lacZ transgenic mice. AB - Poly (ADP-ribose) polymerase-1 (Parp1) has been implicated in DNA base excision repair, single- and double-strand break repair pathways, as well as in cell death by apoptosis or necrosis. We used Parp1(-/-) lacZ plasmid-based transgenic mice to investigate whether Parp1 deficiency influences the in vivo mutagenic and clastogenic response to the alkylating agent N-ethyl-N-Nitrosourea (ENU) in somatic and germ-cell tissues. The comparison of the lacZ mutant frequencies (MFs) between Parp1(+/+) and Parp1(-/-) mice showed that the ablation of Parp1 does not affect the spontaneous or ENU-induced MFs in liver and testis. In addition, the spectrum of the ENU-induced mutations was not dependent on the Parp1 status, given that similar spectra, consisting mostly of point mutations and a small fraction of deletions/insertions, wereobserved in organs of both Parp1(-/-) and Parp1(+/+) mice. Sequencing of point mutations revealed a consistent significant increase in A:T --> T:A base substitutions, typically induced by ENU. Overall, we observed that neither the frequency nor the spectrum of ENU-induced mutations demonstrated a specificity that could be attributed to the Parp1 impairment in mice organs. The analysis of micronucleus frequency in peripheral blood reticulocytes showed that ENU was clastogenic in both Parp1(-/-) and Parp1(+/+) mice and had a strong cytotoxic effect in Parp1(-/-) mice only. The present data suggest that, at a whole-organism level, Parp1-independent repair mechanisms may be operative in the removal of ENU-induced DNA lesions or that highly damaged cells may be preferentially committed to death when Parp1 is inactivated. PMID- 20196133 TI - Targeting and processing of site-specific DNA interstrand crosslinks. AB - DNA interstrand crosslinks (ICLs) are among the most cytotoxic types of DNA damage, and thus ICL-inducing agents such as cyclophosphamide, melphalan, cisplatin, psoralen, and mitomycin C have been used clinically as anticancer drugs for decades. ICLs can also be formed endogenously as a consequence of cellular metabolic processes. ICL-inducing agents continue to be among the most effective chemotherapeutic treatments for many cancers; however, treatment with these agents can lead to secondary malignancies, in part due to mutagenic processing of the DNA lesions. The mechanisms of ICL repair have been characterized more thoroughly in bacteria and yeast than in mammalian cells. Thus, a better understanding of the molecular mechanisms of ICL processing offers the potential to improve the efficacy of these drugs in cancer therapy. In mammalian cells, it is thought that ICLs are repaired by the coordination of proteins from several pathways, including nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR), homologous recombination (HR), translesion synthesis (TLS), and proteins involved in Fanconi anemia (FA). In this review, we focus on the potential functions of NER, MMR, and HR proteins in the repair of and response to ICLs in human cells and in mice. We will also discuss a unique approach, using psoralen covalently linked to triplex-forming oligonucleotides to direct ICLs to specific sites in the mammalian genome. PMID- 20196136 TI - Probing protein colloidal behavior in membrane-based separation processes using spectrofluorometric Rayleigh scattering data. AB - One of the primary problems in membrane-based protein separation is membrane fouling. In this study we explored the feasibility of employing Rayleigh light scattering data from fluorescence studies combined with chemometric techniques to determine whether a correlation could be established with membrane fouling phenomena. Membrane flux was measured in a dead-end UF filtration system and the effect of protein solution properties on the flux decline was systematically investigated. A variety of proteins were used as a test case in this study. In parallel, the colloidal behavior of the protein solutions was assessed by employing multiwavelength Rayleigh scattering measurements. To assess the usefulness of Rayleigh scattering measurements for probing the colloidal behavior of proteins, a protein solution of beta-lactoglobulin was used as a base-case scenario. The colloidal behavior of different beta-lactoglobulin solutions was inferred based on published data for this protein, under identical solution conditions, where techniques other than Rayleigh scattering had been used. Using this approach, good agreement was observed between scattering data and the colloidal behavior of this protein. To test the hypothesis that a high degree of aggregation will lead to increased membrane fouling, filtration data was used to find whether the Rayleigh scattering intensity correlated with permeate flux changes. It was found that for protein solutions which were stable and did not aggregate, fouling was reduced and these solutions exhibited reduced Rayleigh scattering. When the aggregation behavior of the solution was favored, significant flux declines occurred and were highly correlated with increased Rayleigh scattering. PMID- 20196137 TI - Lack of genotype effect on D1, D2 receptors and dopamine transporter binding in triple MOP-, DOP-, and KOP-opioid receptor knockout mice of three different genetic backgrounds. AB - We investigated D1, D2 receptors and dopamine transporter (DAT) binding levels in mice lacking all three opioid receptors and wild-type (WT) mice on three different genetic backgrounds. Quantitative autoradiography was used to determine the level of radioligand binding to the D1 and D2 receptors and DAT labeled with [(3)H]SCH23390, [(3)H]raclopride, and [(3)H]mazindol, respectively in triple opioid receptor knockout (KO) and WT maintained on C57BL/6 (B6) and 129/SvEvTac (129) as well as C57BL/6 x 129/SvPas (B6 x 129) strains. No significant genotype effect was observed in D1, D2 receptors and DAT binding in any regions analyzed in any of the strains studied, suggesting that a lack of all three opioid receptors does not influence D1, D2 receptors and DAT expression, irrespective of their genetic strain background. However, strain differences were observed in D1 binding between the three strains of mice studied. Lower levels of D1 binding were observed in the substantia nigra of B6 x 129 WT mice compared with the 129 WT mice and in the olfactory tubercle of B6 x 129 WT compared with B6 WT and 129 WT mice. Lower levels of D1 binding were observed in the caudate putamen of B6 x 129 KO mice compared with 129 KO mice. In contrast, no significant strain differences were observed in D2 and DAT binding between the three strains of mice in any regions analyzed. Overall, these results indicate a lack of modulation of the dopaminergic system by the deletion of all three opioid receptors regardless of different background strains. PMID- 20196139 TI - Continuous dopaminergic stimulation by pramipexole is effective to treat early morning akinesia in animal models of Parkinson's disease: A pharmacokinetic pharmacodynamic study using in vivo microdialysis in rats. AB - Short-acting dopamine (DA) agonists are usually administered several times a day resulting in fluctuating plasma and brain levels. DA agonists providing continuous dopaminergic stimulation may achieve higher therapeutic benefit for example by alleviating nocturnal disturbances as well as early morning akinesia. In the present study continuous release (CR) of pramipexole (PPX) was maintained by subcutaneous implantation of Alzet minipumps, whereas subcutaneous PPX injections were used to mimic PPX immediate release (IR) in male Wistar rats. In the catalepsy bar test, PPX-CR (1 mg/kg/day) reversed the haloperidol-induced motor impairment in the morning and over the whole observation period of 12h. In contrast, PPX-IR (tid 1 mg/kg, pre-treatment the day before) was not effective in the morning but catalepsy was reduced for 6 h after PPX-IR (1 mg/kg) injection. In the reserpine model, early morning akinesia indicated by the first motor activity measurement in the morning was significantly reversed by PPX-CR (2 mg/kg/day). Again, PPX-IR (tid 0.3 mg/kg, pre-treatment the day before) was not able to antagonise early morning akinesia. These results are in agreement with in vivo microdialysis measurements showing a continuous decrease of extracellular DA levels and a continuous PPX exposure in the PPX-CR (1 mg/kg/day) group. In contrast, PPX-IR (0.3 mg/kg) produced a transient decrease of extracellular DA levels over 6 h and showed maximum PPX levels 2 h after dosing which decreased over the following 6-8 h. The present study demonstrates that PPX-CR may offer a higher therapeutic benefit than PPX-IR on early morning akinesia and confirms earlier reports that PPX-IR reverses motor impairment for several hours. PMID- 20196138 TI - Mineralocorticoid receptor activation restores medial perforant path LTP in diabetic rats. AB - In the hippocampus, glucocorticoids bind to two types of receptors: the mineralocorticoid receptor, which binds corticosterone with high affinity and is tonically occupied; and the glucocorticoid receptor, which is occupied during stress and at certain phases in the circadian cycle. Diabetes mellitus increases levels of glucocorticoids in both humans and animal models. To explore the contributions of hippocampal corticosteroid receptors to the diabetes-induced suppression of neuroplasticity, we manipulated these receptors in hippocampal slices from streptozocin-diabetic rats, a model of Type 1 diabetes mellitus. STZ diabetes reduced long-term potentiation (LTP) at medial perforant path synapses in the dentate gyrus, and induced a bias in favor of long-term depression following intermediate stimulation frequencies. Bath application of the mineralocorticoid receptor agonist aldosterone restored LTP in slices from diabetic animals. These results suggest additional mechanisms for diabetes induced functional alterations and support a restorative role for dentate gyrus mineralocorticoid receptors. PMID- 20196140 TI - Differential effects of serotonin (5-HT)2 receptor-targeting ligands on locomotor responses to nicotine-repeated treatment. AB - We verified the hypothesis that serotonin (5-HT)(2) receptors control the locomotor effects of nicotine (0.4 mg kg(-1)) in rats by using the 5-HT(2A) receptor antagonist M100907, the preferential 5-HT(2A) receptor agonist DOI, the 5-HT(2C) receptor antagonist SB 242084, and the 5-HT(2C) receptor agonists Ro 60 0175 and WAY 163909. Repeated pairings of a test environment with nicotine for 5 days, on Day 10 significantly augmented the locomotor activity following nicotine administration. Of the investigated 5-HT(2) receptor ligands, M100907 (2 mg kg( 1)) or DOI (1 mg kg(-1)) administered during the first 5 days in combination with nicotine attenuated or enhanced, respectively, the development of nicotine sensitization. Given acutely on Day 10, M100907 (2 mg kg(-1)), Ro 60-0175 (1 mg kg(-1)), and WAY 163909 (1.5 mg kg(-1)) decreased the expression of nicotine sensitization. In another set of experiments, where the nicotine challenge test was performed on Day 15 in animals treated repeatedly (Days: 1-5, 10) with nicotine, none of 5-HT(2) receptor ligands administered during the second withdrawal period (Days: 11-14) to nicotine-treated rats altered the sensitizing effect of nicotine given on Day 15. Our data indicate that 5-HT(2A) receptors (but not 5-HT(2C) receptors) play a permissive role in the sensitizing effects of nicotine, while stimulation of 5-HT(2A) receptors enhances the development of nicotine sensitization and activation of 5-HT(2C) receptors is essential for the expression of nicotine sensitization. Repeated treatment with the 5-HT(2) receptor ligands within the second nicotine withdrawal does not inhibit previously established sensitization. PMID- 20196141 TI - Identification and evaluation of [11C]GSK931145 as a novel ligand for imaging the type 1 glycine transporter with positron emission tomography. AB - The type-1 glycine transporter (GlyT1) is an important target for the development of new medications for schizophrenia. A specific and selective positron emission tomography (PET) GlyT1 ligand would facilitate drug development studies to determine whether a drug reaches this target and help establish suitable doses for clinical trials. This article describes the evaluation of three candidate GlyT1 PET radioligands (GSK931145, GSK565710, and GSK991022) selected from a library of compounds based on favorable physicochemical and pharmacological properties. Each candidate was successfully labeled using [(11)C]methyl iodide or [(11)C]methyl triflate and administered to a pig pre- and postadministration with a pharmacological dose of a GlyT1 inhibitor to determine their suitability as PET ligands in the porcine brain in vivo. All three candidate ligands were analyzed quantitatively with compartment analyses employing a plasma input function. [(11)C]GSK931145 showed good brain penetration and a heterogeneous distribution in agreement with reported GlyT1 localization. Following pretreatment with GSK565710, uptake of [(11)C]GSK931145 was reduced to homogeneous levels. Although [(11)C]GSK565710 also showed good brain penetration and a heterogeneous distribution, the apparent level of specific binding was reduced compared to [(11)C]GSK931145. In contrast, [(11)C]GSK991022 showed a much lower brain penetration and resultant signal following pretreatment with GSK565710. Based on these findings [(11)C]GSK931145 was identified as the most promising ligand for imaging GlyT1 in the porcine brain, possessing good brain penetration, specific signal, and reversible kinetics. [(11)C]GSK931145 is now being progressed into higher species. PMID- 20196142 TI - Family-based study shows heterogeneity of a susceptibility locus on chromosome 8q24 for nonsyndromic cleft lip and palate. AB - BACKGROUND: Nonsyndromic cleft lip with or without cleft palate is a common birth defect. Although a number of susceptibility loci have been reported, replication has often been lacking. This is likely due, in part, to the heterogeneity of datasets and methodologies. Two independent genome-wide association studies of individuals of largely western European extraction have identified a possible susceptibility locus on 8q24.21. METHODS: To determine the overall effect of this locus, we genotyped six of the previously associated single nucleotide polymorphisms in our Hispanic and non-Hispanic white family-based datasets and evaluated them for linkage and association. In addition, we genotyped a large African American family with nonsyndromic cleft lip with or without cleft palate that we had previously mapped to the 8q21.3-24.12 region to test for linkage. RESULTS: There was no evidence for linkage to this region in any of the three ethnic groups. Nevertheless, strong evidence for association was noted in the non Hispanic white group, whereas none was detected in the Hispanic dataset. CONCLUSION: These results confirm the previously reported association and provide evidence suggesting that there is ethnically based heterogeneity for this locus. PMID- 20196143 TI - Maternal exposures to endocrine disrupting chemicals and hypospadias in offspring. AB - BACKGROUND: Prenatal exposures to endocrine-disrupting chemicals (EDCs) are suspected risk factors in the etiology of hypospadias. The aim of this case control study was to test the hypothesis of an association between maternal environmental exposures to EDCs and hypospadias in the offspring. METHODS: Detailed questionnaire data on occupational and dietary exposures to EDCs in the perinatal period were collected from 80 mothers with hypospadiac infants and from 80 mothers with healthy controls within 24 months of childbirth. Maternal exposure to selected EDCs was also ascertained by measuring the concentration of dichlorodiphenyldichloroethylene, hexachlorobenzene, and several polychlorinated biphenyl congeners in the serum of primiparous mothers of 37 cases and 21 controls. RESULTS: The risk to bear an hypospadiac infant was associated with perinatal maternal occupational exposures to EDCs evaluated by a job-exposure matrix: jobs with exposure to one class of EDCs (odds ratios [OR](crude), 2.83; 95% confidence intervals [CI], 1.32-6.07; OR(adjusted), 2.44; 95% CI, 1.06-5.61) and jobs with exposure to more than one group of EDCs (OR(crude), 4.27; 95% CI, 1.43-12.78; OR(adjusted), 4.11; 95%CI, 1.34-12.59). Increase in risk was also found among mothers consuming a diet rich in fish or shellfish (OR(crude), 3.41; 95% CI, 1.42-8.23; OR(adjusted), 2.73; 95%CI, 1.09-6.82). Serum hexachlorobenzene concentration above the median of all subjects was significantly associated with the risk of hypospadias (OR(adjusted), 5.50; 95% CI, 1.24-24.31). CONCLUSIONS: This study, although based on a limited number of cases, for the first time provides evidence of an association between maternal exposure to EDCs, in particular elevated plasma hexachlorobenzene concentration, and the development of hypospadias in the offspring. PMID- 20196144 TI - Rationally engineered biotransformation of p-nitrophenol. AB - An operon encoding enzymes responsible for degradation of the EPA priority contaminant para-nitrophenol (PNP) from Pseudomonas sp. ENV2030 contains more genes than would appear to be necessary to mineralize PNP. To determine some necessary genes for PNP degradation, the genes encoding the proposed enzymes in the degradation pathway (pnpADEC) were assembled into a broad-host-range, BioBricks-compatible vector under the control of a constitutive promoter. These were introduced into Escherichia coli DH10b and two Pseudomonas putida strains, one with a knockout of the aromatic transport TtgB and the parent with the native transporter. The engineered strains were assayed for PNP removal. E. coli DH10b harboring several versions of the refactored pathway was able to remove PNP from the medium up to a concentration of 0.2 mM; above which PNP was toxic to E. coli. A strain of P. putida harboring the PNP pathway genes was capable of removing PNP from the medium up to 0.5 mM. When P. putida harboring the native PNP degradation cluster was exposed to PNP, pnpADEC were induced, and the resulting production of beta-ketoadipate from PNP induced expression of its chromosomal degradation pathway (pcaIJF). In contrast, pnpADEC were expressed constitutively from the refactored constructs because none of the regulatory genes found in the native PNP degradation cluster were included. Although P. putida harboring the refactored construct was incapable of growing exclusively on PNP as a carbon source, evidence that the engineered pathway was functional was demonstrated by the induced expression of chromosomal pcaIJF. PMID- 20196145 TI - Genotoxicity of tetracycline as an emerging pollutant on root meristem cells of wheat (Triticum aestivum L.). AB - Increasing attention has been paid to antibiotic contamination as an increasingly serious environmental issue. Tetracycline has been widely used for decades in human and veterinary medicines, with incremental residues in the environment and adverse influences on living organisms. In the present study, the genetic toxicity of tetracycline was investigated using a bioassay method with wheat (Triticum aestivum L.) root-meristem cells at a concentration range of 0.25-300 mg L(-1) and exposure times of 24, 48, and 72 h. The results indicated that tetracycline at lower concentrations (0.25-1 mg L(-1) ) stimulated cell mitotic division, whereas at 50-300 mg L(-1) concentration caused a concentration-related decrease in mitotic index (MI). The lower tetracycline concentrations induced a slight increase in the frequency of micronucleus (MN), chromosomal aberration (CA), and sister chromatid exchange (SCE) in wheat root tips. However, there were significant increases in these indices at higher concentrations in concentration- and time-dependent manners, including the frequencies of MN (25-200 mg L(-1) ), CA (10-200 mg L(-1) ), and SCE (5-200 mg L(-1) ), respectively. The inducement of MN, CA, and SCE decreased at 250 and 300 mg L(-1) due to acute cell toxicity for all tested times. Comparatively, SCE was the most sensitive, followed by CA, with MN the least sensitive to the genotoxicity of tetracycline in wheat. These results imply that tetracycline may be genotoxic to plant cells, and exposure to tetracycline may pose a genotoxic risk to living organisms. The results also suggest that the wheat bioassay was efficient, simple, and reproducible in monitoring the genotoxicity of tetracycline in the environment. PMID- 20196147 TI - Genotoxic effects of chlorpyrifos, cypermethrin, endosulfan and 2,4-D on human peripheral lymphocytes cultured from smokers and nonsmokers. AB - Pesticides often cause environmental pollution and adverse effects on human health. We have chosen four structurally different pesticides (endosulfan, an organochlorine pesticide; chlorpyrifos, an organophosphate insecticide; cypermethrin, type II pyrethroid insecticide, and 2,4-dichlorophenoxyacetic acid, a chlorinated aromatic hydrocarbon acid pesticide) to examine and compare their effects on DNA damage in acutely cultured human lymphocytes by the comet assay. In addition, possible differences in response between smoking and nonsmoking subjects were also investigated. Venous blood samples were obtained from healthy male nonsmoker (n = 7) and smoker (n = 8) donors. Primary cultures of lymphocytes were prepared and test groups were treated with three different concentrations (1, 5, and 10 MUM) of endosulfan, chlorpyrifos, cypermehrin, and 2,4-D. DNA damage was assessed by alkaline comet assay. We determined an increase in the ratio of DNA migration in human lymphocyte cell cultures as a result of treatment with cypermethrin, 2,4-D and chlorpyrifos at high concentration. Endosulfan had no significant genotoxic effect even at 10 MUM concentration. We suggest that chlorpyrifos and cypermethrin are more potentially genotoxic than endosulfan and 2,4-D. Our findings also indicate that the only significant DNA damage between smokers and nonsmokers was observed in the 2,4-D-treated group. PMID- 20196146 TI - Hydrocinchonine, cinchonine, and quinidine potentiate paclitaxel-induced cytotoxicity and apoptosis via multidrug resistance reversal in MES-SA/DX5 uterine sarcoma cells. AB - Multidrug resistance (MDR) is one of important issues to cause the chemotherapy failure against cancers including gynecological malignancies. Despite some MDR reversal evidences of natural compounds including quinidine and cinchonine, there are no reports on MDR reversal activity of hydrocinchonine with its analogues quinidine and cinchonine especially in uterine sarcoma cells. Thus, in the current study, we comparatively investigated the potent efficacy of hydrocinchonine and its analogues quinidine and cinchonine as MDR-reversal agents for combined therapy with antitumor agent paclitaxel (TAX). Hydrocinchonine, cinchonine, and quinidine significantly increased the cytotoxicity of TAX in P glycoprotein (gp)-positive MES-SA/DX5, but not in the P-gp-negative MES-SA cells at nontoxic concentrations by 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay. Rhodamine assay also revealed that hydrocinchonine, cinchonine, and quinidine effectively enhanced the accumulation of a P-gp substrate, rhodamine in TAX-treated MES-SA/DX5 cells compared with TAX treated control. In addition, hydrocinchonine, cinchonine, and quinidine effectively cleaved poly (ADP-ribose) polymerase (PARP), activated caspase-3, and downregulated P-gp expression as well as increased sub-G1 apoptotic portion in TAX-treated MES-SA/DX5 cells. Taken together, hydrocinchonine exerted MDR reversal activity and synergistic apoptotic effect with TAX in MES-SA/DX5 cells almost comparable with quinidine and cinchonine as a potent MDR-reversal and combined therapy agent with TAX. PMID- 20196148 TI - Azathioprine-induced hypersensitivity hepatitis: tolerance to 6-mercaptopurine. PMID- 20196149 TI - Reciprocal changes of Foxp3 expression in blood and intestinal mucosa in IBD patients responding to infliximab. AB - BACKGROUND: Immune therapies may act in inflammatory bowel diseases (IBD) by modulating regulatory T cells (Tregs). Therefore, we investigated the effect of infliximab (IFX) therapy on Forkhead box protein3 (Foxp3) T cells in blood and intestinal mucosa from Crohn's disease (CD) and ulcerative colitis (UC). METHODS: Forty patients with active IBD (23 CD / 17 UC) were treated with IFX 5 mg/kg intravenously at weeks 0, 2, 6, and each 8 weeks thereafter. Blood samples were obtained before every infusion and T-lymphocyte subsets were characterized by flow cytometry. Foxp3 expression in intestinal biopsies from 43 patients with active IBD (19 CD / 24 UC) before and after IFX infusion and from 6 controls were assessed by quantitative reverse-transcription polymerase chain reaction and immunohistochemistry. Plasma C-reactive protein (CRP), clinical response, and endoscopic healing data were collected in parallel. RESULTS: IFX therapy resulted in a significant and sustained relative increase of CD4(+)CD25(+)Foxp3(+) Treg and of CD4(+)CD25(-)Foxp3(+) Treg cells in peripheral blood (both P < 0.0001 compared to baseline), particularly in responders (both P < 0.05 compared to nonresponders). The change in CRP over time inversely correlated with the increase of CD25(+)Foxp3(+) cells (P < 0.001, r = -0.39) and durable clinical response was associated with a sustained increase of circulating Foxp3(+) cells. Surprisingly, IFX therapy downregulated mucosal mRNA and protein expression of Foxp3 in UC and CD responders (both P < 0.001) but not in nonresponders. CONCLUSIONS: IFX therapy has opposite effects in Foxp3(+) Treg cells in blood and gut mucosa, which suggests a redistribution of this important T-cell subset. PMID- 20196150 TI - Heavy metal-induced physiological alterations and oxidative stress in the moss Brachythecium piligerum chad. AB - Antioxidative enzymes (superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), ascorbate peroxidase (APX)), as well as lipid peroxidation and proline were studied in moss Brachythecium piligerum Card. collected from different sites in Shanghai, China, to validate the physiological parameters as biomarkers of atmospheric heavy metal pollution. Results demonstrated that the responses of POD and CAT activities, as well as MDA and proline contents were in accordance with the heavy metal contents in mosses. That is, POD activity, MDA, and proline content were activated and CAT activity was inhibited in heavier polluted sites, indicating that POD and CAT activities, and MDA and proline contents could be used as biomarkers for biomonitoring atmospheric heavy metal pollution. PMID- 20196151 TI - Effects of diazinon on antioxidant defense system and lipid peroxidation in the liver of Cyprinus carpio (L.). AB - Diazinon is a widely used organophosphorus pesticide in agriculture and environmental health, hence its adverse effects on nontarget animals, especially on fish is to be determined. The present study therefore aimed at detecting the biochemical changes caused by diazinon. To accomplish this aim, we studied the effects of sublethal concentrations (0.0036, 0.018, and 0.036 ppb) of diazinon on acetylcholine esterase activity, antioxidant enzyme activities, and lipid peroxidation in the liver of Cyprinus carpio on days 5, 15, and 30 after the exposure. The results revealed that the antioxidant enzyme activities such as superoxide dismutase, glutathione peroxidase, and catalase were induced by diazinon exposure. In addition, the highest catalytic activity of glutathione S transferase (GST) was obtained with 1-chloro-2, 4-dinitrobenzene (CDNB). GST activity toward 1,2-dichloro-4-nitrobenzene (DCNB) was also observed in the liver, yet it was relatively low as opposed to the other substrates tested. On the other hand, hepatic malondialdehyde level did not show any significant alteration except after the exposure on day 15. The exposure of low concentrations of diazinon to C. carpio can induce oxidative stress in liver; yet restoring susceptibility and adapting to oxidative stress are likely to occur when low level of oxidative stress is administered. Furthermore, no significant change was observed in hepatic lipid peroxidation after diazinon treatment indicating that liver tissue resisted to oxidative stress by enhancing their antioxidant mechanisms. The level of lipid peroxidation was assumed to be associated with the concentrations of diazinon and experimentation periods. The induction of glutathione S-transferase and antioxidant enzyme activities were also assumed to have resulted from the defense against the toxicity of diazinon. PMID- 20196152 TI - A rotating bed system bioreactor enables cultivation of primary osteoblasts on well-characterized Sponceram regarding structural and flow properties. AB - The development of bone tissue engineering depends on the availability of suitable biomaterials, a well-defined and controlled bioreactor system, and on the use of adequate cells. The biomaterial must fulfill chemical, biological, and mechanical requirements. Besides biocompatibility, the structural and flow characteristics of the biomaterial are of utmost importance for a successful dynamic cultivation of osteoblasts, since fluid percolation within the microstructure must be assured to supply to cells nutrients and waste removal. Therefore, the biomaterial must consist of a three-dimensional structure, exhibit high porosity and present an interconnected porous network. Sponceram, a ZrO(2) based porous ceramic, is characterized in the presented work with regard to its microstructural design. Intrinsic permeability is obtained through a standard Darcy's experiment, while Young's modulus is derived from a two plates stress strain test in the linear range. Furthermore, the material is applied for the dynamic cultivation of primary osteoblasts in a newly developed rotating bed bioreactor. PMID- 20196153 TI - Poly(arginine)-selective coprecipitation properties of self-assembling apoferritin and Its Tb(3+) complex: a new luminescent biotool for sensing of poly(arginine) and its protein conjugates. AB - The apoferritin protein and apoferritin-Tb(3+) complex were demonstrated to form oligomeric and polymeric self-assemblies in neutral aqueous solutions, based on characterization by using luminescence and UV/Vis spectroscopy, dynamic light scattering, and transmission electron microscopy. Addition of a 20-mer or higher poly(arginine) to the solution resulted in coprecipitation through nanoscale interactions, while biological proteins and other poly(amino acids) rarely yielded precipitates under the conditions employed. The apoferritin-Tb(3+) complex assembly exhibited a particularly long-lived green luminescence in aqueous solution, and its poly(arginine)-selective precipitation behavior was followed by monitoring the changes in luminescence. The poly(arginine)-tagged albumin precipitated selectively and quantitatively, so that the apoferritin Tb(3+) complex can function as a new luminescent biotool for the sensing of poly(arginine) and its protein conjugates. PMID- 20196154 TI - Asymmetric synthesis of bicyclic diol derivatives through metal and enzyme catalysis: application to the formal synthesis of sertraline. AB - Enzyme- and ruthenium-catalyzed dynamic kinetic asymmetric transformation (DYKAT) of bicyclic diols to their diacetates was highly enantio- and diastereoselective to give the corresponding diacetates in high yield with high enantioselectivity (99.9 % ee). The enantiomerically pure diols are accessible by simple hydrolysis (NaOH, MeOH), but an alternative enzyme-catalyzed ester cleavage was also used to give the trans-diol (R,R)-1 b in extremely high diastereomeric purity (trans/cis=99.9:0.1, >99.9 % ee). It was demonstrated that the diols can be selectively oxidized to the ketoalcohols in a ruthenium-catalyzed Oppenauer-type reaction. A formal enantioselective synthesis of sertraline from a simple racemic cis/trans diol 1 b was demonstrated. PMID- 20196155 TI - Chiral induction in lyotropic liquid crystals: insights into the role of dopant location and dopant dynamics. PMID- 20196156 TI - Enantioselective Kita oxidative spirolactonization catalyzed by in situ generated chiral hypervalent iodine(III) species. PMID- 20196157 TI - An unusual marriage: coupling molecular excitons to surface plasmon polaritons in metal nanostructures. PMID- 20196160 TI - Exploring cellular adhesion and differentiation in a micro-/nano-hybrid polymer scaffold. AB - Polymer scaffolds play an important role in three dimensional (3-D) cell culture and tissue engineering. To best mimic the archiecture of natural extracellular matrix (ECM), a nano-fibrous and micro-porous combined (NFMP) scaffold was fabricated by combining phase separation and particulate leaching techniques. The NFMP scaffold possesses architectural features at two levels, including the micro scale pores and nano-scale fibers. To evaluate the advantages of micro/nano combination, control scaffolds with only micro-pores or nano-fibers were fabricated. Cell grown in NFMP and control scaffolds were characterized with respect to morphology, proliferation rate, diffentiation and adhesion. The NFMP scaffold combined the advantages of micro- and nano-scale structures. The NFMP scaffold nano-fibers promoted neural differentiation and induced "3-D matrix adhesion", while the NFMP scaffold micro-pores facilitated cell infiltration. This study represents a systematic comparison of cellular activities on micro only, nano-only and micro/nano combined scaffolds, and demonstrates the unique advantages of the later. PMID- 20196161 TI - Recombinant murine growth hormone from E. coli inclusion bodies: expression, high pressure solubilization and refolding, and characterization of activity and structure. AB - We expressed recombinant murine growth hormone (rmGH) in E. coli as a cost effective way to produce large quantities (gram scale) of the protein for use in murine studies of immunogenicity to therapeutic proteins. High hydrostatic pressure was used to achieve high solubility and high refolding yields of rmGH protein produced in E. coli inclusion bodies. A two-step column purification protocol was used to produce 99% pure monomeric rmGH. Secondary and tertiary structures of purified rmGH were investigated using circular dichroism and 2D-UV spectroscopy. The purified rmGH produced was found to be biologically active in hypophysectomized rats. PMID- 20196162 TI - Spectroscopic investigation on the toxic interaction of melamine with herring sperm DNA. AB - The toxic interaction of melamine with herring sperm DNA (hs-DNA) was investigated by using fluorescence and UV-vis absorption spectra techniques. The experimental results showed that the toxic interaction between melamine and hs DNA occurred. Fluorescence quenching experiments indicated the existence of electrostatic binding between melamine and hs-DNA. The binding constants K(A) and the binding site numbers were calculated by means of the Stern-Volmer equation and were 9.8 * 10(4) L mol(-1) and 1.3, respectively. Both the results of fluorescence spectra and UV-vis absorption spectra verified that there are electrostatic binding between melamine and hs-DNA. The possibility in the presence of a classical intercalation binding mode could be ruled out by using DNA unwinding experiments. PMID- 20196163 TI - Oxidative modifications of proteins by sodium arsenite in human umbilical vein endothelial cells. AB - Epidemiologic studies have demonstrated that chronic arsenic exposure is associated with the incidence of chronic diseases. This association is partly related to the increase in reactive oxygen species (ROS) overload and protein oxidation that result from arsenic exposure. In this study, we intended to identify proteins susceptible to oxidative carbonylation by sodium arsenite and the impact of carbonylation on the function of these proteins in human umbilical vein endothelial cells (HUVECs). The 2,4-dinitrophenylhydrazine (DNPH) dot-blot assay revealed that arsenite (0-50 MUM) dose-dependently increased protein carbonylation. Consistent with these findings, the cellular ROS level as measured by 2',7'-dichlorofluorescein diacetate (DCHF-DA) assay was increased in cells exposed to arsenite. By two-dimensional gel electrophoresis and matrix assist laser desorption ionization time of flight mass spectrometry (MALDI-TOF/MS), one glycolytic enzyme, enolase-alpha, two cytoskeleton proteins, fascin (F-actin associated protein) and vimentin, and two protein quality control proteins, HSC70 (heat-shock cognate protein 70), and PDIA3 (protein disulfide isomerase family A, member 3) were identified to be arsenic-sensitive carbonlyated proteins. Accompanied by carbonylation, enolase-alpha activity was dose-dependently decreased and the F-actin filament network was disturbed. Taken together, our results suggest that arsenite exposure results in the generation of carbonylated proteins, and the resultant changes in energy metabolism and in the cytoskeletal network may partly lead to cell damage. PMID- 20196164 TI - The apoptotic effect of oral administration of microcystin-RR on mice liver. AB - Microcystin produced by cyanobacteria in diverse water systems is a potent hepatotoxin that has been documented to induce hepatocyte apoptosis and liver injury. There are more than eighty reported microcystins. The present work aimed at investigating the apoptotic effect of MC-RR (a common member of microcystin family), and its related mechanism. MC-RR was administered orally to ICR mice for 7 days with different dosages. Apoptotic cell death in liver was detected by TUNEL assay, and the expression levels of Bcl-2, Bax and p53, GRP 78 and CHOP which have been reported to be related to apoptosis and ER stress were determined via western-blot. The activity of PP2A was measured using the serine-threonine phosphatase assay system and PP2A A subunit expression at both transcription and protein levels was measured by RT-PCR and western blot, respectively. A significant difference was observed on the number of TUNEL positive liver cells between the control and MC-RR-treated groups. The expression levels of Bcl-2, Bax, p53, and GRP 78 in MC-RR-treated groups were altered significantly compared to the control, but no obvious alteration was found in CHOP expression. The PP2A activity and A subunit expression did not manifest any obvious change at both transcription and protein levels. The results indicated that oral exposure to MC RR can cause apoptosis as well as moderate ER stress in mice liver. The mitochondrial pathway via Bcl-2 family members may contribute to the apoptosis. However, PP2A may not be involved in the regulation of apoptotic process under the current conditions. PMID- 20196165 TI - Melanocytic bronchopulmonary carcinoid tumor in a patient with multiple endocrine neoplasia syndrome type 1: a case report with emphasis on intraoperative cytological findings. AB - We present the cytological features along with histologic and imaging findings of a melanocytic bronchopulmonary carcinoid tumor in a patient with multiple endocrine neoplasia syndrome type 1 (MEN-1). Intraoperative touch preparations of the lung tumor showed single spindle cells and loosely cohesive aggregates of spindle cells with oval to elongated nuclei, "salt and pepper" chromatin pattern and inconspicuous nucleoli. The spindle cells occasionally contained cytoplasmic pigment, which revealed to be melanin by Fontana Masson stain on permanent processed material. Immunohistochemical stains for both synaptophysin and chromogranin were strongly positive in the spindle cells. The findings were consistent with melanocytic bronchopulmonary carcinoid tumor, which is relatively uncommon in MEN-1. PMID- 20196166 TI - A flow cytometry-based assay for measuring invasion of red blood cells by Plasmodium falciparum. AB - Variability in the ability of the malaria parasite Plasmodium falciparum to invade human erythrocytes is postulated to be an important determinant of disease severity. Both the parasite multiplication rate and erythrocyte selectivity are important parameters that underlie such variable invasion. We have established a flow cytometry-based method for simultaneously calculating both the parasitemia and the number of multiply-infected erythrocytes. Staining with the DNA-specific dye SYBR Green I allows quantitation of parasite invasion at the ring stage of parasite development. We discuss in vitro and in vivo applications and limitations of this method in relation to the study of parasite invasion. PMID- 20196167 TI - Carcinomatous infiltration of cerebrospinal fluid with reactive lymphocytosis and granulocytosis. PMID- 20196169 TI - Pericapillary plasma cells in plasma cell myeloma. PMID- 20196168 TI - Hematological predictors of increased severe anemia in Kenyan children coinfected with Plasmodium falciparum and HIV-1. AB - Malaria and HIV-1 are coendemic in many developing countries, with anemia being the most common pediatric hematological manifestation of each disease. Anemia is also one of the primary causes of mortality in children monoinfected with either malaria or HIV-1. Although our previous results showed HIV-1(+) children with acute Plasmodium falciparum malaria [Pf(+)] have more profound anemia, potential causes of severe anemia in coinfected children remain unknown. As such, children with P. falciparum malaria (aged 3-36 months, n = 542) from a holoendemic malaria transmission area of western Kenya were stratified into three groups: HIV-1 negative [HIV-1(-)/Pf(+)]; HIV-1 exposed [HIV-1(exp)/Pf(+)]; and HIV-1 infected [HIV-1(+)/Pf(+)]. Comprehensive clinical, parasitological, and hematological measures were determined upon enrollment. Univariate, correlational, and hierarchical regression analyses were used to determine differences among the groups and to define predictors of worsening anemia. HIV-1(+)/Pf(+) children had significantly more malarial pigment-containing neutrophils (PCN), monocytosis, increased severe anemia (Hb < 6.0 g/dL), and nearly 10-fold greater mortality within 3 months of enrollment. Common causes of anemia in malaria-infected children, such as increased parasitemia or reduced erythropoiesis, did not account for worsening anemia in the HIV-1(+)/Pf(+) group nor did carriage of sickle cell trait or G6PD deficiency. Hierarchical multiple regression analysis revealed that more profound anemia was associated with elevated PCM, younger age, and increasing HIV-1 status ([HIV-1(-) --> HIV-1(exp) --> HIV-1(+)]. Thus, malaria/HIV-1 coinfection is characterized by more profound anemia and increased mortality, with acquisition of monocytic pigment having the most detrimental impact on Hb levels. PMID- 20196170 TI - A ghostly presence-G6PD deficiency. PMID- 20196171 TI - Characterization of the 12q15 MDM2 and 12q13-14 CDK4 amplicons and clinical correlations in osteosarcoma. AB - The chromosomal region 12q13-15 is recurrently amplified in osteosarcoma (OS), but its importance in bone tumor development remains unknown. Although there are two major candidate genes (MDM2, a TP53 downregulator, and CDK4, involved in cell cycle progression) considered to be the driving genes in this region, the size of the amplicon and number of genes involved have not been determined. In this study, we used 130 classical OS and 15 parosteal OS to determine MDM2 and CDK4 amplification frequency in OS. Tumors in which these genes were amplified were used to map the 12q13-15 amplified region and to determine its correlation with clinical prognosis. The 12q13-15 amplification was more prevalent in parosteal OS (67% of cases) than in high-grade classical OS (12%). Quantitative real-time PCR of MDM2, CDK4, and 25 other genes showed that this region contains two different amplicons: one at 12q15 centered on MDM2 and one at 12q13-14 centered on CDK4. Both regions were frequently co-amplified in both types of OS, and MDM2 and CDK4 amplification was correlated with higher expression levels for both genes. Univariate and multivariate analyses of clinical data indicated that classical OS patients whose tumors exhibited MDM2 amplification were more likely to be older at diagnosis (median age 32.6 vs. 17.8 years) and female (66.7 vs. 33.3%) than those without gene amplification. There was no association with other clinical parameters. In conclusion, co-amplification of MDM2 and CDK4 in two separate amplicons occurs frequently in parosteal OS and less so in classical high-grade OS. PMID- 20196172 TI - Detection of hereditary hemochromatosis and biochemical iron overload in primary care: a multicenter case finding study in Spain. PMID- 20196174 TI - Avoiding errors in the laboratory evaluation of potent lupus anticoagulants. PMID- 20196173 TI - Determinants of the optimal first-line therapy for follicular lymphoma: a decision analysis. AB - Combination immunochemotherapy is the most common approach for initial therapy of patients with advanced-stage follicular lymphoma, but no consensus exists as to the optimal selection or sequence of available regimens. We undertook this decision analysis to systematically evaluate the parameters affecting the choice of early therapy in patients with this disease. We designed a Markov model incorporating the three most commonly utilized regimens (RCVP, RCHOP, and RFlu) in combinations of first- and second-line therapies, with the endpoint of number of quality-adjusted life years (QALYs) until disease progression. Data sources included Phase II and Phase III trials and literature estimates of long-term toxicities and health state utilities. Meta-analytic methods were used to derive the values and ranges of regimen-related parameters. Based on our model, the strategy associated with the greatest number of expected quality-adjusted life years was treatment with RCHOP in first-line therapy followed by treatment with RFlu in second-line therapy (9.00 QALYs). Strategies containing RCVP either in first- or second-line therapy resulted in the lowest number of QALYs (range 6.24 7.71). Sensitivity analysis used to determine the relative contribution of each model parameter identified PFS after first-line therapy and not short-term QOL as the most important factor in prolonging overall quality-adjusted life years. Our results suggest that regimens associated with a longer PFS provide a greater number of total QALYs, despite their short-term toxicities. For patients without contraindications to any of these regimens, use of a more active regimen may maximize overall quality of life. PMID- 20196177 TI - Optimization of electrospray interface and quadrupole ion trap mass spectrometer parameters in pesticide liquid chromatography/electrospray ionization mass spectrometry analysis. AB - Optimization of both the ionization process and ion transportation in the mass spectrometer is of crucial importance in order to achieve high sensitivity and low detection limits and acceptable accuracy in liquid chromatography/electrospray ionization mass spectrometry (LC/ESI-MS) analysis. In this paper four optimization procedures of electrospray interface and quadrupole ion-trap mass spectrometer parameters (ESI-MS) (nebulizer gas and drying gas flow rate, end plate voltage, capillary voltage, skimmer voltage, octopoles direct current and radio frequency, trap drive and lens voltages) were studied on three pesticides--thiabendazole, aldicarb and imazalil. The results demonstrate that the methodology of optimization strongly influences the effectiveness of finding true optima of the operating parameters. Both eluent flow rate and composition during optimization have to mimic the situation during real analysis as closely as possible in order to achieve parameters giving the highest sensitivity. Therefore, post-column addition of analyte to the mobile phase identical in composition to the one in which analyte elutes during real analysis combined with software-based optimization was found to be the most effective and fastest method for achieving intensity maxima. The parameters most strongly affecting ion formation and transportation, hence sensitivity, were capillary voltage, direct current of the first octopole, trap drive and the second lens for all pesticides under study. In addition to sensitivity and detection limit matrix effect was considered in the optimization process. It was found that the matrix effect can be reduced but not eliminated by adjusting the ESI and MS parameters. The optimal parameters from the point of view of the matrix effect can only be found with factorial design. Parameters giving higher sensitivity tended to be more affected by matrix effect causing higher ionization suppression by co-eluting compounds. PMID- 20196175 TI - Splenic sarcoidosis: an unusual aetiology of agranulocytosis. PMID- 20196178 TI - Association between plasma nitric oxide metabolites levels and negative symptoms of schizophrenia: a pilot study. AB - Nitric oxide (NO) is involved in pathophysiology of psychiatric disorders such as depression and schizophrenia. We hypothesize that plasma levels of NO and its metabolites (NO(x)) are decreased in patients with schizophrenia. To examine the hypothesis, we compared plasma NO(x) levels between 30 schizophrenic patients (M/F: 18/12, age: 38 +/- 15 years) and age- and sex-matched 30 healthy controls (M/F: 18/12, age: 41 +/- 19 years), and we also examined the effects of risperidone on plasma NO(x) levels in schizophrenic patients. The baseline plasma NO(x) levels were significantly lower in the schizophrenia group (1.85 +/- 0.70 microM) than those in control group (3.37 +/- 2.27 microM). A significantly negative correlation was found between plasma NO(x) levels and PANSS-N scores before risperidone administration (rho = -0.385, p = 0.0416). Treatment with risperidone significantly increased the plasma NO(x) levels by 8 weeks (before; 1.85 +/- 0.70 microM, after; 2.25 +/- 1.00 microM, p = 0.0491). These results suggest that NO might be one of the candidates factors which are associated with the pathophysiology of negative symptoms of schizophrenia. PMID- 20196179 TI - Neurocognition and its influencing factors in the treatment of schizophrenia effects of aripiprazole, olanzapine, quetiapine and risperidone. AB - BACKGROUND: To examine influencing variables of neurocognition in patients with schizophrenia and to predict cognition during antipsychotic treatment. METHODS: Data were obtained from patients with an acute episode of schizophrenia participating in two double-blind and one open label trial comparing the effects of different atypical antipsychotics on cognition. In total, 129 patients were enrolled in this analysis. Cognitive function was assessed at admission, week 4 and 8. Efficacy and tolerability were assessed weekly using the Positive and Negative Syndrome Scale (PANSS) and the Simpson Angus Sale (SAS). Patients were treated with aripirazole, olanzapine, quetiapine and risperidone. Regression analysis including mixed effect models was performed. RESULTS: A significant improvement in all cognitive domains was observed from baseline to week 8. Regarding the antipsychotic treatment applied quetiapine seemed to achieve the most favourable cognitive improvement. Negative and depressive symptoms, the patient's age and the concomitant and antipsychotic treatment applied were observed to significantly influence and predict neurocognition. CONCLUSION: The results may indicate that schizophrenia is a static disorder with trait and state dependent cognitive components especially in the memory domains. The influence of negative and depressive symptoms should be considered in daily clinical routine. PMID- 20196180 TI - An improved in silico selection of phenotype affecting polymorphisms in SLC6A4, HTR1A and HTR2A genes. AB - OBJECTIVE: Among the experimentally assessed DNA variations in serotonin related genes, some influence physiological expression of personality and mental disorders, others alter the responses to pharmacological and/or psychotherapeutic treatments. Because of the huge number of polymorphisms lying in genes and of the great length of time necessary to perform association studies, a selection of the variations being studied is a necessary and crucial step. METHODS: In this work we used the most updated and assessed bioinformatic tools to predict the phenotype affecting polymorphisms of the human HTR1A, HTR2A and SLC6A4 serotonin related genes. Moreover, we carried out a literature search to collect information about the recent association studies to compare it versus our prediction data. RESULTS: Gene polymorphism analysis indicated the variations that are worth considering in the association studies in the field of psychiatry, psychology and pharmacogenomics. The literature revision allowed to show both the few well and the most not enough investigated polymorphisms. CONCLUSIONS: Our data can be useful to select polymorphisms for new association studies, especially those not yet investigated that can be related to behaviour, mental disorders and individual treatment response. PMID- 20196181 TI - Association of BDNF Val66Met polymorphism with both baseline HRQOL scores and improvement in HRQOL scores in Chinese major depressive patients treated with fluoxetine. AB - OBJECTIVE: To explore the association of brain-derived neurotrophic-factor (BDNF) Val66Met polymorphism with both baseline health related quality of life (HRQOL) scores and improvement in HRQOL scores in Chinese major depressive patients treated with fluoxetine. METHODS: Patients with major depressive disorder (MDD) took fluoxetine (20 mg/day) for 6 weeks. The HRQOL was measured with the Medical Outcomes Study Short Form-36 (SF-36) at baseline and at 6th week. Patients were genotyped for Val66Met polymorphism of BDNF gene. RESULTS: There was a significant association between social function (SF) and BDNF Val66Met polymorphism, and patients with Met/Met genotype had better SF (compared with Val/Val P = 0.004; compared with Val/Met P = 0.005). A significant association was found between improvement in SF and BDNF Val66Met polymorphism, and patients with Met/Met genotype had poorer improvement in SF (compared with Val/Val P = 0.010; compared with Val/Met P = 0.001). Similar association was found between improvement in mental component summary (MCS) and BDNF Val66Met polymorphism, and patients with Met/Met genotype had poorer improvement in MCS (compared with Val/Val P = 0.066; compared with Val/Met P = 0.006). CONCLUSIONS: These results indicate that there may be association between BDNF Val66Met polymorphism and both baseline HRQOL (SF) scores and improvement in HRQOL (SF, MCS) scores in Chinese major depressive patients treated with fluoxetine. PMID- 20196182 TI - Risperidone associated weight, leptin, and anthropometric changes in children and adolescents with psychotic disorders in early treatment. AB - OBJECTIVE: To document prospective weight and anthropometric changes in children and adolescents during the first 12 weeks of treatment with risperidone and evaluate metabolic outcomes including plasma leptin levels. METHOD: Eight patients with psychotic disorders (ages 11-17) who had started risperidone (mean: 1.80 mg/day; sd = 1.04) in the prior 4 weeks participated in this observational study. Fasting morning blood samples were obtained at baseline and week 8 to assess glucose, leptin, cortisol, insulin, and triglycerides. Measures of body mass index (BMI), weight, waist and hip circumference, blood pressure, and heart rate were obtained weekly. RESULTS: Participants increased in mean weight (4.16 kg; sd = 4.36; p = 0.03) and BMI (1.47 kg/m(2); sd = 1.53; p = 0.03) with five out of eight gaining at least 7% of baseline body weight. They had a 4.03 cm (sd = 3.82; p = 0.02) increase in waist circumference and a 5.17 cm (sd = 3.68; p = 0.01) increase in hip circumference. Leptin trended higher, but did not reach statistical significance. There were no significant changes in glucose, insulin, cortisol, blood pressure, or heart rate. CONCLUSION: Subjects experienced significant increases in weight, BMI, hip and waist circumference during the first 3 months of treatment. Better powered research with more advanced anthropometric assessment is warranted to further elucidate mechanisms of antipsychotic associated weight gain in youth. PMID- 20196183 TI - Aripiprazole as adjunct to a mood stabilizer and citalopram in bipolar depression: a randomized placebo-controlled pilot study. AB - OBJECTIVE: The use of atypical antipsychotics (AAPs) for the treatment of unipolar and bipolar depression has been more and more frequently evaluated, and aripiprazole showed positive effects in the treatment of unipolar depression. However, no placebo-controlled studies of adjunctive aripiprazole for the treatment of bipolar depression have been performed yet. METHODS: In this prospective, double-blind, placebo-controlled, randomized trial, 23 inpatients with bipolar depression according to DSM-IV criteria were included. Before randomization, patients had to be on a constant mood stabilizer treatment with lithium or valproate for at least 1 week. After inclusion, all patients were openly treated with additional citalopram and with additional aripiprazole or placebo for 6 weeks. The primary outcome parameter was the reduction in depressive symptoms according to the Hamilton Depression Rating Scale (HDRS) within 6 weeks. RESULTS: After 6 weeks of treatment, the HDRS score decreased in both groups. There was no significant difference between both the groups at any point of time with respect to the HDRS. CONCLUSIONS: Derived from this small pilot study, adjunctive aripiprazole does not seem to be a promising strategy for the acute treatment of bipolar depression. However, this lack of additional benefit seems to stem from the already good effectiveness of the control group, namely the treatment with citalopram. PMID- 20196184 TI - Ultrasonically determined thyroid volume and thyroid functions in lithium-naive and lithium-treated patients with bipolar disorder: a cross-sectional and longitudinal study. AB - OBJECTIVE: This study investigated thyroid volume, hormone levels and antibodies in long-term lithium-treated and lithium-naive bipolar patients, some of whom underwent prospective follow-up evaluations. METHODS: Fourteen lithium-naive patients, 13 long-term lithium-treated patients diagnosed with bipolar disorder and 12 healthy controls were included. Seven lithium-naive patients were followed up during their lithium receiving period (range 6-9 months). Thyroid volume and serum levels of thyroid hormones and antibodies were measured once in the long term lithium-treated patients and controls, and twice in the lithium-naive patients, i.e. before and after lithium treatment. RESULTS: Mean thyroid volumes in the lithium-naive patients were significantly higher than those in the controls. Long-term lithium-treated patients had significantly higher total thyroid volume than the lithium-naive patients and the controls. Total thyroid volume in the patients after the lithium treatment was significantly higher than that before. Serum free thyroxine (fT4) levels in the long-term lithium-treated patients were lower than those in the lithium-naive patients and the controls. In the lithium-naive patients, after lithium treatment, free triiodothyronine (fT3) levels were lower, and thyroid stimulating hormone (TSH) levels were higher compared to those before lithium treatment. CONCLUSIONS: The results suggest that thyroid enlargement and some alterations in thyroid hormones in bipolar patients may present even before lithium treatment and increase further with lithium treatment. PMID- 20196185 TI - Safety and tolerability of once-daily extended release quetiapine fumarate in acute schizophrenia: pooled data from randomised, double-blind, placebo controlled studies. AB - INTRODUCTION: Extended release quetiapine fumarate (quetiapine XR) is a new formulation that allows once-daily dosing and a titration regimen that is simpler than that of immediate release quetiapine (quetiapine IR) and may potentially increase patients' adherence to their prescribed medication. METHODS: The tolerability of quetiapine XR was examined in an analysis of pooled data from three Phase III, double-blind, placebo-controlled, randomised studies with quetiapine IR as a reference treatment. RESULTS: The overall incidence of adverse events (AEs) was similar for quetiapine XR (69.5%) and quetiapine IR (72.5%). Most AEs were mild to moderate in severity and in line with those observed with quetiapine IR. The more rapid dose titration of quetiapine XR did not produce any new safety concerns and was as well tolerated as the regimen for quetiapine IR. CONCLUSIONS: The results of this pooled analysis show that quetiapine XR administered once daily is generally as well tolerated as quetiapine IR given twice daily. These data, together with the simpler dose-titration of quetiapine XR that allowed therapeutically effective doses to be reached by Day 2, suggest that this formulation potentially may improve adherence in patients with schizophrenia. PMID- 20196187 TI - The use of antidepressants in clinical practice: focus on agomelatine. AB - OBJECTIVE: Agomelatine (Valdoxan) is licensed by the European Medicines Agency for the treatment of major depressive episodes in adults. The objective of this review was to consider how the drug should be used in clinical practice in particular starting, stopping and switching to and from the drug. METHODS: The existing clinical evidence was reviewed. RESULTS: Data suggest that when switching to agomelatine from other antidepressants consideration should be given to tapering the previous antidepressant in order to minimize the risk of the original drug causing discontinuation/withdrawal symptoms. The risk of pharmacological interactions between most antidepressants and agomelatine is low and so tapering the previous antidepressant can usually be done after agomelatine has been started. An exception is fluvoxamine which should not be concurrently prescribed with agomelatine. As agomelatine appears to cause no significant discontinuation symptoms, it can probably be stopped abruptly when treatment is completed or when switching to another antidepressant. CONCLUSIONS: While this guidance may change as clinical evidence and experience grows, currently agomelatine appears to have a good tolerability profile and is relatively easy to use, though prescribers should note the requirement to conduct liver function tests (LFTs) in accordance with the Summary of Product Characteristics (SPC). PMID- 20196186 TI - Changes in medication practices for hospitalized psychiatric patients: 2009 versus 2004. AB - BACKGROUND: We tested the hypothesis that combinations and total daily doses of psychotropics for hospitalized patients diagnosed with major psychiatric disorders are rising. METHODS: We evaluated McLean Hospital records of 481 consecutive inpatients with DSM-IV schizophrenia, schizoaffective, or bipolar disorders in 2004 (n = 278) or 2009 (n = 203) to compare characteristics and treatments. RESULTS: In 2009, Clinical Global Impression (CGI)-severity scores were 6% lower at intake and improved 1.7 times more than in 2004, as hospitalization-length decreased by 12%. Polytherapy (> or = 2 psychotropics) increased in 2009 (affective or schizoaffective disorders > schizophrenia). Total psychotropics/patient (3.1-3.2) remained stable but mood-stabilizers/patient increased markedly and antipsychotics/patient decreased somewhat in 2009. Antipsychotic-choice (2009) ranked: quetiapine, aripiprazole, risperidone, and others; mood-stabilizers ranked: lamotrigine, valproate, lithium, and others (1/4 off-label). In 2009, final total antipsychotic doses (mg/day) increased by 97%, and mood-stabilizers by 75%. Adverse-effect rates fell by half. Factors differing independently for 2009 versus 2004 ranked: (a) more CGI improvement, (b) more mood-stabilizers/patient, (c) lower admission CGI scores, and (c) higher total antipsychotic dose. COMMENT: Combinations and doses of antipsychotic and mood stabilizing drugs for inpatients increased markedly (2004 vs. 2009) without consistent correspondence of agents/person and doses, without apparent increase in major adverse effects, and with possibly superior clinical improvement. PMID- 20196188 TI - Pressure-assisted tryptic digestion using a syringe. AB - A simple and effective digestion method was developed using a syringe. A 3 mL syringe was used to apply a pressure of 6 atm to expedite tryptic digestion. Application of a pressure of 6 atm during digestion resulted in better digestion efficiency than digestion under atmospheric pressure. The protein peaks in the matrix-assisted laser desorption/ionization mass spectra of three model proteins (cytochrome c, horse heart myoglobin, and bovine serum albumin (BSA)) completely disappeared within 30 min at 37 degrees C under a pressure of 6 atm, with greater numbers of peptides observed in 30 min pressure-assisted digestion than in overnight atmospheric pressure digestion. This is mostly due to the miscleaved peptides. Similar sequence coverages were obtained for 30 min pressure-assisted digestion and overnight atmospheric pressure digestion of the three model proteins (92% vs. 88% for cytochrome c, 100% vs. 97% for horse heart myoglobin, and 53% vs. 53% for BSA). PMID- 20196189 TI - Probing deamidation in therapeutic immunoglobulin gamma (IgG1) by 'bottom-up' mass spectrometry with electron transfer dissociation. AB - Aspartic acid formed by nonenzymatic deamidation of asparagine often isomerizes to isoaspartic acid through a succinimide intermediate. Accumulation of isoaspartic acid initiates aggregation and degradation in proteins. Deamidation at the antigen-binding region reduces the efficacy and also upregulates immunogenicity of monoclonal antibodies. We report an improved 'bottom-up' tandem mass spectrometric method to detect and decipher the position of isoaspartate formation in therapeutic immunoglobulin gamma in a single chromatographic run. Differentiation between aspartate and isoaspartate residues through collision induced tandem mass spectrometry is formidable due to their identical mass. Signature backbone cleavage ions, c(n) + 57 and z(l-n) - 57, produced upon radical-mediated fragmentation, were used to delineate the site of isomerization. It is more conclusive than monitoring the relative peak intensity and the decrease in hydrophobicity of the isoaspartate-containing peptide in a chromatographic elution. Collectively, this methodology provides a useful tool to monitor deamidation and isomerization in biopharmaceuticals during their production, downstream processing and storage. PMID- 20196190 TI - Selective linkage detection of O-sialoglycan isomers by negative electrospray ionization ion trap tandem mass spectrometry. AB - Sialylated O-linked oligosaccharides are involved in many biological processes, such as cell-cell interactions, cell-substance adhesion, and virus-host interactions. These activities depend on their structure, which is frequently determined by tandem mass spectrometry. However, these spectra are frequently analyzer-dependent, which makes it difficult to develop widely applicable analytical methods. In order to deepen the origin of this behavior, two couples of isomers of sialylated O-linked oligosaccharides, NeuAc alpha2-3Gal beta1 3GalNAc-ol/Gal beta1-3(NeuAc alpha2-6)GalNAc-ol and NeuGc alpha2-3Gal beta1 3GalNAc-ol/Gal beta1-3(NeuGc alpha2-6)GalNAc-ol, were analyzed by liquid chromatography/negative electrospray ionization ion trap tandem mass spectrometry (LC/ESI(-)-MS(n)) using both an ion trap and a triple quadrupole mass spectrometer. Results clearly showed that while ions obtained in the triple quadrupole instrument fitted very well with the standard fragmentation routes, in the ion trap several intense ions could not be explained by these rules, specially a fragment at m/z 597. Furthermore, this ion was observed in the mass spectrum of those isomers that sialic acid binds to GalNAc by an alpha2-6 linkage. From the MS(3) spectrum of this ion an unexpected structure was deduced, and it led to propose alternative fragmentation pathways. Molecular mechanics calculations suggested that the found atypical route could be promoted by a hydrogen bond located only in alpha2-6-linked oligosaccharides. It has also been demonstrated that this process follows a slow kinetic, explaining why it cannot be observed using an ion beam-type mass analyzer. In conclusion, ion traps seem to be more appropriate than triple quadrupoles to develop a reliable analytical method to distinguish between isomeric O-linked glycans. PMID- 20196192 TI - Metabolism of mequindox in liver microsomes of rats, chicken and pigs. AB - Mequindox, 3-methyl-2-quinoxalinacetyl-1,4-dioxide, is a quinoxaline-N,N-dioxide used in veterinary medicine as a antibacterial in China. To gain an understanding of the interspecies differences in the metabolism of mequindox, comparative metabolite profiles were qualitatively and quantitatively carried out for the first time in rat, chicken and pig liver microsomes by high-performance liquid chromatography combined with hybrid ion trap/time-of-flight mass spectrometry. A total of 14 metabolites were characterized based on their accurate MS(2) spectra and known structure of mequindox. The in vitro metabolic pathways of mequindox in three species were proposed as N-->O group reduction, carbonyl reduction, N-->O group reduction followed by carbonyl reduction or methyl mono-hydroxylation. A metabolic pathway involving N-->O group reduction followed by acetyl group mono hydroxylation in only chicken was also proposed. There was also quantitative species difference for mequindox metabolism in three species. 1-Desoxymequindox was the main metabolite in all species, but otherwise there were some qualitative interspecies differences in mequindox major metabolites. This work has revealed biotransformation characteristics of mequindox among different species, and moreover will further facilitate the explanations of the biological activities of mequindox in animals. PMID- 20196191 TI - Black and white--does melanin change the bulk carbon and nitrogen isotope values of feathers? AB - Bird feathers are employed in a wide range of carbon and nitrogen isotope studies relating to diet and migration. Feathers are chemically inert with respect to carbon and nitrogen, after synthesis. It has always been assumed that feathers show isotope values characteristic of keratin, a fibrous structural protein from which they are formed. Little attention has been paid to other components of feathers such as melanin or carotenoids. Melanin is synthesized from tyrosine, which is depleted in both (13)C and (15)N. We compared isotope values of coeval black and white feathers in four different species. Black feather parts were in all cases significantly depleted in (13)C relative to white feather parts but in most species no clear trend was discernable for (15)N. We suggest that additional evaluation may be required to characterize the carbon and nitrogen isotope contribution of feather pigments like carotenoids. Care should be taken in future stable isotope studies when comparing differently coloured feathers. PMID- 20196193 TI - Systematic investigation of ion suppression and enhancement effects of fourteen stable-isotope-labeled internal standards by their native analogues using atmospheric-pressure chemical ionization and electrospray ionization and the relevance for multi-analyte liquid chromatographic/mass spectrometric procedures. AB - In clinical and forensic toxicology, multi-analyte procedures are very useful to quantify drugs and poisons of different classes in one run. For liquid chromatographic/tandem mass spectrometric (LC/MS/MS) multi-analyte procedures, often only a limited number of stable-isotope-labeled internal standards (SIL ISs) are available. If an SIL-IS is used for quantification of other analytes, it must be excluded that the co-eluting native analyte influences its ionization. Therefore, the effect of ion suppression and enhancement of fourteen SIL-ISs caused by their native analogues has been studied. It could be shown that the native analyte concentration influenced the extent of ion suppression and enhancement effects leading to more suppression with increasing analyte concentration especially when electrospray ionization (ESI) was used. Using atmospheric-pressure chemical ionization (APCI), methanolic solution showed mainly enhancement effects, whereas no ion suppression and enhancement effect, with one exception, occurred when plasma extracts were used under these conditions. Such differences were not observed using ESI. With ESI, eleven SIL ISs showed relevant suppression effects, but only one analyte showed suppression effects when APCI was used. The presented study showed that ion suppression and enhancement tests using matrix-based samples of different sources are essential for the selection of ISs, particularly if used for several analytes to avoid incorrect quantification. In conclusion, only SIL-ISs should be selected for which no suppression and enhancement effects can be observed. If not enough ISs are free of ionization interferences, a different ionization technique should be considered. PMID- 20196194 TI - Perturbations produced by electrospray ionization mass spectrometry in the speciation of aluminium(III)/1,6-dimethyl-4-hydroxy-3-pyridinecarboxylate aqueous solutions. AB - Electrospray ionization mass spectrometry (ESI-MS) is very often employed to study metal/ligand equilibria in aqueous solution. However, the ionization process can introduce perturbations which affect the speciation results in an unpredictable way. It is necessary to identify these perturbations in order to correctly interpret the ESI-MS speciation results. Aluminium(III)/1,6-dimethyl-4 hydroxy-3-pyridinecarboxylate (DQ716) aqueous solutions at various pH were analysed by ESI-MS, and speciation results were compared with those obtained by equilibrium techniques. Differences observed were both qualitative and quantitative. The ESI-MS spectral changes due to different settings of the following instrumental parameters were analyzed: the solution flow rate (F(S)), the nebulizer gas flow rate (F(G)), the potential applied at the entrance capillary (E(C)), and the temperature of the drying gas (T(G)). The effects produced by F(S) and E(C) on the spectra strongly suggest the key role of surface activity in determining the relative fraction of the ions reaching the detector. The experimental effects of F(S) and T(G) were interpreted considering the presence of at least two reactions in the gas phase and a dimerization occurring in the droplets. These perturbations cannot be generalized because they appear to be chemical system-related and instrument-dependent. Therefore, the identification of perturbations is a required task for any metal-ligand equilibrium study performed by ESI-MS. Our results indicate that perturbations can be identified by evaluating the effects produced in the spectra by a change of instrumental parameters. PMID- 20196195 TI - Development and validation of a NANOGold immunoassay for the detection of vascular endothelial growth factor (VEGF) in human serum using inductively coupled plasma mass spectrometry. AB - This work aimed to develop and validate a NANOGold based assay, quantified using inductively coupled plasma mass spectrometry (ICP-MS), for the detection of human vascular endothelial growth factor (hVEGF) in serum. The initial assay range based on calibration standards was 62.5-2000 pg/mL with a detection limit of approximately 30 pg/mL. After validation using spiked validation controls, a quantification range between 175 and 1928 pg/mL was obtained. The inter-assay precision was between 2.3 and 18.9% with accuracy between -8.8 and -3.1%. Additional performance parameters, including dilutional linearity, matrix specificity and time-factored drift, were within +/-20%, as defined by the validation acceptance criteria for the validation of macromolecule immunoassays used within our clinical environment. Serum samples from healthy donors were analysed to determine the endogenous levels of VEGF present; these ranged from 164 to 580 pg/mL with a mean of 273 pg/mL. The intra- and inter-assay precision obtained from the healthy donor samples were 1.3-10.7% and 4.2-17.5%, respectively. This demonstration of a validated immunoassay opens further possibilities, utilising the simultaneous detection capabilities of ICP-MS for the detection of multiple analytes in a single validated immunoassay, for routine use within a clinical environment. PMID- 20196196 TI - Active management of the third stage of labour: prevention and treatment of postpartum hemorrhage: No. 235 October 2009 (Replaces No. 88, April 2000). PMID- 20196197 TI - Rhythm quizlet. Possible AV block. PMID- 20196198 TI - Instruments for measuring quality of educational environments: validation not required any longer? PMID- 20196199 TI - Medical students and recent graduates may disagree on the importance of procedural skills education. PMID- 20196200 TI - The use of reflective learning and online continuing professional development. PMID- 20196201 TI - Learning to maintain a 'proper' relationship with the pharmaceutical industry. PMID- 20196202 TI - Teaching crisis intervention to medical students--when is the best timing? PMID- 20196203 TI - Trainee written records: What's wrong? What's right? It depends! PMID- 20196204 TI - First Brazilian experience in web-based course for healthcare professionals. PMID- 20196205 TI - [The area of conflict between the surgeon's duty to inform about diagnosis, prognosis, operation, complications, time schedule, alternative methods and the patient's right of self-determination]. AB - The surgeon's duty to inform patients determines the indication to a therapeutic and/ or diagnostic procedure. Despite ongoing information made available by the professional associations, the complaints against surgeons providing treatment are on the increase. Only careful health education information with records kept of the course of treatment adopted will safeguard the doctor in charge from patients' claims for damages. Case law demands that the doctor put the patient in a position to understand what is happening to him or her and for him or her to be able to make a decision freely. The patient's compliance after being provided with health education information makes the corpus delicti of bodily harm void. A special form is the matter of fact of "transfer negligence", when the doctor and/ or the hospital is aware, prior to execution of the treatment, that treatment is not possible lege artis. What continues to be applicable to health education information is that the more urgent the operation, the less information is indicated, so that in emergencies such operation can be completely done without. Apart from general risks, such as wound infection and/or the danger of thrombosis, information must also be provided about special risks and the course of any follow-up treatment. Legal practice shows that simply handing over forms is not sufficient. The patient may forgo treatment. Aborting an operation for purposes of providing health information is balancing between the patient's interests in immediate execution of the indicated measure, on the one hand, and the right of self-determination on the other. Should the operation be able to be aborted without any serious consequences for the patient, then it is to be thus done.What does principally apply in civil litigation is the rule of the burden of proof. PMID- 20196206 TI - Abel, Takamine, and the isolation of epinephrine. PMID- 20196207 TI - [Comment on the article "Operative Techniques and Outcomes in Metabolic Surgery: Sleeve Gastrectomy"]. AB - The review article "Operative Techniques and Outcomes in Metabolic Surgery: Sleeve Gastrectomy" by Huttl et al. is concerned with laparoscopic sleeve stomach operations ("sleeve gastrectomy") for the surgical treatment of morbid obesity (Zentralblatt fur Chirurgie 2009; 134: 24-31). After an analysis of the available literature and own results, the authors concluded that the laparoscopic sleeve operation is established today as an effective standard procedure in the therapy for obesity.We would like to comment on the content of this article. PMID- 20196208 TI - Promoting quality of genetic testing with guidelines for good laboratory practices. PMID- 20196209 TI - Abstract of Sepsis 2009. Amsterdam, The Netherlands. November 11-14, 2009. PMID- 20196210 TI - Abstracts of the Fifth International Symposium on Intensive Care and Emergency Medicine for Latin America. Sao Paulo, Brazil. June 24-27, 2009. PMID- 20196211 TI - Lessons to be learned. PMID- 20196213 TI - The bucks start here. But some things hospitals want not in 2011 budget. PMID- 20196212 TI - ANA, nurses respond to Haiti quake. PMID- 20196214 TI - Clock watching. New push to limit resident work hours. PMID- 20196215 TI - Radiation gets exposed. Industry, regulators look to nip problem in bud. PMID- 20196216 TI - Broadlane shuffles deck. Ryan takes over as CEO, Sherry moves to president. PMID- 20196217 TI - A nonstarter. Jump in healthcare spending not cranking reform engine. PMID- 20196218 TI - They know not what they do. Perhaps it's time for healthcare to cure Americans' political incorrectness. PMID- 20196219 TI - Raising the bar. Finances, satisfaction and new hospital all going up. PMID- 20196220 TI - Growing a hospital. Leading 20 years of expansion in the Twin Cities. PMID- 20196221 TI - Up-down study--is the analysis adequate? PMID- 20196222 TI - Hazard due to proseal tear. PMID- 20196223 TI - Prone CPR for transient asystole during lumbosacral spinal surgery. PMID- 20196224 TI - Staff drive changes in LEAN process. PMID- 20196225 TI - Insurers get premium roast...Legislators go on offensive over insurers' profits, suggested rate hikes. PMID- 20196226 TI - ...as their fortunes boast. WellPoint, UnitedHealth net combined $8.5 billion. PMID- 20196228 TI - Broward brouhaha. Ongoing investigations bog down Fla. system. PMID- 20196227 TI - Building on Build America. But small hospitals might not benefit: experts. PMID- 20196229 TI - Up-sizing the competition. With health reform foundering, here's a modest proposal to get the ball rolling. PMID- 20196230 TI - Calling up the reserves. Hospitals, systems join up with the Army to help keep skilled staff in their ranks. PMID- 20196231 TI - Top vendors of enterprise EMR systems. Based on total number of installations at acute-care hospitals from January 2009 to January 2010. PMID- 20196232 TI - Mitochondrial fusion and inheritance of the mitochondrial genome. AB - Although maternal or uniparental inheritance of mitochondrial genomes is a general rule, biparental inheritance is sometimes observed in protists and fungi,including yeasts. In yeast, recombination occurs between the mitochondrial genomes inherited from both parents.Mitochondrial fusion observed in yeast zygotes is thought to set up a space for DNA recombination. In the last decade,a universal mitochondrial fusion mechanism has been uncovered, using yeast as a model. On the other hand, an alternative mitochondrial fusion mechanism has been identified in the true slime mold Physarum polycephalum.A specific mitochondrial plasmid, mF, has been detected as the genetic material that causes mitochondrial fusion in P. polycephalum. Without mF, fusion of the mitochondria is not observed throughout the life cycle, suggesting that Physarum has no constitutive mitochondrial fusion mechanism.Conversely, mitochondria fuse in zygotes and during sporulation with mF. The complete mF sequence suggests that one gene, ORF640, encodes a fusogen for Physarum mitochondria. Although in general, mitochondria are inherited uniparentally, biparental inheritance occurs with specific sexual crossing in P. polycephalum.An analysis of the transmission of mitochondrial genomes has shown that recombinations between two parental mitochondrial genomes require mitochondrial fusion,mediated by mF. Physarum is a unique organism for studying mitochondrial fusion. PMID- 20196233 TI - Uniparental inheritance of cpDNA and the genetic control of sexual differentiation in Chlamydomonas reinhardtii. AB - An intriguing feature of most eukaryotes is that chloroplast (cp) and mitochondrial (mt) genomes are inherited almost exclusively from one parent. Uniparental inheritance of cp/mt genomes was long thought to be a passive outcome, based on the fact that eggs contain multiple numbers of organelles, while male gametes contribute,at best, only a few cp/mtDNA. However, the process is likely to be more dynamic because uniparental inheritance occurs in organisms that produce gametes of identical sizes (isogamous). In Chlamydomonas reinhardtii,the uniparental inheritance of cp/mt genomes is achieved by a series of mating type-controlled events that actively eliminate the mating type minus (mt-) cpDNA.The method by which Chlamydomonas selectively degrades mt- cpDNA has long fascinated researchers, and is the subject of this review. PMID- 20196234 TI - Mechanisms for independent cytoplasmic inheritance of mitochondria and plastids in angiosperms. AB - The inheritance of mitochondria and plastids in angiosperms has been categorized into three modes:maternal, biparental and paternal. Many mechanisms have been proposed for maternal inheritance, including: (1) physical exclusion of the organelle itself during pollenmitosis I (PMI); (2) elimination of the organelle by formation of enucleated cytoplasmic bodies (ECB); (3) autophagic degradation of organelles during male gametophyte development; (4) digestion of the organelle after fertilization; and (5)--the most likely possibility--digestion of organellar DNA in generative cells just after PMI. In detailed cytological observations, the presence or absence of mitochondrial and plastid DNA in generative cells corresponds to biparental/paternal inheritance or maternal inheritance of the respective organelle examined genetically. These improved cytological observations demonstrate that the replication or digestion of organellar DNA in young generative cells just after PMI is a critical point determining the mode of cytoplasmic inheritance. This review describes the independent control mechanisms in mitochondria and plastids that lead to differences in cytoplasmic inheritance in angiosperms. PMID- 20196235 TI - Analysis of DNA ligation by microchip electrophoresis. AB - We describe the potential of microchip electrophoresis with a Hitachi SV1100, which can be used to determine DNA sizes between 500 and 5000 bp with good quantification (DNA concentration, <8 ng/l) within 5 min, for the analysis of DNA ligation. On analysis of an electropherogram of a ligation mixture of the pTAC1-T vector and a 789 bp PCR-amplified DNA fragment, the presence of recombinant DNA was easily detected by comparison with an electropherogram obtained without ligase. On analysis of a ligation mixture of pUC19/Eco RI without alkaline phosphatase treatment and a 667 bp Eco RI-digested fragment of foreign DNA, several peaks observed in the electropherogram corresponded to the formation of monomeric and polymeric insert DNAs, self-ligated vector DNA, and recombinant DNA. On the other hand, several peaks were also observed in the electropherogram of the ligation mixture of pUC19/Eco RI with alkaline phosphatase treatment and the 667 bp Eco RI-digested fragment of foreign DNA, the fluorescence intensity corresponding to recombinant DNA apparently being increased. These results indicate the potential of microchip electrophoresis for the analysis of DNA ligation, it offering high resolution in a short time. PMID- 20196236 TI - Single-operator real-time ultrasound-guidance to aim and insert a lumbar epidural needle. AB - PURPOSE: In conventional practice of epidural needle placement, determining the interspinous level and choosing the puncture site are based on palpation of anatomical landmarks, which can be difficult with some subjects. Thereafter, the correct passage of the needle towards the epidural space is a blind "feel as you go" method. An aim-and-insert single-operator ultrasound-guided epidural needle placement is described and demonstrated. METHOD: Nineteen subjects undergoing elective Cesarean delivery consented to undergo both a pre-puncture ultrasound scan and real-time paramedian ultrasound-guidance for needle insertion. Following were the study objectives: to measure the success of a combined spinal-epidural needle insertion under real-time guidance, to compare the locations of the chosen interspinous levels as determined by both ultrasound and palpation, to measure the change in depth of the epidural space from the skin surface as pressure is applied to the ultrasound transducer, and to investigate the geometric limitations of using a fixed needle guide. RESULTS: One subject did not participate in the study because pre-puncture ultrasound examination showed unrecognizable bony landmarks. In 18 of 19 subjects, the epidural needle entered the epidural space successfully, as defined by a loss-of-resistance. In two subjects, entry into the epidural space was not achieved despite ultrasound guidance.Eighteen of the 19 interspinous spaces that were identified using palpation were consistent with those determined by ultrasound. The transducer pressure changed the depth of the epidural space by 2.8 mm. The measurements of the insertion lengths corresponded with the geometrical model of the needle guide, but the needle required a larger insertion angle than would be needed without the guide. CONCLUSION: This small study demonstrates the feasibility of the ultrasound-guidance technique. Areas for further development are identified for both ultrasound software and physical design. PMID- 20196237 TI - Spectroscopy challenge 14. PMID- 20196240 TI - Redefining the angel in the house: Evelyn Everett-Green and the historical novel for girls. AB - The article reassesses the work of Victorian girls' fiction author, Evelyn Everett-Green. Her position as a writer of historical fiction for a juvenile female market has led most critics to dismiss her as an apologist for an oppressive order, the girls' historical romance genre being perceived as one which validates "traditional", restrictive, domestic-oriented versions of femininity by demonstrating that they have long-established historical precedents. The author questions these assertions by focusing upon Everett Green's depiction of matriarchal figures and authority in many of her historical works. The author suggests that Everett-Green depicts her matriarchs as types of "universal mothers", capable of rejuvenating a bigoted and selfish patriarchal society by exerting an explicitly feminine/maternal power. In addition, these women are depicted as the possessors of real economic and political power, which originates from within the domestic sphere but extends far beyond its confines. The article sets her works within the context of late nineteenth- and early twentieth-century women historians, whose work represents a similar attempt to redefine the women's domestic role and reclaim for women a more vital role within history. It also suggests parallels between Everett-Green's imaging of woman as a type of "universal mother" and the use of similar figures which emerge from the work of Virginia Woolf and the ideas of late nineteenth-century feminists. The suggestion is that Everett-Green's historical works responded to a contemporary climate of opinion which perceived society as degenerate and saw the woman's loss of matriarchal power, whereby she had declined from the potentially all powerful "universal mother" of the past to the restricted, passive "angel in the house", as a symptom of this degeneration. PMID- 20196238 TI - Fatigue in neuromuscular disorders: focus on Guillain-Barre syndrome and Pompe disease. AB - Fatigue accounts for an important part of the burden experienced by patients with neuromuscular disorders. Substantial high prevalence rates of fatigue are reported in a wide range of neuromuscular disorders, such as Guillain-Barre syndrome and Pompe disease. Fatigue can be subdivided into experienced fatigue and physiological fatigue. Physiological fatigue in turn can be of central or peripheral origin. Peripheral fatigue is an important contributor to fatigue in neuromuscular disorders, but in reaction to neuromuscular disease fatigue of central origin can be an important protective mechanism to restrict further damage. In most cases, severity of fatigue seems to be related with disease severity, possibly with the exception of fatigue occurring in a monophasic disorder like Guillain-Barre syndrome. Treatment of fatigue in neuromuscular disease starts with symptomatic treatment of the underlying disease. When symptoms of fatigue persist, non-pharmacological interventions, such as exercise and cognitive behavioral therapy, can be initiated. PMID- 20196241 TI - Defining self and others through textile and text. AB - This article examines letters, diaries and fiction by eighteenth- and nineteenth century women travellers and colonists to show the important contribution of sewing, cloth and clothing in defining the self and determining class and racial barriers within a colonial context. Needlework skills often acted as significant props for the performance of socially approved femininity, indicating the complex role of women settlers both as colonisers and as colonial subjects. Upper- and middle-class women directed their supposed social inferiors, along with indigenous women, in approved feminine practices by urging they learn such skills. Issues of appearance and self-presentation, so important in maintaining class boundaries, were a frequent source of anxiety, while indigenous peoples were pressured to follow European notions of "decency" in dress, yet derided if they were perceived to be aping fashionable appearance. PMID- 20196242 TI - "Inhumanly brought back to life and misery": Mary Wollstonecraft, Frankenstein, and the Royal Humane Society. AB - While thorough investigation of many aspects of contemporary scientific developments and Mary Shelley's personal history have provided illuminating contexts for the study of Frankenstein, the activities of the Royal Humane Society, and other bodies and individuals who pioneered and publicized resuscitation techniques, have been comparatively neglected. Here we find a richly documented, highly conspicuous area of scientific endeavour, which generated much excitement in life and literature from the last quarter of the eighteenth century onwards. There are three major points of contact with Frankenstein: Victor Frankenstein's revival of dead tissue to make his creature; the frequent occurrences of unconsciousness and asphyxia, both in the novel and in Mary Shelley's family during the period leading up to its composition, and the widely differing degrees of competence and success with which they are treated; and the possibility that resuscitative techniques were used to revive Mary Shelley's mother, Mary Wollstonecraft, after a suicide attempt. The impact on Frankenstein of Mary Shelley's lifelong distress at the role she played in bringing about her mother's death in childbirth has been thoroughly canvassed by other critics, notably Anne Mellor, but the thought that Mary Shelley, who was herself conceived after her mother's second suicide attempt, might be, in a sense, a child of the dead adds a further turn to the Gothic screw. This study traces a hitherto unexplored intersection between Mary Shelley's first novel and her family history, as well as showing how it launches a formidable attack on the shady ethics and inconsiderate arrogance of some early resuscitators. PMID- 20196239 TI - Progress in phage display: evolution of the technique and its application. AB - Phage display, the presentation of (poly)peptides as fusions to capsid proteins on the surface of bacterial viruses, celebrates its 25th birthday in 2010. The technique, coupled with in vitro selection, enables rapid identification and optimization of proteins based on their structural or functional properties. In the last two decades, it has advanced tremendously and has become widely accepted by the scientific community. This by no means exhaustive review aims to inform the reader of the key modifications in phage display. Novel display formats, innovative library designs and screening strategies are discussed. I will also briefly review some recent uses of the technology to illustrate its incredible versatility. PMID- 20196243 TI - A different voice: Mary Hays's the Memoirs of Emma Courtney. AB - Mary Hays wrote in the decade of the 1790s, a period of intense creative flowering in England. Writing in a period enshrined to the works of the canonical Wordsworth and Coleridge, Hays explored through her Jacobinical novel, The Memoirs of Emma Courtney, the contentious relationship between self and society. Like other Jacobin women writers - Elizabeth Inchbald, Charlotte Smith and Mary Wollstonecraft - Mary Hays too used her novel to explode the insidious connection between education and gender construction. Emma Courtney is a landmark novel that wrestles with the paradigm of decorum and propriety which disallows women from voicing their aspirations. In the process, Hays merges the plots of the domestic novel of courtship and love with the novel of ideas to create a searing portrait of women's intellectual confinement and psychic dissonance in a society that only projects them in terms of their gender construction. Memoirs of Emma Courtney is a remarkable novel in its depiction of the emotional imbalance created by thwarted desire: intellectual and sexual. PMID- 20196244 TI - [Proceedings of the 10th Anniversary of the French-language Thoracic Oncology Intergroup Meetings, 18-19 June 2009, Paris, France]. PMID- 20196246 TI - Reducing excessive and underage alcohol consumption. PMID- 20196245 TI - "Having lived much in the world": inhabitation, embodiment and English women travellers' representations of Russia in the eighteenth century. AB - This article examines representations of Russia in the travel writings of British women in the eighteenth and nineteenth centuries. Using a mid-nineteenth- century text, The Englishwoman in Russia, to introduce the more familiar racialised models of difference deployed by imperial travel writers, the article connects these with two mid-eighteenth-century travel texts by virtue of the women writers' shared preoccupation with the female body as a sign of national culture, and cultural difference. Through a reading of Mrs Vigor's Letters from a Lady (1775), and Eliza Justice's Voyage to Russia (1746), it is argued that images of the female body are not only significant as a mode of cultural negotiation for foreign bodies and practices in this period, but that strategic "inhabitations" of Russian culture contribute to the women travellers' production of themselves as national and authorial "subjects" within their published texts. PMID- 20196247 TI - Medication therapy management: catching errors, saving lives and money. PMID- 20196249 TI - Community health centers in the economic downturn. PMID- 20196248 TI - "Secrets of the female sex": Jane Sharp, the reproductive female body, and early modern midwifery manuals. AB - Early modern midwifery manuals in Britain were usually the work of men. These books were a significant source of information about the body to the wider reading public: many sold well, and their prefatory materials include injunctions to readers not to make improper use of them. What is particularly interesting about Jane Sharp's Midwives Book (1671) is that it both provides a compendium of current beliefs concerning reproduction, and indicates the author's ironic perception of the misogyny that underpinned accepted ideas about the female reproductive body. This article gives key examples of Sharp's interventions, and also refers to Thomas Bartholin, Bartholinus Anatomy (1688); Richard Bunworth, The Doctresse (1656); Hugh Chamberlen, The Accomplisht Midwife (1673); The Compleat Midwifes Practice (1656); Helkiah Crooke, Microcosmographia (1615); Nicholas Culpeper, A Directory for Midwives (1651); Jacques Guillemeau, Childbirth (1612); Jean Riolan, A Sure Guide (1657); Daniel Sennert, Practical Physick (1664); William Sermon, The Ladies Companion (1671); and Percival Willughby, Observations in Midwifery (c. 1675). PMID- 20196250 TI - Improving child nutrition. PMID- 20196251 TI - Reducing sodium to improve health. PMID- 20196253 TI - Questioning starvation. AB - By comparing early modern cases of self-starvation with current theories of anorexia nervosa, this article explores the framing of the starving body as a cultural product, and questions the implications of culture in the perception and representations of the refusal of food. This allows a consideration of self starvation as both a product and reflection of cultural values attributed to consumption, gender, and the body. PMID- 20196252 TI - The absent body: representations of dying early modern women in a selection of seventeenth-century diaries. AB - This article seeks to explore the absence of the body in the depiction of dying women in a selection of seventeenth-century diaries. It considers the cultural forces that made this absence inevitable, and the means by which the physical body was replaced in death by a spiritual presence. The elevation of a dying woman from physical carer to spiritual nurturer in the days before death ensured that gender codes were not broken. The centrality of the body of the dying woman, within a female circle of care and support, was paradoxically juxtaposed with an effacement of the body in descriptions of a good death. In death, a woman might achieve the stillness, silence and compliance so essential to perfect early modern womanhood, and retrospective diary entries can achieve this ideal by replacing the body with images that deflect from the essential physicality of the woman. PMID- 20196254 TI - Older drivers. PMID- 20196256 TI - The politics of retrenchment: the quandaries of social protection under military rule in Chile, 1973-1990. PMID- 20196258 TI - [Microbiological technology and biotechnology in Latvia]. PMID- 20196257 TI - Vitiligo in North-Eastern China: An association between mucosal and acrofacial lesions. AB - Vitiligo is a mucocutaneous pigmentary disorder with worldwide distribution. Little is known about the clinical profile of vitiligo in North-eastern China. Accordingly, we reviewed 692 vitiligo out-patients from seven government hospitals in North-eastern China via a questionnaire in a multi-centre study conducted between June 2007 and June 2008, and hence characterized the epidemiology of vitiligo in North-eastern China. The mean +/- standard deviation age of onset was 23.69 +/- 13.83 years (range < 1-77 years). No gender preponderance was seen. The back was the most common site of involvement (39.6%). Vitiligo vulgaris was the predominant form (53.5%). Mucosal lesions were associated with lesions on the feet (odds ratio (OR) = 3.177, p < 0.001), hands (OR = 2.228, p < 0.01), face (OR = 2.028, p < 0.05) and neck (OR = 0.454, p < 0.05); but were not associated with chest, abdomen, waist, arms, legs or scalp lesions. Mucosal vitiligo is probably a special form of acrofacial vitiligo. PMID- 20196259 TI - [A study of Qing dynasty measures for countering epidemics south of the Yangtze: state and societal responses to plague]. PMID- 20196260 TI - [Proceedings from the Paris Dermatology Meeting, 10 December 2008]. PMID- 20196262 TI - A vessel of sins full of virtues: the ideal image of the female in the occasional writings of the Grand Duchy of Lithuania in the late sixteenth and early seventeenth centuries. PMID- 20196261 TI - Crime born of shame and fear. PMID- 20196263 TI - Health risk appraisal: how sharp is this tool in shaping employee behavior? AB - (1) Voluntary HRA participants are more likely to be women, enrolled in consumer driven health plans, and have fewer chronic conditions. (2) Employees who participate in HRAs experience increased utilization and spending n health services (office visits and prescription drugs) relative to those not offered an HRA through their health plan. (3) Though HRAs have been show to increase use of medical services, they are unlikely the sole solution to engaging consumers in their health. PMID- 20196264 TI - Last call: lawmakers hope new technology could mean the end to drunken driving. PMID- 20196265 TI - Chronic costs: making healthy choices easier for Americans can prevent deadly diseases and save money. PMID- 20196266 TI - [Abstracts of the VII National Congress of AEBI Bioethics. 9-10 October 2009. Madrid, Spain]. PMID- 20196267 TI - Taking a different approach: state are looking for innovative ways to cope with the 1 million cases of child abuse that flood in each year. PMID- 20196268 TI - Constitutional law -- free exercise clause -- Ninth Circuit rejects strict scrutiny for pharmacy dispensing requirement. -- Stormans, Inc. v. Selecky, 571 F.3d 960 (9th Cir. 2009). PMID- 20196269 TI - [Proceedings of the 72nd National SIMLII Conference, 25-28 November 2009, Fortezza da Basso, Italy]. PMID- 20196270 TI - Employment law -- Family and Medical Leave Act of 1993 -- Department of Labor regulations alter substitution of paid leave provision under the FMLA. -- FMLA Final Rule, 73 Fed. Reg. 67,934 (Nov. 17, 2008) (codified at 29 C.F.R. pt. 825 (2009)). PMID- 20196271 TI - [Life cycle of proteins]. PMID- 20196272 TI - [Current status of recurrence tuberculosis cases in Tokyo]. PMID- 20196273 TI - [Recurrence of tuberculosis in the City of Yokohama between 2004 and 2008]. PMID- 20196274 TI - [Comparison of the retreatment cases of pulmonary tuberculosis]. PMID- 20196275 TI - Research review. PMID- 20196277 TI - [Establishment of the standard VNTR analysis systems for Tuberculosis and preparation of databases for TB genotyping]. PMID- 20196276 TI - [Proportion of drug resistance among relapse tuberculosis cases --summary of Ryoken studies 1977-2002]. PMID- 20196278 TI - [Molecular epidemiology of Mycobacterium tuberculosis reviewed by molecular epidemiology of other pathogenic bacteria]. PMID- 20196279 TI - [Progress of research in the molecular epidemiology of Mycobacterium tuberculosis]. PMID- 20196280 TI - [Clinical application of the molecular epidemiology of tuberculosis]. PMID- 20196281 TI - Legal impediments to implementing value-based purchasing in healthcare. PMID- 20196283 TI - Hastening death: dying, dignity and the organ shortage gap. PMID- 20196282 TI - Medical error reduction and tort reform through private, contractually-based quality medicine societies. AB - The current medical malpractice system is broken. Many patients injured by malpractice are not compensated, whereas some patients who recover in tort have not suffered medical negligence; furthermore, the system's failures demoralize patients and physicians. But most importantly, the system perpetuates medical error because the adversarial nature of litigation induces a so-called "Culture of Silence" in physicians eager to shield themselves from liability. This silence leads to the pointless repetition of error, as the open discussion and analysis of the root causes of medical mistakes does not take place as fully as it should. In 1993, President Clinton's Task Force on National Health Care Reform considered a solution characterized by Enterprise Medical Liability (EML), Alternative Dispute Resolution (ADR), some limits on recovery for non-pecuniary damages (Caps), and offsets for collateral source recovery. Yet this list of ingredients did not include a strategy to surmount the difficulties associated with each element. Specifically, EML might be efficient, but none of the enterprises contemplated to assume responsibility, i.e., hospitals and payers, control physician behavior enough so that it would be fair to foist liability on them. Likewise, although ADR might be efficient, it will be resisted by individual litigants who perceive themselves as harmed by it. Finally, while limitations on collateral source recovery and damages might effectively reduce costs, patients and trial lawyers likely would not accept them without recompense. The task force also did not place error reduction at the center of malpractice tort reform -a logical and strategic error, in our view. In response, we propose a new system that employs the ingredients suggested by the task force but also addresses the problems with each. We also explicitly consider steps to rebuff the Culture of Silence and promote error reduction. We assert that patients would be better off with a system where physicians cede their implicit "right to remain silent", even if some injured patients will receive less than they do today. Likewise, physicians will be happier with a system that avoids blame-even if this system placed strict requirements for high quality care and disclosure of error. We therefore conceive of de facto trade between patients and physicians, a Pareto improvement, taking form via the establishment of "Societies of Quality Medicine." Physicians working within these societies would consent to onerous processes for disclosing, rectifying and preventing medical error. Patients would in turn contractually agree to assert their claims in arbitration and with limits on recovery. The role of plaintiffs' lawyers would be unchanged, but due to increased disclosure, discovery costs would diminish and the likelihood of prevailing will more than triple. This article examines the legal and policy issues surrounding the establishment of Societies of Quality Medicine, particularly the issues of contracting over liability, and outlines a means of overcoming the theoretical and practical difficulties with enterprise liability, alternative dispute resolution and the imposition of limits on recovery for non pecuniary damages. We aim to build a welfare enhancing system that rebuffs the culture of silence and promotes error reduction, a system that is at the same time legally sound, fiscally prudent and politically possible. PMID- 20196284 TI - From concierge medicine to patient-centered medical homes: international lessons & the search for a better way to deliver primary health care in the U.S. PMID- 20196285 TI - Beyond politics: A social and cultural history of federal healthcare conscience protections. PMID- 20196286 TI - But doctor, I still have both feet! Remedial problems faced by victims of medical identity theft. PMID- 20196287 TI - Searching for safety: addressing search engine, website, and provider accountability for illicit online drug sales. PMID- 20196288 TI - Apropos "New vaccines for developing countries: will it be feast or famine"? PMID- 20196289 TI - Human factors measurement for future air traffic control systems. AB - OBJECTIVE: This article provides a critical review of research pertaining to the measurement of human factors (HF) issues in current and future air traffic control (ATC). BACKGROUND: Growing worldwide air traffic demands call for a radical departure from current ATC systems. Future systems will have a fundamental impact on the roles and responsibilities of ATC officers (ATCOs). Valid and reliable methods of assessing HF issues associated with these changes, such as a potential increase (or decrease) in workload, are of utmost importance for advancing theory and for designing systems, procedures, and training. METHOD: We outline major aviation changes and how these relate to five key HF issues in ATC. Measures are outlined, compared, and evaluated and are followed by guidelines for assessing these issues in the ATC domain. Recommendations for future research are presented. RESULTS: A review of the literature suggests that situational awareness and workload have been widely researched and assessed using a variety of measures, but researchers have neglected the areas of trust, stress, and boredom. We make recommendations for use of particular measures and the construction of new measures. CONCLUSION: It is predicted that, given the changing role of ATCOs and profound future airspace requirements and configurations, issues of stress, trust, and boredom will become more significant. Researchers should develop and/or refine existing measures of all five key HF issues to assess their impact on ATCO performance. Furthermore, these issues should be considered in a holistic manner. APPLICATION: The current article provides an evaluation of research and measures used in HF research on ATC that will aid research and ATC measurement. PMID- 20196290 TI - Identifying black swans in NextGen: predicting human performance in off-nominal conditions. AB - OBJECTIVE: The objective is to validate a computational model of visual attention against empirical data--derived from a meta-analysis--of pilots' failure to notice safety-critical unexpected events. BACKGROUND: Many aircraft accidents have resulted, in part, because of failure to notice nonsalient unexpected events outside of foveal vision, illustrating the phenomenon of change blindness. A model of visual noticing, N-SEEV (noticing-salience, expectancy, effort, and value), was developed to predict these failures. METHOD: First, 25 studies that reported objective data on miss rate for unexpected events in high-fidelity cockpit simulations were identified, and their miss rate data pooled across five variables (phase of flight, event expectancy, event location, presence of a head up display, and presence of a highway-in-the-sky display). Second, the parameters of the N-SEEV model were tailored to mimic these dichotomies. RESULTS: The N-SEEV model output predicted variance in the obtained miss rate (r = .73). The individual miss rates of all six dichotomous conditions were predicted within 14%, and four of these were predicted within 7%. CONCLUSION: The N-SEEV model, developed on the basis of an independent data set, was able to successfully predict variance in this safety-critical measure of pilot response to abnormal circumstances, as collected from the literature. APPLICATIONS: As new technology and procedures are envisioned for the future airspace, it is important to predict if these may compromise safety in terms of pilots' failing to notice unexpected events. Computational models such as N-SEEV support cost-effective means of making such predictions. PMID- 20196291 TI - The effect of active versus passive training strategies on improving older drivers' scanning in intersections. AB - OBJECTIVE: This study aimed (a) to determine whether older drivers looked less often for potential threats while turning than younger drivers and (b) to compare the effectiveness of active and passive training on older drivers' performance and evaluation of their driving skills in intersections. BACKGROUND: Age-related declines in vision, physical abilities, psychomotor coordination, and cognition combine to make it less likely that older drivers will look for potential threats during a turn. Research suggests that active training should be an effective means of improving older drivers' performance and self-awareness. METHOD: In Experiment 1, younger and older participants drove a series of virtual intersection scenarios, were shown video replays, and were provided feedback. In Experiment 2, older drivers were assigned to one of three cohorts: active simulator training, passive classroom training, or no training. Pre- and posttraining simulator and field drives assessed training effectiveness. RESULTS: In Experiment 1, older drivers looked less often during turns than younger drivers. Customized feedback was successful in altering drivers' perception of their abilities. In Experiment 2, active training increased a driver's probability of looking for a threat during a turn by nearly 100% in both posttraining simulator and field drives. Those receiving passive training or no training showed no improvement. CONCLUSION: Compared with passive training, active training is a more effective strategy for increasing older drivers' likelihood of looking for threats during a turn. APPLICATION: The results of this research can guide the development of programs that could reduce intersection crashes among older drivers. PMID- 20196292 TI - Patterns of functional loss among older people: a prospective analysis. AB - OBJECTIVE: Patterns of capability loss and disability onset among older people were investigated prospectively. BACKGROUND: With aging, the gap between personal capability and environmental demand becomes wider, resulting in higher levels of disability in daily activities. METHODS: Data from a longitudinal, population based study were obtained for analysis, which recruited a representative sample of 13,004 people aged 65 years and older from five sites in Great Britain. Participants completed a baseline interview during 1990 to 1994 and follow-up interviews after 1, 2, 3, 6, 8, and 10 years. Those who reported full vision, hearing, thinking, locomotion, reaching, and dexterity ability as well as no disability in cooking, housework, shopping, and transportation at baseline were included in a survival analysis. RESULTS: Locomotion was the first ability to be lost, followed by reaching, thinking, hearing, vision, and dexterity. Age at onset of disability was earliest for shopping, then housework, transportation, and cooking. Women were consistently younger at capability loss and disability onset than men except in terms of hearing and cooking. CONCLUSION: These findings suggest that capabilities required for product and service interaction follow a hierarchical pattern of loss, which has practical implications for design. Although interventions to reduce disability in the older population are likely to require changes that address more than one demand, capabilities lost early in old age should take precedence over those lost later. APPLICATION: A potential application of this research is in the development of an overall design strategy to enhance older people's ability to live independently. PMID- 20196293 TI - Psychophysiological responses in women during cart pushing on different frictional walkways. AB - OBJECTIVE: The aim of this study was to evaluate psychophysically determined acceptable forces, cardiopulmonary, and calf muscle metabolic responses in 15 workers while they pushed an instrumented cart on two walkways. BACKGROUND: In addition to the potential for increased musculoskeletal disorders in workers, pushing on various terrains is associated with occurrence of slips and falls at the workplace. METHOD: Using a psychophysical approach, participants chose the maximum acceptable cart weight they could push without strain on walkways with coefficient of friction equaling 0.68 (plywood) and 0.26 (Teflon-coated.). Then, while participants pushed their psychophysically chosen cart weight for 2 hr on each walkway, horizontal and vertical forces applied on the cart handle and physiological responses were collected. Cardiopulmonary responses were measured using a telemetric metabolic cart. A tissue hemoglobin index (THI) and a tissue oxygenation index (TOI) from the right and left calf muscles were obtained using near-infrared spectroscopy. RESULTS: Participants generated higher horizontal forces (by 26%) on plywood than that on Teflon. Cardiopulmonary and TOI and THI responses were similar between walkways. However, greater ratios of absolute oxygen uptake per force (by 19%) and TOI per force (by 24%) on Teflon were demonstrated in the horizontal direction than on plywood. CONCLUSIONS: This increased muscle oxygenation-force ratio, coupled with increased oxygen uptake per force generated on Teflon, might suggest that pushing on the slippery surface results in higher metabolic demand. APPLICATION: Findings from the present study will assist in revising previously established acceptable forces and in relating these forces to physiological responses with respect to pushing on different frictional walkways. PMID- 20196294 TI - The potential for actigraphy to be used as an indicator of sitting discomfort. AB - OBJECTIVE: A novel technique that uses actigraphy, the study of activity involving the use of body-mounted accelerometers, to detect the discomfort related movements of a sitting individual has been proposed as a potential indicator of sitting discomfort, and the purpose of this study was to test its validity. BACKGROUND: Objective measurement of sitting discomfort has always been challenging for researchers. Electromyographic measurements, pressure mapping, and a wide range of other techniques have all been investigated with limited success. METHOD: The activity monitor's ability to detect and measure seated movement was assessed, and 12 participants were tested on four different chairs (100-min sessions for each). RESULTS: The activity monitor was able to detect participants' sitting movements (Pearson coefficients > 0.9). The chairs were shown to have significantly different subjective discomfort ratings, all of which increased over time. The movements detected by the activity monitor also increased significantly with time, and the amount measured was greater in the chairs rated as most uncomfortable. Regression analysis indicated that the actigraphy data were able to account for 29.6% of the variation in perceived discomfort ratings. CONCLUSION: Actigraphy can reliably detect sitting movements and may be of use in measuring sitting discomfort. APPLICATION: Potential applications of this technique exist for seating research in the automotive industry, health care, and office and leisure chairs. PMID- 20196295 TI - Hand-handhold coupling: effect of handle shape, orientation, and friction on breakaway strength. AB - OBJECTIVE: The aim was to determine the maximum force that can be exerted on an object before it is pulled or slips from the grasp of the hand ("breakaway strength") for fixed overhead handholds of varying orientation, shape, and friction. BACKGROUND: Many studies have quantified hand strength by having participants squeeze, pull on, or create torque on an object or handle, but few studies have measured breakaway strength directly. METHOD: In two experiments, hand strength was measured as both overhead breakaway strength for handholds typical of fixed industrial ladders and as maximum isometric grip strength measured using a common Jamar grip dynamometer. RESULTS: Breakaway strength was greatest for a fixed horizontal cylinder ("high friction"; 668 +/- 40 N and 691 +/- 132 N for Experiments 1 and 2, respectively), then for a horizontal cylinder that simulated low surface friction ("low friction"; 552 +/- 104 N), then for a vertical cylinder (435 +/- 27 N), and finally, for a vertical rectangular-shaped rail (337 +/- 24 N). Participants are capable of supporting only their own body weight with one hand when grasping the fixed horizontal cylinder. Breakaway strength for both the high- and low-friction horizontal cylinders was significantly greater than isometric grip strength (1.58 +/- 0.25 and 1.26 +/- 0.19 times, respectively). CONCLUSION: Results support the hypothesis that hand handhold coupling is composed of active (isometric or eccentric finger flexion) and passive (frictional) components. Traditional isometric grip strength alone does not predict the strength of a couple between a hand and a handhold well. APPLICATION: This research shows that handhold shape, orientation, and friction are important in the safe design of grab rails or ladders. PMID- 20196296 TI - Auditory decision aiding in supervisory control of multiple unmanned aerial vehicles. AB - OBJECTIVE: This article is an investigation of the effectiveness of sonifications, which are continuous auditory alerts mapped to the state of a monitored task, in supporting unmanned aerial vehicle (UAV) supervisory control. BACKGROUND: UAV supervisory control requires monitoring a UAV across multiple tasks (e.g., course maintenance) via a predominantly visual display, which currently is supported with discrete auditory alerts. Sonification has been shown to enhance monitoring performance in domains such as anesthesiology by allowing an operator to immediately determine an entity's (e.g., patient) current and projected states, and is a promising alternative to discrete alerts in UAV control. However, minimal research compares sonification to discrete alerts, and no research assesses the effectiveness of sonification for monitoring multiple entities (e.g., multiple UAVs). METHOD: The authors conducted an experiment with 39 military personnel, using a simulated setup. Participants controlled single and multiple UAVs and received sonifications or discrete alerts based on UAV course deviations and late target arrivals. RESULTS: Regardless of the number of UAVs supervised, the course deviation sonification resulted in reactions to course deviations that were 1.9 s faster, a 19% enhancement, compared with discrete alerts. However, course deviation sonifications interfered with the effectiveness of discrete late arrival alerts in general and with operator responses to late arrivals when supervising multiple vehicles. CONCLUSIONS: Sonifications can outperform discrete alerts when designed to aid operators to predict future states of monitored tasks. However, sonifications may mask other auditory alerts and interfere with other monitoring tasks that require divided attention. APPLICATIONS: This research has implications for supervisory control display design. PMID- 20196297 TI - To scroll or not to scroll: scrolling, working memory capacity, and comprehending complex texts. AB - OBJECTIVE: The purpose of these experiments was to examine the effects of user characteristics on learning from scrolling interfaces. BACKGROUND: Although scrolling Web pages are now common, few studies have explored the effects of scrolling on understanding the content that is being conveyed. METHOD: This set of studies investigated whether presenting text in two particular formats has an effect on comprehension for readers who differ in working memory capacity. RESULTS: Results from both studies indicated that a scrolling format reduced understanding of complex topics from Web pages, especially for readers who were lower in working memory capacity. CONCLUSION: These findings show that the way text is presented can interact with learner abilities to affect learning outcomes. APPLICATION: These results have implications for both educational technology and human interfaces that present information using displays that can vary in size and construction. PMID- 20196298 TI - Isolating the effects of vection and optokinetic nystagmus on optokinetic rotation-induced motion sickness. AB - OBJECTIVE: This study investigates isolated effects of vection and optokinetic nystagmus (OKN) on visually induced motion sickness (VIMS) provoked by rotating optokinetic drum patterns. BACKGROUND: VIMS was the subject of recent standardization activities, but the effects of OKN have not been studied in the absence ofvection. METHOD: Experiment 1 suppressed OKN by eye fixation and examined VIMS severity (both ordinal and ratio scale) and time spent in saturated vection at four pattern rotating velocities of 0, 2, 14, and 34 degrees per second (dps). Experiment 2 suppressed vection by adding a peripheral visual field rotating in the opposite direction to the rotating patterns. VIMS severity and OKN slow-phase velocity were studied at four rotating velocities of 0, 30, 60, and 90 dps. RESULTS: Results from Experiment 1 indicated that VIMS severity increased as the pattern velocity increased from 0 dps to 34 dps. Results from Experiment 2 indicated that as the velocity of the rotating pattern increased, the slow-phase velocity of OKN and the severity of VIMS increased and peaked in the 60-dps condition. In both experiments, ratio-scaled nausea data significantly correlated with ordinal-scaled nausea ratings. CONCLUSION: VIMS can still occur in the absence of either vection or OKN. Interestingly, the profile of the summed results of the two experiments matches nicely with the profile reported by Hu et al. in which neither OKN nor vection were controlled. APPLICATION: Potential applications include modeling and reduction of VIMS in computer gaming environments. PMID- 20196299 TI - The challenge of uncoupled motion: duration of cognitive and physiological aftereffects. AB - OBJECTIVE: This study aimed to document the cognitive aftereffects of exposure to uncoupled motion and the time course of recovery from these aftereffects. BACKGROUND: Uncoupled motion refers to a situation in which an individual is simultaneously exposed to two asynchronous motions, either real or virtual. These environments are a challenge for designers because technology that is supposed to increase the user's task performance may actually lead to decreased task performance. METHOD: In the study, 11 male participants, (median age =32 years) with prior flight experience (median=600 hr) were exposed to an uncoupled motion environment consisting of a flight simulator on a vertically oscillating platform. Participants completed a cognitive test battery, a balance test, and a dynamic visual acuity test preexposure, immediately postexposure, and 2, 4, 6, 8, and 24 hr postexposure. RESULTS: The uncoupled motion scenario led to significant cognitive aftereffects that cannot be solely attributed to motion sickness. These aftereffects lasted between 2 and 4 hr postexposure. The scenario generated some physiological aftereffects that lasted between 1 and 2 hr postexposure. However, it is likely that these aftereffects can be attributed to motion sickness. CONCLUSION: Uncoupled motion can cause unappreciated effects, such as degraded cognitive performance. APPLICATION: System designs that create uncoupled motion need to be evaluated for the potential to generate operator impairment, and designs should be modified to minimize this potential wherever possible. When redesign is not possible, system-use guidelines should be developed to minimize impairment. The current results suggest operators avoid performing cognitively demanding tasks for at least 2 hr postexposure. PMID- 20196301 TI - Picking up speed. PMID- 20196300 TI - Text messaging during simulated driving. AB - OBJECTIVE: This research aims to identify the impact of text messaging on simulated driving performance. BACKGROUND: In the past decade, a number of on road, epidemiological, and simulator-based studies reported the negative impact of talking on a cell phone on driving behavior. However, the impact of text messaging on simulated driving performance is still not fully understood. METHOD: Forty participants engaged in both a single task (driving) and a dual task (driving and text messaging) in a high-fidelity driving simulator. RESULTS: Analysis of driving performance revealed that participants in the dual-task condition responded more slowly to the onset of braking lights and showed impairments in forward and lateral control compared with a driving-only condition. Moreover, text-messaging drivers were involved in more crashes than drivers not engaged in text messaging. CONCLUSION: Text messaging while driving has a negative impact on simulated driving performance. This negative impact appears to exceed the impact of conversing on a cell phone while driving. APPLICATION: The results increase our understanding of driver distraction and have potential implications for public safety and device development. PMID- 20196302 TI - Stand up and represent. PMID- 20196303 TI - Safeguarding children by means of information sharing. AB - This study explored the purpose and use of children's (aged nought to 16 years) records in an emergency department (ED) as a means of safeguarding children. It aimed to elicit ED staff and local child protection group perceptions of the use of these records. A case study methodology was utilised to uncover the story of why and how ED child records were used.The study was carried out in three stages- an analysis of a purposive sample of ED children's records, a focus group with 12 ED staff members in the case study site, and a focus group with 12 members of the local operational child protection group. The emerging findings indicate that child records are a good tool for communication, however the risk factors are not always recognised and the records are not sufficiently child focused. They also highlight that existing written records did not provide a format that enabled staff to record information comprehensively. PMID- 20196304 TI - Toddler nutrition: food for thought. PMID- 20196305 TI - Barriers to extended nurse prescribing among practice nurses. AB - Practice nurses are defined as those nurses who work in general practices and are employed by GPs.This includes nurses who have gained further qualifications and are working as nurse practitioners and minor illness specialist nurses. Despite the success of nurse-led services in primary care, the move into extended nurse prescribing has not been as high as predicted. A questionnaire survey of all 251 practice nurses in one southern English county was conducted in order to ascertain current roles and responsibilities, prescribing qualifications (both actual and planned), and perceived barriers to acquiring a nurse independent prescriber qualification. The findings identified what local practice nurses perceive to be barriers to nurse prescribing with issues of age, salary, support and training all playing a part in discouraging the uptake of this qualification. PMID- 20196306 TI - Audit as evidence: the effectiveness of '123 magic' programmes. AB - This paper reports on an audit to determine the effectiveness of '123 Magic', a group-based parenting programme that encourages parents to explore, discuss and practice strategies to manage child behaviour. The audit's use at a local level to provide evidence of effectiveness and areas for quality improvement is described. Audit can also be useful to determine outcomes locally and to develop new hypotheses for testing through research. The effectiveness of '123 Magic' was evaluated by measuring whether parenting self-efficacy increased after attending a programme. A total of 74 parents took part from 16 '123 Magic' parenting programmes from October 2007 to June 2009. Parents completed the TOPSE evaluation tool as a pre- and post-course measure of parenting self-efficacy. Scores increased at the end of the parenting programmes for all scales, which suggests that'123 Magic' is effective in terms of improving parenting self-efficacy and also demonstrates the value and contribution of parenting programme facilitators to supporting parents and families in the community. PMID- 20196307 TI - Say 'health visiting'. PMID- 20196308 TI - Measurement, causes and management of overweight and obesity in children. AB - Childhood obesity is a growing problem that has serious implications for future generations. The cause is multifactorial, with contributions from genetics and the environment. Management needs to be targeted at the population as a whole, with improved education and strategies to improve lifestyle and behaviour. Medication and surgery play a very small role in management, for use in exceptional circumstances. Only by empowering individuals and families to change will there be any impact on this epidemic. PMID- 20196309 TI - The cobbler's children's shoes. PMID- 20196310 TI - Comfort amidst the chaos. PMID- 20196312 TI - How to save time, see more patients, and make more money. PMID- 20196311 TI - Out of hospital, not available? PMID- 20196313 TI - CPT 2010. PMID- 20196314 TI - Social networking poses new challenges. PMID- 20196315 TI - Learning from the past. PMID- 20196316 TI - New head of NMC prepares to end impasse on advanced level practice. PMID- 20196317 TI - The NHS Constitution may become a nurse's best friend. PMID- 20196318 TI - Partnership for parents. AB - Family Nurse Partnerships are being piloted around the country to provide intensive and long-term support to young mothers. PMID- 20196319 TI - A good night's sleep. AB - Essex Cardiothoracic Centre is helping people overcome sleep apnoea. A nurse-led tailored service has reduced waiting times and travel costs. PMID- 20196320 TI - Breaking the fall. AB - Specialist nurse Wendy Hartland was frustrated by the lack of information for people with multiple sclerosis who are at risk of falls. She set about compiling an advice booklet for them. PMID- 20196321 TI - One airway, one approach. AB - The risk of poor asthma control is hugely increased by concomitant allergic rhinitis. PMID- 20196322 TI - Road to recovery. PMID- 20196323 TI - Complementary therapies: a challenge for nursing practice. AB - There has been a vast increase in the use of complementary therapies in recent years. Nurses, who are at the forefront of healthcare delivery, require adequate knowledge of complementary therapies and the skills to provide appropriate advice and holistic care incorporating the individual's physical, psychological, social and emotional wellbeing and needs. This article explores the use and development of complementary therapies in health care. The role of, and the need for, an enhanced education approach to expand the current body of knowledge is discussed. PMID- 20196324 TI - Prone positioning in patients with acute respiratory distress syndrome. AB - Acute respiratory distress syndrome (ARDS) is a serious and complex condition. Despite technological advances in treatment, it is associated with a high mortality rate, and the cost to the NHS of treating patients with ARDS is substantial. The condition also presents nurses with many challenges. This article explores the different treatment options available for patients with ARDS, focusing on prone positioning. PMID- 20196325 TI - Nursing care and management of patients with intrapleural drains. AB - Most nurses working in an acute hospital setting will encounter patients with chest drains and underwater seal drainage at some point in their careers. This article is primarily written for the non-specialist nurse who requires a good working knowledge of chest drain insertion and underwater seal drainage. The article discusses the indications for chest drain insertion and the merits of different approaches, and provides a detailed analysis of the nursing care of a patient with a chest drain. PMID- 20196326 TI - Orthopaedic plaster casting. PMID- 20196327 TI - Reputation at stake. PMID- 20196328 TI - Help to improve neonatal care. PMID- 20196329 TI - The effects of students' curriculum engagement, attitudes toward their teachers, and perception of their teachers' skills on school-based prevention curriculum outcomes. AB - We examined the association between changes in the substances and mediating variables targeted by the All Stars drug prevention curriculum, and students' engagement in and enjoyment of the curriculum, their attitudes toward their teachers, and their perceptions of their teachers' skills. Forty-eight school staff administered at least one All Stars class, for up to three consecutive years, to their seventh grade students in 107 classes in a large Midwestern school district. A sample of 2428 students completed a linked pretest and post test, for a response rate of 91%. We found that students' engagement in and enjoyment of the curriculum, their attitudes toward their teachers, and their perceptions of their teachers' skill were all associated with positive changes in the curriculum's five mediators, but not with changes in students' substance use per se. Study findings suggest the importance of these three attributes to the achievement of the objectives of prevention curricula. PMID- 20196330 TI - Evaluating the prevention through alternative learning styles program. AB - This article reports on the evaluation of a two-year alcohol, tobacco and other drug (ATOD) intervention, the Prevention through Alternative Learning Styles (PALS) program, targeting both teachers and middle-school students. Teachers are taught to recognize students' unique learning styles in the context of the ATOD curriculum and adapt the ATOD messages to these learning styles. The student curriculum consists of 5 topic areas with two lessons per topic area. Student goals include enhancing students' knowledge of the effects of ATOD, promoting students' use of refusal skills and decreasing students' intentions to use ATOD. The program was implemented in school dis-tricts in the greater Dayton Ohio area. Support was found for the intervention's overall effectiveness in both years, with statistically significant improvements demonstrated by the students who participated in the PALS program. Students had an increase in their knowledge of ATOD topic areas and a decrease in their intentions to use ATOD. PMID- 20196331 TI - Age of inhalant first time use and its association to the use of other drugs. AB - Inhalants are the 4th most commonly abused drugs after alcohol, tobacco, and marijuana. Although inhalants are often referred as Gateway Drugs this hypothesis is less examined. Using the 2003 National Survey on Drug Use and Health data, age of first time inhalant use was compared with the age of onset of other drugs among 6466 inhalant users who also used at least one of 14 other drugs. Findings indicated that only 4.2% multiple drug users who used inhalants prior to other drugs, especially alcohol, tobacco, and marijuana. Thus, the theory that inhalants are gateway drugs was not supported. PMID- 20196332 TI - Conscientiousness, protective behavioral strategies, and alcohol use: testing for mediated effects. AB - The purpose of this study was to determine if use of protective behavioral strategies mediated the relationship between conscientiousness and alcohol use and alcohol-related problems. Participants were 186 college students at a state university campus in the Northeastern United States participating in a study examining the effectiveness of a brief alcohol intervention. Data were collected during the 2006-2007 academic years. Results indicated that use of protective behavioral strategies mediated the relationship between conscientiousness and both alcohol use and alcohol-related problems. Implications of the findings for researchers and clinicians in the area of preventing high-risk drinking among college students are discussed. PMID- 20196333 TI - Adolescent protective behavior to reduce drug and alcohol use, alcohol-related harm and interpersonal violence. AB - Typically adolescents' friends are considered a risk factor for adolescent engagement in risk-taking. This study took a more novel approach, by examining adolescent friendship as a protective factor. In particular it investigated friends' potential to intervene to reduce risk-taking. Five-hundred-forty adolescents (mean age 13.47 years) were asked about their intention to intervene to reduce friends' alcohol, drug and alcohol-related harms and about psychosocial factors potentially associated with intervening. More than half indicated that they would intervene in friends' alcohol, drug use, alcohol-related harms and interpersonal violence. Intervening was associated with being female, having friends engage in overall less risk-taking and having greater school connectedness. The findings provide an important understanding of increasing adolescent protective behavior as a potential strategy to reduce alcohol and drug related harms. PMID- 20196334 TI - Campus involvement, perceived campus connection, and alcohol use in college athletes. AB - This research study examined the relationship of college athletes' levels of campus involvement and campus connection to their alcohol use. A survey measuring alcohol use, campus involvement and campus connection was administered to 720 athletes at nine institutions. Participants who reported having 5 or more drinks on one occasion in the past two weeks had higher levels of campus connection than those who did not report that level of alcohol consumption; but, conversely these college athletes also reported lower levels of campus involvement. It is suggested that increasing campus involvement of college athletes could be an effective strategy to reduce high-risk alcohol use by college athletes and possibly even college students as a whole. PMID- 20196336 TI - I'm right! and you're wrong! PMID- 20196335 TI - Assessing police community readiness to work on youth access and possession of tobacco. AB - Researchers are only beginning to investigate how to measure a community's readiness to engage in an intervention. In this study, we investigated the readiness of police departments to deal with tobacco policies about youth access to tobacco and youth possession of tobacco. Police officers in 24 towns completed structured interviews designed to assess each police department's community readiness to enforce tobacco sales and possession laws. Community readiness ratings were compared to outcome measures in the community, such as tobacco sales and possession enforcement activity, youth knowledge of such activities, and youth reports of smoking history. Higher readiness ratings on the youth tobacco possession enforcement scale was related to higher youth possession citation rates, higher number of youth reporting knowing someone who received a possession ticket, and a smaller number of youth reporting seeing minors smoking in their community. Youth in communities with higher possession readiness ratings in Efforts and Knowledge Regarding the Efforts had lower reports of youth reporting ever having smoked. Higher readiness ratings in the Leadership dimension of tobacco sales enforcement was related to lower tobacco commercial sales rates in the community. Higher tobacco sales readiness ratings in the Efforts, Knowledge Regarding the Efforts, and Knowledge Regarding the Problem dimensions were related to a lower number of youth reporting ever having smoked. The implications of these findings are discussed. PMID- 20196337 TI - The Endo-Eze TiLOS system. PMID- 20196338 TI - Chemomechanical strategies to manage endodontic infections. PMID- 20196339 TI - Bioceramic technology: closing the endo-restorative circle, Part I. PMID- 20196340 TI - Has resin-based composite replaced amalgam? AB - The major health organizations in the world continue to accept amalgam use, but the "amalgam war" of the 1800s is still going on. The end is not in sight. There is little disagreement that amalgam serves well and, although controversial, it appears to have minimal to no health hazards. There is a wide variation in the relative amount of amalgam placed in developed countries, and many dentists in North America do not use it. However, amalgam is still being used at least some of the time by the majority of practitioners in North America, and most of those practitioners also place resin-based composite in Class II locations. The evolution from amalgam to tooth-colored restorations has been a slow and tumultuous journey. The acceptability of resin-based composite in Class II locations continues to be a question for some dentists, while others have concluded that amalgam is "dead." It would be highly desirable if some of dentists using the alleged poisonous properties of amalgam as a "practice building" ploy would find more legitimate methods to increase their practice activity. PMID- 20196341 TI - Delving into reality: a conversation with Dr. Michael B. Miller. Interview by Damon Adams. PMID- 20196342 TI - Tooth-implant borne RPD: a case report. PMID- 20196343 TI - Template-assisted direct composite veneers. PMID- 20196344 TI - Leave decay in my cavity? You must be kidding! PMID- 20196346 TI - Decoding CAD/CAM and digital impression units. PMID- 20196347 TI - Minimally invasive makeover: platinum foil technique. PMID- 20196348 TI - Incorporating facial rejuvenation into the dental practice. PMID- 20196349 TI - A future for periodontal therapy. PMID- 20196350 TI - Embezzlement prevention--to catch a thief. AB - So far, in part 1 of this 2-part article, the importance of the proper procedures that are needed to be performed in order to hire the best business/financial team members for your practice has been discussed. Utilizing these techniques will give you a fighting chance to eliminate the potential for embezzlement from your business. Also provided were some specific guidelines of embezzlement prevention that you must be alert for, along with the detection of a potential embezzler in the office, by listing the "red flags." Next, in part 2, I will complete the list of specific guidelines that are necessary to prevent embezzlement with the implementation of strong business systems designed to safeguard and control your practice financial system successfully. PMID- 20196351 TI - Re-discovery of silence in pastoral care. AB - Pastoral care within the greater American cultural milieu strongly appraises the use of spoken words and tends to undervalue silence as a powerful and creative element for mutual connection with others and with God. In this essay the author proposes a "counter-cultural" adjustment in the perception of silence and its implications to the practice of, and theological understanding of, pastoral care. The author bases his theses on his own cross-cultural learning experiences, including his training in Clinical Pastoral Education (CPE), in the re vitalization of ancient Christian wisdom, and in his current ministry to nursing home residents. PMID- 20196352 TI - Screening for spiritual struggle. AB - A growing body of research documents the harmful effects of religious or spiritual struggle among patients with a wide variety of diagnoses. We developed a brief screening protocol for use in identifying patients who may be experiencing religious/spiritual struggle, as well as patients who would like a visit from a chaplain. We describe the results of a pilot study in which non chaplain healthcare colleagues administered the screening protocol to patients admitted to an acute medical rehabilitation unit. The protocol identified 7% of the patients as possibly experiencing religious/spiritual struggle. Follow up spiritual assessments by the chaplain confirmed religious/spiritual struggle in all but one of these patients and also identified additional cases of religious/spiritual struggled not identified by the protocol. In addition to areas for future research, the authors describe how using a protocol to screen patients for religious/spiritual can make important contributions to spiritual care. PMID- 20196353 TI - Love's angry lament: confronting our anger with God: based on Lamentations 1-3. AB - The author examines biblical characters who challenged the justice of God. He contends that these lamenters laid the foundation for the rabbinic tradition of chutzpah. They freely faced God with their disillusionment and anger. Their intimacy with the Divine is exemplary. The author acknowledges the ambiguities of God's response to despair and contextualizes lament in the case of a woman who has been sexually abused and seeks pastoral guidance. This article integrates exegesis and theology with theories of anger and intimacy. PMID- 20196354 TI - Topography of referrals to chaplains in the Metropolitan Chaplaincy Study. AB - Understanding referral patterns to chaplains is essential not only to ensure proper patient treatment, but also to assist chaplains seeking to expand the range of patient situations in which they are called to intervene. Information about more than 58,000 chaplain visits was documented during the first two years (2005-2006) of the Metropolitan Chaplaincy Study. Data from 15,655 of these visits, which were made in response to referrals (26.9% of all visits), were analyzed in the present study. Seventy-eight percent of referral requests were met within the same day, and 94.9% of requests and were met within 2 days. Nurses were the most frequent source of referrals to chaplains (45.0%), followed by self referrals from patients or requests from their family members (30.3%), with the remainder coming from a variety of hospital disciplines. The most common reason for referrals was that patients requested to see a chaplain. Other relatively common reasons for referrals were problems or issues related to illness or treatment, and end-of-life issues, concerns about death and the death of patients, with reasons for referrals differing by referral source. The most common reason for referrals among professional staff was that patients were feeling bad or in pain, followed by medical issues, and end-of-life issues. Patient and family referrals usually involved positive patient affect, whereas staff referrals usually involved negative patient affect. PMID- 20196356 TI - Countertransference reactions in treatment with the bereaved. AB - Countertransference is a constant occurrence in the therapeutic interaction between psychotherapist and patient. This article provides a brief discussion of countertransference and explores the particular challenges psychotherapists encounter when working with bereaved patients. A clinical vignette describes the dangers of unconscious defense against the experience of loss and emphasizes the importance of recognizing grieving as a natural and restorative process. PMID- 20196355 TI - Pastoral images: the Good Samaritan and the Unjust Judge. AB - Noting the continuing popularity among pastoral theologians of the Good Samaritan as an image of the pastoral caregiver, the author argues that the parable is not really about the obligation of the pastor to offer care but about accepting help from one toward whom one has deeply-engrained prejudicial attitudes and/or hostility. Thus, if the parable is used for insight into the role of function of the pastor, the negative models of the Priest and the Levite are instructive; but if one is looking for a positive pastoral image from among the parables of Jesus, one might consider the image of the Unjust Judge. PMID- 20196357 TI - The correlates of chaplains' effectiveness in meeting the spiritual/religious and emotional needs of patients. AB - The study was designed to assess the degree to which two sets of measures about chaplains' visits with patients predicted patients' perceptions that their spiritual/religious needs and their emotional needs were met by the chaplain. The first set consisted of seven items about the chaplain's demeanor during the visit. The second set measured patient satisfaction with seven aspects of the chaplain's care, including specific interventions. Overall, the latter items were more highly correlated with, and were better predictors of patients' perceptions that the chaplain met both their spiritual/religious needs and their emotional needs than were the demeanor items. The findings indicate the usefulness of measuring the effectiveness of specific chaplain interventions. The authors discuss that effectiveness measures may be more useful that patient satisfaction measures for assessing pastoral care. PMID- 20196358 TI - Implications for the delivery of spiritual care in Canadian healthcare: a perspective from a Canadian health authority. AB - Recognizing multiple challenges in the delivery of spiritual care, Fraser Health conducted a review of their spiritual care services in comparison to the spiritual care delivered in other Canadian health regions/authorities (2005 2006). Based on data received from the other health service areas, Fraser Health staff, and community focus groups, along with a review of literature and best practices, a reconstruction of spiritual care delivery has been initiated. This article outlines the results of a Canadian survey of health care chaplains, stakeholder consultations, and the implications for spiritual care delivery in Canada. The newly developed Fraser Health Tenets and Model for Spiritual Care, along with the recommendations of the project for the reconstruction and enhancement of spiritual care delivery in Fraser Health are discussed. PMID- 20196360 TI - No regrets? PMID- 20196359 TI - Chaplaincy care pathways and clinical pastoral education. AB - The authors describe the transforming of a tool originally focused on defining and refining the role of chaplaincy care with specific patient populations into a curriculum component for a Clinical Pastoral Education (CPE) residency program. PMID- 20196362 TI - I didn't walk away. PMID- 20196361 TI - Selected quotes from three years of clinical interviews with an older man. PMID- 20196363 TI - "Till death do us part": memoir of a hospice chaplain. PMID- 20196364 TI - A Gethsemane reflection. PMID- 20196365 TI - A tale of three visits: the gift of silence. PMID- 20196366 TI - Words and the chemistry of the soul at end-of-life. PMID- 20196367 TI - The turkey, chaplaincy, and Jewish pastoral care. PMID- 20196368 TI - A hospital chaplain's reflection on Ash Wednesday. PMID- 20196369 TI - Practicing the wounded storyteller. PMID- 20196370 TI - When mom's the patient. AB - This verbatim on the author's mother's death was originally submitted to a Clinical Pastoral Education Group on November 02, 2007. Its purpose was (1) to incorporate a working knowledge of psychosocial disciplines and religious beliefs and practice in the provision of pastoral care, and (2) to process, reflect, and learn from the interpersonal, spiritual, and ethical dynamics that occurred during the chaplain's mother's dying process. PMID- 20196371 TI - Testing the connection. While numerous medical tests are available, some are questioning how often they are necessary--and who will pay for them. AB - With an ever-widening array of medical tests and screenings available for patients, the debate over what tests are necessary, and who should get them, has taken on new intensity. "What we want is targeted screening. You can use things like family history and lifestyle to determine whether it's needed", says David Mongillo, left, of the American Clinical Laboratory Association. PMID- 20196373 TI - A new definition. NQF wants to take 'never' out of 'never events'. PMID- 20196372 TI - Lone Star State showdown. Trial looms for nurses who reported concerns about doctor. PMID- 20196374 TI - Power up the paddles. Add delivery and payment changes to broader coverage to restart reform effort. PMID- 20196375 TI - Remarkable ride. Benchmarking, teamwork help capture awards. PMID- 20196376 TI - Building on their reputation. Universal Health Services subsidiary selling construction/design expertise. PMID- 20196377 TI - Largest travel nurse staffing firms in the U.S. Ranked by estimated 2008 U.S. temporary staffing revenue. PMID- 20196379 TI - The map of health. Geography it seems is destiny, at least when it comes to numbering our years. A global look at longevity. PMID- 20196378 TI - How to live 100 years. PMID- 20196380 TI - Be careful what you wish for. We'd all like an extra decade of life. But there are reasons to think we already hang around long enough. PMID- 20196381 TI - Eat less, live longer? Restricting calories extends animal life, so doctors want to know if going hungry would help us too. PMID- 20196382 TI - Living long and living well. It's not so hard-and it's not all genes. Here's what we can do today to get extra tomorrows. PMID- 20196383 TI - The disaster diet. In Haiti, our correspondent subsists on state-of-the-art survival food--high-energy cookies. PMID- 20196384 TI - Protective effect of breastfeeding on diarrhea among children in a rapidly growing newly developed society. AB - In developed communities, the effect of exclusive breastfeeding (EBF) is encouraged since it has been found to be protective against infantile diarrhea. In a newly developing Qatar, modern water supply and sanitation facilities have become available to everyone during the last two decades. The objectives of the current study were to explore the relationships between breastfeeding and diarrhea and to assess the effect of EBF on the risk reduction of diarrhea in children aged 1-5 years. This is a cross-sectional survey conducted in the Well Baby clinics and pediatric clinics in the 11 Primary Health Care (PHC) Centers and Hamad General Hospital, Hamad Medical Corporation, Qatar. A multistage sampling design was used, and a representative sample of 1500 Qatari infants and pre-school children in the age group of 1-5 years and mothers aged between 18 to 47 years were surveyed during the period from October 2006 to September 2007; 1,278 mothers agreed to participate in this study, with a response rate of 85.2%. The sociodemographic characteristics, feeding modes and diarrhea morbidity were collected from the parents of the children during the interview. Of the 1,278 infants studied, more than half (59.3%) were EBF, followed by those partially breastfed (28.3%), and finally the formula fed (12.4%). The duration of EBF was 11.4 +/- 6.7 months (mean +/- SD) and the duration of partial breastfeeding with bottled milk was 9.2 +/- 4.1 months (mean +/- SD), and the difference was statistically significant (p<0.0010). When compared to the EBF infants, the risk of diarrhea was higher and statistically significant in both the partially breastfed (48.7% vs 32.5%) and in the non-EBF (37.3% vs 32.5%, p<0.001). Upper respiratory tract infection (URTI), short duration of breastfeeding, level of maternal education, and sterilization of bottles were considered as predictors. These results indicate that in Qatar, breastfeeding plays an important role in reducing the incidence and severity of infantile diarrhea. This observation is particularly important given the growing concern that, as an unwanted effect of 'modernization', breastfeeding is on the decline in Qatar and comparable populations elsewhere. PMID- 20196385 TI - Seroprevalence of rubella among Turkish women and children in Afyonkarahisar, Turkey. AB - The objective of this study was to determine the seroprevalence of rubella virus infection among women and female children/youth (0- 17-years-old) in Afyonkarahisar, Turkey. This study was conducted between November 2005 and February 2006. One thousand four hundred nine serum specimens were studied by the enzyme-linked immunosorbent assay (ELISA) method. Age, educational level, economic and marital status, smoking habit, application or not of measles-mumps rubella (MMR) vaccination, and previous skin rash of the patients included in the study were questioned and noted. Positive rubella-specific IgG antibodies prevalence was found as 18.5% in girls between 0-1 years of age, 28.6% in girls between 2-6 years of age, 36.8% in girls between 7-17 years of age, and 80.0%, 80.9%, 78.5%, 73.7% and 78.1% in women between 18-20, 21-30, 31-40, 41-50, and 50+ years of age, respectively. There were no statistically significant correlations between immunity to rubella and other sociodemographic characteristics. In conclusion, nearly 20% of women of reproductive age are sensitive to rubella and should be vaccinated. The clear effects of adding MMR to the routine vaccination schedule will be observed in the following years in Turkey. PMID- 20196387 TI - The effects of nutrition and physical activity on bone development in male adolescents. AB - Peak bone mass (PBM) is defined as the highest bone mineral content (BMC) reached in any period of a person's life. The bone mass once gained at the peak begins to decline and continues to do so until the end of life. The aim of this study was to evaluate the relationship of nutrition and physical activity on bone mineralization during the adolescent period. The study took place at Hacettepe University Ihsan Dogramaci Children's Hospital Adolescent Unit. One hundred fourteen healthy male adolescents applying for different reasons, with ages ranging between 11.1 and 16.5 years, participated in the study. When all adolescents were evaluated, no statistical relationship between the daily calcium intake, BMC and bone mineral density (BMD) was obtained. However, a positive statistical relationship was found for those participants in Tanner stage I. This result is in support of previous studies stating the importance of calcium intake and bone mineralization in the prepubertal stage, suggested by our findings, which yielded a positive correlation only in the prepubertal stage. One of the reasons for the same effect not being observed in puberty is thought to be due to the hormonal changes and active role of sex steroids. This shows how critical the prepubertal period is for future bone health. During this critical period of prepuberty, the significance of nutritions and physical activity is evident. PMID- 20196386 TI - Final height of patients with classical congenital adrenal hyperplasia. AB - The management of children with congenital adrenal hyperplasia (CAH) remains a challenge, especially with regard to their growth potential. We aimed to determine the correlation of the final height of Turkish children with classical CAH to their genetic height potential and to determine the effect of hydrocortisone replacement therapy on the final height. A total of 24 CAH (16 simple virilizing and 8 salt-wasting form) were included in this retrospective longitudinal study. The final height (FH), final height standard deviation score (FHSDS), target height (TH), target height standard deviation score (THSDS), corrected height for target height (CHSDS), weight, and body mass index (BMI) were calculated for all patients. We evaluated the adult height taking into consideration the correlation with the genetic height potential and the country standards. The average follow-up time was 14.2 +/- 3.1 years and the average daily hydrocortisone dose was 19.7 +/- 2.9 mg/m2. The mean FH and FHSDS were 152.2 +/- 7.2 cm and -1.0 +/- 1.1 SD, respectively, in females and 163.1 +/- 6.6 cm and -1.2 +/- 1.0 SD, respectively, in males. The CHSDS was found to be -0.73 +/- 0.9 SD. FH was below the TH in 79.1% of our cases. In 20.8% of our patients, FH was less than the third percentile for the standard height for our country. Interestingly, the FH showed no correlation with the dosage of hydrocortisone. Thirteen of our cases (54.2%) reaching FH were obese/overweight. A positive correlation was detected between hydrocortisone treatment and the BMI. The observations that 79.1% of our classical CAH cases receiving an average daily hydrocortisone dose of 19.7 +/- 2.9 mg/m2 ended up with an adult height below the TH and that 54.2% of the cases were overweight/obese lead us to believe that we should be using the lowest possible dose for treatment. PMID- 20196388 TI - Treatment of severe Henoch-Schonlein nephritis: justifying more immunosuppression. AB - The prognosis of Henoch-Schonlein purpura (HSP) nephritis is more severe than originally thought, with a significant portion progressing to deterioration of renal function in adulthood. Proteinuria adversely affects the outcome. The aim of this study was to evaluate the initial single-center results of a treatment protocol for severe HSP nephritis based on the Heaton classification. Age, gender, clinical features and duration of disease follow-up were assessed. Glomerular filtration rate (GFR), urinalysis and 24-hour urinary protein excretion were analyzed. All patients with severe renal involvement were biopsied and a treatment plan was assigned: Class II received oral steroids, Class III (with crescentic nephritis) received additional oral cyclophosphamide 2 mg/kg/d for 12 weeks, and Classes IV and V received azathioprine for 9 months subsequent to the treatment for Class III. All patients received angiotensin converting enzyme (ACE) inhibitors regardless of their blood pressure values. Eighteen patients presenting with severe HSP nephritis, defined as heavy proteinuria and/or decreased renal function, were evaluated. Based on the renal histology, 5, 10, 1 and 2 of the patients were classified as Classes II, III, IV and V, respectively. At presentation, 7 of the patients had impaired renal function with GFR below 75 ml/min/1.73 m2. With the presented treatment schema, all GFR returned to normal at the end of four years of follow-up. There was no proteinuria in any of the patients; only 8 had microscopic hematuria. This preliminary study suggests a stepwise treatment according to the renal histology. The excellent results with complete disappearance of proteinuria and normal renal function justify the use of the aforementioned immunosuppressive protocol with ACE inhibition. Long-term, multicenter controlled studies are needed to verify our results. PMID- 20196389 TI - Early administration of the second surfactant dose in preterm infants with severe respiratory distress syndrome. AB - The aim of this study was to determine whether early administration (2 hours after the first surfactant dose) of the second surfactant dose would be superior to late surfactant treatment (6 hours after the first surfactant dose) in preterm infants with severe respiratory distress syndrome. Between June 2003 and March 2005, 40 newborns born with respiratory distress syndrome in Uludag University Hospital were investigated in this prospective study. The inclusion criteria for the recruitment of the infants were: age < or = 2 hours, birth weight between 600 2500 g, gestational age between 24-36 weeks, X-ray consistent with respiratory distress syndrome, and need for mechanical ventilation with inspiratory oxygen fraction > or = 0.4 and mean airway pressure > or = 7 cm H2O to obtain arterial pressure of oxygen between 70-80 mmHg. Infants with lethal congenital anomalies or being treated with high-frequency oscillatory ventilation were excluded from the study. Birth weight, gestational age, gender, and Apgar scores were recorded and complications of the surfactant therapy were examined. Twenty boys and 20 girls were enrolled in the study. The first surfactant dose was administered in the first hour of life in all infants. The second surfactant dose was given 2 hours after the first dose in 20 of them and 6 hours after the first dose in the other 20. Infants in both groups (early versus late) were similar with respect to gestational age, birth weight, gender, and the rate of prenatal corticosteroids. There were also no significant differences between the two groups in terms of the response to surfactant therapy and complications. The results of this study show that administration of the second surfactant dose earlier is as effective as late administration, and it may be suggested that the second surfactant dose can be applied earlier in severe respiratory distress syndrome. PMID- 20196390 TI - Cognitive functions in neurofibromatosis type 1 patients and unaffected siblings. AB - Attention, learning, and perceptual problems have been reported at various degrees and rates in neurofibromatosis type 1 (NF1). We aimed to define the cognitive profiles frequently associated with NF1. Children and adolescents with NF1 (n=58) were tested using Wechsler Intelligence Scales for Children-Revised (WISC-R), Judgment of Line Orientation, and Bender Visual-Motor Gestalt tests. Comparison groups were unaffected siblings of NF1 patients (n=20), children with attention deficit and hyperactivity disorder (ADHD, n=40), and normal children (n=40). No difference was found between familial or sporadic NF1 cases. Seventeen/58 (29%) of NF1 cases had a full scale IQ<70. The subgroup of NF1 patients with full scale IQ>80 (n=27) scored lower in WISC-R subtests measuring visual perception when compared to a healthy control group of similar intelligence, and lower in arithmetic but better in Bender-Gestalt and Judgment of Line Orientation tests when compared to an ADHD group of similar intelligence. These results indicate a high prevalence of mental retardation in a clinical NF1 series. NF1 patients who have normal intelligence may have impaired visual perception, but their visual perceptual problems are less than in ADHD. The tendency of unaffected siblings of NF1 patients to have mildly but consistently low test scores compared to healthy controls needs to be studied further for underlying genetic or environmental factors. PMID- 20196391 TI - Seasonal and gender differences in hemoglobin value in infants at 5-7 months of age. AB - Our aims were to analyze the changes in hemoglobin (Hb) value according to gestational age, birth weight, sex, birth season, and weight gain and to detect distribution of Hb values among healthy infants, breastfed for at least four months and receiving routine health care. We conducted a descriptive study using the data of 469 healthy infants at 5-7 months of age in Hacettepe University Ihsan Dogramaci Children's Hospital Well-Baby Clinic between 2001-2004. Infants with acute or chronic illness, exchange transfusion and those who had taken or were currently taking iron supplementation were not included into the study. Information regarding the child was obtained from hospital files. Infants with Hb value <10.5 g/dl and <9.5 g/dl were considered to have mild and moderate anemia, respectively. The mean Hb value was 10.7 g/dl (SD = 0.90). The prevalence of anemia was 41.4%. Boys had significantly lower Hb, hematocrit and mean corpuscular volume values and higher red cell distribution width values than girls. Infants born before 37 weeks of gestational age had moderate anemia more frequently. Anemia at 5-7 months of age was more frequent in infants born in spring and summer than in those born in fall and winter (49.2%, 26.8%, p<0.001). Birth weight was positively correlated with Hb value at 5-7 months of age (r=0.14, p=0.003). In the present study, female gender, at-term birth, birth in winter and fall, weight appropriate for gestational age, and regular weight gain showed the lowest risk for anemia development in infants aged 5-7 months with a breast-feeding period of more than four months. PMID- 20196392 TI - Clinical importance of transesophageal electrophysiologic study in the management of supraventricular tachycardia in children. AB - Transesophageal electrophysiologic study (TEEPS) is a semi-invasive method widely used for evaluation of symptoms related to arrhythmia. In this study, we aimed to determine the accuracy of TEEPS in the diagnosis and differentiation of mechanisms of supraventricular tachycardias (SVTs) by comparing results of transesophageal and intracardiac electrophysiologic studies. We performed TEEPS and a subsequent radiofrequency ablation (RFA) procedure in 76 patients. Indications of TEEPS were risk assessment for Wolff-Parkinson-White syndrome in 32 patients and diagnosis and differentiation of tachycardia mechanisms in 44 patients. The procedure was well tolerated in all patients. Positive predictive value of TEEPS in our study was 91% for differentiation of SVT mechanisms. The results suggest that TEEPS is safe, useful and effective in the evaluation of symptoms related to arrhythmia, in differentiation of mechanisms of SVTs, and finally in defining the treatment options of SVT. The technique also provides an opportunity for risk assessment and deciding the treatment modality in Wolff Parkinson-White patients. PMID- 20196393 TI - Physicians' attitudes and perception of pediatric trauma cost. AB - Pediatric trauma is the leading cause of mortality and morbidity in children. A questionnaire was applied to evaluate physicians' attitudes and perception of pediatric trauma cost. Physicians working in the field of pediatric trauma (namely those who work in emergency services, pediatrics and pediatric surgery departments; who are consulted regarding pediatric traumas; and those for whom pediatric trauma patients constitute the majority of their patient spectrum) were enrolled in the survey. A questionnaire was administered to elicit the demographic data, features of pediatric trauma in their practice, self-perception of pediatric trauma knowledge, estimation of trauma severity, parameters used for pediatric trauma diagnosis, and perception of pediatric trauma score (PTS) and trauma cost. A total of 103 physicians responded to the questionnaire (median age: 30.8 +/- 5.6 years; range: 24-56). Of the 103 respondents, 49 were males (47.6%) and 54 were females (52.4%). Physicians responding to the questionnaire were specialists in Pediatrics (32.9%), Pediatric Surgeons (5.9%), Emergency Medicine Specialists (2.9%), and residents (47.6%) in those three disciplines in University Hospitals, Public Hospitals and Research Hospitals. Physicians reported falls (58.1%) as the most common cause of trauma, and noted head injuries with an incidence of 49.9% in their trauma practice. Physicians' self perception of their pediatric trauma knowledge was questioned in three categories as: overall, diagnosis and treatment of trauma. They reported that their knowledge of pediatric trauma overall and regarding diagnosis and treatment was "efficient" at rates of 87.4%, 83.6% and 74.8%, respectively. However, while 76.7% of physicians perform radiological evaluations in all trauma patients, only 56.3% of them use laboratory tests routinely in diagnosis. Participants reported that cost of trauma was mostly affected by severity of trauma (49.5%) and least affected by the patient's sex (64.1%). They also believed that radiologic evaluations (66%) accounted for the largest portion of trauma cost and the cost of consultations (44.7%) for the smallest portion. In conclusion, we suggest that although most physicians were aware of cost factor in trauma, they did not consider trauma costs in diagnosis and management. PMID- 20196394 TI - 3-phosphoglycerate dehydrogenase deficiency: a case report of a treatable cause of seizures. AB - Serine deficiency disorders are a new group of neurometabolic diseases resulting from a deficiency in one of the three enzymes in the biosynthetic pathway of L serine. Deficiency of the enzyme 3-phosphoglycerate dehydrogenase (3-PGDH), which catalyzes the first step in the biosynthetic pathway, leads to congenital microcephaly, severe psychomotor retardation, and intractable seizures. We report a 4 1/2-year-old boy who presented with congenital microcephaly, psychomotor retardation, hypertonia, strabismus, and drug-resistant seizures due to 3-PGDH deficiency. His seizures responded to L-serine and glycine supplementation only. This potentially treatable disease should be borne in mind in patients with congenital microcephaly, psychomotor retardation and seizures. A timely diagnosis based on the detection of low cerebrospinal fluid levels of L-serine and glycine is expected to further increase the success of L-serine and glycine supplementation in these patients. PMID- 20196395 TI - Edema can be a handicap in treatment of anorexia nervosa. AB - Anorexia and bulimia nervosa are common in western civilized countries. They are among the psychiatric disorders in that they are often accompanied by a variety of life-threatening physical abnormalities. These patients need a close follow-up of the pediatrician in collaboration with the psychiatrist since the changes in bodily functions affect the psychiatric therapy. The challenge to the physician is to use the traditional tools of medicine to diagnose and treat these physical abnormalities using careful medical history, a complete physical examination and appropriate laboratory testing. Peripheral edema is seen as a physical finding in anorexia nervosa (AN) and it is not rare. The estimated frequency is up to 20% among adolescent patients. Peripheral edema in this setting can be easily confused as weight gain. There are five possible mechanisms for its occurrence: hypoproteinemia, electrolyte imbalance, hormonal changes, rapid refeedings, and abuse of laxative, diuretics and diet pills. Patients with eating disorders may ingest a large number of drugs in an attempt to control their weight. We present a case of a female adolescent with AN and peripheral edema who terminated her psychiatric treatment during the refeeding phase because of the unbearable anxiety caused by this edema that affected her body image dramatically. With this case study, we point out the importance of assessing peripheral edema and discriminating it from true weight gain. PMID- 20196396 TI - Spider poisoning: a report of six cases from the Central Anatolian region, Turkey. AB - Spiders exist in every place and ecosystem. Spiders in tropical regions are particularly poisonous and can be dangerous to humans. Nearly 20,000 spider species are known, and almost all are venomous, although only 60 species worldwide are poisonous in humans. In our area, eight species are reported as poisonous in humans. Although most cases of spider bite are benign and require no intervention, severe local and systemic reactions may occur sometimes in the pediatric population, resulting in admission to the pediatric intensive care unit. In this report, we present the cases of six children from the Central Anatolian region in Turkey who were seriously affected by spider bites, and we review the literature on spider envenomation. PMID- 20196397 TI - Salla disease in Turkish children: severe and conventional type. AB - Sialic acid storage disorder, known as Salla disease, is a rare autosomal recessive lysosomal disorder produced by a defect of a proton-driven carrier that is responsible for the efflux of sialic acid from the lysosomal compartment. We report two patients with Salla disease: a two-year-old girl, presented with hypotonia, inability to speak and walk, bilateral optic atrophies, defective myelination, cerebellar atrophy, and thinning of the corpus callosum on magnetic resonance imaging (MRI), who was classified as intermediate severe Salla disease; and a four-year-old girl, presented with relatively late-onset, slight hypotonia, and delayed language and mobility development, and supported by relatively protected MRI findings, who was classified as conventional Salla disease. Diagnosis of Salla disease was confirmed by accumulation of sialic acid in fibroblast culture: 15.1 and 13.2 nmol/mg protein in the first and second patient, respectively. Optic atrophy observed in the first case may be an additional feature besides the characteristic manifestations of Salla disease. PMID- 20196399 TI - A de novo complex chromosomal rearrangement involving chromosomes 2, 8 and 13 in a dysmorphic case with polysyndactyly. AB - We report herein a case with dysmorphic features, polysyndactyly and psychomotor mental retardation, who had an apparently balanced de novo translocation between chromosomes 8 and 13 as well as a de novo insertion within chromosome 2 itself. This case is worth mentioning in the sense that it bears two de novo rearrangements with five breakpoints. The correlation between the possible disrupted genes within the given breakpoints and the phenotype of the case will be discussed. PMID- 20196398 TI - Dentatorubral pallidoluysian atrophy in a Turkish family. AB - Dentatorubral pallidoluysian atrophy is a neurodegenerative disease that generally presents in adulthood. Although rare, it can be observed in childhood due to extreme expansion of the triplet repeat size during spermatogenesis. The diagnosis in childhood is very difficult in the absence of family history. Here we describe a 12-year-old girl with dentatorubral pallidoluysian atrophy who presented with progressive myoclonic epilepsy and ataxia. Family history exhibited similarly affected cases on the paternal side. Molecular testing for dentatorubral pallidoluysian atrophy revealed abnormal "cytosine-adenine guanosine" expansion in the atrophin-1 gene. PMID- 20196400 TI - Acquired partial lipodystrophy associated with varicella. AB - Acquired partial lipodystrophy (Barraquer-Simons syndrome) is a rare condition with onset in childhood, and it is characterized by progressive loss of subcutaneous fat in a cephalocaudal fashion. Although it is known that acquired partial lipodystrophy usually follows acute febrile illness, it is very rarely reported to occur in association with varicella. In this case report, we present a seven-year-old girl with progressive loss of fat in her face just after varicella who was diagnosed as acquired partial lipodystrophy. PMID- 20196402 TI - Pituitary hyperplasia mimicking pituitary macroadenoma in two adolescent patients with long-standing primary hypothyroidism: case reports and review of literature. AB - We report two cases with primary autoimmune hypothyroidism and an ectopic thyroid gland causing pituitary enlargement mimicking pituitary macroadenoma. One of the cases presented with complaints of headache and short stature and the other case with a complaint of menorrhagia. In both cases, the pituitary mass and symptoms resolved with levothyroxine replacement. Normal menses resumed. However, pituitary dynamic tests revealed persistent growth hormone and gonadotropin deficiency in one case and growth hormone deficiency in the other. To our knowledge, this is the first report in an adolescent of hypogonadotropic hypogonadism, growth hormone deficiency, and menorrhagia associated with pituitary hyperplasia secondary to primary hypothyroidism. The recognition of the association between reversible pituitary hyperplasia and primary hypothyroidism might eliminate unnecessary surgery. PMID- 20196401 TI - Primary cutaneous aspergillosis in an extremely low birth weight preterm. AB - Aspergillosis is an uncommon infection in neonates. However, it has been an emerging problem for preterm infants in recent years because of long-term parenteral nutrition, multiple-antibiotic therapy and immune deficiency due to prematurity. We report a preterm neonate with disseminated cutaneous lesions due to primary cutaneous aspergillosis. She died despite an early treatment with liposomal amphotericin B. Fungal infections should be remembered in preterms whose clinical conditions and laboratory tests for infection deteriorate, despite an appropriate antibiotic and supportive therapy. PMID- 20196403 TI - Fetal sodium valproate exposure causes Baller-Gerold syndrome phenotype: both phenotypes in the same family. AB - Baller-Gerold syndrome (BGS) is characterized by craniosynostosis and preaxial upper-limb malformations, and it has an autosomal recessive inheritance. Valproate syndrome occurs after exposure to valproic acid in utero, and is characterized by trigonocephaly. Both syndromes can also present with other malformations. Herein, we report a female newborn and her brother who both had a history of fetal exposure to maternal anti-epileptic drugs, especially sodium valproate. On physical examination of the female patient, craniosynostosis, trigonocephaly, right radius aplasia and hypoplastic thumb, and cardiac and renal malformations were determined, and she was diagnosed with BGS phenotype. The brother's examination revealed trigonocephaly, polymastia and hypospadias, and he was diagnosed with valproate syndrome. Based on these patients, we aimed to add further evidence in the literature indicating that the use of sodium valproate alone and in combination with other anti-epileptic drugs throughout pregnancy can increase the risk of serious fetal congenital malformations depending on the doses. PMID- 20196404 TI - Outcome of teenage pregnancy in Rajavithi Hospital. AB - OBJECTIVE: To compare maternal and neonatal outcomes between pregnant teenage girls (age <20 yrs) and pregnant adults (age 20-34 yrs). MATERIAL AND METHOD: Seven hundred and fifty pregnant teenagers admitted and delivered at Rajavithi Hospital during November 8, 2006 and December 22, 2007 were enrolled in the study. A control group included 750 pregnant adults delivered during the same period. RESULTS: Preterm labor was the significant antepartum complication in the teenage mothers while diabetes mellitus was the significant one in the adult mothers as compared to those in the other groups. Teenage mothers had significantly higher incidence of cesarean delivery than that in the adult mothers. The neonates of the teenage mothers showed higher number of complications than those of the adult mothers. CONCLUSION: Pregnant teenage girls had more maternal and neonatal complications than those of pregnant adults. PMID- 20196405 TI - Prevalence of high-risk human papillomavirus infection (HPV) and correlation with postmenopausal hormonal therapy in Thai women aged more than 45 years old. AB - OBJECTIVE: To determine the prevalence of high-risk HPV infection and to evaluate the association between high-risk HPV infection and hormone replacement therapy in Thai women 45 years old and older. MATERIAL AND METHOD: The present cross sectional study was performed in 600 women aged 45 years old and older who attended the menopausal clinic of Phramongkutklao Hospital. There were 191 hormone users and 392 non-hormone users. The HPV DNA was studied in cellular residual from liquid-based collection tube and analyzed with a hybrid capture two techniques using a mix of high risk viral RNA probe. RESULTS: The prevalence of high-risk HPV infection was 34 (5.67%) of 600 participants. When divided by status of hormone users, the prevalence of this infection in non-users, past user group, and current user group was 5.36%, 4.96%, and 10.00% respectively There was non-significantly elevated risk among past (adjusted odd ratio (OR) = 0.92, 95% confidence interval (CI) = 0.36-2.34) and current (adjusted OR = 1.96, 95% CI = 0.80-4.81) hormonal users compared to never users. However, women who currently used unopposed estrogen orally had a statistically significant higher risk of high-risk HPV detection (adjusted OR = 9.82, 95% CI = 3.02-31.89). CONCLUSION: The prevalence of high-risk HPV infection in Thai women 45 years old and older was 5.67%. The oral, unopposed estrogen was associated with a higher incidence of high-risk HPV infection, but a small number of hormonal users. Further investigations are needed. PMID- 20196406 TI - Comparison of cardiovascular risk factors in five regions of Thailand: InterASIA data. AB - BACKGROUND: Age- and sex- standardized mortality rate of cardiovascular disease (CVD) was high in Bangkok and central Thailand in the year 2000. This may partially be related to differences in risk factors. OBJECTIVE: To compare prevalence of CVD risk factors among regions in Thailand in the same period. MATERIAL AND METHOD: From a survey in 2000 (InterASIA) which involved 5 regions in Thailand, conventional CVD risk factors were compared multivariate-wise among regions and subsequently aligned with CVD deaths obtained within similar regions from the registry. RESULTS: Bangkok and a central province had a higher prevalence of the following: hypertension, elevated body mass index, large waist circumference, elevated lipid associated with low density lipoprotein cholesterol and diabetes mellitus. The Northeast had a higher prevalence of smoking, low values of high density lipoprotein cholesterol and high triglyceride. CONCLUSION: Definite regional differences existed of CVD risks and death in Thailand in 2000. Some of the metabolic risk factors may be more important than smoking in the link with CVD death in Thailand PMID- 20196407 TI - Comparison of efficacy between 1 mg overnight dexamethasone suppression test and 2-day low dose dexamethasone suppression test for diagnosis of Cushing's syndrome. AB - OBJECTIVE: To assess the sensitivity and specificity of 1 mg overnight dexamethasone suppression test (ODST) and the 2-day low dose dexamethasone suppression test (LDST) for diagnosis of Cushing's syndrome, and to compare the accuracy of both tests using cutoff value at below 5 microg/dl and at below 1.8 microg/dl. MATERIAL AND METHOD: The present study is a retrospective study, from 1971-2007, in one academic center of 77 patients with clinical suspicion of Cushing's syndrome. Kappa statistical analysis was used to determine agreement between the two tests. Sensitivity and specificity of the tests were calculated. ROC curves were created to determine the best cutoff value of the two tests. RESULTS: ODST has very good agreement with the more troublesome LDST and has comparable efficacy Lowering the cutoff value from 5 microg/dl to 1.8 microg/dl does not improve the accuracy of ODST but results in decreased specificity of LDST. The best cutoff value of ODST test is > or = 5.3 microg/dl and the best cutoff value of LDST is > or =5 micro/dl. CONCLUSION: ODST is an efficient method for diagnosis of patients suspected of having Cushing's syndrome. The attempt to lowering cutoff value does not improve the efficacy of dexamethasone suppression test. PMID- 20196408 TI - Extensively drug resistant tuberculosis (XDR-TB) in Chest Disease Institute, 1997 2005. AB - OBJECTIVE: To determine prevalence of extensively drug resistant tuberculosis (XDR-TB) in Chest Disease Institute. World Health Organization has given the definition of XDR-TB as multi-drug resistant tuberculosis which also resists fluoroquinolone and aminoglycoside. MATERIAL AND METHOD: The present study was a retrospective review and conducted at Microbiology Unit, Chest Disease Institute. Drug susceptibility testing against fluoroquinolone and aminoglycoside have been done routinely since 1997. Laboratory results were studied to find XDR-TB patients and medical record information were reviewed. Laboratory results in 2006 2007 were not completed so were not included in the review. RESULTS: The result of the present study showed that from 1997 to 2005. 10,289 patients were tested for drug susceptibility. XDR-TB was found in 39 patients. Prevalence of XDR-TB was 6, 6, 9, 4, 3, 3, 2, 4 and 2 patients from 1997-2005 respectively. Most of XDR-TB patients were also resistant to Streptomycin and 39% resistant to Ethambutol. No data of resistance to second line drugs of XDR-TB was done in the present study. CONCLUSION: The present study confirmed the existing of XDR-TB in Thai patient for a long time but not in increasing rate. The authorized TB Control organization should take XDR-TB as an important problem and developed capacity of tuberculosis laboratory in order to be able to diagnose XDR-TB. PMID- 20196409 TI - Hypothalamic-pituitary dysfunction in survivors of childhood brain tumors in Prasat Neurological Institute. AB - OBJECTIVE: To assess hypothalamic-pituitary dysfunction in childhood brain tumor survivors in Prasat Neurological Institute. MATERIAL AND METHOD: Between October 2007 and September 2008, 19 brain tumor survivor children in Prasat Neurological Institute without recurrence at least 2 years after complete treatment were included in the present study. The patients were categorized according to brain tumor location into directly (DHPA) (9 cases) and indirectly (IDHPA) (10 cases) involving hypothalamic-pituitary axis. All patients were treated by surgery. Furthermore, six cases were combined with radiation and chemotherapy and 10 cases were combined with radiation therapy only. Growth Hormone (GH) stimulation test by clonidine and/or L-Dopa, ACTH stimulation test and thyroid function test (TFT) were done. RESULTS: The mean age at diagnosis was 9.9 +/- 4.6 years old and the interval from diagnosis to study was 5.8 +/- 2.2 years. Seven DHPA (77%) and seven IDHPA patients (70%) had low peak GH with significant lower level in the former group (p < 0.05). Six of seven DHPA (85%) and one IDHPA patients (10%) had low response to ACTH stimulation test. All DHPA (100%) and 10% IDHPA patients had central hypothyroidism. By ACTH stimulation test in DHPA patients, hypocortisolism was detected in five and excluded in one who later stopped prednisolone after prolonged continuation. The central hypothyroidism was newly detected in two DHPA patients and replacement therapy was initiated GH deficiency (GHD) was detected by GH stimulation test in 73% of overall brain tumors. Growth hormone therapy would be considered in the appropriate GHD patients. CONCLUSION: With effective therapy and improving survival rates of brain tumor children, hypothalamic-pituitary dysfunction in either DHPA or IDHPA group should be regularly monitored to prevent further morbidity and improve quality of life. PMID- 20196410 TI - Infections and illnesses in children with Bb E beta-thalassemia: a prospective controlled study. AB - The authors performed a prospective, controlled, 3-year, follow-up study on infections and illnesses in Hb E beta-thalassemic pediatric patients. Fifty severe and 24 non-severe patients and 24 controls were included. Siblings with an age difference of no more than 4 years served as controls. All patients and controls were asked to write postcards every two weeks to report on their illnesses and treatments. The respective median follow-up was 32.5, 35.5 and 34 months in 1501, 707 and 785 patient-months at 11.50 +/- 4.74, 10.50 +/- 4.18 and 10.75 +/- 4.56 years of age (+/- SD) for the severe, non-severe Hb E beta thalassemic patients, and controls. The rate per 1000 patient-months of infections was not significantly different between groups despite having 26 (52%) splenectomised patients in the severe group. The infection rate among severe, non severe, Hb E beta-thalassemic, patients and controls was not significantly different. Regular blood transfusions and iron chelation might decrease infections among Hb E beta-thalassemic, pediatric patients. PMID- 20196411 TI - Prevalence of type II diabetes and metabolic syndrome among overweight school children in Khon Kaen, Thailand. AB - BACKGROUND: Childhood obesity has been accompanied by an increase in the prevalence of type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) among children and adolescents worldwide. OBJECTIVE: To determine the prevalence of T2DM and MetS among overweight children and adolescents in Khon Kaen province, Northeast Thailand. MATERIAL AND METHOD: A cross-sectional, prospective pilot study was performed in school children between 10 and 15 years of age. The weight and height measurements and body mass index (BMI) calculations for 2156 school children were analyzed. The BMI for the age and sex value at > or = 85th percentile was considered overweight and the overweight children were evaluated for family history of diabetes, signs of insulin resistance, plasma fasting glucose and lipid level. RESULTS: Five hundred and ninety four (27.6%) overweight children were identified, of whom 186 (31.3%) participated in the present study. T2DM was documented in 4 (2.2%) while MetS was documented in 6 (3.2%) children. At least one type of dyslipidemia was found in 87 (46.8%) children. CONCLUSION: T2DM and MetS are common among overweight school children in Khon Kaen, Thailand Preventive interventions to reduce overweight and consequently prevent T2DM in Thai children should be provided at school and the community level. PMID- 20196412 TI - Incidence and factors influencing the development of fistula-in-ano after incision and drainage of perianal abscesses. AB - OBJECTIVE: The aims of the present study were to evaluate the incidence offistula in-ano following incision and drainage of acute perianal abscess and to determine factors influencing the fistula formation. MATERIAL AND METHOD: Patients with a first-time perianal abscess or intersphincteric abscess who underwent incision and drainage at Siriraj Hospital from January 2005 to June 2008 were reviewed Patients with coexisting fistula or perianal Crohn's disease were excluded. Incidence and risk factors for fistula formation were analyzed. RESULTS: Sixty four patients were reviewed (50 males, 14 females). The average age of the patients was 44 years (range 19-82). The average follow-up period was 30 months (range 10-53). Twenty patients (31%) developed fistula-in-ano following incision and drainage. Gender; smoking, alcohol consumption, fever; leukocytosis, and location of abscess were not predictive of fistula formation. Univariate analysis showed that patients aged under 40 years and non-diabetic patients tended to have a higher risk for developing the fistula (43% vs. 21%, OR 2.95, 95% CI 0.98-8.85; p = 0.05 and 38% vs. 13%, OR 4.2, 95% CI 0.85-20.83; p = 0.071, respectively). However, patients receiving perioperative antibiotics (ATB) were less likely to develop subsequent fistula in both univariate and multivariate analysis. The FIA rate in non-ATB group was 48% and only 17% in ATB group (OR 4.5, 95% CI 1.44 14.13; p = 0.01). CONCLUSION: The incidence of fistula-in-ano following incision and drainage of perianal abscess was 31%. Patients aged under 40 years and non diabetic patients appeared to have a higher risk for fistula formation. Administration of perioperative antibiotics significantly reduced the rate of subsequent fistula formation. PMID- 20196413 TI - The prognostic significance of microvessel density in intrahepatic cholangiocarcinoma. AB - OBJECTIVE: Intrahepatic cholangiocarcinoma (IHCC) is the second most common primary cancer of the liver Tumor angiogenesis seem to play an important role in tumor growth and prognosis of cancer patients. The purpose of the present study was to determine the prognostic value of tumor microvessel density (MVD) in patients with IHCC. MATERIAL AND METHOD: Clinicopathological prognostic factors, recurrence rate, and survival in 22 patients with IHCC who underwent liver resection for IHCC were reviewed. Tumor MVD was estimated using immunohistochemical methods. Overall probabilities of recurrence and survival were estimated using Kaplan-Meier methods. Prognostic significance ofMVD and other factors was tested using Cox proportional hazards regression. RESULTS: There was no significant association between any clinicopathologic factors (age, sex, tumor markers, and pathologic factors including MVD) and time-to-tumor recurrence. The only prognostic factor associated with survival was tumor stage. MVD was neither a significant survival predictor nor a predictor of tumor recurrence. CONCLUSION: The only factor associated with poor prognosis in patients with IHCC in the present study was higher tumor stage. MVD was not a significant prognostic factor in patients with IHCC. PMID- 20196414 TI - Thoracic trauma at Siriraj Hospital 1997-2006. AB - Thoracic trauma is a common injury that has a high mortality rate. Fortunately, most can be treated by a simple maneuver as intercostal drainage (79.4%). During the decade 1997-2006, there were 897 admitted patients in the Trauma division of Siriraj Hospital. Most were men (85.5%) and the common age group was 21-30 years. Blunt trauma was the major type of injury (58.9%) and traffic accidents were common causes. Abdominal injury was the most common associated injury. After the management was improved, the overall mortality rate was reduced from 7.0% to 5.1%. Today, minimally invasive surgery such as laparoscopy can reduce hospital stays and pain in patients with thoracoabdominal injury. PMID- 20196415 TI - Topical steroid is effective for the treatment of phimosis in young children. AB - BACKGROUND AND OBJECTIVE: The purpose of the present study was to evaluate the effects of non-operative treatment using topical steroids on phimosis in infants and young children. MATERIAL AND METHOD: Between June 2003 and May 2005, the parents of the children with phimosis were instructed to apply and massage the phimotic skin with 0.05% betamethasone valerate cream twice daily for 2 months. During non-operative treatment, the patients whose parents were not satisfied with the results would undergo circumcision. RESULTS: Ninety-two phimotic boys with an average age of 32.62 months (range, 1 to 144 months) were enrolled for steroid application. Of the 92 patients, 79 (85.9%) were satisfied with their results. The other 13 patients whose outcomes clinically improved but did not satisfy their parents finally underwent circumcision. Histologically, circumcised skins of patients initially receiving steroid therapy revealed markedly interstitial edema and slightly increased vasculature. There were no systemic side effects or significant dermal atrophy in the present study. CONCLUSION: Topical steroid treatment for phimosis is successful in young children. This therapeutic approach is a safe, easy, and inexpensive alternative to circumcision. PMID- 20196417 TI - Craniometric study of Thai skull based on three-dimensional computed tomography (CT) data. AB - The present study revealed an advanced method using data obtained from three dimensional computed tomography (3D CT) to evaluate the craniometric data of the Thai population. Ninty-one Thai cadaveric dry skulls from the Faculty of Medicine, Khon Kaen University were investigated in the present study. It enabled the authors to assess the three-dimensional anatomical landmarks in digital format without physical measurements. The results have revealed that the craniometric data of Thai males were larger than Thai females with a statistical significant difference, especially, the maximum cranial length, basion-bregma height, nasion-basion length, nasion-bregma length and bizygomatic breadth parameters (p << 0.001). In addition, the craniometric data based on Thai skulls of the people in the northeast region was different from the people in the central region. Furthermore, the linear regression equations obtained from the pairwise parameter, it is useful to predict the craniometric parameters in forensic medicine. PMID- 20196416 TI - Modified Mallampati test and thyromental distance as a predictor of difficult laryngoscopy in Thai patients. AB - BACKGROUND: Preoperative evaluation of anatomical landmarks and clinical factors are important in the detection of patients at risk for difficult laryngoscopy. The modified Mallampati test (MMT) and thyromental distance (TMD) are commonly used for this purpose but there are controversies regarding their accuracy. OBJECTIVE: The objective of the present study was to evaluate the accuracy of MMT and TMD in the prediction of difficult laryngoscopy in Thai patients. MATERIAL AND METHOD: 1888 consecutive patients undergoing general anesthesia requiring endotracheal intubation were evaluated preoperatively using the MMT and TMD. The cut-off points for the difficult airway predictors were: Mallampati 3, 4 and TMD less than 6 cm. During direct laryngoscopy, the laryngeal view was graded using the Cormack and Lehane (CL) classification. CL grades III and IV were considered difficult laryngoscopy. Sensitivity and specificity for each airway predictor in isolation and in combination were determined. RESULTS: The present study found Mallampati grade I 1050 patients (55.6%), grade II 730 patients (38.7%), grade III 104 patients (5.5%), grade IV 4 pateints (0.2%) and TMD less than 6 cm 85 patients (4.5%), TMD more than 6 cm 1803 patients (95.5%). Difficult laryngoscopy occurred in 60 patients (3.2%). The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the two airway predictors were: MMT 41.7%, 95.5%, 23.1% and 98.0% and TMD 23.3%, 96.1%, 16.5% and 97.4% respectively. The combination of two predictors with a sensitivity, specificity PPV and NPV were 55.0%, 92.3%, 19.1% and 98.4%. CONCLUSION: MMT TMD and their combination are good predictors of difficult laryngoscopy in a Thai population. PMID- 20196418 TI - Degree of midline shift from CT scan predicted outcome in patients with head injuries. AB - OBJECTIVE: To evaluate the relationship between the degree of midline shift by Computed Tomography (CT) finding and Glasglow Coma Score (GCS) as a predictive of clinical outcome in patients after head injury. METHOD AND METHOD: The present study was performed by retrospectively reviewing 216 consecutive cases of traumatic head injury admitted to the trauma center in Siriraj Hospital from 1999 until 2004. All patients were evaluated for level of consciousness by a neurosurgeon determining by GCS and underwent CT brain for evaluation of intracranial hemorrhage and midline shift. The final clinical outcome was also divided into two groups; good outcome for the patients who recovered well with moderate disability and the poor outcome for the patients who suffered severe disability, vegetative status and death. Then, the authors compared midline shift vs. GCS and midline shift vs. clinical outcomes. RESULTS: Total of 216 cases, the three most common types of head injury were motorcycle accident, fall or assault and car accident. 96 of 216 patients had midline shifting, 53 of 96 patients had CT scan of midline shifting less than 10 mm whereas 37 of 96 patients had a CT scan of greater than 10 mm of midline shifting. 63.3% with midline shifting up to 10 mm had severe head injury and up to 81% with brain shifting greater than 10 mm had severe head injury. The clinical outcome also showed that poor clinical outcomes correlated to midline shifting greater than 10 mm. CONCLUSION: The increased degree of midline shift in patients with head injuries by CT scan was related to the severity of head injury (GCS = 3-12) and was significantly related to poor final clinical outcome. PMID- 20196419 TI - Factors affecting standardized uptake value (SUV) of positron emission tomography (PET) imaging with l8F-FDG. AB - OBJECTIVE: The purpose of the study was to study factors affecting SUV of PET imaging with 18F-FDG. MATERIAL AND METHOD: PET/CT Biograph 64 was used to acquire the data. A NEMA PET phantom with 6 spheres varying in diameter from 10 to 37 mm was used to mimic the human body and tumors. Background activity of 18F in the phantom was 0.14 microCi/ml and tumor-to-background ratios (TBR) of 2:1, 5:1 and 10:1 were studied. For each TBR, thirty sinograms were acquired with 3-min scan durations. Different scan durations varying from 3 to 20 min using a TBR of 5:1 were studied and three datasets of each scan time were collected Sinograms were reconstructed using the Ordered Subset Expectation Maximization (OSEM) algorithm with 5 mm Full-Width-at-Half-Maximum (FWHM) Gaussian filtering. Sinograms at TBR of 5:1 were reconstructed by varying the number of iterative updates of OSEM (N) from 8 to 168 and SUVavg and SUVmax were measured. The percentage of underestimation of SUVs was used to study the effect of tumor size and TBR. Intraclass correlation coefficient (ICC) was used to test the reliability of SUVmax with different scan durations. RESULTS: The results showed that both the SUVavg and SUVmax rapidly increased when N was <48 and slightly increased afterwards. At TBRs ranging from 2:l to 10:1, the percentages of underestimation of SUVmax ranged from 8.17 to 22.46 and that of SUVavg were ranged from 41.44 to 52.33 for 37-mm sphere and from 40.38 to 54.52 and from 48.97 to 67.73 for 10-mm sphere respectively. Different scan durations gave reliable SUVs(max) with ICC of 0.996. CONCLUSION: SUVs increased as N increased The percentage of underestimation of the SUV depended on tumor size and TBR. Scan duration did not affect SUVs. PMID- 20196420 TI - Effect of Ayurved Siriraj herbal recipe Chantaleela on platelet aggregation. AB - INTRODUCTION: Ayurved Siriraj Chantaleela recipe is a traditional Thai remedy consisting of eight medicinal plants, which is employed for the treatment of fever. OBJECTIVE: To investigate the effects of Ayurved Siriraj Herbal recipe Chantaleela on platelet aggregation. STUDY DESIGN: Clinical research; ex vivo with before and after study design. MATERIAL AND METHOD: Twelve healthy male and female volunteers participated in the present study. Platelet aggregation test before Chantaleela ingestion was done as a control. After administration of 750 mg Chantaleela (3 x 250 mg tablets) every 8 hours for 3 doses, platelet aggregation was measured 8 hours following the first dose using an aggregometer and microplate reader. Adrenaline (Adr) and adenosine diphosphate (ADP) were used as platelet stimulants. Platelet aggregation was measured again at 32 hours and 8 10 days after the first dose. RESULTS: All of the participants completed the present study without any adverse event. Ayurved Siriraj Chantaleela did not affect platelet aggregation; neither Adr nor ADP were used as platelet agonists in both aggregometer and microplate reader Subgroup analysis revealed no significant change in platelet aggregation after Chantaleela administration according to the control for both male and female groups. The same results were also obtained in other subgroup analysis including hyperaggregation group, hypo normal aggregation group. CONCLUSION: From the present study, normal dose of Chantaleela for alleviation of fever does not have an effect on either platelet aggregation or platelet numbers. It may conclude that the present study supports the safety use of Chantaleela for relieving fever as platelet status does not need to be taken into consideration. PMID- 20196421 TI - Frame-composite mesh: a new method to treat complex unstable flail chest: a case report. AB - A middle aged Thai male was admitted suffering from a severely unstable flail chest caused by an elephant having trampled on the upper right part of his chest. He failed to respond to conservative treatment and conventional surgery could not be performed due to the bony defect in the chest wall. Consequently, a frame composite mesh was designed and constructed in close collaboration with Chiang Mai University's Biomedical Polymers Technology Unit. After implantation, the patient could be taken off a mechanical ventilator successfully without any adverse event. Two weeks after surgery, he was found to have good pulmonary function and so the clinical outcome was judged to be successful. PMID- 20196422 TI - Ipsilateral anterior hip dislocation and posterior knee subluxation: a case report. AB - Hip or knee dislocations are two orthopedic emergencies. Concomitant hip and knee dislocations are extremely rare. The authors report a case of ipsilateral anterior hip and posterior knee dislocations. Firstly, closed reduction of the knee and spanning external fixation was performed and then the hip was closely reduced under general anesthesia. PMID- 20196423 TI - Laparoscopic excision of urachal cysts in elderly men and woman following pregnancy. AB - BACKGROUND AND OBJECTIVE: Persistent urachus rarely presents in the aging male or during pregnancy. The authors report their experience with the laparoscopic excision of urachal cysts in two elderly men with significant co-morbidities and following pregnancy in a 32-year-old female. MATERIAL AND METHOD: The two male patients (65 and 70 years old, respectively) presented with a lower abdominal mass and umbilical discharge, while persistent urachus was identified incidentally during pregnancy; patients were managed with laparoscopic excision at 4 weeks, 6 weeks, and one year after diagnosis, respectively. Using 3 port accesses, the urachus and medial umbilical ligament were clipped and divided In 2 cases, specimens were separated from the bladder dome with a bladder cuff. In one patient, an additional port was required to facilitate intracorporeal freehand suturing of the bladder defect. RESULTS: All procedures were completed successfully via laparoscopy. No intraoperative or postoperative complications were reported Operative time ranged from 120, 180 and 160 minutes, respectively; in-hospital convalescence was 1, 7, and 6 days, respectively. Pathological evaluation revealed a benign urachal remnant in each case. CONCLUSION: Laparoscopic excision of urachal cysts in the aging male or following pregnancy is safe and effective. PMID- 20196424 TI - Typhoid spondylodiscitis: the first reported case in Southeast Asia and review of the literature. AB - We describe the first case of typhoid spondylodiscitis in Southeast Asia, and the literature were also reviewed. A 57-year-old diabetic Thai man who presented with a one-month course of progressive low back pain associated with paraparesis and bowel-bladder dysfunction. Examination revealed local tenderness over T12 area, spastic paraparesis, impaired pinprick sensation up to T12 level, and loose anal sphincter tone. Magnetic resonance imaging showed spondylodiscitis of T11 and T12 and epidural abscess causing spinal cord compression. T11 and T12 laminectomy, T11/12 discectomy, and debridement of epidural abscess were performed, and the cultures of the pus grew Salmonella Typhi. He was treated with intravenous ciprofloxacin for three weeks and was discharged from the hospital with oral ciprofloxacin and trimethoprim-sulfamethoxazole for another five months of treatment. The patient was doing well when last seen two months after discontinuation of antimicrobial treatment. In addition, a total of ten cases of typhoid spondylitis/spondylodiscitis were reviewed. PMID- 20196425 TI - [Patrik Vuilleumier: "The challenge is to transfer the functional neuroimaging results to clinical applications"]. PMID- 20196426 TI - [Addiction]. AB - The 2009 news in medicine regarding dependence confirm the bio-psycho-social field of addiction medicine and psychiatry. First a statement is made about the risk of cardiac arythmy in opioid substitution treatments. Then a review of the treatment of C hepatitis shows its importance in an addicted population. In the field of cognitive neuroscience, progress has been made in the knowledge of "craving" and of its endophenotypical components. Electronic medias related disorders are on the border of addiction: a case study is exploring this new domain. At last, recent datas are presented on the relationship between cannabis and psychosis. PMID- 20196427 TI - [Dermatology]. AB - Many significant advances in dermatology were published during 2009, focussing on infectious diseases, inflammatory disorders and oncology. Molecular medicine, as a result of the human genome project, also modifies the field of dermatology. Bioinformatics and biotechnology revolutionize the daily clinical practice in dermatology. A change of paradigm occurs notably in infectious diseases. PMID- 20196428 TI - [Management of thyroid cancers and nodules: what's new]. AB - The use of 18FDG-PET has become standard in the management of various malignancies but its application to thyroid nodules and carcinomas is not yet well defined. For the evaluation of thyroid nodules, 18FDG-PET can not consistently predict the nature of the lesions although there are some trends to higher uptakes in malignant tumours. On the other hand, it helps to detect and localize persistent diseases when progressive dedifferentiation of thyroid tumour tissue leads to a loss of iodine uptake. In addition, the more metabolically active lesions are associated with a poor prognosis. For the treatment of advanced thyroid carcinomas, recent clinical studies have now evidenced the promising results of tyrosine kinases inhibitors which can lead to partial responses in patients with progressive differentiated thyroid cancer. PMID- 20196429 TI - [What's new in geriatric medicine]. AB - Several studies clarified the role of different interventions such as vitamine D replacement, denosumab treatment, and vertebroplasty in the prevention and management of falls and fractures. A trial tested the effectiveness of pharmaceutical assistance at the time of discharge, emphasizing the potential benefits for the patients and the health care system. Syncopal episodes frequently lead to hospital admission. A retrospective study evaluated the diagnostic yield of different tests and emphasized the importance to actively seek orthostatic hypotension in older patients. Finally, advances remain modest in the field of dementias. PMID- 20196430 TI - [Angioedema during ACE and DPP-4 inhibition]. AB - Angioedema is a rare side effect of angiotensin converting enzyme (ACE) inhibitors. Its cause is probably related to the accumulation of bradykinin and substance P, i.e. two proinflammatory peptides normally inactivated by ACE. Angioedema occurs most of the time at the early phase of treatment, but may also develop during long-term treatment. It might involve the gastro-intestinal tract, leading to abdominal pain, vomiting and/or diarrhea, as well as pancreatitis. Dipeptidyl-ptidase-4 (DPP-4) is another enzyme allowing the degradation of bradykinin and substance P. Co-administering an ACE inhibitor and a DPP-4 inhibitor (as an antidiabetic agent) increases significantly the risk of angioedema. PMID- 20196431 TI - [Nephrology]. AB - Some major studies have lately been published in the filed of nephrology. The highlights of 2009 in this area are: a breakthrough in the understanding of the pathogenesis of membranous nephropathy, the beneficial effect of oral bicarbonate on the progression of chronic kidney disease, the disappointing results of the use of statins and erythropoietin in patients with chronic kidney disease and the lack of benefit on survival for patients suffering from acute kidney injury and receiving a higher dose of renal replacement therapy. PMID- 20196432 TI - [What's new in neurology]. AB - This article summarize principal news about treatments in the different specialities in neurology. We don't pretend to be exhaustive and to make a detailed analyse of all treatments, and preferred to present pertinent therapeutic advances, with an evidence-based point of view. We also mentioned some negative studies, to balance our purpose. PMID- 20196433 TI - [Managing impulsivity in obesity with problem solving]. AB - Among factors involved in binge eating episodes of our obese patients, impulsivity plays an important role. The model of Whiteside and Lynam describes four facets of impulsivity (urgency, lack of premeditation, lack of perseverance, sensation seeking). This multifaceted construct sheds light on our patients' impulsive behaviours towards food. To help our patients manage their impulsivity, problem solving technique is described in details. It can be effective in helping patients to cope their binge eating episodes since problem solving can initiate action and change habits. PMID- 20196434 TI - [Antivasoproliferative agents in ophthalmology]. AB - The most important recent advance in the treatment of neovascular age-related macular degeneration (AMD) is the development of antivascular endothelial growth factor (anti-VEGF) therapeutic agents that preserve and improve visual acuity by arresting choroidal neovascular growth and reducing vascular permeability. Two anti-VEGF agents, ranibizumab and pegaptanib sodium, are currently approved by Swissmedic for the treatment of neovascular AMD. A third anti-VEGF agent, bevacizumab, is currently used as an off label treatment option for exsudative AMD. Other anti-VEGF agent strategies that have shown efficacy include among others, small interfering RNA agents to silence the VEGF gene and receptor and the fusion protein VEGF trap. Anti-VEGF therapies have been used successfully in the clinic, encouraging their use in the treatment of other neovascular and exudative eye diseases. PMID- 20196435 TI - [Osteoporosis]. AB - Fracture risk could be evaluated with FRAX. Vitamin D administration decreases the rate of falls and deaths. Denosumab reduces the risk of fracture in postmenopausal women with osteoporosis and shows positive effects in case of breast and prostate cancers with hormone deprivation therapies. Zoledronate and teriparatide alone are more effective than risedronate and alendronate respectively in treatment of glucocorticoids induced osteoporosis. The association zoledronate and teriparatide may be promising. Vertebroplasty is not the first line treatment for symptomatic osteoporotic vertebral fractures. Osteonecrosis of the jaw and subtrochanteric femoral fractures are still events to consider in case of treatments with bisphosphonates. PMID- 20196436 TI - [Perinatal asphyxia and neonatal hydronephrosis]. AB - Perinatal asphyxia. Perinatal asphyxia remains one of the most important causes for high mortality and morbidity in the neonatal population. Despite intensive animal and clinical research in this field, no pharmocological strategy has been shown neuroprotective in humans. Moderate hypothermia for severely and moderately asphyctic babies has been aknowledged since a few years as therapeutical approach to improve the outcome of these infants, specifically the long-term follow up (18 months). Neonatal hydronephrosis. Neonatal hydronephrosis is a pathology that requires regular and efficient follow up by a multidisciplinary team. One of the causes of neonatal hydronephrosis is obstructive pathologies which may endanger the kidney. We have developed a strategy that allows a rapid diagnosis of obstructive pathologies with minimal radiological exams. Moreover, this strategy assures the coordination between obstetricians, neonatologists, pediatric urologists, and pediatric nephrologists. PMID- 20196437 TI - [Vaccine update 2009: questions around the safety of the influenza A (H1N1) vaccine]. AB - This manuscript reviews the main vaccine safety concerns that have limited the confidence of the population vis-a-vis influenza A(H1N1) vaccines and disturbed health professionals: A hasty development process? Excessively strong adjuvants? Notoriously toxic substances such as squalene and mercury salts? High risks of Guillain-Barre syndrome or auto-immune diseases? Deaths and other severe problems following immunization? Providing the available information, this manuscript asks whether a high-quality scientific communication would have reassured health professionals, and thus the population. The huge number of questions sent by professionals to InfoVac experts (www.infovac.ch), and the expressed gratitude, allows for some hope. PMID- 20196438 TI - [You said courage?]. PMID- 20196439 TI - [The return of the "malignant flu"?]. PMID- 20196440 TI - [Questions surrounding sibutramine for obesity]. PMID- 20196442 TI - [2010: is anything new?]. PMID- 20196441 TI - [La peste, Antonin Artaud, 1934]. PMID- 20196443 TI - [Normative EEG spectral characteristics in healthy subjects from 7 to 89 years]. AB - EEGs were recorded at 885 healthy subjects of both sexes with age from 7 to 89 years in "eyes closed" and "eyes opened" conditions. Both average EEG power spectra and EEG independent component power spectra were computed for 20 age groups of subjects separately, and corresponding confidence intervals of average power were estimated for four frequency bands: delta, theta, alpha and beta. These quantitative data can be useful as objective criteria for diagnostics of brain dysfunctions. PMID- 20196444 TI - [Ontogenetic formation of stereognosis brain mechanism (EEG study)]. AB - In this study the age specificity of inter- and intrahemispheric relations during stereognostic task (tactile identification of predetermined chess-like pieces with right or left hand) in adults and children of 5-6, 7-8 an 9-10 years old is considered. The combined pattern of cortical interactions was revealed in adults. Its appeared in significant increasing (compared to baseline) of interhemispheric EEG relations along with increasing of system interactions of anterior and posterior cortex areas bioelectrical activity. This combined pattern is observed both in case of using EEG coherence and correlation analysis. In children interhemispheric EEG relations increasing is appeared already in 5-6 years (maximum in 7-8 yo.), whereas increasing of EEG relations in fronto-occipital direction expanses gradually with age, and only in age 9-10 approaches to definitive level, typical for adults. The data obtained evidence the gradually formation in postnatal ontogenesis of central mechanisms of such important function--stereognosis. Our results suppose that brain mechanisms of right (leading) hand stereognostic activity maturate earlier than left (nonleading) hand activity. Heterochronic involving in stereognostic activity of inter- and intrahemispheric relations can be closely related with gradual and heterochronic processes of commissural and associative hemispheric tracts mielinization. PMID- 20196445 TI - [Structural transformations of cyto- and fibroarchitectonics of the human frontal cerebral cortex from a birth till 20 years]. AB - Research consist in studing cyto-and fibroarchitectonics of the human cerebral cortex (8, 10, 32/10, 44 and 45 frontal areas). Informative parameters of ansemble postnatal features in cortical organizations for studying at cellular population level is established. They have included dimensional parameters of neural groupings at layer III and a parity of specific neuronal and fibrous volumes. It is shown, that associative fields 44, 45, 10 in lateral frontal zones is the most long develop in ontogenesis. Especially important structural transformations to them carry staged character and are marked on the first year of a life, and also by 3, 6-7, 10 and 13-14 years. PMID- 20196446 TI - [The age aspects of cognitive function disorder in local brain damages of various genesis]. AB - The results of neuropsychological investigation of 808 children and adolescents from the age of 7 to 18, out of whom 689--patients with local damages of brain (tumors, arachnoidal cysts, vessel pathology, congenital hydrocephaly), 119- health ones were analyzed. All patients, healthy and ailing were divided into four age groups: preschoolers 7-9 years old, preteenagers 10-12 years old, teenagers 13-15 years old, and adolescents 16-18 years old. Were detected the disorders of cognitive functions and there dependence on the character of pathologic processes of the brain and age. PMID- 20196447 TI - [Genetic and social factors in developing of aggression]. AB - The association of 5-HTTLPR gene polymorthism and aggression was studied in control group of males and females and in the athletes. The sport activities were found to decrease the aggression: the effect persist for the synchronized swimmers and for the wrestlers. Control group of males were characterized by higher aggression scores (Assault, Negativism, Suspicion and Verbal aggression scales of Buss-Durkee Hostility Inventory) compared to females. For all female subjects irrespective of sport activities and age, the association between the variants of 5-HTTLPR gene and the Indirect Aggression and Negativism scores were found: carries of SS genotype has higher scores on Indirect Aggression and lower scores on Negativism. For the males the association was different: The averaged Hostility scores were higher for the carriers of LL-genotype. The brain processes, presumably underlying the association between aggression and 5-HTLPR gene, were studied in male control group. The increased MMN component of ERP, which responsible for the automatic change detection, and decreased P3a component, related to involuntary attention and cognitive control were found in LL-carries. It might be considered as a sign that SS-carries process the information with more cognitive resources. Probably they perceive the stimulus as more complicated, which lead to activation the additional resources of frontal cortex. It might be also suggested that the carries of SS-genotype tend to deeper processing of the incoming information. Probably, it is this more "serious" analysis of external information, which underlies the rejection of impulsive aggressive actions. PMID- 20196448 TI - Activation and inhibition of bimanual movements in school-aged children. AB - The development of motor activation and inhibition was compared in 6-to-12 year olds. Children had to initiate or stop the externally paced movements of one hand, while maintaining that of the other hand. The time needed to perform the switching task (RT) and the spatio-temporal variables show different age-related evolutions depending on the coordination pattern (in- or anti-phase) and the type of transition (activation, selective inhibition, non selective inhibition) required. In the anti-phase mode, activation perturbs the younger subjects' responses while temporal and spatial stabilities transiently decrease around 9 years when activating in the in-phase mode. Aged-related changes differed between inhibition and activation in the anti-phase mode, suggesting either the involvement of distinct neural networks or the existence of a single network that is reorganized. In contrast, stopping or adding one hand in the in-phase mode shows similar aged-related improvement. We suggest that selectively stopping or activating one arm during symmetrical coordination rely on the two faces of a common processing in which activation could be the release of inhibition. PMID- 20196449 TI - [Maximal aerobic potential as a criteria for optimal ontogenesis]. AB - On the basis of theoretical analysis and personal experimental data the methodology of evaluation of the optimal ontogenesis (physical development of children and adolescents) based of the criteria of bioenergetics is evaluated, the low edge of aerobic capacity as development optimum. PMID- 20196450 TI - [The development and training of the coordinatory abilities of young footballists of 11-19 years old]. AB - The goal of the investigation was the reveal the development and training specialties of coordinating abilities (CA) of young football players from 11-19 years old (n = 600). For the evaluation of CA and technical abilities of the football players, educational experiments on aimed development of CA of one and two year length were used. Was shown that the most favorable period for the development of football player's CA is the period from 11 to 13 years old, and the second line period is from 14 until 14 years old. The use of special coordinating training, directed on the development of separate CA lead to a high increase and reliable difference in the CA values (from 2.5 to 38.3%) and the level of technical efficiency (from 3.6 to 12.2 %) in the football players of experimental group as opposed to football players of the control group, who were training according to traditional training, using the dexterity exercises. PMID- 20196451 TI - [Discrimination of the dynamic properties of sound source spatial location in humans (electrophysiology and psychophysics)]. AB - The spatial resolution of human auditory system has been studied while the localization of sound source has been changed according to the different temporal patterns of interaural time delay. Two experimental procedures have been run in the same group of subjects: psychophysical procedure (the transformed staircase method) and electrophysiological one (which requires recording of mismatch negativity, the auditory evoked response component). It has been established that 1) the magnitude of the mismatch negativity reflects the extent of spatial deviance of the sound source 2) the mismatch negativity is elicited even at minimal (20 micros) interaural time delays under both temporal patterns (abrupt azimuth change and gradual sound movement at various velocities) 3) the abrupt change of the sound source azimuth results in greater mismatch negativity than the gradual sound movement does, if the interaural time delay exceeds 40 micros 4) the discrimination threshold values of the interaural delay obtained in the psychophysical procedure are greater than the minimal interaural delays that elicit the mismatch negativity, with the exception of the expert listeners who has shown no significant difference. PMID- 20196452 TI - [The characteristics of cortical interactions in high and low verbal creative subjects]. AB - The characteristics of cortical interactions depending on level of creative achievements were investigated in 40 right-handed subjects (22 men and 18 women). The subjects were divided into the two groups with high and low ability by the originality score median split. EEG was recorded in rest and during task performance (the verbal creative task "Cognitive synthesis"). EEG coherence was computed in the six frequency range from 4 to 30 Hz. Total values of coherence for each of 16 sites, calculated separately for intrahemispheric and interhemispheric connections were analyzed. It was revealed that subjects with higher originality scores (OS) in comparison to low original ones were characterized by decreased the theta 1.2 rhythms interhemispheric coherence, that was expressed in the frontal cortex, and increased beta1-rhythm interhemispheric coherence in the occipital and temporoparietal regions of the brain. The obtained results are discussed from the point of view of the contribution of the right and left hemispheres of the brain to processes "top-down" and "bottom-up" regulation during creative thinking. PMID- 20196453 TI - [On efficiency of biomanagement with negative feedback from patient's EEG in correction of functional disorders, caused by stress]. AB - The perspective approach to non-pharmacological correction of the stress induced functional disorders in humans, based on the double negative feedback from patient's EEG was validated and experimentally tested. The approach implies a simultaneous use of narrow frequency EEG-oscillators, characteristic for each patient and recorded in real time span, in two independent contours of negative feedback--traditional contour of adaptive biomanagement and additional contour of resonance stimulation. In the last the signals of negative feedback from individual narrow frequency EEG oscillators are not recognized by the subject, but serve for an automatic modulation of the parameters of the sensory impact. Was shown that due to combination of active (conscious perception) and passive (automatic modulation) use of signals of negative feedback from narrow frequency EEG components of the patient, opens a possibility of considerable increase of efficiency of the procedures of EEG biomanagement. PMID- 20196454 TI - [The methodological approach to the evaluation of the functional status of the organism according the degree of fatigue]. AB - In the context of complex investigation the monitoring of the functional state of the fire department saviors of the operative department of the MES of Russia in the 24 hour day work condition (faces of extremal profession, males of I-II health groups from the age of 20-45 years old; n = 136) took place. Was revealed that in various systems a signs of fatigue are noticed, and in the organism a total fatigue is formed. A methodological approach to the evaluation to the functional state of the organism according to calculation value "total organism fatigue", included 6 methodological various approaches was developed. PMID- 20196455 TI - [The state of central hemodynamics and variability of hearty rate in sportsmen with various direction of training process]. AB - The state of the central hemodynamic and variability of heart rate (VHR) in high quality sportsmen with various direction of training processes in conditions of relative tranquility was investigated. Was discovered that in sportsmen during the endurance training (group "Endurance", n = 27) and in strength training (group "Strength", n = 17) was noted the decrease in total peripheral blood resistance (TPBR: -15%, p = 0.003 and -16%, p = 0.011 for groups "Endurance" and "Strength" accordingly). However, in group "Strength" the minute blood volume (MBV) was increased (p = 0.012), and temporal and spectral data ofVHR (RMSSD, PNN50, HF)--decreased (p < 0.05) in comparison with control group (n = 56). Part of this differences had to do with increase body mass index (p = 0.005) in the group "Strength". In "Endurance" group the VHR were increased (RMSSD, pNN50, HF, VLF, TP all p < 0.02), the mean arterial pressure was decreased (p < 0.003) without considerable differences in MVB in comparison with the control group. The received data allows to conclude, that in the state of tranquility, the hemodynamic maintenance of the organism of the sportsmen of the "Strength" group takes place on a higher level of MBV and the mechanisms of heart regulation tension. On the other hand, in sportsmen training in endurance, the low level of MBV is taken care of by less tension of the regulation mechanisms of the heart action (higher tonus of vagus). PMID- 20196456 TI - [The change in lipoid spectrum in blood serum in girls of different somatotypes after meals]. AB - State Educational Institution for Professional Education - Prof. Voyno Yasenetzkiy's High School of Krasnoyarsk State Medical Academy of Russian Public Health Ministry. We carried out the analysis of the changes in the spectrum of neutral lipoids and phospholipoids in blood serum as a response to meals in girls of different somatotypes. We revealed statistically true lowering of lipid acids content in representatives of all examined somatotypes after meals. Statistically true increase of simply oxidized fractions of phospholipoids in girls of sub athletic and athletic somatotypes testifies on the change in the ratio of dynamics components of lipoid spectrum of lipoproteids. Balanced fractions of phospholipoids as well as free cholesterol are the main structural components in lipoproteid membranes and they didn't change in any of the studied somatotypes as a response to meals. This proves the stability of membrane structure of lipoproteid complexes as a response to the given physiological stimulus. PMID- 20196457 TI - [Modern concepts of coding mechanisms of the visceral pain stimuli]. AB - The review of the existing concepts on visceral pain mechanisms and mechanisms of processing nociceptive stimuli on the level of the sensory neurons of superficial segments of the dorsal cornus of the spinal cord was presented. Also the information on ion channels and receptors, which participate in transduction of pain signals are discussed. PMID- 20196458 TI - [Vegetative state (prolonged coma) as manifestation of stable pathological state]. AB - Complex examination of 25 patients in vegetative state was performed before and after correction of secondary brain damage. Catamnesis over a period of at least 6 months was traced. Preliminary results showed that better recovery of consciousness and cognitive functions was observed if before treatment diffuse glucose hypometabolism was significantly more widespread than morphological changes. Minimal positive dynamics was detected in cases in which the reduction of glucose metabolism was minimal. This and other paradoxical results become explainable if to consider vegetative state as stable pathological state of the brain. This open new approaches to treatment of this group of patients. PMID- 20196459 TI - [A cross oxidation of lipids and antioxidant erythrocyte defense barbotage aeroionization of the donor erythrocyte mass]. AB - The possibility of the prolonged conservation of the native erythrocyte state of the donor erythrocyte mass with the use of barbotage aeronization was shown. The method of barbotage aero ionization, which was proposed by us in order to prolong the period of storage of donor erythrocytes, allows to decrease the level of destructive processed in storable erythrocyte mass, with the evidence of decrease in intensity of peroxidase lipid oxidation and growth of antioxidant activity in it. PMID- 20196460 TI - Fall prevention takes 'constant attention,' comprehensive interventions. PMID- 20196461 TI - Standardizing withdrawal of life support. PMID- 20196462 TI - Applying reliability to improve infection rates. PMID- 20196464 TI - Patient satisfaction planner. Patient-centric care decreases hospitalizations. PMID- 20196463 TI - Patient satisfaction planner. Throughput drive lowers discharge time, LOS. PMID- 20196465 TI - Engaging your board is a must: here's how. PMID- 20196466 TI - North Shore-LIJ wins NQF Quality Award. PMID- 20196467 TI - Kovacova, E., Kinova, S., Duris, I., Remkova, A. General changes in haemostasis in gastric cancer. Kovacova, E., Kinova, S., Duris, I., Remkova, A. Local changes in haemostasis in patients with gastric cancer. PMID- 20196468 TI - Vitamin D deficiency, atherosclerosis and cancer. AB - Abstract: Recently there has been intense interest to find if vitamin D deficiency may be related to cardiovascular disease, cancer and infection. Inadequate saturation with vitamin D may adversely affect immune and metabolic functions, causing non-skeletal medical disorders. Sunlight exposure induces vitamin D synthesis in the skin from a precursor, 7-dehydrocholesterol. Since the body produces vitamin D, this "vitamin" does not fulfill classical definition for a vitamin, being rather a prohormone. Vitamin D provided in the food has smaller role than the source synthesized in the skin. Vitamin D is hydroxylated in the liver into 25-OH-D. Because this product has a longer biological half life, it is the best indicator of body stores of vitamin D. Biologically active form is the next metabolite, 1-25 (OH)2 D. This product has a high binding affinity to a protein nuclear vitamin D receptor (VDR). Receptors for vitamin D have broad tissue distribution, including vascular smooth muscle, endothelium and even malignant cells. Deficiency of vitamin D in populations is high (30-60% in the USA and Europe). This is particularly true about the northern latitudes where there are insufficient UV-B rays to promote the skin synthesis. In addition, there are campaigns to control sun exposure (fear of skin cancer), together with reduction in outdoor activities. No wonder that in aging people, in chronically ill and in subjects requiring long-term hospitalization, deficiency of vitamin D is very frequent and may adversely affect already compromised immunologic functions and resistance to infection (Fig. 6, Ref. 43). PMID- 20196469 TI - Eisenmenger syndrome--a unique form of pulmonary arterial hypertension. AB - In 5-10% of adults with congenital heart disease (left-to-right shunt defects), pulmonary arterial hypertension (PAH) can develop with variable severity. An extreme manifestation of PAH in this setting is known as the Eisenmenger syndrome. It represents not only PAH associated with congenital heart disease, but also a multi-systemic disorder, presented by variety of complications (cyanosis, bleeding, thrombotic diathesis, high risk of bacterial endocarditis or cerebral abscess, ischemic complications, hepatic and renal involvement, congestive heart failure and sudden death). Authors concisely identify the underlying pathophysiological and hemodynamic aspects of Eisenmenger syndrome and focus on the clinical presentation. Eisenmenger syndrome represents a unique form of PAH with many differences. The preserved right ventricular function seems to play the key role in a better survival of these patients compared to other forms of PAH. To achieve a satisfactory prognosis and life-quality in patients with Eisenmenger syndrome it is necessary not only to treat their hemodynamic features (PAH and/or ventricular dysfunction) but also to adequately manage and prevent all the multi-systemic complications resulting from this disease. This often needs a care in specialized centers with multi-disciplinary approach (Tab. 2, Fig. 6, Ref. 17). PMID- 20196470 TI - Testosterone supplementation therapy as a treatment of hypogonadism. AB - A substantial proportion of older men (ranging from 20% of 60-year-old to 50% of 80-year-old men) have total serum testosterone levels below the normal range for younger men (1). At the age of 75 years, mean plasma testosterone levels are only 65% of levels in young adults, whereas over 25% of these men have bioavailable testosterone levels below the lowest normal limit in young adults. The interindividual variations in the plasma levels are, however, very important and a quarter of men over 75 years old have still testosterone levels within the upper quartile of values in young men (2). Many symptoms associated with aging in men, including muscle atrophy and weakness, osteoporosis, reduced sexual functioning, and increased fat mass, are similar to changes associated with testosterone deficiency in young men. These similarities suggest that testosterone supplementation may prevent or reverse the effects of aging (3), improve the general well being, sexual characteristics and behaviour of elderly men (Fig. 4, Ref. 71). PMID- 20196471 TI - Diabetes--adult stem cells as an future alternative therapy? AB - In both types of the diabetes mellitus, the lack of functional beta-cells is crucial, leading to complications associated with development of hyperglycaemia. One way to achieve a constant normoglycemic state without hypoglycemic episodes is either whole pancreas transplantation, or transplantation of isolated islets of Langerhans. Another approach to correct the beta-cell deficit is the stimulation of beta-cells in pancreas to regeneration. The development of new diabetes therapy is the main goal for many scientists around the world. This article is focused on the stem cells and their potential for clinical applications (Ref. 47). PMID- 20196472 TI - HIV prevalence and clinical care for HIV-positive pregnant women in Slovakia. AB - OBJECTIVE: To evaluate clinical care for HIV positive pregnant women who delivered in Slovakia from 1985 till 2008. BACKGROUND: National guidelines for the prevention of mother-to-child transmission of HIV have not yet been established. METHOD: Retrospective analysis of 14 HIV-infected pregnant women and their infants. Factors examined include maternal social, demographic, immunological and virological characteristics, method of HIV testing, antiretroviral therapy during pregnancy, delivery and puerperium, mode of delivery, mode of infant feeding, pregnancy outcomes and HIV status of infants. CONCLUSIONS: Due to the increase in cases of HIV-infected pregnant women within the last several years, it would be advisable to create National Guidelines for PMTCT (Prevention of Mother-to-Child Transmission) in order to consolidate the care management in all HIV/AIDS care centers around Slovakia (Fig. 4, Ref. 7). PMID- 20196473 TI - The effect of inhaling peppermint odor and ethanol in women athletes. AB - The purpose of this study was to determine whether inhaling peppermint odor has effects on time of running, maximum heart rate (MHR), maximum oxygen consumption (VO2max), oxygen consumption (VO2), minute ventilation (VE) and respiratory exchange ratio (RER) during acute intensive exercise or not. 36 women soccer player were chosen for participating in this research. They were randomly divided in 3 groups (control, inhaling peppermint, inhaling mixture of peppermint and ethanol). In order to be aware of similarity of groups, the subjects' BMI was determined and ANOVA did not show any significant differences (p < 0.05). The subjects of three groups ran on treadmill according to Bruce test. Heart rate, time of running, VO2max, VO2, VE and RER were measured by Gas Analyzer. After collecting the data, ANOVA was done (p < 0.05) and the results showed that in this study the inhaling of fragrant odors did not have any significant effect on the time of running, MHR, VO2max, VO2, VE and RER, which we think is due to the intensity and duration of training. Referring to our results of the present study; we suggest that inhaling peppermint odor during acute intensive exercise has no significant effect on pulmonary indexes and physical performance (Tab. 4, Fig. 1, Ref. 21). PMID- 20196474 TI - Clinical and hemodynamic picture of Eisenmenger syndrome. AB - Eisenmenger syndrome represents a very specific form of pulmonary arterial hypertension (PAH). Unlike patients with idiopathic PAH, in Eisenmenger syndrome the clinical and cardiac status is often relatively stable for a long time. On the other hand, due to cyanosis and due to maladaptive body reactions many noncardiac complications may occur. Fourteen patients (pts) with Eisenmenger syndrome were analyzed, with the mean age 41 years. Invasively measured pre capillary pulmonary hypertension was severe (mean pulmonary arterial pressure 79 mmHg) and a statistically significant difference according to the site of defect was found (pre-tricuspid shunts vs post-tricuspid shunts = 57,5 mmHg vs 88 mmHg; p = 0.01). It is neccessary to keep in mind that non-cardiac events and complications may lead to death sooner then the right ventricular dysfunction or PAH (Tab. 7, Fig. 21, Ref. 16). PMID- 20196475 TI - Corneal arcus: an indicator of severe coronary artery disease in a young adult man. AB - A 32-year-old man was transferred to our emergency service with the diagnosis of sudden cardiopulmonary arrest. During eye examination, a typical corneal arcus was observed. The patient underwent the primary percutaneous coronary intervention. Coronary angiography showed a total occlusion of proximal left anterior descending artery. Primary coronary balloon angioplasty was successfully performed. Independently of total cholesterol, serum high-density lipoprotein cholesterol and smoking, corneal arcus has been suggested as a predictor of coronary heart disease among hyperlipidemic men. Physical examination can yield valuable diagnostic clues in a patient suspected of ischaemic heart disease. In summary, the appearance of corneal arcus in young adult men might be an indicator of severe coronary artery disease and should be screened by means of physical examination especially in the setting of cardiopulmonary arrest (Fig. 1, Ref. 4). PMID- 20196476 TI - "Bochdalek" skull (syngnathia): CT examination. AB - Bony fusion of the jaws (syngnathia) without any other anatomic oral anomalies is an unusual condition. It is believed that important factors can be congenital. Some cases with combination of cleft palate, aglossia, and soft or bony adhesion between the maxilla and mandible have been reported. Congenital syngnathia could also occur with Treacher-Collins syndrome, pterygium syndrome and van der Woude syndrome. In this study, girl skull with jaw anomaly depicted by prof. Bochdalek in XIX. century was re-examined using CT method to explain possible mechanism of this anomaly development. Our report presents a case of syngnathia with bilateral vision where mandible, maxilla, zygomatic and palatal bones are mutually connected. CT findings strongly support the idea about of mechanical trauma triggering a chain of bone disturbances in facial skeleton. With high probability most of the teeth were extracted later to keep the oral cavity open (Fig. 9, Ref. 32). PMID- 20196477 TI - The responsibility of alcohol-impaired road users in fatal road traffic accidents. AB - The purpose of this paper was to identify the impact of intoxicated road users upon the degree of responsibility for fatal road traffic accidents. RESULTS: A total of 373 traffic fatalities was recorded. These cases represented 13.5% of all autopsied cases. Alcohol intoxication was determined in 35.9% of persons involved in road traffic accidents. The degree of responsibility of intoxicated persons was 87.3% of all cases, of non-intoxicated persons 56.7% of all cases. The average determined blood alcohol concentration was 1.91 g/kg. CONCLUSION: The degree of responsibility for fatal road traffic accidents was 1.5 times higher among intoxicated road users than among non-intoxicated road users. Alcohol is still the most abused psychoactive substance in Slovakia. The causes of its excessive consumption are the objectives of many larger studies. It is assumed that excessive alcohol consumption can be considerably attributed to its easy availability and lack of awareness and personal responsibility of road users (Tab. 4, Ref. 35). PMID- 20196478 TI - Functional results in patients with sarcoma around the knee joint. AB - Authors evaluated functional outcomes after three different surgical procedures for sarcoma around the knee joint. Sixteen patients with sarcoma were given four to six preoperative courses of chemotherapy. Patients were separated into three groups according to the pattern of tumour excision. The first group underwent the resection of proximal fibula and tibialis anterior muscle resection, the second group underwent resection of distal femur or proximal tibia with total knee replacement, and the third group underwent radical amputation. The mean functional evaluations were 100, 95 and 80%. All marginal resections of proximal fibula resulted in excellent function. No local evidence of tumour recurrence was seen at mean follow-up of 24 months (Tab. 1, Fig. 2, Ref. 7). PMID- 20196479 TI - IHI program building foundation for more quality-conscious providers. AB - Organization seeks to offset lack of QI education in medical schools. Health systems have started to form their own chapters. Quality managers can play an important role as mentors. PMID- 20196480 TI - Quality award winner takes 'STEPPS' to improve. AB - Evidence-based program seeks to optimize outcomes. Culture of safety survey identified opportunities to improve. OR, ED, and labor and delivery developed departmental goals. PMID- 20196481 TI - Video gets patients more involved in hand hygiene. AB - Video uses a "real-world" clinical setting. Patients are encouraged to overcome reluctance to question providers. Creating a safety culture will make any initiative more successful. PMID- 20196482 TI - Compliance rates low on egress, fire safety. AB - Hospitals still showing noncompliance with standards: LS.02.01.20, LS.02.01.10, RC.02.03.07, EC.02.03.05, NPSG 02.03.01. Egress standard a "double-edged sword". There must be two "separate and remote" doors in and out of the ED suite. PMID- 20196483 TI - Flow strategies cover processes in and out of ED. PMID- 20196484 TI - [Successful tocilizumab therapy for adult onset Still's disease with intractable conditions over ten years]. PMID- 20196485 TI - [Insulin allergy whose local/systemic reactions were reduced by desensitization with long-acting insulin analog, glargine]. PMID- 20196487 TI - [Kinematic aspects of the step movement in Parkinson's disease]. AB - In an attempt to understand the fundamental mechanism for movement disturbances in Parkinson's disease (PD) patients, we investigated their straightforward or right diagonally (laterally) steps and step over a stick. In all tasks, in PD patients, the movement latency was significantly longer and the movement duration was significantly shorter than those of the controls. In the lateral step task, the maximum velocity of PD subjects was significantly faster than that of the controls, while the reaching time to maximum velocity was longer. Moreover, in the task to step over a stick, the reaching time to maximum velocity was significantly longer than that of the controls. In the velocity profiles, in PD patients, the deceleration after the maximum acceleration was rapider than that of the controls. In addition, the PD patients' jerk was significantly larger than that of the controls. These results suggest that PD patients have deficits in motor programming and motor control which may be due to dysfunction of the cortico-basal ganglia loop. PMID- 20196486 TI - [The discovery of an antiparkinsonian drug, zonisamide]. AB - We serendipitously found that zonisamide (ZNS), an antiepileptic agent, has beneficial effects on Parkinson disease. A 25 mg once a day of ZNS (200-600 mg/day for epilepsy), significantly improves motor function of advanced patients with Parkinson disease. Its effects maintained at least one year even in patients with advanced stage. It was finally approved as an anti parkinsonian agent in Japan on January 2009. As the mechanism of antiparkinsonian effects of ZNS, we showed that ZNS increases dopamine contents in the striatum by activating dopamine synthesis through increasing the levels of tyrosine hydroxylase (TH) mRNA and TH protein. It moderately inhibits monoamine oxydase (MAO) activity. ZNS shows significant inhibition on T-type Ca++ channel. It may also affect the beneficial effects of ZNS on Parkinson disease. ZNS also showed neuroprotective effects on several parkinsonian models. It markedly inhibited quinoprotein formation and increased the level of glutathione by enhancing the astroglial cystine transport system and/or astroglial proliferation through S100beta. We will verify the neuroprotective effects of ZNS on patients with Parkinson disease and study the factors responsible for the individual difference of the effects of ZNS by using genome wide association study (GWAS) in the near feature. PMID- 20196488 TI - [Bulbar-onset amyotrophic lateral sclerosis (ALS) with isolated agraphia]. AB - We reported the two cases with bulbar-onset ALS showing isolated agraphia without overt dementia and aphasia. Patient 1 was a 69-year-old man and patient 2 was an 81-year-old woman, and both were right-handed. Each patient developed dysarthria as an initial symptom followed by dysphagia, and neurological examinations showed atrophy and fasciculation of the tongue with upper and lower motor-neuron involvement of the extremities. These characteristic features with electromyographic evidence including widespread acute and chronic denervation led to a diagnosis of bulbar-onset ALS. Around 1 year after the onset of ALS, dysarthria was mild enough to allow oral communication enabling the determination that aphasia was absent with well preserved confrontation naming, repetition, reading and comprehension. The patients were polite without abnormal behavior or character change, and their general intelligence was also well preserved with excellent scores on the Mini Mental State Examination (30 and 27 points for patients 1 and 2, respectively) and Frontal Assessment Battery (16 points for each patient). However, spontaneous writing and dictation revealed abundant writing errors characterized by omission of kana letters and paragraphia of kana and kanji letters in both patients. Some syntactic errors were also observed in writing but in spoken language. A letter-number effect on writing errors was observed in patient 1. Copying of letters or words was intact and structure and orientation of written letters was well preserved, indicating the absence of constructional, apraxic or spatial feature of agraphia. Single photon emission computed tomography demonstrated reduced uptake in the bilateral frontotemporal lobes, predominantly in the left hemisphere, with less evident alternation in magnetic resonance imaging. Our results suggest that patients with bulbar-onset ALS may develop isolated agraphia as a single-domain cognitive impairment, preceding the clinical manifestation of aphasia or dementia. We speculate that the main responsible region might be the posterior part of the middle and inferior frontal gyri including Exner's writing center and Broca's area beyond the primary motor cortex. PMID- 20196489 TI - [A case of Wegener's granulomatosis presenting with tonic-clonic status epilepticus]. AB - A 47-year-old man with a diagnosis of paranasal Wegener's granulomatosis was admitted to our hospital for generalized seizures. He had been treated with long term predonine therapy after the initial onset of Wegener's granulomatosis. The ictal EEG showed generalized spike and wave complexes, mainly presenting in the bifrontal areas. The postictal EEG revealed periodic localized sharp discharges in the left frontal area. At the initial seizure onset, a midline multilobular mass lesion having a heterogeneous enhancement effect was detected in the lower frontal lobe on gadolinium-enhanced T1-weighted imaging (Gd T1-WI). The anterior skull base and bifrontal lobes were encroached by upward contiguous invasion of the midline mass lesion from the ethmoid sinus on Gd T1-WI. The high signal intensity lesions in the bifrontal lobes on T2- and Gd T1-WI resolved with palliative predonine therapy following methylpredonisolone pulse therapy. Recurrent generalized tonic-clonic status epilepticus was caused by the granulomatous lesion encroaching on the frontal lobe with contiguous invasion from the paranasal Wegener's granulomatosis. PMID- 20196490 TI - [A case of immune-mediated encephalopathy showing refractory epilepsy and extensive brain MRI lesions associated with anti-glutamic acid decarboxylase antibody]. AB - We reported a patient with immune-mediated encephalopathy showing refractory epilepsy and multiple brain lesions on MRI. The patient had high titers of anti glutamic acid decarboxylase (GAD) antibody in sera and cerebrospinal fluid (CSF). A 36-year-old previously healthy woman was admitted to our hospital with onset of sudden generalized seizure that then persisted for one month. She had repeated epileptic attacks accompanied with loss of consciousness, and was refractory to valproic acid, zonisamide (200 mg/day) and phenobarbital (200 mg/day). Brain MRI showed multiple hyperintense lesions in predominantly bilateral frontal lobes, parietal lobes, occipital lobes and cingulate cortices. EEG showed epileptic activities (frequent sharp waves) in bilateral frontal regions. After admission, attacks disappeared through the administration of clonazepam (1.5 mg/day), though the patient remained slightly disoriented. As titers of anti-GAD antibody in sera and CSF were extremely high, we implemented plasma exchanges. After treatment, titers of anti-GAD antibody in sera and CSF decreased. The patient completely recovered to an alert state and the abnormal MRI lesions almost disappeared. Since GAD catalyzes production of gamma-aminobutyric acid (GABA), it is proposed that anti-GAD antibodies reduce synthesis of GABA or interferes with exocytosis of GABA in the nervous system. Anti-GAD antibodies are detected in some rare neurological disorders such as stiff-person syndrome. Recently, anti-GAD antibodies have been reported as implicated in cerebellar ataxia, palatal myoclonus, refractory epilepsy and limbic encephalitis. Epilepsy associated with the anti-GAD antibody is mostly pharmacoresistant temporal lobe epilepsy; with brain MRI showing no abnormality or only hippocampal sclerosis. It is very rare that brain MRI shows extensive abnormal lesions except in the hippocampus. This case suggests that anti-GAD antibodies could contribute to unexplained encephalopathy with extensive brain MRI lesions and drug-resistant symptomatic epilepsy. PMID- 20196491 TI - [A patient with cerebellar ataxia, hypogonadotropic hypogonadism and vitelliform macular dystrophy: Boucher-Neuhauser syndrome]. AB - A 28-year-old man had experienced non-progressive gait disturbance since early childhood. He was admitted because of hypogonadism and cerebellar ataxia. On admission, bilateral vitelliform macular dystrophy, fixation nystagmus, slurred speech, cerebellar ataxia, decreased tendon reflexes, and pes cavus were present. Higher brain function, auditory function, and olfactory function were not disturbed. A gene abnormality related to known hereditary spinocerebellar degeneration and Kallman syndrome was not observed. Brain MRI demonstrated cerebellar atrophy. ECD-SPECT revealed decreased blood flow in the brain stem and cerebellum. Endocrinological tests indicated that the hypogonadism seemed to be due to a primary pituitary disturbance. This is the second case of Boucher Neuhauser syndrome in Japan. PMID- 20196492 TI - [Anti-NMDA receptor encephalitis during pregnancy]. AB - A 19-year-old female in her 2nd trimester (17 weeks) of pregnancy became irritable a few days before admission. She became unable to open her mouth and could not talk. She was admitted to the psychiatric hospital due to a rapid change in behavior and a consciousness disturbance. She was diagnosed as having schizophrenia by a psychiatrist. Her EEG showed diffuse high voltage and slow waves. Acute encephalitis was then suspected. Her past and family histories were not suggestive of viral infection. On physical examination, she had a low grade fever. She had hyperhidrosis, autophagia, and repeated oral dyskinesia. Her consciousness level fluctuated from somnolence to stupor. Although her blood CRP level was mildly elevated and she had mild pleocytosis, HSV-PCR was negative in the cerebrospinal fluid (CSF). Abdominal ultrasound examination and MRI showed no ovarian teratoma. Computed tomography (CT) and magnetic resonance imaging (MRI) showed no brain abnormalities. Before analysis for specific nervous system antibodies, the initial diagnosis was non-herpetic limbic encephalitis. She was twice treated with a 6-day course of methylprednisolone (500 mg/day) infusion. She was also given phenobarbital since she had a tonic-clonic seizure about 1 month after admission. Finally, she had a normal delivery at 37 weeks. The baby was healthy, and the patient was discharged without sequelae. We concluded that her diagnosis was anti-N-methyl-D-aspartate (NMDA) receptor (anti-NMDAR) encephalitis based on the presence of anti-NMDAR antibody in the CSF. This report is the first description of a patient with anti-NMDAR antibody encephalitis. The precise mechanism of this encephalitis is not clear, although there have been several reports of autoimmune encephalitis during pregnancy. The patient's CSF anti-NMDAR antibody titer during treatment was measured. Before treatment, the CSF anti-NMDAR antibody titer was strongly positive, but it decreased during treatment and then disappeared after delivery. We hypothesized that the presence of the embryo or placenta may have triggered an antigenic signal and/or antibody through inappropriate immunological modulation. PMID- 20196493 TI - [A case of superficial siderosis with repeated episodes of epilepsy]. AB - We report a patient with superficial siderosis that repeated episodes of epilepsy. The patient was a 62-year-old male, and underwent an operation for the tumor of the spinal cord at 22 years of age. He had become deaf at 50 years of age, and repeated loss of consciousness at 59 years of age and later. Neurological examination revealed cerebellar ataxia and bilateral sensorineural deafness in addition to paraplegia, which was caused by the spinal cord tumor. Brain MRI showed low intensity rim around the brain stem, cerebellar hemisphere, and inferior aspects of the temporal and frontal lobes, being consistent with superficial siderosis. Hemosiderin deposition for an extended period was considered to contribute to the pathogenesis of epilepsy. PMID- 20196494 TI - [A case of subacute myelitis with anti-aquaporin 4 antibody after thymectomy for myasthenia gravis: review of autoimmune diseases after thymectomy]. AB - We report the case of a 60-year-old woman with myasthenia gravis (MG) and Basedow's disease who seven years after thymectomy developed subacute myelitis, a limited form of neuromyelitis optica (NMO). The patient presented with a centrally located long spinal cord lesion (LCL) on cervical cord MRI, anti aquaporin 4 (AQP4) antibody in serum, and HLA DPB1*0501. Brain MRI showed no specific findings of classic multiple sclerosis (MS). CSF study showed elevated protein (67 mg/dl) but a normal IgG index (0.63) and no oligoclonal IgG bands. After repeated methylprednisolone pulse and immunoadsorption therapies, the T2 high signal lesion shrunk and tetraparesis improved. We reviewed the English and Japanese literature and found reports of 30 patients showing MS including NMO complicated with MG; 27 had been diagnosed as MS after thymectomy. Among these 27, 16 of 17 who were examined by spinal cord MRI and for anti-AQP4 antibodies were NMO. Only one patient with signs and symptoms localized to the optic nerves and spinal cord showed no LCL and was not examined for anti-AQP4 antibodies. In autoimmune disorders of the central nervous system after thymectomy in patients with MG, NMO is more predominant than classic MS. PMID- 20196495 TI - Will the bundle improve the way care is delivered? PMID- 20196497 TI - Back on the change, gang. What we may expect from Congress and CMS this year and the impact on nephrology. AB - In short, the lessons of this story are: Don't eat at a place called "Ma's". Don't play poker with a man named Doc. Don't go too far out on a limb making predictions in the 21st century's U.S. health policy arena. PMID- 20196496 TI - CKD dietitians can make a difference--but referrals are the missing link. AB - The best-case scenario would be to have an immediate response to the CKD Stage 1 patient who is showing signs of proteinuria (of course, it is important that the PCP makes sure these tests are done regularly). It has long been know that ace inhibitors and/or angiotensin 2 receptor blockers can reduce proteinuria. If the PCP doesn't do the urinalysis, an opportunity to intervene is lost. The renal dietitian's knowledge and dietary services would best be utilized at Stage 3 CKD. Control of protein may limit the symptoms of uremia. Restriction of phosphorus may aid in the prevention of bone disease that can develop early on in CKD. By partnering with the primary care physician, both renal dietitians, and general practice dietitians, once properly trained, can help to bring CKD under control. PMID- 20196498 TI - San Francisco's health care model offers window into reform. PMID- 20196500 TI - UNOS data shows largest drop in organ donations in 20 years. PMID- 20196499 TI - Nutritional therapy to attenuate inflammation in HD patients: fact or fiction? AB - The hemodialysis (HD) patient is often marked by constant malnutrition, inflammation, and atherosclerosis, resulting in an increased risk of cardiovascular events and mortality. This chronic inflammatory state is often the result of increased oxidative stress. Nutritional supplementation may become an additional therapy to lower this inflammatory burden. By providing these patients with nutritional supplement and antioxidant therapies consisting of alpha-lipoic acid, cholecalciferol, ascorbic acid, and Gamma-Tocopherol, providers may reduce overall inflammation and improve HD outcomes in patients with end-stage renal disease. PMID- 20196501 TI - The future's present: the artificial wearable kidney. PMID- 20196503 TI - [Structure of the emergency service in Germany]. PMID- 20196502 TI - [Body scanning at the airport. Whole body and nude scanner]. PMID- 20196504 TI - [Additions to patient advance directives]. PMID- 20196505 TI - [Education with learning objectives for promoting nursing competence in dealing with families]. PMID- 20196506 TI - [Making decisions in borderline viability--from data to the individual]. PMID- 20196507 TI - [Cannabis as medicine--an hallucinogen for healing?]. PMID- 20196508 TI - [Family centered nursing in neonatology]. PMID- 20196509 TI - [Legal security in pediatric home nursing service--an important topic]. PMID- 20196510 TI - [USA: nearly 40 % of food winds up in the garbage. New measurement method paints a picture of waste]. PMID- 20196511 TI - [Administration of nonprescription drugs is and remains a nursing care service- the Federal Social Court has supported the right of home nursing care]. PMID- 20196512 TI - [Referral of the food hypersensitive patient to the specialist. Allergy societies confirm: immunoglobulin G tests are inaccurate]. PMID- 20196513 TI - [Juvenile fibromyalgia. Taking children's pain seriously]. PMID- 20196514 TI - [Sick juveniles fall into a service gap upon maturation.German Society of Social Pediatrics and Youth Medicine requests clear and smooth flowing care transition regulations]. PMID- 20196515 TI - [Campaign against allergies: immunotherapy occupies a central position. Specialty societies publicize new guidelines for hyposensitization]. PMID- 20196516 TI - [Antibiotics in the treatment of intra-abdominal infection]. PMID- 20196518 TI - [Monitoring skill acquisition in obstetric epidural puncture at a university hospital using the cumulative sum method]. AB - BACKGROUND AND OBJECTIVE: Skill acquisition in anesthesiology is subject to a great deal of interindividual variability. Our aim was to develop and test an individualized tool for monitoring acquisition of technical skills based on the cumulative sum (CUSUM) approach. This system objectively assesses whether an individual has acquired a minimum skill level and identifies the moment when the skill has been learned. MATERIAL AND METHODS: Nine third-year residents in anesthesiology and postoperative recovery care participated. The residents anonymously recorded their first 100 obstetric epidural analgesia procedures in a database. The data were then analyzed with the CUSUM method. We considered acceptable skill acquisition to be reflected by a first-attempt success rate of 80% and a rate of success with help of 20%. RESULTS: A total of 765 epidural blocks were analyzed, giving a mean (SD) of 84.7 (2.8) procedures per resident (range, 47-100 procedures per resident). Seven residents became competent with the skill after 23 procedures and 2 residents were not successful in learning the skill. At the end of the study, 3 residents had required help with more than 20% of the procedures. Data collection from the trainees seemed to vary, leading to possible under- or overestimation of failures and/or need for help. Accidental dural puncture occurred 6 times (0.78%) and blood vessel puncture 40 times (5.2%). CONCLUSIONS: Although some third-year residents reach the targeted rate of success quickly, we believe that close supervision is useful to control progress along the learning curve for individuals who need more help. PMID- 20196517 TI - [Survey of perioperative hemostasis and transfusion management in cardiac surgery: how do anesthesiologists practice?]. AB - OBJECTIVE: To determine practices related to control of perioperative hemostasis and transfusion in patients undergoing cardiac surgery in Spain, including the extent to which protocols are being used. METHODS: A questionnaire was created to collect information from physicians in anesthesiology and postoperative recovery care between July 1 and September 20, 2007. The physicians were asked about practice in the 12 months prior to the survey. RESULTS: Thirty-four hospitals responded. Seventy percent reported that they did not have protocols or guidelines for the control of hemostasis during cardiac surgery. Forty-four percent did not have information on the proportion of patients who received transfusions; 47% gave transfusions to 75% of patients. The standard preoperative tests were platelet counts, activated partial thromboplastin time, and prothrombin time. Acetylsalicylic acid and clopidogrel were suspended before surgery at 15 (44%) and 25 (73%) hospitals, respectively. In cases of resistance to heparin, additional doses of the drug were injected, in combination with plasma or antithrombin in 29% and 12% of the hospitals, respectively. In the intensive postoperative recovery care unit, only 1 hospital used thromboelastography. Only 1 other hospital used a platelet function analyzer. CONCLUSIONS: Hemostasis, perioperative coagulation, and criteria for transfusion vary widely among the hospitals surveyed. Few guidelines are available and they are not often being followed. A high percentage of patients receive transfusions, although not all hospitals can cite a figure. New technology has not been widely applied. PMID- 20196519 TI - [Applications of noninvasive mechanical ventilation in anesthesiology and postanesthesia recovery care]. AB - Noninvasive ventilation (NIV) can be useful to anesthesiologists working in critical care units, postanesthesia recovery units, operating theaters, or other settings. NIV can help in situations of acute respiratory failure or serve as a preventive measure in patients undergoing interventions under local-regional anesthesia or diagnostic or therapeutic procedures requiring sedation. Successful NIV depends on adequately trained health personnel and the proper choice of material (interfaces, respirators, etc.) for each setting where this modality is used. PMID- 20196520 TI - [Project to update training in the specialty of anesthesiology and postoperative recovery care: from the Education and Training Section of the Sociedad Espanola de Anestesiologia y Reanimacion]. PMID- 20196521 TI - [Guidelines for the empirical antibiotic treatment of intra-abdominal infections]. PMID- 20196522 TI - [McGrath video laryngoscope used with a Frova intubating introducer for management of the difficult airway]. AB - The McGrath video laryngoscope is a new airway management device. It is similar to the Macintosh laryngoscope but incorporates a blade at a 60 degrees angle and a camera that sends an image to a color display screen connected to the handle. The device, which requires use of an anti-fog substance and an introducer to guide the angled blade, has been reported to aid in the management of difficult airways. We present 3 cases of difficult oral-tracheal intubation managed with the McGrath video laryngoscope and a Frova intubating introducer. Advantages of this introducer are that it offers the possibility of administering oxygen or changing the size of the endotracheal tube if the first choice proves inappropriate. We discuss whether or not tests to predict difficult airways are applicable when the McGrath video laryngoscope is being used, given that it is not necessary to align the axes of the 3 airways. We conclude it may be useful to combine the McGrath video laryngoscope and the Frova introducer to manage difficult airways. PMID- 20196523 TI - [Use of a laryngeal mask as an alternative for intubation in Klippel-Trenaunay Weber syndrome: a case report]. PMID- 20196524 TI - [Three serious complications related to pulmonary artery catheters in cardiovascular and thoracic surgery]. PMID- 20196525 TI - [Management of an airway leak during orthognathic surgery: a case report]. PMID- 20196526 TI - [Early endocarditis on a central venous catheter]. PMID- 20196527 TI - The relationships of personal and cultural identity to adaptive and maladaptive psychosocial functioning in emerging adults. AB - The present study examined the extent to which cultural identity would be associated with adaptive and maladaptive psychosocial functioning, both directly and indirectly through a personal identity consolidation. A sample of 773 White, Black, and Hispanic university students completed measures of cultural identity, personal identity consolidation, adaptive psychosocial functioning, internalizing symptoms, and proclivity toward externalizing symptoms. Both heritage and American cultural identity were positively related to adaptive psychosocial functioning; American-culture identity was negatively associated with internalizing symptoms; and heritage-culture identity was negatively related to proclivity toward externalizing symptoms. All of these findings were mediated by personal identity consolidation and were fully consistent across ethnic groups. We discuss implications in terms of broadening the study of identity to include both personal and cultural dimensions of self. PMID- 20196528 TI - Stressed and helping: the relations among acculturative stress, gender, and prosocial tendencies in Mexican Americans. AB - Available evidence suggests that stress is not necessarily linked to negative outcomes and, in fact, may lead to increases in sympathy and helping. In this study, we examined whether acculturative stress was associated with prosocial tendencies in a sample of 148 Mexican American college students (M age = 23.05 years; 99 women). Participants completed measures of acculturative stress, sympathy, and prosocial tendencies. The relations between acculturative stress and prosocial tendencies were generally positive but varied by the type of helping and gender. Higher levels of acculturative stress were linked to greater emotional, dire, compliant, and anonymous prosocial tendencies, as well as with fewer costly (altruistic) prosocial tendencies. Sympathy mediated the relations between acculturative stress and prosocial tendencies for men only. PMID- 20196529 TI - The effect of social and situational factors on the intended response to aggression among adolescents. AB - In this study, I explored intended response to aggression among adolescents. I drew hypotheses from social identity theory, cost/benefit considerations, and social information processing model. I asked 217 Jewish and Muslim male adolescents in this study to assess their intended use of aggression in 12 hypothetical conflict situations (vignettes), in which I manipulated the opponent's religion, gender, acquaintance, and severity of aggression. I mainly found that male adolescents respond to aggression by same-religion opponents more moderately than to cross-religion aggression; their response is more moderate to cross-gender aggression than to same-gender aggression; response is more moderate to the aggression of familiar opponents than to that of unfamiliar ones; and response is less severe toward moderate than toward severe aggression. PMID- 20196530 TI - Effects of offenders' age and health on sentencing decisions. AB - Two experiments investigated the effects of age and health on mock judges' sentencing decisions. The effects of these variables on length of prison sentence were examined in the context of offense severity and prior convictions. Experiment 1 involved a violent crime. Main effects were observed for age, health, offense severity and prior convictions. There was also an age by offense severity interaction. Experiment 2 involved a child sexual abuse case. Main effects were observed for health, offense severity, and prior convictions. In addition, an age by offense severity by prior convictions interaction effect was found. Thus, across both experiments, the age leniency effect was moderated by legal factors, suggesting that extra-legal factors affect sentencing in the context of legal factors. Further, for both offenses, offenders in poor health received shorter sentences than offenders in good health, suggesting that health deserves further research attention as an extra-legal variable. PMID- 20196531 TI - Beyond social and temporal comparisons: the role of temporal inter-group comparisons in the context of dramatic social change in Mongolia. AB - In this paper, we argue that the target of comparison should be taken into consideration when evaluating the associated outcomes of negative comparisons in the context of dramatic social change. To achieve this general goal, we considered five distinct targets of comparison: social (my group versus another group), temporal (my group across time), and temporal inter-group (my group versus another group across time). We hypothesised that in times of constant social change, two points of anchors (social and temporal) are simultaneously needed to evaluate one's position. A total of 236 high school and university students from Mongolia participated in the study. We used hierarchical regression analysis to test our hypotheses. As predicted, we found that temporal inter-group comparisons are better predictor of collective esteem than their social and temporal counterparts. Moreover, the link from past and future temporal inter group comparisons to collective esteem was negative as hypothesized. Results are discussed in terms of theoretical implications. PMID- 20196532 TI - Enantioselective organocatalytic mannich reactions with autocatalysts and their mimics. AB - The Mannich reactions previously extensively investigated with organocatalysis of l-proline and other related small molecules were reinvestigated with detailed stereochemical analysis of their autocatalysis pathways, through employment of both the products themselves and their close structural mimics as the catalysts. These organo-autocatalytic processes function as meaningful molecular models toward understanding the origin and maintenance of homochirality under biologically relevant conditions. PMID- 20196533 TI - Nature of alpha and beta particles in glycogen using molecular size distributions. AB - Glycogen is a randomly hyperbranched glucose polymer. Complex branched polymers have two structural levels: individual branches and the way these branches are linked. Liver glycogen has a third level: supramolecular clusters of beta particles which form larger clusters of alpha particles. Size distributions of native glycogen were characterized using size exclusion chromatography (SEC) to find the number and weight distributions and the size dependences of the number- and weight-average masses. These were fitted to two distinct randomly joined reference structures, constructed by random attachment of individual branches and as random aggregates of beta particles. The z-average size of the alpha particles in dimethylsulfoxide does not change significantly with high concentrations of LiBr, a solvent system that would disrupt hydrogen bonding. These data reveal that the beta particles are covalently bonded to form alpha particles through a hitherto unsuspected enzyme process, operative in the liver on particles above a certain size range. PMID- 20196534 TI - Adaptation of caddisfly larval silks to aquatic habitats by phosphorylation of h fibroin serines. AB - Aquatic caddisflies diverged from a silk-spinning ancestor shared with terrestrial moths and butterflies. Caddisfly larva spin adhesive silk underwater to construct protective shelters with adventitiously gathered materials. A repeating (SX)(n) motif conserved in the H-fibroin of several caddisfly species is densely phosphorylated. In total, more than half of the serines in caddisfly silk may be phosphorylated. Major molecular adaptations allowing underwater spinning of an ancestral dry silk appear to have been phosphorylation of serines and the accumulation of basic residues in the silk proteins. The amphoteric nature of the silk proteins could contribute to silk fiber assembly through electrostatic association of phosphorylated blocks with arginine-rich blocks. The presence of Ca(2+) in the caddisfly larval silk proteins suggest phosphorylated serines could contribute to silk fiber periodic substructure through Ca(2+) crossbridging. PMID- 20196535 TI - Synthesis and characterization of fluorinated heterofluorene-containing donor acceptor systems. AB - A series of oligothiophene-perfluoro-9-heterofluorene donor-acceptor (DA) compounds was synthesized via a combination of nucleophilic aromatic substitution (S(N)Ar(F)) and palladium coupling reactions. These compounds are of interest as possible building blocks for materials with useful electron transport properties, since they possess relatively low LUMO energy levels of -3.3 to -3.6 eV (as determined by differential pulse voltammetry). The HOMO-LUMO energy gaps, as determined by UV-vis spectroscopy, range between 2.4 and 2.5 eV, and photoluminescence emission spectra reveal lambda(ems) values in the range of 480 600 nm (corresponding to yellow-orange emission). Dilute solution-state photoluminescence quantum yields were significantly lower than those of the pure acceptor heterofluorenes (0.02-0.38 for the DA compounds vs approximately 1 for the pure acceptors), and notable solvatochromism in the fluorescence suggests emission from a charge-separated state. Theoretical calculations show that HOMO level electron density is more localized on the thiophene fragment, while the LUMO level electron density is mostly associated with the electron-deficient portion of the molecule. Photovoltaic (PV) devices based on DA/poly-3 hexylthiophene (P3HT) blends exhibit improved performance over P3HT-only devices, suggesting the ability of these DA compounds to transport electrons in the solid state. PMID- 20196536 TI - Imaging of meningioma progression by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. AB - Often considered benign, meningiomas represent 32% of intracranial tumors with three grades of malignancy defined by the World Health Organization (WHO) histology based classification. Malignant meningiomas are associated with less than 2 years median survival. The inability to predict recurrence and progression of meningiomas induces significant anxiety for patients and limits physicians in implementing prophylactic treatment approaches. This report presents an analytical approach to tissue characterization based on matrix-assisted laser desorption ionization time-of-flight (MALDI TOF) mass spectrometry imaging (MSI) which is introduced in an attempt to develop a reference database for predictive classification of brain tumors. This pilot study was designed to evaluate the potential of such an approach and to begin to address limitations of the current methodology. Five recurrent and progressive meningiomas for which surgical specimens were available from the original and progressed grades were selected and tested against nonprogressive high-grade meningiomas, high-grade gliomas, and nontumor brain specimens. The common profiling approach of data acquisition was compared to imaging and revealed significant benefits in spatially resolved acquisition for improved spectral definition. A preliminary classifier based on the support vector machine showed the ability to distinguish meningioma image spectra from the nontumor brain and from gliomas, a different type of brain tumor, and to enable class imaging of surgical tissue. Although the development of classifiers was shown to be sensitive to data preparation parameters such as recalibration and peak picking criteria, it also suggested the potential for maturing into a predictive algorithm if provided with a larger series of well defined cases. PMID- 20196537 TI - Enzyme-catalyzed transfer of a ketone group from an S-adenosylmethionine analogue: a tool for the functional analysis of methyltransferases. AB - S-adenosylmethionine (AdoMet or SAM)-dependent methyltransferases belong to a large and diverse family of group-transfer enzymes that perform vital biological functions on a host of substrates. Despite the progress in genomics, structural proteomics, and computational biology, functional annotation of methyltransferases remains a challenge. Herein, we report the synthesis and activity of a new AdoMet analogue functionalized with a ketone group. Using catechol O-methyltransferase (COMT, EC 2.1.1.6) and thiopurine S methyltransferase (TPMT, EC 2.1.1.67) as model enzymes, this robust and readily accessible analogue displays kinetic parameters that are comparable to AdoMet and exhibits multiple turnovers with enzyme. More importantly, this AdoMet surrogate displays the same substrate specificity as the natural methyl donor. Incorporation of the ketone group allows for subsequent modification via bio orthogonal labeling strategies and sensitive detection of the tagged ketone products. Hence, this AdoMet analogue expands the toolbox available to interrogate the biochemical functions of methyltransferases. PMID- 20196538 TI - The unusual electronic structure of dinitrosyl iron complexes. AB - Dinitrosyl iron complexes (DNICs) are implicated in the degradation and reassembly chemistry of iron-sulfur clusters; however, their electronic structure is not well understood. Here, experimentally validated electronic structures of a {Fe(NO)(2)}(9) species and its one-electron reduced form, {Fe(NO)(2)}(10), were reached through a detailed analysis of the Kohn-Sham density functional solutions that successfully reproduce the experimental structures and spectroscopic parameters. The {Fe(NO)(2)}(9) unit is best rationalized by a resonance hybrid consisting of a HS ferric center (S(Fe) = 5/2) antiferromagnetically coupled to two NO(-) ligands (S((NO)(2)) = 2) and a HS ferrous ion (S(Fe) = 2) coupled to an overall (4)(NO)(2)(-) ligand (S((NO)(2)) = 3/2) in an antiferromagnetic fashion. The {Fe(NO)(2)}(10) species is best interpreted as a HS ferrous center (S(Fe) = 2) that is antiferromagnetically coupled to two triplet NO(-) ligands (S((NO)(2)) = 2). A salient feature of this electronic structure description is the very covalent bonding involving the iron center and the two NO ligands. As a result, a "one-above-four" ligand field splitting pattern is identified in DNICs, in which four of the five Fe-3d orbitals are strongly pi-bonding MOs with respect to the Fe-NO interaction while the last Fe 3d-based orbital remains essentially nonbonding. The latter acts as the electron acceptor orbital for the one-electron reduction of the {Fe(NO)(2)}(9) species. This unusual ligand field splitting pattern may have mechanistic implications for the degradation and reassembly chemistry of iron-sulfur clusters involving DNICs. PMID- 20196539 TI - Origin of FM ordering in pristine micro- and nanostructured ZnO. AB - An unexpected presence of ferromagnetic (FM) ordering in nanostructured nonmagnetic metal oxides has been reported previously. Though this property was attributed to the presence of defects, systematic experimental and theoretical studies to pinpoint its origin and mechanism are lacking. While it is widely believed that oxygen vacancies are responsible for FM ordering, surprisingly we find that annealing as-prepared samples at low temperature (high temperature) in flowing oxygen actually enhances (diminishes) the FM ordering. For these reasons, we have prepared, annealed in different environments, and measured the ensuing magnetization in micrometer and nanoscale ZnO with varying crystallinity. We further find from our magnetization measurements and ab initio calculations that a range of magnetic properties in ZnO can result, depending on the sample preparation and annealing conditions. For example, within the same ZnO sample we have observed ferro- to para- and diamagnetic responses depending on the annealing conditions. We also explored the effects of surface states on the magnetic behavior of nanoscale ZnO through detailed calculations. PMID- 20196540 TI - Measuring ensemble-averaged surface-enhanced Raman scattering in the hotspots of colloidal nanoparticle dimers and trimers. AB - We report ensemble-averaged measurements of colloidal hotspots enabled by the synthesis of highly uniform dimers and trimers of Au@Ag nanoparticles and the quantification of the relative concentrations of the nanoclusters. PMID- 20196541 TI - Phosphinidene complexes of scandium: powerful PAr group-transfer vehicles to organic and inorganic substrates. AB - The first phosphinidene complexes of scandium are reported in this contribution. When complex (PNP)Sc(CH(3))Br (1) is treated with 1 equiv of LiPH[Trip] (Trip = 2,4,6-(i)Pr(3)C(6)H(2)), the dinuclear scandium phosphinidene complex [(PNP)Sc(mu(2)-P[Trip])](2) (2) is obtained. However, treating 1 with a bulkier primary phosphide produces the mononuclear scandium ate complex [(PNP)Sc(mu(2) P[DMP])(mu(2)-Br)Li] (3) (DMP = 2,6-Mes(2)C(6)H(3)). The Li cation in 3 can be partially encapsulated with DME to furnish a phosphinidene salt derivative, (PNP)Sc(mu(2)-P[DMP])(mu(2)-Br)Li(DME)] (4). We also demonstrate that complex 3 can readily deliver the phosphinidene ligand to organic substrates such as OCPh(2) and Cl(2)PMes* as well as inorganic fragments such as Cp(2)ZrCl(2), Cp*(2)TiCl(2), and Cp(2)TiCl(2) in the presence of P(CH(3))(3). Complexes 2-4 have been fully characterized, including single crystal X-ray diffraction and DFT studies. PMID- 20196543 TI - Oligooxopiperazines as nonpeptidic alpha-helix mimetics. AB - A new class of nonpeptidic alpha-helix mimetics derived from alpha-amino acids and featuring chiral backbones is described. NMR and circular dichroism spectroscopies, in combination with molecular modeling studies, provide compelling evidence that oligooxopiperazine dimers adopt stable conformations that reproduce the arrangement of i, i+4, and i+7 residues on an alpha-helix. PMID- 20196542 TI - Physical evidence for substrate binding in preventing cyclooxygenase inactivation under nitrative stress. AB - Prostaglandin biosynthesis is catalyzed by two spatially and functionally distinct active sites in cyclooxygenase (COX) enzymes. Despite the crucial role of COXs in biology, molecular details regarding the function and regulation of these enzymes are incompletely defined. Reactive nitrogen species, formed during oxidative stress, produce modifications that alter COX functionalities and prostaglandin biosynthesis. We previously established that COX-1 undergoes selective nitration on Tyr385 via a mechanism that requires the presence of bound heme cofactor. As this is a critical residue for COX-1 catalysis, nitration at this site results in enzyme inactivation. We now show that occupancy of the COX-1 active site with substrate protects against Tyr385 nitration and redirects nitration to alternative Tyr residues on COX-1, preserving catalytic activity. This study reveals a novel role for the substrate in protecting COX-1 from inactivation by nitration in pathophysiological settings. PMID- 20196544 TI - Addition of metal enolate derivatives to unactivated carbon-carbon multiple bonds. PMID- 20196545 TI - Cobalt catalysis at the crossroads: cobalt-catalyzed Alder-ene reaction versus [2 + 2] cycloaddition. AB - The application of bidentate phosphine ligands in cobalt-catalyzed transformations of cyclic alkenes such as cyclopentene and cycloheptene with internal alkynes led to a chemoselective Alder-ene or a [2 + 2] cycloaddition reaction depending on the electronic nature of the alkyne and the bite angle of the ligand used. PMID- 20196546 TI - Controlled and efficient hybridization achieved with DNA probes immobilized solely through preferential DNA-substrate interactions. AB - Quantitative and reproducible data can be obtained from surface-based DNA sensors if variations in the conformation and surface density of immobilized single stranded DNA capture probes are minimized. Both the conformation and surface density can be independently and deterministically controlled by taking advantage of the preferential adsorption of adenine nucleotides (dA) on gold, as previously demonstrated using a model system in Opdahl, A.; Petrovykh, D. Y.; Kimura-Suda, H.; Tarlov, M. J.; Whitman, L. J. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 9-14. Here, we describe the immobilization and subsequent hybridization properties of a 15-nucleotide DNA probe sequence that has additional m adenine nucleotides, (dA)(m), at the 5' end. Quantitative analysis of immobilization and hybridization for these probes indicates that the (dA)(m) block preferentially adsorbs on gold, forcing the probe portion of the strand to adopt an upright conformation suited for efficient hybridization. In addition, a wide range of probe-to-probe lateral spacing can be achieved by coimmobilizing the probe DNA with a lateral spacer, a strand of k adenine nucleotides, (dA)(k). Altering either the length or relative concentration of the (dA)(k) spacers added during probe immobilization controls the average surface density of probes; the density of probes, in turn, systematically modulates their hybridization with solution targets. PMID- 20196547 TI - A concise, phosphate-mediated approach to the total synthesis of (-) tetrahydrolipstatin. AB - An efficient synthesis of (-)-tetrahydrolipstatin (THL) is reported. This method takes advantage of a phosphate tether-mediated, one-pot, sequential RCM/CM/hydrogenation protocol to deliver THL in eight total steps from a readily prepared (S,S)-triene. The strategy incorporates selective cross-metathesis, regioselective hydrogenation, regio- and diastereoselective cuprate addition, and Mitsunobu inversion for installation of the C5 formamide ester subunit. PMID- 20196548 TI - Density functional theory investigations of the homoleptic tris(dithiolene) complexes [M(dddt)(3)](-q) (q = 3, 2 ; M = Nd(3+) and U(3+/4+)) related to lanthanide(III)/actinide(III) differentiation. AB - The structures of the homoleptic lanthanide and actinide tris(dithiolene) complexes [M(dddt)(3)](q-) (q = 3, M = Nd(3+) and q = 3 or 2, M = U(3+/4+)) have been investigated using relativistic Density Functional Theory (DFT) computations including spin-orbit corrections coupled with the COnductor-like Screening Model (COSMO) for a realistic solvation approach. The dithiolene ligands are known to be very efficient at stabilizing metal high oxidation states. The aim of the work is to explain the peculiar symmetric folding of the three Mdddt metallacycles in these complexes, some of them existing under a polymeric form, in relation with the Ln(III)/An(III) differentiation. In the [M(dddt)(3)(py)](q-) species, where an additional pyridine ligand is linked to the metal center, the Mdddt moieties appear to be almost planar. The study brings to light the occurrence of a M...C=C interaction explaining the Mdddt folding of the [U(dddt)(3)](q-) uranium species, the metal 5f electrons playing a driving role. No such interaction appears in the case of the Nd(III) complex, and the folding of the rather flexible dddt ligands in the polymeric structure of this species should be mainly due to steric effects. Moreover, the analysis of the normal modes of vibration shows that the U(III) complex [U(dddt)(3)](3-), which has not yet been isolated, is thermodynamically stable. It appears that the X-ray characterized U(IV) complex [U(dddt)(3)](2-) should be less stable than the calculated U(III) complex in a polar solvent. PMID- 20196549 TI - Metal dilution effects on entropy and light-induced valence tautomeric interconversion in a 1:1 cobalt-dioxolene complex. AB - The entropy and the light-induced valence tautomeric interconversions of solid solutions of the [Co(Me(2)tpa)(diox)](PF(6)).C(6)H(5)CH(3) complex [Me(2)tpa = bis(6-methyl-(2-pyridylmethyl))(2-pyridylmethyl)amine and diox = catecholato (DBCat) or semiquinonato (DBSQ) forms of 3,5-ditert-butylquinone] in the electronically innocent [Zn(Me(2)tpa)(DBSQ)](PF(6)).C(6)H(5)CH(3) host, in four different molar ratios, have been investigated. It has been found that the entropy driven transition is strongly affected by the Co:Zn molar ratio, whereas the relaxation rates of the optically induced high-spin Co(II)-DBSQ metastable state at cryogenic temperatures are nearly independent of the degree of solid dilution. These results are discussed in the framework of the Jortner theory for adiabatic radiationless multiphonon relaxation processes. It is suggested that the optical bistability in these systems is related to the single molecule properties rather than to the cooperative effects active in the lattice. PMID- 20196550 TI - Measurement of active dopant distribution and diffusion in individual silicon nanowires. AB - We have measured the radial distribution and diffusion of active dopant atoms in individual silicon nanowires grown by the vapor-liquid-solid (VLS) method. Our method is based on successive surface etching of a portion of a contacted nanowire, followed by measurement of the potential difference between the etched and unetched areas using Kelvin probe force microscopy (KPFM). The radial dopant distribution is obtained by fitting the measured potentials with a three dimensional solution of Poisson equation. We find that the radial active dopant distribution decreases by almost 2 orders of magnitude from the wire surface to its core even when there is no indication for tapering. In addition, the dopant profile is consistent with a very large diffusion coefficient of D approximately 1 x 10(-19) m(2) s(-1). This implies that phosphorus (P) diffusion during the VLS growth is remarkably high and subsequent thermal annealing must be used when a homogeneous dopant distribution is required. PMID- 20196551 TI - Mechanistic insight on the hydrogenation of conjugated alkenes with h(2) catalyzed by early main-group metal catalysts. AB - Density functional theory calculations have been performed to investigate the molecular mechanism of the hydrogenation reactions of 1,1-diphenylethylene and myrcene catalyzed by the actual calcium hydride catalyst, CaH(dipp-nacnac)(thf) (dipp-nacnac = CH{(CMe)(2,6-iPr(2)-C(6)H(3)N)}(2)). The hydrogenation reactions of these two alkenes proceed via a similar pathway, which includes three steps. First, the hydride migrates from the calcium center to one olefinic carbon in the substrate. Then, the hydride transfer product can easily transform into a key ion pair intermediate. This intermediate provides an intramolecular frustrated Lewis pair, in which the calcium center acts as a Lewis acid, and one olefinic carbon acts as a Lewis base. Next, the H-H bond is heterolytically cleaved by this frustrated Lewis pair through a concerted Lewis acid-Lewis base mechanism, producing the hydrogenation product and regenerating the catalyst. For these two reactions, the rate-limiting step is the hydride transfer step, with free energy barriers of 29.2 kcal for both substrates. In addition, our calculations indicate that the hydrogenation reaction of 1,1-diphenylethylene catalyzed by the analogous strontium hydride complex may readily occur, but the similar magnesium mediated hydrogenation reaction is less likely to take place under similar conditions as adopted by the calcium hydride catalyst. The results can give satisfactory descriptions of experimental facts observed for these two hydrogenation reactions. The hydrogenation mechanism proposed here is different from that of the late transition metal-catalyzed alkene hydrogenation or the organolanthanide-catalyzed alkene hydrogenation. PMID- 20196552 TI - Probing a century old prediction one plasmonic particle at a time. AB - In 1908, Gustav Mie solved Maxwell's equations to account for the absorption and scattering of spherical plasmonic particles. Since then much attention has been devoted to the size dependent optical properties of metallic nanoparticles. However, ensemble measurements of colloidal solutions generally only yield the total extinction cross sections of the nanoparticles. Here, we show how Mie's prediction on the size dependence of the surface absorption and scattering can be probed separately for the same gold nanoparticle by using two single particle spectroscopy techniques, (1) dark-field scattering and (2) photothermal imaging, which selectively only measure scattering and absorption, respectively. Combining the optical measurements with correlated scanning electron microscopy furthermore allowed us to measure the size of the spherical gold nanoparticles, which ranged from 43 to 274 nm in diameter. We found that even though the trend predicted by Mie theory is followed well by the experimental data over a large range of nanoparticle diameters, for small size variations changes in scattering and absorption intensities are dominated by factors other than those considered by Mie theory. In particular, spectral shifts of the plasmon resonance due to deviations from a spherical particle shape alone cannot explain the observed variation in absorption and scattering intensities. PMID- 20196553 TI - Copper-mediated N-heteroarylation of primary sulfonamides: synthesis of mono-N heteroaryl sulfonamides. AB - We describe the coupling of primary sulfonamides and various halogenated heterocyclic cores, with an emphasis on 2-heteroaryl halides, via copper catalysis. These studies enabled the synthesis of many new mono-N-heteroaryl sulfonamides. The electronic factors that influence the course of the reaction have also been investigated. PMID- 20196554 TI - Update 1 of: Over one hundred peptide-activated G protein-coupled receptors recognize ligands with turn structure. PMID- 20196555 TI - Virtual screening discovery of new acetylcholinesterase inhibitors issued from CERMN chemical library. AB - In our quest to find new inhibitors able to inhibit acetylcholinesterase (AChE) and, at the same time, to protect neurons from beta amyloid toxicity, i.e., inhibitors interacting with the catalytic anionic subsite as well as with the peripherical anionic site of AChE, a virtual screening of the Centre d'Etudes et de Recherche sur le Medicament de Normandie (CERMN) chemical library was carried out. Two complementary approaches were applied, i.e., a ligand- and a structure based screening. Each screening led to the selection of different compounds, but only two were present in both screening results. In vitro tests on AChE showed that one of those compounds presented a very good inhibition activity, of the same order as Donepezil. This result shows the real complementary of both methods for the discovery of new ligands. PMID- 20196557 TI - Locked nucleosides based on oxabicyclo[3.2.1]octane and oxabicyclo[2.2.1]heptane skeletons. AB - Intramolecular nitrone cycloaddition (INC) reaction on a d-glucose derived substrate carrying an allyl group at C-1 and an enose-nitrone at C-5 or an aldehyde-nitrone at C-1 and vinyl group at C-4 furnished a tricyclo[6.2.1.0(2,6)]undecane or a tricyclo[5.2.1.0(2,6)]decane ring structure. These tricycles were converted to bicylic nucleosides with oxabicyclo[3.2.1]octane and oxabicyclo[2.2.1]heptane rings in three steps. An oxabicyclo[3.2.1]octane ring compound could alternatively be formed by RCM reaction between C-1-allyl and C-4-vinyl moieties and transformed to nucleoside analogues through a nucleophilic substitution reaction. Participation of a neighboring benzyl ether substituent in one case paved the way for an enantiodivergent synthesis. PMID- 20196558 TI - Potential impact of ZT = 4 thermoelectric materials on solar thermal energy conversion technologies. AB - State-of-the-art methodologies for the conversion of solar thermal power to electricity are based on conventional electromagnetic induction techniques. If appropriate ZT = 4 thermoelectric materials were available, it is likely that conversion efficiencies of 30-40% could be achieved. The availability of all solid state electricity generation would be a long awaited development in part because of the elimination of moving parts. This paper presents a preliminary examination of the potential performance of ZT = 4 power generators in comparison with Stirling engines taking into account specific mass, volume and cost as well as system reliability. High-performance thermoelectrics appear to have distinct advantages over magnetic induction technologies. PMID- 20196559 TI - Receptor- and ligand-based study on novel 2,2'-bithienyl derivatives as non peptidic AANAT inhibitors. AB - Arylalkylamine N-acetyl transferase (serotonin N-acetyl transferase, AANAT) is a critical enzyme in the light-mediated regulation of melatonin production and circadian rythm. With the objective of discovering new chemical entities with inhibitory potencies against AANAT, a medium-throughput screening campaign was performed on a chemolibrary. We found a class of molecules based on a 2,2' bithienyl scaffold, and compound 1 emerged as a first hit. Herein, we describe our progress from hit discovery and to optimization of this new class of compounds. To complete the study, computational approaches were carried out: a docking study which provided insights into the plausible binding modes of these new AANAT inhibitors and a three-dimensional quantitative structure-activity relationship study that applied comparative molecular field analysis (CoMFA) methodology. Several CoMFA models were developed (variable alignments and options), and the best predictive one yields good statistical results (q(2) = 0.744, r(2) = 0.891, and s = 0.273). The resulting CoMFA contour maps were used to illustrate the pharmacomodulations relevant to the biological activities in this series of analogs and to design new active inhibitors. This novel series of 2,2'-bithienyl derivatives gives new insights into the design of AANAT inhibitors. PMID- 20196560 TI - Modeling the crossover between chemically and diffusion-controlled irreversible aggregation in a small-functionality gel-forming system. AB - The analysis of realistic numerical simulations of a gel-forming irreversible aggregation process provides information on the role of cluster diffusion in controlling the late stages of the aggregation kinetics. Interestingly, the crossover from chemically controlled to diffusion-controlled aggregation takes place well beyond percolation, after most of the particles have aggregated in the spanning network and only small clusters remain in the sol. The simulation data are scrutinized to gain insight into the origin of this crossover. We show that a single additional time scale (related to the average diffusion time) is sufficient to provide an accurate description of the evolution of the extent of reaction at all times. PMID- 20196561 TI - Surface-enhanced Raman scattering-based label-free microarray readout for the detection of microorganisms. AB - We report the development of a new technique for label-free microarray readout based on surface-enhanced Raman scattering (SERS). In doing so, an investigation on optimized SERS substrates for the application to in situ microorganism analysis by Raman microscopy was carried out. Chemically synthesized nanoparticles were successfully applied to an immunoassay for label-free detection of single microorganisms. In this way, species specific, reproducible, and strong SERS spectra were collected from different bacteria immobilized on a chip. Furthermore, quantitative analysis of the microorganisms was performed using Raman mapping. Unlike conventional SERS detection of bacteria, which requires dehydration prior to analysis, our system enables us to detect and quantify microorganisms in an aqueous environment in situ. Hence, the nondestructive analysis of living bacteria cells is possible. Moreover, the "whole-organism fingerprint" SERS spectra can be adopted for further chemical characterization of microorganisms. PMID- 20196562 TI - Atomic force microscope-related study membrane-associated cytotoxicity in human pterygium fibroblasts induced by mitomycin C. AB - Mitomycin C (MMC) has been shown to have a therapeutic effect against human pterygium fibroblasts (HPFs) by inducing apoptosis. However, there is little data about the effect of it on plasma membrane. In the present study, the cytotoxicity of MMC to HPFs including inhibiting cell growth, inducing apoptosis and bringing about membrane toxicity was investigated. It was found that MMC could significantly suppress the proliferation of HPFs in a dose-dependent manner by CCK-8 assay. Flow cytometric analysis also revealed that treatment with MMC resulted in increased percentages of apoptotic cells in a dose-dependent manner. Membrane lipid peroxidation level, lactate dehydrogenase (LDH) leakage, membrane surface topography, and membrane rigidity alterations were investigated to assess the membrane toxicity induced by MMC. Treatment with MMC at different concentrations accelerated membrane lipid peroxidation and potentiated LDH leakage, which was consistent with disturbance of membrane surface and decrease of membrane elasticity detected by atomic force microscopy. All the above changes led to the disturbed intracellular Ca(2+) homeostasis, which was an important signal triggering apoptosis. Hence, the membrane toxicity induced by MMC might play an important role in the process of apoptotic induction and the calcium channel may be one of the apoptosis mechanisms. PMID- 20196563 TI - Gold(I)-catalyzed tandem cyclization approach to tetracyclic indolines. AB - Two highly stereoselective cationic gold(I)-catalyzed tandem cyclization reactions of alkynylindoles are described. These reactions demonstrated a novel and general strategy to rapidly construct highly functionalized polycyclic indolines. This approach was successfully employed for a formal synthesis of the akuammiline alkaloid minfiensine. PMID- 20196564 TI - Highly sensitive water-soluble fluorescent ph sensors based on the 7-amino-1 methylquinolinium chromophore. AB - Highly sensitive water-soluble fluorescent pH sensors have been synthesized employing the 7-amino-1-methylquinolinium (7AMQ) chromophore. These compounds, which contained oligomethylene spacers and substituted amine receptor units, were prepared in high yields and purity by a single reaction from the readily available 7-fluoro-1-methylquinolinium iodide. Density functional theory (DFT) and semiempirical INDO/s calculations have been performed to describe the ground state and the locally excited state of the chromophore. The photophysics and the sensor characteristics have been investigated. Dissociation constants pK(A)* ranging from 5.8 to 9.9 have been obtained. An additional quenching process at pH 11, due to excited state deprotonation at N7, has been observed. Fluorescence quantum yields in the protonated "on-state" between 0.75 and 0.85 and fluorescence enhancements (FE) between 2 and 55 were determined. These values are significantly higher than those of molecules based on other CT-chromophores that contain identical spacer-receptor units. The high fluorescence enhancements may be explained by the low rate of fluorescence ( approximately 6 x 10(7) s(-1)) and the high excited state reduction potential ( approximately 1.6 eV) of the 7AMQ chromophore. PMID- 20196565 TI - Effect of cefazolin treatment on the nonresonant Raman signatures of the metabolic state of individual Escherichia coli cells. AB - Laser tweezers Raman spectroscopy (LTRS) was used to characterize the Raman fingerprints of the metabolic states of Escherichia coli (E. coli) cells and to determine the spectral changes associated with cellular response to the antibiotic Cefazolin. The Raman spectra of E. coli cells sampled at different time points in the bacterial growth curve exhibited several spectral features that enabled direct identification of the growth phase of the bacteria. Four groups of Raman peaks were identified based on similarities in the time-dependent behavior of their intensities over the course of the growth curve. These groupings were also consistent with the different biochemical species represented by the Raman peaks. Raman peaks associated with DNA and RNA displayed a decrease in intensity over time, while protein-specific Raman vibrations increased at different rates. The adenine ring-breathing mode at 729 and the 1245 cm(-1) vibration peaked in intensity within the first 10 h and decreased afterward. Application of principal component analysis (PCA) to the Raman spectra enabled accurate identification of the different metabolic states of the bacterial cells. The Raman spectra of cells exposed to Cefazolin at the end of log phase exhibited a different behavior. The 729 and 1245 cm(-1) Raman peaks showed a slight decrease in intensity from 4 to 10 h after inoculation. Moreover, a shift in the spectral position of the adenine ring-breathing mode from 724 to 729 cm(-1), which was observed during normal bacterial growth, was inhibited during antibiotic drug treatment. These results suggest that potential Raman markers exist that can be used to identify E. coli cell response to antibiotic drug treatment. PMID- 20196566 TI - Parallel solution phase synthesis of 3,6,7-4(3H)-quinazolinones and evaluation of their antitumor activities against human cancer. AB - Three diversity points of 4(3H)-quinazolinone are introduced at the 3-, 6-, and 7 positions with an efficient parallel solution-phase synthetic method. A one-pot synthesis was developed that gave the key intermediate in high yield. Five hit compounds exhibit preferable activities against a panel of human tumor cell lines, which pointed out preliminary structure-activity relationships. PMID- 20196567 TI - Plasma induced oxidative cleavage of disulfide bonds in polypeptides during nanoelectrospray ionization. AB - Cleavage of the disulfide bond within a polypeptide was observed when the nanoelectrospray (nanoESI) plume of a peptide solution interacted with a low temperature helium plasma in air. Online mass spectrometric analysis revealed that chain separation accompanied by a mass increase of 1 or 16 Da for each chain was common to peptides having an interchain disulfide bond, while for peptides having intrachain disulfide bonds, the reaction products typically showed mass increases of 17 Da. Experimental results suggested that hydroxyl radicals initiated from the plasma were likely to be responsible via dissociative addition to the disulfide bond (RSSR'), giving rise to RSH and R'SO*. When the hydroxyl radical addition product ions ([M + nH + OH](n*+), n is the charge state) generated from peptides having intrachain peptides were subjected to collision induced dissociation (CID) in an ion trap, a-, b-, and y-type sequence ions within the cyclic structure defined by the disulfide bond were observed in addition to the exocyclic cleavages typically seen from CID of [M + nH](n+) peptide ions. Rich structural information could thus be obtained. These findings were demonstrated in 14 peptides containing disulfide bonds and further by bovine insulin, which has three disulfide bonds. Collisional activation of the [M + 5H + OH](5*+) insulin ions provided 76% of the possible backbone cleavages as compared to 26% acquired from CID of the [M + 5H](5+) ions. PMID- 20196568 TI - Sacrificial template method for fabrication of submicrometer-sized YPO(4):Eu(3+) hierarchical hollow spheres. AB - Large-scale good-quality submicrometer-sized YPO(4):Eu(3+) hollow spheres were synthesized by utilizing the colloidal spheres of Y(OH)CO(3):Eu(3+) as a sacrificial template and NH(4)H(2)PO(4) as a phosphorus source, for the first time. The whole process mainly consists of the hydrothermal reaction and acid erosion. The YPO(4):Eu(3+)@Y(OH)CO(3):Eu(3+) core-shell structures were first obtained after the hydrothermal process. Then, the remaining Y(OH)CO(3):Eu(3+) was removed by selective dissolution in a dilute nitric acid solution. The YPO(4):Eu(3+) hollow spheres were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and photoluminescence (PL). The formation mechanism was also investigated. The obtained YPO(4):Eu(3+) hollow spheres may have potential applications in cell biology, drug release, and diagnosis, due to high chemical stability and luminescence functionality. PMID- 20196569 TI - Nucleation of antiferromagnetically coupled chromium dihalides: from small clusters to the solid state. AB - The nucleation of chromium dihalide clusters is investigated by studying clusters of the form Cr(n)X(2n) (n 2000 head) using best management practices for land application of animal wastes, on estrogenic activity (E Screen), estrogens, and nutrients of associated surface waters and tile drain runoff were evaluated. Farm tile drain and creek samples were collected from the drainage region: above and below a municipal wastewater treatment plant located upstream from the dairy; and downstream from animal housing, parlor, and fields receiving applied wastes. Fifty-four thousand tons of waste (from approximately 1000 milking head) were applied to approximately 809 ha from April to July. Maximum estradiol equivalents (E(2)Eqs) present in tile drain samples (17alpha-E(2) > 17beta-E(2). Creek nutrient concentrations were similar above and below the dairy, with higher concentrations found in tile drain samples: tile ammonia ranged from <0.05 to 0.70 mg/L, nitrate/ite from 1.2 to 14 mg/L, and total phosphorus from 0.04 to 0.34 mg/L. No differences in estrogenic activity or nitrate/ite, ammonia, and phosphorus concentrations were detected in surface waters downstream of a large confinement dairy facility and measured nutrients were within regional norms. PMID- 20196589 TI - PBDEs in 2-5 year-old children from California and associations with diet and indoor environment. AB - This study determined the body burden of PBDEs in 100 California children, and evaluated associations with sociodemographic, household, and dietary factors. In national and international comparisons, California dust, breast milk, and human serum samples contain higher concentrations of PBDEs. Higher levels in children suggest exposure pathways depend upon age. Plasma samples were analyzed for PBDEs using GC/MS. Circulating levels of PBDEs were 10-to 1000-fold higher than similar aged populations in Mexico and Europe, 5-times higher than similar aged children across the U.S., and 2- to 10-fold higher than U.S. adults. Increased levels of higher-brominated congeners were associated with the recent purchase of new upholstered furniture or mattresses and consumption of pork. Concentrations of lower-brominated congeners increased with frequency of poultry consumption. Lower maternal education was independently and significantly associated with higher levels of most congeners in the children. PMID- 20196591 TI - Cryopreserved hepatocytes from rainbow trout (Oncorhynchus mykiss): a validation study to support their application in bioaccumulation assessment. AB - Determination of biotransformation rates of xenobiotics in freshly isolated trout hepatocytes has been demonstrated to significantly improve the performance of bioaccumulation assessment models. In order to promote this in vitro approach, trout hepatocytes need to be cryopreserved to facilitate their availability while ensuring their metabolic competency. In the present study, we obtained basal level metabolic enzyme activities for cytochrome P450 (CYP) 1A, CYP3A, glutathione-S-transferase, and uridine 5'-diphospho-glucuronosyltransferase from trout hepatocytes cryopreserved for various periods of time up to three months and compared their values with those obtained from freshly isolated hepatocytes. Similarly, we compared intrinsic clearance (CL(int)) values determined in cryopreserved trout hepatocytes to those determined in freshly isolated hepatocytes for reference compounds molinate, michler's ketone, 4-nonylphenol, 2,4-ditert-butylphenol, benzo(a)pyrene, and pyrene. Our results show that cryopreserved trout hepatocytes maintained greater than 75% of their basal level enzyme activities and greater than 72% of xenobiotic biotransformation capabilities, regardless of the length of cryostorage. As a result, bioconcentration factors of the reference compounds were adequately predicted based on the CL(int) values. We simulated the condition for shipping cryopreserved trout hepatocytes and demonstrated that 24 h dry ice storage did not negatively affect the rates of xenobiotic biotransformation. We conclude that cryopreserved trout hepatocytes are suitable for biotransformation rate determination of xenobiotics in vitro, and therefore, are an acceptable alternative to freshly isolated trout hepatocytes in the application in bioaccumulation assessment. PMID- 20196592 TI - Fluorescent indicator displacement assay for ligand-RNA interactions. AB - Since the discovery of the RNA functions modulating gene expression, functional RNA has become an attractive drug target. Ligand-RNA interactions have been studied by covalent labeling of either the ligand or RNA with fluorescent dyes or immobilization on the sensing devices. However, it is desirable to investigate the interactions without any chemical modifications in order to keep the native secondary and tertiary structures. Displacement assays satisfy this criterion because neither covalent labeling nor immobilization is necessary for the assay. We here report a fluorescent indicator displacement assay for the investigation of a ligand-RNA interaction that exploits a novel fluorescent indicator, a 2,7 disubstituted 9H-xanthen-9-one derivative. The assay was found to be applicable for screening new ligands binding to RRE RNA from chemical library. PMID- 20196593 TI - Formation of an end-on ferric peroxo intermediate upon one-electron reduction of a ferric superoxo heme. AB - The low-spin end-on ferric peroxo heme intermediate has been proposed as an alternative reactive intermediate involved in the catalytic cycles of enzymes such as nitric oxide synthase and cytochrome P450. This transient heme intermediate has never been captured using synthetic heme models. We demonstrate herein our success in the solution preparation of such an end-on ferric peroxo intermediate derived from a heme model, which features both a group hanging over the porphyrin macrocycle and a covalently appended axial imidazole ligand, through one-electron reduction of its ferric superoxo precursor. The obtained ferric peroxo intermediate was further transformed into the corresponding ferric hydroperoxo species upon protonation. This heme model compound provides a convenient system for sequential preparation of the important and biologically relevant superoxo/peroxo/hydroperoxo heme intermediates through an oxygenation/one-electron reduction/protonation process similar to the mechanisms used by enzyme systems. PMID- 20196596 TI - Palladium-catalyzed benzylic addition of 2-methyl azaarenes to N-sulfonyl aldimines via C-H bond activation. AB - An efficient protocol for the generation of amines by palladium-catalyzed nucleophilic benzylic addition of 2-methyl-substituted azaarenes to N-sulfonyl aldimines under neutral conditions via C-H bond activation has been developed. This reaction represents a very efficient methodology for the synthesis of heterocycle-containing amines and thus opens a new way to access amines through C H bond activation. PMID- 20196595 TI - Mechanism of C-F reductive elimination from palladium(IV) fluorides. AB - The first systematic mechanism study of C-F reductive elimination from a transition metal complex is described. C-F bond formation from three different Pd(IV) fluoride complexes was mechanistically evaluated. The experimental data suggest that reductive elimination occurs from cationic Pd(IV) fluoride complexes via a dissociative mechanism. The ancillary pyridyl-sulfonamide ligand plays a crucial role for C-F reductive elimination, likely due to a kappa(3) coordination mode, in which an oxygen atom of the sulfonyl group coordinates to Pd. The pyridyl-sulfonamide can support Pd(IV) and has the appropriate geometry and electronic structure to induce reductive elimination. PMID- 20196597 TI - [2]Catenanes decorated with porphyrin and [60]fullerene groups: design, convergent synthesis, and photoinduced processes. AB - A new class of [2]catenanes containing zinc(II)-porphyrin (ZnP) and/or [60]fullerene (C(60)) as appended groups has been prepared. A complete description of the convergent synthetic approach based on Cu(I) template methodology and "click" 1,3-dipolar cycloaddition chemistry is described. This new electron donor-acceptor catenane family has been subjected to extensive spectroscopic, computational, electrochemical and photophysical studies. (1)H NMR spectroscopy and computational analysis have revealed that the ZnP-C(60) [2]catenane adopts an extended conformation with the chromophores as far as possible from each other. A detailed photophysical investigation has revealed that upon irradiation the ZnP singlet excited state initially transfers energy to the (phenanthroline)(2)-Cu(I) complex core, producing a metal-to-ligand charge transfer (MLCT) excited state, which in turn transfers an electron to the C(60) group, generating the ZnP-[Cu(phen)(2)](2+)-C(60)(*-) charge-separated state. A further charge shift from the [Cu(phen)(2)](2+) complex to the ZnP subunit, competitive with decay to the ground state, leads to the isoenergetic long distance ZnP(*+)-[Cu(phen)(2)](+)-C(60)(*-) charge-separated radical pair state, which slowly decays back to the ground state on the microsecond time scale. The slow rate of back-electron transfer indicates that in this interlocked system, as in previously studied covalently linked ZnP-C(60) hybrid materials, this process occurs in the Marcus-inverted region. PMID- 20196599 TI - QM/MM MD simulations of iodide ion (I(-)) in aqueous solution: a delicate balance between ion-water and water-water H-bond interactions. AB - The characteristics of an iodide ion (I(-)) in aqueous solution were investigated by means of HF/MM and B3LYP/MM molecular dynamics simulations, in which the ion and its surrounding water molecules were treated at HF and B3LYP levels using the LANL2DZdp and D95 V+ basis sets for I(-) and water, respectively. According to both the HF/MM and B3LYP/MM results, the ion-water interactions are relatively weak, compared to the water-water hydrogen bonds, thus causing an unstructured nature of the hydration shell. Comparing the HF and B3LYP treatments for the description of this hydrated ion, the overestimation of the ion-water hydrogen bond strength by the B3LYP method is recognizable, yielding a remarkably more compact and too rigid ion-water complex. PMID- 20196598 TI - Beta-peptide bundles with fluorous cores. AB - We reported recently that certain beta-peptides self-assemble spontaneously into cooperatively folded bundles whose kinetic and thermodynamic metrics mirror those of natural helix bundle proteins. The structures of four such beta-peptide bundles are known in atomic detail. These structures reveal a solvent sequestered, hydrophobic core stabilized by a unique arrangement of leucine side chains and backbone methylene groups. Here we report that this hydrophobic core can be re-engineered to contain a fluorous subdomain while maintaining the characteristic beta-peptide bundle fold. Like alpha-helical bundles possessing fluorous cores, fluorous beta-peptide bundles are stabilized relative to hydrocarbon analogues and undergo cold denaturation. Beta-peptide bundles with fluorous cores represent the essential first step in the synthesis of orthogonal protein assemblies that can sequester selectively in an interstitial membrane environment. PMID- 20196600 TI - Semipurified fractions from the submerged-culture broth of Agaricus blazei Murill reduce blood glucose levels in streptozotocin-induced diabetic rats. AB - Hypoglycemic action of semipurified fractions from hot-water extracts of the submerged-culture broth of Agaricus blazei Murill was examined in streptozotocin (60 mg/kg, intraperitoneal)-induced diabetic male Sprague-Dawley rats, relative to the diabetes drug metformin. The hot-water extract, treated with ethanol to remove beta-glucans and glycoproteins, was freeze-dried, and fractionated into hexane, chloroform, ethyl acetate (EA), and butanol fractions. The EA fraction (EAF; 200 mg/kg body weight) reduced (p < 0.05) the blood glucose level in the oral glucose tolerance test, relative to the other fractions and control. In a 14 day-treatment study, diabetic rats treated with the EAF displayed a suppressed blood glucose level and elevated plasma insulin and glucose transport-4 proteins; the reactions occurred in a dose-dependent manner (200 and 400 mg/kg body weight) compared to those in control animals. The EAF reduced the levels of triglyceride and cholesterol in plasma, the activity of glutamate-oxaloacetate transaminase and glutamate-pyruvate transaminase in blood, and the content of thiobarbituric acid reactive substance in the liver and kidney. The hypoglycemic efficacy of the EAF (400 mg/kg body weight) was similar to that of metformin (500 mg/kg body weight). The EAF contained substantial amounts of isoflavonoids including genistein, genistin, daidzein, and daidzin, which could have contributed to the fraction's hypoglycemic action. These results indicate that the hot-water extract of the submerged-culture broth of Agaricus blazei contains an EAF having potent hypoglycemic action, which could be useful in the treatment of diabetes mellitus. PMID- 20196601 TI - Purification and identification of 1-deoxynojirimycin (DNJ) in okara fermented by Bacillus subtilis B2 from Chinese traditional food (Meitaoza). AB - This study was to purify an alpha-glucosidase inhibitor from okara (soy pulp) fermented by Bacillus subtilis B2 and to identify its chemical structure. Membrane dialysis, active charcoal, CM-Sepharose chromatography, and preparative thin-layer chromatography (TLC) were used in the purification, while positive mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectrometry were used in the identification. The MS and NMR data showed that the purified alpha glucosidase inhibitor was 1-deoxynojirimycin (DNJ) with a molecular weight of 163 Da. This is the first time that DNJ was isolated from foods fermented with Bacillus species. Okara fermentation with B. subtilis B2 might be used to produce a food-derived DNJ product as a functional food for diabetic patients. PMID- 20196602 TI - Effect of phenolic compounds on the formation of alpha-aminoadipic and gamma glutamic semialdehydes from myofibrillar proteins oxidized by copper, iron, and myoglobin. AB - The effect of selected phenolic compounds, namely, gallic acid, chlorogenic acid, genistein, catechin, cyanidin-3-glucoside and rutin, on the formation of specific protein carbonyls, alpha-aminoadipic and gamma-glutamic semialdehydes (AAS and GGS, respectively), from oxidized myofibrillar proteins, was studied in the present article. Suspensions containing myofibrillar proteins (20 mg/mL) and the aforementioned phenolic compounds (1 mM) were oxidized (37 degrees C for 20 days) in the presence of copper acetate, iron (FeCl(3)), or myoglobin (10 microM) in combination with 1 mM H(2)O(2) and analyzed for AAS and GGS using liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS). Suspensions with added alpha-tocopherol (1 mM) and a control group (with no phenolic compound) were also considered. In the presence of copper, the alpha-tocopherol and most phenolic compounds significantly inhibited the formation of AAS and GGS. In iron- and myoglobin-oxidized suspensions, however, some of those phenolic compounds (i.e., chlorogenic acid and genistein) promoted the formation of the semialdehydes. Besides the influence of the oxidation promoters, the overall effect of plant phenolics on protein oxidation is likely affected by the chemical structure of the phenolics and the result of the interactions between these compounds and myofibrillar proteins. Plausible mechanisms for the antioxidant and pro-oxidant effects of plant phenolics on myofibrillar proteins are proposed in the present article. This study highlights the complexity of redox reactions between plant phenolics and oxidizing myofibrillar proteins. PMID- 20196603 TI - Encapsulation of plant oils in porous starch microspheres. AB - Natural plant products such as essential oils have gained interest for use in pest control in place of synthetic pesticides because of their low environmental impact. Essential oils can be effective in controlling parasitic mites that infest honeybee colonies, but effective encapsulants are needed to provide a sustained and targeted delivery that minimizes the amount of active ingredient used. The present study reports the encapsulation of essential oils in porous microspheres that are within the size range of pollen grains and can be easily dispersed. The microspheres were made by pumping an 8% aqueous high-amylose starch gelatinous melt through an atomizing nozzle. The atomized starch droplets were air-classified into two fractions and collected in ethanol. The size range for each fraction was measured using a particle size analyzer. The mean particle size for the largest fraction was approximately 100 microm with a range from 5 microm to over 300 microm. Part of the reason for the large particle size was attributed to the merging of smaller particles that impinged upon each other before they solidified. The smaller fraction of spheres had a mean particle size of approximately 5 microm. The starch-based porous microspheres were loaded with 16.7% (w/w) essential oils including thymol (5-methyl-2-isopropylphenol), clove, origanum, and camphor white oil. The essential oils appeared to be largely sequestered within the pore structure, since the spheres remained a free-flowing powder and exhibited little if any agglomeration in spite of the high loading rate. Furthermore, SEM micrographs verified that the pore structure was stable, as evidenced by the persistence of pores in spheres that had first been loaded with essential oils and then had the oil removed by solvent extraction. Thermal gravimetric analyses were consistent with a loading rate at predicted levels. PMID- 20196604 TI - Capsule formation, carboxylate exchange, and DFT exploration of cadmium cluster metallocavitands: highly dynamic supramolecules. AB - A family of molecular heptacadmium carboxylate clusters templated inside [3 + 3] Schiff base macrocycles has been isolated and studied by variable temperature solution and solid-state NMR spectroscopy, single-crystal X-ray diffraction (SCXRD), and density functional theory (DFT) calculations. These metallocavitand cluster complexes adopt bowl-shaped structures, induced by metal coordination, giving rise to interesting host-guest and supramolecular phenomena. Specifically, dimerization of these metallocavitands yields capsules with vacant coordination and hydrogen-bonding sites accessible to encapsulated guests. Strong host-guest interactions explain the exceptionally high packing coefficient (0.80) observed for encapsulated N,N-dimethylformamide (DMF). The guest-accessible hydrogen bonding sites arise from an unusual mu(3)-OH ligand bridging three cadmium ions. Thermodynamic and kinetic studies show that dimerization is an entropy-driven process with a highly associative mechanism. In DMF the exchange rate of peripheral cluster supporting carboxylate ligands is intrinsically linked to the rate of dimerization and these two seemingly different events have a common rate determining step. Investigation of guest dynamics with solid-state (2)H NMR spectroscopy revealed 3-fold rotation of an encapsulated DMF molecule. These studies provide a solid understanding of the host-guest and dynamic properties of a new family of metallocavitands and may help in designing new supramolecular catalysts and materials. PMID- 20196605 TI - Mn(II)-based MIL-53 analogues: synthesis using neutral bridging mu2-ligands and application in liquid-phase adsorption and separation of C6-C8 aromatics. AB - Four Mn(II)-based MIL-53 single crystals were prepared using four neutral pyridine N-oxides as bridging mu(2)-ligands. In the case of 4,4'-bipridine-N,N' dioxide (BPNO), the infinite manganese oxide chains were further interconnected by BPNO besides BDC, which allows 1D channels to be accessible for guest molecules. The liquid-phase adsorption and separation of C6-C8 aromatics using the evacuated compound as an absorbent were investigated via crystal-to-crystal transformations. Both structural evolution of the compounds and selectivity of C6 C7 aromatics of one evacuated compound could be attributed to noncovalent interactions, especially pi-pi interaction. PMID- 20196606 TI - Development and interlaboratory validation of a QuEChERS-based liquid chromatography-tandem mass spectrometry method for multiresidue pesticide analysis. AB - A high-throughput, QuEChERS (Quick, Easy, Cheap, Effective, Rugged, Safe) sample preparation and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical method has been developed and validated for the determination of 191 pesticides in vegetation and fruit samples. Using identical LC analytical column and MS/MS instrumentation and operation parameters, this method was evaluated at the U.S. Food and Drug Administration (FDA), National Research Centre for Grapes (NRCG), India, and Ontario Ministry of the Environment (MOE) laboratories. Method validation results showed that all but 1 of these 191 pesticides can be analyzed by LC-MS/MS with instrument detection limits (IDL) in the parts per trillion (ppt) range. Matrix-dependent IDL studies showed that due to either the low ionization efficiency or matrix effect exerted, 14 of these 191 pesticides could not be analyzed by this method. Method recovery (%R) and method detection limits (MDLs) were determined by the three laboratories using four sample matrices in replicates (N = 4). With >79% of %R data from the fortification studies in the range from 80 to 120%, MDLs were determined in the low parts per billion range with >94% of MDLs in the range from 0.5 to 5 ppb. Applying this method to the analysis of incurred samples showed that two multiple reaction monitoring (MRM) transitions may not be enough to provide 100% true positive identification of target pesticides; however, quantitative results obtained from the three laboratories had an excellent match with only a few discrepancies in the low parts per billion levels. The %R data from the fortification studies were subjected to principal component analysis and showed the majority of %R fell into the cluster of 80% < %R < 120%. Due to the matrix effect exerted by ginseng and peach, outliers were observed at the lowest spiking levels of 10 and 25 ppb. The study also showed that QuEChERS samples should be analyzed as soon as prepared or stored in a freezer to avoid any adverse affect on the analytes evaluated. PMID- 20196607 TI - High molecular weight entities in industrial wheat protein hydrolysates are immunoreactive with IgE from allergic patients. AB - Hydrolyzed wheat proteins (HWP) can induce immediate hypersensitivity through skin contact and/or food ingestion. Such patients develop IgE against unmodified wheat proteins without allergy to wheat. Our objective was to study the IgE reacting content of HWP. We compared the reactivity of HWP and unmodified wheat proteins with IgE from patients suffering from immediate hypersensitivity to HWP. We studied the cross-reactivity between one HWP preparation and wheat proteins using immunoblot inhibition experiments. This showed that the tested HWP carried mainly unmodified epitopes originating from wheat proteins. The size distribution of polypeptides from two HWP preparations was analyzed by size-exclusion-high performance liquid chromatography (SE-HPLC), and their reactivity with IgE was studied. This showed that they contained highly IgE-reacting high molecular weight entities, likely resulting in a rearrangement of peptides issued from gluten processes. These multiepitopic entities could explain the high immunogenicity of HWP for sensitized people. PMID- 20196608 TI - Preparation of dimeric procyanidins B1, B2, B5, and B7 from a polymeric procyanidin fraction of black chokeberry ( Aronia melanocarpa ). AB - A semisynthetic approach has been used for the preparative formation of dimeric procyanidins B1, B2, B5, and B7. As starting material for the semisynthesis, polymeric procyanidins from black chokeberry were applied. These polymers were found to consist almost exclusively of (-)-epicatechin units. Under acidic conditions the interflavanoid linkages of the polymeric procyanidins are cleaved and the liberated (-)-epicatechin can react with nucleophiles, such as (+) catechin or (-)-epicatechin. In this way, the polymeric procyanidins are degraded while dimeric procyanidins are formed. During this reaction only dimeric procyanidins are formed that contain (-)-epicatechin in the upper unit, that is, B1 [(-)-EC-4beta-->8-(+)-C)], B2 [(-)-EC-4beta-->8-(-)-EC], B5 [(-)-EC-4beta-->6 (-)-EC], and B7 [(-)-EC-4beta-->6-(+)-C]. The reaction mixtures of the semisynthesis can be successfully fractionated with high-speed countercurrent chromatography (HSCCC), and it is possible to isolate pure procyanidins B1, B2, B5, and B7 on a preparative scale. PMID- 20196610 TI - Determination of microbial carbon sources and cycling during remediation of petroleum hydrocarbon impacted soil using natural abundance (14)C analysis of PLFA. AB - In a petroleum impacted land-farm soil in Sarnia, Ontario, compound-specific natural abundance radiocarbon analysis identified biodegradation by the soil microbial community as a major pathway for hydrocarbon removal in a novel remediation system. During remediation of contaminated soils by a plant growth promoting rhizobacteria enhanced phytoremediation system (PEPS), the measured Delta(14)C of phospholipid fatty acid (PLFA) biomarkers ranged from -793 per thousand to -897 per thousand, directly demonstrating microbial uptake and utilization of petroleum hydrocarbons (Delta(14)C(PHC) = -1000 per thousand). Isotopic mass balance indicated that more than 80% of microbial PLFA carbon was derived from petroleum hydrocarbons (PHC) and a maximum of 20% was obtained from metabolism of more modern carbon sources. These PLFA from the contaminated soils were the most (14)C-depleted biomarkers ever measured for an in situ environmental system, and this study demonstrated that the microbial community in this soil was subsisting primarily on petroleum hydrocarbons. In contrast, the microbial community in a nearby uncontaminated control soil maintained a more modern Delta(14)C signature than total organic carbon (Delta(14)C(PLFA) = +36 per thousand to -147 per thousand, Delta(14)C(TOC) = -148 per thousand), indicating preferential consumption of the most modern plant-derived fraction of soil organic carbon. Measurements of delta(13)C and Delta(14)C of soil CO(2) additionally demonstrated that mineralization of PHC contributed to soil CO(2) at the contaminated site. The CO(2) in the uncontaminated control soil exhibited substantially more modern Delta(14)C values, and lower soil CO(2) concentrations than the contaminated soils, suggesting increased rates of soil respiration in the contaminated soils. In combination, these results demonstrated that biodegradation in the soil microbial community was a primary pathway of petroleum hydrocarbon removal in the PEPS system. This study highlights the power of natural abundance radiocarbon for determining microbial carbon sources and identifying biodegradation pathways in complex remediation systems. PMID- 20196611 TI - "Click" synthesis of nonsymmetrical bis(1,2,3-triazoles). AB - Unsymmetrically 1,1'-disubstituted 4,4'-bis-1H-1,2,3-triazoles 4 have been prepared from 4-ethynyl-1,2,3-triazoles 5 and azides. Following a "double-click" strategy, two complementary approaches were implemented for the preparation of the key 4-ethynyltriazole intermediates 5: (a) the stepwise Swern oxidation/Ohira Bestman alkynylation of readily available 4-hydroxymethyl-1,2,3-triazoles 8 and (b) the stepwise cycloaddition of TMS-1,4-butadiyne 9. The method is highlighted by its compatibility with orthogonally protected and functionalized saccharide peptide hybrids and its ability to be extended to the trisubstituted counterparts 12. PMID- 20196612 TI - Quantum chemical characterization of the X((1)A'), a((3)A'') and A((1)A'') states of CHBr and CHI and computed heats of formation for CHI and CI. AB - The relative energies of the X, a, and A states of CHBr and CHI and their atomization and dissociation energies in the complete basis limit were determined by extrapolating (R/U)CCSD(T) and Davidson corrected MRCI energies calculated with the aug-cc-pVxZ (x = T,Q,5) basis sets, which were corrected for core valence correlation, spin-orbit coupling, and zero point energies. The all electron calculations on the bromine containing molecules were explicitly corrected for scalar relativity, while in the iodo systems they are implicit in the ECP28MDF pseudopotential of iodine. The geometries and vibrational frequencies were calculated at the CASPT2/cc-pVTZ level of theory. The computed singlet-triplet splittings (5.7 and 3.7 kcal mol(-1) for CHBr and CHI respectively) are in close agreement with the recent experimental values, while the predicted A <-- X excitation energies are within approximately 1 kcal mol(-1) of experiment. The barriers to linearity and dissociation on the A surface were also characterized. For CHI and CI, the predicted heats of formation at 298 K are 134.5 +/- 1.0 and 103.9 +/- 1.0 kcal mol(-1), respectively. The spin-orbit splitting in iodomethylidyne (CI) is computed to be 746 cm(-1), although that value may be an underestimate by approximately 20%. PMID- 20196613 TI - Design, synthesis, and biological evaluation of 3-[4-(2-hydroxyethyl)piperazin-1 yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a potent, orally active, brain penetrant inhibitor of phosphodiesterase 5 (PDE5). AB - We recently described a novel series of aminopyridopyrazinones as PDE5 inhibitors. Efforts toward optimization of this series culminated in the identification of 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl) 1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, which possessed an excellent potency and selectivity profile and demonstrated robust in vivo blood pressure lowering in a spontaneously hypertensive rat (SHR) model. Furthermore, this compound is brain penetrant and will be a useful agent for evaluating the therapeutic potential of central inhibition of PDE5. This compound has recently entered clinical trials. PMID- 20196614 TI - Tris(triazolyl)triazine via click-chemistry: a C3 electron-deficient core with liquid crystalline and luminescent properties. AB - The synthesis of a novel core based on tris(triazolyl)triazine has been accomplished by a one-pot procedure that combines a 3-fold deprotection of alkyne groups and "click chemistry" of the aromatic alkyne and azide precursors. The procedure is straightforward for the preparation of functional materials for organic electronics. Indeed, compounds with low reduction potential are obtained. These compounds also show liquid crystalline behavior, displaying columnar mesophases at room temperature, and are luminescent in the visible region both in solution and in thin films. PMID- 20196615 TI - Concise total synthesis of (+/-)-lycopladine A. AB - A concise total synthesis of the Lycopodium alkaloid lycopladine A (1) is described that features sequential conjugate addition and enolate arylation reactions to construct the tricyclic core in two steps. PMID- 20196616 TI - Modular structure of smooth muscle Myosin light chain kinase: hydrodynamic modeling and functional implications. AB - Smooth muscle myosin light chain kinase (smMLCK) is a calcium-calmodulin complex dependent enzyme that activates contraction of smooth muscle. The polypeptide chain of rabbit uterine smMLCK (Swiss-Prot entry P29294) contains the catalytic/regulatory domain, three immunoglobulin-related motifs (Ig), one fibronectin-related motif (Fn3), a repetitive, proline-rich segment (PEVK), and, at the N-terminus, a unique F-actin-binding domain. We have evaluated the spatial arrangement of these domains in a recombinant 125 kDa full-length smMLCK and its two catalytically active C-terminal fragments (77 kDa, residues 461-1147, and 61 kDa, residues 461-1002). Electron microscopic images of smMLCK cross-linked to F actin show particles at variable distances (11-55 nm) from the filament, suggesting that a well-structured C-terminal segment of smMLCK is connected to the actin-binding domain by a long, flexible tether. We have used structural homology and molecular dynamics methods to construct various all-atom representation models of smMLCK and its two fragments. The theoretical sedimentation coefficients computed with HYDROPRO were compared with those determined by sedimentation velocity. We found agreement between the predicted and observed sedimentation coefficients for models in which the independently folded catalytic domain, Fn3, and Ig domains are aligned consecutively on the long axis of the molecule. The PEVK segment is modeled as an extensible linker that enables smMLCK to remain bound to F-actin and simultaneously activate the myosin heads of adjacent myosin filaments at a distance of >or=40 nm. The structural properties of smMLCK may contribute to the elasticity of smooth muscle cells. PMID- 20196617 TI - Proteomic analysis reveals virus-specific Hsp25 modulation in cardiac myocytes. AB - Viruses frequently infect the heart but clinical myocarditis is rare, suggesting that the cardiac antiviral response is uniquely effective. Indeed, the Type I interferon (IFN) response is cardiac cell-type specific and provides one integrated network of protection for the heart. Here, a proteomic approach was used to identify additional proteins that may be involved in the cardiac antiviral response. Reovirus-induced murine myocarditis reflects direct viral damage to cardiac cells and offers an excellent system for study. Primary cultures of murine cardiac myocytes were infected with myocarditic or nonmyocarditic reovirus strains, and whole cell lysates were compared by two dimensional difference gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF/TOF) tandem mass spectrometry. Results were quantitative and reproducible and demonstrated that whole proteome changes clustered according to viral pathogenic phenotype. Moreover, the data suggest that the heat shock protein Hsp25 is modulated differentially by myocarditic and nonmyocarditic reoviruses and may play a role in the cardiac antiviral response. Members of seven virus families modulate Hsp25 or Hsp27 expression in a variety of cell types, suggesting that Hsp25 participation in the antiviral response may be widespread. However, results here provide the first evidence for a virus-induced decrease in Hsp25/27 and suggest that viruses may have evolved a mechanism to subvert this protective response, as they have for IFN. PMID- 20196620 TI - Liquid chromatography electrospray ionization tandem mass spectrometric determination of quassin and neoquassin in fruits and vegetables. AB - Quassia amara wood chips are used by organic farmers as a valid alternative to synthetic insecticides. The powder of Q. amara contains high levels of quassin, neoquassin and picrasinoside B. In this study we developed a liquid chromatography mass spectrometry method for the rapid and accurate quantification of the insecticide quassinoids on fruits and vegetables. Quassinoids were extracted from fruits and vegetables with acetonitrile and separated on a Zorbax Column Eclipse XDB C8 by isocratic elution with a mobile phase consisting of water and methanol with 0.1% of formic acid. Using a high-performance liquid chromatograph coupled with an electrospray ionization tandem mass spectrometer (HPLC/ESI-MS/MS), quassinoids were selectively and simultaneously detected monitoring the multiple reaction (MRM) transitions of proton adduct precursor ions: m/z 389.5 --> 222.9 for quassin, 391.5 --> 372.9 for neoquassin and 576.1 - > 394.5 for picrasinoside B. For all quassinoids calibration was linear over a working range of 1 and 100 microg/kg with r > 0.991. Limit of determination (LOD) and limit of quantification (LOQ) for both quassinoids were 0.5 and 1 microg/kg respectively while for picrasinoside B they were 5 and 10 microg/kg. Quassinoid recoveries ranged from 85.3% to 105.3% with coefficients of variation between 2.5% and 12.8% for fruit and vegetables. The presence of interfering compounds in the fruit and vegetable extract was evaluated and found to be minimal. Due to the linear behavior it was concluded that the multiple reaction transitions of precursor ions can be used for analytical purposes, i.e. for identification and quantification of quassin, neoquassin, and picrasinoside B in fruit and vegetable extracts at trace levels. PMID- 20196619 TI - Binding of MetJ repressor to specific and nonspecific DNA and effect of S adenosylmethionine on these interactions. AB - We have used analytical ultracentrifugation to characterize the binding of the methionine repressor protein, MetJ, to synthetic oligonucleotides containing zero to five specific recognition sites, called metboxes. For all lengths of DNA studied, MetJ binds more tightly to repeats of the consensus sequence than to naturally occurring metboxes, which exhibit a variable number of deviations from the consensus. Strong cooperative binding occurs only in the presence of two or more tandem metboxes, which facilitate protein-protein contacts between adjacent MetJ dimers, but weak affinity is detected even with DNA containing zero or one metbox. The affinity of MetJ for all of the DNA sequences studied is enhanced by the addition of SAM, the known cofactor for MetJ in the cell. This effect extends to oligos containing zero or one metbox, both of which bind two MetJ dimers. In the presence of a large excess concentration of metbox DNA, the effect of cooperativity is to favor populations of DNA oligos bound by two or more MetJ dimers rather than a stochastic redistribution of the repressor onto all available metboxes. These results illustrate the dynamic range of binding affinity and repressor assembly that MetJ can exhibit with DNA and the effect of the corepressor SAM on binding to both specific and nonspecific DNA. PMID- 20196618 TI - Mechanisms of enzymatic degradation of amyloid Beta microfibrils generating nanofilaments and nanospheres related to cytotoxicity. AB - Amyloid beta (Abeta) fibrils are found in the brain tissue of persons with Alzheimer's disease (AD), where they accumulate as plaques. One way to reduce the level of accumulation of Abeta in the brain and potentially treat AD is with Abeta-degrading enzymes such as neprilysin (NEP) and insulin-degrading enzyme (IDE). However, enzymatic responses and degradation mechanisms of Abeta fibrils (crystalline-state Abeta) have not been investigated, particularly with respect to how to avoid cytotoxicity of the degradation products to neuronal cells. Thus, insight into mechanisms of enzymatic degradation of Abeta fibrils would be instructive as a route to elucidating different structural features related to degradation and to cytotoxicity. We report mechanisms of enzymatic degradation of Abeta with cross-beta structures and show the series of steps involved in the digestion of Abeta microfibrils to nanospheres or nanofilaments by protease XIV or alpha-chymotrypsin, respectively. These degradation products, which contained almost the same secondary structures, exhibited different cytotoxicities, indicating that relationships between nanoassembled structures and cytotoxicity of Abeta peptides are more significant than the beta-sheet content. In addition, the enzymatic digestion at the Lys28 loop region linking the two beta-sheets in Abeta fibrils is suggested as a key target related to cytotoxicity, a feature that can be selectively targeted on the basis of the choice of protease. PMID- 20196621 TI - Generation of absolute controlled crystal chirality by the removal of crystal water from achiral crystal of nucleobase cytosine. AB - The enantioselective formation of chiral crystal of achiral nucleobase cytosine was achieved mediated by the crystal direction selective dehydration of crystal water in the achiral crystal of cytosine monohydrate (P2(1)/c). Heat transfer from the enantiotopic face of the single crystal of cytosine monohydrate afforded the enantiomorphous crystal of anhydrous cytosine. PMID- 20196622 TI - Asymmetric synthesis of 1,3-diamines by diastereoselective reduction of enantiopure N-tert-butanesulfinylketimines: unusual directing effects of the ortho-substituent. AB - Chiral, nonracemic 1,3-diamines were prepared in a highly diastereoselective reduction of diaryl N-tert-butanesulfinylketimines. Correlation between facial selectivity of the reduction and E or Z geometry of the starting ketimines suggests involvement of a cyclic transition state for the reduction. The ortho substituent controls the geometry of N-tert-butanesulfinylketimines in the solid state and provides additional stabilization of the cyclic transition state. PMID- 20196623 TI - Cost effectiveness of 5-alpha reductase inhibitors for the prevention of prostate cancer in multiple patient populations. AB - BACKGROUND: Although 5-alpha reductase inhibitors (5ARIs) have demonstrated that they reduce the risk of prostate cancer (PCa), they have not demonstrated cost effectiveness in the patient populations in which they have been examined. OBJECTIVE: A decision-analytic model was created to explore economic benefits from a third-party payer perspective of the use of 5ARIs in preventing PCa in men with different risk factors for developing the disease. METHODS: A Markov model was developed to simulate a cohort of men annually through health states (e.g. healthy male, benign prostatic hyperplasia [BPH], PCa, PCa recurrence) over a man's lifetime. Men with risk factors were treated with a 5ARI and compared with patients given no chemoprevention. Men from the general population were examined along with higher-risk men who had been referred to a PCa centre. Baseline risk was estimated via published risk data, risk factor analyses and risk equations. Clinical efficacy, morality, costs and utilities were obtained from published literature. Outcomes of the model included number of prostate cancers, incremental costs, incremental QALYs, incremental cost per QALY and number needed to treat. Along with sensitivity and scenario analyses, a validation of outcomes was performed. All costs were valued in $US, year 2009 values. Costs were discounted at 3% per annum. RESULTS: Men receiving 5ARIs benefited through a reduction in the number of PCas. Assuming a cost-effectiveness threshold of $US50 000 per QALY, chemoprevention with 5ARIs was cost effective ($US37 900 per QALY) in men from the general population who were aged 50 years with elevated prostate specific antigen (PSA), and who were aged 50 years with PCa family history and elevated PSA ($US31 065 per QALY). Chemoprevention with 5ARIs was not cost effective in men aged 50 years with no additional risk factors, men aged 50 years with abnormal digital rectal examinations (DREs), and men aged 50 years with a family history ($US86 511, $US85 577 and $US84 950 per QALY, respectively). In higher-risk men, chemoprevention could be expected to be cost effective ($US18 490 to $US11 816 per QALY, depending on risk scenario). Results were sensitive to changes in utilities, assumed PCa risk reduction with 5ARIs, and patient age. CONCLUSION: When considering common risk factors associated with PCa, prevention with 5ARIs is expected to be cost effective in 50-year-old men with elevated PSA. As a man's risk increases, the cost effectiveness of 5ARI chemoprevention improves. PMID- 20196624 TI - Late relapses in acute myeloid leukemia: analysis of characteristics and outcome. AB - Relapse after 5 years of complete remission (CR) is uncommon in acute myeloid leukemia (AML). Among 2347 patients seen between 1980 and 2008, 1366 achieved CR; 942 relapsed. Eleven (1.16% of all relapses) relapsed after a CR of >5 years. The median age was 66 years (range, 37-79). Initial therapy was cytarabine plus anthracycline in six, amsacrine-based in three, and other in two. The median CR1 duration was 81 months (range, 60-137). At relapse, the karyotype was different from the initial finding in five of eight (63%) patients with available data. Treatment for relapse included cytarabine with anthracycline in eight, and other in three patients, with a second CR (CR2) achieved in four (36%). The median CR2 duration was 1 month (range, 0-37), and median survival after relapse was 6.4 months (range, 1-39). Late relapses in AML are infrequent, with poor response to therapy. Karyotype at relapse is frequently different, raising the question of second AML versus relapse with the original clone. PMID- 20196625 TI - Influence of liposomal formulation variables on the interaction with Candida albicans in biofilm; a multivariate approach. AB - Candida albicans is a species commonly associated with biofilm formation. The aim of this study was to identify liposomal formulation variables influencing the adhesion of liposomes to C. albicans in biofilm. C. albicans was grown on microtiter plates. Charged liposomes containing a fluorescent phospholipid (fatty acid labeled) were adsorbed onto biofilms of C. albicans in the wells. The adsorption was quantified by fluorescence measurements. Statistical experimental design and multivariate evaluation were used in the studies. The liposomal formulation factors investigated were the type of the main phospholipid (egg-PC, DMPC, and DPPC), the amount of charged component in the liposomes, and the type of the charged lipid (diacyl-TAP, DC-chol, diacyl-PA, diacyl-PG, diacyl-PS, and PI). Full factorial mixed levels designs were created. Saturated positively charged liposomes, with diacyl-TAP as the charged component and a low level of positive charge, was found to be the best choice for interaction with C. albicans. When formulating negatively charged liposomes, liposomes with DPPC as the main lipid adsorbed significantly better than liposomes with egg-PC. The amount of charge and the nature of the charged component were not found to influence the adsorption of the negatively charged liposomes to C. albicans. No synergy was detected between any of the formulation variables studied. PMID- 20196626 TI - Hyperlipidemia induces endothelial-derived foam cells in culture. AB - Endothelial cells (ECs) play a major role in the pathophysiology of various diseases, conditions in which stress proteins are most probably involved. Both in humans and in experimental models, hyperlipidemia induces early alterations of plasma components that in turn have a profound effect on EC. Activated ECs change their basal characteristics becoming more permeable to lipoproteins, increasing the synthesis of their basal lamina, and express new adhesion molecules; the cells are "activated". In lesion-prone areas, the ECs are the first cells to experience the impact of hyperlipidemia. In this study, human ECs were activated by exposure to serum from hyperlipidemic human subjects. In this condition, the EC gradually become loaded with lipid droplets and turn into endothelial-derived foam cells. The EC-derived foam cells express adhesion molecules (VCAM-1, VLA-4), show enhanced intracellular Ca(2+) release, and demonstrate high level of heat shock proteins (Hsp27, Hsp70, and Hsp90). In this study, we bring evidence that the EC-derived foam cells in culture proved to be an useful model to identify the multiple changes induced in activated ECs under hyperlipidemic stress. On the basis of these considerations, future studies using this model system will help to elucidate the molecular basis of the modulator role of molecular chaperones (Hsp) in atherosclerosis under various environmental conditions. PMID- 20196627 TI - Role of VEGF-stromal cell-derived factor-1alpha/CXCL12 axis in pleural effusion of lung cancer. AB - CONTEXT AND OBJECTIVE: It has been suggested that stromal cell-derived factor 1alpha ((SDF-1alpha) or CXCL12, both transcripts, TR1 and TR2) and its cognate receptor CXCR4 may regulate cancer metastasis. We have investigated the role of vascular endothelial growth factor (VEGF), angiopoietins (Ang-1 and Ang-2) and the biological axis of CXCL12-CXCR4, in patients with malignant pleural effusions (PEs). MATERIAL AND METHODS: Twenty five patients, seven with transudative PEs due to heart failure and 18 with exudative malignant PEs (7 with small cell lung cancer (SCLC) and 11 with nonsmall cell lung cancer (NSCLC)) were included in the study. Expression analysis of the mediators was performed in pleural fluid pellet using real-time reverse transcription-PCR. Protein expression has been evaluated by western blot analysis. RESULTS: SDF-TR1 (P = 0.02) but not SDF-TR2 (P = 0.23) or CXCR4 levels (P = 0.23) were higher in malignant PEs than in transudates. SDF TR1 (P = 0.04) and SDF- TR2 levels (P = 0.04) but not CXCR4 levels (P = 0.123) were higher in SCLC PEs than in heart failure PEs. SDF-TR1 (P = 0.03) but not SDF TR2 levels (P = 0.6) and CXCR4 levels (P = 0.4) were higher in NSCLC PEs than in transudates. Ang-1 has not been expressed in PEs, whereas no significant difference has been detected in VEGF and Ang-2 expression between malignant PEs and transudates. However, protein expression showed increased VEGF and SDF expression in malignant PEs. CONCLUSIONS: These results suggest that elevated SDF 1alpha/CXCL12 levels would be suggestive of a link to metastasis and may participate in pleural trafficking in lung cancer. PMID- 20196628 TI - Purification and structure determination of gelatinase and collagenase inhibitors from Viola patrinii fermentation extracts. AB - Investigation of collagenase and gelatinase inhibitory natural components afforded two isoflavonoids. Two isoflavonoids, tectorigenin-7-O-beta-D-glucoside (1) and luteolin-7-O-beta-D-glucuronopyranoside (2), were isolated from ethyl acetate fraction of Viola patrinii fermentation extracts (VPFE). Of these, compounds 1 and 2 exhibited collagenase inhibitory activity (IC(50)) at a concentration of less than 1.5 MUM, and compound 2 showed gelatinases A and B inhibitory activity (IC(50)) at 0.3 MUM and 0.8 MUM, respectively. PMID- 20196630 TI - Thrombocytosis secondary to chronic lead poisoning. AB - We report a case of total hyperpigmentation of the skin, severe itching, muscle weakness and thrombocytosis. Laboratory investigation showed white blood cell (WBC) 8.2 x 10(6)/L, Hb 125 g/L, platelets 1221 x 10(6)/L and urinary lead after DMSA mobilization test 2684 mcg/g creatinine (normal <5). Chelation therapy with DMSA resulted in complete recovery of the hyperpigmentation, itching and thrombocytosis. Lead poisoning should be considered in the differential diagnosis of obscured thrombocytosis. PMID- 20196629 TI - Protein expression in platelets from six species that differ in their open canalicular system. AB - Platelets contain an invaginated, tubular membranous structure called the surface connected open canalicular system (SCCS or OCS), which is contiguous with the plasma membrane and serves as a site for granule fusion and as a reservoir of membrane for platelet spreading. According to ultrastructural studies, platelets from some species lack OCS. In an attempt to correlate biochemical and functional attributes with the presence of an OCS, platelets from human, mouse and dog (OCS(+)), and from cow, camel and horse (OCS(-)) were analysed for differential protein expression and aggregation in response to thrombin. Among the 18 different cytoskeletal and regulatory proteins examined, five (Rac1, RhoA, Ras, calmodulin and Src) were expressed at higher levels in OCS(+) platelets (p < 0.05). Given the role of Arf6 in the formation of tubular invaginations in nucleated cells, the levels of Arf6-GTP were analysed in OCS(+) and OCS(-) platelets. There was no significant correlation between the presence of OCS and total Arf6 or Arf6-GTP levels. Comparison of platelet aggregation between different species suggests that OCS(-) platelets have delayed responses. This comparison of platelets from six different species, which differ in their OCS, shows the differential expression of known signaling components and foreshadows future studies focusing on OCS formation and function. PMID- 20196631 TI - Microencapsulation of sodium alendronate reduces drug mucosal damage in rats. AB - Sodium alendronate is an effective treatment for osteoporosis, but its oral administration is associated with adverse gastrointestinal effects. The aim of this work was to evaluate gastroresistant sodium alendronate-loaded microparticles prepared by spray-drying using Eudragit S100 or a blend of Eudragit S100/Methocel E4M. Both formulations presented high encapsulation efficiencies, mean diameters below 17 microm, and similar collapsed shape. Dissolution experiments showed good gastro-resistance for the microparticles at pH 1.2. At pH 6.8, the blended microparticles retarded the drug release. In vivo studies showed that the formulations were able to protect the rat stomachs against ulcer formation by sodium alendronate. In conclusion, the microparticles seems to be promising oral carriers for sodium alendronate. PMID- 20196632 TI - Polymeric alginate nanoparticles containing the local anesthetic bupivacaine. AB - Bupivacaine (BVC; S75-R25, NovaBupi(r) is an amide-type local anesthetic. Sodium alginate is a water-soluble linear polysaccharide. The present study reports the development of alginate/bis(2-ethylhexyl) sulfosuccinate (AOT) and alginate/chitosan nanoparticle formulations containing BVC (0.5%). The amounts of BVC associated in the alginate/AOT and alginate/chitosan nanoparticles were 87 +/ 1.5 and 76 +/- 0.9%, respectively. The average diameters and zeta potentials of the nanoparticles were measured for 30 days, and the results demonstrated the good stability of these particles in solution. The in vitro release kinetics showed a different behavior for the release profile of BVC in solution, compared with BVC-loaded alginate nanoparticles. In vitro and in vivo assays showed that alginate-chitosan BVC (BVC(ALG-CHIT)) and alginate-AOT BVC (BVC(ALG-AOT)) presented low cytotoxicity in 3T3-fibroblasts, enhanced the intensity, and prolonged the duration of motor and sensory blockades in a sciatic nerve blockade model. PMID- 20196633 TI - The influence of physical activity level on climacteric symptoms in menopausal women. AB - OBJECTIVE: To evaluate the relationship between physical activity level and climacteric symptoms in menopausal women. METHODS: A study was conducted on 336 healthy women aged 45-55 years. They were asked to complete a questionnaire consisting of two parts: (1) a socioeconomic and obstetric/gynecological survey, and (2) the International Physical Activity Questionnaire long form and the Blatt Kupperman Index. RESULTS: The women assigned to the high physical activity group felt better and had less severe climacteric symptoms; 52.08% of the women had no climacteric symptoms. The majority of women in this group were assigned to the total high physical activity group. Significant differences were observed in the relationship between physical activity level and climacteric symptoms. In each domain, women with no climacteric symptoms were classified into either the high or the moderate physical activity level group. In the work domain, 25.30% of the women had a moderate, 20.53% a high, and 6.25% a low physical activity level. In the transportation domain, 32.72% of the women had a moderate, and 19.36% a low physical activity level. In the domestic chores domain, 30.06% of the women had a moderate, 16.07% a high and 5.95% a low physical activity level. In the leisure time domain, 25.61% of the women had a moderate, 16.95% a high and 9.52% a low physical activity level. CONCLUSIONS: Physical activity is associated with less menopausal symptoms. It is important to encourage regular physical activity as it is beneficial to health and relieves menopausal symptoms. PMID- 20196634 TI - Low-dose vaginal estrogens or vaginal moisturizer in breast cancer survivors with urogenital atrophy: a preliminary study. AB - The study aim is to evaluate the efficacy and safety of two low-dose vaginal estrogen treatments (ETs) and of a non-hormonal vaginal moisturizer in postmenopausal breast cancer survivors with urogenital atrophy. Eighteen patients receiving estriol cream 0.25 mg (n = 10) or estradiol tablets 12.5 microg (n = 8) twice/week for 12 weeks were evaluated and compared with eight patients treated with polycarbophil-based moisturizer 2.5 g twice/week. Severity of vaginal atrophy was assessed using subjective [Vaginal Symptoms Score (VSS), Profile of Female Sexual Function (PFSF)] and objective [Vaginal Health Index (VHI), Karyopycnotic Index (KI)] evaluations, while safety by measuring endometrial thickness and serum sex hormones levels. After 4 weeks, VSS and VHI were significantly improved by both vaginal ETs, with further improvement after 12 weeks. PFSF improved significantly only in estriol group (p = 0.02). Safety measurements did not significantly change. Vaginal moisturizer improved VSS at week 4 (p = 0.01), but score returned to pre-treatment values at week 12; no significant modification of VHI, KI, PFSF was recorded. Both low-dose vaginal ET are effective for relieving urogenital atrophy, while non-hormonal moisturizer only provides transient benefit. The increase of serum estrogens levels during treatment with vaginal estrogen at these dosages is minimal. PMID- 20196635 TI - Poor prognosis for ovarian response to stimulation: results of a randomised trial comparing the flare-up GnRH agonist protocol vs. the antagonist protocol. AB - OBJECTIVE: To determine the efficacy of the flare-up agonist and the antagonist protocols in patients with poor prognosis for ovarian response. METHODS: A randomised trial was conducted on two hundred and twenty-one women considered as having poor prognosis for ovarian response to stimulation, based on previous cycles or clinical criteria. All women were prospectively randomised into two groups of treatment (flare-up group and antagonist group) by computer-assisted randomisation in a 1:1 ratio. The main outcome measure was clinical pregnancy rate. RESULTS: Groups were homogeneous in age and baseline characteristics. Duration of stimulation, gonadotropin consumption, number of oocytes retrieved and number and quality of embryos transferred did not differ significantly between the groups. E(2) level the day of hCG administration was significantly higher in the flare-up group. Pregnancy rates per started cycle were 15% in the flare-up group and 14.1% in the antagonist group. Cancellation rates were 12.5% in the flare-up group and 16.3% in the antagonist group. None of these differences reached statistical significance. CONCLUSIONS: No statistically significant differences were observed between the two protocols regarding clinical pregnancy rates. In patients with poor prognosis for ovarian response, the flare-up agonist and the antagonist protocols were comparable regarding clinical pregnancy rates. PMID- 20196636 TI - Placental weight, digitally derived placental dimensions at term and their relationship to birth weight. AB - OBJECTIVE: A few recent studies have investigated the relationship between birth weight and digitally derived placental dimensions, and no standardised methodology has been used. The aims of this study are to compare manually derived placental measurements with those derived digitally and to establish the relationship of birth weight to the placental weight and circumference. METHODS: Three hundred fifty-one consecutive unselected women with singleton pregnancy delivering in a tertiary maternity unit at 37-42 weeks were recruited. Manual and digital placental axis measurements (using calibrated digital imaging and 'Image J' software) were obtained and the circumference derived. The relationship between the two methods was assessed using a Bland-Altman plot analysed. The relationship between z-scores of birth weight, placental weight and placental circumference was investigated. RESULTS: Manually and digitally obtained placental long axis, short axis and circumference measurements show close correlation (r=0.70, 0.70 and 0.83, respectively). The z score of birth weight is significantly correlated with the z score of placental weight (r=0.59, p<0.001) and z score placental digital circumference (r=0.40, p<0.001). Birth weight:placental weight ratio is 7.20 and birth weight:placental circumference=64.57 g/cm. CONCLUSION: There is close though not perfect agreement between the manual and digital placental measurements. Birth weight is strongly correlated with placental weight and circumference at term. PMID- 20196637 TI - Diagnostic and therapeutic modalities in systemic amyloidosis. PMID- 20196638 TI - Biomimetic coating of organic polymers with a protein-functionalized layer of calcium phosphate: the surface properties of the carrier influence neither the coating characteristics nor the incorporation mechanism or release kinetics of the protein. AB - Polymers that are used in clinical practice as bone-defect-filling materials possess many essential qualities, such as moldability, mechanical strength and biodegradability, but they are neither osteoconductive nor osteoinductive. Osteoconductivity can be conferred by coating the material with a layer of calcium phosphate, which can be rendered osteoinductive by functionalizing it with an osteogenic agent. We wished to ascertain whether the morphological and physicochemical characteristics of unfunctionalized and bovine-serum-albumin (BSA)-functionalized calcium-phosphate coatings were influenced by the surface properties of polymeric carriers. The release kinetics of the protein were also investigated. Two sponge-like materials (Helistat(r) and Polyactive(r)) and two fibrous ones (EthisorbTM and poly[lactic-co-glycolic acid]) were tested. The coating characteristics were evaluated using state-of-the-art methodologies. The release kinetics of BSA were monitored spectrophotometrically. The characteristics of the amorphous and the crystalline phases of the coatings were not influenced by either the surface chemistry or the surface geometry of the underlying polymer. The mechanism whereby BSA was incorporated into the crystalline layer and the rate of release of the truly incorporated depot were likewise unaffected by the nature of the polymeric carrier. Our biomimetic coating technique could be applied to either spongy or fibrous bone-defect filling organic polymers, with a view to rendering them osteoconductive and osteoinductive. PMID- 20196639 TI - Role for protein kinase C delta in the functional activity of human UGT1A6: implications for drug-drug interactions between PKC inhibitors and UGT1A6. AB - Many UDP-glucuronosyltransferases (UGTs) require phosphorylation by protein kinase C (PKC) for glucuronidation activity. Inhibition of UGT phosphorylation by PKC inhibitor drugs may represent a novel mechanism for drug-drug interactions. The potential for PKC-mediated inhibition of human UGT1A6, an isoform involved in the glucuronidation of drugs such as acetaminophen (paracetamol) and endogenous substrates including serotonin, was evaluated using various cell model systems. Of ten different PKC inhibitors screened for their effects on acetaminophen glucuronidation by human LS180 colon cells, only rottlerin (PKC delta selective inhibitor; IC(50) = 9.0 +/- 1.2 microM) and the non-selective PKC inhibitors (calphostin-C, curcumin and hypericin) decreased glucuronidation by more than 50%. Using UGT1A6-infected Sf9 insect cells, calphostin-C and hypericin showed three times more potent inhibition of serotonin glucuronidation in treated whole cells versus cell lysates. However, both curcumin and rottlerin showed significant direct inhibition and so (indirect) PKC effects could not be differentiated in this model system. Of nine PKC isoforms co-expressed with UGT1A6 in human embryonic kidney 293T cells only PKC delta increased protein normalized UGT1A6-mediated serotonin glucuronidation significantly (by 63% +/- 4%). These results identify an important role for PKC delta in UGT1A6-mediated glucuronidation and suggest that PKC delta inhibitors could interfere with glucuronidation of UGT1A6 substrates. PMID- 20196641 TI - Two- and three-layer tablet drug delivery systems for oral sustained release of soluble and poorly soluble drugs. AB - BACKGROUND: Multilayer tablets are gaining importance in oral sustained drug delivery. They consist of an active matrix core and one or more layers applied during tableting which may act as barriers and regulate drug release. OBJECTIVE: To examine the release performance of two model drugs, diclofenac sodium and furosemide, from two- and three-layer drug delivery systems using as carriers hydrophilic swellable polymers, namely, Metolose, Polyox, Xantham gum, and an erodible material Gantrez. RESULTS AND DISCUSSION: All prepared formulations demonstrated sustained release profiles. They also indicated that the carrier characteristics (particularly swelling-expansion, erosion-dissolution) and drug solubility in combination with tablet structure considerably influenced the performance of examined formulations as well as their mode and mechanisms of release. In general our findings show that the differences in drug release between the two- and three-layer tablets are small as it appears that two-layer tablets exhibit a slightly higher release. Because of its greater erosion Gantrez formulations displayed faster release relative to Xantham gum, as did Metolose formulations compared to Polyox formulations. A faster release rate was also noted with diclofenac formulations compared to those of furosemide because of diclofenac's higher solubility mainly seen at early time period. CONCLUSIONS: All three-layer Gantrez tablets containing either diclofenac or furosemide and the two-layer furosemide formulation demonstrated a biphasic release. The above indicate that both structures may be used successfully for sustained release drug delivery. In addition the use of multilayer tablets, consisting of materials with suitable properties, may result in modulation of drug release. PMID- 20196640 TI - Health-related quality of life during hormone therapy after breast cancer: a randomized trial. AB - AIM: To study the effects of menopausal hormone therapy (HT) on health-related quality of life in women after breast cancer. PATIENTS AND METHODS: In the Stockholm trial, breast cancer survivors were randomized to HT (estradiol and progestogen) or to a control group (no treatment). A subgroup of 75 women was studied (38 with HT, 37 controls). Fifty patients were on concomitant tamoxifen. Patients completed three questionnaires (EORTC QLQ C-30, EORTC QLQ-BR 23 and the Hospital Anxiety and Depression Scale (HADS)) during 1 year of treatment. RESULTS: A significant group-by-time interaction was found for improvement of insomnia in the HT group (p < 0.001). Within the HT group, but not in the control group, there was significant improvement for HADS anxiety, HADS depression, emotional, cognitive, and social functions and global quality of life. When HT was added to tamoxifen, the increase in global quality of life was significant (p < 0.01). CONCLUSION: The effects of HT on quality of life in breast cancer survivors have not previously been reported. The present data suggest that this controversial treatment may improve quality of life after breast cancer. PMID- 20196642 TI - Studies on nonionic surfactant bilayer vesicles of ciclopirox olamine. AB - CONTEXT: Niosomal delivery can prove an alternative to improve the poor skin penetration and residence of the topical antifungal drugs that account for the long treatment regimes in cutaneous mycosis. OBJECTIVE: To investigate niosomes as carriers for dermal delivery of ciclopirox olamine (CPO), a broad spectrum antifungal drug. MATERIALS AND METHODS: Niosomes were prepared by ethanol injection method using Span 60, cholesterol, diacetyl phosphate according to 3(2) factorial design and evaluated for physicochemical parameters, in vitro and ex vivo deposition in skin and stability study. RESULTS: Unilamellar CPO niosomes of size 170-280 nm, entrapment efficiency 38-68%, and sufficient electrokinetic stability were obtained. Percent drug deposition in artificial membrane varied from 12.75 to 92.74. Deposition of CPO into rat skin from niosomal dispersion and its gel was significantly higher than that of plain CPO solution and its marketed product. Obtained niosomes possessed sufficient stability on storage. DISCUSSION: Increasing amounts of Span 60 and cholesterol increase the vesicle size probably because of entrapment of CPO-ionized molecules in the aqueous compartment and interaction of its unionized counterpart with the bilayer constituents leading to increase in bilayer thickness. Consequently, the percent entrapment efficiency also increased. However, increasing Span 60 levels decreased the in vitro percent drug deposition. This might be attributed to the larger size of vesicles produced by high amounts of surfactant that showed poor deposition. The optimized batch possessed sufficient stability. CONCLUSIONS: The results of this investigation suggest that niosomes are promising tools for cutaneous retention of CPO. PMID- 20196643 TI - Physicochemical characterization of gliclazide-macrogol solid dispersion and tablets based on optimized dispersion. AB - BACKGROUND: This study investigated the physical interaction of gliclazide (GLC) with a hydrophilic carrier, that is, macrogol [polyethylene glycol (PEG)]. Different molecular weights of PEG (4000, 10,000, and 20,000) were used in different drug : carrier weight ratios (1 : 1, 1 : 2, 1 : 5, and 1 : 10). METHOD: Preliminary screening was done by phase solubility studies to characterize the liquid state interaction between the drug and the carrier. Solid dispersions (SDs) of GLC and PEG in different ratios were prepared by fusion technique and by physical mixing. The solid-state interaction between the drug and the carrier was examined by performing differential scanning calorimetry and Fourier transform infrared spectroscopic studies. SD with satisfactory characteristics was selected for the formulation of tablets by wet granulation method and compared with the commercial brand for in vitro dissolution. RESULTS: It was evident from phase solubility studies that the drug solubility increased linearly with increasing PEG concentrations. In vitro dissolution of GLC improved significantly in the SDs prepared by fusion method as compared with the original drug and physical mixtures. Scanning electron microscopy images showed well-defined changes in the surface topography of GLC, thus confirming the effective formation of a fused binary system. The SD tablets showed a significant improvement in the drug release profile than that of the commercial brand. CONCLUSION: It was thus concluded that SD formulations of GLC can be successfully used to design a solid dosage form of the drug, which would have significant advantages over the current marketed tablets. PMID- 20196644 TI - Parameters in three-dimensional osteospheroids of telomerized human mesenchymal (stromal) stem cells grown on osteoconductive scaffolds that predict in vivo bone forming potential. AB - Osteoblastic differentiation of human mesenchymal stem cells (hMSC) in monolayer culture is artefactual, lacking an organized bone-like matrix. We present a highly reproducible microwell protocol generating three-dimensional ex vivo multicellular aggregates of telomerized hMSC (hMSC-telomerase reverse transcriptase (TERT)) with improved mimicry of in vivo tissue-engineered bone. In osteogenic induction medium the hMSC were transitioned with time-dependent specification toward the osteoblastic lineage characterized by production of alkaline phosphatase, type I collagen, osteonectin, and osteocalcin. Introducing a 1-2 mm(3) crystalline hydroxyapatite/beta-tricalcium phosphate scaffold generated osteospheroids with upregulated gene expression of transcription factors RUNX2/CBFA1, Msx-2, and Dlx-5. An organized lamellar bone-like collagen matrix, evident by birefringence of polarized light, was deposited in the scaffold concavities. Here, mature osteoblasts stained positively for differentiated osteoblast markers TAZ, biglycan, osteocalcin, and phospho-AKT. Quantification of collagen birefringence and relatively high expression of genes for matrix proteins, including type I collagen, biglycan, decorin, lumican, elastin, microfibrillar-associated proteins (MFAP2 and MFAP5), periostin, and tetranectin, in vitro correlated predictively with in vivo bone formation. The three-dimensional hMSC-TERT/hydroxyapatite-tricalcium phosphate osteospheroid cultures in osteogenic induction medium recapitulated many characteristics of in vivo bone formation, providing a highly reproducible and resourceful platform for improved in vitro modeling of osteogenesis and refinement of bone tissue engineering. PMID- 20196645 TI - The early fracture hematoma and its potential role in fracture healing. AB - Research regarding the potency and potential of the fracture hematoma has begun to receive increasing attention. However, currently there is a paucity of relevant literature on the capability and composition of the fracture hematoma. This review briefly summarizes the regenerative fracture healing process and the close interplay between the skeletal and immune systems. The role of immune cells in wound healing is also discussed to clarify their involvement in immunological processes during regeneration. We attempt to describe the current state of knowledge regarding the fracture hematoma as the initial stage of the regenerative process of fracture healing. The review discusses how a better understanding of immune reactions in the hematoma may have implications for bone tissue engineering strategies. We conclude the review by emphasizing how additional investigations of the initial phase of healing will allow us to better differentiate between deleterious and beneficial aspects of inflammation, thereby facilitating improved fracture treatment strategies. PMID- 20196646 TI - Comparative review of growth factors for induction of three-dimensional in vitro chondrogenesis in human mesenchymal stem cells isolated from bone marrow and adipose tissue. AB - The ability of bone-marrow-derived mesenchymal stem cells (MSCs) and adipose derived stem cells (ASCs) to undergo chondrogenic differentiation has been studied extensively, and it has been suggested that the chondrogenic potential of these stem cells differ from each other. Here, we provide a comprehensive review and analysis of the various growth factor induction agents for MSC and ASC three dimensional in vitro chondrogenic differentiation. In general, the most common growth factors for chondrogenic induction come from the transforming growth factor beta (TGFbeta) superfamily. To date, the most promising growth factors for chondrogenesis appear to be TGFbeta-3 and bone morphogenetic protein (BMP)-6. A thorough review of the literature indicates that human MSCs (hMSCs) appear to exhibit the highest chondrogenic potential in three-dimensional culture in the medium containing both dexamethasone and TGFbeta-3. Some reports indicate that the addition of BMP-6 to TFGbeta-3 and dexamethasone further increases hMSC chondrogenesis, but these results are still not consistently supported. Induction of human ASC (hASC) chondrogenesis appears most successful when dexamethasone, TGFbeta-3, and BMP-6 are used in combination. However, to date, current formulations do not always result in stable differentiation to the chondrocytic lineage by hMSCs and hASCs. Continued research must be performed to examine the expression cascades of the TFGbeta superfamily to further determine the effects of each growth factor alone and in combination on these stem cell lines. PMID- 20196647 TI - Congenital anomalies of soft tissues: birth defects depending on tissue engineering solutions and present advances in regenerative medicine. AB - Congenital anomalies encompass a wide range of malformations that could affect various organs and tissues in the newborn and infant population. These disorders that involve defects in or injury to a developing fetus may be a result of genetic abnormalities or mutations, alterations in the intrauterine environment, irregularities in morphogenesis, or chromosomal aberration. The outcome of these defects could lead to minor anomalies or major malformations that are dependent on the complex processes between the prenatal deficit and postnatal environment. Often multiple malformations occur within the same fetus and give rise to a malformation syndrome. Since congenital anomalies are evident at birth, solutions must be found to improve the clinical state and quality of life that a newborn has to lead from infancy through adolescence into adulthood. Transplantation options in this age group are limited due to the shortage of organs and the discrepancy in adult donor size mismatch. Over the past 2 decades tremendous strides have been made in the research of biomaterials, stem cells, organ generation, and tissue engineering to provide viable solutions to a wide range of organ and tissue losses focusing on the adult population. This review intends to highlight the shortage of tissue and organs in neonates and infants with congenital malformations. This is also the first monograph that presents estimation of incidences of the congenital malformations based on an extensive literature search. It also outlines the challenges in clinical management of these entities and presents an organ-based demand for engineered tissues. PMID- 20196648 TI - Different facets of aging in human mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) have to be culture expanded to gain relevant cell numbers for therapeutic applications. However, within 2-3 months the proliferation rate of MSCs decays until they ultimately reach a senescent state. This is accompanied by enlarged morphology, reduced expression of surface markers, and decreased differentiation potential. So far it is only scarcely understood how long-term culture affects MSC preparations, and five processes seem to be involved: (1) MSCs are composed of different sub-populations, and due to different proliferation rates the heterogeneity changes in the course of in vitro expansion; (2) cells in culture acquire mutations and other stochastic cellular defects; (3) self-renewal of MSCs may be impaired under culture conditions, leading to gradual differentiation; (4) the number of cell divisions might be restricted (e.g., by loss of telomeres), and (5) replicative senescence might be associated with the aging process of the organism. There is a growing perception that long-term culture has to be taken into account--especially for clinical applications. On the other hand, the state of replicative senescence is poorly defined by the number of population doublings or even by the number of passages. Reliable molecular measures for cellular aging are urgently needed. PMID- 20196649 TI - Virus entry by endocytosis. AB - Although viruses are simple in structure and composition, their interactions with host cells are complex. Merely to gain entry, animal viruses make use of a repertoire of cellular processes that involve hundreds of cellular proteins. Although some viruses have the capacity to penetrate into the cytosol directly through the plasma membrane, most depend on endocytic uptake, vesicular transport through the cytoplasm, and delivery to endosomes and other intracellular organelles. The internalization may involve clathrin-mediated endocytosis (CME), macropinocytosis, caveolar/lipid raft-mediated endocytosis, or a variety of other still poorly characterized mechanisms. This review focuses on the cell biology of virus entry and the different strategies and endocytic mechanisms used by animal viruses. PMID- 20196650 TI - Designing better healthcare environments: interprofessional competencies in healthcare design. AB - There has been considerable interest in bridging educational programs in the United States across healthcare, architecture, industrial design, and human computing disciplines to design more effective and safer healthcare environments. New combinations of professionals including those outside the traditional healthcare disciplines are coming together to solve quality and safety problems and to re-envision the physical and social design of healthcare organizations. Little is known about the knowledge and skills essential to integrate these diverse perspectives and pose innovative solutions. A set of seven interprofessional competencies were identified through review of the literature, interviews of faculty and leaders in the field, and experience of the authors teaching interprofessional courses in healthcare design. The relevance and feasibility of these competencies were assessed through expert review by faculty and consultants and implementation in multiple courses. PMID- 20196651 TI - Detection of a substantial rate of multidrug-resistant tuberculosis in an HIV infected population in South Africa by active monitoring of sputum samples. AB - BACKGROUND: Tuberculosis (TB) coinfection with human immunodeficiency virus (HIV) is a substantial problem in South Africa. There has been a presumption that drug resistant strains of TB are common in South Africa, but few studies have documented this impression. METHODS: In Phidisa, a joint observational and randomized HIV treatment study for South African National Defence Force members and dependents, an initiative was launched to test subjects (by use of microbiologic TB test) who appeared to be at high risk. We report results for HIV infected subjects. RESULTS: TB was identified by culture in 116 (19.9%) of 584 patients selected for sputum examination on the basis of suggestive symptoms. Smear was an insensitive technique for confirming the diagnosis: only 33% of culture-positive patients were identified by smear, with a 0.2% false-positive rate. Of the 107 culture-positive individuals with susceptibility testing, 22 (20.6%) were identified to be multidrug resistant (MDR), and 4 (3.7%) were identified to be extensively drug resistant. Culture-positive cases with a history of TB treatment had more than twice the rate of MDR than those without (27.1% vs 11.9%; P = .05). CONCLUSIONS: TB is common in this cohort of HIV infected patients. Smear was not a sensitive technique for identifying culture positive cases in this health system. Drug susceptibility testing is essential to proper patient management because MDR was present in 20.6% of culture-positive patients. Better management strategies are needed to reduce the development of MDR TB, because so many of these patients had received prior antituberculous therapy that was presumably not curative. PMID- 20196652 TI - Spinal deformity and Parkinson disease: a treatment algorithm. AB - OBJECT: The authors review the literature on the treatment of spinal deformity in patients with Parkinson disease (PD) and formulate a treatment algorithm. METHODS: The authors provide representative cases of patients with PD and spinal deformity who underwent deep brain stimulation (DBS) or spinal surgery. RESULTS: In patients with PD and spinal deformity who undergo spinal surgery there is a high rate of acute and delayed complications. Patients who undergo DBS, while having significantly fewer complications, often do not regain sagittal balance. CONCLUSIONS: Cases involving PD and camptocormia have a high rate of complications when spinal surgery is performed. The authors prefer to offer spinal surgery only to patients with coexisting spinal stenosis causing radiculopathy or myelopathy. Patients with PD and camptocormia without spinal stenosis may be considered for DBS, but the results are mixed. PMID- 20196653 TI - Antiretroviral drug use during pregnancy and risk of premature delivery: is there a connection? PMID- 20196655 TI - Efficient suppression of minority drug-resistant HIV type 1 (HIV-1) variants present at primary HIV-1 infection by ritonavir-boosted protease inhibitor containing antiretroviral therapy. AB - BACKGROUND: Selection of preexisting minority variants of drug-resistant human immunodeficiency virus type 1 (HIV-1) can lead to virological failure in patients who receive antiretroviral therapy (ART) with low genetic resistance barriers. We studied treatment response and dynamics of minority variants during the first weeks of ART containing a ritonavir-boosted protease inhibitor (PI) and 2 nucleoside reverse-transcriptase inhibitors (NRTIs), which is a regimen with a high genetic resistance barrier. METHODS: Plasma samples obtained prior to initiation of ART from 109 patients with primary HIV infection and samples obtained during viral decay during early ART from 17 of these 109 patients were tested by allele-specific polymerase chain reaction for K103N and M184V variants. RESULTS: K103N and/or M184V mutations were detected in 15 (13.8%) of 109 patients prior to ART as minority variants. No selection of these variants was observed within the first weeks of ART in 7 of 15 patients with preexisting drug resistance mutations, nor was any selection observed in 10 patients without preexisting drug resistance mutations. Most patients received ART immediately after diagnosis of HIV-1 infection, showed a rapid decrease in viral load, and experienced sufficient suppression of viremia for 48 months. CONCLUSIONS: Minority variants, in particular viruses harboring the M184V mutation, were efficiently suppressed in patients with acute infection who received a ritonavir boosted PI and 2 NRTIs (most regimens included lamivudine). Under this high genetic resistance barrier regimen, the M184V was not further selected. PMID- 20196654 TI - Prenatal protease inhibitor use and risk of preterm birth among HIV-infected women initiating antiretroviral drugs during pregnancy. AB - BACKGROUND: Conflicting results have been reported among studies of protease inhibitor (PI) use during pregnancy and preterm birth. Uncontrolled confounding by indication may explain some of the differences among studies. METHODS: In total, 777 human immunodeficiency virus (HIV)-infected pregnant women in a prospective cohort who were not receiving antiretroviral (ARV) treatment at conception were studied. Births <37 weeks gestation were reviewed, and deliveries due to spontaneous labor and/or rupture of membranes were identified. Risk of preterm birth and low birth weight (<2500 g) were evaluated by using multivariable logistic regression. RESULTS: Of the study population, 558 (72%) received combination ARV with PI during pregnancy, and a total of 130 preterm births were observed. In adjusted analyses, combination ARV with PI was not significantly associated with spontaneous preterm birth, compared to ARV without PI (odds ratio [OR], 1.22; 95% confidence interval [CI], 0.70-2.12). Sensitivity analyses that included women who received ARV prior to pregnancy also did not identify a significant association (OR, 1.34; 95% CI, 0.84-2.16). Low birth weight results were similar. CONCLUSIONS: No evidence of an association between use of combination ARV with PI during pregnancy and preterm birth was found. Our study supports current guidelines that promote consideration of combination ARV for all HIV-infected pregnant women. PMID- 20196656 TI - Shiga toxin 2-specific but not shiga toxin 1-specific human monoclonal antibody protects piglets challenged with enterohemorrhagic Escherichia coli producing shiga toxin 1 and shiga toxin 2. AB - Escherichia coli strains that produce Shiga toxin 2 (Stx2) are isolated from hemolytic-uremic syndrome (HUS) cases more frequently than are strains that produce both Shiga toxin 1 (Stx1) and Stx2, whereas strains that produce only Stx1 are rarely isolated from HUS cases. Studies have implicated Stx2 as the sole contributor to acute kidney failure and other systemic complications in humans. The aim of the present study was to determine whether Stx2-specific antibody would be as effective against Shiga toxin-producing Escherichia coli (STEC) strains that produce both Stx1 and Stx2 as it is against strains that produce only Stx2, compared with Stx1-specific antibody. We found that Stx2-specific and Stx1-specific antibodies protected 100% and 0% of piglets, respectively, against oral challenge with a Stx1- and Stx2-producing STEC strain. We conclude that Stx2 specific antibody is sufficient to protect piglets, and possibly humans, against STEC strains that produce both toxins. PMID- 20196657 TI - Bacteriophages can treat and prevent Pseudomonas aeruginosa lung infections. AB - Antibiotic-resistant bacteria threaten life worldwide. Although new antibiotics are scarce, the use of bacteriophages, viruses that infect bacteria, is rarely proposed as a means of offsetting this shortage. Doubt also remains widespread about the efficacy of phage therapy despite recent encouraging results. Using a bioluminescent Pseudomonas aeruginosa strain, we monitored and quantified the efficacy of a bacteriophage treatment in mice during acute lung infection. Bacteriophage treatment not only was effective in saving animals from lethal infection, but also was able to prevent lung infection when given 24 h before bacterial infection, thereby extending the potential use of bacteriophages as therapeutic agents to combat bacterial lung infection. PMID- 20196658 TI - The 2009 version of the cancer protocols of the college of american pathologists. PMID- 20196659 TI - Practices of participants in the college of american pathologists interlaboratory comparison program in cervicovaginal cytology, 2006. AB - CONTEXT: Liquid-based preparations (LBPs) and human papillomavirus testing have led to changes in cervical cytology practices. The College of American Pathologists attempts to track practice patterns using a supplemental questionnaire, which allows laboratories to report diagnostic practices. OBJECTIVE: To analyze the 2006 reporting practices and to compare the results with the 2003 survey data. DESIGN: Questionnaire was mailed to 1621 laboratories. Participants included laboratories enrolled in the 2006 College of American Pathologists Gynecologic Proficiency Testing Program or the educational Interlaboratory Comparison Program in Gynecologic Cytology. RESULTS: Of the 679 responding laboratories (response rate, 42%), most (97.8%; n = 664) had implemented the Bethesda 2001 terminology. The median rate for all preparations with low-grade squamous intraepithelial lesions was 2.5% (2.9% for LBPs) compared with a 2003 median rate of 2.1%; the increase was confined to LBPs. Rates for high-grade squamous intraepithelial lesions (median, 0.5%) and atypical squamous cells have changed little. High-grade squamous intraepithelial lesions and unsatisfactory rates varied at statistically significant levels between types of LBPs. Most atypical squamous cell cases were subclassified as undetermined significance (median, 4.3%). The median ratio of atypical squamous cells to squamous intraepithelial lesions and carcinomas for all specimen types combined was 1.5, similar to the 2003 median ratio of 1.4. The median rates for findings of squamous cell abnormalities for 2006 were significantly higher for LBPs than for conventional smears. CONCLUSIONS: Most responding laboratories have implemented the Bethesda 2001 terminology. There is an increase in LBP low-grade squamous intraepithelial lesion rates when compared with 2003 data. Liquid-based preparations have higher median squamous intraepithelial lesion and atypical squamous cell rates. PMID- 20196661 TI - Protocol for the examination of specimens from patients with merkel cell carcinoma of the skin. PMID- 20196660 TI - Protocol for the examination of specimens from patients with hematopoietic neoplasms of the ocular adnexa. PMID- 20196662 TI - Protocol for the examination of specimens from patients with carcinoma of the urethra. PMID- 20196663 TI - Pseudoneoplastic lesions: general considerations. AB - Pseudoneoplastic lesions ("pseudotumors") can be seen in virtually all anatomic locations. Some organ sites, such as the lungs and skin, are overrepresented for unknown reasons, and the histologic images seen in pseudoneoplastic lesions are partially overlapping in disparate locations. More than occasionally, the degree of histologic likeness to true neoplasms-often malignant ones-is striking. This overview outlines the spectrum of pseudoneoplastic lesions and divides them into etiologic categories, including reparative, developmental, functional (usually endocrine), iatrogenic, infectious, and idiopathic. Side-by-side pictorial comparisons of selected pseudoneoplastic lesions and their neoplastic mimics are included. PMID- 20196664 TI - Cardiovascular pseudoneoplasms. AB - CONTEXT: Primary cardiac tumors are rare and the great majority are benign neoplasms. Mass-forming reactive and pseudoneoplastic growths are less common, but recognizing and distinguishing these lesions from the neoplasms they resemble is critical to appropriate patient care. OBJECTIVE: The general clinical, imaging, gross pathologic, and histologic features of 5 important pseudoneoplasms (inflammatory myofibroblastic tumor, hamartoma of mature cardiac myocytes, mesothelial/monocytic cardiac excrescences, calcified amorphous tumor, and lipomatous hypertrophy of the atrial septum) are discussed, with an emphasis on features differentiating them from other benign and malignant tumors. DATA SOURCES: Pertinent citations of the literature and observations from the authors' experience are drawn upon. CONCLUSIONS: While lacking malignant potential, these lesions can be associated with considerable morbidity and occasional mortality. Their recognition is important in guiding patient management, providing both guidance for appropriate therapy and avoidance of inappropriately aggressive and toxic treatments. PMID- 20196665 TI - Selected pseudoneoplastic lesions of the skin. AB - CONTEXT: Pseudoneoplastic cutaneous lesions are diverse, not only morphologically but also with respect to their causes and cellular lineages. They include proliferations of epithelial, as well as mesenchymal, elements. OBJECTIVE: This review aims to consider selected lesions in the aforementioned groups, contrasting them with histologically similar neoplasms of the skin in a differential diagnostic setting. DATA SOURCES: Information used in assembling this discussion was drawn from the published literature on cutaneous pseudoneoplasms, using an Internet-based search engine. The authors' collective experience was also used in writing this review. CONCLUSIONS: Sufficient clinical and morphologic differences exist in virtually all instances to separate pseudoneoplastic cutaneous proliferations from the tumors that they imitate. PMID- 20196666 TI - Pseudoneoplasms of the gastrointestinal tract. AB - CONTEXT: The pathologist plays the leading role in distinguishing pseudoneoplasms from truly neoplastic lesions in the gastrointestinal tract. OBJECTIVE: This review was conducted to heighten awareness of pseudoneoplasms, to help differentiate among the various types of pseudoneoplasms, and to help distinguish pseudoneoplasms from malignancies. DATA SOURCES: This review is based on the medical literature on pseudoneoplasms in MEDLINE and the authors' own experiences. Reference lists of retrieved articles were also reviewed to identify additional articles. CONCLUSIONS: A classification of pseudoneoplasms, according to the mechanism of injury to the gastrointestinal tract, morphologic patterns, and heterotopia, may be useful in providing a diagnostic framework in which ancillary techniques often have a diagnostic role. Several pseudoneoplasms may be closely associated with true neoplasms (eg, malakoplakia, prolapsetype lesions) because of the nonspecific nature of the response of the intestine to injury. PMID- 20196667 TI - Pseudoneoplastic lesions of the female genital tract. AB - CONTEXT: Numerous benign, proliferative, or reactive processes, often related to hormone stimulation or inflammation, occur throughout the female genital tract and may mimic benign or malignant tumors. Several of the more common pseudoneoplastic lesions are discussed in this article, including microglandular hyperplasia of the cervix mimicking well-differentiated endometrial adenocarcinoma, reactive epithelial changes in the fallopian tubes mimicking adenocarcinoma or carcinoma in situ, and pregnancy changes in the ovary including pregnancy luteoma and large solitary luteinized follicular cyst of pregnancy and puerperium that may mimic ovarian neoplasms. OBJECTIVES: To discuss and illustrate several common lesions of the female genital tract that mimic neoplasms. DATA SOURCES: Material derived from consultation cases and review of the literature. CONCLUSIONS: Many benign hyperplastic or reactive processes that occur in the female genital tract may be mistaken for neoplasms both clinically and pathologically. Awareness of the features of such lesions will aid in their correct diagnosis and prevent overtreatment of benign processes. PMID- 20196668 TI - Pseudoneoplasms of the nervous system. AB - CONTEXT: Pseudoneoplasms of the nervous system vary greatly in nature. Ranging from inflammatory to autoimmune, infectious, malformative, reactive, degenerative, and radiation induced, they all mimic true tumors. Thus, they have the potential to mislead clinicians, radiologists, and pathologists alike. Their clinical and/or neuroimaging and histologic features are readily misinterpreted as tumor. Knowledge of the pitfalls is essential to avoid mismanagement, specifically overtreatment. In such instances, pathologists must take the entire clinical picture into consideration, acquainting themselves with presenting symptoms, physical findings, and neuroimaging. OBJECTIVE: To present 10 examples of pseudoneoplasms of the nervous system, analyze the basis for their mimicry, and discuss their differential diagnosis. DATA SOURCES: Review of the pertinent literature related to pseudoneoplasms of the nervous system and review of the consultation files of one of the authors (B.W.S.). CONCLUSIONS: The identification of tumor mimics may be difficult under the best of circumstances, and maintaining a broad differential diagnosis as well as application of a variety of immunocytochemical and occasionally ultrastructural and/or molecular genetic methods is essential to arrive at a correct diagnosis. PMID- 20196669 TI - Pulmonary pseudoneoplasms. AB - CONTEXT: Not uncommonly, a surgical pathologist will be requested to review excised material, with a clinical diagnosis of cancer, in which no malignancy can be identified. Often, sampling may be the issue. However, different nonneoplastic processes may mimic cancer clinically and not be recognized histologically. These are commonly referred to as pseudoneoplasms and can involve the lung, pleura, and mediastinum. OBJECTIVE: To review the most commonly encountered pseudoneoplasms of the thoracic cavity in surgical pathology and discuss the main differential diagnosis. DATA SOURCES: Literature and personal review of cases with focus on inflammatory pseudotumors of the lung, organizing pneumonia, nodular lymphoid hyperplasia, apical cap, round atelectasis, and sclerosing mediastinitis with its pulmonary counterpart, hyalinizing granuloma. CONCLUSIONS: When reviewing specimens that appear nondiagnostic for malignancy, it is important to consider one of these pseudoneoplasms in the differential diagnosis as they may explain the clinical and radiologic information. PMID- 20196670 TI - Pseudoneoplastic mimics of prostate and bladder carcinomas. AB - CONTEXT: The differential diagnoses of prostatic carcinoma and bladder epithelial neoplasms include several histologic mimics that should be known to avoid misdiagnosis. OBJECTIVE: To discuss pseudoneoplastic lesions of the prostate and bladder that could potentially be confused with prostatic carcinoma and bladder epithelial neoplasms, respectively, with specific focus on their distinguishing histopathologic features. DATA SOURCES: Relevant published literature and authors' experience. CONCLUSIONS: Pseudoneoplastic lesions in the prostate include those of prostatic epithelial origin, the most common being atrophy, adenosis (atypical adenomatous hyperplasia), basal cell hyperplasia, and crowded benign glands, as well as those of nonprostatic origin, such as seminal vesicle epithelium. Such lesions often mimic lower-grade prostatic adenocarcinoma, whereas others, such as clear cell cribriform hyperplasia and granulomatous prostatitis, for example, are in the differential diagnosis of Gleason adenocarcinoma, Gleason grade 4 or 5. Pseudoneoplastic lesions of the urinary bladder include lesions that could potentially be confused with urothelial carcinoma in situ, such as reactive urothelial atypia, and others, such as polypoid/papillary cystitis, where papillary urothelial neoplasms are the main differential diagnostic concern. Several lesions can mimic invasive urothelial carcinoma, including pseudocarcinomatous hyperplasia, von Brunn nests, and nephrogenic adenoma. Diagnostic awareness of the salient histomorphologic and relevant immunohistochemical features of these prostatic and urinary bladder pseudoneoplasms is critical to avoid rendering false-positive diagnoses of malignancy. PMID- 20196671 TI - Quantitative real-time polymerase chain reaction detection of BK virus using labeled primers. AB - CONTEXT: BK virus infections among immunocompromised patients are associated with disease of the kidney or urinary bladder. High viral loads, determined by quantitative polymerase chain reaction (PCR), have been correlated with clinical disease. OBJECTIVE: To develop and evaluate a novel method for real-time PCR detection and quantification of BK virus using labeled primers. DESIGN: Patient specimens (n = 54) included 17 plasma, 12 whole blood, and 25 urine samples. DNA was extracted using the MagNA Pure LC Total Nucleic Acid Isolation Kit (Roche Applied Science, Indianapolis, Indiana); sample eluate was PCR-amplified using the labeled primer PCR method. Results were compared with those of a user developed quantitative real-time PCR method (fluorescence resonance energy transfer probe hybridization). RESULTS: Labeled primer PCR detected less than 10 copies per reaction and showed quantitative linearity from 10(1) to 10(7) copies per reaction. Analytical specificity of labeled primer PCR was 100%. With clinical samples, labeled primer PCR demonstrated a trend toward improved sensitivity compared with the reference method. Quantitative assay comparison showed an R(2) value of 0.96 between the 2 assays. CONCLUSIONS: Real-time PCR using labeled primers is highly sensitive and specific for the quantitative detection of BK virus from a variety of clinical specimens. These data demonstrate the applicability of labeled primer PCR for quantitative viral detection and offer a simplified method that removes the need for separate oligonucleotide probes. PMID- 20196672 TI - Activation-induced cytidine deaminase expression in diffuse large B-cell lymphoma with a paracortical growth pattern: a lymphoma of possible interfollicular large B-cell origin. AB - CONTEXT: Activation-induced cytidine deaminase, necessary for immunoglobulin somatic hypermutation and class switch recombination, is usually expressed within the follicular dendritic network but is also expressed in a population of interfollicular large B cells outside the germinal center. OBJECTIVE: To report 7 cases of diffuse large B-cell lymphoma with a distinct paracortical distribution. Expression of activation-induced cytidine deaminase, previously described in interfollicular large B cells, was evaluated. DESIGN: A panel of immunohistochemical markers, including double staining for activation-induced cytidine deaminase and CD20, was used to illustrate the cases. Molecular studies were performed by polymerase chain reaction in the paraffin-embedded tissue for t(14;18) chromosomal translocation and immunoglobulin heavy chain and T-cell receptor rearrangements. RESULTS: Patients included 3 males and 4 females ranging in age from 11 to 59 years (mean, 39 years). All specimens were lymph nodes (4 from the groin, 2 from the neck, and 1 from the axilla). Malignant lymphocytes were positive for CD20 and negative for CD5 and CD10. Staining for CD30, CD43, and BCL-2 was variable. The malignant cells showed at least focal staining with activation-induced cytidine deaminase. All cases were found to be monoclonal by immunoglobulin heavy-chain gene rearrangement or showed light-chain restriction. None of the tested cases showed t(14;18). CONCLUSIONS: Diffuse large B-cell lymphoma with a paracortical distribution is unusual and may be a distinct morphologic variant. More study is necessary to determine the stage of B-cell development and the cell of origin of these tumors. However, activation-induced cytidine deaminase expression suggests they may arise from a putative interfollicular large B cell. PMID- 20196673 TI - Asbestos fiber content of lungs with diffuse interstitial fibrosis: An analytical scanning electron microscopic analysis of 249 cases. AB - CONTEXT: Asbestosis is one of many forms of diffuse interstitial pulmonary fibrosis. Its histologic diagnosis rests on the pattern of fibrosis and the presence of asbestos bodies by light microscopy in lung biopsies. OBJECTIVE: To determine the asbestos fiber burden in patients with diffuse pulmonary fibrosis (DPF) who had a history of asbestos exposure, but whose biopsies did not meet established criteria for asbestosis, and compare it with the fiber burden in confirmed asbestosis cases. DESIGN: Fiber burden analysis was performed using scanning electron microscopy and energy-dispersive x-ray analysis of lung parenchyma from 86 patients with DPF and 163 patients with asbestosis. The correlation of the number of asbestos fibers found for a quantitative degree of fibrosis was analyzed. RESULTS: The fibrosis scores of the asbestosis cases correlated best with the number of uncoated commercial amphibole fibers. Seven DPF cases fell within the 95% interval of asbestos body count by light microscopy and 3 cases within that of the total commercial amphibole fiber count. CONCLUSIONS: Strict histologic criteria are useful for positive identification of asbestosis among cases of advanced pulmonary fibrosis. Few DPF patients with history of asbestos exposure whose biopsies did not meet the criteria for asbestosis may have asbestos fiber counts in the range seen in asbestosis, and fiber type identification by scanning electron microscopy with energy-dispersive x-ray analysis should be considered in these rare instances to avoid false positive and false-negative diagnoses of asbestosis. PMID- 20196674 TI - Pathology of asbestosis- An update of the diagnostic criteria: Report of the asbestosis committee of the college of american pathologists and pulmonary pathology society. AB - Asbestosis is defined as diffuse pulmonary fibrosis caused by the inhalation of excessive amounts of asbestos fibers. Pathologically, both pulmonary fibrosis of a particular pattern and evidence of excess asbestos in the lungs must be present. Clinically, the disease usually progresses slowly, with a typical latent period of more than 20 years from first exposure to onset of symptoms. DIFFERENTIAL DIAGNOSIS: IDIOPATHIC PULMONARY FIBROSIS: The pulmonary fibrosis of asbestosis is interstitial and has a basal subpleural distribution, similar to that seen in idiopathic pulmonary fibrosis, which is the principal differential diagnosis. However, there are differences between the 2 diseases apart from the presence or absence of asbestos. First, the interstitial fibrosis of asbestosis is accompanied by very little inflammation, which, although not marked, is better developed in idiopathic pulmonary fibrosis. Second, in keeping with the slow tempo of the disease, the fibroblastic foci that characterize idiopathic pulmonary fibrosis are infrequent in asbestosis. Third, asbestosis is almost always accompanied by mild fibrosis of the visceral pleura, a feature that is rare in idiopathic pulmonary fibrosis. DIFFERENTIAL DIAGNOSIS: RESPIRATORY BRONCHIOLITIS: Asbestosis is believed to start in the region of the respiratory bronchiole and gradually extends outward to involve more and more of the lung acinus, until the separate foci of fibrosis link, resulting in the characteristically diffuse pattern of the disease. These early stages of the disease are diagnostically problematic because similar centriacinar fibrosis is often seen in cigarette smokers and is characteristic of mixed-dust pneumoconiosis. Fibrosis limited to the walls of the bronchioles does not represent asbestosis. ROLE OF ASBESTOS BODIES: Histologic evidence of asbestos inhalation is provided by the identification of asbestos bodies either lying freely in the air spaces or embedded in the interstitial fibrosis. Asbestos bodies are distinguished from other ferruginous bodies by their thin, transparent core. Two or more asbestos bodies per square centimeter of a 5- mu m-thick lung section, in combination with interstitial fibrosis of the appropriate pattern, are indicative of asbestosis. Fewer asbestos bodies do not necessarily exclude a diagnosis of asbestosis, but evidence of excess asbestos would then require quantitative studies performed on lung digests. ROLE OF FIBER ANALYSIS: Quantification of asbestos load may be performed on lung digests or bronchoalveolar lavage material, employing either light microscopy, scanning electron microscopy, or transmission electron microscopy. Whichever technique is employed, the results are only dependable if the laboratory is well practiced in the method chosen, frequently performs such analyses, and the results are compared with those obtained by the same laboratory applying the same technique to a control population. PMID- 20196675 TI - Pediatric angiosarcoma of soft tissue: a rare clinicopathologic entity. AB - Angiosarcomas are rare tumors that predominantly affect adults and elderly patients. Although angiosarcomas are well described in a variety of clinical settings, they have been poorly studied in children and little is known about their biology, natural history, or optimal treatment. Childhood angiosarcomas are exceedingly rare. The head and neck region and mediastinum seem to be the preferred locations. Most tumors are high-grade tumors. Vasoformative architecture is not always obvious on light microscopy requiring the benefit of immunohistochemical study. The differential diagnosis includes Kaposi sarcoma, epithelioid hemangioendothelioma, hemangiopericytoma, and spindle cell hemangioendothelioma whose prognosis is different. Complete resection is required for patients with localized tumors. Malignant vascular tumors are rare in children in the first 2 decades of life and when they do occur they seem to be more aggressive than in adults. Pathologic diagnosis is difficult particularly in poorly differentiated angiosarcomas requiring immunohistochemical study to confirm vascular differentiation. PMID- 20196676 TI - Determinants of change in paternal smoking trends during pregnancy in Lebanon. AB - For pregnant women and their fetus, secondhand smoking poses major public health effects. This study analyzes the determinants of change in smoking behavior among fathers whose partners were pregnant. The study is a secondary analysis of a nationally representative Lebanese cross-sectional survey of 1,028 households conducted in 2007. Currently smoking fathers with a child of 5 years of age or less were included. The main outcome was the change in the father's smoking behavior during his wife's last pregnancy. The study concluded that fathers who changed their smoking patterns when their wives were pregnant were significantly more educated, more likely to smoke a lesser number of cigarettes per day (OR = 96, 95% CI (0.93, 0.99)), and more knowledgeable about cigarette constitutes and its health risks (OR = 1.37, 95% CI (1.08, 1.74). Public health practitioners and health professionals are recommended to raise awareness and provide cessation programs for parents and especially fathers. PMID- 20196677 TI - Periodontal disease in pregnancy is a risk factor for preeclampsia. AB - Many recent studies have evaluated the relation between periodontitis and pregnancy complications. This study aimed to examine the association between preeclampsia and periodontitis in Indian women. A total of 130 pregnant women were enrolled between 26-32 weeks of gestation. Oral health examinations were performed at recruitment and again within 48 hours of delivery to determine the presence and/or progression of periodontitis in all subjects. Pocket depth, clinical attachment loss (CAL), and gingival index were measured in all subjects. There was significant (p < 0.05) difference between the preeclampsia and normotensive groups in the distribution of periodontitis both at recruitment and after delivery. Multiple logistic regression demonstrated that periodontitis both at enrolment (OR = 5.78, 95% CI 2.41-13.89) as well as within 48 hours of delivery (OR = 20.15, 95% CI 4.55-89.29), may be associated with an increased risk of preeclampsia. PMID- 20196679 TI - Infertility, mental disorders and well-being--a nationwide survey. AB - OBJECTIVE: Earlier studies suggest that infertility and mental health problems are related and that infertility is a different experience for women and men. The aim of this population-based study is to examine mental disorders, depressivity, psychological distress, perceived health and quality of life among women and men who have experienced infertility. DESIGN: Cross-sectional nationwide Health 2000 Survey. SETTING: Population-based. POPULATION: A representative random sample of Finnish people aged 30-44 years (n = 2291). METHODS: Outcomes were compared between those who had experienced infertility (n = 338) and the rest of the population. Age, marital status, education, income, body mass index, and smoking were controlled for using logistic and linear regressions. MAIN OUTCOME MEASURES: Mental disorders (composite international diagnostic interview, CIDI), depressivity (Beck Depression Inventory, BDI), psychological distress (general health questionnaire, GHQ-12), perceived health, and subjective quality of life. RESULTS: Approximately 20% of women and 9% of men reported having experienced infertility. Childless women with infertility experience had increased adjusted risks for dysthymia (OR 3.41, 95% CI; 1.01-11.5) and anxiety disorders (2.67, 1.00-7.12) compared to women who had not experienced infertility. Women with infertility experience but with a current child had an increased risk for panic disorder (2.58, 1.11-6.01). Childless men with infertility experience had a significantly poorer quality of life compared to men without infertility. CONCLUSIONS: Infertility was associated with mental health, especially dysthymia and anxiety. The results differed by gender and the permanency of infertility. Gender-specific psychosocial support and follow-up for infertile people is warranted. PMID- 20196678 TI - Promoting smoking cessation in pregnancy with Video Doctor plus provider cueing: a randomized trial. AB - OBJECTIVE: This study examined the use of a Video Doctor plus provider cueing to promote provider advice and smoking cessation outcomes in pregnancy. DESIGN: A randomized clinical trial was conducted from 2006 to 2008. SETTING: Five community prenatal clinics in the San Francisco Bay Area of the United States. PARTICIPANTS: A total of 410 pregnant patients completed screening for behavioral risks including tobacco use in the past 30 days. Pregnant smokers (n = 42) were randomized regardless of their intention to quit smoking. METHODS: Participants were assigned to either usual care or intervention. Intervention participants received 15-minute Video Doctor sessions plus provider cueing, at baseline and one month, prior to their routine prenatal visit. The Video Doctor delivered interactive tailored messages, an educational worksheet for participants, and a cueing sheet for providers. MAIN OUTCOME MEASURES: Receipt of advice from the provider and 30-day smoking abstinence, both by self-report. RESULTS: Intervention participants were more likely to receive provider advice on tobacco use at both prenatal visits during the intervention period (60.9 vs. 15.8%, p = 0.003). The intervention yielded a significantly greater decrease in the number of days smoked and in cigarettes smoked per day. The 30-day abstinence rate at two months post baseline was 2.5 times greater in the intervention group; the difference was not significant (26.1 vs. 10.5%, p = 0.12). CONCLUSIONS: The Video Doctor plus provider cueing is an efficacious adjunct to routine prenatal care by promoting provider advice and smoking reduction among pregnant smokers. PMID- 20196680 TI - Antigen-specific immunoadsorption of anti-acetylcholine receptor antibodies from sera of patients with myastenia gravis. AB - BACKGROUND: The binding of anti-acetylcholine receptor antibodies (AChRAb) to the main immunogenic region (MIR) of AChR alpha-subunit in the neuromuscular junction is the major pathogenesis of myasthenia gravis (MG). METHODS: A synthetic peptide of 10 amino acids corresponding to the MIR of human AChR was coupled with cellulose beads to make an antigen-specific immunoadsorbent (hMIR10-CB). RESULTS: The hMIR10-CB could remove AChRAb in MG sera by 40.3+/-2.3%, compared to a tryptophan nonspecific adsorbent Trp-CB by only 22.4+/-1.5% as determined in ELISA, and also showed good blood compatibility for blood cells, plasma ions and plasma proteins as checked in whole blood perfusion in rabbits. CONCLUSIONS: The antigen-specific immunoadsorbent hMIR10-CB can serve as a potential candidate in the immunoadsorption treatment of MG. PMID- 20196682 TI - Hypoxia due to shunts in pig lung treated with O2 and fluorocarbon-derived intravascular microbubbles. AB - RATIONALE: Earlier work has shown that experimental conditions calling for improved tissue oxygenation could be assisted by i.v. infusion of a dodecafluoropentane emulsion (DDFPe) forming oxygen-transporting microbubbles. OBJECTIVES: The present work investigated the effect of DDFPe on hypoxia due to experimental shunts in the pig lung. METHODS: Nineteen O(2) breathing, anesthetized pigs had glass beads administered into the trachea so as to significantly depress arterial oxygen tension (PaO(2)). PaO(2) was recorded for up to 12 hrs while 0.1 ml/kg DDFPe was administered 1-3 times. MAIN RESULTS: The animals were divided into two groups based on arterial oxygen saturation (SaO(2)) after shunt induction, combined with oxygen breathing: the "SaO(2) >90% group" (n=6) and the "SaO(2) <90% group" (n=13). In the "SaO(2) <90% group," the PaO(2) increased stepwise with each infusion from 56.6+/-2.9 to 88.6+/-14.6 mmHG (P1 year participated in the study. Two observers measured stump volume twice, two weeks apart, using both Sitzia's method and the water displacement volumetric method (criterion standard test). The mean differences and upper and lower limits of agreement between the water displacement volumetric method and Sitzia's method, between the first and second assessment, and between both assessors were calculated. Intra-class correlation coefficients (ICCs) were derived from random effects two-way analysis of variance. Inter-observer agreements of both methods were high and ranged from 86-96%. Intra-observer agreement ranged between 57% and 71%. In both methods the inter- and intra-observer differences were not significant. ICCs ranged from 0.88-0.99 and were better for inter-observer compared to intra-observer reproducibility. Lower stump volumes were observed in Sitzia's method compared to water displacement volumetric method, with high ICC's (0.92-0.95) between both methods. Although Sitzia's method systematically underestimates stump volume, it is a reliable and feasible alternative to the criterion standard test. To determine its validity to detect (longitudinal) differences in stump volume, follow-up research is needed in participants with recent amputations. PMID- 20196687 TI - Energy expenditure of walking with prostheses: comparison of three amputation levels. AB - Amputee patients spend more energy during walking than able-bodied persons. It is generally accepted that more proximal amputation is associated with more energy need. However, the picture is not clear, especially for partial foot amputees. The purpose of this study was to compare the energy consumption of walking in traumatic unilateral amputees with three different amputation levels (trans femoral, trans-tibial and partial foot amputations). Sixty-four male unilateral traumatic amputees participated in this study. Energy expenditure during walking was measured for four different speed and slope combinations: 1.5 km/h and 0 degrees slope, 3 km/h and 0 degrees slope, 1.5 km/h and 5 degrees slope, 3 km/h and 5 degrees slope. Mean O(2) consumption (ml/kg/min) of the last 2 min of each 5-min session was calculated. In all four combinations, energy expenditure of trans-tibial amputees was the lowest, and energy expenditure of trans-femoral amputees was the highest. Statistical significance, however, could not be obtained for the differences among the groups. In conclusion, walking of partial foot amputees does not seem to be more energy efficient than that of higher level amputees. PMID- 20196685 TI - Magnetic resonance spectroscopy for evaluation of liposome-encapsulated hemoglobin as a resuscitation fluid. AB - Liposome-encapsulated hemoglobin (LEH) based on a novel, synthetic, non phospholipid was developed, and evaluated for cerebral energy metabolism in a 40% hemorrhage rat model. The markers of tissue energetics were monitored by (1)H- and (31)P-magnetic resonance spectroscopy (MRS). After hemorrhage, (1)H-MRS showed an increase in the levels of lactate and pyruvate. These markers returned to baseline values following LEH resuscitation. Both LEH and saline were able to exert a neuron-protective effect as indicated by the recovery of N acetylaspartate. (31)P MRS showed a fall in phosphocreatine after hemorrhage, which upon LEH or saline resuscitation returned to the baseline values. Similarly, inorganic phosphate increased after bleeding, but returned to normal after resuscitation. LEH resuscitation also recovered beta-ATP levels, but saline resuscitation provided only a modest recovery. The results indicate the utility of MRS to monitor cerebral metabolism in hemorrhage/resuscitation. The data is also supportive of the new LEH formulation as an oxygen carrier. PMID- 20196688 TI - Active upper limb prosthesis based on natural movement trajectories. AB - The motion of the current prostheses is sequential and does not allow natural movements. In this work, complex natural motion patterns from a healthy upper limb were characterized in order to be emulated for a trans-humeral prosthesis with three degrees of freedom at the elbow. Firstly, it was necessary to define the prosthesis workspace, which means to establish a relationship using an artificial neural network (ANN), between the arm-forearm (3-D) angles allowed by the prosthesis, and its actuators length. The 3-D angles were measured between the forearm and each axis of the reference system attached at the elbow. Secondly, five activities of daily living (ADLs) were analyzed by means of the elbow flexion (EF), the forearm prono-supination (FPS) and the 3-D angles, from healthy subjects, by using a video-based motion analysis system. The 3-D angles were fed to the prosthesis model (ANN) in order to analyze which ADLs could be emulated by the prosthesis. As a result, a prosthesis kinematics approximation was obtained. In conclusion, in spite of the innovative mechanical configuration of the actuators, it was possible to carry out only three of the five ADLs considered. Future work will include improvement of the mechanical configuration of the prosthesis to have greater range of motion. PMID- 20196689 TI - Impairment variables predicting activity limitation in individuals with lower limb amputation. AB - The purpose of this study was to determine whether measures of impairment (i.e., muscle strength, balance), personal factors (i.e., comorbidities, demographic information) and amputation specific variables (i.e., time since amputation, cause of amputation, level of amputation) were able to predict performance on the six-minute walk test, a measure of activity limitation, in individuals with lower limb amputation. A total of 72 individuals with lower limb amputation ranging in age from 21-83 were tested for balance, limb muscle strength and function. Medical comorbidities were recorded and activity limitation was measured using the six-minute walk test. Data were analyzed and multivariate relationships were examined using multiple linear regression. Impairment variables of strength, balance, subject demographics, time since amputation, cause of amputation and level of amputation were all significant predictors and explained 72% of the variance in the outcome variable. Strength of the hip extensors was the strongest predictor, accounting for 30.9% of the total variance. Multiple factors impact six minute walk scores in individuals with lower limb amputation. Impairments in hip strength and balance appear to be the two most significant. The findings of this study support the use of the six-minute walk test to underscore impairments of the musculoskeletal system that can affect ambulation ability in the amputee. PMID- 20196690 TI - Load on osseointegrated fixation of a transfemoral amputee during a fall: loading, descent, impact and recovery analysis. AB - Falling represents a health risk for lower limb amputees fitted with an osseointegrated fixation mainly because of the potential damage to the fixation. The purpose of this study was to characterize a real forward fall that occurred inadvertently to a transfemoral amputee fitted with an osseointegrated fixation while attending a gait measurement session to assess the load applied on the residuum. The objective was to analyze the load applied on the fixation with an emphasis on the sequence of events, the pattern and the magnitude of the forces and moments. The load was measured directly at 200 Hz using a six-channel transducer. Complementary video footage was also studied. The fall was divided into four phases: Loading (240 ms), descent (620 ms), impact (365 ms) and recovery (2495 ms). The main impact forces and moments occurred 870 ms and 915 ms after the heel contact, and corresponded to 133% BW and 17 % BWm, or 1.2 and 11.2 times the maximum forces and moments applied during the previous steps of the participant, respectively. This study provided key information to engineers and clinicians facing the challenge to design equipment, and rehabilitation and exercise programs to restore safely the locomotion of lower limb amputees. PMID- 20196691 TI - Spermatogenesis and fertility outcome in male hypogonadotrophic hypogonadism. AB - OBJECTIVE: The objective of this retrospective study of male patients with hypogonadotrophic hypogonadism (HH) was to assess the outcome of fertility after induction of spermatogenesis by gonadotrophin injections. METHODS: During 1995 2005 17 men with HH were referred to our department for gonadotrophin treatment to stimulate spermatogenesis. RESULTS: Genetic/idiopathic hypogonadotrophic hypogonadism (IHH) was the most common cause (n = 10) followed by post-operative pituitary failure in three cases. In genetic/IHH, 5 out of 10 cases were born in the Middle East. Gonadotrophin injections induced spermatogenesis in 12 out of 13 HH men indicated by presence of ejaculated motile spermatozoa. All men with proved spermatogenesis and a paternity desire became fathers, five through assisted reproduction with intracytoplasmic sperm injection. A total of 16 children were born as a result of gonadotrophin therapy. Three spontaneously conceived singletons and two twin couples after assisted reproduction were born preterm. Two children from two separate dichorionic twin couples were diagnosed with congenital malformations. CONCLUSIONS: Gonadotrophin therapy is successful for men with HH aiming to initiate or re-establish spermatogenesis. Despite low sperm output in some of these men, the rate of pregnancies both spontaneous and after assisted reproduction, was high. More children than expected were born preterm. PMID- 20196693 TI - Differential expression of biofunctional GM1 and GM3 gangliosides within the plastic-adherent multipotent mesenchymal stromal cell population. AB - BACKGROUND AIMS: It is unclear whether the plastic-adherent multipotent mesenchymal stromal cells (MSC) isolated from human bone marrow (BM) represent a uniform cell population or are heterogeneous in terms of cell-surface constituents and hence functionality. METHODS: We investigated the expression profile of certain biofunctional lipids by plastic-adherent MSC, focusing particularly on two membrane microdomain (lipid raft)-associated monosialogangliosides, GM1 and GM3, using indirect confocal laser scanning fluorescence microscopy and flow cytometry. RESULTS: Phenotypically, we observed a differential expression where certain MSC subsets exhibited GM1, GM3 or both at the plasma membrane. Furthermore, disialoganglioside GD2 detection increased the complexity of the expression patterns, giving rise to seven identifiable cell phenotypes. Variation of standard culture conditions, such as the number of cell passage and period in culture, as well as donors, did not influence the heterologous ganglioside expression profile. In contrast, the binding of various lectins appeared homogeneous throughout the MSC population, indicating that the general glycosylation pattern remained common. Morphologically, the expression of a given ganglioside-based phenotype was not related to a cell with particular size or shape. Interestingly, a segregation of GM1 and GM3 clusters was observed, GM3 being mostly excluded from the highly curved plasma membrane protrusions. CONCLUSIONS: These data highlight the phenotypic heterogeneity of plastic adherent MSC in terms of certain lipid constituents of the plasma membrane, and the presence and/or absence of distinct ganglioside-based membrane microdomains suggest their potential functional diversity. PMID- 20196692 TI - Overcoming the barriers to umbilical cord blood transplantation. AB - Umbilical cord blood (UCB) transplantation (UCBT) has seen a marked increase in utilization in recent years, especially in the pediatric population; however, graft failure, delayed engraftment and profound delay in immune reconstitution leads to significant morbidity and mortality in adults. The lack of cells available for post-transplant therapies, such as donor lymphocyte infusions, has also been considered a disadvantage. To overcome the cell-dose barrier, the combination of two UCB units is becoming commonplace in adolescent and adult populations, and is currently being studied in pediatrics as well. In some studies, the use of two UCB units appears to have a positive impact on outcomes; however, engraftment is still suboptimal. A possible additional way to improve outcome and extend applicability of UCBT is via ex vivo expansion. Studies to develop optimal expansion conditions are still in the exploratory phase; however, recent studies suggest expanded UCB is safe and can improve outcomes. The ability to transplant across HLA disparities, rapid procurement time and decreased graft versus-host disease (GvHD) seen with UCBT makes it a promising stem cell source and, while barriers exist, consistent progress is being made to overcome them. PMID- 20196694 TI - Co-transplantation of olfactory ensheathing glia and mesenchymal stromal cells does not have synergistic effects after spinal cord injury in the rat. AB - BACKGROUND AIMS: Olfactory ensheathing glia (OEG) and mesenchymal stromal cells (MSC) are suitable candidates for transplantation therapy of spinal cord injury (SCI). Both facilitate functional improvement after SCI by producing trophic factors and cytokines. In this study, the co-transplantation of both types of cells was studied to clarify their additive and/ or synergistic effects on SCI. METHODS: A balloon-induced compression lesion was used to produce SCI in rats. OEG, MSC or both OEG and MSC (3 x 10(5) cells of each cell type) were implanted by intraspinal injection 1 week after SCI. The effect of transplantation was assessed using behavioral, electrophysiologic and histologic methods. RESULTS: Hindlimb function was examined with Basso, Beattie and Bresnahan (BBB) and Plantar tests. Improvement was found in all three groups of transplanted rats with different time-courses, but there was no significant difference among the groups at the end of the experiment. Motor-evoked potentials after SCI decreased in amplitude from 7 mV to 10 microV. Linear regression analysis showed a modest recovery in amplitude following transplantation, but no change in the control rats. Histologic findings showed that the white and gray matter were significantly spared by transplantation after SCI. CONCLUSIONS: Functional improvement was achieved with transplantation of OEG and/or MSC, but the co transplantation of OEG and MSC did not show synergistic effects. The poor migration of OEG and MSC might prevent their concerted action. Pre-treatment with a Rho antagonist and a combination of intraspinal and intravenous injection of the cells might be beneficial for SCI therapy. PMID- 20196695 TI - Gene therapy in hemiparkinsonian rhesus monkeys: long-term survival and behavioral recovery by transplantation of autologous human tyrosine hydroxylase expressing neural stem cells. AB - BACKGROUND AIMS: Neural stem cells (NSC) derived from bone marrow stromal cells (BMSC) (BMSC-D-NSC) are remarkably versatile in response to environmental signals, which render them useful in the search for neurodegenerative disease treatments. METHODS: We isolated NSC from rhesus monkey bone marrow (BM), transfected them with the human tyrosine hydroxylase (hTH) gene, and transplanted them into 1-methyl-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned hemiparkinsonian rhesus monkeys to determine changes in neural transmitter production and alterations in behavior. RESULTS: hTH-expressing cells produced monoamine agents in vitro, such as noradrenalin and dopamine. After cell transplantation in the caudate nucleus and substantia nigra of the experimental monkeys, their disease symptoms and dysfunctional glucose metabolism and dopamine transport were ameliorated. CONCLUSIONS: hTH-expressing BMSC-D-NSC survived in transplantation sites and assumed normal dopaminergic neuronal properties, playing an instrumental role in functional restoration. PMID- 20196696 TI - Superparamagnetic iron oxide nanoparticles may affect endothelial progenitor cell migration ability and adhesion capacity. AB - BACKGROUND AIMS: Cell labeling with superparamagnetic iron oxide (SPIO) nanoparticles enables non-invasive tracking of transplanted cells. The aim of this study was to investigate whether SPIO nanoparticles have an effect on endothelial progenitor cell (EPC) functional activity and the feasibility of a protocol for labeling swine- and rat-origin EPC using SPIO nanoparticles at an optimized low dosage. METHODS: EPC were isolated from the peripheral blood of swine and bone marrow of rat and characterized. After ex vivo cultivation, EPC were labeled with SPIO nanoparticles (to make a series of final concentrations, 50, 100, 200 and 400 microg/mL) or vehicle control. We also investigated the long term effects of 200 microg/mL SPIO nanoparticles on EPC (4, 8, 12 and 16 days after labeling). The labeling efficiency was tested through Prussian blue (PB) staining and the intracellular iron uptake was also measured quantitatively and confirmed. EPC proliferation and migration were determined using the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and transwell chamber assay, respectively. An EPC adhesion assay was performed by replating the cells on fibronectin-coated dishes and then counting the adherent cells. EPC apoptosis was evaluated using an Annexin V-FITC apoptosis kit. RESULTS: SPIO nanoparticles impaired EPC migration and promoted EPC adhesion. EPC proliferation and apoptosis were not affected. SPIO nanoparticles could label EPC efficiently at 200 microg/mL overnight without significantly affecting EPC functional activity. CONCLUSIONS: SPIO nanoparticles impaired the EPC migration ability and promoted the EPC adhesion capacity. EPC could be labeled efficiently at an appropriate concentration (200 microg/mL) without significantly affecting their functional activity. PMID- 20196697 TI - Monoclonal antibodies used as prophylactic, therapeutic and diagnostic agents. AB - Monoclonal antibodies can be of mouse, part mouse part human (chimeric, humanized), or of human origin. Their preparation involves hybridoma, gene cloning, gene recombination, phage display, and gene transfection techniques. The preparation, mechanism of action, uses, and possible adverse effects of most of the available monoclonal antibodies used as prophylactic, therapeutic, and diagnostic agents are reviewed. PMID- 20196698 TI - Liposomes incorporating sodium deoxycholate for hexamethylmelamine (HMM) oral delivery: development, characterization, and in vivo evaluation. AB - Liposomes incorporating sodium deoxycholate (NaDC) were prepared by the method of reverse phase evaporation and used for drug delivery by the oral route. Hexamethylmelamine (HMM), an anti-tumor agent, was chosen as a model drug and encapsulated into liposomes incorporating NaDC (NaDC-Lip). Several properties of NaDC-Lip containing HMM (HMM NaDC-Lip), such as particle size, entrapment efficiency, pinacyanol chloride (PIN) spectral characteristics with various molar ratio of NaDC/PC, as well as the vesicle stability measurements with calcein were evaluated. In vivo, the area under the plasma concentration-time curve obtained from the pharmacokinetics study of HMM NaDC-Lip was found to be approximately 9.76- and 1.21-fold higher than that of HMM solution and HMM Lip, respectively, indicating that NaDC-Lip can be used as a potential carrier for oral drug administration. PMID- 20196699 TI - Facilitating children's learning of dynamic-display AAC devices: the effect of two instructional methods on the performance of 6- and 7-year-olds with typical development using a dual-screen prototype. AB - This study compared the operation of a dynamic-display AAC device in two instructional conditions: corrective feedback (CF) and dual-screen guidance (DSG). In the CF condition prompts/feedback were provided for incorrect responses; the DSG condition used errorless guided instruction only. Twenty-one children with typical development - ten 6-year-olds and 11 7-year-olds - were randomly assigned to one instructional condition and completed five sessions: three learning/testing, one generalization, and one maintenance. The children were required to reproduce visual sentence stimuli on the AAC device. Differences were found in accuracy and efficiency of 6- and 7-year-olds. The 7-year-olds were more accurate and quicker than the 6-year-olds. Differences due to instructional condition were observed for 6-year-olds only. All children generalized and maintained learning. PMID- 20196700 TI - A comparison of the performance of 5-year-old children with typical development using iconic encoding in AAC systems with and without icon prediction on a fixed display. AB - Iconic encoding, or the use of a sequence of icons to retrieve a word or phrase from augmentative and alternative communication (AAC) technologies, has previously been shown to be challenging for young children to learn to use. It is possible that the use of icon prediction may facilitate learning in such systems by providing additional visual cues. The goal of the current study was to determine the effect of using icon prediction on the performance of 5-year-old children with typical development who were learning to locate and generalize vocabulary prestored in AAC technologies using iconic encoding. Twenty 5-year-old children were introduced to 30 vocabulary items and asked to locate them using iconic encoding during four learning and testing sessions. Ten of the children completed this task without iconic prediction, and 10 completed the task with icon prediction. They were also asked to locate an additional 30 vocabulary items, not previously introduced, during one generalization session. The results indicated that the children in the icon prediction group did not perform more accurately than the children who did not have prediction available. There was some evidence, however, that using icon prediction may help to facilitate generalization of the use of iconic encoding to novel vocabulary. Potential implications, limitations, and future directions for research are discussed. PMID- 20196701 TI - Improving web access for individuals who rely on augmentative and alternative communication. AB - People with significant speech and motor disabilities often face obstacles attempting to navigate the World Wide Web. This is especially true for the millions of children and adults worldwide who rely on or could benefit from augmentative and alternative communication (AAC). This study was designed to test the usability of WebAACcess, an accessibility enhancement tool designed to bypass some of the barriers to navigating the web. Using a repeated-measures research design, whereby subjects were their own controls, each of the 12 participants (7 with motor disabilities who used AAC and 5 peers without disabilities) navigated equivalent web pages using Internet Explorer alone and Internet Explorer with WebAACcess. Results consistently demonstrated that navigating using WebAACess with Internet Explorer was more efficient, easier, and equally effective for all of the participants than navigating with Internet Explorer alone. PMID- 20196702 TI - Parents' priorities for AAC and related instruction for their children with Angelman Syndrome. AB - This investigation examined the extent to which a set of 98 best practices in AAC, previously agreed upon by a panel of experts in AAC and inclusive education, reflected the actual preferences of 32 parents of children diagnosed with Angelman Syndrome. Parents' responses were examined in relation to whether their children were currently in mostly integrated (MI) settings with children without disabilities, or mostly segregated settings with other children with disabilities. With two exceptions, both groups, regardless of their children's current placements, viewed the practices favorably. When asked to prioritize the most important communication skills they wished their children to attain, all of the most frequently cited priorities were reflected in items contained in the questionnaire, supporting the social validity of the questionnaire as truly reflecting parents' priorities for AAC instruction. Implications of this investigation are discussed, along with next steps. PMID- 20196703 TI - The effect of sequential exposure of color conditions on time and accuracy of graphic symbol location. AB - An important aspect in AAC concerns the user's ability to locate an aided visual symbol on a communication display in order to facilitate meaningful interaction with partners. Recent studies have suggested that the use of different colored symbols may be influential in the visual search process, and that this, in turn will influence the speed and accuracy of symbol location. This study examined the role of color on rate and accuracy of identifying symbols on an 8-location overlay through the use of 3 color conditions (same, mixed and unique). Sixty typically developing preschool children were exposed to two different sequential exposures (Set 1 and Set 2). Participants searched for a target stimulus (either meaningful symbols or arbitrary forms) in a stimuli array. Findings indicated that the sequential exposures (orderings) impacted both time and accuracy for both types of symbols within specific instances. PMID- 20196704 TI - Exploring communication assistants as an option for increasing communication access to communities for people who use augmentative communication. AB - This paper describes the results of a one-year intervention project that aimed to (a) learn about the communication supports required by people who use augmentative and alternative communication (AAC) when accessing their communities, (b) develop and implement a funded communication assistant service as an accessibility support option for people who use AAC when communicating in their communities, (c) evaluate the impact of the communication assistant service on community access for people who use AAC, and (d) make recommendations relating to the role of communication assistants as an option for increasing communication access for people who use AAC in their communities. Nine people who use AAC participated in this project. The findings suggest that the majority of participants experienced a range of communication barriers when communicating with people in their communities, and that the provision of trained communication assistants significantly increased (a) their ability to communicate and participate in their communities; (b) their feelings of dignity, empowerment, autonomy, and privacy, and (d) the quality of their community services. Unfamiliar communication partners reported increased satisfaction communicating with people who used AAC when a communication assistant was present. Implications and recommendations are made for the development of communication assistant services and further research. PMID- 20196705 TI - Optimization of prednisolone acetate-loaded chitosan microspheres using a 2(3) factorial design for preventing restenosis. AB - Prednisolone acetate (PA)-loaded microspheres were prepared by the spray-drying technique using different polymer (1% and 2%) and drug concentrations (10% and 20%). To obtain the optimum formulation, a three-factor two-level (2(3)) design was employed. The independent variables were polymer molecular weight, polymer concentration, and theoretical drug loading. Responses were the particle size, percentage of encapsulation efficiency, and the t(50%) release. The best formulation was prepared with 20% of PA and 1% of chitosan with medium molecular weight showing relative good yield of production (48.0 + or - 6.7%) and encapsulation efficiency (45.7 + or - 0.3%), and released the drug at a constant rate in 11 days. PMID- 20196706 TI - All health professionals should receive the 2009 H1N1 influenza vaccine. PMID- 20196707 TI - Mortality in severe sepsis: an inconvenient truth. PMID- 20196709 TI - Decompressive craniectomy for patients with severe non-traumatic brain injury: a retrospective cohort study. AB - OBJECTIVE: To describe the current utilisation and outcomes for patients receiving decompressive craniectomy (DC) for acute non-trauma-related indications. DESIGN, SETTING AND PARTICIPANTS: Retrospective cohort study of neurosurgical patients who underwent DC to relieve acute intracranial hypertension after a non-traumarelated brain insult. The study was based on data from medical records of a tertiary referral neurosurgical intensive care unit over the period January 2001 to June 2008. MAIN OUTCOME MEASURES: Patient demographics, treatments received, indication for and result of DC, length of stay, hospital outcomes and 6-month outcomes. RESULTS: 54 patients underwent 56 DC procedures during the study period. The number of DCs performed per year increased over this period. Although intracranial pressure was significantly reduced by the procedure, 10 patients later died of uncontrollable intracranial hypertension. The patients had long hospital stays and consumed significant health care resources. Among survivors, about two-thirds had a good outcome, although it was rare for patients to be free of any deficit or complaint at follow-up. Complications were frequent, but not associated with high mortality. Overall 6-month mortality was 39%. CONCLUSIONS: DC has the potential to save lives, but also the potential to leave survivors in a severely debilitated state. The place of DC in managing patients with severe intracranial hypertension due to non-trauma related causes is yet to be definitively established. PMID- 20196710 TI - Particulate face masks for protection against airborne pathogens - one size does not fit all: an observational study. AB - OBJECTIVE: To determine the proportion of hospital staff who pass fit tests with each of three commonly used particulate face masks, and factors influencing preference and fit test results. DESIGN: Observational study. SETTING AND PARTICIPANTS: 50 healthy hospital staff volunteers in an 18-bed general intensive care unit in an Australian teaching hospital. INTERVENTIONS: Participants were administered a questionnaire about mask use and their preferred mask and underwent qualitative fit-testing with each of three different particulate masks: Kimberly-Clark Tecnol FluidShield N95 particulate filter respirator (KC), 3M Flat Fold 9320 particulate respirator and 3M 8822 particulate respirator with exhalation valve. Participants who failed fittesting were trained in correct mask donning, and fittesting was repeated. MAIN OUTCOME MEASURES: Proportion of participants who passed the fit test for each mask and the effect of training. RESULTS: The proportion of participants who passed a fit test was low for all three masks tested (KC, 16%; flat fold, 28%; and valved, 34%). Rates improved after training: the first mask tested fitted in 18% of participants pre-training and 40% post-training (P = 0.02). None of the masks fitted for 28% of participants. There were no significant predictors of fit-test results. CONCLUSIONS: A large proportion of individuals failed a fit test with any given mask, and we were not able to identify any factors that predicted mask fit in individuals. Training on mask use improved the rates of adequate fit. Hospitals should carry a range of P2 masks, and should conduct systematic P2 mask training and fit-testing programs for all staff potentially exposed to airborne pathogens. PMID- 20196708 TI - Venous thromboembolism prophylaxis in the critically ill: a point prevalence survey of current practice in Australian and New Zealand intensive care units. AB - BACKGROUND: Critically ill patients are at high risk of morbidity and mortality caused by venous thromboembolism (VTE). In addition to premorbid predisposing conditions, critically ill patients may be exposed to prolonged immobility, invasive intravascular catheters and frequent operative procedures, and further may have contraindications to pharmaceutical prophylactic measures designed to attenuate VTE risk. There are limited data describing current VTE prophylaxis regimens in Australia and New Zealand. OBJECTIVE: To document current Australian and New Zealand management of VTE prophylaxis in a large mixed cohort of critically ill patients. DESIGN: Prospective, multicentre point prevalence survey endorsed by the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG). SETTING: 30 public hospital ICUs in Australia and New Zealand surveyed on Wednesday 9 May 2007. METHODS: For all patients in each ICU on the study day, demographic data, admission diagnosis and information on VTE prophylaxis were prospectively collected. RESULTS: 502 patients were included in the survey, and 431 of these (86%) received VTE prophylaxis. Of these, 64% (276/431) received pharmacological prophylaxis and 80% (345/431) received mechanical prophylaxis, with 44% (190/431) receiving both. Of those receiving pharmacological prophylaxis, unfractionated heparin was used in 74%, and enoxaparin (low molecular weight heparin) in 23%. Contraindications to pharmacological prophylaxis were reported in 122 patients. Overall, pharmacological prophylaxis was administered to 87% of potentially suitable patients. CONCLUSIONS: We observed a high prevalence of VTE prophylaxis, with many critically ill patients receiving two or more modalities of prophylaxis. These results show that the potential risk of VTE in critically ill patients is recognised in Australia and New Zealand, and strategies to mitigate this serious complication are widely implemented. PMID- 20196711 TI - Palliative care teams in the intensive care unit: a randomised, controlled, feasibility study. AB - OBJECTIVES: To determine whether palliative care teams can improve patient, family and staff satisfaction for patients receiving end-of-life care in the intensive care unit and reduce surrogate markers of health care costs. DESIGN: Randomised controlled, feasibility study. SETTING: 14-bed general ICU over 29 months in 2006-2008. PARTICIPANTS: Patients admitted with a terminal or preterminal condition, for whom the treating intensivist considered that escalating or continuing treatment was unlikely to achieve significant improvement in the patient's clinical condition. INTERVENTION: A consultation from a palliative care team, in addition to usual ICU end-of-life care. MAIN OUTCOME MEASURES: ICU and hospital length of stay, and changes in composite scores of satisfaction obtained from questionnaires administered to families, nursing staff and intensivists. RESULTS: The study was constrained by significant logistical and methodological problems, including low recruitment and questionnaire completion rates, and the lack of an available validated questionnaire. From a total of 2009 admissions over a 29-month period, 20 patients were enrolled, 10 in each group. There were significant differences in baseline characteristics. There were no statistically significant differences between those who had a consultation with the palliative care team and those who did not in median ICU length of stay (3 days v 5 days, P=0.97), median hospital length of stay (5 days v 11 days, P=0.44), or changes in overall composite satisfaction scores reported by families (-6% v -6%, P=0.91), nursing staff (+5% v +15%, P=0.30), and intensivists (-2% v +2%, P=0.42). CONCLUSION: This feasibility study was difficult to conduct and did not generate any robust conclusions about the utility of involving palliative care teams in end-of-life care in the ICU. Larger studies are technically possible but unlikely to be feasible. TRIAL REGISTRATION: Australian Clinical Trials Registry ACTRN012606000110583. PMID- 20196712 TI - Risk-adjusted continuous outcome monitoring with an EWMA chart: could it have detected excess mortality among intensive care patients at Bundaberg Base Hospital? AB - OBJECTIVE: To test whether applying a continuous riskadjusted charting method, using an exponentially weighted moving average (EWMA) chart, would have been useful for monitoring outcomes of patients admitted to the intensive care unit at Bundaberg Base Hospital, Queensland, between November 2000 and December 2005. DESIGN, SETTING AND PARTICIPANTS: An EWMA chart was constructed to show the change in observed compared with predicted mortality over time, using data submitted to the Australian and New Zealand Intensive Care Society Adult Patient Database. Limitations and practical implications of this monitoring technique were evaluated and compared with a routine monitoring technique using the annual standardised mortality ratio. MAIN OUTCOME MEASURE: In-hospital mortality. RESULTS: Data were submitted on three occasions (August 2002, November 2002 and February 2006). In each year before 2005, the EWMA chart showed periods when observed mortality appeared higher than predicted. These periods were not detectable by analysing the data with an annual standardised mortality ratio. Comparison of aggregated data from peer group hospitals suggested that the mortality prediction model (APACHE III-j) was an appropriate risk adjustment model for this analysis. CONCLUSIONS: Continuous monitoring of outcomes using an EWMA chart may have advantages over other techniques. Had data been available, analysis with an EWMA chart might have prompted review of processes and outcomes among patients at Bundaberg Base Hospital ICU. PMID- 20196713 TI - Triage decisions and outcomes for patients with Triage Priority 3 on the Society of Critical Care Medicine scale. AB - OBJECTIVE: To identify factors associated with the triage decision for patients classified as Society of Critical Care Medicine (SCCM) Triage Priority 3, and their outcomes. DESIGN: Single-centre, prospective, observational cohort study. SETTING: General intensive care unit in a tertiary regional hospital, over the 9 months January to September 2007. PATIENTS: SCCM Triage Priority 3 patients. RESULTS: All patients were followed up for at least 6 months. Among the 1346 triaged patients, 250 were classified as SCCM Triage Priority 3. Fewer than a third of these (76, 30.4%) were admitted to the ICU. Medical patients were more likely to be rejected than surgical or neurosurgical patients. Those with a poorer physicianpredicted chance of long-term survival were more likely to be rejected than those with a better predicted prognosis. The MPMII0-predicted mortality was higher for those denied ICU admission. Non-postoperative status (odds ratio [OR], 26.3) and physician-predicted risk > 50% of death within 1 month (OR, 11.8) were independently correlated with denial of ICU admission in a multiple logistic regression analysis. Cox regression analysis showed that independent risk factors for mortality were denial of ICU admission (hazard ratio [HR], 2.80), higher MPMII0-predicted mortality (HR, 1.12 for every 10% increment) and the presence of renal disease as an admission diagnosis (HR, 2.28). CONCLUSIONS: For SCCM Triage Priority 3 patients, postoperative status and better physician-predicted prognosis correlated with ICU admission. Patients had lower medium-term survival if they were denied ICU admission, or had higher MPMII0 predicted mortality, or renal disease as the admission diagnosis. PMID- 20196714 TI - Toxic shock syndrome caused by hospital-acquired methicillin-resistant Staphylococcus aureus in a patient with pancytopenia. AB - Toxic shock syndrome is an uncommon condition in patients with neutropenia. We describe a 44-year-old man who developed toxic shock syndrome caused by hospitalacquired methicillin-resistant Staphylococcus aureus while pancytopenic after chemotherapy. He died of multiorgan failure despite high-level intensive care support and treatment with appropriate antibiotics and intravenous immunoglobulin. This case illustrates the need for a high index of suspicion for toxic shock syndrome in patients with febrile neutropenia, and also highlights the lack of highquality evidence for the various treatment modalities used in this syndrome. PMID- 20196715 TI - Management of acute smoke inhalation injury. AB - Pulmonary injury from smoke inhalation is common in burn victims, significantly contributing to the morbidity and mortality of fire-related injuries. The impacts of improvement in other aspects of burn care have not been mirrored in treatment of smoke inhalation. Smoke is heterogeneous and unique to each fire; it comprises particulates, respiratory irritants and systemic toxins as well as heat, all contributing to the pathological insult. Thermal injury below the vocal cords is rare because of effective heat dissipation in the upper airway. Particulate matter is the chief contributor to the pathophysiology of smoke inhalation injury, which has been extensively described. Of paramount importance is the cascade of inflammatory mediators following interaction of irritant substances with lung parenchyma, leading to pulmonary oedema, cast formation, airway obstruction, loss of hypoxic pulmonary vasoconstriction and ventilation/perfusion mismatch. Current treatment is based on supportive care, with airway management, mechanical ventilation, humidification and aggressive airway toilet the mainstays. Nebulisation of n2-agonists, heparin and N-acetylcysteine have a role in management, as does more specific treatment of carbon monoxide or cyanide intoxication. Many promising treatments are currently under investigation. The therapeutic strategy of decontaminating the lungs early after smoke exposure to prevent inhalation injury has received little attention and may be of significant value. This could potentially utilise amphoteric, hypertonic chelating agents developed for topical and ocular chemical exposures. PMID- 20196716 TI - Expensive care - a rationale for economic evaluations in intensive care. AB - The demand for intensive care services is growing, and the cost of these services is increasing, with newer technologies consuming larger portions of the health care budget. We contend that both the costs and benefits of interventions must be considered to truly understand their value in critical care. Economic evaluations provide an explicit framework to compare the costs and benefits of an intervention. If these factors are not considered together, decisions may be made that do not result in the most efficient use of constrained resources. Despite limitations arising from variations in economic evaluation methodology, logistical complexity and problems of generalisability, the Australian trial environment provides an ideal opportunity to obtain robust economic data to help decision-making. Here, we outline the rationale for conducting economic evaluations in the critical care setting and argue that these evaluations need to be routinely incorporated into all large-scale clinical trials. PMID- 20196717 TI - Prone positioning of influenza H1N1 2009 patients with acute respiratory distress syndrome. PMID- 20196718 TI - When an effect is unclear, questioning its proposed mechanism is appropriate. PMID- 20196719 TI - Gram versus gram. PMID- 20196720 TI - Osteopontin; as a target molecule for the treatment of inflammatory diseases. AB - It has been well recognized that inflammatory responses are part of pathogenesis for various disorders such as autoimmune diseases. For example, multiple sclerosis (MS) is an inflammatory demyelinating disease of central nervous system that is presumably caused by activated T cells specific for myelin antigens. Rheumatoid arthritis (RA) is also a chronic inflammatory disease characterized by synovial inflammation in which several inflammatory cytokines are involved. On the other hand, Osteopontin (Opn) is a pleiotropic cytokine expressed by activated T cells, dendritic cells (DCs) and macrophages and its expression is up regulated during inflammation. Secreted form of Opn (s-Opn), which is modified by phosphorylation, glycosylation and proteolytic cleavage with thrombin, has activities as a T helper type 1 (Th1) cytokine and as a chemoattractant for many types of cells through integrin receptors and CD44. Recently, it has been uncovered that intracellular form of Opn (i-Opn) is a critical regulator for Toll like receptor-9 (TLR-9), TLR-7-dependent interferon-alpha (IFN-alpha) expression by plasmacytoid DCs and Th17 development. In this review, we have summarized recent progress in understanding of Opn's role in variety of inflammatory disorders. PMID- 20196722 TI - Treatment of choroidal neovascularization in high myopia. AB - High myopia affects approximately 2% of general population, and is a major cause of legal blindness in many developed countries. Choroidal neovascularization (CNV) is the most common vision-threatening complication of high myopia. Different therapeutic approaches have been attempted such as thermal laser photocoagulation, surgery and photodynamic therapy with verteporfin (PDT). The visual outcome of these therapies has been reported to be better than the natural history of the condition. However, the limited visual acuity improvement after PDT monotherapy and the appearance of subretinal fibrosis and chorioretinal atrophy prompted the association of other therapies. In the past few years a tremendous advance in the knowledge of the mechanisms underling CNV secondary to high myopia and age related macular degeneration has been achieved, leading to new therapeutic targets and novel drugs and combined therapies. These new therapeutic weapons have been designed to achieve a selective shut down of choroidal new vessels. Recent reviews have been published on the natural history and therapies for myopic CNV. Ohno-Matsui reported on the natural history of the condition as well as the outcome of laser photocoagulation, surgical extraction of CNV, foveal translocation and photodynamic therapy on myopic CNV in the short term. Soubrane et al reviewed the new advances on surgery, laser photocoagulation and PDT, considering some of the potential effects of triamcinolone, pegaptanib and ranibizumab in CNV secondary to age related macular degeneration (AMD). Novack et al reported on the pharmacological therapy of CNV in AMD. The aim of this review is to summarize the recent advances in myopic CNV pathophysiology and the new therapeutic targets and drugs that are changing the clinical management of myopic CNV. PMID- 20196723 TI - Tumor markers: the potential of "omics" approach. AB - Tumor markers are the molecules that indicate the presence or prognosis of malignancy. Most often, tumor markers are produced by the cancer tissue itself. Many of them could be secreted into the body fluids in small quantities. Thus, tumor markers could be useful for early diagnostics of primary tumors and relapsed disease, as well as for determining tumor prognosis and predicting likely response of the tumor to therapy. Tumor markers are part of the clinical routine. Nevertheless, lack of sensitivity and specificity precludes routine usage of single tumor markers in population-based screening. Shortcomings of single tumor markers could be solved by parallel evaluation of multiple tumor markers that can perform with required certainty. Genome and proteome-wide approaches currently lead to identification and initial characterization of hundreds new tumor marker candidates. Most prominent of such methods are serological analyses of recombinant cDNA expression libraries (SEREX), 2 dimensional polyacrylamide gel electrophoresis, mass spectrometry, as well as protein and DNA microarrays. Last but not the least is a computational approach allowing high-throughput detection of tumor marker candidate genes in publicly available datasets. Listed approaches are critically discussed in this review as well as the most crucial tumor-related findings. Finally, a perspective on the future of tumor markers in the tailored medicine is given. PMID- 20196721 TI - New targets of therapy in T-cell lymphomas. AB - T-cell lymphomas (TCL) are characterized by poor response to chemotherapy and generally poor outcome. While molecular profiling has identified distinct biological subsets and therapeutic targets in B-cell lymphomas, the molecular characterization of TCL has been slower. Surface markers expressed on malignant T cells, such as CD2, CD3, CD4, CD25, and CD52 were the first TCL-specific therapeutic targets to be discovered. However, the presence of these receptors on normal T-cells means that monoclonal antibody (mAb)- or immunotoxin (IT)-based therapy in TCL inevitably results in variable degrees of immunosuppression. Thus, although some mAbs/IT have significant activity in selected subsets of TCL, more specific agents that target signaling pathways preferentially activated in malignant T-cells are needed. One such novel class of agents is represented by the histone deacetylase (HDAC) inhibitors. These molecules selectively induce apoptosis in a variety of transformed cells, including malignant T-cells, both in vitro and in vivo. Several HDAC inhibitors have been studied in TCL with promising results, and have recently been approved for clinical use. Immunomodulatory drugs, such as interferons and Toll Receptor (TLR) agonists have significant clinical activity in TCL, and are particularly important in the treatment of primary cutaneous subtypes (CTCL). Although most classical cytotoxic drugs have limited efficacy against TCL, agents that inhibit purine and pyrimidine metabolism, known as nucleoside analogues, and novel antifolate drugs, such as pralatrexate, are highly active in TCL. With improved molecular profiling of TCL novel pharmacological agents with activity in TCL are now being discovered at an increasingly rapid pace. Clinical trials are in progress and these agents are being integrated in combination therapies for TCL, both in the relapsed/refractory setting as well as front line. PMID- 20196724 TI - The balance between von-Willebrand factor and its cleaving protease ADAMTS13: biomarker in systemic inflammation and development of organ failure? AB - PURPOSE: This review investigates and highlights the activity of Willebrand factor (VWF) and its cleaving protease as biomarkers of the development of multiple organ dysfunction in infectious and noninfectious systemic inflammatory response syndrome. STATE OF THE ART: Ultra-large VWF (ULVWF) multimers activate platelets resulting in a prothrombotic situation. Systemic inflammation is associated with increased ULVWF plasma level and a decreased ADAMTS13 activity. The potential role of ADAMTS13 as a diagnostic and prognostic marker of disseminated intravascular coagulopathy is largely underestimated. SUMMARY: VWF is an acute phase protein and its plasma level increases in systemic inflammation. When released from endothelial cells and platelets, the native multimeric glycoprotein is mostly present in the ultralarge form (ULVWF), which may have a major clinical significance under proinflammatory conditions. ULVWF multimers may activate endothelial cells and platelets simultaneously. The multimers undergo limited proteolysis by a specific plasma metalloprotease known as ADAMTS13 (a disintegrin and metalloprotease with thrombospondin motif), thus, in healthy individuals only marginal amounts of circulating ULVWF are detectable. Severe hereditary or acquired ADAMTS13 deficiency causes thrombotic thrombocytopenic purpura (TTP), which contributes to prothrombotic coagulation abnormalities preceding organ dysfunction systemic inflammatory response syndrome (SIRS). In proinflammatory conditions, ADAMTS13 activity decreases due to various mechanisms, (i) down regulation on a transcriptional level, (ii) proteolytic degradation, and (iii) consumption due to the high substrate level. Marked dysbalance as found in patients with severe sepsis or septic shock results in substantial amounts of plasma ULVWF. This level of dysbalance is negatively correlated with platelet count and positively correlated with the severity of inflammation and the degree of organ failure. PMID- 20196725 TI - Approaching clinical reality: markers for monitoring systemic inflammation and sepsis. AB - The 'systemic inflammatory response syndrome (SIRS)' reflects a non-specific inflammatory reaction to various insults. In sepsis, defined as SIRS triggered by infection, a complex and overwhelming network of mediators contributes to the clinical syndrome. The host response in sepsis is characterized by unspecific physiologic criteria, which are unable to identify patients adequately who might benefit from either conventional anti-infective therapies or from novel therapies targeting specific mediators of sepsis. The early diagnosis of sepsis, the identification of the origin, adequate therapeutical management and the monitoring of the disease may help to overcome sepsis-associated mortality, which is unacceptably high and the third leading cause of death in Western Countries. Molecular techniques for identification of pathogens, their associated molecular patterns (PAMPs) and the ensuing host response may help to stratify patients with the urgent need for antibiotic therapy and those where it is safe to withhold or to de-escalate therapy. Beyond analysis of danger associated molecular patterns (DAMPs) at a single molecular level, the advent of genome-wide screening allows for an assessment of a wide variety of effectors and mediators in response to PAMPs. Also their purposeful targeting in animal models of sepsis revolutionized our understanding of pathophysiology in the critically ill. Molecular tools are about to challenge "state-of-the-art" diagnostic tests such as blood culture as they not only increase sensitivity but also dramatically reduce time requirements to identify pathogens and their resistance patterns. Mounting evidence suggests that our pathophysiological understanding might in the near future help to identify "patients at risk", i.e. those with a high likelihood to develop organ dysfunction and/or to guide therapeutic interventions in particular regarding resource-consuming and expensive therapies ("theragnostics"). The clinical utility for most of the discussed markers for monitoring systemic inflammation and sepsis has still to be evaluated in prospective trails. In conclusion, there is an unmet medical need for identification and validation of reliable biomarkers of sepsis; the clinical information obtained from the use of novel biomarkers might contribute to transform sepsis from a physiologic syndrome to a group of distinct biochemical disorders, to improve diagnosis and therapeutic decision making for high-risk patients, to monitor the response to therapy and to ensure the enrollment of seriously characterized patients in clinical studies. PMID- 20196726 TI - Challenges in mass spectrometry based targeted metabolomics. AB - The gap of the post-genomic era is increasingly being filled by the metabolomics approach, comprising a technology for analyzing small molecule endogenous metabolites (<1500 Dalton) in complex biological samples. This new analytical science has progressed within the last years particularly with regard to improvements in mass spectrometry based detection, now allowing highly robust, reproducible, selective and sensitive qualitative or quantitative analysis of endogenous metabolites. The precise and accurate quantitation of these metabolites via targeted metabolomics, now critically contributes to the quantitative analysis of endogenous compounds in biomarker discovery and validation thus to future personalized therapy. The analytical methods of choice in (MS-based) targeted metabolomics primarily are HPLC-API-MS/MS, FIA-APIMS/MS and GC-MS. In the parent paper, we provide an introduction and brief survey on the technological basis of targeted metabolomics in biomarker research, discuss various relevant analytical aspects in mass spectrometry including comparison to non-targeted approaches, effects of sample preparation, impact of sample stability, carryover- and matrix effects, need for standardization and for proficiency tests, standardization of analytical methods as well as the requirement for method validation. PMID- 20196727 TI - Perspectives on emerging biomarkers for non-invasive assessment of embryo viability in assisted reproduction. AB - A key step in assisted reproduction is the assessment of embryo viability in order to identify the embryo(s) most likely to result in pregnancy. Currently used embryo assessment systems are largely based on morphology and cleavage rate. While these systems have been pivotal in improving implantation and pregnancy rates and reducing multiple gestations, their precision is still insufficient. The limitations of strategies based on morphology have led to the investigation of adjunctive technologies for non-invasive assessment of embryo viability in assisted reproduction. These include the measurement of glucose, pyruvate, or amino acid levels in the embryo culture media, assessment of oxygen consumption by the embryo, genomic and proteomic profiling, and most recently, analytical examination of the embryonic metabolome. As the number of ART cycles increases worldwide, improvements in the ability to quickly and non-invasively identify the best embryos for transfer become an increasingly more important goal for reproductive medicine. PMID- 20196728 TI - Novel systemic cardiovascular disease biomarkers. AB - Motivated by the challenge of risk assessment in a heterogeneous population and guided by advances in our knowledge of the pathobiology of cardiovascular diseases (CVD), basic and clinical scientists have maintained substantial interest in the development and application of novel biomarkers for risk stratification of CVD. In particular, strategies to identify and combine multiple biomarkers, which may reflect diverse pathobiological contributors to the onset and complications of CVD, have been arising as an approach to improve more effectively the risk assessment and target therapy. Moreover, comparative evaluations of novel markers are necessary to estimate these candidates for integration into present and future strategies. In this review we consider the recent in-depth knowledge and advances with the use of systemic biomarkers in the area of CVD with special attention on inflammatory markers and those that can predict an individual arteriosclerotic disease stage. PMID- 20196729 TI - Development and validation of predictive molecular signatures. AB - Since the different, so-called omics disciplines generate huge amount of data, the application of appropriate, sophisticated statistical methods for developing and validating predictive molecular signatures for drug development, for prevention, screening, diagnosis, monitoring of treatment or after treatment of diseases as well as for stratification of individuals is fundamental. The development and validation require several steps and it is quite a long journey from the detection of a molecular predictive signature to the routine use in clinical practice. In our review we focus on data obtained from cDNA expression microarrays. We describe the necessary development and validation steps including recent results of the second phase of the MAQC project (MAQC-II) and emphasise on potential pitfalls. PMID- 20196730 TI - Non-invasive diagnostic tests for non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) is a clinico-pathologic spectrum of conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). Although simple or bland steatosis follows a relatively benign clinical course, NASH can potentially progress to cirrhosis (approximately 10 to 15 percent) and hepatocellular carcinoma. NAFLD occurs in an estimated 25 to 30 percent of the US general population, while NASH is reported in 2 to 3 percent of the population. Even though common explanation for the increased prevalence of NAFLD is the increased rate of obesity, the risk of developing NAFLD and NASH is not limited to overweight and obese individuals. Currently, the only way to diagnose NASH or to assess the stage of fibrosis is by obtaining a liver biopsy. Liver biopsy is invasive, expensive, and associated with potential risks, including post biopsy pain, bleeding, organ perforation, and even death; serious complications can occur in 0.3 percent of liver biopsies with 0.01 percent being fatal. This review examines the current strategies for development of the non-invasive techniques that will one day replace liver biopsy and serve as a non-invasive gold standard for the diagnosis and staging of NASH. PMID- 20196731 TI - Circulating nucleic acids as a potential source for cancer biomarkers. AB - Since the association of circulating DNA level changes with tumor growth was discovered many attempts have been made to develop the sensitive and robust blood based tests for early tumor diagnostics. Both genomic as well as mitochondrial DNA quantification in the circulation have been extensively evaluated as a diagnostic and prognostic tool to monitor cancer therapy. Cell-free DNA bearing the same genetic and epigenetic changes as the tumor tissues were shown to be detectable in plasma / serum of cancer patients indicating the principal possibility to create the minimally invasive diagnostic tests based on tumor specific DNA markers. Apart from circulating DNA, tumor-derived RNA in plasma / serum was found to be a promising approach for the development of cancer markers. Results of the last two years establish the quantification of the tumor-derived microRNAs in plasma / serum as an extremely promising approach for cancer diagnostics. The aim of this publication was to review the recently reported studies on the circulating DNA and RNA in cancer patients and to estimate their impact on making the ongoing research closer to clinical application. PMID- 20196732 TI - Nanoparticle technology: addressing the fundamental roadblocks to protein biomarker discovery. AB - Clinically relevant biomarkers exist in blood and body fluids in extremely low concentrations, are masked by high abundance high molecular weight proteins, and often undergo degradation during collection and transport due to endogenous and exogenous proteinases. Nanoparticles composed of a N-isopropylacrylamide hydrogel core shell functionalized with internal affinity baits are a new technology that can address all of these critical analytical challenges for disease biomarker discovery and measurement. Core-shell, bait containing, nanoparticles can perform four functions in one step, in solution, in complex biologic fluids (e.g. blood or urine): a) molecular size sieving, b) complete exclusion of high abundance unwanted proteins, c) target analyte affinity sequestration, and d) complete protection of captured analytes from degradation. Targeted classes of protein analytes sequestered by the particles can be concentrated in small volumes to effectively amplify (up to 100 fold or greater depending on the starting sample volume) the sensitivity of mass spectrometry, western blotting, and immunoassays. The materials utilized for the manufacture of the particles are economical, stable overtime, and remain fully soluble in body fluids to achieve virtually 100 percent capture of all solution phase target proteins within a few minutes. PMID- 20196734 TI - Autoantibodies to tumor-associated antigens as cancer biomarkers. AB - Malignant tumors induce humoral immune response in cancer patients, although the incidence of such autoantibody responses against individual tumor-associated antigens (TAA) is rather low. To increase predictive value of TAA-recognizing autoantibodies as potential cancer biomarkers, TAAs should be combined into protein arrays. Here we review recent advances in the application of such arrays and summarize data concerning most promising antigens. We also review the methods of cloning TAA-recognizing autoantibodies, generation of human hybridomas and screening of recombinant human immunoglobulin libraries. PMID- 20196733 TI - DNA methylation based biomarkers in non-invasive cancer screening. AB - DNA methylation plays a critical role in the regulation of gene expression, differentiation and in the development of cancer and other diseases. Hypermethylation of CpG islands located in the promoter regions of tumor suppressor genes is now firmly established as the most frequent mechanism for gene inactivation in cancers. Feasibility of using DNA methylation based biomarkers for early detection of cancer has been shown. Potential of using DNA methylation for prediction of therapeutic outcome and patient survival has also been shown. DNA originated from cancer cells has been routinely detected in clinical specimens (ex. Plasma/serum, sputum, urine etc.) from cancer patients. Presence of methylated DNA sequences in clinical specimens and potential of using them as biomarkers have been recognized. Novel methylation based biomarkers that can be used in clinical specimens, obtained non-invasively from cancer patients, offer significant practical advantages. More resources need to be committed to this area of biomarker research. Thus, we review recent findings on DNA methylation based cancer biomarkers with particular focus on these applicable to the clinical specimens obtained non-invasively from cancer patients. PMID- 20196735 TI - Autoantibodies in autoimmune diseases. AB - The occurrence of autoantibodies is a common feature of autoimmune diseases. This review is intended to give an overview of the most important autoantibodies and their role in diagnosis, disease activity and prognosis in rheumatoid arthritis (RA), systemic lupus erythematodes (SLE) and multiple sclerosis (MS). Whereas in RA and SLE these antibodies are meaningful for diagnosis and partially for the prognosis of the disease, the situation is quite different in the case of MS. Up to date, no specific antibody is known to be exclusively present in the serum or cerebrospinal fluid (CSF) of MS-patients compared to the respective fluids of healthy individuals. Nevertheless, there are some antigens that are reported to be bound significantly more often by MS-patients' serum or CSF than by comparable samples of healthy volunteers. In addition to the importance of several autoantibodies for diagnosis of the respective disease, the serum concentration of certain antibodies in RA and SLE is associated with therapy response. Since therapy with biologicals (e. g. TNF-alpha blockade, B-cell depletion) is expensive, monitoring these autoantibodies seems to be an additional useful tool for early identification of therapy responders or non-responders. PMID- 20196736 TI - Gene therapy to improve high-density lipoprotein metabolism and function. AB - Plasma levels of high-density lipoprotein (HDL) cholesterol and its major apolipoprotein (apo), apo A-I, are inversely correlated with the incidence of ischemic cardiovascular diseases. Till now, evaluation of the hypothesis that elevation of HDL cholesterol reduces atherosclerotic burden and/or decreases ischemic cardiovascular events in humans has been hampered by the lack of drugs that selectively increase HDL cholesterol. In contrast to the lack of clinical data, evidence for a direct causal role of HDL in modulating atherogenesis in experimental models has been provided by investigations in human apo A-I transgenic mice and rabbits. The development of gene transfer technologies with a sufficiently high therapeutic index may pave the road for a selective and effective HDL raising therapeutic intervention. The goal of a therapeutic strategy that modulates HDL metabolism is not an increase of HDL cholesterol as such, but an enhancement of HDL function. The value of HDL cholesterol as a surrogate end-point to predict reduced atherosclerosis or a decrease in clinical events may be highly dependent on the mechanism leading to an increased level of HDL cholesterol. In the case of gene transfer, this implies that beneficial effects of increasing HDL cholesterol will be dependent on the transgene that is expressed. Here, we critically review HDL metabolism and HDL function in relation to the development of HDL raising gene transfer, advances and drawbacks of different gene transfer technologies, and experimental gene transfer studies evaluating the effect of raised HDL on histological and functional outcomes in animal models. PMID- 20196737 TI - High-density lipoprotein-raising strategies: update 2010. AB - Population studies have consistently shown that high-density lipoprotein (HDL) cholesterol levels are a strong, independent inverse predictor of cardiovascular disease. Every 1 mg/dl increase in HDL cholesterol is associated with a 2% to 3% decrease in coronary artery disease risk, independent of low-density lipoprotein (LDL) cholesterol and triglyceride levels. The primary mechanism for this protective effect is believed to be reverse cholesterol transport, but several other anti-inflammatory, anti-apoptotic, anti-oxidative functions for HDL have also been identified. Low HDL cholesterol is predictive of cardiovascular events in statin-treated patients with low LDL cholesterol, indicating that intensive lipid lowering strategies with statins alone are not sufficient to prevent cardiovascular events, and merging for additional effective HDL-raising therapy. This review focuses at giving an overview of current established HDL-raising pharmaca, including statins, fibrates, thiazolidinediones, and nicotinic acids, and of novel therapies including cholesterol ester transfer protein-inhibitors, liver X receptor agonists, reconstituted HDL, and apolipoprotein A-I mimetics. Working mechanisms are described and results from clinical trials of monotherapy and combination therapy are discussed. PMID- 20196738 TI - High-density lipoprotein at the interface of type 2 diabetes mellitus and cardiovascular disorders. AB - Type 2 diabetes mellitus is associated with low high-density lipoprotein (HDL) cholesterol levels, which is an independent cardiovascular risk factor. Low HDL cholesterol concentrations reflect a dysregulation in HDL metabolism, which is determined by the concerted action of different proteins, including cholesterol ester transfer protein, lecithin: cholesterol acyltransferase, endothelial and lipoprotein lipase, phospholipid transfer protein, and hepatic lipase, as well as different receptors, including the scavenger receptor class B type I and ATP binding cassette transporter A1 and G1. Type 2 diabetes mellitus is besides a dysregulation in HDL metabolism, also associated with dysfunctional HDL: HDL mediated reverse cholesterol transport as well as the anti-oxidative and endothelial-protective features of HDL are impaired in type 2 diabetes mellitus. The first part of the present review gives an overview of how type 2 diabetes mellitus affects the expression and/or activity of receptors and proteins involved in HDL metabolism and how different diabetes-associated factors influence the functionality of HDL. The second part of the review focuses on describing the newest insights in the impact of HDL on glucose metabolism and on diabetes-associated cardiovascular complications. PMID- 20196739 TI - High-density lipoprotein quantity or quality for cardiovascular prevention? AB - Plasma concentrations of HDL cholesterol (HDL-C) are strongly and inversely associated with cardiovascular risk, leading to the concept that therapies to enhance plasma HDL-C levels would be anti-atherogenic and protective against cardiovascular events. However, HDL are highly heterogeneous, with subclasses that can be separated and identified according to density, size, charge, and protein composition. There is evidence that these subclasses may differ in their functional anti-atherogenic properties. As a snapshot of the steady-state cholesterol carried by all HDL subclasses together, the individual HDL-C measurement is insufficient to capture the structural and functional variation in HDL particles. This review addresses the current knowledge on the structural and functional heterogeneity of HDL particles, and their relationship to cardiovascular disease, in the attempt of answering the question on whether certain subclasses of HDL may be better predictors of cardiovascular risk than HDL-C, and may be better targets than HDL-C for further improving cardiovascular disease reduction in the statin era. PMID- 20196740 TI - High-density lipoprotein-mediated anti-atherosclerotic and endothelial-protective effects: a potential novel therapeutic target in cardiovascular disease. AB - Reduced levels of high-density lipoprotein cholesterol (HDL) are associated with a substantially increased risk of coronary disease and cardiovascular events. Furthermore, numerous studies have suggested that HDL may exert several potentially important antiatherosclerotic and endothelial-protective effects. In particular, the promotion of reverse cholesterol transport, i.e. cholesterol efflux from lipid-loaded macrophages in atherosclerotic lesions and the subsequent cholesterol transport back to the liver, has been proposed as an anti atherogenic effect of HDL that may promote regression of atherosclerotic lesions. Moreover, endothelial dysfunction is thought to play a critical role in development and progression of atherosclerosis and several recent studies have suggested that HDL exerts direct endothelial-protective effects, such as stimulation of endothelial production of the anti-atherogenic molecule nitric oxide, anti-oxidant, anti-inflammatory and anti-thrombotic effects. Furthermore, it has been observed that HDL may stimulate endothelial repair processes, involving mobilisation and promotion of endothelial repair capacity of endothelial progenitor cells. The relative significance of these different potential anti-atherosclerotic effects of HDL remains still unclear at present. Importantly, at the same time it has been recognized that the vascular effects of HDL may be variable, i.e. the capacity of HDL to stimulate macrophage cholesterol efflux and endothelial-protective effects may be altered in patients with inflammatory or cardiovascular disease. The further characterisation of underlying mechanisms and the identification of the clinical relevance of this "HDL dysfunction" are currently an active field of research. HDL-targeted treatment strategies are at present intensely evaluated and may lead to increased HDL plasma levels and/or HDL-stimulated anti-atherosclerotic effects. The cardiovascular protection provided by such approaches may likely depend on HDL function or quality, i.e. the anti-atherosclerotic and endothelial-protective properties of the on-treatment HDL. Currently, several HDL-raising treatment strategies are examined in clinical trials, i.e. extended-release niacin, the CETP inhibitors dalcetrapib and anacetrapib, reconstituted forms of HDL (i.e. CSL 111) or apoA-I mimetics, and some of these are already in large clinical outcome studies on top of statin therapy to determine their efficacy and safety for cardiovascular prevention. PMID- 20196741 TI - Relevance of sphingolipids in the pleiotropic protective effects of high-density lipoproteins. AB - Atherosclerosis is the major cause of cardiovascular morbidity and mortality. A multitude of pro-atherogenic mediators are known liable for the initiation and progression of atherogenic vascular lesions. Only few endogenous molecules are known so far with cardiovascular protective properties, whereas high-density lipoprotein (HDL) is one of the most important. Beside cholesterol efflux, many pleiotropic cell-mediated functions of HDL are known so far. HDL is a spherical particle that contains different proteins and lipids. Especially sphingolipids, like sphingosine-1-phosphate (S1P), has gained great attention. The HDL associated S1P seems to be responsible for many of the pleiotropic effects of HDL by activating special S1P receptors. This review focuses on HDL associated sphingolipids as mediators of known protective pleiotropic effects of HDL and their possible therapeutic relevance. PMID- 20196742 TI - Functional interactions between endogenous cannabinoid and opioid systems: focus on alcohol, genetics and drug-addicted behaviors. AB - Although the first studies regarding the endogenous opioid system and addiction were published during the 1940s, addiction and cannabinoids were not addressed until the 1970s. Currently, the number of opioid addiction studies indexed in PubMed-Medline is 16 times greater than the number of cannabinoid addiction reports. More recently, functional interactions have been demonstrated between the endogenous cannabinoid and opioid systems. For example, the cannabinoid brain receptor type 1 (CB1) and mu opioid receptor type 1 (MOR1) co-localize in the same presynaptic nerve terminals and signal through a common receptor-mediated G protein pathway. Here, we review a great variety of behavioral models of drug addiction and alcohol-related behaviors. We also include data providing clear evidence that activation of the cannabinoid and opioid endogenous systems via WIN 55,512-2 (0.4-10 mg/kg) and morphine (1.0-10 mg/kg), respectively, produces similar levels of relapse to alcohol in operant alcohol self-administration tasks. Finally, we discuss genetic studies that reveal significant associations between polymorphisms in MOR1 and CB1 receptors and drug addiction. For example, the SNP A118G, which changes the amino acid aspartate to asparagine in the MOR1 gene, is highly associated with altered opioid system function. The presence of a microsatellite polymorphism of an (AAT)n triplet near the CB1 gene is associated with drug addiction phenotypes. But, studies exploring haplotypes with regard to both systems, however, are lacking. PMID- 20196743 TI - Addiction and pain: cannabinoid and opioid interactions. PMID- 20196744 TI - Epistatic interactions. AB - The term "epistasis" is sometimes used to describe some form of statistical interaction between genetic factors and is alternatively sometimes used to describe instances in which the effect of a particular genetic variant is masked by a variant at another locus. In general statistical tests for interaction are of limited use in detecting "epistasis" in the sense of masking. It is, however, shown that there are relations between empirical data patterns and epistasis that have not been previously noted. These relations can sometimes be exploited to empirically test for "epistatic interactions" in the sense of the masking of the effect of a particular genetic variant by a variant at another locus. PMID- 20196745 TI - Parameter estimation in multiple-hidden i.i.d. models from biological multiple alignment. AB - In this work we deal with parameter estimation in a latent variable model, namely the multiple-hidden i.i.d. model, which is derived from multiple alignment algorithms. We first provide a rigorous formalism for the homology structure of k sequences related by a star-shaped phylogenetic tree in the context of multiple alignment based on indel evolution models. We discuss possible definitions of likelihoods and compare them to the criterion used in multiple alignment algorithms. Existence of two different Information divergence rates is established and a divergence property is shown under additional assumptions. This would yield consistency for the parameter in parametrization schemes for which the divergence property holds. We finally extend the definition of the multiple hidden i.i.d. model and the results obtained to the case in which the sequences are related by an arbitrary phylogenetic tree. Simulations illustrate different cases which are not covered by our results. PMID- 20196746 TI - Asymptotic distribution of the "orthogonal" quantitative transmission disequilibrium test in a structured population: exact formula. AB - Population structure is a recurrent problem for the detection of associations between a marker and a trait, because it can lead to an excess of false positives of the association tests. One popular way of circumventing this problem is the use of family based tests, which consider the transmission of the genotype from the parents to the offspring. Here we focus on quantitative traits and study the Abecasis "orthogonal" quantitative transmission disequilibrium test, which is commonly used in family based association studies. We derive the probability distribution of this test under a general model of structured population. Our derivations show that this test leads to a small excess of false positives due to population structure. They also illustrate and quantify how the heterogeneity in genotypes and phenotypes between populations affect the power of the test. We finally show that the excess of false positives observed for the Abecasis "orthogonal" test may also be found for the Allison "linear" test, though at a lower extent. PMID- 20196747 TI - An alternative model of type A dependence in a gene set of correlated genes. AB - Klebanov et al. (2006) proposed a new type of stochastic dependence, Type A dependence, between gene expression levels. They estimated the abundance of Type A pairs by testing the correlation coefficients of gene pairs. We propose a new model, hidden regulator dependence, as an alternative to Type A dependence. We show that the correlation based procedure proposed by Klebanov et al. (2006) fails to differentiate hidden regulator dependence from Type A dependence, although their probabilistic structures are quite different. PMID- 20196748 TI - Comparing spatial maps of human population-genetic variation using Procrustes analysis. AB - Recent applications of principal components analysis (PCA) and multidimensional scaling (MDS) in human population genetics have found that "statistical maps" based on the genotypes in population-genetic samples often resemble geographic maps of the underlying sampling locations. To provide formal tests of these qualitative observations, we describe a Procrustes analysis approach for quantitatively assessing the similarity of population-genetic and geographic maps. We confirm in two scenarios, one using single-nucleotide polymorphism (SNP) data from Europe and one using SNP data worldwide, that a measurably high level of concordance exists between statistical maps of population-genetic variation and geographic maps of sampling locations. Two other examples illustrate the versatility of the Procrustes approach in population-genetic applications, verifying the concordance of SNP analyses using PCA and MDS, and showing that statistical maps of worldwide copy-number variants (CNVs) accord with statistical maps of SNP variation, especially when CNV analysis is limited to samples with the highest-quality data. As statistical maps with PCA and MDS have become increasingly common for use in summarizing population relationships, our examples highlight the potential of Procrustes-based quantitative comparisons for interpreting the results in these maps. PMID- 20196749 TI - An internal calibration method for protein-array studies. AB - Nuisance factors in a protein-array study add obfuscating variation to spot intensity measurements, diminishing the accuracy and precision of protein concentration predictions. The effects of nuisance factors may be reduced by design of experiments, and by estimating and then subtracting nuisance effects. Estimated nuisance effects also inform about the quality of the study and suggest refinements for future studies.We demonstrate a method to reduce nuisance effects by incorporating a non-interfering internal calibration in the study design and its complemental analysis of variance. We illustrate this method by applying a chip-level internal calibration in a biomarker discovery study. The variability of sample intensity estimates was reduced 16% to 92% with a median of 58%; confidence interval widths were reduced 8% to 70% with a median of 35%. Calibration diagnostics revealed processing nuisance trends potentially related to spot print order and chip location on a slide. The accuracy and precision of a protein-array study may be increased by incorporating a non-interfering internal calibration. Internal calibration modeling diagnostics improve confidence in study results and suggest process steps that may need refinement. Though developed for our protein-array studies, this internal calibration method is applicable to other targeted array-based studies. PMID- 20196750 TI - Weighted-LASSO for structured network inference from time course data. AB - We present a weighted-LASSO method to infer the parameters of a first-order vector auto-regressive model that describes time course expression data generated by directed gene-to-gene regulation networks. These networks are assumed to own prior internal structures of connectivity which drive the inference method. This prior structure can be either derived from prior biological knowledge or inferred by the method itself. We illustrate the performance of this structure-based penalization both on synthetic data and on two canonical regulatory networks (the yeast cell cycle regulation network and the E. coli S.O.S. DNA repair network). PMID- 20196751 TI - Trilocus disequilibrium analysis of multiallelic markers in outcrossing populations. AB - Multiallelic markers, such as microsatellites, provide a powerful tool for studying the genetic structure and organization of an outcrossing population. However, statistical methods of analyzing multiallelic markers in current literature are limited in scope due to the complexity of the multiple alleles. We present a closed-form EM algorithm framework to estimate trigenic linkage disequilibria coefficients of three multiallelic markers and present joint and separate statistical hypothesis tests of different linkage disequilibria. Linkage disequilibria analysis with three multiallelic markers is shown to be considerably more powerful than a two marker analysis or a three marker analysis that treats the multiallelic markers as biallelic markers. A three multiallelic marker model was used to analyze marker data from Lycoris longituba, a tulip-like ornamental plant in China, where each marker consisted of two to four distinct alleles. This algorithm will be useful for studying the pattern of genetic variation for outcrossing populations. PMID- 20196752 TI - Testing for gene-gene interaction with AMMI models. AB - Studies have shown that many common diseases are influenced by multiple genes and their interactions. There is currently a strong interest in testing for association between combinations of these genes and disease, in particular because genes that affect the risk of disease only in the presence of another genetic variant may not be detected in marginal analysis. In this paper we propose the use of additive main effect and multiplicative interaction (AMMI) models to detect and to quantify gene-gene interaction effects for a quantitative trait. The objective of the present research is to demonstrate the practical advantages of these models to describe complex interaction between two unlinked loci. Although gene-gene interactions have often been defined as a deviance from additive genetic effects, the residual term has generally not been appropriately treated. The AMMI models allow for the analysis of a two way factorial data structure and combine the analysis of variance of the two main genotype effects with a principal component analysis of the residual multiplicative interaction. The AMMI models for gene-gene interaction presented here allow for the testing of non additivity between the two loci, and also describe how their interaction structure fits the existing non-additivity. Moreover, these models can be used to identify the specific two genotypes combinations that contribute to the significant gene-gene interaction. We describe the use of the biplot to display the structure of the interaction and evaluate the performance of the AMMI and the special cases of the AMMI previously described by Tukey and Mandel with simulated data sets. Our simulated study showed that the AMMI model is as powerful as general linear models when the interaction is not modeled in the presence of marginal effects. However, in the presence of pure epitasis, i.e. in the absence of marginal effects, the AMMI method was not found to be superior to other tested regression methods. PMID- 20196753 TI - A Bayesian hierarchical model for quantitative real-time PCR data. AB - We present a Bayesian hierarchical model for quantitative real-time polymerase chain reaction (PCR) data, aiming at relative quantification of DNA copy number in different biological samples. The model is specified in terms of a hidden Markov model for fluorescence intensities measured at successive cycles of the polymerase chain reaction. The efficiency of the reaction is assumed to depend on the abundance of the target DNA through fluorescence intensities, and the relationship is specified based on the kinetics of the reaction. The model incorporates the intrinsic random nature of the process as well as measurement error. Taking a Bayesian inferential approach, marginal posterior distributions of the quantities of interest are estimated using Markov chain Monte Carlo. The method is applied to simulated data and an experimental data set. PMID- 20196754 TI - Informative or noninformative calls for gene expression: a latent variable approach. AB - The strength and weakness of microarray technology can be attributed to the enormous amount of information it is generating. To fully enhance the benefit of microarray technology for testing differentially expressed genes and classification, there is a need to minimize the amount of irrelevant genes present in microarray data. A major interest is to use probe-level data to call genes informative or noninformative based on the trade-off between the array-to array variability and the measurement error. Existing works in this direction include filtering likely uninformative sets of hybridization (FLUSH; Calza et al., 2007) and I/NI calls for the exclusion of noninformative genes using FARMS (I/NI calls; Talloen et al., 2007; Hochreiter et al., 2006). In this paper, we propose a linear mixed model as a more flexible method that performs equally good as I/NI calls and outperforms FLUSH. We also introduce other criteria for gene filtering, such as, R2 and intra-cluster correlation. Additionally, we include some objective criteria based on likelihood ratio testing, the Akaike information criteria (AIC; Akaike, 1973) and the Bayesian information criterion (BIC; Schwarz, 1978 ). Based on the HGU-133A Spiked-in data set, it is shown that the linear mixed model approach outperforms FLUSH, a method that filters genes based on a quantile regression. The linear model is equivalent to a factor analysis model when either the factor loadings are set to a constant with the variance of the latent factor equal to one, or if the factor loadings are set to one together with unconstrained variance of the latent factor. Filtering based on conditional variance calls a probe set informative when the intensity of one or more probes is consistent across the arrays, while filtering using R2 or intra-cluster correlation calls a probe set informative only when average intensity of a probe set is consistent across the arrays. Filtering based on likelihood ratio test AIC and BIC are less stringent compared to the other criteria. PMID- 20196755 TI - Detecting genotyping error using measures of degree of Hardy-Weinberg disequilibrium. AB - Tests for Hardy-Weinberg equilibrium (HWE) have been used to detect genotyping error, but those tests have low power unless the sample size is very large. We assessed the performance of measures of departure from HWE as an alternative way of screening for genotyping error. Three measures of the degree of disequilibrium (alpha, ,D, and F) were tested for their ability to detect genotyping error of 5% or more using simulations and a real dataset of 184 children with leukemia genotyped at 28 single nucleotide polymorphisms. The simulations indicate that all three disequilibrium coefficients can usefully detect genotyping error as judged by the area under the Receiver Operator Characteristic (ROC) curve. Their discriminative ability increases as the error rate increases, and is greater if the genotyping error is in the direction of the minor allele. Optimal thresholds for detecting genotyping error vary for different allele frequencies and patterns of genotyping error but allele frequency-specific thresholds can be nominated. Applying these thresholds would have picked up about 90% of genotyping errors in our actual dataset. Measures of departure from HWE may be useful for detecting genotyping error, but this needs to be confirmed in other real datasets. PMID- 20196756 TI - Optimisation of HMM topologies enhances DNA and protein sequence modelling. AB - Hidden Markov models (HMMs) play a major role in applications to unravel biomolecular functionality. Though HMMs are technically mature and widely applied in computational biology, there is a potential of methodical optimisation concerning its modelling of biological data sources with varying sequence lengths. Single building blocks of these models, the states, are associated with a certain holding time, being the link to the length distribution of represented sequence motifs. An adaptation of regular HMM topologies to bell-shaped sequence lengths is achieved by a serial chain-linking of hidden states, while residing in the class of conventional hidden Markov models. The factor of the repetition of states (r) and the parameter for state-specific duration of stay (p) are determined by fitting the distribution of sequence lengths with the method of moments (MM) and maximum likelihood (ML). Performance evaluations of differently adjusted HMM topologies underline the impact of an optimisation for HMMs based on sequence lengths. Secondary structure prediction on internal transcribed spacer 2 sequences demonstrates exemplarily the general impact of topological optimisations. In summary, we propose a general methodology to improve the modelling behaviour of HMMs by topological optimisation with ML and a fast and easily implementable moment estimator. PMID- 20196757 TI - The apportionment of total genetic variation by categorical analysis of variance. AB - We wish to suggest the categorical analysis of variance as a means of quantifying the proportion of total genetic variation attributed to different sources of variation. This method potentially challenges researchers to rethink conclusions derived from a well-known method known as the analysis of molecular variance (AMOVA). The CATANOVA framework allows explicit definition, and estimation, of two measures of genetic differentiation. These parameters form the subject of interest in many research programmes, but are often confused with the correlation measures defined in AMOVA, which cannot be interpreted as relative contributions of particular sources of variation. Through a simulation approach, we show that under certain conditions, researchers who use AMOVA to estimate these measures of genetic differentiation may attribute more than justified amounts of total variation to population labels. Moreover, the two measures can also lead to incongruent conclusions regarding the genetic structure of the populations of interest. Fortunately, one of the two measures seems robust to variations in relative sample sizes used. Its merits are illustrated in this paper using mitochondrial haplotype and amplified fragment length polymorphism (AFLP) data. PMID- 20196758 TI - Dealing with heterogeneity between cohorts in genomewide SNP association studies. AB - In Genomewide association (GWA) studies investigating thousands of SNPs, large sample sizes are needed to obtain a reasonable power after correction for multiple testing. To obtain the necessary sample sizes, data from different populations/cohorts are combined. The problem of pooling evidence across cohorts bears some resemblance with meta-analysis of clinical trials, and in fact classical meta-analytic methodologies from that field are typically used in GWAs. However, in genetics, it can be expected that the cohorts show some amount of heterogeneity in the association measures that are used for significance testing. In this paper, we demonstrate how it is possible to exploit this heterogeneity to improve our ability to detect influential genetic variants. We also discuss how pathway analysis based on summary data can help resolve heterogeneity. The current standard method for testing SNPs across cohorts in GWAs will miss heterogeneous but important genetic variants affecting complex diseases. Our new testing strategy has the potential to detect them while maintaining sensitivity to variants with homogeneous effects. PMID- 20196759 TI - An empirical Bayesian method for estimating biological networks from temporal microarray data. AB - Gene regulatory networks refer to the interactions that occur among genes and other cellular products. The topology of these networks can be inferred from measurements of changes in gene expression over time. However, because the measurement device (i.e., microarrays) typically yields information on thousands of genes over few biological replicates, these systems are quite difficult to elucidate. An approach with proven effectiveness for inferring networks is the Dynamic Bayesian Network. We have developed an iterative empirical Bayesian procedure with a Kalman filter that estimates the posterior distributions of network parameters. We compare our method to similar existing methods on simulated data and real microarray time series data. We find that the proposed method performs comparably on both model-based and data-based simulations in considerably less computational time. The R and C code used to implement the proposed method are publicly available in the R package ebdbNet. PMID- 20196760 TI - Teacher perspectives and the psychosocial climate of the classroom in a traditional BSN program. AB - Developing and implementing a positive psychosocial environment should be one of the main responsibilities of educators. As educators influence the climate, learning is enhanced or hindered. Therefore educators need to understand their own teaching perspectives and how they in turn influence the classroom. Data were collected from nurse educators and BSN nursing students. The relationship between faculty teaching perspectives and the students' perceptions of the learning environment was examined. The data collection tool used to measure the educators' perspective was the Instructional Perspective Inventory (IPI), and to measure the students' perspective was the Adult Classroom Environment Scale (ACES). A MANCOVA was used to determine the relationship and significant differences between educators' and students' perspectives. The results indicated that the teachers in the high group of teacher responsiveness had students who reported greater teacher support, time on task, focus, organization, clarity of subject content, involvement, and satisfaction. PMID- 20196761 TI - Choosing a career in nursing: development of a career search instrument. AB - University students in this millennium will be older, culturally diverse and likely to change their career major several times during the course of their education. Methods to identify and guide appropriate students toward nursing are lacking. The purpose of this study was to develop and initially test a 48-item Likert-scaled instrument, the Career Search Questionnaire (CSQ), which assesses interest in and self-efficacy for nursing. Data were obtained from 300 volunteer students, with implied consent, enrolled in beginning-level courses at a Midwestern university. Response differences were apparent between individuals who reported nursing as a college major compared to those who sought a different major. Participants who reported nursing as their major obtained higher scores in both interest (p = 0.00) and self-efficacy (p = 0.00). The CSQ is psychometrically sound, with a reliability score of 0.87 and capable of identifying the student for whom nursing may be the suitable career. PMID- 20196762 TI - Exploring a pedagogical approach to integrating research, practice and teaching. AB - Application of evidence is accepted as an important component of clinical practice. Teaching research to undergraduate students has been reported internationally as a challenge, particularly for nurse educators. In this paper, reported is a strategy designed to enhance research learning for undergraduate midwifery students at one university, which formed part of a larger, international investigation into women's responses to caesarean birth. Following theory classes and briefings, students worked with their clinical educators in practice to interview women using existing tools, and were engaged in qualitative data analysis. A number of challenges were encountered throughout the process, both for the educators and students. However, the teaching approach provided benefits for students in learning about midwifery research. Recommended as essential is for continued development of pedagogical approaches that make research tangible for students. Furthermore, provision of support for clinical staff working with students is important for success of such approaches. PMID- 20196763 TI - A model for easily incorporating team-based learning into nursing education. AB - A sense of urgency exists among nurse educators to determine the best possible teaching strategies to create a rich, engaging learning environment for students. With the calls for transformation, innovation, and excellence in nursing education from the American Association of Colleges of Nursing, the National Council of State Boards of Nursing, and the National League for Nursing, educators may determine that current teaching strategies fall short. Team-based learning, an innovative teaching strategy, offers educators a structured, student centered learning environment and may be effective in teaching necessary skills to students. An overview of how this strategy fosters many of the essential concepts, such as critical thinking, professionalism, communication, and interprofessional teamwork, is presented. Additionally, this article offers a clearly delineated "recipe" for implementing team-based learning in the classroom. This innovative strategy has the potential to transform nursing education and provide a positive teaching and learning environment for both educators and students. PMID- 20196764 TI - Metacognitive factors that impact student nurse use of point of care technology in clinical settings. AB - The utility of personal digital assistants (PDA) as a point of care resource in health care practice and education presents new challenges for nursing faculty. While there is a plethora of PDA resources available, little is known about the variables that effect student learning and technology adoption. In this study nursing students used PDA software programs which included a drug guide, medical dictionary, laboratory manual and nursing diagnosis manual during acute care clinical experiences. Analysis of student journals comparative reflective statements about the PDA as an adjunct to other available resources in clinical practice are presented. The benefits of having a PDA included readily available data, validation of thinking processes, and facilitation of care plan re evaluation. Students reported increased frequency of use and independence. Significant correlations between user perceptions and computer self-efficacy suggested greater confidence in abilities with technology resulting in increased self-awareness and achievement of learning outcomes. PMID- 20196765 TI - Learner-centered characteristics of nurse educators. AB - The purpose of this study was to describe the learner-centered teaching characteristics of nurse faculty who report using contemporary pedagogy. A secondary analysis of data collected by an international survey of nurse educators regarding pedagogical teaching approaches and strategies was used to answer the research questions. The study sought to: 1) describe characteristics emerging from faculty response, 2) make inferences from faculty responses regarding meaning, and 3) make inferences regarding the importance of the meaning to nursing. A qualitative research design was used to address the research question. Themes that emerged were placed under the concepts of power, role of teacher, responsibility of learner, and philosophy of evaluation guided by Weimer's (2002) conceptual framework of a learner-centered philosophy of teaching. Themes and meaning units derived from the study helped to generate textual and structure statements that represent the characterizations of learner centered nurse educators. PMID- 20196766 TI - Ready for what? An exploration of the meaning of new graduate nurses' readiness for practice. AB - Dialogue continues on the "readiness" of new graduates for practice despite significant advancements in the foundational educational preparation for nurses. In this paper, the findings from an exploratory study about the meaning of new graduate "readiness" for practice are reported. Data was collected during focus group interviews with one-hundred and fifty nurses and new graduates. Themes were generated using content analysis. Our findings point to agreement about the meaning of new graduate nurses' readiness for practice as having a generalist foundation and some job specific capabilities, providing safe client care, keeping up with the current realities of nursing practice, being well equipped with the tools needed to adapt to the future needs of clients, and possessing a balance of doing, knowing, and thinking. The findings from this exploratory study have implications for policies and programs targeted towards new graduate nurses entering practice. PMID- 20196767 TI - Righting writing: strategies for improving nursing student papers. AB - The ability to clearly express complex ideas in writing is necessary for nurses in professional practice at all levels from novice to expert. The community health nursing course is specially designated as writing intensive to provide students with the experience of preparing a major scholarly paper. To address issues of poor paper quality and grade inflation we implemented a program including a writing workshop for faculty, a revision of the grading rubric, and a system of blind review for grading student papers. Changes resulted in a major shift in paper grades which more closely reflects the actual quality of the work. PMID- 20196768 TI - Surface expression of CXCR4 in unrestricted somatic stem cells and its regulation by growth factors. AB - Umbilical cord blood-derived USSCs (unrestricted somatic stem cells) have recently been considered as a potential source for stem cell therapy and transplantation due to their characteristics such as easy accessibility, low immunogenicity, self-renewing and multilineage differentiation potential. Stem cell homing is a key factor in successful transplantation, which is regulated by CXCR4 in stem cells. In this study, we evaluated the expression of CXCR4 in USSCs different passages. Moreover, the effect of VEGF (vascular endothelial growth factor) and IGF-1 (insulin-like growth factor 1) on its expression was assessed. It was shown that the expression of CXCR4 in USSCs decreased with the increase in passage number. It was also revealed that VEGF increased surface expression and mRNA level of CXCR4 in USSCs, while IGF-1 decreased its expression. When VEGF and IGF-1 were administered simultaneously, CXCR4 expression was increased, but the expression level was less than VEGF alone. Finally, it was shown that over expression of CXCR4 enhanced the migratory capacity of USSCs. The increase of CXCR4 expression, here caused by VEGF in USSCs, can improve the efficacy of stem cell therapy and transplantation after long-term culture of stem cells before clinical use. PMID- 20196769 TI - Analysis of the interactions between the C-terminal cytoplasmic domains of KCNQ1 and KCNE1 channel subunits. AB - Ion channel subunits encoded by KCNQ1 and KCNE1 produce the slowly activating K+ current (IKs) that plays a central role in myocardial repolarization. The KCNQ1 alpha-subunit and the KCNE1 beta-subunit assemble with their membrane-spanning segments interacting, resulting in transformation of channel activation kinetics. We recently reported a functional interaction involving C-terminal portions of the two subunits with ensuing regulation of channel deactivation. In the present study, we provide evidence characterizing a physical interaction between the KCNQ1-CT (KCNE1 C-terminus) and the KCNE1-CT (KCNE1 C-terminus). When expressed in cultured cells, the KCNE1-CT co-localized with KCNQ1, co-immunoprecipitated with KCNQ1 and perturbed deactivation kinetics of the KCNQ1 currents. Purified KCNQ1-CT and KCNE1-CT physically interacted in pull-down experiments, indicating a direct association. Deletion analysis of KCNQ1-CT indicated that the KCNE1-CT binds to a KCNQ1 region just after the last transmembrane segment, but N-terminal to the tetramerization domain. SPR (surface plasmon resonance) corroborated the pull-down results, showing that the most proximal region (KCNQ1 amino acids 349 438) contributed most to the bimolecular interaction with a dissociation constant of approximately 4 microM. LQT (long QT) mutants of the KCNE1-CT, D76N and W87F, retained binding to the KCNQ1-CT with comparable affinity, indicating that these disease-causing mutations do not alter channel behaviour by disruption of the association. Several LQT mutations involving the KCNQ1-CT, however, showed various effects on KCNQ1/KCNE1 association. Our results indicate that the KCNQ1 CT and the KCNE1-CT comprise an independent interaction domain that may play a role in IKs channel regulation that is potentially affected in some LQTS (LQT syndrome) mutations. PMID- 20196770 TI - Selective SUMO modification of cAMP-specific phosphodiesterase-4D5 (PDE4D5) regulates the functional consequences of phosphorylation by PKA and ERK. AB - Enzymes from the PDE (phosphodiesterase) 4 cAMP-specific PDE family are crucial for the maintenance of compartmentalized cAMP responses in many cell types. Regulation of PDE activity can be achieved via post-translational modification such as phosphorylation by ERK (extracellular-signal-regulated kinase) MAPKs (mitogen-activated protein kinases) and PKA (protein kinase A). In the present paper, we report for the first time that PDE4 isoforms from the PDE4A and PDE4D subfamilies can be selectively modified by SUMO (small ubiquitin-related modifier). We have identified a single SUMO site within a consensus tetrapeptide motif, PsiKXE (where Psi represents a hydrophobic residue), which lies in the catalytic unit of these enzymes. SUMO modification of PDE4 at this site was observed upon overexpression of the SUMO E3 ligase PIASy [protein inhibitor of activated STAT (signal transducer and activator of transcription) Y] in HEK (human embryonic kidney)-293 cells and we identify PIASy as a novel binding partner for long PDE4 isoforms. Site-directed mutagenesis of the acceptor lysine residue ablated conjugation of PDE4 with SUMO, suggesting the presence of a single SUMO site in the first subdomain of the conserved PDE4 catalytic unit. This observation was supported by both cell-free in vitro SUMOylation assays and analysis of SUMOylated spot-immobilized peptide arrays. SUMO modification of long PDE4 isoforms serves to augment their activation by PKA phosphorylation and repress their inhibition by ERK phosphorylation. Following ligation of beta adrenergic receptors, SUMOylation of PDE4 isoforms sufficiently amplified PKA stimulated PDE4 activity to reduce markedly the PKA phosphorylation status of the beta2-adrenergic receptor. These results highlight a new means whereby cells might achieve the selective regulation of the activity of cAMP-specific PDE4 enyzmes. PMID- 20196771 TI - Structural contributions of delta class glutathione transferase active-site residues to catalysis. AB - GST (glutathione transferase) is a dimeric enzyme recognized for biotransformation of xenobiotics and endogenous toxic compounds. In the present study, residues forming the hydrophobic substrate-binding site (H-site) of a Delta class enzyme were investigated in detail for the first time by site directed mutagenesis and crystallographic studies. Enzyme kinetics reveal that Tyr111 indirectly stabilizes GSH binding, Tyr119 modulates hydrophobic substrate binding and Phe123 indirectly modulates catalysis. Mutations at Tyr111 and Phe123 also showed evidence for positive co-operativity for GSH and 1-chloro-2,4 dinitrobenzene respectively, strongly suggesting a role for these residues in manipulating subunit-subunit communication. In the present paper we report crystal structures of the wild-type enzyme, and two mutants, in complex with S hexylglutathione. This study has identified an aromatic 'zipper' in the H-site contributing a network of aromatic pi-pi interactions. Several residues of the cluster directly interact with the hydrophobic substrate, whereas others indirectly maintain conformational stability of the dimeric structure through the C-terminal domain (domain II). The Y119E mutant structure shows major main-chain rearrangement of domain II. This reorganization is moderated through the 'zipper' that contributes to the H-site remodelling, thus illustrating a role in co substrate binding modulation. The F123A structure shows molecular rearrangement of the H-site in one subunit, but not the other, explaining weakened hydrophobic substrate binding and kinetic co-operativity effects of Phe123 mutations. The three crystal structures provide comprehensive evidence of the aromatic 'zipper' residues having an impact upon protein stability, catalysis and specificity. Consequently, 'zipper' residues appear to modulate and co-ordinate substrate processing through permissive flexing. PMID- 20196772 TI - Calcium- and polyphosphate-containing acidocalcisomes in chicken egg yolk. AB - BACKGROUND INFORMATION: Poly P (inorganic polyphosphate) is a polymer formed by P(i) residues linked by high-energy phosphoanhydride bonds. The presence of poly P in bacteria, fungi, algae and protists has been widely recognized, but the distribution of poly P in more complex eukaryotes has been poorly studied. Poly P accumulates, together with calcium, in acidic vesicles or acidocalcisomes in a number of organisms and possesses a diverse array of functions, including roles in stress response, blood clotting, inflammation, calcification, cell proliferation and apoptosis. RESULTS: We report here that a considerable amount of phosphorus in the yolk of chicken eggs is in the form of poly P. DAPI (4',6 diamidino-2-phenylindole) staining showed that poly P is localized mainly in electron-dense vesicles located inside larger vacuoles (compound organelles) that are randomly distributed in the yolk. These internal vesicles were shown to contain calcium, potassium, sodium, magnesium, phosphorus, chlorine, iron and zinc, as detected by X-ray microanalysis and elemental mapping. These vesicles stain with the acidophilic dye Acridine Orange. The presence of poly P in organellar fractions of the egg yolk was evident in agarose gels stained with Toluidine Blue and DAPI. Of the total phosphate (Pi) of yolk organelles, 16% is present in the form of poly P. Total poly P content was not altered during the first 4 days of embryogenesis, but poly P chain length decreased after 1 day of development. CONCLUSIONS: The results of the present study identify a novel organelle in chicken egg yolk comprising acidic vesicles with a morphology, physiology and composition similar to those of acidocalcisomes, within larger acidic vacuoles. The elemental composition of these acidocalcisomes is proportionally similar to the elemental composition of the yolk, suggesting that most of these elements are located in these organelles, which might be an important storage compartment in eggs. PMID- 20196773 TI - The glycosylphosphatidylinositol anchor is a major determinant of prion binding and replication. AB - The prion diseases occur following the conversion of the cellular prion protein (PrPC) into an alternatively folded, disease-associated isoform (PrPSc). However, the spread of PrPSc from cell to cell is poorly understood. In the present manuscript we report that soluble PrPSc bound to and replicated within both GT1 neuronal cells and primary cortical neurons. The capacity of PrPSc to bind and replicate within cells was significantly reduced by enzymatic modification of its GPI (glycosylphosphatidylinositol) anchor. Thus PrPSc that had been digested with phosphatidylinositol-phospholipase C bound poorly to GT1 cells or cortical neurons and did not result in PrPSc formation in recipient cells. PrPSc that had been digested with phospholipase A2 (PrPSc-G-lyso-PI) bound readily to GT1 cells and cortical neurons but replicated less efficiently than mock-treated PrPSc. Whereas the addition of PrPSc increased cellular cholesterol levels and was predominantly found within lipid raft micro-domains, PrPSc-G-lyso-PI did not alter cholesterol levels and most of it was found outside lipid rafts. We conclude that the nature of the GPI anchor attached to PrPSc affected the binding of PrPSc to neurons, its localization to lipid rafts and its ability to convert endogenous PrPC. PMID- 20196775 TI - Epileptic phenotypes in children with respiratory chain disorders. AB - PURPOSE: Epilepsy is a commonly reported but rarely described clinical hallmark of mitochondrial respiratory chain defects (RCDs) with encephalopathy. METHODS: From 1990-2006 we collected data about 56 children with RCD (single, n = 24 or multiple, n = 20 mitochondrial complex deficiencies; mtDNA mutation, n = 11; mtDNA depletion n = 10 of 21; and nuclear gene mutation n = 11). Epileptic features were reviewed retrospectively. RESULTS: First seizures were frequently (47 patients, 82.5%) preceded by failure to thrive, psychomotor delay, ataxia, or multisystemic dysfunction. Sixty percent of the patients had several seizure types. Six age-related epilepsy phenotypes could be identified: status epilepticus complicating neonatal multivisceral deficiency (2 patients), neonatal myoclonic encephalopathy (3 patients), infantile spasms (8 patients), refractory or recurrent status epilepticus (21 patients), epilepsia partialis continua (4 patients), and myoclonic epilepsy (18 patients). Except for infantile spasms, epilepsy was difficult to control in most patients (95%). Valproate was administered to 25 patients, one of whom developed acute liver failure 6 days later. Twenty-two patients (45%) died, half of them within 9 months from the onset of epilepsy. DISCUSSION: In RCD, epilepsy is not only difficult to control but its occurrence often indicates a severe turn in the course of the disease. For one-third of the patients, classical biochemical measures failed to reveal any abnormality and RCD could be detected in the liver only. PMID- 20196774 TI - Signal peptide peptidase (SPP) assembles with substrates and misfolded membrane proteins into distinct oligomeric complexes. AB - SPP (signal peptide peptidase) is an aspartyl intramembrane cleaving protease, which processes a subset of signal peptides, and is linked to the quality control of ER (endoplasmic reticulum) membrane proteins. We analysed SPP interactions with signal peptides and other membrane proteins by co-immunoprecipitation assays. We found that SPP interacts specifically and tightly with a large range of newly synthesized membrane proteins, including signal peptides, preproteins and misfolded membrane proteins, but not with all co-expressed type II membrane proteins. Signal peptides are trapped by the catalytically inactive SPP mutant SPPD/A. Preproteins and misfolded membrane proteins interact with both SPP and the SPPD/A mutant, and are not substrates for SPP-mediated intramembrane proteolysis. Proteins interacting with SPP are found in distinct complexes of different sizes. A signal peptide is mainly trapped in a 200 kDa SPP complex, whereas a preprotein is predominantly found in a 600 kDa SPP complex. A misfolded membrane protein is detected in 200, 400 and 600 kDa SPP complexes. We conclude that SPP not only processes signal peptides, but also collects preproteins and misfolded membrane proteins that are destined for disposal. PMID- 20196776 TI - Surgery for temporal lobe epilepsy associated with mesial temporal sclerosis in the older patient: a long-term follow-up. AB - PURPOSE: To assess the outcomes from temporal lobectomy for hippocampal sclerosis in patients 50 years or older. Controversy exists as to the suitability of older patients for epilepsy surgery, with most of the previous studies demonstrating a correlation between increasing age and poor outcome. However, the inclusion of temporal lobe epilepsy of multiple etiologies has confounded many previous studies of this age group. METHODS: Twenty-one patients aged 50 years or older (mean 54.9 years) at the time of surgery were included in the study group. All patients had a pathologic diagnosis of hippocampal sclerosis. A retrospective analysis was performed comparing seizure outcomes following a standardized anterior temporal lobectomy with those from 103 patients younger than 50 (mean age 34.7 years) operated upon over the same time period. The mean follow-up period for the study was 9.57 years. RESULTS: Twenty of the 21 patients in the older group (95.2%) had a satisfactory seizure outcome (Engel classes I and II) compared with 90.3% of the younger patients. There was no statistically significant difference in the outcomes between the two groups (p = 0.719). Across both groups of patients combined, there was no significant difference between the mean age in the patients with a satisfactory seizure outcome compared to those with an unsatisfactory outcome (38.3 vs. 34.7 years, p = 0.213). DISCUSSION: Patients 50 years or older with intractable seizures from hippocampal sclerosis have seizure outcomes following temporal lobectomy that are comparable to young patients over the long term. Older patients should not be denied treatment on the basis of age. PMID- 20196777 TI - Involvement of SOX-9 and FGF-23 in RUNX-2 regulation in osteoarthritic chondrocytes. AB - Chondrocytes' hypertrophy includes metabolic changes, matrix remodelling, proliferation and apoptosis, characteristics associated with the progression of osteoarthritis. We investigated a possible association among Runt-related transcription factor 2 (RUNX-2), SOX-9 and fibroblast growth factor (FGF)-23 mRNA expressions in articular chondrocytes in order to elucidate their contribution in the osteoarthritic hypertrophic cartilage. SOX-9, FGF-23, RUNX-2 and matrix metalloproteinase (MMP)-13 mRNA expressions were evaluated in osteoarthritic and normal chondrocytes by real-time PCR whereas MMP-13 protein expression by immunofluorescense. RUNX-2, FGF-23 and SOX-9 were down-regulated using small interfering RNA technology and transfection with liposomes. The effect of human recombinant FGF-23 (hrFGF-23) on SOX-9 and RUNX-2 expression was tested in normal chondrocytes. We found higher expression of RUNX-2 and FGF-23 and a decreased expression of SOX-9 mRNA in osteoarthritic chondrocytes compared to normal (P < 0.0001). RUNX-2 down-regulation resulted in reduced MMP-13 expression in osteoarthritic chondrocytes and inhibition of SOX-9 in increased RUNX-2 and MMP 13 mRNA expression in normal chondrocytes, whereas inhibition of FGF-23 resulted in reduced RUNX-2 mRNA expression in osteoarthritic chondrocytes (all P < 0.0001). Silencing of RUNX-2 or FGF-23 did not affect SOX-9 mRNA levels in osteoarthritic chondrocytes. Moreover simultaneous down-regulation of SOX-9 and up-regulation of FGF-23 mRNA expressions in normal chondrocytes resulted in additive up-regulation of RUNX-2 mRNA expression. Treatment of normal chondrocytes with hrFGF-23 resulted in increased RUNX-2 mRNA expression, whereas it had no effect on SOX-9 mRNA expression. We demonstrated convincing associations among RUNX-2, SOX-9 and FGF-23 in relation to MMP-13 expression in osteoarthritic chondrocytes, contributing to a better understanding of the abnormal gene expression and cartilage degeneration processes associated with osteoarthritis. PMID- 20196778 TI - Toll-like receptor stimulation differentially regulates vasoactive intestinal peptide type 2 receptor in macrophages. AB - Vasoactive intestinal peptide (VIP) was originally isolated as a vasodilator intestinal peptide, then as a neuropeptide. In the immune system, VIP is described as an endogenous macrophage-deactivating factor. VIP exerts its immunological actions in a paracrine and/or autocrine manner, through specific receptors. However, very little is known about the molecular regulation of VIP type 2 receptor (VPAC(2)) in the immune system. We now report that different toll like receptor (TLR) ligands selectively regulate the VPAC(2) receptor gene and show a gene repression system controlled by key protein kinase signalling cascades in macrophages. VPAC(2) gene expression is regulated by gram-positive (TLR2 ligands) and gram-negative bacteria wall constituents (TLR4 ligands). Moreover, VPAC(2) is tightly regulated: TLR2- or TLR2/6- but not TLR2/1-mediated mechanisms are responsible for the induction of VPAC(2). TLR stimulation by viral or bacterial nucleic acids did not modify the VPAC(2) mRNA levels. Remarkably, imiquimod--a synthetic TLR7 ligand--led to a potent up-regulation of VPAC(2) gene expression. TLR5 stimulation by flagellin present in gram-positive and gram negative bacteria did not affect VPAC(2) mRNA. The p38 mitogen-activated protein kinase (MAPK) activity accounted for the TLR4-mediated induction of VPAC(2) gene expression. Surprisingly, our data strongly suggest for the first time a tightly repressed control of VPAC(2) mRNA induction by elements downstream of MAPK kinase 1/2, PI3K/Akt, and particularly Jun-NH(2)-terminal kinase signalling pathways. PMID- 20196779 TI - Formation of lipid raft redox signalling platforms in glomerular endothelial cells: an early event of homocysteine-induced glomerular injury. AB - The present study tested the hypothesis that homocysteine (Hcys)-induced ceramide production stimulates lipid rafts (LRs) clustering on the membrane of glomerular endothelial cells (GECs) to form redox signalling platforms by aggregation and activation of NADPH oxidase subunits and thereby enhances superoxide (O2*-) production, leading to glomerular endothelial dysfunction and ultimate injury or sclerosis. Using confocal microscopy, we first demonstrated a co-localization of LR clusters with NADPH oxidase subunits, gp91(phox) and p47(phox) in the GECs membrane upon Hcys stimulation. Immunoblot analysis of floated detergent resistant membrane fractions found that in LR fractions NADPH oxidase subunits gp91(phox) and p47(phox) are enriched and that the activity of this enzyme dramatically increased. We also examined the effect of elevated Hcys on the cell monolayer permeability in GECs. It was found that Hcys significantly increased GEC permeability, which was blocked by inhibition of LR redox signalling platform formation. Finally, we found that Hcys-induced enhancement of GEC permeability is associated with the regulation of microtubule stability through these LR-redox platforms. It is concluded that the early injurious effect of Hcys on the glomerular endothelium is associated with the formation of redox signalling platforms via LR clustering, which may lead to increases in glomerular permeability by disruption of microtubule network in GECs. PMID- 20196780 TI - Altered SDF-1-mediated differentiation of bone marrow-derived endothelial progenitor cells in diabetes mellitus. AB - In diabetic patients and animal models of diabetes mellitus (DM), circulating endothelial progenitor cell (EPC) number is lower than in normoglycaemic conditions and EPC angiogenic properties are inhibited. Stromal cell derived factor-1 (SDF-1) plays a key role in bone marrow (BM) c-kit(+) stem cell mobilization into peripheral blood (PB), recruitment from PB into ischemic tissues and differentiation into endothelial cells. The aim of the present study was to examine the effect of DM in vivo and in vitro, on murine BM-derived c kit(+) cells and on their response to SDF-1. Acute hindlimb ischemia was induced in streptozotocin-treated DM and control mice; circulating c-kit(+) cells exhibited a rapid increase followed by a return to control levels which was significantly faster in DM than in control mice. CXCR4 expression by BM c-kit(+) cells as well as SDF-1 protein levels in the plasma and in the skeletal muscle, both before and after the induction of ischemia, were similar between normoglycaemic and DM mice. However, BM-derived c-kit(+) cells from DM mice exhibited an impaired differentiation towards the endothelial phenotype in response to SDF-1; this effect was associated with diminished protein kinase phosphorylation. Interestingly, SDF-1 ability to induce differentiation of c kit(+) cells from DM mice was restored when cells were cultured under normoglycaemic conditions whereas c-kit(+) cells from normoglycaemic mice failed to differentiate in response to SDF-1 when they were cultured in hyperglycaemic conditions. These results show that DM diminishes circulating c-kit(+) cell number following hindlimb ischemia and inhibits SDF-1-mediated AKT phosphorylation and differentiation towards the endothelial phenotype of BM derived c-kit(+) cells. PMID- 20196781 TI - Toll-like receptor triggering in cord blood mesenchymal stem cells. AB - Recently, the antagonizing effect on the differentiation of mesenchymal stem cells (MSCs) by toll-like receptor (TLR) ligands, was described. Our study shows that on more primitive cord blood derived MSCs, the expression of TLRs and ligand induced triggering differs from that of bone marrow derived MSCs. At the RNA level, cord blood MSCs (unrestricted somatic stem cells; USSCs) express low levels of TLR1,3,5,9 and high levels of TLR4 and TLR6. At the protein level expression of TLR5 and very low expression of TLR4 was observed. NF-kappaB translocation studies revealed that both TLR4 and TLR5 are functional, although signalling kinetics induced by the individual ligands differed. Stimulation of USSCs with either lipopolysaccharide (LPS) or flagellin resulted in a marked increase of interleukin (IL)-6 and/or IL-8 production although levels differed significantly between both stimuli. Interestingly, tumour necrosis factor (TNF) alpha was undetectable after TLR stimulation, which appeared to be due to an inactivated TNF-alpha promoter in USSCs. Moreover, osteoblastic differentiation was enhanced after triggering USSCs with LPS and flagellin. In summary, TLR4 and 5 signalling in USSCs is slow and results in the up-regulation of a restricted number of pro-inflammatory cytokines and enhanced osteoblastic differentiation. Apparently, the outcome of TLR signalling depends on the cell type that expresses them. PMID- 20196782 TI - Control of chondrocyte gene expression by actin dynamics: a novel role of cholesterol/Ror-alpha signalling in endochondral bone growth. AB - Elucidating the signalling pathways that regulate chondrocyte differentiation, such as the actin cytoskeleton and Rho GTPases, during development is essential for understanding of pathological conditions of cartilage, such as chondrodysplasias and osteoarthritis. Manipulation of actin dynamics in tibia organ cultures isolated from E15.5 mice results in pronounced enhancement of endochondral bone growth and specific changes in growth plate architecture. Global changes in gene expression were examined of primary chondrocytes isolated from embryonic tibia, treated with the compounds cytochalasin D, jasplakinolide (actin modifiers) and the ROCK inhibitor Y27632. Cytochalasin D elicited the most pronounced response and induced many features of hypertrophic chondrocyte differentiation. Bioinformatics analyses of microarray data and expression validation by real-time PCR and immunohistochemistry resulted in the identification of the nuclear receptor retinoid related orphan receptor-alpha (Ror-alpha) as a novel putative regulator of chondrocyte hypertrophy. Expression of Ror-alpha target genes, (Lpl, fatty acid binding protein 4 [Fabp4], Cd36 and kruppel-like factor 5 [Klf15]) were induced during chondrocyte hypertrophy and by cytochalasin D and are cholesterol dependent. Stimulation of Ror-alpha by cholesterol results in increased bone growth and enlarged, rounded cells, a phenotype similar to chondrocyte hypertrophy and to the changes induced by cytochalasin D, while inhibition of cholesterol synthesis by lovastatin inhibits cytochalasin D induced bone growth. Additionally, we show that in a mouse model of cartilage specific (Col2-Cre) Rac1, inactivation results in increased Hif 1alpha (a regulator of Rora gene expression) and Ror-alpha(+) cells within hypertrophic growth plates. We provide evidence that cholesterol signalling through increased Ror-alpha expression stimulates chondrocyte hypertrophy and partially mediates responses of cartilage to actin dynamics. PMID- 20196783 TI - Phenazopyridine induces and synchronizes neuronal differentiation of embryonic stem cells. AB - Embryonic stem (ES) cells are powerful tools to understand mechanisms of neuronal differentiation and to engineer neurons for in vitro studies and cell therapy. We developed a screening approach to identify small organic molecules driving neuronal differentiation of ES cells. For this purpose, we used a lentivector carrying a dual luciferase reporter system to engineer an ES cell line which allowed us to screen for small organic molecules enhancing neuronal differentiation. One of them, phenazopyridine, was further analysed in human ES cells. Phenazopyridine: (i) enhanced neuronal differentiation, (ii) increased cell survival, (iii) decreased the amount of non-neuronal and undifferentiated cells and (iv) synchronized the cellular differentiation state. Phenazopyridine allowed the development of a differentiation protocol compatible with the generation of clinical grade neural precursors, which were able differentiate into different neuronal subtypes, astrocytes and oligodendrocytes. In summary, we describe a powerful approach to identify small molecules directing stem cell differentiation. This led to the establishment of a new application for an old drug and the development of a novel clinical grade protocol for neuronal differentiation of ES cells. PMID- 20196784 TI - AMPK-mediated autophagy inhibits apoptosis in cisplatin-treated tumour cells. AB - The role of autophagy in cisplatin anticancer action was investigated using human U251 glioma, rat C6 glioma and mouse L929 fibrosarcoma cell lines. A dose- and time-dependent induction of autophagy was observed in tumour cells following cisplatin treatment, as demonstrated by up-regulation of autophagy-inducing protein beclin-1 and subsequent appearance of acridine orange-stained acidic autophagic vesicles. The presence of autophagosomes in cisplatin-treated cells was also confirmed by electron microscopy. Inhibition of autophagy with lysosomal inhibitors bafilomycin A1 and chloroquine, or a PI3 kinase inhibitor wortmannin, markedly augmented cisplatin-triggered oxidative stress and caspase activation, leading to an increase in DNA fragmentation and apoptotic cell death. The mechanisms underlying the protective effect of autophagy apparently involved the interference with cisplatin-induced modulation of Bcl-2 family proteins, as inhibition of autophagy potentiated cisplatin-mediated up-regulation of proapoptotic Bax and down-regulation of anti-apoptotic Bcl-2. Autophagy induction in cisplatin-treated cells was preceded by activation of adenosine monophosphate activated protein kinase (AMPK) and concomitant down-regulation of mammalian target of rapamycin (mTOR)-mediated phosphorylation of p70S6 kinase. The ability of cisplatin to trigger autophagy was reduced by small interfering RNA (siRNA) mediated AMPK silencing, while transfection with mTOR siRNA was sufficient to trigger autophagy in tumour cells. Finally, siRNA-mediated AMPK down-regulation and AMPK inhibitor compound C increased cisplatin-induced tumour cell death, while mTOR siRNA and AMPK activator metformin protected tumour cells from cisplatin. Taken together, these data suggest that cisplatin-triggered activation of AMPK and subsequent suppression of mTOR activity can induce an autophagic response that protects tumour cells from cisplatin-mediated apoptotic death. PMID- 20196785 TI - Akt mediates 17beta-estradiol and/or estrogen receptor-alpha inhibition of LPS induced tumor necresis factor-alpha expression and myocardial cell apoptosis by suppressing the JNK1/2-NFkappaB pathway. AB - Evidence shows that women have lower tumour necrosis factor-alpha (TNF-alpha) levels and lower incidences of heart dysfunction and sepsis-related morbidity and mortality. To identify the cardioprotective effects and precise cellular/molecular mechanisms behind estrogen and estrogen receptors (ERs), we investigated the effects of 17beta-estradiol (E(2)) and estrogen receptor alpha (ERalpha) on LPS-induced apoptosis by analyzing the activation of survival and death signalling pathways in doxycycline (Dox)-inducible Tet-On/ERalpha H9c2 myocardial cells and ERalpha-transfected primary cardiomyocytes overexpressing ERalpha. We found that LPS challenge activated JNK1/2, and then induced IkappaB degradation, NFkappaB activation, TNF-alpha up-regulation and subsequent myocardial apoptotic responses. In addition, treatments involving E(2), membrane impermeable BSA-E(2) and/or Dox, which induces ERalpha overexpression, significantly inhibited LPS-induced apoptosis by suppressing LPS-up-regulated JNK1/2 activity, IkappaB degradation, NFkappaB activation and pro-apoptotic proteins (e.g. TNF-alpha, active caspases-8, t-Bid, Bax, released cytochrome c, active caspase-9, active caspase-3) in myocardial cells. However, the cardioprotective properties of E(2), BSA-E(2) and ERalpha overexpression to inhibit LPS-induced apoptosis and promote cell survival were attenuated by applying LY294002 (PI3K inhibitor) and PI3K siRNA. These findings suggest that E(2), BSA-E(2) and ERalpha expression exert their cardioprotective effects by inhibiting JNK1/2-mediated LPS-induced TNF-alpha expression and cardiomyocyte apoptosis through activation of Akt. PMID- 20196786 TI - Inhibition of DNA methyltransferase induces G2 cell cycle arrest and apoptosis in human colorectal cancer cells via inhibition of JAK2/STAT3/STAT5 signalling. AB - DNA methyltransferase inhibitors (MTIs) have recently emerged as promising chemotherapeutic or preventive agents for cancer, despite their poorly characterized mechanisms of action. The present study shows that DNA methylation is integral to the regulation of SH2-containing protein tyrosine phosphatase 1 (SHP1) expression, but not for regulation of suppressors of cytokine signalling (SOCS)1 or SOCS3 in colorectal cancer (CRC) cells. SHP1 expression correlates with down-regulation of Janus kinase/signal transducers and activators of transcription (JAK2/STAT3/STAT5) signalling, which is mediated in part by tyrosine dephosphorylation events and modulation of the proteasome pathway. Up regulation of SHP1 expression was achieved using a DNA MTI, 5-aza-2' deoxycytidine (5-aza-dc), which also generated significant down-regulation of JAK2/STAT3/STAT5 signalling. We demonstrate that 5-aza-dc suppresses growth of CRC cells, and induces G2 cell cycle arrest and apoptosis through regulation of downstream targets of JAK2/STAT3/STAT5 signalling including Bcl-2, p16(ink4a), p21(waf1/cip1) and p27(kip1). Although 5-aza-dc did not significantly inhibit cell invasion, 5-aza-dc did down-regulate expression of focal adhesion kinase and vascular endothelial growth factor in CRC cells. Our results demonstrate that 5 aza-dc can induce SHP1 expression and inhibit JAK2/STAT3/STAT5 signalling. This study represents the first evidence towards establishing a mechanistic link between inhibition of JAK2/STAT3/STAT5 signalling and the anticancer action of 5 aza-dc in CRC cells that may lead to the use of MTIs as a therapeutic intervention for human colorectal cancer. PMID- 20196787 TI - Dual action of apolipoprotein E-interacting HCCR-1 oncoprotein and its implication for breast cancer and obesity. AB - Obese women have an increased risk for post-menopausal breast cancer. The physiological mechanism by which obesity contributes to breast tumourigenesis is not understood. We previously showed that HCCR-1 oncogene contributes to breast tumourigenesis as a negative regulator of p53 and detection of HCCR-1 serological level was useful for the diagnosis of breast cancer(.) In this study, we found that the HCCR-1 level is elevated in breast cancer tissues and cell lines compared to normal breast tissues. We identified apolipoprotein E (ApoE) interacting with HCCR-1. Our data show that HCCR-1 inhibits anti-proliferative effect of ApoE, which was mediated by diminishing ApoE secretion of breast cancer cells. Finally, HCCR-1 induced the severe obesity in transgenic mice. Those obese mice showed severe hyperlipidaemia. In conclusion, our results suggest that HCCR 1 might play a role in the breast tumourigenesis while the overexpression of HCCR 1 induces the obesity probably by inhibiting the cholesterol-lowering effect of ApoE. Therefore, HCCR-1 seems to provide the molecular link between the obesity and the breast cancer risk. PMID- 20196788 TI - Interferon regulatory factor-8 modulates the development of tumour-induced CD11b+Gr-1+ myeloid cells. AB - Tumour-induced myeloid-derived suppressor cells (MDSC) promote immune suppression and mediate tumour progression. However, the molecular basis for the generation of MDSC, which in mice co-express the CD11b(+) and Gr-1(+) cell surface markers remains unclear. Because CD11b(+)Gr-1(+) cells expand during progressive tumour growth, this suggests that tumour-induced events alter signalling pathways that affect normal myeloid cell development. Interferon regulatory factor-8 (IRF-8), a member of the IFN-gamma regulatory factor family, is essential for normal myelopoiesis. We therefore examined whether IRF-8 modulated tumour-induced CD11b(+)Gr-1(+) cell development or accumulation using both implantable (4T1) and transgenic (MMTV-PyMT) mouse models of mammary tumour growth. In the 4T1 model, both splenic and bone marrow-derived CD11b(+)Gr-1(+) cells of tumour-bearing mice displayed a marked reduction in IRF-8 expression compared to control populations. A causal link between IRF-8 expression and the emergence of tumour-induced CD11b(+)Gr-1(+) cells was explored in vivo using a double transgenic (dTg) mouse model designed to express transgenes for both IRF-8 and mammary carcinoma development. Despite the fact that tumour growth was unaffected, splenomegaly, as well as the frequencies and absolute numbers of CD11b(+)Gr-1(+) cells were significantly lower in dTg mice when compared with single transgenic tumour bearing mice. Overall, these data reveal that IRF-8 plays an important role in tumour-induced development and/or accumulation of CD11b(+)Gr-1(+) cells, and establishes a molecular basis for the potential manipulation of these myeloid populations for cancer therapy. PMID- 20196791 TI - Retraction. PMID- 20196789 TI - Targeting of cancer stem cell marker EpCAM by bispecific antibody EpCAMxCD3 inhibits pancreatic carcinoma. AB - Patients with pancreatic cancer have a poor survival rate, and new therapeutic strategies are needed. Epithelial cell adhesion molecule (EpCAM), suggested as a marker for cancer stem cells, is over-expressed on most pancreatic tumour cells but not on normal cells and may be an ideal therapeutic target. We evaluated the anti-tumour efficiency of bispecific EpCAMxCD3 antibody linking tumour cells and T lymphocytes. In NOD SCID mice, EpCAMxCD3 had a long serum half-life (t(1/2) approximately 7 days). EpCAMxCD3 significantly retarded growth of BxPC-3 pancreatic carcinoma xenografts. For mimicking a pancreatic cancer microenvironment in vitro, we used a three-dimensional tumour reconstruct system, in which lymphocytes were co-cultured with tumour cells and fibroblasts in a collagen matrix. In this in vivo-like system, EpCAMxCD3 potently stimulated production of the effector cytokines IFN-gamma and TNF-alpha by extracorporally pre-activated lymphocytes. Moreover, compared with a bivalent anti-CD3 antibody, EpCAMxCD3 more efficiently activated the production of TNF-alpha and IFN-gamma by non-stimulated peripheral blood mononuclear cells. Most excitingly, we demonstrate for the first time that EpCAMxCD3 induces prolonged contacts between lymphocytes and tumour cells, which may be the main reason for the observed anti tumour effects. As an important prerequisite for future use in patients, EpCAMxCD3 did not alter lymphocyte migration as measured by time-lapse video microscopy. Our data may open a way to improve the immune response and treatment outcome in patients with pancreatic cancer. PMID- 20196792 TI - Pregnancy registries: differences, similarities, and possible harmonization. AB - Epilepsy and pregnancy registries have been operational for more than 10 years, have accrued considerable experience, and collected an impressive amount of data. As findings have been published, it has become important to understand how observations from the different registries are comparable, especially since their methodologies differ somewhat. In September 2008, representatives of the UK Epilepsy and Pregnancy Register, the North American AED Pregnancy Registry (NAAPR), and the European and International Registry of Antiepileptic Drugs in Pregnancy (EURAP) met for a workshop. Their objectives were to exchange information on their methodologies and to discuss areas where harmonization might be possible. This report summarizes these discussions. PMID- 20196793 TI - Extrafocal threshold reductions in amygdala-kindled rats. AB - PURPOSE: Racine's classic study suggested that after discharge thresholds were reduced in the primary stimulation site (amygdala) of kindled rats, but that that they were not reduced in secondary (nonstimulated) sites. However, recent reports of neurochemical changes related to excitation and inhibition in nonstimulated sites in kindled brains would be expected to cause reductions in afterdischarge thresholds in these sites. More recently Sanei et al. have reported a significant threshold reduction in the piriform cortex of amygdala- and hippocampus-kindled cats, but not in the entorhinal cortex. The present study was designed to determine whether the results of Sanei et al. in cats could be replicated in rats kindled in the amygdala-a model commonly used in studies of seizure mechanisms and anticonvulsant drug development. METHODS: Adult, male Long-Evans rats were kindled in the amygdala or given matched handling. Beginning 48 h following the last stimulation, afterdischarge thresholds were determined in the ipsilateral piriform and entorhinal cortices. Amygdala thresholds were determined 24 h later. RESULTS: Afterdischarge thresholds were significantly reduced in both the amygdala and the ipsilateral entorhinal cortex of amygdala-kindled rats. Afterdischarge thresholds in the piriform cortex did not differ significantly between kindled and control subjects. DISCUSSION: These data suggest that threshold reduction occurs outside the primary kindling site in rats as well as in cats. Extrafocal changes in afterdischarge threshold may be functionally important, and might possibly relate to extrafocal neurochemical changes and progressive generalization of seizure discharge from discrete focal sites. PMID- 20196794 TI - Delta9-Tetrahydrocannabivarin suppresses in vitro epileptiform and in vivo seizure activity in adult rats. AB - PURPOSE: We assessed the anticonvulsant potential of the phytocannabinoid Delta9 tetrahydrocannabivarin (Delta9-THCV) by investigating its effects in an in vitro piriform cortex (PC) brain slice model of epileptiform activity, on cannabinoid CB1 receptor radioligand-binding assays and in a generalized seizure model in rats. METHODS: Delta9-THCV was applied before (10 MUm Delta9-THCV) or during (10 50 MUm Delta9-THCV) epileptiform activity induced by Mg2(+) -free extracellular media in adult rat PC slices and measured using multielectrode array (MEA) extracellular electrophysiologic techniques. The actions of Delta9-THCV on CB1 receptors were examined using [3H]SR141716A competition binding and [35S]GTPgammaS assays in rat cortical membranes. Effects of Delta9-HCV (0.025-2.5 mg/kg) on pentylenetetrazole (PTZ)-induced seizures in adult rats were also assessed. RESULTS: After induction of stable spontaneous epileptiform activity, acute Delta9 -THCV application (>= 20 MUm) significantly reduced burst complex incidence and the amplitude and frequency of paroxysmal depolarizing shifts (PDSs). Furthermore, slices pretreated with 10 MUm Delta9-THCV prior to induction of epileptiform activity exhibited significantly reduced burst complex incidence and PDS peak amplitude. In radioligand-binding experiments, Delta9-THCV acted as a CB1 receptor ligand, displacing 0.5 nm [3H]SR141716A with a Ki~290 nm, but exerted no agonist stimulation of [35S]GTPgammaS binding. In PTZ-induced seizures in vivo, 0.25 mg/kg Delta9-THCV significantly reduced seizure incidence. DISCUSSION: These data demonstrate that Delta9-THCV exerts antiepileptiform and anticonvulsant properties, actions that are consistent with a CB1 receptor mediated mechanism and suggest possible therapeutic application in the treatment of pathophysiologic hyperexcitability states. PMID- 20196795 TI - Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. AB - The International League Against Epilepsy (ILAE) Commission on Classification and Terminology has revised concepts, terminology, and approaches for classifying seizures and forms of epilepsy. Generalized and focal are redefined for seizures as occurring in and rapidly engaging bilaterally distributed networks (generalized) and within networks limited to one hemisphere and either discretely localized or more widely distributed (focal). Classification of generalized seizures is simplified. No natural classification for focal seizures exists; focal seizures should be described according to their manifestations (e.g., dyscognitive, focal motor). The concepts of generalized and focal do not apply to electroclinical syndromes. Genetic, structural-metabolic, and unknown represent modified concepts to replace idiopathic, symptomatic, and cryptogenic. Not all epilepsies are recognized as electroclinical syndromes. Organization of forms of epilepsy is first by specificity: electroclinical syndromes, nonsyndromic epilepsies with structural-metabolic causes, and epilepsies of unknown cause. Further organization within these divisions can be accomplished in a flexible manner depending on purpose. Natural classes (e.g., specific underlying cause, age at onset, associated seizure type), or pragmatic groupings (e.g., epileptic encephalopathies, self-limited electroclinical syndromes) may serve as the basis for organizing knowledge about recognized forms of epilepsy and facilitate identification of new forms. PMID- 20196796 TI - Electrical source imaging for presurgical focus localization in epilepsy patients with normal MRI. AB - PURPOSE: Patients with magnetic resonance (MR)-negative focal epilepsy (MRN-E) have less favorable surgical outcomes (between 40% and 70%) compared to those in whom an MRI lesion guides the site of surgical intervention (60-90%). Patients with extratemporal MRN-E have the worst outcome (around 50% chance of seizure freedom). We studied whether electroencephalography (EEG) source imaging (ESI) of interictal epileptic activity can contribute to the identification of the epileptic focus in patients with normal MRI. METHODS: We carried out ESI in 10 operated patients with nonlesional MRI and a postsurgical follow-up of at least 1 year. Five of the 10 patients had extratemporal lobe epilepsy. Evaluation comprised surface and intracranial EEG monitoring of ictal and interictal events, structural MRI, [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET), ictal and interictal perfusion single photon emission computed tomography (SPECT) scans. Eight of the 10 patients also underwent intracranial monitoring. RESULTS: ESI correctly localized the epileptic focus within the resection margins in 8 of 10 patients, 9 of whom experienced favorable postsurgical outcomes. DISCUSSION: The results highlight the diagnostic value of ESI and encourage broadening its application to patients with MRN-E. If the surface EEG contains fairly localized spikes, ESI contributes to the presurgical decision process. PMID- 20196797 TI - Diversity of hepatitis B virus infecting Malaysian candidate blood donors is driven by viral and host factors. AB - Malaysia is a medium endemic country for hepatitis B virus (HBV) infection but little is known about HBV strains circulating in Malaysian blood donors. Viral load, HBsAg concentrations and nested PCR products from 84 HBV surface antigen (HBsAg) positive samples were analysed in detail. Median viral load was 3050 IU/mL and median HBsAg 1150 IU/mL. Fifty-six full genome, 20 pre-S/S, 1 S gene and six basic core promoter/precore-only sequences were obtained. Genotypes B and C were present at a ratio of 2:1, and two genotype D samples were obtained, both from donors of Indian background. Phylogenetically, genotype B was more diverse with subgenotypes B2-5, B7 and B8 present, while most genotype C strains were from subgenotype C1. Genotypes B and C were equally frequent in ethnic Malays, but 80% of strains from Chinese were genotype B. HBsAg concentrations were higher in genotype C than in genotype B, in Chinese than Malays and in donors under the age of 30. HBV vaccine escape substitutions (P120S/T, I126N and G145G) were present in six strains. In the large surface protein, immuno-inactive regions were more mutated than CD8 epitopes and the major hydrophilic region. Strains of genotype B or from ethnic Malays had higher genetic diversity than strains of genotype C or from Chinese donors. Hence HBV strains circulating in Malaysia are phylogenetically diverse reflecting the ethnic mix of its population. Ethnic Malays carry lower HBsAg levels and higher genetic diversity of the surface antigen, possibly resulting in more effective immune control of the infection. PMID- 20196798 TI - Proficiency of transient elastography compared to liver biopsy for the assessment of fibrosis in HIV/HBV-coinfected patients. AB - Transient elastography (TE) is a noninvasive technique to evaluate liver fibrosis. We compared the performance of TE with liver biopsy (LB) in patients with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) coinfection. Patients prospectively underwent TE and LB. The diagnosis accuracy of TE was calculated using receiver operating characteristic (ROC) curves for different stages of fibrosis, and optimal cut-off values were defined. A sequential algorithm combining TE with biochemical score (Fibrotest) is proposed. Fifty seven patients had both TE and LB (median time: 3 days) and two with proven cirrhosis, only TE. Forty-six (78%) were under antiretroviral therapy with anti HBV drugs in 98%, and 19 (32%) had elevated alanine aminotransferase (ALT). A significant correlation was observed between liver stiffness measurement (LSM) and METAVIR fibrosis stages (P < 0.0001). Patients with elevated ALT tended to have higher LSM than those with normal ALT. The areas under the ROC curves were 0.85 for significant fibrosis (>= F2), 0.92 for advanced fibrosis (>= F3) and 0.96 for cirrhosis. Using a cut-off of 5.9 kPa for F >= 2 and 7.6 kPa for F >= 3, the diagnosis accuracy was 83% and 86%, respectively. With an algorithm combining TE and Fibrotest, 97% of patients were well classified for significant fibrosis. Using this algorithm, the need for LB can be reduced by 67%. In HIV/HBV coinfected patients, most of them with normal ALT under antiretroviral treatment including HBV active drugs, TE was proficient in discriminating moderate to severe fibrosis from minimal liver disease. PMID- 20196799 TI - Enhanced Liver Fibrosis (ELF) test accurately identifies liver fibrosis in patients with chronic hepatitis C. AB - Assessment of liver fibrosis is important in determining prognosis and evaluating interventions. Due to limitations of accuracy and patient hazard of liver biopsy, non-invasive methods have been sought to provide information on liver fibrosis, including the European liver fibrosis (ELF) test, shown to have good diagnostic accuracy for the detection of moderate and severe fibrosis. Access to independent cohorts of patients has provided an opportunity to explore if this test could be simplified. This paper reports the simplification of the ELF test and its ability to identity severity of liver fibrosis in external validation studies in patients with chronic hepatitis C (CHC). Paired biopsy and serum samples from 347 naive patients with CHC in three independent cohorts were analysed. Diagnostic performance characteristics were derived (AUROC, sensitivity and specificity, predictive values), and clinical utility modelling performed to determine the proportion of biopsies that could have been avoided if ELF test was used in this patient group. It was possible to simplify the original ELF test without loss of performance and the new algorithm is reported. The simplified ELF test was able to predict severe fibrosis [pooled AUROC of 0.85 (95% CI 0.81-0.89)] and using clinical utility modelling to predict severe fibrosis (Ishak stages 4-6; METAVIR stages 3 and 4) 81% of biopsies could have been avoided (65% correctly). Issues of spectrum effect in diagnostic test evaluations are discussed. In chronic hepatitis C a simplified ELF test can detect severe liver fibrosis with good accuracy. PMID- 20196800 TI - Pegylated interferon plus optimized weight-based ribavirin dosing negate the influence of weight and body mass index on early viral kinetics and sustained virological response in chronic hepatitis C. AB - AIM: Elevated body mass index (BMI) in chronic hepatitis C (CHC) has been associated with reduced rates of sustained virological response (SVR). The aims of this study were to determine whether early viral kinetics (and subsequently SVR) are influenced by weight or BMI by measuring HCV RNA at week 4 using two PCR assays with differing sensitivities. METHODS: Patients with CHC treated with peginterferon plus weight-based ribavirin were included in this retrospective study. Body mass index, pretreatment viral load, genotype and liver histology were abstracted from the clinical database. HCV RNA PCR (lower limit of detection (LLD) <50 IU/mL) at treatment week 4 and 6 months after completion of therapy were recorded to determine the presence of rapid virological response (RVR-50) and SVR, respectively. In those who achieved RVR-50, stored week 4 serum was retested using Taqman (LLD < 15 IU/mL, RVR-15). RESULTS: Of 134 patients included (genotype 1 57%, BMI 26.7 +/- 4.5 kg/m2, ribavirin dose 13.9 +/- 2.6 mg/kg/day), 59% achieved SVR. RVR-50 was observed in 39.6% and RVR-15 in 27.6%. Neither body weight nor BMI influenced RVR-50, RVR-15 or SVR. The positive predictive values (PPVs) of RVR-50 and RVR-15 for SVR were 88.7% and 97.3% (P = 0.23). RVR-50 and RVR-15 superceded genotype and viral load as the strongest independent predictors of SVR (OR 9.25 (1.9-45.11) and OR 30.74 (3.08-317.96), respectively). CONCLUSIONS: RVR is the strongest predictor of SVR. Early viral kinetics is not influenced by body weight or BMI when weight-based ribavirin is prescribed. PMID- 20196801 TI - Serum B12 levels predict response to treatment with interferon and ribavirin in patients with chronic HCV infection. AB - Vitamin B12 is stored in hepatocytes and inhibits hepatitis C virus (HCV) RNA translation. The implication of B12 in the setting of antiviral treatment is unknown. This study aims to retrospectively evaluate the discriminative efficacy of pretreatment B12 serum levels (s-B12) on end-of-treatment response (ETR) in patients with chronic HCV. Ninety-nine treatment naive HCV patients, treated with interferon and ribavirin were studied. Serum B12 (s-B12) was analysed in samples collected before treatment start. Pretreatment s-B12 levels were correlated to ETR using univariate analysis. S-B12 and clinical data were evaluated in a multivariate logistic regression model. Mean pretreatment s-B12 was 331 pm in ETR and 260 pm in nonresponders (NR) (P = 0.012). In patients with s-B12 levels <= 360 pm, 23 (31.5%) were NR and 50 (68.5%) had ETR. In patients with s-B12 > 360 pm, one (3.8%) was NR and 25 (96.2%) had ETR (P = 0.0034). The results of the multivariate analysis were as follows: Pretreatment s-B12 > 360 vs <= 360 pm: OR 28.6 CI 2.31-354, P = 0.008. Fibrosis stage 3-4 vs 0-2: OR 0.29 CI 0.074-1.12, P = 0.068. Genotype 2/3 vs 1/4/5: OR 15.5 CI 2.87-83.9, P = 0.0012. Dose reduction vs no dose reduction: OR 0.21, CI 0.048-0.91 P = 0.034. Standard interferon vs pegylated-interferon: OR 0.079, CI 0.0091-0.68 P = 0.019. Age and gender were not correlated to ETR. S-B12 > 360 pm is independently correlated to ETR in HCV patients treated with interferon and ribavirin. This suggests that B12 is involved in suppression of viral replication during anti-HCV treatment. PMID- 20196802 TI - Hepatitis B virus infection in dentistry: a forgotten topic. AB - More than two billion people have been infected with hepatitis B virus (HBV). Globally, 350-400 million suffer from chronic HBV infection. It is postulated that dentists and dental staff are infected and transmit the virus to their patients more than any other occupation. The aim of this article is to review the HBV incidence in dental society, the points of view of dentists and their patients regarding transmission of the virus during dental procedures, the occurrence of HBV outbreaks in dental clinics and the importance of methods of preventing HBV infection in dentistry. PMID- 20196803 TI - Expression of genes involved in lipogenesis is not increased in patients with HCV genotype 3 in human liver. AB - Hepatitis C virus (HCV) infection is frequently associated with hepatic steatosis, particularly in patients with HCV genotype-3 (HCVGT3). It has variously been hypothesized, largely from in-vitro studies, to be the result of increased synthesis, decreased metabolism and export of triglycerides. We measured by real-time PCR the expression of genes involved in lipid metabolism [acetyl-Coenzyme A carboxylase alpha, apolipoprotein B (APOB), diacylglycerol O acyltransferase 2, fatty acid-binding protein 1, fatty acid synthase, microsomal triglyceride transfer protein (MTTP), peroxisome proliferator-activated receptor alpha (PPARA), peroxisome proliferator-activated receptor gamma (PPARG), protein kinase AMP-activated alpha 1 catalytic subunit (PRKAA1) and sterol regulatory element-binding transcription factor 1 (SREBF1)] in liver biopsies from patients infected with HCV genotype-1 (HCVGT1), HCVGT3 and Hepatitis B (HBV) using beta glucuronidase (GUSB) and splicing factor arginine/serine-rich 4 (SFRS4) as housekeeping genes. Patients infected with HCVGT3 were younger than those infected with HCVGT1 (36.3 +/- 2.5 vs 45.6 +/- 1.5, P < 0.05, Mann-Whitney) and were more likely to have steatosis (69.2%vs 11.8%). No significant difference was found in the expression of genes involved in lipogenesis or transport in patients infected with HBV or HCV of either genotype. Contrary to expectation, given the greater degree of steatosis in HCVGT3-infected liver, expression of enzymes involved in lipogenesis was not elevated in HCVGT3 compared with HCVGT1 or HBV infected liver. Significantly less mRNA for SREBF1 was found in HCVGT3-infected liver tissue compared with HCVGT1-infected liver (1.00 +/- 0.06 vs 0.70 +/- 0.15 P < 0.05). These results suggest that steatosis in patients infected with HCVGT3 is not the result of a sustained SREBF1 driven increase in expression of genes involved in lipogenesis. In addition, a significant genotype-independent correlation was found between the expression of APOB, MTTP, PRKAA1 and PPARA, indicating that these networks are functional in HCV-infected liver. PMID- 20196804 TI - Clevudine for chronic hepatitis B: antiviral response, predictors of response, and development of myopathy. AB - Clevudine has been approved for the treatment of chronic hepatitis B (CHB) in South Korea. However, its long-term antiviral effect and safety awaits more study. The aim of this study was to evaluate antiviral efficacy, predictors of virologic response, and development of myopathy after clevudine therapy for CHB. The study included 102 nucleoside naive CHB patients who had received clevudine for more than 6 months with good compliance. The median duration of clevudine treatment was 53 weeks (range, 25-90 weeks). A retrospective analysis of data retrieved from medical records was performed. The cumulative rate of virologic response [hepatitis B virus (HBV) DNA level <2000 copies/mL] at 48 weeks of clevudine therapy was 81%, and cumulative rate of clevudine resistance was 11% at 60 weeks of treatment. Independent predictors of virologic response to clevudine therapy were hepatitis B e antigen (HBeAg) negativity and rapid decrease of viral load during the early phase of treatment. The clevudine-related myopathy developed in 3.9% of patients, and was reversible after discontinuation of clevudine. Clevudine showed a potent antiviral response, and its effect was higher in HBeAg-negative patients, with rapid viral load reduction after therapy. However, long-term therapy for more than 1 year resulted in the development of considerable resistance and myopathy. Therefore, we should consider alternative antiviral agents if clevudine resistance or clevudine-induced myopathy is developed in patients on clevudine for the treatment of CHB. PMID- 20196806 TI - Impact of hepatitis C virus infection on all-cause and liver-related mortality in a large community-based cohort of inner city residents. AB - The aim of this study was to measure the impact of hepatitis C virus (HCV) infection on mortality in a cohort of inner city residents. The Community Health and Safety Evaluation is a community-based study of inner city residents followed retrospectively and prospectively through linkages with provincial virology and mortality databases. We identified participants having received HCV antibody testing, evaluated cause-specific mortality rates and factors associated with all cause and liver-related mortality using Cox Proportional Hazards models. Overall, 2332 participants received HCV antibody testing (recent non-injection drug use - 81%). The prevalence of HCV and HIV was 64% (1495 of 2332) and 21% (485 of 2332), respectively. Between January 2003 and December 2007, there were 180 deaths (192 per 10.000 person-years; 95% CI: 165, 222), with 21% HIV-related, 20% drug related and 7% liver-related. Mortality was associated with age >50 [adjusted hazard ratio (AHR) 2.80 vs < 40 years (referent group); 95% CI 1.93, 4.07, P < 0.001] and HIV infection (AHR 3.81; 95% CI 2.72, 5.34, P < 0.001), but not positive HCV antibody status (AHR 1.19; 95% CI 0.83, 1.72, P = 0.35). Liver related mortality was associated with age >50 [AHR 18.49 vs < 40 years (referent group); 95% CI 2.27, 150.41, P < 0.001] and positive HCV antibody status (AHR 7.69; 95% CI 0.99, 59.98, P = 0.052). This study demonstrates a high rate of mortality in this population, particularly those with HIV. HCV-infected inner city residents >50 years of age were at significant risk of liver-related mortality. Continued surveillance of this population infected with HCV in the 1970s and 1980s is important. PMID- 20196807 TI - Vietnamese community screening for hepatitis B virus and hepatitis C virus. AB - Asian Americans represent an important cohort at high risk for viral hepatitis. To determine the prevalence of Hepatitis B virus (HBV) and Hepatitis C virus (HCV) infection and HBV vaccination in a Vietnamese community, a total of 322 Vietnamese subjects from a local doctor's office and annual Vietnamese Health Fair were included in this study. Demographic and clinical data were collected. 2.2% of the screened cohort tested positive for anti-HCV and 9.3% tested positive for HBsAg. Unlike HBV-positive subjects, HCV-positive subjects had significantly higher liver enzymes (P = 0.0045 and P = 0.0332, respectively). The HBV-positive group was more likely to report jaundice (P = 0.0138) and a family history of HBV (P = 0.0115) compared to HBV-negative subjects. Forty-eight patients (15.5%) reported a family history of liver disease (HBV, HCV, HCC, cirrhosis, other). Of this 48, 68.8% reported no personal history of HBV vaccination and 77.1% reported no family history of vaccination for HBV. Among the 183 subjects without a family history of liver disease, 156 (85.2%) reported no personal history of vaccination and 168 (91.8%) reported no family history of vaccination. HBV vaccination rates in those reporting a family history of liver disease were significantly higher (P =0.020). There was a high prevalence of HBV infection in this community screening. Nevertheless, the rate for HBV vaccination was low. The low prevalence of abnormal liver enzymes in HBV-positive subjects emphasizes the need for screening to be triggered by risk factors and not by abnormal liver enzymes. PMID- 20196805 TI - New trends of HCV infection in China revealed by genetic analysis of viral sequences determined from first-time volunteer blood donors. AB - Recently, we studied hepatitis C virus (HCV) sera-prevalence among 559 890 first time volunteer blood donors in China. From randomly selected 450 anti-HCV positive donors, we detected HCV RNA in 270 donors. In this study, we amplified HCV E1 and/or NS5B sequences from 236 of these donors followed by DNA sequencing and phylogenetic analysis. The results indicate new trends of HCV infection in China. The HCV genotype distribution differed according to the donors' region of origin. Among donors from Guangdong province, we detected subtypes 6a, 1b, 3a, 3b, 2a, and 1a at frequencies of 49.7%, 31.0%, 7.6%, 5.5%, 4.1%, and 2.1%, respectively. Among donors from outside Guangdong, we detected 1b, 2a, 6a, 3b, 3a, 6e, and 6n at frequencies 57.1%, 13.2%, 11.0%, 9.9%, 4.4%, 2.2%, and 2.2%, respectively. Although we found no significant differences among regions in age or gender, subtype 6a was more common (P < 0.001) in donors from Guangdong than those from elsewhere, whilst subtypes 1b (P < 0.02) and 2a (P < 0.001) were more frequent outside Guangdong. Disregarding origins, the male/female ratio was higher for subtype 6a-infected donors (P < 0.05) than for subtype 1b donors, whilst the mean age of subtype 2a donors was 8-10 years older (P < 0.05) than that for all other subtypes. Detailed phylogenetic analysis of our sequence data provides further insight into the transmission of HCV within China, and between China and other countries. The predominance of HCV 6a among blood donors in Guangdong is striking and mandates studies into risk factors for its acquisition. PMID- 20196808 TI - Are FoxP3(+) cells involved in hyporesponsiveness to interferon/ribavirin therapy in chronic hepatitis C? AB - We aimed to clarify the role of liver-infiltrating FoxP3(+) T cells for the response to therapy in chronic hepatitis C. Liver biopsies from 52 patients were collected prior to the start of interferon/ribavirin treatment, and the kinetics of viral decay during treatment were compared in patients with high and low infiltration of FoxP3(+) cells. These groups did not differ with respect to the effectiveness of early viral clearance or the frequency of sustained viral response. Our data imply that FoxP3(+) cell-mediated immunosuppression is not a major mechanism of hyporesponsiveness to interferon-based therapy in chronic hepatitis C. PMID- 20196809 TI - Beyond MHC: signals of elevated selection pressure on Atlantic salmon (Salmo salar) immune-relevant loci. AB - Using Atlantic salmon (Salmo salar) as a model system, we investigated whether 18 microsatellites tightly linked to immune-relevant genes have experienced different selection pressures than 76 loci with no obvious association with immune function. Immune-relevant loci were identified as outliers by two outlier tests significantly more often than nonimmune linked loci (22% vs. 1.6%). In addition, the allele frequencies of immune relevant markers were more often correlated with latitude and temperature. Combined, these results support the hypothesis that immune-relevant loci more frequently exhibit footprints of selection than other loci. They also indicate that the correlation between immune relevant loci and latitude may be due to temperature-induced differences in pathogen-driven selection or some other environmental factor correlated with latitude. PMID- 20196810 TI - Climatic niche and neutral genetic diversity of the six Iberian pine species: a retrospective and prospective view. AB - Quaternary climatic fluctuations have left contrasting historical footprints on the neutral genetic diversity patterns of existing populations of different tree species. We should expect the demography, and consequently the neutral genetic structure, of taxa less tolerant to particular climatic extremes to be more sensitive to long-term climate fluctuations. We explore this hypothesis here by sampling all six pine species found in the Iberian Peninsula (2464 individuals, 105 populations), using a common set of chloroplast microsatellite markers, and by looking at the association between neutral genetic diversity and species specific climatic requirements. We found large variation in neutral genetic diversity and structure among Iberian pines, with cold-enduring mountain species (Pinus uncinata, P. sylvestris and P. nigra) showing substantially greater diversity than thermophilous taxa (P. pinea and P. halepensis). Within species, we observed a significant positive correlation between population genetic diversity and summer precipitation for some of the mountain pines. The observed pattern is consistent with the hypotheses that: (i) more thermophilous species have been subjected to stronger demographic fluctuations in the past, as a consequence of their maladaptation to recurrent glacial cold stages; and (ii) altitudinal migrations have allowed the maintenance of large effective population sizes and genetic variation in cold-tolerant species, especially in more humid regions. In the light of these results and hypotheses, we discuss some potential genetic consequences of impending climate change. PMID- 20196811 TI - Larval food quality affects adult (but not larval) immune gene expression independent of effects on general condition. AB - The potential effect of larval condition on adult immunity in holometabolous insects is rarely considered. We show here that larval food composition can impact adult immunity independent from effects on general condition of the animal. Rather, our data indicate a plastic allocation of resources to immunity in high-protein environments. Specifically, we found that increasing the nutritional yeast (protein) available to larval Drosophila melanogaster increased the adult's constitutive transcription of two genes encoding defensive antimicrobial peptides. Adult dry weight was not significantly affected by larval food composition, while adult fat content decreased when larval yeast increased. Larval immune activity was unaffected by alterations of larval diet, indicating a lack of covariation in this trait across life-stages. We conclude that the nutritional environment of insect larvae can affect adult immunity by influencing plastic allocation of resources. These influences are less predictable than constraints linked to general condition would be. PMID- 20196812 TI - Evidence of selection at the ramosa1 locus during maize domestication. AB - Modern maize was domesticated from Zea mays parviglumis, a teosinte, about 9000 years ago in Mexico. Genes thought to have been selected upon during the domestication of crops are commonly known as domestication loci. The ramosa1 (ra1) gene encodes a putative transcription factor that controls branching architecture in the maize tassel and ear. Previous work demonstrated reduced nucleotide diversity in a segment of the ra1 gene in a survey of modern maize inbreds, indicating that positive selection occurred at some point in time since maize diverged from its common ancestor with the sister species Tripsacum dactyloides and prompting the hypothesis that ra1 may be a domestication gene. To investigate this hypothesis, we examined ear phenotypes resulting from minor changes in ra1 activity and sampled nucleotide diversity of ra1 across the phylogenetic spectrum between tripsacum and maize, including a broad panel of teosintes and unimproved maize landraces. Weak mutant alleles of ra1 showed subtle effects in the ear, including crooked rows of kernels due to the occasional formation of extra spikelets, correlating a plausible, selected trait with subtle variations in gene activity. Nucleotide diversity was significantly reduced for maize landraces but not for teosintes, and statistical tests implied directional selection on ra1 consistent with the hypothesis that ra1 is a domestication locus. In maize landraces, a noncoding 3'-segment contained almost no genetic diversity and 5'-flanking diversity was greatly reduced, suggesting that a regulatory element may have been a target of selection. PMID- 20196813 TI - Modern and ancient DNA reveal recent partial replacement of caribou in the southwest Yukon. AB - The long-term persistence of forest-dwelling caribou (Rangifer tarandus caribou) will probably be determined by management and conservation decisions. Understanding the evolutionary relationships between modern caribou herds, and how these relationships have changed through time will provide key information for the design of appropriate management strategies. To explore these relationships, we amplified microsatellite and mitochondrial markers from modern caribou from across the Southern Yukon, Canada, as well as mitochondrial DNA from Holocene specimens recovered from alpine ice patches in the same region. Our analyses identify a genetically distinct group of caribou composed of herds from the Southern Lakes region that may warrant special management consideration. We also identify a partial genetic replacement event occurring 1000 years before present, coincident with the deposition of the White River tephra and the Medieval Warm Period. These results suggest that, in the face of increasing anthropogenic pressures and climate variability, maintaining the ability of caribou herds to expand in numbers and range may be more important than protecting the survival of any individual, isolated sedentary forest-dwelling herd. PMID- 20196815 TI - Ecological rather than geographical isolation dominates Quaternary formation of Mediterranean Cistus species. AB - The lack of a comparative approach makes it impossible to determine the main factors influencing colonization and evolution in plants. Here we conducted the first comparative study of a characteristic Mediterranean lineage (white-flowered Cistus) taking advantage of its well-known phylogenetic relationships. A two scale approach was applied to address the hypothesis of higher levels of isolation in mountain than in lowland species. First, a time-calibrated phylogeny using plastid sequences of Cistaceae suggested that the origin of Cistus species postdated both the refilling of the Mediterranean Sea (5.59-5.33 Ma) and the onset of the Mediterranean climate (3.2 Ma). Two hundred and sixty-three additional, plastid sequences from 111 populations showed different numbers of haplotypes in C. laurifolius (7), C. monspeliensis (2) and C. salviifolius (7). Although haplotype sharing among disjunct populations was observed in all species, phylogeographic analyses revealed haplotype lineages exclusive to Europe or Africa only in the mountain species (C. laurifolius). Isolation by either geographical distance or sea barriers was not significantly supported for the lowland species (C. monspeliensis; C. ladanifer from a previous study). The same is true for the less habitat-specific species of the lineage (C. salviifolius). Comparative phylogeography of the Cistus species leads us to interpret a general pattern of active colonization surpassing Mediterranean barriers. In contrast, ecological conditions (precipitation, temperature, soils) appear to have determined the distribution of the Cistus species of Mediterranean mountains. This study further provides molecular evidence for multiple colonization patterns in the course of successful adaptation of Cistus species to Mediterranean habitats. PMID- 20196816 TI - Immune surveillance of human cancer: if the cytotoxic T-lymphocytes play the music, does the tumoral system call the tune? AB - Accumulating evidence indicates that the innate and adaptive immune systems participate in the recognition and destruction of cancer cells by a process known as cancer immunosurveillance. Tumor antigen-specific cytotoxic T-lymphocytes (CTL) are the major effectors in the immune response against tumor cells. The identification of tumor-associated antigen (TAA) recognized primarily by CD 8(+) T-lymphocytes has led to the development of several vaccination strategies that induce or potentiate specific immune responses. However, large established tumors, which are associated with the acquisition of tumor resistance to specific lysis, are usually not fully controlled by the immune system. Recently, it has become clear that the immune system not only protects the host against tumor development but also sculpts the immunogenic phenotype of a developing tumor and can favor the emergence of resistant tumor cell variants. Moreover, it has become obvious that the evasion of immunosurveillance by tumor cells is under the control of the tumor microenvironment complexity and plasticity. In this review, we will focus on some new mechanisms associated with the acquisition of tumor resistance to specific lysis during tumor progression, involving genetic instability, structural changes in cytoskeleton, and hypoxic stress. We will also discuss the interaction between CTLs and tumor endothelial cells, a major component of tumor stroma. PMID- 20196817 TI - HLA-B27 and ankylosing spondylitis: tales from China. AB - The two most frequent HLA-B27 subtypes worldwide are B*2704 and B*2705. In the Han population of China B*2704 and, to a lower extent, B*2705 are found with significant frequency, and both are associated to ankylosing spondylitis (AS). Two articles in this issue report that the association to AS in this ethnic group is stronger for B*2704 than for B*2705. Thus, at least among the Han, B*2704 would be the strongest known susceptibility factor for AS. PMID- 20196818 TI - HLA-G and its relation to proliferation index in detection and monitoring breast cancer patients. AB - Recent studies indicate an ectopic upregulation of the human leukocyte antigen G (HLA-G) in tumor cells that may favor their escape from antitumor immune responses. The role of HLA-G in breast cancer has not been defined. Other studies showed that HLA-G transcription may be silenced by epigenetic mechanisms or activated by stress. This work aimed to clarify the expression of HLA-G protein, estimate the possible prognostic role of HLA-G expression and identify if this expression is linked to the DNA index (DI) and S phase fraction (SPF) in breast cancer. HLA-G protein expression and the DNA parameters were studied by flow cytometry and serum secreted HLA-G (sHLA-G) levels were detected by enzyme-linked immunosorbent assay (ELISA) in 45 breast cancer patients and 40 female blood donors as healthy donors. Surface HLA-G was expressed on 40% and the cytoplasmic pattern with no membrane association in 24.4% of the malignant specimens. There was an increased serum sHLA-G level in patients as compared with controls. There were negative correlations between cytoplasmic HLA-G and both DI and SPF and between preoperative sHLA-G and SPF with no relations with patients' clinical outcome. We cannot establish that HLA-G protein can be a useful prognostic marker, but sHLA-G may be used as a tumor marker in breast cancer patients. PMID- 20196819 TI - HLA-B27 polymorphism in patients with juvenile and adult-onset ankylosing spondylitis in Southern China. AB - Distribution of B27 subtypes in juvenile and adult-onset ankylosing spondylitis (JAS and AAS) in Southern China was studied. A total of 505 patients belonged to Han population were included (145 JAS and 360 AAS patients), and 1368 healthy individuals were included as controls. Human leukocyte antigen (HLA)-B27 typing was performed by Luminex liquid array combining polymerase chain reaction sequence specific oligonucleotide probe (PCR-SSOP) and/or serological method. HLA B27 subtyping was performed by polymerase chain reaction-sequence specific primer (PCR-SSP). The sequence-based typing was performed for the B*2715 samples to verify the PCR-SSP results. HLA-B27 was presented in 453 of 505 patients (89.7%), compared with 74 of 1368 controls (5.41%). B*2704 subtype in AS group was significantly higher than controls and B*2705 subtype significantly lower. B*2715 and B*2702 were found in 1.32% and 0.66% of the B27-positive patients but none in controls, and there was no significant difference between either of them and controls. B27-positive patients were 134 (92.4%) in JAS group and 319 (88.6%) in AAS group. There was no significant difference for B27 subtypes distribution between JAS (B*2704, 05, 15) and AAS (B*2704, 05, 15, 02) groups. The frequency of B*2715 in two groups was 3 (2.24%) and 3 (0.94%), respectively. The onset age of three JAS patients carrying B*2715 was 5, 9 and 13 years old, respectively. Our results suggested that B*2704 was the predominant subtype in AS patients in Southern China. B*2715 was observed in AS group only and slightly more in JAS than in AAS, and the patients carrying this allele tended to have early onset, B*2715 may be disease-association subtype. PMID- 20196820 TI - Mapping of susceptibility locus for endometriosis within the HLA region using microsatellite markers in Japanese women. AB - Endometriosis is a female disorder characterized by the presence of uterine endometrial tissue in ectopic loci. Previous studies reported a higher prevalence of particular human leukocyte antigen (HLA) in endometriosis. In order to confirm the association between endometriosis and the HLA region, 15 polymorphic microsatellite markers distributed in the HLA class II to class III region were subjected to association analysis by polymerase chain reaction (PCR)-based DNA typing of 89 patients and 136 healthy controls. Statistical analysis of the allelic frequency at each microsatellite locus showed that there were no statistically significant differences in the allele frequency distributions between the cases and controls. This finding suggests that the etiology of endometriosis does not involve the HLA class II genomic region and a portion of class III genomic region in the Japanese population. PMID- 20196821 TI - HLA-B*4088, a new allele was identified by polymerase chain reaction sequence based typing in a Chinese cord blood donor. AB - HLA-B*4088 shows one nucleotide difference from HLA-B*400101 at position 350 in exon 3 from A to G. PMID- 20196822 TI - Identification of the novel allele Cw*040110 in a German patient. AB - We report here the identification of a novel human leukocyte-Cw*040110 allele detected by polymerase chain reaction sequence-based typing in a German patient. PMID- 20196823 TI - The new HLA-Cw*0442 allele possibly generated by a recombination event involving Cw*04010101 and Cw*1801. AB - A new human leukocyte antigen-C (HLA-C) allele Cw*0442 was identified in a Spanish Caucasian patient by sequencing-based typing (SBT). HLA-Cw*0442 differs from Cw*04010101 by three amino acid replacements at positions 9 (S>D), 11 (S>A), and 14 (W>R). PMID- 20196824 TI - Characterization of the novel HLA-Cw*0624 allele identified by sequence-based typing. AB - A novel HLA-Cw*0624 variant allele differs from the closest allele Cw*06020101 by single nucleotide change at genomic nt 923 T>C (CDS nt 547 T>C, codon 159 TAC>CAC) in exon 3, which results in an amino acid change Tyr159His. PMID- 20196825 TI - HLA polymorphism in three indigenous populations of Sabah and Sarawak. AB - One hundred and fifty-eight Kadazan, Iban and Bidayuh individuals registered with the Malaysian Marrow Donor Registry were typed for human leukocyte antigen (HLA) A, HLA-B and HLA-DR. Six, seven and eight HLA-A alleles as well as 13, 15 and 16 HLA-B alleles were detected in the Kadazan, Bidayuh and Iban, respectively. The most common HLA-A allele in all three groups was HLA-A*24 with a frequency of 0.456, 0.490 and 0.422 in the Kadazan, Bidayuh and Iban, respectively. The most common HLA-B allele detected in the Kadazan was HLA-B*40 with a frequency of 0.333; for the Bidayuh and the Iban it was HLA-B*15 with a frequency of 0.460 and 0.275, respectively. The HLA-DR allele with the highest frequency in the Kadazan was HLA-DR*1502 with a frequency of 0.500. In the Iban and the Bidayuh, HLA DRB1*1202 was the most common DR allele with frequencies of 0.235 and 0.310, respectively. The two most common haplotypes for the Kadazan are A*34-B*38 DR*1502 and A*24-B*40-DR*0405, whereas for the Bidayuh they are A*24-B*15-DR*1602 and A*24-B*35-DR*1202 and for the Iban they are A*34-*B15-DR*1502 and A*24-B*15 DR*1202. PMID- 20196826 TI - HLA-A, -B, -DRB1 allele frequencies and haplotypic association from DNA typing data of 7096 Korean cord blood units. AB - Human leukocyte antigen (HLA) distribution in 7096 Korean cord blood (CB) units preserved at the public CB bank was analyzed by using the polymerase chain reaction with sequence-specific oligonucleotide probe (PCR-SSOP) method. A total of 14 HLA-A, 33 HLA-B, 13 HLA-DRB1 alleles and 2470 three-locus haplotypes were identified. The results are generally similar to those from the previous Korean studies, but the frequencies of less frequent haplotypes < 0.1% are more relevant and infrequent haplotypes with strong linkage disequilibrium were newly found because of the large sample size. Our results showed some similarities to those of other Asians but also some differences, suggesting a rationale for an Asian network for a hematopoietic stem-cell donor registry. Results from this large scale analysis will be useful in Korean and Asian registry planning. PMID- 20196827 TI - Characterization of the novel HLA-B allele, B*4621, in a Chinese individual. AB - We report that a novel HLA-B allele, B*4603 has been identified during routine PCR-SSOP typing in a sample from a registered female donor of Chinese Marrow Donor Program. PMID- 20196828 TI - A novel HLA-B allele, B*5535, was identified by sequence-based typing in a Chinese individual. AB - A novel human leukocyte antigen (HLA)-B allele, B*5535, has been identified in a Chinese individual by sequence-based typing, which has seven nucleotide changes from the closest matching allele B*5502 resulting in two amino acids changes: 69 Glu-->Met; 70 Glu-->Ala. PMID- 20196829 TI - Characterization of the genomic full-length sequence of HLA-Cw*010201, Cw*0706, and Cw*0801 in Chinese individuals. AB - Genomic full-length sequence of human leukocyte antigen (HLA)-Cw*0706, differing from its closet allele Cw*070 101 by six nucleotide exchanges, was detected in two Chinese individuals. PMID- 20196830 TI - Genomic full-length sequence of HLA-Cw*0103 and *0108, identified by cloning and sequencing. AB - Genomic full-length sequences of human leukocyte antigen (HLA)-Cw*0103 and *0108 were identified by cloning and sequencing from two Chinese donors. All introns, exons 4-8, 5'-promoter, and 3'-UTR were found to be identical between these two alleles. PMID- 20196831 TI - Characterization of a novel HLA-Cw*07 variant allele, Cw*075602. AB - The novel human leukocyte antigen (HLA)-Cw*075602 variant allele differs from the closest allele Cw*07020101 by a single nucleotide change at genomic DNA nt 473 G > C (CDS nt 343 G > C , codon 91 GGG > CGG ) in exon 2, which results in an amino acid change Gly91Arg. PMID- 20196832 TI - CTLA4 promoter polymorphisms are associated with canine diabetes mellitus. AB - Canine diabetes mellitus (DM) shares many similarities with human type 1 diabetes (T1D). It is a complex genetic disorder, which shows marked differences in breed susceptibility, with Samoyed dogs being highly susceptible, whereas the Boxer breed is relatively resistant. A number of immune response genes, which have been associated with human T1D, have also been implicated in determining susceptibility to canine DM, suggesting an immune-mediated component to the disease pathogenesis. Single nucleotide polymorphisms (SNPs) in the CTLA4 gene have consistently and reproducibly been associated with human T1D and other autoimmune diseases but the canine CTLA4 gene has not previously been investigated for involvement in canine DM. SNPs of particular interest in the human association studies are those in the promoter region which affect CTLA4 expression levels, and that of exon 1 which results in a non-synonymous amino acid change. We performed a canine SNP discovery investigation of CTLA4 on a region of DNA containing exon 1 and 1.5 kb upstream sequence in order to identify promoter region SNPs. Confirmed SNPs were used in a genetic association study of a canine diabetic cohort showing that CTLA4 promoter polymorphisms were associated with diabetes in crossbreed dogs and in five Pedigree breeds-Samoyed, Miniature Schnauzer, West Highland White Terrier, Border Terrier and Labrador. Meta-analysis of these breeds showed 9 out of 15 SNPs were associated with DM and genotype and haplotype analyses also confirmed the allelic associations in these breeds. PMID- 20196834 TI - Association of Nrf2-encoding NFE2L2 haplotypes with Parkinson's disease. AB - BACKGROUND: Oxidative stress is heavily implicated in the pathogenic process of Parkinson's disease. Varying capacity to detoxify radical oxygen species through induction of phase II antioxidant enzymes in substantia nigra may influence disease risk. Here, we hypothesize that variation in NFE2L2 and KEAP1, the genes encoding the two major regulators of the phase II response, may affect the risk of Parkinson's disease. METHODS: The study included a Swedish discovery case control material (165 cases and 190 controls) and a Polish replication case control material (192 cases and 192 controls). Eight tag single nucleotide polymorphisms representing the variation in NFE2L2 and three representing the variation in KEAP1 were chosen using HapMap data and were genotyped using TaqMan Allelic Discrimination. RESULTS: We identified a protective NFE2L2 haplotype in both of our European case-control materials. Each haplotype allele was associated with five years later age at onset of the disease (p = 0.001) in the Swedish material, and decreased risk of PD (p = 2 x 10(-6)), with an odds ratio of 0.4 (95% CI 0.3-0.6) for heterozygous and 0.2 (95% CI 0.1-0.4) for homozygous carriers, in the Polish material. The identified haplotype includes a functional promoter haplotype previously associated with high transcriptional activity. Genetic variation in KEAP1 did not show any associations. CONCLUSION: These data suggest that variation in NFE2L2 modifies the Parkinson's disease process and provide another link between oxidative stress and neurodegeneration. PMID- 20196835 TI - Distribution of candidate genes for experimentally induced arthritis in rats. AB - BACKGROUND: Rat models are frequently used to link genomic regions to experimentally induced arthritis in quantitative trait locus (QTL) analyses. To facilitate the search for candidate genes within such regions, we have previously developed an application (CGC) that uses weighted keywords to rank genes based on their descriptive text. In this study, CGC is used for analyzing the localization of candidate genes from two viewpoints: distribution over the rat genome and functional connections between arthritis QTLs. METHODS: To investigate if candidate genes identified by CGC are more likely to be found inside QTLs, we ranked 2403 genes genome wide in rat. The number of genes within different ranges of CGC scores localized inside and outside QTLs was then calculated. Furthermore, we investigated if candidate genes within certain QTLs share similar functions, and if these functions could be connected to genes within other QTLs. Based on references between genes in OMIM, we created connections between genes in QTLs identified in two distinct rat crosses. In this way, QTL pairs with one QTL from each cross that share an unexpectedly high number of gene connections were identified. The genes that were found to connect a pair of QTLs were then functionally analysed using a publicly available classification tool. RESULTS: Out of the 2403 genes ranked by the CGC application, 1160 were localized within QTL regions. No difference was observed between highly and lowly rated genes. Hence, highly rated candidate genes for arthritis seem to be distributed randomly inside and outside QTLs. Furthermore, we found five pairs of QTLs that shared a significantly high number of interconnected genes. When functionally analyzed, most genes connecting two QTLs could be included in a single functional cluster. Thus, the functional connections between these genes could very well be involved in the development of an arthritis phenotype. CONCLUSIONS: From the genome wide CGC search, we conclude that candidate genes for arthritis in rat are randomly distributed between QTL and non-QTL regions. We do however find certain pairs of QTLs that share a large number of functionally connected candidate genes, suggesting that these QTLs contain a number of genes involved in similar functions contributing to the arthritis phenotype. PMID- 20196836 TI - The effects of thiopurine therapy on health-related quality of life in Inflammatory Bowel Disease patients. AB - BACKGROUND: The effect of thiopurine immunomodulators on health-related quality of life (HRQoL) in patients with inflammatory bowel disease (IBD) has been controversial. The aims were to evaluate the HRQoL in patients with IBD treated with thiopurines and assess the short- and long-term impacts of the treatment on HRQoL. METHODS: Ninety-two consecutive patients who started treatment with thiopurines were prospectively included. Evaluation of HRQoL was performed at months 0, 6, and 12 using two questionnaires, the Short-Form Health Survey (SF 36) and the Inflammatory Bowel Disease Questionnaire (IBDQ). RESULTS: Baseline score of IBDQ was 4,6, range (2,31-6,84), with an impairment of the five dimensions of HRQoL compared with inactive patients. Results obtained in 8 dimensions of SF-36 showed worse HRQoL than Spanish general population. At 6 months patients had a significant improvement in overall IBDQ score -5,8 (1,58 6,97)- and also in all IBDQ dimensions. All the 8 dimensions of SF-36 obtained a significant improvement. At twelve months score of IBDQ was 6,1, range (2,7 6,98), with improvement in all dimensions compared with baseline and 6 months. SF 36 showed a similar significant improvement in all subscales. CONCLUSIONS: Thiopurine immunomodulators alone or with other treatments have a positive and long lasting impact on HRQoL of IBD patients. PMID- 20196837 TI - Association between C282Y and H63D mutations of the HFE gene with hepatocellular carcinoma in European populations: a meta-analysis. AB - BACKGROUND: Hereditary hemochromatosis (HH) is an autosomal recessive disorder mainly associated with homozygosity for the C282Y and H63D mutations in the hemochromatosis (HFE) gene. The reports about the C282Y and H63D mutations and hepatocellular carninoma (HCC) were controversial. To clarify the relationship between C282Y and H63D mutations and HCC, a meta-analysis including nine studies (1102 HCC cases and 3766 controls, mainly came from European populations) was performed. METHODS: The association was measured using random-effect (RE) or fixed-effect (FE) odds ratios (ORs) combined with 95% confidence intervals (CIs) according to the studies' heterogeneity. RESULTS: Meta-analysis of nine studies showed that Y allele of C282Y was associated with HCC risk: RE OR reached 1.50 (95%CI: 1.05-2.14, p for heterogeneity = 0.02, I2 = 0.57). Subgroup analysis of seven studies also showed Y allele was associated with HCC risk in healthy populations: RE OR reached 1.61 (95%CI: 1.08-2.39, p for heterogeneity = 0.04, I2 = 0.55). We further did subgroup analysis in alcoholic liver cirrhosis (LC) patients of four studies (224 cases and 380 controls) and found that both the dominant model and Y allele of C282Y were associated with HCC risk (FE OR reached 4.06, 95%CI: 2.08-7.92 and 3.41, 95%CI: 1.81-6.41, respectively). There was no distinct heterogeneity among the studies (I2 = 0). Sensitivity analyses showed the results were robust in the subgroup analysis of alcoholic LC patients. CONCLUSIONS: C282Y mutation was associated with HCC in European alcoholic LC patients. PMID- 20196838 TI - Pregnane X Receptor (PXR) expression in colorectal cancer cells restricts irinotecan chemosensitivity through enhanced SN-38 glucuronidation. AB - BACKGROUND: Clinical efficacy of chemotherapy in colorectal cancer is subjected to broad inter-individual variations leading to the inability to predict outcome and toxicity. The topoisomerase I inhibitor irinotecan (CPT-11) is worldwide approved for the treatment of metastatic colorectal cancer and undergoes extensive peripheral and tumoral metabolism. PXR is a xenoreceptor activated by many drugs and environmental compounds regulating the expression of drug metabolism and transport genes in detoxification organs such as liver and gastrointestinal tract. Considering the metabolic pathway of irinotecan and the tissue distribution of Pregnane x Receptor (PXR), we hypothesized that PXR could play a key role in colon cancer cell response to irinotecan. RESULTS: PXR mRNA expression was quantified by RT-quantitative PCR in a panel of 14 colon tumor samples and their matched normal tissues. PXR expression was modulated in human colorectal cancer cells LS174T, SW480 and SW620 by transfection and siRNA strategies. Cellular response to irinotecan and its active metabolic SN38 was assessed by cell viability assays, HPLC metabolic profiles and mRNA quantification of PXR target genes. We showed that PXR was strongly expressed in colon tumor samples and displayed a great variability of expression. Expression of hPXR in human colorectal cancer cells led to a marked chemoresistance to the active metabolite SN38 correlated with PXR expression level. Metabolic profiles of SN38 showed a strong enhancement of SN38 glucuronidation to the inactive SN38G metabolite in PXR-expressing cells, correlated with an increase of UDPglucuronosyl transferases UGT1A1, UGT1A9 and UGT1A10 mRNAs. Inhibition of PXR expression by lentivirus-mediated shRNA, led to SN38 chemoresistance reversion concomitantly to a decrease of UGT1A1 expression and SN38 glucuronidation. Similarly, PXR mRNA expression levels correlated to UGT1A subfamily expression in human colon tumor biopsies. CONCLUSION: Our results demonstrate that tumoral metabolism of SN38 is affected by PXR and point to potential therapeutic significance of PXR quantification in the prediction of irinotecan response. Furthermore, our observations are pharmacologically relevant since many patients suffering from cancer diseases are often exposed to co-medications, food additives or herbal supplements able to activate PXR. A substantial part of the variability observed among patients might be caused by such interactions. PMID- 20196839 TI - Systematic review of methods for evaluating healthcare research economic impact. AB - BACKGROUND: The economic benefits of healthcare research require study so that appropriate resources can be allocated to this research, particularly in developing countries. As a first step, we performed a systematic review to identify the methods used to assess the economic impact of healthcare research, and the outcomes. METHOD: An electronic search was conducted in relevant databases using a combination of specific keywords. In addition, 21 relevant Web sites were identified. RESULTS: The initial search yielded 8,416 articles. After studying titles, abstracts, and full texts, 18 articles were included in the analysis. Eleven other reports were found on Web sites. We found that the outcomes assessed as healthcare research payback included direct cost-savings, cost reductions in healthcare delivery systems, benefits from commercial advancement, and outcomes associated with improved health status. Two methods were used to study healthcare research payback: macro-economic studies, which examine the relationship between research studies and economic outcome at the aggregated level, and case studies, which examine specific research projects to assess economic impact. CONCLUSIONS: Our study shows that different methods and outcomes can be used to assess the economic impacts of healthcare research. There is no unique methodological approach for the economic evaluation of such research. In our systematic search we found no research that had evaluated the economic return of research in low and middle income countries. We therefore recommend a consensus on practical guidelines at international level on the basis of more comprehensive methodologies (such as Canadian Academic of Health Science and payback frameworks) in order to build capacity, arrange for necessary informative infrastructures and promote necessary skills for economic evaluation studies. PMID- 20196840 TI - HAX-1 overexpression, splicing and cellular localization in tumors. AB - BACKGROUND: HAX-1 has been described as a protein potentially involved in carcinogenesis and especially metastasis. Its involvement in regulation of apoptosis and cell migration along with some data indicating its overexpression in cancer cell lines and tumors suggests that HAX-1 may play a role in neoplastic transformation. Here we present the first systematic analysis of HAX-1 expression in several solid tumors. METHODS: Using quantitative RT-PCR, we have determined the mRNA levels of HAX1 splice variant I in several solid tumors. We have also analyzed by semiquantitative and quantitative RT-PCR the expression of five HAX-1 splice variants in breast cancer samples and in normal tissue from the same individuals. Quantitative PCR was also employed to analyze the effect of estrogen on HAX1 expression in breast cancer cell line. Immunohistochemical analysis of HAX-1 was performed on normal and breast cancer samples. RESULTS: The results reveal statistically important HAX1 up-regulation in breast cancer, lung cancer and melanoma, along with some minor variations in the splicing pattern. HAX-1 up regulation in breast cancer samples was confirmed by immunohistochemical analysis, which also revealed an intriguing HAX-1 localization in the nuclei of the tumor cells, associated with strong ER status. CONCLUSION: HAX-1 elevated levels in cancer tissues point to its involvement in neoplastic transformation, especially in breast cancer. The connection between HAX-1 nuclear location and ER status in breast cancer samples remains to be clarified. PMID- 20196841 TI - Anti-tumor therapy with macroencapsulated endostatin producer cells. AB - BACKGROUND: Theracyte is a polytetrafluoroethylene membrane macroencapsulation system designed to induce neovascularization at the tissue interface, protecting the cells from host's immune rejection, thereby circumventing the problem of limited half-life and variation in circulating levels. Endostatin is a potent inhibitor of angiogenesis and tumor growth. Continuous delivery of endostatin improves the efficacy and potency of the antitumoral therapy. The purpose of this study was to determine whether recombinant fibroblasts expressing endostatin encapsulated in Theracyte immunoisolation devices can be used for delivery of this therapeutic protein for treatment of mice bearing B16F10 melanoma and Ehrlich tumors. RESULTS: Mice were inoculated subcutaneously with melanoma (B16F10 cells) or Ehrlich tumor cells at the foot pads. Treatment began when tumor thickness had reached 0.5 mm, by subcutaneous implantation of 107 recombinant encapsulated or non-encapsulated endostatin producer cells. Similar melanoma growth inhibition was obtained for mice treated with encapsulated or non encapsulated endostatin-expressing cells. The treatment of mice bearing melanoma tumor with encapsulated endostatin-expressing cells was decreased by 50.0%, whereas a decrease of 56.7% in tumor thickness was obtained for mice treated with non-encapsulated cells. Treatment of Ehrlich tumor-bearing mice with non encapsulated endostatin-expressing cells reduced tumor thickness by 52.4%, whereas lower tumor growth inhibition was obtained for mice treated with encapsulated endostatin-expressing cells: 24.2%. Encapsulated endostatin secreting fibroblasts failed to survive until the end of the treatment. However, endostatin release from the devices to the surrounding tissues was confirmed by immunostaining. Decrease in vascular structures, functional vessels and extension of the vascular area were observed in melanoma microenvironments. CONCLUSIONS: This study indicates that immunoisolation devices containing endostatin expressing cells are effective for the inhibition of the growth of melanoma and Ehrlich tumors.Macroencapsulation of engineered cells is therefore a reliable platform for the refinement of innovative therapeutic strategies against tumors. PMID- 20196842 TI - Pb-induced cellular defense system in the root meristematic cells of Allium sativum L. AB - BACKGROUND: Electron microscopy (EM) techniques enable identification of the main accumulations of lead (Pb) in cells and cellular organelles and observations of changes in cell ultrastructure. Although there is extensive literature relating to studies on the influence of heavy metals on plants, Pb tolerance strategies of plants have not yet been fully explained. Allium sativum L. is a potential plant for absorption and accumulation of heavy metals. In previous investigations the effects of different concentrations (10(-5) to 10(-3) M) of Pb were investigated in A. sativum, indicating a significant inhibitory effect on shoot and root growth at 10(-3) to 10(-4) M Pb. In the present study, we used EM and cytochemistry to investigate ultrastructural alterations, identify the synthesis and distribution of cysteine-rich proteins induced by Pb and explain the possible mechanisms of the Pb-induced cellular defense system in A. sativum. RESULTS: After 1 h of Pb treatment, dictyosomes were accompanied by numerous vesicles within cytoplasm. The endoplasm reticulum (ER) with swollen cisternae was arranged along the cell wall after 2 h. Some flattened cisternae were broken up into small closed vesicles and the nuclear envelope was generally more dilated after 4 h. During 24-36 h, phenomena appeared such as high vacuolization of cytoplasm and electron-dense granules in cell walls, vacuoles, cytoplasm and mitochondrial membranes. Other changes included mitochondrial swelling and loss of cristae, and vacuolization of ER and dictyosomes during 48-72 h. In the Pb treatment groups, silver grains were observed in cell walls and in cytoplasm, suggesting the Gomori-Swift reaction can indirectly evaluate the Pb effects on plant cells. CONCLUSIONS: Cell walls can immobilize some Pb ions. Cysteine-rich proteins in cell walls were confirmed by the Gomori-Swift reaction. The morphological alterations in plasma membrane, dictyosomes and ER reflect the features of detoxification and tolerance under Pb stress. Vacuoles are ultimately one of main storage sites of Pb. Root meristematic cells of A. sativum exposed to lower Pb have a rapid and effective defense system, but with the increased level of Pb in the cytosol, cells were seriously injured. PMID- 20196844 TI - Lower lid entropion secondary to treatment with alpha-1a receptor antagonist: a case report. AB - INTRODUCTION: The use of alpha-1a receptor antagonists (tamsulosin) is widely accepted in the treatment of benign prostatic hypertrophy (BPH). It has previously been implicated as a causative agent in intra-operative floppy iris syndrome due to its effects on the smooth muscle. We report a case of lower lid entropion that may be related to a patient commencing treatment of tamsulosin. CASE PRESENTATION: A 74-year-old Caucasian man was started on alpha 1-a receptor antagonist (Tamsulosin) treatment for benign prostatic hypertrophy. Eight days later, he presented to the ophthalmology unit with a right lower lid entropion which was successfully treated surgically with a Weiss procedure. CONCLUSION: We report a case of lower lid entropion that may be secondary to the recent use of an alpha-1a blocker (tamsulosin). This can be explained by considering the effect of autonomic blockade on alpha-1 receptors in the Muller's muscle on a patient that may already have an anatomical predisposition to entropion formation due to a further reduction in muscle tone. PMID- 20196843 TI - Components of acquisition-to-acquisition variance in continuous arterial spin labelling (CASL) imaging. AB - BACKGROUND: Images of perfusion estimates obtained with the continuous arterial spin labelling technique are characterized by variation between single acquisitions. Little is known about the spatial determinants of this variation during the acquisition process and their impact on voxel-by-voxel estimates of effects. RESULTS: We show here that the spatial patterns of covariance between voxels arising during the acquisition of these images uncover distinct mechanisms through which this variance arises: through variation in global perfusion levels; through the action of large vessels and other, less well characterized, large anatomical structures; and through the effect of noisy areas such as the edges of the brain. CONCLUSIONS: Knowledge of these covariance patterns is important to experimenters for a correct interpretation of findings, especially for studies where relatively few acquisitions are made. PMID- 20196845 TI - National and subnational HIV/AIDS coordination: are global health initiatives closing the gap between intent and practice? AB - BACKGROUND: A coordinated response to HIV/AIDS remains one of the 'grand challenges' facing policymakers today. Global health initiatives (GHIs) have the potential both to facilitate and exacerbate coordination at the national and subnational level. Evidence of the effects of GHIs on coordination is beginning to emerge but has hitherto been limited to single-country studies and broad-brush reviews. To date, no study has provided a focused synthesis of the effects of GHIs on national and subnational health systems across multiple countries. To address this deficit, we review primary data from seven country studies on the effects of three GHIs on coordination of HIV/AIDS programmes: the Global Fund to Fight AIDS, Tuberculosis and Malaria, the President's Emergency Plan for AIDS Relief (PEPFAR), and the World Bank's HIV/AIDS programmes including the Multi country AIDS Programme (MAP). METHODS: In-depth interviews were conducted at national and subnational levels (179 and 218 respectively) in seven countries in Europe, Asia, Africa and South America, between 2006 and 2008. Studies explored the development and functioning of national and subnational HIV coordination structures, and the extent to which coordination efforts around HIV/AIDS are aligned with and strengthen country health systems. RESULTS: Positive effects of GHIs included the creation of opportunities for multisectoral participation, greater political commitment and increased transparency among most partners. However, the quality of participation was often limited, and some GHIs bypassed coordination mechanisms, especially at the subnational level, weakening their effectiveness. CONCLUSIONS: The paper identifies residual national and subnational obstacles to effective coordination and optimal use of funds by focal GHIs, which these GHIs, other donors and country partners need to collectively address. PMID- 20196846 TI - Studying a disease with no home--lessons in trial recruitment from the PATCH II study. AB - BACKGROUND: Cellulitis is a very common condition that often recurs. The PATCH II study was designed to explore the possibility of preventing future episodes of cellulitis, with resultant cost savings for the NHS. This was the first trial to be undertaken by the UK Dermatology Clinical Trials Network. As such, it was the first to test a recruitment model that involved many busy clinicians each contributing just a few patients. METHODS: A double-blind randomised controlled trial comparing prophylactic antibiotics (penicillin V) with placebo tablets, for the prevention of repeat episodes of cellulitis of the leg. Primary outcome was time to subsequent recurrence of cellulitis. RESULTS: The PATCH II study was closed to recruitment having enrolled 123 participants from a target of 400. Whilst the recruitment period was extended by 12 months, it was not possible to continue beyond this point without additional funds. Many factors contributed to poor recruitment: (i) changes in hospital policy and the introduction of community-based intravenous teams resulted in fewer cellulitis patients being admitted to hospital; ii) those who were admitted were seen by many different specialties, making it difficult for a network of dermatology clinicians to identify suitable participants; and iii) funding for research staff was limited to a trial manager and a trial administrator at the co-ordinating centre. With no dedicated research nurses at the recruiting centres, it was extremely difficult to maintain momentum and interest in the study. Attempts to boost recruitment by providing some financial support for principal investigators to employ local research staff was of limited success. DISCUSSION: The model of a network of busy NHS clinicians all recruiting a few patients into large clinical studies requires further testing. It did not work very well for PATCH II, but this was probably because patients were not routinely seen by dermatologists, and recruitment took place prior to research support being available through the Comprehensive Clinical Research Network (CCRN). There is a balance to be struck between asking a lot of centres to recruit just a few patients, and asking a few centres to recruit a lot of patients. Giving modest funds to principal investigators to buy local research nurse time did not work well, probably because too little research time was bought, and it was difficult to separate research tasks from the nurses existing clinical duties. National research infrastructure networks such as the Comprehensive Clinical Research Network will overcome many of the problems encountered in the PATCH II trial. TRIAL REGISTRATION: The trial registration number is ISRCTN03813200. PMID- 20196847 TI - Sulforaphane induces cell cycle arrest by protecting RB-E2F-1 complex in epithelial ovarian cancer cells. AB - BACKGROUND: Sulforaphane (SFN), an isothiocyanate phytochemical present predominantly in cruciferous vegetables such as brussels sprout and broccoli, is considered a promising chemo-preventive agent against cancer. In-vitro exposure to SFN appears to result in the induction of apoptosis and cell-cycle arrest in a variety of tumor types. However, the molecular mechanisms leading to the inhibition of cell cycle progression by SFN are poorly understood in epithelial ovarian cancer cells (EOC). The aim of this study is to understand the signaling mechanisms through which SFN influences the cell growth and proliferation in EOC. RESULTS: SFN at concentrations of 5-20 microM induced a dose-dependent suppression of growth in cell lines MDAH 2774 and SkOV-3 with an IC50 of ~8 microM after a 3 day exposure. Combination treatment with chemotherapeutic agent, paclitaxel, resulted in additive growth suppression. SFN at ~8 microM decreased growth by 40% and 20% on day 1 in MDAH 2774 and SkOV-3, respectively. Cells treated with cytotoxic concentrations of SFN have reduced cell migration and increased apoptotic cell death via an increase in Bak/Bcl-2 ratio and cleavage of procaspase-9 and poly (ADP-ribose)-polymerase (PARP). Gene expression profile analysis of cell cycle regulated proteins demonstrated increased levels of tumor suppressor retinoblastoma protein (RB) and decreased levels of E2F-1 transcription factor. SFN treatment resulted in G1 cell cycle arrest through down modulation of RB phosphorylation and by protecting the RB-E2F-1 complex. CONCLUSIONS: SFN induces growth arrest and apoptosis in EOC cells. Inhibition of retinoblastoma (RB) phosphorylation and reduction in levels of free E2F-1 appear to play an important role in EOC growth arrest. PMID- 20196848 TI - Persistence on prostaglandin ocular hypotensive therapy: an assessment using medication possession and days covered on therapy. AB - BACKGROUND: Prior research has demonstrated that medication persistence (continued acquisition of therapy over time) is far from optimal among patients with glaucoma. The purpose of the present study was to evaluate persistence with prostaglandin analogs among glaucoma patients in the first therapy year using a modification of a previously published technique. METHODS: This retrospective analysis of medical and pharmacy claims database included treatment-naive patients dispensed bimatoprost, latanoprost, or travoprost between 1/1/04 12/31/04. "Index agent" was defined as the first agent filled; "index date" was defined as the fill date. Follow-up continued for 358 days. Persistence measures for first therapy year were: (1) whether last fill had sufficient days supply to achieve medication possession at year's end, and (2) number of days for which the index agent was available (days covered). Associations between index agent and medication possession (logistic regression) and days covered (linear regression) were evaluated. Models were adjusted for gender, age, and previous ocular hypertension diagnosis. RESULTS: 7873 patients met inclusion criteria (bimatoprost, n = 1464; latanoprost, n = 4994; travoprost, n = 1415). Medication possession was 28% and days covered was 131 when using the unadjusted (pharmacy reported) days supply estimates and rose to 47-48% and days covered to 228-236 days when days supply was imputed. Compared to latanoprost, odds of achieving medication possession at first year's end were 26-34% lower for bimatoprost and 34-36% lower for travoprost (p /= 25 kg*m-2 were randomly assigned into the Ex or Lc+Ex group. Both groups performed 60-100 min of varied resistance exercise twice weekly. Dietary estimates were based on two 4-day weighed records. Body composition was estimated using Dual Energy X-ray Absorptiometry. Fasting blood samples were analyzed for total-, HDL- and LDL-cholesterol, triacylglycerols, and glucose. RESULTS: 16 subjects were included in the analyses. Percentage of energy (En%) from carbohydrates, fat and protein was 6, 66, and 22 respectively in the (Lc+Ex) group and 41, 34, 17 in the Ex group. Mean weight change (pre-post) was -5.6 +/- 2.6 kg in Lc+Ex; (p < 0.001) and 0.8 +/- 1.5 kg in Ex; (p = 0.175). The Lc+Ex group lost 5.6 +/- 2.9 kg of fat mass (p = 0.001) with no significant change in lean body mass (LBM), while the Ex group gained 1.6 +/- 1.8 kg of LBM (p = 0.045) with no significant change in fat mass (p = 0.059). Fasting blood lipids and blood glucose were not significantly affected by the interventions. CONCLUSION: Resistance exercise in combination with a ketogenic diet may reduce body fat without significantly changing LBM, while resistance exercise on a regular diet may increase LBM in without significantly affecting fat mass. Fasting blood lipids do not seem to be negatively influenced by the combination of resistance exercise and a low carbohydrate diet. PMID- 20196856 TI - Are Nepali students at risk of HIV? A cross-sectional study of condom use at first sexual intercourse among college students in Kathmandu. AB - BACKGROUND: Condoms offer the best protection against unintended pregnancies and sexually transmitted infections. Little research has been conducted to determine the prevalence and investigate the influencing factors of condom use at first sexual intercourse among college students. METHODS: A self-administered questionnaire was completed by 1137 college students (573 male and 564 female) in the Kathmandu Valley. Analyses were confined to 428 students who reported that they have ever had sexual intercourse. The association between condom use at first sexual intercourse and the explanatory variables was assessed in bivariate analysis using Chi-square tests. The associations were further explored using multivariate logistic analysis in order to identify the significant predictors after controlling for other variables. RESULTS: Among the sexually active students, less than half (48%) had used condoms during first sexual intercourse. The results from the logistic regression analysis revealed that age, caste and/or ethnicity, age at first sexual intercourse, types of first sex partner, alcohol consumption and mass media exposure are significant predictors for condom use at first sexual intercourse among the college students. Students in the older age groups who had first sex were about four times (16 to 19 years old) (OR = 3.5) more likely and nine times (20 or older) (OR = 8.9) more likely than the students who had sex before 16 years of age to use condoms at first sexual intercourse.Moreover, those students who had first sex with commercial sex worker were five times (OR = 4.9) more likely than those who had first sex with their spouse to use condoms at first sex. Furthermore, students who had higher exposure to both print and electronic media were about twice (OR = 1.75) as likely as those who had lower media exposure to use condoms. On the other hand, students who frequently consumed alcohol were 54% (OR = 0.46) less likely to use condoms at first sexual intercourse than those who never or rarely consumed alcohol. CONCLUSIONS: The rate of condom use at first sexual intercourse is low among the students. It indicates students are exposed to health hazards through their sexual behaviour. If low use of condom at first sex continues, vulnerable sexual networks will grow among them that allow quicker spreading of sexually transmitted diseases and HIV. Findings from this study point to areas that policy and programmes can address to provide youth with access to the kinds of information and services they need to achieve healthy sexual and reproductive lives. PMID- 20196857 TI - Surgical management of mediastinal liposarcoma extending from hypopharynx to carina: case report. AB - We describe the complete resection of a giant, well-differentiated mediastinal liposarcoma extending retropharynx to envelop the aortic arch, trachea and esophagus following preoperative radiotherapy. PMID- 20196858 TI - Transmission blocking activity of a standardized neem (Azadirachta indica) seed extract on the rodent malaria parasite Plasmodium berghei in its vector Anopheles stephensi. AB - BACKGROUND: The wide use of gametocytocidal artemisinin-based combination therapy (ACT) lead to a reduction of Plasmodium falciparum transmission in several African endemic settings. An increased impact on malaria burden may be achieved through the development of improved transmission-blocking formulations, including molecules complementing the gametocytocidal effects of artemisinin derivatives and/or acting on Plasmodium stages developing in the vector. Azadirachtin, a limonoid (tetranortriterpenoid) abundant in neem (Azadirachta indica, Meliaceae) seeds, is a promising candidate, inhibiting Plasmodium exflagellation in vitro at low concentrations. This work aimed at assessing the transmission-blocking potential of NeemAzal(R), an azadirachtin-enriched extract of neem seeds, using the rodent malaria in vivo model Plasmodium berghei/Anopheles stephensi. METHODS: Anopheles stephensi females were offered a blood-meal on P. berghei infected, gametocytaemic BALB/c mice, treated intraperitoneally with NeemAzal, one hour before feeding. The transmission-blocking activity of the product was evaluated by assessing oocyst prevalence, oocyst density and capacity to infect healthy mice. To characterize the anti-plasmodial effects of NeemAzal(R) on early midgut stages, i.e. zygotes and ookinetes, Giemsa-stained mosquito midgut smears were examined. RESULTS: NeemAzal completely blocked P. berghei development in the vector, at an azadirachtin dose of 50 mg/kg mouse body weight. The totally 138 examined, treated mosquitoes (three experimental replications) did not reveal any oocyst and none of the healthy mice exposed to their bites developed parasitaemia. The examination of midgut content smears revealed a reduced number of zygotes and post-zygotic forms and the absence of mature ookinetes in treated mosquitoes. Post-zygotic forms showed several morphological alterations, compatible with the hypothesis of an azadirachtin interference with the functionality of the microtubule organizing centres and with the assembly of cytoskeletal microtubules, which are both fundamental processes in Plasmodium gametogenesis and ookinete formation. CONCLUSIONS: This work demonstrated in vivo transmission blocking activity of an azadirachtin-enriched neem seed extract at an azadirachtin dose compatible with 'druggability' requisites. These results and evidence of anti-plasmodial activity of neem products accumulated over the last years encourage to convey neem compounds into the drug discovery & development pipeline and to evaluate their potential for the design of novel or improved transmission-blocking remedies. PMID- 20196859 TI - The loss of health status in rheumatoid arthritis and the effect of biologic therapy: a longitudinal observational study. AB - INTRODUCTION: The long-term course of rheumatoid arthritis (RA) in terms of health status is not well understood, nor is the degree of effectiveness of biologic therapy in the community. We modeled the progression of loss of health status, and measured incremental costs and effectiveness of biologic therapy in the community. METHODS: We studied change in function and health status in 18,485 RA patients (135,731 observations) at six-month intervals for up to 11 years, including a group of 4,911 patients (59,630 observations) who switched to biologic therapy from non-biologic therapy. We measured the SF-36 Physical Component (PCS) and Mental Component (MCS) Summary scales, the EQ-5D health utility scale, and the Health Assessment Questionnaire (HAQ) disability scale; and we calculated treatment and direct medical costs. RESULTS: RA onset caused an immediate and substantial reduction in physical but not mental health status. Thereafter, the progression of dysfunction in RA was very slow (HAQ 0.016 units and PCS -0.125 units annually), only slightly worse than the age and sex-adjusted US population. We estimated biologic treatment to improve HAQ by 0.29 units, PCS by 5.3 units, and EQ-5D by 0.05 units over a 10-year period. The estimated incremental 10-year total direct medical cost for this benefit was $159,140. CONCLUSIONS: Biologic therapy retards RA progression, but its effect is far less than is seen in clinical trials. In the community, cost-effectiveness is substantially less than that estimated from clinical trial data. The study results represent the incremental benefit of adding biologic therapy to optimum non-biologic therapy. PMID- 20196861 TI - Intravenous levosimendan-norepinephrine combination during off-pump coronary artery bypass grafting in a hemodialysis patient with severe myocardial dysfunction. AB - This the case of a 63 year-old man with end-stage renal disease (on chronic hemodialysis), unstable angina and significantly impaired myocardial contractility with low left ventricular ejection fraction, who underwent off-pump one vessel coronary bypass surgery. Combined continuous levosimendan and norepinephrine infusion (at 0.07 microg/kg/min and 0.05 microg/kg/min respectively) started immediately after anesthesia induction and continued for 24 hours. The levosimendan/norepinephrine combination helped maintain an appropriate hemodynamic profile, thereby contributing to uneventful completion of surgery and postoperative hemodynamic stability. Although levosimendan is considered contraindicated in ESRD patients, this case report suggests that combined perioperative levosimendan/norepinephrine administration can be useful in carefully selected hemodialysis patients with impaired myocardial contractility and ongoing myocardial ischemia, who undergo off-pump myocardial revascularization surgery. PMID- 20196860 TI - Diagnostic value of anti-cyclic citrullinated peptides and association with HLA DRB1 shared epitope alleles in African rheumatoid arthritis patients. AB - INTRODUCTION: The purpose of this study was to examine the diagnostic performance of autoantibodies against citrullinated peptides/proteins (ACPA) and to determine the prevalence of HLA-DRB1 shared epitope alleles (SE) in African patients with rheumatoid arthritis (RA). METHODS: Serum levels of anti-cyclic citrullinated peptides antibodies (anti-CCP2, anti-CCP3), IgM and IgA rheumatoid factors (RF) were measured by enzyme-linked immunosorbent assay in the serum of 56 consecutive RA patients regularly followed in the Rheumatology Unit of the School of Medicine, University of Yaounde, Yaounde, Cameroon. Genotyping of HLA-DRB1 alleles was performed by polymerase chain reaction and hybridization with sequence-specific oligonucleotide probes on microbeads arrays. Fifty-one patients with other inflammatory rheumatic diseases and 50 healthy individuals were included as controls. RESULTS: An anti-CCP2 assay showed the best diagnosis sensitivity (82%) and specificity (98%) with high positive predictive (PPV) (96%) and negative predictive values (NPV) (91%). Thirty percent of RA patients were carrying at least one copy of the HLA-DRB1 shared epitope (SE) compared to 10% and 14% of patients with other inflammatory rheumatic diseases and healthy individuals, respectively. The presence of the SE was associated with the production of ACPA. CONCLUSIONS: Anti-CCP2 antibodies are useful markers of RA in African patients. In this cohort, the prevalence of the SE is higher in RA patients than in controls but lower than that reported in patient cohorts of European ancestry. The discrepancy between the high prevalence of ACPA-positive patients and the relatively low number of SE-positive cases suggest that, in addition to SE, other genetic factors control the development of ACPA in African RA patients. PMID- 20196862 TI - Podoplanin expression in the development and progression of laryngeal squamous cell carcinomas. AB - BACKGROUND: Podoplanin expression is attracting interest as a marker for cancer diagnosis and prognosis. We therefore investigated the expression pattern and clinical significance of podoplanin during the development and progression of laryngeal carcinomas. RESULTS: Podoplanin expression was determined by immunohistochemistry in paraffin-embedded tissue specimens from 84 patients with laryngeal premalignancies and 53 patients with laryngeal squamous cell carcinomas. We found podoplanin expression extending from the basal to the suprabasal layer of the epithelium in 37 (44%) of 84 dysplastic lesions, whereas normal epithelium showed negligible expression. Patients carrying podoplanin positive lesions had a higher laryngeal cancer incidence than those with negative expression reaching borderline statistical significance (51% versus 30%, P = 0.071). Podoplanin expression in laryngeal carcinomas exhibited two distinct patterns. 20 (38%) cases showed diffuse expression in most tumour cells and 33 (62%) focal expression at the proliferating periphery of tumour nests. High podoplanin expression was inversely correlated with T classification (P = 0.033), disease stage (P = 0.006), and pathological grade (P = 0.04). There was a trend, although not significant, towards reduced disease-specific survival for patients with low podoplanin levels (P = 0.31) and diffuse expression pattern (P = 0.08). CONCLUSIONS: Podoplanin expression increases in the early stages of laryngeal tumourigenesis and it seems to be associated with a higher laryngeal cancer risk. Podoplanin expression in laryngeal squamous cell carcinomas, however, diminishes during tumour progression. Taken together, these data support a role for podoplanin expression in the initiation but not in the progression of laryngeal cancers. PMID- 20196863 TI - OrgConv: detection of gene conversion using consensus sequences and its application in plant mitochondrial and chloroplast homologs. AB - BACKGROUND: The ancestry of mitochondria and chloroplasts traces back to separate endosymbioses of once free-living bacteria. The highly reduced genomes of these two organelles therefore contain very distant homologs that only recently have been shown to recombine inside the mitochondrial genome. Detection of gene conversion between mitochondrial and chloroplast homologs was previously impossible due to the lack of suitable computer programs. Recently, I developed a novel method and have, for the first time, discovered recurrent gene conversion between chloroplast mitochondrial genes. The method will further our understanding of plant organellar genome evolution and help identify and remove gene regions with incongruent phylogenetic signals for several genes widely used in plant systematics. Here, I implement such a method that is available in a user friendly web interface. RESULTS: OrgConv (Organellar Conversion) is a computer package developed for detection of gene conversion between mitochondrial and chloroplast homologous genes. OrgConv is available in two forms; source code can be installed and run on a Linux platform and a web interface is available on multiple operating systems. The input files of the feature program are two multiple sequence alignments from different organellar compartments in FASTA format. The program compares every examined sequence against the consensus sequence of each sequence alignment rather than exhaustively examining every possible combination. Making use of consensus sequences significantly reduces the number of comparisons and therefore reduces overall computational time, which allows for analysis of very large datasets. Most importantly, with the significantly reduced number of comparisons, the statistical power remains high in the face of correction for multiple tests. CONCLUSIONS: Both the source code and the web interface of OrgConv are available for free from the OrgConv website http://www.indiana.edu/~orgconv. Although OrgConv has been developed with main focus on detection of gene conversion between mitochondrial and chloroplast genes, it may also be used for detection of gene conversion between any two distinct groups of homologous sequences. PMID- 20196865 TI - Reflections on the responsible conduct of cancer research. AB - Most cancer researchers regularly practice the responsible conduct of research (RCR) without consciously considering it. As professional scientists, we simply do what we are trained to do. However, as we train a new generation of cancer researchers in our laboratories, we must be vigilant against undue complacency. In an age when misconduct in research is receiving more media attention than ever before, we should periodically take a moment of pause and reflect upon the meaning and practice of responsibly conducting research. Rather than meeting minimum standards in a compliance-driven manner, we should practice forethought and periodically consider how we can improve. We, as leaders in cancer research, must then push our peers to do the same. By embedding RCR into the culture of cancer research through a multilayer approach, including regular assessment at the levels of individual research groups, departmentally, and institutionally, we will become a model discipline in the responsible conduct of research. PMID- 20196864 TI - Somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine tumours, current aspects and new perspectives. AB - Gastroenteropancreatic neuroendocrine tumours (GEP NETs) are rare tumours that present many clinical features.They secrete peptides and neuroamines that cause distinct clinical syndromes, including carcinoid syndrome. However, many are clinically silent until late presentation with mass effects.In 2000 the WHO developed a new classification which gives a better description of the characteristics and biological behaviour of the tumour.Surgical resection is the treatment of first choice for a patient with a GEP NET. In metastatic disease multiple therapeutic approaches are possible. In these cases the goal is to improve quality of life and to extent survival.GEP NETs express somatostatin receptors (SSTRs), which are bound by somatostatin (SST) or its synthetic analogues, although the subtypes and number of SSTRs expressed is very variable.Somatostatin analogues are used frequently to control hormone-related symptoms while their anti-neoplastic activity, even if it has not been widely studied and the regarding data are discordant, seems to result prevalently in tumour stabilisation.A few patients who fail to respond or cease to respond to standard SST analogues treatment seem to have a response to higher doses of these drugs.The use of higher doses of somatostatin analogues or the development of new subtype selective agonists and chimaeric somatostatin analogues, or pan somatostatin will probably improve the clinical management of these patients.This review provides an update on the use of somatostatin analogues in the management of GEP NETs and discusses novel clinical strategies based on SSTR 2 gene transfer therapy. PMID- 20196866 TI - Heel raises versus prefabricated orthoses in the treatment of posterior heel pain associated with calcaneal apophysitis (Sever's Disease): a randomised control trial. AB - BACKGROUND: Posterior Heel pain can present in children of 8 to 14 years, associated with or clinically diagnosed as Sever's disease, or calcaneal apophysitis. Presently, there are no comparative randomised studies evaluating treatment options for posterior heel pain in children with the clinical diagnosis of calcaneal apophysitis or Sever's disease. This study seeks to compare the clinical efficacy of some currently employed treatment options for the relief of disability and pain associated with posterior heel pain in children. METHOD: DESIGN: Factorial 2 x 2 randomised controlled trial with monthly follow-up for 3 months. PARTICIPANTS: Children with clinically diagnosed posterior heel pain possibly associated with calcaneal apophysitis/Sever's disease (n = 124). INTERVENTIONS: Treatment factor 1 will be two types of shoe orthoses: a heel raise or prefabricated orthoses. Both of these interventions are widely available, mutually exclusive treatment approaches that are relatively low in cost. Treatment factor 2 will be a footwear prescription/replacement intervention involving a shoe with a firm heel counter, dual density EVA midsole and rear foot control. The alternate condition in this factor is no footwear prescription/replacement, with the participant wearing their current footwear. OUTCOMES: Oxford Foot and Ankle Questionnaire and the Faces pain scale. DISCUSSION: This will be a randomised trial to compare the efficacy of various treatment options for posterior heel pain in children that may be associated with calcaneal apophysitis also known as Sever's disease. TRIAL REGISTRATION: TRIAL NUMBER: ACTRN12609000696291Ethics Approval Southern Health: HREC Ref: 09271B. PMID- 20196867 TI - A scaling normalization method for differential expression analysis of RNA-seq data. AB - The fine detail provided by sequencing-based transcriptome surveys suggests that RNA-seq is likely to become the platform of choice for interrogating steady state RNA. In order to discover biologically important changes in expression, we show that normalization continues to be an essential step in the analysis. We outline a simple and effective method for performing normalization and show dramatically improved results for inferring differential expression in simulated and publicly available data sets. PMID- 20196868 TI - Polymorphisms in IL-1beta, vitamin D receptor Fok1, and Toll-like receptor 2 are associated with extrapulmonary tuberculosis. AB - BACKGROUND: Human genetic variants may affect tuberculosis susceptibility, but the immunologic correlates of the genetic variants identified are often unclear. METHODS: We conducted a pilot case-control study to identify genetic variants associated with extrapulmonary tuberculosis in patients with previously characterized immune defects: low CD4+ lymphocytes and low unstimulated cytokine production. Two genetic association approaches were used: 1) variants previously associated with tuberculosis risk; 2) single nucleotide polymorphisms (SNPs) in candidate genes involved in tuberculosis pathogenesis. Single locus association tests and multifactor dimensionality reduction (MDR) assessed main effects and multi-locus interactions. RESULTS: There were 24 extrapulmonary tuberculosis cases (18 black), 24 pulmonary tuberculosis controls (19 black) and 57 PPD+ controls (49 black). In approach 1, 22 SNPs and 3 microsatellites were assessed. In single locus association tests, interleukin (IL)-1beta +3953 C/T was associated with extrapulmonary tuberculosis compared to PPD+ controls (P = 0.049). Among the sub-set of patients who were black, genotype frequencies of the vitamin D receptor (VDR) Fok1 A/G SNP were significantly different in extrapulmonary vs. pulmonary TB patients (P = 0.018). In MDR analysis, the toll like receptor (TLR) 2 microsatellite had 76% prediction accuracy for extrapulmonary tuberculosis in blacks (P = 0.002). In approach 2, 613 SNPs in 26 genes were assessed. None were associated with extrapulmonary tuberculosis. CONCLUSIONS: In this pilot study among extrapulmonary tuberculosis patients with well-characterized immune defects, genetic variants in IL-1beta, VDR Fok1, and TLR2 were associated with an increased risk of extrapulmonary disease. Additional studies of the underlying mechanism of these genetic variants are warranted. PMID- 20196870 TI - Asymptomatic Achilles tendon pathology is associated with a central fat distribution in men and a peripheral fat distribution in women: a cross sectional study of 298 individuals. AB - BACKGROUND: Adiposity is a modifiable factor that has been implicated in tendinopathy. As tendon pain reduces physical activity levels and can lead to weight gain, associations between tendon pathology and adiposity must be studied in individuals without tendon pain. Therefore, the purpose of this study was to determine whether fat distribution was associated with asymptomatic Achilles tendon pathology. METHODS: The Achilles tendons of 298 individuals were categorised as normal or pathological using diagnostic ultrasound. Fat distribution was determined using anthropometry (waist circumference, waist hip ratio [WHR]) and dual-energy x-ray absorptiometry. RESULTS: Asymptomatic Achilles tendon pathology was more evident in men (13%) than women (5%) (p = 0.007). Men with tendon pathology were older (50.9 +/- 10.4, 36.3 +/- 11.3, p < 0.001), had greater WHR (0.926 +/- 0.091, 0.875 +/- 0.065, p = 0.039), higher android/gynoid fat mass ratio (0.616 +/- 0.186, 0.519 +/- 0.142, p = 0.014) and higher upper body/lower body fat mass ratio (2.346 +/- 0.630, 2.022 +/- 0.467, p = 0.013). Men older than 40 years with a waist circumference >83 cm had the greatest prevalence of tendon pathology (33%). Women with tendon pathology were older (47.4 +/- 10.0, 36.0 +/- 10.3, p = 0.008), had less total fat (17196 +/- 3173 g, 21626 +/- 7882 g, p = 0.009), trunk fat (7367 +/- 1662 g, 10087 +/- 4152 g, p = 0.003) and android fat (1117 +/- 324 g, 1616 +/- 811 g, p = 0.005). They had lower central/peripheral fat mass ratios (0.711 +/- 0.321 g, 0.922 +/- 0.194 g, p = 0.004) than women with normal tendons. Women with tendon pathology were more often menopausal (63%, 13%, p = 0.002). CONCLUSIONS: Men with Achilles tendon pathology were older and had a central fat distribution. Women with tendon pathology were older and had a peripheral fat distribution. An interaction between age and waist circumference was observed among men. PMID- 20196869 TI - Urokinase-type plasminogen activator and arthritis progression: role in systemic disease with immune complex involvement. AB - INTRODUCTION: Urokinase-type plasminogen activator (u-PA) has been implicated in fibrinolysis, cell migration, latent cytokine activation, cell activation, T-cell activation, and tissue remodeling, all of which are involved in the development of rheumatoid arthritis. Previously, u-PA has been reported to play a protective role in monoarticular arthritis models involving mBSA as the antigen, but a deleterious role in the systemic polyarticular collagen-induced arthritis (CIA) model. The aim of the current study is to determine how u-PA might be acting in systemic arthritis models. METHODS: The CIA model and bone marrow chimeras were used to determine the cellular source of u-PA required for the arthritis development. Gene expression of inflammatory and destructive mediators was measured in joint tissue by quantitiative PCR and protein levels by ELISA. The requirement for u-PA in the type II collagen mAb-induced arthritis (CAIA) and K/BxN serum transfer arthritis models was determined using u-PA(-/-) mice. Neutrophilia was induced in the peritoneal cavity using either ovalbumin/anti ovalbumin or the complement component C5a. RESULTS: u-PA from a bone marrow derived cell was required for the full development of CIA. The disease in u-PA(-/ ) mice reconstituted with bone marrow from C57BL/6 mice was indistinguishable from that in C57BL/6 mice, in terms of clinical score, histologic features, and protein and gene expression of key mediators. u-PA(-/-) mice were resistant to both CAIA and K/BxN serum transfer arthritis development. u-PA(-/-) mice developed a reduced neutrophilia and chemokine production in the peritoneal cavity following ovalbumin/anti-ovalbumin injection; in contrast, the peritoneal neutrophilia in response to C5a was u-PA independent. CONCLUSIONS: u-PA is required for the full development of systemic arthritis models involving immune complex formation and deposition. The cellular source of u-PA required for CIA is bone marrow derived and likely to be of myeloid origin. For immune complex mediated peritonitis, and perhaps some other inflammatory responses, it is suggested that the u-PA involvement may be upstream of C5a signaling. PMID- 20196871 TI - PARP-1 Val762Ala polymorphism is associated with reduced risk of non-Hodgkin lymphoma in Korean males. AB - BACKGROUND: Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme that plays a role in DNA repair, differentiation, proliferation, and cell death. The polymorphisms of PARP-1 have been associated with the risk of various carcinomas, including breast, lung, and prostate. We investigated whether PARP-1 polymorphisms are associated with the risk of non-Hodgkin lymphoma (NHL). METHODS: Subjects from a Korean population consisting of 573 NHL patients and 721 controls were genotyped for 5 PARP-1 polymorphisms (Asp81Asp, Ala284Ala, Lys352Lys, IVS13+118A>G, and Val762Ala) using High Resolution Melting polymerase chain reaction (PCR) and an automatic sequencer. RESULTS: None of the 5 polymorphisms were associated with overall risk for NHL. However, the Val762Ala polymorphism was associated with reduced risk for NHL in males [odds ratio (OR), 0.62; 95% confidence interval (CI), 0.41-0.93 for CC genotype and OR, 0.84; 95% CI, 0.60-1.16 for TC genotype] with a trend toward a gene dose effect (p for trend, 0.02). The Asp81Asp (p for trend, 0.04) and Lys352Lys (p for trend, 0.03) polymorphisms revealed the same trend. In an association study of PARP-1 haplotypes, the haplotype-ACAAC was associated with decreased risk of NHL in males (OR, 0.75; 95% CI, 0.59-0.94). CONCLUSION: The present data suggest that Val762Ala, Asp81Asp, and Lys352Lys polymorphisms and the haplotype-ACAAC in PARP 1 are associated with reduced risk of NHL in Korean males. PMID- 20196872 TI - Highly pathogenic avian influenza A virus H5N1 NS1 protein induces caspase dependent apoptosis in human alveolar basal epithelial cells. AB - BACKGROUND: It is widely considered that the multifunctional NS1 protein of influenza A viruses contributes significantly disease pathogenesis by modulating a number of virus and host-cell processes, but it is highly controversial whether this non-structural protein is a proapoptotic or antiapoptotic factor in infected cells. RESULTS: NS1 protein of influenza A/chicken/Jilin/2003 virus, a highly pathogenic H5N1 strain, could induce apoptosis in the carcinomic human alveolar basal epithelial cells (A549) by electron microscopic and flow cytometric analyses. NS1 protein-triggered apoptosis in A549 cells is via caspase-dependent pathway. CONCLUSIONS: Influenza A virus NS1 protein serves as a strong inducer of apoptosis in infected human respiratory epithelial cells and plays a critical role in disease pathogenesis. PMID- 20196873 TI - Development of O-antigen gene cluster-specific PCRs for rapid typing six epidemic serogroups of Leptospira in China. AB - BACKGROUND: Leptospira is the causative agent of leptospirosis. The O-antigen is the distal part of the lipopolysaccharide, which is a key component of outer membrane of Gram-negative bacteria and confers serological specificity. The epidemiology and clinical characteristics of leptospirosis are relative to the serology based taxonomic unit. Identification of Leptospira strains by serotyping is laborious and has several drawbacks. RESULTS: In this study, the O-antigen gene clusters of four epidemic Leptospira serogroups (serogroup Canicola, Autumnalis, Grippotyphosa and Hebdomadis) in China were sequenced and all genes were predicted in silico. Adding published sequences of two serogroups, Icterohaemorrhagiae (strain Lai and Fiocruz L1-130) and Sejroe (strain JB197 and L550), we identified six O-antigen-specific genes for six epidemic serogroups in China. PCR assays using these genes were developed and tested on 75 reference strains and 40 clinical isolates. CONCLUSION: The results show that the PCR-based assays can be reliable and alternative means for rapid typing of these six serogroups of Leptospira. PMID- 20196875 TI - Mycosis fungoides bullosa: a case report and review of the literature. AB - INTRODUCTION: Mycosis fungoides, the most common type of cutaneous T-cell lymphoma, can manifest in a variety of clinical and histological forms. Bulla formation is an uncommon finding in mycosis fungoides and only approximately 20 cases have been reported in the literature. CASE PRESENTATION: We present a case of rapidly progressive mycosis fungoides in a 68-year-old Caucasian man who initially presented with erythematous plaques characterised by blister formation. CONCLUSION: Although mycosis fungoides bullosa is extremely rare, it has to be regarded as an important clinical subtype of cutaneous T-cell lymphoma. Mycosis fungoides bullosa represents a particularly aggressive form of mycosis fungoides and is associated with a poor prognosis. The rapid disease progression in our patient confirms bulla formation as an adverse prognostic sign in cutaneous T cell lymphoma. PMID- 20196874 TI - Immune responses of Helicoverpa armigera to different kinds of pathogens. AB - BACKGROUND: Insects react against pathogens through innate immunity. The cotton bollworm Helicoverpa armigera (H. armigera) is an important defoliator and an extremely destructive pest insect of many crops. The elucidation of the mechanism of the immune response of H. armigera to various pathogens can provide a theoretical basis for new approaches to biologically control this pest. RESULTS: Four kinds of pathogens Bacillus thuringiensis, Klebsiella pneumoniae, Candida albicans, and Autographa californica multiple nucleocapsid nucleopolyhedrovirus harbored green fluorescence protein and polyhedron (AcMNPV-GFP) were used to challenge the insect. The cellular and humoral immune responses to the pathogens were analyzed in the challenged H. armigera. The results show that in the five kinds of haemocytes, only granulocytes phagocytized the Gram-negative and Gram positive bacteria and fungi. All haemocytes can be infected by AcMNPV. Fourteen immune-related genes including pattern recognition receptors (PRRs) such as peptidoglycan recognition proteins (HaPGRP and HaPGRP C) and Gram-Negative Bacteria-Binding Protein (HaGNBP), and antimicrobial peptides (AMPs) such as cecropin-1, 2 and 3 (HaCec-1, 2 and 3), lysozyme (HaLys), attacin (HaAtt), gallerimycin-like (HaGall), gloverin-like (HaGlo), moricin-like (HaMor), cobatoxin-like (HaCob), galiomicin-like (HaGali), and immune inducible protein (HaIip) appeared in different expression profiles to different pathogen infections. The transcripts of 13 immune related genes (except HaPGRPC) are obviously up-regulated by Gram-positive bacteria. HaCec-1 and 3, HaMor, HaAtt, HaLys, HaIip, HaPGRP and HaGNBP are greatly up-regulated after fungal infection. HaGNBP, HaCec-2, HaGall, HaGlo, HaMor, HaCob, HaGali obviously increased in Gram negative bacterial infection. Only five genes, HaGNBP, HaCec-1, HaGali, HaGlo, and HaLys, are weakly up-regulated after viral infection. The AMP transcripts had higher expression levels than the PRR transcripts after the microbial challenge. CONCLUSIONS: These data suggest that the granulocytes are the major phagocytes in H. armigera. All haemocytes can be infected by AcMNPV. The transcripts of 14 immune related genes have different expression patterns in H. armigera infected by different pathogens, which means that the immune-related genes may have different functions against various kinds of pathogens. PMID- 20196876 TI - Prognostic value of the pulmonary dead-space fraction during the early and intermediate phases of acute respiratory distress syndrome. AB - BACKGROUND: Little is known about the alveolar dead-space fraction after the first week of acute respiratory distress syndrome (ARDS). We measured the dead space fraction in the early phase (first week) and the intermediate phase (second week) of ARDS, and evaluated the association of dead-space fraction with mortality. METHODS: We prospectively measured dead-space fraction and other variables in 80 intubated patients during the early phase of ARDS and in 49 patients during the intermediate phase. We used multiple logistic regression analysis to evaluate data. The primary outcome was in-hospital mortality. RESULTS: In the early and intermediate phases the dead-space fraction was higher in patients who died than among those who survived (dead-space fraction 0.64 +/- 0.09 vs 0.53 +/- 0.11, P < .001, and 0.62 +/- 0.09 vs 0.50 +/- 0.10, P < .001, respectively). In both the early and intermediate phases the dead-space fraction was independently associated with a greater risk of death. For every dead-space fraction increase of 0.05 the odds of death increased by 59% in the early phase (odds ratio 1.59, 95% confidence interval 1.18-2.16, P = .003) and by 186% in the intermediate phase (odds ratio 2.87, 95% confidence interval 1.36-6.04, P = .005). Age and Sequential Organ Failure Assessment score were also independently associated with a greater risk of death in both phases. CONCLUSIONS: Increased alveolar dead-space fraction in the early and intermediate phases of ARDS is associated with a greater risk of death. PMID- 20196877 TI - End-tidal and arterial carbon dioxide measurements correlate across all levels of physiologic dead space. AB - BACKGROUND: End-tidal carbon dioxide (P(ETCO(2))) is a surrogate, noninvasive measurement of arterial carbon dioxide (P(aCO(2))), but the clinical applicability of P(ETCO(2)) in the intensive care unit remains unclear. Available research on the relationship between P(ETCO(2)) and P(aCO(2)) has not taken a detailed assessment of physiologic dead space into consideration. We hypothesized that P(ETCO(2)) would reliably predict P(aCO(2)) across all levels of physiologic dead space, provided that the expected P(ETCO(2))-P(aCO(2)) difference is considered. METHODS: Fifty-six mechanically ventilated pediatric patients (0-17 y old, mean weight 19.5 +/- 24.5 kg) were monitored with volumetric capnography. For every arterial blood gas measurement during routine care, we measured P(ETCO(2)) and calculated the ratio of dead space to tidal volume (V(D)/V(T)). We assessed the P(ETCO(2))-P(aCO(2)) relationship with Pearson's correlation coefficient, in 4 V(D)/V(T) ranges. RESULTS: V(D)/V(T) was 0.7 for 54 measurements (11%). The correlation coefficients between P(ETCO(2)) and P(aCO(2)) were 0.95 (mean difference 0.3 +/- 2.1 mm Hg) for V(D)/V(T) 0.7. CONCLUSIONS: There were strong correlations between P(ETCO(2)) and P(aCO(2)) in all the V(D)/V(T) ranges. The P(ETCO(2))-P(aCO(2)) difference increased predictably with increasing V(D)/V(T). PMID- 20196878 TI - Lateral-horizontal patient position and horizontal orientation of the endotracheal tube to prevent aspiration in adult surgical intensive care unit patients: a feasibility study. AB - BACKGROUND: Recent data suggest that during mechanical ventilation the lateral horizontal patient position (in which the endotracheal tube is horizontal) decreases the risk of ventilator-associated pneumonia, compared to the recommended semi-recumbent position (in which the endotracheal tube slopes downward into the trachea). We tested the feasibility of the lateral-horizontal patient position, measured the incidence of aspiration of gastric contents, and watched for any adverse effects related to the lateral-horizontal position. METHODS: Ten adult intensive care unit patients were ventilated for 64 hours in the standard semi-recumbent position, and ten for 12-24 hours in the lateral horizontal position. Tracheal secretions were collected every 8 hours and every 4 hours, respectively, and tested for pepsin, which is a marker of gastric contents. We also recorded clinical, physiologic, and outcome variables. RESULTS: The patients remained stable during ventilation in the lateral-horizontal position, and no adverse events occurred. Pepsin was detected in the trachea of 7 semi-recumbent patients and in five of the lateral-horizontal patients (P = .32). The number of ventilator-free days was 8 days (range 0-21 days) in the semi recumbent patients, versus 24 days (range 12-25 days) in the lateral-horizontal patients (P = .04). CONCLUSIONS: Implementing the lateral-horizontal position for 12-24 hours in adult intubated intensive care unit patients is feasible, and our patients had no adverse events. The incidence of aspiration of gastric contents in the lateral-horizontal position seems to be similar to that in the semi recumbent position. PMID- 20196879 TI - Quality of spirometry performed by 13,599 participants in the World Trade Center Worker and Volunteer Medical Screening Program. AB - OBJECTIVE: To determine the ability of spirometry technicians in the World Trade Center Worker and Volunteer Medical Screening Program to meet American Thoracic Society spirometry quality goals. METHODS: Spirometry technicians were trained centrally and performed spirometry sessions at 6 sites in the greater New York City area. We reviewed and graded the spirometry results for quality every month. RESULTS: About 80% (range 70-88%) of the spirometry sessions met the American Thoracic Society spirometry goals. In general, the spirometry technicians with the most experience were more successful in meeting the quality goals. Participant characteristics explained very little of the quality variability. CONCLUSIONS: The overall spirometry quality in this multicenter program was very good. Efforts to improve spirometry quality should focus on the performance of individual spirometry technicians. PMID- 20196880 TI - Frequency and causes of combined obstruction and restriction identified in pulmonary function tests in adults. AB - BACKGROUND: The frequency of combined obstruction and restriction identified in pulmonary function tests has not been well described. Moreover, although the causes of combined-obstruction-and-restriction patterns are known, the frequency of the various etiologies has received little attention. METHODS: We retrospectively reviewed medical records and surveyed pulmonologists. RESULTS: 43,212 PFT sessions were evaluated, which yielded 130 patients who satisfied our criteria for spirometry evidence of combined obstruction and restriction. Their demographic features were: mean +/- SD age 54 +/- 14 y, 51% male, mean +/- SD body mass index 28.8 +/- 6.7 kg/m(2), mean +/- SD height 174 +/- 9 cm (men) and 162 +/- 7 cm (women). The causes of combined obstruction and restriction were classified as either a pulmonary parenchymal disorder (Group A, n = 49, 38%) or a combination of pulmonary parenchymal and non-pulmonary diseases (Group B, n = 63, 48%). In 18 patients (14%) no clear etiology of combined obstruction and restriction could be determined. The most common pulmonary disease was chronic obstructive pulmonary disease (45/130, 35%), and the most common non-parenchymal disease was congestive heart failure (27/130, 21%). We electronically sent a survey to 55 pulmonary physicians, of whom 30 (55%) responded. The respondents estimated that combined obstruction and restriction occurs in approximately 20% of all the pulmonary function tests performed in their practices and that pulmonary parenchymal diseases were responsible for 35% of all instances of combined obstruction and restriction. CONCLUSIONS: Combined obstruction and restriction occurs infrequently and is more commonly caused by a combination of pulmonary parenchymal and non-pulmonary disorders. Pulmonologists' impressions regarding the frequency and causes are generally discordant with the observed frequencies. PMID- 20196881 TI - Battery performance of 4 intensive care ventilator models. AB - BACKGROUND: Hospital electrical power failure represents an important challenge in the intensive care unit. Despite the presence of backup generators, total electrical power failure may still occur. Life-support equipment should have a reliable internal battery to ensure patient safety. We tested the duration of operation of the internal battery of 4 intensive care ventilators. METHODS: In our laboratory we evaluated one each of 4 ventilator models available in our facility (Evita XL, Puritan Bennett 840, Avea, and Servo 300), with volume control and pressure-control ventilation, and with positive end-expiratory pressure (PEEP) of zero and 20 cm H(2)O. We then randomly selected and tested 6 Evita XL and 4 Servo 300 ventilators from our inventory to determine the variability of internal battery duration among ventilators of the same model. The ventilator settings were identical to the previous tests, other than fraction of inspired oxygen, which was set at 0.6, and PEEP was 5 cm H(2)O. RESULTS: The battery-duration range of the tested ventilators was 20.5-170.5 min, and the mean +/- SD battery duration was 80.4 +/- 49.3 min. Changes in breath type and PEEP did not significantly impact battery duration. Among the ventilators of the same model, the battery-duration range was 5-69 min and the mean +/- SD battery duration was 28.9 +/- 21.4 min. Use of a compressor significantly shortened battery duration. There was no correlation between battery duration and battery age (r = -0.263). CONCLUSIONS: The duration of ventilator operation on internal battery ranged widely among the tested devices. Clinicians need to be aware of these differences in the event of power failure. PMID- 20196882 TI - Knowledge of alpha-1 antitrypsin deficiency among internal medicine house officers and respiratory therapists: results of a survey. AB - BACKGROUND: Alpha-1 antitrypsin deficiency is a common genetic condition that predisposes to emphysema and liver disease. Alpha-1 antitrypsin deficiency is under-recognized, so affected individuals often experience long delays in diagnosis and visits to multiple physicians before correct diagnosis. Reasoning that inadequate knowledge about alpha-1 antitrypsin deficiency could contribute to this under-recognition, we designed this study to evaluate internal medicine house officers' and respiratory therapists' (RTs) knowledge of alpha-1 antitrypsin deficiency. METHODS: We evaluated knowledge of alpha-1 antitrypsin deficiency with a Web-based test containing 30 multiple-choice questions. Invitations to take the test were sent via e-mail to all internal medicine house officers and RTs at The Cleveland Clinic main campus hospital. We assessed test scores by profession, years of training/experience, and self-assessed knowledge of alpha-1 antitrypsin deficiency. RESULTS: Of 332 invitees, 202 (61%) responded, of whom 165 (50%) provided complete responses (99 RTs, 66 physicians). The mean scores (percent of correct answers) were 54% and 52% for physicians and RTs, respectively (P = .25). The scores did not differ among the physicians when examined by subspecialty (pulmonary/critical care vs other) or post-graduate education level (P = .94). RTs who had graduated from a 4-year respiratory therapy program had a higher mean score than those who had graduated from a 2 year program (56% vs 50%, P = .02). Respondents' whose self-assessment of their knowledge about alpha-1 antitrypsin deficiency was "somewhat knowledgeable" had higher test scores than any other self-assessed knowledge level, regardless of profession. CONCLUSIONS: These results indicate a generally low level of knowledge about alpha-1 antitrypsin deficiency among physicians and RTs. Causes of under-recognition of alpha-1 antitrypsin deficiency, including the possibility of poor knowledge as a contributor, warrant further study. PMID- 20196883 TI - Risk factors for extubation failure in infants with severe acute bronchiolitis. AB - OBJECTIVE: To evaluate demographic characteristics, mechanical-ventilation parameters, blood gas values, and ventilatory indexes as predictors of extubation failure in infants with severe acute bronchiolitis. METHODS: We conducted a prospective observational study from March 2004 to September 2005 with consecutive infants (ages 1-12 months) with severe acute bronchiolitis and considered ready to be extubated. We calculated mean airway pressure and oxygenation index. Before extubation we measured respiratory rate, tidal volume, rapid shallow breathing index, maximal inspiratory pressure, and load/force balance. Arterial blood gases were measured 1 hour before extubation. Extubation was classified as a failure if the infant needed re-intubation within 48 hours. RESULTS: Extubation failure occurred in 6 (15%) of the 40 extubated infants. The respective median (and interquartile range) age, weight, and days of mechanical ventilation for the extubation-failure and extubation-success groups were: age 5 (3-8) months versus 4 (4-6) months (P = .87), weight 4 (3-5) kg versus 6 (5-7) kg (P < .001), and mechanical ventilation days 8 (6-23) d versus 6 (5-12) d (P = .52). There were no significant differences in arterial blood gas values or mechanical-ventilation parameters between the extubation-success and extubation failure groups. There were statistically significant differences between the extubation-failure and extubation-success groups for 2 risk factors, weight or= 5 and rapid shallow breathing index >or= 6.7. CONCLUSIONS: In infants with severe acute bronchiolitis the extubation process is complex because of the combined features of this disease. Pediatric studies have not definitely determined predictive factors, weaning protocols, or ventilatory predictive indexes of extubation failure risk in infants with severe acute bronchiolitis. Lower minute volume and lower maximal inspiratory pressure had large areas under the curve of the receiver operating characteristic for extubation-failure risk in infants with severe acute bronchiolitis. PMID- 20196884 TI - Correlation between the %MinVol setting and work of breathing during adaptive support ventilation in patients with respiratory failure. AB - BACKGROUND: Adaptive support ventilation (ASV) is a new mode of mechanical ventilation that seeks an optimal breathing pattern based on the minimum work of breathing (WOB) principle. The operator's manual for the ventilators that provide ASV recommends that the %MinVol setting be started at 100% (the 100%MinVol setting), but it is unclear whether that setting reduces WOB in patients with respiratory failure. METHODS: We studied 22 hemodynamically stable patients with respiratory failure who were on pressure-support ventilation. We switched the ventilation mode to ASV and started at the 100%MinVol setting. We then increased the %MinVol setting by 10% every 5 min until 1-3 mandatory breaths per min appeared, and called that setting the ASV target point. We then tested 2 additional %MinVol settings: 20% below the ASV target point (target-point-20%), and 20% above the ASV target point (target-point+20%). We tested each %MinVol setting for 10 min. At the end of each 10-min period we measured respiratory variables, pressure-time product (PTP), and airway occlusion pressure at 0.1 s after the onset of inspiratory flow (P(0.1)). RESULTS: In 18 patients (82%), at the 100%MinVol setting, the actual minute volume (V(E)) was greater than the target V(E). At the ASV target point the mean +/- SD %MinVol setting was 165 +/- 54% and was associated with a 40% decrease in PTP and P(0.1), but V(E) did not change. At target-point+20%, V(E) increased slightly, primarily due to a small increase in tidal volume, and PTP and P(0.1) further decreased. At target-point 20%, PTP and P(0.1) were similar to those at the 100%MinVol setting. At the ASV target point the 6 patients with chronic obstructive pulmonary disease had a lower mean %MinVol setting (125 +/- 23%) than the 16 patients who did not have chronic obstructive pulmonary disease (180 +/- 55%). CONCLUSIONS: The 100%MinVol setting was frequently not associated with lower WOB in patients with respiratory failure. The %MinVol setting that significantly reduced WOB could be detected by increasing the %MinVol setting until a few mandatory breaths began to appear, and was on average 165% of the MinVol setting. PMID- 20196885 TI - Respiratory distress associated with inadequate mechanical ventilator flow response in a neonate with congenital diaphragmatic hernia. AB - The incidence of congenital diaphragmatic hernia has been reported as 0.17-0.66 per 1,000 births. Despite advances in neonatal intensive care, congenital diaphragmatic hernia is associated with high mortality and morbidity. We report a neonate who was born with a left congenital diaphragmatic hernia and underwent surgical repair. The lack of ventilator flow response and flow cycling was identified via interpretation of the ventilator graphic and clinical assessment. Presumably, the ventilator failed to respond to the patient's peak inspiratory flow demand, despite the clinician's setting the highest peak flow available. A time-cycled pressure-limited mode with adjustable peak flow rate was the only option that met the infant's flow requirement, and alleviated the respiratory distress. This clinical finding follows bench research that raises the concern that so called "cradle-to-grave" ventilators may not optimally support all neonates. PMID- 20196886 TI - Abdominal tuberculosis: an unusual cause of abdominal pain. PMID- 20196887 TI - Measuring dead space: does it really matter? or, What are we waiting for? PMID- 20196888 TI - What is the best position for preventing ventilator-associated pneumonia? PMID- 20196889 TI - Comprehensive quality control for pulmonary function testing: it's time to face the music. PMID- 20196890 TI - The effects of branched-chain amino acid interactions on growth performance, blood metabolites, enzyme kinetics and transcriptomics in weaned pigs. AB - The impact of excess dietary leucine (Leu) was studied in two growth assays with pigs (8-25 kg). In each trial, forty-eight pigs were allotted to one of six dietary groups. The dietary Leu supply increased from treatment L100 to L200 (three increments). To guarantee that interactions between the branched-chain amino acids (BCAA) were not cushioned either surpluses of isoleucine (Ile, expt 1) or valine (Val; expt 2) were avoided. In the fifth treatment, the effects of a simultaneous excess of Leu and Val (expt 1), or of Leu and Ile (expt 2) were investigated. The sixth treatment was a positive control. An increase in dietary Leu decreased growth performance, and increased plasma Leu and serum alpha-keto isocaproate levels in a linear, dose-dependent manner. Levels of plasma Ile and Val, and of serum alpha-keto-beta-methylvalerate and alpha-keto-isovalerate, indicated increased catabolism. Linear increases in the activity of basal branched-chain alpha-keto acid dehydrogenase in the liver confirmed these findings. No major alterations occurred in the mRNA of branched-chain amino acid catabolism genes. In liver tissue from expt 2, however, the mRNA levels of growth hormone receptor, insulin-like growth factor acid labile subunit and insulin-like growth factor 1 decreased significantly with increasing dietary Leu. In conclusion, excess dietary Leu increased the catabolism of BCAA mainly through posttranscriptional mechanisms. The impact of excess Leu on the growth hormone- insulin-like growth factor-1 axis requires further investigation. PMID- 20196891 TI - Support of drug therapy using functional foods and dietary supplements: focus on statin therapy. AB - Functional foods and dietary supplements might have a role in supporting drug therapy. These products may (1) have an additive effect to the effect that a drug has in reducing risk factors associated with certain conditions, (2) contribute to improve risk factors associated with the condition, other than the risk factor that the drug is dealing with, or (3) reduce drug-associated side effects, for example, by restoring depleted compounds or by reducing the necessary dose of the drug. Possible advantages compared with a multidrug therapy are lower drug costs, fewer side effects and increased adherence. In the present review we have focused on the support of statin therapy using functional foods or dietary supplements containing plant sterols and/or stanols, soluble dietary fibre, n-3 PUFA or coenzyme Q10. We conclude that there is substantial evidence that adding plant sterols and/or stanols to statin therapy further reduces total and LDL cholesterol by roughly 6 and 10 %, respectively. Adding n-3 PUFA to statin therapy leads to a significant reduction in plasma TAG of at least 15 %. Data are insufficient and not conclusive to recommend the use of soluble fibre or coenzyme Q10 in patients on statin therapy and more randomised controlled trials towards these combinations are warranted. Aside from the possible beneficial effects from functional foods or dietary supplements on drug therapy, it is important to examine possible (negative) effects from the combination in the long term, for example, in post-marketing surveillance studies. Moreover, it is important to monitor whether the functional foods and dietary supplements are taken in the recommended amounts to induce significant effects. PMID- 20196892 TI - Oral sensitivity to fatty acids, food consumption and BMI in human subjects. AB - Fatty acids are the chemical moieties that are thought to stimulate oral nutrient sensors, which detect the fat content of foods. In animals, oral hypersensitivity to fatty acids is associated with decreased fat intake and body weight. The aims of the present study were to investigate oral fatty acid sensitivity, food selection and BMI in human subjects. The study included two parts; study 1 established in thirty-one subjects (29 (sem 1.4) years, 22.8 (sem 0.5) kg/m2) taste thresholds using 3-AFC (3-Alternate Forced Choice Methodology) for oleic, linoleic and lauric acids, and quantified oral lipase activity. During study 2, fifty-four subjects (20 (sem 0.3) years, 21.5 (sem 0.4) kg/m2) were screened for oral fatty acid sensitivity using oleic acid (1.4 mm), and they were defined as hypo- or hypersensitive via triplicate triangle tests. Habitual energy and macronutrient intakes were quantified from 2 d diet records, and BMI was calculated from height and weight. Subjects also completed a fat ranking task using custard containing varying amounts (0, 2, 6 and 10 %) of fat. Study 1 reported median lipase activity as 2 mumol fatty acids/min per l, and detection thresholds for oleic, linoleic and lauric acids were 2.2 (sem 0.1), 1.5 (sem 0.1) and 2.6 (sem 0.3) mm. Study 2 identified twelve hypersensitive subjects, and hypersensitivity was associated with lower energy and fat intakes, lower BMI (P < 0.05) and an increased ability to rank custards based on fat content (P < 0.05). Sensitivity to oleic acid was correlated to performance in the fat ranking task (r 0.4, P < 0.05). These data suggest that oral fatty acid hypersensitivity is associated with lower energy and fat intakes and BMI, and it may serve as a factor that influences fat consumption in human subjects. PMID- 20196893 TI - Genetic architecture of rainbow trout survival from egg to adult. AB - Survival from birth to a reproductive adult is a challenge that only robust individuals resistant to a variety of mortality factors will overcome. To assess whether survival traits share genetic architecture throughout the life cycle, we estimated genetic correlations for survival within fingerling stage, and across egg, fingerling and grow-out stages in farmed rainbow trout. Genetic parameters of survival at three life cycle stages were estimated for 249 166 individuals originating from ten year classes of a pedigreed population. Despite being an important fitness component, survival traits harboured significant but modest amount of genetic variation (h2=0.07-0.27). Weak associations between survival during egg-fry and fingerling periods, between early and late fingerling periods (rG=0.30) and generally low genetic correlations between fingerling and grow-out survival (mean rG=0.06) suggested that life-stage specific survival traits are best regarded as separate traits. However, in the sub-set of data with detailed time of death records, positive genetic correlations between early and late fingerling survival (rG=0.89) showed that during certain years the best genotypes in the early period were also among the best in the late period. That survival across fingerling period can be genetically the same, trait was indicated also by only slightly higher heritability (h2=0.15) estimated with the survival analysis of time to death during fingerling period compared to the analysis treating fingerling survival as a binary character (h2=0.11). The results imply that (1) inherited resistance against unknown mortality factors exists, but (2) ranking of genotypes changes across life stages. PMID- 20196894 TI - An optimal strategy for functional mapping of dynamic trait loci. AB - As an emerging powerful approach for mapping quantitative trait loci (QTLs) responsible for dynamic traits, functional mapping models the time-dependent mean vector with biologically meaningful equations and are likely to generate biologically relevant and interpretable results. Given the autocorrelation nature of a dynamic trait, functional mapping needs the implementation of the models for the structure of the covariance matrix. In this article, we have provided a comprehensive set of approaches for modelling the covariance structure and incorporated each of these approaches into the framework of functional mapping. The Bayesian information criterion (BIC) values are used as a model selection criterion to choose the optimal combination of the submodels for the mean vector and covariance structure. In an example for leaf age growth from a rice molecular genetic project, the best submodel combination was found between the Gaussian model for the correlation structure, power equation of order 1 for the variance and the power curve for the mean vector. Under this combination, several significant QTLs for leaf age growth trajectories were detected on different chromosomes. Our model can be well used to study the genetic architecture of dynamic traits of agricultural values. PMID- 20196895 TI - Composite interval mapping to identify quantitative trait loci for point-mass mixture phenotypes. AB - Increasingly researchers are conducting quantitative trait locus (QTL) mapping in metabolomics and proteomics studies. These data often are distributed as a point mass mixture, consisting of a spike at zero in combination with continuous non negative measurements. Composite interval mapping (CIM) is a common method used to map QTL that has been developed only for normally distributed or binary data. Here we propose a two-part CIM method for identifying QTLs when the phenotype is distributed as a point-mass mixture. We compare our new method with existing normal and binary CIM methods through an analysis of metabolomics data from Arabidopsis thaliana. We then conduct a simulation study to further understand the power and error rate of our two-part CIM method relative to normal and binary CIM methods. Our results show that the two-part CIM has greater power and a lower false positive rate than the other methods when a continuous phenotype is measured with many zero observations. PMID- 20196896 TI - Specific IgG activity against diarrheagenic bacteria in bovine immune milk and effect of pH on its antigen-binding activity upon heating. AB - Bovine colostrum and milk antibodies of calving and lactating cows immunized with a multivalent vaccine consisting of whole cells of three different species of pathogenic bacteria including four strains of enterotoxigenic Escherischia coli, five strains of enteropathogenic Esch. coli, three strains of enteroinvasive Esch. coli, two strains of Samonella typhi, and one strain each of Shigellia dysenteriae, Sh. sonnei and Sh. flexneri were generated, respectively. A significantly elevated activity and titre of specific IgG from bovine immune colostrum were seen for only 5 days after calving of immunized cows, however, the levels of specific IgG could be obtained continuously from the milk of immunized lactating cows until the 11th week of the entire experiment period. Subsequently, we observed that the high specific IgG activity in immune milk was relatively stable under pH 5.0-7.0 at 37 degrees C. Of importance, we identified that the specific IgG preserved its biological function for high antigen-binding activity at pH 5.5-6.5 for 30 min of heat treatment at 70 degrees C and for 350 s at 72 degrees C. Our findings suggest that the specific IgG from milk antibodies of immunized lactating cows may be used as an abundant source of hyper-immune products for prevention of multibacteria-induced diarrhea, however, the effect of pH on its antigen-binding activity upon heating should be carefully considered and designed. PMID- 20196897 TI - The influence of milk composition on pH and calcium activity measured in situ during heat treatment of reconstituted skim milk. AB - The pH and calcium activity of reconstituted skim milk solutions (9-21% w/w milk solids non-fat) on heating and after cooling were studied as a function of milk pH prior to heating (pH 6.2-7.2 at 25 degrees C) and added calcium complexing agents (phosphate or EDTA). The pH decreased as the temperature was raised from 25 to 90 degrees C and the magnitude of the pH decrease was greater with increase in initial pH at 25 degrees C before heating or milk concentration. The pH decrease on heating from 25 to 90 degrees C in skim milk solutions with added calcium complexing agents was lower than that of milk without the addition of these salts. The calcium activity decreased on heating from 25 to 60 degrees C. The magnitude of the change decreased with increase in initial pH at 25 degrees C before heating and milk concentration. The decrease in calcium activity on heating from 25 to 60 degrees C for skim milk solutions with added calcium complexing agents was lower than that of milk solutions without the addition of calcium complexing agents. The changes in pH and calcium activity on heating milk were largely reversible after cooling the milk. The results suggested that the pH and calcium activity at high temperatures are a function of the milk composition. Knowledge of the initial pH prior to heating alone is not sufficient for predicting the changes that occur during heating. PMID- 20196898 TI - Effect of forage:concentrate ratio on the quality of ewe's milk, especially on milk fat globules characteristics and fatty acids composition. AB - The aim of this study was to evaluate the milk quality of Massese ewes receiving diets with different forage:concentrate ratios (FC ratio), specially on milk fat globules characteristics and fatty acids composition. The diet is one of the main environmental factors that influence the lipidic content of milk. A trial was carried out on twenty ewes, which had been subdivided into two homogeneous groups and kept indoors at 25 days post partum. The experiment lasted 60 days, from 40 to 100 days post partum and the animals were fed two diets that differed in terms of the FC ratio: 60:40 and 40:60, as fed. The results obtained in this study showed that a greater proportion of forage, compared with an higher percentage of concentrate, led to an increase in the percentage of fat (+8.66%) and to a decrease in the percentage of milk fat globules with a size between 2 and 5 microm (-17.32%). However, the average diameter was not affected. There was also a decrease in the percentages of some medium chain fatty acids (C12:0, C14:0; 14.89% and -4.03 respectively) and an increase in mono and polyunsaturated ones such as trans11-C18:1 (+31.71%), total CLA (+22%), EPA (+18.18%) and DHA (+66.67%). In conclusion, a greater proportion of forage seem to improve the milk fatty acid profile by the increase of some fatty acid identified has being beneficial for human health. PMID- 20196899 TI - Improving the fatty acid profile of dairy cow milk by combining grazing with feeding of total mixed ration. AB - Grazing cows could produce milk with a higher proportion of polyunsaturated fatty acids, which is beneficial to human health, compared with non-grazing cows, though grazing alone could compromise milk production. Under oceanic climate conditions, a study involving 15 dairy cows, fed total mixed ration (TMR) ad libitum in combination with different grazing times of 12 h (TMR12), 6 h (TMR06) and zero grazing time (TMR00) with the aim to evaluate different strategies on the fatty acids profile of milk and milk production. No differences were seen between the treatments with respect to milk yield (34.4+/-6.3 kg/d) or milk protein content (30.4+/-1.8 g/kg). The milk produced by the TMR12 cows had less total fat (36.2 vs. 38.2 g/kg) and saturated fatty acid (FA, 69.39 vs. 71.44 g/100 g FA) than that produced by the TMR00 cows. The concentration of vaccenic acid in the TMR06 and TMR12 milk was twice that of the TMR00 milk (4.22, 4.09 and 2.26 g/100 g FA respectively). Linear increases in conjugated linoleic (CLA) and linolenic acids were observed with increasing grazing time. Pasture was an important source of FA especially C18:3 for TMR06 and TMR12 cows. Under oceanic climatic conditions, the grazing of dairy cows as a complement to feeding with TMR can improve the FA profile of milk and increase its CLA content. PMID- 20196900 TI - Cheese liking and consumer willingness to pay as affected by information about organic production. AB - The present study aimed to assess the effect of information about organic production on Pecorino cheese liking and consumer willingness to pay. Mean scores of perceived liking were similar for organic cheese (OC) and conventional cheese (CC). Expected liking scores were higher for OC than for CC (P<0.001). For OC the expected liking was significantly higher (P<0.001) than the perceived liking expressed in blind conditions (negative disconfirmation), whereas for CC the expected liking was significantly lower (P<0.001) than the perceived liking expressed in blind conditions (positive disconfirmation). Consumers assimilated their liking for OC in the direction of expectations, as the difference actual vs. perceived liking was significant (P<0.001). However the assimilation was not complete, as also the difference actual liking vs. expected liking was significant (P<0.001). Consumers showed a willingness to pay OC (mean+/-se=4.20+/ 0.13 euro/100 g) higher than the local retail price for conventional (1.90 euro/100 g) and even organic cheese (3.00 euro/100 g). We conclude that the information about organic farming can be a major determinant of cheese liking and consumer willingness to pay, thus providing a potential tool for product differentiation, particularly for small scale and traditional farms. PMID- 20196901 TI - Children do not overcome lexical biases where adults do: the role of the referential scene in garden-path recovery. AB - In this paper we report on a visual world eye-tracking experiment that investigated the differing abilities of adults and children to use referential scene information during reanalysis to overcome lexical biases during sentence processing. The results showed that adults incorporated aspects of the referential scene into their parse as soon as it became apparent that a test sentence was syntactically ambiguous, suggesting they considered the two alternative analyses in parallel. In contrast, the children appeared not to re analyze their initial analysis, even over shorter distances than have been investigated in prior research. We argue that this reflects the children's over reliance on bottom-up, lexical cues to interpretation. The implications for the development of parsing routines are discussed. PMID- 20196902 TI - First encounter of European bat lyssavirus type 2 (EBLV-2) in a bat in Finland. AB - In Finland, rabies in bats was suspected for the first time in 1985 when a bat researcher, who had multiple bat bites, died in Helsinki. The virus isolated from the researcher proved to be antigenically related to rabies viruses previously detected in German bats. Later, the virus was typed as EBLV-2b. Despite an epidemiological study in bats 1986 and subsequent rabies surveillance, rabies in bats was not detected in Finland until the first case in a Daubenton's bat (Myotis daubentonii) was confirmed in August 2009. The bat was paralysed, occasionally crying, and biting when approached; it subsequently tested positive for rabies. The virus was genetically typed as EBLV-2. This is the northernmost case of bat rabies ever detected in Europe. Phylogenetic analyses showed that the EBLV-2b isolate from the human case in 1985 and the isolate from the bat in 2009 were genetically closely related, demonstrating that EBLV-2 may have been circulating in Finland for many years. PMID- 20196903 TI - Exact confidence limits for prevalence of a disease with an imperfect diagnostic test. AB - Estimation of prevalence of disease, including construction of confidence intervals, is essential in surveys for screening as well as in monitoring disease status. In most analyses of survey data it is implicitly assumed that the diagnostic test has a sensitivity and specificity of 100%. However, this assumption is invalid in most cases. Furthermore, asymptotic methods using the normal distribution as an approximation of the true sampling distribution may not preserve the desired nominal confidence level. Here we proposed exact two-sided confidence intervals for the prevalence of disease, taking into account sensitivity and specificity of the diagnostic test. We illustrated the advantage of the methods with results of an extensive simulation study and real-life examples. PMID- 20196904 TI - The disease pyramid for acute gastrointestinal illness in New Zealand. AB - The disease pyramid of under-ascertainment for surveillance of acute gastrointestinal illness (AGI) in New Zealand has been estimated using 2005-2007 data on notifiable diseases, a community telephone survey, and a survey of diagnostic laboratories. For each notified case of AGI there were an estimated 222 cases in the community, about 49 of which visited a general practitioner. Faecal samples were requested from about 15 of these cases, and 13 samples were provided. Of the faecal samples, pathogens were detected in about three cases. These ratios are similar to those reported in other developed countries, and provide baseline measurements of the AGI burden in the New Zealand community. PMID- 20196905 TI - Prevalence and characteristics of asymptomatic norovirus infection in the community in England. AB - Norovirus is a major cause of infectious intestinal disease, and a substantial prevalence of asymptomatic infection has been reported. We describe the prevalence, seasonality and characteristics of asymptomatic norovirus infection in England. Healthy individuals were recruited at random from the general population during the Study of Infectious Intestinal Disease (1993-1996). Norovirus was identified using real-time RT-PCR. The age-adjusted prevalence of asymptomatic norovirus infection was 12%; prevalence was highest in children aged <5 years and showed wintertime seasonality. More work is needed to understand whether asymptomatic infections are important for norovirus transmission leading to sporadic illness and outbreaks. PMID- 20196906 TI - Nutrition knowledge, attitudes, behaviours and the influencing factors among non parent caregivers of rural left-behind children under 7 years old in China. AB - OBJECTIVE: To explore and compare nutrition knowledge, attitudes and behaviours (KAB) between non-parent and parent caregivers of children under 7 years old in Chinese rural areas, and to identify the factors influencing their nutrition KAB. DESIGN: Face-to-face interviews were carried out with 1691 non-parent caregivers and 1670 parent caregivers in the selected study areas; multivariate logistic regression models were used to identify the factors influencing nutrition KAB in caregivers. RESULTS: The awareness rate of nutrition knowledge, the rate of positive attitudes and the rate of optimal behaviours in non-parent caregivers (52.2 %, 56.9 % and 37.7 %, respectively) were significantly lower than in the parent group (63.8 %, 62.1 % and 42.8 %, respectively). Multivariate logistic regression modelling showed that caregivers' family income and care will, and children's age and gender, were associated with caregivers' nutrition KAB after controlling the possible confounding variables (caregivers' age, gender, education and occupation). CONCLUSIONS: Non-parent caregivers had relatively poor nutrition KAB. Extra efforts and targeted education programmes aimed to improve rural non-parent caregivers' nutrition KAB are wanted and need to be emphasized. PMID- 20196907 TI - Evidence-informed process to identify policies that will promote a healthy food environment in the Pacific Islands. AB - OBJECTIVE: To implement a systematic evidence-informed process to enable Fiji and Tonga to identify the most feasible and targeted policy interventions which would have most impact on diet-related non-communicable diseases. DESIGN: A multisectoral stakeholder group of policy advisers was formed in each country. They used participatory approaches to identify the problem policies and gaps contributing to an unhealthy food environment. Potential solutions to these problems were then identified, and were assessed by them for feasibility, effectiveness, cost-effectiveness and side-effects. Data were gathered on the food and policy environment to support the assessments. A shortlist of preferred policy interventions for action was then developed. RESULTS: Sixty to eighty policy problems were identified in each country, affecting areas such as trade, agriculture, fisheries and pricing. Up to 100 specific potential policy solutions were then developed in each country. Assessment of the policies highlighted relevant problem areas including poor feasibility, limited effectiveness or cost effectiveness and serious side-effects. A shortlist of twenty to twenty-three preferred new policy options for action in each country was identified. CONCLUSIONS: Policy environments in these two countries were not conducive to supporting healthy eating. Substantial areas of potential action are possible, but some represent better choices. It is important for countries to consider the impact of non-health policies on diets. PMID- 20196908 TI - A family-based intervention to increase fruit and vegetable consumption in adolescents: a pilot study. AB - OBJECTIVE: To evaluate the feasibility and effectiveness of a pilot family-based newsletter intervention to increase fruit and vegetable (FV) consumption among adolescents. DESIGN: Family-based, two-group randomised control trial with baseline, post-intervention and follow-up measures. The intervention group received two FV newsletter packs over a 1 month period by postal mail. Social cognitive and behavioural choice theories provide the theoretical framework for the design and development of intervention materials. Control families were provided with all intervention materials at the end of the study. Adolescent FV consumption was assessed by an FFQ. Adolescent-reported barriers to eating FV, FV habits and preferences were the secondary outcomes, along with parent FV consumption, and parents reported knowledge, encouragement, home availability and accessibility of FV. Repeated-measures ANOVA was used to detect differences in behavioural and psychosocial outcomes between groups, time and group-by-time. SETTING: East Midlands, UK. SUBJECTS: Forty-nine parents and adolescents aged 12 14 years. RESULTS: Process evaluation indicated high reach, dose acceptability and fidelity of the intervention. At post-intervention and 6 weeks later at follow-up, adolescents in the intervention group had significantly higher fruit: (P < 0.01) and vegetable (P < 0.05) consumption and higher preferences for vegetables (P < 0.01), compared with the control group. At post-intervention and follow-up, parents in the intervention group had significantly higher fruit (P < 0.001) and vegetable (P < 0.01) consumption and reported higher accessibility of fruit and vegetables (P < 0.001), compared with those in the control group. CONCLUSIONS: Family-based, newsletter interventions promoting FV consumption to adolescents appear to be feasible and effective at increasing FV consumption. PMID- 20196909 TI - Influences on child fruit and vegetable intake: sociodemographic, parental and child factors in a longitudinal cohort study. AB - OBJECTIVE: To examine the sociodemographic, parental and child factors that predict fruit and vegetable consumption in 7-year-old children. DESIGN: Diet was assessed using three 1d unweighed food diaries. The child's daily fruit and vegetable consumption was calculated by summing the weight of each type of fruit, fruit juice and vegetable consumed. The various others factors measured were assessed by a questionnaire at different time points. SETTING: The Avon Longitudinal Study of Parents and Children (ALSPAC). SUBJECTS: A total of 7285 children aged 7 years residing in the south-west of England during 1999-2000. RESULTS: Median daily fruit and vegetable consumption (201 g) was below the recommendations for this age group (320 g). Girls ate more fruit and vegetables per unit energy (30.3 g/MJ) than boys (26.7 g/MJ; P =< 0.001). The predictors of fruit and vegetable consumption were mostly similar. Fruit and vegetable consumption was associated with maternal consumption, maternal education status and parental rules about serving fruit/vegetables every day, food expenditure per person and whether the child was choosy about food. Vegetable consumption was also associated with the other characteristics of the child, such as whether the child enjoyed food and whether the child tried a variety of foods. CONCLUSIONS: Children are not eating recommended amounts of fruit and vegetables, particularly boys. Consumption of fruit and vegetables appears to be influenced by parental rules about daily consumption and parental consumption and by the child's choosiness. Parent's actions could influence this. These findings may prove useful for those planning healthy eating campaigns for children. PMID- 20196910 TI - The International Physical Activity Questionnaire modified for the elderly: aspects of validity and feasibility. AB - OBJECTIVE: To modify the self-administered, short version of the International Physical Activity Questionnaire (IPAQ) for adults to be used in the elderly (aged 65 years and above), and to validate this modified IPAQ for the elderly (IPAQ-E). DESIGN: A direct validity study using accelerometer-measured physical activity (PA) as the criterion measure, and an indirect criterion validity study using high-sensitivity C-reactive protein (hs-CRP) as a biological marker of activity. SETTING: Organisations for retired persons in Sweden. SUBJECTS: The direct validity study consisted of fifty-four participants and the indirect criterion validity study consisted of 359 participants. All participants were retired persons (66-91 years) living independently. RESULTS: All self-reported activity domains (sitting, walking, moderate and vigorous) were positively correlated with the corresponding variable objectively assessed by an accelerometer (rho = 0.277 0.471), but a systematic error was observed. The specificity of IPAQ-E to identify low-active participants was 85 %, and the sensitivity to identify the more active participants was 81 %. A main effect of IPAQ-E category (Low, Moderate or High) was observed for hs-CRP (P = 0.041). CONCLUSIONS: We found this modified version of IPAQ, the IPAQ-E, to be well accepted by our sample of socially active elderly. It provided acceptable estimates of PA, well in line with other questionnaires, even though it had a systematic error. The IPAQ-E was able to identify an expected response of a biomarker (hs-CRP) to PA. We recommend the use of the IPAQ-E to classify participants aged 65 years and above into PA categories, to rank individuals or to identify individuals meeting certain PA criteria. PMID- 20196911 TI - Salt intake of the Slovene population assessed by 24 h urinary sodium excretion. AB - OBJECTIVE: To investigate average sodium excretion in 24 h urine as a marker for salt intake in the Slovene population. DESIGN: Salt intake was determined by measuring sodium excretion in 24 h urine collected from a representative sample of geographically diverse Slovene adults. SETTING: Slovenia. SUBJECTS: A random sample of 600 adults aged 25-65 years was generated from census data. The effective sample yield was 143 people, 42.7 % men and 57.3 % women. RESULTS: Urinary sodium excretion was significantly higher in men (220.9 (sd 86.0) mmol Na/d) than in women (169.8 (sd 73.8) mmol Na/d); t test = 14.5, P < 0.001. Average salt intake was 11.3 (sd 4.9) g/d, higher in men than in women (13.0 (sd 5.1) v. 9.9 (sd 4.3) g/d, respectively). Average intakes of salt among regions were not significantly different. Salt intake increases slightly with increasing age, but there was no significant correlation between age and salt intake. Salt intake was increased with BMI (r = 0.384, P < 0.001). CONCLUSIONS: Salt intake in Slovene adults, especially in men, exceeds the WHO recommended population nutrient intake goal of 5 g by more than twofold. A national programme for reducing salt intake in Slovenia needs to be implemented through systematic efforts including public education and involving the health-care sector and the food industry. PMID- 20196912 TI - Sociodemographic factors associated with physical activity in Mexican adults. AB - OBJECTIVE: To estimate the physical activity level among Mexican adults and to establish the sociodemographic variables that may be linked to active lifestyles. DESIGN: Data from a cross-sectional survey were analysed. Physical activity was assessed using the short version of the International Physical Activity Questionnaire. The independent variables were sex, age, socio-economic status and size of town. Ordinal regression models were fitted to assess the association of physical activity levels with sociodemographic factors. SETTING: Fieldwork was conducted from November 2002 through April 2003; the non-response rate was 3.1%. SUBJECTS: Data from a national representative sample (n 38,746) of Mexican adults aged >18 years old were analysed. RESULTS: Almost 60% of the population was classified into the high physical activity level. Women were less active than men in rural areas; in urban areas, the opposite trend was observed. In women, higher socio-economic status was associated with less physical activity, while among men there were no differences. People from rural and urban areas had a higher probability of engaging in physical activity than those from cities. In urban localities and cities, respondents of low socio-economic status had a lower probability of engaging in physical activity. CONCLUSIONS: Using a validated instrument to measure physical activity, we found that the prevalence of active lifestyle among Mexican adults was high. The socio-economic and gender inequalities are different according to size of town (i.e. an effect modifier), which must be considered in the design of policies and programmes to promote physical activity. PMID- 20196913 TI - Height and weight gains in a nutrition rehabilitation day-care service. AB - OBJECTIVE: To evaluate nutritional recovery patterns in 106 undernourished children assisted by the Center of Nutritional Recovery and Education (CREN, in Portuguese) between January 1995 and December 1999. DESIGN: CREN assists undernourished children aged 0 to 72 months living in the southern regions of Sao Paulo, in an outpatient setting. Nutritional status was assessed by Z-scores of weight-for-age, height-for-age and weight-for-height. Nutritional recovery evaluation considered Z-score gains in weight-for-age and height-for-age, grouping into four categories (Z-score increment of 0.50 between groups). Children with birth weight less than 2500 g were classified as low birth weight (LBW), while those born at term and with LBW were classified as small for gestational age. SETTING: CREN (Center of Nutritional Recovery and Education in Portuguese), Sao Paulo, Brazil. SUBJECTS: One hundred and six children from CREN. RESULTS: Among the 106 evaluated children, ninety-eight (92.5 %) recovered their weight or height and seventy-two (67.9 %) recovered both. Nearly half of studied children presented a nutritional recovery (increase in Z-score) of more than 0.50 in height-for-age (46.2 %) and about 40 % in weight-for-age (38.7 %). Multivariate analysis showed that treatment duration and initial weight-for-age contributed to weight-for-age Z-score increment, explaining 25 % of the variation; and treatment duration, initial height-for-age and weight-for-age Z score increment contributed to height-for-age Z-score increment, explaining 62 % of the variation. CONCLUSIONS: Our findings show that nutritional recovery among children who attended CREN was influenced primarily by the degree of nutritional deficit at admission. It has also been shown that biological variables are more important than socio-economic status in determining the rate of nutritional recovery. PMID- 20196914 TI - The prevalence and correlates of taking folic acid and vitamin supplements among adults aged >= 45 years with CVD. AB - OBJECTIVE: To examine the prevalence and likelihood of taking folic acid or vitamin supplements among adults with CHD or stroke v. adults without these conditions. DESIGN: A cross-sectional Behavioural Risk Factor Surveillance System survey was conducted in twelve states of the United States and Puerto Rico in 2006. Self-reported data from participants were collected. SETTING: The United States. SUBJECTS: US non-institutionalised adults (n 41 792), aged >= 45 years. RESULTS: Of all participants, 5445 had CHD and 2076 had stroke. Significantly higher percentages of women than men reported taking folic acid or vitamin supplements. After adjustment for potential confounders, women with CHD had a significantly lower adjusted prevalence (AP) and adjusted OR (AOR) than women without CHD for taking folic acid less than one time per d (AP = 3.9 % v. 5.5 %; AOR = 0.56; 95 % CI 0.39, 0.81), for taking folic acid one to four times per d (AP = 50.0 % v. 57.5 %; AOR = 0.68; 95 % CI 0.60, 0.79), and for taking vitamin supplements (AP = 60.9 % v. 69.9 %; AOR = 0.66; 95 % CI 0.57, 0.76). Men with CHD had a significantly higher AP (50.4 % v. 46.2 %) and AOR (1.17; 95 % CI 1.02, 1.33) of taking folic acid one to four times per d than men without CHD. In both sexes, adults with stroke were as likely as those without to take these supplements. CONCLUSIONS: Substantial variations in the prevalence and likelihood of taking folic acid or vitamin supplements exist by gender and by CHD status, but not by stroke status. PMID- 20196915 TI - Food insecurity is associated with food consumption patterns and anthropometric measures but not serum micronutrient levels in adults in rural Tanzania. AB - OBJECTIVE: The purpose of the present paper is to assess the relationship between food insecurity and food consumption patterns, anthropometric measures and serum micronutrient levels in rural Kilimanjaro, Tanzania. DESIGN: A population-based cross-sectional study was carried out between March and May of 2005. SETTING: Rural Kilimanjaro, Tanzania. SUBJECTS: Analysis was restricted to 1014 adults aged 15-44 years with children and complete data. RESULTS: A large majority of the participants (91 %) reported some kind of food insecurity. Food insecurity was significantly associated with age, marital status and occupation. Participants reporting food insecurity were significantly less likely to frequently consume animal products, fruits and vegetables compared with participants categorized as food secure. Women categorized as experiencing individual food insecurity had a larger waist circumference than food-secure women (P = 0.026) while the mean BMI of women appeared to decline if they had a child who was food insecure (P = 0.038). There were no observed differences in serum micronutrient levels by food insecurity status. CONCLUSIONS: Food insecurity is highly prevalent and associated with food consumption patterns, waist circumference and BMI of women in rural Tanzania. Further studies should apply self-report measures in assessing food insecurity to larger and more diversified populations. PMID- 20196916 TI - Assessing the relevance of neighbourhood characteristics to the household food security of low-income Toronto families. AB - OBJECTIVE: Although the sociodemographic characteristics of food-insecure households have been well documented, there has been little examination of neighbourhood characteristics in relation to this problem. In the present study we examined the association between household food security and neighbourhood features including geographic food access and perceived neighbourhood social capital. DESIGN: Cross-sectional survey and mapping of discount supermarkets and community food programmes. SETTING: Twelve high-poverty neighbourhoods in Toronto, Ontario, Canada. SUBJECTS: Respondents from 484 low-income families who had children and who lived in rental accommodations. RESULTS: Food insecurity was pervasive, affecting two-thirds of families with about a quarter categorized as severely food insecure, indicative of food deprivation. Food insecurity was associated with household factors including income and income source. However, food security did not appear to be mitigated by proximity to food retail or community food programmes, and high rates of food insecurity were observed in neighbourhoods with good geographic food access. While low perceived neighbourhood social capital was associated with higher odds of food insecurity, this effect did not persist once we accounted for household sociodemographic factors. CONCLUSIONS: Our findings raise questions about the extent to which neighbourhood-level interventions to improve factors such as food access or social cohesion can mitigate problems of food insecurity that are rooted in resource constraints. In contrast, the results reinforce the importance of household-level characteristics and highlight the need for interventions to address the financial constraints that underlie problems of food insecurity. PMID- 20196917 TI - Serotonergic neurotransmission and lapses of attention in children and adolescents with attention deficit hyperactivity disorder: availability of tryptophan influences attentional performance. AB - Deficiencies in serotonergic (5-HT) neurotransmission have frequently been linked to altered attention and memory processes. With attention deficit hyperactivity disorder (ADHD) being associated with impaired attention and working memory, this study investigated the effects of a diminished 5-HT turnover achieved by rapid tryptophan depletion (RTD) on attentional performance in children and adolescents with ADHD. Twenty-two male patients with ADHD (aged 9-15 yr) received the RTD procedure Moja-De and a tryptophan (Trp)-balanced placebo (Pla) in a randomized, double-blind, within-subject crossover design on two separate study days. Lapses of attention (LA) and phasic alertness (PA) were assessed within the test battery for attentional performance under depleted and sham-depleted conditions 120 (T1), 220 (T2) and 300 (T3) min after intake of RTD/Pla. At T1 there was a significant main effect for RTD, indicating more LA under intake of a Trp-balanced Pla compared to diminished 5-HT neurotransmission. For T2/T3 there were no such effects. PA was not affected by the factors RTD/Pla and time. Interactions of 5 HT with other neurotransmitters as possible underlying neurochemical processes could be subject to further investigations involving healthy controls as regards altered attentional performance in children and adolescents. PMID- 20196918 TI - Schizophrenia severity and clozapine treatment outcome association with oxytocinergic genes. AB - Antipsychotic drugs are the best means available for symptomatically treating individuals suffering from schizophrenia; however, there is a significant variability in clinical response to these psychotropic medications. Previous findings connect oxytocin (OXT) with schizophrenia and antipsychotic action. Therefore, we evaluated if OXT and OXT receptor (OXTR) genes might play a role in the symptom severity and clozapine treatment response in schizophrenia subjects. The rs2740204 variant in the OXT gene was significantly associated with treatment response (after 1000 permutations p=0.042) and nominally associated with negative symptoms in our sample. Furthermore, variants in the OXTR were nominally associated with severity of overall symptoms accessed using the Brief Psychiatric Rating Scale (rs237885, rs237887) as well as on the improvement of the positive symptoms (rs11706648, rs4686301, rs237899). Additional association studies in independent samples will be able evaluate whether OXT and OXTR genes are truly playing a role in the clozapine treatment outcome. PMID- 20196920 TI - D3 receptor target engagement in humans with ABT-925 using [11C](+)-PHNO PET. PMID- 20196921 TI - Cannabinoid CB1 receptor antagonism prevents neurochemical and behavioural deficits induced by chronic phencyclidine. AB - Clinical and laboratory studies suggest that the endocannabinoid system is involved in schizophrenia disorders. Recent evidence indicates that cannabinoid receptor (CB1) antagonists have a pharmacological profile similar to antipsychotic drugs. We investigated the behavioural and biochemical effects of the CB1 antagonist AM251 in a phencyclidine (PCP) animal paradigm modelling the cognitive deficit and some negative symptoms of schizophrenia. Chronic AM251 (0.5 mg/kg for 3 wk) improved the PCP-altered recognition memory, as indicated by a significant amelioration of the discrimination index compared to chronic PCP alone (2.58 mg/kg for 1 month). AM251 also reversed the PCP-induced increase in immobility in the forced swim test resembling avolition, a negative sign of schizophrenia. In order to analyse the mechanisms underlying these behaviours, we studied the effects of AM251 on the endocannabinoid system (in terms of CB1 receptor density and functional activity and endocannabinoid levels) and c-Fos protein expression. The antagonist counteracted the alterations in CB1 receptor function induced by PCP in selected cerebral regions involved in schizophrenia. In addition, in the prefrontal cortex, the key region in the integration of cognitive and negative functions, AM251 markedly raised anandamide levels and reversed the PCP-induced increase of 2-arachidonoylglycerol concentrations. Finally, chronic AM251 fully reversed the PCP-elicited expression of c-Fos protein in the prefrontal cortical region. These findings suggest an antipsychotic-like profile of the CB1 cannabinoid receptor antagonist which, by restoring the function of the endocannabinoid system, might directly or indirectly normalize some of the neurochemical maladaptations present in this schizophrenia-like animal model. PMID- 20196922 TI - Conceptions of learning and approaches to studying among White and ethnic minority students in distance education. AB - BACKGROUND: The attainment of White students at UK institutions of higher education tends to be higher than that of students from other ethnic groups, but the causes of this are unclear. AIMS: This study compared White students and students from other ethnic groups in their conceptions of learning, their approaches to studying, and their academic attainment. SAMPLE: A stratified sample of 1,146 White students and 1,146 students from other ethnic groups taking courses by distance learning with the UK Open University. METHODS: The Mental Models section of the Inventory of Learning Styles and the Revised Approaches to Studying Inventory were administered in a postal survey. RESULTS: The students' questionnaire scores were contaminated by response bias, which varied across different ethnic groups. When adjusted to control for response bias, the scores on the two questionnaires shared 37.2% of their variance and made a significant contribution to predicting the students' attainment. White students were more likely to exhibit a meaning-directed learning pattern, whereas Asian and Black students were more likely to exhibit a reproduction-directed learning pattern. However, the variation in attainment across different ethnic groups remained significant when their questionnaire scores and prior qualifications were taken into account. CONCLUSIONS: There is a strong relationship between students' conceptions of learning and their approaches to studying, and variations in conceptions of learning in different ethnic groups give rise to variations in approaches to studying. However, factors other than prior qualifications and conceptions of learning are responsible for variation in attainment across different ethnic groups. PMID- 20196919 TI - Modulation of cell adhesion systems by prenatal nicotine exposure in limbic brain regions of adolescent female rats. AB - Maternal smoking during pregnancy (MS) has long-lasting neurobehavioural effects on the offspring. Many MS-associated psychiatric disorders begin or change symptomatology during adolescence, a period of continuous development of the central nervous system. However, the underlying molecular mechanisms are largely unknown. Given that cell adhesion molecules (CAMs) modulate various neurotransmitter systems and are associated with many psychiatric disorders, we hypothesize that CAMs are altered by prenatal treatment of nicotine, the major psychoactive component in tobacco, in adolescent brains. Pregnant Sprague-Dawley rats were treated with nicotine (3 mg/kg.d) or saline via osmotic mini-pumps from gestational days 4 to 18. Female offspring at postnatal day 35 were sacrificed, and several limbic brain regions (the caudate putamen, nucleus accumbens, prefrontal cortex, and amygdala) were dissected for evaluation of gene expression using microarray and quantitative RT-PCR techniques. Various CAMs including neurexin, immunoglobulin, cadherin, and adhesion-GPCR superfamilies, and their intracellular signalling pathways were modified by gestational nicotine treatment (GN). Among the CAM-related pathways, GN has stronger effects on cytoskeleton reorganization pathways than on gene transcription pathways. These effects were highly region dependent, with the caudate putamen showing the greatest vulnerability. Given the important roles of CAMs in neuronal development and synaptic plasticity, our findings suggest that alteration of CAMs contributes to the neurobehavioural deficits associated with MS. Further, our study underscores that low doses of nicotine produce substantial and long-lasting changes in the brain, implying that nicotine replacement therapy during pregnancy may carry many of the same risks to the offspring as MS. PMID- 20196923 TI - The phosphate makes a difference: cellular functions of NADP. AB - Recent research has unraveled a number of unexpected functions of the pyridine nucleotides. In this review, we will highlight the variety of known physiological roles of NADP. In its reduced form (NADPH), this molecule represents a universal electron donor, not only to drive biosynthetic pathways. Perhaps even more importantly, NADPH is the unique provider of reducing equivalents to maintain or regenerate the cellular detoxifying and antioxidative defense systems. The roles of NADPH in redox sensing and as substrate for NADPH oxidases to generate reactive oxygen species further extend its scope of functions. NADP(+), on the other hand, has acquired signaling functions. Its conversion to second messengers in calcium signaling may have critical impact on important cellular processes. The generation of NADP by NAD kinases is a key determinant of the cellular NADP concentration. The regulation of these enzymes may, therefore, be critical to feed the diversity of NADP-dependent processes adequately. The increasing recognition of the multiple roles of NADP has thus led to exciting new insights in this expanding field. PMID- 20196924 TI - Protective effect of L-ascorbic acid against oxidative damage in the liver of rats with water-immersion restraint stress. AB - We examined whether L-ascorbic acid (AA) (or reduced ascorbic acid) protects against oxidative damage in the liver of rats subjected to water-immersion stress (WIRS). AA (100, 250 or 500 mg/kg) was orally administered at 0.5 h before the onset of WIRS. Rats with 6 h of WIRS had increased serum corticosterone, glucose, total ascorbic acid (T-AA), AA, lipid peroxide (LPO), and NOx concentrations and alanine aminotransferase and aspartate aminotrasferase activities. The stressed rats had increased hepatic LPO, NOx, and dehydroascorbic acid concentrations and myeloperoxidase activity, decreased hepatic T-AA, AA, reduced glutathione concentrations and superoxide dismutase activity, and unchanged hepatic vitamin E concentration. Pre-administered AA attenuated the stress-induced changes in serum LPO and NOx concentrations and alanine aminotransferase and aspartate aminotrasferase activities and hepatic LPO, NOx, and T-AA, AA, dehydroascorbic acid, and reduced glutathione concentrations and myeloperoxidase and superoxide dismutase activities dose-dependently. Pre-administered AA did not affect the stress-induced changes in serum corticosterone and glucose concentrations. These results indicate that pre-administered AA protects against oxidative damage in the liver of rats with WIRS possibly by attenuating disruption of the antioxidant defense system and increases in NO generation and neutrophil infiltration in the tissue. PMID- 20196926 TI - Bioavailability and catalytic properties of copper and iron for Fenton chemistry in human cerebrospinal fluid. AB - A breakdown in homeostasis of redox-active metals represents an important factor for neurodegeneration. We have used EPR spectroscopy and BMPO spin-trap to investigate the catalytic properties and ligand modulation of redox activity of copper and iron in human cerebrospinal fluid (CSF). In contrast to iron, copper supplementation provoked a statistically significant increase in hydroxyl free radical generation in CSF treated with H(2)O(2). However, in a binary copper/iron containing Fenton system, iron catalytically activated copper. The chelator EDTA, which represents a model of physiological metal ligands, completely prevented copper's redox activity in CSF, while iron chelation led to a significant increase in hydroxyl radical generation, indicating that copper and iron do not only have diverse catalytic properties in the CSF but also that their redox activities are differently modulated by ligands. The application of DDC reduced hydroxyl radical generation in the CSF containing catalytically active metals (free Cu(2+) or Fe(3+)-EDTA complex). We conclude that chelators, such as DDC, are capable of preventing the prooxidative activity of both metals and may be suitable for reducing hydroxyl radical formation in certain pathophysiological settings. PMID- 20196925 TI - Antioxidant and antiglycation properties of triterpenoid saponins from Aralia taibaiensis traditionally used for treating diabetes mellitus. AB - Our previous study has demonstrated that the antidiabetic activity of the extract of root bark of Aralia taibaiensis (EAT) was correlated with its combined antioxidant and antiglycation properties. To confirm further the constituents responsible, 12 triterpenoid saponins were isolated from EAT and examined for their antioxidant and antiglycation activities. The antioxidant activities of the pure compounds and EAT were evaluated by studying the inhibition of lipid peroxidation in rat liver microsomes induced by ascorbate/Fe(2+), cumine hydroperoxide (CHP) or CCl(4)/reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH). The antioxidant capacities were also evaluated by studying the scavenging of 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical. The antiglycation activities of the pure compounds and EAT were evaluated by hemoglobin-delta-gluconolactone (delta-Glu) assay, bovine serum albumin (BSA) glucose assay and N-acetyl-glycyllysine methyl ester (GK peptide)-ribose assay. EAT outperformed other compounds in all the assays. The compounds with best antioxidant (TA7, TA24 and TA35) and antiglycation (TA21, TA9 and TA24) activities in different assays were screened out. The results suggest that the antioxidant and antiglycation properties of EAT could be explained, at least in part, by the synergistic effect of pure compounds isolated from it. PMID- 20196927 TI - Protective effect of sesamol against myocardial infarction caused by isoproterenol in Wistar rats. AB - This study was designed to investigate the cardioprotective effect of sesamol on isoproterenol (ISO)-induced myocardial infarction in adult male albino Wistar rats. The heart damage induced by ISO was indicated by elevated levels of the marker enzymes such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase-MB (CK MB) and the levels of troponin T and I in the plasma. In addition, lipid peroxidative markers such as thiobarbituric acid reactive substances (TBARS), conjugated dienes (CD) and lipid hydroperoxides (LHP) significantly increased in the plasma and heart. Activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and glutathione reductase (GR) significantly decreased in the heart and (non-enzymic antioxidants) vitamin C, vitamin E and reduced glutathione (GSH)) levels significantly decreased in the plasma and heart in ISO-rats. Histopathological observations correlated with the biochemical parameters. Administration of sesamol at different doses 50, 100 and 200 mg/kg body weight intraperitoneally for 7 days prevented the above changes and improved towards normality; the 50 mg dose was more effective than the other two doses. PMID- 20196928 TI - Kinetic change of oxidative stress in cerebrospinal fluid of mice infected with Angiostrongylus cantonensis. AB - The cerebrospinal fluid (CSF) of C57BL/6 mice infected with Angiostrongylus cantonensis was examined for kinetic changes in oxidative stress parameters, including reactive oxygen species (ROS), superoxide dismutase (SOD), catalase, malondialdehyde (MDA), 8-isoprostane, and 8-hydroxy-2'-deoxyguanosine (8-OHdG). The ROS increased gradually in the early stage of infection. During days 12-30 post-infection, the infected mice revealed ROS levels significantly higher than that in uninfected controls (P < 0.001). The ROS levels peaked at day 24 and then returned to that observed in uninfected controls at day 45 post-infection. The kinetics of MDA, 8-isoprostane, and 8-OHdG concentration changes observed in the CSF of the infected mice corresponded with kinetic changes in ROS levels. Thus, the excess ROS caused lipid peroxidation and DNA damage to cells in the central nervous system (CNS) of mice infected with A. cantonensis despite the increased antioxidant SOD and catalase enzyme activities during post-infection days 12-30. The oxidative stress in the CNS of C57BL/6 mice was apparently increased by diseases associated with A. cantonensis infection. PMID- 20196929 TI - Anthropometry as a tool for measuring malnutrition: impact of the new WHO growth standards and reference. AB - Anthropometry is a useful tool, both for monitoring growth and for nutritional assessment. The publication by WHO of internationally agreed growth standards in 1983 facilitated comparative nutritional assessment and the grading of childhood malnutrition. New growth standards for children under 5 years and growth reference for children aged 5-19 years have recently (2006 and 2007) been published by WHO. Growth of children <5 years was recorded in a multi-centre growth reference study involving children from six countries, selected for optimal child-rearing practices (breastfeeding, non-smoking mothers). They therefore constitute a growth standard. Growth data for older children were drawn from existing US studies, and upward skewing was avoided by excluding overweight subjects. These constitute a reference. More indicators are now included to describe optimal early childhood growth and development, e.g. BMI for age and MUAC for age. The growth reference for older children (2007) focuses on linear growth and BMI; weight-for-age data are age-limited and weight-for-height is omitted. Differences in the 2006 growth pattern from the previous reference for children <5 are attributed to differences in infant feeding. The 2006 'reference infant' is at first heavier and taller than his/her 1983 counterpart, but is then lighter until the age of 5. Being taller in the 2nd year, he/she is less bulky (lighter for height) than the 1983 reference toddler. The spread of values for height and weight for height is narrower in the 2006 dataset, such that the lower limit of the normal range for both indices is set higher than in the previous dataset. This means that a child will be identified as moderately or severely underweight for height (severe acute malnutrition) at a greater weight for height than previously. The implications for services for malnourished children have been recognised and strategies devised. The emphasis on BMI-for-age as the indicator for thinness and obesity in older children is discussed. The complexity of calculations for health cadres without mathematical backgrounds or access to calculation software is also an issue. It is possible that the required charts and tables may not be accessible to those working in traditional health/nutrition services which are often poorly equipped. PMID- 20196930 TI - Ocular manifestations of sickle cell disease. AB - Sickle cell disease (SCD) is the most common genetic disease worldwide. The increase in life expectancy of SCD patients in recent years has led to the emergence of more complications of the disease, e.g. ocular, which in the past were uncommon. This review describes current knowledge of the ocular manifestations of patients with SCD. SCD can affect virtually every vascular bed in the eye and can cause blindness in the advanced stages. The most significant ocular changes are those which occur in the fundus, which can be grouped into proliferative sickle retinopathy, and non-proliferative retinal changes based on the presence of vascular proliferation. This distinction is important because the formation of new vessels is the single most important precursor of potentially blinding complications. Although various systemic complications of SCD are known to be more common in patients with the Hb SS genotype, visual impairment secondary to proliferative sickle retinopathy is more common in patients with the Hb SC genotype. There is also an increase with age in the incidence and prevalence rates of all ocular complications of SCD. It is therefore recommended that all patients with SCD undergo periodic ophthalmological screening from the age of 10 years. PMID- 20196931 TI - Impact of HAART on survival, weight gain and resting energy expenditure in HIV-1 infected children in India. AB - BACKGROUND: In resource-limited countries, use of highly active antiretroviral therapy (HAART) in HIV-infected children is still poorly documented in terms of impact on survival, the immune system and growth. Since the availability of HAART, nutrition of HIV-infected children has been neglected. AIM: To evaluate the effect of HAART on survival and immune response in HIV-infected children and to investigate the response to nutritional support. METHODS: In December, 2002 a cohort study was carried out on vertically HIV-1-infected children and was observed longitudinally for CD4(+) T-cell count, antiretroviral treatment and weight until 31 December 2007. Z-scores were calculated for CD4(+) T-cell count to account for age-related differences. Nutritional supplementation was given to all the HIV-infected children and resting energy expenditure (REE) was calculated. Mortality rates were also calculated for the perinatally infected children followed up at the HIV clinic. RESULTS: A total of 180 children were assessed, 100 (56%) of whom were on HAART. Baseline body mass index was lower in the HAART group (p<0.05). Median duration of survival from date of diagnosis was 15.1 years. Those who received HAART survived significantly longer. The average annual mortality rate was 1.2% during 2005-2006. During HAART, a CD4 Z-score increase of 1 SD was associated with a 0.35 increase in body weight Z-score (p<0.001). The increase in daily energy intake owing to nutritional supplementation was associated with increase in weight Z-score in both the no HAART and HAART group. REE was independently associated with weight change in the models which tested association of changes in CD4(+) T-cell Z-score and daily REE/kg body weight with changes in body weight Z-score in both the HAART and no HAART group and then separately in the two groups (p<0.001). CONCLUSION: Survival rates of children improved which correlated with an increase in CD4(+) T-cell count concurrent with the expanded use of HAART. HAART had a positive effect on growth in HIV-1-infected children. Nutrition supplementation improved the health of children in both the no-HAART and HAART groups. PMID- 20196932 TI - Cyanide poisoning caused by ingestion of apricot seeds. AB - AIM: To report diagnostic, clinical and therapeutic aspects of cyanide intoxication resulting from ingestion of cyanogenic glucoside-containing apricot seeds. METHODS: Thirteen patients admitted to the Pediatric Intensive Care Unit (PICU) of Erciyes University between 2005 and 2009 with cyanide intoxication associated with ingestion of apricot seeds were reviewed retrospectively. RESULTS: Of the 13 patients, four were male. The mean time of onset of symptoms was 60 minutes (range 20 minutes to 3 hours). On admission, all patients underwent gastric lavage and received activated charcoal. In addition to signs of mild poisoning related to cyanide intoxication, there was severe intoxication requiring mechanical ventilation (in four cases), hypotension (in two), coma (in two) and convulsions (in one). Metabolic acidosis (lactic acidosis) was detected in nine patients and these were treated with sodium bicarbonate. Hyperglycaemia occurred in nine patients and blood glucose levels normalised spontaneously in six but three required insulin therapy for 3-6 hours. Six patients received antidote treatment: high-dose hydroxocobalamin in four and two were treated with a cyanide antidote kit in addition to high-dose hydroxocobalamin. One patient required anticonvulsive therapy. All patients recovered and were discharged from the PICU within a mean (SD, range) 3.1 (1.7, 2-6) days. CONCLUSION: Cyanide poisoning associated with ingestion of apricot seeds is an important poison in children, many of whom require intensive care. PMID- 20196933 TI - Detection of coronaviruses in children with acute gastroenteritis in Maddina, Saudi Arabia. AB - BACKGROUND: The role of coronaviruses in paediatric gastro-enteritis is not well defined. We investigated the detection rate and epidemiological features of infection with coronavirus in children receiving hospital care for acute gastro enteritis in Maddina, Saudi Arabia. METHODS: Stool specimens were collected from children less than 5 years of age who were either hospitalised in Maddina or given oral rehydration therapy as outpatients between April 2004 and April 2005. Coronaviruses were detected by electron microscopy. RESULTS: Coronaviruses were detected in 63 (6%) of 984 children with acute gastro-enteritis and were more commonly detected in outpatients (47/423, 11%) than in inpatients (16/561, 3%). The median age (range) of children with coronavirus infection was 42 months (10 60). Coronaviruses were detected throughout the year with the highest detection rate at the end of the winter season. CONCLUSIONS: Coronaviruses were commonly identified in children with diarrhoea in Saudi Arabia. Their role in paediatric gastro-enteritis warrants further evaluation. PMID- 20196934 TI - Swine-origin influenza A (H1N1) in Indian children. AB - BACKGROUND: Swine-origin influenza A H1N1 (S-OIV) has not been systematically studied in Indian children. OBJECTIVES: To study the clinical characteristics, morbidity and mortality pattern in children with S-OIV infection. METHODS: This prospective study was conducted during the 'containment phase' of the pandemic in New Delhi from 10 June to 5 August 2009. All children suspected of being infected by S-OIV were admitted to the isolation wards and clinically evaluated according to WHO guidelines. Nasal and throat swabs were collected immediately for real time reverse transcriptase polymerase chain reaction (RT-PCR). Haemoglobin, total leucocyte and platelet counts and chest radiography were undertaken in all patients. Those who tested positive for S-OIV infection were treated with oseltamivir for 5 days in isolation wards. RESULTS: Thirty-seven children fulfilled the inclusion criteria. Twenty-one tested positive for S-OIV by RT-PCR and 16 tested negative. Comparison of the clinical characteristics of the two groups showed that duration of cough was longer in children with S-OIV (p<0.03). Total leucocyte and lymphocyte counts were significantly less in the S-OIV group (p<0.001 and , 0.02, respectively). Oseltamivir-related gastritis was seen in 38% of children. All improved and were discharged. CONCLUSION: S-OIV infection in Indian children had features similar to those of seasonal influenza. Lymphopenia is an important feature of S-OIV. PMID- 20196935 TI - Traumatic diaphragmatic hernia masquerading as left-sided hydropneumothorax: a case report. AB - Traumatic diaphragmatic rupture (TDR) is rare in children and can be easily overlooked because of lack of awareness of late presentation and concomitant injuries. A 4-year-old girl presented with respiratory distress 2 months after a road traffic accident. The initial differential diagnosis was pneumonia or pulmonary tuberculosis with associated pleural effusion. On further assessment, a diaphragmatic hernia was suspected. The initial radiograph showed left hydropneumothorax. Fluoroscopy, follow-up chest radiographs and barium swallow confirmed the diagnosis of left TDR. Surgery was undertaken but unfortunately she did not survive. Awareness of delayed presentation of TDR is essential for prompt management. PMID- 20196936 TI - Macrophage activation syndrome: a rare complication of incomplete Kawasaki disease. AB - Macrophage activation syndrome in rheumatological disorders is rare. A 3-year-old girl with incomplete Kawasaki disease complicated by macrophage activation syndrome is reported. PMID- 20196937 TI - Transient quadriparesis after electric shock in a child: case report. AB - Electric shock injuries are commonly encountered by emergency physicians. Various systemic complications owing to electric shock injury have been described. It is important to maintain raised awareness of these different complications to ensure that they are recognised and treated early. We describe a rare case of transient quadriparesis following electric shock in a 10-year-old boy. PMID- 20196938 TI - Fetal head injury from intentional penetrating abdominal trauma in pregnancy. AB - A male fetus was extruded from the uterus following multiple lower abdominal stab wounds to the mother. He was brought to the emergency room at 8 hours of age. He had sustained a compound skull fracture with brain contusion. There was no neurological deficit. Debridement and primary wound closure were undertaken. His mother had multiple lacerations to the uterus and a laceration of the fundus of the bladder. Following resuscitation, she had repair of the uterus and bladder and made an uneventful recovery. At 3 years of age, the boy is developing normally. PMID- 20196939 TI - Ectopic gastric and pancreatic tissue: a rare cause of umbilical discharge. AB - Persistent umbilical drainage may be due to vestigial remnants of the omphalomesenteric duct. Rarely, it may be owing to the presence of ectopic pancreatic tissue within these remnants. An 18-month-old boy underwent surgical exploration for umbilical discharge. An umbilical nodule containing both ectopic gastric and pancreatic tissue was found. This is the first instance where both tissue types have been implicated as a cause. PMID- 20196940 TI - Staphylococcal toxic shock syndrome presenting as acute respiratory distress and cor pulmonale. AB - We describe a 7-year-old boy with staphylococcal toxic shock syndrome who presented with acute respiratory distress and cor pulmonale. We wish to highlight this unusual presentation as the diagnosis of toxic shock syndrome depends chiefly on a high degree of clinical suspicion. Early diagnosis and prompt institution of appropriate therapy will significantly reduce morbidity and mortality. PMID- 20196941 TI - Systemic allergic reaction to a caterpillar in a 3-month-old infant. AB - Systemic reactions to contact with a caterpillar are rare in children. A 3-month old infant presented to the emergency department with acute onset of rash, severe respiratory distress and shock. Her mother volunteered that the infant had been exposed to a tree processionary caterpillar. The infant responded to systemic corticosteroids and antihistamines although the rash persisted for more than 5 days. PMID- 20196942 TI - [Prospect and progression on study associated with severe acute exacerbation of chronic hepatitis B]. PMID- 20196943 TI - [Genotype and mutation of hepatitis B virus and severe hepatitis]. PMID- 20196944 TI - [The relationship between severe acute exacerbation of chronic hepatitis B and host genetic factors]. PMID- 20196945 TI - [Drug resistance, genotype, and serotype of hepatitis B virus in nucleos(t)ide analogue naive patients with chronic hepatitis B]. AB - OBJECTIVE: To investigate drug resistance, genotype and serotype of hepatitis B virus (HBV) in nucleos(t)ide analogue (NA) naive patients with chronic hepatitis B (CHB). METHODS: Full-length reverse transcriptase region of HBV DNA was amplified by semi-nested polymerase chain reaction from 97 NA-naive CHB patients, and the PCR product was sequenced, and analyzed to screen 11 classical antiviral drug resistance mutation sites and to identify HBV genotypes, subgenotypes and serotypes. RESULTS: Wild-type sequences were found at all of the 11 classical antiviral drug resistance mutation sites from all samples. The patients were infected with either genotype B (36.1%, 35/97) or C (63.9%, 62/97) HBV. The former were all belonged to subgenotype B2 strain; while the latter were divided further into subgenotype C2 (91.9%, 57/62), subgenotype C1 (6.5%, 4/62) and unknown subgenotype (1.6%, 1/62). The 71.9% (23/32) of HBV genotype B patients were born in southern China, while 81.6% (40/49) of HBV genotype C patients were from northern China, showing a clear geographic distribution (Chi-square test = 23.19, Probability value less than 0.01). Of 97 CHB patients, 59 (60.8%) were serotype adr associated with genotype C, while 37 (38.1%) were adw related to genotype B (subgenotype B2) (Chi-square test = 87.83, P less than 0.01). CONCLUSION: The wild-type HBV strains prevail in NA-naive CHB patients, whose HBV genotypes, subgenotypes and serotypes are associated with their places of birth. PMID- 20196946 TI - [Expression profile of immune effector molecules in natural killer cells in patients with chronic hepatitis B]. AB - OBJECTIVE: To investigate the expression profile of immune effector molecules in peripheral natural killer cells (NK) in patients with chronic hepatitis virus B. METHODS: According to the infection status, patients were divided into four experiment groups: normal hepatic function and high HBV DNA level group, normal hepatic function and low HBV DNA level group, abnormal hepatic function and high HBV DNA level group and abnormal hepatic function and low HBV DNA level group. The expression of perforin (PF), granzyme B (Gr B), granulysin (GNLY), tumor necrosis factor alpha (TNFa) and interferon gamma (IFNr) in NK cells were detected by flow cytometer. RESULTS: Compared with control group (31.50%+/ 27.64%), the expression of GNLY was significantly increased in normal hepatic function and high HBV DNA level group (59.74%+/-30.82%) and normal hepatic function and low HBV DNA level group (61.89%+/-33.30%); the expression of IFNr in normal hepatic function and high HBV DNA level group (39.89%+/-21.30%) and abnormal hepatic function and high HBV DNA level group (37.54%+/-18.79%) was lower than that in normal control group (57.38%+/-23.69%); the expression of PF, GrB, GNLY in abnormal hepatic function and high HBV DNA level group (35.47%+/ 29.64%, 66.55%+/-22.92%, 42.03%+/-33.17%) was lower than that in normal hepatic function and high HBV DNA level group (56.98%+/-38.34%, 81.53%+/-19.58%, 59.74%+/ 30.82%) and normal hepatic function and low HBV DNA level groups (62.95%+/ 31.98%, 84.51%+/-14.57%, 61.89%+/-33.3%); there were positive correlations between ef PF, Gr B, GNLY, TNFa, and IFNr. CONCLUSION: The expression of IFNr in NK cells from patients with high HBV DNA replication level is lower than that in normal control group; the expression of PF, Gr B and GNLY in NK cells from patients with normal hepatic function is higher than that in NK cells from patients with abnormal hepatic function. PMID- 20196947 TI - [Identification of HBV genotype-specific tag sequences]. AB - OBJECTIVE: To identify the HBV genotype-specific tag sequence. METHODS: The large S region sequences from 930 HBV genomes were aligned to identify the genotype specific tag sequences. PCR was used to check the genotyping effect of these tags. RESULTS: Two tag sequences, sequence between 149-169 and sequence between 461-483, were identified in the large S region. Using primers specific to these tag sequences, the genotype of HBV can be specifically identified. CONCLUSION: These tag sequences can be used for HBV genotyping. PMID- 20196948 TI - [The effects of different PAP domains on hepatitis B virus replication]. AB - OBJECTIVE: To investigate the effects of different PAP domains on hepatitis B virus replication. METHODS: The full length and two truncated PAP mutants were cloned into a eukaryotic expression plasmid, and were transfected into HepG2.2.15 cells using lipofectamine 2000. 3 days after transfection, the medium and cells were collected. HBsAg and HBeAg were measured using ELISA. The titers of HBV DNA were quantified using fluorogenic quantitative PCR (FQ-PCR). HepG2 cells were used to determine the cytotoxicity of the plasmids transfection by MTT assays. RESULTS: The inhibitory effect on HBV replication of the C-terminal 25 amino acids deleted PAP mutant (pXF3H-PAP14) was not significantly different from that of the full length PAP (pXF3H-PAP12) (Chi-square test = 0.5, 2.0, 0.02, probability value more than 0.05), however, the cytotoxicity of pXF3H-PAP14 was lower than that of pXF3H-PAP12 (Chi-square test = 7.7, probability value less than 0.01). Both N-terminal 69 amino acids deleted mutant and C-terminal 25 amino acids deleted mutant had no cytotoxicity and no antiviral activity. CONCLUSION: C terminal 25 amino acid of PAP is related to cytotoxicity but not related to antiviral activity of PAP. N-terminal 69 amino acid of PAP is related to the anti HBV effect of PAP. PMID- 20196949 TI - [Antiviral effects of entecavir in patients with hepatitis B virus-related cirrhosis]. AB - OBJECTIVE: To analyze antiviral effects of entecavir in patients with hepatitis B virus-related cirrhosis. METHODS: 104 patients of hepatitis B virus-related cirrhosis with no previous history of antiviral therapy were treated with entecavir 0.5 mg once daily. 37 patients were taken hepatic histologic examination before and after the treatment. RESULTS: Mean reductions of serum HBV DNA was 5.1 log10 96 weeks after the treatment, HBV DNA became undetectable in 98.1% patients, and ALT became normal in 80.7% patients; HBeAg seroconversion occurred in 13.9% of the 72 HBeAg positive patients; 61.5% of these patients were infected with genotype C HBV, and 26.9% were infected with genotype B HBV. The genotype of HBV was not associated with the therapeutical effect. Child-pugh score was associated with the progression of the disease: the proportion of patients with disease progression was highest in Child-Pugh C grade patients and lowest in Child-Pugh A grade patients. The level of the HBV DNA load was positively correlated with Knodell HAI score at the baseline and 96 weeks after the treatment. CONCLUSION: Entecavir treatment results in suppression of HBV replication and delayed progression of fibrosis in patients with hepatitis B virus-related cirrhosis. PMID- 20196950 TI - [Therapeutic effect of Haobieyangyinruanjianfang on the mouse liver fibrosis caused by schistosomiasis]. AB - OBJECTIVE: To explore therapeutic effect of Haobieyangyinruanjianfang (HBYYRJ) on mouse liver fibrosis by schistosomiasis. METHODS: Mice except for normal control were infected with Japanese schistosome cercarias, after 12 weeks, infected mice were divided into 7 groups: low HBYYRJ group, middle HBYYRJ group, high HBYYRJ group, Fufangbiejiaruangan tablet (FFBJRG) group, colchicine group, 3 months infection group and 6 months infection group. Hepatic fibrosis was found in 3 months infection group. Liver hydroxyproline (Hyp) was determined, matrix metalloproteinase-2 and 9 (MMP-2, MMP-9) were detected with gelatin zymography, serum hyaluronic acid (HA) and precollagen III (PC-III) were detected using RIA. RESULTS: HBYYRJ obviously reduced hepatic fibrosis (probability value less than 0.01). Collagen and HA in 3 months infection group and 6 months infection group were higher than that in normal group (probability value less than 0.01), collagen in high and middle HBYYRJ groups and HA in middle and low HBYYRJ groups were lower than that in 6 months infection group (P less than 0.01, probability value less than 0.05). The expression of MMP-9 and MMP-2 in 3 months infection group and 6 months infection group was higher than that in normal group (probability value less than 0.01), The expression of MMP-9 in three HBYYRJ groups and the expression of MMP-2 in high HBYYRJ group were lower than that in 6 months infection group (probability value less than 0.05). CONCLUSION: HBYYRJ can reduce liver fibrosis caused by schistosomiasis. PMID- 20196951 TI - [Effects of Smad4 on liver fibrosis and hepatocarcinogenesis in mice treated with CCl4/ethanol]. AB - To study the effects of Smad4 on liver fibrosis and hepatocarcinogenesis in mice treated with CCl(4)/ethanol. The wild-type mice (Smad4 +/+) and the Smad4 knockout mice (Smad4 +/-) were injected subcutaneously with carbon tetrachloride(CCl(4))/ethanol twice a week for twenty weeks. The expression of Smad4, TGFbeta1, Smad2, Smad3, Smad6, TIMP1, MMP2 and MMP9 was detected by RT PCR. In the cirrhotic liver, the expression of Smad4 mRNA was significantly higher than that in the normal liver. Comparing with wild-type mice (Smad4 +/+), the TGFbeta1-Smad4 signaling was markedly attenuated in the Smad4 knockout mice (Smad4 +/-). After induction by CCl(4)/ethanol, the hepatic fibrosis in the Smad4 knockout mice (Smad4 +/-) was obviously alleviated compared with the wild-type mice (Smad4 +/+), and the incidence rate of hepatocarcinogenesis of the former was also lower than that of the latter(32.0% vs 41.9%). These results indicate that knocking out Smad4 can delay the progression of liver fibrosis and liver cancer. PMID- 20196952 TI - [Involvement of endoplasmic reticulum stress in development of fatty liver fibrosis induced by methionine-choline-deficient diet in rats]. AB - OBJECTIVE: To study role of endoplasmic reticulum stress in the development of fatty liver fibrosis induced by methionine-choline-deficient diet in rats. METHODS: Non-alcoholic steatohepatitis was induced by 10 weeks- methionine choline-deficient diet (MCDD), Markers of endoplasmic reticulum stress were determined by immunoblotting and real-time PCR. RESULTS: The number of apoptotic hepatocytes, The expression levels of endoplasmic reticulum stress markers were increased significantly in MCDD group compared to control group (probability value less than 0.05 or probability value less than 0.01), while ratio of hepatocyte proliferation/apoptosis was decreased in MCDD group (probability value less than 0.01). The number of hepatocytes apoptosis, and the expression levels of endoplasmic reticulum stress markers were decreased significantly 2 weeks after the feeding with normal diet in MCDD group (probability value less than 0.05 or probability value less than 0.01). CONCLUSION: MCDD induces endoplasmic reticulum stress and fibrosis in rats. PMID- 20196953 TI - [Effects of silencing chloride intracellular channel 1 gene expression on the proliferation and invasion of mouse hepatocellular carcinoma cell lines]. AB - OBJECTIVE: To study the effects of silencing CLIC1 gene expression on the proliferation and invasion of Hca-F cells. METHODS: The mouse CLIC1 cDNA sequence was retrieved from NCBI. Three shRNA sequences were designed and cloned into pGPU6/GFP/Neo plasmids. The plasmids were transfected into Hca-F cells with Lipofectamine 2000. Cell Counting-8 (CCK-8) kit and transwell chamber were used to study the effects of CLIC1 on the proliferation and invasion of Hca-F cells. RESULTS: The pGPU6/GFP/Neo-shRNA-3 plasmid effectively repressed the expression of CLIC1 mRNA. Inhibition of CLIC1 gene expression led to decreased cell proliferation and reduced invasion. CONCLUSION: CLIC1 is essential for the proliferation and invasion of Hca-F cells. PMID- 20196954 TI - [Characteristics of peripheral NK cells in hepatocellular carcinoma patients]. AB - OBJECTIVE: Functional defects in NK cells have been proposed to be responsible for the impairment of anti-tumor immune responses. However, it remained unclear whether the function of NK cells were impaired in patients with hepatocellular carcinoma. To address this issue, we analyzed the frequency and function of peripheral NK cell subsets in hepatocellular carcinoma (HCC) patients. METHODS: 35 HCC patients and 24 healthy controls (HC) were enrolled in the study. Peripheral NK frequency was analyzed using flow cytometry. In addition, the capacity of NK cells to produce IFN gamma and to lyse K562 cells was evaluated. RESULTS: In contrast with the healthy controls, the frequency of peripheral NK cells in hepatocellular carcinoma patients was decreased (12.19%+/-10.85% vs 24.01%+/-8.78%, u = 4.01, probability value less than 0.01), while the frequency of CD56(bright)CD16(neg) NK cells was increased (0.62%+/-0.39% vs 0.48%+/-0.28%, u = 1.96, probability value less than 0.05), and the frequency of CD56(dim)CD16(pos) NK cells was significantly decreased (11.59%+/-7.49% vs 22.66%+/-8.84%, u = 3.92, probability value less than 0.01). In addition, peripheral NK cells from HCC patients exhibited decreased capacity to produce IFN gamma (effective cells 13.31%) and to lyse K562 cells (mixed ratio 30:1, 10:1, 1:1, effective cells 16.72%+/-7.33% vs 26.29%+/-12.36%, u = 2.52, P less than 0.05, 8.01%+/-4.40% vs 13.09%+/-5.03%, u = 3.32, probability value less than 0.05, 3.51%+/-2.82% vs 3.42%+/-1.64%, u = 1.56, probability value more than 0.05, respectively) as compared with healthy subjects. CONCLUSION: Anti-tumor activity of NK cells in HCC patients was impaired. PMID- 20196955 TI - [Study on gene delivery via the bile duct to rat liver using naked DNA particles]. AB - OBJECTIVE: To evaluate the efficacy of gene delivery to the right lateral lobe of the rat liver via a branch of the bile duct using naked DNA. METHODS: We evaluated regional gene delivery to the right lateral lobe of the rat liver via a branch of the bile duct, using naked DNA, including pGL3, pCMV beta and Cy3 labeled CMV beta. RESULTS: Gene expression was observed in right lateral lobe of both the damaged and the normal rats liver. The gene delivery efficiency was similar in two groups (P > 0.05). Gene expression was found in the right lateral lobe of damaged and normal livers. Fluorescence was observed in the region of the portal triads, and occasionally, in the lobule. CONCLUSION: Retrograde infusion of naked DNA via the bile duct is an effective way to deliver genes to in both damaged and normal rat liver. PMID- 20196956 TI - [The effect and clinical significance of methylation of 14-3-3 sigma gene in hepatitis B virus-related hepatocellular carcinoma]. PMID- 20196957 TI - [Norcantharidin induces apoptosis in SMMC-7721 cells via the c-Jun-NH2-terminal kinase signaling pathways]. PMID- 20196958 TI - [Effect of rosiglitazone on cells cycle, apoptosis and expression of Skp2 and p27Kip1 in hepatocellular carcinoma cell line]. PMID- 20196959 TI - [The value of MSCT and MRI in the diagnosis of hepatic veno-occlusive disease]. PMID- 20196960 TI - [Acute liver injury induced by the bark of olive in 12 patients]. PMID- 20196961 TI - [Huge alveolar echinococcosis of liver presenting with organ shift, elevation of the left dome of diaphragm misdiagnosis as diaphragmatic hernia: a case report]. PMID- 20196962 TI - [Noninvasive diagnosis of fatty liver disease]. PMID- 20196963 TI - [The roles of cyclooxygenase-2 and 5-lipoxygenase in liver disease]. PMID- 20196964 TI - The effect of N-3 fatty acids on plasma myeloperoxidase levels in healthy adults. AB - OBJECTIVE: To examine the effect of marine n-3 polyunsaturated fatty acids (PUFA) supplementation in a low to moderate and a high dose on plasma levels of myeloperoxidase (MPO) in healthy individuals. BACKGROUND: Atherosclerosis is a chronic inflammatory disease and MPO, which is secreted primarily from activated neutrophils and monocytes, has pro-inflammatory properties and has been linked with both initiation and propagation of atherosclerosis. Marine n-3 PUFA have anti-inflammatory properties, but whether n-3 PUFA affect plasma levels of MPO is largely unknown. METHODS: Sixty healthy adults were randomized to three groups receiving either 6.6 g PUFA/day, 2.0 g PUFA/day or a control oil (olive oil) for 12 weeks. Blood samples were drawn at baseline and after exposure. Plasma levels of MPO were measured using a MPO ELISA-kit (from Mercodia, Uppsala, Sweden) with specific mouse monoclonal antibodies. RESULTS: Plasma MPO concentrations (microg/L) at baseline were 36.9 +/- 9.4; 36.2 +/- 7.1 and 35.4 +/- 11.3 (for high dose-, low dose- and control-group, respectively). After 12 weeks of supplementation we found no significant changes in plasma MPO in any of the groups nor between groups, with values after intervention of 36.1 +/- 8.6; 37.0 +/- 8.2 and 34.4 +/- 11.1, respectively. CONCLUSION: Supplementation with n-3 PUFA has no effect on plasma levels of MPO in healthy adults with low baseline levels of MPO. PMID- 20196965 TI - Fatty acid composition of the internal mammary artery in relation to dietary intake of marine n-3 polyunsaturated fatty acids and association with flow mediated vasodilation. AB - Some evidence suggests that long-chain marine n-3 polyunsaturated fatty acids (n 3 PUFA) may increase production of vasodilatory nitric oxide from vascular endothelium. Fatty acids may therefore play a role for the left internal mammary artery (LIMA) graft function in coronary artery bypass grafting (CABG). However, little is known about the composition of fatty acids in the vessel wall of the LIMA. Using gas chromatography we investigated fatty acid composition in segments of the LIMA, in plasma nonesterified fatty acids (NEFA), in plasma phospholipid (PL) and in the pericardial adipose tissue (PAT) from 22 patients undergoing CABG. Furthermore, we investigated whether there was an association between the n 3 PUFA composition in LIMA and flow-mediated vasodilation (FMD). Self-reported fish consumption and supplementation of eicosapentaenoic acid and docosahexaenoic acids were reflected by the fatty acid composition in NEFA, PL and in PAT, but less so in the LIMA. There was no association between FMD and fatty acid composition of the LIMA. PMID- 20196966 TI - Studies on very long chain marine n-3 fatty acids in patients with atherosclerotic heart disease with special focus on mechanisms, dosage and formulas of supplementation. AB - Based on experience from randomised trials with n-3 PUFA we intend to answer some relevant questions in patients with coronary heart disease. In the SHOT study supplementation with 3.4 g/day of highly concentrated n-3 PUFA for 1 year significantly reduced the occlusion rate of venous aortocoronary bypass grafts, and this effect correlated significantly to the change in serum levels of n-3 fatty acids. In the CART study 5.1 g/day of highly concentrated n-3 PUFA did not reduce the incidence of restenosis after 6 months. If anything, a negative effect was observed. The background for this was probably a pro-oxidative and proinflammatory mechanism as elucidated in substudies. In the OVITES trial the addition of vitamin E did not counteract the proinflammatory effect of high amounts of n-3 PUFA supplementation as observed in CART, although circulating oxidative substances were unaffected. In the "Fiord-to-table" study replacement of fish oils by vegetable oils in the feed of farmed Atlantic salmon was mirrored in the fatty acid profile of the salmon fillets as well as in that of serum from patients after ingesting about 700 g/week for six weeks. A parallel reduction of the proinflammatory profile was observed only in patients who ingested salmon fed on fish oil. PMID- 20196967 TI - Omega-3 (n-3) fatty acids, cardiovascular disease and stability of atherosclerotic plaques. AB - Long-chain n-3 polyunsaturated fatty acids are found in oily fish and in fish oils and similar preparations. Substantial evidence from epidemiological and case control studies indicates that consumption of fish, oily fish and long-chain n-3 fatty acids reduces risk of cardiovascular mortality. Secondary prevention studies using long-chain n-3 fatty acids in patients post-myocardial infarction have shown a reduction in total and cardiovascular mortality with an especially potent effect on sudden death. Long-chain n-3 fatty acids have been shown to beneficially modify a range of cardiovascular risk factors, which may result in primary cardiovascular prevention. However, reduced non-fatal and fatal events and a reduction in sudden death probably involve other mechanisms. Reduced thrombosis following long-chain n-3 fatty acids may play a role. A decrease in arrhythmias is a favoured mechanism of action of long-chain n-3 fatty acids and is supported by cell culture and animal studies. However human trials using implantable cardiac defibrillators have produced inconsistent findings and a recent meta-analysis does not support this mechanism of action. An alternative mechanism of action may be stabilisation of atherosclerotic plaques by long-chain n-3 fatty acids. This is suggested by one published human study which showed that incorporation of long-chain n-3 fatty acids into plaques collected at carotid endarterectomy resulted in fewer macrophages in the plaque and a morphology indicative of increased stability. These findings are supported from observations in an animal model and suggest that the primary effect of long-chain n-3 fatty acids might be on macrophages within the plaque. PMID- 20196968 TI - Flow-mediated vasodilation and dietary intake of n-3 polyunsaturated acids in healthy subjects. AB - Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the two major marine n-3 polyunsaturated fatty acids (PUFA), have been proposed to decrease the risk of atherosclerosis and coronary heart disease. An early event during atherogenesis is endothelial dysfunction. We studied the correlation between fish consumption, serum phospholipid (sPL) levels of DHA and EPA and flow-mediated vasodilation (FMD), a measure of endothelial function. Furthermore, subjects were classified according to whether they did (Fish+, n = 19) or did not (Fish-, n = 21) follow the Danish recommendations, consuming at least 300 g fish/week. Neither the fish intake, sPL EPA nor sPL DHA significantly correlated with FMD, 0.20 (p = 0.23), -0.23 (p = 0.15) and -0.06 (p = 0.72), respectively. Also, when comparing the Fish+ and the Fish- group we did not find any significant differences in FMD (p = 0.33). In conclusion, our results did not show any correlation between intake and sPL levels of marine n-3 PUFA and FMD in healthy subjects. PMID- 20196969 TI - Effects of marine n-3 fatty acids on circulating levels of soluble adhesion molecules in patients with chronic heart failure. AB - Inflammatory markers as circulating soluble cellular adhesion molecules (sCAMs) and high sensitive C-reactive protein (hsCRP) are elevated in patients with chronic heart failure (CHF), and may constitute an increased risk of adverse outcome. Marine n-3 polyunsaturated fatty acids ( n-3 PUFA) may have anti inflammatory effect and reduce levels of sCAMs (soluble intercellular adhesion molecule-1 (sICAM-1), vascular adhesion molecule-1 (sVCAM-1), P-selectin) and hsCRP. In a randomized, controlled trial, 138 patients with NYHA class II-III CHF were allocated to receive a daily supplement of 0.9 g of n-3 PUFA or olive oil for 24 weeks. After supplementation, no significant changes occurred in sCAMs or hsCRP after adjusting for possible confounders. However, a significant reduction was observed in sP-selectin in patients receiving n-3 PUFA, but this result was only of borderline significance in a between-group analysis. In conclusion, a daily supplement with 0.9 g of n-3 PUFA does not significantly affect plasma levels of sCAMs or hs-CRP in patients with CHF. n-3 PUFA may reduce sP-selectin, indicating a possible effect on platelet (and endothelial) activation. The results also indicate that the low dose of n-3 PUFA used in many intervention trials does not have deleterious effects on sCAMs or hsCRP. PMID- 20196970 TI - Lack of effect of cold water prawns on plasma cholesterol and lipoproteins in normo-lipidaemic men. AB - OBJECTIVE: Dietary guidelines for the prevention of coronary heart disease (CHD) have restricted the intake of foods rich in dietary cholesterol, on the grounds that the dietary cholesterol will increase blood cholesterol. In the case of shellfish, this recommendation may limit the intake of a valuable dietary source of long chain n-3 polyunsaturated fatty acids (LC n-3 PUFA). The objective of this study was to undertake a dietary intervention to determine the effects of cold water prawns on plasma lipids and lipoproteins. METHODS: 23 healthy male subjects were randomised to receive either 225 g of cold water prawns or an equivalent weight of fish ('crab') sticks as a control for 12 weeks in a cross over design. Blood samples were taken at the beginning and end of each intervention for the determination of plasma lipids and lipoproteins by routine enzymatic assays and iodixanol density gradient centrifugation respectively. RESULTS: The diets were well matched for the intake of total energy and macronutrients, and body weight remained stable throughout the study. The prawn intervention increased the intake of dietary cholesterol to 750 mg/d against 200 mg/d on the control. The intake of LC n-3 PUFA from prawns was estimated to be between 0.5-0.7 g/d. The consumption of prawns produced no significant effects on the concentration of plasma total or LDL cholesterol, triacylglycerol, HDL cholesterol or apolipoproteins A-I and B relative to the control, or within each intervention group over time. There was also no significant effect on LDL density (particle size) relative to the control, or any difference between and within treatments in total plasma lipoprotein profiles by density gradient centrifugation. CONCLUSION: These findings provide evidence to suggest that the consumption of cold water prawns, at least in healthy, male subjects, should not be restricted on the grounds of this seafood producing an adverse effect on plasma LDL cholesterol. PMID- 20196971 TI - Omega-3 fatty acids, inflammation and angiogenesis: basic mechanisms behind the cardioprotective effects of fish and fish oils. AB - Atherosclerosis is now widely accepted to be an inflammatory disease, characterized by degenerative as well as proliferative changes and extracellular accumulation of lipid and cholesterol, in which an ongoing inflammatory reaction plays an important role both in initiation and progression/destabilization, converting a chronic process into an acute disorder. Neovascularization has also been recognized as an important process for the progression/destabilization of atherosclerotic plaques. In fact, vulnerable atherosclerotic plaques prone to rupture are characterized by an enlarged necrotic core, containing an increased number of vasa vasorum, apoptotic macrophages, and more frequent intraplaque haemorrhage. Various functional roles have been assigned to intimal microvessels, however the relationship between the process of angiogenesis and its causal association with the progression and complications of atherosclerosis are still challenging and controversial. In the past 30 years, the dietary intake of omega 3 (n-3) polyunsaturated fatty acids--mainly derived from fish--has emerged as an important way to modify cardiovascular risk through beneficial effects on all stages of atherosclerosis, including plaque angiogenesis. This review specifically focuses on the modulating effects of n-3 fatty acids on molecular events involved in early and late atherogenesis, including effects on endothelial expression of adhesion molecules, as well as pro-inflammatory and pro-angiogenic enzymes. By accumulating in endothelial membrane phospholipids, omega-3 fatty acids have been shown to decrease the transcriptional activation of several genes through an attenuation of activation of the nuclear factor-kappaB system of transcription factors. This occurs secondary to decreased generation of intracellular reactive oxygen species. This series of investigations configures a clear example of nutrigenomics--i.e., how nutrients may affect gene expression, ultimately affecting a wide spectrum of human diseases. PMID- 20196972 TI - Omega-3 fatty acids and blood pressure. AB - There is substantial evidence that omega-3 fatty acids reduce blood pressure, with a greater effect in hypertensive patients and those with high-normal blood pressure. The dose of omega-3 fatty acids required to achieve a blood pressure reduction is likely to be at least 3-4 g/day. However, the magnitude of the blood pressure change can be increased by salt restriction or when omega-3 fatty acids are incorporated into a weight reducing program. It is also highly plausible that increased omega-3 fatty acid consumption as part of a dietary change including increased consumption of fruits and vegetables, and moderation of salt intake, will confer significant cardiovascular benefit. PMID- 20196973 TI - Omega-3 fatty acids vs. cardiac disease--the contribution of the omega-3 index. AB - Although statistically and clinically significant, reductions of clinical events seen in large scale intervention studies with omega-3 fatty acids in the cardiovascular field were smaller than would have been predicted from the results of epidemiologic studies. In epidemiologic studies, assessment of intake of fish or eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) predicted clinical events less well than assessing blood levels of EPA and DHA, e.g. by the Omega-3 Index. The Omega-3 Index is the percentage of EPA+DHA in red cell lipids, determined with a highly standardized methodology. Using the perspective of the Omega-3 Index facilitates reconciling discrepancies in results from intervention studies and from epidemiologic studies. Moreover, a low Omega-3 Index can be considered a risk factor for sudden cardiac death and for non-fatal cardiovascular events, whereas a high Omega-3 Index can be used as a therapeutic target. Currently ongoing and future scientific work on the basis of the Omega-3 Index will further define its value. PMID- 20196974 TI - Serum concentrations of matrix metalloproteinase-9, tissue inhibitor of matrix metalloproteinase-1 and alpha2-macroglobulin in healthy subjects after supplementation with different doses of marine n-3 fatty acids. AB - OBJECTIVE: Extracellular matrix modification by matrix metalloproteinase-9 (MMP 9), tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) and alpha2 macroglobulin may affect the stability of atherosclerotic plaques. Marine n-3 polyunsaturated fatty acids (n-3 PUFA) may protect against plaque rupture. The aim was to investigate the effect of marine n-3 PUFA supplementation on serum levels of MMP-9, TIMP-1, and alpha2-macroglobulin. METHODS: Healthy volunteers were randomized to receive capsules contributing either 6.6 g marine n-3 PUFA/day, 2.0 g marine n-3 PUFA/day or 6.6 g of olive oil (control). Serum MMP-9, TIMP-1 and alpha2-macroglobulin was measured at baseline and after 12 weeks of supplementation. One way ANOVA or Kruskal-Wallis test was used to compare groups. RESULTS: 60 healthy volunteers were enrolled and no subjects dropped out of the 12 week study. There were no statistically significant changes in serum levels of MMP-9, TIMP-1, and alpha2-macroglobulin in any of the three treatment groups (P=0.85, P=0.23 and P=0.87, respectively). CONCLUSION: Supplementation with marine n-3 PUFA had no effect on serum levels of MMP-9, TIMP-1 and alpha2 macroglobulin in healthy subjects. The possible protection offered by marine n-3 PUFA against plaque rupture is therefore unlikely to be mediated through a change in serum levels of MMP-9, TIMP-1 and alpha2-macroglobulin. PMID- 20196975 TI - N-3 polyunsaturated fatty acids in heart failure: mechanisms and recent clinical evidence. AB - Over the past 20 years, there has been significant progress in our knowledge of the pathophysiology of heart failure (HF) with consequent considerable development of both pharmacological and non pharmacological approaches. Despite improved therapeutic strategies, HF still remains burdensome in terms of mortality, quality of life, and hospitalization costs. A new and promising medical treatment to improve survival in HF patients stems from the recent results of the Italian study, Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Heart Failure (GISSI-HF). GISSI-HF was a randomized, large scale, double-blind, placebo-controlled trial showing that n-3 PUFA (850 882 mg/d) reduced mortality and admission to the hospital for cardiovascular reasons in patients with chronic heart failure (HF) who were already receiving recommended therapies. The clinical benefit observed in GISSI-HF seemed to be mediated prominently by the antiarrhythmic effects of n-3 PUFA, though an effect on mechanisms related to HF progression cannot be excluded. This article presents the results of GISSI-HF study and reviews the previous clinical evidence on n-3 PUFA and risk of heart failure and discusses in depth the potential mechanisms through which n-3 PUFA treatment can improve clinical outcome in HF patients. PMID- 20196976 TI - N-3 fatty acids and cardiac autonomic function in humans. AB - Studies suggest that marine n-3 polyunsaturated fatty acids (PUFA) offer some protection against sudden cardiac death (SCD). The autonomic nervous system is involved in the pathogenesis of SCD and due to the fact that n-3 PUFA is abundant in the brain and other nervous tissue it is likely that n-3 PUFA might modulate autonomic control of the heart. Heart rate variability (HRV) is a non-invasive marker of cardiac autonomic function and an attenuated HRV is a predictor for SCD and arrhythmic events. Studies on HRV and n-3 PUFA have been performed in several populations such as patients with ischaemic heart disease, patients with diabetes mellitus, patients with chronic renal failure, and in healthy subjects. Many studies have demonstrated a positive association between cellular content of n-3 PUFA and HRV as well as supplementation with n-3 PUFA seems to increase HRV and thereby decreasing the risk of arrhythmic events and SCD. PMID- 20196977 TI - A blinded, randomized comparison of immediate-release and extended-release carbamazepine capsules in manic and depressed bipolar subjects. AB - BACKGROUND: The anticonvulsant carbamazepine is approved by the FDA for treatment of acute mania. It is available in 2 formulations: immediate-release (IR) and extended-release carbamazepine capsules (ERCC). The relative efficacy of these formulations in acutely ill bipolar patients has not been previously investigated. METHODS: This study is a subanalysis of a 3-month, blinded, equal, random-assignment comparison of adverse effect load of an IR carbamazepine formulation (Tegretol) and ERCC (Equetro) in type I or type II bipolar patients already receiving carbamazepine or clinically determined to benefit from carbamazepine treatment. Dosages were titrated to patients' clinical needs. Subjects who scored >15 on the Montgomery Asberg Depression Rating Scale (MADRS) or >14 on the Young Mania Rating Scale (YMRS) were included in this analysis. The primary outcome measures were the relative mood scores at the end of the study. RESULTS: At the end of 3 months of treatment, all patients improved compared with their baseline, but there was no difference in mood ratings in subjects with an initial MADRS >15 (ERCC, 18.2 +/- SD 11.9, vs IR, 12.0 +/- 4.5; P = .3) or YMRS >15 (ERCC, 6.5 +/- 6.4, vs IR, 4.7 +/- 3.1; P = .7). When compared with their baseline, patients receiving IR improved earlier than patients receiving ERCC. There were no differences in overall adverse events in patients receiving IR or ERCC (23.1 +/- 13.42 vs 22.3 +/- 13.40; P = .9). CONCLUSIONS: Carbamazepine is effective in treating symptoms of both mania and depression, and there are no significant differences in the relative efficacy of the IR or ERCC formulations. PMID- 20196978 TI - Assessment of monitoring for glucose and lipid dysregulation in adult Medi-Cal patients newly started on antipsychotics. AB - BACKGROUND: Because patients receiving antipsychotics are at increased risk for coronary heart disease, standards of care for such patients now include periodic glucose and lipid testing. The objective of this study was to examine rates of glucose and lipid monitoring among adult Medicaid patients initiated on antipsychotic therapy. METHODS: California Medicaid (Medi-Cal) claims of 6601 patients identified as "new" antipsychotic users between July 1, 2004 and June 30, 2005 were analyzed. Rates of glucose and lipid testing were compared for 6 months prior to and post-initiation of antipsychotic therapy. Odds ratios (ORs) for testing associated with first-generation antipsychotic (FGA) and second generation antipsychotic (SGA) use were determined while controlling for patient level factors. RESULTS: In a multivariate analysis, SGA patients were more likely than FGA patients to undergo glucose testing (OR, 1.38; 95% confidence interval [CI], 1.13 to 1.70; P < .01) and lipid testing (OR, 1.43; 95% CI, 1.14 to 1.81; P < .01), respectively. SGA patients were also more likely than FGA patients to receive both glucose and lipid testing in the 6 months following initiation of antipsychotic treatment (OR, 1.40; 95% CI, 1.11 to 1.79, P < .01). CONCLUSION: Although increases in glucose and lipid testing rates were observed among Medi Cal patients after initiation of antipsychotic therapy, recommended monitoring does not appear to occur universally in this population. Interventions to increase monitoring of these patients are warranted. PMID- 20196980 TI - Increased incidence of sleep apnea in psychiatric outpatients. AB - BACKGROUND: The rate of mood disorders in patients in sleep centers has been the subject of many studies, yet little has been published on the incidence of sleep apnea in psychiatric patients. METHODS: A retrospective chart review was performed on 330 consecutively seen psychiatric outpatients. Medication history, demographics, and the results of patients' most recent Quick Inventory of Depressive Symptomatology (QIDS) were collected. Patients were checked for a history of apnea through a review of session notes and the results of any polysomnogram that the patient had on file. RESULTS: Of the patients studied, 9.7% were positive for sleep apnea. They required a significantly higher number of medications (3.2 vs 2.4; P < .001). They also scored significantly higher on 3 items on the QIDS: late insomnia (1.0 vs 0.55; P < .01), reduced energy level (1.2 vs 0.76; P < .02), and decreased general interest (1.0 vs 0.64; P < .04). Middle age in men (age 45 to 64) and higher body mass index both in men and women were also associated with a higher frequency of sleep apnea. CONCLUSION: Sleep apnea is more prevalent in psychiatric outpatients than in the general population. Identification of this comorbid condition will likely result in better treatment outcomes. PMID- 20196979 TI - Early childhood adversity and later hypertension: data from the World Mental Health Survey. AB - BACKGROUND: Although many studies have indicated that psychosocial factors contribute to hypertension, and that early childhood adversity is associated with long-term adverse mental and physical health sequelae, the association between early adversity and later hypertension is not well studied. METHOD: Data from 10 countries participating in the World Health Organization (WHO) World Mental Health (WHM) Surveys (N = 18,630) were analyzed to assess the relationship between childhood adversity and adult-onset hypertension, as ascertained by self report. The potentially mediating effect of early-onset depression-anxiety disorders, as assessed by the WHM Survey version of the International Diagnostic Interview (WMH-CIDI), on the relationship between early adversity and hypertension was also examined. RESULTS: Two or more early childhood adversities, as well as early-onset depression-anxiety, were significantly associated with hypertension. A range of specific childhood adversities, as well as early-onset social phobia and panic/agoraphobia, were significantly associated with hypertension. In multivariate analyses, the presence of 3 or more childhood adversities was associated with hypertension, even when early-onset depression anxiety or current depression-anxiety was included in the model. CONCLUSIONS: Although caution is required in the interpretation of self-report data on adult onset hypertension, the results of this study further strengthen the evidence base regarding the role of psychosocial factors in the pathogenesis of hypertension. PMID- 20196981 TI - Dietary saturated fat intake and glucose metabolism impairments in nondiabetic, nonobese patients with schizophrenia on clozapine or risperidone. AB - BACKGROUND: High dietary saturated fat (SF) intake is strongly linked to metabolic disturbances. The goal of this study was to understand the relationship between clozapine and risperidone with glucose and lipid metabolism and dietary fat intake in patients with schizophrenia. METHODS: Thirty-one clozapine-treated patients and 15 risperidone-treated patients were assessed using a 4-day dietary record, an IV glucose tolerance test, and lipid profiles. RESULTS: Clozapine treated patients consumed a significantly higher percentage of SF than did risperidone-treated patients (13.7% +/- 3.4% vs 10.6% +/- 3.0 % of total energy; P = .007). Compared with the risperidone group, the clozapine group also had a significantly higher percentage of total fat in their diet (36% +/- 6.7% vs 30.9% +/- 5.7% of total energy; P = .007). Similarly, the clozapine group had a significant impairment in insulin sensitivity index (SI), glucose effectiveness (SG), and disposition index (DI) compared with the risperidone group (P < .05). Pearson correlation analysis of both groups showed that dietary SF was significantly correlated with impairment in glucose homeostasis (SG: r = -0.43; P = .004; DI: r = -0.35; P = .02). CONCLUSION: Abnormal glucose homeostasis in atypical clozapine-treated patients with schizophrenia may be associated with or aggravated by high dietary SF consumption. PMID- 20196982 TI - Health-related quality of life in depression: a STAR*D report. AB - BACKGROUND: Although major depressive disorder (MDD) is associated with significant impairments in health-related quality of life (HRQOL), few studies have evaluated HRQOL dysfunction in multiple domains. This report examined the psychological, physical, and social domains in a large sample of outpatients who entered the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. METHODS: The relationship of HRQOL and baseline sociodemographic and clinical features, including depressive severity, was evaluated. We assessed HRQOL with the 12-item Short Form Health Survey, the 5-item Work and Social Adjustment Scale, and the 16-item Quality of Life Enjoyment and Satisfaction Questionnaire. RESULTS: Among 2307 participants, greater depressive symptom severity was associated with poorer HRQOL. After controlling for age and depression severity, lower HRQOL was related independently to being African American or Hispanic, less educated, unemployed, divorced or separated, having public medical insurance, and to having more general medical disorders. We found impairments across all 3 domains, with low correlations between the 3 measures of HRQOL chosen, suggesting that they evaluate different and nonoverlapping aspects of function. CONCLUSION: Sociodemographically disadvantaged patients with greater general medical and depressive illness burden are at greatest risk for poorer quality of life. Distinct impairments are seen in the 3 domains of HRQOL. PMID- 20196983 TI - Augmentation with naltrexone to treat compulsive sexual behavior: a case series. AB - BACKGROUND: Compulsive sexual behavior (CSB) is generally characterized by recurrent and intense sexually arousing fantasies, sexual urges, and behaviors, which cause individuals distress or impair daily functioning. Descriptive studies of individuals with paraphilic and nonparaphilic CSB indicate that they experience urges to engage in problematic sexual behavior. The opiate antagonist naltrexone has been successfully used to treat a number of disorders in which urges to engage in problematic behavior are a central feature, such as alcoholism. We hypothesized that naltrexone would reduce the urges and behaviors associated with CSB. METHODS: Records of 19 male patients with CSB who were treated with naltrexone at an outpatient adult sexual health clinic were retrospectively reviewed. RESULTS: Nearly all patients were already taking other psychotropic medications when naltrexone was initiated. Seventeen (89%) of the 19 patients reported a reduction in CSB symptoms when taking naltrexone for a period ranging from 2 months to 2.3 years, as judged by Clinical Global Impression scores of 1 or 2, indicating "very much improved" or "much improved." Five (26%) of the 19 patients chose to discontinue the medication. CONCLUSIONS: Naltrexone may be a useful adjunctive treatment for CSB. PMID- 20196984 TI - Sudden cardiac death in genetic heart diseases and the promise of prevention. PMID- 20196985 TI - Sedentary behaviour and biomarkers of cardiometabolic health risk in adolescents: an emerging scientific and public health issue. PMID- 20196986 TI - Hypertension and analgesic intake: light and shade on an old problem. PMID- 20196987 TI - Characteristics of sudden death in inherited heart disease. AB - INTRODUCTION AND OBJECTIVES: Cardiomyopathy and channelopathy are major causes of sudden death (SD). The little information available on the context in which SD occurs has come from only a few referral centers. The objective was to investigate the circumstances surrounding SD in families with inherited heart disease. METHODS: The study included 152 SD patients (mean age 43+/-19 years) from 103 families. The reasons for inclusion were resuscitated SD in 7%, recent SD in 8%, and a diagnosis of cardiomyopathy or channelopathy in a living relative in 72%. Also, 13% were athletes. Family trees were constructed and each death's circumstances were recorded. Autopsy and medical records were reviewed. RESULTS: Overall, 18% of SDs occurred during physical exercise, 32% during normal daily activities, and 37% during rest or sleep. There was a significant association between male sex and SD: 111 males (73%) vs. 41 females (27%; P=.03). Exercise related SD was associated with young age (P=.01). The percentage of SDs associated with exercise, stress or normal daily activities was significantly greater with cardiomyopathy than channelopathy (61% vs. 41%; P=.057). All athletes were male and the majority died during exercise (50% vs. 11% of non athletes; P=.0002). Patients with Brugada syndrome had the highest percentage of SDs during rest or sleep (i.e. 47%). No clear trigger could be identified in 33%. CONCLUSIONS: SD was common in inherited heart disease, which accounted for a significant number of cases. Males clearly predominated over females (ratio 3:1) among SD cases (irrespective of pathological type). Most SDs occurred during exercise or normal daily activities in cardiomyopathies and during rest or sleep in channelopathies. The percentage of exercise-related SDs (i.e. 18%) was higher than expected. PMID- 20196988 TI - Sedentary behavior, adiposity and cardiovascular risk factors in adolescents. The AFINOS study. AB - INTRODUCTION AND OBJECTIVES: To investigate the association between objective measures of sedentary behavior and cardiovascular risk factors (CRFs) in adolescents. A secondary aim was to evaluate the degree of association between overall and abdominal adiposity and CRFs. METHODS: This cross-sectional study involved 210 adolescents aged 13-17 years. Measurements were made of the sum of the skinfold thicknesses at six locations (sum6), waist circumference (WC), systolic (SBP) and diastolic blood pressure (DBP), glucose, total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), and apolipoproteins A-1 and B-100. A CRF score was calculated from the mean arterial pressure (MAP) and TG, HDL-C and glucose levels. Sedentary behavior was assessed over 7 days using an accelerometer. Participants were divided into tertiles according to sedentary behavior and into low and high levels of overall (sum6) and abdominal (WC) adiposity. RESULTS: Adolescents with a high level of sedentary behavior had less favorable SBP, TG and glucose levels and CRF scores. Adolescents with a high level of overall adiposity demonstrated significant differences in five of the 11 variables analyzed (i.e. DBP, LDL-C, TC, apolipoprotein B-100 and CRF score), while adolescents with a high level of abdominal adiposity had differences in eight (i.e. SBP, MAP, HDL-C, LDL-C, TG, TC, apolipoprotein B-100 and CRF score). Adolescents with high levels of both overall and abdominal adiposity and sedentary behavior had the least favorable CRF scores. CONCLUSIONS: Sedentary behavior was associated with CRFs in adolescents, especially in obese adolescents. Abdominal adiposity seemed to play a more significant role in the development of CRFs than overall adiposity. PMID- 20196989 TI - Aspirin, non-aspirin analgesics and the risk of hypertension in the SUN cohort. AB - INTRODUCTION AND OBJECTIVES: The use of aspirin and non-aspirin analgesics has been associated with changes in blood pressure. The aim of this study was to investigate prospectively the association between the regular use of aspirin and non-aspirin analgesics and the incidence of hypertension. METHODS: The SUN project is an ongoing, continuously expanding, prospective cohort of Spanish university graduates initially free of hypertension, cardiovascular disease, diabetes and cancer; 9986 (mean age 36 years) were recruited during 1999-2005 and followed up for a mean of 51 months. Regular aspirin and non-aspirin analgesic use and the presence of other risk factors for hypertension were assessed by questionnaire at baseline, and the incidence of hypertension was assessed using biennial follow-up questionnaires. RESULTS: In total, 543 new cases of hypertension were identified during follow-up. Regular aspirin use (i.e. 2 or more days/week) was associated with a higher risk of hypertension (hazard ratio=1.45; 95% confidence interval, 1.02-2.04) after adjustment for various confounding factors. Regular use of non-aspirin analgesic drugs was also associated with a higher risk of hypertension (hazard ratio=1.69; 95% confidence interval, 1.28-2.23). CONCLUSIONS: The regular use of aspirin and non-aspirin analgesics were both associated with an increased risk of developing hypertension, independently of other risk factors. PMID- 20196990 TI - Worsening renal function in patients admitted with acute decompensated heart failure: incidence, risk factors and prognostic implications. AB - INTRODUCTION AND OBJECTIVES: Acute decompensated heart failure (ADHF) is a common cause of hospital admission and is associated with an increased risk of worsening renal function (WRF). The aims of this study were to investigate the incidence and predictors of WRF in patients admitted for ADHF and to assess the prognostic significance of WRF at 1 year. METHODS: A retrospective analysis of data on 200 consecutive patients admitted with ADHF was carried out. By definition, WRF occurred when the serum creatinine level increased during hospitalization by 0.3 mg/dL and by > or =25% from admission. RESULTS: Overall, 23% of patients developed WRF. On multivariate analysis, age >80 years (odds ratio [OR]=2.72; 95% confidence interval [CI], 1.86-3.42), admission glomerular filtration rate <60 mL/min per 1.73 m2 (OR=2.05; 95% CI, 1.53-2.27) and admission systolic pressure <90 mmHg (OR=1.61, 95% CI, 1.17-3.22) were independently associated with WRF. The rate of mortality or readmission for heart failure (HF) at 1 year was higher in the WRF group (P< .01 by log-rank test). The median hospital stay was 9 days for patients with WRF and 4 days for those without (P< .05). On multivariate analysis, WRF remained independently associated with mortality or HF rehospitalization (hazard ratio=1.65; 95% CI, 1.12-2.67; P=.003). CONCLUSIONS: In patients admitted for ADHF, WRF was a common complication and was associated with a longer hospital stay and an increased risk of mortality or HF hospitalization. Clinical characteristics at admission can help identify patients at an increased risk of WRF. PMID- 20196991 TI - Mortality and cause of death in patients with heart failure: findings at a specialist multidisciplinary heart failure unit. AB - INTRODUCTION AND OBJECTIVES: Heart failure mortality is similar to or even higher than that due to various cancers. It is usually associated with disease progression, though sudden death has also been reported as a frequent cause of mortality. The objectives of this study were to investigate mortality and its causes in outpatients with heart failure of different etiologies who were treated in a specialist multidisciplinary unit, and to identify associated factors. METHODS: The follow-up cohort study (median duration 36 months) involved 960 patients (70.9% male; median age 69 years; ejection fraction 31%; and the majority had an ischemic etiology and were in functional class II or III). RESULTS: Overall, 351 deaths (36.5%) occurred: 230 due to cardiovascular causes (65.5%), mainly heart failure (33.2%) and sudden death (16%); 94 due to non cardiovascular causes (26.8%), mainly malignancies (10.5%) and septic processes (6.8%); and 27 (7.7%) due to unknown causes. Mortality was independently associated with age, sex, functional class, ejection fraction, time since symptom onset, ischemic etiology, diabetes, creatinine clearance rate, peripheral vascular disease, fragility, and the absence of treatment with an angiotensin converting enzyme inhibitor or angiotensin-II receptor blocker, beta-blockers, statins or antiplatelet agents. The principal factor associated with cardiovascular death was an ischemic etiology. No factor studied clearly predicted sudden death. CONCLUSIONS: Even though mortality in patients treated at a specialist heart failure unit was not low, a quarter died from non cardiovascular causes. The principal factor associated with cardiovascular death was an ischemic etiology. Only 5.8% of the study population experienced sudden death. PMID- 20196992 TI - Prevalence of patent foramen ovale determined by transesophageal echocardiography in patients with cryptogenic stroke aged 55 years or older. Same as younger patients? AB - INTRODUCTION AND OBJECTIVES: To investigate the relationship between patent foramen ovale and cryptogenic stroke in patients aged > or =55 years. METHODS: This prospective study determined the presence of patent foramen ovale and atrial septal aneurysm using transesophageal echocardiography in 262 consecutive patients with a diagnosis of probable cryptogenic stroke. Data from 44 patients aged > or =55 years with cryptogenic stroke (Group A) were compared with those from two other groups: 194 patients aged <55 years with cryptogenic stroke (Group B) and 24 control patients aged > or =55 years with stroke of known origin, namely grade III-V aortic atheromatosis (Group C). RESULTS: The frequency of patent foramen ovale in Group A was similar to that in Group B (38% vs. 36%; P=.85) but significantly higher than that in Group C (38% vs. 8%; P=.029). The frequency of patent foramen ovale with concomitant atrial septal aneurysm was significantly higher in the study group (Group A) than in the control Group C (18% vs. 0; P=.039) and non-significantly higher than in Group B (18% vs. 11%; P=.11). CONCLUSIONS: The frequency of patent foramen ovale alone or in association with atrial septal aneurysm in patients with cryptogenic stroke aged > or =55 years was similar to that in those aged <55 years, but higher than that in patients aged > or =55 years with stroke of atherosclerotic origin. These data suggest that paradoxical embolism could be a cause of stroke in both age groups. PMID- 20196993 TI - Increasing high-density lipoprotein as a therapeutic target in atherothrombotic disease. AB - Atherothrombosis, atherosclerosis and their thrombotic complications have become epidemic. Both an elevated low-density lipoprotein (LDL) cholesterol level and a decreased high-density lipoprotein (HDL) cholesterol level are associated with the increased incidence of atherothrombosis. Reducing LDL using statins has been shown to provide very effective therapy for both primary and secondary prevention. Nevertheless, despite statin treatment, a large percentage of patients continues to experience cardiovascular events. Therapies aimed at increasing HDL have been investigated for several decades, with promising RESULTS: However, because statin treatment was not standardized in earlier trials, it has been difficult to draw clear CONCLUSIONS: Recent advances in both animal studies and clinical trials indicate that increasing the HDL level could result in additional benefits to those achieved by reducing LDL levels using statins. Intravenous infusion of various HDL preparations appears to lead to the accelerated regression and stabilization of atheromatous plaque, and could provide a novel approach to treatment in high-risk patients. This review describes the biological rationale underlying the use of treatments that increase HDL and discusses the potential benefits of such treatment. PMID- 20196994 TI - The right heart and pulmonary circulation (III). The pulmonary circulation in heart failure. AB - Pulmonary hypertension due to left heart disease is a pathophysiological and hemodynamic state which is present in a wide range of clinical conditions that affect left heart structures. Although the pulmonary circulation has traditionally received little attention, it is reasonable to say that today it is a fundamental part of cardiological evaluation. In patients with heart failure, the most important clinical factors are the presence of pulmonary hypertension and right ventricular function. These factors are also essential for determining prognosis and must be taken into account when making some of the most important therapeutic decisions. The pathophysiological process starts passively but later transforms into a reactive process. This latter process, in turn, has one component that can be reversed with vasodilators and another component that is fixed, in which the underlying mechanism is congestive vasculopathy (i.e. essentially medial hypertrophy and pulmonary arterial intimal fibrosis). Currently no specific therapy is available for this type of pulmonary hypertension and treatment is the same as for heart failure itself. The drugs that have been shown to be effective in pulmonary arterial hypertension have generally had a neutral effect in clinical trials. Nevertheless, we are involved in the clinical development of a number of groups of pharmacological compounds that will enable us to make progress in the near future. PMID- 20196995 TI - Image in cardiology. Fracture of an atrial septal defect occluder as a cause of cardiac tamponade. PMID- 20196996 TI - Collateral circulation from the conus coronary artery to the anterior descending coronary artery: assessment using multislice coronary computed tomography. AB - The prognosis of patients with coronary artery disease largely depends on the presence of a collateral circulation. The location and extent of the collateral circulation is highly variable and these parameters determine whether or not ischemic symptoms occur and whether left ventricular contractility is abnormal. The collateral circulation is generally established through small-caliber distal vessels, although many different forms have been described. We report on three patients with severe left coronary artery disease and collateral circulation through a large conus coronary artery that joined a proximal or medial segment of the left anterior descending coronary artery. In all three cases, left ventricular function was preserved. PMID- 20196997 TI - Intraoperative monitoring with transesophageal real-time three-dimensional echocardiography during transapical prosthetic aortic valve implantation. AB - Degenerative aortic stenosis is the most common valvulopathy in Europe. In symptomatic patients, aortic valve replacement with a prosthesis substantially improves prognosis. However, a high percentage of candidates for valve replacement surgery are rejected because of the high risk of serious complications. In recent years, percutaneous and minimally invasive surgical techniques have been developed for the transcatheter implantation of prosthetic aortic valves. These developments could lead to an increase in the number of interventions carried out in high-risk patients as the positive effect of treatment on prognosis would be retained while the complication rate would be reduced. We describe the use of transesophageal echocardiography (TEE) for intraoperative monitoring in 21 patients who underwent transcatheter aortic valve replacement using an transapical approach, and report morphologic findings, hemodynamic results, and complications observed. We propose a standard approach to imaging, in which real-time three-dimensional TEE is used to provide additional information during intraoperative monitoring of transapical transcatheter aortic valve replacement. PMID- 20196998 TI - Different psychological profiles in non-cardiac chest pain and coronary artery disease: a controlled study. AB - The objective of the study was to identify clinical characteristics that enable non-cardiac chest pain to be differentiated from coronary artery disease. An observational case-control study was carried out in 40 patients with non-cardiac chest pain and a control group of 40 patients with coronary artery disease. Sociodemographic, medical and psychological variables were assessed. There was no difference in personality except in "emotional control", which was less in patients with non-cardiac chest pain. These patients had greater alexithymia and more frequently used coping strategies, such as religion and seeking medical help. Multivariate analysis showed that a predictive model comprising four variables (i.e., alexithymia, quality of life, and coping based on religion and seeking medical help) had a sensitivity of 85.4% and a specificity of 80.0%. This predictive model could be used as a screening test to discriminate between the two conditions. PMID- 20196999 TI - Association of short PR interval, long QT interval and sudden cardiac death in a young male. PMID- 20197000 TI - Tako-tsubo syndrome. Atypical presentation. PMID- 20197001 TI - A case of Takayasu's disease presenting as severe secondary hypertension, with angiographic improvement following medical treatment. PMID- 20197002 TI - Alveolar hemorrhage following tirofiban treatment. A misleading diagnosis. PMID- 20197003 TI - 3-D echocardiography does not reveal left atrial anatomy. PMID- 20197005 TI - Chest pain with an elevated troponin level but without significant coronary artery disease is not usually due to an infarction. PMID- 20197007 TI - Impaired glucose homeostasis and acute coronary syndrome. PMID- 20197008 TI - Oral glucose tolerance test and acute coronary syndrome. PMID- 20197011 TI - Relation of the first hypertension-associated event with medication, compliance and persistence in naive hypertensive patients after initiating monotherapy. AB - OBJECTIVE: To analyze the relation of medication, compliance and persistence with the risk of the first hypertension associated event in naive hypertensive patients after initiating monotherapy with any of the first-line antihypertensive drug classes. METHODS: A retrospective cohort study in the IMS Disease Analyzer database was performed. The study cohort comprised all previously untreated hypertensive patients who were free from hypertension-associated comorbidities, in whom new monotherapy with angiotensin II receptor blockers (ARBs), ACE inhibitors (ACEIs), beta-blockers (BBs), calcium channel blockers (CCBs) or diuretics was initiated. Compliance and persistence were determined within 2 years. The relation between medication, compliance, persistence and risk of the first hypertension-associated event was analyzed using a Cox regression model. Outcomes in the ARB cohort were compared with outcomes in each other drug class cohort separately and with outcomes in the group of non-ARBs (pooled data). RESULTS: 7,661 patients were identified with a follow-up of at least 2 years (totaling 45,585 patient-years of follow-up). ARBs were associated with more favorable measures (all p < 0.05) of compliance (0.86 vs. 0.82 and 0.74, respectively) and persistence (509 days vs. 459 and 324 days) compared with the group of non-ARBs and diuretics, respectively. The risk of the first hypertension associated event was higher (all p < 0.05) with diuretics (adjusted hazard ratio (aHR) 0.68), BBs (0.79), CCBs (0.78), and the group of non-ARBs (0.81) and was similar with ACEIs (aHR 0.93, p = 0.37) compared to ARBs. Overall, high compliance was associated with a reduced risk of the first event (p < 0.05). CONCLUSION: Our real-world data suggest that initiating a treatment with ARB monotherapy shows significant benefits in most outcomes including hypertension related complications compared to other antihypertensive drug monotherapies. The documented impact of compliance on the risk of the first event should have clinical and policy implications. PMID- 20197012 TI - Efficacy and tolerability of EPs 7630 in children and adolescents with acute bronchitis - a randomized, double-blind, placebo-controlled multicenter trial with a herbal drug preparation from Pelargonium sidoides roots. AB - OBJECTIVE: The study aim was to demonstrate the efficacy and to investigate the tolerability of EPs 7630, a herbal drug preparation from Pelargonium sidoides roots, in the treatment of patients (1 - 18 years) with acute bronchitis outside the strict indication for antibiotics. MATERIALS AND METHODS: A total of 200 patients were randomized to receive either active drug containing EPs 7630 (1 - 6 years: 3 x 10 drops/d; > 6 - 12 years: 3 x 20 drops/d; > 12 - 18 years: 3 x 30 drops/d) or placebo for 7 consecutive days. PRIMARY OUTCOME MEASURE: change in the total score of bronchitis-specific symptoms (BSS) from Day 0 to Day 7. Main secondary outcome measures: treatment outcome, patients' satisfaction with treatment, onset of effect, bed rest. RESULTS: From baseline to Day 7, the mean BSS score improved significantly more for EPs 7630 compared with placebo (3.4 +/- 1.8 vs. 1.2 +/- 1.8 points, p < 0.0001). On Day 7, treatment outcome was significantly better (p < 0.0001), satisfaction with treatment more pronounced (77.6% vs. 25.8%, p < 0.0001), onset of effect faster, and time of bed rest shorter as compared with placebo. Tolerability was similarly good in both groups. All adverse events were assessed as non-serious. CONCLUSION: EPs 7630 was shown to be efficacious and safe in the treatment of acute bronchitis in children and adolescents outside the strict indication for antibiotics with patients treated with EPs 7630 perceiving a more favorable course of the disease and a good tolerability as compared with placebo. PMID- 20197013 TI - Effect of saquinavir/ritonavir on P-glycoprotein activity in healthy volunteers using digoxin as a probe. AB - BACKGROUND: Saquinavir and ritonavir, both human immunodeficiency virus-1 protease inhibitors, also inhibit the adenosine triphosphate-dependent efflux pump P-glycoprotein (P-gp), which is located at a variety of anatomic sites, including the human intestine. P-gp plays an important role in the absorption, distribution and elimination of numerous drugs. This study investigated the inhibitory potential of multiple administrations of ritonavir-boosted saquinavir at the target therapeutic dose of 1,000 mg saquinavir/100 mg ritonavir twice daily on the pharmacokinetics of oral digoxin, a model P-gp substrate that is predominantly excreted as unchanged drug in the urine. METHODS: In an open-label, 1-sequence, 2-period crossover study, a single digoxin dose of 0.5 mg was administered orally on Day 1. From Days 11 through 26, participants received oral administration of saquinavir/ritonavir 1,000/100 mg twice daily. A second dose of digoxin was administered on Day 24. Blood and urine sampling for pharmacokinetic analyses of digoxin was performed at scheduled time points on Days 1 - 4 and Days 24 - 27. Serial blood samples were drawn to determine plasma levels of saquinavir and ritonavir on Days 21 - 24. Adverse event reports were collected. RESULTS: Of the 17 enrolled participants (9 males and 8 females) who received at least one dose of study medication, 16 completed the study. Two weeks of pretreatment with ritonavir and saquinavir resulted in a 1.27-fold increase in digoxin Cmax (90% confidence interval (1.05 - 1.54)) and a 1.49-fold increase in AUC0-72 (90% CI (1.32 - 1.69)). Renal clearance decreased by a factor 0.88 from 111 to 97.3 ml/min while digoxin half-life increased from 37.0 to 45.3 h. The unbound fraction of digoxin was almost unaffected. The changes in digoxin renal clearance and exposure (AUC0-72) following 2 weeks of treatment with saquinavir/ritonavir were found to be more pronounced among female participants compared with males. Plasma concentrations of saquinavir/ritonavir at trough and at 4 h postdose were within the expected ranges for each gender, with female participants showing higher concentrations than male participants. All three treatments were well tolerated, with no serious adverse events noted. Despite the higher digoxin exposure among females compared to males following saquinavir/ritonavir administration, overall safety profiles were similar. On electrocardiographic readings, a trend of a longer PR interval was noted with triple combination of agents. CONCLUSIONS: Pretreatment with saquinavir/ritonavir 1,000/100 mg twice daily increased digoxin exposure most likely via P-gp-inhibition. Given the relatively narrow therapeutic window of digoxin, caution should be exercised when these three drugs are administered together. It is recommended to reduce digoxin doses and to monitor digoxin serum concentrations. PMID- 20197014 TI - Pediatric iron preparations for infants in Bahrain: some therapeutic concerns. AB - BACKGROUND: Infants and children are at a high risk for medication errors. OBJECTIVES: This retrospective study was conducted to determine the type and prevalence of prescribing errors related to pediatric iron preparations prescribed in primary care in Bahrain. METHODS: Prescriptions issued for infants and collected at 20 health center pharmacies for 2 weeks were audited, specifically for errors. RESULTS: Of 2,282 prescriptions dispensed for infants (mean age 9.14 +/- 0.91 months), 159 (7.0%) included an iron preparation. Iron preparations were mostly prescribed (90.6%) with brand names, several of which were neither listed in the primary care drug list nor were available as pediatric dosage forms. 42 (26.4%) prescriptions were issued without specifying the dosage forms, 14 (8.8%) without the duration of therapy and 4 (2.5%) without dosage. Iron dosage was stated as metric volume (ml) and metric weight (mg elemental iron) units in 78.6% and 9.4% of the prescriptions, respectively. The mean elemental iron (+/- SD) prescribed for treating anemia was 4.5 +/- 1.7 mg/kg body weight. A significant difference was observed between physicians and nurses regarding the amount of elemental iron prescribed for treating anemia. CONCLUSIONS: Prescribing of multiple brands of pediatric iron preparations unavailable in the primary care drug list and in pediatric dosage forms, prescribing iron as inconvenient decimal fractions (metric volume units), and omission errors in prescriptions, were common. This may be related to poor communications between the prescribers and the pharmacy services and a lack of information dissemination on newly introduced iron formulations. Moreover, frequent changes in brand availability in primary care may have created confusion for prescribers. The communication between pharmacy services and prescribers should be strengthened, and the procurement of multiple brands should be discouraged. A better management of drug supply and effective policies to minimize prescribing errors are needed in Bahrain. PMID- 20197015 TI - Blood pressure-lowering and antiproteinuric effect of switching from high-dose angiotensin receptor blockers to normal-dose telmisartan and low-dose hydrochlorothiazide in hypertensive patients with chronic kidney disease. AB - OBJECTIVES: We evaluated the changes in the blood pressure and urinary protein excretion in poorly controlled hypertensive and proteinuric patients with mild to moderate chronic kidney disease (CKD) after switching from the high-dose angiotensin receptor blockers (ARBs) to a combination of normal-dose telmisartan (40 mg) and low-dose hydrochlorothiazide (HCTZ; 12.5 mg). METHODS: 60 adults with Stages 2 - 3 CKD who had been receiving high-dose ARBs and had not achieved their target blood pressure of 130/80 mmHg were switched to a combination of telmisartan (40 mg) and HCTZ (12.5 mg) once daily for a 12-week study period. We measured the blood pressure, pulse rate, urinary protein excretion, and total monthly drug costs before and after the switch. RESULTS: The mean systolic blood pressure dropped from 153 to 133 mm Hg and the mean diastolic blood pressure, from 89 to 78 mmHg (p < 0.0001, for both). Further, the mean blood pressure decreased (p < 0.0001), without any significant change in the pulse rate. Urinary protein excretion adjusted for urinary creatinine was reduced from 3,749 to 2,474 mg/g creatinine (p < 0.0001). No significant change was detected in the estimated glomerular filtration rate and serum creatinine level. With the switching from high-dose ARBs to the combination of normal-dose telmisartan and low-dose HCTZ treatment, the blood pressure decreased in all the subjects, and 36% of all the subjects achieved optimal blood pressure levels. No adverse metabolic effects were noted even among the diabetic patients. The monthly drug costs were significantly reduced after the switch (13,614 +/- 6,108 vs. 9,936 +/- 5,571 yen/month, p < 0.0001). CONCLUSIONS: We concluded that the telmisartan and HCTZ combination may be more efficacious than monotherapy of the high-dose ARBs in reducing blood pressure and urinary protein excretion in hypertensive patients with CKD. Further investigation would be required to assess whether the combination of high-dose ARBs and low-dose HCTZ has a greater antiproteinuric effect than the combination of normal-dose telmisartan (40 mg) and low-dose HCTZ (12.5 mg). PMID- 20197016 TI - Pharmacokinetics and pharmacodynamics of basiliximab in Japanese pediatric renal transplant patients. AB - OBJECTIVES: This study was aimed at evaluating the pharmacokinetics and pharmacodynamics of basiliximab in Japanese pediatric renal transplant patients. MATERIALS AND METHODS: This study was carried out with the approval of the Institutional Review Board of our institution. Written consent was obtained from the legal representative of each patient, as also from the patients themselves where possible. Eligible patients were Japanese pediatric patients weighing less than 35 kg and younger than 15 years of age who were scheduled to undergo renal transplantation. Each patient was given intravenous basiliximab at the total dose of 20 mg administered in two divided doses of 10 mg each on the day of transplantation and on the fourth day after transplantation. Cyclosporine and corticosteroids were also administered as the basic concomitant maintenance immunosuppressive therapy. The time course of changes in the serum basiliximab concentrations and the percentage of CD25+ T-lymphocytes in the peripheral blood were determined up to 26 weeks after the transplantation to calculate the period of suppression of the CD25+ T-lymphocytes. Serum basiliximab was measured by an ELISA technique, and the percentage of CD25+ T-lymphocytes in the peripheral blood was determined by flow cytometry. RESULTS: 6 Japanese pediatric patients weighing less than 35 kg and aged over 1 year and less than 15 years who were scheduled to undergo renal transplantation were enrolled in this study. In regard to the time course of changes of the serum basiliximab concentration, after the peak serum concentration was reached, basiliximab was gradually eliminated from the blood with a mean half-life of 7.06 days. CD25+ T-lymphocytes in the peripheral blood were suppressed completely when the serum concentration of basiliximab was over 0.2 microg/ml, and the period of suppression of the CD25+ T cells was 40.3 - 51.7 days (mean +/- SD; 45.8 +/- 4.9). CONCLUSION: Changes in the serum concentration of basiliximab and the period of suppression of CD25+ peripheral blood T-lymphocytes in Japanese pediatric renal transplant patients were similar to those reported for non-Japanese pediatric transplant patients and Japanese adult renal transplant patients with a cyclosporine and corticosteroid regimen. This indicates that expected efficacy can be obtained in Japanese pediatric renal transplant patients using the recommended dosing regimens validated by non-Japanese studies. PMID- 20197017 TI - Effect of Schisandra sphenanthera extract on the concentration of tacrolimus in the blood of liver transplant patients. AB - BACKGROUND: Tacrolimus (Tac) is widely used to prevent allograft rejection after liver transplantation. We found that the concentration of Tac in blood was significantly increased in liver transplant patients who were receiving Schisandra sphenanthera extract (SchE). The objective of this study was to determine the effect of SchE on the concentration of Tac in the blood of liver transplant patients. MATERIALS AND METHODS: Patients were initially administered Tac (first phase) and then SchE was provided (second phase). During the first phase of treatment, 46 patients received the same oral dose of Tac. In the second phase of treatment, 21 patients (Group A) received the same dose of Tac and 25 patients (Group B) received a lower dose of Tac. The concentration of Tac in the blood and the biochemical indices of liver function, as well as symptoms of Tac related toxicity, were determined, and 14 patients were selected for a pharmacokinetic study. RESULTS: After co-administration of Tac and SchE, the average increase in the mean concentration of Tac in the blood was 339% and 262% in Groups A and B, respectively. The liver function indices were decreased significantly (p < 0.01); whereas the average increase of Cmax, AUC0-12 and AUMC0 12 of Tac was 183%, 212% and 227%, respectively. Tac-associated side-effects, such as diarrhoea and agitation, decreased significantly in all patients, but the incidence of other side-effects did not change significantly. CONCLUSIONS: SchE markedly increased the concentration of Tac in the blood of liver transplant patients, improved liver function and reduced the incidence of Tac-associated side-effects. PMID- 20197018 TI - Celecoxib in a 12-year-old boy with familial adenomatous polyposis. AB - Familial Adenomatous Polyposis (FAP) is an autosomal dominant disorder characterized by colonic polyps in early adult life. Children with this disease are at risk for colonic cancer, so prophylactic colectomy is the standard treatment to prevent this complication. Chemoprevention experience with NSAIDs in children is exceptional. This case report describes our experience with Celecoxib, a COX-2 inhibitor, in a 12-year-old boy. PMID- 20197019 TI - Bioavailability of two oral suspension and two oral tablet formulations of nimesulide 100 mg in healthy Brazilian adult subjects. AB - A specific, fast and sensitive high performance liquid chromatography coupled to an electro spray tandem triple quadrupole mass spectrometer (LC-MS/MS) assay was developed for the determination of nimesulide in human plasma using carbamazepine as the internal standard. The lower limit of quantification (LLOQ) was 50 ng/ml and the calibration curves were linear in the concentration range of 50 - 6,000 ng/ml. Method inter-batch precision and accuracy ranged from 2.78 to 10.80%, and 94.92 to 102.46%, respectively. Intra-batch precision ranged from 2.44 to 7.74%, while intra-batch accuracy ranged from 91.70 to 104.73%. The analytical method was applied to evaluate the pharmacokinetic and relative bioavailability of two different pharmaceutical formulations containing nimesulide, one tablet and one oral suspension, manufactured by the same pharmaceutical factory, comparing with two reference Nisulid formulations in 52 volunteers of both sexes previously divided in two groups of 26 subjects (13 men and 13 females each group). The test tablet formulation was not bioequivalent to the Nisulid 100 mg tablet with respect to the rate of absorption, but was bioequivalent according to the extent of drug absorption. On the other hand, since the 90% CI for Cmax, AUC0-t and AUCinf were within the 80 - 125% interval in the oral suspension study, it was concluded that test oral suspension were bioequivalent to Nisulid 50 mg/ml with respect to both the rate and extent of absorption. PMID- 20197021 TI - Chronic hepatitis C in Austria, 1992-2006: genotype distribution and demographic factors. AB - Chronic hepatitis C is a leading cause of end-stage liver disease and, with a worldwide prevalence of up to 3%, is a pandemic infectious disease. Austria, like most western European countries can be considered as a low prevalence country. This analysis aimed to assess the distribution of hepatitis C virus (HCV) genotypes in patients with chronic HCV infection in Upper Austria. Between September 1992 and December 2006, we identified 1,318 consecutive patients who tested positive for HCV RNA. Genotyping was routinely performed in 1,239 of the 1,318 patients, and in a subgroup of 617 patients data on the source of transmission were collected. Additionally we obtained data on liver histology and body mass index in a subsample of 273 of the 617 patients. Hepatitis C genotypes 1, 2, 3, 4, 6 and co-infections were found in 80.4%, 4.5%, 12.3%, 2.7%, 0.1% and 0.2% of the patients, respectively. There was a highly significant age difference in relation to gender at the time of diagnosis of chronic hepatitis C, with women being older than men (men: 45.0 years; women: 49.3 years; p<0.0001). The number of new cases of chronic hepatitis C decreased substantially over the last decade, but although risk factors for obtaining HCV are well established, we did not find a decrease in the age of first diagnosis. Besides consistent screening in defined risk groups it is important to raise awareness for risk factors for HCV acquisition and liver disease progression. PMID- 20197022 TI - Legionnaires disease in Europe 2007-2008. AB - Each spring, countries that participate in the European Surveillance Scheme for Travel Associated Legionnaires Disease (EWGLINET) are requested to submit their annual dataset of all cases of Legionnaires disease in residents of their country with onset of illness in the preceding year. These data have been collected annually since 1994 and are used to analyse epidemiological and microbiological trends within and between countries over time. This paper presents an overview of the data collected for 2007 and 2008. A total of 5,907 cases were reported by 33 countries in 2007 and 5,960 cases by 34 countries in 2008, a similar two-year total to that recorded in 2005 and 2006 [1]. The only countries with a major difference in case numbers between 2007 and 2008 were Russia, due to a large outbreak in 2007, and Italy where cases increased by 256 in 2008 mainly due to an increase in community-acquired infections. The 779 reported deaths give a two year case fatality rate of 6.6%. Some 243 outbreaks or clusters were detected, 150 of which were linked to travel-associated infections. As in previous years, the overall main method of diagnosis was by urinary antigen detection and the proportion of cases diagnosed by culture remained low at 8.8%, although isolation rates by country ranged from under 1% to over 40%. PMID- 20197023 TI - Chikungunya infection in a French traveller returning from the Maldives, October, 2009. AB - In the last years, cases of chikungunya fever have been reported in international travellers returning from the Indian Ocean region. The cases have been linked to the re-emergence of chikungunya fever on Indian Ocean islands in 2006. We describe the first case of chikungunya fever in a French traveller returning from Male, an island of the Maldives islands, confirming the permanence of virus circulation by the end of 2009. PMID- 20197024 TI - A cluster of Legionnaires' disease caused by Legionella longbeachae linked to potting compost in Scotland, 2008-2009. AB - Three cases of Legionnaires disease caused by Legionella longbeachae Sg 1 associated with potting compost have been reported in Scotland between 2008 and 2009. The exact method of transmission is still not fully understood as Legionnaires disease is thought to be acquired by droplet inhalation. The linked cases associated with compost exposure call for an introduction of compost labelling, as is already in place in other countries where L. longbeachae outbreaks have been reported. PMID- 20197025 TI - Legionella, springtime and potting soils. PMID- 20197026 TI - Cytopathic bovine viral diarrhea viruses (BVDV): emerging pestiviruses doomed to extinction. AB - Bovine viral diarrhea virus (BVDV), a Flaviviridae pestivirus, is arguably one of the most widespread cattle pathogens worldwide. Each of its two genotypes has two biotypes, non-cytopathic (ncp) and cytopathic (cp). Only the ncp biotype of BVDV may establish persistent infection in the fetus when infecting a dam early in gestation, a time point which predates maturity of the adaptive immune system. Such fetuses may develop and be born healthy but remain infected for life. Due to this early initiation of fetal infection and to the expression of interferon antagonistic proteins, persistently infected (PI) animals remain immunotolerant to the infecting viral strain. Although only accounting for some 1% of all animals in regions where BVDV is endemic, PI animals ensure the viral persistence in the host population. These animals may, however, develop the fatal mucosal disease, which is characterized by widespread lesions in the gastrointestinal tract. Cp BVD virus, in addition to the persisting ncp biotype, can be isolated from such animals. The cp viruses are characterized by unrestrained genome replication, and their emergence from the persisting ncp ones is due to mutations that are unique in each virus analyzed. They include recombinations with host cell mRNA, gene translocations and duplications, and point mutations. Cytopathic BVD viruses fail to establish chains of infection and are unable to cause persistent infection. Hence, these viruses illustrate a case of "viral emergence to extinction" - irrelevant for BVDV evolution, but fatal for the PI host. PMID- 20197027 TI - Harmonic oscillations in homeostatic controllers: Dynamics of the p53 regulatory system. AB - Homeostatic mechanisms are essential for the protection and adaptation of organisms in a changing and challenging environment. Previously, we have described molecular mechanisms that lead to robust homeostasis/adaptation under inflow or outflow perturbations. Here we report that harmonic oscillations occur in models of such homeostatic controllers and that a close relationship exists between the control of the p53/Mdm2 system and that of a homeostatic inflow controller. This homeostatic control model of the p53 system provides an explanation why large fluctuations in the amplitude of p53/Mdm2 oscillations may arise as part of the homeostatic regulation of p53 by Mdm2 under DNA-damaging conditions. In the presence of DNA damage p53 is upregulated, but is subject to a tight control by Mdm2 and other factors to avoid a premature apoptotic response of the cell at low DNA damage levels. One of the regulatory steps is the Mdm2 mediated degradation of p53 by the proteasome. Oscillations in the p53/Mdm2 system are considered to be part of a mechanism by which a cell decides between cell cycle arrest/DNA repair and apoptosis. In the homeostatic inflow control model, harmonic oscillations in p53/Mdm2 levels arise when the binding strength of p53 to degradation complexes increases. Due to the harmonic character of the oscillations rapid fluctuating noise can lead, as experimentally observed, to large variations in the amplitude of the oscillation but not in their period, a behavior which has been difficult to simulate by deterministic limit-cycle models. In conclusion, the oscillatory response of homeostatic controllers may provide new insights into the origin and role of oscillations observed in homeostatically controlled molecular networks. PMID- 20197028 TI - Two open states with progressive proton selectivities in the branched channelrhodopsin-2 photocycle. AB - Channelrhodopsins are light-gated ion channels that mediate vision in phototactic green algae like Chlamydomonas. In neurosciences, channelrhodopsins are widely used to light-trigger action potentials in transfected cells. All known channelrhodopsins preferentially conduct H(+). Previous studies have indicated the existence of an early and a late conducting state within the channelrhodopsin photocycle. Here, we show that for channelrhodopsin-2 expressed in Xenopus oocytes and HEK cells, the two open states have different ion selectivities that cause changes in the channelrhodopsin-2 reversal voltage during a light pulse. An enzyme kinetic algorithm was applied to convert the reversal voltages in various ionic conditions to conductance ratios for H(+) and divalent cations (Ca(2+) and/or Mg(2+)), as compared to monovalent cations (Na(+) and/or K(+)). Compared to monovalent cation conductance, the H(+) conductance, alpha, is approximately 3 x 10(6) and the divalent cation conductance, beta, is approximately 0.01 in the early conducting state. In the stationary mixture of the early and late states, alpha is larger and beta smaller, both by a factor of approximately 2. The results suggest that the ionic basis of light perception in Chlamydomonas is relatively nonspecific in the beginning of a light pulse but becomes more selective for protons during longer light exposures. PMID- 20197029 TI - Modulation of KvAP unitary conductance and gating by 1-alkanols and other surface active agents. AB - The actions of alcohols and anesthetics on ion channels are poorly understood. Controversy continues about whether bilayer restructuring is relevant to the modulatory effects of these surface active agents (SAAs). Some voltage-gated K channels (Kv), but not KvAP, have putative low affinity alcohol-binding sites, and because KvAP structures have been determined in bilayers, KvAP could offer insights into the contribution of bilayer mechanics to SAA actions. We monitored KvAP unitary conductance and macroscopic activation and inactivation kinetics in PE:PG/decane bilayers with and without exposure to classic SAAs (short-chain 1 alkanols, cholesterol, and selected anesthetics: halothane, isoflurane, chloroform). At levels that did not measurably alter membrane specific capacitance, alkanols caused functional changes in KvAP behavior including lowered unitary conductance, modified kinetics, and shifted voltage dependence for activation. A simple explanation is that the site of SAA action on KvAP is its entire lateral interface with the PE:PG/decane bilayer, with SAA-induced changes in surface tension and bilayer packing order combining to modulate the shape and stability of various conformations. The KvAP structural adjustment to diverse bilayer pressure profiles has implications for understanding desirable and undesirable actions of SAA-like drugs and, broadly, predicts that channel gating, conductance and pharmacology may differ when membrane packing order differs, as in raft versus nonraft domains. PMID- 20197030 TI - Agonist-induced changes in Ca(2+) permeation through the nociceptor cation channel TRPA1. AB - The Ca(2+)-permeable cation channel TRPA1 acts as an ionotropic receptor for various pungent compounds and as a noxious cold sensor in sensory neurons. It is unclear what proportion of the TRPA1-mediated current is carried by Ca(2+) ions and how the permeation pathway changes during stimulation. Here, based on the relative permeability of the nonstimulated channel to cations of different size, we estimated a pore diameter of approximately 11 A. Combined patch-clamp and Fura 2 fluorescence recordings revealed that with 2 mM extracellular Ca(2+), and at a membrane potential of -80 mV, approximately 17% of the inward TRPA1 current is carried by Ca(2+). Stimulation with mustard oil evoked an apparent dilatation of the pore of 3 A and an increase in divalent cation selectivity and fractional Ca(2+) current. Mutations in the putative pore that reduced the divalent permeability and fractional Ca(2+) current also prevented mustard-oil-induced increases in Ca(2+) permeation. It is interesting that fractional Ca(2+) currents for wild-type and mutant TRPA1 were consistently higher than values predicted based on biionic reversal potentials using the Goldman-Hodgkin-Katz equation, suggesting that binding of Ca(2+) in the pore hinders monovalent cation permeation. We conclude that the pore of TRPA1 is dynamic and supports a surprisingly large Ca(2+) influx. PMID- 20197032 TI - Mouse fibroblast cell adhesion studied by neutron reflectometry. AB - Neutron reflectometry (NR) was used to examine live mouse fibroblast cells adherent on a quartz substrate in a deuterated phosphate-buffered saline environment at room temperature. These measurements represent the first, to our knowledge, successful visualization and quantization of the interface between live cells and a substrate with subnanometer resolution using NR. NR data, attributable to the adhesion of live cells, were observed and compared with data from pure growth medium. Independently of surface cell density, the average distance between the center of the cell membrane region and the quartz substrate was determined to be approximately 180 A. The membrane region ( approximately 80 A thick) contains the membranes of cells that are inhomogeneously distributed or undulating, likely conforming to the nonplanar geometry of the supporting adherence proteins. A second region of cell membranes at a greater distance from the substrate was not detectable by NR due to the resolution limits of the technique employed. Attachment of the live cell samples was confirmed by interaction with both distilled water and trypsin. Distinct changes in the NR data after exposure indicate the removal of cells from the substrate. PMID- 20197031 TI - An iris-like mechanism of pore dilation in the CorA magnesium transport system. AB - Magnesium translocation across cell membranes is essential for numerous physiological processes. Three recently reported crystal structures of the CorA magnesium transport system revealed a surprising architecture, with a bundle of giant alpha-helices forming a 60-A-long pore that extends beyond the membrane before widening into a funnel-shaped cytosolic domain. The presence of divalent cations in putative intracellular regulation sites suggests that these structures correspond to the closed conformation of CorA. To examine the nature of the conduction pathway, we performed 110-ns molecular-dynamics simulations of two of these structures in a lipid bilayer with and without regulatory ions. The results show that a 15-A-long hydrophobic constriction straddling the membrane-cytosol interface constitutes a steric bottleneck whose location coincides with an electrostatic barrier opposing cation translocation. In one of the simulations, structural relaxation after the removal of regulatory ions led to concerted changes in the tilt of the pore helices, resulting in iris-like dilation and spontaneous hydration of the hydrophobic neck. This simple and robust mechanism is consistent with the regulation of pore opening by intracellular magnesium concentration, and explains the unusual architecture of CorA. PMID- 20197033 TI - On the role of acylation of transmembrane proteins. AB - Acylation is a frequent means to ensure membrane association of a variety of soluble proteins in living cells. However, many transmembrane proteins are palmitoylated, indicating that this posttranslational modification may also serve as a means to regulate protein trafficking. Based on coarse-grained membrane simulations, we find that protein acylation significantly alters the tilting of transmembrane proteins with respect to the bilayer normal. In addition, the proteins' partitioning behavior and cluster formation ability due to hydrophobic mismatching is strongly altered. Based on our results, we propose that acylation is a potent means to regulate the trafficking of transmembrane proteins along the early secretory pathway. PMID- 20197034 TI - Effect of membrane thickness on conformational sampling of phospholamban from computer simulations. AB - The conformational sampling of monomeric, membrane-bound phospholamban is described from computer simulations. Phospholamban (PLB) plays a key role as a regulator of sarcoplasmic reticulum calcium ATPase. An implicit membrane model is used in conjunction with replica exchange molecular dynamics simulations to reach mus-ms timescales. The implicit membrane model was also used to study the effect of different membrane thicknesses by scaling the low-dielectric region. The conformational sampling with the membrane model mimicking dipalmitoylphosphatidylcholine bilayers is in good agreement overall with experimental measurements, but consists of a wide variety of different conformations including structures not described previously. The conformational ensemble shifts significantly in the presence of thinner or thicker membranes. This has implications for the structure and dynamics of PLB in physiological membranes and offers what we believe to be a new interpretation of previous experimental measurements of PLB in detergents and microsomal membrane. PMID- 20197036 TI - Transcription within condensed chromatin: Steric hindrance facilitates elongation. AB - During eukaryotic transcription, RNA-polymerase activity generates torsional stress in DNA, having a negative impact on the elongation process. Using our previous studies of chromatin fiber structure and conformational transitions, we suggest that this torsional stress can be alleviated, thanks to a tradeoff between the fiber twist and nucleosome conformational transitions into an activated state named "reversome". Our model enlightens the origin of polymerase pauses, and leads to the counterintuitive conclusion that chromatin-organized compaction might facilitate polymerase progression. Indeed, in a compact and well structured chromatin loop, steric hindrance between nucleosomes enforces sequential transitions, thus ensuring that the polymerase always meets a permissive nucleosomal state. PMID- 20197035 TI - Peptide-induced domain formation in supported lipid bilayers: direct evidence by combined atomic force and polarized total internal reflection fluorescence microscopy. AB - Direct visualization of the mechanism(s) by which peptides induce localized changes to the structure of membranes has high potential for enabling understanding of the structure-function relationship in antimicrobial and cell penetrating peptides. We have applied a combined imaging strategy to track the interaction of a model antimicrobial peptide, PFWRIRIRR-amide, with bacterial membrane-mimetic supported phospholipid bilayers comprised of POPE/TOCL. Our in situ studies revealed rapid reorganization of the POPE/TOCL membrane into localized TOCL-rich domains with a concomitant change in the organization of the membranes themselves, as reflected by changes in fluorescent-membrane-probe order parameter, upon introduction of the peptide. PMID- 20197037 TI - Microscopic basis for the mesoscopic extensibility of dendrimer-compacted DNA. AB - The mechanism of DNA compaction by dendrimers is key to the design of nanotechnologies that can deliver genetic material into cells. We present atomistic simulations, mesoscopic modeling and single-molecule pulling experiments describing DNA dendrimer interactions. All-atom molecular dynamics were used to characterize pulling-force-dependent interactions between DNA and generation-3 PAMAM amine-terminated dendrimers, and a free energy profile and mean forces along the interaction coordinate are calculated. The energy, force, and geometry parameters computed at the atomic level are input for a Monte Carlo model yielding mesoscopic force-extension curves. Actual experimental single molecule curves obtained with optical tweezers are also presented, and they show remarkable agreement with the virtual curves from our model. The calculations reveal the microscopic origin of the hysteresis observed in the phase transition underlying compaction. A broad range of ionic and pulling parameters is sampled, and suggestions for windows of conditions to probe new single-molecule behavior are made. PMID- 20197038 TI - The interaction of alphaB-crystallin with mature alpha-synuclein amyloid fibrils inhibits their elongation. AB - alphaB-Crystallin is a small heat-shock protein (sHsp) that is colocalized with alpha-synuclein (alphaSyn) in Lewy bodies-the pathological hallmarks of Parkinson's disease-and is an inhibitor of alphaSyn amyloid fibril formation in an ATP-independent manner in vitro. We have investigated the mechanism underlying the inhibitory action of sHsps, and here we establish, by means of a variety of biophysical techniques including immunogold labeling and nuclear magnetic resonance spectroscopy, that alphaB-crystallin interacts with alphaSyn, binding along the length of mature amyloid fibrils. By measurement of seeded fibril elongation kinetics, both in solution and on a surface using a quartz crystal microbalance, this binding is shown to strongly inhibit further growth of the fibrils. The binding is also demonstrated to shift the monomer-fibril equilibrium in favor of dissociation. We believe that this mechanism, by which a sHsp interacts with mature amyloid fibrils, could represent an additional and potentially generic means by which at least some chaperones protect against amyloid aggregation and limit the onset of misfolding diseases. PMID- 20197039 TI - Probing the DNA-binding affinity and specificity of designed zinc finger proteins. AB - Engineered transcription factors and endonucleases based on designed Cys(2)His(2) zinc finger domains have proven to be effective tools for the directed regulation and modification of genes. The introduction of this technology into both research and clinical settings necessitates the development of rapid and accurate means of evaluating both the binding affinity and binding specificity of designed zinc finger domains. Using a fluorescence anisotropy-based DNA-binding assay, we examined the DNA-binding properties of two engineered zinc finger proteins that differ by a single amino acid. We demonstrate that the protein with the highest affinity for a particular DNA site need not be the protein that binds that site with the highest degree of specificity. Moreover, by comparing the binding characteristics of the two proteins at varying salt concentrations, we show that the ionic strength makes significant and variable contributions to both affinity and specificity. These results have significant implications for zinc finger design as they highlight the importance of considering affinity, specificity, and environmental requirements in designing a DNA-binding domain for a particular application. PMID- 20197040 TI - Determination of ensemble-average pairwise root mean-square deviation from experimental B-factors. AB - Root mean-square deviation (RMSD) after roto-translational least-squares fitting is a measure of global structural similarity of macromolecules used commonly. On the other hand, experimental x-ray B-factors are used frequently to study local structural heterogeneity and dynamics in macromolecules by providing direct information about root mean-square fluctuations (RMSF) that can also be calculated from molecular dynamics simulations. We provide a mathematical derivation showing that, given a set of conservative assumptions, a root mean square ensemble-average of an all-against-all distribution of pairwise RMSD for a single molecular species, (1/2), is directly related to average B factors () and (1/2). We show this relationship and explore its limits of validity on a heterogeneous ensemble of structures taken from molecular dynamics simulations of villin headpiece generated using distributed-computing techniques and the Folding@Home cluster. Our results provide a basis for quantifying global structural diversity of macromolecules in crystals directly from x-ray experiments, and we show this on a large set of structures taken from the Protein Data Bank. In particular, we show that the ensemble-average pairwise backbone RMSD for a microscopic ensemble underlying a typical protein x-ray structure is approximately 1.1 A, under the assumption that the principal contribution to experimental B-factors is conformational variability. PMID- 20197041 TI - Statistics and physical origins of pK and ionization state changes upon protein ligand binding. AB - This work investigates statistical prevalence and overall physical origins of changes in charge states of receptor proteins upon ligand binding. These changes are explored as a function of the ligand type (small molecule, protein, and nucleic acid), and distance from the binding region. Standard continuum solvent methodology is used to compute, on an equal footing, pK changes upon ligand binding for a total of 5899 ionizable residues in 20 protein-protein, 20 protein small molecule, and 20 protein-nucleic acid high-resolution complexes. The size of the data set combined with an extensive error and sensitivity analysis allows us to make statistically justified and conservative conclusions: in 60% of all protein-small molecule, 90% of all protein-protein, and 85% of all protein nucleic acid complexes there exists at least one ionizable residue that changes its charge state upon ligand binding at physiological conditions (pH = 6.5). Considering the most biologically relevant pH range of 4-8, the number of ionizable residues that experience substantial pK changes (DeltapK > 1.0) due to ligand binding is appreciable: on average, 6% of all ionizable residues in protein-small molecule complexes, 9% in protein-protein, and 12% in protein nucleic acid complexes experience a substantial pK change upon ligand binding. These changes are safely above the statistical false-positive noise level. Most of the changes occur in the immediate binding interface region, where approximately one out of five ionizable residues experiences substantial pK change regardless of the ligand type. However, the physical origins of the change differ between the types: in protein-nucleic acid complexes, the pK values of interface residues are predominantly affected by electrostatic effects, whereas in protein-protein and protein-small molecule complexes, structural changes due to the induced-fit effect play an equally important role. In protein-protein and protein-nucleic acid complexes, there is a statistically significant number of substantial pK perturbations, mostly due to the induced-fit structural changes, in regions far from the binding interface. PMID- 20197042 TI - Left-handed dimer of EphA2 transmembrane domain: Helix packing diversity among receptor tyrosine kinases. AB - The Eph receptor tyrosine kinases and their membrane-bound ephrin ligands control a diverse array of cell-cell interactions in the developing and adult organisms. During signal transduction across plasma membrane, Eph receptors, like other receptor tyrosine kinases, are involved in lateral dimerization and subsequent oligomerization presumably with proper assembly of their single-span transmembrane domains. Spatial structure of dimeric transmembrane domain of EphA2 receptor embedded into lipid bicelle was obtained by solution NMR, showing a left handed parallel packing of the transmembrane helices (535-559)(2). The helices interact through the extended heptad repeat motif L(535)X(3)G(539)X(2)A(542)X(3)V(546)X(2)L(549) assisted by intermolecular stacking interactions of aromatic rings of (FF(557))(2), whereas the characteristic tandem GG4-like motif A(536)X(3)G(540)X(3)G(544) is not used, enabling another mode of helix-helix association. Importantly, a similar motif AX(3)GX(3)G as was found is responsible for right-handed dimerization of transmembrane domain of the EphA1 receptor. These findings serve as an instructive example of the diversity of transmembrane domain formation within the same family of protein kinases and seem to favor the assumption that the so called rotation-coupled activation mechanism may take place during the Eph receptor signaling. A possible role of membrane lipid rafts in relation to Eph transmembrane domain oligomerization and Eph signal transduction was also discussed. PMID- 20197043 TI - Universality in protein residue networks. AB - Residue networks representing 595 nonhomologous proteins are studied. These networks exhibit universal topological characteristics as they belong to the topological class of modular networks formed by several highly interconnected clusters separated by topological cavities. There are some networks that tend to deviate from this universality. These networks represent small-size proteins having <200 residues. This article explains such differences in terms of the domain structure of these proteins. On the other hand, the topological cavities characterizing proteins residue networks match very well with protein binding sites. This study investigates the effect of the cutoff value used in building the residue network. For small cutoff values, <5 A, the cavities found are very large corresponding almost to the whole protein surface. On the contrary, for large cutoff value, >10.0 A, only very large cavities are detected and the networks look very homogeneous. These findings are useful for practical purposes as well as for identifying protein-like complex networks. Finally, this article shows that the main topological class of residue networks is not reproduced by random networks growing according to Erdos-Renyi model or the preferential attachment method of Barabasi-Albert. However, the Watts-Strogatz model reproduces very well the topological class as well as other topological properties of residue network. A more biologically appealing modification of the Watts-Strogatz model to describe residue networks is proposed. PMID- 20197044 TI - Accounting for ligand conformational restriction in calculations of protein ligand binding affinities. AB - The conformation adopted by a ligand on binding to a receptor may differ from its lowest-energy conformation in solution. In addition, the bound ligand is more conformationally restricted, which is associated with a configurational entropy loss. The free energy change due to these effects is often neglected or treated crudely in current models for predicting binding affinity. We present a method for estimating this contribution, based on perturbation theory using the quasi harmonic model of Karplus and Kushick as a reference system. The consistency of the method is checked for small model systems. Subsequently we use the method, along with an estimate for the enthalpic contribution due to ligand-receptor interactions, to calculate relative binding affinities. The AMBER force field and generalized Born implicit solvent model is used. Binding affinities were estimated for a test set of 233 protein-ligand complexes for which crystal structures and measured binding affinities are available. In most cases, the ligand conformation in the bound state was significantly different from the most favorable conformation in solution. In general, the correlation between measured and calculated ligand binding affinities including the free energy change due to ligand conformational change is comparable to or slightly better than that obtained by using an empirically-trained docking score. Both entropic and enthalpic contributions to this free energy change are significant. PMID- 20197045 TI - The epidermal Ca(2+) gradient: Measurement using the phasor representation of fluorescent lifetime imaging. AB - Ionic gradients are found across a variety of tissues and organs. In this report, we apply the phasor representation of fluorescence lifetime imaging data to the quantitative study of ionic concentrations in tissues, overcoming technical problems of tissue thickness, concentration artifacts of ion-sensitive dyes, and calibration across inhomogeneous tissue. We used epidermis as a model system, as Ca(2+) gradients in this organ have been shown previously to control essential biologic processes of differentiation and formation of the epidermal permeability barrier. The approach described here allowed much better localization of Ca(2+) stores than those used in previous studies, and revealed that the bulk of free Ca(2+) measured in the epidermis comes from intracellular Ca(2+) stores such as the Golgi and the endoplasmic reticulum, with extracellular Ca(2+) making a relatively small contribution to the epidermal Ca(2+) gradient. Due to the high spatial resolution of two-photon microscopy, we were able to measure a marked heterogeneity in average calcium concentrations from cell to cell in the basal keratinocytes. This finding, not reported in previous studies, calls into question the long-held hypothesis that keratinocytes increase intracellular Ca(2+), cease proliferation, and differentiate passively in response to changes in extracellular Ca(2+). The experimental results obtained using this approach illustrate the power of the experimental and analytical techniques outlined in this report. Our approach can be used in mechanistic studies to address the formation, maintenance, and function of the epidermal Ca(2+) gradient, and it should be broadly applicable to the study of other tissues with ionic gradients. PMID- 20197047 TI - Lipolysis control: the plot thickens. AB - The complex process of lipolysis mobilizes fatty acids from adipocyte triglyceride stores for energy production in muscle and other organs during fasting and exercise. In this issue of Cell Metabolism, Yang, et al. identify G0S2 as a regulator of the key enzyme, adipose triglyceride lipase. PMID- 20197046 TI - Effect of antenna-depletion in Photosystem II on excitation energy transfer in Arabidopsis thaliana. AB - The role of individual photosynthetic antenna complexes of Photosystem II (PSII) both in membrane organization and excitation energy transfer have been investigated. Thylakoid membranes from wild-type Arabidopsis thaliana, and three mutants lacking light-harvesting complexes CP24, CP26, or CP29, respectively, were studied by picosecond-fluorescence spectroscopy. By using different excitation/detection wavelength combinations it was possible for the first time, to our knowledge, to separate PSI and PSII fluorescence kinetics. The sub-100 ps component, previously ascribed entirely to PSI, turns out to be due partly to PSII. Moreover, the migration time of excitations from antenna to PSII reaction center (RC) was determined for the first time, to our knowledge, for thylakoid membranes. It is four times longer than for PSII-only membranes, due to additional antenna complexes, which are less well connected to the RC. The results in the absence of CP26 are very similar to those of wild-type, demonstrating that the PSII organization is not disturbed. However, the kinetics in the absence of CP29 and, especially, of CP24 show that a large fraction of the light-harvesting complexes becomes badly connected to the RCs. Interestingly, the excited-state lifetimes of the disconnected light-harvesting complexes seem to be substantially quenched. PMID- 20197048 TI - The FOX(O1) blasts off. AB - Systemic glucose homeostasis is primarily regulated by insulin, which targets liver, fat, and skeletal muscle cells, setting up important feedback loops. New studies now show that the osteoblast also has a significant role in modulating systemic insulin responses, via the insulin-regulated transcription factor FOXO1 and the hormone osteocalcin. PMID- 20197049 TI - Peptides signal mitochondrial stress. AB - The unfolded protein response (UPR(mt)) rebalances mitochondrial protein homeostasis upon proteotoxic perturbations. Haynes et al. (2010) show that this retrograde stress signal is based on efflux of peptides derived from damaged proteins from the mitochondrial matrix to the cytosol; this initiates downstream protective responses in the nucleus to restore cellular balance. PMID- 20197050 TI - New uses for old drugs: neonatal diabetes and sulphonylureas. AB - The discovery that their neonatal diabetes is caused by gain-of-function mutations in the K(ATP) channel has enabled many patients to switch from insulin to oral sulphonylurea drugs. Here, I review molecular, physiological, and clinical features of this change in therapy. PMID- 20197051 TI - Loss of TGH/Ces3 in mice decreases blood lipids, improves glucose tolerance, and increases energy expenditure. AB - Excessive accumulation of triacylglycerol in peripheral tissues is tightly associated with obesity and has been identified as an independent risk factor for insulin resistance, type 2 diabetes, and cardiovascular complications. Here we show that ablation of carboxylesterase 3 (Ces3)/triacylglycerol hydrolase (TGH) expression in mice (Tgh(-/-)) results in decreased plasma triacylglycerol, apolipoprotein B, and fatty acid levels in both fasted and fed states. Despite the attenuation of very low-density lipoprotein secretion, TGH deficiency does not increase hepatic triacylglycerol levels. Tgh(-/-) mice exhibit increased food intake, respiratory quotient, and energy expenditure without change in body weight. These metabolic changes are accompanied by improved insulin sensitivity and glucose tolerance. Tgh(-/-) mice have smaller sized pancreatic islets but maintain normal glucose-stimulated insulin secretion. These studies demonstrate the potential of TGH as a therapeutic target for lowering blood lipid levels. PMID- 20197052 TI - The G(0)/G(1) switch gene 2 regulates adipose lipolysis through association with adipose triglyceride lipase. AB - Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme for triacylglycerol (TAG) hydrolysis in adipocytes. The precise mechanisms whereby ATGL is regulated remain uncertain. Here, we demonstrate that a protein encoded by G(0)/G(1) switch gene 2 (G0S2) is a selective regulator of ATGL. G0S2 is highly expressed in adipose tissue and differentiated adipocytes. When overexpressed in HeLa cells, G0S2 localizes to lipid droplets and prevents their degradation mediated by ATGL. Moreover, G0S2 specifically interacts with ATGL through the hydrophobic domain of G0S2 and the patatin-like domain of ATGL. More importantly, interaction with G0S2 inhibits ATGL TAG hydrolase activity. Knockdown of endogenous G0S2 accelerates basal and stimulated lipolysis in adipocytes, whereas overexpression of G0S2 diminishes the rate of lipolysis in both adipocytes and adipose tissue explants. Thus, G0S2 functions to attenuate ATGL action both in vitro and in vivo and by this mechanism regulates TAG hydrolysis. PMID- 20197053 TI - Hepatic FGF21 expression is induced at birth via PPARalpha in response to milk intake and contributes to thermogenic activation of neonatal brown fat. AB - Plasma FGF21 levels and hepatic FGF21 gene expression increase dramatically after birth in mice. This induction is initiated by suckling, requires lipid intake, is impaired in PPARalpha null neonates, and is mimicked by treatment with the PPARalpha activator, Wy14,643. Neonates exhibit reduced FGF21 expression in response to fasting, in contrast to the upregulation occurring in adults. Changes in FGF21 expression due to suckling or nutritional manipulations were associated with circulating free fatty acid and ketone body levels. We mimicked the FGF21 postnatal rise by injecting FGF21 into fasting neonates, and found that this enhanced the expression of genes involved in thermogenesis within brown fat, and increased body temperature. Brown adipocytes treated with FGF21 exhibited increased expression of thermogenic genes, higher total and uncoupled respiration, and enhanced glucose oxidation. We propose that the induction of FGF21 production by the liver mediates direct activation of brown fat thermogenesis during the fetal-to-neonatal transition. PMID- 20197054 TI - Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. AB - During fasting and after exercise, skeletal muscle efficiently switches from carbohydrate to lipid as the main energy source to preserve glycogen stores and blood glucose levels for glucose-dependent tissues. Skeletal muscle cells sense this limitation in glucose availability and transform this information into transcriptional and metabolic adaptations. Here we demonstrate that AMPK acts as the prime initial sensor that translates this information into SIRT1-dependent deacetylation of the transcriptional regulators PGC-1alpha and FOXO1, culminating in the transcriptional modulation of mitochondrial and lipid utilization genes. Deficient AMPK activity compromises SIRT1-dependent responses to exercise and fasting, resulting in impaired PGC-1alpha deacetylation and blunted induction of mitochondrial gene expression. Thus, we conclude that AMPK acts as the primordial trigger for fasting- and exercise-induced adaptations in skeletal muscle and that activation of SIRT1 and its downstream signaling pathways are improperly triggered in AMPK-deficient states. PMID- 20197056 TI - Signaling through the M(3) muscarinic receptor favors bone mass accrual by decreasing sympathetic activity. AB - Bone remodeling is regulated by various neuronal inputs, including sympathetic tone, which is known to inhibit bone mass accrual. This aspect of sympathetic nervous system function raises the prospect that the other arm of the autonomic nervous system, the parasympathetic nervous system, may also affect bone remodeling. Here, we use various mutant mouse strains, each lacking one of the muscarinic receptors that mediate parasympathetic activity, to show that the parasympathetic nervous system acting through the M(3) muscarinic receptor is a positive regulator of bone mass accrual, increasing bone formation and decreasing bone resorption. Gene expression studies, cell-specific gene deletion experiments, and analysis of compound mutant mice showed that the parasympathetic nervous system favors bone mass accrual by acting centrally and by decreasing the sympathetic tone. By showing that both arms of the autonomic nervous system affect bone remodeling, this study further underscores the importance of neuronal regulation of bone. PMID- 20197057 TI - Misconceptions over Forster resonance energy transfer between proteins and ANS/bis-ANS: Direct excitation dominates dye fluorescence. AB - Our aim was to disprove the widespread misconception that Forster resonance energy transfer (FRET) is the only explanation for observing fluorescence from ANS (8-anilino-1-naphthalenesulfonic acid) and bis-ANS (4,4'-dianilino-1,1' binaphthyl-5,5'-disulfonic acid, dipotassium salt) following excitation at 280nm in the presence of protein. From ultraviolet (UV) absorption spectra and fluorescence emission spectra of bis-ANS and ANS in buffer and ethanol, direct excitation at 280nm was found to be the dominant mechanism for the resulting dye fluorescence. Furthermore, Tyr/Trp quenching studies were performed for solutions of N-acetyl-l-tryptophanamide, heat-stressed immunoglobulin G (IgG), and bovine serum albumin (BSA) by monitoring changes in steady state fluorescence spectra and time-resolved fluorescence decays as a function of dye concentration. Stronger quenching of the intrinsic BSA and IgG fluorescence in steady state than in time-resolved fluorescence by bis-ANS and ANS pointed toward static quenching being the dominant mechanism in addition to dynamic quenching and/or FRET. In conclusion, one should consider the role of direct excitation of ANS and bis-ANS at 280nm to ensure a proper interpretation of fluorescence signals resulting from dye-protein interactions. When ANS or bis-ANS is to be used for protein characterization, we recommend selectively exciting the dyes at the higher absorption wavelength maximum (370 or 385nm, respectively). PMID- 20197055 TI - Specific roles of the p110alpha isoform of phosphatidylinsositol 3-kinase in hepatic insulin signaling and metabolic regulation. AB - The class I(A) phosphatidylinsositol 3-kinases (PI3Ks) form a critical node in the insulin metabolic pathway; however, the precise roles of the different isoforms of this enzyme remain elusive. Using tissue-specific gene inactivation, we demonstrate that p110alpha catalytic subunit of PI3K is a key mediator of insulin metabolic actions in the liver. Thus, deletion of p110alpha in liver results in markedly blunted insulin signaling with decreased generation of PIP(3) and loss of insulin activation of Akt, defects that could not be rescued by overexpression of p110beta. As a result, mice with hepatic knockout of p110alpha display reduced insulin sensitivity, impaired glucose tolerance, and increased gluconeogenesis, hypolipidemia, and hyperleptinemia. The diabetic syndrome induced by loss of p110alpha in liver did not respond to metformin treatment. Together, these data indicate that the p110alpha isoform of PI3K plays a fundamental role in insulin signaling and control of hepatic glucose and lipid metabolism. PMID- 20197058 TI - Fluorescence-based high-throughput assay for human DNA (cytosine-5) methyltransferase 1. AB - We have developed the first economical and rapid nonradioactive assay method that is suitable for high-throughput screening of the important pharmacological target human DNA (cytosine-5)-methyltransferase 1 (DNMT1). The method combines three key innovations: the use of a truncated form of the enzyme that is highly active on a 26-bp hemimethylated DNA duplex substrate, the introduction of the methylation site into the recognition sequence of a restriction endonuclease, and the use of a fluorogenic read-out method. The extent of DNMT1 methylation is reflected in the protection of the DNA substrate from endonuclease cleavage that would otherwise result in a large fluorescence increase. The assay has been validated in a high-throughput format, and trivial changes in the substrate sequence and endonuclease allow adaptation of the method to any bacterial or human DNA methyltransferase. PMID- 20197059 TI - Establishment of a novel monoclonal antibody against LGR5. AB - LGR5 is an orphan G-protein-coupled receptor (GPCR) that is expressed on the cell surface membrane. LGR5 is reported to be overexpressed in colon, liver, and ovary tumor compared to normal tissue. However, a specific ligand for LGR5 has not yet been determined, and the function is still not clear. An LGR5-specific monoclonal antibody (mAb) is needed as a tool for detection and analysis of LGR5 biological function and cancer therapy. To date, no mAb against LGR5 that retains high affinity and specificity has been reported. Here, we report successful establishment and characterization of a mAb (KM4056) that specifically recognizes the extracellular N-terminal domain of human LGR5, but not LGR4 or LGR6. This mAb has potent complement-dependent cytotoxicity (CDC) activity in vitro and shows strong anti-tumor activity in vivo against xenograft model by transplanting LGR5 expressing CHO transfectants into SCID mice. Thus, KM4056 can be a useful tool for detection of LGR5 positive cells and analysis of LGR5 biological function. PMID- 20197060 TI - A serine point mutation in the adenosine A2AR C-terminal tail reduces receptor heteromerization and allosteric modulation of the dopamine D2R. AB - Evidence exists that the adenosine receptor A(2A)R and the dopamine receptor D(2)R form constitutive heteromers in living cells. Mass spectrometry and pull down data showed that an arginine-rich domain of the D(2)R third intracellular loop binds via electrostatic interactions to a specific motif of the A(2A)R C terminal tail. It has been indicated that the phosphorylated serine 374 might represent an important residue in this motif. In the present study, it was found that a point mutation of serine 374 to alanine reduced the A(2A)R ability to interact with D(2)R. Also, this point mutation abolished the A(2A)R-mediated inhibition of both the D(2)R high affinity agonist binding and signaling. These results point to a key role of serine 374 in the A(2A)R-D(2)R interface. All together these results indicate that by targeting A(2A)R serine 374 it will be possible to allosterically modulate A(2A)R-D(2)R function, thus representing a new approach for therapeutically modulate D(2)R function. PMID- 20197061 TI - Metalloproteinase mediated occludin cleavage in the cerebral microcapillary endothelium under pathological conditions. AB - Reactive oxygen species (ROS) as well as matrix metalloproteinases (MMPs) induce modifications in the tight junction (TJ) protein occludin which is crucial for the blood-brain barrier (BBB) function. We investigated the role of ROS and MMPs in endothelial autoregulatory response on oxidative stress with respect to occludin and the BBB integrity. The ROS hydrogen peroxide (H(2)O(2)) was applied to our well-established BBB cell culture model based on primary porcine brain capillary endothelial cells (PBCEC). At low concentrations (2.5 mM), H(2)O(2) induced barrier impairment correlated with an altered occludin phosphorylation. At high, cell toxic H(2)O(2) concentrations (>or=10 mM) occludin cleavage occurred and elevated levels of active MMP-2 were detected. Under those conditions intercellular gaps were formed within the monolayer visualizing the barrier breakdown also determined by impedance analysis. A primary structure sequence analysis revealed potential type IV collagenase sensitive motives in the first extracellular loop, thus providing evidence that occludin might be an MMP-2 substrate. MMP inhibition by the metalloproteinase inhibitor GM6001 prevented occludin degradation and reduced the intercellular gap formation. However, the barrier function quantified by impedance measurement could not be maintained despite MMP inhibition. When we applied an enzymatic activity level which caused occludin cleavage in injured PBCEC to intact PBCEC, neither occludin cleavage nor barrier impairment was observed. Thus, in our model occludin cleavage is not an autoregulatory mechanism of microcapillary endothelium in barrier modulation under oxidative stress, but only occurs upon endothelial damage. PMID- 20197062 TI - Interleukin-6 receptor gene polymorphisms were associated with sporadic Alzheimer's disease in Chinese Han. AB - Cytokine interleukin-6 (IL-6) is thought to play a role in Alzheimer's disease (AD) pathogenesis. To explore the correlation between IL-6 receptor gene and sporadic AD (SAD), a case-control study was conducted in a North Chinese Han population. The IL-6R promoter and the exon 9 that contains the proteolytic cleavage site of IL-6R were screened, resulting in three polymorphisms: -530G/T (novel), -208G/A (rs4845617), and +48867A/C (Asp358Ala and rs8192284). There were 328 SAD cases (mean age 75.5+/-9.1 years; mean onset age 69.9+/-8.6 years) and 305 control subjects having a similar age and sex composition. APOE epsilon4 was expectedly more common among the cases (17.7% vs 5.6%; chi(2)=44.375; P<0.001); IL-6R -530T and +48867C were over-represented among the cases (13.4% vs 8.2% P=0.003; 41.8% vs 32.8% P=0.001; OR=2.7 95% CI 1.6-4.5; OR=2.1 95% CI 1.4-3.1). Haplotype analysis indicated five common haplotypes TGA (OR=1.8), GAC, GGC, GAA, and GGA (OR=0.7), from highest to lowest risk. None of the associations appeared to be modified by APOE epsilon4. We conclude that the -530T allele located in a putative regulatory region and the +48867C allele at the splice site may elevate the risk of SAD among the Han Chinese. PMID- 20197063 TI - Transduced PDZ1 domain of PSD-95 decreases Src phosphorylation and increases nNOS (Ser847) phosphorylation contributing to neuroprotection after cerebral ischemia. AB - Over-activation of NMDA receptor has been widely believed to be the main signal resulting in ischemic cell injury. We recently reported that the triplicate complex NR2A-PSD-95-Src is a signaling module to facilitate NMDA receptor over activation. In addition, over-activation of NMDA receptor can activate another signaling molecule nNOS, which is also mediated by PSD-95 after cerebral ischemia. Here, we examined whether overexpression of the PDZ1 domain of PSD-95 could disrupt the functional interaction between NMDA receptor and PSD-95 in rat hippocampal CA1 region, and whether or not it could exert a neuroprotective effect against cerebral ischemia. Our results showed that overexpression of PDZ1 domain not only decreased the assembly of NR2A-PSD-95-Src signaling module and the auto-phosphorylation of Src, which mediates NMDA receptor phosphorylation, but also enhanced nNOS (Ser847) phosphorylation. Most importantly, overexpression of PDZ1 domain protected rat hippocampal CA1 neurons against cerebral ischemia injury. These results suggest that overexpression of the PDZ1 domain can perturb the binding of PSD-95 to NMDA receptor, suppress the activity of both NMDA receptor and nNOS, and thus have a neuroprotective effect. PMID- 20197064 TI - Functional polymorphism of matrix metalloproteinase-9 (MMP-9) gene in alcohol dependence: family and case control study. AB - AIM: Matrix metalloproteinases (MMP) are extracellularly acting endopeptidases, whose substrates are extracellular matrix and adhesion proteins. In the gene polymorphism studies MMP-9 has been suggested to be involved in the pathogenesis of heart disease, cancer, bipolar disorder, and schizophrenia. In animal models MMP-9 has been shown to play a key role in a variety of neuronal plasticity phenomena, including learning and memory as well as drug addiction. METHOD: We studied 139 families, Caucasians, with no history of psychiatric disorder of ICD 10 other than alcohol or nicotine dependence. The control subjects were 136 unrelated individuals, matched for ethnicity and gender, with no mental disorder. Alcohol and family history of alcoholism were assessed by means of a structured interview, based on the Polish version of SSAGA (Semi-Structured Assessment on Genetics in Alcoholism). RESULTS: We found a statistically significant preferential transmission of the T allele (known to produce higher gene transcriptional activity) from parents to alcoholics (59%, p=0.046). In a case control study genotype TT and T alleles were significantly more frequent in the alcoholics than in the controls (OR=2.6). CONCLUSION: Our results suggest that the MMP-9 gene may play a role in the pathogenesis of alcohol dependence. PMID- 20197065 TI - Lateralization of tonal and intonational pitch processing: an MEG study. AB - An MEG experiment was carried out in order to compare the processing of lexical tonal and intonational contrasts, based on the tonal dialect of Roermond (the Netherlands). A set of words with identical phoneme sequences but distinct pitch contours, which represented different lexical meanings or discourse meanings (statement vs. question), were presented to native speakers as well as to a control group of speakers of Standard Dutch, a non-tone language. The stimuli were arranged in a mismatch paradigm, under three experimental conditions: in the first condition (lexical), the pitch contour differences between standard and deviant stimuli reflected differences between lexical meanings; in the second condition (intonational), the stimuli differed in their discourse meaning; in the third condition (combined), they differed both in their lexical and discourse meaning. In all three conditions, native as well as non-native responses showed a clear MMNm (magnetic mismatch negativity) in a time window from 150 to 250 ms after the divergence point of standard and deviant pitch contours. In the lexical condition, a stronger response was found over the left temporal cortex of native as well as non-native speakers. In the intonational condition, the same activation pattern was observed in the control group, but not in the group of native speakers, who showed a right-hemisphere dominance instead. Finally, in the combined (lexical and intonational) condition, brain reactions appeared to represent the summation of the patterns found in the other two conditions. In sum, the lateralization of pitch processing is condition-dependent in the native group only, which suggests that language experience determines how processes should be distributed over both temporal cortices, according to the functions available in the grammar. PMID- 20197067 TI - FMR1/FXR1 and the miRNA pathway are required for eye and neural crest development. AB - FMR1 and FXR1 are RNA binding proteins interacting with the miRNA-induced silencing complex, RISC. Here we describe for the first time the function of these proteins during eye and neural crest (NC) development in Xenopus laevis. A loss of FMR1 or FXR1 results in abnormal eye development as well as defects in cranial cartilage derived from cranial NC cells. We further investigated the possible mechanism of these phenotypes by showing that a depletion of Dicer, an important enzyme for generating all mature miRNAs, in the anterior neural tissue also leads to eye and cranial cartilage defects. Furthermore, we examined the function of 12 miRNAs during anterior neural development. We show a specific requirement of six selected miRNAs during eye and cranial cartilage development. Mir-130a, -219, and -23b are involved in eye formation only whereas loss of miR 200b, miR-96 and miR-196a results in strong defects during eye as well as cranial cartilage development. Our results suggest an essential role for FMR1 and FXR1 for eye and NC development in X.laevis likely through an interaction with the miRNA pathway. PMID- 20197066 TI - GDP-bound Galphai2 regulates spinal motor neuron differentiation through interaction with GDE2. AB - Galphai proteins play major roles in the developing and mature nervous system, ranging from the control of cellular proliferation to modulating synaptic plasticity. Although best known for transducing signals from activated seven transmembrane G-protein coupled receptors (GPCRs) when bound to GTP, key cellular functions for Galphai-GDP are beginning to emerge. Here, we show that Galphai2 is expressed in motor neuron progenitors that are differentiating to form postmitotic motor neurons in the developing spinal cord. Ablation of Galphai2 causes deficits in motor neuron generation but no changes in motor neuron progenitor patterning or specification, consistent with a function for Galphai2 in regulating motor neuron differentiation. We show that Galphai2 function is mediated in part by its interaction with GDE2, a known regulator of motor neuron differentiation, and that disruption of the GDE2/Galphai2 complex in vivo causes motor neuron deficits analogous to Galphai2 ablation. Galphai2 preferentially associates with GDE2 when bound to GDP, invoking GPCR-independent functions for Galphai2 in the control of spinal motor neuron differentiation. PMID- 20197068 TI - Rotavirus infection of murine small intestine causes colonic secretion via age restricted galanin-1 receptor expression. AB - BACKGROUND & AIMS: Mechanisms for age restriction of rotavirus diarrhea are unclear. Because rotavirus primarily infects small intestine, colonic contribution has not been widely studied. Recent data suggest that colonic secretion postbacterial infection is mediated by galanin-1 receptors (Gal1-R). We evaluated age-dependent expression of Gal1-R in Rhesus rotavirus (RRV)-infected mice and its contribution to fluid secretion. METHODS: Twenty-four hours after infection of C57BL/6J mice (wild type or Gal1-R knockout) with RRV or vehicle, closed small intestinal and colon loops were constructed. Net fluid content of the loops was calculated (milligrams/centimeters) at 2 hours post-treatment with galanin, galanin antibody, or lidocaine. Gal1-R expression was quantified by automated chromogen analysis. RESULTS: Viral antigen was detected in small intestinal epithelial cells but not in colon. Developmental Gal1-R was widely expressed in the small intestine but minimally in the colon. Postinfection, markedly increased Gal1-R was seen in the colon but not after day 25. Galanin caused a significantly higher increase in the net fluid content of infected colon than small intestine. Treatment with lidocaine reduced net fluid secretion in the small intestine and the colon. Mean diarrheal scores were significantly reduced in Gal1-R knockout mice compared with wild type (1.19 +/- 0.31, n = 22 vs 3.36 +/ 0.50, n = 35, P = .0001). CONCLUSIONS: These data show that RRV infection of the small intestine increases colonic secretion through Gal1-R and provide a promising start toward understanding the age restriction of rotavirus diarrhea. PMID- 20197069 TI - Transcriptional regulation of the insulin signaling pathway genes by starvation and 20-hydroxyecdysone in the Bombyx fat body. AB - Genetic studies in the fruitfly, Drosophila melanogaster, have uncovered a conserved insulin/insulin growth factor signaling (IIS) pathway that regulates nutrition-dependent growth rates of insects. From the silkworm, Bombyx mori, we have identified and characterized several key genes involved in the IIS pathway, including InR, IRS, PI3K110, PI3K60, PTEN, PDK, and Akt. Tissue distribution analysis showed that most of these genes were highly expressed in the fat body implying that the IIS pathway is functionally important within insect adipose tissue. Developmental profile studies revealed that the expression levels of InR, IRS, PI3K110, and PDK were elevated in the fat body during molting and pupation, periods when animals ceased feeding and hemolymph levels of 20-hydroxyecdysone (20E) were high. Starvation rapidly up-regulated the mRNA levels of these same genes in the fat body, while 20E slowly induced their transcription. We conclude that 20E slowly reduces food consumption and then indirectly induces a state of starvation resulting in the elevation of the mRNA levels of InR, IRS, PI3K110, and PDK in the Bombyx fat body during molting and pupation. PMID- 20197070 TI - Effects of acclimation temperature on thermal tolerance, locomotion performance and respiratory metabolism in Acheta domesticus L. (Orthoptera: Gryllidae). AB - The effects of acclimation temperature on insect thermal performance curves are generally poorly understood but significant for understanding responses to future climate variation and the evolution of these reaction norms. Here, in Acheta domesticus, we examine the physiological effects of 7-9 days acclimation to temperatures 4 degrees C above and below optimum growth temperature of 29 degrees C (i.e. 25, 29, 33 degrees C) for traits of resistance to thermal extremes, temperature-dependence of locomotion performance (jumping distance and running speed) and temperature-dependence of respiratory metabolism. We also examine the effects of acclimation on mitochondrial cytochrome c oxidase (CCO) enzyme activity. Chill coma recovery time (CRRT) was significantly reduced from 38 to 13min with acclimation at 33-25 degrees C, respectively. Heat knockdown resistance was less responsive than CCRT to acclimation, with no significant effects of acclimation detected for heat knockdown times (25 degrees C: 18.25, 29 degrees C: 18.07, 33 degrees C: 25.5min). Thermal optima for running speed were higher (39.4-40.6 degrees C) than those for jumping performance (25.6-30.9 degrees C). Acclimation temperature affected jumping distance but not running speed (general linear model, p=0.0075) although maximum performance (U(MAX)) and optimum temperature (T(OPT)) of the performance curves showed small or insignificant effects of acclimation temperature. However, these effects were sensitive to the method of analysis since analyses of T(OPT), U(MAX) and the temperature breadth (T(BR)) derived from non-linear curve-fitting approaches produced high inter-individual variation within acclimation groups and reduced variation between acclimation groups. Standard metabolic rate (SMR) was positively related to body mass and test temperature. Acclimation temperature significantly influenced the slope of the SMR-temperature reaction norms, whereas no variation in the intercept was found. The CCO enzyme activity remained unaffected by thermal acclimation. Finally, high temperature acclimation resulted in significant increases in mortality (60-70% at 33 degrees C vs. 20-30% at 25 and 29 degrees C). These results suggest that although A. domesticus may be able to cope with low temperature extremes to some degree through phenotypic plasticity, population declines with warmer mean temperatures of only a few degrees are likely owing to the limited plasticity of their performance curves. PMID- 20197071 TI - Vertebrate cytokines interleukin 12 and gamma interferon, but not interleukin 10, enhance phagocytosis in the annelid Eisenia hortensis. AB - Phagocytosis assays employing class I [interleukin 12 (IL-12)], and class II [gamma interferon (gIFN) and IL-10] human recombinant cytokines were carried out to determine the biological effects of these molecules on innate immune responses in the earthworm Eisenia hortensis. Coelomocytes from E. hortensis were pre incubated with the cytokines for 16-20h in vitro followed by introduction of Escherichia coli expressing green fluorescent protein (E. coli/GFP). The pro inflammatory cytokines IL-12 and gIFN stimulated statistically significant (p0.05) enhanced phagocytosis of E. coli/GFP by hyaline amoebocytes as determined by flow cytometry; 10 out of 21 earthworms (48%) responded to IL-12, while eight out of 21 (38%) responded to gIFN. In contrast, the anti-inflammatory cytokine IL 10 neither stimulated nor inhibited phagocytosis in nine earthworms tested. These results demonstrate that vertebrate pro-inflammatory cytokines influence invertebrate cellular responses of immune cells causing enhanced phagocytic activity in earthworm coelomocytes. PMID- 20197073 TI - Parameter identifiability of power-law biochemical system models. AB - Mathematical modeling has become an integral component in biotechnology, in which these models are frequently used to design and optimize bioprocesses. Canonical models, like power-laws within the Biochemical Systems Theory, offer numerous mathematical and numerical advantages, including built-in flexibility to simulate general nonlinear behavior. The construction of such models relies on the estimation of unknown case-specific model parameters by way of experimental data fitting, also known as inverse modeling. Despite the large number of publications on this topic, this task remains the bottleneck in canonical modeling of biochemical systems. The focus of this paper concerns with the question of identifiability of power-law models from dynamic data, that is, whether the parameter values can be uniquely and accurately identified from time-series data. Existing and newly developed parameter identifiability methods were applied to two power-law models of biochemical systems, and the results pointed to the lack of parametric identifiability as the root cause of the difficulty faced in the inverse modeling. Despite the focus on power-law models, the analyses and conclusions are extendable to other canonical models, and the issue of parameter identifiability is expected to be a common problem in biochemical system modeling. PMID- 20197072 TI - A potential link between phosphate and aging--lessons from Klotho-deficient mice. AB - Phosphate homeostasis is maintained primarily by a bone-kidney endocrine axis. When phosphate is in excess, fibroblast growth factor-23 (FGF23) is secreted from bone and acts on kidney to promote phosphate excretion into urine. FGF23 also reduces serum vitamin D levels to suppress phosphate absorption from intestine. Thus, FGF23 functions as a hormone that induces negative phosphate balance. One critical feature of FGF23 is that it requires Klotho, a single-pass transmembrane protein expressed in renal tubules, as an obligate co-receptor to bind and activate cognate FGF receptors. Importantly, defects in either FGF23 or Klotho not only cause phosphate retention but also a premature-aging syndrome in mice, which can be rescued by resolving hyperphosphatemia. In addition, changes in extracellular and intracellular phosphate concentration affect glucose metabolism, insulin sensitivity, and oxidative stress in vivo and in vitro, which potentially affect aging processes. These findings suggest an unexpected link between inorganic phosphate and aging in mammals. PMID- 20197074 TI - Consumers' ratings of the natural and unnatural qualities of foods. AB - An investigation sought to understand what consumers perceive by the term natural. The aim was to test eight hypotheses on food ingredients and processes used for manufactured food. A representative sample (n=190, aged 18-65 years), rated 50 food exemplars for naturalness (0-100 scale). Data were analysed by repeated measures ANOVA. Results support three hypotheses: chemical changes were more potent than physical changes; there was a minimal effect of mixing like entities and the more processing the greater the effect on consumer's deviation away from natural. Two hypotheses were validated conditionally: contagion accounts for naturalness reduction but is independent of dose above a certain level; E-numbers were always perceived to be less natural than the same preservatives described by chemical and common names; however, there were gender and some education interaction effects. The hypothesis that addition has a greater effect than removal was only partially validated. There was no evidence found to support the hypotheses that process has more effect than content, or that novel ingredients have a greater effect than 'known' ingredients, however, this result may have been confounded. The implications for new manufactured food products, suggested by the results, are that products with physical changes, less processing, with like ingredients and described using common named descriptors for ingredients would be perceived to be more natural. PMID- 20197075 TI - Safety evaluation of an enzymatically-synthesized glycogen (ESG). AB - An enzymatically-synthesized glycogen (ESG), intended for use as a food ingredient, was investigated for potential toxicity. ESG is synthesized in vitro from short-chain amylose by the co-operative action of branching enzyme and amylomaltase. In an acute toxicity study, oral administration of ESG to Sprague Dawley rats at a dose of 2000 mg/kg body weight did not result in any signs of toxicity. ESG did not exhibit mutagenic activity in an in vitro bacterial reverse mutation assay. In a subchronic toxicity study, increased cecal weights noted in the mid- (10%) and high-dose (30%) animals are common findings in rodents fed excess amounts of carbohydrates that increase osmotic value of the cecal contents, and thus were considered a physiological rather than toxicological response. The hematological and histopathological effects observed in the high dose groups were of no toxicological concern as they were secondary to the physiological responses resulting from the high carbohydrate levels in the test diets. The no-observed-adverse-effect level for ESG in rats was therefore established to be 30% in the diet (equivalent to approximately 18 and 21 g/kg body weight/day for male and female rats, respectively). These results support the safety of ESG as a food ingredient for human consumption. PMID- 20197076 TI - Relationship of parental bonding styles with gray matter volume of dorsolateral prefrontal cortex in young adults. AB - Previous epidemiologic studies using the parental bonding instrument (PBI), a self-report scale to rate attitudes of parents during the first 16 years, have suggested that a lower parental care score or higher parental overprotection score could lead to an increased risk of several psychiatric disorders, including schizophrenia and mood disorder. However, neuroimaging studies of an association between PBI scores and brain developmental abnormalities are still limited. In this region-of-interest analysis study using a cross-sectional design, we examined 50 normal young adults, in terms of relationships of parental bonding styles during the first 16 years measured by PBI with regional gray matter (GM) volume in the dorsolateral prefrontal cortex (DLPFC). Our study showed that paternal care score positively correlated with the GM volume in the left DLPFC, and paternal and maternal overprotection score negatively correlated with the GM volume in the left DLPFC. In conclusion, our results suggest that in normal young adults, lower paternal care and higher parental overprotection scores correlated with the GM volume reduction in the DLPFC. PMID- 20197077 TI - Gallic acid inhibits the growth of HeLa cervical cancer cells via apoptosis and/or necrosis. AB - Gallic acid (GA) is widely distributed in various plants and foods, and its various biological effects have been reported. Here, we evaluated the effects of GA on HeLa cells in relation to cell growth inhibition and death. HeLa cell growth was diminished with an IC(50) of approximately 80 microM GA at 24h whereas an IC(50) of GA in human umbilical vein endothelial cells (HUVEC) was approximately 400 microM. GA-induced apoptosis and/or necrosis in HeLa cells and HUVEC, which was accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsi(m)). The percentages of MMP (DeltaPsi(m)) loss cells and death cells were lower in HUVEC than HeLa cells. All the tested caspase inhibitors (pan caspase, caspase-3, -8 or -9 inhibitor) significantly rescued HeLa cells from GA induced cell death. GA increased reactive oxygen species (ROS) level and GSH (glutathione) depleted cell number in HeLa cells. Caspase inhibitors reduced GSH depleted cell number but not ROS level in GA-treated HeLa cells. In conclusion, GA inhibited the growth of HeLa cells and HUVEC via apoptosis and/or necrosis. The susceptibility of HeLa cells to GA was higher than that of HUVEC. GA-induced HeLa cell death was accompanied by ROS increase and GSH depletion. PMID- 20197078 TI - Carrier element-free coprecipitation (CEFC) method for separation and pre concentration of some metal ions in natural water and soil samples. AB - A simple, rapid and sensitive separation/pre-concentration procedure for Cd(II), Cr(III), Co(II), Cu(II), Fe(III), Pb(II) and Mn(II) ions in environmental samples has been established. The present procedure is based on a combination of carrier element-free coprecipitation (CEFC) and flame atomic absorption spectrometric (FAAS) determinations of understudy trace metal ions. A cationic surfactant (N cetyl N,N,N trimethyl ammonium bromide (CTAB)) as coprecipitant was used without adding any carrier element for coprecipitation of understudy ions. The optimum conditions for the coprecipitation process were investigated on several commonly tested experimental parameters, such as pH of the solution, amount of coprecipitant. The pre-concentration factor was found to be 10. The detection limits corresponding to three times the standard deviation of the blank (N=20) for Cd(II), Cr(III), Co(II), Cu(II), Fe(III), Pb(II) and Mn(II) ions were found as 0.61, 16.8, 12.7, 1.36, 2.08, 4.30 and 0.22 microg L(-1), respectively. The present procedure was successfully applied for separation and pre-concentration of investigated ions in several liquid environmental samples. In order to support the accuracy of the method, the certified reference materials (BCR 141 R calcareous loam soil and CRM025-050 soil) were analyzed. The experimental results are in good agreement with the certified values. PMID- 20197079 TI - In vitro antioxidant activities and an investigation of neuroprotection by six Salvia species from Iran: a comparative study. AB - Methanolic extracts of six species of Salvia (S. hydrangea, S. lachnocalyx, S. macilenta, S. multicalis, S. sclarea and S. xanthocheila) were analyzed for their antioxidant properties, ability to prevent DNA damage by free radicals, and neuroprotective effects. Several biochemical assays were used to evaluate their antioxidant properties: DPPH(), FRAP, beta-carotene bleaching and TEAC assays. The amounts of phenolics and flavonoids were also determined. Comparison study of Salvia species showed that extracts from S. hydrangea and S. macilenta are strong antioxidants and that from S. lachnocalyx is a weak one. Furthermore, extracts from all of these species can at high concentrations (50mug/ml) inhibit DNA damage by free radicals. Furthermore, these species not only showed no cytotoxic effects in nerve growth factor (NGF)-differentiated PC12 cells, they also protected them against H(2)O(2)-induced cell death. Thus these plants may be candidates for treating neurodegenerative diseases. PMID- 20197080 TI - Spatiotemporal expression of androgen receptors in the female rat brain during the oestrous cycle and the impact of exogenous androgen administration: a comparison with gonadally intact males. AB - Little is known about the regulation and cellular distribution of androgen receptors (ARs) in female rodent brains at various stages of the oestrous cycle. This information is critical for further studies of androgen signalling in the regulation of brain function under physiological and pathophysiological conditions. In this report, we show that the distribution of AR immunoreactivity in the female rat brain is consistent with reported AR mRNA hybridisation signals in the male brain, except for the dentate gyrus of the hippocampus. Immunohistochemical and Western blot analyses performed herein revealed that the onset of region-specific changes in AR proteins was strongly correlated with circulating and ovarian levels of estradiol and testosterone across the oestrous cycle. During the metestrus and diestrus stages, however, the highest levels of AR expression were abolished by chronic dihydrotestosterone (DHT) treatment. This demonstrates that fluctuations in endogenous androgens are required for the regulation of AR expression in the female rat brain. Colocalisation studies revealed that: (1) anatomical variations in AR protein localisation existed between female and male brains, (2) AR immunoreactivity was both neuronal and non neuronal, and (3) AR protein expression was lower in female rat brains at all stages of the oestrous cycle compared to age-matched males. Our results indicate the presence of regional sex differences in AR expression and changes in the proportion of AR between different subcellular compartments. Furthermore, DHT was found to down-regulate the level of AR in the subcellular compartment in females in a region-specific manner. As a whole, the present study provides the first step toward understanding the dynamics of AR expression and regulation in the brain during normal physiological conditions and for differences in neuronal androgen effects based on sex. PMID- 20197081 TI - Involvement of ADAMs in tumorigenesis and progression of hepatocellular carcinoma: Is it merely fortuitous or a real pathogenic link? AB - Hepatocellular carcinoma (HCC) is the most common primary liver cancer and one of the most frequent types of cancer worldwide. It normally develops in patients with chronic liver disease, especially cirrhosis, although some cases without an apparent underlying liver disease have been reported. The pathogenesis of HCC is multi-factorial and complex. Hepatitis viruses are the main factors favoring the development of HCC. In fact, chronic inflammation associated with hepatitis C or B virus infection can lead to progressive liver fibrosis, cirrhosis and ultimately HCC. Chronic inflammation and liver fibrosis cause a continuous remodeling of the extracellular matrix (ECM), a dynamic process that involves several molecules including integrins and matrix processing enzymes. An increasing body of evidence indicates that ADAMs are involved in promoting tumor formation and progression of HCC. A Disintegrin And Metalloproteases (ADAMs) are a group of proteins belonging to the zinc protease superfamily. ADAMs are usually transmembrane proteins that contain disintegrin and metalloprotease domains and are, therefore, able to carry out both cell adhesion and protease activities. Soluble isoforms of ADAMs have also been discovered and characterized. In this review, we focus on the contribution of ADAM proteins to HCC tumorigenesis and cancer progression. The potential role of ADAMs as key modulators of tumor-stroma interactions during tumor progression, by means of the activities of their constituent domains, is also discussed. PMID- 20197082 TI - Plasticity of nodose ganglion neurons after capsaicin- and vagotomy-induced nerve damage in adult rats. AB - Previous reports show that vagal afferent innervation of the stomach eventually regenerates from surviving nodose ganglion (NG) neurons after subdiaphragmatic vagotomy. Systemic capsaicin treatment destroys gastric vagal afferent neurons expressing vanilloid receptor 1 (VR1). However, it is not known whether gastric innervation lost after neuronal destruction can be restored. Here, we report that capsaicin-induced damage of NG neurons innervating the stomach in adult rats is followed by restoration of vagal afferent projections. Specifically, we compared measures of neuronal plasticity in NG and vagi after subdiaphragmatic vagotomy or capsaicin treatment. The numbers of VR1-immunoreactive neurons projecting to the stomach were significantly reduced 10 days after either capsaicin treatment or vagotomy. However, the VR1-immunoreactive afferent innervation of the stomach was restored to levels exceeding those of vagotomized rats by 37 days after capsaicin, whereas neither total afferent innervation nor VR1-immunoreactive innervation reached control levels, even by 67 days after vagotomy. Capsaicin treatment significantly increased NG neuronal nitric oxide synthase (nNOS) immunoreactivity at 10 days after capsaicin, and this increase was sustained for the duration of the study, indicating higher nNOS demand in restoration of vagal projections. Vagotomy was associated with a much smaller increase in the number of nNOS-immunoreactive NG neurons, detectable only at 10 days after surgery. The number of nNOS-immunopositive gastric-projecting neurons was dramatically reduced 10 days after either capsaicin treatment or vagotomy but returned to the control level in both groups at 67 days. We found a significantly higher number of growth cones in capsaicin-treated animals compared with controls. Capsaicin significantly increased the number of nNOS-immunopositive and nNOS-immunonegative growth cones in NG at all time points. Vagotomy did not increase the number of nNOS(-) growth cones in NG. We conclude that capsaicin treatment may result in more significant restorative capacities than vagotomy, mainly because of sprouting of capsaicin-insensitive nerve fibers. PMID- 20197083 TI - Pregnancy modulates precursor cell proliferation in a murine model of focal demyelination. AB - In mice, pregnancy has been shown to have a beneficial effect on the endogenous repair of focal lysolecithin-induced CNS demyelinative lesions, enhancing the genesis of new oligodendrocytes and the degree of remyelination. To identify local cells undergoing mitosis in response to such lesions, we examined the time course of phospho-histone H3 (PH3) and myelin basic protein (MBP) expression by immunohistochemistry. After lysolecithin injection into the corpus callosum of virgin female mice, the number of dividing cells peaked about 48 h after injection and declined gradually to baseline by day 7; in pregnant mice, this initial peak was unchanged, but a new delayed peak on day 4 was induced. Colocalization data using PH3 and NG2 proteoglycan, or bromodeoxyuridine (BrdU) and oligodendrocyte transcription factor 1 (Olig1), suggested that about 75% of the proliferating cells on day 2, and about 40% of the cells on day 4, were likely of oligodendrocyte lineage; these differential percentages were of the same magnitude in both virgin and pregnant animals. Notably, the heightened proliferative response to focal lysolecithin injection during pregnancy was specific to gestational stage (early, but not late) and to lesion location (in the corpus callosum of the periventricular forebrain, but not in the caudal cerebellar peduncle of the hindbrain). PMID- 20197084 TI - Intelligibility of interrupted and interleaved speech for normal-hearing listeners and cochlear implantees. AB - Speech intelligibility is degraded in the presence of a competing talker for cochlear implantees, presumably because of impaired tracking and integration of speech segments glimpsed in the masker valleys. This hypothesis was tested by assessing the intelligibility of periodically-interrupted bisyllables produced by a male and female talker, for normal-hearing listeners and implantees. A 4-Hz square-wave modulator with random phase was used to interrupt bisyllables from each talker. Stimuli were either presented alone (Experiment I) or interleaved (Experiment II: the two talkers were alternated). In Experiment I, the mean identification score for each voice was 88% for normal-hearing listeners and 35% for implantees. In Experiment II, the mean score corresponding to correct identification of both voices was 50% for normal-hearing listeners and 5% for implantees. Implantees identified at least one bisyllable among the two well above chance level but showed difficulties assigning it to the correct talker. This suggests that implantees can make use of partial information, but cannot track and integrate the non-adjacent components of interleaved speech as well as normal-hearing listeners. Additional results obtained with normal-hearing listeners tested with tone-vocoded syllables suggest that impaired tracking/integration for implantees stems from limited reception of spectral and temporal fine structure cues. PMID- 20197085 TI - In vivo analysis of gene expression in long-lived mice lacking the pregnancy associated plasma protein A (PappA) gene. AB - Mice lacking the pregnancy-associated plasma protein A (PappA) gene exhibit diminished localized IGF-1 bioavailability and a 30% increase in mean life span. However, it is uncertain which tissues exhibit reduced IGF-1 signals in the PappA(-/-) mouse, and whether effects of this mutation parallel those of mutations that diminish IGF-1 in serum. Across a panel of 21 tissues, we used RT PCR to evaluate the effects of the PappA(-/-) mutation on expression of Igfbp5, which served as an in vivo indicator of IGF-1 signaling. Among these tissues, expression of Igfbp5 was significantly reduced by PappA(-/-) only in kidney. A broader survey of IGF-associated genes in six organs identified five other genes responsive to PappA(-/-) in kidney, with stronger effects in this organ relative to other tissues. Renal expression of Irs1 and Mt1 was increased by PappA(-/-) as well as by mutations that reduce IGF-1 in serum (i.e., Ghr(-/-), Pit1(dw/dw) and Prop1(df/df)), and we demonstrate that expression of these genes is regulated by growth hormone-treatment and calorie restriction. These results provide in vivo data on an important new model of mammalian aging, and characterize both similar and contrasting expression patterns between long-lived mice with reduced local IGF-1 availability and diminished IGF-1 in serum. PMID- 20197086 TI - Effects of long-term fish oil-enriched diet on the sphingolipid metabolism in brain of old rats. AB - An increase of the neutral sphingomyelinase (SMase) activity in the animal brain at old age is associated with a higher expression of the inflammatory marker, interleukin-1beta and a cognitive decline. Dietary n-3 polyunsaturated fatty acids (n-3 PUFA) are found to exhibit anti-inflammatory effects and normalize the age- or dementia-related cognitive function decline. In the paper we investigate the ceramide, sphingomyelin (SM) and phosphatidylserine (PS) levels in the hippocampus of 3-month-old-32-month-old rats as well as the correction of sphingolipid turnover in the brain of old rats by means of the dietetic fish oil and PS. To study the lipid turnover, the [(14)C]-labeled SM and palmitic acid were used. The [(14)C]ceramide level significantly increased while those of the [(14)C]SM, SM and PS levels decreased in the hippocampus of aged rats as compared with 3-month-old animals. Treatment of the rats with the fish oil or PS reduced the [(14)C]ceramide content and neutral SMase activity in the hippocampus of the 24-month-old animals with respect to control rats of the same age. These results suggest that dietary n-3 PUFA can prevent the age-dependent abnormalities of sphingolipid turnover via increased PS content in the hippocampus of old rats. PMID- 20197087 TI - Impact of assay selection and study design on the outcome of cytotoxicity testing of medical devices: the case of multi-purpose vision care solutions. AB - Medical device biocompatibility testing usually includes a cytotoxicity component. Assay selection and protocol design often depend on a specific testing standard rather than on the characteristics of the medical device. To better understand the impact of assay selection on study outcome of unstructured medical devices, we evaluated contact lens multi-purpose solutions (MPS) in the agar diffusion, direct contact and two elution cytotoxicity assays. To simulate the conditions of use, MPS were evaluated alone and in combination with contact lenses. All MPS passed the agar diffusion assay (n=3) and extracts prepared from contact lenses soaked in MPS passed the USP elution assay (n=3). Both the duration of contact and MPS concentration impacted the outcome of a modified elution assay. When tested at 25% strength for 48 h, all MPS evaluated were non cytotoxic (n>3). Test article movement and mechanical damage were significant issues with the direct contact assay. Movement was effectively controlled by manipulating contact lens orientation while using 0.8 mL culture medium. All MPS passed the USP direct contact cytotoxicity test when evaluated using this optimized methodology (n=3). These data are consistent with MPS results in ocular irritation studies in rabbits (n=3). PMID- 20197088 TI - Naphtho[1,2-b]furan-4,5-dione disrupts Janus kinase-2 and induces apoptosis in breast cancer MDA-MB-231 cells. AB - Naphtho[1,2-b]furan-4,5-dione (NFD), prepared from 2-hydroxy-1,4-naphthoquinone and chloroacetaldehyde in an efficient one-pot reaction, exhibits an anti carcinogenic effect. NFD-induced apoptosis in MDA-MB-231 cells, as indicated by the accumulation of sub-G1 population, externalization of phosphatidylserine, loss of mitochondrial membrane potential (DeltaPsim) with subsequent release of cytochrome c, and activation of both capase-9 and caspase-3. This correlated with up-regulation in Bax and Bad, and down-regulation of various anti-apoptotic proteins, including Bcl-2, Bcl-X(L), Mcl-1, and survivin in NFD-treated cells. In the analysis of signal transduction pathway, NFD suppressed the phosphorylation of JAK2 in MDA-MB-231 cells without altering the expression of JAK2 protein. Activation of STAT3, Src, and PI3K/Akt were also inhibited by NFD. Moreover, the JAK2 inhibitor AG490 blocked JAK2, STAT3, Src, PI3K, and Akt activation, whereas both Src inhibitor PP2 and PI3K inhibitor wortmannin did not affect JAK2 activation. This suggests that STAT3, Src, and PI3K/Akt are downstream molecules of the JAK2 signaling pathway. AG490 treatment also mimics the cytotoxic effects of NFD. Taken together, these results indicate that NFD disrupts JAK2 pathway and induces apoptosis in MDA-MB-231 cells. PMID- 20197089 TI - The role of culture collections as an interface between providers and users: the example of yeasts. AB - The importance and species diversity of yeasts in food production are described, including a listing of agricultural applications. Two yeast species were selected for case studies on distribution patterns from microbial culture collections: the high representation of Saccharomyces cerevisiae in culture collections enabled global comparison, while Dekkera bruxellensis deposits and distributions were analyzed from the perspective of a single culture collection. In conclusion, culture collections need to cover temporal gaps between deposit and application of strains. The further development of culture collections in countries of high but underexplored species diversity should facilitate the conservation and management of microbial resources. PMID- 20197090 TI - Endogenous boldenone-formation in cattle: alternative invertebrate organisms to elucidate the enzymatic pathway and the potential role of edible fungi on cattle's feed. AB - Although beta-boldenone (bBol) used to be a marker of illegal steroid administration in calves, its endogenous formation has recently been demonstrated in these vertebrates. However, research on the pathway leading to bBol remains scarce. This study shows the usefulness of in vivo invertebrate models as alternatives to vertebrate animal experiments, using Neomysis integer and Lucilia sericata. In accordance with vertebrates, androstenedione (AED) was the main metabolite of beta-testosterone (bT) produced by these invertebrates, and bBol was also frequently detected. Moreover, in vitro experiments using feed-borne fungi and microsomes were useful to perform the pathway from bT to bBol. Even the conversion of phytosterols into steroids was shown in vitro. Both in vivo and in vitro, the conversion of bT into bBol could be demonstrated in this study. Metabolism of phytosterols by feed-borne fungi may be of particular importance to explain the endogenous bBol-formation by cattle. To the best of our knowledge, it is the first time the latter pathway is described in literature. PMID- 20197091 TI - Worldwide status of vitamin D nutrition. AB - The vitamin D status depends on the production of vitamin D3 in the skin under the influence of ultraviolet radiation and vitamin D intake through the diet or vitamin D supplements. The serum 25-hydroxyvitamin D (25(OH)D) concentration is the parameter of choice for the assessment of vitamin D status. Low serum levels of calcium and phosphate and an elevated level of alkaline phosphatase can also point to vitamin D deficiency. Usually, between 50% and 90% of vitamin D in the body is coming from the production in the skin and the remainder is from the diet. The production of vitamin D3 in the skin depends on sunshine exposure, latitude, skin-covering clothes, the use of sun block and skin pigmentation. In general, serum 25(OH)D is lower with higher latitudes and with darker skin types, but there are exceptions. Vitamin D deficiency (serum 25(OH)D<25 nmol/l) is highly prevalent in India and China while vitamin D status is better in Japan and South-East Asia. Vitamin D deficiency is very common in the Middle-East and there is a relationship with skin covering clothes and staying outside of the sun. A poor to moderate vitamin D status is also common in Africa, probably caused by the dark skin types and cultural habits of staying outside of the sunshine. Vitamin D status is much better in North America where vitamin D deficiency is uncommon but vitamin D insufficiency (serum 25(OH)D between 25 and 50 nmol/l) is still common. In the United States and Canada milk is usually supplemented with vitamin D and the use of vitamin supplements is relatively common. Vitamin D status in Latin America usually is reasonable but there are exceptions and vitamin D insufficiency still occurs quite often. In Australia and New Zealand a poor vitamin D status was seen in the elderly who were often vitamin D deficient and also in immigrants from Asia. Vitamin D deficiency also occurred in children when the mother was vitamin D deficient. Within Europe, vitamin D status usually is better in the Nordic countries than around the Mediterranean. This may be due to a lighter skin and sun seeking behaviour and a high consumption of cod liver oil in the Northern countries while in Southern Europe people stay out of the sunshine and have a somewhat darker skin. A very poor vitamin D status was observed in non-western immigrants, especially in pregnant women. In conclusion, vitamin D deficiency and insufficiency are globally still very common especially in risk groups such as young children, pregnant women, elderly and immigrants. PMID- 20197092 TI - Identification of Ser2 proteins as major sericin components in the non-cocoon silk of Bombyx mori. AB - Sericins are glue proteins of Bombyx mori silk fibers. They are produced in the middle silk gland (MSG) cells, stored in the lumen, and pushed out from the spinneret surrounding the fibroin fibers. The Ser2 gene was partly cloned from the anterior region of the MSG more than 20 years ago and is regarded as a sericin-encoding gene; however, Ser2 proteins do not appear to be major components of cocoon proteins. We used northern blotting to analyze the expression of three sericin genes--Ser1, Ser2, and Ser3--in the MSG of third to fifth instar larvae, and measured the corresponding cDNA levels by competitive PCR. The results revealed that Ser2 gene expression dominated until the middle period of the fifth instar, while the expression of the other genes was mainly observed after the middle fifth instar. Protein analysis demonstrated that the two Ser2 proteins produced by alternative splicing were major coating proteins of larval silk threads spun during the growing stages. The molecular components of larval silk sericin were completely different from those of cocoon sericin, and the difference may be related to the functions of the two kinds of silk fibers. PMID- 20197093 TI - MEF-2 regulates activity-dependent spine loss in striatopallidal medium spiny neurons. AB - Striatal dopamine depletion profoundly reduces the density of spines and corticostriatal glutamatergic synapses formed on D(2) dopamine receptor expressing striatopallidal medium spiny neurons, leaving D(1) receptor expressing striatonigral medium spiny neurons relatively intact. Because D(2) dopamine receptors diminish the excitability of striatopallidal MSNs, the pruning of synapses could be a form of homeostatic plasticity aimed at restoring activity into a preferred range. To characterize the homeostatic mechanisms controlling synapse density in striatal medium spiny neurons, striatum from transgenic mice expressing a D(2) receptor reporter construct was co-cultured with wild-type cerebral cortex. Sustained depolarization of these co-cultures induced a profound pruning of glutamatergic synapses and spines in striatopallidal medium spiny neurons. This pruning was dependent upon Ca(2+) entry through Cav1.2 L-type Ca(2+) channels, activation of the Ca(2+)-dependent protein phosphatase calcineurin and up-regulation of myocyte enhancer factor 2 (MEF2) transcriptional activity. Depolarization and MEF2 up-regulation increased the expression of two genes linked to synaptic remodeling-Nur77 and Arc. Taken together, these studies establish a translational framework within which striatal adaptations linked to the symptoms of Parkinson's disease can be explored. PMID- 20197094 TI - Distinct PTPmu-associated signaling molecules differentially regulate neurite outgrowth on E-, N-, and R-cadherin. AB - Classical cadherins play distinct roles in axon growth and guidance in the visual system, however, the signaling pathways they activate remain unclear. Growth cones on each cadherin substrate have a unique morphology suggesting that distinct signals are activated by neurite outgrowth on E-, N-, and R-cadherin. We previously demonstrated that receptor protein tyrosine phosphatase-mu (PTPmu) is required for E- and N-cadherin-dependent neurite outgrowth. In this manuscript, we demonstrate that PTPmu regulates R-cadherin-mediated neurite outgrowth. Furthermore, we evaluated whether known PTPmu-associated signaling proteins, Rac1, Cdc42, IQGAP1 and PKCdelta, regulate neurite outgrowth mediated by these cadherins. While Rac1 activity is required for neurite outgrowth on all three cadherins Cdc42/IQGAP1 are required only for N- and R-cadherin-mediated neurite outgrowth. In addition, we determined that PKC activity is required for E- and R cadherin-mediated, but not N-cadherin-mediated neurite outgrowth. In summary, distinct PTPmicro-associated signaling proteins are required to promote neurite outgrowth on cadherins. PMID- 20197095 TI - Automated electron microscopy for evaluating two-dimensional crystallization of membrane proteins. AB - Membrane proteins fulfill many important roles in the cell and represent the target for a large number of therapeutic drugs. Although structure determination of membrane proteins has become a major priority, it has proven to be technically challenging. Electron microscopy of two-dimensional (2D) crystals has the advantage of visualizing membrane proteins in their natural lipidic environment, but has been underutilized in recent structural genomics efforts. To improve the general applicability of electron crystallography, high-throughput methods are needed for screening large numbers of conditions for 2D crystallization, thereby increasing the chances of obtaining well ordered crystals and thus achieving atomic resolution. Previous reports describe devices for growing 2D crystals on a 96-well format. The current report describes a system for automated imaging of these screens with an electron microscope. Samples are inserted with a two-part robot: a SCARA robot for loading samples into the microscope holder, and a Cartesian robot for placing the holder into the electron microscope. A standard JEOL 1230 electron microscope was used, though a new tip was designed for the holder and a toggle switch controlling the airlock was rewired to allow robot control. A computer program for controlling the robots was integrated with the Leginon program, which provides a module for automated imaging of individual samples. The resulting images are uploaded into the Sesame laboratory information management system database where they are associated with other data relevant to the crystallization screen. PMID- 20197098 TI - Phylogeny of the freshwater copepod Mesocyclops (Crustacea: Cyclopidae) based on combined molecular and morphological data, with notes on biogeography. AB - We combined molecular and morphological characters in a copepod taxon for which obtaining a sufficiently high number of characters that evolve at different rates is a challenge. Few molecular markers are known to resolve evolutionary relationships in the copepods, and thus there is potential for morphology to contribute substantially to phylogenetic reconstruction. We used a morphology based tree of the entire Mesocyclops genus to guide our taxon sampling of 10 species for molecular and combined analyses. Morphology including polymorphic characters, 18S rDNA, and ITS2 sequences were analyzed using parsimony, ML, and Bayesian methods. Strong similarities among topologies were observed regardless of the character type or algorithm, with higher levels of support obtained in combined data analyses. In combined analyses Old World species formed a monophyletic group and New World species formed a paraphyletic group in this freshwater, predominantly (sub)tropical genus. Mesocyclops darwini was the single taxon whose relationships showed conflict among the previous reconstructions using only morphological characters and the tree inferred from the combined data set. Support for these alternative positions of M. darwini were compared using constraint tests, with the result supporting monophyly of Old World taxa. PMID- 20197096 TI - Genome-wide analysis reveals novel genes influencing temporal lobe structure with relevance to neurodegeneration in Alzheimer's disease. AB - In a genome-wide association study of structural brain degeneration, we mapped the 3D profile of temporal lobe volume differences in 742 brain MRI scans of Alzheimer's disease patients, mildly impaired, and healthy elderly subjects. After searching 546,314 genomic markers, 2 single nucleotide polymorphisms (SNPs) were associated with bilateral temporal lobe volume (P<5 x 10(-7)). One SNP, rs10845840, is located in the GRIN2B gene which encodes the N-methyl-d-aspartate (NMDA) glutamate receptor NR2B subunit. This protein - involved in learning and memory, and excitotoxic cell death - has age-dependent prevalence in the synapse and is already a therapeutic target in Alzheimer's disease. Risk alleles for lower temporal lobe volume at this SNP were significantly over-represented in AD and MCI subjects vs. controls (odds ratio=1.273; P=0.039) and were associated with mini-mental state exam scores (MMSE; t=-2.114; P=0.035) demonstrating a negative effect on global cognitive function. Voxelwise maps of genetic association of this SNP with regional brain volumes, revealed intense temporal lobe effects (FDR correction at q=0.05; critical P=0.0257). This study uses large scale brain mapping for gene discovery with implications for Alzheimer's disease. PMID- 20197097 TI - Comparison of the disparity between Talairach and MNI coordinates in functional neuroimaging data: validation of the Lancaster transform. AB - Spatial normalization of neuroimaging data is a standard step when assessing group effects. As a result of divergent analysis procedures due to different normalization algorithms or templates, not all published coordinates refer to the same neuroanatomical region. Specifically, the literature is populated with results in the form of MNI or Talairach coordinates, and their disparity can impede the comparison of results across different studies. This becomes particularly problematic in coordinate-based meta-analyses, wherein coordinate disparity should be corrected to reduce error and facilitate literature reviews. In this study, a quantitative comparison was performed on two corrections, the Brett transform (i.e., "mni2tal"), and the Lancaster transform (i.e., "icbm2tal"). Functional magnetic resonance imaging (fMRI) data acquired during a standard paired associates task indicated that the disparity between MNI and Talairach coordinates was better reduced via the Lancaster transform, as compared to the Brett transform. In addition, an activation likelihood estimation (ALE) meta-analysis of the paired associates literature revealed that a higher degree of concordance was obtained when using the Lancaster transform in the form of fewer, smaller, and more intense clusters. Based on these results, we recommend that the Lancaster transform be adopted as the community standard for reducing disparity between results reported as MNI or Talairach coordinates, and suggest that future spatial normalization strategies be designed to minimize this variability in the literature. PMID- 20197099 TI - Gender differences in the effects of post-learning emotion on consolidation of item memory and source memory. AB - Item memory and source memory are two integral elements of episodic memory. Although many studies have examined the effect of emotion on item memory, little research has simultaneously taken into account item memory and source memory. In addition, in the majority of previous studies, learning stimuli are used as the source of emotion, making it difficult to understand whether emotion has an effect on encoding or on consolidation of episodic memory. Furthermore, although gender differences exist in neurophysiological responses to emotional stimuli, in many studies gender differences were neglected and this leaves the picture incomplete regarding the effect of emotion on episodic memory. In this study, we examined gender differences in the effects of post-learning emotion on consolidation of item memory and source memory. Participants learned neutral Chinese nouns, took a memory pretest, and were then randomly assigned to three conditions, in which they either watched a 3-min negative video clip, or watched a 3-min positive video clip, or remained calm and relaxed for 3 min. Thirty minutes after the initial learning, participants took a memory posttest. We found that: (1) For females, post-learning negative emotion enhanced consolidation of item memory; however, neither negative emotion nor positive emotion had a significant effect on consolidation of source memory; (2) For males, neither negative nor positive emotion after learning had a significant effect on either item memory or source memory. Possible reasons for the gender differences, as well as the theoretical significance and practical implications of this study were discussed. PMID- 20197100 TI - Thalidomide-dexamethasone as induction therapy before autologous stem cell transplantation in patients with newly diagnosed multiple myeloma and renal insufficiency. AB - The aim of this study was to evaluate the efficacy and the toxicity of thalidomide-dexamethasone (Thal-Dex) as induction therapy before autologous peripheral blood stem cell (PBSC) transplantation in patients with newly diagnosed multiple myeloma (MM) with renal insufficiency. The study included 31 patients with a baseline creatinine clearance value 4 x 10(6) CD34(+) cells/kg were collected. Double autologous transplantation was performed in 15 patients, and a single autologous transplantation was performed in 7 patients. After a median of 32 months of follow-up, median event-free survival was 30 months, and median survival was not determined. According to our data, Thal-Dex is effective and safe in patients with newly diagnosed MM and renal insufficiency. Given the relationship between recovery of renal function and response to induction treatment, more intensive Thal + bortezomib regimens could be explored to rescue higher numbers of patients. PMID- 20197101 TI - Predictors of late cardiovascular complications in survivors of hematopoietic cell transplantation. AB - Long-term survival after hematopoietic cell transplantation (HCT) is now an expected outcome. The growing population of survivors is at risk of developing treatment-related complications, including cardiovascular disease (CVD). A nested case-controlled design was used to identify clinical and treatment-related risk factors for development of late (1+ years after HCT) CVD. Cases were identified from a cohort of 1+-year survivors who underwent transplantation at City of Hope between 1977 and 2006. Controls (HCT survivors without CVD) were matched on age, year of HCT, type of HCT, and duration of follow-up. Sixty-three patients with late CVD were identified, 44 (69.8%) with a coronary artery event and 19 (30.2%) with a cerebrovascular event. Median age at HCT was 49.0 years. Median age at onset of late CVD was 54.0 years; 66.7% of the affected patients had undergone autologous HCT. Multivariate logistic regression analysis showed that the presence of multiple cardiovascular risk factors (2 or more of the following: obesity, dyslipidemia, hypertension, and diabetes) after HCT was associated with a 5.2-fold increased risk of late CVD (P < .01), and that pre-HCT chest radiation exposure was associated with a 9.5-fold greater risk of coronary artery disease (P = .03). Pre-HCT exposure to chest radiation and the presence of comorbidities were primarily responsible for the risk associated with late CVD after HCT. These data form the basis for developing predictive models for identifying high-risk individuals for targeted surveillance and aggressive management of comorbidities. PMID- 20197102 TI - Phase I/II trial of GN-BVC, a gemcitabine and vinorelbine-containing conditioning regimen for autologous hematopoietic cell transplantation in recurrent and refractory hodgkin lymphoma. AB - Autologous hematopoietic cell transplantation with augmented BCNU regimens is effective treatment for recurrent or refractory Hodgkin lymphoma (HL); however, BCNU-related toxicity and disease recurrence remain challenges. We designed a conditioning regimen with gemcitabine in combination with vinorelbine in an effort to reduce the BCNU dose and toxicity without compromising efficacy. In this phase I/II dose escalation study, the gemcitabine maximum tolerated dose (MTD) was determined at 1250 mg/m(2), and a total of 92 patients were treated at this dose to establish safety and efficacy. The primary endpoint was the incidence of BCNU-related toxicity. Secondary endpoints included 2-year freedom from progression (FFP), event-free survival (EFS), and overall survival (OS). Sixty-eight patients (74%) had 1 or more previously defined adverse risk factors for transplant (stage IV at relapse, B symptoms at relapse, greater than minimal disease pretransplant). The incidence of BCNU-related toxicity was 15% (95% confidence interval, 9%-24%). Only 2% of patients had a documented reduction in diffusing capacity of 20% or greater. With a median follow-up of 29 months, the FFP at 2 years was 71% and the OS at 2 years was 83%. Two-year FFP was 96%, 72%, 67%, and 14% for patients with 0 (n = 24), 1 (n = 37), 2 (n = 23), or 3 (n = 8) risk factors, respectively. Regression analysis identified PET status pretransplant and B symptoms at relapse as significant prognostic factors for FFP. This new transplant regimen for HL resulted in decreased BCNU toxicity with encouraging FFP and OS. A prospective, risk-modeled comparison of this new combination with other conditioning regimens is warranted. PMID- 20197103 TI - Activated allogeneic NK cells as suppressors of alloreactive responses. AB - Donor NK cells have been shown to be able to promote engraftment during allogeneic bone marrow transplantation. They could specifically suppress or delete host reactive cells, thereby facilitating engraftment of donor marrow. To further elucidate the mechanism, we showed that activated H2(d) ALAK cells (adherent lymphokine activated killer, IL-2 activated T cell-depleted bone marrow and spleen cells) from BALB/c mice significantly suppressed the proliferation of H2(b) splenocytes from C57BL/6 mice in mixed lymphocyte responses (MLR) stimulated with irradiated H2(d) splenocytes from BALB/c mice (P < .01). The ability for H2(b) splenocytes to kill H2(d) tumor targets was also significantly inhibited by activated H2(d) ALAK cells (P < .01). The same number of H2(b) ALAK cells or H2(d) splenocytes did not show the same suppressive effect. These results suggested that activated H2(d) ALAK cells could specifically suppress the anti-H2(d) activity of the H2(b) splenocytes. Anti-tumor growth factor (TGF)beta antibody blockade did not diminish this suppressive effect of ALAK cells, suggesting that this activity is not dependent on TGF-beta secretion. ALAKs from gld (FasL mutant) mice suppressed the allo-responses as well as the wild-type ALAK cells. The ALAKs from pfp (perforin knockout) mice did not completely block the inhibitory effect, which suggested that the suppressive effect of the allogeneic ALAK cells could be partially caused by perforin-mediated killing. We further demonstrated that donor ALAK cells could promote engraftment by suppressing host alloreactive responses in a nonmyeloablative allogeneic BMT model. These studies suggest that activated donor NK cells specifically suppress the alloreactive cells and provide a promising way to promote donor engraftment without involving systemic and nonspecific suppression of the immune system. PMID- 20197105 TI - Chitinases from the black tiger shrimp Penaeus monodon: phylogenetics, expression and activities. AB - Chitinases are essential enzymes for crustaceans and animal alike for their molting and digestion of foods containing chitin. From the Penaeus monodon EST database, cDNA contigs and singletons for three chitinases, namely PmChi1, 2 and 3, were identified. The complete sequences for the mature PmChi1, 3 and partial PmChi2 were amplified and cloned. The reading frames of PmChi1 and 3 encoded mature proteins of 644 and 468 amino acids with calculated molecular masses of 72.4 and 51.9kDa, respectively. The amino acid sequence comparison among the penaeid chitinases revealed homology around 90%. Therefore, they were grouped together along with those of other crustaceans and insects into three groups separated from those of mammals. PmChi1, 2 and 3 were expressed mainly in hepatopancreas, gill and hepatopancreas, respectively, though small amounts were expressed in other tissues. After molting, only the expression of PmChi2 was down regulated, while the expression of PmChi1 and 3 was relatively unchanged. The results suggested that the PmChi2 was likely involved in molting while the others might function in the digestion of chitinous foods. The recombinant PmChi1 (rPmChi1) over-produced from Escherichia coli had its optimal pH 5 but it was most stable at neutral pH. Interestingly, the optimal temperature was relatively high at 55 degrees C. Nevertheless, it was stable at lower temperature below 40 degrees C. The rPmChi1 preferentially hydrolyzed the more soluble substrates like partially N-acetylated chitin (PNAC) and colloidal chitin from shrimp shell as compared to the beta-chitin from squid pen. PMID- 20197104 TI - Decreased infections in recipients of unrelated donor hematopoietic cell transplantation from donors with an activating KIR genotype. AB - Infectious complications following allogeneic hematopoietic cell transplantation (HCT) from unrelated donors (URD) result in significant morbidity. We hypothesized that recipients of a URD with an activating natural killer cell immunoglobulin-like receptor (KIR) (B/x) genotype would have decreased infectious complications because of enhanced natural killer (NK) cell function. We compared the infectious complications in 116 recipients of a graft from a donor with an A/A KIR (n = 44) genotype and a B/x KIR (n = 72) genotype. All recipients participated in the prospective National Marrow Donor Program infection project collecting infection data from conditioning until 6 months posttransplant. The cohort with a B/x donor had fewer initial bacterial infections by day 180 (A/A: 86%; 95% confidence interval [CI], 75-95; B/x: 68%; 95% CI, 57-78; P = .02). There was no difference in the incidence of viral or fungal infections. When accounting for multiple infections, fewer bacterial infections were seen in the B/x cohort (A/A: 3.55/patient; B/x: 2.63/patient; P = .09). During the study period, only 19 patients had no infections; of these, 15 had received cells from a B/x KIR donor. The role of donor KIR genotype on infection complications is intriguing and warrants further investigation. PMID- 20197106 TI - Scrutinizing the mechanisms underlying the induction of anemia of inflammation through GPI-mediated modulation of macrophage activation in a model of African trypanosomiasis. AB - In animal trypanosomiasis the severity of infection is reflected by the degree of anemia which resembles anemia of inflammation, involving a skewed iron homeostasis leading to iron accumulation within the reticuloendothelial system. Myeloid cells (M cells) have been implicated in the induction and maintenance of this type of anemia and modulation of M cells through the main trypanosome derived glycosylphosphatidylinositol (GPI)-anchor could attenuate both anemia and trypano-susceptibility in Trypanosoma brucei-infected mice. Herein the GPI-based treatment, allowing a straightforward comparison between trypanotolerance and susceptibility in T. brucei-infected C57Bl/6 mice, was further adopted to scrutinize mechanisms/pathways underlying trypanosome-elicited anemia. Hereby, the following interlinkable observations were made in GPI-based treated (GBT) T. brucei-infected mice: (i) a reduced inflammatory cytokine production and increased IL-10 production associated with alleviation of anemia and restoration of serum iron levels, (ii) a shift in increased liver expression of iron storage towards iron export genes, (iii) increased erythropoiesis in the bone marrow and extramedullar sites (spleen) probably reflecting a normalized iron homeostasis and availability. Collectively, our results demonstrate that reprogramming macrophages towards an anti-inflammatory state alleviates anemia of inflammation by normalizing iron homeostasis and restoring erythropoiesis. PMID- 20197107 TI - Selective and potent furin inhibitors protect cells from anthrax without significant toxicity. AB - Furin and related proprotein convertases cleave the multibasic motifs R-X-R/K/X-R in the precursor proteins and, as a result, transform the latent proproteins into biologically active proteins and peptides. Furin is present both in the intracellular secretory pathway and at the cell surface. Intracellular furin processes its multiple normal cellular targets in the Golgi and secretory vesicle compartments while cell-surface furin appears to be essential only for the processing of certain pathogenic proteins and, importantly, anthrax. To design potent, safe and selective inhibitors of furin, we evaluated the potency and selectivity of the derivatized peptidic inhibitors modeled from the extended furin cleavage sequence of avian influenza A H5N1. We determined that the N- and C-terminal modifications of the original RARRRKKRT inhibitory scaffold produced selective and potent, nanomolar range, inhibitors of furin. These inhibitors did not interfere with the normal cellular function of furin because of the likely functional redundancy existing between furin and other proprotein convertases. These furin inhibitors, however, were highly potent in blocking the furin dependent cell-surface processing of anthrax protective antigen-83 both in vitro and cell-based assays and in vivo. We conclude that the inhibitors we have designed have a promising potential as selective anthrax inhibitors, without affecting major cell functions. PMID- 20197109 TI - Automated analysis of DNA damage in the high-throughput version of the comet assay. AB - Recently a high-throughput version of the comet assay was developed using a special 96-well multichamber plate (MCP) [1]. In this version, the electrophoresis is performed directly on the MCP, which makes transferring of cells to microscope slides unnecessary. In order to facilitate the scoring procedure we adapted an automated slide-scanning system (Metafer MetaCyte with CometScan) to enable unattended analysis of comets on the MCP. The results of the system were compared with the data obtained with two interactive comet-assay analysis systems. For induction of DNA damage in human fibroblasts methylmethane sulfonate (MMS) or H2O2 was used. The three systems revealed similar, concentration-dependent results for all parameters tested: tail moment (tm), % DNA-in-tail and olive tail moment. Near the detection limit of 5-6% DNA-in-tail a significant difference with the untreated control was obtained by use of four parallel samples (p=0.01). With the newly developed automated analysis system, the evaluation of either 50 or 100 comets yielded similar standard errors for either treatment with MMS or H2O2, thus showing that the method is suitable to reveal the crucial low-dose effects with high precision. The results also show that the time needed for automated evaluation of comets on the MCP was reduced by a factor of 10 when compared with the time required for interactive evaluation. In summary, the high-throughput version of the comet assay combined with the automated evaluating system increased the output by a factor up to 180 compared with the standard method. PMID- 20197108 TI - Strategies for optic nerve rescue and regeneration in glaucoma and other optic neuropathies. AB - Glaucoma is the most common age-related optic nerve disease and also the most common neuropathy, affecting approximately 60 million people worldwide in its most common forms. This figure is expected to rise to 80 million by 2020. Glaucoma is a neurodegenerative disease in which various triggers induce cascades of secondary events, which ultimately lead to apoptotic retinal ganglion cell (RGC) death. The main risk factor for glaucomatous nerve damage is raised pressure in the eye. Understanding the cascades mediating optic nerve damage enables the development of new, neuroprotective treatment strategies that might not only target the initial insult but also prevent or delay secondary neurodegeneration. Furthermore, neuroregeneration and repopulation of the visual pathway by stem or neural precursor cells is becoming possible. Increasing understanding of the pathways involved in directed axon growth and manipulation of stem and progenitor cells towards an RGC fate have facilitated first successes in animal models of glaucoma. PMID- 20197110 TI - Monophyly of Opisthorchis viverrini populations in the lower Mekong Basin, using mitochondrial DNA nad1 gene as the marker. AB - The liver fluke, Opisthorchis viverrini, causes serious public-health problems in the Lower Mekong Basin. This study aimed to clarify whether O. viverrini populations may be genetically divided into sub-specific taxa. We collected 6 populations of O. viverrini from different places in Cambodia, Lao PDR, and Thailand, along both sides of the Mekong River, and analyzed the population structure of these using the mitochondrial nad1 gene as a marker. The results of the DNA polymorphism measurements, by theta-w (thetaw) and -pi (thetapi) values, neutrality tests, and mismatch distribution, suggested that the population of O. viverrini has expanded under the influence of purifying selection and selective sweep. The analysis of molecular variance (AMOVA) test revealed no significant genetic differences among the O. viverrini populations on opposite sides of the Mekong River. O. viverrini haplotypes occurred in multiple populations, and no distinct geographical clade. The star-like haplotype network confirmed a demographic expansion of the O. viverrini population. Overall, the genetic data from these populations suggested that the postulated existence of an O. viverrini species complex should be rejected. The bio-geographical diversity of O. viverrini populations should be explored further, using other appropriate markers and a wider range of samples from geographically different areas. PMID- 20197111 TI - Identification of immunoreactive proteins of Dirofilaria immitis and D. repens recognized by sera from patients with pulmonary and subcutaneous dirofilariosis. AB - Human pulmonary and subcutaneous dirofilariosis caused by Dirofilaria immitis and Dirofilaria repens are worldwide diagnosed with increasing frequency. These species are responsible for the development of benign pulmonary and subcutaneous nodules, respectively, that can be confused with lung or cutaneous cancer. The aim of the present work was to identify D. immitis and D. repens proteins differentially recognized by serum samples from individuals with human pulmonary and subcutaneous dirofilariosis, using two-dimensional electrophoresis and mass spectrometry. Twenty-three immunoreactive proteins of D. immitis and 15 of D. repens were identified. The results point to the existence of differential antigenic recognition in each species, both in the number and type of proteins recognized. Individuals with pulmonary dirofilariosis recognized, on the proteome of D. immitis, among others, different isoforms of 6 enzymes involved in glycolysis, 3 redox-related proteins with antioxidant capacity and 3 heat shock proteins. Individuals with subcutaneous dirofilariosis recognized on the proteome of D. repens only 3 glycolytic enzymes, one protein involved in redox processes and one heat shock protein. These data suggest that in cases of pulmonary dirofilariosis there exists a wider recognition of immunoreactive D. immitis proteins related to key survival processes, such as energy generation, the struggle against oxidative stress and molecular repair, than in cases of human subcutaneous dirofilariosis against D. repens. This could contribute to explain the differences described in the capacity of D. immitis and D. repens development and in the frequency of occurrence of pulmonary and subcutaneous dirofilariosis in the human host. PMID- 20197112 TI - E-screen and vitellogenin assay for the detection of the estrogenic activity of alkylphenols and trace elements. AB - The estrogenic potential of 4-nonylphenol (4-NP), 4-octylphenol (4-OP), p-t octylphenol (p-t-OP) and three trace elements, lead (Pb), copper (Cu) and cadmium (Cd(NO(3))(2) and CdCl(2)), were compared in two different tests, a proliferation assay with estrogen receptor-positive human MCF-7 breast cancer cells (E-screen) and the induction of vitellogenin (Vtg) in juvenile goldfish (Carassius auratus). The results showed differences in the bioassays' sensitivity and potency with the following order: E-screen>Vtg. Among alkylphenols, both in vitro and in vivo, 4 NP and 4-OP showed the highest estrogen-like activity while p-t-OP was inferior. For trace elements, Pb and Cu showed estrogenic activity in vitro and they were also active in vivo. A range of estrogenicity was observed for different species of cadmium (Cd(NO(3))(2) and CdCl(2)) which showed the highest relative proliferative effect (RPE %) in vitro, when compared with the 17beta-estradiol (E(2); RPE=100%) but, Cd(NO(3))(2) was not estrogenic in vivo. The results suggest that an integrated approach using in vitro and in vivo assays is necessary for a correct risk assessment of the endocrine disrupting activity induced by environmental contaminants. PMID- 20197114 TI - Henoch-Schonlein purpura. PMID- 20197116 TI - Prevalence, diagnosis, and profile of autoimmune pancreatitis presenting with features of acute or chronic pancreatitis. PMID- 20197113 TI - Effect of high soy diet on the cerebrovasculature and endothelial nitric oxide synthase in the ovariectomized rat. AB - High soy (HS) diets are neuroprotective and promote vascular dilatation in the periphery. We hypothesized that an HS diet would promote vascular dilatation in the cerebrovasculature by mimicking estradiol's actions on the endothelial nitric oxide synthase (eNOS) system including increasing eNOS expression and decreasing caveolin-1 expression to increase nitric oxide (NO) production. Ovariectomized rats were fed HS or a soy-free diet (SF)+/-low physiological estradiol (E2) for 4weeks. Neither E2 nor HS altered middle cerebral artery (MCA) structure or vascular responses to acetylcholine, serotonin, or phenylephrine. Estradiol enhanced bradykinin-induced relaxation in an eNOS-dependent manner. Although E2 and HS increased eNOS mRNA expression in the brain and cerebrovasculature, they had no effect on eNOS protein expression or phosphorylation in the MCA. However, E2 decreased caveolin-1 protein in the MCA. In MCAs neither E2 nor HS altered estrogen receptor (ER) alpha expression, but E2 did reduce ER beta levels. These data suggest that HS diets have no effect on vascular NO production, and that E2 may modulate basal NO production by reducing the expression of caveolin-1, an allosteric inhibitor of NOS activity. However, the effects of E2 and HS on the cerebrovasculature are small and may not underlie their protective actions in pathological states. PMID- 20197117 TI - Congenital long QT syndrome and 2:1 atrioventricular block: an optimistic outcome in the current era. AB - BACKGROUND: Previous studies of patients with long QT syndrome (LQTS) and 2:1 atrioventricular block (AVB) have reported a mortality rate greater than 50% during infancy. OBJECTIVE: The purpose of this study was to determine the outcome of this high-risk population in the current era. METHODS: A retrospective study from four tertiary care pediatric centers assessed patients with congenital LQTS and 2:1 AVB from January 2000 to January 2009. All neonates who presented with 2:1 AVB and prolonged QTc unrelated to medication were included in the study. Statistical analysis was performed using a paired t-test. Medical records were reviewed for ECG findings, genotype, medications, and device therapy. RESULTS: Twelve patients that met the inclusion criteria were identified. All patients underwent diagnostic ECG in the first 24 hours of life. The average QTc interval prior to therapy was 616 +/- 99 ms (range 531-840 ms). Over a follow-up period of 71 +/- 45 months (range 15-158 months), 11 of 12 patients received devices (8 permanent pacemaker, 3 implantable cardioverter-defibrillator). Average age of device placement was 48 months (median 2 months, range 3 days to 10.5 years). All patients were treated with beta-blockers; mexiletine was added in three patients, and mexiletine and flecainide were added in one patient. Three (25%) patients experienced torsades de pointes while receiving beta-blockers, one of which was refractory to medical therapy. This patient underwent left cardiac sympathetic denervation and implantable cardioverter-defibrillator placement. Genotyping was available for 6 (50%) patients (2 SCN5A mutation, 4 KCNH2 mutation). At last follow-up, no mortality was observed. Follow-up QTc intervals had decreased (mean 480 +/- 20 ms, range 450-507 ms, P <.002). CONCLUSION: Management of patients with LQTS and 2:1 AVB presents unique challenges. Despite historical data indicating poor prognosis, our study represents a cohort of high-risk LQTS patients with a relatively optimistic outcome. This finding reflects early diagnosis and intervention, coupled with improved management strategies, in the current era. PMID- 20197119 TI - Meeting report: Identification of biomarkers for early detection of mitochondrial dysfunction. PMID- 20197118 TI - Epicardial neural ganglionated plexus of ovine heart: anatomic basis for experimental cardiac electrophysiology and nerve protective cardiac surgery. AB - BACKGROUND: Sheep are routinely used in experimental cardiac electrophysiology and surgery. OBJECTIVE: The purpose of this study was to (1) ascertain the topography and architecture of the ovine epicardial neural plexus (ENP), (2) determine the relationships of ENP with vagal and sympathetic cardiac nerves and ganglia, and (3) evaluate gross anatomic differences and similarities of ENP in humans, sheep, and other species. METHODS: Ovine ENP and extrinsic sympathetic and vagal nerves were stained histochemically for acetylcholinesterase in whole heart and/or thorax-dissected preparations from 23 newborn lambs, with subsequent examination by stereomicroscope. RESULTS: Intrinsic cardiac nerves extend from the venous part of the ovine heart hilum along the roots of the cranial (superior) caval and left azygos veins to both atria and ventricles via five epicardial routes: dorsal right atrial, middle dorsal, left dorsal, right ventral, and ventral left atrial nerve subplexuses. Intrinsic nerves proceeding from the arterial part of the heart hilum along the roots of the aorta and pulmonary trunk extend exclusively into the ventricles as the right and left coronary subplexuses. The dorsal right atrial, right ventral, and middle dorsal subplexuses receive the main extrinsic neural input from the right cervicothoracic and right thoracic sympathetic T(2) and T(3) ganglia as well as from the right vagal nerve. The left dorsal is supplied by sizeable extrinsic nerves from the left thoracic T(4)-T(6) sympathetic ganglia and the left vagal nerve. Sheep hearts contained an average of 769 +/- 52 epicardial ganglia. Cumulative areas of epicardial ganglia on the root of the cranial vena cava and on the wall of the coronary sinus were the largest of all regions (P <.05). CONCLUSION: Despite substantial interindividual variability in the morphology of ovine ENP, right-sided epicardial neural subplexuses supplying the sinoatrial and atrioventricular nodes are mostly concentrated at a fat pad between the right pulmonary veins and the cranial vena cava. This finding is in sharp contrast with a solely left lateral neural input to the human atrioventricular node, which extends mainly from the left dorsal and middle dorsal subplexuses. The abundance of epicardial ganglia distributed widely along the ovine ventricular nerves over respectable distances below the coronary groove implies a distinctive neural control of the ventricles in human and sheep hearts. PMID- 20197120 TI - Analysis of functional consequences of haplogroup J polymorphisms m.4216T>C and m.3866T>C in human MT-ND1: mutagenesis of homologous positions in Escherichia coli. AB - MtDNA sequence variation is presumed to be neutral in effect, but associations with diseases and mtDNA haplogroups have been reported. The aim here was to evaluate the functional consequences of m.4216T>C present in haplogroup J. Furthermore, we evaluated m.3866T>C in MT-ND1, a variant detected in a child belonging to haplogroup J and with an isolated complex I deficiency. Homologous substitutions were introduced into Escherichia coli. NADH dehydrogenase domain activity of NDH-1 with either one or both mutations was markedly decreased suggesting that m.4216T>C and m.3866T>C may have an effect on the structural integrity of complex I. PMID- 20197121 TI - New SUCLG1 patients expanding the phenotypic spectrum of this rare cause of mild methylmalonic aciduria. AB - Deficiencies in two subunits of the succinyl-coenzyme A synthetase (SCS) have been involved in patients with encephalomyopathy and mild methylmalonic aciduria (MMA). In this study, we described three new SUCLG1 patients and performed a meta analysis of the literature. Our report enlarges the phenotypic spectrum of SUCLG1 mutations and confirms that a characteristic metabolic profile (presence of MMA and C4-DC carnitine in urines) and basal ganglia MRI lesions are the hallmarks of SCS defects. As mitochondrial DNA depletion in muscle is not a constant finding in SUCLG1 patients, this may suggest that diagnosis should not be based on it, but also that alternative physiopathological mechanisms may be considered to explain the combined respiratory chain deficiency observed in SCS patients. PMID- 20197123 TI - The mechanical stress-strain properties of single electrospun collagen type I nanofibers. AB - Knowledge of the mechanical properties of electrospun fibers is important for their successful application in tissue engineering, material composites, filtration and drug delivery. In particular, electrospun collagen has great potential for biomedical applications due to its biocompatibility and promotion of cell growth and adhesion. Using a combined atomic force microscopy (AFM)/optical microscopy technique, the single fiber mechanical properties of dry, electrospun collagen type I were determined. The fibers were electrospun from a 80 mg ml(-1) collagen solution in 1,1,1,3,3,3-hexafluro-2-propanol and collected on a striated surface suitable for lateral force manipulation by AFM. The small strain modulus, calculated from three-point bending analysis, was 2.82 GPa. The modulus showed significant softening as the strain increased. The average extensibility of the fibers was 33% of their initial length, and the average maximum stress (rupture stress) was 25 MPa. The fibers displayed significant energy loss and permanent deformations above 2% strain. PMID- 20197122 TI - Bismuth-doped injectable calcium phosphate cement with improved radiopacity and potent antimicrobial activity for root canal filling. AB - A bismuth-doped injectable calcium phosphate cement (BD-ICPC) with improved radiopacity, potent antimicrobial activity and sealability was developed by introducing bismuth salicylate basic (BSB) into the powder phase of the calcium phosphate cement (CPC). The results showed that the radiopacity and sealability of BD-ICPC were improved compared with pure ICPC. Although BSB had a retarding effect on the setting rate of the cement, the addition of BSB reduced the viscosity and yield stress of BD-ICPC, thus enhanced its injectability. It was noteworthy that BD-ICPC had a potent antimicrobial activity with improved sealability. In addition, BD-ICPC afforded a uniform and tight adaptation to the root canal wall. These results indicate that BD-ICPC possesses a combination of good in vitro radiopacity, high injectability, potent antimicrobial activity, improved sealability and tight adaptation to the root canal. It is expected to be used as a novel root canal filling material. PMID- 20197124 TI - Interactions of human bone cells with diamond-like carbon polymer hybrid coatings. AB - Diamond-like carbon (DLC) coatings produced using the plasma-accelerating filtered pulsed arc discharge (FPAD) method display excellent adherence to the substrate and improve its corrosion resistance. This article reports the interactions of human osteoblastic cells with DLC and two DLC polymer hybrid (DLC p-h) coatings deposited on smooth, matt and rough silicon wafers by the FPAD method. The DLC-p-h materials were DLC-polytetrafluoroethylene hybrid (DLC-PTFE h) and DLC-polydimethylsiloxane hybrid (DLC-PDMS-h) coatings. The biocompatibility of the coatings was assayed by using mesenchymal stem cells, primary osteoblasts and Saos-2 cells. Human mesenchymal stem cells proliferated when cultured on DLC and DLC-PTFE-h, but their numbers diminished on DLC-PDMS-h. In all three cell types studied, phalloidin-TRITC staining disclosed cell-type organization typical of an actin cytoskeleton on DLC and DLC-PTFE-h, but minimal and disorganized stress fibers on cells cultured on DLC-PDMS-h. The microtubular cytoskeleton was similarly disorganized on DLC-PDMS-h. Cells on DLC-PDMS-h developed a peculiar form of membrane damage, with nuclear staining by propidium iodide associated with granular calcein staining of the cytoplasm. Active caspase 3 labeling was only seen in cells cultured on DLC-PDMS-h, indicating that these cells undergo apoptosis induced by defective cell adhesion. Results suggest that DLC-PDMS-h coatings might be useful in orthopedic applications where an implant or implant-facet should be protected against bone overgrowth while DLC and DLC PTFE-h coatings might improve osseointegration. PMID- 20197125 TI - PMMA-based bone cements containing magnetite particles for the hyperthermia of cancer. AB - Polymethylmethacrylate-based cements containing magnetite (Fe(3)O(4)) particles were prepared and their structure and properties were investigated. The Fe(3)O(4) particles were uniformly dispersed in the cement matrix and constituted a maximum of 60 wt.% of the total weight of cement. The setting time of the cement increased and the maximum temperature during the setting reaction decreased with increasing Fe(3)O(4) content. The compressive strength of cement increased with increasing Fe(3)O(4) content. Cement with 50 wt.% Fe(3)O(4) particles generated heat in alternating magnetic fields of 300 and 120 Oe at a frequency of 100 kHz. PMID- 20197126 TI - Effects of TGF-beta3 and preculture period of osteogenic cells on the chondrogenic differentiation of rabbit marrow mesenchymal stem cells encapsulated in a bilayered hydrogel composite. AB - In this work, injectable, biodegradable hydrogel composites of crosslinked oligo(poly(ethylene glycol) fumarate) and gelatin microparticles (MPs) were used to fabricate a bilayered osteochondral construct. Rabbit marrow mesenchymal stem cells (MSCs) were encapsulated with transforming growth factor-beta3 (TGF-beta3) loaded MPs in the chondrogenic layer and cocultured with cells of different periods of osteogenic preculture (0, 3, 6 and 12 days) in the osteogenic layer to investigate the effects of TGF-beta3 delivery and coculture on the proliferation and differentiation of cells in both layers. The results showed that, in the chondrogenic layer, TGF-beta3 significantly stimulated chondrogenic differentiation of MSCs. In addition, cells of various osteogenic preculture periods in the osteogenic layer, along with TGF-beta3, enhanced gene expression for MSC chondrogenic markers to different extents. In the osteogenic layer, cells maintained their alkaline phosphatase activity during the coculture; however, mineralization was delayed by the presence of TGF-beta3. Overall, this study demonstrated the fabrication of bilayered hydrogel composites which mimic the structure and function of osteochondral tissue, along with the application of these composites as cell and growth factor carriers, while illustrating that encapsulated cells of different degrees of osteogenic differentiation can significantly influence the chondrogenic differentiation of cocultured progenitor cells in both the presence and absence of chondrogenic growth factors. PMID- 20197127 TI - Surface modification with an antithrombin-heparin complex for anticoagulation: studies on a model surface with gold as substrate. AB - Gold was used as a substrate for immobilization of an antithrombin-heparin (ATH) covalent complex to investigate ATH as a surface modifier to prevent blood coagulation. Three different surface modification methods were used to attach ATH to gold: (i) direct chemisorption; (ii) using dithiobis(succinimidyl propionate) (DSP) as a linker molecule and (iii) using polyethylene oxide (PEO) as a linker/spacer. The ATH-modified surfaces were compared to analogous heparinized surfaces. Water contact angles and X-ray photoelectron spectroscopy confirmed the modifications and provided data on surface properties and possible orientation. Ellipsometry measurements showed that surface coverage of DSP and PEO was high. ATH and heparin densities were quantified using radioiodination and quartz crystal microbalance, respectively. The surface density of ATH was greatest on the DSP surface (0.17 microg cm(-2)) and lowest on the PEO (0.05 microg cm(-2)). The low uptake on the PEO surface was likely due to the protein resistance of the PEO component. Using radioiodinated antithrombin (AT), it was shown that ATH immobilized surfaces bound significantly greater amounts from both buffer and plasma than the analogous heparinized surfaces. Immunoblot analysis of proteins adsorbed from plasma demonstrated that surfaces chemisorbed with PEO, whether or not subsequently modified with ATH, inhibited non-specific adsorption. The immunoblot response for AT was stronger on the DSP-ATH than on the heparin surfaces, thus confirming the results from radiolabelling. The ATH surfaces again showed higher selectivity for AT binding than analogous heparin-modified surfaces, indicating the enhanced anticoagulant potential of ATH for biomaterial surface modification. PMID- 20197128 TI - Mesoporous silica nanotubes coated with multilayered polyelectrolytes for pH controlled drug release. AB - Two kinds of inorganic/organic hybrid composites based on mesoporous silica nanotubes (MSNTs) and pH-responsive polyelectrolytes have been developed as pH controlled drug delivery systems via the layer by layer self-assembly technique. One system was based on alternatively loading poly(allylamine hydrochloride) and sodium poly(styrene sulfonate) onto as-prepared MSNTs to load and release the positively charged drug doxorubicin. The other system was synthesized by alternately coating sodium alginate and chitosan onto amine-functionalized MSNTs, which were used as vehicles for the loading and release of the negatively charged model drug sodium fluorescein. Controlled release of the drug molecules from these delivery systems was achieved by changing the pH value of the release medium. The results of in vitro cell cytotoxicity assays indicated that the cell killing efficacy of the loaded doxorubicin against human fibrosarcoma (HT-1080) and human breast adenocarcinoma (MCF-7) cells was pH dependent. Thus, these hybrid composites could be potentially applicable as pH-controlled drug delivery systems. PMID- 20197129 TI - Microtopographical effects of natural scaffolding on cardiomyocyte function and arrhythmogenesis. AB - A natural myocardial patch for heart regeneration derived from porcine urinary bladder matrix (UBM) was previously reported to outperform synthetic materials (Dacron and expanded polytetrafluoroethylene (ePTFE)) used in current surgical treatments. UBM, an extracellular matrix prepared from urinary bladder, has intricate three-dimensional architecture with two distinct sides: the luminal side with a smoother surface relief; and the abluminal side with a fine mesh of nano- and microfibers. This study tested the ability of this natural scaffold to support functional cardiomyocyte networks, and probed how the local microtopography and composition of the two sides affects cell function. Cardiomyocytes isolated from neonatal rats were seeded in vitro to form cardiac tissue onto luminal (L) or abluminal (Ab) UBM. Immunocytochemistry of contractile cardiac proteins demonstrated growth of cardiomyocyte networks with mature morphology on either side of UBM, but greater cell compactness was seen in L. Fluorescence-based imaging techniques were used to measure dynamic changes in intracellular calcium concentration upon electrical stimulation of L and Ab-grown cells. Functional differences in cardiac tissue grown on the two sides manifested themselves in faster calcium recovery (p<0.04) and greater hysteresis (difference in response to increasing and decreasing pacing rates) for L vs Ab side (p<0.03). These results suggest that surface differences may be leveraged to engineer the desired cardiomyocyte responses and highlight the potential of natural scaffolds for fostering heart repair. PMID- 20197130 TI - Duplication of the Wolf-Hirschhorn syndrome critical region causes neurodevelopmental delay. AB - Wolf-Hirschhorn Syndrome (WHS) is caused by deletions on chromosome 4p and is clinically well defined. Genotype-phenotype correlations of patients with WHS point to a critical locus to be responsible for the main characteristics of this disorder. Submicroscopic duplications of this region, however, are not known. Here we report a patient with an interstitial 560 kb duplication overlapping this critical locus. The present case shows that not only deletions but also duplications of the Wolf-Hirshhorn critical region cause mental retardation and multiple congenital anomalies. Interestingly, the duplication phenotype overlaps partially with the deletion phenotype. However, his facial phenotype differs from the typical WHS gestalt. PMID- 20197131 TI - Characterizing the acceptability of a vaccine for West Nile virus by public health practitioners. AB - This study examines health care personnel's knowledge of West Nile virus (WNv) and attitudes towards a proposed chimeric yellow fever/WNv vaccine within the province of Saskatchewan. Telephone and in-person interviews with medical health officers and public health nurses provided information with which to assess the acceptability of implementing vaccination as a component for prevention of WNv within the province with the highest number of WNv cases to date in western Canada. The majority of health care professionals felt confident in the potential efficacy of vaccination for prevention of WNv but suggested that targeted vaccination programs could be most effective. PMID- 20197133 TI - Liposomal oral DNA vaccine (mycobacterium DNA) elicits immune response. AB - Tuberculosis is one of the leading causes of mortality from an infectious disease worldwide, however, the efficacy of BCG vaccine against adult pulmonary tuberculosis still remains instability. Therefore, it is an urgent work to develop both safe and effective vaccine to TB. To clarify the liposome encapsulated DNA vaccine was effectively working as a vaccine delivery system to evoke mucosal intestinal immune responses. A Mycobacterium pcDNA3.1(+)/Ag85A DNA was constructed and encapsulated into liposome. Ag85A protein antigen was observed to substantially express in the epithelium, microfold cells (M cells), dendritic cells (DCs) and Peyer's patches (pp) of the small intestine, respectively, after oral administration into C57BL/6 mice 3 times each 14 days interval. Furthermore, levels of IL-2 and IFN-gamma in the IELs isolated from the small intestine were markedly increased, IL-4 level was not significantly changed as compared to those in control group after oral administration of Ag85A DNA encapsulated in liposome, together with the augmented Ag85A-specific cytotoxicity of IELs, indicating a local Th1 dominant cellular immune response was elicited, and thus enhanced cytotoxicity of IELs as compared to those in control mice. Furthermore, sIgA level was also elevated in liposomal encapsulated Ag85A DNA immunized mice. These data indicated that oral vaccination with the liposomal pcDNA 3.1(+)/Ag85A DNA is able to induce antigen specific mucosal cellular and humoral immune responses. Especially, cellular compartment in the epithelium of small intestine plays a key role on the regulation of immune response to eliminate TB. These findings have important understanding and possible implications for the design of new strategies based on oral DNA vaccine on regulation of immune response in protection against TB. Further study is clearly necessary to improve the effectiveness of Ag85A DNA vaccines against TB as compared with BCG. PMID- 20197132 TI - A parenteral DNA vaccine protects against pneumonic plague. AB - The chemokine, lymphotactin (LTN), was tested as a molecular adjuvant using bicistronic DNA vaccines encoding the protective Yersinia capsular (F1) antigen and virulence antigen (V-Ag) as a F1-V fusion protein. The LTN-encoding F1-V or V Ag vaccines were given by the intranasal (i.n.) or intramuscular (i.m.) routes, and although serum IgG and mucosal IgA antibodies (Abs) were induced, F1-Ag boosts were required for robust anti-F1-Ag Abs. Optimal efficacy against pneumonic plague was obtained in mice i.m.-, not i.n.-immunized with these DNA vaccines. These vaccines stimulated elevated Ag-specific Ab-forming cells and mixed Th cell responses, with Th17 cells markedly enhanced by i.m. immunization. These results show that LTN can be used as a molecular adjuvant to enhance protective immunity against plague. PMID- 20197134 TI - Immunogenicity and some safety features of a VEGF-based cancer therapeutic vaccine in rats, rabbits and non-human primates. AB - We have developed a cancer vaccine candidate (hereafter denominated CIGB-247), based on recombinant modified human vascular endothelial growth factor (VEGF) as antigen, and the adjuvant VSSP (very small sized proteoliposomes of Neisseria meningitidis outer membrane). In mice, previous work of our group had shown that vaccination with CIGB-247 extended tumor-take time, slowed tumor growth, and increased animal survival. Immunization elicited anti-human and murine VEGF neutralizing antibodies, and spleen cells of vaccinated mice are cytotoxic in vitro to tumor cells that produce VEGF. We have now tested the immunogenicity of CIGB-247 in Wistar rats, New Zealand White rabbits and the non-human primate Chlorocebus aethiops sabaeus. Using weekly, biweekly and biweekly plus montanide immunization schemes, all three species develop antigen-specific IgG antibodies that can block the interaction of VEGF and VEGF receptor 2 in an ELISA assay. Antibody titers decline after vaccination stops, but can be boosted with new immunizations. In monkeys, DTH and direct cell cytotoxicity experiments suggest that specific T-cell responses are elicited by vaccination. Immunization with CIGB-247 had no effect on normal behavior, hematology, blood biochemistry and histology of critical organs, in the tested animals. Skin deep wound healing was not affected in vaccinated rats and monkeys. PMID- 20197135 TI - A recombinant truncated FMDV 3AB protein used to better distinguish between infected and vaccinated cattle. AB - To distinguish the antibodies induced by Foot-and-mouth disease virus (FMDV) infection from those induced by vaccination, a recombinant N-terminal truncated FMDV non-structural protein (NSP) of 3AB, designated as r3aB, was constructed by deleting 80 amino acids displayed about 30% homology to transposase IS4 family protein of Escherichia coli, expressed in E. coli BL21 (DE3) and then purified. The r3aB was majorly expressed in soluble fraction and presented as homogeneous monomers after purification. Using r3aB as coating antigen, an indirect ELISA was established to specifically identify antibodies induced by FMDV infection but not those induced by vaccination. Compared with 3AB, r3aB was more specific to catch antibodies against NSP. The performance of this assay was validated by two commercial FMDV NSP ELISA kits. The result suggested that the r3aB coated ELISA could be developed into a kit to better distinguish between infected and vaccinated cattle. PMID- 20197136 TI - The potential of 3',5'-cyclic diguanylic acid (c-di-GMP) as an effective vaccine adjuvant. AB - 3', 5'-Cyclic diguanylic acid (c-di-GMP) is a bacterial intracellular signaling molecule that plays a crucial role in the regulation of bacterial motility, adhesion, cell-to-cell communication, exopolysaccharide synthesis, biofilm formation and virulence. The recent finding that c-di-GMP can act as a danger signal on eukaryotic cells has prompted the study of the immunostimulatory and immunomodulatory properties of c-di-GMP in an effort to determine whether c-di GMP might be further developed as a potential vaccine adjuvant. In this review, we discussed the recent in vitro and in vivo studies of the immunostimulatory properties of c-di-GMP and the progress that has been made in the preclinical development of c-di-GMP as a potential vaccine adjuvant for systemic and mucosal vaccination. PMID- 20197137 TI - Identification of a novel vaccine adjuvant that stimulates and maintains diphtheria toxoid immunity. AB - Immunomodulation by plant-derived medicines is well-documented with effects on both innate and adaptive immunity. This study reports potent and long-lasting diphtheria toxoid-specific immunity by the botanical medicinal, Rehmannia Six Formula, using an in vivo mouse model of vaccine immunity. A significant vaccine adjuvant effect was observed with an increase in serum anti-diphtheria toxoid total and IgG antibodies following oral administration of Rehmannia Six Formula to mice. This response was antigen-specific and was still detectable six months following botanical medicinal treatment, suggesting that Rehmannia Six Formula could help maintain protective antibody levels in populations where vaccine coverage is low. Rehmannia Six Formula was well-tolerated with no adverse effects on mouse weight or survival observed in this study and suggests a potential role as a novel vaccine adjuvant preparation. PMID- 20197138 TI - Rotavirus enterotoxin NSP4 has mucosal adjuvant properties. AB - Rotavirus nonstructural protein 4 (NSP4) is a protein with pleiotropic properties. It functions in rotavirus morphogenesis, pathogenesis, and is the first described viral enterotoxin. Since many bacterial toxins function as potent mucosal adjuvants, we evaluated whether baculovirus-expressed recombinant simian rotavirus SA11 NSP4 possesses adjuvant activity by co-administering NSP4 with keyhole limpet hemocyanin (KLH), tetanus toxoid (TT) or ovalbumin (OVA) as model antigens in mice. Following intranasal immunization, NSP4 significantly enhanced both systemic and mucosal immune responses to model immunogens, as compared to the control group, in an antigen-specific manner. Both full-length and a cleavage product of SA11 NSP4 had adjuvant activity, localizing this activity to the C terminus of the protein. NSP4 forms from virulent and avirulent porcine rotavirus OSU strain, and SA11 NSP4 localized within a 2/6-virus-like particle (VLP) also exhibited adjuvant effects. These studies suggest that the rotavirus enterotoxin NSP4 can function as an adjuvant to enhance immune responses for a co administered antigen. PMID- 20197139 TI - Stability and potency of the Plasmodium falciparum MSP1-19/AMA-1(III) chimeric vaccine candidate with Montanide ISA720 adjuvant. AB - The Plasmodium falciparum AMA-1(III) and MSP1-19 proteins have been expressed as a chimera (PfCP-2.9), adjuvanted with Montanide ISA720 and developed as a vaccine candidate tested in human. The PfCP-2.9 protein contains 18 cysteine residues that form nine intramolecular disulfide bonds. The protective immune responses induced by the chimeric protein were dependent on its disulfide bond-based conformation. In this study, we developed a sandwich ELISA to assess the nature of the protein in the emulsion over time (6, 12 and 18 months). Our results showed that the OD(450) values corresponding to vaccine storages were within the 95% confidence interval, indicating that the conformation of the protein in the emulsion stored for up to 18 months at 4 degrees C was unchanged. Furthermore, no protein degradation was detected by Coomassie blue, silver staining, and Western blot analysis for samples stored at 4 degrees C for up to 2 years. Although some protein aggregation was observed in the emulsion preparations, these aggregates were only a small percentage of the total protein in the sample (7.6%). Moreover, the protein multimers maintained their conformational epitope. The potency assay of the formulation showed no significant differences in ED(50) values (50% effective dose for achieving seroconversion) between fresh vaccine formulations (ED(50)=0.057+/-0.024 microg) and formulations stored for up to 6 (ED(50)=0.046 microg) or 12 months (ED(50)=0.040 microg). Importantly, the immune sera of rabbits immunized with formulations stored for 0, 3, 6, 9 and 12 months effectively inhibited parasite growth in vitro at similar levels. These data indicated that the vaccine emulsion was stable over long periods of storage and maintained both its physical and biological properties. PMID- 20197140 TI - Surveillance for adverse events after DTwP/Hib vaccination in Brazil: sensitivity and factors associated with reporting. AB - We estimated the sensitivity, i.e., the proportion of all cases of adverse events following immunization (AEFIs) reported to the Brazilian passive surveillance for adverse events following immunization (PSAEFI) with the diphtheria-tetanus-whole cell pertussis-Haemophilus influenzae type b (DTwP/Hib) vaccine, as well as investigating factors associated with AEFIs reporting. During 2003-2004, 8303 AEFIs associated with DTwP-Hib were reported; hypotonic-hyporesponsive episodes (HHEs), fever and convulsions being the most common. Cure without sequel was achieved in 98.4% of the cases. The mean sensitivity of the PSAEFI was 22.3% and 31.6%, respectively, for HHE and convulsions, varying widely among states. Reporting rates correlated positively with the Human Development Index and coverage of adequate prenatal care, correlating negatively with infant mortality rates. Quality of life indicators and the degree of organization of health services are associated with greater PSAEFI sensitivity. In addition to consistently describing the principal AEFIs, PSAEFI showed the DTwP/Hib vaccine to be safe and allayed public fears related to its use. PMID- 20197141 TI - The Health Technology Assessment of bivalent HPV vaccine Cervarix in Italy. AB - INTRODUCTION: Health Technology Assessment (HTA) approach was applied to Human Papilloma Virus (HPV) vaccine in the Italian context. METHODS: Epidemiology and costs of HPV infection and related diseases, vaccine efficacy, clinical and economic impact of the HPV vaccination and women's knowledge and attitudes towards vaccination were assessed. RESULTS: HPV infections pooled prevalence in Italy was 19% (95%CI: 10-30%) and cervical cancer incidence was 9.8/100,000 per year. The mean costs for in situ and invasive carcinoma hospitalisation were estimated respectively in euro1745.87 and euro2616.16. HPV vaccines have demonstrated high efficacy and good safety profile. The meta-analysis on efficacy results in preventing persistent cervical infections by HPV16 and 18 for both HPV vaccines resulted in 87% (95%CI: 80-91%) and 78% (95%CI: 62-87%). Modelling the impact of vaccination with bivalent vaccine, it would reduce cancer cases by 67% and be cost-effective, with a cost per Quality Adjusted Life Years (QALYs) gained of euro22,055. CONCLUSION: The thoroughness of the evaluation allowed us accounting for all the aspects of HPV infection/diseases. The HTA report on the HPV vaccine demonstrated to be a comprehensive tool for an informed decision making process. PMID- 20197142 TI - Modelling the seasonality of rotavirus disease and the impact of vaccination in England and Wales. AB - Two rotavirus vaccines are currently recommended for inclusion in routine childhood immunization programmes. We developed a deterministic age-structured model of rotavirus transmission and disease to investigate the population-level effects of vaccination in England and Wales. The model explicitly captures the natural history of infection and uses realistic population mixing patterns. The model accurately reproduces the strong seasonal pattern and age distribution of rotavirus disease observed in England and Wales. We predict vaccination will provide both direct and indirect protection within the population. If coverage levels comparable to other childhood vaccines are achieved, we predict that vaccination will reduce rotavirus disease incidence by 61% resulting in a potential fall in burden on health-care services. PMID- 20197143 TI - Innate and acquired immune responses induced by recombinant Lactobacillus casei displaying flagellin-fusion antigen on the cell-surface. AB - Bacterial flagellins are known as antigens that induce innate immune responses through TLR5 and boost immune responses in combination with other antigens. The aim of the present study was to determine the immunological properties of recombinant Lactobacillus casei producing flagellin and flagellin-fusion antigens in vitro and in vivo. Recombinant lactobacilli expressing Salmonella FliC and FliC fused to truncated SipC on the cell-surface were constructed. Fusion and non fusion flagellin associated with L. casei retained the ability to induce IL-8 production by Caco-2 cells. Immunization of mice with these recombinant strains induced antigen-specific antibodies and cytokine production. The results showed that the outside epitope of the heterologous antigen was recognized more easily by the immune system than the inside epitope. The immune responses elicited by the Lactobacillus-associated antigens were mainly Th1 while that by the soluble antigen was Th2, although some of the responses were mixed. PMID- 20197144 TI - Impact of a single dose of the 7-valent pneumococcal conjugate vaccine on colonization. AB - The impact of the 7-valent pneumococcal conjugate vaccine (PCV7) on the pneumococcal flora has been mostly studied without evaluating multiple colonization and the mechanism(s) leading to serotype replacement. These issues are addressed here, while assessing the effect of a single PCV7 dose. A group of children received one PCV7 dose just after nasopharyngeal sampling, with the control receiving no vaccine and both groups being sampled again a month later. Up to 10 pneumococcal isolates were recovered per colonized child-1224 isolates were serotyped and representative ones characterized by pulsed-field gel electrophoresis. In vaccinated children, serotype replacement between vaccine (VT) and non-vaccine (NVT) types occurred in single and multiple carriers, and VTs were less prone to be de novo acquired. NVT unmasking was only detected in the vaccinated group. One month after vaccination with a single dose, PCV7 prevents VT de novo acquisition and promotes NVT unmasking. PMID- 20197145 TI - Evaluating the Brighton Collaboration case definitions, aseptic meningitis, encephalitis, myelitis, and acute disseminated encephalomyelitis, by systematic analysis of 255 clinical cases. AB - AIMS: Brighton Collaboration (BC) case definitions are independent from presumed causes or triggers, hence should be applicable in routine clinical settings. SCOPE: 255 cases with discharge diagnoses of aseptic meningitis (ASM; n=164), encephalitis (ENC; n=48), myelitis (MYE; n=8), ADEM (n=10), or bacterial meningitis (BM; n=59; control group) were tested against the BC case definitions ASM, ENC, MYE, and ADEM. Overall rates of agreement between BC criteria and discharge diagnoses were 70%, 78%, 97%, and 97% for ASM, ENC, MYE and ADEM, respectively. CONCLUSION: BC case definitions are easily applicable in retrospective chart reviews allowing causality assessments with minimal selection bias. PMID- 20197147 TI - Using oral polio vaccine beyond the cold chain: a feasibility study conducted during the national immunization campaign in Mali. AB - We conducted the first systematic documentation of using oral polio vaccine (OPV) out of the cold chain during national immunization day (NID) campaigns in Mali. Using a crossover intervention design, vaccinators compared the transport of OPV in vaccine carriers with or without ice packs. Vaccine integrity was assured through monitoring vaccine vial monitor (VVM) status. Despite ambient temperatures up to 40 degrees C, none of the VVMs on any of the vials used (n=956) reached their discard point. Over 90% of vaccinators and supervisors preferred conducting NIDs without ice packs. In addition, using OPV out of the cold chain reduced vaccine wastage resulting from melting ice packs causing labels to detach from the vial. PMID- 20197146 TI - Anti-tumor immune response correlates with neurological symptoms in a dog with spontaneous astrocytoma treated by gene and vaccine therapy. AB - Gene therapy and vaccination have been tested in malignant glioma patients with modest, albeit encouraging results. The combination of these therapies has demonstrated synergistic efficacy in murine models but has not been reported in large animals. Gemistocytic astrocytoma (GemA) is a low-grade glioma that typically progresses to lethal malignancy despite conventional therapies. Until now there has been no useful animal model of GemA. Here we report the treatment of a dog with spontaneous GemA using the combination of surgery, intracavitary adenoviral interferon gamma (IFNgamma) gene transfer, and vaccination with glioma cell lysates mixed with CpG oligodeoxynucleotides. Surgical tumor debulking and delivery of Ad-IFNgamma into the resection cavity were performed. Autologous tumor cells grew slowly in culture, necessitating vaccination with allogeneic tumor lysate in four of the five vaccinations. Transient left-sided blindness and hemiparesis occurred following the fourth and fifth vaccinations. These neurological symptoms correlated with a peak in the levels of tumor-reactive IgG and CD8(+) T cells measured in the blood. All symptoms resolved and this dog remains tumor-free over 450 days following surgery. This case report preliminarily demonstrates the feasibility of treating dogs with spontaneous glioma using immune-based therapy and warrants further study using this therapeutic approach. PMID- 20197148 TI - Yeast is the best characterized eukaryotic cell and will likely remain so for the foreseeable future. Preface. PMID- 20197153 TI - Infantile swallowing. PMID- 20197155 TI - Three-dimensional orthodontic force measurements. PMID- 20197150 TI - Cardiovascular magnetic resonance imaging of myocardial infarction, viability, and cardiomyopathies. AB - Cardiovascular magnetic resonance provides the opportunity for a truly comprehensive evaluation of patients with a history of myocardial infarction, with regard to characterizing the extent of disease, effect on left ventricular function, and degree of viable myocardium. The use of contrast-enhanced cardiac magnetic resonance (CMR) imaging for first-pass perfusion and late gadolinium enhancement is a powerful technique for delineating areas of myocardial ischemia and infarction. Using a combination of T2-weighted and contrast-enhanced CMR images, information about the acuity of an infarct can be obtained. There is extensive published data using contrast-enhanced CMR to predict myocardial functional recovery with revascularization in patients with ischemic cardiomyopathies. In addition, CMR imaging in patients with cardiomyopathies can distinguish between ischemic and nonischemic etiologies, with the ability to further characterize the underlying pathology of nonischemic cardiomyopathies. PMID- 20197157 TI - "Anything goes" letter. PMID- 20197159 TI - Orthodontic treatment of anterior open-bite malocclusion: stability 10 years postretention. AB - INTRODUCTION: The postretention stability of open-bite treatment is a controversial topic in orthodontics. METHODS: In this study, the lateral cephalometric radiographs of 64 patients treated with orthodontics alone were evaluated to determine the amount of postretention change. The mean postretention interval was 14 years. The sample was divided into 3 groups based on the amounts of pretreatment overbite: (1) the contact group (n = 24), incisal overlap and incisal contact; (2) the overlap group (n = 25), incisal overlap and no incisal contact; and (3) the open-bite group (n = 15), no incisal overlap. The headfilms were digitized, and the values were analyzed. RESULTS: The 3 groups reacted differently. During the postretention period, mean overbite deepened in all groups, with the contact group deepening significantly more than the open-bite group. Overjet increased significantly more in the open-bite group than in the contact group. Pretreatment overjet correlated mildly with postretention overjet relapse in the open-bite group. CONCLUSIONS: All 64 subjects had positive incisal overlap at the postretention recall. PMID- 20197161 TI - Transverse, vertical, and anteroposterior changes from bone-anchored maxillary expansion vs traditional rapid maxillary expansion: a randomized clinical trial. AB - INTRODUCTION: The purpose of this study was to compare the transverse, vertical, and anteroposterior skeletal and dental changes in adolescents receiving expansion treatment with tooth-borne and bone-anchored expanders. Immediate and long-term changes were measured on cone-beam computed tomography (CBCT) images. METHODS: Sixty-two patients needing maxillary expansion were randomly allocated to 1 of 3 groups: traditional hyrax tooth-borne expander, bone-anchored expander, and control. CBCT images were taken at baseline, immediately after expansion, after removal of the appliance (6 months), and just before fixed bonding (12 months). Repeated measures multivariate analysis of variance (MANOVA) was applied to the distances and angles measured to determine the statistical significance in the immediate and long time periods. Bonferroni post-hoc tests were used to identify significant differences between the treatment groups. RESULTS: Immediately after expansion, the subjects in the tooth-borne expander group had significantly more expansion at the crown level of the maxillary first premolars (P = 0.003). Dental crown expansion was greater than apical expansion and skeletal expansion with both appliances. The control group showed little change (growth) over the 6-month interval. At 12 months, no group had a statistically significant difference in angle changes, suggesting symmetric expansion. Both treatment groups had significant long-term expansion at the level of the maxillary first molar crown and root apex, first premolar crown and root, alveolus in the first molar and premolar regions, and central incisor root. Tooth borne expansion resulted in significantly more long-term expansion at the maxillary premolar crown and root than did bone-borne expansion. CONCLUSIONS: Both expanders showed similar results. The greatest changes were seen in the transverse dimension; changes in the vertical and anteroposterior dimensions were negligible. Dental expansion was also greater than skeletal expansion. PMID- 20197165 TI - Evaluation of distances between the mandibular teeth and the alveolar process in Brazilians with normal occlusion. AB - INTRODUCTION: The aims of this study were to evaluate the distances between the mandibular permanent teeth and the alveolar process in Brazilians with normal occlusion and to compare them with normal American values. METHODS: We used 59 mandibular casts from untreated subjects who had permanent dentition and the 6 keys to normal occlusion. A computer program was used to calculate the distances between the dental reference points and the alveolar process for each tooth. The mean values were then compared to the normal values by applying the Student t test at a significance level of 0.05. RESULTS: The results showed a progressive increase of these distances from the anterior region (incisors) to the posterior region (molars), from 0.00 to 2.49 mm. All measurements had statistically significant differences from the American sample, except for the values for canines and first premolars. CONCLUSIONS: Brazilians with normal occlusion have more lingual crown positions for the incisors, second premolars, and molars compared with Americans with normal occlusion. Although these findings were statistically significant, they are unlikely to be clinically significant. PMID- 20197163 TI - Three-dimensional analysis of pharyngeal airway in preadolescent children with different anteroposterior skeletal patterns. AB - INTRODUCTION: In growing patients with skeletal discrepancies, early diagnosis, evidence-based explanations of etiology, and assessment of functional factors can be vital for the restoration of normal craniofacial growth and the stability of the treatment results. The aims of our study were to compare the 3-dimensional pharyngeal airway volumes in healthy children with a retrognathic mandible and those with normal craniofacial growth, and to investigate possible significant relationships and correlations among the studied cephalometric variables and the airway morphology in these children. METHODS: Three-dimensional airway volume and cross-sectional areas of 27 healthy children (12 boys, 15 girls; mean age, 11 years) were measured by using cone-beam computed tomography volume scans, and 2 dimensional lateral cephalograms were created and analyzed. The subjects were divided into 2 groups based on their ANB angles (group I: 2 degrees < or = ANB < or = 5 degrees ; group II: ANB >5 degrees ), and cephalometric variables, airway volumes, and cross-sectional measurements were compared. RESULTS: There were statistically significant differences in the following parameters: height of the posterior nasal plane (P <0.05), pogonion to nasion perpendicular distance (P <0.01), ANB angle (P <0.01), mandibular body length (P <0.01), facial convexity (P <0.01), and total airway volume (P <0.05). No statistically significant differences between the 2 groups were found in the cross-sectional area and the volumetric measurements of the various sections of the airway except for total airway volume, which had larger values in group I (P <0.05). CONCLUSIONS: The mean total airway volume, extending from the anterior nasal cavity and the nasopharynx to the epiglottis, in retrognathic patients was significantly smaller than that of patients with a normal anteroposterior skeletal relationship. On the other hand, differences in volume measurements of the 4 subregions of the airway were not statistically significant between the 2 groups. PMID- 20197166 TI - Rapid palatal expansion for spontaneous Class II correction. AB - INTRODUCTION: Palatal expanders have been advocated for spontaneous correction of some Class II malocclusions. However, little research has been done to determine whether correction or improvement actually occurs with expansion. Past research has not shown whether an anterior functional shift is achieved in patients who have Class II improvement. The objective of this study was to determine whether maxillary expansion causes spontaneous correction or improvement of a Class II malocclusion. METHODS: This was a retrospective study of subjects from an orthodontic office in which models are mounted (articulator) in centric occlusion and maximum intercuspation before and after treatment. The sample included Class II patients (n = 13; mean age, 10 years 3 months) who, during the preceding 2 years, had been treated with expansion alone. Study models made before and after expansion were measured to compare the centric occlusion to the maximum intersuspation position. Condyle position indicator paper was also used to determine whether there was a functional shift after expansion. RESULTS: The only measurements with statistically significant changes from pretreatment to postexpansion were the maxillary intermolar widths. Seven of the 13 patients showed Class II improvement, but none had an anterior functional shift after expansion. CONCLUSIONS: Maxillary expansion does not predictably improve Class II dental relationships. PMID- 20197167 TI - Treatment of pain after initial archwire placement: a noninferiority randomized clinical trial comparing over-the-counter analgesics and bite-wafer use. AB - INTRODUCTION: Pain is a major concern of patients before orthodontic treatment. Currently, the most frequently recommended treatments for pain after archwire placement or appliance adjustment are over-the-counter (OTC) analgesics. Although the overuse of OTC medications and their potential side effects are concerns, particularly for children, no study to date has investigated a nonpharmacologic option for pain management as an alternative for these analgesics. METHODS: A parallel 2-group stratified block randomized clinical trial was designed to assess the pain response of adolescents during the first week after initial archwire placement. The subjects were randomly assigned to 1 of 2 pain management groups: bite wafer (BW) or OTC analgesics. Pain levels were reported on a numerical rating scale. The intensity and unpleasantness of the pain were also assessed. Data were collected at 8 times over a 7-day period. A general linear mixed model with heterogeneous compound symmetry covariance matrix was fitted separately for each outcome. Estimates from the mixed model were used to test a noninferiority hypothesis that the BW group, on average, was not inferior with respect to pain management to the OTC group. RESULTS: The patterns of pain level, intensity, and unpleasantness over time were similar for the 2 groups (P >0.33). Pain management for the BW group as indicated by pain level, intensity, and unpleasantness was not inferior to that of the OTC group (P >0.39). CONCLUSIONS: In adolescents, the BW is a nonpharmacologic option for pain management after orthodontic procedures that is at least as effective as OTC analgesics. PMID- 20197168 TI - Dental effects of interceptive orthodontic treatment in a Medicaid population: interim results from a randomized clinical trial. AB - INTRODUCTION: There are disparities in access to orthodontic treatment for children from low-income families. Systematic programs of limited-care interceptive and preventive orthodontics have been proposed as a solution. The purpose of this randomized clinical trial was to compare dental outcomes and funding eligibility from a group of Medicaid patients randomized to receive interceptive orthodontics (IO) in the mixed dentition or observation (OBS). METHODS: One hundred seventy Medicaid-eligible children were randomized to receive IO or OBS and followed for 2 years, when complete data were available on 72 and 74 children, respectively. The 2-year changes in the peer assessment rating (PAR) were compared using the Student t test. The proportions of children no longer eligible for Medicaid funding as defined by handicapping labiolingual deviation (HLD) scores less than 25 at the 2-year follow-up were compared with the chi-square test. RESULTS: The IO patients had significantly greater decreases in the PAR scores--50%-compared with the OBS subjects, -6% (P <0.001). Negative and positive overjet and maxillary alignment were the components most affected by IO; they decreased by 11.0, 7.2, and 3.7 PAR points, respectively (P <0.001). Overbite showed little change. At the 2-year follow-up, 80% of the IO patients' malocclusions that qualified initially were no longer deemed medically necessary by the HLD index, compared with 6% in the OBS group (P <0.001). CONCLUSIONS: IO significantly reduces the severity of malocclusions and moves most from the "medically necessary" category to elective but does not produce finished results for most patients. Overjet and alignment were most readily corrected by interceptive treatment. Deep overbites were the least susceptible to IO correction. PMID- 20197169 TI - Break-even analysis of Medicaid vs fee for service in orthodontic practice: North Carolina as a case study. AB - INTRODUCTION: Access to orthodontic services for children enrolled in Medicaid is limited nationwide. Orthodontists cite low fee reimbursement as a significant barrier to Medicaid participation. The purpose of this study was to examine, under a specific set of practice assumptions, the simulated effect on profitability of treating patients covered by Medicaid in orthodontic practices in North Carolina by using a break-even analysis for the 2005 fiscal year. METHODS: Questionnaires were mailed to 154 orthodontists in active practice in North Carolina. The response rate was 58%. Seventy respondents met the eligibility criteria. Respondents were categorized into 4 groups based on the number of 2005 Medicaid case starts (I, 0; II, 1-5; III, 6-12; IV, 13 or more). By using the aggregated responses for treatment fees, treatment times, and overhead percentages for each group, average per-patient costs were calculated for each group and used in a break-even analysis. RESULTS: Group I accounted for 60% of respondents; group II, 20%; group III, 9%; and group IV, 11%. Assuming that the break-even point had not been reached, the group I practice would have an average estimated loss of $164 per patient whereas groups II, III, and IV would realize average profits from $98 to $256. The break-even point increased slightly in groups I, II, and III after the total number of patients in the patient pool was increased by 5%, assuming that additional patients were enrolled in Medicaid: group I, 203 to 210; group II, 220 to 226; group III, 158 to 160. The break-even point for group IV was 234 patients. Assuming that the break-even point had been reached, all groups were estimated to realize average per-patient profits of $1483 to $1897. CONCLUSIONS: Break-even analysis is a basic economic concept applicable to orthodontic practices. Under the specific conditions of this study, the inclusion of 5% of patients enrolled in Medicaid in the active patient pool had minimal effect on the financial break-even point and, assuming that the break-even point had been reached, was unlikely to have a negative financial impact on the practice. PMID- 20197170 TI - Relationship between orthodontic expertise and perception of treatment needs for maxillary protrusion: comparison of dental students, residents, and orthodontists. AB - INTRODUCTION: The aims of this study were to assess the peer assessment rating (PAR) index in relation to perceived treatment needs for maxillary protrusion in Japanese subjects and to investigate how perceived orthodontic treatment needs change with increased experience in dentistry and orthodontics. METHODS: The subjects were 155 persons (73 men, 82 women; mean age, 24.2 years; SD, 4.7 years) including dental students, residents, and orthodontists. We showed them casts from 10 patients with untreated maxillary protrusion and gave them a questionnaire with a 100-point visual analog scale (VAS), concerning their perceptions of orthodontic treatment needs. The PAR index was used for cast evaluation. RESULTS: The PAR index showed significant correlations with the VAS scores. On the casts evaluated with a PAR index below 17, there was no difference in VAS scores between the 3 groups; however, orthodontists perceived significantly greater treatment needs than did students and residents on casts with a PAR index of 18 or 19. The VAS scores were significantly increased when casts with a PAR index of more than 20 and overjet above 5.0 mm were evaluated. Orthodontists and residents perceived greater treatment needs than students on assessing occlusions with severe maxillary protrusion. CONCLUSIONS: The PAR index is clinically useful to evaluate malocclusion, and the perception of treatment needs was significantly greater when the maxillary protrusion cast had a PAR index of more than 20 and overjet above 5.0 mm. Perceived needs for orthodontic treatment for maxillary protrusion changed with increasing experience and skills in dentistry and orthodontics. PMID- 20197171 TI - Predictive model of third molar eruption after second molar extraction. AB - INTRODUCTION: Extraction of second permanent molars is an option for providing space in orthodontic treatment. Although many articles have described its impact on the outcome, there are few data on the prognosis of the eruption of the adjacent third molars. The aims of this investigation were to provide predictive models of eruption of third molars after second permanent molar extraction and to validate them. METHODS: A total of 48 patients (ages, 11-23 years) who had 128 second permanent molars (54 maxillary, 74 mandibular) extracted during orthodontic treatment were followed until eruption of the third molars was complete. RESULTS AND CONCLUSIONS: A lineal regression model predicted the final angle of the third molars with the permanent first molar by using the variables of initial angle, jaw, and the developmental stage of the third molar. A logistic regression model predicted the probability of correct eruption by using the variables of initial angle, jaw, sex, age, and the developmental stage of the third molar. PMID- 20197172 TI - Does the center of resistance depend on the direction of tooth movement? AB - INTRODUCTION: The objective of this study was to compare the locations of the centers of resistance (CRes) in the buccolingual (BL) and mesiodistal (MD) directions of the mandibular central incisors of 6 dogs. METHODS: Based on microcomputed tomography images of the teeth and their supporting tissues, solid models were used to build finite element models. RESULTS: The CRes locations for the 6 specimens were determined for displacements in the BL and MD directions with finite element calculations. Measured from the alveolar crest, the BL and MD locations were 43% to 51% and 31% to 43% of root length, respectively. Their average locations, 46.2% and 38.3%, were statistically different at the 95% CI. CONCLUSIONS: The CRes location for BL tooth movement is significantly more apical than its MD counterpart. PMID- 20197173 TI - Evaluation of alternative polymer bracket materials. AB - INTRODUCTION: Polymer brackets still have some disadvantages because of decreased wear resistance and hardness. The aim of this study was to investigate the mechanical properties of alternative bracket polymers; urethane-dimethacrylate, high-density polyethylene, and an experimental bracket polymer (EBP) consisting of polyethylene and a copolymer were tested. Polycarbonate and polyoxymethylene brackets served as controls. METHODS: The mechanical properties of urethane dimethacrylate, high-density polyethylene, EBP, polycarbonate, and polyoxymethylene bracket materials were evaluated after thermocycling (6000 x 5 degrees C-55 degrees C) in a mastication device before testing. Three medium wear, fracture toughness, and Vickers hardness tests were performed. RESULTS: High-density polyethylene had the highest values of wear and the lowest values of fracture toughness and Vickers hardness. The urethane-dimethacrylate bracket material and the EBP had better mechanical properties than polycarbonate. The polyoxymethylene bracket material had the highest values of fracture toughness and Vickers hardness, and the lowest values of wear compared with the other investigated polymers. CONCLUSIONS: High-density polyethylene seems to be unsuitable as bracket material because it demonstrated excessive wear and insufficient fracture toughness. Polyoxymethylene had the best performance during mechanical testing. PMID- 20197174 TI - Surface roughness of the restored enamel after orthodontic treatment. AB - INTRODUCTION: After fixed appliance treatment, one concern is to restore the enamel surface as closely to its original state as possible. A variety of cleanup processes are available, but all are time-consuming and carry some risk of enamel damage. The purpose of this study was to examine tooth surfaces restored with different cleanup protocols. METHODS: Ninety-nine premolars extracted for orthodontic purposes were used. The 2 materials tested were Sof-Lex disks (3 M ESPE AG, Seefeld, Germany) and fiberglass burs (Stain Buster, Carbotech, Ganges, France). These were used alone and in combination with high- and low-speed handpieces, with which they were also compared. Eight groups were ultimately tested. All groups were compared with intact enamel, which served as the control group. From each group, 10 samples were examined with profilometry and 1 with scanning electron microscopy. Adhesive remnant index scores were recorded to ensure equal distributions for the groups. The time required for the cleanup processes and profilometry test results were also recorded. RESULTS: The fastest procedure was performed with high-speed handpieces, followed by low-speed handpieces. Sof-Lex disks and fiberglass burs required more time than carbide burs but did not result in significantly longer times for the cleanup procedure when combined with tungsten carbide-driven low- or high-speed handpieces or when used alone with low-speed handpieces. Although Sof-Lex disks were the most successful for restoring the enamel, it was not necessary to restore the enamel to its original surface condition. Generally, all enamel surface-roughness parameters were increased when compared with the values of intact enamel. The average roughness and maximum roughness depth measurements with Sof-Lex disks were statistically similar to measurements of intact enamel. CONCLUSIONS: No cleanup procedure used in this study restored the enamel to its original roughness. The most successful was Sof-Lex disks, which restored the enamel closer to its original roughness. PMID- 20197175 TI - Effects on shear bond strength and the enamel surface with an enamel bonding agent. AB - INTRODUCTION: The purpose of this study was to evaluate the shear bond strength of orthodontic brackets and the effect of an enamel bonding agent (EBA) on enamel surface after debonding. METHODS: Seventy-five extracted maxillary premolars were collected and randomly divided into 3 groups of 25. The enamel cracks were surveyed with a stereomicroscope. In the first group, 1 layer of EBA was applied before the adhesive resin. In the second group, 2 layers of EBA were used; in the third group, no EBA was used. Bonding was followed by incubation for 48 hours at 37 degrees C and thermocycling for 1000 cycles. Debonding was performed with a shear force. The surfaces of the teeth were evaluated, and the length, depth, direction of cracks, and adhesive remnants on the enamel surface were recorded. Data were analyzed by using analysis of variance and paired samples t tests. RESULTS: There were no significant differences between the shear bond strengths (P = 0.341) of the 3 groups, or in the direction, length, and depth of the cracks before and after debonding (P > 0.05). There was a significant increase in the number of cracks after debonding in the 3 groups (P < 0.05). The evaluation of adhesive remaining on the surface of the teeth indicated that most bond failures occurred at the resin-bracket interface. CONCLUSIONS: The use of EBA does not enhance bond strength or provide greater protection to the enamel surface during debonding. PMID- 20197176 TI - In-vitro assessment of temperature rise in the pulp during orthodontic bonding. AB - INTRODUCTION: In this in-vitro study, we evaluated the temperature changes in the pulp chamber during bracket bonding using 4 different light sources. METHODS: Eighty intact extracted maxillary central incisors were used. The teeth were divided into 4 groups of 20 teeth each. Brackets (Mini Twin, Dentaurum, Ispringen, Germany) were bonded with Transbond XT (3M Unitek, Monrovia, Calif) adhesive and light cured with low-intensity halogen light for 40 seconds, high intensity halogen light for 40 seconds, light-emitting diode (LED) light for 20 seconds, and plasma arc light (PAC) for 6 seconds. Light curing was performed 5 mm from tooth surfaces. A J-type thermocouple wire was positioned in the center of the pulp chamber. The results were analyzed with analysis of variance (ANOVA) and the Tukey HSD test. RESULTS: ANOVA and the Tukey HSD test showed that pulp chamber temperature changes were influenced by the type of light source. All groups showed significant differences between each other (P <0.001). The intrapulpal temperature changes induced by different light sources were the following: high-intensity halogen (6.84 degrees C +/- 2.44 degrees C), low intensity halogen (4.71 degrees C +/- 0.96 degrees C), LED (2.95 degrees C +/- 1.12 degrees C), and PAC (0.96 degrees C +/- 0.83 degrees C). CONCLUSIONS: High- and low-intensity halogen light induced significantly higher intrapulpal temperature changes than did the LED and PAC. Except for the high intensity halogen light, orthodontic bonding with light-curing units did not exceed the critical 5.5 degrees C rise in temperature reported to produce pulpal damage. PMID- 20197177 TI - Severe root resorption in orthodontic patients treated with the edgewise method: prevalence and predictive factors. AB - INTRODUCTION: Our aims in this study were to assess the prevalence of severe root resorption and identify possible associations in orthodontic patients treated with the edgewise method. METHODS: The sample included 1049 patients who had periapical radiographs taken for all incisors before and after treatment. The radiographs were examined by 2 orthodontists using an x-ray viewer with standard light intensity. These variables were collected: root shape, overbite, initial resorption, and hypodontia. The patients were classified according to sex, Angle classification, ethnicity, age, duration of treatment, type of dentition (mixed or permanent), and treatment with or without extraction of 4 premolars. Resorption was considered severe when it affected more than a third of the length of the root. Statistical analysis included the chi-square test and both simple and multiple logistic regression (P < or =0.05). RESULTS: Severe root resorption was observed in 14.5% of the sample. Patients treated with exodontia of the first premolars (odds ratio [95% CI] = 6.38 [4.2-9.7]), those who had triangle-shaped roots at the beginning of treatment (odds ratio [95% CI] = 4.67 [3.1-6.9]), and those with initial root resorption (odds ratio [95% CI] = 4.52 [2.7-7.6]) had a greater chance of developing severe root resorption during orthodontic treatment. CONCLUSIONS: A high prevalence of severe root resorption was observed in Brazilian patients treated with the edgewise method. The main factors directly involved in severe resorption were extraction of first premolars, triangle-shaped roots, and root resorption before treatment. PMID- 20197178 TI - Root-contact evaluation by panoramic radiography and cone-beam computed tomography of super-high resolution. AB - INTRODUCTION: Correct tooth position in the 3 planes of space is a major objective of orthodontic treatment. The aim of this study was to determine whether a panoramic radiograph (OPT) provides a true assessment of the mesiodistal root relationship of adjacent teeth. METHODS: OPTs of 22 patients near the end of treatment with fixed appliances in both arches were taken before debonding. When the roots of adjacent teeth were touching on the OPT, cone-beam computed tomography (CBCT) was used to show the true root relationships. RESULTS: We evaluated 235 interdental sites by OPT and CBCT; 47 areas showed contact between adjacent roots in the OPT images. However, the CBCT images showed true contact in only 5 of these areas; ie, 11% of the diagnoses based on OPT images were true positive, whereas the rest (89%) was false positive. One hundred eighty eight sites showed no contact in the OPT images; this was confirmed by CBCT. CONCLUSIONS: OPT has high sensitivity and relatively high specificity to detect adjacent roots touching each other. Root contacts are overestimated when evaluated by OPT. PMID- 20197179 TI - Continuous torque system with control of the reaction unit. AB - This article describes an orthodontic system used to obtain active continuous torque with movement control of both active and reactive units; the system relies on principles of the segmented technique. A cantilever system with .017 x .025-in beta-titanium alloy wire was designed to provide the desirable moment on the active unit. A transpalatal bar or a lingual arch increases the anchorage and neutralizes the side effects on the reactive unit. This technique is an efficient approach for major corrections of buccolingual inclinations of certain teeth. PMID- 20197180 TI - Conservative treatment of unicystic ameloblastoma. AB - INTRODUCTION: Ameloblastomas are benign asymptomatic intraosseous lesions that affect the bones of the maxillomandibular complex, interfering both in function and facial esthetic appearance. A 14-year-4-month-old girl was referred by her clinician complaining her anterior teeth were crooked and inclined forward. The lower left mandibular tooth presented with increased pericoronal space compatible with dentigerous cyst. METHODS AND RESULTS: The aim of this report is to relate a case of unicystic ameloblastoma with conservative treatment and with indication for orthodontic treatment. The conservative therapy was performed and the lesion had been completely removed. The need for radiographic and clinical follow-up for up to 10 years, initially performed every 6 months during the first 2 years and afterwards annually, in addition to the risk of late recurrence were explained for patient and her guardian. CONCLUSION: The histopathologic exam of the surgical tissue provided the final diagnosis of ameloblastoma, as the lesion had not presented in its classical form and in atypical locations, as in this case involving a tooth that had not yet erupted. PMID- 20197181 TI - Treatment of a severe arch-length deficiency with anteroposterior and transverse expansion: long-term stability. AB - This article describes the nonextraction treatment of a girl in the late mixed dentition with a severe arch-length deficiency. Rapid maxillary expansion and molar distalization were combined with a lip bumper in the mandible, followed by fixed appliances. Although the literature has reported a high rate of relapse with this method of treatment, excellent stability was achieved at 5 years 3 months posttreatment. The merits of extraction vs nonextraction treatment and stability are discussed. PMID- 20197182 TI - Combined maxillary and mandibular midline and mandibular ramus distraction osteogenesis for treatment of a Class II patient with implants as orthodontic anchorage. AB - This case report describes the treatment of a woman with severe mandibular retrusion and maxillomandibular transverse deficiency. Her malocclusion was characterized by a large overjet, a deep overbite, and a V-shaped dental arch, and she had a skeletal Class II profile. Treatement included combined maxillary and mandibular midline expansion, maxillary downward repositioning, and mandibular ramus lengthening with distraction osteogenesis with implants as orthodontic anchorage. During the postdistraction orthodontic treatment period, some skeletal relapse occurred. Implants provided absolute orthodontic anchorage to overcome the unexpected skeletal changes. Combined orthodontic treatment with implants for anchorage and distraction osteogenesis successfully expanded the maxilla and the mandible and corrected the mandibular deficiency. Two-year follow up records show a morphologically and functionally stable result. PMID- 20197183 TI - Three-dimensional comparison of facial morphology in white populations in Budapest, Hungary, and Houston, Texas. AB - INTRODUCTION: The aim of this study was to assess the use of 3-dimensional facial averages in determining facial morphologic differences in 2 white population groups. METHODS: Three-dimensional images were obtained in a reproducible and controlled environment from a commercially available stereo-photogrammetric camera capture system. The 3dMDface system (3dMD, Atlanta, Ga) photographed 200 subjects from 2 population groups (Budapest, Hungary, and Houston, Tex); each group included 50 men and 50 women, aged 18 to 30 years. Each face was obtained as a facial mesh and orientated along a triangulated axis. All faces were overlaid, one on top of the other, and a complex mathematical algorithm was used until an average composite face of 1 man and 1 woman was obtained for each subgroup (Hungarian men, Hungarian women, Texas men, and Texas women). These average facial composites were superimposed (men and women) based on a previously validated superimposition method, and the facial differences were quantified. RESULTS: Distinct facial differences were observed between the population groups. These differences could be seen in the nasal, malar, lips, and lower facial regions. In general, the mean facial differences were 0.55 +/- 0.60 mm between the Hungarian and Texas women, and 0.44 +/- 0.42 mm between the Hungarian and Texas men. The ranges of differences were -2.02 to 3.77 and -2.05 to 1.94 mm for the female and male pairings, respectively. CONCLUSIONS: Three-dimensional facial averages representing the facial soft-tissue morphology of adults can be used to assess diagnostic and treatment regimens for patients by population. Each population is different with respect to their soft-tissue structures, and traditional soft-tissue normative data (eg, white norms) should be altered and used for specific groups. PMID- 20197184 TI - Litigation, Legislation, and Ethics. Are patients covered under a state's consumer protection act from doctors' acts? PMID- 20197185 TI - Identification of salivary proteins at oil-water interfaces stabilized by lysozyme and beta-lactoglobulin. AB - In this research, we investigated the interaction occurring between oil-in-water emulsion droplets, stabilized by different emulsifiers, i.e. lysozyme and beta lactoglobulin (beta-lg), and salivary proteins (SPs) with a molecular mass (M(r)) above about 10kDa. Different techniques, i.e. infrared spectroscopy, Western blotting, PAS staining and SDS-PAGE coupled to MS, were employed for this purpose. This study demonstrated the interaction between several salivary proteins and the emulsifiers at the oil-water interfaces. In particular, results show that the high M(r) mucin MUC5B was strongly bound to lysozyme stabilized emulsions, whereas beta-lg stabilized emulsions associated with MUC7 and, moderately, with MUC5B. Furthermore, we observed that salivary proteins in the range M(r) 10-100kDa associated differently with emulsion droplets. A large majority of SPs was found to interact with lysozyme stabilized emulsion droplets whilst in case of beta-lg stabilized emulsions, the SPs distribute more evenly between the fraction associated and non-associated with the droplets. A clear example is alpha-amylase (M(r) approximately 55kDa) which predominantly associates with lysozyme stabilized emulsion droplets, but not with beta-lg emulsion droplets. To conclude, our findings indicate that adsorption/association of salivary protein components onto the emulsion droplets is related to the type of emulsifying proteins at the oil-water interfaces and it is probably driven by the overall net charge at the droplet's oil-water interfaces, i.e. positive for lysozyme stabilized emulsions and negative for beta-lactoglobulin stabilized emulsion at neutral pH. PMID- 20197186 TI - Influence of the digestive enzymes trypsin and pepsin in vitro on the progression of erosion in dentine. AB - OBJECTIVES: In patients with eating disorders, gastric and pancreatic enzymes could possibly reach the oral cavity during vomiting and could perhaps degrade the organic matrix of eroded dentine. This in vitro study sought to investigate whether pepsin, trypsin or the combination of both, have an influence on erosive mineral loss in dentine and whether they are able to degrade the organic matrix. METHODS: Sixty-four human dentine specimens were prepared and randomly divided into four groups. Specimens were cyclically de- and remineralised for six days. Demineralisation was performed with an HCl-solution (6x 5min daily, pH 1.6) in groups 1 and 3; in groups 2 and 4 the demineralisation solution additionally contained pepsin (750 microg/ml). After demineralisation, specimens of groups 3 and 4 were treated with a trypsin solution (6x 10min daily, 2000 BAEE/ml). After each day, mineral content (mum) was determined microradiographically, and the matrix degradation was determined by hydroxyproline analysis. RESULTS: After six days, treatment with pepsin (group 2) or trypsin (group 3) had no significant influence on mineral loss. The combined impact of pepsin and trypsin led to significantly higher mineral loss (group 4: 202.5+/-37.4) compared to all other groups (group 1: 139.1+/-29.5, p20,000ng/ml) had extremely low fibrinogen levels. Two-thirds of patients receiving HLH protocol died within 20 days of therapy. PMID- 20197200 TI - Polymorphisms of the gamma-glutamyl hydrolase gene and risk of relapse to acute lymphoblastic leukemia in Mexico. AB - This study evaluated the association of -401C/T and +452C/T polymorphisms of gamma-glutamyl hydrolase and the risk of relapse to acute lymphoblastic leukemia. Genotyping was performed in 70 children with acute lymphoblastic leukemia and 140 healthy children. An association between the -401C/T polymorphism and the risk of relapse was found (p=0.028), patients with the -401T/T genotype have 10.83 (95% CI 1.30-90.14) more chance of a relapse of leukemia. No association was found between the +452C/T polymorphism and the risk of relapse. Therefore, our investigation suggests that the -401C/T polymorphism in the gamma-glutamyl hydrolase may be a factor involved in the generation of relapse to disease in patients with ALL. PMID- 20197202 TI - Cloning and expression of canine CD25 for validation of an anti-human CD25 antibody to compare T regulatory lymphocytes in healthy dogs and dogs with osteosarcoma. AB - T regulatory cells (Tregs) are a unique subset of T helper cells that serve to modify/inhibit effector cells of the immune system and thus are essential to prevent autoimmunity. Overzealous Treg activity may contribute to impaired immune responses to cancer. Tregs can be phenotypically identified by proteins expressed on the cell surface (CD4 and CD25) and inside the cell (forkhead box3 (FoxP3)), although in dogs, no anti-canine CD25 antibody exists. We hypothesized that a mouse anti-human CD25 antibody definitively recognizes the canine protein and can be used to identify Tregs in dogs. We describe cloning and transfection of the canine CD25 gene into human HeLa cells with subsequent expression of the canine protein on the cell surface detected using an anti-human CD25 antibody in a flow cytometric assay. Validation of this antibody was used to identify CD4+CD25+FoxP3+ Tregs in 39 healthy dogs and 16 dogs with osteosarcoma (OSA). Results were expressed in five different ways and showed significantly fewer %CD4+CD25+ T lymphocytes expressing FoxP3 in blood of older dogs (>/=7 years) compared with the other two age groups (<2 and 2-6 years) (p<0.001) and fewer %CD4+CD25+FoxP3+ Tregs in the tumor draining lymph nodes of OSA patients compared to the unrelated lymph node (p=0.049). However, there was no significant difference in % Tregs in the peripheral blood or lymph nodes between the control dogs and those with OSA. While the CD25 antibody can be successfully used in a flow cytometric assay to identify Tregs, this study does not support clinical utility of phenotypic recognition of Tregs in dogs with OSA. PMID- 20197203 TI - Relative quantitative kinetics of interferon-gamma and interleukin-10 mRNA and protein production by activated ovine peripheral blood mononuclear cells. AB - Interferon-gamma (IFN-gamma) and interleukin (IL)-10 are cross-regulatory cytokines capable of driving and controlling the adaptive host immune response. The inter-relationship between IFN-gamma and IL-10 expression has not been defined in sheep despite biological evidence suggesting that they perform similar functions to their orthologues described in other species. To address this, we have developed a quantitative (q)PCR method to assess relative levels of IFN gamma and IL-10 mRNA expression in activated ovine peripheral blood mononuclear cells (PBMC) and compared the kinetics of mRNA expression with amounts of cytokine secreted by the cells over a 96h period. PBMC were collected from sheep immunised with the nominal antigen ovalbumin (Ova) and re-stimulated in vitro with antigen and the T cell mitogen concanavalin A (ConA). The recall response to antigen was characterised by a single peak in IFN-gamma mRNA expression at 48h of culture (13-fold increase over unstimulated cells) and relatively lower expression of IL-10 mRNA (average 2-3-fold increase over the 96h culture period). Antigen-driven IFN-gamma protein concentration was greatest at the end of the culture period (96h) whereas IL-10 protein level was not elevated above that observed in unstimulated cells. The typical response to ConA was greater for both cytokines, with IFN-gamma mRNA expression peaking at 6h of culture (133-fold increase) then declining rapidly whereas IL-10 mRNA expression peaked at 24h (16 fold increase) and declined more gradually. Despite these differences in the relative kinetics of mRNA expression in mitogen-activated PBMC, the typical pattern of protein expression of the two cytokines was similar. Both showed a gradual rise in protein concentration starting from 12h of culture which was still rising at the end of the culture period (96h). These data demonstrate that the kinetics of mRNA expression for IFN-gamma and IL-10 in activated ovine PBMC do not necessarily correlate with detectable protein in culture. PMID- 20197204 TI - PO43- dependence of the tolerance of autotrophic and heterotrophic biofilm communities to copper and diuron. AB - Pollution-induced community tolerance (PICT) concept is based on the assumption that the toxicant exerts selection pressure on the biological communities when exposure reaches a critical level for a sufficient period of time and therefore sensitive species are eliminated. However, induced tolerance of microbial biofilm communities cannot be attributed solely to the presence of toxicants in rivers but also to various environmental factors, such as amount of nutrients. An experimental study was undertaken to highlight the potential impact of a phosphorus gradient on the sensitivity of periphytic microbial community to Cu and diuron. Biofilms were exposed to real-world levels of chronic environmental contamination of toxicants with a phosphorus gradient. Biofilm sensitivity to Cu and diuron was assessed by performing short-term inhibition tests based on photosynthetic efficiency to target photoautotrophs, extracellular enzyme activity (beta-glucosidase and leucine-aminopeptidase) and substrate-induced respiration activity to target heterotrophs. The impact of P-gradient associated to pollution was evaluated by measuring pesticide concentrations in biofilms, biomass parameters (chla, AFDW), bacterial cell density, photosynthetic efficiency and community structure (using 18S and 16S rDNA gene analysis to target eukaryotes and DGGE and HPLC pigment analysis to target bacteria and photoautotrophs). The obtained results show that depending on the studied toxicant and the used structural or functional parameter, the effect of the phosphorus gradient was variable. This highlights the importance of using a range of parameters that target all the biological communities in the biofilm. The PICT method can be regarded as a good tool for assessing anthropogenic environmental contamination, but it is necessary to dissociate the real impact of toxicants from environmental factors. PMID- 20197205 TI - What happens after community-based screening for diabetes in rural and Indigenous individuals? AB - Rural individuals (mostly Indigenous) were screened for undiagnosed diabetes and cardiovascular risk. A subsequent survey showed roughly half engaged in timely follow-up with the health care system. The Mobile Diabetes Screening Initiative identifies a substantial number of people needing medical attention, who may otherwise be "missed" through conventional healthcare delivery. PMID- 20197206 TI - Long-term care in Israel: challenges and reform options. AB - OBJECTIVES: This paper has two objectives. The first is to examine the Israeli long-term care (LTC) system that is marked by rapidly increasing demands, and a multitude of public and private LTC arrangements. The second is to propose a reform to improve the system's efficiency and equity. METHODS: The paper studies the LTC services in Israel, and the private-public composition in funding, fund holding, and provision of LTC. It focuses on structural deficiencies in the organization of each of these functions separately, and in combination. RESULTS: In many countries LTC has evolved in a patchwork fashion that at some point in time needs rethinking and rationalization. Israel is a case in point. In spite of numerous LTC arrangements supported by the state, in the absence of a comprehensive strategy, these have not generated a coherent system that can deal efficiently and equitably with existing and fast growing LTC needs, on the one hand, and the resources available to it, on the other. The current system is fragmented. It provides limited coverage and insufficient benefits in a troublesome fashion to public. The findings suggest that Israel can achieve at least in the short term, universal entitlement to LTC at lower financial and social cost, than the current costs of the system. In the medium and long term, the country will need to consider the trade between the burden of direct care on households or the tax burden of publicly supported and organized care. CONCLUSIONS: To remedy the situation the paper suggests a two-planked reform. The first is integration of the current fragmented publicly supported system while deciding on LTC either as a "social endeavor" under a separate authority responsible for implementing the public LTC budget, or as a "medical endeavor", putting this responsibility under the Israeli sickness funds. The second plank, building on the first, comprises extension of universal entitlement to LTC. Such an extension would increase public spending in the long term; simultaneously, it would relieve the tax-paying population of a substantial privately borne burden of a fast aging population. PMID- 20197207 TI - Preference for private hospital-based maternity services in inner-city Lagos, Nigeria: An observational study. AB - OBJECTIVES: To determine factors associated with maternal preference for delivery in private hospitals in an urban community in sub-Saharan Africa. METHODS: A cross-sectional study of socio-demographic and obstetric characteristics of mothers and their newborns attending Bacille Calmette-Guerin (BCG) immunization clinics in inner-city Lagos, Nigeria. Factors associated with delivery in private hospitals were determined using multivariable logistic regression analyses. RESULTS: Of the 3296 mothers enlisted for this study 1659 (50.3%) delivered in private hospitals and 1637 (49.7%) in public hospitals. Government hospitals had a higher proportion of doctors at delivery. Use of private obstetric services was significantly associated with ethnicity, religion, social class and obstetric history. Infants delivered at private hospitals were significantly more likely to be undernourished and have severe hyperbilirubinemia but less likely to be preterm and at no greater risk of hearing loss. CONCLUSIONS: Current global strategies to expand facility-based deliveries in order to reduce maternal and child mortality rates need to be complemented by improved regulatory/supervisory framework at country levels to better serve mothers and their offspring in urban areas who may opt for private hospitals usually lacking adequate obstetric and pediatric facilities against the backdrop of the rapid urban transition in Africa. PMID- 20197208 TI - Poor prognosis in cycles following "genuine" empty follicle syndrome. AB - OBJECTIVES: The aim of this study was to investigate the prognosis in future IVF cycles of patients with empty follicle syndrome (EFS). STUDY DESIGN: EFS cases and their future cycles were reviewed. Clinical pregnancy rate per started cycle was taken as the primary outcome in assessing the future outcome in IVF treatment cycles. RESULTS: A total of 3023 patients underwent 5238 IVF treatment cycles. Twenty-six patients (1%) had a total of 58 (1%) cycles of EFS. Thirteen women went through 32 further IVF treatment cycles following the diagnosis of EFS, yielding only two clinical pregnancies, giving a clinical pregnancy rate of 6.25% per started cycle. In addition, four patients had recurrence in a total of 15 cycles. CONCLUSIONS: The occurrence of EFS will indicate poor IVF success in subsequent IVF cycles. Patients with "genuine EFS" should be counselled about the outcome of their future IVF cycles. PMID- 20197210 TI - Clipping of a vertebral artery aneurysm behind the hypoglossal nerve under the monitoring of lower cranial nerves. AB - Under an operative view, an aneurysm of the vertebral artery is located behind the lower cranial nerves. To prevent neurological deficits we employed electrophysiological monitoring while clipping an aneurysm of the vertebral artery. A 64-year-old woman had suffered a sudden severe headache in the morning. Computed tomography (CT) revealed a subarachnoid hemorrhage (SAH) and CT angiography revealed an aneurysm at a branching point of the left vertebral artery. The condylar fossa approach was taken while recording electromyography (EMG) of the lower cranial nerves. The aneurysm was located just behind the hypoglossal nerve and could not be clipped without strong traction of the hypoglossal nerve. Therefore, the hypoglossal nerve was divided to separate the lower two bundles of the hypoglossal nerve from the other bundles, and the clip was applied to the aneurysm between the nerve bundles without any change of the tongue EMG. The patient went home 10 days after operation with no neurological deficit. In conclusion, we report a case of a ruptured aneurysm of a vertebral artery, which was clipped while monitoring the lower cranial nerves. Tongue EMG monitoring enabled us to clip the aneurysm without nerve injury and revealed that the hypoglossal nerve near the hypoglossal canal can be divided into several bands without neurological deficit. PMID- 20197209 TI - Surgical approaches to meningiomas of the lateral ventricles. AB - BACKGROUND: Intraventricular meningiomas account for 0.5-3% of all intracranial meningiomas. The majority occur in the atrium of the lateral ventricle. Surgical experience with intraventricular meningiomas is rare in the literature, and several surgical approaches exist. METHODS: Between 1987 and 2007, 13 patients underwent resection of intraventricular meningiomas. All patients had tumors of the lateral ventricles. These patients were retrospectively identified and their records reviewed. RESULTS: Eleven tumors were found in the atrium, one in the frontal horn, and one in the body of the lateral ventricle. In 9 of 13 cases, the tumor occurred in the left lateral ventricle. Patients commonly presented with headache and cognitive difficulties. A visual field deficit was noted preoperatively in one patient. Four patients underwent preoperative angiography, but no patients underwent embolization. Gross total resection was achieved in all cases: 6 via a middle temporal gyrus approach, 5 via a superior parietal lobule approach, and 2 via a transcallosal approach. Image-guided stereotaxis was used in 6 cases. Pathology was benign in 12 of 13 cases; atypical features were identified in one case. There was no operative mortality, and no patients showed evidence of recurrence. Postoperatively, 3 patients developed new cognitive linguistic deficits that subsequently resolved. One of these patients developed a new visual field deficit after surgery. CONCLUSIONS: Several approaches are available for the surgical treatment of intraventricular meningiomas. Tumor location, extension, and laterality drive the selection algorithm for these approaches. Preoperative angiography is rarely useful, and surgical cure is the rule. PMID- 20197211 TI - Multiple heavy metals extraction and recovery from hazardous electroplating sludge waste via ultrasonically enhanced two-stage acid leaching. AB - An ultrasonically enhanced two-stage acid leaching process on extracting and recovering multiple heavy metals from actual electroplating sludge was studied in lab tests. It provided an effective technique for separation of valuable metals (Cu, Ni and Zn) from less valuable metals (Fe and Cr) in electroplating sludge. The efficiency of the process had been measured with the leaching efficiencies and recovery rates of the metals. Enhanced by ultrasonic power, the first-stage acid leaching demonstrated leaching rates of 96.72%, 97.77%, 98.00%, 53.03%, and 0.44% for Cu, Ni, Zn, Cr, and Fe respectively, effectively separated half of Cr and almost all of Fe from mixed metals. The subsequent second-stage leaching achieved leaching rates of 75.03%, 81.05%, 81.39%, 1.02%, and 0% for Cu, Ni, Zn, Cr, and Fe that further separated Cu, Ni, and Zn from mixed metals. With the stabilized two-stage ultrasonically enhanced leaching, the resulting over all recovery rates of Cu, Ni, Zn, Cr and Fe from electroplating sludge could be achieved at 97.42%, 98.46%, 98.63%, 98.32% and 100% respectively, with Cr and Fe in solids and the rest of the metals in an aqueous solution discharged from the leaching system. The process performance parameters studied were pH, ultrasonic power, and contact time. The results were also confirmed in an industrial pilot scale test, and same high metal recoveries were performed. PMID- 20197212 TI - Plasma disposition and fecal elimination of doramectin after oral or intramuscular administration in horses. AB - A study was done to compare plasma disposition kinetics and the fecal elimination profile of doramectin (DRM) after oral or intramuscular (IM) administration in horses. Ten clinically healthy horses, 328-502 kg body weight (bw), were assigned to 2 experimental groups of 5 horses each. Group 1 was treated with an oral dose of 0.2 mg DRM/kg bw, while Group 2 was treated with 0.2 mg DRM/kg bw by IM route. Blood and fecal samples were collected at different times between 0.5h and 60 days post-treatment. After plasma and fecal drug extraction and derivatization, samples were analysed by high performance liquid chromatography (HPLC). A non compartmental kinetic analysis was performed. Results were expressed as mean+/ standard deviation and were compared using Mann-Whitney U-test. The parent molecule was detected in plasma between 30 min and either 30 (oral) or 60 (IM) days post-treatment. Peak plasma concentrations (C(max)) of 51.6+/-22.2 and 33.3+/-10.5 ng/mL were obtained after oral administration and IM route, respectively. Differences between administration route were not statistically significant (P=0.42). The value for the area under the concentration-time curve (AUC) was 178.6+/-53.7 and 393.6+/-66.6 ng day/mL for Group 1 and Group 2, respectively. These differences were significant (P<0.0079). The averages for mean residence time (MRT) values were 7.7+/-0.9 and 13.2+/-4.5 days for oral and IM treated groups, respectively. In horses treated using the oral route, the peak fecal concentration (F C max) was 2295+/-593 ng/g observed at 1.9+/-0.5 days after oral treatment. Whereas, for those treated by IM route, the F C max was lower (162+/-26 ng/g) (P<0.0079) and it was observed at 5.6+/-2.9 days. The results of this study showed that the administration route affects plasma disposition kinetics, bioavailability and fecal elimination of DRM. PMID- 20197213 TI - Effectiveness of praziquantel for treatment of peritoneal larval cestodiasis in dogs: a case report. AB - Peritoneal larval cestodiasis (PLC) was incidentally identified in an adult female mixed-breed dog by explorative celiotomy done in response to abnormal blood values found during a routine work-up in preparation for an ovariohysterectomy. Ten days after ovariohysterectomy, treatment with fenbendazole began (50mg/kg, per os, every 12h, for 21 days). Two weeks after the end of treatment, samples of peritoneal fluid were obtained by paracentesis and examined. Motile peritoneal tetrathyridia were still evident. Fenbendazole was discontinued. After 10 days of withdrawal from fenbendazole, the dog was treated with a subcutaneous administration of injectable praziquantel (5mg/kg). The administration was repeated after a 15 days interval. Two weeks after the second administration, samples of peritoneal fluid were obtained again by paracentesis. Motile peritoneal tetrathyridia were not detected. Fourteen months after the last administration of praziquantel, the dog remained still free of peritoneal tetrathyridia as determined by abdominal ecography. Therefore, praziquantel was effective to eliminate peritoneal tetrathyridia definitely. Practitioners should be aware of PLC in order to early recognize this condition in case of incidental finding and implement adequate therapy as soon as possible. PMID- 20197214 TI - Analysis of marine bivalve shellfish from the fish market in Santos city, Sao Paulo state, Brazil, for Toxoplasma gondii. AB - The aim of this study was to determine if Toxoplasma gondii are present in oysters (Crassostrea rhizophorae) and mussels (Mytella guyanensis) under natural conditions using a bioassay in mice and molecular detection methods. We first compared two standard protocols for DNA extraction, phenol-chloroform (PC) and guanidine-thiocyanate (GT), for both molluscs. A total of 300 oysters and 300 mussels were then acquired from the fish market in Santos city, Sao Paulo state, Brazil, between March and August of 2008 and divided into 60 groups of 5 oysters and 20 groups of 15 mussels. To isolate the parasite, five mice were orally inoculated with sieved tissue homogenates from each group of oysters or mussels. For molecular detection of T. gondii, DNA from mussels was extracted using the PC method and DNA from oysters was extracted using the GT method. A nested-PCR (Polymerase Chain Reaction) based on the amplification of a 155 bp fragment from the B1 gene of T. gondii was then performed. Eleven PCR-RFLP (Restriction Fragment Length Polymorphism) markers, SAG1, SAG2, SAG3, BTUB, GRA6, c22-8, c29 2, L358, PK1, CS3 and Apico, were used to genotype positive samples. There was no isolation of the parasite by bioassay in mice. T. gondii was not detected in any of the groups of mussels by nested-PCR. DNA of T. gondii was apparently detected by nested-PCR in 2 groups of oysters (3.3%). Genotyping of these two positive samples was not successful. The results suggest that oysters of the species C. rhizophorae, the most common species from the coast of Sao Paulo, can filter and retain T. gondii oocysts from the marine environment. Ingestion of raw oysters as a potential transmission source of T. gondii to humans and marine mammals should be further investigated. PMID- 20197215 TI - A seroepidemiological study of exposure to Toxoplasma, Leishmania, Echinococcus and Trichinella in equids in Greece and analysis of risk factors. AB - The role of horses in the transmission of parasitic zoonoses either as a source of infection to vectors or through contamination of definitive hosts is gaining importance worldwide. For this reason sera from 773 equids including 753 horses, 13 mules and seven ponies in four regions of Greece were investigated by ELISA for the presence of IgG antibodies against Toxoplasma, Leishmania, Echinococcus and Trichinella. Anti-Toxoplasma antibodies were detected in all regions with an overall prevalence of 1.8%. In contrast, antibodies to Leishmania, Echinococcus, and Trichinella were present only in horses from the equestrian centre located in Attica region, but the status of Trichinella could not be confirmed. The seroprevalence of infection was 0.3% for Leishmania, 0.1% for Echinococcus and 0.1% for Trichinella. Only one horse was positive with a mixed infection of Toxoplasma, Leishmania and Trichinella. The following host characteristics were investigated for any significant effects on the prevalence of Toxoplasma infection: gender, age, species, origin of birth, activity, and location. The type of activity (p<0.05) and location (p<0.01) of the animals were found to be significant risk factors for Toxoplasma infection. The relative risk (RR) for Toxoplasma infection comparing the regions of Peloponnese and Thessaly to Attica were 6.92 and 6.78, respectively. Due to the very low prevalence of Echinococcus, Leishmania, and Trichinella infections, the associated risk factors were not analysed. The low seroprevalences observed suggest that the risk of infection from equids to people is very low, especially when consumption of horse meat is uncommon in this country. PMID- 20197216 TI - Changes in and characteristics of admissions to treatment related to problematic prescription opioid use in Ontario, 2004-2009. AB - BACKGROUND: North America is the region with the world's highest prescription opioid (PO) use. Non-medical use of prescription opioids and PO-related morbidity and mortality have strongly increased in the US in recent years. It is assumed that similar trends are occurring in Canada, but there is less empirical evidence to support this. Treatment demand for problematic PO use is an important indicator of PO-related morbidity. METHODS: Levels and changes related to the caseload of PO-related treatment admissions were assessed using system-level data from the Drug and Alcohol Treatment Information System (DATIS), the reporting system for publicly funded addiction treatment services in the province of Ontario (Canada) for the period April 2004-March 2009 (n=500,217). In addition, basic socio-demographic and clinical characteristics of PO-related treatment admissions in the final year of study (n=10,125) were examined. RESULTS: The number of PO-related treatment admissions in DATIS rose by 60%, and their prevalence in the total caseload increased from 9.4% to 15.7% in the study period. Three-quarters of PO-clients reported other problem substances; the most common co-occurring problem substance was cocaine/crack. The majority of PO clients were <35 years of age, unemployed, and referred to treatment by others. INTERPRETATION: Demand for treatment for problematic PO use has risen substantially in Ontario in the past five years in the wider context of substantially increased overall PO use and related harms in Canada. The interaction dynamics between these different indicators need to be systematically examined and monitored as the basis for evidence-based interventions. PMID- 20197217 TI - Childhood sexual abuse and adolescent substance use: a latent class analysis. AB - Children who have exposure to child sexual abuse (CSA) are at particular risk for developing substance abuse in adolescence, but the extent to which CSA may shape patterns of adolescent substance use remains uncertain. The aim of this paper is to characterize the variations in patterns of adolescent substance use and to examine the association between CSA and qualitatively distinct patterns of adolescent substance use. Latent class analyses identified homogenous groups of adolescents with similar patterns of substance use using a sample of 1019 adolescents (mean age: 15.9 years; range: 13-18) who were selected from five publicly funded service systems. Different patterns of latent class structures were identified in boys and girls (a 4-class solution for girls and a 3-class solution for boys). CSA was associated with an increased risk of being a heavy polysubstance user in girls, even after adjustment of age, race/ethnicity, parental substance use, sibling use, peer use, psychopathology and other forms of childhood maltreatment including physical abuse and neglect. Findings indicate that female victims of CSA who are involved with public service systems are at high risk for developing multiple-substance use in adolescence. PMID- 20197218 TI - Rotavirus-associated diarrhoea in foals in Greece. AB - Severe outbreaks of diarrhoeic syndrome occurred in young foals at the same stud farm during two consecutive breeding periods namely spring 2006 and 2007. Rotavirus-like particles were detected by electron microscopy in the faeces of the affected foals and group A rotavirus infection was confirmed by Reverse Transcription (RT)-PCR with selected sets of rotavirus-specific primers. Sequence analysis of the genes encoding the outer capsid rotavirus proteins VP7 and VP4 enabled classification of the viruses as G3AP[12] and revealed that the viruses were highly similar to recently reported equine rotavirus strains circulating in Europe. All Greek equine rotavirus isolates were genetically identical, suggesting persistence of the same viral strain in the stud farm, over the two consecutive foaling periods. PMID- 20197219 TI - Alphaherpesvirus use and misuse of cellular actin and cholesterol. AB - Two major structural elements of a cell are the cytoskeleton and the lipid membranes. Actin and cholesterol are key components of the cytoskeleton and membranes, respectively, and are involved in a plethora of different cellular processes. This review summarizes and discusses the interaction of alphaherpesviruses with actin and cholesterol during different stages of the replication cycle: virus entry, replication and assembly in the nucleus, and virus egress. Elucidating these interactions not only yields novel insights into the biology of these important pathogens, but may also shed new light on cell biological aspects of actin and cholesterol, and lead to novel avenues in the design of antiviral strategies. PMID- 20197220 TI - Outer membrane proteins of Pasteurella multocida. AB - Pasteurella multocida is a ubiquitous pathogen which causes a range of diseases in diverse animal species. Components of the bacterial outer membrane, such as trans membrane proteins and lipoproteins, play key roles in the interaction of the pathogen with the host environment and in the host immune response to infection. In this review, we evaluate the current knowledge of P. multocida outer membrane proteins and their role in pathogenesis and immunity. PMID- 20197221 TI - Point mutations in BHV-1 Us3 gene abolish its ability to induce cytoskeletal changes in various cell types. AB - The Us3 gene is conserved among alphaherpesviruses and codes for a protein kinase, a multifunctional protein involved in many phases of virus infection, like nuclear egress, modulation of apoptosis and modification of the cellular cytoskeleton. Bovine herpesvirus (BHV-1), a member of the Alphaherpesvirinae, contains an open reading frame homologous to Us3 of other herpesviruses, which has been identified as a serine/threonine kinase (Takashima, Y., Tamura, H., Xuan, X., Otsuka, H., 1999. Identification of the Us3 gene product of BHV-1 as a protein kinase and characterization of BHV-1 mutants of the Us3 gene. Virus Res. 59, 23-34). To study the activity of BHV-1 Us3, we have cloned its sequence under control of the human cytomegalovirus (HCMV) promoter/enhancer and introduced it into a recombinant baculovirus (Bac Us3). Confocal microscopy analysis showed profound cytoskeletal modifications in various BHV-1-permissive and non permissive cells transduced with BacUs3. We observed that Us3 expression changed cellular shape and induced formation of long microtubule-containing cell projections, a phenomenon which had also been observed in cells expressing pseudorabies virus Us3. The intracellular localization of Us3 was mostly nuclear but when the protein accumulated it could be detected in the cytoplasm, cell membranes and projections. Mutated forms of BHV-1 Us3 with point mutations near or within the kinase catalytic domain did not affect cell morphology indicating that kinase activity of BHV-1 Us3 is required for its cytoskeleton remodelling function. PMID- 20197222 TI - Role of leptin in improvement of oocyte quality by regulation of ovarian angiogenesis. AB - Ovarian angiogenesis plays an important role in folliculogenesis. An active blood supply via ovarian angiogenesis seems to be essential for the induction of oocytes with good quality. Leptin is an angiogenic factor which regulates VEGF expression. This study was aimed to investigate whether leptin administration during superovulation influences ovarian response, oocyte quality and VEGF expression in the ovary using different aged mice model. C57BL inbred female mice of two age groups (18-21, and 29-31 weeks) were superovulated by intraperitoneal co-injection with 5IU of pregnant mare's serum gonadotropin (PMSG) supplemented with recombinant mouse leptin at various doses (0.01, 0.1, 1 microg), followed by injection with 5IU of human chorionic gonadotropin (hCG) approximately 48 h later. Then, the mice were immediately paired with an individual male. The control group was superovulated with PMSG and hCG without leptin. After 18 h, one cell embryos were flushed and cultured for 4 days. Proteins were extracted from ovaries removed just after the retrieval of one-cell embryos and VEGF expression was examined by Western blot. Treatment of 0.1 microg and 1 microg leptin significantly increased the number and embryo development rate of one-cell embryos retrieved compared to the control group. This positive effect of leptin was more significant with advancing female age. Ovarian VEGF expression was also significantly increased in 0.1 and 1 microg leptin-treated groups compared to the control group in both age groups (P<0.05). Our present study showed that leptin administration with gonadotropins during superovulation in aged mice increased the ovarian response, developmental competence of oocytes and ovarian VEGF expression. This research may have potential clinical implications in the treatment of age-related decline of fertility. PMID- 20197223 TI - Effects of adding taurine and trehalose to a tris-based egg yolk extender on buffalo (Bubalus bubalis) sperm quality following cryopreservation. AB - Cryopreservation induces sublethal damage to the spermatozoa, which leads to their reduced fertile life. Under the present study, the cryoprotective effect of taurine and trehalose on buffalo sperm quality parameters after freeze-thaw process was studied. Buffalo semen was cryopreserved in tris-based egg yolk extender along with cryoprotectants like taurine (50 mM) or trehalose (100 mM) and used for the assessment of sperm quality parameters like motility, viability, plasma membrane integrity, total antioxidant status and the extent of cryocapacitation. The results were compared to semen cryopreserved in tris-based egg yolk extender only as control. Post-thaw semen evaluation clearly indicated that the addition of taurine or trehalose significantly improved (P<0.05) the motility, viability and membrane integrity compared to control spermatozoa. The extent of sperm cells underwent cryocapacitation was significantly lowered (P<0.05) in presence of taurine or trehalose. Moreover, the percentage of in vitro capacitated cells in the treated samples was comparable to the control spermatozoa along with maintaining other sperm quality parameters. Finally, compared to the control and trehalose treated sample, addition of taurine to the freezing extender showed more positive effect on the total antioxidant power of seminal plasma and spermatozoa. It is concluded that the addition of taurine or trehalose to the freezing extender led to the reduction of cryodamage to the buffalo spermatozoa. PMID- 20197224 TI - Interpreting routine biochemistry in those aged over 65 years: a time for change. AB - In clinical practice, routine biochemistry tests are often performed for diagnostic or screening purposes. We reviewed papers that have reported reference values for people older than 65 years with or without overt health problems. Wider intervals have generally been reported for sodium, potassium, calcium and C reactive protein (CRP) in the elderly. Higher levels of creatinine and lower levels of total cholesterol (TC) and serum albumin (SA) are observed with ageing. Elderly people have been found to be at greater risk for overt abnormalities in sodium, potassium, creatinine, TC, SA and CRP. The consequences of these abnormalities could be severe. For instance, even mild hyponatremia was associated with increased risk of mortality, disability and myocardial infarction. Mild hypernatremia was associated with severe disability. Mild increases in CRP levels were associated with an increased risk of sarcopenia, disability, cardiovascular disease and cognitive decline. Mild decreases in TC levels were associated with an increased risk of disability or mortality, and mild decreases in SA were associated with an increased risk of mortality, disability, sarcopenia and frailty. Nutritional factors could not wholly explain these effects. Modified biochemical reference values are required for elderly patients, as biochemical results can serve as markers of vulnerability to age related diseases, linked to metabolism. Careful diagnosis and corrective interventions are needed for patients in this age group. PMID- 20197225 TI - Reliability and validity assessments of a Japanese version of QOL 20-Item Sino Nasal Outcome Test for chronic rhinosinusitis. AB - OBJECTIVE: The objective of this study was to assess the reliability and validity of a Japanese version of the 20-Item Sino-Nasal Outcome Test SNOT-20, which is one of the quality-of-life (QOL) evaluation sheets for chronic rhinosinusitis (CRS), and assess its reliability and validity. METHODS: The SNOT-20 was conducted in patients with CRS and in healthy volunteers. The response rate was evaluated as the feasibility of this test, and reliability and internal consistency were assessed as reliability. In addition, concurrent validity and discriminant validity were assessed as validity. RESULTS: Regarding the feasibility of this test, the response rate for each question item in the SNOT-20 was nearly 100% for all 20 items. For reliability, test-retest reliability was r=0.890 and the internal consistency was alpha=0.903. For validity, the concurrent validity was r=0.162 when compared with objective findings in the nasal cavity, and was r=0.431 when compared with the score for general physical condition, which evaluate the patient's general condition. Discriminant validity was significantly higher in patients with CRS than in healthy volunteers (p<0.001). Moreover, when the discriminant validity was assessed using an ROC (receiver operating characteristic) curve, it was found that ROC-AUC (the area under the curve)=0.775. CONCLUSION: The reliability and validity of a Japanese version of the SNOT-20 were assessed in this study. It is thought that the SNOT 20 serves as a useful QOL evaluation sheet for CRS. PMID- 20197226 TI - Effect of the evaluation of recall on the rate of information recalled by patients in Primary Care. AB - OBJECTIVE: To analyse whether asking the patient to restate the recommendations they receive before leaving the surgery improves the recall rate once the consultation is finished. METHODS: Observational study in 37 Primary Care Consultant (PCC) in health centres of the city of Albacete. The final sample had 963 patients. RESULTS: The mean rate of recommendations remembered after leaving the surgery was better in the group of patients that restated the recommendations before finishing the doctor-patient encounter than in the group where there was no restatement (p = 0.000). The amount of recommendations showed a negative correlation with the recall rate (r = -0.215). CONCLUSION: Asking patients to repeat treatment recommendations is an effective method of improving the recall of these prescriptions at the end of doctor-patient encounter. PRACTICAL IMPLICATIONS: The importance of communication between health-care professionals and patients justifies the performance of studies so that it can be improved and, according to the results of this study, it would be advisable to use the method proposed on a more regular basis by the PCC as a way of improving communication and recall of medical advice. PMID- 20197227 TI - An examination of the relationship between behavioral approach system (BAS) sensitivity and social interaction anxiety. AB - BACKGROUND: Both behavioral inhibition system (BIS) and behavioral approach system (BAS) sensitivity have been proposed to play a role in social anxiety; however, findings concerning the relationship between BAS and social anxiety have been mixed. Moreover, recent evidence suggests that low levels of BAS may only be associated with the social interaction subdimension of social anxiety. METHOD: Measures of BIS, BAS, social interaction anxiety, and social observation anxiety were administered to three large analogue samples. RESULTS: As hypothesized, BAS was inversely related to social interaction anxiety, but was unrelated to social observation anxiety across all three samples. In addition, individuals with generalized social fears were found to report both higher levels of BIS and lower levels of BAS compared to individuals with few or specific social fears. CONCLUSION: These findings suggest that a complete motivational account of generalized social anxiety should include both BIS and BAS. PMID- 20197228 TI - Angiolipoma in head and neck: report of two cases and review of the literature. AB - Angiolipomas are either encapsulated or non-encapsulated fatty tumours. They are distinguished from other lipomas by the excessive degree of vascular proliferation and because they are mixed with mature adipocytes. They commonly occur in the trunk and extremities and are rare in the maxillofacial area. Only 36 cases in the head and neck have been reported in the literature. The authors report the first non-infiltrating intramasseterine angiolipoma, and a case of non infiltrating angiolipoma of the cheek. These tumours appear as homogenous low density areas on CT with no contrast enhancement. MRI gives better tumour delineation and clear definition of the location and longitudinal extent of the mass. Histopathology demonstrates mature adipose tissue and the proliferation of numerous small branching blood vessels. Management of angiolipomas requires complete surgical excision. PMID- 20197229 TI - Biosynthesis of silver and gold nanoparticles using Brevibacterium casei. AB - The present study demonstrates an unprecedented green process for the production of spherical-shaped Au and Ag nanoparticles synthesized and stabilized using a bacterium, Brevibacterium casei. Aqueous solutions of chloroaurate ions for Au and Ag(+) ions for silver were treated with B. casei biomass for the formation of Au nanoparticles (AuNP) and Ag nanoparticles (AgNP). The nanometallic dispersions were characterized by surface plasmon absorbance measuring at 420 and 540 nm for Ag and Au nanoparticles, respectively. Transmission electron microscopy showed the formation of nanoparticles in the range of 10-50 nm (silver), and 10-50 nm (gold). XRD analysis of the silver and gold nanoparticles confirmed the formation of metallic silver and gold. Further analysis carried out by Fourier Transform Infrared Spectroscopy (FTIR), provides evidence for the presence of proteins as possible biomolecules responsible for the reduction and capping agent which helps in increasing the stability of the synthesized silver and gold nanoparticles. The biological activities of the synthesized particles were confirmed based on their stable anti-coagulant effects. The use of bacterium for nanoparticles synthesis offers the benefits of ecofriendliness and amenability for large-scale production. PMID- 20197231 TI - Modulation of hemocompatibility of polysulfone by polyelectrolyte multilayer films. AB - Polyelectrolyte multilayer (PEM) films have been recently applied to surface modification of biomaterials. Cellular interactions with PEM films consisted of weak polyelectrolytes are greatly affected by the conditions of polyelectrolyte deposition, such as pH of polyelectrolyte solution. Previous studies indicated that the adhesion of several types of mammalian cells to PAH/PAA multilayer films was hindered by low pH and high layer numbers. The objective of this study is to evaluate whether the hemocompatibility of polysulfone can be modulated by deposition of poly(allylamine hydrochloride) (PAH)/poly(acrylic acid) (PAA) multilayer films. PAH/PAA multilayer films with different layer numbers were assembled onto polysulfone at either pH 2.0 or pH 6.5. The number of platelet adhesion and the morphology of adherent platelets were determined to evaluate hemocompatibility of modified substrates. Compared to non-treat polysulfone, the PEM films developed at pH 2.0 decreased platelet adhesion, while those built at pH 6.5 enhanced platelet deposition. Platelet adhesion was found positively correlated to polyclonal antibodies binding to surface-bound fibrinogen. The extent of platelet spreading was increased with layer numbers of PEM films, suggesting that the adherent platelets on thick PEM films were prone to activation. In conclusion, PAH/PAA films with few layers developed at pH 2.0 possessed better hemocompatibility compared to other substrates. PMID- 20197230 TI - Stabilization of phospholipid polymer surface with three-dimensional nanometer scaled structure for highly sensitive immunoassay. AB - A phospholipid polymer platform and an antibody as a bioaffinity ligand were used to construct a biointerface for a highly sensitive immunoassay. The platform had a nanometer-scaled particle deposition surface and it was constructed with poly[2 methacryloyloxyethyl phosphorylcholine (MPC)-co-n-butyl methacrylate (BMA)-co-p nitrophenyloxycarbonyl poly(ethylene glycol) methacrylate (MEONP)] (PMBN) by an electrospray deposition (ESD) method. The PMBN surface could immobilize specific antibodies through covalent chemical bonding by the reaction between MEONP units and amino groups in the antibody. In addition, the PMBN could prevent nonspecific protein adsorption from an analyte. However, the nanometer-scaled structure of the PMBN lost its shape after immersion in an aqueous medium. To stabilize the nanometer-scaled structure in an aqueous medium, the PMBN was cross-linked with 1,4-butylenediamine and then heat-treated. These treatments effectively improved the stability of the nanometer-scaled structure, that is, the structure had a high porosity even after immersing in an aqueous medium. The stabilization affected the specific signal in the enzyme-linked immunosorbent assay (ELISA), that is, the specific signal in ELISA was enhanced. PMID- 20197232 TI - Signaling gene cascade in silver nanoparticle induced apoptosis. AB - Nanoscale materials are presently gaining much importance for biological applications especially in the field of medicine. The large numbers of nanomaterial based products that are currently being developed - with projected applications in medicine - have inspired a growing interest in exploring their impact on cellular gene expression. The present study examines the effects of silver nanoparticles (NPs) on genes expression in an endeavor to assess the fundamental mechanisms that contribute to silver NP induced programmed cell death. Here, we have used RT-PCR to study the gene expression, flow cytometry analyses to probe the extent of apoptosis (FACS) and atomic force microscopy (AFM) to follow the cell membrane topology change induced by Ag NPs. The gene expression study revealed that Ag NP induced p53-mediated apoptotic pathway through which most of the chemotherapeutic drugs trigger apoptosis (programmed cell death). The results also suggest that Ag NPs could be attributed as therapeutic agent for biomedical and pharmaceutical applications. PMID- 20197233 TI - Automated lipid bilayer and ion channel measurement platform. AB - Ion channels and transmembrane proteins play key roles in a wide range of physiological processes. Engineered ion channels have been explored as highly sensitive single molecule sensors. Scientific and sensing measurements of ion channel conductance often utilize artificial lipid bilayers, which have shortcomings limiting their application. We describe a fully automated lipid bilayer formation system that integrates the measurement electronics within the fluidic controls. Unattended operation of this system resulted in highly reproducible automatic bilayer formation and ion channel measurement over dozens of consecutive trials. The fully automated, closed-loop control algorithm enabled autonomous operation of the platform, a step toward applications of ion channel measurements for remote sensing and pharmacological studies requiring minimal operator involvement. PMID- 20197234 TI - Ultra-sensitive detection of cysteine by gold nanorod assembly. AB - In this paper, we have developed a simple, rapid, selective, and ultra-sensitive assay to detect cysteine by means of gold nanorods assembly. This methodology is based on the end-to-end assembly of gold nanorods and it is very sensitive due to the useful formation of the gold nanorods chain in the presence of cysteine under acidic aqueous solution. The sharp absorption peak changes observed from the assembly formed by the gold nanorods allow one to monitor very subtle differences induced by cysteine in an acidic medium and therefore, it can provide a quantitative measure of the cysteine concentration. On the other hand, the high extinction coefficients of gold nanorods allow one to monitor the changes at lower concentrations compared to that accomplished by conventional absorbance based chromophores. Therefore, one of the significant features is the ability to detect cysteine in the presence of other essential alpha-amino acids at concentrations as low as 10 pM, which to the best of our knowledge is the lowest reported for a colorimetric cysteine detection system. More importantly, this assay is particularly attractive because it does not rely on organic cosolvents, enzymatic reactions, light-sensitive dye molecules, lengthy protocols, and sophisticated instrumentation. PMID- 20197236 TI - Practical problems of doing research across different cultures: experiences from the RACHEL study. AB - For many nurses the thought of conducting a research study, even one based in one centre, is daunting but coordinating a multi-centred study across different countries with different cultures can seem overwhelming. Some of the practical problems of doing research across different cultures are predictable and can be planned for, while others may surface as the study is started and need to be reacted to as they happen. Clear lines of communication are therefore essential. This article discusses some of the issues and problems that can occur using examples from a large multi-national nursing study by the RACHEL group. PMID- 20197235 TI - Mining the active proteome in plant science and biotechnology. AB - Protein activity is essential functional information, yet difficult to predict from transcript or protein data. Activity-based protein profiling (ABPP) displays active proteins in proteomes using small molecule probes that irreversibly label proteins in their active state. Here, we review proof-of-concept ABPP studies in plant science. These studies displayed activities of dozens of plant cysteine proteases, lipases, methylesterases and the proteasome. ABPP in plants revealed differential protein activities in development and immunity and uncovered striking selectivity of pathogen-derived inhibitors and unexpected targets of commercial inhibitors. The unique, high-content information of ABPP and the robustness and simplicity of the assays will make ABPP a powerful tool in future plant science and biotechnology. PMID- 20197237 TI - Total port-access robot-assisted pulmonary lobectomy without utility thoracotomy. AB - Robot-assisted lobectomy has been reported elsewhere as a feasible technique for lobectomy. We report a modification of the previously reported technique using a complete port-access approach without utility thoracotomy. PMID- 20197238 TI - Functional diversifications of cyanogenic glucosides. AB - Cyanogenic glucosides are present in many plants and their ability to liberate toxic HCN offers an immediate chemical defense response to herbivores and pathogens causing damage of the plant tissue. Countermeasures have evolved to overcome this type of defense and in some cases herbivores and pathogens are able to exploit the presence of cyanogenic glucosides to their own advantage. In plants, cyanogenic glucosides have gained additional functionalities as transporters of nitrogen and operation of an endogenous turnover pathway may enable plants to withdraw the nitrogen and glucose deposited in cyanogenic glucosides for use in primary metabolism. The aim of this review is to provide an overview of the new knowledge on these diverse functionalities of cyanogenic glucosides. PMID- 20197239 TI - Interaction of an anthracycline disaccharide with ctDNA: Investigation by spectroscopic technique and modeling studies. AB - This study was designed to examine the interaction of an anthracycline disaccharide, 4'-O-(beta-L-oleandrosyl) daunorubicin (DNR-D2), with calf thymus deoxyribonucleic acid (ctDNA) by UV-vis in combination with fluorescence spectroscopy and molecular modeling techniques under physiological conditions (Britton-Robinson buffer solutions, pH 7.4). By the analysis of UV-vis and fluorescence spectrum, it was observed that the binding mode between DNR-D2 and ctDNA might be intercalation, and fluorescence quenching mechanism of DNR-D2 by ctDNA was a static quenching type. Upon binding to ctDNA, the anthraquinone chromophore of DNR-D2 could slide into the C-G rich region of ctDNA. Hydrogen bonding forces may play an essential role in the binding of DNR-D2 to ctDNA. Furthermore, the results obtained from computational modeling corroborated the experimental results obtained from spectroscopic investigations. These studies are valuable for a better understanding the datailed mode of DNR-D2-DNA interaction, which should be important in deeper insight into the therapeutic efficiency of DNR-D2. PMID- 20197240 TI - A PIAS-ed view of DNA double strand break repair focuses on SUMO. AB - Through the action of multiple sensors, mediators, and effectors, the DNA damage response (DDR) orchestrates the repair of DNA damage to ensure maintenance of genomic integrity. Recently, in addition to phosphorylation, other post translational modifications such as ubiquitylation and SUMOylation have emerged as important regulators of the DDR network. Two recent papers highlight the importance of SUMO modifications of proteins that execute the response to DNA damage. PMID- 20197241 TI - Effects of base excision repair proteins on mutagenesis by 8-oxo-7,8 dihydroguanine (8-hydroxyguanine) paired with cytosine and adenine. AB - 8-Oxo-7,8-dihydroguanine (8-oxo-Gua, also known as 8-hydroxyguanine) is a major base lesion that is generated by reactive oxygen species in both the DNA and nucleotide pool. The role of DNA glycosylases, which initiate base excision repair, in the mutagenic processes of 8-oxo-Gua in DNA and 8-oxo-7,8-dihydro-2' deoxyguanosine 5'-triphosphate (8-oxo-dGTP, also known as 8-hydroxy-2' deoxyguanosine 5'-triphosphate) were investigated using supF shuttle plasmids propagated in human cells. The DNA glycosylases, OGG1, MUTYH, NTH1, and NEIL1, in 293T cells were individually knocked-down by siRNAs and plasmid DNAs containing an 8-oxo-Gua:C/8-oxo-Gua:A pair, and 8-oxo-dGTP plus unmodified plasmid DNA were then introduced into the knocked-down cells. The knock-down of OGG1, MUTYH, NTH1, and NEIL1 resulted in a significant increase in G:C-->T:A transversions caused by the 8-oxo-Gua:C pair in the shuttle plasmid. The knock-down of MUTYH resulted in a reduction in A:T-->C:G transversions induced by 8-oxo-dGTP and the 8-oxo-Gua:A pair, but the knockdown of OGG1, NTH1, and NEIL1 had no effect on mutagenesis. These results indicate that all of the above DNA glycosylases suppress mutations caused by 8-oxo-Gua:C in DNA. In contrast, it appears that MUTYH enhances A:T- >C:G mutations caused by 8-oxo-dGTP. PMID- 20197242 TI - Secondary aortoenteric fistula treated by right subclavian-bifemoral bypass. PMID- 20197243 TI - Smoking (active and passive), N-acetyltransferase 2, and risk of breast cancer. AB - BACKGROUND: The relationship between smoking and breast cancer remains controversial. The study aim was to assess the relationship of passive and active smoking to breast cancer risk by N-acetyltransferase 2 (NAT2) phenotype, using a comprehensive assessment of both passive and active smoking. METHODS: We undertook a population-based case-control study in Northeastern Ontario, Canada of 347 women diagnosed (2002-2004) with breast cancer and 775 population-based controls. The mailed study package included a questionnaire requesting information about established breast cancer risk factors, passive and active smoking, and a buccal swab for genetic analyses. RESULTS: Among never-active smokers, a long duration of passive smoking was associated with an increased risk of breast cancer (odds ratio (OR) 1.86 (95% confidence interval (95% CI) 1.01 3.44) (test for trend (p=0.07)); that risk was more elevated for NAT2 slow acetylators (OR 2.76, 95% CI 1.16-6.59) (and highest in extremely slow acetylators), but not elevated for NAT2 fast acetylators (OR 1.17, 95% CI 0.42 3.23). Among active smokers more than 20 pack-years of smoking was associated with an OR of 1.34 (95% CI 0.92-1.96); more elevated among NAT2 fast acetylators OR 1.93 (95% CI 1.01-3.69) but not elevated among NAT2 slow acetylators. Women who were NAT2 fast acetylators in the highest quartile for duration of active smoking had an OR of 2.74 (95% CI 1.42-5.27), with a significant test of trend (p=0.005). CONCLUSIONS: These findings suggest that passive and active smoking may be related to breast cancer, and the effect may be differentially modified by NAT2 phenotype. Further research into the genetic modification of a breast cancer smoking relationship may help to reconcile earlier discrepant findings. PMID- 20197245 TI - TSCA reform under way in Congress. PMID- 20197246 TI - Methodologic issues in using land cover data to characterize living environments of geocoded addresses. PMID- 20197247 TI - What can affect AOD-PM(2.5) association? PMID- 20197249 TI - A comparison of vascular effects from complex and individual air pollutants indicates a role for monoxide gases and volatile hydrocarbons. AB - BACKGROUND: Emerging evidence suggests that the systemic vasculature may be a target of inhaled pollutants of vehicular origin. We have identified several murine markers of vascular toxicity that appear sensitive to inhalation exposures to combustion emissions. OBJECTIVE: We sought to examine the relative impact of various pollutant atmospheres and specific individual components on these markers of altered vascular transcription and lipid peroxidation. METHODS: Apolipoprotein E knockout (ApoE(-/-)) mice were exposed to whole combustion emissions (gasoline, diesel, coal, hardwood), biogenically derived secondary organic aerosols (SOAs), or prominent combustion-source gases [nitric oxide (NO), NO(2), carbon monoxide (CO)] for 6 hr/day for 7 days. Aortas were assayed for transcriptional alterations of endothelin-1 (ET-1), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-2 (TIMP-2), and heme oxygenase-1 (HO-1), along with measures of vascular lipid peroxides (LPOs) and gelatinase activity. RESULTS: We noted transcriptional alterations with exposures to gasoline and diesel emissions. Interestingly, ET-1 and MMP-9 transcriptional effects could be recreated by exposure to CO and NO, but not NO(2) or SOAs. Gelatinase activity aligned with levels of volatile hydrocarbons and also monoxide gases. Neither gases nor particles induced vascular LPO despite potent effects from whole vehicular emissions. CONCLUSIONS: In this head-to-head comparison of the effects of several pollutants and pollutant mixtures, we found an important contribution to vascular toxicity from readily bioavailable monoxide gases and possibly from volatile hydrocarbons. These data support a role for traffic-related pollutants in driving cardiopulmonary morbidity and mortality. PMID- 20197250 TI - [Identification of basal-like carcinomas in clinical practice: "triple zero/BRCA1 like" carcinomas]. AB - Basal-like carcinomas represent 10 to 15% of invasive breast carcinomas and have been identified from gene expression studies. Morphologically, these tumors are undifferentiated histopronostic grade 3 carcinomas, identified in clinical practice according to their immunophenotype "triple zero" (estrogen, progesterone and ERBB2 negative) associated with the high molecular weight cytokeratins 5/6/14 and/or EGFR expression. At the molecular level, these tumors harbour nearly 100% P53 mutations, a high rate of PTEN mutations with an AKT pathway's activation and numerous chromosomal alterations such as gains and losses. They share a high degree of similarity at the morphological, phenotypical and molecular level with BRCA1 tumors that justify the proposal of a different name such as "triple zero/BRCA1 like" carcinomas for sporadic basal-like carcinomas. Indeed, the current "basal-like" name could suggest a myoepithelial cellular origin of such lesions. Furthermore, tumors with such a basal-like immunophenotype constitute a heterogeneous group of tumors encompassing good prognosis tumors such as adenoid cystic and juvenile secretory carcinomas. There is an urgent need for more specific therapies for basal-like/triple zero/BRCA1-like tumors. Therapeutic progresses rely on a better understanding of the molecular alterations that occur in these tumors and the BRCA1 tumors. Indeed, recent clinical trials with PARP inhibitors for basal-like/BRCA1 like tumors should improve the prognosis of these patients and are a direct benefit of a better understanding of the molecular biology of these tumors. PMID- 20197251 TI - Emergency departments are underutilized sites for suicide prevention. PMID- 20197252 TI - Current practices of suicide risk management protocols in research. AB - BACKGROUND: Participant safety is an important concern in mental-health-oriented research. Investigators conducting studies in the United States that include potentially suicidal individuals are often required to develop written suicide risk management (SRM) protocols. But little is known about these protocols. It is possible that such protocols could serve as templates for suicide risk management in clinical settings. AIMS: To elucidate common (best) practices from mental health intervention researchers. METHODS: We conducted a systematic descriptive analysis of written SRM protocols. A convenience sample of studies funded by the United States' National Institute of Mental Health in 2005 were scanned to discover projects in which investigators were likely to identify and take responsibility for suicide risk in their participant pool. Qualitative methodology was used to create a checklist of tasks perceived to be operationally significant for insuring the safety of suicidal participants. The checklist was applied to all protocols to determine the variability of patient safety tasks across protocols. RESULTS: We identified 45 candidate studies, whereof 38 investigators were contacted, resulting in the review of 21 SRM protocols. Three main categories emerged: overview, entry/exit, and process. Overall, 19 specific tasks were identified. Task frequency varied from 7% to 95% across protocols. CONCLUSIONS: The SRM checklist provides a framework for comparing the content of SRM protocols. This checklist may assist in developing SRM protocols in a wide range of settings. Developing guidelines and standard methodologies is an important step to further development of suicide prevention strategies. More research is necessary to determine the impact of SRM protocols on participant safety. PMID- 20197253 TI - Factors associated with the history of attempted suicide. AB - BACKGROUND: The present study examines a population of criminal justice clients for suspected substance-related problems. AIMS: It aims to identify variables associated with a history of suicide attempt (SA). METHOD: 6,836 clients were interviewed with the Addiction Severity Index (ASI). Attempters were compared to nonattempters regarding substance use, medical/psychiatric status, family history, and social relationships in a stepwise forward logistic regression. RESULTS: Attempters (21%) were more likely to report binge drinking, intake of illicit drugs, injection of drugs, physical and mental illness, problematic family history, and history of being abused. After logistic regression, SA was independently associated with older age, female gender, binge drinking, delirium tremens, injection, overdose, medical problems, psychiatric symptoms, family history of alcohol or psychiatric problems, and sexual, physical, and emotional abuse. The psychiatric and family/social domains (including being abused) most strongly separated attempters from nonattempters. CONCLUSIONS: Family background factors, psychiatric symptoms, severity of substance use, and sexual, physical, and emotional abuse appear to be factors associated with SA among criminal justice clients. PMID- 20197254 TI - Attitudes toward suicide in the adolescent population. AB - BACKGROUND: Only few studies have so far confirmed the clear connection of attitudes toward suicide with prevalence of suicidal behavior, and there are several contradictory findings on the balance of this relationship. Slovenia has long had a very high suicide rate, including in the population of adolescents. AIMS: To examine attitudes of Slovene adolescents toward suicide and their connection to different suicide risk factors. METHODS: A questionnaire on attitudes toward suicide was given to 423 high school students from three regions based on the different regional suicide rates. RESULTS: The results proved our expectation of girls having more permissive attitudes toward suicide than boys. Also, a permissive attitude was positively associated with the majority of suicide risk factors. CONCLUSIONS: In the light of certain limitations of the study we discuss the implications of the main finding, namely, that permissive attitudes toward suicide are more likely a risk than a safety factor for suicidal behavior. PMID- 20197255 TI - Prevalence of suicidal ideation in Sri Lanka. AB - BACKGROUND: Suicidal ideation can often lead to suicide attempts and completed suicide. Studies have shown that Sri Lanka has one of the highest rates of suicide in the world but so far no studies have looked at prevalence of suicidal ideation in a general population in Sri Lanka. AIMS: We wanted to determine the prevalence of suicidal ideation by randomly selecting six Divisional Secretariats (Dss) out of 17 in one district. This district is known to have higher than national average rates of suicide. METHODS: 808 participants were interviewed using Sinhala versions of GHQ-30 and Beck's Scale for Suicidal Ideation. Of these, 387 (48%) were males, and 421 (52%) were female. RESULTS: On Beck's Scale for Suicidal Ideation, 29 individuals (4%) had active suicidal ideation and 23 (3%) had passive suicidal ideation. The active suicidal ideators were young, physically ill and had higher levels of helplessness and hopelessness. CONCLUSIONS: The prevalence of suicidal ideation in Sri Lanka is lower than reported from the West and yet suicide rates are higher. Further work must explore cultural and religious factors. PMID- 20197256 TI - Suicide among young Middle Eastern Muslim females. AB - BACKGROUND: Recent epidemiological studies highlight that within Muslim-dominated Middle Eastern countries suicide rates are high or are increasing among young females. This paper discusses the most important reasons behind this trend. METHODS: The literature review started using the PubMed (http://www.ncbi.nlm.nih.gov) search engine, applying four keywords: suicide, young females, Middle East, and Muslim. The search strategy was complemented by hand-searching selected journals or by looking at the reference list of the retrieved papers. RESULTS: All retrieved papers confirm a higher rate of suicide or attempted suicide among young Muslim females in the Middle East. Furthermore, the method chosen for suicide, psychiatric disorders, marriage, and masculine role are among the most important interrelated reasons that increase the likelihood of a young female being a victim of suicide. CONCLUSIONS: Higher suicide rates among young Middle Eastern Muslim females must be considered an important issue, and their root causes should be dealt with properly and without delay. PMID- 20197257 TI - Suicide by firearms on the island of Crete: a 9-year record. AB - BACKGROUND: Whereas firearm suicide mortality has been a longstanding public concern worldwide, in Greece no systematic analysis has been reported so far despite the recent evidence of a rising rate of gun ownership. AIMS: To estimate the proportion of firearm suicides on the island of Crete, Southern Greece, well known for its widespread gun ownership; to describe the victims' sociodemographic profile and firearm-related suicide variables; and to assess the severity of suicidal intention in the group. METHODS: Records of suicides between 1999 and 2007 were reviewed and information was extracted into a computerized database. A rating of the circumstances section of the Beck's Suicide Intent Scale (SIS) for each case was also performed. RESULTS: The firearm suicide rate was 1.3 per 100,000, with males constituting the vast majority. These men were more likely to be less than 55 years of age, to have lived in the western part of the island, to have some degree of planning prior to the suicidal act, and to have used a shotgun, but less likely to have left a note. CONCLUSIONS: As an important first step toward implementing preventive initiatives the authors stress the need for a thorough look at the sociocultural factors associated with firearms in the region. PMID- 20197258 TI - Hallucinations, pseudohallucinations, and severity of suicidal ideation among emergency psychiatry patients. AB - AIMS: This study investigated relative relationships between auditory hallucinations and nonpsychotic hallucinations (pseudohallucinations), and suicidal risk. METHODS: A sample of 206 consecutive patients seen in an emergency psychiatric service was evaluated for the presence and intensity of hallucinatory experiences (the hallucination item of the Positive and Negative Symptoms Scale), suicidal intensity (the suicide item of the Montgomery Asberg Depression Rating Scale), and cumulative suicide risk (the total number of risk factors). RESULTS: Individuals with nonpsychotic hallucinations experienced greater intensity of suicidal ideation versus subjects with no hallucinations or subjects with psychotic hallucinations (p = .0001). CONCLUSIONS: Pseudohallucinosis is associated with higher intensity of suicidal ideation compared with psychotic hallucinations or no hallucinations. PMID- 20197260 TI - The essential oil of turpentine and its major volatile fraction (alpha- and beta pinenes): a review. AB - This paper provides a summary review of the major biological features concerning the essential oil of turpentine, its origin and use in traditional and modern medicine. More precisely, the safety of this volatile fraction to human health, and the medical, biological and environmental effects of the two major compounds of this fraction (alpha- and beta-pinenes) have been discussed. PMID- 20197261 TI - Is the risk of allergic hypersensitivity to fungi increased by indoor exposure to moulds? AB - OBJECTIVES: Moulds are frequently found in the indoor environment of residential houses. An association between domestic mould contamination and respiratory symptoms has been reported, but mould exposure as a risk factor for allergy to moulds is not well documented. The aim of the study was to evaluate the prevalence and associated factors of allergic hypersensitivity to moulds. MATERIALS AND METHODS: A group of 243 participants was examined. Of these 118 lived in dwellings with evident signs of fungal contamination (study group) and 125 in non-contaminated sites (controls). An interview, skin prick tests to common and fungal allergens, evaluation of total serum IgE and specific IgE to moulds, resting spirometry as well as mycological analysis in building were performed for each participant. RESULTS: 19.8% subjects were sensitized to at least one mould allergen. Logistic regression analysis revealed that the history of respiratory and skin symptoms, smoking cigarettes in the past and positive skin prick tests (SPT) to common allergens (dust mite and grass pollens) or the presence of a cat as a pet animal were the significant associated factors of hypersensitivity to moulds. CONCLUSIONS: The association between indoor fungal exposure and the development of fungal allergy was not confirmed in our study. PMID- 20197262 TI - Air pollution and daily emergency department visits for depression. AB - OBJECTIVES: To investigate the potential correlation between ambient air pollution exposure and emergency department (ED) visits for depression. MATERIALS AND METHODS: A hierarchical clusters design was used to study 27 047 ED visits for depression in six cities in Canada. The data used in the analysis contain the dates of visits, daily numbers of diagnosed visits, and daily mean concentrations of air pollutants as well as the meteorological factors. The generalized linear mixed models technique was applied to data analysis. Poisson models were fitted to the clustered counts of ED visits with a single air pollutant, temperature and relative humidity. RESULTS: Statistically significant positive correlations were observed between the number of ED visits for depression and the air concentrations of carbon monoxide (CO), nitrogen dioxide (NO2), sulphur dioxide (SO2) and particulate matter (PM10). The percentage increase in daily ED visits was 15.5% (95% CI: 8.0-23.5) for CO per 0.8 ppm and 20.0% (95% CI: 13.3-27.2) for NO2 per 20.1 ppb, for same day exposure in the warm weather period (April September). For PM10, the largest increase, 7.2% (95% CI: 3.0-11.6) per 19.4 ug/m3, was observed for the cold weather period (October-March). CONCLUSIONS: The results support the hypothesis that ED visits for depressive disorder correlate with ambient air pollution, and that a large majority of this pollution results from combustion of fossil fuels (e.g. in motor vehicles). PMID- 20197263 TI - Awareness of bacterial resistance among physicians, pharmacists and nurses. AB - OBJECTIVE: To assess the level of medical staff awareness of bacterial resistance and characterize the most common resistant bacterial species, the factors contributing to the development of such resistance, and the possible measures to limit the increasing rate of resistance to current antibacterial therapies. METHOD: A questionnaire was administered to 352 health care professionals including physicians, pharmacists and nurses at four central university hospitals in Jordan. RESULTS: Our results indicate that most of the responding physicians and pharmacists considered Pseudomonas aeruginosa and methicilin-resistant Staphylococcus aureus the most frequently encountered resistant bacterial species. However, nurses recognized both methicilin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) as the most prevalent resistant species. Physicians and nurses (50.0% and 61.6%, respectively) reported prolonged hospitalization as a factor likely to contribute to the increased incidence of bacterial resistance. About 58% of pharmacists indicated the use of antibiotics without prescription as a significant reason for the development of bacterial resistance. Most of physicians (61.2%) reported that appropriate infection control is the most important measure to reduce bacterial resistance. Pharmacists (58.1%) recognized better adherence to the infection control guidelines as the most important factor that could reduce the risk of bacterial resistance. CONCLUSION: The findings of this study indicate a varying level of awareness of bacterial resistance among the health care professionals. Thus, serious efforts are still needed to develop and implement strategies to decrease the future risk of bacterial resistance to antibiotics. PMID- 20197264 TI - Return to work after myocardial infarction: a retrospective study. AB - OBJECTIVES: To evaluate the occupational functioning and identify health-related determinants of the continuation of occupational activity in workers with a recent myocardial infarction. MATERIAL AND METHODS: The project was a retrospective study concerning 183 male workers, aged 39-65 years, who had suffered a primary uncomplicated myocardial infarction approximately three years prior to the study. The study group comprised both the persons who returned to work after the incident and those who did not. The subjects' mental health as well as quality of life and occupational functioning were evaluated using NHP scale, Beck Depression Inventory, STAI questionnaire by Spielberger et al., WAI, and own questionnaire "My work". RESULTS: Data analysis revealed that the persons who returned to work after myocardial infarction were characterized by a younger age and a higher level of education, self-rated health and quality of life than the persons who did not resume their occupational activity. The occupationally active individuals showed a varying degree of readaptation to work. In the maladapted group, such disturbances occurred as depression, anxiety and lowered work ability. CONCLUSIONS: The study results indicate that in workers with a recent myocardial infarction, the current procedure for assessment of work ability, which is based solely on the evaluation of physical health, is insufficient and should be supplemented with the assessment of their mental health. The employers should also undertake activities for a better adjustment of working conditions to the abilities of workers who have experienced a cardiac incident. PMID- 20197265 TI - Critical elements of clinical follow-up after hospital discharge for heart failure: insights from the EVEREST trial. AB - AIMS: Hospitalized heart failure (HF) patients are at high risk for death and readmission. We examined the incremental value of data obtained 1 week after HF hospital discharge in predicting mortality and readmission. METHODS AND RESULTS: In the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with tolvaptan, 1528 hospitalized patients (ejection fraction < or =40%) with a physical examination, laboratories, and health status [Kansas City Cardiomyopathy Questionnaire (KCCQ)] assessments 1 week after discharge were included. The ability to predict 1 year cardiovascular rehospitalization and mortality was assessed with Cox models, c-statistics, and the integrated discrimination improvement (IDI). Not using a beta-blocker, rales, pedal oedema, hyponatraemia, lower creatinine clearance, higher brain natriuretic peptide, and worse health status were independent risk factors for rehospitalization and death. The c statistic for the base model (history and medications) was 0.657. The model improved with physical examination, laboratory, and KCCQ results, with IDI increases of 4.9, 7.0, and 3.2%, respectively (P < 0.001 each). The combination of all three offered the greatest incremental gain (c-statistic 0.749; IDI increase 10.8%). CONCLUSION: Physical examination, laboratories, and KCCQ assessed 1 week after discharge offer important prognostic information, suggesting that all are critical components of outpatient evaluation after HF hospitalization. PMID- 20197267 TI - Infantile spinal muscular atrophy with respiratory distress type 1: a case report. AB - The condition, currently known as spinal muscular atrophy with respiratory distress type 1, is an unusual variant of spinal muscular atrophy type 1 that is characterized by early respiratory failure due to diaphragmatic paralysis. The defective gene, the immunoglobulin mu-binding protein 2 (IGHMBP2 gene), of this autosomal recessive disorder is located on chromosome 11q13 and encodes immunoglobulin mu-binding protein 2. The natural history and phenotypic spectrum of the disease are still not clear. The authors present the first genetically proven case of spinal muscular atrophy with respiratory distress type 1 to be reported from Saudi Arabia. The parents are first cousins and the causative gene sequencing revealed mutation in exon 7 reported for the first time in a homozygous form. The clinical scenario of the case is discussed. The findings in the muscle magnetic resonance imaging (MRI) are presented. PMID- 20197266 TI - Prognostic implications of functional mitral regurgitation according to the severity of the underlying chronic heart failure: a long-term outcome study. AB - AIMS: To examine the independent prognostic role of functional mitral regurgitation (FMR) and its impact across the severity of chronic heart failure (CHF) in a large population of outpatients with systolic CHF followed at two multidisciplinary clinics. METHODS AND RESULTS: Echocardiography was performed upon enrolment in 469 CHF patients. Follow-up for death and heart transplant was updated on January 2007. Five-year transplant-free survival was 82.7% in patients with no or Grade I FMR, 64.4% in Grade II, 58.5% in Grade III, and 46.5% in Grade IV (P < 0.0001). There was a strong graded association between FMR and the long term risk of death and heart transplant, which remained significant after multivariable adjustment (P = 0.0003). The association between FMR and events was strong and independent in patients with less severe symptoms and in those at lower overall risk based on a propensity score analysis, while it was not significant in patients with more advanced CHF or in the high-risk subgroup (P < 0.0001 for interactions). CONCLUSION: This study clarifies previous apparently discrepant results by demonstrating that FMR is an independent determinant of death and heart transplantation only in less severe CHF and in patients with a lower risk profile. This finding indicates that FMR plays a major role in the early phase of CHF, suggesting that this should be the focus of strategies attempting to reduce it. PMID- 20197268 TI - Propriospinal myoclonus in a child. AB - A 6-year-old girl was experiencing repetitive involuntary and massive jerks immediately involving limbs and trunk. The first motor events appeared approximately at 1 year old and only 5 months after a back trauma. Myoclonus became progressively more frequent and more violent, causing episodes of falls. Neurological examination showed jerks characterized by upper limb abduction, lower limb abduction, and head-body hyperextension. Apart from these motor events, the neurological examination was normal. The results of vitamin B(12) and folate, antinuclear antibody, anti-DNA, anti-Tiroglobulin, anti-thyroid peroxidase antibody, lupus anticoagulant, anti-cardiolipin antibody, rheumatoid factor, and C3 and C4 were unexceptional. Electroencephalography and brain and spinal magnetic resonance imaging were unremarkable. Electromyographic records with surface electrodes showed that duration of myoclonic jerks was ranging from 100 to 300 ms. We thought she had propriospinal myoclonus because of presence of the spreading through the shoulder, upper limbs, and lower limbs in addition to thoracolumbar paraspinal muscles. PMID- 20197269 TI - Orthostatic heart rate and blood pressure in adolescents: reference ranges. AB - This descriptive population study of 307 public high school students, ages 15 to 17 years, was performed to establish reference ranges for orthostatic changes in heart rate and blood pressure in adolescents, and to identify influential variables. Noninvasive measurements of blood pressure and heart rate were obtained. Reference ranges for orthostatic heart rate change in this population at 2 minutes were -2 to +41 beats per minute and at 5 minutes were -1 to +48 beats per minute. Orthostatic blood pressure changes were within the adult range for 98% of adolescents tested. One-third of participants experienced orthostatic symptoms during testing. In conclusion, this study shows that orthostatic symptoms and large orthostatic heart rate changes occur in adolescents. This suggests that the current orthostatic heart rate criterion aiding the diagnosis of adult orthostatic intolerance syndromes is likely not appropriate for adolescents and should be reevaluated. PMID- 20197270 TI - Childhood-onset CADASIL: clinical, imaging, and neurocognitive features. AB - CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a progressive neurodegenerative condition, associated with mutations in the notch3 gene. Symptoms include migraine with aura, mood disorders, progressive cognitive decline, subcortical ischemic strokes, dementia, and premature death. We present an 8-year-old boy with attention and behavioral difficulties, as well as a family history of the condition. Magnetic resonance imaging revealed subcortical foci of increased T2 hyperintensity, and sequencing of the notch3 gene revealed 1 previously reported mutation and 1 novel sequence variant. Neurocognitive assessment revealed deficits in several aspects of executive functioning and in verbal learning. To our knowledge, this is the youngest reported patient with this condition, and it prompts reconsideration of CADASIL as an adult-onset disease. PMID- 20197271 TI - Hemiatrophy of the spinal cord in a patient with mucopolysaccharidosis type IIIB. AB - The authors describe a girl with mucopolysaccharidosis type IIIB (Sanfilippo disease). She presented with speech delay, macrocephaly, and left lower limb hypoatrophy. Her brain and spinal cord imaging revealed diffuse cystic brain lesions and hemiatrophy of her spinal cord on the left (thoracic levels 11/12). She had marked reduction of her alpha-N-acetylglucosaminidase activity assay consistent with the diagnosis of mucopolysaccharidosis type IIIB. Mutational analysis showed 2 mutations on exon 6 of the alpha-N-acetylglucosaminidase gene, both of which were identified in her parents. At 10 years of age the girl had minor learning difficulties and mild behavioral problems. Her spinal cord hemiatrophy, in association with mucopolysaccharidosis type III, has not previously been described in the literature. PMID- 20197272 TI - Extensive enrichment of N-glycolylneuraminic acid in extracellular sialoglycoproteins abundantly synthesized and secreted by human cancer cells. AB - N-Glycolylneuraminic acid (Neu5Gc) is the second most populous sialic acid (Sia). The only known biosynthetic pathway of Neu5Gc is the hydroxylation of cytidine-5' monophosphate-N-acetylneuraminic acid (CMP-Neu5Ac), catalyzed by CMP-Neu5Ac hydroxylase (CMAH). Neu5Gc is abundantly found in mammals except for human, in which CMAH is inactivated due to mutation in the CMAH gene. Evidence has accumulated to show occurrence of Neu5Gc-containing glycoconjugates in sera of cancer patients, human cancerous tissues and cultured human cell lines. Recently, occurrence of natural antibodies against Neu5Gc was shown in healthy humans and is a serious problem for clinical xenotransplantation and stem cell therapies. Studying human occurrence of Neu5Gc is of importance and interest in a broad area of medical sciences. In this study, using a fluorometric high performance liquid chromatography method, we performed quantitative analyses of Sias both inside and in the external environment of the cell and found that (i) incorporation of Neu5Gc was most prominent in soluble glycoproteins found both in the extracellular space and inside the cell as the major Sia compounds. (ii) Of the total Neu5Gc in the Sia compounds that the cells synthesized, 90% was found in the secreted sialoglycoproteins, whereas for Neu5Ac, 70% was found in the secreted sialoglycoproteins. (iii) The Neu5Gc ratio was higher in the secreted sialoglycoproteins (as high as 40% of total Sias) than in intracellular sialoglycoproteins. (iv) The majority of the secreted sialoglycoproteins was anchored on the culture dishes and solubilized by brief trypsin treatment. Based on these findings, a new idea on the mechanism of accumulation of Neu5Gc in cancer cells was proposed. PMID- 20197273 TI - The importin beta binding domain modulates the avidity of importin beta for the nuclear pore complex. AB - Importin beta mediates active passage of cellular substrates through the nuclear pore complex (NPC). Adaptors such as importin alpha and snurportin associate with importin beta via an importin beta binding (IBB) domain. The intrinsic structural flexibility of importin beta allows its concerted interactions with IBB domains, phenylalanine-glycine nucleoporins, and the GTPase Ran during transport. In this paper, we provide evidence that the nature of the IBB domain modulates the affinity of the import complex for the NPC. In permeabilized cells, importin beta imports a cargo fused to the snurportin IBB (sIBB) with approximately 70% reduced energy requirement as compared with the classical importin alpha IBB. At the molecular level, this is explained by approximately 200-fold reduced affinity of importin beta for Nup62, when bound to the sIBB. Consistently, in vivo, the importin beta.sIBB complex has greatly reduced persistence inside the central channel of the NPC. We propose that by controlling the degree of strain in the tertiary structure of importin beta, the IBB domain modulates the affinity of the import complex for nucleoporins, thus dictating its persistence inside the NPC. PMID- 20197274 TI - Topological location and structural importance of the NBCe1-A residues mutated in proximal renal tubular acidosis. AB - NBCe1-A electrogenically cotransports Na(+) and HCO(3)(-) across the basolateral membrane of renal proximal tubule cells. Eight missense mutations and 3 nonsense mutations in NBCe1-A cause severe proximal renal tubular acidosis (pRTA). In this study, the topologic properties and structural importance of the 8 endogenous residues mutated in pRTA and the in situ topology of NBCe1-A were examined by the substituted cysteine accessibility method. Of the 55 analyzed individually introduced cysteines, 8 were labeled with both membrane permeant (biotin maleimide (BM)) and impermeant (2-((5(6)-tetramethylrhodamine)carboxylamino)ethyl methanethiosulfonate (MTS-TAMRA)) sulfhydryl reagents, 4 with only BM, and 3 with only MTS-TAMRA. The location of the labeled and unlabeled introduced cysteines clearly indicates that the transmembrane region of NBCe1-A contains 14 transmembrane segments (TMs). In this in situ based NBCe1-A topology, residues mutated in pRTA (pRTA residues) are assigned as: Ser(427), TM1; Thr(485) and Gly(486), TM3; Arg(510) and Leu(522), TM4; Ala(799), TM10; and Arg(881), TM12. Substitution of pRTA residues with cysteines impaired the membrane trafficking of R510C and R881C, the remaining membrane-processed constructs had various impaired transport function. Surprisingly, none of the membrane-processed constructs was accessible to labeling with BM and MTS-TAMRA, nor were they functionally sensitive to the inhibition by (2-aminoethyl)methanethiosulfonate. Functional analysis of Thr(485) with different amino acid substitutions indicated it resides in a unique region important for NBCe1-A function. Our findings demonstrate that the pRTA residues in NBCe1-A are buried in the protein complex/lipid bilayer where they perform important structural roles. PMID- 20197275 TI - Conformational changes of the HIV-1 envelope protein during membrane fusion are inhibited by the replacement of its membrane-spanning domain. AB - To help understand the dynamic nature of membrane fusion induced by the human immunodeficiency virus-1 (HIV-1) envelope protein, we developed a new cell-based real-time assay system employing a pair of novel reporter proteins. The reporter proteins consist of a pair of split Renilla luciferase (spRL) fused to split green fluorescent protein (spGFP). The spGFP modules were chosen not only to compensate weak self-association of spRL but also to provide visual reporter signals during membrane fusion. Use of this reporter together with a membrane permeable substrate for Renilla luciferase achieved a simple real-time monitoring of membrane fusion using live cells. We analyzed the HIV-1 envelope mutants whose membrane-spanning domains were replaced with that of glycophorin A or vesicular stomatitis virus G-protein. These mutants showed a slower kinetics of membrane fusion. The analysis of membrane fusion in the presence of fusion inhibitors, soluble CD4 and C34, revealed that these replacements prolonged the period during which the mutants were sensitive to the inhibitors, as compared with the wild type. These results suggest that the mutations within the membrane-spanning domains exerted an allosteric effect on the HIV-1 envelope protein, probably affecting the receptor-induced conformational changes of the ectodomain of the protein. PMID- 20197276 TI - Low density lipoprotein receptor-related protein (LRP1) regulates Rac1 and RhoA reciprocally to control Schwann cell adhesion and migration. AB - LDL receptor-related protein (LRP1) is expressed by Schwann cells in vivo mainly after injury to the peripheral nervous system (PNS). Schwann cells in primary culture, which provide a model of Schwann cells in the injured PNS, also express abundant LRP1. Herein, we show that LRP1 gene-silencing or treatment with receptor-associated protein (RAP) promotes Schwann cell adhesion and inhibits cell migration on fibronectin. LRP1 gene-silencing also resulted in the formation of prominent focal adhesions and actin stress fibers. These changes, which were induced by loss of LRP1 expression or activity, were explained mechanistically by an increase in activated RhoA, coupled with a decrease in activated Rac1. Known LRP1 ligands, including matrix metalloprotease-9, tissue-type plasminogen activator, and alpha(2)-macroglobulin activated Rac1 in LRP1-expressing Schwann cells. An inhibitor of Rac1 activation promoted Schwann cell adhesion. Conversely, in cells in which LRP1 was silenced, a Rho kinase inhibitor promoted migration and inhibited adhesion. These results demonstrate that direct binding of ligands to LRP1 controls activation of small Rho family GTPases. The effects of LRP1 gene-silencing and RAP implicate autocrine pathways involving endogenously produced LRP1 ligands. Regulation of Schwann cell migration by LRP1 may be important in PNS injury. PMID- 20197277 TI - Deficiency of suppressor enhancer Lin12 1 like (SEL1L) in mice leads to systemic endoplasmic reticulum stress and embryonic lethality. AB - Stress in the endoplasmic reticulum (ER) plays an important causal role in the pathogenesis of several chronic diseases such as Alzheimer, Parkinson, and diabetes mellitus. Insight into the genetic determinants responsible for ER homeostasis will greatly facilitate the development of therapeutic strategies for the treatment of these debilitating diseases. Suppressor enhancer Lin12 1 like (SEL1L) is an ER membrane protein and was thought to be involved in the quality control of secreted proteins. Here we show that the mice homozygous mutant for SEL1L were embryonic lethal. Electron microscopy studies revealed a severely dilated ER in the fetal liver of mutant embryos, indicative of alteration in ER homeostasis. Consistent with this, several ER stress responsive genes were significantly up-regulated in the mutant embryos. Mouse embryonic fibroblast cells deficient in SEL1L exhibited activated unfolded protein response at the basal state, impaired ER-associated protein degradation, and reduced protein secretion. Furthermore, markedly increased apoptosis was observed in the forebrain and dorsal root ganglions of mutant embryos. Taken together, our results demonstrate an essential role for SEL1L in protein quality control during mouse embryonic development. PMID- 20197278 TI - Allosteric communication between cAMP binding sites in the RI subunit of protein kinase A revealed by NMR. AB - The activation of protein kinase A involves the synergistic binding of cAMP to two cAMP binding sites on the inhibitory R subunit, causing release of the C subunit, which subsequently can carry out catalysis. We used NMR to structurally characterize in solution the RIalpha-(98-381) subunit, a construct comprising both cyclic nucleotide binding (CNB) domains, in the presence and absence of cAMP, and map the effects of cAMP binding at single residue resolution. Several conformationally disordered regions in free RIalpha become structured upon cAMP binding, including the interdomain alphaC:A and alphaC':A helices that connect CNB domains A and B and are primary recognition sites for the C subunit. NMR titration experiments with cAMP, B site-selective 2-Cl-8-hexylamino-cAMP, and A site-selective N(6)-monobutyryl-cAMP revealed that cyclic nucleotide binding to either the B or A site affected the interdomain helices. The NMR resonances of this interdomain region exhibited chemical shift changes upon ligand binding to a single site, either site B or A, with additional changes occurring upon binding to both sites. Such distinct, stepwise conformational changes in this region reflect the synergistic interplay between the two sites and may underlie the positive cooperativity of cAMP activation of the kinase. Furthermore, nucleotide binding to the A site also affected residues within the B domain. The present NMR study provides the first structural evidence of unidirectional allosteric communication between the sites. Trp(262), which lines the CNB A site but resides in the sequence of domain B, is an important structural determinant for intersite communication. PMID- 20197279 TI - Novel components of an active mitochondrial K(+)/H(+) exchange. AB - Defects of the mitochondrial K(+)/H(+) exchanger (KHE) result in increased matrix K(+) content, swelling, and autophagic decay of the organelle. We have previously identified the yeast Mdm38 and its human homologue LETM1, the candidate gene for seizures in Wolf-Hirschhorn syndrome, as essential components of the KHE. In a genome-wide screen for multicopy suppressors of the pet(-) (reduced growth on nonfermentable substrate) phenotype of mdm38Delta mutants, we now characterized the mitochondrial carriers PIC2 and MRS3 as moderate suppressors and MRS7 and YDL183c as strong suppressors. Like Mdm38p, Mrs7p and Ydl183cp are mitochondrial inner membrane proteins and constituents of approximately 500-kDa protein complexes. Triple mutant strains (mdm38Delta mrs7Delta ydl183cDelta) exhibit a remarkably stronger pet(-) phenotype than mdm38Delta and a general growth reduction. They totally lack KHE activity, show a dramatic drop of mitochondrial membrane potential, and heavy fragmentation of mitochondria and vacuoles. Nigericin, an ionophore with KHE activity, fully restores growth of the triple mutant, indicating that loss of KHE activity is the underlying cause of its phenotype. Mdm38p or overexpression of Mrs7p, Ydl183cp, or LETM1 in the triple mutant rescues growth and KHE activity. A LETM1 human homologue, HCCR-1/LETMD1, described as an oncogene, partially suppresses the yeast triple mutant phenotype. Based on these results, we propose that Ydl183p and the Mdm38p homologues Mrs7p, LETM1, and HCCR-1 are involved in the formation of an active KHE system. PMID- 20197280 TI - Agonist-selective dynamic compartmentalization of human Mu opioid receptor as revealed by resolutive FRAP analysis. AB - Techniques for analyzing the membrane diffusion of molecules are the most promising methods for investigating the compartmentalization of G-protein-coupled receptors, particularly as relevant to receptor signaling processes. Here, we report fluorescence recovery after photobleaching (FRAP) measurements performed at variable spot radius for human mu opioid (hMOP) receptors on SH-SY5Y neuroblastoma cells in the presence of ligands. Although an antagonist did not affect the behavior of the receptors compared with the basal state, two different agonists, DAMGO and morphine, caused markedly different changes to receptor diffusion. Like receptors in the absence of ligand, receptors bound to morphine exhibited diffusion confined to joined semipermeable domains, but with smaller domain size and diffusion coefficient. This effect was inhibited by pertussis toxin, strongly suggesting that this dynamic behavior is associated with early steps of signaling. In the presence of DAMGO, half of the receptors displayed free long-range diffusion and the other half were confined to smaller isolated domains. Hypertonic sucrose buffer suppressed this effect, which we attribute to receptor entry into clathrin-coated pits. It is likely that the observation of distinct receptor dynamics in the presence of DAMGO and morphine involves the agonist-selective phosphorylation of the receptor. PMID- 20197282 TI - The implantable loop recorder in older patients with syncope: is sooner better? PMID- 20197281 TI - Engineered interfaces of an AAA+ ATPase reveal a new nucleotide-dependent coordination mechanism. AB - Homohexameric ring AAA(+) ATPases are found in all kingdoms of life and are involved in all cellular processes. To accommodate the large spectrum of substrates, the conserved AAA(+) core has become specialized through the insertion of specific substrate-binding motifs. Given their critical roles in cellular function, understanding the nucleotide-driven mechanisms of action is of wide importance. For one type of member AAA(+) protein (phage shock protein F, PspF), we identified and established the functional significance of strategically placed arginine and glutamate residues that form interacting pairs in response to nucleotide binding. We show that these interactions are critical for "cis" and "trans" subunit communication, which support coordination between subunits for nucleotide-dependent substrate remodeling. Using an allele-specific suppression approach for ATPase and substrate remodeling, we demonstrate that the targeted residues directly interact and are unlikely to make any other pairwise critical interactions. We then propose a mechanistic rationale by which the nucleotide bound state of adjacent subunits can be sensed without direct involvement of R finger residues. As the structural AAA(+) core is conserved, we propose that the functional networks established here could serve as a template to identify similar residue pairs in other AAA(+) proteins. PMID- 20197283 TI - Blood rheology and cognition in the Edinburgh Type 2 Diabetes Study. AB - BACKGROUND: the association between the rheological factors haematocrit and plasma viscosity and cognitive ability has not been extensively studied. It is possible that blood viscosity affects cerebral blood flow and cognitive function. This study tested the contemporaneous associations between these two markers of rheology and cognitive ability and estimated lifetime cognitive change in an elderly population with type 2 diabetes. METHODS: a cross-sectional cohort of 1,066 men and women with type 2 diabetes (Edinburgh Type 2 Diabetes Study) was used for the analysis. Plasma viscosity and haematocrit were measured in venous blood samples at baseline. Contemporaneously, a battery of seven cognitive tests was administered to all participants. These data were used to derive a general intelligence factor, g. A vocabulary-based test was also administered as an estimate of prior intelligence, and adjustment for scores on this test was used to estimate lifetime cognitive decline. RESULTS: increased plasma viscosity was associated with poorer age- and sex-adjusted scores on the cognitive domains of processing speed, mental flexibility and general intelligence, g, with standardised regression coefficients -0.092 (P < 0.01), -0.077 (P < 0.05) and 0.093 (P < 0.01), respectively. After adjusting for vocabulary, education level, cardiovascular dysfunction, duration of diabetes and glycaemic control, the associations remained significant for the measure of processing speed and g, with standardised regression coefficients -0.059 (P < 0.05) and -0.051 (P < 0.05). Increased haematocrit was significantly associated with better age- and sex adjusted cognitive scores on the majority of the tests and with g. However, significant associations were not retained after adjustments for additional covariates. CONCLUSIONS: increased plasma viscosity is associated with decreased cognitive ability and increased estimated lifetime cognitive decline. The relationship between haematocrit and cognitive ability requires further study. PMID- 20197284 TI - Low-GDP fluid (Gambrosol trio) attenuates decline of residual renal function in PD patients: a prospective randomized study. AB - BACKGROUND: Residual renal function (RRF) impacts outcome of peritoneal dialysis (PD) patients. Some PD fluids contain glucose degradation products (GDPs) which have been shown to affect cell systems and tissues. They may also act as precursors of advanced glycosylation endproducts (AGEs) both locally and systemically, potentially inflicting damage to the kidney as the major organ for AGE elimination. We conducted a clinical study in PD patients to see if the content of GDP in the PD fluid has any influence on the decline of the residual renal function. METHODS: In a multicentre approach, 80 patients (GFF > or = 3 mL/min/1.732 or creatinine clearance > or =3 mL/min/1.73 m(2)) were randomized to treatment with a PD fluid containing low levels of GDP or standard PD fluid for 18 months. RRF was assessed every 4-6 weeks. Fluid balance, mesothelial cell mass marker CA125, peritoneal membrane characteristics, C-reactive protein (CRP), total protein, albumin, electrolytes and phosphate were measured repeatedly. RESULTS: Data from 69 patients revealed a significant difference in monthly RRF change: -1.5% (95% CI = -3.07% to +0.03%) with low GDP (43 patients) vs -4.3% (95% CI = -6.8% to -2.06%) with standard fluids (26 patients) (P = 0.0437), independent of angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker medication. Twenty-four-hour urine volume declined more slowly with low-GDP fluid compared to standard fluids (12 vs 38 mL/month, P = 0.0241), and monthly change of phosphate level was smaller (+0.013 vs +0.061 mg/dL, P = 0.0381). CONCLUSIONS: Our prospective study demonstrates for the first time a significant benefit concerning preservation of RRF and urine volume of using a PD fluid with low GDP levels. These findings suggest that GDPs might affect patient outcome related to RRF. PMID- 20197285 TI - Impact of drought on the temporal dynamics of wood formation in Pinus sylvestris. AB - We determined the temporal dynamics of cambial activity and xylem cell differentiation of Scots pine (Pinus sylvestris L.) within a dry inner Alpine valley (750 m a.s.l., Tyrol, Austria), where radial growth is strongly limited by drought in spring. Repeated micro-sampling of the developing tree ring of mature trees was carried out during two contrasting years at two study plots that differ in soil water availability (xeric and dry-mesic sites). In 2007, when air temperature at the beginning of the growing season in April exceeded the long term mean by 6.4 degrees C, cambial cell division started in early April at both study plots. A delayed onset of cambial activity of c. 2 weeks was found in 2008, when average climate conditions prevailed in spring, indicating that resumption of cambial cell division after winter dormancy is temperature controlled. Cambial cell division consistently ended about the end of June/early July in both study years. Radial enlargement of tracheids started almost 3 weeks earlier in 2007 compared with 2008 at both study plots. At the xeric site, the maximum rate of tracheid production in 2007 and 2008 was reached in early and mid-May, respectively, and c. 2 weeks later at the dry-mesic site. Since in both study years more favorable growing conditions (i.e., an increase in soil water content) were recorded during summer, we suggest a strong sink competition for carbohydrates to mycorrhizal root and shoot growth. Wood formation stopped c. 4 weeks earlier at the xeric compared with the dry-mesic site in both years, indicating a strong influence of drought stress on cell differentiation. This is supported by radial widths of earlywood cells, which were found to be significantly narrower at the xeric than at the dry-mesic site (P < 0.05). Repeated cellular analyses during the two growing seasons revealed that, although spatial variability in the dynamics and duration of cell differentiation processes in P. sylvestris exposed to drought is strongly influenced by water availability, the onset of cambial activity and cell differentiation is controlled by temperature. PMID- 20197286 TI - Inferring dynamic gene networks under varying conditions for transcriptomic network comparison. AB - MOTIVATION: Elucidating the differences between cellular responses to various biological conditions or external stimuli is an important challenge in systems biology. Many approaches have been developed to reverse engineer a cellular system, called gene network, from time series microarray data in order to understand a transcriptomic response under a condition of interest. Comparative topological analysis has also been applied based on the gene networks inferred independently from each of the multiple time series datasets under varying conditions to find critical differences between these networks. However, these comparisons often lead to misleading results, because each network contains considerable noise due to the limited length of the time series. RESULTS: We propose an integrated approach for inferring multiple gene networks from time series expression data under varying conditions. To the best of our knowledge, our approach is the first reverse-engineering method that is intended for transcriptomic network comparison between varying conditions. Furthermore, we propose a state-of-the-art parameter estimation method, relevance-weighted recursive elastic net, for providing higher precision and recall than existing reverse-engineering methods. We analyze experimental data of MCF-7 human breast cancer cells stimulated by epidermal growth factor or heregulin with several doses and provide novel biological hypotheses through network comparison. AVAILABILITY: The software NETCOMP is available at http://bonsai.ims.u tokyo.ac.jp/ approximately shima/NETCOMP/. PMID- 20197287 TI - Religious beliefs influence neural substrates of self-reflection in Tibetans. AB - Previous transcultural neuroimaging studies have shown that the neural substrates of self-reflection can be shaped by different cultures. There are few studies, however, on the neural activity of self-reflection where religion is viewed as a form of cultural expression. The present study examined the self-processing of two Chinese ethnic groups (Han and Tibetan) to investigate the significant role of religion on the functional anatomy of self-representation. We replicated the previous results in Han participants with the ventral medial prefrontal cortex and left anterior cingulate cortex showing stronger activation in self-processing when compared with other-processing conditions. However, no typical self reference pattern was identified in Tibetan participants on behavioral or neural levels. This could be explained by the minimal subjective sense of 'I-ness' in Tibetan Buddhists. Our findings lend support to the presumed role of culture and religion in shaping the neural substrate of self. PMID- 20197288 TI - Infectious olecranon and patellar bursitis: short-course adjuvant antibiotic therapy is not a risk factor for recurrence in adult hospitalized patients. AB - OBJECTIVES: No evidence-based recommendations exist for the management of infectious bursitis. We examined epidemiology and risk factors for recurrence of septic bursitis. Specifically, we compared outcome in patients receiving bursectomy plus short-course adjuvant antibiotic therapy (7 days). PATIENTS AND METHODS: Retrospective study of adult patients with infectious olecranon and patellar bursitis requiring hospitalization at Geneva University Hospital from January 1996 to March 2009. RESULTS: We identified 343 episodes of infectious bursitis (237 olecranon and 106 patellar). Staphylococcus aureus predominated among the 256 cases with an identifiable pathogen (85%). Three hundred and twelve cases (91%) were treated surgically; 142 (41%) with one-stage bursectomy and closure and 146 with two-stage bursectomy. All received antibiotics for a median duration of 13 days with a median intravenous component of 3 days. Cure was achieved in 293 (85%) episodes. Total duration of antibiotic therapy [odds ratio (OR) 0.9; 95% confidence interval (95% CI) 0.8-1.1] showed no association with cure. In multivariate analysis, only immunosuppression was linked to recurrence (OR 5.6; 95% CI 1.9-18.4). Compared with 14 days of antibiotic treatment (OR 0.9; 95% CI 0.1-10.7) was equivalent, as was the intravenous component (OR 1.1; 95% CI 1.0-1.3). CONCLUSIONS: In severe infectious bursitis requiring hospitalization, adjuvant antibiotic therapy might be limited to 7 days in non-immunosuppressed patients. PMID- 20197289 TI - Genetic variations in EGF and EGFR and glioblastoma outcome. AB - Few prognostic factors have been associated with glioblastoma survival. We analyzed a complete tagging of the epidermal growth factor (EGF) and EGF receptor (EGFR) gene polymorphisms as potential prognostic factors. Thirty tagging single nucleotide polymorphisms (SNPs) in EGF and 89 tagging SNPs in EGFR were analyzed for association with survival in 176 glioblastoma cases. Validation analyses were performed for 4 SNPs in a set of 638 glioblastoma patients recruited at The University of Texas M. D. Anderson Cancer Center (MDACC). Three hundred and seventy-four glioblastoma patients aged 50 years or older at diagnosis were subanalyzed to enrich for de novo arising glioblastoma. We found 7 SNPs in haplotype 4 in EGF that were associated with prognosis in glioblastoma patients. In EGFR, 4 of 89 SNPs were significantly associated with prognosis but judged as false positives. Four of the significantly associated EGF polymorphisms in haplotype block 4 were validated in a set from MDACC; however, none of the associations were clearly replicated. rs379644 had a hazard ratio (HR) of 1.19 (0.94-1.51) in the whole population with 18.6 months survival in the risk genotype compared with 24.5 in the reference category. As the median age differed slightly between the 2 study sets, the MDACC cases aged 50 or older at diagnosis were analyzed separately (rs379644, HR 1.32 [0.99-1.78]), which is marginally significant and partially validates our findings. This study is, to our knowledge, the first to perform a comprehensive tagging of the EGF and EGFR genes, and the data give some support that EGF polymorphisms might be associated with poor prognosis. Further confirmation in independent data sets of prospective studies is necessary to establish EGF as prognostic risk factor. PMID- 20197290 TI - Autologous growth factor injections in chronic tendinopathy: a systematic review. AB - Chronic degenerative tendinopathies are frequent and difficult to treat. Tendon healing and regeneration may be improved by injecting autologous growth factors obtained from the patient's blood. Autologous growth factors can be injected with autologous whole blood or platelet-rich plasma (PRP). Electronic databases were searched for prospective clinical trials on treatment with autologous growth factors of patients with chronic tendinopathy. Chronic tendinopathy in this study included wrist extensors, flexors, plantar fasciopathy and patellar tendinopathy. Studies examining the treatment of other tendinopathies were not identified. The Physiotherapy Evidence Database score was used to examine the methodological quality of the assessment, and a qualitative analysis was performed with the levels of evidence. There are many proposed treatment options for chronic tendinopathy. Treatments in the form of injections with autologous whole blood or PRP are increasingly used in clinical practice. There are high expectations of these regenerative injections, and there is a clear need for effective conservative therapies. All studies showed that injections of autologous growth factors (whole blood and PRP) in patients with chronic tendinopathy had a significant impact on improving pain and/or function over time. However, only three studies using autologous whole blood had a high methodological quality assessment, and none of them showed any benefit of an autologous growth factor injection when compared with a control group. At present, there is strong evidence that the use of injections with autologous whole blood should not be recommended. There were no high-quality studies found on PRP treatment. There is limited evidence to support the use of injections with PRP in the management of chronic tendinopathy. There is growing interest in the working mechanisms of autologous growth factors. The amount and mixture of growth factors produced using different cell separating systems are largely unknown and it is also uncertain whether platelet activation prior to injection is necessary. These variables should be taken into account when starting clinical studies. A good experimental model for studying tendinopathy would be helpful for basic research. Future clinical studies using a proper control group, randomization, blinding and validated disease-specific outcome measures for pain and function are needed. PMID- 20197291 TI - Spikelet structure and development in Cyperoideae (Cyperaceae): a monopodial general model based on ontogenetic evidence. AB - BACKGROUND AND AIMS: In Cyperoideae, one of the two subfamilies in Cyperaceae, unresolved homology questions about spikelets remained. This was particularly the case in taxa with distichously organized spikelets and in Cariceae, a tribe with complex compound inflorescences comprising male (co)florescences and deciduous female single-flowered lateral spikelets. Using ontogenetic techniques, a wide range of taxa were investigated, including some controversial ones, in order to find morphological arguments to understand the nature of the spikelet in Cyperoideae. This paper presents a review of both new ontogenetic data and current knowledge, discussing a cyperoid, general, monopodial spikelet model. METHODS: Scanning electron microscopy and light microscopy were used to examine spikelets of 106 species from 33 cyperoid genera. RESULTS: Ontogenetic data presented allow a consistent cyperoid spikelet model to be defined. Scanning and light microscopic images in controversial taxa such as Schoenus nigricans, Cariceae and Cypereae are interpreted accordingly. CONCLUSIONS: Spikelets in all species studied consist of an indeterminate rachilla, and one to many spirally to distichously arranged glumes, each subtending a flower or empty. Lateral spikelets are subtended by a bract and have a spikelet prophyll. In distichously organized spikelets, combined concaulescence of the flowers and epicaulescence (a newly defined metatopic displacement) of the glumes has caused interpretational controversy in the past. In Cariceae, the male (co)florescences are terminal spikelets. Female single-flowered spikelets are positioned proximally on the rachis. To explain both this and the secondary spikelets in some Cypereae, the existence of an ontogenetic switch determining the development of a primordium into flower, or lateral axis is postulated. PMID- 20197292 TI - The spatial expression and regulation of transcription factors IDEF1 and IDEF2. AB - BACKGROUND AND AIMS: Under conditions of low iron availability, rice plants induce genes involved in iron uptake and utilization. The iron deficiency responsive cis-acting element binding factors 1 and 2 (IDEF1 and IDEF2) regulate transcriptional response to iron deficiency in rice roots. Clarification of the functions of IDEF1 and IDEF2 could uncover the gene regulation mechanism. METHODS: Spatial patterns of IDEF1 and IDEF2 expression were analysed by histochemical staining of IDEF1 and IDEF2 promoter-GUS transgenic rice lines. Expression patterns of the target genes of IDEF1 and IDEF2 were analysed using transformants with induced or repressed expression of IDEF1 or IDEF2 grown in iron-rich or in iron-deficient solutions for 1 d. KEY RESULTS: IDEF1 and IDEF2 were highly expressed in the basal parts of the lateral roots and vascular bundles. IDEF1 and IDEF2 expression was dominant in leaf mesophyll and vascular cells, respectively. These expression patterns were similar under both iron deficient and iron-sufficient conditions. IDEF1 was strongly expressed in pollen, ovaries, the aleurone layer and embryo. IDEF2 was expressed in pollen, ovaries and the dorsal vascular region of the endosperm. During seed germination, IDEF1 and IDEF2 were expressed in the endosperm and embryo. Expression of IDEF1 target genes was regulated in iron-rich roots similar to early iron-deficiency stages. In addition, the expression patterns of IDEF2 target genes were similar between iron-rich conditions and early or subsequent iron deficiency. CONCLUSIONS: IDEF1 and IDEF2 are constitutively expressed during both vegetative and reproductive stages. The spatial expression patterns of IDEF1 and IDEF2 overlap with their target genes in restricted cell types, but not in all cells. The spatial expression patterns and gene regulation of IDEF1 and IDEF2 in roots are generally conserved under conditions of iron sufficiency and deficiency, suggesting complicated interactions with unknown factors for sensing and transmitting iron deficiency signals. PMID- 20197293 TI - Deriving reliable change statistics from test-retest normative data: comparison of models and mathematical expressions. AB - The use of reliable change (RC) statistics to determine whether an individual has significantly improved or deteriorated on retesting is growing rapidly in clinical neuropsychology. This paper demonstrates how with only basic test-retest data and a series of simple expressions, the clinician/researcher can implement the majority of contemporary RC model(s). Though sharing a fundamental structure, RC models vary in how they derive predicted retest scores and standard error terms. Published test-retest normative data and a simple case study are presented to demonstrate how to calculate several well-known RC scores. The paper highlights the circumstances under which models will diverge in the estimation of RC. Most importantly variations in individual's performance relative to controls at initial testing, practice effects, inequality of control variability from test to retest, and degree of reliability will see systematic and predictable disagreement among models. More generally, the limitations and opportunities of RC methodology were discussed. Although a consensus on preferred model continues to be debated, the comparison of RC models in clinical samples is encouraged. PMID- 20197294 TI - The oral trail making test: effects of age and concurrent validity. AB - The oral version of the Trail Making Test (OTMT) is a neuropsychological measure that provides an assessment of sequential set-shifting without the motor and visual demands of the written TMT (WTMT). Originally purposed to serve as an oral analog of the WTMT, the OTMT provides a means to evaluate patients with physical restrictions. However, formal validity studies and available normative data remain sparse. In a sample of healthy adults (n = 81), a strong correlation was observed between OTMT-B and its written counterpart (r = .62), but the correlations were weak between OTMT-A and either written version of the TMT. OTMT B was significantly correlated with age but not with education or gender, whereas OTMT-A was not significantly correlated with demographic factors. The WTMT to OTMT ratios observed in the current study were generally lower than previously reported and varied across age groups, suggesting that the recommended use of a uniform conversion factor to predict one performance based on the other should be cautiously undertaken. Normative data that have been stratified by age are provided as well as suggestions for using both versions of the TMT in tandem to better elucidate the nature of cognitive deficits and to aid in the localization of cerebral dysfunction. PMID- 20197295 TI - Untreated mild traumatic brain injury in a young adult population. AB - The current study was conducted to determine (a) the demographic and injury characteristics of individuals who did not receive treatment for mild brain injury and (b) the reasons these individuals do not receive or seek treatment. In a large sample of undergraduate students initially surveyed via an on-line questionnaire (n = 1,853), 35% of those who responded to a subsequent survey acknowledged that they had experienced at least one mild traumatic brain injury (TBI) for which they were not treated. Compared with those who were treated for each TBI, those who were untreated were more likely to be men and were less likely to report persisting symptoms 3 months after the injury. There were no differences in demographics or injury characteristics (e.g., length of time unconscious) between groups. Of those with an untreated TBI, the most common reasons for not seeking treatment were that the symptoms resolved quickly and that they were neither bothersome nor disruptive. Findings are discussed in terms of research on recovery from mild TBI. PMID- 20197296 TI - Normative data for the pyramids and palm trees test in the Quebec-French population. AB - Semantic memory tests assess long-term memory for facts, objects, and concepts as well as words and their meaning. Since it holds culturally shared information, the development of normative data adjusted to the cultural and linguistic reality of the target population is of particular importance. The present study aimed to establish normative data for the Pyramids and Palm Trees Test, a commonly used test of semantic memory, in the French-Quebec population. The normative sample consisted of 214 healthy French-speaking adults and elderly persons from various regions of the province of Quebec. The effects of participants' age, gender, and education level on test performance were assessed. Results indicated that participants' level of education and age, but not sex, were found to be significantly associated with performance on this test. Normative data are presented as means and standard deviations. Overall, the present norms are consistent with those of previous studies with Spanish samples. PMID- 20197297 TI - Impairment in occupational functioning and adult ADHD: the predictive utility of executive function (EF) ratings versus EF tests. AB - Attention deficit hyperactivity disorder (ADHD) is associated with deficits in executive functioning (EF). ADHD in adults is also associated with impairments in major life activities, particularly occupational functioning. We investigated the extent to which EF deficits assessed by both tests and self-ratings contributed to the degree of impairment in 11 measures involving self-reported occupational problems, employer reported workplace adjustment, and clinician rated occupational adjustment. Three groups of adults were recruited as a function of their severity of ADHD: ADHD diagnosis (n = 146), clinical controls self referring for ADHD but not diagnosed with it (n = 97), and community controls (n = 109). Groups were combined and regression analyses revealed that self-ratings of EF were significantly predictive of impairments in all 11 measures of occupational adjustment. Although several tests of EF also did so, they contributed substantially less than did the EF ratings, particularly when analyzed jointly with the ratings. We conclude that EF deficits contribute to the impairments in occupational functioning that occur in conjunction with adult ADHD. Ratings of EF in daily life contribute more to such impairments than do EF tests, perhaps because, as we hypothesize, each assesses a different level in the hierarchical organization of EF as a meta-construct. PMID- 20197298 TI - Coexpression network analysis of neural tissue reveals perturbations in developmental processes in schizophrenia. AB - We performed integrated gene coexpression network analysis on two large microarray-based brain gene expression data sets generated from the prefrontal cortex obtained post-mortem from 101 subjects, 47 subjects with schizophrenia and 54 normal control subjects, ranging in age from 19 to 81 years. Twenty-eight modules of coexpressed genes with functional interpretations were detected in both normal subjects and those with schizophrenia. Significant overlap of "case" and "control" module composition was observed, indicating that extensive differences in underlying molecular connectivity are not likely driving pathology in schizophrenia. Modules of coexpressed genes were characterized according to disease association, cell type specificity, and the effects of aging. We find that genes with altered expression in schizophrenia clustered into distinct coexpression networks and that these were associated primarily with neurons. We further identified a robust effect of age on gene expression modules that differentiates normal subjects from those with schizophrenia. In particular, we report that normal age-related decreases in genes related to central nervous system developmental processes, including neurite outgrowth, neuronal differentiation, and dopamine-related cellular signaling, do not occur in subjects with schizophrenia during the aging process. Extrapolating these findings to earlier stages of development supports the concept that schizophrenia pathogenesis begins early in life and is associated with a failure of normal decreases in developmental-related gene expression. These findings provide a novel mechanism for the "developmental" hypothesis of schizophrenia on a molecular level. PMID- 20197300 TI - Adding cocoa to sucrose: the effect on cold pain tolerance. AB - The sweet taste of sucrose acts as an analgesic, whereas the taste of a bitter substance decreases pain tolerance. The present experiment explores the analgesic effect of a complex taste and asks how adding cocoa, a substance often associated with sweet foods but that has a bitter taste, to a sucrose solution affects cold pain tolerance. The 24 male participants were exposed to Cold Pressor Tests (CPTs) while holding 1 of 3 tastants in their mouths: water, sucrose, or sucrose with cocoa added. After each CPT, participants rated pain intensity and tastant qualities. Intraoral sucrose increased the amount of time that men were able to leave their hands in cold water, whereas the cocoa solution did not. Solutions did not differ in pleasantness or sweetness, but the cocoa solution was rated as more bitter. Bitterness ratings of cocoa exceeded the ratings of sucrose (corrected for water) by an average of 16.9% (P = 0.02), which, in turn, produced a 30% reduction in the duration of pain tolerance (P = 0.002). These results suggest that the addition of a bitter substance reduces cues to the nutritive value of sucrose that may drive its analgesic effect. PMID- 20197302 TI - The GH/IGF1 axis and signaling pathways in the muscle and bone: mechanisms underlying age-related skeletal muscle wasting and osteoporosis. AB - The widespread increase in life expectancy is accompanied by an increased prevalence of features of physical frailty. Signs and symptoms may include sarcopenia and osteopenia, reduced exercise capacity, and diminished sense of well-being. The pathogenesis of age-associated sarcopenia and osteopenia is multifactorial, and hormonal decline may be a contributing factor. Aging is associated with a progressive decrease in GH secretion, and more than 30% of elderly people have circulating IGF1 levels below the normal range found in the young. GH acts directly on target tissues, including skeletal muscle and bone among many others, but many effects are mediated indirectly by circulating (liver derived) or locally produced IGF1. Aging is also associated with reduced insulin sensitivity which, in turn, may contribute to the impairment of IGF1 action. Recent experimental evidence suggests that besides the age-dependent decline in GH and IGF1 serum levels, the dysregulation of GH and IGF1 actions due to impairment of the post-receptor signaling machinery may contribute to the loss of muscle mass and osteopenia. This article will focus on the molecular mechanisms of impaired GH and IGF1 signaling and action in aging, and their role in the pathogenesis of sarcopenia and osteoporosis. PMID- 20197299 TI - MicroRNA-137 promoter methylation in oral rinses from patients with squamous cell carcinoma of the head and neck is associated with gender and body mass index. AB - Head and neck cancer represents 3.3% of all new malignancies and 2.0% of cancer deaths in the USA, the majority of which are squamous in origin. The overall 5 year survival is 60% and worsens with increasing stage at diagnosis. Thus, novel biomarkers for early detection of squamous cell carcinoma of the head and neck (SCCHN) are needed. MicroRNA-137 (miR-137) plays a role in cell cycle control and seems to undergo promoter methylation in oral squamous cell carcinoma tissue. The main objectives of this study were to ascertain whether miR-137 promoter methylation is detectable in oral rinse samples, assess its association with SCCHN and identify potential risk factors for its occurrence. Oral rinse samples were collected from 99 SCCHN patients with no prior history of cancer and 99 cancer-free controls, frequency matched on gender; tumor tissue for 64 patients was also tested. Methylation of the miR-137 promoter, assessed using methylation specific polymerase chain reaction, was detected in 21.2% oral rinses from SCCHN patients and 3.0% from controls [odds ratio (OR) = 4.80, 95% confidence interval (CI): 1.23-18.82]. Among cases, promoter methylation of miR-137 was associated with female gender (OR = 5.30, 95% CI: 1.20-23.44) and inversely associated with body mass index (BMI) (OR = 0.88, 95% CI: 0.77-0.99). Promoter methylation of miR 137 appears to be a relatively frequently detected event in oral rinse of SCCHN patients and may have future utility as a biomarker in DNA methylation panels. The observed associations with gender and BMI help to shed light on potential risk factors for an altered methylation state in SCCHN. PMID- 20197303 TI - Generational jeopardy? Parents' marital transitions and the provision of financial transfers to adult children. AB - OBJECTIVES: Transitions into and out of marriage are becoming more commonplace among persons in middle and later life. We assess the extent to which parental marital transitions influence inter vivos financial transfers to adult children at the family level. METHODS: Panel data from 6,017 households with adult children in the 1992-1998 waves of the Health and Retirement Study are analyzed in this study. RESULTS: Net of familial characteristics, those families experiencing a parental marriage were less likely than stably married households to make a financial transfer to an adult child. The effects of divorce or widowhood were modest. Divorce was associated with a slight increase in the probability of providing a transfer. Widowhood was associated with a slight increase in the total amount transferred to children. DISCUSSION: The study adds weight to the growing argument that marital transitions may alter intergenerational exchanges. The results prompt us to further question how broader demographic and marriage patterns will influence relationships between parents and children in aging societies. PMID- 20197304 TI - Which one is true bladder?--a giant urinary bladder diverticulum. PMID- 20197305 TI - Specialized care of overweight children in community health centers. AB - We have developed a new approach to child obesity that supports the delivery of so-called secondary care-referral-based specialized visits-by primary care teams within community health centers. The Healthy Weight Clinic reorganizes care to provide access to a trained team consisting of a pediatric provider, nutritionist, and case manager during dedicated weight management visits. Our model improves obesity care by promoting local specialization and increasing capacity for specialized care; building multidisciplinary teams within primary care; focusing on health behavior change as a critical determinant of chronic disease outcomes; and using health information technology to promote high-quality care. PMID- 20197306 TI - Organ donation by capital prisoners in China: reflections in Confucian ethics. AB - This article discusses the practice and development of organ donation by capital prisoners in China. It analyzes the issue of informed consent regarding organ donation from capital prisoners in light of Confucian ethics and expounds the point that under the influence of Confucianism, China is a country that attaches great importance to the role of the family in practicing informed consent in various areas, the area of organ donation from capital prisoners included. It argues that a proper form of organ donation from capital prisoners can be justified within the Confucian moral context in which the proper interests of capital prisoners and their families, the benefit of organ receptors, and a rightful order of society should all be appropriately considered. From the Confucian perspective, the act of donating organs from a capital prisoner must be decided by both the prisoner and his/her family (i.e., each side should hold a veto power), whereas such donation, in the proper circumstance protected by a rightful procedure, should be appreciated as a morally praiseworthy act of the prisoner who is willing to make the final effort to repent and correct his/her evil conduct and to leave something good to the world. PMID- 20197307 TI - Effect of oncostatin M on uridine diphosphate-5'-glucuronosyltransferase 1A1 through cross talk with constitutive androstane receptor. AB - Hyperbilirubinemia remains a common condition in neonates. The constitutive androstane receptor (CAR) is an orphan nuclear receptor that has been shown to participate in the activation of the uridine diphosphate-5' glucuronosyltransferase 1A1 (UGT1A1) gene, which plays an important role in bilirubin clearance. Oncostatin M (OSM), a member of the IL-6 family, is involved in the maturation of fetal hepatocytes. We have demonstrated that low OSM levels are a potential indicator of neonatal jaundice and the need for phototherapy. In this study we examined the effects of OSM on CAR-mediated signaling to investigate its potential role in neonatal jaundice via the CAR-UGT1A1 pathway. We observed that OSM positively augmented the CAR and UGT1A1 expressions and CAR mediated signaling in vivo and in vitro, through cross talk between the nuclear CAR receptor and the plasma membrane OSM receptor, via the MAPK cascade. These data suggest that OSM might play a role in bilirubin metabolism via the CAR UGT1A1 pathway. PMID- 20197308 TI - Proinsulin C-peptide antagonizes the profibrotic effects of TGF-beta1 via up regulation of retinoic acid and HGF-related signaling pathways. AB - Novel signaling roles for C-peptide have recently been discovered with evidence that it can ameliorate complications of type 1 diabetes. Here we sought to identify new pathways regulated by C-peptide of relevance to the pathophysiology of diabetic nephropathy. Microarray analysis was performed to identify genes regulated by either C-peptide and/or TGF-beta1 in a human proximal tubular cell line, HK-2. Expression of retinoic acid receptor beta (RARbeta), hepatocyte growth factor (HGF), cellular retinoic acid-binding protein II (CRABPII), vimentin, E-cadherin, Snail, and beta-catenin was assessed by immunoblotting. The cellular localization of vimentin and beta-catenin was determined by immunocytochemistry. Changes in cell morphology were assessed by phase contrast microscopy. Gene expression profiling demonstrated differential expression of 953 and 1458 genes after C-peptide exposure for 18 h or 48 h, respectively. From these, members of the antifibrotic retinoic acid (RA)- and HGF-signaling pathways were selected. Immunoblotting demonstrated that C-peptide increased RARbeta, CRABPII, and HGF. We confirmed a role for RA in reversal of TGF-beta1-induced changes associated with epithelial-mesenchymal transition, including expression changes in Snail, E-cadherin, vimetin, and redistribution of beta-catenin. Importantly, these TGF-beta1-induced changes were inhibited by C-peptide. Further, effects of TGF-beta1 on Snail and E-cadherin expression were blocked by HGF, and inhibitory effects of C-peptide were removed by blockade of HGF activity. This study identifies a novel role for HGF as an effector of C-peptide, possibly via an RA-signaling pathway, highlighting C-peptide as a potential therapy for diabetic nephropathy. PMID- 20197309 TI - The transcription factor ATF4 promotes skeletal myofiber atrophy during fasting. AB - Prolonged fasting alters skeletal muscle gene expression in a manner that promotes myofiber atrophy, but the underlying mechanisms are not fully understood. Here, we examined the potential role of activating transcription factor 4 (ATF4), a transcription factor with an evolutionarily ancient role in the cellular response to starvation. In mouse skeletal muscle, fasting increases the level of ATF4 mRNA. To determine whether increased ATF4 expression was required for myofiber atrophy, we reduced ATF4 expression with an inhibitory RNA targeting ATF4 and found that it reduced myofiber atrophy during fasting. Likewise, reducing the fasting level of ATF4 mRNA with a phosphorylation resistant form of eukaryotic initiation factor 2alpha decreased myofiber atrophy. To determine whether ATF4 was sufficient to reduce myofiber size, we overexpressed ATF4 and found that it reduced myofiber size in the absence of fasting. In contrast, a transcriptionally inactive ATF4 construct did not reduce myofiber size, suggesting a requirement for ATF4-mediated transcriptional regulation. To begin to determine the mechanism of ATF4-mediated myofiber atrophy, we compared the effects of fasting and ATF4 overexpression on global skeletal muscle mRNA expression. Interestingly, expression of ATF4 increased a small subset of five fasting-responsive mRNAs, including four of the 15 mRNAs most highly induced by fasting. These five mRNAs encode proteins previously implicated in growth suppression (p21(Cip1/Waf1), GADD45alpha, and PW1/Peg3) or titin-based stress signaling [muscle LIM protein (MLP) and cardiac ankyrin repeat protein (CARP)]. Taken together, these data identify ATF4 as a novel mediator of skeletal myofiber atrophy during starvation. PMID- 20197310 TI - Involvement of estrogen receptor variant ER-alpha36, not GPR30, in nongenomic estrogen signaling. AB - Accumulating evidence suggested that an orphan G protein-coupled receptor (GPR)30, mediates nongenomic responses to estrogen. The present study was performed to investigate the molecular mechanisms underlying GPR30 function. We found that knockdown of GPR30 expression in breast cancer SK-BR-3 cells down regulated the expression levels of estrogen receptor (ER)-alpha36, a variant of ER-alpha. Introduction of a GPR30 expression vector into GPR30 nonexpressing cells induced endogenous ER-alpha36 expression, and cotransfection assay demonstrated that GPR30 activated the promoter activity of ER-alpha36 via an activator protein 1 binding site. Both 17beta-estradiol (E2) and G1, a compound reported to be a selective GPR30 agonist, increased the phosphorylation levels of the MAPK/ERK1/2 in SK-BR-3 cells, which could be blocked by an anti-ER-alpha36 specific antibody against its ligand-binding domain. G1 induced activities mediated by ER-alpha36, such as transcription activation activity of a VP16-ER alpha36 fusion protein and activation of the MAPK/ERK1/2 in ER-alpha36-expressing cells. ER-alpha36-expressing cells, but not the nonexpressing cells, displayed high-affinity, specific E2 and G1 binding, and E2- and G1-induced intracellular Ca(2+) mobilization only in ER-alpha36 expressing cells. Taken together, our results demonstrated that previously reported activities of GPR30 in response to estrogen were through its ability to induce ER-alpha36 expression. The selective G protein-coupled receptor (GPR)30 agonist G1 actually interacts with ER-alpha36. Thus, the ER-alpha variant ER-alpha36, not GPR30, is involved in nongenomic estrogen signaling. PMID- 20197311 TI - An innovative method to classify SERMs based on the dynamics of estrogen receptor transcriptional activity in living animals. AB - Using a mouse model engineered to measure estrogen receptor (ER) transcriptional activity in living organisms, we investigated the effect of long-term (21 d) hormone replacement on ER signaling by whole-body in vivo imaging. Estrogens and selective ER modulators were administered daily at doses equivalent to those used in humans as calculated by the allometric approach. As controls, ER activity was measured also in cycling and ovariectomized mice. The study demonstrated that ER dependent transcriptional activity oscillated in time, and the frequency and amplitude of the transcription pulses was strictly associated with the target tissue and the estrogenic compound administered. Our results indicate that the spatiotemporal activity of selective ER modulators is predictive of their structure, demonstrating that the analysis of the effect of estrogenic compounds on a single surrogate marker of ER transcriptional activity is sufficient to classify families of compounds structurally and functionally related. For more than one century, the measure of drug structure-activity relationships has been based on mathematical equations describing the interaction of the drug with its biological receptor. The understanding of the multiplicity of biological responses induced by the drug-receptor interaction demonstrated the limits of current approach and the necessity to develop novel concepts for the quantitative analysis of drug action. Here, a systematic study of spatiotemporal effects is proposed as a measure of drug efficacy for the classification of pharmacologically active compounds. The application of this methodology is expected to simplify the identification of families of molecules functionally correlated and to speed up the process of drug discovery. PMID- 20197312 TI - RUNX2 transcription factor regulates gene expression in luteinizing granulosa cells of rat ovaries. AB - The LH surge promotes terminal differentiation of follicular cells to become luteal cells. RUNX2 has been shown to play an important role in cell differentiation, but the regulation of Runx2 expression and its function in the ovary remain to be determined. The present study examined 1) the expression profile of Runx2 and its partner CBFbeta during the periovulatory period, 2) regulatory mechanisms of Runx2 expression, and 3) its potential function in the ovary. Runx2 expression was induced in periovulatory granulosa cells of human and rodent ovaries. RUNX2 and core binding factor-beta (CBFbeta) proteins in nuclear extracts and RUNX2 binding to a consensus binding sequence increased after human chorionic gonadotropin (hCG) administration. This in vivo up-regulation of Runx2 expression was recapitulated in vitro in preovulatory granulosa cells by stimulation with hCG. The hCG-induced Runx2 expression was reduced by antiprogestin (RU486) and EGF-receptor tyrosine kinase inhibitor (AG1478), indicating the involvement of EGF-signaling and progesterone-mediated pathways. We also found that in the C/EBPbeta knockout mouse ovary, Runx2 expression was reduced, indicating C/EBPbeta-mediated expression. Next, the function of RUNX2 was investigated by suppressing Runx2 expression by small interfering RNA in vitro. Runx2 knockdown resulted in reduced levels of mRNA for Rgc32, Ptgds, Fabp6, Mmp13, and Abcb1a genes. Chromatin immunoprecipitation analysis demonstrated the binding of RUNX2 in the promoter region of these genes, suggesting that these genes are direct downstream targets of RUNX2. Collectively, the present data indicate that the LH surge-induced RUNX2 is involved in various aspects of luteal function by directly regulating the expression of diverse luteal genes. PMID- 20197314 TI - Gender and ethnic disparities in outcome following acute myocardial infarction among Bedouins and Jews in southern Israel. AB - BACKGROUND: Previous studies have documented gender-ethnic disparities in outcomes following acute myocardial infarction (AMI). This study evaluates such disparities in the Negev, Israel, and reviews potentially responsible mechanisms. METHODS: Patients discharged with AMI were classified into young (<70 years), elders (>=70 years) and gender-ethnicity groups: Female Bedouins (FB), Female Jews (FJ), Male Bedouins (MB) and Male Jews (MJ). The primary outcome was 1-year all-cause mortality. Prognosis was assessed using Kaplan-Meier approach. Multivariable analyses assessing hazard ratios (HRs) for mortality were performed using the Cox proportional hazards regression models in two steps controlling for (i) the Ontario Acute Myocardial Infarction Mortality Prediction Rules (OAMIMPRs) and (ii) the OAMIMPR and additional potential confounders. RESULTS: Of 2669 subjects, 45.8% were elders, 66.2% male and 10.9% Bedouin. The mortality rate was 12.3% (young 4.6%, elders 22%). Survival was significantly lower in FB compared with MB in the elderly stratum (P = 0.025). Multivariate analyses demonstrated similar risks for dying among the young. In the elders, the first multivariate analysis showed greater risk for mortality in FB. Using FB as the reference group, the HRs were as follows: HR((MB)) = 0.36 [95% confidence interval (CI): 0.14-0.9]; HR((FJ)) = 0.5 (95% CI: 0.27-0.9) and HR((MJ)) = 0.5 (95% CI: 0.28 0.91). In the second analysis, the HRs were as follows: HR((MB)) = 0.37 (95% CI: 0.14-0.93); HR((FJ)) = 0.58 (95% CI: 0.32-1.07) and HR((MJ)) = 0.56 (95% CI: 0.31 1.03). CONCLUSIONS: Elderly FB have poor 1-year prognosis following AMI compared with MB, MJ and FJ when controlling for the OAMIMPR model, yet when controlling for other potential confounders the differences are of borderline significance in relation to Jewish subjects. A culturally and economically sensitive programme focusing on tertiary prevention in these patients is warranted. PMID- 20197313 TI - Regulation of fibroblast growth factor-2 by an endogenous antisense RNA and by argonaute-2. AB - We have previously reported that elevated fibroblast growth factor-2 (FGF-2) expression is associated with tumor recurrence and reduced survival after surgical resection of esophageal cancer and that these risks are reduced in tumors coexpressing an endogenous antisense (FGF-AS) RNA. In the present study, we examined the role of the endogenous FGF-AS transcript in the regulation of FGF 2 expression in the human lung adenocarcinoma cell line Seg-1. FGF-2 and FGF-AS were temporally and spatially colocalized in the cytoplasm of individual cells, and knockdown of either FGF-2 or FGF-AS by target-specific siRNAs resulted in dose-dependent up-regulation of the complementary transcript and its encoded protein product. Using a luciferase reporter system, we show that these effects are mediated by interaction of the endogenous antisense RNA with the 3' untranslated region of the FGF-2 mRNA. Deletion mapping identified a 392 nucleotide sequence in the 5823-nucleotide FGF-2 untranslated tail that is targeted by FGF-AS. Small interfering RNA-mediated knockdown of either FGF-AS or FGF-2 significantly increased the stability of the complementary partner mRNA, demonstrating that these mRNAs are mutually regulatory. Knockdown of FGF-AS also resulted in reduced expression of argonaute-2 (AGO-2) and a number of other elements of the endogenous micro-RNA/RNA interference pathways. Conversely, small interfering RNA-mediated knockdown of AGO-2 significantly increased the stability of the FGF-2 mRNA transcript and the steady-state levels of both FGF-2 mRNA and protein, suggesting a role for AGO-2 in the regulation of FGF-2 expression. PMID- 20197315 TI - Metabolic influences for mutation induction curves after exposure to Sudan-1 and para red. AB - Sudan-1 and para red are industrial dyes that have been illegally added to some foodstuffs, leading to withdrawal of the adulterated products throughout the UK since 2003. This resulted in international concern that arose because Sudan-1 is classified by International Agency for Research on Cancer as a Category 3 carcinogen. However, little is known about the dose response of this chemical at low, more biologically relevant, doses. The study therefore aimed to characterize the dose response for gene mutation and chromosomal damage induced by two azo dyes, namely Sudan-1 and para red. Gene mutations were analysed using the hypoxanthine phosphoribosyltransferase forward mutation assay and chromosomal damage was measured using the cytokinesis-blocked micronucleus assay. Two cell lines were used in these investigations. These were the AHH-1 cell line, which inducibly expresses CYP1A1, and the MCL-5 cell line derived from a subpopulation of AHH-1 cells that expresses a particularly high level of CYP1A1 activity. The MCL-5 cell line has also been transfected with two plasmids that stably express CYP1A2, CYP2A6 and CYP3A4 and all four of these CYP enzymes are known to metabolically activate Sudan-1. AHH-1 cells were used to investigate the dose response of the azo dyes, and MCL-5 cells were used to see if the dose response changed with increased metabolism. Sudan-1 induced a non-linear dose-response curve for gene mutation and chromosomal damage in AHH-1 cells. The genotoxic activity of Sudan-1 was greatly increased in MCL-5 cells. This indicated that the oxidation metabolites from Sudan-1 were both more mutagenic and more clastogenic than the parent compound. Para red also demonstrated a non-linear dose response for both gene mutation and chromosome damage in AHH-1 cells, and an increase in micronuclei induction was observed after increased oxidative metabolism in MCL-5 cells. Sudan-1 and para red are genotoxic chemicals with non-linear dose responses in AHH-1 but not in MCL-5 cells, and oxidative metabolism increases the genotoxic effect of both compounds. PMID- 20197316 TI - Ribosomal RNA diversity predicts genome diversity in gut bacteria and their relatives. AB - The mammalian gut is an attractive model for exploring the general question of how habitat impacts the evolution of gene content. Therefore, we have characterized the relationship between 16 S rRNA gene sequence similarity and overall levels of gene conservation in four groups of species: gut specialists and cosmopolitans, each of which can be divided into pathogens and non-pathogens. At short phylogenetic distances, specialist or cosmopolitan bacteria found in the gut share fewer genes than is typical for genomes that come from non-gut environments, but at longer phylogenetic distances gut bacteria are more similar to each other than are genomes at equivalent evolutionary distances from non-gut environments, suggesting a pattern of short-term specialization but long-term convergence. Moreover, this pattern is observed in both pathogens and non pathogens, and can even be seen in the plasmids carried by gut bacteria. This observation is consistent with the finding that, despite considerable interpersonal variation in species content, there is surprising functional convergence in the microbiome of different humans. Finally, we observe that even within bacterial species or genera 16S rRNA divergence provides useful information about average conservation of gene content. The results described here should be useful for guiding strain selection to maximize novel gene discovery in large-scale genome sequencing projects, while the approach could be applied in studies seeking to understand the effects of habitat adaptation on genome evolution across other body habitats or environment types. PMID- 20197317 TI - Torsional regulation of hRPA-induced unwinding of double-stranded DNA. AB - All cellular single-stranded (ss) DNA is rapidly bound and stabilized by single stranded DNA-binding proteins (SSBs). Replication protein A, the main eukaryotic SSB, is able to unwind double-stranded (ds) DNA by binding and stabilizing transiently forming bubbles of ssDNA. Here, we study the dynamics of human RPA (hRPA) activity on topologically constrained dsDNA with single-molecule magnetic tweezers. We find that the hRPA unwinding rate is exponentially dependent on torsion present in the DNA. The unwinding reaction is self-limiting, ultimately removing the driving torsional stress. The process can easily be reverted: release of tension or the application of a rewinding torque leads to protein dissociation and helix rewinding. Based on the force and salt dependence of the in vitro kinetics we anticipate that the unwinding reaction occurs frequently in vivo. We propose that the hRPA unwinding reaction serves to protect and stabilize the dsDNA when it is structurally destabilized by mechanical stresses. PMID- 20197318 TI - A synthetic low-frequency mammalian oscillator. AB - Circadian clocks have long been known to be essential for the maintenance of physiological and behavioral processes in a variety of organisms ranging from plants to humans. Dysfunctions that subvert gene expression of oscillatory circadian-clock components may result in severe pathologies, including tumors and metabolic disorders. While the underlying molecular mechanisms and dynamics of complex gene behavior are not fully understood, synthetic approaches have provided substantial insight into the operation of complex control circuits, including that of oscillatory networks. Using iterative cycles of mathematical model-guided design and experimental analyses, we have developed a novel low frequency mammalian oscillator. It incorporates intronically encoded siRNA-based silencing of the tetracycline-dependent transactivator to enable the autonomous and robust expression of a fluorescent transgene with periods of 26 h, a circadian clock-like oscillatory behavior. Using fluorescence-based time-lapse microscopy of engineered CHO-K1 cells, we profiled expression dynamics of a destabilized yellow fluorescent protein variant in single cells and real time. The novel oscillator design may enable further insights into the system dynamics of natural periodic processes as well as into siRNA-mediated transcription silencing. It may foster advances in design, analysis and application of complex synthetic systems in future gene therapy initiatives. PMID- 20197319 TI - Spt4/5 stimulates transcription elongation through the RNA polymerase clamp coiled-coil motif. AB - Spt5 is the only known RNA polymerase-associated factor that is conserved in all three domains of life. We have solved the structure of the Methanococcus jannaschii Spt4/5 complex by X-ray crystallography, and characterized its function and interaction with the archaeal RNAP in a wholly recombinant in vitro transcription system. Archaeal Spt4 and Spt5 form a stable complex that associates with RNAP independently of the DNA-RNA scaffold of the elongation complex. The association of Spt4/5 with RNAP results in a stimulation of transcription processivity, both in the absence and the presence of the non template strand. A domain deletion analysis reveals the molecular anatomy of Spt4/5--the Spt5 Nus-G N-terminal (NGN) domain is the effector domain of the complex that both mediates the interaction with RNAP and is essential for its elongation activity. Using a mutagenesis approach, we have identified a hydrophobic pocket on the Spt5 NGN domain as binding site for RNAP, and reciprocally the RNAP clamp coiled-coil motif as binding site for Spt4/5. PMID- 20197320 TI - US pain expert faces prison after pleading guilty to research fraud. PMID- 20197323 TI - Economic impact of disease and injury: counting what matters. PMID- 20197324 TI - Waiting times for radiotherapy after breast cancer. PMID- 20197322 TI - Risk of miscarriage with bivalent vaccine against human papillomavirus (HPV) types 16 and 18: pooled analysis of two randomised controlled trials. AB - OBJECTIVE: To assess whether vaccination against human papillomavirus (HPV) increases the risk of miscarriage. DESIGN: Pooled analysis of two multicentre, phase three masked randomised controlled trials SETTING: Multicentre trials in several continents and in Costa Rica. PARTICIPANTS: 26 130 women aged 15-25 at enrolment; 3599 pregnancies eligible for analysis. INTERVENTIONS: Participants were randomly assigned to receive three doses of bivalent HPV 16/18 VLP vaccine with AS04 adjuvant (n=13 075) or hepatitis A vaccine as control (n=13 055) over six months. MAIN OUTCOME MEASURES: Miscarriage and other pregnancy outcomes. RESULTS: The estimated rate of miscarriage was 11.5% in pregnancies in women in the HPV arm and 10.2% in the control arm. The one sided P value for the primary analysis was 0.16; thus, overall, there was no significant increase in miscarriage among women assigned to the HPV vaccine arm. In secondary descriptive analyses, miscarriage rates were 14.7% in the HPV vaccine arm and 9.1% in the control arm in pregnancies that began within three months after nearest vaccination. CONCLUSION: There is no evidence overall for an association between HPV vaccination and risk of miscarriage. TRIAL REGISTRATION: Clinical Trials NCT00128661 and NCT00122681. PMID- 20197325 TI - Eyes and alkalis. Wave of paediatric eye injuries from liquid detergent capsules. PMID- 20197326 TI - Impact of interval from breast conserving surgery to radiotherapy on local recurrence in older women with breast cancer: retrospective cohort analysis. AB - OBJECTIVES: To determine if the length of interval between breast conserving surgery and start of radiotherapy affects local recurrence and to identify factors that might be associated with delay in older women with breast cancer. DESIGN: Retrospective cohort analysis with Cox proportional hazards models to study the association between time to radiotherapy and local recurrence, and propensity score and instrumental variable analyses to confirm findings. Logistic regression investigated factors associated with later start of radiotherapy. SETTING: Linked database (Surveillance, Epidemiology, and End Results Program Medicare) in the United States PARTICIPANTS: 18 050 women aged over 65 with stage 0-II breast cancer diagnosed in 1991-2002 who received breast conserving surgery and radiotherapy but not chemotherapy. MAIN OUTCOME MEASURE: Local recurrence. RESULTS: Median time from surgery to start of radiotherapy was 34 days, with 29.9% (n=5389) of women starting radiotherapy after six weeks. Just over 4% (n=734) of the cohort experienced a local recurrence. After adjustment for clinical and sociodemographic factors, intervals over six weeks were associated with increased likelihood of local recurrence (hazard ratio 1.19, 95% confidence interval 1.01 to 1.39, P=0.033). When the interval was modelled continuously (assessing accumulation of risk by day), the effect was statistically stronger (hazard ratio 1.005 per day, 1.002 to 1.008, P=0.004). Propensity score and instrumental variable analysis confirmed these findings. Instrumental variable analysis showed that intervals over six weeks were associated with a 0.96% increase in recurrence at five years (P=0.026). In multivariable analysis, starting radiotherapy after six weeks was significantly associated with positive nodes, comorbidity, history of low income, Hispanic ethnicity, non-white race, later year of diagnosis, and residence outside the southern states of the US. CONCLUSIONS: There is a continuous relation between the interval from breast conserving surgery to radiotherapy and local recurrence in older women with breast cancer, suggesting that starting radiotherapy as soon as possible could minimise the risk of local recurrence. There are considerable disparities in time to starting radiotherapy after breast conserving surgery. Regions of the US known to have increased rates of breast conserving surgery had longer intervals before radiotherapy, suggesting limitations in capacity. Given the known negative impact of local recurrence on survival, mechanisms to ameliorate disparities and policies regarding waiting times for treatment might be warranted. PMID- 20197327 TI - Double face of discrimination. Legislation offers protection. PMID- 20197328 TI - Differentiation is not discrimination. PMID- 20197330 TI - The first draft of DSM-V. PMID- 20197331 TI - Chronic fatigue syndrome. More than defeatism greets patients with ME. PMID- 20197332 TI - Time to flag up "detox" drinks? No need to flag up potassium. PMID- 20197333 TI - Chronic fatigue syndrome. Severely affected, severely neglected. PMID- 20197334 TI - Aspirin and primary prevention. BHS reaffirms its guidance. PMID- 20197336 TI - Guidance needed on secondary effects of CS gas on staff. PMID- 20197337 TI - Fair Society, Healthy Lives. Timing is everything. PMID- 20197338 TI - Safety of oxygen treatment. What about acute coronary syndrome? PMID- 20197341 TI - Dancing with dementia. PMID- 20197344 TI - Clinical value of F18-fluorodeoxyglucose positron emission tomography-computed tomography in patients with non-small cell lung cancer after potentially curative surgery: experience with 241 patients. AB - OBJECTIVES: F18-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT), which allows differentiation between malignant and benign lesions based on difference in tissue glucose metabolism, has become increasingly important in lung cancer diagnosis. This study examined the clinical value of FDG-PET/CT in a large number of patients with non-small cell lung cancer (NSCLC) after potentially curative surgery. METHODS: Four hundred and ninety FDG PET/CT of 241 patients (143 males and 98 females; age range 38-87 years; mean 68.0 years) between May 2006 and February 2008 were retrospectively evaluated. All the 241 patients had undergone potentially curative surgery for NSCLC >6 months before FDG-PET/CT and their pathologic stages were stage I and II according to the tumor-node-metastasis (TNM) classification. A final diagnosis of recurrence was confirmed by histologic or cytologic examination of the disease or by clinical and radiologic follow-up image analysis. Confirmation of recurrence free status was based on a clinical and radiologic image analysis follow-up period of at least 12 months with no evidence of active malignancy. The diagnostic performance of FDG-PET/CT was evaluated. Details of false results and incidental detection of diseases other than recurrent lung cancer by FDG-PET/CT was also analyzed. RESULTS: Recurrences were confirmed in 35 (15%) patients, and 206 patients (85%) had no evidence of recurrence. FDG-PET/CT correctly diagnosed recurrence in 34 of 35 patients and provided true negative findings in 198 of 206 patients who had no evidence of recurrence (sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of 97%, 96%, 96%, 81%, and 99%, respectively), indicating a high diagnostic performance. However, one patient had false negative studies and eight patients had false positive studies; misdiagnosis was more frequently in intrathoracic sites associated with postoperative changes. Malignancies other than recurrence were detected in nine of all 241 patients (4%) including five second primary lung cancers. CONCLUSIONS: The present study demonstrated the high diagnostic performance of FDG-PET/CT in detecting recurrences in a large group of patients with NSCLC after potentially curative surgery. FDG-PET/CT is useful not only for diagnosis of recurrence but also for detection of other diseases. PMID- 20197345 TI - A novel porcine model for right ventricular dilatation by external suture plication of the pulmonary valve leaflets--practical and reproducible. AB - The right ventricle (RV) tolerates acute pulmonary valvular regurgitation fairly well, however, in the long-term dilatation and failure often ensues. There is little known of the structural and functional myocardial alterations following this pathophysiology, and therefore animal models are sought. We aimed to develop an animal experimental model for RV dilatation emphasizing feasibility, reproducibility and human compatibility. Free pulmonary valve insufficiency and RV dilatation were created with a novel external suture plication technique in nine 5 kg piglets. Six matched animals served as controls. After 10 weeks cardiac dimensions and physiology were assessed with in vivo cardiovascular MRI and conductance technique. RV end-diastolic volume increased 31% in the intervention group (P=0.03). The regurgitation fraction was 37% in the intervention group compared to -2% in controls (P<0.001). Conductance measurements showed preserved RV contractile function, but significant left ventricular diastolic impairment. This study is the first to show that pulmonary valve regurgitation, RV dilatation and functional impairment can be achieved by external leaflet plication. Compared to known methods, the advantages of this model are: 1) no induction of stenosis over time, 2) no risk of stent migration, and 3) very simple and reproducible. PMID- 20197347 TI - Epicardial radiofrequency ablation and aortic valve replacement through right mini-thoracotomy. AB - The Cobra Adhere XL (Estech, San Ramon, CA, USA) is a multiple-electrode, temperature-controlled, monopolar radiofrequency probe with a vacuum-assisted stabilization system. We describe a new technique for epicardial ablation of atrial fibrillation in patients undergoing aortic valve replacement through right mini-thoracotomy. PMID- 20197346 TI - Reducing the ischemic time of donor hearts will decrease morbidity and costs of cardiac transplantations. AB - With liberalization of donor eligibility criteria, donor hearts are being harvested from remote locations, increasing ischemic times. The aim of this study was to examine the effect of total ischemic time (TIT) on length of stay in the intensive care unit (LOS in ICU) and its economic consequences. The study population included recipients without prior mechanical support undergoing heart transplantation between 1998 and 2008 at a single institution. The mean age of the 72 recipients (56 men, 16 women) was 50.6 years (range 15-68 years) and the mean donor age was 41.5 years (range 11-61 years). The median TIT was 181.2 min (range 107-243) and median LOS in ICU was 11.5 days (range 3-107 days). There was a statistically significant linear relationship between TIT and LOS in ICU r(72)=0.317, P=0.004. Each 5 min and 38 s of TIT equated to one more day in ICU. An ischemic time >180 min was associated with higher LOS in ICU, renal failure, and a more frequent use of nitric oxide in our cohort. For longer distance harvesting, the reduction of TIT by the fastest possible transport (learjet, helicopter) would have economic advantages with regards to the high cost of treatment in ICU. PMID- 20197348 TI - Open-heart surgery in an infant with heterozygous factor VII deficiency. AB - A four-month-old male with Taussig-Bing anomaly and multiple ventricular septal defects underwent an open-heart palliative procedure. He suffered from massive postoperative gastrointestinal bleeding. Heterozygous Arg402Stop-related factor VII deficiency was detected by genomic examinations. When he was 14 months old, a subsequent open-heart surgery with replacement therapy of recombinant factor VIIa was performed without any bleeding or thromboembolic complications. Although heterozygous factor VII deficiency is generally recognized as clinically asymptomatic, this latent bleeding disorder can appear perioperatively or postoperatively in patients who undergo cardiopulmonary bypass procedures. Consequently, the prophylactic replacement therapy with recombinant factor VII is recommended during cardiac operations. PMID- 20197349 TI - Left atrial paraganglioma: diagnosis and surgical management. AB - Cardiac paragangliomas are rare entities, that often remain asymptomatic. Complete surgical resection is the mainstay of treatment even if it can be difficult for the infiltration of the near mediastinal structures. We describe the case of a young man with hypertensive crisis, headache and diabetes, affected by cardiac paraganglioma, infiltrating the left atrial roof. The tumor was completely removed using cardiopulmonary bypass and the infiltrated portion of left atrial wall and the left superior pulmonary vein was excised and repaired with a pericardial patch. The patient was discharged without complications and currently enjoys good health. PMID- 20197350 TI - Short-term outcome following cardiac surgery--a comparison between consultant and trainees' performance. AB - Comparison of the outcome of cardiac operations performed by surgical trainees with those performed by consultant surgeons has been an interesting topic in recent years. We set out to examine the outcome of a high volume-training firm. Cardiac operations performed by surgical trainees and a consultant between January 2006 and March 2009 were studied. Hospital mortality and morbidity were compared in the two groups. Eight hundred and seventy-two operations were performed, 687 (79%) were operated by consultant and 185 (21%) by surgical trainees. Mean logistic EuroSCORE in consultant and surgical trainees groups was 3.7 and 2.7, respectively (P<0.001). One hundred and forty-two (77%) of the cases performed by trainees were coronary artery bypass grafting (CABG). Interestingly, the ratio of urgent cases was higher in the trainees group [156 (23%) compared to 59 (32%), P=0.004]. Mortality in consultant and surgical trainees groups for all operations was 18 (2.6%) and six (3.2%), respectively (P=NS). Mortality for CABG in consultant and surgical trainees groups was six (1.7%) and six (4.2%), respectively (P=NS). There was no significant difference in morbidity outcome measures comparing the two groups. The non-significant higher overall mortality in operations performed by trainees in a fully supervised setting, may reflect the influence of experience and confidence, which are difficult to measure. PMID- 20197351 TI - Extracorporeal bubbles: a word of caution. AB - OBJECTIVES: Gaseous microemboli (GME) are a cause of neurocognitive deficit postcardiac surgery with cardiopulmonary bypass. However, the measurement of microbubbles during cardiopulmonary bypass is not easy, because blood is an opaque fluid and contains microparticles. Recently, two new microbubble counters, the Gampt BC200 and the emboli detection and classification (EDAC) quantifier, were developed for use during cardiac surgery. The accuracy of both devices was validated against industrial standards. METHODS: A clear blood analogue (30%/70% glycerol-water) was pumped, by means of a rollerpump out of a partially filled arterial line screen filter with a nominal pore size of 20 microm. Downstream the pump, all test sensors and an optical cuvette, were inserted in a vertically mounted 3/8 inch tubing. Measurements were taken at flows of 405, 1080, 3000 and 6000 ml/min. Backlight shadowgraphy and optical counting were used as industrial reference techniques for measuring size and counts. RESULTS: On average the EDAC quantifier underestimates average bubble diameter by 35+/-1%, 13+/-8%, 71+/-7% and 33+/-4% at 405, 1080, 3000 and 6000 ml/min, respectively. The Gampt BC200 has good sizing agreement at 1080 ml/min (+5+/-17%) and 3000 ml/min (+33+/-6%) but overestimates average diameter by 220+/-40% and 295+/-49% at 405 and 6000 ml/min, respectively. Both devices only partially count the number of microbubbles at higher flows. At 3 l/min the EDAC counts 38%, the Gampt 18% of total counts and at 6 l/min both the EDAC and Gampt only count 3% of total counts. CONCLUSIONS: Both the EDAC and Gampt can be used in a clinical setting for monitoring basal GME production. However, both devices have some major limitations when used for studying 'worst case' scenarios. One should take great caution when correlating measured data with neurocognitive outcome. Finally, results obtained by one device in a first study cannot be compared nor exchanged with results from the other device in a second study. PMID- 20197352 TI - Pulmonary valve repair late after right ventricular outflow tract reconstruction in children and adolescents. AB - Here, we report our experience with pulmonary valve (PV) repair using neoleaflet implantation in children and adolescents. Between April 2005 and May 2009, 20 patients underwent late PV repair with neoleaflet implantation for pulmonary regurgitation (PR) after reconstruction of the right ventricular outflow tract at <18 years of age. In patients with sufficient remaining native PV leaflets, the neoleaflet was implanted with a polytetrafluoroethylene membrane or fresh autologous pericardium to coapt with the remaining native PV leaflets. The median age at operation was 13 years (2-18 years). The median follow-up duration was 12 months (2-51 months). There was no early or late death. During follow-up, no significant PR was observed, but significant pulmonary stenosis (PS) developed in two patients who had a combined PS. The indexed right ventricular end diastolic dimension decreased during follow-up. At the latest follow-up, all patients were in New York Heart Association functional class I or II. PV repair with neoleaflet implantation can be performed safely and the outcome is satisfactory in the short term, but attention must be paid in cases with combined PS. Longer follow-up should be carried out to investigate the changes in leaflet mobility and function, and pulmonary annular growth. PMID- 20197353 TI - Peroperative fiducial placement for postoperative stereotactic Cyberknife radiosurgery. AB - Radiotherapy is often the treatment used for inoperable early-stage lung cancer as well as pulmonary metastases. In the last decade, efforts were done to increase local control with high-dose radiation without excessive collateral damage. Initially used for cranial lesions, stereotactic radiosurgery enlarged extracranial indications; the Cyberknife radiosurgery system needs metal (gold) markers for image guidance. For lung tumours, fiducials are inserted computed tomography (CT)-guided or bronchoscopy-guided. We describe four patients where fiducial placement was done during surgery. PMID- 20197354 TI - A pilot study comparing the effectiveness of speech language therapy provided by telemedicine with conventional on-site therapy. AB - We compared the progress made by school children in speech language therapy provided through videoconferencing and conventional face-to-face speech language therapy. The children were treated in two groups. In the first group, 17 children received telemedicine treatment for 4 months, and then subsequently conventional therapy for 4 months. In the second group, 17 children received conventional treatment for 4 months and then subsequently telemedicine treatment for 4 months. The outcome measures were student progress, participant satisfaction and any interruptions to service delivery. Student progress reports indicated that the children made similar progress during the study whichever treatment method was used. There was no significant difference in GFTA-2 scores (Goldman-Fristoe Test of Articulation) between students in the two treatment groups. Satisfaction surveys indicated that the students and parents overwhelmingly supported the telemedicine service delivery model. During the study, a total of 148 of the 704 possible therapy sessions was not completed (21%); the pattern of cancellations was similar to cancellations in US public schools generally. Videoconferencing appears to be a promising method of delivering speech language therapy services to school children. PMID- 20197355 TI - Home telehealth for chronic obstructive pulmonary disease: a systematic review and meta-analysis. AB - We conducted a systematic review of the literature about home telehealth for chronic obstructive pulmonary disease (COPD) compared with usual care. An electronic literature search identified 6241 citations. From these, nine original studies (10 references) relating to 858 patients were selected for inclusion in the review. Four studies compared home telemonitoring with usual care, and six randomized controlled trials compared telephone support with usual care. Clinical heterogeneity was present in many of the outcomes measured. Home telehealth (home telemonitoring and telephone support) was found to reduce rates of hospitalization and emergency department visits, while findings for hospital bed days of care varied between studies. However, the mortality rate was greater in the telephone-support group compared with usual care (risk ratio = 1.21; 95% CI: 0.84 to 1.75). Home telehealth interventions were similar or better than usual care for quality of life and patient satisfaction outcomes. PMID- 20197356 TI - Child and adolescent telepsychiatry: variations in utilization, referral patterns and practice trends. AB - Seattle Children's Hospital is a tertiary referral hospital that has provided telepsychiatry to seven partner sites in the north-west since 2001. Service utilization data, patient demographics and diagnoses were collected for the period from the service inception in October 2001 until November 2007. During the study period, 701 patients were treated with a mean of 2.8 appointments per patient (SD 1.9). Five psychiatrists and four psychologists provided care. Utilization varied across referring sites and was largely dependent upon the availability of telepsychiatrists, although the degree of support from administration and stakeholders also contributed to the success of the service. A total of 190 primary care practitioners referred patients to telepsychiatry, including 106 family physicians and 71 paediatricians. Paediatricians referred to the service more frequently than family physicians (t = 2.8, P < 0.05). Overall, telepsychiatry with young people is feasible, acceptable and increases access to mental health care. There appear to be four core components necessary to a successful telepsychiatry programme: psychiatrists who are interested in exploring new ways to reach underserved young people; clearly identified stakeholders who can collaborate with one another to make good use of the telepsychiatry service; a children's mental health 'champion' who represents these stakeholders and wants services for their community; and a stable administration that perceives telepsychiatry as valuable for their patients and their doctors. PMID- 20197357 TI - The first veterinary telemedicine study group. PMID- 20197359 TI - A decolonizing approach to health promotion in Canada: the case of the Urban Aboriginal Community Kitchen Garden Project. AB - Aboriginal people in Canada suffer ill-health at much higher rates compared with the rest of the population. A key challenge is the disjuncture between the dominant biomedical approach to health in Canada and the holistic and integrative understandings of and approaches to health in many Aboriginal cultures. More fundamentally, colonization is at the root of the health challenges faced by this population. Thus, effective approaches to health promotion with Aboriginal people will require decolonizing practices. In this paper, we look at one case study of a health promotion project, the Urban Aboriginal Community Kitchen Garden Project in Vancouver, Canada, which, guided by the teachings of the Medicine Wheel, aims to provide culturally appropriate health promotion. By drawing on Aboriginal approaches to healing, acknowledging the legacy of colonization and providing a context for cultural celebration, we suggest that the project can be seen as an example of what decolonizing health promotion could look like. Further, we suggest that a decolonizing approach to health promotion has the potential to address immediate needs while simultaneously beginning to address underlying causes of Aboriginal health inequities. PMID- 20197360 TI - Exposure to smoking in movies among British adolescents 2001-2006. AB - OBJECTIVE: To estimate youth exposure to smoking in movies in the UK and compare the likely effect with the USA. METHODS: We collected tobacco occurrences data for 572 top-grossing films in the UK screened from 2001 to 2006 and estimated the number of on-screen tobacco impressions delivered to British youths in this time period. RESULTS: 91% of films in our sample that contained smoking were youth rated films (British Board of Film Classification rating '15' and lower), delivering at least 1.10 billion tobacco impressions to British youths during theatrical release. British youths were exposed to 28% more smoking impressions in UK youth-rated movies than American youth-rated movies, because 79% of movies rated for adults in the USA ('R') are classified as suitable for youths in the UK ('15' or '12A'). CONCLUSION: Because there is a dose-response relation between the amount of on-screen exposure to smoking and the likelihood that adolescents will begin smoking, the fact that there is substantially higher exposure to smoking in youth-rated films in the UK than in the USA suggests that the fraction of all youth smoking because of films in the UK is probably larger than in the USA. Other countries with ratings systems that are less conservative (in terms of language and sexuality) than the USA will also be likely to deliver more on screen tobacco impressions to youths. Assigning an '18' classification to movies that contain smoking would substantially reduce youth exposure to on-screen smoking and, hence, smoking initiation among British youths. PMID- 20197361 TI - Early C-reactive protein in the prediction of long-term outcomes after acute coronary syndromes: a meta-analysis of longitudinal studies. AB - OBJECTIVE: To assess the overall effects by a meta-analysis. DATA SOURCES: Electronic searches on PubMed and Ovid Medline from their start to October 2009 were carried out. Objective Cohort studies and secondary analysis of randomised controlled trials reporting the relative risk (RR) of recurrent cardiovascular events or death associated with C-reactive protein (CRP) obtained within 72 h from acute coronary syndromes (ACS) onset. DATA EXTRACTION: Two epidemiologists independently abstracted information on study design, study and participant characteristics, level of CRP, outcomes, control for potential confounding factors and risk estimates using a standardised form. RESULTS: A general variance based method was used to pool the estimates of risk. Thirteen studies containing 1364 new cases identified from 9787 patients during the follow-up periods reported the risk estimates by CRP categories. Compared with the bottom CRP category (< or = 3 mg/l), the pooled RRs and their 95% CIs were 1.40 (1.18 to 1.67) for the middle (3.1 approximately 10 mg/l) category and 2.18 (1.77 to 2.68) for the top (>10 mg/l) category of CRP values with a random-effects model, respectively. Another four and three studies reported the risk by unit of CRP or logarithmically transformed CRP. The pooled RRs (95% CI) were 1.49 (1.06 to 2.08) per 5 mg/l and 1.26 (0.95 to 1.69) per natural logarithm of CRP (mg/l), respectively. CONCLUSIONS: Greater early blood CRP moderately increases long-term risk of recurrent cardiovascular events or death, and may be a valuable prognostic predictor in patients after ACS. PMID- 20197362 TI - Percutaneous mitral valve leaflet repair for mitral regurgitation: NICE guidance. PMID- 20197363 TI - Intracardiac bone cement embolism. PMID- 20197365 TI - Development and validation of a clinical index to predict survival after cardiac resynchronisation therapy. PMID- 20197367 TI - P: the neglected deflection. PMID- 20197368 TI - Three dimensional echocardiography: approaches and clinical utility. PMID- 20197369 TI - Arrhythmias and sport practice. PMID- 20197370 TI - Tako-tsubo cardiomyopathy: findings on cardiac CT and coronary catheterisation. PMID- 20197371 TI - Interventional rescue strategy after malpositioning of a percutaneous aortic valve. PMID- 20197372 TI - Diagnosing an MI: don't trust the monitor! PMID- 20197373 TI - Profiling of superoxide dismutase isoenzymes in compartments of the developing bovine antral follicles. AB - The antral follicle constitutes a complex and regulated ovarian microenvironment that influences oocyte quality. Oxidative stress is a cellular state that may play a role during folliculogenesis and oogenesis, although direct supporting evidence is currently lacking. We thus evaluated the expression of the three isoforms (SOD1, SOD2, and SOD3) of the enzymatic antioxidant superoxide dismutase in all the cellular (granulosa cells, cumulus cells, and oocytes) and extracellular (follicular fluid) compartments of the follicle. Comparisons were made in bovine ovaries across progressive stages of antral follicular development. Follicular fluid possessed increased amounts of SOD1, SOD2, and SOD3 in small antral follicles when compared with large antral follicles; concomitantly, total SOD activity was highest in follicular fluids from smaller diameter follicles. SOD1, SOD2, and SOD3 proteins were expressed in granulosa cells without any fluctuations in follicle sizes. All three SOD isoforms were present, but were distributed differently in oocytes from small, medium, or large antral follicles. Cumulus cells expressed high levels of SOD3, some SOD2, but no detectable SOD1. Our studies provide a temporal and spatial expression profile of the three SOD isoforms in the different compartments of the developing bovine antral follicles. These results lay the ground for future investigations into the potential regulation and roles of antioxidants during folliculogenesis and oogenesis. PMID- 20197374 TI - Scopolamine treatment and muscarinic receptor subtype-3 gene ablation augment azoxymethane-induced murine liver injury. AB - Previous work suggests that vagus nerve disruption reduces hepatocyte and oval cell expansion after liver injury. The role of postneuronal receptor activation in response to liver injury has not been ascertained. We investigated the actions of scopolamine, a nonselective muscarinic receptor antagonist, and specific genetic ablation of a key cholinergic receptor, muscarinic subtype-3 (Chrm3), on azoxymethane (AOM)-induced liver injury in mice. Animal weights and survival were measured as was liver injury using both gross and microscopic examination. To assess hepatocyte proliferation and apoptosis, ductular hyperplasia, and oval cell expansion, we used morphometric analysis of 5-bromo-2'-deoxyuridine-, activated caspase-3-, hematoxylin and eosin-, cytokeratin-19-, and epithelial cell adhesion molecule-stained liver sections. Sirius red staining was used as a measure of collagen deposition and its association with oval cell reaction. In AOM-treated mice, both muscarinic receptor blockade with scopolamine and Chrm3 ablation attenuated hepatocyte proliferation and augmented gross liver nodularity, apoptosis, and fibrosis. Compared with control, scopolamine-treated and Chrm3(-/-) AOM-treated mice had augmented oval cell reaction with increased ductular hyperplasia and oval cell expansion. Oval cell reaction correlated robustly with liver fibrosis. No liver injury was observed in scopolamine-treated and Chrm3(-/-) mice that were not treated with AOM. Only AOM-treated Chrm3(-/-) mice developed ascites and had reduced survival compared with AOM-treated wild type controls. In AOM-induced liver injury, inhibiting postneuronal cholinergic muscarinic receptor activation with either scopolamine treatment or Chrm3 gene ablation results in prominent oval cell reaction. We conclude that Chrm3 plays a critical role in the liver injury response by modulating hepatocyte proliferation and apoptosis. PMID- 20197375 TI - Implementation of a fluorescence-based screening assay identifies histamine H3 receptor antagonists clobenpropit and iodophenpropit as subunit-selective N methyl-D-aspartate receptor antagonists. AB - N-Methyl-D-aspartate (NMDA) receptors are ligand-gated ion channels that mediate a slow, Ca(2+)-permeable component of excitatory synaptic transmission in the central nervous system and play a pivotal role in synaptic plasticity, neuronal development, and several neurological diseases. We describe a fluorescence-based assay that measures NMDA receptor-mediated changes in intracellular calcium in a BHK-21 cell line stably expressing NMDA receptor NR2D with NR1 under the control of a tetracycline-inducible promoter (Tet-On). The assay selectively identifies allosteric modulators by using supramaximal concentrations of glutamate and glycine to minimize detection of competitive antagonists. The assay is validated by successfully identifying known noncompetitive, but not competitive NMDA receptor antagonists among 1800 screened compounds from two small focused libraries, including the commercially available library of pharmacologically active compounds. Hits from the primary screen are validated through a secondary screen that used two-electrode voltage-clamp recordings on recombinant NMDA receptors expressed in Xenopus laevis oocytes. This strategy identified several novel modulators of NMDA receptor function, including the histamine H3 receptor antagonists clobenpropit and iodophenpropit, as well as the vanilloid receptor transient receptor potential cation channel, subfamily V, member 1 (TRPV1) antagonist capsazepine. These compounds are noncompetitive antagonists and the histamine H3 receptor ligand showed submicromolar potency at NR1/NR2B NMDA receptors, which raises the possibility that compounds can be developed that act with high potency on both glutamate and histamine receptor systems simultaneously. Furthermore, it is possible that some actions attributed to histamine H3 receptor inhibition in vivo may also involve NMDA receptor antagonism. PMID- 20197376 TI - The small nucleolar ribonucleoprotein (snoRNP) database. AB - Small nucleolar ribonucleoproteins (snoRNPs) are widely studied and characterized as guide RNAs for sequence-specific 2'-O-ribose methylation and psuedouridylation of ribosomal RNAs. In addition, snoRNAs have also been shown to interact with some tRNAs and direct alternative splicing in mRNA biogenesis. Recent advances in bioinformatics have resulted in new algorithms able to rapidly identify noncoding RNAs generally and snoRNAs specifically in genomic and metagenomic sequences, resulting in a rapid increase in the number and diversity of identified snoRNA sequences. The snoRNP database is a web-based collection of snoRNA and snoRNA associated protein sequences from a wide range of species. The database currently contains 8994 snoRNA sequences from Bacteria, Archaea, and Eukaryotes and 589 snoRNA-associated protein sequences. The snoRNP database can be found at: http://evolveathome.com/snoRNA/snoRNA.php. PMID- 20197378 TI - Klinefelter's syndrome and psychoneurologic function. AB - Klinefelter's syndrome (KS) is due to the presence of one or more supernumerary X chromosomes. Aneuploidy 47,XXY is the most common abnormality of sex chromosomes in humans, with an incidence of 1/500 male live births. Only one-third of subjects with KS is, however, diagnosed. The aim of this work is to present a review of current literature about neurogenetic functions in KS, referring to both clinical and therapeutics aspects. If it is well known that the majority of subjects with 47,XXY karyotype have a normal intellectual level, the identification of strengths and weaknesses of their intellectual functioning is important for the purpose of planning early psycho-educational interventions. Language difficulties are one of the more distinctive traits in cognitive functioning of people with KS. It has also been suggested that the limitations in communication markedly affect social adaptation and behavioral aspects, as well as the development of personality. Moreover, difficulties in learning language appear to be related to an altered functional lateralization; therefore, KS subjects are a suitable model for studying genetic abnormalities of lateralization. In this, perspective psychopathological risk is analyzed. Early recognition of this aspect is needed to address the educational and therapeutic perspectives for KS subjects. PMID- 20197377 TI - Four exons of the serotonin receptor 4 gene are associated with multiple distant branch points. AB - Splicing of vertebrate introns involves recognition of three consensus elements at the 3' end. The branch point (BP) and polypyrimidine tract (PPT) are usually located within 40 nucleotides (nt) of the 3' splice site (3' ss), AG, but can be much more distant. A characteristic of the region between distant BPs (dBPs) and the 3' ss is the absence of intervening AG dinucleotides, leading to its designation as the "AG exclusion zone" (AGEZ). The human HTR4 gene, which encodes serotonin receptor 4 and has been associated with schizophrenia, bipolar disease, and gastrointestinal disorders, has four exons with extensive AGEZs. We have mapped the BPs for HTR4 exons 3, 4, 5, and g generated by in vitro splicing, and validated them by mutagenesis in exon-trapping vectors. All exons used dBPs up to 273 nt upstream of the exon. Strikingly, exons 4 and 5 used combinations of both distant and conventionally located BPs, suggesting that successful splicing of these exons can occur by distinct pathways. Our results emphasize the importance for single nucleotide polymorphism resequencing projects to take account of potential dBPs, as the extended AGEZs are vulnerable to mutations that could affect splicing itself or regulation of alternative splicing. PMID- 20197379 TI - 3-phosphoinositide-dependent protein kinase-1 regulates proliferation and survival of cancer cells with an activated mitogen-activated protein kinase pathway. AB - Engagement of cell surface receptor tyrosine kinases by insulin and growth factors activates phosphatidylinositol 3-kinase (PI3K) and generates the second messenger, phosphatidylinositol 3,4,5-trisphosphate. This second messenger leads to the recruitment of 3-phosphoinositide-dependent protein kinase-1 (PDK1) to the proximal side of the plasma membrane, which results in the activation of AKT kinase. In addition, PDK1 can phosphorylate numerous other kinases, including p90RSK, a kinase downstream of mitogen-activated protein kinase (MAPK) that is important for cell proliferation and survival. Previous studies have shown that the loss of PDK1 sensitizes tumor cells to chemotherapeutic agents and radiation but have not focused on delineating the contribution of PDK1 to pathway-specific mutations associated with various cancers other than the PI3K/AKT pathway. In this study, we show that the reduction of PDK1 by RNAi in melanoma and colon cancer cell lines activated in the MAPK pathway results in significant cell growth inhibition and apoptosis. Furthermore, PDK1 reduction in tumor cells resulted in impaired PAK kinase signaling, altered actin polymerization, and reduced cell migration. These studies show that PDK1 plays a pivotal role in MAPK and PI3K signaling in tumor cells. PMID- 20197380 TI - MLN8054, an inhibitor of Aurora A kinase, induces senescence in human tumor cells both in vitro and in vivo. AB - Aurora A kinase is a serine/threonine protein kinase responsible for regulating several mitotic processes including centrosome separation, spindle assembly, and chromosome segregation. Small molecule inhibitors of Aurora A kinase are being pursued as novel anticancer agents, some of which have entered clinical trials. Despite the progress in developing these agents, terminal outcomes associated with Aurora A inhibition are not fully understood. Although evidence exists that Aurora A inhibition leads to apoptosis, other therapeutically relevant cell fates have not been reported. Here, we used the small molecule inhibitor MLN8054 to show that inhibition of Aurora A induces tumor cell senescence both in vitro and in vivo. Treatment of human tumor cells grown in culture with MLN8054 showed a number of morphologic and biochemical changes associated with senescence. These include increased staining of senescence-associated beta-galactosidase, increased nuclear and cell body size, vacuolated cellular morphology, upregulation/stabilization of p53, p21, and hypophosphorylated pRb. To determine if Aurora A inhibition induces senescence in vivo, HCT-116 xenograft-bearing animals were dosed orally with MLN8054 for 3 weeks. In the MLN8054-treated animals, increased senescence-associated beta-galactosidase activity was detected in tissue sections starting on day 15. In addition, DNA and tubulin staining of tumor tissue showed a significant increase in nuclear and cell body area, consistent with a senescent phenotype. Taken together, this data shows that senescence is a terminal outcome of Aurora A inhibition and supports the evaluation of senescence biomarkers in clinic samples. PMID- 20197381 TI - Autotaxin signaling via lysophosphatidic acid receptors contributes to vascular endothelial growth factor-induced endothelial cell migration. AB - Important roles for vascular endothelial growth factor (VEGF) and autotaxin (ATX) have been established for embryonic vasculogenesis and cancer progression. We examined whether these two angiogenic factors cooperate in regulation of endothelial cell migratory responses. VEGF stimulated expression of ATX and LPA1, a receptor for the ATX enzymatic product lysophosphatidic acid (LPA), in human umbilical vein endothelial cells. Knockdown of ATX expression significantly decreased mRNA levels for the receptors LPA1, LPA2, S1P1, S1P2, S1P3, and VEGFR2 and abolished cell migration to lysophosphatidylcholine, LPA, recombinant ATX, and VEGF. Migration to sphingosylphosphorylcholine and sphinogosine-1-phosphate was also reduced in ATX knockdown cells, whereas migration to serum remained unchanged. Furthermore, ATX knockdown decreased Akt2 mRNA levels, whereas LPA treatment strongly stimulated Akt2 expression. We propose that VEGF stimulates LPA production by inducing ATX expression. VEGF also increases LPA1 signaling, which in turn increases Akt2 expression. Akt2 is strongly associated with cancer progression, cellular migration, and promotion of epithelial-mesenchymal transition. These data show a role for ATX in maintaining expression of receptors required for VEGF and lysophospholipids to accelerate angiogenesis. Because VEGF and ATX are upregulated in many cancers, the regulatory mechanism proposed in these studies could apply to cancer-related angiogenesis and cancer progression. These data further suggest that ATX could be a prognostic factor or a target for therapeutic intervention in several cancers. PMID- 20197383 TI - The tumor suppressor maspin mediates E2F1-induced sensitivity of cancer cells to chemotherapy. AB - The E2F1 transcription factor is a critical downstream target of the tumor suppressor RB. When activated, E2F1 can induce cell proliferation and/or apoptosis. In addition, E2F1 overexpression sensitizes cancer cells to chemotherapeutic drugs. In a screen for genes that are regulated synergistically by E2F1 and chemotherapy in cancer cells, we identified the proapoptotic tumor suppressor gene maspin (mammary serine protease inhibitor) as a novel E2F1 regulated gene. In line with being an E2F-regulated gene, maspin expression is inhibited by short hairpin RNA directed against E2F1 and increases upon activation of endogenous E2F. Furthermore, maspin mRNA and protein levels are elevated upon activation of exogenous E2F1. Importantly, we show that E2F1 mediated upregulation of maspin is enhanced by chemotherapeutic drugs, and inhibition of maspin expression significantly impairs the ability of E2F1 to promote chemotherapy-induced apoptosis. Summarily, our data indicate that maspin is an important effector of E2F1-induced chemosensitization. PMID- 20197382 TI - Skp2 directs Myc-mediated suppression of p27Kip1 yet has modest effects on Myc driven lymphomagenesis. AB - The universal cyclin-dependent kinase inhibitor p27(Kip1) functions as a tumor suppressor, and reduced levels of p27(Kip1) connote poor prognosis in several human malignancies. p27(Kip1) levels are predominately regulated by ubiquitin mediated turnover of the protein, which is marked for destruction by the E3 ubiquitin ligase SCF(Skp2) complex following its phosphorylation by the cyclin E cyclin-dependent kinase 2 complex. Binding of phospho-p27(Kip1) is directed by the Skp2 F-box protein, and this is greatly augmented by its allosteric regulator Cks1. We have established that programmed expression of c-Myc in the B cells of Emu-Myc transgenic mice triggers p27(Kip1) destruction by inducing Cks1, that this response controls Myc-driven proliferation, and that loss of Cks1 markedly delays Myc-induced lymphomagenesis and cancels the dissemination of these tumors. Here, we report that elevated levels of Skp2 are a characteristic of Emu-Myc lymphomas and of human Burkitt lymphoma that bear MYC/Immunoglobulin chromosomal translocations. As expected, Myc-mediated suppression of p27(Kip1) was abolished in Skp2-null Emu-Myc B cells. However, the effect of Skp2 loss on Myc-driven proliferation and lymphomagenesis was surprisingly modest compared with the effects of Cks1 loss. Collectively, these findings suggest that Cks1 targets, in addition to p27(Kip1), are critical for Myc-driven proliferation and tumorigenesis. PMID- 20197384 TI - PAX5alpha enhances the epithelial behavior of human mammary carcinoma cells. AB - Deregulated PAX5 expression has been associated with metastatic mammary carcinoma, although the precise role of PAX5 in cancer progression is unclear. Stable forced expression of PAX5alpha in the mammary carcinoma cell lines MCF-7 and MDA-MB-231 reduced cell cycle progression, cell survival, and anchorage independent cell growth. In xenograft studies, forced expression of PAX5alpha was associated with a significant reduction in tumor volume. Furthermore, forced expression of PAX5alpha in mammary carcinoma cells resulted in altered cell morphology with resultant enhancement of epithelial cell characteristics. Morphologic changes were associated with localization of beta-CATENIN at cell cell junctions and with altered mRNA expression of mesenchymal markers in mammary carcinoma cells. In addition, forced expression of PAX5alpha in MCF-7 and MDA-MB 231 cells significantly reduced cell migration and invasion. Concomitantly, small interfering RNA-mediated depletion of PAX5alpha increased MCF-7 total cell number, cell motility, migration, and invasion. These studies show that PAX5alpha enhances the epithelial characteristics of mammary carcinoma cells, reminiscent of mesenchymal to epithelial transition. PMID- 20197385 TI - CNK1 promotes invasion of cancer cells through NF-kappaB-dependent signaling. AB - Hallmarks of cancer cells are uncontrolled proliferation, evasion of apoptosis, angiogenesis, cell invasion, and metastasis, which are driven by oncogenic activation of signaling pathways. Herein, we identify the scaffold protein CNK1 as a mediator of oncogenic signaling that promotes invasion in human breast cancer and cervical cancer cells. Downregulation of CNK1 diminishes the invasiveness of cancer cells and correlates with reduced expression of matrix metalloproteinase 9 (MMP-9) and membrane-type 1 MMP (MT1-MMP). Ectopic expression of CNK1 elevates MT1-MMP promoter activity in a NF-kappaB-dependent manner. Moreover, CNK1 cooperates with the NF-kappaB pathway, but not with the extracellular signal-regulated protein kinase pathway, to promote cell invasion. Mechanistically, CNK1 regulates the alternative branch of the NF-kappaB pathway because knockdown of CNK1 interferes with processing of NF-kappaB2 p100 to p52 and its localization to the nucleus. In agreement with this, the invasion of CNK1 depleted cells is less sensitive to RelB downregulation compared with the invasion of control cells. Moreover, CNK1-dependent MT1-MMP promoter activation is blocked by RelB siRNA. Thus, CNK1 is an essential mediator of an oncogenic pathway involved in invasion of breast and cervical cancer cells and is therefore a putative target for cancer therapy. PMID- 20197386 TI - Estimation of the population attributable fraction for mortality in a cohort study using a piecewise constant hazards model. AB - Quantification of the impact of exposure to modifiable risk factors on a particular outcome at the population level is a fundamental public health issue. In cohort studies, the population attributable fraction (PAF) is used to assess the proportion of the outcome that is attributable to exposure to certain risk factors in a given population during a certain time interval. This is done by combining information about the prevalence of the risk factor in the population with estimates of the strength of the association between the risk factor and the outcome. In case of mortality, the PAF demonstrates what proportion of mortality can be delayed during the given follow-up time. However, literature on carrying out model-based estimation of PAF and its variance in cohort studies while properly taking follow-up time into account is still scarce. In this article, the authors present formulas for estimation of PAF, its variance, and its confidence interval using the piecewise constant hazards model and apply a SAS macro created for the estimation of PAF (SAS Institute Inc., Cary, North Carolina) to estimate the mortality attributable to some common risk factors. PMID- 20197387 TI - SB939, a novel potent and orally active histone deacetylase inhibitor with high tumor exposure and efficacy in mouse models of colorectal cancer. AB - Although clinical responses in liquid tumors and certain lymphomas have been reported, the clinical efficacy of histone deacetylase inhibitors in solid tumors has been limited. This may be in part due to the poor pharmacokinetic of these drugs, resulting in inadequate tumor concentrations of the drug. SB939 is a new hydroxamic acid based histone deacetylase inhibitor with improved physicochemical, pharmaceutical, and pharmacokinetic properties. In vitro, SB939 inhibits class I, II, and IV HDACs, with no effects on other zinc binding enzymes, and shows significant antiproliferative activity against a wide variety of tumor cell lines. It has very favorable pharmacokinetic properties after oral dosing in mice, with >4-fold increased bioavailability and 3.3-fold increased half-life over suberoylanilide hydroxamic acid (SAHA). In contrast to SAHA, SB939 accumulates in tumor tissue and induces a sustained inhibition of histone acetylation in tumor tissue. These excellent pharmacokinetic properties translated into a dose-dependent antitumor efficacy in a xenograft model of human colorectal cancer (HCT-116), with a tumor growth inhibition of 94% versus 48% for SAHA (both at maximum tolerated dose), and was also effective when given in different intermittent schedules. Furthermore, in APC(min) mice, a genetic mouse model of early-stage colon cancer, SB939 inhibited adenoma formation, hemocult scores, and increased hematocrit values more effectively than 5-fluorouracil. Emerging clinical data from phase I trials in cancer patients indicate that the pharmacokinetic and pharmacologic advantages of SB939 are translated to the clinic. The efficacy of SB939 reported here in two very different models of colorectal cancer warrants further investigation in patients. PMID- 20197388 TI - Wnt inhibitory factor 1 decreases tumorigenesis and metastasis in osteosarcoma. AB - It has been reported that the progression of osteosarcoma was closely associated with the aberrant activation of canonical Wnt signaling. Wnt inhibitory factor-1 (WIF-1) is a secreted Wnt inhibitor whose role in human osteosarcoma remains unknown. In this study, WIF-1 expression in NHOst and osteosarcoma cell lines was determined by real-time reverse transcription-PCR, methylation-specific PCR, and Western blotting analysis. In addition, tissue array from patient samples was examined for WIF-1 expression by immunohistochemistry. Compared with normal human osteoblasts, WIF-1 mRNA and protein levels were significantly downregulated in several osteosarcoma cell lines. The downregulation of WIF-1 mRNA expression is associated with its promoter hypermethylation in these tested cell lines. Importantly, WIF-1 expression was also downregulated in 76% of examined osteosarcoma cases. These results suggest that the downregulation of WIF-1 expression plays a role in osteosarcoma progression. To further study the potential tumor suppressor function of WIF-1 in osteosarcoma, we established stable 143B cell lines overexpressing WIF-1. WIF-1 overexpression significantly decreased tumor growth rate in nude mice as examined by the s.c. injection of 143B cells stably transfected with WIF-1 and vector control. WIF-1 overexpression also markedly reduced the number of lung metastasis in vivo in an orthotopic mouse model of osteosarcoma. Together, these data suggest that WIF-1 exerts potent antiosteosarcoma effect in vivo in mouse models. Therefore, the reexpression of WIF-1 in WIF-1-deficient osteosarcoma represents a potential novel treatment and preventive strategy. PMID- 20197389 TI - 2-methoxyestradiol inhibits Barrett's esophageal adenocarcinoma growth and differentiation through differential regulation of the beta-catenin-E-cadherin axis. AB - The purpose of this study was to evaluate whether 2-methoxyestradiol (2-ME(2)), a promising anticancer agent, modulates Barrett's esophageal adenocarcinoma (BEAC) cell growth and behavior through a cellular pathway involving beta-catenin in partnership with E-cadherin, which seems to play a critical role in the induction of antitumor responses in cancer cells. We found that 2-ME(2) markedly reduced the BEAC cell proliferation through regulating apoptotic machinery such as Bcl-2 and Bax. It may nullify the aggressive behavior of the cells by reducing the migratory behavior. Expressions of beta-catenin and E-cadherin and binding of these two proteins is activated in a 2-ME(2)-dependent fashion in Bic-1 cells. Moreover, overexpressions of these two proteins may be due to the stabilization of these proteins by 2-ME(2). We found that 2-ME(2)-induced antimigratory effects are mediated through the beta-catenin-E-cadherin signaling pathways. In view of these results, we determined whether 2-ME(2) reduces BEAC tumor growth. Administration of 2-ME2 significantly decreased the growth of BEAC cells xenografted on the flank of nude mice. The evidence presented points out that the effect of 2-ME(2) on beta-catenin-orchestrated signal transduction plausibly plays a multifaceted functional role to inhibit the proliferation and cell migration of 2-ME(2)-treated malignant cells and it could be a potential candidate in novel treatment strategies for Barrett's esophageal adenocarcinoma. PMID- 20197392 TI - ABL alternative splicing is quite frequent in normal population - letter. PMID- 20197390 TI - Molecular pharmacology and antitumor activity of PHT-427, a novel Akt/phosphatidylinositide-dependent protein kinase 1 pleckstrin homology domain inhibitor. AB - Phosphatidylinositol 3-kinase/phosphatidylinositide-dependent protein kinase 1 (PDPK1)/Akt signaling plays a critical role in activating proliferation and survival pathways within cancer cells. We report the molecular pharmacology and antitumor activity of PHT-427, a compound designed to bind to the pleckstrin homology (PH) binding domain of signaling molecules important in cancer. Although originally designed to bind the PH domain of Akt, we now report that PHT-427 also binds to the PH domain of PDPK1. A series of PHT-427 analogues with variable C-4 to C-16 alkyl chain length were synthesized and tested. PHT-427 itself (C-12 chain) bound with the highest affinity to the PH domains of both PDPK1 and Akt. PHT-427 inhibited Akt and PDPK1 signaling and their downstream targets in sensitive but not resistant cells and tumor xenografts. When given orally, PHT 427 inhibited the growth of human tumor xenografts in immunodeficient mice, with up to 80% inhibition in the most sensitive tumors, and showed greater activity than analogues with C4, C6, or C8 alkyl chains. Inhibition of PDPK1 was more closely correlated to antitumor activity than Akt inhibition. Tumors with PIK3CA mutation were the most sensitive, and K-Ras mutant tumors were the least sensitive. Combination studies showed that PHT-427 has greater than additive antitumor activity with paclitaxel in breast cancer and with erlotinib in non small cell lung cancer. When given >5 days, PHT-427 caused no weight loss or change in blood chemistry. Thus, we report a novel PH domain binding inhibitor of PDPK1/Akt signaling with significant in vivo antitumor activity and minimal toxicity. PMID- 20197393 TI - Interactions of the p53 protein family in cellular stress response in gastrointestinal tumors. AB - p53, p63, and p73 are members of the p53 protein family involved in regulation of cell cycle, apoptosis, differentiation, and other critical cellular processes. Here, we investigated the contribution of the entire p53 family in chemotherapeutic drug response in gastrointestinal tumors. Real-time PCR and immunohistochemistry revealed complexity and variability of expression profiles of the p53 protein family. Using colon and esophageal cancer cells, we found that the integral transcription activity of the entire p53 family, as measured by the reporter analysis, associated with response to drug treatment in studied cells. We also found that p53 and p73, as well as p63 and p73, bind simultaneously to the promoters of p53 target genes. Taken together, our results support the view that the p53 protein family functions as an interacting network of proteins and show that cellular responses to chemotherapeutic drug treatment are determined by the total activity of the entire p53 family rather than p53 alone. PMID- 20197394 TI - ABT-869 inhibits the proliferation of Ewing Sarcoma cells and suppresses platelet derived growth factor receptor beta and c-KIT signaling pathways. AB - The Ewing Sarcoma (EWS) family of tumors is one of the most common tumors diagnosed in children and adolescents and is characterized by a translocation involving the EWS gene. Despite advances in chemotherapy, the prognosis of metastatic EWS is poor with an overall survival of <30% after 5 years. EWS tumor cells express the receptor tyrosine kinases, platelet-derived growth factor receptor (PDGFR) and c-KIT. ABT-869 is a multitargeted small-molecule inhibitor that targets Fms-like tyrosine kinase-3, c-KIT, vascular endothelial growth receptors, and PDGFRs. To determine the potential therapeutic benefit of ABT-869 in EWS cells, we examined the effects of ABT-869 on EWS cell lines and xenograft mouse models. ABT-869 inhibited the proliferation of two EWS cell lines, A4573 and TC71, at an IC(50) of 1.25 and 2 mumol/L after 72 h of treatment, respectively. The phosphorylation of PDGFRbeta, c-KIT, and extracellular signal regulated kinases was also inhibited. To examine the effects of ABT-869 in vivo, the drug was given to mice injected with EWS cells. We observed inhibition of growth of EWS tumor cells in a xenograft mouse model and prolonged survival in a metastatic mouse model of EWS. Therefore, our in vitro and in vivo studies show that ABT-869 inhibits proliferation of EWS cells through inhibition of PDGFRbeta and c-KIT pathways. PMID- 20197395 TI - Doxorubicin resistance in a novel in vitro model of human pleomorphic liposarcoma associated with alternative lengthening of telomeres. AB - Soft tissue sarcomas are a diverse set of fatal human tumors where few agents have demonstrable clinical efficacy, with the standard therapeutic combination of doxorubicin and ifosfamide showing only a 25% to 30% response rate in large multi institutional trials. Although liposarcomas are the most common histologic form of adult soft tissue sarcomas, research in this area is severely hampered by the lack of experimentally tractable in vitro model systems. To this end, here we describe a novel in vitro model for human pleomorphic liposarcoma. The cell line (LS2) is derived from a pleomorphic liposarcoma that uses the alternative lengthening of telomeres (ALT) mechanism of telomere maintenance, which may be important in modulating the response of this tumor type to DNA-damaging agents. We present detailed baseline molecular and genomic data, including genome-wide copy number and transcriptome profiles, for this model compared with its parental tumor and a panel of liposarcomas covering multiple histologies. The model has retained essentially all of the detectable alterations in copy number that are seen in the parental tumor, and shows molecular karyotypic and expression profiles consistent with pleomorphic liposarcomas. We also show the utility of this model, together with two additional human liposarcoma cell lines, to investigate the relationship between topoisomerase 2A expression and the sensitivity of ALT-positive liposarcomas to doxorubicin. This model, together with its associated baseline data, provides a powerful new tool to develop treatments for this clinically poorly tractable tumor and to investigate the contribution that ALT makes to modulating sensitivity to doxorubicin. PMID- 20197397 TI - Efficacy of PHA-848125, a cyclin-dependent kinase inhibitor, on the K Ras(G12D)LA2 lung adenocarcinoma transgenic mouse model: evaluation by multimodality imaging. AB - K-ras is the most frequently mutated oncogene in non-small cell lung cancer (NSCLC), the most common form of lung cancer. Recent studies indicate that NSCLC patients with mutant K-ras do not respond to epidermal growth factor receptor inhibitors. In the attempt to find alternative therapeutic regimes for such patients, we tested PHA-848125, an oral pan cyclin-dependent kinase inhibitor currently under evaluation in phase II clinical trial, on a transgenic mouse model, K-Ras(G12D)LA2, which develops pulmonary cancerous lesions reminiscent of human lung adenocarcinomas. We used magnetic resonance imaging and positron emission tomography to follow longitudinally disease progression and evaluate therapeutic efficacy in this model. Treatment of K-Ras(G12D)LA2 mice with 40 mg/kg twice daily for 10 days with PHA-848125 induced a significant tumor growth inhibition at the end of treatment (P < 0.005) and this was accompanied by a reduction in the cell membrane turnover, as seen by 11C-Choline-positron emission tomography (P < 0.05). Magnetic resonance imaging data were validated versus histology and the mechanism of action of the compound was verified by immunohistochemistry, using cyclin-dependent kinase-related biomarkers phospho Retinoblastoma and cyclin A. In this study, multimodality imaging was successfully used for the preclinical assessment of PHA-848125 therapeutic efficacy on a lung adenocarcinoma mouse model. This compound induced a volumetric and metabolic anticancer effect and could represent a valid therapeutic approach for NSCLC patients with mutant K-ras. PMID- 20197396 TI - Phase I combination of sorafenib and erlotinib therapy in solid tumors: safety, pharmacokinetic, and pharmacodynamic evaluation from an expansion cohort. AB - The aims of this study were to further define the safety of sorafenib and erlotinib, given at their full approved monotherapy doses, and to correlate pharmacokinetic and pharmacodynamic markers with clinical outcome. In addition, a novel pharmacodynamic marker based on the real-time measurement of RAF signal transduction capacity (STC) is described. Sorafenib was administered alone for a 1-week run-in period, and then both drugs were given together continuously. RAF STC was assessed in peripheral blood monocytes prior to erlotinib initiation. Epidermal growth factor receptor (EGFR) expression and K-RAS mutations were measured in archival tumor samples. Changes in pERK and CD31 were determined in fresh tumor biopsies obtained pretreatment, prior to erlotinib dosing, and during the administration of both drugs. In addition, positron emission tomography computed tomography scans and pharmacokinetic assessments were done. Eleven patients received a total of 57 cycles (median, 5; range, 1-10). Only four patients received full doses of both drugs for the entire study course, with elevation of liver enzymes being the main reason for dose reductions and delays. Among 10 patients evaluable for response, 8 experienced tumor stabilization of >or=4 cycles. Pharmacokinetic analysis revealed no significant interaction of erlotinib with sorafenib. Sorafenib-induced decrease in RAF-STC showed statistically significant correlation with time-to-progression in seven patients. Other pharmacodynamic markers did not correlate with clinical outcome. This drug combination resulted in promising clinical activity in solid tumor patients although significant toxicity warrants close monitoring. RAF-STC deserves further study as a predictive marker for sorafenib. PMID- 20197398 TI - Antiangiogenic activities of 2,5-dimethyl-celecoxib on the tumor vasculature. AB - Our laboratory has previously shown that a novel compound, 2,5-dimethyl-celecoxib (DMC), which is structurally similar to the cyclooxygenase-2 (COX-2) inhibitor celecoxib but lacks the COX-2-inhibitory function, mimics the antitumor effects of celecoxib. Most studies on DMC, however, focused on its effects on tumor cells. Here, we investigated the activities of DMC as an antiangiogenic agent in both in vitro and in vivo systems. Using primary cultures of human glioma specimens, we found that DMC treatment was cytotoxic to tumor-associated brain endothelial cells (TuBEC), which was mediated through the endoplasmic reticulum stress pathway. In contrast, confluent cultures of quiescent human BEC did not undergo cell death. DMC potently suppressed the proliferation and migration of the TuBEC. DMC caused no apparent effects on the secretion of vascular endothelial growth factor and interleukin-8 but inhibited the secretion of endothelin-1 in tumor-associated EC. DMC treatment of glioma xenografts in mice resulted in smaller tumors with a pronounced reduction in microvessel density compared with untreated mice. In vitro and in vivo analyses confirmed that DMC has antivascular activity. Considering that DMC targets both tumor cells and tumor-associated ECs, this agent is a promising anticancer drug. PMID- 20197399 TI - Anacardic acid inhibits estrogen receptor alpha-DNA binding and reduces target gene transcription and breast cancer cell proliferation. AB - Anacardic acid (AnAc; 2-hydroxy-6-alkylbenzoic acid) is a dietary and medicinal phytochemical with established anticancer activity in cell and animal models. The mechanisms by which AnAc inhibits cancer cell proliferation remain undefined. AnAc 24:1(omega5) was purified from geranium (Pelargonium x hortorum) and shown to inhibit the proliferation of estrogen receptor alpha (ERalpha)-positive MCF-7 and endocrine-resistant LCC9 and LY2 breast cancer cells with greater efficacy than ERalpha-negative primary human breast epithelial cells, MCF-10A normal breast epithelial cells, and MDA-MB-231 basal-like breast cancer cells. AnAc 24:1(omega5) inhibited cell cycle progression and induced apoptosis in a cell specific manner. AnAc 24:1(omega5) inhibited estradiol (E(2))-induced estrogen response element (ERE) reporter activity and transcription of the endogenous E(2) target genes pS2, cyclin D1, and cathepsin D in MCF-7 cells. AnAc 24:1(omega5) did not compete with E(2) for ERalpha or ERbeta binding, nor did AnAc 24:1(omega5) reduce ERalpha or ERbeta steady-state protein levels in MCF-7 cells; rather, AnAc 24:1(omega5) inhibited ER-ERE binding in vitro. Virtual screening with the molecular docking software Surflex evaluated AnAc 24:1(omega5) interaction with ERalpha ligand binding (LBD) and DNA binding (DBD) domains in conjunction with experimental validation. Molecular modeling revealed AnAc 24:1(omega5) interaction with the ERalpha DBD but not the LBD. Chromatin immunoprecipitation experiments revealed that AnAc 24:1(omega5) inhibited E(2) ERalpha interaction with the endogenous pS2 gene promoter region containing an ERE. These data indicate that AnAc 24:1(omega5) inhibits cell proliferation, cell cycle progression, and apoptosis in an ER-dependent manner by reducing ER-DNA interaction and inhibiting ER-mediated transcriptional responses. PMID- 20197400 TI - Alisol B, a novel inhibitor of the sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase pump, induces autophagy, endoplasmic reticulum stress, and apoptosis. AB - Emerging evidence suggests that autophagic modulators have therapeutic potential. This study aims to identify novel autophagic inducers from traditional Chinese medicinal herbs as potential antitumor agents. Using an image-based screen and bioactivity-guided purification, we identified alisol B 23-acetate, alisol A 24 acetate, and alisol B from the rhizome of Alisma orientale as novel inducers of autophagy, with alisol B being the most potent natural product. Across several cancer cell lines, we showed that alisol B-treated cells displayed an increase of autophagic flux and formation of autophagosomes, leading to cell cycle arrest at the G(1) phase and cell death. Alisol B induced calcium mobilization from internal stores, leading to autophagy through the activation of the CaMKK-AMPK mammalian target of rapamycin pathway. Moreover, the disruption of calcium homeostasis induces endoplasmic reticulum stress and unfolded protein responses in alisol B-treated cells, leading to apoptotic cell death. Finally, by computational virtual docking analysis and biochemical assays, we showed that the molecular target of alisol B is the sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase. This study provides detailed insights into the cytotoxic mechanism of a novel antitumor compound. PMID- 20197402 TI - IFN-beta restricts tumor growth and sensitizes alveolar rhabdomyosarcoma to ionizing radiation. AB - Ionizing radiation is an important component of multimodal therapy for alveolar rhabdomyosarcoma (ARMS). We sought to evaluate the ability of IFN-beta to enhance the activity of ionizing radiation. Rh-30 and Rh-41 ARMS cells were treated with IFN-beta and ionizing radiation to assess synergistic effects in vitro and as orthotopic xenografts in CB17 severe combined immunodeficient mice. In addition to effects on tumor cell proliferation and xenograft growth, changes in the tumor microenvironment including interstitial fluid pressure, perfusion, oxygenation, and cellular histology were assessed. A nonlinear regression model and isobologram analysis indicated that IFN-beta and ionizing radiation affected antitumor synergy in vitro in the Rh-30 cell line; the activity was additive in the Rh-41 cell line. In vivo continuous delivery of IFN-beta affected normalization of the dysfunctional tumor vasculature of both Rh-30 and Rh-41 ARMS xenografts, decreasing tumor interstitial fluid pressure, increasing tumor perfusion (as assessed by contrast-enhanced ultrasonography), and increasing oxygenation. Tumors treated with both IFN-beta and radiation were smaller than control tumors and those treated with radiation or IFN-beta alone. Additionally, treatment with high-dose IFN-beta followed by radiation significantly reduced tumor size compared with radiation treatment followed by IFN-beta. The combination of IFN-beta and ionizing radiation showed synergy against ARMS by sensitizing tumor cells to the cytotoxic effects of ionizing radiation and by altering tumor vasculature, thereby improving oxygenation. Therefore, IFN-beta and ionizing radiation may be an effective combination for treatment of ARMS. PMID- 20197401 TI - Sorafenib inhibits STAT3 activation to enhance TRAIL-mediated apoptosis in human pancreatic cancer cells. AB - Signal transducers and activators of transcription 3 (STAT3) is constitutively active in human pancreatic cancer cells and can promote cell growth and apoptosis resistance that contribute to tumorigenesis. We determined if sorafenib, a multikinase inhibitor, can induce apoptosis by targeting STAT3 signaling to enhance apoptosis induction by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Human pancreatic cancer cell lines (PANC-1 and BxPC-3) were preincubated with sorafenib (Nexavar) alone or followed by TRAIL. Apoptosis was determined by Annexin V labeling, caspase cleavage, and Bax/Bak activation. Protein expression was analyzed by immunoblotting. Knockdown of STAT3, Mcl-1, and Bim were achieved by lentiviral small hairpin RNA. Adenoviral dominant-negative or retroviral constitutively active (CA) STAT3 were also used. Sorafenib inhibited constitutive STAT3 phosphorylation (Tyr(705)) and suppressed Mcl-1 and Bcl-x(L) proteins in a dose- and time-dependent manner. CA-STAT3 overexpression was shown to attenuate caspase-3 cleavage and suppression of Mcl-1 by sorafenib. STAT3 knockdown or a DN STAT3 was shown to downregulate Mcl-1 and Bcl-x(L) and to sensitize cells to TRAIL-mediated apoptosis. Treatment with sorafenib enhanced TRAIL-induced Annexin V staining and release of mitochondrial cytochrome c and AIF. Because the BH3-only Bim protein is a potent inducer of mitochondrial apoptosis, Bim knockdown was shown to attenuate caspase-3, caspase-9 cleavage, and Bax/Bak activation by sorafenib plus TRAIL. The suppression of STAT3 by genetic means or using sorafenib was shown to downregulate Mcl-1 and Bcl-x(L) and to sensitize cells to TRAIL-mediated apoptosis. These data indicate that targeting STAT3 may enhance treatment efficacy against pancreatic cancer. PMID- 20197403 TI - CXCR7 is an active component of SDF-1 signalling in astrocytes and Schwann cells. AB - The alternative SDF-1 (stromal cell derived factor-1) receptor, CXCR7, has been suggested to act as either a scavenger of extracellular SDF-1 or a modulator of the primary SDF-1 receptor, CXCR4. CXCR7, however, also directly affects the function of various tumor-cell types. Here, we demonstrate that CXCR7 is an active component of SDF-1 signalling in astrocytes and Schwann cells. Cultured cortical astrocytes and peripheral nerve Schwann cells exhibit comparable total and cell-surface levels of expression of both SDF-1 receptors. Stimulation of astrocytes with SDF-1 resulted in the temporary activation of Erk1/2, Akt and PKCzeta/lambda, but not p38 and PKCalpha/beta. Schwann cells showed SDF-1-induced activation of Erk1/2, Akt and p38, but not PKCalpha/beta and PKCzeta/lambda. The respective signalling pattern remained fully inducible in astrocytes from CXCR4 deficient mice, but was abrogated following depletion of astrocytic CXCR7 by RNAi. In Schwann cells, RNAi-mediated depletion of either CXCR4 or CXCR7 silenced SDF-1 signalling. The findings of the astrocytic receptor-depletion experiments were reproduced by CXCR7 antagonist CCX754, but not by CXCR4 antagonist AMD3100, both of which abolished astrocytic SDF-1 signalling. Further underlining the functional importance of CXCR7 signalling in glial cells, we show that the mitogenic effects of SDF-1 on both glial cell types are impaired upon depleting CXCR7. PMID- 20197404 TI - Polarity proteins and Rho GTPases cooperate to spatially organise epithelial actin-based protrusions. AB - Different actin-filament-based structures co-exist in many cells. Here, we characterise dynamic actin-based protrusions that form at distinct positions within columnar epithelial cells, focusing on basal filopodia and sheet-like intermediate-level protrusions that extend between surrounding epithelial cells. Using a genetic analysis, we found that the form and distribution of these actin filament-based structures depends on the activities of apical polarity determinants, not on basal integrin signalling. Bazooka/Par3 acts upstream of the RacGEF Sif/TIAM1 to limit filopodia to the basal domain, whereas Cdc42, aPKC and Par6 are required for normal protrusion morphology and dynamics. Downstream of these polarity regulators, Sif/TIAM1, Rac, SCAR and Arp2/3 complexes catalyse actin nucleation to generate lamellipodia and filopodia, whose form depends on the level of Rac activation. Taken together, these data reveal a role for Baz/Par3 in the establishment of an intercellular gradient of Rac inhibition, from apical to basal, and an intimate association between different apically concentrated Par proteins and Rho-family GTPases in the regulation of the distribution and structure of the polarised epithelial actin cytoskeleton. PMID- 20197405 TI - The Puf-family RNA-binding protein PfPuf2 regulates sexual development and sex differentiation in the malaria parasite Plasmodium falciparum. AB - Translation regulation plays an important role during gametocytogenesis in the malaria parasite, a process that is obligatory for the transmission of the parasite through mosquito vectors. In this study we determined the function of PfPuf2, a member of the Puf family of translational repressors, in gametocytogenesis of Plasmodium falciparum. Tagging of the endogenous PfPuf2 protein with green fluorescent protein showed that PfPuf2 was expressed in both male and female gametocytes, and the protein was localized in the cytoplasm of the parasite. Targeted disruption of the PfPuf2 gene did not affect asexual growth of the parasite, but promoted the formation of gametocytes and differentiation of male gametocytes. Complementation studies were performed to confirm that the resultant phenotypic changes were due to disruption of the PfPuf2 gene. Episomal expression of PfPuf2 under its cognate promoter almost restored the gametocytogenesis rate in a PfPuf2 disruptant to the level of the wild-type parasite. It also partially restored the effect of PfPuf2 disruption on male-female sex ratio. In addition, episomal overexpression of PfPuf2 under its cognate promoter but with a higher concentration of the selection drug or under the constitutive hsp86 promoter in both the PfPuf2-disruptant and wild-type 3D7 lines, further dramatically reduced gametocytogenesis rates and sex ratios. These findings suggest that in this early branch of eukaryotes the function of PfPuf2 is consistent with the ancestral function of suppressing differentiation proposed for Puf-family proteins. PMID- 20197406 TI - Changes in Bni4 localization induced by cell stress in Saccharomyces cerevisiae. AB - Septin complexes at the bud neck in Saccharomyces cerevisiae serve as a scaffold for proteins involved in signaling, cell cycle control, and cell wall synthesis. Many of these bind asymmetrically, associating with either the mother- or daughter-side of the neck. Septin structures are inherently apolar so the basis for the asymmetric binding remains unknown. Bni4, a regulatory subunit of yeast protein phosphatase type 1, Glc7, binds to the outside of the septin ring prior to bud formation and remains restricted to the mother-side of the bud neck after bud emergence. Bni4 is responsible for targeting Glc7 to the mother-side of the bud neck for proper deposition of the chitin ring. We show here that Bni4 localizes symmetrically, as two distinct rings on both sides of the bud neck following energy depletion or activation of cell cycle checkpoints. Our data indicate that loss of Bni4 asymmetry can occur via at least two different mechanisms. Furthermore, we show that Bni4 has a Swe1-dependent role in regulating the cell morphogenesis checkpoint in response to hydroxyurea, which suggests that the change in localization of Bni4 following checkpoint activation may help stabilize the cell cycle regulator Swe1 during cell cycle arrest. PMID- 20197407 TI - Early initiation of a replication origin tethered at the nuclear periphery. AB - Peripheral nuclear localization of chromosomal loci correlates with late replication in yeast and metazoan cells. To test whether peripheral positioning can impose late replication, we examined whether artificial tethering of an early initiating replication origin to the nuclear periphery delays its replication in budding yeast. We tested the effects of three different peripheral tethering constructs on the time of replication of the early replication origin ARS607. Using the dense-isotope transfer method to assess replication time, we found that ARS607 still replicates early when tethered to the nuclear periphery using the Yif1 protein or a fragment of Sir4, whereas tethering using a Yku80 construct produces only a very slight replication delay. Single-cell microscopic analysis revealed no correlation between peripheral positioning of ARS607 in individual cells and delayed replication. Overall, our results demonstrate that a replication origin can initiate replication early in S phase, even if artificially relocated to the nuclear periphery. PMID- 20197408 TI - MAPK scaffolding by BIT1 in the Golgi complex modulates stress resistance. AB - The endoplasmic reticulum (ER) is an essential organelle whose major functions are to ensure proper secretory protein folding and trafficking. These mechanisms involve the activation of specific ER-resident molecular machines, which might be regulated by their membranous environments. Based on this observation, we aimed to characterize the proteome of ER-membrane microdomains to identify new components of the ER that have a role in secretory pathway-associated functions. Using this approach with dog pancreatic rough microsomes, we found that mitochondrial Bcl-2 inhibitor of transcription (BIT1) localized in the early secretory pathway and accumulated in the Golgi complex. Using both a chimeric protein of the luminal and transmembrane domains of ER-resident TRAPalpha and the cytosolic domain of BIT1, and silencing of BIT1 expression, we perturbed endogenous BIT1 oligomerization and localization to the Golgi. This led to enhanced ERK signaling from the Golgi complex, which resulted in improved stress resistance. This work provides the first evidence for the existence of ER microdomains that are involved in the regulation of BIT1 structure and trafficking, and identifies BIT1 as a negative regulator of the ERK-MAPK signaling pathway in the Golgi. PMID- 20197409 TI - Molecular mechanisms underlying nucleocytoplasmic shuttling of actinin-4. AB - In addition to its well-known role as a crosslinker of actin filaments at focal adhesion sites, actinin-4 is known to be localized to the nucleus. In this study, we reveal the molecular mechanism underlying nuclear localization of actinin-4 and its novel interactions with transcriptional regulators. We found that actinin 4 is imported into the nucleus through the nuclear pore complex in an importin independent manner and is exported by the chromosome region maintenance-1 (CRM1) dependent pathway. Nuclear actinin-4 levels were significantly increased in the late G2 phase of the cell cycle and were decreased in the G1 phase, suggesting that active release from the actin cytoskeleton was responsible for increased nuclear actinin-4 in late G2. Nuclear actinin-4 was found to interact with the INO80 chromatin-remodeling complex. It also directs the expression of a subset of cell-cycle-related genes and interacts with the upstream-binding factor (UBF) dependent rRNA transcriptional machinery in the M phase. These findings provide molecular mechanisms for both nucleocytoplasmic shuttling of proteins that do not contain a nuclear-localization signal and cell-cycle-dependent gene regulation that reflects morphological changes in the cytoskeleton. PMID- 20197410 TI - Epigenetic maturation in colonic mucosa continues beyond infancy in mice. AB - Monozygotic twin and other epidemiologic studies indicate that epigenetic processes may play an important role in the pathogenesis of inflammatory bowel diseases that commonly affect the colonic mucosa. The peak onset of these disorders in young adulthood suggests that epigenetic changes normally occurring in the colonic mucosa shortly before adulthood could be important etiologic factors. We assessed developmental changes in colitis susceptibility during the physiologically relevant period of childhood in mice [postnatal day 30 (P30) to P90] and concurrent changes in DNA methylation and gene expression in murine colonic mucosa. Susceptibility to colitis was tested in C57BL/6J mice with the dextran sulfate sodium colitis model. Methylation specific amplification microarray (MSAM) was used to screen for changes in DNA methylation, with validation by bisulfite pyrosequencing. Gene expression changes were analyzed by microarray expression profiling and real time RT-PCR. Mice were more susceptible to chemically induced colitis at P90 than at P30. DNA methylation changes, however, were not extensive; of 23 743 genomic intervals interrogated, only 271 underwent significant methylation alteration during this developmental period. We found an excellent correlation between the MSAM and bisulfite pyrosequencing at 11 gene associated intervals validated (R(2) = 0.89). Importantly, at the genes encoding galectin-1 (Lgals1), and mothers against decapentaplegic homolog 3 or Smad3, both previously implicated in murine colitis, developmental changes in DNA methylation from P30 to P90 were inversely correlated with expression. Colonic mucosal epigenetic maturation continues through early adulthood in the mouse, and may contribute to the age-associated increase in colitis susceptibility. Transcript Profiling: Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/), accession numbers: GSE18031 (DNA methylation arrays), GSE19506 (gene expression arrays). PMID- 20197411 TI - Parkinson's disease-related LRRK2 G2019S mutation results from independent mutational events in humans. AB - Mutations in the leucine-rich-repeat kinase 2 (LRRK2) gene have been identified in families with autosomal dominant Parkinson's disease (PD) and in sporadic cases; the G2019S mutation is the single most frequent. Intriguingly, the frequency of this mutation in PD patients varies greatly among ethnic groups and geographic origins: it is present at <0.1% in East Asia, approximately 2% in European-descent patients and can reach frequencies of up to 15-40% in PD Ashkenazi Jews and North African Arabs. To ascertain the evolutionary dynamics of the G2019S mutation in different populations, we genotyped 74 markers spanning a 16 Mb genomic region around G2019S, in 191 individuals carrying the mutation from 126 families of different origins. Sixty-seven families were of North-African Arab origin, 18 were of North/Western European descent, 37 were of Jewish origin, mostly from Eastern Europe, one was from Japan, one from Turkey and two were of mixed origins. We found the G2019S mutation on three different haplotypes. Network analyses of the three carrier haplotypes showed that G2019S arose independently at least twice in humans. In addition, the population distribution of the intra-allelic diversity of the most widespread carrier haplotype, together with estimations of the age of G2019S determined by two different methods, suggests that one of the founding G2019S mutational events occurred in the Near East at least 4000 years ago. PMID- 20197412 TI - Variation in the uric acid transporter gene (SLC2A9) and memory performance. AB - Understanding human cognitive ageing is important to improve the health of an increasing elderly population. Serum uric acid levels have been linked to many ageing illnesses and are also linked to cognitive functioning, though the direction of the association is equivocal. SLC2A9, a urate transporter, influences uric acid levels. This study first tested four SLC2A9 SNPs, previously associated with uric acid levels, in approximately 1000 Scots: the Lothian Birth Cohort 1936 (LBC1936). These participants were tested on general cognitive ability at ages 11 and 70. At age 70, they took a battery of diverse cognitive tests. Two replication cohorts were investigated. First, the LBC1921, who were tested on general cognitive ability at age 11. At ages 79 (n = 520), 83 (n = 281) and age 87 (n = 177), they completed cognitive ability test batteries. Second, the Edinburgh Type 2 Diabetes Study (ET2DS) were tested for cognitive abilities aged between 60 and 75 years (n = 1066). All analyses were adjusted for age, gender, body mass index and either childhood cognitive ability test score (LBC) or vocabulary-a measure of prior cognitive ability in ET2DS. Significant associations were detected with SLC2A9 and a general memory factor in LBC1936 and other individual cognitive ability tests (lowest P = 0.0002). The association with logical memory replicated in LBC1921 at all ages (all P < 0.05). These associations were not replicated in ET2DS (all P > 0.1). If the positive associations withstand, then this study could suggest that higher uric acid levels may be associated with increased performance on memory-related tasks. PMID- 20197417 TI - Ascidians: an invertebrate chordate model to study Alzheimer's disease pathogenesis. AB - Here we present the ascidian Ciona intestinalis as an alternative invertebrate system to study Alzheimer's disease (AD) pathogenesis. Through the use of AD animal models, researchers often attempt to reproduce various aspects of the disease, particularly the coordinated processing of the amyloid precursor protein (APP) by alpha-, beta- and gamma-secretases to generate amyloid beta (Abeta) containing plaques. Recently, Drosophila and C. elegans AD models have been developed, exploiting the relative simplicity of these invertebrate systems, but they lack a functional Abeta sequence and a beta-secretase ortholog, thus complicating efforts to examine APP processing in vivo. We propose that the ascidian is a more appropriate invertebrate AD model owing to their phylogenetic relationship with humans. This is supported by bioinformatic analyses, which indicate that the ascidian genome contains orthologs of all AD-relevant genes. We report that transgenic ascidian larvae can properly process human APP(695) to generate Abeta peptides. Furthermore, Abeta can rapidly aggregate to form amyloid like plaques, and plaque deposition is significantly increased in larvae expressing a human APP(695) variant associated with familial Alzheimer's disease. We also demonstrate that nervous system-specific Abeta expression alters normal larval behavior during attachment. Importantly, plaque formation and alterations in behavior are not only observed within 24 hours post-fertilization, but anti amyloid drug treatment improves these AD-like pathologies. This ascidian model for AD provides a powerful and rapid system to study APP processing, Abeta plaque formation and behavioral alterations, and could aid in identifying factors that modulate amyloid deposition and the associated disruption of normal cellular function and behaviors. PMID- 20197418 TI - Loss of fibulin-5 binding to beta1 integrins inhibits tumor growth by increasing the level of ROS. AB - Tumor survival depends in part on the ability of tumor cells to transform the surrounding extracellular matrix (ECM) into an environment conducive to tumor progression. Matricellular proteins are secreted into the ECM and impact signaling pathways that are required for pro-tumorigenic activities such as angiogenesis. Fibulin-5 (Fbln5) is a matricellular protein that was recently shown to regulate angiogenesis; however, its effect on tumor angiogenesis and thus tumor growth is currently unknown. We report that the growth of pancreatic tumors and tumor angiogenesis is suppressed in Fbln5-null (Fbln5(-/-)) mice compared with wild-type (WT) littermates. Furthermore, we observed an increase in the level of reactive oxygen species (ROS) in tumors grown in Fbln5(-/-) animals. Increased ROS resulted in elevated DNA damage, increased apoptosis of endothelial cells within the tumor, and represented the underlying cause for the reduction in angiogenesis and tumor growth. In vitro, we identified a novel pathway by which Fbln5 controls ROS production through a mechanism that is dependent on beta1 integrins. These results were validated in Fbln5(RGE/RGE) mice, which harbor a point mutation in the integrin-binding RGD motif of Fbln5, preventing its interaction with integrins. Tumor growth and angiogenesis was reduced in Fbln5(RGE/RGE) mice, however treatment with an antioxidant rescued angiogenesis and elevated tumor growth to WT levels. These findings introduce a novel function for Fbln5 in the regulation of integrin-induced ROS production and establish a rationale for future studies to examine whether blocking Fbln5 function could be an effective anti-tumor strategy, alone or in combination with other therapies. PMID- 20197419 TI - Metabolomic study of the LDL receptor null mouse fed a high-fat diet reveals profound perturbations in choline metabolism that are shared with ApoE null mice. AB - Failure to express or expression of dysfunctional low-density lipoprotein receptors (LDLR) causes familial hypercholesterolemia in humans, a disease characterized by elevated blood cholesterol concentrations, xanthomas, and coronary heart disease, providing compelling evidence that high blood cholesterol concentrations cause atherosclerosis. In this study, we used (1)H nuclear magnetic resonance spectroscopy to examine the metabolic profiles of plasma and urine from the LDLR knockout mice. Consistent with previous studies, these mice developed hypercholesterolemia and atherosclerosis when fed a high fat/cholesterol/cholate-containing diet. In addition, multivariate statistical analysis of the metabolomic data highlighted significant differences in tricarboxylic acid cycle and fatty acid metabolism, as a result of high fat/cholesterol diet feeding. Our metabolomic study also demonstrates that the effect of high-fat/cholesterol/cholate diet, LDLR gene deficiency, and the diet genotype interaction caused a significant perturbation in choline metabolism, notably the choline oxidation pathway. Specifically, the loss in the LDLR caused a marked reduction in the urinary excretion of betaine and dimethylglycine, especially when the mice are fed a high-fat/cholesterol/cholate diet. Furthermore, as we demonstrate that these metabolic changes are comparable with those detected in ApoE knockout mice fed the same high-fat/cholesterol/cholate diet they may be useful for monitoring the onset of atherosclerosis across animal models. PMID- 20197420 TI - Suppression subtractive hybridization analysis of low-protein diet- and vitamin D induced gene expression from rat kidney inner medullary base. AB - Protein restriction and hypercalcemia result in a urinary concentrating defect in rats and humans. Previous tubular perfusion studies show that there is an increased active urea transport activity in the initial inner medullary (IM) collecting duct in low-protein diet (LPD) and vitamin D (Vit D) animal models. To investigate the possible mechanisms that cause the urinary concentrating defect and to clone the new active urea transporter, we employed a modified two-tester suppression subtractive hybridization (ttSSH) approach and examined gene expression induced by LPD and Vit D in kidney IM base. Approximately 600 clones from the subtracted library were randomly selected; 150 clones were further confirmed to be the true positive genes by slot blot hybridization with subtracted probes from LPD and Vit D and sent for DNA sequencing. We identified 10 channel/transporter genes that were upregulated in IM base in LPD and Vit D animal models; 8 were confirmed by real-time PCR. These genes include aquaporin 2 (AQP2), two-pore calcium channel protein 2, brain-specific organic cation transporter, Na(+)- and H(+)-coupled glutamine transporter, and solute carrier family 25. Nine genes are totally new, and twelve are uncharacterized hypothetical proteins. Among them, four genes were shown to be new transmembrane proteins as judged by Kyte-Doolittle hydrophobic plot analysis. ttSSH provides a useful method to identify new genes from two conditioned populations. PMID- 20197422 TI - Time for action regarding cardiovascular emergency care at sports arenas: a lesson from the Arena study. PMID- 20197421 TI - Intermittent and sustained hypoxia induce a similar gene expression profile in human aortic endothelial cells. AB - Obstructive sleep apnea may cause vascular inflammation and atherosclerosis, which has been attributed to intermittent hypoxia (IH). Recent data suggest that IH, but not sustained hypoxia (SH), activates proinflammatory genes in HeLa cells. Effects of IH and SH on the gene expression profile in human aortic endothelial cells (HAEC) have not been compared. We perfused media with alternating flow of 16% and 0% O2 (IH) or constant flow of 4% O2 (SH-4%), 8% O2 (SH-8%), or 16% O2 (control) for 8 h. Illumina gene microarrays were performed, with subsequent verification by real-time PCR. Proinflammatory cytokines in the media were measured by ELISA. Both IH and SH-4% upregulated proinflammatory genes, including heat shock protein 90-kDa B1, tumor necrosis factor superfamily member 4, and thrombospondin 1. Among all proinflammatory genes, only IL-8 mRNA showed significantly higher levels of expression (1.78-fold) during IH, compared with SH-4%, but both types of hypoxic exposure elicited striking three- to eightfold increases in IL-8 and IL-6 protein levels in the media. IH and SH-4% also upregulated antioxidant genes, including heme oxygenase-1 and nuclear factor (erythroid-derived 2)-like 2 (NRF2), whereas classical genes regulated by hypoxia inducible factor 1 (HIF-1), such as endothelin and glucose transporter GLUT1, were not induced. SH-8% induced changes in gene expression and cytokine secretion that were similar to those of IH and SH-4%. In conclusion, short exposures to IH and SH upregulate proinflammatory and antioxidant genes in HAEC and increase secretion of proinflammatory cytokines IL-8 and IL-6 into media in similar fashions. PMID- 20197423 TI - Incremental prognostic significance of left ventricular dysfunction to coronary artery disease detection by 64-detector row coronary computed tomographic angiography for the prediction of all-cause mortality: results from a two-centre study of 5330 patients. AB - AIMS: Early reports indicate a prognostic value of coronary artery disease (CAD) detection by coronary computed tomographic angiography (CCTA), although studies have been limited by small samples in single centres. Coronary computed tomographic angiographic measures of left ventricular ejection fraction (LVEF) to add incremental prognostic value beyond CAD detection have not been examined. METHODS AND RESULTS: We evaluated 5330 consecutive patients without known CAD undergoing CCTA at two centres. Stenosis severity by CCTA was graded as none (0%), mild (1-49%), moderate (50-69%), or obstructive (> or = 70%). Left ventricular ejection fraction was graded as normal (>50%) or reduced (< or = 50%). About 2.3 +/- 0.6 year follow-up of patients for all-cause mortality was performed using multivariate and Cox proportional hazards models; 100 deaths occurred (1.9%). Detection of obstructive CAD correlated with mortality [hazards ratio (HR) 2.44, 95% confidence interval (CI) 1.61-3.72, P < 0.001]. Compared with those without obstructive CAD, individuals with increasing numbers of vessels with obstructive CAD experienced increased risk of death: 1-vessel (HR 2.23, 95% CI 1.34-3.72), 2-vessel (HR 3.29, 95% CI 1.62-6.71), or 3-vessel (HR 7.35, 95% CI 3.79-14.29) (P < 0.001 for all). Compared with those with LVEF >50%, those with LVEF < or = 50% exhibited higher rates of death (HR 1.56, 95% CI 1.04 2.36, P = 0.03). Annualized mortality rates in those with non-obstructive CAD and LVEF >50% were low (0.51%) and increased accordingly for non-obstructive CAD and LVEF < or = 50% (0.74%), obstructive CAD and LVEF >50% (1.76%), and obstructive CAD and LVEF < or = 50% (3.97%) (log-rank test P < 0.001). CONCLUSION: In a large two-centre cohort of patients without known CAD, obstructive CAD detection by CCTA was related to incident death by the absolute presence of as well as increasing numbers of vessels with obstructive CAD. The addition of LVEF by CCTA enhanced risk correlation for death. PMID- 20197424 TI - Prediction of cardiovascular events and all-cause mortality with central haemodynamics: a systematic review and meta-analysis. AB - AIMS: To calculate robust quantitative estimates on the predictive value of central pressures and derived central haemodynamic indices for cardiovascular (CV) outcomes and all-cause mortality by meta-analysis of longitudinal studies. METHODS AND RESULTS: We meta-analysed 11 longitudinal studies that had employed measures of central haemodynamics and had followed 5648 subjects for a mean follow-up of 45 months. The age- and risk-factor-adjusted pooled relative risk (RR) of total CV events was 1.088 (95% CI 1.040-1.139) for a 10 mmHg increase of central systolic pressure, 1.137 (95% CI 1.063-1.215) for a 10 mmHg increase of central pulse pressure (PP), and 1.318 (95% CI 1.093-1.588) for a 10% absolute increase of central augmentation index (AIx). Furthermore, we found that a 10% increase of central AIx was associated with a RR of 1.384 (95% CI 1.192-1.606) for all-cause mortality. When compared with brachial PP, central PP was associated with marginally but not significantly higher RR of clinical events (P = 0.057). CONCLUSION: Central haemodynamic indexes are independent predictors of future CV events and all-cause mortality. Augmentation index predicts clinical events independently of peripheral pressures, while central PP has a marginally but not significantly (P = 0.057) better predictive ability when compared with peripheral PP. PMID- 20197426 TI - Choosing asthma step-up care. PMID- 20197427 TI - Lumbar vertebral chordoma arising from an intraosseous benign notochordal cell tumour: radiological findings and histopathological description with a good clinical outcome. AB - Benign notochordal cell tumours have recently been described as intraosseous benign lesions of notochordal cell origin. The lesions are found in vertebral bodies in 20% of autopsy studies and are a potential precursor of chordoma. We report a rare case of lumbar vertebral chordoma that was thought to arise from a benign intraosseous notochordal cell tumour and which showed significant osteosclerotic change. Radiologically, the lumbar vertebral mass lesion showed hyperintensity on T2 weighted images, with scanty enhancement on post-contrast T1 weighted MR images. High uptake corresponding to the mass was noted on fluorine 18-fluorodeoxyglucose positron emission tomography. Bone biopsy revealed proliferation of the physaliphorous cells between thickened bone trabeculae; no nuclear mitosis was observed. Although the mass was diagnosed clinically as spinal chordoma, histopathology contained both benign notochordal cell tumour and conventional chordoma. After heavy particle (11C)-charged radiation therapy was applied to the lesion with a sufficient radiation field margin, the tumour volume significantly decreased and there was improvement in the patient's symptoms. On follow-up radiological studies, the tumour had markedly regressed and there was no tumour regrowth or distant metastasis. In this case report, benign notochordal cell tumour and conventional chordoma are histopathologically identified in the L1 vertebral body, which contains osteosclerotic and osteolytic areas. It is suggested that the benign notochordal cell tumour coexists with a conventional chordoma and that this histopathological finding supports a hypothetical relationship between benign notochordal cell tumour and chordoma. PMID- 20197428 TI - Small cell lung carcinoma presenting with acute disseminated encephalomyelitis. AB - Acute disseminated encephalomyelitis (ADEM) is a demyelinating disease characterised by subcortical high-signal white matter lesions on T2 weighted MRI. It most commonly occurs in children following an acute viral illness. We present a case study in which ADEM was the presenting condition in an adult female with small cell lung carcinoma. We discuss the evidence in the literature suggesting that ADEM may be viewed as a paraneoplastic syndrome. PMID- 20197429 TI - Pulmonary tuberculosis associated with the reversed halo sign on high-resolution CT. AB - We describe the case of a 32-year-old woman with pulmonary tuberculosis in whom a high-resolution CT scan demonstrated the reversed halo sign. The diagnosis of tuberculosis was made by lung biopsy and the detection of acid-fast bacilli in the sputum smear and culture. Follow-up assessment revealed a significant improvement in the lesions. PMID- 20197425 TI - Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. AB - BACKGROUND: For children who have uncontrolled asthma despite the use of low-dose inhaled corticosteroids (ICS), evidence to guide step-up therapy is lacking. METHODS: We randomly assigned 182 children (6 to 17 years of age), who had uncontrolled asthma while receiving 100 microg of fluticasone twice daily, to receive each of three blinded step-up therapies in random order for 16 weeks: 250 microg of fluticasone twice daily (ICS step-up), 100 microg of fluticasone plus 50 microg of a long-acting beta-agonist twice daily (LABA step-up), or 100 microg of fluticasone twice daily plus 5 or 10 mg of a leukotriene-receptor antagonist daily (LTRA step-up). We used a triple-crossover design and a composite of three outcomes (exacerbations, asthma-control days, and the forced expiratory volume in 1 second) to determine whether the frequency of a differential response to the step-up regimens was more than 25%. RESULTS: A differential response occurred in 161 of 165 patients who were evaluated (P<0.001). The response to LABA step-up therapy was most likely to be the best response, as compared with responses to LTRA step-up (relative probability, 1.6; 95% confidence interval [CI], 1.1 to 2.3; P=0.004) and ICS step-up (relative probability, 1.7; 95% CI, 1.2 to 2.4; P=0.002). Higher scores on the Asthma Control Test before randomization (indicating better control at baseline) predicted a better response to LABA step up (P=0.009). White race predicted a better response to LABA step-up, whereas black patients were least likely to have a best response to LTRA step-up (P=0.005). CONCLUSIONS: Nearly all the children had a differential response to each step-up therapy. LABA step-up was significantly more likely to provide the best response than either ICS or LTRA step-up. However, many children had a best response to ICS or LTRA step-up therapy, highlighting the need to regularly monitor and appropriately adjust each child's asthma therapy. (ClinicalTrials.gov number, NCT00395304.) PMID- 20197430 TI - Papillary adenocarcinoma arising in a tubular duplication of the jejunum. AB - Alimentary tract duplications are uncommon congenital anomalies containing a normal gastrointestinal mucosa and smooth muscle layer. Intestinal duplication in the jejunum is rare, and any malignancy arising in the jejunal duplication is extremely rare. In this report, we present the first case of papillary adenocarcinoma arising in a tubular duplication of the jejunum. Coronal reformatted images from contrast-enhanced CT revealed a well-enhanced tubular mass in the distal jejunum with small bowel obstruction. There were multiple enlarged lymph nodes in the small bowel mesentery around the superior mesenteric artery. The typical macroscopic and histological findings were present. PMID- 20197431 TI - Sciatic hernia causing sciatica: MRI and MR neurography showing entrapment of sciatic nerve. AB - Sciatic hernia is a rare condition with diverse clinical manifestations. We report a case of sciatic hernia causing sciatica, in which the diagnosis made on CT was subsequently confirmed on MRI including magnetic resonance neurography. The salient clinical and imaging features and a brief review are presented. PMID- 20197432 TI - Skull base hydatid cyst with intracranial extension presenting as vocal cord palsy: a case report. AB - Hydatid disease of the skull base is extremely rare, and intracranial extension of hydatid cysts through the skull base is even rarer. We report an interesting case of a 42-year-old man who presented with features of right vocal cord palsy. The diagnosis of hydatid cyst was made based on his history and on pre-operative MRI and was confirmed by surgery and histopathological examination. PMID- 20197433 TI - Image-guided radiation therapy: what is our Utopia? PMID- 20197435 TI - Miliary tuberculosis: a comparison of CT findings in HIV-seropositive and HIV seronegative patients. AB - The aim of this study was to determine the differences in CT findings of miliary tuberculosis in patients with and without HIV infection. Two radiologists reviewed retrospectively the CT findings of 15 HIV-seropositive and 14 HIV seronegative patients with miliary tuberculosis. The decisions on the findings were reached by consensus. Statistical analysis was performed using the chi2 test, Mann-Whitney U-test and Fisher's exact test. All of the HIV-seropositive and -seronegative patients had small nodules and micronodules distributed randomly throughout both lungs. HIV-seropositive patients had a higher prevalence of interlobular septal thickening (p = 0.017), necrotic lymph nodes (p = 0.005) and extrathoracic involvement (p = 0.040). The seropositive patients had a lower prevalence of large nodules (p = 0.031). In conclusion, recognition of the differences in the radiological findings between HIV-seropositive and seronegative patients may help in the establishment of an earlier diagnosis of immune status in patients with miliary tuberculosis. PMID- 20197434 TI - Imaging the pericardium: appearances on ECG-gated 64-detector row cardiac computed tomography. AB - Multidetector row computed tomography (MDCT) with its high spatial and temporal resolution has now become an established and complementary method for cardiac imaging. It can now be used reliably to exclude significant coronary artery disease and delineate complex coronary artery anomalies, and has become a valuable problem-solving tool. Our experience with MDCT imaging suggests that it is clinically useful for imaging the pericardium. It is important to be aware of the normal anatomy of the pericardium and not mistake normal variations for pathology. The pericardial recesses are visible in up to 44% of non electrocardiogram (ECG)-gated MDCT images. Abnormalities of the pericardium can now be identified with increasing certainty on 64-detector row CT; they may be the key to diagnosis and therefore must not be overlooked. This educational review of the pericardium will cover different imaging techniques, with a significant emphasis on MDCT. We have a large research and clinical experience of ECG-gated cardiac CT and will demonstrate examples of pericardial recesses, their variations and a wide variety of pericardial abnormalities and systemic conditions affecting the pericardium. We give a brief relevant background of the conditions and reinforce the key imaging features. We aim to provide a pictorial demonstration of the wide variety of abnormalities of the pericardium and the pitfalls in the diagnosis of pericardial disease. PMID- 20197436 TI - An unusual perisplenic mass. PMID- 20197437 TI - Distant friends, close strangers? Inferring friendships from behavior. PMID- 20197438 TI - Efficiency and specificity of CTXphi chromosomal integration: dif makes all the difference. PMID- 20197439 TI - Final PET CGMP regulation. PMID- 20197450 TI - Development of a traceable calibration methodology for solid (68)Ge/(68)Ga sources used as a calibration surrogate for (18)F in radionuclide activity calibrators. AB - We have developed a methodology for calibrating (68)Ge radioactivity content in a commercially available calibration source for activity calibrators in a way that is traceable to the national standard. Additionally, the source was cross calibrated for equivalent (18)F content by direct comparison with the national standard for (18)F in the same geometry. METHODS: Sources containing standardized (68)GeCl(4) or (18)F-FDG solutions were prepared at the National Institute of Standards and Technology (NIST) with mock syringe blanks used in the construction of a commercially available epoxy-based (68)Ge calibration source. These sources and several NIST-constructed epoxy-based (68)Ge mock syringes were then used as artifact standards to determine calibration factors for NIST-maintained activity calibrators and secondary standard ionization chambers to enable calibration of the actual commercial sources. A direct comparison between the solution-based (68)Ge sources and the (18)F-FDG sources allowed for an empiric determination of the relative response for these radionuclides in several commercial activity calibrators. Potential measurement effects due to differences between the solution composition and the epoxy and theoretic (68)Ge-to-(18)F response ratios were studied by Monte Carlo simulation. RESULTS: The calibration factors developed in this study enabled NIST to calibrate epoxy-based mock syringe sources with a relative combined standard uncertainty of 0.52%. The direct comparisons of the (68)Ge and (18)F standards in the various ionization chambers allowed the activity to be expressed in terms of equivalent (18)F activity with a relative combined standard uncertainty of about 0.9%. CONCLUSION: The ability for NIST to calibrate these epoxy-based mock syringes enabled, for the first time to our knowledge, the direct traceability to the national (68)Ge standard to be established for this type of source. Through a direct comparison with the NIST (18)F standard, the determination of the relative response ratios in activity calibrators enabled the equivalent (18)F activity to be determined in a way that was also traceable to the national (18)F activity standard. PMID- 20197451 TI - RADAR realistic animal model series for dose assessment. AB - Rodent species are widely used in the testing and approval of new radiopharmaceuticals, necessitating murine phantom models. As more therapy applications are being tested in animal models, calculating accurate dose estimates for the animals themselves becomes important to explain and control potential radiation toxicity or treatment efficacy. Historically, stylized and mathematically based models have been used for establishing doses to small animals. Recently, a series of anatomically realistic human phantoms was developed using body models based on nonuniform rational B-spline. Realistic digital mouse whole-body (MOBY) and rat whole-body (ROBY) phantoms were developed on the basis of the same NURBS technology and were used in this study to facilitate dose calculations in various species of rodents. METHODS: Voxel-based versions of scaled MOBY and ROBY models were used with the Vanderbilt multinode computing network (Advanced Computing Center for Research and Education), using geometry and tracking radiation transport codes to calculate specific absorbed fractions (SAFs) with internal photon and electron sources. Photon and electron SAFs were then calculated for relevant organs in all models. RESULTS: The SAF results were compared with values from similar studies found in reference literature. Also, the SAFs were used with standardized decay data to develop dose factors to be used in radiation dose calculations. Representative plots were made of photon electron SAFs, evaluating the traditional assumption that all electron energy is absorbed in the source organs. CONCLUSION: The organ masses in the MOBY and ROBY models are in reasonable agreement with models presented by other investigators noting that considerable variation can occur between reported masses. Results consistent with those found by other investigators show that absorbed fractions for electrons for organ self-irradiation were significantly less than 1.0 at energies above 0.5 MeV, as expected for many of these small sized organs, and measurable cross-irradiation was observed for many organ pairs for high-energy electrons (as would be emitted by nuclides such as (32)P, (90)Y, or (188)Re). PMID- 20197452 TI - Cadmium induced-oxidative stress in pituitary gland is reversed by removing the contamination source. AB - Cadmium (Cd(2+)) is one of the most important environmental contaminants and acts as an endocrine disruptor. Previously, we have demonstrated that the simultaneous administration of Cd(2+) and melatonin (Mel) in drinking water impaired metal induced oxidative stress in rat anterior pituitary gland. The aim of this study was to investigate if a treatment started after the toxic manifestations of Cd( 2+) became evident could reverse the effects of the metal. Animals exposed to Cd(2+) (5 parts per million [ppm], 30 days) were treated with Mel or without the metal during the next 1 or 2 months. Cd(2+) exposure increased the expression of heme oxygenase-1 (HO-1), a biomarker of oxidative stress, and an a posteriori Mel treatment reversed oxidative stress induced by Cd(2+). This effect was also observed 1 month after metal removal. The Cd(2+)-induced increase in metallothionein-1 (MT-1) and nitric oxide synthase 1 (NOS1) expression were also reversed by metal removal. In addition, serum prolactin and luteinizing hormone levels affected by Cd( 2+) exposure were normalized. Considering that the manifestations of Cd(2+) intoxication become evident only after a certain period of metal accumulation, these results show that metal removal is enough to reverse Cd(2+) effects in anterior pituitary gland and bring to light the relevance of moving away the individual from the contamination source. PMID- 20197453 TI - Solanum lyratum extract affected immune response in normal and leukemia murine animal in vivo. AB - Solanum lyratum Thunberg (Solanaceae) has been used as a folk medicine for treating liver, lung and esophagus in the Chinese population. Our previous studies have shown that the crude extract of S. lyratum Thunberg (SLE) induced apoptosis in colo 205 human colon adenocarcinoma cells; however, there is no report to show SLE affect immune responses in vivo. In this study, the in vivo effects of SLE on leukemia WEHI-3 cells and immune responses such as phagocytosis and natural killer (NK) cell activity in normal and leukemia mice were investigated. The SLE treatment decreases surface markers of CD3 and Mac-3 in normal and leukemia mice but promoted the cell markers of CD19 and CD11b in normal mice and CD11b in leukemia mice indicating that the precursors of T cells was inhibited and B cells and macrophage were promoted. The SLE treatment promoted the activity of macrophage phagocytosis in the peripheral blood mononuclear cells (PBMC) and peritoneal cells from normal and leukemia mice. The results also showed that NK cells from the normal and leukemia mice after treatment with SLE can kill the YAC-1 target cells. Therefore, the SLE treatment increased macrophage and NK cell activities. These consistent results indicate SLE could be a potent immune responses agent. PMID- 20197454 TI - Evaluation of Myrtus communis Linn. berries (common myrtle) in experimental ulcer models in rats. AB - The present study was conducted to investigate the protective effect of the dried berries of Myrtus communis L. in gastric ulcer against ethanol, indomethacin and pyloric ligation induced models in Wistar rats. Two doses of aqueous extracts of M. communis (AE( 1) and AE(2)) at the dose 105 and 175 mg/kg, respectively, and methanolic extracts (ME(1) and ME(2)) at the dose of 93 and 154 mg/kg, respectively, were administered orally to animals prior to the exposure of ulcerogens. The parameters taken to assess anti-ulcer activity were ulcer index, gastric juice volume, gastric pH, total acidity, gastric wall mucus and histopathological studies. Oral administration of AE(1) and AE(2) significantly reduced the ulcer index in all models of ulcers. Low dose of aqueous extract and high dose of methanolic extract of M. communis exhibited more significant effect in comparison to omeprazole (standard drug) in ethanol-induced ulcer model. Both the doses of aqueous and methanolic extracts also reduced the gastric juice volume, total acidity and increased the gastric pH and gastric wall mucus content in all the models of ulcers used in the present study. Histopathological examinations of gastric tissues of rats treated with the aqueous and methanolic extracts in indomethacin-induced ulcer exhibited significant ulcer-protective effect at both the dose levels. PMID- 20197455 TI - Surfactant protein-A enhances ureaplasmacidal activity in vitro. AB - BACKGROUND: Persistent respiratory tract colonization with Ureaplasma spp. in preterm infants is a significant risk factor for the development of the chronic lung disorder, bronchopulmonary dysplasia (BPD). Surfactant protein-A (SP-A), a lung collectin critical for bacterial clearance and regulating inflammation, is deficient in the preterm lung. In an experimental Ureaplasma-pneumonia model, infected SP-A deficient mice exhibited delayed bacterial clearance and an exaggerated inflammatory response compared to infected wild-type mice. The objective was to analyze the role of SP-A in Ureaplasma clearance in vitro. SUBJECTS AND METHODS: We analyzed SP-A binding to Ureaplasma isolates and SP-A mediated ureaplasmal phagocytosis and killing by cultured RAW 264.7 macrophages. RESULTS: Calcium-dependent SP-A binding was similar among Ureaplasma isolates tested. Pre-incubation of RAW 264.7 cells with SP-A (10-50 MUg/ml) enhanced phagocytosis of fluorescein-isothiocyanate (FITC)-labeled Ureaplasma. Surfactant protein-A also increased ureaplasmacidal activity of RAW 264.7 cells by 2.1-fold over 4 h. Pre-incubation of RAW 264.7 cells with 10 MUg/ml SP-A reduced lipopolysaccharide (LPS) (100 ng/ml) and Ureaplasma (10(6) color changing units/ml)-stimulated release of tumor necrosis factor-alpha (TNF-alpha) by 46% and 43%, respectively, but did not affect transforming growth factor beta(1) (TGFbeta(1)) release. CONCLUSIONS: These in vitro data confirm that SP-A is important in host defense to perinatally-acquired Ureaplasma infection. PMID- 20197456 TI - How black African and white British women perceive depression and help-seeking: a pilot vignette study. AB - BACKGROUND: The detection of psychological problems of black African people has been found to be substantially lower, compared with white British and black Caribbean people. This may be due to differences in patients' perceptions of illness. Little research has been carried out on factors that may influence the help-seeking behaviour of black Africans. AIMS: To assess differences in the perceptions of depression of black African and white British women that may influence lower detection and to investigate whether there are ethnic group differences in reasons for not seeking formal help. METHODS: A short quantitative illness perception measure, the Brief Illness Perception Questionnaire (BIPQ), was used in a community survey, using a standard text vignette methodology to control for variations in previous experiences of depression. Responses from women who indicated that they would not seek formal help for depressive symptoms were qualitatively analyzed. RESULTS: Differences in perceptions of depression were found between black African (n = 73) and white British groups (n = 72) on five of the nine BIPQ dimensions. Black women were more likely to perceive depression to have less serious consequences; to be associated with fewer symptoms; to be less chronic; to be less amenable to treatment; and more frequently attributed depression to social factors. Over half the participants (n = 74) said they would not seek formal help for depressive symptoms. Six qualitative response categories emerged to explain non-consultation. The most common factor for both groups related to GP consultation difficulties. Significantly more white women cited preferring alternative help sources as a reason for non-consultation. The greater number of black women citing anti medication beliefs was marginally significant. There were no differences between the ethnic groups in their use of the remaining three categories: illness characteristics; service constraints; and stigma/shame. CONCLUSION: Differing perceptions of depression among black and white women could help explain GPs' lower detection rates of depressive problems of black women. Differences in views about the formal help available may explain ethnic differences in help-seeking. PMID- 20197457 TI - A comparison of levels of burden in Indian and white parents with a son or daughter with schizophrenia. AB - BACKGROUND: Caregiver burden in mental illness is believed to differ between ethnic groups, but few studies have examined this in schizophrenia in the UK. AIM: To measure burden in British North Indian Sikh and white British parents with a son or daughter with established schizophrenia managed in outpatient care. METHOD: A cross-cultural cohort study measuring family factors, patient psychopathology and levels of burden and distress. RESULTS: Overall levels of burden were low with no significant differences between the groups. Burden subscale scores showed Indian parents were more affected by psychotic behaviours than white parents. The groups also differed on several sociodemographic variables. CONCLUSION: In stabilized community patients, the overall extent of burden experienced by both Indian and white parents is low and comparable. However, Indian parents were more burdened by psychotic behaviours. This may be a result of co-residence as Indian patients are more likely to live with their families. Social and economic factors in the country of residence and levels of acculturation may also influence levels of burden and the illness behaviours found most bothersome by parents. PMID- 20197458 TI - Does clinical experience or professional training have an impact on what symptoms are thought to be important features of depression? AB - BACKGROUND: Concerning diagnostics of mental disorders, increasing time and cost pressure in the clinical practice often requires an ad hoc and intuitive holistic examination of the patient's clinical presentation instead of the application of standardized diagnostic instruments. This study examined whether attributes of mental healthcare professionals (professional training, clinical experience, socio-demographic variables) affect their implicit weighing of symptoms they encounter in such unstandardized diagnostic situations. METHODS: Twenty psychiatrists and 28 clinical psychologists rated the relevance of 241 items for the diagnosis of a depressive episode. Items referred to the nine A-criteria of DSM-IV and associated features. Intraclass correlations (ICC), regression analysis and t-tests were calculated. RESULTS: Clinicians agreed largely in their relevance judgements on the different items ( ICC = 0.97, F (183,8784) = 44.29, p < 0.001). Stepwise regression analyses with profession, clinical experience, age and gender as predictors for each DSM-IV A-criterion revealed no significant beta coefficient except for one: 'profession' was a significant predictor for the mean relevance judgement on items that could not be assigned to an A-criterion. This effect turned out to be caused by only one item (obsessive-compulsive behaviour). CONCLUSIONS: Clinical experts agree highly in their implicit weighing of depression symptoms regardless of their age, gender, clinical experience and professional training. PMID- 20197459 TI - Antibody-maytansinoid conjugates designed to bypass multidrug resistance. AB - Conjugation of cytotoxic compounds to antibodies that bind to cancer-specific antigens makes these drugs selective in killing cancer cells. However, many of the compounds used in such antibody-drug conjugates (ADC) are substrates for the multidrug transporter MDR1. To evade the MDR1-mediated resistance, we conjugated the highly cytotoxic maytansinoid DM1 to antibodies via the maleimidyl-based hydrophilic linker PEG(4)Mal. Following uptake into target cells, conjugates made with the PEG(4)Mal linker were processed to a cytotoxic metabolite that was retained by MDR1-expressing cells better than a metabolite of similar conjugates prepared with the nonpolar linker N-succinimidyl-4-(maleimidomethyl)cyclohexane-1 carboxylate (SMCC). In accord, PEG(4)Mal-linked conjugates were more potent in killing MDR1-expressing cells in culture. In addition, PEG(4)Mal-linked conjugates were markedly more effective in eradicating MDR1-expressing human xenograft tumors than SMCC-linked conjugates while being tolerated similarly, thus showing an improved therapeutic index. This study points the way to the development of ADCs that bypass multidrug resistance. PMID- 20197460 TI - Pooled analysis of phosphatidylinositol 3-kinase pathway variants and risk of prostate cancer. AB - The phosphatidylinositol 3-kinase (PI3K) pathway regulates various cellular processes, including cellular proliferation and intracellular trafficking, and may affect prostate carcinogenesis. Thus, we explored the association between single-nucleotide polymorphisms (SNP) in PI3K genes and prostate cancer. Pooled data from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium were examined for associations between 89 SNPs in PI3K genes (PIK3C2B, PIK3AP1, PIK3C2A, PIK3CD, and PIK3R3) and prostate cancer risk in 8,309 cases and 9,286 controls. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using logistic regression. SNP rs7556371 in PIK3C2B was significantly associated with prostate cancer risk [OR(per allele), 1.08 (95% CI, 1.03-1.14); P(trend) = 0.0017] after adjustment for multiple testing (P(adj) = 0.024). Simultaneous adjustment of rs7556371 for nearby SNPs strengthened the association [OR(per allele), 1.21 (95% CI, 1.09-1.34); P(trend) = 0.0003]. The adjusted association was stronger for men who were diagnosed before the age of 65 years [OR(per allele), 1.47 (95% CI, 1.20-1.79); P(trend) = 0.0001] or had a family history [OR(per allele) = 1.57 (95% CI, 1.11-2.23); P(trend) = 0.0114], and was strongest in those with both characteristics [OR(per allele) = 2.31 (95% CI, 1.07 5.07), P-interaction = 0.005]. Increased risks were observed among men in the top tertile of circulating insulin-like growth factor-I (IGF-I) levels [OR(per allele) = 1.46 (95% CI, 1.04-2.06); P(trend) = 0.075]. No differences were observed with disease aggressiveness (Gleason grade >or=8 or stage T(3)/T(4) or fatal). In conclusion, we observed a significant association between PIK3C2B and prostate cancer risk, especially for familial, early-onset disease, which may be attributable to IGF-dependent PI3K signaling. PMID- 20197461 TI - CD44 attenuates activation of the hippo signaling pathway and is a prime therapeutic target for glioblastoma. AB - Glioblastoma multiforme (GBM) is the most aggressive brain tumor that, by virtue of its resistance to chemotherapy and radiotherapy, is currently incurable. Identification of molecules whose targeting may eliminate GBM cells and/or sensitize glioblastoma cells to cytotoxic drugs is therefore urgently needed. CD44 is a major cell surface hyaluronan receptor and cancer stem cell marker that has been implicated in the progression of a variety of cancer types. However, the major downstream signaling pathways that mediate its protumor effects and the role of CD44 in the progression and chemoresponse of GBM have not been established. Here we show that CD44 is upregulated in GBM and that its depletion blocks GBM growth and sensitizes GBM cells to cytotoxic drugs in vivo. Consistent with this observation, CD44 antagonists potently inhibit glioma growth in preclinical mouse models. We provide the first evidence that CD44 functions upstream of the mammalian Hippo signaling pathway and that CD44 promotes tumor cell resistance to reactive oxygen species-induced and cytotoxic agent-induced stress by attenuating activation of the Hippo signaling pathway. Together, our results identify CD44 as a prime therapeutic target for GBM, establish potent antiglioma efficacy of CD44 antagonists, uncover a novel CD44 signaling pathway, and provide a first mechanistic explanation as to how upregulation of CD44 may constitute a key event in leading to cancer cell resistance to stresses of different origins. Finally, our results provide a rational explanation for the observation that functional inhibition of CD44 augments the efficacy of chemotherapy and radiation therapy. PMID- 20197462 TI - p53 Regulates the Ras circuit to inhibit the expression of a cancer-related gene signature by various molecular pathways. AB - In this study, we focus on the analysis of a previously identified cancer-related gene signature (CGS) that underlies the cross talk between the p53 tumor suppressor and Ras oncogene. CGS consists of a large number of known Ras downstream target genes that were synergistically upregulated by wild-type p53 loss and oncogenic H-Ras(G12V) expression. Here we show that CGS expression strongly correlates with malignancy. In an attempt to elucidate the molecular mechanisms underling the cooperation between p53 loss and oncogenic H-Ras(G12V), we identified distinguished pathways that may account for the regulation of the expression of the CGS. By knocking-down p53 or by expressing mutant p53, we revealed that p53 exerts its negative effect by at least two mechanisms mediated by its targets B-cell translocation gene 2 (BTG2) and activating transcription factor 3 (ATF3). Whereas BTG2 binds H-Ras(G12V) and represses its activity by reducing its GTP loading state, which in turn causes a reduction in CGS expression, ATF3 binds directly to the CGS promoters following p53 stabilization and represses their expression. This study further elucidates the molecular loop between p53 and Ras in the transformation process. PMID- 20197463 TI - Hsp27 promotes insulin-like growth factor-I survival signaling in prostate cancer via p90Rsk-dependent phosphorylation and inactivation of BAD. AB - Hsp27 is highly expressed in castrate-resistant prostate cancer. Although its overexpression confers resistance to androgen ablation and chemotherapy, the mechanisms by which Hsp27 inhibits treatment-induced apoptosis are incompletely defined. Castrate-resistance often correlates with increased activity of autocrine and/or paracrine growth/survival stimulatory loops including the mitogen-activated protein kinase (MAPK) and Akt pathways and insulin-like growth factor (IGF) axis components. Because Hsp27 can be activated by both MAPK and Akt pathways, it is possible that interactions between IGF-I signaling and Hsp27 phosphoactivation function to promote castrate-resistant progression. Here, we report that Hsp27 expression and phosphorylation levels correlate with IGF-I signaling and castrate-resistant progression in human prostate cancer specimens and cell lines. IGF-I induces Hsp27 phosphorylation in a time- and dose-dependent manner via p90Rsk, which interacts directly with and phosphorylates Hsp27 in vitro and in vivo. Conversely, p90Rsk inhibition using short interfering RNA or a dominant negative mutant abolishes IGF-I-induced Hsp27 phosphorylation. Hsp27 overexpression increases IGF-I-induced phosphorylation of Erk, p90Rsk, and Akt. Conversely, Hsp27 knockdown abrogates IGF-I-induced phosphorylation of Erk, p90Rsk, and Akt, thereby destabilizing Bad/14-3-3 complexes and increasing apoptotic rates. These data elucidate the interactions between Hsp27 phosphorylation and the IGF-I receptor signaling pathway and support targeting Hsp27 as a therapeutic strategy for castrate-resistant prostate cancer. PMID- 20197464 TI - Suppression of tumor growth and metastasis by simultaneously blocking vascular endothelial growth factor (VEGF)-A and VEGF-C with a receptor-immunoglobulin fusion protein. AB - The major cause of cancer mortality is the metastatic spread of tumor cells that can occur via multiple routes, including the vascular system and the lymphatic system. In this study, we developed an IgG-like fusion protein molecule [vascular endothelial growth factor (VEGF) receptor 31-immunoglobulin (VEGFR31-Ig)] which could simultaneously bind the angiogenic growth factor VEGF-A and the lymphangiogenic growth factor VEGF-C. Importantly, VEGFR31-Ig exhibited VEGF-A binding affinity similar to that of VEGFTrap, the most potent VEGF-A binder, and VEGF-C-binding affinity comparable with that of the soluble fusion protein VEGFR3 Ig (sVEGFR3). Pharmacokinetic analysis in mice showed that VEGFR31-Ig had improved pharmacokinetic properties compared with either VEGFTrap or sVEGFR3. In a highly metastatic human hepatocellular carcinoma (HCCLM3) model in severe combined immunodeficient mice, VEGFR31-Ig potently blocked both tumor angiogenesis and lymphangiogenesis, effectively inhibiting primary tumor growth and metastasis to lungs and lymph nodes. In contrast, VEGFTrap only suppressed primary tumor growth and metastasis to lungs by inhibiting tumor angiogenesis, whereas VEGFR3 was only effective in suppressing tumor metastasis to lymph nodes by blocking tumor lymphangiogenesis. Although a combination of VEGFTrap (25 mg/kg twice weekly) and sVEGFR3 (25 mg/kg twice weekly) can achieve the same therapeutic effect as VEGFR31-Ig (25 mg/kg twice weekly) in the HCCLM3 xenograft mouse model, developing two separate receptor-Ig fusion proteins for clinical use as combination therapy is impractical, mainly owing to regulatory hurdles and cost. Taken together, the VEGFR31-Ig fusion protein presented here has been suggested to have great potential for the treatment of metastatic cancer. PMID- 20197465 TI - Oncogenic potential of retinoic acid receptor-gamma in hepatocellular carcinoma. AB - Retinoic acid receptors (RAR; alpha, beta, and gamma), members of the nuclear receptor superfamily, mediate the pleiotropic effects of the vitamin A metabolite retinoic acid (RA) and derivatives (retinoids) in normal and cancer cells. Abnormal expression and function of RARs are often involved in the growth and development of cancer. However, the underlying molecular mechanisms remain largely elusive. Here, we report that levels of RARgamma were significantly elevated in tumor tissues from a majority of human hepatocellular carcinoma (HCC) and in HCC cell lines. Overexpression of RARgamma promoted colony formation by HCC cells in vitro and the growth of HCC xenografts in animals. In HepG2 cells, transfection of RARgamma enhanced, whereas downregulation of RARgamma expression by siRNA approach impaired, the effect of RA on inducing the expression of alpha fetoprotein, a protein marker of hepatocarcinogenesis. In studying the possible mechanism by which overexpression of RARgamma contributed to liver cancer cell growth and transformation, we observed that RARgamma resided mainly in the cytoplasm of HCC cells, interacting with the p85alpha regulatory subunit of phosphatidylinositol 3-kinase (PI3K). The interaction between RARgamma and p85alpha resulted in activation of Akt and NF-kappaB, critical regulators of the growth and survival of cancer cells. Together, our results show that overexpression of RARgamma plays a role in the growth of HCC cells through nongenomic activation of the PI3K/Akt and NF-kappaB signaling pathways. PMID- 20197466 TI - Jun proteins are starvation-regulated inhibitors of autophagy. AB - The growing number of biological functions affected by autophagy ascribes a special significance to identification of factors regulating it. The activator protein-1 (AP-1) transcription factors are involved in most aspects of cellular proliferation, death, or survival, yet no information regarding their involvement in autophagy is available. Here, we show that the AP-1 proteins JunB and c-Jun, but not JunD, c-Fos, or Fra-1, inhibit autophagy. JunB inhibits autophagy induced by starvation, overexpression of a short form of ARF (smARF), a potent inducer of autophagy, or even after rapamycin treatment. In agreement, acute repression of JunB expression, by JunB knockdown, potently induces autophagy. As expected from autophagy-inhibiting proteins, Jun B and c-Jun expression is reduced by starvation. Decrease in JunB mRNA expression and posttranscriptional events downregulate JunB protein expression after starvation. The inhibition of autophagy by JunB is not mediated by mammalian target of rapamycin (mTOR) regulation, as it occurs also in the absence of mTOR activity, and autophagy induced by JunB knockdown is not correlated with changes in mTOR activity. Nevertheless, the transcriptional activities of c-Jun and JunB are required for autophagy inhibition, and JunB incapable of heterodimerizing is a less effective inhibitor of autophagy. Most importantly, inhibition of autophagy in starved HeLa cells by JunB enhances apoptotic cell death. We suggest that JunB and c-Jun are regulators of autophagy whose expression responds to autophagy-inducing signals. PMID- 20197467 TI - Downregulation of Notch pathway by a gamma-secretase inhibitor attenuates AKT/mammalian target of rapamycin signaling and glucose uptake in an ERBB2 transgenic breast cancer model. AB - ERBB2/neu and Notch signaling are known to be deregulated in many human cancers. However, pathway cross-talk and dependencies are not well understood. In this study, we use an ERBB2-transgenic mouse model of breast cancer (neuT) to show that Notch signaling plays a critical role in tumor maintenance. Inhibition of the Notch pathway with a gamma-secretase inhibitor (GSI) decreased both the Notch and the mammalian target of rapamycin/AKT pathways. Antitumor activity resulting from GSI treatment was associated with decreased cell proliferation as measured by Ki67 and decreased expression of glucose transporter Glut1. Positron emission tomography (PET) imaging showed that the functional consequences of decreased Glut1 translated to reduced glucose uptake and correlated with antitumor effects as measured by micro-computed tomography imaging. The decrease of Glut1 in neuT tumors was also observed in several human breast cancer cell lines following GSI treatment. We provide evidence that approximately 27% of ERBB2-positive human breast cancer specimens display high expression of HES1, phospho-S6RP, and GLUT1. Together, these results suggest that pathways downstream of Notch signaling are, at least in part, responsible for promoting tumor growth in neuT and also active in both neuT and a subset of human breast cancers. These findings suggest that GSI may provide therapeutic benefit to a subset of ERBB2-positive breast cancers and that [(18)F]FDG-PET imaging may be useful in monitoring clinical response. PMID- 20197468 TI - Preclinical evaluation of radiation and perifosine in a genetically and histologically accurate model of brainstem glioma. AB - Brainstem gliomas (BSG) are a rare group of central nervous system tumors that arise mostly in children and usually portend a particularly poor prognosis. We report the development of a genetically engineered mouse model of BSG using the RCAS/tv-a system and its implementation in preclinical trials. Using immunohistochemistry, we found that platelet-derived growth factor (PDGF) receptor alpha is overexpressed in 67% of pediatric BSGs. Based on this observation, we induced low-grade BSGs by overexpressing PDGF-B in the posterior fossa of neonatal nestin tv-a mice. To generate high-grade BSGs, we overexpressed PDGF-B in combination with Ink4a-ARF loss, given that this locus is commonly lost in high-grade pediatric BSGs. We show that the likely cells of origin for these mouse BSGs exist on the floor of the fourth ventricle and cerebral aqueduct. Irradiation of these high-grade BSGs shows that although single doses of 2, 6, and 10 Gy significantly increased the percent of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive nuclei, only 6 and 10 Gy significantly induce cell cycle arrest. Perifosine, an inhibitor of AKT signaling, significantly induced TUNEL-positive nuclei in this high-grade BSG model, but in combination with 10 Gy, it did not significantly increase the percent of TUNEL-positive nuclei relative to 10 Gy alone at 6, 24, and 72 hours. Survival analysis showed that a single dose of 10 Gy significantly prolonged survival by 27% (P = 0.0002) but perifosine did not (P = 0.92). Perifosine + 10 Gy did not result in a significantly increased survival relative to 10 Gy alone (P = 0.23). This PDGF-induced BSG model can serve as a preclinical tool for the testing of novel agents. PMID- 20197469 TI - Complementary actions of inhibitors of angiopoietin-2 and VEGF on tumor angiogenesis and growth. AB - Inhibition of angiopoietin-2 (Ang2) can slow tumor growth, but the underlying mechanism is not fully understood. Because Ang2 is expressed in growing blood vessels and promotes angiogenesis driven by vascular endothelial growth factor (VEGF), we asked whether the antitumor effect of Ang2 inhibition results from reduced sprouting angiogenesis and whether the effect is augmented by inhibition of VEGF from tumor cells. Using Colo205 human colon carcinomas in nude mice as a model, we found that selective inhibition of Ang2 by the peptide-Fc fusion protein L1-7(N) reduced the number of vascular sprouts by 46% and tumor growth by 62% over 26 days. Strikingly, when the Ang2 inhibitor was combined with a function-blocking anti-VEGF antibody, the number of sprouts was reduced by 82%, tumor vascularity was reduced by 67%, and tumor growth slowed by 91% compared with controls. The reduction in tumor growth was accompanied by decreased cell proliferation and increased apoptosis. We conclude that inhibition of Ang2 slows tumor growth by limiting the expansion of the tumor vasculature by sprouting angiogenesis, in a manner that is complemented by concurrent inhibition of VEGF and leads to reduced proliferation and increased apoptosis of tumor cells. PMID- 20197470 TI - Simultaneous visualization of protumorigenic Src and MT1-MMP activities with fluorescence resonance energy transfer. AB - Both Src kinase and membrane type 1 matrix metalloproteinase (MT1-MMP) play critical roles in cancer invasion and metastasis. It is not clear, however, how the spatiotemporal activation of these two critical enzymes is coordinated in response to an oncogenic epithelial growth factor (EGF) stimulation. Here, we have visualized the activities of Src and MT1-MMP concurrently in a single live cell by combining two fluorescence resonance energy transfer (FRET) pairs with distinct spectra: (a) cyan fluorescent protein (CFP) and yellow FP (YFP), and (b) orange FP (mOrange2) and red FP (mCherry). The new FRET pair, mOrange2 and mCherry, was first characterized in vitro and in cultured mammalian cells. When integrated with the CFP/YFP pair, this new pair allowed the revelation of an immediate, rapid, and relatively dispersed Src activity. In contrast, the MT1-MMP activity displayed a slow increase at the cell periphery, although Src was shown to play a role upstream to MT1-MMP globally. This difference in the activation patterns of MT1-MMP and Src in response to EGF is further confirmed using an optimized MT1-MMP biosensor capable of being rapidly cleaved by MT1-MMP. The results indicate that although Src and MT1-MMP act globally in the same signaling pathway, their activations differ in space and time upon EGF stimulation, possibly mediated by different sets of intermediates at different subcellular locations. Our results also showed the potential of mOrange2/mCherry as a new FRET pair, together with the popular variants of CFP and YFP, for the simultaneous visualization of multiple molecular activities in a single live cell. PMID- 20197471 TI - Plasma homocysteine and cysteine and risk of breast cancer in women. AB - Homocysteine and cysteine are associated with oxidative damage and metabolic disorders, which may lead to carcinogenesis. Observational studies assessing the association between circulating homocysteine or cysteine and breast cancer are very limited, and findings have been inconsistent. We prospectively evaluated plasma levels of homocysteine and cysteine in relation to breast cancer risk among 812 incident cases of invasive breast cancer and 812 individually matched control subjects from 28,345 women in the Women's Health Study; these women were >or=45 years old, provided blood samples, and had no history of cancer and cardiovascular disease at baseline. Logistic regression controlling for matching factors and risk factors for breast cancer was used to estimate relative risks (RR) and 95% confidence intervals (95% CI). All statistical tests were two sided. Homocysteine levels were not associated with overall risk for breast cancer. However, we observed a positive association between cysteine levels and breast cancer risk; the multivariate RR for the highest quintile group relative to the lowest quintile was 1.65 (95% CI, 1.04-2.61; P for trend = 0.04). In addition, women with higher levels of homocysteine and cysteine were at a greater risk for developing breast cancer when their folate levels were low (P for interaction = 0.04 and 0.002, respectively). Although our study offers little support for an association between circulating homocysteine and overall breast cancer risk, higher homocysteine levels may be associated with an increased risk for breast cancer among women with low folate status. The increased risk of breast cancer associated with high cysteine levels warrants further investigation. PMID- 20197473 TI - Costs of gastrointestinal events after outpatient opioid treatment for non-cancer pain. AB - BACKGROUND: Gastrointestinal (GI) adverse effects are common with oral opioid treatment. OBJECTIVE: To estimate the costs associated with GI events after oral short-acting opioid treatment, from the payer perspective. METHODS: Medical and pharmacy claims from the PharMetrics' Patient-Centric Database were used to identify opioid-naive patients who received a new prescription for oxycodone- or hydrocodone-containing immediate-release oral products between 2002 and 2006. Health-care resource use and costs were determined for patients with claims associated with ICD-9 CM (International Classification of Diseases-9th Clinical Modification) codes for nausea/vomiting (787.0x), constipation (564.0x), bowel obstruction (560, 560.1, 560.3, 560.39, 564.81), or antiemetic and laxative prescriptions during the 3 months after opioid index prescription and compared with patients without these GI event medical or prescription claims. Resource use data were compared using negative binomial regression and cost data were compared using ordinary least squares confirmed by generalized gamma regression analysis while controlling for demographics, treatment duration, and comorbidities. RESULTS: Data from 237,447 patients were analyzed. Patients with GI event claims had significantly more hospitalizations (adjusted mean 0.20 to 0.97 vs 0.17, respectively, p < 0.001), days in the hospital (1.12 to 12.05 vs 1.00 days, p < 0.001), emergency department visits (0.36 to 1.44 vs 0.25 visits, p < 0.001), outpatient office visits (5.68 to 11.81 vs 4.11 visits, p < 0.001), and prescription claims (7.46 to 8.21 vs 6.06 claims, p < 0.001) than did patients without any GI event claims in the 3 months after index opioid prescription. Compared with patients without any GI event claims, incremental adjusted mean total health-care costs for patients with any of the GI event claims ranged from $4,880 to $36,152 and were significant (p < 0.001). CONCLUSIONS: The economic burden of GI events coincident with opioid treatment is significant for patients with a GI event recorded in claims. Reducing GI adverse effects has potential cost savings for the health-care system. PMID- 20197472 TI - Disruption of laminin-integrin-CD151-focal adhesion kinase axis sensitizes breast cancer cells to ErbB2 antagonists. AB - Resistance to anti-ErbB2 agents is a significant problem in the treatment of human ErbB2+ breast cancers. We show here that adhesion of human ErbB2+ breast cancer cells to basement membrane laminin-5 provides substantial resistance to trastuzumab and lapatinib, agents that respectively target the extracellular and kinase domains of ErbB2. Knockdown of laminin-binding integrins (alpha6beta4, alpha3beta1) or associated tetraspanin protein CD151 reversed laminin-5 resistance and sensitized ErbB2+ cells to trastuzumab and lapatinib. CD151 knockdown, together with trastuzumab treatment, inhibited ErbB2 activation and downstream signaling through Akt, Erk1/2, and focal adhesion kinase (FAK). Hence, ErbB2 function in mammary tumor cells is promoted by integrin-mediated adhesion to laminin-5, with strong support by CD151, leading to signaling through FAK. Consequently, removal or inhibition of any of these components (laminin-5, integrin, CD151, FAK) markedly sensitizes cells to anti-ErbB2 agents. These new insights should be useful when devising strategies for overcoming drug resistance in ErbB2+ cancers. PMID- 20197474 TI - Use of daptomycin in a pregnant patient with Staphylococcus aureus endocarditis. AB - OBJECTIVE: To report on 6 weeks of daptomycin treatment for tricuspid valve endocarditis caused by Staphylococcus aureus in a pregnant female in her second trimester. CASE SUMMARY: A 24-year-old, 14-week pregnant patient with no significant medical history, but with a history of intravenous drug abuse presented with tricuspid valve endocarditis caused by methicillin-sensitive S. aureus. After initial treatment with vancomycin, the patient continued to have fever and bacteremia and was initiated on daptomycin 6 mg/kg for 6 weeks of therapy. The treatment resulted in the resolution of the endocarditis, and no adverse sequelae were identified in the mother or baby. DISCUSSION: Infective endocarditis is a common infection encountered in the hospital setting and represents an increased cost burden to institutions due to prolonged lengths of treatment. Antimicrobial resistance, antimicrobial failure, inadequate attainment of effective drug concentrations, drug allergies, and adverse reactions may be factors that limit the use of commonly utilized antimicrobial agents. Therefore, newer therapies like daptomycin may need to be employed in these situations. Although daptomycin is pregnancy category B, limited case reports with neonatal outcomes are reported. CONCLUSIONS: This case provides further support for the safety of daptomycin in pregnancy with the dose of 6 mg/kg, the extended duration of therapy (6 weeks), and the primary exposure in the second trimester. PMID- 20197475 TI - Symptomatic hypoglycemia associated with trimethoprim/sulfamethoxazole and repaglinide in a diabetic patient. AB - OBJECTIVE: To report a case of clinically significant hypoglycemia attributed to the concomitant use of trimethoprim/sulfamethoxazole (TMP/SMX) and repaglinide by a diabetic patient. CASE SUMMARY: A 76-year-old diabetic patient with impaired renal function and no history of hypoglycemia was receiving treatment with repaglinide 1 mg 3 times daily. Five days after TMP/SMX therapy was started for a urinary tract infection, the man developed symptomatic hypoglycemia. Repaglinide and TMP/SMX were stopped and intravenous D-glucose was administered to normalize glucose levels. Repaglinide, but not TMP/SMX, was reintroduced 5 days later and no other hypoglycemic episode occurred. Objective causality assessments revealed that the interaction was probable (World Health Organization-Uppsala Monitoring Centre) or possible (Horn Drug Interaction Probability Scale). DISCUSSION: This interaction between TMP/SMX and repaglinide was predictable according to available pharmacokinetic data in healthy subjects. Trimethoprim induced CYP2C8 inhibition, thus increasing the plasma concentration of repaglinide. This interaction is mentioned in the repaglinide product information. To our knowledge, however, no case of symptomatic hypoglycemia associated with a combination of repaglinide and trimethoprim has been described before. This discrepancy may be explained by the subtherapeutic dosage used in the pharmacokinetic study. Moreover, our patient had impaired renal function, which may have led to trimethoprim accumulation and potentiated its interaction with repaglinide. A direct lowering of blood glucose levels due to sulfamethoxazole, also potentiated by renal failure, could also be involved in triggering hypoglycemia. CONCLUSIONS: This interaction between TMP/SMX and repaglinide may have involved inhibition of CYP2C8 by trimethoprim. Clinicians should be aware that this association may lead to symptomatic hypoglycemia, particularly in patients with renal dysfunction. PMID- 20197476 TI - New combination vaccines: DTaP-IPV (Kinrix) and DTaP-IPV/Hib (Pentacel). AB - OBJECTIVE: To evaluate the clinical utility of diphtheria and tetanus toxoids and acellular pertussis adsorbed and inactivated poliovirus vaccine ([DTaP-IPV]; Kinrix) and diphtheria and tetanus toxoids and acellular pertussis adsorbed,inactivated poliovirus and Haemophilus b conjugate (tetanus toxoid conjugate)vaccine ([DTaP-IPV/Hib]; Pentacel) in the schedule for pediatric immunizations. DATA SOURCES: PubMed was searched (1966-April 2009) using the key words Kinrix and Pentacel. Subject headings included vaccines, combined; diphtheria-tetanus-pertussis vaccine; diphtheria-tetanus-acellular pertussis vaccines; poliovirus vaccine, inactivated; and Haemophilus influenzae type b polysaccharide vaccine tetanus toxin conjugate. The search was limited to English language publications involving humans. Product labeling was obtained from GlaxoSmithKline and Sanofi Pasteur. The Centers for Disease Control and Prevention (CDC) Web site was searched for relevant recommendations published June 2008-October 2009. STUDY SELECTION AND DATA EXTRACTION: Phase 2 and 3 clinical trials evaluating immunogenicity and safety of DTaP-IPV and DTaP-IPV/Hib were reviewed. Published trials were supplemented with abstracts, review articles, manufacturer product labeling, and CDC recommendations. DATA SYNTHESIS: DTaP-IPV is immunogenic compared to its component vaccines,with no effect of concomitantly administered measles, mumps, and rubella vaccine.Although injection site pain has occurred more with the combination vaccine, its use would reduce by 1 the number of injections given when a child is 4-6 years old.DTaP-IPV/Hib is immunogenic and safe compared to separate vaccines.Immunogenicity to 7-valent pneumococcal conjugate vaccine and hepatitis B(HepB) vaccine is not affected by concomitant administration. DTaP-IPV/Hib decreases injections by up to 7 when given at 2, 4, 6, and 15-18 months of age. It fits into the schedule more easily than DTaP-HepB-IPV (Pediarix), the other DTaP containing combination vaccine indicated for the primary infant series. CONCLUSIONS: DTaP-IPV and DTaP-IPV/Hib combination vaccines are immunogenic and safe when given to infants and children. They reduce the number of required injections. Combination vaccines are encouraged to promote timely vaccination and complete immunization schedules. PMID- 20197477 TI - Hypertrophic cranial pachymeningitis induced by long-term administration of nonsteroidal antiinflammatory drugs. AB - OBJECTIVE: To report a case of hypertrophic cranial pachymeningitis (HCP) associated with the long-term administration of nonsteroidal antiinflammatory drugs (NSAIDs). CASE SUMMARY: A 23-year-old man presented with recurrent headaches as the primary clinical manifestation. After the administration of the NSAIDs indomethacin and aceclofenac for 2 years, he developed signs of progressive cranial polyneuropathies (eg, II, III, V, VI, and VII palsy) and damage to the brainstem. Cranial contrast-enhanced magnetic resonance imaging (MRI) revealed curvilinear subdural enhancement and significant tentorium cerebelli and falx cerebri enhancements. Since antituberculosis treatment combined with corticosteroid therapy and analgesia with celecoxib for 40 days had not achieved satisfactory results, NSAIDs were discontinued and a single oral dose of a corticosteroid was given. No headaches were reported at a 6-month follow-up appointment. In addition, his cranial polyneuropathy improved significantly. Reexamination by contrast-enhanced MRI scan demonstrated that tentorial enhancement and thickening of the falx cerebri were markedly alleviated. DISCUSSION: No additional causes of HCP were found during systematic investigation in this patient. In addition to headache, cranial polyneuropathy and thickened cerebral dura mater appeared after administration of NSAIDs for 2 years. The symptoms that appeared during the NSAID therapy were remarkably alleviated 5 months after medication discontinuation. Adverse drug reaction (ADR) assessment revealed that long-term administration of NSAIDs may be associated with the occurrence and development of HCP. CONCLUSIONS: Long-term administration of NSAIDs is a probable cause of HCP. Clinicians should be aware of this ADR and avoid prescribing NSAIDs for an extended period. PMID- 20197478 TI - The role of the CpG island methylator phenotype in colorectal cancer prognosis depends on microsatellite instability screening status. AB - PURPOSE: The aim of this study was to relate the CpG island methylator phenotype (CIMP; characterized by extensive promoter hypermethylation) to cancer-specific survival in colorectal cancer, taking into consideration relevant clinicopathologic factors, such as microsatellite instability (MSI) screening status and the BRAF V600E mutation. EXPERIMENTAL DESIGN: Archival tumor samples from 190 patients from the Northern Sweden Health and Disease Study (NSHDS) and 414 patients from the Colorectal Cancer in Umea Study (CRUMS), including 574 with cancer-specific survival data, were analyzed for an eight-gene CIMP panel using quantitative real-time PCR (MethyLight). MSI screening status was assessed by immunohistochemistry. RESULTS: CIMP-low patients had a shorter cancer-specific survival compared with CIMP-negative patients (multivariate hazard ratio in NSHDS, 2.01; 95% confidence interval, 1.20-3.37; multivariate hazard ratio in CRUMS, 1.48; 95% confidence interval, 1.00-2.22). This result was similar in subgroups based on MSI screening status and was statistically significant in microsatellite stable (MSS) tumors in NSHDS. For CIMP-high patients, a shorter cancer-specific survival compared with CIMP-negative patients was observed in the MSS subgroup. Statistical significance was lost after adjusting for the BRAF mutation, but the main findings were generally unaffected. CONCLUSIONS: In this study, we found a poor prognosis in CIMP-low patients regardless of MSI screening status, and in CIMP-high patients with MSS. Although not consistently statistically significant, these results were consistent in two separate patient groups and emphasize the potential importance of CIMP and MSI status in colorectal cancer research. PMID- 20197479 TI - New developments in tyrosine kinase inhibitor therapy for newly diagnosed chronic myeloid leukemia. AB - The biology of chronic myeloid leukemia (CML) has enabled pioneering studies with targeted therapies. BCR-ABL inhibition with imatinib results in high levels of efficacy in patients with newly diagnosed CML in chronic phase (CP), but an estimated 35% of patients could benefit from more effective treatment. Several novel treatment strategies are being investigated in newly diagnosed CML-CP. These strategies include upfront treatment with next-generation tyrosine kinase inhibitors, such as dasatinib, nilotinib, or bosutinib, which also target BCR-ABL but with increased in vitro potency compared with imatinib, and possibly a reduced potential for resistance. Recent in vitro studies have shown that short term exposure to dasatinib or continuous exposure to imatinib result in equivalent levels of apoptosis, indicating that potent intermittent inhibition is a successful strategy for improving dasatinib tolerability. Modified imatinib regimens are also being investigated in newly diagnosed CML-CP, including higher doses and combination with alternative classes of agents, such as interferon. Existing data suggest that both newer agents and combination approaches can improve treatment responses compared with standard imatinib treatment, although further data are needed, particularly from ongoing phase 3 trials, before the standard of care is revised. PMID- 20197480 TI - Value of magnetic resonance spectroscopy imaging and dynamic contrast-enhanced imaging for detecting prostate cancer foci in men with prior negative biopsy. AB - PURPOSE: This study aimed to prospectively analyze the role of magnetic resonance spectroscopy imaging (MRSI) and dynamic-contrast enhancement magnetic resonance (DCEMR) in the detection of prostate tumor foci in patients with persistently elevated prostate-specific antigen levels (in the range of >or=4 ng/mL to <10 ng/mL) and prior negative random trans-rectal ultrasound (TRUS)-guided biopsy. EXPERIMENTAL DESIGN: This was a prospective randomized single-center study. One hundred and eighty eligible cases were included in the study. Patients in group A were submitted to a second random prostate biopsy, whereas patients in group B were submitted to a (1)H-MRSI-DCEMR examination and samples targeted on suspicious areas were associated to the random biopsy. RESULTS: At the second biopsy, a prostate adenocarcinoma histologic diagnosis was found in 22 of 90 cases (24.4%) in group A and in 41 of 90 cases (45.5%) in group B (P = 0.01). On a patient-by-patient basis, MRSI had 92.3% sensitivity, 88.2% specificity, 85.7% positive predictive value (PPV), 93.7% negative predictive value (NPV), and 90% accuracy; DCEMR had 84.6 % sensitivity, 82.3% specificity, 78.5% PPV, 87.5% NPV, and 83.3% accuracy; and the association MRSI plus DCEMR had 92.6% sensitivity, 88.8% specificity, 88.7% PPV, 92.7% NPV, and 90.7% accuracy, for predicting prostate cancer detection. CONCLUSIONS: The combination of MRSI and DCEMR showed the potential to guide biopsy to cancer foci in patients with previously negative TRUS biopsy. To avoid a potential bias, represented from having taken more samples in group B (mean of cores, 12.17) than in group A (10 cores), in the future a MRSI/DCEMR directed biopsy could be prospectively compared with a saturation biopsy procedure. PMID- 20197482 TI - Death receptor agonists as a targeted therapy for cancer. AB - Apoptosis is integral to normal, physiologic processes that regulate cell number and results in the removal of unnecessary or damaged cells. Apoptosis is frequently dysregulated in human cancers, and recent advancements in our understanding of the regulation of programmed cell death pathways has led to the development of novel agents to reactivate apoptosis in malignant cells. The activation of cell surface death receptors by tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) and death receptor agonists represent an attractive therapeutic strategy to promote apoptosis of tumor cells through the activation of the extrinsic pathway. The observation that Apo2L/TRAIL can eliminate tumor cells preferentially over normal cells has resulted in several potential therapeutics that exploit the extrinsic pathway, in particular, the soluble recombinant human (rh)Apo2L/TRAIL protein and agonist monoclonal antibodies that target death receptors 4 or 5. Many of these agents are currently being evaluated in phase 1 or 2 trials, either as a single agent or in combination with cytotoxic chemotherapy or other targeted agents. The opportunities and challenges associated with the development of death receptor agonists as cancer therapeutics, the status of ongoing clinical evaluations, and the progress toward identifying predictive biomarkers for patient selection and pharmacodynamic markers of response are reviewed. PMID- 20197483 TI - Mesalazine reduces mutations in transforming growth factor beta receptor II and activin type II receptor by improvement of replication fidelity in mononucleotide repeats. AB - PURPOSE: Mesalazine (5-aminosalicylic acid, 5-ASA) has chemopreventive properties in colitis-associated cancer. In vitro, it improves replication fidelity at (CA)13 microsatellites independent of mismatch repair proficiency. Therefore, 5 ASA might be advantageous in patients with hereditary nonpolyposis colorectal cancer. At this point, however, it is uncertain whether this improvement of replication fidelity is specific for (CA)13 repetitive sequences. Here, we tested the effect of 5-ASA on replication fidelity in mononucleotide, dinucleotide, and tetranucleotide repeats. EXPERIMENTAL DESIGN: HCT116 and HCT116+chr3 cells were transfected with pIREShyg2-EGFP reporter plasmids harboring the following microsatellites: A10, G10, (CA)13, (CA)26, (AAAG)17, poly-A tracts, and their flanking sequences of transforming growth factor beta receptor II (TGFBR2; A10) and activin type II receptor (ACVR2; A8). Stably transfected single-cell clones were selected, characterized by Southern blotting, sorted into six-well plates, and cultured with or without 5-ASA. Frameshift mutations that shift the enhanced green fluorescence protein into its proper reading frame were quantified by flow cytometry. RESULTS: In HCT116, 5-ASA reduced the mutant fraction at (CA)13 by 48.3%, at A10 by 35.6-43.6%, at G10 by 74.9-83.6%, and at (AAAG)17 by 37.6-44.4%. Similar results were observed in hMLH1-proficient HCT116+chr3 cells. Moreover, the presence of 5-ASA significantly reduced mutations in TGFBR2 (A10) and ACVR2 (A8) by 39.9% and 46.2%, respectively. CONCLUSIONS: 5-ASA increases replication fidelity in mononucleotide, dinucleotide, and tetranucleotide repeats and reduces mutations in tumor suppressor genes TGFBR2 and ACVR2, a finding that may provoke in vivo studies for the prevention of colorectal cancer in hereditary nonpolyposis colorectal cancer. PMID- 20197484 TI - A phase I pharmacologic study of necitumumab (IMC-11F8), a fully human IgG1 monoclonal antibody directed against EGFR in patients with advanced solid malignancies. AB - PURPOSE: This study aimed to determine a maximum tolerated dose (MTD) and recommended dose for disease-directed studies of necitumumab (IMC-11F8), a fully human IgG(1) monoclonal antibody directed at the epidermal growth factor receptor, and to characterize the safety profile, pharmacokinetics, preliminary antitumor activity, and immunogenicity of necitumumab. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were treated with 100 to 1,000 mg (flat dosing) necitumumab followed by a 2-week pharmacokinetics sampling period, before beginning 6-week cycles of therapy. RESULTS: Sixty patients received necitumumab weekly (29 patients) or every other week (31 patients). Two patients receiving 1,000 mg every 2 weeks experienced dose-limiting toxicities (DLT; grade 3 headache), accompanied by grade 3 nausea and vomiting in one patient. Occurring hours after the initial dose, these DLTs established 800 mg as the MTD. Mild dose related skin toxicity was the most common drug-related toxicity (80%). One patient in each arm experienced grade 3 acneform rash, which responded to oral antibiotics and topical therapy. Toxicity was similar on both schedules. Necitumumab exhibited saturable elimination and nonlinear pharmacokinetics. At 800 mg (both arms), its half-life was approximately 7 days. All patients treated with >or=600 mg necitumumab achieved target trough concentrations (>or=40 microg/mL). Antibodies against necitumumab were not detected. Partial response and stable disease were experienced by 2 and 16 patients, respectively. CONCLUSION: Well tolerated, necitumumab is associated with preliminary evidence of antitumor activity, and achieves biologically relevant concentrations throughout the dosing period. The recommended dose of necitumumab for further clinical development is 800 mg (flat dose) weekly or every 2 weeks based on the clinical setting. PMID- 20197485 TI - Assessment of the effects of renal impairment on the pharmacokinetic profile of laninamivir, a novel neuraminidase inhibitor, after a single inhaled dose of its Prodrug, CS-8958. AB - This open-label, single-dose study assessed the safety and pharmacokinetics of laninamivir, a new long-acting neuraminidase inhibitor, after an inhaled 20-mg dose of its prodrug, CS-8958, to a total of 20 subjects with normal, mild, moderate, or severe renal impairment. CS-8958 and laninamivir concentrations were measured in plasma and urine by validated liquid chromatography tandem mass spectrometry methods. The area under the concentration-time curve extrapolated to infinity (AUC(0-inf)), maximum concentration (C(max)), and time to C(max) of CS 8958 did not change with the degree of renal impairment, whereas the half-life (t(1/2)) of CS-8958 increased with increasing renal insufficiency. The AUC(0-inf) and C(max) of laninamivir tended to increase along with the decrease of creatinine clearance. The AUC(0-inf) of laninamivir compared with normal subjects increased 1.10-, 2.03-, and 4.92-fold in subjects with mild, moderate, and severe renal impairment, respectively, without changing t(1/2) among the subjects. Renal clearance of both CS-8958 and laninamivir was well correlated with creatinine clearance. These data indicate that the rate-limiting step for the elimination of laninamivir would not be the renal excretion rate but rather the drug release rate to plasma from the retained tissues. CS-8958 was well tolerated by all the subjects, although increasing renal dysfunction leads to increasing systemic exposure to laninamivir, particularly in severe renal insufficiency. PMID- 20197486 TI - Effects of laropiprant, a selective prostaglandin D2 receptor 1 antagonist, on the steady-state pharmacokinetics of digoxin in healthy adult subjects. AB - Laropiprant, a prostaglandin D(2) receptor-1 antagonist shown to reduce flushing symptoms, has been combined with niacin for treatment of dyslipidemia. This open label, randomized, 2-period crossover study assessed the effects of laropiprant on the pharmacokinetics of digoxin, with 13 healthy subjects randomized to 2 treatments administered in random order with a 10-day or longer washout period: (A) single-dose digoxin 0.5 mg on day 1 and once-daily oral doses of laropiprant 40 mg for 10 days beginning 5 days prior to digoxin dosing (day -5 to day 5); (B) single-dose digoxin 0.5 mg on day 1. Blood was collected over the course of 120 hours post digoxin dose to assess pharmacokinetics of immunoreactive digoxin. Comparability was declared if the 90% confidence interval for the geometric mean ratio of laropiprant+digoxin to digoxin alone of the area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)) for immunoreactive digoxin fell within 0.80 to 1.25. The AUC(0-infinity) and maximum observed plasma concentration (C(max)) geometric mean ratios of immunoreactive digoxin were 0.91 (90% confidence interval, 0.76-1.10) and 1.04 (90% confidence interval, 0.91-1.21), respectively. Median time of occurrence of C(max) and mean half-life of immunoreactive digoxin were comparable in the presence and absence of laropiprant. Coadministration of digoxin and laropiprant was generally well tolerated. The small decrease in exposure to immunoreactive digoxin (approximately 10%) following coadministration of laropiprant and digoxin is not considered to be clinically meaningful. PMID- 20197487 TI - Single-dose safety, pharmacokinetics, and food effects studies of compound naphthoquine phosphate tablets in healthy volunteers. AB - The compound naphthoquine phosphate is a novel antimalaria drug tablet containing a fixed-dose combination of naphthoquine phosphate and artemisinin in a 1:2.5 ratio. A randomized, open study on the safety and tolerability was conducted in 28 healthy male volunteers using a single oral dose of 350 mg, 700 mg, 1400 mg, or 2100 mg of artemisinin-naphthoquine phosphate. Pharmacokinetics at the last 3 doses were examined in 30 volunteers. Food effects were also determined. Serial blood samples up to 216 hours after single oral dose administration were analyzed for plasma concentrations using a validated high-performance liquid chromatography-tandem mass spectrometry assay. The compound was well tolerated at single doses up to 2100 mg. Increased exposure to naphthoquine phosphate and artemisinin was less than dose proportional and linear. The half-life of naphthoquine phosphate was approximately 255 hours. The combination increased the AUC(0-t) and C(max) of both artemisinin (by 71% and 49%) and naphthoquine phosphate (by 135% and 104%) compared with monotherapy. Food intake greatly increased the AUC(0-t) of artemisinin with a ratio of 77% and reduced that of naphthoquine phosphate from 955 +/- 352 ug.h/L under the fasted state to 446 +/- 231 ug.h/L in the fed condition. The pharmacokinetics and safety profile of the drug support its continued investigation in future clinical studies. PMID- 20197488 TI - Rhabdomyolysis secondary to tetanus toxoid administration in a patient following minor laceration. PMID- 20197489 TI - Does the long plasma half-life of 4beta-hydroxycholesterol impact its utility as a cytochrome P450 3A (CYP3A) metric? AB - Plasma 4beta-hydroxycholesterol (4betaHC) has been proposed as an endogenous marker of cytochrome P450 3A (CYP3A). To assess its utility as a CYP3A metric, a pharmacokinetic model, assuming no alteration in cholesterol plasma concentrations, was developed to simulate the effect of CYP3A induction and inhibition on 4betaHC plasma levels under different treatment durations. By incorporating the long plasma half-life of 4betaHC (~17 days) into the model, the inductive effect of 2 known inducers (carbamazepine and rifampicin) reported in the literature was adequately described. Furthermore, the simulations showed that it was possible to resolve none, weak, moderate, and potent inducers within 2 weeks of dosing. On the other hand, simulations indicated that at least 2 weeks of dosing would be needed to detect the potent inhibition of CYP3A (maximal ~40% decrease in 4betaHC plasma levels). Greater differentiation of weak, moderate, and potent CYP3A inhibitors would require a longer duration of dosing (>=1 month). When considering 4betaHC as a metric, one should take into account assay precision, the anticipated magnitude of the effect, and the feasibility of dosing beyond 2 weeks. In addition, the 4betaHC metric needs to be normalized with the corresponding cholesterol plasma level in the same subject. PMID- 20197490 TI - Self-beating atypically shaped cardiomyocytes survive a long-term postnatal development while preserving the expression of fetal cardiac genes in mice. AB - The present study was designed to examine the postnatal developmental changes of atypically shaped cardiomyocytes (ACMs) prepared from the heart of newborn [postnatal day 1 (day-1)] through aged (12-month-old) mice. ACMs were identified as a novel type of self-beating cardiomyocyte with a peculiar morphology in mouse cardiac ventricles. The cell length of ACMs significantly increased during the first three postnatal months and further increased over the following 9 months. In contrast, the population of ACMs was significantly decreased within the first 5 weeks and reached a plateau in the adult stage. ACMs obtained from newborn and adult mice exhibited similar spontaneous action potentials. The expression of the fetal cardiac gene products atrial natriuretic peptide and voltage-gated T-type Ca(2+) channel Ca(V)3.2 was confirmed by immunostaining in ACMs obtained from both newborn and aged mice. These observations provide evidence that ACMs that exhibit spontaneous beating survive the long-term postnatal development of cardiac ventricles while preserving the expression of fetal cardiac genes. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials. PMID- 20197491 TI - Nestin action during insulin-secreting cell differentiation. AB - Nestin, which was initially identified as a marker of neural stem cells, has been reported in regenerating pancreas as well as in early embryonic stem (ES) cell derivatives. However, little is known about its specific roles in stem cells as a functional regulator. We investigated the source of the action of nestin in ES and adult pancreatic ductal stem (PDS) cells in regard to the neogenesis of insulin-secreting beta-cells. In ES cells, suppression of nestin by gene silencing led to an increased expression of the pluripotency-associated genes, including Oct 4, Nanog, and SSEA-1, before embryoid body (EB) formation, whereas it reduced endodermal and pancreatic transcription factors in EBs. Inhibition of nestin expression in adult PDS cells caused a low expression of pancreatic transcription factors and islet hormones, leading to poor beta-cell development and insulin secretion. These data may indicate not only that nestin is a simple stem cell marker, but also that it constitutes a functional factor at the time of stem cell differentiation. We suggest that nestin plays pivotal roles as an intermediate regulator governing both stemness and differentiation of stem cells in the process of their differentiation into insulin-secreting cells. PMID- 20197492 TI - A novel clinically relevant animal model for studying galectin-3 and its ligands during colon carcinogenesis. AB - Galectin-3 (Gal-3) is a multifunctional protein that plays different roles in cancer biology. To better understand the role of Gal-3 and its ligands during colon carcinogenesis, we studied its expression in tumors induced in rats treated with 1,2-dimethylhydrazine (DMH) and in human tissues. Normal colon from untreated rats showed no staining using two specific monoclonal antibodies. In contrast, morphologically normal colon from DMH-treated rats and dysplastic aberrant crypt foci were strongly stained, indicating that increased Gal-3 expression is an early event during the neoplastic transformation in colon cells. Gal-3 was weakly expressed in adenocarcinomas. Overall, the Gal-3 expression pattern observed in the DMH rat model closely resembles that displayed by human colon stained with the same antibodies. We also found that Gal-3 phosphorylation diminishes in serines while increasing in tyrosines during rat colon carcinogenesis. Finally, we showed that Gal-3-ligands expression is strikingly similar in rat and human malignant colon and in non-malignant tissues. In conclusion, the DMH-induced rat colon cancer model displays expression patterns of Gal-3 and its ligands very similar to those observed in human samples. This animal model should contribute to clarifying the role of Gal-3 in colon carcinogenesis and also to finding effective preventive cancer agents based on Gal-3 targeting. PMID- 20197493 TI - Repair integrity evaluated by second-look arthroscopy after arthroscopic meniscal repair with the FasT-Fix during anterior cruciate ligament reconstruction. AB - BACKGROUND: Although several devices for meniscal repairs have become available, a successful outcome is ultimately due to a healed meniscus on the clinical findings. The authors assessed the repair integrity after meniscal repair with the FasT-Fix device using second-look arthroscopy. HYPOTHESIS: Meniscal repair with the FasT-Fix will lead to arthroscopically evident healing, but some menisci will show incomplete healing even in clinically successful cases and have newly formed injuries on the meniscal substance resulting from the path of the implant. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Sixty-five consecutive patients were studied, in whom 84 menisci were subjected to all-inside meniscal repair with the FasT-Fix device in conjunction with anterior cruciate ligament reconstruction. Repair was only performed on longitudinal or double longitudinal tears within the red-red or red-white zone. The repaired menisci were evaluated by second-look arthroscopy at the time of staged hardware removal after anterior cruciate ligament reconstruction. RESULTS: Sixty-two meniscal tears in 46 patients were available for this study. Eight patients were found to be symptomatic and considered to be clinical failures. The clinical success rate was 83%. At second-look arthroscopy, 46 tears (74%) were healed, 9 (15%) were healed incompletely, and 7 (11%) had failed. In the failed menisci, 1 had meniscal symptoms, while the other 6 were asymptomatic. In the 9 menisci with incomplete healing, 3 were associated with nonspecific knee pain but none showed meniscal symptoms. Newly formed injuries, which occurred in an area different from the original repair site, were confirmed on the surface of 19 menisci (35%) among the healed and incompletely healed menisci. Thirty menisci (48%) displayed successful and complete healing of the original tear site without newly formed tears. CONCLUSION: Meniscal repair with the FasT-Fix in conjunction with anterior cruciate ligament reconstruction resulted in complete healing in 74% of cases. Eighty-three percent of menisci were symptom-free regardless of meniscal integrity. Even when the menisci repaired are asymptomatic and considered to be a clinical success, however, there may be newly formed injuries. PMID- 20197494 TI - Management of tarsal navicular stress fractures: conservative versus surgical treatment: a meta-analysis. AB - PURPOSE: This study was conducted to provide a statistical analysis of previously reported tarsal navicular stress fracture studies regarding the outcomes and effectiveness of conservative and surgical management. STUDY DESIGN: Systematic review. METHODS: A systematic review of the published literature was conducted utilizing MEDLINE through Ovid, PubMed, ScienceDirect, and EBSCOhost. Reports of studies that provided the type of tarsal navicular stress fracture (ie, complete or incomplete), type of treatment, result of that treatment, and the time required to return to full activity were selected for analysis. Using a mixed generalized linear model with study as a random effect and treatment as a fixed effect, cases were separated and compared based on 3 different types of treatment: conservative, weightbearing permitted (WBR); conservative, non weightbearing (NWB); and surgical treatment. The outcome of the treatment was recorded as either successful or unsuccessful based on radiographic and/or clinical healing of the fracture and time from onset of treatment to return to activity. RESULTS: There was no statistically significant difference between NWB conservative treatment and surgical treatment regarding outcome (P = .6441). However, there is a statistical trend favoring NWB management (96% successful outcomes) over surgery (82% successful outcomes). Weightbearing as a conservative treatment was shown to be significantly less effective than either NWB (P = .0001) or surgical treatment (P <.0003). CONCLUSION: Non-weightbearing conservative management should be considered the standard of care for tarsal navicular stress fractures. The authors could find no advantage for surgical treatment compared with NWB immobilization. However, there is a statistical trend favoring NWB over surgery. Rest or immobilization with weightbearing was inferior to both other treatments analyzed. The authors concluded that conservative NWB management is the standard of care for initial treatment of both partial and complete stress fractures of the tarsal navicular. PMID- 20197495 TI - Injuries to kickers in American football: the National Football League experience. AB - BACKGROUND: Very little information is available regarding the incidence, causative mechanisms, and expected duration of time lost after injuries to kickers (placekickers and punters) in American football. HYPOTHESIS: Lower extremity musculotendinous injuries are the most common type of injury in American football kickers. The injuries related to punting differ from injuries related to placekicking. STUDY DESIGN: Descriptive epidemiologic study. METHODS: A retrospective review of all documented injuries to kickers in the National Football League over a 20-year period (1988-2007) was performed using the League's injury surveillance database. The data were analyzed from multiple perspectives, with emphasis on the type of kick or activity at the time of injury and the factors that affect return to play after injury. RESULTS: There were 488 total injuries over the 20-year period: 72% involved the lower extremity, 9% involved the lumbosacral spine, and 7% involved the head. Muscle-tendon injuries (49%) were the most common, followed by ligamentous injuries (17%). There was a significantly higher risk of injury in games (17.7 per 1000) than during practice (1.91 per 1000). Most injuries (93%) did not require surgery, and the mean time to return to play was 15 days if no surgery was necessary. Kickers over 30 years of age took longer to return to play (mean, 21 days) than younger kickers (mean, 12 days) after nonsurgical injuries (P = .03). Mean return to play after injuries that required surgery was 121 days. Lumbosacral soft tissue injury, lateral ankle sprains, and shoulder injuries were more likely to occur in punters than placekickers. CONCLUSION: Kicking athletes face a low risk of injury in professional American football. Injuries most commonly involve the lower extremities. Training and injury prevention efforts should reflect that punting is associated with different injuries than placekicking, and that older kickers take longer to recuperate than younger kickers after certain injuries. PMID- 20197498 TI - Trade-offs between competition and defense specialists among unicellular planktonic organisms: the "killing the winner" hypothesis revisited. AB - A trade-off between strategies maximizing growth and minimizing losses appears to be a fundamental property of evolving biological entities existing in environments with limited resources. In the special case of unicellular planktonic organisms, the theoretical framework describing the trade-offs between competition and defense specialists is known as the "killing the winner" hypothesis (KtW). KtW describes how the availability of resources and the actions of predators (e.g., heterotrophic flagellates) and parasites (e.g., viruses) determine the composition and biogeochemical impact of such organisms. We extend KtW conceptually by introducing size- or shape-selective grazing of protozoans on prokaryotes into an idealized food web composed of prokaryotes, lytic viruses infecting prokaryotes, and protozoans. This results in a hierarchy analogous to a Russian doll, where KtW principles are at work on a lower level due to selective viral infection and on an upper level due to size- or shape-selective grazing by protozoans. Additionally, we critically discuss predictions and limitations of KtW in light of the recent literature, with particular focus on typically neglected aspects of KtW. Many aspects of KtW have been corroborated by in situ and experimental studies of isolates and natural communities. However, a thorough test of KtW is still hampered by current methodological limitations. In particular, the quantification of nutrient uptake rates of the competing prokaryotic populations and virus population-specific adsorption and decay rates appears to be the most daunting challenge for the years to come. PMID- 20197497 TI - Getting in the loop: regulation of development in Caulobacter crescentus. AB - Caulobacter crescentus is an aquatic Gram-negative alphaproteobacterium that undergoes multiple changes in cell shape, organelle production, subcellular distribution of proteins, and intracellular signaling throughout its life cycle. Over 40 years of research has been dedicated to this organism and its developmental life cycles. Here we review a portion of many developmental processes, with particular emphasis on how multiple processes are integrated and coordinated both spatially and temporally. While much has been discovered about Caulobacter crescentus development, areas of potential future research are also highlighted. PMID- 20197499 TI - Biochemistry of microbial degradation of hexachlorocyclohexane and prospects for bioremediation. AB - Lindane, the gamma-isomer of hexachlorocyclohexane (HCH), is a potent insecticide. Purified lindane or unpurified mixtures of this and alpha-, beta-, and delta-isomers of HCH were widely used as commercial insecticides in the last half of the 20th century. Large dumps of unused HCH isomers now constitute a major hazard because of their long residence times in soil and high nontarget toxicities. The major pathway for the aerobic degradation of HCH isomers in soil is the Lin pathway, and variants of this pathway will degrade all four of the HCH isomers although only slowly. Sequence differences in the primary LinA and LinB enzymes in the pathway play a key role in determining their ability to degrade the different isomers. LinA is a dehydrochlorinase, but little is known of its biochemistry. LinB is a hydrolytic dechlorinase that has been heterologously expressed and crystallized, and there is some understanding of the sequence structure-function relationships underlying its substrate specificity and kinetics, although there are also some significant anomalies. The kinetics of some LinB variants are reported to be slow even for their preferred isomers. It is important to develop a better understanding of the biochemistries of the LinA and LinB variants and to use that knowledge to build better variants, because field trials of some bioremediation strategies based on the Lin pathway have yielded promising results but would not yet achieve economic levels of remediation. PMID- 20197500 TI - Virulence and immunomodulatory roles of bacterial outer membrane vesicles. AB - Outer membrane (OM) vesicles are ubiquitously produced by Gram-negative bacteria during all stages of bacterial growth. OM vesicles are naturally secreted by both pathogenic and nonpathogenic bacteria. Strong experimental evidence exists to categorize OM vesicle production as a type of Gram-negative bacterial virulence factor. A growing body of data demonstrates an association of active virulence factors and toxins with vesicles, suggesting that they play a role in pathogenesis. One of the most popular and best-studied pathogenic functions for membrane vesicles is to serve as natural vehicles for the intercellular transport of virulence factors and other materials directly into host cells. The production of OM vesicles has been identified as an independent bacterial stress response pathway that is activated when bacteria encounter environmental stress, such as what might be experienced during the colonization of host tissues. Their detection in infected human tissues reinforces this theory. Various other virulence factors are also associated with OM vesicles, including adhesins and degradative enzymes. As a result, OM vesicles are heavily laden with pathogen associated molecular patterns (PAMPs), virulence factors, and other OM components that can impact the course of infection by having toxigenic effects or by the activation of the innate immune response. However, infected hosts can also benefit from OM vesicle production by stimulating their ability to mount an effective defense. Vesicles display antigens and can elicit potent inflammatory and immune responses. In sum, OM vesicles are likely to play a significant role in the virulence of Gram-negative bacterial pathogens. PMID- 20197502 TI - Space microbiology. AB - The responses of microorganisms (viruses, bacterial cells, bacterial and fungal spores, and lichens) to selected factors of space (microgravity, galactic cosmic radiation, solar UV radiation, and space vacuum) were determined in space and laboratory simulation experiments. In general, microorganisms tend to thrive in the space flight environment in terms of enhanced growth parameters and a demonstrated ability to proliferate in the presence of normally inhibitory levels of antibiotics. The mechanisms responsible for the observed biological responses, however, are not yet fully understood. A hypothesized interaction of microgravity with radiation-induced DNA repair processes was experimentally refuted. The survival of microorganisms in outer space was investigated to tackle questions on the upper boundary of the biosphere and on the likelihood of interplanetary transport of microorganisms. It was found that extraterrestrial solar UV radiation was the most deleterious factor of space. Among all organisms tested, only lichens (Rhizocarpon geographicum and Xanthoria elegans) maintained full viability after 2 weeks in outer space, whereas all other test systems were inactivated by orders of magnitude. Using optical filters and spores of Bacillus subtilis as a biological UV dosimeter, it was found that the current ozone layer reduces the biological effectiveness of solar UV by 3 orders of magnitude. If shielded against solar UV, spores of B. subtilis were capable of surviving in space for up to 6 years, especially if embedded in clay or meteorite powder (artificial meteorites). The data support the likelihood of interplanetary transfer of microorganisms within meteorites, the so-called lithopanspermia hypothesis. PMID- 20197503 TI - Exendin-4 increases blood glucose levels acutely in rats by activation of the sympathetic nervous system. AB - Exendin-4 (Ex-4), an agonist of the glucagon-like peptide-1 receptor (GLP-1R), shares many of the actions of GLP-1 on pancreatic islets, the central nervous system (CNS), and the gastrointestinal tract that mediates glucose homeostasis and food intake. Because Ex-4 has a much longer plasma half-life than GLP-1, it is an effective drug for reducing blood glucose levels in patients with type 2 diabetes mellitus (T2DM). Here, we report that acute administration of Ex-4, in relatively high doses, into either the peripheral circulation or the CNS, paradoxically increased blood glucose levels in rats. This effect was independent of the insulinotropic and hypothalamic-pituitary-adrenal activating actions of Ex 4 and could be blocked by a GLP-1R antagonist. Comparable doses of GLP-1 did not induce hyperglycemia, even when protected from rapid metabolism by a dipeptidyl peptidase IV inhibitor. Acute hyperglycemia induced by Ex-4 was blocked by hexamethonium, guanethidine, and adrenal medullectomy, indicating that this effect was mediated by sympathetic nervous system (SNS) activation. The potency of Ex-4 to elevate blood glucose waned with chronic administration such that after 6 days the familiar actions of Ex-4 to improve glucose tolerance were evident. These findings indicate that, in rats, high doses of Ex-4 activate a SNS response that can overcome the expected benefits of this peptide on glucose metabolism and actually raise blood glucose. These results have important implications for the design and interpretation of studies using Ex-4 in rats. Moreover, since there are many similarities in the response of the GLP-1R system across mammalian species, it is important to consider whether there is acute activation of the SNS by Ex-4 in humans. PMID- 20197504 TI - Adiponectin diminishes platelet aggregation and sCD40L release. Potential role in the metabolic syndrome. AB - The proinflammatory and proatherogenic mediator, soluble CD40 ligand (CD40L), is increased in the metabolic syndrome (MS) and released from platelets. We hypothesized that adiponectin modulates platelet function, and we sought to evaluate the association of adiponectin and sCD40L levels with platelet aggregation in MS and the effects of adiponectin on platelet aggregation and activation. Platelet aggregation and circulating adiponectin, sCD40L and P selectin were determined in 30 controls and 30 patients with MS. Also, in vitro studies were performed in platelet-rich plasma from nine healthy volunteers. Adiponectin receptors were demonstrated by Western blotting and flow cytometry. ADP and epinephrine platelet aggregation was measured after preincubation with adiponectin. sCD40L and P-selectin secretion was measured in the supernatants by ELISA. Patients with MS had higher sCD40L and P-selectin than controls (5.96 +/- 0.50 vs. 4.28 +/- 0.41 ng/ml, P < 0.05, and 151 +/- 8 vs. 122 +/- 9 ng/ml, P < 0.05). By contrast, adiponectin was lower in patients with MS than in controls (5.25 +/- 0.30 vs. 7.35 +/- 0.34 microg/ml, P < 0.001). Higher platelet aggregation was found in MS. Adiponectin inversely correlated with P-selectin (R = -0.35, P = 0.009), sCD40L (r = -0.24, P = 0.05) and epinephrine and collagen induced aggregation (r = -0.80, P = 0.005; r = -0.70, P = 0.011). Platelets express the receptors for adiponectin. Platelet aggregatory response to epinephrine and ADP significantly decreased following preincubation with adiponectin (96 +/- 4 vs. 23 +/- 3%, P < 0.001, and 102 +/- 9 vs. 85 +/- 9%, P = 0.004). Adiponectin prevented platelet sCD40L release (1.63 +/- 0.15 vs. 2.04 +/- 0.20 ng/ml, P < 0.001). Enhanced platelet aggregation and activation markers are found in MS associated with low adiponectin concentrations. Novel evidence is provided demonstrating that adiponectin has antithrombotic properties, since it inhibits platelet aggregation and platelet activation. PMID- 20197501 TI - Alkali metal cation transport and homeostasis in yeasts. AB - The maintenance of appropriate intracellular concentrations of alkali metal cations, principally K(+) and Na(+), is of utmost importance for living cells, since they determine cell volume, intracellular pH, and potential across the plasma membrane, among other important cellular parameters. Yeasts have developed a number of strategies to adapt to large variations in the concentrations of these cations in the environment, basically by controlling transport processes. Plasma membrane high-affinity K(+) transporters allow intracellular accumulation of this cation even when it is scarce in the environment. Exposure to high concentrations of Na(+) can be tolerated due to the existence of an Na(+), K(+) ATPase and an Na(+), K(+)/H(+)-antiporter, which contribute to the potassium balance as well. Cations can also be sequestered through various antiporters into intracellular organelles, such as the vacuole. Although some uncertainties still persist, the nature of the major structural components responsible for alkali metal cation fluxes across yeast membranes has been defined within the last 20 years. In contrast, the regulatory components and their interactions are, in many cases, still unclear. Conserved signaling pathways (e.g., calcineurin and HOG) are known to participate in the regulation of influx and efflux processes at the plasma membrane level, even though the molecular details are obscure. Similarly, very little is known about the regulation of organellar transport and homeostasis of alkali metal cations. The aim of this review is to provide a comprehensive and up-to-date vision of the mechanisms responsible for alkali metal cation transport and their regulation in the model yeast Saccharomyces cerevisiae and to establish, when possible, comparisons with other yeasts and higher plants. PMID- 20197505 TI - Internal architecture of mitochondrial complex I from Arabidopsis thaliana. AB - The NADH dehydrogenase complex (complex I) of the respiratory chain has unique features in plants. It is the main entrance site for electrons into the respiratory electron transfer chain, has a role in maintaining the redox balance of the entire plant cell and additionally comprises enzymatic side activities essential for other metabolic pathways. Here, we present a proteomic investigation to elucidate its internal structure. Arabidopsis thaliana complex I was purified by a gentle biochemical procedure that includes a cytochrome c mediated depletion of other respiratory protein complexes. To examine its internal subunit arrangement, isolated complex I was dissected into subcomplexes. Controlled disassembly of the holo complex (1000 kD) by low-concentration SDS treatment produced 10 subcomplexes of 550, 450, 370, 270, 240, 210, 160, 140, 140, and 85 kD. Systematic analyses of subunit composition by mass spectrometry gave insights into subunit arrangement within complex I. Overall, Arabidopsis complex I includes at least 49 subunits, 17 of which are unique to plants. Subunits form subcomplexes analogous to the known functional modules of complex I from heterotrophic eukaryotes (the so-called N-, Q-, and P-modules), but also additional modules, most notably an 85-kD domain including gamma-type carbonic anhydrases. Based on topological information for many of its subunits, we present a model of the internal architecture of plant complex I. PMID- 20197506 TI - SOMBRERO, BEARSKIN1, and BEARSKIN2 regulate root cap maturation in Arabidopsis. AB - The root cap has a central role in root growth, determining the growth trajectory and facilitating penetration into the soil. Root cap cells have specialized functions and morphologies, and border cells are released into the rhizosphere by specific cell wall modifications. Here, we demonstrate that the cellular maturation of root cap is redundantly regulated by three genes, SOMBRERO (SMB), BEARSKIN1 (BRN1), and BRN2, which are members of the Class IIB NAC transcription factor family, together with the VASCULAR NAC DOMAIN (VND) and NAC SECONDARY WALL THICKENING PROMOTING FACTOR (NST) genes that regulate secondary cell wall synthesis in specialized cell types. Lateral cap cells in smb-3 mutants continue to divide and fail to detach from the root, phenotypes that are independent of FEZ upregulation in smb-3. In brn1-1 brn2-1 double mutants, columella cells fail to detach, while in triple mutants, cells fail to mature in all parts of the cap. This complex genetic redundancy involves differences in expression, protein activity, and target specificity. All three genes have very similar overexpression phenotypes to the VND/NST genes, indicating that members of this family are largely functionally equivalent. Our results suggest that Class IIB NAC proteins regulate cell maturation in cells that undergo terminal differentiation with strong cell wall modifications. PMID- 20197507 TI - Practicing internal medicine onboard the USNS COMFORT in the aftermath of the Haitian earthquake. AB - On 12 January 2010, a 7.0-magnitude earthquake devastated the island nation of Haiti, leading to the world's largest humanitarian effort in over 6 decades. The catastrophe caused massive destruction of homes and buildings and overwhelmed the Haitian health care system. The United States responded immediately with a massive relief effort, sending U.S. military forces and civilian volunteers to Haiti's aid and providing a tertiary care medical center aboard the USNS COMFORT hospital ship. The COMFORT offered sophisticated medical care to a geographically isolated population and helped to transfer resource-intensive patients from other treatment facilities. Working collaboratively with the surgical staff, ancillary services, and nursing staff, internists aboard the COMFORT were integral to supporting the mission of the hospital ship and provided high-level care to the casualties. This article provides the perspective of the U.S. Navy internists who participated in the initial response to the Haitian earthquake disaster onboard the COMFORT. PMID- 20197508 TI - Prevalence of left ventricular regional dysfunction in arrhythmogenic right ventricular dysplasia: a tagged MRI study. AB - BACKGROUND: Although arrhythmogenic right ventricular dysplasia (ARVD) predominantly affects the right ventricle (RV), genetic/molecular and histological changes are biventricular. Regional left ventricular (LV) function has not been systematically studied in ARVD. METHODS AND RESULTS: The study population included 21 patients with suspected ARVD who underwent evaluation with MRI including tagging. Eleven healthy volunteers served as control subjects. Peak systolic regional circumferential strain (Ecc, %) was calculated by harmonic phase from tagged MRI based on the 16-segment model. Patients who met ARVD Task Force criteria were classified as definite ARVD, whereas patients with a positive family history who had 1 additional minor criterion and patients without a family history with 1 major or 2 minor criteria were classified as probable ARVD. Of the 21 ARVD subjects, 11 had definite ARVD and 10 had probable ARVD. Compared with control subjects, probable ARVD patients had similar RV ejection fraction (58.9+/ 6.2% versus 53.5+/-7.6%, P=0.20), but definite ARVD patients had significantly reduced RV ejection fraction (58.9+/-6.2% versus 45.2+/-6.0%, P=0.001). LV ejection fraction was similar in all 3 groups. Compared with control subjects, peak systolic Ecc was significantly less negative in 6 of 16 (37.5%) segments in definite ARVD and 3 of 16 segments (18.7%) in probable ARVD (all P<0.05). CONCLUSIONS: ARVD is associated with regional LV dysfunction, which appears to parallel degree of RV dysfunction. Further large studies are needed to validate this finding and to better define implications of subclinical segmental LV dysfunction. PMID- 20197509 TI - Underutilization of beta-blockers in patients undergoing implantable cardioverter defibrillator and cardiac resynchronization procedures. AB - BACKGROUND: Current guidelines emphasize the need for optimal medical therapy before implantation of cardiac devices (implantable cardioverter-defibrillator, cardiac resynchronization therapy). Our objective was to evaluate use of beta blockers (BB) among patients with heart failure undergoing a cardiac device procedure. METHODS AND RESULTS: We used a large, multistate, managed-care database (January 2003 to December 2006) to identify adults admitted with an International Classification of Diseases, Ninth Revision (ICD-9) procedure code for cardiac device, continuous enrollment for 180 days before and 180 days after device procedure, and a primary or secondary ICD-9 diagnosis code for heart failure during that period. Our primary measures were use of BB before device procedure and changes after discharge. A total of 2766 beneficiaries (78.8% men; median age, 61 years) underwent a device procedure for primary prevention. The median number of days on BB therapy in the 90 days before device procedure was 46. Beneficiaries who did not have a pharmacy fill for BB during that time (n=925, 33.4%) were more elderly and had fewer antecedent outpatient visits with a cardiologist. There was a shift toward greater use of BB after device procedure; 83.4% had at least 1 pharmacy fill for a BB during follow-up. CONCLUSIONS: BB are underused before and after cardiac device procedures. There is a modest increase in use after the procedure. Strategies are required to ensure that patients are on optimal medical therapy before device therapy is selected. PMID- 20197511 TI - Meta-analyses of septal reduction therapies for obstructive hypertrophic cardiomyopathy: comparative rates of overall mortality and sudden cardiac death after treatment. AB - BACKGROUND: Septal reduction for obstructive hypertrophic cardiomyopathy may be performed by surgical myectomy or alcohol septal ablation (ASA). Unlike surgical myectomy, ASA creates an intramyocardial scar that may potentiate the risk of ventricular arrhythmias and sudden cardiac death (SCD). METHODS AND RESULTS: Systematic reviews for ASA and surgical myectomy were performed. Study selection and data extraction were completed independently by 2 investigators. Comparative data analyses were completed using a random effects model and regression analysis. Kappa statistics for agreement on initial study inclusion were high for both ASA (0.78; 95% CI, 0.68 to 0.88) and surgical myectomy studies (0.95; 95% CI, 0.84 to 1.0). Nineteen ASA studies (2207 patients) and 8 surgical myectomy studies (1887 patients) were included. Median follow-up was shorter for ASA than for myectomy studies (51 versus 1266 patient-years; P<0.001). For ASA and surgical myectomy, unadjusted rates (events/patient-years) of all-cause mortality (0.021 versus 0.018, respectively; P=0.37) and SCD (0.004 versus 0.003, respectively; P=0.36) were similar. Patients treated with ASA were older (weighted mean, 55 versus 44 years; P<0.001) and had less septal hypertrophy (weighted mean, 21 versus 23 mm; P<0.001) compared with those treated with myectomy. After adjustment for available baseline characteristics, odds ratios for treatment effect on all-cause mortality and SCD were 0.28 (95% CI, 0.16 to 0.46) and 0.32 (95% CI, 0.11 to 0.97), respectively, favoring ASA. CONCLUSIONS: Rates of all-cause mortality and SCD after both ASA and surgical myectomy were similarly low. Adjusted for baseline characteristics, the odds ratios for treatment effect on all-cause mortality and SCD were lower in ASA cohorts compared with surgical myectomy cohorts. PMID- 20197510 TI - Arterial intima-media thickness, endothelial function, and apolipoproteins in adolescents frequently exposed to tobacco smoke. AB - BACKGROUND: Exposure to tobacco smoke is associated with markers of preclinical atherosclerosis in adults, but its effect on arterial structure in adolescents is unknown. METHODS AND RESULTS: Healthy 13-year-old adolescents from the atherosclerosis prevention trial STRIP were studied. Maximum carotid and aortic intima-media thickness and brachial artery flow-mediated dilation were measured in 494 adolescents using high-resolution ultrasound. Serum lipid, lipoprotein, and apolipoprotein (Apo) A-I and B concentrations were determined using standard methods. Exposure to tobacco smoke was measured annually between ages 8 and 13 years using serum cotinine concentrations, analyzed with gas chromatography. To define longitudinal exposure, cotinine values of children having serum cotinine measured 2 to 6 times during follow-up were averaged and divided into tertiles (exposure groups): low (n=160), intermediate (n=171), and high (n=163). Adolescents with higher longitudinal exposure to tobacco smoke had increased carotid intima-media thickness (exposure groups [mean+/-SD]: low, 0.502+/-0.079 mm; intermediate, 0.525+/-0.070 mm; high, 0.535+/-0.066 mm; P<0.001) and increased aortic intima-media thickness (exposure groups: low, 0.527+/-0.113 mm; intermediate, 0.563+/-0.139 mm; high, 0.567+/-0.126 mm; P=0.008). The flow mediated dilation decreased when cotinine level increased (exposure groups: low, 10.43+/-4.34%; intermediate, 9.78+/-4.38%; high, 8.82+/-4.14%; P=0.004). Moreover, ApoB (P=0.014) and ApoB/ApoA-I ratio (P=0.045) increased with increase in cotinine level. The associations between tobacco smoke exposure and ultrasound variables were unchanged after adjusting for traditional atherosclerosis risk factors and for ApoB. CONCLUSIONS: Frequent exposure to tobacco smoke is independently associated with arterial changes of preclinical atherosclerosis and increased ApoB levels among healthy adolescents. Clinical Trial Registration- clinicaltrials.gov. Identifier: NCT00223600. PMID- 20197512 TI - Drug-eluting stents in bifurcations: bench study of strut deformation and coating lesions. AB - BACKGROUND: The use of a drug-eluting stent (DES) has strongly limited the incidence of in-stent restenosis in bifurcation lesions; nevertheless, restenosis still remains a problem at the origin of the bifurcation side branch. The aim of this study is to analyze the consequences of the kissing postdilatation technique on 5 DESs, using microfocus x-ray computerized tomography and scanning electron microscopy. METHODS AND RESULTS: Five different DESs (Cypher, Cypher Select, Endeavor, Taxus Express, and Taxus Liberte) were deployed using kissing postdilatation protocols in a bench-top model. For all types of DES, microfocus x ray computerized tomography analysis showed that (1) kissing postdilatation of the stent by 2 coaxial balloons caused elliptic deformation in the proximal segment and (2) kissing postdilatation technique reduced the ratio of potential metal to artery (manufacturer's data/calculated ratio [%]: Cypher, 12.7/8.8; Cypher Select, 13.5/10.2; Endeavor, 19.0/13.3; Taxus Express, 20.5/4.7; Taxus Liberte, 17.9/12.5) and the potential drug application to area in the proximal segment, including the ostial struts (struts adjacent to and lying around the side branch ostium) (manufacturer's data/calculated drug application [microg/mm(2)]: Cypher, 1.4/1.0; Cypher Select, 1.4/1.1; Endeavor, 1.6/1.1; Taxus Express, 1.0/0.7; Taxus Liberte, 1.0/0.7). Scanning electron microscopy analysis showed a significantly greater coating damage to the ostial struts in all stents evaluated (P<0.05). CONCLUSIONS: Commercially available DESs subjected to simultaneous kissing balloon postdilatation in an unconstrained model may contribute to side branch ostial restenosis by proximal segment elliptic deformation and damage to the polymer coating. PMID- 20197513 TI - Intravascular ultrasound classification of plaque distribution in left main coronary artery bifurcations: where is the plaque really located? AB - BACKGROUND: Angiographic classifications of the location and severity of disease in the main vessel and side branch of coronary artery bifurcations have been proposed and applied to distal left main coronary artery (LMCA) bifurcation. METHODS AND RESULTS: We reviewed 140 angiograms of distal LMCA and ostial left anterior descending (LAD) and left circumflex (LCX) artery lesions with preintervention intravascular ultrasound (IVUS) of both the LAD and LCX arteries as well as the LMCA. Of 140 patients, 92.9% had at least 1 cross section with > or =40% IVUS plaque burden versus 57.2% of patients with an angiographic diameter stenosis > or =50%. Contrary to angiographic classifications, IVUS showed that bifurcation disease was rarely focal and that both sides of the flow divider were always disease-free. Continuous plaque from the LMCA into the proximal LAD artery was seen in 90%, from the LMCA into the LCX artery in 66.4%, and from the LMCA into both the LAD and LCX arteries in 62%. Plaque localized to either the LAD or LCX ostium and not involving the distal LMCA was seen in only 9.3% of LAD arteries and 17.1% of LCX arteries. Plaque distribution was not influenced by the LAD/LCX angiographic angle, lesion severity, LMCA length, or remodeling. We proposed an IVUS classification for bifurcation lesions illustrating longitudinal and circumferential spatial plaque distribution. CONCLUSIONS: Angiographic classification of LMCA bifurcation lesions is rarely accurate. IVUS shows that the carina is always spared and that the disease is diffuse rather than focal. PMID- 20197514 TI - State payer mandates to cover care in US oncology trials: do science and ethics matter? AB - BACKGROUND: In the United States, Medicare-eligible participants' costs for routine care and complications from cancer clinical trials are covered by Medicare, but other people depend on state insurance mandates to assure coverage. METHODS: State mandates were reviewed for requirements to assure trials' scientific and ethical soundness, whom they covered and omitted, scope, and coverage for participants' research-related injuries in addition to routine care costs. RESULTS: Twenty-six states mandated coverage. Four states (15%) required scientific peer review for all studies. For 20 states (80%), an approved investigational new drug qualified as scientific review. In 10 states (38%), institutional review board (IRB) approval could replace scientific review. Twenty four states (92%) permitted trials without academic medical connection. All states covered privately insured patients; seven (27%) included government and Medicaid patients. Fourteen states (54%) covered phase I to phase IV trials. Sixteen states (62%) covered treatment trials only; one (4%) covered prevention, detection, treatment, and palliation. Thirteen states (50%) covered research related injuries. Only seven states (27%) required IRB approval. Three states (12%) required commensurate risks and benefits; 23 (88%) had no standard. Eight states (31%) required clinical equipoise with standard care; eight (31%) had no standard; and remaining states (46%) had unique standards. Two states (8%) addressed publication or registries. CONCLUSIONS: Most states did not demand independent scientific review, IRB review, or basic ethical features of high quality trials; provided partial coverage; omitted prevention, detection, and palliation research; and omitted mandated coverage for research-related injuries. Few required evaluation, independence in publication, or posting trial results. Further research on the impact of diverse state choices would improve policy making. PMID- 20197519 TI - The cover. Homer and his guide. PMID- 20197520 TI - A piece of my mind. HIV clinic. PMID- 20197521 TI - Treatment given high priority in new White House drug control policy. Interview by Bridget Kuehn. PMID- 20197522 TI - Experts reconsider wisdom of limiting Chlamydia screening only to women. PMID- 20197523 TI - Cardiac patients' herbal supplement use deserves more careful investigation. PMID- 20197524 TI - Improving medication adherence promises great payback, but poses tough challenge. PMID- 20197525 TI - Prone positioning in patients with acute respiratory distress syndrome. PMID- 20197526 TI - Aldosterone antagonists in patients with heart failure. PMID- 20197527 TI - Aldosterone antagonists in patients with heart failure. PMID- 20197528 TI - Modeling cardiovascular disease prevention. PMID- 20197529 TI - Omega-3 fatty acids for CHD with depression. PMID- 20197531 TI - Three-year outcomes for Medicare beneficiaries who survive intensive care. AB - CONTEXT: Although hospital mortality has decreased over time in the United States for patients who receive intensive care, little is known about subsequent outcomes for those discharged alive. OBJECTIVE: To assess 3-year outcomes for Medicare beneficiaries who survive intensive care. DESIGN, SETTING, AND PATIENTS: A matched, retrospective cohort study was conducted using a 5% sample of Medicare beneficiaries older than 65 years. A random half of all patients were selected who received intensive care and survived to hospital discharge in 2003 with 3 year follow-up through 2006. From the other half of the sample, 2 matched control groups were generated: hospitalized patients who survived to discharge (hospital controls) and the general population (general controls), individually matched on age, sex, race, and whether they had surgery (for hospital controls). MAIN OUTCOME MEASURE: Three-year mortality after hospital discharge. RESULTS: There were 35,308 intensive care unit (ICU) patients who survived to hospital discharge. The ICU survivors had a higher 3-year mortality (39.5%; n = 13,950) than hospital controls (34.5%; n = 12,173) (adjusted hazard ratio [AHR], 1.07 [95% confidence interval {CI}, 1.04-1.10]; P < .001) and general controls (14.9%; n = 5266) (AHR, 2.39 [95% CI, 2.31-2.48]; P < .001). The ICU survivors who did not receive mechanical ventilation had minimal increased risk compared with hospital controls (3-year mortality, 38.3% [n = 12,716] vs 34.6% [n=11,470], respectively; AHR, 1.04 [95% CI, 1.02-1.07]). Those receiving mechanical ventilation had substantially increased mortality (57.6% [1234 ICU survivors] vs 32.8% [703 hospital controls]; AHR, 1.56 [95% CI, 1.40-1.73]), with risk concentrated in the 6 months after the quarter of hospital discharge (6-month mortality, 30.1% (n = 645) for those receiving mechanical ventilation vs 9.6% (n = 206) for hospital controls; AHR, 2.26 [95% CI, 1.90-2.69]). Discharge to a skilled care facility for ICU survivors (33.0%; n = 11,634) and hospital controls (26.4%; n = 9328) also was associated with high 6-month mortality (24.1% for ICU survivors and hospital controls discharged to a skilled care facility vs 7.5% for ICU survivors and hospital controls discharged home; AHR, 2.62 [95% CI, 2.50 2.74]; P < .001 for ICU survivors and hospital controls combined). CONCLUSIONS: There is a large US population of elderly individuals who survived the ICU stay to hospital discharge but who have a high mortality over the subsequent years in excess of that seen in comparable controls. The risk is concentrated early after hospital discharge among those who require mechanical ventilation. PMID- 20197530 TI - Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial. AB - CONTEXT: A low ankle brachial index (ABI) indicates atherosclerosis and an increased risk of cardiovascular and cerebrovascular events. Screening for a low ABI can identify an asymptomatic higher risk group potentially amenable to preventive treatments. OBJECTIVE: To determine the effectiveness of aspirin in preventing events in people with a low ABI identified on screening the general population. DESIGN, SETTING, AND PARTICIPANTS: The Aspirin for Asymptomatic Atherosclerosis trial was an intention-to-treat double-blind randomized controlled trial conducted from April 1998 to October 2008, involving 28,980 men and women aged 50 to 75 years living in central Scotland, free of clinical cardiovascular disease, recruited from a community health registry, and had an ABI screening test. Of those, 3350 with a low ABI (< or = 0.95) were entered into the trial, which was powered to detect a 25% proportional risk reduction in events. INTERVENTIONS: Once daily 100 mg aspirin (enteric coated) or placebo. MAIN OUTCOME MEASURES: The primary end point was a composite of initial fatal or nonfatal coronary event or stroke or revascularization. Two secondary end points were (1) all initial vascular events defined as a composite of a primary end point event or angina, intermittent claudication, or transient ischemic attack; and (2) all-cause mortality. RESULTS: After a mean (SD) follow-up of 8.2 (1.6) years, 357 participants had a primary end point event (13.5 per 1000 person years, 95% confidence interval [CI], 12.2-15.0). No statistically significant difference was found between groups (13.7 events per 1000 person-years in the aspirin group vs 13.3 in the placebo group; hazard ratio [HR], 1.03; 95% CI, 0.84 1.27). A vascular event comprising the secondary end point occurred in 578 participants (22.8 per 1000 person-years; 95% CI, 21.0-24.8) and no statistically significant difference between groups (22.8 events per 1000 person-years in the aspirin group vs 22.9 in the placebo group; HR, 1.00; 95% CI, 0.85-1.17). There was no significant difference in all-cause mortality between groups (176 vs 186 deaths, respectively; HR, 0.95; 95% CI, 0.77-1.16). An initial event of major hemorrhage requiring admission to hospital occurred in 34 participants (2.5 per 1000 person-years) in the aspirin group and 20 (1.5 per 1000 person-years) in the placebo group (HR, 1.71; 95% CI, 0.99-2.97). CONCLUSION: Among participants without clinical cardiovascular disease, identified with a low ABI based on screening a general population, the administration of aspirin compared with placebo did not result in a significant reduction in vascular events. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN66587262. PMID- 20197532 TI - Comparative mortality risk of anemia management practices in incident hemodialysis patients. AB - CONTEXT: Controversy exists about optimal management of anemia in end-stage renal disease. OBJECTIVE: To compare the mortality risk of different dialysis center level patterns of anemia management. DESIGN, SETTING, AND PATIENTS: Using data from Medicare's end-stage renal disease program (1999-2007), we characterized each US dialysis center's annual anemia management practice by estimating its typical use of erythropoiesis-stimulating agents (ESAs) and intravenous iron in hemodialysis patients within 4 hematocrit categories. We used Cox proportional hazards regression to correlate center-level patterns of ESA and iron use with 1 year mortality risk in 269,717 incident hemodialysis patients. MAIN OUTCOME MEASURE: One-year all-cause mortality. RESULTS: Monthly mortality rates were highest in patients with hematocrit less than 30% (mortality, 2.1%) and lowest for those with hematocrit of 36% or higher (mortality, 0.7%). After adjustment for baseline case-mix differences, dialysis centers that used larger ESA doses in patients with hematocrit less than 30% had lower mortality rates than centers that used smaller doses (highest vs lowest dose group: hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.90-0.97). Centers that administered iron more frequently to patients with hematocrit less than 33% also had lower mortality rates (highest vs lowest quintile, HR, 0.95; 95% CI, 0.91-0.98). However, centers that used larger ESA doses in patients with hematocrit between 33% and 35.9% had higher mortality rates (highest vs lowest quintile, HR, 1.07; 95% CI, 1.03-1.12). More intensive use of both ESAs and iron was associated with increased mortality risk in patients with hematocrit of 36% or higher. These findings persisted across a range of secondary analyses. CONCLUSIONS: Greater ESA and iron use were associated with decreased mortality risk at lower hematocrit levels, in which mortality rates are the highest. Although the overall mortality rate was lower at higher hematocrit levels, elevated mortality risk was associated with greater use of ESAs and iron in these patients. PMID- 20197534 TI - The Healthcare Innovation Zone: a platform for true reform. PMID- 20197533 TI - Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta analysis. AB - CONTEXT: Trials comparing higher vs lower levels of positive end-expiratory pressure (PEEP) in adults with acute lung injury or acute respiratory distress syndrome (ARDS) have been underpowered to detect small but potentially important effects on mortality or to explore subgroup differences. OBJECTIVES: To evaluate the association of higher vs lower PEEP with patient-important outcomes in adults with acute lung injury or ARDS who are receiving ventilation with low tidal volumes and to investigate whether these associations differ across prespecified subgroups. DATA SOURCES: Search of MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (1996-January 2010) plus a hand search of conference proceedings (2004-January 2010). STUDY SELECTION: Two reviewers independently screened articles to identify studies randomly assigning adults with acute lung injury or ARDS to treatment with higher vs lower PEEP (with low tidal volume ventilation) and also reporting mortality. DATA EXTRACTION: Data from 2299 individual patients in 3 trials were analyzed using uniform outcome definitions. Prespecified effect modifiers were tested using multivariable hierarchical regression, adjusting for important prognostic factors and clustering effects. RESULTS: There were 374 hospital deaths in 1136 patients (32.9%) assigned to treatment with higher PEEP and 409 hospital deaths in 1163 patients (35.2%) assigned to lower PEEP (adjusted relative risk [RR], 0.94; 95% confidence interval [CI], 0.86-1.04; P = .25). Treatment effects varied with the presence or absence of ARDS, defined by a value of 200 mm Hg or less for the ratio of partial pressure of oxygen to fraction of inspired oxygen concentration (P = .02 for interaction). In patients with ARDS (n = 1892), there were 324 hospital deaths (34.1%) in the higher PEEP group and 368 (39.1%) in the lower PEEP group (adjusted RR, 0.90; 95% CI, 0.81-1.00; P = .049); in patients without ARDS (n = 404), there were 50 hospital deaths (27.2%) in the higher PEEP group and 44 (19.4%) in the lower PEEP group (adjusted RR, 1.37; 95% CI, 0.98-1.92; P = .07). Rates of pneumothorax and vasopressor use were similar. CONCLUSIONS: Treatment with higher vs lower levels of PEEP was not associated with improved hospital survival. However, higher levels were associated with improved survival among the subgroup of patients with ARDS. PMID- 20197535 TI - Reformulation of the sedation continuum. PMID- 20197536 TI - Losing the opportunity to study influenza drugs. PMID- 20197537 TI - Aspirin as preventive therapy in patients with asymptomatic vascular disease. PMID- 20197538 TI - How much PEEP in acute lung injury. PMID- 20197539 TI - Abraham Flexner and his remarkable report on medical education: a century later. PMID- 20197540 TI - JAMA patient page. Mechanical ventilation. PMID- 20197541 TI - Economic evaluation of PET and PET/CT in oncology: evidence and methodologic approaches. AB - PET and PET/CT have changed the diagnostic algorithm in oncology. Health care systems worldwide have recently approved reimbursement for PET and PET/CT for staging of non-small cell lung cancer and differential diagnosis of solitary pulmonary nodules because PET and PET/CT have been found to be cost-effective for those uses. Additional indications that are covered by health care systems in the United States and several European countries include staging of gastrointestinal tract cancers, breast cancer, malignant lymphoma, melanoma, and head and neck cancers. Regarding these indications, diagnostic effectiveness and superiority over conventional imaging modalities have been shown, whereas cost-effectiveness has been demonstrated only in part. This article reports on the current knowledge of economic evaluations of PET and PET/CT in oncologic applications. Because more economic evaluations are needed for several clinical indications, we also report on the methodologies for conducting economic evaluations of diagnostic tests and suggest an approach toward the implementation of these tests in future clinical studies. PMID- 20197542 TI - A prospective 1-year study of changes in neuropsychological functioning after implantable cardioverter-defibrillator surgery. AB - BACKGROUND: The testing of the implantable cardioverter-defibrillator (ICD), through the induction of repeated episodes of ventricular fibrillation, has been associated with disturbances in cerebral activity and increased levels of cytoplasmic enzymes. However, the neuropsychological outcomes of cerebral changes and their quality-of-life implications are unknown. METHODS AND RESULTS: Fifty two ICD recipients completed standardized validated neuropsychological tests 1 to 3 days before ICD surgery and then 6 weeks, 6 months, and 12 months after surgery. They also completed psychometric tests measuring anxiety, depression, and quality of life. Between 31% and 39% of patients showed a significant neuropsychological impairment from their baseline function 6 weeks, 6 months, and 12 months after surgery. Ten percent of patients had late-onset deficits at 12 months only. Frequent areas of impairment were auditory and visual memory and attention. Neuropsychological impairment was not related to mood or quality of life at follow-up, although anxiety and depression predicted reduced quality of life. CONCLUSIONS: ICD implantation is associated with neuropsychological impairment that dissipates for the majority of recipients after 12 months. Short term memory function and attention are particularly vulnerable to changes in oxygen during ICD testing. Although anxiety and depression are prevalent, there is little evidence for the direct impact of mood on cognition, and deficits appear not to be associated with reduced quality of life. These results provide evidence for longitudinal outcomes of ICD surgery and have implications for patient rehabilitation and adjustment. PMID- 20197543 TI - Allosteric protein kinase regulation by pseudokinases: insights from STRAD. AB - Protein kinases regulate a plethora of diverse cellular functions. Their highly controlled activation is subject to an equally diverse repertoire of regulatory mechanisms. Pseudokinases, a class of proteins that possess a structurally related protein kinase domain that lacks phospho-transfer function, are emerging as critical yet mysterious regulators of other protein kinases. A new structural and functional analysis of the pseudokinase STRAD provides insight into the mechanism by which it allosterically regulates the catalytic function of the protein kinase LKB1 and hints at an evolution from a classical kinase-substrate relationship. PMID- 20197544 TI - Polycomb group proteins as epigenetic mediators of neuroprotection in ischemic tolerance. AB - Exposing the brain to sublethal ischemia affects the response to a subsequent, otherwise injurious ischemia, resulting in transcriptional suppression and neuroprotection, a response called ischemic tolerance. Here, we show that the proteomic signature of the ischemic-tolerant brain is characterized by increased abundance of transcriptional repressors, particularly polycomb group (PcG) proteins. Knocking down PcG proteins precluded the induction of ischemic tolerance, whereas in an in vitro model, overexpressing the PcG proteins SCMH1 or BMI1 induced tolerance to ischemia without preconditioning. We found that PcG proteins are associated with the promoter regions of genes encoding two potassium channel proteins that show decreased abundance in ischemic-tolerant brains. Furthermore, PcG proteins decreased potassium currents in cultured neuronal cells, and knocking down potassium channels elicited tolerance without preconditioning. These findings reveal a previously unknown mechanism of neuroprotection that involves gene repressors of the PcG family. PMID- 20197545 TI - Characterization of a domain that transiently converts class 2 DYRKs into intramolecular tyrosine kinases. AB - Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) autophosphorylate an essential tyrosine residue in their activation loop and phosphorylate their substrates on serine and threonine residues. Phosphorylation of the activation loop tyrosine occurs intramolecularly, is mediated by a short lived transitional intermediate during protein maturation, and is required for functional serine-threonine kinase activity of DYRKs. The DYRK family is separated into two subclasses. Through bioinformatics and mutational analyses, we identified a conserved domain in the noncatalytic N terminus of a class 2 DYRK that was required for autophosphorylation of the activation loop tyrosine but not for the phosphorylation of serine or threonine residues in substrates. We propose that this domain, which we term the NAPA domain, provides a chaperone-like function that transiently converts class 2 DYRKs into intramolecular kinases capable of autophosphorylating the activation loop tyrosine. The conservation of the NAPA domain from trypanosomes to humans indicates that this form of intramolecular phosphorylation of the activation loop is ancient and may represent a primordial mechanism for the activation of protein kinases. PMID- 20197546 TI - Crystal structure of the alpha-kinase domain of Dictyostelium myosin heavy chain kinase A. AB - Dictyostelium discoideum myosin II heavy chain kinase A (MHCK A) disrupts the assembly and cellular activity of bipolar filaments of myosin II by phosphorylating sites within its alpha-helical, coiled-coil tail. MHCK A is a member of the atypical alpha-kinase family of serine and threonine protein kinases and displays no sequence homology to typical eukaryotic protein kinases. We report the crystal structure of the alpha-kinase domain (A-CAT) of MHCK A. When crystallized in the presence of adenosine triphosphate (ATP), A-CAT contained adenosine monophosphate (AMP) at the active site. However, when crystallized in the presence of ATP and a peptide substrate, which does not appear in the structure, adenosine diphosphate (ADP) was found at the active site and an invariant aspartic acid residue (Asp(766)) at the active site was phosphorylated. The aspartylphosphate group was exposed to the solvent within an active-site pocket that might function as a docking site for substrates. Access to the aspartylphosphate was regulated by a conformational switch in a loop that bound to a magnesium ion (Mg(2+)), providing a mechanism that allows alpha kinases to sense and respond to local changes in Mg(2+). PMID- 20197547 TI - Cleavage of sphingosine kinase 2 by caspase-1 provokes its release from apoptotic cells. AB - Execution of physiologic cell death known as apoptosis is tightly regulated and transfers immunologically relevant information. This ensures efficient clearance of dying cells and shapes the phenotype of their "captors" toward anti inflammatory. Here, we identify a mechanism of sphingosine-1-phosphate production by apoptotic cells. During cell death, sphingosine kinase 2 (SphK2) is cleaved at its N-terminus in a caspase-1-dependent manner. Thereupon, a truncated but enzymatically active fragment of SphK2 is released from cells. This step is coupled to phosphatidylserine exposure, which is a hallmark of apoptosis and a crucial signal for phagocyte/apoptotic cell interaction. Our data link signaling events during apoptosis to the extracellular production of a lipid mediator that affects immune cell attraction and activation. PMID- 20197548 TI - Conditional expression of heterozygous or homozygous Jak2V617F from its endogenous promoter induces a polycythemia vera-like disease. AB - A somatic point mutation (V617F) in the JAK2 tyrosine kinase was found in a majority of patients with polycythemia vera (PV), essential thrombocythemia, and primary myelofibrosis. However, contribution of the JAK2V617F mutation in these 3 clinically distinct myeloproliferative neoplasms (MPNs) remained unclear. To investigate the role of JAK2V617F in the pathogenesis of these MPNs, we generated an inducible Jak2V617F knock-in mouse, in which the expression of Jak2V617F is under control of the endogenous Jak2 promoter. Expression of heterozygous mouse Jak2V617F evoked all major features of human polycythemia vera (PV), which included marked increase in hemoglobin and hematocrit, increased red blood cells, leukocytosis, thrombocytosis, splenomegaly, reduced serum erythropoietin (Epo) levels and Epo-independent erythroid colonies. Homozygous Jak2V617F expression also resulted in a PV-like disease associated with significantly greater reticulocytosis, leukocytosis, neutrophilia and thrombocytosis, marked expansion of erythroid progenitors and Epo-independent erythroid colonies, larger spleen size, and accelerated bone marrow fibrosis compared with heterozygous Jak2V617F expression. Biochemical analyses revealed Jak2V617F gene dosage-dependent activation of Stat5, Akt, and Erk signaling pathways. Our conditional Jak2V617F knock-in mice provide an excellent model that can be used to further understand the molecular pathogenesis of MPNs and to identify additional genetic events that cooperate with Jak2V617F in different MPNs. PMID- 20197549 TI - MyD88-dependent TLR4 signaling is selectively impaired in alveolar macrophages from asymptomatic HIV+ persons. AB - Alveolar macrophages (AMs) are the predominant effector cell in the lungs and contribute to a critical first line of defense against bacterial pathogens through recognition by pattern recognition receptors such as Toll-like receptor 4 (TLR4). TLR4-mediated tumor necrosis factor alpha (TNFalpha) release is significantly impaired in HIV(+) macrophages, but whether HIV impairs myeloid differentiation factor 88 (MyD88)-dependent and/or MyD-independent TLR4 signaling pathways in human macrophages is not known. Comparing human U937 macrophages with HIV(+) U1 macrophages (HIV-infected U937 subclone), the current study shows that HIV infection is associated with impaired macrophage TLR4-mediated signaling, specifically targeting the MyD88-dependent TLR4-mediated signaling pathway (reduced MyD88-interleukin-1 receptor-associated kinase [IRAK] interaction, IRAK phosphorylation, nuclear factor [NF]-kappaB nuclear translocation, and TNFalpha release) while preserving the MyD88-independent TLR4-mediated signaling pathway (preserved STAT1 phosphorylation, interferon regulatory factor [IRF] nuclear translocation, and interleukin-10 [IL-10] and RANTES release). Extracellular TLR4 signaling complex was intact (similar levels of CD14 and MD2), and similar patterns of response were observed in clinically relevant AMs from healthy and asymptomatic HIV(+) persons at high clinical risk of pneumonia. Taken together, these data support the concept that chronic HIV infection is associated with specific and targeted disruption of critical macrophage TLR4 signaling, which in turn may contribute to disease pathogenesis of bacterial pneumonia. PMID- 20197550 TI - Crystal structure and functional interpretation of the erythrocyte spectrin tetramerization domain complex. AB - As the principal component of the membrane skeleton, spectrin confers integrity and flexibility to red cell membranes. Although this network involves many interactions, the most common hemolytic anemia mutations that disrupt erythrocyte morphology affect the spectrin tetramerization domains. Although much is known clinically about the resulting conditions (hereditary elliptocytosis and pyropoikilocytosis), the detailed structural basis for spectrin tetramerization and its disruption by hereditary anemia mutations remains elusive. Thus, to provide further insights into spectrin assembly and tetramer site mutations, a crystal structure of the spectrin tetramerization domain complex has been determined. Architecturally, this complex shows striking resemblance to multirepeat spectrin fragments, with the interacting tetramer site region forming a central, composite repeat. This structure identifies conformational changes in alpha-spectrin that occur upon binding to beta-spectrin, and it reports the first structure of the beta-spectrin tetramerization domain. Analysis of the interaction surfaces indicates an extensive interface dominated by hydrophobic contacts and supplemented by electrostatic complementarity. Analysis of evolutionarily conserved residues suggests additional surfaces that may form important interactions. Finally, mapping of hereditary anemia-related mutations onto the structure demonstrate that most, but not all, local hereditary anemia mutations map to the interacting domains. The potential molecular effects of these mutations are described. PMID- 20197551 TI - Evaluation of enteropathy-associated T-cell lymphoma comparing standard therapies with a novel regimen including autologous stem cell transplantation. AB - Enteropathy associated T-cell lymphoma (EATL) is a rare type of peripheral T-cell lymphoma. At present, there are no standardized diagnostic or treatment protocols for EATL. We describe EATL in a population-based setting and evaluate a new treatment with aggressive chemotherapy and autologous stem cell transplantation (ASCT). From 1979 onward the Scotland and Newcastle Lymphoma Group prospectively collected data on all patients newly diagnosed with lymphoma in the Northern Region of England and Scotland. Between 1994 and 1998, records of all patients diagnosed with EATL were reviewed, and 54 patients had features of EATL. Overall incidence was 0.14/100 000 per year. Treatment was systemic chemotherapy (mostly anthracycline-based chemotherapy) with or without surgery in 35 patients and surgery alone in 19 patients. Median progression-free survival (PFS) was 3.4 months and overall survival (OS) was 7.1 months. The novel regimen IVE/MTX (ifosfamide, etoposide, epirubicin/methotrexate)-ASCT [corrected] was piloted from 1998 for patients eligible for intensive treatment, and 26 patients were included. Five-years PFS and OS were 52% and 60%, respectively, and were significantly improved compared with the historical group treated with anthracycline-based chemotherapy (P = .01 and P = .003, respectively). EATL is a rare lymphoma with an unfavorable prognosis when treated with conventional therapies. The IVE/MTX-ASCT regimen is feasible with acceptable toxicity and significantly improved outcome. PMID- 20197552 TI - Acquired resistance to ABT-737 in lymphoma cells that up-regulate MCL-1 and BFL 1. AB - ABT-737 is a small-molecule antagonist of BCL-2 currently under evaluation in clinical trials in the oral form of ABT-263. We anticipate that acquired resistance to this promising drug will inevitably arise. To study potential mechanisms of resistance to ABT-737, we derived resistant lines from initially sensitive OCI-Ly1 and SU-DHL-4 lymphoma cell lines via long-term exposure. Resistance was based in the mitochondria and not due to an inability of the drug to bind BCL-2. Resistant cells had increased levels of BFL-1 and/or MCL-1 proteins, which are not targeted by ABT-737. Proapoptotic BIM was displaced from BCL-2 by ABT-737 in both parental and resistant cells, but in resistant cells, BIM was sequestered by the additional BFL-1 and/or MCL-1. Decreasing MCL-1 levels with flavopiridol, PHA 767491, or shRNA restored sensitivity to ABT-737 resistant cells. MCL-1 was up-regulated not by protein stabilization but rather by increased transcript levels. Surprisingly, in addition to stable increases in MCL 1 transcript and protein in resistant cells, there was a dynamic increase within hours after ABT-737 treatment. BFL-1 protein and transcript levels in resistant cells were similarly dynamically up-regulated. This dynamic increase suggests a novel mechanism whereby modulation of antiapoptotic protein function communicates with nuclear transcriptional machinery. PMID- 20197553 TI - The Apc(min) mouse has altered hematopoietic stem cell function and provides a model for MPD/MDS. AB - Apc, a negative regulator of the canonical Wnt signaling pathway, is a bona-fide tumor suppressor whose loss of function results in intestinal polyposis. APC is located in a commonly deleted region on human chromosome 5q, associated with myelodysplastic syndrome (MDS), suggesting that haploinsufficiency of APC contributes to the MDS phenotype. Analysis of the hematopoietic system of mice with the Apc(min) allele that results in a premature stop codon and loss of function showed no abnormality in steady state hematopoiesis. Bone marrow derived from Apc(min) mice showed enhanced repopulation potential, indicating a cell intrinsic gain of function in the long-term hematopoietic stem cell (HSC) population. However, Apc(min) bone marrow was unable to repopulate secondary recipients because of loss of the quiescent HSC population. Apc(min) mice developed a MDS/myeloproliferative phenotype. Our data indicate that Wnt activation through haploinsufficiency of Apc causes insidious loss of HSC function that is only evident in serial transplantation strategies. These data provide a cautionary note for HSC-expansion strategies through Wnt pathway activation, provide evidence that cell extrinsic factors can contribute to the development of myeloid disease, and indicate that loss of function of APC may contribute to the phenotype observed in patients with MDS and del(5q). PMID- 20197554 TI - Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity. AB - Indoleamine 2,3-dioxygenase-1 (IDO1; IDO) mediates oxidative cleavage of tryptophan, an amino acid essential for cell proliferation and survival. IDO1 inhibition is proposed to have therapeutic potential in immunodeficiency associated abnormalities, including cancer. Here, we describe INCB024360, a novel IDO1 inhibitor, and investigate its roles in regulating various immune cells and therapeutic potential as an anticancer agent. In cellular assays, INCB024360 selectively inhibits human IDO1 with IC(50) values of approximately 10nM, demonstrating little activity against other related enzymes such as IDO2 or tryptophan 2,3-dioxygenase (TDO). In coculture systems of human allogeneic lymphocytes with dendritic cells (DCs) or tumor cells, INCB024360 inhibition of IDO1 promotes T and natural killer (NK)-cell growth, increases IFN-gamma production, and reduces conversion to regulatory T (T(reg))-like cells. IDO1 induction triggers DC apoptosis, whereas INCB024360 reverses this and increases the number of CD86(high) DCs, potentially representing a novel mechanism by which IDO1 inhibition activates T cells. Furthermore, IDO1 regulation differs in DCs versus tumor cells. Consistent with its effects in vitro, administration of INCB024360 to tumor-bearing mice significantly inhibits tumor growth in a lymphocyte-dependent manner. Analysis of plasma kynurenine/tryptophan levels in patients with cancer affirms that the IDO pathway is activated in multiple tumor types. Collectively, the data suggest that selective inhibition of IDO1 may represent an attractive cancer therapeutic strategy via up-regulation of cellular immunity. PMID- 20197555 TI - Expression of the cytoplasmic NPM1 mutant (NPMc+) causes the expansion of hematopoietic cells in zebrafish. AB - Mutations in the human nucleophosmin (NPM1) gene are the most frequent genetic alteration in adult acute myeloid leukemias (AMLs) and result in aberrant cytoplasmic translocation of this nucleolar phosphoprotein (NPMc+). However, underlying mechanisms leading to leukemogenesis remain unknown. To address this issue, we took advantage of the zebrafish model organism, which expresses 2 genes orthologous to human NPM1, referred to as npm1a and npm1b. Both genes are ubiquitously expressed, and their knockdown produces a reduction in myeloid cell numbers that is specifically rescued by NPM1 expression. In zebrafish, wild-type human NPM1 is nucleolar while NPMc+ is cytoplasmic, as in human AML, and both interact with endogenous zebrafish Npm1a and Npm1b. Forced NPMc+ expression in zebrafish causes an increase in pu.1(+) primitive early myeloid cells. A more marked perturbation of myelopoiesis occurs in p53(m/m) embryos expressing NPMc+, where mpx(+) and csf1r(+) cell numbers are also expanded. Importantly, NPMc+ expression results in increased numbers of definitive hematopoietic cells, including erythromyeloid progenitors in the posterior blood island and c myb/cd41(+) cells in the ventral wall of the aorta. These results are likely to be relevant to human NPMc+ AML, where the observed NPMc+ multilineage expression pattern implies transformation of a multipotent stem or progenitor cell. PMID- 20197556 TI - Pediatric palliative care: feedback from the pediatric intensivist community. AB - With the emergence of a more formalized field of pediatric palliative care (PPC), it is important for individuals and organizations involved in PPC to gather input from patients with life-threatening/life-limiting conditions, their families, and their health care providers. We report the results of a survey completed in late 2007 of the Section on Critical Care of the American Academy of Pediatrics (AAP). The 102 respondents provided information regarding their clinical and educational experiences, perceived barriers to the provision of palliative care in the intensive care environment, currently available PPC resources, and the usefulness of palliative care specialization in the pediatric intensive care unit. PMID- 20197557 TI - Nausea and vomiting in advanced cancer. AB - Nausea and vomiting are relatively common in advanced cancer and is dreaded more than pain by patients. The history, pattern of nausea and vomiting, associated symptoms, and physical examination provides clues as to etiology and may guide therapy. Continuous severe nausea unrelieved by vomiting is usually caused by medications or metabolic abnormalities, while nausea relieved by vomiting or induced by eating is usually due to gastroparesis, gastric outlet obstruction, or small bowel obstruction. Drug choices are empiric or based on etiology. Metoclopramide has the greatest evidence for efficacy followed by phenothiazines and tropisetron. Corticosteroids have not been effective in randomized trials except in the case of bowel obstruction. Treatment of nausea unresponsive to first-line medications involves rotation to medications which bind to multiple receptors (broad-spectrum antiemetics), the addition of another antiemetic to a narrow-spectrum antiemetic (a serotonin receptor antagonist such as tropisetron to a phenothiazine), rotation to a different class of antiemetic (tropisetron for a phenothiazine), or in-class drug rotation. Venting gastrostomy, octreotide, and corticosteroids will reduce nausea and vomiting associated with malignant bowel obstruction. PMID- 20197558 TI - Role of palliative low-molecular-weight heparin for treating venous thromboembolism in patients with advanced cancer. AB - Patients with cancer are at risk of developing venous thromboembolism ([VTE]; deep venous thrombosis, and pulmonary embolism). Although vitamin K antagonists had originally been used to treat VTE in these patients, low-molecular-weight heparins (LMWH) have been shown to be more effective and safe for patients with cancer-associated thrombosis. In cancer patients with advanced disease where curative therapy is no longer the intent of treatment, continued anticoagulation for VTE for palliative purposes continues to remain a controversial topic as no large randomized trials have been conducted to guide clinicians in this setting. This review summarizes the data available for treating VTE in cancer patients receiving palliative services. PMID- 20197559 TI - Continuous monitoring of intrathoracic impedance and right ventricular pressures in patients with heart failure. AB - BACKGROUND: Hemodynamic monitoring using implantable devices may provide early warning of volume overload in patients with heart failure (HF). This study was designed to prospectively compare information from intrathoracic impedance monitoring and continuous right ventricular pressure measurements in patients with HF. METHODS AND RESULTS: Sixteen patients with HF (age, 63.5+/-13.8 years; left ventricular ejection fraction, 23.2+/-11.3%; New York Heart Association, II and III) and a previous HF decompensation received both a cardiac resynchronization therapy defibrillator providing a daily average of intrathoracic impedance and an implantable hemodynamic monitor providing an estimate of the pulmonary artery diastolic pressure. At the end of a 6-month investigator-blinded period, baseline reference hemodynamic values were determined over 4 weeks during which the patient was clinically stable. A major HF event was defined as HF decompensation requiring hospitalization, IV diuretic treatment, or leading to death. Sixteen major HF events occurred in 10 patients. Within 30 days and 14 days before a major HF event, impedance decreased by 0.12+/ 0.21 Omega/d and 0.20+/-0.20 Omega/d, respectively, whereas estimated pulmonary arterial diastolic pressure increased by 0.10+/-0.20 mm Hg/d and 0.16+/-0.15 mm Hg/d, respectively. During these periods, impedance decreased by 3.8+/-5.4 Omega (P<0.02) and 4.9+/-6.1 Omega (P<0.007), respectively, whereas estimated pulmonary arterial diastolic pressure increased by 5.8+/-5.7 mm Hg (P<0.002) and 6.8+/-6.1 mm Hg (P<0.001), respectively, compared with baseline. In all patients, impedance and estimated pulmonary arterial diastolic pressure were inversely correlated (r = -0.48+/-0.25). Within 30 days preceding a major HF event, this correlation improved to r =-0.58+/-0.24. CONCLUSIONS: Decompensated HF develops based on hemodynamic derangements and is preceded by significant changes in intrathoracic impedance and right ventricular pressures during the month prior to a major clinical event. Impedance and pressure changes are moderately correlated. Future research may establish the complementary contribution of both parameters to guide diagnosis and management of patients with HF by implantable devices. PMID- 20197560 TI - Doppler echocardiography in advanced systolic heart failure: a noninvasive alternative to Swan-Ganz catheter. AB - BACKGROUND: Although several studies have demonstrated a good correlation between Doppler echocardiographic and invasive measurements of single hemodynamic variables, the accuracy of echocardiography in providing a comprehensive assessment in individual patients has not been validated. The aim of this study was to assess the accuracy and clinical applicability of Doppler echocardiography in determining the entire hemodynamic profile in stable patients with advanced systolic heart failure. METHODS AND RESULTS: Doppler echocardiography and Swan Ganz catheterization were simultaneously performed in 43 consecutive patients with advanced heart failure. Echocardiographic data required for estimation of right atrial, pulmonary artery systolic, and pulmonary capillary wedge pressures; cardiac output; and pulmonary vascular resistance were obtained and compared with hemodynamic data. For all variables, invasive and noninvasive hemodynamic values were highly correlated (P<0.0001), with very low bias and narrow 95% confidence limits. In 16 patients with elevated pulmonary vascular resistance (>3 Wood U) and pulmonary capillary wedge pressures (>20 mm Hg) at baseline, hemodynamic and Doppler measurements were simultaneously repeated after unloading manipulations. Absolute values and changes of pulmonary vascular resistance and pulmonary capillary wedge pressures after unloading were still accurately predicted (r =0.96 and r =0.92, respectively). CONCLUSIONS: Doppler echocardiography may offer a valid alternative to invasive cardiac catheterization for the comprehensive hemodynamic assessment of patients with advanced heart failure, and it may assist in monitoring and optimization of therapy in potential heart transplant recipients. PMID- 20197562 TI - Magnetic resonance imaging in the diagnosis of ankylosing spondylitis: be aware of gold standards and circularity. PMID- 20197563 TI - Coronary atherosclerosis in rheumatoid arthritis: could endothelial progenitor cells be the missing link? PMID- 20197564 TI - Accelerated atherosclerosis in rheumatoid arthritis: rationale for mannose binding lectins? PMID- 20197565 TI - Synovial osteochondromatosis of the hip. PMID- 20197566 TI - Gout masquerading as a triquetral fracture. PMID- 20197567 TI - Should tuberculin skin test be positive to give latent tuberculosis treatment before tumor necrosis factor-alpha inhibitors in selected patients in developing countries? PMID- 20197568 TI - Is screening for hepatitis necessary in diagnostic evaluation of rheumatoid arthritis in South Korea? PMID- 20197569 TI - More on the resolution of bisphosphonate-associated osteonecrosis of the jaw. PMID- 20197570 TI - Lack of interaction between systemic lupus erythematosus-associated polymorphisms in TYK2 and IRF5. PMID- 20197571 TI - Methotrexate has no antifibrotic effect in bleomycin-induced experimental scleroderma. PMID- 20197572 TI - Gouty tophi presenting as medial patellar plica syndrome and patellofemoral disorder to limit knee range of motion. PMID- 20197573 TI - Efficacy and safety of bivalirudin in patients with diabetes mellitus undergoing percutaneous coronary intervention in current clinical practice. AB - OBJECTIVES: This study sought to evaluate the short- and long-term efficacy and safety of bivalirudin in diabetic patients undergoing percutaneous coronary intervention (PCI) in contemporary clinical practice. BACKGROUND: Early trials of platelet glycoprotein (GP) IIb/IIIa inhibitors have suggested a survival benefit in diabetic patients undergoing PCI. More recently, randomized trials have demonstrated that diabetic patients have similar protection from acute ischemic events, while lowering the risk of bleeding complications, when treated with bivalirudin monotherapy versus heparin plus GP IIb/IIIa blockade. However, the impact of bivalirudin use on long-term outcomes in diabetic patients undergoing PCI remains unclear. METHODS AND RESULTS: Using the Cornell Angioplasty Registry, we studied 786 consecutive diabetic patients undergoing urgent or elective PCI with a mean clinical follow up of 24.6 +/- 7.8 months. Of these, 428 patients (54.5%) received bivalirudin monotherapy and 358 patients (45.5%) received unfractionated heparin (UFH) plus GP IIb/IIIa inhibition. The incidence of in hospital death (0% vs. 0.3%; p = 0.46), post-procedural myocardial infarction (MI) (4.7% vs. 7.0%; p = 0.169), and major adverse cardiovascular events (MACE) (death, MI, stroke or urgent revascularization) (4.9% vs. 7.3%; p = 0.176) was similar in the two groups, with less minor bleeding (9.6% vs. 14.5%; p = 0.035) in the bivalirudin vs. UFH plus GP IIb/IIIa inhibitor group, respectively. By the end of follow up, there were 38 (8.9%) deaths in the bivalirudin vs. 19 (5.3%) deaths in the GP IIb/IIIa inhibitor arm (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.0-3.1; p = 0.04). However, after a propensity score-adjusted multivariate Cox regression analysis, there was no longer a significant difference in long-term mortality between the two groups (HR 1.63; chi(2) = 2.61; 95% CI 0.90-2.94; p = 0.106). CONCLUSIONS: These findings indicate that in diabetic patients, bivalirudin monotherapy results in similar protection from acute ischemic events and long-term mortality, while lowering the risk of minor bleeding in comparison to UFH plus GP IIb/IIIa inhibition. PMID- 20197574 TI - Anticoagulation during percutaneous coronary intervention in diabetics--is simpler always better? PMID- 20197575 TI - Right coronary artery anatomical variants: where and how? AB - BACKGROUND: Ectopic origin of the right coronary artery (RCA) occurs in approximately 1.0% of studied populations. We investigated the prevalence and location of ectopic RCAs among patients undergoing coronary angiography (CA) and assessed its effects on resource utilization. METHODS: Cases of ectopic RCAs were prospectively collected over 21 months among patients undergoing cardiac catheterization at a University Hospital. "Ectopic RCA" was defined as a RCA originating outside the posterior two-thirds of the right coronary sinus. RESULTS: The study population included 2,120 patients, of which 23 (1.1%) had ectopic RCAs. Of these, 15 (65%) originated from the anterior third of the right sinus, while 8 (35%) originated from the anterior half of the left sinus. Mean procedure and fluoroscopy times were 60 +/- 33 and 15 +/- 12 minutes (min) for the former, and 78 +/- 35 and 31 +/- 20 min for the latter, while mean contrast volume for CA was 112 +/- 62 ml and 192 +/- 85 ml, respectively. 26% required a second CA or a second intervention to image the RCA. CONCLUSION: Ectopic RCAs pose a clinical problem, consuming time and resources. The search for an ectopic RCA should have < 90 degree boundaries limited to the anterior third of the right sinus and anterior half of the left sinus. PMID- 20197576 TI - Clinical utility of B-type natriuretic peptide for estimating left ventricular filling pressures in unselected elderly patients undergoing diagnostic coronary angiography. AB - BACKGROUND: B-type natriuretic peptide (BNP) and echocardiographic tissue Doppler indices (TDI) predict elevated filling pressures, but few data exist comparing these methods while adjusting for clinical variables. We hypothesized that BNP would provide incremental value for estimating left ventricular end-diastolic pressure (LVEDP). METHODS: Clinical data, echocardiograms, and BNP levels were obtained in 182 geriatric patients undergoing diagnostic left-heart catheterization. Patients with severe valvular disease or acute myocardial infarction were excluded. LVEDP and standard echocardiographic measurements, including early (E) and late (A) mitral inflow velocities and early (Em) mitral annular velocities by TDI, were measured in blinded fashion. RESULTS: Mean age was 71 years, 51% were female, and 19% were nonwhite. Univariate correlations with LVEDP (p < or = 0.05) included functional class, beta-blocker use, body-mass index (BMI), heart rate, blood urea nitrogen (BUN), hemoglobin, peak tricuspid regurgitation velocity, left atrial volume index, E/A ratio, deceleration time, septal E/Em ratio and BNP. Linear regression analysis revealed independent correlations of LVEDP with BMI (p = 0.002), BUN (p = 0.011), and E/A ratio (p < 0.001). After adjusting for these variables, BNP was an independent correlate of LVEDP (p = 0.001). Predictors of LVEDP > or = 20 mmHg by logistic regression included higher BMI (p = 0.002), lower heart rate (p = 0.042), and septal E/Em ratio < 15 (p = 0.023). BNP was an independent predictor of LVEDP > or = 20 mmHg after adjustment for these variables (p = 0.037, c-statistic 0.663). CONCLUSIONS: Standard clinical variables offer only modest utility for predicting LV filling pressures. BNP provides incremental value for estimating LVEDP, and elevated BNP is an independent predictor of increased LVEDP among older patients undergoing diagnostic cardiac catheterization. PMID- 20197577 TI - Evaluation of balloon withdrawal forces with bare-metal stents, compared with Taxus and Cypher drug-eluting coronary stents: balloon, stent and polymer interactions. AB - BACKGROUND: There have been reports of serious complications related to difficulty removing the deflated Taxus stent delivery balloon after stent deployment. The purpose of this study was to determine whether the Taxus SIBS polymer was "sticky" and associated with an increase in the force required to remove the stent delivery balloon after stent deployment, using a quantitative, ex-vivo model. METHODS: Balloon-polymer-stent interactions during balloon withdrawal were measured with the Taxus Liberte, Liberte bare-metal stent (BMS; no polymer = control), the Cordis Cypher drug-eluting stent (DES; PEVA/PBMA polymer) and the BX Velocity (no polymer). We quantitatively measured the force required to remove the deflated stent delivery balloon from each of these stents in simulated vessels at 37 degrees C in a water bath. Balloon withdrawal forces were measured in straight (0 degree curve), mildly curved (20 degree curve) and moderately curved (40 degree curve) simulated vessel segments. RESULTS: The average peak force required to remove the deflated balloon catheter from the Taxus Liberte DES, the Liberte BMS, the Cypher DES, and the Bx Velocity BMS were similar in straight segments, but were much greater for the Taxus Liberte in the moderately curved segments (1.4 lbs vs. 0.11 lbs, 0.11 lbs and 0.12 lbs, respectively; p < 0.0001). CONCLUSION: The SIBS polymer of the Taxus Liberte DES appears to be "sticky" and is associated with high forces required to withdraw the deflated balloon from the deployed stent in curved segments. This withdrawal issue may help to explain the clinical complications that have been reported with this device. PMID- 20197578 TI - The sticky story of stuck stents. PMID- 20197579 TI - Restenosis rates following vertebral artery origin stenting: does stent type make a difference? AB - OBJECTIVES: To compare our experience with sirolimus and paclitaxel-eluting stents (drug-eluting stents [DES]) and non-drug-eluting stents (NDES) for treatment of vertebral artery (VA) origin stenosis and review the literature. METHODS: A retrospective review of our prospectively collected database was performed. Clinical and radiologic follow up was obtained by reviewing office records and radiology. Data collected included demographics, comorbidities, presenting symptoms, stenosis severity, contralateral VA stenosis and/or carotid stenosis, type of stent used, angioplasty before or after stenting, post treatment residual stenosis, clinical and radiological follow up and retreatment. Patients with symptomatic > 60% stenosis or asymptomatic > 70% stenosis and/or a hypoplastic or occluded contralateral VA or significant carotid occlusion were chosen for revascularization. RESULTS: Thirty-five patients treated with NDES and 15 treated with DES for management of VA origin stenosis were identified. The technical success rate of the procedure was 100%. There were no procedural complications. There were 7 asymptomatic patients (NDES Group-4, DES Group-3). In the NDES Group, 9 patients had pre-stent angioplasty; 2 had post-stent angioplasty. In the DES group, 4 patients had post-stent angioplasty. Symptoms resolved in 30/31 (96.8%) patients treated with NDES and 11/12 (91.7%) treated with DES. Thirty-six patients had radiologic follow up (median 21.3 months); in stent restenosis was documented in 11 patients (NDES 9/24 [38%], DES 2/12 [17%]). Among patients receiving NDES, re-stenotic lesions required angioplasty in 7 patients. No patients in the DES group required angioplasty. CONCLUSIONS: DES for treatment of VA origin stenosis may decrease the incidence of restenosis when compared to NDES. Validation in prospective, randomized, multicenter trials is necessary. PMID- 20197580 TI - The twin-pass dual access catheter for assessment of the no-reflow phenomenon. AB - The absence of antegrade flow in a coronary artery during an intervention is an ominous finding requiring diagnosis of the underlying cause and rapid treatment to limit myocardial necrosis. The Twin-Pass dual access catheter allows for distal coronary contrast injection without loss of wire position. The aim of this analysis was to determine the opacification and flow features of patients with abrupt arrest of antegrade flow to determine the underlying pathology. METHODS: Coronary angiograms of patients with abrupt arrest of antegrade flow during an intervention that underwent distal vessel contrast injection with the Twin-Pass catheter were retrospectively analyzed for five features: antegrade flow, retrograde flow, myocardial blush, presence of contrast stasis in the vessel wall and evidence of an intraluminal filling defect. The features were then correlated with the underlying pathological process and treatment. RESULTS: Seven patients underwent distal contrast injections. Four specific pathological processes were identified: presence of a proximal occlusive lesion; no-reflow due to distal vascular bed dysfunction; long dissection of the vessel with the distal wire residing in the true lumen or alternatively in the dissection plane. The patients were treated according to the pathology with stenting, intracoronary adenosine or wire repositioning. CONCLUSIONS: Distal vessel contrast injection using the Twin Pass catheter in the presence of no-reflow is a simple and rapid technique that allows for the definition of four distinct clinical scenarios. This allows for rapid treatment of the underlying pathological process, reducing the period of end-organ ischemia, limiting occasional unnecessary stent deployment and further improving procedural results. PMID- 20197581 TI - Initial experience of removal of 10-French sheaths using the 8-French Angio-Seal vascular closure device. AB - OBJECTIVES: We studied the use of 8 Fr Angio-Seal in closure of access sites up to 10 Fr. BACKGROUND: The use of larger French catheters for procedures such as valvuloplasty and percutaneous valve replacement has required the use of better methods for arterial closure. The use of 6 and 8 Fr Angio-Seal hemostatic devices (St. Jude Medical, St. Paul, Minnesota) has been well described and are routinely used for diagnostic and interventional procedures up to 8 Fr in size. However, no data are available for the use of an 8 Fr Angio-Seal device in the closure of access sites up to 10 Fr. METHODS: In our center, we evaluate the incidence of vascular complications following the use of an 8 Fr Angio-Seal device with 10 Fr sheaths in patients undergoing aortic valvuloplasty. RESULTS: Of 53 procedures, there was only 1 vascular complication, a ruptured pseudoaneurysm, which required vascular repair. CONCLUSIONS: Our data suggest that an 8 Fr Angio-Seal device can be utilized effectively and safely in procedures requiring larger access sites up to 10 Fr. PMID- 20197582 TI - The relationship between bleeding and adverse outcomes in ACS and PCI: pharmacologic and nonpharmacologic modification of risk. AB - Antithrombotic therapy, including antiplatelet and antithrombin agents, effectively reduces the risk of ischemic events in patients with acute coronary syndromes (ACS) and those undergoing percutaneous coronary intervention (PCI). Unfortunately, these agents intrinsically increase the risk of bleeding complications, which in turn are associated with adverse outcomes, particularly mortality. Accordingly, there is great value in improving the understanding of bleeding complications, including the definitions employed, severity and types of bleeding, as well as the patient characteristics, clinical presentations, and treatment variables that are associated with an increased risk of bleeding. The ultimate goal is to optimize patient outcomes by employing pharmacological and nonpharmacological strategies that minimize bleeding risk while maintaining efficacy. The objective of this article is to present the criteria by which bleeding is expressed and discuss the correlation between bleeding and adverse outcomes, as well as the relative impact of bleeding compared with ischemic events such as myocardial infarction on mortality. Furthermore, the relationship between bleeding and modifications of long-term treatment and methods to predict and prevent bleeding will be explored. PMID- 20197583 TI - Transcatheter coil embolization of multiple bilateral congenital coronary artery fistulae. AB - Coronary artery fistulae represent the most frequent congenital anomalies of the coronary arteries, but remain a relatively uncommon clinical problem. Moreover, multiple fistulae originating from both the left and the right coronary arteries and draining into the left ventricular chamber are a rare condition. Due to the low prevalence of these anomalies, the appropriate management of patients with symptomatic coronary artery fistulae is controversial. Transcatheter closure approaches have emerged as a less invasive strategy and are nowadays considered a valuable alternative to surgical correction with similar effectiveness, morbidity and mortality. The percutaneous management, however, is mainly limited by the individual anatomic features of the fistula and an appropriate patient's selection is considered as a key determining factor to achieve complete occlusion. Thus, success rates of transcatheter closure techniques reported in the literature are extremely variable and highly dependent upon the nature of the follow up, which, at present, is not standardized. The optimal management of symptomatic patients with multiple coronary artery fistulae still remains a challenging problem and has been traditionally considered as an indication for cardiac surgery. We report here the case of a patient with double bilateral congenital coronary artery fistulae arising from both the left and right coronary arteries and draining individually into the left ventricular chamber. This patient underwent successful transcatheter anterograde closure of both fistulae using a microcoil embolization technique. PMID- 20197584 TI - The importance of atrial pacing during alcohol septal ablation. PMID- 20197585 TI - Re.: Provisional vs. complex stenting strategy for coronary bifurcation lesions: meta-analysis of randomized trials. PMID- 20197586 TI - ST-segment elevation myocardial infarction in severe coronary artery stenosis: a case series. AB - Recently, it has been reported that acute ST-segment elevation myocardial infarction (STEMI) frequently develops at the site of severe stenosis. This impression was derived from the observation of stenosis severity after aspiration of the thrombus leading to the event. In the past, STEMI was considered as a thrombotic event on a non-flow limiting coronary plaque mainly. We report a case series of patients who developed STEMI within hours to days of initial angiography, all of whom demonstrated severe flow limiting coronary artery stenosis. PMID- 20197587 TI - The Impella 2.5 L for percutaneous mechanical circulatory support in severe humoral allograft rejection. AB - Heart transplant recipients who experience humoral rejection are at risk for hemodynamic instability. We report a case of a 64-year-old male with cardiogenic shock due to allograft rejection requiring mechanical support while undergoing intense immunosuppression. He underwent implantation of a micro-axial endovascular pump (Impella). To our knowledge, this is the first reported case of successful Impella device deployment as a bridge-to-recovery strategy. PMID- 20197588 TI - Left ventricular pseudoaneurysm found after mitral valve replacement performed 30 years earlier. AB - Pseudoaneurysm of the left ventricle (LV) is a rare cardiac disease that occurs after myocardial infarction or cardiac surgery. Because patients frequently present with nonspecific symptoms, a high index of suspicion is needed to make the diagnosis. This report describes an unusual case demonstrating a large LV pseudoaneurysm after mitral valve replacement performed 30 years earlier. PMID- 20197589 TI - Stitched to the heart--till intervention do us part. AB - The case report describes the situation where a venous infusion catheter was inadvertently stitched to the lateral wall of the right atrium during valve replacement. A dual percutaneous approach was used to first sever the catheter at the suture and then remove both ends safely. The risk of tearing the suture which would have resulted in tamponade had to be avoided. PMID- 20197590 TI - Successful interventional treatment of a retrosternal pseudoaneurysm of the ascending aorta with an Amplatzer Vascular Plug II. AB - Pseudoaneurysm of the aorta is a rare, but potentially dangerous complication after cardiac surgery, trauma or infective aortitis. Potential fatal risk of rupture with severe hemorrhage exists, so that treatment is necessary. Surgical management carries a high morbidity and mortality rate. Using an endovascular transcatheter method seems to be a promising option for treatment of aortic pseudoaneurysms. We report a case of ascending aortic pseudoaneurysm, which was diagnosed 11 years after cardiac surgery and treated successfully by implantation of an Amplatzer Vascular Plug II. PMID- 20197591 TI - Coarctation of distal thoracic aorta--the middle aortic syndrome in an elderly female with severe coronary artery disease. AB - Coarctation of the distal aorta or middle aortic syndrome is a segmental stenosis of the middle portion of the aorta, between the arch and the terminal bifurcation. Middle aortic syndrome is a rare disease of infants and young adults presenting with hypertension, lower limb claudication and renal insufficiency and is diagnosed by aortography or magnetic resonance angiography. Our case is unique because this condition was an incidental finding diagnosed during cardiac catheterization in a 70-year-old patient with hypertension in the absence of lower-limb claudication. Recognition of this rare condition as a potential cause of secondary hypertension is important, especially given the wide age range of presentation. PMID- 20197592 TI - [Clinical research center at Landspitali -University Hospital]. PMID- 20197593 TI - [Organization of emergency medical service for acute myocardial infarction in Iceland]. PMID- 20197594 TI - [Management of patients with STEMI transported with air-ambulance to Landspitali University Hospital in Reykjavik]. AB - INTRODUCTION: A good outcome of patients presenting with STEMI (ST-Segment Elevation Myocardial Infarction) depends on early restoration of coronary blood flow. Pre-hospital fibrinolysis is recommended if primary percutaneous coronary intervention (PPCI) cannot be performed within 90 minutes of first medical contact (FMC). The purpose of this study was to study transport times for patients with STEMI who were transported with air-ambulance from the northern rural areas of Iceland to Landspitali University Hospital in Reykjavik, and to assess if the medical management was in accordance with clinical guidelines. MATERIALS AND METHODS: Retrospective chart review identified 33 patients with STEMI who were transported with air-ambulance to Landspitali University Hospital in Reykjavik during the years 2007 and 2008. RESULTS: The total time from first medical contact to arrival at Landspitali University Hospital emergency room was 3 hours and 7 minutes (median). All patients received aspirin and 26 (78.8%) received clopidogrel and enoxaparin. 16 patients (48.5%) received thrombolytic therapy in median 33 minutes after FMC and 15 patients had PPCI performed in median 4 hours and 15 minutes after FMC. Estimated PCI related delay was 3 hours and 42 minutes (median). One patient died and one was resuscitated within 30 hospital days. Mean hospital stay was 6.0 days. CONCLUSIONS: First medical contact to balloon time of less than 90 minutes is impossible for patients with STEMI transported from the northern rural areas to Landspitali University Hospital in Reykjavik. Medical therapy was in many cases suboptimal and PCI related delay too long. PMID- 20197595 TI - [Hepatotoxicity associated with the use of Herbalife]. AB - OBJECTIVE: Many herbal products are known to be hepatotoxic. In a recent survey in Iceland concerning adverse reactions related to herbal medicines, Herbalife products were implicated in the majority of the reported cases of hepatotoxicity. METHODS: The clinical presentations of five cases of Herbalife related liver injury during the period of 1999-2008 are analysed. Causality was assessed by using the WHO-UMC system for causality assessment and the RUCAM method. RESULTS: Of the five cases there were four females and one male; median age was 46 years (range 29-78). Herbalife had been used for 1 to 7 months prior to presentation. Four patients presented with a hepatocellular and one with a cholestatic reaction. Median values were for bilirubin 190 micromol/L (range: 26-311; ref. < 20 micromol/L), ALP 407 U/L (range: 149-712; ref. 35-105 U/L) and ALT 24 87 U/L (range: 456-2637; ref. 70 and 45 U/L for males and females, respectively). Liver biopsy was performed in 2 patients and was consistent with toxic hepatitis in both cases. Other causes of hepatitis were excluded by appropriate serological testing and ultrasound. Causality assessment according to RUCAM was probable in three cases and possible in two. Using the WHO-UMC criteria causality was certain in one case, probable in two and possible in two cases. CONCLUSIONS: Hepatotoxicity is probably associated with the use of Herbalife products. Hepatotoxicity due to herbal remedies is an important differential diagnosis in the diagnostic work-up of liver injury. PMID- 20197596 TI - [Drug-induced liver injury]. AB - Drug-induced liver injury (DILI) is a well known adverse reaction of many drugs. Direct toxic liver damage is associated with paracetamol toxicity whereas most other drugs causing liver damage have an unpredictable or idiosyncratic pattern of injury. Although idiosyncratic liver injury was initially thought to be dose independent, it has been shown that many drugs leading to idiosyncratic injury have a dose dependent component. Physicians need to bear in mind DILI in all patients who present with symptoms or signs of liver dysfunction. Clinically and histologically DILI can mimick any known liver disease and there are no pathognomonic histological features of DILI. The diagnosis is one of exclusion. In patients with a high clinical suspicion of DILI the causative drug need to be discontinued and patients with jaundice and/or coagulopathy have to be hospitalized and some cases considered for a liver transplantation. PMID- 20197597 TI - [Giant cell arteritis - two cases with acute blindness]. AB - Giant cell arteritis is characterized primarily by inflammation in certain large and medium-sized arteries. The major risk factors are age, female gender and Northern European descent. In this report we describe two cases of acute vision loss due to giant cell arteritis. In both cases the erythrocyte sedimentation rate (ESR) was below 50 mm/hr and the presenting complaint was foggy vision followed by acute blindness. The cases are to some extent different, for example in the former case the patient reported jaw claudication and ophthalmologic evaluation was consistent with anterior ischemic optic neuropathy. In the latter case there was narrowing and box-carring of blood cells in retinal arterioles, consistent with occlusion of the central retinal artery. This patient had recently finished a 2-year long treatment with glucocorticosteroids for polymyalgia rheumatica. The retina and the optic nerve do not survive for long without perfusion. If giant cell arteritis causes blindness in one eye there is significant risk for the other eye to go blind if no treatment is given. Corticosteroids can spare the other eye and suppress the underlying inflammatory disease process as well. It is vital to confirm the diagnosis of giant cell arteritis with a biopsy and start corticosteroid treatment as soon as possible, even before the biopsy is taken. PMID- 20197598 TI - Optimal spacing of surface electrode arrays for brain-machine interface applications. AB - Brain-machine interfaces (BMIs) use signals recorded directly from the brain to control an external device, such as a computer cursor or a prosthetic limb. These control signals have been recorded from different levels of the brain, from field potentials at the scalp or cortical surface to single neuron action potentials. At present, the more invasive recordings have better signal quality, but also lower stability over time. Recently, subdural field potentials have been proposed as a stable, good quality source of control signals, with the potential for higher spatial and temporal bandwidth than EEG. Here we used finite element modeling in rats and humans and spatial spectral analysis in rats to compare the spatial resolution of signals recorded epidurally (outside the dura), with those recorded from subdural and scalp locations. Resolution of epidural and subdural signals was very similar in rats and somewhat less so in human models. Both were substantially better than signals recorded at the scalp. Resolution of epidural and subdural signals in humans was much more similar when the cerebrospinal fluid layer thickness was reduced. This suggests that the less invasive epidural recordings may yield signals of similar quality to subdural recordings, and hence may be more attractive as a source of control signals for BMIs. PMID- 20197599 TI - Temperature dependence of the shear modulus of soft tissues assessed by ultrasound. AB - Soft tissue stiffness was shown to significantly change after thermal ablation. To better understand this phenomenon, the study aims (1) to quantify and explain the temperature dependence of soft tissue stiffness for different organs, (2) to investigate the potential relationship between stiffness changes and thermal dose and (3) to study the reversibility or irreversibility of stiffness changes. Ex vivo bovine liver and muscle samples (N = 3 and N = 20, respectively) were slowly heated and cooled down into a thermally controlled saline bath. Temperatures were assessed by thermocouples. Sample stiffness (shear modulus) was provided by the quantitative supersonic shear imaging technique. Changes in liver stiffness are observed only after 45 degrees C. In contrast, between 25 degrees C and 65 degrees C, muscle stiffness varies in four successive steps that are consistent with the thermally induced proteins denaturation reported in the literature. After a 6 h long heating and cooling process, the final muscle stiffness can be either smaller or bigger than the initial one, depending on the stiffness at the end of the heating. Another important result is that stiffness changes are linked to thermal dose. Given the high sensitivity of ultrasound to protein denaturation, this study gives promising prospects for the development of ultrasound-guided HIFU systems. PMID- 20197600 TI - The effect of energy and source location on gamma camera intrinsic and extrinsic spatial resolution: an experimental and Monte Carlo study. AB - Quantification of nuclear medicine image data is a prerequisite for personalized absorbed dose calculations and quantitative biodistribution studies. The spatial response of a detector is a governing factor affecting the accuracy of image quantification, and the aim of this work was to model this impact. To simulate spatial response, a value for the intrinsic spatial resolution (R(intrinsic)) of the gamma camera is needed. R(intrinsic) for (99m)Tc was measured over the field of view (FOV) and an experimental setup was designed to measure R(intrinsic) for radioisotopes with higher photon energies. Monte Carlo (MC) simulations, using the codes SIMIND and GATE, were used to investigate the extrinsic effect of R(intrinsic) as a function of energy and its variation across the FOV. A method was developed to calculate energy-dependent blurring values for input to MC simulations, by separate consideration of the Compton scatter and photoelectric effect in the crystal and statistical variation in the signal. Inclusion of energy-specific blurring values in simulations showed excellent agreement with experimental measurements. The maximum pixel count rate can change by up to 18% when imaged at two different points in the FOV, and errors in the maximum pixel count rate of up to 11% were shown if a blurring value for (99m)Tc was used for simulations of (131)I. We demonstrate that the accuracy of MC simulations of gamma cameras can be significantly improved by accounting for the effect of energy on intrinsic spatial resolution. PMID- 20197601 TI - Monte Carlo simulation of correction factors for IAEA TLD holders. AB - The IAEA standard thermoluminescent dosimeter (TLD) holder has been developed for the IAEA/WHO TLD postal dose program for audits of high-energy photon beams, and it is also employed by the ESTRO-QUALity assurance network (EQUAL) and several national TLD audit networks. Factors correcting for the influence of the holder on the TL signal under reference conditions have been calculated in the present work from Monte Carlo simulations with the PENELOPE code for (60)Co gamma-rays and 4, 6, 10, 15, 18 and 25 MV photon beams. The simulation results are around 0.2% smaller than measured factors reported in the literature, but well within the combined standard uncertainties. The present study supports the use of the experimentally obtained holder correction factors in the determination of the absorbed dose to water from the TL readings; the factors calculated by means of Monte Carlo simulations may be adopted for the cases where there are no measured data. PMID- 20197602 TI - Computer-assisted analysis of peripheral zone prostate lesions using T2-weighted and dynamic contrast enhanced T1-weighted MRI. AB - In this study, computer-assisted analysis of prostate lesions was researched by combining information from two different magnetic resonance (MR) modalities: T2 weighted (T2-w) and dynamic contrast-enhanced (DCE) T1-w images. Two issues arise when incorporating T2-w images in a computer-aided diagnosis (CADx) system: T2-w values are position as well as sequence dependent and images can be misaligned due to patient movement during the acquisition. A method was developed that computes T2 estimates from a T2-w and proton density value and a known sequence model. A mutual information registration strategy was implemented to correct for patient movement. Global motion is modelled by an affine transformation, while local motion is described by a volume preserving non-rigid deformation based on B splines. The additional value to the discriminating performance of a DCE T1-w based CADx system was evaluated using bootstrapped ROC analysis. T2 estimates were successfully computed in 29 patients. T2 values were extracted and added to the CADx system from 39 malignant, 19 benign and 29 normal annotated regions. T2 values alone achieved a diagnostic accuracy of 0.85 (0.77-0.92) and showed a significantly improved discriminating performance of 0.89 (0.81-0.95), when combined with DCE T1-w features. In conclusion, the study demonstrated a simple T2 estimation method that has a diagnostic performance such that it complements a DCE T1-w-based CADx system in discriminating malignant lesions from normal and benign regions. Additionally, the T2 estimate is beneficial to visual inspection due to the removed coil profile and fixed window and level settings. PMID- 20197603 TI - The spatial resolution of silicon-based electron detectors in beta autoradiography. AB - Thin tissue autoradiography is an imaging modality where ex-vivo tissue sections are placed in direct contact with autoradiographic film. These tissue sections contain a radiolabelled ligand bound to a specific biomolecule under study. This radioligand emits beta - or beta+ particles ionizing silver halide crystals in the film. High spatial resolution autoradiograms are obtained using low energy radioisotopes, such as (3)H where an intrinsic 0.1-1 microm spatial resolution can be achieved. Several digital alternatives have been presented over the past few years to replace conventional film but their spatial resolution has yet to equal film, although silicon-based imaging technologies have demonstrated higher sensitivity compared to conventional film. It will be shown in this work how pixel size is a critical parameter for achieving high spatial resolution for low energy uncollimated beta imaging. In this work we also examine the confounding factors impeding silicon-based technologies with respect to spatial resolution. The study considers charge diffusion in silicon and detector noise, and this is applied to a range of radioisotopes typically used in autoradiography. Finally an optimal detector geometry to obtain the best possible spatial resolution for a specific technology and a specific radioisotope is suggested. PMID- 20197604 TI - Monitoring heat-induced changes in soft tissues with 1D transient elastography. AB - In this paper 1D transient elastography was employed in fresh bovine skeletal muscle samples to assess the shear elastic modulus mu while the tissue was locally heated by means of an electrical resistance. The investigation is based on the study of the time shift of the shear wave propagation produced by the local temperature variation. The experiments show that the thermal expansion contribution to the time shift is negligible when compared with the shear wave speed variation. In such a case, the quantification of mu as a function of temperature becomes possible. Repeated experiments in different samples lead to a reproducible behavior of mu as a function of temperature. Irreversible elasticity changes are produced when the temperature exceeds a certain critical value T(c). The proposed method allows estimating this value as well as the spatial extension of the resulting thermal lesion. This point is important when considering applications in monitoring focused ultrasound surgery (FUS) because the surrounding normal tissue should remain unaffected. PMID- 20197605 TI - Regulation of ciliary trafficking of polycystin-2 and the pathogenesis of autosomal dominant polycystic kidney disease. AB - Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common human hereditary disorder characteristic of development of bilateral multiple fluid-filled kidney cysts. Accumulated evidence has suggested that primary cilium of renal epithelial cell plays a key role in cystogenesis. In this article we will give an overview on the basic information about polycystic kidney disease (PKD) and summarize the recent progresses in studies of regulation of polycystin 1 and -2 trafficking to cilia. We will also discuss the possible role of trafficking defects of polycystins on the pathogenesis of ADPKD. PMID- 20197606 TI - Effect of calcitonin gene-related peptide on the expression of triggering receptor expressed on myeloid cells-1 in lipopolysaccharide-induced macrophages. AB - OBJECTIVE: To determine the effect of calcitonin gene-related peptide (CGRP) on triggering receptor expressed on myeloid cells-1 (TREM-1) in the lipopolysaccharide (LPS)-induced macrophages and its signal transduction pathway. METHODS: The levels of TREM-1 mRNA in the macrophages were observed by reverse transcription-polymerase chain reaction (RT-PCR), and flow cytometry was performed to detect TREM-1 protein expression levels in the macrophages. RESULTS: CGRP had no regulating effect on the expression of TREM-1 in the macrophages; LPS could up-regulate macrophages to express TREM-1; CGRP increased TREM-1 mRNA expression in LPS-induced macrophages in dose and time-dependent manner; CGRP increased TREM-1 protein expression in LPS-induced macrophages, which could be partially reversed by H-7 or H-89 (P<0.05). CONCLUSION: CGRP can regulate the LPS induced macrophages synthesis and secretion of TREM-1, and the intracellular signal transduction pathway is related to PKA and PKC. PMID- 20197607 TI - [Effect of ulinastatin on perioperative inflammatory response to coronary artery bypass grafting with cardiopulmonary bypass]. AB - OBJECTIVE: To determine the effect of ulinastatin on perioperative inflammatory response to coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). METHODS: Forty patients undergoing CABG with CPB were randomly divided into 2 groups: a ulinastatin group (1.5 10(4) U/kg before CPB, n=20) and a control group (n=20). The inflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6, IL-10 and neutrophil elastase (NE) were measured before the anesthesia (T1), 1 h after the start of CPB (T2), 1 h after weaning of CPB (T3), and 24 h after weaning of CPB (T4). The postoperative organ dysfunction in the 2 groups was noted. RESULTS: The concentration of TNF-alpha, IL-6, IL-10, and NE at T2,T3, and T4 and increased more significantly than that at T1 in the 2 groups(P<0.05). The concentration of TNF-alpha, IL-6 and NE at T2, T3, and T4 in the ulinastatin group decreased more significantly than that in the control group (P<0.05), and IL-10 in the ulinastatin group increased at the same time. The postoperative complications of pneumonia, kidney and central nervous system in the ulinastatin group decreased more significantly than that in the control group (P<0.05). There was no significant difference in the postoperative cardio or liver complications and hours in the ICU between the 2 groups. CONCLUSION: Administration of ulinastatin before CPB can decrease the inflammatory response and complication during CABG. PMID- 20197608 TI - [Effect of butylphthalide on the expression of GFAP and VEGF in the hippocampus of rats with Alzheimer's disease]. AB - OBJECTIVE: To determine the expression of glial fibrillary acidic protein(GFAP) and vascular endothelial growth factor(VEGF) in the hippocampus of rats with Alzheimer's disease(AD), and to determine the effect of butylphthalide on them and its significance. METHODS: Sixty male adult rats were randomly divided into a model group, a Butylphthalide group, and a control group. AD models were established by injecting beta-amyloid protein 1-42 into the hippocampus of rats. Sixty days later,the rats were sacrificed and both sides of the hippocampus were sectioned for immunohistochemistry. RESULTS: Positive cells of GFAP in the hippocampus of the model group increased and the expression of VEGF decreased statistically, compared with the control group(P<0.01). The positive cells of GFAP in the hippocampus of the butylphthalide group decreased and the expression of VEGF increased significantly, compared with the model group(P<0.05). CONCLUSION: Butylphthalide may protect the neuron-vascular unit of the hippocampus of Alzheimer model rats by inhibiting the expression of GFAP and increasing the expression of VEGF. PMID- 20197609 TI - [TLR3c.1377, TLR9-1486, and TLR9 2848 gene polymorphisms and multiple sclerosis]. AB - OBJECTIVE: To investigate the relationship between the gene polymorphism of TLR3c.1377,TLR9-1486,and TLR9 2848 and susceptibility to multiple sclerosis(MS)in Han people of south China. METHODS: A total of 123 unrelated MS patients from South China with a clinical or laboratory definition MS according to 2005 Revisions to the McDonald Criteria were studied. Another 126 controls were randomly selected from hospital staff of non-autoimmune diseases and healthy individuals. Toll like receptor (TLR) 3 and TLR 9 genotypes were determined by PCR and digested by specific restriction enzymes. RESULTS: There was significant difference in genotype and allele distribution of TLR3c.1377 polymorphism between the MS patients and the controls (P<0.05), and the MS patients with T allele had a lower risk (OR=0.532, P=0.014). There was no significant difference in genotypes and allele distribution of TLR9-1486 polymorphism between the MS patients and the controls. There was higher TLR9 2848 A allele frequency in the MS patients than in the controls (39.8% vs. 30.6%;P=0.037), and higher risk in MS patients with A allele than those without (OR=1.837, P=0.020). There was no significant interaction among the TLR3c.1377, TLR9-1486 and TLR9 2848 allele. Strong linkage disequilibrium was found between TLR9-1486 and TLR9 2848, but there was no significant interaction between the polymorphism of TLR9-1486 and TLR9 2848 in the MS patients. CONCLUSION: TLR3c.1377 and TLR9 2848 polymorphisms may be related to MS in Han people in south China. TLR3c.1377 and TLR9 2848 may be linked with susceptibility genes. PMID- 20197610 TI - [Effect of tea polyphenols on oxidative damage and apoptosis in human bronchial epithelial cells induced by low-dose cigarette smoke condensate]. AB - OBJECTIVE: To determine the effect of tea polyphenols on oxidative damage and apoptosis in human bronchial epithelial cells induced by low-dose cigarette smoke condensate (CSC). METHODS: We prepared CSC. 3-(4,5-dimethyl thiazoly) 2,5 diphenyl-tetrazoliun bromide (MTT) assay was used to determine the growth of cultured human bronchial epithelial cells (HBE135-E6E7). Fluorescent chemiluminescent analyzer was used to measure cell reactive oxygen species (ROS) level. DNA ladder method was used to detect HBE135-E6E7 apoptosis. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect Bcl-2 and Bax mRNA expression. RESULTS: Concentration of intracellular ROS in the CSC group and CSC + TP group was significantly higher than that in the control group (P<0.01); concentration of intracellular ROS in the CSC + TP group was significantly lower than that in the CSC group (P<0.01). Apparent DNA breakage of the tail belt appeared in the CSC Group,while only a small amount of DNA breakage of the tail belt appeared in the CSC + TP group. Compared with the control group, Bcl-2 mRNA expression was reduced and Bax mRNA expression was increased in the CSC group (all P<0.01). Compared with the CSC group, Bcl-2 mRNA expression was increased and Bax mRNA expression was reduced in the CSC+TP group (all P<0.01). Ratio of Bcl-2 mRNA/ Bax mRNA in the CSC group and CSC+TP group was significantly lower than that in the control group (all P<0.01). CONCLUSION: TP can antagonize CSC induced airway epithelial cell apoptosis through the effective removal of ROS, promoting Bcl-2 mRNA expression and inhibiting the expression of Bax mRNA. PMID- 20197611 TI - [Change and significance of peripheral blood Th17 cells in patients with acute asthma]. AB - OBJECTIVE: To observe the change of peripheral blood Th17 cells and relationship between the severity and Th17 cells in patients with acute asthma. METHODS: We recruited patients with mild acute asthma(n=10) and severe acute asthma(n=10), and healthy volunteers(n=10). T-lymphocytes were collected from the peripheral blood mononuclear cells (PBMC). Flow cytometer (FCM) was used to detect the expression of peripheral blood Th17 cells. IL-17 levels in the peripheral blood were measured by enzyme-linked immunosorbentassay (ELISA). RESULTS: The rate of positive Th17 cells of peripheral blood in the severe acute asthma group was higher than that in the mild acute asthma group(P<0.05) and the rate of positive Th17 cells of peripheral blood in healthy volunteer group were the lowest among all groups (P<0.05, respectively). The level of IL-17 in the peripheral blood of patients with severe acute asthma increased significantly compared with that in patients with mild acute asthma and healthy volunteers (P<0.05). The positive Th17 cells of peripheral blood in patients with acute asthma were positively correlated with the severity of acute asthma(r=0.869, P<0.05). CONCLUSION: The positive rate of Th17 cells in the peripheral blood increases in patients with acute asthma and has positive correlation with the severity of acute asthma. PMID- 20197612 TI - [Change of HIF-1alpha protein expression in the placenta bed and concentration of vWF in maternal peripheral blood of pre-eclampsia]. AB - OBJECTIVE: To investigate the expression of HIF-1alpha protein in the placenta bed and the concentration of von Willrand factor (vWF) in maternal peripheral blood from pre-eclampsia and normal pregnancy, and to determine the effect of HIF 1alpha and vWF on the pathogenesis of pre-eclampsia. METHODS: Forty pre-eclampsia patients (20 mild and 20 severe) were recruited as 2 study groups, and another 20 normal pregnant women were served as a normal group.Western blot was used to detect the expression of HIF-1alpha protein in the placenta bed. ELISA was adopted to detect the concentration of vWF in the maternal peripheral blood.Correlation between HIF-1alpha protein expression and vWF level was analyzed by Spearman method. RESULTS: The expression of HIF-1alpha protein in the placenta bed was the highest in the severe pre-eclampsia patients among 3 groups, followed by the mild pre-eclampsia patients and the normal controls. There was significant difference among 3 groups (P<0.001). The concentration of vWF in the maternal peripheral blood was the highest in the severe pre-eclampsia patients, followed by the mild pre-eclampsia patients and the normal controls. There was significant difference among the 3 groups (P<0.05). Positive correlation was found between the expression of HIF-1alpha protein in the placenta bed and the concentration of vWF in the maternal peripheral blood in patients with pre eclampsia (r1=0.65, P<0.001), and between the concentration of vWF in the maternal peripheral blood and the pathogenetic condition degree of pre-eclampsia (r(2)=0.61,P<0.001). CONCLUSION: HIF-1alpha in coordination with vWF may play an important role in the pathogenesis of pre-eclampsia. PMID- 20197613 TI - [Effect of recombinant pEGFP-N3-APC vectors carrying various APC functional domains on the expression of beta-catenin in HT-29 cells]. AB - OBJECTIVE: To explore the effect of recombinant pEGFP-N3-APC vectors carrying various APC functional domains on the expression of beta-catenin in human colorectal cancer cells HT-29. METHODS: The recombinant plasmids were transfected into HT-29 cells mediated by lipofectamine(TM) 2000, and detected by green fluorescence and RT-PCR. Western blot was applied to detect beta-catenin expression level in HT-29 cells after transfection, and gray scales of electrophoresis strips were analyzed by SPSS 13.0. RESULTS: Green fluorescence and RT-PCR made clear that all 5 recombinant plasmids were successfully expressed in HT-29 cells. Western blot showed that beta-catenin expression level in HT-29 cells was not affected after being transfected with pEGFP-N3-APC1, pEGFP-N3-APC2 and pEGFP-N3-APC3, and was distinctly affected after being transfected with pEGFP N3-APC4 and pEGFP-N3-APC5, especially the later one. CONCLUSION: The selected APC5 gene fragment with 15-amino acid repeats and SAMP repeats, which is relatively short, can degrade beta-catenin level in HT-29 cells and may be applied in the gene therapy. PMID- 20197614 TI - [Expression of RAD51 and MAX in pancreatic cancer rats]. AB - OBJECTIVE: To establish a model of pancreatic cancer induced by 7,12-dimethyl benzathracene (DMBA) in SD rats, and to detect the expression levels of RAD51 and Myc-associated factor X (MAX) and their effect on carcinogenesis of rat pancreas. METHODS: Ninety SD rats were randomly divided into 3 groups: a model group, an intervention group, and a control group. DMBA was directly implanted into the parenchyma of rat pancreas (the model group and the intervention group). Rats in the intervention group were treated with 1 mL trichostatin A (TSA) saline solution (1 mug/mL) via ip weekly. Rats within 3~5 months in the model group and the intervention group were executed and observed by macrograph and under microscope. Meanwhile, the rats in the control group were executed at 5th month. The EnVision(TM) immunohistochemistry to assay the expression levels of RAD51 and MAX was used in conventional paraffin-embedded sections from the above pancreatic specimens. RESULTS: The incidence of pancreatic cancer in the model group within 3-5 months was 48.7% (18/37), including 17 ductal adenocarcinomas and 1 fibrosarcoma. The incidence of pancreatic cancer in the intervention group within 3-5 months was 33.3%(12/36), including 11 ductal adenocarcinomas and 1 fibrosarcoma. The maximal diameter of mass in the model group was significantly higher than that in the intervention group (P<0.05). No pathological changes were found in pancreas of the control group and other extra-pancreatic main organs of the model group and the intervention group (such as the liver, biliary tract, gastrointestine tract, kidney, and lung). The positive rate of RAD51 was significantly higher in ductal adenocarcinoma in the model group, the intervention group, and the model group +the intervention group than those in corresponding groups of non-cancerous pancreatic tissues (P<0.01), but the positive rate of MAX expression was opposite to RAD51 expression(P<0.01). The positive tissues of RAD51 expression and/or negative tissues of MAX expression in non-cancerous tissues showed atypical-hyperplasia of ductal epitheli. Pancreas of the control group showed the negative expression of RAD51 and positive expression of MAX. Two cases of fibrosarcoma showed the negative expression of RAD51 and MAX. CONCLUSION: DMBA directly implanted into the parenchyma of pancreas can obtain an ideal pancreatic cancer model with high incidence in a short time. The TSA might have an inhibitive effect on carcinogenesis and growth of rat pancreas. The over-expression of RAD51 and/or lose-expression might have important effect on carcinogenesis induced DMBA in rat pancreas. PMID- 20197615 TI - [Effect of Cordceps Sinensis on the expression of ICAM-1 and VCAM-1 in the kidney of spontaneously hypertensive rats]. AB - OBJECTIVE: To observe the effect of Cordceps Sinensis (CS) on the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in the kidney of spontaneously hypertensive rats(SHR), and to investigate the mechanism of CS. METHODS: Male SHRs (23 week old) were randomly divided into 4 groups: a group without any treatment (Group S), a group treated with Cordceps sinensis at 4 g/(kg.d)(Group C), a group treated with fosinopril at 10 mg/(kg.d) (Group F), and a group received daily intragastric administration of CS at 4 g/(kg.d) and fosinopril at 10 mg/(kg.d) (Group CF). At the same time, 6 male WKY rats were used as normals controls. At the end of 8 weeks, all rats were sacrificed. Serum creatinine(Scr), 24 h urinary protein count, and the expression of ICAM-1 and VCAM-1 were examined by immunohistochemical technique and RT-PCR. RESULTS: Compared with the WKY rats, blood pressure, 24 h urinary protein count, Scr,and the expression of ICAM-1 andVCAM-1 in the kidney of SHR significantly increased (P<0.05).Compared with Group S, blood pressure decreased after treatment by fosinopril (P<0.05). Compared with Group S, the levels of Scr, 24 h urinary protein count, and glomerular lesion were significantly reduced in the CS and/or fosinopril treatment group. The expression of ICAM-1 and VCAM-1 was significantly decreased in these groups (P<0.05). CONCLUSION: CS may play a role in the protection and anti-fibrosis in the process of renal injury in SHR through reducing the expression of ICAM-1 and VCAM-1. PMID- 20197616 TI - [Effect of TGF-beta1 on epithelial-mesenchymal transition of rat peritoneal mesothelial cells and its mechanism]. AB - OBJECTIVE: To explore the effect of transforming growth factor beta1 (TGF-beta1) on epithelial-mesenchymal transition in rat peritoneal mesothelial cells(RPMCs) and its mechanism. METHODS: Primary peritoneal mesothelial cells of SP rats were cultured in vitro. After synchronization for 24 h, RPMCs were randomly divided into 2 groups: Group A (control), Group B (TGF-beta1, 10 mug/L). RPMCs were stimulated by 10 mug/L TGF-beta1 for different time. The mRNA and protein expression levels of E-cadherin, alpha-smooth muscle actin (alpha-SMA) and collagen I were measured by RT-PCR and Western blot, respectively. The protein expression level of total RhoA was measured by Western blot. Active RhoA was extracted by Plasma Membrane Protein Extraction Kit, and assessed by Western blot. RESULTS: TGF-beta1 down-regulated mRNA and protein expression of E-cadherin in RPMCs, and upregulated mRNA and protein expression of alpha-SMA and CollagenI. TGF-beta1 stimulation elicited a robust increase in RhoA activity in a time dependent manner. RhoA activity peaked at 1 h. CONCLUSION: RPMCs can be transdifferentiated into myofibroblast under the effect of TGF-beta1,and the mechanism may be related to the activation of RhoA associated signal pathway. PMID- 20197617 TI - [Change of ESBLs-KPN and ESBLs-ECO after antimicrobial intervention]. AB - OBJECTIVE: To evaluate the change of extended spectrum beta-lactamase (ESBLs) Producing Klebsiella Pneumoniae (ESBLs-KPN) and Escherichia coli (ESBLs-ECO) causing nosocomial infection after antimicrobial intervention. METHODS: We regularly monitored the data on the yearly consumption [defined as daily dose (DDD) per 1 000 patient-days] of frequently used antibiotics from Dec. 2004 to Dec. 2007. From Jan. 2005 to Dec. 2007, we monitored the resistance of frequently used antibiotics and the timely integrative antimicrobial intervention was based on the outcome of antimicrobial resistance. We also monitored the isolation rate of ESBLs-KPN and ESBLs-ECO causing nosocomial infection. The departments studied were the experimental group and other comparable medical departments were the control group(ICU was excluded). RESULTS: The isolation rate of ESBLs-KPN (43.90%) and ESBLs-ECO (45.83%) in the experimental group was higher than that in the control group (28.04% and 24.90%, respectively) before the intervention (P<0.05). The isolation rate of ESBLs-KPN decreased (from 26.47% to 17.65%) in the experimental group and that in the control group increased ( ESBLs-KPN: from 34.18% to 52.94%; ESBLs-ECO: from 47.13% to 63.78%) from 2005 to 2007 (P<0.05). The isolation rate of ESBLs-KPN and ESBLs-ECO in the experimental group was lower than that in the control group after the antimicrobial intervention (P<0.05). Usage of ceftazidime and cefoperazone/sulbactam and imipenem was reduced and the consumption of cefepime was increased in the experimental group (P<0.05). Consumption of ceftazidime and cefoperazone/sulbactam and cefepime was increased. CONCLUSION: The prevalence of ESBLs-KPN and ESBLs-ECO may be decreased after the integrative antimicrobial intervention. PMID- 20197618 TI - [Effect of Ursodeoxycholi acid on liver cirrhosis with hepatitis B]. AB - OBJECTIVE: To evaluate the therapeutic effect of Ursodeoxycholi acid on the treatment of liver cirrhosis with hepatitis B. METHODS: Eighty-four patients with liver cirrhosis were randomly divided into 2 groups:42 to the treatment group who were given oral capsules of Ursodeoxycholi acid combined with reduced glutathione,and the other 42 to the control group who received Yinzhihuang intravenously, combined with reduced glutathione. Therapeutic efficacy,liver function and its normalization rate,and score of Child-pugh-Turcotte (CPT)were observed after 4 week treatment and 8 week treatment. RESULTS: The therapeutic efficacy had no significant difference between the treatment group and the control group (P>0.05). Compared with the control group, the values of gamma glutamyl transpeptidase (gamma-GT), alkaline phosphatase (AKP) and globulin(GLO) of the treatment group decreased more significantly (P<0.05), and the normalization rates of gamma-GT and AKP in the treatment group was significantly higher than that in the control group at 8 week. The decreased levels of total bilirubin (TBIL) and direct bilirubin(DBIL) were not significantly different between the 2 groups (P>0.05). At 4 week the decrease level of ALT in the 2 groups was similar (P>0.05), while at 8 week the values of ALT reduced more significantly than that of the control group(P<0.05). The score of CPT of the 2 groups were not different after 4 week and 8 week treatment (P>0.05). CONCLUSION: Ursodeoxycholi acid can obviously decrease the values of gamma-GT, AKP and GLO in liver cirrhosis with hepatitis B, which may be related to Ursodeoxycholi acid relieving the injury of bile duct and enhancing biliary transport. PMID- 20197619 TI - [Effect of freezing and pingyangmycin injection on the auricular posterior vein in rabbits]. AB - OBJECTIVE: To observe the change of vascular endothelial cells and structure of the auricular posterior vein caused by freezing or pingyangmycin injection alone and freezing in combination with pingyangmycin injection,to investigate the effect of these treatments on the vein. METHODS: Eighteen rabbits were divided into 3 groups of 6 each, and another rabbit was used as a control. Pingyangmycin was injected into the auricular posterior vein in the first group, spray freezing within 20 seconds on the auricular posterior vein was performed in the second group,and freezing in combination with pingyangmycin injection was performed in the third group. Light microscope and transmission electron microscope were used to observe the change of auricular posterior vein in the rabbits. RESULTS: Proliferation of endothelial cells,and thickening of vessel wall were induced by pingyangmycin. Thrombus formation, tissue oedema and inflammatory infiltration induced by spray freezing within 20 seconds were reversible. Thrombus formation, proliferation of endothelial cells and thickening of the vessel wall was induced by freezing in combination with pingyangmycin injection. CONCLUSION: Freezing and pingyangmycin injection have the synergistic effect, resulting in the proliferation of endothelial cells, thrombus formation, thickening of vessel wall, and even occlusion of vessels. PMID- 20197620 TI - [Influence factors for limb salvage of bone fracture patients with hyperpotassemia caused by earthquake]. AB - OBJECTIVE: To determine the influence factors for limb salvage of bone fracture patients with hyperpotassemia caused by Wenchuan earthquake, to discuss the clinical symptom and to improve the clinical treatment. METHODS: The clinical symptom, drug therapy, limb incision decompression, hemodialysis, and limb salvage of hyperpotassemia caused by earthquake were analyzed by logistic regression. RESULTS: All the 37 patients received drug therapy: 9 patients received incision and decompression singlely,8 received hemodialysis singlely,and the other 20 received decompression and hemodialysis simultaneously. The concentration of potassium decreased from (6.25 +/- 0.91) mmol/L to (4.47+/-0.65) mmol/L,with significant difference (P<0.05). Five patients with Gustilo III grade open injury received amputation at the concentration of potassium of (6.13+/ 0.78) mmol/L, while the concentration of potassium for the other 32 patients was (6.25+/-0.31) mmol/L. There was no significant difference between them(P>0.05). Logistic regression analysis found the time of compression, the time before incision and decompression, and the time before hemodialysis were the main factors to affect limb salvage. The OR value of these factors was 4.394, 3.793 and 5.432;while the P value was 0.013, 0.047, and 0.015, respectively. CONCLUSION: Decreasing the time of compression, appropriate incision and decompression, and hemodialysis help improve the result of limb salvage in hyperpotassemia patients with bone fracture caused by earthquake. PMID- 20197621 TI - A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis. AB - Irreversible cell growth arrest, a process termed cellular senescence, is emerging as an intrinsic tumor suppressive mechanism. Oncogene-induced senescence is thought to be invariably preceded by hyperproliferation, aberrant replication, and activation of a DNA damage checkpoint response (DDR), rendering therapeutic enhancement of this process unsuitable for cancer treatment. We previously demonstrated in a mouse model of prostate cancer that inactivation of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (Pten) elicits a senescence response that opposes tumorigenesis. Here, we show that Pten-loss induced cellular senescence (PICS) represents a senescence response that is distinct from oncogene-induced senescence and can be targeted for cancer therapy. Using mouse embryonic fibroblasts, we determined that PICS occurs rapidly after Pten inactivation, in the absence of cellular proliferation and DDR. Further, we found that PICS is associated with enhanced p53 translation. Consistent with these data, we showed that in mice p53-stabilizing drugs potentiated PICS and its tumor suppressive potential. Importantly, we demonstrated that pharmacological inhibition of PTEN drives senescence and inhibits tumorigenesis in vivo in a human xenograft model of prostate cancer. Taken together, our data identify a type of cellular senescence that can be triggered in nonproliferating cells in the absence of DNA damage, which we believe will be useful for developing a "pro senescence" approach for cancer prevention and therapy. PMID- 20197622 TI - CD99 inhibits neural differentiation of human Ewing sarcoma cells and thereby contributes to oncogenesis. AB - Ewing sarcoma (EWS) is an aggressive bone tumor of uncertain cellular origin. CD99 is a membrane protein that is expressed in most cases of EWS, although its function in the disease is unknown. Here we have shown that endogenous CD99 expression modulates EWS tumor differentiation and malignancy. We determined that knocking down CD99 expression in human EWS cell lines reduced their ability to form tumors and bone metastases when xenografted into immunodeficient mice and diminished their tumorigenic characteristics in vitro. Further, reduction of CD99 expression resulted in neurite outgrowth and increased expression of beta-III tubulin and markers of neural differentiation. Analysis of a panel of human EWS cells revealed an inverse correlation between CD99 and H-neurofilament expression, as well as an inverse correlation between neural differentiation and oncogenic transformation. As knockdown of CD99 also led to an increase in phosphorylation of ERK1/2, we suggest that the CD99-mediated prevention of neural differentiation of EWS occurs through MAPK pathway modulation. Together, these data indicate a new role for CD99 in preventing neural differentiation of EWS cells and suggest that blockade of CD99 or its downstream molecular pathway may be a new therapeutic approach for EWS. PMID- 20197623 TI - Loss of Rab25 promotes the development of intestinal neoplasia in mice and is associated with human colorectal adenocarcinomas. AB - Transformation of epithelial cells is associated with loss of cell polarity, which includes alterations in cell morphology as well as changes in the complement of plasma membrane proteins. Rab proteins regulate polarized trafficking to the cell membrane and therefore represent potential regulators of this neoplastic transition. Here we have demonstrated a tumor suppressor function for Rab25 in intestinal neoplasia in both mice and humans. Human colorectal adenocarcinomas exhibited reductions in Rab25 expression independent of stage, with lower Rab25 expression levels correlating with substantially shorter patient survival. In wild-type mice, Rab25 was strongly expressed in cells luminal to the proliferating cells of intestinal crypts. While Rab25-deficient mice did not exhibit gross pathology, ApcMin/+ mice crossed onto a Rab25-deficient background showed a 4-fold increase in intestinal polyps and a 2-fold increase in colonic tumors compared with parental ApcMin/+ mice. Rab25-deficient mice had decreased beta1 integrin staining in the lateral membranes of villus cells, and this pattern was accentuated in Rab25-deficient mice crossed onto the ApcMin/+ background. Additionally, Smad3+/- mice crossed onto a Rab25-deficient background demonstrated a marked increase in colonic tumor formation. Taken together, these results suggest that Rab25 may function as a tumor suppressor in intestinal epithelial cells through regulation of protein trafficking to the cell surface. PMID- 20197624 TI - The von Hippel-Lindau Chuvash mutation promotes pulmonary hypertension and fibrosis in mice. AB - Mutation of the von Hippel-Lindau (VHL) tumor suppressor protein at codon 200 (R200W) is associated with a disease known as Chuvash polycythemia. In addition to polycythemia, Chuvash patients have pulmonary hypertension and increased respiratory rates, although the pathophysiological basis of these symptoms is unclear. Here we sought to address this issue by studying mice homozygous for the R200W Vhl mutation (VhlR/R mice) as a model for Chuvash disease. These mice developed pulmonary hypertension independently of polycythemia and enhanced normoxic respiration similar to Chuvash patients, further validating VhlR/R mice as a model for Chuvash disease. Lungs from VhlR/R mice exhibited pulmonary vascular remodeling, hemorrhage, edema, and macrophage infiltration, and lungs from older mice also exhibited fibrosis. HIF-2alpha activity was increased in lungs from VhlR/R mice, and heterozygosity for Hif2a, but not Hif1a, genetically suppressed both the polycythemia and pulmonary hypertension in the VhlR/R mice. Furthermore, Hif2a heterozygosity resulted in partial protection against vascular remodeling, hemorrhage, and edema, but not inflammation, in VhlR/R lungs, suggesting a selective role for HIF-2alpha in the pulmonary pathology and thereby providing insight into the mechanisms underlying pulmonary hypertension. These findings strongly support a dependency of the Chuvash phenotype on HIF-2alpha and suggest potential treatments for Chuvash patients. PMID- 20197625 TI - Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome. AB - The glomerular basement membrane (GBM) is a key component of the filtering unit in the kidney. Mutations involving any of the collagen IV genes (COL4A3, COL4A4, and COL4A5) affect GBM assembly and cause Alport syndrome, a progressive hereditary kidney disease with no definitive therapy. Previously, we have demonstrated that the bone morphogenetic protein (BMP) antagonist uterine sensitization-associated gene-1 (USAG-1) negatively regulates the renoprotective action of BMP-7 in a mouse model of tubular injury during acute renal failure. Here, we investigated the role of USAG-1 in renal function in Col4a3-/- mice, which model Alport syndrome. Ablation of Usag1 in Col4a3-/- mice led to substantial attenuation of disease progression, normalization of GBM ultrastructure, preservation of renal function, and extension of life span. Immunohistochemical analysis revealed that USAG-1 and BMP-7 colocalized in the macula densa in the distal tubules, lying in direct contact with glomerular mesangial cells. Furthermore, in cultured mesangial cells, BMP-7 attenuated and USAG-1 enhanced the expression of MMP-12, a protease that may contribute to GBM degradation. These data suggest that the pathogenetic role of USAG-1 in Col4a3-/- mice might involve crosstalk between kidney tubules and the glomerulus and that inhibition of USAG-1 may be a promising therapeutic approach for the treatment of Alport syndrome. PMID- 20197627 TI - Basic principles of platelet biology and clinical implications. AB - Platelet activation and subsequent accumulation at sites of vascular injury are the first steps in hemostasis. Excessive platelet activation after atherosclerotic plaque rupture or endothelial cell erosion may also lead to the formation of occlusive thrombi, which are responsible for acute ischemic events. Multiple pathways are involved in platelet activation, including those activated by adenosine diphosphate (ADP), thromboxane A(2) (TXA(2)), serotonin, collagen, and thrombin. Antiplatelet agents used for prevention of atherothrombosis have focused on blocking the formation of TXA(2) (eg, aspirin) and interfering with ADP stimulation mediated by the P2Y(12) receptor (eg, clopidogrel). These agents, used alone or in combination, significantly decrease the risk for atherothrombotic events, but a significant residual risk for recurrent ischemic events remains. This has been, in part, attributed to persistence of elevated platelet reactivity despite the use of these agents. Several novel antiplatelet agents are currently under clinical development, with the goal of achieving more efficacious platelet inhibition. These include agents that more efficiently block TXA(2)-mediated effects, as well as more potent P2Y(12) receptor antagonists. In addition, inhibition of the protease-activated receptor-1 platelet activation pathway stimulated by thrombin has emerged as a rational target for clinical development. An overview of the basic principles of platelet biology is given and currently available antiplatelet agents, as well as those under clinical development, are reviewed. PMID- 20197626 TI - Comprehensive assessment of chemokine expression profiles by flow cytometry. AB - The chemokines are a large family of mainly secreted molecules involved in the regulation of numerous physiological and pathophysiological processes. Despite many years of investigation, the precise cellular sources of most chemokines have remained incompletely defined as a consequence of the limited availability of suitable reagents to visualize the expression of chemokine proteins at the single cell level. Here, we developed a simple flow cytometry-based assay using commercially available chemokine-specific antibodies for efficient cell associated detection of 37 of 39 murine chemokines. To demonstrate the utility of this methodology, we used it to reevaluate the nature of homeostatic chemokines in the hematopoietic compartment, to delineate the complete chemokine profiles of NK cells and B cells in response to major polyclonal stimuli, and to assess the chemokine response of DCs to bacterial infection. The versatility of this analytical methodology was further demonstrated by its application to selected human chemokines and should greatly facilitate any future investigation into chemokine biology at large. PMID- 20197628 TI - Three-dimensional transesophageal echocardiographic recognition of mobile mass protruding into the left main coronary orifice in a patient with aortic stenosis. PMID- 20197629 TI - Long-term clinical outcome of chronic total occlusive lesions treated with drug eluting stents: comparison of sirolimus-eluting and paclitaxel-eluting stents. AB - BACKGROUND: There are few studies comparing the efficacy of different drug eluting stents and their long-term clinical outcomes in percutaneous coronary intervention (PCI) of chronic total occlusive (CTO) lesions. METHODS AND RESULTS: To compare the efficacy of sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES) for CTO, and to identify predictors of outcome after PCI, 200 patients with at least 1 successfully revascularized CTO were enrolled into either a SES (n=132) or PES (n=71) group. At 6-9-month angiographic follow-up, SES was superior to PES (late loss 0.27+/-0.60 vs 0.53+/-0.62 mm, P=0.04). During mean follow-up of 2 years, the SES group had a significantly lower cumulative target vessel failure (TVF) rate than the PES group (14.9% vs 28.4%, P=0.01), as a consequence of lower target vessel revascularization (9.7% vs 23.9%, P=0.01) and also a partially lower rate of myocardial infarction (MI: 3.1% vs 7.6%, P=0.04). SES was also superior to PES in both early (9 months) TVF (P=0.02 for log-rank test, respectively). Predictors for TVF were use of PES (hazard ratio (HR) 3.81, P<0.01), previous history of MI (HR 4.06, P<0.01), diabetes (HR 2.07, P=0.04) and chronic kidney disease (CKD; HR 3.56, P=0.05). CONCLUSIONS: CTO lesions treated with SES showed better angiographic and long-term clinical outcomes than those treated with PES. Factors such as stent type, infarct-related CTO, diabetes and CKD affect the outcome of CTO intervention. PMID- 20197630 TI - Anatomical study of forearm arteries with ultrasound for percutaneous coronary procedures. AB - BACKGROUND: In recent years, the radial artery (RA) has become an alternative vascular access site for percutaneous coronary procedures, and the ulnar artery (UA) is another possibility. The objective of this study was to investigate the anatomy of the forearm arteries with ultrasound (US) and to evaluate the effect of the anatomy of the right RA (RRA) on the outcomes of transradial coronary procedures. METHODS AND RESULTS: The 638 patients undergoing transradial coronary procedures were examined with US for measurement of the diameters of the forearm arteries and determination of their anatomical abnormalities before the procedures. The next day the incidence of RA occlusion was recorded. The diameters of the radial and ulnar arteries were similar (P>0.05). The procedure time was longer in patients with anatomical abnormalities (P<0.05) and whose RRA had a diameter <2 mm (P<0.05). The incidence of procedure failure, and of RA occlusion one day after the procedure was also higher in patients with an anatomical abnormality of the RRA (P<0.01 and P<0.05, respectively) and whose RRA diameter was <2 mm (P<0.05 and P<0.05, respectively). CONCLUSIONS: The diameters of the forearm arteries of Chinese people are similar. The small diameter and anatomical abnormalities of the RRA could result in longer procedure time, more incidence of procedure failure and RA occlusion. PMID- 20197632 TI - What psychosocial characteristics are associated with smoking cessation behavior and readiness to quit smoking among Japanese male ever-smokers with type 2 diabetes mellitus? AB - AIM: The relationship between psychosocial characteristics and smoking cessation behavior was examined among Japanese male eversmokers with type 2 diabetes mellitus. METHODS: The psychosocial characteristics and smoking cessation behavior of 441 male ever-smokers with type 2 diabetes mellitus were investigated. Personality was assessed using an egogram (five ego states: the Critical Parent, Nurturing Parent, Adult, Free Child, and Adapted Child) and each patient was classified into a high score or low score group based on the median. The current smokers were divided into 2 categories according to their readiness to quit smoking. RESULTS: In multivariate analyses, the ever-smokers with a high Adult score had a lower risk of current smoking (OR=0.67, 95%CI=0.41-0.93), the ever-smokers with a high Free Child score were over 3 times more likely to currently smoke (OR=3.12, 95%CI=1.97-4.97), and the ever-smokers who had a low educational background had a higher risk of current smoking (OR=3.02, 95% CI=1.73 5.28). In addition, the current smokers with a high Adult score had a lower risk of being in the immotive and precontemplation stage (OR=0.55, 95%CI=0.24-0.96). The current smokers who had a low educational background had a higher risk of being in the immotive and precontemplation stage (OR=2.13, 95%CI=1.08-5.42). CONCLUSION: There is a need to develop a smoking cessation program for patients with high "Free Child" scores and a "low education level". PMID- 20197631 TI - Prediction of myocardial infarction using coronary risk scores among Japanese male workers: 3M Study. AB - BACKGROUND: It remains unclear how much coronary risk factors contribute to the prediction of myocardial infarction among Japanese populations. METHODS AND RESULTS: A nested case-control study of Japanese male workers aged 35 to 65 years was conducted between 1997 and 2000 in the Morbidity of Myocardial Infarction Multicenter Study in Japan (3M Study). Two hundred four myocardial infarctions were identified and two controls per case were selected by matching for age. We calculated odds ratios using a conditional logistic regression model, and constructed risk predictive models for the risk of myocardial infarction using coronary risk factors. The multivariable odds ratios (95 percent confidence intervals) of myocardial infarction were 2.02 (1.29-3.16) for high blood pressure, 2.33 (1.51-3.59) for high LDL-cholesterol, 4.16 (2.36-7.33) for low HDL cholesterol, 1.49 (0.94-2.35) for high triglycerides, 1.46 (0.89-2.39) for high glucose, and 2.95 (1.90-4.59) for current smoking. A large reduction of the predictive value for myocardial infarction was shown after exclusion of high LDL cholesterol (reduction of predictive value was -3.4%), further exclusion of low HDL-cholesterol (-7.1%), and further exclusion of current smoking (-16.4%). CONCLUSIONS: High LDL-cholesterol and low HDL-cholesterol as well as current smoking had high predictive values for myocardial infarction among Japanese middle-aged male workers. PMID- 20197633 TI - Small, dense LDL and high-sensitivity C-reactive protein (hs-CRP) in metabolic syndrome with type 2 diabetes mellitus. AB - AIM: To clarify the clinical significance of small,dense LDL (sLDL) in the metabolic syndrome associated with type 2 diabetes. METHODS: One hundred and ten healthy non-diabetic and non-metabolic syndrome subjects (58 male/52 female), 77 non-metabolic diabetic subjects (62/15), 58 non-diabetic metabolic subjects (25/33), and 46 metabolic diabetic subjects (29/17) were enrolled in this study. RESULTS: The subjects with metabolic syndrome (both with and without type 2 diabetes) had significantly higher fasting blood glucose, total-cholesterol (C), LDL-C, triglyceride, sLDL-C and hs-CRP levels than non-metabolic and non-diabetic subjects. HDL-C levels were significantly decreased in the former compared to the latter. Among the metabolic syndrome subjects, those with type 2 diabetes had significantly higher fasting blood glucose, systolic blood pressure and hs-CRP values than those without diabetes. sLDL-C, LDL-C and hs-CRP were the highest and HDL-C was lowest in the metabolic syndrome with diabetes group. A multiple regression analysis revealed the most significant determinant of sLDL-C to be LDL C, followed by HDL-C, total-C, metabolic syndrome, type 2 diabetes mellitus, and triglyceride. CONCLUSION: Metabolic syndrome is a significant determinant of the plasma sLDL-C level. Hs-CRP was the highest in the metabolic syndrome patients with type 2 diabetes. Therefore, type 2 diabetes may further increase the risk of coronary artery disease in the metabolic syndrome subjects through cardiovascular inflammation. PMID- 20197634 TI - Hyperglycemia impairs acetylcholine-induced vasodilation of retinal arterioles through polyol pathway-independent mechanisms in rats. AB - We previously reported that acetylcholine (ACh)-induced vasodilation of retinal arterioles is diminished in diabetic rats; however, the underlying mechanism(s) of this phenomenon has not been fully elucidated. To determine the role of the polyol pathway in the diabetes-induced retinal vascular dysfunction, we investigated the effect of GP-1447, an inhibitor of aldose reductase, on the attenuation of ACh-induced vasodilation of retinal arterioles seen in diabetic rats. Male Wistar rats were treated with streptozotocin (STZ) and experiments were performed 2 weeks later. The STZ-treated animals were given drinking water containing 5% D-glucose to shorten the term for the development of retinal vascular dysfunction. Treatment with GP-1447 was initiated immediately after STZ treatment and continued throughout the 2-week experimental period. The attenuation of retinal vascular responses to ACh were not modified by treatment with GP-1447, whereas the aldose reductase inhibitor completely prevented diabetes-induced thinning of the retina and sorbitol accumulation in the retina and the lens. These results suggest that mechanisms that are independent of the polyol pathway may contribute to the onset of retinal endothelial dysfunction, although the pathway plays an important role in morphological changes of retina and formation of cataracts in diabetic rats. PMID- 20197635 TI - Emerging new roles of GM130, a cis-Golgi matrix protein, in higher order cell functions. AB - GM130 is a peripheral membrane protein strongly attached to the Golgi membrane and is isolated from the detergent and salt resistant Golgi matrix. GM130 is rich in coiled-coil structures and predicted to take a rod-like shape. Together with p115, giantin, and GRASP65, GM130 facilitates vesicle fusion to the Golgi membrane as a vesicle "tethering factor". GM130 is also involved in the maintenance of the Golgi structure and plays a major role in the disassembly and reassembly of the Golgi apparatus during mitosis. Emerging evidence suggests that GM130 is involved in the control of glycosylation, cell cycle progression, and higher order cell functions such as cell polarization and directed cell migration. This creates the potential for novel Golgi-targeted drugs and treatments for various diseases including glycosylation defects, immune diseases, and cancer. PMID- 20197636 TI - Shikonin directly inhibits nitric oxide synthases: possible targets that affect thoracic aorta relaxation response and nitric oxide release from RAW 264.7 macrophages. AB - Recently, an isomeric mixture of herbal anti-inflammatory naphthoquinones shikonin and alkannin, and their derivatives, have been found to impair cellular responses involving nitric oxide (NO) and NO synthesis, like the acetylcholine induced relaxation response of rat thoracic aorta and NO release from murine RAW 264.7 macrophages. However, the mechanisms of such effects, including whether NO synthase (NOS) activity is affected, remained unclear. We herein investigate possible targets of shikonin in these NOS-related events. Shikonin by itself dose dependently inhibited the rat thoracic aorta relaxation in response to acetylcholine (pD'(2) value: 6.29). Its optical enantiomer, alkannin, was equally inhibitory in the aorta relaxation-response assay. In RAW 264.7 cells, shikonin inhibited the lipopolysaccharide-induced NO production by 82% at 1 microM. A cell free assay to verify direct effects on NOS activity showed that shikonin inhibits all isoforms of NOS (IC(50)s, 4 - 7 microM), suggesting NOS as an inhibition target in both the events. Further possible targets of shikonin that might be involved in the inhibitions of the acetylcholine-induced aorta relaxation response and the NO generation by RAW 264.7 cells are also discussed. It is shown for the first time that shikonin inhibits NOS activity. PMID- 20197637 TI - Paradoxical effect of 2,3-dimercapto-1-propanesulfonic acid (DMPS) on enhancing antitumor activity of cisplatin in ascites sarcoma 180 cells. AB - We investigated the enhancing effect of two metal-chelating compounds, 2,3 dimercapto-1-propanesulfonic acid (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA), on the antitumor activity of cisplatin (CDDP). In the in vivo experiments, DMPS showed a clear synergistic effect and significantly enhanced the antitumor activity of CDDP in terms of survival and life span in mice transplanted with ascites sarcoma 180 cells (S180 cells) at a dose of <100 micromol/kg, s.c., but not at a dose of >500 micromol/kg. On the other hand, DMSA did not enhance the antitumor activity of CDDP. DMPS (50 micromol/kg, s.c.) combined with CDDP also potently suppressed [(3)H]thymidine uptake in S180 cells implanted in mice, whereas DMSA did not. In the in vitro experiments, DMPS (10( 6) to 10(-5) M) produced a time- and dose-dependent decrease in intracellular Ca(2+) concentrations ([Ca(2+)](i)) in S180 cells and, in combination with CDDP, yielded a significant increase in intracellular platinum accumulation compared to that in cells treated with CDDP alone. These results indicate that DMPS used in combination with CDDP may be of considerable benefit in enhancing the cytotoxicity of CDDP in tumor cells, especially at a low dose. The results also suggest that the enhancing effect of DMPS is closely related to a decrease in [Ca(2+)](i) and that the suitable dose and adequate administrational time of DMPS are important for its effective action. PMID- 20197638 TI - Histological protection by donepezil against neurodegeneration induced by ischemia-reperfusion in the rat retina. AB - Although a blockade of acetylcholine esterase has been reported to suppress neuronal cell death induced by exogenous glutamate and beta-amyloid, information is still limited regarding the neuroprotective effects of the acetylcholine esterase inhibitor donepezil. We histologically examined the effects of donepezil on neuronal injury induced by ischemia-reperfusion. Intravenous and intravitreous treatment with donepezil 15 min prior to ischemia dramatically reduced the retinal damage. The protective effect of donepezil in the ganglion cell layer was not affected by mecamylamine, a nicotinic acetylcholine-receptor antagonist, nor scopolamine, a muscarinic acetylcholine-receptor antagonist. The protective effect of donepezil in the inner plexiform layer was reduced not by mecamylamine, but by scopolamine. Neostigmine, a choline-esterase inhibitor, and pilocarpine, a muscarinic acetylcholine-receptor agonist, have protective effects in the inner plexiform layer and the inner nuclear layer. These results suggest that not only the activation of acetylcholine receptors but also a mechanism unrelated to acetylcholine-esterase inhibition contribute to the protective effect of donepezil on the ganglion cells in the ischemic-reperfused rat retina. Donepezil may be useful as a therapeutic drug against retinal diseases that cause neuronal cell death such as glaucoma with high intraocular pressure. PMID- 20197639 TI - Effects of KRN633, an inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase, on vascular development of placenta and fetus of mid-pregnancy in mice. AB - Inhibition of the vascular endothelial growth factor (VEGF) signaling pathway during pregnancy contributes to several pathologic pregnancies, such as hypertension, preeclampsia, and intrauterine growth restriction, but its effects on the fetus have not been fully examined. To determine how inhibition of the VEGF signaling pathway affects the fetal vascular development of mid pregnancy, we treated pregnant mice daily with either the VEGF receptor-2 (VEGFR-2) tyrosine kinase inhibitor KRN633 (300 mg/kg, p.o.) or the vehicle from 13.5 to 15.5 day of pregnancy. On the 16.5 day of pregnancy, the vascular beds in the placenta and several organs of the fetus were visualized by fluorescent immunohistochemistry. All mice treated with KRN633 appeared healthy, and total numbers of fetuses per litter were unaffected. However, weights of the placenta and fetus from KRN633 treated mice were lower than those from the vehicle-treated ones. No external malformations and bleeding were observed in the placenta and fetus, whereas immunohistochemical analyses revealed that the vascular development in labyrinthine zone of placenta and fetal organs examined (skin, pancreas, kidney, and lung) were impaired by KRN633 treatment. These results suggest that inhibition of the VEGF signaling pathway during mid pregnancy suppresses vascular growth of both the placenta and fetus without obvious health impairments of mother mice and increases the risk of induction of intrauterine growth restriction. PMID- 20197640 TI - Calmodulin- and Ca2+-dependent facilitation and inactivation of the Cav1.2 Ca2+ channels in guinea-pig ventricular myocytes. AB - The L-type Ca(2+) channel (Ca(V)1.2) shows clear Ca(2+)-dependent facilitation and inactivation. Here we have examined the effects of calmodulin (CaM) and Ca(2+) on Ca(2+) channel in guinea-pig ventricular myocytes in the inside-out patch mode, where rundown of the channels was controlled. At a free [Ca(2+)] of 0.1 microM, CaM (0.15, 0.7, 1.4, 2.1, 3.5, and 7.0 microM) + ATP (2.4 mM) induced channel activities of 27%, 98%, 142%, 222%, 65%, and 20% relative to the control activity, respectively, showing a bell-shaped relationship. Similar results were observed at a free [Ca(2+)] <0.01 microM or with a Ca(2+)-insensitive mutant, CaM(1234), suggesting that apoCaM may induce facilitation and inactivation of the channel activity. The bell-shaped curve of CaM was shifted to the lower concentration side with increasing [Ca(2+)]. A simple model for CaM- and Ca(2+) dependent modulations of the channel activity, which involves two CaM-binding sites, was proposed. We suggest that both apoCaM and Ca(2+)/CaM can induce facilitation and inactivation of Ca(V)1.2 Ca(2+) channels and that the basic role of Ca(2+) is to accelerate CaM-dependent facilitation and inactivation. PMID- 20197641 TI - Similar DNA methylation and histone H3 lysine 9 dimethylation patterns in tripronuclear and corrected bipronuclear human zygotes. AB - After fertilization, male and female gametes undergo extensive reprogramming to restore totipotency. Both DNA methylation and histone modification are important epigenetic reprogramming events. Previous studies have reported that the paternal pronucleus of the human zygote is actively demethylated to some extent, while the maternal pronucleus remains methylated. However, to our knowledge, the relationship between DNA methylation and H3K9 dimethylation patterns in human embryos has not been reported. In this study, we examined the dynamic DNA methylation and H3K9 dimethylation patterns in triploid and bipronucleated zygotes and early developing embryos. We sought to gain further insight into the relationship between DNA methylation and H3K9 dimethylation and to investigate whether removing a pronucleus from triploid zygotes affects DNA methylation and H3K9 dimethylation patterns. We found that active DNA demethylation of the two male pronuclei occurred in tripronuclear human zygotes while the female pronucleus remained methylated at 20 h post-insemination. In tripronuclear human zygotes, H3K9 was hypomethylated in the two paternal pronuclei relative to the maternal pronucleus. Our data show that there are no differences in the DNA methylation and H3K9 dimethylation patterns between tripronuclear and corrected bipronuclear human zygotes. However, correction of 3PN human zygotes dispermic in origin could not improve subsequent embryo development. In conclusion, DNA methylation and H3K9 dimethylation patterns are well correlated in tripronuclear zygotes and embryos; early embryo development is not affected by removal of a male pronucleus. Our results imply that limited developmental potential of either 3PN or corrected 2PN embryos may not be caused by the abnormalities in DNA methylation or H3K9 dimethylation modification. PMID- 20197642 TI - Dilution of boar ejaculates with BTS containing HEPES in place of bicarbonate immediately after ejaculation can reduce the increased inducibility of the acrosome reaction by treatment with calcium and calcium ionophore A23187, which is potentially associated with boar subfertility. AB - The present study investigated whether substitution of HEPES for bicarbonate in BTS (BTS-H) used to dilute boar ejaculates immediately after ejaculation could reduce the increased inducibility of the acrosome reaction by calcium and calcium ionophore A23187. When an ejaculate was split, diluted 5-fold with regular BTS (BTS-B) and BTS-H and stored at 17 C for 12 h or 60 h, the extender or storage time had no significant influence on sperm motility or viability measured by the eosin-nigrosin method. When spermatozoa diluted serially with BTS-B and stored (36 h) were stimulated with Ca2+ (3 mM) and A23187 (0.3 microM), the proportion of spermatozoa that underwent the acrosome reaction (% acrosome reactions) significantly increased as the magnifications of dilution increased (bicarbonate content almost unchanged by dilution). By contrast, the % acrosome reactions in spermatozoa similarly diluted and stored with BTS-H decreased with the increasing magnifications of dilution (bicarbonate decreased). Sperm motility immediately after the end of incubation without A23178 tended to be lower for BTS-H than BTS B, and the ejaculates for BTS-H had a tendency to have a lower total protein in seminal plasma than those for BTS-B. These results implied that the samples for BTS-H could be used as a model for ejaculates possibly collected during summer and showing subfertility. When an ejaculate was split, diluted serially with BTS B and BTS-H and stored, viability measured by staining with propidium iodide was extremely similar between the 2 extenders and among the different dilution magnifications, regardless of whether spermatozoa were washed (stored for 36-66 h) or not (stored for 66-72 h). These results suggest that boar ejaculate can be stored with BTS-H at least according to the results for sperm motility and viability and that hypersensitivity of spermatozoa to Ca2+ and A23187 potentially associated with boar subfertility could be lessened by diluting ejaculates with BTS-H. PMID- 20197643 TI - Electrical activities of neurones in the dorsomedial hypothalamic nucleus projecting to the supraoptic nucleus during milk-ejection reflex in the rat. AB - Using urethane-anesthetized lactating rats, extracellular action potentials were recorded from single cells in the dorsomedial hypothalamus (DMH), which were identified as projecting to the supraoptic nucleus (SON). Sixty-two DMH cells were identified as projecting to the SON. Of these 53, 4 and 5 cells had ipsilateral, contralateral and bilateral projections, respectively. Two cells (1 ipsilaterally and 1 contralaterally projecting cell) showed bursting activities preceding milk ejection that were similar to those of oxytocin (OT) cells in the SON or paraventricular nucleus. Two ipsilaterally and 2 bilaterally projecting cells reduced their firing rates preceding milk ejection. The results suggest that some of the projections from the DMH to the SON are contralateral or bilateral and that these projections may contribute to synchronized activation of OT cells bilaterally distributed in the hypothalamus during milk-ejection reflex. PMID- 20197644 TI - Seasonal changes in spermatogenesis and immunolocalization of cytochrome P450 17alpha-hydroxylase/c17-20 lyase and cytochrome P450 aromatase in the wild male ground squirrel (Citellus dauricus Brandt). AB - The purpose of this study was to investigate seasonal changes of spermatogenesis and the cellular localization of P450c17 and P450arom in wild male ground squirrels during the breeding and non-breeding seasons. The testicular weight, testicular size and score count of spermatogenesis from April to September were measured, and histological and immunohistochemical observations of testicular tissues were performed in wild male ground squirrels. In addition, total proteins were extracted from testicular tissue in the breeding and non-breeding seasons and were used for Western blotting analysis for P450c17 and P450arom. There were marked variations in testicular weight, testicular size and score count of spermatogenesis from the breeding season (April) to the non-breeding season (September). Histologically, spermatogonia, primary spermatocytes, secondary spermatocytes and spermatozoa were identified in the breeding season (April). Immunolocalization of P450c17 was detected in Leydig cells and spermatozoa during the breeding season and was only found in Leydig cells during the non-breeding season. The positive signals of P450c17 by Western blotting were both observed in the breeding and non-breeding seasons. Immunolocalization of P450arom was observed in Leydig cells, Sertoli cells and all types of spermatogenic cells including mature-phase spermatozoa in the breeding season, while immunoreactivity for P450arom was not present in the testis of the non-breeding season. With P450arom antibody, a band was also only detected in the breeding season by Western blotting. These results suggest that the seasonal changes in testicular weight and size are correlated with spermatogenesis and immunolocalization of P450c17 and P450arom, and androgen and estrogen may play an important role in the spermatogenesis and testicular recrudescence and regression process. PMID- 20197645 TI - AT cells show dissimilar hypersensitivity to heavy-ion and X-rays irradiation. AB - Ataxia telangiectasia (AT) cells, with their defective double-strand break (DSB) repair processes, exhibit high sensitivity to low-LET radiation such as X-rays irradiation and gamma beams. Since heavy ion beam treatment for cancer is becoming increasingly common in Japan and elsewhere, it is important to also determine their sensitivity to high-LET radiation. For this purpose we irradiated AT and normal human cells immortalized with the human telomerase gene using high- (24-60 keV/microm carbon and 200 keV/microm iron ions) or low-LET (X-rays) radiation in non-proliferative conditions. In normal cells the RBE (relative biological effectiveness) of carbon and iron ions increased from 1.19 to 1.81 in proportion to LET. In contrast, their RBE in AT cells increased from 1.32 at 24 keV/microm to 1.59 at 40 keV/microm, and exhibited a plateau at over 40 keV/microm. In normal cells most gamma-H2AX foci induced by both carbon- and iron ion beams had disappeared at 40 h. In AT cells, however, a significant number of gamma-H2AX foci were still observed at 40 h. The RBEs found in the AT cells after heavy-ion irradiation were consistent with the effects predicted from the presence of non-homologous end joining defects. The DSBs remaining after heavy ion irradiation suggested defects in the AT cells' DSB repair ability. PMID- 20197646 TI - Investigation of activation rate uniformity in a prompt-gamma rays IVNAA facility. AB - The preliminary design studies for developing a prompt-gamma rays in vivo neutron activation analysis facility are in construction at Neutron Activation Research Centre of Ferdowsi University of Mashhad. In this work, activation rate distribution is studied in different bilateral configurations in order to reduce the CV of activation rate distribution throughout the body to less than 10%. It means that the maximum RMS deviation from the mean value of distribution must be smaller than 0.5%. The best case includes two pairs of (241)Am-Be neutron sources. Each pair (with 70 cm distance between two sources) is positioned within up and down 40 x 110 cm(2) area graphite collimators. Also, four moderator/reflector objects are added to transversal body surfaces with 5 cm thick water and 3 cm thick graphite. The proper thickness of polyethylene pre moderators is chosen 8 mm. The RMS deviation of distribution is 0.3% with the mean activation rate of 1.85 x 10(-6) cm(-3). PMID- 20197647 TI - Low dosage of rasagiline and epigallocatechin gallate synergistically restored the nigrostriatal axis in MPTP-induced parkinsonism. AB - BACKGROUND: The anti-Parkinson monoamine oxidase B inhibitor rasagiline appears to be the first neuroprotective disease-modifying therapy in early-stage Parkinson's disease (PD). OBJECTIVE: Using a polypharmacy paradigm, we tested whether the distinct neuroprotective pharmacological profile of rasagiline would complement that of (-)-epigallocatechin-3-gallate (EGCG), the main antioxidant/iron chelator polyphenol constituent of green tea, and restore the neuronal loss and molecular targets damaged in animal parkinsonism. METHODS/RESULTS: We show by high-performance liquid chromatography, immunohistochemistry and Western blot analyses that the combination of rasagiline and EGCG, at subliminal doses which have no profound protective effect, acts synergistically to restore the nigrostriatal axis in N-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-treated mice. A detailed analysis revealed a complementary action of these drugs, differentially acting at MPTP-injured molecules/targets in the substantia nigra (SN): induction of brain-derived neurotrophic factor by rasagiline, increased membranal levels of the protein kinase C alpha-isoform by EGCG and a synergistic replenishment of their downstream effector, the serine/threonine kinase Akt/protein kinase B, suggesting that this kinase might represent one point of convergence of the distinct mechanisms of action of the drug cocktail. CONCLUSION: These results provide molecular evidence that activation of multiple brain targets by the combination of rasagiline and EGCG may synergistically contribute to the rescue of the dopamine neurons in the SN and replenishment of striatal dopamine. This may have important implications for rasagiline-treated PD patients who could further benefit from an adjunct administration of EGCG. PMID- 20197649 TI - Glutamate dehydrogenase activity in leukocytes and ageing. AB - BACKGROUND: Glutamate dehydrogenase (GLDH) is an intracellular enzyme normally located in mitochondria and the rough endoplasmic reticulum. The metabolism of neuroexcitotoxic glutamate is lowered in many neurodegenerative disorders. OBJECTIVE: Defining the GLDH activity in leukocytes can provide indirect data about neurodegenerative processes in the brain. METHOD: We have developed our own method of defining the GLDH activity in leukocytes. RESULTS: The GLDH activity was researched in the leukocytes of 130 healthy subjects (45 females, 85 males). The mean catalytic activity was 0.618 +/- 0.380 mu kat/g. The highest values were discovered in <30-year-old persons: 0.772 +/- 0.434 mu kat/g (0.712 +/- 0.406 mu kat/g in men, 0.934 +/- 0.5 mu kat/g in women). The GLDH activity decreases more slowly in the 30- to 60-year age group, yet evidently more rapidly afterwards, particularly in men, where the activity drops to 0.333 mu kat/g and in women to 0.414 mu kat/g. The older persons had a lower leukocyte GLDH activity than the younger ones (ANOVA, p = 0.000). CONCLUSION: Gradual decrease in GLDH activity may be one of the key factors for neurodegenerative ageing processes. PMID- 20197648 TI - Improved synthesis of ADAM10 inhibitor GI254023X. AB - BACKGROUND: The metalloproteinases ADAM10 and ADAM17 are involved in various diseases: neurodegeneration, cancer and inflammation. OBJECTIVE: The inhibition of these proteases is a promising target in the treatment of inflammation and cancer. METHODS AND RESULTS: In this study, we present an improved synthesis of the ADAM10 reference inhibitor GI254023X with a higher overall yield, enhanced detection ability and increased acid stability, providing easier handling. CONCLUSION: This upscaled synthesis, free of diastereomeric intermediates, ensures single-batch identity, thus warranting its reproducibility in further biological investigations. PMID- 20197650 TI - TDP43-positive intraneuronal inclusions in a patient with motor neuron disease and Parkinson's disease. AB - BACKGROUND: The role of the 43-kDa transactivation-responsive DNA-binding protein (TDP43) in neurodegenerative diseases is not yet clearly established. OBJECTIVE: To assess for the first time the presence of TDP43 in a patient with motor neuron disease (MND) and Parkinson's disease (PD). METHODS: A 78-year-old woman developed poorly dopa-responsive parkinsonism without cognitive alteration. Three years later, MND appeared and led to death in less than a year. Neuropathologic examination was performed. RESULTS: We observed the presence of PD and MND lesions with TDP43-positive cytoplasmic inclusions in the spinal cord and bulbar nuclei but not in the dentate gyrus and neocortex. The MND was characterized by a severe degeneration of bulbar and cervical lower motor neurons. Numerous senile plaques and topographically limited neurofibrillary tangles were also observed. CONCLUSION: The mechanisms underlying the rare co-occurrence of PD and MND are still unclear. The assessment of an abnormal reactivity for TDP43 in our case might gain more insight into the pathophysiology of this association of two diseases. Further studies are needed to confirm these findings and to understand the role of TDP43 in neurodegenerative diseases. PMID- 20197651 TI - Anakinra for difficult-to-treat neutrophilic panniculitis: IL-1 blockade as a promising treatment option for neutrophil-mediated inflammatory skin disease. AB - The treatment of neutrophilic panniculitis can be challenging. We report a patient with a difficult-to-treat neutrophilic panniculitis who had a spectacular response to a short treatment course with the IL-1 antagonist anakinra. A 61-year woman had a 12-year history of a serious febrile neutrophilic panniculitis and a personal history of steroid-induced pancreatitis and life-threatening methemoglobinemia under antimalarials and dapsone. When she developed a new flare, she was treated successfully with a 15-day course of subcutaneously administered injections of 100 mg anakinra. This observation is the first report attesting the efficiency of anakinra in neutrophilic panniculitis. It expands the potential indications of IL-1 inhibition in the field of the neutrophilic dermatoses, or more generally, in neutrophil-mediated systemic diseases. It underscores the potential pathogenic involvement of IL-1 in those diseases, a hallmark of autoinflammation, and supports their nosologic classification among diseases involving primarily the innate immune system. PMID- 20197652 TI - The ankle retinacula: morphological evidence of the proprioceptive role of the fascial system. AB - STUDY DESIGN: Research report. OBJECTIVES: To evaluate the anatomical characteristics of the ankle retinacula and their relationship with the fasciae and muscles in healthy subjects and in patients with ankle sprain outcomes. BACKGROUND: The role of the retinacula in proprioception has begun to emerge, but without clear anatomical bases or descriptions of their possible damage in patients with ankle sprain outcomes. METHODS: Dissection, histological and immunohistochemical analysis of 27 legs. An in vivo radiological study by MRI was also performed on 7 healthy volunteers, 17 patients with outcomes of ankle sprain, and 3 amputated legs. RESULTS: The retinacula are thickenings of the deep fascia presenting bone or muscular connections. They are formed of 2-3 layers of parallel collagen fibre bundles, densely packaged with a little loose connective tissue, without elastic fibres but many nervous fibres and corpuscles. By MRI, the retinacula appeared as low-signal-intensity bands with a mean thickness of 1 mm. In patients with outcomes of ankle sprain, MR findings were abnormal retinacula thickness, signal intensity, and full-thickness gap. DISCUSSION: The retinacula are not static structures for joint stabilisation, like the ligaments, but a specialisation of the fascia for local spatial proprioception of the movements of foot and ankle. Their anatomical variations and accessory bundles may be viewed as morphological evidence of the integrative role of the fascial system in peripheral control of articular motility. PMID- 20197654 TI - The mouse gene Noto is expressed in the tail bud and essential for its morphogenesis. AB - The mouse transcription factor Noto is expressed in the notochord and involved in its development. Noto mouse mutants, Noto(tc/tc)(truncate) and Noto(GFP/GFP) (Noto null mutant), exhibit a segmental lack of the notochord in the caudal part of the embryo and subsequent tail truncation in adult animals. In order to address the relationship between the tail bud (the undifferentiated mesenchymal cells in the tip of the embryo tail) and the caudal notochord, Noto(GFP/GFP), a loss- of-function mutant, was analyzed. Taking advantage of Noto(GFP/+) heterozygotes, we could track Noto-GFP-expressing cells from the tail bud over the tail cord to the caudal notochord, and confirm a morphological continuum from the tail bud mesenchyme to the caudal notochord. Loss of Noto affected tail bud morphogenesis: Noto-GFP-expressing cells were scattered in the tail bud mesenchyme. They segregated in the notochord-like structure within the medullary cord instead at the tail cord, which subsequently disappeared. In the tail cord, instead of the notochord, additional lumen of the tail gut was formed. These findings suggest that Noto is involved in both rearrangement and morphogenesis of the tail bud during notochord formation. PMID- 20197653 TI - Interwoven four-compartment capillary membrane technology for three-dimensional perfusion with decentralized mass exchange to scale up embryonic stem cell culture. AB - We describe hollow fiber-based three-dimensional (3D) dynamic perfusion bioreactor technology for embryonic stem cells (ESC) which is scalable for laboratory and potentially clinical translation applications. We added 2 more compartments to the typical 2-compartment devices, namely an additional media capillary compartment for countercurrent 'arteriovenous' flow and an oxygenation capillary compartment. Each capillary membrane compartment can be perfused independently. Interweaving the 3 capillary systems to form repetitive units allows bioreactor scalability by multiplying the capillary units and provides decentralized media perfusion while enhancing mass exchange and reducing gradient distances from decimeters to more physiologic lengths of <1 mm. The exterior of the resulting membrane network, the cell compartment, is used as a physically active scaffold for cell aggregation; adjusting intercapillary distances enables control of the size of cell aggregates. To demonstrate the technology, mouse ESC (mESC) were cultured in 8- or 800-ml cell compartment bioreactors. We were able to confirm the hypothesis that this bioreactor enables mESC expansion qualitatively comparable to that obtained with Petri dishes, but on a larger scale. To test this, we compared the growth of 129/SVEV mESC in static two dimensional Petri dishes with that in 3D perfusion bioreactors. We then tested the feasibility of scaling up the culture. In an 800-ml prototype, we cultured approximately 5 x 10(9) cells, replacing up to 800 conventional 100-mm Petri dishes. Teratoma formation studies in mice confirmed protein expression and gene expression results with regard to maintaining 'stemness' markers during cell expansion. PMID- 20197655 TI - Antenatal Sonography and MRI of Iniencephaly apertus and clausus. AB - Iniencephaly is a lethal and an extremely rare neural tube defect. It is characterized by fixed retroflection of the head, cervical dysraphism and occipital bone defect. Associated anomalies of the nervous and other systems are frequently present. Most cases are diagnosed prenatally by ultrasound. We report prenatal ultrasonographic, fetal MRI and pathological findings of 2 cases of iniencephaly (one each of iniencephaly apertus and clausus). PMID- 20197656 TI - Congenital giant cervical teratoma: pre- and postnatal imaging. AB - Pre- and postnatal imaging findings are presented in a fetus/neonate with congenital cervical teratoma (CCT). Prenatal fetal MRI proved to be essential in the exact localization and characterization of the CCT while excluding potentially life-threatening prenatal complications. The provided information improved outcome by guiding decisions concerning delivery and postnatal care. PMID- 20197657 TI - Impact of quality of nuchal translucency measurements on detection rates of trisomies 13 and 18. AB - OBJECTIVE: To determine the relative contribution of nuchal translucency (NT) to the biochemical detection rates of combined screening for trisomies 13 and 18 in two healthcare systems practicing different quality-control systems of nuchal measurement. METHODS: De-identified data collected from the Fetal Medicine Foundation in the United Kingdom and laboratory data from NTD laboratories in the United States were compared for detection rate and false-positive rate (FPR) for combined trisomies 13 and 18 screening and were subcategorized by biochemical only and biochemistry combined with NT measurement. RESULTS: US and UK biochemical detection rates were virtually identical: 83% for a FPR of 1.8%. When NT measurement was added, the US rate increased to 88% for a 0.7 FPR, but in the UK the rate increased to 94% for a FPR of 0.3%. The mean NT was 1.69 mm in the US and 2.82 mm in the UK. CONCLUSIONS: NT measurement as practiced in the UK system with tight quality control significantly increased the detection rate and significantly reduced the FPR of combined screening for trisomies 13 and 18, when compared to the US with apparently less rigid quality control. PMID- 20197658 TI - Gender difference in the prediction of weight loss by leptin among overweight adults. AB - BACKGROUND/AIM: Leptin plays an important role in energy metabolism. The primary objective of the study was to investigate whether baseline leptin levels predict weight loss during a dietary intervention in overweight and obese individuals. METHODS: A total of 324 individuals (138 men and 186 women, aged 20-40 years, BMI 27.5-32.5) were recruited in Iceland, Ireland and Spain. The intervention lasted for 8 consecutive weeks, and subjects were instructed to follow a diet, energy restricted by 30%. Anthropometric variables were assessed before and after the intervention. Leptin concentration was measured at baseline and corrected for fat mass. Linear models were used to find out which variables predicted weight loss. RESULTS: At end point, significant weight loss was observed (5.16 +/- 3.06 kg, p < 0.001). High baseline leptin concentrations were a significant negative predictor of weight loss in men (p = 0.028), with a predicted difference of 1.8 kg between the lowest and highest leptin quartile. CONCLUSION: Our study underlines the importance of leptin in energy metabolism. Plasma leptin concentrations at baseline are a predictor of weight loss in overweight men after an 8-week dietary intervention. The same effect was not observed in overweight women, which suggests that the role of leptin in the regulation of weight is gender specific. PMID- 20197659 TI - Pharmacokinetics and bioavailability of moxifloxacin in calves following different routes of administrations. AB - BACKGROUND: Moxifloxacin is a new fourth-generation 8-methoxy fluoroquinolone developed primarily for the treatment of community-acquired pneumonia and upper respiratory tract infections. The aim of the study was to investigate the plasma pharmacokinetics characteristic of moxifloxacin in calves, after intravenous, intramuscular and subcutaneous administration of a single dose. Meanwhile, plasma protein binding and bioavailability of moxifloxacin were also estimated. METHODS: Plasma concentrations of moxifloxacin were measured using a modified HPLC method, and the extent of plasma protein binding was determined in vitro using ultrafiltration. RESULTS: Following intravenous administration, the half life of elimination, the volume of distribution at steady state and the area under the curve were 3.29 h, 0.94 l/kg and 24.72 microg x h/ml, respectively. After intramuscular and subcutaneous administration of moxifloxacin at the same dose, the peak plasma concentrations were 2.41 and 2.20 microg/ml and were obtained at 1.54 and 1.59 h, respectively. The systemic bioavailabilities were 87.19 and 75.94%, respectively. The in vitro plasma protein binding of moxifloxacin in plasma of calves was 27%. CONCLUSION: A high peak plasma concentration, area under the curve, rapid absorption and bioavailability following intramuscular and subcutaneous administration characterize the pharmacokinetics of moxifloxacin in calves. PMID- 20197660 TI - Non-invasive measurement of cardiac output during atrial fibrillation: comparison between cardiac magnetic resonance imaging and inert gas rebreathing. AB - OBJECTIVES: Atrial fibrillation (AF) is one of the most frequent heart rhythm disorders. It potentially influences cardiac function and its measurement. Cardiac magnetic resonance imaging (CMR) has become the new gold standard for non invasive assessment of cardiac output (CO). A novel inert gas rebreathing (IGR) device based on the Fick Principle also proved promising in patients in sinus rhythm (SR). The aim of our study was to compare the agreement of non-invasive CO measurements between CMR and IGR in AF patients. METHODS: A total of 68 patients, 34 with AF and 34 pair-matched controls in SR, were included. RESULTS: Bland Altman analysis showed good agreement between both methods, with an average deviation of 0.2 +/-1.2 l/min in the AF group versus 0.3 +/-1.0 l/min in the SR group (p = 0.77). IGR demonstrated good agreement for CO between 2.0 and 5.4 l/min. However, in hyperdynamic circulatory conditions (CO >5.5 l/min), the increasing disagreement of IGR and CMR measurements reached statistical significance. CONCLUSIONS: Non-invasive CO measurements using CMR and IGR are feasible in patients suffering from AF. Good agreement was found between the two methods in an unselected cohort. Hyperdynamic circulatory conditions can lead to significant measurement differences which, however, do not affect the reproducibility of IGR. PMID- 20197661 TI - Hydrogen breath test--diet and basal H2 excretion: a technical note. AB - BACKGROUND: Hydrogen breath tests are widely used in clinical practice. For a correct evaluation of data, low basal H2 excretion is required, thus, 12-hour fasting is usually prescribed. An additional reduction in the intake of complex carbohydrates in the preceding 24 h is suggested in some centers. The issue, however, has never been directly investigated. AIM: The aim of the present study was to analyze the effect of the pretest diet on the basal H2 excretion and the number of subjects excluded from the test due to high basal H2 excretion. METHODS: Two cohorts of 500 consecutive patients undergoing a lactose tolerance test in the years 1997-1998 (when 12-hour fasting was required) and in 2007-2008 (when a low-carbohydrate diet in the preceding 24 h was also prescribed) were retrospectively reviewed. RESULTS: The mean basal H2 excretion was significantly lower (p < 0.0001) in the low-carbohydrate diet group (2.46 +/- 6.8 vs. 4.73 +/- 3.3 ppm). In 1997-1998, 46/500 patients (9.2%) were excluded from the test due to basal H2 values as compared to 7/500 (1.4%) in the period 2007-2008. DISCUSSION: To the best of our knowledge, ours is the first study to provide objective data on the advantage offered by reducing the intake of complex carbohydrates before H2 breath tests. PMID- 20197662 TI - Suicide attempts after subthalamic nucleus stimulation for Parkinson's disease. AB - A higher risk of suicidal attempt after subthalamic nucleus deep brain stimulation (STN-DBS) for Parkinson's disease (PD) has been consistently reported. We retrospectively analyzed 3 PD patients with suicide attempts after STN-DBS. All patients had normal pre- and immediate postoperative psychopathological and cognitive evaluations, with STN-DBS yielding a good motor benefit. Levodopa medication was markedly reduced. Albeit there was a significant reduction in dopaminergic medication, there was also a considerable time lag to suicide attempt. Impulsive behavior could have played a higher role, going unnoticed in punctual psychopathological examinations. STN-DBS patients need a closer postoperative psychiatric and behavioral follow-up. PMID- 20197663 TI - Neurological symptoms accompanying urinary tract infections. AB - The spectrum of para-infectious neurological symptoms was examined by a retrospective study of 57 patients admitted with acute neurological symptoms which were eventually interpreted as secondary to urinary tract infection. The symptoms encountered most frequently were confusion, gait disturbances, and drowsiness. Patients with Parkinson's disease, multiple sclerosis or a previous stroke often experienced a deterioration of their preexisting neurological deficits. We suggest that para-infectious encephalopathy (PE) is a mild form of septic encephalopathy with a distinct clinical pattern. PMID- 20197664 TI - Cross-amplified polymorphic microsatellites for Campbell's monkey. AB - Population genetic analyses are of considerable importance for conservation strategies to protect endangered primates. We tested microsatellites of human origin with an aim to understand the genetic diversity of a West African forest guenon, Campbell's monkey, Cercopithecus campbelli. Twelve markers amplified successfully, were polymorphic and were inherited in a Mendelian fashion in a group of 4 individuals kept in captivity. These 12 markers were further amplified from 35 faecal samples collected in Tai National Park. These samples proved to originate from 18 free-ranging monkeys and showed that the 12 markers we developed for this species are polymorphic and suitable for future population genetic and parentage analyses. PMID- 20197666 TI - GH/IGF-I regulation in obesity--mechanisms and practical consequences in children and adults. AB - Growth hormone (GH) secretion in children and adults is profoundly, but reversibly, suppressed in obesity. Since GH deficiency leads to increased fat mass, differentiation of both conditions remains challenging. Here we review the known and still speculative mechanisms underlying the inhibitory effects of obesity on GH secretion including peripheral factors like IGF-I and insulin, as well as central hypothalamic/pituitary modulators. We further discuss the basis of current testing for GH deficiency in obesity and the validity of the various provocative tests in overweight subjects. PMID- 20197665 TI - Maternal serum ADAM12 levels correlate with PAPP-A levels during the first trimester. AB - BACKGROUND: We wished to investigate the correlation between a new Down screening marker ADAM12 (a disintegrin and metalloproteinase-12) and pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotropin (fbeta-hCG) during the first trimester of pregnancy. METHODS: ADAM12, PAPP-A and fbeta-hCG were measured in 225 serum samples of randomly chosen pregnancies with completely normal outcome. The samples were taken between pregnancy weeks 9+0 and 12+6. RESULTS: The ADAM12 levels tended to increase with advanced gestational age and the highest levels were detected at pregnancy week 12. The ADAM12 levels correlated with PAPP-A levels. After weight correction and logarithmic transformation the multiples of median (MoM) of ADAM12 still correlated with the MoMs of PAPP-A and also with the MoMs of fbeta-hCG. Smokers had lower ADAM12 levels than non-smokers. CONCLUSION: The secretion of ADAM12 seems to resemble the secretion of PAPP-A in the end of the first trimester. Accordingly ADAM12 appears not to be a separate marker independent of PAPP-A. It remains to be assessed whether adding ADAM12 in Down screening risk calculation will reduce the false positive rate during the first trimester of pregnancy. PMID- 20197667 TI - Hormones and genes of importance in bone physiology and their influence on bone mineralization and growth in Turner syndrome. AB - This mini review summarizes papers presented in a Joint Symposium between the Bone, Growth Plate and Turner Syndrome Working Groups of the European Society for Paediatric Endocrinology (ESPE) that was held on September 9, 2009, in New York.The program had been composed to give an update on hormones and genes of importance in bone physiology and their influence on bone mineralization and growth in Turner syndrome. This paper summarizes the data and highlights the main topics and discussions related to each presentation. PMID- 20197668 TI - Sex hormones, insulin resistance and high-density lipoprotein cholesterol levels in children. AB - Cardiovascular risk starts early in life; therefore, it is of interest to clarify the relation between puberty, sex hormones, insulin resistance and lipid levels in children. This is a cross sectional study of 365 school students (8-18 years of age). We analyzed the associations of sex hormones (testosterone, free androgen index, estradiol, free estradiol index) and sex hormone-binding globulin (SHBG) with insulin resistance and lipid levels. Analyses were performed in prepubertal versus adolescent girls and boys. Among prepubertal boys, estradiol was significantly associated with increased log homeostasis model assessment estimated insulin resistance (HOMA-IR; B = 0.9, model R(2) = 0.62, p < 0.001) and insulin levels (B = 0.8, model R(2) = 0.58, p < 0.001). Testosterone was associated with increased high-density lipoprotein cholesterol (HDL-C) levels among prepubertal boys (B = 10, model R(2) = 0.42, p = 0.04). Among adolescent girls, SHBG was significantly associated with decreased HOMA-IR (B = -0.8, model R(2) = 0.34, p = 0.01) and insulin levels (B = -0.7, model R(2) = 0.34, p = 0.01). SHBG was also related to increased HDL-C levels among prepubertal (B = 24, model R(2) = 0.42, p = 0.047) and adolescent girls (B = 21, model R(2) = 0.44, p = 0.002). In conclusion, sex hormone levels and SHBG have important effects on HDL-C and insulin resistance among children and adolescents. PMID- 20197669 TI - Analyses of treatment variables for patients with childhood craniopharyngioma- results of the multicenter prospective trial KRANIOPHARYNGEOM 2000 after three years of follow-up. AB - BACKGROUND: Controversies surround various treatment variables for patients with childhood craniopharyngioma such as growth hormone (GH) replacement, which some believe can exacerbate recurrence/progression. We prospectively assessed the risk of tumor recurrence/progression in survivors of childhood craniopharyngioma. METHODS: Multivariable analyses of risk factors (age at diagnosis, degree of resection, irradiation, GH treatment and gender) and descriptive analyses of overall survival (OS) and event-free survival (EFS) rates were performed in 117 patients, recruited prospectively and evaluated after 3 years of follow-up in the German, Austrian and Swiss multicenter trial KRANIOPHARYNGEOM 2000. RESULTS: We observed a 3-year OS of 0.97 and a 3-year EFS of 0.46, indicating high recurrence rates after complete resection (CR) (n = 47; 3-year-EFS: 0.64) and high progression rates after incomplete resection (IR) (n = 64; 3-year EFS: 0.31). The risk of an event decreased by 80% after CR compared to IR (hazard ratio = 0.20; p < 0.001). Irradiation had protective effects on EFS: irradiated patients had an 88% lower risk of recurrence/progression compared to patients without/before irradiation (hazard ratio = 0.12; p < 0.001). GH treatment had no impact on 3 year EFS rates. CONCLUSIONS: Tumor recurrences/progressions are frequent and occur early after initial treatment of childhood craniopharyngioma. A radical resection preserving the integrity of hypothalamic structures appears optimal at original diagnosis. Irradiation was efficient in preventing recurrences/progressions. GH treatment had no impact on the low 3-year EFS observed in our study. However, further conclusions on the influence of GH on recurrence rates have to be refined to long-term follow-up studies of patients with childhood craniopharyngioma. PMID- 20197670 TI - Metabolic syndrome in children: comparison of the International Diabetes Federation 2007 consensus with an adapted National Cholesterol Education Program definition in 300 overweight and obese French children. AB - BACKGROUND/AIMS: Former definitions of metabolic syndrome (MS) in children have been adapted from adult MS definitions using age-related thresholds for each biochemical component, whereas the International Diabetes Federation (IDF) definition is based on absolute values. We compared the IDF childhood MS definition (IDF-MS) to the adapted National Cholesterol Education Program (adapted-NCEP) definition in overweight children. METHODS: 300 overweight and obese children were included with a median age of 11 years and BMI SDS of +4.7. RESULTS: Below 10 years of age, the frequency of MS according to the adapted-NCEP MS definition was 18.6%, and 86.1% had abdominal obesity. In children aged 10 to <16 years (n = 214), the frequency of IDF-MS was 8.9% compared to 14.5% by adapted-NCEP. IDF-MS children had a larger waist circumference, and higher triglycerides, fasting insulin and tended to be older than the intermediate severity group of children with MS only according to adapted-NCEP. Children with MS only according to adapted-NCEP (IDF-MS negative), differed from non-MS children in systolic blood pressure, triglycerides and high-density lipoprotein cholesterol. CONCLUSIONS: The recent IDF-MS criterion in children represents a more severe definition and appears to identify a group of children with higher fasting insulin than the adapted-MS definition which uses age-related thresholds (90th percentile). PMID- 20197671 TI - Hyperprolactinemia: different clinical expression in childhood. AB - BACKGROUND: Hyperprolactinemia is the most common disturbance in pituitary gland secretion. Functional diversity of prolactin action is responsible for different initial clinical expressions of hyperprolactinemia. PATIENTS AND METHODS: We investigated causes of hyperprolactinemia in 11 children and adolescents (6 females and 5 males), aged from 1.5 to 17.5 years. Children with primary hypothyroidism, iatrogenic hyperprolactinemia and adolescents with polycystic ovaries were excluded. RESULTS: Four patients had short stature or growth deceleration, the same number were clinically obese, 2 adolescent girls had secondary amenorrhea, 1 girl had premature thelarche and gynecomastia, and hypogonadism was the indication for the endocrinologic examination of two adolescent boys. Delayed pubertal development was present in both sexes. Hyperprolactinemia was also found in the youngest girl with multiple ovarian cysts. A very high prolactin (PRL) level was documented in the PRL profile of all patients (mean 2,553.00 +/- 1,020.97 mU/l). MRI of the pituitary was indicated and revealed 4 microprolactinomas, one congenital hypophyseal cyst and one tumor of the hypothalamus. Dopamine agonist treatment was efficacious in almost all the patients. CONCLUSION: Hyperprolactinemic children expressed a wide variety of initial clinical presentations. The most common were growth and puberty disorders and obesity. PRL determination should be included in investigation protocols of obese and short stature children. PMID- 20197672 TI - Thyroid function in obese children and adolescents. AB - OBJECTIVE: Obesity is frequently associated with modifications of thyroid size and function. We evaluated the prevalence of thyroid function abnormalities and the effects of puberty and weight loss in obese children and adolescents. METHODS: We examined 468 obese children (255 girls and 213 boys aged 3.7-17.9 years) and 52 normal-weight age-matched children as controls. TSH, fT3, fT4, fasting serum insulin and glucose were measured at baseline. fT3, fT4 and TSH were also measured after 6 months of lifestyle intervention in a subset of 43 patients. RESULTS: 109 obese children showed abnormal circulating thyroid hormone concentrations (84 had elevated fT3 levels, 15 elevated TSH, 6 elevated fT4, 3 elevated fT3 and TSH, and 1 elevated fT3, fT4 and TSH levels). Serum TSH and fT3 concentrations were positively correlated with BMI-SDS. The prevalence of patients with abnormal thyroid hormone concentrations was similar between sexes and between prepubertal and pubertal subjects. After 6 months of lifestyle intervention, thyroid hormone concentrations normalized in 27 of the patients with decreased BMI-SDS, and in 2 patients in whom BMI-SDS increased. CONCLUSIONS: In obese children, an increased fT3 concentration is the most frequent thyroid function abnormality. Serum fT3 and TSH correlate with BMI. Moderate weight loss frequently restores these abnormalities. PMID- 20197673 TI - Clinical, genetic and functional characteristics of three novel CYP17A1 mutations causing combined 17alpha-hydroxylase/17,20-lyase deficiency. AB - BACKGROUND: P450c17 has two distinct activities: 17alpha-hydroxylase activity and 17,20-lyase activity. Combined 17alpha-hydroxylase/17,20-lyase deficiency leads to a severe defect in the production of cortisol and sex steroids. In affected males this results in impaired masculinization with ambiguous or female external genitalia. Female patients have normal genitalia but show a lack of pubertal development in adolescence. An increased production of mineralocorticoids often leads to hypertension and hypokalemia in both sexes. METHODS: To better understand the mechanisms of P450c17 deficiency, we studied 2 patients (both 46,XY) with combined 17alpha-hydroxylase/17,20-lyase deficiency of different severity: one with complete lack of masculinization and one with ambiguous genitalia. RESULTS: Four mutations were identified by sequencing of the CYP17A1 gene: I332T and A355T in the less severely affected patient; G111S and R440H in the patient with complete lack of masculinization. The three novel mutations were expressed in COS1 cells and all mutant proteins except I332T showed a complete loss of both enzymatic activities. I332T retained some residual 17alpha hydroxylase as well as 17,20-lyase activity. CONCLUSION: We identified 2 patients with the phenotypical spectrum of P450c17 deficiency. Three novel mutations in the CYP17A1 gene were identified and their functional characterization provided a good phenotype-genotype correlation. The location of the mutated residues in the three-dimensional model of P450c17 gave some additional insights into its structure-function relationship. PMID- 20197674 TI - Magnetic resonance imaging and pituitary function in children with panhypopituitarism. AB - BACKGROUND: To explore the relationship between magnetic resonance imaging (MRI) findings and multiple pituitary-target hormones in patients with panhypopituitarism or multiple pituitary hormone deficiency (MPHD). METHODS: 125 patients with MPHD (102 boys, MPHD group) and 90 age-, sex- and Tanner stage matched normal children (control group) were enrolled. 96 of the patients with MPHD underwent MRI scans of the hypothalamic-pituitary area. The patients were subdivided into five stages according to their MRI findings. The serum concentrations of GH, IGF-1, FT(4), TSH, ACTH, cortisol, FSH, LH, prolactin, testosterone and estradiol were measured in patients and in controls. RESULTS: MRI stage was significantly positively correlated with the number of pituitary hormone deficiencies (r = 0.9, p < 0.001). MRI stage was negatively correlated with peak GH, IGF-1, FT(4), cortisol and anterior pituitary height (r = -0.43, 0.47, -0.67, -0.54, and -0.49, respectively, p < 0.01). Diabetes insipidus patients could be stratified according to their MRI stage; diabetes insipidus was found mainly in patients with absence of the posterior pituitary bright spot or small ectopic posterior pituitary bright spot on MRI. CONCLUSION: An abnormal MRI finding is evidence of MPHD and, correspondingly, there is a noteworthy correlation between MRI and pituitary function. PMID- 20197675 TI - Tall stature and gonadal dysgenesis in a non-mosaic girl 45,X. AB - Turner's syndrome, also known as 'monosomy X', is a genetic disorder that occurs in 1/2,500 female births and is hypothesized to result from haploinsufficiency of certain genes expressed from both sex chromosomes that escape X inactivation. While the classic karyotype related to Turner's syndrome is 45,X, the majority of those affected actually have a mosaic chromosomal complement, most often with a second normal cell line (46,XX). The resulting phenotype is variable and related to the underlying chromosomal pattern, but it is characterized by three cardinal features: short stature (around 100%), ovarian failure (>90%) and congenital lymphedema (>80%). In this paper we report a molecular and cytogenetic investigation of a 26-year-old female with non-mosaic 45,X karyotype, who has a stature of 170 cm without GH treatment, and whose only apparent Turner feature is gonadal dysgenesis. The only possible explanation for the absence of Turner phenotype is the hidden mosaicism combined with an untreated gonadal dysgenesis. Our results support the theory that significant ascertainment bias exists in our understanding of Turner's syndrome. PMID- 20197676 TI - Unusual phenotypical variations in a boy with McCune-Albright syndrome. AB - BACKGROUND: McCune-Albright syndrome (MAS) typically comprises the constellation of polyostotic fibrous dysplasia, cafe-au-lait spots, and associated endocrinopathies including gonadotropin-independent precocious puberty, excessive growth hormone production and gigantism, hyperthyroidism, and hyperparathyroidism. OBJECTIVE: We report the unique case of a boy with the diagnostic criteria of MAS accompanied by atypical short stature and macroorchidism without precocious puberty. PATIENT: An 8.4-year-old prepubertal boy presented with a history of recurrent bone fractures, multiple cafe-au-lait spots, bilateral macroorchidism, and short stature. X-ray of the extremities was consistent with polyostotic fibrous dysplasia. Serum inhibin B (IB) and anti mullerian hormone (AMH) were elevated; testosterone, LH, and FSH were normal for age. RESULTS: PCR-based DNA analysis of bone tissue revealed a substitution of arginine for cysteine at position 201 in the G(s)alpha protein resulting in activation of the G(s)alpha subunit. CONCLUSIONS: We report a second case of MAS associated with macroorchidism. In this case, isolated Sertoli cell hyperfunction was also associated with microlithiasis and was not associated with peripheral precocious puberty. Short stature not associated with GH-IGF-1 axis abnormality was a second anomalous finding in this case. Our experience suggests that the phenotypic variation in MAS is wider than previously described. PMID- 20197677 TI - Development of an e-learning portal for pediatric endocrinology: educational considerations. AB - BACKGROUND: Global accessibility and dissemination of developments in pediatric endocrinology prompted to examine how to develop an educational interactive e-SPE web portal. METHODS: A systematic approach was used to identify the relevant aspects of accessibility and dissemination. An orientation at the big idea was made, executed by an analysis of the needs of student and teacher pediatric endocrinologists, a definition of the learning objectives, a research in educational literature and an exploration of ICT design specifications. RESULTS: The intensive collaboration between medical, educational and information technology disciplines resulted in a portal design. The portal meets requirements of adult learning, stresses interaction between partners in learning and offers direct feedback during the learning process. The portal supports the development of not only knowledge but also competences both at junior and advanced levels. CONCLUSION: When the e-SPE portal is completed, the options for summative assessment will be examined as a medium for international certification in conjunction with local and national requirements (http://espe.elearning.nl). PMID- 20197678 TI - Characteristics and prognosis of childhood atopic dermatitis: a multicenter study in Turkey. AB - BACKGROUND: Childhood atopic dermatitis (AD) is classically accepted as initial finding of atopic march; however, nonatopic cases do not follow this course. The aim of this study was to determine the characteristics and prognosis of AD in childhood in Turkey. METHODS: The study included 531 children with AD that presented to pediatric allergy departments in 11 different regions of Turkey. Age at diagnosis, total serum and inhalant-specific immunoglobulin E (IgE) levels and allergen skin prick test results were recorded retrospectively. Clinical characteristics like additional allergic diseases at presentation or during follow-up were recorded as well as duration of follow-up. RESULTS: Mean age at diagnosis was 37.8 +/- 36.2 months. Mean IgE level was 318.3 +/- 677.8 IU/ml (median 100 IU/ml). Skin prick tests yielded positive results in 47% of children. At presentation, 31.6% of children reported additional allergic disease, while 11.7% developed allergic disease during follow-up. Among all, 46.6% had additional allergic disease at any point. IgE levels were significantly higher in children with additional allergic diseases (p = 0.001). Allergen skin prick test positivity and family history of allergic diseases increased the risk of additional allergic diseases significantly (OR = 3.90, 95% CI = 2.3-6.6 and OR = 1.89, 95% CI = 1.3-2.8, respectively). CONCLUSIONS: Allergic sensitization is not present in all cases of AD. Coexistence of additional allergic diseases is not as high as expected but more common in children who have been demonstrated to have atopic sensitization with high IgE levels and allergen skin prick test positivity. PMID- 20197679 TI - Prevalence of Tyrophagus putrescentiae hypersensitivity in subjects over 70 years of age in a veterans' nursing home in Taiwan. AB - BACKGROUND: Domestic mites are present in house dust samples throughout the world. Reports have shown a high prevalence of Tyrophagus putrescentiae (Tp) sensitization in Europe and Asia, and its importance and clinical relevance in elderly subjects have grown rapidly. The main objective of this study was to investigate the prevalence of Tp sensitization in elderly subjects in a veterans' nursing home using mite allergen extracts and recombinant allergens. METHODS: A total of 199 subjects were enrolled in this study: 112 elderly subjects from a nursing home and 87 healthy young adults from the hospital staff as controls. The prevalence of Tp hypersensitivity was determined by specific IgE measurements and basophil histamine release. Immunoblotting with or without inhibition with Dermatophagoides pteronyssinus (Dp) was performed to identify the major allergens and species-specific allergen to Tp. RESULTS: It was determined that 39.3% (44/112) of the elderly population were sensitized to Tp and 17.9% (20/112) to Tp alone. There was a significantly higher prevalence of Tp hypersensitivity in elderly subjects in comparison with the young adult population. In the age association study of Tp and Dp sensitization, the elderly subjects were more sensitized to Tp than to Dp (p = 0.02). Among the elderly subjects with chronic obstructive pulmonary disease (COPD) 45.8% (11/24) were Tp sensitive. The major allergens, Tyr p 2 and Tyr p 3, were identified with molecular weights of 16 kDa (53%) and 26 kDa (50%) as determined by ELISA and immunoblot inhibition analyses. CONCLUSION: The prevalence of Tp sensitization was higher in elderly subjects, especially in patients with COPD. The high percentage of IgE-binding components to the allergens Tyr p 2 and Tyr p 3 indicated that both allergens may play a role in the pathogenesis of IgE-mediated allergic diseases in elderly populations. PMID- 20197680 TI - Concordance of lateral flow and skin prick tests in the assessment of allergen sensitisation in the epidemiological field in children. AB - BACKGROUND: A new lateral flow test (LFT) for office use provides information about sensitisation to common allergens. Concordance between LFT and skin-prick test (SPT) has not been assessed in epidemiological studies. The aim of this study is to determine LFT-SPT concordance in this field. METHODS: Plasma samples (n = 270) from children aged 9-12 years previously SPT tested were used for the analysis. We selected 180 samples from children SPT positive to any of the 6 allergens which were common to SPT and LFT (cat, birch, timothy-grass, olive, pellitoryand Dermatophagoides pteronyssinus), and 90 samples from children SPT negative. The intensity of the LFT colour line which indicates a positive reaction was rated from 0 to 4. RESULTS: Only results on cat, olive and D. pteronyssinus were analysed, as only these had an acceptable number of individuals. When atopy was defined as at least 1 wheal with a mean diameter > or =3 mm, agreement was excellent (Cohen's kappa = 0.81) when a lightly visible line was considered positive in the LFT, and dropped substantially (Cohen's kappa = 0.68) when this value of LFT was considered negative. The correlation between the SPT wheal diameter and the intensity of the LFT line was 0.71 for cat, 0.81 for olive and 0.78 for D. pteronyssinus. CONCLUSIONS: As compared to SPT, LFT is a reliable method to screen for sensitisation to cat dander, olive pollen and D. pteronyssinus in the epidemiological field among schoolchildren. There is a good correlation between the SPT wheal diameter and the intensity of the LFT line. PMID- 20197681 TI - Two newly diagnosed HLA class II-deficient patients identified by rapid vector based complementation analysis reveal discoordinate invariant chain expression levels. AB - BACKGROUND: Primary immunodeficiencies represent the 'molecular Achilles' heels' of human immunity. Detailed analyses of primary immunodeficiencies extend our knowledge of pivotal immunological processes, lead to novel diagnostic algorithms and shorten the time to diagnosis. METHODS: Clinical/immunological phenotypes of 2 unrelated patients from Austria with combined immunodeficiency were determined. Leukocyte subpopulations of these patients, their parents and healthy controls were analyzed by flow cytometry. Patient-derived Epstein-Barr virus (EBV) transformed B cell lines were established and complemented by candidate cDNAs. Suspected mutations were confirmed by DNA sequencing. RESULTS: Phenotyping revealed a lack of constitutive human leukocyte antigen (HLA) class II expression on antigen-presenting cells of both patients, compatible with MHC class II deficiency. Rapid vector-based complementation analysis of the patients' B cells identified HLA class II transactivator (CIITA) deficiency in patient VIP1 and regulatory factor X (RFX)AP deficiency in patient VIP2. CIITA deficiency was caused by a homozygous p.Glu381X mutation. RFXAP deficiency resulted from a homozygous p.Ser123ThrfsX15 mutation, not described in the Middle European population so far. Of note, HLA class II-associated invariant chain (Ii) expression levels were significantly reduced in VIP1 and 3 additional EBV transformed B cell lines of CIITA-deficient patients but normal in EBV transformed B cells from VIP2. In addition, peripheral blood B cells from the parents of VIP1 showed significantly reduced HLA-DR and -DP expression levels compared to healthy controls. CONCLUSIONS: Analysis of patients' intracellular Ii and their parents' surface HLA class II expression levels might help to identify CIITA-deficient patients already during initial phenotyping. PMID- 20197682 TI - Autoimmune response of IgE antibodies to cellular self-antigens in systemic Lupus Erythematosus. AB - BACKGROUND: Systemic lupus erythematosus (SLE) patients may exhibit high total IgE and antinuclear IgE antibodies (ANA-IgE). Here, we investigated the specificity of ANA-IgE in SLE patients and the involvement of cytokines in this immune response. METHODS: Sera from 92 SLE patients and 68 healthy controls were evaluated for the presence of antinuclear IgE antibodies by immunoperoxidase with HEp-2,000(R) cells and immunoblotting with IgG-depleted sera. Total IgE, IgE specific to allergens, and serum cytokine levels were determined by ELISA. RESULTS: Antinuclear IgE antibodies were detected only in SLE patients (29/92, 31.5%). High total IgE was associated with ANA-IgE (p < 0.0001), but was not associated with IgE antibodies to allergens. In the immunoblotting, ANA-IgE reacted with nucleosomes (23/29, 79.3%), dsDNA (14/29, 48.3%), SS-A/Ro (14/29, 48.3%), SS-B/La (2/29, 18.7%), Sm (14/29, 48.3%) and RNP (18/29, 62.1%). Patients with ANA-IgE had very low serum IL-4, less IL-5 than controls (p < 0.05), more IL 10 than seronegative patients (p < 0.05), and unaltered IFN-gamma levels. The IL 5/IL-10 ratio was lower in ANA-IgE seropositive patients in comparison with either seronegative patients (p < 0.05) or healthy controls (p = 0.001). Controls displayed higher IL-5/IFN-gamma ratios than either SLE patients with ANA-IgE (p < 0.05) or patients without these immunoglobulins (p < 0.01). CONCLUSIONS: We conclude that IgE antibodies against cell autoantigens involved in protein expression, cellular proliferation, and cell death are present in patients with SLE. Interleukin-10 seems to down-regulate this IgE autoimmune response in SLE. PMID- 20197683 TI - Disappearing myelodysplastic syndrome-associated hemolytic anemia in leukemic transformation. AB - BACKGROUND: Here we report 2 rare cases of acute myeloid leukemia (AML) complicated with hemolytic anemia limited to the myelodysplastic syndrome (MDS) stage, and disappearing in leukemic transformation. METHODS/RESULTS: A 66-year old man with MDS-RAEB-2 was admitted to hospital for severe anemia with increased reticulocyte counts. Hemolytic anemia was suspected, and it was ameliorated by methylprednisolone pulse therapy. Although anemia grew worse when steroids were tapered off, later improvement coincided with an increase in myeloblasts in the peripheral blood, i.e. with leukemic transformation. In another case, a 68-year old man was admitted to hospital when laboratory findings showed a white blood cell count of 24,800/microl with increased myeloblasts (62.5%), leading to the diagnosis of AML with multilineage dysplasia. Following a decrease in blasts due to anti-cancer drugs, supporting the MDS-RAEB-2 status, severe anemia with increased reticulocytes and positive direct antiglobulin test was diagnosed, suggesting the existence of autoimmune hemolytic anemia, which was then ameliorated by steroid therapy. CONCLUSIONS: The simultaneous loss of autoimmunity and leukemic cell expansion observed in our cases may possibly suggest a common underlying mechanism. PMID- 20197684 TI - Pharmacokinetic interaction between indinavir and darunavir with low-dose ritonavir in healthy volunteers. AB - OBJECTIVE: To investigate the potential for a pharmacokinetic interaction between darunavir (DRV, TMC114, Prezista), indinavir (IDV, Crixivan) and low-dose ritonavir (RTV, Norvir). METHODS: In three 7-day sessions, 17 HIV-negative healthy volunteers received treatment A (DRV/r 400/100 mg b.i.d.), treatment B (IDV/r 800/100 mg b.i.d.) and treatment C (DRV/r 400/100 mg b.i.d. + IDV 800 mg b.i.d.). On day 7, full pharmacokinetic profiles of DRV, IDV and RTV were determined. Safety and tolerability were also assessed. RESULTS: Based on the least-squares means ratios, the steady-state exposure (area under the curve, AUC(12h)) and plasma concentrations (C(min) and C(max)) of IDV were increased by 23, 125 and 8%, respectively, when DRV was co-administered. The co-administration of IDV with DRV/r resulted in increases of 24, 44 and 11% for, respectively, DRV AUC(12h), C(min) and C(max), compared with administration of DRV/r alone. Eight volunteers discontinued due to an adverse event. Overall, adverse events and laboratory abnormalities were more commonly reported during treatments including IDV. CONCLUSIONS: When used in combination with DRV/r, dose adjustment of IDV from 800 mg b.i.d. to 600 mg b.i.d. may be warranted in cases of intolerance. PMID- 20197685 TI - Immunocompromised patients with HBsAg a determinant mutants: comparison of HBsAg diagnostic assays. AB - Hepatitis B surface antigen (HBsAg) is considered the best marker for the diagnosis of hepatitis B virus (HBV) infection. Mutations of the s gene involving amino acid substitutions within the a determinant could affect the sensitivity of diagnostic tests. In the present study, HBsAg mutants were detected in 3 immunocompromised patients, previously found to be HBsAg negative and anti-HBs positive. All patients had high levels of HBV-DNA, whereas HBsAg tests gave discordant results. Immunosuppression can cause viral reactivation of occult HBV infection in these patients and favour the selection of HBsAg a determinant mutants. PMID- 20197686 TI - Extending combination therapy with peginterferon plus ribavirin for genotype 2 chronic hepatitis C virological responders: a pilot study of 7 cases. AB - OBJECTIVE: In treatment-resistant patients with genotype 2 chronic hepatitis C the suitable treatment duration is still unclear. The aims were to investigate extending combination therapy with peginterferon plus ribavirin for genotype 2. METHODS: 7 patients infected with genotype 2 at a high viral load and who did not achieve a sustained virological response (SVR) with the first course of 24-week IFN plus ribavirin were recruited into the study protocol with a total of 48 weeks of peginterferon plus ribavirin therapy. RESULTS: SVR was achieved in 5 of 7 patients (71%). All 4 patients (100%) who were in relapse with the first course achieved SVR. Only 1 of 3 patients (33%) who had a non-virological response (NVR) with the first course achieved SVR. All 4 patients who had an early virological response (EVR) with the first course achieved EVR and SVR. Two of 3 patients who had no EVR with the first course also did not achieve EVR and SVR. One patient who had no EVR or a NVR during the first course achieved EVR and SVR with the second course. CONCLUSIONS: Our results suggest that extending combination therapy for genotype 2 chronic hepatitis C might be useful for patients who relapse following 24-week combination therapy. PMID- 20197687 TI - Impact of mycophenolate mofetil on wound complications and lymphoceles after kidney transplantation. AB - BACKGROUND/AIMS: Despite improved efficacy, modern immunosuppressive agents may show unanticipated side effects. In this study we investigated the possible interactions of mycophenolate mofetil (MMF) with wound healing and lymphocele formation. METHODS: We conducted a retrospective single-center analysis in 144 patients receiving a cyclosporine A-based immunosuppression with prednisolone and either MMF (n = 77) or azathioprine (AZA, n = 77). Endpoints were incidences of lymphocele formation and non-primary wound healing during 6 months' follow-up. RESULTS: AZA-treated patients had more rejection episodes and consecutively more steroid pulses, both being potential risk factors for endpoints. No graft was lost in any group and graft function was comparable. AZA patients demonstrated a trend for more frequent wound infections. Fluid accumulation around the graft, however, was more frequent in the MMF group (OR = 2.6; p = 0.03). Consequently, more drainage maneuvers (17 vs. 5 interventions) and sclerotherapies (8 vs. 0 interventions) were undertaken in MMF patients. Pre-assigned risk factors for lymphoceles reported before did not differ between both cohorts; patients experiencing acute rejection episodes had even less symptomatic lymphoceles (n = 23). CONCLUSION: We found a possible relationship between the administration of MMF and lymphocele formation. To avoid the hazard of reinterventions, the prolongation of hospitalization and impairment of graft function, it requires awareness and attention in patients treated with this immunosuppressant. PMID- 20197688 TI - FPTIII mitigates peroxisome-mediated oxidative stress in kidneys of spontaneously hypertensive diabetic rats. AB - AIM: Peroxisomes are known to play a role in cellular oxidative stress during pathogenesis of diabetes and hypertension. We reported earlier that FPTIII (a farnesyl protein transferase inhibitor) attenuates ischemia-reperfusion injury and renal dysfunction in diabetic hypertensive (DH) rats. In this study, we have examined the effect of FPTIII on peroxisomal enzymes in relation to oxidative stress in kidneys of DH rats. METHODS: Male Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats were treated with streptozotocin (STZ) and/or FPTIII. Activities of key peroxisomal enzymes, catalase, acyl-CoA oxidase and beta oxidation of lignoceric acid were measured in kidney homogenates. Lipid peroxidation in kidney was measured by malondialdehyde (MDA) assay. RESULTS: Catalase activity was significantly (p < 0.01) reduced in diabetic WKY or SHR, and FPTIII markedly attenuated (p < 0.01) diabetes-induced inhibition of catalase. FPTIII also reduced STZ-induced increase in acyl-CoA oxidase activity. Fatty acid beta-oxidation and lipid peroxides were significantly increased in kidneys of DH rats. FPTIII reduced (p < 0.01) diabetes and hypertension-induced increase in fatty acid oxidation and lipid peroxides. CONCLUSION: Our results suggest that farnesyl transferase inhibition modulates peroxisome enzyme activities and alleviates oxidative stress, thus providing a possible mechanism for reported FPTIII-mediated protection against renal dysfunction in DH rats. PMID- 20197689 TI - Undercarboxylated osteocalcin is a biomarker of carotid calcification in patients with essential hypertension. AB - The development of vascular calcification is an active, highly regulated process with similarities to bone formation. Osteocalcin (OC), a vitamin K-dependent protein expressed by osteoblasts, contains 3 gamma-carboxyglutamic acid residues derived from the vitamin K-dependent posttranslational modification of glutamic acid residues. Circulating undercarboxylated OC (ucOC) is increased in vitamin K deficiency and serum ucOC is reported to be a clinical marker of vitamin K status. Vitamin K deficiency is associated with vascular calcification as well as osteoporosis. We evaluated the relationship between ucOC and carotid artery calcification in 92 patients with essential hypertension. Ultrasound of the common carotid artery was performed to identify vascular calcification and subjects were divided into 2 groups: a calcification (+) group and a calcification (-) group. Serum creatinine and ucOC levels were higher in the calcification (+) group than in the calcification (-) group and serum ucOC correlated with serum creatinine. To identify the independent determinant factor for carotid artery calcification, we applied both ucOC and estimated glomerular filtration rate as independent factors in logistic regression analysis. Serum ucOC was an independent determinant of carotid calcification, suggesting that circulating ucOC may be an important biomarker of carotid artery calcification. PMID- 20197690 TI - Fatty acid-bearing albumin induces VCAM-1 expression through c-Src kinase-AP-1/NF kB pathways: effect of L-carnitine. AB - BACKGROUND: Fatty acid-bearing albumin [FA(+) albumin] exerts more deleterious effects in tubular cells than albumin alone. We investigated the effect of FA(+) albumin on the vascular cell adhesion molecule-1 (VCAM-1) expression and elucidated the underlying signaling pathways. We further examined the effect of L carnitine, since it was known to modulate intracellular fatty acid concentration. METHODS: Activation of AP-1 and NF-kappaB was assessed by electrophoretic mobility shift assay. Phosphorylation of protein kinase was examined by Western blot analysis. VCAM-1 mRNA and protein expression were measured by Northern blot analysis and cell ELISA. RESULTS: FA(+) albumin induced VCAM-1 expression via activation of AP-1 and NF-kappaB, which was mediated through activation of c-Src kinase, followed by MAP kinases (p38, ERK 1/2, JNK-1) and IkappaB kinase and IkappaB-alpha, respectively. Inhibitors of protein kinase C and tyrosine kinase, anti-oxidants and intracellular calcium chelator suppressed the FA(+) albumin induced activation of c-Src kinase. L-Carnitine suppressed the FA(+) albumin induced VCAM-1 expression via inhibition of c-Src kinase. CONCLUSIONS: VCAM-1 expression with activation of c-Src kinase-AP-1/NFkappaB pathways might be one of the possible mechanisms that linked FA(+) albumin to tubulointerstitial injury. L Carnitine might be beneficial in attenuating FA(+) albumin-induced tubular injury. PMID- 20197691 TI - Early detection of Alzheimer's disease with PET imaging. AB - Preclinical diagnosis of Alzheimer's disease (AD) is one of the major challenges for the prevention of AD. AD biomarkers are needed not only to reveal preclinical pathologic changes, but also to monitor progression and therapeutics. PET neuroimaging can reliably assess aspects of the molecular biology and neuropathology of AD. The aim of this article is to review the use of FDG-PET and amyloid PET imaging in the early detection of AD. PMID- 20197692 TI - Amyloid imaging in early detection of Alzheimer's disease. AB - Amyloid imaging has provided evidence for early detection of amyloid (Abeta) load in prodromal Alzheimer's disease (AD). Several amyloid tracers have been developed for studies with positron emission tomography (PET). Early detection of at-risk subjects will be important in the future for a successful treatment of AD. The high Abeta load in the brain measured by PET in patients with mild cognitive impairment that later will convert to AD suggests early, significant, ongoing pathological processes prior to cognitive impairment. PET Abeta imaging will also be used for discrimination of AD from other dementia disorders, as well for the evaluation of anti-Abeta drugs. PMID- 20197693 TI - Inability of plasma and urine F2A-isoprostane levels to differentiate mild cognitive impairment from Alzheimer's disease. AB - BACKGROUND: Oxidative stress has been implicated in the pathogenesis of Alzheimer's disease (AD). The pathobiological changes related to AD occur long before the overt clinical symptoms. The plasma lipid peroxidation enzyme F2 isoprostane has been suggested as a biomarker to detect the progression from mild cognitive impairment (MCI) to AD. OBJECTIVE: To test whether plasma and urine F2 isoprostane was diagnostic for dementia in living people. METHODS: Plasma and urine were collected from 222 Religious Orders Study participants with a clinical diagnosis of no cognitive impairment, MCI or AD at time of fluid collection. Isoprostane levels were determined using gas chromatography/mass spectroscopy. RESULTS: Plasma and urine F2-isoprostane levels did not differ between the three clinical groups. Postmortem neuropathologic diagnosis of subjects who died during the course of the study was not associated with baseline blood or plasma F2 isoprostane levels. CONCLUSIONS: In living people, plasma or urine isoprostane levels were not sensitive enough to discriminate between individuals with a clinical diagnosis of no cognitive impairment, MCI or AD. PMID- 20197694 TI - Increased CD44 gene expression in lymphocytes derived from Alzheimer disease patients. AB - In this study, we demonstrated for the first time an increased CD44 gene expression in lymphocytes derived from Alzheimer's disease (AD) patients in comparison with healthy subjects. CD44 is a surface antigen expressed by cells of the immune and central nervous system as well as in a variety of other tissues. Functioning as adhesion molecule, CD44 is furthermore involved in driving immune response into infected tissues, including the CNS. We also found that lymphocytes of the same patients expressed significant levels of unfolded p53 isoform, confirming what we already demonstrated in fibroblasts and lymphocytes derived from other cohorts of AD patients. A correlation between p53 and CD44 expression has been well demonstrated in cancer cells, suggesting that CD44 could be a target gene of mutant p53, or either mutant p53 could lack its ability to negatively regulate CD44 expression. The contemporaneous increased expression of unfolded p53 and CD44 in AD lymphocytes may suggest that these two molecules cross-talk together participating in peripheral immune response during the development of the disease. PMID- 20197695 TI - Human analogue of the morris water maze for testing subjects at risk of Alzheimer's disease. AB - BACKGROUND: Patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (MCI) have difficulties with spatial orientation. OBJECTIVE: To test hypothesis that spatial navigation is impaired early in MCI patients representing the presymptomatic stage of AD. METHODS: We tested patients with probable AD (n = 21), MCI, further classified according to Petersen's criteria as amnestic MCI (aMCI) single domain (n = 11), aMCI multiple domain (n = 31), or nonamnestic MCI (n = 7). The aMCI group was also stratified using cued recall according to Dubois' criteria into memory impairment of the hippocampal type (n = 10) and isolated memory retrieval impairment-nonhippocampal (n = 32) and also according to ApoE4 status into E4+ (n = 12) and E4- (n = 30). These patients and controls (n = 28) were tested in the human variant of the Morris water maze. Depending on the subtest, the subjects could use the egocentric or allocentric (hippocampus dependent) navigation. RESULTS: The AD and aMCI multiple domain groups were impaired in all subtests. The aMCI single domain group was impaired in allocentric subtests. The hippocampal MCI group performed poorer than the nonhippocampal MCI group and similarly to the AD group. The ApoE4+ group was as bad as the AD group when compared with the E4- group. CONCLUSION: aMCI subjects represent a very heterogeneous population, and spatial memory or cued recall examination can add more value to aMCI classification. ApoE4+ patients are more impaired than ApoE4- patients. PMID- 20197696 TI - Social odor recognition: a novel behavioral model for cognitive dysfunction in Parkinson's disease. AB - BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative condition characterized by an increasing loss of dopaminergic neurons resulting in motor dysfunction. However, cognitive impairments in PD patients are a common clinical feature that has gained increased attention. OBJECTIVE: The purpose of the current study was to evaluate the effects of an MPTP-induced dopaminergic lesion in mice on social odor recognition (SOR) memory. METHODS: Mice were acutely treated with MPTP and evaluated for memory impairments in the SOR assay and characterized using biochemical and immunohistochemical methods approximately 2 weeks later. RESULTS: Here we demonstrate that SOR memory is sensitive to MPTP treatment and that it correlates with multiple measures of nigrostriatal integrity. MPTP treatment of C57BL/6N mice produced a profound decrease in dopamine levels, dopamine transporter binding and tyrosine hydroxylase immunoreactivity in the striatum. These impairments in stratial dopaminergic function were blocked by pretreatment with the MAO-B inhibitor deprenyl. Changes in the dopaminergic system parallel those observed in SOR with MPTP treatment impairing recognition memory in the absence of a deficit in odor discrimination during learning. Deprenyl pretreatment blocked the MPTP-induced impairment of SOR memory. CONCLUSION: The use of the SOR memory model may provide a preclinical method for evaluating cognitive therapies for PD. PMID- 20197697 TI - Cognitive event-related potentials and oscillations in the subthalamic nucleus. AB - BACKGROUND: The cognitive role of the subthalamic nucleus (STN) remains largely unknown. METHODS/RESULTS: A modified protocol with a dual task elicited local field event-related potentials (ERPs) within the STN. No generators of ERPs were elicited by the standard oddball protocol in the STN (at variance with recordings from the putamen, caudate and pallidum). Repetitive transcranial magnetic stimulation (rTMS) over the right inferior frontal cortex caused a shortening of latencies of ERPs in standard and dual protocols. No changes were observable after the rTMS over the dorsolateral prefrontal cortex and sham stimulation. In the STN, only the tasks with an increased demand on executive functions produced the alpha-/beta-event-related desynchronization/synchronization in visuomotor tasks with single letters writing. CONCLUSION: Our results indicate a specific, task-related involvement of the STN in the cognitive activities. Cognitive processing in the STN is possibly processed via hyperdirect cortico-STN pathway. Certain effects of deep brain stimulation surgery on cognitive performance could be explained by a direct effect on 'cognitive' parts of the STN. PMID- 20197699 TI - Pharmacogenomic protocols in CNS disorders and dementia. AB - The application of genomic procedures as diagnostic and therapeutic tools is a major challenge for the coming decades. Pharmacogenomic factors may account for 60-90% of drug variability in drug disposition and pharmacodynamics. About 25% of the 100 most prescribed drugs in the USA and the EU are psychotropic drugs, currently used in dementia. Approximately 60-80% of CNS drugs are metabolized via enzymes of the CYP gene superfamily; 18% of neuroleptics are major substrates of CYP1A2 enzymes, 40% of CYP2D6, and 23% of CYP3A4; 24% of antidepressants are major substrates of CYP1A2 enzymes, 5% of CYP2B6, 38% of CYP2C19, 85% of CYP2D6, and 38% of CYP3A4; 7% of benzodiazepines are major substrates of CYP2C19 enzymes, 20% of CYP2D6, and 95% of CYP3A4. About 57.76% of patients with Alzheimer's disease are extensive metabolisers (EMs) for CYP2D6 enzymes, 31.06% are intermediate metabolisers (IMs), 5.28% are poor metabolisers (PMs), and 5.90% are ultrarapid metabolisers (UMs); 73.71% are CYP2C19-EMs, 25.12% IMs, and 1.16% PMs; 60.87% are CYP2C9-EMs, 34.16% IMs, and 4.97% PMs; 82.75% are CYP3A4/5-EMs, 15.88% IMs, and 1.37% UMs. A trigenic cluster integrating CYP2D6+CYP2C19+CYP2C9 polymorphic variants yields 82 different haplotype-like profiles, representing 36 different pharmacogenetic phenotypes in which only 26.51% of patients show a pure 3EM phenotype. These data clearly indicate that the incorporation of pharmacogenomic protocols to dementia research and clinical trials can foster therapeutics optimization by helping to develop cost-effective pharmaceuticals and improve drug efficacy and safety. PMID- 20197698 TI - Oophorectomy, menopause, estrogen, and cognitive aging: the timing hypothesis. AB - BACKGROUND: The concept of neuroprotective effects of estrogen in women remains controversial. OBJECTIVE: To explore the timing hypothesis in relation to cognitive aging and dementia. METHODS: We reviewed existing literature, conducted some reanalyses, and combined results graphically. RESULTS: Current evidence suggests that estrogen may have either protective effects or harmful effects on the brain depending on age, type of menopause (natural versus surgical), or stage of menopause. The comparison of women with ovarian conservation versus women who underwent bilateral oophorectomy provided evidence for a sizeable neuroprotective effect of estrogen in women in the premenopausal years (most commonly before age 50 years). Several case-control studies and cohort studies also showed a neuroprotective effect in women who received estrogen treatment in the early postmenopausal phase (most commonly at ages 50-60 years). However, recent clinical trials showed that women who initiated estrogen treatment in the late postmenopausal phase (ages 65-79 years) experienced an increased risk of dementia and cognitive decline. CONCLUSION: The neuroprotective effects of estrogen depend on age, type of menopause, and stage of menopause (timing hypothesis). PMID- 20197700 TI - Common variant in GRN is a genetic risk factor for hippocampal sclerosis in the elderly. AB - BACKGROUND: Hippocampal sclerosis (HpScl) is common in elderly subjects with dementia, either alone or accompanied by other pathologic processes. It is also found in >70% of frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP). TDP-43 inclusions are detected in >20% of Alzheimer disease (AD) and >70% of HpScl cases. The most common cause of FTLD-TDP is mutation in the progranulin gene (GRN). Recently, a common genetic variant in the 3' untranslated region (3'UTR) of GRN (rs5848; c.*78C>T) located in a microRNA binding site regulated progranulin expression, and the T-allele was increased in FTLD-TDP compared to controls. OBJECTIVE: The goal of this study was to determine if the 3'UTR variant in GRN was associated with TDP-43 immunoreactivity in AD with and without HpScl. METHODS: 644 cases of pathologically confirmed AD, including 57 with HpScl, were screened for TDP-43 immunoreactivity and were genotyped at the GRN 3'UTR single-nucleotide polymorphism rs5848 using previously published methods. RESULTS: There was a trend (p = 0.06) for TDP-43 immunoreactivity, but a very significant (p = 0.005) association of HpScl with the variant, with 72% of AD with HpScl carrying a T-allele, compared to 51% of AD without HpScl carrying a T-allele. CONCLUSION: The results suggest that a genetic variant in GRN leading to decreased levels of progranulin may be a risk factor for HpScl in AD, while its role in TDP-43 immunoreactivity in AD remains less certain. PMID- 20197701 TI - Leucine-rich repeat kinase 2 gene-associated disease: redefining genotype phenotype correlation. AB - BACKGROUND: Leucine-rich repeat kinase 2 (LRRK2) has emerged as the most prevalent genetic cause of Parkinson's disease (PD) among Caucasians. Patients carrying an LRRK2 mutation display significant variability of clinical and pathologic phenotypes across and within affected families. METHODS: Herein, we review available clinical and pathologic data on patients with an LRRK2 mutation who have come to autopsy. RESULTS: Thirty-eight patients have been reported who presented clinically with PD; parkinsonism with resistance to levodopa, supranuclear gaze palsy, or autonomic dysfunction; or tremor and dementia. Pathology showed typical PD-type Lewy body disease (LBD) in most patients, whereas in others there was 'pure' nigral degeneration (one with TDP-43-positive inclusions), diffuse LBD, or tau-, alpha-synuclein- or ubiquitin-positive pathology reminiscent of progressive supranuclear gaze palsy, multisystem atrophy, and frontotemporal dementia with ubiquitin-positive inclusions. CONCLUSIONS: Such clinical and pathologic variability suggests Lrrk2 acts upstream from other proteins implicated in neurodegeneration. Specific mutations may be associated with alternative progressive supranuclear gaze palsy-like or 'pure' nigral degeneration phenotypes. A different effect on Lrrk2 kinase activity may play a role in such heterogeneity. PMID- 20197702 TI - Derivation and validation of a clinical system for predicting pneumonia in acute stroke. AB - AIMS: We derived and validated a clinical prediction rule that can be used to predict post-stroke pneumonia. METHODS: We conducted a retrospective cohort study of patients admitted to hospital with a stroke. The cohort was subdivided into a derivation group and a validation group. Within the derivation group, a point scoring system was developed to predict pneumonia based on a logistic regression model. The point scoring system was then tested within the validation group. RESULTS: Of the 1,363 patients with stroke, 10.5% of patients experienced new pneumonia. The most points were assigned for abnormal swallowing result and history of pneumonia (4 points), followed by greater NIHSS score (3 points), patient being 'found down' at symptom onset (3 points), and age >70 years (2 points). A 3-level classification system was created denoting low, medium and high risks of pneumonia, which accurately predicted pneumonia in the validation group. The discriminatory accuracy of the 3-level clinical prediction rule exceeded the acceptable range in both the derivation group (c statistic: 0.78) and validation group (c statistic: 0.76). CONCLUSION: A simple scoring system was derived and validated. This clinical scoring system may better identify stroke patients who are at high risk of developing new pneumonia. PMID- 20197703 TI - Fasting plasma insulin, C-peptide and cognitive change in older men without diabetes: results from the Physicians' Health Study II. AB - BACKGROUND: Type 2 diabetes has been associated with diminished late-life cognition; less is known about relations of insulin levels and insulin secretion to cognitive change among persons without diabetes. We examined prospectively relations of fasting insulin levels and insulin secretion to cognitive decline among healthy, community-dwelling older men without diabetes. METHODS: Fasting plasma insulin and C-peptide (insulin secretion) levels were measured in 1,353 nondiabetic men, aged 60-92 years (mean = 71.3 years), in the Physicians' Health Study II, who participated in cognitive testing an average of 3.3 years later. Two assessments were administered 2 years apart (range = 1.5-4.0 years) using telephone-based tests (general cognition, verbal memory and category fluency). Primary outcomes were the Telephone Interview for Cognitive Status (TICS), global cognition (averaging all tests) and verbal memory (averaging 4 verbal tests). Multivariable linear regression models were used to estimate the relations of insulin and C-peptide to cognitive decline. RESULTS: Higher fasting insulin was associated with a greater decline on all tests, after adjustment. Findings were statistically significant for the TICS and category fluency, e.g. the multivariable-adjusted mean difference (95% CI) in decline for men with the highest versus lowest insulin levels was -0.62 (-1.15, -0.09) points on the TICS (p for trend = 0.04); this difference was similar to that between men 7 years apart in age. Similarly, there was a greater decline across all tests with increasing C-peptide, but the findings were statistically significant only for the global score (p for trend = 0.03). CONCLUSIONS: Higher fasting insulin and greater insulin secretion in older men may be related to overall cognitive decline, even in the absence of diabetes. PMID- 20197704 TI - Ethnic disparities in first primary intracerebral hemorrhage in northern Israel. AB - BACKGROUND: Ethnic differences among first primary intracerebral hemorrhage (PICH) patients in an Israeli biethnic population have not yet been studied. PATIENTS AND METHODS: We included in the study 546 patients (counting warfarin related hemorrhages) hospitalized during the period from December 1999 through June 2008. RESULTS: The mean age was 71.1 +/- 14 years for the Jewish patients and 63.3 +/- 13.9 years for the Arab patients (p < 0.0001). Diabetes and smoking were significantly more frequent among the Arab patients. No difference was found between groups by location, extent, or ventricular involvement of PICH. Although the in-hospital mortality rate was significantly higher among the Jewish patients, adjustment of the model combining multiple risk factors for PICH eliminated this difference. CONCLUSIONS: There are differences in the demographic and vascular risk factor profiles between Arab and Jewish PICH patients, with the Arabs found to be younger and to suffer more from diabetes. The location and extent of intracerebral hemorrhage as well as functional outcome were similar between the two groups. The apparent higher in-hospital mortality in the group of Jewish patients was eliminated when the influence of multiple covariates other than ethnicity, main vascular risk factors and international normalized ratio level were taken into consideration. PMID- 20197705 TI - Incidence of lobar and non-lobar spontaneous intracerebral haemorrhage in a predominantly Hispanic-Mestizo population--the PISCIS stroke project: a community based prospective study in Iquique, Chile. AB - BACKGROUND: The incidence of intracerebral haemorrhage (ICH) in Hispanics is high, especially of non-lobar ICH. Our aim was to ascertain prospectively the incidence of first-ever spontaneous ICH (SICH) stratified by localisation in a Hispanic-Mestizo population of the north of Chile. METHODS: Between July 2000 and June 2002 all possible cases of ICH were ascertained from multiple overlapping sources. The cases were allocated according to localisation. Those with vascular malformations or non-identifiable localisations were excluded. RESULTS: We identified a total of 69 cases of first-ever ICH. Of these, 64 (92.7%) had SICH, of which we allocated 58 cases (84%) to non-lobar or lobar localisation. The mean age was 57.3 +/- 17 years, and 62.3% of the subjects were male. The age-adjusted incidence rates were 13.8 (non-lobar) and 4.9 (lobar) per 100,000 person-years. Non-lobar SICH was more frequent in young males and lobar SICH in older women. The non-lobar-to-lobar ratio was similar to previous findings in Hispanics. Hypertension was more frequent in non-lobar SICH and in diabetes, heavy drinking and antithrombotic use in lobar SICH, but in none significantly. There was no association between localisation and prognosis. CONCLUSIONS: The incidence of non lobar SICH was high, but lower than in most non-white populations. This lower incidence could be due to a lower population prevalence of risk factors, a higher socioeconomic level in this population, or chance. PMID- 20197706 TI - Weekly intravenous and intraperitoneal paclitaxel combined with S-1 for malignant ascites due to advanced gastric cancer. AB - Malignant ascites caused by gastric cancer are chemotherapy resistant and carry a poor prognosis. The efficacy of a regimen including intraperitoneal paclitaxel (PTX) was evaluated in 33 gastric cancer patients with ascetic fluid in the peritoneal cavity diagnosed with computed tomography (CT) scanning. Synchronous administration of intravenous (50 mg/m(2)) and intraperitoneal (20 mg/m(2)) PTX was performed via a subcutaneously placed intraperitoneal catheter on days 1 and 8, and S-1 was administered twice daily at 80 mg/m(2)/day for 14 consecutive days from day 1 to day 14, followed by 7 days of rest. The ascitic fluid volume was calculated with NIH Image J software using continuous CT images. After 2-4 treatment cycles, 23 (70%) patients showed reductions in their ascitic volumes of >50%. Ascites disappeared completely in 8 patients and were markedly reduced (to <3% of the original volume) in 4 of the 9 patients (44%) who initially had massive (>2,500 ml) ascites. Median overall survival was significantly better in patients with ascitic reduction. Weekly intravenous and intraperitoneal PTX combined with S-1 was highly effective in gastric cancer with malignant ascites. The change in ascitic fluid volumes determined by CT image measurements is a useful predictor of outcome in these patients. PMID- 20197707 TI - Depersonalization in patients with schizophrenia spectrum disorders, first-degree relatives and normal controls. AB - BACKGROUND: Depersonalization occurs in healthy individuals and across a broad range of psychiatric patients. Data on depersonalization in persons linked to patients through genetics, environment or education are scarce. Due to their higher risk of developing psychosis, first-degree healthy relatives might show differences with the general population. This study examines depersonalization in patients with schizophrenia or schizophrenia spectrum disorders, their first degree healthy relatives and normal controls. METHODS: The Cambridge Depersonalization Scale was used to measure depersonalization in a sample of 147 clinically stable patients with schizophrenia or schizophrenia spectrum disorders, 73 first-degree relatives with no psychiatric history and 172 healthy controls. Mixed effect models were used to account for both the familial structure of the data and the effect of sociodemographic characteristics. RESULTS: Patients obtained higher scores than relatives and controls for frequency and duration of depersonalization experiences, number of items responded positively and total depersonalization, while first-degree relatives obtained lower scores than patients and controls for all these characteristics. CONCLUSIONS: First-degree relatives of patients reported fewer episodes of depersonalization, which were less intense and of shorter duration, than healthy controls. This finding might be related to a protection mechanism that keeps first-degree relatives away from near-psychotic experiences. The nature of such a mechanism remains to be discovered. PMID- 20197708 TI - Development and factorial validation of a short version of the narcissism inventory (NI-20). AB - BACKGROUND: Narcissism is seen as a normal but heterogeneously formed personality variable, ranging from 'grandiosity-exhibitionism' to 'vulnerability sensitivity'. This article reports the development and factorial validation of a short version of a narcissism inventory. SAMPLING AND METHODS: The sample includes data of 4,509 consecutive psychosomatic inpatients. The overall sample was divided in 2 equally sized randomized subsamples. One sample (n = 2,262) was used for exploratory factor analysis (principal component analysis). The other sample (n = 2,265) was used for confirmatory tests of the model fit of the newly built NI-20 version, and to analyze the model fit separately for men and women using structural equation modeling with AMOS software. RESULTS: The short version (NI-20) consists of 20 items, with items representing almost all of the original 18 subscales and 4 second-order dimensions. The NI-20 possesses properties similar to the NI-90, with a considerable gain in test economy. The 4-factor structure of the NI-20 was confirmed, and reaches good fit indices. CONCLUSIONS: The NI-20 is an economical instrument with acceptable psychometric characteristics that reflects the heterogeneous aspects of narcissism. A methodological limitation is that the interactions between sociodemographic variables were not included as potential predictors. PMID- 20197709 TI - Gender differences among patients with a single depressive episode. AB - BACKGROUND: Studies on gender differences in depression have usually included a mixture of patients with first-episode, chronic and recurrent depression. Consequently, the results might be confounded by the history of depression among participants. The present study evaluated gender differences in sociodemographic, clinical and treatment variables among patients suffering exclusively from single episode depression. METHOD: Systematic recruitment of 301 participants via the Danish Psychiatric Central Research Register and assessment by means of questionnaires and interviews regarding psychiatric diagnoses, personality traits and disorders, stressful life events, family history, and treatment response. RESULTS: Female patients showed a higher level of neuroticism and more residual anxiety symptoms after treatment of the depression. There were no gender differences in severity of depression, psychiatric co-morbidity (including personality disorders), stressful life events prior to onset, family loading of psychiatric disorders, or treatment outcome. CONCLUSION: The results provide evidence for a higher level of anxiety and neuroticism among females with a recent onset of depression, whereas other clinical characteristics of first episode depression were equivalent between male and female patients. Only patients with contact to a psychiatric hospital were included; thus, the results cannot be generalized to patients in primary care. PMID- 20197710 TI - Impact of alexithymia on treatment outcome: a naturalistic study of short-term cognitive-behavioral group therapy for panic disorder. AB - BACKGROUND: It is often suggested in the literature that alexithymic patients are less responsive to psychotherapy than nonalexithymic patients. However, few empirical studies have examined this issue. Furthermore, it is unclear whether or not alexithymia itself may improve during psychotherapy. METHODS: Fifty-five consecutive outpatients with panic disorder received short-term cognitive behavioral group therapy (CBGT) and were followed up 6 months later. Nineteen patients (35%) were on concomitant antidepressant medication. Alexithymia was measured using the 20-item Toronto Alexithymia Scale (TAS-20). Both completers and intention-to-treat analyses were calculated, taking into consideration the potentially confounding effect of comorbid conditions. RESULTS: Baseline alexithymia did not predict outcome of CBGT, neither at posttreatment nor at follow-up. The presence of comorbid axis I disorders predicted nonresponse at posttreatment but not at follow-up. TAS-20 total scores decreased over time, with the TAS-20 factors 1 (difficulty identifying feelings) and 2 (difficulty describing feelings) decreasing significantly, while factor 3 (externally oriented thinking) remained largely stable. CONCLUSIONS: These findings are encouraging for cognitive-behavioral therapists working with patients with alexithymia who suffer from panic disorder: CBGT outcome does not appear to be negatively affected by alexithymia, and some alexithymic characteristics may even be reduced following CBGT. Assessing alexithymia at treatment onset may be useful for individually tailoring therapeutic interventions. PMID- 20197711 TI - Should we consider Vim thalamic deep brain stimulation for select cases of severe refractory dystonic tremor. AB - Dystonic tremor, which may present with many different clinical presentations (rhythmic oscillations, abnormal posture, pain, and/or a null point) has proven to be a challenge for the clinician to effectively treat. Although recent studies have demonstrated excellent outcomes in select cases following deep brain stimulation (DBS) of the internal globus pallidus, the optimal target for dystonia and particularly for dystonic tremor remains unknown. We report 3 cases of dystonic tremor which were successfully addressed through the use of ventral intermediate nucleus (Vim) DBS. We also review the literature concerning the efficacy of Vim DBS for addressing dystonia. This case series illustrates the potential use of Vim DBS for select cases of dystonic tremor. PMID- 20197712 TI - A novel stereotactic device for spinal irradiation in rats designed for a linear accelerator. AB - OBJECTIVE: Our purpose was to report the design and positioning accuracy testing of a stereotactic device designed for a linear accelerator to perform spinal radiosurgery in rats. METHODS: To define the spatial and repositioning accuracy of the device, we measured the 3-dimensional (3D) translation of a paraspinal fiducial mark implanted by microsurgery in 5 Wistar rats during a sequence of setups and treatment simulations, thus obtaining final 3D translation vectors and maximum displacements. RESULTS: For spatial accuracy, the differential coordinate translations were 0.8 +/- 0.3, 0.6 +/- 0.2 and 0.5 +/- 0.1 mm in the x-, y- and z directions, respectively. The median magnitude of the 3D vector was 1.3 mm (sigma = 0.2 mm), with a maximum error of 2.2 mm. The differential coordinate translation for the repositioning accuracy showed values of 1.4 +/- 0.3, 1.3 +/- 0.3 and 0.8 +/- 0.1 mm for the x-, y- and z-coordinates, resulting in a 3D displacement vector of 2.2 mm (sigma = 0.2 mm) and a maximum displacement error of 3.6 mm. CONCLUSIONS: Using a linear accelerator, our novel stereotactic device provides accurate immobilization and repositioning of paraspinal structures under experimental conditions in rats. PMID- 20197713 TI - Occipital nerve stimulator placement via a retromastoid to infraclavicular approach: a technical report. AB - Occipital nerve stimulation is a form of peripheral nerve stimulation used to treat refractory headache disorders. Various techniques have been described for occipital nerve stimulator implantation; these include midline cervical or retromastoid lead insertion with internal pulse generator placement in the infraclavicular, gluteal or low abdominal regions. Lead migration is one of the most common complications of occipital nerve stimulators. Implantation approaches that include remote battery sites may contribute to mechanical stress on the components, as the leads or extensions may traverse highly mobile body regions. In this technical report, we describe an occipital stimulator implantation technique that may be advantageous in terms of patient positioning, ease of surgical approach and minimization of mechanical stress on components. PMID- 20197714 TI - Non-coding RNAs in mammalian sexual development. AB - The present decade is witnessing a paradigm shift in our understanding of gene regulation. RNA, once relegated to an intermediary between DNA and protein, has emerged as a key contributor in the coordination of complex developmental pathways. For sexually reproducing organisms, propagation of the species is accomplished via an elaborate sexual phenotype. In mammals this consists of a highly complex cell lineage that has the capacity for intricate self differentiation whilst maintaining the potential to generate all cell types upon fertilization. In addition, mammals possess a diverse range of somatic reproductive tissues and organs that often undergo dynamic morphological changes in response to a variety of external and internal cues. Although the protein component required to mediate these processes continues to be vigorously investigated, it is becoming increasingly apparent that an understanding of the non-coding RNA (ncRNA) component is required to develop a comprehensive picture of mammalian sexual development. PMID- 20197715 TI - [Prognostic significance of TEL/AML1 rearrangement and its additional genetic changes in Korean childhood precursor B-acute lymphoblastic leukemia]. AB - BACKGROUND: TEL (ETV6)/AML1 (RUNX1) rearrangement is observed in approximately 20 25% of childhood precursor B-ALL and is associated with a favorable outcome. Additional genetic changes, associated with TEL/AML1, are frequently found. We evaluated the prevalence and prognostic significance of TEL/AML1 rearrangement and additional genetic changes in the TEL and AML1 genes in Korean childhood precursor B-ALL. METHODS: We performed FISH using LSITEL/AML1 ES probe (Vysis, USA) in 123 children diagnosed as having precursor B-ALL and assessed clinical relevance of the TEL/AML1 rearrangement and additional genetic abnormalities. RESULTS: The frequency of TEL/AML1 was 17.1% (21/123) in patients with precursor B-ALL. TEL/ AML1-positive group showed male predominance (P=0.012) and younger age of onset than TEL/ AML1-negative group by 1.6 yr (P=0.013). The outcome of TEL/AML1-positive group tended to show lower incidences of relapse (1/21 vs 20/102), death (1/21 vs 17/102) and longer event free survival. Among TEL/AML1 positive patients, unrearranged TEL deletion, AML1 gain, and unrearranged TEL deletion combined with AML1 gain were detected in 61.9%, 23.8%, and 9.5%, respectively. There were no significant differences in the clinical features and outcome according to the presence or absence of additional genetic changes. CONCLUSIONS: The frequency of TEL/AML1 and additional genetic changes in TEL and AML1 is higher than previous studies in Korean children, and in close agreement with usually reported one, 20-25%. TEL/AML1-positive group showed a tendency toward better prognosis. Further study is needed to clarify the prognostic significance of additional changes in TEL and AML1 based on a large sample size. PMID- 20197716 TI - [Evaluation of analytical measurement ranges of three full range C-reactive protein tests using immunoturbidimetric assay]. AB - BACKGROUND: Recently developed full-range C-reactive protein (CRP) tests, which are based on the immunoturbidimetric method, have wider analytical measurement ranges (AMR) than previously used tests. We evaluated the AMR of 3 full-range CRP tests-2 new and 1 previously used test. METHODS: We analyzed the precision and AMR of 2 full-range CRP tests (Sekisui, Nanopia CRP, N-CRP and Iatron, IATRO CRP EX, I-CRP) and compared the values obtained for these tests with those obtained for the conventional full-range CRP test (Sekisui, PureAuto S CRP, P-CRP). We evaluated the tests for the limit of quantification and for linearity. We also compared these results of these tests by using the comparative test (Dade Behring, cCRP) for cardiovascular risk assessment. RESULTS: Coefficients of variation (CVs) of all the full-range CRP tests were less than 10% for concentrations greater than 0.6 mg/L, and CVs of N-CRP and I-CRP were lower than those of P-CRP for concentrations less than 1 mg/L. N-CRP (0.1-467 mg/L) and I CRP (0.1-280 mg/L) had wider AMR than P-CRP (3-233 mg/L). All the full-range CRP tests showed more than 90% agreement with the cCRP values for the assessment of cardiovascular risk. CONCLUSIONS: The 3 full-range CRP tests, by virtue of their wide AMR, may be used for the detection of acute inflammation as well as for the assessment of cardiovascular risk. N-CRP and I-CRP may be more useful than P-CRP for determining the CRP concentration, especially for the detection of concentrations close to the lower or upper limit of the analytical range, without the need for repetition of the test. PMID- 20197717 TI - [HDL cholesterol reduction during rosiglitazone and fenofibrate treatment in a type 2 diabetes mellitus patient with dyslipidemia]. AB - Thiazolidinediones (TZD), which are widely used as insulin sensitizers, and fibrates, which are lipid-lowering drugs, are used in the treatment of dyslipidemia that commonly accompanies diabetes. Several reports suggest elevated levels of high-density lipoprotein (HDL) cholesterol, but the paradoxical reduction of HDL cholesterol level during single or combined TZD and fibrate therapies has been occasionally reported. Herein, we report a case of paradoxical decrease in HDL cholesterol and apolipoprotein A-1 levels during rosiglitazone and fenofibrate treatment for the first time in Korea. The patient was a 56-yr old man presenting with type 2 diabetes mellitus and dyslipidemia. His HDL cholesterol and apolipoprotein A-1 levels returned to normal after the cessation of fenofibrate therapy. Since diabetes is an established risk factor of cardiovascular diseases, low HDL cholesterol can be a key cause of concern for patients with diabetes. Therefore, HDL cholesterol level should be determined before and after starting TZD and/or fibrate therapy in diabetic patients. PMID- 20197718 TI - [Comparison of the efficacies of silver-containing dressing materials for treating a full-thickness rodent wound infected by methicillin-resistant Staphylococcus aureus]. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) may cause infections during wound dressing. We aimed to compare the antibacterial activities and wound-healing effects of commercially available silver-coated or silver-impregnated wound dressings on MRSA-infected wounds. METHODS: Full thickness skin defects were made on the back of rats (N=108) and were infected with MRSA. The rats were divided into the following 6 groups according to the dressing used for the wounds: nanocrystalline silver (Acticoat), silver carboxymethylcellulose (Aquacel-Ag), silver sulfadiazine (Medifoam silver), nanocrystalline silver (PolyMem silver), silver sulfadiazine (Ilvadon), and 10% povidone iodide (Betadine). We analyzed the wound sizes, histological findings, and bacterial colony counts for the groups. We also inoculated the silver materials on Mueller-Hinton agar plates containing MRSA and compared the inhibition zones in the agar plates. RESULTS: The order of the rate of wound-size decrease was Acticoat>Aquacel-Ag>PolyMem silver>Medifoam silver>Ilvadon>Betadine. The histological findings revealed that the Acticoat showed more reepithelialization and granulation tissue formation and less inflammatory cell infiltration than the other materials. The order of the time required for wound healing was Acticoat>Aquacel -Ag>PolyMem silver>Ilvadon>Medifoam silver>Betadine. The bacterial colony counts reduced in all the groups, except in the Medifoam silver group. The order of the size of the inhibition zone was Acticoat>Aquacel Ag>Ilvadon>PolyMem silver>Betadine>Medifoam silver. CONCLUSIONS: Silver-coated or silver-impregnated wound dressings can be used for treating MRSAinfected wounds. Considering its superior efficacy in comparison to the efficacies of other silver coated or silver-impregnated wound dressings, Acticoat should be preferentially used for the treatment of MRSA-infected skin wounds. PMID- 20197719 TI - [Antimicrobial susceptibility patterns of Legionella isolates in the environment and in patients]. AB - BACKGROUND: Antimicrobial susceptibility of Legionella spp. has rarely been studied in Korea. Therefore, we aimed to determine the susceptibility of Legionella spp. to various antibiotics. METHODS: We assessed the antimicrobial susceptibility of 66 environmental and clinical Legionella isolates collected between January 2001 and December 2008 from Korea and Japan. The minimum inhibitory concentrations (MICs) of 6 antibiotics, namely, azithromycin, ciprofloxacin, clarithromycin, clindamycin, gatifloxacin, and gemifloxacin were determined by the broth microdilution method using buffered starch yeast extract broth. RESULTS: The MIC ranges of the 6 antibiotics used against the Legionella isolates were as follows: 0.004-0.062 microg/mL (azithromycin), 0.002-0.5 microg/mL (ciprofloxacin), 0.004-0.5 microg/mL (clarithromycin), 0.12-4 microg/mL (clindamycin), 0.002-0.12 microg/mL (gatifloxacin), and 0.008-1 microg/mL (gemifloxacin). CONCLUSIONS: Legionella spp. isolates from Korea and Japan were most susceptible to gatifloxacin. Azithromycin, clarithromycin, ciprofloxacin, and gemifloxacin were also effective for treating legionellosis. PMID- 20197720 TI - A report of cat scratch disease in Korea confirmed by PCR amplification of the 16S-23S rRNA intergenic region of Bartonella henselae. AB - We report a case of cat scratch disease in an 8-yr-old girl who presented with fever and enlargement of both axillary lymph nodes. Both aerobic and anaerobic cultures of the lymph node aspirate were negative for microbial growth. Gram staining and Warthin-Starry silver staining did not reveal any organism. Purified DNA from the PCR-amplicon of the 16S-23S rRNA intergenic region was sequenced and showed 99.7% identity with the corresponding sequence of Bartonella henselae strain Houston-1. Our findings suggest that the internal transcribed spacer is a reliable region for PCR identification of Bartonella species. In patients with lymphadenitis, a history of contact with cats or dogs necessitates the use of diagnostic approaches that employ not only the conventional staining and culture but also molecular methods to detect B. henselae. PMID- 20197721 TI - Prevalence and clinical associations of lupus anticoagulant, anticardiolipin antibodies, and anti-beta2-glycoprotein I antibodies in patients with systemic lupus erythematosus. AB - BACKGROUND: The presence of antiphospholipid antibodies (aPLs) is associated with the clinical features of antiphospholipid syndrome (APS), which comprises venous and arterial thrombosis and pregnancy loss, and systemic lupus erythematosus (SLE). The prevalence of aPLs has been reported to be different in patient populations affected by either of these conditions. We performed a retrospective study to evaluate the prevalence and clinical associations of aPLs, including lupus anticoagulant (LAC), anticardiolipin (aCL), and anti-beta2-glycoprotein I antibodies (anti-beta2-GPI) in a cohort of Korean patients with SLE. METHODS: This study included samples from 88 SLE patients for whom aPL testing had been advised between June 2006 and July 2009 at the Dong-A University Hospital. Serum and plasma samples were tested for LAC, aCL (IgG, IgM), and anti-beta2-GPI (IgG, IgM) antibodies. Clinical data from patients were obtained from a review of medical records. RESULTS: LAC was the most common (34.1% of total patients, 30/88) antibody, followed by IgM aCL (31.8%, 28/88), IgG aCL (18.2%, 16/88), and IgM and IgG anti-beta2-GPI (both 5.7%, 5/88 each). Positivity for LAC was strongly associated with venous/arterial thrombosis (P=0.002). CONCLUSIONS: LAC was the most common antibody detected in Korean SLE patients and is shown to have a significant association with the presence of venous/arterial thrombosis. The measurement of LAC may be clinically useful in identifying patients with SLE who are at a high risk for venous/arterial thrombosis. PMID- 20197722 TI - [Evaluation of the virus-elimination efficacy of nanofiltration (Viresolve NFP) for the parvovirus B19 and hepatitis A virus]. AB - BACKGROUND: The safety of plasma derivatives has been reinforced since 1980s by variable pathogen inactivation or elimination techniques. Nucleic acid amplification test (NAT) for the source plasma has also been implemented worldwide. Recently nanofiltration has been used in some country for ensuring safety of plasma derivatives to eliminate non-enveloped viruses such as parvovirus B19 (B19V) and hepatitis A virus (HAV). We evaluated the efficacy of nanofiltration for the elimination of B19V and HAV. METHODS: To verify the efficacy of nanofiltration, we adopted a 20 nm Viresolve NFP (Millipore, USA) in the scaling down (1:1,370) model of the antithrombin III production. As virus stock solutions, we used B19V reactive plasma and porcine parvovirus (PPV) and HAV obtained from cell culture. And 50% tissue culture infectious dose was consumed as infectious dose. The methods used to evaluate the virus-elimination efficacy were reverse-transcriptase polymerase chain reaction for B19V and the cytopathic effect calculation after filtration for PPV and HAV. RESULTS: B19V was not detected by RT-PCR in the filtered antithrombin III solutions with initial viral load of 6.42 x 10(5) IU/mL and 1.42 x 10(5) IU/mL before filtration. The virus-elimination efficacy of nanofiltration for PPV and HAV were > or = (3.32) and > or = (3.31), respectively. CONCLUSIONS: Nanofiltration would be an effective method for the elimination of B19V and HAV. It may be used as a substitute for NAT screening of these viruses in source plasma to ensure safety of plasma derivatives in Korea. PMID- 20197723 TI - The relationship between Lewis/Secretor genotypes and serum carbohydrate antigen 19-9 levels in a Korean population. AB - BACKGROUND: The Lewis histo-blood group system consists of 2 major antigens-Lea and Leb-and a sialyl Lewis antigen-carbohydrate antigen (CA) 19-9. We investigated the distribution of Lewis genotypes and evaluated the relationship between the Lewis/Secretor genotypes and the serum level of CA 19-9 in a Korean population to identify whether the serum CA 19-9 levels are influenced by the Lewis/Secretor genotypes. METHODS: The study included 242 individuals who had no malignancies. Lewis genotyping was performed for the 59T>G, 508G>A and 1067T>A polymorphic sites. The Secretor genotype was determined through analysis of the 357C>T and 385A>T polymorphic sites and the fusion gene. Serum CA 19-9 level was analyzed using an electrochemiluminescence immunoassay. RESULTS: Individuals carrying the 3 common genotypes-Le/Le, Le/le(59,508), and Le/le(59,1067) accounted for 95% of the study population. In the Korean population, the allelic frequencies of Le, Le(59), le(59,508), and le(59,1067) were 0.731, 0.010, 0.223, and 0.035, respectively. We found a significant difference in serum CA 19-9 concentrations among the 9 Lewis/Secretor genotype groups (P<0.001). The serum CA 19-9 levels in subjects with genotype groups 1 and 2 (Le/- and se/se) were higher than those with genotype groups 3-6 (Le/- and Se/-; 15.63 vs 6.64 kU/L, P<0.001). CONCLUSIONS: Le/Le, Le/le(59,508), and Le/le(59,1067) are frequent Lewis genotypes in Koreans. Because serum CA 19-9 levels are significantly influenced by the Lewis/Secretor genotypes, caution is suggested when interpreting the serum CA 19-9 levels. PMID- 20197724 TI - Investigation of the prevalence of human parvovirus B19 DNA in Korean plasmapheresis donors. AB - BACKGROUND: To ensure the safety of plasma derivatives, some countries have been screening for the human parvovirus B19 (B19V) antigen or DNA in blood donors. We investigated the prevalence of B19V DNA and anti-B19V antibodies in Korean plasmapheresis donors to evaluate the necessity of B19V DNA screening test. METHODS: Plasma samples were collected between March and July 2008 from 10,032 plasmapheresis donors. The B19V DNA test was performed using the LightCycler 2.0 (Roche, Germany) with quantification kits. Anti-B19V IgM and IgG were tested in 928 randomly selected samples from the 10,032 donors using recomWell Parvovirus B19 ELISA IgM, IgG assay (Mikrogen, Germany). RecomLine Parvovirus B19 LIA IgG, IgM assay (Mikrogen, Germany) was used to analyze the epitopes of antibodies in donors showing positive results for B19V DNA and anti-B19V antibodies. DNA sequencing was performed to identify the genotypes. RESULTS: The prevalence of B19V DNA was 0.1% (10/10,032). Virus titers in B19V DNA positive donors were less than 10(5) IU/mL (range: 2.7 x 10(1)-3.2 x 10(4) IU/mL) except for 1 donor (1.33 x 10(8) IU/mL). All the isolated B19V DNAs from 6 donors were identified as genotype I. Nine out of 10 B19V DNA positive donors also possessed anti-B19V IgG only or IgG and IgM. The prevalence of anti-B19V IgG was 60.1% (558/928). CONCLUSIONS: The prevalence of B19V DNA in Korean blood donors was not high and most donors also possessed neutralizing anti-B19V antibodies. Thus, the implementation of a B19V screening test for Korean blood donors does not appear to be imperative. PMID- 20197725 TI - The M142T mutation causes B3 phenotype: three cases and an in vitro expression study. AB - The B3 phenotype is the most common B subtype in Korea. The B305 allele (425 T>C, M142T) was first reported in 2 Chinese individuals; however, it has not yet been reported in the Koreans, and the impact of the M142T mutation on the expression of the B3 phenotype has also not been studied. To resolve an ABO discrepancy between a group O neonate and her group O father and A(1)B(3) mother, blood samples from these individuals and other family members were referred to our laboratory for ABO gene analysis. The B305 allele was discovered in the neonate (B305/O01), her mother (A102/ B305), and her maternal aunt (B305/O02), while her father was typed as O01/O02. Transient transfection experiments were performed in HeLa cells using the B305 allele synthesized by site-directed mutagenesis; flow cytometric analysis revealed that this transfect expressed 35.5% of the total B antigen produced by the B101 allele transfect. For comparison, Bx01 allele transfects were also created, and they expressed 11.4% of the total B antigen expressed on the surface of B101 transfects. These experiments demonstrate that the M142T (425 T>C) mutation is responsible for the B subtype phenotype produced by the B305 allele. PMID- 20197726 TI - [Identification of a novel deletion region in 3q29 microdeletion syndrome by oligonucleotide array comparative genomic hybridization]. AB - BACKGROUND: The 3q29 microdeletion syndrome is a genomic disorder characterized by mental retardation, developmental delay, microcephaly, and slight facial dysmorphism. In most cases, the microdeletion spans a 1.6-Mb region between low copy repeats (LCRs). We identified a novel 4.0- Mb deletion using oligonucleotide array comparative genomic hybridization (array CGH) in monozygotic twin sisters. METHODS: G-banded chromosome analysis was performed in the twins and their parents. Highresolution oligonucleotide array CGH was performed using the human whole genome 244K CGH microarray (Agilent Technologies, USA) followed by validation using FISH, and the obtained results were analyzed using the genome database resources. RESULTS: G-banding revealed that the twins had de novo 46,XX,del(3)(q29) karyotype. Array CGH showed a 4.0-Mb interstitial deletion on 3q29, which contained 39 genes and no breakpoints flanked by LCRs. In addition to the typical characteristics of the 3q29 microdeletion syndrome, the twins had attention deficit-hyperactivity disorder, strabismus, congenital heart defect, and gray hair. Besides the p21-activated protein kinase (PAK2) and discs large homolog 1 (DLG1) genes, which are known to play a critical role in mental retardation, the hairy and enhancer of split 1 (HES1) and antigen p97 (melanoma associated; MFI2) genes might be possible candidate genes associated with strabismus, congenital heart defect, and gray hair. CONCLUSIONS: The novel 4.0-Mb 3q29 microdeletion found in the twins suggested the occurrence of genomic rearrangement mediated by mechanisms other than nonallelic homologous recombination. Molecular genetic and functional studies are required to elucidate the contribution of each gene to a specific phenotype. PMID- 20197727 TI - Estrogen receptor 1, glutathione S-transferase P1, glutathione S-transferase M1, and glutathione S-transferase T1 genes with dysmenorrhea in Korean female adolescents. AB - BACKGROUND: Dysmenorrhea is the most common gynecologic complaint among adolescent females. We investigated the association between genetic polymorphisms and dysmenorrhea. METHODS: A total of 202 postmenarcheal Korean female adolescents 16-17 yr old participated in this study. Genotyping for glutathione S transferase mu 1 (GSTM1), glutathione S-transferase theta 1 (GSTT1), glutathione S-transferase pi 1 (GSTP1), and estrogen receptor 1 (ESR1) was performed using PCR-based methods. RESULTS: The PP+Pp genotype of the ESR1 gene was more frequent than pp genotypes in subjects with dysmenorrhea than in subjects without dysmenorrhea (odds ratio=2.440; 95% confidence interval, 1.036-5.753; P=0.040) using an unadjusted univariate logistic regression analysis. The relationship between dysmenorrhea and ESR1 gene polymorphisms remained significant after adjustment for premenstrual syndrome, years elapsed after menarche, and family history of dysmenorrhea. No significant difference was observed between subjects with dysmenorrhea and subjects without dysmenorrhea for polymorphisms of GSTM1, GSTT1, and GSTP1 genes. CONCLUSIONS: Our results suggest that ESR1 gene polymorphisms may be associated with dysmenorrhea. PMID- 20197728 TI - A de novo proximal 6q deletion confirmed by array comparative genomic hybridization. AB - Deletions of chromosome 6q, particularly in the proximal region, are relatively rare. Here, we report on a de novo interstitial deletion of (6)(q13q16.2) in a girl with facial dysmorphism, congenital hip dislocation, porencephaly, and brain atrophy. Array comparative genomic hybridization analysis showed arr 6q13q16.2(73,378,824?99,824,130), demonstrating higher resolution than the conventional cytogenetic findings, del(6)(q12q15). The clinical data were analyzed and compared with those of similar patients previously reported in the literature. PMID- 20197729 TI - [Recombinant chromosome 4 with partial 4p deletion and 4q duplication inherited from paternal pericentric inversion]. AB - Pericentric inversion of chromosome 4 can give rise to 2 alternate recombinant (rec) chromosomesby duplication or deletion of 4p. The deletion of distal 4p manifests as Wolf-Hirschhorn syndrome (WHS). Here, we report the molecular cytogenetic findings and clinical manifestations observed in an infant with 46,XX,rec(4)dup(4q)inv(4)(p16q31.3)pat. The infant was delivered by Cesarean section at the 33rd week of gestation because pleural effusion and polyhydramnios were detected on ultrasonography. At birth, the infant showed no malformation or dysfunction, except for a preauricular skin tag. Array comparative genomic hybridization analysis of neonatal peripheral blood samples showed a gain of 38 Mb on 4q31.3-qter and a loss of 3 Mb on 4p16.3, and these results were consistent with WHS. At the last follow-up at 8 months of age (corrected age, 6 months), the infant had not achieved complete head control. PMID- 20197730 TI - Determination of SMN1 and SMN2 copy numbers in a Korean population using multiplex ligation-dependent probe amplification. AB - Determination of the copy number of the survival motor neuron (SMN) gene is important for detecting spinal muscular atrophy (SMA) carriers and compound heterozygous patients. Multiplex ligationdependent probe amplification (MLPA) assay is a simple and efficient technique used for detecting variations in the copy numbers of different genes. Race- and ethnicity-based variation in the SMA carrier frequency and the '2+0' genotype of SMN1 are important factors that should be considered when estimating the risk of being an SMA carrier. Since SMN2 plays a disease-modifying role, accurate determination of SMN2 copy numbers in SMA patients can serve as a useful prognostic tool. Therefore, information on the SMN2 genotype distributions in normal populations will be helpful in selecting appropriate reference samples for MLPA analysis. To determine SMA carrier frequencies and SMN genotype distribution, we determined the copy numbers of SMN1 and SMN2 genes using the MLPA assay in 100 unrelated Korean individuals with no family history of SMA. The frequency of SMA carriers in the Korean population appears to be 1 in 50, which indicates that the prevalence of SMA among Koreans is the same as that among individuals in the Western countries. Two of the 100 normal individuals enrolled in this study showed 3 copies of the SMN1 gene. Therefore, 1.0% of the 198 normal alleles in this population was estimated to be 2-copy alleles ('2+0' genotype). SMN2 copy numbers showed a high degree of individual variation. Our results showed that 64% of the individuals had 2 copies of SMN2, but 36% individuals had between 0, 1, or 3 copies of the gene. PMID- 20197731 TI - The Mars trial: resolution of the surgical controversies in mesothelioma? PMID- 20197732 TI - Time to diagnosis of lung cancer: technical and pyschological factors that slow down diagnostic and treatment timelines. PMID- 20197733 TI - Imatinib mesylate in patients with WHO B3 thymomas and thymic carcinomas. AB - Thymic malignancies are rare tumors of the mediastinum. c-KIT is highly expressed in thymic carcinomas (TC) but infrequently in thymomas. Anecdotal experience suggests activity of imatinib mesylate in TC. Patients with unresectable World Health Organization B3 thymomas or TC, performance status 0 to 2, good organ function, and measurable disease were enrolled in this study. Imatinib was administered at 600 mg PO daily. Seven patients were recruited at one institution: two World Health Organization B3 thymomas and five TC. Imatinib treatment was generally well tolerated. Two patients had stable disease and five progressed. Median survival was 4 months, and median time to progression was 2 months. c-KIT expression was found in one of four samples by immunohistochemistry. No mutations were detected in the c-KIT or PDGFRA genes in three samples analyzed. Imatinib has no major activity in this rare tumor. Given the small number of patients treated in this study, selection based on presence of c-KIT mutations might be warranted. PMID- 20197734 TI - Extreme delay in care for enlarging breast mass. AB - Phyllodes tumor (PT) of the breast is an uncommon fibroepithelial tumor accounting for 0.37% of primary breast cancers. Most PT are <5.0 cm, averaging 4 7 cm. We present a case of PT measuring 28 cm in diameter with an extreme computed tomography image with tumor size larger than the adjacent thoracic circumference. A 59-year-old uninsured woman without significant medical history presented with a massive ulcerated chest wall tumor. The mass was resected, and microscopic examination demonstrated spindled cells within a myxoid stroma, consistent with PT. PMID- 20197735 TI - New endobronchial ultrasound imaging for differentiating metastatic site within a mediastinal lymph node. AB - A newly developed endobronchial ultrasound processor system (EU-ME1; Olympus Ltd., Tokyo, Japan) improves the quality of ultrasound image by elevating cycles per minute. We report identification of mediastinal lymph node metastasis in a patient with small cell lung cancer. The new endobronchial ultrasound system images enabled visualization of metastatic site within the subcarinal lymph node by the combination of ultrasound image and Doppler mode. PMID- 20197736 TI - A nonresponding small cell lung carcinoma. AB - We present a case with limited disease small cell lung carcinoma with persisting disease and a troublesome syndrome of inappropriate antidiuretic hormone, despite concurrent chemoradiotherapy and second-line chemotherapy. To gain local control, a lobectomy was performed. PMID- 20197737 TI - Recent advances in lung cancer: summary of presentations from the 45th annual meeting of the American Society of Clinical Oncology (2009). AB - Over the past decade, gradual progress has been made in improving the outcomes of patients with lung cancer. This review summarizes the findings from selected studies presented at the recently concluded 45th annual meeting of the American Society of Clinical Oncology. This report will focus only on findings that are of immediate relevance to clinical practice. The topics discussed here range from the long-term safety of adjuvant chemotherapy and a new systemic chemotherapy regimen for locally advanced non-small cell lung cancer to the emerging issue of maintenance chemotherapy and the use of biomarkers in the treatment of patients with metastatic non-small cell lung cancer. PMID- 20197739 TI - New tumor, node, metastasis staging system for lung cancer. PMID- 20197740 TI - Epidemiology of Tinea pedis in Cagliari, Italy. AB - AIM: Observational study of all incident Tinea pedis cases, realised from 2001 to 2007 at the Dermatology Clinic of the University of Cagliari, Italy, which is the main reference centre for dermatologic diseases in central southern Sardinia. METHODS: All patients referred for foot inflammatory pathologies were included in the study. Samples of all clinically visible lesions were taken for mycological examination (20% KOH and culture). When lesions were absent samples were also taken from the IV inter-digital space of both feet to identify eventual sane carriers. Detailed anamneses investigated work, life habits, sports and predisposing conditions such as hyperhidrosis and previous pathologies of the feet. RESULTS: The study enrolled 1568 patients, of which 918 (510 male-408 female) presented clinical manifestations whereas other 650 (426 male-224 female) were asymptomatic. Tinea pedis was diagnosed in 232 (14.79%), 163 male-69 female aged between 11 and 78 years, all in the group with clinical manifestations. The identified dermatophytes were Trichophyton mentagrophytes 115 cases (49.56%), Trichophyton rubrum 110 cases (47.42%) and Epidermophyton floccosum 7 cases (3.08%). Mycological exams in patients without clinical signs were always negative for dermatophytes, while rare colonies of Candida albicans were identified in 3 cases (0.46%). CONCLUSION: Tinea pedis represents a common public health problem, which occurs mainly in male ageing from 16 to 45 years, when working and leisure activities are at their maximum. The absence of dermatophytes identification in 650 asymptomatic patients suggests that the sane carrier condition is a very rare event. PMID- 20197742 TI - Imaging skin: past, present and future perspectives. AB - Skin imaging modalities relevant to the range of skin conditions encountered in clinical settings are described with respect to the information provided, advantages and limitations, current status and indications for further development. The methods use the interaction of energy with the skin, penetrating to various depths in the stratum corneum, epidermis, dermis and subcutaneous layers. They include a detection system such as the retina, film or a digital array, and a processing system to deconstruct, analyze and interpret the information. Similarly, the areas of interest, or targets, have common features. The skin conditions deviate from the ideal or normal state with respect to skin integrity and function. The deviations include evidence of barrier disruption, inflammation, dispigmentation, and vascular change. The user of skin imaging is often interested in the extent and severity of disease. Part of the task in skin imaging is to establish the criteria for the normal condition. The review encompasses the past, present and future of visual assessment, photographic image collection, spectrophotometric techniques, noninvasive histology, and three dimensional scanning. The analytical techniques for processing and extracting specific parameters that inform about the underlying biological status are presented. PMID- 20197741 TI - Evaluation of cutaneous tolerance to Kouriles Acne during sun exposure. AB - AIM: One of the main problems with the use of topical anti-acne agents during the summer season is the risk of inducing photosensitization and contact photoallergy. The aim of this study was to evaluate cutaneous tolerance to Kouriles Acne during sun exposure. METHODS: The study population was 29 subjects with mild-to-moderate acne. The study product was applied to areas of the back which were then irradiated with a solar simulator. RESULTS: The solar simulator produces imitation sunlight with a continuous emission spectrum approximating fairly closely that of terrestrial sunlight. CONCLUSION: No changes in the study variables were observed in the skin areas treated with Kouriles Acne, demonstrating the complete absence of photosensitization reactions after use of the study product. PMID- 20197743 TI - Fluorescence in situ hybridization as a diagnostic modality in melanocytic neoplasma. AB - It has well been established by comparative genomic hybridizations that melanocytic neoplasms have chromosomal copy number aberrations not seen in benign melanocytic nevi. In a rigorous study involving over 400 melanocytic neoplasms we recently evaluated the potential of a number of chromosomal loci frequently altered in melanoma but not in nevi as potential targets for a fluorescence in situ based assay. After evaluating 14 potential chromosomal loci arranged in various 4 probe panels, 6p25, 6q23, Cep6 and 11q13 were identified as the combination of targets best able to differentiate between malignant melanoma and benign nevi. Melanocytic neoplasms were considered as positive for melanoma if any of the following criteria were met; greater than 29% of enumerated cells showed gains in 6p25; greater than 38% of cells showed gains in 11q13; greater than 55% of cells show more copies of 6p25 than Cep6; or if greater than 42% of cells have less copies of 6q23 than Cep6. In a validation set, this 4 probe assay targeting these loci was able to differentiate between melanoma and nevi with a sensitivity of 86.7% and specificity of 95.4%. In this paper we review the multiple steps involved in development of this assay as well as the subsequent performance of this assay in a number of studies looking at its utility in specific differential diagnoses in melanocytic pathology. PMID- 20197744 TI - Genetics of pigmentation and melanoma predisposition. AB - About 5-10% of human cutaneous malignant melanoma is hereditary and known to involve rare germline mutations in highly penetrant, autosomal dominant genes. These genes are important in cell cycle control but are not responsible for all familial cases of melanoma. Epidemiologic studies have linked specific phenotypic traits including fair skin, light-colored eyes, and poor tanning ability to melanoma risks. The ability to visually discern and define pigmentary phenotypes in humans and in animal models has permitted elucidation of many genes involved in pigmentation and melanin biosynthesis. Additional genetic epidemiological studies have recently identified a subset of these pigmentation genes that are associated with risk for melanoma and other cutaneous malignancies as well as photosensitivity. Genome-wide association studies (GWAS) have unveiled single nucleotide polymorphisms (SNPs) or genetic variants in MC1R, TPCN2, ASIP, KITLG, NCKX5, TYR, IRF4, OCA2, and TYRP1 pigmentation genes. These findings emphasize the contribution of pigmentation pathways to melanoma predisposition and tumorigenesis through gene-environment interactions. Since pigmentation genes in the melanin synthesis pathway also confer risk for cutaneous malignancy, a better understanding of the operative molecular mechanisms involved in this relationship has the potential to impact individual risk assessment for cutaneous malignant melanoma in the future. This paper is an overview of our current understanding of pigmentation gene modifications that have been associated with melanoma risk and how these genes can enrich clinical management, prevention, and early detection of malignant melanoma. PMID- 20197745 TI - Recent progresses in understanding pigmentation. AB - Human pigmentation involves production and dispersion of melanin by epidermal melanocytes to neighboring keratinocytes. Melanin synthesis or melanogenesis occurs within the specialized organelle termed melanosomes where the amino acid L tyrosine serves as the starting precursor. Melanocytes from individuals of different pigmentary phenotypes differ in their rate and types of melanin synthesis, as well as in the rate and manner of melanosome transfer. Modern molecular biology methods and the use of transgenic animals have greatly advanced our understanding in the molecular and cellular mechanisms regulating human pigmentation and its disorders. This review examines recent advances in the regulation of human pigmentation and their implication in treatments for the pigmentary disorders. PMID- 20197747 TI - Vitiligo surgery: its evolution as a definite treatment in the stable vitiligo. AB - Vitiligo is a common pigmentary disorder which causes immense psychosocial impact on the patients. This condition is still an enigma in terms of its pathogenesis and management. Although there are various treatment modalities, till date none of it takes care of the cause. Surgical management has evolved significantly and given a ray of hope in stable vitiligo. The main purpose is to review the various surgical modalities available along with a look on the milestones and an effort to find answers to "why, when, whom and how" of vitiligo surgery. This article is based on the review of medical literature regarding various surgical management of vitiligo and also author's experience in this particular field. In addition with this review authors tried to shed light on the factors affecting the outcome of vitiligo surgery. The outcome any surgical procedure in vitiligo depends on the proper patient selection, a proper knowledge of this condition and also about its mystery, an expertise in the procedure and a dedication towards patient care. It is certain that surgical modality will be chosen by many with the hope that it succeeds where medical modality fails. However, there is lot of scope for improvement. So more research should happen in this field so that our aim will shift from "any repigmentation" to "complete and normal repigmentation" and we can achieve a scar less healing of those "bruised souls". PMID- 20197746 TI - Topical treatment and combination approaches for vitiligo: new insights, new developments. AB - Despite much research done involving elucidation of the pathogenesis of vitiligo, a precise cause is still not known. Prevalent hypotheses include the autoimmune, genetic, neural, self-destruction, growth factor deficiency, viral, and convergence theories, which have served as the basis for treatment formulation. Topical therapies have been a mainstay of vitiligo treatment, with or without phototherapy. Topical treatments used in the treatment of vitiligo include steroids, calcineurin inhibitors, vitamin D analogues, pseudocatalase, and depigmenting agents. Combination therapies are used to improve the success rate of repigmentation. In this article, we have examined randomized controlled trials utilizing topical treatments used as monotherapy or combination therapy. Although psoralen and khellin can be used as topical agents, used in conjunction with UV radiation, we have not included them in the review due to their inability to be used as monotherapy. We have also excluded less used or ineffective topical agents, such as melagenina, topical phenylalanine, topical L-DOPA, coal tar, anacarcin forte oil and topical minoxidil. According to current guidelines, a less than two month trial of potent or very potent topical corticosteroids or topical calcineurin inhibitors may be used for therapy of localized vitiligo (<20% skin surface area). Combinations of topical corticosteroids with excimer laser and UVA seem to be more effective than steroids alone. Pseudocatalase plus NB-UVB does not seem to be more effective than placebo with NB-UVB. Combinations of vitamin D analogues have varied efficacy based on which type is used and the type of UV light. Efficacy of calcineurin inhibitor combinations also vary based on the type used and UV light combined, with tacrolimus being more effective with excimer laser. Pimecrolimus has been effective with NB-UVB and excimer laser on facial lesions, and microdermabrasion on localized areas. PMID- 20197748 TI - A North American perspective on dermoscopy: benefits, limitations, and grey zones. AB - Dermoscopy offers novel and cost-effective diagnostic information to guide patient care for melanocytic and non-melanocytic dermatoses. This article reviews the current use of dermoscopy, including its clinical benefits and limitations. Surveys of U.S. and Canadian dermatology residents have demonstrated a desire for improved dermoscopy teaching; an abundance of evidence calls for increasing its use in the clinical setting. Using the current evidence framework, North American dermatology training centers and professional societies should work to foster dermoscopy training and use by both dermatologists and other health care providers. PMID- 20197749 TI - Dermoscopy patterns of nevi associated with melanoma. AB - It is well known that dermoscopy improves the diagnostic accuracy of pigmented skin lesions. Many dermoscopic criteria can be found both in nevi and in melanoma. For the correct interpretation of those criteria, formal training and clinical experience in dermoscopy is needed. This paper reviews the global and local dermoscopic features seen both in nevi and melanoma and focuses on the interpretation of those findings in order to differentiate between benign and malignant melanocytic skin tumors. PMID- 20197750 TI - Melanomas difficult to diagnose via dermoscopy. AB - Due to the potentially lethal nature of melanoma, prompt diagnosis and timely excision are of paramount importance. The clinical ABCD mnemonic (asymmetry, boarder irregularity, color variegation and diameter greater than 6mm) is one of the first and most widely used methods introduced to teach early melanoma recognition. Unfortunately, some melanomas can evade the clinical ABCD rule and mimic benign melanocytic nevi or mimic benign and/or malignant variants of non melanocytic lesions. Over the last two decades, knowledge and insight have been gained into the dermoscopic primary morphology of melanocytic and non-melanocytic lesions. This has allowed for the use of dermoscopy to substantially increase the diagnostic accuracy for melanoma over clinical naked-eye examination alone. Unfortunately, even with dermoscopy, some melanomas remain difficult to diagnose. However, these difficult to diagnose melanomas often reveal subtle dermoscopic clues that allow for their correct identification. In this review, we focus on five variants of melanoma that are challenging to identify and discuss the dermoscopic features that can assist in their diagnosis. PMID- 20197751 TI - Teledermoscopy: education, discussion forums, teleconsulting and mobile teledermoscopy. AB - Teledermoscopy has become in the last years one of the most florid reality of teledermatology. Parallel to the achievement of dermoscopy in clinical settings, teledermoscopy has grown in different fields, namely tele-education and teleconsulting. Blogs, atlases, discussion forums, on line courses and Diploma Courses do not only offer a second opinion consultation but give the opportunity to residents in dermatology and dermatologists with different level of expertise in dermoscopy to easily learn at home, to train or to improve their level in dermoscopy. On the other side, in some countries demand for melanoma screening has led to commercialization of "teledermoscopy" by different companies. Images nowadays can be transmitted over telecommunication networks not only via e-mail or a specific web application but also with last generation cellular phones. This reality opens the new incoming field of mobile teledermatology. Mobile teledermoscopy is a new horizon that might become in the future the basis of the self examination of pigmented skin lesions as a screening tool for malignant cutaneous tumors or to follow-up of high risk patients. PMID- 20197752 TI - A case of airborne allergic contact dermatitis by rubber additives. AB - The authors report a case of acute eyelid dermatitis, arised during the wintertime, and showing symmetric purpuric erythema of both eyelids along with a moderate infiltration and minimal fine scaling. Clinical history and data highlighted that this dermatitis could be related to the contact with the rubber additives contained in a hot-water bottle. In fact, patch test revealed a sensitization to mercaptobenzothiazole (MBT) and MBT mix.For this reason, the use of hot water bottle was forbidden to the patient and the dermatitis rapidly ended up. The aim was our study is to investigate carefully the cause of dermatitis that is often hidden. PMID- 20197753 TI - Lichen amyloidosis in a dark skinned patient. AB - Lichen amyloidosis is a primary localized cutaneous amyloidosis without systemic involvement, characterized by a persistent pruritic eruption of multiple discrete hyperkeratotic papules. The etiology is unknown, but chronic irritation of the skin has been proposed as an etiological factor. We herein report a typical case of lichen amyloidosis in a dark skinned patient. Physical examination revealed slightly shiny, brownish and fine uniform papules approximately 1 cm in diameter, with no accompanying macular lesions. Biopsy specimens taken from some of these papules on the legs showed small globular deposits of an amorphous and slightly eosinophilic substance in the dermis. This substance stained positively with Congo red, indicating the presence of amyloid. In addition, amyloid gave an apple green birefringence when viewed with polarized light. PMID- 20197754 TI - Caffeine as a novel addition to the antivitiligo ammunition. PMID- 20197755 TI - Analyzing responses of mouse olfactory sensory neurons using the air-phase electroolfactogram recording. AB - Animals depend on olfaction for many critical behaviors, such as finding food sources, avoiding predators, and identifying conspecifics for mating and other social interactions. The electroolfactogram (EOG) recording is an informative, easy to conduct, and reliable method to assay olfactory function at the level of the olfactory epithelium. Since the 1956 description of the EOG by Ottoson in frogs, the EOG recording has been applied in many vertebrates including salamanders, rabbits, rats, mice, and humans (reviewed by Scott and Scott Johnson, 2002, ref. 2). The recent advances in genetic modification in mice have rekindled interest in recording the EOG for physiological characterization of olfactory function in knock-out and knock-in mice. EOG recordings have been successfully applied to demonstrate the central role of olfactory signal transduction components, and more recently to characterize the contribution of certain regulatory mechanisms to OSN responses. Odorant detection occurs at the surface of the olfactory epithelium on the cilia of OSNs, where a signal transduction cascade leads to opening of ion channels, generating a current that flows into the cilia and depolarizes the membrane. The EOG is the negative potential recorded extracellularly at the surface of the olfactory epithelium upon odorant stimulation, resulting from a summation of the potential changes caused by individual responsive OSNs in the recording field. Comparison of the amplitude and kinetics of the EOG thus provide valuable information about how genetic modification and other experimental manipulations influence the molecular signaling underlying the OSN response to odor. Here we describe an air-phase EOG recording on a preparation of mouse olfactory turbinates. Briefly, after sacrificing the mouse, the olfactory turbinates are exposed by bisecting the head along the midline and removing the septum. The turbinate preparation is then placed in the recording setup, and a recording electrode is placed at the surface of the olfactory epithelium on one of the medial turbinates. A reference electrode is electrically connected to the tissue through a buffer solution. A continuous stream of humidified air is blown over the surface of the epithelium to keep it moist. The vapor of odorant solutions is puffed into the stream of humidified air to stimulate the epithelium. Responses are recorded and digitized for further analysis. PMID- 20197756 TI - Ad.Egr-TNF and local ionizing radiation suppress metastases by interferon-beta dependent activation of antigen-specific CD8+ T cells. AB - Ad.Egr-TNF is a radioinducible adenovector currently in phase 3 trials for inoperable pancreatic cancer. The combination of Ad.Egr-TNF and ionizing radiation (IR) contributes to local tumor control through the production of tumor necrosis factor-alpha (TNFalpha) in the tumor microenvironment. Moreover, clinical and preclinical studies with Ad.Egr-TNF/IR have suggested that this local approach suppresses the growth of distant metastatic disease; however, the mechanisms responsible for this effect remain unclear. These studies have been performed in wild-type (WT) and TNFR1,2(-/-) mice to assess the role of TNFalpha induced signaling in the suppression of draining lymph node (DLN) metastases. The results demonstrate that production of TNFalpha in the tumor microenvironment induces expression of interferon (IFNbeta). In turn, IFNbeta stimulates the production of chemokines that recruit CD8(+) T cells to the tumor. The results further demonstrate that activation of tumor antigen-specific CD8(+) CTLs contributes to local antitumor activity and suppression of DLN metastases. These findings support a model in which treatment of tumors with Ad.Egr-TNF and IR is mediated by local and distant immune-mediated antitumor effects that suppress the development of metastases. PMID- 20197757 TI - Disease activity, ANCA, and IL23R genotype status determine early response to infliximab in patients with ulcerative colitis. AB - OBJECTIVES: We analyzed the efficacy and safety of the antitumor necrosis factor alpha antibody infliximab (IFX) for induction therapy in patients with moderate to-severe ulcerative colitis (UC) in a large single-center cohort. METHODS: A total of 90 UC patients treated with IFX for 14 weeks were analyzed retrospectively. Colitis activity index (CAI) and markers of inflammation were measured during IFX induction therapy. Genotyping for UC-associated variants in the IL23R gene and in the IL2/IL21 region was performed. RESULTS: At week 2 (after the first IFX infusion), 64.1% of IFX-treated patients had clinical response to IFX and 52.6% were in remission. At week 14 (after three infusions), 61.0% showed clinical response and 52.5% were in remission. The mean CAI decreased significantly from 10.4 points at week 0 to 5.1 at week 2 (P<0.001), to 4.4 at week 6 (P<0.001), and to 5.0 at week 14 (P<0.001). Similarly, IFX therapy significantly decreased C-reactive protein levels and leukocyte counts (P=0.01 and P=0.001 at week 2 and week 0, respectively). Multivariate regression analysis identified high CAI before IFX therapy (P=0.01) and negative antineutrophil cytoplasmatic autoantibody (ANCA) status (P=0.01) as independent positive predictors for response to IFX. Homozygous carriers of inflammatory bowel disease (IBD) risk-increasing IL23R variants were more likely to respond to IFX than were homozygous carriers of IBD risk-decreasing IL23R variants (74.1 vs. 34.6%; P=0.001). No serious adverse IFX-related events requiring hospitalization were recorded. CONCLUSIONS: Our findings suggest that IFX therapy is safe and effective in patients with moderate-to-severe UC. A high CAI before IFX therapy, ANCA seronegativity, and the IL23R genotype were predictors of early response to IFX. PMID- 20197758 TI - Association between colonoscopy rates and colorectal cancer mortality. AB - OBJECTIVES: Although colonoscopy use has increased in the United States and Canada since the early 1990s, it is unclear whether this has been associated with benefit at the population level. Our objective was to evaluate the association between regional colonoscopy rates and death from colorectal cancer (CRC). METHODS: We conducted a natural experiment involving a 14-year follow-up of a cohort of all men and women 50-90 years of age living in Ontario on 1 January 1993 exposed to different intensities of colonoscopy use. Each member of the study cohort was assigned to a region each year, on the basis of his/her residence. Each individual was followed up through 31 December 2006; age- and sex standardized CRC incidence rates were calculated and all CRC deaths were identified. Each year, for each region, the rate of colonoscopies performed on persons 50-90 years of age, per 1,000 population 50-90 years of age, living in the region, was calculated. Multivariable cox proportional hazards models were used to evaluate the association between colonoscopy rate and death from CRC, adjusting for age, sex, comorbidity, income, and location of residence (urban/rural). RESULTS: The study cohort comprised 2,412,077 persons 50-90 years of age. The mean age was 64 years, and 53.7% were women. Colonoscopy rates increased in all regions during 1993-2006. The increased rate of complete colonoscopy was inversely associated with death from CRC. For every 1% increase in complete colonoscopy rate, the hazard of death decreased by 3%. CONCLUSIONS: Increased colonoscopy use was associated with mortality reduction from CRC at the population level. PMID- 20197759 TI - Ischemic colitis and complications of constipation associated with the use of alosetron under a risk management plan: clinical characteristics, outcomes, and incidences. AB - OBJECTIVES: Alosetron is a potent, selective 5-HT(3) receptor antagonist prescribed for women with severe diarrhea-predominant irritable bowel syndrome (IBS-D) under a risk management plan (RMP). The RMP was implemented following cases of ischemic colitis (IC) and complications of constipation (CoC) associated with the use of alosetron. The objectives of this study were to characterize IC and CoC clinical features, outcomes, and incidence rates in the new restricted patient population to evaluate the effectiveness of the RMP in the prevention of serious outcomes. METHODS: Safety data from adverse event reporting from November 2002 through June 2008 were reviewed for probable and possible IC and CoC using the US Food and Drug Administration/sponsor-defined criteria and definitions. Evidence for IC included medical documentation, colonoscopy, and sigmoidoscopy+/ biopsy. Evidence for CoC included medical history and confirmation from health care professionals. RESULTS: Within the inclusion dates, 29,072 patients received 203,939 alosetron prescriptions. Although the absolute numbers of IC and CoC cases have declined, the incidence rates for IC and CoC (0.95 and 0.36 cases per 1,000 patient-years, respectively) were similar to rates during the postmarketing cycle before alosetron withdrawal. In patients with severe IBS-D receiving alosetron (n=998) or placebo (n=411) in clinical trials since reintroduction, incidence rates for IC were 4 and 2 cases per 1,000 patients, respectively. Rates for CoC were 2 and 0 cases per 1,000 patients in the alosetron and placebo groups, respectively. No mesenteric ischemia, surgeries, transfusions, or deaths occurred in patients with IC and no cases of CoC were associated with toxic megacolon, perforation, surgeries, transfusions, or deaths. IC and CoC cases were typically of short duration and all improved on prompt withdrawal of alosetron. CONCLUSIONS: Serious outcomes associated with IC and CoC appear to be mitigated since introduction of alosetron under the RMP. PMID- 20197760 TI - Relative roles of HBsAg seroclearance and mortality in the decline of HBsAg prevalence with increasing age. AB - OBJECTIVES: Mortality and hepatitis B surface antigen (HBsAg) seroclearance are the two extremes of prognostic destination of chronic hepatitis B virus (HBV) infection. Their relative roles in the decline of HBsAg prevalence with increasing age are unknown. METHODS: HBsAg-seropositive subjects with near normal alanine aminotransferase (ALT) were followed up every 3 to 12 months for >1 year. Serum HBsAg was assayed at entry and re-assayed at 3- to 5-year intervals. The morbidity and mortality data were obtained from hospital records, cancer registration, and the national mortality database. The mortality and HBsAg seroclearance rates were examined by survival analysis. RESULTS: At entry, 1,386 subjects (20.9%) were hepatitis B e antigen (HBeAg) seropositive and 5,235 were HBeAg seronegative. The mean follow-up period was 13.6+/-5.4 years (median 13.2; range 1-29.1). HBsAg seroclearance occurred more frequently (555 cases, 8.4%) than mortality (97 cases, 1.5%; P<0.001; overall HBsAg seroclearance/mortality ratio: 5.6), of which only 40% were liver-related cases. Cox regression analysis revealed that male sex, HBeAg negativity, older age, low maximal ALT level, and hepatic steatosis were factors associated with HBsAg seroclearance. The estimated annual HBsAg seroclearance rate was around 1.05-1.61% after the age of 50 years, whereas the estimated mortality rate was quite low before the age of 60 and increased from 0.41% per year at ages 60-64 to 1.19% per year at ages 70-74 years. CONCLUSIONS: The HBsAg seroclearance over mortality rate was 5.6 in this cohort. This suggests that HBsAg seroclearance is the main reason for decreasing HBsAg prevalence with increasing age in the population. PMID- 20197761 TI - Is irritable bowel syndrome a diagnosis of exclusion?: a survey of primary care providers, gastroenterologists, and IBS experts. AB - OBJECTIVES: Guidelines emphasize that irritable bowel syndrome (IBS) is not a diagnosis of exclusion and encourage clinicians to make a positive diagnosis using the Rome criteria alone. Yet many clinicians are concerned about overlooking alternative diagnoses. We measured beliefs about whether IBS is a diagnosis of exclusion, and measured testing proclivity between IBS experts and community providers. METHODS: We developed a survey to measure decision-making in two standardized patients with Rome III-positive IBS, including IBS with diarrhea (D-IBS) and IBS with constipation (C-IBS). The survey elicited provider knowledge and beliefs about IBS, including testing proclivity and beliefs regarding IBS as a diagnosis of exclusion. We surveyed nurse practitioners, primary care physicians, community gastroenterologists, and IBS experts. RESULTS: Experts were less likely than nonexperts to endorse IBS as a diagnosis of exclusion (8 vs. 72%; P<0.0001). In the D-IBS vignette, experts were more likely to make a positive diagnosis of IBS (67 vs. 38%; P<0.001), to perform fewer tests (2.0 vs. 4.1; P<0.01), and to expend less money on testing (US$297 vs. $658; P<0.01). Providers who believed IBS is a diagnosis of exclusion ordered 1.6 more tests and consumed $364 more than others (P<0.0001). Experts only rated celiac sprue screening and complete blood count as appropriate in D-IBS; nonexperts rated most tests as appropriate. Parallel results were found in the C-IBS vignette. CONCLUSIONS: Most community providers believe IBS is a diagnosis of exclusion; this belief is associated with increased resource use. Experts comply more closely with guidelines to diagnose IBS with minimal testing. This disconnect suggests that better implementation of guidelines is warranted to minimize variation and improve cost-effectiveness of care. PMID- 20197762 TI - Prospective cytological assessment of gastrointestinal luminal fluid acquired during EUS: a potential source of false-positive FNA and needle tract seeding. AB - OBJECTIVES: Endoscopic ultrasound (EUS) fine needle aspiration (FNA) can result in false-positive cytology and can also cause needle tract seeding. Our goal was to evaluate a potential cause, namely, the presence of malignant cells within gastrointestinal (GI) luminal fluid, either as a result of tumor sloughing from luminal cancers or secondary to FNA of extraluminal sites. METHODS: During EUS, luminal fluid that is usually aspirated through the echoendoscope suction channel and discarded was instead submitted for cytological analysis among patients with cancer and benign disease. Pre- and post-FNA luminal fluid samples were collected to discern the role of FNA in inducing a positive cytology. When not performing FNA, one sample was collected for the entire examination. The final diagnosis was based on strict clinicopathological criteria and >or=2-year follow-up. This study was conducted in a tertiary referral center. RESULTS: We assessed the prevalence of luminal fluid-positive cytology among patients with luminal (e.g., esophageal), extraluminal (e.g., pancreatic), and benign disease. Among the 140 patients prospectively enrolled with sufficient sampling and follow-up, an examination of luminal fluid cytology showed positive results for malignancy in luminal and extraluminal cancer patients, 48 and 10%, respectively. This included 8 out of 23 esophageal, 4 of 5 gastric, and 9 of 15 rectal cancers. The positive luminal fluid cytology rate with luminal cancers was not affected by performing FNA. Post-FNA luminal fluid cytology was positive in 3 out of 26 with pancreatic cancers. Cytological examination of luminal fluid aspirates did not demonstrate malignant cells in any patient with nonmalignant disease. CONCLUSIONS: Malignant cells are commonly present in the GI luminal fluid of patients with luminal cancers and can also be found in patients with pancreatic cancer after EUS FNA. Further study is needed to determine the impact of these findings on cytological interpretation, staging, risk of needle tract seeding, and patient care and outcomes. PMID- 20197763 TI - Infant nutritional factors and functional constipation in childhood: the Generation R study. AB - OBJECTIVES: Food allergy and celiac disease may lead to childhood constipation. Early introduction of food allergens and gluten in the first year of life has been suggested to have a function in these food intolerances, but it is unclear whether this also holds true for development of childhood constipation. The aim of this study was to assess the association between the timing of introduction of food allergens and gluten early in life and functional constipation in childhood. METHODS: This study was embedded in the Generation R study, a population-based prospective cohort study from fetal life until young adulthood. Functional constipation at 24 months of age was defined in 4,651 children according to the Rome II criteria of defecation frequency <3 times a week or the presence of mainly hard feces for at least 2 weeks. RESULTS: At the age of 24 months, 12% of the children had functional constipation. Children with functional constipation got introduced to gluten more often before or at the age of 6 months than children without functional constipation (37% and 27%, respectively). After adjustment for birth weight, gestational age, gender, ethnicity, maternal education, and family history of atopy and chronic intestinal disorders, functional constipation was significantly associated with early gluten introduction (odds ratio (OR): 1.35; 95% confidence interval (CI): 1.10-1.65). No association was found between timing of introduction of cow's milk, hen's egg, soy, peanuts, and tree nuts with functional constipation. A history of cow's milk allergy in the first year of life was significantly associated with functional constipation in childhood (OR: 1.57; 95% CI: 1.04-2.36). CONCLUSIONS: These results suggest that early gluten introduction in the first year of life provide a trigger for functional constipation in a subset of children. In case of functional constipation, there also might be a role for cow's milk allergy initiated in the first year of life. PMID- 20197764 TI - Gene expression in histologically normal epithelium from breast cancer patients and from cancer-free prophylactic mastectomy patients shares a similar profile. AB - INTRODUCTION: We hypothesised that gene expression in histologically normal (HN) epithelium (NlEpi) would differ between breast cancer patients and usual-risk controls undergoing reduction mammoplasty (RM), and that gene expression in NlEpi from cancer-free prophylactic mastectomy (PM) samples from high-risk women would resemble HN gene expression. METHODS: We analysed gene expression in 73 NlEpi samples microdissected from frozen tissue. In 42 samples, we used microarrays to compare gene expression between 18 RM patients and 18 age-matched HN (9 oestrogen receptor (ER)+, 9 ER-) and 6 PM patients. Data were analysed using a Bayesian approach (BADGE), and validated with quantitative real-time PCR (qPCR) in 31 independent NlEpi samples from 8 RM, 17 HN, and 6 PM patients. RESULTS: A total of 98 probe sets (86 genes) were differentially expressed between RM and HN samples. Performing hierarchical analysis with these 98 probe sets, PM and HN samples clustered together, away from RM samples. qPCR validation of independent samples was high (84%) and uniform in RM compared with HN patients, and lower (58%), but more heterogeneous, in RM compared with PM patients. The 86 genes were implicated in many processes including transcription and the MAPK pathway. CONCLUSION: Gene expression differs between the NlEpi of breast cancer cases and controls. The profile of cancer cases can be discerned in high-risk NlEpi from cancer-free breasts. This suggests that the profile is not an effect of the tumour, but may mark increased risk and reveal the earliest genomic changes of breast cancer. PMID- 20197765 TI - A comprehensive evaluation of the accuracy of cervical pre-cancer detection methods in a high-risk area in East Congo. AB - BACKGROUND: Given the high burden of cervical cancer in low-income settings, there is a need for a convenient and affordable method for detecting and treating pre-cancerous lesions. METHODS: Samples for comparing the accuracy of cytology, virology and histology were collected. Identification of HPV E6/E7 mRNA was performed using PreTect HPV-Proofer. HPV DNA detection was performed by GP5+/6+ PCR, followed by reverse line blot (RLB) for typing. RESULTS: A total of 343 women, aged 25-60 years, attending gynaecological polyclinics in DR Congo were included for sample enrolment. The test positivity rate was conventional and liquid-based cytology (LBC) at cutoff ASCUS+ of 6.9 and 6.6%, respectively; PreTect HPV-Proofer of 7.3%; and consensus DNA PCR for 14 HR types of 18.5%. Sixteen cases of CIN2+ lesions were identified. Of these, conventional cytology identified 66.7% with a specificity of 96.2%, LBC identified 73.3% with a specificity of 96.9%, all at cutoff ASCUS+. HR-HPV DNA detected all CIN2+ cases with a specificity of 85.9%, whereas PreTect HPV-Proofer gave a sensitivity of 81.3% and a specificity of 96.6%. CONCLUSION: Both HPV detection assays showed a higher sensitivity for CIN2+ than did cytological methods. Detecting E6/E7 mRNA from only a subset of HR HPVs, as is the case with PreTect HPV-Proofer, resulted in a similar specificity to cytology and a significantly higher specificity than consensus HR HPV DNA (P<0.0001). PMID- 20197766 TI - Preferences for colorectal cancer screening strategies: a discrete choice experiment. AB - BACKGROUND: Guidelines underline the role of individual preferences in the selection of a screening test, as insufficient evidence is available to recommend one screening test over another. We conducted a study to determine the preferences of individuals and to predict uptake for colorectal cancer (CRC) screening programmes using various screening tests. METHODS: A discrete choice experiment (DCE) questionnaire was distributed among naive subjects, yet to be screened, and previously screened subjects, aged 50-75 years. Subjects were asked to choose between scenarios on the basis of faecal occult blood test (FOBT), flexible sigmoidoscopy (FS), total colonoscopy (TC) with various test-specific screening intervals and mortality reductions, and no screening (opt-out). RESULTS: In total, 489 out of 1498 (33%) screening-naive subjects (52% male; mean age+/-s.d. 61+/-7 years) and 545 out of 769 (71%) previously screened subjects (52% male; mean age+/-s.d. 61+/-6 years) returned the questionnaire. The type of screening test, screening interval, and risk reduction of CRC-related mortality influenced subjects' preferences (all P<0.05). Screening-naive and previously screened subjects equally preferred 5-yearly FS and 10-yearly TC (P=0.24; P=0.11), but favoured both strategies to annual FOBT screening (all P-values <0.001) if, based on the literature, realistic risk reduction of CRC-related mortality was applied. Screening-naive and previously screened subjects were willing to undergo a 10-yearly TC instead of a 5-yearly FS to obtain an additional risk reduction of CRC-related mortality of 45% (P<0.001). CONCLUSION: These data provide insight into the extent by which interval and risk reduction of CRC-related mortality affect preferences for CRC screening tests. Assuming realistic test characteristics, subjects in the target population preferred endoscopic screening over FOBT screening, partly, due to the more favourable risk reduction of CRC-related mortality by endoscopy screening. Increasing the knowledge of potential screenees regarding risk reduction by different screening strategies is, therefore, warranted to prevent unrealistic expectations and to optimise informed choice. PMID- 20197767 TI - Participants' uptake of clinical trial results: a randomised experiment. AB - BACKGROUND: Participants are showing great interest these days in obtaining the results of clinical trials. The aim of this study was to assess patients' uptake and understanding of the results of the trial in which they have participated and the impact of a letter offering patients the possibility of consulting the trial results on a specific website. METHODS: Breast cancer patients participating in a trial on the efficacy of Trastuzumab were randomly subdivided into an Internet group (who received the letter of invitation) and a control group (who did not receive it). Among 115 HER2-positive women from 21 centres, 107 (93%) answered a self-administered questionnaire. RESULTS: Most of the patients in both groups had access to the Internet (72.0%). The majority (97.2%) stated that receiving information about the trial results would be useful, and the oncologist was the most frequently preferred information provider. The Internet group's declared uptake of the trial results was only slightly higher (47.1% vs 33.9%; P=0.166); however, they understood the results significantly more accurately (18.8% vs 5.6%; P=0.039). INTERPRETATION: Although Internet was not the respondents' preferred source of information, the possibility of using this source slightly increased the uptake and understanding of the results. PMID- 20197768 TI - The G-protein-coupled formylpeptide receptor FPR confers a more invasive phenotype on human glioblastoma cells. AB - BACKGROUND: The G-protein-coupled formylpeptide receptor (FPR) that mediates chemotaxis of phagocytic leucocytes induced by bacterial and host-derived chemotactic peptides is selectively expressed by highly malignant human gliomas and contributes to tumour growth and angiogenesis. As invasion of surrounding normal tissues is one of the important features of tumour malignancy, we investigated the function of FPR in the invasive behaviour of human glioblastoma cells. METHODS: Cells (FPR(+) and FPR(-)) were isolated by single-cell cloning from a human glioblastoma cell line U-87MG. The FPR expression was assayed by flow cytometry and reverse transcription PCR. The function of FPR was investigated by chemotaxis and calcium flux induced by FPR agonist fMLF. Tumour cell motility was assayed by a wound-healing model in vitro. The growth and invasive phenotype were observed with subcutaneous implantation of tumour cells in nude mice. Over-expression of FPR in FPR(-) cells was performed by transfection of a plasmid vector-containing human FPR gene. RESULTS: One of the glioma clones F9 that expressed high level of FPR showed a more 'motile' phenotype in vitro as compared with a clone G3 without FPR expression. Although F9 and G3 clones both formed subcutaneous tumours in nude mice, only F9 tumours invaded surrounding mouse connective tissues. Over-expression of FPR in G3 clone (G3F) increased the cell motility in vitro and the capacity of the cells to form more rapidly growing and invasive tumours in nude mice. We further found that, in addition to supernatant of necrotic tumour cells, foetal calf serum and human serum used in culture media contained FPR agonist activity and increased the motility of FPR-expressing glioblastoma cells. CONCLUSION: The expression of FPR is responsible for increased motility of human glioblastoma cells and their formation of highly invasive tumours. PMID- 20197769 TI - High frequency of beta-catenin heterozygous mutations in extra-abdominal fibromatosis: a potential molecular tool for disease management. AB - BACKGROUND: Fibromatosis comprises distinct clinical entities, including sporadic extra-abdominal fibromatosis, which have a high tendency for recurrence, even after adequate resection. There are no known molecular biomarkers of local recurrence. We searched for beta-catenin mutations in a European multicentre series of fibromatosis tumours to relate beta-catenin mutational status to disease outcome. METHODS: Direct sequencing of exon 3 beta-catenin gene was performed for 155 frozen fibromatosis tissues from all topographies. Correlation of outcome with mutation rate and type was performed on the extra-abdominal fibromatosis group (101 patients). RESULTS: Mutations of beta-catenin were detected in 83% of all cases. Among 101 extra-abdominal fibromatosis, similar mutation rates (87%) were observed, namely T41A (39.5%), S45P (9%), S45F (36.5%), and deletion (2%). None of the clinico-pathological parameters were found to be significantly associated with beta-catenin mutational status. With a median follow-up of 62 months, 51 patients relapsed. Five-year recurrence-free survival was significantly worse in beta-catenin-mutated tumours regardless of a specific genotype, compared with wild-type tumours (49 vs 75%, respectively, P=0.02). CONCLUSION: A high frequency (87%) of beta-catenin mutation hallmarks extra abdominal fibromatosis from a large multicentric retrospective study. Moreover, wild-type beta-catenin seems to be an interesting prognostic marker that might be useful in the therapeutic management of extra-abdominal fibromatosis. PMID- 20197770 TI - Are GPs under-investigating older patients presenting with symptoms of ovarian cancer? Observational study using General Practice Research Database. AB - BACKGROUND: Recent studies suggest that older patients in the United Kingdom are not benefiting as much from improvements in cancer treatments as their younger counterparts. We investigate whether this might be partly due to differential referral rates using ovarian cancer as an example. METHODS: From the General Practice Research Database (GPRD), we identified all women aged 40-80 years on 1 June 2002 with a Read code for ovarian cancer between 1 June 2002 and 31 May 2007. Using these records, we compared the GPRD incidence of ovarian cancer with rates compiled from the UK cancer registries and investigated the relationship between age and coded investigations for suspected ovarian cancer. RESULTS: The GPRD rates peaked earlier, at 70-74, and were lower than registry rates for nearly all ages particularly for patients over 59. The proportion investigated or referred by the GP decreased significantly with age and delays between first coded symptom and investigation showed a U-shaped distribution by age. CONCLUSIONS: GPs appear to be less likely to recognise and to refer patients presenting with ovarian cancer as they get older. If our findings extend to other cancers, lack of or delays in referral to secondary care may partly explain poor UK cancer mortality rates of older people. PMID- 20197771 TI - High expression of gabarapl1 is associated with a better outcome for patients with lymph node-positive breast cancer. AB - BACKGROUND: This study evaluates the relation of the early oestrogen-regulated gene gabarapl1 to cellular growth and its prognostic significance in breast adenocarcinoma. METHODS: First, the relation between GABARAPL1 expression and MCF 7 growth rate was analysed. Thereafter, by performing macroarray and reverse transcriptase quantitative-polymerase chain reaction (RT-qPCR) experiments, gabarapl1 expression was quantified in several histological breast tumour types and in a retrospective cohort of 265 breast cancers. RESULTS: GABARAPL1 overexpression inhibited MCF-7 growth rate and gabarapl1 expression was downregulated in breast tumours. Gabarapl1 mRNA levels were found to be significantly lower in tumours presenting a high histological grade, with a lymph node-positive (pN+) and oestrogen and/or progesterone receptor-negative status. In univariate analysis, high gabarapl1 levels were associated with a lower risk of metastasis in all patients (hazard ratio (HR) 4.96), as well as in pN+ patients (HR 14.96). In multivariate analysis, gabarapl1 expression remained significant in all patients (HR 3.63), as well as in pN+ patients (HR 5.65). In univariate or multivariate analysis, gabarapl1 expression did not disclose any difference in metastasis risk in lymph node-negative patients. CONCLUSIONS: Our data show for the first time that the level of gabarapl1 mRNA expression in breast tumours is a good indicator of the risk of recurrence, specifically in pN+ patients. PMID- 20197772 TI - Adenovirus DNA in Guthrie cards from children who develop acute lymphoblastic leukaemia (ALL). AB - BACKGROUND: In search of a proposed viral aetiology of childhood acute lymphoblastic leukaemia (ALL), the common species C adenoviruses were analysed in Guthrie cards. METHODS: Guthrie cards from 243 children who later developed ALL and from 486 matched controls were collected and analysed by nested polymerase chain reaction for the presence of adenovirus DNA. RESULTS: Adenovirus DNA was reliably detected from only two subjects, both of whom developed ALL. CONCLUSION: Adenovirus DNA is detected in Guthrie card samples at too low a frequency to reveal an association between adenovirus and the development of leukaemia. PMID- 20197773 TI - Rheumatoid arthritis: RA--lowering cardiovascular risk with statins. PMID- 20197774 TI - Connective tissue diseases: Belimumab for systemic lupus erythematosus: breaking through? PMID- 20197775 TI - Therapy: Assessing cancer risk of cytokine inhibitors in RA. PMID- 20197776 TI - Vasculitis syndromes: Inducing remission in ANCA-positive vasculitis: time to RAVE? PMID- 20197777 TI - Methotrexate--how does it really work? AB - Methotrexate remains a cornerstone in the treatment of rheumatoid arthritis and other rheumatic diseases. Folate antagonism is known to contribute to the antiproliferative effects that are important in the action of methotrexate against malignant diseases, but concomitant administration of folic or folinic acid does not diminish the anti-inflammatory potential of this agent, which suggests that other mechanisms of action might be operative. Although no single mechanism is sufficient to account for all the anti-inflammatory activities of methotrexate, the release of adenosine from cells has been demonstrated both in vitro and in vivo. Methotrexate might also confer anti-inflammatory properties through the inhibition of polyamines. The biological effects on inflammation associated with adenosine release have provided insight into how methotrexate exerts its effects against inflammatory diseases and at the same time causes some of its well-known adverse effects. These activities contribute to the complex and multifaceted mechanisms that make methotrexate efficacious in the treatment of inflammatory disorders. PMID- 20197778 TI - Histone variants--ancient wrap artists of the epigenome. AB - Histones wrap DNA to form nucleosome particles that compact eukaryotic genomes. Variant histones have evolved crucial roles in chromosome segregation, transcriptional regulation, DNA repair, sperm packaging and other processes. 'Universal' histone variants emerged early in eukaryotic evolution and were later displaced for bulk packaging roles by the canonical histones (H2A, H2B, H3 and H4), the synthesis of which is coupled to DNA replication. Further specializations of histone variants have evolved in some lineages to perform additional tasks. Differences among histone variants in their stability, DNA wrapping, specialized domains that regulate access to DNA, and post-translational modifications, underlie the diverse functions that histones have acquired in evolution. PMID- 20197781 TI - Inhibition of bradykinin receptor B1 protects mice from focal brain injury by reducing blood-brain barrier leakage and inflammation. AB - Kinins are proinflammatory and vasoactive peptides that are released during tissue damage and may contribute to neuronal degeneration, inflammation, and edema formation after brain injury by acting on discrete bradykinin receptors, B1R and B2R. We studied the expression of B1R and B2R and the effect of their inhibition on lesion size, blood-brain barrier (BBB) disruption, and inflammatory processes after a focal cryolesion of the right parietal cortex in mice. B1R and B2R gene transcripts were significantly induced in the lesioned hemispheres of wild-type mice (P<0.05). The volume of the cortical lesions and neuronal damage at 24 h after injury in B1R(-/-) mice were significantly smaller than in wild type controls (2.5+/-2.6 versus 11.5+/-3.9 mm(3), P<0.001). Treatment with the B1R antagonist R-715 1 h after lesion induction likewise reduced lesion volume in wild-type mice (2.6+/-1.4 versus 12.2+/-6.1 mm(3), P<0.001). This was accompanied by a remarkable reduction of BBB disruption and tissue inflammation. In contrast, genetic deletion or pharmacological inhibition of B2R had no significant impact on lesion formation or the development of brain edema. We conclude that B1R inhibition may offer a novel therapeutic strategy after acute brain injuries. PMID- 20197780 TI - Increased plasma and tissue MMP levels are associated with BCSFB and BBB disruption evident on post-contrast FLAIR after experimental stroke. AB - In this study, we examined the relationship between tissue and blood levels of matrix metalloproteinase (MMP)-2 and MMP-9 through gelatin zymography at multiple time points after experimental stroke. We additionally investigated the association between these levels and the evidence of blood-cerebrospinal fluid (CSF) barrier (BCSFB) and blood-brain barrier (BBB) disruption on post-contrast fluid-attenuated inversion-recovery (FLAIR) imaging. Increased plasma MMP-9 was associated with BCSFB disruption at 1h post-reperfusion. Ventricular enhancement ipsilateral to the stroke was 500+/-100%, significantly higher than sham, 24, and 48 h groups. Increased tissue MMP-2 and MMP-9 were associated with BBB disruption at 48 h post-reperfusion. Parenchymal enhancement was 60+/-20% for a volume equivalent to 260+/-80 mm(3). Although the percent enhancement was comparable across groups, the volume of enhancing lesion was significantly higher at 48 h (260+/-80 mm(3), 100%) in comparison to 1 h (8+/-3 mm(3), 3%) and 24 h (51 mm(3), 18%). These findings support the use of imaging markers of BCSFB and BBB status as indirect measures of MMP regulation in the blood and brain tissue. The methods presented herein should be useful in understanding the link between MMPs, barrier integrity, and subsequent hemorrhagic transformation. PMID- 20197782 TI - A spectral analysis approach for determination of regional rates of cerebral protein synthesis with the L-[1-(11)C]leucine PET method. AB - A spectral analysis approach was used to estimate kinetic model parameters of the L-[1-(11)C]leucine positron emission tomography (PET) method and regional rates of cerebral protein synthesis (rCPS) in predefined regions of interest (ROIs). Unlike analyses based on the assumption that tissue ROIs are kinetically homogeneous, spectral analysis allows for heterogeneity within a region. To improve estimation performance, a new approach was developed-spectral analysis with iterative filter (SAIF). In simulation SAIF produced low bias, low variance estimates of the influx rate constant for leucine (K(1)), blood volume fraction (V(b)), fraction of unlabeled leucine in the tissue precursor pool for protein synthesis derived from arterial plasma (lambda), and rCPS. Simulation of normal count rate studies showed that SAIF applied to ROI time-activity curves (TACs) performed comparably to the basis function method (BFM) applied to voxel TACs when voxelwise estimates were averaged over all voxels in the ROI. At low count rates, however, SAIF performed better. In measured L-[1-(11)C]leucine PET data, there was good agreement between ROI-based SAIF estimates and average voxelwise BFM estimates of K(1), V(b), lambda, and rCPS. We conclude that SAIF sufficiently addresses the problem of tissue heterogeneity in ROI data and provides a valid tool for estimation of rCPS, even in low count rate studies. PMID- 20197784 TI - Iron excess in recreational marathon runners. AB - BACKGROUND/OBJECTIVES: Iron deficiency and anemia may impair athletic performance, and iron supplements are commonly consumed by athletes. However, iron overload should be avoided because of the possible long-term adverse health effects. METHODS: We investigated the iron status of 170 male and female recreational runners participating in the Zurich marathon. Iron deficiency was defined either as a plasma ferritin (PF) concentration <15 microg/l (iron depletion) or as the ratio of the concentrations of transferrin receptor (sTfR) to PF (sTfR:log(PF) index) of > or =4.5 (functional iron deficiency). RESULTS: After excluding subjects with elevated C-reactive protein concentrations, iron overload was defined as PF >200 microg/l. Iron depletion was found in only 2 out of 127 men (1.6% of the male study population) and in 12 out of 43 (28.0%) women. Functional iron deficiency was found in 5 (3.9%) and 11 (25.5%) male and female athletes, respectively. Body iron stores, calculated from the sTfR/PF ratio, were significantly higher (P<0.001) among male compared with female marathon runners. Median PF among males was 104 microg/l, and the upper limit of the PF distribution in males was 628 microg/l. Iron overload was found in 19 out of 127 (15.0%) men but only 2 out of 43 in women (4.7%). Gender (male sex), but not age, was a predictor of higher PF (P<0.001). CONCLUSIONS: Iron depletion was present in 28% of female runners but in <2% of males, whereas one in six male runners had signs of iron overload. Although iron supplements are widely used by athletes in an effort to increase performance, our findings indicate excess body iron may be common in male recreational runners and suggest supplements should only be used if tests of iron status indicate deficiency. PMID- 20197785 TI - Effects of alpha-glucans from Agaricus bisporus on ex vivo cytokine production by LPS and PHA-stimulated PBMCs; a placebo-controlled study in slightly hypercholesterolemic subjects. AB - INTRODUCTION: Mushrooms are known for their immune modulating effect for which the polysaccharide fraction, mainly glucans, seem to be responsible. Fungal beta glucans have been studied extensively, whereas little is known about mushroom alpha-glucans. We have earlier shown that the polysaccharide fraction from the mushroom A. bisporus, consisting 90% of alpha-glucans, induced in vitro tumor necrosis factor (TNF)alpha and nitric oxide production. The purpose of this study was to evaluate the effects of consuming. METHOD: A. bisporus alpha-glucan on ex vivo cytokine production by human peripheral mononuclear blood cells (PBMCs). A double-blind randomized trial was designed in which 56 mildly hypercholesterolemic subjects consumed a control fruit juice with no added alpha glucans (200 ml/day) for a 2-week run-in period. For the next 5 weeks, the control group (N=30) continued consumption of the control fruit juice, whereas the intervention group (N=26) consumed the same fruit juice enriched with alpha glucans from A. bisporus (5 g glucans/day). Changes in interleukin (IL)-1beta, IL 6 and TNFalpha cytokine production by lipopolysaccharide (LPS)-stimulated PBMCs were evaluated, as well as changes in T-helper (Th)1/Th2 cytokines by phytohemaggutinin (PHA)-stimulated PBMCs. RESULTS: Consumption of A. bisporus alpha-glucans lower LPS-induced TNFalpha production by 69% (P=0.017) as compared with the control group, whereas no effect on IL-1beta and IL-6 was observed. No obvious Th1-Th2 skewing by PHA-stimulated PBMCs was observed. However, we observed a trend towards a decreased production of IL-12 and IL-10. CONCLUSION: Our current finding suggests that in vivo, alpha-glucans have lost their efficacy to stimulate the immune response as observed in our in vitro mouse model. PMID- 20197783 TI - Activation of PKC isoform beta(I) at the blood-brain barrier rapidly decreases P glycoprotein activity and enhances drug delivery to the brain. AB - P-glycoprotein is an ATP (adenosine triphosphate)-driven drug efflux transporter that is highly expressed at the blood-brain barrier (BBB) and is a major obstacle to the pharmacotherapy of central nervous system diseases, including brain tumors, neuro-AIDS, and epilepsy. Previous studies have shown that P-glycoprotein transport activity in rat brain capillaries is rapidly reduced by the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha) acting through protein kinase C (PKC)-dependent signaling. In this study, we used isolated rat brain capillaries to show that the TNF-alpha-induced reduction of P-glycoprotein activity was prevented by a PKCbeta(I/II) inhibitor, LY333531, and mimicked by a PKCbeta(I/II) activator, 12-deoxyphorbol-13-phenylacetate-20-acetate (dPPA). Western blotting of brain capillary extracts with phospho-specific antibodies showed that dPPA activated PKCbeta(I), but not PKCbeta(II). Moreover, in intact rats, intracarotid infusion of dPPA potently increased brain accumulation of the P-glycoprotein substrate, [(3)H]-verapamil without compromising tight junction integrity. Thus, PKCbeta(I) activation selectively reduced P-glycoprotein activity both in vitro and in vivo. Targeting PKCbeta(I) at the BBB may prove to be an effective strategy for enhancing the delivery of small molecule therapeutics to the brain. PMID- 20197786 TI - Association between dietary calcium and vitamin D intake and cervical carcinogenesis among Japanese women. AB - BACKGROUND/OBJECTIVES: To examine the association between dietary calcium and vitamin D intake and cervical neoplasia risk, we conducted a case-control study. SUBJECTS/METHODS: We selected 405 incident cervical neoplasias (333 invasive carcinomas and 72 cervical intraepithelial neoplasias grade III (CIN3)) and 2025 age-matched non-cancer controls. Dietary information was collected using a semiquantitative food-frequency questionnaire (FFQ). The effect on cervical neoplasia risk was evaluated using conditional logistic regression models. RESULTS: The inverse association between invasive carcinoma and milk, yogurt and fish was observed. On the other hand, the marginally significant inverse association between CIN3 and tofu and green leafy vegetables was observed. Compared with the lowest quartile (Q1) of calcium intake, adjusted odds ratios (ORs) for each of the three upper quartiles (Q2, Q3 and Q4) on invasive carcinoma risk were 0.86 (95% confidence interval (CI) 0.63-1.17), 0.50 (95% CI 0.34-0.73) and 0.68 (95% CI 0.48-0.97), respectively (P for trend=0.004). However, no association between calcium and cancer risk was evident among CIN3 cases (P for trend=0.528). Vitamin D intake showed a similar inverse association (Q2: OR 1.03, 95% CI 0.74-1.44; Q3: OR 0.80, 95% CI 0.56-1.15; and Q4: OR 0.64, 95% CI 0.43 0.94; P for trend=0.013). Similar to calcium, no association between vitamin D intake among CIN3 was evident (P for trend=0.109). An inverse association with calcium was evident in women whose vitamin D intake was low. However, this combined effect was not significant (invasive carcinoma: interaction P=0.819; and CIN3: interaction P=0.101). CONCLUSION: We found an inverse association between dietary calcium and vitamin D intake and cervical neoplasia risk among a group of Japanese women. PMID- 20197787 TI - Association between serum lipoprotein lipase mass concentration and subcutaneous fat accumulation during neonatal period. AB - BACKGROUND/OBJECTIVES: Subcutaneous adipose tissue grows rapidly during the first months of life. Lipoprotein lipase (LPL) has a quantitatively important function in adipose tissue fat accumulation and insulin-like growth factor-I (IGF-I) is a determinant of neonatal growth. Recent studies showed that LPL mass in non heparinized serum (LPLm) was an index of LPL-mediated lipolysis of plasma triacylglycerol (TG). The objective was to know the influence of serum LPL and IGF-I on neonatal subcutaneous fat growth, especially on catch-up growth in low birth weight infants. SUBJECTS/METHODS: We included 47 healthy neonates (30 males, 17 females), including 7 small for gestational age. We measured serum LPLm and IGF-I concentrations at birth and 1 month, and analyzed those associations with subcutaneous fat accumulation. RESULTS: Serum LPLm and IGF-I concentrations increased markedly during the first month, and positively correlated with the sum of skinfold thicknesses both at birth (r=0.573, P=0.0001; r=0.457, P=0.0035) and at 1 month (r=0.614, P<0.0001; r=0.787, P<0.0001, respectively). In addition, serum LPLm concentrations correlated inversely to very low-density lipoprotein (VLDL)-TG levels (r=-0.692, P<0.0001 at birth; r=-0.429, P=0.0052 at 1 month). Moreover, the birth weight Z-score had an inverse association with the postnatal changes in individual serum LPLm concentrations (r=-0.639, P<0.0001). CONCLUSIONS: Both serum LPLm and IGF-I concentrations were the determinants of subcutaneous fat accumulation during the fetal and neonatal periods. During this time, LPL-mediated lipolysis of VLDL-TG may be one of the major mechanisms of rapid growth in subcutaneous fat tissue. Moreover, LPL, as well as IGF-I, may contribute to catch-up growth in smaller neonates. PMID- 20197788 TI - Healthy eating index-C is positively associated with family dinner frequency among students in grades 6-8 from Southern Ontario, Canada. AB - BACKGROUND/OBJECTIVES: Unhealthy eating behaviours may contribute to the rising prevalence of childhood obesity in Canada. The purpose of this study was to describe family dinner frequency (FDF) and its associations with overall diet quality. SUBJECTS/METHODS: The sample included grades six (n=372), seven (n=429) and eight (n=487) students from Southern Ontario. Data were collected with the Food Behaviour Questionnaire, including a single 24-h dietary recall and questions about individual meals. Diet quality was calculated using the Healthy Eating Index-C (HEI-C), which is a recently modified diet quality index. RESULTS: The majority of participants (65%) reported frequent family dinner meals (6-7 days/week versus 20% on 3-5 days/week and 15% on 0-2 days/week). Diet quality scores were higher among participants reporting 6-7 dinners/week (HEI-C=66.2 versus 62.1 and 62.8 for 0-2 and 3-5 days/week, respectively, P<0.001). Adjusted models reported that diet quality scores were also associated with whom participants consumed breakfast (P<0.001), lunch (P<0.001) and dinner (P<0.001), yet they were most strongly associated (negatively) with participants who skipped the meal altogether. CONCLUSIONS: Increased family dinner meals were positively associated with daily diet quality and negatively associated with breakfast and lunch skipping. Promoting family dinner meals in healthy living intervention strategies is advised. PMID- 20197789 TI - Berry meals and risk factors associated with metabolic syndrome. AB - BACKGROUND/OBJECTIVES: Nonalcoholic fatty liver disease is commonly associated with obesity, insulin resistance, dyslipidemia and type 2 diabetes, and can thus be regarded as the hepatic manifestation of metabolic syndrome. In this study we compared the effects of lifestyle intervention with and without industrial berry products, on risk factors associated with metabolic syndrome on slightly overweight women. SUBJECTS/METHODS: Sixty-one female volunteers (average age 42.9 years) were recruited and randomized for a 20-week dietary intervention trial with two parallel treatment groups, one lifestyle intervention group with berry products equaling with an average daily dose of 163 g of northern berries (berry group, diet 1, N=31, of which 28 completed the study) and the other group with lifestyle intervention only (control group, diet 2, N=30, of which 22 completed the study). RESULTS: Increased berry consumption as part of the normal daily diet was the only lifestyle difference between the two intervention groups. The major effects achieved by diet 1 were changes in the levels of alanine aminotransferase (ALAT) and adiponectin (at P-values <0.001 and 0.002, respectively). A statistically significant difference between the two intervention groups was the higher decrease in the ALAT value in the berry group (P=0.003). CONCLUSIONS: The 23% decrease in the ALAT value, from 20.29 to 15.66 U/l in the berry group may be regarded as nutritionally significant by enhancing the liver function. This may contribute positively to the low-grade systemic inflammation in body and decrease the risk of cardiovascular diseases. PMID- 20197791 TI - Dispose to the pole-protein aggregation control in bacteria. PMID- 20197790 TI - Neuromarketing: the hope and hype of neuroimaging in business. AB - The application of neuroimaging methods to product marketing - neuromarketing - has recently gained considerable popularity. We propose that there are two main reasons for this trend. First, the possibility that neuroimaging will become cheaper and faster than other marketing methods; and second, the hope that neuroimaging will provide marketers with information that is not obtainable through conventional marketing methods. Although neuroimaging is unlikely to be cheaper than other tools in the near future, there is growing evidence that it may provide hidden information about the consumer experience. The most promising application of neuroimaging methods to marketing may come before a product is even released - when it is just an idea being developed. PMID- 20197792 TI - Reconsidering reproductive benefit through newborn screening: a systematic review of guidelines on preconception, prenatal and newborn screening. AB - The expansion of newborn screening (NBS) has been accompanied by debate about what benefits should be achieved and the role of parental discretion in their pursuit. The opportunity to inform parents of reproductive risks is among the most valued additional benefits gained through NBS, and assumes prominence where the primary goal of identifying a treatable condition is not assured. We reviewed 53 unique guidelines addressing prenatal, preconception and newborn screening to examine: (1) how generating reproductive risk information is construed as a benefit of screening; and (2) what conditions support the realization of this benefit. Most preconception and prenatal guidelines - where generating reproductive risk information is described as a primary benefit - required that individuals be given a 'cascade of choices', ensuring that each step in the decision-making process was well informed, from deciding to pursue information about reproductive risks to deciding how to manage them. With the exception of three guidelines, NBS policy infrequently attended to the potential for reproductive benefits; further, most guidelines that acknowledged such benefits construed voluntarism narrowly, without attention to the choices attendant on receiving reproductive risk information. This review suggests that prenatal and preconception guidance identifies a coherent framework to support the pursuit of reproductive benefits through population screening programmes. Interestingly, attention to reproductive benefits is increasing among NBS guidance, yet reflection on how such benefits ought to be pursued remains limited. Traditional norms for NBS may require reconsideration where the remit of screening exceeds the primary goal of clinical benefits for infants. PMID- 20197793 TI - The p.A897KfsX4 frameshift variation in desmocollin-2 is not a causative mutation in arrhythmogenic right ventricular cardiomyopathy. AB - Mutations in genes encoding desmosomal proteins have been reported to cause arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), an autosomal dominant disease characterised by progressive myocardial atrophy with fibro-fatty replacement. We screened 112 ARVC/D probands for mutations in desmocollin-2 (DSC2) gene and detected two different amino-acid substitutions (p.E102K, p.I345T) and a frameshift variation (p.A897KfsX4) in 7 (6.2%) patients. DSC2a variant p.A897KfsX4, previously reported as a p.E896fsX900 mutation, was identified in five unrelated probands. Four of them were found to carry one or two mutations in different ARVC/D genes. Unexpectedly, p.A897KfsX4 variation was also found in 6 (1.5%) out of 400 control chromosomes. In vitro functional studies showed that, unlike wild-type DSC2a, this C-terminal mutated protein was localised in the cytoplasm. p.A897KfsX4 variation affects the last five amino acids of the DSC2a isoform but not of DSC2b. In contrast with what we found in other human tissues, in the heart DSC2b is more expressed than DSC2a, suggesting that relative deficiency of DSC2a might be compensated by isoform b. In conclusion, DSC2 gene mutations are not frequently involved in ARVC/D. The p.A897KfsX4 variation, identified in several Italian healthy control subjects, which affects only one of the two DSC2 isoforms, may be considered a rare variant, though possibly affecting phenotypic expression of concomitant ARVC/D mutations. PMID- 20197794 TI - Landscape-epidemiological study design to investigate an environmentally based disease. AB - Cost-effective approaches for identifying and enrolling subjects in community based epidemiological studies face many challenges. Additional challenges arise when a neighborhood scale of analysis is required to distinguish between individual- and group-level risk factors with strong environmental determinants. A stratified, two-stage, cross-sectional, address-based telephone survey of Greater Tucson, Arizona, was conducted in 2002-2003. Subjects were recruited from direct marketing data at neighborhood resolution using a geographic information system (GIS). Three geomorphic strata were divided into two demographic units. Households were randomly selected within census block groups, selected using the probability proportional to size technique. Purchased direct marketing lists represented 45.2% of Census 2000 households in the surveyed block groups. Survey design effect (1.6) on coccidioidomycosis prevalence (88 per 100,000 per year) was substantially reduced in four of the six strata (0.3-0.9). Race-ethnicity was more robust than age and gender to compensate for significant selection bias using poststratification. Clustered, address-based telephone surveys provide a cost-effective, valid method for recruiting populations from address-based lists using a GIS to design surveys and population survey statistical methods for analysis. Landscape ecology provides effective methods for identifying scales of analysis and units for stratification that will improve sampling efficiency when environmental variables of interest are strong predictors. PMID- 20197795 TI - Internal exposure to pollutants and sexual maturation in Flemish adolescents. AB - Flanders is densely populated with much industry and intensive farming. Sexual maturation of adolescents (aged 14-15 years) was studied in relation to internal exposure to pollutants. Serum levels of pollutants and sex hormones were measured in 1679 participants selected as a random sample of the adolescents residing in the study areas. Data on sexual development were obtained from the medical school examination files. Self-assessment questionnaires provided information on health, use of medication and lifestyle factors. In boys, serum levels of hexachlorobenzene (HCB), p,p'-DDE and polychlorinated biphenyls (sum of marker PCB138, 153 and 180) were significantly and positively associated with pubertal staging (pubic hair and genital development). Higher levels of serum HCB and blood lead were associated with, respectively, a lower and a higher risk of gynecomastia. In girls, significant and negative associations were detected between blood lead and pubic hair development; higher exposure to PCBs was significantly associated with a delay in timing of menarche. Environmental exposures to pollutants at levels actually present in the Flemish population are associated with measurable effects on pubertal development. However, further understanding of toxic mode of action and sensitive windows of exposure is needed to explain the current findings. PMID- 20197796 TI - Analysis of the self-imaging effect in plasmonic multimode waveguides. AB - We present studies on the propagation of plasmon waves in metallic multimode waveguides surrounded by a dielectric medium. The permittivity of the metal was determined by a Drude model. The propagation was simulated by the method of lines. The propagating field exhibited the well-known self-imaging phenomenon known as the Talbot effect. The metallic waveguides are lossy. The influence of various parameters on the losses was examined. By a suitable choice of parameters, propagation distances of several Talbot periods are possible. Our investigation also includes simulations for the propagation of eigenmodes of the waveguides and results for the calculation of the effective index. PMID- 20197797 TI - Visible frequency magnetic activity in silver nanocluster metamaterial. AB - We experimentally observe magnetic resonance in the visible frequency region from self-assembled silver nanocluster metamaterials. Extensive numerical modeling studies were conducted to find the optimal nanocluster dimensions. Self-assembly of silver nanoparticles coated with nanoscale silica coating was then performed on polymer templates fabricated by laser interference lithography. The nanoclusters supported magnetic resonance in the visible region, and the extracted effective permeability exhibited Lorentz-like resonance. The experimentally observed lowest value for the real part of permeability was 0.06. The nanocluster metamaterial represents a practical metamaterial architecture that is compatible with the scalable bottom-up manufacturing process. PMID- 20197798 TI - Focusing surface waves with an inhomogeneous metamaterial lens. AB - We propose a new type of surface wave lens that is made of a circular in-plane inhomogeneous metamaterial slab and numerically demonstrate its capability to focus surface waves at optical frequencies. This approach can achieve a smaller focal spot size than the previously demonstrated Ag plasmonic lens. The use of inhomogeneous metamaterials is to decrease the high losses that are usually associated with metamaterials that support large surface k vectors by reducing the propagation distance in high loss metamaterials. PMID- 20197799 TI - Analysis of the coupling of light into a metal-dielectric composite waveguide structure and its application for use as a wavelength-band selection filter. AB - We analyzed and experimentally tested a metal-dielectric composite waveguide structure. After coating the surface of the metal layer in the Kretschmann attenuated total internal reflection configuration with a dielectric layer, we explain the coupling of incident light into the coated layer. After finding the dispersion relationships for the layered media including the metal-dielectric composite waveguide, we can determine a solution for its existence in a complex domain. By inscribing a periodic grating structure in the dielectric layer of the metal-dielectric composite waveguide, we experimentally verify the coupling of incident light on the metal-dielectric composite waveguide structure and propose its application for use as a wavelength-band selection filter. PMID- 20197800 TI - Optical beam focusing with a metal slit array arranged along a semicircular surface and its optimization with a genetic algorithm. AB - A metal slit array arranged along a semicircular surface achieving subwavelength optical beam focusing along the lateral direction is proposed. Taking into consideration surface plasmon polaritons that pass through a metal slit array, we design the array with a curvature. By use of a genetic algorithm, the size of the metal slit and the corresponding curvature are to be determined. Based on our metal slit array configuration, the full width at half-maximum can be achieved on a subwavelength scale. PMID- 20197801 TI - Improving imaging performance of a metallic superlens using the long-range surface plasmon polariton mode cutoff technique. AB - The metallic superlens is based on excitation and amplification of coupled surface plasmon polariton (SPP) modes through a metal slab. However, the narrow and too-high peaks of the SPP resonance modes in the transfer function can jeopardize imaging performance, such that high sidelobes occur in the image of isolated subwavelength patterns. We propose to design a metallic superlens by approaching the cutoff condition of the long-range SPP mode to flatten the transfer function and to improve imaging performance significantly. PMID- 20197803 TI - Emissivity of microstructured silicon. AB - Infrared transmittance and hemispherical-directional reflectance data from 2.5 to 25 microm on microstructured silicon surfaces have been measured, and spectral emissivity has been calculated for this wavelength range. Hemispherical-total emissivity is calculated for the samples and found to be 0.84 before a measurement-induced annealing and 0.65 after the measurement for the sulfur-doped sample. Secondary samples lack a measurement-induced anneal, and reasons for this discrepancy are presented. Emissivity numbers are plotted and compared with a silicon substrate, and Aeroglaze Z306 black paint. Use of microstructured silicon as a blackbody or microbolometer surface is modeled and presented, respectively. PMID- 20197805 TI - Windowed Fourier filtered and quality guided phase unwrapping algorithm: on locally high-order polynomial phase. AB - A windowed Fourier filtered and quality guided (WFF-QG) phase unwrapping algorithm was proposed recently [Appl. Opt. 47, 5420-5428 (2008)], based on the windowed Fourier transform [Appl. Opt. 47, 5408-5419 (2008)] where the phase is assumed to be locally quadric. We consider a locally higher order polynomial phase. After the phase is filtered and unwrapped by the WFF-QG, it is postprocessed by a congruence operation (CO), so that the unwrapped phase is congruent to the original wrapped phase. The unwrapped phase can now be assumed to be a locally high-order polynomial, and, consequently, least squares fitting (LSF) is proposed to suppress the noise. This postprocessing algorithm is abbreviated as CO-LSF. The CO-LSF is theoretically a reasonable choice to improve the WFF-QG results, especially when the noise is severe. This is because for severe noise, a large window is necessary for reliable phase extraction in the WFF-QG. However, this large window makes the quadric phase assumption less reasonable and leads to a large phase error. The CO-LSF thus helps to reduce the phase error by more reasonably assuming that the phase is a high-order polynomial. The polynomial order of 4 is suggested for the CO-LSF, as higher order polynomials do not give significant improvement to the WFF-QG. One disadvantage of the CO-LSF is that it is more sensitive to phase discontinuities than the WFF-QG. PMID- 20197804 TI - Polarization-selective diffractive optical elements with a twisted-nematic liquid crystal display. AB - We propose a method for realizing a polarization-selective diffractive optical element by using of a single twisted-nematic liquid-crystal display (TN-LCD). We have demonstrated that two orthogonal polarization-encoding channels can be formed using a single TN-LCD operated in some special conditions. Based on the two orthogonal encoding channels, two orthogonal polarized components of a field with any complex amplitude can be holographically encoded and reconstructed and, hence, different output images with different polarization states could be obtained, or a vector beam with spatially inhomogeneous polarization distributions, as well as the desired complex amplitude distributions, could be combined. PMID- 20197807 TI - Optical limiting behavior of carbon nanotubes exposed to infrared laser irradiations studied by the Z-scan technique. AB - The optical limiting behavior of multiwalled carbon nanotube (MWCNT) powder in chloroform solution under CO(2) infrared laser irradiations is reported for, to our knowledge, the first time. Here we demonstrate the pure thermal origin of the optical limiting effect in the 160 ns time scale studied. The Z-scan technique appears to be an excellent tool for experimental evaluation of the nonlinear refractive index. An experimental model for the optical limiting behavior of MWCNT suspensions in chloroform is presented. The occurrence of a laser-induced thermal lens through the absorption of energy by the MWCNTs and subsequent heat transfer to the solvent, followed by solvent vapor bubble growth, is the main factor governing the observed drop in transmittance. Pump-probe experiments have been performed to obtain some quantitative estimation of both the rise and decay times of the thermal lensing phenomenon. It was found that the early probe signal decay, tau(1)=149 ns, was of the same order of magnitude as the rise time of the thermal lens, tau(r)=121 ns. When the nonlinear scattering was considered, a total decay time of tau=1.8 micros was obtained. A recovery time for the thermal lens of several tens of milliseconds has been experimentally determined, which is in good accordance with the theoretical value. PMID- 20197806 TI - Effective permittivities with exact second-order accuracy at inclined dielectric interface for the two-dimensional finite-difference time-domain method. AB - Accuracy degradation at a dielectric interface in simulations using the finite difference time-domain method can be prevented by assigning suitable effective permittivities at the nodes in the vicinity of the interface. The effective permittivities with exact second-order accuracy at the interface inclined to the Yee-lattice axis are analytically derived for what we believe to be the first time. We discuss two interfaces with different inclined angles between their normal and the Yee-lattice axis in the case of two-dimensional TE polarization. The tangent of the angle is 1 for one interface and 1/2 for the other. With the derived effective permittivities, reflection and transmission at the interface are simulated with second-order accuracy with respect to cell size. The accuracy is demonstrated by numerical examples. PMID- 20197808 TI - Nonsinusoidal phase modulations for high-power laser performance control: stimulated Brillouin scattering and FM-to-AM conversion. AB - High-power lasers, such as the Laser MegaJoule (LMJ), have to be phase modulated to avoid stimulated Brillouin scattering (SBS) that may strongly damage optics at the end of the laser chain. Current spectral broadening on LMJ is performed with a sinusoidal phase modulation. This pure sinusoidal phase modulation leads to inhomogeneous spectral power densities (SPD). Thus, for a same SBS power threshold, the sinusoidal phase-modulated spectrum has to be larger than the equivalent ideal SPD with isoenergetic peaks. We present in this paper a technique to generate energy-balanced Dirac peaks spectra thanks to nonsinusoidal phase modulations. Thus, we can build a narrower spectrum with a nonsinusoidal phase modulation that has the same SBS threshold as a sinusoidal phase modulation, and we show that FM-to-AM conversion can be strongly reduced, which is of great interest for LMJ laser performance, with reductions up to 40%. PMID- 20197809 TI - Correct equations and common approximations for calculating Rayleigh scatter in pure gases and mixtures and evaluation of differences. AB - Equations for Rayleigh scattering in a mixture of gases are derived and compared to frequent approximations in the literature. The traditional Rayleigh scattering equation as modified by King for scatter from a pure gas is correct, whereas another version sometimes appearing in modern literature is erroneous. Use of a mixture's refractive index, which is equivalent to assuming the isotropic molecular polarizabilities of the component gases are identical, is an approximation. Another common approximation is using only number-density weighting of the King factors. Approximation errors can be large when the major components of a mixture have disparate optical properties. Fortunately, the errors for Earth's air are much smaller and comparable to errors from other sources. PMID- 20197810 TI - Monitoring intermediate states of bacteriorhodopsin monolayers using near-field optical microscopy. AB - We demonstrate single-molecule-level features using near-field optical microscopy on bacteriorhodopsin (bR), a membrane protein that functions as a light-driven proton pump. The photophysical properties of bR are utilized in this imaging technique, using a combination of photoexcitation sources, to accurately identify the active regions and quantify the optical parameters. The studies of bR monolayers are carried out on inert quartz substrates as well as active conducting polymer (polyaniline) substrates. The substrate also plays an important role in the photocycle quantum efficiencies. We speculate on mechanisms governing the higher near-field absorption strength of bR molecules. PMID- 20197811 TI - Smart agile lens remote optical sensor for three-dimensional object shape measurements. AB - We demonstrate what is, to the best of our knowledge, the first electronically controlled variable focus lens (ECVFL)-based sensor for remote object shape sensing. Using a target illuminating laser, the axial depths of the shape features on a given object are measured by observing the intensity profile of the optical beam falling on the object surface and tuning the ECVFL focal length to form a minimum beam spot. Using a lens focal length control calibration table, the object feature depths are computed. Transverse measurement of the dimensions of each object feature is done using a surface-flooding technique that completely illuminates a given feature. Alternately, transverse measurements can also be made by the variable spatial sampling scan technique, where, depending upon the feature sizes, the spatial sampling spot beam size is controlled using the ECVFL. A proof-of-concept sensor is demonstrated using an optical beam from a laser source operating at a power of 10 mW and a wavelength of 633 nm. A three dimensional (3D) test object constructed from LEGO building blocks forms has three mini-skyscraper structures labeled A, B, and C. The (x, y, z) dimensions for A, B, and C are (8 mm, 8 mm, 124.84 mm), (24.2 mm, 24.2 mm, 38.5 mm), and (15.86 mm, 15.86 mm, 86.74 mm), respectively. The smart sensor experimentally measured (x,y,z) dimensions for A, B, C are (7.95 mm, 7.95 mm, 120 mm), (24.1 mm, 24.1 mm, 37 mm), and (15.8 mm, 15.8 mm, 85 mm), respectively. The average shape sensor transverse measurement percentage errors for A, B, and C are +/-0.625%, +/ 0.41%, and +/-0.38%, respectively. The average shape sensor axial measurement percentage errors for A, B, and C are +/-4.03%, +/-3.9%, and +/-2.01%, respectively. Applications for the proposed shape sensor include machine parts inspection, 3D object reconstruction, and animation. PMID- 20197812 TI - Photon-trap spectroscopy applied to molecules adsorbed on a solid surface: probing with a standing wave versus a propagating wave. AB - We apply photon-trap spectroscopy, a generalized scheme of cavity ringdown spectroscopy, to infrared spectroscopy of molecular adsorbates on a solid substrate. The storage lifetime of light in a high-finesse Fabry-Perot cavity provides a high absorbance sensitivity for the substrate sample, which is placed exactly normal to the light beam in the cavity to minimize optical losses. Infrared spectra of the C-H stretching vibration of alkylsiloxane monolayer films on a silicon substrate are measured in three ways, namely by employing pulsed and continuous-wave lasers as well as by conventional Fourier transform infrared spectroscopy. The magnitude of optical absorption is shown to vary by the character of the interacting light used in the measurement, i.e., a standing wave versus a propagating wave. PMID- 20197813 TI - Investigation of all-optical nonreturn-to-zero-to-return-to-zero format converter based on a semiconductor optical amplifier and a reconfigurable delayed interferometer. AB - A simple and robust all-optical nonreturn-to-zero to return-to-zero (RZ) format converter is demonstrated and investigated using a semiconductor optical amplifier (SOA) and a reconfigurable delayed interferometer. The scheme can be used to convert input signals at different bit rates and obtain converted signals with tunable duty cycles. Format conversion at 10 Gb/s is achieved with a negative power penalty of -4.9 dB at a bit-error rate of 10(-9). Transmission of the converted RZ signal over a dispersion-managed fiber link of 80 km results in only a small power penalty of 0.9 dB. In addition, the format converter is found to be insensitive to the power fluctuation of the optical clock, as the SOA works in the saturation regime. PMID- 20197814 TI - Controlling surface plasmon of several pair arrays of silver-shell nanocylinders. AB - We studied, numerically, the characteristics of the surface plasmon of a system consisting of several pair arrays of silver-shell nanocylinders. Effects from different numbers of pair arrays, illumination wavelengths, and the core refractive index of silver-shell nanocylinders are studied by using the finite element method. Results show that the peak wavelengths shift to shorter wavelengths (blueshifted) when the number of pair arrays increases from three to six. The near-field intensities in the gaps of the proposed type 1 structure can be tuned much stronger with a redshift by varying the wavelength of the incident light. The main features of surface plasmon effects can be qualitatively understood from some simple models of three, four, five, and six pairs of silver shell nanocylinders. PMID- 20197815 TI - Hologram-based watermarking capable of surviving print-scan process. AB - We propose a watermarking scheme for hardcopy pictures based on computer generated holography. A hologram of the watermark is produced using a conjugate symmetric extension technique, and its spectrum is inserted into the discrete cosine transform domain of the image. Adjusting the watermark placement in a data array, a trade-off between transparency and robustness is achieved. Anticropping and the interference-resisting capability of holograms make the watermark robust against manipulations commonly performed on digital images during postprocessing, including contrast enhancement, moderate smoothing and sharpening, and, in particular, geometric transformation. Most importantly, the proposed hologram based watermarking can withstand the printing-scanning attack and, therefore, is useful in protecting copyright of digital photographs both as electronic and hardcopy versions. PMID- 20197816 TI - Resonances in the efficiency factors for absorption: Mie scattering theory. PMID- 20197817 TI - Discrete absorptions and emissions in crop spectra. PMID- 20197818 TI - Optical activities in the universities. PMID- 20197819 TI - Closed form expression for optical pulse broadening in multiple-scattering media. PMID- 20197820 TI - Additional property of interferometer symmetry. PMID- 20197821 TI - Argon lines from electrodeless mercury-198 lamps. PMID- 20197822 TI - AFGL trace gas compilation. PMID- 20197823 TI - Total internal reflection: a deeper look. AB - In the present paper, we have presented a Maxwellian boundary-type solution for total internal reflection with unbounded incident waves at an interface between two nonabsorbing media, in which the instantaneous, time varying, and time averaged radiant fluxes have been determined at all points in the two media. Solutions for the s and p polarizations were found for which the instantaneous tangential E and H components and normal components of the radiant flux were continuous in crossing the interface. From these radiant fluxes, it was possible to derive equations for the flow lines, to determine the instantaneous radiant fluxes along these flow lines, and to see how the methods of propagation differed in the two media and for the two polarizations. At the interface, the flow lines and their radiant fluxes experience unusual reflection and refraction processes, follow curved flow lines in the second medium, and return into the first medium with boundary conditions, which are mirror images of those at the points of incidence. These unfamiliar processes in the second medium are due to inhomogeneous waves, whose properties have not been understood. When these instantaneous solutions are extended to time varying and time averaged radiant fluxes, it is interesting to see how incident planes of constant radiant flux and phase experience such complex processes in the second medium and are still able to generate other reflected planes of constant radiant flux and phase in the first medium. These ideas prescribe specific detailed functions for the E and H fields and radiant fluxes in the second medium, which help to answer many long standing questions about the physical processes involved in total internal reflection. PMID- 20197824 TI - Nonlinear reflection properties of germanium associated with thermal effects. AB - Thermal excitations on a germanium surface under simultaneous irradiation by two monochromatic optical beams, one strong and one weak, are predicted as functions of the angular separation and frequency difference between the beams, their relative polarization, their intensities, and pulse durations. Nonlinear optical reflection for Q-switched ruby laser pulses is then described. Weak reflected and diffracted beam intensities show tendencies in which the former is preferentially enhanced for a downshifted weak beam frequency, while the latter depends only on the shift magnitude. Both are suppressed for large shifts or large angular separations between input beams. PMID- 20197825 TI - Refractive index changes in germanium due to intense radiation. AB - The changes in the real and imaginary parts of the index of refraction of germanium have been measured at 6943 A as a function of incident power up to 5 MW/cm(2). The results indicate that for nanosecond pulses the primary cause of the change is heating with temperature changes of up to 350 degrees C. In addition, a diffraction grating formed on the surface by interference between the intense beam and a probing beam produces an additional effective change in reflectivity as well as a spatially separated diffracted beam. It is shown that, for a grating spacing of 20 mum, transverse diffusion effects cause no degradation in the effectiveness of the grating. PMID- 20197826 TI - Generalized equations for the calculation of absorptance, reflectance, and transmittance of a number of parallel surfaces. AB - Derivations of general equations to describe the absorptance, reflectance, and transmittance of any number of parallel surfaces are presented. Two corollaries describing the propagation of light by two surfaces are derived and then used to derive the general equations. These general equations have wide utility because they describe exactly the propagation of light by any number or type of parallel surfaces (interfaces), using relatively simple expressions, which are readily adaptable for digital computer use. PMID- 20197827 TI - Fast computation method for derivatives of multilayer stack reflectance. AB - An analytical procedure for the calculation of the derivatives of the reflectance R of a dielectric multilayer stack is presented. Considered are the derivatives ( partial differentialR/ partial differentialn(k))d, ( partial differentialR/ partial differentialn(k))D, ( partial differentialR/ partial differentiald(k))n, and ( partial differentialR/ partial differentialD(k))n, n(k), d(k), and D(k) being the refractive index, the thickness, and the effective optical thickness of the kth layer, respectively. These calculations lead to a computational algorithm which, as compared with the method using finite difference approximation, reduces the computer time by a factor of f (the total number of layers). PMID- 20197828 TI - Wavelength-scanning polarization-modulation ellipsometry: some practical considerations. AB - A discussion is presented of the practical considerations involved in wavelength scanning polarization-modulation ellipsometry. Emphasis is placed on factors affecting accuracy and precision and on the alignment of the optical elements. The system described is used to measure the optical properties of air-cleaved KCI and of clean and tarnished Ag surfaces in ultrahigh vacuum in the 250-650-nm range. PMID- 20197829 TI - Measurement of steep aspheric surfaces. AB - A method of measuring the shape of high numerical aperture (NA <0.95), convex or concave, aspheric surfaces is described. The aspheric slope may be as large as 1200 waves/rad. The method is applied in two steps. First, a standard measurement is performed to obtain a reference surface. Second, the reproducibility of the fabrication of aspheric surfaces is tested by means of a holographic comparison method. The measuring error is smaller than 0.1 microm. PMID- 20197830 TI - Interferometric testing with computer-generated holograms: aberration balancing method and error analysis. AB - When testing aspheric surfaces with a computer-generated hologram, some problems should be considered. In this paper, first, we compare two types of hologram: Lohmann and interference. The phase error in the Lohmann type hologram is estimated, and a method of compensating the error is described. Second, we discuss the relation between the shape of the required wavefront and the number of resolution cells of the hologram. Since testing smaller f number optical elements increases the required number of resolution cells of the hologram, we propose the aberration balancing method to reduce the number of resolution cells. The optimum values of the defocus aberration are calculated. Especially, it is shown that the number of resolution cells in the hologram is capable of being reduced to 25%. Third, we discuss the error due to incorrect hologram size and due to misalignment of the optical system when the aberration balancing method is applied. Finally, an experimental example for testing an aspheric mirror 150 mm in diameter and 300 mm in focal length is given. PMID- 20197831 TI - Latent-imaging photopolymer systems. AB - A new high-resolution latent-imaging photopolymer system is reported for recording thick refractive-index patterns such as volume phase holograms and grating devices. A photosensitive polymerization initiator is chemisorbed on the surfaces of a porous glass matrix (average pore diameter 4 nm). The latent image is recorded by exposing the sensitized glass such that the initiator is selectively destroyed in the desired pattern. During this step, there are only small changes in the optical properties of the material, thus preventing interactions between the image being written and the optical fields writing it. The image is then developed by filling the matrix with a suitable monomer mixture and using a uniform optical exposure to initiate polymerization. During the development step, the spatially modulated initiator concentration, which constitutes the latent image, leads to a corresponding modulation of the refractive index of the polymer, and increases in the amplitude of the image of as much as a factor of 50 (Deltan up to 3 x 10(-4)) have been observed. PMID- 20197832 TI - Self-scanned photodiode array: high performance operation in high dispersion astronomical spectrophotometry. AB - We have developed a multichannel spectrophotometric detector system using a 1024 element self-scanned silicon photodiode array, which is now in routine operation with the high-dispersion coude spectrograph of the University of Texas McDonald Observatory 2.7-m telescope. We discuss operational considerations in the use of such arrays for high precision and low light level spectrophotometry. A detailed description of the system is presented. Performance of the detector as measured in the laboratory and on astronomical program objects is described, and it is shown that these arrays are highly effective detectors for high dispersion astronomical spectroscopy. PMID- 20197833 TI - Spectral irradiance standard for the ultraviolet: the deuterium lamp. AB - A set of deuterium lamps is calibrated as spectral irradiance standards in the 200-350-nm spectral region utilizing both a high accuracy tungsten spectral irradiance standard and a newly developed argon mini-arc spectral radiance standard. The method which enables a transfer from a spectral radiance to a spectral irradiance standard is described. The following characteristics of the deuterium lamp irradiance standard are determined: sensitivity to alignment; dependence on input power and solid angle; reproducibility; and stability. The absolute spectral radiance is also measured in the 167-330-nm region. Based upon these measurements, values of the spectral irradiance below 200 nm are obtained through extrapolation. PMID- 20197834 TI - Soft x-ray imaging with toroidal mirrors. AB - The fabrication of small toroidal mirrors in tandem for x-ray imaging is discussed. First, a male mandrel is made by grinding and polishing a molybdenum rod. Then. a glass replica is cast and lightly polished. The method of polishing the male mandrel is described. A photograph of a copper mesh taken with a 8.3-A x ray is shown. PMID- 20197835 TI - Balloon-borne ultraviolet stellar echelle spectrograph. AB - During the nights of 19, 20 May 1976 and 16, 17 September 1976, an 800-kg astronomical payload, developed by the NASA Johnson Space Center at Houston and the Astronomical Institute at Utrecht, was floating at 40-km altitude and recorded high-resolution uv spectra of stars. The spectral region of 200-340 am was covered with a spectral resolution of 0.01 nm. The optical system consisted of a 40-cm diam telescope with 1-sec of arc pointing capabilities, an echelle spectrograph working in spectral orders 66 to 112 and a SEC-vidicon integrating detector. Due to the high spectral simultaneity gain of the system 53 complete spectra of thirty-three different stars, with spectral types between 09.5 and M2 and with visual magnitudes between 0 and 4.5, could be obtained during the two nights of observation. Ozone in the residual atmosphere above 40 km reduces the atmospheric transmission around 250 nm to approximately 0.1, but with suitable integration times also in this region stars can be studied spectroscopically from balloon altitudes. PMID- 20197836 TI - Four-component polarization measurement of lidar atmospheric scattering. AB - Measurements of the backscattering from the lower atmosphere of linearly polarized ruby lidar pulses at 694 nm are described. A four-channel receiver provides simultaneous measurements of the four components of the Stokes vector of the scattered radiation. These data are used to obtain information on the polarization state of the scattering and its dependence on atmospheric conditions. Results are presented and discussed for clear air, hazes, and several cloud types. In water droplet clouds some rotation of the plane of polarization and changes in ellipticity are noted in the backscattered wave. Linear polarization of the penetrating lidar beam is strongly preserved even in quite dense clouds. In view of the increased complexity of the four-component measurement technique it would appear that in such cases two-channel measurements of delta would be the most efficient lidar approach. PMID- 20197838 TI - Analysis of differential absorption lidar from the space shuttle. AB - A parametric analysis of the Shuttle-borne differential absorption lidar concept for the measurement of atmospheric trace constituent profiles in the nadir viewing mode is presented. The criterion of an optimum constituent optical depth is developed and applied to generate estimates of range resolved measurement errors. These errors emphasize the fundamental limitations for establishing the feasibility of range-resolved differential absorption lidar measurements from Shuttle. With current lidar system technology, atmospheric backscatter density profiles may be adequately determined up to about 60-km altitude at the doubled ruby wavelength, 3472 A, for a 1-J/pulse laser and a 1-m(2) receiver. Potential range-resolved measurements of stratospheric and mesospheric trace constituents by differential absorption from Shuttle altitudes are limited to H(2)O, CH(4), N(2)O, O(3), and CO, species which can be more easily measured by passive limb viewing techniques. Range-resolved water vapor data for the lower troposphere may be obtained with accuracies which would be competitive with those from passive sensors. Technology advances in laser power and efficiency and in heterodyne detectors may allow other tropospheric species measurements from Shuttle in the future. PMID- 20197837 TI - Reflectivity of gold coated surfaces in the soft x-ray range. AB - Reflectivity of gold surfaces strongly depends on sample conditions. A set of measurements in the soft x-ray range is presented. The results are compared with those computed on the basis of Fresnel law and the other available data. We also indicate some procedural steps for the calibration of grazing incidence optics. PMID- 20197839 TI - Particle size measuring device in real time for dense particulate systems. AB - The design and performance of a real-time particle size measuring device for dense particulate systems are reported. Based on measuring the ratio of scattered light at two angles, this device, in contrast to particle sizing instruments previously reported, allows more than one particle in the focal volume at any time and selects the scattered light pulses for processing. Size distributions have been determined with an average number of particles in the focal volume of up to 2.5. This represents a potential increase of more than an order of magnitude in particle concentration over single particle sizing devices. PMID- 20197840 TI - Exploding PbS film Q-switch laser. AB - Exploding PbS film Q-switches in a Nd(3+) glass laser produce approximately 40 nsec. giant pulses. This investigation characterizes the laser giant pulse energy, over-all efficiency and ratio of giant pulse energy to total output energy as functions of flashlamp input energy, PbS film reflectivity, output mirror reflectivity, and flashlamp pulse width for both an apertured and unapertured laser. The laser emits giant pulses which contain 0.88 J and 1.8 J of energy, at an over-all efficiency of 0.086% and 0.21% for an apertured and unapertured laser, respectively, and ratios of giant pulse energy to total output energy approaching 100%. This investigation has illustrated that a laser Q switched by a PbS exploding film can emit more energy, more efficiently, than the same laser Q-switched by a conventional Pockels cell. It is suspected that PbS is not the most efficient material; however, other material could be tested in a similar manner to determine a more optimum material. PMID- 20197841 TI - Measurement of loss and output numerical aperture of optical fiber splices. AB - An ensemble of optical fiber splices has been evaluated to determine how source launching conditions and length of fiber between the source, splice, and detector affect the splice loss and far field output NA. The loss of a splice is strongly dependent upon the energy distribution and NA of the beam at the input of the splice. For the range of NA's considered, the splice loss varied by 0.5 dB. The average NA at the output of the ensemble of splices was greater than its corresponding input NA by as much as 12%. The splice appears to act as a transformer converting the input energy distribution into one at the output that contains a greater amount of its energy in higher order modes. As a consequence of this, the loss of a fiber following the splice in a long transmission path is greater than the loss the fiber would exhibit if measured with steady state excitation conditions. PMID- 20197842 TI - Fiber optic sheet formation by selective photopolymerization. AB - Fiber optic sheets (8 lines/mm), applicable as image convertors in a facsimile input system, have been formed by a selective monomer photopolymerization in polymer films. In this method, the monomer is doped in a plane film with a higher refractive index and then photopolymerized selectively through a mask pattern by uv light irradiation, so that all light paths are formed simultaneously, instead of arranging individual optical fibers. The attenuation was 0.15-0.20 dB/cm at lambda = 633 nm, and the output light intensity distribution formed by a test chart through light paths showed a resolution of up to ~5 lines/mm. PMID- 20197844 TI - Multiple-invariant space-variant optical processors. AB - Multiple invariant optical correlators are considered. By multiple invariance, we mean invariance to more than one distortion parameter per axis of the processor. Space variant optical processors using coordinate transformations and a new phase detection scheme are used to realize such correlators. A theoretical analysis and experimental verification are included. PMID- 20197843 TI - Baseband frequency response measurement system for optical components. AB - Knowledge of the baseband frequency responses of optical components is prerequisite to the design of optical fiber transmission systems. The sweep frequency method is effective for obtaining frequency responses because of its large SNR. However, the use of GaAs lasers as optical signal sources involves several problems such as resonances below 1 GHz and spectrum broadening. In order to overcome these problems, a single transverse mode GaAs laser called a buried heterostructure GaAs laser was employed as an optical signal source in the sweep frequency measurement system. This measurement system has a wideband flat sweep frequency range of 0.5-1300 MHz as well as a wide dynamic range of more than 60 dB at optical levels. PMID- 20197845 TI - Image restoration by spline functions. AB - Spline functions, because of their highly desirable interpolating and approximating characteristics, are used as a potential alternative to the conventional pulse approximation method in digital image processing. In space invariant imaging systems, the object and point-spread function are represented by a class of spline functions called B-splines. Exploiting the convolutional property of B-splines, the deterministic part of the degraded image is another B spline of higher degree. A minimum norm principle leading to pseudoinversion is used for the restoration of space-invariant degradations with underdetermined and overdetermined models. The singular-value-decomposition technique is used to determine the pseudoinverse. PMID- 20197847 TI - Optical activities in industry. PMID- 20197846 TI - Laser Doppler particle measuring system using nonsinusoidal forced vibration and bispectral analysis. AB - A new laser Doppler particle measuring method which resists additive Gaussian noises is proposed. Particles are forced-vibrated by nonsinusoidal waves with fixed bispectral characteristics, and the responses are measured by using a velocity measuring system which consists of the optics of a laser Doppler velocimeter, FM discriminator, and a bispectral analyzer. Application of bispectral analysis is very effective in eliminating additive Gaussian noise even when the power of noise is fairly large. The principle, practical construction, and some experimental results are shown. The results show clearly the effectiveness of the method. PMID- 20197848 TI - Meeting reports. PMID- 20197850 TI - Patents. AB - 3,978,429; 3,984,784; 3,986,139; 3,986,141; 3,987,373; 4,013,365; 4,016,427; 4,017,807; 4,019,151. PMID- 20197849 TI - Giant mirror of Birr. PMID- 20197851 TI - Interferometric measurement of thermal expansion. PMID- 20197852 TI - Ultraviolet limit of solar radiation at the earth's surface with a photon counting monochromator. PMID- 20197853 TI - Signal-to-noise ratios of multiplexing spectrometers in high backgrounds. PMID- 20197854 TI - Focus errors in laser beam divergence measurements. PMID- 20197855 TI - Influence of Brewster angle windows on confocal unstable resonator beam properties. PMID- 20197856 TI - Cone collectors for finite sources. PMID- 20197857 TI - Nonlinear interaction of a powerful light beam with crystal lattice vibrations. PMID- 20197858 TI - Accurate three-dimensional eyetracker. AB - A combined optometer and eyetracking instrument has been developed to measure both the dynamic refractive power and the direction of gaze of the same eye. In effect, this instrument measures, as a function of time, the point in 3-D space on which the eye is fixated. Nothing is attached to the subject (patient), who is easily aligned in the device. The measuring wavelength is in the near ir and is invisible. The usable field of the instrument is greater than 20 degrees ; the horizontal and vertical directions of gaze are measured with a noise level and repeatability of about 1 min of arc. The range of the optometer is approximately 4 to +12 diopters; refractive power is measured to about 0.1 diopter. Two instruments may be aligned side by side for tracking both eyes simultaneously. Three-dimensional monocular and binocular eye movement records are shown. PMID- 20197859 TI - Three-dimensional visual stimulus deflector. AB - A 3-D visual stimulus deflector has been designed so that a subject can view any stimulus pattern or object through it, and the pattern (up to 25 degrees in diameter) can be moved over a range of 40 degrees horizontally and 30 degrees vertically. The optical distance of the object being viewed can be changed over a 15-diopter range, while the brightness and visual angle subtended by the object remain fixed. Further, the observer can view the object through a pupil of any desired shape and transmittance. Horizontal and vertical movements are independent, with time delays of 1 msec and a response range from dc to 200 Hz. Focus change is independent of lateral field motion and has a time delay of 12 msec and a maximum slewing rate of approximately 40 diopters/sec. Two such devices can be aligned side by side in a binocular configuration for independent 3-D control of the fixation of each eye. PMID- 20197860 TI - Lens design merit functions: rms image spot size and rms optical path difference. AB - The chief lens design problem is to get all the optical paths from object point to image point equal within a small fraction of a wavelength to ensure that spherical wavefronts will be converging on all image points in the field of view. The LASL lens design program minimizes the lateral deviations of the rays from their ideal image points. Results given here show that this procedure also minimizes the optical path difference and that there is a linear relationship between the rms image spot size and the rms optical path difference. PMID- 20197861 TI - Image processing system using incoherent image feedback. AB - By combining a TV system with suitable optical systems an image processor which uses the technique of image feedback is constructed. The special features are the simplicity of the arrangement and the flexibility for the treatable input images as well as the ability as a real-time processor. Results for ghost image elimination under several conditions and for sharping of images are shown. PMID- 20197862 TI - Continuous wave uv radiation tunable from 285 nm to 400 nm by harmonic and sum frequency generation. AB - Broadly tunable cw uv radiation has been generated by frequency doubling and sum frequency mixing in ADP, ADA, and RDP, using the output of a Kr laser, a Rh6G dye laser, and an oxazine 1 dye laser. Continuous tunable uv radiation has been obtained from 285 nm to 400 nm with a maximum power of 750 microW at 313 nm and with powers in excess of 5 microW from 290 nm to 390 nm. PMID- 20197863 TI - Improving analysis from second-derivative uv-absorption spectrometry. AB - Methods for improving the analytical results obtained from second-derivative spectrometry are presented. By using a combination of the first and second derivatives of the spectral data, a response varying linearly with concentration can be obtained at all wavelengths if Beer's law applies. A least-squares analysis of the data using standard spectra can then be utilized. Special emphasis is given to improving the response from a wavelength-modulated derivative uv-absorption spectrometer. Simulated examples are provided showing the improved analytical capabilities using the procedure outlined. PMID- 20197864 TI - Astro 7 zodiacal light uv polychromator and its absolute radiometric calibration. AB - The uv polychromator, flown in 1975 on the Astro 7 zodiacal light rocket experiment, and its absolute radiometric calibration are described. The instrument is essentially a broadband double polychromator with high stray light suppression. The spectral ranges of +/-20-nm width are cenyered at 180 nm, 220 nm, and 260 nm, respectively. The absolute calibration is based on the synchrotron radiation of the Deutsches Elektronen Synchrotron, Hamburg with deuterium lamps as transfer standards. PMID- 20197865 TI - Metal-dielectric photosystems. AB - Thin film photosystems based on copper doped lead iodide are presented. A photodecomposable Fabry-Perot type interference filter is described and also a cerment system in which copper and lead iodide are evaporated simultaneously. These systems do not require any development, and additional information can be added subsequent to the first exposure. The proposed systems are generalizable to several metals and dielectrics. PMID- 20197866 TI - Interferometric surface mapping with variable sensitivity. AB - In the photolithographic process, presently employed for the production of integrated circuits, sets of correlated masks are used for exposing the photoresist on silicon wafers. Various sets of masks which are printed in different printing tools must be aligned correctly with respect to the structures produced on the wafer in previous process steps. Even when perfect alignment is considered, displacements and distortions of the printed wafer patterns occur. They are caused by imperfections of the printing tools or/and wafer deformations resulting from high temperature processes. Since the electrical properties of the final integrated circuits and therefore the manufacturing yield depend to a great extent on the precision at which such patterns are superimposed, simple and fast overlay measurements and flatness measurements as well are very important in IC manufacturing. A simple optical interference method for flatness measurements will be described which can be used under manufacturing conditions. This method permits testing of surface height variations by nearly grazing light incidence by absence of a physical reference plane. It can be applied to polished surfaces and rough surfaces as well. PMID- 20197867 TI - Mapping of optical surfaces with quarter wavelength fringes. AB - A contactless interference surface testing method is described that is capable of creating fringe patterns with fringe separations corresponding to a surface deformation of a quarter-wavelength of the illumination light. Contrary to common Fizeau fringes where the interference pattern occurs by superposing two wavefronts, the described method is based upon a superposition of four wavefronts. These wavefronts are created by a diffraction transmission grating which is contactlessly placed over the surface to be tested. Basically, this technique provides a beat frequency pattern with adaptable fringe separation. Practical applications of this method to semiconductor silicon wafers are presented. PMID- 20197868 TI - Design considerations of 2-D holographic scanners. AB - Two-dimensional holographic scanners utilizing an auxiliary reflector are described. The design equations and procedures are derived and outlined. Multiplexing techniques for increasing the resolution are proposed. Scanners of reasonable size and operating at a moderate speed can achieve a total resolution of 10(7)and a temporal signal of 100 mHz. Applications in the visible and other spectra regions including millimeter or microwave and ultrasonic wave are suggested. PMID- 20197869 TI - Radiation losses of parabolic-index slabs and fibers with bent axes. AB - Using first-order perturbation theory, radiation losses of the lowest-order mode caused by deformations of the axes of slab waveguides and fibers with parabolic index distributions were computed. It was found that sinusoidal bends, with a period that produces a very nearly forward directed radiation lobe, cause far more loss than bends with a shorter period that give rise to radiation escaping at larger angles relative to the axes of the waveguides. Parabolic-index fibers and slabs are far more tolerant of periodic sinusoidal axis distortions than step index fibers and slabs, provided that the period of the distortion causes the beam to escape from the waveguide at relatively large angles (typically more than 10 degrees ). The result of this study suggests that single-mode fibers with parabolic-index profiles may have somewhat lower microbending losses than single mode step-index fibers. PMID- 20197870 TI - Length optimization of an S-shaped transition between offset optical waveguides. AB - We derive expressions for the radiation loss of an S-shaped waveguide transition used to connect two straight integrated optics waveguides that are offset with respect to each other. It is assumed that the diffused integrated optics waveguides are produced with the help of an electron beam machine that allows beam positioning in the y direction only in discrete steps. We thus must consider staircase approximations to the desired smooth S-shaped curves. A waveguide whose axis consists of a staircase suffers radiation losses due to the quasi-periodic deformation of its axis. A second loss contribution comes from the S-shape of the waveguide axis. The sum of these loss contributions assumes a minimum that defines the optimum length of the transition waveguide. PMID- 20197871 TI - Optical directional couplers with variable spacing. AB - Optical directional couplers with variable separation are introduced and analyzed. Closed form solutions to the coupled-mode equations with variable coupling coefficient are presented. A procedure for the design of the best geometry of a variety of applications utilizing variable spacing couplers is also presented. PMID- 20197872 TI - Improvements to a home-built nitrogen laser. AB - Several major design improvements to a previously described nitrogen laser are presented. The active region has a larger cross section but shorter length resulting in an output beam of better optical quality and a laser channel which is cheaper and easier to build. The gas flow is transverse to the channel, and the pressure is more uniform. These and other improvements result in a 9-nsec pulse FWHM (full width at half-maximum) whose peak power exceeds 0.7 MW when the laser is supplied with 24 kV and pulsed at 10 Hz. PMID- 20197873 TI - Thermal performance and limitations of silicon-substrate packaged GaAs laser arrays. AB - Thermal resistance and crosstalk have been investigated for a source package consisting of a monolithic, multilaser heterojunction array mounted on a single crystalline silicon substrate, which is in turn laminated to a copper heatsink. Models for 2-D and 3-D heat spreading are used to calculate the heat flow distribution and to obtain upper and lower bounds for both resistance of single devices and crosstalk in arrays. Results for experimental five-laser arrays are shown to fall within these limits. Active cooling is required to maintain junctions at safe operating temperatures prerequisite to stable, long-lived operation. PMID- 20197874 TI - Depletion optimization and photon efficiency in laser isotope separation of deuterium. AB - The depletion optimization of one of the isotopic components in a gas stream is considered, using a one-photon laser separation process, when the absorption path is in the kilometer range. A multiple-pass cylindrical geometry is proposed with the gas flowing through a tube enclosed by aspherical mirrors. Radiation is injected such that adjustment of the mirror parameters establishes a flux distribution which optimizes the depletion while it minimizes losses from incomplete absorption. The mirror parameters are derived and application to deuterium separation is discussed. This approach it also useful in optical amplifiers and resonators to maximize energy extraction. PMID- 20197875 TI - Rayleigh-Gans-Debye applicability to scattering by nonspherical particles. AB - Rayleigh-Gans-Debye scattering theory is applicable to particles satisfying |m - 1| << 1 and 2ka |m - 1| << 1. It is often applied to large nonspherical particles such as bacteria where its validity is uncertain. The purpose of this study is to define the range of validity of the RGD approximation as applied to homogeneous nonspherical particles. Scattering calculations are made for a set of prolate spheroidal particles using the RGD approximation, and the results are compared to those obtained by the recently developed extended boundary condition method, a technique known to give accurate scattering results for nonspherical particles. Calculations for oriented particles with m = 1.05 verify that RGD error is dependent on particle orientation relative to the incident wave. Also, the error is found to increase with ka and to decrease with axial ratio for small particles, but increase with axial ratio for larger particles. Calculations for a particular randomly oriented particle show that the RGD approximation is more accurate for this case than if the incident wave is along the major dimension of the oriented particle. PMID- 20197876 TI - Backscattering cross sections for hydrometeors: measurements at 6328 A. AB - Reported are estimates of backscattering cross sections and other scattering parameters determined experimentally at 6328 A for major atmospheric hydrometeor types. PMID- 20197877 TI - Simulator for remote sensing and its application to soil moisture measurements. AB - It is of great significance to experiment with a simulator for remote sensing to confirm the properties and meaning of remote-sensed information and to forecast certain phenomena. This paper describes a simulator for remote sensing. The simulator, suitable for the measurement of soil moisture, consists of an optical source, a polarimeter, orbital guides for them, and a sample stage. SiC and MgO were used as soil models. The moisture in beach sand was also estimated. The degree of polarization increases with the moisture content and particle size of the sample. The field capacity point of each sample is determined by means of the polarimeter. PMID- 20197878 TI - Remote measurement of ethylene using a CO(2) differential-absorption lidar. AB - Ethylene has been monitored with a single-ended CO(2) lidar using topographical scattering. Foliage on the foothills 5 km away provided the backscattered signal. Interference due to water vapor was found to be equivalent to 7.6 ppb of ethylene, and this correction was applied to the data. The total measurement uncertainty was found to average 1.6 ppb. The lidar-measured concentrations agree with point monitor samples over a wide range of ambient concentrations. PMID- 20197879 TI - Comparison of measured 3.8-microm scattering from naturally occurring aerosols with that predicted by measured particle size statistics. AB - Recent field measurements of scattered 3.8-microm laser radiation from naturally occurring aerosols were made during a 4-week period in coastal Southern California. Simultaneously, aerosol distribution measurements were made, which, in conjunction with Mie scattering theory, gave estimates of the volume scattering coefficient at the various angles. A comparison shows that (a) calculated volume scattering coefficients generally decrease more rapidly in angle than measurements indicate; (b) on the average, the calculation gives volume backscattering coefficients that are a factor of 2 larger than measured but underpredicts forward scattering by 33%. A second unrelated observation of interest is that volume scattering coefficients in the visible showed 65% correlation with 3.8-microm backscatter (177 degrees ) coefficients. PMID- 20197880 TI - Diffuse-direct ultraviolet ratios with a compact double monochromator. AB - An improved system has been implemented for measuring the ratio of the diffuse skylight to the direct sunlight in the biologically active region of the uv near the atmospheric limit. It combines a double monochromator employing holographic gratings for reduction of stray light with a cooled photomultiplier tube to provide a greatly improved SNR below 300 nm. Data may be obtained in either a scan mode or a narrowband photometry mode; in the latter mode accurate ratios have been obtained near 290 nm. Representative data are discussed along with a theoretical model of the ratio. The system is compact enough for use in a mobile monitoring system. PMID- 20197881 TI - Quantitative schlieren visualization. AB - Using a closed circuit television camera (CCTV), a method is developed to obtain quantitative sound pressure measurements directly from the sound field imaged in a schlieren system. By using the exact time format of the composite video signal and a series of time delay circuits, it is possible to take vertical intensity scans of a schlieren image at any position on the TV raster. The method uses the camera's horizontal blanking pulse to trigger a broadband, high-speed sample-hold amplifier. This amplifier is triggered to sample each horizontal scan line at a selected time in the horizontal scan sweep and to feed this value into a transient recorder. The signal is digitized, and a continuous analog voltage signal corresponding to the black-white information from a schlieren image is displayed on a scope. The same analog signal is also plotted on an X-Y recorder. The schlieren system can be operated using only a single calibration curve at each frequency. The curves plotted applied transducer voltage against the video output level. Thus, by comparing the video output levels for several vertical image intensity scans on a schlieren image, relative sound pressure measurements are routinely obtained. PMID- 20197882 TI - Numerical study of the displacement of a three-dimensional Gaussian beam transmitted at total internal reflection. Near-field applications. AB - Longitudinal and transverse shifts of a light beam at total internal reflection was experimentally studied by far-field measurements on the reflected field. We propose to use a scanning tunneling optical microscope (STOM) to study these shifts in transmission, and we present a theoretical model of this proposed experiment to obtain a numerical estimation of these shifts. We study the reflection and the transmission of a three-dimensional polarized incident beam. We verify the validity of our formalism by studying the Goos-Hanchen shift in reflection and by comparing our results with published ones. Then we calculate STOM images of the transmitted field distribution. On the images the well-known Goos-Hanchen shift is easily observed. But we also encounter a smaller shift, perpendicular to the plane of incidence. This transverse shift was also observed in reflection by Imbert and Levy [Nouv. Rev. Opt. 6, 285 (1975)]. We study the variations of the two shifts versus various parameters such as the angle of incidence, the optical index, and the incident polarization. Then we discuss the feasibility of the near-field observation of these shifts. PMID- 20197883 TI - X-ray efficiencies of gratings. PMID- 20197885 TI - Holographic nondestructive testing at the Fourier plane. PMID- 20197884 TI - Cure for the dead or dying He-Ne laser. PMID- 20197886 TI - Wavenumber calibration of tunable diode lasers using etalons. PMID- 20197887 TI - Interferometric measurement of cryogenic laser fusion target uniformity. PMID- 20197888 TI - Laser isotope separation of rare earth elements. AB - The experimental results on the laser isotope separation of the neodimium, samarium, europium, gadolinium, dysprosium, and erbium by the selective two-step photoionization are given. The rare earth elements have been chosen for the investigation because they constitute a good series of the very similar but different atoms that are heavy enough and allow experiments to be carried out that are representative enough. The experimental technique developed for the laser isotope separation experiments has been applied to measure the excitation energy transfer cross sections at the collisions in the gas of the same atoms ((153)Eu ? (151)Eu, sigma = 1.4 x 10(-13) cm(2)). The combination of the selective two-step photoionization and ion mass filtration allowed us to develop a very convenient technique for the precise measurement of hyperfine structure in the spectrum of odd isotopes. The examples of dysprosium and erbium are given. The technique is good for the rare and unstable isotopes as well. The ionization cross sections for the transition starting off the excited level have been estimated ( approximately 10(-17) cm(2)). For the example of gadolinium the possibility of creating neutral atomic vapor dense enough for laser isotope separation by the electron-beam evaporation technique has been demonstrated. PMID- 20197889 TI - Use of heterostructure diode lasers in video disk systems. AB - The application of heterostructure lasers to video disk systems is described. The buried heterostructure diode laser is used as a light source of the optical pickup for the optical video disks. This pickup enables video signals to be reproduced with a SNR of more than 40 dB. These lasers can be not only used as a light source to read out the signal from the disk but also as a detector of the reflected light. PMID- 20197890 TI - Pulsed GaAs laser terrain profiler. AB - A pulsed GaAs laser terrain profiler has been successfully tested and flown. Preliminary flight data indicate excellent resolution, with terrain features easily identifiable. Unique design features and typical flight results are given. The laser profiler is to be used as part of an airborne surveying package which will contain an inertial measurement unit and laser tracker to provide three coordinate position information as well as base motion isolation and stabilization control for the profiler. PMID- 20197891 TI - Laser printer scanning system with a parabolic mirror. AB - A high quality nonimpact printer at a speed of 10,000 1/min is realized by a new laser scanning system and an electrophotographic process. The laser scanning system uses a parabolic mirror for correcting line scanning distortion. When a polygonal mirror facet is placed on the axis of the parabolic mirror at about two thirds of the focal length from the mirror surface, and the focus of the parabolic mirror is on a photosensitive drum surface. The scanning velocity distortion is reduced to less than 0.1% over +/-30 degrees of the scanning angle. The confusion circle induced by the parabolic mirror is 1 order of magnitude smaller than the spot size determined by diffraction limit. The tolerance of the length from the rotating mirror to the parabolic mirror for 0.1% distortion over +/-30 degrees scanning angle is 10% of focal length. This high speed laser printer has demonstrated the high quality printing of 10-dots/mm resolution. PMID- 20197892 TI - Pulsed CO(2) TEA laser rangefinder. AB - A compact laser rangefinder has been developed, which incorporates a sealed-off pulsed CO(2) TEA laser and uses direct (i.e., nonheterodyne) detection. This device is essentially eye safe and benefits from the superior atmospheric transmission at 10.6-microm wavelength. Design parameters are presented and illustrated, and system performance is discussed. PMID- 20197893 TI - Single-mode GaAs-Al(x)Ga(1-x)As rib waveguide switches. AB - Metal-oxide-semiconductor rib waveguides are low loss for any polarization and are efficiently electrooptically modulated. We show COBRA switching of 90% with 15 V and a 2 x 4 switch matrix. These suggest versatile applications in integrated optical circuits. PMID- 20197894 TI - Light beam switching and modulation using a built-in dielectric channel in LiNbO(3) planar waveguide. AB - The results of light beam switching and modulation experiments utilizing electrooptic control of the refractive index of a built-in dielectric channel in a Y-cut LiNbO(3) planar waveguide are reported. The resulting device is capable of simultaneously providing a combination of desirable characteristies. PMID- 20197895 TI - Optical coupling from fibers to channel waveguides formed on silicon. AB - Direct coupling of light from fibers supported in preferentially etched grooves on a silicon surface to channel waveguides formed in the same grooves is demonstrated. Criteria are presented for choosing a groove geometry that matches the center of the fiber to the center of the waveguide and thereby yielding optimum coupling. Channel waveguide tapering and integration of detectors into the channel waveguide termination are demonstrated. A general configuration allowing CCD time multiplexing is introduced. PMID- 20197896 TI - Propagation experiments in low-visibility atmospheres. AB - An experimental program aimed at measuring critical channel parameters of atmospheric optical communication channels under low-visibility weather conditions is described. Multipath and angular spectrum measurements made under a variety of weather conditions over a 13.6-km line-of-sight propagation path are reported. The latter measurements are used to examine the dependence of scattered plus unscattered optical transmission on optical thickness. PMID- 20197897 TI - Characteristics of laser surface melted aluminum alloys. AB - Specimens of Al-Fe 1-4 w/o, 2024 and 6061 Al have been surface melted with a pulsed Nd-glass laser. A TEM and SEM study showed that the dendrite spacings were from 2500 A to 4000 A which corresponds to a cooling rate of over 10(6) degrees C/sec. Melt depths obtained were in the range of 30-100 microm. No significant surface vaporization was observed at energy densities up to 440 J/cm(2). Fracture surfaces of the commerical alloys demonstrated elongated porosity in the melt areas, probably due to internal hydrogen. PMID- 20197898 TI - Optical processing techniques in the quality control of micromechanics. AB - Coherent optical processing methods have been investigated for the real-time recognition and control of mass-produced pieces in automatic machining and assembling lines. In particular, an optical correlator is proposed in which the information of a master piece is stored in a hologram. Problems such as the optimization and generation of the hologram, the detection of particular defects, the adaptation of the response curve to the practically given tolerances, and the reliability have been investigated, and prototypes of control systems have been realized. PMID- 20197899 TI - Electronic heterodyne recording and processing of optical holograms using phase modulated reference waves. AB - The use of a phase-modulated reference wave for the electronic heterodyne recording and processing of a hologram is described. Heterodyne recording is used to eliminate the self-interference terms of a hologram and to create a Leith Upatnieks hologram with coaxial object and reference waves. Phase modulation is also shown to be the foundation of a multiple-view hologram system. When combined with hologram scale transformations, heterodyne recording is the key to general optical processing. Spatial filtering is treated as an example. PMID- 20197900 TI - Practical improvements of writing and reading algorithm in computer-generated polarization holography. AB - This paper reports on a newly developed algorithm for improving the previously reported basic theory of computer-generated polarization holography. An application of the algorithm to the basic theory shortens the hologram making time, which uses a limited quantity energy of an illuminating uv spot light. A relation between a polarization angle of the illuminating uv beam and an effective amplitude transmittance Tp of a crystal-analyzer pair is derived. Furthermore, a method for correcting an effect of the pre-existing unbalance of the degree of the density balance of M-centers in a binary state is proposed. Also, the theory of the method is theoretically discussed in detail together with a derivation of the theta vs Tp curves characteristic of this case. PMID- 20197901 TI - A 1-J high-brightness frequency-doubled Nd: YAG laser. AB - The authors report development of a 1-J high-brightness, frequency-doubled, Nd: YAG laser consisting of a TEM(00)-mode oscillator, four amplifiers, an optical isolator, and a KD*P doubler cut for type II phase matching at 1064 nm. The system operates at a pulse repetition rate of 10 pps, a pulse width of 17 nsec, and a beam divergence of 0.4 mrad in a 12.5-mm diam beam. The system has run damage-free for greater than twenty million shots with a mean-time-between failure (MTBF), limited by flashlamp life, of greater than five million shots. PMID- 20197902 TI - Unstable resonator mode control in a transverse flow dye laser. AB - Using suitable correcting optics, a 2x diffraction-limited beam has been obtained from a high power transverse flow dye laser. Beam divergence in the direction parallel to flow is controlled by a sound wave and may be compensated for externally. PMID- 20197903 TI - Unstable resonators for annular gain volume lasers. AB - Experimental performance of several different unstable resonators with annual cylindrical mode volumes is reported. Laser output beam quality and its sensitivity to resonator component misalignments and figure errors are described. Near diffraction-limited beam quality was obtained from an annular cylindrical He Xe laser employing a half-symmetric unstable resonator with an intracavity axicon. PMID- 20197904 TI - Holographic microscopy. AB - An off-axis transmission holographic scheme, in which a 1:1 lens and a hologram are treated as a single rigid entity, is found to reconstruct a 3-D diffraction limited image when reconstructed, with a reference beam reversed back through the original lens-hologram unit. Reconstruction can be performed with wavelengths other than the recording wavelength, provided achromatic lenses are used, and the reference beam angle is properly changed for reconstruction. Comparisons are made between He-Ne and ruby laser holograms. Two-micron resolution of the combustion of solid rocket propellants at high pressures is achieved at a working distance of 6 cm. PMID- 20197905 TI - Holographic motion pictures of microscopic plankton. AB - A high-speed cine-camera system utilizing holographic principles to circumvent the restrictive depth of field limitations of photomicrography is being used for behavioral studies of rapidly moving marine zooplankton. High resolution is achieved from small format, flexible 35-mm movie film by the development of a lens-assisted holocamera. The lens images subjects close to the film in the recording process in order to reduce flatness requirements of the film. Aberrations introduced by the lens are cancelled by positioning it in precisely the same relationship to the film during reconstruction as it occupied in recording. New alignment and pathlength matching techniques for complex holocameras were developed. PMID- 20197906 TI - Affinement spectral dans les lasers a colorants pulses. AB - Spectral narrowing in pulsed dye lasers is studied theoretically. Fabry-Perot etalons, gratings, and prisms are considered as tuning elements. Each one is characterized by a new parameter: the spectral width associated with a round trip in the laser cavity. Numerical examples show that depending on cavity parameters it is either the round-trip spectral width or the width due to beam divergence which limits the bandwidth of the laser emission. Instantaneous spectral narrowing is found to be proportional to the square root of the time elapsed after the laser onset when a Fabry-Perot etalon or grating is used. When a prism is set in the laser cavity the instantaneous narrowing is proportional to time. PMID- 20197907 TI - Thin-wedge-shaped cell for highly absorbent liquids. AB - The construction, physical function, and use of a wedge-shaped cell for measuring the Lambert adsorption coefficient of highly absorbent liquids is described. Liquids are held in the cell by surface tension, thus avoiding the use of seals. The cell is simple in its design and is about as convenient to use as an ordinary cuvette. PMID- 20197908 TI - Included power for obscured circular pupils. AB - Power contained in a square area of an image formed by a diffraction-limited imaging system with a centrally obscured circular pupil is calculated and compared with the power contained in a circular area. It is shown that, regardless of the amount of obscuration, the difference between the corresponding ensquared and encircled powers is less than 9% of the total image power. Approximate expressions are obtained for the power lying outside a large square or a circular area. PMID- 20197909 TI - Concentration of the sun's rays using catenary curves. AB - An examination has been carried out of the difficulties a horizontally placed parabola would encounter in concentrating the sun's rays when the angle of incidence between the axis of the parabola and parallel incident rays grows from 0 degrees to 50 degrees . The results obtained with two catenary curves formed by hypothetical reflecting adjustable sheets were compared with the parabola, showing that the concentration can be held at interesting levels as regards technical application. PMID- 20197910 TI - Infrared absorption coefficients of gaseous H(2)SO(4) and SO(3). PMID- 20197912 TI - Of optics and opticists. PMID- 20197911 TI - Optical activities in industry. PMID- 20197913 TI - Generation of tunable coherent vacuum uv radiation in KB5. PMID- 20197914 TI - Imaging coding in variable phenomena using a vidicon system on line with a minicomputer. PMID- 20197915 TI - Generalized model for noncoherent optical convolvers and correlators. PMID- 20197916 TI - Mach-Zehnder interferometer errors resulting from test section misalignment. PMID- 20197917 TI - Simulation of synthetic aperture radar data film using holographic techniques. PMID- 20197919 TI - Reflectivity of steel at 10.6-microm wavelength. PMID- 20197918 TI - Use of an average complex refractive index in atmospheric propagation calculations. PMID- 20197920 TI - Analyzing spectral data: use of a graphics display terminal. PMID- 20197921 TI - Patents. PMID- 20197922 TI - Argus laser system: performance summary. AB - The Argus Nd:glass laser system, presently operating as an experimental facility for laser fusion experiments, is described. The laser consists of a master oscillator and two identical amplifier chains, each of 20-cm output aperture. Argus is presently capable of delivering more than 4 TW of power in short (<100 psec) pulses, or more than 2 kJ of energy in 1-nsec pulses, to 100-microm targets. Short pulse performance enhancement obtained by increased aperture filling and implementation of image relaying with high power vacuum spatial filters is described. Experimentally recorded near-field and far-field data for several power levels are presented and discussed in terms of the limiting effects of nonlinear beam instabilities upon focal spot intensity. PMID- 20197923 TI - Statistics of photoelectric pulses for Gaussian-Lorentzian light. AB - The practical treatment of statistics for Gaussian-Lorentzian light is studied theoretically and experimentally by using the time interval distribution of photoelectric pulses, which is derived in two approaches that are based on Markovian processes and the generating function of photon counting statistics, taking the experimental conditions into account. The limits of the validity of the Markovian assumption are made clear. In arbitrary light intensity it is valid experimentally to employ the practical generating function of photon counting distribution expressed as the product of an ideal generating function and a Poissonian one. PMID- 20197924 TI - Polarization of light from a pulsed dye laser. AB - Experiments are described whose aim is to understand the way in which the light from a pulsed dye laser becomes polarized when there is a simple tilted glass plate in the cavity. If the process consists of a competition between orthogonal linear polarizations, the way the degree of polarization depends on the anisotropy of the cavity loss can be understood approximately by using results of a two-mode rate equation analysis of the laser. It is necessary to suppose that there is a delay between onset of laser action and detection of the laser pulse, however; the delay required is much less than the pulse length. The detailed time dependences of the light in the two orthogonal modes do not follow this model. PMID- 20197925 TI - Simultaneous frequency stabilization and injection in a TEA-CO(2) oscillator. AB - A novel technique that uses a single master oscillator to serve both the injection and the stabilization function in a TEA-CO(2) laser transmitter is described. The method, based on a two-polarization scheme, provides sufficient optical isolation between the TEA laser pulse and the probing laser beam to prevent anydamage or saturation of the controlling system. Reproducible and stable SLM operation in the MW power levels is achieved on a long term basis. PMID- 20197926 TI - Pressure and temperature dependence of Freon-12 absorption coefficients for CO(2) waveguide laser radiation. AB - Freon-12 absorption coefficients for the P(22) through P(48) CO(2) waveguide laser transitions of the 00 degrees 1-(10 degrees 0, 02 degrees 0)(I) band are presented. For pressures below 10 Torr and a spectral resolution of 0.1 MHz, the absorption coefficients show considerable spectral structure within +/-250 MHz of the CO(2) laser line center; but individual absorption lines are only resolved for pressures below 100 microm. The absorption coefficients around the CO(2) waveguide laser lines are shown to be spectrally structureless as well as pressure independent above 20 Torr. The temperature dependence of the absorption coefficients are presented for the first time, and they are shown to be linearly dependent on temperature. PMID- 20197927 TI - Dispersion in optical fibers: new aspects. AB - Group delay differences among modes, which limit the bandwidth of optical fibers, arise not only from distortions of the refractive profile but also from profile dispersion caused by the dependence of the profile contour on wavelength. An efficient method is presented which helps to explain the interaction of both effects, shows a new way of minimizing the total dispersion by matching the two effects, and simplifies the calculation of pulse broadening in imperfect real fibers. PMID- 20197928 TI - Birefringent prism couplers for thin-film optical waveguides. AB - The coupling from a laser to a thin-film optical waveguide by a prism coupler composed of a birefringent material can be strongly dependent on the orientation of the optic axis. It is shown that when the effective index of the wave guided by the film lies between the ordinary and extraordinary refractive indices of the prism, the coupling depends strongly on the orientation of the optic axis. Differences in orientation of only a few degrees separate ranges of orientation in which strong coupling occurs from ranges in which there is no coupling. The orientation dependence of the coupling is considered both for the pure mode case wherein the optic axis lies in the plane of incidence and for the case when the optic axis is rotated out of the plane of incidence, so that mode coupling occurs. When the effective refractive index of the guided wave is less than both the ordinary and extraordinary refractive indices of the prism, the coupling properties are found to be similar to those obtained with an isotropic prism. PMID- 20197929 TI - Optical monitoring of nonquarterwave multilayer filters. AB - Many spectral filtering problems require the use of assemblies of layers having thicknesses which bear no obvious relationship to each other. Successful production of these multilayers requires films with thicknesses approximating theoretical values. We show that the optical methods currently used in the production of film assemblies of quarterwave layer thicknesses, which are based on the use of just one single wavelength, are poorly adapted to monitoring the deposition of nonintegral thickness multilayers. In contrast we show that with an optical control system utilizing a broad spectral bandwidth, thickness errors can be reduced. Transmittance measurements with the precision necessary to achieve this improved thickness control are attainable with existing instrumentation. This result is established by a computer simulation of the construction of a specific multilayer and remains valid for other nonquarterwave multilayer filters. PMID- 20197930 TI - Frequency determination of visible laser light by interferometric comparison with upconverted CO(2) laser radiation. AB - A servocontrolled 1-m plane-parallel Fabry-Perot interferometer has been developed at NPL for the precise intercomparison of laser wavelengths. This instrument has been used to measure the wavelength ratio of a 679-nm radiation and that from a 633-nm iodine-stabilized He-Ne laser, achieving an accuracy of 2.9 parts in 10(11). The 679-nm light was derived from a stabilized CO(2) laser radiation by upconversion, and the wavelength of this 9.3-microm laser radiation can be calculated from the visible wavelength result. Frequency measurements on the same CO(2) laser radiation have already been made in this laboratory, so that the experiment reported here leads to a precise value for the speed of light in vacuum and to the value of 473, 612, 380.5 +/- 0.3 MHz for the absolute frequency of the visible radiation from a He-Ne laser stabilized to component d of (127)I(2). PMID- 20197931 TI - Mylar beam-splitter efficiency in far infrared interferometers: angle of incidence and absorption effects. AB - Absorption and complete multipath interference have been included in the calculation of the modulation efficiency of a far i.r. Michelson interferometer with 25-mum and 100-mum Mylar beam splitters over the range of wavenumbers between 20 cm(-1) and 125 cm(-1) for angles of incidence between 45 degrees and 80 degrees . These results show that optimum performance of an interferometer in terms of highest and most uniform modulation efficiency for unpolarized radiation will be obtained by selecting the beam-splitter thickness to cover the wavenumber range of interest within the first interference lobe and by utilizing higher angles of incidence than the mechanically convenient 45 degrees . Practical constraints will usually limit this angle to a value somewhat less than the optimum of about 75 degrees for Mylar beam splitters. PMID- 20197932 TI - Archival characteristics of Fourier color holograms. AB - The archival characteristics of Fourier color holograms (FCH) have been analyzed. The color registrations are not affected by film binding, shrinkage, and wavefront deviation of the reconstruction beam. The image contrast has been analyzed using a simple Fourier decomposition model. This model predicts that the image contrast is preserved if films of low negative gamma (-2 0.6 have been produced on GaAs. PMID- 20197957 TI - Optical waveguide switch (3 x 3) for an optical switching system. AB - A new optical switch element is proposed for a switching system which exchanges optical signals in optical transmission lines without optoelectric conversion. It consists of three parallel equidistant straight singlemode waveguides fabricated of an electrooptic material with electrodes deposited on them. The element, whose interaction length is pi/(2)((1/2))k (k is the coupling coefficient of neighboring guides), serves as a 3 x 3 optical switch by control of the differences in propagation constants between those waveguides. Control conditions to realize all the six connecting states of a 3 x 3 switch are discussed with the solution of the coupling equation for those guides. PMID- 20197958 TI - Propagation characteristics of trapezoidal cross-section ridge optical waveguides: an experimental and theoretical investigation. AB - A detailed experimental and theoretical study of narrow ridge waveguides in glass films formed by ion-etching of patterns in photoresist has been carried out. Because the resultant waveguide profiles are trapezoidal a numerical approach, the finite-element method, has been used to compute theoretical dispersion curves. Experimental dispersion curves were obtained from measurements of output m-lines. Agreement between experiment and theory varies from moderately good to excellent over the range of waveguide profiles studied. PMID- 20197959 TI - Bandpass filtering of moving-object laser heterodyne-signals by finite apertures. AB - Expressions for the frequency power spectral density and power spectral density SNR of a heterodyne detection system are derived assuming the signal radiation field results from a laser illuminated, moving rough object. The calculated spectral density is attenuated at large spectral spread frequencies (resulting from target rotation) by averaging of the high spatial frequency speckle pattern by the finite extent (aperture) of the local oscillator field. Optimum signal detection is obtained only at the Doppler shifted frequency. Spatial anisotropy of the radiation field mutual coherence function precludes exact calculations for arbitrary local oscillator field distributions. PMID- 20197960 TI - Transmission characteristics of graded-index optical fibers with a lossy outer layer. AB - Changes in transmission characteristics caused by an outer layer have been investigated for graded-index fibers. Equations have been derived using the WKB method for calculating baseband frequency response and excess loss in a general type of the graded-index fiber. Numerical examples have been given for a square law fiber, mainly with cladding thickness and index difference between outer layer and cladding as parameters. Measurement of the excess loss has been carried out for fibers with various cladding thickness and outer layer-cladding index differences. The measured loss is in agreement with the theoretical value. PMID- 20197961 TI - Laser Raman a fibre emettant dans un tres large domaine spectral. AB - A very broad stimulated emission of light covering almost the entire visible spectrum is provided by a fused silica fiber Raman laser. The fiber is 3.5-50 m long with a 50-microm diameter, and the exciting light at 5320 A has a power of about 60 kW. PMID- 20197962 TI - Optical fiber end preparation using a CO(2) laser. AB - A new method for obtaining good fiber ends with the help of a CO(2) laser is described. In principle, the fiber is exposed to a focused CO(2) laser beam and then fractured by applying tensile stress. Average coupling losses of a step index and a graded-index multimode fiber, whose endfaces were prepared by this method, were both 0.35 dB without index-matching fluid. Average splice losses of these fibers were 0.05-0.06 dB, when their ends were fused with a CO(2) laser. PMID- 20197963 TI - Direction-sensitive displacement analysis by multiple frequency holographic interferometry. AB - A method for determining the directions of displacement in double exposure holographic interferometry is described. The technique requires the use of different frequencies in each of the two holographic exposures and thus can be thought of as a combination of conventional multifrequency contouring and holographic interferometry. The necessary equations to describe the resulting fringe pattern are developed. Two deformation fields, one theoretical and one experimental, are used to illustrate the phenomena. The experimental deformation was the result of a Rayleigh surface wave propagating in a rock specimen. The holograms were obtained with a Q-switched, multifrequency pulsed ruby laser. PMID- 20197964 TI - Designing and constructing thick holographic optical elements. AB - Previously, holographic optical elements have been constructed with two spherical waves. Better image quality and efficiency can be achieved by constructing thick HOE's with spherically aberrated wavefronts. We include an exact lens equivalent for a HOE to allow computer optimization of such systems. The effect of changes in the index of refraction and thickness of the emulsion are considered along with the quality of the substrate. Optical systems to construct such HOE's are discussed and analytically described. Many examples are presented. PMID- 20197965 TI - Estimation of images degraded by film-grain noise. AB - Film-grain noise describes the intrinsic noise produced by a photographic emulsion during the process of image recording and reproduction. In this paper we consider the restoration of images degraded by film-grain noise. First a detailed model for the over-all photographic imaging system is presented. The model includes linear blurring effects and the signal-dependent effect of film-grain noise. The accuracy of this model is tested by simulating images according to it and comparing the results to images of similar targets that were actually recorded on film. The restoration of images degraded by film-grain noise is then considered in the context of estimation theory. A discrete Wiener filer is developed which explicitly allows for the signal dependence of the noise. The filter adaptively alters its characteristics based on the nonstationary first order statistics of an image and is shown to have advantages over the conventional Wiener filter. Experimental results for modeling and the adaptive estimation filter are presented. PMID- 20197966 TI - Upconversion of broadband infrared spectra. AB - An experimental device successfully upconverts ir radiation in the 3.2-5.0-microm wavelength range simultaneously to "visible" light at 0.80-0.88 microm, while preserving frequency coding and is thus applicable to ir spectroscopy. The 1.8 microm bandwidth of ir radiation that is upconverted without temperature or phase match tuning is the largest yet reported. The over-all system quantum efficiency of the upconverter/spectrometer system is 0.01% and could be improved to 0.4%. PMID- 20197967 TI - Viking infrared thermal mapper. AB - The infrared thermal mapper (IRTM) was designed to measure the emitted and reflected radiance of Mars. Carried by the Viking Orbiter, the IRTM contains four small Cassegrainian telescopes which each image the same, seven circular areas. There is a total of twenty-eight channels in four surface and one atmospheric thermal bands from 6 microm to 30 microm and a broad solar reflectance band. All channels are sampled simultaneously, using the spacecraft scanning capability to map the radiance over small and large areas of the planet. All channels use thermopile detectors; spectral passbands are determined by a combination of interference filters, detector lense materials, antireflection coatings, and restrahlen optics. PMID- 20197968 TI - Aspheric grating for extreme ultraviolet astronomy. AB - A family of plane curves is developed which can diffract incident parallel rays to a point focus. These curves, termed diffractoidal curves, are rotated around an axis to produce surfaces of revolution correspondingly termed diffractoids, whose imaging properties for sources at infinity are studied by ray tracing in a few examples. The paraboloid emerges as a limiting case of the diffractoid. A comparison is made between the stigmatic focusing properties of the diffractoid and the toroidal grating. PMID- 20197969 TI - Design criteria for reflection polarizers and analyzers in the vacuum ultraviolet. AB - Reflection polarizers and analyzers for the extreme uv spectral region are discussed. The conditions for optimum polarization are presented, and the polarization characteristics of a number of metal coatings, including gold and some of the platinum metals, are given. The performance of three- and four-mirror polarizers, using these metal coatings, is discussed. The properties required of a polarization analyzer are presented, and the performance of single and three- and four-reflection analyzers are discussed in terms of the optical properties of coating materials that might be useful for analyzers. PMID- 20197970 TI - Direct, quasi-telecentric, and telecentric combinations of interference filters with large astronomical Schmidt cameras. AB - Several ways of combining narrow bandwidth interference filters with a Schmidt camera, of 1.2-m aperture, are described. A completely telecentric method is proposed in which very narrow filters can be used. PMID- 20197971 TI - Beam deviation method as a diagnostic tool for the plasma focus. AB - The application of an optical method for density measurements in cylindrical plasmas is described. The angular deviation of a probing light beam sent through a plasma is proportional to the maximum of the density in the plasma column. The deviation does not depend on the plasma dimensions; however, it is influenced to a certain degree by the density profile. The method is successfully applied to the investigation of a dense plasma focus with a time resolution of 2 nsec and a spatial resolution (in axial direction) of 2 mm. PMID- 20197972 TI - Coherence of a light beam through an optically dense turbid layer. AB - A light beam propagating through a turbid medium (e.g., aerosol) can be severely attenuated by scattering losses and still retain coherence over distances comparable to particle diameters. An expression for the two-detector mutual coherence function is rederived by means of approximations clarified by a physical model. Its spatial and temporal properties are further examined by means of a simplified physical aerosol model leading to tractable mathematical analysis. PMID- 20197973 TI - Detector nonlinearity effects on the statistics of a fluctuating signal. AB - The effect of the detector nonlinearity on the statistics of a fluctuating signal is evaluated. The input signal is assumed to be log-normally distributed, which is of interest in the study of the laser propagation through the turbulent atmosphere. Both detector threshold and saturation effects are taken into account. PMID- 20197974 TI - Absorption characteristics of the gamma-0 band of nitric oxide. AB - The absorption by the gamma-0 band of nitric oxide at 2260 A has been studied. Its apparent absorption cross section depends both on total pressure and its concentration. In order to investigate these absorption characteristics quantitatively, a line by line analysis was made. Good agreement was obtained between the experimental and computed results of the absorption cross section. PMID- 20197975 TI - Oscillation characteristics of an external-cavity system as used with the spin flip Raman laser. AB - A model external-cavity system is investigated to describe the tuning characteristics appropriate to the various experimental procedures used in the operation of the spin-flip Raman laser. In particular a calculation is made of the amount by which internal subcavities pull the oscillation frequency away from the Raman frequency under the servocontrolled conditions used to achieve continuous tuning. PMID- 20197977 TI - Determination of the atmospheric extinction coefficient by measurement of distant contrasts. PMID- 20197976 TI - Infrared vibration-rotation spectra of the CIO radical using tunable diode laser spectroscopy. PMID- 20197978 TI - Optical activities in industry. PMID- 20197979 TI - Applied optics of optics and opticists. PMID- 20197980 TI - Generation of tunable coherent radiation below 250 nm at MW power levels. PMID- 20197981 TI - Fourier transform infrared spectroscopy: recent developments. AB - The 1977 International Conference on Fourier Transform Infrared Spectroscopy was held 20-24 June 1977 at Columbia, S.C. The manuscripts of most of the invited speakers at this meeting follow this report. This paper summarizes the seven papers in this category which could not be submitted. These papers described the application of cryogenic interferometers to atmospheric sounding (Stair), to the measurement of cosmic background radiation (Richards), and to the study of chemical reaction dynamics (McDonald). The use of ultrasensitive far infrared detectors for studying the properties of solids was described by Sievers. Genzel and Griffiths described applications of the optical subtraction technique for far infrared and mid infrared measurements, respectively. Finally Wyntjes summarized his views on the present and future of interferometry. PMID- 20197982 TI - Of Fourier, Pasteur, and sundry others. AB - Twenty years of Fourier spectroscopy revival may be long enough to present some reminiscences and general comments. It is necessary to read the text to ascertain how Pasteur fits in. PMID- 20197983 TI - High-accuracy Doppler-limited 10(6) samples Fourier transform spectroscopy. AB - The contribution of the third-generation Fourier spectrometer, built at the Laboratoire Aime Cotton and currently at the Laboratoire d'Infrarouge, to meteorological and high resolution Doppler-limited measurements is reported citing typical examples and the latest instrumental improvements. A tilt compensated triple-pass system for use with previously built Fourier spectrometers to increase the resolution by 3 is described. The resulting width of the apparatus function of the triple-pass third-generation interferometer is better than 10(-3)cm(-1) and can be meaningfully expressed in frequency units. Its actual value is 27 MHz. For the first time a spectrometer is able to give very wide spectral range information with a resolving power sufficient to analyze sub-Doppler spectra. PMID- 20197984 TI - Fourier transform spectroscopy in the visible and ultraviolet range. AB - In cases where the photon noise is the limiting factor, the multiplex gain is not always conserved; however the throughput (Jacquinot's advantage) is not affected. Therefore extension of Fourier transform spectroscopy to higher frequencies has great possibilities. Studies at high resolution, both in emission and in absorption, show that the performance achieved by Fourier transform spectroscopy in the visible and uv range is comparable with that reached in the ir. PMID- 20197985 TI - Expanding field of far infrared Fourier transform spectroscopy in the laboratory, industry, and the environment. AB - Twenty-five years of development and sophistication have taken place in Fourier transform spectroscopy since Fellgett drew attention to the multiplex advantage in 1952. Three important applications are reviewed. First, high resolution broadband submillimeter-wave spectroscopy at high wavenumber and spectroradiometric accuracy is discussed, with particular reference to its application in measuring the composition of the high atmosphere. Second, a rapid scan technique applicable to the measurement of the emission from pulsed tokamak plasmas for diagnostic purposes is described, and finally some results using the technique of dispersive Fourier spectroscopy applied to solids and liquids are given. PMID- 20197986 TI - Improvements in time resolved Fourier spectroscopy. AB - The technique of Fourier spectroscopy, the full realization of its advantage, has been applied to a time-dependent study. The principle of the technique, the SNR expected, and the instrumentation involved are discussed together with some recent results. PMID- 20197987 TI - Infrared spectroscopic studies of transients. AB - Fourier transform spectroscopy has been demonstrated to provide outstanding results in astronomical and high resolution spectral studies of cw sources. However, techniques for the study of reacting or transient systems have been less than satisfactory in cases where one is seriously interested in obtaining detailed spectroscopic data. It has been demonstrated that Fourier transform techniques can also be utilized in the study of systems which are transient as well. This paper discusses the use of Michelson interferometers in the study of transients, and new results will be presented. PMID- 20197988 TI - Airborne infrared astronomical observations by Fourier transform spectroscopy. AB - Infrared spectroscopic observations from NASA-operated aircraft constitute a rapidly maturing application of FTS methods initially developed for ground-based telescopes. Coupled to airborne telescopes up to 36 in. in diameter, these experiments are now producing new astronomical results as exciting and unexpected as those derived from Connes's first high resolution planetary observations at mountain-top observatories. This review examines the special problems of the ir spectral region that led to aircraft observatories and includes a brief survey of the facilities themselves and their modes of operation. The special problems of operating FTS devices on aircraft and the scientific results achieved with current capabilities are discussed. Finally, airborne observations are compared to the ultimate in high-altitude observing platforms: earth-orbiting cooled and uncooled telescopes carried by the space shuttle vehicle. PMID- 20197989 TI - Air pollution measurement by Fourier transform spectroscopy. AB - The use of infrared methods in pollution measurement has been hampered by sensitivity limitations and by interferences from water vapor. Fourier transform spectrometer systems reduce these limitations by their high optical efficiency and their ability to manipulate spectra for removal of interfering bands. At the Environmental Protection Agency we have sought to further increase the sensitivity of the infrared technique by evolving optimal long path cell designs and sample concentration techniques. Reactive pollutants such as O(3), H(2)O(2), HNO(3), HNO(2), H(2)CO, HCOOH, PAN, HCl, NH(3), NO, and NO(2) are best measured in the open atmosphere. In this case one strives toward large absorption cells with the paths as long as practical. Our largest cell is being used to measure pollutants in the smog at Riverside, California. This cell uses an eight-mirror system for multiple-passing radiation along a 23-m base path, yielding total paths measured in kilometers. Reactive gases at levels of just a few ppb have been measured. For measuring nonreactive pollutants, such as hydrocarbons and halocarbons, maximum detection sensitivity is achieved with small folded-path cells rather than with large cells. In this case a pollutant concentrate is prepared and introduced into a miniaturized multiple-pass cell designed for maximum path-to-volume ratio. Cryogenic trapping to separate the pollutants from the major constituents of the air has yielded concentration factors as high as one million. The smallest multiple-pass cell we have built to date encloses a 115 cm light path within a volume of 3 cm(3). This cell when used with the FTS spectrometer and mercury-cadmium-telluride detector permits the detection of nanogram quantities of pollutant gases. Measurements have been made of trace gases in the air at mixing ratios as low as 2 x 10(-11). PMID- 20197990 TI - Fourier transform infrared spectrometers: their recent history, current status, and commercial future. AB - The commercial FT-IR market has grown to a respectable $8,000,000 annual business area. It is of importance to both the users and suppliers alike that this market continues to solidify its gains and embark into new areas and applications. This paper reviews the evolution of commercial FT-IR in the context of the over-all infrared field. The purpose of the review is to discuss the progress to date and to relate the growth of this field to the future. The future uses of the FT-IR are projected as well as the requirements for new instrumentation. PMID- 20197991 TI - Recent applications of FT-IR spectroscopy to polymer systems. AB - Fourier transform infrared spectroscopy has recently become an important analytical method for investigation of many polymer systems. Several new methods, concerned primarily with digital subtraction of absorbance spectra, are presented. Applications of the method to synthetic polymer research include conformational and configurational analyses, elucidation of degradation mechanisms, and interactions with filler surfaces. Many researchers in the biopolymer and medical fields have utilized the sensitivity and digital data processing capabilities of FT-IR to obtain information inaccessible by other methods. PMID- 20197992 TI - Transformed world of industrial infrared analysis. AB - Infrared spectroscopy is a widely used industrial tool for the structural and compositional analysis of organic, inorganic, or polymeric samples and for quality control of raw materials and commercial products. The increased sensitivity of Fourier transform infrared has greatly enhanced the problem solving opportunities for infrared in research and development laboratories. Examples are given where FT-IR has been particularly effective in the rapid identification of very small quantities of product from unusual chemical reactions without the necessity of separating the product from the reactants. The good SNR attainable with FT-IR, with the data processing capability, has increased the ability to observe very small differences between the spectra of supposedly similar polymers. These differences have been related to changes in processing conditions and polymer physical properties. FT-IR has been used successfully to characterize structural changes in petroleum products, which may occur as a result of chemical and physical treatment. FT-IR spectra of a series of acrylonitrile-containing copolymers have also been correlated with NMR monomer sequence data to delineate sequence-sensitive infrared bands. PMID- 20197993 TI - New trends in the application of Fourier transform infrared spectroscopy to analytical chemistry. AB - Four major trends will characterize the evolution of Fourier transform spectroscopy's analytical laboratory applications in the remaining seventies and early eighties: (1) A more thorough analysis of the nonidealities of real FT-IR systems will allow the quantitative accuracy of FT-IR to approach its SNR capability, or to be corrected to this level. (2) The power of FT methods is severely mismatched to current practice and habits in the infrared analytical laboratory. New operating procedures, combination techniques such as GCIR (a much better match to FT-IR capabilities) and more demanding spectroscopic techniques, will become more common. In the wake of this development, greater emphasis will be placed on automatic sample preparation and interpretation. (3) At the same time, the importance of spectra as the final output of spectroscopic measurements will decrease. Instead, higher order spectroscopic functions, or even final analytical data, will become a frequent instrumental output, with or without high level operator interaction. (4) The domain of application of Fourier transform spectroscopy will tee steady extension into new spectral regions, such as the near infrared and UV-VIS regions, while its extension to Raman spectroscopy still appears elusive. The analysis embodies a strong conservative bias, in that it excludes from consideration the consequences of new technology. This also insures its relevance to currently existing instrumentation. PMID- 20197994 TI - Demonstrating Fourier transform spectroscopy for students. AB - A Michelson interferometer with 230-mm mirror displacement is used to study coherence length and line shape of several light sources in the visible range. The instrument's construction is simple. Using quasimonochromatic symmetric spectral lines, a method is described for obtaining information about the source line shape from the envelope of the interferogram. Doppler-and pressure-broadened lines can easily be distinguished. The instrument gives a good demonstration of the Fourier relation of interferogram and spectrum. PMID- 20197995 TI - Pressure dependence of integrated CARS power. AB - The pressure dependence of the integrated power of coherent anti-Stokes Raman scattering (CARS) has been investigated experimentally as well as theoretically. The integrated CARS power has been found to be inversely proportional to linewidth, in contrast to the spontaneous Raman scattering for which the integrated power is independent of linewidth. Because of the pressure broadening of the Raman lines and the interference among them, the integrated power deviates from a simple square-law dependence, the degree of deviation being a function of molecular species. Experimental results are presented for CH(4), CO, N(2), and H(2), with collisional narrowing being demonstrated for H(2). PMID- 20197996 TI - Approximation to the Lorentzian coefficient for efficient calculation of transmittance profiles. AB - A major problem in the calculation of line-by-line profiles of atmospheric transmittance lies in the excessive computational times associated with the evaluation of the Lorentzian coefficient for every gas, wavenumber, line, temperature, and pressure along the path. An approach to the solution of this problem is presented, whereby use is made of an approximating function that allows for the quantities involving temperature and pressure to be factored out of the wavenumber-dependent terms. Although the approximating function is restricted to wavenumbers farther than about a line halfwidth at STP from the line center, a numerical procedure is presented for dealing with the remaining few cases. This approach results in a significant reduction in the number of arithmetic operations from the use of the exact coefficient and generally yields a transmittance with a numerical accuracy of four significant figures or better. An application is made to five Nimbus 6 center-filter frequencies in the 4.3-mum CO(2) band for H(2)O, CO(2), N(2)O, and CO in a 33-level atmosphere with average computational times reduced by a factor of over 9. PMID- 20197997 TI - Color of the ocean. AB - The color of the ocean is calculated from a model that realistically takes into account the various types of scattering and absorption events that occur in both the atmosphere and ocean. Solar photons are followed through the atmosphere and into the ocean by a Monte Carlo technique. The reflection and refraction at the ocean surface are included in the calculation. The upward and downward flux is calculated at several different heights in the atmosphere, at thirteen different wavelengths from 0.4 mum to 0.7 mum. These results are compared with two approximate theories: (1) one-dimensional; (2) single scattering. The first of these theories gives results which are accurate within 10% in most cases and are easy to calculate. The chromaticity coordinates as well as the dominant wavelength and purity of the color are calculated from the Monte Carlo results for the variation of upward flux with wavelength. The ocean color near the horizon is almost entirely determined by the color of the sky reflected by the ocean surface. The upwelling light from the ocean can be observed near the nadir if precautions are taken to exclude as much light as possible reflected from the ocean surface. The color of this upwelling light from the ocean contains much information about the hydrosol, chlorophyll, and yellow substance amounts in the ocean water. The model calculations show how the ocean color changes from a deep blue of high purity for relatively pure water to a greenish blue and then to green of low purity as the cholorphyll and yellow substance amounts increase. Further increases in these substances cause the color to change to yellow green of a higher purity. A large increase in the hydrosol amount usually causes a marked decrease in the purity of the color. PMID- 20197998 TI - Improved random spatial phase modulation for speckle elimination. AB - An improved version of the random spatial phase modulator (RSPM) reported recently by one of us is described. Using the improved RSPM, a theoretical value of the SNR of several thousand can be achieved. Experimental results are presented verifying that speckle can be completely eliminated using RSPM. The measured SNR exceeds 100, and there is no visually detectable difference between images obtained with RSPM laser light and those with white light even for an optical system of f/600. The effective decorrelation distances for different diffusers and their dependence on the aperture of the RSPM are investigated. An application of RSPM to coherent spatial filtering is demonstrated. PMID- 20197999 TI - Image plane holograms for holographic microscopy. AB - We have studied the use of image holograms in holographic microscopy. Reducing the degree of spatial coherence in the reconstructing light source reduces the speckle in the reconstructed real image field. A careful choice of recording parameters is necessary to retain the resolution needed to study microscopic objects. Sample photomicrographs of test targets, blood cells, and human hairs are included. PMID- 20198000 TI - Thin film optical coatings. 6: Design method for two given wavelength antireflection coatings. AB - This paper considers the relations between thin film indices for making an antireflection coating when all optical thicknesses are equal. In this way, it is possible to determine antireflection coatings for two given wavelengths. Various cases are studied according to the two wavelengths and the index of the substrate. PMID- 20198001 TI - Ray tracing through funnel concentrator optics. AB - A procedure and equations are presented for tracing meridional and skew rays through some funnel concentrators proposed as solar energy collectors. These concentrators are general toroids generated from parabolic or elliptical surfaces. The ray tracing procedure uses an iterative technique with exact tracing to conical surfaces tangent to the concentrator. PMID- 20198002 TI - Patents. AB - 3,868,173; 3,868,174; 3,871,741; 3,889,208; 3,894,789; 3,916,338; 3,934,211; 3,936,155; 3,936,772; 3,938,172; 3,940,713; 3,942,132; 3,946,334; 3,949,319; 3,969,016; 3,969,573; 3,974,376; 3,977,767; 3,977,018; 3,977,793; 3,978,458; 3,980,390; 3,980,392; 3,980,395; 3,981,591; 3,982,816; 3,982,818; 3,982,833; 3,990,770; 3,992,081; 3,992,083; 3,992,084; 3,992,623; 3,994,573; 3,994,576; 3,998,528; 3,998,529; 4,001,840; 4,002,406; 4,002,407; 4,005,285; 4,009,934; 4,009,938; 4,009,945; 4,009,956; 4,013,347; 4,014,608; 4,015,896; 4,015,897; 4,017,147; 4,017,148; 4,017,163; 4,017,171; 4,018,509; 4,018,512; 4,018,523; 4,019,157; 4,021,099; 4,025,157; 4,025,199; 4,025,783; 4,027,951; 4,027,952; 4,027,976; 4,028,544; 4,028,548; 4,028,719; 4,029,396; 4,029,419; 4,030,805; 4,033,052; 4,033,667; 4,033,674; 4,033,688; 4,037,934; 4,040,039; 4,040,056; 4,040,720; 4,042,295; 4,045,127; 4,045,128; 4,046,459; 4,046,460; 4,048,587; 4,050,778; 4,050,779; 4,052,121; 4,054,369; 4,055,378; 4,056,306; 4,056,310; 4,056,311; 4,057,328; 4,057,330; 4,059,340; 4,059,342; 4,059,344; 4,059,348; 4,060,306; 4,060,312; 4,061,418. PMID- 20198003 TI - Time-of-flight laser anemometer for velocity measurements in the atmosphere. PMID- 20198004 TI - Ocular hazard from uv laser exhibiting self-modelocking. PMID- 20198005 TI - Simultaneous electron density and ion temperature measurements of a moderately dense plasma using Doppler and Stark broadened He II lines. PMID- 20198006 TI - All-dielectric compound parabolic concentrator: corrigenda. PMID- 20198007 TI - Molecular interpretation of the infrared water vapor continuum. PMID- 20198008 TI - Thin film optical coatings: errata. PMID- 20198009 TI - Far infrared laser resonator for TEM(00) mode operation. PMID- 20198010 TI - Typical photoefficiency between 20-250 eV of windowless XUV photodiodes with tungsten and anodized aluminum oxide photocathodes. PMID- 20198011 TI - Generation of color images with one-step rainbow holograms. PMID- 20198012 TI - Guided wave electrooptic devices for logic and computation. AB - The use of guided wave optical components for performing logic and computation is proposed. The basic logic gates are switches and intensity modulators fabricated on an electrooptic substrate. The states of the switches and modulators are determined by electrical signal voltages. The output signal from each of the gates is intensity-modulated light, while inputs can be electrical signals or a combination of electrical and optical signals. Individual gates can be interconnected on a substrate by dielectric waveguides, so that sequential operations are possible. This is illustrated by a configuration for a serial parallel binary adder. The propagation delay, as determined by the optical pathlength, is calculated to be of the order of 20-40 psec/gate, assuming that the substrate material is lithium niobate, and the logic voltage level is 5 V. PMID- 20198013 TI - Bending loss of propagation modes in arbitrary-index profile optical fibers. AB - A bending loss formula for optical fibers with an axially symmetric arbitrary index profile is derived by approximating the refractive-index profile with a staircase function. The permissible bending radius R* defined for a given value of bending loss is derived. It is deduced that R* is nearly proportional to wavelength lambda when the normalized frequency nu and the refractive-index difference Delta are fixed. The ratio of R* at two different values of nu depends only on the ratio of nu. The influence of an index dip and profile smoothing on R* is numerically evaluated. PMID- 20198014 TI - Temporal response of the acoustooptic modulator: physical optics model in the low scattering efficiency limit. AB - The Green's function model of the acoustooptic modulator proposed by E. I. Gordon et al. is reformulated in Fourier transform space to simplify the mathematics and to underscore the physics. Numerical studies of response to sinusoidal video signals and to square pulse trains indicate that the modulator can be approximated by a linear invariant model with a suitably scaled Gaussian impulse response. An angular scattering window analogy is proposed to explain the characteristics of the modulator. PMID- 20198015 TI - Compound catadioptric telescopes with all spherical surfaces. AB - Catadioptric, all spherical Cassegrainian and Gregorian telescopes with one and two full aperture corrector lenses are investigated. Appropriate closed form third-order aberration equations are presented, and a variety of aplanatic and anastigmatic solutions are indicated. PMID- 20198016 TI - Intensity mapping optical aberrations. AB - Intensity mapping aberrations for high average power laser beams are examined from the point of view of diffraction theory. For the Fresnel ripple aberrations, it was determined that indeed they behave like a circular diffraction grating where energy is diffracted into the far wings of the far-field intensity distribution without significantly affecting the width of the central diffraction lobe, only its energy. It was further established that the effect of such aberrations on the far field may well be characterized by techniques where the aberration is randomized, and on-axis intensities are obtained through approximate methods. PMID- 20198017 TI - Linear, annular, and radial focusing with axicons and applications to laser machining. AB - New optical combinations of axicons and axicons with spherical mirrors and lenses suitable for laser machining are presented. Linear and annular focusing, coaxially and radially to the laser beam, are possible. Most combinations allow continuous adjustment of exit beam parameters, focal line length, focal ring diameter, and magnification, by varying the relative position of one of the axicons. Potential new laser applications are also discussed in relation to these optical devices. PMID- 20198018 TI - Distributed aperture effect in laser rods with negative lenses. AB - Negative lenses have been ground on the ends of laser rods to increase the TEM(00) mode volume. With the negative lenses on the ends, the laser rod acts like a distributed aperture. The distributed aperture radius and its effect on the useful volume of the laser rod are calculated. The mode radius and the diffraction loss for a laser rod with negative lenses ground on the ends are presented as a function of laser rod focal length and the Fresnel number. PMID- 20198019 TI - Ultraviolet-visible absorption in highly transparent solids by laser calorimetry and wavelength modulation spectroscopy. AB - The requirements for low-loss optical materials for use on excimer lasers have stimulated the investigation of optical absorption in a variety of highly transparent materials at visible and uv wavelengths. To provide information over a wide spectral range at low absorption levels ( approximately 10(-5) cm(-1)), laser calorimetric and wavelength modulation spectroscopic techniques were used. Blending these two methods provided, for the first time, spectral information well below the usual levels of absorption measured in studies of the Urbach tail. PMID- 20198020 TI - Refractive index of Irtran 2 as a function of wavelength and temperature. AB - Data are presented for the refractive index of Irtran 2, a hot-pressed microcrystalline compact of ZnS, made by the Eastman Kodak Company, from 1 microm to 15 microm and from 93 K to 283 K. The values range from 2.35 at both high temperatures and short wavelengths to 2.12 at the opposite extremes. The average value of dn/dT is about 4 x 10(-5) K(-1) at 104 K for all wavelengths, with a value of 2 x 10(-7) K(-2) for the temperature variation of dn/dT. PMID- 20198021 TI - Real-time recording medium: photodichroic KF:LiF. AB - Laser recording and readout measurements using the photodichroic crystal KF:LiF indicate that the material has potential as an input transducer and an adaptive spatial filter in an optical spectrum analyzer. These crystals are among the most photosensitive recording materials without gain, can be produced in large sizes at relatively low cost, and can be operated close to room temperature using thermoelectric coolers. Experiments using a high precision laser scanner providing 96.6-MHz subnsec pulses at 514 nm show that adequate recording can be accomplished with exposures less than 10 mJ/cm(2). An MTF of 40% at 72 1/mm was measured with uniform readout illumination of the recorded signal, but this is reduced if the signal is recovered by rescanning due to the convolution of the scanning beam profile with the recorded spot profile. The readout is destructive at the recording wavelength but can be read out with a much reduced decay rate by using 488 nm. The linear dynamic range in the Fourier plane was measured to be 40 dB. PMID- 20198022 TI - Polar camera for space-variant pattern recognition. AB - Optical pattern recognition invariant to a rotation between the input and reference opjects is described. This is achieved by a space-variant optical system using coordinate transformations. The use of a polar camera to realize the coordinate transformation in real-time and the application of this system to real imagery rather than simple geometrical objects are presented for the first time. PMID- 20198023 TI - Composite bolometers for submillimeter wavelengths. AB - The fabrication and optimization of composite submillimeter wave bolometers with metal film absorbing elements and doped Ge thermometers are described. Performance characteristics are given for 4 x 4-mm bolometers designed for operation at both (4)He and (3)He temperatures. The performance expected from such bolometers when they are optimized for various values of background loading is calculated. Current dependent noise, which can arise from any of several sources, is included in the analysis. This can make it impossible to reach the background fluctuation noise limit. Feed structures for these bolometers which employ Winston light concentrators are described. PMID- 20198024 TI - Gallium arsenide electroabsorption avalanche photodiode waveguide detectors. AB - Gallium arsenide electroabsorption avalanche photodiode (EAP) detectors have been fabricated in n - n(+) GaAs waveguides. Since these EAP detectors respond to wavelengths beyond the normal absorption edge of GaAs, due to the Franz-Keldysh effect, they have been used to detect the below band gap radiation from GaAs lasers and the 1.06-mum radiation from Nd:YAG lasers. The measured absorption and responsivity at these wavelengths suggest a number of applications. These EAP devices have been used to detect analog signals with a distortion less than 6%. Methods for utilizing them in time- and frequency-demultiplexing applications are also described. PMID- 20198025 TI - Algorithm for determining the optical constants of thin films. AB - An algorithm for determining the optical constants of thin films from normal incidence reflection and transmission measurements is presented. To facilitate the solution of the equations described in this problem, properties of the plot of the function k(1) (n(1)) are utilized. The algorithm obtained is more effective than the one proposed by Tomlin. PMID- 20198026 TI - Computer-produced holograms for scanners utilizing an auxiliary reflector. AB - Computer-produced holograms for scanners utilizing an auxiliary reflector have been constructed and demonstrated. Mathematic formalism for the calculation and detailed fabrication procedures are described. This method can be used for producing holograms for operation at any wavelengths whenever direct recording is not practical or inconvenient. This method is particularly suitable for producing holograms for 2-D scanners in the longer wavelengths, such as ir, far ir, mm, microwave, and ultrasonic waves. Simplicity in operation of the 2-D scanner will make real-tme imaging systems practical in the long-wavelength region. PMID- 20198027 TI - Correcting errors in the optical path difference in Fourier spectroscopy: a new accurate method. AB - A new computational method for calculating and correcting the errors of the optical path difference in Fourier spectrometers is presented. This method only requires an one-sided interferogram and a single well-separated line in the spectrum. The method also cancels out the linear phase error. The practical theory of the method is included, and an example of the progress of the method is illustrated by simulations. The method is also verified by several simulations in order to estimate its usefulness and accuracy. An example of the use of this method in practice is also given. PMID- 20198028 TI - Martin-Puplett interferometer: an analysis. AB - A detailed analysis is presented of the Michelson polarizing interferometer suggested by Martin and Puplett. This instrument has many favorable properties for use as a far ir Fourier spectrometer. The effect of misalignments and imperfections of the optical components on the instrumental performance is calculated. Based on these results, we give a method of aligning the interferometer which optimizes its performance. In addition, this instrument may be used to measure the optical transfer function of a component in the output beam as a function of both spatial and optical frequency. A procedure is described by which this may be done. PMID- 20198029 TI - Automated data acquisition and stabilization system for Fabry-Perot interferometry. AB - A data acquisition system for high-resolution Fabry-Perot interferometry is described. Used in conjunction with a piezoelectrically scanned Fabry-Perot, this apparatus compensates for all frequency drifts, maintains interferometer alignment, and allows extended data acquisition times in selected regions of a spectrum. PMID- 20198030 TI - Pressure-broadened linewidths of the R(9.5)(3/2) NO transition. AB - Pressure-broadened ir linewidths of nitric oxide are currently used in measurement of its concentration for studies on combustion, chemical kinetics, and air pollution.(1) We have measured the self-broadened width of the R(9.5)(3/2) transition in the NO fundamental band by CO laser transmittance and found a halfwidth of gamma = 0.0783 +/- 0.0067 cm(-1) atm(-1). The analysis is shown to depend on the treatment of A-doubling, even though the doublet spacing is less than the Doppler width. The foreign gas broadening by N(2) of this transition is similarly measured, and the ratio of self-broadening ability to the broadening ability of N(2) is found to be 1.30 +/- 0.31. PMID- 20198031 TI - Detectability limit and uncertainty considerations for laser induced fluorescence spectroscopy in flames. AB - Uncertainty relations are derived for fluorescence caused by laser excitation in flames. The effect of statistical and systematic uncertainties on the detectability limits for excited states are examined. Fluorescence trapping is discussed and shown to establish an upper limit on the number density that can be measured. Methods for minimizing the trapping effect are discussed. PMID- 20198032 TI - Application de la methode des GETS a la preparation de films minces monocristallins de TGS et TGSe deuteries pour spectroscopie infrarouge. AB - The GETS method (germination epitaxique dans des trous submicroscopiques) needs only a drop of TGS or TGSe solution in heavy water to give a single crystal film. The thickness e (e approximately 1 microm) is perfectly suited for mid-ir spectroscopy with polarized radiations. New lines are observed. In opposition to previous studies, there is no observation of lines disappearing at the Curie temperature, but several lines are continuously broadening when the temperature is increased from 80 K to 300 K. PMID- 20198033 TI - Removal of I(2)absorption lines from 514-nm excited Raman spectra. AB - The intense excitation of an Ar(+) laser operating at 514 nm enhances the grating ghosts and general stray light within most double monochromators at wavelengths close to the exciting line. The I(2) filter technique provides an effective means of reducing this interference and, in so doing, makes possible the measurement of Raman bands close to the exciting line. However, at an instrument resolution less than 3 cm(-1), the I(2) absorption spectrum seriously interferes with the Raman spectrum. Ratioing the Raman spectrum with a white light absorption spectrum of I(2) removes the I(2) absorption lines. However, with slit widths <3 cm(-1), the wavelength reproducibility of the monochromator on successive scans is not high enough to insure successful ratioing. A technique is described for obtaining, approximately within the same time interval, the Raman spectra and white light spectrum at each wavelength that data are acquired. This procedure accurately removes the I(2) absorption spectrum. PMID- 20198034 TI - Time-resolved laser fluorosensors: a laboratory study of their potential in the remote characterization of oil. AB - The fluorescence decay profiles have been determined for a number of light, crude, and heavy oils under ideal laboratory conditions to assess their utility in the remote characterization and identification of oil spills using remote laser fluorosensors. The fluorescence decay of light and crude oils can best be described by double exponential kinetics with the former having longer. decay constants. The heavy oils are described by only a single exponential decay function with a lifetime less than 1 nsec. PMID- 20198035 TI - Removal of atmospheric effects from satellite imagery of the oceans. AB - In attempting to observe the color of the ocean from satellites, it is necessary to remove the effects of atmospheric and sea surface scattering from the upward radiance at high altitude in order to observe only those photons which were backscattered out of the ocean and hence contain information about subsurface conditions. The observations that (1) the upward radiance from the unwanted photons can be divided into those resulting from Rayleigh scattering alone and those resulting from aerosol scattering alone, (2) the aerosol scattering phase function should be nearly independent of wavelength, and (3) the Rayleigh component can be computed without a knowledge of the sea surface roughness are combined to yield an algorithm for removing a large portion of this unwanted radiance from satellite imagery of the ocean. It is assumed that the ocean is totally absorbing in a band of wavelengths around 750 nm and shown that application of the proposed algorithm to correct the radiance at a wavelength lambda requires only the ratio () of the aerosol optical thickness at lambda to that at about 750 nm. The accuracy to which the correction can be made as a function of the accuracy to which can be found is in detail. A possible method of finding from satellite measurements alone is suggested. PMID- 20198036 TI - Rayleigh-Debye scattering with focused laser beams. AB - A focused beam technique has been developed for diagnosing the characteristics of individual particles within a polydisperse ensemble. In the Rayleigh-Debye approximation the scattered fields are related to the orientation and properties of a scatterer by means of explicit analytic formulas. The results simplify when the particle size is small compared to the minimum beam diameter. PMID- 20198037 TI - Particle sizing by forward lobe scattered intensity-ratio technique: errors introduced by applying diffraction theory in the Mie regime. AB - Hodkinson proposed that Fraunhofer diffraction theory could be used as an approximation to Mie theory in particle size measurement by a forward lobe scattering intensity ratio technique. This paper describes a technique for quantifying theoretical errors involved in this approximation. Theoretical errors are computed for monodisperse latex spheres in air and in water at angle pairs of 5 degrees /2.5 degrees , and 10 degrees /5 degrees , and 20 degrees /10 degrees . Errors oscillate with particle size in a manner related to oscillations in particle extinction coefficient and are generally within +/-40%. These are somewhat greater than suggested previously. Oscillations are stronger and errors generally larger in air than in water. PMID- 20198038 TI - Ultraviolet spectrophotometer for measuring columnar atmospheric ozone from aircraft. AB - An ultraviolet spectrophotometer (UVS) to measure downward solar fluxes from an aircraft or other high altitude platform is described. The UVS uses an ultraviolet diffuser to obtain large angular response with no aiming requirement, a twelve-position filter wheel with narrow (2-nm) and broad (20-nm) bandpass filters, and an ultraviolet photodiode. The columnar atmospheric ozone above the UVS (aircraft) is calculated from the ratios of the measured ultraviolet fluxes. Comparison with some Dobson station measurements gives agreement to 2%. Some UVS measured ozone profiles over the Pacific Ocean for November 1976 are shown to illustrate the instrument's performance. PMID- 20198040 TI - Highly efficient reflection-type polarizers for 10.6-microm CO(2) laser radiation using aluminum oxide coated aluminum mirrors. PMID- 20198039 TI - Analytical inversions in remote sensing of particle size distributions. 1: Multispectral extinctions in the anomalous diffraction approximation. PMID- 20198041 TI - Optical activities in industry. PMID- 20198042 TI - Applied optics of optics and opticists. PMID- 20198043 TI - Patents. PMID- 20198044 TI - Ideal flux concentrators with reflector gaps. PMID- 20198045 TI - Virtual Fourier transform as an analytical tool in Fourier optics. PMID- 20198046 TI - Active laser resonator control techniques. PMID- 20198047 TI - Fiber optic guides of noncircular cross section. PMID- 20198048 TI - Optical time domain reflectometer: comment. PMID- 20198049 TI - Analytical inversions in remote sensing of particle size distributions. 2: Angular and spectral scattering in diffraction approximations. PMID- 20198050 TI - Light waves guided by a single curved surface: comments. PMID- 20198051 TI - Optical absorption in KCI and NaCI at infrared laser wavelengths. PMID- 20198052 TI - Bandstrength determination of the fundamental vibration-rotation spectrum of CIO. PMID- 20198053 TI - Photographic nucleonics: a record of many lost opportunities in the history of science. AB - Underexposed photographic negatives were toned with uranium around the turn of the century. Such radioactive photographs permit image transfer by autoradiography, and this confers several new options in photography. It is surprising that about half a century elapsed before the implications of such image transfer were described. The full possibilities of such transfer in processes of intensification, relief imaging, and photographic research are only now being realized. PMID- 20198054 TI - Rearview periscope comprised of two concave cylindrical mirrors. AB - Using novel ray-tracing techniques and methods of evaluation, optical devices comprised of two cylindrically concave mirrors have been designed and constructed which function satisfactorily as periscopic rearview systems. By following the design principles as described, mirror positions and curves are determinable which result in systems which are free of objectionable amounts of distortion and astigmatism over large fields of view. Comfortable binocular vision is obtainable along with latitude for movements of the observer's head. Examples of successful designs are given. PMID- 20198055 TI - Tolerance of the refractive index gradient in optical elements. AB - In this work the influence of the refractive index gradient was calculated in convergent and divergent lenses, disks, and deflecting prisms on the diffraction measurement of optical imaging-Strehl definition. PMID- 20198056 TI - Phase error model for simple Fourier transform lenses. AB - The effects of amplitude nonuniformities and phase errors on the accuracy of the optical Fourier transform are considered for the case of a simple lens. A quadratic phase model is derived, analyzed, and compared to experimental and point-by-point optical path difference data. The goal is to determine the lens specifications needed to produce an optical Fourier transform of given accuracy rather than the design of the lens itself. PMID- 20198057 TI - High-resolution lamellar-grating Fourier-transform spectrometer for the submillimeter region. AB - A lamellar-grating Fourier-transform spectrometer has been constructed for high resolution studies and for general measurements in the submillimeter region. The instrument has a maximum working resolution of 0.034 cm(-1) and an accuracy of frequency of +/-0.0015 cm(-1). To illustrate the performance of the instrument, the results of high-resolution measurements of H(2)O, CO, N(2)O, and CH(3)CN gases, and, in addition, the magnetic resonance measurements of some biological substances and the refractive index measurements of some III-V compounds are presented. PMID- 20198058 TI - High resolution Fourier transform spectrometer (0.005 cm(-1)) for the 0.6-100 microm spectral range. AB - The construction of a high resolution (0.005-cm(-1)) Michelson interferometer with cat's eye retroreflectors is described in some detail. The instrument line shape function of the Fourier spectrometer at 0.63 microm agrees with theory at 0.02-cm(-1) resolution. Absorption spectra of gases have been measured using a 40 m White cell. Infrared luminescence spectra have also been measured using a calcium fluoride crystal doped with divalent dysprosium, cooled to 4.2 K, and excited with radiation from a quartz halogen lamp. PMID- 20198059 TI - Ultrahigh (10(-4) cm(-1)) resolution study of the 8.2-microm and 11.3-microm bands of H(2)SO(4): accurate determination of absorbance and dissociation constants. AB - Using a tunable diode laser spectrometer with a spectral resolution of about 10( 4) cm(-1), the important central portions of the two ir absorption bands of H(2)SO(4) at 8.2 microm (1222 cm(-1)) and 11.3 microm (880 cm(-1)) have been scanned at low pressure (0.67 Torr of H(2)SO(4)) and atmospheric pressure (H(2)SO(4) with ~1 atm N(2)). Maximum absorption coefficients have been measured to be 6.5 cm(-1)-atm(-1) and 6.9 cm(-1)-atm(-1) at the 8.2-microm and 11.3-microm bands, respectively. A novel spectroscopic method was used to determine the temperature dependence of the dissociation of H(2)SO(4) into SO(3) and H(2)O in the 127-220 degrees C range. PMID- 20198060 TI - Implementation of hologram interferometry with a continuously scanning reconstruction beam. AB - A system for fringe evaluation in hologram interferometry is studied in which a conjugate reconstruction beam scans the hologram, and the resulting fringe motion is observed in the real image of the object. The principle is suitable for semiautomatic evaluation. An earlier article presented a detailed theoretical analysis of the measuring principle, and the present paper deals with the practical aspects. It is shown that the system is capable of interpolating fringes to 1/100 of a fringe, which is experimentally verified by the determination of 3-D displacement components with an accuracy of about 40 nm and of strain with an accuracy of about 10 microstrain over an observation length of 1 cm. An analysis of the different error sources shows that the mechanical measures of the recording and evaluation setup have to be known to a small fraction of a millimeter. PMID- 20198061 TI - Computer-aided holographic vibration analysis for vectorial displacements of bladed disks. AB - Photographs of hologram reconstructions which display vibration modes of bladed disks are digitized and numerically processed to determine translations and rotations of blade segments at radial locations. Because the blades are assumed not to move in the radial direction, only two holograms, each with a different sensitivity vector, are required of each vibration mode. In addition, a photograph of fringes projected onto the bladed disk is used to determine blade surface contours and compensate for their effect on the holographic fringes. PMID- 20198062 TI - All-reflection Michelson interferometer: analysis and test for far ir Fourier spectroscopy. AB - The beam splitter of the all-reflection Michelson interferometer consists of a combination of three parallel diffraction gratings. This paper extends the analysis of the instrument to include the effects of lateral errors in the grating adjustment (i.e., displacements parallel to the grating faces and perpendicular to the grooves). Such errors are shown to introduce a phase shift independent of wavenumber and proportional to grating order number. Tests of an instrument designed for Fourier transform spectroscopy in the 500-1000-microm spectral range are reported and shown to be in agreement with the analysis. For wavenumbers which pass through the instrument in 2 or more orders, cross-order interference effects are expected to occur which cause rapid variations in the efficiency vs wavenumber curve. This possibility should be eliminated in the design of a practical instrument. The resolution of the test instrument (1.6 cm( 1)) was insufficient to reveal this effect. PMID- 20198063 TI - Techniques of holographic displacement measurement: an experimental comparison. AB - Several of the existing methods of holographic displacement measurement have been discussed, procedures for their use outlined, and the techniques themselves compared experimentally for a variety of test situations. The results show that each technique has a unique application depending on the degree of accuracy and precision required for a particular measurement. PMID- 20198064 TI - Criterion for Bragg and Raman-Nath diffraction regimes. AB - The idea is well entrenched in the literature that thin phase gratings (whether holographic or acoustically induced) should exhibit Raman-Nath behavior (and thus give several diffracted waves), and that thick phase gratings should show Bragg behavior (one diffracted beam and that only for Bragg angle incidence). The parameter Q of Klein and Cook, which is a normalized measure of grating thickness, has been extensively used as a criterion for deciding which regime will apply. It is perhaps not generally realized that Q is not a reliable parameter for this purpose but requires, as indeed Klein and Cook noted, a limitation on grating strength. This limitation is a matter of practical concern. For example, we have observed Raman-Nath behavior with Fe-doped LiNbO(3) even for very large values of Q. The purpose of the present paper is to note that a parameter rho (first defined by Nath) is an effective replacement for Q, since rho is reliable and Q is not. rho is defined as lambda(0)(2)/Lambda(2)n(0)n(1), where lambda(0) is the vacuum wavelength of the light, Lambda is the grating spacing, n(0) is the mean refractive index, and n(1) is the amplitude of the sinusoidal modulation of the refractive index. The grating thickness does not enter rho, so the terms thin and thick are, strictly speaking, irrelevant to the question of which regime is operative. However, thin enough gratings will tend to operate in the Raman-Nath regime because the index modulation must be large for a thin grating to produce appreciable diffraction. PMID- 20198065 TI - Limitation of the observable surface acoustic wave amplitude in frequency-shift holography. AB - The theoretical and experimental analysis of the limitation of the observable amplitude of surface acoustic waves in a frequency-shift holography is presented. In this holography technique the object beam is filtered optically, and the frequency of the reference beam is shifted by the same amount as that of the surface acoustic wave. Several parameters that determine the limitation are analyzed, and a subangstrom amplitude has been observed experimentally. PMID- 20198066 TI - Measurement of diffraction efficiency, SNR, and resolution of single- and multiple-exposure amplitude and bleached holograms. AB - Five bleaching techniques for Agfa Gevaert Scientia 10E75 high-resolution plates were evaluated to determine resultant diffraction efficiency and SNR for identically recorded single-exposure holograms. We determined the optimum recording conditions for both single- and multiple-exposure bleached holograms using a cupric bromide bleach, judged to be the "best bleach." Data are presented for diffraction efficiency, SNR, and resolution of diffuse and focused-image holograms for both single- and multiple-exposure holograms, using a 1951 Air Force resolution chart as the object. Bleaching improved the diffraction efficiency of both types of holograms by up to 3 orders of magnitude. The SNR of diffuse holograms is degraded by bleaching, but that of the focused-image holograms is improved, while the resolution of both types is not affected by bleaching. Bleached multiple-exposure holograms are similar in response to single exposure holograms except that their diffraction efficiencies are lower. The diffraction efficiency of bleached holograms decreases with age. PMID- 20198067 TI - Refractive index determination using reflectance extrema. AB - Contours of n and k vs the reflectance and transmittance of a thin film on a glass (n = 1.5) substrate are presented. These contours provide a unique value of (n - ik) and the film thickness, given the normal incidence R and T values at a reflectance extremum, wavelength, and the interference order of the extremum. The results are corrected for the reflectance of the rear of the substrate, and for the wavelength shifts of the extrema, and cover the range n = 1.6-4, k = 0-1. A simple model of strongly scattering films is used to provide n and k contours vs the total reflectance and transmittance of scattering layers: n and k appear to retain their usefulness in this situation. PMID- 20198068 TI - Infrared characterization of surfaces and coatings by internal-reflection spectroscopy. AB - Some problems which arise in the characterization of surfaces and coatings by internal reflection spectroscopy are described. The ir spectra of bare CaF(2) trapezoids and of ThF(4)- and ZnSe-coated trapezoids exhibit absorption bands in the same spectral region as those of H(2)O and hydrocarbon impurities. In accord with previous investigations, it is observed that the absorptance due to water is much greater in the ThF(4) films than in the ZnSe films or on the CaF(2) surfaces. These results suggest that the water is distributed throughout the ThF(4) films, whereas for ZnSe it resides primarily on the surface. In addition, a number of interesting observations on the desorption and adsorption of water and hydrocarbons to these materials are made. The experimentally observed absorptances are analyzed on the basis of the reflectance for a threelayer system. The analysis enables reasonably quantitative values for the absorption coefficient to be determined for these thin-film coatings. PMID- 20198069 TI - Modeling solar cells for use as optical detectors: background illumination effects. AB - Solar cells have traditionally been used for direct sunlight to energy conversion, but there has been relatively little investigation into their use as a low data rate optical detector. This paper presents an experimental procedure used to determine the ac model of a specific solar cell. A lumped circuit model and governing equations are developed. Open circuit responses to pulses are used to determine values for the internal capacitances as a function of background illumination. Possible problems encountered with noise generation are also reviewed. PMID- 20198070 TI - Field-enhancement of photoemission from cesium telluride. AB - The responsive quantum efficiency of semitransparent cesium telluride photocathodes has been found to be significantly increased by the application of high electric fields (a few MV m(-1)) such as are encountered in proximity focused image converters. Measurements of the magnitude of the effect are presented as functions of applied field and of wavelength over the 120-800 nm range. An interesting anomaly was found in the pair-production region in the vacuum uv; otherwise, the results are fairly consistent with the effects of a simple Schottky lowering of the surface potential barrier of the photoemitter. PMID- 20198071 TI - Radiative transfer in two dimensions through fog. AB - The 3-D time-independent unpolarized radiative transfer equation is developed into a form amenable to numerical solution by expansion of the total intensity in orders of scattering. A 2-D numerical algorithm is formulated using an eight direction quadrature approximation to the source function and an optimized path by-path intensity integration scheme. Computer code generated from the algorithm is used to examine the multiple scattering effects at 1.06 microm, 3.0 microm, and 10.6 microm in Deirmendjian C3 fog on a finite uniform intensity profile beam and an infinite Gaussian intensity profile beam. Transmission and backscatter for both beams are examined as well as contrast degradation of the uniform beam and spread of the Gaussian beam. PMID- 20198072 TI - High sensitivity point monitoring of atmospheric gases employing tunable diode lasers. AB - A laser absorption spectrometer is described which employs a wavelength tunable diode laser in conjunction with a multipass White cell. The instrument is sensitive to absorption coefficients as low as 3 x 10(-8) m(-1) and is designed for use as a portable pollution monitor. The performance of the instrument is illustrated by describing the measurement of three gases commonly found in the atmosphere: SO(2) and N(2)O with sensitivities of 1 ppb and NH(3) with a sensitivity of better than 0.1 ppb. The linearity of response and calibration of the instrument are also discussed in some detail. PMID- 20198073 TI - Novel spectrophotometer for the investigation of short term variability in stellar spectra. AB - A variety of astronomical objects (e.g., O(f) stars, B(e) stars, optical counterparts of X-ray sources, etc.) exhibit emission line spectra. For some of these objects the emission line strengths are suspected as being variable (and possibly periodic) over time scales as short as minutes or less. A spectrophotometer has been built whose output signal is a measure of the line strength only. The spectrophotometer is used to look at the emission feature and the adjacent continuum in rapid succession by means of magnetic modulation of the electron image of the optical spectrum in an image tube, thus generating a modulated signal which is detected with a lockin amplifier. This detection technique essentially subtracts off an instrumental dark current signal due to sky background and the signal due to the continuum of the star giving a real time measure of the line strength only. The design of the instrument, its laboratory calibration, and some preliminary observational data are presented. PMID- 20198074 TI - New monochromators of concave grating suitable for space telescopes. AB - Three types of new monochromators based on the new mounting of concave grating by Singh-Majumdar (SM) are described. These monochromators are very compact and simple in operation, fulfilling the requirements of a monochromator in a space telescope in the VUV region. It is found theoretically (by geometric optics theory of concave diffraction grating given by Beutler and modified by Namioka, and by a ray tracing procedure by drawing spot diagrams at different wavelengths) as well as experimentally in the laboratory by setting up the monochromator and taking sample spectra photographically that the spectral images have very little aberration as compared to other monochromators in the VUV region. The improvement obtained is three times. PMID- 20198075 TI - Thermal detuning effects in a standing wave acoustooptic modulator. AB - The acoustic absorption loss in a standing wave acoustooptic modulator produces a temperature rise in the acoustooptic medium that can lead to distortion, discrete transitions, and hysteresis in curves of diffracted optical power vs frequency or temperature. Experimental data obtained with a barium sodium niobate standing wave modulator are presented. PMID- 20198076 TI - Differential mode attenuation measurements in graded-index fibers. AB - An automated apparatus is described for measuring mode-dependent scattering and total attenuation in graded-index waveguides. Measurements are reported for two low-loss waveguides and several high-loss waveguides. The results illustrate the ability of this technique to identify different types of loss mechanisms. PMID- 20198077 TI - Low-loss single-mode fibers with different B(2)O(3)-SiO(2) compositions. AB - Design considerations, fabrication, and transmission characteristics of single mode optical fibers made with different borosilicate compositions are discussed. Fibers with core sizes as large as 15 microm and refractive-index differences below 0.1% were made with the modified chemical vapor deposition (MCVD) process. Minimum losses achieved with fibers up to 1-km lengths were 1.3-1.4 dB/km in the 1.02-1.1-microm range. Microbending losses were avoided by jacketing the fibers with silicone resin. Single-mode operation is maintained in moderately overmoded fibers (V ~ 3.0) because of leakage loss through a finite cladding thickness and because of bends in the fiber axis. PMID- 20198078 TI - Notes on optical coating removal. PMID- 20198079 TI - Lyman-alpha radiation source with high spectral purity: addendum. PMID- 20198080 TI - Optics is Light Work. PMID- 20198081 TI - Safelight for Agfa 10E75 and 8E75 plates. PMID- 20198082 TI - Rocket observations of auroral albedo over snow. PMID- 20198083 TI - Some polarization properties of volume holograms in Bi(12)SiO(20) crystals and applications. PMID- 20198084 TI - Fringe localization. PMID- 20198085 TI - Retroreflection from spherical glass beads in highway pavement markings. 1: Specular reflection. AB - The use of spherical glass beads in both vertical and horizontal highway markings to enhance nighttime visibility is common throughout the world. There has been, however, little theoretical analysis performed in order to optimize the various parameters for maximum retroreflection, especially for the case of horizontal reflectors. This paper presents a study of the retroreflection of spherical lenses used in horizontal pavement markings, concentrating initially on the specular contribution. The retroreflection characteristics are studied as a function of index of refraction and multiple specular internal reflection. It is shown that specular reflection does not contribute significantly to the total flux of retroreflected light reaching the motorist's eyes. PMID- 20198086 TI - Retroreflection from spherical glass beads in highway pavement markings. 2: Diffuse reflection (a first approximation calculation). AB - A first approximation calculation of the radiance or the retroreflected flux of light received by the automobile driver from a glass sphere partially embedded in highway marking paint is presented. The observed retroreflection arises mainly from the diffuse reflection at the painted region of the spherical cap on the rear surface of the sphere. It is found that the optimum value of embedment in paint for glass beads of refractive index 1.50 is 59% (+5%, -0%) of the diameter for high retroreflection at all distances. PMID- 20198087 TI - Flat-sided rectilinear trough as a solar concentrator: an analytical study. AB - Formulas are derived for the concentration factor and irradiance distribution at the base of the flat-sided linear trough. Performance is affected by the number of reflections the solar rays undergo before reaching the base, the cone apex angle, and the coefficient of reflection. Results are presented graphically in such a way that one can choose the optimum configuration, which is the minimum material required, to achieve a given concentration factor. Practical concentration factors range from 1.5 to 4 depending on the geometry and coefficient of reflection. PMID- 20198088 TI - Effect of substrate on graphite and other solar selective surfaces. AB - Solar selective surfaces consisting of a substrate of copper, silver, or nickel underlying a single layer of material of refractive index N = n + ik are compared using the criterion of maximum available power. Copper is shown to be slightly superior to silver, and both are shown to be superior to nickel for operating temperatures of 200 degrees C. For operating temperatures of 100 degrees C and below the three metals are comparable as substrates. The absorptance and emittance properties of graphite films on copper, silver, nickel, and titanium are found. The effect of aging of these films at temperatures up to 400 degrees C is investigated and interpreted in terms of diffusion. Graphite films on copper and silver are candidates for high temperature evacuated collectors. PMID- 20198089 TI - Fabrication using the computer controlled polisher. AB - The computer controlled polisher uses a small grinding-polishing tool assembly which travels over the work-piece surface under computer control. The machine has been used to fabricate successfully a number of difficult substrates including a beryllium mirror, a nonrotationally symmetric corrector plate, and a flexible aspheric mirror. These efforts have demonstrated the capability of CCP to fabricate 1/15 wave surfaces for difficult substrates. PMID- 20198090 TI - Remote sensing of optical properties in continuously stratified waters. AB - The radiative transfer equation is solved by Monte Carlo methods for natural waters in which the optical properties are distributed with depth. It is demonstrated that interpreting the reflectance of a continuously stratified ocean in terms of an equivalent homogeneous ocean yields the average of a particular combination of the water's optical properties over the dimensionless penetration depth tau(90). Although in general the dimensionless penetration depth cannot be remotely measured, a method is presented for estimating the actual penetration depth z(90) from the remote observations if the medium's absorption coefficient is known, independent of depth, and sufficiently large. The application of this to the remote measurement of the vertical distribution of suspended sediments is discussed in detail. PMID- 20198091 TI - Influence of ground scattering on satellite auroral observations. AB - Satellite observations of the optical emission features in the aurora and nighttime airglow are usually contaminated by scattering from clouds and snow. It is shown here that this contamination can easily be removed when the emission layer is viewed against a surface of known albedo. The effect of the earth's curvature, parallax, and varying image angle are found to be significant but can be removed from the observation. PMID- 20198092 TI - Lidar measurements of rotational Raman and double scattering. AB - The analysis of unusually strong Raman backscattering signals from clouds shows that such signals cannot be merely related to filter on-line leakage. Theoretical calculations of Raman double scattering in an atmosphere with high optical depth values are presented, and it is shown that the Raman multiple scattering effect is not negligible. The results of the calculations are in good agreement with the experimental data. PMID- 20198093 TI - Aureole radiance field about a source in a scattering-absorbing medium. AB - A technique is described for computing the aureole radiance field about a point source in a medium that absorbs and scatters according to an arbitrary phase function. When applied to an isotropic source in a homogenous medium, the method uses a double-integral transform which is evaluated recursively to obtain the aureole radiances contributed by successive scattering orders, as in the Neumann solution of the radiative transfer equation. The normalized total radiance field distribution and the variation of flux with field of view and range are given for three wavelengths in the uv and one in the visible, for a sea-level model atmosphere assumed to scatter according to a composite of the Rayleigh and modified Henyey-Greenstein phase functions. These results have application to the detection and measurement of uncollimated uv and visible sources at short ranges in the lower atmosphere. PMID- 20198094 TI - Ultraviolet aureole around a source at a finite distance. AB - We calculate the direct and scattered spectral irradiance expected at a detector from an uv source at a finite range and different altitude in a realistic stmosphere. We first present numerical calculations which allow accurately for attenuation by tropospheric ozone for single scattering by air molecules and aerosols and approximately for multiple scattering by air molecules. Such an approximation is reasonably accurate for short ranges and low aerosol concentrations. To include arbitrarily high orders of multiple scattering by both air molecules and aerosols, we assume a uniform atmosphere and use Monte Carlo techniques. Our method is quite general and should work for multiple scattering in any medium at various wavelengths and with arbitrary absorption and scattering functions. Our results should be of interest for remote sensing of the tropospheric ozone layer, measurement of aerosol concentrations, and other trace atmospheric species. PMID- 20198095 TI - Structural effects in quasi-elastic light scattering from motile bacteria of E. coli. AB - An extensive study has been made of the angular dependence of the intensity as well as the quasi-elastic intensity correlation function of light scattered from a dilute suspension of E. Coli K(12) bacteria in solution using the photon correlation technique. We have demonstrated that it is essential to consider the shape as well as the internal structure of bacteria in order to account fully for both the scattered intensity and the field self-correlation function as reduced from the intensity correlation function. The simple structure model previously proposed accounts well for both the intensity and diffusion data with a reasonable set of parameters. For the case of motile bacteria the observed field correlation function at small scattering angles is well represented by assuming a mixture of diffusive and straight line swimming motions of the bacteria. At larger scattering angles contributions of rotational motions become significant. PMID- 20198096 TI - Automation of a laser absorption calorimeter. AB - The widespread use of laser calorimetry for small absorption coefficient measurements implies that the procedure has reached a certain maturity. With several wavelengths available with significant power levels from different lasers, calorimetry can be considered as an extension of spectroscopy. In this sense, it becomes desirable to automate the calorimetric measurements. We describe the automated calorimeter built at Honeywell. Measurements can be made on bulk samples and on thin films deposited on substrates. Details of the experiment and computer control approach are given. This automated calorimeter has given us the capability to examine large numbers of samples and to determine the effects of various processing steps on bulk absorption. PMID- 20198097 TI - Birefringent filters for tuning flashlamp-pumped dye lasers: simplified theory and design. AB - The theory of a birefringent filter in a laser cavity simplifies when the Jones matrix of a tilted birefringent plate is reduced to its most fundamental form. Theorems relating to stacks of plates are deduced. For example, certain periodic stacks are shown to have no secondary peaks. Approximate expressions are derived for the important parameters of the filters. Designs with maximum tuning range and minimum total number of plates are achieved by tailoring the secondary peaks to meet the inverse of the laser gain curve. PMID- 20198098 TI - Reduction of resonancelike peak in direct modulation due to carrier diffusion in injection laser. AB - It is shown theoretically that the relaxation oscillation in the direct modulation of the injection laser is reduced by transverse carrier diffusion when the stripe width is comparable to the carrier diffusion length. Modified rate equations are derived by considering the distribution of the light intensity, the carrier density, and the diffusion of the carrier. By small-signal analysis of the rate equations it is found that the height of the resonancelike peak in the modulation characteristics is a minimum when the transverse width in which both the light and the carriers are confined is around the diffusion length. PMID- 20198099 TI - Strip-loaded waveguide formed in a graded-index LiNbO(3) planar waveguide. AB - An As(40)Se(50-x)S(x)Ge(10) film strip loaded waveguide, formed in the graded index LiNbO(3) planar waveguide, has been demonstrated. Analytical results show that the optical field confinement in the waveguide loaded by the high refractive index film becomes large near the film cutoff thickness for the fundamental mode. Photostructural effect of the chalcogenide glass overcomes difficulty in precisely controlling film thickness. A 3-D waveguide has been achieved by loading As(40) Se(10)S(40)Ge(10) film 10 microm wide on a Ti diffused LiNbO(3) planar waveguide. Optical confinement in the waveguide has been improved intensively with the aid of the photostructural effect of the film. PMID- 20198100 TI - Fusion splices for optical fibers by discharge heating. AB - A new type of electric discharge fusion splicing apparatus for optical fibers offering several advantages is developed and evaluated. An average splicing loss of 0.10 dB is obtained for step-index multimode silica fibers with a 60-microm core diameter. Tolerances in discharge energy, fiber misalignment, compression force and stroke length during fusion, and end face conditions are discussed experimentally. No accurate fiber axis adjustment is necessary in this apparatus. Mechanical strength of the splice is also excellent. PMID- 20198101 TI - Optical field mapping using single-mode optical fibers. AB - A new method of measuring the complete optical field distribution (optical field mapping) is proposed and is applied to the measurement of Gaussian beam distribution at its beam waist. This method utilizes an interference technique and uses two single-mode optical fibers as flexible paths. The interference pattern caused by the output beams from the reference fiber and pickup fiber directly gives the relative phase distribution at the input end. For the intensity and phase distribution measurements the experimental ambiguity is as small as 0.1 microm and 1/10 of the wavelength, respectively. Stability of the interference fringe against the distortion of the fiber is also examined experimentally. PMID- 20198102 TI - Formulas for calculating the refractive index profile of optical fibers from their transverse interference patterns. AB - A set of successive approximation formulas for calculating the refractive index profile of optical fibers from their transverse interference patterns has been derived. The probing ray refraction due to the index gradient in the core is corrected for by these formulas, and the accuracy of index determination is improved. The error is confirmed to be less than 3 x 10(-3)% of the index difference by means of computer simulations. The index profiles of some optical fibers are practically determined with the help of these formulas. PMID- 20198103 TI - Your conflict matters to me! Behavioral and neural manifestations of control adjustment after self-experienced and observed decision-conflict. AB - In everyday life we tune our behavior to a rapidly changing environment as well as to the behavior of others. The behavioral and neural underpinnings of such adaptive mechanisms are the focus of the present study. In a social version of a prototypical interference task we investigated whether trial-to-trial adjustments are comparable when experiencing conflicting action tendencies ourselves, or simulate such conflicts when observing another player performing the task. Using behavioral and neural measures by means of event-related brain potentials we showed that both own as well as observed conflict result in comparable trial-to trial adjustments. These adjustments are found in the efficiency of behavioral adjustments, and in the amplitude of an event-related potential in the N2 time window. In sum, in both behavioral and neural terms, we adapt to conflicts happening to others just as if they happened to ourselves. PMID- 20198104 TI - Computerized assessment of social approach behavior in mouse. AB - Altered sociability is a core feature of a variety of human neurological disorders, including autism. Social behaviors may be tested in animal models, such as mice, to study the biological basis of sociability and how this is altered in neurodevelopmental disorders. A quantifiable social behavior frequently used to assess sociability in the mouse is the tendency to approach and interact with an unfamiliar mouse. Here we present a novel computer-assisted method for scoring social approach behavior in mice using a three-chambered apparatus and freely available software. We find consistent results between data scored using the computer-assisted method and a human observer, making computerized assessment a reliable, low cost, high-throughput method for testing sociability. PMID- 20198105 TI - Differential odor processing in two olfactory pathways in the honeybee. AB - An important component in understanding central olfactory processing and coding in the insect brain relates to the characterization of the functional divisions between morphologically distinct types of projection neurons (PN). Using calcium imaging, we investigated how the identity, concentration and mixtures of odors are represented in axon terminals (boutons) of two types of PNs - lPN and mPN. In lPN boutons we found less concentration dependence, narrow tuning profiles at a high concentration, which may be optimized for fine, concentration-invariant odor discrimination. In mPN boutons, however, we found clear rising concentration dependence, broader tuning profiles at a high concentration, which may be optimized for concentration coding. In addition, we found more mixture suppression in lPNs than in mPNs, indicating lPNs better adaptation for synthetic mixture processing. These results suggest a functional division of odor processing in both PN types. PMID- 20198106 TI - Lingering prenatal effects of the 1918 influenza pandemic on cardiovascular disease. AB - Prenatal exposure to the 1918 influenza pandemic (Influenza A, H1N1 subtype) is associated with ?20% excess cardiovascular disease at 60 to 82 years of age, relative to cohorts born without exposure to the influenza epidemic, either prenatally or postnatally (defined by the quarter of birth), in the 1982-1996 National Health Interview Surveys of the USA. Males showed stronger effects of influenza on increased later heart disease than females. Adult height at World War II enlistment was lower for the 1919 birth cohort than for those born in adjacent years, suggesting growth retardation. Calculations on the prevalence of maternal infections indicate that prenatal exposure to even uncomplicated maternal influenza may have lasting consequences later in life. These findings suggest novel roles for maternal infections in the fetal programming of cardiovascular risk factors that are independent of maternal malnutrition. PMID- 20198107 TI - Optimal Hypothesis Testing: From Semi to Fully Bayes Factors. AB - We propose and examine statistical test-strategies that are somewhat between the maximum likelihood ratio and Bayes factor methods that are well addressed in the literature. The paper shows an optimality of the proposed tests of hypothesis. We demonstrate that our approach can be easily applied to practical studies, because execution of the tests does not require deriving of asymptotical analytical solutions regarding the type I error. However, when the proposed method is utilized, the classical significance level of tests can be controlled. PMID- 20198108 TI - Variability in the Length and Frequency of Steps of Sighted and Visually Impaired Walkers. AB - The variability of the length and frequency of steps was measured in sighted and visually impaired walkers at three different paces. The variability was low, especially at the preferred pace, and similar for both groups. A model incorporating step counts and step frequency provides good estimates of the distance traveled. Applications to wayfinding technology are discussed. PMID- 20198109 TI - DNP-Hyperpolarized C Magnetic Resonance Metabolic Imaging for Cancer Applications. AB - Critical factors in characterizing the aggressiveness and response to therapy for tumors are the availability of noninvasive biomarkers that can be combined with other clinical parameters to tailor treatment regimens to each individual patient. While conventional magnetic resonance (MR) images are widely used to estimate changes in tumor size, they do not provide the rapid readout that is required to make an early decision on whether a change in therapy is required. The use of hyperpolarized (13)C agents to obtain metabolic imaging data is of great interest for in vivo assessment of tumors. One of the first agents being considered for in vivo studies with dynamic nuclear polarization (DNP) is 1-(13)C labeled pyruvate, which is converted to lactate or alanine, dependent upon the needs of the tissue in question. The development of this new technology and its implementation in preclinical cancer model systems has clearly demonstrated the potential for highlighting tumor aggressiveness and for monitoring changes associated with disease progression. While there is further work to do in terms of studying new agents, improving the DNP process itself and developing efficient MR methods for acquiring and analyzing the data, the preliminary results are extremely promising and provide strong motivation for considering cancer as one of the first applications of the technology. PMID- 20198110 TI - Ebolavirus glycoprotein structure and mechanism of entry. AB - Ebolavirus (EBOV) is a highly virulent pathogen capable of causing a severe hemorrhagic fever with 50-90% lethality. The EBOV glycoprotein (GP) is the only virally expressed protein on the virion surface and is critical for attachment to host cells and catalysis of membrane fusion. Hence, the EBOV GP is a critical component of vaccines as well as a target of neutralizing antibodies and inhibitors of attachment and fusion. The crystal structure of the Zaire ebolavirus GP in its trimeric, prefusion conformation (3 GP(1) plus 3 GP(2)) in complex with a neutralizing antibody fragment, derived from a human survivor of the 1995 Kikwit outbreak, was recently determined. This is the first near complete structure of any filovirus glycoprotein. The overall molecular architecture of the Zaire ebolavirus GP and its role in viral entry and membrane fusion are discussed in this article. PMID- 20198112 TI - Variation in stop consonant voicing in two regional varieties of American English. AB - This study is an acoustic investigation of the nature and extent of consonant voicing of the stop /b/ in two dialectal varieties of American English spoken in south-central Wisconsin and western North Carolina. The stop /b/ occurred at the juncture of two words such as small bids, in a position between two voiced sonorants, i.e. the liquid /l/ and a vowel. Twenty women participated, ten representing the Wisconsin and ten the North Carolina variety, respectively. Significant dialectal differences were found in the voicing patterns. The Wisconsin stop closures were usually not fully voiced and terminated in a complete silence followed by a closure release whereas North Carolina speakers produced mostly fully voiced closures. Further dialectal differences included the proportion of closure voicing as a function of word emphasis. For Wisconsin speakers, the proportion of closure voicing was smallest when the word was emphasized and it was greatest in non-emphatic positions. For North Carolina speakers, the degree of word emphasis did not have an effect on the proportion of closure voicing. The results suggest different mechanisms by which closure voicing is maintained in these two dialects, pointing to active articulatory maneuvers in North Carolina speakers and passive in Wisconsin speakers. PMID- 20198111 TI - Explorations in metalloporphyrin stereochemistry, physical properties and beyond. AB - A review of selected portions of our work in the area of porphyrin structure and physical characterization is presented. Topics covered include early work on periodic trends in first row transtion metalloporphyrins, a survey of electronic structure of iron derivatives including spin-state trends, ligand orientation effects and the elucidtion of unusual low-spin states for iron(II). A discussion of the different tlypes of high-spin iron(II) complexes and the effects of hydrogen bonding is given. A survey of nitric oxide (NO) derivatives is presented as well as a brief introduction into the use of nuclear resonance vibrational spectroscopy for the study of iron porphyrins and heme proteins. PMID- 20198113 TI - Vowel Duration in Three American English Dialects. AB - The article reports on an acoustic investigation into the duration of five American English vowels, those found in hid, head, had, hayed, and hide. We compare duration across three major dialect areas: the Inland North, Midlands, and South. The results show systematic differences across all vowels studied, with the longest durations in the South and the shortest in the Inland North, with the Midlands in an intermediate but distinct position. More generally, the sample differs from and complements other work on this question by including detailed evidence from relatively small, cohesive areas, each within a different established dialect region. PMID- 20198115 TI - A Compact Soft X-Ray Microscope using an Electrode-less Z-Pinch Source. AB - Soft X-rays (< 1Kev) are of medical interest both for imaging and microdosimetry applications. X-ray sources at this low energy present a technological challenge. Synchrotrons, while very powerful and flexible, are enormously expensive national research facilities. Conventional X-ray sources based on electron bombardment can be compact and inexpensive, but low x-ray production efficiencies at low electron energies restrict this approach to very low power applications. Laser-based sources tend to be expensive and unreliable. Energetiq Technology, Inc. (Woburn, MA, USA) markets a 92 eV, 10W(2pi sr) electrode-less Z-pinch source developed for advanced semiconductor lithography. A modified version of this commercial product has produced 400 mW at 430 eV (2pi sr), appropriate for water window soft X-ray microscopy. The US NIH has funded Energetiq to design and construct a demonstration microscope using this source, coupled to a condenser optic, as the illumination system. The design of the condenser optic matches the unique characteristics of the source to the illumination requirements of the microscope, which is otherwise a conventional design. A separate program is underway to develop a microbeam system, in conjunction with the RARAF facility at Columbia University, NY, USA. The objective is to develop a focused, sub-micron beam capable of delivering > 1 Gy/second to the nucleus of a living cell. While most facilities of this type are coupled to a large and expensive particle accelerator, the Z-pinch X-ray source enables a compact, stand-alone design suitable to a small laboratory. The major technical issues in this system involve development of suitable focusing X-ray optics. Current status of these programs will be reported. PMID- 20198114 TI - Conformational Analysis of Stiff Chiral Polymers with End-Constraints. AB - We present a Lie-group-theoretic method for the kinematic and dynamic analysis of chiral semi-flexible polymers with end constraints. The first is to determine the minimum energy conformations of semi-flexible polymers with end constraints, and the second is to perform normal mode analysis based on the determined minimum energy conformations. In this paper, we use concepts from the theory of Lie groups and principles of variational calculus to model such polymers as inextensible or extensible chiral elastic rods with coupling between twisting and bending stiffnesses, and/or between twisting and extension stiffnesses. This method is general enough to include any stiffness and chirality parameters in the context of elastic filament models with the quadratic elastic potential energy function. As an application of this formulation, the analysis of DNA conformations is discussed. We demonstrate our method with examples of DNA conformations in which topological properties such as writhe, twist, and linking number are calculated from the results of the proposed method. Given these minimum energy conformations, we describe how to perform the normal mode analysis. The results presented here build both on recent experimental work in which DNA mechanical properties have been measured, and theoretical work in which the mechanics of non-chiral elastic rods has been studied. PMID- 20198116 TI - 3D RESOLUTION MEASURE FOR MULTIFOCAL PLANE MICROSCOPY. AB - The distance separating two biomolecules in close proximity is an important determinant of the nature of their interaction. While much focus has been given to resolving distances in 2D, the 3D cell in which biological interactions occur necessitates the evaluation of resolution in 3D. Recently, we introduced an information-theoretic 3D resolution measure which predicts that the resolution of an optical microscope is unlimited, and that it improves as more photons are detected from the imaged molecules. Here, we investigate the 3D resolution measure for a multifocal plane microscope. Used for the simultaneous imaging of distinct focal planes within a specimen, multifocal plane microscopy has important applications in the tracking of microscopic objects in 3D. By comparing their 3D resolution measures, we determine the circumstances under which a two plane microscope setup offers better resolvability than a comparable conventional microscope. PMID- 20198117 TI - Extreme Goal Setting and Vulnerability to Mania Among Undiagnosed Young Adults. AB - During euthymia people with bipolar disorder and their unaffected family members accomplish more than the general population. People with bipolar disorder, or those who are at risk for it, also set higher goals in laboratory tasks than other people. The work reported here examines whether persons vulnerable to mania set elevated goals in their lives. In two studies, a measure of lifetime vulnerability to mania was related to traits bearing on incentive sensitivity, and also to endorsement of high ambitions for fame, wealth, and political influence (assessed by a new measure). Relations were weaker to ambitions for other kinds of extreme goals. The effects were independent of current symptoms of mania and depression and lifetime depression. There was also evidence that incentive sensitivity and elevated aspirations made independent contributions to variance in the measure of manic risk. Discussion focuses on the implications of high goal setting for understanding goal dysregulation and mania. PMID- 20198118 TI - Review: Semiconductor Piezoresistance for Microsystems. AB - Piezoresistive sensors are among the earliest micromachined silicon devices. The need for smaller, less expensive, higher performance sensors helped drive early micromachining technology, a precursor to microsystems or microelectromechanical systems (MEMS). The effect of stress on doped silicon and germanium has been known since the work of Smith at Bell Laboratories in 1954. Since then, researchers have extensively reported on microscale, piezoresistive strain gauges, pressure sensors, accelerometers, and cantilever force/displacement sensors, including many commercially successful devices. In this paper, we review the history of piezoresistance, its physics and related fabrication techniques. We also discuss electrical noise in piezoresistors, device examples and design considerations, and alternative materials. This paper provides a comprehensive overview of integrated piezoresistor technology with an introduction to the physics of piezoresistivity, process and material selection and design guidance useful to researchers and device engineers. PMID- 20198119 TI - TRAJECTORIES OF ACCULTURATION AND ENCULTURATION IN RELATION TO HEAVY EPISODIC DRINKING AND MARIJUANA USE IN A SAMPLE OF MEXICAN AMERICAN SERIOUS JUVENILE OFFENDERS. AB - This study examines the longitudinal relations of multiple dimensions of acculturation and enculturation to heavy episodic drinking and marijuana use in a sample of 300 male, Mexican-American, serious juvenile offenders. We track trajectories between ages 15 and 20 and also consider the effects of participants' time spent residing in supervised settings during these years. Results showed some (although not entirely consistent) support for the hypothesis that bicultural adaptation is most functional in terms of lowered substance use involvement. The current findings demonstrate the importance of examining these relations longitudinally and among multiple dimensions of acculturation and enculturation, and they call into question simple models that suggest that greater acculturation is associated with greater substance use among Mexican American adolescents. PMID- 20198120 TI - Modular self-assembling biomaterials for directing cellular responses. AB - Self-assembling biomaterials are promising as cell-interactive matrices because they can be constructed in a modular fashion, which enables the independent and simultaneous tuning of several of their physicochemical and biological properties. Such modularity facilitates the optimization of multi-component matrices for use in complex biological environments such as 3-D cell culture or scaffolds for regenerative medicine. This Highlight will discuss recent strategies for producing modular self-assembling biomaterials, with a particular focus on how ligand presentation and matrix mechanics can be controlled in modular ways. In addition, it will discuss key hurdles that remain for employing these materials as cell-interactive scaffolds in biomedical applications, particularly those that relate to how they may interface with the immune system. PMID- 20198121 TI - Prenatal Development of Interlimb Motor Learning in the Rat Fetus. AB - The role of sensory feedback in the early ontogeny of motor coordination remains a topic of speculation and debate. On E20 of gestation (the 20th day after conception, 2 days before birth), rat fetuses can alter interlimb coordination after a period of training with an interlimb yoke, which constrains limb movement and promotes synchronized, conjugate movement of the yoked limbs. The aim of this study was to determine how the ability to express this form of motor learning may change during prenatal development. Fetal rats were prepared for in vivo study at 4 ages (E18-21) and tested in a 65-min training-and-testing session examining hind limb motor learning. A significant increase in conjugate hind limb activity was expressed by E19, but not E18 fetuses, with further increases in conjugate hind limb activity on E20 and E21. These findings suggest substantial development of the ability of fetal rats to modify patterns of interlimb coordination in response to kinesthetic feedback during motor training before birth. PMID- 20198123 TI - Child Welfare Workers' Adoption of Decision Support Technology. AB - Child welfare workers must process complex information in deciding to refer clients to appropriate mental health services. Decision support systems (DSS) have been demonstrated in other fields to be an important tool, yet little research has been done in child welfare. This study focused on the adoption of a specific DSS into child welfare practice. Quantitative analysis was used to demonstrate the diffusion of innovation process among a sample of state child welfare workers, while qualitative analysis was used to explain the facilitators and barriers to DSS adoption. Results indicate that for DSSs to be widely adopted in child welfare practice, they should be integrated into the referral system and include workers' knowledge and experiences with referral resources. For successful adoption, DSSs need to respect the natural logic and flow of worker interaction, as well as organizational constraints. PMID- 20198124 TI - Variance Estimation in a Model with Gaussian Sub-Models. AB - This paper considers the problem of estimating the dispersion parameter in a Gaussian model which is intermediate between a model where the mean parameter is fully known (fixed) and a model where the mean parameter is completely unknown. One of the goals is to understand the implications of the two-step process of first selecting a model among a finite number of sub-models, and then estimating a parameter of interest after the model selection, but using the same sample data. The estimators are classified into global, two-step, and weighted-type estimators. While the global-type estimators ignore the model space structure, the two-step estimators explore the structure adaptively and can be related to pre-test estimators, and the weighted estimators are motivated by the Bayesian approach. Their performances are compared theoretically and through simulations using their risk functions based on a scale invariant quadratic loss function. It is shown that in the variance estimation problem efficiency gains arise by exploiting the sub-model structure through the use of two-step and weighted estimators, especially when the number of competing sub-models is few; but that this advantage may deteriorate or be lost altogether for some two-step estimators as the number of sub-models increases or as the distance between them decreases. Furthermore, it is demonstrated that weighted estimators, arising from properly chosen priors, outperform two-step estimators when there are many competing sub models or when the sub-models are close to each other, whereas two-step estimators are preferred when the sub-models are highly distinguishable. The results have implications regarding model averaging and model selection issues. PMID- 20198122 TI - Leptin and Inflammation. AB - The past few years of research on leptin have provided important information on the link between metabolism and immune homeostasis. Adipocytes influence not only the endocrine system but also the immune response through several cytokine-like mediators known as adipokines, which include leptin. It is widely accepted that leptin can directly link nutritional status and pro-inflammatory T helper 1 immune responses, and that a decrease of leptin plasma concentration during food deprivation can lead to an impaired immune function. Additionally, several studies have implicated leptin in the pathogenesis of chronic inflammation, and the elevated circulating leptin levels in obesity appear to contribute to the low grade inflammatory background which makes obese individuals more susceptible to increased risk of developing cardiovascular diseases, type II diabetes, or degenerative disease including autoimmunity and cancer. Conversely, reduced levels of leptin such as those found in malnourished individuals have been linked to increased risk of infection and reduced cell-mediated immune responses. We discuss here the functional influences of leptin in the physiopathology of inflammation, and the effects of leptin in the modulation of such responses. PMID- 20198125 TI - The Continued Promise of Neuroprotection for Acute Stroke Treatment. AB - Stroke is the second leading cause of death. However, effective pharmocologic treatment options are still extremely limited and applicable to only a small fraction of patents. The translational failure in finding an effective neuroprotectant for ischemic strokes has generated an active discussion in this field. One focus has been on validating systems for testing neuroprotectants. This review discusses some fundamental issues in experimental stroke that are worthy of further exploration. We begin with a general review of the current status of experimental stroke research and then move on to a discussion of the determining factors and processes that control and differentiate the fate of ischemic ischemic cells and tissue. We propose several strategies of neuroprotection for ischemic strokes with an emphasis on manipulating cellular energy state. PMID- 20198126 TI - Autofluorescence imaging findings in long-standing chorioretinal folds. AB - BACKGROUND: Chorioretinal folds typically involve the choroid, Bruch membrane, retinal pigment epithelium (RPE), and sometimes overlying neurosensory retina. von Winning hypothesized that the alternate banding pattern of choroidal folds shown by fluorescein angiography is explained by RPE density. To our knowledge, autofluorescence imaging of chorioretinal folds has not been previously described. METHODS: Case report. PATIENT: A 47-year-old healthy hyperopic man had best-corrected visual acuity of 20/30 in the right eye and 20/25 in the left eye. Posterior segment examination revealed bilateral chorioretinal folds with subtle streaks of RPE hyperpigmentation and hypopigmentation emanating from both optic nerve heads. RESULTS: Early-phase fluorescein angiography revealed the characteristic pattern of alternating light and dark bands. Autofluorescence imaging disclosed a similar pattern as well as peripapillary mottling. The alternating patterns of light and dark bands observed using autofluorescence imaging and fluorescein angiography were found to be precisely in register but inverted. CONCLUSIONS: Autofluorescence imaging noninvasively demonstrates the pathognomonic pattern of alternating light and dark bands shown by fluorescein angiography diagnostic of choroidal folds but in an inverse fashion. This observation provides independent support of von Winning's hypothesis regarding the etiopathogenesis of the banding pattern. PMID- 20198127 TI - Are inmates' subjective sleep problems associated with borderline personality, psychopathy, and antisocial personality independent of depression and substance dependence? AB - Previous research investigating the relationship between Borderline Personality Disorder (BPD) and sleep problems, independent of depression, has been conducted on small atypical samples with mixed results. This study extends the literature by utilizing a much larger sample and by statistically controlling for depression and substance dependence. Subjective reports of sleep problems were obtained from 513 jail inmates (70% male) incarcerated on felony charges. Symptoms of BPD were significantly associated with sleep problems even when controlling for depression. Thus, sleep problems associated with BPD cannot be attributed simply to co-morbid symptoms of depression and substance dependence was ruled out as proximal causes for this relationship. Symptoms of depression, but not Antisocial Personality features, were related to sleep problems independent of substance dependence. Treatment of individuals with BPD may be more effective if sleep problems are explicitly addressed in the treatment plan. PMID- 20198128 TI - DECISION UTILITY, THE BRAIN, AND PURSUIT OF HEDONIC GOALS. AB - How do brain representations of the utility of a hedonic goal guide decisions about whether to pursue it? Our focus here will be on brain mechanisms of reward utility operating at particular decision moments in life. Moments such as when you encounter an image, sound, scent or other cue associated in your past with a particular reward; or perhaps just vividly imagine that cue. Such a cue can often trigger a sudden motivational urge to pursue that goal, and sometimes a decision to do so. In drug addicts trying to quit, a cue for the addicted drug might trigger urges that rise to compulsive levels of intensity, despite prior commitments to abstain, leading to the decision to relapse into taking the drug again. Normal or addicted, the urge and decision may well have been lacking immediately before the cue was encountered. The decision to pursue the cued reward might never have happened if the cue had not been encountered. Why can such cues momentarily dominate decision making? The answer involves brain mesolimbic dopamine mechanisms that amplify the incentive salience of reward cues, selectively elevating decision utility to trigger "wanting" for the goal. We describe affective neuroscience studies of brain limbic generators of "wanting" that shed light on how cues trigger pursuit of their goals, both normally and even under intense conditions of irrational goal pursuit. PMID- 20198129 TI - Impacting student anxiety for the USMLE Step 1 through process-oriented preparation. AB - BACKGROUND: Standardized examinations are the key components of medical education. The USMLE Step 1 is the first of these important milestones. Success on this examination requires both content competency and efficient strategies for study and review. Students employ a wide variety of techniques in studying for this examination, with heavy reliance on personal study habits and advice from other students. Nevertheless, few medical curricula formally address these strategies. METHODS: In response to student-generated critique at our institution, a five-part seminar series on process-oriented preparation was developed and implemented to address such concerns. The series focused on early guidance and preparation strategies for Step 1 and the many other important challenges in medical school. Emphasis was placed on facilitating conversation and mentorship opportunities between students. RESULTS & CONCLUSIONS: A profoundly positive experience was reported by our medical students that included a decreased anxiety level for the Step 1 examination. PMID- 20198130 TI - An update on neurocognitive impairment in schizophrenia and depression. PMID- 20198132 TI - Electric field dependence of nonlinearity parameters and third order elastic constants of 0.70Pb(Mg(13)Nb(23))O(3)-0.30PbTiO(3) single crystal. AB - Through second harmonic measurements, the ultrasonic nonlinearity parameters of [001](c) and [111](c) polarized 0.70Pb(Mg(13)Nb(23))O(3)-0.30PbTiO(3)(PMN-0.3PT) single crystals have been measured as a function of bias electric field. It was found that the nonlinearity parameter increases almost linearly with field at low field but shows a drastic increase near the coercive field. The [111](c) polarized single domain crystal has much smaller nonlinearity parameter than that of the [001](c) polarized multidomain crystal. Based on effective symmetries of these crystals, we were able to derive the field dependence of several third order elastic constants, which are important parameters for high field applications. PMID- 20198131 TI - Phenomenology of Early Childhood Onset Obsessive Compulsive Disorder. AB - This paper describes the phenomenological features of early childhood onset obsessive compulsive disorder (OCD; defined as children meeting DSM-IV criteria for OCD with age of onset <8 years). Fifty-eight children (ages 4-8) were included in the sample. OCD and comorbid diagnoses were determined by structured interview, and OCD severity was measured using the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS). Mean age of OCD onset was almost five, and mean age of presentation was between 6 and 7. Mean symptom severity was in the moderately severe range. Comorbidity and family history of OCD were common. Contamination and aggressive/catastrophic obsessions and washing and checking compulsions were endorsed most frequently. Results indicate that early childhood onset OCD may have a lower boy to girl ratio and lower rates of depressive disorders, but may be similar to later childhood onset OCD in terms of OCD symptom presentation and severity. PMID- 20198133 TI - Phytophthora multivora sp. nov., a new species recovered from declining Eucalyptus, Banksia, Agonis and other plant species in Western Australia. AB - A new Phytophthora species, isolated from rhizosphere soil of declining or dead trees of Eucalyptus gomphocephala, E. marginata, Agonis flexuosa, and another 13 plant species, and from fine roots of E. marginata and collar lesions of Banksia attenuata in Western Australia, is described as Phytophthora multivora sp. nov. It is homothallic and produces semipapillate sporangia, smooth-walled oogonia containing thick-walled oospores, and paragynous antheridia. Although morphologically similar to P. citricola, phylogenetic analyses of the ITS and cox1 gene regions demonstrate that P. multivora is unique. Phytophthora multivora is pathogenic to bark and cambium of E. gomphocephala and E. marginata and is believed to be involved in the decline syndrome of both eucalypt species within the tuart woodland in south-west Western Australia. PMID- 20198134 TI - Polyphasic taxonomy of the heat resistant ascomycete genus Byssochlamys and its Paecilomyces anamorphs. AB - Byssochlamys and related Paecilomyces strains are often heat resistant and may produce mycotoxins in contaminated pasteurised foodstuffs. A comparative study of all Byssochlamys species was carried out using a polyphasic approach to find characters that differentiate species and to establish accurate data on potential mycotoxin production by each species. Phylogenetic analysis of the ITS region, parts of the beta-tubulin and calmodulin genes, macro- and micromorphological examinations and analysis of extrolite profiles were applied. Phylogenetic analyses revealed that the genus Byssochlamys includes nine species, five of which form a teleomorph, i.e. B. fulva, B. lagunculariae, B. nivea, B. spectabilis and B. zollerniae, while four are asexual, namely P. brunneolus, P. divaricatus, P. formosus and P. saturatus. Among these, B. nivea produces the mycotoxins patulin and byssochlamic acid and the immunosuppressant mycophenolic acid. Byssochlamys lagunculariae produces byssochlamic acid and mycophenolic acid and thus chemically resembles B. nivea. Some strains of P. saturatus produce patulin and brefeldin A, while B. spectabilis (anamorph P. variotii s.s.) produces viriditoxin. Some micro- and macromorphological characters are valuable for identification purposes, including the shape and size of conidia and ascospores, presence and ornamentation of chlamydospores, growth rates on MEA and CYA and acid production on CREA. A dichotomous key is provided for species identification based on phenotypical characters. PMID- 20198135 TI - Phylogeny and character evolution of the coprinoid mushroom genus Parasola as inferred from LSU and ITS nrDNA sequence data. AB - Phylogenetic relationships, species concepts and morphological evolution of the coprinoid mushroom genus Parasola were studied. A combined dataset of nuclear ribosomal ITS and LSU sequences was used to infer phylogenetic relationships of Parasola species and several outgroup taxa. Clades recovered in the phylogenetic analyses corresponded well to morphologically discernable species, although in the case of P. leiocephala, P. lilatincta and P. plicatilis amended concepts proved necessary. Parasola galericuliformis and P. hemerobia are shown to be synonymous with P. leiocephala and P. plicatilis, respectively. By mapping morphological characters on the phylogeny, it is shown that the emergence of deliquescent Parasola taxa was accompanied by the development of pleurocystidia, brachybasidia and a plicate pileus. Spore shape and the position of the germ pore on the spores showed definite evolutionary trends within the group: from ellipsoid the former becomes more voluminous and heart-shaped, the latter evolves from central to eccentric in taxa referred to as 'crown' Parasola species. The results are discussed and compared to other Coprinus s.l. and Psathyrella taxa. Homoplasy and phylogenetic significance of various morphological characters, as well as indels in ITS and LSU sequences, are also evaluated. PMID- 20198136 TI - Co-occurring species of Teratosphaeria on Eucalyptus. AB - A common leaf spot disease occurring on Eucalyptus cladocalyx and E. lehmannii in the Western Cape Province of South Africa is known from literature to be caused by the fungus Coniothyrium ovatum, which is a pathogen native to several eucalypts in Australia. Recent collections have shown that Australian material identified as C. ovatum is morphologically and phylogenetically distinct from the South African specimens, and that all these taxa would be better accommodated in the genus Teratosphaeria. South African specimens previously identified as C. ovatum were found to represent two species that co-occur in the same leaves and even spots and are described here as T. juvenalis and T. verrucosa. Furthermore, a fresh collection of T. ovata from E. phoenicea in Australia, is distinguished morphologically and phylogenetically from similar, newly described taxa such as T. veloci on E. miniata, and Readeriella dimorpha, which is also placed in Teratosphaeria. Although these leaf pathogens appear to be of minor economic importance, they are morphologically similar to two serious eucalypt canker pathogens, namely T. gauchensis and T. zuluensis, which predominantly cause stem cankers, but could also be found occurring in leaf spots on their own, or in association with some of the other species treated here. Further research is, therefore, required to develop molecular detection techniques for these taxa to enable researchers to rapidly distinguish the minor pathogens from the more serious quarantine pathogens that co-occur on leaves. PMID- 20198137 TI - Cymadothea trifolii, an obligate biotrophic leaf parasite of Trifolium, belongs to Mycosphaerellaceae as shown by nuclear ribosomal DNA analyses. AB - The ascomycete Cymadothea trifolii, a member of the Dothideomycetes, is unique among obligate biotrophic fungi in its capability to only partially degrade the host cell wall and in forming an astonishingly intricate interaction apparatus (IA) in its own hyphae, while the attacked host plant cell is triggered to produce a membranous bubble opposite the IA. However, no sequence data are currently available for this species. Based on molecular phylogenetic results obtained from complete SSU and partial LSU data, we show that the genus Cymadothea belongs to the Mycosphaerellaceae (Capnodiales, Dothideomycetes). This is the first report of sequences obtained for an obligate biotrophic member of Mycosphaerellaceae. PMID- 20198138 TI - Multiple Didymella teleomorphs are linked to the Phoma clematidina morphotype. AB - The fungal pathogen Phoma clematidina is used as a biological agent to control the invasive plant species Clematis vitalba in New Zealand. Research conducted on P. clematidina as a potential biocontrol agent against C. vitalba, led to the discovery of two perithecial-forming strains. To assess the diversity of P. clematidina and to clarify the teleomorph-anamorph relationship, phylogenetic analyses of 18 P. clematidina strains, reference strains representing the Phoma sections in the Didymellaceae and strains of related species associated with Clematis were conducted. Partial sequences of the ITS1, ITS2 and 5.8S rRNA gene, the ss-tubulin gene and 28S rRNA gene were used to clarify intra- and inter species relationships. These analyses revealed that P. clematidina resolves into three well-supported clades which appear to be linked to differences in host specificity. Based on these findings, Didymella clematidis is newly described and the descriptions of P. clematidina and D. vitalbina are amended. PMID- 20198139 TI - Molecular systematics of the cotton root rot pathogen, Phymatotrichopsis omnivora. AB - Cotton root rot is an important soilborne disease of cotton and numerous dicot plants in the south-western United States and Mexico. The causal organism, Phymatotrichopsis omnivora (= Phymatotrichum omnivorum), is known only as an asexual, holoanamorphic (mitosporic) fungus, and produces conidia resembling those of Botrytis. Although the corticoid basidiomycetes Phanerochaete omnivora (Polyporales) and Sistotrema brinkmannii (Cantharellales; both Agaricomycetes) have been suggested as teleomorphs of Phymatotrichopsis omnivora, phylogenetic analyses of nuclear small- and large-subunit ribosomal DNA and subunit 2 of RNA polymerase II from multiple isolates indicate that it is neither a basidiomycete nor closely related to other species of Botrytis (Sclerotiniaceae, Leotiomycetes). Phymatotrichopsis omnivora is a member of the family Rhizinaceae, Pezizales (Ascomycota: Pezizomycetes) allied to Psilopezia and Rhizina. PMID- 20198140 TI - Ceratocystis larium sp. nov., a new species from Styrax benzoin wounds associated with incense harvesting in Indonesia. AB - Styrax benzoin trees, native to the island Sumatra, Indonesia are wounded to produce resin that is collected and burned as incense. These wounds on trees commonly develop into expanding cankers that lead to tree death. The aim of this study was to consider whether Ophiostomatoid fungi, typically associated with wounds on trees might be associated with resin harvesting on S. benzoin. Samples were collected from the edges of artificially induced wounds, and particularly where cankers and staining of the vascular tissue was evident. Tissue samples were incubated in moist chambers and carrot baiting was also used to detect the presence of Ceratocystis spp. Fruiting structures with morphology typical of species in the C. fimbriata s.l. species complex and species in the anamorph genus Thielaviopsis were found, on both the incubated wood and the carrot baits. DNA sequences were generated for the Internal Transcribed Spacer regions 1 and 2 including the 5.8S rRNA gene, part of the beta-tubulin and the Transcription Elongation Factor 1-alpha gene regions. These data were compared with those of other species in the C. fimbriata s.l. species complex and Thielaviopsis using phylogenetic analysis. Morphology of the isolates in culture as well as phylogenetic inference showed that the Thielaviopsis sp. present on the wounds was T. basicola. The Ceratocystis sp. from S. benzoin represents a new taxon in the C. fimbriata s.l. complex described here as C. larium sp. nov. PMID- 20198141 TI - Niche sharing reflects a poorly understood biodiversity phenomenon. AB - Eucalyptus spp. are susceptible to a large number of foliar pathogens, some of which can cause serious defoliation and die-back. In this study, a single leaf spot on a Eucalyptus leaf collected in Madagascar revealed an unusual association of microfungi with disease symptoms. Initial observations indicated that the leaf spot was associated with Mycosphaerella marksii, a common pathogen of eucalypts. However, more intensive scrutiny showed the presence of several other microfungi co-occurring in this, and other leaf spots on the leaf. A total of 41 single conidial propagules were subsequently obtained from a single lesion for morphological study and DNA sequence comparisons. Based on these data, 11 members of the Capnodiales, including one species of Pestalotiopsis (Xylariales), were observed. Of the capnodialean taxa, nine could be cultivated, which revealed one known species, M. marksii, two taxa in the Cladosporium cladosporioides species complex that were not treated here, and six new species, including Passalora intermedia, Pseudocercospora madagascariensis, Teratosphaeria hortaea, Toxicocladosporium chlamydosporum, T. rubrigenum and T. veloxum. Results of this study highlight a remarkable fungal biodiversity that can occur within a very specific niche. Furthermore, the results emphasise the importance of verifying the identity of fungal isolates in culture, as many taxa, especially those of the Capnodiales, frequently co-occur in the same niche, lesion or leaf spot. PMID- 20198142 TI - Re-evaluation of Phytophthora citricola isolates from multiple woody hosts in Europe and North America reveals a new species, Phytophthora plurivora sp. nov. AB - During large-scale surveys for soilborne Phytophthora species in forests and semi natural stands and nurseries in Europe during the last decade, homothallic Phytophthora isolates with paragynous antheridia, semipapillate persistent sporangia and a growth optimum around 25 degrees C which did not form catenulate hyphal swellings, were recovered from 39 host species in 16 families. Based on their morphological and physiological characters and the similarity of their ITS DNA sequences with P. citricola as designated on GenBank, these isolates were routinely identified as P. citricola. In this study DNA sequence data from the internal transcribed spacer regions (ITS1 and ITS2) and 5.8S gene of the rRNA operon, the mitochondrial cox1 and beta-tubulin genes were used in combination with morphological and physiological characteristics to characterise these isolates and compare them to the ex-type and the authentic type isolates of P. citricola, and two other taxa of the P. citricola complex, P. citricola I and the recently described P. multivora. Due to their unique combination of morphological, physiological and molecular characters these semipapillate homothallic isolates are described here as a new species, P. plurivora sp. nov. PMID- 20198143 TI - New foliicolous species of Cladosporium from South America. AB - Two new species of Cladosporium found on necrotic needles of Pinus ponderosa trees in Patagonia, Argentina, are described as C. chubutense and C. pini ponderosae. An additional isolate from dead leaves of Cortaderia collected in Colombia, which is a sister taxon to the species occurring on Pinus, is described as Cladosporium colombiae. These species are phylogenetically closely related, but differ from each other and other known species by multilocus sequence data, phenetic characters and culture characteristics. PMID- 20198144 TI - A new species of Albugo parasitic to Arabidopsis thaliana reveals new evolutionary patterns in white blister rusts (Albuginaceae). AB - The obligate biotrophic lineages of the white blister rusts (Albuginales, Oomycota) are of ancient origin compared to the rather recently evolved downy mildews, and sophisticated mechanisms of biotrophy and a high degree of adaptation diversity are to be expected in these organisms. Speciation in the biotrophic Oomycetes is usually thought to be the consequence of host adaptation or geographic isolation. Here we report the presence of two distinct species of Albugo on the model plant Arabidopsis thaliana, Albugo candida and Albugo laibachii, the latter being formally described in this manuscript. Both species may occupy the same host within the same environment, but are nevertheless phylogenetically distinct, as inferred from analyses of both mitochondrial and nuclear DNA sequences. Different ways of adapting to their host physiology might constitute an important factor of their different niches. Evidence for this can be gained from the completely different host range of the two pathogens. While Albugo candida is a generalist species, consisting of several physiological varieties, which is able to parasitize a great variety of Brassicaceae, Albugo laibachii has not been found on any host other than Arabidopsis thaliana. Therefore, Albugo laibachii belongs to a group of highly specialised species, like the other known specialist species in Albugo s.s., Albugo koreana, Albugo lepidii and Albugo voglmayrii. The comparative investigation of the effector genes and host targets in the generalist and the specialist species may constitute a model system for elucidating the fundamental processes involved in plant pathogen co-adaptation and speciation. PMID- 20198145 TI - Phylogeny and taxonomy of obscure genera of microfungi. AB - The recently generated molecular phylogeny for the kingdom Fungi, on which a new classification scheme is based, still suffers from an under representation of numerous apparently asexual genera of microfungi. In an attempt to populate the Fungal Tree of Life, fresh samples of 10 obscure genera of hyphomycetes were collected. These fungi were subsequently established in culture, and subjected to DNA sequence analysis of the ITS and LSU nrRNA genes to resolve species and generic questions related to these obscure genera. Brycekendrickomyces (Herpotrichiellaceae) is introduced as a new genus similar to, but distinct from Haplographium and Lauriomyces. Chalastospora is shown to be a genus in the Pleosporales, with two new species, C. ellipsoidea and C. obclavata, to which Alternaria malorum is added as an additional taxon under its oldest epithet, C. gossypii. Cyphellophora eugeniae is newly described in Cyphellophora (Herpotrichiellaceae), and distinguished from other taxa in the genus. Dictyosporium is placed in the Pleosporales, with one new species, D. streliziae. The genus Edenia, which was recently introduced for a sterile endophytic fungus isolated in Mexico, is shown to be a hyphomycete (Pleosporales) forming a pyronellea-like synanamorph in culture. Thedgonia is shown not to represent an anamorph of Mycosphaerella, but to belong to the Helotiales. Trochophora, however, clustered basal to the Pseudocercospora complex in the Mycosphaerellaceae, as did Verrucisporota. Vonarxia, a rather forgotten genus of hyphomycetes, is shown to belong to the Herpotrichiellaceae and Xenostigmina is confirmed as synanamorph of Mycopappus, and is shown to be allied to Seifertia in the Pleosporales. Dichotomous keys are provided for species in the various genera treated. Furthermore, several families are shown to be polyphyletic within some orders, especially in the Capnodiales, Chaetothyriales and Pleosporales. PMID- 20198146 TI - PERSOONIAL Reflections. PMID- 20198147 TI - Consequences of non-uniform active currents in dendrites. PMID- 20198148 TI - A new phase for two-photon microscopy. PMID- 20198149 TI - Sharing with python. PMID- 20198150 TI - Intracortical cartography in an agranular area. AB - A well-defined granular layer 4 is a defining cytoarchitectonic feature associated with sensory areas of mammalian cerebral cortex, and one with hodological significance: the local axons ascending from cells in thalamorecipient layer 4 and connecting to layer 2/3 pyramidal neurons form a major feedforward excitatory interlaminar projection. Conversely, agranular cortical areas, lacking a distinct layer 4, pose a hodological conundrum: without a laminar basis for the canonical layer 4-->2/3 pathway, what is the basic circuit organization? This review highlights current challenges and prospects for local-circuit electroanatomy and electrophysiology in agranular cortex, focusing on the mouse. Different lines of evidence, drawn primarily from studies of motor areas in frontal cortex in rodents, support the view that synaptic circuits in agranular cortex are organized around prominent descending excitatory layer 2/3- >5 pathways targeting multiple classes of projection neurons. PMID- 20198151 TI - Untangling neural networks with dual retrograde transsynaptic viral infection. AB - Using recombinant rabies virus (RV), we developed a dual transsynaptic retrograde tracing technique in the rat central nervous system. Two strains of recombinant RV, injected into two separate loci of the brain, were taken up through axon terminals and carried retrogradely and transsynaptically from neuron to neuron. Each viral strain expresses a unique marker in infected neurons. Therefore, neurons that project transsynaptically to two brain loci can be detected by double-labeling. In this review, we will introduce the advantage of dual viral tracing by recombinant RV, and will also address some potential weaknesses of this technique. Although false negative results may arise due to interference between two strains of RV, the ability of the recombinant RV to visualize the morphology of the infected cell and to infect primates in addition to rodents will make this technique a potential tool to provide new insights into the complex organization of brain networks. PMID- 20198152 TI - Reward networks in the brain as captured by connectivity measures. AB - An assortment of human behaviors is thought to be driven by rewards including reinforcement learning, novelty processing, learning, decision making, economic choice, incentive motivation, and addiction. In each case the ventral tegmental area/ventral striatum (nucleus accumbens) (VTA-VS) system has been implicated as a key structure by functional imaging studies, mostly on the basis of standard, univariate analyses. Here we propose that standard functional magnetic resonance imaging analysis needs to be complemented by methods that take into account the differential connectivity of the VTA-VS system in the different behavioral contexts in order to describe reward based processes more appropriately. We first consider the wider network for reward processing as it emerged from animal experimentation. Subsequently, an example for a method to assess functional connectivity is given. Finally, we illustrate the usefulness of such analyses by examples regarding reward valuation, reward expectation and the role of reward in addiction. PMID- 20198154 TI - Trends in programming languages for neuroscience simulations. AB - Neuroscience simulators allow scientists to express models in terms of biological concepts, without having to concern themselves with low-level computational details of their implementation. The expressiveness, power and ease-of-use of the simulator interface is critical in efficiently and accurately translating ideas into a working simulation. We review long-term trends in the development of programmable simulator interfaces, and examine the benefits of moving from proprietary, domain-specific languages to modern dynamic general-purpose languages, in particular Python, which provide neuroscientists with an interactive and expressive simulation development environment and easy access to state-of-the-art general-purpose tools for scientific computing. PMID- 20198153 TI - Relating Population-Code Representations between Man, Monkey, and Computational Models. AB - Perceptual and cognitive content is thought to be represented in the brain by patterns of activity across populations of neurons. In order to test whether a computational model can explain a given population code and whether corresponding codes in man and monkey convey the same information, we need to quantitatively relate population-code representations. Here I give a brief introduction to representational similarity analysis, a particular approach to this problem. A population code is characterized by a representational dissimilarity matrix (RDM), which contains a dissimilarity for each pair of activity patterns elicited by a given stimulus set. The RDM encapsulates which distinctions the representation emphasizes and which it deemphasizes. By analyzing correlations between RDMs we can test models and compare different species. Moreover, we can study how representations are transformed across stages of processing and how they relate to behavioral measures of object similarity. We use an example from object vision to illustrate the method's potential to bridge major divides that have hampered progress in systems neuroscience. PMID- 20198155 TI - Micropatterned substrates for studying astrocytes in culture. AB - Recent studies of the physiological roles of astrocytes have ignited renewed interest in the functional significance of these glial cells in the central nervous system. Many of the newly discovered astrocytic functions were initially demonstrated and characterized in cell culture systems. We discuss the use of microculture techniques and micropatterning of cell-adhesive substrates in studies of astrocytic Ca(2+) excitability and bidirectional neuron-astrocyte signaling. This culturing approach aims to reduce the level of complexity of the system by limiting the interacting partners and by controlling the localization of cells. It provides tight control over experimental conditions allowing detailed characterization of cellular functions and intercellular communication. Although such a reductionist approach yields some difference in observations between astrocytic properties in culture and in situ, general phenomena discovered in cell culture systems, however, have also been found in vivo. PMID- 20198156 TI - Barriopsis iraniana and Phaeobotryon cupressi: two new species of the Botryosphaeriaceae from trees in Iran. AB - Species in the Botryosphaeriaceae are well known as pathogens and saprobes of woody hosts, but little is known about the species that occur in Iran. In a recent survey of this family in Iran two fungi with diplodia-like anamorphs were isolated from various tree hosts. These two fungi were fully characterised in terms of morphology of the anamorphs in culture, and sequences of the ITS1/ITS2 regions of the ribosomal DNA operon and partial sequences of the translation elongation factor 1-alpha. Phylogenetic analyses placed them within a clade consisting of Barriopsis and Phaeobotryon species, but they were clearly distinct from known species in these genera. Therefore, they are described here as two new species, namely Barriopsis iraniana on Citrus, Mangifera and Olea, and Phaeobotryon cupressi on Cupressus sempervirens. PMID- 20198157 TI - Ophiostoma denticiliatum sp. nov. and other Ophiostoma species associated with the birch bark beetle in southern Norway. AB - Ophiostomatoid fungi were isolated from Scolytus ratzeburgi infesting Betula pendula and B. pubescens in Norway. Fungi were identified based on morphology, DNA sequence comparison for two gene regions and phylogenetic analyses. The most abundant fungus was Ophiostoma karelicum, suggesting a specific relationship between the fungus, the vector insect and the host tree. Our results suggest that O. karelicum occurs across the geographic range of S. ratzeburgi and its close relatedness to the Dutch elm disease fungi suggests that it could be important if introduced into other parts of the world. Other fungi, only occasionally isolated from S. ratzeburgi, were identified as O. quercus and a novel taxon, described here as O. denticiliatum sp. nov. PMID- 20198158 TI - Taxonomic study of the Japanese Dacrymycetes. AB - The class Dacrymycetes is a rather small group of brown-rot wood-decaying jelly fungi characterised by forked basidia and an orange to yellow gelatinous to cartilaginous fruit body. In Japan, dacrymycetous fungi had not been investigated for a long time, justifying a taxonomic re-examination. In the present study we attempted an investigation of the dacrymycetous fungal flora of Japan, and recognised 28 taxonomic entities, including five new taxa, i.e. Dacrymyces ancyleus, D. aureosporus, D. pinacearum, D. subarcticus and Dacryopinax sphenocarpa, and nine new records. Due to the present survey, the total number of dacrymycetous species recorded from Japan increased from 28 to 42. Of the newly described species, Dacrymyces ancyleus is characterised by recurved, cylindrical basidiocarps and hyphae with clamp connections. Dacrymyces aureosporus resembles D. chrysospermus, but differs in wall thickness of its marginal hyphae. Dacrymyces pinacearum and D. subarcticus represent new coelomycetous anamorphic species. Dacryopinax sphenocarpa has sharp, spathulate basidiocarps, and hyphae with clamp connections. Descriptions, illustrations and photographs of fruit bodies are presented with some taxonomic notes. Molecular phylogenetic analyses were conducted to verify the species identification, and the remaining problems in Dacrymycetes taxonomy are discussed based on these data. PMID- 20198159 TI - New primers for promising single-copy genes in fungal phylogenetics and systematics. AB - Developing powerful phylogenetic markers is a key concern in fungal phylogenetics. Here we report degenerate primers that amplify the single-copy genes Mcm7 (MS456) and Tsr1 (MS277) across a wide range of Pezizomycotina (Ascomycota). Phylogenetic analyses of 59 taxa belonging to the Eurotiomycetes, Lecanoromycetes, Leotiomycetes, Lichinomycetes and Sordariomycetes, indicate the utility of these loci for fungal phylogenetics at taxonomic levels ranging from genus to class. We also tested the new primers in silico using sequences of Saccharomycotina, Taphrinomycotina and Basidiomycota to predict their potential of amplifying widely across the Fungi. The analyses suggest that the new primers will need no, or only minor sequence modifications to amplify Saccharomycotina, Taphrinomycotina and Basidiomycota. PMID- 20198160 TI - Calonectria (Cylindrocladium) species associated with dying Pinus cuttings. AB - Calonectria (Ca.) species and their Cylindrocladium (Cy.) anamorphs are well known pathogens of forest nursery plants in subtropical and tropical areas of the world. An investigation of the mortality of rooted Pinus cuttings in a commercial forest nursery in Colombia led to the isolation of two Cylindrocladium anamorphs of Calonectria species. The aim of this study was to identify these species using DNA sequence data and morphological comparisons. Two species were identified, namely one undescribed species, and Cy. gracile, which is allocated to Calonectria as Ca. brassicae. The new species, Ca. brachiatica, resides in the Ca. brassicae species complex. Pathogenicity tests with Ca. brachiatica and Ca. brassicae showed that both are able to cause disease on Pinus maximinoi and P. tecunumanii. An emended key is provided to distinguish between Calonectria species with clavate vesicles and 1-septate macroconidia. PMID- 20198161 TI - Phylogenetic and morphological assessment of two new species of Amniculicola and their allies (Pleosporales). AB - Two new species of Amniculicola, A. immersa sp. nov. and A. parva sp. nov. from submerged wood in a freshwater environment in Denmark and France are respectively described and illustrated. In addition, partial 28S rDNA sequence data is analysed to investigate their phylogenetic relationships with other pleosporalean taxa. All presently known Amniculicola species, A. immersa, A. lignicola and A. parva, form a robust clade together with the anamorphic species Anguillospora longissima, Spirosphaera cupreorufescens and Repetophragma ontariense. These six species, which are all from freshwater and mostly from Europe, constitute a well supported group containing Pleospora rubicunda and Massariosphaeria typhicola. This putative monophyletic assemblage may represent an aquatic group in the Pleosporales. It is also pertinent that all five ascomycete taxa in this group stain their host substrates purple. PMID- 20198162 TI - Myrtaceae, a cache of fungal biodiversity. AB - Twenty-six species of microfungi are treated, the majority of which are associated with leaf spots of Corymbia, Eucalyptus and Syzygium spp. (Myrtaceae). The treated species include three new genera, Bagadiella, Foliocryphia and Pseudoramichloridium, 20 new species and one new combination. Novelties on Eucalyptus include: Antennariella placitae, Bagadiellalunata, Cladoriella rubrigena, C. paleospora, Cyphellophora eucalypti, Elsinoe eucalypticola, Foliocryphia eucalypti, Leptoxyphium madagascariense, Neofabraea eucalypti, Polyscytalum algarvense, Quambalaria simpsonii, Selenophoma australiensis, Sphaceloma tectificae, Strelitziana australiensis and Zeloasperisporium eucalyptorum.Stylaspergillus synanamorphs are reported for two species of Parasympodiella, P. eucalypti sp. nov. and P. elongata, while Blastacervulus eucalypti, Minimedusa obcoronata and Sydowia eucalypti are described from culture. Furthermore, Penidiella corymbia and Pseudoramichloridium henryi are newly described on Corymbia, Pseudocercospora palleobrunnea on Syzygium and Rachicladosporium americanum on leaf litter. To facilitate species identification, as well as determine phylogenetic relationships, DNA sequence data were generated from the internal transcribed spacers (ITS1, 5.8S nrDNA, ITS2) and the 28S nrDNA (LSU) regions of all taxa studied. PMID- 20198163 TI - Taxonomy and evolutionary relationships within species of section Rimosae (Inocybe) based on ITS, LSU and mtSSU sequence data. AB - The present study aimed at elucidating the structure of Inocybe subg. Inosperma sect. Rimosae but included also representatives from subg. Mallocybe and the genus Auritella. Phylogenetic relationships were inferred using ITS, LSU and mtSSU sequence data. The analyses recovered the ingroup as a monophyletic, strongly supported clade. The results indicate that recognizing Auritella on the genus level renders Inocybe paraphyletic. The species traditionally placed in sect. Rimosae were found to be distributed over two strongly supported clades, Maculata and Rimosae s.s. The Maculata clade clusters with sect. Cervicolores and the two represent subg. Inosperma in a strict sense. Rimosae s.s. emerges as an independent, supported clade well separated from Inosperma s.s. Twenty-one terminal groups were correlated with morphologically distinct species. In addition several taxa on single branches and minor less supported clades were recovered. A key to the identified species of the Maculata and Rimosae s.s. clades which occur in Northwest Europe is provided. PMID- 20198164 TI - Unravelling Mycosphaerella: do you believe in genera? AB - Many fungal genera have been defined based on single characters considered to be informative at the generic level. In addition, many unrelated taxa have been aggregated in genera because they shared apparently similar morphological characters arising from adaptation to similar niches and convergent evolution. This problem is aptly illustrated in Mycosphaerella. In its broadest definition, this genus of mainly leaf infecting fungi incorporates more than 30 form genera that share similar phenotypic characters mostly associated with structures produced on plant tissue or in culture. DNA sequence data derived from the LSU gene in the present study distinguish several clades and families in what has hitherto been considered to represent the Mycosphaerellaceae. In some cases, these clades represent recognisable monophyletic lineages linked to well circumscribed anamorphs. This association is complicated, however, by the fact that morphologically similar form genera are scattered throughout the order (Capnodiales), and for some species more than one morph is expressed depending on cultural conditions and media employed for cultivation. The present study shows that Mycosphaerella s.s. should best be limited to taxa with Ramularia anamorphs, with other well defined clades in the Mycosphaerellaceae representing Cercospora, Cercosporella, Dothistroma, Lecanosticta, Phaeophleospora, Polythrincium, Pseudocercospora, Ramulispora, Septoria and Sonderhenia. The genus Teratosphaeria accommodates taxa with Kirramyces anamorphs, while other clades supported in the Teratosphaeriaceae include Baudoinea, Capnobotryella, Devriesia, Penidiella, Phaeothecoidea, Readeriella, Staninwardia and Stenella. The genus Schizothyrium with Zygophiala anamorphs is supported as belonging to the Schizothyriaceae, while Dissoconium and Ramichloridium appear to represent a distinct family. Several clades remain unresolved due to limited sampling. Mycosphaerella, which has hitherto been used as a term of convenience to describe ascomycetes with solitary ascomata, bitunicate asci and 1-septate ascospores, represents numerous genera and several families yet to be defined in future studies. PMID- 20198165 TI - Novel species of Mycosphaerellaceae and Teratosphaeriaceae. AB - Recent phylogenetic studies based on multi-gene data have provided compelling evidence that the Mycosphaerellaceae and Teratosphaeriaceae represent numerous genera, many of which can be distinguished based on their anamorph morphology. The present study represents the second contribution in a series describing several novel species in different capnodealean genera defined in a previous study. Novelties on Eucalyptus from Australia include: Penidiella pseudotasmaniensis, P. tenuiramis, Phaeothecoidea intermedia, P. minutispora, Pseudocercospora tereticornis, Readeriella angustia, R. eucalyptigena, R. menaiensis, R. pseudocallista, R. tasmanica, Teratosphaeria alboconidia, T. complicata, T. majorizuluensis, T. miniata, T. profusa, Zasmidium aerohyalinosporum and Z. nabiacense, while Teratosphaeria xenocryptica is described on Eucalyptus from Chile. Novelties on other hosts include Phaeophleospora eugeniicola on Eugenia from Brazil, and Zasmidium nocoxi on twig litter from the USA. PMID- 20198166 TI - Molecular phylogeny and spore evolution of Entolomataceae. AB - The phylogeny of the Entolomataceae was reconstructed using three loci (RPB2, LSU and mtSSU) and, in conjunction with spore morphology (using SEM and TEM), was used to address four main systematic issues: 1) the monophyly of the Entolomataceae; 2) inter-generic relationships within the Entolomataceae; 3) genus delimitation of Entolomataceae; and 4) spore evolution in the Entolomataceae. Results confirm that the Entolomataceae (Entoloma, Rhodocybe, Clitopilus, Richoniella and Rhodogaster) is monophyletic and that the combination of pinkish spore prints and spores having bumps and/or ridges formed by an epicorium is a synapomorphy for the family. The Entolomataceae is made up of two sister clades: one with Clitopilus nested within Rhodocybe and another with Richoniella and Rhodogaster nested within Entoloma. Entoloma is best retained as one genus. The smaller genera within Entoloma s.l. are either polyphyletic or make other genera paraphyletic. Spores of the clitopiloid type are derived from rhodocyboid spores. The ancestral spore type of the Entolomataceae was either rhodocyboid or entolomatoid. Taxonomic and nomenclatural changes are made including merging Rhodocybe into Clitopilus and transferring relevant species into Clitopilus and Entoloma. PMID- 20198167 TI - PERSOONIAL Reflections. PMID- 20198168 TI - Phylogenetics of an antibiotic producing Streptomyces strain isolated from soil. AB - Traditional methods of species classification and identification of the organism are based on morphological, physiological, biochemical, developmental and nutritional characteristics. Accurate assignment of taxonomic status to the new biologically active microbial isolates through existing bioinformatics methods is now very essential and also helpful in chemical characterization of the active molecule produced by microorganisms. The bacterial strain M4 (ckm7) was isolated from the pre-treated soil sample collected from the agricultural field of Eastern Uttar Pradesh (U.P.), India and was found to be producing antibacterial and antifungal antibiotics. Taxonomic identification of the isolate belongs to the genus Streptomyces which was done with the help of sequence analysis and later confirmed by biological activity. Sequence comparison study of ckm7 showed 98% identical similarity with 16S rRNA gene sequences of Streptomyces spinichromogenes, Streptomyces triostinicus and Streptomyces capoamus. On the basis of both biological activity and phylogenetic analysis of ckm7, it was concluded that the isolated strain is a new variant of S. triostinicus. PMID- 20198169 TI - Molecular dynamics simulation of a human thiopurine S-methyltransferase complexed with 6-mercaptopurine model. AB - Human thiopurine S-methyltransferase (TPMT) is an essential protein in 6 mercaptopurine (6MP) drug metabolism. To understand the pharmacogenetics of TPMT and 6MP, X-ray co-crystal structures of TPMT complexes with S-adenosyl-L methionine (AdoMet) and 6MP are required. However, the co-crystal structure of this complex has not been reported because 6MP is poorly water soluble. We used molecular dynamics (MD) simulation to predict the structure of the complex of human TPMT-AdoHcy(CH(2))6MP, where the sulfur atoms of AdoHcy and 6MP were linked by a CH(2) group. After 1300 picoseconds of MD simulation, the trajectory showed that 6MP was stabilized in the TPMT active site by formation of non-bonded interactions between 6MP and Phe40, Pro196 and Arg226 side chains of TPMT. The intersulfur distance between AdoHcy and 6MP as well as the binding modes and the interactions of our TPMT-AdoHcy model are consistent with those observed in the X ray crystal structure of murine TPMT-AdoHcy-6MP complex. The predicted binding modes of AdoHcy and 6MP in our model are consistent with those observed in murine TPMT X-ray crystal structures, which provides structural insights into the interactions of TPMT, AdoHcy, and 6MP at the atomic level and may be used as a starting point for further study of thiopurine drug pharmacogenetics. PMID- 20198170 TI - On finding poorly translated codons based on their usage frequency. AB - Long stretches of "rare" codons are known to severely inhibit the efficiency of translation. Understanding the distribution of such rare codons is of critical importance in improving the efficiency of heterologous gene expression systems. Accurate estimates of codon usage take the abundance of each protein into consideration. In this paper, we analyze the correlation between approximate measures of codon usage and the availability of tRNA at various growth rates in E coli. We show that the computationally derived estimates of tRNA isoacceptor concentration enable the finding of poorly translated codons. PMID- 20198171 TI - Predicted metal binding sites for phytoremediation. AB - Metal ion binding domains are found in proteins that mediate transport, buffering or detoxification of metal ions. The objective of the study is to design and analyze metal binding motifs against the genes involved in phytoremediation. This is being done on the basis of certain pre-requisite amino-acid residues known to bind metal ions/metal complexes in medicinal and aromatic plants (MAP's). Earlier work on MAP's have shown that heavy metals accumulated by aromatic and medicinal plants do not appear in the essential oil and that some of these species are able to grow in metal contaminated sites. A pattern search against the UniProtKB/Swiss Prot and UniProtKB/TrEMBL databases yielded true positives in each case showing the high specificity of the motifs designed for the ions of nickel, lead, molybdenum, manganese, cadmium, zinc, iron, cobalt and xenobiotic compounds. Motifs were also studied against PDB structures. Results of the study suggested the presence of binding sites on the surface of protein molecules involved. PDB structures of proteins were finally predicted for the binding sites functionality in their respective phytoremediation usage. This was further validated through CASTp server to study its physico-chemical properties. Bioinformatics implications would help in designing strategy for developing transgenic plants with increased metal binding capacity. These metal binding factors can be used to restrict metal update by plants. This helps in reducing the possibility of metal movement into the food chain. PMID- 20198172 TI - InPACdb--Indian plant anticancer compounds database. AB - Indian Plant Anticancer Compounds Database (InPACdb) is a web-based open access database of phytochemicals. The objective of this initiative is to project the potential of anticancer phytochemicals from Indian pharmacopoeia in an integrated environment. This database is unique in providing comprehensive information covering cancer type, molecular target, 3D Stereochemical structures (tautomers, stereoisomers, conformers and resonance structures) and Chemical descriptors etc. for each entry, enabling effective cheminformatics analysis. The complete dataset of InPACdb encompasses 32 descriptive fields for each entry, and is freely available for download at http://www.inpacdb.org. PMID- 20198173 TI - MIC database: a collection of antimicrobial compounds from literature. AB - We describe a database named MIC database containing 2-dimensional structures of synthesized compounds/antibiotics, IUPAC name, smiles notation and the MIC values / zone of inhibition against a particular organism, strain and culture conditions. The data was collected from various literature sources such as Arkivoc, Bioorganic Medicinal Chemistry Letters, Antimicrobial Agents and Chemotherapy, Journal of Clinical Microbiology and Journal of Bacteriology. MIC Database can be accessed at www.trimslabs.com/mic/index.htm. PMID- 20198174 TI - Phyto-mellitus: a phyto-chemical database for diabetes. AB - Herbs are the base used for treatment in Ayurveda. We describe a database named Phyto-Mellitus with information on plants traditionally used for diabetes with their chemical constituents. The active principles of these plants are antioxidant and free radical scavenging. AVAILABILITY: http://www.bicmlacw.org/bt/ PMID- 20198175 TI - HNHDb: a database on pattern based classification of HNH domains reveals functional relevance of sequence patterns and domain associations. AB - The HNH Database is a collection and sequence-based classification of HNH domain proteins. The database contains about 1913 HNH domain containing proteins, and is classified into 10 subsets based on the sequence pattern. Each of these subsets has unique signature sequences. We have shown a correlation between the subset combination and their domain association and function. Functional divergence of this domain may be due to the combination of these conserved patterns and the large variations in the non-conserved regions. HNHDb is freely available at http://bicmku.in:8081/hnh. PMID- 20198176 TI - A utility script for automating and integrating AutoDock and other associated programs for virtual screening. AB - AutoDock is one of the most widely used docking programs but, is under utilized for the purpose of virtual screening. In order to overcome the difficulties that arise during virtual screening with AutoDock especially for GUI users an attempt is taken to automate the entire docking process, starting from grid map generation through ligand preparation and finally docking. Additional features from software like FILTER, OMEGA, ROCS and EON are also incorporated to create a complete virtual screening platform. The program completely reduced user intervention so that the program can be left unattended for longer period of time and there by improving the computational efficacy. AVAILABILITY: The script is available upon request from the authors. PMID- 20198177 TI - A perspective on healthcare related web interfaces. AB - Consumer retrieval of health information through the internet has become prevalent. In the past, physicians provided filtered health information to the consumer. However, the availability of health related information including disease specific research trends over the World Wide Web is useful for clinicians and consumers. The use of internet based health care information by clinicians and consumers have increased in recent years. Nonetheless, consumers often have difficulties in evaluating such data in a comprehensive manner. Here, we describe the current status of health care related data over the World Wide Web. PMID- 20198178 TI - The expanding HIV-1 epidemic aggravates therapeutics and vaccine development programs in India. AB - Human Immunodeficiency Virus Type 1 (HIV-1) displays extensive genetic diversity globally that poses a serious challenge in designing suitable therapeutic measures for protective immune responses in the host. After the first detection of AIDS cases in 1986, India now has the third largest HIV epidemic in world. The HIV-1 epidemic in India is still growing with introduction of new strains/subtypes and this creates a serious problem for the clinician and basic science researchers to find the effective measures. Neighboring countries in the North and North-eastern regions play an important role in the HIV-1 pandemic. An extensive multinational collaborative research effort is needed in order to identify the risk groups and geographic locales is required to monitor HIV-1 spread in Asia and to produce a successful preventive program. PMID- 20198179 TI - CytokineDB: a database collecting biological information. AB - Cytokines are subdivided in 12 sub-families and are described as multi-functional molecules that play an important biological activity in host defense system against pathogens, in homeostasis, tissue repair, cell growth and development. CytokineDB is an annotated database that collects biological information regarding the cytokines family in human and will be periodically updated by including new biological information. This database is freely available online and can be accessed at the URL: http://www.cro-m.eu/CytokineDB/ PMID- 20198180 TI - Phylogenetic analysis of surface proteins of novel H1N1 virus isolated from 2009 pandemic. AB - Swine Influenza Virus (H1N1) is a known causative agent of swine flu. Transmission of Swine Influenza Virus form pig to human is not a common event and may not always cause human influenza. The 2009 outbreak by subtype H1N1 in humans is due to transfer of Swine Influenza Virus from pig to human. Thus to analyze the origin of this novel virus we compared two surface proteins (HA and NA) with influenza viruses of swine, avian and humans isolates recovered from 1918 to 2008 outbreaks. Phylogenetic analyses of hemagglutinin gene from 2009 pandemic found to be clustered with swine influenza virus (H1N2) circulated in U.S.A during the 1999-2004 outbreaks. Whereas, neuraminidase gene was clustered with H1N1 strains isolated from Europe and Asia during 1992-2007 outbreaks. This study concludes that the new H1N1 strain appeared in 2009 outbreak with high pathogenicity to human was originated as result of re-assortment (exchange of gene). Moreover, our data also suggest that the virus will remain sensitive to the pre-existing therapeutic strategies. PMID- 20198181 TI - Recognition of protein complexation based on hydrophobicity distribution. AB - The identification of the surface area able to generate the protein-protein complexation ligand and ion ligation is critical for the recognition of the biological function of particular proteins. The technique based on the analysis of the irregularity of hydrophobicity distribution is used as the criterion for the recognition of the interaction regions. Particularly, the exposure of hydrophobic residues on the surface of protein as well as the localization of the hydrophilic residues in the hydrophobic core is treated as potential area ready to interact with external molecules. The model based on the "fuzzy oil drop" approach treating the protein molecule as the drop of hydrophobicity concentrated in the central part of structure with the hydrophobicity close to zero on the surface according to 3-dimensional Gauss function. The comparison with the observed hydrophobicy in particular protein reveals some irregularities. These irregularities seem to represent the aim-oriented localization. PMID- 20198182 TI - Types of interfaces for homodimer folding and binding. AB - Homodimers have a role in catalysis and regulation through the formation of stable interfaces. These interfaces are formed through different folding mechanisms such as 2-state without stable intermediate (2S), 3-state with monomer intermediate (3SMI) and 3-state with dimer intermediate (3SDI). Therefore, it is of interest to understand folding mechanism using structural features at the interfaces. Several studies have documented the significance of structural features for the understanding of homodimer folding mechanisms. However, the known features provide limited information for understanding homodimer folding mechanisms. Hence, we created an extended dataset of 47 homodimers (twenty eight 2S, twelve 3SMI and seven 3SDI) to examine the types of interfaces in protein homodimers. 2S are usually small sized, 3SMI are often medium sized and 3SDI often exist as large sized proteins. The ratio of interface to total (I/T) residue is large in 2S and small in 3SMI and 3SDI. Hence, we used I/T measure to group 2S, 3SMI and 3SDI into categories with large I/T (>> 50%), moderate I/T (50 - 25%) and small I/T (<< 25%) interfaces. The grouping is further sub-grouped based on the type of physical interaction visualized at the interface using representations in two dimensions (2D). 2D representation of the interface shows eight different forms of interactions in these homodimers. 2S homodimers frequently have large I/T and thus, utilize the entire protein structure in the formation of the interface where the individual subunits are heavily inter communicated with each other. This is not true in the case of 3SMI and 3SDI. 3SMI subunits usually interact with each other at the interface with a gentle touch like contact and hence, they have low I/T ratio. 3SDI are often quite different in interaction compared to 3SMI and their subunits do deeply interact at the interface with only one part of the surface and hence also having low I/T ratio. PMID- 20198183 TI - Identification of host encoded microRNAs interacting with novel swine-origin influenza A (H1N1) virus and swine influenza virus. AB - The discovery of microRNAs (miRNAs) is a remarkable breakthrough in the field of life science, and they are important actors which regulate gene expression in diverse cellular processes. Recently, several reports indicated that miRNAs can also target viruses and regulate virus replication. Here we discovered 36 pig encoded miRNAs and 22 human-encoded miRNAs which have putative targets in swine influenza virus (SIV) and Swine-Origin 2009 A/H1N1 influenza virus (S-OIV) genes respectively. Interestingly, the putative interactions of ssc-miR-124a, ssc-miR 136 and ssc-miR-145 with their SIV target genes had been found to be maintained almost throughout all of the virus evolution. Enrichment analysis of previously reported miRNA gene expression profiles revealed that three miRNAs are expressed at higher levels in human lung or trachea tissue. The hsa-miR-145 and hsa-miR-92a putatively target the HA gene and hsa-miR-150 putatively targets the PB2 gene. Analysis results based on the location distribution from which virus was isolated and sequence conservation imply that some putative miRNA-mediated host-virus interactions may characterize the location-specificity. PMID- 20198184 TI - Identification of single nucleotide polymorphism in ginger using expressed sequence tags. AB - Ginger (Zingiber officinale Rosc) (Family: Zingiberaceae) is a herbaceous perennial, the rhizomes of which are used as a spice. Ginger is a plant which is well known for its medicinal applications. Recently EST-derived SNPs are a free by-product of the currently expanding EST (Expressed Sequence Tag) databases. The development of high-throughput methods for the detection of SNPs (Single Nucleotide Polymorphism) and small indels (insertion/deletion) has led to a revolution in their use as molecular markers. Available (38139) Ginger EST sequences were mined from dbEST of NCBI. CAP3 program was used to assemble EST sequences into contigs. Candidate SNPs and Indel polymorphisms were detected using the perl script AutoSNP version 1.0 which has used 31905 ESTs for detecting SNPs and Indel sites. We found 64026 SNP sites and 7034 indel polymorphisms with frequency of 0.84 SNPs / 100 bp. Among the three tissues from which the EST libraries had been generated, Rhizomes had high frequency of 1.08 SNPs/indels per 100 bp whereas the leaves had lowest frequency of 0.63 per 100 bp and root is showing relative frequency 0.82/100bp. Transitions and transversion ratio is 0.90. In overall detected SNP, transversion is high when compare to transition. These detected SNPs can be used as markers for genetic studies. AVAILABILITY: The results of the present study hosted in our webserver www.spices.res.in/spicesnip. PMID- 20198185 TI - A docking model of human ribonucleotide reductase with flavin and phenosafranine. AB - Ribonucleotide Reductase (RNR) is an enzyme responsible for the reduction of ribonucleotides to their corresponding Deoxyribonucleotides (DNA), which is a building block for DNA replication and repair mechanisms. The key role of RNR in DNA synthesis and control in cell growth has made this an important target for anticancer therapy. Increased RNR activity has been associated with malignant transformation and tumor cell growth. In recent years, several RNR inhibitors, including Triapine, Gemcitabine and GTI-2040, have entered the clinical trials. Our current work focuses on an attempted to dock this inhibitors Flavin and Phenosafranine to curtail the action of human RNR2. The docked inhibitor Flavin and Phenosafranine binds at the active site with THR176, which are essential for free radical formation. The inhibitor must be a radical scavenger to destroy the tyrosyl radical or iron metal scavenger. The iron or radical site of R2 protein can react with one-electron reductants, whereby the tyrosyl radical is converted to a normal tyrosine residue. However, compounds such as Flavin and Phenosafranine were used in most of the cases to reduce the radical activity. The docking study was performed for the crystal structure of human RNR with the radical scavengers Flavin and Phenosafranine to inhibit the human RNR2. This helps to understand the functional aspects and also aids in the development of novel inhibitors for the human RNR2. PMID- 20198186 TI - Sequence and structural analysis of 4SNc-Tudor domain protein from Takifugu Rubripes. AB - The fugu SN4TDR protein belongs to an evolutionarily conserved family, consisting of four repeat staphylococcal nuclease-like domains (SN1-SN4) at the N-terminus followed by Tudor and SN-like domains (TSN). Sequence analysis showed that the C terminal TSN domain is composed of a complete SN-like domain interdigitated with a Tudor domain. In despite of low level of sequence identities, five SN-like domains have a few conserved amino acids that may play essential roles in the function of the protein. Computer modeling and secondary structural prediction of the SN-like domains revealed the presence of similar structural features of beta1 beta2-beta3-alpha1-beta4-beta5-alpha2-alpha3, which provides a structural basis for oligonucleotides binding. The loop region L(3alpha) for binding sites between beta3 and alpha1 of SN-like domains are different from human p100, implying the divergence in the structures of binding sites. These results indicate that fugu SN4TDR may bind methylated ligands and/or oligonucleotides through its distant domains. PMID- 20198187 TI - CARON--average RMSD of NMR structure ensembles. AB - The NMR protein structures are often deposited in the Protein Data Bank as ensembles of models that agree with the experimental restraints. Information about stereochemical variability and the molecular flexibility can be obtained by systematic comparison of all models. Here we describe CARON, a software that allows the computation of the root-mean-square-distances between equivalent atoms and residues in all models and introduces these values into the occupancy and the B-factor fields of PDB-formatted files. This tool allows the user to both get a quantitative estimation of the conformational homogeneity of the models and to exploit this information in common computer graphics programs. PMID- 20198188 TI - Identification of differentially expressed gene modules between two-class DNA microarray data. AB - Identifying biologically useful genes from massive gene expression data is a critical issue in DNA microarray data analysis. Recent studies on gene module discovery have shown a substantial effect on identifying transcriptional regulatory networks involved in complex diseases for different sample subsets. These have targeted a single disease class, but discovering discriminative modules in different classes has remained to be addressed. In this paper, we propose a novel method that can discover differentially expressed gene modules from two-class DNA microarray data. The proposed method is applied to breast cancer and leukemia datasets, and the biological functions of the extracted modules are evaluated by functional enrichment analysis. As a result, we show that our method can extract genes well reflecting known biological functions compared to a traditional t-test-based approach. PMID- 20198189 TI - A model for the evaluation of domain based classification of GPCR. AB - G-Protein Coupled Receptors (GPCR) are the largest family of membrane bound receptor and plays a vital role in various biological processes with their amenability to drug intervention. They are the spotlight for the pharmaceutical industry. Experimental methods are both time consuming and expensive so there is need to develop a computational approach for classification to expedite the drug discovery process. In the present study domain based classification model has been developed by employing and evaluating various machine learning approaches like Bagging, J48, Bayes net, and Naive Bayes. Various softwares are available for predicting domains. The result and accuracy of output for the same input varies for these software's. Thus, there is dilemma in choosing any one of it. To address this problem, a simulation model has been developed using well known five softwares for domain prediction to explore the best predicted result with maximum accuracy. The classifier is developed for classification up to 3 levels for class A. An accuracy of 98.59% by Naive Bayes for level I, 92.07% by J48 for level II and 82.14% by Bagging for level III has been achieved. PMID- 20198190 TI - Genome subtraction for novel target definition in Salmonella typhi. AB - Large genomic sequencing projects of pathogens as well as human genome leads to immense genomic and proteomic data which would be very beneficial for the novel target identification in pathogens. Subtractive genomic approach is one of the most useful strategies helpful in identification of potential targets. The approach works by subtracting the genes or proteins homologous to both host and the pathogen and identify those set of gene or proteins which are essential for the pathogen and are exclusively present in the pathogen. Subtractive genomic approach is employed to identify novel target in salmonella typhi. The pathogen has 4718 proteins out of which 300 are found to be essential (" indispensable to support cellular life") in the pathogen with no human homolog. Metabolic pathway analyses of these 300 essential proteins revealed that 149 proteins are exclusively involved in several metabolic pathway of S. typhi. 8 metabolic pathways are found to be present exclusively in the pathogen comprising of 27 enzymes unique to the pathogen. Thus, these 27 proteins may serve as prospective drug targets. Sub-cellular localization prediction of the 300 essential proteins was done which reveals that 11 proteins lie on the outer membrane of the pathogen which could be probable vaccine candidates. PMID- 20198191 TI - High GC content: critical parameter for predicting stress regulated miRNAs in Arabidopsis thaliana. AB - Plants like Arabidopsis thaliana are convenient model systems to study fundamental questions related to regulation of the stress transcriptome in response to stress challenges. Microarray results of the Arabidopsis transcriptome indicate that several genes could be upregulated during multiple stresses. High-salinity, drought, and low temperature are three common environmental stress factors that seriously influence plant growth and development worldwide. Recently, microRNAs (miRNAs) have emerged as a class of gene expression regulators that have also been linked to stress responses. However, the relationship between miRNA expression and stress responses is just beginning to be explored. Here we have computationally analyzed 123 non redundant miRNA sequences reported for Arabidopsis thaliana, including 17 miRNA sequences which were reported to be stress regulated in literature. A significant increase in the GC content of stress regulated miRNA sequences was observed which further extends the view that miRNAs act as ubiquitous regulators under stress conditions. GC content may also be considered as a critical parameter for predicting stress regulated miRNAs in plants like Arabidopsis thaliana. PMID- 20198192 TI - Molecular interactions between Bos taurus interferon-tau1c and human type I interferon receptor. AB - Interferon (IFN)-tau secreted only by ruminant endometrium, helps in maternal recognition of pregnancy and exhibit antiviral and antiproliferative activity. Among different types of IFN-tau, IFN-tau1c and IFN- tau3a are the most highly expressed isoforms. In the present study structure of INF-tau1c was predicted using homology modelling. The best model was selected based on overall stereo chemical quality. The generated 3D structure of the Interferon-tau1c protein of Bos taurus was predicted using the ovine interferon-tau (PDB ID: 1B5L_A) as template. The structure comprises of 5 alpha helices separated by loop regions, which is similar to the one predicted for other IFNs. Molecular interactions of bovine IFN-tau1c with human interferon Type 1 receptor (IFNAR1) was explored in an attempt to predict human IFNAR1 binding sites of IFN-tau1c. PMID- 20198193 TI - SSR repeat dynamics in mitochondrial genomes of five domestic animal species. AB - SSR (simple sequence repeats) are ubiquitously abundant in genomes. In organellar mitochondrial genome of animals, its distribution, size dynamics and effectiveness for phylogenetic relationship have not been understood. Present investigation reveals organisation of SSR in genic and intergenic region, its length and repeat motif dynamics, extent of conservation of flanking regions, appropriateness of these SSR data in establishing phylogenetic relationship. Contrary to eukaryotic nuclear abundance of SSR in non-coding region, we found abundance in coding region. Like nuclear SSR, most hyper mutable repeats were found in non coding region having di nucleotide motifs of mitochondrial genome but contrary to human having high mutable tetra repeats in case of mitochondrial genomes this was found to be with tri-motif repeats. SSR of mitochondrial genomes also show cyclical expansion and shrinkage in pattern of SHM (simple harmonic motion) with respect to time its non- linear thus not appropriate for phylogenetic analysis though the flanking regions of these SSR also conserved like nuclear SSR. PMID- 20198194 TI - Predicting highly-connected hubs in protein interaction networks by QSAR and biological data descriptors. AB - Hub proteins (those engaged in most physical interactions in a protein interaction network (PIN) have recently gained much research interest due to their essential role in mediating cellular processes and their potential therapeutic value. It is straightforward to identify hubs if the underlying PIN is experimentally determined; however, theoretical hub prediction remains a very challenging task, as physicochemical properties that differentiate hubs from less connected proteins remain mostly uncharacterized. To adequately distinguish hubs from non-hub proteins we have utilized over 1300 protein descriptors, some of which represent QSAR (quantitative structure-activity relationship) parameters, and some reflect sequence-derived characteristics of proteins including domain composition and functional annotations. Those protein descriptors, together with available protein interaction data have been processed by a machine learning method (boosting trees) and resulted in the development of hub classifiers that are capable of predicting highly interacting proteins for four model organisms: Escherichia coli, Saccharomyces cerevisiae, Drosophila melanogaster and Homo sapiens. More importantly, through the analyses of the most relevant protein descriptors, we are able to demonstrate that hub proteins not only share certain common physicochemical and structural characteristics that make them different from non-hub counterparts, but they also exhibit species-specific characteristics that should be taken into account when analyzing different PINs. The developed prediction models can be used for determining highly interacting proteins in the four studied species to assist future proteomics experiments and PIN analyses. AVAILABILITY: THE SOURCE CODE AND EXECUTABLE PROGRAM OF THE HUB CLASSIFIER ARE AVAILABLE FOR DOWNLOAD AT: http://www.cnbi2.ca/hub-analysis/ PMID- 20198195 TI - Shewregdb: database and visualization environment for experimental and predicted regulatory information in Shewanella oneidensis mr-1. AB - Shewanella oneidensis MR-1 is an important model organism for environmental research as it has an exceptional metabolic and respiratory versatility regulated by a complex regulatory network. We have developed a database to collect experimental and computational data relating to regulation of gene and protein expression, and, a visualization environment that enables integration of these data types. The regulatory information in the database includes predictions of DNA regulator binding sites, sigma factor binding sites, transcription units, operons, promoters, and RNA regulators including non-coding RNAs, riboswitches, and different types of terminators. AVAILABILITY: http://shewanella knowledgebase.org:8080/Shewanella/gbrowserLanding.jsp. PMID- 20198196 TI - GeneComps and ChemComps: a new CTD metric to identify genes and chemicals with shared toxicogenomic profiles. AB - The Comparative Toxicogenomics Database is a public resource that promotes understanding about the effects of environmental chemicals on human health. Currently, CTD describes over 184,000 molecular interactions for more than 5,100 chemicals and 16,300 genes/proteins. We have leveraged this dataset of chemical gene relationships to compute similarity indices following the statistical method of the Jaccard index. These scores are used to produce lists of comparable genes ("GeneComps") or chemicals ("ChemComps") based on shared toxicogenomic profiles. GeneComps and ChemComps are now provided for every curated gene and chemical in CTD. ChemComps are particularly significant because they provide a way to group chemicals based upon their biological effects, instead of their physical or structural properties. These metrics provide a novel way to view and classify genes and chemicals and will help advance testable hypotheses about environmental chemical-genedisease networks. AVAILABILITY: CTD is freely available at http://ctd.mdibl.org/ PMID- 20198198 TI - Spontaneous coronary artery dissection: Report of two unsuspected cases initially treated with thrombolysis. AB - Two young women, without risk factors for atherosclerotic coronary artery disease, were admitted to hospital because of an acute anterior myocardial infarction and treated with thrombolysis. Thrombolysis failed and the immediate coronary angiography performed displayed spontaneous occlusive left anterior descending artery dissection in both cases. The patients underwent successful left internal mammary artery grafting to the left anterior descending artery. The present article highlights the pathology and angiographic presentation of spontaneous coronary artery dissection as well as the possible adverse effect of thrombolysis. Evolution of a dissection into a flap and, ultimately, into a stenosis without a flap is described, and is proposed as a potential mechanism of recurrent ischemia. PMID- 20198199 TI - Effects of nebivolol versus bisoprolol on endothelial function in hypertensive patients. AB - OBJECTIVE: To determine the effects of two beta-blockers, nebivolol and bisoprolol, on endothelial function in newly diagnosed hypertensive patients. METHODS: Twenty-five hypertensive patients with a mean (+/- SD) age of 45.3+/ 11.5 years were randomly assigned to receive either nebivolol or bisoprolol for eight weeks in an open-label, crossover design. Flow-mediated endothelial dependent vasodilation (FMD) was measured at baseline and after each eight-week treatment period. At the end of each treatment period, 24 h ambulatory blood pressure (BP) monitoring was performed. RESULTS: The effect of the two beta blockers on BP was similar. The mean FMD before initiation of treatment was 4.14+/-3.55%. After treatment with nebivolol, FMD increased to 8.99+/-4.21%, with a statistically significant difference from baseline (P<0.001). The effect of bisoprolol treatment on FMD was not as dramatic (3.72+/-6.84%), with no statistically significant difference from baseline. Comparing FMD after each therapeutic regimen, nebivolol treatment resulted in a marked increase in the reactivity of the brachial artery (ie, improvement of endothelial function) compared with bisoprolol treatment (P<0.001). CONCLUSION: Nebivolol treatment of untreated hypertensive patients led to a significant improvement in endothelial function compared with bisoprolol treatment, despite the similar effect on BP with either therapeutic agent. PMID- 20198200 TI - Aberrant right coronary artery origin from the left aortic sinus with interarterial course manifesting acute myocardial infarction. AB - A 43-year-old patient was admitted to hospital because of an inferior-posterior myocardial infarction. The admission electrocardiogram was suggestive of a right coronary artery (RCA) culprit lesion. Coronary angiography following successful thrombolysis revealed a normal left system and mild intraluminal disease of the dominant RCA, which arose from the left aortic sinus and travelled an interarterial course; the latter was depicted in a subsequent computed tomographic angiogram. The lack of ST segment elevation in V4R and the absence of right ventricular wall motion abnormalities on echocardiography precluded the proximal ectopic vessel from being the culprit. The patient was managed medically; one year following discharge, he is asymptomatic. In cases of aberrant anomalous origin of a coronary artery from the opposite sinus with interarterial course, the proximal ectopic vessel is intussuscepted within the aortic wall, potentially leading to ischemia. The present article highlights that, although medical treatment in cases of such an aberrant RCA without apparent ischemia driven sequelae may be valid, the need for interventional treatment could be substantiated following investigation of the anatomofunctional features of the intussuscepted proximal ectopic segment with intravascular ultrasound. PMID- 20198201 TI - Misleading echocardiographic diagnosis of a prosthetic heart valve vegetation due to the cavitation phenomenon. AB - The cavitation phenomenon is caused by the local pressure depression that occurrs during the closure and/or opening of prosthetic valve leaflets. Occasionally, peculiar features of echocardiographic images generated by cavitation can simulate a mass or vegetation, and are a potential source of diagnostic error. A clinical case that illustrates this phenomenon is described. PMID- 20198202 TI - Desalinated underground seawater of Jeju Island (Korea) improves lipid metabolism in mice fed diets containing high fat and increases antioxidant potential in t BHP treated HepG2 cells. AB - This study was performed to investigate the effect of desalinated underground seawater (named as 'magma seawater', MSW) of Jeju Island in Korea on lipid metabolism and antioxidant activity. MSW was collected from underground of Han Dong in Jeju Island, and freely given to high fat diet (HFD)-fed C57BL/6 mice for 10 weeks. Although there were no significant differences in the body weight changes and plasma lipid levels, hepatic triglyceride levels were significantly lower in the MSW group than in the normal tap water (TW)-drunken control group. Furthermore, the activity of fatty acid synthase (FAS) was significantly decreased and carnitine palmitoyltransferase (CPT) activity was increased in MSW group compared to TW group. Similarly, real-time PCR analysis revealed that mRNA expressions of lipogenic genes were lowered in MSW groups compared to the control group. In a morphometric observation on the liver tissue, accumulation of fats was remarkably reduced in MSW group. Meanwhile, in vitro assay, free radical scavenging activity measured by using diphenylpicrylhydrazyl (DPPH) was increased in MSW group. The 2'-7'-dichlorofluorescein diacetate (DCF-DA) staining followed with fluorescent microscopy showed a low intensity of fluorescence in MSW-treated HepG2 cells, compared to TW-treated HepG2 cells, which indicated that the production of reactive oxygen species by tert-butyl hydroperoxide (t-BHP) in HepG2 cells was decreased by MSW treatment. The antioxidant effect of MSW on t BHP-induced oxidative stress in HepG2 cells was supported by the increased activities of intracellular antioxidant enzymes such as catalase and glutathione reductase. From these results, we speculate that MSW has an inhibitory effect on lipogenesis in liver and might play a protective role against cell damage by t BHP-induced oxidative stress. PMID- 20198203 TI - Effect of ethanol extracts from red pepper seeds on antioxidative defense system and oxidative stress in rats fed high-fat . high-cholesterol diet. AB - The purpose of the present study was to investigate the effect of ethanol extracts from red pepper seeds on the antioxidative defense system and oxidative stress in rats fed a high fat . high cholesterol diet. Rats were divided into four experimental groups which were composed of high fat . high cholesterol diet group (HF), high fat . high cholesterol diet with 0.1% ethanol extracts from red pepper seeds supplemented group (HEA), high fat . high cholesterol diet with 0.2% ethanol extracts from red pepper seeds supplemented group (HEB) and high fat.high cholesterol diet with 0.5% ethanol extracts from red pepper seeds supplemented group (HEC). Supplementation of ethanol extracts from red pepper seeds groups (HEA, HEB and HEC) resulted in significantly increased activities of hepatic glutathione peroxidase and catalase. Hepatic superoxide radical contents in microsome and mitochondria were significantly reduced in the groups supplemented with red pepper seeds ethanol extracts. Hepatic hydrogen peroxide content in the mitochondria was reduced in ethanol extracts from red pepper seeds supplemented groups. TBARS values in the liver were reduced in red pepper seeds ethanol extracts supplemented groups. Especially, HEB and HEC groups were significantly decreased compared to the HF group. Hepatic carbonyl values were significantly reduced in mitochondria in these supplemented groups. These results suggest that red pepper seeds ethanol extracts may reduce oxidative damage, by activation of antioxidative defense system in rats fed high fat . high cholesterol diets. PMID- 20198204 TI - Comparison of methods for proanthocyanidin extraction from pine (Pinus densiflora) needles and biological activities of the extracts. AB - Flavonoids are known to be effective scavengers of free radicals. In particular, proanthocyanidins are flavonoids that possess cardiovascular protection, antioxidative activities, and immunomodulatory activities. Here, we evaluated proanthocyanidin contents in the total polyphenolic compounds of pine needle extracts prepared by hot water, ethanol, hexane, hot water-hexane (HWH), and hot water-ethanol (HWE). Analysis of each extract indicated that the ethanol extract contained the highest proanthocyanidin concentration. The HWH and hexane extracts also contained relatively high concentrations of proanthocyanidin. On the other hand, proanthocyanidin content analyses out of the total polyphenolic compounds indicated that the HWH extract contained the highest content. These results suggest that HWH extraction is a suitable method to obtain an extract with a high level of pure proanthocyanidins and a relatively high yield. The HWH extract possessed superior activity in diverse antioxidative analyses such as 2,2 diphenyl-1-picrylhydrazyl (DPPH), ferrous ion chelating (FIC), and ferric-ion reducing power (FRAP) assays. In addition, upon assessing the effects of the pine needle extracts on macrophages (Raw 264.7 cell), the HWH extract exhibited the highest activity. In this study, we discerned an efficient extraction method to achieve relatively pure proanthocyanidins from pine needles and evaluated the biological functions of the resulting extract, which could potentially be used for its efficacious components in functional food products. PMID- 20198205 TI - Effects of poly-gamma-glutamic acid on serum and brain concentrations of glutamate and GABA in diet-induced obese rats. AB - Poly-gamma-glutamic acid (gamma-PGA) is a mucilaginous and biodegradable compound produced by Bacillus subtilis from fermented soybeans, and is found in the traditional Korean soy product, cheongkukjang. This study was carried out to evaluate the effects of gamma-PGA from a food source on the concentration of the neurotransmitter GABA and its metabolic precursor glutamate in diet-induced obese rats. Eight-week old male Sprague-Dawley rats (n=60) were used. The rats were divided into two groups and obesity was induced by providing either a 10% control fat or 45% high fat diet for 5 weeks. The rats were then blocked into 6 groups and supplemented with a 0.1% gamma-PGA diet for 4 weeks. After sacrifice, brain and serum GABA and glutamate concentrations were analyzed by high performance liquid chromatography with fluorometric detection. The rats fed the high fat diet had significantly increased body weights. gamma-PGA supplementation significantly increased serum concentrations of glutamate and GABA in the control fat diet groups while this effect was not found in the high fat groups. In the brain, glutamate concentrations were significantly higher in the gamma-PGA supplemented groups both in rats fed the normal and high fat diets than in the no gamma-PGA controls. GABA concentrations showed the same tendency. The results indicated that gamma-PGA intake increased GABA concentrations in the serum and brain. However, the effects were not shown in obese rats. PMID- 20198206 TI - The antioxidant and chemopreventive potentialities of Mosidae (Adenophora remotiflora) leaves. AB - Our study focused on the antioxidant activities of Mosidae leaf ethanol extract (MLE) and included measurements of reducing power, total phenolic compounds, DPPH radical scavenging activity, and hydroxyl radical scavenging activity. In order to determine whether or not MLE evidences any chemopreventive activities, experimental lung metastasis was induced via the i.v. inoculation of colon26-M3.1 carcinoma cells into BALB/c mice. Additionally, we attempted to characterize any possible cytotoxic effects in murine normal splenocytes and tumor cells (B16-BL6 and colon26-M3.1). The total phenolic content and reducing capacity were measured at 39 mg/100 mL and 1.24, respectively, whereas the DPPH and hydroxyl radical scavenging activities of MLE were measured to be 88.89% and 22.10%, respectively. Prophylactic i.v. treatment with MLE resulted in a dose-dependent and significant inhibition of lung metastasis. Specifically, a MLE dose of 200 ug per mouse resulted in an 88.90% inhibition of lung metastasis. For the cytotoxicity assay, MLE doses up to 100 ug/mL were not shown to affect the growth of normal murine splenocytes. Additionally, the survival of normal cells was not affected at MLE doses below 500 ug/mL. However, MLE doses up to 500 ug/mL reduced the percentage of tumor cell growth for B16BL6 (67% alive) and colon26-M3.1 (62% alive) cells. PMID- 20198207 TI - Prevalence of overweight and obesity, and dieting attitudes among Caucasian and African American college students in Eastern North carolina: A cross-sectional survey. AB - A cross-sectional survey was used to investigate the rates of overweight and obesity (BMI >/= 25), and eating attitudes among college students. Data were collected at a large southeastern university. Adolescents (ages 18-25) self reported weight and height (to calculate BMI), and, in addition to demographic information, completed the eating attitudes (EAT 26) scale to assess dieting tendencies. Significance of the mean BMI differences between gender and ethnic background were assessed by one-way analysis of variance (one-way ANOVA). Chi square was used to determine whether the rate of those with BMI>/=25 between gender and ethnic background was statistically significant. While 52.7% of the students' BMI were within the normal weight category, 15.2% were underweight, 21.3% were overweight, and 10.8% were obese. The rate of BMI>/=25 differed by gender and ethnicity, with males and African Americans having higher rates. About 12 % of the participants reported disturbed eating behavior, which is lower than previously reported. Even so, results support the generally held belief that disturbed eating attitudes and unhealthy dieting are common among college students, especially among females. At the same time, disturbed eating attitudes are not just the domain of young female students; about 10% of college males reported disturbed eating attitudes. Findings of this study call for obesity prevention/intervention and lifestyle modification outreach programs among college students. Weight status and unhealthy eating behaviors of college students should be a concern to health care professionals. While obese young adults will likely remain obese throughout their adult life, excessive dieting among students, which is linked to eating disorders and other health hazards, does not provide healthy and adequate alternatives for maintaining a normal BMI. Implications for obesity prevention programs are discussed. PMID- 20198208 TI - Energy intake and snack choice by the meal patterns of employed people. AB - The aim of this study was to provide descriptive information on meal and snack patterns and to investigate snacks in relation to energy intake and food choice according to the meal patterns of employed people in Korea. 683 employed people (292 males, 391 females) were interviewed to collect one day dietary data by using 24-h dietary recall. A recorded day was divided into 3 meal and 3 snack periods by the respondent's criteria and the time of consumption. To analyze the eating pattern participants were divided as the more frequent snack eaters (MFSE) and the less frequent snack eaters (LFSE). They were also categorized into 6 groups according to the frequency of all eating occasions. The common meal pattern in nearly half of the subjects (47.6%) was composed of three meals plus one or two snacks per day. A trend of an increasing the number of snacks in between main meals emerges, although the conventional meal pattern is still retained in most employed Korean adults. Women, aged 30-39, and urban residents, had a higher number of being MFSE than LFSE. Increasing eating occasions was associated with higher energy, protein, and carbohydrate intakes, with the exception of fat intakes. 16.8% of the total daily energy intake came from snack consumption, while the 3 main meals contributed 83.2%. Energy and macronutrient intakes from snacks in the MFSE were significantly higher than the LFSE. Instant coffee was the most popular snack in the morning and afternoon, whereas heavy snacks and alcohol were more frequently consumed by both of the meal skipper groups ( or = 93% accuracy is rare. Low cost and wide availability of various polymers and indicators could make this approach useful in numerous applications. PMID- 20198235 TI - Small molecule-triggered assembly of DNA nanoarchitectures. AB - The utilization of toehold-containing DNA strands allows for the assembly of complex nanostructures via kinetically driven hybridization reactions. Here, we have rendered this strategy ligand-dependent, resulting in small-molecule inducible DNA nanoarchitectures. PMID- 20198236 TI - Ultralong Pt-on-Pd bimetallic nanowires with nanoporous surface: nanodendritic structure for enhanced electrocatalytic activity. AB - We for the first time report a facile, wet-chemical strategy for the high-yield (approximately 100%) synthesis of ultralong Pt-on-Pd bimetallic nanowires (NWs) with the cores being Pd NWs and the shells being made of dendritic Pt, which exhibit high surface area and enhanced electrocatalytic activity towards methanol oxidation reaction. PMID- 20198237 TI - Template synthesis of ordered arrays of mesoporous titania spheres. AB - Three-dimensionally ordered arrays of submicron-sized mesoporous titania spheres with high surface area and high crystallinity have been prepared through triblock copolymer templating within the confinement of polymer inverse opals. PMID- 20198238 TI - Combined Cu(I)-catalysed alkyne-azide cycloaddition and furan-maleimide Diels Alder "click" chemistry approach to thermoresponsive dendrimers. AB - A divergent dendrimer construction methodology that employs Cu(I)-catalysed alkyne-azide cycloaddition (CuAAC) and furan-maleimide Diels-Alder (DA) "click" chemistry in a layer-by-layer fashion, is described. This synergistic approach yields dendrimers that undergo thermal disassembly via a retro-DA reaction. PMID- 20198239 TI - Metal-dependent alternative activation of O-H and C-H bonds of methanol: on the formation and structure of "bare" [M,C,H3,O]+ complexes (M = Fe, Co, Ni) in the gas phase. AB - Structural aspects of the 'bare' [M(C,H(3),O)](+) complexes (M = Fe, Co, Ni), generated by electrospray ionization of aqueous methanolic solutions of MX(2) (X = Br, I), have been probed in the gas phase by a combination of labeling studies and collision-induced dissociation (CID) experiments. PMID- 20198240 TI - Pressure-induced Jahn-Teller switching in a Mn12 nanomagnet. AB - Pressure-induced switching of a fast-relaxing single-molecule magnet to a slow relaxing isomer is observed for the first time by using a combination of high pressure single-crystal X-ray diffraction and high pressure magnetic measurements. PMID- 20198241 TI - Highly fluorescent water-soluble polyglycerol-dendronized perylene bisimide dyes. AB - Water-soluble perylene tetracarboxylic acid bisimides (PBIs) with terminally linked polyglycerol dendrons of four different generations have been synthesized. These PBI dyes reveal a strong dendritic effect, enabling outstanding fluorescence quantum yields in water up to almost 100% for the highest dendron generation. PMID- 20198242 TI - Size dependent oxygen buffering capacity of ceria nanocrystals. AB - The structural, chemical and electronic changes of ceria as a function of decreasing particle size have been studied: at sizes below 5 nm the total amount of reducible oxygen dramatically increases due to superoxide formation on the ceria surface, a result indicative of a size dependent oxygen buffering capacity. PMID- 20198243 TI - Synthesis, structure and reactions of triarylgermyl anion with alpha,delta ambiphilic character. AB - Benzosilagermacyclobutene bearing two Ar groups on the germanium atom [Ar = o (fluorodimethylsilyl)phenyl] undergoes cleavage of the Ge-Si bond with KF in the presence of a cryptand to form Ar(3)Ge(-)[K(+)(cryptand)] with alpha,delta ambiphilic character consisting of the germyl anion center and the fluorosilyl moieties. In the presence of LiBPh(4).3dme or BF(3).Et(2)O, the germylpotassium is converted back into the benzosilagermacyclobutene. PMID- 20198244 TI - Synthesis of bismuth vanadate nanoplates with exposed {001} facets and enhanced visible-light photocatalytic properties. AB - Well-defined m-BiVO(4) nanoplates with exposed {001} facets have been synthesized by a facile hydrothermal route, without the use of any template or organic surfactant. The as-prepared m-BiVO(4) nanoplates exhibit greatly enhanced activity in the visible-light photocatalytic degradation of organic contaminants and photocatalytic oxidation of water for O(2) generation. PMID- 20198245 TI - Reversible aggregation of X-shaped bolaamphiphiles with partially fluorinated lateral chains at the air/water interface. AB - Langmuir films of four X-shaped bolaamphiphiles were studied using surface pressure and Kelvin potential measurements, Brewster angle microscopy and X-ray reflectivity. The partially fluorinated bolaamphiphiles exhibit an unusual reversibility and reproducibility of Langmuir isotherms, and create very stable and well defined single- or triple layers which can be transferred to solid substrates. PMID- 20198246 TI - Modified Kirkendall effect for fabrication of magnetic nanotubes. AB - In this paper, we successfully synthesize Fe(OH)(3) nanotubes involving the Kirkendall effect. Depending on the calcination conditions, both haematite and magnetite nanotubes are produced. This approach also provides a new synthetic alternative to nanotubes of nonlamellar-structured materials. The as-synthesized magnetite nanotubes have an application as a magnetic resonance imaging contrast agent. PMID- 20198247 TI - Synthesis of delaminated LDH: a facile two step approach. AB - One-step synthesis of carbonate-free nitrate containing LDHs was achieved using hexamine hydrolysis at low temperature and the products were delaminated successfully in water; materials showed total delamination in formamide while restacking behavior depended critically on the medium. PMID- 20198248 TI - Brilliant reversible luminescent mechanochromism of silver(I) complexes containing o-bis(diphenylphosphino)benzene and phosphinesulfide. AB - The Ag(I) complex with o-bis(diphenylphosphino)benzene shows reversible interconversion between blue-emitting (1b) and green-emitting (1g) materials on grinding and heating; comparison of the structure of 1b with another green emitting crystals (2) having the same formula suggests the chromism results from intermolecular interactions between adjacent phenylene rings. PMID- 20198249 TI - Proton-regulated rectified ionic transport through solid-state conical nanopores modified with phosphate-bearing polymer brushes. AB - We describe the use of polyprotic polymer brushes to construct robust signal responsive chemical devices mimicking the transport properties of proton regulated biological channels. PMID- 20198251 TI - Drastic selectivity reversal on crown-ether based ion-sensing membranes made of ordered mesoporous silica and conventional sol-gel derived one. AB - A crown-ether based ion sensor, in which ordered mesoporous silica was used as a membrane material, was fabricated for the first time, and drastic selectivity reversal was attained in comparison with conventional sol-gel derived membrane based on the same crown ether. PMID- 20198250 TI - Protein nanoarrays on a highly-oriented lamellar surface. AB - Well-aligned nanopatterns of various serum, antithrombogenic and cell adhesive proteins, such as gamma-globulin, fibrinogen, thrombomodulin, fibronectin and type I collagen, were fabricated on a highly-oriented block copolymer lamellar surface, and these bioactive protein nanoarrays will be useful in biological research. PMID- 20198252 TI - Excitation-wavelength-dependent photoluminescence of a pyromellitic diimide nanowire network. AB - Nanowires from deposition of pyromellitic diimide (PMDI) from the gas phase and their unique excitation-wavelength-dependent photoluminescence were demonstrated. The luminescence peaks of the PMDI nanowires red-shifted as the excitation wavelength increased. The relationship between the luminescence peak and the excitation wavelength is nearly linear in a broad range of excitation. PMID- 20198253 TI - Successive catalytic reactions specific to Pd-based rotaxane complexes as a result of wheel translation along the axle. AB - Rotaxane-structure-specific Pd-catalyzed rearrangement of propargyl or allyl urethane groups to oxazolidinone moieties proceeded efficiently. The conversion took place successively by the translation of the wheel along the axle, thus providing a novel macrocyclic catalytic system. PMID- 20198254 TI - Cobalt-catalyzed regio- and stereoselective intermolecular enyne coupling: an efficient route to 1,3-diene derivatives. AB - The reaction of alkynes with vinyl arenes or vinyl trimethyl silane in the presence of a cobalt(II) complex, Zn and ZnI(2) in CH(2)Cl(2) at rt to 50 degrees C provides 1,3-dienes in good to excellent yields. PMID- 20198255 TI - Tetrachloro-tetra(perylene bisimides): an approach towards N-type graphene nanoribbons. AB - An extraordinarily large pi system based on tetrachloro-tetra(perylene bisimides) with very broad absorption spectra from the UV to the NIR region and an extremely strong electron-accepting ability has been synthesized from tetrachloro di(perylene bisimides). PMID- 20198256 TI - Synthesis and characterization of a tin(II) bis(phosphinoyl)methanediide complex: a stannavinylidene derivative. AB - The reaction of [CH(2)(PPh(2)=NSiMe(3))(PPh(2)=S)] (1) with two equivalents of [Sn{N(SiMe(3))(2)}(2)] in refluxing toluene afforded novel tin(II) bis(phosphinoyl)methanediide complex 3. The structure of compound 3 has been determined by X-ray crystallography and DFT calculations. The topological analysis of the electron densities of compound 3 was performed. PMID- 20198257 TI - A new aspect of nickel-catalyzed Grignard cross-coupling reactions: selective synthesis, structure, and catalytic behavior of a T-shape three-coordinate nickel(I) chloride bearing a bulky NHC ligand. AB - Novel T-shape three-coordinate nickel(I) chlorides bearing an N-heterocyclic carbene ligand, NiCl(IPr)(2) (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazolin-2 ylidene), were isolated by a reaction of Ni(0)(NHC)(2) with aryl chlorides. This Ni(I) complex was shown to act as a catalyst in a cross-coupling reaction of aryl halides with phenylmagnesium chloride. PMID- 20198258 TI - Structure control of organized mesoporous TiO2 films templated by graft copolymers for dye-sensitized solar cells. AB - Randomly microphase-separated graft copolymers have been self-reorganized so as to exhibit a micellar structure with excellent connectivity upon tuning the solvent affinity. These copolymers are used as a structure-directing agent for organized mesoporous TiO(2) films with no grain boundaries, leading to enhanced solar conversion efficiency of dye-sensitized solar cells. PMID- 20198259 TI - Synthesis of 4,5-diheteroarylphenanthrenes and their dinuclear ruthenium(II) bis(2,2':6',2''-terpyridine) complexes possessing severe helical twists. AB - Three 4,5-diheteroarylphenanthrenes 2a, 2b and 2c and two dinuclear Ru(ii) bis(terpyridine) complexes 13 and 14 possessing severe helical twists were synthesized. PMID- 20198260 TI - Aqueous solubilization of photochromic compounds by bile salt aggregates. AB - Bile salts form aggregates in aqueous solutions which were shown to efficiently solubilize aqueous insoluble photochromic compounds. Photochromic switching was observed for a spiropyran and a diarylethene. In the case of the spiropyran, the incorporation into the bile salt aggregate led to improved hydrolytic stability and changes in thermal rate constants. PMID- 20198261 TI - Rational design of a highly selective and sensitive fluorescent PET probe for discrimination of thiophenols and aliphatic thiols. AB - A novel highly sensitive and selective 'off-on' fluorescent probe for thiophenols has been developed by a PET mechanism through a rational design. PMID- 20198262 TI - The cascade carbo-carbonylation of unactivated alkenes catalyzed by an organocatalyst and a transition metal catalyst: a facile approach to gamma diketones and gamma-carbonyl aldehydes from arylalkenes under air. AB - A novel cascade carbo-carbonylation reaction of unactivated arylalkenes with ketones or aldehydes was catalyzed by an organocatalyst and a transition metal catalyst via a SOMO-enamine under air, affording a simple approach to gamma diketones and gamma-carbonyl aldehydes. PMID- 20198263 TI - Amphiphilic block copolymer nano-fibers via RAFT-mediated polymerization in aqueous dispersed system. AB - Self-assembled block copolymer nanofibers are attractive materials for multiple applications. We propose here a novel, very simple and straightforward method to prepare polymeric nanofibers at high solids contents directly in water. It is based on an aqueous emulsion polymerization process performed under living radical polymerization conditions, using the RAFT method. PMID- 20198264 TI - A chiral diphosphine as trans-chelate ligand and its relevance to catalysis. AB - The chiral diphosphine ligand R,R-trans-1,2-C(6)H(10)(NHCOC(6)H(4)PPh(2))(2), 1, gives the fluxional trans-chelate complexes [M(1)]X, 2a-2c, M = Au or Ag. It is suggested that a similar trans-chelate conformation may be present in the catalytic intermediate [Pd(1)]. PMID- 20198265 TI - Alpha-functionalization of non-activated aliphatic amines: ruthenium-catalyzed alkynylations and alkylations. AB - Novel catalytic alpha-functionalizations of non-activated aliphatic amines with silylated alkynes are reported. In the presence of the Shvo catalyst alkylations and alkynylations proceed highly selectively to the branched amines. PMID- 20198266 TI - Spin capturing with nitrones: radical coupling reactions with concurrent introduction of mid-chain functionality. AB - Nitrones are demonstrated to efficiently mediate radical coupling reactions on the example of the conjugation of ATRP-made polymers, yielding macromolecules with distinct functional alkoxyamine centres in mid-chain locations of the chains. PMID- 20198267 TI - Autoxidation of thiol-containing amino acid to its disulfide derivative that links two copper(II) centers: the important role of auxiliary ligand. AB - Treatment of Cu(AcO)(2) with D-penicillamine or L-cysteine in the presence of 2,2'-bipyridine afforded dicopper(II) complexes with a bis(bidentate-N,O) disulfide ligand, the formation mechanism of which was discussed on the basis of Cu(II)-thiolate interaction affected by an auxiliary ligand. PMID- 20198268 TI - Supported N-alkylimidazole-decorated dendrons as heterogeneous catalysts for the Baylis-Hillman reaction. AB - The Baylis-Hillman reaction between methyl vinyl ketone and aromatic aldehydes, catalyzed by N-alkylated imidazoles immobilized on polystyrene via dipolar cycloaddition, esterification or nucleophilic substitution, exhibits a remarkable positive dendritic effect. PMID- 20198276 TI - [Myocardial perfusion scintigraphy 2008 in Germany - results of the fourth query]. AB - AIM: The working group Cardiovascular Nuclear Medicine of the German Society of Nuclear Medicine in cooperation with the working group Nuclear Cardiology of the German Cardiac Society herewith present the results of the 4th survey on myocardial perfusion scintigraphy (MPS) of the year 2008. METHOD: 310 questionnaires (191 private practices (PP), 93 hospitals (HO), 31 university hospitals (UH)) were evaluated. RESULTS: MPS of 98947 patients were reported. 15% of them were younger than 50 y, 57% between 50 and 70 y and 28% older than 70 y. 88% [2007: 83%] of all were studied with Tc-99m perfusion tracers. The patient radiation exposure of a stress and rest protocol considering German standard recommended doses was 8.5 mSv, of a stress-only protocol 1.9 mSv. 77% [2007: 76%] of the MPS were performed in PP, 15% [2007: 15%] in HO and 8% [2007: 9%] in UH. From 2005 to 2008 there was a mild increase in the MPS numbers by 1.2% (PP +7.1%, HO -5.5%, UH -31.4%). The type of stress was pharmacological in 30% [2007: 27%]; 68% adenosine (of these 22% with exercise), 29% dipyridamole (of these 64% with exercise), and <1% dobutamine. Gated SPECT was performed in 46% [2007: 47%] of all rest and in 42% [2007: 44%] of all stress MPS. 62% [2007: 61%] of all institutions did not use perfusion scores. CONCLUSION: The MPS numbers from 2005 to 2008 in Germany can be regarded as stable. However, there are considerable shifts from HO and UH to PP. The well known potential of MPS considering risk stratification and functional analysis has not been tapped so far. Both gated SPECT and a quantitative perfusion analysis should be performed routinely in every patient. PMID- 20198277 TI - [Positron emission tomography 2008 in Germany - results of the query and current status]. AB - AIM: The working group on positron emission tomography (PET) of the DGN (German Society of Nuclear Medicine) initiated this first survey to collect and analyse information on the practise of PET in Germany in the year 2008. METHODS: A questionnaire was sent to PET performing facilities (medical practices, hospitals, university hospitals and others) for retrospective data acquisition. Details regarding the equipment and examination procedures were examined as well as indications and number of studies. In addition, the role of PET within the diagnostic process was evaluated. RESULTS: Responses from 65 sites were analysed. Their technical equipment consisted of 77 PET scanners (40 of them were combined PET/CT devices). About 63500 PET studies had been performed with 86% in the field of oncology, 8% in neurology and 3% in cardiology. The radiotracers were labelled with 18F in 91% of the studies, whereas 68Ga was used in 4% and 11C in 3%. The analyses revealed lung tumours as the most investigated tumour entity, followed by malignant lymphoma, tumours of the gastro-intestinal tract and prostate cancer (about 14000, 6000, 5000 and 2000). Corresponding to the new scanners and software procedures, the number of studies with attenuation correction by CT was high (68%) and nearly all studies were reconstructed iteratively (99%). The PET images were analysed quantitatively in the majority of cases (91%). The clinical reports, which included image documentation for the greater part, were posted regularly within 3 days. However, in 70% of the sites electronic transfer possibilities were used additionally to speed up the diagnostic process. The high standard of quality was demonstrated by the fact, that 40 facilities were engaged in a tumour board. Further on, one third of the physicians had gained a PET certification awarded by the DGN. CONCLUSION: Relative to the high general standard of diagnostic instrumentation in Germany, PET is less established, in particular when compared with other industrialised countries such as USA and Switzerland. PMID- 20198278 TI - [Nuclear medical inpatient treatment in Germany - analysis of structured quality reports 2004-2008]. AB - All public licensed hospitals of Germany are obligated since 2004 to establish and to publish a structured biennial quality report. The aim of this study was to analyse the quality reports from 2008 of clinics with nuclear-medicine therapy ward and to investigate developments for the inpatient nuclear-medicine therapy by comparing the results with the quality reports of the years 2004 and 2006. METHODS: All available structured quality reports of clinics with a nuclear medicine therapy ward of the years 2004, 2006 and 2008 were evaluated. RESULTS: The total number of inpatient treatment cases in 2008 amounted to 54190 (2006: 54884; 2004: 57366). This corresponds to a decrease of 5.5% in comparison to 2004. The number of the therapy wards decreased at the same time to currently 117 (2006: 120; 2004: 124). Remarkable changes were found in the spectrum of the main diagnosis. Thus, the most frequent diagnosis with the ICD-code E05 (hyperthyroidism) decreased continuously from 37747 treatments in 2004 and 34764 in 2006 to 31756 in the year 2008. In contrast, the ICD-diagnoses for thyroid cancer (C73, Z08) with 14761 cases in 2008 increased with time (2006: 13426; 2004: 12581). CONCLUSIONS: In analogy to the observations from Europe after introduction of an iodine prophylaxis the improved iodine supply in Germany has led to a decline of the radioiodine therapy due to hyperthyroidism. PMID- 20198279 TI - [Efficacy of mud-bath therapy with Mineral Water from the Sillene spring at Italy's Chianciano Spa for osteoarthritis of the knee: a clinical statistical study]. AB - AIMS: Many previous researches showed clinical benefits, effects on inflammatory mediators and pain, immune system, hormones and on the diencephalic-pituitary adrenal axis. Our study evalues the efficacy of mud-bath therapy with mineral water from the Sillene Spring at Italy's Chianciano Spa in patients with osteoarthritis of the knee. MATERIALS AND METHODS: In study we compared: physical examination of the knee joint, visual analogue scale (VAS) assessment of pain, and Lequesne Algo-functional Index. Tests were performed in 61 patients divided into 2 groups. The group A underwent three full cycles of mud-bath therapy over 1 year's time, the group B did not. An observational longitudinal study was also conducted on the patients of group A, before and after completion of the treatment protocol. Statistical analyses were based on use of Pearson's chi2 test, Student's t tests for paired and unpaired data. RESULTS: The percentage of patients with no symptoms or mild symptoms was higher in group A than in group B (differences were highly significant); the mean value of VAS and the overall Lequesne indexes mean score reported in group A was significantly lower than that reported in group B. The same we observed comparing the clinical conditions of group A patients before and after mud-bath therapy. No adverse effects were observed in any of the patients in group A. CONCLUSIONS: The mud-bath therapy at Chianciano Spa significantly improves the clinical conditions of patients with knee osteoarthritis and significantly reduces the frequency and severity of symptoms and the disability they cause. PMID- 20198280 TI - [Intervertebral instability]. AB - The clinic diagnosis of degenerative lumbar intervertebral instability is a controversial topic and have not yet been clarified clinical criteria for to define this condition with accuracy. Although the lumbar pain is the most common symptom in patients who have lumbar intervertebral instability its clinical presentation is not specific; moreover in patients with lumbar pain there are no agreed signs and symptoms that can be truly attributable to instability. Despite better imaging techniques of testing spinal instability there is not a clear relations between radiologic signs of instability and clinical symptoms. It is, however, still far from unanimous definition of degenerative lumbar intervertebral instability accepted from all specialists involved in diagnosis and treatment of this condition; however, seem there is most agree about suspected vertebral instability. Nevertheless this unresolved topic, it is possible to state that imaging play an increasing role in diagnosis and management of patients with suspected instability. The aim of this study is to investigate the different imaging modalities most indicated in diagnosis if vertebral instability and whether degenerative change can be associated with lower back pain. PMID- 20198281 TI - [Towards a multi-step informed consent: considerations and proposals for a good practice]. AB - Any therapeutic intervention needs consent from the patient, after have received information from the physician. This is often seen as a bureaucratic accomplishment but it could enhance therapeutic alliance. We propose to divide consent from information, offering a place in which doubts and emotions can be explored, with the assistance of a psychological interview. We believe that this new approach can enhance physician-patient relationship, with an improvement in patient satisfaction and a decrease of claims and complaints. PMID- 20198282 TI - An insight into industrial accidents involving the hand. AB - BACKGROUND: Industrial hand injuries are a common occurrence and contributes to a large segment of workers' morbidity. The main aim of this study was to look into the day pattern, types and location of upper limbs injures, identify the types of machines involved and highlight the treatment received. MATERIALS AND METHODS: The present study was performed on 57 industrial workers admitted and treated by the Orthopaedic team of Universiti Kebangsaan Malaysia Medical Centre (UKMMC) for acute injuries sustained whilst working. RESULTS: The majority of the workers were male (93%). The commonest age group involved was between 25-35 years (48%). The right hand was injured more then the left with majority of injuries involving the fingers. Interestingly, we also observed that injuries occurred more on Saturdays. Laceration was the most common injury followed by fractures and crush injuries. Treatment depends on the type and severity of injuries. For most lacerated wounds, treatment was debridement, primary suturing and antibiotic therapy. Injuries on Saturdays indicated that workers needed a longer time break especially during weekends after a long hectic week. CONCLUSIONS: Injuries sustained by workers may be prevented by proper working techniques and conditions together with wearing of protective gadgets. PMID- 20198283 TI - [Immunolocalization of HB-EGF in human atherosclerotic plaques]. AB - AIMS: Heparin-binding epidermal growth factor is a member of the EGF family, it is a potent mitogen for smooth muscle cells and has been implicated in atherosclerosis, angiogenesis. In athererogenesis, HB-EGF has been detected in medial smooth cells and foamy macrofages. In this work, we have investigate about immunohistocemical localization of HB-EGF in atherosclerotic plaques. MATERIALS AND METHODS: Three cases of man affected by atherosclerosis have been examined. We have collected and examined atherosclerotic plaques by immunohistochemical procedure in optical microscopy. Samples have been incubated with primary Ac (anti-human HB-EGF- goat IgG). RESULTS: In the three examined cases, results are partly overlap-ping, but with some difference in relation to location of positivity to HB-EGF. Only in one case, HB-EGF staining is rather weak and located just below endothelium where is a thickened area of tissue rich in fibres and few cells, In another case, positivity to HB-EGF is present in an area of connective tissue of the intima. In the last case, positivity to HB-EGF is evident in the context of a presumed elastic tissue with fusiform cells following fibres orientation, and that could be fibroblasts or smooth muscle cells. CONCLUSIONS: These results indicate that HB-EGF is involved in the development of atherosclerotic plaques and that HB-EGF is a possible target for atherosclerosis therapy. PMID- 20198284 TI - [Our experience in the chemical spinal neuromodulation in chronic pain from spinal collapse due to osteoporosis.]. AB - AIMS: Osteoporosis is a metabolic disease of the bone characterized by reduced bone mass and microstructural deterioration of bone tissue with a consequent increase in bone fragility and risk of vertebral collapse. Treatment of osteoporosis with the new molecule is effective in improving the density and quality of bone but does not provide an analgesic effect for patients with vertebral collapse. The treatment of chronic pain from vertebral collapse is difficult and may require the use of opioids, but for some patients the intake of these drugs is burdened with systemic side effects. The aim of our study is to use the way in reducing intrathecal opioid dosage and at the same time have good pain control without significant side-effects. We report our experience in the use of continuous infusion pump for intrathecal morphine in patients with chronic pain from osteoporotic vertebral collapse that can not tolerate therapy with systemic opioids because of severe side effects. MATERIALS AND METHODS: 24 patients (19 women and 5 men with average age of 73.3 years) with a diagnosis of chronic pain from vertebral collapse refractory to treatment for systemic analgesic were treated with the use of pumps for intrathecal infusion of morphine. All patients were fit the criteria for inclusion. For the measurement of pain the visual analogue scale (VAS) in three stages: T0, T1, T2 was administered to all patients. For the evaluation of the quality of life the Questionnaire of quality of life of the European Foundation for Osteoporosis (QUALEFFO) was administered in three times. RESULTS: In the one year follow-up there was a significant reduction in pain measured by VAS, from 8.5 to 1.9 in T0 to T2 in all patients. Similarly there was a reduction in the average score of QUALEFFO of all variables, from T0 equal to 114.7 to T2 equal to 79.1. With the intrathecal infusion of morphine no patient required an additional systemic treatment. CONCLUSIONS: This study demonstrates that intrathecal-morphine therapy offers patients relief from pain and a good quality of life. Continuous intrathecal infusion of morphine is a valuable therapy and is particularly suitable for those patients who show side effects with the administration of systemic opioids. PMID- 20198285 TI - [Our experiences in chronic benign pain by injecting local anaesthetic into scars]. AB - OBJECTIVES: To refer a possible resolving treatment of chronic benign pain by injecting local anaesthetics into scars. MATERIALS AND METHODS: This original article consists of 7 interesting cases who have been extracted by a group of 2145 patients treated with local anaesthetic (lidocaine 0.5-1%), of one or more than one scar. RESULTS: The clinical and therapeutical data of a 2 years follow up show that in these 7 cases of chronic benign pain, treated by injecting local anaesthetic (lidocaine 0.5-1%) into one or more scars, the algic symptomatology stably disappeared. CONCLUSIONS: This record of cases confirms the hypothesis of a possible aetiological role of scars in causing benign chronic painful syndromes, as stated by Brothers Huneke in the 40's and validated by a recent review on the topic. PMID- 20198286 TI - Study of bone metabolism in patients with chronic HIV infection. AB - AIMS: Various studies have confirmed the high incidence of skeletal homeostasis modifications in subjects who are carriers of chronic HIV infections, and specific pharmacological treatments, which modify the metabolism and condition both the weight loss and the reshaping of the bones. The presence of a reduction in body mass index seems to contribute to the progressive deterioration of the skeletal framework. The aim of this study was to see whether the presence of HIV seropositivity could constitute a risk factor for the development of osteoporosis/osteopenia, even in the light of the fact that our group was composed of patients with a concentrated age span well under the limit for both post-menopausal and senile osteoporosis, and with a median age superimposable for both sexes. MATERIALS AND METHODS: Our study involved 26 HIV+ patients with an average duration of infection equal to 6.7 +/- 4.8 years, and a range of seropositive duration between 6 months to 16 years. The prominent ultrasonometrical parameters are as follows: Broadband Ultrasound Attenuation, Speed of Sound, Stiffness Index or Quantitative Ultra-sound Index, Bone Mineral Density, and T-score. The biochemical study was carried out by assessing a marker of neoformation such as seric osteocalcine, and uninary pyridinoline and deoxipyridonoline as resorption markers. RESULTS: The results confirmed the presence of osteoporosis/osteopenia in 46% of the samples (11%, and 35%, respectively), with a progressive reduction in bone mineral density in relation to the duration of HIV infection. Assessment of the marker for bone metabolism showed a significant increase in osteocalcine in the female population compared to the males, without any significant variations in the normal values. CONCLUSIONS: Extreme variability in the morphological appearance at bone level during the course of HIV infection would lead us to believe that in the genesis of various forms, depending on the mechanisms and the time involved only in the parts defined, other attributable factors are responsible, not only for the progression of the core pathology and the possible interference of hormonal factors (behavioural and/or nutritional) directly correlated with the state of infection, but also for the dismetabolic effects of the antiretroviral drugs. PMID- 20198287 TI - Five years of Telemedicine in Cystic Fibrosis Disease. AB - AIMS: We studied the effect of Telehomecare (THC) in a group of Cystic Fibrosis (CF) patients, with the aim to early recognize the relapses of pulmonary infections. Data obtained with Vivisol (OXYTEL) instrumentation were collected from 2001 to 2005. MATERIALS AND METHODS: The study has involved 17 patients (11 f, 6 m) affected by CF, treated with THC, in addition to the usual therapeutic protocol, for an average period of 29.6 months +/- 13.5. The mean age for THC enrollment was 15.74 years +/- 5.8. As controls, the study has involved the same patients during the 12 months prior to THC start-up and 28 patients affected by CF treated at our Unit (13 f, 15 m; average age 14.77 +/- 5.22). RESULTS: The results show a statistically significant decrease of outpatient accesses and increase of therapy cycles, and a trend of higher stability of the respiratory function, in THC treated subjects compared to controls. CONCLUSIONS: Our study suggests that THC programs may not be optimally accepted by CF patients, and that its use seems to increase in general the rate of access to health care without demonstrating any clear effect of pulmonary function. PMID- 20198288 TI - Functional assessment of patients with systemic sclerosis by the use of 'Six minutes-walking-test'. AB - AIMS: Systemic Sclerosis (SS) is a chronic inflammatory disease of the connective tissues, characterised by alterations in the functions and structures of the small blood vessels (capillaries and arterioles) and by modifications associated with the disposition of collagen in the tissues. One of the most frequent complication of the SS is the pulmonary arterial hypertension (PAH). Aim of this study was to assess the various pathophysiological relationships betweens SS and PAH in order to establish whether the presence of this systemic disease can represent a risk factor. MATERIALS AND METHODS: Ten patients affected by SS (9 women and 1 man, with a mean age of 55.7 +/- 11.4 years) were enrolled in our study, as inpatients at Dept. of Internal Medicine and Rheumatology Unit of Perugia University School of Medicine in the "Santa Maria" General Hospital in Terni, Italy. A control group of 10 clinically healthy subjects (CHS, 9 women and 1 man, ranging in age from 35 to 55 years) was also recruited in order to obtain normal clinical data of reference In subjects recruited, we have conducted a functional evaluation, based on physical tests (6-minute-walking-test, 6MWT), equipment and laboratory, on subjects suffering from SS with suspected PAH, in order to calculate the degree of cardio-pulmonary compromission brought on by this disease, taking into consideration important variables such as age and gender. RESULTS: The 6 MWT showed that the mean value at rest of the O2 saturation (%) was 97.1 +/- 1.20, heart rate (hr/min) 76 +/- 8.8, and respiratory rate (rr/min) 20.4 +/- 2.8. HS had 98.6 +/- 0.52, 75.7 +/- 6.86, and 16.8 +/- 1.61, respectively. After the the test, the results showed that the patients had O2 saturation 93.8 +/- 3.42, hr 113 +/- 20.27, and rr 31 +/- 2.86. HS had 97.6 +/ 0.69, 90.7 +/- 5.67, and 20.1 +/- 1.59, respectively. CONCLUSIONS: Our study has confirmed the high involvement of PAH and other cardio-respiratory disturbances in patients with SS. In fact, we have verified PAP to be above the normal range in 3 out of 10 patients, while the other 3 patients presented borderline values. Because it is a simple method to conduct at low cost, in addition to being non invasive, reproducible and well accepted, we must affirm that the 6MWT should be more utilized and exploited, especially during the fi rst phases of diagnosis. This in turn can help us to assess the patients and to determine a course of treatment which is more complex and onerous, as in therapeutic monitoring for verifying efficacy. PMID- 20198289 TI - Evaluation of oxidative stress in rheumatoid and psoriatic arthritis and psoriasis. AB - INTRODUCTION: The aim of the present study is to discuss the importance of the processes of oxidative stress in the pathogenesis of certain autoimmune diseases, to search for an appropriate assessment marker, and to debate current approaches which have been proposed for the treatment of Rheumatoid Arthritis (RA), Psoriatic Arthritis (PsA), and Psoriasis (Ps). MATERIALS AND METHODS: The total antioxidant capacity (TAC), the thiolic capacity (TC), and the serum hydroperoxide concentration (SHC) were measured in 37 subjects: 13 with RA, 8 with PsA, 8 with Ps, and 8 healthy controls. RESULTS: SHC levels were significantly higher in patients with RA (p = 0.01), as well as in those with PsA (p = 0.005) and Ps (p = 0.002) in comparison with the control group. However, a significant reduction in the TAC values in the serum of all three groups (RA, p = 0.03; PsA, p = 0.005; Ps, p = 0.001) were observed in comparison with the healthy controls. The thiolic concentration were found to have significantly diminished in patients with RA (p =0.0005) and Ps (p = 0.0005) in comparison with the control group. Our findings have brought out the fact that the therapeutic treatment of RA using biological drugs is more than satisfactory in accord with the considerable increase in the TAC values, although not significantly, compared to those patients treated with DMARDs. CONCLUSIONS: The determination of the parameters of oxidative stress utilising these methods may be useful as a quick test, and as routine in monitoring the state of oxidative stress in patients suffering from RA, PsA, and Ps, so that a more effective treatment for ROS can be undertaken accordingly. The administration of biological drugs seems to have a role in increasing the mechanism of the barrier which the body possesses against oxidative stress. PMID- 20198290 TI - The predictive values of urinalysis in intravenous urogram. Is intravenous urography really necessary in mild hydronephrotic patient? AB - BACKGROUND AND AIMS: Many patients who presented to Universiti Kebangsaan Malaysia Medical Centre (UKMMC) with signs and symptoms of urolithiasis had mild hydronephrosis with non visualization of calculus on ultrasound examination. These patients underwent an intravenous urogram (IVU) in order to determine the presence of urolithiasis and most of them had normal IVU. The main aim of this study was to determine the predictive value of urinalysis in this group of patients in determining the need for IVU examinations. MATERIALS AND METHODS: Retrospectively the ultrasound, urinalysis and intravenous urography reports of 53 patients were reviewed and evaluated. RESULTS: The positive predictive and negative predictive value of urinalysis was found to be 68% and 96.4%, respectively. CONCLUSIONS; The results indicate that the urinalysis was an excellent negative predictor for IVU. In view of high radiation dose, risk of contrast reaction and contrast induced nephropathy of IVU, we suggest that it should not be performed in patient with non visualization of calculus mild hydronephrosis when the urinalysis is negative for blood. PMID- 20198291 TI - A study on nurses' perception on the medication error at one of the hospitals in East Malaysia. AB - BACKGROUND AND AIMS: Medication error is defined as any preventable event that might cause or lead to an inappropriate use or harming of the patient. Such events could be due to compounding, dispensing, distribution, administration and monitoring. The aim of the present study was to determine the nurses' perception on medication error that were related directly or indirectly to the process of administration of drugs. MATERIALS AND METHODS. This was a descriptive cross sectional study conducted on 92 staff nurses working in the selected wards in one of the hospitals in East Malaysia. Data was obtained through structured questionnaires. RESULTS. Analysis of data was done through SPSS program for descriptive inferential statistics. Out of a total of 92 subjects, sixty-eight (73.9%) indicated medication error occurred because the nurses were tired and exhausted. Seventy nine subjects (85.9%) believed that any medication error should be reported to the doctors; another 74 (80.2%) knew that their colleagues committed medication error and 52 (56.5%) did not report the case. Forty eight (52.17%) subjects committed medication error at least once throughout their life. Of the 48 committed medication, 45 (93.75%) nurses believed that the error committed was not serious; while 39 (81.25%) believed the error occurred during the 1st 5 years of their working experience. CONCLUSIONS: The findings showed that the incidence of medication error was due to the defect in the organizational system itself and not solely due to the mistakes on the part of any individual. PMID- 20198292 TI - [Adjuvant chemotherapy in hormone-receptor positive HER2-negative early breast cancer]. AB - Adjuvant treatment in hormone-receptor positive, HER2-negative early breast cancer is controversial. Chemotherapy benefit in this subset of patients is generally small, and a wide variability exists among dif-ferent subgroups of patients, depending on various patient and tumor characteristics. To select subsets of patients who will really benefit from chemotherapy, one of the possible strategy is based on multigene expression analysis. This approach is providing deeper insights into the biological heterogeneity of breast cancer, allowing to further sub-divide hormone-receptor positive tumors into groups, with different clinical behavior and response to treatments. Among less expensive and better validated methods, high levels of Ki67, a routinely assessed immunohistochemical marker of cell proliferation, can suggest the use of chemotherapy in this subset of patients. Generally, regimen used should include a taxane. In fact, retrospective analyses of clinical trials suggest that anthracyclines may be less active in hormone-receptor positive HER2-negative patients, while several other trials and meta-analyses involving taxanes, showed a benefit in terms of risk of relapse and death reduction. Among taxanes, docetaxel should be preferred because of a better therapeutic index, and a higher activity in comparison to paclitaxel. At present, reliable and accurate evaluation of histopathological and immunohistochemical factors may allow the choice of omitting adjuvant chemotherapy in patients with low risk hormone receptor positive HER2-negative breast cancer. Uncertainty still exists about chemotherapy benefit for a substantial proportion of women of this subgroup. Nevertheless, the addition of taxanes, mainly docetaxel, to anthracyclines, seems to overcome the relative chemoresistance of hormone-receptor positive tumors, providing a benefit in disease free survival and overall survival. PMID- 20198294 TI - Non respiratory manifestations of swine flu. AB - Swine flu is the big public health problem at present. In early 2009, emerging of swine flu in Mexico rapidly spread worldwide. The pandemic of swine flu brings attention to the medical society. Basically, swine flu is a respiratory virus infection. However, there are also some other uncommon non-respiratory manifestations of swine flu. In this specific article, the author will briefly summarize on those important non respiratory manifestations of swine flu. PMID- 20198293 TI - [Role of adjuvant chemotherapy in the choice of chemotherapeutic treatment of metastatic breast cancer]. AB - Adjuvant treatment of early breast cancer has changed considerably in recent years, and the majority of patients are currently treated with the most active single agents in this setting. As a result, the decisions regarding the treatment of patients with metastatic breast cancer have become more difficult. In patients who have not received chemotherapy for early-stage breast cancer or were treated with CMF, many choices are available, including regimens containing anthracyclines or taxanes. Patients who received anthracyclines in the adjuvant setting, may sometimes be re-treated with these agents, and the inclusion of a taxane is frequently the most reasonable choice. Among taxanes, docetaxel should be preferred because it is the most active single agent, and has a synergistic action with several other drugs, when used in combination. Taxanes can be used also in selected patients who had received these agents as adjuvant treatment. In particular, docetaxel did not show complete cross-resistance with paclitaxel, whereas weekly paclitaxel is only minimally effective in patients resistant to docetaxel. Retreatment with trastuzumab combined with chemotherapeutic agents might be a reasonable option in patients who had received adjuvant chemotherapy with trastuzumab. Nevertheless, another recent option is the combination of chemotherapy with lapatinib. Currently, novel target agents are being developed, with the potential to improve survival in patients with metastatic breast cancer. Arguably, the future for treatment of these patients appears to be the combination of effective single agents, such as docetaxel, with novel biologic therapies. PMID- 20198295 TI - Pathophysiology and modern treatment of ulcer disease. AB - This is an overview of the pathophysiological abnormalities of gastroduodenal (GD) ulcers [duodenal ulcer (DU), gastric ulcer (GU) and Dragstedt ulcers (combined DU and GD)], as well as the effects of the different treatments (surgical, medicinal and physiological) described since the introduction of stomach resections. The intention is to demonstrate whether the peptic ulcer diseases are a homogeneous entity with a characteristic pathophysiology or whether they represent the final expression of many heterogeneous causes including impairment of upper gastrointestinal motility. The review also asks whether DU and GU have a common or different pathogenesis and whether ulcers in the stomach might be predominantly due to impaired mucosal resistance and the DU to gastric hypersecretion. The symptoms of both diseases are also compared with the findings in the normal controls. PMID- 20198296 TI - Autophagy: Can it become a potential therapeutic target? AB - Autophagy is a cellular lysosomal degradation pathway involved in proteins and organelles recycling for promoting cell survival, development and homeostasis. It is a multistep process and genetic studies have identified many proteins that participate in autophagosome formation and fusion with lysosomes, and various signaling factors that associate with the regulation of autophagy. In general, autophagy acts as a cell protector and its dysfunction is correlated with diverse pathologies, such as neurodegeneration, liver, heart and muscle diseases, cancer, inflammation and ageing. However, its role in cell death increases the complexity of the autophagic degradation system. A broad understanding of autophagy, ranging from detailed processes, including induction, formation and degradation, to function in physiology and pathology, revealed by accumulating studies, may be helpful for formulating therapeutic strategies for autophagy-associated human diseases. PMID- 20198297 TI - PAT protein mRNA expression in primary rat hepatocytes: Effects of exposure to fatty acids. AB - Excess energy is stored as neutral lipids in lipid droplets (LDs) whose surface is coated by PAT proteins, each playing a distinct cellular function. The adipocyte differentiation-related protein (ADRP) and tail-interacting protein (TIP47) are expressed almost ubiquitously, whereas the oxidative tissue-enriched PAT protein (OXPAT) is expressed in specific tissues, such as the liver. In rat liver, only ADRP expression has been documented. This study was aimed at identifying OXPAT and TIP47 transcripts in rat hepatocytes, and investigating how their expression is modulated by excess lipids, using fat-enriched hepatocytes to mimic different degrees of steatosis. Primary rat hepatocytes were exposed to fatty acids (FFAs) for 12, 24 and 36 h. Lipid accumulation was estimated by spectrophotometric quantification of triacylglycerol. Expression of PAT proteins as well as of PPARgamma was evaluated by real-time RT-PCR. Hepatocytes exposed to FFAs showed progressive lipid accumulation. The increase in lipid content was associated with the induction of PAT protein expression. At 12 h, OXPAT and TIP47 mRNA expression was up-regulated. At longer times, the level of OXPAT transcripts remained high, whereas that of TIP47 slowly declined. Conversely, ADRP expression showed a time-dependent increase with exposure to FFAs. This study demonstrates, for the first time, the presence of OXPAT and TIP47 transcripts in rat hepatocytes, as well as their up-regulation with lipid accumulation. The distinct time courses observed for the three PAT proteins during FFA exposure might reflect the different roles played by each protein in lipid metabolism in the hepatocyte. Up-regulation of TIP47 and OXPAT might represent an early response to excess lipids, while, in correspondence with a lipid overload, up-regulation of ADRP could address lipids towards storage. PMID- 20198298 TI - Growth factor expression in ophthalmic pterygia and normal conjunctiva. AB - The expression of growth factors in ophthalmic pterygium and phenotypically normal conjunctiva was examined and correlated with the clinical findings. Fifteen specimens of ophthalmic pterygia and 8 specimens of phenotypically normal conjunctiva were examined. Total RNA was extracted from all specimens and mRNA levels for transforming growth factor (TGFB1), vascular endothelial growth factor (VEGFA), basic fibroblast growth factor (FGF2), epidermal growth factor (EGF) and insulin-like growth factor (IGF1) were measured using real-time reverse transcription PCR (qRT-PCR). Differences in the expression of these factors between pterygium and conjunctival specimens were examined, as well as correlations between RNA levels and clinical parameters. mRNA levels for VEGFA and FGF2 were significantly higher in pterygium, compared with conjunctival specimens, whereas the respective differences for other factors examined were statistically not significant. The mRNA levels for VEGFA and FGF2 were also significantly higher in recurrent compared with primary pterygium. Correlations between the mRNA levels and other clinical parameters were statistically not significant for the growth factors examined. The higher levels of FGF2 or VEGFA mRNA in pterygium imply that these factors may be involved in the pathogenesis or clinical behavior of the pterygium, including postoperative recurrence. VEGFA expression may have potential for use in the selective treatment of pterygium with anti-VEGFA agents. PMID- 20198299 TI - PTEN/pAkt/p53 signaling pathway correlates with the radioresponse of non-small cell lung cancer. AB - The sensitivity or resistance of cancer cells and normal tissues to ionizing radiation plays an important role in the clinical setting of lung cancer treatment. However, to date the exact molecular mechanisms of intrinsic radiosensitivity have not been well explained. In this study, we compared the radiosensitivity or radioresistance in two non-small cell lung cancers (NSCLCs), H460 and A549, and investigated the signaling pathways that confer radioresistance. H460 cells showed a significant G(2)/M arrest after 12 h of irradiation (5 Gy), reaching 60% of G(2)/M phase arrest. A549 cells also showed a significant G(2)/M arrest after 12 h of exposure; however, this arrest completely disappeared after 24 h of exposure. A549 has higher methylated CpG sites in PTEN, which is correlated with tumor radioresistance in some cancer cells, than H460 cells, and the average of the extent of the methylation was approximately 4.3 times higher in A549 cells than in H460 cells. As a result, PTEN expression was lower in A549 than in H460. Conducting Western blot analysis, we found that PTEN acted as a negative regulator for pAkt, and the pAkt acted as a negative regulator for p53 expression. According to the above results, we concluded that the radiosensitivity shown in H460 cells may be due to the higher expression of PTEN through p53 signaling pathway. PMID- 20198300 TI - A cell-microelectronic sensing technique for the screening of cytoprotective compounds. AB - In recent years, a new cell-based high throughput paradigm has emerged, which seeks to identify novel, pharmacologically active cytoprotective compounds. The essence of this approach is to create experimental models of cell injury relevant for a particular disease by establishing in vitro cell-based models, followed by high-throughput testing of compounds that affect the cellular response in a desired manner. Prior approaches typically used simple end-point analyses. To assess the cytoprotective effects of novel drug candidates in real-time, we have applied a cell-microelectronic sensing technique (RT-CES), which measures changes in the impedance of individual microelectronic wells that correlates linearly with cell index (reflecting cell number, adherence and cell growth), thereby allowing the continuous determination of cell viability during oxidative stress. In vitro cytotoxicity was elicited by hydrogen peroxide in myocytes (H9c2) and hepatocytes (Hep3B). Cells were post-treated at 30 min with various reference molecules and novel cytoprotective compounds. Cytoprotection detected in the RT CES system correlated well with the results of two classical end-point-based methods (improvement in MTT and reduction of LDH release). The RT-CES method, when used as described in the current report, is suitable for the screening of molecular libraries to identify molecules or molecule combinations that attenuate oxidative stress-induced cell damage. PMID- 20198301 TI - Corilagin inhibits the double strand break-triggered NF-kappaB pathway in irradiated microglial cells. AB - Microglia, the resident immune cells of the central nervous system (CNS), are activated by various stimuli. Resting microglia are the basis of normal neurogenesis, while activated microglia may inhibit neurogenesis through the production of pro-inflammatory mediators and cytokines. Recent research suggests that microglia are activated by irradiation. This may play a role in radiation induced brain injury (RIBI). DNA double-strand breaks (DSBs), the most deleterious form of DNA damage after ionizing radiation, may rapidly trigger the activation of the NF-kappaB pathway via p53-induced protein leading to the release of pro-inflammatory mediators and cytokines. Thus, a negative regulator of the NF-kappaB pathway that inhibits radiation-induced microglia activation could be used to treat RIBI. Corilagin, a member of the tannin family, inhibits NF-kappaB pathway activation. In the present study, we examined the inhibitory effects of corilagin on radiation-induced microglia activation using a variety of techniques. Our data suggest that corilagin inhibits radiation-induced microglia activation via suppression of the NF-kappaB pathway and the compound is a potential treatment for RIBI. PMID- 20198302 TI - RecQL1 DNA repair helicase: A potential tumor marker and therapeutic target against hepatocellular carcinoma. AB - RecQL1 in the human RecQ DNA helicase family participates in DNA repair and recombination pathways in cell cycle replication. Immunohistochemical analysis of human hepatocellular carcinoma (HCC) tissues showed that RecQL1 expression is strongly correlated with histological grade and MIB-1 indices of HCC, and that the expression was greater in simple HCCs inducing extranodular growth or portal vein invasion than in HCCs not inducing extranodular growth or portal vein invasion. These histological data reveal the potential of RecQL1 as a biological marker predicting the malignancy and progression of liver cancer. High expression profiles were also produced by various HCC cells, including HCC cell lines established by us. When RecQL1 expression was silenced by siRNA in vitro, most HCC cells died of mitotic catastrophe. In a mouse orthotopic xenograft model of liver cancer with transplanted human HCC, RecQL1-siRNA mixed with cationic liposomes exhibited a strong anticancer effect that prevented the growth of the cancer. RecQL1-siRNA inhibited the growth of human HCC in the mouse liver, confirming that RecQL1 is an excellent molecular agent against liver cancer and suggests that RecQL1-siRNA formulated with liver-prone liposomes has excellent potential as a therapeutic drug against liver cancers. PMID- 20198303 TI - Preventive effects of enzyme-treated rice fiber in a restraint stress-induced irritable bowel syndrome model. AB - Irritable bowel syndrome (IBS) is a common health issue that is characterized by abdominal pain, abnormal bowel movements, altered visceral perception, and abnormal metabolism of 5-hydroxy triptamine (serotonin; 5HT). The use of prebiotics or probiotics treatment for IBS has become increasingly important as an adjunct to pharmaceutical options. The aim of this study was to determine the efficacy of enzyme-treated rice fiber (ERF) on an IBS model. We obtained a new prebiotic from defatted rice bran that was developed as an insoluble dietary fiber through amylase and hemicellulase treatment followed by removal of the soluble fraction. Containing approximately 70% hemicellulose, ERF is utilized by lactobacilli and subsequently converted to butyrate using Eubacterium limosum. We employed a restraint stress IBS model which involved the continuous application of stress for 4 h per day for 3 days. Polycarbophil Ca (PC) (500 mg/kg body weight) was used as a positive control and ERF was added to the diet at 4% in diet. During restraint stress, ERF significantly attenuated urgent fecal excretion, colonic mucosal 5HT secretion, and hyperalgesthesia compared with the control. ERF also significantly increased cecal butyrate production as well as total organic acid content. PC was only effective in regard to preventing increases in 5HT levels. Furthermore, there were no significant levels of pro inflammatory markers CINC-1 and TNF-alpha among the groups. Although more detailed studies are needed, the ERF prebiotic demonstrated potency in attenuating major symptoms of IBS. PMID- 20198304 TI - Binding proteins internalized by PTD-fused ligands allow the intracellular sequestration of selected targets by ligand exchange. AB - The targeted inactivation of intracellular molecules has important therapeutic potential. For this purpose, it could be envisioned to introduce specifically designed binding proteins into cells by covalent linkage to protein transduction domains (PTDs). However, stable linkage of a PTD to a cargo may affect its conformation and, hence, its binding property inside the cell. Here, we analyzed the ability of non-covalently linked PTDs to internalize the model binding proteins streptavidin (SA) and Strep-Tactin (ST). Notably, inside the cell, the PTD-Strep-tag II ligand used for internalization of SA was displaced by the model target biotin which exhibits a higher binding affinity for the same binding pocket. Thus, specifically designed binding proteins can be internalized into cells by non-covalent binding to a PTD and subsequently be used for capturing given intracellular target molecules by ligand exchange. Under therapeutic aspects, it could be envisioned to further develop such systems for the intracellular sequestration, and consequently, functional inactivation of pathologically relevant factors. PMID- 20198305 TI - Hsa-miR-34c suppresses growth and invasion of human laryngeal carcinoma cells via targeting c-Met. AB - MicroRNAs (miRNAs) are small noncoding RNA molecules that negatively modulate gene expression at the post-transcriptional level. A growing number of studies has shown that more and more miRNAs are aberrantly expressed and involved in the pathogenesis of several types of cancers. Here, we report that the down-regulated hsa-miR-34c was also involved in oncogenesis of laryngeal carcinoma. Our studies indicated that hsa-miR-34c functioned as a tumor suppressor which inhibited growth and invasion of human laryngeal carcinoma cells. Furthermore, in our study, an inverse relationship between the expression of hsa-miR-34c and c-Met was identified in 10 paired fresh samples from tumor tissues and adjacent normal tissues. Infection of hsa-miR-34c mediated by lentivirus suppressed the expression of c-Met directly. In addition, introduction of c-Met cDNA lacking 3' UTR largely abrogated hsa-miR-34c-induced cell growth and invasion inhibition. These findings suggest aberrantly down-regulated hsa-miR-34c is a critical factor that contributes to malignancy in human laryngeal carcinoma by a mechanism involving targeting of c-Met. PMID- 20198306 TI - Expression of MLN64 influences cellular matrix adhesion of breast cancer cells, the role for focal adhesion kinase. AB - The metastatic lymph node 64 (MLN64) gene was initially identified as highly expressed in the metastatic lymph node from breast cancer. It is localized in q12 q21 of the human chromosome 17 and is often co-amplified with erbB-2. However, the role played by MLN64 in breast cancer remains unclear. In the present study, the expression of MLN64 was examined in a breast cancer cohort using quantitative real-time PCR and immunohistochemical staining. It demonstrated that MLN64 was highly expressed in breast tumours compared to corresponding background tissues at both transcript level and protein level. The elevated level of MLN64 transcripts was correlated with the poor prognosis and overall survival of the patients. A panel of breast cancer cell sublines was subsequently developed by knockdown of MLN64 expression. Loss of MLN64 expression in MCF-7 cells resulted in a significant reduction of cell growth (absorbance for MCF-7DeltaMLN64 being 0.87+/-0.07, P<0.01 vs. wild-type control (MCF-7WT 1.13+/-0.06) and transfection control (MCF-7pEF 1.27+/-0.05). In cell-matrix adhesion assay, MDA-MB 231DeltaMLN64 cells showed a significant increase in adhesion (86+/-14), p<0.01 compared with both MDA-MB-231WT (61+/-20) and MDA-MB-231pEF (45+/-27). Further investigations demonstrated an increase in protein level of the focal adhesion kinase (FAK) in MDA-MB-231DeltaMLN64 cells using Western blot analysis and immunofluorescent staining of FAK. Moreover, addition of FAK inhibitor to these cells diminished the effect of MLN64 on cell-matrix adhesion, suggesting that FAK contributed to the increased adhesion in MDA-MB-231DeltaMLN64 cells. In conclusion, MLN64 is overexpressed in breast cancer, and its level correlates with poor prognosis and patient survival. MLN64 contributes to the development and progression of breast cancer through the regulation of cell proliferation and adhesive capacity. PMID- 20198307 TI - Involvement of capsular polysaccharide via a TLR2/NF-kappaB pathway in Vibrio vulnificus-induced IL-8 secretion of human intestinal epithelial cells. AB - In a previous study, we reported that a wbpP gene mutation in Vibrio vulnificus was significantly impaired in its ability to synthesize surface capsular polysaccharide (CPS). In this study, we evaluated the functions of the V. vulnificus capsular polysaccharide on interleukin (IL)-8 production, as well as its underlying mechanisms in human intestinal epithelial cells. The CPS-defective wbpP mutant induced significantly lower levels of IL-8 production, IL-8 gene promoter activation and NF-kappaB activity in INT-407 cells than was noted with the wild-type or wbpP-complemented V. vulnificus. The expression levels of Toll like receptor (TLR)2 mRNA and protein were also found to be lower in INT-407 cells infected with the CPS-defective wbpP mutant than in those cells infected with the wild-type or the wbpP-complemented strains. Additionally, the treatment of INT-407 cells with anti-TLR2 antibody proved to significantly block IL-8 production and NF-kappaB minimal promoter activity induced by the wild-type or the wbpP-complemented strains. Furthermore, purified V. vulnificus CPS was found to significantly induce IL-8 production and NF-kappaB activation, both of which were inhibited upon the addition of the anti-TLR2 antibody. Taken together, these results demonstrate that V. vulnificus capsular polysaccharide is involved in the induction of IL-8 production of human intestinal epithelial cells via a TLR2/NF kappaB-dependent pathway. PMID- 20198308 TI - Activation of epidermal growth factor receptor gene is involved in transforming growth factor-beta-mediated fibronectin expression in a chondrocyte progenitor cell line. AB - Chondrocytes produce many types of ECM to maintain elasticity and plasticity in articular cartilage of revolute joints. Both transforming growth factor beta (TGF beta) and bone morphogenetic proteins (BMPs) induce extracellular matrix proteins such as type IIalpha1 collagen and aggrecan during chondrogenic differentiation in vitro. However, differences in the matrix gene expression pattern by the stimulation of TGF-betas and BMPs remains unclear. In the present study, we created a customized PCR-based ECM array to investigate the pattern of ECM expression genes in the chondrocyte progenitor cell line ATDC5, that was stimulated by TGF-betas or BMPs. Fibronectin (Fn) expression was drastically induced after TGF-beta stimulation, but not BMP-4. Epidermal growth factor receptor (Egfr) gene was also significantly activated in TGF-beta1-induced chondrogenic differentiation as compared to BMP-4-mediated differentiation. Furthermore, EGFR-knockdown assay of the cells showed decreasing Fn expression during TGF-beta1-induced chondrogenic differentiation. These data indicated that Egfr gene activation by TGF-beta is involved in the differences in the expression of cellular matrix genes such as Fn, as compared to the expression pattern induced by BMPs. PMID- 20198309 TI - Classification of hypocholesterolemia lipid patterns using Chol/Trig Combination System. AB - Patterns of hypocholesterolemic lipid fractions in 295 patients with liver diseases, malignant tumors, arteriosclerotic and renal diseases with cholesterol (Chol) levels of <30 mg/dl were classified using a simultaneous analytical method for the Chol and triglyceride (TG) fractions (Chol/Trig Combo System). Hypocholesterolemia was classified as follows: IV, Type IV on WHO hyperlipidemia phenotype classification; intermediate density lipoprotein (IDL), cases with appearance of IDL, including appearance of Lp(a); high + low density lipoproteins (HDL+LDL), lipids mostly consisting of HDL and LDL fractions; HDL abnormality, cases with slow alphaHDL or fast HDL; abnormal LDL, both Chol and TG fractions mostly consisting of LDL fraction; normal type, ratios of HDL, very low density lipoproteins (VLD) and LDL fractions were almost normal; and low HDL, HDL-C was <30 mg/dl. Many patients with liver diseases had HDL+LDL (45%), and abnormal LDL was noted in 13% of the cases. In malignant tumors, the frequencies of low HDL, normal type, and HDL+LDL cases were similar (22-30%). In arteriosclerosis, normal type accounted for 46% of the cases, and the frequency of normal type was higher (60%) in renal diseases. Mortality rate (within 1 year after measurement) was then compared among lipid patterns. In liver diseases, mortality rate increased in the following order: abnormal LDL (55%); low HDL (31%); HDL abnormality (25%); and HDL+LDL (21%). No deaths were seen among patients with normal type. In malignant tumors, mortality rate was very high (88%) in patients with HDL+LDL, but low in patients with normal type (22%) and low HDL (9%). Mortality rate was low in patients with arteriosclerosis and renal diseases in the short-term follow up period (1 year). In the comparisons of distribution, mean, and appearance rate of charge modification frequency (CMF) among lipid patterns, parameters were high in all patterns other than HDL+LDL. Classification of hypocholesterolemia lipid patterns and evaluation of CMF may therefore be clinically useful. PMID- 20198310 TI - Association of genetic variants with myocardial infarction in Japanese individuals with different lipid profiles. AB - Dyslipidemia is an important risk factor for myocardial infarction (MI). We previously showed that gene polymorphisms associated with MI differed among individuals with different lipid profiles. We further examined whether genetic variants that confer susceptibility to MI might differ among individuals with low or high serum concentrations of triglycerides, high density lipoprotein (HDL) cholesterol, or low density lipoprotein (LDL)-cholesterol. The study population comprised 5270 Japanese individuals, including 1188 subjects with MI and 4082 controls. The 150 polymorphisms examined in the present study were selected by genome-wide association studies of MI and ischemic stroke with the use of the Affymetrix GeneChip Human Mapping 500K Array Set. The initial Chi-square test revealed that the A->G polymorphism (rs12632110) of SEMA3F was significantly (false discovery rate <0.05) associated with MI among individuals with high serum HDL-cholesterol or among those with low serum LDL-cholesterol. Subsequent multivariable logistic regression analysis with adjustment for covariates revealed that rs12632110 was significantly (P<0.01) associated with MI in individuals with high serum HDL-cholesterol or with low serum LDL-cholesterol. The genetic variants that confer susceptibility to MI differ among individuals with different lipid profiles, and the genetic component for the development of MI is more apparent in individuals at low-risk (high HDL- and low LDL-cholesterol levels) compared to those at high-risk. Stratification of subjects according to lipid profiles may thus be important for personalized prevention of MI based on genetic information. PMID- 20198311 TI - Effects of stent implementation on plasma levels of asymmetric dimethylarginine in patients with or without ST-segment elevation acute myocardial infarction. AB - The study was designed to compare the response pattern of plasma l-arginine and methylarginines to stent placement in patients with or without ST segment elevation myocardial infarction (STEMI). Two groups of patients with obstructive coronary artery disease (OCAD) undergoing percutaneous coronary intervention (PCI) with stenting were enrolled in the study. Group I consisted of 16 patients with STEMI, whereas group II included 24 patients without STEMI (controls). Before PCI and at <1 h, 5 and 30 days after reperfusion, blood samples were taken for measurement of l-arginine and methylarginines. L-arginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), N-monomethylarginine (MMA) and l-ornithine plasma levels were measured by LC-MS-MS. Arginine methylation index (Arg-MI) was calculated according to the formula, Arg-MI = (ADMA+SDMA)/MMA. In patients without STEMI, stenting induced a prompt and sustained depression of ADMA (p<0.000), and l-ornithine (p<0.000) with simultaneous increase of l-arginine (p<0.001), l-arginine/ADMA ratio (p<0.000) and an inconsistent change in MMA. Arg-MI remained at the baseline value. By contrast, STEMI patients responded to stent placement with a variable increase in l-arginine (p<0.01), ADMA (p<0.069), SDMA, MMA (p<0.01) and l-ornithine (p<0.000), whereas there was an early fall of Arg-MI after stenting, followed by a steady increase approaching the initial values. The differences in the time course for ADMA (p<0.000), MMA (p<0.007), Arg-MI (p<0.01) and l-ornithine (p<0.003) proved to be significant between the STEMI and control group. It can be concluded therefore, that stent placement improves endothelial dysfunction in patients with OCAD when it is not complicated by STEMI. PMID- 20198312 TI - Oral treatment with HE3286 ameliorates disease in rodent models of rheumatoid arthritis. AB - HE3286 (17alpha-ethynyl-5-androstene-3beta, 7beta, 17beta-triol) is an orally bio available synthetic derivative of naturally occurring androstene-3beta, 7beta, 17beta-triol. Our present data show that oral treatment with HE3286, favourably influenced the course of arthritis in the rat model of adjuvant-induced arthritis (reduced cumulative disease scores and paw edema), and in the mouse model of collagen antibody-induced arthritis (reduced clinical paw scores). Importantly, HE3286 was not immune suppressive in human mixed lymphocyte reaction or in animals challenged with Coxsackie B3 virus. HE3286 is currently in phase I/II clinical trials in rheumatoid arthritis and ulcerative colitis and these findings further strengthen the possibility that HE3286 may represent an effective anti inflammatory agent useful for treating chronic inflammation with a more attractive safety profile than glucocorticoids or cyclooxygenase inhibitors. PMID- 20198313 TI - Decursin inhibits growth of human bladder and colon cancer cells via apoptosis, G1-phase cell cycle arrest and extracellular signal-regulated kinase activation. AB - Decursin, a pyranocoumarin isolated from the Korean Angelica gigas root, has demonstrated anti-cancer properties. In the present study, we found that decursin inhibited cell viability in cultured human urinary bladder cancer 235J cells and colon cancer HCT116 cells. The inhibited proliferation was due to apoptotic induction, because both cells treated with decursin dose-dependently showed a sub G1 phase accumulation and an increased cytoplasmic DNA-histone complex. Cell death caused by decursin was also associated with the down-regulation of anti apoptotic factor Bcl-2 and the up-regulation of pro-apoptotic molecules cytochrome c, caspase 3 and Bax. Treatment of both types of cancer cells with decursin resulted in G1-phase cell cycle arrest, as revealed by FACS analyses. In addition, decursin increased protein levels of p21WAF1 with a decrease in cyclins and cyclin dependent kinases (CDKs). Furthermore, decursin induced the activation of extracellular signal-regulated kinases (ERK) in both cancer cell lines, with the notable exceptions of c-Jun N-terminal kinase (JNK) and p38 mitogen activated protein (MAP) kinase. Finally, pretreatment with ERK-specific inhibitor PD98059 reversed decursin-induced p21WAF1 expression and decursin-inhibited cell growth. Thus, these findings suggest that decursin has potential therapeutic efficacy for the treatment of bladder and colon cancer. PMID- 20198314 TI - Elevation of nucleocytoplasmic beta-N-acetylglucosaminidase (O-GlcNAcase) activity in thyroid cancers. AB - Single N-acetylglucosamine residues attached by O-linkage to serine or threonine (O-GlcNAc) are an abundant, dynamic and inducible post-translational modification of cytoplasmic and nuclear proteins. This study analyzes the activity of the enzyme involved in the removal of these sugar residues, i.e. beta-N acetylglucosaminidase (O-GlcNAcase) as well as the level of O-GlcNAc in benign and malignant thyroid lesions. Our results demonstrate increased activity of the enzyme in thyroid cancers in comparison to non-neoplastic lesions and adenomas. O GlcNAc-modified proteins in thyroid cells have a predominantly nuclear distribution and are more abundant in non-neoplastic lesions than in tumors. Understanding the aberrant O-GlcNAc metabolism in thyroid cancer cells may be helpful for developing new diagnostic or treatment methods. PMID- 20198315 TI - Association of genetic variants with hemorrhagic stroke in Japanese individuals. AB - Although genetic epidemiological studies have implicated several genetic variants as risk factors for hemorrhagic stroke, the genetic determinants of this condition remain largely unknown. We examined an association of genetic variants with intracerebral or subarachnoid hemorrhage among Japanese individuals. The study population comprised 4,304 unrelated Japanese individuals, including 377 subjects with intracerebral hemorrhage, 205 subjects with subarachnoid hemorrhage, and 3,722 controls. The 150 polymorphisms examined in the present study were selected by genome-wide association studies of ischemic stroke and myocardial infarction with the use of the GeneChip Human Mapping 500K Array Set. The chi-square test, multivariable logistic regression analysis with adjustment for covariates, as well as a stepwise forward selection procedure revealed that the C->T polymorphism (rs1324694) of ERLIN1, the C->T polymorphism (rs12679196) of TRAPPC9, and the G->T polymorphism (rs16936752) of WNK2 were significantly (P<0.05) associated with the prevalence of intracerebral hemorrhage, and that the A->G polymorphism (rs3111754) of ITM2C and the A->G polymorphism (rs10986769) of MAPKAP1 were significantly associated with the prevalence of subarachnoid hemorrhage. Genotypes for ERLIN1, TRAPPC9, and WNK2 may prove informative for assessment of the genetic risk for intracerebral hemorrhage, and those for ITM2C and MAPKAP1 may be beneficial in assessment of the genetic risk for subarachnoid hemorrhage in Japanese individuals. PMID- 20198316 TI - The effects of N-acetyl cysteine on the MG132 proteasome inhibitor-treated lung cancer cells in relation to cell growth, reactive oxygen species and glutathione. AB - MG132 as a proteasome inhibitor has been shown to induce apoptotic cell death through formation of reactive oxygen species (ROS). Here, we investigated the effects of N-acetyl cysteine (NAC; a well-known antioxidant), L-buthionine sulfoximine (BSO; an inhibitor of GSH synthesis) or diethyldithiocarbamate (DDC; an inhibitor of Cu/Zn-SOD) on MG132-treated Calu-6 or A549 lung cancer cells in relation to cell growth, ROS and GSH levels. MG132 inhibited the growth of Calu-6 and A549 cells at 24 h. MG132 induced apoptosis in both cell lines, which was accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsim). ROS levels including O(2)(.-) were increased in both MG132-treated lung cells. MG132 also induced GSH depletion in both lung cell types. Treatment with 10 microM BSO or 1 microM DDC affected ROS and GSH levels in MG132-treated Calu-6 cells. However, these changes did not influence cell growth and death in the cells. NAC prevented cell growth inhibition and death in MG132-treated lung cells, which was accompanied by decreased ROS, but not by decreased GSH depletion. In conclusion, the changes of ROS and GSH by MG132, NAC, BSO or DDC were partially related to cell growth and death in the lung cancer cell lines Calu-6 and A549. PMID- 20198317 TI - Quantification of internalization of EGFR-binding Affibody molecules: Methodological aspects. AB - Tumor cell internalization of targeting agents is of interest, since internalization influences the local retention time of a radionuclide and thereby imaging quality in PET and SPECT and effects of radionuclide therapy. In cases where nuclear methods are not applicable at the cellular level, quantitative fluorescent techniques are useful as described in this article. Two fluorescence based methods to study cellular internalization were applied: the CypHer and the Alexa488-quenching methods, both utilized in fluorescence microscopy and flow cytometry. Two EGFR-binding Affibody molecules were analyzed in A431 cells: the monomer Z1907 and the dimer (Z1907)2. EGF, cetuximab and non-specific Affibody molecules were used as controls. For comparison, internalization of 111In-labeled Z1907 was studied with the acid wash internalization assay. The Cypher method is straightforward, but requires equal labeling of all compounds for accurate quantification. The Alexa488-quenching method is preferable since it is independent of the dye-to-protein ratio. According to this method, about 45% of EGF and 19-24% of the bound Affibody molecules and cetuximab were internalized within one hour. Similar results were seen with 111In-Z1907 in the acid wash method, while (Z1907)2 was not removed by acid and thus could not be studied this way. The fluorescence-based Alexa488-quenching method is well suited to quantitatively analyze internalization of targeting agents, also those that resist acid wash. The internalized fraction showed that both the monomeric and dimeric Affibody molecules are expected to give good uptake and thereby good retention of metallic radionuclides which will render good tumor to background values. PMID- 20198318 TI - MUC2 gene promoter methylation in mucinous and non-mucinous colorectal cancer tissues. AB - Abundant mucin production and MUC2 expression is the key feature of mucinous colorectal cancer (CRC). Although MUC2 gene methylation has been thought to play an important role in loss of MUC2 expression, the tissues are difficult to analyze because of the cellular heterogeneity of tissue samples. In the present study, we determined the role of region-specific methylation in the MUC2 promoter in MUC2 expression in CRC. Additionally, we optimized the conditions for quantification of methylation analysis in mucinous and non-mucinous CRC tissues. We identified two regions in MUC2 promoter, region A (-289 and -274) and region C (-193 and -160), that correlated with loss of MUC2 expression by comparing the methylation status in 13 CRC cell lines with no or low MUC2 expression and those in 4 cell lines with high MUC2 expression. To prove the correlation of MUC2 methylation status and loss of expression in CRC tissues, MUC2 methylation status in tumors needs to be determined. Since the critical CpG sites have been identified in cell lines by sequencing, a more rapid and sensitive methylation specific PCR (MSP) was used. We conducted MSP at 3 CpG sites (-289, -274, -193) in 19 mucinous and 34 non-mucinous CRC tissues because this analysis worked at only these sites in the preliminary cell line experiments. Our results showed that methylation status of mucinous CRC was significantly lower than that of non mucinous CRC at 3 sites (-289; p=0.001, -274; p=0.013, -193; p=0.001), and correlated with high level of MUC2 expression as determined by immunohistochemistry. Besides, these results indicated that MUC2 expression and mucin contents decreased in accordance with the increase of methylation status. We concluded that low methylation status of MUC2 gene plays a predominant role in high level MUC2 expression in mucinous CRC. PMID- 20198320 TI - HIF1-positive and HIF1-negative glioblastoma cells compete in vitro but cooperate in tumor growth in vivo. AB - Glioblastoma multiforme (GBM) is characterized by extensive angiogenesis that is mostly orchestrated by the hypoxia inducible factor HIF-1. Deregulation of HIF-1 is believed to contribute to cancer initiation and progression. However, instances have been described in which loss of HIF-1 leads to more aggressive tumors. Here we investigated the consequences of downregulating HIF-1 function in the human GBM cell line TB10, both on cell proliferation in vitro and on tumor growth in vivo. RNA interference targeting the O2-regulated HIF-1alpha subunit efficiently reduced HIF-1alpha expression and transcriptional induction of HIF-1 responsive genes without affecting cell growth. Thus, singularly grown wild-type and HIF-1alpha-inhibited GBM cell populations did not significantly differ in proliferation rate. However, when the two populations were co-cultured, wild-type cells overgrew the HIF-1alpha-inhibited cells. Subcutaneous grafting in nude mice of wild-type and HIF-1alpha-inhibited GBM cells lead to comparable tumor formation and growth. Interestingly, cografting of wt and HIF-1alpha- inhibited GBM cells in nude mice resulted in more aggressive tumors, both in terms of tumor appearance and tumor growth. This suggests that cellular populations that differ in their ability to mount a response to hypoxia may compete in vitro but cooperate in vivo resulting in increased tumor aggressiveness. PMID- 20198319 TI - Targeted photodynamic therapy for prostate cancer: inducing apoptosis via activation of the caspase-8/-3 cascade pathway. AB - The limitation of specific delivery of photosensitizers to tumor sites, represents a significant shortcoming of photodynamic therapy (PDT) application at present. Prostate-specific membrane antigen (PSMA), a validated biomarker for prostate cancer, has attracted considerable attention as a target for imaging and therapeutic applications for prostate cancer. The present study focuses on the investigation of a PSMA inhibitor-conjugate of pyropheophorbide-a (Ppa-conjugate 2.1) for a targeted PDT application and the mechanism of its mediated-cell death in prostate cancer cells. Multiple fluorescence labeling methods were employed to monitor PDT-treated prostate cancer cells by confocal laser scanning microscopy. Our results demonstrate that Ppa-conjugate 2.1 mediated apoptosis is specific to PSMA+ (positive) LNCaP cells, but not PSMA- (negative) PC-3 cells. Furthermore, these results indicate that following PDT, the activation of caspase-8, -3, -9, cleavage of poly(ADP-ribose) polymerase (PARP) and DNA fragmentation is sequential. The appearance of cleaved beta-actin further supported involvement of caspase-3. Specific caspase inhibitor blocking studies reveal that the caspase-8/ 3 cascade pathway plays a key role in apoptosis of LNCaP cells induced by Ppa conjugate 2.1. The demonstrated selective targeting and efficacy of this agent suggests that targeted PDT could serve as an alternative treatment option for prostate cancer. PMID- 20198321 TI - Tumor-derived trypsin enhances proliferation of intrahepatic cholangiocarcinoma cells by activating protease-activated receptor-2. AB - In primary malignant liver tumors, trypsinogen-immunoreactivity was present in 70% of intrahepatic cholangiocarcinoma (ICC) specimens, but absent in hepatocellular carcinoma (HCC) specimens. We suggest the secretion of trypsinogen to be a key difference in biological behavior between ICC and HCC cells. The purpose of this study was to investigate the secretion of tumor-derived trypsin and the expression of its specific receptor, protease-activated receptor-2 (PAR 2), in ICC using cell lines and surgical specimens. The expression of trypsinogen 1 mRNA was observed in three of four ICC cell lines, but none of three HCC cell lines. Western blot analysis detected trypsinogen-1 in serum-free conditioned medium from one of the ICC cell lines positive for the mRNA. Gelatin zymography revealed a gelatinolytic activity for trypsin, the activated form of trypsinogen, in the same conditioned medium. PAR-2 mRNA and protein were observed in ICC cell lines. The proliferative activity of ICC cells was increased by concentrations of trypsin as low as 10 nM, and peaked at 100 nM. The effect of trypsin was suppressed by a serine protease inhibitor, gabexate mesilate. PAR-2 expression was detected in 64% of ICC surgical specimens immunohistochemically. In addition, stroma fibroblasts expressed PAR-2 in 52% of ICC specimens. These results suggest that trypsinogen-1 contributes to the growth of ICC cells and also tumor associated fibroblasts. PMID- 20198322 TI - Photoactivation of 9-hydroxypheophorbide alpha triggers apoptosis through the reactive oxygen species-mediated mitochondrial pathway and endoplasmic reticulum stress in AMC-HN-3 laryngeal cancer cells. AB - Photodynamic therapy (PDT) is a promising treatment modality for a variety of cancers. It utilizes light-absorbing compounds combined with direct illumination to generate reactive oxygen species in photosensitizer-targeted tumor cells resulting in the final photodamage of tumors. Recently, we demonstrated that a combination modality of 9-hydroxypheophorbide alpha (9-HPbD)-based PDT and carboplatin exerts enhanced cytotoxic and apoptotic effects on AMC-HN-3 laryngeal cancer cells. The present study aimed to investigate the potential apoptotic pathways initiated by 9-HPbD-PDT-mediated reactive oxygen species (ROS) in AMC-HN 3 cells. Cytotoxicity and apoptosis induced by 9-HPbD-PDT were exhibited in a ROS dependent manner. Mitochondria and the endoplasmic reticulum (ER) were observed as preferential sites of 9-HPbD accumulation in AMC-HN-3 cells. ROS induced by 9 HPbD-PDT directly led to downregulated expression of Bcl-2, loss of mitochondrial membrane potential, release of cytochrome c from mitochondria, elevation of intracellular calcium due to ER stress, as well as induction of CHOP and activation of caspase-3, -8, -9 and -12. Our results demonstrated that ROS induced by 9-HPbD-PDT play a causative role in triggering mitochondrial events, ER stress and probable involvement of the extrinsic apoptotic pathway in AMC-HN-3 cells. PMID- 20198323 TI - Radiation-inducible silencing of uPA and uPAR in vitro and in vivo in meningioma. AB - Stereospecific radiation treatment offers a distinct opportunity for temporal and spatial regulation of gene expression at tumor sites by means of inducible promoters. To this end, a plasmid, pCArG-U2, was constructed by incorporating nine CArG elements (in tandem) of EGR1 gene upstream to uPA and uPAR siRNA oligonucleotides in a pCi-neo vector. Radiation-induced siRNA expression was detected in a meningioma cell line (IOMM-Lee). Immunoblotting and RT-PCR analyses confirmed downregulation of uPA and uPAR. A similar effect was observed in transfected cells followed by H2O2 treatment. Moreover, pre-treatment of transfected cells with N-acetyl L-cysteine blocked the silencing of uPA and uPAR, which further confirmed the oxidative damage-mediated downregulation. Cell proliferation assays and Western blot analysis for apoptotic molecules confirmed cell death in a radiation-inducible fashion. Migration and matrigel invasion assays also revealed a marked decrease in migration and invasion. Immunocytochemistry showed a marked decrease in uPA and uPAR levels in transfected and irradiated cells. H&E staining revealed a decrease in the pre established tumor volume among the animals treated with pCArG-U2 and radiation. Immunohistochemistry of the brain sections established with intracranial tumors also revealed a marked decrease in uPA and uPAR in a radiation-inducible fashion. Taken together, our data suggest pCArG-U2 as a suitable candidate for radiation inducible gene therapy. PMID- 20198324 TI - Upregulation of Notch pathway molecules in oral squamous cell carcinoma. AB - The constitutive activation of the Notch pathway has been demonstrated in various types of malignancies. However, it remains unclear how the Notch pathway is involved in the pathogenesis of oral squamous cell carcinoma (OSCC). We investigated the expression of Notch pathway molecules in OSCC cell lines and biopsy specimens and examined the effect of Notch pathway inhibition. Reverse transcription-polymerase chain reaction revealed upregulation of Notch1, Notch2, Jagged1, HES1 and HEY1 in both OSCC cell lines and biopsy specimens. Immunohistochemical examination showed that the Notch intracellular domain accumulates in the nucleus of cells in OSCC cell lines and biopsy specimens. In addition, Jagged1 is expressed in the cytoplasm of cells in OSCC cell lines and biopsy specimens. Furthermore, Notch pathway inhibition using a gamma-secretase inhibitor prevented the growth of OSCC in vitro. These findings suggest that inhibition of the Notch pathway suppresses OSCC growth and may be a useful approach for the treatment of patients with OSCC. PMID- 20198325 TI - Downregulation of SS18-SSX1 expression in synovial sarcoma by small interfering RNA enhances the focal adhesion pathway and inhibits anchorage-independent growth in vitro and tumor growth in vivo. AB - Synovial sarcoma (SS) is an aggressive soft-tissue malignancy characterized by a unique t(X;18) translocation resulting in expression of SS18-SSX fusion protein. In order to investigate the biological function of this fusion protein and to develop a novel therapeutic option, we examined downregulation of SS18-SSX1 expression by small interfering RNA targeting SS18-SSX1 in three human SS cell lines. Microarray analysis comparing SS18-SSX1-silenced cells with control cells in three SS cell lines showed that SS18-SSX1 mainly affected the focal adhesion pathway. In accord with the array data, silencing of SS18-SSX1 enhances adhesion to the extracellular matrix through the induction of expression of myosin light chain kinase. Furthermore, the silencing of SS18-SSX1 inhibits anchorage independent growth in vitro and systemic delivery of siRNA against SS18-SSX1 using a nanoparticle system inhibited tumor growth in a nude mouse xenograft model. Our results demonstrate that siRNA targeting of SS18-SSX1 has therapeutic potential for the treatment of SS. PMID- 20198326 TI - Neoplastic progression of the human breast cancer cell line G3S1 is associated with elevation of cytoskeletal dynamics and upregulation of MT1-MMP. AB - The newly established breast cancer cell line G3S1, derived from EM-G3 breast cancer progenitors, was analyzed for functional changes related to neoplastic progression manifested by elevated invasiveness and enhanced capability to degrade gelatin. Degradation of gelatin and invasiveness of G3S1 cells was found to be dependent on the activity of matrix proteinases and actin cytoskeletal dynamics. Therefore, the expression and activity of these proteases was compared in G3S1 and EM-G3 cells. Despite enhanced capability of G3S1 cells to degrade gelatin, these cells exhibited lower levels of secreted extracellular matrix degrading proteases than parental EM-G3 cells. However, the expression of membrane-bound MT1-MMP was strongly elevated in G3S1 cells. While the degradation of gelatin was associated with invadopodia-like structures in both EM-G3 and G3S1 cells, the cytoskeletal remodeling dynamics was greatly elevated in G3S1 cells, suggesting that upregulation of MT1-MMP, together with elevation of cytoskeletal remodeling dynamics can effectively cause elevated invasiveness and enhanced matrix degrading capability in G3S1 cells. PMID- 20198328 TI - Development of an oral cancer recurrence mouse model after surgical resection. AB - Oral squamous cell carcinomas (OSCC) are frequent epithelial malignancies and afflicted with a poor prognosis. The majority of these cancers are treated with surgical resection and local recurrences are predominantly responsible for a fatal outcome. In order to provide a better understanding of the development of these local recurrences after surgical ablation, we developed an orthotopic floor of-mouth squamous cell carcinoma murine model, in which local recurrences occur at a high frequency (55%, 8 out of 15 mice) within 6-21 days after microsurgical removal of the primary. Expression of the enhanced green fluorescent protein (eGFP) in the cancer cells allows in this new model to confirm complete surgical resection under the microscope and helps to track repopulating primary tumor cells in the local recurrence by optical imaging. In addition the model resembles all typical features of invasive head and neck cancers including the formation of lymph node metastasis and local infiltration. PMID- 20198327 TI - Regulatory T cell depletion enhances tumor specific CD8 T-cell responses, elicited by tumor antigen NY-ESO-1b in hepatocellular carcinoma patients, in vitro. AB - Immunotherapy in hepatocellular carcinoma based on one or a few tumor specific antigens have shown limited antitumor efficacy. As a major suppressive factor in tumor immune response, better understanding of the role of regulatory T cells (Tregs) in hepatocellular carcinoma might be important for design of future immunotherapy-based clinical protocols. Tregs from 49 HCC patients and 40 controls were identified by flow cytometric analysis for the phenotype. Functional studies were performed by analyzing their inhibition to immune responses. Finally investigating whether elimination of Tregs was capable of enhancing the immunostimulatory efficacy of NY-ESO-1b peptides. In HCC peripheral blood and tumor-infiltrating lymphocytes, we found increased numbers of Tregs, which expressed high levels of HLA-DR, GITR and CD103. The prevalence of Tregs increased with during progressive stages in HCC patients. Moreover, the elimination of Treg cells followed by stimulating with NY-ESO-1b peptide significantly improved the anti-tumor cytotoxic T lymphocytes responses in HCC patients compared with stimulating with NY-ESO-1b peptide alone. The immune response efficiency increased from 37.5 to 62.5%. In conclusion, the increase in frequency of Treg cells might play a role in suppression of the immune response against HCC and for the design of immunotherapy the incorporation of the Treg cell depletion strategy will achieve potent anti-tumor immunity with therapeutic impact. PMID- 20198329 TI - Carvedilol in glioma treatment alone and with imatinib in vitro. AB - The purpose of the study was to investigate whether carvedilol has an antiproliferative effect alone and whether carvedilol provides an additive, synergistic or antagonistic effect on imatinib mesylate-induced cytotoxicity in both C6 glioma monolayer and spheroid culture. The C6 rat glioma chemoresistant experimental brain tumour cell line, that is notoriously difficult to treat with combination chemotherapy, was used both in monolayer and spheroid cultures. We treated C6 glioma cells with carvedilol alone and a combination of carvedilol and imatinib mesylate at a concentration of 10 microM. Following treatment, we evaluated cell proliferation index, bromodeoxyuridine labelling index (BrDU-LI), cell cycle distributions, apoptotic cell percentages, cAMP levels and three dimensional cell morphology at monolayer cultures. In addition BrDU-LI, volume and morphology of spheroids were also assessed. Carvedilol and imatinib mesylate alone reduced cell number, BrDU-LI, cAMP levels and spheroid volume. Carvedilol and imatinib mesylate arrested cells at G0/G1 phase in a time-dependent manner and time-independent manner, respectively. Carvedilol increased apoptosis rate only at the 24th h, but imatinib mesylate did for all time intervals. Interestingly carvedilol, drug with well-known protective effect on mitochondria, induced severe mitochondria damage, and imatinib mesylate induced autophagy confirmed only by transmission electron microscopy. These results suggest that carvedilol showed antitumour activity against rat C6 glioma cells and a combination of carvedilol with imatinib mesylate resulted in enhanced in vitro antitumour activity. PMID- 20198330 TI - The antitumor effect of PLK1 and HSF1 double knockdown on human oral carcinoma cells. AB - High levels of mitotic progression-associated PLK1 and stress-associated HSF1 have been observed in various human cancers. In the present study, we investigated the effects of PLK1 and HSF1 knockdown on the proliferation of oral cancer cells using small interfering RNA. In human oral squamous cell carcinoma (SCC) tissues, the levels of PLK1 and HSF1 were higher compared to normal tissues. The expression levels of PLK1 and HSF1 were also elevated in the human oral SCC cell lines FaDu and HEp-2. Disruption of PLK1 induced cell cycle arrest at G2/M phase as well as apoptosis in oral cancer cells. Interestingly, knockdown of both PLK1 and HSF1 expression decreased cell proliferation while increasing apoptotic cell death in synergistic fashion. These results establish the potential value of PLK1 and HSF1 as targets for oral cancer therapy. PMID- 20198331 TI - Targeting the cell cycle and the PI3K pathway: a possible universal strategy to reactivate innate tumor suppressor programmes in cancer cells. AB - Corruption of the Rb and p53 pathways occurs in virtually all human cancers. This could be because it lends oncogene-bearing cells a surfeit of Cdk activity and growth, enabling them to elaborate strategies to evade tumor-suppressive mechanisms and divide inappropriately. Targeting both Cdk activities and the PI3K pathway might be therefore a potentially universal means to palliate their deficiency in cancer cells. We showed that the killing efficacy of roscovitine and 16 other purines and potentiation of roscovitine-induced apoptosis by the PI3K inhibitor, LY294002, decreased with increasing corruption of the Rb and p53 pathways. Further, we showed that purines differing by a single substitution, which exerted little lethal effect on distant cell types in rich medium, could display widely-differing cytotoxicity profiles toward the same cell types in poor medium. Thus, closely-related compounds targeting similar Cdks may interact with different targets that could compete for their interaction with therapeutically relevant Cdk targets. In the perspective of clinical development in association with the PI3K pathway inhibitors, it might thus be advisable to select tumor cell type-specific Cdk inhibitors on the basis of their toxicity in cell-culture-based assays performed at a limiting serum concentration sufficient to suppress their interaction with undesirable crossreacting targets whose range and concentration would depend on the cell genotype. PMID- 20198332 TI - PKCepsilon induces Bcl-2 by activating CREB. AB - Protein kinase C epsilon (PKCepsilon) is a transforming oncogene and an important anti-apoptotic protein. We previously demonstrated that overexpression of PKCepsilon in MCF-7 breast cancer cells caused an increase in anti-apoptotic Bcl 2 and a decrease in pro-apoptotic Bid, attenuating tumor necrosis factor-alpha (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. The objective of our present study was to determine the mode of induction of Bcl-2 by PKCepsilon in breast cancer cells. siRNA silencing of either PKCepsilon or Akt in MCF-7 cells, which overexpress Akt, decreased Bcl-2 protein and mRNA levels. However, knockdown of PKCepsilon, but not Akt, led to the decrease in Bcl-2 at both protein and mRNA levels in MDA-MB-231 breast cancer cells, which overexpress PKCepsilon but contain little constitutively-active Akt. Knockdown of PKCepsilon decreased phosphorylation of cAMP response element-binding protein (CREB) at Ser133 in MDA-MB-231 cells, and depletion of CREB by siRNA decreased Bcl-2 at both the protein and mRNA levels. In addition, knockdown of CREB sensitized MDA MB-231 cells to TRAIL-mediated cell death. These results suggest that PKCepsilon regulates Bcl-2 induction through activation of the transcription factor CREB. PMID- 20198333 TI - Immunohistochemical profiling of node negative breast carcinomas allows prediction of metastatic risk. AB - The aim of this study was to identify a prognostic immunohistochemical signature indicative of risk of early metastasis in node-negative breast carcinomas that would also be relevant to the development of new tailored therapy. Quantitative measurements of the immunohistochemical expression of 64 markers (selected from literature data) using high-throughput densitometry (as a continuous variable) of digitised microscopic micro-array images were correlated with clinical outcome in 667 node-negative breast carcinomas (mean follow-up 102 months). Multivariable fractional polynomials model of logistic regression allowed the selection of the best combination of markers (in terms of sensitivity and specificity) to predict patient outcome without any categorisation using predefined cut-points for individual marker measurements. A highly predictive ten-marker (out of 64) signature was identified comprising PI3K, pmTOR, pMAPKAPK-2, SHARP-2, P21, HIF 1alpha, Moesin, p4EBP-1, pAKT and P27 that well classified 91.4% of node-negative patients (specificity 90.9%, sensitivity 93.7%, area under ROC curve 0.958) independently of estrogen receptors (ER), and progesterone receptors (PR) and HER 2 status (91.6% well classified patients when ER, PR, HER-2 excluded). It is concluded that quantitative immunoprofiling of node-negative breast carcinomas is helpful in selecting patients who should not receive aggressive adjuvant chemotherapy and provides data for the development of tailored therapy. PMID- 20198334 TI - Overexpression of Apg-2 increases cell proliferation and protects from oxidative damage in BaF3-BCR/ABL cells. AB - Apg-2, a mammalian heat-shock protein belonging to the heat-shock protein 110 (Hsp110) family, was previously found to be overexpressed in BaF3-BCR/ABL cells that were treated with hydrogen peroxide (H2O2) through our comparative proteomics study. The expression of Apg-2 in chronic myelogenous leukemia (CML) cells and its role have not been investigated, forming the basis for this study. BaF3-MIGR1 and BaF3-BCR/ABL cell lines stably overexpressing Apg-2 were established and exposed to 50 microM H2O2 for 10 min. Western blot analysis of Apg-2 expression confirmed that H2O2 treatment significantly up-regulated Apg-2 expression. Apg-2 overexpression elevated BaF3-BCR/ABL cell proportions in S and G2/M phase, increased cell proliferation and colony formation in vitro. Moreover, BaF3-MIGR1 and BaF3-BCR/ABL cells were exposed to 50 microM H2O2 in the absence or presence of Apg-2 overexpression and induction of H2AX phosphorylation, the reporters of DNA damage were assessed by Western blot and immunofluorescence. Results showed that exposure to H2O2 induced H2AX phosphorylation in BaF3-MIGR1 cells, but no increase was observed in BaF3-BCR/ABL cells. Together, the data indicate that Apg-2 is overexpressed and overexpression of Apg-2 in BaF3-BCR/ABL cells increases cell proliferation and protects cells from oxidative damage, which may play an important role in CML carcinogenesis and progression. PMID- 20198335 TI - A new system for regulated functional gene expression for gene therapy applications: nuclear delivery of a p16INK4A-estrogen receptor carboxy terminal fusion protein only in the presence of estrogen. AB - The clinical use of gene therapy requires tight regulation of the gene of interest and functional expression only when it is needed. Thus, it is necessary to develop ways of regulating functional gene expression with exogenous stimuli. Many regulatable systems are currently under development. For example, the tetracycline-dependent transcriptional switch has been successfully employed for in vivo preclinical applications. However, there are no examples of regulatable systems that have been employed in human clinical trials. In the present study, we established an adenovirus-delivered functional gene expression system that is regulated by estrogen. This system uses p16INK4A fused at its C-terminus to the ligand-binding domain of the estrogen receptor (DeltaERalpha). We were able to establish cell lines expressing this gene wherein the functional expression of p16INK4A is estrogen-dependent and causes the arrest of several ovarian cancer cell lines. This inducible and adenovirus-mediated gene transfer system may allow gene therapy using nuclear functioning genes in postmenopausal or ovariectomized women. PMID- 20198336 TI - miR-221/222 promote malignant progression of glioma through activation of the Akt pathway. AB - MicroRNAs (miRNAs) are short regulatory RNAs that negatively modulate protein expression at a post-transcriptional level. Emerging evidence suggests that miRNAs play important roles in the pathogenesis of several types of cancers. However, the further mechanisms of miRNA remain unknown. In this study, we aimed to explore the coordinated function of miR-221/222 in glioma by bioinformatics and experiment methods. Bioinformatics analysis revealed that miR-221/222 had the potential to regulate about 70 common target genes and may exert a cooperative effect on regulation and function via Akt signaling pathway. Overexpression of miR-221/222 increased glioma cell proliferation and invasion in vitro and induced glioma growth in a subcutaneous mouse model. Furthermore, miR-221/222 overexpression resulted in an obvious activation of p-Akt and significant changes of Akt-related gene expression in glioma cells. Our results suggest that miR 221/222 co-enhance the glioma malignant phenotype via activation of the Akt pathway mediated by regulation of common gene expression. PMID- 20198337 TI - 17beta-estradiol induces up-regulation of PTEN and PPARgamma in leiomyoma cells, but not in normal cells. AB - The tumor suppressor protein, PTEN (phosphatase and tensin homologue), has been reported to play a crucial role in a variety of tumor cells. Recent studies indicate that the transcription factor, PPARgamma (peroxisome proliferator activated receptor gamma) up-regulates PTEN expression transcriptionally through the binding of two response elements in the genomic sequence upstream of PTEN in tumor cells. Here, we determined the PTEN and PPARgamma expression in human leiomyomas, and whether estrogen can change their protein expressions in cultured leiomyoma cells. Immunohistochemical staining and Western blot analysis revealed that PTEN protein levels in leiomyomas were higher than that the adjacent normal myometrial tissues, which was paralleled with decrease in phospho-Akt (ser-473) and phosphatidylinositol 3,4,5-tris phosphate (PIP3) level. Interestingly, leiomyomas exhibit high PPARgamma expression compared to the adjacent normal myometrial tissues. In addition, we found that 17beta-estradiol (E2) significantly stimulated PTEN and PPARgamma expression in cultured leiomyoma cells, but did not change both protein levels in normal cells. This report shows the first evidence that PTEN and PPARgamma are up-regulated in leiomyoma tissues, and estrogen stimulates expression of PTEN and PPARgamma in leiomyoma cells, but not in normal cells. PMID- 20198338 TI - Global screening and extended nomenclature for 230 aphidicolin-inducible fragile sites, including 61 yet unreported ones. AB - Since the first description of human fragile sites (FS) more than 40 years ago, a variety of substances were reported to induce chromosomal breaks at non-random, breakage-prone regions. According to information available from human genome browsers aphidicolin, an inhibitor of DNA replication induces 77 of 88 known common FS. However, in the literature additional FS are reported, which are also, at least in part, inducible by aphidicolin. To the best of our knowledge, here we present the first and largest ever done systematic, whole genome-directed and comprehensive screening for aphidicolin-inducible breakage-prone regions. The study was performed on stimulated peripheral blood lymphocytes of 3 unrelated healthy individuals. Twenty-five thousand metaphase spreads were analyzed and overall 22,537 FS located in 230 different loci were recorded. Sixty-one of those FS were never observed before and 52 were already previously reported but not included in genome browsers and yet verified. Interestingly, aphidicolin was able to induce all types of rare and common FS, suggesting that these breakage-prone regions are less dependent on the inducing chemicals than originally supposed. Overall, we provide the first comprehensive genome wide map for FS and studied possible correlations of chromosome length and GTG-banding level with FS frequency. To handle FS better in future, an extension of the already existing alphabetical nomenclature for FS on single chromosomes is suggested. PMID- 20198339 TI - Bile acid regulates MUC2 transcription in colon cancer cells via positive EGFR/PKC/Ras/ERK/CREB, PI3K/Akt/IkappaB/NF-kappaB and p38/MSK1/CREB pathways and negative JNK/c-Jun/AP-1 pathway. AB - MUC2 is a major secretory mucin normally expressed by goblet cells of the intestine, but is aberrantly expressed in colonic neoplasia. Bile acids have been implicated in colorectal carcinogenesis and, therefore, we sought to determine the effects of bile acids on MUC2 expression and regulation in colon cancer cells. Since deoxycholic acid (DCA), a secondary bile acid, has been reported to be a potent mucin secretagogue and tumor promoter, DCA-treated HM3 colon cancer cells were analyzed using promoter-reporter assays of the 5' flanking region of the MUC2 gene. Chemical inhibitors, mutant reporter constructs and EMSA showed that DCA upregulates MUC2 transcription via multiple pathways involving activation of EGFR/PKC/Ras/Raf-1/MEK1/ERK/CREB, PI3/Akt/IkappaB/NF-kappaB and p38/MSK1/CREB while DCA induced MUC2 transcription is inhibited by JNK/c-Jun/AP-1 pathway. These results provide new insight into the complex molecular mechanisms involved in the regulation of mucin gene by bile acids in colon cancer cells that may contribute to further elucidation of colorectal carcinogenesis. PMID- 20198340 TI - SIRT3 SNPs validation in 640 individuals, functional analyses and new insights into SIRT3 stability. AB - Sirtuins are critical players within multiple cellular pathways such as stress response, apoptosis and energy metabolism. They are associated with metabolic and degenerative diseases, the pathogenesis of cancer and are key elements in the regulation of cellular life span. From within the 7 known human sirtuins, SIRT3 recently stepped out of the shadow of SIRT1 showing strong effects on stress response, apoptosis, cell cycle and energy metabolism, mimicking effects of caloric restriction. We have identified two non-synonymous human SIRT3 SNPs and evaluated their impact on SIRT3 activity and stability. We assessed their influence on cellular energy metabolism in relation to SIRT1 and identified SIRT3 to increase cellular respiration by 80% when compared to SIRT1, which increased cellular respiration by only 30%. PMID- 20198341 TI - Isostrychnopentamine, an indolomonoterpenic alkaloid from Strychnos usambarensis, with potential anti-tumor activity against apoptosis-resistant cancer cells. AB - Isostrychnopentamine (ISP) is an indolomonoter-penic alkaloid that is present in the leaves of Strychnos usambarensis, an East African small tree. We have reported previously pro-apoptotic effects induced in vitro by ISP in the human HCT-116 colon cancer cell line, a model that displays relative sensitivity to apoptosis. In the present study, we observed that the in vitro growth inhibitory activities of ISP are similar in cancer cells that display sensitivity versus resistance to apoptosis. We made use of the U373 glioblastoma and the A549 non small cell lung cancer (NSCLC) cell lines as models relatively resistant to apoptosis, and the human PC-3 prostate cancer cell line as a model relatively sensitive to apoptosis. While ISP induced transient decreases in [ATP]i and apoptosis in human U373 GBM cells, it did not provoke such features in A549 NSCLC cells. It thus seems that ISP-induced anti-cancer activity can lead to pro apoptotic effects as a consequence, while apoptosis seems not to be the main cause by which ISP induces cancer cell death. ISP is a compound that merits further investigations in order to: i) identify the mechanism(s) of action by which it kills cancer cells, and ii) hemisynthesize novel ISP derivatives aiming to overcome, at least partly, the resistance of metastatic cancers to apoptosis. PMID- 20198342 TI - Effects of an EGFR-binding affibody molecule on intracellular signaling pathways. AB - Effects on intracellular signaling were studied in cells treated with the affibody molecule (ZEGFR:955)2 that targets the epithelial growth factor receptor (EGFR). EGFR is overexpressed in many types of cancers and plays a fundamental role in cell signaling and it is of interest to find targeting agents capable of blocking the receptor. The clinically approved antibody cetuximab (Erbitux) and the natural ligand EGF were included as reference molecules. Two EGFR-rich cell lines, A-431 and U-343, were exposed to the three targeting agents and lysed. The cell lysates were immunoprecipitated with the receptors, or directly separated by SDS-Page. Autophosphorylation of the receptors and phosphorylation of the downstream signaling proteins Erk and Akt, were evaluated by Western blotting. Although the three different agents compete for the same binding site on EGFR, they influenced the signaling differently. The affibody molecule did not induce autophosphorylation of EGFR or any other receptor in the EGFR-family but, in spite of this, induced phosphorylation of Erk in both cell lines and Akt in the A 431 cells. Thus, the results suggest that the signaling pattern induced by (ZEGFR:955)2 is only partly similar to that induced by cetuximab. This makes the affibody molecule a potentially interesting alternative to cetuximab for EGFR targeted therapy since it might give different therapy-related effects on tumor cells and different side effects on normal tissues. PMID- 20198343 TI - Mass spectrometric detection of candidate protein biomarkers of cancer cachexia in human urine. AB - Increased membrane permeability and myofibrillar protein breakdown are established features of cancer cachexia. Proteins released from cachectic muscle may be excreted in urine to act as biomarkers of the cachectic process. One dimensional SDS polyacrylamide gel electrophoresis followed by matrix-assisted laser desorption/ionisation or liquid chromatography tandem mass spectrometry was used to compare the protein content of urine from cachectic (>10% weight loss) (n=8) and weight-stable (n=8) gastro-oesophageal cancer patients and healthy controls (n=8). Plasma creatine kinase concentration was used as a marker of gross muscle breakdown. The number of protein species identified in cachectic samples (median 42; range 28-61; total 199) was greater than that identified in weight-stable cancer (median 15; range 9-28; total 79) and control samples (median 12.5; range 5-18; total 49) (P<0.001). Many of the proteins identified have not been reported previously in the urine of cancer patients. Proteins identified specifically in cachectic samples included muscle (myosin species), cytoskeletal (alpha-spectrin; nischarin) and microtubule-associated proteins (microtubule-actin crosslinking factor; microtubule-associated protein-1B; bullous pemphigoid antigen 1), whereas immunoglobulin kappa-light chain and zinc alpha-2 glycoprotein appeared to represent markers of cancer. The presence of myosin in urine (without an increase in plasma creatine kinase) is consistent with a specific loss of myosin as part of the cachectic process. Urinary proteomics using mass spectrometry can identify muscle-specific and non-muscle specific candidate biomarkers of cancer cachexia. PMID- 20198344 TI - Heterozygous TP53stop146/R72P fibroblasts from a Li-Fraumeni syndrome patient with impaired response to DNA damage. AB - The Li-Fraumeni syndrome (LFS) is a rare autosomal dominant hereditary cancer syndrome, characterized by a wide spectrum of neoplasms, occurring in children and young adults. The identification of germline TP53 mutations in LFS has given rise to a number of in vitro studies using cultures of cancer cells and non tumoral fibroblasts presenting germline TP53 mutations. In the present study, we performed a detailed documentation of the pedigree of an LFS family with a comprehensive analysis of genotype-phenotype correlations. We sequenced the TP53 gene and verified that the proband carries a germline nonsense mutation in codon 146 in one allele, the TP53Arg72Pro polymorphism in the second, and other intronic polymorphisms in the TP53 gene. In order to investigate the disruption of the p53 function in a patient presenting this mutation and the TP53Arg72Pro polymorphism who had so far suffered five malignant tumors and a benign meningioma, we tested her fibroblasts in response to DNA damage by evaluating the proliferation rate, apoptosis, and disruption of the TP53 pathway. The proband's heterozygous fibroblasts were not as efficient as control fibroblasts or those of her mother, who carried only the TP53Arg72Pro polymorphism, in causing cell arrest and cell death after DNA damage, which was correlated with diminished TP21 protein levels. PMID- 20198345 TI - The cell cycle effects of docosahexaenoic acid on human metastatic hepatocellular carcinoma proliferation. AB - Given the reported side effects associated with chemotherapy and surgical resection, dietary intervention with omega-3 polyunsaturated fatty acids (PUFAs) has been postulated to be an alterative way to prevent liver cancer progression and metastasis. We studied the effects of an omega-3 PUFA, docahexaenoic acid (DHA) on COX-2 expression and the cell cycle control machinery that co-ordinately regulate the HCC cells growth. Our data showed that DHA (0-200 microM) retarded proliferation of the human metastatic HCC cell line MHCC97L dose-dependently. In addition, inhibition of cyclin A/Cdk2 interfered with S-phase progression further in agreement with the result of bivariate flow cytometric analysis which indicated that DNA synthesis time (Ts) was significantly prolonged by DHA in MHCC97L. The N-myc oncogene, the heat shock proteins Hsp27 and glucose-related protein 78 (GRP78) as well as the antioxidant enzymes superoxide dismutase may play significant roles in the cell cycle control and reduced-proliferation of MHCC97L by DHA. Our data indicated that it is imperative to develop therapeutic strategy with omega-3 PUFA that simultaneously targets COX-2 and other cell cycle regulators in hepatocarcinogenesis. This study provides novel mechanistic insights into the modulation of DHA on human hepatocarcinoma. PMID- 20198346 TI - Synergistic antineoplastic effect of DLC1 tumor suppressor protein and histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), on prostate and liver cancer cells: perspectives for therapeutics. AB - Inactivation of tumor suppressor genes is a major contributing alteration in the initiation or progression of cancer. The human tumor suppressor gene DLC1 (deleted in liver cancer 1) is frequently downregulated or silenced in multiple cancers, predominantly by epigenetic mechanisms. With the current considerable interest and progress in epigenetic therapy, a number of promising antineoplastic agents, particularly histone deacetylase (HDAC) inhibitors, have been developed and used successfully in clinical trials. Both DLC1 and HDAC inhibitors exert antineoplastic functions, and their combined action could be exploited for a more effective cancer therapy. To evaluate the potential benefits of this approach, we examined the antineoplastic effects of adenoviral (Ad)-DLC1-mediated transduction and exposure to suberoylanilide hydroxamic acid (SAHA), a powerful HDAC inhibitor, in two human cancer cell lines that lack intrinsic DLC1 expression, 22Rv1 prostate cancer cells and 7703K human hepatocellular carcinoma cells. Consistent with the oncosuppressive function of DLC1 in several cancers, including prostate and liver cancer, transduction of 22Rv1 and 7703K cells with an Ad-DLC1 expression vector resulted in alterations of cell morphology, induction of apoptosis, and inhibition of cell proliferation, migration, and anchorage-independent growth. A low concentration of SAHA (5 microM) efficiently restored the expression of DLC1 in 22Rv1 cells that lack DLC1 expression due to histone deacetylation but had a minimal effect in 7703K cells in which silencing of the DLC1 gene is due mainly to promoter hypermethylation. Regardless of the epigenetic mechanism of DLC1 inactivation, SAHA treatment of DLC1-transduced cells had a synergistic inhibitory effect on tumor cell proliferation and tumorigenesis in both cell lines. In 22Rv1 cells, this combination regimen nearly abolished the formation of colonies in semisolid media as a measure of tumorigenicity in vitro. Current in vitro results validate this protocol as a potentially new therapeutic option in certain cancers. PMID- 20198347 TI - Differential effects of resveratrol and novel resveratrol derivative, HS-1793, on endoplasmic reticulum stress-mediated apoptosis and Akt inactivation. AB - Since resveratrol (3,4',5 tri-hydroxystilbene), which has been shown to inhibit multistage carcinogenesis, is not a potent cytotoxic compound, several studies were undertaken to obtain synthetic analogues of resveratrol with potent activity. We previously reported that a resveratrol derivative HS-1793 exhibits stronger antitumor effects than resveratrol in several cancer cell types. The present study was undertaken to reveal precise mechanism by which HS-1793 induces cell death. The induction of CCAAT/enhancer-binding protein-homologous protein (CHOP) and glucose-regulated protein (GRP)-78, and ER stress-specific XBP1 splicing were found in HT29 human colon carcinoma cells treated with resveratrol. Conversely, these manifestations were not observed in HT29 cells treated with HS 1793. Inhibition of caspase-4 activity by z-LEVD-fmk significantly reduced the induction of apoptosis by resveratrol but not by HS-1793. These findings suggest that HS-1793, contrary to resveratrol, does not induce ER stress-mediated apoptosis. Importantly, we observed that HS-1793 but not resveratrol decreased phosphorylated Akt level. We also demonstrated that HS-1793, compared to resveratrol, exerted more effective apoptosis inducing activity in Akt-activated cells. Taken together, the stronger antitumor activity of HS-1793 originates, at least in part, from its ability for Akt inactivation. PMID- 20198348 TI - Porcupine expression is associated with the expression of S100P and other cancer related molecules in non-small cell lung carcinoma. AB - The omicron-acyltransferase porcupine contributes to secretion and function of Wnt signaling molecules, which stimulate the expression of various cancer-related genes. Porcupine is also involved in the Wnt-induced cell signaling via beta catenin in non-small cell lung carcinoma (NSCLC) cells. Herein, we report that the expression level of porcupine in human NSCLC tissues (n=89) positively correlates with the expression of several genes coding for cancer-related molecules such as beta-catenin, hypoxia-inducible factor-1alpha and jun B. However, the mRNA expression of porcupine was not generally increased in NSCLC compared to normal lung tissues. In NSCLC tissues we also found a positive correlation between the expression level of porcupine and the calcium-binding protein S100P, which contributes to initiation and invasion of cancer cells. Subsequent studies showed that the DNA hypomethylation with 5-aza-2'deoxycytidine increased the mRNA expression of S100P in NSCLC cells but did not alter that of porcupine. Silencing the expression of porcupine with small interfering (si)RNA reduced the expression of S100P in NSCLC cells, whereas silencing the expression of S100P with siRNA did not effect the level of Porcupine expression. In conclusion, besides DNA methylation processes, porcupine might regulate the expression of some cancer-related molecules including S100P in human NSCLC. PMID- 20198349 TI - Reovirus infection induces apoptosis of TRAIL-resistant gastric cancer cells by down-regulation of Akt activation. AB - The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been used to treat a variety of cancer cells. However, since some gastric cancer cells are resistant to TRAIL, we explored whether reovirus induces cytolysis in TRAIL-resistant gastric cancer cells. We found that TRAIL-resistant SNU-216 gastric cancer cells were susceptible to apoptosis by reovirus infection. Furthermore, co-treatment with reovirus and TRAIL accelerated apoptosis of SNU 216 cells by down-regulation of Akt activation as assessed by a very low activation of Akt in TRAIL-sensitive SNU-668 gastric cancer cells. Inhibition of Akt signaling with wortmannin or suppression of Akt expression with sh-Akt lentivirus promoted reovirus-mediated apoptosis of SNU-216 gastric cancer cells. Reovirus infection also down-regulates the activation of signaling molecules such as Ras and ERK involved in cell proliferation and survival but not the activation of p38 MAPK involved in cellular stress. In addition, the co-treatment with reovirus and TRAIL resulted in cleavage of caspase-8, caspase-9 and Bid, leading to a decrease in the mitochondrial membrane potential, indicating that reovirus may utilize the mitochondrial intrinsic apoptotic pathway in TRAIL-resistant SNU 216 gastric cancer cells. Accordingly, we first demonstrate that reovirus infection down-regulates Akt activation, leading to apoptosis of TRAIL-resistant gastric cancer cells. PMID- 20198350 TI - Identification of a functional p53 responsive element within the promoter of XAF1 gene in gastrointestinal cancer cells. AB - It has been reported that XAF1 expression in gastric cancer is negatively correlated with p53. Our purpose was to clarify the regulatory mechanism of p53 on XAF1 expression. The effects of overexpressed wild-type and mutant p53 on XAF1 expression were evaluated. Binding capacity of core XAF1 promoter sequence to the recombinant p53 protein was examined. Site-directed mutation of putative p53 binding sequence and p53 knockdown by siRNA were performed. The protein expression and promoter activities of XAF1 in cells with null p53 were higher than that with wild-type and mutant p53. Ectopic overexpression of wild-type p53 suppressed XAF1 expression. A half-site (-95 to -86 nt) and a quarter-site (-4 to +1 nt) of p53 responsive element were found within XAF1 promoter. Both sequences bound to recombinant p53 effectively and specifically. Site-mutation of p53 responsive sequences abrogated the binding capacity. However, only the mutation of half-site increased XAF1 promoter activities. Suppression of p53 not only decreased the binding capacity of p53 responsive halfsite but also increased XAF1 transcription. In conclusion, we demonstrated that p53 could suppress the transcription of XAF1 through interaction with a high affinity responsive element (-95 to -86 nt) within XAF1 promoter, indicating a novel exclusive mechanism between these two tumor suppressors. PMID- 20198351 TI - Increase of the therapeutic effect by treating nasopharyngeal tumor with combination of HER-2 siRNA and paclitaxel. AB - Therapeutic agents targeting HER-2/neu have been intensively addressed over the past decades. Previously, we reported that HER-2 synthetic small interfering RNA (HER-2 siRNA) could suppress the growth of human nasopharyngeal KB tumor xenografts by intratumoral injection with lipid-based nanoparticles; however, complete regression of the tumor was not achieved. In this study, we investigated antitumor activity by RNA interference in combination with paclitaxel (PTX) for KB cells using HER-2 siRNA and HER-2 short hairpin RNA-expressing plasmid DNA (HER-2 shRNA pDNA). Suppression of HER-2 expression by siRNA or shRNA pDNA caused significant reduction of proliferation by inducing apoptosis and enhancing the sensitivity for PTX in HER-2 positive KB cells. Interestingly, an HER-2 antibody trastuzumab could not increase the antitumor effect by PTX in KB xenografts. Combination therapy by intratumoral injection of HER-2 siRNA or HER-2 shRNA pDNA with PTX significantly inhibited the tumor growth of xenografts compared with each therapy used individually. In particular, HER-2 shRNA pDNA plus PTX largely extended the mean survival days compared with HER-2 siRNA plus PTX. Collectively, these findings suggest that HER-2 shRNA-based combined therapy with PTX could be a novel strategy to inhibit the progression of HER-2-positive cancer. PMID- 20198353 TI - Freiburg neuropathology case conference: a diffusely infiltrating lesion. PMID- 20198354 TI - On our own behalf. PMID- 20198355 TI - The 20th year. PMID- 20198356 TI - Armin Thron. PMID- 20198357 TI - [Sexual addiction? When sexual behavior gets out of control]. AB - The authors differentiates deviant (paraphilic) and non-deviant forms of a sexual addictive symptomatology. For the non-deviant forms, the diagnostic term paraphilia-related disorder is used. According to etiological factors, the authors discuss an interaction of a biological vulnerability, attachment and relationship problems, disorders of affect regulation as well as disinhibition of sexual excitation. Some individuals react to negative emotions, like depression or anxiety, with an increased sexual arousal. They may try to cope with negative emotions by being sexually active. However, the importance of the sexual stimulus itself should not be ignored. The authors describe specific psychotherapy, the attendance of self-help groups, and pharmacological treatment, especially with selective serotonin reuptake inhibitors. PMID- 20198358 TI - [Medication dependency and physician's role]. AB - The administration of benzodiazepines in suicidal, anxious, or agitated patients with depression is common international practice. Nevertheless, the prescription of BZDs is recommended to be limited to a period of a few weeks. There are several epidemiological studies about the situation in Germany, but many questions are still unanswered. The BfArM sought a new method to track prescription of medications with the risk to induce dependency. The present article describes the methodology and the early results of the pilot study. As a new approach, data from a processing center for pharmacies were used; patient years, a risk scale with six steps, and diazepam-equivalence dose instead of defined daily dose were used for the analysis. About 35% of prescriptions were long-term treatment. Even if several physicians prescribe the medication, the main physician prescribing the medication can identify the risk level of the patient in 80-90% of cases. PMID- 20198359 TI - [Medical education in otorhinolaryngology in Germany. Implementation of the new licensing regulations for physicians]. AB - BACKGROUND: In 2003 new regulations for the licensing of German physicians came into effect. The aim of this study was to survey the present status of realization in German otorhinolaryngology (ORL) university departments. METHODS: A questionnaire containing 31 items was sent to all German ORL university departments. RESULTS: A total of 31 (86%) ORL departments responded to the questionnaire. Most faculties reacted correctly in the practical realization of the new regulation demands. Regarding the quality of written and practical examinations, some changes have to be considered in order to maintain high quality standards. CONCLUSION: The demands of the new licensing regulations have not yet been fully implemented. Therefore, medical education must gain importance in the daily clinical routine. Establishment of nationwide learning objectives and resources pooling for written examinations would be helpful. PMID- 20198360 TI - [Tinnitus and psychological comorbidities]. AB - Comorbidity is the presence of one or more disorders in addition to the main disorder. Comorbidities negatively influence the development of the main disease. For patients with tinnitus a comorbidity is an additional component complicating the habituation of ear noise and patients with decompensated tinnitus often have psychological comorbidities, e.g. affective, somatoform or anxiety disorders. At the time of first presentation and also during further follow-up, it is essential to pay particular attention to the presence of potential comorbid mental disorders. This is of special importance for patients with decompensated ear noise (severity grades 3 and 4). For ENT specialists it is important that the mental discomfort of patients must be taken seriously and should be identified through a targeted diagnosis. Effective treatment of the co-symptoms using cognitive behavior therapy (CBT) in conjunction with medication often reduces the severity of tinnitus perception and discomfort. PMID- 20198362 TI - Seventeen-year observation on urinary cadmium and beta2-microglobulin in inhabitants after cessation of cadmium-exposure in Japan. AB - The purpose of this study was to clarify the change and relationship of urinary cadmium (Cd) and beta(2)-microglobulin (beta(2)-MG) concentrations of inhabitants in Cd-polluted areas after soil restoration. The urinary Cd and beta(2)-MG concentrations of 25 males and 28 females did not show a significant change, 22 years after the Cd-polluted soil was restored. Once exposed to Cd, it was found to remain in the body, 22 years after the Cd -polluted soil was restored. However, this did not influence renal tubular dysfunction in most of the younger generation compared with elders heavily exposed to Cd. PMID- 20198361 TI - Global microRNA expression profiles in insulin target tissues in a spontaneous rat model of type 2 diabetes. AB - AIMS/HYPOTHESIS: MicroRNAs regulate a broad range of biological mechanisms. To investigate the relationship between microRNA expression and type 2 diabetes, we compared global microRNA expression in insulin target tissues from three inbred rat strains that differ in diabetes susceptibility. METHODS: Using microarrays, we measured the expression of 283 microRNAs in adipose, liver and muscle tissue from hyperglycaemic (Goto-Kakizaki), intermediate glycaemic (Wistar Kyoto) and normoglycaemic (Brown Norway) rats (n = 5 for each strain). Expression was compared across strains and validated using quantitative RT-PCR. Furthermore, microRNA expression variation in adipose tissue was investigated in 3T3-L1 adipocytes exposed to hyperglycaemic conditions. RESULTS: We found 29 significantly differentiated microRNAs (p(adjusted) < 0.05): nine in adipose tissue, 18 in liver and two in muscle. Of these, five microRNAs had expression patterns that correlated with the strain-specific glycaemic phenotype. MiR-222 (p(adjusted) = 0.0005) and miR-27a (p(adjusted) = 0.006) were upregulated in adipose tissue; miR-195 (p(adjusted) = 0.006) and miR-103 (p(adjusted) = 0.04) were upregulated in liver; and miR-10b (p(adjusted) = 0.004) was downregulated in muscle. Exposure of 3T3-L1 adipocytes to increased glucose concentration upregulated the expression of miR-222 (p = 0.008), miR-27a (p = 0.02) and the previously reported miR-29a (p = 0.02). Predicted target genes of these differentially expressed microRNAs are involved in pathways relevant to type 2 diabetes. CONCLUSION: The expression patterns of miR-222, miR-27a, miR-195, miR 103 and miR-10b varied with hyperglycaemia, suggesting a role for these microRNAs in the pathophysiology of type 2 diabetes, as modelled by the Gyoto-Kakizaki rat. We observed similar patterns of expression of miR-222, miR-27a and miR-29a in adipocytes as a response to increased glucose levels, which supports our hypothesis that altered expression of microRNAs accompanies primary events related to the pathogenesis of type 2 diabetes. PMID- 20198363 TI - Involvement of central beta2-adrenergic, NMDA and thromboxane A2 receptors in the pressor effect of anandamide in rats. AB - Intravenous (i.v.) injection of the endocannabinoid anandamide induces triphasic cardiovascular responses, including a pressor effect mediated via unknown central and peripheral mechanism(s). The aim of the present study was to determine the central mechanism(s) responsible for the pressor response to anandamide. For this purpose, the influence of antagonists at thromboxane A(2) TP (sulotroban, daltroban, SQ 29548), NMDA (MK-801) and beta(2)-adrenergic receptors (ICI 118551) on the pressor effect induced by i.v. and intracerebroventricularly (i.c.v.) administered anandamide was examined in urethane-anaesthetized rats. Anandamide (1.5-3 micromol/kg, i.v.) or its stable analogue methanandamide (0.75 micromol/kg, i.v.) increased blood pressure by 25%. Anandamide (0.03 mumol per animal i.c.v.) caused a pure pressor effect (by 20%) but only in the presence of antagonists of CB(1) and TRPV1 receptors. The effects of cannabinoids (i.v. or i.c.v.) were diminished by i.v. daltroban, sulotroban (10 mumol/kg each), and/or SQ 29548 (1 mumol/kg). The effect of anandamide i.v. was reduced by SQ 29548 (0.02 mumol per animal i.c.v.) and by the thromboxane A(2) synthesis inhibitor furegrelate i.c.v. (1.8 micromol per animal). ICI 118551, MK-801 (1 micromol/kg i.v. each), and bilateral adrenalectomy diminished the effect of anandamide i.c.v. Sulotroban (i.v.) failed to affect the response to anandamide (i.v.) in pithed rats, and anandamide and methanandamide did not bind to TP receptors in rat platelets. The present study suggests that central beta(2)-adrenergic, NMDA and thromboxane A(2) receptors are involved in the anandamide-induced adrenal secretion of catecholamines and their pressor effect in urethane-anaesthetized rats. PMID- 20198364 TI - Kinematic redundancy and variance of eye, head and trunk displacements during large horizontal gaze reorientations in standing humans. AB - Shifting the direction of the line of sight in everyday life often involves rotations not only of the eyes and head but also of the trunk. Here, we investigated covariation patterns of eye-in-orbit, head-on-trunk and trunk-in space angular horizontal displacements during whole-body rotations to targets of up to 180 degrees eccentricity performed by standing healthy human subjects. The spatial covariation was quantified statistically across various behavioral task conditions (unpredictable, memory driven predictable, visual feedback) and constraints (accuracy) by principal components (PC) analysis. Overall, the combined movement was stereotyped such that the first two PCs accounted for essentially the whole data variance of combined gaze transfers up to about 400 ms, suggesting that the three mechanical degrees of freedom under consideration are reduced to two kinematic degrees of freedom. Moreover, quantification of segment velocity variability across repetitions showed that velocities of eye-in space and head-in-space (i.e. 'end-point' velocity) were less variable than those of the elemental variables composing them. In contrast, three statistically significant PCs accounted for the covariation of the three segments during presumably vestibularly mediated nystagmic transfers, suggesting control by a separate driving circuit. We conclude that progression of the line of sight is initially stereotypic and fulfills criteria defining a motor synergy. PMID- 20198365 TI - Adaptation of egocentric distance perception under telestereoscopic viewing within reaching space. AB - Telestereoscopic viewing provides a method to distort egocentric distance perception by artificially increasing the interpupillary distance. Adaptation to such a visual rearrangement is little understood. Two experiments were performed in order to dissociate the effects of a sustained increased vergence demand, from those of an active calibration of the vergence/distance mapping. Egocentric distances were assessed within reaching space through open-loop pointing to small targets in the dark. During the exposure condition of the first experiment, subjects were instructed to point to the targets without feedback, whereas in the second experiment, hand visual feedback was available, resulting in a modified relationship between vergence-specified distance and reach distance. The visual component of adaptation in the second experiment was assessed on the unexposed hand. In the post-tests of both experiments, subjects exhibited a constant distance overestimation across all targets, with a more than twice larger aftereffect in the second one. These findings suggest two different processes: (1) an alteration in the vergence effort following sustained increased vergence; (2) a calibration of the vergence/distance mapping uncovering the visual component of adaptation. PMID- 20198367 TI - Enhancing the prebiotic relevance of a set of covalently self-assembling, autorecombining RNAs through in vitro selection. AB - An in vitro form of the self-splicing group-I intron interrupting the Azoarcus tRNA(Ile) was shortened by ~10% with the removal of helix P6a. This deletion reduced the reverse-splicing activity of the ribozyme about 10-fold. Through in vitro selection, this activity was restored in several low-error mutants. A number of mutations were found that improved reverse-splicing activity through both increased k (obs) and better folding. The deletion mutant could be fragmented into as many as three discrete pieces, which, when incubated together, were capable of covalent self-assembly through energy-neutral transesterification reactions, a process called autorecombination. A subset of the mutations identified through in vitro selection for reverse-splicing were exaptations in that they were also shown to augment the autorecombination reactions, leading to higher yields of covalently self-assembled products, making this the smallest such system yet discovered. PMID- 20198369 TI - Changes in pelagic bacteria communities due to leaf litter addition. AB - In many limnetic systems, the input of allochthonous organic matter, e.g., leaf litter, is a substantial source of dissolved organic carbon (DOC) for pelagic bacteria, especially in fall and winter when autochthonous DOC production is low. However, relatively little is known about community changes of pelagic lake bacteria due to leaf litter input which includes both the release of leaf leachates and microorganisms from the leaf litter into the surrounding water. Therefore, we have experimentally studied the effects of different types of leaf litter (Betula pendula, Fagus silvatica, and Pinus silvestris) on the pelagic bacterial community composition by adding leaves to different treatments of epilimnic water samples (unfiltered, 0.2 um and 5.0 um-pre-filtered) from humic Lake Grosse Fuchskuhle (Northeastern Germany). The addition of leaf litter led to a significant increase in DOC concentration in lake water, and each leaf litter type produced significantly different amounts of DOC (p = <0.001) as well as of specific DOC fractions (p = <0.001), except of polysaccharides. DGGE banding patterns varied over time, between types of leaf litter, and among treatments. Bacteria belonging to known bacterial phylotypes in the southwest basin of Lake Grosse Fuchskuhle were frequently found and even persisted after leaf litter additions. Upon leaf litter addition, alpha-proteobacteria (Azospirillum, Novosphingobium, and Sphingopyxis) as well as beta-proteobacteria (Curvibacter and Polynucleobacter) were enriched. Our results indicate that supply of leaf litter DOM shifted the bacterial community in the surrounding water towards specific phylotypes including species capable of assimilating the more recalcitrant DOC pools. Statistical analyses, however, show that DGGE banding patterns are not only affected by DOC pools but also by treatment. This indicates that biological factors such as source community and grazing may be also important for shifts in bacterial community structure following leaf litter input into different lakes. PMID- 20198371 TI - Amylase concentration of the drainage fluid as a risk factor for intra-abdominal abscess following gastrectomy for gastric cancer. AB - BACKGROUND: Insertion of drainage tubes at gastric cancer surgery could be useful for the prediction and management of postoperative complications. However, drains should be removed as soon as they are deemed unnecessary for various reasons. Amylase concentration of the drainage fluid following total gastrectomy for gastric cancer has been reported to be a useful risk factor for surgical complications. METHODS: Between January 2002 and December 2008, the authors measured amylase concentration of the drainage fluid on the first postoperative day for 372 patients who underwent gastrectomy with lymphadenectomy for gastric cancer at the Department of Surgery II, Nagoya University. Univariate and multivariate analyses were performed to evaluate the significance of various covariates as risk factors for the pancreas-related complications. RESULTS: Postoperative complications developed in 111 patients, of which 27 were pancreas related. Amylase concentration was significantly higher in patients who underwent splenectomy, pancreaticosplenectomy, total/proximal gastrectomies, and extended lymphadenectomy and in those who eventually developed intra-abdominal abscess. Amylase concentration > or =1,000 IU/l on the first postoperative day, along with the body mass index, was an independent risk factor for pancreas-related intra abdominal abscess. CONCLUSIONS: With a negative predictive value of 97.7%, pancreas-related complications are highly unlikely to be observed when amylase concentration is less than 1,000 IU/l, and early removal of the drainage tube could be recommended for these patients. PMID- 20198372 TI - Phase II trial of induction irinotecan-cisplatin followed by concurrent irinotecan-cisplatin and radiotherapy for unresectable, locally advanced gastric and oesophageal-gastric junction adenocarcinoma. AB - PURPOSE: The prognosis of patients with unresectable M0 gastric cancer remains very poor. We performed a phase II trial to explore the efficacy and toxicity of induction irinotecan-cisplatin (IC) followed by concurrent irinotecan-cisplatin and radiotherapy (IC/RT) in this setting. METHODS AND MATERIALS: Patients with unresectable M0 gastric (GC) or oesophageal-gastric junction (EGJC) adenocarcinomas were treated with two courses of IC (irinotecan, 65 mg/m(2); cisplatin, 30 mg/m(2) on days 1 and 8 every 21 days) followed by IC/RT (daily radiotherapy-45 Gy-with concurrent IC: irinotecan, 65 mg/m(2), and cisplatin, 30 mg/m(2), on days 1, 8, 15, and 22). Resectability was reassessed after this treatment, and surgical resection was performed if feasible. The primary endpoint was the R0 resection rate after induction treatment. RESULTS: Seventeen patients were included in the study (EGJC: 6; GC: 11). An R0 resection was achieved in only 5 patients (29%), and according to the design of the trial (Simon's optimal two-stage) accrual of patients was terminated after the first stage. No patient died during IC, whereas 3 patients (24%) died during IC/RT and one of 5 resected patients (20%) died during the first 30 days after resection. The median survival was 10.5 months, and the actuarial 2-year survival rate was 27%. CONCLUSIONS: Induction IC followed by IC/RT showed poor efficacy and significant toxicity in patients with unresectable GC/EGJC. PMID- 20198373 TI - Oxygen-dependence of metabolic rate in the muscles of craniates. AB - We present evidence that oxygen consumption (VO2) is oxygen partial pressure (PO2)dependent in striated muscles and PO2-independent in the vasculature in representatives of three craniate taxa: two teleost fish, a hagfish and a rat. Blood vessel VO2 displayed varying degrees of independence in a PO2 range of 15 95 mmHg, while VO2 by striated muscle tissue slices from all species related linearly to PO2 between 0 and 125 mmHg, despite VO2 rates varying greatly between species and muscle type. In salmon red muscle, lactate concentrations fell in slices incubated at a PO2 of either 30 or 100 mmHg, suggesting aerobic rather than anaerobic metabolism. Consistent with this finding, potential energy, a proxy of ATP turnover, was PO2-dependent. Our data suggest that the reduction in VO2 with falling PO2 results in a decrease in ATP demand, suggesting that the hypoxic signal is sensed and cellular changes effected. Viability and diffusion limitation of the preparations were investigated using salmon cardiac and skeletal muscles. Following the initial PO2 depletion, reoxygenation of the Ringer bathing salmon cardiac muscle resulted in VO2S that was unchanged from the first run. VO2 increased in all muscles uncoupled with p-trifluoromethoxylphenyl hydrazone (FCCP) and 2,4-dinitrophenol (DNP). Mitochondrial succinate dehydrogenase activity, quantified by reduction of 3-(4,5-dimethylthiazol)-2,5 diphenyl-2H-tetrazolium bromide (MTT) to formazan, was constant over the course of the experiment. These three findings indicate that the tissues remained viable over time and ruled out diffusion-limitation as a constraint on VO2. PMID- 20198374 TI - Bioelectrical activity in the heart of the lugworm Arenicola marina. AB - Standard microelectrode technique was used to study electrical activity of the isolated heart of the polychaete annelid, Arenicola marina. Typical pacemaker activity with slow diastolic depolarization was observed in all recordings. The average maximum diastolic potential (-58.4 +/- 3.2 mV), the average amplitude of the action potential (28.7 +/- 4.7 mV) and the average total duration of the action potential (2,434 +/- 430 ms) were determined. There has been no gradient of automaticity observed in our studies, which suggests that all regions of the Arenicola heart could possess pacemaker functions. Acetylcholine (ACh) produced a concentration dependent (5 x 10(-8)-5 x 10(-5) M) increase of the beating rate via increase in the rate of the diastolic depolarization. ACh (5 x 10(-5) M) increased beating rate by 2.5-fold compared to the control rate. A stronger action of ACh resulted in depolarization, block of action potential generation and contracture of the heart. The non-hydrolysable ACh analog carbacholine (10( 8)-10(-6) M) produced similar effects. All effects of ACh and carbacholine were abolished by 5 x 10(-6) M atropine. D-Tubocurarine (5 x 10(-5) M) did not significantly alter effects of ACh or carbacholine. Epinephrine (10(-8)-10(-6) M) caused the slowing of pacemaker activity and marked decrease of action potential duration. 10(-6) M epinephrine produced complete cardiac arrest. The effects of epinephrine were not significantly altered by the beta-blocker propranolol (5 x 10(-6) M). The beta-agonist isoproterenol (10(-7)-10(-5) M) and the alpha-agonist xylometazoline (10(-6)-10(-5) M) did not produce significant effects. Thus, cholinergic effects in the Arenicola heart are likely to be mediated via muscarinic receptors, while the nature of adrenergic effects needs further investigation. PMID- 20198375 TI - The clinical spectrum of Blake's pouch cyst: report of six illustrative cases. AB - INTRODUCTION: Although Blake's pouch cyst (BPC) is frequently mentioned in the spectrum of posterior fossa cysts and cystlike malformations since its first description in 1996, its natural history, clinical presentation, specific imaging characteristics, optimal treatment, and outcome are relatively unknown. Consequently, BPC may still be underdiagnosed. We therefore report six cases ranging from a fatal hydrocephalus in a young boy, over an increasing head circumference with or without impaired neurological development in two infants, to a decompensating hydrocephalus at an advanced age. DISCUSSION: We focus on their radiological uniformity, which should help making the correct diagnosis, and widely variable clinical presentation, which includes adult cases as well. Differentiating BPC from other posterior fossa cysts and cystlike malformations and recognizing the accompanying hydrocephalus are essentially noncommunicating, not only have important implications on clinical management but also on genetic counseling, which is unnecessary in case of BPC. In our experience, endoscopic third ventriculostomy is a safe and effective treatment option, avoiding the risks and added morbidity of open surgery, as well as many shunt-related problems. PMID- 20198376 TI - Priorities of elderly dizzy patients in general practice. Findings and psychometric properties of the"Dizziness Needs Assessment" (DiNA). AB - BACKGROUND: Dizziness as a geriatric syndrome needs to be assessed using a multi dimensional, patient-centred approach in addition to a disease-orientated strategy. The aim of the study was to determine the priorities of elderly patients by a specific needs questionnaire, the"Dizziness Needs Assessment" (DiNA), and to evaluate its psychometric properties. METHODS: General practitioners (GPs) distributed questionnaires containing the DiNA as well as the Patients' Intentions Questionnaire (PIQ) to patients aged at least 65 years and suffering from dizziness. Items of both questionnaires were analysed by frequencies, means and rank correlations. Factor structure was explored by principal component analysis. RESULTS: A total of n=123 patients (mean age 76 years, 73% women) had suffered from dizziness on average for more than 3 years (57% chronic, i.e. >6 months). Knowing the cause of the dizziness was rated as very important by patients, and about half of them wished that their doctor would make more effort to investigate this. Among other differences, chronically dizzy patients ranked the risk of falling significantly higher than those with acute dizziness. Factor analysis revealed four subscales: "handicap and mobility" showed a very good reliability of 0.77 (Cronbach's alpha), indicating a "trait", whereas the other subscales rather indicated "state" characteristics. Validation coefficients showed that PIQ assesses general patient needs compared to the more specific dizziness-related needs revealed by the DiNA. CONCLUSION: The DiNA proved to be a valuable instrument to assess the specific priorities of elderly patients suffering from dizziness. Regarding the limited therapy options for dizziness in old age, a doctor-guided shift of patients' attention from causes to symptom-related implications could be a promising approach. PMID- 20198377 TI - [Stored electrograms in pacemakers and ICD systems from the Sorin Group]. AB - Stored electrograms (EGMs) can improve therapy with pacemakers and ICDs by detecting technical problems (e.g., over- or undersensing) and medical problems (e.g., atrial tachyarrhythmias). Analysis of stored EGMs and their interpretation requires knowledge about EGM recording (e. g., channels, summation EGM) and marker annotations. This review presents stored EGMs in pacemaker and ICD systems from the Sorin Group with tips on the potential and interpretation of memory capabilities. PMID- 20198379 TI - A common FMO3 polymorphism may amplify the effect of nicotine exposure in sudden infant death syndrome (SIDS). AB - Smoking during pregnancy has been identified as one of the major modifiable risk factors of sudden infant death syndrome (SIDS). It has been demonstrated that the risk of SIDS increases with increasing cigarette consumption. A variety of hypotheses have been proposed for explanation, including a genetic predisposition. The flavin-monooxygenase 3 (FMO3) is one of the enzymes metabolising nicotine, and several polymorphisms have already been described in this gene. Here, we studied variations in the exons and introns of the FMO3 gene by direct sequencing analysis and minisequencing in 159 SIDS cases and 170 controls. The three common variants G472A (E158K), G769A (V257M) and A923G (E308G) in the exons of the FMO3 gene were identified. The homozygote 472AA genotype occurred more frequently in SIDS cases than in controls (p = 0.0054) and was more frequent in those SIDS cases for which the mothers reported heavy smoking (p = 0.0084). This study is the first to demonstrate a gene-environment interaction in SIDS. The findings suggest that the common polymorphism G472A of FMO3 could act as an additional genetic SIDS risk factor in children whose mothers smoke. Parents who could pass on the 472A allele should be informed of the increased risk associated with smoking. Smoking mothers should be strongly advised to give up smoking during pregnancy and for at least the first year of the child's life. PMID- 20198380 TI - Age estimation in children by measurement of open apices in teeth: an Indian formula. AB - The aim of this paper is twofold: first, to evaluate an Indian sample by Cameriere's European formula; and second, if this formula turns out to be unsuitable, to study a specific formula for Indian children. Orthopantomographs taken from 480 Indian children (227 girls and 253 boys) aged between 3 and 15 years were analyzed. Following the pilot study, subjects' age was modeled as a function of gender (g), region of country (C), and morphological variables (predictors: x (5), the distance between the inner sides of the open apex of the second premolar divided by the tooth length; s=x1+x2+x3+x4+x5+x6+x7, sum of normalized open apices; N (0,) the number of teeth with root development complete. Results showed that all these variables except gender and second premolar contributed significantly to the fit so that all were included in the regression model, yielding the following linear regression formula: Age=9.402 0.879C+0.663 N0-0.711s-0.106s N0 where C is a dummy variable equal to 0 for the center or north of India and 1 for the south. The above equation, with the variables considered, explained 89.7% (R (2) = 0.897) of total deviance. The median of the residuals (observed age minus predicted age) was -0.063 years, with an interquartile range of 1.10 years. PMID- 20198381 TI - Imaging results in a consecutive series of 530 new patients in the Birmingham Headache Service. AB - Guidelines recommend imaging only headache patients with sinister features in the history or on examination. We prospectively collected data on imaging newly presenting patients to a UK headache service. CT and MRI results were classified as normal or showing an insignificant or significant abnormality. Over 5 years, 3,655 new patients (69% female; mean age 42.0 years) with headache disorders were seen. Five hundred thirty (14.5%) underwent imaging with large differences in the proportion referred by each consultant. There were more insignificant abnormalities on MRI (46%) than CT (28%). There were 11 significantly abnormal results (2.1% of those imaged). Significant abnormalities were found in patients diagnosed with migraine in 1.2% and in 0.9% of those with tension-type headache. Significant abnormalities in those suspected to have an intracranial abnormality occurred in 5.5%. This supports the practice of selecting patients with suspicious findings for imaging, rather than imaging all patients. PMID- 20198382 TI - Corpus callosum index and long-term disability in multiple sclerosis patients. AB - Prediction of long-term disability in patients with multiple sclerosis (MS) is essential. Magnetic resonance imaging (MRI) measurement of brain volume may be of predictive value but sophisticated MRI techniques are often inaccessible in clinical practice. The corpus callosum index (CCI) is a normalized measurement that reflects changes of brain volume. We investigated medical records and 533 MRI scans at diagnosis and during clinical follow-up of 169 MS patients (mean age 42 +/- 11 years, 86% relapsing-remitting MS, time since first relapse 11 +/- 9 years). CCI at diagnosis was 0.345 +/- 0.04 and correlated with duration of disease (p = 0.002; r = -0.234) and expanded disability status scale (EDSS) score at diagnosis (r = -0.428; p < 0.001). Linear regression analyses identified age, duration of disease, relapse rate and EDSS at diagnosis as independent predictors for disability after mean of 7.1 years (Nagelkerkes' R:0.56). Annual CCI decrease was 0.01 +/- 0.02 (annual tissue loss: 1.3%). In secondary progressive MS patients, CCI decrease was double compared to that in relapsing-remitting MS patients (p = 0.04). There was a trend of greater CCI decrease in untreated patients compared to those who received disease modifying drugs (p = 0.2). CCI is an easy to use MRI marker for estimating brain atrophy in patients with MS. Brain atrophy as measured with CCI was associated with disability progression but it was not an independent predictor of long-term disability. PMID- 20198383 TI - National estimates of blood lead, cadmium, and mercury levels in the Korean general adult population. AB - OBJECTIVES: To assess the extent of exposure to lead, cadmium, and mercury in the Korean general adult population using a representative sample. METHODS: We studied blood concentrations of three heavy metals in a representative sample of 1,997 Koreans as part of the Third Korean National Health and Nutrition Examination Survey (KNHANES III) performed in 2005. RESULTS: The geometric means of the blood lead, cadmium, and mercury concentrations were 2.61 MUg/dL, 1.53 MUg/L, and 4.15 MUg/L, respectively [95% confidence intervals (CIs), 2.50-2.71, 1.48-1.58, and 3.94-4.36, respectively]. Women had significantly lower blood lead and mercury concentrations in adjusted and unadjusted analyses but no difference between genders was observed in blood cadmium analysis. The geometric means of blood lead and mercury levels were higher in subjects older than 40 years than in those younger than 40 years. Smoking status only affected the blood lead concentration, with this being higher in smokers than in nonsmokers. Blood cadmium levels did not differ with demographic and lifestyle variables after covariate adjustment. Blood mercury concentrations were higher in those who consumed alcohol and also increased with the frequency of fish consumption. CONCLUSIONS: This biomonitoring study of blood heavy metals in the Korean general population as part of KNHANES III provides important reference data stratified by demographic and lifestyle factors that will be useful for the ongoing surveillance of environmental exposure of the Korean general population to heavy metals. PMID- 20198384 TI - Effect of menstrual cycle phase on sprinting performance. AB - This study examined the effects of menstrual cycle phase (MCP) upon sprinting and recovery as well as upon metabolic responses to such exercise. Eight females performed a repeated 30-s sprint on a non-motorised treadmill interspersed with a 2-min rest in three phases of the MCP, follicular (low 17beta-estradiol and progesterone), just prior to ovulation (midcycle trial, highest 17beta-estradiol concentration and low progesterone) and in the luteal phase (high 17beta estradiol and high progesterone). MCP was verified later by radioimmunoassay of 17beta-estradiol and progesterone. Peak power output (PPO) and mean power output (MPO) were unaltered (P > 0.05) due to MCP [PPO for sprint 1: 463 (18) W vs. 443 (15) W vs. 449 (18) W; PPO for sprint 2: 395 (17) W vs. 359 (16) W vs. 397 (17) W; MPO for sprint 1: 302 (15) W vs. 298 (13) W vs. 298 (14) W; MPO for sprint 2: 252 (10) W vs. 248 (10) W vs. 259 (12) W for follicular, midcycle and luteal trial, mean (SEM), respectively]. Similarly, percentage recovery of PPO and MPO (the PPO or MPO during sprint 2 expressed as a percentage of the PPO or MPO during sprint 1) was also unchanged (P > 0.05). Blood lactate, blood pH and plasma ammonia after sprinting and estimated plasma volume were also unaltered by MCP (P > 0.05). These findings suggest that hormonal fluctuations due to MCP do not interfere with maximal intensity whole body sprinting and the metabolic responses to such exercise. PMID- 20198385 TI - External divalent cations increase anion-cation permeability ratio in glycine receptor channels. AB - The functional role of ligand-gated ion channels in the central nervous system depends on their relative anion-cation permeability. Using standard whole-cell patch clamp measurements and NaCl dilution potential measurements, we explored the effect of external divalent ions on anion-cation selectivity in alpha1 homomeric wild-type glycine receptor channels. We show that increasing external Ca(2+) from 0 to 4 mM resulted in a sigmoidal increase in anion-cation permeability by 37%, reaching a maximum above about 2 mM. Our accurate quantification of this effect required rigorous correction for liquid junction potentials (LJPs) using ion activities, and allowing for an initial offset potential. Failure to do this results in a considerable overestimation of the Ca(2+)-induced increase in anion-cation permeability by almost three-fold at 4 mM external Ca(2+). Calculations of LJPs (using activities)_ were validated by precise agreement with direct experimental measurements. External SO (4) (2-) was found to decrease anion-cation permeability. Single-channel conductance measurements indicated that external Ca(2+) both decreased Na(+) permeability and increased Cl(-) permeability. There was no evidence of Ca(2+) changing channel pore diameter. Theoretical modeling indicates that the effect is not surface charge related. Rather, we propose that, under dilution conditions, the presence of an impermeant Ca(2+) ion in the channel pore region just external to the selectivity filter tends to electrostatically retard outward movement of Na(+) ions and to enhance movement of Cl(-) ions down their energy gradients. PMID- 20198386 TI - A novel collagen scaffold supports human osteogenesis--applications for bone tissue engineering. AB - Collagen glycosaminoglycan (CG) scaffolds have been clinically approved as an application for skin regeneration. The goal of this study has been to examine whether a CG scaffold is a suitable biomaterial for generating human bone tissue. Specifically, we have asked the following questions: (1) can the scaffold support human osteoblast growth and differentiation and (2) how might recombinant human transforming growth factor-beta (TGF-beta(1)) enhance long-term in vitro bone formation? We show human osteoblast attachment, infiltration and uniform distribution throughout the construct, reaching the centre within 14 days of seeding. We have identified the fully differentiated osteoblast phenotype categorised by the temporal expression of alkaline phosphatase, collagen type 1, osteonectin, bone sialo protein, biglycan and osteocalcin. Mineralised bone formation has been identified at 35 days post-seeding by using von Kossa and Alizarin S Red staining. Both gene expression and mineral staining suggest the benefit of introducing an initial high treatment of TGF-beta(1) (10 ng/ml) followed by a low continuous treatment (0.2 ng/ml) to enhance human osteogenesis on the scaffold. Osteogenesis coincides with a reduction in scaffold size and shape (up to 70% that of original). A notable finding is core degradation at the centre of the tissue-engineered construct after 49 days of culture. This is not observed at earlier time points. Therefore, a maximum of 35 days in culture is appropriate for in vitro studies of these scaffolds. We conclude that the CG scaffold shows excellent potential as a biomaterial for human bone tissue engineering. PMID- 20198387 TI - Involvement of insulin-like growth factor-I for the regulation of prolactin synthesis by estrogen and postnatal proliferation of lactotrophs in the mouse anterior pituitary. AB - Estradiol (E2) stimulates not only secretion of prolactin (PRL) and proliferation of PRL-producing cells (PRL cells) in the anterior pituitary, but also the expression of growth factors. In insulin-like growth factor-I (IGF-I) knockout (KO) mice, the number of PRL cells is decreased and administration of IGF-I does not increase either the number of PRL cells or plasma PRL levels, indicating that IGF-I plays a pivotal role in PRL cells. The effect of E2 on PRL cells in KO mice was investigated by immunohistochemistry and real-time RT-PCR. The number of PRL cells in KO mice was significantly lower than in the wild-type (WT) control mice. E2 increased the PRL mRNA in WT and KO mice; however, an increase of PRL mRNA in KO was less than that in WT. In addition, no vasoactive intestinal peptide (VIP) immunoreactive cells were found in KO mice, therefore IGF-I is essential for VIP expression. To investigate the roles of IGF-I on PRL cells in the postnatal development, double-immunostaining with PRL and BrdU was performed in WT and KO mice from days 5-20. The percentages of PRL cells and BrdU-labeled cells in the anterior pituitary of KO mice were lower than in WT mice. Thus, IGF-I may be responsible for proliferation and differentiation of PRL cells in this postnatal period. Differentiation and the proliferation of PRL cells are controlled by IGF I during the postnatal development, and IGF may be a mediator of E2 action through VIP induction in PRL cells of adults. PMID- 20198388 TI - Geographic variation in a facultative mutualism: consequences for local arthropod composition and diversity. AB - Geographic variation in the outcome of interspecific interactions may influence not only the evolutionary trajectories of species but also the structure of local communities. We investigated this community consequence of geographic variation for a facultative mutualism between ants and wild cotton (Gossypium thurberi). Ants consume wild cotton extrafloral nectar and can protect plants from herbivores. We chose three sites that differed in interaction outcome, including a mutualism (ants provided the greatest benefits to plant fitness and responded to manipulations of extrafloral nectar), a potential commensalism (ants increased plant fitness but were unresponsive to extrafloral nectar), and a neutral interaction (ants neither affected plant fitness nor responded to extrafloral nectar). At all sites, we manipulated ants and extrafloral nectar in a factorial design and monitored the abundance, diversity, and composition of other arthropods occurring on wild cotton plants. We predicted that the effects of ants and extrafloral nectar on arthropods would be largest in the location with the mutualism and weakest where the interaction was neutral. A non-metric multidimensional scaling analysis revealed that the presence of ants altered arthropod composition, but only at the two sites in which ants increased plant fitness. At the site with the mutualism, ants also suppressed detritivore/scavenger abundance and increased aphids. The presence of extrafloral nectar increased arthropod abundance where mutual benefits were the strongest, whereas both arthropod abundance and morphospecies richness declined with extrafloral nectar availability at the site with the weakest ant-plant interaction. Some responses were geographically invariable: total arthropod richness and evenness declined by approximately 20% on plants with ants, and extrafloral nectar reduced carnivore abundance when ants were excluded from plants. These results demonstrate that a facultative ant-plant mutualism can alter the composition of arthropod assemblages on plants and that these community level consequences vary across the landscape. PMID- 20198389 TI - Abdominal compartment syndrome occurring due to uterine perforation during a hysteroscopy procedure. AB - We report a case of abdominal compartment syndrome occurring due to uterine perforation while the patient was undergoing hysteroscopic uterine adhesiolysis for uterine synechia. The cause of the patient's abdominal compartment syndrome was irrigation fluid moving from the uterine cavity into the peritoneal space via defects in the uterus. Anesthesiologists must be alert for these complications during hysteroscopy procedures. PMID- 20198390 TI - An insight into vertebral fractures. PMID- 20198391 TI - The diabetic cardiomyopathy. AB - Diabetic cardiomyopathy has been defined as "a distinct entity characterized by the presence of abnormal myocardial performance or structure in the absence of epicardial coronary artery disease, hypertension, and significant valvular disease". The diagnosis stems from the detection of myocardial abnormalities and the exclusion of other contributory causes of cardiomyopathy. It rests on non invasive imaging techniques which can demonstrate myocardial dysfunction across the spectra of clinical presentation. The presence of diabetes is associated with an increased risk of developing heart failure, and the 75% of patients with unexplained idiopathic dilated cardiomyopathy were found to be diabetic. Diabetic patients with microvascular complications show the strongest association between diabetes and cardiomyopathy, an association that parallels the duration and severity of hyperglycemia. Metabolic abnormalities (that is hyperglycemia, hyperinsulinemia, and hyperlipemia) can lead to the cellular alterations characterizing diabetic cardiomyopathy (that is myocardial fibrosis and/or myocardial hypertrophy) directly or indirectly (that is by means of renin angiotensin system activation, cardiac autonomic neuropathy, alterations in calcium homeostasis). Moreover, metabolic abnormalities represent, on a clinical ground, the main therapeutic target in the patients with diabetes since the diagnosis of diabetes is made. Since diabetic cardiomyopathy is highly prevalent in the asymptomatic type 2 diabetic patients, screening for its presence at the earliest stage of development can lead to prevent the progression to chronic heart failure. The most sensitive test is standard echocardiogram, while a less expensive pre-screening method is the detection of microalbuminuria. PMID- 20198392 TI - Markedly increased serum and urinary fructose concentrations in diabetic patients with ketoacidosis or ketosis. AB - To investigate fructose concentrations in diabetic patients with ketoacidosis or ketosis, serum fructose concentrations and daily urinary fructose excretion were measured in 23 patients with ketoacidosis (n = 16) and ketosis (n = 7) on the first day of admission. Seventeen patients were diagnosed with type 1, one patient with mitochondrial, and 4 patients with atypical diabetes. In 16 of the 23 patients, serum and urinary fructose could be assessed after starting treatments. Mean serum fructose concentration was 71.6 +/- 108.1 MUmol/l, and mean daily urinary fructose excretion was 352.1 +/- 473.7 MUmol/day. Serum fructose levels in patients with atypical diabetes were much higher (205.0 +/- 213.3 MUmol/l) than those in patients with type 1 diabetes (45.1 +/- 44.5 MUmol/l), while urinary fructose levels in atypical diabetes (249.7 +/- 92.4 MUmol/day) tended to be lower than those in type 1 diabetes (382.6 +/- 533.2 MUmol/day). Serum fructose concentrations decreased significantly (P < 0.05) from 88.1 +/- 126.3 to 18.0 +/- 11.0 MUmol/l, and daily urinary fructose excretion also decreased significantly (P < 0.05) from 459.8 +/- 530.9 to 75.1 +/- 62.0 MUmol/day in accordance with glycemic normalization after treatment. Marked and reversible increases in serum and urinary fructose concentrations were observed in diabetics with ketoacidosis and ketosis. PMID- 20198393 TI - Screening for bipolar disorder during pregnancy and the postpartum period. AB - Bipolar disorder is a significant mental health problem among perinatal women; however, little attention has been devoted to methods of screening for bipolar disorder during this phase of women's life cycle. There is a need for reliable and valid screening instruments for perinatal women. This paper presents a review of 11 self-report measures used to screen bipolar disorder in the general population and discusses their applicability to screening among perinatal women. Published psychometric data, including reliability, sensitivity, specificity, and positive predictive value of each self-report instrument, is presented and critiqued. We make recommendations for screening in clinical practice and highlights priorities for future research. The need for more research in this area is emphasized. PMID- 20198394 TI - Identification of sequence polymorphisms in CALM2 and analysis of association with hip osteoarthritis in a Japanese population. AB - Osteoarthritis (OA) is a degenerative disease characterized by gradual loss of articular cartilage and is a leading cause of disability in elderly populations. In a previous study, we demonstrated an association between a functional single nucleotide polymorphism (SNP) in the core promoter region of the calmodulin (CaM) 1 gene (CALM1) and hip OA. CaM plays an important role in maintaining cartilage phenotype. Three genes, CALM1, CALM2, and CALM3, encode completely identical CaM proteins. In the present study, we investigated the susceptibility of these three genes for hip OA. Expression analyses revealed that CALM2 was most abundantly expressed in articular chondrocytes and OA cartilage. We then identified sequence polymorphisms in the CALM2 region and analyzed their associations with hip OA in a Japanese population. None of the polymorphisms was significantly associated with hip OA, but when the population was stratified according to acetabular dysplasia status, two SNPs located in intron 1 were found to be significantly associated in a subpopulation of the hip OA patients without acetabular dysplasia (P = 0.036 and 0.031, respectively). These findings suggest that the CALM2 gene may be a genetic determinant of hip OA. PMID- 20198395 TI - Highlights from the scientific and educational abstracts presented at the ASER 2009 Annual Scientific Meeting and Postgraduate Course. AB - The American Society of Emergency Radiology 2009 Annual Scientific Meeting and Postgraduate Course encompassed a wide range of topics: traumatic and nontraumatic emergencies, radiation dose management, technical innovations and advancements, emergency preparedness, mass casualties, military radiology, and teleradiology. This article highlights the scientific and educational abstracts presented at the meeting (Scientific and Educational Abstracts Presented at the ASER, Emerg Radiol 16:501-516, 2009). PMID- 20198396 TI - A case of laryngeal carcinoma in a young adult with dyskeratosis congenita. AB - Dyskeratosis congenita (DC) is an inherited disorder that is characterized by the triad of skin pigmentation, nail dystrophy, and mucosal leukoplakia. Individuals with DC suffer from premature mortality because of bone marrow failure, pulmonary disease, or malignant transformation within the areas of mucosal leukoplakia, caused by telomerase dysfunction. We present a case of a 31-year-old Japanese man with DC who developed laryngeal cancer (supraglottic T4aN0M0). To avoid the serious risks of accelerating the DC-associated complications by DNA-damaging therapies, he was treated with a total laryngectomy plus right modified neck dissection (levels IB, IIA, III, and IV). A contralateral nodal metastasis appeared 4 months after initial surgery and was salvaged by a left radical neck dissection. Our strategy to spare DNA-damaging therapies has proven effective so far. This is the first reported case of laryngeal cancer in a patient with DC in the English-language medical literature. PMID- 20198397 TI - Giant cell tumor of the sacrum treated with selective arterial embolization. AB - Giant cell tumor of the sacrum is extremely difficult to manage. Standard treatments, including surgery and radiation, are associated with significant complications and recurrence rates. In this manuscript, we report an early clinical result of a case of giant cell tumor of the sacrum successfully managed with selective arterial embolization. A 56-year-old woman underwent selective embolization for management of giant cell tumor of the sacrum. Radiologically, massive shrinkage of the extraosseous mass and increased peripheral ossification were obvious. Clinically, rapid pain relief was achieved and gait disability recovered. At final follow-up 28 months after completion of treatment, she retained normal activity in daily life. We stress the effectiveness of selective arterial embolization as a less invasive and less complicated primary treatment of giant cell tumors of the sacrum. PMID- 20198398 TI - Out-of-pocket payment and cost-effectiveness of XELOX and XELOX plus bevacizumab therapy: from the perspective of metastatic colorectal cancer patients in Japan. AB - OBJECTIVE: The purpose of our study was to estimate the out-of-pocket payment and cost-effectiveness of capecitabine plus oxaliplatin (XELOX) or XELOX plus bevacizumab from the perspective of patients with metastatic colorectal cancer (MCRC). METHODS: Based on the NO16966 and NO16967 trials, the mean out-of-pocket payment was calculated from patient-level data. Out-of-pocket payments for 16 cycles (11 months) of first-line chemotherapy and 8 cycles (5 months) of second line chemotherapy were included. In addition, incremental cost-effectiveness ratios (ICERs) for first-line bevacizumab were calculated by dividing the difference of the out-of-pocket payment by the difference of the mean number of progression-free survival (PFS) years or quality-adjusted PFS (QAPFS) years. RESULTS: The mean out-of-pocket payments for middle-income patients under 70 years of age were JPY 328,000 for 16 cycles of first-line XELOX and JPY 376,000 for XELOX plus bevacizumab. The mean out-of-pocket payment for 8 cycles of second line XELOX was calculated to be JPY 175,000. Middle-income patients over 70 years of age were required to pay JPY 61,000 and JPY 72,000 for first-line XELOX and XELOX plus bevacizumab, respectively. The ICERs of middle-income patients <70 years of age were JPY 430,000/PFS-year and JPY 720,000/QAPFS-year, and those of middle-income patients >70 years of age were JPY 100,000/PFS-year and JPY 170,000/QAPFS-year. CONCLUSIONS: We clarified the out-of-pocket payment and cost effectiveness of chemotherapy of MCRC patients in Japan. Our previous survey shows it is highly possible that many patients prefer to pay that incremental out of-pocket payment to gain one additional QAPFS year. However, our cost effectiveness analysis was not conducted from the perspective of society or healthcare payers. PMID- 20198399 TI - Ewing's sarcoma of the kidney. AB - Primitive neuroectodermal tumors (PNETs) are small, round-cell tumors of neural crest origin classically found in the central nervous system (CNS) but more recently characterized in the periphery. Peripherally located PNETs (pPNETs) are members of the Ewing's sarcoma family of tumors (EFTs). Renal localization of pPNETs is very rare, is found in young adults, and is characterized by an aggressive clinical course and poor prognosis. We present the case of a young man with renal pPNET characterized by psuedorosette formation, cluster of differentiation 99 (CD 99+), focally positive for neuron-specific enolase (NSE), with cytogenetic findings of the translocation t(11;22)(q24;q12) and the unique abnormality of trisomy 7. To our knowledge, we report the first case of trisomy 7 and PNET. PMID- 20198400 TI - Evaluation of S-1 as third- or further-line chemotherapy in advanced non-small cell lung cancer. AB - BACKGROUND: No investigation of S-1 monotherapy in previously treated advanced non-small-cell lung cancer (NSCLC) patients has yet been reported. We conducted a retrospective study to evaluate the efficacy and tolerability of S-1 in patients with failure of second- or further-line chemotherapy. PATIENTS AND METHODS: The records of NSCLC patients who had received S-1 monotherapy between January 2005 and November 2006 with the following eligibility criteria were reviewed: previously treated with at least two regimens including platinum and docetaxel in the case of nonadenocarcinoma patients, and including platinum, docetaxel and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) in the case of adenocarcinoma patients. S-1 was administered for 28 consecutive days, followed by a 14-day drug-free period (42 days in one course). The drug was administered in two divided doses daily at 80 mg/day for patients with a body surface area <1.25 m(2), 100 mg/day for those with a body surface area of 1.25 1.5 m(2), and 120 mg/day for those with a body surface area > or = 1.5 m(2). RESULTS: Thirty-five patients were registered. The median number of courses administered per patient was 2 (range 1-9). The toxicity profile was mild, and grade 3 or more severe toxicity was rare. The overall response and disease control rates were 5.7% and 40%, respectively. The median survival time was 208 days. CONCLUSION: S-1 exhibits modest activity and acceptable toxicity when used as a third or subsequent line of chemotherapy in patients with advanced NSCLC. PMID- 20198401 TI - Fatal Clostridium difficile infection associated with vinorelbine chemotherapy: case report and literature review. AB - Differentiating between chemotherapy-related diarrhoea and Clostridium difficile associated diarrhoea (CDAD) can be extremely difficult. There is increasing evidence that CDAD can be seen in patients on chemotherapy without prior antibiotic usage. We report the first case of CDAD secondary to vinorelbine chemotherapy and review the literature. PMID- 20198402 TI - Ceftriaxone plus gentamicin or ceftriaxone alone for streptococcal endocarditis in Japanese patients as alternative first-line therapies. AB - This study included 31 patients who had definite or possible infectious endocarditis as defined by the modified Duke's criteria Of these patients, 27 were treated with ceftriaxone plus gentamycin combination therapy and four with ceftriaxone monotherapy. Of these 31 cases, 29 had infections with Streptococcus species, and showed good responses to penicillin G and cefotaxime. Excluding one patient who died because of the underlying disease, all patients achieved clinical cure after treatment with either of the two regimens, showing no recurrence during a follow-up period of 6 months after completion of drug treatment. Although valve replacement was performed in 10 patients during the follow-up period, there were no recurrences in any of these patients 6 months postoperatively. Ceftriaxone allows a simple regimen of once-daily administration. Although indications are limited, ceftriaxone therapy is feasible on an outpatient basis, offering favorable medical economics. Consistent with previous reports, the therapeutic effect of ceftriaxone was equivalent to that of penicillin G in this study, showing this agent to be an alternative first-line drug for infectious endocarditis. PMID- 20198403 TI - A prospective randomised radiostereometric analysis trial of SmartSet HV and Palacos R bone cements in primary total hip arthroplasty. AB - BACKGROUND: Introduction of new bone cements into clinical practice should include radiostereometric studies. MATERIALS AND METHODS: A prospective randomised radiostereometric study was performed, comparing SmartSet HV and Palacos R acrylic bone cements (without antibiotics) using third-generation cementing techniques in primary total hip arthroplasty. Thirty-five patients (36 hips) undergoing Charnley total hip arthroplasty were randomised to receive either of the two cements and were followed with repeated clinical, radiographic and radiostereometric examinations over 24 months. Twenty-seven patients (28 hips) attended 2 years postoperatively. RESULTS: The mean distal translation observed was -0.15 mm for SmartSet HV and -0.16 mm for Palacos R. The mean rotation around the longitudinal axis was 0.9 degrees for SmartSet HV and 1.2 degrees for Palacos R. The Merle d'Aubigne Postel score was the maximum of 18 points for all patients in both groups. CONCLUSIONS: No statistically significant difference in stem fixation with use of SmartSet HV and Palacos R was found at 2 year follow-up. PMID- 20198404 TI - Massive rotator cuff tears: functional outcome after debridement or arthroscopic partial repair. AB - BACKGROUND: The surgical treatment of massive rotator cuff tears (RCT) is still controversial and can be based on a variety of different surgical repair methods. This study investigated the effectiveness of arthroscopic debridement or arthroscopic partial repair in patients with massive RCT. MATERIALS AND METHODS: This prospective, randomized study involved forty-two patients with massive RCT (fatty infiltration stage 3 or 4) treated with either arthroscopic partial repair or arthroscopic debridement were selected to detect possible differences in functional outcome. Both groups were matched according to age and gender. Patients were examined before, and 16 +/- 3 and 24 +/- 2 months after surgery. The status of the rotator cuff repair was determined using ultrasonographic evaluation. RESULTS: Regardless of the treatment group, postoperative results demonstrated highly significant improvements compared with preoperative values in most parameters. The overall Constant score in the partial repair group was superior to the outcome in the debridement group (P < 0.01, F = 8.561), according to better results in abduction (P < 0.01, F = 13.249), activity (P < 0.01, F = 21.391) and motion (P < 0.01, F = 4.967). All treatment groups had similar pain relief (P = 0.172, F = 1.802) and satisfaction, reflected in equal values of disabilities of the arm, shoulder and hand (DASH) score (P = 0.948, F = 0.004). Ultrasonography revealed structural failure of the partial rotator cuff repair in 52% at final follow-up. CONCLUSIONS: During the follow-up period all patients in our series had good or satisfactory outcome after rotator cuff surgery. Regardless of high rates of structural failure of the partial rotator cuff repair, the results of arthroscopic partial rotator cuff repair demonstrated slightly better functional outcome than debridement. PMID- 20198405 TI - No differences in outcomes between cemented and uncemented acetabular components after 12-14 years: results from a randomized controlled trial comparing Duraloc with Charnley cups. AB - BACKGROUND: Even though there are multiple studies documenting the outcome of the Charnley low-friction arthroplasty as well as abundant studies on uncemented arthroplasties, there is a dearth of comparative studies of the uncemented acetabular component and a cemented component. In this study we aimed to document the long-term clinical and radiographic outcome as well as component survival in a randomized controlled trial. MATERIALS AND METHODS: Two hundred fifteen patients (240 hips) were randomly allocated to receive a cemented Charnley cup or uncemented Duraloc 1200 cup. All patients received cemented Charnley stems and were evaluated clinically and radiographically after 6 months, and 2, 5, and 10 years. RESULTS: Harris Hip Scores improved from 48.3 [95% confidence interval (CI) 45.0-51.6] to 90.2 [95% CI 87.9-92.6] in the Charnley group and from 49.3 [95% CI 86.9-91.3] in the Duraloc group at 6 months. After 10 years, the Charnley group's Harris Hip Score was 89.8 [95% confidence interval (CI) 87.0-92.6], and the Duraloc group's score was 87.3 (95% CI 84.1-90.6). In the radiographic analysis after 10 years, there was no statistical difference in the prevalence of radiographic signs of loosening. Nine cups were revised in the Charnley group, and five cups were removed in the Duraloc group. The difference was not statistically significant. There was no statistical difference between the cups when aseptic loosening was the end-point, nor in survival analyses. CONCLUSIONS: There is no statistically significant difference in clinical or radiological outcome between the Charnley cup and the Duraloc after 10 years, and no difference in implant survival after 12-14 years. The uncemented Duraloc cup is as good as the cemented Charnley cup after 10 years. PMID- 20198406 TI - Hemorrhagic cystitis and possible neurologic disease from BK virus infection in a patient with AIDS. AB - BK virus (BKV)-associated hemorrhagic cystitis occurs in bone marrow transplant recipients but is rare among other immunosuppressed patients. We present a rare case of BKV-associated hemorrhagic cystitis in a 48-year-old man with AIDS and previously diagnosed progressive multifocal leukoencephalopathy. PMID- 20198407 TI - Magnetic deposition of aerosols composed of aggregated superparamagnetic nanoparticles. AB - PURPOSE: The deposition of magnetic particles was examined for the possibility of further enhancing the selectivity of inhalation drug administration for the treatment of lung cancer. METHODS: Superparamagnetic magnetite nanoparticles were prepared and ultrasonically atomized, dried, and passed through glass tubes in the presence and absence of a wedge-shaped permanent magnet. The change in the outlet aerosol size distribution due to magnetic deposition under various well defined aerodynamic conditions and a measured magnetic field was determined by an aerodynamic particle sizer. In addition, computational fluid dynamics (CFD) simulations of magnetic aerosol transport and deposition were conducted. RESULTS: The deposition fraction increased nearly linearly with particle diameter and was greater with lower air flow rates. The effect of tube diameter was complicated but well described by CFD simulations, as was the effect of particle size and air flow rate. CONCLUSIONS: The descriptive power of CFD simulations was demonstrated in the in vitro deposition of magnetic aerosol particles. This suggests that CFD simulations can potentially be used in future studies to design systems for selective drug delivery in vivo as a function of magnetic properties, aerosol characteristics, and respiratory physiology. PMID- 20198408 TI - Bitter melon: antagonist to cancer. AB - The incidence of cancer is increasing worldwide, in spite of substantial progress in the development of anti-cancer therapies. One approach to control cancer could be its prevention by diet, which inhibits one or more neoplastic events and reduces cancer risk. Dietary compounds offer great potential in the fight against cancer by inhibiting the carcinogenesis process through the regulation of cell homeostasis and cell-death machineries. For centuries, Ayurveda (Indian traditional medicine) has recommended the use of bitter melon (Momordica charantia) as a functional food to prevent and treat diabetes and associated complications. It is noteworthy to mention that bitter melon extract has no-to low side effects in animals as well as in humans. The anti-tumor activity of bitter melon has recently begun to emerge. This review focuses on recent advancements in cancer chemopreventive and anti-cancer efficacy of bitter melon and its active constituents. Several groups of investigators have reported that treatment of bitter-melon-related products in a number of cancer cell lines induces cell cycle arrest and apoptosis without affecting normal cell growth. Therefore, the effect of bitter melon should be beneficial for health, and use of the non-modified dietary product is cost effective. PMID- 20198409 TI - Drug delivery systems for intraperitoneal therapy. AB - Disorders associated with the peritoneal cavity include peritoneal adhesions and intraperitoneal (IP) malignancies. To prevent peritoneal adhesions, physical barrier devices are used to prevent organs from contacting other structures in the abdomen and forming adhesions, or pharmacological agents that interfere with adhesion formation are administered intraperitoneally. IP malignancies are other disorders confined to the peritoneal cavity, which are treated by combination of surgical removal and chemotherapy of the residual tumor. IP drug delivery helps in the regional therapy of these disorders by providing relatively high concentration and longer half-life of a drug in the peritoneal cavity. Various studies suggest that IP delivery of anti-neoplastic agents is a promising approach for malignancies in the peritoneal cavity compared to the systemic administration. However, IP drug delivery faces several challenges, such as premature clearance of a small molecular weight drug from the peritoneal cavity, lack of target specificity, and poor drug penetration into the target tissues. Previous studies have proposed the use of micro/nanoparticles and/or hydrogel based systems for prolonging the drug residence time in the peritoneal cavity. This commentary discusses the currently used IP drug delivery systems either clinically or experimentally and the remaining challenges in IP drug delivery for future development. PMID- 20198410 TI - Hormonal regulation of uterine natural killer cells in mouse preimplantation uterus. AB - Uterine Natural Killer (uNK) cells are the most abundant lymphocyte population recruited in the uteri during murine and human pregnancy. Previous investigation on uNK cells during mouse pregnancy focused more on its accumulation in postimplantation periods, which were believed to play important roles in regulating trophoblast invasion and angiogenesis towards successful placentation. However, by using recently developed methods of Dolichos biflorus agglutinin (DBA) lectin, a closer examination during mouse preimplantation revealed that there were also dynamic regulations of uNK cell, suggesting a major regulation by steroid hormones. Here we provide a detailed examination of uNK cells distribution during mouse early pregnancy by DBA lectin reactivity, with emphasis on preimplantation period and its hormonal regulation profiles. Our results showed that uNK precursor cells or its cell membrane specific components could be recruited in the uterus by estrogen or/and progesterone, and the effects could be completely abolished by specific antagonists of their nuclear receptors (estrogen and progesterone receptor). These results suggested that the preimplantation uterus, through concerted hormone regulation, could recruit uNK precursor cell or its specific cellular component, which might be conducive for uterine receptivity and further uNK construction/function during postimplantation. PMID- 20198411 TI - Styryl dyes as two-photon excited fluorescent probes for DNA detection and two photon laser scanning fluorescence microscopy of living cells. AB - Spectral-fluorescent properties of benzothiazole styryl monomer (Bos-3) and homodimer (DBos-21) dyes in presence of DNA were studied. The dyes enhance their fluorescence intensity in 2-3 orders of magnitude upon interaction with DNA. Studied styrylcyanines in DNA presence demonstrate rather high values of two photon absorption (TPA) cross-section, which are comparable with the values of TPA cross section of the rhodamine dyes. An applicability of the styrylcyanines as probes for the fluorescence microscopy of living cells was studied. It was shown that both dyes are cell-permeable but homodimer dye DBos-21 produces noticeably brighter staining of HeLa cells comparing with monomer dye Bos-3. Molecules of DBos-21 initially bind to the nucleic acids-containing cell organelles (presumable mitochondria) and are able to penetrate into the cell nucleus. Thus, homodimer styryl DBos-21 dye is viewed as efficient stain for single-photon and two-photon excitation fluorescence imaging of living cells. PMID- 20198412 TI - Fluorescent property of the Gd3+-doped terbium complexes and crystal structure of [Tb(TPTZ)(H2O)6]Cl3.3H2O. AB - The complex of Tb(TPTZ)Cl(3).3H(2)O was synthesized by adding the ethyl alcohol solution of TbCl(3) (1 mmol) to the solution of 2,4,6-tris-(2-pyridyl)-s triazine(TPTZ, 1 mmol) with constant stirring. The solution which had been filtered was kept at the room temperature for 4 weeks, and then a kind of transparent crystal was formed. Besides, nine kinds of solid complexes in the different molar proportion of terbium to gadolinium had been synthesized by adopting the similar method mentioned above. It was inferred from the elemental analysis and rare earth complexometry that the composition of these complexes is (Tb(x)Gd(y))(TPTZ)Cl(3).3H(2)O (x : y = 0.9 : 0.1, 0.8 : 0.2, 0.7 : 0.3, 0.6 : 0.4, 0.5 : 0.5, 0.4 : 0.6, 0.3 : 0.7, 0.2 : 0.8, 0.1 : 0.9). The absorption spectra and photoluminescence of the complexes were determined in dimethylsulfoxide (DMF), which showed that the excitation of the complexes is mostly ligand based. The triplet state energy level of TPTZ was measured, indicating that the lowest excitation state energy level of Tb(III) and the triplet state energy level of TPTZ match well each other. The fluorescent data indicated that the fluorescent emission intensity of Tb(3+) ions would be enhanced in the complexes after terbium was doped with Gd(3+) ion. When x : y was 0.5 : 0.5, the fluorescent emission intensity was the largest. The result obtained by testing the X-ray diffraction of the monocrystal revealed that the molecular formula of the mono-crystal complex is [Tb(TPTZ)(H(2)O)(6)]Cl(3).3H(2)O. The number of metal ion coordinates is nine, and the tridentate TPTZ and six water molecules are bonded with terbium respectively. Besides, it also revealed that the monocrystal belongs to the monoclinic system, and space group Cc with the following unit cell parameters is a = 1.4785 (3) nm, b = 1.0547 (2) nm, c = 1.7385 (4) nm, beta = 94.42 (3) degrees, V = 2.7028 (9) nm(3) and Z = 4. PMID- 20198413 TI - Screening for autism spectrum disorders in Flemish day-care centres with the checklist for early signs of developmental disorders. AB - A new screening instrument for ASD was developed that can be filled out by child care workers: the Checklist for Early Signs of Developmental Disorders (CESDD). The predictive validity of the CESDD was evaluated in a population of 6,808 children between 3 and 39 months attending day-care centres in Flanders. The CESDD had a sensitivity of .80 and a specificity of .94. Based on the screening procedure used in this study, 41 children were diagnosed with ASD or got a working diagnosis of ASD. Thus, including child care workers' report on signs of ASD in screening procedures can help to identify cases of ASD at a young age. PMID- 20198414 TI - Viewing time effects revisited: prolonged response latencies for sexually attractive targets under restricted task conditions. AB - Sexually attractive stimuli are watched longer than unattractive stimuli. The processes underlying this robust and reliable viewing time effect are presently not well understood. In the present research comprising four experiments (total N = 250), four classes of potential explanations are proposed and the derived implications were experimentally tested. Contrary to explanations based on either deliberate delay or attentional adhesion to sexually attractive stimuli, prolonged response latencies were also found under restricted task conditions. Sexually preferred targets elicited longer response latencies in a self-paced evaluation task when stimulus pictures were presented for 750 ms (Experiment 1) or for 500 ms and followed by a pattern mask (Experiment 2). Prolonged latencies for sexually preferred targets were also observed when sexual attractiveness was rated in a speeded binary decision task with a response window of 1000 ms (Experiment 3). Eventually, it was shown that the response latency effect in the speeded binary choice task was still preserved when only the heads of target individuals were presented instead of the bodies (Experiment 4). Mate identification and schematic processes are discussed as the remaining plausible mechanisms for prolonged response latencies for sexually attractive targets under restricted conditions. PMID- 20198415 TI - The single cell as a tool for genetic testing: credibility, precision, implication. AB - PURPOSE: To investigate the influence of amplicons size and cell type on allele dropout and amplification failures in single-cell based molecular diagnosis. METHODS: 730 single lymphocytes and amniotic cells were collected from known heterozygotes individuals to one of the common Ashkenazi Jewish mutations: 1278+TATC and IVS12+1G>C which cause Tay Sachs Disease, IVS20+6T and 854A>C which underlie Familial Dysautonomia and Canavan Disease. DNA was extracted and analyzed by our routine methods. RESULTS: Reduced rates of allele dropout and amplification failure were found when smaller amplification product were designed and in amniotic cultured cells compared to peripheral lymphocytes. Cultured lymphocytes, induced to divide, demonstrated significantly less allele dropout than non induced lymphocytes suggesting the role of division potential on amplification efficiency. CONCLUSION: Single cell based diagnosis should be designed for each mutation. Minimal sized amplicons and cell having division potential should be preferred, as well as sensitive techniques to detect preferential amplification. PMID- 20198416 TI - Activin A inhibits activation of human primordial follicles in vitro. AB - PURPOSE: To determine whether Activin A affects the activation and survival of human primordial follicles in vitro. METHODS: Ovarian cortical biopsies from eight women undergoing elective caesarean sections or benign gynaecological procedures were taken and cut into small pieces (1-3 mm(3)), cultured in serum free medium for 7 days with/without human recombinant Activin A at a concentration of either 50 or 100 ng/ml. Ovarian tissue were analysed by histology for follicle viability, development and density. RESULT(S): Significant activation of primordial follicles within cultured cortical tissue was observed after 7 days in control medium. However, medium supplemented with Activin A at 50 ng/ml resulted in significant inhibition of follicular activation. Increasing the concentration of Activin A to 100 ng/ml reversed the inhibitory effect. The effect of Activin A appeared to be specific to activation of non-growing (primordial) follicles into the growing population since no significant differences in follicle viability was observed between treatment groups. CONCLUSION(S): Activin A at a concentration of 50 ng/ml can inhibit the spontaneous activation of human primordial follicles in vitro indicating that this may be a component of the signalling mechanisms that maintain follicular quiescence. PMID- 20198417 TI - Reciprocal chromosome painting between white hawk (Leucopternis albicollis) and chicken reveals extensive fusions and fissions during karyotype evolution of accipitridae (Aves, Falconiformes). AB - Evolutionary cytogenetics can take confidence from methodological and analytical advances that promise to speed up data acquisition and analysis. Drastic chromosomal reshuffling has been documented in birds of prey by FISH. However, the available probes, derived from chicken, have the limitation of not being capable of determining if breakpoints are similar in different species: possible synapomorphies are based on the number of segments hybridized by each of chicken chromosome probes. Hence, we employed FACS to construct chromosome paint sets of the white hawk (Leucopternis albicollis), a Neotropical species of Accipitridae with 2n = 66. FISH experiments enabled us to assign subchromosomal homologies between chicken and white hawk. In agreement with previous reports, we found the occurrence of fusions involving segments homologous to chicken microchromosomes and macrochromosomes. The use of these probes in other birds of prey can identify important chromosomal synapomorphies and clarify the phylogenetic position of different groups of Accipitridae. PMID- 20198418 TI - Molecular cytogenetic mapping of Cucumis sativus and C. melo using highly repetitive DNA sequences. AB - Chromosomes often serve as one of the most important molecular aspects of studying the evolution of species. Indeed, most of the crucial mutations that led to differentiation of species during the evolution have occurred at the chromosomal level. Furthermore, the analysis of pachytene chromosomes appears to be an invaluable tool for the study of evolution due to its effectiveness in chromosome identification and precise physical gene mapping. By applying fluorescence in situ hybridization of 45S rDNA and CsCent1 probes to cucumber pachytene chromosomes, here, we demonstrate that cucumber chromosomes 1 and 2 may have evolved from fusions of ancestral karyotype with chromosome number n = 12. This conclusion is further supported by the centromeric sequence similarity between cucumber and melon, which suggests that these sequences evolved from a common ancestor. It may be after or during speciation that these sequences were specifically amplified, after which they diverged and specific sequence variants were homogenized. Additionally, a structural change on the centromeric region of cucumber chromosome 4 was revealed by fiber-FISH using the mitochondrial-related repetitive sequences, BAC-E38 and CsCent1. These showed the former sequences being integrated into the latter in multiple regions. The data presented here are useful resources for comparative genomics and cytogenetics of Cucumis and, in particular, the ongoing genome sequencing project of cucumber. PMID- 20198419 TI - FISH mapping of microsatellite loci from Drosophila subobscura and its comparison to related species. AB - Microsatellites are highly polymorphic markers that are distributed through all the genome being more abundant in non-coding regions. Whether they are neutral or under selection, these markers if localized can be used as co-dominant molecular markers to explore the dynamics of the evolutionary processes. Their cytological localization can allow identifying genes under selection, inferring recombination from a genomic point of view, or screening for the genomic reorganizations occurring during the evolution of a lineage, among others. In this paper, we report for the first time the localization of microsatellite loci by fluorescent in situ hybridization on Drosophila polytene chromosomes. In Drosophila subobscura, 72 dinucleotide microsatellite loci were localized by fluorescent in situ hybridization yielding unique hybridization signals. In the sex chromosome, microsatellite distribution was not uniform and its density was higher than in autosomes. We identified homologous segments to the sequence flanking the microsatellite loci by browsing the genome sequence of Drosophila pseudoobscura and Drosophila melanogaster. Their localization supports the conservation of Muller's chromosomal elements among Drosophila species and the existence of multiple intrachromosomal rearrangements within each evolutionary lineage. Finally, the lack of microsatellite repeats in the homologous D. melanogaster sequences suggests convergent evolution for high microsatellite density in the distal part of the X chromosome. PMID- 20198420 TI - Suppression of glutamate-induced excitotoxicity by 2-cyclopropylimino-3-methyl 1,3-thiazoline hydrochloride in rat glial cultures. AB - We have screened new drugs with a view to developing effective drugs against glutamate-induced excitotoxicity. In the present work, we show effects of a new drug, 2-cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride against glutamate induced excitotoxicity in primary rat glial cultures. Pretreatment of glial cells with 2-cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride for 2 h significantly protected glial cells against glutamate-induced excitotoxicity in a time- and dose-dependent manner with an optimum concentration of 100 microM. The drug significantly reduced production of proinflammatory cytokines, tumor necrosis factor-alpha, and interlukin-1beta in glutamate-induced excitotoxicity. The drug also prevented glutamate-induced intracellular Ca2+ influx and reduced the subsequent overproduction of nitric oxide and reactive oxygen species. Furthermore, the drug preserved the mitochondrial potential and inhibited the overproduction of cytochrome c. In addition, the drug effectively attenuated the protein level changes of beta-catenin and glycogen synthase kinase-3beta. These results suggest that 2-cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride effectively protected primary cultures of rat glial cells against glutamate induced excitotoxicity. PMID- 20198421 TI - Involvement of a cysteine protease in the secretion process of human xylosyltransferase I. AB - Xylosylation of core proteins takes place in the Golgi-apparatus as the transfer of xylose from UDP-xylose to specific serine residues in proteoglycan core proteins. This initial and rate-limiting step in glycosaminoglycan biosynthesis is catalyzed by human xylosyltransferase I (XT-I). XT-I is proteolytically cleaved from the Golgi surface and shed in its active form into the extracellular space. The secreted, circulating glycosyltransferase represents a serum biomarker for various diseases with an altered proteoglycan metabolism, whereas a physiological function of secreted XT-I is still unknown. To shed light on the secretion process of XT-I and on its biological function, the cleavage site was examined and the group of proteases involved in the cleavage was identified in this study. The peptide mass fingerprint from partly purified secreted XT-I revealed the cleavage site to be localized in the aminoterminal 231 amino acids. The addition of a cysteine protease inhibitor cocktail to cells recombinantly expressing XT-I led to a concentration-dependent shift of enzyme activity towards the cell lysates attended by consistent total intracellular and extracellular XT I activities. In conclusion, our findings provide a first insight into the XT-I secretion process regulated by a cysteine protease and may contribute to understanding the biological and pathological role of this process. PMID- 20198422 TI - Expanding cyclitol structural diversity by biocatalysis and metalocatalysis. A click chemistry approach. AB - The palladium catalyzed cross-coupling reaction of phenyltrifluoroborate with a chemoenzymatically derived bromoazidoconduritol, combined with 1,3-dipolar cycloaddition, with a variety of alkynes is described. Fourteen new compounds were synthesized in moderate to good yields. The click chemistry reaction can be effected by using sodium ascorbate and CuSO(4) . 5H(2)O as catalyst in toluene H(2)O at room temperature. PMID- 20198423 TI - The role of verbal threat information in the development of childhood fear. "Beware the Jabberwock!". AB - Rachman's (Behaviour Research and Therapy 15:372-387, 1977; Clinical Psychology Review 11:155-173, 1991) three pathways theory proposed that childhood fears not only arise as a consequence of direct learning experiences, but can also be elicited by means of threat information transmission. This review looks at the scientific evidence for this idea, which has accumulated during the past three decades. We review research on the influences of media exposure on children's fears, retrospective parent and child reports on the role of threat information in fear acquisition, and experimental studies that explored the causal effects of threat information on childhood fears. We also discuss possible mechanisms by which threat information exerts its influence and the processes relevant to understand the role of this type of learning experience in the origins of fear. Finally, implications for the prevention and intervention of childhood fears are briefly explored, and potential leads for future research will be highlighted. PMID- 20198424 TI - Management of recurrence of symptoms of gastroesophageal reflux disease: synergistic effect of rebamipide with 15 mg lansoprazole. AB - BACKGROUND: Proton pump inhibitors (PPIs) are effective in healing reflux esophagitis and relieving the symptoms of gastroesophageal reflux disease (GERD). Prevention of recurrence of symptoms has become a therapeutic aim in patients with these conditions. AIMS: We investigated the effects of rebamipide, a mucosal protective anti-ulcer agent, on recurrence of reflux symptoms during PPI maintenance therapy. METHODS: Patients with esophagitis of Los Angeles classification A or B were treated with PPIs for 8 weeks. Patients with relief of symptoms were enrolled for further study. Forty-one patients were randomized to maintenance therapy with 15 mg of lansoprazole daily or 15 mg of lansoprazole and 300 mg rebamipide daily, and recurrence of symptoms was monitored over 12 months. In some patients, concentration of rebamipide and interleukin(IL)-8 expression in the esophageal mucosa were estimated. RESULTS: During the 12-month period, 11/20 patients (52.4%) taking lansoprazole 15 mg daily suffered recurrence of symptoms, compared to 4/20 patients (20%) treated with lansoprazole 15 mg and rebamipide 300 mg daily (P < 0.05). Rebamipide was detected in the esophageal mucosa 90-180 min after oral administration. IL-8 mRNA expression in the esophageal mucosa of patients with rebamipide was significantly decreased compared with that of patients without rebamipide. CONCLUSIONS: Combination therapy with rebamipide and lansoprazole appears to be highly effective in preventing recurrence of symptoms during long-term maintenance treatment for GERD. PMID- 20198426 TI - Azathioprine and ulcerative colitis: a "second-look" meta-analysis. PMID- 20198425 TI - Quantification of the effects of the volume and viscosity of gastric contents on antral and fundic activity in the rat stomach maintained ex vivo. AB - AIMS: The aim of this study was to examine the effect of varying the rheological properties of perfusate on the volume and muscular activity of the various compartments of the rat stomach. METHODS: Image analysis was used to quantify the activity of the ex vivo stomach preparations when perfused according to a ramp profile. RESULTS: The area of the fundus increased to a greater extent than that of the body when watery or viscous material was perfused. However, initial distension of the corpus was greater and occurred more rapidly when viscous material was perfused. Only the fundus expanded when perfusion followed the administration of verapamil. The frequency of antrocorporal contractions decreased significantly and the amplitude of antrocorporal contractions increased significantly with increase in gastric volume. The velocity of antrocorporal contractions did not vary with gastric volume but varied regionally in some preparations being faster distally than proximally. Neither the frequency, amplitude or velocity of antrocorporal contractions differed when pseudoplastic rather than watery fluid was perfused. However, the characteristics of antrocorporal contractions changed significantly when the stomach was perfused with material with rheological characteristics that induce different patterns of wall tension to those normally encountered. Hence, the mean frequency and speed of propagation of antrocorporal contractions increased and their direction of propagation became inconstant. PMID- 20198427 TI - Low prevalence of CMV infection in patients with Crohn's disease in comparison with ulcerative colitis: effect of different immune response on prevalence of CMV infection. PMID- 20198428 TI - Primary intestinal lymphangiectasia: four case reports and a review of the literature. AB - BACKGROUND: Primary intestinal lymphangiectasia (PIL) is a rare digestive disease and most articles on this condition are isolated case reports. AIMS: Our purpose is to investigate the clinical characteristics, therapeutic management, and outcome of PIL through case studies. METHODS: We conducted a retrospective analysis and obtained detailed clinical information for four PIL patients treated at our institution. A MEDLINE database search was also performed using the search term "intestinal lymphangiectasia" and all pertinent literature was carefully reviewed. RESULTS: Four children treated in our department showed elevated IgE and a good response to diet intervention. After reviewing the literature, we conducted statistical analysis on the basis of all the cases, with a total of 84 cases. Thirty-eight cases have been reported with diet treatment, 24 (63%) of whom showed apparent improvement in clinical symptoms and laboratory parameters. Four cases (5%) had a malignant transformation of lymphoma, and the average time from PIL onset to lymphoma diagnosis was 31 years (range, 19-45 years). No difference was observed regarding the presence of major clinical manifestations among children and adults. Diet intervention in children was more effective than that in adults. CONCLUSIONS: Diet intervention is the cornerstone of PIL medical management, which was found to be more effective in children than in adults. Early diagnosis and treatment of IL is of great importance for effective diet therapy. An elevated IgE level should be monitored periodically since it could be an indication of malignant transformation-lymphoma. PMID- 20198429 TI - Systemic inflammatory response associated with distant metastasis of T1 or T2 colorectal cancer. AB - BACKGROUND: There are currently no studies examining the relationship between systemic inflammatory response and distant metastasis in colorectal cancer patients. AIMS: The aim of this study was to evaluate the association of a systemic inflammatory response on distant metastasis by examining clinicopathological factors in patients with colorectal cancer infiltrating the submucosal layer (T1) or the proper muscular layer (T2). METHODS: Univariate analysis was performed to evaluate the influence of a systemic inflammatory response on distant metastasis in patients with T1 or T2 colorectal cancer using collected clinicopathological data. RESULTS: Between 1993 and 2008, 156 patients with pathologically diagnosed T1 or T2 colorectal cancer were enrolled. Univariate analysis using clinicopathological factors and Glasgow Prognostic Score (GPS) (0, 1/2) demonstrated that, as well as lymph node metastasis, administration of oral anti-cancer drug and CEA, CRP (odds ratio, 36.25; 95% CI 4.026-326.4; P = 0.001) and GPS (odds ratio, 24.50; 95% CI 1.715-349.9; P =0.018) were associated with distant metastasis. CONCLUSIONS: CRP and GPS are associated with distant metastasis of T1 or T2 colorectal cancer. Because of the small number of patients with stage IV disease (n =4), a multi-center retrospective study is needed to confirm these findings. PMID- 20198430 TI - Naturally occurring glycoalkaloids in potatoes aggravate intestinal inflammation in two mouse models of inflammatory bowel disease. AB - BACKGROUND: Inflammatory bowel disease (IBD) may be initiated following disruption of the intestinal epithelial barrier. This disruption, in turn, permits luminal antigens unfettered access to the mucosal immune system and leads to an uncontrolled inflammatory response. Glycoalkaloids, which are found in potatoes, disrupt cholesterol-containing membranes such as those of the intestinal epithelium. Glycoalkaloid ingestion through potatoes may play a role in the initiation and/or perpetuation of IBD. AIM: To determine if commercial and high glycoalkaloids containing fried potato skins aggravate intestinal inflammation using two different animal models of IBD. METHODS: Fried potato skins from commercial potatoes containing low/medium glycoalkaloid levels and high glycoalkaloids potatoes were fed for 20 days to interleukin 10 gene deficient mice and dextran sodium sulfate-induced colitic mice. Intestinal permeability, mucosal cytokine and myeloperoxidase levels and body weight were determined to assess intestinal injury. RESULTS: Deep frying potato skins markedly increased glycoalkaloid content. Interleukin 10 gene-deficient mice fed fried commercial potato skins with medium glycoalkaloid content exhibited significantly elevated levels of ileal IFN-gamma relative to controls. Mice in the dextran sodium sulfate colitis model that were fed the same strain of potatoes demonstrated significantly elevated levels of pro-inflammatory cytokines IFN-gamma, TNF-alpha, and IL-17 in the colon in addition to an enhanced colonic permeability. Inflammatory response was intensified when the mice were fed potatoes with higher glycoalkaloid contents. CONCLUSIONS: Our results demonstrate that consumption of potato skins containing glycoalkaloids can significantly aggravate intestinal inflammation in predisposed individuals. PMID- 20198431 TI - Gastroduodenal ulceration associated with radioembolization for the treatment of hepatic tumors: an institutional experience and review of the literature. AB - BACKGROUND: Microsphere radioembolization is a method of delivering radiation therapy directly to tumors, thereby minimizing toxicity to adjacent structures. Despite the relatively high precision of this modality, numerous adverse effects have been recognized. One particularly untoward complication is the development of severe gastroduodenal ulceration. METHODS: In order to further characterize gastroduodenal ulceration associated with radioembolization, our institutional experience as well as the reported literature were reviewed. RESULTS: The current evidence suggests that radioembolization-associated gastroduodenal ulceration results from inadvertent delivery of microspheres to the microvasculature of the gastrointestinal tract, leading to direct radiation toxicity. The reported incidence of this entity ranges between 2.9% and 4.8%. Most patients with this complication present with abdominal pain, often associated with nausea, vomiting, and anorexia. Symptoms can arise from hours to months after radioembolization treatment; diagnosis is made by endoscopic biopsy and histopathologic evaluation of the ulcer specimen. Radiation-induced ulcers have proven to be extremely difficult to treat. Current therapy based on acid suppression has had limited success, and the evidence for the addition of antioxidants and anti-inflammatory agents is still sparse. CONCLUSIONS: The increasing utilization of radioembolization will lead to adverse events including gastroduodenal ulceration. This entity must be considered in any patient treated with radioactive microspheres presenting with symptoms of dyspepsia. Accurate diagnosis and aggressive treatment are necessary to improve patient outcomes. PMID- 20198432 TI - The protective effect of capsaicin receptor-mediated genistein postconditioning on gastric ischemia-reperfusion injury in rats. AB - BACKGROUND: No published study has addressed the effect of genistein postconditioning on gastric ischemia-reperfusion (GI-R) injury in rats. AIM: To examine whether capsaicin receptor-mediated genistein postconditioning protects against gastric ischemia-reperfusion injury via the PI3K/Akt signal pathway. METHODS AND RESULTS: Chloraldurat-anesthetized rats underwent occlusion of the celiac artery for 30 min, followed by 60 min of reperfusion. Based on this animal model of gastric ischemia-reperfusion injury, genistein at doses of 100, 500 or 1,000 MUg/kg was administered via peripheral vein 5 min before reperfusion. The dose of 500 MUg/kg was optimal for postconditioning, at which the severity of I-R induced gastric injury significantly decreased. Immunohistochemistry also showed that gastric mucosal cell apoptosis decreased. Capsazepine (CPZ), a specific antagonist for the capsaicin receptor, was administered (1,000 MUg/kg, i.v.) just before ischemia. Capsaicin (50 mg/kg, s.c.) once a day for 4 days reversed the protective effects of genistein. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting showed increased calcitonin gene-related peptide (CGRP) expression in genistein group but not in capsazepine or capsaicin group. CGRP inhibitor CGRP8-37 also prevented the effects of genistein in decreasing gastric mucosal injury index. In addition, PI3K inhibitor LY294002 (1.5 mg/kg) reversed the protective effect of genistein. Compared with genistein group, Western blots also demonstrated decreased Akt phosphorylation in LY294002 group. CONCLUSION: Our data suggest that capsaicin receptors mediated the protective effects of genistein postconditioning. CGRP secreted by activated capsaicin sensitive neurons played an important role in the protective effects of genistein. PI3K/Akt pathway was also involved in the protective effects of genistein. PMID- 20198433 TI - Vitamin D deficiency in refugee children from conflict zones. AB - Vitamin D deficiency is common in newly resettled refugee children and is associated with significant morbidity including rickets. To determine risk factors and burden of vitamin D deficiency in newly resettled refugee children in Australia. A descriptive epidemiological study and survey on refugee children attending an outpatient general health clinic at the Children's Hospital Westmead, Sydney. 215 patients were examined (age range 0-17 years), (76%) majority were from Africa. Mean serum 25OHD level was 46 nmol/L (SD = 24) (sufficiency range 50-150 nmol/L). 40% had mild deficiency (26-50 nmol/L), 19% moderate deficiency (13-25 nmol/L) and 2% were severely deficient (<13 nmol/L). Deficiency was most common in East African (72%) and Middle Eastern (66%) refugees, children in early puberty (89%) and those living in Australia >6 months (71%). Deficient children were more likely to have had movement restrictions and longer time in hiding in their country of refuge (OR 3:1[CI 0.9-9.7], P = .062). PMID- 20198434 TI - On what it is to fly can tell us something about what it is to live. AB - The plurality of definitions of life is often perceived as an unsatisfying situation stemming from still incomplete knowledge about 'what it is to live' as well as from the existence of a variety of methods for reaching a definition. For many, such plurality is to be remedied and the search for a unique and fully satisfactory definition of life pursued. In this contribution on the contrary, it is argued that the existence of such a variety of definitions of life undermines the very feasibility of ever reaching a unique unambiguous definition. It is argued that focusing on the definitions of specific types of 'living systems' somehow in the same way that one can define specific types of 'flying systems' could be more fruitful from a heuristic point of view than looking for 'the' right definition of life, and probably more accurate in terms of carving Nature at its joints. PMID- 20198435 TI - Which way to life? AB - If the emergence of life is seen as the evolutionary transition between the non living and the living, then it may be meaningless to draw a strict line between these two worlds. A comparison between the metabolic- and genetic-first origin-of life proposals is made. A comparison of the empirical evidence used in favor of the metabolic-first and genetic-first theories of the origin of life shows that many of the observations and experimental findings that are used to argue in favor of one or another view are equally consistent with the premises of both theories and do not unambiguously support neither of them. However, current biology indicates that life could not have evolved in the absence of a genetic replicating mechanism insuring the stability and diversification of its basic components. PMID- 20198436 TI - Defining life: the virus viewpoint. AB - Are viruses alive? Until very recently, answering this question was often negative and viruses were not considered in discussions on the origin and definition of life. This situation is rapidly changing, following several discoveries that have modified our vision of viruses. It has been recognized that viruses have played (and still play) a major innovative role in the evolution of cellular organisms. New definitions of viruses have been proposed and their position in the universal tree of life is actively discussed. Viruses are no more confused with their virions, but can be viewed as complex living entities that transform the infected cell into a novel organism-the virus-producing virions. I suggest here to define life (an historical process) as the mode of existence of ribosome encoding organisms (cells) and capsid encoding organisms (viruses) and their ancestors. I propose to define an organism as an ensemble of integrated organs (molecular or cellular) producing individuals evolving through natural selection. The origin of life on our planet would correspond to the establishment of the first organism corresponding to this definition. PMID- 20198437 TI - Inefficient clearance of dying cells in patients with SLE: anti-dsDNA autoantibodies, MFG-E8, HMGB-1 and other players. AB - Systemic lupus erythematosus (SLE) is a complex disease resulting from inflammatory responses of the immune system against several autoantigens. Inflammation is conditioned by the continuous presence of autoantibodies and leaked autoantigens, e.g. from not properly cleared dying and dead cells. Various soluble molecules and biophysical properties of the surface of apoptotic cells play significant roles in the appropriate recognition and further processing of dying and dead cells. We exemplarily discuss how Milk fat globule epidermal growth factor 8 (MFG-E8), biophysical membrane alterations, High mobility group box 1 (HMGB1), C-reactive protein (CRP), and anti-nuclear autoantibodies may contribute to the etiopathogenesis of the disease. Up to date knowledge about these key elements may provide new insights that lead to the development of new treatment strategies of the disease. PMID- 20198438 TI - Antioxidant and anti-inflammatory effects of mild hypothermia in the attenuation of liver injury due to azoxymethane toxicity in the mouse. AB - Previous studies have demonstrated protective effects of mild hypothermia following acetaminophen (APAP)-induced acute liver failure (ALF). However, effects of this treatment in ALF due to other toxins have not yet been fully investigated. In the present study, the effects of mild hypothermia in relation to liver pathology, hepatic and cerebral glutathione, plasma ammonia concentrations, progression of encephalopathy, cerebral edema, and plasma proinflammatory cytokines were assessed in mice with ALF resulting from azoxymethane (AOM) hepatotoxicity, a well characterized model of toxic liver injury. Male C57BL/6 mice were treated with AOM (100 microg/g; i.p.) or saline and sacrificed at coma stages of encephalopathy in parallel with AOM mice maintained mildly hypothermic (35 degrees C). AOM treatment led to hepatic damage, significant increase in plasma transaminase activity, decreased hepatic glutathione levels, and brain GSH/GSSG ratios as well as selective increases in expression of plasma proinflammatory cytokines. Mild hypothermia resulted in reduced hepatic damage, improvement in neurological function, normalization of glutathione levels, and selective attenuation in expression of circulating proinflammatory cytokines. These findings demonstrate that the beneficial effects of mild hypothermia in experimental AOM-induced ALF involve both antioxidant and anti-inflammatory mechanisms. PMID- 20198439 TI - Antioxidant properties of extracts obtained from raw, dry-roasted, and oil roasted US peanuts of commercial importance. AB - Raw, skinless peanut kernels from US commercial production lines were dry- and oil-roasted according to standard industrial practices. Eighty percent (v/v) methanolic extracts from the peanut cultivars were prepared and characterized by RP-HPLC: five predominant compounds were found comprising free p-coumaric acid and potential p-coumaric acid derivatives, as elucidated by DAD-UV spectra with comparisons to those of commercial standards. A Spanish high-oleic peanut possessed the greatest naturally-occurring level of p-coumaric acid and its derivatives, followed by a high-oleic Runner, a normal Runner, and a Virginia peanut. Upon thermal processing, p-coumaric acid was liberated at the expense of its derivatives according to the relationship: oil roasting > dry roasting > raw. A high-oleic Runner exhibited the greatest increase (~785%) in free p-coumaric acid levels after oil roasting. For many of the samples from the 2007 crop, processing increased the TPC and antioxidant capacities in the order of raw < dry roast < oil roast, but results were cultivar dependent. Oil-roasted peanuts were more effective at scavenging O2(.-) than their dry-roasted counterparts, as determined by a photochemiluminescence assay. Overall findings indicate that although thermal processing altered the composition of peanut kernel antioxidants, TPC values and radical-scavenging activities are preserved. Depending on peanut type, cultivar, and harvest date, enhanced antioxidant capacities can result. PMID- 20198440 TI - Six edible wild fruits as potential antioxidant additives or nutritional supplements. AB - Total antioxidant activity of six non-cultivated but traditionally collected fruits from the south of Europe was assessed by measuring their ability to reduce the hydroxyl radical (OH) and hydrogen peroxide (H(2)O(2)), and their Trolox equivalent antioxidant capacity (TEAC). This antioxidant activity was compared with that shown by the synthetic antioxidants BHA (E-320), BHT (E-321) and propyl gallate (E-310). Total phenolics, ascorbic acid and the carotenoid content of the fruits were also analyzed. All fruits showed a high ability to scavenge the OH radical, ranging from 60.61% to 81.04% inhibition for Rosa canina and Crataegus monogyna, respectively. The H(2)O(2) scavenging capacity and the TEAC value varied widely, ranging between 3.63% and 87.26% inhibition of H(2)O(2) and between 0.47 and 416.64 mM trolox g(-1) FW for Sorbus domestica and Rosa canina, respectively. The antioxidant activity of fruits was higher than that of the synthetic additives analyzed, except in the TEAC assay. The phenolic and carotenoid content of R. canina was much higher than that of the other fruits analyzed and its ascorbic acid concentration was also high, reflecting its higher efficacy towards ABTS- (TEAC assay) and H(2)O(2) species(.) In spite of these associations, the correlation coefficients between total antioxidant activity and the antioxidant compounds analyzed were not very significant; only phenolics and carotenoids showed a marginal correlation with the TEAC assay. The results support the possible use of R. canina as natural antioxidant to replace the synthetic additives, as well as their use in the production of functional foods with a high antioxidant activity. PMID- 20198441 TI - Pomological and nutraceutical properties in apricot fruit: cultivation systems and cold storage fruit management. AB - We have investigated the effect of cultivation systems and fruit post-harvest management on the antioxidant properties of apricot fruits. Trees of five cultivars 'Tyrinthos', 'Cafona', 'Bella d'Italia', 'Vitillo' and 'Pellecchiella' were cultivated under integrated and organic systems. Fruits were collected at full maturity stage and analyzed either immediately or after storage at 4+/-0.5 degrees C and 85% of relative humidity for seven and 14 days. The main pomological traits (weight, colour, flesh firmness, total soluble sugars, titratable acidity) and antioxidant properties were analyzed. The total antioxidant capacity (TAC by TEAC method), total phenols content (TP by Folin Ciocalteu method) and carotenoid content by HPLC-DAD were monitored. Cultivar characterization by principal component analysis (PCA) indicated a large variability on pomological and antioxidant properties of apricot fruits. 'Bella d'Italia' showed better TAC and TP values compared to the other cultivars. ANOVA interactions between cultivar and cultivation system (organic/integrated) were found for the antioxidant properties. These interactions may help to select a set of genotypes with better performances under organic system, which in our study might be indicated in 'Cafona' and 'Bella d'Italia'. PMID- 20198442 TI - Evaluation of antioxidant capacity and phenol content in jackfruit (Artocarpus heterophyllus Lam.) fruit pulp. AB - The antioxidant capacity of jackfruit (Artocarpus heterophyllus Lam. Fam. Moracae) fruit pulp (JFP) obtained from Western Ghats India was determined by evaluating the scavenging activity using 1,1-diphenyl-2-picrylhydrazyl (DPPH), ferric reducing power assays and N, N-dimethyl-p-phenylendiamine (DMPD) radical cation decolorization assay. JFP was analyzed for total phenolic content (TPC) and total flavonoids content (TFC). The ethanol and water are the best solvents for the extracting phenols and flavonoids from the JFP. The antioxidant activities of JFP extracts were correlated with the total phenolic and flavonoids content. The results indicated that the jackfruit pulp is one natural source of antioxidant compounds. PMID- 20198443 TI - HER-2-negative breast cancer limitations and next-generation sequencing technology promises. PMID- 20198445 TI - Distal pancreatectomy combined with celiac axis resection in treatment of carcinoma of the body/tail of the pancreas: a single-center experience. AB - BACKGROUND: Few comparison studies have been carried out on patients with distal pancreatectomy (DP) combined with celiac axis (CA) resection. The aim of this study was to assess the safety and efficacy of this extended procedure in treatment of advanced carcinoma of the body/tail of the pancreas. METHODS: This was a retrospective analysis of 206 patients with carcinoma of the body/tail of the pancreas from January 2003 through June 2008. Patients were divided into three groups based on the relationship of tumor and CA/common hepatic artery (CHA) as well as different treatment strategies. Data for operation time, blood loss, complications, and survival time were collected and statistically analyzed. RESULTS: Sixty-five patients (31.6%) received radical distal pancreatectomy (DP), including 11 patients who underwent DP combined with celiac axis resection (group A) and 54 patients who received conventional DP (group B). Twenty patients did not undergo DP because of CA and/or CHA invasion only (group C). Group A had longer mean operative time than group B (323 versus 225 min, P = 0.000); there was no difference in mean estimated blood loss, percentage of pancreatic fistula or median survival time (14 versus 15 months, P = 0.197). However, group A had significantly prolonged median survival time compared with the 20 patients in group C (14 versus 5 months, P = 0.013), and quality of life was also dramatically improved. CONCLUSIONS: DP combined with CA resection can be safely performed in certain patients with carcinoma of body/tail of the pancreas and significantly improves patient survival and quality of life. PMID- 20198446 TI - Derivation of 30 human embryonic stem cell lines--improving the quality. AB - We have derived 30 human embryonic stem cell lines from supernumerary blastocysts in our laboratory. During the derivation process, we have studied new and safe method to establish good quality lines. All our human embryonic stem cell lines have been derived using human foreskin fibroblasts as feeder cells. The 26 more recent lines were derived in a medium containing serum replacement instead of fetal calf serum. Mechanical isolation of the inner cell mass using flexible metal needles was used in deriving the 10 latest lines. The lines are karyotypically normal, but culture adaptation in two lines has been observed. Our human embryonic stem cell lines are banked, and they are available for researchers. PMID- 20198447 TI - Derivation of three new human embryonic stem cell lines. AB - Human embryonic stem cells are pluripotent cells capable of extensive self renewal and differentiation to all cells of the embryo proper. Here, we describe the derivation and characterization of three Sydney IVF human embryonic stem cell lines not already reported elsewhere, designated SIVF001, SIVF002, and SIVF014. The cell lines display typical compact colony morphology of embryonic stem cells, have stable growth rates over more than 40 passages and are cytogenetically normal. Furthermore, the cell lines express pluripotency markers including Nanog, Oct4, SSEA3 and Tra-1-81, and are capable of generating teratoma cells derived from each of the three germ layers in immunodeficient mice. These experiments show that the cell lines constitute pluripotent stem cell lines. PMID- 20198448 TI - Derivation and characterisation of hESC lines from supernumerary embryos, experience from Odense, Denmark. AB - The derivation and characterisation of human embryonic stem cells provides a source of pluripotent stem cells with potential for clinical applications. Utilising locally sourced embryos from two IVF clinics, we derived and characterised five new cell lines for use in a non-clinical setting. Analysis of clinical data showed that the majority of embryos (94.5%) failed to reach the blastocyst stage of development and of all embryos, regardless of developmental status, 248 embryos were needed to create one stem cell line. From the number of embryos (69) which developed to the blastocyst stage 8.7% developed into cell lines. Using outgrowth of the whole blastocyst, we derived five new, unreported cell lines in Odense, Denmark between 2005 and 2006. Characterisation was carried out using RT-PCR, staining, karyotyping, EB formation and teratoma formation. The KMEB hESC lines will, in the future, be made available through the UK Stem Cell Bank (http://www.ukstemcellbank.org.uk/). PMID- 20198449 TI - Activation of CD74 inhibits migration of human mesenchymal stem cells. AB - Therapeutic administration of mesenchymal stem cells (MSCs) by systemic delivery utilizes the innate ability of the cells to home to damaged tissues, but it can be an inefficient process due to a limited knowledge of cellular cues that regulate migration and homing. Our lab recently discovered that a potent pro inflammatory cytokine, macrophage migration inhibitory factor (MIF), inhibits MSC migration. Because MIF may act on multiple cellular targets, an activating antibody (CD74Ab) was employed in this study to examine the effect of one MIF receptor, CD74 (major histocompatibility complex class II-associated invariant chain), on MSC motility. CD74 activation inhibits in a dose-dependent manner up to 90% of in vitro migration of MSCs at 40 mug/ml CD74Ab (p < 0.001), with consistent effects observed among three MSC donor preparations. A blocking peptide from the C-terminus of CD74 eliminates the effect of CD74Ab on MSCs. This suggests that MIF may act on MSCs, at least in part, through CD74. Late-passage MSCs exhibit less chemokinesis than those at passage 2. However, MSCs remain responsive to CD74 activation during ex vivo expansion: MSC migration is inhibited approximately 2-fold in the presence of 5 microg/ml CD74Ab at passage 9 vs. approximately 3-fold at passage 2 (p < 0.001). Consistent with this result, there were no significant differences in CD74 expression at all tested passages or after CD74Ab exposure. Targeting CD74 to regulate migration and homing potentially may be a useful strategy to improve the efficacy of a variety of MSC therapies, including those that require ex vivo expansion. PMID- 20198451 TI - Intraoperative fluid replacement and postoperative creatine phosphokinase levels in laparoscopic bariatric patients. AB - BACKGROUND: Morbid obesity and bariatric surgery are both risk factors for the development of postoperative rhabdomyolysis (RML). RML results from injury to skeletal muscle, and a serum creatine phosphokinase (CK) level >1,000 IU/L is considered diagnostic of RML. The aim of this study was to determine if intraoperative intravenous fluid (IVF) volume affects postoperative CK levels following laparoscopic bariatric operations. STUDY DESIGN: Prospective, single blinded, and randomized trial was conducted. METHODS: Patients scheduled to undergo laparoscopic sleeve gastrectomy, adjustable gastric band, or Roux-en-Y gastric bypass operations were randomized into two groups. Subjects in Group A received 15 ml/kg total body weight (TBW) of IV crystalloid solution during surgery, while subjects in Group B received 40 ml/kg TBW. Preoperative and postoperative CK and creatinine levels and intra- and postoperative urine output were monitored and recorded. RESULTS: Forty-seven patients were assigned to Group A and 53 patients to Group B. Group B patients had significantly higher urine output in the operating room, in the post-anesthesia care unit (PACU), and on postoperative days 0 and 1. Group B patients also had significantly lower serum creatinine level in the PACU and a trend towards lower creatinine levels on postoperative days 0, 1, and 2. There were no statistical differences in CK levels at any time between the two groups. Four patients in Group A and three patients in Group B developed postoperative RML. CONCLUSIONS: Conservative (15 ml/kg) versus liberal (40 ml/kg) intraoperative IVF administration did not change the incidence of RML in patients undergoing laparoscopic bariatric operations. Since the occurrence of RML in this patient population is relatively high, postoperative CK levels should be routinely obtained in patients at special risk. PMID- 20198452 TI - Surgical site infections following bariatric surgery in community hospitals: a weighty concern? AB - BACKGROUND: Although obesity is a well-known risk factor for surgical site infection (SSI), specific risk factors for SSI among obese patients undergoing bariatric surgery (BS) have not been well-defined. METHODS: We performed a prospective cohort study on patients who underwent BS at nine community hospitals in the USA between 7/1/2007 and 12/31/2008. Each patient had the following data recorded: National Nosocomial Infection Surveillance (NNIS) risk index; the choice, timing, and dose of antibiotic prophylaxis; age; body mass index; and duration of surgery. NNIS criteria were used to define SSI. Cases were detected during the post-operative hospital stay, on readmission to hospital within 30 days of the procedure and by post-discharge surveillance. RESULTS: A total of 2,012 patients were included in the study. The majority of procedures were laparoscopic (82%). The overall rate of SSI was 1.4% (28/2012). Patients who received vancomycin surgical prophylaxis were more likely to develop SSI than patients who received other antibiotics (relative risk [RR] = 9.4; 95% confidence interval [CI] = 3.1-26.1; p = 0.005). More specifically, patients who received vancomycin prophylaxis as a single agent at a dose less than 2 g were more likely to develop SSI than patients who received other antibiotic regimens (RR = 7.1; 95% CI = 1.9-23.8; p = 0.035). CONCLUSIONS: Inadequate dosing of vancomycin prophylaxis prior to BS is associated with increased risk of SSI. If vancomycin is used for prophylaxis, the appropriate dose should be calculated using actual bodyweight rather than lean bodyweight in accordance with Infectious Disease Society of America recommendations. PMID- 20198453 TI - Bileopancreatic diversion with duodenal switch lowers both early and late phases of glucose, insulin and proinsulin responses after meal. AB - BACKGROUND: Hyperproinsulinemia is associated with obesity and type 2 diabetes. We explored the after-meal dynamics of proinsulin and insulin and postprandial effects on glucose and lipids in patients treated with bileopancreatic diversion with duodenal switch (BPD-DS) surgery compared with normal-weight controls [body mass index (BMI)+/-SD, 23.2 +/- 2.4 kg/m(2)]. METHODS: Ten previously morbidly obese (BMI+/-SD, 53.5 +/- 3.8 kg/m(2)) patients free from diabetes who had undergone BPD-DS (BMI+/-SD, 29.0 +/- 5.2 kg/m(2)) 2 years earlier were recruited. A standardised meal (2400 kJ) was ingested, and glucose, proinsulin, insulin, free fatty acids and triglycerides (TGs) were determined during 180 min. Follow up characteristics yearly on glucose, lipids, creatinine and uric acid over 3 years after BPD-DS are presented. RESULTS: Fasting glucose and insulin were lower, 0.4 mmol/L and 4.6 pmol/L, respectively, in the BPD-DS group despite higher BMI. Fasting proinsulin was similar in both groups. Postprandial area under the curve (AUC) for glucose, proinsulin and insulin did not differ between the two groups (p = 0.106-734). Postprandial changes in glucose, proinsulin and insulin were essentially similar but absolute concentrations of proinsulin and insulin were lower in the later phases in the BPD-DS group (p = 0.052-0.001). Postprandial AUC for TGs was lower in the BPD-DS group (p = 0.005). Postprandial changes in TGs were lowered in the intermediate phase (p = 0.07-0.08) and in the late phase (0.002). Follow-up data showed markedly lowered creatinine and uric acid after BPD-DS. CONCLUSIONS: BPD-DS surgery induces a large weight loss and lowers, close to normal, postprandial responses of glucose, proinsulin and insulin but with marked lowering of TGs. PMID- 20198454 TI - Effect of supplemental inorganic Zn and Mn and their interactions on the performance of broiler chicken, mineral bioavailability, and immune response. AB - The purpose of this study was to investigate the interaction and main effects of supplemental Zn and Mn levels on growth, tissue mineral uptake, and immune response in broiler chicken. A basal diet of corn-soybean meal was supplemented with Zn at 40, 80, or 160 ppm and Mn at 60, 120, or 240 ppm in a factorial pattern to constitute nine experimental diets. Each diet was offered to nine replicates of six chicks in stainless steel battery brooders. At 35 days of age, body weight gain, feed conversion efficiency, hock joint scores, tibia weight, tibia strength, and percent ash were not influenced by Zn and Mn levels and their interactions. The concentration of Zn (207-238 ppm) and Mn (11.8-16.3 ppm) in tibia increased linearly with progressive raise of mineral inclusion in diets. Mn at 240 ppm level caused higher retention of Zn in tibia, but not vice versa. Manganese either alone or in combination with Zn (Zn160/Mn120 ppm) significantly reduced Cu retention (10.1-7.2 ppm) in tibia. Even in the hepatic tissue, Zn (93.6-98.4 ppm) and Mn (9.3-10.2 ppm) concentration increased linearly with their levels of inclusion in diets. When Zn and Mn levels were maintained at 4:3 ratio (80:60 or 160:120 ppm), the concentration of Zn (100-106 ppm) in liver was higher, while that of Mn was significantly more with low level of Zn (40 ppm) in diet. However, Mn supplementation at 120 ppm level and above significantly decreased Cu accumulation (19.5-17.1 ppm) in liver, but Mn * Zn interaction had no effect on Cu retention. The immune response measured as antibody titers to sheep RBC increased (5.9-7.9 log(2)) significantly with higher Zn (80 ppm) supplementation and cell-mediated immune response to phytohemagglutinin (0.57 0.78) with Mn level at 120 ppm. In summary, Zn (40 ppm) and Mn (60 ppm) as recommended by NRC was sufficient for broiler performance and bone parameters. Mn complimented Zn retention in tibia and antagonized Cu in tibia and liver tissues. Higher levels of Zn (80 ppm) and Mn (120 ppm) than those recommended by NRC were needed for improved immune response in broilers at 35 days of age. PMID- 20198455 TI - Universal markers of thyroid malignancies: galectin-3, HBME-1, and cytokeratin 19. AB - Difficulties in diagnosis of thyroid lesions, even with histologic analysis, are well known. This study has been carried on to evaluate the role of immunohistochemical markers including galectin-3, Hector Battifora mesothelial cell-1 (HBME-1), and cytokeratin-19 in the diagnosis and differential diagnosis of benign and malignant thyroid lesions. The expressions of galectin-3, HBME-1, and cytokeratin-19 were tested in formalin-fixed, paraffin-embedded tissues from 458 surgically resected thyroid lesions including non-neoplastic and neoplastic lesions. Immunostaining with standard avidin-biotin complex technique was performed by using monoclonal antibodies. In malignant neoplastic thyroid lesions, galectin-3, HBME-1, and cytokeratin-19 were diffusely expressed in general. Diffuse expression rates of these three markers were 72.3% (47/65), 70.7% (46/65), and 76.9% (50/65), respectively. The use of galectin-3, HBME-1, and cytokeratin-19 may provide significant contributions in the differential diagnosis of malignant thyroid tumors. Although focal galectin-3, HBME-1, and cytokeratin-19 expression may be encountered in benign lesions, diffuse positive reactions for these three markers are characteristic of malignant lesions. It has concluded that cytokeratin-19 alone and its combinations with other markers were more sensitive in accurate diagnosis of papillary carcinoma than the other combinations; meanwhile, there were similar results for follicular carcinomas with HBME-1 alone and its combinations. PMID- 20198456 TI - Endocarditis with pulmonary and systemic embolization. PMID- 20198457 TI - The risk of myocardial infarction in patients with atrial fibrillation: an unresolved issue. PMID- 20198459 TI - Differential diagnosis of angioimmunoblastic T-cell lymphoma with seropositivity for anti-HTLV antibody from adult T-cell leukemia/lymphoma. AB - Angioimmunoblastic lymphoma (AITL) is a nodal peripheral T-cell lymphoma characterized by a proliferation of arborizing vessels and hyperplastic follicular dendritic cells as well as a polymorphous lymphoid infiltrate including neoplastic cells with clear cytoplasm. Adult T-cell leukemia/lymphoma (ATLL) is caused by the retrovirus human T-cell leukemia virus type I (HTLV-I), and the neoplastic cells are usually large and pleomorphic. Recently, a rare morphologic variant of ATLL with AITL-like features has been reported. Here, we presented a case of peripheral T-cell lymphoma with morphological features of AITL in Taiwan, a country non-endemic for HTLV, and the patient was seropositive for anti-HTLV antibody, which raised the possibility of ATLL with AITL-like features. Immunohistochemically, there were hyperplastic follicular dendritic meshworks by CD21 immunostaining, and the neoplastic cells expressed CD10, programmed death-1, and CXCL13. Furthermore, Southern blot analysis using DNA extracted from the nodal tissue was negative for HTLV-I proviral integration. Our investigations indicated that in an HTLV-I non-endemic area, a peripheral T-cell lymphoma with typical morphologic and immunophenotypic features of AITL could be confidently diagnosed as AITL even if the patient was seropositive for anti-HTLV antibody. PMID- 20198458 TI - Irinotecan plus carboplatin in patients with extensive-disease small-cell lung cancer. AB - This study was designed to evaluate the efficacy and safety of irinotecan in combination with carboplatin in previously untreated, extensive-disease small cell lung cancer (ED-SCLC). Patients with histologically or cytologically confirmed ED-SCLC received irinotecan (60 mg/m(2) on days 1, 8, and 15) plus carboplatin (AUC 5 on day 1) every 4 weeks. Treatment was repeated until disease progression, unacceptable toxicity, or up to 6 cycles. Forty-four patients were enrolled. In an intent-to-treat analysis, the overall response rate (RR) was 75% (8 complete responses and 25 partial responses). The median progression-free (PFS) and overall survival (OS) were 5.6 and 8.7 months, respectively. The principle toxicities were neutropenia and diarrhea. Grade 3-4 neutropenia occurred in 30% of the patients and 7% of patients presented with febrile neutropenia. Grade 3-4 diarrhea occurred in 21% of the patients. A subgroup consisting of patients >= 65 years of age had outcomes similar to the younger group <65 years of age. The objective RR was 72% in the patients <65 years of age and 77% in the patients >= 65 years of age (P = .738). The median PFS and OS (<65 years vs. >= 65 years) were 5.3 vs. 5.6 months (P = .835) and 9.0 vs. 8.7 months (P = .648), respectively. The combination of irinotecan and carboplatin is active and tolerable in patients with ED-SCLC. This regimen could be considered as a treatment option for patients of advanced age. PMID- 20198460 TI - Improved treatment outcome of primary mediastinal large B-cell lymphoma after introduction of rituximab in Korean patients. AB - The addition of rituximab to cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) improved the outcome of patients with diffuse large B-cell lymphoma (DLBCL). However, the impact of rituximab (R-CHOP) is still not determined in primary mediastinal large B-cell lymphoma (PMBCL), a subtype of DLBCL, especially in Asian patients. Thus, we analyzed the treatment outcome of PMBCL patients (n = 21) treated with R-CHOP and compared it with the historical group treated with CHOP (n = 14). The rate of complete response for R-CHOP was higher than that of CHOP (17/21, 81.0% vs. 8/14, 57.2%), although the difference was not statistically significant (P = 0.151). The number of patients with disease progression or relapse was higher in the CHOP group (6/14, 42.9%) than the R-CHOP group (2/21, 9.5%). Thus, patients treated with R-CHOP had higher 2 year progression-free survival (79.0%) than those treated with CHOP (50.0%, P = 0.043). Although the 2-year overall survival of the R-CHOP was also superior to that of the CHOP group (82.7% vs. 57.1%), this survival benefit did not reach statistical significance (P = 0.081). In conclusion, our comparison suggests that R-CHOP may increase response and reduce relapse resulting in prolongation of progression-free survival of patients with PMBCL. PMID- 20198461 TI - Prognostic analysis and a new risk model for Hodgkin lymphoma in Japan. AB - The Japan Clinical Oncology Group conducted two multicenter phase II trials in 200 patients with advanced Hodgkin lymphoma (HL) in the 1990s. Among 181 patients whose histopathological specimens were available and reviewed by 6 hematopathologists, 167 (92.3%) were diagnosed with HL. Five-year overall survival (OS) among these 167 patients was 88.3%, including 89.2% among nodular sclerosis and 82.2% among mixed cellularity cases. International prognostic score was not closely associated with OS. Seven unfavorable prognostic factors for OS on univariate analysis were male, B symptoms, clinical stage of III or IV, elevated serum LDH, elevated alkaline phosphatase, elevated beta2-microglobulin, and pathological subtype (mixed cellularity and lymphocyte depletion). On multivariate analysis, male [HR 3.30 (95% CI 1.15-9.52, p = 0.027)] and elevated serum LDH [HR 2.41 (95% CI 1.07-5.43, p = 0.034)] were independent factors for OS. Based on these prognostic factors, the 5-year OS was 95.7% in the low-risk group (no adverse factor), 87.9% in the intermediate-risk group (1 adverse factor) and 73.3% in the high-risk group (2 adverse factors). This simple prognostic model for HL warrants further validation studies. PMID- 20198463 TI - [Sponsorship of medical congresses, workshops and symposia by pharmaceutical companies]. PMID- 20198464 TI - Microbial siderophores. PMID- 20198465 TI - Resin glycosides from the morning glory family. PMID- 20198462 TI - Pancreatic cancer: pathobiology, treatment options, and drug delivery. AB - Pancreatic cancer is the fourth leading cause of cancer-related deaths in the USA. The high mortality rate is partly due to lack of effective treatments. This review summarizes the pathobiology and current treatment options for pancreatic cancer. Moreover, the review discusses the opportunities of developing novel therapies for pancreatic cancer provided by the progress in understanding the genetic mutations, tumor microenvironment, cancer stem cells, and drug delivery. PMID- 20198466 TI - Molecular mapping of a gene for stripe rust resistance in spring wheat cultivar IDO377s. AB - Stripe rust, caused by Puccinia striiformis f. sp. tritici, is one of the most important diseases of wheat worldwide. The best strategy to control stripe rust is to grow resistant cultivars. One such cultivar resistant to most races in North America is 'IDO377s'. To study the genetics of its resistance this spring wheat cultivar was crossed with 'Avocet Susceptible' (AvS). Seedlings of the parents, F(2) plants, and F(3) lines were tested under controlled greenhouse conditions with races PST-43 and PST-45 of P. striiformis f. sp. tritici. IDO377s carries a single dominant gene for resistance. Resistance gene analog polymorphism (RGAP) and simple sequence repeat (SSR) techniques were used to identify molecular markers linked to the resistance gene. A total of ten markers were identified, two of which flanked the locus at 4.4 and 5.5 cM. These flanking RGAP markers were located on chromosome 2B with nulli-tetrasomic lines of 'Chinese Spring'. Their presence in the ditelosomic 2BL line localized them to the long arm. The chromosomal location of the resistance gene was further confirmed with two 2BL-specific SSR markers and a sequence tagged site (STS) marker previously mapped to 2BL. Based on the chromosomal location, reactions to various races of the pathogen and tests of allelism, the IDO377s gene is different from all previously designated genes for stripe rust resistance, and is therefore designated Yr43. A total of 108 wheat breeding lines and cultivars with IDO377s or related cultivars in their parentage were assayed to assess the status of the closest flanking markers and to select lines carrying Yr43. The results showed that the flanking markers were reliable for assisting selection of breeding lines carrying the resistance gene. A linked stripe rust resistance gene, previously identified as YrZak, in cultivar Zak was designated Yr44. PMID- 20198467 TI - Identification of a second major resistance gene to Rice yellow mottle virus, RYMV2, in the African cultivated rice species, O. glaberrima. AB - Rice yellow mottle virus (RYMV) is the most damaging rice-infecting virus in Africa. However, few sources of high resistance and only a single major resistance gene, RYMV1, are known to date. We screened a large representative collection of African cultivated rice (Oryza glaberrima) for RYMV resistance. Whereas high resistance is known to be very rare in Asian cultivated rice (Oryza sativa), we identified 29 (8%) highly resistant accessions in O. glaberrima. The MIF4G domain of RYMV1 was sequenced in these accessions. Some accessions possessed the rymv1-3 or rymv1-4 recessive resistance alleles previously described in O. glaberrima Tog5681 and Tog5672, respectively, and a new allele, rymv1-5, was identified, thereby increasing the number of resistance alleles in O. glaberrima to three. In contrast, only a single allele has been reported in O. sativa. Markers specific to the different alleles of the RYMV1 gene were developed for marker-assisted selection of resistant genotypes for disease management. In addition, the presence of the dominant susceptibility allele (Rymv1-1) in 15 resistant accessions suggests that their resistance is under different genetic control. An allelism test involving one of those accessions revealed a second major resistance gene, i.e., RYMV2. The diversity of resistance genes against RYMV in O. glaberrima species is discussed in relation to the diversification of the virus in Africa. PMID- 20198468 TI - Deleterious amino acid polymorphisms in Arabidopsis thaliana and rice. AB - Plant genetic diversity has been mainly investigated with neutral markers, but large-scale DNA sequencing projects now enable the identification and analysis of different classes of genetic polymorphisms, such as non-synonymous single nucleotide polymorphisms (nsSNPs) in protein coding sequences. Using the SIFT and MAPP programs to predict whether nsSNPs are tolerated (i.e., effectively neutral) or deleterious for protein function, genome-wide nsSNP data from Arabidopsis thaliana and rice were analyzed. In both species, about 20% of polymorphic sites with nsSNPs were classified as deleterious; they segregate at lower allele frequencies than tolerated nsSNPs due to purifying selection. Furthermore, A. thaliana accessions from marginal populations show a higher relative proportion of deleterious nsSNPs, which likely reflects differential selection or demographic effects in subpopulations. To evaluate the sensitivity of predictions, genes from model and crop plants with known functional effects of nsSNPs were inferred with the algorithms. The programs predicted about 70% of nsSNPs correctly as tolerated or deleterious, i.e., as having a functional effect. Forward-in-time simulations of bottleneck and domestication models indicated a high power to detect demographic effects on nsSNP frequencies in sufficiently large datasets. The results indicate that nsSNPs are useful markers for analyzing genetic diversity in plant genetic resources and breeding populations to infer natural/artificial selection and genetic drift. PMID- 20198469 TI - Fine mapping Fhb4, a major QTL conditioning resistance to Fusarium infection in bread wheat (Triticum aestivum L.). AB - Qfhi.nau-4B is a major quantitative trait locus (QTL) against Fusarium graminearum infection identified in the Fusarium head blight-resistant germplasm Wangshuibai. To fine map this QTL, a recombinant inbred line (RIL) population of 530 lines derived from Nanda2419 x Wangshuibai and the BC(3)F(2) population derived from the cross of a Qfhi.nau-4B near isogenic line (NIL) with susceptible cultivar Mianyang 99-323 as the recurrent parent were screened for recombinants occurred between microsatellite markers Xbarc20 and Xwmc349 that flank Qfhi.nau 4B. A total of 95 recombinants were obtained, including 45 RIL recombinants obtained through reverse-selection of Qfhi.nau-5A and 50 NIL recombinants from the BC(3)F(2) population. Genotyping these recombinant lines with 22 markers mapping to the Xbarc20 and Xwmc349 interval revealed fourteen genotypes of the RIL recombinants as well as of the NIL recombinants. Two-year field evaluation of their resistance to Fusarium infection showed that these lines could be clearly classified into two groups according to percentage of infected spikes. The more resistant class had over 60% less infection than the susceptible class and were common to have Wangshuibai chromatin in the 1.7-cM interval flanked by Xhbg226 and Xgwm149. None of the susceptible recombinants had this Wangshuibai chromatin. Qfhi.nau-4B was thus confined between Xhbg226 and Xgwm149 and named Fhb4. The interval harboring Fhb4 was mapped to 4BL5-0.86-1.00 bin using Chinese Spring deletion lines, a region with about 5.7 times higher recombination rate than the genome average. This study established the basis for map-based cloning of Fhb4. PMID- 20198470 TI - Pyramiding QTL increases seedling resistance to crown rot (Fusarium pseudograminearum) of wheat (Triticum aestivum). AB - Crown rot of wheat (Triticum aestivum), predominantly caused by the fungus Fusarium pseudograminearum, has become an increasingly important disease constraint in many winter cereal production regions in Australia. Our group has previously identified a range of quantitative trait loci (QTL) for partial resistance to crown rot in various bread wheat sources. Here, we report on work that has assessed the effectiveness of pyramiding QTL to improve resistance to crown rot. Two doubled haploid populations were analysed--one from a cross between two previously characterised sources of partial seedling resistance (2-49 and W21MMT70; n = 208) and one from a cross between 2-49 and the commercial variety Sunco, a source of adult field resistance (n = 134). Both populations were phenotyped for seedling resistance to crown rot. Microsatellite and DArT markers were used to construct whole genome linkage maps for use in composite interval mapping (CIM) to identify QTL. Three QTL were detected in both trials conducted on the 2-49/W21MMT70 population. These were located on chromosomes 1D (QCr.usq-1D.1), 3B (QCr.usq-3B.1) and 7A. QCr.usq-1D.1 and the previously undetected 7A QTL were inherited from 2-49. QCr.usq-3B.1, inherited from W21MMT70, was the most significant of the QTL, explaining up to 40.5% of the phenotypic variance. Three QTL were identified in multiple trials of the Sunco/2 49 population. These were located on chromosomes 1D (QCr.usq-1D.1), 2B (QCr.usq 2B.2) and 4B (QCr.usq-4B.1). Only QCr.usq-2B.2 was inherited from Sunco. QCr.usq 4B.1 was the most significant of these QTL, explaining up to 19.1% of the phenotypic variance. In the 2-49/W21MMT70 population, several DH lines performed significantly better than either parent, with the best recording an average disease severity rating of only 3.8% of that scored by the susceptible check cultivar Puseas. These lines represent a new level of seedling crown rot resistance in wheat. PMID- 20198471 TI - D-Serine and a glycine transporter-1 inhibitor enhance social memory in rats. AB - RATIONALE: Glutamatergic abnormalities are involved in the etiology of schizophrenia. Clinical evidence demonstrates that positive modulation of "glycine modulatory sites" on N-methyl-D: -aspartic acid (NMDA) receptors improve cognitive deficits as well as positive and negative symptoms in schizophrenic patients. OBJECTIVES: In the present study, we investigated the effects of positive modulation of glycine sites on the NMDA receptor using an agonist of the glycine modulatory site, D: -serine, and a glycine transporter-1 inhibitor, (R) (N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl])sarcosine (NFPS). In particular, we focused on the effects on cognitive functioning using social recognition test in rats. We then compared these effects with those of an atypical antipsychotic clozapine and a typical antipsychotic haloperidol. RESULTS: Both D: -serine and NFPS significantly enhanced social memory in naive rats, as did clozapine, while the typical antipsychotic haloperidol was ineffective. A noncompetitive NMDA receptor antagonist, MK-801, significantly impaired social memory, which was significantly attenuated by pretreatment with clozapine, but not with haloperidol. Likewise, NFPS significantly improved MK-801 disrupted cognition in the social recognition test. None of these drugs affected social interaction time. CONCLUSIONS: The present results show that stimulation of the glycine modulatory sites on the NMDA receptor either directly with D: serine or by blocking glycine transporter-1 enhances social memory and may be an effective approach for the treatment of the cognitive dysfunction observed in schizophrenic patients. PMID- 20198472 TI - Current concepts of polymicrogyria. AB - Polymicrogyria is one of the most common malformations of cortical development. It has been known for many years and its clinical and MRI manifestations are well described. Recent advances in imaging, however, have revealed that polymicrogyria has many different appearances on MR imaging, suggesting that is may be a more heterogeneous malformation than previously suspected. The clinical and imaging heterogeneity of polymicrogyria is explored in this review. PMID- 20198473 TI - Guidelines for the labelling of leucocytes with (99m)Tc-HMPAO. Inflammation/Infection Taskgroup of the European Association of Nuclear Medicine. AB - We describe here a protocol for labelling autologous white blood cells with (99m)Tc-HMPAO based on previously published consensus papers and guidelines. This protocol includes quality control and safety procedures and is in accordance with current European Union regulations and International Atomic Energy Agency recommendations. PMID- 20198474 TI - Guidelines for the labelling of leucocytes with (111)In-oxine. Inflammation/Infection Taskgroup of the European Association of Nuclear Medicine. AB - We describe here a protocol for labelling autologous white blood cells with (111)In-oxine based on previously published consensus papers and guidelines. This protocol includes quality control and safety procedures and is in accordance with current European Union regulations and International Atomic Energy Agency recommendations. PMID- 20198475 TI - Highlights of the EANM Congress Barcelona 2009: increasing our impact in diagnostic imaging. AB - The EANM Congress 2009 took place in Barcelona from 10 to 14 October under the chairmanship of Dr. Martin-Comin. As always, the meeting was successful with high level scientific content and a great number of participants. In spite of the economic crisis, industry made an important contribution presenting new revolutionary equipment and tracers, and in particular the pharmaceutical industry has increased its involvement in our speciality. This article is a brief summary of the major scientific contributions presented at the annual congress 2009, highlighting the fields of nuclear medicine at a higher level of development, including those with an increased clinical impact (especially oncology, but also cardiology, neurology and other clinical sciences), new detectors and multimodality imaging, and those fields showing important progress, including radiochemistry and pharmacy (with the development of new tracers and increased collaboration of industry). PMID- 20198476 TI - Chiari's network: review of the literature. AB - The Chiari network, present in approximately 2% of the population, and is a reticulated network of fibers originating from the Eustachian connecting to different parts of the right atrium. Its presence results from incomplete reabsorption of the right valve of the sinus venosus. Chiari's network is often clinically insignificant. However, it has been reported to be involved in the pathogenesis of thromboembolic disease, endocarditis, arrhythmias, and entrapment of catheters upon percutaneous intervention. While initially discovered and researched using autopsy dissections, Chiari's network is often found as an incidental finding on diagnostic imaging studies, thus providing new methods for studying its incidence and clinical significance. PMID- 20198477 TI - The role of the retrograde colonic enema in children with spina bifida: is it inferior to the antegrade continence enema? AB - OBJECTIVES: The aim of this study was to evaluate the efficacy of the retrograde colonic enema relative to the Malone antegrade continence enema. METHODS: We retrospectively investigated 25 children with spina bifida and fecal incontinence. Thirteen children had started retrograde colonic enema and twelve had started Malone antegrade continence enema. Fecal continence, water volume, time to washout, procedure frequency, pain during procedure, performance independence and demographical data were compared between the two groups. RESULTS: Fecal continence was achieved for 10 of 13 (76.9%) in the retrograde group and 9 of 12 (75.0%) in the antegrade group. In the antegrade group 8 of 12 (66.7%) performed procedure independently, while 3 of 13 (23.1%) did so in the retrograde group. Achievement of fecal continence did not differ between the groups, but procedure independence was significantly better in the antegrade group. CONCLUSIONS: Our results suggest that retrograde colonic enema was not inferior to Malone antegrade continence enema on fecal continence. We recommend considering retrograde colonic enema prior to introduction of Malone antegrade continence enema in children with spina bifida. PMID- 20198478 TI - Ectopic breast tissue at the anal verge--an unusual finding. PMID- 20198479 TI - Analysis of microdissected human neurons by a sensitive ELISA reveals a correlation between elevated intracellular concentrations of Abeta42 and Alzheimer's disease neuropathology. AB - In Alzheimer's disease (AD), Purkinje neurons in the cerebellum are spared, while, for instance, pyramidal neurons in the hippocampus are neuropathologically affected. Several lines of evidence suggest that the pathogenesis could be induced by the concentration-dependent polymerization of the amyloid beta-peptide (Abeta) into extracellular oligomers. The role of intracellular Abeta is not fully investigated, but recent data indicate that also this pool could be of importance. Here, we use laser capture microdissection microscopy for isolation of Purkinje neurons from AD cases and controls, and quantify the low levels of intracellular Abeta using a novel and highly sensitive ELISA. Similar to Cornu Ammonis 1 pyramidal neurons, the intracellular levels of the most toxic variant, Abeta42, as well as the Abeta42/Abeta40 ratio, were increased in Purkinje neurons from sporadic AD cases as compared to controls. However, the levels of Abeta42 as well as Abeta40 were clearly lower in Purkinje neurons than in pyramidal neurons. Based on the volume of the captured Purkinje neurons, the intraneuronal concentrations of Abeta42 were calculated to be 200 nM in sporadic AD cases and 90 nM in controls. The corresponding concentrations in pyramidal neurons from hippocampus were 3 muM and 660 nM, respectively. The Abeta40 concentration was not significantly altered in AD cases compared to controls. However, we found ten times higher concentration of Abeta40 in pyramidal neurons (10 muM) compared to Purkinje neurons (1 muM). Finally, we suggest that high concentration of intracellular Abeta42 correlates with vulnerability to AD neuropathology. PMID- 20198480 TI - Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis. AB - Abnormal TDP-43 aggregation is a prominent feature in the neuropathology of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. Mutations in TARDBP, the gene encoding TDP-43, cause some cases of ALS. The normal function of TDP-43 remains incompletely understood. To better understand TDP-43 biology, we generated mutant mice carrying a genetrap disruption of Tardbp. Mice homozygous for loss of TDP-43 are not viable. TDP-43 deficient embryos die about day 7.5 of embryonic development thereby demonstrating that TDP 43 protein is essential for normal prenatal development and survival. However, heterozygous Tardbp mutant mice exhibit signs of motor disturbance and muscle weakness. Compared with wild type control littermates, Tardbp (+/-) animals have significantly decreased forelimb grip strength and display deficits in a standard inverted grid test despite no evidence of pathologic changes in motor neurons. Thus, TDP-43 is essential for viability, and mild reduction in TDP-43 function is sufficient to cause motor deficits without degeneration of motor neurons. PMID- 20198481 TI - Protein coding of neurodegenerative dementias: the neuropathological basis of biomarker diagnostics. AB - Neuropathological diagnosis of neurodegenerative dementias evolved by adapting the results of neuroanatomy, biochemistry, and cellular and molecular biology. Milestone findings of intra- and extracellular argyrophilic structures, visualizing protein deposition, initiated a protein-based classification. Widespread application of immunohistochemical and biochemical investigations revealed that (1) there are modifications of proteins intrinsic to disease (species that are phosphorylated, nitrated, oligomers, proteinase-resistant, with or without amyloid characteristics; cleavage products), (2) disease forms characterized by the accumulation of a single protein only are rather the exception than the rule, and (3) some modifications of proteins elude present neuropathological diagnostic procedures. In this review, we summarize how neuropathology, together with biochemistry, contributes to disease typing, by demonstrating a spectrum of disorders characterized by the deposition of various modifications of various proteins in various locations. Neuropathology may help to elucidate how brain pathologies alter the detectability of proteins in body fluids by upregulation of physiological forms or entrapment of different proteins. Modifications of at least the five most relevant proteins (amyloid beta, prion protein, tau, alpha-synuclein, and TDP-43), aided by analysis of further "attracted" proteins, are pivotal to be evaluated simultaneously with different methods. This should complement the detection of biomarkers associated with pathogenetic processes, and also neuroimaging and genetic analysis, in order to obtain a highly personalized diagnostic profile. Defining clusters of patients based on the patterns of protein deposition and immunohistochemically or biochemically detectable modifications of proteins ("codes") may have higher prognostic predictive value, may be useful for monitoring therapy, and may open new avenues for research on pathogenesis. PMID- 20198482 TI - Focal demyelination in Alzheimer's disease and transgenic mouse models. AB - We have investigated alterations in myelin associated with Abeta plaques, a major pathological hallmark of Alzheimer's disease (AD), in human tissue and relevant transgenic mice models. Using quantitative morphological techniques, we determined that fibrillar Abeta pathology in the grey matter of the neocortex was associated with focal demyelination in human presenilin-1 familial, sporadic and preclinical AD cases, as well as in two mouse transgenic models of AD, compared with age-matched control tissue. This demyelination was most pronounced at the core of Abeta plaques. Furthermore, we found a focal loss of oligodendrocytes in sporadic and preclinical AD cases associated with Abeta plaque cores. In human and transgenic mice alike, plaque-free neocortical regions showed no significant demyelination or oligodendrocyte loss compared with controls. Dystrophic neurites associated with the plaques were also demyelinated. We suggest that such plaque associated focal demyelination of the cortical grey matter might impair cortical processing, and may also be associated with aberrant axonal sprouting that underlies dystrophic neurite formation. PMID- 20198483 TI - A novel seven-octapeptide repeat insertion in the prion protein gene (PRNP) in a Dutch pedigree with Gerstmann-Straussler-Scheinker disease phenotype: comparison with similar cases from the literature. AB - Human prion diseases can be sporadic, inherited or acquired by infection and show considerable phenotypic heterogeneity. We describe the clinical, histopathological and pathological prion protein (PrP(Sc)) characteristics of a Dutch family with a novel 7-octapeptide repeat insertion (7-OPRI) in PRNP, the gene encoding the prion protein (PrP). Clinical features were available in four, neuropathological features in three and biochemical characteristics in two members of this family. The clinical phenotype was characterized by slowly progressive cognitive decline, personality change, lethargy, depression with anxiety and panic attacks, apraxia and a hypokinetic-rigid syndrome. Neuropathological findings consisted of numerous multi- and unicentric amyloid plaques throughout the cerebrum and cerebellum with varying degrees of spongiform degeneration. Genetic and molecular studies were performed in two male family members. One of them was homozygous for valine and the other heterozygous for methionine and valine at codon 129 of PRNP. Sequence analysis identified a novel 168 bp insertion [R2-R2-R2-R2-R3g-R2-R2] in the octapeptide repeat region of PRNP. Both patients carried the mutation on the allele with valine at codon 129. Western blot analysis showed type 1 PrP(Sc) in both patients and detected a smaller ~8 kDa PrP(Sc) fragment in the cerebellum in one patient. The features of this Dutch kindred define an unusual neuropathological phenotype and a novel PRNP haplotype among the previously documented 7-OPRI mutations, further expanding the spectrum of genotype-phenotype correlations in inherited prion diseases. PMID- 20198485 TI - Hemoperitoneum in pregnancy from a ruptured varix of broad ligament. AB - We present a case of a 31-year-old woman, gravida 4 para 1, pregnant at 33 + 2 weeks of gestational age with acute abdomen due to hemoperitoneum. Hemoperitoneum was suspected for non-specific symptoms such as acute abdominal pain, vomit, cardiotocography alterations and maternal acute anaemia. An emergency caesarean section was performed; 3 L of blood was present in abdomen. Careful exploration of the uterus, placenta, abdominal organs and vessels was negative; only a bleeding from a rupture in a varix of the left broad ligament was observed. Hemoperitoneum due to a ruptured uterine varix in pregnancy is a rare condition. The solution to prevent the development of maternal hypovolemic shock is an immediate surgical intervention. A good foetal prognosis principally depends from gestational age and from good hemodynamic maternal conditions. PMID- 20198486 TI - May platelet count be a predictor of low-risk persistent gestational trophoblastic disease? AB - PURPOSE: The aim of this paper was to determine whether platelet count could be used as an early marker to predict low-risk persistent trophoblastic disease (PTD) from complete hydatidiform mole (CHM). METHODS: This study included 27 PTD, 30 CHM, and 30 healthy pregnant women. All patients were evaluated with respect to age, gestational age, parity, BMI, and platelet count. All women had low-risk disease using FIGO and WHO scoring systems. RESULTS: There were no significant differences in terms of age, gestational age, parity, BMI between the groups (P > 0.05, for all). Platelet levels were lower in patients with low-risk PTD compared with CHM and healthy pregnant group (P = 0.001 and P < 0.0001, respectively). Platelet levels were also found to be lower in patients with CHM than in healthy pregnancies (P = 0.006). There was a negative relationship between platelet count and low-risk PTD (r = 0.47, P < 0.0001) in the study. The receiver operating characteristic curve analysis revealed a high diagnostic value for platelet count with respect to low-risk PTD with an area under curve of 0.80 (95% confidence interval = 0.89-0.90), sensitivity = 77% and specificity = 75%. CONCLUSION: Platelet count was significantly decreased in low-risk PTD compared with CHM and healthy pregnant controls. Platelet count can be used as a reliable marker for the early detection of low-risk PTD. PMID- 20198484 TI - The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes. AB - Autism is characterized by a broad spectrum of clinical manifestations including qualitative impairments in social interactions and communication, and repetitive and stereotyped patterns of behavior. Abnormal acceleration of brain growth in early childhood, signs of slower growth of neurons, and minicolumn developmental abnormalities suggest multiregional alterations. The aim of this study was to detect the patterns of focal qualitative developmental defects and to identify brain regions that are prone to developmental alterations in autism. Formalin fixed brain hemispheres of 13 autistic (4-60 years of age) and 14 age-matched control subjects were embedded in celloidin and cut into 200-mum-thick coronal sections, which were stained with cresyl violet and used for neuropathological evaluation. Thickening of the subependymal cell layer in two brains and subependymal nodular dysplasia in one brain is indicative of active neurogenesis in two autistic children. Subcortical, periventricular, hippocampal and cerebellar heterotopias detected in the brains of four autistic subjects (31%) reflect abnormal neuronal migration. Multifocal cerebral dysplasia resulted in local distortion of the cytoarchitecture of the neocortex in four brains (31%), of the entorhinal cortex in two brains (15%), of the cornu Ammonis in four brains and of the dentate gyrus in two brains. Cerebellar flocculonodular dysplasia detected in six subjects (46%), focal dysplasia in the vermis in one case, and hypoplasia in one subject indicate local failure of cerebellar development in 62% of autistic subjects. Detection of flocculonodular dysplasia in only one control subject and of a broad spectrum of focal qualitative neuropathological developmental changes in 12 of 13 examined brains of autistic subjects (92%) reflects multiregional dysregulation of neurogenesis, neuronal migration and maturation in autism, which may contribute to the heterogeneity of the clinical phenotype. PMID- 20198487 TI - Visualization and follow-up of acute macular neuroretinopathy with the Spectralis HRA+OCT device. AB - BACKGROUND: Acute macular neuroretinopathy (AMNR) is a rare disease entity, the diagnosis of which is frequently complicated by the subtlety of biomicroscopic findings. METHODS: Two cases of AMNR are presented, in which the diagnosis and follow-up was enabled using the Spectralis HRA+OCT in the absence of clear biomicroscopic findings. RESULTS: The typical lesions were visualized by hyporeflexion during infrared imaging and faded over time. With spectral domain optical coherence tomography, changes in the outer retina in the affected regions were documented, with no change over time. CONCLUSION: The broader availability of this technology may enhance the diagnosis and follow-up of AMNR. PMID- 20198489 TI - Can intraoperative manometry during laparoscopic fundoplication predict postoperative dysphagia? AB - BACKGROUND: Many trials have used intraesophageal manometry (IEM) to measure the adequacy of fundoplication. This pilot study aimed to assess the value of IEM in predicting postoperative dysphagia. METHODS: A series of 40 patients underwent IEM studies before operative correction of gastroesophageal reflux disease and repeat studies 3 months after the procedure. During the operation, IEM studies were undertaken before pneumoperitoneum was established, after pneumoperitoneum, after pneumoperitoneum with fundoplication, and after fundoplication without pneumoperitoneum. All the patients were followed up 1, 6, and 12 months after the procedure for assessment to detect persistent reflux and postfundoplication dysphagia. RESULTS: Three patients demonstrated persistent dysphagia at the 12 month follow-up point. No statistically significant differences in preoperative manometry findings were observed in the dysphagic and nondysphagic groups, with the dysphagic group showing higher pressures. However, at the operation, statistically significant differences in the lower esophageal sphincter pressures were observed after anesthesia and no pneumoperitoneum (30.3 vs. 13.4 cm H(2)O; p =0.002), after anesthesia with pneumoperitoneum (40.3 vs. 18.3 cm H(2)O; p < 0.001), and after fundoplication with pneumoperitoneum (47.3 vs. 23.4 cm H(2)O; p = 0.001). No statistically significant differences were demonstrated in postoperative manometry at the 3-month follow-up point. CONCLUSION: Intraoperative manometry may be a useful tool compared with postoperative manometry in identifying patients who may experience postfundoplication dysphagia. PMID- 20198490 TI - Single-incision laparoscopic cholecystectomy is feasible: initial experience with 80 cases. AB - BACKGROUND AND OBJECTIVE: Single-incision laparoscopic surgery (SILS) is a new advance wherein laparoscopic surgery is carried out through a single small incision hidden in the umbilicus. Advantages of this technique over standard laparoscopy are still under investigation. The objective of this study is to describe the short-term outcomes of SILS cholecystectomy in a single community based institution. METHODS: A retrospective review of a prospectively collected database for all patients who underwent SILS cholecystectomy was carried out. Both true single-incision and dual-incision (training) cases were included in the analysis. Operative and perioperative outcomes were analyzed. RESULTS: Eighty SILS cholecystectomies (4 dual incision and 76 single incision) were performed from May 30, 2008 to April 23, 2009 (indications: 48 stones, 20 cholecystitis, 11 biliary dyskinesia, and 1 polyp). Mean body mass index (BMI) was 26.5 kg/m(2) (range 17.3-39.1 kg/m(2)), mean operating room (OR) time was 69.5 min (range 29 126 min), mean estimated blood loss (EBL) was 5 cc, and mean incision length was 1.6 cm. There were no open conversions, but there were six conversions to dual port and three conversions to four-port laparoscopic cholecystectomy due to poor visualization. Complications include three bile leaks managed with endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous drainage (3.7%). Two leaks were from accessory ducts and one was from a cystic duct stump. Number of days of postoperative oral narcotic use was described as none in 11 patients (23%), minimal (1 day) in 21 patients (45%), moderate (1-3 days) in 6 patients (13%), and heavy (>= 4 days) in 9 patients (19%), with mean follow-up of 4.7 months in 60 patients. CONCLUSION: SILS cholecystectomy is feasible, with acceptable morbidity. Although not directly compared in this study, postoperative recovery appears shorter than after standard laparoscopy, but more studies are needed. PMID- 20198491 TI - Prospective randomized controlled trial of an injectable esophageal prosthesis versus a sham procedure for endoscopic treatment of gastroesophageal reflux disease. AB - BACKGROUND: This study aimed to assess whether endoscopic implantation of an injectable esophageal prosthesis, the Gatekeeper Reflux Repair System (GK), is a safe and effective therapy for controlling gastroesophageal reflux disease (GERD). METHODS: A prospective, randomized, sham-controlled, single-blinded, international multicenter study planned final enrollment of 204 patients in three groups: up to 60 lead-in, 96 GK, and 48 sham patients. The sham patients were allowed to cross over to the GK treatment arm or exit the study at 6 months. The primary end points were (1) reduction in serious device- and procedure-related adverse device effects compared with a surgical composite complication rate and (2) reduction in heartburn symptoms 6 months after the GK procedure compared with the sham procedure. The secondary end point was improved esophageal pH (total time pH was <4) 6 months after the GK procedure compared with baseline. RESULTS: A planned interim analysis was performed after 143 patients were enrolled (25 lead-in, 75 GK, and 43 sham patients), and the GK study was terminated early due to lack of compelling efficacy data. Four reported serious adverse events had occurred (2 perforations, 1 pulmonary infiltrate related to a perforation, and 1 severe chest pain) at termination of the study with no mortality or long-term sequelae. Heartburn symptoms had improved significantly at 6 months compared with baseline in the GK group (p < 0.0001) and the sham group (p < 0.0001), but no significant between-group difference in improvement was observed (p = 0.146). Esophageal acid exposure had improved significantly at 6 months compared with baseline in the GK group (p = 0.021) and the sham group (p = 0.003), but no significant between-group difference in improvement was observed (p = 0.27). CONCLUSIONS: The GK procedure was associated with some serious but infrequent complications. No statistically significant difference in outcomes was observed between the treatment and control groups at 6 months compared with baseline. PMID- 20198492 TI - Novel antimicrobial peptides from the venom of the eusocial bee Halictus sexcinctus (Hymenoptera: Halictidae) and their analogs. AB - Two novel antimicrobial peptides, named halictines, were isolated from the venom of the eusocial bee Halictus sexcinctus. Their primary sequences were established by ESI-QTOF mass spectrometry, Edman degradation and enzymatic digestion as Gly Met-Trp-Ser-Lys-Ile-Leu-Gly-His-Leu-Ile-Arg-NH2 (HAL-1), and Gly-Lys-Trp-Met-Ser Leu-Leu-Lys-His-Ile-Leu-Lys-NH2 (HAL-2). Both peptides exhibited potent antimicrobial activity against Gram-positive and Gram-negative bacteria but also noticeable hemolytic activity. The CD spectra of HAL-1 and HAL-2 measured in the presence of trifluoroethanol or SDS showed ability to form an amphipathic alpha helical secondary structure in an anisotropic environment such as bacterial cell membrane. NMR spectra of HAL-1 and HAL-2 measured in trifluoroethanol/water confirmed formation of helical conformation in both peptides with a slightly higher helical propensity in HAL-1. Altogether, we prepared 51 of HAL-1 and HAL-2 analogs to study the effect of such structural parameters as cationicity, hydrophobicity, alpha-helicity, amphipathicity, and truncation on antimicrobial and hemolytic activities. The potentially most promising analogs in both series are those with increased net positive charge, in which the suitable amino acid residues were replaced by Lys. This improvement basically relates to the increase of antimicrobial activity against pathogenic Pseudomonas aeruginosa and to the mitigation of hemolytic activity. PMID- 20198493 TI - Shotgun strategy-based proteome profiling analysis on the head of silkworm Bombyx mori. AB - Insect head is comprised of important sensory systems to communicate with internal and external environment and endocrine organs such as brain and corpus allatum to regulate insect growth and development. To comprehensively understand how all these components act and interact within the head, it is necessary to investigate their molecular basis at protein level. Here, the spectra of peptides digested from silkworm larval heads were obtained from liquid chromatography tandem mass spectrometry (LC-MS/MS) and were analyzed by bioinformatics methods. Totally, 539 proteins with a low false discovery rate (FDR) were identified by searching against an in-house database with SEQUEST and X!Tandem algorithms followed by trans-proteomic pipeline (TPP) validation. Forty-three proteins had the theoretical isoelectric point (pI) greater than 10 which were too difficult to separate by two-dimensional gel electrophoresis (2-DE). Four chemosensory proteins, one odorant-binding protein, two diapause-related proteins, and a lot of cuticle proteins, interestingly including pupal cuticle proteins were identified. The proteins involved in nervous system development, stress response, apoptosis and so forth were related to the physiological status of head. Pathway analysis revealed that many proteins were highly homologous with the human proteins which involved in human neurodegenerative disease pathways, probably implying a symptom of the forthcoming metamorphosis of silkworm. These data and the analysis methods were expected to be of benefit to the proteomics research of silkworm and other insects. PMID- 20198494 TI - Radiolabeled CCK/gastrin peptides for imaging and therapy of CCK2 receptor expressing tumors. AB - Cholecystokinin (CCK) receptors are overexpressed in numerous human cancers, like medullary thyroid carcinomas, small cell lung cancers and stromal ovarian cancers. The specific receptor-binding property of the endogenous ligands for these receptors can be exploited by labeling peptides with a radionuclide and using these as carriers to guide the radioactivity to the tissues that express the receptors. In this way, tumors can be visualized using positron emission tomography and single photon emission computed tomography imaging. A variety of radiolabeled CCK/gastrin-related peptides has been synthesized and characterized for imaging. All peptides have the C-terminal CCK receptor-binding tetrapeptide sequence Trp-Met-Asp-Phe-NH(2) in common or derivatives thereof. This review focuses on the development and application of radiolabeled CCK/gastrin peptides for radionuclide imaging and radionuclide therapy of tumors expressing CCK receptors. We discuss both preclinical studies as well as clinical studies with CCK and gastrin peptides. PMID- 20198495 TI - Resection of the nerves bundle from the sphenopalatine ganglia tend to increase the infarction volume following middle cerebral artery occlusion. AB - Blocking or impairment of the sphenopalatine ganglia (SPG) is an effective therapy of cluster headache and other pain syndromes. Contrarily, unilateral SPG stimulation reduces infarction size in the rat permanent suture model. Well, what are the effects of the SPG damage on the following brain ischemia? This study was aimed to investigate the effects of resection of the nerves bundle from the SPG of rat on the brain lesions following middle cerebral artery occlusion (MCAO), and evaluated the roles of the nitric oxygen synthase (NOS) immunoreactive perivascular nerves of cerebral arteries in MCAO. We found that 7 days after bilateral resections of the nerves bundle from the SPG, the NOS activity perivascular nerves in the middle cerebral arteries disappeared, and the infarction volume and the TUNEL positive cells increased significantly after 24 h MCAO, which implicated that the NOS contained nerves from the SPG maybe have an important role in the MCAO. PMID- 20198496 TI - Magnetic resonance imaging of pachymeningeal enhancement in Vogt-Koyanagi-Harada disease. AB - Vogt-Koyanagi-Harada (VKH) disease is a systemic disease consisting of bilateral granulomatous panuveitis combined with cutaneous and neurologic manifestations. However, there have been few reports of brain magnetic resonance imaging (MRI) in VKH disease. A 54-year-old Korean woman presented with severe periorbital pain, blurred vision and meningismus. Ophthalmologic examination disclosed bilateral optic disc edema with peripapillary nerve fiber hemorrhages. Lumbar puncture revealed monocytic pleocytosis. After a diagnosis of VKH disease was made, the patient was treated with high-dose corticosteroid. Brain MRI showed diffusely thickened posterior ocular walls with retinal detachment and perineural infiltrative changes along the optic nerves and adjacent pachymeningeal enhancement of the anterior temporal lobes bilaterally. We report a case of VKH disease with panuveitis and meningeal involvement of the anterior temporal lobe detected by brain MRI. PMID- 20198497 TI - Acute multiple cranial neuropathy in a patient with neurosarcoidosis. PMID- 20198498 TI - Analysis of association between bleomycin hydrolase and apolipoprotein E polymorphism in Alzheimer's disease. AB - Alzheimer's disease (AD) is the leading cause of dementia. Several studies indicate a possible relationship between different genes and Alzheimer's disease. To further investigate, we have analyzed the association between the bleomycin hydrolase (BLMH) and apolipoprotein E (ApoE) polymorphisms in 93 AD patients and age- and sex-matched 113 controls from the Tunisian population. The frequency of ApoE epsilon 4 allele was found to differ significantly in AD patients compared to the control [29.5% vs. 8.8 (chi (2) = 26, df = 1, p < 0.001)] leading to an increased risk of AD in subjects with this allele (OR = 3.29, 95% CI = 1.7-6.5; p = 0.001]. This risk was found to decrease from OR = 8.4, CI = 3.3-23; p < 0.001 in subjects less than 75 years old to OR = 1.2, CI = 1.031-14; p = 0.0297 in subjects 75 years and older. No association was observed between carrying the BLMH-G genotype and AD in epsilon4 negative or positive subjects. PMID- 20198499 TI - Tolosa-Hunt syndrome with reversible dissection aneurysm. AB - A 49-year-old female presented with recurrent intolerable right retro-orbital pain, ptosis and diplopia for 4 months. Neurological evaluation revealed right oculomotor nerve and abducent nerve injuries. Neuroimaging found enlarged right cavernous sinus, right intracavernous carotid dissection aneurysm and a stenosis proximal to it. Tolosa-Hunt syndrome (THS) was suggested and treated with steroid. The clinical symptoms were alleviated after the treatment. After 3 months of follow-up cerebral angiography showed the lesions of the right intracavernous carotid stenosis and the dissection almost disappeared. Therefore, we proposed that the dissection and the stenosis are directly induced by the inflammation of THS. PMID- 20198500 TI - Hemangiopericytoma: collision with meningioma and recurrence. AB - Intracranial hemangiopericytomas are a rare type of primary brain tumor, representing only about 0.5% of all primary brain tumors. Even more rare is the co-existence of two juxtaposed primary brain tumors, termed a "collision" tumor. This report provides the first documentation in the literature of a hemangiopericytoma colliding with a meningioma, and recurring after treatment with gross total resection. Surgical samples were fully evaluated with hematoxylin and eosin and reticulin staining, as well as immunohistochemical analysis. Results were classically representative of a hemangiopericytoma (World Health Organization grade II) and of a meningioma (World Health Organization grade I). This report of a unique collision tumor not only augments the repertoire of collision tumor combinations described in literature but also provides follow-up on the clinical outcome of the patient, thereby raising clinically relevant issues ranging from presentation to treatment paradigms. PMID- 20198501 TI - Intensities of DNA ion-phosphate modes in the low-frequency Raman spectra. AB - The Raman intensities of counterion vibrations with respect to the phosphate groups of the double-helix backbone (ion-phosphate modes) in the low-frequency spectra (< 200 cm(-1)) of B -DNA with different alkali metal counterions have been calculated using the model for DNA conformational vibrations and the valence optic approach. The results have showed that the spectra of DNA with heavy counterions (Rb(+) and Cs(+)) differ from the spectra of DNA with light counterions (Na(+) and K(+)). The calculated spectra of DNA with heavy counterions are characterized by intensive modes of ion-phosphate vibrations that form one united band near 115 cm(-1). Ion-phosphate modes in the spectra of DNA with light counterions are characterized by higher frequencies (near 180 cm(-1)) and much lower intensity. Our calculations explain why the modes of ion-phosphate vibrations are observed in Cs-DNA spectra rather than in Na-DNA. The determined sensitivity of the intensities of DNA low-frequency spectra to the counterion type proves the existence of the ion-phosphate modes. PMID- 20198503 TI - Emerging therapies for atrial fibrillation: is the paradigm shifting? PMID- 20198502 TI - Tumor necrosis factor-mediated cell death: to break or to burst, that's the question. AB - In this review, we discuss the signal-transduction pathways of three major cellular responses induced by tumor necrosis factor (TNF): cell survival through NF-kappaB activation, apoptosis, and necrosis. Recruitment and activation of caspases plays a crucial role in the initiation and execution of TNF-induced apoptosis. However, experimental inhibition of caspases reveals an alternative cell death pathway, namely necrosis, also called necroptosis, suggesting that caspases actively suppress the latter outcome. TNF-induced necrotic cell death crucially depends on the kinase activity of receptor interacting protein serine threonine kinase 1 (RIP1) and RIP3. It was recently demonstrated that ubiquitination of RIP1 determines whether it will function as a pro-survival or pro-cell death molecule. Deeper insight into the mechanisms that control the molecular switches between cell survival and cell death will help us to understand why TNF can exert so many different biological functions in the etiology and pathogenesis of human diseases. PMID- 20198504 TI - Same morphology of ventricular premature complexes triggering repeated ventricular fibrillation. AB - BACKGROUND: Episodes ventricular fibrillation (VF) initiated by ventricular premature complexes (VPCs) of a single morphology have been reported. However, the characteristics of the VPCs over long periods of time are unknown. OBJECTIVES: To compare the morphologies and coupling intervals of VPCs that initiate episodes of VF that occur at different time periods. METHODS: The database of the follow-up of the International Classification of Diseases (ICD) unit was reviewed and patients having at least two spontaneous VF episodes with available recorded EGMs in unipolar and bipolar configuration were included in the study. The coupling interval and morphology of the initiating beat were analyzed. RESULTS: Nine out of 300 patients with ICD had two or more spontaneous VF episodes. The time interval between episodes ranged from seconds (arrhythmic storm) to 3 years. The fibrillatory VPCs presented the same morphology in both recordings in all episodes of each patient. The coupling intervals of VPCs initiating VF were close for the episodes that occurred during a single arrhythmic storm and were more variable when the time intervals between episodes of VF were longer. CONCLUSION: VPCs triggering VF that occur at different times in the same patient have similar morphologies suggesting similar sites of origin for the initial VPC of VF in each patient. PMID- 20198505 TI - Impact of left ventricular lead position on the incidence of ventricular arrhythmia and clinical outcome in patients with cardiac resynchronization therapy. AB - PURPOSE: The aim of the study was to evaluate the incidence of ventricular arrhythmia and clinical outcome in patients receiving a cardiac resynchronization therapy (CRT) depending on the left ventricular (LV) lead position. METHODS: A total of 187 consecutive patients with advanced heart failure who received a CRT implantable cardioverter defibrillator were analyzed. Forty patients (21%) had a LV lead in the anterior/apical (anterior) and 147 patients (79%) in the posterior/posterolateral (posterior) region. The total median follow-up time was 644 days. RESULTS: The incidence of ventricular arrhythmia was 35% in patients with an anterior LV lead versus 30% in patients with a posterior LV lead (p = 0.53). The 1- and 2-year mortality in the anterior LV lead group was 19% and 22%, as compared with 0.7% and 3.2%, respectively, in the posterior LV lead group (p < 0.001). In a multivariable analysis, an anterior LV lead was independently associated with an increased mortality (hazard ratio 5.88, 95% confidence interval 2.22-16.67). The major cause of death was end-stage heart failure whereas the incidence of sudden cardiac death was not different between both groups. CONCLUSIONS: Thus, biventricular pacing with an anterior LV lead seems to have no impact on the incidence of ventricular arrhythmia but may be associated with an increased mortality rate due to worsening heart failure. PMID- 20198506 TI - Poverty and childhood cancer incidence in the United States. AB - This study examined socioeconomic differentials in cancer incidence rates during 2000-2005 among children aged 0-19 in the United States. The data on childhood cancers, which were classified by the International Classification of Childhood Cancer, Third Edition (ICCC-3), were obtained from the Surveillance, Epidemiology, and End Results program. The socioeconomic status of residential area at diagnosis was estimated by county-level poverty rate in Census 2000, i.e., percentage of persons in the county living below the national poverty thresholds. Counties were categorized as low-, medium-, and high-poverty areas when the poverty rates were <10, 10-19.99, and 20% or higher, respectively. The results showed that medium- and high-poverty counties had lower age-adjusted incidence rates than low-poverty counties for total childhood cancers combined, central nervous system neoplasms (ICCC group III), neuroblastoma (group IV), renal tumors (group VI), and other malignant epithelial neoplasms and malignant melanomas (group XI). When the data were stratified by race, these associations were observed among whites, but not blacks. For leukemia (group I), poor counties had higher incidence rates than affluent counties for whites, but lower rates for blacks. This ecologic study provides perspective on area socioeconomic variations in childhood cancer incidence that warrants further research. PMID- 20198507 TI - Dietary patterns and risk of advanced prostate cancer: a principal component analysis in Uruguay. AB - OBJECTIVE: In order to explore the role of broader eating patterns in the etiology of prostate cancer, we conducted a principal components analysis among Uruguayan men. METHODS: The study included 345 newly diagnosed cases of advanced prostate cancer and 690 hospitalized controls. The factor analysis was performed using the control population. RESULTS: Factor analysis allowed the extraction of five patterns, labeled as prudent, traditional, substituter, drinker, and Western. Whereas the traditional and Western patterns were directly associated with risk of prostate cancer (OR for high quartile versus the low quartile of the Western diet was 2.35, 95% CI 1.44-3.85, p-value for trend < 0.0001), the prudent, drinker, and substituter patterns were not associated with risk of the disease. After adjustment of each pattern for the foods with high loadings, these three patterns did not modify substantially their original ORs. CONCLUSION: The Western and traditional patterns could partially explain the high incidence of advanced prostate cancer in Uruguay, a main producer of beef in the World. PMID- 20198508 TI - Salinity variations in the water resources fed by the Etnean volcanic aquifers (Sicily, Italy): natural vs. anthropogenic causes. AB - In this paper, in an attempt to reveal possible changes connected to natural or anthropogenic causes, the main results of hydrogeochemical monitoring carried out at Mount Etna are evaluated. We report on the salinity contents of the groundwaters that flow in fractured volcanics, which make up the flanks of the volcano. These waters, analyzed for major ion chemistry, were sampled regularly from 1994 to 2004. Basing on nonparametric Sen's slope estimator, time series of groundwater composition reveal that the salinity of most of the Etnean aquifers increased by 0.5% to 3.5% each year during this period. This change in the water chemistry is clearly referable to the overexploitation of the aquifers. This increasing trend needs to be inverted urgently; otherwise, it will cause a shortage of water in the near future, because the maximum admissible concentration of salinity for drinking water will be exceeded. PMID- 20198509 TI - An exploratory factor analysis of the Burden Assessment Scale with a sample of African-American families. AB - It remains unclear if the factor structures of commonly used caregiver burden scales normed on white samples are similar with samples from different ethnic communities. Our study tests the factor structure of the Burden Assessment Scale (BAS) using Exploratory Factor Analysis (EFA) with data from low-income, African American families caring for a family member with schizophrenia. The EFA solution included a 2 factor structure of subjective burden and objective burden with strong loadings demonstrating a clear differentiation between the factors. Our results suggest that low income, African American families appear to experience caregiving burden as one major or broad component in their lives similar to other areas that demand ongoing coping and adaptation. Likewise, the factor structure found with this sample as compared to the factor structure found with white samples suggests differences in the perception of and/or the reporting of burden. Study limitations as well as implications for practice are provided. PMID- 20198510 TI - Electrically active bioceramics: a review of interfacial responses. AB - Electrical potentials in mechanically loaded bone have been implicated as signals in the bone remodeling cycle. Recently, interest has grown in exploiting this phenomenon to develop electrically active ceramics for implantation in hard tissue which may induce improved biological responses. Both polarized hydroxyapatite (HA), whose surface charge is not dependent on loading, and piezoelectric ceramics, which produce electrical potentials under stress, have been studied in order to determine the possible benefits of using electrically active bioceramics as implant materials. The polarization of HA has a positive influence on interfacial responses to the ceramic. In vivo studies of polarized HA have shown polarized samples to induce improvements in bone ingrowth. The majority of piezoelectric ceramics proposed for implant use contain barium titanate (BaTiO(3)). In vivo and in vitro investigations have indicated that such ceramics are biocompatible and, under appropriate mechanical loading, induce improved bone formation around implants. The mechanism by which electrical activity influences biological responses is yet to be clearly defined, but is likely to result from preferential adsorption of proteins and ions onto the polarized surface. Further investigation is warranted into the use of electrically active ceramics as the indications are that they have benefits over existing implant materials. PMID- 20198511 TI - Growth patterns of abdominal atherosclerotic calcified deposits from lumbar lateral X-rays. AB - The aim of this study is to investigate new methods for describing the progression of atherosclerosis based on novel information of the growth patterns of individual abdominal aortic calcifications (AACs) over time. Lateral X-ray images were used due to their low cost, fast examination time, and wide-spread use, which facilitates a large statistical model (n > 100) based on longitudinal data. The examined cohort consisted of 103 post-menopausal women aged 62.4 years (+/- 7.0 years) with an average number of AACs of (4.7 +/- 8.0) at baseline. The subjects had X-ray images taken in 1992-1993 (baseline) and again in 2000-2001 (follow-up). The growth patterns of the individual AACs were derived based on registered baseline and follow-up images. Area, height, width, centre of mass position, and movement of the centre of mass, and upper and lower boundary of the matched AACs were measured. The AACs occurred first, mainly, on the posterior aortic wall. The AACs grew on average 41 in the longitudinal direction and 21 in the radial direction. A correlation of 0.48 (P < 0.001) between growth in width and height of the AACs was present. The centre of mass of the AACs moved 0.60 mm (P < 0.001) downstream in the aorta, on average. The growth patterns of AACs may give new insights into the progression of atherosclerosis. The downstream asymmetry in the growth patterns indicates variability in microscopic environments around the AACs. PMID- 20198512 TI - Inflammation accelerates atherosclerotic processes in obstructive sleep apnea syndrome (OSAS). AB - Obstructive sleep apnea syndrome (OSAS) is an often underestimated sleep disorder that has been associated with cardiovascular disease. OSAS is characterized by cycles of apnea and/or hypopnea during sleep caused by the collapse of the upper airways. Intermittent hypoxia deriving from the cycles of apnea/arousals (to retrieve the ventilation) plays a pivotal role in the pathogenesis of the disease. Obesity is the most frequent predisposing condition of OSAS. Recent evidence suggests that OSAS could be considered as a pro-atherosclerotic disease, independently of visceral fat amount. Oxidative stress, cardiovascular inflammation, endothelial dysfunction, and metabolic abnormalities in OSAS could accelerate atherogenesis. The present review is focused on the possible pathophysiological mediators which could favor atherosclerosis in OSAS. PMID- 20198513 TI - Use of EEG monitoring and management of non-convulsive seizures in critically ill patients: a survey of neurologists. AB - BACKGROUND: Continuous EEG monitoring (cEEG) of critically ill patients is frequently utilized to detect non-convulsive seizures (NCS) and status epilepticus (NCSE). The indications for cEEG, as well as when and how to treat NCS, remain unclear. We aimed to describe the current practice of cEEG in critically ill patients to define areas of uncertainty that could aid in designing future research. METHODS: We conducted an international survey of neurologists focused on cEEG utilization and NCS management. RESULTS: Three hundred and thirty physicians completed the survey. 83% use cEEG at least once per month and 86% manage NCS at least five times per year. The use of cEEG in patients with altered mental status was common (69%), with higher use if the patient had a prior convulsion (89%) or abnormal eye movements (85%). Most respondents would continue cEEG for 24 h. If NCS or NCSE is identified, the most common anticonvulsants administered were phenytoin/fosphenytoin, lorazepam, or levetiracetam, with slightly more use of levetiracetam for NCS than NCSE. CONCLUSIONS: Continuous EEG monitoring (cEEG) is commonly employed in critically ill patients to detect NCS and NCSE. However, there is substantial variability in current practice related to cEEG indications and duration and to management of NCS and NCSE. The fact that such variability exists in the management of this common clinical problem suggests that further prospective study is needed. Multiple points of uncertainty are identified that require investigation. PMID- 20198515 TI - Transcranial Doppler ultrasound CO2 challenge complicated by subarachnoid hemorrhage in patient with moyamoya syndrome. AB - INTRODUCTION: Studies to assess the hemodynamic status of patients with moyamoya syndrome are often done to determine the need for surgical revascularization. These studies, including transcranial Doppler (TCD) ultrasonography to assess vasomotor reactivity (VMR) to CO(2), are generally considered safe. CASE: We describe a patient with moyamoya syndrome who experienced a subarachnoid hemorrhage (SAH) following TCD with CO(2) challenge. CONCLUSION: SAH has not previously been described as a complication of CO(2) challenge in patients with moyamoya syndrome. While such complications are rare, it is important to consider the possibility of harm related to VMR testing in patients with advanced vasculopathy. PMID- 20198514 TI - Dexmedetomidine controls agitation and facilitates reliable, serial neurological examinations in a non-intubated patient with traumatic brain injury. AB - INTRODUCTION: We report the effective use of dexmedetomidine in the treatment of a patient with a history of chronic alcohol abuse and an acute traumatic brain injury who developed agitation that was unresolved if from traumatic brain injury, or alcohol withdrawal or the combination of both. Treatment with benzodiazepines failed; lorazepam therapy obscured our ability to do reliable neurological testing to follow his brain injury and nearly resulted in intubation of the patient secondary to respiratory suppression. Upon admission to hospital, the patient was first treated with intermittent, prophylactic doses of lorazepam for potential alcohol withdrawal based upon our institution's standard of care. His neurological examinations including a motor score of 6 (obeying commands) on his Glasgow Coma Scale testing, laboratory studies, and repeat CT head imaging remained stable. For lack of published literature in diagnosing symptoms of patients with a history of both alcohol withdrawal and traumatic brain injury, a diagnosis of agitation secondary to presumed alcohol withdrawal was made when the patient developed acute onset of tachycardia, confusion, and extreme anxiety with tremor and attempts to climb out of bed requiring him to be restrained. Additional lorazepam doses were administered following a hospital-approved protocol for titration of benzodiazepine therapy for alcohol withdrawal. The patient's mental status and respiratory function deteriorated with the frequent lorazepam dosing needed to control his agitation. Dexmedetomidine IV infusion at a rate of 0.5 mcg/kg/h was then administered and was titrated ultimately to 1.5 mcg/kg/h. After 8 days of therapy with dexmedetomidine, the patient was transferred from the ICU to a step-down unit with an intact neurological examination and no evidence of alcohol withdrawal. Airway intubation was avoided during the patient's entire hospitalization. This case report highlights the intricate balance between the side effects of benzodiazepine sedation for treatment of agitation and the difficulties of monitoring the neurological status of non-intubated patients with traumatic brain injury. CONCLUSION: Given the large numbers of alcohol-dependent patients who suffer a traumatic brain injury and subsequently develop agitation and alcohol withdrawal in hospital, dexmedetomidine offers a novel strategy to facilitate sedation without neurological or respiratory depression. As this case report demonstrates, dexmedetomidine is an emerging treatment option for agitation in patients who require reliable, serial neurological testing to monitor the course of their traumatic brain injury. PMID- 20198516 TI - Stem cell research in the Greater Middle East: the importance of establishing policy and ethics interoperability to foster international collaborations. AB - While fossil fuel reserves have strengthened the economies of numerous countries in the Greater Middle East (GME) for decades, multiple nations within this region are now increasingly investing in internal science and engineering programs as a mechanism to develop more extensive knowledge-based economies. One of these newly pursued disciplines is stem cell research. Nations such as Saudi Arabia and Qatar have founded nascent programs while Iran, Turkey, and Israel are more established in the field. The extent to which these investments have been productive, as measured by publication quantity and impact, remains unknown. Here we assess the state of stem cell research in the GME, report on the policy and ethical considerations facing the region, and determine the impact of international research collaborations in this area. In the majority of the region, there is no legal framework regulating stem cell research. Instead, scientists often rely on religious decrees outlining acceptable practices. These guidelines do not provide the necessary structure to foster international collaborations with nations that have enacted formal laws recognized worldwide. Our results illustrate that international collaborations in the GME produce publications of greater impact despite the fact that political tensions and issues unrelated to science have the potential to dramatically hinder cross-border relationships in the region. Overall, we conclude that the national governments of countries within the GME have the unique opportunity to establish stem cell research policies which confer interoperability between nations to foster crucial international collaborations throughout the region. PMID- 20198518 TI - Human bone marrow mesenchymal stem cells: a systematic reappraisal via the genostem experience. AB - Genostem (acronym for "Adult mesenchymal stem cells engineering for connective tissue disorders. From the bench to the bed side") has been an European consortium of 30 teams working together on human bone marrow Mesenchymal Stem Cell (MSC) biological properties and repair capacity. Part of Genostem activity has been dedicated to the study of basic issues on undifferentiated MSCs properties and on signalling pathways leading to the differentiation into 3 of the connective tissue lineages, osteoblastic, chondrocytic and tenocytic. We have evidenced that native bone marrow MSCs and stromal cells, forming the niche of hematopoietic stem cells, were the same cellular entity located abluminally from marrow sinus endothelial cells. We have also shown that culture-amplified, clonogenic and highly-proliferative MSCs were bona fide stem cells, sharing with other stem cell types the major attributes of self-renewal and of multipotential priming to the lineages to which they can differentiate (osteoblasts, chondrocytes, adipocytes and vascular smooth muscle cells/pericytes). Extensive transcription profiling and in vitro and in vivo assays were applied to identify genes involved in differentiation. Thus we have described novel factors implicated in osteogenesis (FHL2, ITGA5, Fgf18), chondrogenesis (FOXO1A) and tenogenesis (Smad8). Another part of Genostem activity has been devoted to studies of the repair capacity of MSCs in animal models, a prerequisite for future clinical trials. We have developed novel scaffolds (chitosan, pharmacologically active microcarriers) useful for the repair of both bone and cartilage. Finally and most importantly, we have shown that locally implanted MSCs effectively repair bone, cartilage and tendon. PMID- 20198517 TI - The current status of engineering myocardial tissue. AB - Myocardial infarction (MI) remains a common fatal disease all over the world. The adult cardiac myocytes regenerative capability is very limited after infarct injury. Heart transplantation would be the best therapeutic option currently but is restricted due to the lack of donor organs and the serious side effects of immune suppression. The emerging of tissue engineering has evolved to provide solutions to tissue repair and replacement. Engineering myocardial tissue is considered to be a new therapeutic approach to repair infarcted myocardium and ameliorate cardiac function after MI. Engineering myocardial tissue is the combination of biodegradable scaffolds with viable cells and has made much progress in the experimental phase. However, the largest challenge of this field is the revascularization of the engineering constructs to provide oxygen and nutrients for cells. This review will give an overview on the current evolution of engineering myocardial tissue and address a new method to improve the vascularization of myocardium tissue in vivo. PMID- 20198519 TI - Ethical aspects of human embryonic stem cell research in the islamic world: positions and reflections. AB - Rapid technological developments in human embryonic stem cell research are holding promises of future new medical treatment for a range of currently incurable chronic diseases. At the same time, stem cell research using human embryos raises radically new, previously unimaginable ethical issues posing a dramatic challenge to humankind. By analysing the discourses on these ethical issues we can show that the cultural values and religious convictions of all stakeholders involved play a decisive role in formulating ethical positions. In the Islamic world, too, stem cell research using human embryos provokes new discussions about the moral status of the embryo according to Islamic ethical norms. In our paper we describe the theological and philosophical criteria used in this debate and discuss some ethical positions vis-a-vis embryonic stem cell research formulated in the Islamic world, including official regulations existing in some Muslim countries. While most of the existing literature in this field is primarily descriptive, the present paper endeavours to examine not only the arguments and their historical conditions as such; in addition, we will for the first time provide a critical reflection on the methodology underlying commonly held positions. In our view, this reflection is of paramount importance in establishing a straightforward constructive dialogue between different cultures and academic disciplines. PMID- 20198520 TI - The emotional experience associated with worrying: anxiety, depression, or stress? AB - Avoidance theories propose that worrying results in a reduction of the physiological arousal symptoms of anxiety. However, relatively little is known about the emotional symptoms that remain associated with worrying. This study explored whether the emotional states of anxiety, depression, or stress are specifically associated with excessive and uncontrollable worry. A group of 126 university students were selected to represent a wide range on the dimension of worry proneness. They completed a worry questionnaire, monitored the frequency and uncontrollability of their worry episodes for 1 week, and completed the Depression Anxiety Stress Scales (DASS) to indicate their level of negative affect during the monitoring period. Hierarchical regression analyses showed that all measures of worrying had a unique positive association with stress, over and above their associations with anxiety and depression. Item-level analyses showed that stress symptoms were uniformly strongly associated with worrying, while anxiety symptoms had the weakest associations. These results increase our knowledge regarding the phenomenology of worrying and underline the potential theoretical significance of the emotional state assessed by the DASS Stress scale. This scale fills the current need for a psychometrically sound instrument to assess the emotional experience associated with worrying. PMID- 20198521 TI - Using enzymes to remove biofilms of bacterial isolates sampled in the food industry. AB - The aim of this study was to analyze the cleaning efficiency of polysaccharidases and proteolytic enzymes against biofilms of bacterial species found in food industry processing lines and to study enzyme effects on the composition of extracellular polymeric substances (EPS) and biofilm removal in a Clean-in-Place (CIP) procedure. The screening of 7 proteases and polysaccharidases for removal of biofilms of 16 bacterial species was first evaluated using a microtiter plate assay. The alkaline pH buffer removed more biofilm biomass as well as affecting a larger range of bacterial species. The two serine proteases and alpha-amylase were the most efficient enzymes. Proteolytic enzymes promoted biofilm removal of a larger range of bacterial species than polysaccharidases. Using three isolates derived from two bacterial species widely found in food processing lines (Pseudomonas fluorescens and the Bacillus cereus group), biofilms were developed on stainless steel slides and enzymatic solutions were used to remove the biofilms using CIP procedure. Serine proteases were more efficient in removing cells of Bacillus biofilms than polysaccharidases. However, polysaccharidases were more efficient in removing P. fluorescens biofilms than serine proteases. Solubilization of enzymes with a buffer containing surfactants, and dispersing and chelating agents enhanced the efficiency of polysaccharidases and proteases respectively in removing biofilms of Bacillus and P. fluorescens. A combination of enzymes targeting several components of EPS, surfactants, dispersing and chelating agents would be an efficient alternative to chemical cleaning agents. PMID- 20198522 TI - A general neuropsychological model of delusion. AB - INTRODUCTION: Neurocognitive accounts of delusion have traditionally highlighted perceptual misrepresentation, as the primary trigger in addition to other cognitive deficits that maintain the delusion. Here, a general neurocognitive model of delusional disorder (DSM-IV) is proposed, not so much based on perceptual or cognitive deficits after right hemisphere damage as on cognitive propensities, specifically excessive inferencing (especially jumping to conclusions) and excessive reference to the self, due to left hemisphere overactivity. METHOD: The functional imaging, topographic EEG, and experimental imaging literatures on delusional disorder are reviewed, and 37 previously published cases of postunilateral lesion delusion (DSM-IV type, grandeur, persecution, jealousy, erotomania, or somatic), are reviewed and analysed multivariately. RESULTS: Functional imaging and EEG topography data were slightly more indicative of left hemisphere overactivity in delusional disorder. In addition, 73% of the postunilateral lesion cases (chi(2)=7.8, p=.005) of delusional disorder (DSM-IV type) had a right hemisphere lesion, whereas only 27% had a left hemisphere lesion. CONCLUSION: Left hemisphere release appears to be a more primary cause of delusional disorder than right hemisphere impairment, the latter merely entailing loss of inhibition of delusional beliefs. We propose that most patients with DSM-IV diagnoses of delusional disorder could be afflicted by excessive left hemisphere activity, but further research is necessary. PMID- 20198523 TI - Fusarium head blight and associated mycotoxin occurrence on winter wheat in Luxembourg in 2007/2008. AB - Fusarium head blight (FHB) is among the major causes of reduced quality in winter wheat and its products. In addition, the causal fungi produce a variety of toxins. A relatively high FHB infection rate in winter wheat was observed in 2007 and 2008 in Luxembourg. A fusariotoxin survey was carried out in 17 different geographical locations. Three groups of Fusarium mycotoxins (trichothecenes A and B and zearalenone) were analysed by a multi-detection HPLC-MS/MS method. Fusarium strains were also investigated by morphological and molecular methods. In addition, questionnaires relating to cultural practices were sent to the farmers managing the 17 fields investigated. FHB prevalence ranged from 0.3 to 65.8% (mean: 8.5%) in 2007 and from 0 to 24.5% (mean: 8.3%) in 2008. Results of morphological and molecular identification showed that the most common species isolated from diseased wheat spikes was F. graminearum (33.1%), followed by F. avenaceum (20.3%) and F. poae (17.8%). The chemical analysis revealed that 75% of the investigated fields were contaminated by deoxynivalenol (DON, range 0-8111 microg/kg). The preceding crop was highly and significantly correlated to the number of grains infected and had a significant impact on disease prevalence (p = 0.025 and 0.017, respectively, Fisher's F-test). A trend was found for maize as the preceding crop (p = 0.084, Tukey's test) to predict the amount of DON in the fields. This is the first report on the occurrence of DON and ZON in naturally infected wheat grains sampled from Luxembourg. PMID- 20198524 TI - Multi-residue method for detecting coccidiostats at carry-over level in feed by HPLC-MS/MS. AB - A multi-residue HPLC-ESI-MS/MS method has been developed for the simultaneous extraction, detection and confirmation of the 11 coccidiostats referenced by Regulation 2009/8/EC (lasalocid sodium, narasin, salinomycin sodium, monensin sodium, semduramicin sodium, maduramicin ammonium alpha, robenidine hydrochloride, decoquinate, halofuginone hydrobromide, nicarbazin, and diclazuril) in feedstuffs at carry-over level. The sensitivity of the method allows quantification and confirmation for all coccidiostats below target concentration. The method was in-house validated and meets all criteria of European legislation (2002/657/EC). The precision of the method was determined under repeatability and within-laboratory reproducibility conditions; RSD(r) and RSD(R) were below the maximum permitted values for every tested concentration. The specificity was checked by analysing representative blank samples and blank samples fortified with potentially interfering substances (benzimidazoles, corticosteroides, triphenylmethane dyes, quinolones, nitrofurans, nitroimidazoles, phenicols); no interference were found. Concerning quantification, a quadratic regression model was fitted to every calibration curve with a regression coefficient r2 above 0.99 on each data set. Finally, the expanded uncertainty U was calculated with data obtained within the laboratory while applying the method during validation and in routine tests. PMID- 20198525 TI - Dietary intake estimate for perfluorooctanesulphonic acid (PFOS) and other perfluorocompounds (PFCs) in UK retail foods following determination using standard addition LC-MS/MS. AB - The analysis of 252 food samples (UK-produced and imported) purchased from a variety of retail outlets in the UK was undertaken for the presence of perfluorooctanesulphonic acid (PFOS), perfluorooctanoic acid (PFOA) and nine other perfluorocompounds (PFCs). A limit of quantification (LOQ) of 1 microg/kg was achieved for all target analytes, in all samples. Standard addition was used for quantification of PFC levels. All 11 of the targeted PFCs were detected in 75 individual food items. In 70% of the samples, including all meat other than offal, none of the analytes were present above the LOD. The highest levels found were 59 microg/kg perfluorooctanesulphonic acid (PFOS) and 63 microg/kg total PFCs (SigmaPFCs) in an eel sample, and 40 microg/kg PFOS (62 microg/kg SigmaPFCs) in a whitebait sample. The highest level in an offal sample was 10 microg/kg, in a wild roe deer liver. There were six samples with SigmaPFCs >15 microg/kg (fish, shellfish, crustaceans), a further seven samples with SigmaPFCs ranging 11-15 microg/kg (including a liver), nine with SigmaPFCs ranging 6-10 microg/kg (fish and livers), 31 with SigmaPFCs in the range 2-5 microg/kg (including kidneys, popcorn and processed peas) and a further 22 with SigmaPFCs close to the LOD of 1 microg/kg (including eggs and potatoes). These concentrations indicate that UK consumers are being exposed to a low level of PFC contamination from food. The estimated upper bound dietary intake of 10 ng/kg bodyweight (bw)/day of PFOS for average adult consumers is well below the 0.15 microg (150 ng)/kg bw tolerable daily intake (TDI) set by the European Food Safety Authority. The lower bound adult dietary intake estimate of 1 ng/kg bw/day is similar to estimates undertaken and reported in countries such as Canada, Germany and Spain. PMID- 20198526 TI - Detection of Clostridium perfringens in yearling lamb meat (barbacoa), head, and gut tacos from public markets in Mexico City. AB - No reports on the incidence of Clostridium perfringens in popularly-consumed food from Mexico City have been published; neither are there any reports that have analyzed food consumed in popular markets and less established restaurants. Therefore, this study is aimed at providing data to evaluate the relevance of C. perfringens as an etiologic agent of food-borne diseases. Of the 650 analyzed samples, 106 (16.3%) were positive for C. perfringens; 6.4% (16/250) isolates were from barbacoa, 19% (38/200) from head, and 13% (52/200) from gut tacos. The presence of C. perfringens in these popular-consumed foods demonstrates its relevance as an etiologic agent of food-borne diseases, and confirms the great sanitary risk involved in their consumption. These results may serve as a basis for the Mexican sanitary authorities to control the microbiological quality of street-made foods. PMID- 20198528 TI - Neurocognitive function in schizophrenia with comorbid posttraumatic stress disorder. AB - Individuals with schizophrenia are at a greater risk for experiencing trauma and developing posttraumatic stress disorder (PTSD) than the general population. Despite an increased incidence of neurocognitive dysfunction in both schizophrenia and PTSD, there are few studies that have examined the potential compounding effects of these diagnoses when they co-occur. The current study examined this issue by administering comprehensive diagnostic, symptom, and neurocognitive evaluations to four groups including normal controls (C), as well as individuals with PTSD (PTSD), schizophrenia (SZ), or both schizophrenia and PTSD (SZP). Results indicated that when compared to the SZ group, the SZP group exhibited higher rates of positive symptoms, general psychopathology, and PTSD symptoms, as well as lower rates of negative symptoms. Regarding neurocognitive test performance, both schizophrenia groups performed significantly worse than the C and PTSD groups across all neurocognitive domains. However, differences were not significant between the SZP and SZ groups, although a differential pattern of performance between the groups was indicated. Results of this study do not support the idea that the presence of comorbid PTSD in SZ results in a substantial increase in cognitive impairment. PMID- 20198531 TI - Persistent symptoms in mild to moderate traumatic brain injury associated with executive dysfunction. AB - In order to improve detection of subtle cognitive dysfunction and to shed light on the etiology of persistent symptoms after mild-to-moderate traumatic brain injury (TBI), we employed an experimental executive reaction time (RT) test, standardized neuropsychological tests, and diffusion tensor imaging (DTI). The Executive RT-Test, an Executive Composite Score from standardized neuropsychological tests, and DTI-indices in the midbrain differentiated between patients with persistent symptoms from those fully recovered after mild-to moderate TBI. We suggest that persistent symptoms in mild-to-moderate TBI may reflect disrupted fronto-striatal network involved in executive functioning, and the Executive RT-Test provides an objective and novel method to detect it. PMID- 20198527 TI - Longer term improvement in neurocognitive functioning and affective distress among methamphetamine users who achieve stable abstinence. AB - Chronic use of methamphetamine (MA) is associated with neuropsychological dysfunction and affective distress. Some normalization of function has been reported after abstinence, but little in the way of data is available on the possible added benefits of long-term sobriety. To address this, we performed detailed neuropsychological and affective evaluations in 83 MA-dependent individuals at a baseline visit and following an average one-year interval period. Among the 83 MA-dependent participants, 25 remained abstinent, and 58 used MA at least once during the interval period. A total of 38 non-MA-addicted, demographically matched healthy comparison (i.e., HC) participants were also examined. At baseline, both MA-dependent participants who were able to maintain abstinence and those who were not performed significantly worse than the healthy comparison subjects on global neuropsychological functioning and were significantly more distressed. At the one-year follow-up, both the long-term abstainers and healthy comparison groups showed comparable global neuropsychological performance and affective distress levels, whereas the MA dependent group who continued to use MA were worse than the comparison participants in terms of global neuropsychological functioning and affective distress. An interaction was observed between neuropsychological impairment at baseline, MA abstinence, and cognitive improvement, with abstinent MA-dependent participants who were neuropsychologically impaired at baseline demonstrating significantly and disproportionately greater improvement in processing speed and slightly greater improvement in motor abilities than the other participants. These results suggest partial recovery of neuropsychological functioning and improvement in affective distress upon sustained abstinence from MA that may extend beyond a year or more. PMID- 20198532 TI - Inter-worker variability in lower body postures during assembly line work: implications for exposure assessment. AB - This study evaluated inter-worker variability in lower body posture and work activity during highly-structured assembly line work. Data were collected from 79 unique assembly line workstations in an engine manufacturing plant. Because the plant utilized work teams, 4-8 workers rotated through each workstation. At least 30 min of videotape was collected from at least three workers at each workstation. A computer-assisted work sampling procedure randomly selected 200 video "freeze-frames" for each worker. Lower body posture/movement (e.g., sit, stand, walk, etc.) was determined for each frame and used to estimate the percentage of time the worker spent in various postures and activities. Chi square analyses were performed for each workstation to assess the significance of inter-worker differences. Due to variations in individual work methods, significant differences (p <.05) were found at 57 out of 79 workstations (72%). The greatest differences occurred when workers had the option to choose between standing and sitting (significant in 8 of 8 cases; in extreme examples, sit time ranged between 0-100% on one job, and 6.5-98% on another). Studying a single worker (or "proxy") can contribute to substantial error when estimating exposures in workplace studies of ergonomic stressors, since the proxy may not be representative of all workers who perform the job. Individual measurements are preferable, particularly for jobs where workers have substantial latitude to develop individualized work methods. PMID- 20198533 TI - Laterality in the rubber hand illusion. AB - In patient studies, impairments of sense of body ownership have repeatedly been linked to right-hemispheric brain damage. To test whether a right-hemispheric dominance for sense of body ownership could also be observed in healthy adults, the rubber hand illusion was elicited on both hands of 21 left-handers and 22 right-handers. In this illusion, a participant's real hand is stroked while hidden from view behind an occluder, and a nearby visible hand prosthesis is repeatedly stroked in synchrony. Most participants experience the illusionary perception of touch sensations arising from the prosthesis. The vividness of the illusion was measured by subjective self-reports as well as by skin conductance responses to watching the rubber hand being harmed. Handedness did not affect the vividness of the illusion, but a stronger skin conductance response was observed, when the illusion was elicited on the left hand. These findings suggest a right hemispheric dominance for sense of body ownership in healthy adults. PMID- 20198535 TI - A new butanolide and a new secobutanolide from Litsea lii var. nunkao tahangensis. AB - The chloroform-soluble portion of the leaf extract of Litsea lii var. nunkao tahangensis was further studied and these studies led to the isolation of a new butanolide, litsealiicolide C (1), and a new secobutanolide, secoisolitsealiicolide B (2), along with seven known compounds, linderanolide B (3), isolinderanolide C (4), secolincomolide A (5), secokotomolide A (6), (+) beta-eudesmol (7), trans-phytol (8), and (-)-matairesinol (9). Their structures were established on the basis of spectral analysis and comparison with the literature data. In addition, the cytotoxicities against MCF-7, NCI-H460, and SF 268 cancer cell lines were measured in vitro and the results demonstrated that these metabolites have no cytotoxicity against the selected tumour cells. PMID- 20198536 TI - Is desire for social relationships mediated by the serotonergic system in the prefrontal cortex? An [(18)F]setoperone PET study. AB - Social behavior and desire for social relationships have been independently linked to the serotonergic system, the prefrontal cortex, especially the orbitofrontal cortex (OFC), and the anterior cingulate cortex (ACC). The goal of this study was to explore the role of serotonin 5HT(2A) receptors in these brain regions in forming and maintaining close interpersonal relationships. Twenty-four healthy subjects completed the Temperament and Character Inventory (TCI) prior to undergoing [(18)F]setoperone brain positron emission tomography (PET) to measure serotonin 5HT(2A) receptor availability within the OFC (BA 11 and 47) and ACC (BA 32). We explored the relationship between desire for social relationships, as measured by the TCI reward dependence (RD) scale, and 5HT(2A) receptor non displaceable binding potential (BP(nd)) in these regions. Scores of RD were negatively correlated with 5HT(2A) BP(nd) in the ACC (BA 32, r = -.528, p = .012) and OFC (BA 11, r = -.489, p = .021; BA 47, r = -.501, p = .017). These correlations were corroborated by a voxel-wise analysis. These results suggest that the serotonergic system may have a regulatory effect on the OFC and ACC for establishing and maintaining social relationships. PMID- 20198537 TI - Self-face recognition is characterized by "bilateral gain" and by faster, more accurate performance which persists when faces are inverted. AB - We examine interhemispheric cooperation in the recognition of personally known faces whose long-term familiarity ensures frequent co-activation of face sensitive areas in the right and left brain. Images of self, friend, and stranger faces were presented for 150 ms in upright and inverted orientations both unilaterally, in the right or left visual field, and bilaterally. Consistent with previous research, we find a bilateral advantage for familiar but not for unfamiliar faces, and we demonstrate that this gain occurs for inverted as well as upright faces. We show that friend faces are recognized more quickly than unfamiliar faces in upright but not in inverted orientations, suggesting that configural processing underlies this particular advantage. Novel to this study is the finding that people are faster and more accurate at recognizing their own face over both stranger and friend faces and that these advantages occur for both upright and inverted faces. These findings are consistent with evidence for a bilateral representation of self-faces. PMID- 20198538 TI - Noncriterial recollection influences metacognitive monitoring and control processes. AB - When retrieving information from memory, temporarily irrelevant material may influence future retrieval endeavours. According to an accessibility account, the amount and intensity of this information can be used to predict the availability of related material. A dual-source paradigm was used to investigate whether information that was not relevant (i.e., noncriterial recollection) to the current memory search would influence metacognitive judgements about a relevant, criterial dimension. In two experiments, participants gave higher feelings-of knowing judgements for a weakly encoded source dimension when they could subsequently recall the other source dimension later. Furthermore, the influence of the noncriterial information appeared to be driven more so by the subjective state of remembering rather than knowing. Thus, strong memorial information that is temporarily irrelevant influences behaviour. PMID- 20198539 TI - [Pneumology: what is the current status?]. PMID- 20198540 TI - [Systemic manifestations and comorbidities in patients with chronic obstructive pulmonary disease (COPD) and their effect on clinical state and course of the disease--an overview of the cohort study COSYCONET]. AB - BACKGROUND AND RATIONALE: The integrated project COSYCONET, as part of the competence network ASCONET funded by the BMBF, has the aim to investigate the relationship between the pulmonary disorder, comorbidities and systemic inflammation in patients with chronic obstructive pulmonary disease (COPD) by adopting cross-sectional as well as longitudinal analyses. METHODOLOGICAL APPROACH: COSYCONET includes a number of projects addressing the issue of comorbidities at the basic science level. Its core project, however, is the establishment of a cohort of patients with COPD, which is compared with two population-based control cohorts. The COPD cohort will include 3,000 patients, among them 1,500 with severity according to GOLD category I/II and 1,500 with category III/IV. Patients will be recruited in study centers covering all major regions of Germany, and this will be achieved in close cooperation with pneumologists from private practices. After recruitment, patients will be studied upon an initial visit as well as 6 and 18 months later. Each visit includes a comprehensive battery of functional tests and questionnaires that aim at assessing the state of the disease as accurately and completely as feasible, comprising lung function and the individual pattern and risk factors of comorbidities including cardiovascular disorders, metabolic disorders, osteoporosis, exercise capacity, acticity and mental status. In addition blood samples will be taken and asservated in a biobank in order to assess markers of systemic inflammation and aging as well as organ-specific markers. Moreover morphological information on the lung as available from HR-CT pictures that have not been specifically taken for the study will be analysed semi-quantitatively in a central facility and standardised manner. PMID- 20198541 TI - [Drug-induced pulmonary interstitial disease]. AB - HISTORY AND CLINICAL FINDINGS: Patient 1, a 72-year-old man, was admitted with a history of flu-like symptoms and dry cough for three weeks and exertional dyspnea. Prophylactic antibiotic treatment with nitrofurantoin (100 mg/day) had been given for one year for renal calculi. Patient 2, a 64-year-old man, was admitted with increasing dyspnea at rest. He was known to have several cardiological disorders, including episodes of ventricular tachycardia, for which he had been on amiodarone (200 mg/d) for 8 years. Both patients were in reduced general state of health. INVESTIGATIONS: In both patients the pO(2) was 68 mm Hg, in Patient 1 while breathing ambient air, in Patient 2 while breathing oxygen (15 l/min). Chest X-ray revealed bronchiectatic infiltrative changes bilaterally in the middle and lower lung fields in Patient 1. High-resolution computed tomography showed massive generalized interstitial infiltrates in the lung of Patient 2. TREATMENT AND COURSE: Nitrofurantoin and amiodarone, as potential causes of the pulmonary changes, were discontinued while steroid treatment was begun. This quickly resulted in improvement of symptoms and clinical findings. CONCLUSION: Drug induced pathogenesis has to be taken into account in the differential diagnosis of interstitial lung diseases. A causal association with the administered drugs is often difficult to establish. If suspicion is strong, treatment should be discontinued (replacement by a drug from another class). Depending on severity of clinical symptoms corticosteroids should also be given. PMID- 20198542 TI - [68-year-old woman with chronic obstructive pulmonary disease. Tracheobronchomalacia in COPD]. PMID- 20198543 TI - [Rare cystic lung diseases: lymphangioleiomyomatosis, pulmonary Langerhans' cell histiocytosis and lymphocytic interstitial pneumonia]. PMID- 20198544 TI - [Healthcare-associated pneumonia - is this new entity important for diagnosis and treatment of pneumonia? pro]. PMID- 20198545 TI - [Healthcare-associated pneumonia - is this new entity important for diagnosis and treatment of pneumonia? contra]. PMID- 20198546 TI - [Does phenotyping asthma help to improve differential treatment?]. AB - Asthma is a syndrome characterized by airway inflammation, airway hyperresponsiveness (AHR) and airway obstruction. The diagnosis asthma comprises a very heterogeneous patient population. In recent years different strategies have been developed to classify the patients into different phenotypes. The phenotypes can be based on clinical findings, etiology and triggers or be defined by the type of airway inflammation. These classifications are still very crude and confusing and often a clear-cut differentiation between different described phenotypes is not possible. Still some phenotypes depend on different pathophysiological mechanisms and can differ profoundly in their clinical course. Also for some of these phenotypes specifical treatpeuthic options are available. Therefore a good definition and classification of asthma phenotypes is important in regard of diagnosis, prognosis and therapy of these patients. PMID- 20198547 TI - [What degree of hypoxemia is tolerable for human beings?]. AB - According to the literature, hypoxemia is considered to be severe when oxygen saturation (Sa O(2)) falls below 90 %. Frequently one can discover lower values without impairment of the patient. Especially patients with the obesity hypoventilation syndrome (OHS) will have frequent night time desaturations of significant duration below 50 % Sa O(2), but do still cope with their daytime jobs. This discrepancy can only be explained by the fact, that hypoxemia is not equivalent to tissue hypoxia. The latter is mainly being determined by oxygen delivery (DO2) which is being calculated by multiplying cardiac output (CO) and oxygen content (CaO2). Ca O(2) is determined by the product of Sa O(2) and haemoglobin (Hb) times 1.35. From this context it becomes evident, that assessing hypoxemia without considering oxygen content will frequently be misleading. The human organism has several possible ways of compensation in order to avoid tissue hypoxia. In case of acute hypoxemia that evolves within minutes the organism can shift the oxygen binding curve by changing 2 - 3-DGP erythrocytic activity. Additionally non vital organ systems might reduce their oxygen uptake. During sustained hypoxia (lasting 2 - 3 days) the Krebs cycle and the respiratory chain will express hypoxia-resistant iso-enzymes. Long lasting hypoxia can be compensated by polycythemia. Indirect data suggest, that the critical number for the oxygen content is rather low and is estimated to be somewhere around 33 % of the normal value. These mechanism of hypoxia-resistance are hardly ever maxed out in patients on critical care units.Lack of knowledge of the above described mechanisms does frequently result in diseases like ARDS which frequently develops due to excessive ventilatory pressures and excessive inspired O(2) concentrations. PMID- 20198548 TI - [Bronchiectasia: prevention of recurrent pneumonia and definite surgical treatment]. PMID- 20198549 TI - [Dual energy CT of the peripheral arteries: a phantom study to assess the effect of automatic plaque removal on stenosis grading]. AB - PURPOSE: To evaluate the accuracy of dual energy (DE)-based plaque removal in a vessel phantom. MATERIALS AND METHODS: Acrylic vessel phantoms of different diameters (3, 5, 8 mm), degrees of stenoses (25 - 100%) and plaque densities (300 - 750 HU) were filled with contrast-enhanced blood (150 - 450 HU). Dual source CT was used for simultaneous image acquisition at 80 and 140 kV. Beside a DE-based plaque-subtracted dataset (DE-PS), a virtual 120 kV non-plaque subtracted dataset (N-PS) was generated. Agreement between the known and measured luminal diameter in both datasets was determined using Lin's concordance correlation coefficient (kappaLin). RESULTS: A total of 8260 measurements were taken. The correlation of measured diameter in DE-PS images was excellent (kappaLin = 0.83 - 0.96) for 5 - 8 mm vessel phantoms with high luminal enhancement (300 - 450 HU) and plaque density (500 - 750 HU), moderate (kappaLin = 0.6 - 0.67) for 5 mm vessels with lower luminal enhancement and plaque density and poor (kappaLin = 0.10 - 0.64) in the 3 mm vessels. The correlation of N-PS-based stenosis quantification was excellent (kappaLin = 0.86 - 0.99) for 5 - 8 mm vessel phantoms if the contrast between lumen and plaque was above 100 HU. The correlation decreased in 3 mm vessels (kappaLin = 0.45 - 0.93), while the lowest correlation was observed for the lowest contrast between plaque and vessel lumen. CONCLUSION: Automatic DE based plaque removal is highly effective for heavily calcified plaques and high luminal enhancement in larger diameter vessels > or = 5 mm). However, accuracy is limited for low density calcified plaque, lower luminal enhancement and smaller caliber vessels mainly due to poor specificity. PMID- 20198550 TI - [Ortner syndrome]. PMID- 20198551 TI - [Spontaneous perforation of a port catheter into the mediastinum]. PMID- 20198552 TI - Trauma in pregnancy: a systematic approach. AB - Trauma in pregnancy remains one of the major contributors to maternal and fetal morbidity and mortality. Potential complications include maternal injury or death, shock, internal hemorrhage, intrauterine fetal demise, direct fetal injury, abruptio placentae, and uterine rupture. The leading causes of obstetric trauma are motor vehicle accidents, falls, assaults, and gunshots, and ensuing injuries are classified as blunt abdominal trauma, pelvic fractures, or penetrating trauma. Many of the assessment and management aspects of obstetric trauma are unique to pregnancy, although initial evaluation and resuscitation should always be maternally directed. Once maternal stability is established, vigilant evaluation of fetal well-being becomes warranted. Continuous fetal heart monitoring, ultrasonography, computed tomography, open peritoneal lavage, and/or exploratory laparotomy may be indicated in a case of obstetric trauma. In view of the significant impact of trauma on the pregnant woman and her fetus, preventive strategies are paramount. PMID- 20198553 TI - A systematic approach to first-trimester ultrasound assessment of twins. AB - The incidence of twin pregnancies has increased for the last 20 years mainly as a result of assisted reproduction technologies and pregnancies occurring in older women. Both maternal and perinatal mortality and morbidity are increased in twin pregnancies when compared with singletons. A systematic and detailed first trimester ultrasound can be a useful tool for detecting chorionicity, growth discordance, and congenital malformations. Prediction of complications at an early stage can help with directing future management and counseling of patients. PMID- 20198554 TI - Nomogram of fetal liver volume by three-dimensional ultrasonography at 27 to 38 weeks of pregnancy using a new multiplanar technique. AB - We sought to establish normative data for fetal liver volume (FLV) between 27 and 38 weeks' gestation using three-dimensional ultrasonography. The study design was a longitudinal prospective study involving 53 participants. A total of 250 FLV measurements were obtained, using the multiplanar method with 3.0-mm intervals. Polynomial regressions with adjustments using the determination coefficient ( R2) were used to assess the correlation between FLV and gestational age (GA) and fetal parameters (biparietal diameter, head circumference, abdominal circumference, and estimated fetal weight). The mean, standard deviation, and median, minimum, and maximum values were calculated for each gestational age. The intraclass correlation coefficient (ICC) was used to determine inter- and intraobserver reliability. There was a high correlation between FLV and GA. The mean FLV went from 43.5 +/- 7.6 cm (3) (29.1 to 62.2 cm (3)) to 130.5 +/- 20.1 cm3 (87.5 to 191.1 cm3). There was a high correlation between FLV and all fetal biometric parameters (all P < 0.0001). Intraobserver and interobserver correlations were excellent with an ICC = 0.993 and 0.984, respectively. There was a high correlation between GA and biometric parameters. Reference limits were generated for FLV between 27 and 38 weeks. FLV is highly reproducible. PMID- 20198555 TI - Current concepts in perioperative care for the prevention of deep surgical site infections in elective spinal surgery. AB - INTRODUCTION: Postoperative deep wound infections are the third most common reason for nosocomial infections after pneumonia and urinary tract infections. Deep wound infections lead to higher rates of morbidity and mortality and increased costs of treatment. Infection rates following spinal surgery are reported to lie between 1.9 and 10%. This study was carried out to prove whether a new internal concept for perioperative management could reduce the infection rates following spinal surgery. METHODS: Based on the current literature we developed a concept for perioperative care in spinal surgery in order to prevent postoperative deep wound infections. We retrospectively compared infection rates of 2006 and 2007 after the implementation of our perioperative care concept in spinal surgery patients. Total annual operations were comparable. RESULTS: After the introduction of our predominantly evidence-based concept of perioperative care for spinal surgery patients, we found a considerable decrease in infection rates from 0.6% in 2006 to 0% in 2007. CONCLUSION: A new concept for perioperative care in spinal surgery for the prevention of deep wound infections was found to effectively reduce infection rates. Due to the limitations of our single-center retrospectively selected cohort, further research is necessary to support our results. PMID- 20198556 TI - Leydig-cell-tumor of the ovary that responded to GnRH-analogue administration - case report and review of the literature. AB - Progressive hirsutism can be a symptom of an androgen-producing tumor, especially in postmenopausal women. We report a case of a 58-year-old woman who complained of progressive hirsutism, nervousness, irritability, anxiousness and an increased libido. Examination showed an unusual redness of her head, decollete, palms and soles of her feet. Basal laboratory tests revealed a profound elevation of testosterone levels (7.5 microg/l) and normal levels of androstendione, dehydroepiandrosterone-sulfate, 17alpha-hydroxy-progesterone and thyroid stimulating hormone. Also remarkable was that her red blood count, hemoglobin and hematocrit values were elevated while erythropoietin was within normal limits. Functional laboratory tests ruled out heterozygous C21-hydroxylase deficiency and showed a moderate insulin resistance on the oral glucose tolerance test. Transvaginal ultrasound revealed a slightly hyperdensic area of 6 mm in the left ovary. Magnetic resonance imaging showed a contrast medium-accumulating area of 2 cm in the left ovary. Since the patient was initially reluctant to undergo surgery, a GnRH-analogue (triptoreline) was administered VIA intramuscular injection once per month for two months and testosterone levels were lowered to less than one third of the initial level (2 microg/l). Surgery was eventually performed with laparoscopic bilateral salpingoophorectomy, hysteroscopy and uterine curettage. The histologic examination revealed a Leydig cell tumor in the hilus and stroma of the left ovary. Postoperatively testosterone levels dropped dramatically and instantly into the normal range. Within months, the red blood count and hematocrit levels were within normal limits. The patient's face became more feminine, the redness of her face and hirsutism regressed. Her anxiousness and nervosity resolved and the insulin sensitivity improved. In this paper, polyglobulia, the metabolic and psychological changes due to hyperandrogenism are discussed, as well as the phenomenon that the tumor responded to a GnRH-analogue. Such a response implies that the tumor is either under gonadotropin control or that GnRH analogues have direct effects via receptors on tumorous Leydig cells. PMID- 20198557 TI - Growth impairment in a boy with late-onset congenital adrenal hyperplasia and anorexia nervosa. AB - Treatment of congenital adrenal hyperplasia (CAH) in its salt-wasting form with appropriate doses of glucocorticoids and mineralocorticoids should promote growth, puberty and final height in a similar to normal pattern. However, the individual requirements for these drugs to normalize the hormonal profile and to achieve a physiologic growth pattern may differ. Moreover, the time of onset of puberty is also unpredictable since the course of the disease may predispose for precocity. The aim of this study was to explain the unexpected arrest of growth during puberty in a boy with late-onset CAH, who had been treated with glucocorticoid from early childhood. A short course of GnRH agonist treatment was also introduced in later years. The growth chart reflects two periods of impaired growth velocity preceded by weight loss. The reason for the first decline is difficult to prove retrospectively, but during the second episode the boy became both clinically and hormonally hypogonadal. At that time the anorexia nervosa (AN) was diagnosed according to APA DSM-IV criteria. We conclude that there were several reasons for the discontinued growth spurt and reduced final height in this boy with CAH: (a) early variant of puberty and subsequent late treatment with GnRH agonist, (b) AN possibly occurring during mid-childhood and clearly during puberty and (c) the repeated use of high doses of glucocorticoids. AN, a relatively rare disorder in boys, appears to have had a significant negative effect on this patient's growth and should be considered in the differential diagnosis in CAH children with impaired growth. PMID- 20198558 TI - The role of activin A in the human osteoblast cell cycle: a preliminary experimental in vitro study. AB - Animal studies have previously shown that activin A enhances osteoblast proliferation IN VITRO and increases bone formation and bone mechanical strength IN VIVO. For the further understanding of its action in human osteoblast, we studied the pattern of a cell cycle response to the treatment with activin A. We hypothesize that activin A alters the cell cycle pattern of human osteoblast. Primary cultures of human osteoblast-like cells were treated by activin A in a biologically effective concentration (100 ng/mL). The cells in cultured samples were counted, assayed for cellular alkaline phosphatase activity and calcitonin expression, LDH activity in the medium, cellular BrdU incorporation, cell cycle cytometry and compared to untreated controls. The treated by activin A cells responded by a significant shift toward the G1 phase of the cell cycle with parallel decrease in cell death rate (lower LDH activity and less necrotic cells in cytometric analysis). The treated cells also showed a lower alkaline phosphatase activity and calcitonin expression, indicating their undifferentiated state, and didn't change their proliferation rate. The number of cells in culture increased following treatment with activin A. We show that activin A increases the net osteoblast number in culture by reducing the cell death rate without affecting the cell proliferation. These findings should be part of cellular pathways that are involved in the initial stages of bone tissue generation. PMID- 20198559 TI - Dipeptidyl-peptidase 4 and attractin expression is increased in circulating blood monocytes of obese human subjects. AB - Dipeptidyl-peptidase (DPP)-4, which catalizes the degradation of the insulinotropic incretin glucagon-like-peptide (GLP)-1, and the DPP-4 like enzyme attractin are involved in activation of T-lymphocytes and monocytes. Recently, it has been demonstrated, that the risk for certain infections is increased in type 2 diabetic patients under DPP-4 inhibitor treatment. The aim of the present study was to examine the expression of DPP-4 and attractin in circulating blood monocytes of obese and type 2 diabetic subjects. Monocytes were isolated by CD14 antibody based magnetic cell sorting from blood samples of 17 lean controls, 20 obese, non-diabetic subjects and 19 obese patients with type 2 diabetes. FACS analysis was performed to test purity of the cell preparations. Expression was measured by multiplex RT-PCR on RNA-level. DPP-4 and attractin were detectable in human circulating monocytes with attractin being expressed at higher levels compared to DPP-4. Both enzymes were significantly higher expressed in circulating blood monocytes of obese subjects compared to lean controls. In contrast, type 2 diabetes did not significantly affect expression levels. Finally, neither DPP-4 nor attractin expression was altered by sitagliptin or insulin treatment. In conclusion, our data demonstrate, that expressions of DPP-4 and attractin in circulating blood monocytes of human subjects are influenced by metabolic abnormalities with obesity being an important factor. PMID- 20198560 TI - Type-1 diabetes induces depot-specific alterations in adipocyte diameter and mass of adipose tissues in the rat. AB - Type-1 diabetes (T1D) is a metabolic disorder associated with massive reduction in mass of adipose tissue. Measuring cell diameter, an index of fat metabolism, we determined depot-specific alterations in weight of adipose tissue, fat cell diameter and size heterogeneity and distribution at 5 depots in streptozotocin (STZ)-induced diabetic rats. T1D was induced by a single injection of STZ. Seven days after the injection, fat depots were isolated, weighted, washed and maintained in tissue culture medium. Using a microscope equipped with calibrated micrometer, cell diameter as well as size distribution pattern and heterogeneity of adipocytes were determined in fresh tissue slices of subcutaneous (SC), proximal epididymal (PE), distal epididymal (DE), perirenal (PR) and retroperitoneal (RP) fat depots. The T1D induced marked reductions in fat mass and mean of fat cell diameter at all depots. The most affected depot was the SC. With the exception of PE, adipocytes at all depots showed significant increases in size heterogeneity. The effect of the diabetes on mean fat cell diameter and size heterogeneity was minimal at PE depot. Depots with similar cell size distribution pattern exhibited similar fat mass reduction. However, the DE depot with a unique cell size distribution pattern showed a fat mass reduction similar to that of PE and PR depots. These data indicate that T1D induces a massive fat mass reduction in a reasonably depot-specific manner and that the fat depots close to survival organs are less vulnerable to fat mobilization. Moreover, peculiar disagreement between cell size distribution and heterogeneity as well as the level of fat mass reduction at DE and PE depots suggests that not only cell size and heterogeneity but also local factors may play roles in depot-specific fat mobilization. PMID- 20198561 TI - In vitro effect of octyl - methoxycinnamate (OMC) on the release of Gn-RH and amino acid neurotransmitters by hypothalamus of adult rats. AB - OMC (octyl-methoxycinnamate), an endocrine disruptor having estrogenic activity, is used in sunscreen creams as UV filter. We studied its "in vitro" effects on the hypothalamic release of Gn-RH as well as on the amino acid neurotransmitter system. OMC significantly decreased Gn-RH release in normal male and female rats as well as in castrated rats with substitutive therapy. No effects were observed in castrated rats without substitutive therapy. In males OMC increases the release of GABA, decreasing the production of glutamate (GLU) while in the female decreases the excitatory amino acid aspartate (ASP) and GLU without modifications in the hypothalamic GABA release. These results suggest that OMC acting as endocrine disruptor could alter the sex hormone-neurotransmitter-Gn-RH axis relationships in adult rats. PMID- 20198562 TI - Do we need to repair the nerves when replanting distal finger amputations? AB - Distal replantation is an excellent model to study the results of nerve repair. We aim to demonstrate differences in aesthetic, sensory, and functional outcomes in fingertip replantation, with and without nerve repair. We recruited 28 fingers in 28 patients, who had successful distal replantation in 5 years. Half of the fingers had nerves repaired. Mean follow-up was 39 months. Symptoms of pain, numbness, cold intolerance, scar hypersensitivity, pulp atrophy, and weakness were reported. Nail width, pulp length, 2-point discrimination, Semmes-Weinstein test, and power were evaluated. We used chi-square tests of independence to examine association between nerve repair and symptoms, and independent T tests and Mann-Whitney U tests to analyze difference between replantation with and without nerve repair according to objective results. Chi-square tests reviewed no significant association between nerve repair and symptoms. Mann-Whitney U tests showed no significant difference between the groups, with and without nerve repair. All fingers showed mean 2-point discrimination of 5.6 mm, and Semmes Weinstein test results of green in 3 fingers and blue in 17. There was no significant difference in overall outcomes in repairing nerve or not in distal finger replantation. Both groups had satisfactory outcomes. Possibly, spontaneous neurotization is present, and nerve repair is not necessary, which may help to shorten the operation time and decrease extensiveness of surgeries. PMID- 20198563 TI - Distally based extended peroneal artery septocutaneous perforator cross-bridge flap without microvascular anastomoses for reconstruction of contralateral leg and foot soft tissue defects. AB - A cross-leg or cross-bridge free flap is one of the choices for the reconstruction of serious leg soft tissue defects. Here, we report on six cases of leg and foot reconstruction with a distally based extended peroneal artery septocutaneous perforator cross-bridge flap without microvascular anastomoses. The vascular pedicle includes the peroneal artery, its perforator branch, and concomitant veins. The total pedicle length ranges from 10 to 14 cm, and the size ranges from 18 x 8 to 21 x 10 cm. All flaps survived completely without complications. Compared with a cross-leg or cross-bridge free flap, a distally based extended peroneal artery septocutaneous perforator cross-bridge flap without microvascular anastomoses does not require the use of some instruments or techniques for microsurgery, leading to a shorter operation duration and a lower risk of thrombosis in the vessel because microvascular anastomosis is not required. PMID- 20198564 TI - [Prevention of neural tube defects: regional policies in folic acid enrichment and supplementation]. AB - BACKGROUND: The USA and Canada had already started an obligatory food fortification with folic acid in 1998; In 2009, Australia and New Zealand also started to do so. METHODS: A survey was carried out among members of The European Consumers' Organisation (BEUC). RESULTS: Most of the European countries go along with the recommendation of 200 MUg folic acid (or 400 MUg folic acid equivalents) for adults and 300 MUg (600 MUg) for pregnant women. To prevent neural tube defects, an additional supplementation of 0,4 mg folic acid is recommended for women before conception. So far, none of the European countries has implemented an obligatory folic acid enrichment of grain or other food, but this step is under discussion. CONCLUSION: In a European market with free trading of goods it is of utmost importance that especially those (socially deprived) women in most need of folic acid, are reached. A common European decision for/against fortification should be considered. Public Health ethics demand not only good evidence for the benefit, but also a good estimation of the (potential) risks. Due to a paucity of good risk estimation, no European country has plans to decide in favour of an obligatory fortification on its own. PMID- 20198565 TI - [Knowledge of school pupils about the HIV/AIDS topic at selected schools in Mecklenburg-Western Pomerania]. AB - AIM OF THE STUDY: The increasing numbers of new HIV diagnoses in Germany generate a need to measure the level of knowledge of the young generation about the issue of HIV/AIDS. METHODOLOGY: A survey was conducted of 769 pupils of different age groups and from different schools in Mecklenburg-Western Pomerania. Data analysis was performed using SPSS; statistically significant differences (p<0.05) were tested between the groups using the chi-square test. RESULTS: The level of knowledge within the sample differs: more precise knowledge is demonstrated by pupils following an awareness event (60%) and by pupils interested in HIV (69%) than by those who have attended no awareness event (40%) and those who have little interest in the issue (31%). Moreover, it was noted that grammar school pupils generally achieve better results than pupils from comprehensive and intermediate secondary schools. Furthermore, there are significant differences between the genders: girls give correct answers more frequently than boys and more often show an interest in the HIV/AIDS issue. In addition, age-specific differences are also identifiable: from the age of 14, there is a considerable increase in knowledge, which then remains static at the age of 16. AIDS education in biology lessons is common among pupils and 93% are familiar with this. Over 70% of pupils are unfamiliar with local AIDS awareness teams. CONCLUSIONS: There are significant gaps in the level of knowledge about methods of infection, particularly with respect to questions about the no risk areas, which should thus be particularly dealt with in awareness events. As to knowledge transfer, the pupils' interest should be aroused while taking the type of school, gender and age of the pupils into consideration. In the course of the school career, every pupil should take part in at least one awareness event since our survey showed that only 60% attended such an event. Local AIDS awareness teams should be more frequently active in the schools since 73% stated to be unfamiliar with them in our survey. PMID- 20198566 TI - [Hospital referrals from the general practitioner's perspective - a descriptive analysis based on the CONTENT morbidity register]. AB - BACKGROUND: Hospital referrals cause high costs in the health-care system. Information on hospital referrals from general practices in Germany is sparse. As a starting point for further research we describe the characteristics of hospital referrals and referred patients. METHODS: In the CONTENT project (CONTinuous morbidity registration Epidemiologic NeTwork) the data sets of the patients of 23 general practices were gathered with the help of a modified electronic patient record system. The data of 49,423 patients (yearly contact group 2007) were analysed. RESULTS: Approximately 4% of the patients were referred to a hospital. Most frequent diagnoses (International Classification of Primary Care) were: D75 "malignant neoplasm colon/rectum", K74 "ischaemic heart disease with angina" and L90 "osteoarthrosis of knee". Patients referred to hospital had a higher comorbidity (p<0.0001), higher contact frequencies (p<0.0001), higher prescribing rates (p<0.0001) and were older (p<0.0001) than patients not referred to hospitals. Variations of the referral rates over the year and the week were dependent on parallel variations of the contact frequencies between doctors and patients. CONCLUSION: Patients referred to hospital from general practice are older and have a higher morbidity than patients not referred. Hospital referrals to rule out diseases with a potentially dangerous course as a means of managing uncertainty seem to be the most effective field under control of general practitioners to reduce hospital referrals. PMID- 20198567 TI - Towards an intraoperative engineering of osteogenic and vasculogenic grafts from the stromal vascular fraction of human adipose tissue. AB - Grafts generated by cultivation of progenitor cells from the stromal vascular fraction of human adipose tissue have been proven to have osteogenic and vasculogenic properties in vivo. However, in vitro manufacture of such implants is challenged by complex, impractical and expensive processes, and requires implantation in a separate surgery. This study investigates the feasibility of an intraoperative approach to engineer cell-based bone grafts with tissue harvest, cell isolation, cell seeding onto a scaffold and subsequent implantation within a few hours. Freshly isolated adipose tissue cells from a total of 11 donors, containing variable fractions of mesenchymal and endothelial progenitors, were embedded at different densities in a fibrin hydrogel, which was wrapped around bone substitute materials based on beta-tricalcium phosphate (ChronOS), hydroxyapatite (Engipore), or acellular xenograft (Bio-Oss). The resulting constructs, generated within 3 hours from biopsy harvest, were immediately implanted ectopically in nude mice and analysed after eight weeks. All explants contained blood vessels formed by human endothelial cells, functionally connected to the recipient's vasculature. Human origin cells were also found within osteoid structures, positively immunostained for bone sialoprotein and osteocalcin. However, even with the highest loaded cell densities, no frank bone tissue was detected, independently of the material used. These results provide a proof-of principle that an intraoperative engineering of autologous cell-based vasculogenic bone substitutes is feasible, but highlight that - in the absence of in vitro commitment--additional cues (e.g., low dose of osteogenic factors or orthotopic environmental conditions) are likely needed to support complete osteoblastic cell differentiation and bone tissue generation. PMID- 20198568 TI - Association between male infertility and androgen receptor mutations in Brazilian patients. AB - The androgen receptor is encoded by a single-copy gene located in the long arm of the X chromosome (Xq11-12); it consists of eight exons and encodes an intracellular transcription factor that belongs to the steroid/nuclear receptor superfamily. Disturbances in the function of the androgen receptor can lead to several forms of male pseudohermaphroditism, such as androgen insensitivity syndrome, which can lead to infertility. Infertility affects around 20% of couples, and in half of the cases it is a male problem. Seventy male patients with idiopathic infertility were selected; data were obtained on age, drinking and smoking habits, occupation, and family history. The mean age of the patients was 37 years old (standard deviation = 12.3); 44% were azoospermic, 33% were oligozoospermic and 24% did not have alterations in the spermogram. Our objective was to evaluate a possible association between male infertility and mutations in the androgen receptor gene based on the presence or absence of exons 1 and 4 of this gene. These two exons were tested by PCR, and their products were separated on 1.5% agarose gels. We found that azoospermic patients had higher mutation rates on exons 1 and 4 of the androgen receptor gene, when compared to other alterations that also lead to infertility, such as oligozoospermia and teratozoospermia. So, we conclude that patients who do not produce sperm have a higher number of mutations in the androgen receptor gene when compared to those who only have impaired sperm production. Based on molecular analysis, we found that there was no correlation between alterations in the spermogram and mutations on exons 1 and 4 of the androgen receptor gene and no association between alterations in the spermogram and alcohol drinking or smoking. PMID- 20198569 TI - Ring chromosome instability evaluation in six patients with autosomal rings. AB - Ring chromosomes are often associated with abnormal phenotypes due to loss of genomic material and also because of ring instability at mitosis after sister chromatid exchange events. We investigated ring chromosome instability in six patients with ring chromosomes 4, 14, 15, and 18 by examining 48- and 72-h lymphocyte cultures at the first, second and subsequent cell divisions after bromodeoxyuridine incorporation. Although most cells from all patients showed only one monocentric ring chromosome, ring chromosome loss and secondary aberrations were observed both in 48- and 72-h lymphocyte cultures and in metaphase cells of the different cell generations. We found no clear-cut correlation between ring size and ring instability; we also did not find differences between apparently complete rings and rings with genetic material loss. The cytogenetic findings revealed secondary aberrations in all ring chromosome patients. We concluded that cells with ring chromosome instability can multiply and survive in vivo, and that they can influence the patient's phenotype. PMID- 20198570 TI - Adaptive evolution of the mitochondrial ND6 gene in the domestic horse. AB - Mitochondria play a crucial role in energy metabolism through oxidative phosphorylation. Organisms living at high altitudes are potentially influenced by oxygen deficits and cold temperatures. The severe environmental conditions can impact on metabolism and direct selection of mitochondrial DNA. As a wide-ranging animal, the domestic horse (Equus caballus) has developed various morphological and physiological characteristics for adapting to different altitudes. Thus, this is a good species for studying adaption to high altitudes at a molecular level. We sequenced the complete NADH dehydrogenase 6 gene (ND6) of 509 horses from 24 sampling locations. By comparative analysis of three horse populations living at different altitudes (>2200 m, 1200-1700 m, and <900 m), we found that the high altitude population had the lowest genetic diversity and significant negative Tajima's D; both values declined with increasing elevation. Moreover, non directional selection was identified for the ND6 gene by a tree-based relative ratio test (P = 0.007); the highest proportion of high-altitude horses was found distributed on the selected branches. We conclude that the high-altitude environment has directed adaptive evolution of the mitochondrial ND6 gene in the plateau horse. PMID- 20198571 TI - Caspase-3/-8/-9, Bax and Bcl-2 expression in the cerebellum, lymph nodes and leukocytes of dogs naturally infected with canine distemper virus. AB - Canine distemper is an immunosuppressive disease caused by the canine distemper virus (CDV). Pathogenesis mainly involves the central nervous system and immunosuppression. Dogs naturally infected with CDV develop apoptotic cells in lymphoid tissues and the cerebellum, but this apoptotic mechanism is not well characterized. To better understand this process, we evaluated the expression of Bax, Bcl-2, and caspase-3, -8 and -9, by evaluating mRNA levels in the peripheral blood, lymph nodes and cerebellum of CDV-infected (CDV+) and uninfected (CDV-) dogs by real-time polymerase chain reaction (PCR). Blood samples from 12 CDV+ and 8 CDV- dogs, diagnosed by reverse transcription-PCR, were subjected to hematological analysis and apoptotic gene expression was evaluated using real time-PCR. Tissues from the cerebellum and lymph nodes of four CDV+ and three CDV dogs were also subjected to real time-PCR. No significant differences were found between CDV+ and CDV- dogs in the hemotological results or in the expression of caspase-3, -8, -9, Bax, and Bcl-2 in the peripheral blood. However, expression of Bax, caspase-3, -8 and -9 was significantly higher in the cerebellum of CDV+ compared to CDV- dogs. Expression of caspase-3 and -8 was significantly higher in the lymph nodes of CDV+ compared to CDV- dogs. We concluded that infection with CDV induces apoptosis in the cerebellum and lymph nodes in different ways. Lymph node apoptosis apparently occurs via caspase-3 activation, through the caspase-8 pathway, and cerebellum apoptosis apparently occurs via caspase-3 activation, through the caspase-8 and mitochondrial pathways. PMID- 20198572 TI - A rapid method for isolation of total DNA from pathogenic filamentous plant fungi. AB - DNA isolation from some fungal organisms of agronomic importance is difficult because they have cell walls or capsules that are relatively unsusceptible to lysis. We have developed a fast DNA isolation protocol for Fusarium oxysporum, which causes fusarium wilt disease in more than 100 plant species, and for Pyrenochaeta terrestris, which causes pink root in onions. This protocol was based on the sodium dodecyl sulfate/phenol method, without beta-mercaptoethanol and without maceration in liquid nitrogen; it uses phenol/chloroform extraction to remove proteins and co-precipitated polysaccharides. The A(260/280) absorbance ratios of isolated DNA were around 1.9, suggesting that the DNA fraction was pure and may be used for further analysis. Additionally, the A(260/230) values were higher than 1.8, suggesting negligible contamination by polysaccharides. The DNA isolated by this protocol is of sufficient quality for molecular applications; this technique could be applied to other organisms that have similar substances that hinder DNA extraction. PMID- 20198573 TI - Functional analysis of a TGA factor-binding site located in the promoter region controlling salicylic acid-induced NIMIN-1 expression in Arabidopsis. AB - TGA factors play a key role in plant defense by binding to the promoter region of defense genes, inducing expression. Salicylic acid (SA) induces the expression of the gene encoding NIMIN-1, which interacts with NPR1/NIM1, a key regulator of systemic acquired resistance. We investigated whether the TGA2-binding motif TGACG located upstream of the NIMIN-1 gene is necessary for SA induction of NIMIN 1 expression. A mutated version of the NIMIN-1 promoter was created by site directed mutagenesis. We generated T-DNA constructs in which native NIMIN-1 and mutated promoters were fused to green fluorescent protein and beta-glucuronidase reporters. We produced transgenic Arabidopsis plants and observed NIMIN-1 promoter-driven green fluorescent protein expression in the roots, petiole and leaves. Constructs were agroinfiltrated into the leaves for transient quantitative assays of gene expression. Using quantitative real-time RT-PCR, we characterized the normal gene response to SA and compared it to the response of the mutant version of the NIMIN-1 promoter. Both the native NIMIN-1 construct and an endogenous copy of NIMIN-1 were induced by SA. However, the mutated promoter construct was much less sensitive to SA than the native NIMIN-1 promoter, indicating that this TGA2-binding motif is directly involved in the modulation of SA-induced NIMIN-1 expression in Arabidopsis. PMID- 20198574 TI - Additive genetic relationship of longevity with fertility and production traits in Nellore cattle based on bivariate models. AB - Survival or longevity is an economically important trait in beef cattle. The main inconvenience for its inclusion in selection criteria is delayed recording of phenotypic data and the high computational demand for including survival in proportional hazard models. Thus, identification of a longevity-correlated trait that could be recorded early in life would be very useful for selection purposes. We estimated the genetic relationship of survival with productive and reproductive traits in Nellore cattle, including weaning weight (WW), post weaning growth (PWG), muscularity (MUSC), scrotal circumference at 18 months (SC18), and heifer pregnancy (HP). Survival was measured in discrete time intervals and modeled through a sequential threshold model. Five independent bivariate Bayesian analyses were performed, accounting for cow survival and the five productive and reproductive traits. Posterior mean estimates for heritability (standard deviation in parentheses) were 0.55 (0.01) for WW, 0.25 (0.01) for PWG, 0.23 (0.01) for MUSC, and 0.48 (0.01) for SC18. The posterior mean estimates (95% confidence interval in parentheses) for the genetic correlation with survival were 0.16 (0.13-0.19), 0.30 (0.25-0.34), 0.31 (0.25- 0.36), 0.07 (0.02-0.12), and 0.82 (0.78-0.86) for WW, PWG, MUSC, SC18, and HP, respectively. Based on the high genetic correlation and heritability (0.54) posterior mean estimates for HP, the expected progeny difference for HP can be used to select bulls for longevity, as well as for post-weaning gain and muscle score. PMID- 20198575 TI - Chicken skeletal muscle-associated macroarray for gene discovery. AB - Macro- and microarrays are well-established technologies to determine gene functions through repeated measurements of transcript abundance. We constructed a chicken skeletal muscle-associated array based on a muscle-specific EST database, which was used to generate a tissue expression dataset of ~4500 chicken genes across 5 adult tissues (skeletal muscle, heart, liver, brain, and skin). Only a small number of ESTs were sufficiently well characterized by BLAST searches to determine their probable cellular functions. Evidence of a particular tissue characteristic expression can be considered an indication that the transcript is likely to be functionally significant. The skeletal muscle macroarray platform was first used to search for evidence of tissue-specific expression, focusing on the biological function of genes/transcripts, since gene expression profiles generated across tissues were found to be reliable and consistent. Hierarchical clustering analysis revealed consistent clustering among genes assigned to 'developmental growth', such as the ontology genes and germ layers. Accuracy of the expression data was supported by comparing information from known transcripts and tissue from which the transcript was derived with macroarray data. Hybridization assays resulted in consistent tissue expression profile, which will be useful to dissect tissue-regulatory networks and to predict functions of novel genes identified after extensive sequencing of the genomes of model organisms. Screening our skeletal-muscle platform using 5 chicken adult tissues allowed us identifying 43 'tissue-specific' transcripts, and 112 co-expressed uncharacterized transcripts with 62 putative motifs. This platform also represents an important tool for functional investigation of novel genes; to determine expression pattern according to developmental stages; to evaluate differences in muscular growth potential between chicken lines, and to identify tissue-specific genes. PMID- 20198576 TI - Association between the -1438A/G polymorphism of the serotonin 2A receptor gene and late-onset psoriasis in a Thai population. AB - Expression of serotonin 2A receptor (5-HTR2A) is known to increase in psoriasis, a chronic inflammatory skin disease. We investigated a possible association between the -1438A/G single nucleotide polymorphism (rs6311) in the promoter region of 5-HTR2A gene and psoriasis in a Thai population. One hundred and twelve psoriatic patients and 151 unrelated healthy controls were included in our study. Genotyping was performed using the polymerase chain reaction and restriction fragment length polymorphism techniques. We found no overall differences in genotype distributions and allele frequencies when comparing between the two groups. When we analyzed a subset of psoriatic patients classified by onset and severity, only the -1438A allele was significantly increased in patients with late-onset psoriasis when compared with the healthy control group (chi(2) = 4.77, d.f. = 1, P = 0.029, odds ratio = 2.298 [95% confidence interval = 1.126-4.691]). This single nucleotide polymorphism may be involved in late-onset psoriasis in this Thai population. PMID- 20198577 TI - The kinin B(2) receptor gene structure, product processing and expression in adult and fetal rats: evidence for gene evolution. AB - We examined the structure of the rat kinin B2 receptor gene (KB2r) and encoding messenger RNA (mRNA) processing. Differently from the closely related mouse and rabbit genes that have three exons and two introns, the rat gene purportedly consists of four exons and three introns. There are two purported gene products; one of them contains an upstream approximately 180-bp open reading frame region ("exon-X") potentially expressed as a result of alternative processing. To examine the processing of rat KB2r mRNA, cDNA amplicons were generated using primer pairs directed towards 5' or 3' exon or intron flanking regions. Analyses of intron/exon primary cDNA amplicons showed that introns 1 to 3 are removed sequentially and that "exon-X" removal follows that of intron-3. No evidence was found for "exon-X" expression in polyadenylated (mature) mRNA of adult Wistar, Wistar Kyoto, spontaneously hypertensive or Sprague-Dawley rat tissues. Nor was "exon-X" detected in tissues subject to inflammatory stimulus expressing B1 kinin receptor mRNA or in 1- to 21-day-old rat embryos or fetuses. The lack of evidence for the expression of "exon-X" in mature mRNA indicates that the structure of the rat gene is similar to that of the mouse, rabbit and human genes, all consisting of three exons and two introns. The "exon-X" fragment may result from interstitial gene duplication, be a fragment of the ancestral gene, or most likely heterologous transposon insertion of an exon-like fragment into intron-2 of the KB2r gene. PMID- 20198578 TI - Mitotic crossing-over induced by two commercial herbicides in diploid strains of the fungus Aspergillus nidulans. AB - Some herbicides are suspected of promoting teratogenic, carcinogenic and mutagenic events. Detection of induced mitotic crossing-over has proven to be an indirect way of testing the carcinogenic properties of suspicious substances, because mitotic crossing-over is involved in the multistep process of carcinogenesis. We examined mitotic crossing-over induced by two commercial herbicides (diuron and trifluralin) in diploid strains of Aspergillus nidulans based on the homozygotization index. Low doses (2.5 microg/mL) of diuron were sufficient to increase the mean homozygotization index in 2.1 and 11.3 times for UT448//UT196 and Dp II-I//UT196, respectively, whereas the same dose of trifluralin increased this mean only 1.2 (UT448//UT196) and 3.5 (Dp II-I//UT196) times, respectively. The lower homozygotization index value found for trifluralin could be due to its interference with mitotic crossing-over in eukaryotic cells. We concluded that the diploid Dp II-I//UT196 of A. nidulans is more sensitive to organic compounds than UT448//UT196; these compounds cause recombinational events at a greater frequency in the latter diploid. This system holds promise as an initial test for carcinogenicity of organic compounds, including herbicides. PMID- 20198579 TI - Investigation of NQO1 genetic polymorphism, NQO1 gene expression and PAH-DNA adducts in ESCC. A case-control study from Iran. AB - We evaluated the effect of NQO1 genetic variation on PAH-DNA adducts in esophageal squamous cell carcinoma (ESCC) in northeast Iran. Golestan Province in northeast of Iran has one of the highest esophageal cancer incidences in the world. The study included 93 ESCC cases and 50 control individuals who were seen at the clinical cancer center in Golestan province. NQO1 C609T genotypes were determined by PCR-RFLP analysis. NQO1 gene expression in tissue samples was determined by quantitative real-time PCR. Immunohistochemical techniques were used to detect PAH-DNA adducts in ESCC and normal esophageal tissues. The distributions of NQO1 genetic polymorphism between cases and the control group were not significantly different. NQO1 gene expression was not higher in tumor tissues than in normal esophageal tissues adjacent to the ESCC; expression was higher in tumor tissues that had the NQO1 T allele. NQO1 gene expression was high in normal esophageal tissues. The level of PAH-DNA adducts was significantly higher in ESCC tissues of cases than in normal tissues adjacent to tumor tissues and in normal esophageal tissues of healthy controls. There were no significant differences between the adduct levels of normal esophageal tissues of patients and controls. There was also no significant relationship between cigarette smoking and PAH-DNA adducts. We concluded that PAHs are a risk factor for ESCC and that PAH-DNA adducts have potential as a biomarker for risk of ESCC. PMID- 20198580 TI - Diversity of endophytic bacteria in Brazilian sugarcane. AB - Endophytic bacteria live inside plant tissues without causing disease. Studies of endophytes in sugarcane have focused on the isolation of diazotrophic bacteria. We examined the diversity of endophytic bacteria in the internal tissues of sugarcane stems and leaves, using molecular and biochemical methods. Potato-agar medium was used to cultivate the endophytes; 32 isolates were selected for analysis. DNA was extracted and the 16S rRNA gene was partially sequenced and used for molecular identification. Gram staining, catalase and oxidase tests, and the API-20E system were used to characterize the isolates. The strains were divided into five groups, based on the 16S rRNA sequences. Group I comprised 14 representatives of the Enterobacteriaceae; group II was composed of Bacilli; group III contained one representative, Curtobacterium sp; group IV contained representatives of the Pseudomonadaceae family, and group V had one isolate with an uncultured bacterium. Four isolates were able to reduce acetylene to ethylene. Most of the bacteria isolated from the sugarcane stem and leaf tissues belonged to Enterobacteriaceae and Pseudomonaceae, respectively, demonstrating niche specificity. Overall, we found the endophytic bacteria in sugarcane to be more diverse than previously reported. PMID- 20198581 TI - Interpretation of electrophoretograms of seven microsatellite loci to determine the genetic diversity of the Arabian Oryx. AB - Microsatellite markers are commonly used for examining population structure, especially inbreeding, outbreeding and gene flow. An array of microsatellite loci, preferably with multiallelic presentation, is preferable for ensuring accurate results. However, artifact peaks or stutters in the electrophoretograms significantly hamper the reliable interpretation of genotypes. We interpreted electrophoretograms of seven microsatellite loci to determine the genetic diversity of the Arabian Oryx. All the alleles of different loci exhibited good peak resolutions and hence were clearly identified. Moreover, none of the stutter peaks impaired the recognition or differentiation between homozygote and heterozygote. Our findings suggest that correct identification of alleles in the presence of co-amplified nonspecific fragments is important for reliable interpretation of microsatellite data. PMID- 20198582 TI - Molecular cloning and expression of epsilon toxin from Clostridium perfringens type D and tests of animal immunization. AB - Epsilon toxin produced by Clostridium perfringens types B and D causes enterotoxemia in sheep, goats and calves. Enterotoxemia can cause acute or superacute disease, with sudden death of the affected animal. It provokes huge economic losses when large numbers of livestock are affected. Therapeutic intervention is challenging, because the disease progresses very rapidly. However, it can be prevented by immunization with specific immunogenic vaccines. We cloned the etx gene, encoding epsilon toxin, into vector pET-11a; recombinant epsilon toxin (rec-epsilon) was expressed in inclusion bodies and was used for animal immunization. Serum protection was evaluated and cross-serum neutralization tests were used to characterize the recombinant toxin. To analyze the potency of the toxin (as an antigen), rabbits were immunized with 50, 100 or 200 microg recombinant toxin, using aluminum hydroxide gel as an adjuvant. Titers of 10, 30 and 40 IU/mL were obtained, respectively. These titers were higher than the minimum level required by the European Pharmacopoeia (5 IU/mL) and by the USA Code of Federal Regulation (2 IU/mL). This rec-epsilon is a good candidate for vaccine production against enterotoxemia caused by epsilon toxin of C. perfringens type D. PMID- 20198583 TI - Transferability of microsatellite loci from exotic Cervidae to Brazilian brocket deer (Mazama spp, Mammalia: Cervidae). AB - Transferability of microsatellite loci between closely related species has been reported in several species. This helps reduce costs involved with the development of primers for newly investigated species. Fifteen microsatellite primers developed for Rangifer tarandus, Cervus elaphus, C. axis, and Moschus berezovskii were tested on five species of Brazilian brocket deer of the genus Mazama (M. americana, M. bororo, M. gouazoubira, M. nana, and M. nemorivaga). These primers were tested with DNA extracted from blood samples of two individuals of each species obtained from the Nucleo de Pesquisa e Conservacao de Cervideos (NUPECCE) of Universidade Estadual Paulista (UNESP). Fourteen of the 15 primers tested amplified microsatellite regions of all five species of Mazama, confirmed by sequencing of the amplified fragments. We conclude that these primers could be used for population studies of brocket deer. PMID- 20198584 TI - Genetic variability in domesticated Capsicum spp as assessed by morphological and agronomic data in mixed statistical analysis. AB - Capsicum species are very important in Brazil because of economic, cultural and biological factors, and the country is considered to be a diversity center for this genus. Collection and maintenance of the genetic diversity in Capsicum are important to avoid genetic erosion. Besides the identification of species, the characterization and evaluation of accessions maintained in gene banks are of fundamental importance. For this purpose, multivariate methods have become an important tool in the classification of conserved genotypes. The objectives of this study were: i) to identify and characterize accessions of the Capsicum spp collection and draw conclusions about the potential use of certain accessions in different production sectors; ii) to estimate the genetic divergence among accessions using the Ward-MLM procedure, and iii) to evaluate the efficiency of the analysis of continuous and categorical data using the Ward-MLM procedure. Fifty-six Capsicum spp accessions were evaluated based on 25 descriptors, 14 of which were morphological and 11 agronomic. Based on the qualitative descriptors, it was possible to identify all species and, together with the agronomic descriptors, genotypes could be indicated with potential for use in various production sectors. Five was determined as the ideal number of groups by the criteria pseudo-F and pseudo-t2. The Ward-MLM procedure allowed the differentiation of the species C. annuum, C. frutescens, C. baccatum, and C. chinense in separate groups. The Ward-MLM procedure showed some level of efficiency in clustering Capsicum species analyzing morphological and agronomic data simultaneously. PMID- 20198585 TI - In vitro development of cloned bovine embryos produced by handmade cloning using somatic cells from distinct levels of cell culture confluence. AB - The relationship between the level of cell confluence near the plateau phase of growth and blastocyst yield following somatic cell cloning is not well understood. We examined the effect of distinct cell culture confluence levels on in vitro development of cloned bovine embryos. In vitro-matured bovine oocytes were manually bisected and selected by DNA staining. One or two enucleated hemi cytoplasts were paired and fused with an adult skin somatic cell. Cultured skin cells from an adult Nellore cow harvested at three distinct culture confluence levels (70-80, 80-90, and >95%) were used for construction of embryos and hemi embryos. After activation, structures were cultured in vitro as one embryo (1 x 100%) or as aggregates of two hemi-embryos (2 x 50%) per microwell. Fusion, cleavage and blastocyst rates were compared using the chi(2) test. The fusion rate for hemi-embryos (51.4%) was lower than for embryos (67.6%), with no influence of degree of cell confluence. However, blastocyst rates improved linearly (7.0, 17.5, and 29.4%) with increases in cell confluence. We conclude that degree of cell culture confluence significantly influences subsequent embryo development; use of a cell population in high confluence (>90%) for nuclear transfer significantly improved blastocyst yield after cloning. PMID- 20198586 TI - RAPD identification of Varroa destructor genotypes in Brazil and other regions of the Americas. AB - The mite Varroa destructor is the main pest causing damage to apiculture worldwide. In Brazil and other parts of the world, where bees of African origin and their hybrids predominate, the bees can survive these mites without treatment. Studies have shown a correlation between the various genotypes of the mite and its fertility in different geographical regions. Information about mite genotype could be helpful in understanding the diverse effects and relationships of the mite with bees in different regions of the world. DNA analysis by RAPD technique has permitted identification of three distinct genotypes in the mite V. destructor, namely Russian, Japanese and Papua New Guinea. We found predominance of the Russian genotype in Brazil, along with other parts of South America, and in Cuba and Mexico. The Japanese genotype was exclusively found on Fernando de Noronha Island in Brazil. PMID- 20198587 TI - Somatic cell nuclear transfer is associated with altered expression of angiogenic factor systems in bovine placentomes at term. AB - Low efficiency of somatic cell cloning by nuclear transfer has been associated with alterations of placental vascular architecture. Placental growth and function depend on the growth of blood vessels; VEGF-A and bFGF are the most important factors controlling neovascularization and vascular permeability in the placenta. We hypothesize that the VEGF-A and bFGF systems are disrupted in placentomes from cloned animals, contributing to the placental abnormalities that are common in these clones. We determined mRNA expression and protein tissue localization of VEGF-A, bFGF, and their receptors in placentomes from cloned and non-cloned bovine fetuses at term. Real-time RT-PCR revealed that VEGFR-2 mRNA was increased in cloned male-derived placentomes, while mRNA of bFGF and its receptors were decreased in placentomes of cloned females. VEGF-A system proteins were found to be located in placentomal endothelial, maternal and fetal epithelial and stromal cells; there was a variable pattern of cellular distribution of these proteins in both cloned and non-cloned animals. Alterations in the expression of VEGF-A and bFGF systems suggest that angiogenic factors are involved in abnormal placental development in cloned gestations, contributing to impaired fetal development and poor survival rates. PMID- 20198588 TI - SSR-based molecular analysis of economically important Turkish apricot cultivars. AB - Turkey is not only the main apricot (Prunus armeniaca) producer and exporter in the world, but it also has a wide variety of apricot germplasms, owing to its close proximity to the centers of apricot origin. However, there is little or no genetic information on many apricot cultivars that are extensively cultivated in Turkey. We examined the genetic relatedness of 25 Turkish and four exotic apricot cultivars using SSR (simple sequence repeat) markers that were either previously developed for apricot, or for peach (P. persica), a close relative of apricot. Allele diversity (with an average allele number of 6.37) at the SSR loci and the heterozygosity rates (with an average Ho value of 0.648) of these cultivars were found to be higher than in previous studies that used the same loci for apricot. This fact might be attributed to the analysis of different numbers of accessions in the different studies. No correlations were found between the genetic relatedness and the geographical distributions of these cultivars. The data reported here will assist in the prevention of confusions in the apricot propagation and breeding in Turkey. The findings can also be directly compared with other studies that used the same SSR markers on apricot. PMID- 20198589 TI - Lack of association between paraoxonase-1 Q192R polymorphism and rheumatoid arthritis in southeast Iran. AB - Decreased paraoxonase-1 (PON1) activity has been associated with rheumatoid arthritis. There are two polymorphisms in serum PON1; one differs in the amino acid at position 192 (Q192R) and the other one differs at position 55 (L55M). We looked for a possible association between Q192R polymorphism and rheumatoid arthritis. The Q192R polymorphism in 88 rheumatoid arthritis patients and 78 healthy subjects was determined using tetra amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and PCR-restriction fragment length polymorphism (RFLP) methods. We found no significant differences between rheumatoid arthritis patients and control subjects regarding PON1 Q192R polymorphism. PON1 Q192R polymorphism was not found to be correlated with increased risk for rheumatoid arthritis in this Iranian population. PMID- 20198590 TI - [Biomarkers in the cerebrospinal fluid of patients with mild cognitive impairment: a meta-analysis of their predictive capacity for the diagnosis of Alzheimer's disease]. AB - INTRODUCTION: Several studies have reported alterations in the cerebrospinal fluid biomarkers (Abeta-42, T-tau and P-tau proteins), both in Alzheimer's disease (AD) and in mild cognitive impairment (MCI). AIM: To perform a meta analysis of the diagnostic yield of this technique for the prediction of patients with MCI who are going to progress to AD. MATERIALS AND METHODS: A search was conducted in PubMed and Embase of papers published between 1999 and September 2008, and as a result only prospective studies were included for the systematic review. The sensitivity and specificity for each biomarker were studied separately and also jointly. RESULTS: Of the 12 studies that were included, 6 quantified the Abeta-42 protein, 11 the T-tau protein and seven the P-tau protein. In three of the studies data was obtained from the three biomarkers in combination. The sensitivity of the quantification of the T-tau and P-tau proteins is 82%, with a diagnostic odds ratio of 12.09 (confidence interval 95%, CI 95% = 7.71-18.99; p = 0.1) and 16.29 (CI 95% = 9.69-27.4; p = 0.9), respectively. Alteration of any of the three biomarkers has a specificity of 87%, with a diagnostic odds ratio of 35.97 (CI 95% = 7.8-164.6; p = 0.04). CONCLUSIONS: The isolated alteration of T-tau or P-tau levels in cerebrospinal fluid is very sensitive for differentiating between patients with MCI who are going to develop AD and those who are going to remain stable. Normality of the three biomarkers is a very reliable way of ruling out the progression of AD in patients with MCI. PMID- 20198591 TI - [Evaluation of changes in the treatment of spontaneous intracerebral haemorrhage in a regional hospital in Mexico]. AB - INTRODUCTION: The spontaneous intracerebral hemorrhage (ICH) shows a high lethal rate. In 1999 appeared the first therapeutic guidelines, after that new therapies have been assessed without substantial success. AIM: To describe treatment changes for ICH in a regional Mexican hospital and to assess their impact on clinical evolution. PATIENTS AND METHODS: We accomplished a retrospective study of patients admitted between 2000 and 2006. We included those elder than 15 years with tomographyc diagnostic of ICH. Patients with head injury four weeks before or undetermined initial National Institute of Health Stroke Scale (NIHSS) were excluded. Epidemiological, clinical characteristics and kind of therapy were studied. RESULTS: We analyzed 175 patients with mean age of 62 years. Etiology and localization more frequently were arterial hypertension and lobar, respectively. More than 20% were intubated and approximately one half of these admitted in intensive care unit. Angiotensin converter enzyme inhibitors were the medicaments more usually used for controlling blood pressure. An initial NIHSS > 15 or Glasgow < 9 were associated to poor outcome. Additional administration of calcium antagonist, statins and surgical decompression was associated to a better outcome. CONCLUSIONS: Use of intensive care units is a measure highly suggested as standard for ICH-therapy. In our center it was not regularly accomplished because of infrastructural deficiencies. This problem could be generated in other Mexican hospitals; attention to that phenomenon is urgently required. Evaluation of new therapeutic strategies is required. PMID- 20198592 TI - [Utility of the Wender-Utah rating scale and the checklists for the diagnosis of familial attention deficit hyperactivity disorder in adults. Convergent and concurrent validities]. AB - INTRODUCTION: Standard questionnaires to characterize familial attention deficit hyperactivity disorder (ADHD) of adults have been studied in some studies. AIM: To observe convergent and concurrent validity of four standard rating scales to quantify the familial ADHD symptoms of adults. PATIENTS AND METHODS: The sample was constituted by the 392 adults; aged 18 through 84 years, belonging to 141 Antioquian families with multiple ADHD affected members, who fulfilled by self report the Wender-Utah Rating Scale and the ADHD checklist; and, beside, answered a questionnaire asking for current and past ADHD symptoms, in a neurological interview. Correlation analyses were done. Sensitivity and specificity for ADHD diagnosis were also determined. RESULTS: Significant and over 0.6 correlations were observed between scales that explored past ADHD symptoms. Distant cut-off points for 90% sensitivity and specificity were observed for all questionnaires. The best LR+ (12.15) was found for the report of 5 or more past hyperactivity impulsivity symptoms; follow by the report of 7 or more past ADHD symptoms (6.92). CONCLUSIONS: Cut-off points should be taken with caution when these rating scales were used for adult ADHD screening. Psychometric properties do not allow using these scales as substitution of structured clinical interview for the gold standard ADHD diagnosis in adults. PMID- 20198593 TI - [Transient topographical amnesia: a description of a series of eight cases]. AB - INTRODUCTION: Impaired memory, and more particularly spatial orientation, occurs in pathologies such as dementia, cerebrovascular accidents or traumatic brain injuries. Less frequently it also appears as a transient disorder in healthy people with no apparent brain damage, in which case it is known as transient topographical amnesia (TTA). The aim of this work is to report on a series of eight cases of TTA that were evaluated in a neurology unit. CASE REPORTS: We study the cases of eight patients diagnosed with TTA over the period 2002-2008. Patients were considered to fulfil eligibility criteria if they had presented at least one episode of spatial disorientation, with no loss of memory or consciousness, and were able to describe the events that had taken place, without any previous cognitive impairment and with a normal neurological examination. The demographic characteristics taken into account in the study were: predominance of females (75%) and a mean age of 69.13 +/- 8.79 years. The mean number of episodes was 1.75 (range: 1-3), which lasted an average of 24.5 minutes. Three of the eight patients had associated vascular risk factors. Neuroimaging studies did not reveal any relevant findings in any of the eight patients, except one case of a bilateral frontal porencephalic area resulting from a traumatic brain injury suffered in the past. Simple single-photon emission tomography and Doppler ultrasound imaging scans of the brain, as well as an electroencephalogram, were performed on two patients, the results being normal in all cases. Follow-ups were performed on all the patients, without any kind clinical change being observed, except for one patient who developed dementia at six years after the episode of amnesia. CONCLUSIONS: TTA is possibly an underdiagnosed condition which we believe should be included in the differential diagnosis of patients who are referred owing to suspected cognitive impairment. PMID- 20198594 TI - [Caffeine as a preventive drug for Parkinson's disease: epidemiologic evidence and experimental support]. AB - INTRODUCTION AND DEVELOPMENT: Prospective epidemiologic studies performed in large cohorts of men (total: 374,003 subjects) agree in which the risk of suffering Parkinson's disease diminishes progressively as the consumption of coffee and other caffeinated beverages increases. In the case of women (total: 345,184 subjects) the protective effect of caffeine is only observed in menopausal women which do not receive estrogen replacement therapy. Studies with models of acute parkinsonism in rodents have shown that caffeine reduces the loss of nigrostriatal dopaminergic neurons induced with the neurotoxins 6 hidroxidopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, effect that seems to be mediated through blockade of A(2A) adenosine receptors. Recently, it was shown that male rats treated with moderate doses of caffeine (5 mg/kg/day) during six months, followed by a withdrawal period of at least two weeks, developed a greater resistance to the catalepsy induced with the dopaminergic antagonist haloperidol, which was possibly mediated by an increase of dopaminergic transmission in the corpus striatum. CONCLUSIONS: More studies are needed to demonstrate unequivocally that caffeine prevents the degeneration of dopaminergic neurons in animal models of moderate, chronic, and progressive parkinsonism, since it could lead to the discovery of more effective drugs for the prevention of aging-related degenerative diseases of the central nervous system. PMID- 20198595 TI - [Repeated transcranial magnetic stimulation in children and adolescents]. AB - AIMS: To gather the knowledge that currently exist on transcranial magnetic stimulation applied in children and adolescents, as well as its possible future therapeutic applications in disorders that have so far shown more chances of being effective. DEVELOPMENT: First, we provide a general review of the history of the technique, from its early days until the present day, and we also highlight the studies in the literature that refer to the harmlessness of the technique by referring to histological studies where no pathological changes were found. We then focus on the repeated mode, which is the technique that is most widely used for therapeutic purposes, both in adults and in children and adolescents, despite the fact that its frequency of use is clearly lower than that of other modes. We centre our attention on the disorders in which the technique has been applied, the ones that to date have been most successful (therapeutically speaking), the subjective experiences of the patients themselves and the side effects that they have suffered. CONCLUSIONS: Further studies need to be conducted on the use of repeated transcranial magnetic stimulation to treat different neurological and psychiatric disorders in children and adolescents, especially in diseases like depression and obsessive-compulsive disorder. PMID- 20198596 TI - [Vitamin treatments that lower homocysteine concentration: can they decrease cerebrovascular disease in primary prevention?]. AB - INTRODUCTION: High plasma homocysteine (Hcy) concentration or hyperhomocysteinemia is associated with an increased vascular risk of disease in case-control studies and, to a lesser extent, in prospective studies. DEVELOPMENT: Several large randomized, double-blind, placebo-controlled trials have been already conducted using specific vitamin therapies with the aim of reducing secondary cardiovascular (HOPE, NORVIT, WAFACS and WENBIT studies) and cerebrovascular (VISP study) disease risk. The results from these major secondary prevention trials and one meta-analysis, that included other smaller studies up to 12 of them, showed that treatment decreased plasma Hcy concentration but failed to reduce cardiovascular risk. It is nevertheless noteworthy that a recent meta-analysis addressing the effects of these vitamin treatments on cerebrovascular risk found a positive effect on primary stroke prevention. These data would be consistent with the fact that increased Hcy is known to be associated more strongly with stroke risk than with cardiovascular risk. Moreover, folic acid supplementation in grain food has recently been shown to be associated with a decreased stroke incidence in USA and Canada. CONCLUSIONS: Obviously, these data on primary stroke prevention will require extensive confirmation. However, there now appear to be more reasons to expect a positive outcome of Hcy intervention studies. PMID- 20198597 TI - [The role of the ventromedial prefrontal cortex in the response to negative emotional events]. AB - INTRODUCTION: This review presents data showing the key role of ventromedial prefrontal cortex (here defined as an extensive area that includes ventral and medial prefrontal cortices) in the neural circuitry in charge of responding to negative events (i.e., dangerous, painful or disgusting). DEVELOPMENT: Ventromedial prefrontal cortex has rapid access to visual information and, in consequence, is able to react to negative visual events at approximately 100-150 ms from the stimulus onset. Its response to this type of stimulation, even when it is unconsciously perceived, is more intense than to non-negative stimuli. The main connections of this prefrontal area with sensorial structures (both up, in order to get incoming sensory information, and down, modulating the activity of these areas), with regions in charge of cognitive processes relevant to take a decision on how to cope with the negative stimulus (e.g., memory, action planning), and with areas in charge of autonomic and motor execution, are described. CONCLUSIONS: An integrative schema of the role of ventromedial prefrontal cortex in the response to negative events is provided. PMID- 20198598 TI - [Congenital toxoplasmosis and cortical development malformation: an infrequent association]. PMID- 20198599 TI - [Diffuse leukoencephalopathy due to congenital infection by cytomegalovirus]. PMID- 20198600 TI - [Application of robotic systems in infantile cerebral palsy]. PMID- 20198601 TI - The assay of pterostilbene in spiked matrices by liquid chromatography tandem mass spectrometry and isotope dilution method. AB - Pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene) is an active component found in several plant species, exhibiting important pharmacological properties. A new and reliable method of assaying this phyto compound in various matrices is presented; the assay is based on (1) the selectivity of liquid chromatography (LC) hyphenated with electrospray ionisation (ESI), (2) the specificity of a two step mass spectrometric analysis (MS/MS) and (3) the accuracy of the isotope dilution method. The labelled analogue may be conveniently synthesised in a few steps. The sensitivity of the method is confirmed by the very low limit of detection (LOD) and limit of quantitation (LOQ) values achieved in the assay of pterostilbene in two distinct fortified matrices, and is further supported by the observed accuracy values. PMID- 20198602 TI - Characterization and de novo sequencing of snow crab tropomyosin enzymatic peptides by both electrospray ionization and matrix-assisted laser desorption ionization QqToF tandem mass spectrometry. AB - The protein tropomyosin (TM) is a known major allergen present in shellfish causing frequent food allergies. TM is also an occupational allergen generated in the working environment of snow crab (Chionoecetes opilio) processing plants. The TM protein was purified from both claw and leg meats of snow crab and analyzed by electrospray ionization and matrix-assisted laser desorption/ionization (MALDI) using hybrid quadruple time-of-flight tandem mass spectrometry (QqToF-MS). The native polypeptide molecular weight of TM was determined to be 32,733 Da. The protein was further characterized using the 'bottom-up' MS approach. A peptide mass fingerprinting was obtained by two different enzymatic digestions and de novo sequencing of the most abundant peptides performed. Any post-translational modifications were identified by searching their calculated and predicted molecular weights in precursor ion spectra. The immunological reactivity of snow crab extract was evaluated using specific antibodies and allergenic reactivity assessed with serum of allergic patients. Subsequently, a signature peptide for TM was identified and evaluated in terms of identity and homology using the basic local alignment search tool (BLAST). The identification of a signature peptide for the allergen TM using MALDI-QqToF-MS will be critical for the sensitive and specific quantification of this highly allergenic protein in the work place. PMID- 20198603 TI - Electrospray tandem mass spectrometry of longipedlactone triterpenoids. PMID- 20198604 TI - The carbon versus mass diagram to visualize and exploit FTICR-MS data of natural organic matter. AB - A two-dimensional diagram is proposed, in which the carbon number of each formula is plotted against its nominal mass, to visualize large sets of molecular formula data that can be derived from data generated by ultrahigh-resolution Fourier transform ion cyclotron resonance-MS. In such a carbon versus mass (CvM) diagram, each formula (C(c)H(h)O(o)) is unambiguously described by c, its (nominal) mass and the parameter i = c + o. Calculations of chemically allowable formulas illustrate that organic molecules occupy only certain spaces in such a diagram. The extension of these spaces increases with molecular mass in x-direction (hydrogenation) and y-direction (oxygenation). The data sets of molecules determined in natural organic matter(NOM) occupy only a certain range of the allowable space. The intensity of the mass spectrometric signals can be included as the third dimension into a CvM diagram. Separate CvM diagrams can be plotted for NOM molecules that include different heteroatoms. The benefits of the CvM diagram are illustrated by application onto data sets of fulvic acids from riverine and marine origin, of secondary organic aerosol, including organosulfates and organonitrates, as well as of ozonation of fulvic acids. The CvM diagram is a useful tool to visualize the elemental regularities in NOM isolates as well as the differences between isolates. It may also be applicable to large sets of molecular formula data generated in other disciplines such as petroleum biogeochemistry or metabolomics. PMID- 20198605 TI - Modelling mass analyzer performance with fields determined using the boundary element method. AB - Computer modelling is widely used in the design of mass analysers to evaluate proposed designs and determine the effects of manufacturing imperfections. For quadrupole mass filters and ion traps, the models require accurate values of the electric field throughout the regions of the analyser in which ions travel. Most published results using models to predict mass analyser behaviour use electric fields computed with finite element (FE) or finite difference (FD) method. However, the boundary element method (BEM) is capable of achieving the same, or higher, accuracy with both computation times and memory requirements that are at least an order of magnitude less than those required by FE and FD methods. In this paper, electric field evaluation is performed using the BEM formulated in a manner described by previous workers; modifications to their method are described, which lead to higher accuracy field values. Simultaneous equation solution techniques are incorporated, which avoid solutions that are physically not realistic. The performance of linear quadrupole mass spectrometers with hyperbolic, circular and planar section electrodes has been determined using fields computed using these methods and compared with previous results obtained by alternative field computation techniques and with experiment. Behaviour of an ion trap mass spectrometer with circular symmetry has also been investigated. The results demonstrate that in each case using the BEM to determine the fields produces the observed behaviour. PMID- 20198606 TI - Intent-to-treat analysis in the presence of off-treatment or missing data. AB - Intent-to-treat (ITT) analysis is viewed as the analysis of a clinical trial that provides the least bias, but difficult issues can arise. Common analysis methods such as mixed-effects and proportional hazards models are usually labeled as ITT analysis, but in practice they can often be inconsistent with a strict interpretation of the ITT principle. In trials where effective medications are available to patients withdrawing from treatment, ITT analysis can mask important therapeutic effects of the intervention studied in the trial. Analysis of on treatment data may be subject to bias, but can address efficacy objectives when combined with careful review of the pattern of withdrawals across treatments particularly for those patients withdrawing due to lack of efficacy and adverse events. PMID- 20198607 TI - p53 flow cytometry evaluation in leukemias: correlation to factors affecting clinical outcome. AB - p53 is a cell cycle checkpoint control protein that assesses DNA damage and acts as a transcription factor regulating genes, which control cell growth, DNA repair, and apoptosis. p53 mutations have been found in a wide variety of different cancers including flow cytometric assessment of p53 protein expression using anti-p53 monoclonal antibodies. We studied p53 protein expression by flow cytometry (FC) assay in 223 blood and/or bone marrow samples from 72 patients with chronic myeloid leukemia (CML): 54 in chronic phase (CML-CP), 7 in accelerated phase (CML-AP), and 11 in blastic phase (CML-BP); 64 patients with chronic lymphoid leukemia (CLL): (34 at diagnosis, 21 in previously treated, and 9 with Richter's syndrome); 44 patients with acute lymphoid leukemia (ALL): 36 at diagnosis and 8 in relapse; and 43 acute myeloid leukemia (AML): 27 de novo, 7 in relapse, and 9 secondary. p53 protein expression was observed in 64 of 223 patient's samples: 14/64 (21.9%) CLL, 13/44 (29.5%) ALL, 19/43 (44.2%) AML, and 17/72 (23.6%) CML. Highest levels were detected in the advanced phases of CLL, ALL, and CML. In addition, in patients with AML, high levels of p53 expression were detected in secondary and relapse disease and also in de novo AML cases. Our results demonstrated that p53 expression levels are strongly associated with advanced disease. On the basis of these results, we concluded that FC can be a reliable approach to study p53 protein expression in leukemic patients. PMID- 20198608 TI - Multiparameter immunophenotyping by flow cytometry in multiple myeloma: The diagnostic utility of defining ranges of normal antigenic expression in comparison to histology. AB - BACKGROUND: Numerous studies have reported on the immunophenotype of plasma cells (PCs) in monoclonal gammopathy of undetermined significance (MGUS) and in plasma cell myeloma (PCM), but very few have examined the immunophenotype of normal PCs. In this study, an objective definition of normal range of expression for each antigen was found on normal control PCs. Using these new ranges of normal expression (new method) is different from using a static 20% of PCs cut-off for all antigens as described in the literature (traditional method). These newly calculated normal ranges for each antigen were applied to our data, and compared to histologic and immunohistochemical findings. METHODS: Bone marrow samples from 46 patients with PC neoplasms and 15 normal controls were studied. A minimum of 100 PC were analyzed for each patient and control sample. An 8-color staining method was applied to study the immunophenotype of PCs, using a BD FACSCanto II. RESULTS: By the new ranges of normality calculated in this study it was determined that different antigens have different level of expression on polyclonal PCs. CD19 correlated with histology by both the traditional and new methods, but had superior correlation by the new method. CONCLUSIONS: This report is the first 8-color immunophenotypic study of PCM in which a "range of normal expression" for each antigen is defined. This is a critical step to help distinguish between a normal and neoplastic PC immunophenotype and discern which antigens are of diagnostic importance. PMID- 20198609 TI - Theoretical study of bifurcated hydrogen bonding effects on the 1J(N,H), 1hJ(N,H), 2hJ(N,N) couplings and 1H, 15N shieldings in model pyrroles. AB - According to the density functional theory calculations, the X...H...N (X=N, O) intramolecular bifurcated (three-centered) hydrogen bond with one hydrogen donor and two hydrogen acceptors causes a significant decrease of the (1h)J(N,H) and (2h)J(N,N) coupling constants across the N-H...N hydrogen bond and an increase of the (1)J(N,H) coupling constant across the N-H covalent bond in the 2,5 disubstituted pyrroles. This occurs due to a weakening of the N-H...N hydrogen bridge resulting in a lengthening of the N...H distance and a decrease of the hydrogen bond angle at the bifurcated hydrogen bond formation. The gauge independent atomic orbital calculations of the shielding constants suggest that a weakening of the N-H...N hydrogen bridge in case of the three-centered hydrogen bond yields a shielding of the bridge proton and deshielding of the acceptor nitrogen atom. The atoms-in-molecules analysis shows that an attenuation of the (1h)J(N,H) and (2h)J(N,N) couplings in the compounds with bifurcated hydrogen bond is connected with a decrease of the electron density rho(H...N) at the hydrogen bond critical point and Laplacian of this electron density nabla(2)rho(H...N). The natural bond orbital analysis suggests that the additional N-H...X interaction partly inhibits the charge transfer from the nitrogen lone pair to the sigma*(N-H) antibonding orbital across hydrogen bond weakening of the (1h)J(N,H) and (2h)J(N,N) trans-hydrogen bond couplings through Fermi-contact mechanism. An increase of the nitrogen s-character percentage of the N-H bond in consequence of the bifurcated hydrogen bonding leads to an increase of the (1)J(N,H) coupling constant across the N-H covalent bond and deshielding of the hydrogen donor nitrogen atom. PMID- 20198610 TI - Distribution and mobility of phosphates and sodium ions in cheese by solid-state 31P and double-quantum filtered 23Na NMR spectroscopy. AB - The feasibility of solid-state magic angle spinning (MAS) (31)P nuclear magnetic resonance (NMR) spectroscopy and (23)Na NMR spectroscopy to investigate both phosphates and Na(+) ions distribution in semi-hard cheeses in a non-destructive way was studied. Two semi-hard cheeses of known composition were made with two different salt contents. (31)P Single-pulse excitation and cross-polarization MAS experiments allowed, for the first time, the identification and quantification of soluble and insoluble phosphates in the cheeses. The presence of a relatively 'mobile' fraction of colloidal phosphates was evidenced. The detection by (23)Na single-quantum NMR experiments of all the sodium ions in the cheeses was validated. The presence of a fraction of 'bound' sodium ions was evidenced by (23)Na double-quantum filtered NMR experiments. We demonstrated that NMR is a suitable tool to investigate both phosphates and Na(+) ions distributions in cheeses. The impact of the sodium content on the various phosphorus forms distribution was discussed and results demonstrated that NMR would be an important tool for the cheese industry for the processes controls. PMID- 20198611 TI - 1H-, 13C-, and 15N-NMR chemical shifts for selected glucosides and ribosides of aromatic cytokinins. AB - The (1)H and (13)C NMR resonances of 16 purine glucosides were assigned by a combination of one- and two-dimensional NMR experiments, including gs-COSY, gs HSQC, and gs-HMBC, in order to characterize the effect of substituent and the position of glucose unit on the NMR chemical shifts. In addition, (15)N NMR chemical shifts for selected derivatives were investigated by using (1)H-(15)N chemical shift correlation techniques. To map the influence of sugar moiety on the directly bonded nitrogen atom, selected N(9)-glucosides and their ribose analogs were compared. Characteristic long-range (1)H-(15)N coupling constants, measured by using (1)H-(15)N gradient-selected single-quantum multiple bond correlation (GSQMBC), are also reported and discussed. All compounds investigated here belong to cytokinins, an important group of plant hormones. PMID- 20198612 TI - Curcumin does not bind or intercalate into DNA and a note on the gray side of curcumin. PMID- 20198617 TI - Immune evasion of microsatellite unstable colorectal cancers. AB - Colorectal cancers (CRC) develop through 2 major pathways of genetic instability. In contrast to the majority of CRCs, which are characterized by chromosomal instability, high-level microsatellite unstable (MSI-H) CRCs arise as a consequence of the loss of DNA mismatch repair (MMR) functions and show accumulation of insertion and deletion mutations particularly in microsatellite sequences. MSI-H occurs in about 15% of CRCs, and virtually all CRCs occurring in the context of the hereditary cancer-predisposing Lynch syndrome. These tumors are characterized by a comparably good prognosis and a low frequency of distant metastases. Because of the expression of a defined set of tumor-specific antigens, MSI-H CRCs elicit a strong local and systemic antitumoral immune response of the host and therefore use different strategies to evade the control of the immune system. In this review, we will summarize novel molecular mechanisms that at the same time drive pathogenesis, immunogenicity and immune evasion during the development and progression of MSI-H CRCs. We will focus on the current knowledge about alterations in human leukocyte antigen (HLA) antigen presentation and discuss how immune evasion-while offering protection against local antitumoral immune responses-paradoxically might interfere with the ability of the tumor to form distant organ metastases. PMID- 20198618 TI - Adventures in time and space: Nonlinearity and complexity of cytokine effects on stem cell fate decisions. AB - Cytokines are central factors in the control of stem cell fate decisions and, as such, they are invaluable to those interested in the manipulation of stem and progenitor cells for clinical or research purposes. In their in vivo niches or in optimized cultures, stem cells are exposed to multiple cytokines, matrix proteins and other cell types that provide individual and combinatorial signals that influence their self-renewal, proliferation and differentiation. Although the individual effects of cytokines are well-characterized in terms of increases or decreases in stem cell expansion or in the production of specific cell lineages, their interactions are often overlooked. Factorial design experiments in association with multiple linear regression is a powerful multivariate approach to derive response-surface models and to obtain a quantitative understanding of cytokine dose and interactions effects. On the other hand, cytokine interactions detected in stem cell processes can be difficult to interpret due to the fact that the cell populations examined are often heterogeneous, that cytokines can exhibit pleiotropy and redundancy and that they can also be endogenously produced. This perspective piece presents a list of possible biological mechanisms that can give rise to positive and negative two-way factor interactions in the context of in vivo and in vitro stem cell-based processes. These interpretations are based on insights provided by recent studies examining intra- and extra-cellular signaling pathways in adult and embryonic stem cells. Cytokine interactions have been classified according to four main types of molecular and cellular mechanisms: (i) interactions due to co-signaling; (ii) interactions due to sequential actions; (iii) interactions due to high-dose saturation and inhibition; and (iv) interactions due to intercellular signaling networks. For each mechanism, possible patterns of regression coefficients corresponding to the cytokine main effects, quadratic effects and two-way interactions effects are provided. Finally, directions for future mechanistic studies are presented. PMID- 20198619 TI - More research is needed to establish the benefit-risk profile of curcumin. PMID- 20198621 TI - Synergistic antitumor activity of the SN-38-incorporating polymeric micelles NK012 with S-1 in a mouse model of non-small cell lung cancer. AB - The combination therapy of CPT-11, a prodrug of SN-38, with S-1, a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, shows a high clinical response rate in non-small cell lung cancer (NSCLC). However, this combination causes severe toxicities such as diarrhea. Here, we investigated the advantages of treatment with the SN-38-incorporating polymeric micelles NK012 over CPT-11 in combination with S-1 in mice bearing a NSCLC xenograft in terms of antitumor activity and toxic effects, particularly intestinal toxicity. In vitro cytotoxic effects were examined in human NSCLC cell lines (A549, PC-9, PC-14, EBC 1 and H520). In vivo antitumor effects were evaluated in PC-14- and EBC-1-bearing mice after NK012 or CPT-11 administration on Days 0 and 7 and S-1 administration on Days 0-13. Pathological changes in the small intestine were also investigated. The in vitro growth inhibitory effects of NK012 were 56.8- to 622-fold more potent than those of CPT-11. NK012/S-1 treatment showed significantly higher antitumor activity both in PC-14-bearing (p = 0.0007) and EBC-1-bearing mice (p < 0.0001) than CPT-11/S-1 treatment. The deformity and decrease in the density of intestinal villi were more severe in CPT-11/S-1-treated mice than in NK012/S-1 treated mice. NK012/S-1 combination is a promising candidate regimen against NSCLC without inducing toxicities such as severe diarrhea and therefore warrants clinical evaluation. PMID- 20198625 TI - What's in a name? PMID- 20198626 TI - The Institute of Medicine report on viral hepatitis: a call to action. PMID- 20198623 TI - NK depletion results in increased CCL22 secretion and Treg levels in Lewis lung carcinoma via the accumulation of CCL22-secreting CD11b+CD11c+ cells. AB - Tumor-induced immune suppression involves the accumulation of suppressive infiltrates in the tumor microenvironment such as regulatory T-cells (Tregs). Previous studies demonstrated that NK-dependant increases in CCL22 secretion selectively recruit Tregs toward murine lungs bearing Lewis Lung Carcinoma (LLC). To extend the in vitro studies, the present studies utilized in vivo depletion of NK cells to ascertain the contribution of NK-derived CCL22 toward total CCL22 and subsequent Treg levels in both normal and LLC-bearing lungs. However, NK depletion had the unexpected effect of increasing both CCL22 secretion and Treg levels in the lungs of NK-depleted LLC-bearing mice. This was concurrent with an increase in tumor burden. Flow cytometry and a series of both immunomagnetic and FACS isolations were used to identify the CCL22-producing cellular fractions in LLC-bearing lungs. A novel CD11b(+)CD11c(+) cell population was identified that accumulates in large numbers in NK-depleted LLC-bearing lung tissue. These CD11b(+)CD11c(+) cells secreted large amounts of CCL22 that may overcompensate for the loss of NK-derived CCL22 in the lungs of NK-depleted LLC-bearing mice. Taken together, these data suggest that NK cells play both a positive and negative role in the regulation of CCL22 secretion and, in turn, the recruitment of Tregs toward LLC-bearing lungs. PMID- 20198627 TI - Where are we in the chemoprevention of hepatocellular carcinoma? PMID- 20198628 TI - The epithelial-to-mesenchymal transition in liver fibrosis: here today, gone tomorrow? PMID- 20198629 TI - Metformin improves sustained virologic response in difficult-to-cure hepatitis C: more questions than answers. PMID- 20198630 TI - What is the true origin of the bright red-orange autofluorescence in the hepatocytes? PMID- 20198633 TI - Expression of pituitary tumor-transforming gene 1 (PTTG1)/securin in hepatitis B virus (HBV)-associated liver diseases: evidence for an HBV X protein-mediated inhibition of PTTG1 ubiquitination and degradation. AB - Chronic infection with hepatitis B virus (HBV) is strongly associated with hepatocellular carcinoma (HCC), and the viral HBx protein plays a crucial role in the pathogenesis of liver tumors. Because the protooncogene pituitary tumor transforming gene 1 (PTTG1) is overexpressed in HCC, we investigated the regulation of this protein by HBx. We analyzed PTTG1 expression levels in liver biopsies from patients chronically infected with HBV, presenting different disease stages, and from HBx transgenic mice. PTTG1 was undetectable in biopsies from chronic hepatitis B patients or from normal mouse livers. In contrast, hyperplastic livers from transgenic mice and biopsies from patients with cirrhosis, presented PTTG1 expression which was found mainly in HBx-expressing hepatocytes. PTTG1 staining was further increased in HCC specimens. Experiments in vitro revealed that HBx induced a marked accumulation of PTTG1 protein without affecting its messenger RNA levels. HBx expression promoted the inhibition of PTTG1 ubiquitination, which in turn impaired its degradation by the proteasome. Glutathione S-transferase pull-down and co-immunoprecipitation experiments demonstrated that the interaction between PTTG1 and the Skp1-Cul1-F-box ubiquitin ligase complex (SCF) was partially disrupted, possibly through a mechanism involving protein-protein interactions of HBx with PTTG1 and/or SCF. Furthermore, confocal analysis revealed that HBx colocalized with PTTG1 and Cul1. We propose that HBx promotes an abnormal accumulation of PTTG1, which may provide new insights into the molecular mechanisms of HBV-related pathogenesis of progressive liver disease leading to HCC development. PMID- 20198634 TI - The histogenesis of regenerative nodules in human liver cirrhosis. AB - Here, we investigate the clonality and cells of origin of regenerative nodules in human liver cirrhosis using mitochondrial DNA (mtDNA) mutations as markers of clonal expansion. Mutated cells are identified phenotypically by deficiency in the entirely mtDNA encoded cytochrome c oxidase (CCO) enzyme by histochemical and immunohistochemical methods. Nodules were classified as either CCO-deficient or CCO-positive, and among 526 nodules from 10 cases, 18% were homogeneously CCO deficient, whereas only 3% had a mixed phenotype. From frozen sections, hepatocytes were laser-capture microdissected from several sites within individual CCO-deficient nodules. Mutations were identified by polymerase chain reaction sequencing of the entire mtDNA genome. In all cases except for one, the nodules were monoclonal in nature, possessing up to four common mutations in all hepatocytes in a given nodule. Moreover, the identification of identical mutations in hepatic progenitor cells abutting CCO-deficient nodules proves that nodules can have their origins from such cells. CONCLUSION: These data support a novel pathway for the monoclonal derivation of human cirrhotic regenerative nodules from hepatic progenitor cells. PMID- 20198635 TI - Insulin-like growth factor I gene transfer to cirrhotic liver induces fibrolysis and reduces fibrogenesis leading to cirrhosis reversion in rats. AB - We investigated whether gene transfer of insulin-like growth factor I (IGF-I) to the hepatic tissue was able to improve liver histology and function in established liver cirrhosis. Rats with liver cirrhosis induced by carbon tetrachloride (CCl(4)) given orally for 8 weeks were injected through the hepatic artery with saline or with Simian virus 40 vectors encoding IGF-I (SVIGF-I), or luciferase (SVLuc). Animals were sacrificed 8 weeks after vector injection. In cirrhotic rats we observed that, whereas IGF-I was synthesized by hepatocytes, IGF-I receptor was predominantly expressed by nonparenchymal cells, mainly in fibrous septa surrounding hepatic nodules. Rats treated with SVIGF-I showed increased hepatic levels of IGF-I, improved liver function tests, and reduced fibrosis in association with diminished alpha-smooth muscle actin expression, up regulation of matrix metalloproteases (MMPs) and decreased expression of the tissue inhibitors of MMPs TIM-1 and TIM-2. SVIGF-I therapy induced down regulation of the profibrogenic molecules transforming growth factor beta (TGFbeta), amphiregulin, platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF), and vascular endothelium growth factor (VEGF) and induction of the antifibrogenic and cytoprotective hepatocyte growth factor (HGF). Furthermore, SVIGF-I-treated animals showed decreased expression of Wilms tumor-1 (WT-1; a nuclear factor involved in hepatocyte dedifferentiation) and up regulation of hepatocyte nuclear factor 4 alpha (HNF4alpha) (which stimulates hepatocellular differentiation). The therapeutic potential of SVIGF-I was also tested in rats with thioacetamide-induced liver cirrhosis. Also in this model, SVIGF-I improved liver function and reduced liver fibrosis in association with up regulation of HGF and MMPs and down-regulation of tissue inhibitor of metalloproteinase 1 (TIMP-1). CONCLUSION: IGF-I gene transfer to cirrhotic livers induces MMPs and hepatoprotective factors leading to reversion of fibrosis and improvement of liver function. IGF-I gene therapy may be a useful alternative therapy for patients with advanced cirrhosis without timely access to liver transplantation. PMID- 20198636 TI - Theoretical and computational studies of organometallic reactions: successful or not? AB - Theoretical and computational methods are powerful in studying transition metal complexes. Our theoretical studies of C-H sigma-bond activation of benzene by Pd(II)-formate complex and that of methane by Ti(IV)-imido complex successfully disclosed that these reactions are understood to undergo heterolytic sigma-bond activation and the driving force is the formation of strong O-H and N-H bonds in the former and the latter, respectively. Orbital interactions are considerably different from those of sigma-bond activation by oxidative addition. The transmetallation, which is a key process in the cross-coupling reaction, is understood to be heterolytic sigma-bond activation. Our theoretical study clarified how to accelerate this transmetallation. Also, we wish to discuss weak points in theoretical and computational studies of large systems including transition metal elements, such as the necessity to incorporate solvation effect and to present quantitatively correct numerical results. The importance of solvation effects is discussed in the oxidative addition of methyliodide to Pt(II) complex which occurs in a way similar to an S(N)2 substitution. To apply the CCSD(T) (coupled cluster singles and doubles with perturbative triples correction) method, which is the gold standard of electronic structure theory, to large system, we need to reduce the size of the system by employing a small model. But, such modeling induces neglects of electronic and steric effects of substituents which are replaced in the small model. Frontier-orbital-consistent quantum-capping potential (FOC-QCP) was recently proposed by our group to incorporate the electronic effects of the substituents neglected in the modeling. The CCSD(T) calculation with the FOC-QCP was successfully applied to large systems including transition metal elements. PMID- 20198637 TI - Implementation fidelity in community-based interventions. AB - Implementation fidelity is the degree to which an intervention is delivered as intended and is critical to successful translation of evidence-based interventions into practice. Diminished fidelity may be why interventions that work well in highly controlled trials may fail to yield the same outcomes when applied in real life contexts. The purpose of this paper is to define implementation fidelity and describe its importance for the larger science of implementation, discuss data collection methods and current efforts in measuring implementation fidelity in community-based prevention interventions, and present future research directions for measuring implementation fidelity that will advance implementation science. PMID- 20198638 TI - OVNIp: an open source application facilitating the interpretation, the validation and the edition of proteomics data generated by MS analyses and de novo sequencing. AB - Several academic software are available to help the validation and reporting of proteomics data generated by MS analyses. However, to our knowledge, none of them have been conceived to meet the particular needs generated by the study of organisms whose genomes are not sequenced. In that context, we have developed OVNIp, an open-source application which facilitates the whole process of proteomics results interpretation. One of its unique attributes is its capacity to compile multiple results (from several search engines and/or several databank searches) with a resolution of conflicting interpretations. Moreover, OVNIp enables automated exploitation of de novo sequences generated from unassigned MS/MS spectra leading to higher sequence coverage and enhancing confidence in the identified proteins. The exploitation of these additional spectra might also identify novel proteins through a MS-BLAST search, which can be easily ran from the OVNIp interface. Beyond this primary scope, OVNIp can also benefit to users who look for a simple standalone application to both visualize and confirm MS/MS result interpretations through a simple graphical interface and generate reports according to user-defined forms which may integrate the prerequisites for publication. Sources, documentation and a stable release for Windows are available at http://wwwappli.nantes.inra.fr:8180/OVNIp. PMID- 20198639 TI - Cell-free expression profiling of E. coli inner membrane proteins. AB - The high versatility and open nature of cell-free expression systems offers unique options to modify expression environments. In particular for membrane proteins, the choice of co-translational versus post-translational solubilization approaches could significantly modulate expression efficiencies and even sample qualities. The production of a selection of 134 alpha-helical integral membrane proteins of the Escherichia coli inner membrane proteome focussing on larger transporters has therefore been evaluated by a set of individual cell-free expression reactions. The production profiles of the targets in different cell free expression modes were analyzed independently by three screening strategies. Translational green fluorescent protein fusions were analyzed as monitor for the formation of proteomicelles after cell-free expression of membrane proteins in the presence of detergents. In addition, two different reaction configurations were implemented and performed either by robotic semi-throughput approaches or by individually designed strategies. The expression profiles were specified for the particular cell-free modes and overall, the production of 87% of the target list could be verified and approximately 50% could already be synthesized in preparative scales. The expression of several selected targets was up-scaled to milliliter volumes and milligram amounts of production. As an example, the flavocytochrome YedZ was purified and its sample quality was demonstrated. PMID- 20198640 TI - Identification of toxicological biomarkers of di(2-ethylhexyl) phthalate in proteins secreted by HepG2 cells using proteomic analysis. AB - The effects of di(2-ethylhexyl) phthalate (DEHP) on proteins secreted by HepG2 cells were studied using a proteomic approach. HepG2 cells were exposed to various concentrations of DEHP (0, 2.5, 5, 10, 25, 50, 100, and 250 microM) for 24 or 48 h. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and comet assays were then conducted to determine the cytotoxicity and genotoxicity of DEHP, respectively. The MTT assay showed that 10 microM DEHP was the maximum concentration that did not cause cell death. In addition, the DNA damage in HepG2 cells exposed to DEHP was found to increase in a dose- and time dependent fashion. Proteomic analysis using two different pI ranges (4-7 and 6-9) and large size 2-DE revealed the presence of 2776 protein spots. A total of 35 (19 up- and 16 down-regulated) proteins were identified as biomarkers of DEHP by ESI-MS/MS. Several differentiated protein groups were also found. Proteins involved in apoptosis, transportation, signaling, energy metabolism, and cell structure and motility were found to be up- or down-regulated. Among these, the identities of cystatin C, Rho GDP inhibitor, retinol binding protein 4, gelsolin, DEK protein, Raf kinase inhibitory protein, triose phosphate isomerase, cofilin 1, and haptoglobin-related protein were confirmed by Western blot assay. Therefore, these proteins could be used as potential biomarkers of DEHP and human disease associated with DEHP. PMID- 20198641 TI - Proteome analysis of fungal and bacterial involvement in leaf litter decomposition. AB - Fungi and bacteria are key players in the decomposition of leaf litter, but their individual contributions to the process and their interactions are still poorly known. We combined semi-quantitative proteome analyses (1-D PAGE-LC-MS/MS) with qualitative and quantitative analyses of extracellular degradative enzyme activities to unravel the respective roles of a fungus and a bacterium during litter decomposition. Two model organisms, a mesophilic Gram-negative bacterium (Pectobacterium carotovorum) and an ascomycete (Aspergillus nidulans), were grown in both, pure culture and co-culture on minimal medium containing either glucose or beech leaf litter as sole carbon source. P. carotovorum grew best in co culture with the fungus, whereas growth of A. nidulans was significantly reduced when the bacterium was present. This observation suggests that P. carotovorum has only limited capabilities to degrade leaf litter and profits from the degradation products of A. nidulans at the expense of fungal growth. In accordance with this interpretation, our proteome analysis revealed that most of the extracellular biodegradative enzymes (i.e. proteases, pectinases, and cellulases) in the cultures with beech litter were expressed by the fungus, the bacterium producing only low levels of pectinases. PMID- 20198642 TI - Pathway Palette: a rich internet application for peptide-, protein- and network oriented analysis of MS data. AB - Recent improvements in proteomic technologies have collectively yielded data sets that far exceed the capabilities of typical low-throughput interpretation strategies. Unfortunately, tools designed to leverage the "peptide-centric" content of MS-based proteomics lag the current rate of data production. Here, we describe Pathway Palette (http://blaispathways.dfci.harvard.edu), a freely accessible internet application that enables researchers to easily transition from peptides to biological pathways, while simultaneously retaining the qualitative and quantitative aspects of the underlying MS data. PMID- 20198643 TI - Tyrosine hydroxylase deficiency in three Greek patients with a common ancestral mutation. AB - We present the clinical, biochemical, and molecular findings of three Greek patients with tyrosine hydroxylase (TH) deficiency. All patients presented with a severe clinical phenotype characterized by prominent motor delay, infantile parkinsonism, oculogyric crises, and signs of autonomic dysfunction. Cerebrospinal fluid analysis disclosed reduced dopamine metabolites and normal pterins. Response to levodopa was favorable though not dramatic. All patients were homozygous for a previously reported mutation (p.L236P). SNP haplotype analysis was consistent with a common ancestral mutation, thus indicating a founder effect in Greek patients with TH deficiency. PMID- 20198644 TI - The specific contributions of set-shifting to freezing of gait in Parkinson's disease. AB - Freezing of gait (FOG) in Parkinson's disease (PD) is common and the pathophysiology of FOG is poorly understood. It has been hypothesized to reflect complementary yet competing frontostriatal pathways that reduce the ability to keep different tasks (motor or cognitive) on-line. This inability to "set-shift" has been proposed to trigger a freezing episode. If correct, this hypothesis would predict a differential pattern of executive dysfunction with FOG being most specifically related to attentional set-shifting. In this study, 31 patients with a range of self-reported FOG symptom severities were administered tests of executive functioning. The results demonstrate that FOG symptoms were selectively correlated with poorer performance on tasks of set-shifting, but not with a range of other executive tasks. This was apparent even after controlling for slowed processing speed, disease stage and depressive symptoms. The results support the recently proposed hypothesis for the pathophysiology underlying FOG in PD. PMID- 20198645 TI - Characterization of Lewy body pathology in 12- and 16-year-old intrastriatal mesencephalic grafts surviving in a patient with Parkinson's disease. AB - We previously reported the occurrence of Lewy bodies in grafted human fetal mesencephalic neurons in two patients with Parkinson's disease. Here, we have used immunohistochemistry and electron microscopy to characterize the development of Lewy bodies in one of these cases. This patient was operated in putamen on both sides at 12 or 16 years before death, respectively. We demonstrate that 2% of the 12-year-old and 5% of the 16-year-old grafted, presumed dopaminergic neurons contained Lewy bodies immunoreactive for alpha-synuclein. Based on morphological analysis, two forms of alpha-synuclein-positive aggregates were distinguished in the grafts, the first a classical and compact Lewy body, the other a loose meshwork aggregate. Lewy bodies in the grafts stained positively for ubiquitin and thioflavin-S, and contained characteristic alpha-synuclein immunoreactive electron dense fibrillar structures on electron microscopy. Our data indicate that Lewy bodies develop gradually in transplanted dopaminergic neurons in a fashion similar to that in dopaminergic neurons in the host substantia nigra. PMID- 20198646 TI - Rhabdomyolysis after low-dose quetiapine in a patient with Parkinson's disease with drug-induced psychosis: a case report. PMID- 20198647 TI - Unilateral lower limb rest tremor is not necessarily a presenting symptom of Parkinson's disease. AB - Lower leg rest tremor is an uncommon symptom of neurological disease. Review of the files of 16 patients who presented with lower leg tremor (average age 58 +/- 16 years; average disease duration 6.8 +/- 8.5 years) yielded a diagnosis of Parkinson's disease (PD) in 5 and probable multiple system atrophy (MSA) in 3. In 4 patients with an indeterminate diagnosis, cardiac MIBG SPECT was positive in 3, indicating PD, and negative in one, suggesting MSA. Two patients each had psychogenic tremor and drug-induced parkinsonism. Although lower leg tremor is considered an unusual presentation of PD, it should raise suspicions of MSA and other neurodegenerative disorders. PMID- 20198648 TI - A two-year follow-up study of executive dysfunctions in parkinsonian patients with freezing of gait at on-state. PMID- 20198649 TI - Long-term antidyskinetic efficacy of amantadine in Parkinson's disease. AB - Several randomized placebo-controlled trials have consistently shown antidyskinetic effects of amantadine in levodopa treated patients with advanced Parkinson's disease (PD). However, all of these were of short duration and there have been claims that the effect of amantadine on levodopa induced dyskinesias (LID's) wear off after about 9 months of treatment. This randomized placebo controlled parallel-group study was performed to assess the long-term antidyskinetic effect of amantadine in 32 PD patients, who after having been on stable amantadine therapy for LID over at least one year- were switched in a double blind manner to amantadine or placebo and followed for 3 weeks. Dyskinesia duration and intensity were assessed by UPDRS IV items 32 and 33 as well as by patient's diaries. The primary outcome was the score change of UPDRS IV items 32 + 33 between baseline and 3 weeks after treatment as well as the between treatment group comparison of the score change of UPDRS IV items 32 + 33. There was a significant increase of UPDRS IV items 32 + 33 in patients treated with placebo from 3.06 (95% CI, 2.1-4.03) at baseline to 4.28 (95% CI, 3.1-5.4) at three-week follow-up (P = 0.02) compared with no significant change between baseline 3.2 (95% CI, 2.1-4.4) to follow-up 3.6 (95% CI, 2.3-4.8) in patients staying on amantadine. These findings argue for long-term antidyskinetic efficacy of amantadine in PD patients with LID's. PMID- 20198650 TI - The natural history of anencephaly. AB - OBJECTIVE: Early elective termination of pregnancy is the most common outcome of a diagnosis of anencephaly in developed countries. Experience and expertise with management of ongoing pregnancies is limited. We aimed to investigate the natural history of these pregnancies from diagnosis to delivery and to determine timing of death. METHOD: A retrospective review of cases of anencephaly diagnosed between 2003 and 2009 in tertiary-referral university teaching hospitals in Cork. RESULTS: The majority of cases (25/26; 96%) were diagnosed prenatally at a median gestation of 21(+2) weeks (range 13(+4)-32(+4)). The median maternal age was 30 years (range 17-41) and 50% were primigravidae. Seven pregnancies were complicated by polyhydramnios and four deliveries were complicated by shoulder dystocia. The median gestation at delivery was 35 weeks (range 22(+5)-42(+6)); 69% of labours were induced at a median gestation of 34 weeks. Six women (6/26; 23%) had a pre-labour intrauterine fetal death and nine women (9/26; 35%) had an intrapartum fetal death. Median neonatal survival time was 55 min (range 10 min to 8 days). Six parents donated neonatal organs for transplantation. CONCLUSION: This study provides useful information for health professionals caring for patients with a diagnosis of anencephaly. The majority of these infants die prior to delivery but short-term survival is possible. PMID- 20198651 TI - Mutational analysis of FOXL2 codon 134 in granulosa cell tumour of ovary and other human cancers. AB - A missense somatic mutation in the FOXL2 gene affecting codon 134 has recently been reported in granulosa cell tumour (GCT) and thecoma of the ovary. Such a recurrent nature of the mutation strongly suggests that the FOXL2 mutation may play an important role in the development of ovarian sex cord-stromal tumours. The aim of this study was to characterize the FOXL2 mutation in human tumour tissues. We analysed 1353 tumour tissues from various origins, including ovarian tumours and other common cancers, by single-strand conformation polymorphism analysis. We found the FOXL2 codon 134 missense mutation in 53 of 56 adult GCTs (94.6%) and two of the 16 thecomas (12.5%), but none in other tumours. Histologically, FOXL2 mutation-negative adult GCT showed that GCT cells were admixed with fibrothecomatous cells, and FOXL2 mutation-positive thecomas showed that luteinized theca cells were predominant. However, immunostaining of either inhibin alpha or FOXL2 did not differentiate the FOXL2 mutation status of adult GCTs and thecomas. There was no FOXL1 mutation and no common oncogenic mutation in the adult GCTs and thecomas. Our data indicate that the FOXL2 codon 134 mutation occurs exclusively in GCT and thecoma, and suggest the possibility that the development of most GCTs and a fraction of thecomas may be dependent on this mutation. Our data also suggest that the FOXL2 mutation status, as well as some histological features, may be important in the diagnosis of ovarian sex cord stromal tumours. PMID- 20198653 TI - New milliliter-scale stirred tank bioreactors for the cultivation of mycelium forming microorganisms. AB - A novel milliliter-scale stirred tank bioreactor was developed for the cultivation of mycelium forming microorganisms on a 10 milliliter-scale. A newly designed one-sided paddle impeller is driven magnetically and rotates freely on an axis in an unbaffled reaction vessel made of polystyrene. A rotating lamella is formed which spreads out along the reactor wall. Thus an enhanced surface-to volume ratio of the liquid phase is generated where oxygen is introduced via surface aeration. Volumetric oxygen transfer coefficients (k(L)a) > 0.15 s(-1) were measured. The fast moving liquid lamella efficiently prevents wall growth and foaming. Mean power consumption and maximum local energy dissipation were measured as function of operating conditions in the milliliter-scale stirred tank bioreactor (V = 10 mL) and compared to a standard laboratory-scale stirred tank bioreactor with six-bladed Rushton turbines (V = 2,000 mL). Mean power consumption increases with increasing impeller speed and shows the same characteristics and values on both scales. The maximum local energy dissipation of the milliliter-scale stirred tank bioreactor was reduced compared to the laboratory-scale at the same mean volumetric power input. Hence the milliliter impeller distributes power more uniformly in the reaction medium. Based on these data a reliable and robust scale-up of fermentation processes is possible. This was demonstrated with the cultivation of the actinomycete Streptomyces tendae on both scales. It was shown that the process performances were equivalent with regard to biomass concentration, mannitol consumption and production of the pharmaceutical relevant fungicide nikkomycin Z up to a process time of 120 h. A high parallel reproducibility was observed on the milliliter-scale (standard deviation < 8%) with up to 48 stirred tank bioreactors operated in a magnetic inductive drive. Rheological behavior of the culture broth was measured and showed a highly viscous shear-thinning non-Newtonian behavior. The newly developed one-sided paddle impellers operated in unbaffled reactors on a 10 milliliter-scale with a magnetic inductive drive for up to 48 parallel bioreactors allows for the first time the parallel bioprocess development with mycelium forming microorganisms. This is especially important since these kinds of cultivations normally exhibit process times of 100 h and more. Thus the operation of parallel stirred tank reactors will have the potential to reduce process development times drastically. PMID- 20198652 TI - Somatic mutations and losses of expression of microRNA regulation-related genes AGO2 and TNRC6A in gastric and colorectal cancers. AB - Mounting evidence indicates that deregulation of microRNAs (miRNAs) are involved in development of many human diseases, including cancers. Regulation of miRNA is a complicated process and some components in the regulation are known to be altered in human cancers. Among the miRNA regulation-related genes, we found that AGO1, AGO2, TNRC6A, TNRC6C, TARBP2 and EXPORTIN5 genes have mononucleotide repeats in their coding sequences. To see whether these genes are mutated in cancers with microsatellite instability (MSI), we analysed the mononucleotide repeats in 27 gastric cancers (GCs) with high MSI (MSI-H), 18 GC with low MSI (MSI-L), 45 GC with stable MSI (MSS), 41 colorectal cancers (CRCs) with MSI-H, 14 CRCs with MSI-L and 45 CRCs with stable MSI (MSS) by single-strand conformation polymorphism (SSCP) analysis and DNA sequencing. We found AGO2, TNRC6A, TARBP2, TNRC6C and EXPORTIN5 mutations in 10, six, one, one and one cancer(s), respectively. They were detected in MSI-H but not in MSI-L or MSS cancers. The GCs and CRCs with MSI-H harboured one or more mutations of the genes in 22% and 27%, respectively. We also analysed Ago2 and TNRC6A protein expressions in GCs and CRCs with MSI-H. In cancers with MSI-H, loss of Ago2 expression was observed in 40% of GCs and 35% of CRCs, while loss of TNRC6A was observed in 52% of the GCs and 54% of the CRCs. Our data indicate that frameshift mutations in AGO2 and TNRC6A and their losses of expression are common in GCs and CRCs with MSI-H, and suggest that these alterations may contribute to the cancer development by deregulating miRNA regulation. PMID- 20198654 TI - Effect of chloride on ferrous iron oxidation by a Leptospirillum ferriphilum dominated chemostat culture. AB - Biomining is the use of microorganisms to catalyze metal extraction from sulfide ores. However, the available water in some biomining environments has high chloride concentrations and therefore, chloride toxicity to ferrous oxidizing microorganisms has been investigated. Batch biooxidation of Fe(2+) by a Leptospirillum ferriphilum-dominated culture was completely inhibited by 12 g L( 1) chloride. In addition, the effects of chloride on oxidation kinetics in a Fe(2+) limited chemostat were studied. Results from the chemostat modeling suggest that the chloride toxicity was attributed to affects on the Fe(2+) oxidation system, pH homeostasis, and lowering of the proton motive force. Modeling showed a decrease in the maximum specific growth rate (micro(max)) and an increase in the substrate constant (K(s)) with increasing chloride concentrations, indicating an effect on the Fe(2+) oxidation system. The model proposes a lowered maintenance activity when the media was fed with 2-3 g L(-1) chloride with a concomitant drastic decrease in the true yield (Y(true)). This model helps to understand the influence of chloride on Fe(2+) biooxidation kinetics. PMID- 20198655 TI - Rapid monitoring of recombinant antibody production by mammalian cell cultures using fourier transform infrared spectroscopy and chemometrics. AB - Fourier transform infrared (FT-IR) spectroscopy combined with multivariate statistical analyses was investigated as a physicochemical tool for monitoring secreted recombinant antibody production in cultures of Chinese hamster ovary (CHO) and murine myeloma non-secreting 0 (NS0) cell lines. Medium samples were taken during culture of CHO and NS0 cells lines, which included both antibody producing and non-producing cell lines, and analyzed by FT-IR spectroscopy. Principal components analysis (PCA) alone, and combined with discriminant function analysis (PC-DFA), were applied to normalized FT-IR spectroscopy datasets and showed a linear trend with respect to recombinant protein production. Loadings plots of the most significant spectral components showed a decrease in the C-O stretch from polysaccharides and an increase in the amide I band during culture, respectively, indicating a decrease in sugar concentration and an increase in protein concentration in the medium. Partial least squares regression (PLSR) analysis was used to predict antibody titers, and these regression models were able to predict antibody titers accurately with low error when compared to ELISA data. PLSR was also able to predict glucose and lactate amounts in the medium samples accurately. This work demonstrates that FT-IR spectroscopy has great potential as a tool for monitoring cell cultures for recombinant protein production and offers a starting point for the application of spectroscopic techniques for the on-line measurement of antibody production in industrial scale bioreactors. PMID- 20198656 TI - Effects of topography on the functional development of human neural progenitor cells. AB - We have fabricated a topographical substrate with a packed polystyrene bead array for the development of cell-based assay systems targeting voltage-gated calcium channels (VGCCs). Human neural progenitor cells (H945RB.3) cultured on both flat and topographical substrates were analyzed in terms of morphological spreading, neuronal commitment, resting membrane potential (V(m)) establishment and VGCC function development. We found, by SEM imaging, that arrayed substrates, formed with both sub-micrometer (of 0.51 microm in mean diameter) and micrometer (of 1.98 microm in mean diameter) beads, were capable of promoting the spreading of the progenitor cells as compared with the flat polystyrene surfaces. With the micrometer beads, it was found that arrayed substrates facilitated the neural progenitor cells' maintenance of less negative V(m) values upon differentiation with bFGF starvation, which favored predominant neuronal commitment. Almost all the progenitor cells were responsive to 50 mM K(+) depolarization with an increase in [Ca(2+)](i) either before or upon differentiation, suggesting the expression of functional VGCCs. Compared to the flat polystyrene surfaces, microbead arrayed substrates facilitated the development of higher VGCC responsiveness by the progenitor cells upon differentiation. The enhancement of both VGCC responsiveness and cell spreading by arrays of micrometer beads was most significant on day 14 into differentiation, which was the latest time point of measurement in this study. This study thus rationalized the possibility for future substrate topography engineering to manipulate ion channel function and to meet the challenge of low VGCC responsiveness found in early drug discovery. PMID- 20198657 TI - Characterization of a whole-cell catalyst co-expressing glycerol dehydrogenase and glucose dehydrogenase and its application in the synthesis of L glyceraldehyde. AB - A whole-cell catalyst using Escherichia coli BL21(DE3) as a host, co-expressing glycerol dehydrogenase (GlyDH) from Gluconobacter oxydans and glucose dehydrogenase (GDH) from Bacillus subtilis for cofactor regeneration, has been successfully constructed and used for the reduction of aliphatic aldehydes, such as hexanal or glyceraldehyde to the corresponding alcohols. This catalyst was characterized in terms of growth conditions, temperature and pH dependency, and regarding the influence of external cofactor and permeabilization. In the case of external cofactor addition we found a 4.6-fold increase in reaction rate caused by the addition of 1 mM NADP(+). Due to the fact that pH and temperature are also factors which may affect the reaction rate, their effect on the whole-cell catalyst was studied as well. Comparative studies between the whole-cell catalyst and the cell-free system were investigated. Furthermore, the successful application of the whole-cell catalyst in repetitive batch conversions could be demonstrated in the present study. Since the GlyDH was recently characterized and successfully applied in the kinetic resolution of racemic glyceraldehyde, we were now able to transfer and establish the process to a whole-cell system, which facilitated the access to L-glyceraldehyde in high enantioselectivity at 54% conversion. All in all, the whole-cell catalyst shows several advantages over the cell-free system like a higher thermal, a similar operational stability and the ability to recycle the catalyst without any loss-of-activity. The results obtained making the described whole-cell catalyst an improved catalyst for a more efficient production of enantiopure L-glyceraldehyde. PMID- 20198658 TI - Motif-based search for a novel fructosyl peptide oxidase from genome databases. AB - The measurement of glycated hemoglobin A1c (HbA1c) has important implications for diagnosis of diabetes and assessment of treatment effectiveness. We proposed specific sequence motifs to identify enzymes that oxidize glycated compounds from genome database searches. The gene encoding a putative fructosyl amino acid oxidase was found in the Phaeosphaeria nodorum SN15 genome and successfully expressed in Escherichia coli. The recombinant protein (XP_001798711) was confirmed to be a novel fructosyl peptide oxidase (FPOX) with high specificity for alpha-glycated compounds, such as HbA1c model compounds fructosyl-(alpha)N valine (f-(alpha)Val) and fructosyl-(alpha)N-valyl-histidine (f-(alpha)Val-His). Unlike previously reported FPOXs, the P. nodorum FPOX has a K(m) value for f (alpha)Val-His (0.185 mM) that is considerably lower than that for f-(alpha)Val (0.458 mM). Based on amino acid sequence alignment, three dimensional structural modeling, and site-directed mutagenesis, Gly60 was found to be a determining residue for the activity towards f-(alpha)Val-His. A flexible surface loop region was also found to likely play an important role in accepting f-(alpha)Val-His. PMID- 20198659 TI - Semicontinuous bioreactor production of a recombinant human therapeutic protein using a chemically inducible viral amplicon expression system in transgenic plant cell suspension cultures. AB - Plant cell culture is an alternative for the production of recombinant human therapeutic proteins because of improved product safety, lower production cost, and capability for eukaryotic post-translational modification. In this study, bioreactor production of recombinant human alpha-1-antitrypsin (rAAT) glycoprotein using a chemically inducible Cucumber mosaic virus (CMV) viral amplicon expression system in transgenic Nicotiana benthamiana cell culture is presented. Optimization of a chemically inducible plant cell culture requires evaluation of effects of timing of induction (TOI) and concentration of inducer (COI) on protein productivity and protein quality (biological functionality). To determine the optimal TOI, the oxygen uptake rate (OUR) of the plant cell culture was chosen as a physiological indicator for inducing maximum rAAT expression. Effects of COI on rAAT production were investigated using a semicontinuous culture, which enables the distinction between effects of growth rate and effects of inducer concentration. An optimized semicontinuous bioreactor operation was further proposed to maximize the recombinant protein production. The results demonstrated that the transgenic plant cells, transformed with the inducible viral amplicon expression system, maintain higher OUR and exhibit lower extracellular protease activity and lower total phenolics concentration in the optimized semicontinuous bioreactor process than in a traditional batch bioreactor operation, resulting in a 25-fold increase in extracellular functional rAAT (603 microg/L) and a higher ratio of functional rAAT to total rAAT (85-90%). Surprisingly, sustained rAAT production and steady state, long-term bioreactor operation is possible following chemical induction and establishment of the viral amplicons. PMID- 20198660 TI - Rapid construction and characterization of synthetic antibody libraries without DNA amplification. AB - We report on a simple method to rapidly generate very large libraries of genes encoding mutant proteins without the use of DNA amplification, and the application of this methodology in the construction of synthetic immunoglobulin variable heavy (V(H)) and light (V(kappa)) libraries. Four high quality, chemically synthesized polynucleotides (90-140 bases) were annealed and extended using T4 DNA polymerase. Following electroporation, >10(9) transformants could be synthesized within 1 day. Fusion to beta-lactamase and selection on ampicillin resulted in 3.7 x 10(8) V(H) and 6.9 x 10(8) V(kappa) clones highly enriched for full-length, in-frame genes. High-throughput 454 DNA sequencing of >250,000 V(H) and V(kappa) genes from the pre- and post-selection libraries revealed that, in addition to the expected reduction in reading-frame shifts and stop codons, selection for functional expression also resulted in a statistical decrease in the cysteine content. Apart from these differences, there was a good agreement between the expected and actual diversity, indicating that neither oligonucleotide synthesis nor biological constrains due to protein synthesis of V(H)/V(kappa)-beta-lactamase fusions introduce biases in the amino acid composition of the randomized regions. This methodology can be employed for the rapid construction of highly diverse libraries with the near elimination of PCR errors in invariant regions. PMID- 20198661 TI - Identification of Mxr1p-binding sites in the promoters of genes encoding dihydroxyacetone synthase and peroxin 8 of the methylotrophic yeast Pichia pastoris. AB - Expression of genes involved in methanol metabolism of Pichia pastoris is regulated by Mxr1p, a zinc finger transcription factor. In this study, we studied the target gene specificity of Mxr1p by examining its ability to bind to promoters of genes encoding dihydroxyacetone synthase (DHAS) and peroxin 8 (PEX8), since methanol-inducible expression of these genes is abrogated in mxr1 null mutant strains of P. pastoris. Different regions of DHAS and PEX8 promoter were isolated from P. pastoris genomic DNA and their ability to bind to a recombinant Mxr1p protein containing the N-terminal 150 amino acids, including the zinc finger DNA-binding domain, was examined. These studies reveal that Mxr1p specifically binds to promoter regions containing multiple 5'-CYCC-3' sequences, although all DNA sequences containing the 5'-CYCC-3' motif do not qualify as Mxr1p-binding sites. Key DNA-binding determinants are present outside 5'-CYCC-3' motif and Mxr1p preferably binds to DNA sequences containing 5'-CYCCNY-3' than those containing 5'-CYCCNR-3' sequences. This study provides new insights into the molecular determinants of target gene specificity of Mxr1p, and the methodology described here can be used for mapping Mxr1p-binding sites in other methanol-inducible promoters of P. pastoris. PMID- 20198662 TI - Quantitative proteomics study of breast cancer cell lines isolated from a single patient: discovery of TIMM17A as a marker for breast cancer. AB - The proteins involved in breast cancer initiation and progression are still largely elusive. To gain insights into these processes, we conducted quantitative proteomic analyses with 21T series of breast cell lines, which include a normal, primary tumor and a metastatic tumor that were isolated from a single patient. Stable isotope labeling of amino acid in cell culture followed by LC-MS/MS analysis was performed and deregulated proteins were identified using statistical analysis. Gene ontology analysis revealed that proteins involved in metabolic processes were the most deregulated in both tumorigenesis and metastasis. Interaction network analysis indicated that ERBB2 signaling played a critical role in tumorigenesis. In addition to known markers such as ERBB2 and E-cadherin, novel markers, including BRP44L, MTHFD2 and TIMM17A, were found to be overexpressed in 21T breast cancer cells and verified in additional breast cell lines. mRNA expression analysis as well as immunohistochemistry analysis in breast cancer tissues indicated that expression level of TIMM17A was directly correlated with tumor progression, and survival analysis suggested that TIMM17A was a powerful prognosis factor in breast cancer. More interestingly, overexpression and siRNA knockdown experiments indicated an oncogenic activity of TIMM17A in breast cancer. Our study provides a list of potential novel markers for breast cancer tumorigenesis and metastasis using a unique cell model. Further studies on TIMM17A as well as other markers on the list may reveal mechanisms that result in more effective therapeutics for cancer treatment. PMID- 20198663 TI - Prevention of lymphatic injuries in surgery. AB - BACKGROUND: The problem of prevention of lymphatic injuries in surgery is extremely important if we think about the frequency of both early complications such as lymphorrhea, lymphocele, wound dehiscence, and infections and late complications such as lymphangites and lymphedema. Nowadays, it is possible to identify risk patients and prevent these lesions or treat them at an early stage. This article helps to demonstrate how it is important to integrate diagnostic and clinical findings to better understand how to properly identify risk patients for lymphatic injuries and, therefore, when it is useful and proper to do prevention. METHODS: Authors report their experiences in the prevention and treatment of lymphatic injuries after surgical operations and trauma. After an accurate diagnostic approach, prevention is based on different technical procedures among which microsurgical procedures. It is very important to follow-up the patient not only clinically but also by lymphoscintigraphy. RESULTS AND CONCLUSIONS: It was identified a protocol of prevention of secondary limb lymphedema that included, from the diagnostic point of view, lymphoscintigraphy and, as concerns therapy, it also recognized a role to early microsurgery. It is necessary to accurately follow-up the patient who has undergone an operation at risk for the appearance of lymphatic complications and, even better, to assess clinically and by lymphoscintigraphy the patient before surgical operation. PMID- 20198664 TI - Fabrication of fluorescent silica nanoparticles hybridized with AIE luminogens and exploration of their applications as nanobiosensors in intracellular imaging. AB - Highly emissive inorganic-organic nanoparticles with core-shell structures are fabricated by a one-pot, surfactant-free hybridization process. The surfactant free sol-gel reactions of tetraphenylethene- (TPE) and silole-functionalized siloxanes followed by reactions with tetraethoxysilane afford fluorescent silica nanoparticles FSNP-1 and FSNP-2, respectively. The FSNPs are uniformly sized, surface-charged and colloidally stable. The diameters of the FSNPs are tunable in the range of 45-295 nm by changing the reaction conditions. Whereas their TPE and silole precursors are non-emissive, the FSNPs strongly emit in the visible vision, as a result of the novel aggregation-induced emission (AIE) characteristics of the TPE and silole aggregates in the hybrid nanoparticles. The FSNPs pose no toxicity to living cells and can be utilized to selectively image cytoplasm of HeLa cells. PMID- 20198665 TI - Preparation and characterization of a bifunctional aldolase/kinase enzyme: a more efficient biocatalyst for C-C bond formation. AB - A bifunctional aldolase/kinase enzyme named DLF has been constructed by gene fusion through overlap extension. This fusion enzyme consists of monomeric fructose-1,6-bisphosphate aldolase (FBPA) from Staphylococcus carnosus and the homodimeric dihydroxyacetone kinase (DHAK) from Citrobacter freundii CECT 4626 with an intervening linker of five amino acid residues. The fusion protein was expressed soluble and retained both kinase and aldolase activities. The secondary structures of the bifunctional enzyme and the parental enzymes were analyzed by circular dichroism (CD) spectroscopy to study the effect of the covalent coupling of the two parent proteins on the structure of the fused enzyme. Because S. carnosus FBPA is a thermostable protein, the effect of the fusion on the thermal stability of the bifunctional enzyme has also been studied. The proximity of the active centers in the fused enzyme promotes a kinetic advantage as the 20-fold increment in the initial velocity of the overall aldol reaction indicates. Experimental evidence supports that this increase in the reaction rate can be explained in terms of substrate channeling. PMID- 20198666 TI - Highly water-soluble superparamagnetic ferrite colloidal spheres with tunable composition and size. PMID- 20198667 TI - Copper(I) phenoxide complexes in the etherification of aryl halides. PMID- 20198668 TI - [Ind2TiMe2]: a catalyst for the hydroaminomethylation of alkenes and styrenes. PMID- 20198669 TI - Tetranuclear uranium clusters by reductive cleavage of 3,5-dimethylpyrazolate. PMID- 20198670 TI - Characterization of picomole amounts of oligosaccharides from glycoproteins by 1H NMR spectroscopy. PMID- 20198671 TI - Potentiometric sensing of neutral species based on a uniform-sized molecularly imprinted polymer as a receptor. PMID- 20198672 TI - Protonation-induced rearrangement of an oxaphosphirane complex. PMID- 20198673 TI - Surface chemistry and cell biological tools for the analysis of cell adhesion and migration. PMID- 20198674 TI - Direct synthesis of 1,4-disubstituted-5-alumino-1,2,3-triazoles: copper-catalyzed cycloaddition of organic azides and mixed aluminum acetylides. PMID- 20198676 TI - Advances in photoelectrocatalysis with nanotopographical photoelectrodes. AB - The design of photoelectrodes for high efficiency solar fuel energy conversion devices is based on the search for adequate surface conditioning to achieve efficient light harvesting, stability, minimized surface recombination losses and high electron-transfer rates at the electrolyte interface. An overview on established and novel approaches is given. A recent viable solution is provided by electroplating of nanoscale catalytic metals on passivated semiconductor surfaces, thereby forming reactive centers and avoiding contact between the semiconductor surface and the electrolyte. At these nano-dimensioned Schottky type junctions, light-induced excess minority carriers are scavenged and transferred to the electrolyte. Various possible device configurations are outlined and envisaged systems for hydrogen or oxygen evolution and carbon dioxide reduction are presented. The role of ultrathin passivating films is emphasized and methods to fabricate open as well as compact conformal films are described. PMID- 20198677 TI - Biomimetic synthesis of metal ion-doped hierarchical crystals using a gel matrix: formation of cobalt-doped LiMn(2)O(4) with improved electrochemical properties through a cobalt-doped MnCO(3) precursor. AB - We have synthesized spinel type cobalt-doped LiMn(2)O(4) (LiMn(2-y)Co(y)O(4), 050 mg/mL and reduce aggregation to an acceptable level. These strategies can be readily applied to other proteins with solubility issues. PMID- 20198685 TI - Bone marrow cells from myelodysplastic syndromes show altered immunophenotypic profiles that may contribute to the diagnosis and prognostic stratification of the disease: a pilot study on a series of 56 patients. AB - A heterogeneous spectrum of immunophenotypic abnormalities have been reported in myelodysplastic syndromes (MDS). However, most studies are restricted to the analysis of CD34(+) cells and/or other major subsets of CD34(-) cells, frequently not exploring the diagnostic and prognostic impact of immunophenotyping. METHODS: We propose for the first time an immunophenotypic score (IS) based on the altered distribution and immunophenotypic features of maturing/mature compartments of bone marrow (BM) hematopoietic cells in 56 patients with MDS that could contribute to a refined diagnosis and prognostic evaluation of the disease. RESULTS: Although MDS-associated phenotypes were detected in reactive BM, the overall immunophenotypic profile of BM cells allowed an efficient discrimination between MDS and both normal and reactive BM, once the number and degree of severity of the abnormalities detected per patient were simultaneously considered in the proposed IS. Interestingly, increasingly higher IS were found among patients with MDS showing adverse prognostic factors and in low- versus high grade cases. The most informative prognostic factors included the number of CD34(+) cells, presence of aberrant CD34(-)/CD117(+) precursors, decreased mature neutrophils and CD34(-) erythroid precursors, and increased numbers of CD36(-/lo) erythroid precursors; in addition, the IS was an independent prognostic factor for overall survival. CONCLUSIONS: Assessment of immunophenotypic abnormalities of maturing/mature BM cells allows an efficient discrimination between MDS and both normal and reactive BM, once the number and degree of severity of the abnormalities detected are simultaneously scored. Interestingly, progressively higher IS were found among patients with MDS with adverse prognostic features and shorter overall survival. PMID- 20198687 TI - The effect of novel surfactants and Solutol HS 15 on paclitaxel aqueous solubility and permeability across a Caco-2 monolayer. AB - The effect of novel surfactants on the aqueous solubility and the permeability of paclitaxel across a Caco-2 cell monolayer were examined in this work. The solubility and permeability of paclitaxel was evaluated in the presence of four soft surfactants (SS) KXN441, KXN424, KXN437, and KXN 337 and Solutol HS15. All surfactants increased the aqueous solubility of paclitaxel. Caco-2 cell membrane integrity in the presence of SS and Solutol HS15 was assessed by mannitol permeability and LDH release. All surfactants were tested at 0.5x CMC, 5x CMC and 1.5 mM concentrations. The effect of SSs on paclitaxel permeability was concentration dependent. At all concentrations tested, KXN 441 and Solutol HS 15 showed partially inhibition of drug efflux with no discernable change in mannitol permeability or cytotoxicity as observed with LDH release. At these concentrations, other SSs exhibited some partial efflux inhibition along with compromised membrane integrity and increasing mannitol permeability. In conclusion, all SSs were able to increase the aqueous solubility and permeability of paclitaxel across Caco-2 cells monolayer. However, KXN441 and Solutol HS15 were able to enhance paclitaxel permeability across Caco-2 monolayer without cytotoxicity. PMID- 20198688 TI - Dry powder aerosols generated by standardized entrainment tubes from drug blends with lactose monohydrate: 1. Albuterol sulfate and disodium cromoglycate. AB - The major objective of this study was: discriminatory assessment of dry powder aerosol performance using standardized entrainment tubes (SETs) and lactose-based formulations with two model drugs. Drug/lactose interactive physical mixtures (2%w/w) were prepared. Their properties were measured: solid-state characterization of phase behavior and molecular interactions by differential scanning calorimetry and X-ray powder diffraction; particle morphology and size by scanning electron microscopy and laser diffraction; aerosol generation by SETs and characterization by twin-stage liquid impinger and Andersen cascade impactor operated at 60 L/min. The fine particle fraction (FPF) was correlated with SET shear stress (tau(s)), using a novel powder aerosol deaggregation equation (PADE). Drug particles were <5 microm in volume diameter with narrow unimodal distribution (Span <1). The lowest shear SET (tau(s) = 0.624 N/m(2)) gave a higher emitted dose (ED approximately 84-93%) and lower FPF (FPF(6.4) approximately 7-25%). In contrast, the highest shear SET (tau(s) = 13.143 N/m(2)) gave a lower ED (ED approximately 75-89%) and higher FPF (FPF(6.4) approximately 15-46%). The performance of disodium cromoglycate was superior to albuterol sulfate at given tau(s), as was milled with respect to sieved lactose monohydrate. Excellent correlation was observed (R(2) approximately 0.9804 0.9998) when pulmonary drug particle release from the surface of lactose carriers was interpreted by PADE linear regression for dry powder formulation evaluation and performance prediction. PMID- 20198689 TI - Restless legs syndrome in a population of northern Tanzania: a community-based study. AB - Restless legs syndrome (RLS) is a highly prevalent movement disorder. However, prevalences seem to vary amongst different ethnicities. To date, no community based prevalence studies on RLS have been reported from the African continent. We have conducted a community-based, door-to-door study in northern Tanzania. Over a period of 16 months, 7,654 people aged 14 years and older were screened for the RLS Essential Diagnostic Criteria. Sampling was performed according to the method of "multistage cluster sampling." People who screened positive where reinterviewed and physically examined by a specialist neurologist. During the screening phase, 10 people answered "yes" to at least one of the screening questions. After reinterviewing those people, the result was confirmed in five people only. After careful re-evaluation of the results, only one person was diagnosed with RLS. Because of methodological limitations a definite prevalence may only be calculated from larger population-based studies of different African ethnicities with screening questions adapted to the cultural context. PMID- 20198690 TI - Bioactivity of immobilized EGF on self-assembled monolayers: optimization of the immobilization process. AB - Last trends in Biomaterials focus the mimic of cellular environments capable to control cellular responses. Epidermal growth factor (EGF) is a pleiotropic cytokine known to regulate cell proliferation, differentiation, and death. This study aims to optimize the immobilization of EGF on 11-mercapto-1-undecyl tetra(ethylene)glycol (EG4)-self-assembled monolayers (SAMs) and to establish a new model surface to study EGF-mediated signaling. Gold substrates were modified with a monolayer of EG4 and N,N'-carbonyldiimidazole (CDI) was used to activate hydroxyl terminated groups of EG4-SAMs. EGF was then immobilized on activated EG4 SAMs at pH 7.4, 4 degrees C, and 100 rpm. Different immobilization reaction times were tested as well as different CDI concentrations to optimize the reaction conditions and obtain a range of immobilized EGF concentrations on the surfaces. Surface characterization of EGF-SAMs was performed using radiolabeling, water contact angle measurements, X-ray photoelectron spectroscopy, and ELISA. Phosphorylation of EGFR on BT-20 breast cancer cell line by EGF-SAMs was tested by immunostaining. EGF was successfully immobilized on EG4-SAMs, at 4 degrees C and pH 7.4 in a range of concentrations from 3.6 +/- 0.8 to 17.6 +/- 1.5 ng/cm(2). The concentration of EGF increases with immobilization time and with the CDI concentration reaching the maximum for surfaces activated with 30 mg/mL of CDI after 48 h. The bioactivity of EGF-SAMs was confirmed by immunostaining of phospho-EGFR of BT-20 cells. This study described EGF immobilization on EG4-SAMs at different concentrations, which could be important surface models to study specific protein interactions at the molecular level evolving EGF-family of proteins. PMID- 20198691 TI - Modification of titanium alloy surfaces for percutaneous implants by covalently attaching laminin. AB - Percutaneous implants require a seal at the skin interface. Laminin (L-332) is a component of the basement membrane, integral to epidermal attachment. To enhance the attachment of keratinocytes onto the surface of titanium alloy (Ti(6)Al(4)V), we attached L-332 onto the surface using silanization (L-332==Ti(6)Al(4)V). Iodinated L-332 was used to investigate protein attachment kinetics. L 332==Ti(6)Al(4)V remained attached after immersion in serum compared with adsorbed L-332. Cells from a keratinocyte line (HaCaT) grown on L 332==Ti(6)Al(4)V were significantly smaller (p < 0.05) with over a 20-fold increase in the number of adhesion plaques compared with nontreated Ti(6)Al(4)V control discs or with adsorbed L-332 surfaces. We have shown that it is possible to augment the surface of Ti(6)Al(4)V with L-332 and that this significantly increases the attachment of keratinocytes. PMID- 20198692 TI - Tissue-engineered matrices as functional delivery systems: adsorption and release of bioactive proteins from degradable composite scaffolds. AB - A tissue-engineered bone graft should imitate the ideal autograft in both form and function. However, biomaterials that have appropriate chemical and mechanical properties for grafting applications often lack biological components that may enhance regeneration. The concept of adding proteins such as growth factors to scaffolds has therefore emerged as a possible solution to improve overall graft design. In this study, we investigated this concept by loading porous hydroxyapatite-poly(lactide-co-glycolide) (HA-PLAGA) scaffolds with a model protein, cytochrome c, and then studying its release in a phosphate-buffered saline solution. The HA-PLAGA scaffold has previously been shown to be bioactive, osteoconductive, and to have appropriate physical properties for tissue engineering applications. The loading experiments demonstrated that the HA-PLAGA scaffold could also function effectively as a substrate for protein adsorption and release. Scaffold protein adsorptive loading (as opposed to physical entrapment within the matrix) was directly related to levels of scaffold HA content. The HA phase of the scaffold facilitated protein retention in the matrix following incubation in aqueous buffer for periods up to 8 weeks. Greater levels of protein retention time may improve the protein's effective activity by increasing the probability for protein-cell interactions. The ability to control protein loading and delivery simply via composition of the HA-PLAGA scaffold offers the potential of forming robust functionalized bone grafts. PMID- 20198693 TI - PHBV and predifferentiated human adipose-derived stem cells for cartilage tissue engineering. AB - This study was conducted to investigate whether in vitro chondrogenic differentiated human adipose-derived stem cells (hASCs) can maintain the chondrogenic phenotype in (3-hydroxybutrate-co-3-hydroxyvalerate) (PHBV) scaffolds and whether differentiated hASCs/PHBV construct can produce neocartilage in a heterotopic animal model. hASCs were cultured with or without chondrogenic media in vitro and then seeded on PHBV foams. Differentiated cell/PHBV constructs were subcutaneously implanted in nude mice for 8 or 16 weeks; nondifferentiated cell/PHBV constructs were implanted in the control group. The results in the control group showed no cartilage formation and the disappearance of the scaffold at 8 weeks. Conversely, all differentiated hASCs/PHBV implants kept their original shape throughout 16 weeks. These implants at 16 weeks had stronger chondrocytes-specific histochemical staining than those at 8 weeks, with GAG, total collagen, and compressive moduli increased with implantation time. Cartilage lacunae were observed in all retrieved implants at 16 weeks. The chondrocytes-specific genes were detected by RT-PCR at 16 weeks. The remnants of PHBV were observed in the implants throughout 16 weeks. This study demonstrates that chondrogenic predifferentiated hASCs have the ability to maintain a chondrogenic phenotype in PHBV and that cell/PHBV constructs can produce neocartilage in a heterotopic site, but the degradation rates of PHBV in different environments needs more investigation. PMID- 20198694 TI - Differences in the bone differentiation properties of MC3T3-E1 cells on polished bulk and sputter-deposited titanium specimens. AB - The roughness and cleanness of a titanium surface must be controlled in order to investigate the expression mechanism of hard tissue compatibility on titanium. In this study, osteogenic MC3T3-E1 cells were cultured and differentiation-induced on bulk and sputter-deposited titanium specimens, and the osteogenesis were investigated. For the preparation of bulk specimens, titanium discs were mirror polished. On the other hand, titanium was sputter-deposited on smooth and clean cover glasses as sputter-deposited specimens. As a result, no significant difference was observed in the cell morphology and attached number. On the other hand, the time showing maximum activity in the alkaline phosphatase and gene expressions, which are related to bone differentiation on the bulk titanium, were superior to those on the sputter-deposited titanium. From the surface observation of the specimens with a scanning electron microscope and a scanning probe microscope, the surface on the sputter-deposited titanium was more uniform and cleaner than that on the bulk titanium. According to X-ray photoelectron spectroscopy, the thickness of surface oxide film on the sputter-deposited titanium was smaller than that on the bulk titanium. In addition, the proportions of TiO and Ti(2)O(3) in the surface oxide film on the sputter-deposited titanium were larger than those on the bulk titanium. These differences might influence the differentiation of osteoblastic cells. PMID- 20198695 TI - Cationic copolymers nanoparticles for nonviral gene vectors: synthesis, characterization, and application in gene delivery. AB - The major aim of nonviral delivery systems for gene therapy is to mediate high levels of gene expression with low toxicity. Nowadays, one of the most successful synthetic polycations used in gene delivery research is poly(ethylenimine) (PEI) in its high-molecular weight (HMW) branched form. However, PEI is not the ideal transfection agent in vivo because of its overwhelming cytotoxicity. To overcome its toxic effects with a minimal impact on transfection efficiency, PEI has been conjugated with several nonionic biocompatible polymers. Here, we describe the synthesis of nanosized particles consisting of HMW PEI (25 kDa) crosslinked with poly(epsilon-caprolactone) (PCL, 50-60 kDa), a biodegradable aliphatic polyester. PCL was modified by the insertion of glycidyl groups able to condense with the amines of PEI to chemically bind PEI onto PCL. The nanoparticles obtained have been characterized in relation to their physicochemical and biological properties, and the results are extremely promising in terms of low cell toxicity and high transfection efficiency. These biological effects might be related to the peculiar DNA binding to covalently connected polymeric nanoparticles, without the formation of entangled DNA/polymer-soluble aggregates. PMID- 20198697 TI - A cross-linking model for estimating Young's modulus of artificial bone tissue grown on carbon nanotube scaffold. AB - Carbon nanotubes (CNTs) provide a suitable environment for growth and proliferation of bone cells. The elastic properties exhibited by CNTs can enhance mechanical characteristics of bone mineral phase, hydroxyapatite (HAp), precipitated on such a scaffold. In this article, a simplified model for estimating the axial Young's modulus of a representative volume element (RVE) of CNT-HAp composite is presented. The model is based on the idea of HAp formation on functionalized sites on CNTs as cross-links between HAp matrix and CNT. Modeling results show that the reinforcement role contributed by CNT in the RVE causes a significant increase in the Young's modulus of the composite material which is a direct consequence of transferring stresses from the HAp matrix to the CNT through the cross-links. Similar conclusions may be suggested regarding the improvement of overall mechanical properties of the material. The prediction made by the model lies reasonably well within the limits proposed by conventional Rule of-Mixtures, and sliding below Voigt's model. The Young's modulus predicted by the model lies adjacent to the Hashin-Shtrikman upper bound as a function of the RVE length (or equivalently CNT aspect ratio). The model simulation indicates that an increase in the CNT aspect ratio and/or number of cross-links in the RVE, results in the prediction to move closer to the estimation made by Voigt as the assumption of perfect bonding between composite phases is approached. PMID- 20198696 TI - Identification of osteoconductive and biodegradable polymers from a combinatorial polymer library. AB - Combinatorial polymer syntheses are now being utilized to create libraries of materials with potential utility for a wide variety of biomedical applications. We recently developed a library of photopolymerizable and biodegradable poly(beta amino ester)s (PBAEs) that possess a range of tunable properties. In this study, the PBAE library was assessed for candidate materials that met design criteria (e.g., physical properties such as degradation and mechanical strength and in vitro cell viability and osteoconductive behavior) for scaffolding in mineralized tissue repair. The most promising candidate, A6, was then processed into three dimensional porous scaffolds and implanted subcutaneously and only presented a mild inflammatory response. The scaffolds were then implanted intramuscularly and into a critical-sized cranial defect either alone or loaded with bone morphogenetic protein-2 (BMP-2). The samples in both locations displayed mineralized tissue formation in the presence of BMP-2, as evident through radiographs, micro-computed tomography, and histology, whereas samples without BMP-2 showed minimal or no mineralized tissue. These results illustrate a process to identify a candidate scaffolding material from a combinatorial polymer library, and specifically for the identification of an osteoconductive scaffold with osteoinductive properties via the inclusion of a growth factor. PMID- 20198698 TI - Biomedical research of novel biodegradable copoly(amino acid)s based on 6 aminocaproic acid and L-proline. AB - The biomedical properties of novel biodegradable copoly(amino acid)s based on 6 aminocaproic acid and L-proline were analyzed in this article. The cytotoxicity of the copolymer films was tested in vitro using human embryonic kidney (HEK) 293 cells. The cell proliferation, cell cycle, cell apoptosis, and hemolysis of the polymers were also investigated. No significant cytotoxic response was detected statistically by cytotoxicity assay, and the results of cell apoptosis and cell cycle showed that there were no statistically significant differences in them. Generally, the cells spread and grew well on polymer film. Meanwhile, the extent of hemolysis on the polymers was acceptable. Evaluation of cytotoxicity by cell cycle and apoptosis as a supplementary assay is correspondingly discussed in this article. PMID- 20198699 TI - Collagen supramolecular and suprafibrillar organizations on osteoblasts long-term behavior: benefits for bone healing materials. AB - This study compares the behavior of osteoblastic cells seeded on three structurally distinct collagen-based materials. Adhesion and long-term behavior were evaluated in vitro in regard to collagen scaffolds forming loose or dense fibrillar networks or exempt of fibrils. In this purpose collagen solutions at concentrations of 5 and 40 mg/mL were processed by freeze-drying or by sol/gel fibrillogenesis to form either sponges or hydrogels. Macroscopic and microscopic images of sponges showed a light material exhibiting large pores surrounded by dense collagen walls made of thin unstriated microfibrils of 20 nm in diameter. In comparison collagen hydrogels are more homogeneous materials, at 5 mg/mL the material consists of a regular network of cross-striated collagen fibrils of 100 nm in diameter. At 40 mg/mL the material appears stiffer, the ultrastructure exhibits cross-striated collagen fibrils packed in large bundles of 300-800 nm of width. Human osteoblastic cells seeded on top of the 5 mg/mL matrices exhibit a squared shaped osteoblast-like morphology over 28 days of culture and express both alkaline phosphatase and osteocalcin. Osteoblastic cells seeded on top of sponges or of 40 mg/mL matrices exhibit both flat and elongated resting osteoblast morphology. Osteoblastic cells have mineralized the three collagen based materials after 28 days of culture but collagen sponges spontaneously mineralized in absence of cells. These results highlight, in an in vitro cell culture approach, the benefit of fibrils and of dense fibrillar networks close to in vivo-like tissues, as positive criteria for new bone tissue repair materials. PMID- 20198700 TI - Detachment of the basal body from the sperm tail is not required to organize functional centrosomes during Drosophila embryogenesis. AB - The formation of the zygotic spindle at fertilization requires in most animals the central contribution of the sperm-inherited basal body that recruits maternal cytoplasmic components to assemble a functional centrosome. Although as a general rule the entire sperm enters the egg during fertilization, the fate of the sperm basal body during further development is not clear. We have found that the sperm centriole remains linked to the apical end of the sperm tail through early development and is able to duplicate and recruit maternal components to assemble functional centrosomes. The basal body, therefore, needs not to be detached from the sperm tail to perform its centriole function during organization of the centrosome. By cellularization and early gastrulation the sperm centriole has lost both these capabilities. The persistence of the sperm axoneme and its close association with its centriole during development presents a paradox. If the sperm centriole is a true basal body, then the widespread idea that cells with a primary cilium must resorb the axoneme and transform the basal body into a centriole to enable proper mitosis will have to be re-examined. PMID- 20198701 TI - Preventing hepatitis C virus recurrence in liver transplant recipients: a role for adoptive immunotherapy? PMID- 20198702 TI - The chicken or the egg: adipocytes and hepatic insulin resistance. PMID- 20198704 TI - Dendritic cells in liver fibrosis: conductor of the inflammatory orchestra? PMID- 20198705 TI - Mucosal melanoma of the nose and paranasal sinuses, a contemporary experience from the M. D. Anderson Cancer Center. AB - BACKGROUND: Sinonasal mucosal melanoma is a rare disease associated with a very poor prognosis. Because most of the series extend retrospectively several decades, we sought to determine prognostic factors and outcomes with recent treatment modalities. METHODS: A retrospective chart review of 58 patients treated for sinonasal melanoma at a tertiary cancer center between 1993 and 2004. The patients were retrospectively staged according to the sinonasal American Joint Committee on Cancer (AJCC) staging system. Demographic, clinical and pathological parameters were identified and correlated with outcomes. RESULTS: There were 35 males and 23 females with a median age of 63 years; 56 patients were treated surgically and 33 received radiation therapy. According to Ballantyne's clinical staging system, 88% of the patients presented with stage I (local) disease. Classification by the AJCC staging classified yielded 27% of the patients with T1, 33% with T2, 21% with T3, and 19% with T4. T-stage and the degree of tumor pigmentation were associated with a worse survival (P = .0096 and P = .018, respectively), while pseudopapillary architecture was associated with a higher locoregional failure (P = .0144). Postoperative radiation therapy improved locoregional control when a total dose greater than 54 Gy was used (P = .0215), but did not affect overall survival. CONCLUSIONS: Tumor stage according to sinonasal AJCC staging system is an effective outcome predictor and should be the staging system of choice. Postoperative radiation therapy improves locoregional control when a higher dose and standard fractionations are used. Histological features such as pigmentation and pseudopapillary architecture are associated with worse outcome. PMID- 20198706 TI - Quality of end-of-life care in low-income, uninsured men dying of prostate cancer. AB - BACKGROUND: The quality of end-of-life care was assessed in disadvantaged men prospectively enrolled in a public assistance program. That end-of-life care would be aggressive, more so than recommended by quality-of-care guidelines, was hypothesized. METHODS: Included in the study were all 60 low-income, uninsured men in a state-funded public assistance program who had died since its inception in 2001. To measure quality of end-of-life care, information was collected regarding timing of the institution of new chemotherapeutic regimens, time from administration of last chemotherapy dose to death, the number of inpatient admissions and intensive care unit stays made in the 3 months preceding death, and the number of emergency room visits made in the 12 months before dying. Also noted were hospice use and the timing of hospice referrals. RESULTS: Eighteen men (30%) enrolled in hospice before death and the average hospice stay lasted 45 days (standard deviation, 32; range, 2-143 days; median, 41 days). Two patients (11%) were enrolled for fewer than 7 days, and none were enrolled for more than 180 days. The average time from administration of the last dose of chemotherapy to death was 104 days. Chemotherapy was never initiated within 3 months of death, and in only 2 instances (6%) was the final chemotherapeutic regimen administered within 2 weeks of dying. Use of hospital resources (emergency room visits, inpatient admissions, and intensive care unit stays) was uniformly low (mean, 1.0 +/- 1.0, 0.65 +/- 0.82, and 0.03 +/- 0.18, respectively). CONCLUSIONS: End-of life care in disadvantaged men dying of prostate cancer, who enroll in a comprehensive statewide assistance program, is high-quality. PMID- 20198707 TI - American Society of Clinical Oncology-recommended surveillance and physician specialty among long-term breast cancer survivors. AB - BACKGROUND: It is unclear whether it is appropriate to transfer the follow-up care of breast cancer (BrCa) survivors from cancer specialists to primary care physicians (PCPs). This contemporary study compared physician specialty and documented the long-term surveillance of survivors who underwent surgery at an American academic center. METHODS: Women in this institutional review board approved study underwent breast surgery between 1996 and 2006. Data were collected for 270 patients with stage I to III BrCa (mean follow-up, 6 years). Charts were reviewed based on American Society of Clinical Oncology (ASCO) guidelines for recommended surveillance frequency and care. RESULTS: The majority of patients (90%; n = 242) were followed by specialists with 10% (n = 28) followed by PCPs. Patients with advanced disease and a greater risk of disease recurrence more often received specialist care. Patients followed by specialists were more often seen at ASCO-recommended intervals (eg, 89% vs 69% of patients followed by a PCP at follow-up Year 6; P < .01); however, many patients were followed inconsistently. Breast disease was often not the focus of PCP visits or mentioned in clinic notes (18% patients). Women seen by specialists were more likely to have documented clinical examinations of the breast (93% vs 44% at Year 6), axilla (94% vs 52%), or annual mammograms (74% vs 48%; P = .001-.02). CONCLUSIONS: Consistent compliance with surveillance guidelines and chart documentation needs improvement among all providers; however, specialists more consistently met ASCO guidelines. If transfer of care to a PCP occurs, it should be formalized and include follow-up recommendations and defined physician responsibilities. Providers and patients should be educated regarding surveillance care and current guidelines incorporated into standard clinical practice. PMID- 20198709 TI - Beta-2-microglobulin is an independent predictor of progression in asymptomatic multiple myeloma. AB - BACKGROUND: Although serum beta-2 microglobulin (B2M) represents a key variable for symptomatic multiple myeloma (MM) prognostication, its role in predicting the risk of progression of asymptomatic MM to symptomatic disease has not been explored. METHODS: This study was bases on a consecutive series of 148 patients with asymptomatic MM and explored the cumulative probability of progression to symptomatic MM as the primary endpoint. RESULTS: In univariate analysis, a serum B2M level >2.5 mg/L was associated with an increased probability of disease progression (5-year risk, 64.5%; P < .001) along with serum monoclonal component (sMC) (P < .001), urinary monoclonal component (uMC) (P < .001), and bone marrow plasma cells (BMPCs) (P < .001). In multivariate analysis, serum B2M was selected as an independent predictor of progression (hazard ratio, 3.30; P = .002). Serum B2M was combined with sMC, uMC, and BMPC to create a risk-stratification model based on 4 groups with different risk of progression: very low (5-year risk, 0%), low-intermediate (5-year risk, 19.6%), high-intermediate (5-year risk, 60.7%), and high (5-year risk, 80.7%). The model that included serum B2M along with sMC, uMC, and BMPC was able to predict disease progression better than the model that was based on sMC, uMC, and BMPC without serum B2M (C statistics, 0.760 vs 0.726). CONCLUSIONS: The current results indicated that 1) serum B2M is an independent predictor of asymptomatic MM progression, and 2) serum B2M adds prognostic information when combined with the most widely used prognosticators of asymptomatic MM progression. PMID- 20198710 TI - CDK5 is present in sea urchin and starfish eggs and embryos and can interact with p35, cyclin E and cyclin B3. AB - While most cyclin-dependent kinases (CDKs) are involved in cell cycle control, CDK5 is mostly known for crucial functions in neurogenesis. However, we cloned sea urchin CDK5 from a two-cell stage cDNA library and found that the protein is present in eggs and embryos, up to the pluteus stage, but without associated kinase activity. To investigate the potential for nonneuronal roles, we screened a starfish cDNA library with the yeast two-hybrid system, for possible CDK5 partners. Interactions with clones expressing part of cyclin B3 and cyclin E proteins were found and the full-length cyclins were cloned. These interactions were verified in vitro but not in extracts of starfish oocytes and embryos, at any stages, despite the presence of detectable amounts of CDK5, cyclin B3, and cyclin E. We then looked for p35, the CDK5-specific activator, and cloned the sea urchin ortholog. A sea urchin-specific anomaly in the amino acid sequence is the absence of N-terminal myristoylation signal, but nucleotide environment analysis suggests a much higher probability of translation initiation on the second methionine(Met44), that is associated with a conserved myristoylation signal. p35 was found to associate with CDK5 and, when bacterially produced, to confer protein kinase activity to CDK5 immunoprecipitated from sea urchin eggs and embryos. However, p35 mRNA expression was found to begin only at the end of the blastula stage, and the protein was undetectable at any embryonic stage, suggesting a neuronal role beginning in late larval stages. PMID- 20198711 TI - Cathepsin B activity is related to the quality of bovine cumulus oocyte complexes and its inhibition can improve their developmental competence. AB - Recently, the quantity of cathepsin transcripts in cumulus cells was found to be associated with low-developmental competence of bovine oocytes. In the present study, we investigated (1) the relation between cathepsin B activity and the quality of in vitro-matured cumulus-oocyte complexes (IVM COCs) and denuded oocytes and (2) the effect of a cathepsin B inhibitor (E-64) on embryo development and quality. The activity of cathepsin B was evaluated in IVM COCs and denuded oocytes. After maturation of COCs with or without E-64, followed by in vitro fertilization, zygotes were cultured for 8 days. Cleavage and blastocyst rates were evaluated on days 2 and 8, respectively. Quality of embryos was evaluated by differential staining of day 8 blastocysts. TUNEL staining was conducted on IVM COCs and blastocysts. Cathepsin B activity was clearly detected in the low-quality oocytes, and in the cumulus cells of both high- and low quality oocytes. This latter activity was diminished by addition of E-64. The presence of E-64 during IVM also significantly increased both the blastocyst rate and the total cell number, and improved blastocyst quality associated with a significant increase of trophoectoderm cells. TUNEL staining revealed that inhibition of cathepsin B significantly decreased the number of apoptotic nuclei in both the cumulus cell layer of matured oocytes and blastocysts. These results indicate that cathepsin B activity can be a useful marker of oocyte quality. Furthermore, inhibition of cathepsin B greatly improves the developmental competence of bovine oocytes and increases the number of high-quality embryos. PMID- 20198712 TI - Hepatopancreatobiliary manifestations and complications associated with inflammatory bowel disease. AB - Diseases involving the hepatopancreatobiliary (HPB) system are frequently encountered in patients with inflammatory bowel disease (IBD). Hepatobiliary manifestations constitute some of the most common extraintestinal manifestations of IBD. They appear to occur with similar frequency in patients with Crohn's disease or ulcerative colitis. HPB manifestations may occur in following settings: 1) disease possibly associated with a shared pathogenetic mechanism with IBD including primary sclerosing cholangitis (PSC), small-duct PSC/pericholangitis and PSC/autoimmune hepatitis overlap, acute and chronic pancreatitis related to IBD; 2) diseases which parallel structural and physiological changes seen with IBD, including cholelithiasis, portal vein thrombosis, and hepatic abscess; and 3) diseases related to adverse effects associated with treatment of IBD, including drug-induced hepatitis, pancreatitis (purine-based agents), or liver cirrhosis (methotrexate), and reactivation of hepatitis B, and biologic agent-associated hepatosplenic lymphoma. Less common HPB manifestations that have been described in association with IBD include autoimmune pancreatitis (AIP), IgG4-associated cholangitis (IAC), primary biliary cirrhosis (PBC), fatty liver, granulomatous hepatitis, and amyloidosis. PSC is the most significant hepatobiliary manifestation associated with IBD and poses substantial challenges in management requiring a multidisciplinary approach. The natural disease course of PSC may progress to cirrhosis and ultimately require liver transplantation in spite of total proctocolectomy with ileal-pouch anal anastomosis. The association between AIP, IAC, and elevated serum IgG4 in patients with PSC is intriguing. The recently reported association between IAC and IBD may open the door to investigate these complex disorders. Further studies are warranted to help understand the pathogenesis of HPB manifestations associated with IBD, which would help clinicians better manage these patients. An interdisciplinary approach, involving gastroenterologists, hepatologists, and, in advanced cases, general, colorectal, and transplant surgeons is advocated. PMID- 20198713 TI - Double-blind study of pardoprunox, a new partial dopamine agonist, in early Parkinson's disease. AB - This study examined the efficacy and safety of the partial dopamine agonist, pardoprunox (SLV308), in the treatment of patients with early Parkinson's disease (PD). Patients were randomized to receive pardoprunox (n = 69) or placebo (n = 70). Pardoprunox was titrated to each patient's optimal dose (9-45 mg/d) over 2 to 6 weeks and then maintained at this dose for a further 3 weeks. Concomitant anti-Parkinson treatment was not permitted. In the primary analysis, Unified PD Rating Scale (UPDRS)-Motor score was improved in pardoprunox-treated patients (overall mean dose 23.8 mg/d; -7.3 points), as compared with placebo (-3.0 points; P = 0.0001), from baseline to end point. At end point, there were more responders (> or = 30% reduction in UPDRS-Motor score) in the pardoprunox group (50.7%) than in the placebo group (15.7%; P < 0.0001). In other secondary analyses, UPDRS-activities of daily living (ADL) and -ADL+Motor scores were also significantly more improved in the pardoprunox group. Nausea was reported by 32 of 68 (47.1%) pardoprunox-treated patients (vs. 3/70, 4.3%, placebo-treated patients), with dizziness, somnolence, headache, and asthenia also reported by > or = 10 patients. In this exploratory proof-of-concept study, pardoprunox significantly improved motor function in patients with early PD. The efficacy and safety profile of pardoprunox justifies its further investigation in PD. PMID- 20198714 TI - Discriminative power of different nonmotor signs in early Parkinson's disease. A case-control study. AB - The objective of this study was to evaluate the discriminative power of different nonmotor signs for early diagnosis of Parkinson's disease (PD). Thirty patients with PD with =5 days in 2007 to 2008 who survived the intensive care unit, families of survivors, and families of patients who died in the intensive care unit. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Focus group facilitator used open-ended questions and scripted probes from a written guide. Three investigators independently coded meeting transcripts, achieving consensus on themes. From 48 subjects (15 patients, 33 family members) in nine focus groups across three sites, a shared definition of high-quality intensive care unit palliative care emerged: timely, clear, and compassionate communication by clinicians; clinical decision-making focused on patients' preferences, goals, and values; patient care maintaining comfort, dignity, and personhood; and family care with open access and proximity to patients, interdisciplinary support in the intensive care unit, and bereavement care for families of patients who died. Participants also endorsed specific processes to operationalize the care they considered important. CONCLUSIONS: Efforts to improve intensive care unit palliative care quality should focus on domains and processes that are most valued by critically ill patients and their families, among whom we found broad agreement in a diverse sample. Measures of quality and effective interventions exist to improve care in domains that are important to intensive care unit patients and families. PMID- 20198728 TI - Proceedings of the 14th International Symposium on Dental Morphology. August 27 30, 2008. Greifswald, Germany. PMID- 20198729 TI - Holding on to hope. Providers optimistic after Obama's address. PMID- 20198730 TI - No fix in sight. Senate tackles SGR; docs still seek lasting solution. PMID- 20198731 TI - Struggling with shortages. Adapt to long-term staffing shortfalls: AHA report. PMID- 20198732 TI - Extreme makeover. HHS should offer more emergency guidance: GAO. PMID- 20198733 TI - Katrina closure. $475 million for charity hospital; Pendleton settles. PMID- 20198734 TI - CDC targets hospital infections. Studies will be agency's first on subject since '80s. PMID- 20198735 TI - One and done. Michigan study aims to cut readmission rates. PMID- 20198736 TI - Time to restore trust. Lawmakers, administration need to reform their 'closed door' policy. PMID- 20198737 TI - Getting personal. Advances in biotechnology and the promise of personalized medicine help drive record investment in 2009. PMID- 20198738 TI - Largest per diem nurse staffing firms in the U.S. Ranked by estimated 2008 U.S. temporary staffing revenue. PMID- 20198739 TI - [Johnny Hallyday, a French icon]. PMID- 20198740 TI - Endovascular coiling in 131 patients with low complication rate justifies treating most unruptured intracranial aneurysms. AB - BACKGROUND: The management of unruptured intracranial aneurysms (UIAs) remains controversial. The International Study of UIAs (ISUIA) found low rates of rupture and appreciable treatment risks. This finding could be interpreted as suggesting that many UIAs should not be treated. Coiling technology has continuously improved over the years and, since the publication of the International Subarachnoid Aneurysm Trial results, increasing numbers of aneurysms have been coiled, and neurointerventional skills have significantly improved. We present the results of endovascular coiling of 131 patients with UIAs from a high volume unit and a risk-benefit analysis based on patient and aneurysm characteristics. PATIENTS AND METHODS: From December 1996 to September 2005, 131 patients (93 women and 38 men, mean age 51 years) with 151 UIAs were treated using detachable coil embolisation. Data on procedural complications, patient and aneurysm characteristics, clinical and radiological follow up were entered into a prospectively collected database. A risk-benefit analysis was performed. FINDINGS: Endovascular treatment was successful in 145 (96 %) aneurysms. One aneurysm ruptured intraoperatively with a fatal outcome. Ten thromboembolic events occurred, leaving one patient moderately disabled. The combined morbidity and mortality rate per patient at 6 months is 1.5 % (95 % confidence interval: 0.07 - 5.7 %). A risk-benefit analysis comparing these data with the published natural history suggests that treatment with low complication rates can be offered to most patients with UIAs. CONCLUSION: UIAs can be coiled with low morbidity and mortality. The risk-benefit analysis suggests that it is reasonable to off er treatment to patients with the exception of patients over 60 years of age with incidentally found aneurysms less than 7 mm in diameter of the anterior circulation. PMID- 20198741 TI - Journal publication ethics 201: culture in crisis? PMID- 20198742 TI - Radiation dose and screening for vesicoureteral reflux. PMID- 20198743 TI - Molecular and physiological aspects.Foreward. PMID- 20198744 TI - Improved infrared thermography based image construction for biomedical applications using Markov Chain Monte Carlo method. AB - Breast thermography is one of the scanning techniques used for breast cancer detection. Looking at breast thermal image it is difficult to interpret parameters or tumor such as depth, size and location which are useful for diagnosis and treatment of breast cancer. In our previous work (ITBIC) we proposed a framework for estimation of tumor size using clever algorithms and the radiative heat transfer model. In this paper, we expand it to incorporate the more realistic Pennes bio-heat transfer model and Markov Chain Monte Carlo (MCMC) method, and analyze it's performance in terms of computational speed, accuracy, robustness against noisy inputs, ability to make use of prior information and ability to estimate multiple parameters simultaneously. We discuss the influence of various parameters used in its implementation. We apply this method on clinical data and extract reliable results for the first time using breast thermography. PMID- 20198745 TI - Molecular and physiological aspects. Preface. PMID- 20198746 TI - miRNA regulation of the translational machinery. Preface. PMID- 20198747 TI - The Great War's human plight. PMID- 20198748 TI - Mainstreaming Middle East gender research: promise or pitfall? PMID- 20198749 TI - [The 55th Conference of the Central Subsection of the Physiological Society of Japan. Aichi, Japan, October 17-18, 2008. Abstract]. PMID- 20198751 TI - New HIV recommendations to improve health, reduce infections and save lives. PMID- 20198752 TI - Malaria progress report shows that development aid for health is working. PMID- 20198753 TI - Does tort reform reduce health care costs? PMID- 20198755 TI - Withdrawn from publication. "A fatal addict with myocardial lesion". PMID- 20198754 TI - Expectations outpace reality: physicians' use of care management tools for patients with chronic conditions. AB - Use of care management tools--such as group visits or patient registries--varies widely among primary care physicians whose practices care for patients with four common chronic conditions--asthma, diabetes, congestive heart failure and depression--according to a new national study by the Center for Studying Health System Change (HSC). For example, less than a third of these primary care physicians in 2008 reported their practices use nurse managers to coordinate care, and only four in 10 were in practices using registries to keep track of patients with chronic conditions. Physicians also used care management tools for patients with some chronic conditions but not others. Practice size and setting were strongly related to the likelihood that physicians used care management tools, with solo and smaller group practices least likely to use care management tools. The findings suggest that, along with experimenting with financial incentives for primary care physicians to adopt care management tools, policy makers might consider developing community-level care management resources, such as nurse managers, that could be shared among smaller physician practices. PMID- 20198756 TI - [Caesarean section by vertical incision of lower uterine segment]. AB - OBJECTIVES: The aim of the study is to analyze the use of vertical incision of the lower uterine segment when performing Caesarean section (CS). MATERIAL AND METHODS: The study includes 89 pregnant women who delivered by CS. The main group includes 40 cases with vertical incision in lower uterine segment (preliminary intention, but final decision made during surgery) and controls--49 cases with transversal incision of lower uterus segment with difficulties/complications of fetus extraction (30 with uterine lacerations and 19 with T-form incision). The mean gestational age in the main group is 32 g.w. (range 26-39) vs. 31 in control group (27-39). RESULTS. Vertical incision of the uterus is performed in 57.5% due to prematurity and lack of enough space for transversal incision (lower uterine segment not yet formed), in 25 % the cause is situs transverses of the foetus and the rest of the cases are related with technical difficulties in isthmicotransversal approach (myoma praevia, anomalies of the uterus, adhesions of the omentum). C.S. is performed for mean 66 min. in the main group vs. 74 min. with controls (p < 0.05). Time to extraction of the foetus is less than a minute in main group vs more than a minute with controls. No lacerations are found with vertical incision of uterus. Blood loss in main group is 664 ml, vs. 884 ml in control group (p < 0.05). Mean values of pH from umbilical artery of the newborn is 7.257 in main group vs. 7.19 in controls (p < 0.05), resp. Apgar scores atb 5 th min. is 7 vs 6. CONCLUSIONS. Vertical incision of lower uterine segment before the formation of the latter, with situs transversus of the foetus and difficult approach renders the option for less lacerations intra operationem, less birth trauma with better final outcome for the newborn. PMID- 20198757 TI - [Menarche in Bulgarian--secular trend in twenty century]. AB - The aim of the study was to determine the time of menarche in Bulgarian girls and specify the changes in menarcheal age during 20 century. MATERIAL AND METHODS: We examined in a longitudinal study 93 girls from 3 schools in Sofia in the period from 1994-2000. RESULTS: Mean age of menarche in girls was 11.96 + 0.75 years, (x + SD), median 12, 00 years. At the age of eleven 41.9% of the investigated girls have already had menarche and at the age of 10--4.3%. By the completion of the 12 years 90.3% were with menarche and at 14 years of age--100%. In a study in Bulgaria, done by the beginning of 20 century (1904-1906), the mean age of menarche was 15.0 + 3.32 years, 3 years later than it was found by us at the end of the century. CONCLUSION: We observed a secular trend of earlier time of menarche in Bulgarian girls during 20th century. PMID- 20198758 TI - [Prognostic factors in diagnosed endometrial cancers determining the type of radical surgery]. AB - AIM: Our aim was to research and evaluate for 10 years period the most important prognostic factors, related and determining the choice of suitable type of radical surgical treatment. It was performed in diagnosed endometrial cancer patients. MATERIAL AND METHODS: We researched 460 patients with endometrial cancer for 10 years period. All of them were operated by radical programme. We evaluated the following prognostic factors: stage, age, histological type, tumor grading, invasion of the tumor in myometrium, tumor volume, peritoneal cytology, LVSI, hormonal receptor status, nuclear grading, DNA--ploidy, the extent of the lymph node dissection (number of lymph nodes) and specific genetic alterations connected with endometrial cancers. RESULTS: The surgical determined stage was the most important prognostic factor. The age was independent factor. The histological type was very important prognostic factor--the endometrioid cancers were with better survival rate (89%) in comparison with the rare papillary-serous and clear cell cancers (30%). The tumor grading and myometrical invasion had a very important prognostic significance. When the patients were with grade 3 and infiltration in the outer third of myometrium--the positive pelvic lymph nodes were 30% and the paraaortal--20%. The tumor volume according to us is an independent prognostic factor. When the diameter of the tumor was less than 2 cm- the metastases in the lymph nodes were 3% and when the diameter was more than 2 cm--the metastases were 18%. If the tumor volume occupied the whole endometrial cavity and invasion in myometrium was deep, we had 40% metastases in the lymph nodes. The peritoneal cytology had a relative risk. The LVSI was independent prognostic factor. The ER and PR were independent prognostic factors. The nuclear grading--according to our results is a significant prognostic factor. The aneuploidy was the strongest independent factor for bad survival after age and stage. The extent (the volume) of the lymph node dissection was considered as an independent prognostic factor. In type I endometrioid endometrical cancers we evaluated the microsatelite instability and mutations in PIEN, pikCA, etc. The non estrogen related type 2 nonendometrioid endometrial cancers (serous, clear cell) showed mutations in P53 gene and chromosomal instability. DISCUSSION: Researching and evaluating the prognostic factors for endometrial cancers, we wanted to help and determine the best surgical treatment (the extent, the need for pelvic and paraaortal lymph node dissection). CONCLUSIONS: The radical surgical treatment with lymph node dissection gives better survival rate, as in low risky groups as well in high risky groups of endometrial cancers. The extent (the number of the lymph nodes) is an independent prognostic factor. PMID- 20198759 TI - [Analysis of single oocytes and follicles from surgically recovered ovarian tissue of patients with ovarian polycystosis]. AB - Our study included material of 30 patients with ovarian polycystosis (PCOS polycystic ovary syndrome). Informed consent was obtained from patients before their laparoscopic surgery and biopsy. A total of 16 oocytes and small follicles were isolated from (33.33%) of cases by stereomicroscopic dissection. This was followed by follicle cells removing, zona pellucida dissolving, hypotonic incubation and fixation onto slides. On the fixed samples, FISH with markers for chromosomes 18, 21 and X was performed. Analysis was successful in 11 (68.75%) of objects (5 follicles and 6 oocytes). Five oocytes (31.25%) had a negative FISH reaction because of condensed chromatin. This indicated cellular ageing which is characteristic of atretic follicles. CONCLUSIONS: (1) We obtained data about chromatin and chromosomal status of analysed oocytes, which correlated with ovarian reserve dynamics in PCOS and the processes of maturation and chromatin ageing in growing and atretic follicles. (2) The study has provided information about biological parameters of ovarian tissue in PCO that could be useful for obtaining precise patients' diagnosis and for their reproductive prognosis. (3) The problem needs more extensive studies because the number of analyzed oocytes was insufficient to allow data comparison for aneuploidy in PCOS ovaries vs. normally functioning ovaries. PMID- 20198760 TI - [Incidence of synchronous primary neoplasms of the female reproductive tract in women with ovarian endometriosis: a retrospective analysis of 811 cases]. AB - PURPOSE: Although endometriosis is a benign disorder recent studies suggest endometriosis could be viewed as a neoplastic process. Objective of this study is to explore the epidemiology of synchronous neoplasms (SPN) in women with severe endometriosis. PATIENTS & METHODS: The prevalence of SPN in cases with endometriotic ovarian cysts that underwent surgery at "Lito" Maternity hospital of Athens and at Anticancer Institute of Sophia was investigated. The review period was 2000 through 2009. The medical records and pathology were reviewed to confirm the diagnosis and stage of tumors. RESULTS: 5 women with synchronous cancers of the genital tract were identified. All of our patients had a grade-I endometrioid carcinoma of the uterus (Ia in 3, Ib in 2). Myometrium was invaded less than 1/3 in 4 cases and less than 1/2 in one. Similarly, 4 out of 5 ovarian cancers were endometrioid, while one was serum cystadenosarcoma. All of the ovarian malignancies were grade I (Ib in 3 and Ia in 2). Median diameter of the ovarian neoplasias was 4.3 cm, in contradiction to 4.5 cm that was the median diameter of all endometrioid cysts. When only the larger ovarian malignant cyst in each patient was accounted, then median diameter was calculated as 5.8 cm. CONCLUSIONS: Women with synchronous primary cancers of the endometrium and ovary have distinct clinical characteristics including younger age, premenopausal status, and nulliparity. This suggests that a hormonal "field effect" may account for the development of these simultaneous endometrioid cancers, supporting the theory of estrogen receptors. PMID- 20198761 TI - [Azoospermia and male genital diseases]. AB - This study includes 1227 patients with congenital, inflammatory and vascular diseases of male genital system and proved the frequency of azoospermia. PMID- 20198762 TI - [Prophylactic episiotomy--a historical heritage with no medical foundation?]. AB - The purpose of this study was to determine the historical roots of so called routine or prophylactic episiotomy and its real value in now-a-day obstetric practice. We made a retrospective study on clinical trails and medical anthropology data. PMID- 20198763 TI - [Vulvar dystrophy--morphological, clinical and therapeutical aspects]. PMID- 20198764 TI - [Scar uterine rupture after 6 pregnancies with cerclage]. AB - The scar uterine rupture is the most common reason for uterine rupture, because of the increased frequency of the myomectomia, cesarean sections and others. We present a case of a scar rupture in multiparous woman with seventh pregnancy, six of them with cerclage. The numerous cerclages has caused changes (lacerations) in the cervix, which made necessary each next cerclage to be placed higher and probably in the uterine isthmus. In our case the rupture started in the lower uterine segment and is combined with rupture of the bladder, which is the most common complication of the uterine rupture. We conclude that in cases with several cerclages the status of the uterus and the cervix should be evaluated very carefully and the way of delivery should be discussed. PMID- 20198765 TI - [A clinical case of twin pregnancy with intrauterine death of one of the twin (foetus papiraceus)]. AB - Multiple pregnancy is associated with some specific syndromes: twin to twin transfusion syndrome, syndrome of the disappeared twin, intrauterine loss of one of the twin, development of foetus papiraceus and syndrome of asymmetric growth of the twin. We present a case of term pregnancy with death of one of the twin and normal delivery of healthy baby and Foetus papiraceus. PMID- 20198766 TI - [Ovarian cancer with metastatic lesion in the vagina (foetus papiraceus)]. AB - Ovarian cancer spreads primarily by intraperitoneal implantation of exfoliated cancer cells, by lymphatic dissemination, and by haematogenous spread. Very rarely it metastasizes to cervix, vulva and vagina; this type of metastases present a diagnostic challenge to the gynecologist and pathologist. We present a case of ovarian cancer with initial clinical manifestation-lesion of the vagina. PMID- 20198767 TI - [Mixed gonadal dysgenesis combined with gonadoblastoma]. AB - Gonadal dysgenesis is defined by incomplete or defect forming of gonads, a result of disturbed process of migration of germ cells or and their correct organization in gonadal ridge. The combination of dysgenetic gonads and Y chromosome is a prerequisite for developing ovarian neoplasma--most frequent gonadoblastoma. We present a case of mixed gonadal dysgenesis at a patient with caryotype 46XY in combination with gonadoblastoma. PMID- 20198768 TI - [Clinical study on the effect of vaginal administration of micronized progesterone at dysfunctional uterine bleeding in premenopause]. AB - The aim of the present study was to establish the effectiveness of vaginal administration of micronized progesterone at 37 premenopausal women aged between 40-49 years (mean 44.5) with dysfunctional uterine bleeding. All women were subject of classical dilatation and curettage and after that micronized progesterone (Utrogestan) was applied vaginally 3 tablets 2 times per day, starting at 14 day of the menstrual cycle for 12 days. The control examination has been performed after finishing of 6 months therapy. The main criteria for the assessment of the therapeutic effect was the comparison of the character of genital bleeding, vegetative symptoms before and after the administration of the gestagene, as well as the examination of the level of hemoglobin, the thickness of the endometrium and at 12 women the histological findings from the control curettage. The results of our study show the presence of statistically significant difference for the effectiveness of micronized progesterone at dysfunctional uterine bleeding according to the intensity (p = 0.0068), duration of the bleeding (p = 0.00), decreasing of the endometrial thickness (p = 0.00), as well as lack of such difference when follow the level of hemoglobin (p = 0.4663) and vegetative symptoms (p = 0.9555). On the basis of conducted clinical study the authors confirm the preventive effect of the micronized progesterone, as an effective and safe alternative in treating of premenopausal women with dysfunctional uterine bleeding. PMID- 20198769 TI - [Immunohistochemical profile of colorectal and ovarian carcinomas--examination with cytokeratin 7, cytokeratin 20, beta catenin and cDX 2]. AB - INTRODUCTION: Metastases from colorectal adenocarcinomas can be histologically similar to serous, mucinous and endometrioid ovarian adenocarcinomas. The differentiation between primary and metastatic ovarian tumours is of great importance for the patients because of the different treatment and prognosis. AIM: The aim of the study was to determine whether the differences in the expression of Cytokeratin 7, Cytokeratin 20, Beta catenin and CDX2 can be used to distinguish the different types of carcinomas and their metastases. MATERIALS AND METHODS: The immunohistochemical expression of the listed above antibodies was examined retrospectively and prospectively in 38 colorectal adenocarcinomas (primary and metastatic) and 32 ovarian adenocarcinomas (primary and metastatic). The metastases in both types of adenocarcinomas are located in the peritoneum. RESULTS: The immunohistochemical expression was evaluated using a semi quantitative method. The ovarian adenocarcinomas are mostly positive for Cytokeratin 7 (in 63%), while colorectal carcinomas are mostly positive for Cytokeratin 20 (in 73%). Regarding Beta catenin, in colorectal carcinomas the expression is mostly nuclear (in 65%) and in ovarian carcinomas mostly membrane (in 68%). In cases of uncertain expression of the markers mentioned above, CDX2 was used. Positive nuclear expression was observed only in intestinal tumours (in 86%). CONCLUSION: For differential diagnosis between ovarian and colorectal adenocarcinomas, the use of antibodies, determining the intestinal differentiation of the tumours like Cytokeratin 20, Beta catenin and CDX2 is recommended. PMID- 20198770 TI - [Our experience in the surgical treatment of advanced endometrial cancers]. AB - AIM: Our aim was to summarise our experience in the surgical treatment of advanced endometrial cancers for 20 years period. MATERIAL AND METHODS: The patients were treated surgically by extrafascial hysterectomy, radical hysterectomy with pelvic and paraaortal lymph node dissection, by pelvic exenteration and by cytoreductive surgery (350 patients). The radical hysterectomy was applied in patients with stage II endometrial cancer. RESULTS: When cytoreductive surgery was used, we observed difference in the five years survival rate when the residual tumour was < or = 2 cm and > 2 cm in diameter. Better survival rate was observed in the first group with < or = 2 cms in diameter. The five years survival rate in patients treated with radical hysterectomy versus patients treated by extrafascial hysterectomy was 89% vs.68%. In patients with pelvic and paraaortal lymph node dissection the survival was 69%, while in patients only with pelvic dissection was 38%. According to our results the aggressive cytoreductive surgery betters the survival in endometrial cancer stage III-IV. CONCLUSIONS: The improvement in the adjuvant therapy may give an additional light in the treatment of advanced endometrial cancers. The radical hysterectomy with pelvic and paraaortal lymph node dissection improves significantly the overall survival rate of these patients. The optimal cytoreduction also leads to improvement of the survival in patients with advanced endometrial cancers. PMID- 20198771 TI - [The expression of p16(INK4a) and Ki-67 in atrophic-hyperplastic and dysdysplastic lesions of the vulva]. AB - The aim of present study is to investigate the immunohistochemical expression of tumor suppressor gene p16(INK4a) and proliferative marker Ki-67 in dysplastic vulvar lesions and nondysplastic ones. MATERIALS AND METHODS: 30 female patients (mean age = 49.5 +/- 4.5) - Ca in situ (n = 2), VIN (n = 10), lichen sclerorosus (n = 8), squamous cell hyperplasia (n = 1), mixed vulvar dystrophy (n = 5), papilloma (n = 1), condyllomata accuminata (n = 3) are separated into two groups (first group of non-dysplastic- and second group of dysplastic lesions). The immunohistochemical method with monoclonal antibody for identification of p16(INK4a) and Ki-67 was applied. RESULTS: P16(INK4a) is expressed in 1 patient (5.56%) in first group and in 8 patients (66.67%) in second group (chi2 = 84.93; p < 0.001). Ki-67 is positive in 4 patients (22.22%) in first group and in 12 of cases (100%) in second group (chi2 = 41.3; p < 0.001). CONCLUSIONS: There is a significant statistical difference between immunohistochemical expression of p16(INK4a) and Ki-67 in HPV-associated dysplastic and non-dysplastic vulvar lesions. PMID- 20198772 TI - [Modern tendencies in HRT of patients treated for endometrial cancer]. AB - AIM: Our aim was to evaluate the effect of HRT on endometrial cancer patients MATERIAL AND METHODS: We applied HRT in 250 patients-locally (cream) and in 300 patients in other routes and doses-tablet form, estradermal form, implant form. The research and the follow up were done for 10 years period. RESULTS: When we applied unopposed estrogen (0.3 mg) we had 5 fold increase in the risk of endometrial cancer. The application of local cream with low doses estrogen did not increase the risk of endometrial proliferation and the development of endometrial cancer. The addition of progestogens for 10-14 days led the patients to lower risk of endometrial cancer development. Applying Tibolone lowered the risk of endometrial cancer and had a protective effect on the endometrium. CONCLUSIONS: The application of progestogens for 10-14 days reduced the risk for endometrial cancer and had a protective effect on the endometrium. The HRT was mostly applied in early endometrial cancer grade 1,2. PMID- 20198773 TI - [Cryopreservation of embrional stem cells]. PMID- 20198774 TI - [Uterine carcinosarcoma with chondroid differentiation--immuhistochemical examination]. AB - Uterine carcinosarcomas are highly aggressive malignant tumours, consisting of both epithelial and mesenchymal components. They represent 1-3% of the malignant uterine neoplasms. Their histogenesis is unclear. Because of their rarity and the very few clinical data available, the studies of potential therapeutic goals are scarce. We present clinical and pathohistological description of a rare case of a 76-year-old woman with a uterine carcinosarcoma with a chondroid differentiation, examined immunohistochemically with Cytokeratin, Vimentin and S-100 protein. PMID- 20198776 TI - [Rare case of Crimean haemorrhagic fever in a pregnant woman]. AB - A rare case of Crimean haemorrhagic fever in a pregnant woman during the sixth month of gestation is described. The typical clinical course of the disease is present with positive anamnesis and visible locus from tick bite. After several days, fever and local lymphadenitis appear, followed by severe toxicoinfectious and haemorrhagic syndromes. The disease is proved virologically and serologically. The outcome is favourable for the pregnant woman. She is discharged home after 16-day hospital treatment. During the illness no complications of the fetus are documented. The pregnancy terminates with a normal term delivery of a healthy newborn baby with birthweight of 3350g. The clinical and laboratory follow up of the baby showed no abnormalities. The case is of interest because of the rarely and often severe course of the disease during pregnancy. In this case the outcome is favourable for both the mother and the newborn child. PMID- 20198777 TI - [Monural--choice of treatment in acute cystitis]. PMID- 20198775 TI - [First live birth in Bulgaria after in vitro maturation (IVM) procedure (case report)]. AB - The objective is to report the first healthy live birth in Bulgaria from immature oocytes retrieved in a natural menstrual cycle, followed by in vitro maturation (IVM). In vitro maturation protocol was performed in a case with male factor of infertility. Twentyone immature oocytes were retrieved by transvaginal ultrasound guided follicle aspiration on day 10 of a 28-year-old woman and matured in vitro. 28 hours late, 14 of them were in metaphase II. After insemination 13 were fertilizated. Three embryos were transfered at day two. The woman went on to deliver a single healthy live baby at term. We provide proof-of-principle evidence that the novel strategy of infertility treatment by IVM protocol can lead to successful pregnancy and healthy live birth. PMID- 20198778 TI - [Inherited thrombophilic factors in women with unexplained intrauterine fetal deaths]. AB - The aim of the study was to investigate a relationship between carrier status for factor V Leiden (FVL), prothrombin gene mutation 20210 G>A (PTM 20210 G>A) and development of unexplained intrauterine fetal deaths (UIFD). Thirty three women with one or more UIFD and stillbirths were investigated for carriers status for FVL and PTM 20210 G>A. Women with multiple pregnancies, congenital anomalies, intrauterine infection or chorioamnionitis were excluded from the study. Control group consisted of 79 women without reproductive failure were selected and investigated. The prevalence of FVL was significantly higher in the study group (21.1%) compared with 6.3% in the control group (OR 3.98, 95% CI 1.02- 16.14, p = 0.045). The prevalence of PTM 20210 G>A was also much higher in patients (10%) than in controls (2.5%) (OR 3.85, 95% CI 0.49-35.08, p-ns). Seven patients with UIFD and other obstetrics complications (preeclampsia, placental abruption, intrauterine growth retardation) showed high prevalence (over 40%) of FVL and PTM 20210 G>A. We found an important association between UIFD and FVL and PTM 20210 G>A, although the data on PTM 20210 G>A was non-significant because of low rate of the mutation and small group of investigated women. This data serves as a background to suggest a routine testing for inherited thrombophilia in women with UIFD aiming and individual approach of preventive use of low-molecular-weight heparin to avoid obstetric complication in future pregnancy. PMID- 20198779 TI - [Meconiophages and fetal hypoxia]. AB - Meconium may normally be passed by term fetuses during labour. Common after 40 weeks and not a sign of fetal distress Before 40 weeks can implicate fetal distress If occurring in preterm fetuses or if present prior to labour, it may be considered a possible indication of fetal distress. Histopathology may estimate the duration of meconium passage. Macrophages containing meconium are present at the chorionic surface or deeper portions of the membrane and can be easily identified not only on routine hematoxylin-eosin staining but also with the help of immunohistochemistry. PMID- 20198780 TI - [Influence of the very low dose oral contraception on the blood presure, body weight and general condition of the patients]. AB - The aim of the study is to follow the influence of the very low dose oral contraception on the blood presure, body weight and general condition of the patients. MATERIAL AND METHODS: 302 women at a mean age of 25.65 +/- 6.81 years were enroled in the study. They were treated with Lindynette-20 (20 mcg ethinyl estradiol and 75 mcg gestodene) for six months. RESULTS: The mean systolic and diastolic blood pressure of the patients is as follows: at inclusion--Systolic 106.62 mmHg/Diastolic 67.88 mmHg, at the 3-th month--Systolic 106.84 mmHg/Diastolic 68.00 mmHg and at the 6-th month--Systolic 106.40 mmHg / Diastolic 68.51 mmHg. No statistically significant difference was found (p > 0.05). At the end of the sixth month 89.04% of the patients did not increased their body weight with more than 2 kg, in 6.31% it was reduced with more than 2 kg and in 4.65% was increased with more than 2 kg. The most frequent side effects were: headache (14%), breast tenderness (7%), nausea (3%), emotional instability (6%). At the end of the period most of the patients have excellent--81.13%, very good--17.55% and good--0.99% tolerance to the treatment. CONCLUSIONS: Use of a very low dose oral contraception does not lead to a significant changes in the blood pressure and clinically significant changes in the body weight with an excellent and very good treatment tolerance of the patients. PMID- 20198781 TI - [Therapeutic results in patients with endometrial cancer]. AB - The aim of the present study is to analyze the patients with endometrial cancer, treated at Gynecology Clinic of the National Oncology Hospital, Sofia according to the stage of the disease, histological type, differentiation, the peculiarities of the spreading and metastases, the therapeutic methods applied and the obtained results. For the period 2002-2004, 152 women with endometrial cancer were treated at the clinic. Predominate the patients with first stage cancer 117 (77%) and with endometroid adenocarcinoma/adenoacantoma 116 (76.3%), as well as these who were treated with surgery 134 (88.2%), followed by radio, hormonotherapy. Among the surgical procedures the simple total hysterectomy with bilateral salpingoophorectomy was the most frequent applied method - 119 (79.2%) patients, followed by radical hysterectomy with bilateral salpingoophorectomy and lymph node dissection 25 (16.7%). At the end of the 3 years study period 118 (77.6%) women are alive and 34 (22.4%) are dead. For 28 (18.5%) patients the reason for the death was the oncological disease and for 6 (3.9%)--other type of disease. Our results demonstrate once again, that therapeutic success of patients with endometrial cancer depends directly of the exact determination of the prognostic factors and administration of complex approach in the treatment of every patient. PMID- 20198782 TI - [Male genital system diseases and degree of fertilizing ability]. AB - This study includes 1302 patients with congenital, inflammatory and vascular diseases of male genital system and proved man fertilizing ability mination of the prognostic factors and administration of complex approach in the treatment of every patient. PMID- 20198783 TI - [CDX2--an immunochystochemistry marker of intestinal differentiation of adenocarcinomas]. AB - CDX2 is a nuclear transcribing factor, important for the development and differentiation of the bowels. According to the recent publications, CDX2 expression is immunochystochemisry detector in the normal enterocytes of the bowels and is normally met in the most, but not at all colorectal carcinomas. Two homeostatic genes are detected at people CDX1 u CDX2. We present examination of CDX2 expression at 15 adenomas and 30 colorectal carcinomas. All the adenomas are positive for CDX2, 27 /90%/ of the adenocarcinomas show nuclear expression of CDX2. PMID- 20198784 TI - [The assisted reproduction and the newborn child]. AB - A review of the literature was made concerning the perinatal complications of children conceived through assisted reproduction technology. The main complications were due to the high frequency of multiple gestation and prematurity. There is convicting data for a twofold increase of the frequency of congenital malformations: neural tube defects, intestinal atresia and hypospadias. Chromosomal disorders are more frequent when Intracytoplasmic spermal injection is used. There is no evidence of increased risk of tumors. The psychomotor and intellectual development of the children conceived by assisted reproduction is normal. Nowadays, in order to decrease the incidence of multiple pregnancy, elective single embryo transfer if the preferable technology of assisted reproduction. PMID- 20198785 TI - [Vulvar intraepithelial neoplasia--morphological, clinical and therapeutical aspects]. PMID- 20198786 TI - [Asymmetric obstructed uterus didelphys/incomplete Herlyn-Werner-Wunderlich syndrome/diagnosed by transvaginal 3D ultrasound--a case report]. AB - Asymmetric obstructed uterus didelphys (Herlyn-Werner-Wunderlich syndrome-HWWS) is a rare congenital Mullerian anomaly consisting of uterus didelphys, hemivaginal septum and ipsilateral renal agenesis. We present a case of an incomplete HWWS diagnosed by 3D transvaginal ultrasound in a 22 year old patient with absence of the hemivaginal septum. The most contributive diagnostic factors as well as the appropriate therapeutic management in such cases are discussed. PMID- 20198787 TI - [Factor V Leiden and C677T MTHFR thrombophilic mutations associated with hyperfibrinogenemia, persistent high CRP and leucocytosis in newborn baby with perinatal infection--a clinical case]. AB - We present a clinical case of newborn baby with perinatal infection. Despite the solidity antibiotic therapy and good condition of the neonate, we observed hyperfibrinogenemia, persistent high CRP and leucocytosis. These inflammatory markers and the extravasation of blood during correction of anaemic syndrome draw attention to the role of other causal factors. DNA analysis for thrombophilic mutations identifies factor V Leiden and C677T MTHFR variant. PMID- 20198788 TI - [Chemotherapy-sensitive uterine choriocarcinoma: a case report]. AB - We report a case of uterine choriocarcinoma in a 42-year-old female presenting with abdominal pain, uterus enlargement, high serum levels of beta human chorionic gonadotropin (b-hCG) and a positive pregnancy test on two separate occasions. At laparatomy, blood and clots were observed in the abdomen, an enlarged uterus with tumor infiltrates in the uterus, appendix, bladder and plica vesico-uterina. Follwing hysterectomy and bilateral oophoorectomy, the patient received chemotherapy and was followed for two years. No tumor recurrences were observed and the b-hCG levels returned to normal. In conclusion, the condition responds favorably the chemotherapy and recurrences are rate when there are no metastases to the liver or the brain. PMID- 20198789 TI - [Velamentous insertion of the umbilical cord--diagnosis and management]. AB - OBJECTIVE: To assess the feasibility of ultrasound to identify velamentous insertion of the umbilical cord in B-mode, combined with Color/Power Doppler and 3D Power Angio Doppler during routine obstetric ultrasound follow up. DESIGN: This was a prospective cross-sectional ultrasound study in 145 second and third trimester high-risk singleton pregnancies. Color/Power Doppler ultrasound was done in all cases to identify the placental cord insertion site. Evaluation with three-dimensional (3D) ultrasound combined with Power Doppler (3D Power Angio Doppler) was also performed in all cases with suspected velamentous insertion. RESULTS: The insertion placental site of the umbilical cord was identified in 143/145 (98.6%) cases by conventional gray-scale ultrasound, combined with Color/Power Doppler. Visualization was not accomplished in 2 third trimester cases (beyond 30 w.g.) with a posterior placenta, intrauterine growth restriction (IUGR) and tendency of oligohydramnios. Velamentous insertion of the umbilical cord was suspected prenatally in 9 cases, including 2 cases with vasa previa. Three-dimensional ultrasound was of little clinical value and compared poorly with conventional gray-scale and Color Doppler imaging. CONCLUSIONS: Velamentous insertion of the umbilical cord can be reliably detected prenatally by gray-scale and Color/Power Doppler ultrasound. Three-dimensional imaging has limited clinical value in the evaluation of the placental cord insertion site. Its systematic assessment during routine obstetric ultrasound follow up has the potential of identifying most pregnancies with velamentous insertion and, therefore, those at risk for some important obstetric complications, including vasa previa. PMID- 20198790 TI - [Routine episiotomy--a five year practice at University Hospital "Majchin Dom"]. AB - Episiotomy continues to be a frequently used procedure in obstetrics despite little scientific support for its routine use. The rationale for routine episiotomy is based on two foundation arguments: that episiotomy reduces perineal trauma and that it prevents subsequent pelvic relaxation. A careful review finds little evidence to support these arguments. Although episiotomy does decrease the occurrence of anterior lacerations, it fails to accomplish the majority of goals stated as reasons for its use. Episiotomy does not decrease damage to the perineum but rather increases it. The midline episiotomy increases the risk for third-degree and fourth-degree lacerations. Episiotomy fails to prevent the development of pelvic relaxation and its attendant complications. Rather than decreasing maternal morbidity, episiotomy increases blood loss and is related to greater initial postpartum pain and dyspareunia. The claims of a protective effect on the fetus in shortening the second stage of labor, improving Apgar scores, and preventing perinatal asphyxia have not been borne out. Efforts should be directed to determine whether episiotomy is beneficial. It is now very important to improve new birthing techniques that maintain the integrity of the perineum and do not involve surgical procedures. More trials are necessary to clarify which are the real indications to use episiotomy. Meanwhile, without the proper scientific evidence, the most correct attitude seems to be a careful use of episiotomy, with decisions on a case-by-case basis. PMID- 20198791 TI - [Frequency of cytolytic vaginosis--examination of 1152 patients]. AB - The aim of the study was to evaluate the frequency of cytolitic vaginosis amongst women with symptoms that mimic vulvovaginal candidiasis. We include 1152 patients, which are microbiologically and citologically tested. We found in 3.9% cytolytic vaginosis. The clinical presentation is suggestive of vulvovaginal candidiasis. The differentiation of these two conditions is essential for appropriate treatment and resolution of chronic vaginal subjective complaints. PMID- 20198792 TI - [Evaluation of menstrual cycle length and spinal bone mineral density in postmenopausal women]. PMID- 20198793 TI - [Differential diagnostic importance of immunochistochemistry applied at metastases of adenocarcinomas of the peritoneum]. AB - Patients with metastatic carcinomas with unclear primary tumor site are often clinical and pathological problem. They are diagnosed in about 3-65 of the cases with solid tumors. In 60% of cases the reason is adenocarcinomas. The most frequent reason for peritoneal carcinomas at women is the ovarian cancer. In such cases we must exclude the probability of colorectal cancer. In fact there are not international standards for prove the origin of adenocarcinomas; different research groups use different criteria. We present the use of four antibodies- Cytokeratin 7 and 20, Beta cathenin and CDX2 and define their positiveness at metastases from different groups of adenocarcinomas in the peritoneum. PMID- 20198794 TI - [Evaluation of mammography and risk of developing breast cancer in patients with ovarian or endometrial cancer]. AB - AIM: In this study our aim is to evaluate the reproductive factors determining the risk for breast cancer and the mammographical density in patients with ovarian or endometrial carcinoma. MATERIALS AND METHODS: 24 patients with epithelial ovarian carcinoma and 35 patients with endometrial adenocarcinoma who were hospitalized at Izmir Ataturk Training and Research Hospital between the dates of May 2005 and June 2006 for diagnosis, treatment and follow-up were included to our study. The control group was formed with 25 healthy women of over 40 years of age applied to our mammography unit for routine screening. All patients were questioned by means of reproductive risk factors for breast cancer. Mammographical images were gained in two projections as craniocaudal and mediolateral. Mammographical images were evaluated by using BI-RADS scoring system in terms of density and by one radiologist. Plasma E2 levels were taken from all postmenaupausal patients. RESULTS: Mean age was higher in patients with endometrial carcinoma. The age of menarche was higher in patients with ovarian carcinoma. There were no significant differences between the groups in terms of age of menaupose, age of first delivery, lactation and duration of lactation, HRT use and incidence of type-2 diabetes. No any significant difference was detected in terms of E2 levels and mammographical density. DISCUSSION: Reproductive risk factors for breast cancer in patients with ovarian and endometrial carcinoma were not different from the healthy population. The results of our study didn't reflect the reported increased risk rates for breast cancer. PMID- 20198795 TI - [Extreme prematurity--medical and social problem]. AB - The survival rate for extremely preterm newborns born at the threshold of viability (25 or fewer completed weeks of gestation) improved in the early 1990s, largely as the result of a greater use of assisted ventilation in the delivery room and surfactant therapy. This led WHO in 1993 to define the perinatal period as commencing at 22 completed weeks of gestation. Infants born at 22-28 weeks gestation have been termed as having "threshold viability", though in developed countries this term is more often used in reference to infants of < 26 weeks. However, this improvement in survival has not been associated with an equal improvement in morbidity The increasing potential risk of residual disability or early death associated with decreasing gestational age raises serious medical, social and ethical problems in respect to appropriate management. These include whether elective delivery for fetal indication is appropriate or whether intensive care should be provided following delivery. PMID- 20198796 TI - [Placental parameters and fetal outcome]. AB - The examination of the placenta may discover the hidden complications of the pregnancy which may give insight into the pathogenesis of neurologic and other developmental disorders. Histologic examinations prove unequivocal associations between placental findings and preterm delivery, stillbirth, neonatal death and hypoxic problems. Few epidemiologic studies have related placental abnormalities to gestational age or adverse outcome of the newborn. In the present review we point the most common placental findings related to clinical data and fetal outcome with implications of placental careful examination. PMID- 20198797 TI - [Molecular genetics of ovarian cancer]. AB - Ovarian cancer is the most lethal gynecologic neoplasia. The risk of ovarian cancer in Europe is 1 to 80. In 80-90% of cases, the clinical manifestation is in advanced stage. The 5 year survival is for III /IV stage 25%, but for I/II stage is 90%. In the present study we present the molecular and genetic changes of hereditary and sporadic ovarian cancer. PMID- 20198798 TI - [Placental chorangiosis associated with abruption and hypoxia]. AB - Chorangiosis is a rare abnormality of placental capillary proliferation, associated with hypoxia in utero. A 23-year-old primigravida developed placental abruption at 33 weeks' gestation, and an emergency cesarean section was performed. Placental histology revealed chorangiosis. The infant was in critical state and died on the next day. Our case confirms that perinatal mortality can be associated with chorangiosis. This diagnosis should be considered especially when no other significant obstetric incident is identified. Placentas should be monitored for placental abruption, a known consequence of chorangiosis. PMID- 20198799 TI - [Adrenal hemorrhage in a newborn with factor V Leiden--a clinical case]. AB - Neonatal adrenal hemorrhage is frequently associated with birth trauma, perinatal asphyxia, septicemia, coagulation defects and thromboembolism. We report a case of bilateral adrenal hemorrhage in newborn baby with perinatal asphyxia. Ultrasound findings of subacute adrenal hemorrhage draw attention to its presumable antenatal genesis. DNA analysis for thrombophilic mutations identifies factor V Leiden. PMID- 20198800 TI - [Ovarian endometriosis, fibroma-thecoma and colonic cancer--accidental combination or regularity?]. AB - Malignant transformation of endometriosis accounts for less than 1% of the cases. Most often it occurs in ovaries--75%. Extragenital tumor progression of endometriosis in pelvis and bowel constitutes 21.3%, the recto-sygmoid part of the colon occupying the majority of the cases. A case with rare combination of endometriosis, fibroma-thecoma and recto-sygmoid colonic cancer is presented. The presence of synchronous ovarian endometriosis and colonic cancer suggests the latter has developed on the grounds of endometriosis. More interesting is the association of the second tumor-ovarian fibroma-thecoma with the above mentioned hypothesis. To search for supporting arguments, we performed additional morphological, histochemical and immunohistochemical methods to define the origin of the intestinal neoplasm and the ovarian tumor. Regretfully the morphological analysis supports an accidental coincidence. PMID- 20198801 TI - Ensuring a healthy and productive workforce: comparing the generosity of paid sick day and sick leave policies in 22 countries. AB - National paid sick day and paid sick leave policies are compared in 22 countries ranked highly in terms of economic and human development. The authors calculate the financial support available to workers facing two different kinds of health problems: a case of the flu that requires missing 5 days of work, and a cancer treatment that requires 50 days of absence. Only 3 countries--the United States, Canada, and Japan--have no national policy requiring employers to provide paid sick days for workers who need to miss 5 days of work to recover from the flu. Eleven countries guarantee workers earning the national median wage full pay for all 5 days. In Ireland and the United Kingdom, the full-time equivalent benefits are more generous for low-wage workers than for workers earning the national median. The United States is the only country that does not provide paid sick leave for a worker undergoing a 50-day cancer treatment. Luxembourg and Norway provide 50 full-time equivalent working days of leave, while New Zealand provides the least, at 5 days. In 6 countries, paid sick leave benefits are more generous for low-wage workers than for median-wage workers. PMID- 20198802 TI - Time to call it quits? The safety and health of older workers. AB - The workforces of many countries are aging, creating pressure for older workers to retire later despite greater vulnerability to various occupational safety and health (OSH) risks. Some specific risks to older workers arise from age-related physical or psychological changes, while others reflect exposures to poor work organization or employment conditions. This article reviews evidence on the nature of the OSH risks faced by older workers, focusing on work ability, contingent work, and working hours. Work ability, the capacity to meet the physical, mental, and social demands of a job, has been linked to positive health outcomes for older workers. However, work characteristics seem to be more critical than workers' individual capacities. Contingent work is generally associated with poorer OSH outcomes, and older workers are more likely to be contingent, with special implications for their safety and health. There has been limited research on age and working hours, but risks for many physical and mental health problems are known to increase with shift work experience, and physiological and psychosocial changes associated with age may also increase injury risks. The authors discuss organizational practices and regulatory policies to protect and enhance the OSH of older workers. PMID- 20198804 TI - Inequality as a cause of social murder. AB - The conservative attack on the poor draws from a long intellectual history. More modern conservative opponents of income redistribution have ceased to claim that the poor are somehow inferior beings to the rich. However, they share with their more strident predecessors a belief that redistribution is entirely unnecessary, due to the ability of the market to justly and efficiently allocate income among members of society. Further, they argue that state redistribution is damaging both to society as a whole and to those low-income people that income transfers are designed to help. The authors contrast the myth of conservative economic policy with the reality. PMID- 20198803 TI - Occupational health and safety in China: the case of state-managed enterprises. AB - The widely held image, inside and outside China, of the total absence of an occupational health and safety (OHS) system in that country is not an accurate picture. This article argues that the unsafe working conditions and prevalent occupational diseases and injuries widely reported in the Chinese and foreign media occur mostly in private mines and in the Asian foreign-funded and domestic private manufacturing sectors. In contrast, the capital-intensive, larger state owned enterprises and enterprises that have been transformed from state enterprises generally have better OHS systems. An in-depth study of two such enterprises reveals viable OHS systems, worker-management OHS committees, regular health and safety inspections, and trade unions' and workers congresses' oversight and supervision. Above all, there is an enterprise culture that regards accidents as avoidable, and both workers and management feel distressed and guilty when accidents happen. The authors believe it is important to acknowledge and champion these positive examples of "best practices" that can be emulated in workplaces throughout China, which is under great pressure from competitive domestic and global forces to relax its OHS standards. PMID- 20198805 TI - From apartheid to neoliberalism: health equity in post-apartheid South Africa. AB - In 1994, the African National Congress (ANC) won South Africa's first ever democratic election. It inherited a health service that was indelibly marked with the inequities of the apartheid era, highly privatized and distorted toward the hospital needs of urban Whites. The ANC's manifesto promised major improvements, but this study finds only two significant health equity improvements: (1) primary care had funding increased by 83 percent and was better staffed; and (2) health care workers became significantly more race-representative of the population. These improvements, however, were outweighed by equity losses in the deteriorating public-private mix. Policy analysis of the elite actors attributes this failure to the dominance of the Treasury's neoliberal macroeconomic policy (GEAR), which severely limited any increases in public spending. The ANC's nationalist ideology underpinned GEAR and many of the health equity decisions. It united the ANC, international capital, African elites, and White capital in a desire for an African economic renaissance. And it swept the population along with it, becoming the new hegemonic ideology. As this study finds, the successful policies were those that could be made a part of this active hegemonic reformation, symbolically celebrating African nationalism, and did not challenge the interests of the major actors. PMID- 20198806 TI - Double jeopardy: the impact of neoliberalism on care workers in the United States and South Africa. AB - Many researchers have explored how neoliberal restructuring of the workplace has reduced the standard of living and increased workplace stress among private sector employees. However, few have focused on how neoliberal restructuring of public policy has had similar effects on the public sector workforce. Using original case study research, the authors examine how two iconic pieces of neoliberal policy--the 1996 welfare reform bill in the United States and the GEAR macroeconomic policy in South Africa--affected public/nonprofit human service workers in New York City, United States, and public sector nurses in KwaZulu Natal, South Africa. The authors argue that in both situations, despite national differences, these policies created a "double jeopardy," in which patients/clients and care workers are adversely affected by neoliberal public policy. This "double jeopardy" creates significant hardship, but also the opportunity for new social movements. PMID- 20198807 TI - Prospects for a genuine revival of primary health care--through the visible hand of social justice rather than the invisible hand of the market: Part II. AB - This second part of a two-part article explores the prospects for genuine revival of primary health care (PHC) as announced by the WHO in 2008, with reference, briefly, to Global Health Watch 2, published by the People's Health Movement, Medact, and Equity Gauge Alliance, and, in more depth, to the positions of social and people's movements most closely aligned with the original values and principles of Alma-Ata and the structural foundations of the PHC project. The author argues that the social justice struggle for health cannot be limited to curbing capitalism's excesses. The multiple crises of today--in energy, water, food, the environment, finance, science, information, and democracy--must be recognized as capitalist crises and addressed as such. Particular attention is given to ideology, including the distortion of human nature and society under neoliberal capitalism, and to moral foundations of Health for All. Not only must the invisible hand of the market be replaced by the visible hand of social justice, but the single ideology proclaiming the "end of history" and, by implication, the end of politics and political struggle must be exposed and rejected as neoliberal, totalitarian propaganda. In line with the spirit and intention of the U.N. Charter, PHC remains a political project for a fair and safe world in which Health for All is both possible and necessary. PMID- 20198808 TI - Visits to family physicians or specialists by elderly persons in Canada and the United States: an exploratory comparative study. AB - The objective of this exploratory study was to compare elderly persons likelihood of visiting a family doctor/general practitioner or a medical specialist and the association of that likelihood with socioeconomic factors and health-related quality of life (a measure of perceived need) in Canada and the United States. The data were obtained from the 2002-2003 Joint Canada/United States Survey of Health. The main dependent measure was whether respondents saw a medical specialist or a general practitioner during their last health care visit. U.S. patients in the highest household income group were more likely to have seen a specialist during their last health care visit, after adjusting for potential confounding factors. Further, visits to a specialist in Canada were determined by need rather than by household income. In Canada, likelihood of specialist visits by elderly persons is systematically related to the burden of illness (need) and not systematically related to income. In the United States, the opposite is the case. These results suggest that there may be important lessons from Canada on the organization of health care services. PMID- 20198809 TI - Small-business employment in 22 rich economies. AB - Opponents of health care reform in the United States have often argued that such reform will be detrimental to small and medium-sized enterprises. The authors review the most recent data from a sample of 22 rich countries in the Organization for Economic Cooperation and Development (OECD), all of which, except the United States, have universal health care systems. By every measure of small-business employment, the United States has among the world's smallest small business sectors (as a proportion of total national employment). These findings hold for self-employed workers and across all industry groups for which the Paris based OECD publishes internationally comparable data, including manufacturing, computer-related services, and research and development. PMID- 20198810 TI - The adverse effects of International Monetary Fund programs on the health and education workforce. AB - Decades of underinvestment in public sectors and in teachers and health workers have adversely affected the health and educational outcomes of women. This is partly explained by a general lack of resources. However, the amount a country can spend on social sectors, including teachers and health workers, is also determined by its macroeconomic framework, which is set in agreement with the International Monetary Fund. There is now ample evidence of how IMF-imposed wage ceilings have constrained the ability of governments to hire adequate numbers of trained professionals and increase investment in social sectors. Though the IMF has recently removed wage ceilings from its basket of conditions, little change has taken place to ensure that women are better supported by macroeconomic policies or, at the least, are less adversely affected. Thus far, the IMF's neoliberal policies have either ignored gender concerns or instrumentalized equity, health, and education to support economic development. Unless macroeconomic policies are more flexible and deliberately take into account the different needs of women and men, social outcomes will continue to be poor and inequitable. Governments must pursue alternative, feminist policies that put the goals of social equity at the center of macroeconomic policy. These policies can facilitate increased investment in education and health care, which are vital measures for achieving gender equality and providing both women and men with the skills and training needed to soften the impact of the current economic crisis. PMID- 20198811 TI - The need to include Health Impact Assessment at the International Monetary Fund. AB - The lending and technical support provided by the International Monetary Fund affect the determinants of health and healthy equity. Most health determinants lie outside the control of the health sector, and thus non-health-sector policies have profound positive and negative effects on population health. Health Impact Assessment (HIA) is an instrument for identifying the effect of policies, plans, programs, and projects on population health and health equity. It is a feasible, cost-effective, and transparent process that has been adopted by several financial institutions, including members of the World Bank Group. Adopting HIA would assist the IMF in ensuring that the potential health consequences of its policies are identified and addressed. PMID- 20198812 TI - Why health advocates must get involved in development economics: the case of the International Monetary Fund. AB - International health advocates have traditionally focused on calling for external strategies for achieving health goals in developing countries, such as more foreign aid, foreign direct investment, loans, and debt cancellation, as opposed to internal approaches, such as building domestic productive capacity and accumulating capital. They have largely neglected questions of development economics, particularly the effectiveness, or lack thereof, of the currently dominant neoliberal development model promoted by the rich countries and aid agencies for poor countries. While critics have been correct to blame the International Monetary Fund for its policies curtailing public health spending in developing countries, their analysis generally neglects the underlying issue of why developing countries are seemingly unable to build their domestic tax base on which health budgets depend. International health advocates should engage with such macroeconomic questions and challenge the failures of the dominant neoliberal economic model that blocks countries from industrializing and building their own productive capacities with which to generate their own resources for financing their health budgets over time. PMID- 20198813 TI - The hemispheric lateralization for processing geometric word/shape combinations: the Stroop-shape effect. AB - The authors conducted 4 experiments to test whether hemispheric lateralization occurs for the processing of geometric word-shape combinations. In 3 experiments, participants responded to geometric shapes combined with geometric words (square, circle, triangle). In the 4th experiment, stimuli were combinations of geometric shapes and non-geometric words. The authors predicted that it would take longer to respond in incongruent conditions (e.g., the word "square" combined with the shape of a circle) than in congruent conditions. The authors found the strongest incongruency effects for the dominant hemisphere--that is, the left hemisphere for responding to words and the right hemisphere for responding to shapes. A Shape Interfering Properties hypothesis (SIP) is a possible explanation for these results. PMID- 20198814 TI - Generalizing Kant's distinction between perfect and imperfect duties to trust in different situations. AB - Based on previous research that violations of perfect duties cause stronger correspondent inferences than violations of imperfect ones, the authors performed four experiments to generalize this effect to trust. In Experiment 1, abstract violations of perfect duties resulted in less trust than violations of imperfect ones for specific trust scenarios. In Experiments 2 and 3, the authors experimented with different levels of abstractness of the duty violations and obtained similar effects. Experiment 4 was concerned with generalizing further- from duty violations in one situation to trust in a different situation. Although mostly consistent with the findings from Experiments 1-3, the data also demonstrated partial generalization for violations of both perfect and imperfect duties. PMID- 20198815 TI - Humor in the eye tracker: attention capture and distraction from context cues. AB - The humor effect refers to a robust finding in memory research that humorous information is easily recalled, at the expense of recall of nonhumorous information that was encoded in close temporal proximity. Previous research suggests that memory retrieval processes underlie this effect. That is, free recall is biased toward humorous information, which interferes with the retrieval of nonhumorous information. The present research tested an additional explanation that has not been specifically addressed before: Humor receives enhanced attention during information encoding, which decreases attention for context information. Participants observed humorous, nonhumorous positive, and nonhumorous neutral texts paired with novel consumer brands, while their eye movements were recorded using eye-tracker technology. The results confirmed that humor receives prolonged attention relative to both positive and neutral nonhumorous information. This enhanced attention correlated with impaired brand recognition. PMID- 20198816 TI - Sex differences in the haptic change task. AB - Three experiments examined gender differences in picture location memory in the sense of touch involving the change task. In Experiments 1 and 2, blindfolded sighted participants felt 15 tangible raised-line pictures and memorized their locations for 8 min. Subsequently, they felt another set of raised-line pictures that were identical to the original set, but locations were exchanged for 6 of them. The change task required participants to indicate which raised-line pictures were moved to new locations and which were not moved. It was expected that females would show superior picture location memory compared with males. The results showed that females had a significantly higher number of correct picture location judgments than males in Experiment 1. No differences appeared between males and females on the change task when the task was much more difficult and the raised-line pictures were irregularly arrayed in the second experiment. Task difficulty was too high in Experiment 2, and a third experiment reduced the number of pictures in the irregular array to 12. Females performed better than males in Experiment 3. Gender differences in the change task are small in magnitude in touch as well as in vision. The results of the present experiments using touch are consistent with the larger literature in vision. PMID- 20198817 TI - The effect of variety and dietary restraint on food intake in lean young women: a preliminary study. AB - When satiety develops specific to sensory properties of food, variety leads to increased eating. The relationship between meal variety and dietary restraint was explored here in lean young women (18-20 years), classified into unrestrainers versus restrainers using the Dutch Eating Behavior Questionnaire Restrained Eating Scale. The expected variety effect obtained for unrestrainers (p < .05) but not for restrainers, despite a typical sensitivity to sensory-specific satiety and the same rate of habituation to sensory-based food responses (i.e., hedonics) across them. Unrestrainers' eating appeared guided by hedonics (p < .05), but not restrainers'. These results suggest the potential involvement of an internal or participant characteristic, instead of an external factor, in moderating unrestrainers' versus restrainers' food consumption when offered a highly desired food (the favorite in the plain condition) versus less desired (but accepted) foods (presented successively with the favorite in the variety condition). Study limitations and suggestions for further research were discussed. PMID- 20198818 TI - Investigating the role of instructional focus in incidental pattern learning. AB - The authors used a novel dual-component training procedure that combined a serial reaction time task and an artificial grammar learning task to investigate the role of instructional focus in incidental pattern learning. In Experiment 1, participants either memorized letter strings as a primary task and reacted to the stimuli locations as a secondary task or vice versa. In Experiment 2, participants were given the same dual-component stimuli but performed only one of the two training tasks. Instructional focus affected the amount of learning and the likelihood of acquiring explicit knowledge of the underlying pattern. However, the effect of instructional focus varied for the different types of stimuli. These results are discussed in terms of the role of focused attention in incidental learning. PMID- 20198819 TI - System-wide versus component-specific trust using multiple aids. AB - Previous research in operator trust toward automated aids has focused primarily on single aids. The current study focuses on how operator trust is affected by the presence of multiple aids. Two competing theories of multiple-trust are presented. A component-specific trust theory predicts that operators will differentially place their trust in automated aids that vary in reliability. A system-wide trust theory predicts that operators will treat multiple imperfect aids as one "system" and merge their trust across aids despite differences in the aids' reliability. A simulated flight task was used to test these theories, whereby operators performed a pursuit tracking task while concurrently monitoring multiple system gauges that were augmented with perfect or imperfect automated aids. The data revealed that a system-wide trust theory best predicted the data; operators merged their trust across both aids, behaving toward a perfectly reliable aid in the same manner as they did towards unreliable aids. PMID- 20198820 TI - Detection of coronary artery anomalies and coronary aneurysms by multislice computed tomography coronary angiography. AB - We report some variants, anomalies and aneurysms of the coronary artery tree observed in patients referred to our radiology department for suspected or known coronary artery diseases. 265 patients, with heart rate < 70 beats per minute and stable clinical conditions, underwent 64-MSCT. They were intravenously given contrast medium followed by saline as a chaser. Images and data were reconstructed and evaluated by two radiologists. Seven out of these patients (5 males and two females) were found to have abnormalities (variants or anomalies) of coronary arteries or coronary aneurysms, with an incidence respectively of 1.88% and 0.75%. Two patients had an anomalous origin of the left coronary artery from the pulmonary artery, as previously described (Castorina S et al., 2008). As regards the other patients, one had separate origins of the anterior descendant and circumflex arteries from the left lateral sinus with two ostia, one had quadrifurcation of the left coronary trunk, one had agenesis of the left coronary ostium and trifurcation of the right coronary artery and two had coronary aneurysms. Images acquired by 64-MSCT, because of their spatial dislocation, permit anatomical study from different perspectives. Our data confirm the ability of MSCT to evaluate, in a few seconds, anomalies of coronary arteries offering additional information for a more complete diagnosis. PMID- 20198821 TI - Immunolocalization of hepatocyte growth factor receptor, c-Met, in human fetal tooth germ. AB - To evaluate c-Met expression in human tooth germ development. An immunohistochemical study on c-Met expression in tooth germs of 8 human fetus between the 7th and 9th week. In the Bud stage C-Met immunopositivity was, moderately to strongly, detected both in the inner and the outer epithelium of the enamel organ. In particular, moderate staining was detected in a specific portion of tooth germs that corresponds to apical portion of the enamel organ. In the bell stage tooth germs were characterized by much stronger c-Met immunopositivity in cytoplasm, inner enamel epithelium, bilateral cusps and above all in the plasma apical membrane on the mesenchymal side. In conclusion because enamel organ cells can interact with mesenchymal cells directly, and c-Met is expressed in the stages at which mesenchymal induction is guided by the dental epithelium, it is conceivable that c-Met is related to tooth germ morphogenesis and cell differentiation. PMID- 20198822 TI - On the risk of contracting AIDS at the dissection table. AB - Didactic dissection of the human body is still considered the best tool to teach and learn anatomy. Although the risk of being infected with pathogens during dissection has dramatically decreased, fear of infection is still widespread among medical students and health care professionals. The fear of contracting AIDS at the dissection table is of particular relevance because of the emotional implications accompanying the syndrome. In this study we analyze the actual risks of contracting AIDS during dissection in Italy by evaluating health policies and proportions of the epidemic. According to the Italian Ministry of Health, HIV infection and AIDS are not to be considered relevant threats to public health from the epidemiological point of view, and it is estimated that 99.7% of health care workers, who are exposed to HIV, will not be infected. In fact, there is only one well-documented case of an autopsy acquired HIV infection that happened in 1992 the United States. Furthermore, HIV infection is not necessarily associated with AIDS, and most HIV-positive subjects do not develop AIDS, provided that they do not assume toxic drugs or engage in risky behaviours. Conversely, according to the Ministry, AIDS can occur in the absence of signs of HIV infection. Taken together these considerations should help rationalizing the fear of contracting AIDS at the dissection table. The dissection hall can still be a dangerous place and the adoption of safe working practices and awareness of potential risks are mandatory; HIV serophobia, however, is unjustified. PMID- 20198823 TI - Amyloid beta: a putative intra-spinal microtubule-depolymerizer to induce synapse loss or dentritic spine shortening in Alzheimer's disease. AB - A loss or shortening of dendritic spines has been described in patients with neurodegenerative disorders such as Alzheimer's disease, but the underlying mechanisms are poorly understood. Recently, there have been four reports of capture of the plus-ends of microtubules in the dendritic spines. One report, based on acute hippocampal slices that were fixed by a microtubule preserving process after LTP-inducing stimulation, showed that microtubules of the dendritic shaft ramified into spines in a manner that was specific to the stimulated postsynaptic membranes. This resulted in enlarged protrusion of the dendritic spines. Other reports using living cultured neurons, showed that growing microtubule plus-ends enter spines and modulate spine morphology. Since microtubules originate from the centrosome, these four reports strongly suggest a stimulation-dependent connection between the nucleus and the stimulated postsynaptic membrane by microtubules. Several pieces of evidence suggest that spine elongation may be caused by microtubule polymerization. Firstly, the entry of plus-ends of microtubules into spines accompanies spine enlargement. Further, microtubule-associated protein-1B is over-expressed in Fragile X syndrome, in which spines are much elongated. Chronic stress causes neurite outgrowth and spine elongation. Polymerization of microtubules caused neurite outgrowth and microtubules-depolymerizing agents neurite retraction, both consistent with the proposition that spine elongation is caused by microtubule polymerization. This structural mechanism for spine elongation suggests, conversely, that synapse loss or spine shortening observed in Alzheimer's disease may be caused by depolymerization of intraspinal microtubules. The fact that a new drug, dimebon, shows promising results against memory disturbance in Alzheimer's patients and can also cause neurite outgrowth in cultured neurons may also support this idea. Amyloid activates GSK-3beta and it causes the abnormal hyperphosphorylation of tau and depolymerization of axonal microtubules, resulting in the impairment of axonal transport. Normal tau is mainly present in the axon, but hyperphosphorylated tau newly distributes to the dendrites and sequesters normal tau, MAP1A/MAP1B and MAP2, and may cause disruption of intraspinal microtubules by losing the microtubule-preserving effect of MAPs. Nevertheless, it may be strongly suspected that amyloid beta may be a putative intra-spinal microtubule depolymerizer to induce spine shortening, synaptic loss and finally the memory disturbance in Alzheimer's disease. PMID- 20198824 TI - Evaluation of the pattern of proximal and distal occlusion and collateral circulation of lower limb arteries using combined contrast arteriography and color doppler ecography. AB - Lower limb peripheral arterial occlusive disease (PAOD) is highly prevalent and causes disability and poor quality of life. The purpose of our study was to evaluate the pattern of proximal and distal occlusion and collateral circulation of lower limb arteries using combined contrast arteriography and color doppler ecography. The study concerned 140 subjects (88 men and 52 women, age range 65-88 years) with symptomatic lower limb arterial disease (Fontaine's stage II) subsequent to the occlusion of vessels downstream from the subrenal aorta. The assessment of lower-extremity PAOD was performed by using the FRASI study three step protocol. The calculation of the Winsor index showed progressively lower haemodynamic compromission in distal occlusion. The more the site of occlusion was proximal, and the greater was its hemodynamic effect, although there was no statistically significance. A combined use of contrast arteriography and color doppler ecography appeared very useful in studying the anatomy of the occlusions and their haemodynamic impact, as well as in analysing the presence and the effects of collateral circles. These findings may be fundamental for identifying the most correct indications for surgical therapy and for selecting optimal strategies and prostheses. PMID- 20198826 TI - Nurses can enjoy personal and professional benefits from social networking. PMID- 20198825 TI - Atrial natriuretic factor, but not oxytocin, is present in atherosclerotic plaques of human common carotid arteries. AB - We performed a study on 25 common carotid arteries (CCA) affected by atherosclerotic plaques, comparing them to 25 normal CCA. We researched the presence and localisation of atrial natriuretic factor (ANF) and oxytocin (OX) by immunohistochemistry. We found ANF abundantly expressed in plaques, mainly localising in intima and subintima layers; by contrast normal vessels were scarcely positive or negative; finally, OX resulted negative or weakly positive in both atherosclerotic and normal vessels. Our results show for the first time ANF presence in atherosclerotic plaques of CCA and are in agreement with other studies, mainly performed in vitro, that hypothesise the involvement of this molecule in the modulation of atherosclerotic inflammatory lesions and its use as anti-inflammatory agent. PMID- 20198827 TI - H1N1 vaccination keeps you and your patients safe. PMID- 20198828 TI - Where to draw the line. Professional boundaries in social networking. PMID- 20198829 TI - Put evidence into practice to manage nociceptive and neuropathic cancer pain. PMID- 20198830 TI - New guidelines recommend less frequent cervical cancer screening. PMID- 20198831 TI - Adonis Brown. Self advocate and independent living consultant. PMID- 20198832 TI - North Carolina all-terrain vehicle (ATV) safety legislation: an assessment of the short-term impact on ATV-related morbidity and mortality. AB - OBJECTIVE: All-terrain vehicle (ATV)-related morbidity and mortality has increased in the US, and states have attempted to combat this trend with ATV specific safety legislation. The objective of this study was to examine the short term changes in ATV-related injuries and deaths following the enactment of legislation regulating the operation and sale of ATVs in North Carolina. STUDY DESIGN AND DATA COLLECTION: The study is a retrospective analysis comparing ATV collisions during the six month pre and post period of the effective date of legislation. Demographics, medical outcomes, passenger seat position, helmet use, and alcohol use were analyzed. DATA: Subjects were identified through the North Carolina Trauma Registry and data from the Office of the Chief Medical Examiner. FINDINGS: A total of 102 (51 in both pre- and post-legislation) subjects required medical treatment or were declared dead secondary to ATV collisions in North Carolina. Children under the age of eight years, who were forbidden from using ATVs under the new legislation, had significantly fewer total medical evaluations and deaths in the post-legislative time period. There was no association between legislative time period and ATV-related passenger, helmet, or alcohol use. CONCLUSIONS: In the six months following the enactment of North Carolina's ATV bill, children under the age of eight years were seriously injured or died less often due to ATV-related crashes. No other significant changes in ATV riding patterns were seen between the two time periods, and the morbidity and mortality of all ATV riders did not change. LIMITATIONS: The examined data sets do not include data from all North Carolina hospitals. PMID- 20198833 TI - The Kidney Education Outreach Program's community-based screenings: participants' demographics and screening results. AB - OBJECTIVE: To outline the Kidney Education Outreach Program (KEOP) screening protocol, to describe the context in which these chronic kidney disease (CKD) screenings were administered, and to report the characteristics and screening results for participants from October 2005 to September 2008. METHODS: A cohort of 1742 people participated in targeted, free, community-based CKD screenings. Screenings included a self-report questionnaire regarding sociodemographic information, lifestyle behaviors, and personal and family health history. This survey was followed by urine dipstick testing for proteinuria and microalbuminuria. RESULTS: Medical histories were provided by 1694 individuals: 1522 through the complete questionnaire and 172 through an abbreviated questionnaire that differed principally in lack of information on family history of disease. Urine samples were collected from 1706 participants. The mean age of screening participants was 54 years old; 70% were female, 50% were African American, and 13% were Latino. More than 40% of subjects were obese. Roughly one quarter (23%) had been diagnosed with diabetes mellitus and about half (47%) had been diagnosed with hypertension. Twenty-four percent reported a family history of kidney disease. While 60% of the participants tested positive for microalbuminuria, less than 4% of these persons had ever been told they had kidney disease. LIMITATIONS: Lack of confirmatory testing with a serum creatinine (and estimated glomerular filtration rate) or, alternatively, with a 24-hour urine collection for creatinine clearance and protein excretion; no standardized follow-up for screened participants. DISCUSSION: The KEOP targeted screenings disclosed a high prevalence of known risk factors for CKD--diabetes mellitus, hypertension, obesity, advanced age, and family history of kidney disease. However, despite these factors, less than 4% of screened participants were aware of a diagnosis of CKD. PMID- 20198834 TI - Senate passed health care reform: what it means for you. PMID- 20198835 TI - Health insurance reform and the doctor-patient relationship. PMID- 20198836 TI - Putting people first: services and supports for people with developmental disabilities. PMID- 20198837 TI - Successful transitions for people with intellectual and other developmental disabilities. PMID- 20198838 TI - North Carolina developmental disability services and supports: steps to system improvement. PMID- 20198839 TI - North Carolina's public system of services and supports for individuals with intellectual and developmental disabilities. PMID- 20198840 TI - Constructing the new service paradigm: responding to today's challenges. PMID- 20198841 TI - Filling the gaps through partnerships, collaboration, and flexible funding. PMID- 20198842 TI - Improving educational outcomes and post-school success for students with disabilities. PMID- 20198843 TI - College: an option for people with intellectual or developmental disabilities. PMID- 20198844 TI - The need for employment supports for persons with intellectual and developmental disabilities in North Carolina. PMID- 20198845 TI - Bridges to community: the challenges and necessity of building a quality direct support workforce. PMID- 20198846 TI - Embedding developmental disabilities into medical training. PMID- 20198847 TI - A personal perspective on the future of the developmental centers in North Carolina. PMID- 20198848 TI - Don't fence me in. PMID- 20198849 TI - Resources for individuals with intellectual and other developmental disabilities and their families. PMID- 20198850 TI - Guilford Child Health, Inc. PMID- 20198851 TI - Children with special health care needs in North Carolina. PMID- 20198852 TI - Solo and small group mental health care professionals. PMID- 20198853 TI - [Relationship between two distinct families of tandem repeats in rye heterochromatin]. AB - BAC library constructed from the short arm of the first rye (Secale cereale L.) chromosome 1R was screened extensively in order to identify clones containing the copies of a tandemly organized repetitive DNA family, pSc200, which is the most abundant in the rye subtelomeric heterochromatin. Molecular organization of the monomers array and adjacent sequences have been studied in BAC 126/C20. The pSc200 array does not demonstrate the higher-order organization under treatment by different restrictases. The DNA adjacent to the pSc200 array consists of the different repeats included retrotransposon derivatives and another tandemly repeated XbaI family with monomer length of 576 bp, 475 of these show 82% similarity to part of the long terminal repeat of known retrotransposon Cereba. The sequencing of the 13 kb region in BAC 126/C20 revealed the direct junction of the pSc200 and XbaI monomers. The junction between these monomers was abrupt in the identical AT-rich site, CAAAAAT. Another recombinational signal is the palindromes in the close proximity to the site ofjunction. The presence of microhomologies promotes the efficiency action of the proteins involved in the mechanisms of double strand DNA break repair. To our knowledge, for the first time we revealed the direct junction of the monomers, which are longer than 100 bp length and belong to distinct families of tandem repeats from plant genomes. PMID- 20198854 TI - [Characterization and expression of DjPreb gene in the planarian Dugesia japonica]. AB - In this study we report the expression and identification of a PREB-related gene from the planarian Dugesia japonica, DjPreb. The planarian DjPreb cDNA is comprised of 1101 bp and contains a 972 bp open reading frame corresponding to a deduced protein of 323 amino acids with a 69 bp 5'-UTR and a 60 bp 3'-UTR. Phylogenetic analysis shows that DjPreb belongs to PREB/PREB-like members. We examined its spatial and temporal expression and distribution in both intact and regenerating planarians by Relative quantitative real-time PCR and Whole-mount in situ hybridization. The analysis indicates that DjPreb shows a gradient of expression with peak levels present in the anterior and posterior regions and progressively lower levels in central regions in intact and regenerating planarians. During regeneration the expression of DjPreb is upregulated. Strong expression of DjPreb is observed in the anterior and posterior blastemas. These results suggest that DjPreb may participate in head and tail formation. PMID- 20198855 TI - Isolation, sequence identification and expression profile of three novel genes Rab2A, Rab3A and Rab7A from Black-boned sheep (Ovis aries). AB - Complete coding sequences of three Black-boned sheep (Ovis aries) genes Rab2A, Rab3A and Rab7A were amplified using reverse transcription polymerase chain reaction (RT-PCR) based on the conserved sequence information of cattle or other mammals known to be highly homologous to sheep ESTs. The Black-boned sheep Rab2A gene encodes a protein of 226 amino acids which contains the conserved putative RabL2 domain and is highly homologous to the Rab2A proteins of seven other species--cattle (96%), human (83%), Sumatran orangutan (82%), rat (81%), mouse (80%), African clawed frog (72%) and zebrafish (71%). The Black-boned sheep Rab3A gene encodes a protein of 220 amino acids that contains the conserved putative Rab3 domain and is very similar to the Rab3A proteins of four species--cattle (99%), African clawed frog (99%), Western clawed frog (98%) and zebrafish (95%). And the Black-boned sheep Rab7A gene encodes a protein of 207 amino acids that contains the conserved putative Rab7 domain and has high homology with the Rab7A proteins of six other species--human (99%), dog (99%), Sumatran orangutan (99%), zebrafish (97%), rabbit (97%) and African clawed frog (96%). Analysis of the phylogenetic tree has demonstrated that the Black-boned sheep Rab2A, Rab3A and Rab7A proteins share a common ancestor and the tissue expression analysis has shown that the corresponding genes are expressed in a range of tissues including leg muscle, kidney, skin, longissimus dorsi muscle, spleen, heart and liver. Our experiment is the first to provide the primary foundation for a further insight into these three sheep genes. PMID- 20198856 TI - ["Genes for mitochondria" in arterial hypertension and left ventricular hypertrophy]. AB - Study is devoted to "genes for mitochondria"--genes of mitochondrial genome and mitochondrial DNA polymerase gamma gene (POLG1). We compared frequencies of polymorphisms in mitochondrial DNA and in POLG1 between healthy individuals and patients with arterial hypertension, as well as between patients with and without left ventricular hypertrophy. We did not discover significant differences of distribution of C allele of MspI-polymorphism in POLG1 in studied group. We have shown higher prevalence of mitochondrial haplogroup H of mtDNA in patients without left ventricle hypertrophy (OR = 0.42; 95% CI 0.17-0.98; p = 0.043), while compared with patients having this complication. Haplogroup T was more frequently detected in patients with left ventricle hypertrophy (OR = 6.16; 95% CI 1.17-9.74; p = 0.018). This result suggest implication of mitochondrial DNA in hypertension-induced left venticular hypertrophy. PMID- 20198857 TI - [The CYP1B1 and CYP2F1 genes polymorphisms frequency in three ethnic groups of Bashkortostan and chronic obstructive pulmonary disease patients]. AB - Chronic obstructive pulmonary disease is a multifactorial respiratory disorder. Members of the cytochrome P450 family catalyze the oxidative metabolism of exogenous chemicals and activate their substrates into reactive intermediates that may initiate lung injury. The aim of this study was to learn interethnic variation in frequency distribution patterns of CYP1B1 and CYP2F1 genes polymorphic markers and to analyse its association withchronic obstructive pulmonary disease. The polymorphic markers Leu432Val(CYP1B1) and c.14_15insC(CYP2F1) were studied at chronic obstructive pulmonary disease patients (Russian (N=169), Tatar (N=137)) and cases of healthy individuals (Russian (N=191), Tatar (N=198) and Bashkir (N=78)), residents of Bashkortostan by PCR-RFLP method. It was shown that the CYP2F1 gene genotype frequency distribution patterns differed between three ethnic groups (chi2 = 21.29, df=4, P = 0.0001), because of high frequency of c.14_15insC/c.14_15insC genotype in Tatars (6.38%). On the other hand, high frequency (39.74%) of normal/ c.14_15insC genotype was appeared in Bashkirs. Association analysis of CYP2F1 geneinsertion variant with chronic obstructive pulmonary disease have shown high frequency (87.5%) of normal allele in Tatars patients with very severe stage and manifestation of chronic obstructive pulmonary disease after 55 years (chi2 = 3.964, df=1, P = 0.046; OR = = 2.268). It was shown that allele and genotype frequency distribution of Leu432ValCYP1B1 gene not differed between Russian, Tatar and Bashkir ethnic groups. We did not find any association of Leu432Val CYP1B1 gene with chronic obstructive pulmonary disease. PMID- 20198858 TI - [Screening efficient siRNAs in vitro as the candidate genes for chicken anti avian influenza virus H5N1 breeding]. AB - The frequent disease outbreaks caused by avian influenza virus not only affect the poultry industry but also pose a threat to human safety. To address the problem, RNA interference (RNAi) has recently been widely used as a potential antiviral approach. Transgenesis in combination with RNAi to specifically inhibit avian enza virus gene expression has been proposed to make chickens resistant to the infection. For the transgenic breeding, screening in vitro efficient siRNAs as the candidate genes is one of the most important tasks. Here, we combined an online search tool and a series of bioinformatics programs with a set of rules for designing siRNAs targeted towards different mRNA regions of H5N1 avian influenza virus. Five rational siRNAs were chosen by this method, five U6 promoter-driven shRNA expression plasmids containing the siRNA genes were constructed and used for producing stably transfected MDCK cells. The data obtained by virus titration, IFA, PI-stained flow cytometry, real-time quantitative RT-PCR, and DAS-ELISA analyses showed that all five stably transfected cell lines we re resistant to virusreplication when exposed to 100 CCID50 of avian influenza virus H5N1. Finally, most effective plasmids (pSi-604i and pSi-1597i) as the candidates for making the transgenic chickens were chosen. These findings provide baseline information on use of RNAi technique for breeding transgenic chickens resistant to avian influenza virus. PMID- 20198859 TI - [Mutations in the Sup35 gene impairs degradation of mRNA containing premature stop codons]. AB - Eukaryotic cells possess special mechanism of the degradation of mRNAs containing premature termination codons (PTCs)--nonsense-mediated mRNA decay (NMD) pathway. In yeast Saccharomyces cerevisiae the activity of this pathway depends on the recognition of the PTC by the translational machinery and interaction of translation termination factors eRF1 (Sup45) and eRF3 (Sup35) with Upfl, Upf2 and Upf3 proteins. Previously we have shown that decreasing of eRF1 amount causes an impairment of NMD. Here we show that sup35 nonsense and missense mutations lead to accumulation of PTC-containing transcripts such as his7-1 mRNA and CYH2 pre mRNA. Thus sup35 mutations do not only decrease translation fidelity but also influence mRNA stability. Remarkably, deletion of either UPF1 or UPF2 increased viability of sup35 mutants, while UPF3 deletion leads to decreased viability of sup35 mutants. PMID- 20198860 TI - [Lysogenic infection of a Shiga toxin 2-converting bacteriophage changes host gene expression, enhances host acid resistance and motility]. AB - Shiga toxin 2 (Stx2)-converting bacteriophages can infect and lysogenize other bacteria in vivo and in vitro, and, thus, contribute to a genotypic heterogeneity of infected host. However, the global transcription patterns accompanying the lysogenic infection of E. coli host have not been clearly resolved. In this study, gene expression profiles of Stx2 phage phi Min27(delta stx::cat) converted and native E. coli MG1655 hosts were compared using microarray assay. The phi Min27(delta stx::cat) conversion had a direct effect on the global expression of bacterial host genes as 166 genes were found to be differentially expressed (104 up-regulated and 62 downregulated). These genes were predominantly responsible for bacterial central metabolism, transport and transcription. It was shown that in addition to the down-regulation of genes involved in synthesis of thiamine and protein transporters, expression of genes associated with bacterial energy production (e.g., fadABDEHIJL, aceK, and acnA) was also suppressed. Conversely, most up-regulated genes were transport genes, flagellar synthesis genes (fliDESTZ), and acid resistance genes (e.g., gadEW, hdeABD, and adiY). Futhermore, conversion of phi Min27(delta stx::cat) was shown to change physiological properties of the host cell. In comparison with the uninfected cells the converted bacteria host had increased acid tolerance and promoted swimming motility on a semisolid agar surface. PMID- 20198861 TI - [Expression of the starfish complement component C3 gene homologue under the influence of bacterial lipopolysaccharide]. AB - The fragment of a homologue of complement component C3 gene has been cloned and sequenced from the starfish, Asterias rubens. Phylogenetic analysis of ArC3-like gene demonstrates that ArC3-like gene has close similarity to C3 gene homologues of Deuterostomia invertebrate animals. High level of ArC3-like gene expression was identified in circulating cells (coelomocytes), in a gut's derivate (hepatopancreas) and in male gonada but not in stomach, female gonad and rectal gland of A. rubens starfish. ArC3-like gene expression was shown in all types of starfish coelomocytes: in lymphocyte-like cells, granular and nongranular amebocytes. Injection of bacterial lipopolysaccharide (LPS) solution into the coelomic cavity of starfish leads to the increase of ArC3-like gene expression in coelomocytes and hepatopancreas over the control level of sterile sea water injection. The level of ArC3-like gene expression increased in response to LPS reaching the maximum 6 h after the stimulation, and decreased to basal level 24 h after the stimulation. Injection of LPS solution stimulated the increase of ArC3 like gene expression level in hepatopancreas reaching the maximum 6-12 h after the stimulation, and the level of mRNA of ArC3-like gene had still been increased 48 h after LPS injection. The data demonstrates sustained positive regulation of ArC3-like gene expression under the influence of LPS. PMID- 20198862 TI - Molecular cloning, characterization, and expression of the endothelial differentiation-related factor-1 (EDF-1) in Gekko japonicus. AB - Full-length cDNA of the Endothelial Differentiation-related Factor-1 (EDF-1) of Gekkojaponicus was obtained by the method of rapid amplification of cDNA ends polymerase chain reaction (RACE-PCR). EDF-1 is 1025 bp in length and contains an open reading frame (ORF) corresponding to a deduced protein of 148 amino acids. The molecular mass of the predicted protein is 16.28 kDa and its theoretical isoelectric point is 9.87. Its amino acid sequence shares 57-93% similarity with EDF-1 of a number of other species. Gecko EDF-1 is expressed in most gecko tissues examined including the brain, spinal cord, liver, and kidney, with higher levels in the last two. In situ hybridization (ISH) revealed that positive hybridization signals were present in both the gray and white matter of the spinal cord. PMID- 20198863 TI - [Human ribosomal protein S16 inhibites excision of the first intron from its own]. AB - Recombinant human ribosomal protein S16 (rpS16) is shown to bind specifically to a fragment of its own pre-mRNA that includes exons 1 and 2, intron 1, and part of intron 2, and to inhibit the splicing of the fragment in vitro. The weaker binding of other recombinant human ribosomal proteins, S10 and S13, to this pre mRNA fragment indicated that the binding of rpS16 was specific. Besides, poly(AU) and rpS16 mRNA fragment affected poorly the binding of rpS16 to its pre-mRNA, providing another evidence that the interaction was specific. RpS16 specifically inhibited the pre-mRNA fragment splicing whereas recombinant rpS10 and rpS16 did not affect excision of intron from this pre-mRNA fragment in contrast to rpS16. Those positions in rpS16 pre-mRNA fragment that were protected by rpS16 against cleavage by RNases T1, T2 and V1 were found to be located closely to the branch point and 3' splice site in the pre-mRNA. Results obtained support the possibility of the autoregulation of rpS13 pre-mRNA splicing through feedback mechanism. PMID- 20198864 TI - [The CCNB1, HER2, and PKC silencing induced by small interfering RNA decreases a division of different human cancer cells with interfering RNA decreases a different efficiency]. AB - An abnormality in expression of genes encoding proteins responsible for the cell cycle regulation frequently results to a malignant cell transformation and switches the cellular program from differentiation and apoptosis to continuous cell division. To evaluate therapeutic potential resulted from silencing gene expression of key cell circle regulators in different human cancer cells the siRNAs targeted to HER2, protein kinase C (PKC), and cyclin B1 (CCNB1) mRNAs were used. An effective and specific reducing the CCNB1, HER2 or PKC mRNA level was observed through 48 h after the siCycB1, siHER2 or siPKC transfection, respectively. The HER2, PKC, and CCNB1 gene silencing substantially reduced a growth rate of the cell lines, except HL-60, but did not affect the cell death and apoptosis. The best cell division inhibition was induced by the siCycB1 in SK N-MC cells and by the siPKC in MCF-7 cells. The data obtained suggest the siRNAs selected inhibit the cell division, and the genes investigated may be used as effective targets for curing oncologic diseases. PMID- 20198865 TI - [Characterization of hepatitis C virus structural proteins and HCV-like particles produced in recombinant baculovirus infected insect cells]. AB - Three proteins, namely: "core" protein C and glycoproteins E1 and E2, are main structural proteins forming a hepatitis C vius (HCV) virion. The virus structure and assembly, a role of the structural proteins in virion morphogenesis remain unknown because of the lack of an efficient culture system for HCV to be grown in vitro. Using recombinant baculoviruses expressing HCV structural protein genes in insect cells the specific structural proteins at the level of 25-35% relative to a common cell protein content, heterodimers of the glcoproteins, and HCV-like particles have been obtained. It has been demonstrated that recombinant proteins C, E1, and E2 go through the posttranslation modification, the glycoproteins form the non-covalent heterodimer, and HCV-like particles are located in endoplasmatic reticulum membrains of infected cells. An ability of the expressed proteins for forming E1E2 dimers and HCV-like particles was used for studying the role of E1 protein glcosylation upon expression and processing of the glycoproteins. PMID- 20198866 TI - [Protein structure prediction from analogy. III. Optimization of a combination of substitution matrices and pseudo-potentials used to align protein]. AB - We describe a general and fast method of maximization of a "recognition ability" of a linear combination of an arbitrary number of various methods used to recognize protein structures and produce the sequence-to-structure alignments. It is shown that, at a low level of sequence similarity, the optimal combined method has a significantly higher "recognition ability" than each of participating separate method, the leading role in this combination being played by (1) pseudo potentials of long-range interactions; (2) matrices of secondary structure similarity; and, finally, (3) amino acid substitution matrices. As to a high level of sequence similarity, here the leading and virtually the sole role in the optimal combination is played by substitution matrices, although admixture of pseudo-potentials of long-range interactions and matrices of secondary structure similarity somewhat increases the "recognition ability" of the combined method. PMID- 20198867 TI - [TEpredict: software for T-cell epitope prediction]. AB - A program named TEpredict was developed for T-cell epitope prediction. Original models for T-cell epitope prediction were constructed by means of Partial Least Squares regression method on the basis of data, extracted from the IEDB (Immune Epitope Database)--the most complete resource of experimental peptide-MHC binding data known to date. TEpredict is also able to predict proteasomal processing of protein antigens, and the ability of produced oligopeptides to bind to TAP (Tansporters Associated with Processing). TEpredict could exclude peptides, shearing local similarity with human proteins, from the set of predicted T-cell epitopes. It is also able to estimate expected population coverage by selected peptides, using known HLA allele genotypic frequencies data. The majority of produced models demonstrated high sensitivity of predictions (0.50-0.80) concurrent with high specificity (0.75-0.99). TEpredict was shown to be highly competitive or even superior in comparison with such programs as ProPred1, SVRMHC, SVMHC and SYFPEITHI. TEpredict demonstrated high quality of predictions and we expect that it could become a useful tool in the development ofpolyepitope vaccines against dangerous human pathogens, including HIV, influenza etc. The program and its source code could be freely downloaded from the project web-site: http://tepredict.sourceforge.net. PMID- 20198868 TI - [Attenuation regulation of amino acid and amino acyl-tRNA biosynthetic operons in bacteria: comparative genomics analysis]. AB - We performed a large-scale search for attenuation regulation in bacteria based on two original computer programs modeling attenuation regulation and multiple alignment along a phylogenetic tree. The programs are available from http://lab6.iitp.ru. Candidate attenuations are predicted in many bacteria from alpha-, beta-, gamma-, delta-proteobacteria, Actinobacteria, Bacteroidetes/Chlorobi, Firmicutes and Thermotogae; in Cloroflexi--upstream genes hisG, hisZ, hisS, pheA, pheST, trpEG, trpA, trpB, trpE, trpS, thrA, thrS, leuA, leuS, ilvB, ilvI, ilvA, ilvC, ilvD, ilvG. Other bacterial taxa were not predicted to have attenuation; searches were conducted across all bacterial genomes contained in GenBank, NCBI. Evolution of attenuation is discussed. PMID- 20198869 TI - [Construction of protein semantic networks using PubMed/MEDLINE]. AB - Method is described to produce the protein semantic networks based on the information from PubMed/MEDLINE. In this work we used semantic score to assess the connectivity between two proteins based on the number of shared relevant or related articles. Using such score we created the semantic network for 150 human proteins belonging to different metabolic pathways. Analysis of the network has shown that proteins involved into the same molecular processes were separated into distinct subgraphs. PMID- 20198870 TI - [Quaternary structure formation by recombinant analogues of spider silk]. AB - A study has been conducted on the morphology of artificial spider silk fibers, prepared from recombinant analogues of spiridons 1 and 2. It has been shown that by stretching out the "as spun" fiber, a reorganization of its spongy matrix occurs, which leads to the formation of microfibrills, followed by a reduction of the diameter of the fiber. The durability of an artificial fiber depends on the degree of stretching and on the substructure of the microfibrills. The model process of artificial fibers preparation reproduces to the great detail the natural process of spider web spinning. Future applications of this model include production of biomaterials with unique properties. PMID- 20198871 TI - [CpG-methylation in Helicobacter pylori genome: high methionine concentration impact]. PMID- 20198872 TI - The use of the ccdB lethal gene for constructing a zero background vector in order to clone blunt-end PCR products. PMID- 20198873 TI - [RNA editing in eukaryotic genome expression]. AB - The present review surveys the available data on the involvement of adenine deamination in RNA molecules in the formation of structurally and functionally diverse RNA and protein subforms in eukaryotic cells. Deamination of adenine by adenosine deaminases that act on RNA (ADARs) leads to the conversion of adenine into inosine (A-I editing) recognized by the splicing and translation systems as guanine. This may modify splicing sites in pre-mRNA and codons in translated regions ofmRNA and also affect the RNA secondary structure. Apart from mRNA, editing also involves microRNAs whose regulatory functions in multicellular animals are associated with the inhibition of transcription of target genes or with the degradation of certain RNA transcripts. ADARs can inhibit the production of mature microRNAs or modify microRNAs so that their specificity to target genes is altered. Adenosine deaminases editing adenines in transport RNAs (ADATs) convert adenine into inosine in tRNAs of all eukaryotes; as a result, the diversity of tRNA forms in the cell increases. PMID- 20198874 TI - [Establishment of a new continuous cell line of Drosophila melanogaster strain infected by the intracellular endosymbiotic bacterium Wolbachia pipientis under natural conditions]. AB - Wolbachia pipientis is an obligately intracellular bacterium infecting a number of arthropod and nematode species. At the body level, Wolbachia infection may cause parthenogenesis, feminization of genetic males, male killing, or cytoplasmic incompatibility; it may also be asymptomatic. Of special interest is DNA transfer from Wolbachia to the host insect genome, which was discovered recently. At the cellular level, the effects caused by Wolbachia have been studied more poorly. Only one of the known insect cell lines has been obtained from an insect species (the mosquito Aedes albopictus) infected by Wolbachia. In this study, a continuous cell line Dm2008Wb1 has been obtained from embryos of Drosophila melanogaster infected under natural conditions. Wolbachia both persists in a primary cell culture and is retained upon its transformation into a continuous culture. The presence of this bacterium in cells in a free form is evidenced by the fact that tetracycline treatment can cure the cells of Wolbachia and by successful transfer of Wolbachia to another cell line (S2), where it has not been detected before. PMID- 20198875 TI - [Effects of functional interactions between nonhomologous insulators Wari and Su(Hw)]. AB - Insulators are regulatory DNA elements restricting gene activation by enhancers. Interactions between insulators can lead to both insulation and activation of promoters by enhancers. In this work, we analyzed the effects of interaction of two Drosophila insulators, Wari and Su(Hw). The functional interaction between these insulators was found to enhance the activity of the Su(Hw) insulator only, but not of the Wari insulator. This suggests that the formation of a chromatin loop between interacting insulators is not a key factor for enhancement of insulation, which is in disagreement with the main idea of structural models. In addition, the effect of interaction between Wari and Su(Hw) depends on a distance between them and on the position in the system relative to other regulatory elements. PMID- 20198876 TI - [Pseudolysogeny of Pseudomonas aeruginosa bacteria infected with phiKZ-like bacteriophages]. AB - In this work, a final piece of evidence proving that bacteria Pseudomonas aeruginosa are capable of transition to the pseudolysogenic state after infection with phiKZ-like phages has been produced. It was shown that the decisive factor in this process is multiple infection of bacteria with bacteriophages belonging to this genus. In the course of this work, stable clinical isolates of bacteria liberating novel bacteriophages of this genus (Che2/2 and Che21/5) were detected and attributed to species phiKZ and EL, respectively, according to their phenotypic characters and the results of DNA analysis. For three bacteriophages belonging to species EL (EL, RU, and Che21/5), mutants with disorders in the capability for pseudolysogenization were isolated. One of the mutants of phage EL possesses properties of virulent mutants of typical temperate phages (vir mutant). This mutant fails to form pseudolysogens and, moreover, provides the effect of dominance upon coinfection of bacteria with the wild-type phage EL, but however is unable to exhibit this effect upon joint infection of bacteria with wild-type phages of species phiKZ and Lin68. It is assumed that the effect of pseudolysogeny may be connected with functioning of phiKZ and EL genes that control the products similar to repressors of other phages. Because earlier wild type phiKZ-like phages were shown to be present in commercial phage-therapeutic preparations (which represents certain problems), it is expedient to use virulent mutants of phages belonging to this genus rather than phages of the wild type. PMID- 20198877 TI - [Characterization of the transfer-related tra region of the conjugative plasmid p19 from a Bacillus subtilis soil strain]. AB - The nucleotide sequences of three DNA fragments (total size 30574 bp) of the plasmid p19 from the Bacillus subtilis 19 soil strain have been determined. Thirty open reading frames (ORFs) have been identified in these fragments. oriT of the plasmid has also been identified. As shown by the search for homologs of hypothetical protein products of these ORFs in databases, such homology exists for 18 ORFs. The protein products of nine ORFs can be assumed to have specific functions. Several ORFs were inactivated via insertional mutagenesis, and the conjugation capacity of the mutant plasmids was estimated. According to the data on homology of protein products and the results of ORF inactivation, regions of a total size of about 20 kb from the DNA fragments sequenced by us were inferred to belong to the tra region of p19. As follows from the analysis of the identified ORFs of the p19 tra region, it differs from the earlier described tra regions of other plasmids, irrespective of a certain similarity with the corresponding regions of plasmids of gram-positive bacteria from the genera Bacillus, Clostridium, and Listeria. PMID- 20198878 TI - [Using IRAP markers for analysis of genetic variability in populations of resource and rare species of plants]. AB - Species-specific LTR retrotransposons were first cloned in five rare relic species of drug plants located in the Perm' region. Sequences of LTR retrotransposons were used for PCR analysis based on amplification of repeated sequences from LTR or other sites of retrotransposons (IRAP). Genetic diversity was studied in six populations of rare relic species of plants Adonis vernalis L. by means of the IRAP method; 125 polymorphic IRAP-markers were analyzed. Parameters for DNA polymorphism and genetic diversity of A. vernalis populations were determined. PMID- 20198879 TI - [Global diversity of durum wheat Triticum durum desf. for alleles of gliadin coding loci]. AB - Genetic diversity for the alleles of gliadin-coding loci was studied with 465 durum wheat cultivars from 42 countries. A total of 108 alleles were identified for four loci; 60 alleles were described for the first time. Broad diversity of rare gliadin-coding alleles was observed. The highest genetic diversity was characteristic of durum wheat cultivars from the Middle East, Trans-Caucasia, the Pyrenean Peninsula, and the Balkans. Two genetically isolated ancient branches were isolated. A southern branch included mostly cultivars from the Mediterranean region, the Middle East, and Trans-Caucasia. A northern branch included Russian and Ukrainian durum wheat cultivars and varieties obtained on their basis. An additional group included durum wheat cultivars that had been obtained in several past decades on the basis of the material of international breeding centers (CIMMYT and ICARDA) and had low genetic diversity. PMID- 20198880 TI - [Analysis of the marker and target genes inheritance in the seed and vegetative progeny of transgenic tobacco with buckwheat serine protease inhibitor gene]. AB - The stability of marker nptII and target gene of serine proteinase inhibitor BWI 1a (ISP) from buckwheat seeds after agrobacterial transformation in the new foreign genome environment has been investigated. Different vegetative and seed progeny of self-pollinated transgenic tobacco was studied after propagation at selective and nonselective in vitro conditions. For the majority of transgene lines among random sample of independent transgenic plants stable and coupled PCR confirmed inheritance and expression of marker and target genes has been demonstrated after prolonged microcutting and repeated regeneration cycles at unselective in vitro conditions. The most of the seed T1 progeny of the studied lines has maintained Km-resistance too. However all transgenic lines had significant disturbances at the microsporogenesis process. Two lines (C5 and C12) after 4-year microcutting lacked Km-resistance and at the same time lacked their antibacterial activity. Two other clones revealed variability in Km-resistance (line C7) and seedlings size (line C22) that might be a result of more than 1 transgene insertion or chimaeric nature of transgene plants so it require an additional study. PMID- 20198881 TI - Development of boron-efficient near isogenic lines of Brassica napus and their response to low boron stress at seedling stage. AB - Rapeseed (Brassica napus) is sensitive to low boron (B) stress and plentiful variation exists in response to B deficiency. One major QTL, BE1, and three minor loci controlling B efficiency in Brassica napus were previously detected. To fine map and clone the B-efficient gene (s), the development of B-efficient NILs in Brassica napus was conducted, combining the identification of B efficiency at seedling stage with genetic background selection using random AFLP markers. The molecular marker assisted background selection proved its optimum and necessary in an early backcrossing generation to select the backcross individuals with high genetic background similarity to accelerate the construction of NILs. Based on B efficiency investigated at seedling stage under the low B conditions, the B efficient backcross line can produce biomass twice about the B-inefficient parent's and show low B concentration and effective utilization of B under low B condition. Thus, the B efficiency of the B efficient NILs might be attributed to the higher B utilization efficiency or less demand for B. PMID- 20198882 TI - [Intraspecific structure of sable Martes zibellina inferred from nucleotide variation of the mitochondrial DNA cytochrome b gene]. AB - A fragment of the mitochondrial DNA (mtDNA) cytochrome b gene was sequences in sable from Magadan oblast, Khabarovsk krai, and Kamchatka. Using phylogenetic analysis, the presence of two clusters (A and BC), with the divergence value of 1.4%, was demonstrated. Analysis of the cytochrome b gene median networks indicated that split of the ancestral population took place in early Pleistocene (about one Myr ago), while expansion of its more young phylogenetic group A occurred in late Pleistocene, about 120,000 years ago. PMID- 20198883 TI - [Phylogenetic analysis of smelts (Osmeridae) based on the variation of cytochrome b gene]. AB - Putative phylogenetic relationships between all smelt species inhabiting Russian waters were studied using RFLP and the data on divergence between nucleotide sequences of the mitochondrial gene encoding cytochrome b. All types of phylogenetic trees (NJ, MP, and Bayesian) displayed stable clustering into isolated groups corresponding to the division of the subfamily Osmerinae into three genera, Mallotus, Osmerus, and Hypomesus. It was demonstrated that the Mallotus phylum was the first to diverge from a hypothetical common ancestor of the smelts. Later, it divided into two clusters corresponding to the modern subspecies Mallotus villosus villosus and M. v. catervarius. The phylum of the genus Osmerus diverged later than the genus Mallotus and also divided into two clusters, one including O. mordax of the Pacific (Sea of Japan) and Arctic (Kara and Barents Seas) basins and the other, anadromous and resident ecotypes of the O. eperlanus from the Baltic Sea basin. The smelts of the genus Hypomesus is the youngest phylogenetic group among the taxa studied; it forms three individual clusters matching the species H. olidus, H. nipponensis, and H. japonicus. The proposed phylogenetic hypothesis is discussed from the standpoint of its compliance with the phylogenetic constructions based on the external morphological and osteological traits. PMID- 20198884 TI - STAT5A/AvaI restriction polymorphism in cows of Polish red-and-white variety of Holstein Friesian breed. AB - The study on polymorphism within the STAT5A gene (transition C6853T) was conducted using the PCR-RFLP method and AvaI restrictase. The study covered a herd of 723 cows of the Polish Red-and-White variety of Holstein Friesian breed, kept for dairy purposes in the Opole region, Poland. Two alleles (C and 7) of the analyzed STAT5A polymorphism were found in the studied herd. The alleles determined the occurrence of two genotypes: CC and CT. The homozygous TT genotype was not found. The STAT5A/AvaI allele frequencies were as follows: C--88.31% and T--11.69%, whereas the genotype frequencies were 76.6% for CC and 23.4% for CT. The analysis of associations between the STAT5A/AvaI polymorphism and milk utility traits considered in the study showed that these traits were different in animals with different STAT5A/AvaI genotypes. PMID- 20198885 TI - Variation of 18 STR loci in Shahabadi sheep of India. AB - Shahabadi sheep represent an important but uninvestigated source of genetic diversity. Eighteen microsatellite markers were employed to analyze the genetic diversity of Shahabadi sheep population found in Bihar, India with fifty samples. Microsatellites were highly polymorphic with a mean allelic number 5.56 +/- 1.79. The observed heterozygosity, expected heterozygosity and observed and effective number of alleles were used to estimate the genetic variation of this breed. The observed heterozygosity in the population varied from 0.279-0.739 with the mean of 0.501 +/- 0.151, reflecting substantial genetic variation in this population. Population was observed to be heterozygote deficient (21.5%). The results of this study indicated that conservation of genetic variation in Shahabadi population should be considered by breeders, in the interest of long term future of the breed in its native tract. PMID- 20198886 TI - [Expression of the FOSL1 gene in psoriasis and atherosclerosis]. AB - Psoriatic and atherosclerotic plaques were examined using the real-time polymerase chain reaction. Expression of the FOSL1 gene proved to substantially increase in both psoriatic lesions of the skin and atherosclerotic lesions of vessels as compared with nonlesion samples. PMID- 20198887 TI - [Association of interleukin-13 gene polymorphisms with atopic bronchial asthma]. AB - A comparative analysis of allele and genotype distribution of C(-1055)T and R130Q IL13 gene polymorphisms has been performed in Russian patients from the Moscow region. In the study, 283 DNA specimens of atopic bronchial asthma (BA) patients and 227 DNA specimens of healthy donors were used. No association of these markers with ABA development as well as with total IgE concentration has been found. Haplotype frequency analysis did not reveal significant difference between samples. However, significant association ofC(-1055)Tpolymorphism with the disease severity has been revealed (OR = 2.39, 95% confidence interval 1.44-3.98, p = 0.001). Therefore, C(-1055)T polymorphism was shown to be associated with atopic BA progression. PMID- 20198888 TI - [Analytical estimation of the power of linkage in large pedigrees]. AB - Different approaches to calculation of the power in linkage analysis whose efficiencies have been demonstrated in small pedigrees are described. The possibility of applying them to large pedigrees has been estimated. Equivalence of the analytical estimates of power obtained using different approaches based on analysis of individual pairs of relatives has been shown. The accuracy of the resultant analytical estimation of the power has been analyzed for three large pedigrees and a wide range of inheritance models; the accuracy has been demonstrated to be sufficiently high and equal to the accuracy in the case of small pedigrees. PMID- 20198889 TI - [Identification of the barley accessions to serve as donors of thermostable beta amylase alleles]. AB - Molecular analysis was performed with 88 barley accessions, including varieties cultivated in Belarus and those obtained from the collection of the All-Russian Institute of Plant Industry (IPI). A marker directed to the single nucleotide substitution (SNP) C698 --> T of the Bmy1 beta-amylase gene showed that the Sd2H and Sd3 alleles were absent from the Belarussian varieties. Five accessions with the Bmyl1 alleles determining thermostable isoforms of beta-amylase I were identified among the accessions from the IPI collection. PMID- 20198890 TI - [Silencing of the nk1 gene in the SR1 Nicotiana tabacum plants by RNA interference]. AB - Primary transformants of SR1 Nicotiana tabacum plants with RNA interference-based silencing of the gene for extracellular ribonuclease Nk1 were constructed. It was demonstrated that the profiles of ribonuclease activities of leaf protein extracts from these plants lacked ribonuclease with electrophoretic mobility corresponding to that of the Nk1 protein. Primary transformants did not differ phenotypically from control plants. They represent a new model for investigation of the biological role of extracellular ribonucleases, including the molecular mechanisms of resistance to pathogens. PMID- 20198891 TI - [Analysis of changes in the population genetic parameters of Afanas'evo raion of Kirov oblast with time]. AB - The results of two studies on the population genetic structure of Afanas'evo raion of Kirov oblast are compared. The changes that have occurred during two decades are insignificant. PMID- 20198893 TI - [Molecular diagnosis of hepatitis C and hepatitis B infection]. AB - Molecular methods are a well-established part of routine diagnostic work-up in patients infected with hepatitis B virus (HBV) and hepatitis C virus (HCV). Confirmation of active viral replication in infected patients is based on detection and/or quantification of viral genome in serum by molecular assays. Diagnostic algorithm for hepatitis C includes detection and/or quantification of HCV RNA in serum of infected patients and HCV genotyping. Diagnostic work-up in patients with hepatitis B includes quantification of HBV DNA in serum, HBV genotyping, and determination of resistance to nucleoside and nucleotide analogues. Real-time polymerase chain reaction (PCR) is the standard recommended molecular method for quantification of HCV RNA and HBV DNA in clinical samples. Due to superior sensitivity, real-time PCR assays can provide both qualitative detection of viral genome and quantification. Molecular diagnosis of HCV and HBV infections in clinical laboratories should be limited to certified standardized assays. PMID- 20198892 TI - [Viral hepatitis. Croatian consensus conference--2009]. AB - Summarized text of Croatian Consensus Conference on Viral Hepatitis of 2009 comprises the following chapters: 1) Epidemiology, 2) Clinical Picture, 3) Diagnostic Procedure, 4) Aims of Treatment of Viral Hepatitis, 5) Terminology, 6) Medicaments (6.1. Interferon, 6.2. Analogues of Nucleozides and Nucleotides), 7) Hepatitis B (7.1. Serologic and Molecular HBV Diagnostics, 7.2. Terminology, 7.3.Whom to Treat? 7.4. Therapy), 8) Hepatitis C (8.1. Serologic and Molecular HCV Diagnostics, 8.2. Terminology, 8.3. Whom to Treat? 8.4. Therapy). Clinical, laboratory and histologic assessment of patients with chronic viral hepatitis (algorythm of pretherapeutic treatment; histologic evaluation) and notions related to therapy of viral hepatitis (category of the patient and category of the response to treatment) are presented in related tables. PMID- 20198894 TI - [Assessment of hepatic injury in patients with chronic viral hepatitis]. AB - The management and prognosis of chronic viral hepatitis greatly depend on the extent and progression of liver fibrosis. Although liver biopsy is still considered as the gold standard to evaluate hepatic fibrosis, it is an invasive procedure with rare but potentially severe complications. It is also prone to sampling errors. These limitations have stimulated the search for new noninvasive approaches. A number of noninvasive techniques such as indirect or direct markers and measurement of liver stiffness using transient elastography have been proposed for the assessment of hepatic fibrosis. The performance of simple tests derived from routine laboratory parameters appears to be similar to that of more complex and expensive fibrosis panels. Transient elastography seems to be more accurate than blood tests for diagnosing cirrhosis. The goal of disease specific, accurate and sensitive markers of fibrosis is worth the effort. The true success in such an attempt can be characterized as hopeful; however, these noninvasive methods can be anticipated to become an important tool in clinical practice. PMID- 20198895 TI - [Monitoring patients with chronic hepatitis during and after therapy]. AB - Chronic viral hepatitis C and B are one of the major public health and medical problems. Both viruses cause life threatening liver diseases, i.e. cirrhosis, liver failure and hepatocellular carcinoma (HCC). Effective treatment for both hepatitis B and hepatitis C to reduce the rate of adverse outcomes is now available. There is no recommendation for mass screening for HBV and HCV in the general population but only in the high risk groups. There is wide availability of diagnostic tests for HCV and HBV infection with high sensitivity and specificity. Prior to therapy initiation, serum HCV RNA by quantitative assay and HCV genotype should be determined. Liver biopsy is performed to assess the disease severity, not always including genotype 3. Response to antiviral therapy should be assessed by AST, ALT and qualitative HCV RNA, and in patients with liver cirrhosis early detection of HCC by alpha fetoprotein, ultrasound, CT, or MR should be done every 6 months. Chronic HCV infection with cirrhosis and HCC is the leading indication for liver transplantation. The current hepatitis B vaccination policy is universal neonatal vaccination. HBsAg, HbBeAg and antiHBe positive patients should be qualitatively tested for HBV DNA and liver biopsy is performed according HBV DNA level. Patients are treated with interferon and nucleos(t)ide analogues. Treated patients should be tested for HBsAg, HBeAg and HBV DNA every 3 and 6 months. The optimal duration of therapy for oral drugs is not well established and life long treatment is generally recommended. Chronic HBV infection is the leading cause of HCC and its early detection is essential. Liver transplantation is successfully performed for HBV cirrhosis, liver failure and HCC. Patients with HBV/HDV, HBV/HCV or HIV/HBV/HCV co-infection should be treated accordingly. TTV, GBV-C and HEV hepatitis do not cause chronic liver diseases. PMID- 20198896 TI - [Hepatitis B: who should be treated?]. AB - Current therapy for hepatitis B has a limited effect and can rarely eradicate viral infection (normalization of ALT, nullification of HBV DNA, or seroconversion of HBsAg to anti-HBs). Progress in hepatitis B therapy over the last 5 years did not have much influence in this segment. Modifications in therapeutic indications for both acute and chronic hepatitis B presented below are based on standings of the Consensus Conference of the American National Institutes of Health (NIH) from 2008, Canadian Consensus Conference from 2007, and Consensus Conference of the European Association for the Study of the Liver (EASL) from 2009. It seemed appropriate to retain the division of treatable patients in 3 groups: 1) patients in whom therapy is indicated; 2) patients in whom therapy may be indicated; and 3) patients in whom immediate therapy is not routinely indicated, as stated in the guidelines of the 2002 EASL Consensus Conference, 2004 Croatian Consensus Conference and 2008 NIH Consensus Conference. PMID- 20198897 TI - [Chronic hepatitis B therapy]. AB - Chronic hepatitis B is associated with the development of cirrhosis in more than one third of patients and in a large proportion of patients with hepatocellular carcinoma. Current standard treatment includes pegylated interferon alfa-2a and five oral nucleoside/nucleotide analogues: entecavir, tenofovir, adefovir, telbivudine and lamivudine (listed according to antiviral efficacy). The advantage of interferon treatment is the possibility of long-term remission in one third of carefully selected HbeAg+ patients without development of resistance. However, interferon treatment is not efficient in the majority of patients. The advantage of treatment with nucleoside and nucleotide analogues is the possibility to suppress HBV DNA to undetectable levels in 70%-90% of patients. However, analogue treatment is a long-term treatment (possibly life long) and is associated with the development of resistance. PMID- 20198898 TI - [Hepatitis B virus and chronic progressive kidney disease]. AB - The prevalence and incidence of hepatitis B virus (HBV) infection in end-stage renal disease patients has significantly decreased over the past few decades. HBV infection in dialysis patients presents a distinct clinical problem in view of the immunosuppressive effect of renal failure, susceptibility to de novo infection and nosocomial transmission, long-term implications on morbidity and mortality, and change in clinical course after kidney transplantation. In order to prevent nosocomial transmission, standard precautionary measures must be rigorously followed. In addition to these standard precautions, measures specific to hemodialysis units are also important to prevent nosocomial HBV infection. Hepatitis B vaccination of patients and medical personnel is important both to prevent susceptible patients from acquiring HBV and to reduce the pool of HBV infected patients. Decisions on the treatment of chronic HBV infection are based in part upon an accurate assessment of the presence or absence of virus replication and active liver disease. Optimal therapy may involve the administration of interferon-alfa, nucleotide or nucleoside analogues, combination therapy, liver transplantation, or only observation. In patients infected with HBV that undergo kidney transplantation, the use of a preventive or preemptive approach is recommended to reduce the risk of HBV reactivation post transplantation. The prophylactic strategy includes the administration of antiviral agents to patients at an increased risk of developing HBV reactivation either prior to or immediately after transplantation. The preemptive strategy includes periodic post-transplantation monitoring for viremia with prompt treatment upon detection and/or increase in HBV DNA levels. HBV infection may be directly associated with a variety of renal diseases, including polyarteritis nodosa, membranous glomerulonephritis and membranoproliferative glomerulonephritis. In the patient suspected of having renal disease associated with HBV, testing for HBV DNA is recommended to confirm active viral replication and kidney biopsy to confirm the presence of an underlying glomerular process, or biopsy at another tissue site to confirm polyarteritis nodosa. It is recommended to treat these patients with an antiviral agent using appropriate dose adjustment for the level of kidney function. In patients with associated vasculitis or rapidly progressive glomerulonephritis, a short course of glucocorticoids may be considered. PMID- 20198899 TI - [Hepatitis C--who should be treated?]. AB - All patients with hepatitis C virus (HCV) infection should be considered as candidates for antiviral therapy. In order to make decision whom to treat, it is necessary to evaluate the following parameters: stage of disease, comorbidity, patient age, contraindications and therapy risks. Therapy is strongly recommended in patients with acute infection, with elevated ALT levels, with normal ALT level and F > or = 2 METAVIR score, in non-responders to standard interferon monotherapy, in relapsers to antiviral therapy, in patients with compensated cirrhosis, and in hemodialysis patients. It is possible to treat patients with persistent normal ALT levels and without fibrosis, patients with HBV and HIV co infection, patients with severe extrahepatic manifestations of HCV infection, and patients with liver transplant. Drug addicts and alcoholics can be treated after 6 months of abstinence, but also with supportive therapy. Therapy is not recommended in patients with fulminant hepatitis, kidney transplant recipients and pregnant women. PMID- 20198900 TI - [Treatment of naive patients with chronic hepatitis C]. AB - According to published data, 60% of hepatitis C virus (HCV)-infected patients in Croatia have HCV genotype 1. The second most common genotype is 3a (36%). Standard treatment regimen for patients with chronic hepatitis C is a combination of pegylated interferon alfa (2a or 2b) with ribavirin, in duration guided by genotype: patients with genotype 1 are treated for 48 weeks and patients with genotypes 2 and 3 for 24 weeks in order to achieve virus elimination defined as HCV RNA undetectability 24 weeks after the treatment period (SVR). These treatment regimens fail to achieve SVR in 50% of patients with genotype 1 and 25% of patients with genotype 3. On the other hand, patients with low viral load (<600 000 IU HCV RNA/mL) and rapid viral response (RVR) could benefit from shortened treatment. Recent studies and meta-analyses have shown the importance of liver fibrosis, viral kinetics and viremia as predictors of SVR. Currently, treatment of chronic hepatitis C should be individualized (treatment guided) according to the genotype, liver fibrosis, early viral kinetics and viremia. In patients with genotype 1 who are late responders (pEVR), therapy should be prolonged to 72 weeks in order to achieve 12% better SVR. In patients with genotype 2,3 with low viremia who are rapid responders (RVR+), therapy can be shortened to 16 weeks. Patients with higher fibrosis rates (presence of fibrotic septa) should not be treated according to the level of viremia, as it has been shown that viremia does not correlate with SVR in these patients. Liver biopsy is still recommended in the pretreatment evaluation protocol for its prognostic features. In patients with acute hepatitis C, treatment should be started if HCV RNA is still present at week 12. The suggested treatment regimen is monotherapy with pegylated interferon alfa (2a or 2b) for 24 weeks. PMID- 20198901 TI - [Retreatment options for patients with chronic hepatitis C]. AB - Despite impressive therapy improvements, there still are a huge proportion of patients that will fail to achieve undetectable HCV. On the other hand, not all patients that demonstrate some response to treatment attain a sustained viral response. Patients with HCV non-response can be classified into several groups: 1) non-response (where the patient does not achieve undetectable HCV RNA at any time); 2) partial response (when the patient experiences some drop in HCV viremia but never below the detectable limit); 3) viral breakthrough (those associated with an initial virologic response, which is subsequently lost during treatment); and 4) relapse (those with an initial virologic response, which is lost upon treatment discontinuation). Most studies suggest that the major reason for breakthrough is missing the peginterferon alfa and/or ribavirin doses for various causes (significant adverse events, poor compliance, etc.). The main reasons for relapse include treatment initiation with insufficient ribavirin dosage or failure to continue treatment long enough, especially in patients with a slow virologic response. Patients with a well-defined non-response are poor candidates for retreatment. Such patients have no significant decline in HCV RNA during treatment and are essentially refractory to the effects of interferon. Patients with partial virologic response are excellent candidates for retreatment and can achieve undetectable HCV RNA if switched to a more intensive interferon regimen. Many other patients can be retreated successfully. The likelihood of achieving SVR (Sustained Virologic Response) with peginterferon alfa plus ribavirin retreatment depends on several factors, e.g., the agents used in previous treatment courses, total dose and duration of treatment, HCV genotype, level of viremia and previous drop in viremia. Patients previously treated with standard interferon alpha monotherapy are good candidates for retreatment, regardless of baseline liver histology. In this group, those that were previous responder relapsers are most likely to respond to a course of peginterferon/ribavirin combination therapy, whereas previous non-responders can also achieve significant rates of SVR, particularly those infected with genotype 2 or 3 HCV There are several options for peginterferon alpha/ribavirin non-responders: 1) retreatment with the same protocol if adherence was a major problem; 2) administration of a longer treatment course (72 weeks) in slow responders; 3) retreatment with another interferon-based product (different peginterferon alpha, consensus interferon); 4) maintenance therapy; 5) clinical trials; and 6) wait and watch approach (respectable in many non-responders, particularly if fibrosis is not advanced and/or the patient experienced difficulties in tolerating therapy). Ongoing retreatment trials using specific antiviral drugs (valopicitabine, boceprevir, telaprevir) are of great interest, particularly in triple combination regimens. PMID- 20198902 TI - [Treatment of chronic hepatitis C in human immunodeficiency virus infected patients]. AB - Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) co-infected individuals have a higher risk of advanced liver fibrosis compared to those that are HCV mono-infected. Treatment of HCV offers the possibility of virus eradication, thus every person with detectable HCV viral load is a candidate for treatment. Treatment is recommended for all HCV/HIV co-infected patients with: 1) repeatedly elevated aminotransferase levels; 2) F2 stage of liver fibrosis or higher regardless of alanine aminotransferase level; and 3) more than 200 CD4+ T lymphocytes per microL of blood. Treatment is not recommended for patients that are active injection drug users, consume large amounts of alcohol, or have or had a severe psychiatric disorder. Liver biopsy is generally recommended, however, because of faster progression to liver fibrosis in HIV and HCV co-infected patients, if the patient declines liver biopsy it should not exclude him from treatment. Treatment with a combination of pegylated interferon and weight-based ribavirin (1000 mg/day if <75 kg and 1200 mg/day if >75 kg) is recommended. Pegylated interferon is used as 180 microg for alfa-2a form and 1.5 mg/kg for alfa-2b form once weekly subcutaneously. HCV RNA should be measured after 4 weeks of treatment, and later as needed, in weeks 12, 24, 48 or 72. For evaluation of a sustained viral response, HCV RNA should be measured 24 weeks after the end of treatment. In patients with rapid viral response (undetectable levels of HCV RNA after 4 weeks of treatment), treatment duration is 24 weeks (genotypes 2 and 3) or 48 weeks (genotypes 1 and 4). In patients without rapid viral response but with an adequate response after 12 and 24 weeks, we generally recommend treatment for 48 weeks, however, 72 weeks of treatment can be considered for genotypes 1 and 4. Treatment discontinuation is recommended in patients with <2 log viral load decline after 12 weeks or with a detectable viral load after 24 weeks of treatment. If concurrent treatment of HCV and HIV is necessary, treatment with zidovudine and didanosine should be avoided and caution is needed with the administration of potentially hepatotoxic antiretroviral drugs such as nevirapine and ritonavir. PMID- 20198903 TI - [Hepatitis C virus and chronic progressive kidney disease]. AB - Soon upon its discovery, hepatitis C virus (HCV) was recognized as an important cause and consequence of chronic kidney disease (CKD). HCV is a significant cause of some forms of glomerulonephritis (GN), especially membranoproliferative GN (MPGN). Subsequent population-based studies found an association between HCV positivity and CKD markers such as albuminuria or proteinuria. HCV infection is a frequent sequel of CKD. Blood transfusions (before effective screening of blood donors for HCV was instituted), nosocomial transmission in dialysis units, and transmission by kidney grafts all have contributed to the much higher prevalence of HCV infection in end-stage renal disease (ESRD) and transplant patients as compared to the general population. The current prevalence of HCV in dialysis centers is between 5% and 10% in European Union, and around 8.4% in Croatia. Strict adherence to 'universal precautions', careful attention to hygiene and strict sterilization of dialysis machines is recommended. The prevalence of HCV infection in CKD transplant patients is also high. Consistent risk factors include total time spent on dialysis and a history and/or number of blood transfusions, yet paralleling the prevalence in the general population of the same country or region. Patients with CKD who are considered for treatment should have virologic evidence of chronic HCV infection (i.e. HCV RNA detectable in serum). Treating chronic HCV infection in CKD patients is associated with a number of challenges. As the glomerular filtration rate (GFR) decreases, the half life of both interferons (IFNs) (standard and pegylated) and ribavirin increases, resulting in a potentially poorer tolerance and the need for dosage adaptations in severe CKD. In kidney graft recipients, the use of IFNs and immunostimulants further entails a substantial risk of rejection. IFN therapy in hemodialysis patients results in good biochemical and virologic response and appears to exert a beneficial effect on the course of liver disease following renal transplantation. IFN-alpha therapy for the treatment of HCV-infected ESRD patients on maintenance dialysis, administered prior to renal transplantation, is associated with high rates of sustained biochemical and virologic response in the post-transplant period. Thus, IFN-alpha therapy seems to be advisable for HCV infected dialysis patients that are candidates for renal transplantation. PMID- 20198904 TI - [Prevention and treatment of hepatitis C in illicit drug users]. AB - Drug use is a complex behavior with multidimensional determinants, including social, psychological, cultural, economic, and biological factors. Blood borne viral infections including hepatitis C virus are transmitted when an uninfected intravenous drug user (IVDU) uses injection equipment, especially syringes, that have previously been used by an infected person. The transmission can also result from sharing other injection equipment such as 'cookers' and 'cottons'. Recent studies have shown that the prevalence and incidence of drug abuse have declined substantially since the introduction of needle exchange. Infection with hepatitis C may spontaneously resolve during the acute stage and never progress to chronic infection, or the infection may become chronic without medical complications, or the infection may become chronic with progressive medical complications. Regular testing for infection is an important strategy for secondary prevention of chronic hepatitis C infection. Care for hepatitis C is a vital component of a comprehensive health program for persons using illicit drugs. Such care includes screening for transmission risk behavior, prevention counseling and education, testing for HCV antibody and RNA. IDUs found to have chronic HCV infection should be assessed for the presence and degree of liver disease and evaluated for treatment for HCV Hepatitis C care also requires providing access to treatment for substance use and abuse. Therapy with opioid agonists, including methadone maintenance treatment, has been shown to diminish and often eliminate opioid use and reduce transmission of infection. Approval of buprenorphine makes office based pharmacotherapy for opioid addiction possible. When considering treatment for hepatitis C, particular attention must be paid to mental health conditions. As a group, IDUs exhibit higher rates of comorbid psychiatric disorders than the general population. IFN-based regimens for hepatitis C are often complicated by neuropsychiatric adverse effects, including depression, insomnia, and irritability. Strong linkages with mental health services, whether on-site or within the community, are a vital component of comprehensive health programs for IDUs and are particularly important during treatment for hepatitis C. Past episodes of depression or other psychiatric disorders are not absolute contraindications for the treatment for HCV infection. Some authors recommend prophylactic antidepressant therapy before initiating treatment for HCV in patients thought to be at a high risk of depression. PMID- 20198905 TI - [Treatment for viral hepatitis in institutionalized individuals]. AB - The presence and spread of viral hepatitis infection in the prison population is much higher than in the general population. Prisoners represent a combination of several high risk subpopulations and are therefore generally considered a high risk category. When outside the prison system, members of these high risk groups are generally not available for education, prevention and therapy. While within the prison system, they are available for systematic and continuing monitoring and therapy. This includes testing of their HBV, HCV and HIV status. Due to the high incidence of viral hepatitis in the prison population and based on the results of a study from 2007, we established the Prison System Viral Hepatitis Counseling Center. The Center operates within the internal ward of the Prison Hospital. Currently, 42 patients are treated for chronic hepatitis C. The Center's Plan and Operating Program and treatment results are presented. PMID- 20198906 TI - [Prevalence of hepatitis B and C among prison population in Croatia]. AB - In 2007, incarcerated persons accounted for 0.41% (approximately 16,500) of the Croatian population. In the heterogeneous structure of the prison population in Croatia, some 25%-30% of the prisoners are drug abusers. In this study, we intended to determine precisely the structure of the prison population in Croatia and the prevalence of HBV and HCV markers in this population. It is well known that HBV and HCV infection can spread within prisons, and therefore we tried to determine the rate of acute HBV and HCV infection among prisoners in Croatian prisons. In total, 25.7% of prisoners were positive for some viral hepatitis markers (HBV 11.3%, HCV 8.3%, and HBV/HCV 6.3%). The rate of HBV infection was very high among intravenous drug users (26.2%) and relatively high among highly promiscuous individuals (19.9%). HCV infection was most prevalent among intravenous drug users (50.2%) and relatively high among highly promiscuous individuals (7.5%). HBV/HCV coinfection was recorded in 23.5% of prisoners. Acute infection with HBV was detected in 0.3% and with HCV in 1.2% of the study population. One fourth of all prisoners had contact with HBV, HCV, or both viruses. It is evident that both hepatitis virus infections (HCV more and HBV less) are spreading within prisons among prisoners. The opportunity of screening, testing, vaccination, treatment and education of high-risk individuals while they are in the controlled environment of a correctional facility is a good policy for both individuals and the community. PMID- 20198907 TI - [Treatment of recurrent hepatitis C infection after liver transplantation]. AB - Recurrent infection with HCV after liver transplantation is almost universal and is associated with substantial morbidity, mortality and graft loss. In contrast to immunocompetent individuals, HCV infection in immunosuppressed transplant recipients usually has an accelerated course. Acute hepatitis develops in approximately 75% of HCV recipients in the first six months following orthotopic liver transplantation (OLT). By the fifth postoperative year, over 80% of HCV infected liver transplant recipients will develop histologic evidence of chronic allograft injury secondary to hepatitis C, with up to 30% developing cirrhosis. While the choice of calcineurin inhibitor has not been clearly shown to affect histologic recurrence of hepatitis C or the frequency of rejection in HCV infected recipients, cumulative exposure to corticosteroids is associated with increased mortality, higher levels of HCV viremia and more severe histologic recurrence. Unfortunately, treatment of chronic HCV in liver transplant recipients is suboptimal. Combination therapy with interferon (pegylated and nonpegylated forms) plus ribavirin appears to provide maximum benefits. Drug therapy is usually administered for recurrent disease. No prophylactic therapy is available. Preemptive regimens offer no distinctive advantages over treatments initiated for recurrent disease. Overall, treatment is poorly tolerated, with frequent need for dose reductions, especially for cytopenias, and drug discontinuation in up to 50% of patients. Optimizing drug doses is important in maximizing sustained virologic response rates. The achieved SVR is between 33% and 42% in randomized studies treating patients with histologic recurrence and 0% to 33% when used in a preemptive protocol. The potential factors that influence this low SVR rate are: 1) high percentage of patients with genotype 1 virus; 2) high viral load at the start of treatment; 3) high percentage of prior non responders to therapy; 4) side effects that often make the use of standard doses and duration of treatment difficult; 5) the use or not of growth factors; and 6) the effect of immunosuppression. In post-transplant patients with recurrent HCV disease, combination Peg alfa-2b or alfa-2a in standard dose and ribavirin (800 1200 mg either ab initio or as an increasing dose) regimen for 48 weeks was significantly better than no therapy, but not than any other therapy. PMID- 20198908 TI - [Treatment of viral hepatitis in children]. AB - Having compared prior recommendations in our country, we found no essential differences in treating chronic hepatitis B and C in children. The recommended therapy for chronic hepatitis B in children is still monotherapy with interferon alfa or lamivudine. Although a recently published pilot study showed good results with combined therapy, it is not included in therapeutic recommendations. As for prevention, improvement is achieved with introducing immunization in infancy, in addition to immunization of elementary school sixth-graders. Adopting this measure, we expect further decrease in the prevalence of chronic hepatitis B. The best treatment option for chronic hepatitis C in children is combined therapy with interferon alfa-2b and ribavirin, as supported by multicenter studies. Children with chronic viral hepatitis are at a higher risk of hepatocellular carcinoma as compared to healthy children. Thus, alpha fetoprotein level and liver ultrasonography should be obtained once or twice yearly in order to detect the possible hepatocellular carcinoma at an early stage. PMID- 20198909 TI - [Management of side effects during antiviral therapy]. AB - The adverse effects of antiviral drugs are dose dependent and often reversible. The major side effects include influenza-like symptoms, hematologic abnormalities and neuropsychiatric symptoms. The influenza-like syndrome can be prevented by paracetamol taken at the time of injection. Psychiatric adverse effects range from irritability to severe depressive syndrome. Antidepressants such as selective serotonin reuptake inhibitors may be useful. Adverse hematologic effects can occur very early during treatment. The platelet count often stabilizes rapidly, but neutropenia can deteriorate throughout the treatment. In selected patients, treatment with hematopoietic growth factor (filgrastim) may be useful. Ribavirin therapy may result in a dose-dependent reversible intravascular hemolytic anemia in 10% of patients. Therapy with erythropoietin for ribavirin induced anemia can be useful; however, are insufficient data to recommend its routine use in all patients. Interferon and ribavirin are contraindicated in pregnancy. Contraception must be continued for 4 months (women) and 7 months (men) after ribavirin cessation. Lactic acidosis may be a rare complication of combination therapy in patients undergoing therapy for HIV and HCV. Any sign of mitochondrial DNA depletion syndrome calls for blood lactate measurement and, possibly, a modification of antiretroviral treatment. Lamivudine is well tolerated but the emergence of lamivudine-resistant (YMDD) HBV mutants is associated with the loss of clinical response. Adefovir, entecavir, telbivudin and tenofovir effectively suppress lamivudine-resistant HCV in chronic hepatitis B. PMID- 20198910 TI - Effects of concentrated ambient particles and diesel engine exhaust on allergic airway disease in Brown Norway rats. AB - Increased concentrations of airborne fine particulate matter (PM2.5; particulate matter with an aerodynamic diameter < or = 2.5 microm) are associated with increases in emergency room visits and hospitalizations of asthmatic patients. Emissions from local stationary combustion sources (e.g., coal-burning power plants) or mobile motor vehicles (e.g., diesel-powered trucks) have been identified as potential contributors to the development or exacerbation of allergic airway disease. In the present study, a rodent model of allergic airway disease was used to study the effects of concentrated ambient particles (CAPs) or diesel engine exhaust (DEE) on the development of allergic airway disease in rats sensitized to the allergen ovalbumin (OVA). The overall objective of our project was to understand the effects of PM2.5 on the development of OVA-induced allergic airway disease. Our specific aims were to test the following hypotheses: (1) exposure to CAPs during OVA challenge enhances epithelial remodeling of the airway and inflammation in rats previously sensitized to the allergen; and (2) exposure to DEE during OVA sensitization, or during OVA challenge, exacerbates epithelial remodeling of the airway and inflammation in rats. In the DEE studies, Brown Norway (BN) rats were sensitized with three daily intranasal (IN) instillations of 0.5% OVA, and then two weeks later were challenged with IN OVA or saline for 3 consecutive days. Rats were exposed to DEE diluted to mass concentrations of 30 or 300 microg/m3 diesel exhaust particles (DEPs) or to filtered air during either the sensitization or challenge periods. For the CAPs studies, the same OVA sensitization and challenge rat model was used but exposures to Detroit, Michigan, CAPs were limited to the OVA challenge period. Two separate 3-day CAPs exposures were conducted (week 1, high mean mass concentration = 595 microg/m3; week 2, low mean mass concentration = 356 microg/m3) during OVA challenge. In both the DEE and CAPs studies, rats were killed 24 hours after the last OVA challenge, bronchoalveolar lavage fluid (BALF) was collected and analyzed for cellularity and secreted mediators, and lungs and nose were processed for histopathologic examination and morphometric analysis of intraepithelial mucosubstances (IM). The results of our animal inhalation studies in the southwest (SW) Detroit community, an area with elevated ambient PM2.5 concentrations, suggested that, during allergen challenge, exposure to CAPs that were predominantly associated with emissions from combustion sources markedly enhanced the OVA-induced allergic airway disease, which was characterized by an increased infiltration in the lungs of eosinophilic and lymphocytic inflammation, increased IM in conducting airways, and increased concentrations in BALF of mucin specific proteins and inflammatory cytokines. These findings suggest that urban airborne PM2.5 derived from stationary combustion sources (e.g., refineries, coal burning power plants, waste-treatment plants) may enhance the development of human allergic airway diseases like childhood asthma. Previous animal inhalation studies in this community have also suggested that these fine, ambient combustion derived particles may also exacerbate preexisting allergic airway disease. In contrast to our CAPs studies in Detroit, the controlled DEE exposures of allergen sensitized BN rats, during either allergen sensitization or challenge periods, caused only a few mild modifications in the character of the allergen-induced disease. This finding contrasts with other reported studies that indicate that DEPs at relatively higher exposure doses do enhance allergic airway disease in some rodent models. The reasons for these disparities between studies likely reflect differences in exposure dose, animal models, the timing of exposures to the allergens and DEP exposures, the methods of allergen sensitization and challenge, or physicochemical differences among DEEs. PMID- 20198911 TI - [Extremophilic microorganisms: biochemical adaptation and biotechnological application (review)]. AB - The analysis of modern data on biochemical adaptation of microorganisms for living in extreme conditions is presented in this review. Special attention has been paid to the analysis of adaptive responses of microorganisms to the conditions of increased radiation at the molecular and cellular levels. The data on the practical application of extremophils and extremoenzymes, synthesized by them, biologically active substances, biopolymers and so on, have been systematized. PMID- 20198912 TI - [Reactive oxygen and nitrogen species in legume-rhizobial symbiosis: a review]. AB - Published data on the role of reactive oxygen and nitrogen species (ROS and RNS, respectively) in the formation and functioning of the legume-rhizobial symbiosis are summarized. It is assumed that ROS and RNS fulfill a double function in the legume-rhizobial symbiosis by triggering the mechanisms enabling symbiosis formation and the mechanisms preventing the development of symbiotic structures (i.e., the defensive responses). A hypothetic scheme illustrating the involvement of ROS and RNS in the formation of legume-rhizobial symbiosis is proposed. PMID- 20198913 TI - [Effect of the structure of the brassinosteroid side chain on monooxygenase activity of liver microsomes]. AB - Possible pathways by which brassinosteroids affect the monooxygenase enzymatic system of mammalian liver microsomes, which is involved in the transformation of a broad spectrum of xenobiotics, were studied. The role of the structure of the side chain of brassinosteroids in the regulation of monooxygenase activity was studied using two natural compounds (24-epibrassinolide and 28-homobrassinolide) and two synthetic analogues, (22S, 23S-dihydroxy) stereoisomers. The results of this study show that brassinosteroids can directly influence the functioning of the microsomal enzymatic system. It was found that the degree of this influence depends on the side chain structure. This suggests the possibility of targeted modification of natural compounds to ensure the desired physiological effects. PMID- 20198914 TI - [Characteristics of the response of natural and recombinant luminescent microorganisms in the presence of Fe2+ ions]. AB - It was found that divalent iron ions have alternative effects on the bioluminescence of the natural marine microorganism Photobacterium phosphoreum and the recombinant Escherichia coli strain with a cloned lux operon of P. leiognathi. In the presence of 0.25-5.0 mM FeSO4, the bioluminescence intensity of the former and the latter increased and decreased, respectively. To establish the causes of these differences, we studied the characteristics of the fatty acid composition of the compared microorganisms. The fatty acid profile of E. coli was characterized by a high proportion of unsaturated 11-octadecenoic (vaccenic) acid. A study of this acid in a cell-free enzyme system used for bioluminescence generation showed that it is a potent inhibitor of bacterial bioluminescence. It was found that such effects are enhanced if 11-octadecenoid acid is preincubated with Fe2+. PMID- 20198915 TI - [Growth and bioluminescence of luminous bacteria under the action of aflatoxin B1 before and after its treatment with nanodiamonds]. AB - The effect of aflatoxin B1 on growth and luminescence of marine luminous bacteria P. phosphoreum and recombinant E. coli Z905 cells was investigated. The bidirectional effect of aflatoxin B1 on the studied bacterial species was detected--an inhibition of luminescence in P. phosphoreum and its stimulation in E. coli. It was shown that aflatoxin B1 influences the cell luminescence in the freshly grown cultures and bacteria restored after lyophilization. It was detected that the effect of aflatoxin B1 was graded after interaction with the modified nanodiamond (MND) of detonation synthesis. After mycotoxin's treatment with MND, it does not cause significant changes in bacterial luminescence. The possibilities for the use of P. phosphoreum and E. coli bacteria in the bioluminescent monitoring of aflatoxin B1 and the use of MND for mycotoxin deactivation are discussed. PMID- 20198916 TI - [Rhizosphere bacteria Pseudomonas aureofaciens and Pseudomonas chlororaphis oxidizing naphthalene in the presence of arsenic]. AB - Rhizosphere strains of P. aureofaciens BS1393(pBS216, pKS1) and P. chlororaphis PCL1391(pBS216, pKS1), exhibiting the ability to stimulate the growth of plants and protect them from phytopathogens, have been obtained. In these strains, plasmid pBS216 ensures naphthalene degradation and plasmid pKS1 confers resistance to arsenic. In the presence of arsenic and naphthalene, the number of living cells and the growth rate of the arsenic-resistant strains were higher than those of the arsenic-sensitive strains BS1393(pBS216) and PCL1391(pBS216). During the cultivation of the resistant strains, arsenic had no inhibitory effect on the activity of the key enzymes of naphthalene biodegradation, except for catechol-2,3-dioxygenase. In a model system containing plant-microbial associations, strains BS1393(pBS216, pKS1) and PCL1391(pBS216, pKS1) degraded as much as 97% of added naphthalene in the presence of arsenic. PMID- 20198917 TI - [Production of auxins by the endophytic bacteria of winter rye]. AB - The ability of the actinomycetes and coryneform bacteria isolated from the root tissues of winter rye to produce auxin in a liquid culture was studied. The isolates of coryneform bacteria produced indolyl-3-acetic acid (IAA) into the medium in the amount of 9.0-95.0 microg/ml and the isolates of actinomycetes in the amount of 39.5-83.0 microg/ml. The maximal IAA accumulation in culture liquid of actinomycetes coincided, in general, with the beginning of the stationary growth phase. The dependences of IAA synthesis by actinomycetes on the composition and pH of nutrient medium, tryptophan concentration, and aeration conditions were determined. Biological activity of the bacterial IAA was assessed. Treatment of winter rye seeds with coryneform auxin-producing bacteria increased the germination capacity and enhanced an intensive seedling growth in vitro. PMID- 20198918 TI - [Chemotactic and adhesive properties of Azotobacter vinelandii and Bacillus subtilis]. AB - The effects of some factors on the chemotaxis of Azotobacter vinelandii IMV V 7076 and Bacillus subtilis IMV V-7023 and on their adhesion to cucumber roots have been studied. Glucose chemotaxis and adhesion to roots reach peak values in pH ranges characteristic of each strain. These ranges are 7.0-8.0 for A. vinelandii IMV V-7076 and 6.0-7.0 for B. subtilis IMV V-7023. The adhesion values of each species decrease significantly in their mixed suspension. The interaction of each of the strains with the clay mineral montmorillonite improves their adhesion to cucumber roots. The clay mineral palygorskite improves the adhesion of A. vinelandii but reduces that of B. subtilis. PMID- 20198919 TI - Effects of bovine milk lactoperoxidase system on some bacteria. AB - Bovine lactoperoxidase (LPO) was purified from skimmed milk using amberlite CG-50 H+ resin, CM sephadex C-50 ion-exchange chromatography, and sephadex G-100 gel filtration chromatography. Lactoperoxidase was purified 20.45-fold with a yield of 28.8%. Purity of enzyme checked by sodium dodecyl sulphate-polyacrylamide gel electrophoresis method and a single band was observed. Km was 0.25 mM at 20 degrees C, Vmax value was 7.95 micromol/ml min at 20 degrees C (pH 6.0). Antibacterial study was done by disk diffusion method of Kir-by-Bauer using Mueller-Hinton agar medium with slight modification. Bovine LPO showed high antibacterial activity in 100 mM thiocyanate-100 mM H2O2 medium for some bacteria (Brevibacillus centrosaurus, B. choshinensis, B. lyticum, Cedecea davisae, Chryseobacterium indoltheticum, Clavibacter michiganense pv. insidiosum, Kocuria erythromyxa, K. kristinae, K. rosea, K. varians, Paenibacillus validus, Pseudomonas syringae pv. populans, Ralstonia pickettii, Rhodococcus wratislaviensis, Serratia fonticola, Streptomyces violaceusniger, Vibrio cholerae nonO1) respectively, and compared with well known antibacterial substances (levofloxacin, netilmicin). LPO system has inhibition effects on all type bacteria and concentration is really important such as LPO-100 mM thiocyanate-100 mM H2O2 system was proposed as an effective agent against many factors causing several diseases. PMID- 20198920 TI - [Electrooptical properties of the microbial suspensions during a cell's interaction with the antibodies of a different specificity]. AB - The electrooptical abilities of the microbial suspensions during a cells interaction with antibodies (ABs) of a different specificity have been studied on the example of the Azospirillum brasilense Sp245 cells and their interaction with the polyclonal monospecific and polyspecific antibodies. Measuring of the orientational spectra of the cells has been performed using the ELUS electrooptical analyzer. A discrete frequency set of an orienting electric field (740, 1000, 1450, 2000, and 2800 kHz) was used. It has been shown that an interaction of the polyspecific AB with the investigated cells redoubles the value of an electrooptical signal of the cells' suspension as compared with the monospecific antibodies. These findings can be used for a development a new method of microorganism detection. PMID- 20198921 TI - [Luminol oxidation by hydrogen peroxide with chemiluminescent signal formation catalyzed by peroxygenase from the fungus Agrocybe aegerita V.Brig]. AB - Conditions of luminol oxidation by hydrogen peroxide in the presence of peroxygenase from the mushroom Agrocybe aegerita V.Brig have been optimized. The pH value (8.8) at which fungal peroxygenase produces a maximum chemiluminescent signal has been shown to be similar to the pH optimum value of horseradish peroxidase. Luminescence intensity changed when the concentration of Tris buffer was varied; maximum intensity of chemiluminescence was observed in 40 mM solution. It has been shown that enhancer (p-iodophenol) addition to the substrate mixture containing A. aegerita peroxygenase exerted almost no influence on the intensity of the chemiluminescent signal, similarly to soybean, palm, and sweet potato peroxidases. Enzyme detection limit in the reaction of luminol oxidation by hydrogen peroxide was 0.8 pM. High stability combined with high sensitivity make this enzyme a promising analytical reagent. PMID- 20198922 TI - [7alpha-hydroxylation of steroid 5-olefins by mold fungi]. AB - Hydroxylation activity of the mold fungi belonging to the orders Dothideales, Hypocreales, and Mucorales towards delta(5)-3beta-hydroxysteroids was studied. The fungi Bipolaris sorokiniana, Fusarium sp., and Rhizopus nigricans were able to introduce hydroxy group at position 7alpha; however, this ability was detected only at a low substrate load and with a low yield. A 7alpha-hydroxylase activity of the Curvularia lunata VKPM F-981 culture was shown for the first time. It was demonstrated that the studied strain was capable of stereo- and regioselective transformations of androstane 5-olefins at a load not less than 2 g/l. Conversion of pregnane steroids by this culture yielded both 7alpha and 11beta-hydroxy derivatives. The introduction of 7alpha-hydroxy group by this strain occurred concurrently with enzymatic hydrolysis of ester groups, which proceeded under mild conditions to give the corresponding alcohols in the cases of both 3-acetate of delta(5)-androstenes and mono- and triacetates of delta(5)-pregnenes. PMID- 20198923 TI - [Isolation, identification, and characteristics of the phytotoxin produced by the fungus Alternaria cirsinoxia]. AB - An individual substance (20 mg/l) exhibiting phytotoxic properties, which, on the basis its spectral characteristics, was identified as zinniol, was obtained from the fungus Alternaria cirsinoxia. The nonspecific activity of this phytotoxin, with respect to plants of different families, was demonstrated. The minimum concentration (200 microg/ml) at which zinniol damages creeping thistle leaves and the median inhibition concentration (IC50) for rat embryonic fibroblasts (264 microg/ml) were determined. PMID- 20198924 TI - [Generation of sugar beet transgenic plants expressing bar gene]. AB - The parameters of transformation using Agrobacterium tumefaciens EHA 105 for 5 domestic sorts and lines of sugar beet (Beta vulgaris L. var. saccharifera (Alef) Krass) were optimized. The system of transgenic tissue selection based on resistance to phosphinothricin, allowing to avoid the appearing of chimeric shoots among initial transformants was developed. The transgenic plants of sugar beet sorts Ramonskaya single seed 47, L'govskaya single seed 52 and RMS 73, and LBO 17 and LBO 19 lines expressing the gene of phosphinothricin acetyl transferase bar have been obtained. The resistance of these sorts and lines to the effect of phosphinothricin in vitro has been shown. PMID- 20198925 TI - [Role of lipoxygenase in the determination of wheat grain quality]. AB - Analysis of the correlation between endogenous lipoxygenase activity and 15 wheat grain quality parameters in three bread wheat populations has shown that enzyme activity influences the weight of 1000 grains, dough deformation energy, dough tenacity, and mixing properties. The correlations between the enzyme activity and the basic quality parameters are negative at high activity levels. The optimum values of specific lipoxygenase activity at which all quality parameters studied have the maximum values range from 108.5 +/- 1.2 to 126.4 +/- 1.9. It has been found that the ability of lipoxygenase to strengthen gluten is related to the lowering of dough extensibility. PMID- 20198926 TI - [Preparation and properties of isocitrate lyase isoforms from the cotyledons of Glycine max L]. AB - A four-stage purification procedure including ammonium sulfate precipitation and ion exchange chromatography on DEAE cellulose has been elaborated for isolation of isocitrate lyase (EC 4.1.3.1) isoforms from the cotyledons of soybean Glycine max L. Electrophoretically homogeneous preparations of two forms of the enzyme with specific activity of 5.28 and 5.81 U/mg protein have been obtained. Comparison of physicochemical, kinetic, and regulation characteristics of the isoforms obtained revealed fundamental differences between them. Thus, the isoform that migrated quickly in PAAG had a much lower affinity to isocitrate (K(M) - 50 microM) than the slowly migrating form (K(M) - 16 microM). It has been shown that the conservation of activity of the isoforms obtained depends on the presence of divalent cations (Mn2+ and Mg2+) in the medium. It is suggested to use the isoforms of isocitrate lyase isolated from soybeans for the development of biosensors for biochemical and kinetic assays. PMID- 20198927 TI - [The influence of 24-epibrassidinole on the hormone status of wheat plants under sodium chloride]. AB - We studied the influence of the preconditioning of wheat germ (Triticum aestivum L.) with 0.4 microM 24-epibrassidinole (EB) on the growth and hormone status of plants under the influence of 2% NaCl. The preconditioning with EB promoted the lowering of the extent of the damaging influence of pickling on the growth of germs. The important contribution to the realization of the protective action of EB in the preconditioning of plants is probably that of its ability to lower the level of stress-induced abscisic acid accumulation and the decrease in the content of indole-acetic acid. At the same time, the cytokinin concentration in plants preconditioned with EB under pickling was practically the same as in plants without stress. This fact combined with data about the ability of EB to induce the increase in cytokinin content in wheat, obtained before, allowed us to assume that the protective action of EB on plants is connected, first of all, with the prevention of the increase in level of hormones of cytokinin nature under pickling. PMID- 20198928 TI - [Galactomannan from the seeds of Chinese honey locust (Gleditsia sinensis Lam)]. AB - By the hot water extraction method, galactomannan was extracted (4.5% yield of the seed mass) from the seeds of Chinese honey locust (Gleditsia sinensis Lam). It had a molecular weight of 1230 kDa, and its solutions had a high viscosity [eta] of 1064 ml/g and optical activity [alpha]D + 21.4 degrees. The polysaccharide consists of mannose and galactose residues in the molar ratio 2.69 : 1. In the galactomannan macromolecule the backbone is formed by 1,4-beta-D mannopyranose residues, 37% of which are substituted by alpha-D-galactopyranose at C-6. By 13C-NMR-spectroscopy, fragments of differently galactose-substituted mannobiose units were found to be in the galactomannan being studied: Man-Man, (Gal)Man-Man, and Man-Man(Gal) in the ratio of 0.23 : 0.47 : 0.30. PMID- 20198930 TI - Calculating fracture risk in primary care. PMID- 20198929 TI - [Formation of flavor of dry champignons (Agaricus bisporus)]. AB - The composition of aroma compounds of dry champignons (Agaricus bisporus L.) were identified using capillary gas chromatography and chromatography-mass spectrometry. In total, 56 compounds were identified. It was found that the flavor of dry mushrooms was formed by the volatile compounds produced as a result of enzymatic and oxidative conversion of unsaturated fatty acids as well as in the Maillard reaction. Unsaturated alcohols and ketones containing eight carbon atoms determined the mushroom note of the product. The specific aroma of dry mushrooms was determined by a complex composition of substituted sulfur-, oxygen , and nitrogen-containing heterocyclic compounds as well as by aliphatic carbonyl compounds and methional. It was found that the concentrations of volatile carbonylic and heterocyclic compounds increased after the addition of a mixture of amino acids to mushrooms before drying. As a result, the intensity of the aroma of dry mushrooms increased. PMID- 20198931 TI - Diagnosing joint pain in the older people. AB - There are many potential causes of joint pain in older patients. The most likely aetiology is OA. However, the differential diagnosis includes conditions which should not be missed such as septic arthritis and inflammatory disease. The pattern of joint involvement points to the diagnosis. Bilateral symmetrical small joint pain, swelling and stiffness should arouse the suspicion of RA. The wrist and knee are commonly affected by pseudogout and the first metatarsophalangeal joint or knee joint involvement may represent gout. Stiffness in the shoulder and hip girdles, worse in the morning, suggests polymyalgia rheumatica. In straightforward cases of OA no specific investigations are required. If doubt exists, however, tests may be necessary including FBC, ESR and CRP, uric acid for suspected gout and X-rays of the affected joints especially following trauma, or pseudogout. Patients with OA should be offered education and advice as well as strengthening exercises and aerobic fitness training (if physically possible). If the patient is overweight, weight loss is critical, especially in OA of the knee. Paracetamol and topical NSAIDs are the first-line drug treatments. Elderly onset RA differs from younger onset RA in the following ways: a more balanced gender distribution; a higher frequency of acute onset; an association with systemic features; more frequent involvement of the shoulder girdle and higher disease activity. DMARD therapy should be used according to disease severity, as in younger onset RA. The current approach is for early, intensive intervention with combination therapy. Corticosteroids may be very effective in the elderly, however, prolonged use and/or high dosage may lead to marked toxicity especially osteoporosis and diabetes. PMID- 20198932 TI - Normal cognitive decline or dementia? AB - Cognitive speed, inhibitory function, and memory decline with age while crystallised, particularly verbal, abilities remain largely intact. Poor health, fewer years of education, lower activity, the presence of the APOE E4 allele, and high BP appear to predict faster cognitive decline. Dementia is diagnosed in the presence of objective cognitive impairment, both long- and short-term memory, plus at least one additional (cortical) cognitive deficit, such as dysphasia, dyspraxia, agnosia, or disturbance in executive functioning. In addition, patients have to show significant impairment in social or occupational functioning and a significant decline from previous levels. Both smoking and diabetes increase the risk of all types of dementia, not smoking or even stopping smoking reduces this risk, but better control of type 2 diabetes does not appear to have a measurable effect. Drinking small to moderate amounts of alcohol appears to confer some benefit in ameliorating cognitive decline. There is some evidence that HRT, DHEA, BP lowering in patients without prior cerebrovascular disease, statins, vitamin B6 and procaine are NOT helpful. There is insufficient evidence to establish or refute a beneficial effect for exercise, treatment of type 2 diabetes, omega-3 fatty acids, folic acid with/without vitamin B12, antioxidant vitamins, or ginkgo biloba. Depressive symptoms are more prevalent than dementia. Clinical (major) depression can present with cognitive deterioration, often associated with subjective complaints. Patients with subjective or objective memory impairment, but without functional deterioration, can be referred to the local memory clinic, while demented patients eligible for acetylcholinesterase inhibitor treatment, patients whose diagnosis is unclear and who may need some specific investigations, as well as patients who may benefit from a combined approach with psychotropic drugs and behavioural support should be referred to the local mental health team. PMID- 20198933 TI - Tackling depression in patients with chronic conditions. AB - Compared with the general population, patients with a chronic physical health problem are two to three times more likely to be depressed. Their depression is less likely to be recognised and they are less likely to accept and tolerate antidepressant treatment. Comorbid depression is associated with increased pain, greater functional impairment and reduced quality of life. Depressed patients may lack confidence to self-manage their condition, increasing the risk of long-term complications. The new NICE guidance on depression in adults with a chronic physical health problem recommends a shift of emphasis from screening to identification. We should be alert to the possibility of depression in high-risk patients and consider using the two question screen. When used in this way, its main value is in ruling out depression. The DSM-IV definition of depression can lead to overdiagnosis in patients with a chronic condition, if somatic symptoms are caused by the illness, rather than depression. One proposed solution is to simplify the diagnostic criteria by restricting these to the five psychological symptoms. Three symptoms would then be needed for a diagnosis. PMID- 20198934 TI - Evils of the modern British diet. 1910. PMID- 20198935 TI - Foot problems. PMID- 20198938 TI - [Myocardial infarction, a national calamity]. PMID- 20198939 TI - [Myocardial infarction treatment and complications]. PMID- 20198940 TI - [Rehabilitation after a myocardial infarction]. PMID- 20198941 TI - [Patient education, lifestyle and prognosis after an acute coronary syndrome]. PMID- 20198942 TI - [Pediatric nurse in a forensic unit]. PMID- 20198943 TI - [The nursing prescription in practice]. PMID- 20198944 TI - [Hospital biography for terminally-ill patients]. PMID- 20198945 TI - [A standard of quality for home care]. PMID- 20198946 TI - [Musical evening at the patient's bedside]. PMID- 20198947 TI - [Prevention in the heart of vulnerable populations]. PMID- 20198948 TI - [The informal interview, a clinical competence]. PMID- 20198949 TI - [Sister Catherine of Jesus Christ (1869-1957)]. PMID- 20198950 TI - [Frovatriptan. For treatment of acute migraine]. PMID- 20198951 TI - [Shattering accepted ideas about gout]. PMID- 20198952 TI - An integrated approach to infrastructure. AB - In an edited version of a paper presented at the IHEA (Institute of Hospital Engineering Australia) 60th National Conference 2009, Stewart Hayes, principal consultant at Jakeman Business Solutions, argues that, with "traditional" means of purchasing and maintaining critical hospital infrastructure systems "becoming less viable", a more integrated, strategic approach to procuring and providing essential hospital services that looks not just to the present, but equally to the facility's anticipated future needs, is becoming ever more important. PMID- 20198953 TI - Fumigation success for California facility. AB - As Robert Hacker, at the time director of facilities management at the St John's Regional Medical Center in Oxnard, California, explains, the hospital, one of the area's largest, recently successfully utilised a new technology to eliminate mould, selecting a cost and time-saving fumigation process in place of the traditional "rip and tear" method. Although hospital managers knew the technology had been used extremely effectively in other US buildings, this was reportedly among the first ever healthcare applications. PMID- 20198954 TI - Smoothing the path to the theatre. AB - How operating theatre design has changed, and the considerable differences in approach taken in the UK, mainland Europe, and North America in the past 5-10 years to enhancing the design of both the theatre itself, and the associated waiting, preparation and recovery facilities, were the subject of a fascinating presentation by Keith Millay, director--health sciences, at London-based Swanke Hayden Connell Architects, at the recent Healthcare Estates conference. Jonathan Baillie reports. PMID- 20198955 TI - Are you set to commit to carbon reduction? AB - This April's introduction of the Carbon Reduction Commitment (CRC) should, argues Dave Covell, a principal at international environmental consultancy Environ, lead to major improvements in energy efficiency in the healthcare arena, potentially enabling Trusts to significantly reduce future energy bills. However, ensuring that they are properly prepared means starting to think about the data they will need and acting now, requiring the well planned step-by-step approach set out below. PMID- 20198956 TI - Age-old technologies jostle for position. AB - With the focus on combating hospital-acquired infection never greater, debate over the respective merits of using silver ion and copper-based anti-microbial surface treatments to "beat the bugs" will no doubt continue as new study evidence emerges for each. Health Estate Journal highlights the contrasting claims made by both "sides", and reports on two recent studies in particular, one expounding the advantages of copper, and the other painting an equally positive picture for silver. PMID- 20198957 TI - Growing estates role in theatre arena. AB - NHS Trust boards' growing demands for major capital purchases to offer both short term "added value", and sound longer-term ROI, coupled with estates and facilities teams' growing involvement in specifying, installing, and subsequently maintaining, the sophisticated equipment and control systems found in modern-day operating theatres, have meant a radical re-think in approach to winning new business for Trumpf Medical Systems. MD Oliver Law explained the background and thinking to the change in strategy, and discussed the company's ambitious future plans, with HEJ's Jonathan Baillie. PMID- 20198958 TI - Controlled humidity could hit flu hard. AB - With regular flu outbreaks a significant concern and cost/resource drain for the NHS, Vapac Humidity Control, reportedly the UK's only manufacturer of specialist humidifier equipment for hospital use, is highlighting a recently published US study which it says backs over 60 years' evidence that carefully controlling humidity in operating theatres and wards could significantly reduce transmission and survival of both the influenza virus, and potentially also other infection and virus-causing organisms. Jonathan Baillie reports. PMID- 20198959 TI - Mapping a world for the disabled. AB - Agreeing to spend 88,000 pound to sign her Trust up to a new online guide that will provide information on disabled access provision for some individual 300 healthcare sites throughout the county was "an extremely easy decision", NHS Suffolk chief executive Carole Taylor-Brown told a London audience recently. She was speaking at the London launch of DisabledGo - Health, a national online guide to disabled access at UK healthcare facilities that provides data on everything from the location of handrails and the degree of slope in corridors to the size of "disabled" parking spaces. Jonathan Baillie reports. PMID- 20198960 TI - Rehabilitation facility to set world standard. AB - A new healthcare facility for the rehabilitation of patients with brain, spinal, and other neurological conditions, that architects Murray O'Laoire and Brian O'Connell Associates say will "raise the stakes" internationally in the treatment and care of such patients and, on its 2014 completion, be "among the world's most accessible buildings", is planned for Dun Laoghaire near Dublin. The design philosophy was explained in detail by Hugh Murray, a founding director at Murray O'Laoire, at the recent Healthcare Estates conference. PMID- 20198961 TI - [Estimation of the biological age in females of the taiga tick Ixodes persulcatus by changes in the body shape and surface of cuticle]. AB - A method of visual estimation of the biological age of living hungry tick females by visible changes in the depth of marginal groove and the structure of the alloscutum cuticle during natural ageing is developed. In recently activated individuals, the body is convex and the marginal groove is exposed, demonstrating distinctly visible cuticular microfolds (Figs 1-4). In attenuated ticks, the body is flattened and marginal fold overlays the marginal groove, concealing cuticular microfolds (Figs 5-8). PMID- 20198962 TI - [Dispersion of the nematodes belonging to the Bursaphelenchus xylophilus species group with saw timber in Russian Federation]. AB - Four new records of Bursaphelenchus mucronatus in saw-timbers from the Asian part of Russia (Irkutsk Oblast and Krasnoyarsk Krai, larch, pine and spruce wood) intercepted in St. Petersburg, are described, measured and illustrated. The diagnosis of B. mucronatus is amended and its relationships within species group xylophilus, and especially its differences from a quarantine pests B. xylophilus, are given. The record of the B. mucronatus transition from Asiatic into European part of Russia suggests possible transcontinental way of the xylophilus group penetration with saw-timber. Pest risk analysis of B. xylophilus for the European part of Russia is discussed in scope of the global warming. PMID- 20198963 TI - [Reexamination of the life cycle of Isthmiophora melis (Trematoda: Echinostomatidae) on material from southeast Europe]. AB - The life cycle of Isthmiophora melis (Schrank, 1788) on material from Southeast Europe was experimentally reexamined. Thirteen names or combinations can be accepted as true synonyms of I. melis: Distoma melis (Schrank, 1788) Zeder, 1800; Echinocirrus melis (Schrank, 1788) Mendhaim, 1943; Isthmiophora spiculator (Dujardin, 1845); Echinostoma trigonocephalum (Rud., 1802) Cobbold, 1861; E. melis (Schrank, 1788) Dietz, 1909; E. spiculator Dujardin, 1845; Euparyphium jassyense Leon and Ciurea, 1922; E. melis (Schrank, 1788) Railliet, 1919; E. suinum Ciurea, 1921; Fasciola armata Rud., 1802; F. melis Schrank, 1788; F. putorii Gmelin, 1791; F. trigonocephala Rud., 1802. The first intermediate hosts are the pulmonate freshwater snail Lymnaea stagnalis. The second intermediate hosts are many amphibians and freshwater fishes. The list of definitive hosts includes more than 30 species of vertebrates including humans. I. melis occurs in Europe, Asia and North America. PMID- 20198964 TI - [Pararodentolepis gen. n., a new genus of cestodes from rodents, with the description of P. sinistra sp. n. (Cyclophyllidea: Hymenolepididae)]. AB - A new cestode genus and speies with armed scolex, Pararodentolepis sinistra gen. et sp. n. (Cyclophyllidea: Hymenolepididae), is described ex brown rat Rattus norvegicus Berkentheut, 1769 from the western Siberia. The differential diagnosis is also given. PMID- 20198965 TI - [On the infecstation of musculature in the Pacific salmons from Okhotsk Sea at early sea stage of their life]. AB - Data on the infection of the musculature of juvenile salmons Oncorhynchus gorbuscha (Walbaum, 1792) and O. keta (Walbaum, 1792) with the nematode Anisakis sp. l. and cestode Diphyllobothriidae gen. sp. l. in Okhotsk Sea and adjacent Pacific waters are given. Probable regions where the infestation of juvenile salmons may take place are established. Interspecific differences in the levels of infestation, as well as differences in the invasion of fishes during their migration to ocean are revealed. PMID- 20198966 TI - [Age structure and dynamics of abundance of the adult Trematode Opisthioglyphe ranae (Fasciolida, Plagiorchidae) hemipopulation in lake frog from the Saratov reservoir]. AB - Age structure and dynamics of abundance of adult Opisthioglyphe ranae, a parasite of intestine of lake frog, are analyzed. In the period of activity of the host (May-October), the hemipopulation of O. ranae maritae is represented by two generations, which are situated in host lesser than one year and differ from each other in the rate of maturation. PMID- 20198967 TI - [World fauna of Dactylogyrus spp. (Plathelminthes; Monogenea; Dactylogyridae) with five rayed ventral bar of the haptor. 1. Composition and structure]. AB - Systematization and description of composition and structure of the monogeneans from the genus Dactylogyrus Diesing, 1850 mostly having five rayed ventral (additional) bar of the haptor and parasitizing mainly Palaearctic Barbinae and Leuciscinae, were carried out. These dactylogyrids have Palaearctic origin and occur in the north-western Africa, central and southern Europe, Transcaucasia, middle Asia, Mesopotamia and also in India and the Malacca Peninsula. Previously the analysis of dactylogyrids' distribution by continents (Gerasev et al., 1996), geographical regions (Gerasev, Timofeeva, 1997), taxonomic groups of hosts (Gerasev, 2008a, 6), and different taxonomic groups of host inside one geographical division (Kolpakov et al., 2007; Gerasev et al., 2007, 2008) was performed. This analysis have not been always resulted in the understanding of conjugate evolution of these parasites and their fish hosts, as well as in the resolving of problems concerned with speciation of monogeneans and phylogeography of their hosts. Therefore, in present work we consider more than one geographical region, different fish taxa, and the morphological groups of worms reflecting morphological variational series of types of copulatory organ and additional bar. Typification of copulatory organ, additional bar, anchors, and type of seating for 11 Palaearctic morphological groups of dactylogyrids mainly having five rayed additional ventral bar, were carried out. Four morphological groups of dactylogyrids of African, Indian, and different Palaearctic origin also parasitizing Palaearctic barbs were additionally included into analysis. In all, 92 species of dctylogyrids from 78 host species were considered. Analysis of speciation and phylogeny of dactylogyrids having five rayed additional ventral bar of haptor; conjugate evolution of these dactylogyrids and their fish hosts (mainly Barbinae); point of origin of Palaearctic polyploids Barbinae, and expansion of these fishes over the territory of Palaearctic will be discussed in next article. PMID- 20198968 TI - [On the problem of identification of homoxenous trypanosome cultures with the description of a new species Wallaceina podlipaevi sp. n. (Kinetoplastida: Trypanosomatidae)]. AB - The type culture of Leptomonas peterhoffi Podlipaev, 1985 (stamm P-101) was examined using light and electron microscopy. The hapantotype of L. peterhoffi Podlipaev, 1985 was reexamined with a light microscope. As a result, a new species of homoxenous trypanosomes, Wallaceina podlipaevi, sp. n. was described. PMID- 20198969 TI - [Aneugenic effect of ionizing radiation in mammalian and human somatic cells]. AB - Aneuploidy is among the most serious impairments of hereditary material in somatic and germline cells of living organisms. Chromosome loss or the appearance of an extra homolog in the chromosome set can result in either cell death or the development of various neoplasms with high probability of malignancy. It was traditionally believed that ionizing radiation produces primarily a clastogenic effect. However, there is apparently an aneugenic component of radiation, with mechanism different from that of structural chromosome damage. The present review focuses on the evidence for the existence of the aneugenic effect of ionizing radiation in mammalian and human somatic cells. PMID- 20198970 TI - [Differentiation of chromosome banding sequence pools and genomic DNA in holarctic natural populations of Chironomus entis Shobanov (Diptera, Chironomidae)]. AB - Polymorphism and differentiation of the chromosome banding sequence pools and genomic DNA were studied in three natural populations of Chironomus entis from Europe and North America. These populations showed a moderate level of chromosome polymorphism and high RAPD polymorphism of genomic DNA. The Palearctic and Nearctic populations of this species did not differ significantly in the levels of chromosome and genomic DNA polymorphism. Estimation of the cytogenetic (GDcg) and genetic (GD(DNA)) distances between these C. entis populations showed that their chromosome banding sequence pools and cytogenetic structures are differentiated to a greater extent than genomic DNA. The values of cytogenetic and genetic distances between the Palearctic and Nearctic populations of C. entis are higher than the values of the corresponding distances between the Nearctic populations, but they do not reach the level of divergence between species. PMID- 20198971 TI - [Taxonomic genetics of Zygowilliopsis yeasts]. AB - Genetic hybridization analysis was conducted with 16 natural Zygowilliopsis strains isolated in different geographical regions and maintained in collections under species names Z. californica, Hansenula dimennae, and Pichia populi. Genetic relatedness was determined on the basis of mating, viability of hybrid progeny, and meiotic recombination of markers. Four new biological species are recognized in the former monotypic genus Zygowilliopsis. Species Z. californica and Zygowilliopsis sp. 3 probably include divergent geographical populations. It is necessary to reconsider the species composition of the genus Zygowilliopsis and generic assignment of P. populi yeasts. Genetic and molecular identifications of the Zygowilliopsis species are in perfect agreement. PMID- 20198972 TI - [Comparative cytological and molecular analysis of introgressive common wheat lines containing genetic material of Triticum timopheevii Zhur]. AB - A total of 40 introgressive lines of common wheat (2n = 42) Triticum aestivum L x T. timopheevii Zhuk., resistant to brown rust and partly to powdery mildew, were examined. Based on cytological analysis of meiosis in pollen mother cells (PMC), hybrid lines were subdivided into two groups characterized by either stable or unstable meiosis. In cytologically stable lines, chromosome configuration at the MI stage of meiosis was mostly bivalent (21II) with small proportion of defect cells (almost 10%), which at most contained two univalents (20II + + 21). Cytologically unstable group was comprised of the lines, containing high proportions of cells with abnormal chromosome pairing in meiotic PMC, as well as the cells with multivalents, and the lines containing aneuploid plants. Localization of the T. timopheevii fragments performed with the use of SSR markers showed that the lines with unstable meiosis were characterized by higher numbers of introgressions compared to stable lines. The influence of certain chromosomes of T. timopheevii on chromosome pairing stability was also demonstrated. In cytologically unstable lines, the increased frequency of 2A substitutions along with the high frequency of introgression of T. timopheevii genetic material into chromosome 7A was observed. Multivalents were scored in all cases of introgression in chromosome 7A. It was suggested that the reason for the genome instability in hybrid forms lied in insufficient compensating ability of certain T. timopheevii chromosomes and/or their parts, involved into recombination processes. PMID- 20198973 TI - [Production of alloplasmic and euplasmic wheat-barley ditelosomic substitution lines 7H(1)Lmar(7D) and analysis of the 18S/5S mitochondrial repeat in these lines]. AB - Alloplasmic lines of common wheat with disomic substitution of chromosome 7D for telocentric chromosome 7H(1)Lmar of barley H. marinum subsp. gussoneanum Hudson were isolated from the plants of generation BC3, produced as a result of backcrossing of barley-wheat hybrids H. marinum subsp. gussoneanum (2n = 28) x x T. aestivum (2n = 42), Pyrotrix, cultivar, with 28 common wheat cultivars Pyrotrix 28 and Novosibirskaya 67. Chromosome substitution pattern was determined using SSR analysis and C-banding. In preliminary genomic in situ hybridization experiments, telocentric chromosomes were assigned to wild barley was established. In the BC3F8-generations of three alloplasmic lines with the 7H(1)Lmar(7D) substitution type the differences in fertility manifestation were observed: most of the L-32(1) plants were sterile, in line L-32(2) only sporadic plants were sterile, and line L-32(3) was fertile. Simultaneously with these experiments, using self-pollinated progeny of the hybrids obtained in crosses of common wheat cultivar Saratovskaya 29 (2n = 41), monosomic for chromosome 7D, with common wheat cultivar Pyrotrix 28 with addition of pair of telocentric chromosomes 7H(1)Lmar(7D) of barley H. marinum subsp. gussoneanum, euplasmic wheat-barley ditelosomic substitution 7H(1)Lmar(7D) lines were isolated. The lines obtained had normal fertility. PCR analysis of the 18S/5S mitochondrial repeat (hereafter, mtDNA sequence) in alloplasmic and euplasmic ditelosomic substitution lines 7H(1)Lmar(7D) was performed. In the plants from alloplasmic sterile line L-32(1), the sequences only of the barley (maternal) type were revealed, while the plants from alloplasmic fertile lines L-32(2) and L-32(3) demonstrated heteroplasmy (the presence of barley- and wheat-like sequences within one individual). In euplasmic ditelosomic substitution lines the presence of only wheat-like 18S/5S mitochondrial repeat sequences was observed. The results indicate that the presence of barley-like mtDNA sequences in alloplasmic substitution lines was not associated with the presence of barley chromosomes in their nuclear genomes. PMID- 20198974 TI - [Molecular genetic mapping of the sy1 and sy9 asynaptic genes in rye (Secale cereale L.) using microsatellite and isozyme markers]. AB - Studies of phenotypical expression of synaptic mutations in combination with the localization of corresponding genes on a genetic map permit individual stages of the meiotic process to be differentiated. Two rye asynaptic genes, sy1 and sy9, were mapped with the use of microsatellite markers (SSR) in the pericentromeric regions of the long chromosome arms 7R and 2R, respectively. The sy9 gene cosegregated with two SSR markers Xscm43 and Xgwm132. The asynaptic gene sy1 was mapped within the interval between the isozyme locus Aat2 and two cosegregating loci Xrems1188 and Xrems1135 that are located at a distance of 0.4 cM proximally and 0.1 cM distally with respect to the gene lous. Possible evolutionary relationships of the mapped genes with homeological loci of the Triticeae species and more distant cereal species, such as maize and rice, are discussed. PMID- 20198975 TI - [Effects of monorecessive and double recessive mutations affecting coat color on the monoamine content of the brain of the American mink (Mustela vison Schreber, 1777)]. AB - The effects of mutations affecting the coat color on the dopamine, noradrenaline, and serotonin contents of the hypothalamus and brainstem of the American mink have been studied. The sample comprised standard (+/+) and mutant minks, including the monorecessive pastel (b/b), silver-blue (p/p), and white hedlund (h/h) and the combination double recessive sapphire (a/a p/p) and pearl (k/k p/p) ones. The dopamine content of the brainstem of the monorecessive pastel (b/b) and silver-blue (p/p) minks has been found to be higher than in standard (+/+) minks. Conversely, the homozigosity for two coat color loci in double recessive pearl minks (k/k p/p) significantly decreases the noradrenaline and serotonin contents of the hypothalamus. In addition, monorecessive and double recessive minks differ from each other in the serotonin contents of the midbrain and medulla. PMID- 20198976 TI - SNP detection and haplotype analysis in partial sequence of MSTN gene in sheep. AB - Polymerase chain reaction (PCR) products of the MSTN gene amplified from sixty sheep of nine Chinese indigenous sheep breeds and one imported sheep breed were sequenced to identify the single-nucleotide polymorphisms (SNPs) in a 378-bp fragment including intron 2 and exon 3 of the MSTN gene. A total of fifteen SNPs (A1937C, T1942G, C1956T, A1972C, A1990G, A2008C, A2011G, C2019T, A2025C, A2027C, T2085G, T2173C, C2198T, C2210T and C2213T) were detected among the sixty sequenced individuals and they were all located in intron 2. Twelve haplotypes were identified from these fifteen SNPs, of which haplotype I (CGTCGCGTCCGCTTT) and VIII (ATCAAAACAATTCCC) were the two major and basic ones with frequencies of 12.25% and 77.80%, respectively. Haplotype VIII was distributed in all sheep breeds and all individuals of the meat or meat-wool type sheep breeds were homozygous with respect to this haplotype. This suggests that haplotype VIII might be related to meat production traits in sheep. Haplotype I was only distributed in the fur, lambskin type and fur-meat type sheep breeds. This suggests that haplotype I may have some relationship with fur traits in sheep. PMID- 20198977 TI - [Formation and chromosome evolution of the palaearctic species of chironomids of the genus Sergentia Kieffer (Diptera, Chironomidae)]. AB - Chromosome polymorphism was studied in populations of three palaearctic species of chironomids of the genus Sergentia Kieffer (Diptera, Chironomidae) from the Irkutsk reservoir: S. baueri Wulker et al., 1999, S. prima Proviz et al., 1997, and S. electa Proviz et al., 1999. It was found that in S. baueri heterozygous individuals constitute 72% of the population with 0.8 of inversion per individual. In total, three inversion sequences were detected. The most widespread was the inversion in regions 7-12 of the arm IIIR with the borders similar to those of the inversion in the Far East S. baueri populations and in populations of other species of the genus. In S. prima, heterozygotes constituted 60%, with the number of inversions per individual was 1.3. Seven inversion sequences were revealed, of which three were found in chromosome IV. In the S. electa population, only one inversion sequence was observed in chromosome III in 36% of larvae (0.4 of inversion per individual). The level of chromosome polymorphism in the populations of the palaearctic species is comparable with that in the populations of endemic Sergentia from the Baikal Lake. Ten rearrangements were revealed in each of the two groups, but similar borders of chromosome regions were established only for two inversions. In the studied Sergentia species, chromosome IV has the most variable structure. PMID- 20198978 TI - [Genetic variants of CYP1B1 and WDR36 in the patients with primary congenital glaucoma and primary open angle glaucoma from Saint-Petersburg]. AB - In 32 patients with primary congenital glaucoma (PCG), a search for mutations in the myocilin (MYOC), cytochrome P450B1 (CYP1B1), and WDR36 genes was performed. The Q368X mutation in myocilin gene, typical of the patients with adult-onset primary open-angle glaucoma (POAG), was not detected in the PCG patients. Screening of the CYP1B1 introns 2 and 3 for the presence of mutations in PCG patients revealed only six DNA polymorphisms, including IVS1-12ntT>C (g.3793 T>C), A119S (g.4160 G>T; GCC>TCC), G188G (g.4369 C>A; GGC>GGA), L432V (G.8131 C>G; CTG>GTG), D449D (g.8184 C>T; GAC>GAT), and N453S (g.8195 A>G; AAC>AGC) (nucleotide numbering is given in accordance with the GenBank sequence U56438). In the groups of PCG patients and donors without eye diseases, the frequencies of these variants were not statistically significantly different, pointing to the neutrality of these polymorphisms. Furthermore, the CYP1B1 polymorphism L432V, considered to be associated with POAG in some world populations, was not associated with this disease in the patients from St. Petersburg. DNA collections obtained from the POAG and PCG patients and from the control group were tested for the carriage of the worldwide distributed mutations of the WRD36 gene, D658G, R529Q, A449T, and N355S. D658G variant was found with equally low frequencies in the groups of POAG and PCG patients, as well as in the control group. Mutations A449T and R529Q were found only once each, while mutation N355S was not detected in any of the groups examined. Our results indicate that the WDR36 variants make no substantial contribution to the development of POAG and PCG in the patients from St. Petersburg and represent normal DNA polymorphism. It is likely that in most of the PCG patients from the population examined the disease is not associated with the CYP1B1 gene defects. PMID- 20198979 TI - [Association between the tryptophan hydroxylase (TPH) gene polymorphic markers and endogenous psychoses]. AB - Tryptophan hydroxylase is one of the key enzymes involved in serotonergic metabolism. In many studies, an association between the TPH gene and human mentality, as well as mental disorder was demonstrated. This study was designed to analyze the association between three TPH gene polymorphisms (A218C, T3792A, and (CT)n(CA)n(CT)n) and endogenous psychoses. The patients included into investigation were represented by those with manic-depressive psychosis (93 individuals) and those with the schizophrenia spectrum disorders (307 individuals). An association between the A218C polymorphism with the disorders of the schizophrenia spectrum was demonstrated. These findings confirmed the data obtained earlier for other populations. In addition, an association between the (CT)n(CA)n(CT)n microsatellite repeats and bipolar disease was shown for the first time. PMID- 20198980 TI - [Efficiency of evaluating the carcinogenicity of chemical substances in short term tests and the SAR model]. AB - The efficiency of estimating the carcinogenic activity of chemical substances was compared for five short-term tests and structure-activity relationships (SAR) analysis. The sample included 84 substances with known biological testing results obtained by the Ames test, bacterial SOS chromotest (SOS), chromosome aberration (CA) cytogenetic test, sister chromatid exchange (SHE) test, and gene mutation (GM) test with mammalian cells in vitro and by carcinogenicity assays in rodents in vivo. Structural descriptors were selected using an original database, which included the structural formulas of substances with known carcinogenic activity in rodents. Original software was created to generate and select the descriptors that statistically coincided with carcinogenic activity. The descriptors that were associated exclusively with carcinogenic substances from the database and the tests that produced positive results exclusively with carcinogens were used to evaluate the carcinogenic activity of the substances. A combination of three short-term tests (Ames, SOS, and CA tests) and the SAR model proved to identify carcinogenicity for more than 60% of carcinogens. PMID- 20198981 TI - [Metabolic markers of the head and neck cancers--clinical applications and the biochemical background]. AB - The problem of diagnosis in the field of head and neck region is still valid. Specific diagnosis and precise estimation of the tumor's size with the use of CT and MRI imaging is generally unsatisfactory. The Positron Emission Tomography (PET) supports this process with additional information about the tumor's metabolism. Numerous publications show that PET-CT has a great influence on the evaluation of the size of the tumor, presence of lymph node metastases, choice of treatment and the prognosis of the recurrence. Cancer cells represent a specific metabolic state. These cells intake large quantities of glucose and utilize it in the process of glycolysis. The oxidative phosphorylation is not efficient in the transformed cells and defects in mitochondrial functions are at the heart of malignant cell transformation. Disruption of the oxidative phosphorylation chain has been described in the neoplasms. As a consequence, in cancer the glycolysis is active even in the normoxic environment. This metabolic shift in cell transformation has been described in early XX century and so called Warburg's hypothesis profoundly influenced the present perception of cancer metabolism, positioning what is termed aerobic glycolysis in the mainstream of clinical oncology. Today we know that neoplastic cells differ at the proteomic level. A subset of different proteins such as hexokinase II or HIF are upregulated. These abnormalities might be used as the neoplastic markers. PMID- 20198982 TI - [Facelift incision parotidectomy: preliminary report]. AB - INTRODUCTION: Traditional approaches parotidectomy leaves a visible scar and a hollow on the face and neck, which might be dissappointing to some patients. AIM OF THE STUDY: Assessment of usefulness of facelift approach to the parotid gland PATIENT AND METHODS: A retrospective study was performed. In June 2009 eight patients with benign parotid tumour underwent superficial parotidectomy. Four of them were included in the rhytidectomy approach parotidectomies and SMAS advancement flap was carried out to reconstruct the parotid bed and prevent Frey's syndrome. The latter patients underwent the classical technique parotidectomies. After two months from the operation both groups of patients were asked to assess the cosmetic outcome of the surgery in five degree scale. RESULTS: The duration of the operation increased by an average of 20 minutes in the rhytidectomy approach group. No major difficulties in exposing the facial nerve and its branches were observed. Patients were more satisfied when facelift approach was performed. CONCLUSION: A rhytidectomy approach to the parotid gland seems to be safe method and aesthetic results are more satisfactory as comparing to classical approach. PMID- 20198983 TI - [Hexosoaminidase gene expression in cholesteatoma in adults]. AB - BACKGROUND: Middle ear cholesteatoma is a cyst like structure composed of keratinizing squamous epithelium that contains keratin debris and subepithelial connective tissue. Bone resorption may lead to destruction of ossicular chain and temporal bone. The higher activity of N-acetyl-beta3-glucosaminidase (HEX) was noted in cholesteatoma tissue, compared to the controls. It is supposed, that HEX takes part in bone resorption in middle ear cholesteatoma. Using of HEX inhibitors in cultured fibroblasts and evaluation HEX mRNA expression may contribute to showing new ways of understanding cholesteatoma pathogenesis. THE AIM OF THE STUDY: was to elaborate cholesteatoma fibroblast cell culture (CF) technique and evaluate in vitro inhibition potential of pyrimethamine. MATERIAL AND METHODS: Cholesteatoma and normal retroauricular skin sample obtained during surgical treatment were used in the study. CF served as a study group and fibroblast derived from skin specimens--as controls. Pyrimethamine was used at the concentrations of 1.5, 3, 10 and 20 microg/ml. The reverse transcriptase polymerase chain reaction (RT-PCR) was carried out for the determination of HEX gene expression. RESULTS: RT-PCR established the elevated expression of HEXA and HEXB mRNA in cholesteatoma. HEXA mRNA in CF was six times higher than in the controls. HEX mRNA expression found to be regulated by pyrimethamine. Inhibition of HEXA and HEXB mRNA expression was achieved when the highest concentration of PYR was used. Low concentrations of pyrimethamine upregulated HEX gene in CF. CONCLUSIONS: Pyrimethamine, depending on its concentration, contributes to regulating the HEX gene expression in CF and controls. Pyrimethamine may be regarded as a new future research direction on factors, that may limit development of cholesteatoma. PMID- 20198984 TI - [Morphology of the glottis and perceptiv-acoustic characteristic of the voice and speech after extended fronto-lateral epiglotttoplasty]. AB - For optimalisation glottis morphology and its phonatory function after frontolateral laryngectomy (FLL) the reconstruction of larynx is made; in Clinic of Otolaryngology the most common is using epiglottis wit or without its vertical incision. AIM OF THE STUDY: the influence of widening laryngeal resection and epiglottis incision on shape of reconstructed glottis, level and degree of phonatory closure and perceptive--acoustic characteristic of voice and speech. MATERIAL: 39 patients (38 M and 1 F) after FLL widened of false vocal cord (n = 11), false vocal cord and part of cricoid cartilage (n = 22), whole cricoid cartilage (n = 6). Vertical incision of epiglottis was made in 31 cases. Mean age was 52 (min.-39, max.-70) years. METHODICS: videolaryngoscopic examination, subjective voice estimation using GRBAS scale, objective phonetic--acoustic voice analysis. RESULTS: In videolaryngoscopic examination the most common shape of glottis was irregular triangle (n = 24), rhombus (n = 7), half--moon (n = 2), irregular (n = 6). 2 patients were using whisper. In spectrographic recordings (n = 39) only noise character of stimulation source was in 2 patients, noise- periodic with noise component present in whole acoustic spectrum in 37. F0 for single word and sentence vocalized in affirmative and interrogative form had the value of male voices and its changes during speaking were well noted. In subjective and objective estimation, the worse voice quality was after FLL widened of false vocal cord, part or whole cricoid cartilage. CONCLUSION: 1) FLL with subsequent epiglottoplasty in 94% of patients makes satisfactory morphologic and biophysical conditions for production of voice and sociological efficient speech. 2) Widening resection of false vocal cord, part or whole cricoid cartilage has unbeneficial influence on perceptive--acoustic characteristic of voice and speech. PMID- 20198985 TI - [Evaluation of percentage of lymphocytes B with expression of co-receptors CD 40, CD22 and CD72 in hypertrophied adenoid at children with otitis media with effusion]. AB - INTRODUCTION: In hypertrophied adenoid lymphocytes B make up about 60% all lymphocytes. When the lymphocytes B come in interaction with antigens this membranes signal be passed through their receptor (BCR) to interior of cell. This signal affect modulation on gene expression, activation from which depends activation, anergy or apoptosis of lymphocyte B. Accompany BCR co-receptors regulate his functions influence stimulate or inhibitive. To the most important co-receptors stepping out on lymphocyte B belong: CD40, CD22, CD72. AIM OF STUDY: The aim of study was evaluation of lymphocytes B (CD19) with co-expression with CD72 and CD40 receptors in hypertrophied adenoid with at children with otitis media with effusion. MATERIAL: An investigation was executed in hypertrophied adenoids with or without otitis media with effusion. METHODS: By flow cytometry percentage of lymphocytes B with co-receptors CD 40, CD22 and CD72 in was analyzed. RESULTS: The percentages of CD19+CD72+ lymphocytes in the group of children with adenoid hypertrophy and exudative otitis media were lower as compared to the reference group. However, the percentages of CD19+CD22+, CD19+CD40+ in the study group was approximate to the reference group. CONCLUSIONS: The lower percentage of lymphocytes B CD72 + near approximate percentages of lymphocytes B CD40+ and BCD22+ at children with otitis media with effusion can be the cause of incorrect humoral response in hypertrophied adenoid at children. Maybe it is cause reduced spontaneous production IgA and IgG through lymphocyte at children with otitis media with effusion. PMID- 20198986 TI - [Assessment of Polish physicians' therapy behaviour and patterns of prescribing antihistaminic medicines in day-to-day outpatient care]. AB - AIM OF THE STUDY: The aim of the study was to assess management of patients with allergies, to evaluate frequency of use of specific antihistamines in population with diagnosed allergy, to evaluate causes and frequency of antihistamines' discontinuation, as well as frequency of allergen identification. MATERIAL AND METHOD: This was a multi-centre, observational study, in the form of epidemiological registry. The study was conducted in 1200 centres all over the country. 23 997 patients with diagnosed allergic condition were enrolled into this study. RESULTS: The most frequent allergic condition in the surveyed population was allergic rhinitis (51% of all enrolled patients), urticaria (28%), and allergic conjunctivitis (20%). Only 6 562 subjects (27%) had been examined with skin prick tests or specific IgE antibodies tests and their allergens had been identified. The remaining subjects had been treated so far with no attempts to identify allergy triggers (allergens). In the surveyed population, the dominant type was pollen allergy (62%) and house dust mites allergy (33%). Only 48% of subjects were on antiallergic treatment at the time of the enrollement into this epidemiological registry. The main causes of medication discontinuation were side effects observed, predominantly sedation. CONCLUSIONS: The most frequent allergic condition treated in outpatient setting is allergic rhinitis. Only 48% of allergic patients take antiallergic medicines (predominantly antihistamines). The most prevalent reason for treatment discontinuation are side effects, mainly sedation. PMID- 20198987 TI - [Emergence pathogens infections in ENT Department of Children's hospital in 2005 2008]. AB - INTRODUCTION: The development of medicine, in this the new techniques and antibiotic therapy enlarged the survivability of patients in hospital. Applying antibiotics caused breakthrough in treatment stepping out in ill's group infections treated in hospital, however enlarging resistance is natural this effect, resulting from: the selection of resistant strains, the formation of new mechanisms of resistance, and/or the spreading of gene of resistance. Multidrug resistant strains were included to emergence-pathogens group: MRSA, penicillin resistant Streptococcus pneumoniae, VRE, Gram-negative producing beta-lactamase of type the ESBL and/or resistant to carbapenems. Emergence-pathogens occurrence leads to: therapeutic failures, the use extorts in therapy of dear medicines or with possibility of workings undesirable. The multidrug-resistant strains spread in hospital environment easily, especially on departments about high waste of medicines with the patients' simultaneously large susceptibility on infection, resulting mainly with state of reduced resistance of organism. The control of hospital infections recognize by present hospitality for the most important criterion of quality of work. AIM: Analysis of the emergence-pathogens isolated during treatment in hospital in 2005-2008, from special regard the ENT Department. MATERIAL AND METHODS: 50586 children treated in this period in hospital in which was executed 39386 bacteriological investigations, in this 6528 (12.9%) children in ENT Department in which was executed 1566 bacteriological investigations (3.98%). The diagnostics were executed according to routine microbiological procedures with qualification of resistance to antibiotics. RESULTS: Emergence-pathogens infection was confirmed at 2369 children's (4.68%) treated in Hospital, in this in ENT Department at 84 children (1.29%). The most frequent emergence-pathogens in ENT Department were Streptococcus pyogenes, Streptococcus pneumoniae penicillin-resistant and average sensitive on penicillin, Staphylococcus aureus methicillin-resistant and Rotavirus. CONCLUSIONS: Streptococcus pneumoniae penicillin-resistant and average sensitive to penicillin and Rotavirus infections are the most frequent hospital infections. The systematic microbiological supervision is indispensable in prevention the spreading of infections of the emergence-pathogens in hospital. PMID- 20198988 TI - Endovascular treatment of hereditary hemorrhagic telangiectases of the tongue. AB - Hereditary hemorrhagic telangiectasia, also known as Osler-Weber-Rendu disease, is an autosomal dominant disorder involving vascular abnormalities of various organs. Telangiectases are frequently observed, predominantly on the nasal and oral mucosa. We present a case a of 53-year-old man with the tonge hemorrhagic telangiectases and epistaxis. Selective catheterization and embolization of the right lingual artery led to size redution and no bleeding from tongue telangiectases. PMID- 20198989 TI - [Tracheal stenting in patients treated due to carcinoma of the larynx]. AB - INTRODUCTION: Stenosis of the trachea and main bronchia can occur in patients with lung, larynx, thyroid gland, esophagus, in metastatic tumors, can be also caused by trauma and foreign bodies. Treatment in this condition can be difficult. Tracheal stenosis in patients after total removal of the larynx is relatively rare. It can be caused by recidiv tumor and inflammation processes. AIM OF THE STUDY: Was to evaluate usefulness of stents in patient with stenosis of the trachea after total laryngectomy due to squamous cell carcinoma. MATERIAL AND METHODS: Authors described two cases of patient after total laryngectomy. Nitinol, expandable, tracheal stents were used in both cases. Placement of the stent into the trachea was relatively simple. Patients have undergone this procedure in short general anesthesia. RESULTS: After stenting patients exhibited dramatic improvement in their respiratory symptoms and quality of life. CONCLUSIONS: Stents are useful in cases of tracheal stenosis and the effect is related to the reason of stenosis. PMID- 20198990 TI - [Mediastinal emphysema as a complication of the tonsilloadenotomy in child]. AB - AIM OF THE PAPER: Authors present the case of a 6 years old boy with rare complication of mediastinal emphysema after tonsilloadenotomy. MATERIAL AND METHODS: Authors detailed describe the evolution of this complication and methods of its treatment. This complication was treated in Child's Surgery Clinic where the digestive and respiratory tracts were controlled and upper mediastinotomy with drainage of the mediastinum was performed. Subsequently, the child was treated on the Intensive Care Unit where prolonged intubation and parenteral feeding were used and was discharged completely healed after 7 days. Authors discuss possible causes of this complication as a result of injury of the pharyngeal wall during the operation due to vomits after general anastesia. RESULTS OF THE TREATMENT: Total period of treatment of this complication was 14 days. The authors deal as well with the issue of underestimating the risk associated with the operational procedures on tonsils, especially in the case of children. They also consider the possibility of performing such procedures in the one day surgery conditions. CONCLUSIONS: The analysed complication associated with tonsils operation are rather unusual and its successfull treatment depends on quick and accurate diagnosis, which is possible due to meticulous postoperational care. PMID- 20198991 TI - [Our experience with Denti root form implants in clinical practice]. AB - In the past 40 years, dental implantology has developed significantly in Hungary just like all over the world. This development refers to the implant materials, the diagnostics, the surgical techniques and the implantation prosthetics equally. According to the available statistics, approximately 66,000 implants are used annually in Hungary, which are provided by 32 implant systems. DenTi System founded in 1989, takes a prominent place among the 32 systems developing and preparing the implants in cooperation with the German Hager & Meisinger Company since 2003. The author of this paper has been using the system since 1995 and summarizes the experience gained in the past 5 years with the most ecently developed Denti implants: the one-stage root form implants, the one-stage Denti zirconium root form implants, the two-stage Denti root form implants and the two stage Denti root form zirconium implants. Based on the findings, the author concludes that Denti implants belong to the best implants both in Hungary and worldwide. PMID- 20198993 TI - [Immediate replacement of missing lower front teeth using Denti One-Piece and needle implants]. AB - The Denti one-stage root form implant made of pure titanium (so called DOP implant type) was introduced in 2004 and the Denti Needle implants was introduced in 2007. The author of this paper was one of the first who used these systems in Hungary. The observation period of the implanted DOP implants ranges between 1 to 5 years with a success rate of 95.1%. So far, only a small number of these type of implants have been placed, with an observation period of 1 to 5 years, therefore statistical analysis could not be made. Clinical experiences obtained during the course of the use of these implants are most favourably primarily because of their easy use and special indication (small volume of vestibulo oralis bone). In this way these implants are especially suitable for the replacement of missing front tooth. PMID- 20198992 TI - [Long term (10 years) experience of immediate implant placement]. AB - Immediate placement of dental implants have been widely used to retain and support cross-arch partial dentures. 3-6 months after implantation the osseointegration is established. This period may be shortened with immediate implant placement technique. The purpose of this study was to evaluate the factors that may influence the long term success of immediate implantation. Clinical results of 10 yrs period of immediate implant placement were investigated in case of 184 patients and 258 Denti implants. The control was carried out with 121 patients and with 192 implants placed with submerged technique. The retrospective long term follow-up examination has revailed that the success rate of Denti implants with traditional two stage surgery was 97,4%. The success rate of Denti implants with immediate placement was 95.75%. According to the data, the prognosis of immediate implantations-method are compatible (comparable) to the traditional inserted implants. PMID- 20198994 TI - [10 years experience of immediate implant placement using Denti implants and the results found in the literature]. AB - Immediate placement of dental implants have been widely used to retain the single crowns and support cross-arch partial dentures. 3-6 months after implantation the osseointegration is established. This period may be shortened with immediate implant placement and immediate or deleyed loading of implants. The purpose of this study was to compare the long term experience of immediate placement of Dent implants and the results reported in available literature. The most relevant articles were selected from current available literature. The influencing factors of success of method of immediate implantation/surgery,- host,- implant and esthetic-related factors/were investigated and discussed in this article. The result of the evaluation showed that the success rate of the immediate placement of Denti implants with large grit sandblasted treatment and acid etched surface in the examined period was higher than 95%. The success rate of the method of immediate implantation using of Denti implants is similar to the ones reported in the available literature. PMID- 20198995 TI - [Commemorating the foundation of the dental clinics. I. The foundation of the stomatology clinic (in Budapest, Hungary)]. AB - The roots of the Hungarian dental education date from the mid-19th century. After several unsuccessful attempts, the University Dental Institution was founded in 1890 under the leadership of Jozsef Akovy in provisional premises. To improve the bad infrastructural circumstances, a new building was erected in February 1909 to accommodate the new Clinic of Stomatology. PMID- 20198996 TI - Tories: degrees should be an aspiration, not a barrier. PMID- 20198997 TI - 'We need to be clear about our primary responsibility'. PMID- 20198998 TI - Using general nurses to fill health visitor gaps puts children at risk. PMID- 20198999 TI - How to ensure patient observations lead to effective management of bradycardia. AB - Bradycardia can be a normal physiological sign in fit young adults. However, in acute illness it may indicate life threatening heart block or precede asystole. This article outlines the assessment and management of patients with this condition. PMID- 20199000 TI - NICE guidance to reduce the risk of venous thromboembolism in hospital patients. PMID- 20199001 TI - How to improve services for dying patients in critical care: adapting protocols. AB - This article outlines a project to improve end of life care for those who are critically ill, by adapting and implementing a national protocol specially developed for the intensive care unit. The rollout of the pathway is discussed along with an audit which found the trajectory towards death following withdrawal of treatment can be swift. The extent of documentation is, therefore, an important consideration to ensure nurses can balance patients' needs with those of grieving relatives while ensuring bereavement care is accurately documented. PMID- 20199002 TI - Weaning from ventilation needs to be tailored to individual patients and involve them. AB - AIM: To improve understanding of how nurses use technology to wean patients from mechanical ventilation. BACKGROUND: The literature tends to focus on weaning indices, predictors of success or weaning methods. Few papers address patients' experiences of weaning. DESIGN: An ethnographic approach was adopted to understand how nurses used technology to wean patients from ventilation. METHODS: Data was gathered by participant observation and interviews over six months. In total, 250 hours of field notes were recorded. RESULTS: Data was analysed using the content analysis method. A central theme of knowing the patient was identified, as well as three sub-themes: ways of knowing; continuity of care; and patients' role in the weaning trajectory. CONCLUSION: Participants implied during interviews that "knowing the patient" was essential to delivering patient centred care. Two main factors are necessary for nurses to know their patients: continuity of care and expertise. "Ways of knowing" relied on gaining information about patients and their role as passive recipients of treatment. IMPLICATIONS FOR PRACTICE: Staff allocation systems should enable them to learn from experienced nurses, while work schedules should be organised to ensure nurses begin weaning when they can offer continuity of care. Knowing the patient has been defined as a characteristic of expert nursing. To be truly patient centred, nurses need to address the barriers that prevent them from getting to "know" patients. PMID- 20199003 TI - Whistleblowing: what influences nurses' decisions on whether to report poor practice? AB - Several recent high profile examples demonstrate that nurses fear and have reason to fear the consequences of reporting poor practice. This article examines the ethical issues surrounding whistleblowing, discussing in detail the reasons for and against reporting concerns about poor practice, and how nurses can be supported to do this. PMID- 20199004 TI - Conservative policy will be directly influenced by you. PMID- 20199005 TI - Modern life makes me dizzy, but I'm certain about this. PMID- 20199006 TI - Miradas-the art and science of visual expression. PMID- 20199007 TI - LASIK flap creation with the Ziemer femtosecond laser in 787 consecutive eyes. AB - PURPOSE: To present the flap characteristics and short-term efficacy and safety of 787 consecutive LASIK procedures with the FEMTO LDV femtosecond laser (Ziemer Ophthalmic Systems) for the treatment of refractive errors. METHODS: Seven hundred eighty-seven consecutive eyes of 405 previously non-operated patients were treated with the FEMTO LDV. Intended flap thickness was 110 microm and intended flap diameter varied from 8.5 to 9.5 mm. Refractive treatment was performed with the WaveLight ALLEGRETTO WAVE Concerto 500 Hz excimer laser. All eyes were wavefront-optimized. RESULTS: The mean flap thickness, measured by ultrasound pachymetry, was 90.0+/-5.5 microm (range: 67 to 107 microm) in right eyes and 90.1+/-4.6 microm (range: 77 to 106 microm) in left eyes. Mean flap diameter was 9.1+/-0.2 mm (range: 8.4 to 9.9 mm) in right eyes and 9.1+/-0.2 mm (range: 8.0 to 10.0 mm) in left eyes. Increasing flap thickness was correlated with increasing corneal thickness in right eyes and flatter keratometric value K(1) in left eyes. The most common complication was minor bleeding during the procedure (12.7%). All other complications were rare (8.4%), and none prevented further laser ablation. CONCLUSIONS: The Ziemer FEMTO LDV laser created thinner LASIK flaps than intended but with a low standard deviation and minimal intraoperative complications. PMID- 20199008 TI - Static and dynamic rotational eye tracking during LASIK treatment of myopic astigmatism with the Zyoptix laser platform and Advanced Control Eye Tracker. AB - PURPOSE: To evaluate the amount of cyclotorsion and the effect of static and dynamic rotational eye tracking with the Advanced Control Eye Tracker (Bausch & Lomb) based on iris recognition in the treatment of myopic astigmatism with LASIK. METHODS: All patients with myopic LASIK and attempted cylinder correction >0.75 diopters (D) on the Zyoptix 217z100 excimer laser platform between May 2005 and May 2007 were identified retrospectively through the existing databank. Pre- and postoperative refraction and the amount of cyclotorsion during treatment were extracted and analyzed in 828 eyes with >3-month follow-up. RESULTS: Preoperative mean manifest refraction spherical equivalent (MRSE) was -4.31+/-1.84 D (range: 0.37 to -9.50 D), and mean cylinder was -1.27+/-0.87 D (range: -0.75 to -6.75 D). Mean static rotation was 3.96+/-2.96 degrees (maximum 14.8 degrees ). Median dynamic rotation was 1.32+/-1.85 degrees (maximum 24 degrees). At 3 months postoperatively, MRSE was -0.10+/-0.36 D (range: -2.25 to +1.25 D), and mean cylinder was -0.33+/-0.35 D (range: -2.00 to 0 D). Predictability was 90.2% within +/-0.50 D and 98.2% within +/-1.00 D (MRSE), and 82.5% within +/-0.50 D and 96.9% within +/-1.00 D (cylinder). The efficacy ratio was 0.99. Safety was 99.4% (5 dry eyes), reaching 100% at 12 months. Stability from 3 to 12 months (n=275) was 98.2% for sphere, 95.3% for cylinder, and 96.0% for MRSE. CONCLUSIONS: Our study demonstrates that significant cyclotorsion occurs before and during treatment. By using the dynamic rotational eye tracker presented, the efficacy of cylinder correction can be improved compared to those studies not performing cyclotorsional correction. PMID- 20199009 TI - Use of brimonidine before LASIK with femtosecond laser-created flaps for the correction of myopia: a contralateral eye study. AB - PURPOSE: To evaluate the changes in the incidence of subconjunctival hemorrhage, hyperemia, photophobia, flap displacements, and flap retractions in myopic patients who have undergone LASIK with an IntraLase 15-kHz femtosecond laser (intraLASIK) with or without the application of brimonidine tartrate 0.2% in one eye. METHODS: Two hundred eyes of 100 myopic patients were enrolled in this brimonidine tartrate fellow eye control study. These myopic patients were treated with the intraLASIK technique in both eyes. Only 1 eye was treated with brimonidine tartrate 0.2% 30 minutes before surgery. One day after surgery, subconjunctival hemorrhage, photophobia, and hyperemia were evaluated. Flap slippage and flap retractions were evaluated 1 day, 1 week, 1 month, and 3 months after surgery. RESULTS: Of the 100 eyes treated with brimonidine tartrate before intraLASIK, 3 (3%) eyes showed subconjunctival hemorrhage. Complex hyperemia photophobia was found in 8 (8%) of 100 eyes immediately after the surgery compared with non-brimonidine tartrate treated eyes (79% and 92%, respectively). Eyes treated with brimonidine showed no incidence of flap complications, whereas eyes not treated with brimonidine showed 11% flap retraction. CONCLUSIONS: This study suggests that brimonidine tartrate 0.2% administered before intraLASIK provides a reduction in the incidence of subconjunctival hemorrhage, hyperemia, and photophobia without increasing flap complications. PMID- 20199011 TI - Introduction to the Proceedings of the 10th International Congress of Wavefront and Presbyopic Refractive Corrections (Lens, Refractive & Wavefront Summit ARI/WFC 2009). PMID- 20199010 TI - Conductive keratoplasty for the treatment of astigmatism induced by corneal trauma or incision. AB - PURPOSE: To assess the efficacy, safety, and predictability of conductive keratoplasty for the treatment of corneal trauma/incision-induced hyperopic or compound astigmatism. METHODS: Thirteen eyes with corneal trauma/incision-induced astigmatism underwent conductive keratoplasty in this prospective study. The main outcome measures included distance uncorrected visual acuity (UCVA), near UCVA, best spectacle-corrected visual acuity (BSCVA), manifest refraction cylinder, keratometric astigmatism, manifest refraction spherical equivalent (MRSE), contrast sensitivity, glare sensitivity, intraocular pressure, tear break-up time, endothelial cell count, and pachymetry. Patients were followed 1 week and 1, 3, and 6 months postoperatively. RESULTS: Mean logMAR scores for distance UCVA, near UCVA, and BSCVA significantly improved from 0.87+/-0.31, 1.32+/-0.41, and 0.18+/-0.18, respectively, to 0.32+/-0.21, 0.59+/-0.21, and 0.08+/-0.11 (P65% RH) in the predeliquescence process and monolayer thin film water was formed at about 30% RH. It demonstrated that this instrument was practicable for studying the hygroscopic behavior of both soluble and insoluble but wettable atmospheric nonviolate aerosol particles. PMID- 20199047 TI - Hydroxyl ionic liquids: the differentiating effect of hydroxyl on polarity due to ionic hydrogen bonds between hydroxyl and anions. AB - The polarity of a series of ionic liquids (ILs) based on hydroxyethyl-imidazolium moiety with various anions ([PF(6)], [NTf(2)], [ClO(4)], [DCA], [NO(3)], [AC], and [Cl]) and their corresponding nonhydroxyl ILs was investigated by solvatochromic dyes and fluorescence probe molecules. Most of the nonhydroxyl ILs exhibit anion-independent polarity with similar E(T)(30) in the narrow range of 50.7-52.6 kcal/mol, except [EMIm][AC] (49.7 kcal/mol). However, the polarity of the hydroxyl ILs covers a rather wide range (E(T)(30) = 51.2-61.7 kcal/mol) and is strongly anion-dependent. According to their E(T)(30) or E(T)(33) values, the hydroxyl ILs can be further classified into the following three groups: (Iota) acetate-based hydroxyl ILs [HOEMIm][AC] exhibit polarity scale (E(T)(30) = 51.2 kcal/mol) similar to short chain alcohol and fall in the range of the nonhydroxyl ILs; (II) Hydroxyl ILs containing anions [NO(3)], [DCA], and [Cl] exhibit comparable polarity (E(T)(30) = 55.5-56.9 kcal/mol), moderately higher than those of their nonhydroxyl ILs; (III) Hydroxyl ILs containing anions [PF(6)], [NTf(2)], and [ClO(4)] possess unusual "hyperpolarity" (E(T)(30) = 60.3-61.7 kcal/mol) close to protic ILs and water. Kamlet-Taft parameters and density functional theory calculations indicated that the greatly expanded range of polarity of hydroxyl ILs is correlated to an intramolecular synergistic solvent effect of the ionic hydrogen-bonded HBD/HBA complexes generated by intrasolvent HBD/HBA association between the anions and the hydroxyl group on cations, wherein hydroxyl group exhibits a significant differentiating effect on the strength of H bonding and thus the polarity. Spiropyran-merocyanine equilibrium acted as a model polarity-sensitive reaction indeed shows obviously polarity-dependent solvatochromism, photochromism, and thermal reversion in hydroxyl ILs. PMID- 20199048 TI - Alpha-benzoin oxime in higher oxidation state 3d metal cluster chemistry: structural and magnetic study of a new Mn(III)(9) complex. AB - The initial employment of alpha-benzoin oxime (bzoxH(2)) in higher oxidation state 3d metal cluster chemistry has provided access to a new enneanuclear Mn(III) complex with an unprecedented metal-core topology consisting of two triangular [Mn(3)(mu(3)-Omicron(2-))(mu-OmicronNu)(3)](4+) fragments connected by a linear [Mn(3)(mu-OmicronNu)(6)](3+) unit. The Mn(III)(9) cluster is antiferromagnetically coupled and has an S = 3 spin ground state. PMID- 20199049 TI - Pi-back-donation effect of the cyanide ligands on the electron correlation and charge transfer in Prussian blue RbMn[Fe(CN)(6)]. AB - The temperature-induced charge transfer between the Mn and Fe sites in RbMn[Fe(CN)(6)] was analyzed by density functional theory calculations. Our analysis indicates that the extent of electron correlation (equivalently, the pairing energy or the on-site repulsion) is much greater for the Mn(n+) ion than for the Fe(n+) ion (n = 2, 3). This surprising and counterintuitive finding is a consequence of the pi-back-donation effect of the CN ligands. PMID- 20199050 TI - Theoretical revisit of a Fe(CO)(5)-catalyzed water-gas shift reaction. AB - We have revisited the water-gas shift reaction catalyzed by iron pentacarbonyl at the DFT-B3LYP level. The reaction mechanism proposed by Rozanska and Vuilleumier (Inorg. Chem. 2008, 47, 8635-8640) has been followed and revised. The results show that transition states TS4/5 and TS5/2_a actually connect other intermediates rather than those suggested by Rozanska and Vuilleumier. Furthermore, the entire reaction has been proven to proceed with processes 1 --> 2 --> 3 --> 4 --> 6 --> 7 --> 2. It is the first time that species 6 and 7 are reported as intermediates for this reaction mechanism. PMID- 20199051 TI - Impact of the carbon chain length of novel palladium(II) complexes on interaction with DNA and cytotoxic activity. AB - A series of Pd(II) complexes with a benzenealkyl dicarboxlate chain, with the formulas [Pd(L(n))(bipy)].mH(2)O (bipy = 2,2'-bipyridine, complex 1: L(1) = phenylmalonate, m = 2.5; complex 2: L(2) = benzylmalonate, m = 1; complex 3: L(3) = phenethylmalonate, m = 2; complex 4: L(4) = phenylpropylmalonate, m = 5), have been prepared in an attempt to correlate factors about the carbon chain of the compounds with DNA binding and cytotoxic activity. The binding of complexes with fish sperm DNA (FS-DNA) was carried out by UV absorption and fluorescence spectra. A gel electrophoresis assay demonstrated the ability of the complexes to cleave the pBR322 plasmid DNA. The cytotoxic effects of these complexes were examined on four cancer cell lines, HeLa, Hep-G2, KB, and AGZY-83a. The four complexes exhibited cytotoxic specificity and a significant cancer cell inhibitory rate. An apparent dependence of DNA-binding properties and cytotoxicity on the carbon chain length was obtained: the longer the carbon chain length, the higher the efficiency of DNA-binding and the greater the cytotoxicity. PMID- 20199052 TI - Dual selectivity expressed in [2 + 2 + 1] dynamic clipping of unsymmetrical [2]catenanes. AB - A pi-templated dynamic [2 + 2 + 1] clipping protocol is established for the synthesis of [2]catenanes from two parts dialdehyde, two parts diamine, and one part tetracationic cyclophane. It is further diversified for the selective formation of an unsymmetrical [2]catenane showing great translational selectivity by employing two different dialdehydes in a one-pot reaction. The dual selectivity and the dynamic nature are verified by (1)H NMR spectroscopy, X-ray single-crystal structural studies, and exchange experiments. PMID- 20199053 TI - Effects of the antifolates pemetrexed and CB3717 on the tissue distribution of (99m)Tc-EC20 in xenografted and syngeneic tumor-bearing mice. AB - Administration of certain antifolates before radiofolate application has previously proven to have a positive effect on undesired kidney uptake of radiofolates in mice bearing human tumor xenografts. The aims of this study were to (i) test the effects of the antifolates, pemetrexed and CB3717, on tissue distribution of the clinically investigated radiofolate, (99m)Tc-EC20, and (ii) to determine if pemetrexed's kidney-selective blocking effect also functions in mice bearing syngeneic tumors. Relative binding affinities of pemetrexed and CB3717 were determined in folate receptor (FR)-positive KB cells at 0 and 37 degrees C using (3)H-folic acid. In vivo studies were performed in nude mice with KB tumor xenografts (A) and in Balb/c mice bearing FR-positive M109 tumor grafts (B). (99m)Tc-EC20 was prepared via a kit formulation. The antifolates pemetrexed and CB3717 (20 mumol/kg body weight) were administered intravenously 1 h before injection of (99m)Tc-EC20 (67 nmol/kg body weight). Similar to previously published data we found that FR-binding affinities of pemetrexed and CB3717 at 0 degrees C were in the same range as that of folic acid. Interestingly, experiments performed at 37 degrees C showed that pemetrexed has a nearly approximately 700-fold lower FR-affinity than CB3717. Tissue distribution of (99m)Tc-EC20 was largely comparable in both animal models (A and B). Radiofolate accumulation was found in FR-positive tumors (A, 8.92 +/- 2.14% ID/g; B, 15.02 +/ 0.95% ID/g) and FR-positive kidneys (A, 59.10 +/- 8.03% ID/g; B, 69.44 +/- 4.66% ID/g, 4 h p.i.). Preinjection of pemetrexed resulted in a significant decrease of (99m)Tc-EC20 uptake in kidney (A, 18.80 +/- 2.73% ID/g; B, 15.27 +/- 2.64% ID/g; 4 h p.i), whereas uptake in the tumors was unaltered. However, administration of the CB3717 resulted in a reduction of (99m)Tc-EC20 uptake in both the kidney and tumor (<1% ID/g, 4 h p.i.). We have thus demonstrated that pemetrexed effectively reduces kidney uptake of radiofolates not only in xenografted mice but also in a syngeneic tumor mouse model, thereby indicating that the kidney-specific blocking effect is not based on differences between human and murine FRs that are expressed in xenografts and kidneys, respectively. This effect was not observed with the antifolate, CB3717, which targets the FR selectively in contrast to pemetrexed that is predominantly transported into cells through carrier systems. PMID- 20199054 TI - Multiplex detection of microbial and plant toxins by immunoaffinity enrichment and matrix-assisted laser desorption/ionization mass spectrometry. AB - Plant and microbial toxins such as ricin, staphylococcal enterotoxin B (SEB), and the botulinum neurotoxins (BoNT) are considered as potential biological warfare agents. Specific screening methods are, therefore, required that enable unambiguous and sensitive identification of these biohazards, particularly for the occurrence of the toxins in complex sample matrixes. The present study describes a combination of a multiplex-immunoaffinity purification approach, followed by matrix-assisted laser desorption/ionization (MALDI)-based detection for the simultaneous identification of ricin, SEB, BoNT/A, and BoNT/B. The method comprises an affinity enrichment step, using specific monoclonal antibodies for each of the four toxins which have been selected from a pool of antibodies. The selected antibodies allow for specific and simultaneous capture of ricin, SEB, BoNT/A, BoNT/B, and the corresponding BoNT complexes. These were subsequently identified by MALDI time-of-flight (TOF) mass spectrometry (MS), following tryptic digest. The sensitivity of the technique was approximately 500 fmol for each of the toxins. These toxins were detectable within 8 h, even when present in complex matrixes such as milk or juice. Furthermore, the MALDI-based multiplex assay allowed for the discrimination of closely related BoNT sero- and subtypes, including a real case of food-borne botulism in Germany. PMID- 20199055 TI - Coupling strong anion-exchange monolithic capillary with MALDI-TOF MS for sensitive detection of phosphopeptides in protein digest. AB - Protein phosphorylation is one of the most biologically relevant and ubiquitous post-translational modifications. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) is a powerful tool for the analysis of protein phosphorylation by detection of phosphopeptides in phosphoprotein digest. Enrichment of phosphopeptides by immobilized metal ion affinity chromatography (IMAC) or metal oxide affinity chromatography (MOAC) followed with MALDI analysis is the common approach. However, the pH for loading and elution of phosphopeptides is incompatible with protein digestion as well as the preparation of the MALDI matrix solution. Therefore, some pretreatment steps, such as pH adjustment and desalting, are required, which make the approach tedious and insensitive. In this study, a strong anion-exchange (SAX) capillary monolith was prepared to enrich phosphopeptides from protein digest for MALDI-TOF MS analysis. It was found that phosphopeptides could be specifically retained on the SAX column at high pH around 8 and could be eluted by 5% formic acid. Thus, the protein digests without any pretreatment could be loaded onto the SAX column under basic pH condition; after removing nonphosphopeptides by washing, the bound phosphopeptides could be eluted directly onto a MALDI target and analyzed by MALDI-TOF MS. This approach significantly simplified the analytical procedures and reduced the sample loss. Because of the excellent MALDI MS compatible procedure and the microscale SAX column, a detection limit as low as 50 amol for the analysis of phosphopeptides from beta-casein digest was achieved. To circumvent the inconvenience of the sample loading, a new simple sample introducing method based on capillary action was proposed, which further reduced the detection limit to 10 amol. PMID- 20199056 TI - Non-Kolmogorov-Avrami-Ishibashi switching dynamics in nanoscale ferroelectric capacitors. AB - Switching dynamics of nanoscale ferroelectric capacitors with a radius of 35 nm were investigated using piezoresponse force microscopy. Polarization switching starts with only one nucleation event occurring only at the predetermined places. The switching dynamics of nanoscale capacitors did not follow the classical Kolmogorov-Avrami-Ishibashi model. On the basis of the consideration of two separate (nucleation and growth) steps within a nonstatistical finite system, we have proposed a model which is in good agreement with the experimental results. PMID- 20199057 TI - Atomic structure of reduced graphene oxide. AB - Using high resolution transmission electron microscopy, we identify the specific atomic scale features in chemically derived graphene monolayers that originate from the oxidation-reduction treatment of graphene. The layers are found to comprise defect-free graphene areas with sizes of a few nanometers interspersed with defect areas dominated by clustered pentagons and heptagons. Interestingly, all carbon atoms in these defective areas are bonded to three neighbors maintaining a planar sp(2)-configuration, which makes them undetectable by spectroscopic techniques. Furthermore, we observe that they introduce significant in-plane distortions and strain in the surrounding lattice. PMID- 20199058 TI - Glycosylation catalyzed by a chiral Bronsted acid. AB - The use of a chiral Bronsted acid catalyst for the activation of trichloroacetimidate glycosyl donors has been demonstrated for the first time. In toluene the chirality of the acid catalyst is seen to influence the stereochemical outcome of the glycosylation processes, hinting that perhaps diastereocontrol of glycosylation processes may become achievable through the judicious use of chiral organic catalysts. PMID- 20199059 TI - Heterogeneous allylsilylation of aromatic and aliphatic alkenes catalyzed by proton-exchanged montmorillonite. AB - Allylsilylation of an alkene is the only known procedure to install both silyl and allyl groups onto a carbon-carbon double bond directly. Proton-exchanged montmorillonite showed excellent catalytic performances for the allylsilylation of alkenes. For example, the reaction of p-chlorostyrene with allyltrimethylsilane proceeded smoothly to afford the corresponding allylsilylated product in 95% yield. We also attempted to isolate the reaction intermediate on the montmorillonite surface to investigate the reaction mechanism. PMID- 20199060 TI - Acoustophoretic synchronization of mammalian cells in microchannels. AB - We report the first use of ultrasonic standing waves to achieve cell cycle phase synchronization in mammalian cells in a high-throughput and reagent-free manner. The acoustophoretic cell synchronization (ACS) device utilizes volume-dependent acoustic radiation force within a microchannel to selectively purify target cells of desired phase from an asynchronous mixture based on cell cycle-dependent fluctuations in size. We show that ultrasonic separation allows for gentle, scalable, and label-free synchronization with high G(1) phase synchrony (approximately 84%) and throughput (3 x 10(6) cells/h per microchannel). PMID- 20199061 TI - Formation of nanopatterned polymer blends in photovoltaic devices. AB - In this paper, we demonstrate a double nanoimprinting process that allows the formation of nanostructured polymer heterojunctions of composition and morphology that can be selected independently. We fabricated photovoltaic (PV) devices with extremely high densities (10(14)/mm(2)) of interpenetrating nanoscale columnar features in the active polymer blend layer. The smallest feature sizes are as small as 25 nm on a 50 nm pitch, which results in a spacing of heterojunctions at or below the exciton diffusion length. Photovoltaic devices based on double imprinted poly((9,9-dioctylfluorene)-2,7-diyl-alt-[4,7-bis(3-hexylthien-5-yl) 2,1,3-benzothiadiazole]-2',2''-diyl) (F8TBT)/ poly(3-hexylthiophene) (P3HT) films are among the best polymer-polymer blend devices reported to date with a power conversion efficiency (PCE, eta(e)) of 1.9%. PMID- 20199062 TI - Succinylphosphonate esters are competitive inhibitors of MenD that show active site discrimination between homologous alpha-ketoglutarate-decarboxylating enzymes. AB - MenD is a thiamin diphosphate-dependent enzyme catalyzing the first unique step in menaquinone biosynthesis in bacteria. We have synthesized acylphosphonate ester analogues of alpha-ketoglutarate, a substrate of MenD. These compounds are competitive inhibitors of MenD, with K(i) values as low as 700 nM. Observed structure-activity relationships are in notable contrast to those reported previously for succinylphosphonate inhibition of the alpha-ketoglutarate dehydrogenase complex, despite the apparent homology of these enzymes, and the identical decarboxylation reactions catalyzed. Inhibiting menaquinone biosynthesis is a proposed approach to inhibiting Mycobacterium tuberculosis growth. These inhibitors showed no significant inhibition of M. tuberculosis growth in vitro under aerobic and hypoxic conditions but give new information about the binding characteristics of the MenD active site. Site-directed mutation of Ser391 to alanine had only a minor effect on catalysis, but even the conservative mutation of Arg395 to lysine had a significant effect on the catalytic processing of isochorismate. PMID- 20199063 TI - Synthesis of diphenylamine-based novel fluorescent styryl colorants by Knoevenagel condensation using a conventional method, biocatalyst, and deep eutectic solvent. AB - Novel Y-shaped acceptor-pi-donor-pi-acceptor-type compounds, synthesized from 4,4'-hexyliminobisbenzaldehyde as electron donors and different active methylene compounds as electron acceptors, were produced by conventional Knoevenagel condensation alone, with a deep eutectic solvent, or with a lipase biocatalyst to compare the yield and recyclability among the three methods. Yield, reaction time, reaction temperature, and recyclability were compared among the three methods. The photophysical properties and thermal stability of the products were also investigated. PMID- 20199064 TI - Direct measurements of the ozone formation potential from livestock and poultry waste emissions. AB - The global pattern of expanding urban centers and increasing agricultural intensity is leading to more frequent interactions between air pollution emissions from urban and agricultural sources. The confluence of these emissions that traditionally have been separated by hundreds of kilometers is creating new air quality challenges in numerous regions across the United States. An area of particular interest is California's San Joaquin Valley (SJV), which has an agricultural output higher than many countries, a rapidly expanding human population, and ozone concentrations that are already higher than many dense urban areas. New regulations in the SJV restrict emissions of reactive organic gases (ROGs) from animal sources in an attempt to meet Federal and State ozone standards designed to protect human health. The objective of this work is to directly measure the ozone formation potential (OFP) of agricultural animal plus waste sources in representative urban and rural atmospheres using a transportable "smog" chamber. Four animal types were examined: beef cattle, dairy cattle, swine, and poultry. Emissions from each animal plus waste type were captured in a 1 m(3) Teflon bag, mixed with representative background NO(x) and ROG concentrations, and then exposed to UV radiation so that ozone formation could be quantified. The emitted ROG composition was also measured so that the theoretical incremental reactivity could be calculated for a variety of atmospheres and directly compared with the measured OFP under the experimental conditions. The results demonstrate that OFP associated with waste ROG emissions from swine (0.39 +/- 0.04 g-O(3) per g-ROG), beef cattle (0.51 +/- 0.10 g-O(3) per g-ROG), and dairy cattle (0.42 +/- 0.07 g-O(3) per g-ROG) are lower than OFP associated with ROG emissions from gasoline powered light-duty vehicles (LDV) (0.69 +/- 0.05 g O(3) per g-ROG). The OFP of ROG emitted from poultry waste (1.35 +/- 0.73 g-O(3) per g-ROG) is approximately double the LDV OFP. The measured composition of ROG emitted from animal plus waste sources is nine times less reactive than the current regulatory profiles that are based on dated measurements. The new animal waste ROG OFP measurements combined with adjusted animal waste ROG emissions inventory estimates predict that actual ozone production in the SJV from livestock and poultry (5.7 +/- 1.3 tons O(3) day(-1)) is 40 +/- 10% of the ozone produced by light duty gasoline vehicles (14.3 +/- 1.4 tons O(3) day(-1)) under constant NO(x) conditions. PMID- 20199065 TI - Application of an uncertainty analysis approach to strategic environmental assessment for urban planning. AB - Urban planning has been widely applied as a regulatory measure to guide a city's construction and management. It represents official expectations on future population and economic growth and land use over the urban area. No doubt, significant variations often occur between planning schemes and actual development; in particular in China, the world's largest developing country experiencing rapid urbanization and industrialization. This in turn leads to difficulty in estimating the environmental consequences of the urban plan. Aiming to quantitatively analyze the uncertain environmental impacts of the urban plan's implementation, this article developed an integrated methodology combining a scenario analysis approach and a stochastic simulation technique for strategic environmental assessment (SEA). Based on industrial development scenarios, Monte Carlo sampling is applied to generate all possibilities of the spatial distribution of newly emerged industries. All related environmental consequences can be further estimated given the industrial distributions as input to environmental quality models. By applying a HSY algorithm, environmentally unacceptable urban growth, regarding both economic development and land use spatial layout, can be systematically identified, providing valuable information to urban planners and decision makers. A case study in Dalian Municipality, Northeast China, is used to illustrate applicability of this methodology. The impacts of Urban Development Plan for Dalian Municipality (2003-2020) (UDP) on atmospheric environment are also discussed in this article. PMID- 20199066 TI - Quantification of electron transfer rates to a solid phase electron acceptor through the stages of biofilm formation from single cells to multicellular communities. AB - Microbial fuel cell (MFC) technology has enabled new insights into the mechanisms of electron transfer from dissimilatory metal reducing bacteria to a solid phase electron acceptor. Using solid electrodes as electron acceptors enables quantitative real-time measurements of electron transfer rates to these surfaces. We describe here an optically accessible, dual anode, continuous flow MFC that enables real-time microscopic imaging of anode populations as they develop from single attached cells to a mature biofilms. We used this system to characterize how differences in external resistance affect cellular electron transfer rates on a per cell basis and overall biofilm development in Shewanella oneidensis strain MR-1. When a low external resistance (100 Omega) was used, estimates of current per cell reached a maximum of 204 fA/cell (1.3 x 10(6) e(-) cell(-1) sec(-1)), while when a higher (1 MOmega) resistance was used, only 75 fA/cell (0.4 x 10(6) e(-) cell(-1) sec(-1)) was produced. The 1 MOmega anode biomass consistently developed into a mature thick biofilm with tower morphology (>50 microm thick), whereas only a thin biofilm (<5 microm thick) was observed on the 100 Omega anode. These data suggest a link between the ability of a surface to accept electrons and biofilm structure development. PMID- 20199067 TI - Feather lead concentrations and (207)Pb/(206)Pb ratios reveal lead exposure history of California Condors (Gymnogyps californianus). AB - Lead poisoning is a primary factor impeding the survival and recovery of the critically endangered California Condor (Gymnogyps californianus). However, the frequency and magnitude of lead exposure in condors is not well-known in part because most blood lead monitoring occurs biannually, and biannual blood samples capture only approximately 10% of a bird's annual exposure history. We investigated the use of growing feathers from free-flying condors in California to establish a bird's lead exposure history. We show that lead concentration and stable lead isotopic composition analyses of sequential feather sections and concurrently collected blood samples provided a comprehensive history of lead exposure over the 2-4 month period of feather growth. Feather analyses identified exposure events not evident from blood monitoring efforts, and by fitting an empirically derived timeline to actively growing feathers, we were able to estimate the time frame for specific lead exposure events. Our results demonstrate the utility of using sequentially sampled feathers to reconstruct lead exposure history. Since exposure risk in individuals is one determinant of population health, our findings should increase the understanding of population level effects from lead poisoning in condors; this information may also be helpful for other avian species potentially impacted by lead poisoning. PMID- 20199068 TI - Sequestering CO(2) by mineral carbonation: stability against acid rain exposure. AB - Mineral carbonation is a potentially attractive alternative to storage of compressed CO(2) in underground repositories, known as geosequestration. Processes for the conversion of basic ores, such as magnesium silicates, to carbonates have been proposed by various researchers, with storage of the carbonate as backfill in the original mine representing a solid carbon sink. The stability of such carbon sinks against acid rain and other sources of strong acids is examined here. It is acknowledged that in the presence of strong acid, carbonates will dissolve and release carbon dioxide. A sensitivity analysis covering annual average rainfall and pH that may be encountered in industrialized areas of the United States, China, Europe, and Australia was conducted to determine maximum CO(2) rerelease rates from mineral carbonation carbon sinks. This analysis is based on a worst-case premise that is equivalent to assuming infinitely rapid kinetics of dissolution of the carbonate. The analysis shows that under any likely conditions of pH and rainfall, leakage rates of stored CO(2) are negligible. This is illustrated in a hypothetical case study under Australian conditions. It is thus proposed that sequestration by mineral carbonation can be considered to be permanent on practical human time scales. Other possible sources of acid have also been considered. PMID- 20199069 TI - Single-particle characterization of summertime arctic aerosols collected at Ny Alesund, Svalbard. AB - Single-particle characterization of summertime Arctic aerosols is useful to understand the impact of air pollutants on the polar atmosphere. In the present study, a quantitative single particle analytical technique, low-Z particle electron probe X-ray microanalysis, was used to characterize 8100 individual particles overall in 16 sets of aerosol samples collected at Ny-Alesund, Svalbard, Norway on 25-31 July, 2007. Based on their X-ray spectral and secondary electron image data of individual particles, 13 particle types were identified, in which particles of marine origin were the most abundant, followed by carbonaceous and mineral dust particles. A number of aged (reacted) sea salt (and mixture) particles produced by the atmospheric reaction of genuine sea-salts, especially with NO(x) or HNO(3), were significantly encountered in almost all the aerosol samples. They greatly outnumbered genuine sea salt particles, implying that the summertime Arctic atmosphere, generally regarded as a clean background environment, is disturbed by anthropogenic air pollutants. The main sources of airborne NO(x) (or HNO(3)) are probably ship emissions around the Arctic Ocean, industry emission from northern Europe and northwestern Siberia, and renoxification of NO(3)(-) within or on the melting snow/ice surface. PMID- 20199070 TI - Metal-organic polyhedral frameworks: high h(2) adsorption capacities and neutron powder diffraction studies. AB - Neutron powder diffraction experiments on D(2)-loaded NOTT-112 reveal that the axial sites of exposed Cu(II) ions in the smallest cuboctahedral cages are the first, strongest binding sites for D(2) leading to an overall discrimination between the two types of exposed Cu(II) sites at the paddlewheel nodes. Thus, the Cu(II) centers within the cuboctahedral cage are the first sites of D(2) binding with a Cu-D(2) distance of 2.23(1) A. PMID- 20199071 TI - Total synthesis of cyclosporine: access to N-methylated peptides via isonitrile coupling reactions. AB - Recent developments in the use of isonitriles to furnish secondary and tertiary amide bond formations have been applied to a novel total synthesis of the important cyclic polypeptide cyclosporine A. Specifically, the disclosed synthetic route demonstrates the utility of microwave-mediated carboxylic acid isonitrile couplings, thioacid isonitrile couplings at ambient temperature, and isonitrile-mediated couplings of carboxylic acids and thioacids with amines to form challenging amide bonds. PMID- 20199072 TI - Catalytic enantioselective 1,3-dipolar cycloaddition of C,N-cyclic azomethine imines with alpha,beta-unsaturated aldehydes. AB - A yet-unexploited class of azomethine imines, C,N-cyclic azomethine imines, could be successfully employed in highly enantioselective 1,3-dipolar cycloaddition with enals catalyzed by titanium-BINOLate to give pharmaceutically attractive tetrahydroisoquinoline and piperidine motifs. PMID- 20199073 TI - A stable lipid-induced aggregate of alpha-synuclein. AB - The Parkinson's disease-related protein alpha-Synuclein (alphaS) is a 140 residue intrinsically disordered protein. Its membrane-binding properties are thought to be relevant for its physiological or pathologic activity. Here, the interaction of alphaS with POPG [1-Palmitoyl-2-Oleoyl-sn-Glycero-3-(Phosphorac-(1-glycerol))] small unilamellar vesicles (SUVs) is investigated by spin-label EPR using double electron-electron resonance (DEER). Intermolecular distances between four single mutants reveal that well-defined aggregates are formed. The data suggest a coexistence of two dimer structures with main interactions in the helix 2, encompassing residues 50-100. Previously, the horseshoe conformation was detected by intramolecular restraints obtained by DEER on alphaS double mutants (Drescher et al. J. Am. Chem. Soc. 2008, 130, 7796). The present study suggests that interdigitation of two monomers in the aggregate fills the void between the two helices of each of the monomers thus providing a rationale for the horseshoe structure. This aggregate is lipid induced and affects the structure of the POPG SUVs, which become leaky and diminish in size upon contact with alphaS suggesting a possible origin of conflicting results in the recent literature (Jao et al. Proc. Natl. Acad. Sci. U.S.A. 2008, 105 (50), 19666; Georgieva et al. J. Am. Chem. Soc. 2008, 130 (39), 12856; Bortolus et al. J. Am. Chem. Soc. 2008, 130, 6690). PMID- 20199074 TI - Transparent and flexible field electron emitters based on the conical nanocarbon structures. AB - The fabrication of conical nanocarbon structures (CNCSs) on a transparent and flexible nafion substrate at room temperature using an ion irradiation technique and their application toward field emission displays (FEDs) have been demonstrated. The main advantage of this technique is that CNCSs can be fabricated directly on the transparent substrate while retaining the transparency of the substrate. A scanning electron microscopy (SEM) image revealed that the sputtered surface was entirely covered with CNCSs with a calculated numerical density of 6 x 10(6) /mm(2). Such nafion based CNCSs have proved to be an effective electron emitter with turn-on and threshold fields of 6.1 and 9.5 V/mum, respectively. The field enhancement factor was estimated to be 1020 from the Fowler-Nordheim (F-N) plot. Thus the room temperature fabricated CNCSs based on transparent and flexible nafion substrate would be very promising for future flexible (roll-up) and transparent FEDs. PMID- 20199075 TI - Infrared thermography investigation of an evaporating sessile water droplet on heated substrates. AB - The present study is an experimental investigation of the thermal evolution of millimeter-sized sessile water droplets deposited on heated substrates. Infrared thermography is used to record temperature profiles on the droplet interface in time as evaporation takes place. The local measurements of the interface temperature allowed us to deduce the local evaporation rate and its evolution in time. To our knowledge, this is the first time that such measurements have been performed. The deduced evaporation rate using thermography data has been validated with optical measurements. Temperature evolution is used to reveal the contact line location and transient temperature fields. Temperature differences between the apex of the droplet and the contact line are shown to decrease in time. The rate of local temperature increase at the interface is found to behave linearly with time. The slope of this linear increase turns out to be more pronounced as the substrate temperature is increased. A generalized linear trend, using dimensionless properties for the interface temperature rise, is deduced from the measurements. PMID- 20199076 TI - Spatial and seasonal distribution of polychlorinated biphenyls (PCBs) in the vicinity of an iron and steel making plant. AB - Four consecutive passive air samplings (September 2006-July 2007) were conducted at 15 sites around an iron and steel making plant in Pohang, Korea to investigate the spatial and seasonal distributions of polychlorinated biphenyls (PCBs) and ultimately the source-receptor relationships. Annual mean values of Sigma(8)PCBs (IUPAC number 8, 28, 52, 101, 118, 138, 153, 180) were in the range of 15.1-166 pg/m(3) with an average of 53.0 pg/m(3). The spatial distribution of PCBs for each sampling period clearly suggests that the steel complex is a major source of PCBs in this area, and the prevailing winds facilitated the atmospheric transport and dispersion of PCBs from the steel complex to the surrounding areas. Seasonal patterns of PCBs were observed clearly, which were influenced by meteorological conditions; the highest levels of PCBs were observed with the highest average air temperature, and the influence of rainfall (i.e., wet scavenging) was also observed. In addition, PCB 11, a non-Aroclor congener, was detected in high concentrations at all sites, implying that the sources of PCB 11 are both unique and ubiquitous. This study confirms that passive air sampling is a useful tool to obtain seasonal and spatial distributions of time-averaged POPs data at a local scale. PMID- 20199077 TI - Conductive, physiologically responsive hydrogels. AB - Coupling molecular sensing with electrical conductivity may provide an important and valuable resource in assessing disease pathology. Here, we introduce pH responsive hydrogels with homogeneously synthesized gold (Au) nanoparticles that reversibly alter conductivity through pH-induced volumetric swelling. These intelligent hybrid materials respond to physiological pH shifts (pH 7.4 to 5.5) that can (1) alter the conductivity of the gel or (2) create conductive conduits via micropatterned arrays. PMID- 20199078 TI - Persistent photoinduced magnetism in heterostructures of prussian blue analogues. AB - Heterostructured ABA thin films consisting of two different Prussian blue analogues, where A is a ferromagnet and B is a photoinducible ferrimagnet, have been fabricated for the first time. This novel arrangement allows the magnetization to be decreased by irradiation with white light and significantly increases the ordering temperature of the photoinduced magnetism from 18 to 75 K. PMID- 20199079 TI - Coordination chemistry-assembled porphyrinic catenanes. AB - Non covalent [2]catenanes were synthesized in high yield as kinetic products or as thermodynamic products after completion of an equilibrium. These sophisticated architectures were assembled in two steps, from an oblique bis-zinc(II) porphyrin and two different dipyridyl chelates, by using Cu(I)-N interactions to assemble acyclic complexes and Zn(II)-N interactions to generate rings. (1)H NMR including 2D COSY and ROESY experiments were used to characterize each compound. Spectrophotometric titrations highlight the influence of geometry in terms of distances and angles in non covalent coordinated assemblies. In fact, it was proved that a perfect fit leads to highly stable coordination chemistry-assembled species. PMID- 20199080 TI - Multiresidue pesticide analysis in fresh produce by capillary gas chromatography mass spectrometry/selective ion monitoring (GC-MS/SIM) and -tandem mass spectrometry (GC-MS/MS). AB - A multiresidue method for the analysis of pesticides in fresh produce has been developed using salt-out acetonitrile extraction, solid-phase dispersive cleanup with octadecyl-bonded silica (C(18)), and graphitized carbon black/primary secondary amine (GCB/PSA) sorbents and toluene, followed by capillary gas chromatography-mass spectrometry in selected ion monitoring mode (GC-MS/SIM) or tandem mass spectrometry (GC-MS/MS). Quantitation was determined from calibration curves using matrix-matched standards ranging from 3.3 to 6667 ng/mL with r(2) > 0.99, and geometric mean limits of quantitation were typically 8.4 and 3.4 microg/kg for GC-MS/SIM and GC-MS/MS, respectively. Identification was determined by using target and qualifier ions and qualifier-to-target ratios for GC-MS/SIM and two ion transitions for GC-MS/MS. Fortification studies (10, 25, 100, and 500 microg/kg) were performed on 167 organohalogen, organophosphorus, and pyrethroid pesticides in 10 different commodities (apple, broccoli, carrot, onion, orange, pea, peach, potato, spinach, and tomato). The mean percent recoveries were 90 +/- 14, 87 +/- 14, 89 +/- 14, and 92 +/- 14% for GC-MS/SIM and 95 +/- 22, 93 +/- 14, 93 +/- 13, and 97 +/- 13% for GC-MS/MS at 10, 25, 100, and 500 microg/kg, respectively. GC-MS/MS was shown to be more effective than GC-MS/SIM due to its specificity and sensitivity in detecting pesticides in fresh produce samples. The method, based on concepts from the multiresidue procedure used by the Canadian Food Inspection Agency and QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe), was shown to be efficient in screening, identifying, and quantitating pesticides in fresh produce samples. PMID- 20199081 TI - HS-SPME comparative analysis of genotypic diversity in the volatile fraction and aroma-contributing compounds of Capsicum fruits from the annuum-chinense frutescens complex. AB - Volatile constituents of ripe fruits of 16 Capsicum accessions from the annuum chinense-frutescens complex, with different aroma impressions and geographical origins, were isolated by headspace-solid phase microextraction (HS-SPME) and analyzed by gas chromatography-olfactometry-mass spectrometry (GC-sniffing port MS). More than 300 individual compounds could be detected in the studied genotypes; most of them could be identified by comparing mass spectra and retention times with authentic reference substances or literature data. Esters and terpenoids were the main groups, although other minor compounds, such as nitrogen and sulfur compounds, phenol derivatives, norcarotenoids, lipoxygenase derivatives, carbonyls, alcohols, and other hydrocarbons, were also identified. The sniffing test revealed that the diversity of aromas found among the studied cultivars is due to qualitative and quantitative differences of, at least, 23 odor-contributing volatiles (OCVs). C. chinense, and C. frutescens accessions, with fruity/exotic aromas, were characterized by a high contribution of several esters and ionones and a low or nil contribution of green/vegetable OCVs. Different combinations of fruity/exotic and green/vegetable OCVs would explain the range of aroma impressions found among C. annuum accessions. Implications of these findings for breeding and phylogeny studies in Capsicum are also discussed. PMID- 20199082 TI - Silica nanotubes and their assembly assisted by boric acid to hierachical mesostructures. AB - Fine control of the self-assembly of silicon species to hierachical materials has attracted research attention for many years. The mesostructures produced by such processes under weak acidic-basic conditions mimic bioenvironments are the focus of current research. In this study, mesoporous silicas with various novel morphologies such as mesoporous spheres, nanotubes, and oligomeric nanotubes have been systematically synthesized by using boric acid in the system, which is the key reagent for the fine control of the assembly of the silica precursors. The as prepared materials are characterized using transmission electron microscopy (TEM), small-angle X-ray diffraction (XRD), Fourier transform infrared (FT-IR) spectroscopy, and nitrogen sorption measurements. The results support the assembly process of the nanomicelle of silica and surfactant under the conditions of boric acid, from which the synergistic weak interactions cause the morphology evolution of silicas. The current research provides effective information for understanding the formation of mesoporous silica under conditions mimicking biosilification processes. PMID- 20199083 TI - Properties of synthetic homoisoflavonoids to reduce oxidants and to protect linoleic acid and dna against oxidation. AB - 3-(2'-, 3'-, and 4'-Hydroxybenzylidene)-7-methoxychroman-4-one (o-, m-, and p HBMC) was synthesized for the clarification of the influence of the hydroxyl group at the B ring on the antioxidant activity of homoisoflavonoid. The three homoisoflavonoids used herein can reduce peroxynitrite. p-HBMC exhibited high activity to reduce singlet oxygen. Furthermore, o-, m-, and p-HBMC can scavenge the 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS(*+)) and 2,2'-diphenyl-1-picrylhydrazyl (DPPH) and galvinoxyl radicals. The rates of o HBMC trapping of DPPH and galvinoxyl radicals were higher than those of m- and p HBMC, whereas m-HBMC can trap ABTS(*+) rapidly. o-HBMC was found to possess high activity in the beta-carotene-linoleic acid bleaching test and to protect methyl linoleate against 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH)-induced oxidation efficiently. Finally, o-HBMC served as a prooxidant in Cu(2+)/glutathione (GSH)- and hydroxyl radical-mediated oxidations of DNA. m- and p-HBMC protected DNA against hydroxyl radical-mediated oxidation of DNA effectively, and o- and p-HBMC behaved as antioxidants to protect DNA against AAPH-induced oxidation. Thus, the hydroxyl group attaching to the ortho- and para positions in the B ring was of importance for the homoisoflavonoid's enhancement of antioxidant activity. PMID- 20199084 TI - Isoflavones and antioxidant capacity of commercial soy-based beverages: effect of storage. AB - Samples of 11 different brands of commercially available soy-based beverages (n = 65), including products made from soy protein isolate (SPI) and soy milk, mixed with fruit juice and/or flavoring, were analyzed for their isoflavone content and in vitro antioxidant activity. There was a large variation in isoflavone and total phenolics contents ranging from 0.7 to 13 mg of isoflavones/200 mL and from 6 to 155 mg equivalents of catechin/200 mL, respectively. The antioxidant activity also varied significantly among products. Storage of the beverages at room temperature caused a significant decrease of antioxidant capacity, soluble phenolics, and isoflavone contents after 9 months. When soybeans used for beverage production were stored for up to 6 months in silos, the resulting products were not affected. However, a decrease of malonyl and a proportional increase of free glucosidic forms of isoflavones were observed after storage of both the raw material and the beverages. PMID- 20199085 TI - Effects of a novel pathogenesis-related class 10 (PR-10) protein from Crotalaria pallida Roots with papain inhibitory activity against root-knot nematode Meloidogyne incognita. AB - A novel pathogenesis-related class 10 (PR-10) protein with papain inhibitory activity, named CpPRI, was purified from Crotalaria pallida roots by ammonium sulfate precipitation followed by three reverse-phase high-performance liquid chromatographies (HPLCs). CpPRI is made up of a single polypeptide chain with a M(r) of 15 kDa, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). This protein exhibited a K(i) value of 1.8 x 10(-9) M and operates via a noncompetitive inhibition mechanism. The alignment of the N terminal amino acid sequence of CpPRI with other proteins revealed its identity with PR-10 proteins. CpPRI acts against digestive proteinase from root-knot nematode Meloidogyne incognita and demonstrated nematostatic and nematicide effects on this parasite in bioassays. In a localization study, fluorescein-5 isothiocyanate (FITC)-CpPRI was observed to internalize and diffuse over the entire J2 body after 6 h of incubation. This fact could explain the natural tolerance of this plant species to nematodes. PMID- 20199086 TI - Evolution of S-cysteinylated and S-glutathionylated thiol precursors during oxidation of Melon B. and Sauvignon blanc musts. AB - Thiol precursor content in Melon B. and Sauvignon blanc grape juices obtained under vacuum was determined by quantifying cysteinylated and glutathionylated conjugates of 3-mercaptohexan-1-ol (3MH) and 4-methyl-4-mercaptopentan-2-one (4MMP). This characterization allowed the study of thiol precursor evolution during ripening of Sauvignon blanc grapes in several viticultural situations together with grape reaction product (GRP) and the main substrate of polyphenoloxidase, that is, caftaric acid. Concentration of precursors greatly increased during ripening except for the cysteinylated conjugate of 4MMP. Precursor evolution was also monitored during the oxidation of grape juice. Addition of oxygen to a grape juice set off the enzymatic oxidation of hydroxycinnamic acids but did not negatively affect precursor concentrations. Part of the glutathionylated precursor of the 3MH was produced during prefermentative operations (up to 140% in Sauvignon blanc). Consequently, this precursor naturally occurring in grapes was also formed during prefermentative operations. The proportion of biogenetic and prefermentary formation of the glutathionylated precursor of 3MH was different under industrial conditions depending on the grape variety considered. Addition of glutathione and hexenal in grape juices of Melon B. and Sauvignon induced an increase of the production of 3MH and consequently of its acetate in the resulting wines. Residual glutathione in must has to be preserved to enhance the aromatic potential of grapes. PMID- 20199087 TI - Development of novel, highly potent inhibitors of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF): increasing cellular potency through optimization of a distal heteroaromatic group. AB - We describe the design, synthesis, and optimization of a series of new inhibitors of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF), a kinase whose mutant form (V600E) is implicated in several types of cancer, with a particularly high frequency in melanoma. Our previously described inhibitors with a tripartite A-B C system (where A is a hinge binding pyrido[4,5-b]imidazolone system, B is an aryl spacer group, and C is a heteroaromatic group) were potent against purified (V600E)BRAF in vitro but were less potent in accompanying cellular assays. Substitution of different aromatic heterocycles for the phenyl based C-ring is evaluated herein as a potential means of improving the cellular potencies of these inhibitors. Substituted pyrazoles, particularly 3-tert-butyl-1-aryl-1H pyrazoles, increase the cellular potencies without detrimental effects on the potency on isolated (V600E)BRAF. Thus, compounds have been synthesized that inhibit, with low nanomolar concentrations, (V600E)BRAF, its downstream signaling in cells [as measured by the reduction of the phosphorylation of extracellular regulated kinase (ERK)], and the proliferation of mutant BRAF-dependent cells. Concomitant benefits are good oral bioavailability and high plasma concentrations in vivo. PMID- 20199089 TI - Diffusion of alpha-chymotrypsin in solution-crowded media. A fluorescence recovery after photobleaching study. AB - Fluorescence recovery after photobleaching (FRAP) is one of the most powerful and used techniques to study diffusion processes of macromolecules in membranes or in bulk. Here, we study the diffusion of alpha-chymotrypsin in different crowded (Dextran) in vitro solutions using a confocal laser scanning microscope. In the considered experimental conditions, confocal FRAP images could be analyzed applying the uniform circular disk approximation described for a nonscanning microscope generalized to take into account anomalous diffusion. Considering the slow diffusion of macromolecules in crowded media, we compare the fitting of confocal FRAP curves analyzed with the equations provided by the Gaussian and the uniform circular disk profile models for nonscanning microscopes. As the fitted parameter variation with the size and concentration of crowders is qualitatively similar for both models, the use of the uniform circular disk or the Gaussian model is justified for these experiments. Moreover, in our experimental conditions, alpha-chymotrypsin shows anomalous diffusion (alpha < 1), depending on the size and concentration of Dextran molecules, until a high concentration and high size of crowding agent are achieved. This result indicates a range of validity of the idealized fitting expressions used, beyond which other physical phenomena must be considered. PMID- 20199088 TI - Microcup arrays for the efficient isolation and cloning of cells. AB - Arrays of transparent, releasable micrometer-scale structures termed "microcups" were created for the purpose of patterning and isolating viable cells from small cell samples. Cells were captured by the microcups without the need for barriers or walls on the intervening substrate. Furthermore, in contrast to prior methods for creating cell arrays with releasable elements, no chemical modification of the substrate was required. Individual microcups were released from the array using a pulsed laser at very low energy. Improvements in microcup design enabled cells in suspension to be loaded into the microcups with greater than 90% efficiency. Cells cultured within the microcups displayed 100% viability and were cultured over 4 days yielding colonies that remained sequestered within the microcups to generate pure clonal populations. Standard microscopic imaging was used to identify cells or colonies of interest, and the microcups containing these cells were then released and collected. Individual target cells isolated in this manner remained viable as demonstrated by clonal expansion of 100% of collected cells. Direct comparisons with cell isolation by fluorescence-activated cell sorting and magnetic-bead-based isolation systems demonstrated that the microcup cell isolation procedure yielded higher purity, yield, and viability than these standard technologies when separating samples with small numbers of cells. The power of this technique was demonstrated by the isolation of hematopoietic stem cells from a human bone marrow aspirate possessing only 4000 total cells. PMID- 20199090 TI - Small-angle neutron scattering of percolative perfluoropolyether water in oil microemulsions. AB - A water in oil microemulsion system composed of water, surfactant, and oil, the latter two components of perfluoropolyether (PFPE) type, has been studied by small-angle neutron scattering (SANS) with the aim of knowing the microstructure of the system and to have an insight on the connection between microstructure characterization and percolation behavior. In fact, along the dilution line W/S = 11 of the phase diagram, dielectric spectroscopy and conductivity studies revealed a dynamic percolation process taking place approaching and above the dynamic percolation threshold, leading to a system composed of droplet clusters with percolation thresholds varying with temperature from a 0.501 volume fraction of the dispersed phase at 9.3 degrees C to 0.205 at 32.5 degrees C. The SANS experimental spectra of this work have been studied by modeling the microemulsion droplets as adhesive hard spheres. For all of the samples, the surfactant area per polar head has been also measured in the Porod region of the SANS spectra. Geometric and potential parameters as well as the osmotic pressure, the second virial coefficient, and the distance between droplets have been extracted from data as a function of droplets concentration. At low concentration, that is, below percolation thresholds, the droplets behave as hard spheres, whereas at threshold and above, adhesion changes significantly the samples. In fact, for each temperature, the measured size increases versus concentration from 30 to 50 A, and the area per polar head decreases correspondingly, suggesting that a process of dynamic fusion of droplets occurs in the system above threshold, that is, couples of droplets stick and unstick continuously with interdigitation of the surfactant tails. PMID- 20199092 TI - Ions and hydrogen bonding in a hydrophobic environment: CCl(4). AB - It is generally expected that ions in an aqueous ionic solution in contact with a hydrophobic phase enter the hydrophobic phase accompanied by a hydration shell. This expectation suggests that the ion mole fraction in the hydrophobic phase is less than, or at most, equal to that of water. Both gravimetric and spectroscopic evidence shows that for a model hydrophobic phase, carbon tetrachloride, this is not the case: In contact with a 1 M simple salt solution (sodium or potassium halide), the salt concentration in carbon tetrachloride ranges from 1.4 to nearly 3 times that of water. Infrared spectra of the OH stretch region support a model in which water associates with the cation, primarily as water monomers. Salts containing larger, more polarizable anions can form outer-sphere ion pairs that support water dimers, giving rise to a spectral signature at 3440 cm(-1). In CCl(4), the infrared spectral signature of the normally strongly ionized acid HCl clearly shows the presence of molecular HCl. Additionally, the presence of a Q branch for HCl indicates restricted rotational motion. The spectral and gravimetric data provide compelling evidence for ion clusters in the hydrophobic phase, which is a result that may have implications for hydrophobic matter in both biological and environmental systems. PMID- 20199093 TI - Synthesis of dihydroplakortin, 6-epi-dihydroplakortin, and their C10-desethyl analogues. AB - The first synthesis of the marine endoperoxide 9,10-dihydroplakortin, of its C10 desethyl analogue, and of their corresponding C6 epimers is described. Stereogenic centers at C4 and at the lateral chain have been stereoselectively synthesized through Evans' chiral auxiliary chemistry. Moreover, the reported synthesis features a one-pot three-step hydroperoxysilylation/cyclization reaction for the construction of the endoperoxide ring system. Homologation of the aldehyde resulting from diol cleavage through a Wittig-based strategy gave access to the ester-containing lateral chain at C3. PMID- 20199094 TI - Intramolecular direct C-H arylation approach to fused purines. Synthesis of purino[8,9-f]phenanthridines and 5,6-dihydropurino[8,9-a]isoquinolines. AB - Intramolecular C-H arylations were employed as a key step in the synthesis of hitherto unknown fused purine systems: 13-substituted purino[8,9 f]phenanthridines and 11-substituted 5,6-dihydropurino[8,9-a]isoquinolines. The purino[8,9-f]phenanthridines were prepared in moderate yields by double C-H arylations of 9-phenylpurines with 1,2-diiodobenzene or, more efficiently, by consecutive Suzuki coupling of 9-(2-bromophenyl)purines with 2-bromophenylboronic acid followed by intramolecular C-H arylation. 5,6-Dihydropurino[8,9 a]isoquinolines were prepared in quantitative yields by intramolecular C-H arylations of 9-(2-chlorophenethyl)purines. PMID- 20199095 TI - Spectroscopic and computational studies of a trans-mu-1,2-disulfido-bridged dinickel species, [{(tmc)Ni}(2)(S(2))](OTf)(2): comparison of end-on disulfido and peroxo bonding in (Ni(II))(2) and (Cu(II))(2) species. AB - A powerful means of enhancing our understanding of the structures and functions of enzymes that contain nickel-sulfur bonds, such as Ni superoxide dismutase, acetyl-coenzyme A synthase/carbon monoxide dehydrogenase, [NiFe] hydrogenase, and methyl-CoM reductase, involves the investigation of model compounds with similar structural and/or electronic properties. In this study, we have characterized a trans-mu-1,2-disulfido-bridged dinickel(II) species, [{(tmc)Ni}(2)(S(2))](2+) (1, tmc = 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane) by using electronic absorption, magnetic circular dichroism (MCD), and resonance Raman (rR) spectroscopic techniques, as well as density functional theory (DFT) and time dependent DFT computational methods. Our computational results, validated on the basis of the experimental MCD data and previously reported (1)H NMR spectra, reveal that 1 is best described as containing two antiferromagnetically coupled high-spin Ni(II) centers. A normal coordinate analysis of the rR vibrational data was performed to quantify the core bond strengths, yielding force constants of k(Ni-S) = 2.69 mdyn/A and k(S-S) = 2.40 mdyn/A. These values provide a useful basis for a comparison of metal-S/O bonding in 1 and related Ni(2)(O(2)), Cu(2)(O(2)), and Cu(2)(S(2)) dimers. In both the disulfido and the peroxo species, the lower effective nuclear charge of Ni(II) as compared to Cu(II) results in a decreased covalency, and thus relatively weaker metal-S/O bonding interactions in the Ni(2) dimers than in the Cu(2) complexes. PMID- 20199096 TI - Investigating the mechanisms of aromatic amine-induced protein free radical formation by quantitative structure-activity relationships: implications for drug induced agranulocytosis. AB - Aromatic amine drugs have been associated with agranulocytosis (neutrophil depletion) for which the mechanism is unknown. We have previously shown that the metabolism of two aromatic amine drugs by human myeloperoxidase (MPO) results in phenyl radical metabolite formation and also in protein free radical formation on MPO. Because the concentration of drug required to produce a maximum signal for MPO protein free radical (MPO*) detection was different for each drug, this prompted us to consider that other aromatic amines may also show varying degrees of ability to induce MPO* formation. Immunoassay experiments using the immuno spin-trapping technique were performed, which evaluated the potency of different aromatic amines containing the aniline substructure to generate the MPO*. Each reaction contained equal amounts of H(2)O(2), 5,5-dimethyl-1-pyrroline-N-oxide, MPO, and variable concentrations of aniline derivatives. Several physicochemical parameters for aniline derivatives were used to derive quantitative structure activity relationship equations, which showed that the Hammett constant (sigma) best correlated with the MPO* formation for all aniline derivatives. More statistically robust equations were derived if the anilines were separated into mono- and disubstituted groups. However, some aniline derivatives did not induce MPO* formation. Using electron spin resonance spectroscopy, we evaluated the ability of all aniline derivatives tested to produce phenyl radical metabolites, as previously shown by spin trapping for the aromatic amine drugs. Interestingly, we found that only those aniline derivatives that produced a phenyl radical also formed MPO*. We propose that the phenyl radical is the reactive free radical metabolite responsible for generating the MPO*. PMID- 20199097 TI - High-throughput all-atom molecular dynamics simulations using distributed computing. AB - Although molecular dynamics simulation methods are useful in the modeling of macromolecular systems, they remain computationally expensive, with production work requiring costly high-performance computing (HPC) resources. We review recent innovations in accelerating molecular dynamics on graphics processing units (GPUs), and we describe GPUGRID, a volunteer computing project that uses the GPU resources of nondedicated desktop and workstation computers. In particular, we demonstrate the capability of simulating thousands of all-atom molecular trajectories generated at an average of 20 ns/day each (for systems of approximately 30 000-80 000 atoms). In conjunction with a potential of mean force (PMF) protocol for computing binding free energies, we demonstrate the use of GPUGRID in the computation of accurate binding affinities of the Src SH2 domain/pYEEI ligand complex by reconstructing the PMF over 373 umbrella sampling windows of 55 ns each (20.5 mus of total data). We obtain a standard free energy of binding of -8.7 +/- 0.4 kcal/mol within 0.7 kcal/mol from experimental results. This infrastructure will provide the basis for a robust system for high throughput accurate binding affinity prediction. PMID- 20199099 TI - Self-assembly of 1,4-benzenedimethanethiol self-assembled monolayers on gold. AB - A study of the self-assembly of 1,4-benzenedimethanethiol (BDMT; HS-CH(2) (C(6)H(4))-CH(2)-SH) monolayers on gold is presented. Self-assembled monolayers (SAMs) are characterized by reflection-absorption infrared spectroscopy (RAIRS), X-ray photoelectron spectroscopy (XPS), and spectroscopic ellipsometry (SE) measurements. The ensemble of measurements consistently shows that well-organized BDMT SAMs, with "standing-up" molecules, can be obtained on high quality gold films with incubation in n-hexane provided that N(2)-degassed solutions are used and all preparation steps are performed at 60 degrees C in the absence of ambient light. SE data indicate that the optical interface properties of the BDMT-Au system are different from those of simple alkanethiol SAMs. A possible mechanism for the formation of the "standing-up" phase from the lying-down phase via a hydrogen exchange reaction involving chemisorbed lying-down and free dithiol molecules is discussed. PMID- 20199098 TI - Site-specific backbone amide (15)N chemical shift anisotropy tensors in a small protein from liquid crystal and cross-correlated relaxation measurements. AB - Site-specific (15)N chemical shift anisotropy (CSA) tensors have been derived for the well-ordered backbone amide (15)N nuclei in the B3 domain of protein G (GB3) from residual chemical shift anisotropy (RCSA) measured in six different mutants that retain the native structure but align differently relative to the static magnetic field when dissolved in a liquid crystalline Pf1 suspension. This information is complemented by measurement of cross-correlated relaxation rates between the (15)N CSA tensor and either the (15)N-(1)H or (15)N-(13)C' dipolar interaction. In agreement with recent solid state NMR measurements, the (15)N CSA tensors exhibit only a moderate degree of variation from averaged values, but have larger magnitudes in alpha-helical (-173 +/- 7 ppm) than in beta-sheet (-162 +/- 6 ppm) residues, a finding also confirmed by quantum computations. The orientations of the least shielded tensor component cluster tightly around an in peptide-plane vector that makes an angle of 19.6 +/- 2.5 degrees with the N-H bond, with the asymmetry of the (15)N CSA tensor being slightly smaller in alpha helix (eta = 0.23 +/- 0.17) than in beta-sheet (eta = 0.31 +/- 0.11). The residue specific (15)N CSA values are validated by improved agreement between computed and experimental (15)N R(1rho) relaxation rates measured for (15)N-{(2)H} sites in GB3, which are dominated by the CSA mechanism. Use of residue-specific (15)N CSA values also results in more uniform generalized order parameters, S(2), and predicts considerable residue-by-residue variations in the magnetic field strengths where TROSY line narrowing is most effective. PMID- 20199100 TI - Spectroscopic and computational studies of a mu-eta(2):eta(2)-disulfido-bridged dinickel(II) species, [{(PhTt(tBu))Ni}(2)(mu-eta(2):eta(2)-S(2))]: comparison of side-on disulfido and peroxo bonding in (Ni(II))(2) and (Cu(II))(2) species. AB - In this study, a combined spectroscopic and computational approach has been employed to generate a detailed description of the electronic structure of a binuclear side-on disulfido (Ni(II))(2) complex, [{(PhTt(tBu))Ni}(2)(mu eta(2):eta(2)-S(2))] (1, where PhTt(tBu) = phenyltris[(tert butylthio)methyl]borate). The disulfido-to-Ni(II) charge-transfer transitions that dominate the electronic absorption spectrum have been assigned on the basis of time-dependent density functional theory (DFT) calculations. Resonance Raman spectroscopic studies of 1 have revealed that the S-S stretching mode occurs at 446 cm(-1), indicating that the S-S bond is weaker in 1 than in the analogous mu eta(2):eta(2)-S(2) dicopper species. DFT computational data indicate that the steric bulk of PhTt(tBu) stabilize the side-on core enough to prevent its conversion to the electronically preferred bis(mu-sulfido) (Ni(III))(2) structure. Hence, 1 provides an interesting contrast to its O(2)-derived analogue, [{(PhTt(tBu))Ni}(2)(mu-O)(2)], which was shown previously to assume a bis(mu-oxo) (Ni(III))(2) "diamond core". By a comparison of 1 to analogous disulfidodicopper and peroxodinickel species, new insight has been obtained into the roles that the metal centers, bridging ligands, and supporting ligands play in determining the core structures and electronic properties of these dimers. PMID- 20199101 TI - Structural and electrochemical studies of Co(III) cage amine complexes with pendent thienylmethylamino groups. AB - Various 2- and 3-thienylmethylamino-substituted cobalt(III) cage amine complexes, prepared with the objective of obtaining cage-functionalized polythienyls, have been found to be resistant to oxidative polymerization by both electrochemical and chemical procedures. X-ray structure determinations indicate that there is negligible perturbation of the physical dimensions of the thiophene moieties by the cage substituents and thus that the resistance to polymerization must be associated with the high positive charge carried by these substituents. PMID- 20199102 TI - An efficient route for the synthesis of a Tin(II) substituted carbodiimide from a diazo compound. AB - The reaction of beta-diketiminate substituted tin(II) chloride, LSnCl (1; L = HC{(CMe)(2,6-iPr(2)C(6)H(3)N)}(2)), with the lithium salt of trimethylsilyl diazomethane (LiC(N(2))SiMe(3)) is described. In the course of the reaction, the exclusive formation of tin(II) substituted carbodiimide LSnNCNSiMe(3) (2) is observed in good yield. This reaction occurs at room temperature without any side products. Furthermore, we reacted diiron nonacarbonyl, Fe(2)(CO)(9), with compound 2 to confirm the carbodiimide skeleton (N=C=N) without rearrangement. The latter reaction leads to the tin(II) coordinate iron carbonyl complex LSnNCNSiMe(3)Fe(CO)(4) (3). Compounds 2 and 3 were investigated by microanalysis and multinuclear NMR spectroscopy and were further characterized by X-ray structural analysis. PMID- 20199103 TI - A series of new manganese(II) sulfonate-arsonates with 2D layer, 1D chain, and 0D clusters structures. AB - Hydrothermal reactions of manganese(II) salts with o-sulfophenylarsonic acid (o HO(3)S-C(6)H(4)-AsO(3)H(2), H(3)L) afforded Mn(3)(L)(2)(H(2)O)(3).H(2)O (1) with a layered structure. When 1,10-phenanthroline (phen), 2,2'-bipyridine (bipy), and 2,2':6',2''-terpyridine (terpy) were used as auxiliary chelating ligands, a series of mixed-ligand manganese(II) sulfonate-arsonates with lower dimensional structures, namely, [Mn(HL)(phen)(2)](2).8.5H(2)O (2), Mn(HL)(phen)(2)(H(2)O).2H(2)O (3), [Mn(HL)(bipy)(2)][Mn(H(2)L)(bipy)(2)](ClO(4)).3H(2)O (4), [Mn(HL)(phen)][Mn(HL)(phen)(H(2)O)] (5), [Mn(2)(HL)(phen)(4)(H(2)O)](ClO(4))(2).4H(2)O (6), [Mn(2)(HL)(phen)(4)(H(2)O)](ClO(4))(2).H(2)O (7), Mn(2)(HL)(2)(bipy)(3)(H(2)O).H(2)O (8), [Mn(HL)(terpy)](2) (9), Mn(7)(OH)(2)(L)(4)(phen)(8).10H(2)O.phen (10), and Mn(HL)(bipy)(H(2)O).2H(2)O (11) have been obtained. 2-4 are mononuclear (4 contains two different mononuclear cluster units) whereas 5-9 feature three types of isolated dinuclear cluster units in which the two Mn(2+) ions are bridged by one or two sulfonate arsonate ligands. 10 exhibits an interesting heptanuclear cluster in which the Mn(2+) centers are bridged by arsonate, sulfonate groups and hydroxyl anions. 11 features a one-dimensional (1D) chain in which two neighboring Mn(2+) centers are bridged by an arsonate group of a sulfonate-arsonate ligand. Magnetic measurements indicate that 1 exhibits an unprecedented spin topology and behaves as a homospin ferrimagnet whereas 2-4 are essentially paramagnetic. 5-9 and 11 are weakly antiferromagnetic. PMID- 20199104 TI - Post-translational modifications and protein-specific isoforms in endometriosis revealed by 2D DIGE. AB - Endometriosis is a chronic disorder affecting approximately 10% of women in whom endometrial tissue forms painful lesions outside the uterus. It has a major impact on their physical, mental and social well-being but has no known cure, and there is no nonsurgical means of diagnosis. We have used a proteomic approach to identify proteins with altered abundance in the eutopic endometrium of endometriosis patients in the midsecretory phase of the menstrual cycle. 2D differential in gel electrophoresis (DIGE) and mass spectrometry identified 20 proteins that were present at different levels in endometriosis patients (p < 0.05), many of which have not previously been associated with endometriosis. Protein abundance changes did not correlate well with published gene array data, emphasizing the extensive post-translational modification that occurs in this tissue. Abundance or localization changes in endometrial tissue were validated by immunohistochemistry and Western blotting for three proteins, vimentin (VIM), peroxiredoxin 6 (PRDX6), and ribonuclease/angiogenin inhibitor 1 (RNH1), while observed changes could not be confirmed for coronin 1A (CORO1A) or transgelin (TAGLN2). In addition, multiple charge and size isoforms were observed for PDRX6 and vimentin (VIM), and an additional PDRX6 isoform was observed in endometriosis patients that was below the level of detection in healthy women. Biological pathway analysis identified that cytoskeletal remodeling via keratin intermediate filaments, processing of the cystic fibrosis transmembrane receptor (CFTR), the glucocorticoid receptor subunit alpha (GCR), and heat shock factor 1 (HSF1) were all significantly over-represented features in endometriosis patients. This study highlights the highly dynamic nature of endometrial tissue and suggests that considerable post-translational modification of proteins is a key factor in the pathology of endometriosis. PMID- 20199105 TI - N-glycan-dependent quality control of the Na,K-ATPase beta(2) subunit. AB - Bulky hydrophilic N-glycans stabilize the proper tertiary structure of glycoproteins. In addition, N-glycans comprise the binding sites for the endoplasmic reticulum (ER)-resident lectins that assist correct folding of newly synthesized glycoproteins. To reveal the role of N-glycans in maturation of the Na,K-ATPase beta(2) subunit in the ER, the effects of preventing or modifying the beta(2) subunit N-glycosylation on trafficking of the subunit and its binding to the ER lectin chaperone, calnexin, were studied in MDCK cells. Preventing N glycosylation abolishes binding of the beta(2) subunit to calnexin and results in the ER retention of the subunit. Furthermore, the fully N-glycosylated beta(2) subunit is retained in the ER when glycan-calnexin interactions are prevented by castanospermine, showing that N-glycan-mediated calnexin binding is required for correct subunit folding. Calnexin binding persists for several hours after translation is stopped with cycloheximide, suggesting that the beta(2) subunit undergoes repeated post-translational calnexin-assisted folding attempts. Homology modeling of the beta(2) subunit using the crystal structure of the alpha(1)-beta(1) Na,K-ATPase shows the presence of a relatively hydrophobic amino acid cluster proximal to N-glycosylation sites 2 and 7. Combined, but not separate, removal of sites 2 and 7 dramatically impairs calnexin binding and prevents the export of the beta(2) subunit from the ER. Similarly, hydrophilic substitution of two hydrophobic amino acids in this cluster disrupts both beta(2) calnexin binding and trafficking of the subunit to the Golgi. Therefore, the hydrophobic residues in the proximity of N-glycans 2 and 7 are required for post translational calnexin binding to these N-glycans in incompletely folded conformers, which, in turn, is necessary for maturation of the Na,K-ATPase beta(2) subunit. PMID- 20199106 TI - Glycomic and transcriptomic response of GSC11 glioblastoma stem cells to STAT3 phosphorylation inhibition and serum-induced differentiation. AB - A glioblastoma stem cell (GSC) line, GSC11, grows as neurospheres in serum-free media supplemented with EGF (epidermal growth factor) and bFGF (basic fibroblast growth factor), and, if implanted in nude mice brains, will recapitulate high grade glial tumors. Treatment with a STAT3 (signal transducer and activator of transcription 3) phosphorylation inhibitor (WP1193) or 10% FBS (fetal bovine serum) both led to a decrease in expression of the stem cell marker CD133 in GSC11 cells, but differed in phenotype changes. Altered glycolipid profiles were associated with some differentially expressed glycogenes. In serum treated cells, an overall increase in glycosphingolipids may be due to increased expression of ST6GALNAC2, a sialyltransferase. Serum treated cells express more phosphatidylcholine (PC), short chain sphingomyelin (SM) and unsaturated long chain phosphatidylinositol (PI). Decrease of a few glycosphingolipids in the STAT3 phosphorylation inhibited cells may be linked to decreased transcripts of ST6GALNAC2 and UGCGL2, a glucosylceramide synthase. A rare 3 sulfoglucuronylparagloboside carrying HNK1 (human natural killer-1) epitope was found expressed in the GSC11 and the phenotypically differentiated cells. Its up regulation correlates with increased transcripts of a HNK1 biosynthesis gene, B3GAT2 after serum treatment. Taken together with a quantitative phosphoproteomic study of the same GSC line (C. L. Nilsson, et al. J. Proteome Res. 2010, 9, 430 443), this report represents the most complete systems biology study of cancer stem cell (CSC) differentiation to date. The synergies derived by the combination of glycomic, transcriptomic and phosphoproteomic data may aid our understanding of intracellular and cell-surface events associated with CSC differentiation. PMID- 20199108 TI - MUDE: a new approach for optimizing sensitivity in the target-decoy search strategy for large-scale peptide/protein identification. AB - The target-decoy search strategy has been successfully applied in shotgun proteomics for validating peptide and protein identifications. If, on one hand, this method has proven to be very efficient for error estimation, on the other hand, little attention has been paid to the resulting sensitivity. Only two scores are normally used and thresholds are explored in a very simplistic way. In this work, a multivariate decoy analysis is described, where many quality parameters are considered. This analysis is treated in our approach as an optimization problem for sensitivity maximization. Furthermore, an efficient heuristic is proposed to solve this problem. Experiments comparing our method, termed MUDE (multivariate decoy database analysis), with traditional bivariate decoy analysis and with Peptide/ProteinProphet showed that our procedure significantly enhances the retrieved number of identifications when comparing the same false discovery rates. Particularly for phosphopeptide/protein identifications, we could demonstrate more than a two-fold increase in sensitivity compared with the Trans-Proteomic Pipeline tools. PMID- 20199107 TI - Molecular mechanism of flop selectivity and subsite recognition for an AMPA receptor allosteric modulator: structures of GluA2 and GluA3 in complexes with PEPA. AB - Glutamate receptors are important potential drug targets for cognitive enhancement and the treatment of schizophrenia in part because they are the most prevalent excitatory neurotransmitter receptors in the vertebrate central nervous system. One approach to the application of therapeutic agents to the AMPA subtype of glutamate receptors is the use of allosteric modulators, which promote dimerization by binding to a dimer interface thereby reducing the degree of desensitization and deactivation. AMPA receptors exist in two alternatively spliced variants (flip and flop) that differ in desensitization and receptor activation profiles. Most of the structural information about modulators of the AMPA receptor targets the flip subtype. We report here the crystal structure of the flop-selective allosteric modulator, PEPA, bound to the binding domains of the GluA2 and GluA3 flop isoforms of AMPA receptors. Specific hydrogen bonding patterns can explain the preference for the flop isoform. This includes a bidentate hydrogen bonding pattern between PEPA and N754 of the flop isoforms of GluA2 and GluA3 (the corresponding position in the flip isoform is S754). Comparison with other allosteric modulators provides a framework for the development of new allosteric modulators with preferences for either the flip or flop isoforms. In addition to interactions with N/S754, specific interactions of the sulfonamide with conserved residues in the binding site are characteristics of a number of allosteric modulators. These, in combination with variable interactions with five subsites on the binding surface, lead to different stoichiometries, orientations within the binding pockets, and functional outcomes. PMID- 20199109 TI - Aggregation mechanisms of cystatins: a comparative study of monellin and oryzacystatin. AB - Identification of diseases caused by protein misfolding has increased interest in the way proteins adopt non-native conformations and form aggregates. In this study we address the question of how proteins sharing the same fold respond to destabilizing environmental conditions. We have studied the behavior of two members of the cystatin superfamily, MNEI, a single chain monellin, and oryzacystatin_I, a plant cystatin. Despite the close similarity of their three dimensional architecture, these two proteins aggregate in a different way: MNEI gives rise to amyloid aggregation whereas oryzacystatin_I yields amorphous aggregates. Mutants of oryzacystatin_I, designed to make it more similar to MNEI, generally behave like the parent protein, but a construct devoid of the disordered N- and C-terminal sequences does show a tendency to form amyloid fibers. Our results suggest that precise sequence details may be more important than the three-dimensional architecture in determining the type of aggregate formed. Oryzacystatin_I appears to be a very promising model system for further studies of protein aggregation. PMID- 20199110 TI - Mycobacterium tuberculosis Rv0899 adopts a mixed alpha/beta-structure and does not form a transmembrane beta-barrel. AB - The membrane protein Rv0899 (OmpATb) from Mycobacterium tuberculosis, has been proposed to act as an outer membrane porin and to contribute to the bacterium's adaptation to the acidic environment of the phagosome during infection. The gene is restricted to pathogenic mycobacteria and, thus, is an attractive candidate for the development of anti-tuberculosis chemotherapy. The 326-residue protein contains three domains: an N-terminal domain (residues 1-72) that includes a sequence of 20 hydrophobic amino acids required for membrane translocation, a central B domain (residues 73-200) with homology to the conserved putative lipid binding BON (bacterial OsmY and nodulation) superfamily, and a C domain (residues 201-326) with homology to the OmpA-C-like superfamily of periplasmic peptidoglycan-binding sequences, found in several types of bacterial membrane proteins, including in the C-terminus of the Escherichia coli outer membrane protein OmpA. We have characterized the structure and dynamics of the B and C domains and have determined the three-dimensional structure of the B domain. Rv0899 does not form a transmembrane beta-barrel. Residues 73-326 form a mixed alpha/beta-globular structure, encompassing two independently folded modules corresponding to the B and C domains connected by a flexible linker. The B domain folds with three parallel/antiparallel alpha-helices packed against six parallel/antiparallel beta-strands that form a flat beta-sheet. The core is hydrophobic, while the exterior is polar and predominantly acidic. The structure of a BON homology domain is revealed here for the first time. In light of this unexpected structure, it is hard to reconcile an outer membrane porin activity with the central domain of the protein. The structure of the B domain and the overall architecture of the protein suggest alternative modes of membrane association. PMID- 20199111 TI - Proteomic profiling of lipopolysaccharide-activated macrophages by isotope coded affinity tagging. AB - Lipopolysaccharide (LPS), a glycolipid component of the outer membranes of Gram negative bacteria, initiates proinflammatory, proapoptotic, and antiapoptotic pathways upon binding to macrophage TLR4. Macrophages that are exposed to LPS become activated and exhibit altered morphology and response to infection. We performed isotope coded affinity tagging (ICAT), multidimensional liquid chromatography, and mass spectrometry to identify proteins that are differently expressed between naive and LPS-activated macrophages. We performed replicate ICAT analyses on RAW 264.7 cultured mouse macrophages as well as C57BL/6 bone marrow derived mouse macrophages. We identified and obtained relative abundances for 1064 proteins, of which we identified 36 as having significantly different expression levels upon activation by LPS. We also compared our results with a two color microarray gene expression assay performed by the Institute for Systems Biology and observed approximately 75% agreement between mRNA transcription and protein expression regarding up- or down-regulation of gene products. We used Western blot analysis to confirm the findings of ICAT and mRNA for one protein, sequestosome 1, the cellular concentration of which was observed to increase upon activation by LPS. PMID- 20199115 TI - Publications of Benoit Soep. PMID- 20199113 TI - Autobiography of Benoit Soep. PMID- 20199116 TI - Electronic spectroscopy of the 6p <-- 6s transition in Au-Ne: trends in the Au-RG series. AB - We report electronic spectra of the Au-Ne complex, obtained in the vicinity of the Au atomic 6p <-- 6s transition. The structured spectrum found near the (2)P(3/2) <-- (2)S(1/2) transition is analyzed. We also explain the nonobservance of a spectrum close to the 6(2)P(1/2) state, using the results of high level ab initio calculations and insight from previous work on other Au-RG complexes (where RG = Ar, Kr, and Xe). Basis set extrapolated RCCSD(T) potential energy curves are also presented for the X(2)Sigma(+) ground state of Au-Ne, and the derived D(e) value is compared to experimental values. We then present an overview of trends through the Au-RG series: included in this are calculations on the X states of Au-He and Au-Rn, as well as for Au(+)-He. We also report further calculations on the states which arise from the interaction of Au(6(2)P(J)) with the rare gas atoms and include a Franck-Condon simulation of the D(2)Pi(3/2) <-- X(2)Sigma(1/2)(+) transition for Au-Ar. Trends in the spectroscopy across this series are summarized, and the Hund's case (a)/(c) character discussed. PMID- 20199117 TI - Fluorescence turn-on responses of anionic and cationic conjugated polymers toward proteins: effect of electrostatic and hydrophobic interactions. AB - Cationic and anionic poly(fluorenyleneethynylene-alt-benzothiadiazole)s (PFEBTs) are designed and synthesized via Sonagashira coupling reaction to show light-up signatures toward proteins. Due to the charge transfer character of the excited states, the fluorescence of PFEBTs is very weak in aqueous solution, while their yellow fluorescence can be enhanced by polymer aggregation. PFEBTs show fluorescence turn-on rather than fluorescence quenching upon complexation with proteins. Both electrostatic and hydrophobic interactions between PFEBTs and proteins are found to improve the polymer fluorescence, the extent of which is dependent on the nature of the polymer and the protein. Changes in solution pH adjust the net charges of proteins, providing an effective way to manipulate electrostatic interactions and in turn the increment in the polymer fluorescence. In addition, the effect of protein digestion on the fluorescence of polymer/protein complexes is probed. The results indicate that electrostatic interaction induced polymer fluorescence increase cannot be substantially reduced through cleaving protein into peptide fragments. In contrast, hydrophobic interactions, mainly determined by the hydrophobicity of proteins, can be minimized by digestion, imparting a light-off signature for the polymer/protein complexes. This study thus not only highlights the opportunities of exerting nonspecific interactions for protein sensing but also reveals significant implications for biosensor design. PMID- 20199118 TI - Measuring deficits in visually guided action post-concussion. AB - Recent concussion research has led to the development of computerized test batteries designed to measure working memory and psychomotor speed deficits in acute stage post-concussion. These tests lack a measure of motor control deficits, which may linger well after other symptoms have remitted. For athletes, this may mean returning to play while still uncoordinated or neurologically fragile. The present research involved the development of a visuomotor pointing task designed to induce a speed-accuracy trade off to measure motor planning and execution performance in concussed athletes. Data collected using this tool were contrasted with CogSport, a commercially available computerized test battery designed to assess residual cognitive effects of concussion in athletes. Results suggest that a motor task may be able to detect long-term effects of concussion not measurable with CogSport. If future research can confirm these findings, we suggest that a measure of motor control may need to be added to existing batteries to improve their sensitivity to long term effects. PMID- 20199119 TI - New horizons for the methodology and physiology of training periodization. AB - The theory of training was established about five decades ago when knowledge of athletes' preparation was far from complete and the biological background was based on a relatively small amount of objective research findings. At that time, traditional 'training periodization', a division of the entire seasonal programme into smaller periods and training units, was proposed and elucidated. Since then, international sport and sport science have experienced tremendous changes, while the traditional training periodization has remained at more or less the same level as the published studies of the initial publications. As one of the most practically oriented components of theory, training periodization is intended to offer coaches basic guidelines for structuring and planning training. However, during recent decades contradictions between the traditional model of periodization and the demands of high-performance sport practice have inevitably developed. The main limitations of traditional periodization stemmed from: (i) conflicting physiological responses produced by 'mixed' training directed at many athletic abilities; (ii) excessive fatigue elicited by prolonged periods of multi targeted training; (iii) insufficient training stimulation induced by workloads of medium and low concentration typical of 'mixed' training; and (iv) the inability to provide multi-peak performances over the season. The attempts to overcome these limitations led to development of alternative periodization concepts. The recently developed block periodization model offers an alternative revamped approach for planning the training of high-performance athletes. Its general idea proposes the sequencing of specialized training cycles, i.e. blocks, which contain highly concentrated workloads directed to a minimal number of targeted abilities. Unlike the traditional model, in which the simultaneous development of many athletic abilities predominates, block-periodized training presupposes the consecutive development of reasonably selected target abilities. The content of block-periodized training is set down in its general principles, a taxonomy of mesocycle blocks, and guidelines for compiling an annual plan. PMID- 20199120 TI - The effect of the menstrual cycle on exercise metabolism: implications for exercise performance in eumenorrhoeic women. AB - The female hormones, oestrogen and progesterone, fluctuate predictably across the menstrual cycle in naturally cycling eumenorrhoeic women. Other than reproductive function, these hormones influence many other physiological systems, and their action during exercise may have implications for exercise performance. Although a number of studies have found exercise performance - and in particular, endurance performance - to vary between menstrual phases, there is an equal number of such studies reporting no differences. However, a comparison of the increase in the oestrogen concentration (E) relative to progesterone concentration (P) as the E/P ratio (pmol/nmol) in the luteal phase in these studies reveals that endurance performance may only be improved in the mid-luteal phase compared with the early follicular phase when the E/P ratio is high in the mid-luteal phase. Furthermore, the late follicular phase, characterized by the pre-ovulatory surge in oestrogen and suppressed progesterone concentrations, tends to promote improved performance in a cycling time trial and future studies should include this menstrual phase. Menstrual phase variations in endurance performance may largely be a consequence of changes to exercise metabolism stimulated by the fluctuations in ovarian hormone concentrations. The literature suggests that oestrogen may promote endurance performance by altering carbohydrate, fat and protein metabolism, with progesterone often appearing to act antagonistically. Details of the ovarian hormone influences on the metabolism of these macronutrients are no longer only limited to evidence from animal research and indirect calorimetry but have been verified by substrate kinetics determined with stable tracer methodology in eumenorrhoeic women. This review thoroughly examines the metabolic perturbations induced by the ovarian hormones and, by detailed comparison, proposes reasons for many of the inconsistent reports in menstrual phase comparative research. Often the magnitude of increase in the ovarian hormones between menstrual phases and the E/P ratio appear to be important factors determining an effect on metabolism. However, energy demand and nutritional status may be confounding variables, particularly in carbohydrate metabolism. The review specifically considers how changes in metabolic responses due to the ovarian hormones may influence exercise performance. For example, oestrogen promotes glucose availability and uptake into type I muscle fibres providing the fuel of choice during short duration exercise; an action that can be inhibited by progesterone. A high oestrogen concentration in the luteal phase augments muscle glycogen storage capacity compared with the low oestrogen environment of the early follicular phase. However, following a carbo-loading diet will super-compensate muscle glycogen stores in the early follicular phase to values attained in the luteal phase. Oestrogen concentrations of the luteal phase reduce reliance on muscle glycogen during exercise and although not as yet supported by human tracer studies, oestrogen increases free fatty acid availability and oxidative capacity in exercise, favouring endurance performance. Evidence of oestrogen's stimulation of 5'-AMP-activated protein kinase may explain many of the metabolic actions of oestrogen. However, both oestrogen and progesterone suppress gluconeogenic output during exercise and this may compromise performance in the latter stages of ultra-long events if energy replacement supplements are inadequate. Moreover, supplementing energy intake during exercise with protein may be more relevant when progesterone concentration is elevated compared with menstrual phases favouring a higher relative oestrogen concentration, as progesterone promotes protein catabolism while oestrogen suppresses protein catabolism. Furthermore, prospective research ideas for furthering the understanding of the impact of the menstrual cycle on metabolism and exercise performance are highlighted. PMID- 20199121 TI - Alterations in central fatigue by pharmacological manipulations of neurotransmitters in normal and high ambient temperature. AB - The scientific evidence is reviewed for the involvement of the brain monoamines serotonin, dopamine and noradrenaline (norepinephrine) in the onset of fatigue, in both normal and high ambient temperatures. The main focus is the pharmacological manipulations used to explore the central fatigue hypothesis. The original central fatigue hypothesis emphasizes that an exercise-induced increase in serotonin is responsible for the development of fatigue. However, several pharmacological studies attempted and failed to alter exercise capacity through changes in serotonergic neurotransmission in humans, indicating that the role of serotonin is often overrated. Recent studies, investigating the inhibition of the reuptake of both dopamine and noradrenaline, were capable of detecting changes in performance, specifically when ambient temperature was high. Dopamine and noradrenaline are prominent in innervated areas of the hypothalamus, therefore changes in the catecholaminergic concentrations may also be expected to be involved with the regulation of body core temperature during exercise in the heat. Evidence from different studies suggests that it is very unlikely that one neurotransmitter system is responsible for the appearance of central fatigue. The exact mechanism of fatigue is not known; presumably a complex interplay between both peripheral and central factors induces fatigue. Central fatigue will be determined by the collaboration of the different neurotransmitter systems, with the most important role possibly being for the catecholamines dopamine and noradrenaline. PMID- 20199123 TI - Targeted therapies in cancer. AB - Recent advances in understanding the biologic mechanisms underlying cancer development have driven the design of new therapeutic approaches, termed 'targeted therapies', that selectively interfere with molecules or pathways involved in tumor growth and progression. Inactivation of growth factors and their receptors on tumor cells as well as the inhibition of oncogenic tyrosine kinase pathways and the inhibition of molecules that control specific functions in cancer cells constitute the main rational bases of new cancer treatments tailored for individual patients. Small-molecule inhibitors and monoclonal antibodies are major components of these targeted approaches for a number of human malignancies. As the studies of the bio-molecular features of cancer progress, new exciting strategies have arisen, such as targeting cancer stem cells that drive tumor relapses or the selective induction of apoptosis in malignant cells. This article primarily focuses on the biologic bases of the new cancer drugs and summarizes their mechanisms of action, the clinical evidence of their anti-cancer effectiveness as well as the rationale for their use in clinical practice. PMID- 20199124 TI - Bispecific antibodies for cancer immunotherapy: Current perspectives. AB - The concept of using bispecific antibodies to retarget immune effector cells for cancer therapy was conceived more than 20 years ago. However, initial clinical studies were rather disappointing mainly due to low efficacy, severe adverse effects and immunogenicity of the bispecific antibodies. A deeper understanding of effector cell biology and especially developments in the field of antibody engineering has led to the generation of new classes of bispecific antibodies capable of circumventing many of these obstacles. Furthermore, new applications were established for bispecific antibodies, such as pre-targeting strategies in radioimmunotherapy or dual targeting approaches in order to improve binding, selectivity, and efficacy. This review summarizes recent progress in the development of bispecific antibodies and describes some new concepts developed for cancer immunotherapy. PMID- 20199122 TI - Muscle carnosine metabolism and beta-alanine supplementation in relation to exercise and training. AB - Carnosine is a dipeptide with a high concentration in mammalian skeletal muscle. It is synthesized by carnosine synthase from the amino acids L-histidine and beta alanine, of which the latter is the rate-limiting precursor, and degraded by carnosinase. Recent studies have shown that the chronic oral ingestion of beta alanine can substantially elevate (up to 80%) the carnosine content of human skeletal muscle. Interestingly, muscle carnosine loading leads to improved performance in high-intensity exercise in both untrained and trained individuals. Although carnosine is not involved in the classic adenosine triphosphate generating metabolic pathways, this suggests an important role of the dipeptide in the homeostasis of contracting muscle cells, especially during high rates of anaerobic energy delivery. Carnosine may attenuate acidosis by acting as a pH buffer, but improved contractile performance may also be obtained by improved excitation-contraction coupling and defence against reactive oxygen species. High carnosine concentrations are found in individuals with a high proportion of fast twitch fibres, because these fibres are enriched with the dipeptide. Muscle carnosine content is lower in women, declines with age and is probably lower in vegetarians, whose diets are deprived of beta-alanine. Sprint-trained athletes display markedly high muscular carnosine, but the acute effect of several weeks of training on muscle carnosine is limited. High carnosine levels in elite sprinters are therefore either an important genetically determined talent selection criterion or a result of slow adaptation to years of training. beta Alanine is rapidly developing as a popular ergogenic nutritional supplement for athletes worldwide, and the currently available scientific literature suggests that its use is evidence based. However, many aspects of the supplement, such as the potential side effects and the mechanism of action, require additional and thorough investigation by the sports science community. PMID- 20199125 TI - Pluripotent human stem cells: A novel tool in drug discovery. AB - The need for new and improved pharmacotherapies in medicine, high late-stage compound attrition in drug discovery, and upcoming patent expirations is driving interest by the pharmaceutical industry in pluripotent stem cells for in vitro modeling and early-stage testing of toxicity and target engagement. In particular, human embryonic and induced pluripotent stem cells represent potentially cost-effective and accessible sources of organ-specific cells that foretell in vivo human tissue response to new chemical entities. Here we consider the potential of these cells as novel tools for drug development, including toxicity screening and metabolic profiling. We hold that despite various challenges to translating proof-of-concept screening platforms to industrial use, the promise of research is considerable, and close to being realized. PMID- 20199127 TI - Selective suicide gene therapy of colon cancer exploiting the urokinase plasminogen activator receptor promoter. AB - Colon cancer is the third and fourth most prevalent cancer among Iranian men and women, respectively. Suicide gene therapy is one of the alternative therapeutic modalities for cancer. The application of specific promoters for therapeutic genes should decrease the adverse effects of this modality. The combined aims of this study were to design a specific suicide gene therapy construct for colon cancer and study its effect in distinct representatives of transformed and nontransformed cells. The KRAS oncogene signaling pathway is one of the most important signaling pathways activated in colon cancer; therefore, we inserted the urokinase plasminogen activator receptor (uPAR; PLAUR gene) promoter as one of the upregulated promoters by this pathway upstream of a suicide gene (thymidine kinase [TK]) and a reporter gene (beta-galactosidase, beta-gal [LacZ]). This promoter is a natural combination of different motifs responsive to the RAS signaling pathway, such as the transcription factors AP1 (FOS/JUN), SP1, SP3, and AP2alpha, and nuclear factor kappa B (NFkappaB). The reporter plasmid under the control of the uPAR promoter (PUCUPARLacZ) had the ability to express beta-gal in colon cancer cells (human colon adenocarcinoma [SW480] and human colorectal carcinoma [HCT116] cell lines), while it could not express beta-gal in nontransformed human umbilical vein endothelial cells (HUVEC) and normal colon cells. After confirming the ability of pUCUPARTK (suicide plasmid) to express TK in SW480 and HCT116 cells by real-time PCR, cytotoxicity assays showed that pUCUPARTK decreased the viability of these cells in the presence of ganciclovir 20 and 40 microg/mL (and higher), respectively. Although M30 CytoDEATH antibody could not detect a significant rate of apoptosis induced by ganciclovir in pUCUPARTK-transfected HCT116 cells, the percentage of stained cells was marked in comparison with untreated cells. While this antibody could detect apoptosis in HCT116 cell line transfected with positive control plasmid, it could not detect apoptosis in SW480 cells transfected with the same positive control. This discrepancy could be attributed to the different mechanisms of TK/ganciclovir induced apoptosis in tumor protein p53 (TP53)-expressing (HCT116) and -deficient (SW480) cells. Annexin-propidium iodide staining could detect apoptosis in treated, pUCUPARTK-transfected SW480 and HCT116 cells. This study showed that the uPAR promoter can be considered as a suitable candidate for specific suicide gene therapy of colon cancer and probably other cancers in which the RAS signaling pathway is involved in their carcinogenesis process. PMID- 20199128 TI - Medicine, poison, and mystic potion: a personal perspective on paracetamol Louis Roche lecture, Stockholm, 2009. AB - BACKGROUND: Paracetamol poisoning has been a clinical problem for over 40 years. This article reflects the content of the Louis Roche lecture given on this topic in 2009. HISTORICAL CONTEXT: Initially key work illustrated the relationship between plasma paracetamol concentration and risk of liver injury facilitating the development of antidote strategies. Much of this work was done in the Edinburgh clinical toxicology unit. DISCUSSION: The antidote most widely used, acetylcysteine, was developed in Edinburgh and subsequently shown to be associated with adverse effects. Studies on this aspect and on key problems remaining in patient management are described. These include the identification of patients at greatest risk of toxicity, in order that they may be targeted for appropriate early intervention. More recent work suggests that the inflammatory response to paracetamol-induced liver injury may offer new targets for drug therapy in this major poisoning. CONCLUSION: Paracetamol poisoning remains a challenging problem, but new approaches to treatment seem possible based on recent experimental studies in animals and humans. PMID- 20199129 TI - p16 promoter methylation in Pb2+ -exposed individuals. AB - BACKGROUND: One of the principle symptoms of lead poisoning is the development of neurological disorders. Neuronal response is closely related to DNA methylation changes. Aim. In this study, we estimated p16 methylation in nine individuals exposed to lead using methylation-specific polymerase chain reaction followed by analysis of the methylated cytosine content of the product by thermal denaturation. RESULTS: We found that, based on lead blood concentration, lead exposed individuals were divided into two groups. Among highly exposed individuals (blood Pb(2+) concentration = 51-100 microg/dL), we observed complete CpG methylation, whereas for low Pb(2+) concentrations (blood Pb(2+) concentration = 6-11 microg/dL), we observed partial methylation. CONCLUSION: Our results show that among lead-overexposed individuals, p16 methylation is frequent and extensive, and suggest that DNA methylation could be involved in the mechanism by which lead induces neurotoxicity. PMID- 20199126 TI - Immunotherapy for cervical cancer: Research status and clinical potential. AB - The high-risk types of human papillomavirus (HPV) have been found to be associated with most cervical cancers and play an essential role in the pathogenesis of the disease. Despite recent advances in preventive HPV vaccine development, such preventive vaccines are unlikely to reduce the prevalence of HPV infections within the next few years, due to their cost and limited availability in developing countries. Furthermore, preventive HPV vaccines may not be capable of treating established HPV infections and HPV-associated lesions, which account for high morbidity and mortality worldwide. Thus, it is important to develop therapeutic HPV vaccines for the control of existing HPV infection and associated malignancies. Therapeutic vaccines are quite different from preventive vaccines in that they require the generation of cell-mediated immunity, particularly T cell-mediated immunity, instead of the generation of neutralizing antibodies. The HPV-encoded early proteins, the E6 and E7 oncoproteins, form ideal targets for therapeutic HPV vaccines, since they are consistently expressed in HPV-associated cervical cancer and its precursor lesions and thus play crucial roles in the generation and maintenance of HPV-associated disease. Our review covers the various therapeutic HPV vaccines for cervical cancer, including live vector-based, peptide or protein-based, nucleic acid-based, and cell-based vaccines targeting the HPV E6 and/or E7 antigens. Furthermore, we review the studies using therapeutic HPV vaccines in combination with other therapeutic modalities and review the latest clinical trials on therapeutic HPV vaccines. PMID- 20199130 TI - Caustic injury: can CT grading system enable prediction of esophageal stricture? AB - BACKGROUND: The aim of this study was to test the utility of our computed tomography (CT) grading system, compared with endoscopy, for association with the development of esophageal stricture in patients with caustic ingestion. METHODS: This retrospective case series involved 49 patients with caustic ingestion from 1998 to 2009. The degree of esophageal damage was graded using a scoring system based on the extent of esophageal wall edema and the damage in adjacent tissue as seen on thoracoabdominal CT scans. The presence of esophageal stricture was established by esophagography. Diagnostic performance was compared using receiver operating characteristic (ROC) analysis. Sensitivity and specificity were calculated for the grading system. RESULTS: The CT grading score results showed that grade III was the most common injury (20 cases, 40.8%), followed by grade IV (14 cases, 28.6%), grade II (9 cases, 18.4%), and grade I (6 cases, 12.2%). In addition, damage to the esophagus was significantly correlated with esophageal stricture when the extent of damage approached grades III and IV (p < 0.001). The CT grading system for esophageal stricture resulted in a slightly larger area under the receiver operating characteristic curve (0.90) compared with endoscopic grading system (0.79). The sensitivity and specificity of CT grading system were moderately higher than those of endoscopic grading system. CONCLUSION: Assessment of the degree of esophageal damage using CT, a noninvasive modality, in patients who visit the emergency department following caustic ingestion should be useful in estimating the occurrence of complications including esophageal stricture. PMID- 20199131 TI - A case of torsades de pointes induced by severe QT prolongation after an overdose of eperisone and triazolam in a patient receiving nifedipine. AB - INTRODUCTION: Eperisone hydrochloride is a centrally acting muscle relaxant, and triazolam is a short-acting benzodiazepine. Although commonly prescribed, cardiotoxicity induced by a single overdose of either drug is comparatively rare. A patient receiving nifedipine developed torsades de pointes (TdP) because of prolongation of the corrected QT (QTc) interval after an overdose of eperisone hydrochloride and triazolam. CASE REPORT: A 60-year-old man receiving nifedipine was admitted in a comatose condition 3 h after ingesting 5,000 mg of eperisone and 2.5 mg of triazolam. Electrocardiogram showed sinus rhythm with prolongation of the QTc interval (820 ms). The serum electrolyte levels were as follows: potassium, 3.8 mEq/L; magnesium, 2.4 mg/dL. The serum drug concentrations were high: eperisone, 15,360 ng/mL; triazolam, 110.8 ng/mL. A temporary cardiac pacemaker was implanted immediately after the development of TdP, 11 h after the ingestion. The serum triazolam concentration normalized on day 2. The QTc interval and eperisone concentration normalized on day 6. CONCLUSION: Eperisone and triazolam overdose can cause life-threatening cardiotoxicity. Electrocardiographic monitoring and serial determination of QTc interval are likely the best way to observe these patients and evaluate the risk of cardiotoxicity. PMID- 20199132 TI - Massive acetaminophen ingestion with early metabolic acidosis and coma: treatment with IV NAC and continuous venovenous hemodiafiltration. AB - CONTEXT: We report the extraction of acetaminophen by continuous venovenous hemodiafiltration (CVVHD) during treatment of an acute ingestion of 200 g with a peak recorded serum acetaminophen level of 1,614 mg/L (10,652 micromol/L). CASE DETAILS: The patient presented with early onset of coma, metabolic acidosis, and hypotension in the absence of significant hepatic injury. In addition to N acetylcysteine (NAC) therapy, CVVHD was performed to manage the acid-base disturbance. Flow rate, effluent volume, and serum and effluent drug concentrations were obtained at hourly intervals. During 16 h of CVVHD the acetaminophen level dropped from 1,212 to 247 mg/L. DISCUSSION: The average clearance of acetaminophen by CVVHD was 2.53 L/h, with removal of 24 g of acetaminophen over 16 h. As NAC is effective in preventing hepatic injury after acute acetaminophen overdose, the role of dialysis or CVVHD is limited. PMID- 20199134 TI - Synthesis, structural characterisation and antibacterial activity of bis(1-phenyl 1,3-butanedionato)non-oxovanadium(IV) hydroxamates. AB - Complexes with a composition of VCl(2-n)(bzac)(2)(HL(1,2))(n) (I - IV) (where bzac = 1-phenyl-1,3-butanedionate anion (C(6)H(5)COCHCOCH(3)(-)); HL(1)=C(6)H(5)OCH(2)C(O)NHO(-), HL(2) = C(6)H(5)CH=CHC(O)NHO(-), n = 1 and 2) have been synthesised from the reactions of (VCl(2)(bzac)(2)) with equi- and bi molar amounts of potassium phenoxyacetohydroxamate and cinnamohydroxamate (KHL(1,2)) in THF + MeOH solvent medium. The complexes have been characterised by elemental analyses, molar conductivity, magnetic measurements, IR, electronic and mass spectral studies. The physicochemical and spectral studies suggest a distorted octahedral geometry around vanadium in the complexes. The antibacterial activities of the newly synthesised complexes, vanadium precursor and ligands have been screened in vitro against six bacterial species. The complexes have shown higher antibacterial effect than the free ligands. PMID- 20199135 TI - Propionibacterium acnes causing delayed postoperative spine infection: review. AB - Propionibacterium acnes was previously considered a contaminant and its role in spine infection has been understated. Although rare, such infections are present especially after instrumented spine surgery. They are usually delayed and hard to diagnose. Delayed infection should be suspected in patients with pain and a history of spine surgery. In this article, we review the diagnostic challenges associated with delayed P. acnes infection after spine surgery, guided by relevant studies in the literature. The medical databases of PubMed, Medline and Embase were searched for the literature on delayed spine infections and osteomyelitis following spinal procedures. The medical literature was reviewed for articles published between 1955 and 2008. Our review of the literature revealed 13 cases of P. acnes osteomyelitis following surgical procedures involving the spine. We also present a clinical case of delayed P. acnes osteomyelitis following discectomy and fusion with instrumentation. PMID- 20199136 TI - Patient reported outcomes in adults with type 2 diabetes on basal insulin randomized to addition of mealtime pramlintide or rapid-acting insulin analogs. AB - OBJECTIVE: To determine whether treatment satisfaction and quality of life were affected by adding mealtime pramlintide or rapid-acting insulin analogs (RAIAs) to basal insulin therapy for patients with inadequately controlled type 2 diabetes. RESEARCH DESIGN AND METHODS: In this 24-week open-label, multicenter study of adults with type 2 diabetes, mealtime pramlintide (PRAM) (120 microg fixed dose; n = 56) or titrated RAIAs (n = 56) was added to basal insulin therapy with or without oral antidiabetic medications. CLINICAL TRIAL REGISTRATION: ClinicalTrials.Gov NCT00467649. MAIN OUTCOME MEASURES: Quality of life (Diabetes Distress Scale - DDS, and Pittsburgh Sleep Quality Index - PSQI), and treatment satisfaction (Diabetes Treatment Satisfaction Questionnaire - DTSQ, and Pramlintide Treatment Satisfaction Questionnaire - PRAM-TSQ) were assessed at baseline and week 24. Mixed-effect models estimated mean group changes from baseline to week 24 (adjusted for baseline scores) in patient reported outcomes. RESULTS: PRAM patients experienced significant improvement in total diabetes distress, while RAIA patients did not; both groups experienced significant improvement in regimen-related distress and physician-related distress. Between group differences in DDS measures were not significant. PRAM patients experienced significant improvement in sleep latency and daytime dysfunction, while RAIA patients did not; the difference between groups was significant for daytime dysfunction. Both treatment groups experienced significant improvement in most individual DTSQ items and total diabetes treatment satisfaction, while only PRAM patients experienced significant improvement in perceived hypoglycemia. Between group differences in DTSQ measures were not significant. Both treatment groups experienced significant improvement in most individual PRAM-TSQ items and total treatment satisfaction; RAIA patients experienced increased eating flexibility and reduced perceived weight control. PRAM patients experienced significantly better perceived weight and appetite control than RAIA patients. LIMITATIONS: The sample size was relatively small and there were few non-white subjects. The schedule for implementation of change in therapy may have affected study outcomes. CONCLUSIONS: Adding pramlintide on a background of basal insulin improved some aspects of treatment satisfaction and quality of life relative to adding rapid-acting insulin analogs. PMID- 20199137 TI - Efficacy and safety of the once-daily human GLP-1 analogue, liraglutide, vs glibenclamide monotherapy in Japanese patients with type 2 diabetes. AB - OBJECTIVE: Liraglutide is a once-daily human glucagon-like peptide-1 (GLP-1) analogue developed for the treatment of type 2 diabetes mellitus (T2DM). In Phase 2 and Phase 3 trials, largely conducted in populations of European descent, liraglutide has been shown to lower HbA(1C), weight and systolic blood pressure with a low risk of hypoglycaemia. This Phase 3, 24-week, multi-centre, double blind, double dummy, randomised parallel-group trial compared the efficacy and safety of liraglutide and glibenclamide monotherapy in Japanese subjects with T2DM, inadequately controlled with diet therapy or oral antidiabetic drug (OAD) monotherapy. RESEARCH DESIGN AND METHODS: A total of 411 Japanese subjects were randomised 2:1 to liraglutide (n = 272) or glibenclamide (n = 139). Liraglutide was administered at a maximum planned dose of 0.9 mg once daily. Glibenclamide was administered once or twice daily at a planned maximum dose of 2.5 mg/day, before or after meals. CLINICAL TRIAL REGISTRATION: NCT00393718. RESULTS: After 24 weeks, glycaemic control with liraglutide was non-inferior/superior to glibenclamide, with HbA(1C) at 24 weeks of 6.99% (SE +/- 0.07) with liraglutide and 7.50% (+/-0.09) with glibenclamide (difference, -0.5%; 95% CI -0.70 to 0.30; p < 0.0001). Mean fasting plasma glucose (FPG) levels at 24 weeks were significantly lower with liraglutide (7.6 mmol/l [SE +/- 0.1]) vs glibenclamide (8.3 mmol/l [+/-0.1]; difference, -0.72 mmol/l; 95% CI -1.0 to -0.4; p < 0.0001). Weight was reduced by -0.92 kg from a baseline of 65.2 kg in liraglutide-treated patients, compared with weight gain of +0.99 kg from a baseline of 64.8 kg with glibenclamide (difference, -1.91 kg; 95% CI -2.34 to -1.48; p < 0.0001). A significantly lower rate of minor hypoglycaemic episodes was achieved with liraglutide compared with glibenclamide (p < 0.0001), and no major hypoglycaemic episodes were reported in either treatment group. The most common gastrointestinal AEs were diarrhoea (liraglutide, 6.3%; glibenclamide, 3.8%) and constipation (liraglutide, 5.6%; glibenclamide, 3.8%). Nausea was infrequent (liraglutide, 4.5%; glibenclamide, 1.5%). CONCLUSIONS: Liraglutide monotherapy, administered once daily for 24 weeks in Japanese subjects with T2DM, was well tolerated. Compared with glibenclamide monotherapy, liraglutide achieved superior glycaemic control and weight outcome, and a significantly lower incidence of hypoglycaemia. Future studies, comprising a greater proportion of true therapy naive Japanese patients, will be beneficial in order to establish the true add-on efficacy of liraglutide monotherapy in patients with T2DM. PMID- 20199138 TI - Impact of persistence with antiplatelet therapy on recurrent ischemic stroke and predictors of nonpersistence among ischemic stroke survivors. AB - OBJECTIVE: Medication adherence is an important component of effective secondary stroke prevention. The objectives of this study were to examine the impact of persistence with two prescription antiplatelet therapies on the outcome of recurrent hospitalized stroke, and to identify the predictors of nonpersistence with these antiplatelet therapies. RESEARCH DESIGN AND METHODS: Administrative claims from a large, geographically diverse US health plan were used to evaluate acetylsalicylic acid / extended-release dipyridamole (ASA/ERDP) treated and clopidogrel treated patients from November 1, 2002 - December 31, 2005 who had an ischemic stroke requiring hospitalization. Nonpersistence was defined as failure to refill index medication within 30 days from the run-out date of the prior prescription. A Cox proportional hazards model was used to identify key factors associated with time to nonpersistence. MAIN OUTCOME MEASURES: Patient demographic variables, clinical characteristics, comorbidities hypothesized to affect the risk of current stroke, stroke outcomes, treatment patterns, and compliance were assessed. RESULTS: A total of 1413 patients hospitalized for ischemic stroke were identified. Mean age was 63.4 years and 44.2% were female. The proportion of patients persistent per person-year was 45.1%. Persistence with medication was significantly associated with a longer time to recurrent hospitalized stroke (HR 0.275; 95% CI 0.134-0.564; p < 0.0004). A medication copayment of >$40 (relative to a copayment of < or =$20) was the only significant factor predicting time to nonpersistence (HR 1.320; 95% CI 1.091-1.596; p < 0.0042). CONCLUSIONS: Persistence with antiplatelet medication within a cohort of hospitalized ischemic stroke patients was associated with a 72.5% lower likelihood of recurrent hospitalized stroke. Higher medication copayment was found to negatively impact patient persistence with antiplatelet therapy. The findings of this study must be considered within the limitations of database analysis, as claims data are collected for the purpose of payment and not research. PMID- 20199139 TI - Urinary flow and urinary symptoms in elderly males exposed to either escitalopram or duloxetine. AB - OBJECTIVE: To profile the effects of escitalopram with duloxetine on urinary flow rate and symptoms in elderly males aged 55-75 years. RESEARCH DESIGN AND METHODS: This was an open, randomised pilot study. A total of 34 male volunteers with no existing urinary symptoms were randomised: 17 to escitalopram 10 mg once daily and 17 to duloxetine 60 mg once daily for 16 days. Doses were then tapered to 5 mg and 30 mg, respectively for 14 days. Subjects measured their urinary flow at home using a Urospec device for 48 hours pre-dose, immediately after the first dose, at 2 weeks and 5 days after stopping treatment. MAIN OUTCOME MEASURES: The primary variable was the maximum urinary flow rate (Q(max)). Secondary variables were time to maximum flow rate (TQ(max)) and mean flow rate (Q(m)). The percentage of voided volume voided when the maximum flow was reached (VQ(max)), average voided volume (V(v)) and urinary symptoms assessed using the American Urological Association symptom index were also measured. RESULTS: Mean Q(max) values increased from baseline in escitalopram-treated subjects and decreased in duloxetine-treated subjects. The maximum difference in treatment effect was observed after 2 days of treatment and was statistically significant (4.27 mL/sec, 95% CI 1.14-7.39, p = 0.009). Similar results were obtained with TQ(max). There were no significant differences between treatments in other urinary flow measures or urinary symptoms. Urinary flow measures reverted towards baseline values after stopping treatment. There were no treatment-related adverse events. CONCLUSIONS: The results of this small, pilot study suggest that duloxetine may cause a decline in urinary flow in elderly men. A larger study in patients with urinary flow symptoms would be required to determine the clinical relevance of these findings. PMID- 20199140 TI - Efficacy of intranasal fentanyl spray versus other opioids for breakthrough pain in cancer. AB - OBJECTIVE: To compare the efficacy of intranasal fentanyl spray (INFS), oral transmucosal fentanyl citrate (OTFC), fentanyl buccal tablet (FBT) and oral morphine (OM) for the treatment of breakthrough cancer pain (BTCP). METHODS: A systematic literature review (Medline, EMBASE, BIOSIS; 1996-2007) identified six randomised controlled trials (RCTs) investigating the effects of INFS, OTFC, FBT and OM for the treatment of BTCP. The endpoint of interest was pain intensity difference (PID, reported on a 0-10 numeric rating scale [NRS]) up to 60 minutes after intake. Results of all trials were analysed simultaneously with a mixed treatment comparison (extended meta-analysis). MTC can be considered a valid method when included studies are comparable regarding effect modifying baseline patient and study characteristics. RESULTS: INFS provided the greatest reduction in pain relative to placebo: PID 1.7 points (95% CrI: 1.4; 1.9) at 15 minutes, 2.0 (1.6; 2.3) at 30 minutes, 2.0 (1.5; 2.4) at 45 minutes and 1.9 (1.5; 2.4) at 60 minutes. PID for OTFC and FBT relative to placebo were 0.4 (0.0; 0.8) and 0.5 (0.3; 0.7) at 15 minutes. Both treatments provided a reduction in pain superior to placebo at other time points. INFS displayed a more than 99% probability of providing the greatest pain reduction out of all interventions compared at 15 minutes after intake. This was maintained for any measured time point before 45 minutes when compared to FBT and for any measured time point before 60 minutes when compared to OTFC. Only from 45 minutes onwards did OM show a greater pain reduction than placebo. CONCLUSION: Based on currently available evidence, INFS is expected to provide the greatest improvement in the treatment of BTCP. Due to its slow onset to effect OM cannot be considered an efficacious treatment for BTCP. PMID- 20199143 TI - Cost estimation of patients admitted to the intensive care unit: a case study of the Teaching University Hospital of Thessaly. AB - OBJECTIVE: This study aimed to estimate the cost of patients admitted to the Intensive Care Unit (ICU) of the Teaching University Hospital of Thessaly (TUHT) in 2006 and to demonstrate discrepancies between actual hospitalisation cost and social funds' reimbursement. METHODS: Cost analysis was performed using a macro costing approach, which focused on the estimation of nominal and actual cost per ICU patient. Data were derived from the annual records of resources consumed in each hospital unit and from hospital balance sheets. Sensitivity analysis was also performed by inflating nominal costs to present values. RESULTS: There were 312 patients admitted to the ICU. Mean actual cost per ICU patient was estimated at ?16,516, whereas actual reimbursement from social funds was only ?1,671. This means that reimbursement accounted for just 10% of the actual hospitalisation cost. Once nominal costs were inflated to present values, the reimbursement accounted for 25% of the actual hospitalisation cost. The major cost drivers of ICU hospitalisation were personnel costs followed by infrastructure, hotel services and pharmaceutical expenditure. These results may be limited by a lack of consideration for clinical outcomes along with a high level of aggregation in cost data. CONCLUSION: Reimbursement should be re-adjusted in order to balance public hospital deficits and make public-private mix viable. This way, intensive care capacity would increase and allow a more equitable distribution of healthcare resources. PMID- 20199141 TI - FGF-2-responsive and spinal cord-resident cells improve locomotor function after spinal cord injury. AB - The adult central nervous system has only a limited capacity for axonal regeneration. In this study, fibroblast growth factor-2 (FGF-2) was injected once into the spinal cord tissue around the injury site immediately after complete spinal cord transection in rats. This treatment markedly improved the locomotor function of the animals. Histological analysis demonstrated that tissue composed of FGF-2-induced fibronectin-positive cells (FIFs) had infiltrated the injury site and filled large cystic cavities, into which numerous axons with growth associated protein-43 immunoreactivity penetrated. The FIFs could also be cultured from the intact spinal cord tissue, demonstrating that they were resident in the non-injured spinal cord. They had a spindle-shaped morphology and enhanced expression of mRNAs of N-cadherin and neurotrophic factors, suggesting the beneficial properties of the FIFs for axonal regeneration. Thus, these results argue for the continual use of autologous transplantation as a novel and promising cell therapy for the treatment of spinal cord injury. PMID- 20199144 TI - Cloning, prokaryotic expression, and biological analysis of recombinant chicken IFN-gamma. AB - The full-length chicken interferon-gamma (CHIFN-gamma) gene was amplified by reverse transcription-PCR using total RNA extracted from the spleen cells of white Leghorn chicken, a local Chinese breeding species. A truncated CHIFN-gamma gene without the N-terminal signal peptide sequence was cloned into prokaryotic expression vector pET30a, resulting in a recombinant plasmid pET-30a-CHIFN-gamma. After the recombinant plasmid was transformed into host cells BL21(DE3)pLysS, the expression of CHIFN-gamma was induced by isopropyl beta-D-thiogalactoside (IPTG). Rabbit antiserum was raised using the soluble CHIFN-gamma as immunogen. Immunoreactivities of the CHIFN-gamma and its antiserum were investigated using immunoblotting and ELISA. Moreover, the antiviral effect of the CHIFN-gamma was analyzed. Our data indicate that the CHIFN-gamma is biologically active. PMID- 20199145 TI - Production of rat monoclonal antibodies against RNA-binding protein Hzf. AB - The hematopoietic zinc finger protein, Hzf, is induced in response to DNA damage or by Arf tumor suppressor in a p53-dependent manner. Recent studies have revealed that Hzf is an RNA-binding protein that regulates localization and translation of specific mRNA. The RNA-binding activity of Hzf is required for the functions of cerebellar purkinje cells and adipocytes, although their molecular mechanisms underlying the mRNA regulation largely remain unknown. To further investigate the molecular function of Hzf, we raised two rat monoclonal antibodies (MAb) against a peptide corresponding to the C-terminal region of the mouse/human Hzf protein. Both MAbs reacted with the native protein expressed in mammalian cells, and were highly efficient in detecting endogenous Hzf by immunoblotting, immunoprecipitation, and immunofluorescence. These MAbs should therefore be useful for further analysis of molecular functions of the Hzf protein and for identification of Hzf-binding proteins. PMID- 20199146 TI - Generation and identification of monoclonal antibodies against FNIII domain D of human tenascin-C. AB - Tenascin-C (TN-C), a key component of extracellular matrix (ECM), is strongly expressed in fetal and cancer tissues. Large-molecular-weight variants of TN-C, including different combinations of its alternative spliced FNIII repeats, are specifically expressed in tissues under certain pathological conditions. Here we report the production of monoclonal antibodies (MAbs) against FNIII domain D (FNIII D) of human TN-C. Complementary DNA encoding the FNIII D region was generated by RT-PCR from human osteosarcoma (OS) cell line, and the recombinant FNIII D-GST fusion protein was expressed and purified. Two hybridoma cell lines secreting monoclonal antibodies (MAbs) against FNIII D were obtained by routine murine hybridoma technique. The MAbs were identified by indirect enzyme-linked immunosorbent assay (ELISA), Western blot, and immunohistochemistry (IHC). Both of them were applicable in Western blot and IHC. With our MAbs, we found TN-C was positive in OS and most of it was among the tumor stroma. To conclude, these MAbs to human FNIII D domain of TN-C may be useful for exploring OS pathogenesis and potential clinical application. PMID- 20199147 TI - Generation of anti-proteinase 3 monoclonal antibodies and development of immunological methods to detect endogenous proteinase 3. AB - Proteinase 3 (PR3), a neutrophil granule serine protease, is the major autoantigen for autoantibodies in the systemic vasculitic disease, Wegener's granulomatosis. It is also found to be involved in various inflammatory diseases including Crohn's disease, rheumatoid arthritis, cystic fibrosis, and gingivitis. However, there is no high quality antibody available to detect endogenous PR3 in biological samples such as plasma and tissue. Several commercial anti-PR3 monoclonal antibodies (MAbs) were obtained by using HMC-1/PR3 cell granule extracts as the antigen, but the resulting antibodies could not be applied for immunoblotting or other immunological methods. Therefore, we produced human recombinant PR3 in Escherichia coli and developed several MAbs that are highly sensitive and can be used for immunoblotting, FACS analysis, and immunofluorescent staining. The PR3 MAbs recognized both rhPR3 and human plasma derived neutrophil PR3 in reducing and non-reducing conditions at low nanogram levels. In addition, new MAbs detect endogenous PR3 from normal human plasma and urine with high specificity. The new anti-PR3 MAbs will be an essential tool for investigating the role of PR3 in inflammatory and autoimmune diseases. PMID- 20199148 TI - Monoclonal antibody MG7 as a screening tool for gastric cancer. AB - MG7 is a gastric cancer-specific MAb with high specificity and sensitivity. By using MG7 MAb, we found that MG7Ag was increasingly detected in superficial gastritis, atrophic gastritis, intestinal metaplasia, atypical hyperplasia, and gastric cancer, indicating that MG7Ag could be considered an important early warning molecule of gastric cancer and MG7 MAb could be used as a tool for screening gastric cancer. We have developed a new and sensitive system, immuno realtime PCR, for detection of MG7Ag in the serum. The use of qIPCR assays enabled the detection of MG7Ag in complex biological samples that were poorly accessible by conventional immunoassays. PMID- 20199149 TI - A monoclonal antibody specific to human myxovirus resistance protein A. AB - Recombinant human myxovirus resistance protein A (MxA) was successfully expressed by an Escherichia coli expression system. After immunization and cell fusion, a mouse hybridoma (3C2) producing MAbs to MxA was established. Hybridoma 3C2 was further characterized using indirect ELISA, Western blot analysis, immunofluorescent staining, and immunoprecipitation. The ELISA results showed that the titer of 3C2 was between 1:6400 and 1:12800 in ascitic fluids. The isotype of the monoclonal antibody was tested to be IgG1kappa. 3C2 can also specifically recognize human MxA protein in various formats by Western blot analysis, immunofluorescent staining, and immunoprecipitation assay. We further demonstrated that 3C2 could be used to detected MxA expression induce by type I interferon in A549 cell line and human peripheral blood mononuclear cells by Western blot in a dose-dependent manner. PMID- 20199150 TI - Simple method of monoclonal antibody production against mammalian cellular prion protein. AB - Monoclonal antibodies (MAbs) against prion protein (PrP) are powerful tools for diagnosis and research in transmissible spongiform encephalopathies. Ten MAbs to recombinant/native cellular PrP (PrPc) in mammals were prepared with a simple method and identified in detail. Normal BALB/c mice were immunized with the recombinant bovine mature PrP (rbomPrP) and PrP27-30 (rboPrP27-30) expressed in Escherichia coli. The immunized splenocytes were fused with SP2/0 mouse myeloma cells, and positive hybridomas were selected by indirect enzyme-linked immunosorbent assay (ELISA). The characterizations of these MAbs, such as Ig, Ig subclass, titer, affinity index, specificity, epitopes recognized, and binding to recombinant/native PrPc of cattle, sheep, or human beings, were evaluated by Western blotting and indirect or sandwich ELISA. Ten MAbs could be divided into five groups depending on the results of indirect ELISA additivity test and their reaction to E. coli-expressed truncated-PrPs. Isotyping of the MAbs revealed that they belong to IgG1, IgG2a, and IgG2b subclass. Their indirect ELISA titers were between 10(3) and 10(6). Affinity constants were between 10(9) and 10(12) M(-1). Ten MAbs specifically reacted with the rbomPrP, without binding to prion-like protein Doppel and the lysates of E. coli. These MAbs could also respond to the recombinant mature PrP (rmPrP) of sheep and human beings. Also of interest was the ability of the MAbs to bind with dimer of rmPrP and PrP extracted from the brain tissue of cattle or sheep. We conclude that anti-PrP MAbs successfully prepared with a simple method could potentially be useful in mammalian prion research. PMID- 20199151 TI - A Competitive ELISA for quantifying serum CD147: reduction of soluble CD147 levels in cancer patient sera. AB - CD147/EMMPRIN (extracellular matrix metalloproteinase inducer) is a cell surface glycoprotein that displays increased expression in many cancers. It has been previously demonstrated to participate in cancer metastasis and progression. In this study we used an anti-CD147 monoclonal antibody and a recombinant CD147 protein generated in our laboratory to establish a competitive ELISA for quantifying serum CD147 levels. Unexpectedly, the CD147 level was highest in sera of normal subjects and significantly reduced in sera of cancer patients. There was no significant difference in serum CD147 level between benign, non metastatic, and metastatic stages of cancers. In regard to liver diseases, the maximal CD147 level was observed in sera of patients with hepatitis and hepatocellular carcinoma, and significantly decreased in patients with liver cirrhosis and cholangiocarcinoma. Our results imply that there may be homeostasis of CD147 levels in sera under normal physiological conditions, while such a level is altered in cancer patients. PMID- 20199152 TI - Production and characterization of monoclonal antibodies to mouse germ cells. AB - In mammals, primordial germ cells (PGCs) are generated in the extra-embryonic epiblast, and thereafter migrate into the developing gonads. Following the development of the gonads to the testes or ovaries, germ cells mature into sperms or eggs. In the present study, we report production and characterization of monoclonal antibodies (MAb) that recognize PGCs. Extracts from E12.5 mouse embryonic gonads were immunized as an antigen, and hybridomas were generated using the rat medial iliac lymph node method. The hybridoma supernatants were screened by immunohistochemical analyses of E12.5 mouse embryonic sections. The antibody, referred to herein as MAb 5B5, provided strong signals on PGCs. Moreover, immunofluorescence analyses using a variety of the tissue sections of mouse embryos revealed that MAb 5B5 also recognizes the ventricular zone of the cerebral cortex and the neural canal in the spinal cord in which neural specific stem cells are present in abundance. Based on these findings, MAb 5B5 might recognize stem cell-associated antigens. PMID- 20199153 TI - Production of a rat monoclonal antibody specific for Myf5. AB - Myogenic regulatory factors (MRFs) are transcription factors that possess a characteristic basic helix-loop-helix domain. Myf5, MyoD, MRF4, and myogenin are well-known MRF family members that activate muscle-specific genes during differentiation. Myf5 is expressed first among MRFs at the very early phase and plays an important role in myoblast specificity and cell proliferation. Myf5 shares high homology with MyoD, and therefore some commercial Myf5 antibodies are cross-reactive for Myf5 and MyoD. To allow for detailed studies of the function of Myf5, we generated a monoclonal antibody specific for Myf5 utilizing a rat medial iliac lymph node method. Immunoblot analysis using our monoclonal antibody enabled us to identify Myf5 protein from rat myoblast L6E9 cell extract. Moreover, cell immunostaining revealed the nuclear localization of Myf5 in the L6E9 cells. This monoclonal antibody against Myf5 will allow us to perform further detailed studies of Myf5 and Myf5 function. PMID- 20199154 TI - A rat monoclonal antibody against the chromatin remodeling factor CHD5. AB - CHD5 (chromodomain/helicase/DNA-binding protein 5) is a member of the CHD subfamily of chromatin remodeling Swi/Snf proteins, and has been recently identified as a tumor suppressor in a diverse range of human cancers. We report here on the establishment of a hybridoma cell line for producing a monoclonal antibody against CHD5 by the rat medial iliac lymph node method. Immunoblotting analyses indicated that this antibody, MAb 5A10, specifically recognizes endogenous CHD5. In immunostaining using the antibody, a nuclear staining pattern was observed. The monoclonal antibody will be useful in immunoblotting and immunolocalization experiments in a variety of cells and tissues, as well as in further studies of the biological function and cellular dynamics of this protein. PMID- 20199155 TI - Monoclonal antibodies against recombinant hemolysin BL complex of Bacillus cereus. AB - A three component complex system, designated hemolysin BL (HBL), is believed to be the major diarrheal toxin of Bacillus cereus. Identification of HBL toxin by immunoassay is advantageous over PCR as it detects the expressed form of the gene, thereby differentiating pathogenic strains from nonpathogenic strains. However, most of the immunoassays, like the BCET RPLA kit, are based on the utilization of polyclonal antisera, which show cross-reactivity at times with other Bacillus species. The use of monoclonal antibodies (MAbs) binding specifically to the B. cereus HBL toxin epitopes could be advantageous. To address the problems of non-specificity of the reported detection systems and toxicity of L(1) and L(2) components during expression, we made use of recombinant chimeric rHBL protein to generate murine monoclonal antibodies. From among the L(2) MAbs stabilized, immunoblotting analyses on B. cereus strains revealed nine MAbs to be directed against the hbl D encoded L(1) protein, two to the hbl A encoded B protein, and one with the hbl C encoded L(2) protein. When tested on a large number of B. cereus standard and other related Bacillus species, there was no cross-reactivity observed among the group of MAbs. The presence of HBL component toxins among the strains recovered from food and environmental sources was evaluated by these sets of MAbs and the results compared with that of PCRs for the individual HBL toxin gene components. The HBL toxin profile characterization of the strains by Western blot using MAbs almost matched with the PCR profiles. The MAbs reported here, therefore, can be of immense help in providing the B. cereus identification/detection reliably, rapidly, and at a relatively low cost. PMID- 20199159 TI - Anti-human myxovirus resistance protein a antibody. PMID- 20199166 TI - FNIII domain D of human tenascin-C. PMID- 20199168 TI - Bond strength of a self-adhesive resinous cement to root dentin irradiated with a 980-nm diode laser. AB - OBJECTIVE: To assess the bond strength of Rely-X Unicem (RX), in comparison with Cement-Post (CP), to the cervical, middle and apical thirds of root canal dentin irradiated with a 980-nm diode laser. MATERIAL AND METHODS: Forty maxillary canines were separated into four equal groups according to the cement used and the laser surface treatment: RX/laser irradiation (LI) group; RX/no irradiation (NI) group; CP/LI group; and CP/NI group. Two slices (2-mm thick) of each root third were submitted to a push-out test to assess the bond strength of the cement to the root canal dentin. The data obtained were submitted to two-way ANOVA and fracture analysis was performed by scanning electron microscopy. RESULTS: The type of cement as well as 980-nm LI at the different root canal thirds significantly affected the bond strength values (p < 0.05). LI promoted an increase in bond strength of RX in all root thirds (p < 0.05). For all groups, bond strength to the cervical third was highest, followed by the middle and apical thirds (p < 0.05). When the cements were compared, RX always presented the highest bond strength in comparison with CP, irrespective of the laser application (p < 0.05). Fracture analysis showed a predominance of mixed failures for RX and of adhesive failure between dentin and cement for CP, irrespective of the laser application. CONCLUSION: The 980-nm LI promoted an increase in bond strength of the self-adhesive resinous cement to root dentin. PMID- 20199169 TI - WITHDRAWN: Kalpana C, Menon V. : Protective effect of curcumin on circulatory lipid peroxidation and antioxidant status during nicotine-induced toxicity.2004, 14, 339-343. PMID- 20199170 TI - A revised Swedish version of the Ward Atmosphere Scale: usability and psychometrics. AB - BACKGROUND: The ward atmosphere of psychiatric care units has a major impact on treatment and satisfaction for both patients and staff. The Ward Atmosphere Scale (WAS) was developed to capture the ward atmosphere in different psychiatric settings and is a well-established instrument for this purpose. However, there is need for an update and revision of the WAS. AIM: The aim of the present study was to test a Swedish version of the revised WAS in terms of its internal consistency, content and construct validity, and usability. METHODS: Data collection took place at four psychiatric wards and 31 patients and 34 staff completed the WAS, as well as content and construct validity questions. RESULTS: Results showed that the WAS had acceptable to satisfactory internal consistency for all subscales, except for autonomy. Low correlation values between the WAS and the Good Milieu Index were obtained, against which construct validity was discussed. Results of the content validity and usability questionnaires indicate that the WAS is easy to understand and complete, but some of the items were difficult for the respondents to understand and some of the subjects were missing aspects of the physical ward environment. CONCLUSIONS: The present study confirms that the Swedish version of the revised WAS can be useful for examining the ward atmosphere in psychiatric care. However, more studies are needed in order to further test the psychometric properties of the WAS and the results of the usability questionnaire may indicate a need to use supplementary instruments in order to capture the physical ward environment as well. PMID- 20199171 TI - Filamentous fungi recovered from the water distribution system of a Belgian university hospital. AB - A study was carried out over a 4-month winter period in order to assess the presence of filamentous fungi in the water distribution system of the University Hospital of Liege. A total of 197 hot and cold water samples were collected from the main water supply lines and from the taps at three different hospital sites. Overall, filamentous fungi were recovered from 55% and 50% of the main water distribution system and tap water samples, respectively, with a mean of 3.5 +/- 1.5 colony forming units per 500 ml water. Nine different genera were identified, all belonging to the Hyphomycetes class. Aspergillus spp. were recovered from 6% of the samples of the water distribution system and A. fumigatus was the most frequently recovered species (66.6%). However, this species was not isolated from water taps. Fusarium spp. was predominant at one site, where it was found in 28% of tap water samples. No Aspergillus spp. but some Fusarium spp. isolates were identified in samples collected from high-risk units. Filters were introduced at the point-of-use in the haematology unit after completion of the study. The findings of the present study confirm the need for further documented studies to evaluate the safety of the hospital water system and to define new preventive measures. PMID- 20199172 TI - Mucoadhesive chitosan microspheres of carvedilol for nasal administration. AB - The aim of the present study was to develop and characterize chitosan mucoadhesive microspheres of carvedilol (CRV) for nasal delivery to improve bioavailability for treatment of hypertension and angina pectoris. The microspheres were prepared by emulsification-cross-linking method and evaluated for size, shape, entrapment efficiency (EE), in vitro mucoadhesion, in vitro drug release, differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The mucoadhesive properties were also evaluated by Freundlich and Langmuir adsorption isotherms. In vivo tests were carried out in rabbits. The microspheres were spherical with size of 20-50 microm, which is favorable for intranasal absorption. The EE was observed from 42% to 68% while percentage mucoadhesion was from 74% to 88%. A strong interaction between mucin and chitosan microspheres was detected explaining adsorption with electrostatic interaction. The microspheres released around 75% of drug in 8 h. DSC and XRD studies revealed that CRV was molecularly dispersed. The absorption rate was rapid and the absolute bioavailability was high, 72.29%. The gamma scintigraphy indicated that the microspheres cleared slowly from the nasal cavity. It was concluded that chitosan microspheres could be used to deliver CRV following nasal administration for improving the bioavailability. PMID- 20199173 TI - Reduced fractional anisotropy does not change the shape of the hemodynamic response in survivors of severe traumatic brain injury. AB - The hemodynamic response (HDR) function is the basis for standard functional magnetic resonance imaging (fMRI) analysis. HDR is influenced by white matter inflammation. Traumatic brain injury (TBI) is frequently accompanied by diffuse white matter injury, but the effect of this on the HDR has not been investigated. The aims of the present study were to describe the HDR in visual cortex and examine its relationship with the microstructure of the optic radiation in severe TBI survivors and controls. Ten severe TBI survivors without visual impairments, but with known diffuse axonal injury, and 9 matched controls underwent diffusion tensor imaging (DTI) and fMRI. From the fMRI time series obtained during brief randomized visual stimuli, blood oxygenation level-dependent (BOLD) signal changes for each subject were estimated in V1, and group HDR curves were produced. Standard between-group analysis of BOLD activation in V1 + V2 was performed. For each individual the optic radiations were identified and fractional anisotropy (FA) plus mean apparent diffusion coefficient (ADC(mean)) values for these tracts were calculated. Group HDR curves from the visual cortex were fully transposable between TBI survivors and controls, despite a significant reduction in FA in the optic radiation in TBI survivors. A significant correlation between BOLD signal in the visual cortex and FA values in the optical tract was present in controls, but not in TBI survivors. Between-group comparisons showed that TBI survivors had increased areas of activation in V1 and V2. The HDR appears to be intact in traumatic white matter damage, supporting the validity of using standard fMRI methodology to study neuroplasticity in TBI. PMID- 20199174 TI - Quantitative evaluation of proteinuria by estimation of the protein/creatinine ratio in a random urine sample. AB - The aim of this study was to evaluate the severity of proteinuria using the protein/creatinine ratio in a random urine sample. In 45 patients (male 28, female 17; mean age 50.68 +/- 18.26 years) with proteinuria of various causes, we measured the 24-hour protein excretion per 1.73 m(2) of body surface and, during the same day, the protein/creatinine ratio in three different urine samples (8 am, 12 pm, 4 pm). The 24 h proteinuria was defined as mild (<1 g), moderate (1 3.4 g), and severe (>3.4 g) in 7, 27, and 11 patients, respectively. The sensitivity for protein/creatinine ratio compared to the 24 h proteinuria as a method of reference was 86-100% in the mild, 78-100% in the moderate, and 73-82% in the severe proteinuria, whereas the specificity was 84-100%, 78-83%, and 100% respectively. The patients with better renal function had significantly higher proteinuria levels. There was a similarity in the 24 h proteinuria and the protein/creatinine ratio measurements in all renal function and level-of proteinuria groups. The protein/creatinine ratio of the morning and midday samples had a very good association with the 24 h sample, whereas it was not associated significantly with the evening sample (4 pm). In conclusion, the degree of 24 h proteinuria levels can be evaluated by calculating the protein/creatinine ratio in a random urine sample collected at any time from morning until midday. Protein/creatinine ratio is independent of the severity of proteinuria or renal function, and it can replace in clinical practice the cumbersome 24 h urine collections. PMID- 20199175 TI - The effects of L-carnitine therapy on respiratory function tests in chronic hemodialysis patients. AB - BACKGROUND: Respiratory functions are affected during hemodialysis. The strength of respiratory muscles, ultrafiltration rate, and acid-base balance have been suggested as important factors. L-carnitine is crucial for energy producing, utilization of fatty acid, and possible amino acids. A lack of carnitine in hemodialysis patients is caused by insufficient carnitine synthesis and especially by its loss during dialysis. This study was performed to investigate the chronic effects of L-carnitine treatment on respiratory functions in adults receiving chronic hemodialysis therapy. METHODS: A total of 20 hemodialysis patients were scheduled to take L-carnitine supplementation (20 mg/kg three times/week) (group 1), and the rest of 20 hemodialysis patients served as the control group and were observed without supplementation with L-carnitine (group 2). Pre- and post-dialytic L-carnitine levels and post-dialytic respiratory functions tests were performed in both groups at baseline and after six months. RESULTS: The average concentration of free and total carnitine levels increased significantly after six months of supplementation (p < 0.01). While a statistically significant increase between postdialytic forced expiratory volume in one second/forced vital capacity values after treatment period (77.10 +/- 12.15 and 83.00 +/- 14.49, before and after treatment, respectively, p < 0.05) was observed, the increase of vital capacity, forced expiratory volume in one second, and forced expiratory flow between 25-75% of expired vital capacity were not significant in the treatment group (p > 0.05). CONCLUSION: Intravenous L carnitine supplementation could contribute to the management of respiratory dysfunction in chronic hemodialysis patients by improving FEV1/FVC. The mechanism by which LC causes these effects merits further investigation. PMID- 20199176 TI - Investigation of histopathologic changes in pelviureteral junction obstruction. AB - OBJECTIVES: This study aimed to determine histopathologic changes in the pelviureteral junction in children with pelviureteral junction obstruction. MATERIAL AND METHODS: Seventeen pelviureteral junction specimens obtained from children were divided into two groups: pelviureteral junction obstruction (n = 7) and control (n = 10). Wall thickness of the pelviureteral junction, tunica muscularis of the pelviureteral junction, uroepithelium thickness of the pelviureteral junction, and collagen thickness of the pelviureteral junction were evaluated in resected pelviureteral junctions in children with pelviureteral junction obstruction. MAIN FINDINGS: The mean wall thickness of the pelviureteral junction, mean tunica muscularis of the pelviureteral junction, and uroepithelium thickness of the pelviureteral junction were not significantly higher than those in the control group. Collagen thickness values in the pelviureteral junction obstruction group were significantly higher than those in the control group. CONCLUSIONS: Our data suggest that wall thickness (tunica muscularis and uroepithelium) was not significantly increased, but collagen thickness of the ureter was increased in the pelviureteral junctions of children with pelviureteral junction obstruction. PMID- 20199177 TI - Incidence of thyroid dysfunction and thyroid cancer in renal transplant recipients: a single center experience. AB - BACKGROUND: The prevalence of thyroid cancer in renal transplant population has not been widely studied, and there is no consensus on the management of thyroid cancer in transplant patients. The aim of this study was to evaluate changes in thyroid hormone levels and investigate the incidence of the thyroid cancer after renal transplantation. MATERIALS AND METHODS: From October 1989 to April 2007, 122 renal allograft recipients that were being followed underwent thyroid ultrasonography to determine nodules together with thyroid hormone levels. Ultrasound-guided fine-needle aspiration biopsy (FNAB) was performed to the nodules > 10 mm or those with 8-10 mm diameter but with calcifications. RESULTS: One hundred and eight patients (88.5%) had normal thyroid function. None of the patients had overt hypothyroidism, 2 had subclinical hypothyroidism, 10 subclinical thyrotoxicosis, and 2 low T3 syndrome. Mean thyroid volume was 14.2 +/- 7.2 ml. In all, 91.8% was diagnosed with goiter (n = 112). Seventy-two thyroid nodules were detected in 49 kidney allograft recipients (single nodule in 30, multiple in 19 patients). Eighty-four biopsy samples were reported as benign (n = 21, 87.5%), 8 as suspicious (n = 2, 8.3%), and 4 as inadequate (n = 1, 4.1%). After surgery, one of the patients (0.8%) with suspicious FNAB was reported as papillary thyroid carcinoma. CONCLUSION: Because of the high incidence of thyroid dysfunction in transplant patients, screening of thyroid function should be a part of follow-up. Our results suggest that although frequency of nodules is increased in kidney transplant patients, prevalence of thyroid cancer is slightly, but not significantly, higher than that of the normal population. PMID- 20199178 TI - Captopril and combination therapy of captopril and pentoxifylline in reducing proteinuria in diabetic nephropathy. AB - Chronic kidney disease is a worldwide health problem. Type II diabetes mellitus is now a major cause of end stage renal disease. The effect of diabetes mellitus through the dysregulation of the innate immunity results in increased tumor necrosis factor-alpha. This can lead to an increasing protein trafficking through the glomerular capillary, which can have an intrinsic renal toxicity. Seventy four patients with type II diabetes mellitus with overt proteinuria were included in the study. They were randomly assigned to two groups of 37 patients (group 1: captopril 25 mg three times a day, group 2: captopril 25 mg and pentoxifylline 400 mg each three times per day). In the course of the study, two patients were excluded from each group. Daily urinary protein excretion was assessed at baseline and at two and six months. The reduction of urinary protein to creatinine clearance ratio in group 2 was 15.16 points more than in group 1 from baseline to the end of the study (p = 0.001). The difference in reduction only started after two months of pentoxifylline use. The differences in HbA1c and duration of diabetes mellitus at baseline in the two groups had not adversely affected the outcome of the study. There was a modest decrease in systolic blood pressure in group 2 as well (p = 0.041). Combining an angiotensin-converting enzyme inhibitor and pentoxifylline can lead to a greater reduction in proteinuria. PMID- 20199179 TI - Correlation between hearing loss and peritonitis frequency and administration of ototoxic intraperitoneal antibiotics in patients with CAPD. AB - AIM: Aminoglycosides have been used in the treatment of CAPD peritonitis despite their potential risk for ototoxicity. The ototoxicity risk of intraperitoneally administered aminoglycosides has been investigated by a number of studies. However, their results are somewhat conflicting. The aim of the present study was to examine the frequency of hearing loss and the correlation between the repeated doses of aminoglycosides and hearing loss in CAPD peritonitis therapy. METHODS: Hearing functions of the CAPD patients who had developed peritonitis and had been treated with various antibiotics including aminoglycosides were compared with those CAPD patients who had never developed peritonitis. Threshold values for hearing were determined through "pure tone audiometry" measurements. RESULTS: Hearing threshold levels of the patients with history of peritonitis were found to be significantly higher in both lower [pure tone averages - 1 (PTA-1)] and higher [pure tone averages - 2 (PTA-2)] frequencies, when compared to the ones with no history of peritonitis (p values were 0.001 and 0.007, respectively). CONCLUSION: The present study showed that intraperitoneal aminoglycoside administration in CAPD patients is associated with the development of hearing loss. The severity of hearing loss may range from mild hearing loss to profound deafness. A remarkable correlation exists between the severity of the hearing loss and the repeated and total aminoglycoside dose received. PMID- 20199180 TI - A reference equation for objectively adjusting dwell volume to obtain more ultrafiltration in daily practice of peritoneal dialysis. AB - OBJECTIVES: Few studies mention how to objectively adjust peritoneal dialysis (PD) dwell volume for adult continuous ambulatory peritoneal dialysis (CAPD) patients. We proposed a reference equation composed of parameters from the peritoneal equilibrium test (PET) for adjusting daily dialysate dwell volume to obtain more ultrafiltration volume. Better fluid control could reduce more fluid overload-related complications. DESIGN: We used body mass index, waist circumference, intraperitoneal pressure, and other parameters from peritoneal equilibrium test to compose a reference equation for fine-tuning daily dwell volume. PATIENTS AND SETTING: Eighty-eight PD patients in one center with laboratory data collected during half-yearly PET evaluations were enrolled. Instilled dialysate was composed of 2.57% glucose PD fluid, either 1500 ml or 2000 ml in volume. In addition to other demographic data, intraperitoneal pressure (IPP) was also measured twice in the supine position four hours apart. We applied statistical multivariate techniques of discrimination analysis and logistic regression to verify the most feasible and optimal formula to determine infill volumes for patients. RESULTS: We determined a novel formula for calculating daily dialysate dwell volume, Z: Z = (0.523 x waist circumference) + (0.852 x body mass index), derived from rotating axes to obtain an accurate prediction rate of 80.68% using the multivariate approach. CONCLUSION: The novel formula used objective, real-time parameters for determining appropriate dwell volumes for PD patients to optimize maximal ultrafiltration volumes and reduce subjective abdominal discomfort. The novel formula makes frequent adjustment of daily dwell volume by physicians or patients easy to calculate. PMID- 20199181 TI - Treatment of proteinuria with lercanidipine associated with renin-angiotensin axis-blocking drugs. AB - OBJECTIVE: Most calcium antagonists do not seem to reduce microalbuminuria or proteinuria. We have tried to assess the antiproteinuric effect of a calcium channel blocker, lercanidipine, in patients previously treated with ACE inhibitors or angiotensin receptor blockers. DESIGN AND METHODS: The study included 68 proteinuric (> 500 mg/day) patients (age 63.1 +/- 12.9 years, 69.1% males and 30.9 females). All patients were receiving ACE inhibitors (51.4%) or angiotensin II receptor blockers (48.6%) therapy but had higher blood pressure than recommended for proteinuric patients (<130/80 mmHg). Patients were clinically evaluated one, three, and six months after starting treatment with lercanidipine (20 mg/day). Samples for urine and blood examination were taken during the examination. When needed, a third drug was added to treatment. Creatinine clearance was measured using 24 h urine collection. RESULTS: BP significantly decreases from 152 +/- 15/86 +/- 11 mmHg to 135 +/- 12/77 +/- 10 mmHg at six months of follow-up (p < 0.001). After six months of treatment, the percentage of normalized patients (BP < 130/80 mmHg) was 42.5%, and the proportion of patients whose BP was below 140/90 mmHg was 58.8%. Plasmatic creatinine did not change nor did creatinine clearance. Plasmatic cholesterol also decreased from 210 +/- 48 to 192 +/- 34 mg/dL (p < 0.001), as did plasma triglycerides (from 151 +/- 77 to 134 +/- 72 mg/dL, p = 0.022). Basal proteinuria was 1.63 +/- 1.34 g/day; it was significantly (p < 0.001) reduced by 23% at the first month, 37% at three months, and 33% at the last visit. CONCLUSIONS: Lercanidipine at 20 mg dose, associated to renin-angiotensin axis-blocking drugs, showed a high antihypertensive and antiproteinuric effect. This antiproteinuric effect seems to be dose-dependent as compared with previous reports and proportionally higher than blood pressure reduction. PMID- 20199182 TI - Relationship between insulin resistance and inflamation markers in hemodialysis patients. AB - OBJECTIVE: The prevalence and risk factors of cardiovascular disease (CVD) are increasing in end stage renal disease (ESRD) patients. In this study, we sought to research the relationship between the insulin resistance, which is one of the risk factors for CVD, and the inflammation markers, especially C-reactive protein, fibrinogen, uric acid, and homocysteine levels in our patients who were recently diagnosed with ESRD and started hemodialysis. MATERIALS AND METHODS: 64 HOMA-IR-positive and 114 HOMA-IR-negative patients were enrolled in this study. Blood samples were obtained from the patients for fasting plasma glucose, insulin, CRP, fibrinogen, uric acid, total homocysteine, urea, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglyceride, total protein, and albumin analysis after physical examinations and anamnesis were completed. RESULTS: Fibrinogen and CRP levels of HOMA-IR-positive HD patients were significantly increased compared to non-insulin resistants. Furthermore, there is significant positive relationship between insulin resistance and serum CRP and fibrinogen levels in these HOMA-IR-positive HD patients (r = 0.258, p < 0.001). CONCLUSION: We found out that the fibrinogen and CRP levels are significantly high in HOMA-IR positive HD patients, according to determine the risk ratio for coronary artery disease in HD patients, and think that an assessment of insulin resistance is necessary. PMID- 20199183 TI - Multiple antioxidants and L-arginine modulate inflammation and dyslipidemia in chronic renal failure rats. AB - The kidney is an important source of L-arginine, the endogenous precursor of nitric oxide (NO). Surgical problems requiring extensive renal mass reduction (RMR) decrease renal NO production, leading to multiple hemodynamic and homeostatic disorders manifested by hypertension, oxidative stress, and increased inflammatory cytokines. Using the RMR model of chronic renal failure (CRF), we assessed the effects of twelve weeks' administration of L-arginine and/or a mixture of antioxidants (L-carnitine, catechin, vitamins E and C) on plasma cytokines, soluble intercellular adhesion molecule-1 (sICAM-1), nitrate and nitrites (NO(2)/NO(3)), lipid profile, blood pressure, and renal function. CRF rats showed increased plasma IL-1 alpha, IL1-beta, IL-6, TNF-alpha, and sICAM-1 levels and decreased anti-inflammatory cytokines IL-4 and 10 levels, hypertension, and dyslipidemia. L-arginine treatment improved kidney functions, decreased systolic blood pressure, and decreased inflammatory cytokines levels. Antioxidants administration decreased inflammatory cytokines and sICAM-1 levels and increased IL-4 levels. Combined use of both L-arginine and the antioxidant mixture were very effective in their tendency to recover normal values of kidney functions, plasma cytokines, sICAM-1, blood pressure, NO(2)/NO(3), cholesterol, and triglycerides concentrations. Indeed, the effects of L-arginine and the antioxidants on the reduction of proinflammatory cytokines may open new perspectives in the treatment of uremia. PMID- 20199184 TI - Reduced expression of perlecan in the aorta of secondary hyperparathyroidism model rats with medial calcification. AB - BACKGROUND: Vascular calcification is an important complication that worsens the prognosis for dialysis patients, although its detailed molecular mechanisms are still unknown. METHODS: We produced a rat model for vascular calcification with hyperphosphatasemia and hyperparathyroidism, performing a 5/6 nephrectomy and providing a high-phosphorus, low-calcium diet for eight weeks. We examined mRNA obtained from the calcified aortae using microarray analysis, and searched for alterations in gene expression specifically in the calcified lesions. RESULTS: Medial calcification was demonstrated in the abdominal aorta of 12 out of 42 hyperparathyroidism rats. In the aortae of hyperparathyroid rats with vascular calcification, the genes for heparan sulfate proteoglycans, including perlecan, were found to be down-regulated using microarray analysis and real time PCR. Immunohistochemistry also demonstrated reduced production of perlecan in the aortae of hyperparathyroid rats. DISCUSSION: Perlecan is a major component of the vascular wall basement membrane and may play a role in protecting vascular smooth muscle cells from inflammatory cells and various toxins. It has also been reported that heparan sulfate chains may inhibit osteogenesis. Our findings indicate that perlecan may protect vascular smooth muscle cells from various factors that promote vascular calcification. CONCLUSIONS: It may be that reduced expression of perlecan in the calcified aortae of hyperparathyroid rats is a risk factor for vascular calcification. PMID- 20199185 TI - Effects of Aulosira fertilisima against cisplatin-induced nephrotoxicity and oxidative stress in rats. AB - Oxidative stress due to abnormal production of reactive oxygen molecules (ROM) is believed to be involved in the etiology of toxicities of many xenobiotics. Evidence suggested that ROM is involved in the nephrotoxicity of a widely used synthetic anticancer drug cisplatin. The nephroprotective effects of ethanol extract of Aulosira fertilisima Ghose (EEA) was evaluated using cisplatin (5 mg/kg(-1) i.p.)-induced renal damage in rats. EEA showed higher significant effect on DPPH radical scavenging activity as compared with methanol extract of A. fertilisima (MEA) and water extract of A. fertilisima (WEA). Thus, EEA was selected for further in vivo studies. The serum urea and creatinine levels in the cisplatin alone-treated group were significantly elevated with respect to normal group of animals. The levels were reduced in the EEA (100 mg/kg, p.o) plus cisplatin-treated groups. Renal oxidative stress was determined by renal TBARS, CD and reduced glutathione levels, and by enzymatic activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and glutathione transferase (GST). A single dose of cisplatin-produced marked renal oxidative and nitrosative stress and significantly deranged renal functions. Chronic EEA treatment significantly and dose-dependently restored renal functions, reduced lipid peroxidation, and enhanced reduced glutathione levels, superoxide dismutase, and catalase activities. The results of the study indicated that A. fertilisima significantly and dose-dependently protected the nephrotoxicity induced by cisplatin. This protection is mediated either by preventing the cisplatin-induced decline of renal antioxidant defense system or by their direct free radical scavenging activity. PMID- 20199186 TI - Pretreatment with oxygen protects rat kidney from cisplatin nephrotoxicity. AB - Cisplatin (CP) nephrotoxicity is mainly due to reactive oxygen species. Oxygen pre-exposure as a mild oxidative stress may enhance some endogenous defense mechanisms, so its effect on cisplatin-induced acute renal failure was investigated in present study. Twenty-four rats were divided into four groups. The O(2)+ CP and Air + CP groups were were subjected to i.p. injection of 5 mg/kg cisplatin, and in the Air + Saline and O(2) + Saline groups, saline was injected instead of cisplatin. O(2)+ CP and O(2)+ Saline groups were pretreated with oxygen (3h/d for two days), and the other two groups were pretreated with room air. Cisplatin was administered 24 h after last pretreatment session. Three days after cisplatin injection, plasma samples were obtained, and parts of kidney tissue were frozen for biochemical analysis or fixed in formalin for histological assessments. Preconditioning with oxygen prior to cisplatin administration led to reduced tubular necrosis and luminal cast formation and improvement of renal function, as was evidenced by significant reduction in plasma creatinine and urea levels. Oxygen pretreatment also significantly reversed cisplatin-induced reduction in renal catalase activity and glutathione level. It could be concluded that oxygen pretreatment could have a delayed protective effect against cisplatin nephrotoxicity, and that increased renal catalase activity may be involved in this protective effect of hyperoxia. PMID- 20199187 TI - Transcription factor Sp1 expression is upregulated in human glomerulonephritis: correlation with pSmad2/3 and p300 expression and renal injury. AB - BACKGROUND: Sp1 is a ubiquitous transcription factor that mediates the fibrogenic factor transforming growth factor beta (TGF-beta) signals through cooperation with Smad proteins. The transcriptional coactivator p300 is also suggested to play a role in Smad signal transduction. METHODS: We investigated the immunohistochemical expression of Sp1 as well as the expression of pSmad2/3 and the coactivator p300 in 157 renal biopsy specimens from patients with various types of glomerulonephritis (GN). Correlations between immunohistochemical, clinical, and histologic parameters were performed. RESULTS: Sp1 exhibited an increased glomerular and proximal tubular expression in all forms of GN compared to controls. The proximal tubular expression of Sp1 was significantly increased in proliferative GNs (p = 0.025), whereas in secondary GNs, there was a significant increase in the molecule's glomerular expression (p = 0.008). Sp1 correlated positively with pSmad2/3 and p300 expression in proximal tubules (r = 0.241, p = 0.018 and r = 0.244, p = 0.014, respectively), while in proliferative GNs, its expression correlated positively with pSmad2/3 expression in glomeruli (r = 0.32, p = 0.028). Sp1 glomerular and proximal tubular immunostaining correlated positively with serum creatinine levels (r = 0.265, p = 0.02 and r = 0.306, p = 0.006, respectively), while its proximal tubular expression showed a similar correlation with interstitial fibrosis (r = 0.213, p = 0.025). Sp1 was constantly detected in hyperplastic lesions and cellular crescents (each 100%), and very often in micro adhesions (94%) and segmentally or globally sclerotic areas (each 83%). CONCLUSIONS: This study documents the upregulation of Sp1 expression in glomeruli and proximal tubules of GN specimens. Our findings suggest a possible cooperation of Sp1 with pSmad2/3 and p300 in mediating renal injury as well as a possible role for this molecule in the pathogenesis and the progression of human GN. PMID- 20199188 TI - Heme oxygenase-1 modulates mesangial cell proliferation by p21 Waf1 upregulation. AB - Mesangial cell (MC) proliferation is a hallmark of many progressive renal diseases. Heme oxygenase-1 (HO-1) has been shown to have an anti-proliferative effect on vascular smooth muscle cells. In the present study, we evaluated the role of HO-1 on MC proliferation and the involved molecular mechanism. Both epidermal growth factor (EGF) and hepatocyte growth factor (HGF) not only enhanced mesangial cell HO-1 expression but also stimulated proliferation of MCs. Interestingly, inhibition of HO-1 induction (by zinc protoporphyrin, ZnP) was associated with an accelerated mitogenic response to EGF and HGF in MCs. Induction of HO-1 was associated with enhanced mesangial cell p21 expression. On the other hand, hemoglobin and ZnP inhibited mesangial cell p21 expression. It appears that the effect of HO-1 on MC growth may be mediated through upregulation of p21 expression. PMID- 20199189 TI - Urinary proteomics--a tool for biomarker discovery. AB - The strong need for the discovery of novel disease markers together with the development of high-throughput techniques that provide highly sensitive analysis of protein content in tissues and bodily fluids, using proteomics, has opened the completely new chapter in biomarker discovery. The detection of biomarkers based on urinary proteome analysis is rapidly advancing and may provide new tools to improve non-invasive diagnostics, prognostics, and therapy enhancement. As a tool for biomarker discovery, urinary proteomics is especially fruitful in the area of early diagnostics and differentiation of renal damage, and it possesses enormous potential for improving and expanding non-invasive cancer diagnostics. An abundance of urinary proteins could provide a wide variety of biomarkers for the diagnosis and follow-up of many systemic diseases as well. This article reviews the utility of urinary proteomics for biomarker discovery from the perspective of clinical application. Despite huge potential and prompt development of urinary proteomics, many challenges are still in front of us. Research effort and financial investment have to be oriented on providing strategies for exceeding current methodological and technical obstacles in a way to ensure the successful validation and implementation of newly discovered urinary biomarkers. The result is expected to be the development of new non-invasive tests and procedures able to guarantee higher efficiency of patient care and provide needed personalized medical approach. PMID- 20199190 TI - Cardiovascular risk in uremic patients: darkness after AURORA. PMID- 20199191 TI - Focal segmental glomerulosclerosis associated with idiopathic myelofibrosis. AB - A patient with idiopathic myelofibrosis with nephrotic syndrome is reported. Seven months after the initial diagnosis of myelofibrosis, the patient was presented with dyspnea, generalized edema, heavy proteinuria, massive pleural effusion, and ascites. Renal biopsy showed focal segmental glomerulosclerosis. After starting immunosuppressive therapy consisting of cyclosporine and steroids, his renal function and proteinuria improved and transfusion requirements decreased. PMID- 20199192 TI - Rare presentation of cystinosis mimicking Bartter's syndrome: reports of two patients and review of the literature. AB - We present here two girls with cystinosis initially diagnosed as Bartter syndrome. Both cases were admitted with hypokalemic, hypochloremic alkalosis. Their proximal tubular functions, ophthalmologic and bone marrow examinations were normal. They were started on therapies with the diagnosis of Bartter syndrome. The first patient developed signs of rickets, and the second patient was lost to follow-up and readmitted with chronic renal failure. On reevaluation cystine crystals were detected in cornea and bone marrow aspirates of both patients. We aimed to remind the rare presentation of cystinosis with metabolic alkalosis mimicking Bartter syndrome by these two cases and review the literature. PMID- 20199193 TI - Splenic marginal lymphoma and glomerulonephritis: case report and review of the literature. AB - Malignant lymphomas can affect kidneys in several ways. They may precipitate acute renal failure by causing ureteral or renal vascular obstruction, or by direct renal parenchymal infiltration. Furthermore, they may insult renal function via paraneoplastic mechanisms such as hypercalcemia. Lymphomas only rarely can cause glomerulonephritis (GN). We report a case of a 72-year-old male who presented with mild renal function impairment, proteinuria, and microscopic hematuria, suggesting active glomerulonephritis, and pancytopenia of immune origin. A bone marrow biopsy led to a diagnosis of splenic marginal zone lymphoma. Although a kidney biopsy was not performed, glomerulonephritis was attributed to the lymphoma and splenic marginal zone lymphoma-related glomerulonephritis was the final diagnosis. The course of splenic marginal zone lymphoma is extremely indolent. The first manifestation in some patients can be immune cytopenia or other autoimmune phenomena. These patients may respond well to corticosteroids. Therefore, our patient was started on prednisolone resulting in a good hematologic response. Renal function also improved and proteinuria and hematuria disappeared, suggesting a lymphoma-related origin of the GN. Two years after full steroids withdrawal, the patient remained stable with a good renal function and daily protein excretion less than 300 mg. Lymphomas rarely are the cause of secondary glomerulonephritis; however, with a lack of an apparent cause, the clinician should be aware of them, particularly in the elderly with autoimmune manifestations. PMID- 20199195 TI - Treatment with insulin glargine (Lantus) increases the proliferative potency of the serum of patients with type-1 diabetes: a pilot study on MCF-7 breast cancer cells. AB - CONTEXT AND OBJECTIVE: Insulin glargine (Lantus) stimulates growth of MCF-7 cells stronger than human insulin. We investigated if serum from diabetic patients treated with glargine versus human insulin may display a similar effect. METHODS: Pairs of serum samples from 31 C-peptide negative type-1 diabetic patients were investigated. In cross-over fashion, 23 patients were treated with glargine plus rapid-acting insulin analogues, and similar doses of human NPH and rapid-acting insulin. For comparison, eight patients were treated with insulin detemir (Levemir) and human NPH. MCF-7 cells were incubated with 10% serum and proliferation was assessed after 72 hours. RESULTS: Serum containing insulin glargine was 1.11(95% CI 1.05-1.18) fold more mitogenic than human insulin containing serum (p < 0.005); mitogenicity of serum containing detemir was 0.99(95% CI 0.98-1.02) fold that of human insulin-containing serum. CONCLUSION: The serum of diabetic patients was slightly stronger mitogenic when using glargine as compared to human insulin or detemir for treatment. PMID- 20199194 TI - Finite element analysis of controlled cortical impact-induced cell loss. AB - The controlled cortical impact (CCI) model has been extensively used to study region-specific patterns of neuronal injury and cell death after a focal traumatic brain injury. Although external parameters such as impact velocity and depth of penetration have been defined in this injury model, little is known about the intracranial mechanical responses within cortical and subcortical brain regions where neuronal loss is prevalent. At present, one of the best methods to determine the internal responses of the brain is finite element (FE) modeling. A previously developed and biomechanically validated detailed three-dimensional FE rat brain model, consisting of 255,700 hexahedral elements and representing all essential anatomical features of a rat brain, was used to study intracranial responses in a series of CCI experiments in which injury severity ranged from mild to severe. A linear relationship was found between the percentage of the neuronal loss observed in vivo and the FE model-predicted maximum principal strain (R(2) = 0.602). Interestingly, the FE model also predicted some risk of injury in the cerebellum, located remote from the point of impact, with a 25% neuronal loss for the "severe" impact condition. More research is needed to examine other regions that do not have histological data for comparison with FE model predictions before this injury mechanism and the associated injury threshold can be fully established. PMID- 20199196 TI - Symphysiolysis as an independent risk factor for cesarean delivery. AB - OBJECTIVES: To investigate whether symphysiolysis during pregnancy is a risk factor for cesarean delivery (CD). METHODS: A retrospective population-based study comparing all singleton pregnancies of women with and without symphysiolysis was conducted. Deliveries occurred between the years 2000 and 2007. Multiple logistic regression models were used to control for confounders. RESULTS: Out of 80,898 patients, 0.2% (n = 154) were diagnosed with symphysiolysis during pregnancy. Patients with symphysiolysis were significantly older as compared to the comparison group. These patients had higher rates of mild pre-eclampsia, gestational diabetes mellitus (GDM) and labor induction as compared to patients without symphysiolysis. Higher rates of CD were noted in pregnancies complicated by symphysiolysis [22.1% vs. 15.9%; Odds ratio (OR) = 1.5, 95% confidence interval (CI) 1.02-2.2; P = 0.036]. Using multiple logistic regression model, with symphysiolysis as the outcome variable, controlling for labor induction, mild pre-eclampsia and GDM, symphysiolysis was noted as an independent risk factor for CD (weighted OR = 1.7, 95% CI 1.1-2.5; P = 0.009). Perinatal outcomes such as low Apgar scores (<7) at 1 and 5 min and perinatal mortality were comparable between the groups. CONCLUSIONS: Symphysiolysis is an independent risk factor for CD. PMID- 20199198 TI - Migraine associated with patent foramen ovale may be caused by reactivation of cerebral toxoplasmosis triggered by arterial blood oxygen desaturation. AB - Approximately two billion people worldwide are chronically infected with T. gondii and yet with largely unknown consequences. On the other hand, several authors reported an association between migraine and patent foramen ovale (PFO), and different types of headaches, including migraine, may be precipitated by various diseased states or medications associated with marked immune irregularities, which sometimes cause reactivation of latent cerebral toxoplasmosis (CT). Recently, in a group of 104 subjects with migraine, 46 individuals (44.2%) were found to be seropositive for T. gondii. PFO, atrial septal defects, as well as pulmonary right-to-left shunts are usually associated with a various degree of arterial blood oxygen desaturation. Hypoxia is associated with an increase in the generation of several proinflammatory cytokines and other inflammation mediators, such as TNF-alpha, IL-1-beta, IL-6, IL-8, chemokines (monocyte chemoattractant protein-1, CC-chemokine receptor 2, macrophage inflammatory protein-1alpha, intercellular adhesion molecule-1), acute phase protein gene expressions, COX-2 gene transcription, induction of iNOS, and reactive oxygen species. Moreover, hypoxia markedly decreased T-lymphocyte IL-2 mRNA, a key cytokine responsible for B-cell proliferation and immunoglobulin secretion, and ischemic tissues demonstrated intravascular neutrophil accumulation, vascular damage, and increased vascular wall permeability. Interestingly, T. gondii activates hypoxia-inducible factor 1 already at physiologically relevant oxygen levels and requires HIF1 for growth and survival. These abnormalities may cause imbalance in the host/T. gondii immune system, which finally results in the reactivation of CT. In addition, hypoxia may participate in paradoxical microembolism because arterial oxygen desaturation enhances expression of plasminogen activator inhibitor-1, an important factor which suppresses fibrinolysis, and this effect may be further amplified by a decreased expression of plasminogen activators, finally causing blood hypercoagulability and paradoxical microembolism. In summary, further studies are required to verify the above-presented pathomechanisms probably responsible for the association between PFO and the development of migraine. It is possible that some migraineurs with PFO may benefit from evaluation and treatment of toxoplasmosis in the future once more information is known. PMID- 20199197 TI - Unexplained fetal death is associated with increased concentrations of anti angiogenic factors in amniotic fluid. AB - OBJECTIVE: Angiogenesis is critical for successful pregnancy. An anti-angiogenic state has been implicated in preeclampsia, fetal growth restriction and fetal death. Increased maternal plasma concentrations of the anti-angiogenic factor, soluble vascular endothelial growth factor receptor (sVEGFR)-1, have been reported in women with preeclampsia and in those with fetal death. Recent observations indicate that an excess of sVEGFR-1 and soluble endoglin (sEng) is also present in the amniotic fluid of patients with preeclampsia. The aim of this study was to determine whether fetal death is associated with changes in amniotic fluid concentrations of sVEGFR-1 and sEng, two powerful anti-angiogenic factors. Study design. This cross-sectional study included patients with fetal death (n = 35) and controls (n = 129). Fetal death was subdivided according to clinical circumstances into: (1) unexplained (n = 25); (2) preeclampsia and/or placental abruption (n = 5); and (3) chromosomal/congenital anomalies (n = 5). The control group consisted of patients with preterm labor (PTL) who delivered at term (n = 92) and women at term not in labor (n = 37). AF concentrations of sVEGFR-1 and sEng were determined by ELISA. Non-parametric statistics and logistic regression analysis were applied. Results. (1) Patients with a fetal death had higher median amniotic fluid concentrations of sVEGFR-1 and sEng than women in the control group (p < 0.001 for each); (2) these results remained significant among different subgroups of stillbirth (p < 0.05 for each); and (3) amniotic fluid concentrations of sVEGFR-1 and those of sEng above the third quartile were associated with a significant risk of unexplained preterm fetal death (adjusted OR = 10.8; 95%CI 1.3-89.2 and adjusted OR 87; 95% CI 2.3-3323, respectively). Conclusion. Patients with an unexplained fetal death at diagnosis are characterized by an increase in the amniotic fluid concentrations of sVEGFR-1 and sEng. These observations indicate that an excess of anti-angiogenic factors in the amniotic cavity is associated with unexplained fetal death especially in preterm gestations. PMID- 20199199 TI - EEG evidence of posterior cortical disconnection in PD and related dementias. AB - Electroencephalogram (EEG) reactivity to eyes opening and 12-Hz photic stimulation was investigated in 14 healthy elderly subjects, 21 parkinsonian patients (PD), 7 demented parkinsonian patients (PDD), and 10 patients with Lewy body dementia (LBD) using global field synchronization (GFS). During eyes closed Theta GFS was increased in Parkinson's disease and patients and alpha1 GFS was decreased in LBD subjects. During 12-Hz intermittent photic stimulation (IPS), reactivity of posterior electrodes was decreased in PD and LBD patients. No reactivity was observed in PDD. Results are consistent with a graded posterior cortical disconnection in parkinsonian syndromes and with a model of dopamine modulated thalamocortical interplay in visual processing. PMID- 20199200 TI - Anti-glutamate receptor antibodies in pediatric enteroviral encephalitis. AB - In order to better understand enteroviral encephalitis we investigated the clinical symptoms and several disease markers. Between 2000 and 2005 eight patients aged between 9 months and 5 years were admitted to our hospital with one case having sequela. Glutamic oxaloacetic transaminase (GOT), serum IL-6, and ferritin were elevated in most of the cases. Their IL-6 and diacron-reactive oxygen metabolites (d-ROM) in cerebral spinal fluid (CSF) were also high (86%). However, pleocytosis and high protein levels in CSF were rarely found. In viral loads of the first CSF, there were no differences between the patient with sequela and the ones without sequela. However, anti-glutamate receptor IgMdelta2 was only detected in the CSF of the patient with sequela. These findings suggest that the immunological phenomenon is more closely related to the development of sequela related to enteroviral encephalitis than other disease markers, such as inflammatory cytokine, free radicals, and viral loads. Therefore, a specific therapy against immunological status might decrease the sequela; however, further research is necessary to confirm this. PMID- 20199201 TI - Premovement facilitation of corticospinal excitability in patients with Parkinson's disease. AB - The purpose of this study was to investigate the abnormality of premovement facilitation in patients with Parkinson's disease. Seven patients with Parkinson's disease and seven healthy subjects participated in this study. The subjects attempted abduction of the index finger in response to a visual start cue, and motor-evoked potentials were recorded from the first dorsal interosseous muscle before movement onset. The rate of premovement facilitation in patients with Parkinson's disease was slower than that in healthy subjects. Additionally, the rate of premovement facilitation as a function of delay from the start cue was positively correlated with the reaction time. These findings indicate that premovement facilitation is abnormal in patients with Parkinson's disease. This abnormality may be partially related to akinesia. PMID- 20199202 TI - Interrelationship of limb dominance and sensory function across age. AB - Side dominance (upper and lower extremities, visual and auditory dominance) of 3,474 subjects of different age groups (9-83 years) was assessed using a 22-item questionnaire. Data were analyzed using a trichotomous (left, mixed, and right) association analysis among indices of side dominance. The contingency coefficients showed significantly high association between hand and foot preference across age groups compared to other paired associations of side dominance. A general rightward shift was observed with increasing age in all forms of side dominance. PMID- 20199203 TI - Serological and clinical features of patients with myasthenia gravis in north Indian population. AB - Myasthenia gravis (MG) is a disorder of neuromuscular junction associated with presence of antibodies against nicotinic acetylcholine receptors (nAChRs). Here, we compared the clinical and serological profile of seropositive myasthenia gravis (SPMG) and seronegative myasthenia gravis (SNMG) patients. Anti-AChR antibody was measured using radio receptor immunoassay and correlated with clinical phenotype in 250 MG patients over 2004 and 2006. Out of 250 MG patients, 161 (64.4%) were males (male:female = 1.8:1). SNMG patients formed 40% (n = 101) of our MG patients which is much higher as compared to Caucasian and Oriental population (15%-20%). The median age of disease onset in SPMG was significantly higher than SNMG patients (43 years; range 8-74 vs. 35 years; range 4-72, p = .022). A bimodal peak of age of disease onset in both genders was observed (first peak in second-third decades and second one in fifth-sixth decades). Among the MG patients with late-onset of disease, male were significantly higher compared to Caucasian and Oriental MG population (p = .047). MG patients with thymoma were significantly older and consisted of higher percent of males. Bulbar symptoms and severe grade (IIB+ III+ IV) at disease onset were more frequent in SPMG than SNMG patients. PMID- 20199204 TI - Self-reported differences on measures of executive function and hypersexual behavior in a patient and community sample of men. AB - Patients seeking help for hypersexual behavior often exhibit features of impulsivity, cognitive rigidity, poor judgment, deficits in emotion regulation, and excessive preoccupation with sex. Some of these characteristics are also common among patients presenting with neurological pathology associated with executive dysfunction. These observations led to the current investigation of differences between a group of hypersexual patients (n = 87) and a non hypersexual community sample (n = 92) of men using the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) and the Hypersexual Behavior Inventory (HBI). Significant differences between the groups emerged on eight subscales and all of the general indices of executive functioning with the most dramatic differences on BRIEF-A's Shift, Emotional Control, Initiate, and Plan/Organize subscales. Hypersexual behavior was positively correlated (r = .37, p < .01) with global indices of executive dysfunction and several subscales of the BRIEF-A. These findings provide preliminary evidence supporting the hypothesis that executive dysfunction may be implicated in hypersexual behavior. PMID- 20199205 TI - Reliability of soleus H-reflexes in standing and walking post-incomplete spinal cord injury. AB - OBJECTIVE: To establish the reliability of soleus H-reflex in individuals with incomplete spinal cord injury (SCI) during the standing and the swing and stance phases of overground walking. METHODS: Fourteen SCI (40 +/- 10 years) and eight noninjured subjects (32 +/- 9 years) participated. The noninjured and SCI subjects walked at self-selected speed overground. H-reflexes in the soleus muscle (at M-wave 7%-13% maximum-M) were tested on two separate days by stimulating the tibial nerve. Intraclass correlation coefficients (two-way mixed model-ICC (1, 2)) and standard error of measurement (SEM) were calculated. RESULTS: Relative reliability of the H-reflexes was good to excellent; intra class correlation coefficients (ICCs) ranged from 0.64-0.91 in noninjured and SCI subjects. SEM expressed as percentage of the mean H-reflex was 13%-62% in noninjured and 12%-18% in SCI individuals. CONCLUSIONS: H-reflexes can be reliably assessed in standing and walking in post-SCI and noninjured subjects. SIGNIFICANCE: H-reflexes can be reliably used in longitudinal studies to investigate mechanisms of recovery post-SCI. PMID- 20199206 TI - Actigraphic evaluation of motor fluctuations in patients with Parkinson's disease. AB - BACKGROUND: There is growing interest in developing inexpensive and objective motor fluctuation evaluation methods for Parkinson's disease (PD). OBJECTIVES: We aim to compare activity level in the off state, on state, and dyskinetic periods as evaluated either by a physician during a levodopa challenge or by a 72-hr on off diary self-evaluation in the ambulatory setting. Finally, the effect of daily activities on motor activity in PD and healthy controls was further explored. METHODS: The study was conducted in three consecutive phases. For phase I, in which the on state, off state, and dyskinesia were evaluated using actigraphy, recordings were made during standard acute levodopa challenge in nine dyskinetic PD patients. For phase II, a different set of 16 dyskinetic PD patients was monitored in the ambulatory setting for 72 consecutive hours by actigraphy and a standardized on-off diary. For phase III, 62 PD patients and 14 age- and sex matched healthy controls wore an actigraph and completed a daily activities diary for 7 days. RESULTS: No differences in activity level between on state and off state during the acute levodopa challenge (phase I) or the 72-hr ambulatory period (phase II) were found. Activity during dyskinesia periods was significantly higher than during on state periods without dyskinesia (p < .01). During the third phase, dyskinetic PD patients and healthy controls showed higher actigraphy-measured activity as compared to de novo, stable, or fluctuating PD (p < .0001), which remained unaltered by daily activities performed during the study period. Tremor UPDRS scores did not correlate with activity level. CONCLUSIONS: These results confirm the lack of specificity of simple wrist-worn actigraphy and further suggest it may be suitable for dyskinesia assessment but not for on state and off state evaluation. PMID- 20199208 TI - Complementary acupuncture in Parkinson's disease: a spect study. AB - We studied cerebral effects of complementary acupuncture in Parkinson's disease using single photon emission computed tomography (SPECT) measures of 99mTc-ECD and 99mTc-TRODAT-4, before and after five weeks of treatment. Ten patients were randomly assigned to receive levodopa alone (controls) or levodopa and complementary scalp electro-acupuncture. Before treatment, no hemispheric regional cerebral blood flow (rCBF) differences were found, whereas striatal dopamine transporter (DAT) activity was lower in the most affected hemisphere. Treatment with levodopa alone did not change rCBF, whereas it increased basal ganglion DAT activity in the most affected hemisphere. Patients who received levodopa and complementary acupuncture had increased rCBF in the frontal lobe, the occipital lobe, the basal ganglion, and the cerebellum in the most affected hemisphere as compared to baseline, but there were no changes in basal ganglia DAT levels. Thus, complementary acupuncture treatment in Parkinson's disease may affect rCBF but not basal ganglion DAT. PMID- 20199207 TI - Dysbindin, syncoilin, and beta-synemin mRNA levels in dystrophic muscles. AB - Progressive muscular dystrophies are genetic diseases with various modes of transmission. Duchenne muscular dystrophy (DMD) is caused by the defect of dystrophin, and Fukuyama congenital muscular dystrophy (FCMD) is caused by an abnormal fukutin gene leading to the glycosylation defect of alpha-dystroglycan. Dystrobrevin is one member of the dystrophin glycoprotein complex and its binding partners include dysbindin, syncoilin, and beta-synemin (desmuslin). Dysbindin is reported to be upregulated at the protein level in mdx mouse muscles, and syncoilin protein is also reported to be upregulated in biopsied muscles with neuromuscular disorders. In the present study we measured mRNA levels of dysbindin, syncoilin, and beta-synemin in biopsied muscles with DMD and FCMD. Upregulation of human dysbindin mRNA was observed in DMD muscles in comparison with normal muscles (p < .05). The differences in human syncoilin and beta synemin mRNA ratios between DMD and normal muscles were not statistically significant, although upregulation tendency of human syncoilin mRNA was noted in DMD muscles (.05 < p < .1). Furthermore, the differences of human dysbindin, syncoilin, and beta-synemin mRNA ratios between FCMD and normal muscles were not statistically significant. These data provide insight into the pathophysiology of these muscular dystrophies. PMID- 20199209 TI - A new kind of and reversible brainstem involvement in primary Sjogren's syndrome as an initial manifestation. AB - The prevalence of abnormalities on brain magnetic resonance imaging (MRI) varies in primary Sjogren's syndrome (pSS) patients and they are generally multiple hyperintense areas in the subcortical and periventricular white matter on T2 weighted and fluid-attenuated inversion recovery sequences. Here, we report brainstem involvement in a patient with pSS that was extensive on MRI, but reversible. The patient's outcome was positive. To our knowledge, a similar case has not previously been described. PMID- 20199210 TI - A spinocerebellar ataxia family with expanded alleles in the TATA-binding protein gene and ataxin-3 gene. AB - We report on a Chinese family with three members who have CAG repeat expansion in the ataxin-3, two members present with expanded trinucleotide repeat in both the ataxin-3 and tata-binding protein (TBP) and an individual who carries expanded CAG/CAA repeat in the TBP. Only the patients who carry an allele with expansion in the ataxin-3 gene presented with clinical symptoms. This interesting family presents a unique mutation state. We will continue to track this family in the future, which may help us further elucidate the pathogenic mechanism of spinocerebellar ataxia (SCA) type 3 and 17. The study also provides us a novel conception that mutations from two pathogenetic genes may coexist in one patient and SCA-affected patients with intermediate allele need to be further excluded for other SCA subtypes. PMID- 20199211 TI - A Monte Carlo study of the radiation quality dependence of DNA fragmentation spectra. AB - We simulated the irradiation of human fibroblasts with gamma rays, protons and helium, carbon and iron ions at a fixed dose of 5 Gy. The simulations were performed with the biophysical Monte Carlo code PARTRAC. From the output of the code, containing in particular the genomic positions of the radiation-induced DNA double-strand breaks (DSBs), we obtained the DNA fragmentation spectra. Very small fragments, in particular those related to "complex lesions" (few tens of base pairs), are probably very important for the late cellular consequences, but their detection is not possible with the common experimental techniques. We paid special attention to the differences among the various ions in the production of these very small fragments; in particular, we compared the fragmentation spectra for ions of the same specific energy and for ions of the same LET (linear energy transfer). As found previously for iron ions, we found that the RBE (relative biological effectiveness) for DSB production was considerably higher than 1 for all high-LET radiations considered. This is at variance with the results obtainable from experimental data, and it is due to the ability to count the contribution of small fragments. It should be noted that for a given LET this RBE decreases with increasing ion charge, due mainly to the increasing mean energy of secondary electrons. A precise quantification of the DNA initial damage can be of great importance for both radiation protection, particularly in open-space long term manned missions, and hadrontherapy. PMID- 20199212 TI - Clustered DNA damage in irradiated human diploid fibroblasts: influence of chromatin organization. AB - Clustered DNA damages are induced by ionizing radiation and are defined as two or more lesions within one or two helical turns. The aim of this study was to investigate the induction and repair of clustered DNA damage in cells with emphasis on the influence of structural differences in the chromatin organization. Human fibroblasts were irradiated with X rays and induced DSBs and clustered damages were quantified using pulsed-field gel electrophoresis combined with postirradiation incubation with the base excision repair endonuclease Fpg, which recognizes oxidized purines and cleaves the strand at sites inducing strand breaks. Hence clustered damages appear in enzyme-treated samples as additional DSBs. The chromatin was modified by different pretreatments that resulted in structures with varying compactness and levels of free radical scavenging capacity. We found that the induction of DSBs and clustered damages increased linearly with dose in all structures and that both types of lesions were allocated randomly within the nucleus. The induction yields increased with decreasing compactness of chromatin, and the chromatin effect was larger for clustered lesions than for DSBs. Clustered damages were processed efficiently with a fast and a slow repair component similar to that for induced DSBs. PMID- 20199213 TI - Cytogenetic damage in cells exposed to ionizing radiation under conditions of a changing dose rate. AB - The current international paradigm on the biological effects of radiation is based mainly on the effects of dose with some consideration for the dose rate. No allowance has been made for the potential influence of a changing dose rate (second derivative of dose), and the biological effects of exposing cells to changing dose rates have never been analyzed. This paper provides evidence that radiation effects in cells may depend on temporal changes in the dose rate. In these experiments, cells were moved toward or away from an X-ray source. The speed of movement, the time of irradiation, and the temperature during exposure were controlled. Here we report the results of the first experiments with TK6 cells that were exposed at a constant dose rate, at an increasing dose rate, or at a decreasing dose rate. The average dose rate and the total dose were same for all samples. Micronuclei were scored as the end point. The results show that the level of cytogenetic damage was higher in cells exposed to a decreasing dose rate compared to both an increasing and a constant dose rate. This finding may suggest that the second derivative of dose may influence radiation risk estimates, and the results should trigger further studies on this issue. PMID- 20199214 TI - Characteristic 8 keV X rays possess radiobiological properties of higher-LET radiation. AB - Electronic brachytherapy systems are being developed that can deliver X rays of varying energy depending on the material of a secondary target. A copper target produces characteristic 8 keV X rays. Our aim was to determine whether 8 keV X rays might deliver greater biological effectiveness than megavoltage photons. Cells of the U251 human glioma cell line were used to compare the biological effects of 8 keV X rays and (60)Co gamma rays in terms of relative biological effectiveness (RBE), oxygen enhancement ratio (OER), and DNA damage. The RBE at 50% and 10% survival was 2.6 and 1.9, respectively. At 50% survival, the OER for cells treated with 8 keV X rays was 1.6 compared with 3.0 for (60)Co gamma rays. The numbers of H2AX foci per Gy after treatment with 8 keV X rays and (60)Co gamma rays were similar; however, the size of the foci generated at 8 keV was significantly larger, possibly indicating more complex DNA damage. The mean area of H2AX foci generated by 8 keV X rays was 0.785 microm(2) (95% CI: 0.756-0.814) compared with 0.491 microm(2) (95% CI: 0.462-0.520) for (60)Co gamma rays (P < 0.0001). Characteristic 8 keV X rays produce two to three times the biological effectiveness of megavoltage photons, with a radiobiological profile similar to higher-LET radiations. PMID- 20199215 TI - Involvement of purinergic signaling in cellular response to gamma radiation. AB - Recent studies have suggested a bystander effect in nonirradiated cells adjacent to irradiated cells; however, the mechanism is poorly understood. In this study, we investigated the involvement of both extracellular nucleotides and activation of P2 receptors in cellular responses to gamma radiation using human HaCaT keratinocytes. The concentration of ATP in culture medium was increased after gamma irradiation (0.1-1.0 Gy), suggesting that radiation induces ATP release from cells. Intracellular Ca(2+) concentration was elevated when conditioned medium from irradiated cells was transferred to nonirradiated cells, and this elevation was suppressed by apyrase (ecto-nucleotidase), indicating the involvement of extracellular nucleotides in this event. Further, we examined the activation of ERK1/2 by gamma radiation and nucleotides (ATP and UTP). Both gamma radiation and nucleotides induced activation of ERK1/2. Next, the effect of inhibitors of P2 receptors on radiation-induced activation of ERK1/2 was examined. The activation of ERK1/2 was blocked by suramin (P2Y inhibitor), MRS2578 (P2Y(6) antagonist) and apyrase. These results suggest that both released nucleotides and activation of P2Y receptors are involved in gamma-radiation induced activation of ERK1/2. We conclude that ionizing radiation induces release of nucleotides from cells, leading to activation of P2Y receptors, which in turn would result in a variety of biological effects. PMID- 20199216 TI - Unique characteristics of radiation-induced apoptosis in the postnatally developing small intestine and colon of mice. AB - Abstract We examined the response of the developing mouse intestine to X radiation using neonates (1 day postpartum), infants (2 weeks postpartum) and adults (7 weeks postpartum). Irradiated adult small intestinal crypts displayed two waves of apoptosis. The first wave peaked at 3 h and was followed by a broad wave with a peak persisting from 24 to 48 h. p53 was expressed during the first wave but not the second wave. For the infant small intestine, the intensity of the first wave was approximately half that of the adult wave, and for the colon the intensity was even smaller. In neonates, apoptosis was delayed, peaking at 6 h for small intestinal crypts and at 24 h for colonic crypts. Although no apoptosis occurred at 3 h postirradiation in neonates, p53 was present in both the small intestine and colon, owing at least in part to the inability of p53 to increase the level of Noxa, a p53-dependent pro-apoptosis protein, suggesting a discontinuity in the p53-Noxa-caspase pathway in neonates. By contrast, the induction of p21, a pro-survival protein, was greater in neonatal cells than in adult cells. Thus it appears that the developing and adult intestine mount distinct apoptotic responses to radiation. PMID- 20199217 TI - Wound trauma increases radiation-induced mortality by activation of iNOS pathway and elevation of cytokine concentrations and bacterial infection. AB - Abstract Although it is documented that concurrent wounding increases mortality from radiation injury, the molecular mechanism of combined injury is unknown. In this study, mice were exposed to gamma radiation followed by skin wounding. Wound trauma exacerbated radiation-induced mortality, reducing the LD(50/30) from 9.65 Gy to 8.95 Gy. Analyses of histopathology, inducible nitric oxide synthase (iNOS), and serum cytokines were performed on mouse ileum and skin at various times after 9.75 Gy and/or wounding. In the ileum, the villi were significantly shortened 3 days postirradiation but not after wounding; combined injury resulted in decreased villus width and tunica muscularis thickness. The skin of mice subjected to combined injury was less cellular and had a smaller healing bud than the skin of mice subjected to wounding alone. Combined injury significantly delayed wound closure times; it also prolonged the increased levels of iNOS protein in the skin and ileum. iNOS up-regulation was correlated with increases in transcription factors, including NF-kappaB and NF-IL6. The increase in NF-IL6 may be due to increases in cytokines, including IL-1beta, -6, -8, -9, -10 and 13, G-CSF, eotaxin, INF-gamma, MCP-1, MIP-1alpha and MIP-1beta. Combined injury resulted in early detection of bacteria in the blood of the heart and liver, whereas radiation alone resulted in later detection of bacteria; only a transient bacteremia occurred after wounding alone. Results suggest that enhancement of iNOS, cytokines and bacterial infection triggered by combined injury may contribute to mortality. Agents that inhibit these responses may prove to be therapeutic for combined injury and may reduce related mortality. PMID- 20199218 TI - Adiposity in female B6C3F1 mice continuously irradiated with low-dose-rate gamma rays. AB - Abstract We previously reported significant increases in body weight in B6C3F1 mice continuously exposed to low-dose-rate (21 mGy/day) gamma rays compared to that of nonirradiated control mice (Tanaka et al., Radiat. Res. 167, 417-437, 2007). To further study the underlying cause of the increase in body weight, feed consumption, adipose tissue weight, liver and serum lipid contents, and selected factors related to glucose and lipid metabolism such as serum levels of insulin and adipocytokines were examined in female B6C3F1 mice irradiated continuously with gamma rays at 20 mGy/day in group-housed or individually housed rearing conditions. Increased body weight, adipose tissue weight, serum levels of leptin, and lipid contents of the liver and serum were observed in both group-housed (accumulated dose = 6 Gy, 43 weeks from start of irradiation) and individually housed (accumulated dose = 4.4 Gy, 31 weeks from start of irradiation) irradiated mice compared to nonirradiated controls. Feed consumption measurements, however, revealed no significant difference between irradiated mice and nonirradiated controls when mice were housed individually. Our results show for the first time that the increase in the body weight of mice continuously irradiated with low dose-rate gamma rays is due to adiposity with no corresponding increase in feed consumption. PMID- 20199219 TI - Exposure to 56Fe-particle radiation accelerates electrophysiological alterations in the hippocampus of APP23 transgenic mice. AB - Abstract An unavoidable complication of space travel is exposure to high-charge, high-energy (HZE) particles. In animal studies, exposure of the CNS to HZE particle radiation leads to neurological alterations similar to those seen in aging or Alzheimer's disease. In this study we examined whether HZE-particle radiation accelerated the age-related neuronal dysfunction that was previously described in transgenic mice overexpressing human amyloid precursor protein (APP). These APP23 transgenic mice exhibit age-related behavioral abnormalities and deficits in synaptic transmission. We exposed 7-week-old APP23 transgenic males to brain-only (56)Fe-particle radiation (600 MeV/nucleon; 1, 2, 4 Gy) and recorded synaptic transmission in hippocampal slices at 2, 6, 9, 14 and 18-24 months. We stimulated Schaeffer collaterals and recorded field excitatory postsynaptic potentials (fEPSP) and population spikes (PS) in CA1 neurons. Radiation accelerated the onset of age-related fEPSP decrements recorded at the PS threshold from 14 months of age to 9 months and reduced synaptic efficacy. At 9 months, radiation also reduced PS amplitudes. At 6 months, we observed a temporary deficit in paired-pulse inhibition of the PS at 2 Gy. Radiation did not significantly affect survival of APP23 transgenic mice. We conclude that irradiation of the brain with HZE particles accelerates Alzheimer's disease related neurological deficits. PMID- 20199220 TI - Dietary supplements reduce the cataractogenic potential of proton and HZE particle radiation in mice. AB - Abstract The present study was undertaken to investigate the ability of dietary supplements to reduce the formation and severity of cataracts in mice irradiated with high-energy protons or iron ions, which are important components of the radiation encountered by astronauts during space travel. The mice were exposed to proton or iron-ion radiation and fed with a control diet or diets supplemented with the soybean-derived protease inhibitor, Bowman-Birk inhibitor (BBI), in the form of BBI Concentrate (BBIC) or an antioxidant formulation [containing l selenomethionine (SeM), N-acetyl cysteine (NAC), ascorbic acid, co-enzyme Q10, alpha-lipoic acid and vitamin E succinate] both before and after the radiation exposure. At approximately 2 years after the radiation exposure, the animals were killed humanely and lenses were harvested and characterized using an established classification system that assigns discrete scores based on the severity of the lens opacifications. The results showed that exposure to 1 GeV/nucleon proton (3 Gy) or iron-ion (50 cGy) radiation significantly increased the cataract prevalence and severity in CBA/J mice to levels above the baseline levels of age induced cataract formation in this mouse strain. Treatment with BBIC or the antioxidant formulation significantly reduced the prevalence and severity of the lens opacifications in the mice exposed to iron-ion radiation. Treatment with BBIC or the antioxidant formulation also decreased the severity of the lens opacifications in the mice exposed to proton radiation; however, the decrease did not reach statistical significance. These results indicate that BBIC and the antioxidant formulation evaluated in this study could be useful for protecting astronauts against space radiation-induced cataracts during or after long-term manned space missions. PMID- 20199221 TI - Lack of adverse effects of whole-body exposure to a mobile telecommunication electromagnetic field on the rat fetus. AB - Abstract The recent steep increase in the number of users of cellular phones is resulting in marked increase of exposure of humans to radiofrequency electromagnetic fields (EMFs). Children are of particular concern. Our goal was to evaluate potential adverse effects of long-term whole-body exposure to EMFs simulating those from base stations for cellular phone communication. Pregnant rats were given low, high or no exposure. At the high level, the average specific absorption rate (SAR)for the dams was 0.066-0.093 W/kg. The SAR for the fetuses and the F(1) progeny was 0.068-0.146 W/kg. At the low level, the SARs were about 43% of these. The 2.14 GHz signals were applied for 20 h per day during the gestation and lactation periods. No abnormal findings were observed in either the dams or the F(1) generation exposed to the EMF or in the F(2) offspring. Parameters evaluated included growth, gestational condition and organ weights for dams and survival rates, development, growth, physical and functional development, hormonal status, memory function and reproductive ability of the F(1) offspring (at 10 weeks of age) along with embryotoxicity and teratogenicity in the F(2) rats. Thus, under our experimental conditions, whole-body exposure to 2.14 GHz for 20 h per day during gestation and lactation did not cause any adverse effects on pregnancy or the development of rats. PMID- 20199222 TI - Latitudinal variations over Australia of the solar UV-radiation exposures for vitamin D3 in shade compared to full sun. AB - Abstract This paper reports on the variation of UV radiation in full sun and in shade and how this relates to the physiological production of vitamin D(3) for various latitudes. Calibrated spectral measurements were used to measure the UV radiation in the shade of numerous shade environments for varying solar zenith angles and seasons. This was for exposures to the horizontal, 45 degrees and vertical planes for the solar zenith angle (SZA) range of approximately 5 degrees to 80 degrees. For an SZA of approximately 5 degrees, average UV irradiances required for vitamin D(3) production (UV(D3)) were 0.67 W/m(2) and 0.20 W/m(2) for global and for shade with a sky view of greater than 40%, respectively. The best time to expose the human body to UV radiation while using shaded environments with a sky view of greater than 40% for vitamin D(3) synthesis is for SZAs less than approximately 45 degrees. Shade can be used throughout Australia during summer and winter. However, winter exposure times will vary depending on the latitude. Using shade for UV(D3) exposures can reduce total UV radiation exposure by 37% to 58% compared to full sun UV(D3) exposures. This research indicates that an improved approach to optimize UV-radiation exposures for the production of vitamin D(3) is to use diffuse UV radiation under shade in and around the middle of the day. PMID- 20199223 TI - Bystander cell killing in normal human fibroblasts is induced by synchrotron X ray microbeams. AB - Abstract The radiation-induced bystander response is defined as a response in cells that have not been directly targeted by radiation but that are in the neighborhood of cells that have been directly exposed. In the work described here, it is shown that bystander cell killing of normal human fibroblast WI-38 cells was induced by synchrotron microbeam X radiation. Cell nuclei in confluent WI-38 cells were irradiated with the microbeam. All of the cells on the dish were harvested and plated 24 h after irradiation. It was found that the bystander cell killing effect showed a parabolic relationship to the radiation dose when five cells were irradiated. At doses above 1.9 Gy, the surviving fraction increased to approximately 1.0. This suggests that induction of bystander cell killing may require some type of activity in the targeted cells, because the dose resulting in 37% cell survival was about 2.0 Gy. Bystander cell killing was suppressed by a pretreatment with aminoguanidine [an inhibitor of inducible nitric oxide (NO) synthase] or carboxy-PTIO (a scavenger of NO). These results suggest that NO is the chief initiator/mediator of bystander cell killing induced by X-ray microbeams. PMID- 20199224 TI - Radiosensitization of murine normoblasts in vivo by bromodeoxyuridine to the genotoxicity and cytotoxicity of the bone-seeking radiopharmaceutical 153Sm EDTMP. AB - Abstract To establish a basis for a possible strategy for bone marrow ablation or therapy, we examined the effect of bromodeoxyuridine (BrdU) incorporation into DNA on the genotoxic and cytotoxic effects of samarium-153 ethylenediaminetetramethylene phosphonate ((153)Sm-EDTMP) in normoblasts in vivo. Cytotoxicity and genotoxicity were established by time-response curves of polychromatic erythrocyte (PCE) and micronucleated polychromatic erythrocyte (MN PCE) frequencies, respectively, in mouse peripheral blood samples. The group treated with (153)Sm-EDTMP showed a clear induction of MN-PCEs; however, the group treated with BrdU plus (153)Sm-EDTMP paradoxically showed only a slight increase with respect to untreated controls. Treatment with (53)Sm-EDTMP caused a small reduction in PCE frequency, but exposure to BrdU or to BrdU plus (53)Sm EDTMP reduced the PCE frequency significantly from 32 h to the end of the experiment. The PCE frequencies in the BrdU plus (53)Sm-EDTMP group were significantly lower than in the BrdU control group at the final time and were much lower than the group treated with only (53)Sm-EDTMP, which returned to basal values. The results suggest the radioinduction of a lethal lesion in BrdU substituted DNA that cannot be repaired easily and does not permit cell division and micronucleus formation. PMID- 20199225 TI - New developments and future directions in radiation research. American Statistical Association Conference on Radiation and Health. Vail, Colorado, June 15-18, 2008. PMID- 20199228 TI - Out-of-hospital fluid in severe sepsis: effect on early resuscitation in the emergency department. AB - BACKGROUND: Early identification and treatment of patients with severe sepsis improves outcome, yet the role of out-of-hospital intravenous (IV) fluid is unknown. OBJECTIVE: To determine if the delivery of out-of-hospital fluid in patients with severe sepsis is associated with reduced time to achievement of goal-oriented resuscitation in the emergency department (ED). METHODS: We performed a secondary data analysis of a retrospective cohort study in a metropolitan, tertiary care, university-based medical center supported by a two tiered system of out-of-hospital emergency medical services (EMS) providers. We studied the association between delivery of out-of-hospital fluid by advanced life support (ALS) providers and the achievement of resuscitation endpoints (central venous pressure [CVP] > or =8 mmHg, mean arterial pressure [MAP] > or =65 mmHg, and central venous oxygen saturation [ScvO(2)] > or =70%) within six hours after triage during early goal-directed therapy (EGDT) in the ED. RESULTS: Twenty five (48%) of 52 patients transported by ALS with severe sepsis received out-of-hospital fluid. Data for age, gender, source of sepsis, and presence of comorbidities were similar between patients who did and did not receive out-of hospital fluid. Patients receiving out-of-hospital fluid had lower out-of hospital mean (+/- standard deviation) systolic blood pressure (95 +/- 40 mmHg vs. 117 +/- 29 mmHg; p = 0.03) and higher median (interquartile range) Sequential Organ Failure Assessment (SOFA) scores in the ED (7 [5-8] vs. 4 [4-6]; p = 0.01) than patients not receiving out-of-hospital fluid. Despite greater severity of illness, patients receiving out-of-hospital fluid approached but did not attain a statistically significant increase in the likelihood of achieving MAP > or =65 mmHg within six hours after ED triage (70% vs. 44%, p = 0.09). On average, patients receiving out-of-hospital fluid received twice the fluid volume within one hour after ED triage (1.1 L [1.0-2.0 L] vs. 0.6 L [0.3-1.0 L]; p = 0.01). No difference in achievement of goal CVP (72% vs. 60%; p = 0.6) or goal ScvO(2) (54% vs. 36%; p = 0.25) was observed between groups. CONCLUSIONS: Less than half of patients with severe sepsis transported by ALS received out-of-hospital fluid. Patients receiving out-of-hospital IV access and fluids approached but did not attain a statistically significant increase in the likelihood of achieving goal MAP during EGDT. These preliminary findings require additional investigation to evaluate the optimal role of out-of-hospital resuscitation in treating patients with severe sepsis. PMID- 20199229 TI - State requirements for physician emergency medical services providers. AB - OBJECTIVE: To describe requirements of physicians wishing to function as primary field emergency medical services (EMS) providers and variation of these requirements among states. METHODS: A simple mailed survey was developed and distributed to all 50 U.S. state EMS directors. The survey gathered information about each state's regulations concerning physicians performing as a primary EMS crew member. Data were entered into a Microsoft Excel spreadsheet and reported using simple descriptive statistics, including proportions and 95% confidence intervals (CIs). RESULTS: Forty-four (88%) of the states responded. In 32 states (73%), physicians can work as a primary member of either a basic life support (BLS) or an advanced life support (ALS) ambulance crew without any specific additional training. In 30 states (68%), physicians can work as a primary member of either a BLS or an ALS ambulance crew without any specific prehospital certification. All of the reporting states will allow a physician to become certified as an emergency medical technician (EMT) or paramedic and then work as a primary member of a BLS or ALS ambulance crew. Seventy-nine percent allow the provision of physician-level care on BLS ambulances, and 81% on ALS ambulances. There was no meaningful difference between the training requirements for becoming a certified BLS provider vs. a certified ALS provider. States were significantly less likely to require a skills examination of physicians wishing to become certified as a BLS provider (9%) compared with those wishing to become certified as an ALS provider (82%). CONCLUSION: Most states allow physicians to become certified prehospital care providers, although few states require physicians wishing to work as a primary EMS provider to do so, or even to undergo any specific EMS training. There is no national standardization of the preparatory requirements of physicians wishing to provide in-field EMS. PMID- 20199230 TI - Effectiveness and safety of fentanyl compared with morphine for out-of-hospital analgesia. AB - BACKGROUND: Fentanyl has several potential advantages for out-of-hospital analgesia, including rapid onset, short duration, and less histamine release. Objective. To compare the effectiveness and safety of fentanyl with that of morphine. METHODS: This was a retrospective before-and-after study of a protocol change from morphine to fentanyl in an advanced life support emergency medical services system in January 2007. Charts from nine months prior to the change and for nine months afterward were abstracted by two reviewers using a standardized instrument. The first three months after the change were excluded. Effectiveness was measured by change in pain scores on a 0-10 scale. A priori-defined adverse events included out-of-hospital events: respiratory rate <12 breaths/min, pulse oximetry <92%, systolic blood pressure <90 mmHg, any fall in Glasgow Coma Scale score, nausea or vomiting, intubation, and use of antiemetic agents or naloxone. Emergency department charts were reviewed for initial pain scores and the same adverse events during the first two hours. Events clearly not attributable to the opioid were discounted. The changes in pain scores were also compared adjusting for confounders by multivariable linear regression. RESULTS: Three hundred fifty five patients aged 13 to 99 years received morphine during the nine months before the protocol change and 363 received fentanyl following the washout period. Initial pain scores for morphine (8.1) and fentanyl (8.3) were comparable (95% confidence interval [CI] for difference -1.1 to 0.3). Fentanyl patients received a higher equivalent dose of opioid (7.7 mg morphine equivalents for morphine, 9.2 mg for fentanyl, CI for the difference 0.9 to 2.3). The mean decreases in pain score were similar between the drugs (2.9 for morphine, 3.1 for fentanyl, CI for the difference -0.3 to 0.7). With regard to adverse events, 9.9% of the morphine patients and 6.6% of the fentanyl patients experienced an adverse event in the field (CI for the difference -0.8 to 7.3%). The most common event was nausea, with a rate of 7.0% for morphine vs. 3.8% for fentanyl (CI for the difference 0.1% to 6.5%). CONCLUSION: Morphine and fentanyl provide similar degrees of out of-hospital analgesia, although this was achieved with a higher dose of fentanyl. Both medications had low rates of adverse events, which were easily controlled. PMID- 20199231 TI - Prevalence of methicillin-resistant Staphylococcus aureus in ambulances in southern Maine. AB - OBJECTIVE: To determine whether methicillin-resistant Staphylococcus aureus (MRSA) could be found in ambulances in a predominantly rural state. METHODS: Samples were obtained from specified areas in 51 ambulances in southern Maine. These samples were tested on mannitol salt agar containing 4 microg/mL oxacillin. Resulting colonies were gram-stained and tested for the presence of catalase and coagulase. RESULTS: Of the 51 ambulances tested, 25 (49%) had at least one area positive for MRSA contamination. CONCLUSIONS: A significant number of ambulances operating in southern Maine have MRSA contamination, and ambulances may represent an important reservoir for the transmission of potentially serious infections to patients and EMS personnel. There was no statistical difference between the service types (fire-based vs. non-fire-based) or annual call volume. There was, however, a statistically significant lower rate of contamination in services that provided paid, 24-hour coverage versus those that did not. PMID- 20199232 TI - Analysis of emergency medical services activations in Shenandoah National Park from 2003 to 2007. AB - BACKGROUND: Wilderness activities continue to be popular in the United States, but may lead to both direct injuries and exacerbations or complications from chronic diseases. Appropriate response planning requires information on the type and location of emergency medical services (EMS) activations in large outdoor areas with many visitors. OBJECTIVES: To describe EMS calls in Shenandoah National Park in Virginia and explore the resultant implications for EMS resources and staging, medical provider training, and potential public health interventions in similar wilderness recreation areas. METHODS: A retrospective, descriptive review was conducted of all park EMS activations in Shenandoah National Park from 2003 to 2007. RESULTS: There were 335 EMS activations within the park over the study period. Both call volume and call rate increased during the study period. There were 197 calls (58.8%) for injuries and 138 (41.2%) for illnesses. Weakness/dizziness was the most frequent illness complaint, and lower extremity injury was the most frequent injury. Those with illnesses were more likely to be seen by EMS at a lodge, tended to be female, and were more likely to require emergency transportation to a hospital. Chronic medical problems were reported for twice as many of the illness patients as for those who were injured. CONCLUSIONS: EMS runs in Shenandoah are increasing and the majority of calls from 2003 to 2007 were for injuries. A notable number of patients with both injuries and illnesses reported chronic medical conditions. These data may be used to help with EMS support availability planning, provider education, and safety planning within the park, and provide baseline data for future public-safety interventions. PMID- 20199233 TI - Sleep quality and fatigue among prehospital providers. AB - BACKGROUND: Fatigue is common among medical professionals and has been linked to poor performance and medical error. Objective. To characterize sleep quality and its association with severe fatigue in emergency medical services (EMS) providers. METHODS: We studied a convenience sample of EMS providers who completed three surveys: the Pittsburgh Sleep Quality Index (PSQI), the Chalder Fatigue Questionnaire (CFQ), and a demographic survey. We used established measures to examine survey psychometrics and performed t-tests, analysis of variance (ANOVA), and chi-square tests to identify differences in PSQI and CFQ scores. RESULTS: One hundred nineteen surveys were completed. The eight-hour shift was most commonly reported (35.4%). A majority of subjects were overweight (41.9%) or obese (42.7%), and 59.6% had been diagnosed with one or more health conditions (e.g., diabetes). Results from psychometric tests were positive. The mean (+/- standard deviation) PSQI score was 9.2 (+/- 3.7). A CFQ score > or =4, indicating severe mental and physical fatigue, was present in 44.5% of the subjects. The mean PSQI score was higher among those reporting severe fatigue (11.3 +/- 3.2) than among those not reporting fatigue (7.5 +/- 3.0, p < 0.0001). CONCLUSIONS: The results from this study suggest that the sleep quality and fatigue status of EMS workers are at unhealthy levels. The health and safety of the EMS worker and patient population should be considered in light of these results. PMID- 20199234 TI - Occupational health and safety assessment of exposure to jet fuel combustion products in air medical transport. AB - INTRODUCTION: Transport medicine personnel are potentially exposed to jet fuel combustion products. Setting-specific data are required to determine whether this poses a risk. OBJECTIVE: This study assessed exposure to jet fuel combustion products, compared various engine ignition scenarios, and determined methods to minimize exposure. METHODS: The Beechcraft King Air B200 turboprop aircraft equipped with twin turbine engines, using a kerosene-based jet fuel (Jet A-1), was used to measure products of combustion during boarding, engine startup, and flight in three separate engine start scenarios ("shielded": internal engine start, door closed; "exposed": ground power unit start, door open; and "minimized": ground power unit right engine start, door open). Real-time continuous monitoring equipment was used for oxygen, carbon dioxide, carbon monoxide, nitrogen dioxide, hydrogen sulfide, sulfur dioxide, volatile organic compounds, and particulate matter. Integrated methods were used for aldehydes, polycyclic aromatic hydrocarbons, volatile organic compounds, and aliphatic hydrocarbons. Samples were taken in the paramedic breathing zone for approximately 60 minutes, starting just before the paramedics boarded the aircraft. Data were compared against regulated time-weighted exposure thresholds to determine the presence of potentially harmful products of combustion. RESULTS: Polycyclic aromatic hydrocarbons, aldehydes, volatile organic compounds, and aliphatic hydrocarbons were found at very low concentrations or beneath the limits of detection. There were significant differences in exposures to particulates, carbon monoxide, and total volatile organic compound between the "exposed" and "minimized" scenarios. Elevated concentrations of carbon monoxide and total volatile organic compounds were present during the ground power unit assisted dual-engine start. There were no appreciable exposures during the "minimized" or "shielded" scenarios. CONCLUSION: Air medical personnel exposures to jet fuel combustion products were generally low and did not exceed established U.S. or Canadian health and safety exposure limits. Avoidance of ground power unit-assisted dual-engine starts and closing the hangar door prior to start minimize or eliminate the occupational exposure. PMID- 20199235 TI - The longitudinal study of turnover and the cost of turnover in emergency medical services. AB - BACKGROUND: Few studies have examined employee turnover and associated costs in emergency medical services (EMS). OBJECTIVE: To quantify the mean annual rate of turnover, total median cost of turnover, and median cost per termination in a diverse sample of EMS agencies. METHODS: A convenience sample of 40 EMS agencies was followed over a six-month period. Internet, telephone, and on-site data collection methods were used to document terminations, new hires, open positions, and costs associated with turnover. The cost associated with turnover was calculated based on a modified version of the Nursing Turnover Cost Calculation Methodology (NTCCM). The NTCCM identified direct and indirect costs through a series of questions that agency administrators answered monthly during the study period. A previously tested measure of turnover to calculate the mean annual rate of turnover was used. All calculations were weighted by the size of the EMS agency roster. The mean annual rate of turnover, total median cost of turnover, and median cost per termination were determined for three categories of agency staff mix: all-paid staff, mix of paid and volunteer (mixed) staff, and all volunteer staff. RESULTS: The overall weighted mean annual rate of turnover was 10.7%. This rate varied slightly across agency staffing mix (all-paid = 10.2%, mixed = 12.3%, all-volunteer = 12.4%). Among agencies that experienced turnover (n = 25), the weighted median cost of turnover was $71,613.75, which varied across agency staffing mix (all-paid = $86,452.05, mixed = $9,766.65, and all volunteer = $0). The weighted median cost per termination was $6,871.51 and varied across agency staffing mix (all-paid = $7,161.38, mixed = $1,409.64, and all-volunteer = $0). CONCLUSIONS: Annual rates of turnover and costs associated with turnover vary widely across types of EMS agencies. The study's mean annual rate of turnover was lower than expected based on information appearing in the news media and EMS trade magazines. Findings provide estimates of two key workforce measures--turnover rates and costs--where previously none have existed. Local EMS directors and policymakers at all levels of government may find the results and study methodology useful toward designing and evaluating programs targeting the EMS workforce. PMID- 20199236 TI - Fatal airway injuries during Operation Enduring Freedom and Operation Iraqi Freedom. AB - INTRODUCTION: Airway compromise is the third leading cause of potentially preventable death on the battlefield. An understanding of the injuries associated with fatal airway compromise is necessary to develop improvements in equipment, training, and prehospital management strategies in order to maximize survival. OBJECTIVE: To determine injury patters resulting in airway compromise in the combat setting. METHODS: This was a subgroup analysis of cases previously examined by Kelly and colleagues, who reviewed autopsies of military personnel who died in combat in Iraq and Afghanistan between 2003 and 2006. Casualties with potentially survivable (PS) injuries and deaths related to airway compromise previously identified by Kelly et al. were reviewed in depth by a second panel of military physicians. RESULTS: There were 982 cases that met the inclusion criteria. Of these, 232 cases had PS injuries. Eighteen (1.8%) cases were found to have airway compromise as the likely cause of primary death. All had penetrating injuries to the face or neck. Twelve deaths (67%) were caused by gunshot wounds, while six deaths (33%) were caused by explosions. Nine cases had concomitant injury to major vascular structures, and eight had significant airway hemorrhage. Cricothyroidotomy was attempted in five cases; all were unsuccessful. CONCLUSION: Airway compromise from battlefield trauma results in a small number of PS fatalities. Penetrating trauma to the face or neck may be accompanied by significant hemorrhage, severe and multiple facial fractures, and airway disruption, leading to death from airway compromise. Cricothyroidotomy may be required to salvage these patients, but the procedure failed in all instances in this series of cases. Further studies are warranted to determine the appropriate algorithm of airway management in combat casualties sustaining traumatic airway injuries. PMID- 20199237 TI - Comparison of traditional versus video laryngoscopy in out-of-hospital tracheal intubation. AB - BACKGROUND: Out-of-hospital tracheal intubation is controversial because of questions regarding its safety as well as its impact on patient care. Factors contributing to the controversy include failed intubations, number of attempts required, prolonged periods without ventilation, and misplaced tracheal tubes. However, the most important factors are the decision-making and clinical skills of the intubator. Unfortunately, the limited number of outcome studies adds to the controversy. New technology, the video laryngoscope, has been introduced to facilitate tracheal intubation. At least one model of video laryngoscope (GlideScope Ranger) has been designed for out-of-hospital use. In an effort to assess the effect this technology might have on out-of-hospital intubation, a study comparing traditional laryngoscopy (TL) versus video laryngoscopy (VL) was performed. The study endpoint was the number of attempts to achieve intubation. Data were also collected on time to intubate, nonventilated periods, unrecognized misplaced tubes, and complications of the procedure. METHODS: Data were collected on 300 consecutive patients, 6 years of age or older, weighing at least 20 kg, who were intubated using TL. They were compared with data on 315 patients who were intubated using VL. All intubations were confirmed by visualization where possible, auscultation, misting, and capnography. In addition, all were continuously monitored by capnography. RESULTS: The average time to intubate in the VL group was 21 seconds (range 8-43 seconds) versus 42 seconds (range 28-90 seconds) in the TL group. The average number of attempts was 1.2 (range 1-3) in the VL group versus 2.3 (range 1-4) in the TL group. Successful intubation was 97% in the VL group versus 95% in the TL group. There were no unrecognized misplaced tubes in either group. For failed intubations, an alternative airway was successful in 99% of the VL group and 99% of the TL group. Maximum nonventilated time during any one intubation attempt was 37 seconds in the VL group and 55 seconds in the TL group. CONCLUSIONS: The numbers of attempts were significantly reduced in the VL group. This suggests that the use of VL has a positive effect on the number of attempts to achieve tracheal intubation. PMID- 20199239 TI - The generation of programmable cells of monocytic origin involves partial repression of monocyte/macrophage markers and reactivation of pluripotency genes. AB - We have recently demonstrated that peripheral blood monocytes can be differentiated in vitro into hepatocyte-like cells using appropriate differentiation media. Phenotype conversion required prior in vitro culture in the presence of M-CSF, IL-3, and human serum, during which the cells acquired a state of plasticity, so were termed "programmable cells of monocytic origin" (PCMO). Here, we have further characterized the process of PCMO generation with respect to markers of monocyte-to-macrophage transition and pluripotency. During a 6-day culture period, various monocyte/macrophage differentiation markers were down-regulated being indicative of a process of partial dedifferentiation. Dedifferentiation and hepatic redifferentiation also proceeded in highly purified monocyte preparations, albeit with different kinetics, suggesting that the presence of nonmonocytes, or soluble factors derived from them, is not essential in order for monocytes to acquire a multipotent state. PCMOs expressed various markers of human embryonic stem cells with early induction of NANOG and OCT4. Expression of the pluripotency-associated OCT4A isoform was paralleled by a global rise in histone H3 methylation on Lys-4, a marker of active chromatin, and coincided with peak sensitivity to tissue-specific differentiation. These results show that peripheral blood monocytes can be induced in vitro to transiently acquire stem cell-like properties and concomitantly a state of increased differentiation potential toward the hepatocytic phenotype. PMID- 20199238 TI - Mutations in bone marrow-derived stromal stem cells unmask latent malignancy. AB - Neoplastic epithelia may remain dormant and clinically unapparent in human patients for decades. Multiple risk factors including mutations in tumor cells or the stromal cells may affect the switch from dormancy to malignancy. Gene mutations, including p53 mutations, within the stroma of tumors are associated with a worse clinical prognosis; however, it is not known if these stromal mutations can promote tumors in genetically at-risk tissue. To address this question, Apc(Min/+) and Apc(Min/+) Rag2(-/-) mice, which have a predilection to mammary carcinoma (as well as wild-type (wt) mice), received mesenchymal stem cells (MSC) with mutant p53 (p53MSC) transferred via tail vein injection. In the wt mouse, p53MSC circulated in the periphery and homed to the marrow cavity where they could be recovered up to a year later without apparent effect on the health of the mouse. No mammary tumors were found. However, in mice carrying the Apc(Min/+) mutation, p53MSC homed to mammary tissue and significantly increased the incidence of mammary carcinoma. Tumor necrosis factor (TNF)-alpha-dependent factors elaborated from mesenchymal cells converted quiescent epithelia into clinically apparent disease. The increased cancer phenotype was completely preventable with neutralization of TNF-alpha or by transfer of CD4(+) regulatory T cells from immune competent donors, demonstrating that immune competency to regulate inflammation was sufficient to maintain neoplastic dormancy even in the presence of oncogenic epithelial and stromal mutations. The significant synergy between host immunity and mesenchymal cells identified here may restructure treatments to restore an anticancer microenvironment. PMID- 20199240 TI - Development of dendritic cell-based immunotherapy for autoimmunity. AB - Dendritic cells are professional antigen-presenting cells that maintain immune tolerance to self-antigens by deleting or controlling the pathogenicity of auto reactive T-cells. Dendritic cell-based immunotherapies show great promise for the restoration of tolerance in autoimmune disease. Dendritic cells can be modified ex vivo to induce stable tolerogenic function and be used as cellular 'vaccines' or they can be targeted in vivo with sophisticated antigen delivery systems. Tolerogenic dendritic cells induce antigen-specific T-cell tolerance in vivo and have therapeutic effects in animal models of autoimmunity. The current challenge is to bring tolerogenic dendritic cell therapy to the clinic. PMID- 20199242 TI - Human infection with a triple-reassortant swine influenza A(H1N1) virus containing the hemagglutinin and neuraminidase genes of seasonal influenza virus. AB - A reassortant influenza A(H1N1) virus of swine origin distinct from the pandemic H1N1 2009 strain was isolated from 3 patients, all of whom worked at the same large hog operation in Saskatchewan, Canada. The genomic composition of the isolates has not been previously reported, to our knowledge, and was the product of a genetic reassortment between seasonal H1N1 and triple-reassortant influenza virus that emerged in North American swine during the late 1990s. The neuraminidase and hemagglutinin genes of A/Saskatchewan/5350/2009, A/Saskatchewan/5351/2009, and A/Saskatchewan/5131/2009 were derived from human H1N1 virus and were closely related to those of A/Brisbane/59/2007. PMID- 20199241 TI - Population structure and capsular switching of invasive Neisseria meningitidis isolates in the pre-meningococcal conjugate vaccine era--United States, 2000 2005. AB - BACKGROUND: A quadrivalent meningococcal conjugate vaccine (MCV4) was licensed in the United States in 2005; no serogroup B vaccine is available. Neisseria meningitidis changes its capsular phenotype through capsular switching, which has implications for vaccines that do not protect against all serogroups. METHODS: Meningococcal isolates from 10 Active Bacterial Core surveillance sites from 2000 through 2005 were analyzed to identify changes occurring after MCV4 licensure. Isolates were characterized by multilocus sequence typing (MLST) and outer membrane protein gene sequencing. Isolates expressing capsular polysaccharide different from that associated with the MLST lineage were considered to demonstrate capsular switching. RESULTS: Among 1160 isolates, the most common genetic lineages were the sequence type (ST)-23, ST-32, ST-11, and ST-41/44 clonal complexes. Of serogroup B and Y isolates, 8 (1.5%) and 3 (0.9%), respectively, demonstrated capsular switching, compared with 36 (12.9%) for serogroup C (P < .001); most serogroup C switches were from virulent serogroup B and/or serogroup Y lineages. CONCLUSIONS: A limited number of genetic lineages caused the majority of invasive meningococcal infections. A substantial proportion of isolates had evidence of capsular switching. The high prevalence of capsular switching requires surveillance to detect changes in the meningococcal population structure that may affect the effectiveness of meningococcal vaccines. PMID- 20199243 TI - Local hyperthermia at 44 degrees C for the treatment of plantar warts: a randomized, patient-blinded, placebo-controlled trial. AB - There have been anecdotal reports that local hyperthermia was effective in the treatment of viral warts. We conducted a randomized, patient-blinded, placebo controlled trial to test the effect of local hyperthermia (44 degrees C for 30 min a day for 3 consecutive days plus 2 additional days 2 weeks later) on plantar warts. By the end of 3 months, 53.57% of patients (15/28) in the treatment group and 11.54% of patients (3/26) in the control group were cured (P < .01). The effect was not influenced by patient age, duration of disease, or number or size of lesions. PMID- 20199244 TI - Microbial translocation correlates with the severity of both HIV-1 and HIV-2 infections. AB - Microbial translocation has been linked to systemic immune activation during human immunodeficiency virus (HIV) type 1 infection. Here, we show that an elevated level of microbial translocation, measured as plasma lipopolysaccharide (LPS) concentration, correlates with AIDS in both individuals infected with HIV type 1 and individuals infected with HIV type 2. LPS concentration also correlates with CD4+ T cell count and viral load independently of HIV type. Furthermore, elevated plasma LPS concentration was found to be concomitant with defective innate and mitogen responsiveness. We suggest that microbial translocation may contribute to loss of CD4+ T cells, increase in viral load, and defective immune stimuli responsiveness during both HIV type 1 and HIV type 2 infections. PMID- 20199245 TI - Abstracts of the International Congress XXIII in Endovascular Interventions. February 28-March 4, 2010. PMID- 20199258 TI - Ten years of endovascular aortic arch repair. AB - PURPOSE: To evaluate a 10-year single-center experience of arch endovascular aortic repair (AEVAR) using the hybrid approach. METHODS: Between 1999 and 2009, 311 patients were treated with endografts for thoracic aortic pathologies. The aortic arch was involved in 116 (37.3%) patients (97 men; mean age 70.3+/-10.7 years, range 27-84). There were 83 atherosclerotic aneurysms, 21 type B dissections, and 12 other lesions whose proximal landing zones were categorized according to Ishimaru's classification as 24 zone 0, 27 zone 1, and 65 zone 2. A hybrid approach was performed for all zone 0 and zone 1 procedures and in nearly half (47.7%) of zone 2 procedures. Early and midterm outcomes were reviewed retrospectively. RESULTS: The initial clinical success in zone 0 aneurysms was 83.3%, with a 30-day mortality of 12.5% due to intraoperative stroke in all the cases. The respiratory failure rate was 12.5%, and there was 1 type I endoleak that spontaneously resolved at follow-up. Midterm clinical success at a mean 26+/ 21 months was 83.3%. In zone 1 aneurysms, the initial clinical success was 82.1% without 30-day mortality or perioperative stroke. The midterm clinical success was 81.5% at a mean 21+/-17 months [2 (7.4%) late aneurysm-related deaths]. Four type I endoleaks spontaneously resolved in 3 patients. In zone 2 cases, the initial clinical success was 90.8%. There was 1 (1.5%) intraoperative death and another (1.5%) within 30 days; 1 (1.5%) patient suffered a stroke, and the respiratory and renal failure rates were 3.0%, respectively. This is the only zone in which paraplegia (2 patients, 3.0%) was encountered. The midterm clinical success was 93.9% at a mean 34+/-20 months. Four type I endoleaks spontaneously resolved in 3 patients at follow-up. CONCLUSION: In selected patients, early and midterm outcomes of AEVAR using the hybrid approach are promising; however, mortality and morbidity, especially for zones 0 and 1, are not negligible. Our results may have practical implications for the ongoing evolution of the hybrid procedure in the aortic arch, as well as for patients fit for traditional surgery. PMID- 20199259 TI - Direct videoscopic approach to the thoracic aorta for aortic endograft delivery: evaluation in a human cadaver circulation model. AB - PURPOSE: To examine the feasibility of a direct videoscopic approach to the descending thoracic aorta for branched endograft delivery to the aortic arch and abdominal aorta. METHODS: Aneurysms were created in the aortic arch and pararenal aorta of 3 human cadavers, and pulsatile flow was established using a roller pump. Thoracoscopically, 2 double-felted purse-string sutures were placed on the thoracic aorta. Via the most distal trocar, an endoscopic needle was used to insert a stiff guidewire into the aorta through the center of the purse-string suture. Under direct videoscopic control, a 20-F sheath was advanced over the wire into the aorta. Switching to fluoroscopic control, a fenestrated endograft was deployed in the aortic arch followed by placement of a branch graft into the left subclavian artery. The delivery sheath was withdrawn from the aorta while simultaneously tightening the purse-string sutures. A similar procedure was performed in the same cadaver for antegrade branched endograft delivery to the pararenal aorta. Correct deployment of the branched endografts was evaluated by post implant angiography and autopsy. RESULTS: The procedure was successfully completed in all cadavers. "Hemostasis" was obtained in all cadavers without aortic cross clamping. Median fluid loss was 165 mL. Autopsy proved all purse string sutures to be adequately placed and all branched endografts to be deployed in the correct position. CONCLUSION: A direct videoscopic approach to the descending thoracic aorta proved a feasible technique for branched endograft delivery to the aortic arch and abdominal aorta in a human cadaver model. PMID- 20199260 TI - Commentary: a look to the future? Videoscopically-assisted delivery of branched aortic endografts. PMID- 20199261 TI - Reversal of fortune: induced endoleak to resolve neurological deficit after endovascular repair of thoracoabdominal aortic aneurysm. AB - PURPOSE: To describe a direct anatomical treatment approach using an induced type Ib endoleak to increase spinal cord perfusion and reverse paraplegia occurring after endovascular exclusion of a type 2 thoracoabdominal aortic aneurysm (TAAA). TECHNIQUE: The approach is illustrated in an 82-year-old woman who underwent branched endovascular repair of an asymptomatic, 6.8-cm-diameter type 2 TAAA. In 4-hour procedure, 3 aortic components were implanted beginning 50 mm distal to the origin of the left subclavian artery and ending 33 mm proximal to the aortic bifurcation. Upon awakening, the patient had sluggish movement in her legs. She responded to vasoactive agents and cerebrospinal fluid (CSF) drainage, but 3 recurrent episodes of paraplegia within 24 hours and severe headache indicated that the limits of CSF drainage had been reached. The patient was taken back to the operating room, and a type Ib (distal) endoleak was created by placing a balloon-expandable stent between the distal end of the infrarenal stent-graft component and the aortic wall, partially re-establishing flow into the aneurysm. The patient had no further recurrence of lower extremity paraplegia or paraparesis. At 3.5 months postoperatively, a Palmaz stent was deployed inside the distal end of the infrarenal stent-graft component to crush and occlude the Express LD stent, re-establishing a complete seal to preclude flow into the aneurysm. The patient remains clinically stable without lower extremity neurological deficit 3 months after the last procedure and 7 months after endovascular TAAA repair. CONCLUSION: A direct anatomical approach to reverse spinal cord ischemia following endovascular TAA or TAAA repair is feasible by creating a type I or type III endoleak to afford partial, temporary reperfusion of the excluded aorta. PMID- 20199262 TI - Commentary: an anatomical alternative to improve circulation to the spinal cord after stent-graft placement. PMID- 20199263 TI - In-hospital safety and effectiveness of bivalirudin in percutaneous peripheral interventions: data from a real-world registry. AB - PURPOSE: To present real-world data to evaluate the safety and effectiveness of bivalirudin, a direct thrombin inhibitor, in an unselected group of patients undergoing percutaneous peripheral interventions (PPI). METHODS: Data were extracted from a prospectively collected peripheral vascular registry developed for quality assurance measures at 2 centers. Of 398 consecutive patients (195 men; mean age 69.4+/-11.3 years) who underwent PPI in a 2-year period, 369 (92.7%) received bivalirudin (0.75 mg/kg bolus followed by a 1.75 mg/kg/h infusion) and 29 (7.3%) received unfractionated heparin (UFH). In the bivalirudin sample, critical limb ischemia was present in 28.0% of patients, TASC D lesion in 29.5%, and angiographic thrombus in 7.8% of vessels. Demographic, clinical, procedural, and angiographic variables and in-hospital complications were analyzed. All in-hospital adverse events were independently adjudicated. RESULTS: Procedural success (<30% residual narrowing) was achieved in 359 (97.3%) patients receiving bivalirudin. Adverse events included stroke (1, 0.3%), acute renal failure (1, 0.3%), major bleeding (3, 0.8%), distal embolization (11, 3.0%), vascular access complications (2, 0.5%), and minor amputation (2, 0.5%). CONCLUSION: Bivalirudin had an excellent safety profile in a real-life cohort of patients undergoing PPI, including high-risk patients with critical limb ischemia and TASC D lesions. In-hospital major bleeding and other adverse events were infrequent. A randomized trial of bivalirudin versus UFH is needed to verify these results and establish bivalirudin as a standard anticoagulant in PPI. PMID- 20199264 TI - Commentary: bivalirudin is a safe and effective anticoagulant in the percutaneous treatment of complex infrainguinal disease. PMID- 20199265 TI - An angiographic analysis of atherosclerosis progression in below-the-knee arteries after femoropopliteal angioplasty in claudicants. AB - PURPOSE: To report an angiographic investigation of midterm atherosclerotic disease progression in below-the-knee (BTK) arteries of claudicants. METHODS: Angiograms were performed in 58 consecutive claudicants (35 men; mean age 68.3+/ 8.7 years) with endovascular treatment of femoropopliteal arteries in 58 limbs after a mean follow-up of 3.6+/-1.2 years. Angiograms were reviewed in consensus by 2 experienced readers blinded to clinical data. Progression of atherosclerosis in 4 BTK arterial segments (tibioperoneal trunk, anterior and posterior tibial arteries, and peroneal artery) was assessed according to the Bollinger score. The composite per calf Bollinger score represented the average of the 4 BTK arterial segment scores. The association of the Bollinger score with cardiovascular risk factors and gender was scrutinized. RESULTS: A statistically significant increase in atherosclerotic burden was observed for the mean composite per calf Bollinger score (5.7+/-8.3 increase, 95% CI 3.5 to 7.9, p<0.0001), as well as for each single arterial segment analyzed. In multivariate linear regression analysis, diabetes mellitus was associated with a more pronounced progression of atherosclerotic burden in crural arteries (beta: 5.6, p = 0.035, 95% CI 0.398 to 10.806). CONCLUSION: Progression of infrapopliteal atherosclerotic lesions is common in claudicants during midterm follow-up. Presence of diabetes mellitus was confirmed as a major risk factor for more pronounced atherosclerotic BTK disease progression. PMID- 20199266 TI - The StarClose vascular closure device in antegrade and retrograde punctures: a single-center experience. AB - PURPOSE: To evaluate the StarClose device and compare its success rates in antegrade and retrograde puncture closures. METHODS: A retrospective review of all StarClose deployments from April 2005 to July 2007 was performed in a single tertiary referral institution radiology department. In this time period, 143 StarClose devices were deployed in 132 patients (102 men; mean age 68+/-14 years). Of these, 40 (28%) were deployed after antegrade and 103 (72%) after retrograde common femoral arterial punctures. Hospital notes were reviewed to evaluate minor (managed conservatively with compression) and major (requiring surgical intervention) complication rates in the immediate postprocedure period and the following 24 hours. Late complications were also assessed. RESULTS: There were 11 (7.7%) immediate failures of device deployment: 4/40 (10.0%) antegrade and 7/103 (6.8%) retrograde. Within these 11 punctures, 1 major complication occurred that required surgical retrieval of the device following a retrograde puncture. No other major and 12 (9.1%) minor complications occurred following the 132 successful StarClose deployments. No late complications were seen on clinical or radiological follow-up. The total major complication rate was 0.7% (1/143). The total minor complication rate was 15.4% (22/143): 9/40 (22.5%) following antegrade punctures and 13/103 (12.6%) following retrograde punctures. CONCLUSION: The StarClose device is associated with a low major complication rate. A higher rate of minor complications was observed following antegrade punctures but all were managed with simple compression. Prospective randomized trials comparing closure devices are needed to evaluate their relative efficacy and safety in antegrade and retrograde punctures. PMID- 20199267 TI - A novel percutaneous solution to limb ischemia due to arterial occlusion from a femoral artery ECMO cannula. AB - PURPOSE: To describe a novel percutaneous technique for distal limb perfusion in the face of femoral artery occlusion secondary to extracorporeal membrane oxygenation (ECMO) cannula placement. TECHNIQUE: The technique is described in a 59-year-old man who presented with an inferior wall myocardial infarction and a large ventricular septal defect (VSD) requiring the initiation of ECMO via right femoral artery and vein cannulae. He subsequently developed right lower limb ischemia secondary to cannula occlusion of the femoral artery. Percutaneous transfemoral placement of a flush catheter in the right common femoral artery was performed angiographically. Ischemic symptoms resolved, and the patient was subsequently able to undergo repair of his VSD without any further lower limb ischemic sequelae. CONCLUSION: Percutaneous transfemoral placement of a flush catheter in the common femoral artery distal to ECMO cannula insertion has not to our knowledge been reported and carries the added benefit of restoring perfusion to both superficial and profunda femoris arteries. PMID- 20199268 TI - Application of the Willis covered stent in the treatment of aneurysm in the cisternal segment of the internal carotid artery: a pilot comparative study with midterm follow-up. AB - PURPOSE: To compare the use of the Willis stent-graft versus coil embolization for complicated aneurysms in the cisternal segment of the internal carotid artery (ICA). METHODS: Thirty-four patients (19 women; mean age 46.7+/-16.8 years, range 3-79) with 36 complicated aneurysms were treated either by Willis covered stents (n = 19) or by coil embolization (n = 17). Follow-up angiography was performed to investigate aneurysm recurrence, endoleak, and parent artery stenosis. Kaplan Meier curves were constructed to compare the freedom from recurrence and parent artery stenosis rates in both groups. Clinical follow-up data were retrospectively analyzed and categorized as fully recovered, improved, unchanged, or worsened. RESULTS: In the covered stent group, total exclusion was immediately achieved in 13 aneurysms; there were 5 minor endoleaks and 1 delivery failure. In the patients treated with coil embolization, total/near-total occlusion was achieved in 7 aneurysms, subtotal in 8, and partial in 2. Acute thrombosis occurred in 1 patient in each group, while 1 patient experienced recurrent hemorrhage after embolotherapy. Follow-up angiography (mean 14.3+/-9.4, range 3 31) revealed that 16 aneurysms were completely isolated in the stent-graft group, with only 2 mild in-stent stenoses. Eighteen months after the procedure, Kaplan Meier analysis showed recurrence-free rates of 93.3% and 50% for the stent-graft versus coil groups, respectively; freedom from parent artery stenosis was 87.5% and 100%. Symptoms were fully eliminated in 9 patients in each group; they were improved in 3 and 5, unchanged in 2 and 2, and worsened in 1 and 0, respectively, at the end of the follow-up period. CONCLUSION: Willis stent-graft application is an alternative to treat complicated aneurysms in the cisternal segment of the ICA. In the case of a tortuous parent artery or potential side branch coverage, however, it is still not a first choice therapy. PMID- 20199269 TI - Commentary: new generation of covered stents for the treatment of intracranial aneurysms. PMID- 20199270 TI - Mapping the aorta: a new look at vascular anatomy in the era of endograft repair. PMID- 20199271 TI - Importance of aortic morphology in planning aortic interventions. PMID- 20199272 TI - Toward an "off-the-shelf" fenestrated endograft for management of short-necked abdominal aortic aneurysms: an analysis of current graft morphological diversity. AB - PURPOSE: To examine the feasibility of an "off-the-shelf" fenestrated endograft repository to broaden the applicability of fenestrated endovascular aneurysm repair (f-EVAR) to a greater number of emergent cases. METHODS: Graft dimensions of 438 consecutive customized fenestrated endografts for juxtarenal aneurysms were obtained from the commercial manufacturer, classified into tolerance ranges, and encoded in a database for statistical analysis. Limits of variability for tolerance ranges were set to maintain target vessel patency within acceptable surgical limits at deployment. Key independent structural variables were identified and analyzed for trends. Detailed analysis was performed of 282 (64%) 3-fenestration endografts, representing 232 structurally unique grafts. RESULTS: Seven key individual structural variables were identified, constituting 21,952 possible combinations. Only 8/232 (3.5%) graft configurations were compatible with > or =3 patients. Nearly a third of the patients (86/282, 30.5%) were treated by a range of 36 customized endografts. Graft dimensions were not uniformly distributed; there were modal sizes that were likely to recur at a median 39 cases (95% CI 17-121). Deploying endografts incorporating double diameter-reducing tie technology increased the tolerance such that 28 grafts would treat 81% of this population. CONCLUSION: The current design of fenestrated stent-grafts means that an "off-the-shelf" option is not practicable. However, there is evidence of recurrent patterns of morphology. Statistical modeling is capable of predicting demand for graft configurations. Innovations in f-EVAR endograft technology may decrease the required variability in graft morphology, paving the way for ready-to-deploy fenestrated stent-grafts. PMID- 20199273 TI - Commentary: "off-the-shelf" fenestrated endografts for short-necked abdominal aortic aneurysms: an attractive prospect that may be viable with advances in technology. PMID- 20199274 TI - Endovascular treatment of abdominal aortic aneurysms in high-surgical-risk patients using commercially available stent-grafts. AB - PURPOSE: To analyze the initial and long-term results of endovascular aneurysm repair (EVAR) in high-surgical-risk patients (i.e., age > or =80 years, serum creatinine level > or =3 mg/dL, severe pulmonary dysfunction, severe cardiac dysfunction). METHODS: From April 2002 to June 2009, 50 consecutive high-surgical risk patients (42 men; mean age 74.0+/-8.7, range 54-91) with an abdominal aortic aneurysm (AAA; mean diameter 64.8 mm) who were treated electively using a bifurcated aortic endograft (32 Excluder, 18 Zenith) were entered in a prospective registry. Thirty-five (70%) patients were classified ASA III and 15 (30%) were ASA IV. High-risk status was corroborated using the Customized Probability Index (CPI). Primary endpoints were operative mortality and long-term survival; secondary endpoints were the frequency of reintervention, evolution of the aneurysm sac, and rates of primary and secondary patency and rupture. RESULTS: The mean CPI score was 11.04+/-6.3. Operative mortality was 2% (1/50). There were 4 endoleaks, 1 case of endotension, and 1 endograft limb occlusion. Two patients required reintervention during the mean follow-up of 35.6 months. Survival at 3 years was 94%. Primary and secondary patency rates at 3 years were 98% and 100%, respectively. There were no ruptures. CONCLUSION: Initial and long term results with endovascular treatment of AAA in high-surgical-risk patients were satisfactory and appear to justify this approach in this patient population. PMID- 20199275 TI - An improved methodology for investigating the parameters influencing migration resistance of abdominal aortic stent-grafts. AB - PURPOSE: To develop an improved methodology for investigating the parameters influencing stent-graft migration, with particular focus on the limitations of existing methods. METHODS: A physiological silicone rubber abdominal aortic aneurysm (AAA) model for fixation studies was manufactured based on an idealized AAA geometry: the model had a 24-mm neck, a 50-mm aneurysm, 12-mm-diameter legs, a 60 degrees bifurcation angle, and 2-mm-thick walls. The models were authenticated in neck fixation experiments. The displacement force required to migrate stent-grafts in physiological pulsatile flow was tested dynamically in water at 37 degrees C. A commercially available longitudinally rigid stent-graft (AneuRx) and a homemade device with little longitudinal rigidity were studied in a number of different configurations to investigate the effect of neck fixation length and systolic pressure on displacement force. RESULTS: The AneuRx (6.95+/ 0.49 to 8.52+/-0.5 N) performed significantly better than the homemade device (2.57+/-0.11 to 4.62+/-0.25 N) in pulsatile flow. The opposite was true in the neck fixation tests because the longitudinal stiffness of the AneuRx was not accounted for. Increasing pressure or decreasing fixation length compromised the fixation of the homemade device. This relationship was not as clear for the AneuRx because decreasing proximal fixation resulted in an increase in iliac fixation, which could assist fixation in this device. CONCLUSION: Assessing the migration resistance of stent-grafts based solely on proximal fixation discriminates against devices that are longitudinally stiff. Current in vivo models may give inaccurate displacement forces due to the high degree of oversizing in these studies. A novel in vitro approach, accounting for longitudinal rigidity and realistic graft oversizing, was developed to determine the resistance of aortic stent-grafts to migration in the period immediately after device implantation. PMID- 20199276 TI - Adjunctive iliac stents reduce the risk of stent-graft limb occlusion following endovascular aneurysm repair with the Zenith stent-graft. AB - PURPOSE: To determine whether the introduction of a policy of adjunctive stent insertion based on preoperative CT assessment or completion angiography reduced the incidence of limb occlusion after stent-graft implantation for endovascular aneurysm repair (EVAR). METHODS: A tertiary referral unit's endovascular database was retrospectively interrogated to compare the incidence of endograft limb occlusion in Zenith grafts following the introduction of a policy of selective adjunctive stent insertion. Group A included 288 limbs at risk in 146 patients (134 men; mean age 74+/-8 years) treated prior to August 2005 in whom adjunctive stents were inserted on an ad hoc basis only. Group B included 293 limbs at risk in 149 patients (127 men; mean age 76+/-7 years) treated after this date in whom a more aggressive adjunctive stenting strategy was adopted. Kaplan-Meier analysis was employed to compare outcomes. RESULTS: In total, 295 patients underwent EVAR involving 581 iliac vessels, of which 11 (1.8%) occluded at a median of 24 months (0-27). Of 65 limbs extended into the external iliac segment, 5 (7.6%) subsequently occluded; in the remaining 516 limbs, there were 6 (1.1%) occlusions (p = 0.004). Across the study group, 38 (6.5%) adjunctive stents were deployed in limbs deemed at risk; 1 (2.6%) of these occluded. In the remaining 543 unstented limbs, 10 (1.8%) occlusions occurred (p = 0.15). There were 11 occlusions in group A, in which 5 (1.7%) adjunctive stents had been deployed, but none in group B, which had received 33 (11.2%) stents (p<0.0001). Kaplan-Meier survival curves identified primary patency rates at 36 months of 96% and 100%, respectively (p = 0.001). CONCLUSION: Adjunctive stenting significantly reduces the risk of postoperative stent-graft limb occlusion without obvious compromise to the aneurysm repair. PMID- 20199277 TI - Isolated pharmacomechanical thrombolysis plus primary stenting in a single procedure to treat acute thrombotic superior vena cava syndrome. AB - PURPOSE: To report a combined procedure that opens the acutely thrombosed superior vena cava (SVC) to rapidly alleviate symptoms in seriously ill patients with SVC syndrome. CASE REPORTS: Four patients aged 54 to 63 years old with underlying malignancies were referred for treatment of SVC syndrome. All received isolated pharmacomechanical thrombolysis (IPMT) with tissue plasminogen activator delivered in a Trellis Peripheral Infusion System that removed obstructive clot in minutes versus the 24 to 48 hours required for traditional catheter-directed thrombolysis. In each case, stents were inserted immediately following IPMT in a combined procedure lasting <1 hour. Patients exhibited near-immediate relief of debilitating symptoms; completion venography demonstrated patent vessels with excellent blood flow. CONCLUSION: Combining IPMT with immediate stenting during the same session is an effective method for managing acute thrombotic SVC syndrome and limiting the exposure time and number of interventions performed on seriously ill patients. PMID- 20199278 TI - Commentary: an important step forward in the treatment of SVC syndrome: rapid relief of symptoms using the Trellis system. PMID- 20199279 TI - Graft perforation by a dislocated rib fracture after open thoracoabdominal aortic repair: emergent endovascular and open repair. AB - PURPOSE: To describe perforation of a Dacron aortic graft due to a post thoracotomy dislocated rib fracture in a young Marfan patient. CASE REPORT: Six months after a successful open repair of a type II dissecting thoracoabdominal aortic aneurysm (TAAA), a 40-year-old woman with Marfan syndrome underwent elective repair of a post-thoracotomy dislocated rib fracture. During the procedure, the graft ruptured; 2 TAG stent-grafts were emergently implanted to reline the existing aortic graft. The fractured rib was then resected. The postoperative course was uneventful, without residual leak at computed tomography at 3 days. At 18 months, the patient is well, without need of further operations. CONCLUSION: Early correction of any dislocated rib fracture close to a thoracic aortic graft should be considered, especially if the graft is not wrapped by the aneurysm sac. In these patients, in-graft endovascular relining associated with repair of the rib fracture may be a feasible and effective alternative to redo thoracotomy and surgical graft repair. Prior to attempting rib resection, appropriate thoracic endografts should be on hand in case an endovascular bailout is needed. PMID- 20199280 TI - Traumatic transection of the aorta and thoracic spinal cord injury without radiographic abnormality in an adult patient. AB - PURPOSE: To describe a rare case of spinal cord injury without radiographic abnormalities (SCIWORA) associated with a traumatic aortic transection. CASE REPORT: A 48-year-old man was transferred for endovascular treatment of a traumatic aortic transection. Primary traumatic paraplegia had been documented at the scene of the accident. No osseous or ligamentous injuries were found in the conventional radiographic images. The transection was treated successfully with an endovascular stent-graft, but the patient remained paraplegic. On the magnetic resonance images 8 days later, discrete trauma of the intraspinal ligament at T1/T2 was seen, without signs of injury to the myelum. The patient made a slow but incomplete recovery after that. CONCLUSION: SCIWORA very rarely affects the thoracic spinal cord in adults; therefore, a vascular injury in relation to the trauma of the aorta is assumed. When spinal cord damage is noted after stent grafting or open aortic surgery for traumatic transection, SCIWORA should be ruled out by history and neurological examination. PMID- 20199335 TI - Highlight: signal transduction and disease. PMID- 20199336 TI - Transanal irrigation for disordered defecation: a systematic review. AB - Transanal irrigation for treatment of disordered defecation has been widely used among caregivers. Unique in its simplicity, reversible and minimally invasive, transanal irrigation has begun to find its place in the treatment hierarchy. Scheduled transanal irrigation aims to ensure emptying of the left colon and rectum. This prevents faecal leakage between washouts, providing a state of pseudocontinence, and re-establishes control over the time and place of defecation. Furthermore, regular evacuation of the rectosigmoid prevents constipation. The studies presented in this review represent the continuum of increasing evidence and knowledge of transanal irrigation for disordered defecation: from proof in principle through better knowledge of the physiology, towards establishing the indications and ensuring the safety of the treatment. Evidence of the superiority of transanal irrigation in spinal cord injury patients with neurogenic bowel dysfunction is provided, also from a health economic perspective. Finally, a proposal is presented for an algorithm for the introduction of transanal irrigation for disordered defecation before irreversible surgery is considered. PMID- 20199337 TI - Involvement of apoptosis in mediating mitomycin C-induced teratogenesis in vitro. AB - Mitomycin C (MMC) is among the most commonly used drugs worldwide and is known to cause congenital malformations and fetal death in animals. In this study, the effect of MMC on major organogenesis period and the role of apoptosis in mediating congenital malformations have been carried out. In the present study, post-implantation rat embryos of day 11 were cultured for 24 h with various concentrations of MMC, i.e. 1, 10, and 100 microg/ml cultures. The growth and developmental of each embryo was evaluated and compared with control ones for the presence of any malformations. The MMC decreased all growth and developmental parameters in a concentration-dependent manner, when compared with control. However, exposure to MMC at 1 microg/ml culture did not show any significant effect on embryonic growth and development. Parallel to this, flow cytometric analysis (cell cycle and annexin V binding) and DNA fragmentation assay were carried out followed by quantitation by 3'-OH labeling of cultured rat embryos to evaluate the role of apoptosis in bringing about MMC-induced teratogenesis. All results were found to be dose-dependent and an increase in apoptosis in embryonic tissues may be related to the increased risk of congenital malformations. The data suggested that apoptosis might be involved in mediating teratogenesis of MMC in vitro. PMID- 20199338 TI - Antibiotic resistance of Helicobacter pylori in Israeli children. AB - OBJECTIVES: To determine the antibiotic susceptibility of Helicobacter pylori isolates from Israeli children; assess the role of previous antibiotic use in the development of antibiotic resistance and examine the possibility of simultaneous colonization of strains with different resistance patterns in the same patients. MATERIAL AND METHODS: A prospective case-series design was used. The study group included 174 patients aged 1-18 years referred to the Schneider Children's Medical Center of Israel for gastroscopy over a 2.5-year period. Antibiotic susceptibility to amoxicillin, clarithromycin, metronidazole, tetracycline, and levofloxacin was determined by E-test on gastric biopsies (2 per patient). Clinical and demographic data were obtained by questionnaire. RESULTS: Cultures for H. pylori yielded 55 isolates from 53 children. In treatment-naive children, the prevalence rate of primary resistance to clarithromycin was 25% and to metronidazole, 19%. Respective rates in children previously treated for H. pylori infection were 42% (p = 0.22) and 52% (p = 0.016). Simultaneous resistance to both drugs was found in 13% of isolates (n = 7), all from children with previous treatment failure. No resistance was found to amoxicillin, tetracycline or levofloxacin. Clarithromycin resistance was associated with macrolide use for any indication during the previous year (p = 0.033). In 2 patients (3.8%), a different H. pylori strain was cultured from each biopsy. CONCLUSIONS: H. pylori resistance to clarithromycin and metronidazole is high in Israeli children, particularly in those previously treated for H. pylori infection, in whom culture based treatment should be considered. The simultaneous colonization of multiple strains in a minority of patients needs to be further characterized. PMID- 20199339 TI - Comment to "The prognosis of pregnancy conceived despite the presence of an intrauterine device (IUD)". PMID- 20199340 TI - Advanced maternal age and prenatal diagnosis. PMID- 20199343 TI - Reversible renal impairment caused by thyroid disease. AB - Renal impairment is a common finding in clinical practice and is increasingly recognized with the routine reporting of estimated glomerular filtration rates. Clinical assessment is essential to determine which of the many possible investigations are appropriate. Thyroid hormones regulate many cellular functions, and abnormalities of the active thyroid hormones, thyroxine (T(4)) and tri-iodothyronine (T(3)), can influence serum creatinine levels. Evaluation of thyroid function is easily overlooked, but important in this context, as hypothyroidism is common and can cause renal impairment, which is typically reversible. Renal dysfunction may also be more frequent in hyperthyroidism than is recognized. This report describe how a dramatic elevation in serum creatinine paralleled the development of hyperthyroidism, with a return of the creatinine to normal following treatment of the hyperthyroid state. PMID- 20199345 TI - On a cold winter's day. PMID- 20199344 TI - Transient acute liver failure complicating transurethral resection syndrome. AB - Transurethral resection (TUR) syndrome, resulting from dilutional hyponatraemia for excessive absorption of irrigating fluid, represents the most relevant complication of transurethral resection of prostate (TURP). Ethanol is used as a tracer in the irrigant solution to monitor fluid absorption with a breathalyser. An unusual case of transient acute liver failure complicating TUR syndrome is reported. A 54-year-old male patient, without risk factors for the development of toxic hepatitis, was subjected to TURP for treatment of benign prostatic hyperplasia. Fluid absorption (2275 ml), estimated by breathalyser, exceeded maximum allowed absorption (2000 ml) only at the end of the surgical intervention. No signs of possible toxicity were evident in the few hours following the intervention. About 10 h after the end of TURP, the patient developed sweating, vomiting and diarrhoea. Laboratory analysis revealed severe hyponatraemia (116 meq/l) with signs of severe liver impairment (total bilirubin 5.8 mg/dl, alanine aminotransferase 56,500 U/l, aspartate aminotransferase 32,700 U/l), kidney failure (serum creatinine 1.93 mg/dl) and serum ethanol levels of 219 mg/dl (0.2%). The patient was treated with acetylcysteine 150 mg/kg i.v. and furosemide 50 mg i.v. Liver and renal functions improved in few days and recovered completely within 30 days. The TUR syndrome observed in this case was probably extravascular in nature, and could have been identified and prevented by measuring ethanol levels 10 min after ending the surgical procedure. The performance of such a test should be strongly recommended to all surgeons. The clinicians attributed the development of liver impairment in this case to ethanol toxicity. However, further studies are warranted to confirm whether hepatic injury can represent a possible complication of TUR syndrome when ethanol solution is used as irrigant fluid. PMID- 20199347 TI - The need for serum biomarker development for diagnosing and excluding tubal ectopic pregnancy. PMID- 20199348 TI - A systematic review of etiological factors for postpartum fecal incontinence. AB - BACKGROUND: Conflicting results are reported about the contribution of maternal, obstetric and fetal characteristics to postpartum fecal incontinence (FI), which is hampering prevention and management of FI. OBJECTIVE: To perform a systematic review identifying delivery-related etiological factors for postpartum FI. Search strategy. Literature searches of PubMed, EMBASE, CINAHL, DocOnline and reference lists from 1980 up to 2009 were conducted. Selection criteria. Prospective cohort studies evaluating maternal, obstetric or fetal risk factors for postpartum FI, with a follow-up period of at least three months, were assessed. We reviewed full reports in English, German or Dutch, with anal incontinence (AI), FI, flatus incontinence, soiling, urgency and FI severity scores as reported outcomes. Data collection and analysis. Data on study characteristics, methodological quality and outcome were extracted from 31 studies according to a standardized protocol. Clinical and methodological sources of heterogeneity permitted only a qualitative analysis. MAIN RESULTS: A third- or fourth-degree sphincter rupture was the only etiological factor strongly (AI) or moderately (flatus incontinence) associated with postpartum FI. No association with other postulated risk factors was found, for example, birth weight or instrumental delivery. The potential co-existence of different risk factors impedes the interpretation of the influence of a single delivery-related risk factor. CONCLUSIONS: This systematic review, including only longitudinal studies and recognizing the importance of separating results for different outcomes, identifies that a third- or fourth-degree sphincter rupture is the only factor that is strongly (AI) or moderately (flatus incontinence) associated with postpartum FI. PMID- 20199349 TI - Iron deficiency anemia and iron stores in adult and adolescent women in pregnancy. AB - OBJECTIVE: To determine whether primiparous adolescent pregnancy is associated with increased risk of iron deficiency anemia and iron deficiency when compared with older primiparas. DESIGN: Prospective cohort. SETTING: Caratinga city, Minas Gerais State, Brazil. SAMPLE: A total of 183 women, being 61 adolescents and 122 adults. METHODS: Five peripheral vein blood samples were collected from each participant, at 9-16 and 29-36 weeks, upon admission for delivery, within the first hour after delivery and 30-60 days post-partum. We measured hemoglobin (Hb), transferrin saturation index and ferritin. MAIN OUTCOME MEASURES: Adolescent and adult women using chi-squared test, Student's t-test and hotelling test. RESULTS: There were significant differences in Hb concentration during the various sampling periods, for the whole cohort. The prevalence of anemia (Hb < 11 g/dl) did not differ significantly between adults and adolescents. The decrease in the mean transferrin levels was more intense in adolescents than in adults, especially during the second half of pregnancy. Low ferritin levels (<12 microg/l) were more frequent in adolescents than in adults during pregnancy and throughout the study period. CONCLUSIONS: Although there were no significant differences in the prevalence of iron deficiency anemia (Hb < 11 g/dl) in adolescents compared to adult women, low body iron stores and ferritin (< 12 microg/l) were significantly more frequent in adolescents. PMID- 20199350 TI - Quality assured ultrasound simulator training for the detection of fetal malformations. AB - OBJECTIVE: Sonographic training in obstetrics differs broadly in Germany, although there are clearly defined quality-oriented requirements. In order to improve professional education, a training concept was devised utilizing an ultrasound simulator system. DESIGN: Between October 2004 and May 2006, 100 obstetric ultrasound training courses were held in 12 federal states of Germany. In these daily courses, doctors were trained in the detection of the most common malformations. SAMPLE: One hundred training courses with a total of 1,266 participants. METHODS: As a measure of quality assurance, a standardized questionnaire focusing on testing sonographic proficiency before and after the courses was issued in order to analyze the effect of these simulator-based ultrasound courses. MAIN OUTCOME MEASURES: Effectiveness of the method with reference to its potential role in structured sonographic training. RESULTS: The concept found prevailing approval (90%) at the level of principle, practical implementation, and clinical usefulness. Of the participants, 91% estimated their subjective training effect as good. The questionnaire analysis showed significant improvement. On average, 75.3% of the questions relating to sonographic proficiency were answered correctly at the end of the course as opposed to 48.6% at the beginning. CONCLUSION: Structured ultrasound training courses based on an ultrasound simulator system seem to be useful for defining a basic standardized quality of training and significantly improving examiners' skills. This is a suitable additional instrument to improve the education in obstetric ultrasound. PMID- 20199351 TI - Wound length and corticosteroid administration as risk factors for surgical-site complications following cesarean section. AB - OBJECTIVE: To evaluate the effect of some specific gestational factors and other known variables associated with poor wound healing in women who delivered by cesarean section. DESIGN: Observational, prospective study. SETTING: University Hospital of Messina. POPULATION: A total of 212 consecutive pregnant women at term delivering by elective cesarean section. METHODS: All data regarding demographic and gestational characteristics were collected at admission. The subcutaneous tissue depth was intra-operatively measured from the fascia to the skin surface, while the incision length was measured after skin closure. MAIN OUTCOME MEASURES: Onset of wound complications such as infection, seroma, hematoma, abscess or dehiscence > 1 cm. RESULTS: Body mass index (BMI) at term [odd ratio (OR) 1.2, 95%CI 1.03-1.38; p = 0.01], wound length (OR 1.03, 95%CI 1.01-1.05; p < 0.001) and corticosteroid administration (OR 3.4, 95%CI 1.5-7.9; p = 0.004) were found to be correlated with wound complications. The receiver operating characteristics curve analysis suggested a cut-off of 31.1 for the BMI at term and 166 mm for the wound length with an OR of 2.28 (95%CI 1.18-4.39; p = 0.013) and 4.3 (95%CI 2.2-8.6; p < 0.001), respectively. The multivariate logistic regression model, applied to these variables and to corticosteroid administration, showed an independent correlation (at term BMI > 31.1: OR 2.04, 1.01-4.13, p = 0.047; wound length > 166 mm: OR 4.89, 2.36-10.14, p < 0.001; corticosteroid administration: OR 3.11, 1.38-6.95, p = 0.006). CONCLUSIONS: To avoid wound complications obstetricians should be careful in the administration of steroids before surgery, in the skin incision length that should be kept as short as possible and in carefully observing gestational BMI. PMID- 20199352 TI - Plasma interleukin-18 (IL-18) levels are correlated with antioxidant vitamin coenzyme Q(10) in preeclampsia. AB - OBJECTIVE: Alteration of cytokines level and oxidative stress are both associated with preeclampsia (PE). We have investigated if IL-6 and IL-18 levels were related to coenzyme Q(10) (CoQ(10)), an antioxidant and a marker of oxidative stress in the plasma from normotensive and preeclamptic pregnancies. DESIGN: IL-6 and IL-18 levels were determined by enzyme-linked immunosorbent assays in plasmas from preeclamptic (n = 29) and normotensive pregnancies (n = 30). The concentrations of CoQ(10) in the different redox forms were measured in plasma using liquid chromatography coupled to electrochemical detection. Data were analyzed using the Wilcoxon Rank-Sum test and correlations were obtained by the Spearman's Rho test. MAIN OUTCOME MEASURES: IL-6 concentrations were 2.8-fold higher in preeclamptic plasmas than in controls (p = 0.0006), and IL-18 concentrations were found significantly lower in preeclamptic samples than in controls (p = 0.007). No correlation was found between IL-18 or IL-6 and antioxidant vitamin CoQ(10) in plasmas from normotensive pregnant women. However, in PE, IL-18 level was positively correlated with the reduced form of CoQ(10) (r = 0.3680, p = 0.0495). CONCLUSION: This is the first demonstration that IL-18 is potentially linked to oxidative stress in PE, since its level correlates with the concentration of the powerful antioxidant CoQ(10). These results also associate the immune system with the oxidant/antioxidant imbalance observed in PE. PMID- 20199353 TI - Abnormal uterine bleeding refractory to medical therapy assessed by saline infusion sonohysterography. AB - OBJECTIVE: The primary aim of the study was to assess the incidence of intracavitary pathology visualized by saline infusion sonohysterography (SIS) in premenopausal women suffering from abnormal uterine bleeding refractory to medical therapy. Secondary aims were to evaluate the clinical course when a minimally invasive therapeutic approach was applied and to examine the need for hysterectomy in this group of women over a follow-up period of two years. DESIGN: Prospective cohort study. SETTING: Tertiary referral university hospital. POPULATION: Between February 2004 and June 2006, 104 premenopausal women suffering from abnormal uterine bleeding refractory to medical treatment were included. METHODS: Transvaginal ultrasonography and SIS were performed as first line procedures of the investigation. Hysteroscopy was undertaken for removal of focal intrauterine anomalies. Hysterectomy was only carried out when other approaches failed or were regarded as unsuitable. Women who did not undergo hysterectomy had regular follow-up consultations for at least two years. MAIN OUTCOME MEASURES: Incidence of intrauterine focal anomalies, clinical course, and need for hysterectomy. RESULTS: Following saline infusion sonohysterograhy intracavitary anomalies were visualized in 58 (55.8%) women. Over the follow-up period 80 women had successful minimally invasive treatment, while 24 women underwent hysterectomy. CONCLUSIONS: The study shows that focal intracavitary lesions are common in premenopausal women with abnormal uterine bleeding refractory to medical treatment. By applying minimally invasive diagnostic and therapeutic approaches acceptable bleeding patterns can be re-established in most cases, thereby resulting in a low rate of hysterectomies. PMID- 20199354 TI - Sonographic quantification of endometrial changes after abortion with computer assisted image analysis. AB - OBJECTIVE: To examine the diagnostic feasibility of sonographic gray scale histograms to assess changes in the endometrium following abortion induced by mifepristone and misoprostol. DESIGN: Retrospective study. SETTING: Taipei Medical University-Wan Fang academic medical center. POPULATION OR SAMPLE: A total of 109 patients who matched eligibility criteria were divided into three groups: (a) complete abortion, (b) normal menstrual cycles, and (c) incomplete abortion. METHODS: Ultrasonographic examination of the uterus with fixed settings on each patient and sonographic gray scale histograms with image analysis software, using multivariate analysis by the partial least square model. MAIN OUTCOME MEASURES: Thickness, brightness, area and distribution of pixels of the endometrium and its contents. RESULTS: The groups could be discriminated (p < 0.01, Kruskal-Wallis test) using the analyzed gray scale histograms. The classification between complete and incomplete abortion reached 97% sensitivity and 100% specificity. CONCLUSIONS: Partial least square analysis of gray scale histograms of the endometrium in ultrasonographic images is useful in assessing endometrial changes. PMID- 20199355 TI - Prognostic significance of estrogen and progesterone receptor expression in LNG IUS (Mirena) treatment of endometrial hyperplasia: an immunohistochemical study. AB - We performed immunohistochemical analysis of estrogen (ERalpha) and progesterone receptors (PRA and PRB), phosphatase and tensin homolog (PTEN) and aromatase in endometrial hyperplasia treated with Mirena (levonorgestrel-releasing intrauterine system; LNG-IUS) and explored their prognostic significance. The baseline pre-treatment endometrial hyperplasia of a selected prospective cohort was analyzed [complex (n = 29) and atypical (n = 5)]. Study participants were categorized into those that showed endometrial regression (responders, n = 28) and those that showed non-regression or histological progression to atypia or malignancy (non-responders, n = 6). Immunohistochemical expression was expressed as a histological score (HS). Responders compared to non-responders showed significantly higher HSs for estrogen and progesterone receptors. Absence of estrogen and progesterone receptors predicted non-responder status with likelihood ratios of 9.33 (95% CI 2.19-39.81) and 2.92 (95% CI 1.47-5.79), respectively. Neither PTEN nor aromatase expression were associated with LNG-IUS therapy responsiveness. Responsiveness of endometrial hyperplasia to LNG-IUS therapy may be determined through analysis of baseline estrogen and progesterone receptors, but these exploratory findings require confirmation in a larger dataset. PMID- 20199356 TI - Prenatal and neonatal Group B Streptococcus screening and serotyping in Lebanon: incidence and implications. AB - The study aimed at determining the prevalence, risk factors, perinatal transmission, and serotypes of Group B Streptococcus (GBS) among pregnant women and their newborns in Beirut, Lebanon. This was a cross-sectional study of all pregnant women admitted from February to September 2006 to three major hospitals. Overall, 137 of 775 (17.7%) mothers and 50 of 682 newborns (7.3%) tested positive for GBS. Maternal colonization was not associated with maternal age, household income, gravidity, intrapartum fever, preterm labor, or premature rupture of membrane. Transmission rate was 40/120 (30%). Serotype 5 (24.1%) was the most common followed by serotype 1a (15.0%), 3 (14.4%), 2 (11.8%) and 1b (7.5%). Pregnant women in Lebanon appear to have a relatively high prevalence of GBS colonization with no identifiable risk factors for its acquisition. These results could provide basis for the institution of a national policy for universal maternal GBS screening to reduce neonatal morbidity and mortality. PMID- 20199359 TI - Vaginal hysterectomy as a primary route for morbidly obese women. AB - Vaginal hysterectomy is a least invasive and the choicest route when hysterectomy is possible by recourse to all the three available techniques. However in obese women, the common method is by the more invasive abdominal or laparoscopic route, with attendant morbidity. Vaginal hysterectomy was reviewed in 102 morbidly obese women (body mass index, BMI > or = 40) and compared with 50 comparable morbidly obese women who underwent abdominal hysterectomy and with vaginal hysterectomy in 200 normal weight women (BMI < 25). Time for vaginal hysterectomy was slightly but significantly longer in the morbidly obese compared to those of normal weight, while the abdominal approach was significantly longer in the morbidly obese. Hospital stay was significantly longer for the abdominal operations in the obese. Surgical and anesthetic complications did not differ. In the absence of specific contraindications for vaginal hysterectomy it is recommended that the surgeon should perform hysterectomy vaginally and consider obesity as a contraindication for taking the abdominal route. PMID- 20199360 TI - A randomized controlled trial of 24-hour vaginal dinoprostone pessary compared to gel for induction of labor in term pregnancies with a Bishop score < or = 4. AB - OBJECTIVE: To compare 24-hour controlled-release vaginal dinoprostone pessary vs. gel for induction of labor at term in women with an unfavorable cervix. DESIGN: Randomized controlled trial. SETTING: University hospital. POPULATION: A total of 133 women with singleton pregnancies, fetal cephalic presentation, Bishop score < or = 4, gestational age of 37-42 weeks, no previous cesarean section and intact membranes admitted for induction of labor. METHODS: Random allocation to either 24-hour 10-mg controlled-release vaginal dinoprostone pessary or repeat doses of 2 mg vaginal dinoprostone gel. MAIN OUTCOME MEASURES: Rate of spontaneous vaginal, operative vaginal and cesarean delivery. RESULTS: The rate of spontaneous vaginal delivery was significantly higher in the pessary group (72%) than in the gel group (54%), paralleled by a lower rate of operative vaginal deliveries (3 vs. 15%). The difference in cesarean section rate (25 vs. 31%) did not reach statistical significance. Both methods of induction of labor appeared to be safe, with no cases of 5-minute Apgar scores < 7 or episodes of uterine hyperstimulation in either group. The medication cost was lower in the pessary group, with a median saving of 50.20 euro compared to the gel group. CONCLUSIONS: Both the 24-hour dinoprostone vaginal pessary and the vaginal gel appear to be safe for labor induction. In women induced at term with a Bishop score < or = 4 the pessary achieved a significantly higher rate of spontaneous vaginal delivery. PMID- 20199361 TI - Denial of smoking-related risk among pregnant smokers. AB - OBJECTIVE: To examine pregnant women's denial of risk, tobacco dependence and their partner's smoking status on smoking behavior during pregnancy. DESIGN: Cross-sectional design with convenience sampling. SETTING: Data collection was carried out in hospitals and antenatal clinics in Budapest and 12 other Hungarian cities. POPULATION OR SAMPLE: A total of 406 adult pregnant women (mean age: 28.2 years; SD = 5.6) with a mean gestational age of 23.3 weeks ranging from 4 to 40 (SD = 8.9). METHODS: Pregnant women were enrolled in the study by midwives and home-care attendants. MAIN OUTCOME MEASURES: Smoking status was assessed by self report questions. Further measures included the Fagerstrom Test of Nicotine Dependence to assess nicotine dependence, and the Wisconsin Inventory of Smoking Dependence Motives to assess the motivational background of smoking. Risk perception was assessed by Haslam and Draper's (2000) 12-item risk perception questionnaire. RESULTS: Prevalence of occasional and daily smokers was 21.7 and 29.3%, respectively. Some 59.7% of the pregnant women have a partner who smokes. Daily smokers had a higher level of risk denial than occasional or non-smokers (Welch F = 91.607; p < 0.001). Current smokers also had a higher denial than temporary quitters (t = -3.153; p = 0.003). Denial of risk correlated significantly with nicotine dependence (r = 0.30) and the main motivational factors (r = 0.34-0.48). A multinomial logistic regression model of denial of risk concurrently predicted women's smoking status (p = 0.001), even when controlling for age, education, partner's smoking status and parity. CONCLUSIONS: A higher level of risk denial seems to be one of the major determinants of women's smoking status during pregnancy. PMID- 20199358 TI - Prolyl 4-hydroxylase. AB - Posttranslational modifications can cause profound changes in protein function. Typically, these modifications are reversible, and thus provide a biochemical on off switch. In contrast, proline residues are the substrates for an irreversible reaction that is the most common posttranslational modification in humans. This reaction, which is catalyzed by prolyl 4-hydroxylase (P4H), yields (2S,4R)-4 hydroxyproline (Hyp). The protein substrates for P4Hs are diverse. Likewise, the biological consequences of prolyl hydroxylation vary widely, and include altering protein conformation and protein-protein interactions, and enabling further modification. The best known role for Hyp is in stabilizing the collagen triple helix. Hyp is also found in proteins with collagen-like domains, as well as elastin, conotoxins, and argonaute 2. A prolyl hydroxylase domain protein acts on the hypoxia inducible factor alpha, which plays a key role in sensing molecular oxygen, and could act on inhibitory kappaB kinase and RNA polymerase II. P4Hs are not unique to animals, being found in plants and microbes as well. Here, we review the enzymic catalysts of prolyl hydroxylation, along with the chemical and biochemical consequences of this subtle but abundant posttranslational modification. PMID- 20199362 TI - Male fetal sex is associated with earlier onset of placental abruption. AB - OBJECTIVE: Placental abruption is an important cause of preterm birth, and perinatal morbidity and mortality. Although more common with male fetuses, outcomes have not been evaluated by sex. Our aim was to find out whether short term morbidity differs by infant sex in cases with placental abruption and in controls. DESIGN: Register-based case-control study. SETTING: National Hospital Discharge Register and Medical Birth Register data 1987-2005. POPULATION: The study population consisted of 4,081 women with placental abruption and singleton infant. Three control women without placental abruption were selected for each case matched by maternal age, parity, year of birth, and hospital district. A total of 3,688 cases and 12,695 controls had liveborn infants. METHODS: Data on pregnancy, delivery, and perinatal outcomes were collected. MAIN OUTCOME MEASURE: Placental abruption. RESULTS: The sex ratio (proportion of male) of cases was 0.548 and of controls 0.516 (p = 0.001). Compared with females, male fetuses in the placental abruption group were born earlier (p = 0.018). Compared with controls, cases with placental abruption were born earlier (p < 0.001), had lower birthweight (p < 0.001), were more often growth restricted (p < 0.001), had lower Apgar scores (p < 0.001) and pH (p < 0.001). Newborn cases needed special care, respirator treatment, antimicrobial and phototherapy more often (p < 0.001) than controls. There was no difference in perinatal outcomes between female and male infants in the placental abruption group. CONCLUSIONS: Placental abruption occurred earlier in pregnancy with male fetal sex but otherwise the outcomes were similar. Compared with controls newborns in the placental abruption group had a worse outcome. PMID- 20199363 TI - Role of ischemic preconditioning in liver transplant: a review of literature. AB - Interruption of blood flow and subsequent organ reperfusion lead to significant tissue damage. This well-studied phenomenon is recognized as ischemia/reperfusion injury. Ischemic preconditioning refers to a mechanism in which a prior, short, ischemic period induces some protection against a subsequent prolonged ischemic and reperfusion damage. The mechanisms involved in ischemic preconditioning and its applications for clinical and basic research are discussed in this paper. PMID- 20199364 TI - Effect of liver transplant on pulmonary functions in adult patients with alpha 1 antitrypsin deficiency: 7 cases. AB - OBJECTIVES: Alpha 1 antitrypsin (A1A) is a 52 kD glycoprotein that is mainly synthesized in the liver. As a major protease inhibitor, it binds to and neutralizes neutrophil elastase, thereby limiting the damage to the normal tissues after an inflammatory response. A deficiency in A1A leads to end-stage liver disease, both in children and in adults. In addition, the deficiency also has a detrimental effect in the lungs of the adult population. Alpha 1 antitrypsin deficiency is corrected with hepatic replacement; however, the changes in pulmonary functions have not been studied before and after liver transplant. The purpose of this study was to observe the changes in the pulmonary functions of patients who underwent liver transplant for the treatment of A1A deficiency. MATERIALS AND METHODS: Nine patients underwent liver transplant for A1A deficiency. Seven patients (5 men, 2 women; mean age, 49.95 -/+ 7.09 years) had their pulmonary function tests available before the liver transplant (mean, 5.6 -/+ 3.4; range, 0.9-10.1 months) and after the liver transplant (mean, 30.3 /+ 18.4, range 7.8-48.1 months) for analysis. RESULTS: The mean, preliver, transplant, FEV1 was 2.69 -/+ 0.9 L, which was nearly unchanged after the liver transplant to a mean of 2.7 -/+ 1.2 L. During the mean total interval of nearly 3 years, an estimated decline of 250 mL in FEV1 was expected. CONCLUSIONS: It appears from the results of our study that liver transplant probably prevented the progression of pulmonary disease in A1A-deficient patients. Further study and close, postliver, transplant follow-up is warranted to support our initial findings. PMID- 20199365 TI - Neuromuscular complication after liver transplant in children: a single-center experience. AB - OBJECTIVES: Neurologic complications are a significant cause of morbidity in children after liver transplant. In this study, we sought to evaluate the neurologic complications in children after liver transplant. MATERIALS AND METHODS: All children aged younger than 18 years old who had undergone liver transplant between June 2004 and June 2007 were included in this prospective study. There were 30 boys (62.5%) and 18 girls (37.5%) (mean age, 9.6 -/+ 4.3 years; mean duration of follow-up, 21.6 -/+ 9.4 months). The most common indications for liver transplant were biliary atresia (n=12, 25%), Wilson disease (n=7, 14.6%), tyrosinemia (n=7, 14.6%), progressive familial intrahepatic cholestasis (n=6, 12.5%), and autoimmune cirrhosis (n=5, 10.4%). RESULTS: Immunosuppressive medication consisted tacrolimus (n=44, 91.7%) or cyclosporine (n=4, 8.3%) combined with mycophenolate mofetil (n=33, 68.7%) and prednisolone (n=18, 37.5%). The most-common neurologic complications were tremor (n=8, 16.7%), convulsions (n=6, 12.5%), insomnia (n=6, 12.5%), headache (n=5, 10.4%), muscle cramps (n=5, 10.4%), paresthesia (n=3, 6.2%), and weakness (n=3, 6.2%). CONCLUSIONS: We conclude that the most-common neurologic complication after liver transplant in children in contrast to other studies is tremor, same as adult patients. This may be due to higher rate of use of tacrolimus in our patients. PMID- 20199366 TI - Conversion of cyclosporine to sirolimus before 12 months is associated with marked improvement in renal function and low proteinuria in a South African renal transplant population. AB - OBJECTIVES: Avoidance of calcineurin inhibitor-associated nephrotoxicity has recently gained focus. To assess the impact of the conversion to sirolimus, we performed a retrospective audit on renal transplant patients switched to sirolimus at the Inkosi Albert Luthuli Central Hospital (South Africa) from 2003 until June 2007. MATERIALS AND METHODS: Medical records of transplant recipients were analyzed. Twenty-four-hour urine protein excretion and estimated glomerular filtration rates before initiation of sirolimus (baseline), and at their last clinic visit, were compared. Patients were then subcategorized according to their specific indications for switching to sirolimus. RESULTS: Thirty patients were included. Average follow-up was 25 months. Indications for use of sirolimus were group 1 (cyclosporine-induced biochemical toxicity, n=6); group 2 (chronic allograft nephropathy, n=6); group 3 (severe gum hypertrophy, n=9); group 4 (posttransplant diabetes, n=4); group 5 (calcineurin-inhibitor-induced histologic nephrotoxicity, n=2); and group 6 (calcineurin inhibitor-associated malignancy, n=3). Average urine protein excretion rate and estimated glomerular filtration rate before starting sirolimus were 0.44 -/+ 0.08 g/24 h and 50.1 -/+ 3.1 mL/min respectively, compared to 0.94 -/+ 0.2 g/24 h and 52.1 -/+ 4.8 mL/min, at an average follow-up of 25 months. On subgroup analysis, estimated glomerular filtration rate was increased/unchanged in groups 1 (47.3 vs 51.16 mL/min) and 4 (60.0 vs 60.0 mL/min) when compared to baseline, but decreased in groups 2 (47 vs 27.6 mL/min), 3 (51.3 vs 42.2 mL/min), 5 (54.0 vs 29.5 mL/min), and 6 (60.0 vs 56.5 mL/min). Combining the latter 2 groups, most patients (80%) received sirolimus within 1 year of transplant, whereas only 2 patients in the former groups (10%) received the drug within 1 year of transplant. CONCLUSIONS: Overall, sirolimus therapy was associated with improved estimated glomerular filtration rate, and also an increase in urine protein excretion rates. Maximum benefit was achieved when patients were switched to sirolimus within the first transplant year. PMID- 20199367 TI - Impact of rituximab therapy on response to tetanus toxoid vaccination in kidney transplant patients. AB - OBJECTIVES: Rituximab is used after kidney transplant to prevention or treat kidney-allograft rejection. However, the impact of rituximab on the ability of patients to respond to tetanus toxoid vaccination has not yet been studied. MATERIALS AND METHODS: The response to tetanus toxoid vaccination was analyzed in 39 kidney transplant recipients immunosuppressed by corticoids, antiproliferative agents, and/or calcineurin inhibitors. Thirteen patients had previously received rituximab (group 1), 26 patients had not (group 2). Response to control bacterial antigens and immunologic parameters (lymphocyte count, B-cell subsets, serum immunoglobulin level) were analyzed before and at 1 month after vaccination. Thirty healthy blood donors were used as controls for the before-vaccination immunologic parameters. RESULTS: Before vaccination, neither patient group differed from controls in serum levels of immunoglobulins and antibodies against bacterial antigens, but they did display lower levels of CD4 T cells and B cells compared with controls. Responders to the tetanus toxoid vaccination were slightly fewer in group 1 (4/13) than in group 2 (16/26), but the intensity of the anti-tetanus toxoid response was not significantly different between these 2 groups. None of the parameters studied at the time of vaccination (anti-tetanus toxoid level, peripheral B or CD4 T-cell count, memory B-cell subsets, treatment with rituximab, time since transplant) were associated with an ability to respond to vaccination. The ability to respond to vaccination and graft outcomes were not correlated in each patient group. CONCLUSIONS: Rituximab impaired the secondary immune response after tetanus toxoid vaccination, but did not abolish it in all patients. PMID- 20199368 TI - Family history of diabetes as a new determinant of insulin sensitivity and secretion in patients who have undergone a simultaneous pancreas-kidney transplant. AB - OBJECTIVES: We used homeostasis model assessment to investigate insulin sensitivity and secretion after a simultaneous pancreas-kidney transplant or kidney transplant alone. In that model, fasting plasma glucose and C-peptide levels are used to evaluate insulin sensitivity and beta-cell function. MATERIALS AND METHODS: Factors (eg, age, sex, race, delayed kidney allograft function) were correlated with homeostasis model assessment of beta-cell function and homeostasis model assessment of insulin sensitivity values after simultaneous pancreas-kidney transplant (n=89) or kidney transplant alone (n=68), and the results were compared with those in healthy subjects (n=49). RESULTS: Homeostasis model assessment of beta-cell function values were similar in patients who underwent kidney transplant alone or a simultaneous pancreas-kidney transplant, and were higher than homeostasis model assessment of beta cell function values in healthy subjects. The homeostasis model assessment of insulin sensitivity showed intermediate values for patients who underwent a simultaneous pancreas-kidney transplant and correlated with prednisone dosages (in those who underwent kidney transplant alone) and tacrolimus levels (in patients who underwent a simultaneous pancreas-kidney transplant). Homeostasis model assessment of beta-cell function values correlated with prednisone dosages in both groups and with tacrolimus levels in only those who underwent a simultaneous pancreas-kidney transplant. The body mass index of subjects who underwent kidney transplant alone correlated with both homeostasis model assessment of beta-cell function results and homeostasis model assessment of insulin sensitivity results. A family history of diabetes in subjects who underwent a simultaneous pancreas-kidney transplant correlated with homeostasis model assessment of beta-cell function results and homeostasis model assessment of insulin sensitivity results. CONCLUSIONS: Immunosuppressive regimen and body mass index were linked with reduced insulin sensitivity after kidney transplant. A family history of diabetes was linked with higher values of insulin secretion and lower insulin sensitivity in patients who underwent a simultaneous pancreas-kidney transplant. PMID- 20199369 TI - Oxidative stress status in renal transplant recipients. AB - OBJECTIVES: Despite the demonstration of oxidative stress in patients with end stage renal disease, the oxidative status during and after a renal transplant are not completely understood. Hepatocyte growth factor is reported to act as an endogenous factor against oxidative stress. The aim of this study was to evaluate the pattern of changes in plasma oxidative status and hepatocyte growth factor levels in living-donor renal transplant recipients during the early phase after transplant. MATERIALS AND METHODS: Nineteen patients who underwent a renal transplant were included. All were on cyclosporine-based immunosuppression. Plasma levels of malondialdehyde, ferric reducing activity, hepatocyte growth factor, vitamin E, erythrocyte glutathione, and superoxide dismutase activities were determined before, and on the second, seventh, and 12th days after the transplant. RESULTS: High malondialdehyde concentration and low superoxide dismutase activity were seen before and 48 hours after transplant compared with healthy subjects. Significant reductions in plasma ferric reducing activity, malondialdehyde, and hepatocyte growth factor were seen on the seventh and twelfth days after transplant, compared with the before-transplant data. Direct correlations were found between hepatocyte growth factor levels and ferric reducing activity of plasma as well as hepatocyte growth factor and creatinine or uric acid. CONCLUSIONS: Renal transplant recipients display persistent oxidative stress during the early phase of transplant. The pattern of oxidative changes should be considered for appropriate time, dosage, type, and the duration of antioxidant therapy in these patients. PMID- 20199370 TI - Renal transplant outcome after endoscopic treatment of vesicoureteral reflux using the subureteric injection of calcium hydroxyapatite. AB - OBJECTIVES: To evaluate the results of end-stage renal failure in transplanted cases due to vesicoureteral reflux after a subureteric injection of calcium hydroxyapatite (Coaptite). MATERIALS AND METHODS: Twenty-three patients (39 renal units) with end-stage renal failure secondary to vesicoureteral reflux were included. Reflux was bilateral in 16 cases and unilateral in 7 of the cases. There were 3 degrees of reflux according to the distribution of renal units. They were low-grade reflux (grades 1 and 2; n=10); medium-grade reflux (grade 3; n=23); and high-grade reflux (grades 4 and 5; n=6). RESULTS: Reflux resolved completely in 17 patients (28 renal units; 71.8%). There was a regression to grade 1 in 3 patients (5 renal units; 12.8%). Twenty-one patients underwent renal transplant; however, 2 of the patients were excluded from the study as it was not possible to monitor them after transplant. Within an approximately 18.6 month follow-up (range, 3-36 months), 1 of the cases had acute, and 3 of the cases had chronic rejection. CONCLUSIONS: Successful results can be achieved in reflux treatment by an injection of subureteric calcium hydroxyapatite before transplant in patients with end-stage renal failure that developed secondary to vesicoureteral reflux. PMID- 20199371 TI - Trauma does not aggravate deleterious effects of ischemia reperfusion injury on the lung. AB - OBJECTIVES: Our purpose was to investigate the effects of ischemia-reperfusion injury on traumatized lungs. MATERIALS AND METHODS: Twenty-four Wistar rats were used in the study. Rats were randomly divided into 4 groups. In the control group (group 1), only anesthesia and ventilation were used. In group 2, only lung ischemia-reperfusion injury was instituted. In group 3, only blunt chest trauma was instituted. And in group 4, lung ischemia reperfusion injury, consisting of 24 hours after the constitution of blunt chest trauma, was used. Lung damage and systemic inflammation parameters were evaluated. RESULTS: All parameters (alveolar degeneration grades, alveolar macrophage and lymphocyte counts, antioxidant enzyme activities, cytokine levels, and bronchoalveolar lavage fluid albumin level) were higher in all groups than they were in the control group (P < .05). Only tissue malondialdehyde, tissue interleukin-8, and serum glutathione peroxidase levels were significantly higher in the lung ischemia-reperfusion group than they were in the trauma group (P < .05). The trauma + ischemia reperfusion group showed no significant difference when compared with the only ischemia-reperfusion or only trauma groups in any parameters (P > .05). CONCLUSIONS: The findings showed that lung trauma does not aggravate the deleterious effects of lung ischemia-reperfusion injury. PMID- 20199372 TI - An ex-vivo model for hypothermic pulsatile perfusion of porcine pancreata: hemodynamic and morphologic characteristics. AB - OBJECTIVES: Hypothermic machine perfusion is a well-established preservation method for kidneys that allows for better preservation over longer periods and pretransplant assessment of graft viability. This technique has only sporadically been used for pancreatic grafts. The aim of this study was to establish a hypothermic machine perfusion model for porcine pancreas perfusion. MATERIALS AND METHODS: Fifteen porcine pancreata were subjected to 25 minutes of warm ischemia and 149 minutes of cold ischemia before undergoing meticulous bench work preparation and perfusion, via an aortic segment, on the RM3 perfusion machine with University of Wisconsin (Barr Laboratories Inc., Pomona, NY, USA) solution. Perfusion variables (degrees C, temperature; mm Hg, systolic perfusion pressure; mL/min, flow volume; mm Hg/mL/min, resistance) were recorded every 30 minutes. Tissue samples were assessed for each pancreas preperfusion and postperfusion using a semiquantitative scoring scale to grade histopathologic changes: acinar cell damage (0-4), islet cell damage (0-3), inflammation (0-3), and edema (0-3). RESULTS: Hypothermic machine perfusion time was set at 315 minutes, and all grafts were maintained between 4-10 degrees C. The results were as follows (range, mean -/+ SD): systolic perfusion pressures were 5-13 mm Hg (9.61 -/+ 3.25 mm Hg) during the first 60 minutes (priming), and 15-23 mm Hg (21.07 -/+ 4.26 mm Hg) during the maintenance period. Target flow volumes reached 141-152 mL/min (147.6 -/+ 8.969 mL/min) at 60 pulses per minute. Intrapancreatic resistance decreased throughout priming to 0.03-0.09 mm Hg/mL/min (0.083 -/+ 0.042 mm Hg/mL/min), and remained unchanged until completion of perfusion. Pancreatic weight increase varied from 3.2% to 18.3% (13.36% -/+ 4.961%). There was significant postperfusion reduction in islet and acinar cell damage (P = .001 and P = .01 respectively). CONCLUSIONS: We have developed a model of machine perfusion for porcine pancreata which is simple, reliable, and protects graft histopathologic integrity. The model can be used in further studies to improve the quality of pancreas preservation, and assess and improve the viability of the condition of borderline pancreatic grafts. PMID- 20199373 TI - Results of hematopoietic stem cell transplant in Shiraz: 15 years experience in southern Iran. AB - OBJECTIVES: Over the past 2 decades, hematopoietic stem cell transplant has evolved from an experimental procedure to the standard of care, and it is integrated into the management of many diseases. Hematopoietic stem cell transplant was established at Shiraz University of Medical Sciences in 1993. Here, we describe 15 years experience with stem cell transplant at our center in southern Iran. We provide information on indication, donor type, conditioning chemotherapy regimen, outcome, survival, and long-term follow-up in our stem cell activity. PATIENTS AND METHODS: From May 1993 to October 2008, 423 patients underwent allogeneic (n=311) and autologous (n=112) stem cell transplants at our center. For allogeneic stem cell transplant, the conditioning chemotherapy regimen comprised busulfan, cyclophosphamide, and antithymocyte globulin for thalassemic patients; busulfan and cyclophosphamide for leukemia patients; and cyclophosphamide and antithymocyte globulin for patients with aplastic anemia. RESULTS: During this period, 155 B-thalassemia major patients (mean age, 9.5 years; range, 2-20 years) underwent allogeneic marrow transplant. Of 155 patients with a diagnosis of thalassemia major, 112 are alive (72%) with full engraftment after a median follow-up of about 8.1 years (range, 12-184 months). During this time, 127 leukemia patients including acute myelogenous leukemia (n=68), acute lymphoblastic leukemia (n=30) and chronic myelogenous leukemia (n=29), received allogeneic stem cell transplant. In this group, long-term, disease-free survival (cure rate) was 67%, 60%, and 62%. CONCLUSIONS: These data reflect the important role of hematopoietic stem cell transplant in improving survival for a variety of hematopoietic system disorders at our center in Southern Iran. In patients with B thalassemia major hematopoietic stem cell transplant seems to be the treatment of choice, because it leads to a cure in all classes (Lucarelli risk group, I-III). Based on high success rates in patients with class II and III thalassemia with the addition of the antithymocyte globulin to conditioning regimen of stem cell transplant, we also recommend using this new method of conditioning in transplant of thalassemia patients. PMID- 20199374 TI - Comparison of peripheral blood stem cell transplant with bone marrow transplant in class 3 thalassemic patients. AB - OBJECTIVES: This study aimed to compare outcome of bone marrow transplant with peripheral blood stem cell transplant in class 3 thalassemic patients. MATERIALS AND METHODS: Respectively, 32 and 20 class 3 thalassemic patients received bone marrow transplant and peripheral blood stem cell transplant from human leukocyte antigen identical sibling donors. Conditioning regimen consisted of busulfan (16 mg/kg) and cyclophosphamide (160 mg/kg) followed by cyclosporine and methotrexate as graft-versus-host disease prophylaxes. RESULTS: Median time to absolute neutrophil count was significantly shorter in the peripheral blood stem cell transplant group (12 vs 23 days); however, there was no significant difference regarding platelet recovery between the 2 groups (20 vs 28 days). Acute graft versus-host disease occurred in 47% of patients. Chronic graft-versus-host disease developed in 28% of patients which was significantly higher in the peripheral blood stem cell transplant group (P = .06). During 50 months follow up, thalassemia recurrence, overall survival, and thalassemia-free survival were 17%, 80%, and 65%, respectively, and there were no significant differences between the 2 groups. CONCLUSIONS: These results showed that stem cell transplant is an effective treatment in class 3 thalassemic patients with the outcome relatively similar to bone marrow transplant. Although engraftment time is shorter in peripheral blood stem cell transplant method, it is associated with higher rate of chronic graft-versus-host disease. PMID- 20199375 TI - Horseshoe kidneys: an underutilized resource in kidney transplant. AB - OBJECTIVES: Although the number of patients awaiting renal transplant is rapidly increasing, the donor pool has remained relatively stable. Horseshoe kidneys, a common renal fusion anomaly, can provide a useful solution to the ever increasing gap between supply and demand. MATERIALS AND METHODS: These kidneys can be transplanted, en bloc, into a single recipient or divided and transplanted into 2 recipients. RESULTS: We report 2 cases of successful kidney transplants. CONCLUSIONS: The first is a split horseshoe kidney, transplanted into a single recipient, and the second, a horseshoe kidney from a donor after cardiac death split and transplanted into a single recipient. The second case is the first reported case of a horseshoe kidney transplant from a donor after cardiac death. We also performed a review of the literature of horseshoe kidneys with the hope of raising awareness of the necessity and promise of such transplants. PMID- 20199376 TI - Heart transplant in a childhood leukemia survivor: a case report. AB - OBJECTIVES: Children with acute leukemia often receive therapy that is potentially cardiotoxic. Development of irreversible cardiac impairment requiring heart transplant may appear many years after anticancer therapy. Other possible causes are discussed. MATERIAL AND METHODS: We describe a young leukemia survivor who developed severe heart failure needing a heart transplant. RESULTS: A 4-year old boy was treated with standard doses of chemotherapy containing cardiotoxic daunorubicin and mitoxantrone, and later, with an allogeneic bone marrow transplant. Twelve years after the diagnosis of acute myeloid leukemia, and following a viral infection of an unknown cause, he developed symptoms of heart failure. Severe dilated cardiomyopathy; and severe, left ventricular dysfunction with ejection fraction of 12% were noted on echocardiography. The patient required a heart transplant 19 years after the diagnosis of leukemia. CONCLUSIONS: Cardiac failure may progressively occur in childhood leukemia survivors. Heart transplant is indicated in patients with refractory hemodynamic decompensation. PMID- 20199377 TI - High-density lipoprotein: key molecule in cholesterol efflux and the prevention of atherosclerosis. AB - Accumulation of cholesterol by macrophages, leading to their transformation into foam cells is a key event in the initiation of atherosclerosis. As maintenance of cholesterol homeostasis in macrophages is essential to prevent foam cell formation, mechanisms by which macrophages export cellular cholesterol have been intensively investigated in recent years. Several epidemiological studies have shown that plasma levels of high-density lipoprotein (HDL) cholesterol are inversely correlated with the risk of atherosclerosis. The protective effect of HDL against macrophage foam cell formation and atherosclerosis is primarily attributed to its role in reverse cholesterol transport (RCT), a process by which excess cholesterol in peripheral tissues is transported to the liver for excretion. The present review discusses current knowledge on the biological activities of the major apolipoproteins, enzymes, lipid transfer proteins, receptors, and lipid transporters associated with HDL function and levels. In addition, current views on the molecular mechanisms underlying the atheroprotective functions of HDL beyond promotion of RCT, including the anti oxidant, anti-thrombotic, anti-inflammatory and anti-apoptotic properties of HDL are summarized. PMID- 20199378 TI - Microbattery technologies for miniaturized implantable medical devices. AB - Implanted medical devices (IMDs), in particular neuro-stimulators, drug delivery chips and cochlear implants are undergoing miniaturization. Some of these miniaturized IMDs are "active" in the sense that they require a power source for operation. In most cases, the ideal power source needs to be an implanted battery of dimensions similar to that of the device. The state-of-the-art of battery miniaturization is reviewed with emphasis on novel Li and Li-ion two- and three dimensional thin-film microbatteries. It is shown that three-dimensional thin film batteries may provide a solution to the power requirements of miniaturized IMDs. PMID- 20199379 TI - Fiber-optic technologies in laser-based therapeutics: threads for a cure. AB - In the past decade, novel fiber structures and material compositions have led to the introduction of new diagnostic and therapeutic tools. We review the structure, the material composition and the fabrication processes behind these novel fiber systems. Because of their structural flexibility, their compatibility with endoscopic appliances and their efficiency in laser delivery, these fiber systems have greatly extended the reach of a wide range of surgical lasers in minimally invasive procedures. Much research in novel fiber-optics delivery systems has been focused on the accommodation of higher optical powers and the extension to a broader wavelength range. Until recently, CO2 laser surgery, renowned for its precision and efficiency, was limited to open surgeries by the lack of delivery fibers. Hollow-core photonic bandgap fibers are assessed for their ability to transmit CO2 laser at surgical power level and for their applications in a range of clinical areas. Current fiber-delivery technologies for a number of laser surgery modalities and wavelengths are compared. PMID- 20199380 TI - Optical and electrical interfacing technologies for living cell bio-chips. AB - Whole-cell bio-chips for functional sensing integrate living cells on miniaturized platforms made by micro-system-technologies (MST). The cells are integrated, deposited or immersed in a media which is in contact with the chip. The cells behavior is monitored via electrical, electrochemical or optical methods. In this paper we describe such whole-cell biochips where the signal is generated due to the genetic response of the cells. The solid-state platform hosts the biological component, i.e. the living cells, and integrates all the required micro-system technologies, i.e. the micro-electronics, micro-electro optics, micro-electro or magneto mechanics and micro-fluidics. The genetic response of the cells expresses proteins that generate: a. light by photo luminescence or bioluminescence, b. electrochemical signal by interaction with a substrate, or c. change in the cell impedance. The cell response is detected by a front end unit that converts it to current or voltage amplifies and filters it. The resultant signal is analyzed and stored for further processing. In this paper we describe three examples of whole-cell bio chips, photo-luminescent, bioluminescent and electrochemical, which are based on the genetic response of genetically modified E. coli microbes integrated on a micro-fluidics MEMS platform. We describe the chip outline as well as the basic modeling scheme of such sensors. We discuss the highlights and problems of such system, from the point of view of micro-system-technology. PMID- 20199381 TI - MEMS and microfluidics for diagnostics devices. AB - There are conditions in clinical medicine demanding critical therapeutic decisions. These conditions necessitate accuracy, rapidity, accessibility, cost effectiveness and mobility. New technologies have been developed in order to address these challenges. Microfluidics and Micro Electro-Mechanical Systems are two of such technologies. Microfluidics, a discipline that involves processing fluids at the microscale in etched microchannels, is being used to build lab- on a-chip systems to run chemical and biological assays. These systems are being transformed into handheld devices designed to be used at remote settings or at the bedside. MEMS are microscale electromechanical elements integrated in lab chip systems or used as individual components. MEMS based sensors represents a highly developed field with successful commercialized products currently being incorporated into vitro,ex vivo and in vivo devices. In the present paper several examples of microfluidic devices and MEMS sensors are introduced together with some current examples of commercialized products. Future challenges and trends will be discussed. PMID- 20199382 TI - Nanochannel systems for personalized therapy and laboratory diagnostics. AB - Significant recent progress has been made in the development of microfabricated nanofluidic devices for use in the biomedical sciences. Novel nanotechnological approaches have been explored in view of a more individualized medical approach. Much of the development has been fuelled by the advantages derived from utilizing nanoscale phenomena to manipulate fluid samples or mediate drug delivery. As such, we present a comprehensive review of nanochannel technologies, highlighting their potential for diagnostic and therapeutic applications. PMID- 20199383 TI - Biomedical applications of hydroxyapatite nanoparticles. AB - Nanotechnologies have the potential to improve current disease diagnosis due to their ability to circulate in the blood and distribute in the body to image tissues and cells or therapeutical applications to deliver a payload. Among nanoparticles with different materials composition, inorganic nanoparticles composed of calcium phosphate have numerous advantages including ease of synthesis, control of physico-chemical properties, strong interactions with their payload, and biocompatibility. In this review we discuss the different routes of synthesis of calcium phosphate nanoparticles, novel systems, strategies to load agents, biostability and cytotoxicity, biodistribution and pharmacokinetics, bio imaging and therapeutical applications. PMID- 20199384 TI - Can adenoidal hypertrophy be treated with intranasal steroids? AB - Adenoidal hypertrophy is probably the most frequent pathology in the pediatric population. This disorder manifests with several symptoms such as bilateral nasal obstruction, rhinorrhea, cough, snoring, hyponasal speech, hypopnea, and sleep apnea. When tonsillar hypertrophy is also present, obstructive sleep apnea syndrome can manifest. To date, nasal endoscopic examination is the standard technique to diagnose and estimate adenoid mass. Adenoidectomy is considered the surgical treatment of choice to resolve nasopharyngeal obstruction due to adenoidal hypertrophy. At present, several pitfalls of adenotomy (i.e., alteration of the immunological system, postoperative bleeding, and recurrence of adenoids) are object of criticism. For this reason, some researchers have tested the efficacy of topical nasal steroids in decreasing the severity of nasal symptoms and adenoidal mass. Herein, we review the literature on conservative treatments including also our personal experience. PMID- 20199385 TI - A critical reappraisal of off-label indications for topical photodynamic therapy with aminolevulinic acid and methylaminolevulinate. AB - Photodynamic therapy (PDT) with methylaminolevulinate (MAL) has demonstrated high efficacy, minimal side effects, and improved cosmetic outcome in the treatment of its EU-approved clinical indications, i.e. actinic keratoses (AKs), basal cell carcinoma, and Bowen's disease. In addition, PDT with MAL or 5-aminolevulinic acid (ALA) is approved in the US for the treatment of AK. However, besides anti tumoral activity, PDT has also demonstrated various anti-inflammatory and anti infectious effects as well as those on the metabolism of connective tissue, keratinization of normal keratinocytes and maturation processes of sebaceous glands and hair follicles. These findings have expanded the spectrum of possible applications of PDT that now encompasses infectious (viral, bacterial, fungal, protozoal) disorders, epidermal and dermal inflammatory diseases, tumors of lymphocytes, adnexal diseases and premature skin aging due to sun exposure. However, the findings obtained so far must be considered in most off-label indications only preliminary and more detailed studies are required to clarify the role of PDT beyond the treatment of non-melanoma skin cancer. In addition, possible advantages over standard treatments remain to be clarified. PMID- 20199386 TI - Clinical development of selective anticoagulants: a state of the art. AB - Although standard anticoagulation, including heparins and vitamin K antagonists (VKA), is clinically beneficial, several unmet needs remain due to several pharmacokinetic and pharmacodymamic limitations. Selective anticoagulant agents have been developed to overcome the drawbacks associated with both heparins and VKA. Agents selectively targeting factor Xa, IXa and thrombin are alternative anticoagulants in the most advanced phases of clinical development. Compared to traditional anticoagulants these drugs have the potential to be more effective, safer and easier to use and to provide a more predictable dose response, without need for routine monitoring and dose adjustment. This review will summarize the current status of selective anticoagulant drugs, which are already licensed or being evaluated in advanced phases clinical studies for antithrombotic treatment in non-valvular atrial fibrillation, percutaneous coronary intervention and acute coronary syndromes, focusing on design and results of studies in these specific clinical settings. PMID- 20199387 TI - Stable disease in renal cell carcinoma after using signal transduction inhibitors. AB - Malignant solid tumors have been traditionally treated utilizing cytotoxic chemotherapies, which work against rapidly multiplying tumors. The current response evaluation in solid tumor is based on the Response Evaluation Criteria in Solid Tumors (RECIST). This method relies mainly on compufterized tomography (CT scans) and other imaging modalities by which the diameter of tumors is taken into consideration to assess response to therapy. Recent years have witnessed the introduction of a series of new signal transduction inhibitors in the management of metastatic RCC. Stable disease (SD) is more frequently seen with morphologic lesion changes such as, change in attenuation, pattern of intra-tumoral enhancement / necrosis and cavitation, all of which pose a challenge for the investigator in the accurate assessment of response to therapy. This article attempts to introduce the reader to various alternate concepts of monitoring response following biologic therapy and offers a detailed analysis of a few lesions. PMID- 20199388 TI - To seek shelter from the WNT in osteoarthritis? WNT-signaling as a target for osteoarthritis therapy. AB - Recent evidence from animal experiments and clinical samples points at a role for Wnt-signaling in osteoarthritis (OA) pathology. These pathways are key inducers and regulators of joint development, and are involved in formation of bone, cartilage and also synovium. Disregulation of members from this pathways have been described in OA. This makes the Wnt-family of proteins and signaling pathways an attractive target for therapy. Although knowledge is increasing rapidly it is still a challenge to decide on the best approach in targeting Wnt signaling. Activation of the canonical signaling pathway, which features intra cellular accumulation of beta-catenin, is most often implicated in recent studies in OA pathology, in experimental OA and spondyloarthritis. However, direct targeting of beta-catenin is anticipated to be too hazardous, because of its importance for the maintenance of stability of articular chondrocyte phenotype and because of its proven role in carcinogenesis. A more attractive approach will be identifying the misexpression of specific Wnt-proteins or their inhibitors in various tissues that are important in OA, bone, cartilage and synovium, to point out targets for therapy. For example, recently it was shown that Wnt16 is strongly upregulated in cartilage after injury and in synovium in experimental OA, and the expression of this canonical Wnt may be responsible for OA-like changes. Alternatively, identifying more down stream Wnt signaling effector molecules, like WISP-1, for more specific therapy promises to be a safer and more efficient approach to find a treatment for this disease that heavily constrains millions of people each year. PMID- 20199389 TI - Novel therapies in OA. AB - Therapeutic alleviation of the pathophysiology of osteoarthritis (OA) is a great and unmet medical challenge. At the basic science level, significant progress has facilitated the identification of distinct pathways and targets which appear to be central to the OA-associated deterioration of articular cartilage. For example, the dysregulated activities of aggrecanases such as ADAMTS-4 and ADAMTS 5, and collagenases such as MMP-13, point to strategies for the development of selective protease inhibitors to curtail OA disease progression. Likewise, blockade of disease-associated "pro-catabolic" cytokines may offer promising opportunities in this regard. Other novel biotherapeutic approaches are also emerging, including the use of recombinant lubricin molecules for intraarticular supplementation. Expression profiling of cartilage (and other joint tissues) to identify OA-associated genes continues to yield new potential therapeutic options, including the 'upstream' targeting of key intracellular regulators. Moving forward into the clinic, the critical evaluation and optimization of modalities for therapeutic delivery, as well as the availability and utility of appropriate disease biomarkers and ability to determine relevant patient populations, will be other important considerations in directing the advancement of novel OA therapies. PMID- 20199391 TI - Obesity and inflammation--targets for OA therapy. AB - Obesity is one of the main risk factors for osteoarthritis (OA). For many years the association of obesity and OA has been simply attributed to the effects of overload on weight-bearing joints, and epidemiological surveys have shown a strict correlation between an increased body mass index and the severity of knee or hip OA, as well as some relief of pain and disability following weight loss. Instead, there is now a growing body of evidence that obesity is a complex syndrome in which an abnormal activation of neuroendocrine and pro-inflammatory pathways leads to an altered control of food intake, fat expansion and metabolic changes. Activated white adipose tissue increases the synthesis of pro inflammatory cytokines, such as IL-6, IL-1, IL-8, TNFalpha, IL-18, while regulatory cytokines, such as IL-10, are decreased. Adipocytes also produce peculiar cytokines, namely adipokines, that exert multiple effects, being capable of promoting synovial inflammation, cartilage degrading enzymes, and bone matrix remodeling. Furthermore, pro-inflammatory cytokines stimulate adipocytes to synthesize neuropeptides, such as substance P and nerve growth factor, that have been shown to be critical in regulating both the appetite and cartilage homeostasis. In this scenario, where the influence of obesity on OA stems from a complex interaction of genetic, metabolic, neuroendocrine, and biomechanical factors, there may be various different potential targets for OA therapy. PMID- 20199392 TI - Activated synovial macrophages as targets for osteoarthritis drug therapy. AB - The great success of targeted biologic therapy against rheumatoid arthritis (RA) in recent years has meant that much research has been devoted to investigating the pathophysiology of osteoarthritis (OA) in the hope of defining novel therapeutic targets. In contrast to RA, with its pannus and erosions, OA has long been thought of as a degenerative disease of cartilage, with secondary bony damage and osteophytes. But in recent years, the importance of the synovium, and in particular the synovial macrophages, in OA, has been highlighted in both in vitro and in vivo studies. This review will discuss the potential of synovial macrophages and their mediators, in particular the proinflammatory cytokines tumour necrosis factor alpha and interleukin-1, as potential therapeutic targets in OA. PMID- 20199393 TI - Is cartilage matrix breakdown an appropriate therapeutic target in osteoarthritis -insights from studies of aggrecan and collagen proteolysis? AB - Progressive cartilage degradation is considered a hallmark of osteoarthritis (OA), and as such methods to inhibit this process have been extensively investigated as potential disease-modifying therapies. However, all tissues of the joint are affected by disease in OA, and it is likely that the pain and disability which are the major clinical symptoms of OA, arise predominantly from pathology in these extra-cartilaginous structures. It is unclear therefore, whether specifically targeting inhibition of cartilage matrix breakdown will ameliorate global joint pathology and thereby affect the clinically-relevant OA related disability. We have investigated this question by reviewing the literature and data available from studies of genetically-modified (GM) mice. A total of 79 different GM strains were identified in which OA-like cartilage erosion was analysed, 53 with increased, 18 with no change, and 8 with decreased cartilage damage. Inhibition of OA cartilage damage was afforded by mutations that either reduced chondrocyte hypertrophy or abrogated proteolysis of aggrecan and collagen II in cartilage. There was an association between increased cartilage breakdown and changes in subchondral bone, osteophytosis and synovial hyperplasia in GM mice. However, the effect of significantly inhibiting cartilage damage on pathology in other joints tissues has been less well examined. There appeared to be no diminution of osteophyte development in chondroprotected GM mice strains, but a possible reduction in subchondral bone plate changes. To date, there is no conclusive data on the effect of inhibiting cartilage breakdown on clinical signs of OA in GM mice. These studies have highlighted the tremendous advances studies of GM mice have afforded us in understanding the pathophysiology of cartilage degradation in OA. Furthermore they demonstrate the feasibility of targeting cartilage matrix destruction. However, it is evident that an important direction for ongoing research will be to determine the effect of successful protection of cartilage structural integrity on pathology in other tissues in the OA joint, and the clinical signs of the disease. PMID- 20199390 TI - NF-kappaB signaling: multiple angles to target OA. AB - In the context of OA disease, NF-kappaB transcription factors can be triggered by a host of stress-related stimuli including pro-inflammatory cytokines, excessive mechanical stress and ECM degradation products. Activated NF-kappaB regulates the expression of many cytokines and chemokines, adhesion molecules, inflammatory mediators, and several matrix degrading enzymes. NF-kappaB also influences the regulated accumulation and remodeling of ECM proteins and has indirect positive effects on downstream regulators of terminal chondrocyte differentiation (including beta-catenin and Runx2). Although driven partly by pro-inflammatory and stress-related factors, OA pathogenesis also involves a "loss of maturational arrest" that inappropriately pushes chondrocytes towards a more differentiated, hypertrophic-like state. Growing evidence points to NF-kappaB signaling as not only playing a central role in the pro-inflammatory stress-related responses of chondrocytes to extra- and intra-cellular insults, but also in the control of their differentiation program. Thus unlike other signaling pathways the NF-kappaB activating kinases are potential therapeutic OA targets for multiple reasons. Targeted strategies to prevent unwanted NF-kappaB activation in this context, which do not cause side effects on other proteins or signaling pathways, need to be focused on the use of highly specific drug modalities, siRNAs or other biological inhibitors that are targeted to the activating NF-kappaB kinases IKKalpha or IKKbeta or specific activating canonical NF-kappaB subunits. However, work remains in its infancy to evaluate the effects of efficacious, targeted NF kappaB inhibitors in animal models of OA disease in vivo and to also target these strategies only to affected cartilage and joints to avoid other undesirable systemic effects. PMID- 20199394 TI - Intraarticular treatments for osteoarthritis: new perspectives. AB - To date, no targeted treatments for osteoarthritis have been developed. Therefore the challenge for the next years is to find a treatment that may slow down the progression of the disease. Osteoarthritis of the weight-bearing joints, such as knee OA, is more a local mechanical driven disease than a generalized one. To reach a non-vascularised tissue such as the cartilage, local intra-articular administration of drugs should be considered. The purpose of this review is to evaluate the advantages of local intra-articular drug administration compared with a systemic one in patients with osteoarthritis of weight-bearing joints. New perspectives of such strategy are reviewed, including anti-cytokine therapy, gene therapy, delivery of growth factors, stem cells therapy and new lubricant agents such as lubricin. The main goal in the future will be to increase the residence time of the drug in the joint while improving its diffusion within the target tissues. One key question will be how to better define the patients likely to benefit by such an approach and when the treatment is most likely to work. Most importantly, the treatment strategy must be selected according to the pattern in an individual patient. Finally, with all intra-articular treatments, the risk/benefit ratio must be carefully evaluated. PMID- 20199396 TI - Disease modifying osteoarthritis drugs: facing development challenges and choosing molecular targets. AB - Osteoarthritis (OA) is a slowly, progressive, ultimately degenerative disorder of movable joints, mainly characterized by joint pain and functional limitation and affecting all joint structures not just articular cartilage, but also the subchondral bone, ligaments, capsule, synovial membrane, and menisci. OA occurs when the equilibrium between breakdown and repair of the joint tissues becomes unbalanced. There are currently no pharmacological interventions available to patients for modifying the underlying disease (DMOADs) in relation to major drug development challenges. The current regulatory draft guidances for clinical development programs for DMOAD agents suggest radiographic joint space narrowing (JSN) as a primary endpoint. However, research efforts must continue to characterize imaging alternatives with greater sensitivity to change to enable development of new DMOADs. Past experience with DMOAD clinical trials indicate that pharmacologic agents must demonstrate pristine safety, and that consideration for special populations is important to avoid failed studies. More research is needed to determine what constitutes clinically meaningfulness for DMOAD activity in particular as it relates to OA progression. Current research pursues a variety of molecular targets including anti-catabolic agents to slow or halt OA progression and anabolic drugs to induce cartilage re-growth. PMID- 20199395 TI - A pathway and approach to biomarker validation and qualification for osteoarthritis clinical trials. AB - This narrative review outlines the work done in other fields with regards biomarker validation and qualification and the lessons that we may learn from this experience. Defining a universally agreed upon path for biomarker validation and qualification is urgently needed to circumvent many of the hurdles faced in OA therapeutic development irrespective of whether we are discussing biochemical markers, imaging markers or other measures. This review proposes a path that may be suitable for osteoarthritis and poses some logical next steps that will take us in this direction. PMID- 20199397 TI - Targets to tackle--the pathophysiology of the disease. AB - Osteoarthritis, the degeneration of the joints, is the leading source of physical disability with severely impaired quality of life due to pain and loss of joint functioning in industrialized nations. Clinically, degeneration affects mostly the large weight bearing joints of the legs like the hip or the knees, but in principle it can affect any joint of the body. Osteoarthritis represents a disease group with disease subsets that have different underlying pathophysiological mechanisms. Therefore primary osteoarthritis has to be distinguished from secondary forms of the disease, which are due to traumatic events, endocrine or metabolic disorders etc. The enormous frequency of this disease makes osteoarthritis one of the most expensive conditions in the Western world, both in terms of direct as well as indirect costs. So far, despite intensive efforts over several decades, the success of disease-modifying approaches have been rather limited and mostly restricted to analgesis and non pharmacologic therapy (e.g. nonsteroidal anti-inflammatory agents, exercise, and physiotherapy). Joint replacement is still the unsurpassed therapy for the symptomatic relief of advanced and incapacitating OA. It is evident that there is a great need for the development of disease modifying agents in order to improve quality of life as well as to relieve the community of the enormous socio economic burden of the disease. PMID- 20199398 TI - Waiting for action on the osteoarthritis front. PMID- 20199399 TI - Ambulatory blood pressure and diabetes: targeting nondipping. AB - A reduced fall in nocturnal blood pressure (BP) (i.e. non-dipping) has been related to an increase in target organ damage and cardiovascular (CV) events. Numerous studies have shown that non-dipping is highly prevalent in patients with type 1 and 2 diabetes mellitus. In this paper we reviewed recent literature and our personal data on the prevalence and clinical correlates of abnormal diurnal BP rhythm in diabetic patients; in particular we examined the association of this condition with renal, cardiac, and vascular pre-clinical organ damage as well as CV prognosis. A consistent body of evidence based on cross-sectional and longitudinal studies indicates that the lack of the physiologic nocturnal fall in BP may be considered a true clinical trait, a reliable marker of preclinical CV and renal disease and an independent predictor of future CV events. Thus, in the diabetic setting ambulatory BP monitoring (ABPM) should be regarded as a pivotal tool for improving CV risk stratification and therapeutic interventions. PMID- 20199400 TI - Adaptor protein 2 regulates receptor-mediated endocytosis and cyst formation in Giardia lamblia. AB - The parasite Giardia lamblia possesses PVs (peripheral vacuoles) that function as both endosomes and lysosomes and are implicated in the adaptation, differentiation and survival of the parasite in different environments. The mechanisms by which Giardia traffics essential proteins to these organelles and regulates their secretion have important implications in the control of parasite dissemination. In the present study, we describe the participation of the heterotetrameric clathrin-adaptor protein gAP2 (Giardia adaptor protein 2) complex in lysosomal protein trafficking. A specific monoclonal antibody against the medium subunit (gmu2) of gAP2 showed localization of this complex to the PVs, cytoplasm and plasma membrane in the growing trophozoites. gAP2 also co-localized with clathrin in the PVs, suggesting its involvement in endocytosis. Uptake experiments using standard molecules for the study of endocytosis revealed that gAP2 specifically participated in the endocytosis of LDL (low-density lipoprotein). Targeted down-regulation of the gene encoding gmu2 in growing and encysting trophozoites resulted in a large decrease in the amount of cell growth and cyst wall formation, suggesting a distinct mechanism in which gAP2 is directly involved in both endocytosis and vesicular trafficking. PMID- 20199401 TI - Direct repression of Sonic Hedgehog expression in the stomach by Cdx2 leads to intestinal transformation. AB - Shh (Sonic Hedgehog) is a morphogen involved in gastric fundic gland differentiation in the adult. Shh expression is reduced in Helicobacter pylori associated intestinal metaplastic change of the gastric epithelium and mice that lack Shh show intestinal transformation of the gastric mucosa. Similarly, in the stomach of Cdx2 (caudal-type homeobox 2)-transgenic mice, the gastric mucosa is replaced by intestinal metaplastic mucosa. The aim of the present study was to use Cdx2-transgenic mice to investigate: (i) Shh expression in the intestinal metaplastic mucosa of the Cdx2-transgenic mouse stomach; and (ii) the relationship between Shh and Cdx2. We determined that Shh mRNA levels were dramatically reduced in the intestinal metaplastic mucosa of the Cdx2-transgenic mouse stomach compared with the normal (wild-type) mouse stomach. This was not due to hypermethylation of the Shh promoter, but instead we showed that Cdx2 directly bound to the TATA box region of the Shh promoter. Cdx2 also down regulated transcription of the Shh gene in the human gastric carcinoma cell lines AGS, MKN45 and MKN74. In conclusion, Cdx2 reduced Shh expression by binding to the unmethylated Shh promoter in the intestinal metaplastic mucosa of Cdx2 transgenic mouse stomach. PMID- 20199402 TI - Effect of standardized skin care regimens on neonatal skin barrier function in different body areas. AB - The effect of topical skin care products on neonatal skin barrier during first 8 weeks of life has not been scientifically evaluated. In a prospective, randomized clinical study, we compared the influence of three skin care regimens to bathing with water on skin barrier function in newborns at four anatomic sites. A total of 64 healthy, full-term neonates (32 boys and 32 girls) aged <48 hours were randomly assigned to four groups receiving twice-weekly: WG, bathing with wash gel (n = 16); C, bathing and cream (n = 16); WG + C, bathing with wash gel plus cream (n = 16); and B, bathing with water (n = 16). Transepidermal water loss, stratum corneum hydration, skin pH, sebum were measured on day 2, week 2, 4, 8 of life on front, abdomen, upper leg, and buttock. Skin condition was scored and microbiologic colonization was documented. After 8 weeks, group WG + C showed significantly lower transepidermal water loss on front, abdomen, and upper leg as well as higher stratum corneum hydration on front and abdomen compared with group B. Similarly, group C showed lower transepidermal water loss and higher stratum corneum hydration on these body regions. Group WG revealed significantly lower pH on all sites compared with group B at week 8. No differences in sebum level, microbiologic colonization and skin condition score were found. Skin care regimens did not harm physiologic neonatal skin barrier adaptation within the first 8 weeks of life. However, significant influence of skin care on barrier function was found in a regional specific fashion. PMID- 20199403 TI - Sunburns, sun protection and indoor tanning behaviors, and attitudes regarding sun protection benefits and tan appeal among parents of U.S. adolescents-1998 compared to 2004. AB - This study presents nationally representative trends (1998-2004) and patterns in skin cancer risk behaviors, including sunburns, sun protection, and indoor tanning behaviors, and attitudes regarding ultraviolet radiation exposure among parents of U.S. adolescents. Data were from the American Cancer Society Sun Surveys I and II, telephone-based random digit dialed cross-sectional surveys of U.S. adolescents and their parents conducted in the summers of 1998 and 2004. Between 1998 and 2004, use of sunscreen, wide-brimmed hats and composite use of three to five behaviors increased significantly; concurrently, indoor tanning use increased significantly and sunburn prevalence changed a little. In 2004, 47% reported summer sunburns and more than half of those received painful sunburns. Parents continued to report low compliance with recommended behaviors; sunscreen use was most frequently reported, but many followed inappropriate application practices. About 13% practiced indoor tanning in the past year. Parents reported high levels of positive attitudes toward sun protection benefit, but at the same time, significant proportions reported positive tan appeal and outdoor sun exposure attitudes. The low rates and mixed progress in safe ultraviolet radiation exposure behaviors demand more attention for primary skin cancer prevention among parents of adolescents that focuses on changing beliefs about tanning appeal and promotes comprehensive ultraviolet radiation exposure protection. PMID- 20199404 TI - The clinical trials supporting benzyl alcohol lotion 5% (Ulesfia): a safe and effective topical treatment for head lice (pediculosis humanus capitis). AB - Benzyl alcohol lotion 5% (BAL 5%) is a non-neurotoxic topical head lice treatment that is safe and effective in children as young as 6 months of age. The safety and efficacy of this pediculicide has been studied in 695 (confirm number) subjects in all phases of clinical development. Scanning electron micrographs (SEM) demonstrated that the active agent appears to stun the breathing spiracles open, enabling the vehicle to penetrate the respiratory mechanism (spiracles), therefore asphyxiating the lice. Initial phase II trials compared this novel product to RID using identical volumes of treatment (4 oz/application) and yielding, almost, identical efficacy. This outcome pointed to the significant importance of completely saturating the hair with the product in order to achieve maximum treatment success. A second phase II trial, which allowed the use of sufficient product to saturate the hair, resulted in 100% efficacy after both 10 and 30 minute treatments. A third phase II trial verified an effective dose. Phase III trials compared BAL 5% to vehicle placebo for two 10-minute applications. It proved to be safe and effective (p < 0.001) for treatment of head lice and is the first FDA-approved non-neurotoxic lice treatment, now available in the United States as Ulesfia lotion. PMID- 20199405 TI - Common wound colonizers in patients with epidermolysis bullosa. AB - One of the major morbidities of patients with epidermolysis bullosa is the tendency to develop chronic wounds, which predisposes them to multiple complications including life-threatening infections, failure to thrive, and squamous cell carcinomas. Chronic wounds frequently become colonized with bacteria, and we sought to identify the most common microorganisms isolated on cultures from patients with epidermolysis bullosa. We conducted a retrospective review of positive wound, nasal, and blood cultures, including bacterial, fungal and viral, in 30 patients with epidermolysis bullosa. Staphylococcus sp., Streptococcus sp., diptheroids, Pseudomonas aeruginosa, and Candida sp. were the most commonly isolated microorganisms in wound cultures from our epidermolysis bullosa patients. Two patients had viral cultures that grew herpes simplex virus type-1. Bacterial colonization of chronic wounds can lead to infections and may also impact wound healing. Results from this study provide data on which to base empiric antibiotic choice in patients with epidermolysis bullosa when needed and may be useful in planning strategies for decolonization and improved wound healing in this population. PMID- 20199406 TI - Infantile myofibromatosis: report of nine patients. AB - Infantile myofibromatosis is a rare fibrous tumor of infancy that can be solitary or multiple. Although most of the cases are limited to the skin, in some instances systemic involvement can be present. Solitary tumors limited to the skin usually present a good prognosis with spontaneous regression. We performed a retrospective observational review of the clinical and pathologic characteristics of nine patients diagnosed as having infantile myofibromatosis, followed during a 10-year period in a Pediatric Dermatology Department. PMID- 20199407 TI - Childhood lichen planus: demographics of a U.S. population. AB - Lichen planus is an inflammatory dermatosis of unknown origin that is relatively uncommon in children. Demographic data for lichen planus of children in the United States are lacking, with most large case reports originating from India, Kuwait, Mexico, and the United Kingdom. We hypothesized that a greater proportion of our pediatric lichen planus patients were African American, an observation not previously documented. A retrospective chart review was performed to investigate characteristics of our pediatric lichen planus patients. The ethnicity of the lichen planus patients was compared with the data for our general patient population. The proportion of African American patients in each group was compared using the chi-squared test. We report 36 children (female to male ratio 2:1) who presented with lichen planus to the pediatric dermatology clinic at Children's Hospital of Wisconsin. Twenty-six (72%) of these patients were African American (OR 9.63, p < 0.0001). A personal or family history of autoimmune disease was present in six (17%) patients. Although there has been no reported racial predominance of lichen planus, we observed lichen planus to occur more commonly in African American children. Interestingly, the incidence of autoimmune disease was higher than has previously been reported. Future studies will confirm or refute these observations and advance our understanding of potential genetic or environmental risk factors for the development of lichen planus. PMID- 20199408 TI - A selective approach to treatment of ulnar polydactyly: preventing painful neuroma and incomplete excision. AB - Ulnar polydactyly is common. The condition is often successfully treated by pediatricians using string (or suture) ligation in the newborn nursery. Patients with ulnar polydactyly or complications of unsuccessful string ligation such as traumatic neuroma may be referred to pediatric dermatologists. In some cases, the condition is better treated surgically. In case of a bony or ligamentous attachment, surgery is required. Additionally, a wide-base-precluding-string ligation would be better treated with surgery to avoid the need for later revision. We present a series of 10 patients (13 hands) in which previous string ligation produced an unsightly incomplete amputation, a tender neuroma, or both. Patients were successfully treated with completion amputation of the residual stump combined with proximal ligation of the supernumerary digital nerves. We advocate a selective approach in the management of this condition. Treatment options should be fully discussed with families prior to proceeding with suture ligation. PMID- 20199409 TI - A newborn with acanthosis nigricans: can it be Crouzon syndrome with acanthosis nigricans? AB - Crouzon syndrome is a craniosynostosis syndrome, characterized by cloverleaf skull, hypertelorism, exophthalmos, external strabismus, parrot-beaked nose, short upper lip, hypoplastic maxilla, and mandibular prognathism. The 5% of individuals with Crouzon syndrome who have pigmentary changes in the skin are said to have Crouzon syndrome with acanthosis nigricans (CAN). Choanal atresia, hydrocephalus and the cranial features of Crouzon syndrome should suggest the diagnosis of CAN even before acanthosis appears. We present a 10-hour-old newborn who presented with bilateral choanal atresia, craniosynostosis and acanthosis nigricans. Molecular tests identified the FGFR3 Ala391Glu substitution confirming the diagnosis of CAN. Of the 35 cases of CAN reported in literature till date, only one child had acanthosis nigricans at birth. This is the first case from India to have been reported with this mutation. PMID- 20199410 TI - Morphea, diabetes mellitus type I, and celiac disease: case report and review of the literature. AB - An 11-year-old girl with a history of diabetes mellitus type I and celiac disease presented with multiple, depressed patches of purple-brown skin on the right lower extremity and central back, with histopathologic features of early morphea. Though morphea may coexist with other autoimmune diseases, its presentation with both diabetes mellitus type I and celiac disease has not yet been described. PMID- 20199411 TI - Lipoatrophic connective tissue panniculitis. AB - Many causes of what was formerly called Weber-Christian and Rothmann-Makai diseases are being clarified as specific forms of panniculitis. Among them, an autoimmune process involving the subcutaneous fat without criteria for another defined disorder coined "connective tissue panniculitis" by Winckelman et al in 1980 has been described. We describe this disease in a 4-year-old boy who presented with multiple subcutaneous inflammatory nodules that extended in an annular fashion, resolved leaving lipoatrophy, with recurrence 8 years later. The histologic findings were consistent with a granulomatous lipophagic panniculitis. We review previous reports and emphasize the limited therapeutic options, chronic evolution, severe esthetic sequelae and possible association with other autoimmune disorders of this uncommon condition. PMID- 20199412 TI - Lymphatic compression by sclerotic patches of morphea: an original mechanism of lymphedema in a child. AB - Lymphedema in children is mostly primary, due to lymphatic hypoplasia. Secondary lymphedema is caused by lymphatic injury or obstruction. We report the case of a child that developed a lymphedema of the left upper and lower extremities, with a simultaneous onset of ipsilateral hemicorporal morphea. We concluded that lymphatic obstruction was due to sclerosis from morphea. This is a unique, rarely reported mechanism of lymphedema. Lymphoscintigraphy revealed attenuated lymphatic flow in the left upper and lower limbs. Systemic corticosteroids were associated with slow improvement in the sclerotic patches. We simultaneously noticed an improvement in the lymphedema of limbs. Repeat lymphoscintigraphy revealed dramatically improved lymphatic function. This case suggests that at least in some cases lymphedema may be caused by morphea. PMID- 20199414 TI - The H syndrome. AB - The H syndrome is a recently defined autosomal recessive genodermatosis caused by mutations in the nucleoside transporter hENT3. It is characterized by cutaneous changes of progressive sclerosis, hyperpigmentation, and hypertrichosis that follow a specific pattern and are associated with multiple systemic manifestations. A case is presented and a brief review is introduced based on the few related reports. PMID- 20199413 TI - Vaccination as a probable cause of incontinentia pigmenti reactivation. AB - We report a female infant with recurrent biopsy-proven vesicobullous incontinentia pigmenti occurring after her 12-month and 18-month immunizations. To our knowledge, incontinentia pigmenti vesicobullous recurrence following immunizations has not been reported. We propose that vaccinations may serve as triggers for incontinentia pigmenti reactivation. PMID- 20199415 TI - Sporadic Blau syndrome with onset of widespread granulomatous dermatitis in the newborn period. AB - Blau syndrome is a dominantly inherited, chronic autoinflammatory disorder characterized by the clinical triad of granulomatous dermatitis, symmetric arthritis, and recurrent uveitis with onset below 4 years of age. It is caused by activating mutations in the nucleotide-binding oligomerization domain 2 (NOD2) gene, previously referred to as CARD15 gene. Noncaseating granulomas in affected tissues are the pathologic hallmark of the condition. We report the lifelong severe disease course in a 14-year-old Caucasian boy with sporadic Blau syndrome. Unusually, granulomatous dermatitis started in the first week of life. Whereas skin involvement faded away spontaneously in subsequent years, polyarthritis and anterior uveitis appeared in the second and third year of life respectively. Mutational analysis of the NOD2 gene revealed a missense mutation (R334W) previously detected in other Blau syndrome pedigrees. With this report, we would like to stress the rare possibility of Blau syndrome in generalized papular rashes of infancy and the importance of histopathologic study for clarification. The finding of early-onset widespread granulomatous dermatitis should prompt eye and joint examination in regular intervals and entail mutational analysis of the NOD2 gene. PMID- 20199417 TI - A case of Michelin tire baby syndrome with a thickened epiglottis. AB - Multiple circumferential skin folds have been reported as part of the Michelin tire baby syndrome (MTBS). There has been a wide spectrum of associated clinical findings reported in children with MTBS. We report a case of MTBS associated with a thickened epiglottis. PMID- 20199416 TI - Chemical scalp burns secondary to the hair highlighting process: clinical and histopathologic features. AB - Hair highlighting procedures are very common throughout the world. While rarely reported, potential adverse events to such procedures include allergic and irritant contact dermatitis, thermal burns, and chemical burns. Herein, we report two cases of female adolescents who underwent a hair highlighting procedure at local salons and sustained a chemical burn to the scalp. The burn etiology, clinical and histologic features, the expected sequelae, and a review of the literature are described. PMID- 20199418 TI - Aicardi-Goutieres syndrome: cutaneous, laboratory, and radiologic findings: a case report. AB - Aicardi-Goutieres syndrome is a primarily autosomal recessive disorder characterized by congenital encephalopathy, basal ganglia calcifications, elevated interferon-alpha in blood and cerebral spinal fluid, and negative studies for intrauterine infections that can mimic the syndrome. Cutaneous manifestations include pernio, photosensitivity, and cutaneous vasculitis. We present a case of Aicardi-Goutieres syndrome to increase awareness of the disorder and its possible relation to systemic lupus erythematosus. PMID- 20199419 TI - Case report--papular xanthoma in a 10-year-old female with abnormal lipid profile. AB - Papular xanthoma is a rare normolipemic xanthomatous skin disease which primarily occurs in adults. While this rare disorder has been documented in children, all but one reported in the literature had a normal lipid profile. We report a 10 year-old girl with multiple papule xanthomas on her face that had an abnormal lipid profile. To our knowledge this is only the second reported case of papular xanthoma in the pediatric population with an abnormal lipid profile. PMID- 20199420 TI - Acquired cutis laxa type II (Marshall syndrome) in an 18-month-old child: a case report. AB - Cutis laxa is a rare disorder resulting from degradation and clumping of elastic fibers in dermis. Type II acquired cutis laxa, shows only cutaneous changes without any systemic involvement. We describe an infant with acquired cutis laxa type II following a generalized inflammatory dermatitis. PMID- 20199421 TI - Verrucous plaques on the hands and feet. PMID- 20199422 TI - Congenital wart-like papules on hands and feet. PMID- 20199423 TI - Sweating nodule on the finger. PMID- 20199424 TI - Nail-patella syndrome with an emphasis on the risk of renal and ocular findings. AB - We describe a 6-year-old girl presenting with nail dysplasia affecting all nails and hands for 2 years. Changes were seen on the ulnar side of the nails. She was assessed for limitation of elbow movements at 3 weeks of age and underwent physiotherapy for thickened biceps tendon. She subsequently developed laxity of knees and ankles, and x-ray revealed absent patellae at 32 weeks. She had behavioral abnormalities and sleep disturbances. X-ray of the pelvis revealed iliac horns, and urinalysis showed 3+ proteinuria. She had mixed hyperlipidemia. Her chromosomal analysis was normal but showed a mutation in the LMX1B gene. She was diagnosed to have Nail-patella syndrome or Hereditary osteo-onychodysplasia (HOOD Syndrome). Her renal imaging was normal, as were her ocular pressures. She is under regular surveillance by a multi-disciplinary team of genetic counselors, orthopedists, rheumatologists and ophthalmologists. She is currently prescribed enalapril, melatonin and simvastatin. PMID- 20199425 TI - Chronic actinic prurigo presenting in an adopted child. AB - In diagnosing actinic prurigo (AP), the patients' ethnic background is very helpful as this condition is associated with very specific ethnic groups. We discuss a patient with an unknown family history who presented with a rash that initially seemed like lupus, but was subsequently diagnosed as AP upon further evaluations. PMID- 20199426 TI - Cutaneous alternariosis in an adolescent patient. AB - Cutaneous alternariosis is a rare infection typically observed only in immunocompromised adults, but we report here that the infection can occur in apparently healthy adolescents. We saw a clinically healthy adolescent boy who presented with cutaneous alternariosis 6 weeks after suffering a laceration to his right ankle. Treatment with itraconazole resulted in significant improvement after 1 month. PMID- 20199427 TI - Woolly hair nevus with an ipsilateral associated epidermal nevus and additional findings of a white sponge nevus. AB - We report a case of a 16-year-old male with a woolly hair nevus, an associated ipsilateral epidermal nevus who also had a white plaque on his tongue, clinically diagnosed as a white sponge nevus. The concurrent findings of a white sponge nevus, a woolly hair nevus, and an ipsilateral epidermal nevus, to our knowledge, have not been previously reported. PMID- 20199428 TI - Childhood lichen sclerosus: a long-term follow-up. AB - Lichen sclerosus (LS) shows a predilection for the genital area and occurs mostly in postmenopausal women and in prepubertal girls. We conducted a retrospective review of 15 young girls whit genital LS with onset before the menarcheal age and treated with topical clobetasol propionate 0.05%. The mean duration of follow-up was 4.7 years with relapses in nine patients after approximately 1 year from the first clearing. At the end of the study we observed that (i) potent topical steroids are safe and effective in childhood, (ii) an early aggressive treatment gives the best therapeutic response, (iii) one follow-up visit a year is required to monitor for relapsing. PMID- 20199429 TI - Reactions to Aquaphor: is bisabolol the culprit? AB - Bisabolol is a sesquiterpene alcohol compound derived from the German chamomile plant, a member of the Compositae family. Only two case reports of adults with allergic contact dermatitis to this chemical exist in the literature, and we describe three more cases of children with recalcitrant atopic dermatitis found to have potential allergic contact dermatitis to bisabolol- a component of the Aquaphor emollient they were using to treat their atopic dermatitis. Of note, Compositae dermatitis has been shown to have a higher prevalence in children with atopic dermatitis, so it is important for physicians to be aware of the potential allergens (like bisabolol) in products they are recommending as first line treatments. PMID- 20199430 TI - Lupus erythematosus-like lesions by voriconazole in an infant with chronic granulomatous disease. AB - We report the first case of lupus-like lesions in an infant with chronic granulomatous disease during the treatment with voriconazole for chronic invasive aspergillosis. The lesions disappeared with termination of the treatment. PMID- 20199431 TI - A novel splice site mutation in the EDAR gene underlies autosomal recessive hypohidrotic ectodermal dysplasia in a Pakistani family. AB - Hypohidrotic ectodermal dysplasia is a rare congenital disorder that results in abnormalities in the structures of ectodermal origin: hair, teeth, and eccrine sweat glands. DNA sequence analysis of EDAR gene in a Pakistani family, demonstrating autosomal recessive form of hypohidrotic ectodermal dysplasia, identified a novel homozygous mutation affecting splice donor site of exon 5 [IVS5+1G > or = C] of the gene. PMID- 20199432 TI - Chronic urticaria and celiac disease: a case report. AB - We describe a case of a 9-year-old girl who presented chronic urticaria associated with celiac disease. The prevalence of the manifestation of chronic urticaria in celiac disease is unknown but increase in atopic immunologic disorders has been reported in the setting of gluten enteropathy. Relationship between the clinical manifestations is not clear. The present case of subclinical celiac disease diagnosis in an otherwise asymptomatic child with chronic urticaria further reinforces the evidence that differential for celiac disease warrants to be always considered in children with refractory urticaria. PMID- 20199433 TI - Congenital lupus erythematosus presenting at birth with widespread erosions, pancytopenia, and subsequent hepatobiliary disease. AB - Neonatal lupus erythematosus is an uncommon disease caused by transplacental passage of maternal anti-Ro (SS-A), anti-LA (SS-B), or anti-U1RNP antibodies. Cutaneous findings of neonatal lupus are variable, but annular, erythematous plaques occurring within a few weeks of birth are most typical. Cutaneous lesions of congenital onset lupus erythematosus can differ from that of neonatal lupus erythematosus, presenting with atrophy or scarring, and less commonly, erosions. We report an unusual case of congenital lupus erythematosus presenting at birth with widespread erosions, pancytopenia, and subsequent hepatobiliary disease. PMID- 20199434 TI - Erythrokeratoderma variabilis responding to low-dose isotretinoin. AB - A 2-year-old male child was diagnosed with erythrokeratoderma variabilis, and showed an excellent response to low-dose isotretinoin, with remarkable improvement in all the affected areas within just 2 weeks of treatment. PMID- 20199435 TI - Recurrent herpes simplex infection in multiple locations in an otherwise healthy boy. AB - An 8-year-old boy developed vesicular lesions on the skin in different parts of the body, occurring four to six times a year. He had a history of eczema herpeticum as a young child. We confirmed a diagnosis of multifocal herpes simplex infection, and hypothesize that this was a result of his previous eczema herpeticum, an unusual complication, in an otherwise healthy and immunocompetent child. PMID- 20199436 TI - Neonatal onychomadesis. PMID- 20199437 TI - Using ringed scissor handles to dry the operative field. PMID- 20199440 TI - The benefits of sunflower oleodistillate (SOD) in pediatric dermatology. AB - For millennia, sunflower seed oil has been used in folk medicine for both skin care and the treatment of skin disorders. In its natural state, the oil contains high levels of essential fatty acids, particularly linoleic acid, which has skin barrier-enhancing properties. A sunflower oleodistillate (SOD), which is produced through a molecular distillation process without the use of solvents, has been shown to increase the epidermal key lipid synthesis and to reduce inflammation in vitro and in animal models. It has also been shown to activate peroxisome proliferative-activated receptor-alpha (PPAR-alpha) in vitro. As PPAR-alpha agonists have been shown to stimulate keratinocyte differentiation, improve barrier function, and enhance lipid metabolism in the skin, it has been suggested that SOD might also be efficacious in atopic dermatitis (AD). An initial clinical evaluation of the care effect of a 2% SOD emulsion in 20 adult volunteers with atopic skin revealed the moisturizing properties of SOD. Finally, a strong steroid-sparing effect and a positive effect on quality-of-life parameters were clearly demonstrated for the 2% SOD cream in studies in infants and babies with AD. PMID- 20199441 TI - The frequency and intensity of topical pimecrolimus treatment in children with physician-confirmed mild to moderate atopic dermatitis. AB - Atopic dermatitis (AD) is often treated with multiple modalities, including topical medications such as corticosteroids and topical calcineurin inhibitors (TCIs). The aim of this study was to describe the natural history of the utilization characteristics of topical treatment in those with AD. We conducted a longitudinal study of the first 4,105 children with physician-confirmed mild to moderate AD enrolled in an ongoing postmarketing safety study of pimecrolimus. Information was obtained from participants every six months using a questionnaire. Drug utilization was solely determined by the physician and patient. Over the three years of our study, an increasing number of individuals reported at least 6 months of complete control of their disease, without the continued use of a topical medication. While all study participants used pimecrolimus at the start of the study less than 40% continued to use it after 3 years of study participation. If an individual was still using a topical medication after three years of follow-up, it was most likely a topical corticosteroid. For those who continued to use pimecrolimus, the use was limited to about 60 grams of pimecrolimus in 6 months. Community-based use of topical pimecrolimus to treat AD is limited both with respect to the duration of exposure and amount or total dose of the exposure. If a topical therapy is persistent, it is most likely to a topical corticosteroid. PMID- 20199442 TI - A prospective study of cutaneous manifestations of spinal dysraphism from India. AB - Recognition of cutaneous markers of spinal dysraphism is important to prevent the morbidity associated with underlying spinal anomalies. To investigate the frequency and type of cutaneous stigmata in different forms of spinal dysraphism and to assess the role of ultrasonography and/or magnetic resonance imaging in diagnosing spinal dysraphism at two pediatric dermatology tertiary care centers. Over a 4-year period, all pediatric patients presenting to the dermatology clinic with dorsal midline cutaneous stigmata were evaluated clinically and with imaging studies (radiography, ultrasonographic examination and magnetic resonance imaging/Doppler). Surgical interventions were planned in conjunction with neurosurgery and orthopedic specialists. On examination, 245 (4.2%) had 285 cutaneous stigmata. Of the 180 patients evaluated with radiography, ultrasonographic examination and magnetic resonance imaging, 50 patients (28%) had spinal dysraphism (with 64 cutaneous stigmata). The most common stigmata associated with occult spinal dysraphism were lipoma (10) and dimples (12) and in open spinal dysraphism lipomeningomyelocoele (10) and meningomyelocoele (10). Statistically, lipomeningomyelocoele/myelomeningocoele, atypical dimples and port wine stains were most associated with spinal dysraphism (p < 0.001). In 80 children less than 6 months of age, radiography with ultrasonographic examination revealed an SD in 16, while magnetic resonance imaging was diagnostic in four cases. Ultrasonographic examination performed fairly well in children less than 6 months and in cases of flat cutaneous stigmata it missed only 5% of cases, but in cases with bulky overlying masses (lipoma, hemangioma) it missed 15% of cases. PMID- 20199443 TI - Recent microbiological shifts in perianal bacterial dermatitis: Staphylococcus aureus predominance. AB - Traditionally, bacterial infections of the anal skin have been found to be caused by Streptococcus. The aim of this study was to determine the breakdown of bacterial isolates and the current presentation of bacterial diseases involving the perineum. From the chart review of children who had bacterial cultures of the anus from 2005 to 2008 in a pediatric dermatology practice population in New York City, 26 pediatric patients (ages 5 months to 12 yrs) who had the indications of anal erythema or recurrent buttocks dermatitis were identified. Bacterial cultures of 17 patients grew pathogens, that of 14 (82% of identifiably infected patients) grew Staphylococcus aureus, in 11 as a solo pathogen (6 MSSA and 5 MRSA in 2 family clusters). Streptococcus was identified in three patients, two on culture and one on latex agglutination test; and two patients were identified as having both group A beta hemolytic Streptococcus and Staphylococcus aureus (2 MSSA and 1 MRSA). In patients with S. aureus perianally, concurrent small papules and pustules of the buttocks or extension of the erythema to adjacent buttock skin was the primary clinical feature distinguishing this condition from isolated streptococcal disease. Whereas Streptococcal infections of the anus and buttocks occur commonly, Staphylococcus aureus has become the leading cause of anal bacterial infection in the setting of skin involvement; therefore, antibacterial therapy for anal and buttock bacterial infections should be tailored accordingly. PMID- 20199444 TI - Prevalence of pediculosis capitis among schoolchildren in Greece and risk factors: a questionnaire survey. AB - Pediculosis capitis is a common problem worldwide. The aim of this study was to estimate the prevalence of pediculosis capitis in children of preschool or school age in Greece, as well as to investigate the potential risk factors. The study included children of preschool and school age from all over Greece, including urban, semi-urban, and rural areas of Greece. A questionnaire with both closed and open-type questions, which was constructed by the researcher and filled in by the children's parents, was used. A total of 5,084 questionnaires were distributed, of which 2,792 were adequately filled and subsequently evaluated. Descriptive statistics and logistic regression models were used. The median age of the children was 8 years (range: 3-13 yrs) and 54% of them were girls. Pediculosis was found to be prevalent in 12% of the tested population. The prevalence of the disease seems to be increased after the age of 10 years and the risk is higher in girls. The number of family members was correlated positively with the risk of being infected with pediculosis at least once. The children's gender, their age, and family size were correlated with the risk of infection. PMID- 20199445 TI - Halo scalp ring in a premature newborn and review of the literature. AB - Unusually prolonged pressure on the scalp by the cervical os during or before the delivery may result in a distinctive pattern of annular alopecia that has been referred to as halo scalp ring. This rare form of hair loss is most commonly a temporary, non-scarring process that is attributed to caput succedaneum. We report a new case of halo scalp ring in a premature newborn. Review of previously reported cases suggests that prematurity is an important, previously unrecognized, risk factor for developing a halo scalp ring. PMID- 20199446 TI - Systemic juvenile xanthogranuloma with fatal outcome. AB - Juvenile xanthogranuloma is a benign and self-limited disease which usually appears in the skin of children. Visceral involvement has been rarely reported, as has fatal outcome in some affected individuals. We report a case of systemic juvenile xanthogranuloma in a female newborn with mainly skin, bone marrow, and liver involvement, leading to death at the age of 2 months. PMID- 20199447 TI - Cutaneous presentation of plasmablastic post-transplant lymphoproliferative disorder in a 14-month-old. AB - We present a 14-month-old female child who developed multiple erythematous nodules on her abdomen 5 months after liver and small bowel transplantation. Skin biopsy revealed a dense infiltrate of large cells in the dermal and subcutaneous layers with frequent mitotic figures. The cells were noted to have abundant cytoplasm, prominent nucleoli, and open chromatin. Immunohistochemical stains were positive for CD138, CD56, Ki67 (>90%), and lambda chain restriction. Rare mature B cells (CD20) and rare T cells (CD3) were noted. She was diagnosed with high-grade post-transplant lymphoproliferative disorder most consistent with plasmablastic lymphoma. PMID- 20199448 TI - Milia en plaque: three new pediatric cases. AB - Milia en plaque (MEP) is an unusual and extremely rare clinical variant of milia, characterized by multiple milia-like lesions overlying an erythematous edematous plaque with histologic findings consistent with milia. MEP tends to affect the middle-aged patients and shows a predilection for women. Among children, this entity is rarely described and, to our knowledge, only four cases have been reported to date in the dermatologic literature. We add three new cases of children, one of whom had an unusual site of presentation. PMID- 20199449 TI - Primary cutaneous CD30 positive anaplastic large cell lymphoma in an adolescent. AB - We present a case of a 14-year-old boy with a large ulcerated plaque on the scalp for 6 months, who was found to have primary cutaneous CD30-positive, anaplastic kinase-negative, anaplastic large cell lymphoma with post-auricular lymphadenopathy. MRI, bone marrow biopsy, and laboratory data demonstrated no other systemic involvement. He was treated with radiation and low-dose oral methotrexate, with improvement of the lesion and lymphadenopathy. Very few cases of primary cutaneous CD30-positive anaplastic large cell lymphoma in the pediatric population have been reported, and our case represents one of the first pediatric patients with local lymph node involvement. PMID- 20199450 TI - Childhood onset vulvar lichen sclerosus does not resolve at puberty: a prospective case series. AB - When vulvar lichen sclerosus occurs in prepubertal children it is widely believed that it is likely to remit at puberty. However when it occurs in adult women it is accepted that remission is unlikely and that in addition untreated or inadequately treated disease may be complicated by significant disturbance of vulvar architecture and less commonly squamous cell carcinoma. Our database reveals 18 girls who developed lichen sclerosus prior to puberty who are now adolescents or young adults. Twelve have remained under surveillance and the other six patients have been lost to follow-up. We report a prospective series of these 12 patients. Three patients have achieved complete remission sustained for three or more years, all prior to menarche. Nine patients, or 75% of the cohort, who still had active lichen sclerosus at puberty continue to require maintenance therapy after menarche. Of the 12, six have had significant disturbance of vulvar architecture. The concept that prepubertal lichen sclerosus resolves at puberty would appear not to be true in the majority of patients. Even when diagnosed early and treated effectively, childhood onset lichen sclerosus may be complicated by distortion of vulvar architecture. PMID- 20199451 TI - PHACES syndrome--report of two cases and their evolution over time. AB - We describe two cases of PHACES syndrome that illustrate the importance of recognizing this rare syndrome. As children with this syndrome can present to general pediatricians, dermatologists, pediatric cardiologists, ophthalmologists, and neurologists, it is important that all are aware of the spectrum of associated abnormalities. PMID- 20199452 TI - Congenital erosive and vesicular dermatosis with reticulated scarring in a newborn: an innovative treatment using a silicone dressing. AB - Congenital erosive and vesicular dermatosis healing with reticulated supple scarring is a rare entity presenting in the newborn with crusted erosions and vesicles that heal relatively rapidly, forming unique reticulated scars. We report the case of a premature baby 31 weeks old. Diagnosis was confirmed by skin biopsies, and the clinical improvement was excellent, with complete healing observed within 7 weeks. This report highlights clinical and histopathologic features, and a new successful treatment approach using a silicone dressing. PMID- 20199453 TI - Systematized contact dermatitis and montelukast in an atopic boy. AB - Upon ingestion, the artificial sweetener, aspartame is metabolized to formaldehyde in the body and has been reportedly associated with systemic contact dermatitis in patients exquisitely sensitive to formaldehyde. We present a case of a 9-year-old Caucasian boy with a history of mild atopic dermatitis that experienced severe systematized dermatitis after being started on montelukast chewable tablets containing aspartame. Patch testing revealed multiple chemical sensitivities which included a positive reaction to formaldehyde. Notably, resolution of his systemic dermatitis only occurred with discontinuation of the montelukast chewables. PMID- 20199454 TI - A first case of trimethoprim-sulfamethoxazole induced Sweet's syndrome in a child. PMID- 20199455 TI - Warty plaque in a boy with recessive dystrophic epidermolysis bullosa. PMID- 20199456 TI - A firm nodule on the great toe of a 13-year-old boy. PMID- 20199457 TI - Diffuse clusters of vesicles on the face and extremities of a 10-month-old girl. PMID- 20199458 TI - Onychomadesis: a rare side-effect of valproic acid medication? AB - Valproic acid (VPA) is frequently used as an antiepileptic drug. Several side effects are known. We report on a child with onychomadesis as a possible side effect of treatment with VPA. Normal nail growth was observed after stopping VPA. The pathomechanism of onychomadesis due to VPA treatment remains unclear. PMID- 20199459 TI - Childhood pityriasis rosea. AB - Pityriasis rosea (PR) is an acute, self-limiting papulosquamous disorder of unknown etiology. Published studies of childhood PR are scarce and most are reviews. The aim of this study was to determine the demographic and clinical features of childhood PR. PMID- 20199460 TI - Isolated Langerhans cell histiocytosis of the vulva in an infant. AB - Langerhans cell histiocytosis affecting only the vulva of a child is very rare. We report a 1-year-old female infant with isolated Langerhans cell histiocytosis presenting as pruritic papules confined to the vulva, confirmed by histopathology with immunohistochemical staining. PMID- 20199461 TI - Rhabdomyomatous mesenchymal hamartoma of the vagina. AB - Rhabomyomatous mesenchymal hamartoma (RMH) is a rare hamartomatous lesion in the dermis and subcutaneous tissue. We report a case of solitary RMH occurring on the vagina of a newborn infant. PMID- 20199462 TI - Vitiligo occurring after halo formation around congenital melanocytic nevi. AB - We present two cases wherein vitiligo developed after the onset of halo formation involving congenital melanocytic nevi to emphasize the possibility of this finding as a potential albeit unusual presentation of vitiligo. PMID- 20199463 TI - Isotretinoin use in a case of chronic granulomatous disease. AB - Chronic granulomatous disease (CGD) is a rare, inherited disorder, in which phagocytic cells, through an enzyme defect, are unable to produce microbicidal oxidants; affected individuals are thereby unduly susceptible to certain life threatening bacterial and fungal infections and require lifelong antibiotic and antifungal prophylaxis. We present the case of an adolescent CGD patient whose recalcitrant acne vulgaris and subsequent recurrent facial abscesses were successfully treated with isotretinoin; swift resolution of this and similar patients' acne lesions is paramount, as these lesions may serve as a portal of entry for systemic infections and may pose a significant risk for scarring. Isotretinoin is associated with an increased rate of cutaneous Staphylococcus aureus carriage as well as exuberant granulation responses, both of theoretical concern in CGD patients. The therapeutic outcome of isotretinoin in treatment resistant cases of acne in CGD patients has not been reported in the literature; we present this case to advocate an underreported use of isotretinoin in the prevention of acne, its subsequent cyst formation, and scarring patients with CGD. PMID- 20199464 TI - Syringocystadenoma papilliferum: an unusual presentation. AB - An 8-year-old boy presented with a rapidly growing, unusually large, fleshy, lobulated, cauliflower-like mass on the lower back. Incisional biopsy revealed the histologic picture of syringocystadenoma papilliferum. The case is reported in this study for its unusual site, very large size, and peculiar morphology. PMID- 20199465 TI - Waardenburg syndrome type I with heterochromia iridis and circumscribed hypopigmentation of the skin. AB - We report a 3-year-old girl with autosomal dominant inherited Waardenburg syndrome type I showing circumscribed hypopigmentation of the skin, heterochromia iridis, sensorineural deafness, and dental aberrations. Clinical diagnosis was confirmed by the identification of an underlying missense mutation (C811T) in the PAX3 gene. Early diagnosis of Waardenburg syndrome among children with pigment anomalies enables a successful interdisciplinary medical care. PMID- 20199466 TI - Onychomycosis in a very young child. AB - A child was diagnosed with onychomycosis before he was 2 months of age; however, he had noticeable nail lesions from the second week of life. PMID- 20199467 TI - Persistent agmination of lymphomatoid papulosis. AB - A 12-year-old boy had lesions clinically and histopathologically consistent with lymphomatoid papulosis (LP) which were persistent and appeared grouped in a circumscribed area of normal looking background skin on the right abdomen. Staging work-up did not disclose systemic disease. Persistent agmination of lymphomatoid papulosis (PALP) is somewhat different from classical LP because it involves a circumscribed, patch-sized area of the skin and the papules within never resolve completely despite some waxing and waning. PALP might be considered a localized or regional form of LP or a distinct lymphoproliferative disorder; in any case, at least a cautious long-term follow up is recommended, with attention to the possible development of true lymphoma. PMID- 20199468 TI - The use of oral ketamine for analgesia with dressing change in an infant with epidermolysis bullosa: report of a case. AB - Epidermolysis bullosa (EB) describes a spectrum of disease from occasional bullae and callus formation to a debilitating life-threatening condition. In this study, we report the use of intravenous ketamine given orally to an infant with a phenotypically severe form of EB simplex, Dowling-Meara subtype, to achieve analgesia during painful dressing changes. PMID- 20199469 TI - Niemann-Pick disease in association with syringocystadenoma papilliferum. AB - This report describes a solitary syringocystadenoma papilliferum, a rare skin tumor, in a 9-year-old boy who was known to have Niemann-Pick disease. To our knowledge, this association has not been described in the medical literature and this is the first report describing such association. PMID- 20199470 TI - Henoch-Schonlein purpura associated with helicobacter pylori infection: the pathogenic roles of IgA, C3, and cryoglobulins? PMID- 20199471 TI - Transient pigmentary lines of the newborn. PMID- 20199473 TI - Evidence, early intervention and the tipping point. PMID- 20199476 TI - A descriptive review of qualitative studies in first episode psychosis. AB - AIM: The aim of this paper is to provide a descriptive review of published qualitative research studies on first episode psychosis (FEP). METHODS: A review was undertaken to describe the findings of qualitative studies in early psychosis. Keyword searches in Medline, CINAHL, ASSIA, PsychINFO databases, as well as manual searches of other relevant journals and reference lists of primary papers, were conducted. RESULTS: Thirty-one qualitative papers (representing 27 discrete studies) were identified. The majority reported research concerning young people based in community settings. The research studies were organized according to the following generic social processes: (i) achieving identity; (ii) acquiring perspectives; (iii) doing activity; and, (iv) experiencing relationships. The papers reviewed are based on first-person accounts obtained from individuals who have experienced FEP, their family members and service providers. CONCLUSION: This descriptive review contributes to our understanding of the complex social processes of achieving identity, acquiring perspectives, doing activities and developing relationships as experienced by young people and the significant others in their world. The cumulative findings highlight the contextually rich and detailed information made possible through qualitative studies of FEP. They begin to account for the active engagement of individuals affected by psychosis in making sense of their experience and suggest that this experience should be understood from within young people's own framework of meaning. PMID- 20199477 TI - Is a national framework for implementing early psychosis services necessary? Results of a survey of Australian mental health service directors. AB - AIM: Expert opinion holds that the rate of implementation of specialist services for first presentation psychosis in Australia is much too slow. We aimed to collect evidence regarding this view from the first national survey of adult public mental health services about their self-reported efforts to implement specialist early psychosis intervention (EPI). METHODS: Using a purpose-designed Census form for assessing EPI implementation, adult public mental health service directors throughout Australia were asked about EPI-relevant local service activities. RESULTS: Sixty Census forms were returned (response rate = 61%), representing a total catchment population of 12.5 million people. A minority of services reported high levels of EPI implementation, which varied widely between area services and across state and territory jurisdictions. Rural and remote services were overrepresented in the lowest levels of reported EPI implementation. Only one service characteristic, the value of identifiable funding committed specifically to EPI, was predictive of level of reported EPI implementation. CONCLUSIONS: The disturbingly high levels of variability in EPI implementation across jurisdictions suggest a pressing need for a set of nationally agreed uniform EPI implementation standards. Additional specific strategies for rural and remote mental health services may be needed for these services to implement EPI. PMID- 20199478 TI - Assessing clinicians' management of first episode schizophrenia using clinical case vignettes. AB - BACKGROUND: Patients with first episode schizophrenia may present in a variety of clinical settings to providers who have a range of knowledge and skills. A thoughtful workup of patients with new-onset psychosis is critical, and the treatment of first episode schizophrenia differs from that of chronic psychotic disorders. Clinical case vignettes with free-form responses can be used to carefully assess whether front line practitioners provide guideline-adherent management of first episode psychosis. METHODS: A clinical case vignette, presenting a patient with first episode schizophrenia, was created and administered to the attendees of a continuing medical education programme. Free form responses to questions regarding differential diagnosis, workup, treatment and treatment duration were scored based on published practice guidelines. Response frequencies were tabulated and performance was compared among professional disciplines. RESULTS: Sixty-two attendees completed the vignette. Though the attendees typically considered a broad differential diagnosis and appropriately initiated treatment with antipsychotics, the respondents' proposed medical workup was limited, and they prescribed antipsychotics at higher doses and for a shorter duration than recommended in the literature. The prescribers outperformed the non-prescribers on treatment questions (P = 0.006), but the two groups' performance did not significantly differ on the assessment questions (P = 0.08). CONCLUSIONS: The front line clinicians who encounter patients with first episode schizophrenia may have significant practice gaps in the initial and follow-up care of these patients. Given the preliminary nature of this study and the debate about the optimal care for first episode psychosis, further study is needed. If such gaps are confirmed, additional educational interventions are required to align clinical management with published practice guidelines. PMID- 20199479 TI - Eating disorders mental health literacy in Singapore: beliefs of young adult women concerning treatment and outcome of bulimia nervosa. AB - AIM: We examined the eating disorders 'mental health literacy' of young adult women in Singapore. METHODS: A self-report questionnaire was completed by 255 women recruited from three university campuses. A vignette of a fictional (female) person exhibiting the characteristic features of bulimia nervosa was presented, followed by a series of questions concerning the treatment and outcome of the problem described. A measure of eating disorder symptoms was included in the questionnaire. RESULTS: Consulting a primary care practitioner, counsellor or psychologist; seeking the advice of a (female) family member or friend; getting advice about diet and nutrition; and taking vitamins and minerals were the interventions most often considered helpful. Participants were less positive about the benefits of psychiatristsand were ambivalent about the use of psychotropic medication. Participants' mothers were most often considered helpful as they are an initial source of help. Among participants with a high level of eating disorder symptoms, recognition of an eating problem was poor. A minority of participants believed that treatment would result in full recovery. CONCLUSIONS: Aspects of the eating disorders mental health literacy of young Singaporean women may be conducive to low or inappropriate treatment seeking. Health promotion programmes need to target not only at-risk individuals, but also their family members and social circle. PMID- 20199480 TI - Stigma and treatment delay in first-episode psychosis: a grounded theory study. AB - AIM: A longer duration of untreated psychosis (DUP) is associated with greater morbidity in the early course of schizophrenia. This formative, hypothesis generating study explored the effects of stigma, as perceived by family members, on DUP. METHODS: Qualitative interviews were conducted with 12 African American family members directly involved in treatment initiation for a relative with first-episode psychosis. Data analysis relied on a grounded theory approach. A testable model informed by constructs of Link's modified labelling theory was developed. RESULTS: Four main themes were identified, including: (i) society's beliefs about mental illnesses; (ii) families' beliefs about mental illnesses; (iii) fear of the label of a mental illness; and (iv) a raised threshold for the initiation of treatment. A grounded theory model was developed as a schematic representation of the themes and subthemes uncovered in the family members' narratives. CONCLUSIONS: The findings suggest that due to fear of the official label of a mental illness, certain coping mechanisms may be adopted by families, which may result in a raised threshold for treatment initiation, and ultimately treatment delay. If the relationships within the grounded theory model are confirmed by further qualitative and quantitative research, public educational programs could be developed with the aim of reducing this threshold, ultimately decreasing DUP. PMID- 20199481 TI - Early intervention with second-generation antipsychotics in first-episode psychosis: results of an 8-week naturalistic study. AB - OBJECTIVE: The objective was to compare short-term effectiveness of aripiprazole with three other second-generation antipsychotics (SGAs) in the treatment of first-episode psychosis. METHOD: In a naturalistic, 'single-blind' design, 60 subjects experiencing their first psychotic episode were treated for 8 weeks with aripiprazole (n = 19), risperidone (n = 16), olanzapine (n = 14) or quetiapine (n = 11). Medication and dosing decisions were made by treating psychiatrists, constrained to once-a-day dosing, low initial doses and no clozapine. Weekly ratings were obtained using the Positive and Negative Syndrome Scale (PANSS), Simpson-Angus Rating Scale and Barnes Akathasia Rating Scale. Weight and vital signs were also collected weekly. RESULTS: The group presented with severe psychotic symptoms (mean baseline PANSS total score of 105.2), which were reduced rapidly (P < 0.0005). The between-group and group by time interaction terms were non-significant. Similar reductions were seen across all PANSS sub-scales. At Week 1 the mean PANSS Activation Scale score was reduced more with olanzapine than in the other groups (P < 0.002). Few instances of extrapyramidal symptoms occurred; all were sporadic and did not require treatment. Group body weight increased by 7.3% over the study. Vital signs remained unchanged. CONCLUSIONS: Early intervention with low doses of four SGAs led to rapid symptom reduction in first-episode psychotic patients with severe psychopathology. Although no clear medication advantages were observed in the short term, longer duration studies with larger samples will be required for determining efficacy, rates of compliance, relapse prevention and diminished incidence of extrapyramidal signs and symptoms. PMID- 20199482 TI - Paliperidone extended-release tablets in patients with recently diagnosed schizophrenia. AB - AIM: Effective early and persistent antipsychotic treatment in recently diagnosed schizophrenia may positively impact long-term outcomes. Paliperidone extended release (ER) was assessed in this population. METHODS: Post hoc analysis of pooled data from three 6-week, double-blind (DB), placebo-controlled, and three 1 year open-label (OL) studies of paliperidone ER in schizophrenia patients. Data stratified by time since diagnosis (< or =3 vs. >3 years). RESULTS: At DB (n = 1193) and OL baselines (n = 744), 259 (21.9%) and 188 (25.3%) patients were diagnosed < or =3 years. At DB end point, both populations improved with paliperidone ER versus placebo on Positive and Negative Syndrome Scale (PANSS) total, Clinical Global Impressions-Severity and Personal and Social Performance (PSP) scale scores (all P < 0.05). At OL end point, there were significant improvements from DB baseline in both populations on these scales (P < 0.0001), with greater improvement in the < or =3-year population on PANSS total (P < 0.001) and PSP (P < 0.001) scores. During DB treatment, only the < or =3-year population reported adverse events (AEs) in > or =5% (placebo-adjusted rate) of subjects receiving paliperidone ER: akathisia, extrapyramidal disorder not otherwise specified and somnolence. During OL treatment, akathisia and somnolence occurred more frequently (> or =5%) in the < or =3- versus >3-year population. OL study completion rates were 51.1% in < or =3-year, and 48.2% in >3-year subjects. CONCLUSIONS: Paliperidone ER significantly improved symptoms and functioning in schizophrenia patients, regardless of time since diagnosis. Recently diagnosed patients who continued treatment exhibited greater symptom reduction and functional benefit over the long term. Results also suggest that these patients may be more susceptible to certain AEs. PMID- 20199484 TI - Promoting recovery: service user and staff perceptions of resilience provided by a new Early Intervention in Psychosis service. AB - AIM: The principles and practice of recovery are guiding many changes in mental health service provision. As a new Early Intervention in Psychosis (EIP) service, we were interested in finding out if both staff and users perceive the service as promoting resilience and in turn, recovery. METHODS: A naturalistic sample of service users and staff completed the Organizational Climate questionnaire to assess the degree to which the service promotes resilience in overcoming a first episode psychosis. RESULTS: The results indicated that both staff and service users similarly perceive the service as positively supporting resilience. The one exception was the staff rated the 'available resources to meet people's needs' as less than service users. CONCLUSIONS: The positive rating of resilience indicated that the service is working in a manner consistent with a recovery orientation. The results will act as a benchmark to compare with both other EIP services and future performance. PMID- 20199483 TI - A 12-month outcome study of insight and symptom change in first-episode psychosis. AB - AIM: We first aimed to evaluate the progression of insight and psychopathology over the first year of treatment for a psychosis. We hypothesized that improvement in insight would associate with improvement in positive and negative symptoms, and depressive and anxious symptom exacerbation. Secondly, in an exploratory analysis, we aimed to identify quantitatively distinct insight trajectory groups, and to describe the impact of psychopathology over time on the different trajectory groups. METHODS: One-hundred and sixty-five patients were administered a comprehensive clinical evaluation, and insight was rated on the Scale for Assessment for Unawareness of Mental Disorder, item 1 (awareness of mental disorder), at admission and after 1, 2, 3, 6, 9 and 12 months. RESULTS: In a generalized estimating equation (GEE) model of change, insight improved concurrently with positive, negative and anxious symptoms between baseline and month 1 in the entire cohort. Latent group-based trajectory analysis revealed five insight groups: good, increasing, decreasing, moderate poor and very poor. GEE modelling revealed that the very poor and moderate poor insight groups displayed greater overall negative symptoms than patients with good and increasing insight trajectories. The good insight group showed significantly greater overall depressive symptoms than the diminished and very poor insight groups. CONCLUSIONS: The results suggest that specific longitudinal insight trajectories were driving the observed associations between insight and negative and depressive symptoms in the entire first-episode psychosis cohort. Persistently poor insight may be an important factor in negative symptom maintenance. Good or increasing course of insight may be early clinical indicators of a liability to depression. PMID- 20199485 TI - Pervasive developmental disorder and early intervention in psychosis services: a survey of care coordinators' experiences. AB - AIM: To evaluate the experience of care coordinators encountering clients with co morbid diagnoses or features of pervasive development disorder (PDD) in an Early Intervention in Psychosis (EIP) service. METHODS: A cross-sectional survey was conducted using a semi-structured face-to-face interview schedule. RESULTS: Thirty-three care coordinators were interviewed. One-third of the care coordinators had previously encountered at least one client with a co-morbid diagnosis of PDD, with the majority feeling confident that they could recognize the features of the syndrome. The estimated reported prevalence of diagnosed PDD in this group was around 4-5%, although social and communication impairments were regularly encountered in clients by at least a quarter of the clinicians interviewed. CONCLUSIONS: Social and communication problems are commonly observed by clinicians in this population and some may represent the presence of a co morbid PDD. Further efforts should be made to better identify and support this sub-population of EIP clients. PMID- 20199486 TI - 'Programma2000': a multi-modal pilot programme on early intervention in psychosis underway in Italy since 1999. AB - AIM: The aim of this study was to describe a service operating in Milan, Italy, that provides early intervention for young people aged 17-30 years at the onset and at high risk of psychosis. METHOD: Following 2 years of preliminary study and organization, Programma2000 was launched in Milan in 1999. This programme was targeted at early detection and intervention in subjects at the onset of, at risk of, or showing 'prodromal' signs of psychosis. This paper contains data on the organization and activities of Programma2000. RESULTS: The service has been active since its launch and has received 378 referrals as of March 2009, 342 of which were thoroughly evaluated. At entry, patients undergo a detailed evaluation of their psychopathology, personal and social role functioning, and cognitive status, with repeated testing over time in order to multidimensionally assess outcome. Treatment involves cognitive-behavioural psychotherapy, structured and unstructured psychosocial interventions, and pharmacotherapy when deemed necessary. Treatment appears effective in reducing morbidity and improving social functioning. CONCLUSION: A team dedicated to the early identification and treatment of young people with early psychosis is a feasible and sustainable extension of the traditional methods of care for people with mental disorders in Italy. PMID- 20199487 TI - Objective measurement of motor activity during cognitive performance in adults with attention-deficit/hyperactivity disorder. AB - OBJECTIVE: This study investigates whether hyperactivity, i.e. an increased level of motor activity, can be observed in adults with attention-deficit/hyperactivity disorder (ADHD). METHOD: An infrared motion-tracking system was used to measure motor activity in 20 unmedicated adults with ADHD and 20 matched healthy controls (HC) during a 1-back working memory task. RESULTS: Motor activity was higher in ADHD. It increased with the duration of testing and co-varied with cognitive performance in ADHD only. Subjective and objective measurements of motor activity were related in HC, but not in ADHD. CONCLUSION: Higher levels of motor activity in ADHD are objectively measurable not only in children, but in adults as well. It is linked to cognitive performance arguing against distinguishable diagnostic subtypes. The objective measurement of motor activity seems to extend the description of ADHD symptoms derived from rating scales and might thus help to bridge the gap between psychopathological symptom description and neurobiological alterations. PMID- 20199488 TI - Internet use and suicide among younger age groups between 1989 and 2008 in Japan. PMID- 20199489 TI - Cannabis use and non-clinical dimensions of psychosis in university students presenting to primary care. AB - OBJECTIVE: To explore the relationship between cannabis use and self-reported dimensions of psychosis in a population of university students presenting for any reason to primary care. METHOD: One thousand and forty-nine students attending the Student Health Unit, National University of Ireland, Galway, completed self report questionnaires on alcohol and substance misuse, non-clinical dimensions of psychosis [Community Assessment of Psychic Experiences (CAPE)], anxiety and depression [Hospital Anxiety and Depression Scale (HADS)]. Association of cannabis use with psychiatric symptoms was explored whilst controlling for confounds. RESULTS: More frequent cannabis use was independently associated with greater intensity of positive, negative and depressive psychotic symptoms. The earlier the age of onset of cannabis use, the more positive psychotic symptoms were reported. CONCLUSION: These findings support the hypotheses that cannabis use increases the risk of developing psychotic symptoms and that this risk is further increased in those individuals who use cannabis more heavily and commence it at a younger age. PMID- 20199490 TI - Risk factors predicting onset and persistence of subthreshold expression of bipolar psychopathology among youth from the community. AB - OBJECTIVE: To examine factors increasing the risk for onset and persistence of subthreshold mania and depression. METHOD: In a prospective cohort community study, the association between risk factors [a family history of mood disorders, trauma, substance use, attention-deficit/hyperactivity disorder (ADHD) and temperamental/personality traits] and onset of manic/depressive symptoms was determined in 705 adolescents. The interaction between baseline risk factors and baseline symptoms in predicting 8-year follow-up symptoms was used to model the impact of risk factors on persistence. RESULTS: Onset of manic symptoms was associated with cannabis use and novelty seeking (NS), but NS predicted a transitory course. Onset of depressive symptoms was associated with a family history of depression. ADHD and harm avoidance (HA) were associated with persistence of depressive symptoms, while trauma and a family history of depression predicted a transitory course. CONCLUSION: Different risk factors may operate during onset and persistence of subthreshold mania and depression. The differential associations found for mania and depression dimensions suggest partly different underlying mechanisms. PMID- 20199494 TI - Experience of trauma and conversion to psychosis in an ultra-high-risk (prodromal) group. AB - OBJECTIVE: We aimed to replicate a recent finding of high prevalence of trauma history in patients at 'ultra-high risk' (UHR) of psychotic disorder and to investigate whether trauma predicts conversion to psychosis in this population. METHOD: A consecutive sample of UHR patients was assessed. History of trauma was accessed with the General Trauma Questionnaire. Cox regression models were used to explore relationship between conversion to psychosis and trauma. RESULTS: Of 92 UHR patients nearly 70% had experienced a traumatic event and 21.7% developed psychosis during follow-up (mean 615 days). Patients who had experienced a sexual trauma (36%) were significantly more likely to convert to first-episode psychosis (OR 2.96) after controlling for meeting multiple UHR intake groups. CONCLUSION: UHR patients have a high prevalence of history of trauma. Previous sexual trauma may be a predictor of onset of psychotic disorder in this population. PMID- 20199491 TI - Is late-onset schizophrenia a subtype of schizophrenia? AB - OBJECTIVE: To determine whether late-onset schizophrenia (LOS, onset after age 40) should be considered a distinct subtype of schizophrenia. METHOD: Participants included 359 normal comparison subjects (NCs) and 854 schizophrenia out-patients age >40 (110 LOS, 744 early-onset schizophrenia or EOS). Assessments included standardized measures of psychopathology, neurocognition, and functioning. RESULTS: Early-onset schizophrenia and LOS groups differed from NCs on all measures of psychopathology and functioning, and most cognitive tests. Early-onset schizophrenia and LOS groups had similar education, severity of depressive, negative, and deficit symptoms, crystallized knowledge, and auditory working memory, but LOS patients included more women and married individuals, had less severe positive symptoms and general psychopathology, and better processing speed, abstraction, verbal memory, and everyday functioning, and were on lower antipsychotic doses. Most EOS-LOS differences remained significant after adjusting for age, gender, severity of negative or deficit symptoms, and duration of illness. CONCLUSION: Late-onset schizophrenia should be considered a subtype of schizophrenia. PMID- 20199493 TI - The 10-year course of psychosocial functioning among patients with borderline personality disorder and axis II comparison subjects. AB - OBJECTIVE: The purpose of this study was to determine the 10-year course of the psychosocial functioning of patients with borderline personality disorder (BPD). METHOD: The social and vocational functioning of 290 inpatients meeting both the Revised Diagnostic Interview for Borderlines (DIB-R) and DSM-III-R criteria for BPD and 72 axis II comparison subjects were carefully assessed during their index admission. Psychosocial functioning was reassessed using similar methods at five contiguous 2-year time periods. RESULTS: Borderline patients without good psychosocial functioning at baseline reported difficulty attaining it for the first time. Those who had such functioning at baseline reported difficulty retaining and then regaining it. In addition, over 90% of their poor psychosocial functioning was due to poor vocational but not social performance. CONCLUSION: Good psychosocial functioning that involves both social and vocational competence is difficult for borderline patients to achieve and maintain over time. In addition, their vocational functioning is substantially more compromised than their social functioning. PMID- 20199495 TI - Clinics of coeliac disease in children in the 2000s. AB - OBJECTIVE: To describe the clinical picture of patients with coeliac disease (CD) and the change in its presentation over the past decades. STUDY DESIGN: Patients with CD were identified and clinical data collected from hospital records over a 6-year period (2000-2005). RESULTS: Altogether 197 patients aged 0.6-15.9 (mean 7.2) years were identified. They were found amongst the child population served by the hospital, the mean number of children at age 0.5-16 years was 268 000 during 2000-2005. The presenting symptom amongst the youngest patients (<3 years) was chronic diarrhoea (in 67%), and amongst older patients, abdominal pain. At the time of diagnosis, growth was severely retarded (height <2 SD for age) in 6.6%; mean height was -0.06 SD and weight + 1% for height. After diet treatment for a mean of 6 months, both height and weight increased significantly. Anaemia and iron deficiency were present in 25% and 43% of patients respectively. Intraepithelial T-cell receptor gamma/delta cells were pathologic in all 150 specimens studied. CONCLUSIONS: The presentation of CD depends on age. Even when we found six times more patients than during years 1976-1985 in the same hospital, published data on the prevalence of CD suggest that we found only a small minority of children with CD. PMID- 20199496 TI - The natural history of daytime urinary incontinence in children: a large British cohort. AB - AIM: Few studies have looked at the prevalence of daytime incontinence in a longitudinal cohort of children. This study set out to determine the prevalence of daytime incontinence and relationships between daytime incontinence and bedwetting, faecal incontinence and urgency in a large cohort of British children. METHODS: Parents of children taking part in the Avon Longitudinal Study of Parents and Children (ALSPAC) were asked questions concerning the child's daytime wetting, bedwetting and faecal incontinence at different time points, 4.5, 5.5, 6.5, 7.5 and 9.5 years. The difference between the sexes for these different conditions was compared. RESULTS AND LIMITATIONS: Data were available for 10 819 of the 13 973 children who entered the study. The prevalence of any daytime incontinence declined from 15.5% at 4.5 years to 4.9% at 9.5 years, and was mainly described as infrequent. Daytime incontinence was more common in girls than boys and frequent (DSM-IV) incontinence was more commonly related to urgency, bedwetting and faecal incontinence than infrequent incontinence. CONCLUSIONS: Daytime incontinence is relatively common among children of primary school age and frequent incontinence more commonly coexists with other conditions, such as bedwetting and urgency. This study suggests the need for treatment to focus on children with frequent incontinence. PMID- 20199497 TI - Hormonal alterations in adolescent chronic fatigue syndrome. AB - AIM: The chronic fatigue syndrome is associated with alterations in the hypothalamus-pituitary-adrenal axis and cardiovascular autonomic nervous activity, suggesting a central dysregulation. This study explored differences among adolescent chronic fatigue syndrome patients and healthy controls regarding antidiuretic hormone, the renin-angiotensin-aldosterone-system, sex hormones and cardiac peptides. METHODS: We included a consecutive sample of 67 adolescents aged 12-18 years with chronic fatigue syndrome diagnosed according to a thorough and standardized set of investigations, and a volunteer sample of 55 healthy control subjects of equal gender and age distribution. Hormones were assayed with standard laboratory methods. RESULTS: Among patients, plasma antidiuretic hormone was significantly decreased and serum osmolality and plasma renin activity were significantly increased (p < or = 0.001). Serum concentration of aldosterone, cortisol, NT-proBNP and sex hormones were not significantly different in the two groups. CONCLUSION: Chronic fatigue syndrome in adolescents is associated with alterations in hormonal systems controlling osmolality and blood volume, possibly supporting a theory of central dysregulation. PMID- 20199498 TI - Depression and treatment with antidepressants are associated with the development of gastro-oesophageal reflux disease. AB - BACKGROUND: The roles of depression and antidepressants in triggering reflux symptoms remain unclear. AIM: To compare the incidence of gastro-oesophageal reflux disease (GERD) in individuals with and without a depression diagnosis and to evaluate risk factors for a GERD diagnosis. The relationship between antidepressant treatment and GERD was also assessed. METHODS: The Health Improvement Network UK primary care database was used to identify patients with incident depression and an age- and sex-matched control cohort with no depression diagnosis. Incident GERD diagnoses were identified during a mean follow-up of 3.3 years. Furthermore, we performed nested case-control analyses where odds ratios (OR) with 95% confidence intervals (CI) were estimated by unconditional logistic regression in multivariable models. RESULTS: The incidence of GERD was 14.2 per 1000 person-years in the depression cohort and 8.3 per 1000 person-years in the control cohort. The hazard ratio of GERD in patients with depression compared with controls was 1.72 (95% CI: 1.60-1.85). Among patients with depression, tricyclic antidepressant use was associated with an increased risk of GERD (OR: 1.71; 95% CI: 1.34-2.20), while selective serotonin reuptake inhibitors were not associated with GERD. CONCLUSIONS: A depression diagnosis is associated with an increased risk of a subsequent GERD diagnosis, particularly in individuals using tricyclic antidepressants. PMID- 20199499 TI - The influence of socioeconomic deprivation on outcomes following renal transplantation in the United kingdom. AB - Socio-economic deprivation is an important determinant of poor health and is associated with a higher incidence of end-stage renal disease, higher mortality for dialysis patients and lower chance of being listed for transplantation. The influence of deprivation on outcomes following renal transplantation has not previously been reported in the United Kingdom. The Welsh Index of Multiple Deprivation was used to assess the influence of socio-economic deprivation on outcomes for 621 consecutive renal transplant recipients from a single centre in the United Kingdom transplanted between 1997 and 2005. Outcomes measured were rate of acute rejection and graft survival. Patients from the most deprived areas were significantly more likely to experience an episode of acute rejection requiring treatment (36% vs. 27%, p=0.01) and increasing overall deprivation correlated with increasing rates of rejection (p=0.03). Income deprivation was significantly and independently associated with graft survival (HR 1.484, p=0.046). Among patients who experienced acute rejection 5-year graft survival was 79% for those from the most deprived areas compared with 90% for patients from the least deprived areas (p = 0.018). Overall socio-economic deprivation is associated with higher rate of acute rejection following renal transplantation and income deprivation is a significant and independent predictor of graft survival. PMID- 20199500 TI - Ex vivo application of carbon monoxide in UW solution prevents transplant-induced renal ischemia/reperfusion injury in pigs. AB - I/R injury is a major deleterious factor of successful kidney transplantation (KTx). Carbon monoxide (CO) is an endogenous gaseous regulatory molecule, and exogenously delivered CO in low concentrations provides potent cytoprotection. This study evaluated efficacies of CO exposure to excised kidney grafts to inhibit I/R injury in the pig KTx model. Porcine kidneys were stored for 48 h in control UW or UW supplemented with CO (CO-UW) and autotransplanted in a 14-day follow-up study. In the control UW group, animal survival was 80% (4/5) with peak serum creatinine levels of 12.0 +/- 5.1 mg/dL. CO-UW showed potent protection, and peak creatinine levels were reduced to 6.9 +/- 1.4 mg/dL with 100% (5/5) survival without any noticeable adverse event or abnormal COHb value. Control grafts at 14 days showed significant tubular damages, focal fibrotic changes and numerous infiltrates. The CO-UW group showed significantly less severe histopathological changes with less TGF-beta and p-Smad3 expression. Grafts in CO UW also showed significantly lower early mRNA levels for proinflammatory cytokines and less lipid peroxidation. CO in UW provides significant protection against renal I/R injury in the porcine KTx model. Ex vivo exposure of kidney grafts to CO during cold storage may therefore be a safe strategy to reduce I/R injury. PMID- 20199502 TI - Recurrent primary biliary cirrhosis after liver transplantation. AB - Recurrent primary biliary cirrhosis (PBC) is an important clinical outcome after liver transplantation (LT) in selected patients. Prevalence rates for recurrent PBC (rPBC) reported by individual LT programs range between 9% and 35%. The diagnostic hallmark of rPBC is histologic identification of granulomatous changes. Clinical and biochemical features are frequently absent with rPBC and cannot be used alone for diagnostic purposes. Some of the risk factors of rPBC may include recipient factors such as age, gender, HLA status and immunosuppression, as well as donor factors such as age, gender and ischemic time, although controversy exists. Most patients have early stage disease at the time of diagnosis, and there may be a role for therapy with ursodeoxycholic acid. While short- and medium-term outcomes remain favorable, especially if compared to patients transplanted for other indications, continued follow-up may identify reduced long-term graft and patient survival. PMID- 20199501 TI - Database comparison of the adult-to-adult living donor liver transplantation cohort study (A2ALL) and the SRTR U.S. Transplant Registry. AB - Data submitted by transplant programs to the Organ Procurement and Transplantation Network (OPTN) are used by the Scientific Registry of Transplant Recipients (SRTR) for policy development, performance evaluation and research. This study compared OPTN/SRTR data with data extracted from medical records by research coordinators from the nine-center A2ALL study. A2ALL data were collected independently of OPTN data submission (48 data elements among 785 liver transplant candidates/recipients; 12 data elements among 386 donors). At least 90% agreement occurred between OPTN/SRTR and A2ALL for 11/29 baseline recipient elements, 4/19 recipient transplant or follow-up elements and 6/12 donor elements. For the remaining recipient and donor elements, >10% of values were missing in OPTN/SRTR but present in A2ALL, confirming that missing data were largely avoidable. Other than variables required for allocation, the percentage missing varied widely by center. These findings support an expanded focus on data quality control by OPTN/SRTR for a broader variable set than those used for allocation. Center-specific monitoring of missing values could substantially improve the data. PMID- 20199503 TI - How different conceptions of risk are used in the organ market debate. AB - The success of kidney and liver transplantation is hindered by a shortage of organs available for transplantation. Although currently illegal in nearly all parts of the world, a living 'donor' or 'vendor' kidney market has been proposed as a means to reduce or even end this shortage. Physician members of the American Society of Transplantation, the American Society of Transplant Surgeons and the American Association for the Study of Liver Disease were surveyed regarding organ markets for both living kidney and living liver transplantation. The survey queried respondents about their attitudes toward directed living donation, nondirected living donation, the potential legalization of living donor organ markets and the reasons for their support or opposition to organ markets. Partial or completed surveys were returned by 346 of 697 eligible respondents (50%). While virtually all supported or strongly supported directed living donation (98% and 95% for kidney and liver lobes, respectively), the vast majority disagreed or strongly disagreed with the legalization of living donor organ markets (80% for kidneys and 90% for liver lobes). Both those who support and those who oppose a legalized living donor organ market rate risk to the donor among the most important factors to justify their position. PMID- 20199504 TI - Altruistic donor triggered domino-paired kidney donation for unsuccessful couples from the kidney-exchange program. AB - Between January 2000 and July 2009, 132 individuals inquired about altruistic kidney donation to strangers. These donors were willing to donate to genetically and emotionally unrelated patients. Some altruistic donors wished to donate to a specific person, but most wished to donate anonymously. In domino-paired donation, the altruistic donor donates to the recipient of an incompatible couple; the donor of that couple (domino-donor) donates to another couple or to the waiting list. In contrast to kidney-exchange donation where bilateral matching of couples is required, recipient and donor matching are unlinked in domino-paired donation. This facilitates matching for unsuccessful couples from the kidney-exchange program where blood type O prevails in recipients and is under-represented in donors. Fifty-one altruistic donors (39%) donated their kidney and 35 domino-donors were involved. There were 29 domino procedures, 24 with 1 altruistic donor and 1 domino-donor, 5 with more domino-donors. Eighty-six transplantations were performed. Donor and recipient blood type distribution in the couples limited allocation to blood type non-O waiting list patients. The success rate of domino-paired donation is dependent on the composition of the pool of incompatible pairs, but it offers opportunities for difficult to match pairs that were unsuccessful in the kidney-exchange program. PMID- 20199505 TI - Evolving paradigms that determine the fate of an allograft. AB - Despite the many advances in both immunological knowledge and the practical application of clinical immunosuppression, the holy grail of indefinite graft survival with immune tolerance in clinical solid organ transplantation remains a distant dream. The tremendous progress made in understanding the molecular and cellular basis of allograft rejection has not been translated into durable modalities that have advanced clinical care and outcomes. Indeed, currently used drugs and treatment protocols, largely directed at inhibiting alloreactive T cells, have not optimally improved allograft survival or function. A shift in emphasis, focusing on under appreciated immune pathways must now be considered to make further improvement. We highlight three areas of recent interest, complement, NK cells and lymphatics, which reinforce the concept that the transplant community must direct attention on how the immune system as a whole responds to a transplant. The current challenge is to integrate molecular, cellular and anatomic concepts to achieve the equivalent of a unified field theory of the immune response to organ transplants. PMID- 20199506 TI - MicroRNAs as immune regulators: implications for transplantation. AB - The explosion of genetic information from recent advances in sequencing technologies, bioinformatics and genomics highlights the importance of understanding mechanisms involved in gene expression and regulation. Over the last decade, it has become clear that small ribonucleic acids (RNAs) are a central component of the cellular gene regulatory network. MicroRNAs (miRNAs) are a family of endogenous, small, noncoding single-stranded RNA of approximately 22 nucleotides in length that act as posttranscriptional gene regulatory elements. MicroRNAs can inhibit de novo protein synthesis by blocking translation through base-pairing with complementary messenger RNA (mRNA) and also suppress translation by promoting degradation of target mRNA. MicroRNAs are intimately involved in a variety of biologic processes including development, hematopoietic cell differentiation, apoptosis and proliferation. To date, over 800 human miRNAs have been identified, though the biologic function of only a fraction of miRNAs has been elucidated. Here, we discuss how miRNAs are produced, identified and quantitated, and focus on several key miRNAs that govern expression of genes relevant to allograft rejection, tolerance induction and posttransplant infection. Finally, we discuss potential ways in which the miRNA network can be modulated that ultimately may offer new strategies to promote long-term graft survival. PMID- 20199509 TI - Low-dose rituximab for posttransplant recurrent membranous nephropathy. PMID- 20199510 TI - Immediate posttransplantation cotrimoxazole-induced immune thrombocytopenia. AB - Drug-induced immune thrombocytopenia (DITP) can be caused by numerous drugs. When this condition develops, platelet destruction results from binding of antibodies to normal platelets only in the presence of a sensitizing drug. A recently proposed model suggests that these drug-dependent antibodies are derived from a pool of naturally occurring antibodies with weak affinity for specific epitopes on certain platelet membrane glycoproteins. We describe here a case of DITP secondary to cotrimoxazole exposure in the immediate posttransplantation phase in a renal transplant recipient. Apart from heparin-induced thrombocytopenia, DITP posttransplantation has to the best of our knowledge never been described, perhaps because of its immune-mediated origin. Our case demonstrates that DITP can occur posttransplantation, that cotrimoxazole due to its intensive use in the transplanted population is one of the most likely causative agents and that a timely recognition and treatment might have important consequences for both graft and patient. PMID- 20199511 TI - An unexpected counter-regulatory role of IL-10 in B-lymphocyte-mediated transplantation tolerance. AB - Monoclonal antibody against the CD45RB protein induces stable transplantation tolerance to multiple types of allograft. We have previously established that this tolerance protocol relies on the regulatory function of B lymphocytes for its effect. B lymphocytes have also been reported to participate in immune regulation in several other settings. In most of these systems, the regulatory function of B lymphocytes depends on the production of IL-10. Therefore, we investigated the role of IL-10 in the anti-CD45RB model of B-cell-mediated transplantation tolerance. Surprisingly, using antibody-mediated neutralization of IL-10, IL-10-deficient recipients and adoptive transfer of IL-10-deficient B lymphocytes, we found that IL-10 actually counter-regulates tolerance induced by anti-CD45RB. Furthermore, neutralization of IL-10 reduced the development of chronic allograft vasculopathy compared to anti-CD45RB alone and reduced the production of graft reactive alloantibodies. These data suggest that the participation of regulatory B lymphocytes in transplantation tolerance may be distinct from how they operate in other systems. Identifying the specific B lymphocytes that mediate transplantation tolerance and defining their mechanism of action may yield new insights into the complex cellular network through which antigen-specific tolerance is established and maintained. PMID- 20199512 TI - 'Normal for now' or 'at future risk': a double standard for selecting young and older living kidney donors. AB - Transplant centers medically evaluate potential living kidney donors in part to determine their baseline remaining lifetime risk for end stage renal disease (ESRD). If baseline risk is increased by the presence of a risk factor for ESRD, donation is often refused. However, as only about 13% of ESRD occurs in the general population by age 44, a normal medical evaluation cannot be expected to significantly reduce the 7% lifetime risk for a 'normal' 25-year-old black donor or the 2-3% risk for a similar white donor. About half of newly diagnosed ESRD in the United States occurs by age 65, and about half of that is from diabetic nephropathy, which takes about 25 years to develop. Therefore, the remaining baseline lifetime risk for ESRD is significantly lower in the normal, nondiabetic 55-year-old donor candidate. Some older donors with an isolated medical abnormality such as mild hypertension will be at lower or about the same overall baseline lifetime risk for ESRD as are young 'normal' donor candidates. Transplant centers use a 'normal for now' standard for accepting young donors, in place of the long-term risk estimates that must guide selection of all donors. PMID- 20199513 TI - Rituximab for severe myasthenia gravis--experience from five patients. AB - BACKGROUND: Rituximab (RTX), a monoclonal antibody directed against CD20+ B cells, is used in the treatment of several autoimmune disorders including severe generalized myasthenia gravis (MG). AIMS OF THE STUDY: To describe the experience with RTX in five MG patients treated at our Neuromuscular Centre. METHODS: Effect of RTX treatment was monitored by quantitative MG score (QMG score), forced vital capacity (FVC) and records of clinical parameters. Three patients had thymoma. Duration of MG prior to the first course of RTX was 3, 7, 26, 26 and 38 years. RESULTS: We found favourable response to RTX treatment in all five patients. QMG score was markedly lower after RTX and in the three patients with respiratory muscle affection the FVC was increased. A good relief of bulbar, respiratory or extremity MG weakness was thus also found in the three patients who had long standing severe MG. Repeated RTX treatment was needed in four patients. CONCLUSIONS: We conclude that RTX is effective in recent onset MG as well as in long-standing cases. As thymoma is prevalent in patients with severe MG, further studies are needed to evaluate the risk of thymoma recurrence following RTX treatment. PMID- 20199514 TI - Activities of daily living and quality of life in persons with newly diagnosed Parkinson's disease according to subtype of disease, and in comparison to healthy controls. AB - OBJECTIVE: To describe activity of daily living (ADL) and quality of life (QoL) at first visit to a neurological centre, in patients subsequently diagnosed with Parkinson's disease (PD), according to subtype of disease and compared to healthy controls. MATERIALS AND METHODS: 99 patients and 31 controls were included. Patients were classified into three groups according to predominant symptoms: 50 Postural instability-gait difficulties (PIGD), 37 tremor dominant, 12 indeterminate. Evaluations included ADL-taxonomy, SF-36, and the Parkinson disease questionnaire (PDQ-39). RESULTS: Patients experienced early on limitations in ADL and QoL compared to controls. Patients with PIGD subtype had already at first visit a worse status, clinically and in ADL and QoL, than patients with tremor dominant type. CONCLUSIONS: Already at first visit to a neurological centre, patients who will eventually receive the diagnosis of PD exhibited restrictions in ADL and QoL. Patients with axial symptoms were affected most. PMID- 20199515 TI - Acute postoperative seizures after epilepsy surgery - a long-term outcome predictor? AB - OBJECTIVES: The prognostic value of acute postoperative seizures (APS) after epilepsy surgery is much debated. This study evaluated APS, defined as seizures in the first week post-surgery, as a predictor of long-term seizure outcome, and investigated the utility of other potential outcome predictors. MATERIALS AND METHODS: Medical records of 48 patients with temporal and extra-temporal epilepsy surgery were studied. Forty patients had lesional surgery. All had at least 2 year postoperative follow-up. RESULTS: At 2 year follow-up, 25 patients (53%) were seizure free. Univariate analysis showed that APS (P = 0.048), using >= six AEDs prior to surgery (P = 0.03), pathological postoperative EEG (P = 0.043) and female gender (P = 0.012) were associated with seizure recurrence. CONCLUSIONS: Univariate analysis indicate that APS, a high number of AEDs used prior to surgery, and pathological postoperative EEG are possible predictors of seizure recurrence after epilepsy surgery. Only gender retained significance in the multivariate analysis. PMID- 20199516 TI - Lacosamide as treatment of epileptic seizures - cost utility results for Sweden. AB - OBJECTIVES: To calculate cost per additional quality-adjusted life-year (QALY) for lacosamide as adjunctive treatment for patients with uncontrolled partial onset seizures as compared to no adjunctive treatment. MATERIALS AND METHODS: A decision-tree simulation model was constructed to calculate the number of seizures and health-care utilization for treated and untreated with lacosamide, respectively. Prices from 2007 were used for all costs. RESULTS: All results were calculated for a 24-, 18-, 12- and 6-months follow-up. The cost per additional QALY was estimated to euro 27,641 (24 months). Using a willingness-to-pay threshold for a QALY of euro 50,000 the net marginal value of using lacosamide was estimated to about euro 850,000 per 1000 patients. CONCLUSIONS: The estimated cost per QALY gained falls within the range of reported estimates of the willingness-to-pay for an additional QALY. The results imply that lacosamide is cost-effective in the treatment of uncontrolled partial-onset seizures (1 euro approximately 9.6 SEK). PMID- 20199517 TI - Chitotriosidase activity in controls and multiple sclerosis. PMID- 20199518 TI - Exercise and Parkinson's: benefits for cognition and quality of life. AB - OBJECTIVES: The benefits of physical exercise for psychological aspects of quality of life (QoL) are well established in normally ageing adults, yet potential benefits for people with Parkinson's disease (PD) have received limited attention. This study evaluated the benefits of exercise for cognitive functioning, mood and disease-specific QoL for people with PD. METHODS: Twenty eight individuals with PD were allocated to an exercise intervention program (EIP, n = 15) or control group (n = 13). The EIP group undertook a programme of progressive anabolic and aerobic exercise twice weekly for 12 weeks. The control group maintained their usual lifestyle. RESULTS: Exercise was shown to have selective benefits for cognitive functioning by improving frontal lobe based executive function. No significant effects were demonstrated for mood or disease specific QoL. CONCLUSIONS: These results are consistent with previous research demonstrating selective benefits of exercise for executive function among normal ageing adults and PD. PMID- 20199519 TI - Recovery in personal care related to cognitive impairment before and after stroke - a 1-year follow-up. AB - OBJECTIVE: To examine whether there were any differences in the recovery in performance of personal activities of daily living (P-ADL) in elderly persons in relation to cognitive impairments pre- and post-stroke from discharge to 6 and 12 months in elderly persons. METHODS: Forty-five elderly persons after stroke were assessed at discharge from hospital and at 6 and at 12 months after stroke onset. A questionnaire posed to the next of kin was used to evaluate the person's pre- and post-stroke cognitive status. P-ADL was assessed with the Barthel Index. The Mini Mental State Examination and neuropsychological tests were used to measure cognitive functions after stroke. The National Institute of Health Stroke Scale was used to measure neurological deficits. RESULTS: Persons with cognitive impairments before and after stroke did not improve in P-ADL from the acute phase until 6 and 12 months, while persons with intact cognition pre- and post-stroke did. CONCLUSION: Since cognitive problems pre- and post-stroke hinder recovery in P-ADL, it is important to understand the connection between cognitive impairment and activity limitations when planning the optimal rehabilitation, which could include special compensation strategies, learnt by the patients, cognitive assistive devices and/or appropriate personal support trained in meaningful activities in daily life in their natural environment. PMID- 20199520 TI - Re-evaluation of the dysequilibrium syndrome. AB - OBJECTIVES: To re-evaluate middle-aged Swedish patients diagnosed with dysequilibrium syndrome (DES) in childhood and to compare their clinical and neuroimaging features to DES with VLDLR gene mutations (DES-VLDR). MATERIALS AND METHODS: Six patients from five families underwent neurological examination and magnetic resonance imaging (MRI) of the brain. Blood samples from the patients were screened for serum carbohydrate-deficient transferrin (s-CDT; disialotransferrin). The very-low-density lipoprotein receptor (VLDLR) gene was sequenced. RESULTS: Five patients had non-progressive cerebellar ataxia (NPCA), dysarthria and short stature. Mental retardation and strabismus, characteristic for DES-VLDLR, were inconsistent among our patients. None of our patients had VLDLR mutations or MRI findings characteristic of DES-VLDLR. MRI findings were variable from a normal cerebellum to marked cerebellar hypoplasia or atrophy and signal intensity changes. One patient was diagnosed with congenital disorder of glycosylation type 1a (CDG-1a). CONCLUSIONS: DES was originally coined on mainly clinical grounds before MRI and specific genetic tests were available, both of which should be used to arrive at an appropriate diagnosis. PMID- 20199521 TI - Adjunctive rufinamide in Lennox-Gastaut syndrome: a long-term, open-label extension study. AB - OBJECTIVE: This open-label extension evaluated the long-term efficacy and tolerability of rufinamide in patients with Lennox-Gastaut syndrome (LGS) who had previously completed a 12-week double-blind study. MATERIALS AND METHODS: In total, 124 patients (aged 4-37 years), receiving 1-3 concomitant antiepileptic drugs, were treated with rufinamide approximately 25-60 mg/kg/day. Efficacy was assessed by seizure frequency; tolerability by adverse events (AEs) and laboratory tests. RESULTS: Overall, patients were treated with rufinamide for a median (range) of 432 (10-1149) days. Reductions in seizure frequency were observed throughout the study; during the last 12 months of treatment, 41.0% and 47.9% of patients had > or = 50% reduction in total and tonic-atonic seizure frequency, respectively. The most common AEs were vomiting (30.6%) and pyrexia (25.8%). CONCLUSIONS: In this open-label extension, rufinamide appeared to be an effective long-term adjunctive therapy for the treatment of LGS-associated seizures in children and young adults. PMID- 20199523 TI - Fever is associated with doubling of odds of short-term mortality in ischemic stroke: an updated meta-analysis. AB - OBJECTIVE: Association between fever and ischemic stroke mortality is known, but the magnitude and independence of the association is controversial. This paper aims to determine the size of independent effect of fever on short term mortality in acute ischemic stroke. METHODS: We searched the Medline and Cochrane library databases for papers studying the relationship between fever in acute ischemic stroke and short term mortality from January, 1990 to November, 2008. Two authors independently selected the studies for inclusion in the review using explicit criteria. Data was entered into software Revman 4.2.8. Heterogeneity was assessed using I2 and chi-square statistics. Odds ratios (OR) from logistic regression were combined. Magnitude of association was determined using meta-analysis of the adjusted odds ratio using fixed effects model. RESULTS: Six cohort studies involving 2986 patients were included. There was no significant heterogeneity among studies reporting short-term mortality (I2 = 21.2%, P = 0.28). Meta analysis yielded a combined OR of 2.20 (95% CI 1.59-3.03, P < 0.00001). CONCLUSIONS: This meta-analysis suggests that fever within first 24 h of hospitalization in patients with ischemic stroke is associated with doubling of odds of mortality within one month of the onset of stroke. PMID- 20199522 TI - Inverse relationship of baseline body temperature and outcome between ischemic stroke patients treated and not treated with thrombolysis: the Bergen stroke study. AB - BACKGROUND: High body temperature may promote clot lysis whereas low body temperature is neuroprotective in patients with cerebral infarction. We hypothesized that high body temperature is associated with favorable outcome in patients treated with tissue plasminogen activator (tPA) and that low body temperature is associated with favorable outcome in patients not treated with tPA. METHODS: Patients (n = 111) who were treated with tPA and patients (n = 139) who were not treated with tPA, but presented within 6 h of stroke onset were included. Patients with no temperature measurements within 6 h of stroke onset were excluded. National Institute of Health Stroke Scale (NIHSS) score was obtained on admission. Modified Rankin score (mRS) was obtained after 1 week. Favorable outcome was defined as mRS 0-2 and unfavorable outcome as mRS 3-6. RESULTS: On logistic regression analysis, high body temperature was independently associated with favorable outcome among patients treated with tPA (OR = 3.7, P = 0.009) and low body temperature was independently associated with favorable prognosis among patients not treated with tPA (OR = 2.0, P = 0.042). CONCLUSIONS: Our study suggests that the effect of high body temperature on clot lysis is more important than the neuroprotective effect of low body temperature in the early phase after cerebral infarction treated with tPA. PMID- 20199535 TI - Determination of the optimal stylet strategy for the C-MAC videolaryngoscope. AB - The C-MAC videolaryngoscope is a novel intubation device that incorporates a camera system at the end of its blade, thereby facilitating obtaining a view of the glottis without alignment of the oral, pharyngeal and tracheal axes. It retains the traditional Macintosh blade shape and can be used as a direct or indirect laryngoscope. We wished to determine the optimal stylet strategy for use with the C-MAC. Ten anaesthetists were allowed up to three attempts to intubate the trachea in one easy and three progressively more difficult laryngoscopy scenarios in a SimMan manikin with four tracheal tube stylet strategies: no stylet; stylet; directional stylet (Parker Flex-It); and hockey-stick stylet. The use of a stylet conferred no advantage in the easy laryngoscopy scenario. In the difficult scenarios, the directional and hockey-stick stylets performed best. In the most difficult scenario, the median (IQR [range]) duration of the successful intubation attempt was lowest with the hockey-stick stylet; 18 s (15-22 [12-43]) s, highest with the unstyletted tracheal tube; 60 s (60-60 [60, 60]) s and styletted tracheal tube 60 s (29-60 [18-60]) s, and intermediate with the directional stylet 21 s (15-60 [8-60]) s. The use of a stylet alone does not confer benefit in the setting of easy laryngoscopy. However, in more difficult laryngoscopy scenarios, the C-MAC videolaryngoscope performs best when used with a stylet that angulates the distal tracheal tube. The hockey-stick stylet configuration performed best in the scenarios tested. PMID- 20199537 TI - A case of cholinergic urticaria associated with acquired generalized hypohidrosis and abnormal neurological findings: association with incomplete Ross syndrome? PMID- 20199538 TI - Identification of novel and known KRT5 and KRT14 mutations in 53 patients with epidermolysis bullosa simplex: correlation between genotype and phenotype. AB - BACKGROUND: Basal epidermolysis bullosa simplex (EBS) is a hereditary skin blistering disorder resulting in most cases from missense mutations in the keratin 5 (KRT5) or keratin 14 (KRT14) genes. OBJECTIVES: To identify the underlying mutations in different EBS subtypes and correlate genotype and phenotype. METHODS: Mutation analysis was performed in 53 patients with EBS and their families by direct sequencing of the KRT5 and KRT14 genes. RESULTS: We identified 39 different mutations, of which 15 have not been published previously. Three novel deletion/insertion mutations, among them one in-frame duplication, were associated with the rare phenotype of EBS with mottled pigmentation. We identified for the first time a patient with compound heterozygosity for KRT5 mutations causing Dowling-Degos disease and EBS. CONCLUSIONS: Identification of novel mutations and genotype-phenotype correlations in EBS allow improved understanding of disease pathogenesis as well as better patient management. PMID- 20199539 TI - H syndrome: novel and recurrent mutations in SLC29A3. AB - The H syndrome (OMIM 612391) is a recently described autosomal recessive disorder characterized by cutaneous hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, short stature (low height), hyperglycaemia/diabetes mellitus, hallux valgus, and fixed flexion contractures of the toe and finger joints.(1,2) Histologically, there is an inflammatory infiltrate consisting mainly of histiocytes, later replaced by fibrosis of the deep dermis and subcutis.(3) In total, 31 patients have been reported in the literature with the clinical phenotype characteristic of this syndrome.(1-7) PMID- 20199540 TI - The role of transforming growth factor-beta1 and oxidative stress in podoconiosis pathogenesis. AB - BACKGROUND: Podoconiosis (endemic nonfilarial elephantiasis) occurs in susceptible individuals who go barefoot in regions of irritant volcanic soil. Silicate particles absorbed via the skin are thought to induce an inflammatory process and a consequent endolymphangitis of the lower leg lymphatics. OBJECTIVES: To establish which oxidative stress biomarkers play a part in the inflammatory process, and to test whether transforming growth factor (TGF)-beta1 also has a pathogenetic role. PATIENTS AND METHODS: We enrolled 50 patients with early clinical stage disease, 43 patients with advanced stage disease and 35 local healthy controls. Oxidative stress biomarkers included serum total peroxides (TP), total antioxidant capacity (TAC), total nitrate plus nitrite (TN), malondialdehyde (MDA) and total superoxide dismutase (SOD) activity. The oxidative stress index (OSI) was also determined. Serum total TGF-beta1 was assayed using sandwich enzyme-linked immunosorbent assay. RESULTS: Compared with healthy controls, patients with early stage disease showed significantly higher mean levels of TP (P < 0.001), MDA (P < 0.05) and OSI (P < 0.01); and significantly lower mean concentrations of SOD (P < 0.001) and TGF-beta1 (P < 0.001). Mean levels of TGF-beta1 were even lower among patients with advanced stage disease (P < 0.001). Mean TAC levels were significantly lower among patients with advanced disease than either other group (P < 0.001). CONCLUSIONS: This is the first study, to our knowledge, to attempt to elucidate the molecular pathogenetic events in podoconiosis. We conclude that TGF-beta1 may have a pathogenetic role, with oxidative stress playing a minor role in the early stages of disease. PMID- 20199541 TI - Radiotherapy: a protective role for toxic epidermal necrolysis? PMID- 20199542 TI - Infliximab therapy induces increased polyclonality of CD4+CD25+ regulatory T cells in psoriasis. PMID- 20199543 TI - A case of antilaminin 332 mucous membrane pemphigoid showing a blister on the bulbar conjunctiva and a unique epitope on the alpha3 subunit. PMID- 20199544 TI - Identification of a primarily neurological phenotypic expression of xeroderma pigmentosum complementation group A in a Tunisian family. AB - Xeroderma pigmentosum (XP) is a rare genodermatosis predisposing to skin cancers. The disease is classified into eight groups. Among them, XP group A (XP-A) is characterized by the presence of neurological abnormalities in addition to cutaneous symptoms. In the present study, we report a particular family with XP-A in which some members showed an atypical clinical presentation, i.e. unexplained neurological abnormalities with discrete skin manifestations. Molecular investigation allowed identification of a novel XPA mutation and complete phenotype-genotype correlation for this new phenotypic expression of XP-A. PMID- 20199545 TI - Comparison of the two techniques for measurement of the density of Demodex folliculorum: standardized skin surface biopsy and direct microscopic examination. AB - BACKGROUND: In daily dermatological practice, many dermatologists do not include demodicosis in their differential diagnoses, or the diagnosis of demodicosis is frequently masked by other skin diseases such as papulopustular or erythematotelangiectatic rosacea, seborrhoeic dermatitis, perioral dermatitis and contact dermatitis. There are two methods for measurement of the density of Demodex folliculorum (Dd): standardized skin surface biopsy (SSSB) and direct microscopic examination of fresh secretions from sebaceous glands (DME). No study has been reported in the literature comparing the diagnostic value of these two techniques. OBJECTIVES: To compare the value of the two techniques, SSSB and DME, for the measurement of Dd in patients with suspected demodicosis. METHODS: Mite density was investigated using SSSB and DME in 37 patients with facial skin lesions suggesting demodicosis. Two samples, one for SSSB and one for DME, were obtained from a cheek lesion of each patient. RESULTS: Twenty-three (62%) patients were diagnosed with demodicosis according to their clinical manifestations combined with a high Dd (Dd > 5 mites cm(-2)) with SSSB and/or DME. In all the patients, the mean Dd measured with SSSB was higher than that with DME (22.9 +/- 5.9 and 2.2 +/- 0.8, respectively; P = 0.001). Also, among the 23 patients with demodicosis, the mean Dd measured using SSSB was higher than the mean Dd with DME (36.5 +/- 8.3 and 3.4 +/- 1.2, respectively; P = 0.0001). CONCLUSIONS: We recommend the use of SSSB for the measurement of Dd as more patients with demodicosis can be diagnosed with this method compared with the DME method. PMID- 20199546 TI - Interactions between ultraviolet light exposure and DNA repair gene polymorphisms may increase melanoma risk. PMID- 20199547 TI - Measuring disease activity and damage in discoid lupus erythematosus. AB - BACKGROUND: Discoid lupus erythematosus (DLE) is a disfiguring inflammatory skin disease. There is no specific tool for measuring disease severity. OBJECTIVES: To determine the features needed in a score measuring activity and damage in DLE and to investigate the score's reliability and its correlation with the physician's global assessment of disease severity and the patient-reported Dermatology Quality of Life Index (DLQI). METHODS: The content of the score was determined following a peer review, pilot work in patients and a preliminary inter-rater reliability study. The Score of Activity and Damage in DLE (SADDLE) measures severity of activity (erythema, scale, induration) and damage (scarring/atrophy and dyspigmentation) attributable to DLE. Summed scores range between 0 and 195. Inter- and intrarater reliability of the score was tested using six assessors and nine patients with DLE. Intraclass correlation coefficients (ICCs) > 0.7 were considered evidence of good inter- and intrarater agreement. RESULTS: The mean +/ SD SADDLE score of nine patients in the inter-rater reliability study was 47 +/- 22 (range 14-102). There was good inter-rater agreement for the total score [ICC 0.82; 95% confidence interval (CI) 0.61-0.95] and for the activity and damage scales, the individual physical signs and the total scores at individual body sites. The total score demonstrated excellent intrarater reliability (ICC 0.98; 95% CI 0.86-1.00). Although there was poor inter-rater agreement for global assessments (ICC 0.28; 95% CI 0.06-0.66), a good correlation was demonstrated between total scores and global assessments (r = 0.7). A weaker positive correlation was observed between disease activity scores and DLQI (r = 0.4). CONCLUSIONS: The SADDLE measures activity and damage in patients with DLE. It demonstrates good inter- and excellent intrarater agreement, over and above that for global assessment. It correlates well with global assessment scores. Further studies are required to investigate SADDLE's responsiveness to change with therapy. PMID- 20199548 TI - A 'D.I.Y.' nasal plug with airway: an alternative approach. PMID- 20199549 TI - Flammability of paraffin-based products: an under-recognized hazard and methods to reduce it. PMID- 20199550 TI - A double-blind, randomized study to assess the effectiveness of different moisturizers in preventing dermatitis induced by hand washing to simulate healthcare use. AB - BACKGROUND: Healthcare-associated infection is an important worldwide problem that could be reduced by better hand hygiene practice. However, irritant contact dermatitis of the hands as a result of repeated hand washing is a potential complication that may be preventable by the regular use of an emollient. OBJECTIVES: To assess the effect of moisturizer application after repeated hand washing (15 times daily) vs. soap alone. METHODS: In a double-blind, randomized study, the effect of five different moisturizers on skin barrier function was determined by assessment after repeated hand washing over a 2-week period in healthy adult volunteers. Assessments of transepidermal water loss (TEWL), epidermal hydration and a visual assessment using the Hand Eczema Severity Index (HECSI) were made at days 0, 7 and 14. RESULTS: In total, 132 patients were enrolled into the study. A statistically significant worsening of the clinical condition of the skin as measured by HECSI was seen from baseline to day 14 (P = 0.003) in those subjects repeatedly washing their hands with soap without subsequent application of moisturizer. No change was seen in the groups using moisturizer. Subclinical assessment of epidermal hydration as a measure of skin barrier function showed significant increases from baseline to day 14 after the use of three of the five moisturizing products (P = 0.041, 0.001 and 0.009). Three of the five moisturizers tested led to a statistically significant decrease in TEWL at day 7 of repeated hand washing. This effect was sustained for one moisturizing product at day 14 of hand washing (P = 0.044). CONCLUSIONS: These results support the view that the regular application of moisturizers to normal skin offers a protective effect against repeated exposure to irritants, with no evidence of a reduction in barrier efficiency allowing the easier permeation of irritant substances into the skin as has been suggested by other studies. Regular use of emollient in the healthcare environment may prevent the development of dermatitis. PMID- 20199551 TI - Randomized, double-blinded, placebo controlled study to assess the effect of topical 1% nicotinamide on actinic keratoses. PMID- 20199553 TI - Home vs. outpatient narrowband ultraviolet B therapy for the treatment of nonsegmental vitiligo: a retrospective questionnaire study. PMID- 20199556 TI - Community-associated methicillin-resistant Staphylococcus aureus and impetigo. PMID- 20199554 TI - Polymorphisms in human histamine receptor H4 gene are associated with atopic dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) is a chronic skin disease affecting more than 15% of children and 2% of adults. A strong connection between genetic factors and AD has been described for a long time. Histamine receptor H4 (HRH4) has been shown to be related to different kinds of allergic and autoimmune disorders. However, an association between HRH4 and AD has not yet been reported. OBJECTIVES: To examine a possible association between HRH4 and AD. METHODS: Genomic DNA from 301 patients with AD and 313 healthy controls was extracted and three exons of HRH4 were sequenced. RESULTS: We found three new single nucleotide polymorphisms (SNPs) in HRH4 which were significantly associated with AD: ss142022671 [odds ratio (OR) 1.87, 95% confidence interval (CI) 1.24-2.81; P = 0.002], ss142022677 (OR 4.40, 95% CI 2.42-8.00; P = 1.5 x 10(-7)) and ss142022679 (OR 4.26, 95% CI 2.38-7.61; P = 1.3 x 10(-7)). The SNPs ss142022677 and ss142022679 were found to be in strong linkage disequilibrium (D' = 0.98; r(2) = 0.92). Two-SNP haplotype analysis (ss142022677 and ss142022679) showed that the major AA haplotype was protective against AD (OR 0.22, 95% CI 0.12-0.40; P = 3.1 x 10(-8)) and the minor TT haplotype was significantly associated with AD (OR 4.13, 95% CI 2.27-7.54; P = 6.6 x 10(-7)). In addition, in a three-SNP haplotype analysis (ss142022671, ss142022677 and ss142022679), the major TAA haplotype was protective against AD (OR 0.46, 95% CI 0.31-0.69; P = 0.0001), while the complementary ATT haplotype was found to be significantly associated with AD (OR 3.81, 95% CI 2.03-7.14; P = 8.3 x 10(-6)). CONCLUSIONS: Polymorphisms of ss142022671, ss142022677 and ss142022679 in HRH4 are associated with AD. PMID- 20199557 TI - Fine mapping of the human AR/EDA2R locus in androgenetic alopecia. PMID- 20199558 TI - Dynamics of polyploid formation in Tragopogon (Asteraceae): recurrent formation, gene flow, and population structure. AB - Polyploidy is a major feature of angiosperm evolution and diversification. Most polyploid species have formed multiple times, yet we know little about the genetic consequences of recurrent formations. Among the clearest examples of recurrent polyploidy are Tragopogon mirus and T. miscellus (Asteraceae), each of which has formed repeatedly in the last approximately 80 years from known diploid progenitors in western North America. Here, we apply progenitor-specific microsatellite markers to examine the genetic contributions to each tetraploid species and to assess gene flow among populations of independent formation. These data provide fine-scale resolution of independent origins for both polyploid species. Importantly, multiple origins have resulted in considerable genetic variation within both polyploid species; however, the patterns of variation detected in the polyploids contrast with those observed in extant populations of the diploid progenitors. The genotypes detected in the two polyploid species appear to represent a snapshot of historical population structure in the diploid progenitors, rather than modern diploid genotypes. Our data also indicate a lack of gene flow among polyploid plants of independent origin, even when they co occur, suggesting potential reproductive barriers among separate lineages in both polyploid species. PMID- 20199559 TI - Onset of glaciation drove simultaneous vicariant isolation of Alpine insects in New Zealand. AB - The origin of the New Zealand "beech gap," a low-diversity zone in the central South Island corresponding with a disjunction in the distribution of many taxa, has been the focus of biogeographical debate for many decades. Here, we use comparative phylogeographic analysis (COI; H3) of six alpine stonefly genera (116 individuals, 102 localities) to test a vicariant evolutionary hypothesis for the origin of this "biotic gap." We find strikingly similar phylogeographic patterns in all six genera, with the deepest genetic divergences always found between samples north and south of the beech gap. The magnitude of north-south genetic differentiation for COI is similar across all six genera (ranging from 0.074 to 0.091), with a test for simultaneous vicariance confirming that divergence is consistent with a single evolutionary event. The concordant cladogenesis detected across multiple taxa is consistent with vicariant isolation caused by the onset of glaciation in the late Pliocene. This study thus indicates an important cladogenetic role for glaciation, an abiotic evolutionary process that is more typically associated with loss of biodiversity. PMID- 20199560 TI - Evolution of variation and variability under fluctuating, stabilizing, and disruptive selection. AB - How variation and variability (the capacity to vary) may respond to selection remain open questions. Indeed, effects of different selection regimes on variational properties, such as canalization and developmental stability are under debate. We analyzed the patterns of among- and within-individual variation in two wing-shape characters in populations of Drosophila melanogaster maintained under fluctuating, disruptive, and stabilizing selection for more than 20 generations. Patterns of variation in wing size, which was not a direct target of selection, were also analyzed. Disruptive selection dramatically increased phenotypic variation in the two shape characters, but left phenotypic variation in wing size unaltered. Fluctuating and stabilizing selection consistently decreased phenotypic variation in all traits. In contrast, within-individual variation, measured by the level of fluctuating asymmetry, increased for all traits under all selection regimes. These results suggest that canalization and developmental stability are evolvable and presumably controlled by different underlying genetic mechanisms, but the evolutionary responses are not consistent with an adaptive response to selection on variation. Selection also affected patterns of directional asymmetry, although inconsistently across traits and treatments. PMID- 20199561 TI - Handedness and asymmetry in scale-eating cichlids: antisymmetries of different strength. AB - Individual symmetry is believed to be advantageous and reflecting developmental stability, but frequency-dependent selection can also maintain polymorphisms of asymmetric phenotypes. There are many examples of so-called antisymmetry, where mirror image morphs occur at equal frequencies. With very few exceptions, these are caused by nongenetic variation. One notable exception is handedness and mouth bending variation in the scale-eating cichlid Perissodus microlepis, which has been suggested to be an example of antisymmetry determined by a single genetic locus of large effect. Here, we report that this handedness and mouth bending asymmetry are not jointly and exclusively determined by a single major locus. We found no evidence of a major locus for asymmetry and some support for a major handedness locus. Also, asymmetry is plastic in this species: it can change in adults. We suggest that behavioral handedness in this system precedes and guides morphological asymmetry. PMID- 20199562 TI - Dilemmas of partial cooperation. AB - Related to the often applied cooperation models of social dilemmas, we deal with scenarios in which defection dominates cooperation, but an intermediate fraction of cooperators, that is, "partial cooperation," would maximize the overall performance of a group of individuals. Of course, such a solution comes at the expense of cooperators that do not profit from the overall maximum. However, because there are mechanisms accounting for mutual benefits after repeated interactions or through evolutionary mechanisms, such situations can constitute "dilemmas" of partial cooperation. Among the 12 ordinally distinct, symmetrical 2 x 2 games, three (barely considered) variants are correspondents of such dilemmas. Whereas some previous studies investigated particular instances of such games, we here provide the unifying framework and concisely relate it to the broad literature on cooperation in social dilemmas. Complementing our argumentation, we study the evolution of partial cooperation by deriving the respective conditions under which coexistence of cooperators and defectors, that is, partial cooperation, can be a stable outcome of evolutionary dynamics in these scenarios. Finally, we discuss the relevance of such models for research on the large biodiversity and variation in cooperative efforts both in biological and social systems. PMID- 20199563 TI - Mate choice and human stature: homogamy as a unified framework for understanding mating preferences. AB - Assortative mating for human height has long attracted interest in evolutionary biology, and the phenomenon has been demonstrated in numerous human populations. It is often argued that mating preferences generate this pattern, but other processes can also induce trait correlations between mates. Here, we present a methodology tailored to quantify continuous preferences based on choice experiments between pairs of stimuli. In particular, it is possible to explore determinants of interindividual variations in preferences, such as the height of the chooser. We collected data from a sample of 200 individuals from France. Measurements obtained show that the perception of attractiveness depends on both the height of the stimuli and the stature of the individual who judged them. Therefore, this study demonstrates that homogamy is present at the level of preferences for both sexes. We also show that measurements of the function describing this homogamy are concordant with several distinct mating rules proposed in the literature. In addition, the quantitative approach introduced here fulfills metrics that can be used to compare groups of individuals. In particular, our results reveal an important disagreement between sexes regarding height preferences in the context of mutual mate choice. Finally, both women and men prefer individuals who are significantly taller than average. All major findings are confirmed by a reanalysis of previously published data. PMID- 20199564 TI - Sequential female assessment drives complex sexual selection on bower shape in a cichlid fish. AB - In many animals, sexual selection on male traits results from female mate choice decisions made during a sequence of courtship behaviors. We use a bower-building cichlid fish, Nyassachromis cf. microcephalus, to show how applying standard selection analysis to data on sequential female assessment provides new insights into sexual selection by mate choice. We first show that the cumulative selection differentials confirm previous results suggesting female choice favors males holding large volcano-shaped sand bowers. The sequential assessment analysis reveals these cumulative differentials are the result of selection acting on different bower dimensions during the courtship sequence; females choose to follow males courting from tall bowers, but choose to engage in premating circling with males holding bowers with large diameter platforms. The approach we present extends standard selection analysis by partitioning the variances of increasingly accurate estimates of male reproductive fitness and is applicable to systems in which sequential female assessment drives sexual selection on male traits. PMID- 20199565 TI - Unraveling cryptic reticulate relationships and the origin of orphan hybrid disjunct populations in Narcissus. AB - Evolutionary consequences of natural hybridization between species may vary so drastically depending on spatial, genetic, and ecological factors that multiple approaches are required to uncover them. To unravel the evolutionary history of a controversial hybrid (Narcissus x perezlarae), here we use four approaches: DNA sequences from five regions (four organellar, one nuclear), cytological studies (chromosome counts and genome size), crossing experiments, and niche modeling. We conclude that (1) it actually consists of two different hybrid taxa, N.xperezlarae s.s. (N. cavanillesii x N. miniatus) and N.xalentejanus (N. cavanillesii x N. serotinus); (2) both have been formed several times independently, that is, polytopically; (3) N. cavanillesii was the mother progenitor in most hybridization events. We also address the origin of orphan hybrid populations of N.xperezlarae in eastern Spain, hundreds of kilometers away from N. cavanillesii. Although long-distance dispersal of already formed hybrids cannot be completely rejected, extirpation of N. cavanillesii via demographic competition is a more likely explanation. Low-reproductive barriers to fertilization by foreign pollen in N. cavanillesii, molecular footprints of the former presence of this species in the area, active asexual propagation by bulbs in N.xperezlarae, and overlapping ecological niches are consistent with the extirpation scenario. PMID- 20199566 TI - Foraging trait (co)variances in stickleback evolve deterministically and do not predict trajectories of adaptive diversification. AB - How does natural selection shape the structure of variance and covariance among multiple traits, and how do (co)variances influence trajectories of adaptive diversification? We investigate these pivotal but open questions by comparing phenotypic (co)variances among multiple morphological traits across 18 derived lake-dwelling populations of threespine stickleback, and their marine ancestor. Divergence in (co)variance structure among populations is striking and primarily attributable to shifts in the variance of a single key foraging trait (gill raker length). We then relate this divergence to an ecological selection proxy, to population divergence in trait means, and to the magnitude of sexual dimorphism within populations. This allows us to infer that evolution in (co)variances is linked to variation among habitats in the strength of resource-mediated disruptive selection. We further find that adaptive diversification in trait means among populations has primarily involved shifts in gill raker length. The direction of evolutionary trajectories is unrelated to the major axes of ancestral trait (co)variance. Our study demonstrates that natural selection drives both means and (co)variances deterministically in stickleback, and strongly challenges the view that the (co)variance structure biases the direction of adaptive diversification predictably even over moderate time spans. PMID- 20199567 TI - The adaptation rate of asexuals: deleterious mutations, clonal interference and population bottlenecks. AB - The rate at which a population adapts to its environment is a cornerstone of evolutionary theory, and recent experimental advances in microbial populations have renewed interest in predicting and testing this rate. Efforts to understand the adaptation rate theoretically are complicated by high mutation rates, to both beneficial and deleterious mutations, and by the fact that beneficial mutations compete with each other in asexual populations (clonal interference). Testable predictions must also include the effects of population bottlenecks, repeated reductions in population size imposed by the experimental protocol. In this contribution, we integrate previous work that addresses each of these issues, developing an overall prediction for the adaptation rate that includes: beneficial mutations with probabilistically distributed effects, deleterious mutations of arbitrary effect, population bottlenecks, and clonal interference. PMID- 20199568 TI - Shiga toxin A subunit mutant of Escherichia coli O157:H7 releases outer membrane vesicles containing the B-pentameric complex. AB - Shiga toxins (STx) are secreted extracellularly through the outer membrane vesicles (OMVs) of Escherichia coli O157:H7. In an attempt to produce STxA deficient OMVs from E. coli O157:H7, site-specific deletions of the stx1A and stx2A subunit genes were carried out. The STxA-deficient phenotype of the stx1A/stx2A mutant was confirmed by Vero cell cytotoxicity and VTEC-RPLA assay. Western blot analyses showed that the B (STxB) subunits were present without coupling to STxA in the OMVs of the STxA-deficient mutant. Furthermore, STxB was located in its homo-pentameric complexes, as revealed by immunoprecipitation and immunoblotting with anti-STxB antibodies. These results suggest that STxB alone can be oligomerized into the B pentamer in the periplasm, and subsequently entrapped into the OMVs. Determination of the median lethal dose concentration for the OMV preparations suggests that the STxA-deficient OMVs containing STxB complex could be safely used as vaccine delivery vehicles. PMID- 20199569 TI - The ectomycorrhizal community in natural Tuber borchii grounds. AB - Although Tuber borchii is a commercially valuable truffle, its habitat has been virtually ignored. Here, we examine the ectomycorrhizal fungal communities in natural T. borchii grounds. Ectomycorrhizas under T. borchii ascomata and up to 1 m away were collected and morphologically assigned to pine or oak host plants. They were then morphotyped and molecular typed using internal transcribed spacer regions. Seventy ectomycorrhizal taxa were identified, many of which were rare. Tuber borchii dominated, forming 20% of ectomycorrhizas, with Thelephoraceae, Inocybaceae and Sebacinaceae being the other main species. Species composition was markedly affected by the host plant, although community structure and composition was also influenced by the location from which the soil cores were collected. Tuber dryophilum, an edible truffle, but without commercial value, shared the habitat with T. borchii. Its mycorrhizas were never found together with those of T. borchii. Tuber borchii was present on both oaks and pines, but was more abundant in soil cores where the roots of both hosts were present. It is suggested that the presence of young oaks contributed to the maintenance of T. borchii colonization on pines. PMID- 20199570 TI - Ultramafic soils from New Caledonia structure Pisolithus albus in ecotype. AB - Isolates of ectomycorrhizal Pisolithus albus were sampled from both ultramafic and volcano-sedimentary soils in New Caledonia, a tropical hotspot of biodiversity, to investigate the relationships between genetic diversity and edaphic constraint through tolerance to nickel (Ni). Carpophore description, spore morphology and phylogenetic analysis based on internal transcribed spacer (ITS) rDNA sequences confirmed that all isolates belong to P. albus and are closely related to other Australasian specimens. Using molecular tools, ITS restriction fragment length polymorphism and amplified fragment length polymorphism markers, we showed the existence of two distinct genetic clusters within P. albus: ultramafic and volcano-sedimentary. Mycelia response to Ni toxicity supports such a population structure. Pisolithus albus from ultramafic soils included isolates with a high diversity of in vitro Ni tolerance, with both Ni-tolerant isolates (average Ni EC(50) at 575 microM) and Ni-sensitive isolates (average Ni EC(50) at 37 microM). In contrast, all isolates from volcano sedimentary soils were found to be Ni sensitive (average Ni EC(50) at 32 microM). We highlight that (1) P. albus population from ultramafic soils of New Caledonia are genetically structured in ecotype, and that (2) Ni tolerance among ultramafic isolates suggests an adaptive physiological response to Ni toxicity. PMID- 20199571 TI - Staphylococcus aureus extracellular adherence protein contributes to biofilm formation in the presence of serum. AB - Staphylococcus aureus extracellular adherence protein (EAP) is secreted, but it can redock on the bacterial cell surface via neutral phosphatase (Nptase). EAP binds to certain blood proteins and to itself, and through these affinities, it contributes to adherence and aggregation. It has been demonstrated previously that EAP expression is iron regulated and it contributes to biofilm formation under iron-deplete conditions. In this study, we found that EAP and Nptase also play a role in biofilm formation under iron-replete conditions in the presence of human serum. PMID- 20199572 TI - The fine structure of the Acanthamoeba polyphaga cyst wall. AB - Members of the genus Acanthamoeba are present in diverse environments, from freshwater to soil, and also in humans, causing serious brain and corneal infections. Their life cycle presents two stages: the dividing trophozoite and the quiescent cyst. The structures of these life stages have been studied for many years, and structural data have been used for taxonomy. The ultrastructural work on Acanthamoeba cysts was carried out previously by routine transmission electron microscopy (TEM), a process that requires the use of chemical fixation, a procedure that can cause serious artifacts in the ultrastructure of the studied material. In order to prevent fixation artifacts, we processed Acanthamoeba polyphaga cysts by ultrarapid freezing, followed by freeze-fracturing and deep etching, in order to obtain a 3D visualization of the arrangements of the cyst wall. The exocyst presented an irregular surface, with vesicles located within or near this layer. The endocyst, instead, showed a biphasic arrangement with a more compact district in its innermost part, and a more loosened outer layer. For this reason, it was difficult to distinguish the filaments present in the intercyst space from those forming the endocyst. Surprisingly, the intercyst space was thinner when compared with samples processed by conventional TEM, evidencing the possible damage consequent to the use of chemical fixation. PMID- 20199573 TI - Presence of psychrotolerant phenanthrene-mineralizing bacterial populations in contaminated soils from the Greenland High Arctic. AB - Fuel-contaminated soils from Station Nord (St. Nord) in Greenland were sampled with the aim of assessing the intrinsic attenuation potential by quantifying the presence and activity of degradative microbial populations using phenanthrene as a model compound. Mineralization of [(14)C]phenanthrene to (14)CO(2) was measured in contaminated soils at temperatures down to 0 degrees C and sizable naphthalene , undecane-, biphenyl- and phenanthrene-degrading populations were measured by microplate-based most-probable-number analysis. Cloning and 16S rRNA gene sequencing, focused on the dominant phenanthrene-degrading bacteria, revealed strains related to bacteria previously found in cold and contaminated environments. Overall, we provide evidence for the presence and potential activity of phenanthrene-degrading bacteria in polluted St. Nord soils and this study is the first to indicate an intrinsic bioremediation potential in hydrocarbon-contaminated soils from the Greenland High Arctic. PMID- 20199574 TI - Solopathogenic strain formation strongly differs among Ustilaginaceae species. AB - The pathogenicity of smut fungi is initiated by the fusion of two compatible saprotrophic yeasts that give rise to the formation of dikaryotic pathogenic hyphae. It has been described in the literature that complementation assays of auxotrophic yeasts of Ustilago maydis have allowed the isolation of diploid strains that are solopathogenic, i.e. pathogenic in the absence of mating. The occurrence of such strains from germinating teliospores was not investigated. We evaluated the ability of teliospores to generate solopathogenic strains in three species of smut fungi: Sporisorium reilianum f.sp. zeae, U. maydis and Moesziomyces penicillariae. Using an approach based on the stability of pseudohyphae of solopathogenic strains, we isolated the strain SRZS1 from teliospores of S. reilianum. Microscopic observations and analyses of mating-type alleles showed that SRZS1 is monokaryotic and diploid. Inoculation tests on maize plantlets indicated that SRZS1 is infectious. The same protocol was applied to polyteliosporal isolates from M. penicillariae, U. maydis and S. reilianum of diverse geographic origin. Surprisingly, all strains from teliospores of M. penicillariae were solopathogenic, whereas only few solopathogenic strains were obtained from the other two species. The possible incidence of solopathogenic strain production in the biology of these species is discussed. PMID- 20199575 TI - Isolation and characterization of a transposon mutant of Pseudomonas fluorescens BM07 enhancing the production of polyhydroxyalkanoic acid but deficient in cold induced exobiopolymer production. AB - Pseudomonas fluorescens BM07 is known to produce cold-induced exobiopolymer, which is mainly composed of water-insoluble hydrophobic polypeptides (up to 85%) and saccharides (8%), by decreasing the culture temperature down to as low as 10 degrees C. We screened for transposon insertion mutants of P. fluorescens BM07 that were unable to produce the exobiopolymer. Among the eight mutants that showed the deficiency of exobiopolymer and O-lipopolysaccharide, one mutant BM07 59 that had the highest polyhydroxyalkanoates (PHA) production was selected. The transposon inserted gene in BM07-59 was identified as galU. The disruption of the gene galU coded for the putative product, UDP-glucose pyrophosphorylase (GalU), resulted in 1.5-fold more accumulation of PHA compared with the wild-type strain from 70 mM fructose or galactose at 30 degrees C. Electrophoretic analysis of lipopolysaccharide showed that the mutant lacked the O-antigen lipopolysaccharide bands. The glycosyl composition of the lipopolysaccharide produced by the mutant strain was significantly different from that of the wild-type strain. We suggest that the deletion of galU could be a way to shift carbon flux efficiently from exobiopolymer toward PHA in P. fluorescens BM07. PMID- 20199577 TI - A pivotal role for the Streptococcus iniae extracellular polysaccharide in triggering proinflammatory cytokines transcription and inducing death in rainbow trout. AB - Streptococcus iniae is a major pathogen of fish, causing considerable economic losses in Israel, the United States and the Far East. Containment of mortalities through vaccination was recently compromised due to the emergence of novel vaccine-escape strains that are distinguished from previous strains by their ability to produce large amounts of extracellular polysaccharide (EPS) that is released to the medium. In vitro and in vivo data now indicate that the EPS is a major virulence factor, capable of triggering the proinflammatory cytokine machinery and inducing mortality of fish. Streptococcus iniae EPS might therefore be considered to be responsible for sepsis and death just as lipopolysaccharide is for Gram-negative pathogens. PMID- 20199578 TI - Differential glucose repression in common yeast strains in response to HXK2 deletion. AB - Under aerobic, high glucose conditions, Saccharomyces cerevisiae exhibits glucose repression and thus a predominantly fermentative metabolism. Here, we show that two commonly used prototrophic representatives of the CEN.PK and S288C strain families respond differently to deletion of the hexokinase 2 (HXK2) - a key player in glucose repression: In CEN.PK, growth rate collapses and derepression occurs on the physiological level, while the S288C descendant FY4 Deltahxk2 still grows like the parent strain and shows a fully repressed metabolism. A CEN.PK Deltahxk2 strain with a repaired adenylate cyclase gene CYR1 maintains repression but not growth rate. A comparison of the parent strain's physiology, metabolome, and proteome revealed higher metabolic rates, identical biomass, and byproduct yields, suggesting a lower Snf1 activity and a higher protein kinase A (PKA) activity in CEN.PK. This study highlights the importance of the genetic background in the processes of glucose signaling and regulation, contributes novel evidence on the overlap between the classical glucose repression pathway and the cAMP/PKA signaling pathway, and might have the potential to resolve some of the conflicting findings existing in the field. PMID- 20199576 TI - Polar localization of the Coxiella burnetii type IVB secretion system. AB - Coxiella burnetii is a Gram-negative pleomorphic bacterium and the causative agent of Q fever. During infection, the pathogen survives and replicates within a phagosome-like parasitophorous vacuole while influencing cellular functions throughout the host cell, indicating a capacity for effector protein secretion. Analysis of the C. burnetii (RSA 493 strain) genome sequence indicates that C. burnetii contains genes with homology to the Legionella pneumophila Dot/Icm type IVB secretion system (T4BSS). T4BSSs have only been described in L. pneumophila and C. burnetii, marking it a unique virulence determinate. Characterization of bacterial virulence determinants ranging from autotransporter proteins to diverse secretion systems suggests that polar localization may be a virulence mechanism hallmark. To characterize T4BSS subcellular localization in C. burnetii, we analyzed C. burnetii-infected Vero cells by indirect immunofluorescent antibody (IFA) and immunoelectron microscopy (IEM). Using antibodies against the C. burnetii T4BSS homologs IcmT, IcmV, and DotH, IFA show that these proteins are localized to the poles of the bacterium. IEM supports this finding, showing that antibodies against C. burnetii IcmT and DotH preferentially localize to the bacterial cell pole(s). Together, these data demonstrate that the C. burnetii T4BSS localizes to the pole(s) of the bacterium during infection of host cells. PMID- 20199579 TI - Carnitine supplementation has protective and detrimental effects in Saccharomyces cerevisiae that are genetically mediated. AB - l-Carnitine plays a well-documented role in eukaryotic energy homeostasis by acting as a shuttling molecule for activated acyl residues across intracellular membranes. This activity, supported by carnitine acyl-transferases and transporters, is referred to as the carnitine shuttle. However, several pleiotropic and often beneficial effects of carnitine in humans have been reported that appear to be unrelated to shuttling activity, but little conclusive evidence regarding molecular mechanisms exists. We have recently demonstrated a role of carnitine, independent of the carnitine shuttle, in yeast stress protection. Here, we show that carnitine specifically protects against oxidative stress caused by H(2)O(2) and the superoxide-generating agent menadione. Surprisingly, carnitine has a detrimental effect on survival when combined with thiol-modifying agents. Central elements of the oxidative stress response, specifically the transcription factors Yap1p and Skn7p, are shown to be required for carnitine's protective effect, but several downstream effectors are dispensable. A DNA microarray-based analysis identifies Cyc3p, a cytochrome c heme lyase, as being important for carnitine's impact during oxidative stress. These findings establish a direct genetic link to a carnitine-related phenotype that is independent of the shuttle system and suggests that Saccharomyces cerevisiae should provide a useful model for further elucidation of carnitine's physiological roles. PMID- 20199580 TI - Regulation of drug transporter mRNA expression by interferon-gamma in primary human hepatocytes. AB - Interferon (IFN)-gamma is known to downregulate expression of drug detoxifying proteins such as cytochromes P-450 (CYPs) in human hepatocytes. The present study was designed to determine whether IFN-gamma may also impair expression of influx and efflux drug transporters, which constitute important determinants of the liver detoxification pathway. Exposure of primary human hepatocytes to 10 ng/mL IFN-gamma was found to downregulate mRNA levels of sinusoidal influx transporters such as sodium-taurocholate cotransporting polypeptide, organic anion transporting polypeptide (OATP) 2B1, OATP1B1, and OATP1B3. IFN-gamma concomitantly reduced mRNA expression of drug efflux pumps such as multidrug resistance gene 1, multidrug resistance protein (MRP) 2, MRP3, breast cancer resistance protein and bile salt export pump. Such IFN-gamma-mediated repression of major hepatic drug transporters may contribute to impaired liver clearance of drugs administrated to patients suffering from inflammation or viral infections associated with increased secretion of IFN-gamma. PMID- 20199581 TI - French summaries of product characteristics: content in relation to therapeutic monitoring of psychotropic drugs. AB - The prescription information (summary of product characteristics, SPC) is compiled by the pharmaceutical industry as required by the national regulatory authorities. They vary in their content about the properties of drugs and about the usefulness of therapeutic drug monitoring (TDM) in the blood of patients. Based on a previous study carried out in Germany, the degree of agreement of French SPC for 59 psychotropic drugs with the existing medico-scientific evidence in the area of TDM was examined using a recently developed instrument. A summary score of SPC content (SPCC) related to TDM (SPCC(TDM)) has been calculated and compared with the level of recommendation of TDM of the AGNP-TDM expert group consensus guidelines for TDM in psychiatry [AGNP: Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie (Association for neuropsychopharmacology and pharmacopsychiatry)]. Among the antidepressants, antipsychotics, tranquillizers/hypnotic agents and mood stabilizers, the highest SPCC(TDM) scores in the French SPC were reached for imipramine (16), haloperidol (6), clonazepam (8) and lithium (23), respectively. Results were similar to those obtained from the analysis of German SPC, and considerable disagreement was found between the information on TDM in SPC and existing medico-scientific evidence, albeit less in the case of mood stabilizers. Taking into account the recommendations of the AGNP-TDM expert group guidelines, there is a deficit in the French SPC concerning TDM-relevant information. An amelioration of this situation could help to improve the clinical practice of TDM of psychotropic drugs, as the SPC is a widely used tool. PMID- 20199582 TI - Angiogenic targets for potential disorders. AB - This review shall familiarize the readers with various fundamental aspects of angiogenesis. Angiogenesis is a feature of a limited number of physiological processes like wound healing, ovulation, development of the corpus luteum, embryogenesis, lactating breast, during immune response, and during Inflammation. It is driven by a cocktail of growth factors and pro-angiogenic cytokines and is tempered by an equally diverse group of inhibitors of neovascularization. The properties and biological functions of angiogenic growth factors such as VEGF, FGF-2, nitric oxide, MMP, angiopoietin, TGF-beta as well as various inhibitors such as angiostatin, endostatin, thrombospondin, canstatin, DII4, PEDF are discussed in this review with respect to their impact on angiogenic process. In recent years, it has become increasingly evident that excessive, insufficient, or abnormal angiogenesis contributes to the pathogenesis of many more disorders. A long list of disorders is characterized or caused by excessive or insufficient angiogenesis whereas several congenital or inherited diseases are also caused by abnormal vascular remodeling. It may be possible in the future to develop specific anti-angiogenic agents that offer a potential therapy for cancer and angiogenic diseases. PMID- 20199583 TI - Hesperidin attenuates mitochondrial dysfunction during benzo(a)pyrene-induced lung carcinogenesis in mice. AB - The present study is designed to assess the mitochondrial status during benzo(a)pyrene (B(a)P)-induced lung carcinogenesis in Swiss albino mice and to reveal the modulatory effect of hesperidin over it. B(a)P (50 mg/kg body weight) induced mitochondrial abnormalities was evident from alterations in mitochondrial lipid peroxides, antioxidant status (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, reduced glutathione, vitamin E, and vitamin C), major tricarboxylic acid (TCA) cycle enzyme activities (isocitrate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, alpha-ketoglutarate dehydrogenase), electron transport chain (ETC) complexes activities and ATP levels. Ultrastructural changes in lung mitochondria were also in accord with the above aberrations. Hesperidin (25 mg/kg body weight) supplementation effectively counteracted all the above changes and restored cellular normalcy, indicating its protective role during B(a)P-induced lung cancer. PMID- 20199584 TI - Complement receptor 3 (CD11b/CD18) is implicated in the elimination of beta amyloid peptides. AB - Microglia are the professional phagocytes of the brain and express phagocytic receptors such as complement receptor 3 (CR3 or CD11b/CD18). Using mimics of the amyloid deposit made of heat-killed yeasts coated with either Abeta 1-40 or Abeta 1-42, we were able to study how microglia interacted with and ingested these particles in vitro. We have shown previously that the low density lipoprotein receptor-related protein (LRP) is largely implied in the phagocytosis of Abeta 1 42-opsonized heat-killed yeasts and partly in that of Abeta 1-40-opsonized heat killed yeasts. Here, we report that antibodies against CD11b or CD18 reduced the uptake of the artificial amyloid deposit by microglial cell showing that CR3 is involved in the mechanism. Moreover, a concomitant inhibition of LRP and CR3 completely blocked the ingestion of both kinds of particles suggesting that no other receptors participate to this mechanism. PMID- 20199585 TI - Gender differences in the cardiovascular effects of sex hormones. AB - Over the last decade, compelling evidence supports the idea that the different impact of cardiovascular disease (CVD) and the differences in vascular biology in men and women may be, at least in part, related to the cardiovascular and metabolic effects of sex steroid hormones. Indeed, androgens and oestrogens influence a multitude of vascular biological processes and their cardiovascular effects are multifaceted. While in women the effects of androgens mainly depend upon oestrogens' levels and, ultimately, upon the estradiol/testosterone ratio, the effects of androgens in men mostly relate to their aromatization into oestrogens. Oestrogens exert potential beneficial effects on the cardiovascular system in both sexes. In women, the effect of oestrogens, alone or in association with progestins, has been widely investigated, but data obtained from older patient populations have lead the medical community and the general public to misleading conclusions. Growing evidence supports the 'timing hypothesis', which suggests that oestrogen/hormone replacement therapy may increase CVD risk if started late after menopause, but produce beneficial cardiovascular effects in younger postmenopausal women. Because in men adequate interventional studies with testosterone are lacking, specific investigations should be performed. PMID- 20199586 TI - Vitamin use among children attending a Canadian pediatric emergency department. AB - Increasing use of vitamins has been documented worldwide in children and adolescents, and potential for vitamin-drug interactions exists. The aim of this study was to identify vitamin use by children visiting a pediatric emergency department (ED). A survey of parents and/or patients 0-18 years was conducted at a large pediatric ED in Canada. A total of 1804 families were interviewed. The main outcome measure was prevalence of vitamin use by children in the preceding 3 months. A third (32.3%) of the patients in our cohort had used vitamins in the preceding 3 months, and 48% of them were taking vitamins daily. Over 8% of all children used vitamins within the last 24 h. The use of vitamins was higher with older patient and parental age (P<0.001), chronic patient illness (P<0.001), completed immunization (P<0.001), concurrent patient use of prescribed medications (P=0.02), higher parental education (P<0.01), and English as a primary language spoken at home (P=0.002). Prevalence of vitamin use among children in the ED is 32% in the preceding 3 months and 8% within the last 24 h. In light of these findings, pediatricians should ask about vitamin use and discuss with parents potential interactions and possible adverse effects. PMID- 20199587 TI - Deoxyuridine analog nucleotides in deoxycytidine analog treatment: secondary active metabolites? AB - Deoxycytidine analogs (dCa's) are nucleosides widely used in anticancer and anti (retro) viral therapies. Intracellularly phosphorylated dCa anabolites are considered to be their main active metabolites. This article reviews the literature on the formation and pharmacological activity of deaminated dCa nucleotides. Most dCa's are rapidly deaminated into deoxyuridine analogs (dUa's) which are only slowly phosphorylated and therefore relatively inactive. dUa nucleotides are, however, also formed via deamination of dCa monophosphates by deoxycytidine monophosphate deaminase (dCMPD). dUa-monophosphates can interact with thymidylate synthase (TS), whereas dUa-triphosphates are incorporated into nucleic acids and interfere with polymerases. Administration of dCa's as monophosphate prodrugs or co-administration of the cytidine deaminase inhibitor tetrahydrouridine (THU) does not prevent dUa nucleotide formation which is, on the other hand, influenced by the dose and dCMPD activity. Taken together, these observations show that the formation of dUa nucleotides is a common phenomenon in treatment with dCa's and these compounds may play a role in treatment outcome. We conclude that more attention should be given to these relatively unknown, but potentially important metabolites. PMID- 20199588 TI - Norovirus outbreak caused by a new septic system in a dolomite aquifer. AB - Septic systems that are built in compliance with regulations are generally not expected to be the cause of groundwater borne disease outbreaks, especially in areas with thick vadose zones. However, this case study demonstrates that a disease outbreak can occur in such a setting and outlines the combination of epidemiological, microbiological, and hydrogeological methods used to confirm the source of the outbreak. In early June 2007, 229 patrons and employees of a new restaurant in northeastern Wisconsin were affected by acute gastroenteritis; 6 people were hospitalized. Epidemiological case-control analysis indicated that drinking the restaurant's well water was associated with illness (odds ratio = 3.2, 95% confidence interval = 0.9 to 11.4, P = 0.06). Microbiological analysis (quantitative reverse transcription-polymerase chain reaction) measured 50 genomic copies per liter of norovirus genogroup I in the well water. Nucleotide sequencing determined the genotype as GI.2 and further showed the identical virus was present in patrons' stool specimens and in the septic tank. Tracer tests using dyes injected at two points in the septic system showed that effluent was traveling from the tanks (through a leaking fitting) and infiltration field to the well in 6 and 15 d, respectively. The restaurant septic system and well (85-m deep, in a fractured dolomite aquifer) both conformed to state building codes. The early arrival of dye in the well, which was 188 m from the septic field and located beneath a 35-m thick vadose zone, demonstrates that in highly vulnerable hydrogeological settings, compliance with regulations may not provide adequate protection from fecal pathogens. PMID- 20199589 TI - On integrating groundwater transport models with wireless sensor networks. AB - The emerging technology of wireless sensor networks (WSNs) is an integrated, distributed, wireless network of sensing devices. It has the potential to monitor dynamic hydrological and environmental processes more effectively than traditional monitoring and data acquisition techniques by providing environmental information at greater spatial and temporal resolutions. Furthermore, due to continuing high-performance computing development, these data may be introduced into increasingly robust and complex numerical models; for instance, the parameters of subsurface transport simulators may be automatically updated. Early field deployments and laboratory experiments conducted using in situ sensor technology and WSNs indicated significant fundamental issues concerning sensor and network hardware reliability-suggesting that investigations should first be conducted in controlled environments before field deployment. A first step in this validation process involves evaluating the predictive capability of a computational advection-dispersion transport model when incorporating concentration data from a WSN simulation. Data quality is a major concern, especially when sensor readings are automatically fed into data assimilation procedures. The appropriate employment of an independent WSN fault detection service can ensure that erroneous data (e.g., missing or anomalous values) do not mislead the model. Parameter estimation regularization techniques may then deal with remaining data noise. The primary purpose of this study is to determine the suitability of WSNs (and other in situ data delivery technologies) for use in contaminant transport modeling applications by conducting research in a realistic simulative environment. PMID- 20199590 TI - Quadriceps sarcopenia and visceral obesity are risk factors for postural instability in the middle-aged to elderly population. AB - AIM: Aging shifts body composition to comprising more fat and less muscle. Sarcopenia, particularly in the knee extensors, and obesity, particularly visceral obesity, either alone or in combination, may exacerbate age-related physical disability. We investigated the association between age-related quadriceps (Qc) sarcopenia and visceral obesity, as measured by cross-sectional area (CSA), on postural instability. METHODS: Mid-thigh muscle CSA and abdominal visceral and subcutaneous fat area at the level of the umbilicus were assessed from computed tomography (CT) images in 410 apparently healthy independent middle aged to elderly subjects attending the medical check-up program in Ehime University Hospital. Static postural instability using a posturograph and one-leg standing time with eyes open were assessed. RESULTS: Both abdominal visceral fat area and Qc muscle CSA corrected by body weight (BW) were associated with static postural instability, in addition to age and sex, while BW-corrected Qc muscle CSA predicted a short one-leg standing time. The combination of Qc sarcopenia, defined as greater than 1 standard deviation below the mean of a young group (age <60 years), and visceral obesity, defined as a visceral fat area of more than 100 cm(2), were associated with static postural instability, while Qc sarcopenia was related to a higher prevalence of one-leg standing time of less than 30 s, irrespective of visceral obesity. CONCLUSION: Thigh Qc sarcopenia and visceral obesity are associated with postural instability in middle-aged to elderly subjects. These findings suggest that age-related, site-specific fat and muscle mass alterations are associated with functional impairment. PMID- 20199592 TI - Proteomics of life at low temperatures: trigger factor is the primary chaperone in the Antarctic bacterium Pseudoalteromonas haloplanktis TAC125. AB - The proteomes expressed at 4 degrees C and 18 degrees C by the psychrophilic Antarctic bacterium Pseudoalteromonas haloplanktis have been compared using two dimensional differential in-gel electrophoresis, showing that translation, protein folding, membrane integrity and anti-oxidant activities are upregulated at 4 degrees C. This proteomic analysis revealed that the trigger factor is the main upregulated protein at low temperature. The trigger factor is the first molecular chaperone interacting with virtually all newly synthesized polypeptides on the ribosome and also possesses a peptidyl-prolyl cis-trans isomerase activity. This suggests that protein folding at low temperatures is a rate limiting step for bacterial growth in cold environments. It is proposed that the psychrophilic trigger factor rescues the chaperone function as both DnaK and GroEL (the major bacterial chaperones but also heat-shock proteins) are downregulated at 4 degrees C. The recombinant psychrophilic trigger factor is a monomer that displays unusually low conformational stability with a Tm value of 33 degrees C, suggesting that the essential chaperone function requires considerable flexibility and dynamics to compensate for the reduction of molecular motions at freezing temperatures. Its chaperone activity is strongly temperature-dependent and requires near-zero temperature to stably bind a model unfolded polypeptide. PMID- 20199591 TI - The differential affinity of the usher for chaperone-subunit complexes is required for assembly of complete pili. AB - Attachment to host cells via adhesive surface structures is a prerequisite for the pathogenesis of many bacteria. Uropathogenic Escherichia coli assemble P and type 1 pili for attachment to the host urothelium. Assembly of these pili requires the conserved chaperone/usher pathway, in which a periplasmic chaperone controls the folding of pilus subunits and an outer membrane usher provides a platform for pilus assembly and secretion. The usher has differential affinity for pilus subunits, with highest affinity for the tip-localized adhesin. Here, we identify residues F21 and R652 of the P pilus usher PapC as functioning in the differential affinity of the usher. R652 is important for high-affinity binding to the adhesin whereas F21 is important for limiting affinity for the PapA major rod subunit. PapC mutants in these residues are specifically defective for pilus assembly in the presence of PapA, demonstrating that differential affinity of the usher is required for assembly of complete pili. Analysis of PapG deletion mutants demonstrated that the adhesin is not required to initiate P pilus biogenesis. Thus, the differential affinity of the usher may be critical to ensure assembly of functional pilus fibres. PMID- 20199593 TI - Candida glabrata tryptophan-based pigment production via the Ehrlich pathway. AB - Pigments contribute to the pathogenicity of many fungi, mainly by protecting fungal cells from host defence activities. Here, we have dissected the biosynthetic pathway of a tryptophan-derived pigment of the human pathogen Candida glabrata, identified key genes involved in pigment production and have begun to elucidate the possible biological function of the pigment. Using transcriptional analyses and a transposon insertion library, we have identified genes associated with pigment production. Targeted deletion mutants revealed that the pigment is a by-product of the Ehrlich pathway of tryptophan degradation: a mutant lacking a tryptophan-upregulated aromatic aminotransferase (Aro8) displayed significantly reduced pigmentation and a recombinantly expressed version of this protein was sufficient for pigment production in vitro. Pigment production is tightly regulated as the synthesis is affected by the presence of alternative nitrogen sources, carbon sources, cyclic AMP and oxygen. Growth of C. glabrata on pigment inducing medium leads to an increased resistance to hydrogen peroxide, an effect which was not observed with a mutant defective in pigmentation. Furthermore, pigmented yeast cells had a higher survival rate when exposed to human neutrophils and caused increased damage in a monolayer model of human epithelia, indicating a possible role of pigmentation during interactions with host cells. PMID- 20199594 TI - Adenylate cyclase toxin translocates across target cell membrane without forming a pore. AB - The adenylate cyclase toxin-haemolysin of Bordetella (CyaA) targets CD11b(+) myeloid phagocytes and translocates across their cytoplasmic membrane an adenylate cyclase (AC) enzyme that catalyses conversion of cytosolic ATP into cAMP. In parallel, CyaA acts as a cytolysin forming cation-selective pores, which permeabilize cell membrane and eventually provoke cell lysis. Using cytolytic activity, potassium efflux and patch-clamp assays, we show that a combination of substitutions within the pore-forming (E570Q) and acylation-bearing domain (K860R) ablates selectively the cell-permeabilizing activity of CyaA. At the same time, however, the capacity of such mutant CyaA to translocate the AC domain across cytoplasmic membrane into cytosol of macrophage cells and to elevate cellular cAMP concentrations remained intact. Moreover, the combination of E570Q+K860R substitutions suppressed the residual cytolytic activity of the enzymatically inactive CyaA/OVA/AC(-) toxoid on CD11b-expressing monocytes, while leaving unaffected the capacity of the mutant toxoid to deliver in vitro a reporter CD8(+) T cell epitope from ovalbumin (OVA) to the cytosolic pathway of dendritic cells for MHC class I-restricted presentation and induce in vivo an OVA specific cytotoxic T cell response. CyaA, hence, employs a mechanism of AC enzyme domain translocation across cellular membrane that avoids passage across the cytolytic pore formed by toxin oligomers. PMID- 20199595 TI - Temperature-dependent FlgM/FliA complex formation regulates Campylobacter jejuni flagella length. AB - Regulation of the biosynthesis of the flagellar filament in bacteria containing multiple flagellin genes is not well understood. The major food-borne pathogen Campylobacter jejuni possesses on both poles a flagellum that consists of two different flagellin subunits, FlaA and FlaB. Here we identify the protein Cj1464 as a regulator of C. jejuni flagellin biosynthesis. The protein shares characteristics of the FlgM family of anti-sigma factor proteins: it represses transcription of sigma(28)-dependent genes, forms a complex with sigma factor FliA, and is secreted through the flagellar filament. However, unlike other FlgM proteins, the interaction of C. jejuni FlgM with FliA is regulated by temperature and the protein does not inhibit FliA activity during the formation of the hook basal body complex (HBB). Instead, C. jejuni FlgM limits the length of the flagellar filament by suppressing the synthesis of both the sigma(28)- and the sigma(54)-dependent flagellins. The main function of the C. jejuni FlgM therefore is not to silence sigma(28)-dependent genes until the HBB is completed, but to prevent unlimited elongation of the flagellum, which otherwise leads to reduced bacterial motility. PMID- 20199596 TI - Vitronectin binds to the head region of Moraxella catarrhalis ubiquitous surface protein A2 and confers complement-inhibitory activity. AB - The serum resistance of the common respiratory pathogen Moraxella catarrhalis is mainly dependent on ubiquitous surface proteins (Usp) A1 and A2 that interact with complement factor 3 (C3) and complement inhibitor C4b binding protein (C4BP) preventing the alternative and classical pathways of the complement system respectively. UspA2 also has the capacity to attract vitronectin that in turn binds C9 and hereby inhibits membrane attack complex (MAC) formation. We found UspA2 as a major vitronectin binding protein and hence the UspA2/vitronectin interaction was studied in detail. The affinity constant (K(D)) for vitronectin binding to UspA2 was 2.3 x 10(-8) M, and the N-terminal region encompassing residues UspA2 30-170 bound vitronectin with a K(D) of 7.9 x 10(-8) M. Electron microscopy verified that the active binding domain (UspA2(30-177)) was located at the head region of UspA2. Experiments with recombinantly expressed vitronectin also revealed that UspA2(30-177) bound to the C-terminal region of vitronectin residues 312-396. Finally, when human serum was pre-incubated with UspA2, bacteria showed significantly less serum resistance. Our study directly reveals the binding mode between the N-terminal domain of UspA2 and the C-terminal part of vitronectin and thus sheds light upon the mechanism of M. catarrhalis dependent serum resistance. PMID- 20199598 TI - Influence of the nucleoid and the early stages of DNA replication on positioning the division site in Bacillus subtilis. AB - Although division site positioning in rod-shaped bacteria is generally believed to occur through the combined effect of nucleoid occlusion and the Min system, several lines of evidence suggest the existence of additional mechanisms. Studies using outgrown spores of Bacillus subtilis have shown that inhibiting the early stages of DNA replication, leading up to assembly of the replisome at oriC, influences Z ring positioning. Here we examine whether Z ring formation at midcell under various conditions of DNA replication inhibition is solely the result of relief of nucleoid occlusion. We show that midcell Z rings form preferentially over unreplicated nucleoids that have a bilobed morphology (lowering DNA concentration at midcell), whereas acentral Z rings form beside a single-lobed nucleoid. Remarkably however, when the DnaB replication initiation protein is inactivated midcell Z rings never form over bilobed nucleoids. Relieving nucleoid occlusion by deleting noc increased midcell Z ring frequency for all situations of DNA replication inhibition, however not to the same extent, with the DnaB-inactivated strain having the lowest frequency of midcell Z rings. We propose an additional mechanism for Z ring positioning in which the division site becomes increasingly potentiated for Z ring formation as initiation of replication is progressively completed. PMID- 20199599 TI - Regulation of phosphate uptake via Pst transporters in Halobacterium salinarum R1. AB - The genome of the archaeon Halobacterium salinarum contains two copies of the pst (phosphate-specific transport) operon, the genes of which are related to well studied bacterial homologues. Both operons (pst1 and pst2) were shown to be polycistronic and, when under P(i)-limited conditions, transcription initiated 1 bp upstream of the translational starts. Under P(i) saturation, the pst1 operon utilized an additional transcription start site 59 bp upstream of the first one. The leaderless pst1 transcript was found to be more efficiently translated than the leadered transcript. Promoter strengths differed significantly between the two operons and when P(i) levels changed. The basal pst1 promoter activity in P(i)-saturated conditions was minimal while the pst2 promoter was active. In contrast, phosphate limitation induced the pst1 operon threefold more than the pst2 operon. We identified basic and phosphate-dependent cis-acting elements in both promoters. Phosphate-uptake assays conducted with several Pst1 and Pst2 mutant strains revealed differences in the substrate affinities between the two transporters and also suggested that the P(i)-binding proteins PstS1 and PstS2 can interact with either of the two permease subunits of the transporters. The tactic behaviour of wild type and pst-deletion strains showed that the Pst1 transporter plays an important role for phosphate-directed chemotaxis. PMID- 20199597 TI - Identification of residues within ligand-binding domain 1 (LBD1) of the Borrelia burgdorferi OspC protein required for function in the mammalian environment. AB - Borrelia burgdorferi outer surface protein C (ospC) is required for the establishment of infection in mammals. However, its precise function remains controversial. The biologically active form of OspC appears to be a homodimer. Alpha helix 1 and 1' of the apposing monomers form a solvent-accessible pocket at the dimeric interface that presents a putative ligand-binding domain (LBD1). Here we employ site-directed and allelic-exchange mutagenesis to test the hypothesis that LBD1 is a determinant of OspC function in the mammalian environment. Substitution of residues K60, E61 and E63 which line LBD1 resulted in the loss of infectivity or influenced dissemination. Analyses of the corresponding recombinant proteins demonstrated that the loss of function was not due to structural perturbation, impaired dimer formation or the loss of plasminogen binding. This study is the first to assess the involvement of individual residues and domains of OspC in its in vivo function. The data support the hypothesis that OspC interacts with a mammalian derived ligand that is critical for survival during early infection. These results shed new light on the structure-functions relationships of OspC and challenge existing hypotheses regarding OspC function in mammals. PMID- 20199600 TI - Complex interplay between the LysR-type regulator AtzR and its binding site mediates atzDEF activation in response to two distinct signals. AB - AtzR is a LysR-type regulator responsible for activation of the cyanuric acid utilization operon atzDEF. AtzR binds the PatzDEF promoter region at a strong recognition element, designated the repressor binding site, and a weaker binding determinant, the activator binding site (ABS). AtzR activates transcription in response to two dissimilar signals, nitrogen limitation and cyanuric acid. In the present work we analyse the structure and function of the cis-acting elements involved in AtzR activation of atzDEF. Hydroxyl radical footprinting assays revealed that the ABS is composed of three functional subsites spaced at one helix-turn intervals. Two modes of interaction with the ABS are detected in vitro: AtzR binds at the ABS-2 and ABS-3 subsites in the absence of inducer, and relocates to interact with the ABS-1 and ABS-2 subsites in the presence of cyanuric acid. In vivo mutational analysis indicates that ABS-1 and ABS-2 are required for full PatzDEF activation in all conditions. In contrast, ABS-3 acts as a 'subunit trap' that hinders productive AtzR interactions with ABS-1 and ABS 2. Our results strongly suggest an activation model in which cyanuric acid and nitrogen limitation cooperate to reposition AtzR from an inactive, ABS-3 bound configuration to an active, ABS-1- and ABS-2-bound configuration. PMID- 20199602 TI - The moonlighting protein fructose-1, 6-bisphosphate aldolase of Neisseria meningitidis: surface localization and role in host cell adhesion. AB - Fructose-1, 6-bisphosphate aldolases (FBA) are cytoplasmic glycolytic enzymes, which despite lacking identifiable secretion signals, have also been found localized to the surface of several bacteria where they bind host molecules and exhibit non-glycolytic functions. Neisseria meningitidis is an obligate human nasopharyngeal commensal, which has the capacity to cause life-threatening meningitis and septicemia. Recombinant native N. meningitidis FBA was purified and used in a coupled enzymic assay confirming that it has fructose bisphosphate aldolase activity. Cell fractionation experiments showed that meningococcal FBA is localized both to the cytoplasm and the outer membrane. Flow cytometry demonstrated that outer membrane-localized FBA was surface-accessible to FBA specific antibodies. Mutational analysis and functional complementation was used to identify additional functions of FBA. An FBA-deficient mutant was not affected in its ability to grow in vitro, but showed a significant reduction in adhesion to human brain microvascular endothelial and HEp-2 cells compared to its isogenic parent and its complemented derivative. In summary, FBA is a highly conserved, surface exposed protein that is required for optimal adhesion of meningococci to human cells. PMID- 20199601 TI - NAD+ auxotrophy is bacteriocidal for the tubercle bacilli. AB - The human tubercle bacillus Mycobacterium tuberculosis can synthesize NAD(+) using the de novo biosynthesis pathway or the salvage pathway. The salvage pathway of the bovine tubercle bacillus Mycobacterium bovis was reported defective due to a mutation in the nicotinamidase PncA. This defect prevents nicotinic acid secretion, which is the basis for the niacin test that clinically distinguishes M. bovis from M. tuberculosis. Surprisingly, we found that the NAD(+)de novo biosynthesis pathway (nadABC) can be deleted from M. bovis, demonstrating a functioning salvage pathway. M. bovisDeltanadABC fails to grow in mice, whereas M. tuberculosisDeltanadABC grows normally in mice, suggesting that M. tuberculosis can acquire nicotinamide from its host. The introduction of M. tuberculosis pncA into M. bovisDeltanadABC is sufficient to fully restore growth in a mouse, proving that the functional salvage pathway enables nicotinamide acquisition by the tubercle bacilli. This study demonstrates that NAD(+) starvation is a cidal event in the tubercle bacilli and confirms that enzymes common to the de novo and salvage pathways may be good drug targets. PMID- 20199603 TI - Structure of the cytoplasmic domain of FlhA and implication for flagellar type III protein export. AB - FlhA is the largest integral membrane component of the flagellar type III protein export apparatus of Salmonella and is composed of an N-terminal transmembrane domain (FlhA(TM)) and a C-terminal cytoplasmic domain (FlhA(C)). FlhA(C) is thought to form a platform of the export gate for the soluble components to bind to for efficient delivery of export substrates to the gate. Here, we report a structure of FlhA(C) at 2.8 A resolution. FlhA(C) consists of four subdomains (A(C)D1, A(C)D2, A(C)D3 and A(C)D4) and a linker connecting FlhA(C) to FlhA(TM). The sites of temperature-sensitive (ts) mutations that impair protein export are distributed to all four domains, with half of them at subdomain interfaces. Analyses of the ts mutations and four suppressor mutations to the G368C ts mutation suggested that FlhA(C) changes its conformation for its function. Molecular dynamics simulation demonstrated an open-close motion with a 5-10 ns oscillation in the distance between A(C)D2 and A(C)D4. These results along with further mutation analyses suggest that a dynamic domain motion of FlhA(C) is essential for protein export. PMID- 20199606 TI - Septum formation is regulated by the RHO4-specific exchange factors BUD3 and RGF3 and by the landmark protein BUD4 in Neurospora crassa. AB - Rho GTPases have multiple, yet poorly defined functions during cytokinesis. By screening a Neurospora crassa knock-out collection for Rho guanine nucleotide exchange factor (GEF) mutants that phenocopy rho-4 defects (i.e. lack of septa, slow growth, abnormal branching and cytoplasmic leakage), we identified two strains defective in homologues of Bud3p and Rgf3 of budding and fission yeast respectively. The function of these proteins as RHO4-specific GEFs was determined by in vitro assays. In vivo microscopy suggested that the two GEFs and their target GTPase act as two independent modules during the selection of the septation site and the actual septation process. Furthermore, we determined that the N. crassa homologue of the anillinrelated protein BUD4 is required for septum initiation and that its deficiency leads to typical rho4 defects. Localization of BUD4 as a cortical ring prior to septation initiation was independent of functional BUD3 or RGF3. These data position BUD4 upstream of both RHO4 functions in the septation process and make BUD4 a prime candidate for a cortical marker protein involved in the selection of future septation sites. The persistence of both BUD proteins and of RHO4 at the septal pore suggests additional functions of these proteins at mature septa. PMID- 20199604 TI - A dominant-negative needle mutant blocks type III secretion of early but not late substrates in Yersinia. AB - Yersinia pseudotuberculosis uses a type III secretion system (T3SS) to deliver effectors into host cells. A key component of the T3SS is the needle, which is a hollow tube on the bacterial surface through which effectors are secreted, composed of the YscF protein. To study needle assembly, we performed a screen for dominant-negative yscF alleles that prevented effector secretion in the presence of wild-type (WT) YscF. One allele, yscF-L54V, prevents WT YscF secretion and needle assembly, although purified YscF-L54V polymerizes in vitro. YscF-L54V binds to its chaperones YscE and YscG, and the YscF-L54V-EG complex targets to the T3SS ATPase, YscN. We propose that YscF-L54V stalls at a binding site in the needle assembly pathway following its release from the chaperones, which blocks the secretion of WT YscF and other early substrates required for building a needle. Interestingly, YscF-L54V does not affect the activity of pre-assembled actively secreting machines, indicating that a factor and/or binding site required for YscF secretion is absent from T3SS machines already engaged in effector secretion. Thus, substrate switching may involve the removal of an early substrate-specific binding site as a mechanism to exclude early substrates from Yop-secreting machines. PMID- 20199605 TI - Distinct roles of ppGpp and DksA in Legionella pneumophila differentiation. AB - To transit between hosts, intracellular Legionella pneumophila transform into a motile, infectious, transmissive state. Here we exploit the pathogen's life cycle to examine how guanosine tetraphosphate (ppGpp) and DksA cooperate to govern bacterial differentiation. Transcriptional profiling revealed that during transmission alarmone accumulation increases the mRNA for flagellar and Type IV secretion components, secreted host effectors and regulators, and decreases transcripts for translation, membrane modification and ATP synthesis machinery. DksA is critical for differentiation, since mutants are defective for stationary phase survival, flagellar gene activation, lysosome avoidance and macrophage cytotoxicity. The roles of ppGpp and DksA depend on the context. For macrophage transmission, ppGpp is essential, whereas DksA is dispensable, indicating that ppGpp can act autonomously. In broth, DksA promotes differentiation when ppGpp levels increase, or during fatty acid stress, as judged by flaA expression and evasion of degradation by macrophages. For flagella morphogenesis, DksA is required for basal fliA (sigma(28)) promoter activity. When alarmone levels increase, DksA cooperates with ppGpp to generate a pulse of Class II rod RNA or to amplify the Class III sigma factor and Class IV flagellin RNAs. Thus, DksA responds to the level of ppGpp and other stress signals to co-ordinate L. pneumophila differentiation. PMID- 20199608 TI - Beyond pain: predictors of postoperative maladaptive behavior change in children. AB - OBJECTIVES & AIM: Using well-validated measures and controlling for potential confounding variables such as pain and surgical and anesthetic technique, the goal of this project was to identify the incidence of and risk factors for the development of behavior change in children after surgery. BACKGROUND: Although researchers have described maladaptive behavior change following surgery, many previous studies are limited by potential confounding variables, including postoperative pain, type of surgery, and surgical and anesthetic procedure. METHODS: Participants included 260 children undergoing tonsillectomy and adenoidectomy. Baseline and demographic data were collected prior to surgery and pain and behavioral recovery were recorded for 2 weeks following surgery. A standardized approach to anesthesia and surgical procedure was implemented and well-validated assessment measures were used. RESULTS: On the first day at home following surgery, 80.4% of children exhibited negative behavior change. Nearly one-third of children continued to exhibit behavior changes 2 weeks after surgery. Logistic regression analyses that controlled for pain severity identified several predictors of behavior change: preexisting somatic and anxious/depressed problems predicted new onset postoperative general anxiety, chi(2) (8) = 20.10, P = 0.010; younger age predicted separation anxiety, chi(2) (4) = 20.41, P < 0.01; and inhibited temperament predicted postoperative sleep disturbance, chi(2) (2) = 9.19, P = 0.010. CONCLUSIONS: Individual child factors above and beyond pain predict maladaptive postoperative behavior change; identification of these predictors may be helpful in both preventing and ameliorating difficulties with behavioral recovery following surgery. PMID- 20199607 TI - Mycoplasma pneumoniae Community Acquired Respiratory Distress Syndrome toxin expression reveals growth phase and infection-dependent regulation. AB - Mycoplasma pneumoniae causes acute and chronic respiratory infections, including tracheobronchitis and community acquired pneumonia, and is linked to asthma and an array of extra-pulmonary disorders. Recently, we identified an ADP ribosylating and vacuolating toxin of M. pneumoniae, designated Community Acquired Respiratory Distress Syndrome (CARDS) toxin. In this study we analysed CARDS toxin gene (annotated mpn372) transcription and identified its promoter. We also compared CARDS toxin mRNA and protein profiles in M. pneumoniae during distinct in vitro growth phases. CARDS toxin mRNA expression was maximal, but at low levels, during early exponential growth and declined sharply during mid-to late log growth phases, which was in direct contrast to other mycoplasma genes examined. Between 7% and 10% of CARDS toxin was localized to the mycoplasma membrane at mid-exponential growth, which was reinforced by immunogold electron microscopy. No CARDS toxin was released into the medium. Upon M. pneumoniae infection of mammalian cells, increased expression of CARDS toxin mRNA was observed when compared with SP-4 broth-grown cultures. Further, confocal immunofluorescence microscopy revealed that M. pneumoniae readily expressed CARDS toxin during infection of differentiated normal human bronchial epithelial cells. Analysis of M. pneumoniae-infected mouse lung tissue revealed high expression of CARDS toxin per mycoplasma cell when compared with M. pneumoniae cells grown in SP-4 medium alone. Taken together, these studies indicate that CARDS toxin expression is carefully controlled by environmental cues that influence its transcription and translation. Further, the acceleration of CARDS toxin synthesis and accumulation in vivo is consistent with its role as a bona fide virulence determinant. PMID- 20199609 TI - Perioperative anxiety in children. AB - OBJECTIVES & AIM: The purpose of this investigation was to examine children's anxiety across the perioperative setting. BACKGROUND: Although several studies have examined preoperative anxiety in children, few researchers have illustrated perioperative anxiety; that is, anxiety in children throughout the pre and postoperative continuum. METHODS: Participants were 261 children ages 2-12. Anxiety was rated prior to surgery, immediately after surgery, and for 2 weeks at home following surgery. RESULTS: Low child sociability and high parent anxiety predicted perioperative anxiety. Perioperative anxiety was related to postoperative pain and negative postoperative behavioral change. CONCLUSIONS: Identification and prevention of anxiety in children can help prevent negative outcomes following surgery. PMID- 20199610 TI - A new approach for peri-operative analgesia of cleft palate repair in infants: the bilateral suprazygomatic maxillary nerve block. AB - BACKGROUND: Congenital cleft palate (CP) is a common and painful surgical procedure in infants. CP repair is associated with the risk of postoperative airway obstruction, which may be increased with administration of opioids, often needed for analgesia. No described regional anesthesia technique can provide adequate pain control following CP repair in infants. The primary aim of this prospective and descriptive study was to observe the effectiveness of bilateral maxillary nerve blocks (BMB) using a suprazygomatic approach on pain relief and consumption of rescue analgesics following CP repair in infants. Analgesic consumption was compared to retrospective data. Complications related to this new technique in infants were also reviewed. METHODS: The landmarks and measurements recently defined in a three-dimensional study using computed tomography in infants were used. After general anesthesia, a BMB was performed bilaterally with 0.15 ml x kg(-1) 0.2% ropivacaine in infants scheduled for CP repair. Postoperative analgesia, administration of rescue analgesics, adverse effects, and time to feed were recorded in the 48-h period following surgery and compared to retrospective data. RESULTS: Thirty-three children, mean age 5 +/- 1.8 months and weight 8.3 +/- 1.2 kg, were studied. Eighteen patients out of 33 (55%) did not require additional opioids intra-operatively, vs two out of 20 (10%) without block. None needed morphine postoperatively, and intravenous nalbuphine was required in only six children (18%), vs 16 (80%) without block. Median time to feed was 8 h (range 2-24 h), vs 13 h (4-25) without block. No technical failure or complication related to the BMB was reported. CONCLUSION: BMB using a suprazygomatic approach seems to improve pain relief, to decrease peri-operative consumption of opioids, and to favor early feeding resumption after CP repair in infants. PMID- 20199611 TI - Anesthetic considerations for the pediatric oncology patient--part 2: systems based approach to anesthesia. AB - One of the prices paid for chemo- and radiotherapy of cancer in children is damage to the vulnerable and developing healthy tissues of the body. Such damage can exist clinically or subclinically and can become apparent during active antineoplastic treatment or during remission decades later. Furthermore, effects of the tumor itself can significantly impact the physiologic state of the child. The anesthesiologist who cares for children with cancer or for survivors of childhood cancer should understand what effects cancer and its therapy can have on various organ systems. In part two of this three-part review, we review the anesthetic issues associated with childhood cancer. Specifically, this review presents a systems-based approach to the impact from both tumor and its treatment in children, followed by a discussion of the relevant anesthetic considerations. PMID- 20199612 TI - The production of hemagglutinin-based virus-like particles in plants: a rapid, efficient and safe response to pandemic influenza. AB - During the last decade, the spectre of an influenza pandemic of avian origin has led to a revision of national and global pandemic preparedness plans and has stressed the need for more efficient influenza vaccines and manufacturing practices. The 2009 A/H1N1 (swine flu) outbreak has further emphasized the necessity to develop new solutions for pandemic influenza vaccines. Influenza virus-like particles (VLPs)-non-infectious particles resembling the influenza virus-represent a promising alternative to inactivated and split-influenza virions as antigens, and they have shown uniqueness by inducing a potent immune response through both humoral and cellular components of the immune system. Our group has developed a plant-based transient influenza VLP manufacturing platform capable of producing influenza VLPs with unprecedented speed. Influenza VLP expression and purification technologies were brought to large-scale production of GMP-grade material, and pre-clinical studies have demonstrated that low doses of purified, plant-produced influenza VLPs induce a strong and broad immune response in mice and ferrets. This review positions the recent developments towards the successful production of influenza VLPs in plants, including the production of VLPs from other human viruses and other forms of influenza antigens. The platform developed for large-scale production of VLPs is also presented along with an assessment of the speed of the platform to produce the first experimental vaccine lots from the identification of a new influenza strain. PMID- 20199613 TI - Relations of sugar composition and delta 13C in phloem sap to growth and physiological performance of Eucalyptus globulus (Labill). AB - We characterized differences in carbon isotopic content (delta(13)C) and sugar concentrations in phloem exudates from Eucalyptus globulus (Labill) plantations across a rainfall gradient in south-western Australia. Phloem sap delta(13)C and sugar concentrations varied with season and annual rainfall. Annual bole growth was negatively related to phloem sap delta(13)C during summer, suggesting a water limitation, yet was positively related in winter. We conclude that when water is abundant, variations in carboxylation rates become significant to overall growth. Concentrations of sucrose in phloem sap varied across sites by up to 600 mm, and raffinose by 300 mm. These compounds play significant roles in maintaining osmotic balance and facilitating carbon movement into the phloem, and their relative abundances contribute strongly to overall delta(13)C of phloem sap. Taken together, the delta(13)C and concentrations of specific sugars in phloem sap provide significant insights to functions supporting growth at the tree, site and landscape scale. PMID- 20199614 TI - A computational algorithm addressing how vessel length might depend on vessel diameter. AB - The objective of this method paper was to examine a computational algorithm that may reveal how vessel length might depend on vessel diameter within any given stem or species. The computational method requires the assumption that vessels remain approximately constant in diameter over their entire length. When this method is applied to three species or hybrids in the genus Populus, vessel length is sometimes a linear function of vessel diameter and sometimes an exponential function of vessel diameter within a stem, based on R(2) values. Our results give within-species variation of vessel length versus diameter, and we compare this to between-species variation of mean diameter versus mean length. PMID- 20199616 TI - Photosynthetic redox imbalance influences flavonoid biosynthesis in Lemna gibba. AB - Plants accumulate flavonoids in response to a myriad of environmental challenges, especially when exposed to ultraviolet (UV) radiation or situations causing oxidative stress. However, the origin and nature of the signal triggering their accumulation remain obscure. In this study, a group of flavonoids belonging to the flavone class was identified in Lemna gibba (duckweed). These flavones accumulated upon exposure to UV radiation, low temperature, copper and the photosynthetic electron transport (PET) inhibitors 2,5-dibromo-3-methyl-6 isopropyl-p-benzoquinone (DBMIB) and 1,2-dihydroxyanthraquinone (DHATQ). All of these stressors were also shown to promote PET chain (PETC) reduction; however, in the co-presence of 3-(3,4-dichlorophenyl)-1,1-dimethyl urea (DCMU) or a light regime that oxidized the PETC, flavonoid accumulation ceased. Chloroplast-derived reactive oxygen species (ROS) were not associated with all of the stress conditions that promoted both PETC reduction and flavonoid synthesis, indicating that ROS were not a strict requisite for flavonoid accumulation. Transcripts for the flavonoid biosynthetic genes, chalcone synthase (CHS) and chalcone isomerase, were similarly responsive to the PETC redox state, as were a panel of transcripts revealed by differential display PCR. Collectively, these results provide evidence that PETC redox status is one of the factors affecting flavonoid biosynthesis. PMID- 20199615 TI - Use of the growing environment as a source of variation to identify the quantitative trait transcripts and modules of co-expressed genes that determine chlorogenic acid accumulation. AB - Developing Coffea arabica seeds accumulate large amounts of chlorogenic acids (CGAs) as a storage form of phenylpropanoid derivatives, making coffee a valuable model to investigate the metabolism of these widespread plant phenolics. However, developmental and environmental regulations of CGA metabolism are poorly understood. In the present work, the expression of selected phenylpropanoid genes, together with CGA isomer profiles, was monitored throughout seed development across a wide set of contrasted natural environments. Although CGA metabolism was controlled by major developmental factors, the mean temperature during seed development had a direct impact on the time-window of CGA biosynthesis, as well as on final CGA isomer composition through subtle transcriptional regulations. We provide evidence that the variability induced by the environment is a useful tool to test whether CGA accumulation is quantitatively modulated at the transcriptional level, hence enabling detection of rate-limiting transcriptional steps [quantitative trait transcripts (QTTs)] for CGA biosynthesis. Variations induced by the environment also enabled a better description of the phenylpropanoid gene transcriptional network throughout seed development, as well as the detection of three temporally distinct modules of quantitatively co-expressed genes. Finally, analysis of metabolite-to-metabolite relationships revealed new biochemical characteristics of the isomerization steps that remain uncharacterized at the gene level. PMID- 20199617 TI - Genotype-dependent response to carbon availability in growing tomato fruit. AB - Tomato fruit growth and composition depend on both genotype and environment. This paper aims at studying how fruit phenotypic responses to changes in carbon availability can be influenced by genotype, and at identifying genotype-dependent and -independent changes in gene expression underlying variations in fruit growth and composition. We grew a parental line (Solanum lycopersicum) and an introgression line from Solanum chmielewskii harbouring quantitative trait loci for fresh weight and sugar content under two fruit loads (FL). Lowering FL increased fruit cell number and reduced fruit developmental period in both genotypes. In contrast, fruit cell size was increased only in the parental line. Modifications in gene expression were monitored using microarrays and RT-qPCR for a subset of genes. FL changes induced more deployments of regulation systems (transcriptional and post-transcriptional) than massive adjustments of whole primary metabolism. Interactions between genotype and FL occurred on 99 genes mainly linked to hormonal and stress responses, and on gene expression kinetics. Links between gene expression and fruit phenotype were found for aquaporin expression levels and fruit water content, and invertase expression levels and sugar content. In summary, the present data emphasized age- and genotype dependent responses of tomato fruit to carbon availability, at phenotypic as well as gene expression level. PMID- 20199618 TI - Variability in mesophyll conductance between barley genotypes, and effects on transpiration efficiency and carbon isotope discrimination. AB - Leaf internal, or mesophyll, conductance to CO(2) (g(m)) is a significant and variable limitation of photosynthesis that also affects leaf transpiration efficiency (TE). Genotypic variation in g(m) and the effect of g(m) on TE were assessed in six barley genotypes (four Hordeum vulgare and two H. bulbosum). Significant variation in g(m) was found between genotypes, and was correlated with photosynthetic rate. The genotype with the highest g(m) also had the highest TE and the lowest carbon isotope discrimination as recorded in leaf tissue (Delta(p)). These results suggest g(m) has unexplored potential to provide TE improvement within crop breeding programmes. PMID- 20199619 TI - Exploring the soluble proteome of Tobacco Bright Yellow-2 cells at the switch towards different cell fates in response to heat shocks. AB - Tobacco (Nicotiana tabacum) Bright Yellow-2 (TBY-2) cells undergo different fates when exposed for 10 minutes to heat stresses of different severity. A 35 degrees C treatment causes a homeostatic response (HRE) allowing cells to cope with the stress; 55 degrees C triggers processes leading to programmed cell death (PCD), which is complete after 72 h. We have used a proteomic approach to gain insight into the molecular mechanisms defining the fate of TBY-2 cells induced by these two heat stresses. Tandem mass spectrometry (MS/MS) and two-dimensional electrophoresis (2-DE) analysis revealed little overlap of differentially accumulated proteins: the different severities of heat treatment induced the modulation of specific proteins, some of which are responsible for different cell fates. When the imposed heat shock is beyond a certain threshold, the overall reduced metabolism may be the result of a series of events involving gene expression and oxidative damage that would lead to PCD. Our data suggest that the down-accumulation of several proteins involved in cellular redox homeostasis could provide, until now, an unappreciated contribution to understanding how many partners are involved in promoting the redox impairment leading to PCD. Moreover post-translational modifications seem to play important regulatory roles in the adaptation of TBY-2 cells to different intensities of heat stress. PMID- 20199620 TI - Nitrogen supply and cyanide concentration influence the enrichment of nitrogen from cyanide in wheat (Triticum aestivum L.) and sorghum (Sorghum bicolor L.). AB - Cyanide assimilation by the beta-cyanoalanine pathway produces asparagine, aspartate and ammonium, allowing cyanide to serve as alternate or supplemental source of nitrogen. Experiments with wheat and sorghum examined the enrichment of (15)N from cyanide as a function of external cyanide concentration in the presence or absence of nitrate and/or ammonium. Cyanogenic nitrogen became enriched in plant tissues following exposure to (15)N-cyanide concentrations from 5 to 200 microm, but when exposure occurred in the absence of nitrate and ammonium, (15)N enrichment increased significantly in sorghum shoots at solution cyanide concentrations of > or =50 microm and in wheat roots at 200 microm cyanide. In an experiment with sorghum using (13)C(15)N, there was also a significant difference in the tissue (13)C:(15)N ratio, suggestive of differential metabolism and transport of carbon and nitrogen under nitrogen-free conditions. A reciprocal (15)N labelling study using KC(15)N and (15)NH(4)(+) and wheat demonstrated an interaction between cyanide and ammonium in roots in which increasing solution ammonium concentrations decreased the enrichment from 100 microm cyanide. In contrast, with increasing solution cyanide concentrations there was an increase in the enrichment from ammonium. The results suggest increased transport and assimilation of cyanide in response to decreased nitrogen supply and perhaps to ammonium supply. PMID- 20199621 TI - Over-expression of bacterial gamma-glutamylcysteine synthetase (GSH1) in plastids affects photosynthesis, growth and sulphur metabolism in poplar (Populus tremula x Populus alba) dependent on the resulting gamma-glutamylcysteine and glutathione levels. AB - We compared three transgenic poplar lines over-expressing the bacterial gamma glutamylcysteine synthetase (GSH1) targeted to plastids. Lines Lggs6 and Lggs12 have two copies, while line Lggs20 has three copies of the transgene. The three lines differ in their expression levels of the transgene and in the accumulation of gamma-glutamylcysteine (gamma-EC) and glutathione (GSH) in leaves, roots and phloem exudates. The lowest transgene expression level was observed in line Lggs6 which showed an increased growth, an enhanced rate of photosynthesis and a decreased excitation pressure (1-qP). The latter typically represents a lower reduction state of the plastoquinone pool, and thereby facilitates electron flow along the electron transport chain. Line Lggs12 showed the highest transgene expression level, highest gamma-EC accumulation in leaves and highest GSH enrichment in phloem exudates and roots. This line also exhibited a reduced growth, and after a prolonged growth of 4.5 months, symptoms of leaf injury. Decreased maximum quantum yield (F(v)/F(m)) indicated down-regulation of photosystem II reaction centre (PSII RC), which correlates with decreased PSII RC protein D1 (PsbA) and diminished light-harvesting complex (Lhcb1). Potential effects of changes in chloroplastic and cytosolic GSH contents on photosynthesis, growth and the whole-plant sulphur nutrition are discussed for each line. PMID- 20199622 TI - Thermal de-acclimation: how permanent are leaf phenotypes when cold-acclimated plants experience warming? AB - We quantified a broad range of Arabidopsis thaliana (Col-0) leaf phenotypes for initially warm-grown (25/20 degrees C day/night) plants that were exposed to cold (5 degrees C) for periods of a few hours to 45 d before being transferred back to the warm, where leaves were allowed to mature. This allowed us to address the following questions: (1) For how long do warm-grown plants have to experience cold before developing leaves become irreversibly cold acclimated? (2) To what extent is the de-acclimation process associated with changes in leaf anatomy and physiology? We show that leaves that experience cold for extended periods during early development exhibit little plasticity in either photosynthesis or respiration, and they do not revert to a warm-associated carbohydrate profile. The eventual expansion rate in the warm was inversely related to the duration of previous cold treatment. Moreover, cold exposure of immature/developing leaves for as little as 5 d resulted in irreversible changes in the morphology of leaves that subsequently matured in the warm, with 15 d cold being sufficient for a permanent alteration of leaf anatomy. Collectively, these results highlight the impact of transitory cold during early leaf development in determining the eventual phenotype of leaves that mature in the warm. PMID- 20199623 TI - Cytosolic NADP-dependent isocitrate dehydrogenase contributes to redox homeostasis and the regulation of pathogen responses in Arabidopsis leaves. AB - Cytosolic NADP-dependent isocitrate dehydrogenase (cICDH) produces 2-oxoglutarate (2-OG) and NADPH, and is encoded by a single gene in Arabidopsis thaliana. Three allelic lines carrying T-DNA insertions in this gene showed less than 10% extractable leaf ICDH activity, but only relatively small decreases in growth compared to wild-type Col0. Metabolite profiling by gas chromatography-time of flight-mass spectrometry (GC-TOF-MS) and high-performance liquid chromatography (HPLC) revealed that loss of cICDH function produced only small effects on leaf compounds involved in carbon and nitrogen assimilation. To analyse whether cICDH contributes to NADPH production under conditions of oxidative stress, the icdh mutation was introduced into the cat2 background, in which increased availability of H(2)O(2) causes perturbed redox homeostasis and induction of stress-related genes. Accumulation of oxidized glutathione and pathogen-related responses were enhanced in double cat2 icdh mutants compared to cat2. Single icdh mutants presented constitutive induction of PR genes, and enhanced resistance to bacteria in icdh, cat2 and cat2 icdh was quantitatively correlated with PR gene expression. However, the effect of icdh in both Col0 and cat2 backgrounds was not associated with enhanced accumulation of salicylic acid (SA). The results suggest that cICDH, previously considered mainly as an enzyme involved in amino acid synthesis, plays a role in redox signalling linked to pathogen responses. PMID- 20199624 TI - Differential anatomical responses to elevated CO2 in saplings of four hardwood species. AB - To determine whether an elevated carbon dioxide concentration ([CO(2)]) can induce changes in the wood structure and stem radial growth in forest trees, we investigated the anatomical features of conduit cells and cambial activity in 4 year-old saplings of four deciduous broadleaved tree species - two ring-porous (Quercus mongolica and Kalopanax septemlobus) and two diffuse-porous species (Betula maximowicziana and Acer mono) - grown for three growing seasons in a free air CO(2) enrichment system. Elevated [CO(2)] had no effects on vessels, growth and physiological traits of Q. mongolica, whereas tree height, photosynthesis and vessel area tended to increase in K. septemlobus. No effects of [CO(2)] on growth, physiological traits and vessels were seen in the two diffuse-porous woods. Elevated [CO(2)] increased larger vessels in all species, except B. maximowicziana and number of cambial cells in two ring-porous species. Our results showed that the vessel anatomy and radial stem growth of Q. mongolica, B. maximowicziana and A. mono were not affected by elevated [CO(2)], although vessel size frequency and cambial activity in Q. mongolica were altered. In contrast, changes in vessel anatomy and cambial activity were induced by elevated [CO(2)] in K. septemlobus. The different responses to elevated [CO(2)] suggest that the sensitivity of forest trees to CO(2) is species dependent. PMID- 20199625 TI - Leafminers help us understand leaf hydraulic design. AB - Leaf hydraulics of Aesculus hippocastanum L. were measured over the growing season and during extensive leaf mining by the larvae of an invasive moth (Cameraria ohridella Deschka et Dimic) that specifically destroy the palisade tissue. Leaves showed seasonal changes in hydraulic resistance (R(lamina)) which were related to ontogeny. After leaf expansion was complete, the hydraulic resistance of leaves and the partitioning of resistances between vascular and extra-vascular compartments remained unchanged despite extensive disruption of the palisade by leafminers (up to 50%). This finding suggests that water flow from the petiole to the evaporation sites might not directly involve the palisade cells. The analysis of the temperature dependence of R(lamina) in terms of Q(10) revealed that at least one transmembrane step was involved in water transport outside the leaf vasculature. Anatomical analysis suggested that this symplastic step may be located at the bundle sheath where the apoplast is interrupted by hydrophobic thickening of cell walls. Our findings offer some support to the view of a compartmentalization of leaves into well-organized water pools so that the transpiration stream would involve veins, bundle sheath and spongy parenchyma, while the palisade tissue would be largely by-passed with the possible advantage of protecting cells from short-term fluctuations in water status. PMID- 20199626 TI - Importance of pre-anthesis anther sink strength for maintenance of grain number during reproductive stage water stress in wheat. AB - Reproductive stage water stress leads to spikelet sterility in wheat. Whereas drought stress at anthesis affects mainly grain size, stress at the young microspore stage of pollen development is characterized by abortion of pollen development and reduction in grain number. We identified genetic variability for drought tolerance at the reproductive stage. Drought-tolerant wheat germplasm is able to maintain carbohydrate accumulation in the reproductive organs throughout the stress treatment. Starch depletion in the ovary of drought-sensitive wheat is reversible upon re-watering and cross-pollination experiments indicate that the ovary is more resilient than the anther. The effect on anthers and pollen fertility is irreversible, suggesting that pollen sterility is the main cause of grain loss during drought conditions in wheat. The difference in storage carbohydrate accumulation in drought-sensitive and drought-tolerant wheat is correlated with differences in sugar profiles, cell wall invertase gene expression and expression of fructan biosynthesis genes in anther and ovary (sucrose : sucrose 1-fructosyl-transferase, 1-SST; sucrose : fructan 6-fructosyl transferase, 6-SFT). Our results indicate that the ability to control and maintain sink strength and carbohydrate supply to anthers may be the key to maintaining pollen fertility and grain number in wheat and this mechanism may also provide protection against other abiotic stresses. PMID- 20199627 TI - Stomatal responses to humidity and temperature in darkness. AB - Stomatal responses to leaf temperature (T(l)) and to the mole fractions of water vapour in the ambient air (w(a)) and the leaf intercellular air spaces (w(i)) were determined in darkness to remove the potential effects of changes in photosynthesis and intercellular CO(2) concentration. Both the steady-state and kinetic responses of stomatal conductance (g(s)) to w(a) in darkness were found to be indistinguishable from those in the light. g(s) showed a steep response to the difference (Deltaw) between w(a) and w(i) when w(a) was varied. The response was much less steep when w(i) was varied. Although stomatal apertures responded steeply to T(l) when Deltaw was held constant at 17 mmol mol(-1), the response was much less steep when Deltaw was held constant at about zero. Similar results were obtained in the light for Deltaw = 15 mmol mol(-1) and Deltaw approximately 0 mmol mol(-1). These results are discussed in the context of mechanisms for the stomatal response to humidity. PMID- 20199628 TI - Ozone-induced reductions in below-ground biomass: an anatomical approach in potato. AB - Potato plants were grown in open-top chambers under three ozone concentrations during two complete cropping seasons (93 and 77 d in 2004 and 2005, respectively). The effects of chronic exposure to ozone on leaf anatomy, cell ultrastructure and crop yield were studied. Severe cell damage was found, even at ambient ozone levels, mainly affecting the spongy parenchyma and areas near the stomata. Damage to the cell wall caused loss of cell contact, and loss of turgor pressure due to tonoplast disintegration, contributed to cell collapse. Phloem sieve plates were obstructed by callose accumulation, and damaged mesophyll cells increased their starch stores. Tuber yield fell sharply (24-44%), due to the biggest tubers becoming smaller, which affected commercial yield. These anatomical findings show the mechanisms of ozone effect on assimilate partitioning, and thus crop yield decrease, in potato. Further implications of ozone causing reductions in below-ground biomass are also discussed. PMID- 20199629 TI - The impact of vessel size on vulnerability curves: data and models for within species variability in saplings of aspen, Populus tremuloides Michx. AB - The objective of this study was to quantify the relationship between vulnerability to cavitation and vessel diameter within a species. We measured vulnerability curves (VCs: percentage loss hydraulic conductivity versus tension) in aspen stems and measured vessel-size distributions. Measurements were done on seed-grown, 4-month-old aspen (Populus tremuloides Michx) grown in a greenhouse. VCs of stem segments were measured using a centrifuge technique and by a staining technique that allowed a VC to be constructed based on vessel diameter size classes (D). Vessel-based VCs were also fitted to Weibull cumulative distribution functions (CDF), which provided best-fit values of Weibull CDF constants (c and b) and P(50) = the tension causing 50% loss of hydraulic conductivity. We show that P(50) = 6.166D(-0.3134) (R(2) = 0.995) and that b and 1/c are both linear functions of D with R(2) > 0.95. The results are discussed in terms of models of VCs based on vessel D size-classes and in terms of concepts such as the 'pit area hypothesis' and vessel pathway redundancy. PMID- 20199630 TI - A prologue to the respirology tuberculosis review series 2010: Impact of tuberculosis on patients: learning from the past? PMID- 20199631 TI - Iodopovidone as a pleurodesis agent: setting standards for clinical pleural research. PMID- 20199632 TI - Current clinical trials for the treatment of idiopathic pulmonary fibrosis. AB - Most pulmonary consultants are called upon to discuss IPF management with their patients. The gravity of IPF treatment discussion is immense in view of the data that 3- and 5-year mortality rates are approximately 50% and 80%, respectively. Although IPF occurs in older patients with comorbid diseases, most patients with IPF die as a direct consequence of their lung fibrosis. Here, the results of recently completed IPF trials and the rationale for ongoing studies are succinctly reviewed. There are a number of novel agents in clinical trials that are in the earlier stages of development, and there is new evidence supporting palliative therapies, which may help in managing symptoms of IPF, such as cough, without necessarily altering the course of the disease. The information provided herein should facilitate informed physician-patient dialogue. PMID- 20199633 TI - Stopping tuberculosis in the 21st century: goals and strategies. AB - The Stop TB Strategy and the Global Plan to Stop TB were launched in 2006 to achieve the tuberculosis (TB)-related Millennium Development Goals and the Stop TB Partnership targets, and to address new challenges such as that of HIV associated TB and multi-drug-resistant TB. This paper reviews the historical and recent progress in TB control to show what has changed since the introduction of directly observed therapy (DOTS) in the mid-1990s, why we needed the new strategy and what the global agenda is today. Major progress was seen in most countries in the last two decades. Globally, the estimated rates of TB prevalence and mortality are declining, but not quickly enough to reach the 2015 Stop TB Partnership targets of halving TB prevalence and death rates compared with 1990. In 2007, it was estimated that more than one-third of TB patients were not detected or properly treated under proper conditions. Enhancing case detection, while maintaining high treatment success rates, is essential to achieve the 2015 targets. The ultimate goal of TB control is the elimination of the disease as a public health problem. The Stop TB Partnership aims at eliminating TB by 2050 by reaching a global incidence of disease of less than one case per million population. This target will not be achieved unless TB control efforts are further intensified and effective and affordable new technologies to prevent both disease and infection are developed and rapidly introduced in all countries worldwide. PMID- 20199634 TI - Lung cancer: progress in diagnosis, staging and therapy. AB - Lung cancer remains one of the greatest medical challenges with nearly 1.5 million new cases worldwide each year and a growing tobacco epidemic in the developing world. This review summarizes briefly the current status in growing areas of clinical research. The value of screening for early disease is not yet established and trials to see if mortality can be improved as a result are in progress. Better and more accurate staging will both streamline investigation and prove cost-effective once ultrasound-guided biopsy and aspiration of mediastinal nodes become universally accepted. This, allied to the new staging classification, will improve selection of cases for surgery, intensive multimodality therapy and for adjuvant treatment postoperatively. Much still needs to be done to refine staging as within a particular stage group, the outcome shows great variation. More information is needed on the genetic make-up in some groups of tumours and not just their size; that is, more biological data on tumour growth patterns are likely to be at least as discriminating. The place of the stem cell theory of tumorigenesis is also explored in this paper. Finally, targeted therapy for advanced non-small-cell lung cancer is highlighted as a development with early promise, but still much clarification is required, before it can be considered as a universal approach in late disease. PMID- 20199635 TI - Public health management of pandemic (H1N1) 2009 infection in Australia: a failure! AB - In April 2009, severe cases of pneumonia preceded by influenza-like illness were noted to occur in Mexico and North America. A novel influenza A (H1N1) virus was identified as the cause and it rapidly evolved into a pandemic, leading to a large number of cases in Australia despite implementation of public health control measures. In this paper, two senior academics discuss the management of pandemic (H1N1) 2009 infection in Australia from the public health perspective. PMID- 20199636 TI - Iodopovidone is as effective as doxycycline in producing pleurodesis in rabbits. AB - BACKGROUND AND OBJECTIVE: The mechanism by which iodopovidone achieves pleurodesis is unknown. This study investigated whether iodopovidone is as effective as doxycycline in producing pleurodesis and whether systemic corticosteroids diminish its efficacy. METHODS: Four groups of seven New Zealand rabbits were assigned to the following intrapleural treatment groups: 2 mL of 2% iodopovidone, 2 mL of 4% iodopovidone, 2 mL of 4% iodopovidone plus 0.8 mg/kg triamcinolone intramuscularly weekly and 10 mL/kg doxycycline in 2 mL. Pleural fluid was collected 24, 48 and 72 h after intrapleural injections and analysed for WCC, protein and LDH levels. The rabbits were killed 2 weeks after the injections. Pleurodesis was graded macroscopically on a scale from 1 to 8. The degree of microscopic pleural fibrosis and pleural inflammation was graded from the HE stain slides. RESULTS: The mean volume of pleural fluid as well as the mean total WCC was significantly lower in the steroid-treated group than in the other groups. The degree of the resulting pleurodesis was similar in the 2% iodopovidone (7.00 +/- 1.29), 4% iodopovidone (7.71 +/- 0.76) and doxycycline (7.14 +/- 0.90) groups (P > 0.05) whereas the pleurodesis score of the steroid group (3.71 +/- 1.98) was significantly lower than all other groups (P < 0.05). The degree of microscopic pleural fibrosis and pleural inflammation was significantly lower in the steroid group than in the 2% iodopovidone or 4% iodopovidone group. CONCLUSIONS: Both 2% and 4% iodopovidone can induce pleurodesis as efficaciously as doxycycline in rabbits. Systemic corticosteroids significantly decrease the efficacy of iodopovidone in producing pleurodesis. PMID- 20199637 TI - Population-based study of cystic fibrosis disease severity and haemochromatosis gene mutations. AB - BACKGROUND AND OBJECTIVE: Haemochromatosis (HFE) mutations increase the risk of bowel obstruction in cystic fibrosis (CF), but the impact on other disease manifestations is unknown. METHODS: We determined the prevalence of HFE mutations (C282Y and H63D) in the Tasmanian CF population and assessed the relationship to systemic iron stores, Pseudomonas aeruginosa infection, lung disease severity and prevalence of diabetes. RESULTS: DNA was obtained from 82 individuals (96% of the entire CF population); 19 (23.2%) were H63D heterozygotes, three (3.7%) were H63D homozygotes and two patients were compound C282Y/H63D (2.4%). Seven (8.5%) patients were heterozygous for the C282Y mutation. Overall, 31 (37.8%) patients carried a HFE mutation. CF patients possessing HFE mutations had significantly better iron stores than non-carriers (P < 0.05). The mean slopes of annual decline in FEV1 and FVC % predicted were significantly steeper in HFE carriers compared with non-carriers (P < 0.01). Patients with HFE mutations were more likely to have had childhood bowel obstruction (RR 2.44, 95% CI: 1.04-5.74, P < 0.05). Diabetes was more common in HFE carriers (RR 2.96, 95% CI: 0.99-8.8, P = 0.05), but this effect attenuated when corrected for age (RR 2.89, 95% CI: 0.91 9.21, P = 0.07). CONCLUSIONS: HFE gene mutations modify disease severity in CF, through probable effects on iron homeostasis. PMID- 20199638 TI - Year in review 2009: Interstitial lung diseases, acute injury, sleep, physiology, imaging and bronchoscopic intervention. PMID- 20199639 TI - The highs and lows of gas exchange during sleep. PMID- 20199640 TI - Asthma: time to confront some inconvenient truths. AB - Despite major advances in the understanding of the pathogenesis of asthma and improvements in management, the accompanying benefits from public health initiatives and clinical practice have arguably been less than expected. For example, there are no effective public health strategies or treatment regimes that reduce the risk of developing asthma or influence its natural history. These represent priority areas for future translational research, which would need to investigate genetic and environmental interactions and vaccine strategies. In terms of asthma management it is tempting to focus on novel drug therapies; however, a case can be made that the priority is to undertake research that leads to improvements in the use of existing treatments through public health and primary care initiatives. Guidelines represent an important component of this approach, with recommendations for asthma imbedded within respiratory guidelines that can be implemented in the developing world where other acute and chronic respiratory disorders are common. This approach offers the best opportunity to close the gap between what is currently achieved in asthma management and that which is potentially achievable. PMID- 20199641 TI - Advances in the diagnosis of tuberculosis. AB - Tuberculosis ranges among the leading causes of morbidity and mortality worldwide. A diagnostic approach to a patient with possible tuberculosis includes a detailed medical history and clinical examination as well as radiological, microbiological, immunological, molecular-biological and histological investigations, where available. Recently, important advances have been achieved in these fields that have led to substantial improvements in the accuracy and the timing of the diagnosis of tuberculosis. Novel methods allow for a better identification of latently infected individuals who are at risk of developing active tuberculosis, they also offer the possibility for a rapid diagnosis of active tuberculosis in patients with negative sputum smears for acid-fast bacilli and enable prompt identification of drug-resistant strains of Mycobacterium tuberculosis directly from respiratory specimen with a high accuracy. In addition, promising methods that will further optimize the diagnosis of tuberculosis are under development. In the future, therapeutic interventions based on the results of novel diagnostic procedures can be made earlier leading to improvements in patient care. PMID- 20199642 TI - Genetic susceptibility in tuberculosis. AB - The importance of host genetic factors in determining susceptibility to tuberculosis (TB) has been studied extensively using various methods, such as case-control, candidate gene and genome-wide linkage studies. Several important candidate genes like human leucocyte antigen/alleles and non-human leucocyte antigen genes, such as cytokines and their receptors, chemokines and their receptors, pattern recognition receptors (including toll-like receptors, mannose binding lectin and the dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin), solute carrier family 11A member 1 (formerly known as natural resistance-associated macrophage protein 1) and purinergic P2X7 receptor gene polymorphisms, have been associated with differential susceptibility to TB in various ethnic populations. This heterogeneity has been explained by host pathogen and gene-environment interactions and evolutionary selection pressures. Although the achievements of genetics studies might not yet have advanced the prevention and treatment of TB, researchers have begun to widen their scope of investigation to encompass these practical considerations. PMID- 20199643 TI - New acoustic method for detecting upper airway obstruction in patients with sleep apnoea. AB - This article investigates a new acoustic device to assess the behaviour of the upper airway in patients with OSA. Currently there is no simple non-invasive method to perform such measurements. As such this paper describes the device in probing the patency of the airway during sleep and increasing the efficiency of diagnosing OSA. BACKGROUND AND OBJECTIVE: OSA is a common disorder resulting in health and economic burdens. Currently identifying OSA in patients involves expensive techniques that require overnight studies in a laboratory setting with qualified staff. This paper tests a new acoustic device (AirwayClear (AC)) for assessing upper airway patency in human subjects with OSA. We hypothesize that obstructive apnoeas would be detected equally well with AC and polysomnography (PSG). METHODS: Twenty-three patients with severe OSA underwent an overnight CPAP titration study. We introduced pseudorandom noise (600-1200 Hz) using AC to the patient's nasal mask during 1 h of subtherapeutic CPAP. AC determined a measure of airway patency based on the level of pseudorandom noise reaching a sternal notch sensor. The ability of AC to detect obstructive respiratory events was compared with standard PSG. RESULTS: Three hundred and twenty-two obstructive events (obstructive and mixed apnoeas) were identified by PSG. AC scored 80% as complete obstructions and 16% as partial obstructions. Conversely, AC detected 281 complete obstructions. PSG recognized 84% as apnoeas and scored 11% as hypopnoeas. Of the 204 hypopnoeas identified with PSG, AC indicated the airway was partially or completely obstructed in 69% of patients. A Bland-Altman analysis for the apnoeas from the two measures showed a mean difference of 2.3 events/h and 95% confidence intervals of +/-15.5 events/h. CONCLUSIONS: We conclude that AC is able to track airway patency and to identify airway closure in patients with OSA. PMID- 20199644 TI - Validation of Embletta portable diagnostic system for identifying patients with suspected obstructive sleep apnoea syndrome (OSAS). AB - The Embletta portable diagnostic system is highly sensitive and specific in quantifying the AHI and differentiating obstructive and supine events when compared against hospital-based PSG in patients with suspected OSAS. The simple device may be useful for screening and diagnostic purpose when access to PSG is limited. BACKGROUND AND OBJECTIVES: This study aimed to evaluate the diagnostic accuracy of Embletta portable diagnostic system (PDS, Medcare, Reykjavik, Iceland) for the screening of sleep apnoea in clinical practice. METHODS: The Embletta PDS is a digital three-channel recording device that measures airflow through a nasal cannula connected to a pressure transducer, oxygen saturation plus both respiratory and abdominal movements via built-in effort and body position sensors. An AHI is determined based on recording time. Nocturnal polysomnography (Alice 4, Healthdyne, Atlanta, USA), with airflow measured by a nasal pressure transducer (PTAF2, Pro-Tech, Woodinville, WA, USA)) and Embletta PDS recordings, was performed simultaneously in consecutive patients with suspected OSA syndrome. The PSG recordings were analysed manually by a blinded investigator. RESULTS: Ninety subjects were recruited and 10 failed Embletta PDS studies due to measurement failure. Among the remaining 80 subjects, 63 were males. The mean age (SD) was 51.4 (11.9) years old, BMI 27.1(4.2) kg/m2, neck circumference 38.6 (3.6) cm and Epworth Sleepiness Score 9.7 (5.3). The AHI obtained by the Embletta PDS correlated closely with that obtained by PSG (Pearson correlation, r=0.979, P<0.001). Comparison of AHI based on the Embletta PDS against the PSG demonstrated high sensitivity at AHI>or=5/h (sensitivity 0.924 and specificity 0.857) and high specificity at AHI>or=20/h (sensitivity 0.853 and specificity 0.957). CONCLUSIONS: The Embletta PDS is a highly sensitive and specific screening device in quantifying AHI when compared against PSG in patients with suspected OSA syndrome. PMID- 20199645 TI - High concentrations of vascular endothelial growth factor reduce stretch-induced apoptosis of alveolar type II cells. AB - Vascular endothelial growth factor (VEGF) has protective as well as injurious effects in ARDS/acute lung injury. The influence of VEGF was investigated in a model of stretch-induced apoptosis. High-amplitude mechanical stretch induced the secretion of VEGF. High VEGF concentrations may prevent stretch-induced apoptosis by restoring stretch-impaired phospatidylinositol-3 kinase signalling. BACKGROUND AND OBJECTIVE: Vascular endothelial growth factor (VEGF) is strongly expressed in the alveolar epithelium. VEGF has been shown to exhibit protective as well as injurious effects in ARDS/acute lung injury. We therefore investigated the influence of VEGF in a model of stretch-induced apoptosis. METHODS: Isolated rat alveolar type II (ATII) cells were subjected to high-amplitude cyclic mechanical stretch (40 per minute, 30% change in surface area) for 24 h. VEGF gene expression was investigated by real-time reverse transcription-PCR. Concentrations of VEGF in culture supernatants of stretched cells were determined by ELISA. Apoptosis of cells following stretching was assessed by flow cytometry. RESULTS: Vascular endothelial growth factor gene expression increased during the first 4 h of stretching and then declined to a similar level to that of static control cells. VEGF concentrations in cell supernatants increased in response to mechanical stretch, as compared with those in supernatants of static control cells. Incubation of ATII cells with higher concentrations of VEGF (50 ng/mL) during stretching inhibited apoptosis, presumably by restoring stretch-impaired phosphatidylinositol-3 kinase signalling. However, blocking free VEGF in the supernatant with an anti-VEGF antibody did not influence stretch-induced apoptosis. CONCLUSIONS: These findings suggest that high-amplitude mechanical stretch induced secretion of VEGF, which in high concentrations, may prevent stretch-induced apoptosis. In this model, however, the protective influence of VEGF was not essential for survival of ATII cells subjected to high-amplitude mechanical stretch. PMID- 20199646 TI - Oxidative stress in non-small cell lung cancer patients after chemotherapy: association with treatment response. AB - Levels of lipid peroxidation, nitric oxide and glutathione, as well as superoxide dismutase activity were evaluated in non-small cell lung cancer patients before and after chemotherapy. Oxidative stress was shown to influence treatment efficacy and survival of these patients. BACKGROUND AND OBJECTIVE: The aim of this study was to assess the level of oxidative stress after chemotherapy in non small cell lung cancer patients, and its association with treatment response and survival. METHODS: Two hundred and three previously untreated non-small cell lung cancer patients and 150 healthy subjects were selected for the study. Patients received cisplatin+etoposide, and were followed for up to six cycles, for evaluation of oxidative stress. Blood levels of lipid peroxidation products (LPO), glutathione (GSH) and nitric oxide (NO), and superoxide dismutase (SOD) activity were measured at day 0 and after the third and sixth cycles of chemotherapy. Response and survival were measured at the end of follow up. Survival was estimated by the Kaplan-Meier method using the log-rank test. RESULTS: In the patients, pretreatment levels of LPO and NO were low, while GSH and SOD levels were high compared with those after the third and sixth cycles of chemotherapy. Among the 203 patients, there were 51 deaths, 82 non-responders and 70 responders at the end of the sixth cycle. Overall mean survival was higher among responders than non-responders (24.6 vs 21.2 weeks, P<0.01). The hazard ratio was 2.4 (95% CI: 1.3-3.77). Pretreatment levels of oxidative stress were similar among responders and non-responders (P>0.05). After the third and sixth cycles of chemotherapy, LPO and NO levels were low (P<0.05 or P<0.01) and GSH levels and SOD activity were high (P<0.05 or P<0.01) in responders as compared with non-responders. CONCLUSIONS: In lung cancer patients, oxidative stress increased and anti-oxidant enzymes decreased as the disease progressed. Chemotherapy may suppress oxidative stress and decreased anti-oxidant enzyme activity in responders as compared with non-responders. These effects may contribute to improved survival among responders. PMID- 20199647 TI - A bench test to confirm the core features of volume-assured non-invasive ventilation. AB - Volume-assured non-invasive ventilation (NIV) theoretically guarantees minute ventilation with circuit leak compensation unlike other modes of NIV. Bench testing demonstrated that minute ventilation was maintained with varying lung compliance and resistance with minimal effect from circuit leak, confirming for the first time the core features of volume-assured NIV. BACKGROUND AND OBJECTIVE: Volume-assured non-invasive positive pressure ventilation (va-NIPPV) is a novel mode designed to adapt pressure support (PS) to achieve a target minute ventilation (TgV). This may optimize ventilation; however, no data confirm that va-NIPPV compensates appropriately for the changes in pulmonary mechanics and circuit leak seen in clinical practice. Bench testing assessed these principles. METHODS: A ventilator featuring a va-NIPPV mode was studied. A test lung with varying compliance and resistance, and pneumotachograph were used. Eight lung model settings were chosen: (i) low resistance and high compliance; (ii) low resistance and low compliance; (iii) high resistance and high compliance; and (iv) high resistance and low compliance, all with and without additional circuit leak. An expiration valve, respiratory rate of 15, inspiratory time of 1 s and PS between 3 and 21 cm H2O were used. Va-NIPPV was tested with varying TgV after establishing the range of minute ventilation possible in a pressure preset mode. RESULTS: At a TgV of 10 L/min, va-NIPPV delivered minute ventilation of (median (interquartile range) ): 11 (10.9-11, 10.2 (10.2-10.3), 12.4 (12.4-12.4) and 11.2 (10.9-11.2) L/min in test lung settings 1, 2, 3 and 4, respectively. Additional leak between 8-33 L/min had little effect. Similar results were seen at other TgV, within the ventilator's PS capabilities. CONCLUSIONS: These data confirm that va-NIPPV is able to approximate a preset TgV with varying lung compliance and resistance, and that additional circuit leak has little effect on the delivered minute ventilation. PMID- 20199648 TI - Year-in-review 2009: Asthma, COPD and airway biology. PMID- 20199649 TI - The role of nasal CPAP in obstructive sleep apnoea syndrome due to mandibular hypoplasia. AB - Melnick Needles syndrome (MNS), Treacher Collins syndrome (TCS) and Pierre Robin syndrome (PRS) are congenital abnormalities with characteristic facial appearances that include micrognathia. A 20-year-old girl with MNS, a 16-year-old boy with TCS and a 12-year-old girl with PRS attended the sleep apnoea clinic at our institution at different times. Diagnostic sleep studies were initially performed on all three patients to confirm the diagnosis of obstructive sleep apnoea syndrome (OSAS). They subsequently commenced nasal CPAP (nCPAP) treatment and their progress was followed. A limited sleep study on the patient with MNS demonstrated moderate/severe OSAS with an AHI of 33 events/h. Commencement of nCPAP resulted in symptomatic improvement. Overnight oximetry in the patient with TCS showed repeated desaturation to SpO2<90%. Subsequent treatment by nCPAP almost completely abolished the desaturation events. Overnight polysomnography in the patient with PRS demonstrated severe OSAS with an AHI of 49 events/h. After 3 years of nCPAP therapy, this patient requested discontinuation of treatment. Subsequent polysomnography without nCPAP revealed an AHI of <5 events/h. The use of nCPAP in the patients with MNS and TCS resulted in effective control of their sleep abnormalities. Mandibular growth and enlargement of the posterior airway space led to resolution of OSAS in the patient with PRS. There is a definite role for nCPAP therapy in patients with congenital micrognathia and OSAS. The use of nCPAP may obviate the need for more invasive corrective surgery for OSAS and is not necessarily a life-long requirement. PMID- 20199650 TI - Estimation of risk assessment of some heavy metals intake through black scabbardfish (Aphanopus carbo) consumption in Portugal. AB - The intake of Cd, methyl-Hg, and Pb through consumption of black scabbardfish (BSF) (Aphanopus carbo) in Portugal as well as the associated probability of exceeding the respective provisional tolerable weekly intakes (PTWIs) was estimated. For this purpose, the contamination levels of heavy metals in this fish species were combined with constructed consumption scenarios or with a hypothesized consumption distribution. Whereas Cd and Pb posed no serious risk, the consumption of at least one portion of BSF per month as well as the hypothetical study in the Portuguese population produced nonnegligible probabilities of surpassing the PTWI for Me-Hg. Risk assessment for Portuguese consumers revealed a higher risk regarding Me-Hg, 1.19% and 1.81% with the plug in (PI) and the tail estimation (TE) estimators, respectively. On the other hand, the risk for Cd and Pb was less than 1 in 100,000. TE was more realistic and accurate for Cd and Pb. Concerning Me-Hg, TE and PI estimators produced similar results. Furthermore, the limitations of a deterministic approach were shown. PMID- 20199651 TI - Can overconfidence be debiased by low-probability/high-consequence events? AB - During the first half of 2008, China suffered three natural disasters: a heavy snow storm, an outbreak of hand-foot-mouth disease, and a severe earthquake. The aim of the present study is to explore how low-probability/high-consequence events influence overconfidence. In Study 1, opportunity samples were obtained by recruiting residents in three different types of disaster-hit areas to answer a peer-comparison probability judgment questionnaire about 1 month after the corresponding disaster occurred. The performance of 539 participants in disaster hit areas was compared with that of 142 residents in a nondisaster area. The findings indicate that residents in disaster-hit areas were less overconfident than those in the nondisaster area on both positive and negative events. In Study 2, we surveyed a total of 336 quake-victims 4 and 11 months after the earthquake to examine whether the impact of disasters on overconfidence would decay with time. The resulting data indicate that the disaster victims became more overconfident as time elapsed. The overall findings suggest that low probability/high-consequence events could make people less overconfident and more rational and seem to serve as a function of debiasing. PMID- 20199652 TI - Deceptive detection methods for effective security with inadequate budgets: the testing power index. AB - Detection of contraband depends on countermeasures, some of which involve examining cargo containers and/or their associated documents. Document screening is the least expensive, physical methods, such as gamma ray detection are more expensive, and definitive manual unpacking is most expensive. We cannot apply the full array of methods to all incoming cargoes, for budgetary reasons. We study the problem using principles of game theory, and find that best detection rates are achieved when the available budget is allocated between screening and definitive unpacking using a mixture of strategies that maximize detection rate and, further, serve to deceive opponents as to the specific tests to which contraband will be subjected. This yields increases of as much as 100% in detection, with essentially no increase in inspection cost. PMID- 20199653 TI - A risk-based approach for identifying key economic and infrastructure systems. AB - This article introduces approaches for identifying key interdependent infrastructure sectors based on the inventory dynamic inoperability input-output model, which integrates an inventory model and a risk-based interdependency model. An identification of such key sectors narrows a policymaker's focus on sectors providing most impact and receiving most impact from inventory-caused delays in inoperability resulting from disruptive events. A case study illustrates the practical insights of the key sector approaches derived from a value of workforce-centered production inoperability from Bureau of Economic Analysis data. PMID- 20199654 TI - Evaluation of scenarios for reducing human salmonellosis through household consumption of fresh minced pork meat. AB - Nontyphoidal salmonellosis is the second most frequently reported zoonotic disease in the European Union (EU) and is considered to be a major threat to human health worldwide. The most reported Salmonella serovar in the EU is S. Enteritidis, mainly associated with egg contamination, followed by S. Typhimurium, with the latter being the most predominant serovar isolated from pork. These findings suggest that reducing the Salmonella contamination in the pork production might be a good strategy to prevent and control human salmonellosis in the EU. Recently, a quantitative microbial risk assessment (QMRA) has been developed to assess the risks for human salmonellosis due to home consumption of fresh minced pork meat in Belgium. The newly developed risk model is called the METZOON model. In the current study, the METZOON model was used to evaluate the effectiveness of different hypothetical Salmonella mitigation strategies implemented at different stages of the minced pork production and consumption chain by means of a scenario analysis. To efficiently evaluate the mitigation strategies, model results were obtained by running simulations using the randomized complete block design. The effectiveness of a mitigation strategy is expressed using point and interval estimates of the effect size for dependent observations, expressed as the standardized difference in population means. The results indicate that the most effective strategies are taken during the slaughter processes of polishing, evisceration, and chilling, and during postprocessing, whereas interventions in the primary production and at the beginning of the slaughter process seem to have only a limited effect. Improving consumer awareness is found to be effective as well. PMID- 20199655 TI - Testing branching process estimators of cascading failure with data from a simulation of transmission line outages. AB - We suggest a statistical estimator to quantify the propagation of cascading transmission line failures in large blackouts of electric power systems. We use a Galton-Watson branching process model of cascading failure and the standard Harris estimator of the mean propagation modified to work when the process saturates at a maximum number of components. If the mean number of initial failures and the mean propagation are estimated, then the branching process model predicts the distribution of the total number of failures. We initially test this prediction on failure data generated by a simulation of cascading transmission line outages on two standard test systems. We discuss the effectiveness of the estimator in terms of how many cascades need to be simulated to predict the distribution of the total number of line outages accurately. PMID- 20199656 TI - A methodology for determining interactions in probabilistic safety assessment models by varying one parameter at a time. AB - In risk analysis problems, the decision-making process is supported by the utilization of quantitative models. Assessing the relevance of interactions is an essential information in the interpretation of model results. By such knowledge, analysts and decisionmakers are able to understand whether risk is apportioned by individual factor contributions or by their joint action. However, models are oftentimes large, requiring a high number of input parameters, and complex, with individual model runs being time consuming. Computational complexity leads analysts to utilize one-parameter-at-a-time sensitivity methods, which prevent one from assessing interactions. In this work, we illustrate a methodology to quantify interactions in probabilistic safety assessment (PSA) models by varying one parameter at a time. The method is based on a property of the functional ANOVA decomposition of a finite change that allows to exactly determine the relevance of factors when considered individually or together with their interactions with all other factors. A set of test cases illustrates the technique. We apply the methodology to the analysis of the core damage frequency of the large loss of coolant accident of a nuclear reactor. Numerical results reveal the nonadditive model structure, allow to quantify the relevance of interactions, and to identify the direction of change (increase or decrease in risk) implied by individual factor variations and by their cooperation. PMID- 20199657 TI - Medically unexplained pain complaints are associated with underlying unrecognized mood disorders in primary care. AB - BACKGROUND: Patients with chronic pain frequently display comorbid depression, but the impact of this concurrence is often underestimated and mistreated. The aim of this study was to determine the prevalence of unrecognized major depression and other mood disorders and comorbid unexplained chronic pain in primary care settings and to explore the associated factors.Also, to compare the use of health services by patients with unexplained chronic pain, both with and without mood disorder comorbidity. METHODS: A cross-sectional study was carried out in a sample of primary care centers. 3189 patients consulting for "unexplained chronic pain" were assessed by the Visual Analogue Scales (VAS) and the Primary Care Evaluation of Mental Disorders (PRIME-MD) questionnaire. RESULTS: We report: a) a high prevalence of unrecognized mood disorders in patients suffering from unexplained chronic pain complaints (80.4%: CI 95%: 79.0%; 81.8%); b) a greater susceptibility of women to mood disorders (OR adjusted = 1.48; CI 95%:1.22; 1.81); c) a direct relationship between the prevalence of mood disorders and the duration of pain (OR adjusted = 1.01; CI 95%: 1.01; 1.02) d) a higher comorbidity with depression if the pain etiology was unknown (OR adjusted = 1.74; CI 95%: 1.45; 2.10) and, e) an increased use of health care services in patients with such a comorbidity (p < 0.0001). CONCLUSIONS: The prevalence of undiagnosed mood disorders in patients with unexplained chronic pain in primary care is very high, leading to dissatisfaction with treatment processes and poorer outcomes. Consequently, it seems necessary to explore this condition more regularly in general practice in order to reach accurate diagnoses and to select the appropriate treatment. PMID- 20199658 TI - Summary of 615 patients of chronic myeloid leukemia in Shanghai from 2001 to 2006. AB - BACKGROUND: To retrospectively review the incidence, treatment efficacy, we followed up newly diagnosed chronic myelogenous leukemia (CML) patients residing in Shanghai during 2001-2006. METHODS: All eligible cases were reviewed with the data of efficacy responses as well as overall survival (OS) and progression-free survival (PFS) time. RESULTS: A total of 615 cases entered the study. CML mainly afflicted those aged 40-60 years old and was slightly more frequent in males than females. More than 85% of the patients were in chronic phase (CP) when diagnosed. All patients were divided into four groups based on the main regimens - hydroxyurea, interferon alpha (IFN-alpha), imatinib, and hemopoietic stem cell transplantation (HSCT). With the median follow-up of 18 months, imatinib treatment induced 92.2% complete hematologic responses, and 64.3% complete cytogenetic responses among CML-CP patients. Overall the therapeutic efficacy in the imatinib group was higher than that in the hydroxyurea or IFN-alpha group. Meanwhile, in the imatinib group, all response rates of patients in CP were significantly greater than that in accelerated or blastic crisis phase. The patients treated with imatinib also showed the most promising results regarding OS and PFS. Patients receiving HSCT decreased markedly in number with the introduction of imatinib. CONCLUSIONS: The number of new patients arising in Shanghai increased from 2001 to 2006. There were still patients receiving hydroxyurea and IFN-alpha. As the first-line regime for CML, imatinib was less administered in Shanghai before, but has received considerable development and great responses since 2003. PMID- 20199659 TI - Entamoeba histolytica Phosphoserine aminotransferase (EhPSAT): insights into the structure-function relationship. AB - BACKGROUND: Presence of phosphorylated Serine biosynthesis pathway upstream to the de novo cysteine biosynthesis pathway makes PSAT a crucial enzyme. Besides this, phoshoserine produced by the enzyme can also be taken up directly by cysteine synthase as a substrate. PSAT is a PLP dependent enzyme where the cofactor serves as an epicenter for functional catalysis with the active site architecture playing crucial role in optimum function of the enzyme. FINDINGS: EhPSAT is a homodimer of molecular mass 86 kDa. To understand the structural modulations associated with pH dependent changes in functional activity of EhPSAT detailed biophysical studies were carried out. pH alterations had no significant effect on the secondary structure, cofactor orientation and oligomeric configuration of the enzyme however, pH dependent compaction in molecular dimensions was observed. Most interestingly, a direct correlation between pH induced modulation of functional activity and orientation of Trp 101 present in the active site of the enzyme was observed. Sodium halides nullified the pH induced global changes in the enzyme, however differential effect of these salts on the active site microenvironment and functional activity of the enzyme was observed. CONCLUSIONS: The study unequivocally demonstrates that pH induced selective modification of active site microenvironment and not global change in structure or oligomeric status of the enzyme is responsible for the pH dependent change in enzymatic activity of PSAT. PMID- 20199660 TI - Detection of siRNA induced mRNA silencing by RT-qPCR: considerations for experimental design. AB - BACKGROUND: RNA interference (RNAi) has been one of the most rapidly expanding areas of biological research in the past decade, revolutionizing the ability to analyze gene function. Thorough validation of siRNA duplexes is required prior to use in experimental systems, ideally by western blotting to show a reduction in protein levels. However, in many cases good antibodies are not available, and researchers must rely on RT-qPCR to detect knockdown of the mRNA species. FINDINGS: We have observed a phenomenon that gives a disparity between analyzing small interfering RNA (siRNA) efficacy by western blotting of the protein levels and real-time quantitative PCR (RT-qPCR) measurement of mRNA levels. Detection of this phenomenon was dependent upon the location of the target amplicon for PCR primers within the mRNA. CONCLUSIONS: Our data suggests that for certain mRNAs, degradation of the 3' mRNA fragment resulting from siRNA mediated cleavage is blocked, leaving an mRNA fragment that can act as a template for cDNA synthesis, giving rise to false negative results and the rejection of a valid siRNA duplex. We show that this phenomenon may be avoided by the careful design of RT-qPCR primers for each individual siRNA experiment. PMID- 20199664 TI - The usefulness of immunohistochemistry in tissue microarrays of Human Papillomavirus negative adenocarcinoma of the uterine cervix. AB - BACKGROUND: The origin of adenocarcinomas presenting on the cervix uteri may be doubtful, i.e. whether it is of cervical or endometrial origin, due to the overlapping morphological features. In HPV negative samples, further tests may be needed to ascertain the nature of the tumours. We aimed to explore the use of immunohistochemistry profiles in tissue microarrays in archived samples of adenocarcinoma (ADC) of the cervix from Uganda that tested negative for HPV DNA. FINDINGS: Five commercially available antibodies were tested in tissue array sections immunostained utilizing the avidin-biotin (AB) technique. In 26 ADC samples, HPV was detected in 13, p16 in 15 (8 in HPV positive and 7 in HPV negative), CEA in 12, vimentin in 6, ER in 0, and PR in 2. Among the 13/25 HPV negative ADC samples, five were positive for CEA suggesting endocervical origin, and three were vimentin positive (one had a mucinous endocervical histological pattern and two were ADC, not otherwise specified, most likely of endometrial origin). CONCLUSIONS: The immunoprofiles of ADC with the antibodies studied are rather nonspecific. By using immunohistochemistry in 13 HPV negative ADC, endocervical tumour origin was suspected in five CEA positive cases while two out of three vimentin positive samples were probably of endometrial origin, suggesting that CEA and vimentin may be valuable in distinguishing HPV negative cervical adenocarcinomas from endometrial adenocarcinomas. PMID- 20199663 TI - Large kidneys predict poor renal outcome in subjects with diabetes and chronic kidney disease. AB - BACKGROUND: Renal hypertrophy occurs early in diabetic nephropathy, its later value is unknown. Do large kidneys still predict poor outcome in patients with diabetes and Chronic Kidney Disease (CKD)? METHODS: Seventy-five patients with diabetes and CKD according to a Glomerular Filtration Rate (GFR, by 51Cr-EDTA clearance) below 60 mL/min/1.73 m2 or an Albumin Excretion Rate above 30 mg/24 H, had an ultrasound imaging of the kidneys and were cooperatively followed during five years by the Diabetology and Nephrology departments of the Centre Hospitalier Universitaire de Bordeaux. RESULTS: The patients were mainly men (44/75), aged 62 +/- 13 yrs, with long-standing diabetes (duration:17 +/- 9 yrs, 55/75 type 2), and CKD: initial GFR: 56.5 (8.5-209) mL/min/1.73 m2, AER: 196 (20 2358) mg/24 H. Their mean kidney lenght (108 +/- 13 mm, 67-147) was correlated to the GFR (r = 0.23, p < 0.05). During the follow-up, 9/11 of the patients who had to start dialysis came from the half with the largest kidneys (LogRank: p < 0.05), despite a 40% higher initial isotopic GFR. Serum creatinine were initially lower (Small kidneys: 125 (79-320) micromol/L, Large: 103 (50-371), p < 0.05), but significantly increased in the "large kidneys" group at the end of the follow up (Small kidneys: 129 (69-283) micromol/L, Large: 140 (50-952), p < 0.005 vs initial). The difference persisted in the patients with severe renal failure (KDOQI stages 4,5). CONCLUSIONS: Large kidneys still predict progression in advanced CKD complicating diabetes. In these patients, ultrasound imaging not only excludes obstructive renal disease, but also provides information on the progression of the renal disease. PMID- 20199662 TI - Identification and characterization of Dlc1 isoforms in the mouse and study of the biological function of a single gene trapped isoform. AB - BACKGROUND: The Dlc1 (deleted in liver cancer 1) tumour suppressor gene codes for a RhoGTPase activating protein that is found inactivated in many tumour types. Several transcriptional isoforms have been described but the functional significance and tissue distribution of each form is presently poorly understood. Also, differences in the number of isoforms and splice variants reported still exist between different mammalian species. In order to better understand the number and function of the different variants of the Dlc1 gene in the mouse, we have carried out a detailed analysis. Extensive 3' RACE experiments were carried out in order to identify all possible Dlc1 isoforms and splice variants in the mouse. In addition, we have generated a gene trapped mouse that targets one of these isoforms in order to study its biological function. The effect of this gene trap insertion on the splicing of other isoforms has also been studied. RESULTS: In addition to the known 6.1 and 6.2 Kb transcripts of Dlc1, our study revealed the existence of a novel 7.6 Kb transcriptional isoform in the mouse, which corresponds to the human 7.4 Kb (KIAA1723) cDNA transcript. A gene trapped embryonic cell line, with an insertion between Exon 1 and 2 of the 6.1 Kb transcriptional isoform, was used to generate a transgenic mouse. This line showed a significant reduction in the expression of the trapped isoform. However, reduced expression of the other isoforms was not seen. Mice heterozygous for the gene trapped allele were phenotypically normal, but homozygous mutant embryos did not survive beyond 10.5 days post coitum. Dlc1gt/gt embryos showed defects in the brain, heart, and placental blood vessels. Cultured serum-free mouse embryo cells from Dlc1 deficient embryos had elevated RhoA activity and displayed alterations in the organization of actin filaments and focal adhesions. The Dlc1 deficient cells also exhibited increased wound closure in an in vitro scratch assay. CONCLUSIONS: The mouse has three major transcriptional isoforms of the Dlc1 gene that are differentially expressed in various tissues. A mouse with exon 1 of the 6.1 Kb transcript gt resulted in hypomorphic expression of Dlc1 protein and an embryonic lethal phenotype in the homozygous condition, which indicates that this isoform plays a major role in mouse development. The Dlc1 deficient cells showed altered cytoskeleton structure, increased RhoA activity and cellular migration. PMID- 20199661 TI - Multifunctional Nanocarriers for diagnostics, drug delivery and targeted treatment across blood-brain barrier: perspectives on tracking and neuroimaging. AB - Nanotechnology has brought a variety of new possibilities into biological discovery and clinical practice. In particular, nano-scaled carriers have revolutionalized drug delivery, allowing for therapeutic agents to be selectively targeted on an organ, tissue and cell specific level, also minimizing exposure of healthy tissue to drugs. In this review we discuss and analyze three issues, which are considered to be at the core of nano-scaled drug delivery systems, namely functionalization of nanocarriers, delivery to target organs and in vivo imaging. The latest developments on highly specific conjugation strategies that are used to attach biomolecules to the surface of nanoparticles (NP) are first reviewed. Besides drug carrying capabilities, the functionalization of nanocarriers also facilitate their transport to primary target organs. We highlight the leading advantage of nanocarriers, i.e. their ability to cross the blood-brain barrier (BBB), a tightly packed layer of endothelial cells surrounding the brain that prevents high-molecular weight molecules from entering the brain. The BBB has several transport molecules such as growth factors, insulin and transferrin that can potentially increase the efficiency and kinetics of brain-targeting nanocarriers. Potential treatments for common neurological disorders, such as stroke, tumours and Alzheimer's, are therefore a much sought after application of nanomedicine. Likewise any other drug delivery system, a number of parameters need to be registered once functionalized NPs are administered, for instance their efficiency in organ-selective targeting, bioaccumulation and excretion. Finally, direct in vivo imaging of nanomaterials is an exciting recent field that can provide real-time tracking of those nanocarriers. We review a range of systems suitable for in vivo imaging and monitoring of drug delivery, with an emphasis on most recently introduced molecular imaging modalities based on optical and hybrid contrast, such as fluorescent protein tomography and multispectral optoacoustic tomography. Overall, great potential is foreseen for nanocarriers in medical diagnostics, therapeutics and molecular targeting. A proposed roadmap for ongoing and future research directions is therefore discussed in detail with emphasis on the development of novel approaches for functionalization, targeting and imaging of nano-based drug delivery systems, a cutting-edge technology poised to change the ways medicine is administered. PMID- 20199665 TI - Conservation and divergence of known apicomplexan transcriptional regulons. AB - BACKGROUND: The apicomplexans are a diverse phylum of parasites causing an assortment of diseases including malaria in a wide variety of animals and lymphoproliferation in cattle. Little is known about how these varied parasites regulate their transcriptional regulons. Even less is known about how regulon systems, consisting of transcription factors and target genes together with their associated biological process, evolve in these diverse parasites. RESULTS: In order to obtain insights into the differences in transcriptional regulation between these parasites we compared the orthology profiles of putative malaria transcription factors across species and examined the enrichment patterns of four binding sites across eleven apicomplexans. About three-fifths of the factors are broadly conserved in several phylogenetic orders of sequenced apicomplexans. This observation suggests the existence of regulons whose regulation is conserved across this ancient phylum. Transcription factors not broadly conserved across the phylum are possibly involved in regulon systems that have diverged between species. Examining binding site enrichment patterns in light of transcription factor conservation patterns suggests a second mode via which regulon systems may diverge - rewiring of existing transcription factors and their associated binding sites in specific ways. Integrating binding sites with transcription factor conservation patterns also facilitated prediction of putative regulators for one of the binding sites. CONCLUSIONS: Even though transcription factors are underrepresented in apicomplexans, the distribution of these factors and their associated regulons reflect common and family-specific transcriptional regulatory processes. PMID- 20199666 TI - Mechanical ventilation modulates TLR4 and IRAK-3 in a non-infectious, ventilator induced lung injury model. AB - BACKGROUND: Previous experimental studies have shown that injurious mechanical ventilation has a direct effect on pulmonary and systemic immune responses. How these responses are propagated or attenuated is a matter of speculation. The goal of this study was to determine the contribution of mechanical ventilation in the regulation of Toll-like receptor (TLR) signaling and interleukin-1 receptor associated kinase-3 (IRAK-3) during experimental ventilator-induced lung injury. METHODS: Prospective, randomized, controlled animal study using male, healthy adults Sprague-Dawley rats weighing 300-350 g. Animals were anesthetized and randomized to spontaneous breathing and to two different mechanical ventilation strategies for 4 hours: high tidal volume (VT) (20 ml/kg) and low VT (6 ml/kg). Histological evaluation, TLR2, TLR4, IRAK3 gene expression, IRAK-3 protein levels, inhibitory kappa B alpha (IkappaBalpha), tumor necrosis factor-alpha (TNF alpha) and interleukin-6 (IL6) gene expression in the lungs and TNF-alpha and IL 6 protein serum concentrations were analyzed. RESULTS: High VT mechanical ventilation for 4 hours was associated with a significant increase of TLR4 but not TLR2, a significant decrease of IRAK3 lung gene expression and protein levels, a significant decrease of IkappaBalpha, and a higher lung expression and serum concentrations of pro-inflammatory cytokines. CONCLUSIONS: The current study supports an interaction between TLR4 and IRAK-3 signaling pathway for the over-expression and release of pro-inflammatory cytokines during ventilator induced lung injury. Our study also suggests that injurious mechanical ventilation may elicit an immune response that is similar to that observed during infections. PMID- 20199667 TI - Statistical model comparison applied to common network motifs. AB - BACKGROUND: Network motifs are small modules that show interesting functional and dynamic properties, and are believed to be the building blocks of complex cellular processes. However, the mechanistic details of such modules are often unknown: there is uncertainty about the motif architecture as well as the functional form and parameter values when converted to ordinary differential equations (ODEs). This translates into a number of candidate models being compatible with the system under study. A variety of statistical methods exist for ranking models including maximum likelihood-based and Bayesian methods. Our objective is to show how such methods can be applied in a typical systems biology setting. RESULTS: We focus on four commonly occurring network motif structures and show that it is possible to differentiate between them using simulated data and any of the model comparison methods tested. We expand one of the motifs, the feed forward (FF) motif, for several possible parameterizations and apply model selection on simulated data. We then use experimental data on three biosynthetic pathways in Escherichia coli to formally assess how current knowledge matches the time series available. Our analysis confirms two of them as FF motifs. Only an expanded set of FF motif parameterizations using time delays is able to fit the third pathway, indicating that the true mechanism might be more complex in this case. CONCLUSIONS: Maximum likelihood as well as Bayesian model comparison methods are suitable for selecting a plausible motif model among a set of candidate models. Our work shows that it is practical to apply model comparison to test ideas about underlying mechanisms of biological pathways in a formal and quantitative way. PMID- 20199668 TI - Neuroprotective effects of bis(7)-tacrine against glutamate-induced retinal ganglion cells damage. AB - BACKGROUND: Glutamate-mediated excitotoxicity, primarily through N-methyl-D aspartate (NMDA) receptors, may be an important cause of retinal ganglion cells (RGCs) death in glaucoma and several other retinal diseases. Bis(7)-tacrine is a noncompetitive NMDA receptors antagonist that can prevent glutamate-induced hippocampal neurons damage. We tested the effects of bis(7)-tacrine against glutamate-induced rat RGCs damage in vitro and in vivo. RESULTS: In cultured neonatal rats RGCs, the MTT assay showed that glutamate induced a concentration- and time-dependent toxicity. Bis(7)-tacrine and memantine prevented glutamate induced cell death in a concentration-dependent manner with IC50 values of 0.028 microM and 0.834 microM, respectively. The anti-apoptosis effects of bis(7) tacrine were confirmed by annexin V-FITC/PI staining. In vivo, TUNEL analysis and retrograde labeling analysis found that pretreatment with bis(7)-tacrine(0.2 mg/kg) induced a significant neuroprotective effect against glutamate-induced RGCs damage. CONCLUSIONS: Our results showed that bis(7)-tacrine had neuroprotective effects against glutamate-induced RGCs damage in vitro and in vivo, possibly through the drug's anti-NMDA receptor effects. These findings make bis(7)-tacrine potentially useful for treating a variety of ischemic or traumatic retinopathies inclusive of glaucoma. PMID- 20199669 TI - A survey of castration methods and associated livestock management practices performed by bovine veterinarians in the United States. AB - BACKGROUND: Castration of male calves destined for beef production is a common management practice performed in the United States amounting to approximately 15 million procedures per year. Societal concern about the moral and ethical treatment of animals is increasing. Therefore, production agriculture is faced with the challenge of formulating animal welfare policies relating to routine management practices such as castration. To enable the livestock industry to effectively respond to these challenges there is a need for more data on management practices that are commonly used in cattle production systems. The objective of this survey was to describe castration methods, adverse events and husbandry procedures performed by U.S. veterinarians at the time of castration. Invitations to participate in the survey were sent to email addresses of 1,669 members of the American Association of Bovine Practitioners and 303 members of the Academy of Veterinary Consultants. RESULTS: After partially completed surveys and missing data were omitted, 189 responses were included in the analysis. Surgical castration with a scalpel followed by testicular removal by twisting (calves <90 kg) or an emasculator (calves >90 kg) was the most common method of castration used. The potential risk of injury to the operator, size of the calf, handling facilities and experience with the technique were the most important considerations used to determine the method of castration used. Swelling, stiffness and increased lying time were the most prevalent adverse events observed following castration. One in five practitioners report using an analgesic or local anesthetic at the time of castration. Approximately 90% of respondents indicated that they vaccinate and dehorn calves at the time of castration. Over half the respondents use disinfectants, prophylactic antimicrobials and tetanus toxoid to reduce complications following castration. CONCLUSIONS: The results of this survey describe current methods of castration and associated management practices employed by bovine veterinarians in the U.S. Such data are needed to guide future animal well-being research, the outcomes of which can be used to develop industry-relevant welfare guidelines. PMID- 20199670 TI - Glucocorticoid receptor gene polymorphisms do not affect growth in fetal and early postnatal life. The Generation R Study. AB - BACKGROUND: Glucocorticoids have an important role in early growth and development. Glucocorticoid receptor gene polymorphisms have been identified that contribute to the variability in glucocorticoid sensitivity. We examined whether these glucocorticoid receptor gene polymorphisms are associated with growth in fetal and early postnatal life. METHODS: This study was embedded in a population based prospective cohort study from fetal life onwards. The studied glucocorticoid receptor gene polymorphisms included BclI (rs41423247), TthIIII (rs10052957), GR-9beta (rs6198), N363S (rs6195) and R23K (rs6789 and6190). Fetal growth was assessed by ultrasounds in second and third trimester of pregnancy. Anthropometric measurements in early childhood were performed at birth and at the ages of 6, 14 and 24 months postnatally. Analyses focused on weight, length and head circumference. Analyses were based on 2,414 healthy, Caucasian children. RESULTS: Glucocorticoid receptor gene polymorphisms were not associated with fetal weight, birth weight and early postnatal weight. Also, no associations were found with length and head circumference. Neither were these polymorphisms associated with the risks of low birth weight or growth acceleration from birth to 24 months of age. CONCLUSIONS: We found in a large population-based cohort no evidence for an effect of known glucocorticoid receptor gene polymorphisms on fetal and early postnatal growth characteristics. Further systematic searches for common genetic variants by means of genome-wide association studies will enable us to obtain a more complete understanding of what genes and polymorphisms are involved in growth in fetal life and infancy. PMID- 20199671 TI - A microsatellite polymorphism in IGF1 gene promoter and longevity in a Han Chinese population. AB - BACKGROUND: Previous studies have suggested a probable association between the polymorphism of a microsatellite locus located in the promoter of IGF1 (Insulin like growth factor 1) gene and the serum level of IGF1, as well as many age related diseases. Based on these results, we hypothesized that this polymorphism may influence longevity in humans. We performed an association study in a Han Chinese population to test this hypothesis. FINDINGS: We recruited 493 elderly Han Chinese individuals (females >/= 94; males >/= 90) and 425 young individuals (controls) from Dujiangyan (Sichuan province, China). The genotype distributions and allele frequencies of the microsatellite site in the elderly and control groups were compared by chi square test.Our results suggested that there was no association between the microsatellite polymorphism and longevity in our Han Chinese population. However, there were more male persons with 18/21 genotype in elderly group than that in control group (11.11 vs. 5.45%, p = 0.011). As the difference was not significant when corrected by Bonferroni method, we speculate that the 18/21 genotype can not be functional in longevity; however, it may link with the real functional loci as there is a long haplotype block embracing the microsatellite locus. CONCLUSIONS: There was no association between polymorphism of the microsatellite in promoter of IGF1 gene and longevity in our study. Future association studies containing the long haplotype block are deserved and can test our speculation of the potential linkage of 18/21 genotype and functional loci. PMID- 20199672 TI - Automatic prediction of catalytic residues by modeling residue structural neighborhood. AB - BACKGROUND: Prediction of catalytic residues is a major step in characterizing the function of enzymes. In its simpler formulation, the problem can be cast into a binary classification task at the residue level, by predicting whether the residue is directly involved in the catalytic process. The task is quite hard also when structural information is available, due to the rather wide range of roles a functional residue can play and to the large imbalance between the number of catalytic and non-catalytic residues. RESULTS: We developed an effective representation of structural information by modeling spherical regions around candidate residues, and extracting statistics on the properties of their content such as physico-chemical properties, atomic density, flexibility, presence of water molecules. We trained an SVM classifier combining our features with sequence-based information and previously developed 3D features, and compared its performance with the most recent state-of-the-art approaches on different benchmark datasets. We further analyzed the discriminant power of the information provided by the presence of heterogens in the residue neighborhood. CONCLUSIONS: Our structure-based method achieves consistent improvements on all tested datasets over both sequence-based and structure-based state-of-the-art approaches. Structural neighborhood information is shown to be responsible for such results, and predicting the presence of nearby heterogens seems to be a promising direction for further improvements. PMID- 20199673 TI - Galactomannan testing of bronchoalveolar lavage fluid is useful for diagnosis of invasive pulmonary aspergillosis in hematology patients. AB - BACKGROUND: Invasive pulmonary aspergillosis (IPA) is a major cause of morbidity and mortality in patients with hematological malignancies in the setting of profound neutropenia and/or hematopoietic stem cell transplantation. Early diagnosis and therapy has been shown to improve outcomes, but reaching a definitive diagnosis quickly can be problematic. Recently, galactomannan testing of bronchoalveolar lavage (BAL) fluid has been investigated as a diagnostic test for IPA, but widespread experience and consensus on optical density (OD) cut-offs remain lacking. METHODS: We performed a prospective case-control study to determine an optimal BAL galactomannan OD cutoff for IPA in at-risk patients with hematological diagnoses. Cases were subjects with hematological diagnoses who met established definitions for proven or probable IPA. There were two control groups: subjects with hematological diagnoses who did not meet definitions for proven or probable IPA and subjects with non-hematological diagnoses who had no evidence of aspergillosis. Following bronchoscopy and BAL, galactomannan testing was performed using the Platelia Aspergillus seroassay in accordance with the manufacturer's instructions. RESULTS: There were 10 cases and 52 controls. Cases had higher BAL fluid galactomannan OD indices (median 4.1, range 1.1-7.7) compared with controls (median 0.3, range 0.1-1.1). ROC analysis demonstrated an optimum OD index cutoff of 1.1, with high specificity (98.1%) and sensitivity (100%) for diagnosing IPA. CONCLUSIONS: Our results also support BAL galactomannan testing as a reasonably safe test with higher sensitivity compared to serum galactomannan testing in at-risk patients with hematological diseases. A higher OD cutoff is necessary to avoid over-diagnosis of IPA, and a standardized method of collection should be established before results can be compared between centers. PMID- 20199674 TI - Community-wide benefits of targeted indoor residual spray for malaria control in the western Kenya highland. AB - BACKGROUND: Interest in indoor residual spray (IRS) has been rekindled in recent years, as it is increasingly considered to be a key component of integrated malaria management. Regular spraying of each human dwelling becomes less and less practical as the control area increases. Where malaria transmission is concentrated around focal points, however, targeted IRS may pose a feasible alternative to mass spraying. Here, the impact of targeted IRS was assessed in the highlands of western Kenya. METHODS: Indoor residual spray using lambda cyhalothrin insecticide was carried out during the last week of April 2005 in 1,100 targeted houses, located in the valley bottom areas of Iguhu village, Kakamega district of western Kenya. Although the uphill areas are more densely populated, valleys are believed to be malaria transmission hotspots. The aim of the study was to measurably reduce the vector density and malaria transmission in uphill areas by focusing control on these hotspots. A cohort of 1,058 children from 1-5 yrs of age was randomly selected from a 4 km by 6 km study area for the baseline malaria prevalence survey after pre-clearing malaria infections during the third week of April 2005, and the prevalence of Plasmodium infections was tested bi-weekly. Seasonal changes in mosquito densities 12 months before the IRS and 12 months after the IRS was monitored quarterly based on 300 randomly selected houses. Monthly parasitological surveys were also carried out in the same area with 129-661 randomly selected school children of age 6-13 yrs. RESULTS: The result of monthly parasitological surveys indicated that malaria prevalence in school children was reduced by 64.4% in the intervention valley area and by 46.3% in the intervention uphill area after 12 months of follow-ups in contrast to nonintervention areas (valley or uphill). The cohort study showed an average of 4.5% fewer new infections biweekly in the intervention valley compare to nonintervention valley and the relative reduction in incidence rate by week 14 was 65.4%. The relative reduction in incidence rate in intervention uphill by week 14 was 46.4%. Anopheles gambiae densities were reduced by 96.8% and 51.6% in the intervention valley and intervention uphill, respectively, and Anopheles funestus densities were reduced by 85.3% and 69.2% in the intervention valley and intervention uphill, respectively. CONCLUSION: Vector control had significant indirect impact on the densely populated uphill areas when IRS was targeted to the high-risk valleys. Additionally, the wide-reaching benefits of IRS in reducing vector prevalence and disease incidence was observed for at least six months following spraying, suggesting targeted IRS as an effective tool in malaria control. PMID- 20199675 TI - MicroRNAs of Bombyx mori identified by Solexa sequencing. AB - BACKGROUND: MicroRNA (miRNA) and other small regulatory RNAs contribute to the modulation of a large number of cellular processes. We sequenced three small RNA libraries prepared from the whole body, and the anterior-middle and posterior silk glands of Bombyx mori, with a view to expanding the repertoire of silkworm miRNAs and exploring transcriptional differences in miRNAs between segments of the silk gland. RESULTS: With the aid of large-scale Solexa sequencing technology, we validated 257 unique miRNA genes, including 202 novel and 55 previously reported genes, corresponding to 324 loci in the silkworm genome. Over 30 known silkworm miRNAs were further corrected in their sequence constitutes and length. A number of reads originated from the loop regions of the precursors of two previously reported miRNAs (bmo-miR-1920 and miR-1921). Interestingly, the majority of the newly identified miRNAs were silkworm-specific, 23 unique miRNAs were widely conserved from invertebrates to vertebrates, 13 unique miRNAs were limited to invertebrates, and 32 were confined to insects. We identified 24 closely positioned clusters and 45 paralogs of miRNAs in the silkworm genome. However, sequence tags showed that paralogs or clusters were not prerequisites for coordinated transcription and accumulation. The majority of silkworm-specific miRNAs were located in transposable elements, and displayed significant differences in abundance between the anterior-middle and posterior silk gland. CONCLUSIONS: Conservative analysis revealed that miRNAs can serve as phylogenetic markers and function in evolutionary signaling. The newly identified miRNAs greatly enrich the repertoire of insect miRNAs, and provide insights into miRNA evolution, biogenesis, and expression in insects. The differential expression of miRNAs in the anterior-middle and posterior silk glands supports their involvement as new levels in the regulation of the silkworm silk gland. PMID- 20199677 TI - Causal beliefs about obesity and associated health behaviors: results from a population-based survey. AB - BACKGROUND: Several genetic variants are associated with obesity risk. Promoting the notion of genes as a cause for obesity may increase genetically deterministic beliefs and decrease motivation to engage in healthy lifestyle behaviors. Little is known about whether causal beliefs about obesity are associated with lifestyle behaviors. Study objectives were as follows: 1) to document the prevalence of various causal beliefs about obesity (i.e., genes versus lifestyle behaviors), and 2) to determine the association between obesity causal beliefs and self reported dietary and physical activity behaviors. METHODS: The study data were drawn from the 2007 Health Information National Trends Survey (HINTS). A total of 3,534 individuals were included in the present study. RESULTS: Overall, 72% of respondents endorsed the belief that lifestyle behaviors have 'a lot' to do with causing obesity, whereas 19% indicated that inheritance has 'a lot' to do with causing obesity. Multinomial logistic regression analyses indicated that the belief that obesity is inherited was associated with lower reported levels of physical activity (OR = 0.87, 95% CI: 0.77-0.99) and fruit and vegetable consumption (OR = 0.87, 95% CI: 0.76-0.99). In contrast, the belief that obesity is caused by lifestyle behaviors was associated with greater reported levels of physical activity (OR = 1.29, 95% CI: 1.03-1.62), but was not associated with fruit and vegetable intake (OR = 1.07, 95% CI: 0.90-1.28). CONCLUSIONS: Causal beliefs about obesity are associated with some lifestyle behaviors. Additional research is needed to determine whether promoting awareness of the genetic determinants of obesity will decrease the extent to which individuals will engage in the lifestyle behaviors essential to healthy weight management. PMID- 20199676 TI - Markers of anti-malarial drug resistance in Plasmodium falciparum isolates from Swaziland: identification of pfmdr1-86F in natural parasite isolates. AB - BACKGROUND: The development of Plasmodium falciparum resistance to chloroquine (CQ) has limited its use in many malaria endemic areas of the world. However, despite recent drug policy changes to adopt the more effective artemisinin-based combination (ACT) in Africa and in the Southern African region, in 2007 Swaziland still relied on CQ as first-line anti-malarial drug. METHODS: Parasite DNA was amplified from P. falciparum isolates from Swaziland collected in 1999 (thick smear blood slides) and 2007 (filter paper blood spots). Markers of CQ and sulphadoxine-pyrimethamine (SP) resistance were identified by probe-based qPCR and DNA sequencing. RESULTS: Retrospective microscopy, confirmed by PCR amplification, found that only six of 252 patients treated for uncomplicated malaria in 2007 carried detectable P. falciparum. The pfcrt haplotype 72C/73V/74I/75E/76T occurred at a prevalence of 70% (n = 64) in 1999 and 83% (n = 6) in 2007. Prevalence of the pfmdr1-86N allele was 24% in 1999 and 67% in 2007. A novel substitution of phenylalanine for asparagine at codon 86 of pfmdr1 (N86F) occurred in two of 51 isolates successfully amplified from 1999. The pfmdr1-1246Y allele was common in 1999, with a prevalence of 49%, but was absent among isolates collected in 2007. The 86N/184F/1246D pfmdr1 haplotype, associated with enhanced parasite survival in patients treated with artemether-lumefantrine, comprised 8% of 1999 isolates, and 67% among 2007 isolates. The pfdhfr triple mutant 16C/51I/59R/108N/164I haplotype associated with pyrimethamine resistance was common in both 1999 (82%, n = 34) and 2007 (50%, n = 6), as was the wild-type 431I/436S/437A/540K/581A/613A haplotype of pfdhps (100% and 93% respectively in 1999 and 2007). The quintuple-mutant haplotype pfdhfr/pfdhps-CIRNI/ISGEAA, associated with high-level resistance to SP, was rare (9%) among 1999 isolates and absent among 2007 isolates. CONCLUSIONS: The prevalence of pfcrt and pfmdr1 alleles reported in this study is consistent with a parasite population under sustained CQ drug pressure. The low prevalence of dhps-437G and dhps-540E mutations (ISGEAA) and the rarity of quintuple-mutant haplotype pfdhfr/pfdhps CIRNI/ISGEAA suggest that SP retains some efficacy in Swaziland. Anti-malarial policy changes in neighbouring countries may have had an impact on the prevalence of molecular markers of anti-malarial resistance in Swaziland, and it is hoped that this new information will add to understanding of the regional anti-malarial resistance map. PMID- 20199678 TI - The value of SPECT in the detection of stress injury to the pars interarticularis in patients with low back pain. AB - The medical cost associated with back pain in the United States is considerable and growing. Although the differential diagnosis of back pain is broad, epidemiological studies suggest a correlation between adult and adolescent complaints. Injury of the pars interarticularis is one of the most common identifiable causes of ongoing low back pain in adolescent athletes. It constitutes a spectrum of disease ranging from bone stress to spondylolysis and spondylolisthesis. Bone stress may be the earliest sign of disease. Repetitive bone stress causes bone remodeling and may result in spondylolysis, a non displaced fracture of the pars interarticularis. A fracture of the pars interarticularis may ultimately become unstable leading to spondylolisthesis. Results in the literature support the use of bone scintigraphy to diagnose bone stress in patients with suspected spondylolysis. Single photon emission computed tomography (SPECT) provides more contrast than planar bone scintigraphy, increases the sensitivity and improves anatomic localization of skeletal lesions without exposing the patient to additional radiation. It also provides an opportunity for better correlation with other imaging modalities, when necessary. As such, the addition of SPECT to standard planar bone scintigraphy can result in a more accurate diagnosis and a better chance for efficient patient care. It is our expectation that by improving our ability to correctly diagnose bone stress in patients with suspected injury of the posterior elements, the long-term cost of managing this condition will be lowered. PMID- 20199679 TI - Alterations in the red blood cell membrane proteome in alzheimer's subjects reflect disease-related changes and provide insight into altered cell morphology. AB - BACKGROUND: Our earlier studies have shown that red blood cell (RBC) morphology in Alzheimer's disease (AD) subjects was altered (> 15% of the RBCs were elongated as compared to 5.9% in normal controls (p < 0.0001)). These results suggested alterations in the RBC membrane architecture in AD subjects, possibly due to RBC-beta-amyloid interactions and/or changes in the expression of membrane proteins. We hypothesized that the observed changes could be due to changes in the level of the protein components of the cytoskeleton and those linked to the RBC membrane. To examine this, we performed a proteomic analysis of RBC membrane proteins of AD subjects, and their age-matched controls using one pool of samples from each group, following their separation by SDS-PAGE, in-gel Tryptic digestion, LC-MS-MS of peptides generated, and a label-free approach of semi quantitative analysis of their relative MS spectral intensities. RESULTS: The data suggest, (1) RBC shape/morphology changes in AD subjects are possibly attributed primarily to the changes (elevation or decrease) in the level of a series of membrane/cytoskeleton proteins involved in regulating the stability and elasticity of the RBC membrane, and (2) changes (elevation or decrease) in the level of a second series of proteins in the RBC membrane proteome reflect similar changes reported earlier by various investigators in AD or animal model of AD. Of particular interest, elevation of oxidative stress response proteins such as heat shock 90 kDa protein 1 alpha in AD subjects has been confirmed by western blot analysis in the RBC membrane proteome. CONCLUSIONS: The results suggest that this study provides a potential link between the alterations in RBC membrane proteome in AD subjects and AD pathology. PMID- 20199681 TI - Web GIS in practice VIII: HTML5 and the canvas element for interactive online mapping. AB - HTML5 is being developed as the next major revision of HTML (Hypertext Markup Language), the core markup language of the World Wide Web. It aims at reducing the need for proprietary, plug-in-based rich Internet application (RIA) technologies such as Adobe Flash. The canvas element is part of HTML5 and is used to draw graphics using scripting (e.g., JavaScript). This paper introduces Cartagen, an open-source, vector-based, client-side framework for rendering plug in-free, offline-capable, interactive maps in native HTML5 on a wide range of Web browsers and mobile phones. Cartagen was developed at MIT Media Lab's Design Ecology group. Potential applications of the technology as an enabler for participatory online mapping include mapping real-time air pollution, citizen reporting, and disaster response, among many other possibilities. PMID- 20199680 TI - The development of a web- and a print-based decision aid for prostate cancer screening. AB - BACKGROUND: Whether early detection and treatment of prostate cancer (PCa) will reduce disease-related mortality remains uncertain. As a result, tools are needed to facilitate informed decision making. While there have been several decision aids (DAs) developed and tested, very few have included an exercise to help men clarify their values and preferences about PCa screening. Further, only one DA has utilized an interactive web-based format, which allows for an expansion and customization of the material. We describe the development of two DAs, a booklet and an interactive website, each with a values clarification component and designed for use in diverse settings. METHODS: We conducted two feasibility studies to assess men's (45-70 years) Internet access and their willingness to use a web- vs. a print-based tool. The booklet was adapted from two previous versions evaluated in randomized controlled trials (RCTs) and the website was created to closely match the content of the revised booklet. Usability testing was conducted to obtain feedback regarding draft versions of the materials. The tools were also reviewed by a plain language expert and the interdisciplinary research team. Feedback on the content and presentation led to iterative modifications of the tools. RESULTS: The feasibility studies confirmed that the Internet was a viable medium, as the majority of men used a computer, had access to the Internet, and Internet use increased over time. Feedback from the usability testing on the length, presentation, and content of the materials was incorporated into the final versions of the booklet and website. Both the feasibility studies and the usability testing highlighted the need to address men's informed decision making regarding screening. CONCLUSIONS: Informed decision making for PCa screening is crucial at present and may be important for some time, particularly if a definitive recommendation either for or against screening does not emerge from ongoing prostate cancer screening trials. We have detailed our efforts at developing print- and web-based DAs to assist men in determining how to best meet their PCa screening preferences. Following completion of our ongoing RCT designed to test these materials, our goal will be to develop a dissemination project for the more effective tool. TRIAL REGISTRATION: NCT00623090. PMID- 20199682 TI - Identification of a new mechanism for targeting myosin II heavy chain phosphorylation by Dictyostelium myosin heavy chain kinase B. AB - BACKGROUND: Heavy chain phosphorylation plays a central role in regulating myosin II bipolar filament assembly in Dictyostelium, as well as in higher eukaryotic nonmuscle cells. Our previous work has demonstrated that the WD-repeat domain of Dictyostelium myosin II heavy chain kinase B (MHCK-B), unlike its counterpart in MHCK-A, is not absolutely required for targeting of the kinase to phosphorylate MHC. Thus, we tested the hypothesis that an asparagine-rich and structurally disordered region that is unique to MHCK-B can by itself function in substrate targeting. FINDINGS: Biochemical assays comparing the activities of full-length MHCK-B, a truncation lacking only the WD-repeat domain (B-Delta-WD), and a truncation lacking both the N-rich region and the WD-repeat domain (B-Delta-N-WD) revealed that the N-rich region targets MHCK-B to phosphorylate MHC in a manner that leads to bipolar filament disassembly. This targeting is physiologically relevant since cellular over-expression of the B-Delta-WD truncation, but not the B-Delta-N-WD truncation, leads to dramatically reduced levels of myosin II filament assembly and associated defects in cytokinesis and multicellular development. CONCLUSIONS: The results presented here demonstrate that an intrinsically unstructured, and asparagine-rich, region of a MHCK-B can mediate specific targeting of the kinase to phosphorylate myosin II heavy chain. This targeting involves a direct binding interaction with myosin II filaments. In terms of regulating myosin bipolar filament assembly, our results suggest that factors affecting the activity of this unique region of MHCK-B could allow for regulation of MHCK-B in a manner that is distinct from the other MHCKs in Dictyostelium. PMID- 20199683 TI - Complementary genetic and genomic approaches help characterize the linkage group I seed protein QTL in soybean. AB - BACKGROUND: The nutritional and economic value of many crops is effectively a function of seed protein and oil content. Insight into the genetic and molecular control mechanisms involved in the deposition of these constituents in the developing seed is needed to guide crop improvement. A quantitative trait locus (QTL) on Linkage Group I (LG I) of soybean (Glycine max (L.) Merrill) has a striking effect on seed protein content. RESULTS: A soybean near-isogenic line (NIL) pair contrasting in seed protein and differing in an introgressed genomic segment containing the LG I protein QTL was used as a resource to demarcate the QTL region and to study variation in transcript abundance in developing seed. The LG I QTL region was delineated to less than 8.4 Mbp of genomic sequence on chromosome 20. Using Affymetrix Soy GeneChip and high-throughput Illumina whole transcriptome sequencing platforms, 13 genes displaying significant seed transcript accumulation differences between NILs were identified that mapped to the 8.4 Mbp LG I protein QTL region. CONCLUSIONS: This study identifies gene candidates at the LG I protein QTL for potential involvement in the regulation of protein content in the soybean seed. The results demonstrate the power of complementary approaches to characterize contrasting NILs and provide genome-wide transcriptome insight towards understanding seed biology and the soybean genome. PMID- 20199684 TI - The genetic effects of the dopamine D1 receptor gene on chicken egg production and broodiness traits. AB - BACKGROUND: The elevation of egg production and the inhibition of incubation behavior are the aims of modern poultry production. Prolactin (PRL) gene is confirmed to be critical for the onset and maintenance of these reproductive behaviors in birds. Through PRL, dopamine D1 receptor (DRD1) was also involved in the regulation of chicken reproductive behavior. However, the genetic effects of this gene on chicken egg production and broodiness have not been studied extensively. The objective of this research was to evaluate the genetic effects of the DRD1 gene on chicken egg production and broodiness traits. RESULTS: In this study, the chicken DRD1 gene was screened for the polymorphisms by cloning and sequencing and 29 variations were identified in 3,342 bp length of this gene. Seven single nucleotide polymorphism (SNPs) among these variations, including a non-synonymous mutation (A+505G, Ser169Gly), were located in the coding region and were chosen to analyze their association with chicken egg production and broodiness traits in 644 Ningdu Sanhuang individuals. Two SNPs, G+123A and C+1107T, were significantly associated with chicken broody frequency (P < 0.05). Significant association was also found between the G+1065A - C+1107T haplotypes and chicken broody frequency (P < 0.05). In addition, the haplotypes of G+123A and T+198C were significantly associated with weight of first egg (EW) (P = 0.03). On the other hand, the distribution of the DRD1 mRNA was observed and the expression difference was compared between broodiness and non-broodiness chickens. The DRD1 mRNA was predominantly expressed in subcutaneous fat and abdominal fat of non-broodiness chicken, and then in heart, kidney, oviduct, glandular stomach, hypothalamus, and pituitary. In subcutaneous fat and abdominal fat, the level of non-broodiness was 26 to 28 times higher than that of broodiness. In pituitary, it was 5-fold higher. In heart, oviduct, and kidney, a 2-3 times decrease from non-broodiness to broodiness was displayed. In glandular stomach and hypothalamus, the level seen in non-broodiness and broodiness was almost the same. CONCLUSION: The polymorphisms of the DRD1 gene and their haplotypes were associated with chicken broody frequency and some egg production traits. The mRNA distribution was significant different between broodiness and non-broodiness chickens. PMID- 20199685 TI - The disease management program for type 2 diabetes in Germany enhances process quality of diabetes care - a follow-up survey of patient's experiences. AB - BACKGROUND: In summer 2003 a disease management program (DMP) for type 2 diabetes was introduced on a nationwide basis in Germany. Patient participation and continuity of care within the DMP are important factors to achieve long-term improvements in clinical endpoints. Therefore it is of interest, if patients experience any positive or negative effects of the DMP on their treatment that would support or hamper further participation. The main objective of the study was to find out if the German Disease Management Program (DMP) for type 2 diabetes improves process and outcome quality of medical care for patients in the light of their subjective experiences over a period of one year. METHODS: Cohort study with a baseline interview and a follow-up after 10.4 +/- 0.64 months. Data on process and outcome measures were collected by telephone interviews with 444 patients enrolled and 494 patients not enrolled in the German DMP for type 2 diabetes. Data were analyzed by multivariate logistic regression analyses. RESULTS: DMP enrolment was significantly associated with a higher process quality of care. At baseline enrolled patients more often reported that they had attended a diabetes education course (OR = 3.4), have > or = 4 contacts/year with the attending physician (OR = 3.3), have at least one annual foot examination (OR = 3.1) and one referral to an ophthalmologist (OR = 3.4) and possess a diabetes passport (OR = 2.4). Except for the annual referral to an ophthalmologist these parameters were also statistically significant at follow-up. In contrast, no differences between enrolled and not enrolled patients were found concerning outcome quality indicators, e.g. self-rated health, Glycated hemoglobin (GHb) and blood pressure. However, 16-36% of the DMP participants reported improvements of body weight and/or GHb and/or blood pressure values due to enrolment - unchanged within one year of follow-up. CONCLUSIONS: In the light of patient's experiences the DMP enhances the process quality of medical care for type 2 diabetes in Germany. The lack of significant differences in outcome quality between enrolled and not enrolled patients might be due to the short program duration. Our data suggest that the DMP for type 2 diabetes should not be withdrawn unless an evidently more promising approach is found. PMID- 20199686 TI - Selective regain of egfr gene copies in CD44+/CD24-/low breast cancer cellular model MDA-MB-468. AB - BACKGROUND: Increased transcription of oncogenes like the epidermal growth factor receptor (EGFR) is frequently caused by amplification of the whole gene or at least of regulatory sequences. Aim of this study was to pinpoint mechanistic parameters occurring during egfr copy number gains leading to a stable EGFR overexpression and high sensitivity to extracellular signalling. A deeper understanding of those marker events might improve early diagnosis of cancer in suspect lesions, early detection of cancer progression and the prediction of egfr targeted therapies. METHODS: The basal-like/stemness type breast cancer cell line subpopulation MDA-MB-468 CD44high/CD24-/low, carrying high egfr amplifications, was chosen as a model system in this study. Subclones of the heterogeneous cell line expressing low and high EGF receptor densities were isolated by cell sorting. Genomic profiling was carried out for these by means of SNP array profiling, qPCR and FISH. Cell cycle analysis was performed using the BrdU quenching technique. RESULTS: Low and high EGFR expressing MDA-MB-468 CD44+/CD24 /low subpopulations separated by cell sorting showed intermediate and high copy numbers of egfr, respectively. However, during cell culture an increase solely for egfr gene copy numbers in the intermediate subpopulation occurred. This shift was based on the formation of new cells which regained egfr gene copies. By two parametric cell cycle analysis clonal effects mediated through growth advantage of cells bearing higher egfr gene copy numbers could most likely be excluded for being the driving force. Subsequently, the detection of a fragile site distal to the egfr gene, sustaining uncapped telomere-less chromosomal ends, the ladder like structure of the intrachromosomal egfr amplification and a broader range of egfr copy numbers support the assumption that dynamic chromosomal rearrangements, like breakage-fusion-bridge-cycles other than proliferation drive the gain of egfr copies. CONCLUSION: Progressive genome modulation in the CD44+/CD24-/low subpopulation of the breast cancer cell line MDA-MB-468 leads to different coexisting subclones. In isolated low-copy cells asymmetric chromosomal segregation leads to new cells with regained solely egfr gene copies. Furthermore, egfr regain resulted in enhanced signal transduction of the MAP kinase and PI3-kinase pathway. We show here for the first time a dynamic copy number regain in basal-like/stemness cell type breast cancer subpopulations which might explain genetic heterogeneity. Moreover, this process might also be involved in adaptive growth factor receptor intracellular signaling which support survival and migration during cancer development and progression. PMID- 20199687 TI - Prevalence and characteristics of sleep apnoea in patients with stable heart failure: Results from a heart failure clinic. AB - BACKGROUND: Heart failure (HF) and sleep apnoea (SA) association has been recognized but whether it results from confounding factors (hypertension, ischaemia, obesity) remains unclear.We aimed to determine the prevalence of SA in HF and to identify potential risk factors for SA in HF population. METHODS: We prospectively evaluated 103 patients with stable HF on optimized therapy. In laboratory polysomnography was performed. Type and severity of SA were defined according international criteria. Demographic, anthropometric and clinical characteristics were collected. Continuous data are expressed as median and interquartile range. RESULTS: SA was found in 72.8%, moderate to severe in a significant proportion (apnoea-hypopnoea index > or = 15- 44.7% of all patients) and predominantly obstructive (60.0% of patients with SA). Most patients were non sleepy (Epworth < 10- 66%). SA patients were predominantly men (85.3 vs 60.7%, p 0.015), had larger neck (38.0 (35.0-42.0) vs 35.0 (33.2-38.0) cm, p-0.003), severe systolic dysfunction, (63.9 vs 33.3%, p-0.018), left ventricle (LV) hypertrophy (16.2 vs 0.0%, p-0.03), LV and left atria (LA) dilatation (49.0 (44.0 52.0) vs 42.0 (38.0-48.0) mm, p < 0.001; 60.0 (54.0-65.0) vs 56.0 (52.0-59.0) mm, p-0.01). However, only LA diameter was an independent predictor of SA. Higher body-mass index (BMI) was associated with moderate to severe SA. Patients with obstructive SA had larger neck and a trend for higher BMI, snoring and sleepiness. Hypocapnia was not associated with central SA. CONCLUSIONS: In our HF population, SA was prevalent, frequently asymptomatic and without characteristic risk factors. Unlike previously reported, obstructive SA was the predominant type. These results suggest that SA is underdiagnosed in HF and there is a possible correlation between them, independent of confounding factors. Recent advances in HF therapy might influence prevalence and type of SA in this population. PMID- 20199688 TI - Transcribed-ultra conserved region expression profiling from low-input total RNA. AB - BACKGROUND: Ultra Conserved Regions (UCRs) are a class of 481 noncoding sequences located in both intra- and inter-genic regions of the genome. The recent findings that they are significantly altered in adult chronic lymphocytic leukemias, carcinomas, and pediatric neuroblastomas lead to the hypothesis that UCRs may play a role in tumorigenesis. RESULTS: We present a novel application of Ribo SPIA isothermal linear amplification of minute RNA quantities for quantifying Transcribed-UCR (T-UCR) expression by quantitative PCR. Direct comparison of non amplified with amplified cDNA in two neuroblastoma cell lines showed that the amplification approach increases sensitivity and repeatability in T-UCR quantification. It is noteworthy that the Ribo-SPIA step allowed us to analyze all 481 T-UCRs by using 150 ng of RNA, while introducing a minimal bias and preserving the magnitude of relative expression. Only the less abundant T-UCRs have high intra-assay variability, consistently with the Poisson distribution statistics and stochastic effects on PCR repeatability. CONCLUSIONS: We demonstrated that the quantification procedure shown here is an accurate and reliable technique for genome-wide non coding gene (i.e., UCRs) profiling using small amounts of RNA. This issue is particularly important because studies of transcription regulation are increasingly conducted in small homogeneous samples, such as laser capture microdissected or sorted cell populations. PMID- 20199689 TI - Expression of ZIC family genes in meningiomas and other brain tumors. AB - BACKGROUND: Zic zinc finger proteins are present in the developing rodent meninges and are required for cell proliferation and differentiation of meningeal progenitors. Although human ZIC genes are known to be molecular markers for medulloblastomas, their expression in meningioma has not been addressed to date. METHODS: We examined the mRNA and protein expression of human ZIC1, ZIC2, ZIC3, ZIC4 and ZIC5 genes in meningiomas in comparison to other brain tumors, using RT PCR, analysis of published microarray data, and immunostaining. RESULTS: ZIC1, ZIC2 and ZIC5 transcript levels in meningiomas were higher than those in whole brain or normal dura mater, whereas all five ZIC genes were abundantly expressed in medulloblastomas. The expression level of ZIC1 in public microarray data was greater in meningiomas classified as World Health Organization Grade II (atypical) than those classified as Grade I (benign). Immunoscreening using anti ZIC antibodies revealed that 23 out of 23 meningioma cases were ZIC1/2/3/5 immunopositive. By comparison, nuclear staining by the anti-ZIC4 antibody was not observed in any meningioma case, but was strongly detected in all four medulloblastomas. ZIC-positive meningiomas included meningothelial, fibrous, transitional, and psammomatous histological subtypes. In normal meninges, ZIC like immunoreactivities were detected in vimentin-expressing arachnoid cells both in human and mouse. CONCLUSIONS: ZIC1, ZIC2, and ZIC5 are novel molecular markers for meningiomas whereas ZIC4 expression is highly selective for medulloblastomas. The pattern of ZIC expression in both of these tumor types may reflect the properties of the tissues from which the tumors are derived. PMID- 20199691 TI - Decomposing socioeconomic inequality for binary health outcomes: an improved estimation that does not vary by choice of reference group. AB - BACKGROUND: Decomposition of concentration indices yields useful information regarding the relative importance of various determinants of inequitable health outcomes. But the two estimation approaches to decomposition in current use are not suitable for binary outcomes. FINDINGS: The paper compares three estimation approaches for decomposition of inequality concentration indices: Ordinary Least Squares (OLS), probit, and the Generalized Linear Model (GLM) binomial distribution and identity link. Data are from the Thai Health and Welfare Survey 2003. The OLS estimates do not take into account the binary nature of the outcome and the probit estimates depend on the choice of reference groups, whereas the GLM binomial identity approach has neither of these problems. CONCLUSIONS: The GLM with binomial distribution and identity link allows the inequality decomposition model to hold, and produces valid estimates of determinants that do not vary according to choice of reference groups. This GLM approach is readily available in standard statistical packages. PMID- 20199690 TI - Genome-wide transcriptome analysis of the transition from primary to secondary stem development in Populus trichocarpa. AB - BACKGROUND: With its genome sequence and other experimental attributes, Populus trichocarpa has become the model species for genomic studies of wood development. Wood is derived from secondary growth of tree stems, and begins with the development of a ring of vascular cambium in the young developing stem. The terminal region of the developing shoot provides a steep developmental gradient from primary to secondary growth that facilitates identification of genes that play specialized functions during each of these phases of growth. RESULTS: Using a genomic microarray representing the majority of the transcriptome, we profiled gene expression in stem segments that spanned primary to secondary growth. We found 3,016 genes that were differentially expressed during stem development (Q value 2-fold expression variation), and 15% of these genes encode proteins with no significant identities to known genes. We identified all gene family members putatively involved in secondary growth for carbohydrate active enzymes, tubulins, actins, actin depolymerizing factors, fasciclin-like AGPs, and vascular development-associated transcription factors. Almost 70% of expressed transcription factors were upregulated during the transition to secondary growth. The primary shoot elongation region of the stem contained specific carbohydrate active enzyme and expansin family members that are likely to function in primary cell wall synthesis and modification. Genes involved in plant defense and protective functions were also dominant in the primary growth region. CONCLUSION: Our results describe the global patterns of gene expression that occur during the transition from primary to secondary stem growth. We were able to identify three major patterns of gene expression and over-represented gene ontology categories during stem development. The new regulatory factors and cell wall biogenesis genes that we identified provide candidate genes for further functional characterization, as well as new tools for molecular breeding and biotechnology aimed at improvement of tree growth rate, crown form, and wood quality. PMID- 20199692 TI - Absolute risk representation in cardiovascular disease prevention: comprehension and preferences of health care consumers and general practitioners involved in a focus group study. AB - BACKGROUND: Communicating risk is part of primary prevention of coronary heart disease and stroke, collectively referred to as cardiovascular disease (CVD). In Australia, health organisations have promoted an absolute risk approach, thereby raising the question of suitable standardised formats for risk communication. METHODS: Sixteen formats of risk representation were prepared including statements, icons, graphical formats, alone or in combination, and with variable use of colours. All presented the same risk, i.e., the absolute risk for a 55 year old woman, 16% risk of CVD in five years. Preferences for a five or ten-year timeframe were explored. Australian GPs and consumers were recruited for participation in focus groups, with the data analysed thematically and preferred formats tallied. RESULTS: Three focus groups with health consumers and three with GPs were held, involving 19 consumers and 18 GPs. Consumers and GPs had similar views on which formats were more easily comprehended and which conveyed 16% risk as a high risk. A simple summation of preferences resulted in three graphical formats (thermometers, vertical bar chart) and one statement format as the top choices. The use of colour to distinguish risk (red, yellow, green) and comparative information (age, sex, smoking status) were important ingredients. Consumers found formats which combined information helpful, such as colour, effect of changing behaviour on risk, or comparison with a healthy older person. GPs preferred formats that helped them relate the information about risk of CVD to their patients, and could be used to motivate patients to change behaviour.Several formats were reported as confusing, such as a percentage risk with no contextual information, line graphs, and icons, particularly those with larger numbers. Whilst consumers and GPs shared preferences, the use of one format for all situations was not recommended. Overall, people across groups felt that risk expressed over five years was preferable to a ten-year risk, the latter being too remote. CONCLUSIONS: Consumers and GPs shared preferences for risk representation formats. Both groups liked the option to combine formats and tailor the risk information to reflect a specific individual's risk, to maximise understanding and provide a good basis for discussion. PMID- 20199693 TI - The height-, weight-, and BMI-for-age of Polish school-aged children and adolescents relative to international and local growth references. AB - BACKGROUND: The growth of children is an indicator of health and society's wellbeing. Growth references are useful in monitoring a child's growth, which is a very important part of child care. Poland's growth references are not updated regularly. Although several growth reference ranges have been developed in Poland over recent years, sampling was restricted to urban populations of major cities. The aim of this study was to assess how well Polish children match with, or diverge from, regional charts and to compare them with international growth references. METHODS: Four Polish and two international (WHO 2007 and USCDC2000) growth references were used to calculate the height, weight and BMI z-scores in a recent, large, population-representative sample of school-aged children and adolescents in Poland. The distributions of z-scores were analysed with descriptive and inferential statistical methods. RESULTS: Mean height z-scores calculated with the use of the WHO 2007 and USCDC2000 references were positive and significantly different from zero over the entire age range. The mean height z-score was closest to zero in the Poznan reference for boys (0.05) and Warszawa reference for girls (0.01). Median weight z-scores were positive under all weight references over the entire age range with only the exception of 18-year-old girls' weight z-score calculated relative to USCDC2000. Median BMI z-scores were positive in males in early childhood, decreasing with age. In the case of girls, the median BMI z-score calculated using WHO 2007 and USCDC2000 was close to zero in early childhood, decreased in adolescents and reached minimum values at age 18 years. Median BMI z-scores calculated with the use of the Lodz reference fluctuated between 0.05 and 0.2 over the studied age range. CONCLUSIONS: In this contemporary sample of Polish school-aged children, distributions of height, weight and BMI differed from those of children from the international growth references. These differences should be considered when using the references. There exist certain limitations to the analysis of height, weight, and BMI z scores when Polish regional references are used. PMID- 20199695 TI - Another approach to estimating the reliability of the glycaemic index: a different interpretation. PMID- 20199694 TI - Effect of diet, sex and age on fatty acid metabolism in broiler chickens: SFA and MUFA. AB - The present study was conducted to evaluate the effect of different dietary lipid sources, age and sex on the SFA and MUFA metabolism in broiler chickens using a whole body fatty acid balance method. Four dietary lipid sources (palm fat, Palm; soyabean oil, Soya; linseed oil, Lin; and fish oil, Fish) were added at 3 % to a basal diet containing 5 % Palm. Diets were fed to female and male chickens from day 1 to either day 21 or day 42 of age. The accumulation (percentage of net intake and ex novo production) of SFA and MUFA was significantly lower in broilers fed on Palm than in broilers fed on the other diets (85.7 v. 97.4 %). Conversely, beta-oxidation was significantly higher in Palm-fed birds than the average of the other dietary treatments (14.3 v. 2.6 %). On average, 33.1 % of total SFA and MUFA accumulated in the body were elongated, and 13.8 % were Delta 9 desaturated to longer chain or more unsaturated metabolites, with lower proportions being elongated and desaturated for the Palm and Fish diets than for the Soya and Lin diets. Total in vivo apparent elongase activity decreased exponentially in relation to the net intake of SFA and MUFA, while it increased with age. Total in vivo apparent Delta-9 desaturase activity was not significantly affected by dietary treatment or age. Total ex novo production and beta-oxidation of SFA and MUFA showed a negative and positive curvilinear relationship with net intake of SFA and MUFA, respectively. Sex had no effect on SFA and MUFA metabolism. PMID- 20199696 TI - Mapping interacting QTL for count phenotypes using hierarchical Poisson and binomial models: an application to reproductive traits in mice. AB - We proposed hierarchical Poisson and binomial models for mapping multiple interacting quantitative trait loci (QTLs) for count traits in experimental crosses. We applied our methods to two counted reproductive traits, live fetuses (LF) and dead fetuses (DF) at 17 days gestation, in an F2 female mouse population. We treated observed number of corpora lutea (ovulation rate) as the baseline and the total trials in our Poisson and binomial models, respectively. We detected more than 10 QTLs for LF and DF, most having epistatic and pleiotropic effects. The epistatic effects were larger, involved more QTLs, and explained a larger proportion of phenotypic variance than the main effects. Our analyses revealed a complex network of multiple interacting QTLs for the reproductive traits, and increase our understanding of the genetic architecture of reproductive characters. The proposed statistical models and methods provide valuable tools for detecting multiple interacting QTLs for complex count phenotypes. PMID- 20199698 TI - Quantitative risk assessment model of canine rabies introduction: application to the risk to the European Union from Morocco. AB - Although rabies incidence in humans in Western Europe is low, the repeated importation of rabid animals from enzootic areas threatens the rabies-free status of terrestrial animals and challenges the public health systems in this area. Most rabid animals imported into the European Union (EU) in recent years came from Morocco. The aim of this study was to develop a probabilistic risk assessment model to estimate the probability of rabies introduction, which was applied to the risk to the EU from dogs coming from Morocco. The mean annual probability of rabies introduction was 0.21 (90% CI 0.02-0.65). The pathways that contributed the most to this probability were: (a) EU citizens who adopted a dog in Morocco (59% of the total probability) and (b) EU citizens who travelled with their dog to Morocco by ferry (34% of the total probability). The model showed a marked seasonality in the risk of rabies with almost 40% of the annual probability occurring during the months of July and August. The application of stricter border controls (assuming 100% compliance) would result in a >270-fold reduction in the likelihood of rabies introduction into the EU from Morocco. PMID- 20199697 TI - Immunohistological studies on neoplasms of female and male Onchocerca volvulus: filarial origin and absence of Wolbachia from tumor cells. AB - Up to 5% of untreated female Onchocerca volvulus filariae develop potentially fatal pleomorphic neoplasms, whose incidence is increased following ivermectin treatment. We studied the occurrence of 8 filarial proteins and of Wolbachia endobacteria in the tumor cells. Onchocercomas from patients, untreated and treated with antibiotics and anthelminthics, were examined by immunohistology. Neoplasms were diagnosed in 112 of 3587 female and in 2 of 1570 male O. volvulus. The following proteins and other compounds of O. volvulus were expressed in the cells of the neoplasms: glutathione S-transferase 1, lysosomal aspartic protease, cAMP-dependent protein kinase, alpha-enolase, aspartate aminotransferase, ankyrin E1, tropomyosin, heat shock protein 60, transforming growth factor-beta, and prostaglandin E(2). These findings prove the filarial origin of the neoplasms and confirm the pleomorphism of the tumor cells. Signs indicating malignancy of the neoplasms are described. Wolbachia were observed in the hypodermis, oocytes, and embryos of tumor-harbouring filariae using antibodies against Wolbachia surface protein, Wolbachia HtrA-type serine protease, and Wolbachia aspartate aminotransferase. In contrast, Wolbachia were not found in the cells of the neoplasms. Further, neoplasm-containing worms were not observed after more than 10 months after the start of sufficient treatment with doxycycline or doxycycline plus ivermectin. PMID- 20199699 TI - Ethical and practical concerns of surveillance technologies in residential care for people with dementia or intellectual disabilities: an overview of the literature. AB - BACKGROUND: Technology has emerged as a potential solution to alleviate some of the pressures on an already overburdened care system, thereby meeting the growing needs of an expanding population of seriously cognitively impaired people. However, questions arise as to what extent technologies are already being used in residential care and how ethically and practically acceptable this use would be. METHODS: A systematic literature review was conducted to explore what is known on the moral and practical acceptability of surveillance technologies in residential care for people with dementia or intellectual disabilities, and to set forth the state of the debate. RESULTS: A total of 79 papers met the inclusion criteria. The findings show that application and use of surveillance technologies in residential care for vulnerable people generates considerable ethical debate. This ethical debate centers not so much around the effects of technology, but rather around the moral acceptability of those effects, especially when a conflict arises between the interests of the institution and the interests of the resident. However, the majority of articles lack in depth analysis. Furthermore, there are notable cultural differences between the European literature and American literature whereby in Britain there seems to be more ethical debate than in America. Overall however, there is little attention for the resident perspective. CONCLUSION: No ethical consensus has yet been reached, underlining the need for clear(er) policies. More research is thus recommended to determine ethical and practical viability of surveillance technologies whereby research should be specifically focused on the resident perspective. PMID- 20199700 TI - Incidence and predictors of excess disability in walking among nursing home residents with middle-stage dementia: a prospective cohort study. AB - BACKGROUND: Inability to walk compromises the well-being of the growing number of nursing home residents with dementia. The purpose of this study was to estimate the incidence and identify predictors of walking disability that may be remediable. METHODS: A cohort was followed fortnightly for a year in 15 nursing homes in western Canada. The study participants comprised 120 ambulatory residents with middle-stage Alzheimer's, vascular or mixed dementia. Standardized measures of potential predictors of disability included the Charlson Comorbidity Index, Global Deterioration Scale, and Professional Environment Assessment Protocol. Walking disability was defined as using a wheelchair to go to meals in the dining room. RESULTS: Incidence of walking disability was 40.8% (95% confidence interval (CI): 32.7-50.2). Approximately half of this (27.0%; 95% CI: 19.7-36.5) was excess disability. Residents with more advanced dementia and living in a less supportive nursing home environment experienced an increased hazard of walking disability (Hazard Ratio (HR): 2.1; 95% CI: 1.2-3.8 and HR: 2.4; 95% CI: 1.3-4.4 respectively). After adjusting for age, comorbidity and stage of dementia, predictors of excess disability in walking included using antidepressants (HR: 2.2; 95% CI: 1.02-4.6), and not using cognitive enhancers (HR: 2.6; 95% CI: 1.03-6.4). CONCLUSIONS: Over half of walking disability in nursing home residents with middle-stage dementia may be modifiable. Creating supportive environments, ensuring access to cognitive enhancer drugs, and preventing and treating depression and the adverse effects of antidepressants, may help to reduce walking disability and excess disability. PMID- 20199701 TI - Changes to psychotropic medications in the six months after admission to nursing homes in Melbourne, Australia. AB - BACKGROUND: Nursing home residents are often prescribed large numbers of psychotropic medications. Previous studies suggest that antipsychotic medications are often unnecessary and can be withdrawn without ill effects. Depression, in contrast, is believed to be under-recognized and under-treated. METHOD: A six month audit was carried out of the antipsychotic, antidepressant, anxiolytic and hypnotic medications prescribed to 166 newly admitted residents of a convenience sample of seven nursing homes in Melbourne, Australia. RESULTS: Over the six month period, antidepressants were started in 6% of all cases and stopped in 2% of treated cases. Antipsychotics were added in 5% of all cases and stopped in 15% of treated cases. Residents were switched from one antidepressant to another in 5% of treated cases and from one antipsychotic to another in 4%. Benzodiazepine use was relatively modest. CONCLUSIONS: Judging from epidemiological data, treatment revisions were almost certainly insufficient to address residents' mental health needs. We discuss ways of harnessing existing nursing and pharmacy resources to ensure better care for aged residents. PMID- 20199702 TI - Adjunct treatment with levodopa in a patient with dementia with Lewy bodies, delusions and severe neuroleptic hypersensitivity syndrome. AB - We report on the treatment of a patient suffering from dementia with Lewy bodies who initially presented with severe neurological and psychopathological symptoms. After treating the patient with levodopa and clozapine, these symptoms remitted. PMID- 20199703 TI - The case of an aging person with borderline personality disorder and possible dementia. AB - There is little literature on older adults with borderline personality disorder during neuropsychological assessment. Here we report on a 59-year-old woman with borderline personality disorder who referred herself for assessment because she feared the onset of dementia. Results showed an above average level of intelligence, with scores on memory tests that ranged from well below to well above average in a pattern that was not consistent with a dementia or with common forms of neurologically based memory impairments. A test of memory malingering was within normal limits. Results are discussed in terms of somatization within this personality disorder. PMID- 20199704 TI - Do neonates, infants and young children need a higher dose of enoxaparin in the cardiac intensive care unit? AB - BACKGROUND: Thromboembolic events are a serious complication occurring in critically ill children admitted to the cardiac intensive care unit. Although enoxaparin is one of the current anticoagulants of choice, dosages in children are extrapolated from adult guidelines. Recent data suggest that this population may need a higher dose than what is currently recommended to achieve target anti factor Xa levels. The purpose of this study was to evaluate whether children less than 2 years old admitted to the cardiac intensive care unit require a higher enoxaparin dose than that currently recommended to achieve target anti-factor Xa levels. METHODS: Retrospective chart review including patients who received enoxaparin for the treatment or prophylaxis of venous thrombosis between January, 2005 and October, 2007. Patients were classified as younger and older as well as prophylactic and therapeutic on the basis of age and enoxaparin dose, respectively. Younger patients were those 2 month old or less and older patients were those older than 2 months of age. RESULTS: A total of 31 patients were identified; 13 (42%) were 2 months or younger and 25 (81%) were postoperative patients. Ten (32%) received prophylactic and 21 (68%) received therapeutic enoxaparin doses. To achieve optimal anti-factor Xa levels, enoxaparin dose was increased in all groups and reached statistical significance in all patients except those older than 2 months who received prophylactic enoxaparin. An average of 2.8 dosage adjustments was needed. No bleeding complications were reported. CONCLUSIONS: Young children, infants, and neonates admitted to the cardiac intensive care unit required a significantly higher enoxaparin dose than that currently recommended to achieve target anti-factor Xa levels. PMID- 20199705 TI - Experience from a single centre concerning the surgical spectrum and outcome of adolescents and adults with congenitally malformed hearts in West Africa. AB - BACKGROUND: This study was undertaken to review the spectrum and surgical outcome of adolescents and adults with congenitally malformed hearts from January, 1993 to December, 2008. The lack of data on this emerging problem from the West African sub-region prompted this report. PATIENTS AND METHOD: This retrospective study is based on 135 adolescents and adults with congenitally malformed hearts. A review of their case notes and operative records was carried out and results analysed. RESULTS: Selected patients made up 23% of all congenital cardiac surgeries performed at our institution in the same period. A total of 23 patients (17%) were non-Ghanaian West Africans. There was a female preponderance of 53.3%. The ages ranged from 16 to 70 years (mean 28.6 plus or minus 10.3 years). The mean follow-up was 7.5 plus or minus 4.4 years. Patients were functionally classified (New York Heart Association) as class I (23%), II (58%), and III (19%). In 14 (10.4%) patients, the defects were discovered incidentally. Ventricular septal defects, oval fossa type atrial septal defects, Fallot's tetralogy, and patent arterial duct together accounted for 77.8% of the cases. Surgical correction was undertaken in 117 (86.7%) patients; the remainder had palliative procedures. There were six (4.3%) reoperations. The functional class improved to class I or II in 95% of patients within the first postoperative year. The overall hospital mortality was 3% with two late deaths (1.5%). CONCLUSION: The study demonstrates the feasibility of surgery for adolescents and adults with congenitally malformed hearts in the sub-region with a good outcome. Majority (77.8%) of patients present with less complex lesions. PMID- 20199706 TI - Improving results of atrioventricular valve repair in challenging patients with heterotaxy syndrome. AB - OBJECTIVES: Heterotaxy syndrome, which is often associated with atrioventricular valvar regurgitation, has been considered a risk factor for the surgical repair for Fontan candidates. The results of atrioventricular valve repair in this challenging patient population remain largely unknown. METHODS: From July, 1994 to January, 2007, 25 patients with the heterotaxy syndrome consisting of 22 right isomerism and three left isomerism presented to the Shizuoka Children's Hospital Japan with significant (3-4+) atrioventricular valvar regurgitation necessitating atrioventricular valve repair. The clinical and Doppler/echocardiographic data were retrospectively reviewed to determine the efficacy of the repair and patient outcome. RESULTS: Patients were divided into two groups on the basis of atrioventricular valvar regurgitation at the most recent follow-up: those with a successful late outcome, (0-2) and those with a poor outcome (3-4). There were 17 (67%) patients with a successful outcome and 8 (33%) with a poor outcome. The repair technique including leaflet apposition was predictive of a successful outcome (p = 0.003). Overall survival was 64% (16/25). Survival was 88.2% (15/17) for patients with a successful result versus 12.5% (1/8) for those with a poor outcome (p = 0.0007). Of the 15 survivors, 13 have reached final completion of the Fontan circulation, and two currently remain at the bi-directional Glenn shunt stage. CONCLUSION: Atrioventricular valve repair can be accomplished in this challenging patient population with excellent results. The combination of the leaflet apposition technique and the Kay suture can be performed with an excellent outcome in the majority of patients with heterotaxy syndrome, even with significant atrioventricular valvar regurgitation. PMID- 20199707 TI - Fibrillin-1 gene intron 56 polymorphism in Turkish children with mitral valve prolapse. AB - OBJECTIVE: Mitral valvar prolapse is the most common anomaly of the mitral valve apparatus throughout childhood. Fibrillin is one of the structural components of the elastin-associated microfibrils found in the mitral valve. A case-controlled study has performed to investigate the relationship between fibrillin 1 gene intron 56 polymorphism and risk of mitral valvar prolapse in Turkish children. PATIENTS AND METHODS: A total of 77 patients with mitral valvar prolapse diagnosed by clinical evaluation and echocardiography and 89 normal children of same age and sex were studied. The fibrillin-1 gene intron 56 polymorphism was identified by the polymerase chain reaction-based restriction analysis. RESULTS: There was a significant difference in the distribution of fibrillin-1 gene intron 56 genotypes (p = 0.0001) and allelic frequency (p = 0.0001) between the cases and the controls. CONCLUSIONS: Patients with mitral valvar prolapse have higher frequencies of fibrillin-1 gene intron 56 GC genotypes. Healthy children have higher frequencies of fibrillin-1 gene intron 56 CC genotypes. We speculate that the higher frequency of fibrillin-1 gene intron 56 G-allele increases the risk of mitral valvar prolapse. PMID- 20199708 TI - Direct non-medical and indirect costs for families with children with congenital cardiac defects in Germany: a survey from a university centre. AB - INTRODUCTION: Parents of children with congenital cardiac disease suffer from psychological stress and financial burdens. These costs have not yet been quantified. MATERIALS AND METHODS: In cooperation with paediatricians, social workers, and parents, a questionnaire was devised to calculate direct non-medical and indirect costs. Direct non-medical costs include all costs not directly related to medical services such as transportation. Indirect costs include lost productivity measured in lost income from wages. Parents were retrospectively queried on costs and refunds incurred during the child's first and sixth year of life. The questionnaire was sent out to 198 families with children born between 1980 and 2000. Costs were adjusted for inflation to the year 2006. Children were stratified into five groups according to the severity of their current health status. RESULTS: Fifty-four families responded and could be included into the analysis (27.7%). Depending on severity, total direct non-medical and indirect costs in the first year of life ranged between an average of euro1654 in children with no or mild (remaining) cardiac defects and an average euro2881 in children with clinically significant (residual/remaining) findings. Mean expenses in the sixth year of life were as low as euro562 (no or mild (remaining) cardiac defects) and as high as euro5213 (potentially life-threatening findings). At both points in time, the highest costs were lost income and transportation; and day care/ babysitting for siblings was third. DISCUSSION: Families of children with congenital cardiac disease and major sequelae face direct non-medical and indirect costs adding up to euro3000 per year on average. We should consider compensating families from low socioeconomic backgrounds to minimise under-use of non-medical services of assistance for their children. PMID- 20199709 TI - Magnetic resonance imaging findings in Loeys-Dietz syndrome. AB - Loeys-Dietz syndrome is a newly described entity characterised by a constellation of arterial tortuosity, cranial malformations, and hypertelorism. We report a case of a 7-year old boy with confirmed Loeys-Dietz syndrome and discuss magnetic resonance imaging as a complete technique for assessment and follow-up of aggressive vascular pathology in the brain, thorax, and abdomen, which may dictate early surgical intervention. PMID- 20199710 TI - Chaotic atrial tachycardia-related ventricular fibrillation in a 2-month-old baby with Wolff-Parkinson-White syndrome. AB - A 2-month-old baby was resuscitated from ventricular fibrillation attributed to a concurrent chaotic atrial tachycardia with Wolff-Parkinson-White syndrome. He underwent successful radiofrequency catheter ablation of an accessory pathway. Throughout the 4-year follow-up after the procedure, the boy remained free of any drugs, was in sinus rhythm without ventricular pre-excitation and his growth and development were normal. PMID- 20199711 TI - Pregnancy-associated cardiomyopathy occurring in a young patient with nephropathic cystinosis. AB - Cystinosis is a rare autosomal recessive metabolic disorder characterised by an intracellular accumulation of cystine leading to severe organ dysfunction. It affects renal function, has extra-renal complications but has rarely been associated with cardiac disease. Renal transplantation and cysteamine have dramatically improved the prognosis in the nephropathic form. We present the case of a young adult Caucasian female diagnosed with nephropathic cystinosis and receiving haemodialysis who subsequently developed dilated cardiomyopathy. She presented with acute cardiac failure occurring early after stillbirth following an unplanned pregnancy when her cysteamine had been stopped. Transthoracic echocardiography showed typical features of dilated cardiomyopathy which was absent on pre-pregnancy scans. Investigations failed to identify an underlying cause for her cardiomyopathy. She responded to conventional treatment and currently has had full recovery of her cardiac function confirmed on follow-up echocardiography. As cardiomyopathy rarely co-exists with cystinosis, we believe that this case represents pregnancy-associated cardiomyopathy rather than direct involvement by her cystinosis, particularly as a minority of pregnant patients with associated cardiomyopathy develop heart failure early before the conventional period for peripartum cardiomyopathy. Patient characteristics and maternal outcomes are similar, albeit with higher risk of premature delivery suggesting the same underlying pathological process. PMID- 20199712 TI - A transmission electron microscopy study of CoFe2O4 ferrite nanoparticles in silica aerogel matrix using HREM and STEM imaging and EDX spectroscopy and EELS. AB - Magnetic nanocomposite materials consisting of 5 and 10 wt% CoFe2O4 nanoparticles in a silica aerogel matrix have been synthesized by the sol-gel method. For the CoFe2O4-10wt% sample, bright-field scanning transmission electron microscopy (BF STEM) and high-resolution transmission electron microscopy (HREM) images showed distinct, rounded CoFe2O4 nanoparticles, with typical diameters of roughly 8 nm. For the CoFe2O4-5wt% sample, BF STEM images and energy dispersive X-ray (EDX) measurements showed CoFe2O4 nanoparticles with diameters of roughly 3 +/- 1 nm. EDX measurements indicate that all nanoparticles consist of stoichiometric CoFe2O4, and electron energy-loss spectroscopy measurements from lines crossing nanoparticles in the CoFe2O4-10wt% sample show a uniform composition within nanoparticles, with a precision of at best than +/-0.5 nm in analysis position. BF STEM images obtained for the CoFe2O4-10wt% sample showed many "needle-like" nanostructures that typically have a length of 10 nm and a width of 1 nm, and frequently appear to be attached to nanoparticles. These needle-like nanostructures are observed to contain layers with interlayer spacing 0.33 +/- 0.1 nm, which could be consistent with Co silicate hydroxide, a known precursor phase in these nanocomposite materials. PMID- 20199714 TI - European policymaking on the tobacco advertising ban: the importance of escape routes. AB - This article analyses the European Union policymaking process regarding tobacco advertising. While others already highlighted the importance of intergovernmental bargaining between member states to explain the outcome of the tobacco advertising case, the main aim of this article is to identify the use of escape routes by the Commission, the European Parliament, the Council and interest groups that played an important role in overcoming the deadlock. When looking at the different institutions that structure policymaking, we argue that indeed focusing on escape routes provides a clear insight in the process and in what strategies were necessary to 'make Europe work'. In the end, it appears to be a combination of escape routes that resulted in the final decision. PMID- 20199713 TI - Visualization of morphological and molecular features associated with chronic ischemia in bioengineered human skin. AB - We present an in vitro model of human skin that, together with nonlinear optical microscopy, provides a useful system for characterizing morphological and structural changes in a living skin tissue microenvironment due to changes in oxygen status and proteolytic balance. We describe for the first time the effects of chronic oxygen deprivation on a bioengineered model of human interfollicular epidermis. Histological analysis and multiphoton imaging revealed a progressively degenerating ballooning phenotype of the keratinocytes that manifested after 48 h of hypoxic exposure. Multiphoton images of the dermal compartment revealed a decrease in collagen structural order. Immunofluorescence analysis showed changes in matrix metalloproteinase (MMP)-2 protein spatial localization in the epidermis with a shift to the basal layer, and loss of Ki67 expression in proliferative basal cells after 192 h of hypoxic exposure. Upon reoxygenation MMP-2 mRNA levels showed a biphasic response, with restoration of MMP-2 levels and localization. These results indicate that chronic oxygen deprivation causes an overall degeneration in tissue architecture, combined with an imbalance in proteolytic expression and a decrease in proliferative capacity. We propose that these tissue changes are representative of the ischemic condition and that our experimental model system is appropriate for addressing mechanisms of susceptibility to chronic wounds. PMID- 20199715 TI - Evolution of Taiwan's health care system. AB - This study aims to present an overview of the evolutionary policy process in reforming the health care system in Taiwan, through dissecting the forces of knowledge, social-cultural context, economic resources and political system. We further identify factors, which had a significant impact on health care reform policies in Taiwan through illustrative policy examples. One of the most illuminating examples highlighted is the design and implementation of a single payer National Health Insurance (NHI) program in 1995, after nearly five years of planning efforts (1988-1993) and a two-year legislative marathon. The NHI is one of the most popular social programs ever undertaken in the history of Taiwan, which greatly enhances financial protection against unexpected medical expenses and assures access to health services. Nonetheless, health care reform still has an unfinished agenda. Despite high satisfaction ratings, Taiwan's health care system today is encountering mounting pressure for new reforms as a result of its rapidly aging population, economic stagnation, and imbalanced NHI checkbook. Although there may exist some heterogeneous system characteristics and challenges among different health care systems around the world, Taiwan's experiences in reforming its health care system for the past few decades may provide valuable lessons for countries going through rapid economic and political transition. PMID- 20199716 TI - [Investigation of nosocomial infection in the neonatal intensive care unit]. AB - OBJECTIVE: A perspective study was conducted to describe the epidemiologic profile of nosocomial infection in the neonatal intensive care unit (NICU). METHODS: The newborn infants who were admitted in the NICU for more than 48 hrs were enrolled from February 2006 to January 2007. The clinical data were collected. The rate of nosocomial infection was calculated according to the CDC surveillance system. The risk factors of nosocomial infection were investigated by multivariate regression analysis. RESULTS: A total of 1 159 neonates were recruited. A total of 169 nosocomial infections occurred, with a cumulative rate for nosocomial infection of 14.58%. The incidence of nosocomial infection was 19.52 per 1 000 patient-days. Ninety-two cases of pneumonia, including 38 cases of ventilator-associated pneumonia (VAP), were reported, with a nosocomial infection rate of 7.94%, which was the most common nosocomial infection in the NICU. Among these infants the rate of VAP was 48.8 per 1 000 ventilator days. The major microorganisms isolated from the infected patients were Acinetobacter baumannii, Klebsiella pneumoniae, Coagulase negative staphylococcus, and aeruginosus Bacillus. Birth weight (OR 2.130, 95%CI 1.466-3.094), mechanical ventilation (OR 7.038, 95%CI 3.901-12.698), chest tube drainage (OR 7.004, 95%CI 1.841-26.653) and ibuprofen therapy (OR 2.907, 95% CI 1.303-6.487) were the risk factors for the development of nosocomial infection. CONCLUSIONS: Pulmonary infection is the most common nosocomial infection in the NICU, and the Gram negative bacillus is the main pathogen. Low birth weight, mechanical ventilation, chest tube drainage and ibuprofen therapy are independent risk factors for nosocomial infection in the NICU. PMID- 20199717 TI - [Changes of iron metabolism indices in children with various genotypes of thalassema]. AB - OBJECTIVE: To study the value of iron metabolism indices, serum iron (SI), total iron blinding capacity (TIBC) and transferring (Tf), in thalassema. METHODS: The serum samples from 9 children with silent alpha thalassema, 56 with standard alpha thalassema, 26 with HbH disease, 40 with beta+ thalassema, 56 with beta0 thalassema, 45 with iron deficiency anemia (IDA) and 70 healthy children were detected for SI, TIBC and Tf levels. RESULTS: The SI level increased (p<0.01), while the TIBC level decreased significantly in the beta0 thalassema group compared with those in the other groups (p<0.05 or 0.01), but the Tf level was not different. The Tf level of both the silent alpha thalassema and the standard alpha thalassema groups was statistically lower than that of the healthy group (p<0.01), but the levels of SI and TIBC were similar to the healthy group. Though the SI level of the HbH disease group was similar to the healthy group, the TIBC and Tf levels were statistically lower (p<0.01). CONCLUSIONS: Compared with Tf, SI and TIBC are better indices for monitoring iron loading in children with thalassema. The increased SI level and decreased TIBC level are two indices for the diagnosis of beta(0) thalassema in children with cellule anaemia. PMID- 20199718 TI - [Linkage analysis and gene mapping of one Chinese family with benign familial infantile convulsions]. AB - OBJECTIVE: The present study performed linkage analysis and gene mapping to find the possible chromosome locus harboring in one family with benign familial infantile convulsions (BFIC) and investigate the possible molecular pathogenesis of BFIC. METHODS: A four-generation family with BFIC was investigated. The family was genotyped using eight hypervariable microsatellite markers covering four loci: D19S245 and D19S250 for the 19q12-13.1 region, D16S3131 and D16S3133 for the 16p12-q12 region, D2S156 and D2S286 for the 2q24 region, and D20S480 and D20S481 for the 20q13.3 region. Polymorphism fragments were amplified using polymerase chain reaction (PCR) method. PCR products for the markers were subjected to electrophoresis on 8% denatured polyacrylamide gel and silver staining for length judgment of amplification fragment. Linkage analysis was performed by use of MLINK in the LINKAGE computer package. Two-point LOD scores were calculated to estimate the linkage relationship. RESULTS: The two-point LOD scores were less than -2.0 for the genetic markers at chromosomes 19q12-13.1, 16p12-q12 and 2q24 at the recombination rate between 0.000 and 0.01. The two point LOD scores for D20S481 at the 20q13.3 region were 0.3 and 0.25 at the recombination rate of 0.000 and 0.01, respectively. CONCLUSIONS: There is no evidence that this family with BFIC is linked to one of the following loci: 19q12 13.1, 16p12-q12 and 2q24, but a possible linkage with 20q13.3 region cannot be excluded. PMID- 20199719 TI - [Characteristics of continuous spike-and-wave during slow wave sleep syndrome in children]. AB - OBJECTIVE: Continuous spike-and-wave during slow wave sleep (CSWS) syndrome is one of the presentations of electrical status epilepticus during sleep (ESES). The purpose of this study was to investigate the characteristics of CSWS syndrome in children. METHODS: Between 2007 and 2009, a total of 778 nocturnal long-term or 24-hr video-EEG records were included. The EEG, clinical and neuroimaging characteristics were studied in children who met standard criteria for CSWS. RESULTS: Nine children met standard criteria for CSWS in video-EEGs. Their ages ranged 6 to 13 years. Their EEGs were characterized by continuous spike-and-wave (SW) discharges during non-rapid eye movement (NREM) sleep, accounting for 85% 100% of the period of NREM sleep. Clinically, these children had various types of epileptic seizures and exhibited different degrees of neuropsychiatric impairments, language dysfunction, and/or behavioral disturbances. Neuroimaging abnormalities were found in 6 cases, including atelencephalia or atrophy, gray matter heterotopia and leucomalacia. CONCLUSIONS: This study indicates the characteristics of CSWS syndrome in clinical manifestations, EEG and neuroimaging examinations. This will be helpful in understanding CSWS syndrome. PMID- 20199720 TI - [Effect of topiramate and carbamazepine on bone metabolism in children with epilepsy]. AB - OBJECTIVE: To assess bone health in epileptic children who have been treated with topiramate (TPM) or carbamazepine (CBZ). METHODS: Sixty-three epileptic children who received TPM or CBZ treatment and 36 eileptic children who did not receive any drug treatment (control group) were enrolled. Bone mineral density (BMD) at lumbar vertebrae (L1-L4) and radius-ulna was evaluated by the dual-energy X-ray absorptiometry method. Biochemical indices of bone metabolism, including serum calcium, phosphorus and alkaline phosphatase contents were measured. RESULTS: The serum calcium content was higher in the TPM group (2.41+/-0.17 mmol/L), but it was lower in the CBZ group (2.15+/-0.26 mmol/L) than that (2.26+/-0.11 mmol/L) in the control group (p<0.05). The serum phosphorus content in both the TPM (1.55+/ 0.17 mmol/L) and the CBZ groups (1.52+/-0.26 mmol/L) was significantly lower than that in the control group (1.70+/-0.30 mmol/L) (p<0.05). There were no significant differences in the serum content of alkaline phosphatase between three groups. BMD was significantly reduced in both the TPM and the CBZ groups when compared to the control group (p<0.05). CONCLUSIONS: TPM and CBZ may result in alterations in serum contents of calcium, phosphorus and alkaline phosphatase as well as BMD reduction. PMID- 20199721 TI - [Echocardiography diagnosis of fetal cardiac structural abnormalities]. AB - OBJECTIVE: To investigate the application of echocardiography diagnosis of fetal cardiac structural abnormalities. METHODS: The echocardiography findings of 9 352 fetus were studied. RESULTS: A total of 472 cases showed cardiac structural abnormalities, including 7 cases of ventricular septal defect, 53 cases of atrioventricular septal defect, 49 cases of atrial septal defect, 26 cases of tetralogy of Fallot, 21 cases of persistent truncus arteriosus, 20 cases of Ebstein's anomaly and 206 cases of other cardiac abnormalities. There were 17 cases with cardiac arrhythmia, 9 with heart failure, and 5 with hydrops. CONCLUSIONS: Fetal echocardiography is a promising diagnostic tool for prenatal evaluation of cardiac structural abnormalities. The echocardiography diagnosis and evaluation for fetal congenital cardiovascular malformations is the foundation of the guidance and monitoring in intrauterine fetal cardiac intervention. PMID- 20199722 TI - [A modified management of the transcatheter occlusion of patent ductus arteriosus: using angiography combined with transthoracic echocardiography]. AB - OBJECTIVE: To evaluate the feasibility of angiography combined with transthoracic echocardiography (TEE) as a modified management of the transcatheter occlusion of patent ductus arteriosus (PDA). METHODS: Forty children with PDA were randomly divided into two groups (n=20 each): observed and control. The control group accepted traditional transcatheter occlusion, and the observed group received a modified management (angiography combined with TEE). The children in the observed group were monitored by realtime TTE. RESULTS: A complete occlusion was acquired by one occlusion operation in each child in the observed group. The TTE demonstrated that the occlusion device was in place, and that the blood flow velocities in the left and right pulmonary artery and the descending aorta were in normal ranges. There were shorter X-ray exposure time, shorter recovering time and less ICU stay time in the observed group than in the control group. The complications associated with blood vessel puncturation occurred in four children from the control group, but none of the observed group had the complications. The total hospitalization cost in the observed group was less than in the control group. CONCLUSIONS: Angiography combined with TEE as a modified management of the transcatheter occlusion of PDA is recommended. PMID- 20199723 TI - [DRD2/ANKK1 Taq IA polymorphism and early infant temperament]. AB - OBJECTIVE: To investigate whether there is an association between DRD2/ANKK1 Taq IA polymorphism and early infant temperament. METHODS: DRD2/ANKK1 Taq IA polymorphism (rs1800497) was determined using polymerase chain reaction-ligase detection reaction (PCR-LDR) techniques in 149 Chinese Han infants from Changsha City. Their mothers were asked to complete the Early Infant Temperament Questionnaires (EITQ) when the infants were 1 to 4 months old (mean: 2.75 months). There were three genotypes found in these infants: C/C, T/T and C/T. The subjects were subdivided into T-carrier (CT, TT) and non-T-carrier (CC) groups for statistical analysis. RESULTS: There were no differences in the temperament style distribution between the T-carrier and non-T carrier groups. There were also no statistically significant differences between the two groups in the score of the nine temperament dimensions. CONCLUSIONS: DRD2/ANKK1 Taq IA polymorphism is not associated with early infant temperament. PMID- 20199724 TI - [Expression of apoptosis-related proteins in gastric mucosa of children with Helicobacter pylori infection]. AB - OBJECTIVE: To investigate the relationship between apoptosis-related proteins in gastric mucosa, p53 and Bax, and Helicobacter pylori (H. pylori) infection in children. METHODS: p53 and Bax expression in gastric mucosa were measured using immunohistochemical technique in 33 children with gastric mucosal lesions. Presence/absence of H. pylori infection was detected by the rapid urease and pathological tests. RESULTS: Fifteen children (88%) showed positive expression of p53 in 17 children who were confirmed with H. pylori infection, compared with 9 (56%) in 16 H. pylori negative children. Thirteen children (76%) showed positive expression of Bax in the 17 children with H. pylori infection, compared with 6 (38%) in the 16 H. pylori negative children. The expression levels of p53 and Bax in the H. pylori positive group were significantly higher than those in the H. pylori negative group (p<0.05). CONCLUSIONS: H. pylori infection is associated with the over-expression of p53 and Bax proteins in gastric mucosa in children. PMID- 20199725 TI - [Measurement of eosinophils and interleukin-17 in nasopharyngeal secretions of children under 5 years old with wheezing]. AB - OBJECTIVE: To study the value of eosinophils (EOS) and interleukin-17 (IL-17) in nasopharyngeal secretions in the evaluation of progress of wheezing in children under 5 years old. METHODS: Fifty-three children under five years old who had recurrent wheezing were classified into two groups: wheezing group I with atopic body (n=27) and wheezing group II without atopic body (n=26). Twenty pre-surgical children with non-infectious disease were used as the control group. Nasopharyngeal secretions were collected. Inflammatory cells in nasopharyngeal secretions were counted under the microscope. IL-17 levels in supernatants were measured using ELISA. RESULTS: EOS counts in nasopharyngeal secretions in wheezing group I were significantly higher than those in wheezing group II and the control group (p<0.05, p<0.01, respectively). There were no significant differences in EOS counts between wheezing II and the control groups. The IL-17 levels in both wheezing groups were significantly higher than those in the control group (p<0.01), and the wheezing group I had increased IL-17 levels than wheezing group II (1 474+/-974 pg/mL vs 788+/-132 pg/mL; p<0.05). The IL-17 level was positively correlated with the EOS counts in wheezing group I (r=0.62, p<0.05). CONCLUSIONS: EOS counts and IL-17 levels in nasopharyngeal secretions may be used as indices for identifying the tendency to develop asthma in children under 5 years old with wheezing. PMID- 20199726 TI - [Concentrations of granulocyte colony-stimulating factor in children with moyamoya disease]. AB - OBJECTIVE: To explore the roles of granulocyte colony-stimulating factor in the pathogenesis of moyamoya disease. METHODS: Serum G-CSF concentrations were measured using enzyme linked immunosorbent assay (ELISA) in 20 children with moyamoya disease and 20 healthy children. RESULTS: Serum G-CSF concentration (35.7+/-10.3 pg/mL) in children with moyamoya disease was significantly higher than that in healthy controls (23.5+/-3.8 pg/mL) (p<0.01). CONCLUSIONS: The elevated serum G-CSF concentration in children with moyamoya disease suggests that G-CSF may play an important role in the pathogenesis of moyamoya disease. PMID- 20199728 TI - [Renal expression of macrophage migration inhibitory factor in children with Henoch-Sch-nlein purpura nephritis]. AB - OBJECTIVE: To examine the expression of macrophage migration inhibitory factor (MIF) in renal tissues obtained from children with Henoch-Sch-nlein purpura nephritis (HSPN). METHODS: The renal tissue samples were obtained from 11 children with different pathological grades of HSPN and 8 children with thin glomerular basement membrane disease (controls). The MIF expression was measured by immunohistochemistry. The correlation between MIF expression and 24 hrs urinary protein excretions was evaluated using a linear correlation analysis. RESULTS: MIF expression was seldom found in renal tissues obtained from controls. However, a significantly increased MIF expression was found and was concordant with the increased severity of renal pathology in renal tissues obtained from children with HSPN. The MIF expression in renal tissues of grade III-IV of renal pathology was significantly higher than that in grade I-II in children with HSPN (p<0.01). In children with HSPN, there was an increased MIF expression in renal tissues with crescent formation and inflammatory cell infiltration. Renal MIF expression was significantly positively correlated with 24 hrs urinary protein excretions in children with HSPN (p<0.01). CONCLUSIONS: MIF may play an important role in renal injury of HSPN. Up-regulation of MIF expression may reflect the degree of renal lesions in HSPN. PMID- 20199729 TI - [Prevalence of psychiatric disorders in primary and middle school students in Hunan Province]. AB - OBJECTIVE: To investigate the prevalence of psychiatric disorders in a representative sample of primary and middle school students in Hunan Province. METHODS: A total of 9 495 children aged 5-17 years from Hunan urban and rural schools were enrolled by a cluster sampling and a two-phase design. The students' psychiatric status was assessed using the Investigation Screening Inventory for Child Mental Disorder and a semi-structured interview designed based on the DSM IV criteria. RESULTS: The overall prevalence of psychiatric disorders was 16.22%. Attention-deficit and disruptive behavior disorders were the commonest in the diagnostic categories of psychiatric disorders (10.69%). Regarding specific disorders, the most prevalent was attention-deficit/hyperactivity disorder (5.95%). Psychiatric disorders were more prevalent in boys than in girls (20.49% vs 11.16%; p<0.01). The prevalence of attention-deficit and disruptive behavior disorders in boys was higher than in girls (14.76% vs 5.87%; p<0.01). The prevalence of psychiatric disorders in middle school students (12-17 years) was significantly higher than in primary students (5-11 years) (18.38% vs 14.64%; p<0.01). There were no significant differences in the prevalence of psychiatric disorders between urban and rural students. CONCLUSIONS: Psychiatric disorders are common among primary and middle school students in Hunan Province. The prevalence of this disorder in boys is higher than in girls. The middle school students have higher prevalence than primary students. PMID- 20199730 TI - [Levetiracetam therapy for childhood epilepsy: a systematic review]. AB - OBJECTIVE: Levetiracetam has been widely used for childhood epilepsy, but there is no high quality evidence to support its use. This study performed a systematic review to evaluate the effectiveness and safety of levetiracetam therapy for childhood epilepsy. METHODS: The papers related to levetiracetam therapy for childhood epilepsy published up to March, 2009 were retrieved electronically from the PubMed, Embase, the Cochrane Library, Chinese Biomedical Database, Wanfang and Weipu Chinese Journals Full-text Database. The relevant papers on randomized control trials (RCTs) or quasi-RCTs were studied by meta analysis. RESULTS: Two papers that met the inclusion criteria were included. The first paper involved 198 patients, including 108 cases in the levetiracetam therapy group and 97 cases in the placebo group. Seven cases (6.9%) were seizure free in the levetiracetam therapy group compared with 1 case (1%) in the placebo group (p<0.01) 14 weeks after treatment. Levetiracetam therapy decreased significantly the frequency of seizures compared with the placebo treatment. The second paper involved 39 patients, including 21 cases in the levetiracetam therapy group and 18 cases in the oxcarbazepine therapy group. Nineteen cases (90.5%) were seizure-free in the levetiracetam therapy group compared with 13 cases (72.2%) in the oxcarbazepine therapy group (P=0.410) during a follow-up of 12-24 months. The adverse effects in the levetiracetam therapy group were not significantly different from the placebo and the oxcarbazepine therapy groups. CONCLUSIONS: The current evidence shows that levetiracetam therapy is effective for childhood epilepsy. However, it needs to be proved by the multi-centre, large sample RCTs. PMID- 20199731 TI - [Protective effects of curcumin on neonatal rats with necrotizing enterocolitis]. AB - OBJECTIVE: This study examined the effects of curcumin on intestinal histopathological changes, cyclooxygenase-2 (COX-2) expression, and tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) concentrations in neonatal rats with necrotizing enterocolitis (NEC), in order to investigate the effects of curcumin against NEC. METHODS: Forty neonatal rats were randomly divided into four groups (n=10 each): normal control, solvent control, NEC model, and curcumin intervention. The general situations of rats were observed for 3 consecutive days, and the rats were then sacrificed on the 4th day. Intestinal tissues were obtained for examining the histopathological changes, COX-2 expression, and TNF-alpha and IL-10 concentrations. RESULTS: Curcumin treatment ameliorated the general situations and histopathological signs in rats with NEC. TNF-alpha and IL-10 concentrations in the NEC model and the curcumin intervention groups increased significantly compared with those in the normal and solvent control groups (p<0.05). The concentration of TNF-alpha decreased (p<0.05), while the concentration of IL-10 increased significantly in the curcumin intervention group in comparison with the NEC model group (p<0.05). Immunohistochemistry results indicated that the positive expression of COX-2 in the curcumin intervention group was significantly lower than that in the NEC model group. CONCLUSIONS: Curcumin has protective effects against NEC in neonatal rats, possibly through inhibiting COX-2 expression, reducing TNF-alpha content, and increasing IL-10 content. PMID- 20199732 TI - [Effect of epidermal growth factor receptor on airway remodeling in asthmatic mice and its mechanism]. AB - OBJECTIVE: To explore the relationship of airway remodeling with epidermal growth factor receptor (EGFR) and heparin-binding epidermal growth factor-like growth factor (HB-EGF) levels in asthmatic mice and the effect of EGFR tyrosine kinase inhibitor (AG1478) on airway remodeling. METHODS: Twenty-four male BALB/c mice were randomly divided into three groups: normal control, asthma, AG1478-treated. Mice were sensitized and challenged with ovalbumin (OVA) and a mouse mode1 of asthma was prepared. Collagen deposition was determined in Masson-stained lung sections. Periodic acid Schiff (PAS) staining was used to observe the proliferation of goblet cells. Immunohistochemistry was used to determine the protein expression of HB-EGF. RT-PCR was used to determine the mRNA expression of HB-EGF and EGFR. RESULTS: The characteristic changes of airway remodeling occurred in the asthma group. The expression of HB-EGF and EGFR in the epithelial cells of bronchi in the asthma group was significantly higher than that in the normal control group. Compared with the asthma group, the AG1478-treated group had decreased inflammation reactions, decreased collagen deposition and proliferation of goblet cells and lower expression of EGFR and HB-EGF. CONCLUSIONS: EGFR tyrosine kinase inhibitor (AG1478) ameliorates the progression of airway remodeling in mice with asthma by inhibitions of EGFR and HB-EGF expression and EGFR signal pathway. PMID- 20199733 TI - [Prognosis of children with sepsis complicated by gastrointestinal dysfunction]. PMID- 20199734 TI - [Clinical analysis of 15 cases of abdominal compartment syndrome]. PMID- 20199735 TI - [Detection of enterovirus RNA by fluorescent quantitative PCR in children with hand-foot-mouth disease]. PMID- 20199736 TI - [Diagnosis and treatment of severe hand-foot-mouth disease: experience of 33 cases]. PMID- 20199737 TI - [Investigation on hepatitis B virus infection in children from Guiyang area]. PMID- 20199738 TI - [Efficacy of low-dose oral erythromycin as an adjuvant therapy for cytomegalovirus infection]. PMID- 20199739 TI - [Neonatal sepsis caused by Listeria monocytogenes: case report of 7 cases]. PMID- 20199740 TI - [Huge pneumatocele in a child]. PMID- 20199741 TI - [3-methyl-crotonyl-CoA carboxylase deficiency: a case report]. PMID- 20199742 TI - [Research advance in the etiology of West syndrome]. PMID- 20199743 TI - [Equal treatment irrespective of ethnic origin]. PMID- 20199744 TI - [Foreign patients in a community psychiatry centre]. AB - INTRODUCTION: Over the last ten years more patients have been referred to the District Psychiatric Centre (DPC) in Odense. We therefore found it relevant to investigate the following in this study: - To register patients with foreign background, who are receiving psychiatric treatment in DPC. - Through a nested case control study to evaluate if/how foreign patients in DPC differ from the remaining patient group. MATERIAL AND METHODS: The study was a nested case control study. Relevant clinical information concerning foreign patients was compared to Danish controls. RESULTS: A total of 168 patients participated in the study, among these 60 with a foreign background. The study showed that Danish patients more often received early retirement pension, more frequently received 2nd generation antipsychotics, and more frequently received the social support services offered for psychotic patients in the community. Foreign patients more frequently lived with family and children than the Danes. Furthermore, they had a shorter illness duration and had less frequently been admitted to a psychiatric department. CONCLUSION: Based on this study it is emphasised that the efforts to assist foreign patients with psychiatric disorders should be improved. I.e. through inexpensive medicine, specialised teams, better coordination between psychiatrist and the municipality, and improved knowledge of the consequences of psychiatric disorders among the foreign patients. PMID- 20199745 TI - [Iatrogenic dural lesions in lumbar neural decompressive surgery]. AB - INTRODUCTION: Iatrogenic dural tear with cerebrospinal fluid leakage is a known complication of lumbar surgery of the columna. In the literature, the incidence is 3-16%. MATERIAL AND METHODS: The study was a retrospective, consecutive review of electronic patient records after spinal surgery at the Private Hospital Hamlet. The study covers cases from the 10-month period from September 1, 2007 to June 30, 2008. Data was collected after this period and consists of surgeon documented dural tears. At the time of surgery, the surgeon was unaware that there would be a subsequent registration. A total of 634 patients had lumbar neural decompressive surgery - 479 patients were treated for spinal stenosis and 155 for prolapsed disc. RESULTS: The incidence of dural tear was 3.9% (25 dural tears in 634 operations). The risk of a dural tear after secondary surgery was 7.9% versus 3.3% for primary (p = 0.02) and the mean age was 65.9 years for patients with dural tear compared with 58.1 years for patients without (p = 0.00). The difference in the mean duration of surgery was significant being 72 minutes in the group suffering a dural tear compared with 56 minutes (p = 0.03) among the remaining patients, and in the former group length of stay was increased by 1.1 day (p = 0.00). CONCLUSION: The incidence of iatrogenic dural tear was 3.9%. The incidence of dural tear was doubled in secondary surgery. The duration of surgery increased by 16 minutes and the patients with dural tear were also hospitalized one day longer. PMID- 20199746 TI - [Use of prostate-specific antigen testing]. AB - BACKGROUND: Prostate cancer (PC) is the most frequent type of cancer among Danish men and its incidence is rising. PC is often asymptomatic, which makes it very difficult to diagnose clinically. The general practitioner can use prostate specific antigen (PSA) testing as a diagnostic tool in PC. The use of PSA testing has been recommended by the Danish Urological Society since 1997. Our objective was to study the application and results of PSA testing in the former County of Aarhus, Denmark, in the period 1995-2006. MATERIAL AND METHODS: We extracted data from the laboratory database, LABKA, and the National Patient Registry (NPR) during the period 1995 to 2006. Data were merged by civil registration number, and the unit ordering PSA was identified as general practice or specialized healthcare system. Furthermore, we categorized samples as incident, repeated normal, repeated raised samples, or controls. RESULTS: The use of PSA increased 43-fold in this period and the proportion of samples ordered by general practice increased from 38.6% (95% confidence interval: 36.4-40.8%) in 1998 to 66.1% (65.4 66.8%) in 2006. The proportion of incident samples ordered by general practice, with results below four mikromol/l increased rapidly, whereas it decreased in the specialized healthcare system. In this population, the PC incidence increased the same period, but remained stable from 2004 onwards. Furthermore, we found that the mean number of tests per man per year increased in general practice. CONCLUSION: PSA testing in general practice is conducted more frequently, a tendency which may be explained by more check-ups after PC treatment, watchful waiting and opportunistic screening. PMID- 20199747 TI - [Assessment and treatment of osteoporotic hip fractures]. AB - INTRODUCTION: Osteoporosis is a major cause of low-energy hip fractures. Although there are pharmacologic agents available for both prevention and treatment, less than 10% of hip fracture cases initiate anti-osteoporotic treatment. MATERIAL AND METHODS: In 1995 and 2008, questionnaires were sent to all Danish orthopaedic surgery departments treating patients with low-energy hip fractures, asking them to explain a) whether patients with osteoporosis are identified, b) whether the patients identified are treated for osteoporosis, and c) whether physicians need more information about osteoporosis. RESULTS: 56 departments (97%) returned the questionnaires in 1995 and 25 (95%) in 2008. 40% of the departments did (12% in 1995) refer any patients with low-energy fractures to bone densitometry. 84% treated (11% in 1995) patients with hip fractures with calcium and D vitamin. In 2008, 28% (0% in 1995) of the departments used bisfosfonates after hip fractures (none used yearly zoledronate). More than 80% (54% in 1995) of the departments informed the patients about in the advantages of lifestyle changes. Half of the departments' doctors wanted more information about osteoporosis in 1995 compared with only 16% in 2008. In 2008, 48% of the departments informed the GPs that their patient with a low-energy fracture may have osteoporosis and that further evaluation and treatment may be needed. CONCLUSION: Medical treatment after fractures was more widespread in 2008 than in 1995. About half of the Danish departments with orthopaedic surgery functions refer patients to further investigation. There is, however, still room for improvement. PMID- 20199748 TI - [Treatment of borderline personality disorder]. AB - Patients with borderline personality disorder entail a considerable strain on mental health services. Previously, the prognosis for these patients was regarded pessimistically, but this perspective has been radically altered during the latest ten years because of the development of structured and evidence-based treatment programs. In this article a short introduction to Mentalisation-Based Treatment of BPD is given. PMID- 20199749 TI - [Leiomyomatous hamartoma at base of tongue]. AB - We report a case of a leiomyomatous hamartoma located in the midline of the base of the tongue. The two-year-old girl had an asymptomatic pedunculated tubular tumour measuring 1.6 x 1.3 x 1.1 cms. The lesion was surgically excised, and histopathological examination disclosed a non-neoplastic mass composed of irregular arranged bundles of smooth muscle cells embedded in a fibrovascular stroma. The diagnosis was confirmed by immunohistochemistry with positivity for smooth muscle actin and desmin. Until now, only 19 cases have been reported in English-language literature. PMID- 20199750 TI - [Computed tomography showing universal bone lesions in a patient with myelomatosis]. AB - A 71-year-old man was referred to the lung department with pain in the right side of the chest through three months, especially when physically active. The patient presented with a tendency to shortness of breath, fatigue, low energy level and night sweats. The tentative diagnosis of pleural tumour/metastases was made. Chest x-ray showed pleural thickening and poorly defined ribs on the right side, consistent with bone destruction. Computed tomography showed a big mass in the 5th rib and universal bone lesions. Biopsy from the rib revealed the diagnosis of myelomatosis. PMID- 20199751 TI - [Luxation of total hip prosthesis as a complication of electroconvulsive therapy]. AB - In this case, a 62-year-old female suffering from depression luxated her hip prosthesis as a complication of electroconvulsive therapy (ECT). During the ECT a strong clinical convulsion was observed indicating that the patient had possibly not been sufficiently relaxed during treatment. Searches for similar cases in medical databases revealed five cases with fractures since 1985. Searches for luxation of joints retrieved no previous cases. PMID- 20199752 TI - [Relapsing polychondritis]. AB - A case of relapsing polychondritis in a 55-year-old man is described. The patient had suffered from recurrent pneumonia, bilateral auricular chondritis, unilateral hearing loss, skin lesions and an erosive seronegative polyarthritis. Biochemically, anemia, an elevated ESR and periodically elevated levels of C reactive protein were present. A pulmonary function test showed an obstructive pattern. A computed tomography of the thorax and a bronchoscopy revealed tracheobronchial stenosis. The patient was treated with corticosteroids/methotrexate and ultimately a tracheobronchial stent due to worsened respiratory involvement. PMID- 20199753 TI - [Sixteen-year-old woman with multiorgan dysfunction after HELLP]. AB - HELLP is a syndrome with haemolysis, elevated liver enzymes and thrombocytopenia. It occurs in 1 to 6 per 1,000 parturient. Approximately 10% of the cases occur post partum. A 16-year-old woman delivered twins in the 34th gestational week. During the following hours, she developed symptoms of hypovolaemic shock. Blood sample values were critical and the patient was diagnosed with HELLP with DIC. She developed liver shock with encephalopathy and acute renal failure. Her condition stabilized on the 8th day of admission and the woman was extubated on the 16th day. She was discharged without complications on the 22 th day. PMID- 20199754 TI - [Staphylococcal scalded skin syndrome in adults]. AB - We describe a case of adult staphylococcal scalded skin syndrome (SSSS) in a 91 year-old woman. The patient had a Staphylococcus aureus infection in her right ear with redness and yellow secretion. A few days later she developed Nikolsky sign-positive tender enlarged flaccid bullae involving most parts of her body. The bullae ruptured easily and left a erythematous base. The histopathological changes were characteristic for adult SSSS. The patient was well-treated with intravenous dicloxacillin, topical antibiotic and antiseptic treatment. The patient had marked thrombocytosis, but no interest in further examination. PMID- 20199755 TI - [Regression of severe periarticular calcifications during treatment with bisphosphonate in a dialysis patient]. AB - Treatment with etidronate, 400 mg daily, induced total regression of severe, disabling periarticular calcifications during a treatment period of 42 months in a patient with chronic kidney disease on dialysis treatment. All symptoms disappeared. No adverse effects were recorded during the treatment. Thus, treatment with etidronate can induce regression of the periarticular calcifications which comprise a complication to chronic renal failure. PMID- 20199756 TI - Effect of food coupon incentives on timely completion of DTP immunization series in children from a low-income area in Karachi, Pakistan: a longitudinal intervention study. AB - This study introduced food/medicine vouchers as an incentive to mothers of infants visiting Expanded Program on Immunization (EPI) centers in a low socio economic area. The timely completion of diphtheria, tetanus and pertussis vaccines combined (DTP) series immunization rates between intervention and control cohorts were compared. The DTP up-to-date immunization coverage at 18 weeks of age increased two-fold (RR 2.20, 95% CI: 1.95-2.48, p<0.001) in the incentive cohort compared to the no-incentive cohort. While increasing immunization coverage is a complex structural and behavioral process, food/medicine coupon may improve routine immunization coverage in developing countries. PMID- 20199757 TI - Determinants of influenza immunization uptake in Canadian youths. AB - OBJECTIVE: To describe rate and determinants of influenza vaccination among Canadian youths. METHODS: We conducted an analysis of cross-sectional data from the Canadian Community Health Survey (CCHS) cycle 3.1 collected by Statistics Canada in 2005. This is a population-based survey collecting information pertaining to the Canadian population health status, health care utilization and health determinants. The CCHS 3.1 included 12,170 respondents age 12-17 years old who answered questions pertaining to influenza vaccination. We used multivariate logistic regression to estimate the odds of having received the influenza vaccination in the last 12 months, adjusting for potential confounders. RESULTS: Less than a quarter of Canadian youth reported receiving the influenza vaccination in the previous year. The most common reason for not getting the vaccination was "did not think it was necessary" (40.82%). Having chronic illness, and being an immigrant was significantly associated with a higher odds of receiving the influenza vaccination, while having an allergy and increasing frequency of alcohol drinking was associated with lower odds of receiving influenza vaccination. Smoking status acted as an effect modifier for many variables except for immigration status. CONCLUSIONS: Influenza vaccination rate in Canadian youths is low. Judgement values on its necessity are a major factor in the decision to receive influenza vaccination. Strategies to involve youths in influenza vaccination programs and campaigns will be essential to achieve better national coverage. PMID- 20199758 TI - "Is cancer contagious?": Australian adolescent girls and their parents: making the most of limited information about HPV and HPV vaccination. AB - INTRODUCTION: Australia has implemented a nation-wide program providing HPV vaccination to girls at school. To date, there are no published studies that explore knowledge about HPV and HPV vaccine post-implementation of the national school-based HPV vaccination program. METHODS: A purposive sample of schools was selected to reflect a range of vaccination coverage (high versus lower uptake), and different school types (Catholic, Independent or Government). Semi-structured focus groups and interviews were conducted with girls and their parents respectively, until saturation was reached. Transcripts were analysed, letting themes emerge from the data. RESULTS: A core theme from both girls and parents was lack of knowledge. Supporting themes were lack of knowledge of HPV, lack of knowledge of vaccine, and realisation of their lack of knowledge. Their lack of knowledge was common in three areas: what HPV is, how HPV is transmitted, and the HPV and cervical cancer connection. The lack of knowledge about HPV vaccination was reflected in what the vaccine protects against, how the vaccine works, HPV vaccination recommendations, the vaccine and Pap smear connection, and myths about HPV vaccination. Both girls and parents wanted more information, had a tendency to defer responsibility, and parents expressed judgment of themselves as parents. DISCUSSION: Low levels of knowledge and understanding about HPV vaccination among adolescents and parents have implications for adolescents' future health practices, including sexual risk behaviour, condom usage, and cervical screening. Reasons for the low levels of knowledge are explored, as are implications for school-based educational interventions. PMID- 20199759 TI - Serotype coverage of pneumococcal conjugate vaccine and drug susceptibility of Streptococcus pneumoniae isolated from invasive or non-invasive diseases in central Thailand, 2006-2009. AB - The serotype of 172 S. pneumoniae isolates obtained from normally sterile sites from January 2006 to February 2009 in Thai patients was evaluated. The most common serotypes were 6B, 23F, 14, 19F, and 19A in patients <5 year-old, and 6B, 19A, 23F, 4, 9V in patients >65-year old. Seven-valent pneumococcal conjugated vaccine (PCV-7) covered 70.3%, 43.6%, and 43.5% of patients <5, 5-64 and > or = 65 years of age, respectively, while PCV-13 covered 81.2%, 59.7%, and 60.9%, respectively. PCV-9, PCV-10, PCV-11 had very similar coverage as PCV-7. The antibiotic susceptibility rates of the isolates from sterile sites were 88.7 95.7% for penicillin, 90.6-98.4% for cefotaxime, 92.2-100% for ofloxacin and 100% for ciprofloxacin. PCV-7 covered 83% and 100%, respectively, of penicillin and cefotaxime non-susceptible isolates in patients <5-year old. PMID- 20199760 TI - Vaccination of turkeys against Chlamydophila psittaci through optimised DNA formulation and administration. AB - We have demonstrated that vaccination of turkeys with an unformulated DNA vaccine induces significant protection against Chlamydophila (Cp.) psittaci infections. Nevertheless, the immunogenicity of the DNA vaccine can still be improved by increasing translation and transfection efficiency. Therefore, the ompA codon was adapted to the codon usage in birds, resulting in pcDNA1/MOMP(opt). To increase gene transfer, polyplexes of pcDNA1/MOMP(opt)-EGFP with different cationic polymers, such as linear and branched polyethyleneimine (lPEI and brPEI) and starburst PAMAM dendrimers, and lipoplexes with cationic DOTAP/DOPE liposomes were created. Transfection of lPEI and brPEI polyplexes with an N/P ratio of 8 resulted in the highest transfection efficiencies, but lPEI polyplexes were completely destroyed following nebulisation. Secondly, we examined the capacity of nebulised or intramuscularly (IM) administered brPEI-pcDNA1/MOMP(opt) to induce a significant protective immune response in SPF turkeys experimentally infected with 10(8) TCID(50) of a virulent Cp. psittaci strain. Results were compared to IM administration of naked plasmid DNA and to results of non vaccinated animals. Intramuscular administration of brPEI-pcDNA1/MOMP(opt) increased the immunogenicity of the Cp. psittaci DNA vaccine as compared to IM administration of pcDNA1/MOMP(opt) or aerosol delivery of brPEI-pcDNA1/MOMP(opt). Improved immunogenicity was correlated with increased protection. Vaccinated groups were significantly protected against Cp. psittaci challenge. PMID- 20199761 TI - Marker vaccine potential of a foot-and-mouth disease virus with a partial VP1 G-H loop deletion. AB - Previous work in cattle and pigs demonstrated that protection against foot-and mouth disease (FMD) could be achieved following vaccination with chimeric foot and-mouth disease virus (FMDV) vaccines, in which the VP1 G-H loop had been substituted with that from another serotype. This indicated that the VP1 G-H loop may not be essential for the protection of natural hosts against FMDV. If this could be substantiated there would be potential to develop FMD marker vaccines, characterised by the absence of this region. Here, we investigate the serological responses to vaccination with a virus with a partial VP1 G-H loop deletion in order to determine the likelihood of achieving protection and the potential of this virus as a marker vaccine. Inactivated, oil adjuvanted, vaccines, consisting of chemically inactivated virus with or without a partially deleted VP1 G-H loop, were used to immunise cattle. Serum was collected on days 0, 7, 14 and 21 and antibody titres calculated using the virus neutralisation test (VNT) to estimate the likelihood of protection. We predict a good likelihood that cattle vaccinated with a vaccine characterised by a partial VP1 G-H loop would be protected against challenge with the same virus containing the VP1 G-H loop. We also present evidence on the potential of such a construct to act as a marker vaccine, when used in conjunction with a novel serological test. PMID- 20199762 TI - The immunization-induced antibody response to the Anaplasma marginale major surface protein 2 and its association with protective immunity. AB - Many vector-borne pathogens evade clearance via rapid variation in their immunogenic surface expressed proteins. This is exemplified by Anaplasma marginale, a tick-borne bacterial pathogen that generates major surface protein 2 (Msp2) variants to provide for immune escape and allow long-term pathogen persistence. In contrast to persistence following infection, immunization with a surface protein complex, which includes Msp2, induces a response that prevents infection upon challenge. We hypothesized that the immune response induced by immunization altered the anti-Msp2 antibody repertoire as compared to that induced during infection, shifting the immune response toward conserved and thus broadly protective epitopes. The antibody response to the conserved (CR) and hypervariable (HVR) regions encoded by the full set of msp2 variant alleles was determined for immunized animals prior to challenge and non-immunized, infected animals. While both groups of animals had a similar antibody repertoire in terms of breath and magnitude, the titers to the Msp2 CR were strongly correlated (p<0.005) with control of bacteremia only in the infected animals. Among the immunized animals, there was no correlation between the breadth or magnitude of the anti-Msp2 antibody response and either complete protection from infection or control of bacteremia. This is consistent with separate immunologic mechanisms being responsible for control of bacteremia in infected animals as compared to immunized animals and suggests that conserved outer membrane proteins other than Msp2 are responsible for the complete clearance observed following challenge of vaccinees. PMID- 20199763 TI - Modeling the impact of one- and two-dose varicella vaccination on the epidemiology of varicella and zoster. AB - In many countries, policymakers are being asked to make recommendations regarding the introduction of a 2-dose varicella vaccination program. The objective of this study was to examine the potential impact of 1-dose versus 2-dose varicella vaccination programs on varicella and zoster incidence, using Canada as an example. We developed a deterministic realistic age-structured model that fits 1- and 2-dose vaccine efficacy, varicella force of infection and zoster incidence. Assuming 90% coverage, the base case model (range: min; max) predicts that 1-dose vaccination will reduce varicella and zoster cases by 64% (14%; 96%) and 5% (-2%; 22%), respectively, over 80-years. Adding a second dose is predicted to reduce varicella and zoster by an additional 22% (0%; 82%) and 6% (0%; 14%), respectively. Most varicella cases prevented by the second dose are breakthrough infections. Although the incremental effectiveness of adding the second dose is highly sensitive to vaccine efficacy and mixing, predictions of the overall benefit of a 2-dose program is relatively robust to model assumptions. Adding a 2 dose program may help guarantee high population-level effectiveness against varicella. However, the incremental benefit of a second dose is highly dependant on the effectiveness of the first dose and its impact on zoster. PMID- 20199764 TI - Safety and immunogenicity of the 23-valent pneumococcal polysaccharide vaccine at 12 months of age, following one, two, or three doses of the 7-valent pneumococcal conjugate vaccine in infancy. AB - Fijian infants aged 6 weeks were stratified by ethnicity and randomized to receive 0, 1, 2, or 3 PCV-7 doses with or without the 23-valent pneumococcal polysaccharide vaccine (PPV-23) at 12 months. Strong booster effects for all 7 PCV-7 serotypes were elicited, and for 4/7 serotypes these responses were highest in the single PCV-7 group. There were fourfold rises in GMC for all non-PCV-7 serotypes. By 17 months the PPV-23 group still had significantly higher GMC (each p<0.001) for all serotypes. The PPV-23 was well tolerated and induced excellent responses for all serotypes which were greatest in the single PCV-7 group. PMID- 20199766 TI - Fear, misinformation, and innumerates: how the Wakefield paper, the press, and advocacy groups damaged the public health. PMID- 20199767 TI - On inverse miniemulsion polymerization of conventional water-soluble monomers. AB - Inverse monomer miniemulsions can be generated by sonification of the polar monomer, water, stabilizer and costabilizer in organic solvents as the unpolar continuous phase. The inverse miniemulsion obtains its stability by using a combination of effective surfactant and osmotic pressure agent, so called lypophobe, which is practically insoluble in the continuous phase and prevents the minidroplets from Ostwald ripening. Inverse miniemulsions are typically sterically stabilized with a nonionic surfactant blend so as to provide a relatively condensed interface. The monomer droplet nucleation proceeds under an uncomplete coverage of the monomer and polymer particles with surfactant. Inverse monomer miniemulsions can be easily polymerized to latexes by using water and oil soluble initiators. The rate of inverse miniemulsion polymerization of water soluble monomers increased with increasing both initiator and emulsifier concentrations. The inverse polymerization is very fast and the high conversion is reached during a few minutes. The dependence of the polymerization rate vs. conversion can be described by a curve with the two rate intervals. The abrupt increase in the polymerization rate can be attributed to the increased number of reaction loci and the gel effect. The partitioning of unsaturated monomers between the aqueous and continuous phases favours the contribution of homogeneous nucleation. The desorption of monomeric radicals from the small polymer particles favours the polymerization in the continuous phase. The miniemulsion polymerization and copolymerization is ideal process for the preparation of composite nanoparticles with different structures. This procedure can be used to develop novel thermally responsive polymer microspheres, for example, based on N isopropylacrylamide monomer. The composite magnetic nanoparticles are prepared by polymerization of both water-soluble and oil-soluble monomers in the presence of water- and oil-soluble iron oxide nanoparticles. The inverse miniemulsion copolymerization of acrylic acid and sodium acrylate in the presence of inorganic nanoparticles and substances produces poly(acrylic acid-co-sodium acrylate)/inorganic phase composite nanoparticles. The presence of hydrophobic monomer in the miniemulsion system favours the formation of hollow nanoparticles. The composite latex particles owned better thermal stability and higher colloidal stability than pure latex particles. PMID- 20199768 TI - Explicit memory bias for positively valenced body-related cues in women with binge eating disorder. AB - Overweight women with and without binge eating disorder (BED) are characterized by a marked body dissatisfaction, which may in part be due to the negative comments about their weight. Weight-related teasing and discrimination is reported both by healthy overweight women and women with BED, whereas body dissatisfaction is markedly increased among women with BED. Therefore, a memory bias for negatively valenced body-related cues is suspected to occur as a mediating factor in women with BED. In an experimental study, 18 women with BED were compared to 18 overweight healthy female controls (HC) on a free recall task containing four word categories: positively valenced with and without body related content and negatively valenced with and without body-related content. While both groups showed a bias towards negatively valenced shape-/weight-related words, women with BED retrieved positively valenced shape-/weight-related words significantly less often compared to overweight HC. Findings suggest that it may be the reduced ability to attend to positively valenced shape-/weight-related information, rather than the activation of negative body schemata that differentiates overweight women with BED from overweight women without BED. Results are discussed in the context of cognitive biases in the maintenance of body dissatisfaction. PMID- 20199765 TI - Bottleneck effects on vaccine-candidate antigen diversity of malaria parasites in Thailand. AB - A number of cell surface antigens of the infective stages of malaria parasites (genus Plasmodium) have been proposed as vaccine candidates, but high levels of polymorphism at the loci encoding these antigens are problematic for vaccine effectiveness. In order to test for the effects of anti-malarial control measures (including drugs and vector control) on polymorphism at antigen-encoding loci, we analyzed sequences of four antigen-encoding loci from P. vivax and two from P. falciparum collected in 2006-2007 from two areas of Thailand: (1) the NW, where malaria cases have remained high until recently; and (2) the South, where control measures have caused a dramatic decline in numbers of cases since 1990. Polymorphism in non-repeat regions of antigen-encoding loci was dramatically reduced in the South compared to the NW. These results suggest a two-pronged strategy for malaria eradication: (1) strenuous non-vaccine control measures that will cause a severe population bottleneck in the parasite; and (2) a subsequent local vaccine focused on one or a few locally occurring alleles at antigen encoding loci. PMID- 20199769 TI - Structure of the O-polysaccharide of Salmonella enterica O41. AB - An O-polysaccharide was obtained by mild acid degradation of the lipopolysaccharide of Salmonella enterica O41, and the following structure of the O-unit was determined by chemical analyses along with 1D and 2D (1)H and (13)C NMR spectroscopy: -->2)-beta-d-Manp-(1-->4)-alpha-d-Glcp-(1-->3)-alpha-l-QuipNAc (1-->3)-alpha-d-GlcpNAc-(1--> where QuiNAc stands for 2-acetamido-2,6 dideoxyglucose. The structure established is in agreement with the O-antigen gene cluster of S. enterica O41 and tentative assignment of the gene functions reported earlier. PMID- 20199770 TI - DC-expressed MHC class I single-chain trimer-based vaccines prime cytotoxic T lymphocytes against exogenous but not endogenous antigens. AB - The poor immunogenicity of many tumors can be partly explained by the inefficiency of the MHC class I peptide presentation pathway. MHC-I-based single chain trimers (SCT) represent a new class of molecules with the potential to overcome this limitation. We here evaluated the ability of SCT presenting a melanoma antigen peptide (TRP-2) to prime cytotoxic T lymphocyte (CTL) responses in mice when given as DNA vaccines via Gene Gun or when expressed by dendritic cells. The SCT was unable to induce detectable priming or significant anti-tumor activity of CTL using either vaccination strategy, whereas control SCT (with an exogenous peptide) primed strong responses. This study thus provides the first data related to the use of SCT in combination with DC and their application toward self antigens and suggest this potent technology, alone, is insufficient to overcome self tolerance. PMID- 20199771 TI - [Gallbladder torsion]. PMID- 20199772 TI - [Hypertonic saline and hypernatraemia in hepatic hydatidosis]. PMID- 20199773 TI - [Subcapsular liver haematoma after cardiac resuscitation]. PMID- 20199774 TI - Insulin resistance, dyslipidemia, and metabolic syndrome in women with polycystic ovary syndrome. AB - OBJECTIVE: To investigate the association of insulin resistance with dyslipidemia and metabolic syndrome (MBS) in women with polycystic ovary syndrome (PCOS). METHODS: Fasting glucose (G), insulin (I), and lipid levels were measured in 50 infertile women with PCOS. A fasting G/I ratio of 4.5 or less (n=29) defined insulin resistance (IR). RESULTS: The mean levels of total cholesterol (P<0.001), low-density lipoprotein (P=0.02), and triglycerides (P<0.001) were significantly higher and the mean levels of high-density lipoprotein were significantly lower (P<0.001) in the IR group. The prevalence of MBS (P=0.02) and obesity (P=0.04), hypertension (P=0.02), fasting hyperglycemia (P=0.03), low high-density lipoprotein levels (P=0.02), and hypertriglyceridemia (P=0.02) were also significantly higher in the IR group. CONCLUSION: Insulin resistance is associated with dyslipidemia and MBS in women with PCOS. Lifestyle modification and insulin-sensitizing agents should be part of the management plan. PMID- 20199775 TI - Uterine diverticulum complicating pregnancy diagnosed by ultrasound and uteroscopy. PMID- 20199776 TI - Rimonabant during early pregnancy. PMID- 20199777 TI - A survey of Russian women regarding the presence of a companion during labor. AB - OBJECTIVE: To assess qualitatively the attitudes of Russian women toward the presence of a support person during labor. METHODS: Pregnant and postpartum women were surveyed at the Omsk County Maternity and Delivery Hospital, Omsk, Russia. Demographic information was obtained, and each woman was asked about her opinions regarding the presence of a companion during labor. RESULTS: Of the 70 women interviewed, 68.6% declined to have a partner present during labor. The most common reasons were that they: felt afraid for their husband (15.7%); felt personally embarrassed (17.1%); wanted to have a private experience (22.9%); and thought it would adversely affect their sex life (8.6%). Only 17.1% of the women agreed and were able to have a companion present during labor. In total, 31.4% of women were unable to have a companion present, for the following reasons: family matters; husband declined; husband did not undergo necessary laboratory tests; or spontaneous labor. CONCLUSION: Many Russian women viewed childbirth as a medical process that should not involve social interaction. It is important for physicians to understand that there is a wide range of cultural differences in childbirth practice. PMID- 20199778 TI - Digital fluoroscopic video assessment of glenohumeral migration: Static vs. Dynamic conditions. AB - The purpose was to compare glenohumeral (GH) migration, during dynamic shoulder elevation and statically held positions using digital fluoroscopic videos (DFV). Thirty male volunteers (25+/-4 years) without right shoulder pathology were analyzed using DFV (30Hz) during arm elevation in the scapular plane. DFV were obtained at the arm at side position, 45 degrees , 90 degrees , and 135 degrees for static and dynamic conditions. GH migration was measured as the distance from the center of the humeral head migrated superiorly or inferiorly relative to the center of the glenoid fossa. Inter-rater reliability was considered good; ICC (2,3) ranged from 0.83 to 0.92. A main effect was revealed for contraction type (p=0.031), in which post-hoc t-tests revealed that humeral head was significantly more superior on the glenoid fossa during dynamic contraction. A main effect was also revealed for arm angle (p<0.001), in which post-hoc t-tests revealed significantly more superior humeral head positioning at 45 degrees , 90 degrees , and 135 degrees when compared to arm at side (p<0.001), as well as at 90 degrees compared to 45 degrees (p=0.024). There was no interaction effect between angle and contraction type (p=0.400). Research utilizing static imaging may underestimate the amount of superior GH migration that occurs dynamically. PMID- 20199779 TI - Influences of properties of protein and adsorption surface on removal kinetics of protein adsorbed on metal surface by H2O2-electrolysis treatment. AB - "H(2)O(2)-electrolysis" treatment is an alternative method for removing proteinaceous materials that are adsorbed to metal surfaces. The method is based on the generation of hydroxyl radicals by electrolysis of hydrogen peroxide and the subsequent decomposition of organic substances adhering to the metal surface. We herein investigated the influence of some parameters on the kinetics of protein removal by H(2)O(2)-electrolysis. These parameters included the properties of proteins and the type of metal surface. Sixteen types of proteins and nine types of metal surfaces were used. The removal of adsorbed protein from a metal surface during the treatment was monitored by ellipsometry. Apparent first-order rate constants for removal, k(c)(l), for various adsorption and treatment conditions were determined. The k(c)(l) value varied markedly with the type of protein and was also influenced by the pH used in the adsorption. The isoelectric point (pI) of protein used was found to be a major factor. The amount of adsorbed protein removed by a unit amount of (.)OH was larger for a metal surface with a lower pI. The impact of the properties of the protein and metal surface on the removal kinetics are discussed, focusing on relationships with the adsorption characteristics of the protein. PMID- 20199781 TI - [Adverse events after administration of A/H1N1 vaccine to patients]. PMID- 20199782 TI - Plasma fetuin-A concentrations in young and older high- and low-active men. AB - Fetuin-A is a liver-derived factor that may play a role in insulin resistance and age-related chronic diseases (eg, type 2 diabetes mellitus and cardiovascular [CV] disease). Regular exercise improves CV risk and insulin sensitivity; however, it is unknown whether chronic exercise training is related to circulating levels of fetuin-A. Therefore, this study examined whether plasma fetuin-A levels were related to age and chronic physical activity in men. We hypothesized that chronic physical activity would be related to lower plasma fetuin-A levels in younger and older men. In healthy high-active (HI) and low active (LO) young (HI, n = 7; LO, n = 8) and older (HI, n = 12, LO, n = 11) men, we determined cardiorespiratory fitness (maximal oxygen uptake), plasma fetuin-A levels, plasma insulin, insulin resistance (homeostasis model assessment of insulin resistance), and the standard risk factors for CV disease. Groups were matched for body mass index. Fetuin-A was significantly higher (~20%) in both young and older LO men compared with their HI counterparts, and fetuin-A was inversely related to maximal oxygen uptake (r = -0.40, P = .014). Plasma fetuin-A levels showed trends to be significantly correlated with insulin (r = -0.34, P = .052) and homeostasis model assessment of insulin resistance (r = 0.33, P = .058) in the older individuals. In younger participants, fetuin-A was related to blood pressure and cholesterol measures. These results indicate that low levels of fetuin-A are related to cardiorespiratory fitness and a number of conventional CV and metabolic disease risk factors independent of age and body mass index. Therefore, the maintenance of low levels of circulating fetuin-A may be a novel mechanism contributing to enhanced insulin sensitivity with regular physical activity. PMID- 20199783 TI - Venous blood gas and metabolite response to low-intensity muscle contractions with external limb compression. AB - The effect of low-intensity resistance exercise with external limb compression (100 [EC100] and 160 [EC160] mm Hg) on limb blood flow and venous blood gas metabolite response was investigated and compared with that of high-intensity resistance exercise (no external compression). Unilateral elbow flexion muscle contractions were performed at 20% (75 repetitions, 4 sets, 30-second rest intervals) and 70% of 1-repetition maximum (1-RM; 3 sets, each set was until failure, 3-minute rest intervals). Precontraction brachial arterial blood flow (Doppler ultrasound) was reduced with EC100 or EC160 (56% and 39% of baseline value, respectively) compared with no external compression (control). At 20% 1 RM, brachial arterial blood flow increased after contractions performed with EC160 (190%), but not with the others. Decreases in venous oxygen partial pressure (P(v)O(2)) and venous oxygen saturation (S(v)O(2)) were greater during EC100 and EC160 than control (mean [SE]: P(v)O(2), 28 [3] vs 26 [2] vs 33 [2] mm Hg; S(v)O(2), 41% [5%] vs 34% [4%] vs 52% [5%], respectively). Changes in venous pH (pH(v)), venous carbon dioxide partial pressure (P(v)CO(2)), and venous lactate concentration ([L(-)](v)) were greater with EC160 than EC100 and/or control (pH(v), 7.19 [0.01] vs 7.25 [0.01] vs 7.27 [0.02]; P(v)CO(2), 72 [3] vs 64 [2] vs 60 [3] mm Hg; [L(-)](v), 5.4 [0.6] vs 3.7 [0.4] vs 3.0 [0.4] mmol/L, respectively). Seventy percent 1-RM contractions resulted in greater changes in pH(v) (7.14 [0.02]), P(v)CO(2) (91 [5] mm Hg), and [L(-)](v) (7.0 [0.5] mmol/L) than EC100 and EC160, but P(v)O(2) (30 [4] mm Hg) and S(v)O(2) (40% [3%]) were similar. In conclusion, changes in pH(v), P(v)CO(2), and [L(-)](v), but not in P(v)O(2) and S(v)O(2), are sensitive to changes in relative, "internal" intensity of low-intensity muscle contractions caused by reduced blood flow (EC160) or high intensity muscle contractions. Given the magnitude of the changes in pH(v), P(v)CO(2), and [L(-)](v), it appears plausible that they may be involved in stimulating the observed increase in muscle activation via group III and IV afferents. PMID- 20199784 TI - Adiponectin is associated with abnormal lipid profile and coronary microvascular dysfunction in patients with dilated cardiomyopathy without overt heart failure. AB - Reduced plasma adiponectin has been associated with abnormal lipid profile, reduced left ventricle (LV) function, and the extent of coronary atherosclerosis in coronary artery disease. The aim of this study was to assess these relationships in patients with dilated cardiomyopathy (DCM) without overt heart failure. Plasma adiponectin was measured in 55 DCM patients (age, 59 +/- 12 years; male, 36; body mass index [BMI], 26.9 +/- 0.49 kg/m2; LV ejection fraction, 39.8% +/- 1.3%; New York Heart Association class I-II) and in 40 age- and BMI-matched healthy controls. In a subset of 25 patients, myocardial blood flow (MBF) was measured at rest and during intravenous dipyridamole (0.56 mg/kg in 4 minutes) by positron emission tomography and 13N-ammonia as a flow tracer. Adiponectin was 6.6 +/- 0.34 MUg/mL in controls and 10.9 +/- 0.85 MUg/mL in DCM patients (P < .001), where it was related inversely with BMI (P = .009) and directly with brain natriuretic peptide (P = .017), high-density lipoprotein (HDL) cholesterol (P = .002), and MBF dipyridamole (P = .020). Adiponectin lesser than median value in patients was associated with higher total to HDL cholesterol ratio (4.8 +/- 0.24 vs 3.9 +/- 0.18, P = .009) and lower MBF reserve (1.76 +/- 0.16 vs 2.43 +/- 0.19, P = .01). These results could suggest that down-regulation of the adiponectin levels and reduced HDL cholesterol have a key role in causing impaired coronary function and myocardial perfusion in DCM. PMID- 20199785 TI - The relationship between heat shock protein 72 expression in skeletal muscle and insulin sensitivity is dependent on adiposity. AB - Decreased gene expression of heat shock protein 72 (HSP72) in skeletal muscle is associated with insulin resistance in humans. We aimed to determine whether HSP72 protein expression in insulin-sensitive tissues is related to criterion standard measures of adiposity and insulin resistance in a young healthy human population free of hyperglycemia. Healthy participants (N = 17; age, 30 +/- 3 years) underwent measurement of body composition (dual-energy x-ray absorptiometry), a maximum aerobic capacity test (VO(2max)), an oral glucose tolerance test, and a hyperinsulinemic-euglycemic clamp (M) to access insulin sensitivity. Skeletal muscle and subcutaneous adipose tissue biopsies were obtained by percutaneous needle biopsy. HSP72 protein expression in skeletal muscle was inversely related to percentage body fat (r = -0.54, P < .05) and remained significant after adjustment for age and sex (P < .05). Insulin sensitivity was also related to HSP72 protein expression in skeletal muscle (r = 0.52, P < .05); however, this relationship disappeared after adjustment for percentage body fat (P = .2). In adipose tissue, HSP72 protein expression was not related to adiposity or insulin sensitivity. Physical activity and aerobic fitness did not show any association with HSP72 protein expression in either tissue studied. A lower expression of HSP72 protein in human skeletal muscle was associated with increased adiposity and decreased insulin sensitivity in healthy individuals. These findings are consistent with rodent data suggesting that HSP72 stimulates fat oxidation with consequent reduction in fat storage and adiposity. PMID- 20199786 TI - Improved endothelial function with simvastatin but unchanged insulin sensitivity with simvastatin or ezetimibe. AB - In addition to their expected effects on lipid profile, lipid-lowering agents may reduce cardiovascular events because of effects on nonclassic risk factors such as insulin resistance and inflammation. Ezetimibe specifically blocks the absorption of dietary and biliary cholesterol as well as plant sterols. Although it is known that an additional reduction of low-density lipoprotein cholesterol (LDL-C) levels can be induced by the combination of ezetimibe with statins, it is not known if this can enhance some pleiotropic effects, which may be useful in slowing the atherosclerotic process. This study assessed the effects of simvastatin and ezetimibe, in monotherapy or in combination, on markers of endothelial function and insulin sensitivity. Fifty prediabetic subjects with normo- or mild-to-moderate hypercholesterolemia were randomly allocated to 2 groups receiving either ezetimibe (10 mg/d) or simvastatin (20 mg/d) for 12 weeks, after which the drugs were combined for both groups for an additional 12 week period. Clinical and laboratory parameters were measured at baseline and after 12 and 24 weeks of therapy. Homeostasis model assessment of insulin resistance index and the area under the curve of insulin were calculated. As expected, both groups receiving drugs in isolation significantly reduced total cholesterol, LDL-C, apolipoprotein B, and triglyceride levels; and additional reductions were found after the combination period (P < .05). After 12 weeks of monotherapy, plasminogen activator inhibitor-1 levels and urinary albumin excretion were lower in the simvastatin than in the ezetimibe group. No change in homeostasis model assessment of insulin resistance index, area under the curve of insulin, and adiponectin levels was observed after either the monotherapies or the combined therapy. However, simvastatin combined with ezetimibe provoked significant reductions in E-selectin and intravascular cellular adhesion molecule 1 levels that were independent of LDL-C changes. Our findings support claims that simvastatin may be beneficial in preserving endothelial function in prediabetic subjects with normo- or mild-to-moderate hypercholesterolemia. Alternatively, a deleterious effect of ezetimibe on the endothelial function is suggested, considering the increase in intravascular cellular adhesion molecule-1 and E selectin levels. Simvastatin and ezetimibe, in isolation or in combination, do not interfere with insulin sensitivity. PMID- 20199787 TI - Metabolic classification of South American Ilex species by NMR-based metabolomics. AB - The genus Ilex to which mate (Ilex paraguariensis) belongs, consists of more than 500 species. A wide range of metabolites including saponins and phenylpropanoids has been reported from Ilex species. However, despite the previous works on the Ilex metabolites, the metabolic similarities between species which can be used for chemotaxonomy of the species are not clear yet. In this study, nuclear magnetic resonance (NMR) spectroscopy-based metabolomics was applied to the classification of 11 South American Ilex species, namely, Ilex argentina, Ilex brasiliensis, Ilex brevicuspis, Ilex dumosa var. dumosa, I. dumosa var. guaranina, Ilex integerrima, Ilex microdonta, I. paraguariensis var. paraguariensis, Ilex pseudobuxus, Ilex taubertiana, and Ilex theezans. (1)H NMR combined with principal component analysis (PCA), partial least square discriminant analysis (PLS-DA) and hierarchical cluster analysis (HCA) showed a clear separation between species and resulted in four groups based on metabolomic similarities. The signal congestion of (1)H NMR spectra was overcome by the implementation of two-dimensional (2D)-J-resolved and heteronuclear single quantum coherence (HSQC). From the results obtained by 1D- and 2D-NMR-based metabolomics it was concluded that species included in group A (I. paraguariensis) were metabolically characterized by a higher amount of xanthines, and phenolics including phenylpropanoids and flavonoids; group B (I. dumosa var. dumosa and I. dumosa var. guaranina) with oleanane type saponins; group C (I. brasiliensis, I. integerrima, I. pseudobuxus and I. theezans) with arbutin and dicaffeoylquinic acids, and group D (I. argentina, I. brevicuspis, I. microdonta and I. taubertiana) with the highest level of ursane-type saponins. Clear metabolomic discrimination of Ilex species and varieties in this study makes the chemotaxonomic classification of Ilex species possible. PMID- 20199788 TI - The ORF37 (UL24) is a neuropathogenicity determinant of equine herpesvirus 1 (EHV 1) in the mouse encephalitis model. AB - Equine herpesvirus 1 (EHV-1) bacterial artificial chromosome clone (Ab4p BAC) was established based on neuropathogenic strain Ab4p. ORF37 encoding UL24 was replaced with a selection cassette, rpsL-neo gene, to produce an ORF37 deletion mutant, Ab4pORF37. Transfection of RK-13 cells with Ab4pORF37 genome DNA produced infectious virus, indicating that ORF37 is not essential for EHV-1 replication in cell culture. Deletion of ORF37 had no effect on the transcript expression of neighboring genes, ORF36 and ORF38, and the growth activity in MDBK cells. Ab4pDeltaORF37 lost neuropathogenicity in CBA/N1 mice as indicated by the absence of any neurological disorders and death. The growth of Ab4pDeltaORF37 in cultivated neural cells was one order of magnitude lower than that of parental and revertant viruses. These results indicated that the ORF37 is a neuropathogenicity determinant of EHV-1 in the mouse encephalitis model. PMID- 20199789 TI - The DNA damage response to non-replicating adeno-associated virus: Centriole overduplication and mitotic catastrophe independent of the spindle checkpoint. AB - Adeno-associated virus (AAV) type 2 or UV-inactivated AAV (UV-AAV2) infection provokes a DNA damage response that leads to cell cycle arrest at the G2/M border. p53-deficient cells cannot sustain the G2 arrest, enter prolonged impaired mitosis, and die. Here, we studied how non-replicating AAV2 kills p53 deficient osteosarcoma cells. We found that the virus uncouples centriole duplication from the cell cycle, inducing centrosome overamplification that is dependent on Chk1, ATR and CDK kinases, and on G2 arrest. Interference with spindle checkpoint components Mad2 and BubR1 revealed unexpectedly that mitotic catastrophe occurs independently of spindle checkpoint function. We conclude that, in the p53-deficient cells, UV-AAV2 triggers mitotic catastrophe associated with a dramatic Chk1-dependent overduplication of centrioles and the consequent formation of multiple spindle poles in mitosis. As AAV2 acts through cellular damage response pathways, the results provide information on the role of Chk1 in mitotic catastrophe after DNA damage signaling in general. PMID- 20199790 TI - Redundancy in the immune system restricts the spread of HSV-1 in the central nervous system (CNS) of C57BL/6 mice. AB - Resistance to lethal encephalitis in mice infected with HSV-1 via the oral mucosa is mouse strain dependent. In susceptible BALB/c, HSV-1 spreads throughout the CNS but in resistant BL/6 mice, virus is restricted to the brainstem. To examine the contribution of cellular immunity in restricting viral spread, we used a combination of antibody depleted and KO mice. Individually, NK/NKT, iNKT, CD4(+), CD8(+), and gammadelta T-cells do not restrict HSV-1 spread. In contrast, virus spreads throughout the CNS of BL/6 CL I KO mice and BL/6 mice treated with either anti-asialoGM1 Ab or both anti-CD8 and anti-NK1.1 mAbs. The results highlight the importance of redundancy in the immune system in restricting viral spread in the CNS, argue for a role of NK/NKT and CD8(+) T-cells in mediating the restriction, and provide a hierarchical order of the individual elements in controlling virus in BL/6 mice infected with HSV-1 via the oral mucosa. PMID- 20199791 TI - Pilot treatment of olive pomace leachate by vertical-flow constructed wetland and electrochemical oxidation: an efficient hybrid process. AB - A hybrid process comprising biological degradation in a vertical-flow constructed wetland (CW) and electrochemical oxidation over boron-doped diamond electrodes to decolorize, mineralize and detoxify a leachate from olive pomace processing (OPL) was investigated. Two alternative treatment schemes were compared: According to the first treatment scheme, OPL was treated by electrochemical oxidation followed by treatment in a constructed wetland pilot unit (CW-A). The second scheme comprised of treatment in a constructed wetland followed by electrochemical treatment (CW-B). The constructed wetlands units were planted with Phragmites australis (reeds) and were fed intermittently at organic loadings between 5 and 15 g COD m(-2) d(-1) and a residence time of 3 d. Electrochemical oxidation (EO) was performed for 360 min at 20 A. Treatment of OPL in the wetland at 15 g COD m( 2) d(-1) led to mean COD and color reduction of 86% and 77%, respectively; the wetland effluent with a COD of about 800 mg L(-1) was polished electrochemically for 360 min after which the overall COD and color removal of the combined process (i.e. CW-B/EO) was around 95%, while the final effluent was not toxic against the marine bacteria Vibrio fischeri. Electrochemical oxidation of the original OPL at COD values between 6250 and 14 100 mg L(-1) led to moderate COD and color reduction (i.e. less than 40%) through zero order kinetics. When this was coupled to constructed wetland post-treatment (i.e. EO/CW-A), the overall COD and color removal was 81% and 58%, respectively. The decreased efficiency may be assigned to the increased toxicity of the electrochemically treated effluent which was only partially removed in the natural treatment system. PMID- 20199792 TI - The effect of free nitrous acid on the anabolic and catabolic processes of glycogen accumulating organisms. AB - Nitrite/Free Nitrous Acid (FNA) has previously been shown to inhibit aerobic and anoxic phosphate uptake by polyphosphate accumulating organisms (PAOs). The inhibitory effect of FNA on the aerobic metabolism of Glycogen Accumulating Organisms (GAOs) is investigated. A culture highly enriched (92+/-3%) in Candidatus Competibacter phosphatis (hereafter called Competibacter) was used. The experimental data strongly suggest that FNA likely directly inhibits the growth of Competibacter, with 50% inhibition occurring at 1.5 x 10(-3)mgN HNO(2)/L (equivalent to approximately 6.3 mgN-NO(2)(-)/L at pH 7.0). The inhibition is well described by an exponential function. The organisms ceased to grow at an FNA concentration of 7.1 x 10(-3) mgN-HNO(2)/L. At this FNA level, glycogen production, another anabolic process performed by GAOs in parallel to growth, decreased by 40%, while the consumption of polyhydroxyalkanoates (PHAs), the intracellular carbon and energy sources for GAOs, decreased by approximately 50%. FNA likely inhibited either or both of the PHA oxidation and glycogen production processes, but to a much less extent in comparison to the inhibition on growth. The comparison of these results with those previously reported on PAOs suggest that FNA has much stronger inhibitory effects on the aerobic metabolism of PAOs than on GAOs, and may thus provide a competitive advantage to GAOs over PAOs in enhanced biological phosphorus removal (EBPR) systems. PMID- 20199793 TI - Characterization of the degradation performance of the sulfamethazine antibiotic by photo-Fenton process. AB - The present study provides results describing the degradation performance of the Sulfamethazine (SMT) antibiotic via photo-Fenton treatment. Experiments were carried out using 1 L solution samples of SMT (50 mg L(-1)) under different conditions. HPLC results reveal that both Fenton and photo-Fenton reactions were able to completely remove SMT antibiotic from the studied samples in less than 2 min treatment. Half-life times and kinetic parameters (assuming a pseudo-first order kinetics at reaction initial stage, far from the equilibrium) for SMT degradation were determined and discussed. Hence, appropriate Fenton reagent loads are given to attain different targets proposed. TOC and HPLC data also revealed the presence of reaction intermediates; thus toxicity assays were performed regarding bacterial growth rate. The toxicity of an SMT solution was shown to increase during its degradation by means of photo-Fenton reactions. PMID- 20199794 TI - Comment on "using Bayesian statistics to estimate the coefficients of a two component second-order chlorine bulk decay model for a water distribution system" by Huang, J.J., McBean, E.A. Water Res. (2007). PMID- 20199795 TI - 1,4-Dioxane biodegradation at low temperatures in Arctic groundwater samples. AB - 1,4-Dioxane biodegradation was investigated in microcosms prepared with groundwater and soil from an impacted site in Alaska. In addition to natural attenuation conditions (i.e., no amendments), the following treatments were tested: (a) biostimulation by addition of 1-butanol (a readily available auxiliary substrate) and inorganic nutrients; and (b) bioaugmentation with Pseudonocardia dioxanivorans CB1190, a well-characterized dioxane-degrading bacterium, or with Pseudonocardia antarctica DVS 5a1, a bacterium isolated from Antarctica. Biostimulation enhanced the degradation of 50 mg L(-1) dioxane by indigenous microorganisms (about 0.01 mg dioxane d(-1) mg protein(-1)) at both 4 and 14 degrees C, with a simultaneous increase in biomass. A more pronounced enhancement was observed through bioaugmentation. Microcosms with 50 mg L(-1) initial dioxane (representing source-zone contamination) and augmented with CB1190 degraded dioxane fastest (0.16 +/- 0.04 mg dioxane d(-1) mg protein(-1)) at 14 degrees C, and the degradation rate decreased dramatically at 4 degrees C (0.021 +/- 0.007 mg dioxane d(-1) mg protein(-1)). In contrast, microcosms with DVS 5a1 degraded dioxane at similar rates at 4 degrees C and 14 degrees C (0.018 +/- 0.004 and 0.015 +/- 0.006 mg dioxane d(-1) mg protein(-1), respectively). DVS 5a1 outperformed CB1190 when the initial dioxane concentration was low (500 microg L(-1), which is representative of the leading edge of plumes). This indicates differences in competitive advantages of these two strains. Natural attenuation microcosms also showed significant degradation over 6 months when the initial dioxane concentration was 500 microg L(-1). This is the first study to report the potential for dioxane bioremediation and natural attenuation of contaminated groundwater in sensitive cold-weather ecosystems such as the Arctic. PMID- 20199796 TI - Phosphorylation of thymidylate synthase from various sources by human protein kinase CK2 and its catalytic subunits. AB - Thymidylate synthase (TS) was found to be a substrate for both catalytic subunits of human CK2, with phosphorylation by CK2alpha and CK2alpha' characterized by similar K(m) values, 4.6microM and 4.2microM, respectively, but different efficiencies, the apparent turnover number with CK2alpha being 10-fold higher. With both catalytic subunits, phosphorylation of human TS, like calmodulin and BID, was strongly inhibited in the presence of the regulatory subunit CK2beta, the holoenzyme being activated by polylysine. Phosphorylation of recombinant human, rat, mouse and Trichinella spiralis TSs proteins was compared, with the human enzyme being apparently a much better substrate than the others. Following hydrolysis and TLC, phosphoserine was detected in human and rat, and phosphotyrosine in T. spiralis, TS, used as substrates for CK2alpha. MALDI-TOF MS analysis led to identification of phosphorylated Ser(124) in human TS, within a sequence LGFS(124)TREEGD, atypical for a CK2 substrate recognition site. The phosphorylation site is located in a region considered important for the catalytic mechanism or regulation of human TS, corresponding to the loop 107-128. Following phosphorylation by CK2alpha, resulting in incorporation of 0.4mol of phosphate per mol of dimeric TS, human TS exhibits unaltered K(m) values for dUMP and N(5,10)-methylenetetrahydrofolate, but a 50% lower turnover number, pointing to a strong influence of Ser(124) phosphorylation on its catalytic efficiency. PMID- 20199797 TI - Residues of persistent organic pollutants (POPs) in human milk in Hong Kong. AB - Data on pesticide body load in the south China region are scarce. Here, we report the concentrations of 24 persistent organic pollutants (POPs), in 10 pools of human milk samples, collected at 2-6weeks postpartum from 238 primiparous women living in Hong Kong and south China, who participated in the 2002-2003 WHO exposure study. Residues were determined by gas chromatography with electron capture detector and confirmed by gas chromatography with mass spectrometry. The mean levels of alpha-HCH (mean 0.6ngg(-1) fat), beta-HCH (940ngg(-1) fat), gamma HCH (1.8ngg(-1) fat), dieldrin (1.0ngg(-1) fat) and HCB (21.8ngg(-1) fat) were much lower than the 1985 estimates. Mean levels of alpha-HCH, gamma-HCH, dieldrin, cis-heptachlor-epoxide (0.7ngg(-1) fat), sum-chlordane (6.1ngg(-1) fat), trans-nonachlor (12.0ngg(-1) fat), BDE 47 (1.9ngg(-1) fat) and sum PBDE (3.4ngg(-1) fat) were comparable to the international median levels of the 15 other countries participating in the 2002-03 WHO exposure study. Hong Kong had the highest level of beta-HCH, possibly a residual effect of previous high exposures in the 1970s. Body loads of beta-HCH and chlordane were lower among mothers with younger age while mothers born in mainland China had lower levels of beta-HCH, cis-heptachlor-epoxide, oxy-chlordane and trans-nonachlor. Levels of toxaphene, endrin, endosulfan, bromcyclene and nitrofen were not detected in all or almost all of the milk pools. Continuous monitoring of POPs in human milk, especially beta-HCH, is needed for surveillance and interpretation of time trends, and for linkage to strict enforcement of agricultural regulations. PMID- 20199798 TI - Development of a biodegradation model for the prediction of metabolites in soil. AB - The awareness of air, soil and water pollution has driven the search for better methods for the assessment of the environmental fate of industrial chemicals. This paper is focused on the simulation of formation and transformation of metabolites in soil. The key challenges in the development of a simulator for predicting metabolic fate of chemicals in soil are the complexity of the soil compartment and incompleteness of metabolic information. Based on the collected data for metabolic fate of 183 chemicals a set of soil specific transformations were defined and used to develop a simulator for metabolism in soil. The analysis of outliers showed that the low predictability for some chemicals is due to: 1) incomplete documented metabolic pathways with missing intermediates and/or 2) reactions of condensation that are not simulated in the current version of the model. Hence, further improvement of the model requires expanding the metabolism database and further refinement of the logic of metabolic transformations used in the simulator. PMID- 20199799 TI - Mass balance soil ingestion estimating methods and their application to inhabitants of rural and wilderness areas: a critical review. AB - Quantitative soil ingestion studies employing a mass balance tracer approach have been used to provide a defensible means to estimate soil ingestion for human health risk assessments. Past studies have focused on soil ingestion in populations living in urban/suburban environments. There is a paucity of reliable quantitative soil ingestion data to support human health risk assessments of other lifestyles that may be predisposed to ingesting soil, such as agricultural workers or indigenous populations following traditional lifestyles. The results of a preliminary analysis of sampling and analytical variability that would result from assessing activities typical of populations in rural or wilderness areas and conducted over wide areas show that approximately 225 subject days would be required to detect a difference of 20mg/d in soil ingestion. Given the typically small populations in these areas, future soil ingestion studies should be focused on specific activities with a high potential for soil ingestion. PMID- 20199801 TI - Postnatal development of interstitial cells of Cajal in mouse colon in response to Kit signal blockade with Imatinib (Glivec). AB - This study investigated the response of interstitial cells of Cajal (ICC) in postnatal mouse colon to treatment with Imatinib (Glivec), a potent inhibitor of Kit receptor). ICC were revealed by immunofluorescent staining on frozen cross sections and whole-mount preparations by anti-Kit and DOG1 antibodies. Kit and p Kit protein were also evaluated by Western blot. After administration of Imatinib for 4 days beginning at 8 days post-partum (P8), the mean density of Kit+ ICC, which were localized around the myenteric nerve plexus (ICC-MY), within smooth muscle layers (ICC-IM) and in the connective tissue beneath the serosa (ICC-SS), was dramatically decreased to about 50% when compared with controls, but those Kit+ cells located at the submucosal border of circular smooth muscle layer (ICC SM) seemed to be unchanged in both cell number and morphology. A small number of DOG1+/Kit(-) cells appeared during Imatinib administration. However, these Kit+ ICC were not changed in mice even after 12 days of Imatinib treatment from P24. When Imatinib was discontinued, the number of ICC recovered to normal within 4 days. Our results indicate that the postnatal development of ICC in the mouse colon is Kit dependent, but ICC-SM are unlikely, and the Kit dependence of ICC development is also age-dependent. PMID- 20199800 TI - A glycobiology review: carbohydrates, lectins and implications in cancer therapeutics. AB - This review is intended for general readers who would like a basic foundation in carbohydrate structure and function, lectin biology, and the implications of glycobiology in human health and disease, particularly in cancer therapeutics. These topics are among the hundreds included in the field of glycobiology and are treated here because they form the cornerstone of glycobiology or the focus of many advances in this rapidly expanding field. PMID- 20199802 TI - Clinicopathologic features of bone metastases and outcomes in patients with primary endometrial cancer. AB - OBJECTIVE: Patients with advanced or recurrent endometrial cancer often have distant metastases found within the lymph nodes, liver, and/or lung. However, there have been reported cases of primary endometrial cancer with metastasis to the bone. The objective of this study was to describe the clinical and pathologic features of endometrial cancer metastatic to bone. METHODS: A retrospective chart review of our clinical and pathology database was performed to identify women diagnosed with endometrial cancer metastatic to the bone between 1990 and 2007. Clinical data and outcomes were obtained from medical records. Slides were re reviewed to confirm the diagnosis. RESULTS: Twenty-one patients with endometrial cancer metastatic to the bone were identified; in 12 patients (57%), the diagnosis was confirmed by a bone biopsy. The median age of diagnosis of primary endometrial cancer was 60 years (range, 32-84). Fourteen patients (67%) had FIGO stage III/IV disease. Six patients (29%) had a bone metastasis at the time of diagnosis while 15 patients (71%) had a bone lesion as a recurrence. The median time to a diagnosis of bone metastasis recurrence was 10 months (range, 3-148). The overall survival of those patients with bone metastases at primary diagnosis was 17 months (95% CI: 2-32) compared to 32 months (95% CI: 14-49) for those with a recurrent bone metastasis. CONCLUSION: Although a rare event, endometrial cancer can metastasize to the bone. If a bone lesion is identified, treatment using a multimodality approach is reasonable, especially if found as an isolated recurrence. PMID- 20199803 TI - Genetic variation in CYP11A1 and StAR in relation to endometrial cancer risk. AB - OBJECTIVE: Together, steroidogenic acute regulator (StAR) and the cholesterol side chain cleavage enzyme (P450scc), which is encoded by CYP11A1, mediate the initial and rate-limiting step in steroidogenesis. Given the role of estrogens in endometrial carcinogenesis, we hypothesized that genetic variation in StAR and CYP11A1 genes may influence endometrial cancer risk. METHODS: We genotyped four CYP11A1 tagging single nucleotide polymorphisms (SNPs) and two StAR SNPs in endometrial cancer case-control studies nested within the Nurses' Health Study (553 cases and 1339 controls) and the Women's Health Study (137 cases and 411 controls). We calculated odds ratios and 95% confidence intervals using conditional and unconditional logistic regression adjusted for endometrial cancer risk factors to examine the association between SNPs/haplotypes and endometrial cancer. RESULTS: We observed an increased risk for women carrying the variant allele for rs4555110 (odds ratio (OR)=1.3, 95% confidence interval (CI)=1.1-1.7), rs3825944 (OR=1.4, 95% CI=1.1-1.8), and rs7173655 (OR=1.3, 95% CI=1.0-1.7) CYP11A1 SNPs but no significant associations with CYP11A1 haplotypes. CYP11A1 SNPs were not predictive of plasma estradiol levels. We observed no associations between StAR SNPs and endometrial cancer risk. CONCLUSIONS: Genetic variants in CYP11A1 may influence endometrial cancer risk or may be markers for causal variants elsewhere. Polymorphisms in StAR are not associated with endometrial cancer risk, but further research is needed. PMID- 20199804 TI - Prevalence and distribution of human papillomavirus types in cervical cancer, squamous intraepithelial lesions, and with no intraepithelial lesions in women from Southern Mexico. AB - OBJECTIVE: This study was to establish the frequency of HPV infection and which HPV types are circulating in women with cervical cancer (CC), with squamous intraepithelial lesions (SIL), and with no intraepithelial lesion (non-IL) from the State of Guerrero in Southern Mexico. Additionally, we investigated the frequency and distribution of HPV 16 intratypic variants found in this population. METHODS: This cross-sectional study was conducted in 4150 women who attended five public health centers seeking cytological screening or for gynecological complaints. Pap smears or biopsies, as appropriate, were obtained for cytological and/or histological diagnosis. HPV detection was done by MY09/11 and GP5+/GP6+ PCR systems and typing by restriction fragment length polymorphism or DNA sequencing. HPV 16 variants were also analyzed. RESULTS: HPV was found in 100% of CC, 83.5% in HSIL, 94.5% in LSIL, and 40.9% in non-IL. HR-HPV was the most frequent in all groups. HPV 16 was the most commonly identified HPV genotype in CC and HSIL. HPV 33 was the most frequent in LSIL and non-IL. The highest HPV prevalence was found in the youngest women, HR-HPV and HPV 16 were more frequent in women less than 25 years and more than 55 years of age. The HPV 16 variants E, AA-a and AA-c were found, AA-c was found only in CC. CONCLUSION: This study contributes to the knowledge of regional prevalence of HPV types in the whole spectrum of disease, which can be useful in the application of prophylactic vaccines against HPV and in the viral screening methods. PMID- 20199805 TI - Vocal learning in Grey parrots: A brief review of perception, production, and cross-species comparisons. AB - This chapter briefly reviews what is known-and what remains to be understood about Grey parrot vocal learning. I review Greys' physical capacities-issues of auditory perception and production-then discuss how these capacities are used in vocal learning and can be recruited for referential communication with humans. I discuss cross-species comparisons where applicable and conclude with a description of recent research that integrates issues of reference, production and perception. PMID- 20199806 TI - PHBV microspheres--PLGA matrix composite scaffold for bone tissue engineering. AB - Polymer scaffolds, particularly in the form of microspheres, have been employed to support cells growth and deliver drugs or growth factors in tissue engineering. In this study, we have established a scaffold by embedding poly (beta-hydroxybutyrate-co-beta-hydroxyvalerate) (PHBV) microspheres into poly (L lactic-co-glycolic acid) (PLGA) matrix, according to their different solubility in acetone, with the aim of repairing bone defects. PLGA/PHBV scaffolds had good pore parameters, for example, the porosity of PLGA/30% PHBV scaffold can reach to 81.273 +/- 2.192%. Besides, the pore size distribution of the model was evaluated and the results revealed that the pore size mainly distributed between 50 mum and 200 mum. With increasing the amount of PHBV microspheres, the compressive strength of the PLGA/PHBV scaffold enhanced. The morphology of the hybrid scaffold was rougher than that of pure PLGA scaffold, which had no significant effect on the cell behavior. The in vitro evaluation suggested that the model is suitable as a scaffold for engineering bone tissue, and has the potential for further applications in drug delivery system. PMID- 20199807 TI - Decontamination of chemical and biological warfare agents with a single multi functional material. AB - We report the synthesis of new polymers based on a dimethylacrylamide methacrylate (DMAA-MA) co-polymer backbone that support both chemical and biological agent decontamination. Polyurethanes containing the redox enzymes glucose oxidase and horseradish peroxidase can convert halide ions into active halogens and exert striking bactericidal activity against gram positive and gram negative bacteria. New materials combining those biopolymers with a family of N alkyl 4-pyridinium aldoxime (4-PAM) halide-acrylate co-polymers offer both nucleophilic activity for the detoxification of organophosphorus nerve agents and internal sources of halide ions for generation of biocidal activity. Generation of free bromine and iodine was observed in the combined material resulting in bactericidal activity of the enzymatically formed free halogens that caused complete kill of E. coli (>6 log units reduction) within 1 h at 37 degrees C. Detoxification of diisopropylfluorophosphate (DFP) by the polyDMAA MA-4-PAM iodide component was dose-dependent reaching 85% within 30 min. A subset of 4-PAM halide co-polymers was designed to serve as a controlled release reservoir for N hydroxyethyl 4-PAM (HE 4-PAM) molecules that reactivate nerve agent-inhibited acetylcholinesterase (AChE). Release rates for HE 4-PAM were consistent with hydrolysis of the HE 4-PAM from the polymer backbone. The HE 4-PAM that was released from the polymer reactivated DFP-inhibited AChE at a similar rate to the oxime antidote 4-PAM. PMID- 20199808 TI - An in vitro regenerated functional human endothelium on a nanofibrous electrospun scaffold. AB - The capacity of the luminal layer of an electrospun bi-layer scaffold composed of gelatin, elastin, polycaprolactone (PCL), and poliglecaprone (PGC) to promote endothelial regeneration was investigated using human aortic endothelial cells (HAECs). HAECs of different densities were cultured on a thin film of the luminal layer of the scaffold mounted on a cell crown for desired periods. Fluorescent images showed that HAECs formed a mono-layer within 24 h after having successfully adhered to the scaffold's surface. Scanning electron microscopy (SEM) revealed a satisfactory coverage by the HAECs. Death rates of HAECs populations determined by fluorescent staining were below 5% within the initial 3 days while the profile of proliferation exhibited an exponential increase within 11 days as determined by the 3-[4,5-dimethyl(thiazol-2yl)-3,5-diphery] tetrazolium bromide (MTT) assay. The functionalities of the endothelial mono layer were probed by ZO-1 staining for tight junction formation, by 6-keto PGF(1alpha) assay for prostacyclin (PGI(2)) secretion, and by human platelets for its anti-thrombotic capability. The results indicated that the regenerated endothelium possessed normal functions associated with native endothelium. This study suggests that this electrospun bi-layer scaffold is a promising candidate for cardiovascular grafting for its capability of promoting the regeneration of a functional endothelium to prevent blood clotting in small diameter grafts. PMID- 20199809 TI - The role of three-dimensional polymeric scaffold configuration on the uniformity of connective tissue formation by adipose stromal cells. AB - To form tissues with uniform cell distribution and extracellular matrix arrangement is of great relevance to obtain the desirable function and maintain structural integrity. Scaffold configuration is believed to play a critical role in regulating cell spatial distribution and consequently tissue formation. In this study, three types of poly(ethyleneglycol-terephthalate)-poly (butylenes terephthalate) (PEGT/PBT) scaffolds [compression molded scaffold (CM), compression molded scaffold after chloroform/isopropanol reticulation (CMR), 3D rapid prototyped fibrous scaffold (RP)] with various configurations were used to support the tissue formation of adipose stromal cells for up to 21 days. Characterization of the scaffolds with muCT revealed that RP scaffolds were composed of repeating structural units with well controlled interconnected pores, in contrast to the irregular pore morphology in CM or CMR. Cell seeding efficacy onto various scaffolds was comparable (from 67 +/- 4% to 82 +/- 3%), while only RP scaffold led to even cell attachment onto the inner fibers of the scaffolds. Continuous cell proliferation and deposition of new collagen and glycosaminoglycans (GAG) were measured for all three scaffolds, while with a significant amount measured in RP at 21 days. By 21 days, complete uniform tissue formation was only achieved in RP scaffolds under a dynamic cell culture in spinner flasks. The present study successfully demonstrates the feasibility of controlling uniform tissue formation at a microscale by manipulating the structural configuration of the scaffold. PMID- 20199810 TI - The proliferation and differentiation of placental-derived multipotent cells into smooth muscle cells on fibrillar collagen. AB - Type I collagen constitutes a major portion of the extracellular matrix (ECM) in arterial wall and it is the major substrate for cell growth and differentiation. The goal of this study was to evaluate the differentiation and proliferation of placenta-derived multipotent cells (PDMCs) on polymerized type I collagen fibrils and monomer collagen. PDMCs grown on both polymerized collagen and monomer collagen with transforming growth factor (TGF)-beta treatment increases the expression of smooth muscle cell (SMC)-specific markers, including calponin, alpha-smooth muscle actin (alpha-SMA) and smooth muscle-myosin heavy chain (SM MHC). Polymerized collagen increased the expressions of p21(CIP1) and p27(KIP1); decreased cyclin A, cyclin D1, cyclin-dependent protein kinase 2 (Cdk2); and led to G(0)/G(1) arrest in PDMCs. Furthermore, PDMC-differentiated SMCs exhibited significant collagen contractility in the presence or absence of endothelin-1 (ET 1) stimulation. By using specific inhibitors and small interfering RNA (siRNA), we demonstrated that p38 MAPK pathway and serum response factor (SRF)-DNA binding activity is critical for the polymerized collagen-induced PDMC differentiation into SMCs. Thus, polymerized collagen exhibits the great potential in inducing PDMCs differentiation into SMCs, and exerts anti-proliferative effect on PDMC differentiated SMCs. PMID- 20199811 TI - Implicit and explicit behavioral tendencies in male and female depression. AB - Emotional facial expressions are the most salient cues in social life. Successful social interaction is based on correct recognition, interpretation and appropriate reaction to these cues. However, social skill deficits are among the most debilitating symptoms of depression, leading to social withdrawal and aggravating the disorder in various domains. We used an implicit joystick task to measure automatic behavioral tendencies in response to evoked facial expressions (anger, fear, sadness, happiness and neutral). Additionally, we implemented a rating procedure to assess explicit approach and avoidance reactions to these social stimuli. Our sample consisted of 24 depressed patients and 24 healthy controls. Data analysis indicated that depressed patients appear to understand the expression depicted on the emotional faces but react differently to these social cues. Female patients displayed stronger avoidance tendencies in the explicit condition whereas social withdrawal was less pronounced in the implicit condition. Our data suggest that a cognitive bias negatively influences the unimpaired automatic reactions to emotional expressions in depressed patients, and this bias may result in the characteristic social withdrawal. PMID- 20199812 TI - Emotional functioning of individuals with borderline personality traits in a nonclinical population. AB - Relatively few studies have evaluated the emotional functioning of individuals with borderline personality disorder traits, especially in nonclinical populations. This study therefore sought to understand further the emotional skills and subjective emotional experiences of adults with borderline traits in a community sample. Adult volunteers (N=523) were recruited from community and student populations, and borderline personality was determined via three self report measures. Close to one in six respondents (17.2%) self-reported borderline personality traits above the threshold on the three instruments. Poor skills in managing and understanding emotion were characteristic of these individuals. They also possessed significantly poorer subjective perception of emotion, management of their own emotions and management of others' emotions, relative to the non borderline personality controls. Skills in managing and understanding emotion and the subjective experience of managing one's own emotions were significant multivariate predictors of borderline personality trait status. We conclude that persons with borderline personality traits have pronounced deficits in emotional understanding and management. Interventions targeting these deficits are needed, given the high prevalence of borderline traits in the community. PMID- 20199813 TI - Changes in weight and body mass index during treatment with melperone, clozapine and typical neuroleptics. AB - Melperone is an atypical antipsychotic drug that has been reported to be effective in treatment-resistant schizophrenia and L-DOPA psychosis. There are limited data concerning its effect on weight or body mass index (BMI). Weight and BMI were retrospectively compared in patients with schizophrenia treated with melperone (n=34), clozapine (n=225), or typical neuroleptics (n=74) for up to 3 months. Clozapine resulted in significant increases in weight and BMI from baseline to 6 weeks and 3 months. Neither melperone nor typical neuroleptics resulted in significant weight gain at either time point. Melperone did not result in significant increases in BMI. Weight and BMI were significantly lower with melperone compared with clozapine, but similar to typical neuroleptics. The proportion of melperone patients who experienced a >or=7% weight increase was lower than that in patients treated with clozapine and similar to that in patients treated with typical neuroleptics. Percent change in weight and BMI predicted improvement in BPRS total scores at 3 months in the clozapine group, but not in the melperone or typical neuroleptic groups. Because of the relationship between BMI and cardiovascular risk, melperone deserves further study as both a first line treatment and as an alternative to clozapine in refractory schizophrenia. PMID- 20199814 TI - The effect of an educational leaflet on depressive patients' attitudes toward treatment. AB - Improving patient adherence to antidepressant treatment is an important issue. Patients' attitudes toward symptoms, results, causes, disease course, and effective treatment of depression can influence their adherence to therapy. We aimed to assess the efficacy of an educational leaflet designed to improve patients' attitudes toward depression and antidepressant treatment. Participants were one hundred twenty-two outpatients of three psychiatric clinics in Japan who met the DSM-IV criteria for depression. Patients in the intervention group received an educational leaflet at the start of the study. Participants filled in The Antidepressant Compliance Questionnaire (ADCQ) and Beck Depression Inventory (BDI) before and after the intervention. Intervention group showed greater improvements on the total score of ADCQ, the score on the "positive beliefs regarding antidepressants" subscale. They maintained the scores on the "perceived doctor-patient relationship" subscale, where the control group lowered those scores. No significant difference in improvement in BDI scores was observed between groups. The intervention using an educational leaflet had a significant positive impact on patients' attitudes toward depression and antidepressant treatment. Our results indicate that the educational leaflet is an effective tool for enhancement of face-to-face education by medical professionals. Trial registration UMIN000002981, www.umin.ac.jp/ctr/index.htm. PMID- 20199815 TI - The effect of intravenous administration of erythropoietin on the infarct size in primary percutaneous coronary intervention. AB - BACKGROUND: After an acute myocardial infarction, the early restoration of coronary blood flow is mandatory for reducing infarct size. However, the process of reperfusion itself may also cause irreversible myocardial injury and contribute to the final infarct size. Recent animal studies have suggested that erythropoietin could protect the myocardium when administered after the onset of reperfusion. We investigated whether the administration of erythropoietin at the time of PCI would limit the size of the infarct during acute myocardial infarction by analysis of MRI and cardiac enzymes in this pilot study. METHODS: We randomly assigned 57 patients with acute, anterior wall ST-elevation myocardial infarction who were presented within 12h after the onset of chest pain to one group which was given an intravenous bolus of recombinant human erythropoietin (rhEPO, 50 U/kg) immediately before undergoing PCI or the control group without the IV treatment before PCI. Infarct size was assessed by measuring the release of cardiac enzymes (CK, CK-MB) and by performing MRI on day 4 after infarction. RESULTS: The injection of erythropoietin did not result in thrombotic or hypertensive complications. The release of cardiac enzyme was not different between two groups. On day 4, the absolute infarct volume of the area of hyperenhancement on MRI did not differ between two groups (EPO group 52.4 +/- 23.6 cm(3) vs. control group 54.8 +/- 28.6 cm(3), p=0.74). Two groups did not differ in the percentage of total infarct volume over left ventricle volume (EPO group 34.4 +/- 11.7% vs. 37.0 +/- 13.8%, p=0.50). CONCLUSIONS: Intravenous administration of erythropoietin was safe and was not associated with thrombotic or hypertensive side effects. However, it did not reduce the infarct size when assessed by MRI and cardiac enzyme. Further studies about the dose or routes of administration of EPO are needed (ClinicalTrials.gov Identifier NCT00882466). PMID- 20199816 TI - Biodistribution of bone marrow mononuclear cells in chronic chagasic cardiomyopathy after intracoronary injection. AB - BACKGROUND: Animal and human clinical studies have indicated that bone marrow (BM) mononuclear cell (MNC) therapy for Chagasic Cardiomyopathy (ChC) is feasible, safe and potentially efficacious. Nevertheless, little is known about the retention of these cells after intracoronary (IC) infusion. METHODS: Our study investigated the homing of technetium-99m ((99m)Tc) labeled BM MNCs and compared it to thallium-201 ((201)Tl) myocardial perfusion images using the standard 17-segment model. Six patients with congestive heart failure of chagasic etiology were included. RESULTS: Scintigraphic images revealed an uptake of 5.4%+/-1.7, 4.3%+/-1.5 and 2.3%+/-0.6 of the total infused radioactivity in the heart after 1, 3 and 24h, respectively. The remaining activity was distributed mainly to the liver and spleen. Of 102 segments analyzed, homing took place in 36%. Segments with perfusion had greater homing (58.6%) than those with decreased or no perfusion (6.8%), p<0.0001. There was no correlation between the number of injected cells and the number of segments with homing for each patient (r=-0.172, p=0.774). CONCLUSIONS: These results indicate that (99m)Tc-BM MNCs delivered by IC injection homed to the chagasic myocardium. However, cell biodistribution was heterogeneous and limited, being strongly associated with the myocardial perfusion pattern at rest. These initial data suggest that the IC route may present limitations in chagasic patients and that alternative routes of cell administration may be necessary. PMID- 20199817 TI - Asymptomatic left ventricular dysfunction in puerperal women: an echocardiographic-based study. AB - BACKGROUND: Peripartum cardiomyopathy is a rare but significant cause of maternal morbidity and mortality. Identification of silent forms of ventricular dysfunction associated with the peripartum period is challenging, yet necessary to establish specific counseling and therapeutic measures to prevent progression to overt heart failure. Our aims were to determine the prevalence of asymptomatic left ventricular systolic dysfunction in puerperium and compare its progression with that of cases of peripartum cardiomyopathy occurring in the same study period. METHODS: Cross-sectional study conducted from September 2002 to April 2005 to determine by echocardiography the prevalence of asymptomatic ventricular dysfunction in early puerperium and a nested cohort study from November 2007 to January 2008 to obtain clinical and echocardiography follow-up data of positively screened patients. All clinically diagnosed cases of peripartum cardiomyopathy occurring in the same study period were also examined. RESULTS: We screened 1182 puerperal women; ten cases (0.85%) of asymptomatic ventricular dysfunction were detected characterized by either decreased left ventricular systolic function and/or increased end-diastolic diameter. Incidence of peripartum cardiomyopathy was 6 cases/10,866 deliveries (1/1811 live births) in the same period. An echocardiogram-based follow-up study performed after a mean of 4.0years (2.9 5.2years), showed significant and similar improvement in parameters of left ventricular function in both groups (p>0.05). CONCLUSIONS: Asymptomatic left ventricular dysfunction in puerperal women shows a high prevalence and a pattern of long term echocardiographic changes similar to those found in overt peripartum cardiomyopathy. PMID- 20199818 TI - Multiinstitutional study on target volume delineation variation in breast radiotherapy in the presence of guidelines. AB - PURPOSE: This study aims to determine magnitude, causes and consequences of post operative breast tumour target volume delineation variation among radiation oncologists in the presence of guidelines. MATERIALS AND METHODS: Excision cavities, CTVs and PTVs of eight breast cancer patients were delineated on CT scans by 13 Dutch radiation oncologists (observers) from 12 Dutch institutes participating in the international Young Boost Trial. Delineated volumes and conformity indices were determined. CTV delineation variation (SD) was determined for anatomically relevant regions. Non-parametric statistics were performed to establish effects of observers, patient characteristics and regions on delineation variation. RESULTS: Even in the presence of delineation guidelines considerable delineation variation is present (0.24=2, >=2.5, >=3, >=3.5 (SUV(n)); >=40%, >=45%, and >=50% of the maximum (SUV(n%)); and mean liver SUV + 1, 2, 3, and 4 standard deviations (SUV(Lnsigma)). The volume ratio and conformality index were determined between MTVs, and the corresponding CT/endoscopic ultrasound-based gross tumor volume (GTV) at the epicenter. Means were analyzed by one-way analysis of variance for repeated measures and further compared using a paired t test for repeated measures. RESULTS: The mean conformality indices ranged from 0.33 to 0.48, being significantly (p < 0.05) closest to 1 at SUV(2.5) (0.47 +/- 0.03) and SUV(L4sigma) (0.48 +/- 0.03). The mean volume ratios ranged from 0.39 to 2.82, being significantly closest to 1 at SUV(2.5) (1.18 +/- 0.36) and SUV(L4sigma) (1.09 +/- 0.15). The mean value of the SUVs calculated using the SUV(L4sigma) approach was 2.4. CONCLUSIONS: Regardless of the SUV thresholding method used (i.e., absolute or relative to liver mean), a threshold of approximately 2.5 yields the highest conformality index and best approximates the CT-based GTV at the epicenter. These findings may ultimately aid radiation oncologists in the delineation of the entire GTV in esophageal cancer patients. PMID- 20199851 TI - Combined vertebral fracture assessment and bone mineral density measurement: a patient-friendly new tool with an important impact on the Canadian Risk Fracture Classification. AB - PURPOSE: Vertebral fractures often go unnoticed, while they constitute a significant risk factor for new fractures, independent of the bone density. Vertebral Fracture Assessment (VFA) is a new feature on DXA bone densitometry equipment. Our purpose was to determine the added value of VFA and its impact on the Canadian fracture risk classification using data from a Dutch academic cohort. METHODS: All 958 consecutive patients (64% female, mean age 53 [20-94], mean weight 75 kg [32-150]) who underwent BMD measurement at the University Medical Center Groningen, The Netherlands also underwent VFA in the same session. RESULTS: The prevalence of vertebral fractures was 26%. In 68% of these patients this fracture was unknown. The severity was "mild" (20%-25% height loss) in 43%, "moderate" (25%-35%) in 44% and "severe" (>35% height loss) in 13%. Even after excluding mild fractures, the prevalence of vertebral fractures was 17%. In the 28% with normal BMD the vertebral fracture prevalence was still 18%, in the 43% with osteopenia 23%, and in the 29% with osteoporosis 36%. The Canadian risk classification was "low fracture risk" in 68%, "moderate" in 19%, and "high" in 13%. Adding VFA altered the classification in 20% of the patients, to become 54%, 27%, and 19%, respectively. CONCLUSIONS: VFA added to BMD is a patient friendly diagnostic tool with a high diagnostic yield, as it detected unknown vertebral fractures and altered diagnostic classification in approximately 1 out of every 5 patients. These results suggest that BMD plus VFA may become the new standard in osteoporosis testing. PMID- 20199852 TI - Paraneoplastic Raynaud's phenomenon--good palliation after a multidisciplinary approach. AB - Paraneoplastic Raynaud's phenomenon is a rare complication of a number of different malignancies (carcinomas, sarcomas, lymphomas, and leukemias). We present a case of paraneoplastic Raynaud's phenomenon in a patient with non-small cell lung cancer that was associated with significant morbidity, involved a multidisciplinary approach, and eventually responded to a specialized intervention (i.e., iloprost trometamol). PMID- 20199853 TI - Impaired off-line memory consolidation in depression. AB - Sleep is critically involved in the consolidation of procedural memory. In major depression (MD) and during antidepressant pharmacotherapy, changes in sleep EEG are well documented. Here, we test if off-line motor memory consolidation is impaired in MD. 50 medicated patients with an acute episode of MD, 50 normal controls and 12 patients with a remitted episode of MD were assessed using a sequential finger tapping task before and after a night of sleep. Although depressed patients and control subjects did not differ in practice-dependent learning, healthy subjects showed markedly overnight improvements in tapping performance of 18% while patients failed to show any improvement. This pattern became even more striking when the subjects were divided by an age threshold of 30years: In the 30+yrs group the healthy subjects showed 16% overnight increase in motor performance, whereas the patients showed -10% overnight decrease. In contrast, patients and controls in the 6)-linked backbone with a single beta-d-fructose at the C-1 position every seven residue, on average, along the main chain. Preliminary in vitro tests revealed that EPS could significantly stimulate the proliferation of spleen lymphocyte. PMID- 20199861 TI - Evaluation of allelopathic, decomposition and cytogenetic activities of Jasminum officinale L. f. var. grandiflorum (L.) Kob. on bioassay plants. AB - Methanolic extracts prepared from dried leaves of Jasminum officinale f. var. grandiflorum (L.) Kob. (Spanish jasmine) inhibited seed germination and stunted both root and shoot length of the weeds Echinochloa crus-galli (L.) Beauv. and Phaseolus lathyroides L. The main active compound was isolated and determined by spectral data as a secoiridoid glucoside named oleuropein. In addition, a decrease in allelopathic efficacy appeared as the decomposition periods increased. The mitotic index in treated onion root tips decreased with increasing concentrations of the extracts and longer periods of treatment. Likewise, the mitotic phase index was altered in onion incubated with crude extract. Furthermore, crude extract produced mitotic abnormalities resulting from its action on chromatin organization and mitotic spindle. PMID- 20199862 TI - Campomelic dysplasia: a rare cause of congenital spinal deformity. AB - Campomelic dysplasia is a rare autosomal dominant syndrome that often results in congenital spinal deformity. As a result of improvements in respiratory care, some patients survive into childhood, requiring treatment of their spinal deformities. We present a neonate who was diagnosed with campomelic dysplasia, resulting in severe cervical and thoracic kyphoscoliosis and respiratory compromise. A review of the literature and reported treatment options are discussed. Campomelic dysplasia is a rare cause of congenital spinal deformity; however, intervention may be appropriate in certain patients. PMID- 20199863 TI - Tibial avulsion fracture of the posterior root of the medial meniscus in a skeletally-immature child - a case report. AB - It has been theorized that a traumatic tibial avulsion fracture of the posterior root of the medial meniscus (MM) is the cause of the so-called meniscus ossicle (MO). We report the delayed appearance of a tibial avulsion fracture of the posterior root of the MM after a valgus, twisting injury in a 12-year-old boy with open physes. Magnetic resonance imaging (MRI) scans performed 3 days after the injury did not demonstrate a definitive tibial avulsion fracture of the posterior root of the MM; whereas, a repeat MRI for 3 months post-injury did. Medial extrusion of the MM was also noted on the 3 month MRI. Arthroscopic reattachment of the avulsed posterior root of the MM using a trans-physeal nonabsorbable suture tied over a proximal tibia staple was performed. Follow-up MRI at 6 months postoperatively demonstrated healing of the tibial avulsion fracture of the posterior root of the MM in an anatomic position. The patient had a complete resolution of symptoms and there was no angular deformity or limb length discrepancy at 2 years postoperatively. To our knowledge, this is the first report describing a tibial avulsion fracture of the posterior root of the MM in a skeletally-immature patient successfully treated by a trans-physeal arthroscopic suture. This case also illustrates the development of the MO of the posterior root of the MM. PMID- 20199864 TI - Fixation strength of the interference screw in the femoral tunnel: The effect of screw divergence on the coronal plane. AB - Clinical studies to examine the effect of screw divergence have not been applied to the fixation of hamstring grafts. A few previous reports have addressed the correlations between the loss of pullout strength and divergence on hamstring tendon fixation in biomechanical tests. The purpose of this study was to examine the effect of interference screw divergence on the coronal plane when digital flexor tendons were fixed with an interference screw. Twenty fresh porcine hindlimb specimens were chosen. The grafts were fixed using titanium soft tissue interference screws. The hindlimbs were divided into two groups according to the insertion method of the screw. The screw was placed along the graft parallel to the long axis of the femoral tunnel in 10 specimens (parallel placement group), and the others were placed laterally at a 15 degrees divergent angle from the bone tunnel on the coronal plane (divergence group). The cyclic-loading test was loaded for 1500cycles. Five specimens failed because of a pull-out of the tendon in divergence group. The number of specimens that failed before the completion of cycles in the divergence group was significantly greater than that in the parallel placement group. Although the residual displacement after 1500cycles for the divergence group was greater than that for the parallel placement group, no statistically significant difference was found between the groups. This study suggests that the screw placed laterally at a 15 degrees divergent angle on the coronal plane decreases the fixation strength of the digital flexor tendons fixed with an interference screw. PMID- 20199865 TI - Synthesis and biological evaluation of 2',5'-dimethoxychalcone derivatives as microtubule-targeted anticancer agents. AB - A series of novel 2',5'-dimethoxylchalcone derivatives including 18 new compounds were synthesized and evaluated for cytotoxicities against two human cancer cell lines, NTUB1 (human bladder cancer cell line) and PC3 (human prostate cancer cell line). All these derivatives except for 21 exhibited significant cytotoxic effect against NTUB1 and PC3 cell lines. Compounds 13 and 17 with 4-carbamoyl moiety showed potent inhibitory effect on growth of NTUB1 and PC3 cells. Flow cytometric analysis demonstrated that treatment of NTUB1 cells with 1 microM 13 and 17 induced G1 phase arrest accompanied by an increase in apoptotic cell death of NTUB1 cells after 24 h. Treatment of PC3 cells with 1 microM and 3 microM 13, and 1 microM and 3 microM 17 induced S and G1, and G1 and G2/M phase arrests, respectively, accompanied by an increase in apoptotic cell death. These data suggested that 13 and 17 with different 4-carbamoyl moiety displayed same cell cycle arrest in NTUB1 cells while different doses of 13 and 17 revealed different cell cycle arrest in PC3 cells. Cell morphological study of 17 indicated that more cells rounding up or dead associated with tubulin polymerization. Compound 17 showed an increased alpha-tubulin level in polymerized microtubule fraction in a dose-dependent manner while 500 nM paclitaxel also showed similar effect in NTUB1 cells by Western blot analysis. The result suggested that 17 may be used as microtubule-targeted agents. PMID- 20199866 TI - Biosynthesis and emission of insect-induced methyl salicylate and methyl benzoate from rice. AB - Two benzenoid esters, methyl salicylate (MeSA) and methyl benzoate (MeBA), were detected from insect-damaged rice plants. By correlating metabolite production with gene expression analysis, five candidate genes encoding putative carboxyl methyltransferases were identified. Enzymatic assays with Escherichia coli expressed recombinant proteins demonstrated that only one of the five candidates, OsBSMT1, has salicylic acid (SA) methyltransferase (SAMT) and benzoic acid (BA) methyltransferase (BAMT) activities for producing MeSA and MeBA, respectively. Whereas OsBSMT1 is phylogenetically relatively distant from dicot SAMTs, the three-dimensional structure of OsBSMT1, which was determined using homology-based structural modeling, is highly similar to those of characterized SAMTs. Analyses of OsBSMT1 expression in wild-type rice plants under various stress conditions indicate that the jasmonic acid (JA) signaling pathway plays a critical role in regulating the production and emission of MeSA in rice. Further analysis using transgenic rice plants overexpressing NH1, a key component of the SA signaling pathway in rice, suggests that the SA signaling pathway also plays an important role in governing OsBSMT1 expression and emission of its products, probably through a crosstalk with the JA signaling pathway. The role of the volatile products of OsBSMT1, MeSA and MeBA, in rice defense against insect herbivory is discussed. PMID- 20199867 TI - Redox regulation of water stress responses in field-grown plants. Role of hydrogen peroxide and ascorbate. AB - Abiotic stresses, such as drought, can increase the production of reactive oxygen species (ROS) in plants. An increase in ROS levels can provoke a partial or severe oxidation of cellular components inducing redox status changes, so continuous control of ROS and therefore of their metabolism is decisive under stress conditions. The present work focuses on the contribution of one pro oxidant, hydrogen peroxide (H(2)O(2)) and one antioxidant, ascorbate (AA) and its redox status, in the control of plant responses to drought-oxidative stress in resistant plants growing in field conditions. After a general introduction to the concept of drought and oxidative stress and its relationship, we describe the role of H(2)O(2) in drought stress responses, emphasizing the importance of studies in H(2)O(2) subcellular localization, needed for a better understanding of its role in plant responses to stress. Although more studies are needed in the study of changes of redox status in plants subjected to stress, the AA pools and its redox status can be indicative of its involvement as a part of cellular mechanisms by which the plant respond to drought-induced oxidative stress. The mechanism of resistance and/or tolerance to drought-oxidative stress is complex, especially when studies are carried out in plants growing in field conditions, where an interaction of stresses occurs. This study sheds light on the mechanisms of plant responses to water-oxidative stress in plants growing in the field. PMID- 20199868 TI - Analysis of expressed sequence tags from a NaHCO(3)-treated alkali-tolerant plant, Chloris virgata. AB - Chloris virgata Swartz (C. virgata) is a gramineous wild plant that can survive in saline-alkali areas in northeast China. To examine the tolerance mechanisms of C. virgata, we constructed a cDNA library from whole plants of C. virgata that had been treated with 100 mM NaHCO(3) for 24 h and sequenced 3168 randomly selected clones. Most (2590) of the expressed sequence tags (ESTs) showed significant similarity to sequences in the NCBI database. Of the 2590 genes, 1893 were unique. Gene Ontology (GO) Slim annotations were obtained for 1081 ESTs by BLAST2GO and it was found that 75 genes of them were annotated with GO terms "response to stress", "response to abiotic stimulus", and "response to biotic stimulus", indicating these genes were likely to function in tolerance mechanism of C. virgata. In a separate experiment, 24 genes that are known from previous studies to be associated with abiotic stress tolerance were further examined by real-time RT-PCR to see how their expressions were affected by NaHCO(3) stress. NaHCO(3) treatment up-regulated the expressions of pathogenesis-related gene (DC998527), Win1 precursor gene (DC998617), catalase gene (DC999385), ribosome inactivating protein 1 (DC999555), Na(+)/H(+) antiporter gene (DC998043), and two component regulator gene (DC998236). PMID- 20199869 TI - Haemangiopericytoma of the mandible. AB - Haemangiopericytomas (HPCs) found in bony structures are rare sarcomas of vascular origin. Here, we report the case of a 41-year-old female with a HPC originating in the right ramus of the mandible. After tumour staging and biopsy for histological reference the tumour was surgically removed. The surgical technique is described and therapy options of these rare cases are discussed and compared with these cases already documented. To the best of our knowledge, this is the 6th case of mandibular HPC reported in the literature. PMID- 20199870 TI - Symptomatic plate removal after treatment of facial fractures. AB - AIMS: To identify the rates and reasons for plate removal (PR) among patients treated for facial fractures. MATERIALS AND METHODS: A retrospective review of files of 238 patients. RESULTS: Forty-eight patients (20.2%) had plates removed. The reason for removal was objective in 33.3% and subjective in 29.2%. The most common subjective reason was cold sensitivity, and the most common objective reason was wound dehiscence/infection. Women had PR for subjective reasons more often than men (p=0.018). Removal was performed more often for subjective reasons after zygomatico-orbital fractures than after mandibular fractures (p=0.002). Plates inserted in the mandible from an intraoral approach were removed more frequently than extraorally inserted mandibular plates, intraorally inserted maxillary plates, and extraorally inserted plates in other locations (p<0.001). Orbital rim plates had a higher risk of being removed than maxillary or frontal bone plates (p=0.02). CONCLUSIONS: Subjective discomfort is a notable reason for PR among Finnish patients, suggesting that the cold climate has an influence on the need for removal. Patients receiving mandibular osteosynthesis with miniplates from an intraoral approach are at risk of hardware removal because of wound dehiscence/infection and loose/broken hardware, reminding us that more rigid fixation devices should not be forgotten despite the widespread use of miniplates. PMID- 20199871 TI - Towards the development of an immuno MALDI (iMALDI) mass spectrometry assay for the diagnosis of hypertension. AB - The renin-angiotensin-aldosterone system (RAAS) plays an essential role in the regulation of plasma volume and arterial blood pressure. One of the most common diseases of the RAAS is the autonomous production of aldosterone by the adrenal glands, caused by either bilateral adrenal hyperplasia or an aldosterone producing adenoma. This condition, known as primary aldosteronism, is a treatable and often curable form of hypertension. The measurement of plasma renin activity (PRA), as determined by radioimmunoassay for angiotensin I is essential to the diagnosis of primary aldosteronism. However, accurate determination of PRA is often hampered by low plasma concentrations of angiotensin I. Here, we report the use of immuno-MALDI (iMALDI) as a highly sensitive and specific method for the absolute quantitation of angiotensin I in plasma. iMALDI permits concentration determination by affinity-capture of angiotensin I and a stable-isotopically labeled standard (SIS) peptide on immobilized anti-peptide antibodies. The affinity beads are placed on the MALDI target, permitting automated analysis of large numbers of patient samples. Pretreatment of the plasma is not required, and this method is suitable for the accurate determination of angiotensin I in whole plasma. The calibration curve generated using this method was linear over a 50 fold concentration range in plasma, with a correlation coefficient of 0.984. MS/MS sequence confirmation provides absolute specificity. The iMALDI angiotensin I assay, therefore, has the potential to be developed into a method for determining PRA that has advantages in time, in specificity, and in safety. PMID- 20199872 TI - Quantitative top-down proteomics of SILAC labeled human embryonic stem cells. AB - Human embryonic stem cells (hESCs) are self-renewing pluripotent cells with relevance to treatment of numerous medical conditions. However, a global understanding of the role of the hESC proteome in maintaining pluripotency or triggering differentiation is still largely lacking. The emergence of top-down proteomics has facilitated the identification and characterization of intact protein forms that are not readily apparent in bottom-up studies. Combined with metabolic labeling techniques such as stable isotope labeling by amino acids in cell culture (SILAC), quantitative comparison of intact protein expression under differing experimental conditions is possible. Herein, quantitative top-down proteomics of hESCs is demonstrated using the SILAC method and nano-flow reverse phase chromatography directly coupled to a linear-ion-trap Fourier transform ion cyclotron resonance mass spectrometer (nLC-LTQ-FT-ICR-MS). In this study, which to the best of our knowledge represents the first top-down analysis of hESCs, we have confidently identified 11 proteins by accurate intact mass, MS/MS, and amino acid counting facilitated by SILAC labeling. Although quantification is challenging due to the incorporation of multiple labeled amino acids (i.e., lysine and arginine) and arginine to proline conversion, we are able to quantitatively account for these phenomena using a mathematical model. PMID- 20199873 TI - Comparative efficacy of peste des petits ruminants (PPR) vaccines. AB - Peste des petits ruminants (PPR) is a highly contagious, economically important viral disease of sheep and goats with high morbidity and mortality rates. In order to control the disease effectively, highly sensitive diagnostic tests coupled with potent vaccines are important pre-requisites. At present, there are three live attenuated PPR vaccines available in India including Sungri 96, Arasur 87 and Coimbatore 97. Indian Veterinary Research Institute (IVRI) Mukteswar developed the PPR Sungri 96 (isolate of goat origin) vaccine; while Tamil Nadu Veterinary and Animal Sciences University (TANUVAS) developed the Arasur 87 (isolate of sheep origin) and Coimbatore 97 (isolate of goat origin). In this study, the potency of these vaccines including a fourth vaccine from Institute of Animal Health and Veterinary Biologicals, Bangalore (IAH&VB) were tested as per the office International des Epizooties (OIE) guidelines by challenge studies in sheep and goats and their efficacies were evaluated using PPR C-ELISA. Potency tests of these vaccines in sheep and goats revealed that three of the vaccines were potent; however, the IAH &VB vaccine was comparatively less potent. The three vaccines could presumably be used for mass vaccination of both sheep and goats while contemplating PPR control program. PMID- 20199874 TI - Weight management tips for patients on hemodialysis. PMID- 20199876 TI - Physical exercise prevents the exacerbation of oxidative stress parameters in chronic kidney disease. AB - OBJECTIVE: Reactive oxygen species play an important role in the pathogenesis of chronic kidney disease (CKD). Physical exercise was suggested as a useful approach to diminish impaired oxidative defense mechanisms. This study sought to observe the effects of physical training before the induction of renal lesions on oxidative stress parameters in animals induced for CKD. METHODS: Twenty-four male Wistar rats were divided into four groups (n = 6): sham, sham plus exercise, CKD, and CKD plus exercise. Exercise groups performed physical training on a treadmill for 8 weeks (up to 1 km/h for 50 min/day, 5 days/week). Forty-eight hours after the final exercise session, a surgical reduction of renal mass was performed (5/6 nephrectomized). Thirty days later, blood samples were collected to determine serum creatinine and urea concentrations, and the right kidney was surgically removed and stored at -70 degrees C for later analysis of superoxide production, antioxidant enzymes (superoxide dismutase and catalase), and oxidative damage of lipids (thiobarbituric acid reactive susbstances level) and proteins (carbonyl groups and sulfhydryl content). RESULTS: A significant increase occurred in creatinine and urea levels, superoxide production, antioxidant enzymes, and oxidative damage in the CKD group, compared with sham-treated animals (P < .05). Physical training prevented superoxide production, and decreased the oxidative damage in the CKD group (P < .05), but did not increase the effect of antioxidants. CONCLUSION: Physical training before induction of a renal lesion is capable of improving oxidative damage parameters and oxidant production, without altering renal function and the antioxidant defense system. PMID- 20199875 TI - Association of relatively low serum parathyroid hormone with malnutrition inflammation complex and survival in maintenance hemodialysis patients. AB - BACKGROUND: Low serum parathyroid hormone (PTH) has been implicated as a primary biochemical marker of adynamic bone disease in individuals with chronic kidney disease (CKD) who undergo maintenance hemodialysis (MHD) treatment. We hypothesized that the malnutrition-inflammation complex is associated with low PTH levels in these patients and confounds the PTH-survival association. METHODS: We examined 748 stable MHD outpatients in southern California and followed them for up to 5 years (October 2001-December 2006). RESULTS: In 748 MHD patients, serum PTH <150pg/mL was more prevalent among non-blacks and diabetics. There was no association between serum PTH and coronary artery calcification score, bone mineral density, or dietary protein or calorie intake. Low serum PTH was associated with markers of protein-energy wasting and inflammation, and this association confounded the relationship between serum PTH and alkaline phosphatase. Although 5-year crude mortality rates were similar across PTH increments, after adjustment for the case-mix and surrogates of malnutrition and inflammation, a moderately low serum PTH in 100-150pg/mL range was associated with the greatest survival compared to other serum PTH levels, i.e., a death hazard ratio of 0.52 (95% confidence interval: 0.29-0.92, p<0.001) compared to PTH of 300-600pg/mL (reference). CONCLUSIONS: Low serum PTH may be another facet of the malnutrition-inflammation complex in CKD, and after controlling for this confounder, a moderately low PTH in 100-150pg/mL range appears associated with the greatest survival. Limitations of observational studies should be considered. PMID- 20199877 TI - Lung perfusion with dual-energy multi-detector row CT: can it help recognize ground glass opacities of vascular origin? AB - RATIONALE AND OBJECTIVES: The aim of this study was to evaluate whether the spectral characterization of the iodine content of lung microcirculation could help identify ground-glass opacity (GGO) of vascular origin. MATERIALS AND METHODS: Thirty-five consecutive patients with GGO of bronchioloalveolar (group 1; n = 24) and vascular (group 2; n = 11) origin underwent dual-energy multi detector computed tomographic angiography of the chest using a standard injection protocol. For each patient, two radiologists evaluated by consensus the presence, location, and extent of GGO on diagnostic computed tomographic scans (ie, contiguous 1-mm-thick averaged images from both tubes) and characteristics of the corresponding areas on perfusion scans. RESULTS: A total of 443 segments with GGO were depicted on the diagnostic scans (group 1, n = 231; group 2, n = 212), always intermingled with areas of normal lung attenuation, with a mean of 12.7 segments with GGO per patient. Areas of GGO were located at the level of the upper lobes (n = 128), middle lobe and/or lingula (n = 81), and lower (n = 234) lobes, involving <25% (n = 165), 25% to 50% (n = 103), 50% to 75% (n = 155), and >75% (n = 20) of the segmental surface. The overall quality of perfusion scans was rated as interpretable in all patients. Perfusion scans depicted areas of hyperattenuation within segments of GGO with a significantly higher frequency in group 2 (211 of 212 [99.5%]) than in group 1 (27 of 231 [12%]) (P < .0001). Hyperattenuated areas of vascular origin were observed to match the areas of GGO in surface (203 of 211 [96%]) and contours (208 of 211 [98.6%]). CONCLUSION: Dual energy computed tomography can help recognize GGO of vascular origin. PMID- 20199878 TI - Isolated microvesicles from peripheral blood and body fluids as observed by scanning electron microscope. AB - Microvesicles are sub-micron structures shed from the cell membrane in a final step of the budding process. After being released into the microenvironment they are free to move and carry signaling molecules to distant cells, thereby they represent a communication system within the body. Since all cells shed microvesicles, it can be expected that they will be found in different body fluids. The potential diagnostic value of microvesicles has been suggested, however, a standardized protocol for isolation has not yet been agreed upon. It is unclear what is the content of the isolates and whether the isolated microvesicles were present in vivo or-have they been created within the isolation procedure. To present evidence in this direction, in this work we focus on the visualization of the material obtained by the microvesicle isolation procedure. We present scanning electronic microscope images of microvesicles isolated from blood, ascites, pleural fluid, cerebrospinal fluid, postoperative drainage fluid and chyloid fluid acquired from human and animal patients. Vesicular structures sized from 1microm downto 50nm are present in isolates of all considered body fluids, however, the populations differ in size and shape reflecting also the composition of the corresponding sediments. Isolates of microvesicles contain numerous cells which indicates that methods of isolation and determination of the number of microvesicles in the peripheral blood are to be elaborated and improved. PMID- 20199879 TI - Effect of interleukin-8 and RANTES on the Gardos channel activity in sickle human red blood cells: role of the Duffy antigen receptor for chemokines. AB - We investigated the effects of the chemokines IL-8 and RANTES on the activity of the Gardos channel (GC) of sickle red blood cells (SSRBCs). SSRBCs expressing the Duffy antigen receptor for chemokines (DARC) incubated under oxygenated conditions exhibit GC activation. The deoxygenation-stimulated K(+) loss via the GC is activated by the chemokines in the Duffy-positive SSRBCs. The percentage of cells with high density is 17 times higher in the Duffy-positive group. These findings are consistent with a greater susceptibility of Duffy-positive SSRBCs to inflammatory chemokines leading to GC activation and cellular dehydration and suggest a coupling, promoted by the sickling process, between DARC and the GC. PMID- 20199880 TI - Final version of the Distance Randot Stereotest: normative data, reliability, and validity. AB - PURPOSE: Measurement of distance stereoacuity may be useful in assessing strabismic patients, especially those with intermittent exotropia. We developed the Distance Randot Stereotest as an easily administered quantitative test for distance stereoacuity in children. By using a prototype, we reported testability, validity, and normative data. Here we report normative and validity data for the final, commercially available version of the test. METHOD: We administered both the Prototype and the Final Version Distance Randot Stereotest to 156 normal volunteers (2-40 years of age) and 77 strabismic patients (4-62 years of age). Test-retest data were collected for the Final Version. RESULTS: Normative Final Version scores were similar to those obtained with the Prototype; 96% were < or = 100 arcsec. Test-retests were identical in 82% and within one disparity level in 100%. Final Version scores were correlated with Prototype scores (rs = 0.64, p < 0.001). Among strabismic patients, 62.3% had abnormal stereoacuity; those with normal scores had incomitant or intermittent deviations. Nil stereoacuity was found in 27 patients, confirmed in 90.9% of retests; 17 had measurable stereoacuity, confirmed in 96.3% of retests. Patients with constant strabismus were more likely to have nil stereoacuity than patients who had intermittent strabismus (95% vs 12.2%). CONCLUSIONS: Distance Randot scores from normal subjects have low variability within each age group and high test-retest reliability. There is little overlap between Distance Randot scores from normal control and strabismic patients. The Distance Randot Stereotest is a sensitive measurement of binocular sensory status that may be useful in monitoring progression of strabismus and/or recovery after strabismus surgery. PMID- 20199881 TI - Glaucoma drainage device implantation in children using fibrin glue. AB - Glaucoma drainage devices (GDDs) are often used in refractory cases of pediatric glaucoma. Traditionally, sutures are used during GDD implantation for securing the plate and silicone tube to the sclera, for suturing a patch graft over the silicone tube, and for conjunctival closure. The use of fibrin glue as an alternative to standard suturing techniques has been studied in adults but not in the pediatric population. The purpose of this study was to analyze the use of fibrin glue as an alternative to standard suturing techniques during certain stages of GDD implantation in the pediatric population. PMID- 20199882 TI - Ocular findings of oral sildenafil use in term and near-term neonates. AB - BACKGROUND: Sildenafil is a phosphodiesterase type 5 inhibitor used as a therapeutic adjunct in critically ill neonates with persistent pulmonary hypertension. Sildenafil is associated with several ocular complications in adults and is suspected to exacerbate retinopathy of prematurity (ROP). The risk of ocular complication in sildenafil-treated newborns, not otherwise at risk for the development of ROP, is unknown. METHODS: Twenty-two neonates with birth gestational age greater than 34 weeks and birth weight over 2,100 g who received oral sildenafil for more than 2 weeks were assessed by a pediatric ophthalmologist for potential ocular complications. RESULTS: Four patients had ocular findings: 2 had bacterial conjunctivitis; 1 had optic nerve hypoplasia, choroidal coloboma, and nystagmus; 1 had previously suffered from a hypotensive episode and had a documented cortical injury accompanied by bilateral optic disk atrophy and nystagmus. All cases seemed unrelated to sildenafil use and improved despite continued use of the drug. CONCLUSIONS: Our results do not support the need for a routine ophthalmologic examination in term and near-term neonates receiving sildenafil. PMID- 20199883 TI - Body composition, endocrine and metabolic profiles in adults with Prader-Willi syndrome. AB - OBJECTIVE: Prader-Willi syndrome (PWS) is a complex genetic disease associated with hypothalamic-pituitary dysfunction and severe obesity. The aim of the present study was to describe the relationships between body composition, metabolic and hormonal profiles in PWS adults. METHOD: Forty six adults with genetically verified PWS, 25 women and 21 men, median age 28 years were studied. Body composition was evaluated by standard anthropometric procedures and with computed tomography (CT) of the abdomen and at the mid-femur level. CT of abdomen was compared to 22 healthy, unmatched adults. Circulating lipids were measured and oral glucose tolerance test (OGTT) and hormonal screening including GH secretory capacity (GHRH/arginine test) was carried out. RESULTS: Median body mass index (BMI) was 27.2 kg/m(2), with women being more obese than men. Sixteen patients had dyslipidaemia, 10 impaired glucose tolerance and seven had diabetes. Fifty percent were hypogonadal and six fulfilled BMI related criteria for growth hormone deficiency (GHD). Visceral to subcutaneous abdominal fat ratio was reduced in PWS. Visceral abdominal fat fraction correlated with both subcutaneous fat, BMI and peak GH-response. Thigh muscle volume was about half of the thigh fat volume. Beneficial effects of sex-steroid replacement on body composition were not observed. CONCLUSIONS: Body fat was primarily located subcutaneously and metabolic consequences of obesity limited. The abnormal body composition similar to that in non-PWS GHD adults increases the interest of GH treatment in the prevention of obesity in adults with PWS. PMID- 20199884 TI - Physical characterization and comparison of two commercially available micro MLCs. AB - In this study, the physical characteristics (penumbra width variation with the source size and shape, interleaf leakage, transmission through the leaves, and the tongue-and-groove effect) of two linear accelerators (BrainLAB's Novalis and Elekta's Synergy-S Beam Modulator) have been investigated. For similar square fields (about 4.5 cm x 4.5 cm) with source-to-surface/skin-distance (SSD) ranging from 90 cm to 115 cm and measurements taken at the depth of D(max)=1.5 cm for 6 MV photon beam. The Novalis MLC has penumbra width of 2.4 +/- 0.11 mm-2.8 +/- 0.11 mm at the leaf-end and 2.2 +/- 0.1 mm-2.7 +/- 0.1 mm on the leaf-side; and those for the Synergy-S MLC are 4.4 +/- 0.17 mm-5.2 +/- 0.2 mm and 3.0 +/- 0.12 mm-3.5 +/- 0.12 mm. Upon rotating the Synergy-S collimator by 90 degrees (i.e., shifting the leaf movement to the gun-target direction), significant reduction of the leaf-end penumbra width (17%) and increase of leaf-side penumbra width (28%) suggest an elliptical shape of the radiation source spot. Similar rotation of the collimator yielded reduction of the penumbras on both leaf-end (34%) and leaf side (28%) for Novalis, indicating that the Novalis has a more symmetric source size. For all the field sizes and settings, BrainLAB's Novalis MUMLC produce a smaller penumbra for simple square fields compared to the Elekta's Synergy-S. However, this difference became less pronounced for leaf-side penumbra and also for circular fields. The tongue-and-groove effect of the Novalis (23 +/- 0.9%) is slightly smaller than that of the Synergy-S (25 +/- 1%); while the interleaf leakage and leakage directly through leaves for Synergy-S (1.6 +/- 0.07% & 0.9 +/ 0.04%) are lower than that of Novalis (2 +/- 0.08% & 1.3 +/- 0.05%). PMID- 20199885 TI - Generalized EPID calibration for in vivo transit dosimetry. AB - Many researchers are studying new in vivo dosimetry methods based on the use of Elelctronic portal imaging devices (EPIDs) that are simple and efficient in their daily use. However the need of time consuming implementation measurements with solid water phantoms for the in vivo dosimetry implementation can discourage someone in their use. In this paper a procedure has been proposed to calibrate aSi EPIDs for in vivo transit dosimetry. The dosimetric equivalence of three aSi Varian EPIDs has been investigated in terms of signal reproducibility and long term stability, signal linearity with MU and dose per pulse and signal dependence on the field dimensions. The signal reproducibility was within +/- 0.5% (2SD), while the long term signal stability has been maintained well within +/- 2%. The signal linearity with the monitor units (MU) was within +/- 2% and within +/- 0.5% for the EPIDs controlled by the IAS 2, and IAS 3 respectively. In particular it was verified that the correction factor for the signal linearity with the monitor units, k(lin), is independent of the beam quality, and the dose per pulse absorbed by the EPID. For 6, 10 and 15 MV photon beams, a generalized set of correlation functions F(TPR,w,L) and empirical factors f(TPR,d,L) as a function of the Tissue Phantom Ratio (TPR), the phantom thickness, w, the square field side, L, and the distance, d, between the phantom mid-plane and the isocentre were determined to reconstruct the isocenter dose. The tolerance levels of the present in vivo dosimetry method ranged between +/- 5% and +/- 6% depending on the tumor body location. In conclusion, the procedure proposed, that use generalized correlation functions, reduces the effort for the in vivo dosimetry method implementation for those photon beams with TPR within +/- 0.3% as respect those here used. PMID- 20199886 TI - [Assessment of changes in body composition in critically ill patients]. AB - Critically ill patients are especially prone to malnutrition because their hypermetabolic state produces an increase in nutritional requirements that often are not covered with the formulae supplied. Evaluation of the body composition (BC) makes it possible to quantify the main structural components of the body: muscle, bone and fat. An anthropometry study was made for the assessment of these elements to obtain information on the protein-calorie nutritional status of critically ill patients. We have aimed to describe the variations in the BC of the critical ill patient during the first seven days after ICU admission. The observational study included 50 critically ill patients, of whom 78% were male and 22% women with a mean age of 56 years. Height, weight, body mass index (BMI), bone diameters, muscle perimeters and skinfolds of patients were recorded. The body composition (BC) calculations were performed using the Faulkner, Rocha, Wurch and Matiegka formulae. We obtained the baseline energy expenditure of each patient with the Harris-Benedict formula. After analyzing the data, a decrease was found in the percentage of muscle mass (mean+/-SD: 3+/-0.76), an increase in the percentage of body fat (2+/-0.76) and an increase in BMI at the expense of an augment of weight. We have concluded that during the first week of ICU admission patients lose critical muscle mass and have an increase in fat mass. Awareness of these changes in the BC of patients may be useful to determine the appropriate nutrition for critically ill patients. PMID- 20199888 TI - It's not the end: physiologic assessment of E-C coupling of muscle. PMID- 20199887 TI - [The daily experience of the patient with an implantable cardioverter defibrillator]. AB - OBJECTIVE: To describe the daily experience of patients with an automatic defibrillator (AD) implant and the adaptive changes of the patient. METHOD: Qualitative and phenomenological research. Collection of data through; initially unstructured interview with half of the informants, semi-structured interviews through an open questions guide after the initial unstructured interviews and use of personal narratives of the informants. Analysis of the data using the Van Manen proposal. RESULTS: We analysed the interviews of 10 participants. We collected socio-demographic variables and identified the following themes, which respond to the question "How is life with an AD": It is life "with the two sides of the coin," living in constant wait and uncertainty, accepting change, developing adaptation strategies, renegotiating relationships and sexuality and it is to live transformed. CONCLUSIONS: The results of this study can be integrated into nurse clinical practice in areas such as valuation after discharge, changes in habits, control of treatment, notification of shocks, masking detection of symptoms and strategies that can jeopardise the bearer. Research needs to be developed that looks closer into the influence of other technological devices in people. PMID- 20199889 TI - Rhythmic movements and sleep paralysis in narcolepsy with cataplexy: a video polygraphic study. PMID- 20199891 TI - Quality of life after surgery for temporal lobe epilepsy: a 5-year follow-up. AB - The authors carried out a 5-year prospective study about the effects epilepsy surgery can have on a patient's quality of life (QOL). They looked for the relationship between improvement on QOL after surgery and reduction of seizure frequency, seizure focus, age at surgery and previous psychopathology. They concluded that improvement in overall, cognitive and social function scores were statistically significant throughout the study. Seizure worry score ceased to be significant at the fifth year. Previous psychopathology was a negative influence on social and seizure worry score. Compared to left lobectomies, right lobectomies showed significant better results in overall scores at six months and one year follow-up. At 1 month follow-up, cognitive function was also significantly better in right lobectomies. Engels class I patients demonstrated statistically better results in the fourth and fifth years of follow-up. Neither years of disease nor patient age at surgery seemed to influence QOL. PMID- 20199892 TI - Association between respiratory and herpes viruses on pulmonary exacerbations in cystic fibrosis patients. AB - Respiratory viruses discovered in the 21st century and human herpes viruses (N=13) were seldom (4/50) detected in our cystic fibrosis patients although exacerbation frequency (7.75+/-2.9/a versus 4.45+/-2.1/a; p=0.03) and colonization with Aspergillus fumigatus (RR: 2.6; CI95: 1.8-3.7), Pseudomonas aeruginosa (RR: 1.84; CI95: 1.4-2.4), and Staphylococcus aureus (RR: 1.5; CI95: 1.2-1.9) including MRSA (RR: 4.6; CI95: 1.3-16.6) were associated with virus positivity. Further studies should clarify whether this finding reflects non specific colonization (human Bocavirus) or reactivation (Epstein-Barr virus) or rather an acceleration of lung tissue inflammation. PMID- 20199893 TI - [Acute mastoiditis: experience in a tertiary-care center in the South of Spain during 1999-2008 period]. AB - INTRODUCTION: An increase in both the incidence and severity of acute mastoiditis (AM) has been recently recorded in many different geographical areas. Causes remain unclear. This study aims to evaluate our clinical and epidemiological data in paediatric patients with AM and to compare them with recent reports. MATERIAL AND METHODS: Retrospective chart review of 145 patients diagnosed of AM from 1999 to 2008 in our tertiary-care centre, including clinical, epidemiological, microbiological, treatment and outcome data. RESULTS: The annual incidence showed a changeable trend throughout the study period. The average number of cases was 14.5 cases per year, with a median age of 3 years, and 57.9% males. A total of 53.8% received pre-admission oral antibiotics, mainly beta-lactamics. Most frequent presenting clinical findings were fever (77.9%), ear displacement (73.8%), otalgia (71.7%), and postauricular swelling (70.3%). Microbiological cultures were performed in 53 cases; S. pneumoniae was the most isolated microorganism. CT scans were performed in 56.6% cases. All patients received parenteral antibiotic treatment with a median duration of treatment of 5 days. Surgery was performed on 32.6%. Complications were seen in 20% of patients: 13.1% had extracranial complications, and 8.2% had intracranial complications. A significant increase in intracranial complications was detected in the second half of the study period. CONCLUSIONS: A changeable trend in the annual incidence of AM throughout the time of study was observed. A higher proportion of intracranial complications was detected in the last five years of the study period. PMID- 20199890 TI - Diversity in Mycobacterium tuberculosis mannosylated cell wall determinants impacts adaptation to the host. AB - Mycobacterium tuberculosis (the causal agent of TB) has co-evolved with humans for centuries. It infects via the airborne route and is a prototypic highly adapted intracellular pathogen of macrophages. Extensive sequencing of the M. tuberculosis genome along with recent molecular phylogenetic studies is enabling us to gain insight into the biologic diversity that exists among bacterial strains that impact the pathogenesis of latent infection and disease. The majority of the M. tuberculosis cell envelope is comprised of carbohydrates and lipids, and there is increasing evidence that these microbial determinants that are readily exposed to the host immune system play critical roles in disease pathogenesis. Studies from our laboratory and others have raised the possibility that M. tuberculosis is adapting to the human host by cloaking its cell envelope molecules with terminal mannosylated (i.e. Man-alpha-(1-->2)-Man) oligosaccharides that resemble the glycoforms of mammalian mannoproteins. These mannosylated biomolecules engage the mannose receptor (MR) on macrophages during phagocytosis and dictate the intracellular fate of M. tuberculosis by regulating formation of the unique vesicular compartment in which the bacterium survives. The MR is highly expressed on alveolar macrophages (predominant C-type lectin on human cells) and functions as a scavenger receptor to maintain the healthiness of the lung by clearing foreign particles and at the same time regulating dangerous inflammatory responses. Thus M. tuberculosis exploits MR functions to gain entry into the macrophage and survive. Key biochemical pathways and mycobacterial determinants involved in the development and maintenance of the M. tuberculosis phagosome are being identified. The phylogenetic diversity observed in M. tuberculosis strains that impact its cell wall structure together with the genetic diversity observed in human populations, including those elements that affect macrophage function, may help to explain the extraordinary evolutionary adaptation of this pathogen to the human host. Major developments in these areas are the focus of this review. PMID- 20199894 TI - [Frequency and clinical presentation of congenital ocular anomalies in Asturias 1990-2004]. AB - INTRODUCTION: Congenital ocular anomalies (COAs) can produce serious disability. OBJECTIVE: The purpose of this investigation was to assess the prevalence of COAs, their trends and to describe the associated malformations and syndromes in a geographically defined population. METHOD: Data from the Asturias Registry of Congenital Defects were used. The period studied was from 1990 to 2004 and the study population the 103,452 births of mothers living in the region. Total prevalence was calculated. RESULTS: A total of 3035 cases with congenital defects were recorded, of these 70 had COAs. The total prevalence was 6.8 per 10000 births, with a stable trend during this period. The most common COAs were: congenital cataract (2.0 per 10000 births), anophthalmos/microphthalmos (1.4 per 10000 births) and coloboma (1.3 per 10000 births). 40% of COAs occurred as isolated defects, 37% were syndromes and 23% were associated with other congenital defects. CONCLUSIONS: The prevalence of COAs in Asturias over this period had a stable trend and the congenital cataract was the commonest COAs. COAs, particularly the anophthalmos/microphthalmos were associated with other congenital anomalies. PMID- 20199895 TI - [Neuroretinitis in cat-scratch disease]. PMID- 20199896 TI - Progressive maturation in contracting cardiomyocytes derived from human embryonic stem cells: Qualitative effects on electrophysiological responses to drugs. AB - The field of drug testing currently needs a new integrated assay system, as accurate as systems using native tissues, that will allow us to predict arrhythmia risks of candidate drugs and the relationship between genetic mutations and acquired electrophysiological phenotypes. This could be accomplished by combining the microelectrode array (MEA) system with cardiomyocytes (CMs) derived from human embryonic stem cells (hESC) and induced pluripotential stem cells. CMs have been successfully induced from both types, but their maturation process is not systematically controlled; this results in loss of beating potency and insufficient ion channel function. We generated a transgenic hESC line that facilitates maintenance of hESC-CM clusters every 2 weeks by expressing GFP driven by a cardiac-specific alphaMHC promoter, thereby producing a compact pacemaker lineage within a ventricular population over a year. Further analyses, including quantitative RT-PCR, patch-clamp, and MEA mediated QT tests, demonstrated that replating culturing continuously enhanced gene expression, ionic current amplitudes, and resistance to K(+) channel blockades in hESC-CMs. Moreover, temporal three-dimensional (3D) culturing accelerated maturation by restoring the global gene repressive status established in the adhesive status. Replating/3D culturing thus produces hESC-CMs that act as functional syncytia suitable for use in regenerative medicine and accurate drug tests. PMID- 20199897 TI - Molecular phylogenetic diversity of the emerging mucoralean fungus Apophysomyces: proposal of three new species. AB - BACKGROUND: Apophysomyces is a monotypic genus belonging to the order Mucorales. The species Apophysomyces elegans has been reported to cause severe infections in immunocompromised and immunocompetent people. In a previous study of Alvarez et al.(3) [J Clin Microbiol 2009;47:1650-6], we demonstrated a high variability among the 5.8S rRNA gene sequences of clinical strains of A. elegans. MATERIAL AND METHODS: We performed a polyphasic study based on the analysis of the sequences of the histone 3 gene, the internal transcribed spacer region of the rDNA gene, and domains D1 and D2 of the 28S rRNA gene, as well as by evaluation of some relevant morphological and physiological characteristics of a set of clinical and environmental strains of A. elegans. RESULTS AND CONCLUSIONS: We have demonstrated that A. elegans is a complex of species. We propose as new species Apophysomyces ossiformis, characterised by bone-shaped sporangiospores, Apophysomyces trapeziformis, with trapezoid-shaped sporangiospores, and Apophysomyces variabilis, with variable-shaped sporangiospores. These species failed to assimilate esculin, whereas A. elegans was able to assimilate that glycoside. Amphotericin B and posaconazole are the most active in vitro drugs against Apophysomyces. PMID- 20199906 TI - Robust adaptive 3-D segmentation of vessel laminae from fluorescence confocal microscope images and parallel GPU implementation. AB - This paper presents robust 3-D algorithms to segment vasculature that is imaged by labeling laminae, rather than the lumenal volume. The signal is weak, sparse, noisy, nonuniform, low-contrast, and exhibits gaps and spectral artifacts, so adaptive thresholding and Hessian filtering based methods are not effective. The structure deviates from a tubular geometry, so tracing algorithms are not effective. We propose a four step approach. The first step detects candidate voxels using a robust hypothesis test based on a model that assumes Poisson noise and locally planar geometry. The second step performs an adaptive region growth to extract weakly labeled and fine vessels while rejecting spectral artifacts. To enable interactive visualization and estimation of features such as statistical confidence, local curvature, local thickness, and local normal, we perform the third step. In the third step, we construct an accurate mesh representation using marching tetrahedra, volume-preserving smoothing, and adaptive decimation algorithms. To enable topological analysis and efficient validation, we describe a method to estimate vessel centerlines using a ray casting and vote accumulation algorithm which forms the final step of our algorithm. Our algorithm lends itself to parallel processing, and yielded an 8 x speedup on a graphics processor (GPU). On synthetic data, our meshes had average error per face (EPF) values of (0.1 1.6) voxels per mesh face for peak signal-to-noise ratios from (110-28 dB). Separately, the error from decimating the mesh to less than 1% of its original size, the EPF was less than 1 voxel/face. When validated on real datasets, the average recall and precision values were found to be 94.66% and 94.84%, respectively. PMID- 20199907 TI - Discrimination of breast tumors in ultrasonic images using an ensemble classifier based on the AdaBoost algorithm with feature selection. AB - This paper proposes a novel algorithm to estimate a log-compressed K distribution parameter and presents an algorithm to discriminate breast tumors in ultrasonic images. We computed a total of 208 features for discrimination, including those based on a parameter of a log-compressed K-distribution, which quantifies the homogeneity of the echo pattern in the tumor, but is influenced by compression parameters in the ultrasonic device. The proposed algorithm estimates the parameter of the log-compressed K-distribution in a manner free from this influence. To quantify irregularities in tumor shape, pattern-spectrum-based features were newly developed in this paper. The discrimination process uses an ensemble classifier trained by a multiclass AdaBoost learning algorithm (AdaBoost.M2), combined with a sequential feature-selection process. A 10-fold cross-validation test validated the performance, and the results were compared with those of a Mahalanobis distance-based classifier and a multiclass support vector machine. A total of 200 carcinomas, 50 fibroadenomas, and 50 cysts were used in the experiments. This paper demonstrates that the combination of a classifier trained by AdaBoost.M2 and features based on the estimated parameter of a log-compressed K-distribution, as well as those of the pattern spectrum, are useful for the discrimination of tumors. PMID- 20199908 TI - Detection and segmentation of colonic polyps on implicit isosurfaces by second principal curvature flow. AB - Today's computer aided detection systems for computed tomography colonography (CTC) enable automated detection and segmentation of colorectal polyps. We present a paradigm shift by proposing a method that measures the amount of protrudedness of a candidate object in a scale adaptive fashion. One of the main results is that the performance of the candidate detection depends only on one parameter, the amount of protrusion. Additionally the method yields correct polyp segmentation without the need of an additional segmentation step. The supervised pattern recognition involves a clear distinction between size related features and features related to shape or intensity. A Mahalanobis transformation of the latter facilitates ranking of the objects using a logistic classifier. We evaluate two implementations of the method on 84 patients with a total of 57 polyps larger than or equal to 6 mm. We obtained a performance of 95% sensitivity at four false positives per scan for polyps larger than or equal to 6 mm. PMID- 20199909 TI - Estimation of optimal fiducial target registration error in the presence of heteroscedastic noise. AB - We study the effect of point dependent (heteroscedastic) and identically distributed anisotropic fiducial localization noise on fiducial target registration error (TRE). We derive an analytic expression, based on the concept of mechanism spatial stiffness, for predicting TRE. The accuracy of the predicted TRE is compared to simulated values where the optimal registration transformation is computed using the heteroscedastic errors in variables algorithm. The predicted values are shown to be contained by the 95% confidence intervals of the root mean square TRE obtained from the simulations. PMID- 20199910 TI - Computer-assisted scan protocol and reconstruction (CASPAR)-reduction of image noise and patient dose. AB - X-ray computed tomography is a powerful medical imaging device. It allows high resolution 3-D visualization of the human body. However, one drawback is the health risk associated with ionizing radiation. Simply downscaling the radiation intensities over the entire scan results in increased quantum noise. This paper proposes the concept of computer-assisted scan protocol and reconstruction. More specifically, we propose a method to compute patient and task-specific intensity profiles that achieve an optimal tradeoff between radiation dose and image quality. Therefore, reasonable image variance and dose metrics are derived. Conventional third-generation systems as well as inverted geometry concepts are considered. Two dose/noise minimization problems are formulated and solved by an efficient algorithm providing optimized milliampere (mA)-profiles. Thorax phantom simulations demonstrate the promising advantage of this technique: in this particular example, the dose is reduced by 53% for third-generation systems and by 86% for an inverted geometry in comparison to a sinusoidal mA-profile at a constant upper noise limit. PMID- 20199911 TI - A normalized framework for the design of feature spaces assessing the left ventricular function. AB - A through description of the left ventricle functionality requires combining complementary regional scores. A main limitation is the lack of multiparametric normality models oriented to the assessment of regional wall motion abnormalities (RWMA). This paper covers two main topics involved in RWMA assessment. We propose a general framework allowing the fusion and comparison across subjects of different regional scores. Our framework is used to explore which combination of regional scores (including 2-D motion and strains) is better suited for RWMA detection. Our statistical analysis indicates that for a proper (within interobserver variability) identification of RWMA, models should consider motion and extreme strains. PMID- 20199913 TI - Estimation of inferential uncertainty in assessing expert segmentation performance from STAPLE. AB - The evaluation of the quality of segmentations of an image, and the assessment of intra- and inter-expert variability in segmentation performance, has long been recognized as a difficult task. For a segmentation validation task, it may be effective to compare the results of an automatic segmentation algorithm to multiple expert segmentations. Recently an expectation-maximization (EM) algorithm for simultaneous truth and performance level estimation (STAPLE) was developed to this end to compute both an estimate of the reference standard segmentation and performance parameters from a set of segmentations of an image. The performance is characterized by the rate of detection of each segmentation label by each expert in comparison to the estimated reference standard. This previous work provides estimates of performance parameters,but does not provide any information regarding the uncertainty of the estimated values. An estimate of this inferential uncertainty, if available, would allow the estimation of confidence intervals for the values of the parameters. This would facilitate the interpretation of the performance of segmentation generators and help determine if sufficient data size and number of segmentations have been obtained to precisely characterize the performance parameters. We present a new algorithm to estimate the inferential uncertainty of the performance parameters for binary and multi-category segmentations. It is derived for the special case of the STAPLE algorithm based on established theory for general purpose covariance matrix estimation for EM algorithms. The bounds on the performance parameters are estimated by the computation of the observed information matrix.We use this algorithm to study the bounds on performance parameters estimates from simulated images with specified performance parameters, and from interactive segmentations of neonatal brain MRIs. We demonstrate that confidence intervals for expert segmentation performance parameters can be estimated with our algorithm. We investigate the influence of the number of experts and of the segmented data size on these bounds, showing that it is possible to determine the number of image segmentations and the size of images necessary to achieve a chosen level of accuracy in segmentation performance assessment. PMID- 20199914 TI - Axial anisotropic conductivity imaging based on projected current density in MREIT. AB - An aim of magnetic resonance electrical impedance tomography (MREIT) is to visualize the internal current density and/or the conductivity of an imaging object. In MREIT, it is desirable to use just one component of the internal magnetic flux density vector B=(B(x),B(y),B(z)) caused by the injected current, measured without rotating the object. We present a method of visualizing the axial anisotropic conductivity tensor by use of the measured magnetic flux density B(z) data. The method involves the use of a projected current density, which is a uniquely and stably determined component of the internal current generated by the injected current, derived from the measured B(z) data. Each component of the axial anisotropic conductivity is recovered by matching the measured B(z) data with a determined intermediate isotropic conductivity and the projected currents. Results from numerical simulations demonstrate that the proposed algorithm is robust to noise and stably determines the anisotropic conductivity tensor on the imaging slice. For a practical implementation, we studied a postmortem canine brain case to visualize each component of the anisotropic conductivity. We observed that the reconstructed anisotropic conductivity images clearly reflects the anisotropic property of the white matter in the direction parallel to its fibers. PMID- 20199912 TI - Magnetic resonance poroelastography: an algorithm for estimating the mechanical properties of fluid-saturated soft tissues. AB - Magnetic resonance poroelastography (MRPE) is introduced as an alternative to single-phase model-based elastographic reconstruction methods. A 3-D finite element poroelastic inversion algorithm was developed to recover the mechanical properties of fluid-saturated tissues. The performance of this algorithm was assessed through a variety of numerical experiments, using synthetic data to probe its stability and sensitivity to the relevant model parameters. Preliminary results suggest the algorithm is robust in the presence of noise and capable of producing accurate assessments of the underlying mechanical properties in simulated phantoms. Furthermore, a 3-D time-harmonic motion field was recorded for a poroelastic phantom containing a single cylindrical inclusion and used to assess the feasibility of MRPE image reconstruction from experimental data. The elastograms obtained from the proposed poroelastic algorithm demonstrate significant improvement over linearly elastic MRE images generated using the same data. In addition, MRPE offers the opportunity to estimate the time-harmonic pressure field resulting from tissue excitation, highlighting the potential for its application in the diagnosis and monitoring of disease processes associated with changes in interstitial pressure. PMID- 20199916 TI - In vivo supervised analysis of stent reendothelialization from optical coherence tomography. AB - The aim of this study is to interactively assess reendothelialization of stents at an accuracy of down to a few micrometer by analyzing endovascular optical coherence tomography (OCT) sequences. Vessel wall and stent struts are automatically detected by using morphological, gradient, and symmetry operators coupled with active contour models; alerts are issued to ask for user supervision over some extreme irregular geometries caused by thrombotic lesions or dissections. A complete distance map is then computed from sparse distances measured between wall and struts. Missing values are interpolated by thin-plate spline (TPS) functions. Accuracy and robustness are increased by taking into account the inhomogeneity of data points and integrating in the same framework orthogonalized forward selection of support points, optimal selection of regularization parameters by generalized cross-validation, and rejection of detection outliers. Validation is performed on simulated data, phantom acquisitions and 11 typical in vivo OCT sequences. The comparison against manual expert measurements demonstrates a bias of the order of OCT resolution (less than 10 microm) and a standard deviation of the order of the strut width (less than 150 microm). PMID- 20199915 TI - Modeling the performance characteristics of computed radiography (CR) systems. AB - Computed radiography (CR) using storage phosphors is widely used in digital radiography and mammography. A cascaded linear systems approach wherein several parameter values were estimated using Monte Carlo methods was used to model the image formation process of a single-side read ;;flying spot'' CR system using a granular phosphor. Objective image quality metrics such as modulation transfer function and detective quantum efficiency were determined using this model and show good agreement with published empirical data. A model such as that addressed in this work could allow for improved understanding of the effect of storage phosphor physical properties and CR reader parameters on objective image quality metrics for existing and evolving CR systems. PMID- 20199917 TI - Optimal experimental design for diffusion kurtosis imaging. AB - Diffusion kurtosis imaging (DKI) is a new magnetic resonance imaging (MRI) model that describes the non-Gaussian diffusion behavior in tissues. It has recently been shown that DKI parameters, such as the radial or axial kurtosis, are more sensitive to brain physiology changes than the well-known diffusion tensor imaging (DTI) parameters in several white and gray matter structures. In order to estimate either DTI or DKI parameters with maximum precision, the diffusion weighting gradient settings that are applied during the acquisition need to be optimized. Indeed, it has been shown previously that optimizing the set of diffusion weighting gradient settings can have a significant effect on the precision with which DTI parameters can be estimated. In this paper, we focus on the optimization of DKI gradients settings. Commonly, DKI data are acquired using a standard set of diffusion weighting gradients with fixed directions and with regularly spaced gradient strengths. In this paper, we show that such gradient settings are suboptimal with respect to the precision with which DKI parameters can be estimated. Furthermore, the gradient directions and the strengths of the diffusion-weighted MR images are optimized by minimizing the Cramer-Rao lower bound of DKI parameters. The impact of the optimized gradient settings is evaluated, both on simulated as well as experimentally recorded datasets. It is shown that the precision with which the kurtosis parameters can be estimated, increases substantially by optimizing the gradient settings. PMID- 20199918 TI - Gap-filling for the high-resolution PET sinograms with a dedicated DCT-domain filter. AB - High-resolution positron emission tomography (PET) scanners have brought many improvements to the nuclear medicine imaging field. However, the mechanical limitations in the construction of the scanners introduced gaps between the detectors, and accordingly, to the acquired projection data. When the methods requiring full-sinogram dataset, e.g., filtered backprojection (FBP) are applied, the missing parts degrade the reconstructed images. In this study, we aim to compensate the sinograms for the missing parts, i.e., gaps. For the gap filling, we propose an iterative discrete-cosine transform (DCT) domain method with two versions: 1) with basic DCT domain filter and 2) with dedicated and gap-dependent DCT domain filter. For the testing of the methods, 2-D FBP reconstructions were applied to the gap-filled sinograms. The proposed DCT domain gap-filling method with two different filters was compared to the constrained Fourier space (CFS) method. For the quantitative analysis, we used numerical phantoms at eight different Poisson noise levels with 100 realizations. Mean-square error, bias, and variance evaluations were performed over the selected regions of interest. Only the dedicated gap-dependent DCT domain filter showed quantitative improvement in all regions, at each noise level. We also assessed the methods visually with a [(11) C] raclopride human brain study reconstructed by 2-D FBP after gap filling. The visual comparisons of the methods showed that the gap filling with both DCT domain filters performed better than the CFS method. The proposed technique can be used for the sinograms, not only with limited range of projections as in the high-resolution research tomograph (ECAT HRRT) PET scanner, but also with detector failure artifacts. PMID- 20199919 TI - Topomorphologic separation of fused isointensity objects via multiscale opening: separating arteries and veins in 3-D pulmonary CT. AB - A novel multiscale topomorphologic approach for opening of two isointensity objects fused at different locations and scales is presented and applied to separating arterial and venous trees in 3-D pulmonary multidetector X-ray computed tomography (CT) images. Initialized with seeds, the two isointensity objects (arteries and veins) grow iteratively while maintaining their spatial exclusiveness and eventually form two mutually disjoint objects at convergence. The method is intended to solve the following two fundamental challenges: how to find local size of morphological operators and how to trace continuity of locally separated regions. These challenges are met by combining fuzzy distance transform (FDT), a morphologic feature with a topologic fuzzy connectivity, and a new morphological reconstruction step to iteratively open finer and finer details starting at large scales and progressing toward smaller scales. The method employs efficient user intervention at locations where local morphological separability assumption does not hold due to imaging ambiguities or any other reason. The approach has been validated on mathematically generated tubular objects and applied to clinical pulmonary noncontrast CT data for separating arteries and veins. The tradeoff between accuracy and the required user intervention for the method has been quantitatively examined by comparing with manual outlining. The experimental study, based on a blind seed selection strategy, has demonstrated that above 95% accuracy may be achieved using 25-40 seeds for each of arteries and veins. Our method is very promising for semiautomated separation of arteries and veins in pulmonary CT images even when there is no object-specific intensity variation at conjoining locations. PMID- 20199920 TI - Advanced level-set-based cell tracking in time-lapse fluorescence microscopy. AB - Cell segmentation and tracking in time-lapse fluorescence microscopy images is a task of fundamental importance in many biological studies on cell migration and proliferation. In recent years, level sets have been shown to provide a very appropriate framework for this purpose, as they are well suited to capture topological changes occurring during mitosis, and they easily extend to higher dimensional image data. This model evolution approach has also been extended to deal with many cells concurrently. Notwithstanding its high potential, the multiple-level-set method suffers from a number of shortcomings, which limit its applicability to a larger variety of cell biological imaging studies. In this paper, we propose several modifications and extensions to the coupled-active surfaces algorithm, which considerably improve its robustness and applicability. Our algorithm was validated by comparing it to the original algorithm and two other cell segmentation algorithms. For the evaluation, four real fluorescence microscopy image datasets were used, involving different cell types and labelings that are representative of a large range of biological experiments. Improved tracking performance in terms of precision (up to 11%), recall (up to 8%), ability to correctly capture all cell division events, and computation time (up to nine times reduction) is achieved. PMID- 20199921 TI - Automatic 3-D breath-hold related motion correction of dynamic multislice MRI. AB - Magnetic resonance (MR) cine images are often used to clinically assess left ventricular cardiac function. In a typical study, multiple 2-D long axis (LA) and short axis (SA) cine images are acquired, each in a different breath-hold. Differences in lung volume during breath-hold and overall patient motion distort spatial alignment of the images thus complicating spatial integration of all image data in three dimensions. We present a fully automatic postprocessing approach to correct these slice misalignments. The approach is based on the constrained optimization of the intensity similarity of intersecting image lines after the automatic definition of a region of interest. It uses all views and all time frames simultaneously. Our method models both in-plane and out-of-plane translations and full 3-D rotations, can be applied retrospectively and does not require a cardiac wall segmentation. The method was validated on both healthy volunteer and patient data with simulated misalignments, as well as on clinical multibreath-hold patient data. For the simulated data, subpixel accuracy could be obtained using translational correction. The possibilities and limitations of rotational correction were investigated and discussed. For the clinical multibreath-hold patient data sets, the median discrepancy between manual SA and LA contours was reduced from 2.83 to 1.33 mm using the proposed correction method. We have also shown the usefulness of the correction method for functional analysis on clinical image data. The same clinical multibreath-hold data sets were resegmented after positional correction, taking newly available complementary information of intersecting slices into account, further reducing the median discrepancy to 0.43 mm. This is due to the integration of the 2-D slice information into 3-D space. PMID- 20199922 TI - Target tracking errors for 5D and 6D spatial measurement systems. AB - In recent years, magnetic tracking systems, whose fundamental unit of measurement is a 5D transformation (three translational and two rotational degrees-of freedom), have become much more popular. Two 5D sensors can be combined to obtain a 6D transformation similar to the ones provided by the point-based registration in optical tracking. However, estimates of the tool tip uncertainty, which we have called the target tracking error (TTE) since no registration is explicitly performed, are not available in the same manner as their optical counterpart. If the systematic bias error can be corrected and estimates of the 5D or 6D fiducial localizer error (FLE) are provided in the form of zero mean normally distributed random variables in [Formula: see text] and [Formula: see text], respectively, then the TTE can be modeled. In this paper, the required expressions that model the TTE as a function of the systematic bias, FLE and target location are derived and then validated using Monte Carlo simulations. We also show that the first order approximation is sufficient beyond the range of errors typically observed during an image-guided surgery (IGS) procedure. Applications of the models are described for a minimally invasive intracardiac surgical guidance system and needle-based therapy systems. Together with the target registration error (TRE) statistical models for point-based registration, the models presented in this article provide the basic framework for estimating the total system measurement uncertainty for an IGS system. Future work includes developing TRE models for commonly used registration methods that do not already have them. PMID- 20199923 TI - Synthetic magnetic resonance imaging revisited. AB - Synthetic magnetic resonance (MR) imaging is an approach suggested in the literature to predict MR images at different design parameter settings from at least three observed MR scans. However, performance is poor when no regularization is used in the estimation and otherwise computationally impractical to implement for 3-D imaging methods. We propose a method which accounts for spatial context in MR images by the imposition of a Gaussian Markov random field (MRF) structure on a transformation of the spin-lattice relaxation time, the spin-spin relaxation time and the proton density at each voxel. The MRF structure is specified through a matrix normal distribution. We also model the observed magnitude images using the more accurate but computationally challenging Rice distribution. A one-step-late expectation-maximization approach is adopted to make our approach computationally practical. We evaluate predictive performance in generating synthetic MR images in a clinical setting: our results indicate that our suggested approach is not only computationally feasible to implement but also shows excellent performance. PMID- 20199925 TI - Three-dimensional imaging properties of rotation-free square and hexagonal micro CT systems. AB - We study the 3-D imaging properties of a rotation-free micro-computed tomography (CT) system with square and hexagonal geometries. These systems use linear arrays of carbon-nanotube-based X-ray sources that are individually addressable. The source arrays and area detectors in the square and the hexagonal geometries form the sides of a polygon. The tomographic angular sampling for both geometries requires no motion of the sources, the detectors, or the subject. We demonstrate that the hexagonal geometry has improved angular coverage as compared to the square geometry. The ordered-subset convex iterative algorithm is implemented in both geometries for reconstructions from cone-beam projection data. Simulation studies show that both geometries can be effectively reconstructed with polychromatic or monochromatic source spectra. As a result of the incomplete tomographic sampling of the two geometries, some streaking artifacts appear in the reconstructed images. The hexagonal geometry, in general, produces fewer streaking artifacts than the square geometry. On the other hand, the two geometries perform quite similarly in resolution-noise trade-off, so we conclude that the proposed geometries are comparably effective for the rotation-free micro CT and the hexagonal geometry is superior in reducing streaking artifacts. PMID- 20199924 TI - A coupled level set framework for bladder wall segmentation with application to MR cystography. AB - In this paper, we propose a coupled level set (LS) framework for segmentation of bladder wall using T(1)-weighted magnetic resonance (MR) images with clinical applications to virtual cystoscopy (i.e., MR cystography). The framework uses two collaborative LS functions and a regional adaptive clustering algorithm to delineate the bladder wall for the wall thickness measurement on a voxel-by-voxel basis. It is significantly different from most of the pre-existing bladder segmentation work in four aspects. First of all, while most previous work only segments the inner border of the wall or at most manually segments the outer border, our framework extracts both the inner and outer borders automatically except that the initial seed point is given by manual selection. Secondly, it is adaptive to T(1)-weighted images with decreased intensities in urine, as opposed to enhanced intensities in T(2)-weighted scenario and computed tomography. Thirdly, by considering the image global intensity distribution and local intensity contrast, the defined image energy function in the framework is more immune to inhomogeneity effect, motion artifacts and image noise. Finally, the bladder wall thickness is measured by the length of integral path between the two borders which mimic the electric field line between two iso-potential surfaces. The framework was tested on six datasets with comparison to the well-known Chan Vese (C-V) LS model. Five experts blindly scored the segmented inner and outer borders of the presented framework and the C-V model. The scores demonstrated statistically the improvement in detecting the inner and outer borders. PMID- 20199926 TI - Registering preprocedure volumetric images with intraprocedure 3-D ultrasound using an ultrasound imaging model. AB - For many image-guided interventions there exists a need to compute the registration between preprocedure image(s) and the physical space of the intervention. Real-time intraprocedure imaging such as ultrasound (US) can be used to image the region of interest directly and provide valuable anatomical information for computing this registration. Unfortunately, real-time US images often have poor signal-to-noise ratio and suffer from imaging artefacts. Therefore, registration using US images can be challenging and significant preprocessing is often required to make the registrations robust. In this paper we present a novel technique for computing the image-to-physical registration for minimally invasive cardiac interventions using 3-D US. Our technique uses knowledge of the physics of the US imaging process to reduce the amount of preprocessing required on the 3-D US images. To account for the fact that clinical US images normally undergo significant image processing before being exported from the US machine our optimization scheme allows the parameters of the US imaging model to vary. We validated our technique by computing rigid registrations for 12 cardiac US/magnetic resonance imaging (MRI) datasets acquired from six volunteers and two patients. The technique had mean registration errors of 2.1-4.4 mm, and 75% capture ranges of 5-30 mm. We also demonstrate how the same approach can be used for respiratory motion correction: on 15 datasets acquired from five volunteers the registration errors due to respiratory motion were reduced by 45%-92%. PMID- 20199927 TI - Application and evaluation of a measured spatially variant system model for PET image reconstruction. AB - Accurate system modeling in tomographic image reconstruction has been shown to reduce the spatial variance of resolution and improve quantitative accuracy. System modeling can be improved through analytic calculations, Monte Carlo simulations, and physical measurements. The purpose of this work is to improve clinical fully-3-D reconstruction without substantially increasing computation time. We present a practical method for measuring the detector blurring component of a whole-body positron emission tomography (PET) system to form an approximate system model for use with fully-3-D reconstruction. We employ Monte Carlo simulations to show that a non-collimated point source is acceptable for modeling the radial blurring present in a PET tomograph and we justify the use of a Na22 point source for collecting these measurements. We measure the system response on a whole-body scanner, simplify it to a 2-D function, and incorporate a parameterized version of this response into a modified fully-3-D OSEM algorithm. Empirical testing of the signal versus noise benefits reveal roughly a 15% improvement in spatial resolution and 10% improvement in contrast at matched image noise levels. Convergence analysis demonstrates improved resolution and contrast versus noise properties can be achieved with the proposed method with similar computation time as the conventional approach. Comparison of the measured spatially variant and invariant reconstruction revealed similar performance with conventional image metrics. Edge artifacts, which are a common artifact of resolution-modeled reconstruction methods, were less apparent in the spatially variant method than in the invariant method. With the proposed and other resolution-modeled reconstruction methods, edge artifacts need to be studied in more detail to determine the optimal tradeoff of resolution/contrast enhancement and edge fidelity. PMID- 20199928 TI - Auto-calibrated parallel imaging reconstruction for arbitrary trajectories using k-space sparse matrices (kSPA). AB - Image acquisition of magnetic resonance imaging (MRI) can be accelerated by using multiple receiving coils simultaneously. The problem of reconstructing an unaliased image from partially sampled k-space data can be formulated as a large system of sparse linear equations. The k-space sparse matrix (kSPA) algorithm proposes to solve the system of equations by finding a sparse approximate inverse. This algorithm has been shown to accelerate the image reconstruction for a large number of coils. The original kSPA algorithm requires knowledge of coil sensitivities. Here, we propose and demonstrate an auto-calibrated kSPA algorithm that does not require the explicit computation of the coil sensitivity maps. We have also shown that calibration data, in principle, can be acquired at any region of k-space. This property applies to arbitrary sampling trajectories and all reconstruction algorithms based on k-space. In practice, because of its higher SNR, calibration data acquired at the center of k-space performed more favorably. Such auto-calibration can be advantageous in cases where an accurate sensitivity map is difficult to obtain. PMID- 20199930 TI - Exploring cross-species-related miRNAs based on sequence and secondary structure. AB - MicroRNA (miRNA) plays an important role as a regulator of mRNA. But how miRNAs relate with each other in gene regulation network is still remaining. Understanding the reactions between miRNAs can be very significant for exploring miRNA target, gene regulation mechanism, and gene conservation in evolution process. We explore cross-species-related miRNAs to find out how miRNAs regulate each other by using joint entropy and mutual information, respectively. Our contribution includes the following: 1) our algorithms are based on the combination of sequence and secondary structure analysis because miRNAs are conserved much better in the secondary structure; and 2) when we consider if two miRNAs A and B are related, we consider the relationship between A (B) and other miRNAs in their own species too. If A (B) has a very close relationship with other miRNAs in its own species and the relationship of A and B is close too, then the relationship between A and B is more important. Therefore, this related miRNA pair is more significant. So, our algorithms confirm to the reality that genes regulate each other as a network. Through experiments on miRNAMap 2.0, it has been proven that we can not only find out the known related miRNA pairs but also predict some novel ones. PMID- 20199931 TI - A Bayesian reconstruction method with marginalized uncertainty model for camera motion in microrotation imaging. AB - Reconstruction of a 3-D structure from multiple projection images requires prior knowledge of projection directions or camera motion parameters that describe the relative positions and orientations of 3-D structure with respect to the camera. These parameters can be estimated using, for instance, the conventional correlation alignment and feature-based methods. However, the alignment methods are not perfect, where the inaccuracy of the estimated motion parameters causes artifacts in the reconstruction. To overcome this problem, we propose a bayesian approach to reconstruct the object that takes the motion uncertainty distribution into account. Moreover, we consider the motion parameters as nuisance parameters and integrate them out from the posterior distribution, assuming a gaussian uncertainty model, which yields a statistical cost function to be minimized. The proposed method is applied in microrotation fluorescence imaging, where we aim at 3-D reconstruction of a rotating object from an image series, acquired by an optical microscope. The experiments with simulated and real microrotation datasets demonstrate that the proposed method provides visually and numerically better results than the traditional reconstruction methods, which ignore the uncertainty of the motion estimates. PMID- 20199932 TI - Integrated laser Doppler blood flowmeter designed to enable wafer-level packaging. AB - The authors propose a new sensor structure for an integrated laser Doppler blood flowmeter that consists of two silicon cavities with a PD and laser diode inside each cavity. A silicon lid formed with a converging microlens completes the package. This structure, which was achieved using micromachining techniques, features reduced optical power loss in the sensor, resulting in its small size and significantly low power consumption. Measurements using a model tissue blood flow system confirmed that the new sensor had high linearity and a wide dynamic range for measuring tissue blood flow. PMID- 20199933 TI - Automatic area classification in peripheral blood smears. AB - Cell enumeration and diagnosis using peripheral blood smears are routine tasks in many biological and pathological examinations. Not every area in the smear is appropriate for such tasks due to severe cell clumping or sparsity. Manual working-area selection is slow, subjective, inconsistent, and statistically biased. Automatic working-area classification can reproducibly identify appropriate working smear areas. However, very little research has been reported in the literature. With the aim of providing a preprocessing step for further detailed cell enumeration and diagnosis for high-throughput screening (HTS), we propose an integrated algorithm for area classification and quantify both cell spreading and cell clumping in terms of individual clumps and the occurrence probabilities of the group of clumps over the image. Comprehensive comparisons are presented to compare the effect of these quantifications and their combinations. Our experiments using images of Giemsa-stained blood smears show that the method is efficient, accurate (above 88.9% hit rates for all areas in the validation set of 140 images), and robust (above 78.1% hit rates for a test set of 4878 images). This lays a good foundation for fast working-area selection in HTS. PMID- 20199934 TI - Neural mechanisms of the mind, Aristotle, Zadeh, and fMRI. AB - Processes in the mind: perception, cognition, concepts, instincts, emotions, and higher cognitive abilities for abstract thinking, beautiful music are considered here within a neural modeling fields (NMFs) paradigm. Its fundamental mathematical mechanism is a process "from vague-fuzzy to crisp," called dynamic logic (DL). This paper discusses why this paradigm is necessary mathematically, and relates it to a psychological description of the mind. Surprisingly, the process from "vague to crisp" corresponds to Aristotelian understanding of mental functioning. Recent functional magnetic resonance imaging (fMRI) measurements confirmed this process in neural mechanisms of perception. PMID- 20199935 TI - Invariant set of weight of perceptron trained by perceptron training algorithm. AB - In this paper, an invariant set of the weight of the perceptron trained by the perceptron training algorithm is defined and characterized. The dynamic range of the steady-state values of the weight of the perceptron can be evaluated by finding the dynamic range of the weight of the perceptron inside the largest invariant set. In addition, the necessary and sufficient condition for the forward dynamics of the weight of the perceptron to be injective, as well as the condition for the invariant set of the weight of the perceptron to be attractive, is derived. PMID- 20199936 TI - Low-resolution gait recognition. AB - Unlike other biometric authentication methods, gait recognition is noninvasive and effective from a distance. However, the performance of gait recognition will suffer in the low-resolution (LR) case. Furthermore, when gait sequences are projected onto a nonoptimal low-dimensional subspace to reduce the data complexity, the performance of gait recognition will also decline. To deal with these two issues, we propose a new algorithm called superresolution with manifold sampling and backprojection (SRMS), which learns the high-resolution (HR) counterparts of LR test images from a collection of HR/LR training gait image patch pairs. Then, we incorporate SRMS into a new algorithm called multilinear tensor-based learning without tuning parameters (MTP) for LR gait recognition. Our contributions include the following: 1) With manifold sampling, the redundancy of gait image patches is remarkably decreased; thus, the superresolution procedure is more efficient and reasonable. 2) Backprojection guarantees that the learned HR gait images and the corresponding LR gait images can be more consistent. 3) The optimal subspace dimension for dimension reduction is automatically determined without introducing extra parameters. 4) Theoretical analysis of the algorithm shows that MTP converges. Experiments on the USF human gait database and the CASIA gait database show the increased efficiency of the proposed algorithm, compared with previous algorithms. PMID- 20199937 TI - On cooperative and efficient overlay network evolution based on a group selection pattern. AB - In overlay networks, the interplay between network structure and dynamics remains largely unexplored. In this paper, we study dynamic coevolution between individual rational strategies (cooperative or defect) and the overlay network structure, that is, the interaction between peer's local rational behaviors and the emergence of the whole network structure. We propose an evolutionary game theory (EGT)-based overlay topology evolution scheme to drive a given overlay into the small-world structure (high global network efficiency and average clustering coefficient). Our contributions are the following threefold: From the viewpoint of peers' local interactions, we explicitly consider the peer's rational behavior and introduce a link-formation game to characterize the social dilemma of forming links in an overlay network. Furthermore, in the evolutionary link-formation phase, we adopt a simple economic process: Each peer keeps one link to a cooperative neighbor in its neighborhood, which can slightly speed up the convergence of cooperation and increase network efficiency; from the viewpoint of the whole network structure, our simulation results show that the EGT-based scheme can drive an arbitrary overlay network into a fully cooperative and efficient small-world structure. Moreover, we compare our scheme with a search-based economic model of network formation and illustrate that our scheme can achieve the experimental and analytical results in the latter model. In addition, we also graphically illustrate the final overlay network structure; finally, based on the group selection model and evolutionary set theory, we theoretically obtain the approximate threshold of cost and draw the conclusion that the small value of the average degree and the large number of the total peers in an overlay network facilitate the evolution of cooperation. PMID- 20199938 TI - Special issue on game theory. PMID- 20199939 TI - Networked synchronization control of coupled dynamic networks with time-varying delay. AB - This paper is concerned with the networked synchronization control problem of coupled dynamic networks (CDNs) with time-varying delay. First, both the data packet dropouts and network-induced delays are taken into account in the synchronization controller design. A Markovian jump process is induced to describe the packet dropouts. The network-induced delays are interval time varying and depend on the Markovian jump modes. A new closed-loop coupled dynamic error system (CDES) with Markovian jump parameters and interval time-varying delays is constructed. Second, using the Kronecker product technique and the stochastic Lyapunov method, a delay-dependent sufficient criterion of stochastic stability is obtained for the closed-loop CDES, which also guarantees that the CDNs are stochastically synchronized. Finally, a simulation example is given to demonstrate the effectiveness of the proposed result. PMID- 20199940 TI - The role of radiology in head and neck tumours in children. AB - Head and neck malignancy is rare in children. However, distinguishing malignant tumours from the more common and numerous benign causes of neck masses in childhood is crucial as many malignant conditions have an excellent prognosis with appropriate oncological management. Ultrasound, computed tomography and magnetic resonance imaging all have crucial roles in the diagnosis of head and neck malignancy in children and there is an emerging role for positron emission tomography, particularly in the management and follow-up of lymphoma. We describe the imaging appearances of the common malignant tumours arising in the extracranial head and neck in children, focusing on lymphoma, rhabdomyosarcoma and nasopharyngeal carcinoma. The clinical presentation and radiological appearances of benign tumours in the head and neck in children may overlap with those seen in malignant disease. We describe the imaging appearances of juvenile angiofibroma, vascular abnormalities involving the extracranial head and neck and cervical teratomas. Advances in both imaging techniques and cancer staging systems, many of the latter aimed at avoiding over-treatment and treatment related complications, will lead to an increasingly central role for imaging in childhood head and neck cancer. PMID- 20199941 TI - Ultrasound of the prostate. AB - Ultrasound is a widely used imaging modality for evaluation of the prostate. The main topic of diagnostic imaging is an improvement of prostate cancer diagnosis. The current available systematic prostate biopsy is performed only under ultrasound guidance, but new imaging techniques allow prostate cancer visualization and therefore improved detection. Evolving methods such as contrast enhanced colour Doppler imaging, contrast-specific ultrasound techniques and elastography may dramatically change the role of ultrasound for prostate cancer diagnosis. The purpose of this review is to provide an overview of ultrasound and its different techniques for imaging of the prostate and to discuss current trends and future directions. PMID- 20199943 TI - Selection of ideal candidates for extratemporal resective epilepsy surgery in a country with limited resources. AB - AIM: To investigate how to select ideal candidates for extratemporal resective epilepsy surgery, without compromising efficacy and safety, in countries with limited pre-surgical diagnostic facilities. METHOD: From the prospective database maintained at an epilepsy surgery centre in southern India, we reviewed the attributes of consecutive patients who had completed at least two years of follow up after resections involving frontal, parietal and occipital lobes for medically refractory focal seizures. RESULTS: Of 386 patients diagnosed with extratemporal refractory epilepsies during the study period, 61 (15.8%) were selected based on the presence of magnetic resonance imaging (MRI)-identified lesions (in all) and concordant scalp recorded electroencephalographic (EEG) data (in nearly two thirds). Seventeen (27.8%) required invasive investigations either to define the ictal onset zone, eloquent area, or both. During a median follow-up period of five years, 63% of our patients were seizure-free, excluding the presence of auras. Permanent disabling neurological sequelae occurred in three (4.9%) patients. According to univariate analysis, pre-operative secondary generalised seizures and interictal epileptiform discharges (IEDs), during a one-year post operative EEG monitoring period, portended unfavourable seizure outcome. In multivariate analysis, frontal lobe resections and IEDs in post-operative EEGs were independent predictors of unfavourable outcome. CONCLUSIONS: Extratemporal resective epilepsy surgery can be undertaken in countries with limited resources with efficacy and safety, comparable to that in developed countries, when patients are selected based on the presence of MRI-identified lesions and scalp EEG concordance. In such patients, invasive EEG examinations, when necessary, can be undertaken by limited coverage of cortical areas at an affordable cost. PMID- 20199942 TI - mot-2-Mediated cross talk between nuclear factor-B and p53 is involved in arsenite-induced tumorigenesis of human embryo lung fibroblast cells. AB - BACKGROUND: Inactivation of p53 is involved in arsenite-induced tumorigenesis; however, the molecular mechanisms remain poorly understood. OBJECTIVE: We investigated the molecular mechanisms underlying the inactivation of p53 and neoplastic transformation induced by arsenite in human embryo lung fibroblast (HELF) cells. METHODS: Anchorage-independent growth assays were performed, and tumorigenicity in intact animals was assessed to confirm arsenite-induced neoplastic transformation. We determined the levels and functions of p53, nuclear factor-kappa B (NF-B; a key transcriptional regulator), and mot-2 (a p53 inhibitor) and their relationships in arsenite-induced transformed HELF cells by two-dimensional electrophoresis, reverse-transcriptase polymerase chain reaction, Western blot, immunofluorescence, and co-immunoprecipitation assays. RESULTS: Exposure of HELF cells to low levels of arsenite increased their proliferation rate and anchorage-independent growth and disrupted normal contact inhibition. When introduced into nude mice, transformed cells were tumorigenic. We used proteomic analysis to identify proteins with altered expression between untreated and arsenite-exposed cells. We found decreased expression of NF-B repressing factor (NKRF; an inhibitor of NF-B-mediated gene transcription), increased expression of mot-2, and increased activation of NF-B. Changes in cells exposed to 1.0 microM arsenite were more marked than changes in cells exposed to 0.5 or 2.0 microM arsenite. Inactivation of NF-B prevented malignant transformation induced by 1.0 microM arsenite. Moreover, we also identified a mechanism whereby NF-B regulated p53. Specifically, activation of NF-B up-regulated mot-2 expression, which prevented nuclear translocation of p53 and switched the binding preference of the p53 and NF-B coactivator CBP [cyclic AMP-responsive element binding protein (CREB) binding protein] from p53 to NF-B. CONCLUSIONS: mot-2 mediated cross talk between NF-B and p53 appears to be involved in arsenite induced tumorigenesis of HELF cells. PMID- 20199944 TI - Long-term and late seizure outcome after surgery for temporal lobe epilepsy. AB - AIM: Although surgery for temporal lobe epilepsy (TLE) harbours a good prognosis, post-operative seizures may occur. Long-term, post-operative seizure follow-ups are rare but necessary to properly define outcome. METHODS: Longitudinal, long term, post-operative seizure follow-up in TLE patients with outcome analysed using Engel's classification. Three groups were considered according to the type of resection: isolated amygdalohippocampectomy (IAH), further divided into anterior and complete, AH plus focal neocortical resections (AH + FR) and focal neocortical resections (FR). RESULTS: Eighty-nine patients were enrolled (61 in the IAH group, 24 in the AH + FR group, and four in the FR group), with a mean follow-up time of 46.7 months. For the three groups together, 90.9% and 86.7% of the patients were in Engel class I for six months and five years, respectively. Kaplan-Meir analysis of the IAH and AH + FR groups showed that, while 82.2% of patients of the IAH group tended to remain in class I within 84 months after surgery, 86.7% of the AH + FR group tended to remain in class I within 12 months. Kaplan-Meier analysis of the IAH sub-groups showed that more patients (91.0%) with anterior resection tended to remain in class I, although for a longer period of time (36 months), compared to those with complete resection (84.0% of patients and 12 months, respectively). For the IFR group, only three patients were in Engel class I for long-term follow-up. CONCLUSIONS: High rates of seizure freedom were obtained and stably maintained for years. The reasons for better long-term prognosis of the anterior IAH group are so far unclear, the IFR group was too small to draw any conclusive data. PMID- 20199945 TI - [Trilateral retinoblastoma in Burkina Faso: three cases]. AB - The authors describe three cases of trilateral retinoblastoma, a rare syndrome that occurs most often in young children. Two of these children were 3 years old at diagnosis, and the other 4 years old. The retinoblastoma was unilateral in one child and bilateral in the others. All underwent computed tomography (CT) imaging, which made it possible to locate the intraocular tumor lesions, to specify the extent of the tumor and to look for a possible intracranial neoplasm. Unfortunately, the cost of CT is high, which limits its use in our context. PMID- 20199946 TI - Health information technology: A new world for pharmacy. AB - OBJECTIVES: To provide a health information technology (HIT) primer for pharmacists, including the current state of HIT, future expectations, basic information and vocabulary, HIT vendors, communication standards, barriers to implementation, and strategies for pharmacists to ensure success. DATA SOURCES: By the authors. SUMMARY: HIT is expected to provide integrated electronic health care with interactive exchange among patients, providers, government agencies, and insurers, resulting in an increase in the overall quality, safety, and efficiency of health care delivery with fewer medical errors, increased administrative efficiency, decreased health care costs, and expanded patient access to affordable health care. Government incentives are in place in an effort to expedite the nationwide implementation of HIT. CONCLUSION: With the government and IT industry applying pressure, HIT is a reality; the only remaining questions are how quickly and how thoroughly HIT will affect the health care system. PMID- 20199947 TI - Scope of contemporary pharmacy practice: roles, responsibilities, and functions of pharmacists and pharmacy technicians. AB - OBJECTIVE: To provide an overview of the current context and scope of pharmacy practice, the range of professional services offered by pharmacists, and the supporting role of pharmacy technicians. DATA SYNTHESIS: A synopsis of the current state of pharmacy practice as it relates to the spectrum of professional roles and responsibilities, the diversity of patient populations served, the complexities of patient services provided, and various aspects of emerging pharmacy practice is provided. The current work focuses on patient care services provided by pharmacists; it does not address all possible activities of pharmacists, such as administration and general management. This is a descriptive analysis. It does not take a position regarding future changes but is intended to serve as a foundation for understanding the relationship and alignment between the profession's various mandatory and voluntary credentials and the scope of practice continuum. The key educational and credentialing standards for pharmacists and pharmacy technicians are summarized and referenced. CONCLUSION: The evolutions in health care and pharmacy practice are presenting many new opportunities for pharmacists to perform functions and provide services not considered as traditional roles. The profession of pharmacy is working to achieve a pervasive model and standard of care determined only by the needs of patients and populations. The Council on Credentialing in Pharmacy hopes that the material presented herein, including the framework for credentialing in pharmacy practice, will allow audiences to gain a better understanding of where pharmacy is today and what future pharmacy practice will look like. PMID- 20199949 TI - Single standard for education, training, and certification of pharmacy technicians. PMID- 20199951 TI - Pharmacists in public health: It's a good start! PMID- 20199952 TI - Comparative effectiveness research: Promising area of study for pharmacists. PMID- 20199953 TI - Vaccination delivery by chain pharmacies in California: Results of a 2007 survey. AB - OBJECTIVE: To better understand the practice standards and scope of pharmacist administered vaccination services at chain pharmacies in California. DESIGN: Cross sectional. SETTING: California in 2006-2007. PARTICIPANTS: Eight state level immunization coordinator corporate liaisons to chain pharmacies' immunization programs. INTERVENTION: Key informant phone survey with follow-up written survey. MAIN OUTCOME MEASURES: Policies, procedures, and vaccine usage. RESULTS: All eight chains provided immunization services to adults; four chains also vaccinated adolescents. More than 1,000 California pharmacists employed at chain pharmacies have been trained to vaccinate; more than 500 locations participate with evening, weekend, and walk-in hours. Influenza and pneumococcal vaccines were the most common vaccines administered. Other vaccines were used less frequently. Respondents expressed interest in partnering with public health to improve record sharing, build awareness, receive vaccine news updates, and explore other activities. CONCLUSION: Chain pharmacies in California have started to vaccinate adults and adolescents--two commonly undervaccinated age groups. To date, patients seeking vaccination at pharmacies are most likely to receive influenza and pneumococcal vaccines. Community locations and extended hours offer patients convenience, although out-of-pocket fees may be a barrier to some patients. Opportunities exist to build and strengthen partnerships among public health, the medical community, and pharmacists in order to vaccinate and protect patients not vaccinated in traditional settings. PMID- 20199954 TI - Comparison of injection drug users accessing syringes from pharmacies, syringe exchange programs, and other syringe sources to inform targeted HIV prevention and intervention strategies. AB - OBJECTIVE: To describe injection drug users (IDUs) who access syringes through different outlets to help inform the prevention needs of IDUs who underuse safe syringe sources in New York City (NYC), where syringe availability is high compared with other U.S. cities. DESIGN: Cross sectional. SETTING: NYC, 2005 2007. PARTICIPANTS: 285 IDUs. INTERVENTION: Participants were recruited using random street-intercept sampling in 36 socioeconomically disadvantaged neighborhoods. MAIN OUTCOME MEASURES: IDUs using syringe exchange programs (SEPs), pharmacies, or other outlets as a primary syringe source were compared based on sociodemographic characteristics, injection practices, and medical service use. RESULTS: Chi-square tests and polytomous logistic regression were used to compare IDUs with different self-reported primary syringe sources used in the 6 months preceding study entry. Compared with IDUs using other syringe sources, those primarily using SEPs were less likely to be black (adjusted odds ratio 0.26 [95% CI 0.11-0.57]), more likely to inject daily (3.32 [1.58-6.98]), and more likely to inject with a new syringe (2.68 [1.30-5.54]). Compared with IDUs using other syringe sources, those primarily using pharmacies were less likely to be black (0.39 [0.17-0.90]). CONCLUSION: These data suggest that pharmacies and SEPs may be reaching different populations of IDUs and highlight a subpopulation of highly marginalized IDUs (i.e., black race, infrequent injectors) who are underusing safe syringe sources in NYC. Targeted interventions are needed to reduce racial disparities and increase use of safe syringe outlets. PMID- 20199955 TI - Syringe exchange programs: Impact on injection drug users and the role of the pharmacist from a U.S. perspective. AB - OBJECTIVE: To present a summary of the existing literature on syringe exchange programs (SEPs) and to discuss the potential role of pharmacists in providing support for injection drug users (IDUs) and such programs. DATA SOURCES: To identify relevant articles published since 2000, a search of PubMed and Medline was conducted using syringe exchange programs and needle exchange programs as search terms. A manual review of each article's citation list was also conducted. DATA EXTRACTION: By the authors. DATA SYNTHESIS: Information is presented in four categories: state and federal support of SEPs, characteristics of SEP users, epidemiological studies, and social reluctance for SEP support. The information summarized in these sections is then used as a foundation for a review of the potential role of the pharmacist. CONCLUSION: SEPs have demonstrated a clear effect in improving the health outcomes of IDUs by decreasing the transmission of blood-borne disease and lowering high-risk injecting behaviors. Despite conflicting support for SEPs at both the federal and local levels, pharmacists can play a pivotal role in the health of IDUs by providing sound medical advice and, in some states, acting as an alternative channel for obtaining clean syringes. Efforts should continue to focus on educating pharmacists about this role and how their individual actions can benefit the health of the entire population. PMID- 20199956 TI - Call to action: Integrating student pharmacists, faculty, and pharmacy practitioners into emergency preparedness and response. AB - OBJECTIVES: To describe the pharmacist experience in emergency preparedness and response and to provide information and resources to help practitioners engage in this public health effort in their local communities. SETTING: Spokane, WA, health care community, 1998 through 2009. PRACTICE DESCRIPTION: The College of Pharmacy at Washington State University, Spokane, has developed partnerships with local public health and community providers to address emergency preparedness and response needs. Working through the Metropolitan Medical Response System has created opportunities to participate in emergency preparedness planning and exercises. Collaboration with local agencies has provided opportunities for faculty and student pharmacists to respond to meet emergency needs in the community. PRACTICE INNOVATION: Emergency preparedness and response education, training, and service implemented in partnership with public health and community providers prepared student pharmacists and experienced pharmacy practitioners to respond to emergency needs in our community. MAIN OUTCOME MEASURES: Not applicable. RESULTS: Not applicable. CONCLUSION: Colleges and schools of pharmacy can take a lead in preparing student pharmacists for this role by incorporating emergency preparedness training into curricula. Community pharmacists can develop their knowledge and skills in emergency preparedness through individualized continuing education plans and integration into community teams through volunteerism. Partnerships developed with local public health and emergency response agencies provide opportunities for pharmacists to become integral members of planning and response teams. Training exercises provide opportunities to test preparedness plans and provide professional education and experience. Actual emergency response activities demonstrate the value of the pharmacist as an important member of the emergency response team. PMID- 20199957 TI - Roles and contributions of pharmacists in regulatory affairs at the Centers for Disease Control and Prevention for public health emergency preparedness and response. AB - OBJECTIVE: To provide a general description of the roles and contributions of three pharmacists from the Regulatory Affairs program (RA) at the Centers for Disease Control and Prevention (CDC) who are involved in emergency preparedness and response activities, including the 2009 pandemic influenza A (H1N1) public health emergency. SETTING: Atlanta, GA. PRACTICE DESCRIPTION: RA consists of a staff of nine members, three of whom are pharmacists. The mission of RA is to support CDC's preparedness and emergency response activities and to ensure regulatory compliance for critical medical countermeasures against potential threats from natural, chemical, biological, radiological, or nuclear events. CONCLUSION: RA was well involved in the response to the H1N1 outbreak through numerous activities, such as submitting multiple Emergency Use Authorization (EUA) requests to the Food and Drug Administration, including those for medical countermeasures to be deployed from the Strategic National Stockpile, and developing the CDC EUA website (www.cdc.gov/h1n1flu/eua). RA will continue to support current and future preparedness and emergency response activities by ensuring that the appropriate regulatory mechanisms are in place for the deployment of critical medical countermeasures from the Strategic National Stockpile against threats to public health. PMID- 20199958 TI - Encouraging safe medication disposal through student pharmacist intervention. AB - OBJECTIVES: To (1) determine the public's current method of medication disposal, (2) identify the public's knowledge of the environmental impact of inappropriate medication disposal, (3) determine whether student-facilitated education improves the public's awareness of safe medication disposal, and (4) determine whether the public recognizes student pharmacists as a public health information resource for issues such as safe disposal of medications. DESIGN: Cross sectional. SETTING: Albany, NY, pharmacies during August and September 2009. PARTICIPANTS: 242 patrons at 13 Albany College of Pharmacy and Health Sciences Community Pharmacy Advanced Pharmacy Practice Experience (CPAPPE) sites (2 mass merchandiser, 5 community chain, and 6 grocery store pharmacies). INTERVENTION: Nine-question baseline and five-question postintervention anonymous surveys were administered to a convenience sample of store patrons 18 years of age or older. MAIN OUTCOME MEASURES: Medication disposal practices before and after education, beliefs on the environmental importance of inappropriate disposal practices, and perceptions of student pharmacists as sources of information. RESULTS: Students from CPAPPE sites completed 242 educational interventions. Respondents were primarily women (72%). At baseline, 12.8% of patients disposed of medication appropriately. Respondents frequently flushed medications down the toilet (27.2%) or incorrectly dumped medications in the trash (34.6%). Only 30.9% had received previous advice on safe medication disposal. Posteducation survey results indicated that 80.1% of respondents were willing to change their disposal methods. Increased numbers of respondents viewed inappropriate medication disposal as a moderate to substantial problem (from 57.2% preeducation to 83.9% posteducation). Of participants, 59.7% strongly agreed that student pharmacists were a good resource for information on safe medication disposal. CONCLUSION: Additional public education on safe medication disposal is needed. Student pharmacists produced positive outcomes toward reducing this environmental and potential public health risk. PMID- 20199959 TI - Measuring outcomes of a pharmacist-run travel health clinic located in an independent community pharmacy. AB - OBJECTIVES: To describe the acceptance and refusal rates of travel-related vaccine and medication recommendations in a pharmacist-run travel health clinic, to evaluate the change in patient understanding of travel-related issues, to determine patient satisfaction with this clinic, and to determine factors influencing both patient acceptance and satisfaction. SETTING: Southern California (Claremont) between July 2007 and October 2008. PRACTICE DESCRIPTION: Hendricks Pharmacy is an independently owned community pharmacy that is part of the Good Neighbor Pharmacy Provider Network. The pharmacy offers a range of services including home delivery, compounding, and blood glucose, blood pressure, and cholesterol screenings. PRACTICE INNOVATION: Comprehensive pharmacist-run travel health clinic. MAIN OUTCOME MEASURES: Patient acceptance and refusal rates of pharmacist-made recommendations, changes in patient understanding of travel related issues resulting from pharmacist counseling, and patient satisfaction with this travel health clinic. RESULTS: In a sample of 283 patients, overall patient acceptance of pharmacist-made recommendations was 84.7%. The primary reason for patient refusal of a recommendation was self-perceived low risk for infection. A subsample of patients (n = 82) completing a patient satisfaction survey found that 96% were satisfied with their overall visit. Patient satisfaction with the clinic and pharmacist services was correlated with overall patient acceptance. CONCLUSIONS: The high rate of patient acceptance and satisfaction with this clinic supports adoption of pharmacists as nontraditional providers of travel health services. PMID- 20199960 TI - Comparative effectiveness of two pharmacy-based colorectal cancer screening interventions during an annual influenza vaccination campaign. AB - OBJECTIVE: To compare the effectiveness of two different pharmacy-based colorectal cancer screening (CRCS) interventions taking place during an annual influenza vaccination campaign. DESIGN: Time-randomized clinical trial. SETTING: San Francisco, CA, in late 2008. PARTICIPANTS: 133 adults aged 50 to 80 years visiting a pharmacy during an influenza vaccination campaign and also due for CRCS. INTERVENTION: On five dates, eligible patients were provided education and encouraged to obtain screening from their primary care clinician. On 17 dates, a home fecal immunochemical test (FIT) for CRCS was provided. A 16-item questionnaire was administered by phone 3 to 6 months after study enrollment. MAIN OUTCOME MEASURE: Self-reported CRCS activity, comparing CRCS completion rates for participants provided with the FIT versus those provided with education and encouragement to obtain screening from patients' primary care clinician. RESULTS: 86 participants in the FIT arm and 28 the CRCS education arm were interviewed. Interviews revealed that 19.8% of the FIT group and 50% of the CRCS education group discussed CRCS with their primary care clinician (P = 0.002). Of these participants, 59.3% in the FIT arm and 14.8% in the CRCS education arm reported completing screening (P < 0.001). Of participants in the FIT group, 52.2% completed FIT dispensed to them by the investigators. Most participants in both groups reported interest in receiving CRCS education and home CRCS tests from pharmacists in the future. CONCLUSION: Pharmacy patients are receptive to CRCS interventions delivered in community pharmacies. Providing FIT to eligible patients during a pharmacy-based influenza vaccination campaign increases screening rates more than CRCS education alone. PMID- 20199961 TI - Know your diabetes risk project: Student pharmacists educating adults about diabetes risk in a community pharmacy setting. AB - OBJECTIVES: To determine the feasibility of educating adults about their risk of prediabetes/diabetes in a community pharmacy, to determine the common risk factors for prediabetes/diabetes in adults visiting a community pharmacy, and to assess any association between risk factors and age. DESIGN: Cross sectional. SETTING: Oklahoma community pharmacies between April 1 and December 31, 2008. PARTICIPANTS: 1,852 patients aged 18 to 80 years. INTERVENTION: Student pharmacists invited adults to complete a survey to assess their risk for diabetes/prediabetes. Students reviewed participants' risk and educated them on lifestyle changes to lower diabetes risk. MAIN OUTCOME MEASURES: Patient risk factors, pharmacy identifier, and pharmacy type (independent, chain, or clinic pharmacy) and location (rural, suburban, or city). RESULTS: Diabetes risk assessment and education of 1,852 adults was performed by 110 student pharmacists in 52 community pharmacies located in 27 cities across 13 (of 77) Oklahoma counties. Obesity/overweight was the most common risk factor (57%), with positive family history, hypertension, elevated cholesterol, member of high-risk ethnic group, and sedentary lifestyle being reported by at least 20% of participants. The number of risk factors increased with age, with a significant increase occurring in participants older than 40 years of age. CONCLUSION: This project demonstrated that it is feasible to perform diabetes risk assessment and to provide education on lowering that risk through community pharmacies. PMID- 20199962 TI - Depression and diabetes: Establishing the pharmacist's role in detecting comorbidity in pregnant women. AB - OBJECTIVES: To determine the prevalence of depression in women with diabetes receiving prenatal care and to determine whether pregnant women with comorbid depression and diabetes are receiving adequate care for depression. SETTING: Little Rock, AR, between June and August 2007. PRACTICE DESCRIPTION: At a women's health clinic providing obstetrical services to local and statewide patients, the clinical pharmacist functions as a diabetes educator, provides treatment recommendations for the OB/GYN medical residents, and precepts fourth-year student pharmacists. PRACTICE INNOVATION: The pharmacist and student pharmacists screened patients with diabetes for depression using the Beck Depression Inventory, 2nd ed. (BDI-II). MAIN OUTCOME MEASURES: Patient demographics, including obstetrical history, type of diabetes, depression history, and current treatments. RESULTS: 50 patients were screened in this pilot study. Of participants, 42% reported scores that indicated clinical depression. Among patients with clinical depression, only 19% were receiving treatment for depression. Obstetrical history (number of pregnancies) showed a positive correlation with the BDI-II total scores (P = 0.0078). CONCLUSION: This population had a high prevalence of depressive symptoms, but very few women were receiving treatment for depression. Depression screenings should be integrated into routine prenatal care, offering adequate treatment when needed. This study implies that pharmacists can assist with screening for depression in diabetes and thus ensure that at-risk patients receive the attention needed to better manage their illnesses. PMID- 20199963 TI - Does the health status of intimate partner violence victims warrant pharmacies as portals for public health promotion? AB - OBJECTIVES: To explore whether the health status of intimate partner violence (IPV) victims warrants pharmacies to be portals for public health promotion. Specific objectives included (1) identifying prevalence of IPV including domestic violence (DV) and sexual assault (SA) in a community sample, (2) describing characteristics and correlates of DV/SA between participants who reported and did not report DV/SA, and (3) exploring whether DV/SA status is related to mental health medication use. DESIGN: Cross sectional. SETTING: Upstate New York during 2006. PARTICIPANTS: English- and Spanish-speaking respondents younger than 65 years of age answering four questions to assess DV/SA. INTERVENTION: Secondary analysis of a countywide random telephone survey, the 2006 Monroe County Adult Health Survey, which collects prevalence data on health behaviors and health status indicators. MAIN OUTCOME MEASURE: To determine whether those reporting DV/SA are at increased odds for mental health medication use, controlling for other sociodemographic- and health-related variables. RESULTS: The survey response rate was 30.3%, with 1,881 respondents meeting inclusion criteria. Those reporting DV/SA were almost twice as likely to use mental health medications. However, when controlling for other variables, only poor mental and physical health were significant in increasing the odds of mental health medication use. CONCLUSION: The analyses reported here suggest that DV/SA victims in a community sample use mental health medications. When controlling for other variables, survey respondents reported worse physical and mental health. If pharmacies are suitable portals for DV/SA outreach, curricula would need to provide the knowledge and skills needed to take an active role in this public health promotion. PMID- 20199964 TI - Rural public health education as a pharmacist-led team endeavor. AB - OBJECTIVE: To examine the state of public health provision and education in North Dakota and to identify the current and potential future roles pharmacists and pharmacy educators play in these activities. SETTING: Rural, medically underserved areas of North Dakota, as well as professional training sites for the practitioners working in these areas. PRACTICE DESCRIPTION: Practice sites encompass both rural community pharmacies and critical-access hospital pharmacies. The primary education practice site is North Dakota State University. PRACTICE INNOVATION: Pharmacists in rural North Dakota are proactive leaders in providing public health care to their patients. For example, they participate in a statewide diabetes disease management project similar to the Asheville, NC, project. Pharmacy educators are leading the formation of a new interprofessional Master of Public Health program. MAIN OUTCOME MEASURE: Development of an interprofessional public health education program that allows for greater collaboration among rural health practitioners. RESULTS: The new degree program is successfully negotiating the academic approval process. CONCLUSION: Because of the efforts of pharmacists and pharmacy educators, North Dakota is better prepared to face current and future public health challenges. PMID- 20199965 TI - Meeting the challenge of public health information delivery in the digital age. AB - OBJECTIVE: To discuss the current status of public health messaging and how pharmacists can become more active participants. SUMMARY: Public health needs can be addressed by using Internet videos as a model to disseminate medical information. Introducing student pharmacists to new ways of developing and delivering targeted public health messages can increase their awareness that public health intervention is part of the emerging scope of practice. CONCLUSION: For pharmacy to affect change in public health at the local and national level, pharmacists should consider providing public health advocacy messages through virtual platforms. PMID- 20199967 TI - Carl Svante Nicanor Hallberg (1856-1910): Pharmacy's rough diamond. PMID- 20199968 TI - Updated recommendations for the use of pneumococcal polysaccharide vaccine. PMID- 20199969 TI - New drugs: Ustekinumab, tocilizumab, and telavancin hydrochloride. PMID- 20199970 TI - Science snippets. Chain pharmacy blood pressure intervention, Medicare nonadherence, and prestroke depression. PMID- 20199972 TI - The polyamine metabolism: renaissance of an old pathway in oncology. PMID- 20199973 TI - The role of anti-epidermal growth factor receptor and anti-vascular endothelial growth factor therapies in the treatment of non-small-cell lung cancer. AB - Standard first-line therapy for non-small-cell lung cancer (NSCLC) with platinum based agents, given in combination with cytotoxic compounds, has reached a relative plateau in its therapeutic efficacy. Novel molecular targeted agents acting on specific pathways have emerged as effective agents for treating NSCLC; some have already produced positive results in phase III trials. Notably, inhibition of the vascular endothelial growth factor (VEGF) pathway with an anti VEGF antibody, bevacizumab, and targeting the epidermal growth factor receptor (EGFR) pathway with a small-molecule EGFR tyrosine kinase inhibitor erlotinib or a monoclonal antibody (cetuximab) have demonstrated prolonged survival in patients with advanced disease in both the first- and second-line settings. The heterogeneity of signaling processes leading to tumor cell survival and proliferation supports the targeting of multiple signaling pathways as an effective anticancer treatment strategy. Consequently, rational combinations of molecular targeted agents might offer superior clinical efficacy and an alternative treatment option to patients refractory to, or unable to tolerate, standard chemotherapy. The challenge lies in determining which molecular entities should be pursued and the best approach to combine them. This review discusses the potential clinical utility of combining bevacizumab and erlotinib to inhibit both angiogenesis and EGFR signaling as a valid nonchemotherapeutic approach for the treatment of NSCLC. Other combinations of novel therapies that block EGFR and angiogenic pathways, as well as complementary signaling pathways, with unique modes of action and low toxicity profiles could offer an increased repertoire of individualized treatment options for patients with advanced NSCLC. PMID- 20199974 TI - New molecular targeted therapies integrated with radiation therapy in lung cancer. AB - Non-small-cell lung cancer (NSCLC) accounts for approximately 80%-85% of all cases of lung cancer; for patients with stage III disease, it accounts for approximately 40% of all cases. The treatment for unresectable stage III NSCLC is the combination of platinum-based chemotherapy and thoracic radiation. In this article, new targeted agents under investigation for possible integration into the combined therapy are reviewed. One of the most promising strategies is the inhibition of the epidermal growth factor receptor (EGFR) pathway. Radiation activates EGFR signaling, leading to radio-resistance by inducing cell proliferation and enhanced DNA repair. Several preclinical models have shown synergistic activity when cetuximab was combined with radiation therapy. Some phase II trials have evaluated the safety and efficacy of synchronous cetuximab and radiation therapy with promising results. Gefitinib has a radiosensitizing effect on cell lines and has been investigated in combination with radiation therapy for unresectable stage III NSCLC. However, disappointing results were observed in the maintenance treatment with gefitinib after chemoradiation therapy. Erlotinib has been tested in a phase I trial with chemoradiation therapy. Radiation induces tumor death by damaging cell membranes, DNA, and microvascular endothelial cells, which in response increase proangiogenic growth factors. Antiangiogenic agents reduce vascular density but improve tumor oxygenation. Use of vascular endothelial growth factor receptor (VEGFR) inhibitors enhances the therapeutic efficacy of irradiation in human NSCLC by hindering the repair of sublethal radiation damage. Trials combining erlotinib and bevacizumab with thoracic radiation are ongoing. New strategies must be developed for the integration of this triple-combination treatment. As radiation therapy enhances HSP90 chaperone function, causing radio-resistant lung cancer cells, therapeutic agents that block this path are likely candidates for decreasing radio-resistance by suppressing HIF-1alpha and VEGF expression and thus inhibiting the survival and angiogenic potential of lung cancer cells. Aurora kinase inhibitors with radiation therapy seem to have an additive effect in preclinical models in NSCLC and mesothelioma. PMID- 20199975 TI - Prognostic value of computed tomography morphologic characteristics in stage I non-small-cell lung cancer. AB - BACKGROUND: In this study, we describe the prognostic value of NSCLC morphologic characteristics obtainable by computed tomography (CT) in the preoperative staging. Starting with the initial hypothesis that CT morphologic characteristics of NSCLC have a prognostic value, we conducted a retrospective study that included 194 patients. PATIENTS AND METHODS: All patients underwent surgery because of stage IA or IB non-small-cell lung carcinoma (NSCLC). Surgical procedures were performed in our clinic over the period of 9 years and 8 months starting in June 1996 and ending in February 2006. Preoperative CT scans and clinical data available for each patient were analyzed retrospectively. RESULTS: Over the study period, 93 patients died. The mean survival time was 78.6 months (95% confidence interval was 72.63-84.57 months). After a 2-year follow-up, 85.57% of patients were alive, but this decreased to 63.9% living patients after 5 years. Morphologic tumor characteristics were obtained by analyzing CT images available for each patient. These CT morphologic characteristics were divided into 5 categories: size, tumor edges, structure, and periphery of the tumor, as well as its relation to visceral pleura. We correlated each of these characteristics to the survival of patients. CONCLUSION: We conclude that, within stage I NSCLC, patient survival and disease prognosis vary significantly depending on such morphologic characteristics. This fact is one of the weakest points of the current tumor-node-metastasis (TNM) classification. Along with already-established tumor prognostic attributes such as size and TNM grade, we identified CT morphologic characteristics as powerful additional prognostic factors for NSCLC. PMID- 20199976 TI - Phase I/II and pharmacokinetic study of intravenous vinflunine in combination with cisplatin for the treatment of chemonaive patients with advanced non-small cell lung cancer. AB - BACKGROUND: A multicenter phase I/II trial of vinflunine administered in combination with cisplatin at 80 mg/m(2) was conducted in order to determine the dose-limiting toxicities, the maximum tolerated dose, and the recommended dose of the combination. An eventual mutual pharmacokinetic drug-drug interaction when vinflunine and cisplatin were coadministered was also evaluated. The study was also intended to define the response rate of vinflunine in combination with cisplatin as first-line chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC) at the recommended dose. PATIENTS AND METHODS: Patients were required to have a histologically confirmed diagnosis of NSCLC not amenable to curable treatment or stage IV disease. Patients may have had previous surgery for NSCLC but were to be chemonaive and have at least 1 bidimensional measurable lesion outside an irradiated area. RESULTS: The recommended dose was established at cisplatin 80 mg/m2 combined with vinflunine 320 mg/m(2). No unexpected adverse events were seen. Pharmacokinetic analysis supported the absence of mutual pharmacokinetic interaction when vinflunine and cisplatin are given in combination. Treatment of 53 patients at this recommended dose demonstrated a tumor response rate of 32.1% in the intent-to-treat population; disease control was achieved in 79.2% of the patients. The median progression-free survival and overall survival were estimated at 5 months and 10.4 months, respectively, and the 1-year survival rate was 43.4%. CONCLUSION: These results place the vinflunine/cisplatin combination among the most active doublets in this treatment setting and warrant further development in phase III trials of first-line treatment of patients with advanced metastatic NSCLC. PMID- 20199977 TI - Ornithine decarboxylase mRNA expression in curatively resected non-small-cell lung cancer. AB - BACKGROUND: The effect of ornithine decarboxylase (ODC) on the pathogenesis of non-small-cell lung cancer (NSCLC) remains poorly investigated. Hence, the aim of this study was to explore the potential role of ODC mRNA expression as a prognostic biomarker in patients with curatively resected NSCLC. PATIENTS AND METHODS: A total of 91 tumor and matching nontumorous lung tissue samples from patients with NSCLC were analyzed using a quantitative real-time reverse transcriptase polymerase chain reaction method. The relative ODC mRNA expression was measured in tumorous and nontumorous lung tissue using beta-actin as a reference gene. Squamous cell carcinoma was found in 43 patients (47%), adenocarcinoma in 33 (36%), and large-cell carcinoma in 15 of the patients (17%). All patients' disease was R0 resected. RESULTS: Ornithine decarboxylase was detected in all 91 tumor and nontumorous lung tissue samples. The median tumorous expression of 9.11 (range, 0.92-155.35) was significantly elevated compared with the median ODC expression of 7.89 (range, 0.0-45.8) in nontumorous lung tissue. Ornithine decarboxylase expression levels were not associated with any clinicopathologic parameters. Using an ODC/beta-actin ratio of 10 as a cutoff, tumorous ODC (tODC) expression is a significant prognostic factor in NSCLC. The ODC ratio between tumorous and nontumorous expression was even more prognostic. Moreover, Cox proportional hazards model analysis showed ODC expression to be an independent prognostic factor. CONCLUSION: In this study, ODC is shown to have a prognostic potential in NSCLC. Low levels of tODC expression are associated with a more aggressive tumor biology. Also, an increase of ODC mRNA expression during carcinogenesis seems to have a favorable prognostic effect. Measuring the ODC expression in patients with NSCLC could aid in further chemotherapy decisions. Our results suggest that further investigation of ODC mRNA expression in NSCLC may be warranted. PMID- 20199978 TI - Clinical experience of lobectomy with pulmonary artery reconstruction for central non-small-cell lung cancer. AB - BACKGROUND: In patients with central lung cancer, lobectomy can be achieved without pneumonectomy by surgical reconstruction of the pulmonary artery (PA). Herein, we report our clinical experience of 34 patients who had lobectomy with PA reconstruction, including perioperative administration, morbidity, mortality, and long-term survival. PATIENTS AND METHODS: The clinical records of 34 patients who received lobectomy with PA reconstruction in our department between August 2003 and September 2005 were reviewed. RESULTS: In our series, PA reconstruction with end-to-end anastomosis was performed in 18 patients (52.9%). Seven patients (20.6%) required partial PA reconstruction with autologous pericardium patch. Five patients (14.7%) with a lower lobe tumor required PA reconstruction with artery flap. The perioperative mortality was 2.9%, and 1 patient died on postoperative day 13 because of severe bronchopleural fistula. Another 2 patients had acute respiratory distress syndrome (ARDS) and required reintubation in our Intensive Care Unit. The overall Kaplan-Meier 3-year and 5-year survival rates were 46% and 37%, respectively. As compared with the stage III patients, stage I patients had significantly greater 5-year survival (80% vs. 11%; P = .005). Patients with pN0 disease also had greater 5-year survival than patients with pN2 3 disease (71% vs. 9%; P = .004). CONCLUSION: In our department, PA reconstruction has been more frequently and actively performed for patients with central lung cancer, especially for some patients with a lower lobe tumor. Although the morbidity and mortality is acceptable, surgeons should be more attentive to lethal postoperative complications such as ARDS induced by lung ischemia-reperfusion injury. PMID- 20199979 TI - Comparison of patient outcomes according to histology among pemetrexed-treated patients with stage IIIB/IV non-small-cell lung cancer in two phase II trials. AB - INTRODUCTION: Recent phase III studies in advanced non-small-cell lung cancer (NSCLC) have demonstrated differential efficacy for pemetrexed according to NSCLC histology. The results of 2 phase II studies of pemetrexed and a platinum agent (carboplatin or oxaliplatin) were pooled to determine whether outcomes in the studies differed by tumor histology. PATIENTS AND METHODS: Chemotherapy-naive patients with stage IIIB/IV NSCLC received pemetrexed 500 mg/m2 plus carboplatin area under the curve of 6 (n = 89) or pemetrexed 500 mg/m2 plus oxaliplatin 120 mg/m2 (n = 41); both regimens were administered every 21 days. The primary endpoint of both trials was response rate. Treatment arms were pooled, and Cox models with main effects for squamous histology were used to assess overall survival and progression-free survival. Cofactor adjustments incorporated terms for performance status, disease stage, and sex. RESULTS: More than three quarters of enrolled patients had a nonsquamous histology. Mean age was 59.9 years for patients with nonsquamous histology and 63.7 years for patients with squamous histology. Response rates were 30% for patients with nonsquamous histology and 17.2% for patients with squamous histology. Overall survival was 10.5 months for patients with nonsquamous histology and 9.8 months for patients with squamous histology (hazard ratio [HR], 0.95; 95% CI, 0.52-1.74). Progression-free survival was 5.6 months for patients with nonsquamous histology and 4.7 months for patients with squamous histology (HR, 0.72; 95% CI, 0.43-1.19). CONCLUSION: In patients treated with pemetrexed/ platinum doublets, nonsquamous histology was associated with better outcomes. The benefit of pemetrexed treatment among patients with nonsquamous histology is consistent with the results reported from previous studies. PMID- 20199981 TI - Economic analysis of a diabetes-specific nutritional meal replacement for patients with type 2 diabetes. AB - This study extends nutritional intervention results reported by short-term clinical trials of a diabetes-specific nutritional meal replacement by assessing the ten-year impact of the interventions on patient outcomes and costs compared to usual care. We developed and validated a computer simulation of type 2 diabetes based on published data from major clinical trials. The model tracks patients through microvascular and macrovascular health states and reports cumulative costs and quality adjusted life years. We modeled different scenarios that include a diabetes-specific nutritional meal replacement as part of a structured lifestyle intervention, and also as the only difference between the intervention and usual care treatment groups, and compared them to usual care with diet and physical activity recommendations. We used sensitivity analysis to explore the robustness of results. When a diabetes-specific nutritional meal replacement is the only treatment difference and is considered an equal cost meal replacement, the diabetes-specific nutritional meal replacement interventions are less costly and more effective than usual care. As an added cost meal replacement, the diabetes-specific nutritional meal replacement has an incremental cost-effectiveness ratio between $50,414 and $55,036 depending on improvement in percent glycated hemoglobin. A hypothetical lifestyle intervention using a diabetes-specific nutritional meal replacement has an incremental cost effectiveness ratio of $47,917. The diabetes-specific nutritional meal replacement was found to be cost-effective under the various conditions simulated. PMID- 20199982 TI - Composition of weight gain during nutrition rehabilitation of severely under nourished children in a hospital based study from India. AB - Concerns are raised that rapid catch up growth during nutrition rehabilitation of severely malnourished children may be associated with disproportionately higher amounts of body fat deposition. This study examined the composition of weight gain in severely undernourished children who underwent nutrition rehabilitation in a hospital from India. Body composition of 80 severely malnourished children (age 6-60 months) was assessed using skin-fold thickness measurements on admission and after 1 month of supplementary feeding. On admission, children had severe weight and height deficits and were severely wasted. The mean weight for age z score, height for age z score and weight for height z score (WHZ) were 5.0, -4.2 and -4.1 respectively. Children consumed a mixed diet and mean energy intake was 177 kcal/kg/day with a protein energy ratio of 13. Overall, the mean weight gain was 6.1 g/kg/day and fat mass contributed to about 40% of the weight gain. When the composition of weight gain was analysed in tertiles of baseline WHZ score, children in the lowest tertile of WHZ score had significantly higher weight gain and fat free mass (FFM) gain. Gain in fat mass did not differ in relation to the baseline WHZ score. The study demonstrates that it is possible to achieve rapid weight gain with recovery of lost tissue in severely malnourished children with mixed diets. Children with lowest WHZ scores at baseline gained higher FFM during nutrition rehabilitation when compared to the children with relatively higher WHZ score probably in an attempt to recover the lost tissue. PMID- 20199983 TI - Correspondence of two procedures to measure abdominal circumference in a convenience sample of urban, middle-class schoolchildren in Guatemala City. AB - BACKGROUND: Given an emerging concern for juvenile overweight and obesity, even in populations of developing countries, techniques to assess central obesity, such as abdominal circumference (AC), are of increasing interest. OBJECTIVE: To compare two procedures for measuring AC in schoolchildren from a convenience sample of middle-class, urban children aged 72 to 131 months in Guatemala City. METHODS: We conducted a cross-sectional study (August 2004- April 2005) in 363 schoolchildren; 190 boys and 173 girls. The AC was recorded using both the conventional natural waist circumference (NWC) and the umbilical-level abdominal circumference (UAC) methods; each of which was measured over a thin T-shirt. Height and weight were also measured. The NWC and UAC methods were compared between genders and age groups. In addition, correlation coefficients and Bland Altman regression were performed. A reproducibility study was performed on a subsample of 50 children. RESULTS: Mean NWC was 63.2+/-10.0 cm for boys and 60.2+/-7.7 cm for girls (p=0.001), and mean UAC was 65.9+/-11.0 cm for boys and 63.2+/-8.8 cm for girls (p=0.008). Both measures of AC generally increased with age. The UAC - NWC difference increased with abdominal girth. The Pearson correlation coefficient of BMI vs. NWC and BMI vs. UAC was r=0.92, CV=0.46+/ 0.27%. A high test-retest reproducibility (r > 0.98, CV= 0.50+/-0.24%) of the NWC and UAC measurements was found. CONCLUSION: Reliable NWC and UAC measurements may be obtained by applying a correction term to account for light clothing. Both measurements are applicable methodologies for the collection of data in populations with cultural limitations. PMID- 20199984 TI - Dietary patterns by reduced rank regression predicting changes in obesity indices in a cohort study: Tehran Lipid and Glucose Study. AB - OBJECTIVE: To examine the association between dietary patterns and obesity indices (BMI, WC, WHR) among Tehranian adults in a 6-year follow-up study. METHODS: Within frame of a cohort study in Tehran (mean follow up 6.6+/-0.9 years), 141 adults were recruited with: two 24 hour dietary recalls at the beginning, as well as obesity indices at the beginning and end of the study period. Dietary intakes were converted into grams of intakes of food items and categorized into 16 groups. Reduced rank regression analysis derived five patterns with total and polyunsaturated-to-saturated fat intake, cholesterol, fiber and calcium intake as response variables. Factors (dietary patterns) were generated retaining a corresponding factor loading > or = |0.17| on the food groups. Changes in obesity indices were scrutinized within quintiles of factor scores. RESULTS: There were high loadings on refined carbohydrates, whole grain, starchy vegetables, other vegetables, red and refined meat, saturated/trans fat, and egg for the first factor named "traditional". All obesity indices had increasing trend across quintiles of pattern score. The fifth pattern (namely egg pattern) had high loading for eggs, salty snacks, as well as fruits and dry fruits, and negative loadings for red and processed meat, saturated and trans fat, plant oils, and dairy products. This pattern showed increasing trends for WC and WHR after adjustment for potential confounders. Other patterns showed non significant trends for obesity indices. CONCLUSIONS: The results were indicative of a traditional pattern which is dominated in the Tehran region and associated with increase in obesity indices. PMID- 20199985 TI - Effect of soy isoflavone extract supplements on bone mineral density in menopausal women: meta-analysis of randomized controlled trials. AB - This study was conducted to clarify the effect of ingesting soy isoflavone extracts (not soy protein or foods containing isoflavones) on bone mineral density (BMD) in menopausal women. PubMed, CENTRAL, ICHUSHI, CNKI, Wanfang Data, CQVIP, and NSTL were searched for randomized controlled trials published in English, Japanese, or Chinese reporting the effects of soy isoflavone extracts on lumbar spine or hip BMD in menopausal women. Trials were identified and reviewed for inclusion and exclusion eligibility. Data on study design, participants, interventions, and outcomes were extracted. Eleven, seven, five, and five trials were finally selected for estimation of the effects on spine, femoral neck, hip total, and trochanter BMD, respectively. Meta-analysis including data from1240 menopausal women revealed that daily ingestion of an average of 82 (47-150) mg soy isoflavones (aglycone equivalent) for 6-12 months significantly increased spine BMD by 22.25 mg/cm2 (95% CI: 7.62, 32.89; p=0.002), or by 2.38% (95% CI: 0.93, 3.83; p=0.001) compared with controls (random-effects model). Subgroup analyses indicated that the varying effects of isoflavones on spine BMD across trials might be associated with study characteristics of intervention duration (6 vs. 12 months), region of participant (Asian vs. Western), and basal BMD (normal bone mass vs. osteopenia or osteoporosis). No significant effects on femoral neck, hip total, and trochanter BMD were found. Soy isoflavone extract supplements increased lumbar spine BMD in menopausal women. Further studies are needed to address factors affecting the magnitudes of effect on spine and to verify the effect on hip. PMID- 20199986 TI - Serum 25-hydroxyvitamin D concentration of Indigenous-Fijian and Fijian-Indian women. AB - BACKGROUND: Serum 25-hydroxyvitamin D (25OHD) concentrations are lower in Pacific people compared to Caucasians living in New Zealand. However, there are no data on the 25OHD concentrations of Pacific people living in the Pacific Islands. AIM: To assess the vitamin D status of indigenous and Indian Fijian women living in Fiji by measuring 25OHD concentrations. METHODS: 25OHD concentrations in a national sample of 511 Fijian women (15-44 y). RESULTS: The mean 25OHD concentration of Fijian women was 76 nmol/L (95% CI: 73, 78). 25OHD was lower in Fijian Indian [70 (66, 74) nmol/L; n=205] women compared to indigenous Fijians [80 (76, 84) nmol/L; n=306] (p<0.0001). The mean 25OHD was higher in rural [77 (74, 80) nmol/L; n=392] than urban [70 (65, 76) nmol/L; n=119] women (p<0.0001). Body mass index (BMI) and age were not predictors of 25OHD concentrations. Of Fijian females, 3%, 11%, and 56% had 25OHD concentrations indicative of 25OHD insufficiency using cut-offs of < or =37.5, < or =50 and < or =80 nmol/L, respectively. CONCLUSION: Mean 25OHD in Fijian women was generally adequate and exceed concentrations reported in Pacific females living in New Zealand. PMID- 20199987 TI - Hypovitaminosis D and K are highly prevalent and independent of overall malnutrition in the institutionalized elderly. AB - There have been methodological problems for studying hypovitaminosis D and K in the elderly. First, studies were done either by evaluating food intake or measuring their circulating levels, but rarely by both in Japan. In this paper, vitamin D and K intakes and their circulating levels were simultaneously determined. Second issue is whether hypovitaminosis D and K are independent of general malnutrition, prevalent in the elderly. We tried to statistically discriminate them by principal component analysis (PCA). Fifty institutionalized elderly were evaluated for their circulating 25 hydroxy-vitamin D (25OH-D), intact parathyroid hormone (PTH), phylloquinone (PK), menaquinone-7 (MK-7) levels, and their food intake. Although average vitamin D intake (7.0 microg/day) exceeded the Japanese Adequate Intake (AI) of 5.0 microg/day, average serum 25OH D concentration was in the hypovitaminosis D range (11.1 ng/mL). Median vitamin K intake was 168 microg/day, approximately 2.5 times as high as AI for vitamin K. Nevertheless, plasma PK and MK-7 concentrations were far lower than those of healthy Japanese elderly over 70 years old. PCA yielded four components; each representing overall nutritional, vitamin K2, vitamin D, and vitamin K1 status, respectively. Since these components are independent of each other, vitamin D- and K-deficiency in these subjects could not be explained by overall malnutrition alone. In summary, institutionalized elderly had a high prevalence of hypovitaminosis D and K, and the simultaneous determination of their circulating level and dietary intake is mandatory in such studies. PCA would yield fruitful results for eliminating the interference by confounders in a cross-sectional study. PMID- 20199989 TI - Family nutritional support improves survival, immune restoration and adherence in HIV patients receiving ART in developing country. AB - In developing countries, access to antiretroviral treatment for persons living with HIV is still in progress. Malnutrition represents another cause of acquired immunodeficiency and premature death. This evaluation program estimated the impact of family nutritional support during the first year of antiretroviral treatment in West Africa's sub-Sahara region. Family nutritional support was proposed to patients with CD-4 cell count <200 /mm3 and/or developing a WHO stage III/IV or with body mass index <18.5 kg/m2 and receiving antiretroviral treatment. Follow-up of 62 patients receiving support was compared to 118 patients who had only received antiretroviral treatment the year before. Average body mass index, CD-4 cell count were 20.7 and 20.5, 217 and 191/mm3 respectively in supported and control groups (NS). Twenty-two (36%) and 56 (48%) were WHO stage III/IV (NS) respectively in supported and control groups. One patient who received support and twelve controls died (Mortality Ratio=0.19; p<0.05). Increase in CD-4 cell count was around 1.7 times higher (+ 114 vs. + 68 CD-4 cells/mm3 respectively in supported and control groups; p<0.05) and observance was improved in supported group (p<0.005). The evolutions of WHO stage and body mass index were not different but the study period was short. Family nutritional support for persons living with HIV initiating antiretroviral treatment in a developing country showed a positive impact after six months. This family intervention could be integrated into AIDS interventions as an effective and comprehensive community-based primary care. PMID- 20199990 TI - Dietary habits and overweight/obesity in adolescents in Xi'an City, China. AB - This study explored the association between dietary habits and overweight and obesity in adolescents from Xi'an City, China. A cross-sectional sample of 1804 adolescents was recruited in 2004 from 30 junior high schools in six districts of Xi'an City, northwest China. Weight and height was measured and eating habits assessed using a self-administered questionnaire. Logistic regression was used to identify dietary patterns associated with overweight and obesity and adjusted for socio-demographic factors. Consumption of foods and beverages outside three main meals, and potato chips was more popular in boys than in girls, while girls consumed more fried food and soft drinks than boys. In boys, an increased consumption of soft drinks was associated with increased risk of overweight and obesity (1100 mL/day, OR: 1.9, 95% CI: 1.1-3.8), while consuming preserved fruit was associated with decreased risk (OR: 0.6, 95% CI: 0.5-0.9). In girls, having breakfast outside the home (OR: 1.7, 95% CI: 1.1-2.3) and an increased consumption of energy-dense foods (OR: 1.7, 95% CI: 1.04-2.9), was associated with increased risk of overweight and obesity, while frequently having foods and beverages outside the three main meals (OR: 0.6, 95% CI: 0.4-0.9) was associated with decreased risk. The consumption of breakfast outside the home, soft drinks and energy-dense fast foods were positively associated with overweight and obesity in adolescents. Future health education programs to prevent excess weight gain should target such unhealthy eating habits. PMID- 20199988 TI - High prevalence of low HDL-c in the Philippines compared to the US: population differences in associations with diet and BMI. AB - Cardiovascular disease (CVD) is a leading cause of death in the Philippines, although few studies here have examined the lipid profiles underlying disease risk. The isolated low high density lipoprotein cholesterol (HDL-c) phenotype has been implicated as a CVD risk factor, the prevalence of which exhibits significant variation across populations. To assess population variation in individual lipid components and their associations with diet and anthropometric characteristics, we compare lipid profiles in a population of adult Filipino women (n=1877) to US women participating in the National Health and Nutrition Examination Survey (NHANES, n=477). We conducted multiple regression models to assess the relationship between lipid components, body mass index, and dietary variables in the two populations. We measured the prevalence of lipid phenotypes, and logistic regression models determined the predictors of the isolated low HDL c phenotype. High density lipoprotein cholesterol was lower in the Philippines (40.8+/-0.2 mg/dL) than in NHANES (60.7+/-0.7 mg/dL). The prevalence of the isolated low HDL-c phenotype was 28.8%, compared to 2.10% in NHANES. High prevalence among Filipinos was relatively invariant across all levels of BMI, but was strongly inversely related to BMI in NHANES and exhibited only at the BMI>25 kg/m2 threshold. Diet did not consistently predict the low-HDL phenotype in Filipinos. Filipino women exhibit a high prevalence of the isolated low HDL-c phenotype, which is largely decoupled from anthropometric factors. The relationship of CVD to population variation in dyslipidemia and body composition needs further study, particularly in populations where the burden of cardiovascular and metabolic disease is rapidly increasing. PMID- 20199991 TI - Maintained total body water content and serum sodium concentrations despite body mass loss in female ultra-runners drinking ad libitum during a 100 km race. AB - We investigated in 11 female ultra-runners during a 100 km ultra-run, the association between fluid intake and prevalence of exercise-associated hyponatremia in a cross-sectional study. Athletes drank ad libitum and recorded their fluid intake. They competed at 8.0 (1.0) km/h and finished within 762 (91) min. Fluid intake was 4.1 (1.3) L during the race, equal to 0.3 (0.1) L/h. Body mass decreased by 1.5 kg (p< 0.01); pre race body mass was related to speed in the race (r = -0.78, p< 0.05); and change (Delta) in body mass was not associated with speed in the race. Change in body mass was positively (r = 0.70; p< 0.05), and Delta urinary specific gravity negatively (r = -0.67; p< 0.05), correlated to Delta percent total body water. Changes in body mass were not related to fluid intake during the race. Fluid intake was not correlated to running speed and showed no association with either Delta percent total body water nor Delta [Na] in plasma. Fluid intake showed no relationship with both Delta haematocrit and Delta plasma volume. No exercise-associated hyponatremia occurred. Female ultra- runners consuming fluids ad libitum during the race experienced no fluid overload, and ad libitum drinking protects against exercise-associated hyponatremia. The reported higher incidence of exercise-associated hyponatremia in women is not really a gender effect but due to women being more prone to overdrink. PMID- 20199992 TI - Male ironman triathletes lose skeletal muscle mass. AB - We investigated whether male triathletes in an Ironman triathlon lose body mass in the form of fat mass or skeletal muscle mass in a field study at the Ironman Switzerland in 27 male Caucasian non-professional Ironman triathletes. Pre- and post-race body mass, fat mass and skeletal muscle mass were determined. In addition, total body water, hematological and urinary parameters were measured in order to quantify hydration status. Body mass decreased by 1.8 kg (p< 0.05), skeletal muscle decreased by 1.0 kg (p< 0.05) whereas fat mass showed no changes. Urinary specific gravity, plasma urea and plasma volume increased (p< 0.05). Pre- to post-race change (Delta) in body mass was not associated with ? skeletal muscle mass. Additionally, there was no association between Delta plasma urea and Delta skeletal muscle mass; Delta plasma volume was not associated with Delta total body water (p< 0.05). We concluded that male triathletes in an Ironman triathlon lose 1.8 kg of body mass and 1 kg of skeletal muscle mass, presumably due to a depletion of intramyocellular stored glycogen and lipids. PMID- 20199994 TI - Folate intake associated with lung function, breathlessness and the prevalence of chronic obstructive pulmonary disease. AB - A case-control study was conducted in central Japan to investigate the relationship between dietary intake of folate and lung function, breathlessness and chronic obstructive pulmonary disease (COPD). A total of 278 referred patients (244 men and 34 women) aged 50-75 years with COPD diagnosed within the past four years and 340 community-based controls (272 men and 68 women) were assessed for dyspnoea and undertook spirometric measurements of lung function. A structured questionnaire was administered face-to-face to obtain information on demographics, lifestyle and habitual food consumption. Folate intake was derived from the Japanese food composition tables. The COPD patients had significantly lower habitual intake of folate (mean 231, SD 90 microg/day) than control subjects (mean 261, SD 110 microg/day), p<0.001. Lung function measures were found to be positively associated with dietary folate level. Reductions in prevalence of COPD and especially breathlessness were observed, the respective adjusted odds ratio (OR) being 0.74 (95% confidence interval (CI) 0.35 to 1.58) and 0.43 (95% CI 0.21 to 0.91) for the highest versus lowest quartile of folate intake. The corresponding tests for linear trend were also significant (p<0.05). In conclusion, an inverse association was evident between dietary folate intake and the prevalence of breathlessness for Japanese adults, together with a significant dose-response relationship for the COPD risk. Moreover, increased folate intake might be beneficial to lung function. PMID- 20199993 TI - Prevalence and characteristics of the metabolic syndrome among adults in Beijing, China. AB - This study was performed to investigate the prevalence of the metabolic syndrome using a large representative sample in Beijing. Data from a total of 16442 adults (6489 men and 9953 women) aged > or =18 years from a survey of behavioral risk factors for chronic diseases in Beijing, in 2005, was analyzed. The prevalence of the metabolic syndrome increased with age and the age-standardized prevalence of the metabolic syndrome defined by International Diabetes Federation IDF and National Cholesterol Education Program Adult Treatment Panel III ATPIII criteria were 23.2% (24.5% in men and 22.7% in women) and 16.2% (16.1% in men and 16.6% in women), respectively. The metabolic syndrome was higher in semi-urban areas and associated with higher rates of hypertension, central obesity, salt intake and smoking. PMID- 20199995 TI - Health benefits of nuts in prevention and management of diabetes. AB - The effects of tree nuts on risk factors for coronary heart disease (CHD), in particular blood lipids, have been investigated in a number of studies and the beneficial effects are now recognized. The beneficial effects of nuts on CHD in cohort studies have also been clearly demonstrated. However, while there is also reason to believe the unique micro- and macronutrient profiles of nuts may help to control blood glucose levels, relatively few studies have investigated their role in diabetes control and prevention. Nuts are low in available carbohydrate, have a healthy fatty acid profile, and are high in vegetable protein, fiber and magnesium. Acute feeding studies indicate that when eaten alone nuts have minimal effects on raising postprandial blood glucose levels. In addition, when nuts are consumed with carbohydrate rich foods, they blunt the postprandial glycemic response of the carbohydrate meal. Despite the success of these acute studies, only a limited number of trials have been conducted with nuts in type 2 diabetes. These studies have either been of insufficient duration to observe changes in HbA1c, as the standard measure of glycemic control, or have been underpowered. Therefore, more long-term clinical trials are required to examine the role of nuts on glycemic control in patients with prediabetes and diabetes. Overall, there are good reasons to justify further exploration of the use of nuts in the prevention of diabetes and its micro- and macrovascular complications. PMID- 20199997 TI - Nuts, inflammation and insulin resistance. AB - The beneficial effects of nut consumption on cardiovascular disease (CVD) have been widely documented. These protective effects are mainly attributed to the role of nuts in the metabolism of lipids and lipoproteins. As chronic inflammation is a key early stage in the atherosclerotic process that predicts future CVD events and is closely related to the pathogenesis of insulin resistance, many recent studies have focused on the potential effect of nut consumption on inflammation and insulin resistance. Through different mechanisms, some components of nuts such as magnesium, fiber, alpha-linolenic acid, L arginine, antioxidants and MUFA may protect against inflammation and insulin resistance. This review evaluates the epidemiologic and experimental evidence in humans demonstrating an association between nut consumption and these two emergent cardio-protective mechanisms. PMID- 20199996 TI - The phytochemical composition and antioxidant actions of tree nuts. AB - In addition to being a rich source of several essential vitamins and minerals, mono- and polyunsaturated fatty acids, and fiber, most tree nuts provide an array of phytochemicals that may contribute to the health benefits attributed to this whole food. Although many of these constituents remain to be fully identified and characterized, broad classes include the carotenoids, hydrolyzable tannins, lignans, naphthoquinones, phenolic acids, phytosterols, polyphenols, and tocopherols. These phytochemicals have been shown to possess a range of bioactivity, including antioxidant, antiproliferative, anti-inflammatory, antiviral, and hypocholesterolemic properties. This review summarizes the current knowledge of the carotenoid, phenolic, and tocopherol content of tree nuts and associated studies of their antioxidant actions in vitro and in human studies. Tree nuts are a rich source of tocopherols and total phenols and contain a wide variety of flavonoids and proanthocyanidins. In contrast, most tree nuts are not good dietary sources of carotenoids and stilbenes. Phenolic acids are present in tree nuts but a systematic survey of the content and profile of these compounds is lacking. A limited number of human studies indicate these nut phytochemicals are bioaccessible and bioavailable and have antioxidant actions in vivo. PMID- 20199998 TI - Nuts, blood lipids and cardiovascular disease. AB - The aim of this paper is to evaluate nut-related epidemiological and human feeding study findings and to discuss the important nutritional attributes of nuts and their link to cardiovascular health. Frequent nut consumption has been found to be protective against coronary heart disease in five large epidemiological studies across two continents. A qualitative summary of the data from four of these studies found an 8.3% reduction in risk of death from coronary heart disease for each weekly serving of nuts. Over 40 dietary intervention studies have been conducted evaluating the effect of nut containing diets on blood lipids. These studies have demonstrated that intake of different kinds of nuts lower total and LDL cholesterol and the LDL: HDL ratio in healthy subjects or patients with moderate hypercholesterolaemia, even in the context of healthy diets. Nuts have a unique fatty acid profile and feature a high unsaturated to saturated fatty acid ratio, an important contributing factor to the beneficial health effects of nut consumption. Additional cardioprotective nutrients found in nuts include vegetable protein, fiber, alpha-tocopherol, folic acid, magnesium, copper, phytosterols and other phytochemicals. PMID- 20199999 TI - Nuts and healthy body weight maintenance mechanisms. AB - Nuts are rich sources of multiple nutrients and phytochemicals associated with health benefits, including reduced cardiovascular disease risk. This has prompted recommendations to increase their consumption. However, they are also high in fat and are energy dense. The associations between these properties, positive energy balance and body weight raise questions about such recommendations. Numerous epidemiological and clinical studies show that nuts are not associated with weight gain. Mechanistic studies indicate this is largely attributable to the high satiety and low metabolizable energy (poor bioaccessibility leading to inefficient energy absorption) properties of nuts. Compensatory dietary responses account for 55-75% of the energy provided by nuts. Limited data suggest that routine nut consumption is associated with elevated resting energy expenditure and the thermogenic effect of feeding, resulting in dissipation of another portion of the energy they provide. Additionally, trials contrasting weight loss through regimens that include or exclude nuts indicate improved compliance and greater weight loss when nuts are permitted. Nuts may be included in the diet, in moderation, to enhance palatability, nutrient quality, and chronic disease risk reduction without compromising weight loss or maintenance. PMID- 20200000 TI - Tree nut consumption improves nutrient intake and diet quality in US adults: an analysis of National Health and Nutrition Examination Survey (NHANES) 1999-2004. AB - Recent epidemiologic studies assessing tree nut (almonds, Brazil nuts, cashews, hazelnuts, macadamia nuts, pecans, pine nuts, pistachios, and walnuts) consumption and the association with nutrient intake and diet quality are lacking. This study determined the association of tree nut consumption and nutrient intake and diet quality using a nationally representative sample of adults. Adults 19+ years (y) (n=13,292) participating in the 1999-2004 National Health and Nutrition Examination Survey were used. Intake was determined from 24 hour diet recalls; tree nut consumers were defined as those consuming > or =(1/4) ounce/day (7.09 g). Means, standard errors, and ANOVA (adjusted for covariates) were determined using appropriate sample weights. Diet quality was measured using the Healthy Eating Index-2005. Among consumers, mean intake of tree nuts/tree nut butters was 1.19 +/- 0.04 oz/d versus 0.01 +/- 0.00 oz/d for non-consumers. In this study, 5.5 +/- 0.3 % of individuals 19-50 y (n=7,049) and 8.4 +/- 0.6 % of individuals 51+ y (n=6,243) consumed tree nuts/tree nut butters. Mean differences (p<0.01) between tree nut consumers and non-consumers of adult shortfall nutrients were: fiber (+5.0 g/d), vitamin E (+3.7 mg AT/d), calcium (+73 mg/d), magnesium (+95 mg/d), and potassium (+260 mg/d). Tree nut consumers had lower sodium intake (-157 mg/d, p<0.01). Diet quality was significantly higher in tree nut consumers (58.0+/-0.4 vs. 48.5+/-0.3, p<0.01). Tree nut consumption was associated with a higher overall diet quality score and improved nutrient intakes. Specific dietary recommendations for nut consumption should be provided for consumers. PMID- 20200001 TI - Sequential changes in myocardial function after valve replacement for aortic stenosis by speckle tracking echocardiography. AB - AIMS: Regional myocardial function may change differently in different pathology. Speckle tracking echocardiography (STE) was applied to evaluate longitudinal, radial, and circumferential function in patients with aortic stenosis (AS) before, within 1 week, and 6 months after aortic valve replacement (AVR). METHODS AND RESULTS: In 40 consecutive patients with severe AS, we acquired apical four-, three-, and two-chamber views and standard short-axis view pre- and post-AVR and after 6 months. Longitudinal, radial, and circumferential (LS, RS, and CS) were calculated by commercial STE software. Further, we analysed diastolic myocardial function by measuring E/e' ratio. With AVR, valve area increased and remained stable at 6 months follow-up. Left ventricular mass was unchanged 1 week after AVR (270 +/- 58 g vs. 267 +/- 58 g, n.s.) but decreased significantly during the next 6 months (219 +/- 50 g, P < 0.05). Left ventricular ejection fraction remained unchanged. Strain values did not change significantly within 1 week after AVR but increased significantly after 6 months (LS by 16%, RS by 21%, and CS by 28% of baseline values). E/e' ratio was highly augmented before AVR (26.1 +/- 12.5) and decreased significantly 6 months after AVR (15.9 +/- 5.9). CONCLUSION: Myocardial function significantly recovers after replacing the stenosed aortic valve. However, there is a considerable difference between the response of longitudinal, radial, and circumferential function. Our data suggest that echocardiographic assessment of regional function is feasible and of potential clinical importance. PMID- 20200002 TI - Two tricuspid asymmetric parachutes: a double diagnostic odyssey. PMID- 20200003 TI - Behavioural abnormalities in children with nephrotic syndrome. AB - BACKGROUND: Glucocorticoid therapy in children with nephrotic syndrome can lead to many adverse effects including behavioural problems. The present study was undertaken to assess the changes in individual behaviour among different sub groups of patients with idiopathic nephrotic syndrome (INS) and also to find out the relationship, if any, between different behavioural problems with cumulative dose of steroid therapy. METHODS: This was a prospective hospital-based study. We assessed behavioural patterns in 131 children and adolescents with steroid responsive INS aged 1.5-15 years. Fifty healthy children matched for age and gender were included to serve as controls. The Achenbach Child Behaviour Checklist was used to assess individual behaviour. Patients were sub-grouped according to age (1.5-5 and 6-15 years) and disease status (first attack before and after 12-week prednisolone, infrequent relapser, frequent relapser/steroid dependent). RESULTS: All groups had significantly elevated mean behavioural abnormality scores for dimensions assessed in both age groups, except rule breaking behaviour. Besides sleep problems, frequent relapsers/steroid-dependent patients exhibited maximum scores in comparison to first attack and infrequent relapsers in the 1.5- to 5-year age group. Total and individual behavioural scores showed close associations with cumulative prednisolone dose in both groups. CONCLUSIONS: It is evident that nephrotic syndrome patients should be given due consideration in clinical practice for behavioural abnormalities especially after steroid therapy. PMID- 20200004 TI - Parathyroid hormone-related protein induces hypertrophy in podocytes via TGF beta(1) and p27(Kip1): implications for diabetic nephropathy. AB - BACKGROUND: Hypertrophy of podocytes is characteristic in diabetic nephropathy (DN). Previously, we observed the upregulation of parathyroid hormone-related protein (PTHrP) and its receptor PTH1R, in experimental DN, associated with renal hypertrophy. Herein, we test the hypothesis that PTHrP participates in the mechanism of high glucose (HG)-induced podocyte hypertrophy. METHODS: On mouse podocytes, hypertrophy was assessed by protein content/cell and [H(3)]leucine incorporation. Podocytes were stimulated with HG (25 mM), PTHrP(1-36) (100 nM), angiotensin II (AngII) (100 nM) or TGF-beta(1) (5 ng/mL) in the presence or absence of PTHrP-neutralizing antibodies (alpha-PTHrP), the PTH1R antagonist JB4250 (10 microM), PTHrP silencer RNA (siRNA) or TGF-beta(1) siRNA. Protein expression was analysed by western blot and immunohistochemistry. RESULTS: HG induced hypertrophy was abolished in the presence of either alpha-PTHrP or PTHrP siRNA. This effect was associated with an inhibition of the upregulation of TGF beta(1) and p27(Kip1). JB4250 also inhibited HG-induced p27(Kip1) upregulation. Interestingly, whilst HG and AngII were unable to stimulate the expression of p27(Kip1) on PTHrP siRNA-transfected podocytes, TGF-beta(1) was still able to upregulate p27(Kip1) in these cells. Moreover, HG and PTHrP-induced hypertrophy as well as p27(Kip1) upregulation were abolished on TGF-beta(1) siRNA-transfected podocytes. Furthermore, the glomeruli of transgenic PTHrP-overexpressing mice showed a constitutive overexpression of TGF-beta(1) and p27(Kip1) to a degree similar to that of diabetic animals. CONCLUSIONS: PTHrP seems to participate in the hypertrophic signalling triggered by HG. In this condition, AngII induces the upregulation of PTHrP, which might induce the expression of TGF-beta(1) and p27(Kip1). These findings provide new insights into the protective effects of AngII antagonists in DN, opening new paths for intervention. PMID- 20200005 TI - Influence of tonsillectomy on the progression of mesangioproliferative glomerulonephritis. AB - BACKGROUND: Little information is available about the efficacy of tonsillectomy on long-term renal survival of patients with primary IgA nephropathy (IgAN). METHODS: In this retrospective cohort study, we considered 61 patients with IgAN who had tonsillectomy (n = 15) or not (n = 46) and compared them with 121 control patients with mesangioproliferative glomerulonephritis (MesGN) free of IgA deposits, who had tonsillectomy (n = 49) or not (n = 72). We evaluated the progression from a normal function [estimated glomerular filtration rate 60-220 mL/min/1.73 m(2), chronic kidney disease (CKD) stage 1 and 2] to a moderate renal dysfunction in CKD stage 3, which was considered the outcome. RESULTS: The mean duration of follow-up was 250 months (12-300 months) in the whole group of 182 patients. The survival to progression to stage 3 was 88% after 10 years, 71% after 20 years and 53% after 25 years. It was 72% after 20 years in both groups. Tonsillectomy was not significantly associated with CKD progression. Significant prognostic factors were age (P = 0.01), initial CKD stage (P = 0.03), proteinuria (P = 0.03), persistent proteinuria (P < 0.001) and diastolic blood pressure (P = 0.01). In the multivariate analysis (Cox model), there was no significant effect of tonsillectomy adjusted for the type of glomerulonephritis, initial CKD stage, persistent proteinuria, diastolic blood pressure and age. Only persistent proteinuria adjusted for the other factors was significantly associated with CKD progression (hazard ratio of 6.2, 95% confidence interval 3.1-12.7, P < 0.001). CONCLUSIONS: Tonsillectomy was not associated with a different progression rate of IgAN nor of MesGN after 20 years of follow-up. PMID- 20200006 TI - The effect of progressive glomerular disease on megalin-mediated endocytosis in the kidney. AB - BACKGROUND: A well-characterized dog model of the X-linked collagen disease Alport syndrome (XLAS) was used to study the effect of progressive glomerular disease on megalin-mediated endocytosis. In XLAS, altered structure and function of the glomerular basement membrane induces a progressive proteinuric nephropathy. METHODS: The investigation was performed in male XLAS dogs and age matched normal male littermates. The urine profile and megalin-mediated endocytosis in the proximal tubule of six healthy and six XLAS dogs were examined at 2, 4, 6, 8 and 10 months of age using SDS-PAGE, immunoblotting and immunohistochemistry. RESULTS: Gradually increasing urinary excretion of proteins over time and a reduced content of the same proteins in proximal tubule cells were found. Besides the glomerular component of the proteinuria, a significant tubular component was seen, which is due to a progressive change in the uptake of low-molecular-weight (LMW) ligands by megalin. Furthermore, the protein overload present in the lumen of the proximal tubule exceeds the reabsorption capacity of megalin and the co-receptor cubilin and results in a combined low- and high molecular-weight (HMW) proteinuria. Also, a shift in the distribution of lysosomes was seen in the XLAS dogs suggesting changes in the lysosomal degradation pattern in response to the altered endocytosis. CONCLUSIONS: The present study shows that the increased glomerular permeability and the subsequently altered megalin-mediated and megalin-dependent cubilin-mediated endocytosis lead to a partial LMW proteinuria and partial HMW proteinuria. PMID- 20200007 TI - Time to Reconsider Evidence for Anaemia Treatment (TREAT) = Essential Safety Arguments (ESA). PMID- 20200008 TI - The vaptans: just landed. But how was the trip? PMID- 20200009 TI - Modeling sample variables with an Experimental Factor Ontology. AB - MOTIVATION: Describing biological sample variables with ontologies is complex due to the cross-domain nature of experiments. Ontologies provide annotation solutions; however, for cross-domain investigations, multiple ontologies are needed to represent the data. These are subject to rapid change, are often not interoperable and present complexities that are a barrier to biological resource users. RESULTS: We present the Experimental Factor Ontology, designed to meet cross-domain, application focused use cases for gene expression data. We describe our methodology and open source tools used to create the ontology. These include tools for creating ontology mappings, ontology views, detecting ontology changes and using ontologies in interfaces to enhance querying. The application of reference ontologies to data is a key problem, and this work presents guidelines on how community ontologies can be presented in an application ontology in a data driven way. AVAILABILITY: http://www.ebi.ac.uk/efo. PMID- 20200010 TI - PaperMaker: validation of biomedical scientific publications. AB - MOTIVATION: The automatic analysis of scientific literature can support authors in writing their manuscripts. IMPLEMENTATION: PaperMaker is a novel IT solution that receives a scientific manuscript via a Web interface, automatically analyses the publication, evaluates consistency parameters and interactively delivers feedback to the author. It analyses the proper use of acronyms and their definitions, and the use of specialized terminology. It provides Gene Ontology (GO) and Medline Subject Headings (MeSH) categorization of text passages, the retrieval of relevant publications from public scientific literature repositories, and the identification of missing or unused references. RESULT: The author receives a summary of findings, the manuscript in its corrected form and a digital abstract containing the GO and MeSH annotations in the NLM/PubMed format. AVAILABILITY: http://www.ebi.ac.uk/Rebholz-srv/PaperMaker. PMID- 20200011 TI - Cross-species common regulatory network inference without requirement for prior gene affiliation. AB - MOTIVATION: Cross-species meta-analyses of microarray data usually require prior affiliation of genes based on orthology information that often relies on sequence similarity. RESULTS: We present an algorithm merging microarray datasets on the basis of co-expression alone, without any requirement for orthology information to affiliate genes. Combining existing methods such as co-inertia analysis, back transformation, Hungarian matching and majority voting in an iterative non-greedy hill-climbing approach, it affiliates arrays and genes at the same time, maximizing the co-structure between the datasets. To introduce the method, we demonstrate its performance on two closely and two distantly related datasets of different experimental context and produced on different platforms. Each pair stems from two different species. The resulting cross-species dynamic Bayesian gene networks improve on the networks inferred from each dataset alone by yielding more significant network motifs, as well as more of the interactions already recorded in KEGG and other databases. Also, it is shown that our algorithm converges on the optimal number of nodes for network inference. Being readily extendable to more than two datasets, it provides the opportunity to infer extensive gene regulatory networks. AVAILABILITY AND IMPLEMENTATION: Source code (MATLAB and R) freely available for download at http://www.mchips.org/supplements/moghaddasi_source.tgz. PMID- 20200012 TI - Sarcopenia: characteristics, mechanisms and functional significance. AB - Sarcopenia reflects a progressive withdrawal of anabolism and an increased catabolism, along with a reduced muscle regeneration capacity. Muscle force and power decline more than muscle dimensions: older muscle is intrinsically weak. Sarcopenic obesity (SO) among the elderly corroborates to the loss of muscle mass increasing the risk of metabolic syndrome development. Recent studies on the musculoskeletal adaptations with ageing and key papers on the mechanisms of muscle wasting, its functional repercussions and on SO are included. Neuropathic, hormonal, immunological, nutritional and physical activity factors contribute to sarcopenia. Selective fast fibre atrophy, loss of motor units and an increase in hybrid fibres are typical findings of ageing. Satellite cell number decreases reducing muscle regeneration capacity. SO promotes further muscle wasting and increases risk of metabolic syndrome development. The proportion of fast to slow fibres seems maintained in old age. In elderly humans, nuclear domain is maintained constant. Basal protein synthesis and breakdown show little changes in old age. Instead, blunting of the anabolic response to feeding and exercise and of the antiproteolytic effect of insulin is observed. Further understanding of the mechanisms of sarcopenia requires disentangling of the effects of ageing alone from those of disuse and disease. The causes of the greater anabolic resistance to feeding and exercise of elderly women need elucidating. The enhancement of muscle regeneration via satellite cell activation via the MAPK/notch molecular pathways seems particularly promising. PMID- 20200013 TI - New understanding and approaches to treatment in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is the most common autoimmune inflammatory polyarthritis. Significant advances in the understanding of its pathogenesis have led in the past two decades to major advancement in its therapy. We used data from articles in Cochrane Database of Systematic Reviews on 'rheumatoid arthritis', meta-analyses and randomized controlled trials on adult RA (age >19 years) published in English within the past 5 years and identified in PubMed, and other key papers on management of RA. Appropriate, early and aggressive therapy is required for confirmed active cases of RA. The choice of disease-modifying drugs and different combinations, especially the newer biologic agents in regards of their early and long-term usage remains debated because of high costs and long term safety concerns. Development of newer biologic agents working on different pathways of inflammation is underway in different stages. It remains to be determined how and when each of these agents will fit in the overall management of RA. Furthermore, post-marketing surveillance of the safety and response sustainability of these drugs is warranted. PMID- 20200014 TI - Cell therapy for cardiac repair. AB - Heart failure is a leading cause of morbidity and mortality worldwide. The current strategies for treatment are limited and new therapeutic approaches are needed. This review describes research performed in animal models of cardiac disease and clinical trials and discusses the mechanisms involved in possible beneficial effects of cell therapy. Cell therapy is a promising strategy to treat heart failure, as it aims to replenish the failing myocardium with contractile elements. However, cell therapy with adult progenitor cells induces a small improvement in heart function without significant cardiomyogenesis. Paracrine mechanisms are likely to be important. The most effective cell type for therapy remains unclear. Induced pluripotent stem cells have the greatest potential but more information on the properties of this cell type is needed. The integration of cells in the host myocardium and the routes of delivery remain controversial. The differentiation of cardiac cells from pluri- and multipotent cells and the understanding of their properties are growing points in cell therapy. More research is needed to correctly assess the physiological properties of differentiating cells, to dissect the role of the host environment in the integration and differentiation and to define the stage of differentiation required for cell transplantation. PMID- 20200015 TI - Plasma aldosterone levels are associated with increased cardiovascular mortality: the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. AB - AIMS: Evidence has accumulated that elevated aldosterone levels are associated with increased risks of fatal cardiovascular (CV) events. With the present analysis, we aimed at evaluating prospectively whether plasma aldosterone correlates with all-cause and CV disease (CVD) mortality in a large cohort of patients. METHODS AND RESULTS: Median plasma aldosterone concentration (PAC) was 79.0 (48.0-124.0) pg/mL (normal range: 30-160) in 3153 patients [median age: 63.5 (56.3-70.6) years; 30.1% women] who had undergone coronary angiography. After a median follow-up of 7.7 (7.2-8.5) years, a total of 716 participants died [22.7%; 454 (14.4%) due to CV causes and 262 (8.3%) due to non-CV causes]. In multivariable Cox proportional hazard analysis, adjusted for age, gender, antihypertensive treatment, and established CV risk factors, PAC levels stratified in quartiles were significantly associated with all-cause and CVD mortality. Compared with the reference (first) PAC quartile, hazard ratios (confidence interval 95%) for the fourth, third, and second PAC quartiles were 1.30 (1.02-1.65, P = 0.033), 1.32 (1.04-1.68, P = 0.021), and 1.20 (0.93-1.54, P = 0.155) for total mortality and 1.58 (1.15-2.16, P = 0.004), 1.39 (1.01-1.90, P = 0.041), and 1.63 (1.20-2.20, P = 0.002) for CVD mortality, respectively. Analyses for specific causes of CV death revealed strong associations between PAC levels and higher risk for fatal stroke and sudden cardiac death. CONCLUSION: In a large cohort of patients scheduled for coronary angiography, variation in PAC levels within the normal range is associated with increased all-cause and CVD mortality independent of major established CV risk factors. PMID- 20200016 TI - Effect of continuous versus episodic amiodarone treatment on quality of life in persistent atrial fibrillation. AB - AIMS: Amiodarone is associated with significant adverse effects. We hypothesized that episodic amiodarone treatment would be associated with better quality of life (QoL) compared with continuous treatment in the prevention of recurrent atrial fibrillation (AF). METHODS AND RESULTS: Quality of life was assessed in 158 patients from the Continuous vs. Episodic Prophylactic Treatment with Amiodarone for the Prevention of AF (CONVERT) study, using the Short Form (SF)-36 health survey and University of Toronto AF Severity Scale (AF severity scale) questionnaires at baseline and 1 year. The episodic group received amiodarone 1 month peri-cardioversion, the continuous group continued amiodarone. Patients were assessed for major adverse events and maintenance of sinus rhythm during follow-up (i.e. no AF recurrences at every follow-up visit). Quality of life (assessed by SF-36 and AF severity scale) was comparable between both treatment groups at baseline and 12 months, with similar incidence rates of major adverse events. Fewer patients in the episodic group had maintenance of sinus rhythm during follow-up [27 (36%) vs. 49 (59%), P = 0.004]. In the episodic group, maintenance of sinus rhythm was associated with a significant improvement on four SF-36 subscales and AF severity scale at 12 months. In contrast, in the continuous group no significant differences in QoL were seen between patients with continued maintenance of sinus rhythm compared with those with AF recurrence at the end of follow-up. CONCLUSION: Quality of life was comparable in the episodic and continuous treated group after 12 months of follow-up. Continued maintenance of sinus rhythm was associated with an improvement in QoL in the episodic but not the continuous treated group. PMID- 20200017 TI - Tracing the European course of cardiac resynchronization therapy from 2006 to 2008. AB - Cardiac resynchronization therapy (CRT) is a highly efficient treatment modality for patients with severe congestive heart failure and intraventricular dyssynchrony. However, the high individual cost and technical complexity of the implantation may limit its widespread utilization. The European Heart Rhythm Association (EHRA) launched a project to assess treatment of arrhythmias in all European Society of Cardiology member countries in order to have a platform for a progressive harmonization of arrhythmia treatment. As a result, two EHRA White Books have been published in 2008 and 2009 based on governmental, insurance, and professional society data. Our aim was to analyse the local differences in the utilization of CRT, based on these surveys. A total of 41 countries provided enough data to analyse years 2006-2008. Significant differences were found in the overall number of implantations and the growth rate between 2006 and 2008. Other contributing factors include local reimbursement of CRT, the existence of national guidelines, and a high number of conventional implantable cardioverter defibrillator implantations, while GDP or healthcare spending has less effect. Focusing on improving these factors may increase the availability of CRT in countries where it is currently underutilized. PMID- 20200018 TI - Left ventricular endocardial pacing improves the clinical efficacy in a non responder to cardiac resynchronization therapy: role of acute haemodynamic testing. PMID- 20200019 TI - Long-term patient acceptance of and satisfaction with implanted device remote monitoring. AB - AIMS: To evaluate patients' acceptance and satisfaction of the Home Monitoring (HM) remote control system after 1 year of follow-up by a self-made questionnaire (HM Acceptance and Satisfaction Questionnaire, HoMASQ) specifically designed for this purpose. METHODS AND RESULTS: The HoMASQ contains 12 items designed to investigate five different aspects strictly connected to patient's acceptance and satisfaction of remote monitoring: (i) relationship with their healthcare provider, (ii) easy of use of HM technology, (iii) related psychological aspects, (iv) implications on general health, and (v) overall satisfaction. Each item was rated on a five-point scale: from 0 to 4 with favourable responses score > or =2. The theoretical maximum total score (the highest detected acceptance and satisfaction level) was 48. The HoMASQ was given to 119 patients followed by HM during the 1-year follow-up visit. Ninety-nine percent of all the administered questionnaire items were answered. The mean total score was 40.8 +/- 5.4 with a mean percentage of favourable answers of 96.3 +/- 18.8% (CI 95.2 - 97.2%). The mean scores for each of the five areas of the HoMASQ were: 3.0 +/- 0.9 for relationship, 3.4 +/- 0.6 for easy of use, 3.4 +/- 0.9 for psychological aspects, and 3.4 +/- 0.8 for clinical implication and overall satisfaction. Cronbach's alpha for reliability of the HoMASQ was 0.73. CONCLUSION: A high level of acceptance and satisfaction after 1-year remote control by HM was detected by the five-point scale HoMASQ, which showed a good internal reliability. PMID- 20200021 TI - The impact of a Naturally Occurring Retirement Communities service program in Maryland, USA. AB - Most older adults prefer to age in place and it is therefore vital to support them in maintaining a high quality of life in their place of residence. Many Naturally Occurring Retirement Communities (NORCs) have implemented services to fulfill a range of needs of their residents. Community Partners (CP) provided 58 NORC residents in six apartment buildings within two suburban neighborhoods in Maryland with health and social work services, activities and transportation services. Participants were compared with 70 residents who did not receive these services. Residents were assessed prior to initiation of services (e.g. transportation, social work and recreation) and after service usage through a membership program. Members had significantly increased satisfaction with recreational activities and social life in the community as well as significant decreases in depressed affect. Members' self-reports showed that they were more likely to get out of the house, felt less isolated, and were happier since joining CP activities. This study is unique in examining the impact of utilization of a variety of services for older persons, while comparing these individuals to a local group of community-dwelling older persons who are without NORC services. PMID- 20200022 TI - Hypothesis: a potential further cause of endocrine disruption. PMID- 20200023 TI - More individuals but fewer species: testing the 'more individuals hypothesis' in a diverse tropical fauna. AB - A positive relationship between species richness and productivity is often observed in nature, but the causes remain contentious. One mechanism, the 'more individuals hypothesis' (MIH), predicts richness increases monotonically with density, as a function of resource flux. To test the MIH, we manipulated resource abundance in a community of tropical rainforest litter ants and measured richness and density responses. A unimodal relationship between richness and density most closely fitted the control and disturbance (resource removal) treatments in contrast to expectations of the MIH. Resource addition resulted in a monotonic increase in richness relative to density, a shift from the pattern in the control. In the disturbance treatment, richness was greater than in the control, opposite to expectations of the MIH. While large-scale correlations between ant diversity and net primary productivity or temperature are reconcilable with the MIH, key elements of the hypothesis are not supported. PMID- 20200024 TI - Phase II trial of pazopanib (GW786034), an oral multi-targeted angiogenesis inhibitor, for adults with recurrent glioblastoma (North American Brain Tumor Consortium Study 06-02). AB - The objective of this phase II single-arm study was to evaluate the efficacy and safety of pazopanib, a multi-targeted tyrosine kinase inhibitor, against vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3, platelet-derived growth factor receptor-alpha and -beta, and c-Kit, in recurrent glioblastoma. Patients with < or =2 relapses and no prior anti-VEGF/VEGFR therapy were treated with pazopanib 800 mg daily on 4-week cycles without planned interruptions. Brain magnetic resonance imaging and clinical reassessment were made every 8 weeks. The primary endpoint was efficacy as measured by 6-month progression-free survival (PFS6). Thirty-five GBM patients with a median age of 53 years and median Karnofsky performance scale of 90 were accrued. Grade 3/4 toxicities included leukopenia (n = 1), lymphopenia (n = 2), thrombocytopenia (n = 1), ALT elevation (n = 3), AST elevation (n = 1), CNS hemorrhage (n = 1), fatigue (n = 1), and thrombotic/embolic events (n = 3); 8 patients required dose reduction. Two patients had a partial radiographic response by standard bidimensional measurements, whereas 9 patients (6 at the 8-week point and 3 only within the first month of treatment) had decreased contrast enhancement, vasogenic edema, and mass effect but <50% reduction in tumor. The median PFS was 12 weeks (95% confidence interval [CI]: 8-14 weeks) and only 1 patient had a PFS time > or =6 months (PFS6 = 3%). Thirty patients (86%) had died and median survival was 35 weeks (95% CI: 24-47 weeks). Pazopanib was reasonably well tolerated with a spectrum of toxicities similar to other anti-VEGF/VEGFR agents. Single-agent pazopanib did not prolong PFS in this patient population but showed in situ biological activity as demonstrated by radiographic responses. ClinicalTrials.gov identifier: NCT00459381. PMID- 20200025 TI - Expression of hepatocyte growth factor and its receptor c-Met in human pituitary adenomas. AB - Hepatocyte growth factor (HGF) and its receptor c-Met have been known as key determinants of growth and angiogenesis in some brain tumors like gliomas, meningiomas, and schwannomas. But little is known about their expression in pituitary adenomas. In this study, the expression of HGF and c-Met in pituitary adenomas of different histology types was investigated by immunohistochemistry, and correlative analysis of their expression with microvessel density (MVD), Ki 67 expression, and other clinicopathologic factors was made. The results showed that the expression of HGF and c-Met exists in 98% (64 of 65) and 92% (60 of 65) pituitary adenomas, respectively, and co-expression of them existed in 91% (59 of 65) adenomas. HGF had significant correlation with MVD (Spearman's correlation coefficient, r = .31, P = .01) and Ki-67 (r = .32, P = .01). c-Met had significant correlation with MVD (r = .30, P = .02) and Ki-67 (r = .38, P = .00). HGF and c-Met expression had no significant correlation with age or extrasellar extension. There were no significant differences in HGF and c-Met expression between pituitary adenomas of different histology types. The results indicate that HGF and c-Met are widely expressed in pituitary adenomas, and their expression correlates with MVD and Ki-67 expression. PMID- 20200026 TI - A naturally occurring variant of Hsp90 that is associated with decanalization. AB - The heat shock protein Hsp90 has been the focus of many studies since it was suggested that it acts to mediate the buffering of phenotypic variation. Hsp90 mediated buffering may result in the accumulation of cryptic genetic variation that, when released either as a consequence of environmental or genetic stress, increases the evolvability of a population. Recent studies using laboratory induced mutations of Hsp90 and/or chemical inhibition to disrupt Hsp90 function confirm that Hsp90 can buffer cryptic genetic variation. We have previously identified a naturally occurring variant in the charged linker region of the Hsp90 gene, and now examine whether this variant is associated with altered levels of trait variability. The variant is associated with the release of cryptic genetic variation for canalized morphological (bristle) traits, but not for uncanalized morphological (wing and bristle) traits, and the effect on canalized traits depends on culture temperature. This suggests that natural genetic variation in Hsp90 may mediate the evolution of canalized morphological traits even if it does not influence the expression of variation for uncanalized traits. PMID- 20200027 TI - Acellular pertussis vaccination facilitates Bordetella parapertussis infection in a rodent model of bordetellosis. AB - Despite over 50 years of population-wide vaccination, whooping cough incidence is on the rise. Although Bordetella pertussis is considered the main causative agent of whooping cough in humans, Bordetella parapertussis infections are not uncommon. The widely used acellular whooping cough vaccines (aP) are comprised solely of B. pertussis antigens that hold little or no efficacy against B. parapertussis. Here, we ask how aP vaccination affects competitive interactions between Bordetella species within co-infected rodent hosts and thus the aP-driven strength and direction of in-host selection. We show that aP vaccination helped clear B. pertussis but resulted in an approximately 40-fold increase in B. parapertussis lung colony-forming units (CFUs). Such vaccine-mediated facilitation of B. parapertussis did not arise as a result of competitive release; B. parapertussis CFUs were higher in aP-relative to sham-vaccinated hosts regardless of whether infections were single or mixed. Further, we show that aP vaccination impedes host immunity against B. parapertussis-measured as reduced lung inflammatory and neutrophil responses. Thus, we conclude that aP vaccination interferes with the optimal clearance of B. parapertussis and enhances the performance of this pathogen. Our data raise the possibility that widespread aP vaccination can create hosts more susceptible to B. parapertussis infection. PMID- 20200028 TI - Dynamics and ecological consequences of avian influenza virus infection in greater white-fronted geese in their winter staging areas. AB - Recent outbreaks of highly pathogenic avian influenza (HPAI) in poultry have raised interest in the interplay between avian influenza (AI) viruses and their wild hosts. Studies linking virus ecology to host ecology are still scarce, particularly for non-duck species. Here, we link capture-resighting data of greater white-fronted geese Anser albifrons albifrons with the AI virus infection data collected during capture in The Netherlands in four consecutive winters. We ask what factors are related to AI virus prevalence and whether there are ecological consequences associated with AI virus infection in staging white fronted geese. Mean seasonal (low pathogenic) AI virus prevalence ranged between 2.5 and 10.7 per cent, among the highest reported values for non-duck species, and occurred in distinct peaks with near-zero prevalence before and after. Throat samples had a 2.4 times higher detection frequency than cloacal samples. AI virus infection was significantly related to age and body mass in some but not other winters. AI virus infection was not related to resighting probability, nor to maximum distance travelled, which was at least 191 km during the short infectious lifespan of an AI virus. Our results suggest that transmission via the respiratory route could be an important transmission route of AI virus in this species. Near-zero prevalence upon arrival on their wintering grounds, in combination with the epidemic nature of AI virus infections in white-fronted geese, suggests that white-fronted geese are not likely to disperse Asian AI viruses from their Siberian breeding grounds to their European wintering areas. PMID- 20200029 TI - Ergatoid queen development in the ant Myrmecina nipponica: modular and heterochronic regulation of caste differentiation. AB - Caste polyphenism in social insects provides us with excellent opportunities to examine the plasticity and robustness underlying developmental pathways. Several ant species have evolved unusual castes showing intermediate morphologies between alate queens and wingless workers. In some low-temperature habitats, the ant Myrmecina nipponica produces such intermediate reproductives (i.e. ergatoids), which can mate and store sperm but cannot fly. To gain insight into the developmental and evolutionary aspects associated with ergatoid production, we conducted morphological and histological examinations of the post-embryonic development of compound eyes, gonads and wings during the process of caste differentiation. In compound eyes, both the queen-worker and ergatoid-worker differences were already recognized at the third larval instar. In gonads, queen worker differentiation began at the larval stage, and ergatoid-worker differentiation began between the prepupal and pupal stages. Wing development in ergatoids was generally similar to that in workers throughout post-embryonic development. Our results showed that the developmental rate and timing of differentiation in body parts differed among castes and among body parts. These differences suggest that the rearrangement of modular body parts by heterochronic developmental regulation is responsible for the origination of novel castes, which are considered to be adaptations to specific ecological niches. PMID- 20200030 TI - Reproductive competition promotes the evolution of female weaponry. AB - Secondary sexual traits in females are a relatively rare phenomenon. Empirical studies have focused on the role of male mate choice in their evolution; however, recently it has been suggested that secondary sexual traits in females are more likely to be under selection via reproductive competition. We investigated female competition and the influence of female phenotype on fitness in Onthophagus sagittarius, a species of dung beetle that exhibits female-specific horns. We compared reproductive fitness when females were breeding in competition versus breeding alone and found that competition for breeding resources reduced fitness for all females, but that smaller individuals suffered a greater fitness reduction than larger individuals. When females were matched for body size, those with the longest horns gained higher reproductive fitness. The fitness function was positive and linear, favouring increased horn expression. Thus, we present evidence that female body size and horn size in O. sagittarius are under directional selection via competition for reproductive resources. Our study is a rare example of female contest competition selecting for female weaponry. PMID- 20200031 TI - Parasite virulence when the infection reduces the host immune response. AB - Parasite infections often induce a reduction in host immune response either because of a direct manipulation of the immune system by the parasite or because of energy depletion. Although infection-induced immunodepression can favour the establishment of the parasite within the host, a too severe immunodepression may increase the risk of infection with opportunistic pathogens, stopping the period over which the parasite can be transmitted to other hosts. Here, we explore how the risk of contracting opportunistic diseases affects the survival of the amphipod Gammarus pulex infected by the acanthocephalan Pomphorhynchus laevis. Previous work with this system has shown that upon infection, G. pulex has a substantially reduced immune response. Non-infected and P. laevis-infected hosts were maintained either in control or in micro-organism-enriched water, so as to vary the risk of encountering opportunistic pathogens. As predicted, we found that host mortality was exacerbated when infected gammarids were maintained in micro-organism-enriched water compared with clean, control water; whereas for non infected gammarids, living in micro-organism-enriched water only moderately increased the risk of mortality. These results show that the virulence of parasites that reduce the host immune response is an environmentally sensitive trait that depends on the concomitant risk for the host of contracting opportunistic diseases. This extra source of host mortality probably represents a cost for P. laevis, and we tentatively predict that the optimal level of parasite exploitation should depend on environmental conditions. PMID- 20200032 TI - The asymmetry of the carpal joint and the evolution of wing folding in maniraptoran theropod dinosaurs. AB - In extant birds, the hand is permanently abducted towards the ulna, and the wrist joint can bend extensively in this direction to fold the wing when not in use. Anatomically, this asymmetric mobility of the wrist results from the wedge-like shape of one carpal bone, the radiale, and from the well-developed convexity of the trochlea at the proximal end of the carpometacarpus. Among the theropod precursors of birds, a strongly convex trochlea is characteristic of Coelurosauria, a clade including the highly derived Maniraptora in addition to tyrannosaurs and compsognathids. The shape of the radiale can be quantified using a 'radiale angle' between the proximal and distal articular surfaces. Measurement of the radiale angle and reconstruction of ancestral states using squared-change parsimony shows that the angle was small (15 degrees) in primitive coelurosaurs but considerably larger (25 degrees) in primitive maniraptorans, indicating that the radiale was more wedge-shaped and the carpal joint more asymmetric. The radiale angle progressively increased still further within Maniraptora, with concurrent elongation of the forelimb feathers and the forelimb itself. Carpal asymmetry would have permitted avian-like folding of the forelimb in order to protect the plumage, an early advantage of the flexible, asymmetric wrist inherited by birds. PMID- 20200033 TI - Partner choice in Medicago truncatula-Sinorhizobium symbiosis. AB - In nitrogen-fixing symbiosis, plant sanctions against ineffective bacteria have been demonstrated in previous studies performed on soybean and yellow bush lupin, both developing determinate nodules with Bradyrhizobium sp. strains. In this study, we focused on the widely studied symbiotic association Medicago truncatula Sinorhizobium meliloti, which forms indeterminate nodules. Using two strains isolated from the same soil and displaying different nitrogen fixation phenotypes on the same fixed plant line, we analysed the existence of both partner choice and plant sanctions by performing split-root experiments. By measuring different parameters such as the nodule number, the nodule biomass per nodule and the number of viable rhizobia per nodule, we showed that M. truncatula is able to select rhizobia based on recognition signals, both before and after the nitrogen fixation step. However, no sanction mechanism, described as a decrease in rhizobia fitness inside the nodules, was detected. Consequently, even if partner choice seems to be widespread among legumes, sanction of non-effective rhizobia might not be universal. PMID- 20200035 TI - A novel route for processing cobalt-chromium-molybdenum orthopaedic alloys. AB - Spark plasma sintering has been used for the first time to prepare the ASTM F75 cobalt-chromium-molybdenum (Co-Cr-Mo) orthopaedic alloy composition using nanopowders. In the preliminary work presented in this report, the effect of processing variables on the structural features of the alloy (phases present, grain size and microstructure) has been investigated. Specimens of greater than 99.5 per cent theoretical density were obtained. Carbide phases were not detected in the microstructure but oxides were present. However, harder materials with finer grains were produced, compared with the commonly used cast/wrought processing methods, probably because of the presence of oxides in the microstructure. PMID- 20200034 TI - DNA topoisomerases in apicomplexan parasites: promising targets for drug discovery. AB - The phylum Apicomplexa includes a large group of protozoan parasites responsible for a wide range of animal and human diseases. Destructive pathogens, such as Plasmodium falciparum and Plasmodium vivax, causative agents of human malaria, Cryptosporidium parvum, responsible of childhood diarrhoea, and Toxoplasma gondii, responsible for miscarriages and abortions in humans, are frequently associated with HIV immunosuppression in AIDS patients. The lack of effective vaccines, along with years of increasing pressure to eradicate outbreaks with the use of drugs, has favoured the formation of multi-drug resistant strains in endemic areas. Almost all apicomplexan of medical interest contain two endosymbiotic organelles that contain their own mitochondrial and apicoplast DNA. Apicoplast is an attractive target for drug testing because in addition to harbouring singular metabolic pathways absent in the host, it also has its own transcription and translation machinery of bacterial origin. Accordingly, apicomplexan protozoa contain an interesting mixture of enzymes to unwind DNA from eukaryotic and prokaryotic origins. On the one hand, the main mechanism of DNA unwinding includes the scission of one-type I-or both DNA strands-type II eukaryotic topoisomerases, establishing transient covalent bonds with the scissile end. These enzymes are targeted by camptothecin and etoposide, respectively, two natural drugs whose semisynthetic derivatives are currently used in cancer chemotherapy. On the other hand, DNA gyrase is a bacterial-borne type II DNA topoisomerase that operates within the apicoplast and is effectively targeted by bacterial antibiotics like fluoroquinolones and aminocoumarins. The present review is an update on the new findings concerning topoisomerases in apicomplexan parasites and the role of these enzymes as targets for therapeutic agents. PMID- 20200036 TI - Predictors of persistent methicillin-resistant Staphylococcus aureus bacteraemia in patients treated with vancomycin. AB - OBJECTIVES: The high prevalence of methicillin-resistant Staphylococcus aureus (MRSA) coupled with an increase in vancomycin use have induced vancomycin tolerance in MRSA, adversely affecting the outcome of MRSA bacteraemia. This study aimed to identify predictors of persistent MRSA bacteraemia (PMRSAB) in patients treated with vancomycin. METHODS: A retrospective, case-control study was performed at a university hospital in Korea from January 2006 to February 2009. Subjects included 96 patients who had MRSA bacteraemia and received vancomycin under therapeutic drug monitoring. We compared the clinical characteristics, management and outcomes of cases with PMRSAB (>or=7 days, n = 31) with controls with non-PMRSAB ( 8 mg/L) and with a positive double-disc synergy test between ceftazidime and clavulanate were serotyped and screened for the presence of ESBL-encoding genes. Genes encoding metallo-beta-lactamases (bla(MBL)) were sought by PCR in ESBL producing isolates with positive imipenem/EDTA synergy tests. PFGE of SpeI digested genomic DNA was used to compare isolates and selected strains were characterized by multilocus sequence typing. RESULTS: Forty-eight (2.2%) of 2150 P. aeruginosa isolates were confirmed as class A ESBL-producing isolates by molecular testing. bla(BEL) and bla(PER) alleles were detected, respectively, in 39 and 10 P. aeruginosa isolates originating from 16 hospitals (two isolates were simultaneously positive for BEL and PER). Fifteen of the isolates were found to co-produce ESBLs and VIM carbapenemases. These strains were pan-resistant and remained susceptible only to colistin (MICs or =18 years of age with a histological diagnosis of GIST (Kit(+)), resected tumor size > or =3 cm, and a complete gross resection within 14-70 days prior to registration. Imatinib, 400 mg orally, was administered once daily for 1 year. The study was terminated after completion of the third protocol-specified interim analysis. At that time, 100 RFS events were confirmed by a blinded central independent review. With a median follow-up of 14 months, 30 RFS events were observed in the imatinib group and 70 were observed in the placebo group (hazard ratio, 0.398; 95% confidence interval, 0.259-0.610; two-sided p-value < .0001). OS results are immature. Most patients in both groups experienced at least one adverse reaction, and 31% of the imatinib group and 18% of the placebo group experienced grade > or =3 adverse reactions. The most frequently reported adverse reactions (> or =20%) were diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain. Drug was discontinued for adverse reactions in 17% and 3% of the imatinib and placebo-treated patients, respectively. PMID- 20200042 TI - Metformin attenuates cardiac fibrosis by inhibiting the TGFbeta1-Smad3 signalling pathway. AB - AIMS: The mechanism of the cardioprotective action of metformin is incompletely understood. We determined the role of metformin in cardiac fibrosis and investigated the mechanism. METHODS AND RESULTS: Ten-week-old male mice (C57BL/6) were subjected to left ventricular pressure overload by transverse aortic constriction. Mice received metformin (200 mg/kg/day) or normal saline for 6 weeks. Metformin inhibited cardiac fibrosis (fibrosis area/total heart area: 0.6 +/- 0.3 vs. 3.6 +/- 0.9%, P < 0.01) induced by pressure overload and improved cardiac diastolic function (left ventricular end-diastolic pressure: 5.2 +/- 0.9 vs. 11.0 +/- 1.6 mmHg, P < 0.05). Metformin inhibited the pressure overload induced transforming growth factor (TGF)-beta(1) production in mouse hearts and the TGF-beta(1)-induced collagen synthesis in cultured adult mouse cardiac fibroblasts (CFs). Metformin suppressed the phosphorylation of Smad3 in response to TGF-beta(1) in CFs. Metformin also inhibited the nuclear translocation and transcriptional activity of Smad3 in CFs. CONCLUSION: Metformin inhibited cardiac fibrosis induced by pressure overload in vivo and inhibited collagen synthesis in CFs probably via inhibition of the TGF-beta(1)-Smad3 signalling pathway. These findings provide a new mechanism for the cardioprotective effects of metformin. PMID- 20200043 TI - Microvascular fluid exchange and the revised Starling principle. AB - Microvascular fluid exchange (flow J(v)) underlies plasma/interstitial fluid (ISF) balance and oedematous swelling. The traditional form of Starling's principle has to be modified in light of insights into the role of ISF pressures and the recognition of the glycocalyx as the semipermeable layer of endothelium. Sum-of-forces evidence and direct observations show that microvascular absorption is transient in most tissues; slight filtration prevails in the steady state, even in venules. This is due in part to the inverse relation between filtration rate and ISF plasma protein concentration; ISF colloid osmotic pressure (COP) rises as J(v) falls. In some specialized regions (e.g. kidney, intestinal mucosa), fluid absorption is sustained by local epithelial secretions, which flush interstitial plasma proteins into the lymphatic system. The low rate of filtration and lymph formation in most tissues can be explained by standing plasma protein gradients within the intercellular cleft of continuous capillaries (glycocalyx model) and around fenestrations. Narrow breaks in the junctional strands of the cleft create high local outward fluid velocities, which cause a disequilibrium between the subglycocalyx space COP and ISF COP. Recent experiments confirm that the effect of ISF COP on J(v) is much less than predicted by the conventional Starling principle, in agreement with modern models. Using a two-pore system model, we also explore how relatively small increases in large pore numbers dramatically increase J(v) during acute inflammation. PMID- 20200044 TI - Astroglia are a possible cellular substrate of angiotensin(1-7) effects in the rostral ventrolateral medulla. AB - AIMS: Angiotensin(1-7) (Ang1-7) acting at the level of the rostral ventrolateral medulla (RVLM) affects arterial pressure. The cellular substrate of Ang1-7 remains unknown. We sought to determine which cell types in RVLM could mediate its actions and whether these are altered in the spontaneously hypertensive rat (SHR). METHODS AND RESULTS: Astrocytes, catecholaminergic (CA-ergic) and non-CA ergic neurones were targeted with adenoviral vectors in organotypic slice cultures from Wistar rats and SHR. Astrocytic Ca(2+) signalling was monitored using a genetically engineered Ca(2+) sensor Case12. CA-ergic neurones expressed enhanced green fluorescent protein (EGFP) under control of the PRS x 8 promoter, whereas non-CA-neurones expressed EGFP under control of the synapsin-1 promoter. Neurones were recorded in whole cell mode while [Ca(2+)](i) was monitored using Rhod-2. RVLM astrocytes responded to Ang1-7 (200-1000 nM) with concentration dependent [Ca(2+)](i) elevation. In SHR, the response to 1000 nM was significantly attenuated. The competitive Ang1-7 receptor antagonist A779, but not the AT(1) receptor blocker (losartan), suppressed Ang1-7-induced [Ca(2+)](i) elevations, which were also antagonized by blocking intracellular Ca(2+) stores. Ang1-7 evoked no consistent changes in [Ca(2+)](i) or membrane excitability in CA ergic or non-CA-ergic neurones in either rat strain. CONCLUSION: Astroglia are a plausible cellular target of Ang1-7 in RVLM. Our data suggest that astrocytic responsiveness to Ang1-7 is reduced in SHR. We hypothesise that Ang1-7 modulates astrocytic signalling which in vivo may affect local metabolism and microcirculation, resulting in changes in activity of RVLM pre-sympathetic neurones and hence blood pressure. PMID- 20200045 TI - Dissecting the influence of Mg2+ on 3D architecture and ligand-binding of the guanine-sensing riboswitch aptamer domain. AB - Long-range tertiary interactions determine the three-dimensional structure of a number of metabolite-binding riboswitch RNA elements and were found to be important for their regulatory function. For the guanine-sensing riboswitch of the Bacillus subtilis xpt-pbuX operon, our previous NMR-spectroscopic studies indicated pre-formation of long-range tertiary contacts in the ligand-free state of its aptamer domain. Loss of the structural pre-organization in a mutant of this RNA (G37A/C61U) resulted in the requirement of Mg(2+) for ligand binding. Here, we investigate structural and stability aspects of the wild-type aptamer domain (Gsw) and the G37A/C61U-mutant (Gsw(loop)) of the guanine-sensing riboswitch and their Mg(2+)-induced folding characteristics to dissect the role of long-range tertiary interactions, the link between pre-formation of structural elements and ligand-binding properties and the functional stability. Destabilization of the long-range interactions as a result of the introduced mutations for Gsw(loop) or the increase in temperature for both Gsw and Gsw(loop) involves pronounced alterations of the conformational ensemble characteristics of the ligand-free state of the riboswitch. The increased flexibility of the conformational ensemble can, however, be compensated by Mg(2+). We propose that reduction of conformational dynamics in remote regions of the riboswitch aptamer domain is the minimal pre-requisite to pre-organize the core region for specific ligand binding. PMID- 20200046 TI - Distinct RNA-dependent RNA polymerases are required for RNAi triggered by double stranded RNA versus truncated transgenes in Paramecium tetraurelia. AB - In many eukaryotes, RNA-dependent RNA polymerases (RdRPs) play key roles in the RNAi pathway. They have been implicated in the recognition and processing of aberrant transcripts triggering the process, and in amplification of the silencing response. We have tested the functions of RdRP genes from the ciliate Paramecium tetraurelia in experimentally induced and endogenous mechanisms of gene silencing. In this organism, RNAi can be triggered either by high-copy, truncated transgenes or by directly feeding cells with double-stranded RNA (dsRNA). Surprisingly, dsRNA-induced silencing depends on the putatively functional RDR1 and RDR2 genes, which are required for the accumulation of both primary siRNAs and a distinct class of small RNAs suggestive of secondary siRNAs. In contrast, a third gene with a highly divergent catalytic domain, RDR3, is required for siRNA accumulation when RNAi is triggered by truncated transgenes. Our data further implicate RDR3 in the accumulation of previously described endogenous siRNAs and in the regulation of the surface antigen gene family. While only one of these genes is normally expressed in any clonal cell line, the knockdown of RDR3 leads to co-expression of multiple antigens. These results provide evidence for a functional specialization of Paramecium RdRP genes in distinct RNAi pathways operating during vegetative growth. PMID- 20200047 TI - Iron fortification strategies for the control of childhood anemia in Brazil. AB - This article presents data on the fortification of foods, necessary as an important public health approach for the success in reducing anemia. The use of food vehicles, iron salts and their costs, as well as recent work on iron fortification of foods in Brazil are reviewed. Recent research serves as a cornerstone for countries that attempt to implement permanent, long-lasting iron fortification programs aimed at the prevention of anemia considering cultural habits, type of iron salts and at-risk groups. PMID- 20200051 TI - Chitosan oligosaccharides modulate the supramolecular conformation and the biological activity of oligogalacturonides in Arabidopsis. AB - Plant cell walls undergo remodeling during growth and development and are the first target of many invading pathogens. Acidic pectin (homogalacturonans) binds calcium and forms chain dimers called egg boxes and even multimers at higher calcium ion concentrations. Chitosan, the deacetylated form of chitin produced by fungi when invading plant tissues, is a cationic polymer that can interact with negatively charged pectin. The interaction between chitosan oligomers (COS) and pectic egg boxes was investigated using 2F4, a monoclonal antibody specific for calcium-associated dimers of pectin. Depending on the size of the pectic molecules, the COS to pectin ratio, the degree of polymerization and the degree of acetylation of COS in the mixture, the calcium-induced egg box conformation of oligogalacturonides (OGA) was strongly stabilized or destroyed. The biological activity of COS-stabilized egg boxes was assayed on Arabidopsis cell suspensions. COS-OGA egg boxes strongly enhanced extracellular alkalinization and decreased potassium fluxes compared to control COS and OGA alone. Furthermore, OGA rescued Arabidopsis from cell death induced by higher concentrations of deacetylated COS. The stabilized COS-OGA egg boxes could constitute a combined emergency signal that informs plant cells on both cell wall degradation and pathogen presence, triggering a much stronger response than individual components alone. PMID- 20200055 TI - More than skin deep? PMID- 20200052 TI - Protein tyrosine O-glycosylation--a rather unexplored prokaryotic glycosylation system. AB - Glycosylation is a frequent and heterogeneous posttranslational protein modification occurring in all domains of life. While protein N-glycosylation at asparagine and O-glycosylation at serine, threonine or hydroxyproline residues have been studied in great detail, only few data are available on O-glycosidic attachment of glycans to the amino acid tyrosine. In this study, we describe the identification and characterization of a bacterial protein tyrosine O glycosylation system. In the Gram-positive, mesophilic bacterium Paenibacillus alvei CCM 2051(T), a polysaccharide consisting of [-->3)-beta-d-Galp-(1[alpha-d Glcp-(1-->6)] -->4)-beta-d-ManpNAc-(1-->] repeating units is O-glycosidically linked via an adaptor with the structure -[GroA-2-->OPO(2)-->4-beta-d-ManpNAc-(1- >4)] -->3)-alpha-l-Rhap-(1-->3)-alpha-l-Rhap-(1-->3)-alpha-l-Rhap-(1-->3)-beta-d Galp-(1--> to specific tyrosine residues of the S-layer protein SpaA. A +AH4-24.3 kb S-layer glycosylation (slg) gene cluster encodes the information necessary for the biosynthesis of this glycan chain within 18 open reading frames (ORF). The corresponding translation products are involved in the biosynthesis of nucleotide activated monosaccharides, assembly and export as well as in the transfer of the completed polysaccharide chain to the S-layer target protein. All ORFs of the cluster, except those encoding the nucleotide sugar biosynthesis enzymes and the ATP binding cassette (ABC) transporter integral transmembrane proteins, were disrupted by the insertion of the mobile group II intron Ll.LtrB, and S-layer glycoproteins produced in mutant backgrounds were analyzed by mass spectrometry. There is evidence that the glycan chain is synthesized in a process comparable to the ABC-transporter-dependent pathway of the lipopolysaccharide O-polysaccharide biosynthesis. Furthermore, with the protein WsfB, we have identified an O oligosaccharyl:protein transferase required for the formation of the covalent beta-d-Gal-->Tyr linkage between the glycan chain and the S-layer protein. PMID- 20200059 TI - Chinese would resist having larger families if one child policy was relaxed. PMID- 20200060 TI - Bad medicine: type 2 diabetes. PMID- 20200062 TI - Strategies are needed to deal with migration resulting from climate change. PMID- 20200064 TI - Graphic medicine: use of comics in medical education and patient care. PMID- 20200065 TI - The role of phloem loading reconsidered. PMID- 20200066 TI - Trafficking of the plant cellulose synthase complex. PMID- 20200067 TI - Concerted modification of flowering time and inflorescence architecture by ectopic expression of TFL1-like genes in maize. AB - TERMINAL FLOWER1 (TFL1)-like genes are highly conserved in plants and are thought to function in the maintenance of meristem indeterminacy. Recently, we described six maize (Zea mays) TFL1-related genes, named ZEA CENTRORADIALIS1 (ZCN1) to ZCN6. To gain insight into their functions, we generated transgenic maize plants overexpressing their respective cDNAs driven by a constitutive promoter. Overall, ectopic expression of the maize TFL1-like genes produced similar phenotypes, including delayed flowering and altered inflorescence architecture. We observed an apparent relationship between the magnitude of the transgenic phenotypes and the degree of homology between the ZCN proteins. ZCN2, -4, and -5 form a monophylogenetic clade, and their overexpression produced the strongest phenotypes. Along with very late flowering, these transgenic plants produced a "bushy" tassel with increased lateral branching and spikelet density compared with nontransgenic siblings. On the other hand, ZCN1, -3, and -6 produced milder effects. Among them, ZCN1 showed moderate effects on flowering time and tassel morphology, whereas ZCN3 and ZCN6 did not change flowering time but still showed effects on tassel morphology. In situ hybridizations of tissue from nontransgenic plants revealed that the expression of all ZCN genes was associated with vascular bundles, but each gene had a specific spatial and temporal pattern. Expression of four ZCN genes localized to the protoxylem, whereas ZCN5 was expressed in the protophloem. Collectively, our findings suggest that ectopic expression of the TFL1-like genes in maize modifies flowering time and inflorescence architecture through maintenance of the indeterminacy of the vegetative and inflorescence meristems. PMID- 20200068 TI - MISSA is a highly efficient in vivo DNA assembly method for plant multiple-gene transformation. AB - We describe a highly efficient in vivo DNA assembly method, multiple-round in vivo site-specific assembly (MISSA), which facilitates plant multiple-gene transformation. MISSA is based on conjugational transfer, which is driven by donor strains, and two in vivo site-specific recombination events, which are mediated by inducible Cre recombinase and phage lambda site-specific recombination proteins in recipient strains, to enable in vivo transfer and in vivo assembly of multiple transgenic DNA. The assembly reactions can be performed circularly and iteratively through alternate use of the two specially designed donor vectors. As proof-of-principle experiments, we constructed a few plant multigene binary vectors. One of these vectors was generated by 15 rounds of MISSA reactions and was confirmed in transgenic Arabidopsis (Arabidopsis thaliana). As MISSA simplifies the tedious and time-consuming in vitro manipulations to a simple mixing of bacterial strains, it will greatly save time, effort, and expense associated with the assembly of multiple transgenic or synthetic DNA. The principle that underlies MISSA is applicable to engineering polygenic traits, biosynthetic pathways, or protein complexes in all organisms, such as Escherichia coli, yeast, plants, and animals. MISSA also has potential applications in synthetic biology, whether for basic theory or for applied biotechnology, aiming at the assembly of genetic pathways for the production of biofuels, pharmaceuticals, and industrial compounds from natural or synthetic DNA. PMID- 20200069 TI - The development of an efficient multipurpose bean pod mottle virus viral vector set for foreign gene expression and RNA silencing. AB - Plant viral vectors are valuable tools for heterologous gene expression, and because of virus-induced gene silencing (VIGS), they also have important applications as reverse genetics tools for gene function studies. Viral vectors are especially useful for plants such as soybean (Glycine max) that are recalcitrant to transformation. Previously, two generations of bean pod mottle virus (BPMV; genus Comovirus) vectors have been developed for overexpressing and silencing genes in soybean. However, the design of the previous vectors imposes constraints that limit their utility. For example, VIGS target sequences must be expressed as fusion proteins in the same reading frame as the viral polyprotein. This requirement limits the design of VIGS target sequences to open reading frames. Furthermore, expression of multiple genes or simultaneous silencing of one gene and expression of another was not possible. To overcome these and other issues, a new BPMV-based vector system was developed to facilitate a variety of applications for gene function studies in soybean as well as in common bean (Phaseolus vulgaris). These vectors are designed for simultaneous expression of multiple foreign genes, insertion of noncoding/antisense sequences, and simultaneous expression and silencing. The simultaneous expression of green fluorescent protein and silencing of phytoene desaturase shows that marker gene assisted silencing is feasible. These results demonstrate the utility of this BPMV vector set for a wide range of applications in soybean and common bean, and they have implications for improvement of other plant virus-based vector systems. PMID- 20200071 TI - Auxin metabolism and function in the multicellular brown alga Ectocarpus siliculosus. AB - Ectocarpus siliculosus is a small brown alga that has recently been developed as a genetic model. Its thallus is filamentous, initially organized as a main primary filament composed of elongated cells and round cells, from which branches differentiate. Modeling of its early development suggests the involvement of very local positional information mediated by cell-cell recognition. However, this model also indicates that an additional mechanism is required to ensure proper organization of the branching pattern. In this paper, we show that auxin indole-3 acetic acid (IAA) is detectable in mature E. siliculosus organisms and that it is present mainly at the apices of the filaments in the early stages of development. An in silico survey of auxin biosynthesis, conjugation, response, and transport genes showed that mainly IAA biosynthesis genes from land plants have homologs in the E. siliculosus genome. In addition, application of exogenous auxins and 2,3,5 triiodobenzoic acid had different effects depending on the developmental stage of the organism, and we propose a model in which auxin is involved in the negative control of progression in the developmental program. Furthermore, we identified an auxin-inducible gene called EsGRP1 from a small-scale microarray experiment and showed that its expression in a series of morphogenetic mutants was positively correlated with both their elongated-to-round cell ratio and their progression in the developmental program. Altogether, these data suggest that IAA is used by the brown alga Ectocarpus to relay cell-cell positional information and induces a signaling pathway different from that known in land plants. PMID- 20200072 TI - Probing the reproducibility of leaf growth and molecular phenotypes: a comparison of three Arabidopsis accessions cultivated in ten laboratories. AB - A major goal of the life sciences is to understand how molecular processes control phenotypes. Because understanding biological systems relies on the work of multiple laboratories, biologists implicitly assume that organisms with the same genotype will display similar phenotypes when grown in comparable conditions. We investigated to what extent this holds true for leaf growth variables and metabolite and transcriptome profiles of three Arabidopsis (Arabidopsis thaliana) genotypes grown in 10 laboratories using a standardized and detailed protocol. A core group of four laboratories generated similar leaf growth phenotypes, demonstrating that standardization is possible. But some laboratories presented significant differences in some leaf growth variables, sometimes changing the genotype ranking. Metabolite profiles derived from the same leaf displayed a strong genotype x environment (laboratory) component. Genotypes could be separated on the basis of their metabolic signature, but only when the analysis was limited to samples derived from one laboratory. Transcriptome data revealed considerable plant-to-plant variation, but the standardization ensured that interlaboratory variation was not considerably larger than intralaboratory variation. The different impacts of the standardization on phenotypes and molecular profiles could result from differences of temporal scale between processes involved at these organizational levels. Our findings underscore the challenge of describing, monitoring, and precisely controlling environmental conditions but also demonstrate that dedicated efforts can result in reproducible data across multiple laboratories. Finally, our comparative analysis revealed that small variations in growing conditions (light quality principally) and handling of plants can account for significant differences in phenotypes and molecular profiles obtained in independent laboratories. PMID- 20200070 TI - The protein kinase SnRK2.6 mediates the regulation of sucrose metabolism and plant growth in Arabidopsis. AB - In higher plants, three subfamilies of sucrose nonfermenting-1 (Snf1)-related protein kinases have evolved. While the Snf1-related protein kinase 1 (SnRK1) subfamily has been shown to share pivotal roles with the orthologous yeast Snf1 and mammalian AMP-activated protein kinase in modulating energy and metabolic homeostasis, the functional significance of the two plant-specific subfamilies SnRK2 and SnRK3 in these critical processes is poorly understood. We show here that SnRK2.6, previously identified as crucial in the control of stomatal aperture by abscisic acid (ABA), has a broad expression pattern and participates in the regulation of plant primary metabolism. Inactivation of this gene reduced oil synthesis in Arabidopsis (Arabidopsis thaliana) seeds, whereas its overexpression increased Suc synthesis and fatty acid desaturation in the leaves. Notably, the metabolic alterations in the SnRK2.6 overexpressors were accompanied by amelioration of those physiological processes that require high levels of carbon and energy input, such as plant growth and seed production. However, the mechanisms underlying these functionalities could not be solely attributed to the role of SnRK2.6 as a positive regulator of ABA signaling, although we demonstrate that this kinase confers ABA hypersensitivity during seedling growth. Collectively, our results suggest that SnRK2.6 mediates hormonal and metabolic regulation of plant growth and development and that, besides the SnRK1 kinases, SnRK2.6 is also implicated in the regulation of metabolic homeostasis in plants. PMID- 20200074 TI - Frequent silencing of protocadherin 17, a candidate tumour suppressor for esophageal squamous cell carcinoma. AB - Protocadherins are a subfamily of the cadherin superfamily, but little is known about their functions. We identified a homozygous loss of protocadherin (PCDH) 17 in the course of a program to screen a panel of esophageal squamous cell carcinoma (ESCC) cell lines for genomic copy number aberrations. PCDH17 messenger RNA was expressed in normal esophageal tissue but not in the majority of ESCC cell lines without a homozygous deletion of this gene and restored in gene silenced ESCC cells after treatment with 5-aza-2'-deoxycytidine. The DNA methylation status of the PCDH17 CpG island correlated inversely with the PCDH17 expression, and a putative methylation target region showed promoter activity. The methylation of the PCDH17 promoter was also associated with the silencing of gene expression in primary ESCC partly. Among primary ESCC cases, the silencing of PCDH17 protein expression was associated with a poorer differentiation status of ESCC cells and possibly with prognosis in a subset of this tumour. Restoration of PCDH17 expression in ESCC cells reduced cell proliferation and migration/invasion. These results suggest that silencing of PCDH17 expression through hypermethylation of the promoter or other mechanisms leads to loss of its tumour-suppressive activity, which may be a factor in the carcinogenesis of a subgroup of ESCCs. PMID- 20200073 TI - The alpha-subunit of the Arabidopsis heterotrimeric G protein, GPA1, is a regulator of transpiration efficiency. AB - Land plants must balance CO2 assimilation with transpiration in order to minimize drought stress and maximize their reproductive success. The ratio of assimilation to transpiration is called transpiration efficiency (TE). TE is under genetic control, although only one specific gene, ERECTA, has been shown to regulate TE. We have found that the alpha-subunit of the heterotrimeric G protein in Arabidopsis (Arabidopsis thaliana), GPA1, is a regulator of TE. gpa1 mutants, despite having guard cells that are hyposensitive to abscisic acid-induced inhibition of stomatal opening, have increased TE under ample water and drought stress conditions and when treated with exogenous abscisic acid. Leaf-level gas exchange analysis shows that gpa1 mutants have wild-type assimilation versus internal CO2 concentration responses but exhibit reduced stomatal conductance compared with ecotype Columbia at ambient and below-ambient internal CO2 concentrations. The increased TE and reduced whole leaf stomatal conductance of gpa1 can be primarily attributed to stomatal density, which is reduced in gpa1 mutants. GPA1 regulates stomatal density via the control of epidermal cell size and stomata formation. GPA1 promoter::beta-glucuronidase lines indicate that the GPA1 promoter is active in the stomatal cell lineage, further supporting a function for GPA1 in stomatal development in true leaves. PMID- 20200076 TI - Simultaneous spontaneous ruptures of both flexor tendons in the little finger. PMID- 20200077 TI - Spontaneous rupture of the flexor digitorum superficialis tendon of the little finger with aplasia of the flexor digitorum profundus tendon. PMID- 20200078 TI - Closed ruptures of both flexor tendons of the little finger. PMID- 20200079 TI - Spare parts surgery: the adipofascial cross finger flap. PMID- 20200080 TI - Combined triggering at the wrist and severe carpal tunnel syndrome caused by gouty infiltration of a flexor tendon. PMID- 20200081 TI - Bilateral pisiform fractures. PMID- 20200082 TI - Bilateral stress fractures of the radial styloid processes in a gymnast. PMID- 20200083 TI - Steroid infiltration of tendon sheath: a contraindication to subsequent tendon use for reconstruction? PMID- 20200084 TI - Isolated cruciate pulley injuries in rock climbers. PMID- 20200085 TI - Malignant peripheral nerve sheath tumour of the hand. PMID- 20200086 TI - Bilateral hand amputation due to clenched fist syndrome. PMID- 20200088 TI - Effects of growth hormone and thyroxine replacement therapy on insulin signaling in Ames dwarf mice. AB - Ames dwarf (Prop1(df), df/df) mice lack growth hormone (GH), prolactin, and thyrotropin and live remarkably longer than their normal siblings. Significance of reduced activity of the somatotropic and thyroid axes during development and adulthood on longevity are unknown. Because enhanced insulin sensitivity and reduced insulin levels are among likely mechanisms responsible for increased longevity in these mutants, we compared the effects of GH and thyroxine (T4) replacement on various parameters related to insulin signaling in young and old male df/df mice. The results suggest that altered plasma adiponectin and insulin like growth factor-1 (IGF-1) and hepatic IGF-1, insulin receptor (IR), IR substrate-1, peroxisome proliferator-activated receptor (PPAR) gamma, and PPARgamma coactivator-1 alpha may contribute to increased insulin sensitivity in Ames dwarfs. The stimulatory effect of GH and T4 treatment on plasma insulin and inhibitory effect on expression of hepatic glucose transporter-2 were greater in old than in young dwarfs. These results indicate that GH and T4 treatment has differential impact on insulin signaling during development and adulthood. PMID- 20200089 TI - Exposure to flour dust in South African supermarket bakeries: modeling of baseline measurements of an intervention study. AB - INTRODUCTION: Exposure to flour dust has been reported as an important risk factor for allergic respiratory disease among bakery workers. A high prevalence of allergic sensitization and asthma was recently reported in South African supermarket bakeries. The aim of this study was to conduct a detailed exposure assessment of these bakeries so as to provide the baseline for a broader intervention study. METHODS: A total of 211 full-shift personal samples were collected on randomly selected individuals within five different job categories in 18 bakeries. The samples were analyzed for particulate mass and specific flour dust allergens (wheat, rye, and fungal alpha-amylase). Exposure models were developed using job, bakery size, tasks, and specific ingredients used. Bakery and worker were regarded as random effect components. RESULTS: Bread bakers had the highest average (geometric mean) exposures (1.33 mg m(-3) flour dust particulate, 13.66 microg m(-3) wheat allergens, and 5.14 microg m(-3) rye allergens). For alpha-amylase allergens, most samples were below the limit of detection for several occupational titles. In the mixed effect models, the significant predictors of elevated exposure to inhalable dust particulate as well as wheat and rye allergen concentrations were large bakery size, bread baking, and use of cereal flours, while tasks such as confectionery work were negatively correlated with these exposure metrics. Weighing tasks and use of premix products were associated with increased exposure to fungal alpha-amylase. A high correlation between particulate dust and wheat (r = 0.84) as well as rye (r = 0.86) was observed, with a much lower correlation between particulate dust and fungal alpha-amylase (r = 0.33). Overall, a low proportion (39%) of bakery stores implemented various control measures to reduce dust exposures in the bakeries. CONCLUSIONS: This study confirms that current exposure control strategies in supermarket bakery stores are inadequate in reducing dust exposures to protect the health of bakery workers. PMID- 20200090 TI - Respiratory symptoms and exposure-response relations in workers exposed to metalworking fluid aerosols. AB - The aim of the study was to identify specific health risks and exposure-response relationships associated with exposure to metalworking fluid (MWF) aerosols. In a cross-sectional study of machine workers exposed to MWF aerosols in five companies in Sweden, a self-administered questionnaire about health symptoms, work tasks, and exposure situations was sent out to 2294 employees, 1632 exposed and 662 referents. Referents were office workers and metal workers not working with MWFs. In four of the companies, there were recent measurements of personal exposure to MWF aerosols. Log-binomial regression models were used to estimate prevalence ratios with 95% confidence intervals for different health outcomes in relation to different variables of exposure. The response rate after two reminders was 67% resulting in 1048 (923 male, 125 female) workers exposed to MWF aerosols and 451 (374 male, 77 female) referents. The study indicates that metal workers in Sweden currently exposed to a mean value of MWF aerosols of 0.4 mg m( 3) have a significantly higher prevalence of wheeze, chronic bronchitis, chronic rhinitis, and eye irritation compared to the referents. At a mean exposure of 0.4 mg m(-3), a level below the Swedish 8-h exposure limit value of 1 mg m(-3), machine operators showed increased prevalence of symptoms in eyes and airways. Thus, the current exposure limit value does not seem to protect the workers from such symptoms. PMID- 20200091 TI - Post-traumatic stress disorder in physicians from an underserviced area. AB - BACKGROUND: Studies suggest a high prevalence of mental illness in physicians. The rate of post-traumatic stress disorder (PTSD) has been examined in physicians exposed to traumatic circumstances and physicians in training but never in physicians in regular practice. OBJECTIVE: To estimate the prevalence of PTSD in physicians practicing in a predominantly rural and remote and medically underserviced region of Canada. METHODS: The PTSD Checklist-Civilian Version (PCL C) was mailed to all 331 physicians in Northwestern Ontario, Canada. A PCL-C score of >or=50 was used to define 'probable' PTSD and >or=30 defined 'possible' PTSD. Additional comments and demographic information were also requested. RESULTS: Completed questionnaires were received from 159 physicians (48%). The prevalence of probable PTSD was 4.4%. No differences between demographic groups were observed for probable PTSD, but possible PTSD was more frequent in males than females (47.3% versus 20.4%, chi-square = 10.59, P = 0.001). Mean scores were also higher for males than for females (30.4 versus 25.4, 95% confidence interval for the difference: 1.4-8.5, P = 0.006). Respondents identified overwork, insufficient resources and relationships with colleagues and patients as common stressors. CONCLUSIONS: Results suggest a high rate of PTSD in Northwestern Ontario physicians. The prevalence of possible PTSD and mean PCL-C scores are higher in men than in women in this region, which may relate to differences in practice characteristics and the opportunity for exposure to traumatic events. PMID- 20200092 TI - Pentosan polysulfate treatment preserves renal autoregulation in ANG II-infused hypertensive rats via normalization of P2X1 receptor activation. AB - Inflammatory factors are elevated in animal and human subjects with hypertension and renal injury. We hypothesized that inflammation contributes to hypertension induced renal injury by impairing autoregulation and microvascular reactivity to P2X(1) receptor activation. Studies were conducted in vitro using the blood perfused juxtamedullary nephron preparation. Rats receiving ANG II (60 ng/min) infusion were treated with the anti-inflammatory agent pentosan polysulfate (PPS) for 14 days. The magnitude and progression of hypertension were similar in ANG II and ANG II+PPS-treated rats (169 +/- 5 vs. 172 +/- 2 mmHg). Afferent arterioles from control rats exhibited normal autoregulatory behavior with diameter decreasing from 18.4 +/- 1.6 to 11.4 +/- 1.7 MUm when perfusion pressure was increased from 70 to 160 mmHg. In contrast, pressure-mediated vasoconstriction was markedly attenuated in ANG II-treated rats, and diameter remained essentially unchanged over the range of perfusion pressures. However, ANG II-treated rats receiving PPS exhibited normal autoregulatory behavior compared with ANG II alone rats. Arteriolar reactivity to ATP and beta,gamma-methylene ATP was significantly reduced in ANG II hypertensive rats compared with controls. Interestingly, PPS treatment preserved normal reactivity to P2 and P2X(1) receptor agonists despite the persistent hypertension. The maximal vasoconstriction was 79 +/- 3 and 81 +/- 2% of the control diameter for ATP and beta,gamma-methylene ATP, respectively, similar to responses in control rats. PPS treatment significantly reduced alpha smooth muscle actin staining in afferent arterioles and plasma transforming growth factor-beta1 concentration in ANG II-treated rats. In conclusion, PPS normalizes autoregulation without altering ANG II-induced hypertension, suggesting that inflammatory processes reduce P2X(1) receptor reactivity and thereby impair autoregulatory behavior in ANG II hypertensive rats. PMID- 20200093 TI - Multiple mechanisms act to maintain kidney oxygenation during renal ischemia in anesthetized rabbits. AB - We examined the mechanisms that maintain stable renal tissue PO(2) during moderate renal ischemia, when changes in renal oxygen delivery (DO(2)) and consumption (VO(2)) are mismatched. When renal artery pressure (RAP) was reduced progressively from 80 to 40 mmHg, VO(2) (-38 +/- 7%) was reduced more than DO(2) (-26 +/- 4%). Electrical stimulation of the renal nerves (RNS) reduced DO(2) (-49 +/- 4% at 2 Hz) more than VO(2) (-30 +/- 7% at 2 Hz). Renal arterial infusion of angiotensin II reduced DO(2) (-38 +/- 3%) but not VO(2) (+10 +/- 10%). Despite mismatched changes in DO(2) and VO(2), renal tissue PO(2) remained remarkably stable at >=40 mmHg RAP, during RNS at <=2 Hz, and during angiotensin II infusion. The ratio of sodium reabsorption to VO(2) was reduced by all three ischemic stimuli. None of the stimuli significantly altered the gradients in PCO(2) or pH across the kidney. Fractional oxygen extraction increased and renal venous PO(2) fell during 2-Hz RNS and angiotensin II infusion, but not when RAP was reduced to 40 mmHg. Thus reduced renal VO(2) can help prevent tissue hypoxia during mild renal ischemia, but when renal VO(2) is reduced less than DO(2), other mechanisms prevent a fall in renal PO(2). These mechanisms do not include increased efficiency of renal oxygen utilization for sodium reabsorption or reduced washout of carbon dioxide from the kidney, leading to increased oxygen extraction. However, increased oxygen extraction could be driven by altered countercurrent exchange of carbon dioxide and/or oxygen between renal arteries and veins. PMID- 20200095 TI - Renal capsule as a stem cell niche. AB - Renal resident stem cells were previously reported within the renal tubules and papillary area. The aim of the present study was to determine whether renal capsules harbor stem cells and whether this pool can be recruited to the renal parenchyma after ischemic injury. We demonstrated the presence of label-retaining cells throughout the renal capsule, at a density of ~10 cells/mm(2), and their close apposition to the blood vessels. By flow cytometry, in vitro cultured cells derived from the renal capsule were positive for mesenchymal stem cell (MSC) markers (CD29+, vimentin+, Sca-1+, nestin+) but did not express hematopoietic and endothelial stem cell markers. Moreover, renal capsule-derived cells also exhibited self-renewal, clonogenicity, and multipotency in differentiation conditions, all favoring stem cell characteristics and identifying them with MSC. In situ labeling of renal capsules with CM-DiI CellTracker demonstrated in vivo a directed migration of CM-DiI-labeled cells to the ischemic renal parenchyma, with the rate of migration averaging 30 MUm/h. Decapsulation of the kidneys during ischemia resulted in a modest, but statistically significant, deceleration of recovery of plasma creatinine compared with ischemic kidneys with intact renal capsule. Comparison of these conditions allows the conclusion that renal capsular cells may contribute ~25-30% of the recovery from ischemia. In conclusion, the data suggest that the renal capsule may function as a novel stem cell niche harboring MSC capable of participating in the repair of renal injury. PMID- 20200094 TI - Effect of paricalcitol and cinacalcet on serum phosphate, FGF-23, and bone in rats with chronic kidney disease. AB - Calcimimetics activate the calcium-sensing receptor (CaR) and reduce parathyroid hormone (PTH) by increasing the sensitivity of the parathyroid CaR to ambient calcium. The calcimimetic, cinacalcet, is effective in treating secondary hyperparathyroidism in dialysis patients [chronic kidney disease (CKD 5)], but little is known about its effects on stage 3-4 CKD patients. We compared cinacalcet and paricalcitol in uremic rats with creatinine clearances "equivalent" to patients with CKD 3-4. Uremia was induced in anesthetized rats using the 5/6th nephrectomy model. Groups were 1) uremic control, 2) uremic + cinacalcet (U+Cin; 15 mg x kg(-1) x day(-1) po for 6 wk), 3) uremic + paricalcitol (U+Par; 0.16 microg/kg, 3 x wk, ip for 6 wk), and 4) normal. Unlike U+Par animals, cinacalcet promoted hypocalcemia and marked hyperphosphatemia. The Ca x P in U+Cin rats was twice that of U+Par rats. Both compounds suppressed PTH. Serum 1,25-(OH)(2)D(3) was decreased in both U+Par and U+Cin rats. Serum FGF-23 was increased in U+Par but not in U+Cin, where it tended to decrease. Analysis of tibiae showed that U+Cin, but not U+Par, rats had reduced bone volume. U+Cin rats had similar bone formation and reduced osteoid surface, but higher bone resorption. Hypocalcemia, hyperphosphatemia, low 1,25-(OH)(2)D(3), and cinacalcet itself may play a role in the detrimental effects on bone seen in U+Cin rats. This requires further investigation. In conclusion, due to its effects on bone and to the hypocalcemia and severe hyperphosphatemia it induces, we believe that cinacalcet should not be used in patients with CKD without further detailed studies. PMID- 20200096 TI - Compelling "metabolomic" biomarkers may signal PKD pathogenesis. PMID- 20200098 TI - Direct fibrogenic effects of aldosterone on normotensive kidney: an effect modified by 11beta-HSD activity. AB - Aldosterone (Aldo) can be a profibrotic factor in cardiovascular and renal tissues. This study tests the hypothesis that prolonged Aldo exposure is able to directly induce fibrotic changes in the kidney of a normal nonhypertensive animal. Immortalized rat proximal tubule cells (IRPTC) containing 11beta hydroxysteroid dehydrogenase (11beta-HSD1) but no mineralocorticoid receptors (MR) and mouse inner medullary collecting duct cells (IMCD) containing 11beta HSD2 and MR were examined. IRPTC exposed to Aldo or corticosterone (10 nM) for 48 h demonstrated no change in collagen production as assessed by Sirius red staining. In contrast, IMCD treated with Aldo exhibited a marked increase in the expression of collagen, fibronectin, and connective tissue growth factor (CTGF), whereas corticosterone alone had no effect. The Aldo-induced overexperession of collagen, fibronectin, and CTGF was substantially attenuated by the MR antagonist RU-318 and by the 11beta-HSD end product 11-dehydrocorticosterone, but not by the glucocorticoid receptor antagonist RU-486. In vivo, early fibrotic changes with elevated collagen, fibronectin, and CTGF expression were observed in kidneys isolated from normotensive adrenalectomized mice receiving a continuous infusion of Aldo (8 MUg.kg(-1).day(-1)) for 1 wk. These changes were not present in corticosterone-treated mice. Aldo-induced changes were attenuated in adrenally intact mice and in mice treated with RU-318 or 11-dehydrocorticosterone. Thus, extended Aldo exposure produces fibrotic changes in cells containing MR and in normal kidneys. MR antagonists and the end products of 11beta-HSD attenuate these fibrogenic effects. PMID- 20200099 TI - Comparison of three methods for determining CT dose profile: presenting the tritium method. AB - The purpose of the present work was to describe a method of using an imaging plate from a computed radiography system to determine the computed tomography (CT) dose profile (the tritium method) and to compare this method with point-dose measurements using a solid-state detector (CT Dose Profiler; RTI Electronics, Molndal, Sweden) and the indirect method of comparing the air kerma-length product (P(KL)) at different beam collimations. The three methods were used to determine the full width at half maximum (FWHM) of the dose profile of a multi slice CT at different nominal beam collimations. For all beam collimations, the obtained deviation between the tritium method and the CT Dose Profiler was smaller than 0.1 mm. The maximum relative error was 2 %. For the P(KL) method, the deviation from the CT Dose Profiler was between 0.2 and 0.4 mm, resulting in a relative error larger than 10 % for the smallest beam collimation even after normalisation to a known FWHM. In conclusion, the proposed method of using an imaging plate to determine the FWHM of the CT dose profile has a high accuracy and shows good agreement with the more advanced method of point-dose measurements using a solid-state detector. PMID- 20200100 TI - The resulting skin dose in two-view mammography examinations. AB - The entrance surface dose (ESD) (skin dose) and its variation due to overlapping radiation fields at mammography have been experimentally investigated on patients during two-view mammography screening examinations of both breasts and on phantoms of silicon gel. Measurements were done using multiple thermoluminescence dosemeters for mapping the variations in absorbed dose at the surface of the breast phantoms. It was found that the total resulting skin dose at the reference point on the breast surface, described in the European Protocol [Zoetelief, Fitzgerald, Leitz and Sabel (European protocol on dosimetry in mammography. EUR 16263 (Luxemburg: EC), 1996)] after multiple exposure of patient's breasts during two-view, four exposures mammography screening examinations is approximately 50 % higher as compared with the skin dose at the same point measured during one single (CC) exposure. The dose distributions on the breast phantom surface were non-uniform and indicated areas of higher doses, which were related to the regions of the superimposed fields on the surface during the examinations. The dosimetric importance of the superposition of X-ray fields on the ESD is discussed. PMID- 20200101 TI - Monte Carlo simulations of the dosimetry of chest tomosynthesis. AB - The aims of this work were to explore the dosimetry of chest tomosynthesis and to determine conversion factors between air kerma-area product (KAP) and the effective dose for different system configurations and patient sizes. Tomosynthesis systems were modelled with different angular intervals and tube voltages for the collection of the projection images as well as different distributions of the total exposure over the projections. The Monte Carlo-based computer software PCXMC developed by STUK (Radiation and Nuclear Safety Authority in Finland) was used to calculate the effective doses for each modelled tomosynthesis system for various patient sizes. The conversion factor between KAP and effective dose was obtained both for the zero-degree projection alone and for the entire tomosynthesis examination for each system configuration and patient size. The results reveal that the conversion factor for the zero-degree projection can be used to estimate the total effective dose from a tomosynthesis examination with acceptable accuracy, leading to an error smaller than 10 % irrespective of the system configuration and patient size. For higher accuracy, conversion factors between the total KAP and the total effective dose that take the angular interval and exposure configuration into account are presented for each system. PMID- 20200097 TI - Acute kidney injury: a springboard for progression in chronic kidney disease. AB - Recently published epidemiological and outcome analysis studies have brought to our attention the important role played by acute kidney injury (AKI) in the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD). AKI accelerates progression in patients with CKD; conversely, CKD predisposes patients to AKI. This research gives credence to older, well-thought-out wisdom that recovery from AKI is often not complete and is marked by residual structural damage. It also mirrors older experimental observations showing that unilateral nephrectomy, a surrogate for loss of nephrons by disease, compromises structural recovery and worsens tubulointerstitial fibrosis after ischemic AKI. Moreover, review of a substantial body of work on the relationships among reduced renal mass, hypertension, and pathology associated with these conditions suggests that impaired myogenic autoregulation of blood flow in the setting of hypertension, the arteriolosclerosis that results, and associated recurrent ischemic AKI in microscopic foci play important roles in the development of progressively increasing tubulointerstitial fibrosis. How nutrition, an additional factor that profoundly affects renal disease progression, influences these events needs reevaluation in light of information on the effects of calories vs. protein and animal vs. vegetable protein on injury and progression. Considerations based on published and emerging data suggest that a pathology that develops in regenerating tubules after AKI characterized by failure of differentiation and persistently high signaling activity is the proximate cause that drives downstream events in the interstitium: inflammation, capillary rarefaction, and fibroblast proliferation. In light of this information, we advance a comprehensive hypothesis regarding the pathophysiology of AKI as it relates to the progression of kidney disease. We discuss the implications of this pathophysiology for developing efficient therapeutic strategies to delay progression and avert ESRD. PMID- 20200102 TI - PET/CT: nuclear medicine imaging in the future. AB - Nuclear medicine has evolved from the use of radioiodine compounds to visualise thyroid function to the use of radiopharmaceuticals that can visualise complicated intracellular molecular functions with very high sensitivity in order to be a part of personalised medicine with individualised treatment planning and evaluation of therapy early during treatment. The development has been taken place for the equipment and also of the chemistry of the labelled compounds used. Introduction of hybrid imaging--a combination of structural and functional or molecular imaging--has been an important step in the development of imaging in nuclear medicine. The combination of structural and molecular imaging adds important information and contributes to a better clinical handling of the patients. Hybrid imaging raises new demands of the competence of the personnel which have so far been solved by collaboration between nuclear medicine and radiology departments. It has been shown that hardware fusion of positron emission tomography (PET) and computed tomography (CT) is better than the fusion of the images in the evaluation by the physician allowing more accurate diagnoses. Patients with oncological diseases constitute the majority at a PET/CT department today, and approximately 25-35 % of the patients are treated differently by when PET/CT is added to the routine workup before treatment or follow up. PMID- 20200103 TI - Semi-automatic tumour segmentation by selective navigation in a three-parameter volume, obtained by voxel-wise kinetic modelling of 11C-acetate. AB - Positron emission tomography (PET) is increasingly used for delineation of tumour tissue in, for example, radiotherapy treatment planning. The most common method used is to outline volumes with a certain per cent uptake over background in a static image. However, PET data can also be collected dynamically and analysed by kinetic models, which potentially represent the underlying biology better. In the present study, a three-parameter kinetic model was used for voxel-wise evaluation of (11)C-acetate data of head/neck tumours. These parameters which represent the tumour blood volume, the uptake rate and the clearance rate of the tissue were derived for each voxel using a linear regression method and used for segmentation of active tumour tissue. This feasibility study shows that it is possible to segment images based on derived model parameters. There is, however, room for improvements concerning the PET data acquisition, noise reduction and the kinetic modelling. In conclusion, this early study indicates a strong potential of the method even though no 'true' tumour volume was available for validation. PMID- 20200104 TI - Comparison of organ doses and image quality between CT and flat panel XperCT scans in wrist and inner ear examinations. AB - The aim of this study was to evaluate and compare organ doses delivered to patients in wrist and petrous bone examinations using a multislice spiral computed tomography (CT) and a C-arm cone-beam CT equipped with a flat-panel detector (XperCT). For this purpose, doses to the target organ, i.e. wrist or petrous bone, together with those to the most radiosensitive nearby organs, i.e. thyroid and eye lens, were measured and compared. Furthermore, image quality was compared for both imaging systems and different acquisition modes using a Catphan phantom. Results show that both systems guarantee adequate accuracy for diagnostic purposes for wrist and petrous bone examinations. Compared with the CT scanner, the XperCT system slightly reduces the dose to target organs and shortens the overall duration of the wrist examination. In addition, using the XperCT enables a reduction of the dose to the eye lens during head scans (skull base and ear examinations). PMID- 20200105 TI - VIEWDEX: an efficient and easy-to-use software for observer performance studies. AB - The development of investigation techniques, image processing, workstation monitors, analysing tools etc. within the field of radiology is vast, and the need for efficient tools in the evaluation and optimisation process of image and investigation quality is important. ViewDEX (Viewer for Digital Evaluation of X ray images) is an image viewer and task manager suitable for research and optimisation tasks in medical imaging. ViewDEX is DICOM compatible and the features of the interface (tasks, image handling and functionality) are general and flexible. The configuration of a study and output (for example, answers given) can be edited in any text editor. ViewDEX is developed in Java and can run from any disc area connected to a computer. It is free to use for non-commercial purposes and can be downloaded from http://www.vgregion.se/sas/viewdex. In the present work, an evaluation of the efficiency of ViewDEX for receiver operating characteristic (ROC) studies, free-response ROC (FROC) studies and visual grading (VG) studies was conducted. For VG studies, the total scoring rate was dependent on the number of criteria per case. A scoring rate of approximately 150 cases h( 1) can be expected for a typical VG study using single images and five anatomical criteria. For ROC and FROC studies using clinical images, the scoring rate was approximately 100 cases h(-1) using single images and approximately 25 cases h( 1) using image stacks ( approximately 50 images case(-1)). In conclusion, ViewDEX is an efficient and easy-to-use software for observer performance studies. PMID- 20200106 TI - The effect of radiation dose reduction on clinical image quality in chest radiography of premature neonates using a dual-side readout technique computed radiography system. AB - The purpose of the present study was to investigate if the exposure could be reduced from the clinical setting (resulting in an effective dose of 8 microSv for a neonate of weight 0.7 kg and height 25 cm at a tube voltage of 90 kV) without negatively influencing the image quality for a dual-side readout technique computed radiography (CR) system in chest radiography of premature neonates. Chest radiographs of premature neonates were acquired with the double side readout technique CR system. The images underwent simulated dose reduction in steps of 20 % to represent five different radiation dose levels. Four image quality criteria, related to the visibility of important anatomical structures, were used in a visual grading study where five experienced radiologists rated how well the criteria were fulfilled for all images. When reducing the radiation dose, a decrease in image quality could be observed already at the 80 % dose level for all the structures. The results indicate that a decrease in exposure from the clinically used setting affects the image quality negatively for the CR system. PMID- 20200107 TI - CXCR4 is required for proper regional and laminar distribution of cortical somatostatin-, calretinin-, and neuropeptide Y-expressing GABAergic interneurons. AB - Cortical GABAergic interneurons are divided into various subtypes, with each subtype contributing to rich variety and fine details of inhibition. Despite the functional importance of each interneuron subtype, the molecular mechanisms that contribute to sorting them to their appropriate positions within the cortex remain unclear. Here, we show that the chemokine receptor CXCR4 regulates the regional and layer-specific distribution of interneuron subtypes. We removed Cxcr4 specifically in a subset of interneurons at a specific mouse embryonic developmental stage and analyzed the number of interneurons and their laminar distribution in 9 representative cortical regions comprehensively in adults. We found that the number of Cxcr4-deleted calretinin- and that of neuropeptide Y expressing interneurons were reduced in most caudomedial and lateral cortical regions, respectively, and also in superficial layers. In addition, Cxcr4-deleted somatostatin-expressing interneurons showed a reduction in the number of superficial layers in certain cortical regions but of deep layers in others. These findings suggest that CXCR4 is required for proper regional and laminar distribution in a wider interneuron subpopulation than previously thought and may regulate the establishment of functional cortical circuitry in certain cortical regions and layers. PMID- 20200108 TI - Origin of active states in local neocortical networks during slow sleep oscillation. AB - Slow-wave sleep is characterized by spontaneous alternations of activity and silence in corticothalamic networks, but the causes of transition from silence to activity remain unknown. We investigated local mechanisms underlying initiation of activity, using simultaneous multisite field potential, multiunit recordings, and intracellular recordings from 2 to 4 nearby neurons in naturally sleeping or anesthetized cats. We demonstrate that activity may start in any neuron or recording location, with tens of milliseconds delay in other cells and sites. Typically, however, activity originated at deep locations, then involved some superficial cells, but appeared later in the middle of the cortex. Neuronal firing was also found to begin, after the onset of active states, at depths that correspond to cortical layer V. These results support the hypothesis that switch from silence to activity is mediated by spontaneous synaptic events, whereby any neuron may become active first. Due to probabilistic nature of activity onset, the large pyramidal cells from deep cortical layers, which are equipped with the most numerous synaptic inputs and large projection fields, are best suited for switching the whole network into active state. PMID- 20200109 TI - A multilevel-based study of school policy for tobacco control in relation to cigarette smoking among children in elementary schools: gender differences. AB - The aim was to comprehensively examine school-based tobacco policy status, implementation and students' perceived smoking at school in regard to gender specific differences in smoking behavior. We conducted a multilevel-based study to assess two-level effects for smoking among 2350 grades three to six students in 26 randomly selected elementary schools in southern Taiwan. A series of multilevel models were analyzed separately for male and female students. The school-level variables appear to be related to smoking behavior in male students. Among males, the risk of ever-smoking was significantly associated with those schools without antitobacco health education activities or curricula [adjusted odds ratio (aOR) = 6.23, 95% confidence interval (CI): 2.55-15.24], with a high perceived smoking rate (aOR = 3.08, 95% CI: 1.41-6.72) and located in a mountainous region (aOR = 2.53, 95% CI: 1.15-5.58). The risk of ever-smoking among females was significantly associated with those schools without antitobacco activities or curricula (aOR = 3.10, 95% CI: 1.27-7.55). As compared with female counterparts, the specific school that the male students attended had a positive significant effect on the risk of being ever-smokers. The findings suggest that effective tobacco policy implementation should be considered in elementary schools that are currently putting children at the greatest risk for cigarette smoking, especially in regard to male students. PMID- 20200110 TI - American Cancer Society guideline for the early detection of prostate cancer: update 2010. AB - In 2009, the American Cancer Society (ACS) Prostate Cancer Advisory Committee began the process of a complete update of recommendations for early prostate cancer detection. A series of systematic evidence reviews was conducted focusing on evidence related to the early detection of prostate cancer, test performance, harms of therapy for localized prostate cancer, and shared and informed decision making in prostate cancer screening. The results of the systematic reviews were evaluated by the ACS Prostate Cancer Advisory Committee, and deliberations about the evidence occurred at committee meetings and during conference calls. On the basis of the evidence and a consensus process, the Prostate Cancer Advisory Committee developed the guideline, and a writing committee drafted a guideline document that was circulated to the entire committee for review and revision. The document was then circulated to peer reviewers for feedback, and finally to the ACS Mission Outcomes Committee and the ACS Board of Directors for approval. The ACS recommends that asymptomatic men who have at least a 10-year life expectancy have an opportunity to make an informed decision with their health care provider about screening for prostate cancer after they receive information about the uncertainties, risks, and potential benefits associated with prostate cancer screening. Prostate cancer screening should not occur without an informed decision-making process. Men at average risk should receive this information beginning at age 50 years. Men in higher risk groups should receive this information before age 50 years. Men should either receive this information directly from their health care providers or be referred to reliable and culturally appropriate sources. Patient decision aids are helpful in preparing men to make a decision whether to be tested. PMID- 20200111 TI - Introducing the 2010 American Cancer Society prostate cancer screening guideline. PMID- 20200112 TI - Patient pages. Should I be tested for prostate cancer? PMID- 20200113 TI - Restricted feeding phase shifts clock gene and sodium glucose cotransporter 1 (SGLT1) expression in rats. AB - The intestine exhibits striking diurnal rhythmicity in glucose uptake, mediated by the sodium glucose cotransporter (SGLT1); however, regulatory pathways for these rhythms remain incompletely characterized. We hypothesized that SGLT1 rhythmicity is linked to the circadian clock. To investigate this, we examined rhythmicity of Sglt1 and individual clock genes in rats that consumed food ad libitum (AL). We further compared phase shifts of Sglt1 and clock genes in a second group of rats following restricted feeding to either the dark (DF) or light (LF) phase. Rats fed during the DF were pair-fed to rats fed during the LF. Jejunal mucosa was harvested across the diurnal period to generate expression profiles of Sglt1 and clock genes Clock, Bmal1 (brain-muscle Arnt-like 1), ReverbA/B, Per(Period) 1/2, and Cry (Cryptochrome) 1/2. All clock genes were rhythmic in AL rats (P < 0.05). Sglt1 also exhibited diurnal rhythmicity, with peak expression preceding nutrient arrival (P < 0.05). Light-restricted feeding shifted the expression rhythms of Sglt1 and most clock genes (Bmal1, ReverbA and B, Per1, Per2, and Cry1) compared with dark-restricted feeding (P < 0.05). The Sglt1 rhythm shifted in parallel with rhythms of Per1 and ReverbB. These effects of restricted feeding highlight luminal nutrients as a key Zeitgeber in the intestine, capable of simultaneously shifting the phases of transporter and clock gene expression, and suggest a role for clock genes in regulating Sglt1 and therefore glucose uptake. Understanding the regulatory cues governing rhythms in intestinal function may allow new therapeutic options for conditions of dysregulated absorption such as diabetes and obesity. PMID- 20200114 TI - Maternal serum 25-hydroxyvitamin D concentrations are associated with small-for gestational age births in white women. AB - Maternal vitamin D deficiency has been associated with numerous adverse health outcomes, but its association with fetal growth restriction remains uncertain. We sought to elucidate the association between maternal serum 25-hydroxyvitamin D [25(OH)D] concentrations in early pregnancy and the risk of small-for-gestational age birth (SGA) and explore the association between maternal single nucleotide polymorphisms (SNP) in the vitamin D receptor (VDR) gene and the risk of SGA. We conducted a nested case-control study of nulliparous pregnant women with singleton pregnancies who delivered SGA infants (n = 77 white and n = 34 black) or non-SGA infants (n = 196 white and n = 105 black). Women were followed from <16 wk gestation to delivery. Women's banked sera at <22 wk were newly measured for 25(OH)D and DNA extracted for VDR genotyping. SGA was defined as live-born infants that were <10th percentile of birth weight according to nomograms based on gender and gestational age. After confounder adjustment, there was a U-shaped relation between serum 25(OH)D and risk of SGA among white mothers, with the lowest risk from 60 to 80 nmol/L. Compared with serum 25(OH)D 37.5-75 nmol/L, SGA odds ratios (95% CI) for levels <37.5 and >75 nmol/L were 7.5 (1.8, 31.9) and 2.1 (1.2, 3.8), respectively. There was no relation between 25(OH)D and SGA risk among black mothers. One SNP in the VDR gene among white women and 3 SNP in black women were significantly associated with SGA. Our results suggest that vitamin D has a complex relation with fetal growth that may vary by race. PMID- 20200115 TI - Covalent modification of Thr302 in cytochrome P450 2B1 by the mechanism-based inactivator 4-tert-butylphenylacetylene. AB - The mechanism of inactivation of cytochrome P450 2B1 (CYP2B1) by 4-tert butylphenylacetylene (BPA) has been characterized previously to be caused by the covalent binding of a reactive intermediate to the apoprotein rather than heme destruction (J Pharmacol Exp Ther 331:392-403, 2009). The identification of a BPA glutathione conjugate and the increase in the mass of the BPA-adducted apoprotein have indicated that the mass of adduct is 174 Da, equivalent to the mass of BPA plus one oxygen atom. To identify the adducted residue, BPA-inactivated CYP2B1 was digested with trypsin, and the digest was then analyzed by using capillary liquid chromatography with a LTQ linear ion trap mass spectrometer as the detector. A mass shift of 174 Da was used for a SEQUEST database search. The tandem mass spectrometry fragmentation of the modified peptide and the identity of modified residue were determined. The results revealed a mass increase of 174 Da for the peptide sequence (296)FFAGTSSTTLR(308) in the I-helix of CYP2B1 and that the site of adduction formation is Thr302. Homology modeling and ligand docking studies showed that BPA binds in close proximity to both the heme iron and Thr302 with the distances being 2.96 and 3.42 A, respectively. The identification of Thr302 in the CYP2B1 active site as the site of covalent modification leading to inactivation by BPA supports previous hypotheses that this conserved Thr residue may play a crucial role for various functions in P450s. PMID- 20200116 TI - Treatment of heart failure by a methanocarba derivative of adenosine monophosphate: implication for a role of cardiac purinergic P2X receptors. AB - Evidence is accumulating to support a potentially important role for purinergic (P2X) receptors in heart failure (HF). We tested the hypothesis that a hydrolysis resistant nucleotide analog with agonist activity at myocardial P2X receptors (P2XRs) improves the systolic HF phenotype in mouse and dog models. We developed a hydrolysis-resistant adenosine monophosphate derivative, (1'S,2R,3S,4'R,5'S)-4 (6-amino-2-chloro-9H-purin-9-yl)-1-[phosphoryloxymethyl] bicycle[3.1.0]hexane-2,3 diol) (MRS2339), with agonist activity at native cardiac P2XRs. Chronic MRS2339 infusion in postinfarct and calsequestrin (CSQ) mice with HF resulted in higher rates of pressure change (+dP/dt), left ventricle (LV)-developed pressure, and cardiac output in an in vitro working heart model. Heart function in vivo, as determined by echocardiography-derived fractional shortening, was also improved in MRS2339-infused mice. The beneficial effect of MRS2339 was dose-dependent and was identical to that produced by cardiac myocyte-specific overexpression of the P2X(4) receptor. The HF improvement was associated with the preservation of LV wall thickness in both systole and diastole in postinfarct and CSQ mice. In dogs with pacing-induced HF, MRS2339 infusion reduced left ventricular end-diastolic pressure, improved arterial oxygenation, and increased +dP/dt. MRS2339 treatment also decreased LV chamber size in mice and dogs with HF. In murine and canine models of systolic HF, in vivo administration of a P2X nucleotide agonist improved contractile function and cardiac performance. These actions were associated with preserved LV wall thickness and decreased LV remodeling. The data are consistent with a role of cardiac P2XRs in mediating the beneficial effect of this agonist. PMID- 20200117 TI - Nicotinic receptor-mediated reduction in L-DOPA-induced dyskinesias may occur via desensitization. AB - L-DOPA-induced dyskinesias in Parkinson's disease are a significant clinical problem for which few therapies are available. We recently showed that nicotine reduces L-DOPA-induced abnormal involuntary movements (AIMs) in parkinsonian animals, suggesting it may be useful for the treatment of L-DOPA-induced dyskinesias. The present experiments were performed to understand the mechanisms whereby nicotine reduces L-DOPA-induced AIMs. We used a well established model of dyskinesias, L-DOPA-treated unilateral 6-hydroxydopamine-lesioned rats. Dose ranging studies showed that injection of 0.1 mg/kg nicotine once or twice daily for 4 or 10 days most effectively reduced AIMs, with no worsening of parkinsonism. Importantly, a single nicotine injection did not reduce AIMs, indicating that nicotine's effect is caused by long-term rather than short-term molecular changes. Administration of the metabolite cotinine did not reduce AIMs, suggesting a direct effect of nicotine. Experiments with the nicotinic receptor (nAChR) antagonist mecamylamine were done to determine whether nicotine acted via a receptor-mediated mechanism. Unexpectedly, several days of mecamylamine injection (1.0 mg/kg) alone significantly ameliorated dyskinesias to a comparable extent as nicotine. The decline in AIMs with combined nicotine and mecamylamine treatment was not additive, suggesting that nicotine exerts its effects via a nAChR interaction. This latter finding, combined with data showing that mecamylamine reduced AIMs to a similar extent as nicotine, and that nicotine or mecamylamine treatment both decreased alpha6beta2* and increased alpha4beta2* nAChR expression, suggests that the nicotine-mediated improvement in L-DOPA induced AIMs may involve a desensitization block. These data have important implications for the treatment of L-DOPA-induced dyskinesias in Parkinson's disease. PMID- 20200119 TI - Behavioral indices in antipsychotic drug discovery. AB - Schizophrenia is characterized by three major symptom classes: positive symptoms, negative symptoms, and cognitive deficits. Classical antipsychotics (phenothiazines, thioxanthenes, and butyrophenones) are effective against positive symptoms but induce major side effects, in particular, extrapyramidal symptoms (EPS). The discovery of clozapine, which does not induce EPS and is thought effective against all three classes of symptom, has driven research for novel antipsychotics with a wider activity spectrum and lower EPS liability. To increase predictiveness, current efforts aim to develop translational models where direct parallels can be drawn between the processes studied in animals and in humans. The present article reviews existing procedures in animals for their ability to predict compound efficacy and EPS liability in relation to their translational validity. Rodent models of positive symptoms include procedures related to dysfunction in central dopamine and glutamatergic (N-methyl-D aspartate) and serotonin (5-hydroxytryptamine) neurotransmission. Procedures for evaluating negative symptoms include rodent models of anhedonia, affective flattening, and diminished social interaction. Cognitive deficits can be assessed in rodent models of attention (prepulse inhibition) and of learning/memory (object and social recognition, Morris water maze and operant-delayed alternation). The relevance of the conditioned avoidance response is also discussed. A final section reviews procedures for assessing EPS liability, in particular, parkinsonism (catalepsy in rodents), acute dystonia (purposeless chewing in rodents, dystonia in monkeys), akathisia (defecation in rodents), and tardive dyskinesia (long-term antipsychotic treatment in rodents and monkeys). It is concluded that, with notable exceptions (attention, learning/memory, EPS liability), current predictive models for antipsychotics fall short of clear translational validity. PMID- 20200118 TI - Ethanol stabilizes the open state of single 5-hydroxytryptamine(3A)(QDA) receptors. AB - Ethanol enhancement of 5-hydroxytryptamine (5-HT)(3A) receptor-mediated responses may have important consequences in the intoxicating and addictive properties of ethanol. Although the exact mechanism is unknown, ethanol-mediated enhancement of 5-HT(3) receptor current has been proposed to occur due to stabilization of the open-channel state. It has not been possible to directly measure the open state of the channel due to the extremely low single-channel conductance of 5-HT(3A) channels. Recently, three arginine residues within the large intracellular loop of the 5-HT(3A) subunit were substituted by their equivalent residues (glutamine, aspartate, and alanine) of the 5-HT(3B) subunit to produce a 5-HT(3A)(QDA) subunit that forms functional homomeric channels exhibiting a measurable single channel conductance. Using whole-cell rapid-agonist application techniques and the cell-attached single-channel recording configuration, we examined human 5 HT(3A)(QDA) receptors expressed in human embryonic kidney 293 cells. The agonist sensitivity, macroscopic kinetics, and modulation by ethanol were similar between mutant and wild-type channels, suggesting the substitutions had not altered these channel structure-function properties. The open time histogram for single-channel events mediated by 5-HT(3A)(QDA) receptors in the presence of maximal 5-HT was best fit by three exponentials, but in the presence of ethanol a fourth open state was evident. In summary, the QDA substitution greatly enhanced single channel conductance with little effect on 5-HT(3A) channel's kinetic properties and ethanol enhances agonist action on 5-HT(3A) receptors by inducing a new, long lived open-channel state. Furthermore, the 5-HT(3A)(QDA) receptor appears to be suitable for pharmacological studies of 5-HT(3A) receptor modulation at a single channel level. PMID- 20200120 TI - The regulation of MADS-box gene expression during ripening of banana and their regulatory interaction with ethylene. AB - Six MaMADS-box genes have been cloned from the banana fruit cultivar Grand Nain. The similarity of these genes to tomato LeRIN is low and neither MaMADS2 nor MaMADS1 complement the tomato rin mutation. Nevertheless, the expression patterns, specifically in fruit and the induction during ripening and in response to ethylene and 1-MCP, suggest that some of these genes may participate in ripening. MaMADS1, 2, and 3, are highly expressed in fruit only, while the others are expressed in fruit as well as in other organs. Moreover, the suites of MaMADS box genes and their temporal expression differ in peel and pulp during ripening. In the pulp, the increase in MaMADS2, 3, 4, and 5 expression preceded an increase in ethylene production, but coincides with the CO(2) peak. However, MaMADS1 expression in pulp coincided with ethylene production, but a massive increase in its expression occurred late during ripening, together with a second wave in the expression of MaMADS2, 3, and 4. In the peel, on the other hand, an increase in expression of MaMADS1, 3, and to a lesser degree also of MaMADS4 and 2 coincided with an increase in ethylene production. Except MaMADS3, which was induced by ethylene in pulp and peel, only MaMADS4, and 5 in pulp and MaMADS1 in peel were induced by ethylene. 1-MCP applied at the onset of the increase in ethylene production, increased the levels of MaMADS4 and MaMADS1 in pulp, while it decreased MaMADS1, 3, 4, and 5 in peel, suggesting that MaMADS4 and MaMADS1 are negatively controlled by ethylene at the onset of ethylene production only in pulp. Only MaMADS2 is neither induced by ethylene nor by 1-MCP, and it is expressed mainly in pulp. Our results suggest that two independent ripening programs are employed in pulp and peel which involve the activation of mainly MaMADS2, 4, and 5 and later on also MaMADS1 in pulp, and mainly MaMADS1, and 3 in peel. Hence, our results are consistent with MaMADS2, a SEP3 homologue, acting in the pulp upstream of the increase in ethylene production similarly to LeMADS-RIN. PMID- 20200121 TI - Human medial orbitofrontal cortex is recruited during experience of imagined and real rewards. AB - Human decision-making frequently relies on mental simulation of future rewards to guide action choice. In this study, we sought to uncover brain regions engaged during reward imagery and to address whether these regions functionally overlap with regions activated by tangible rewards. We found that medial orbitofrontal cortex (mOFC) is engaged both for real and imagined rewards and is preferentially engaged for imagery with rewarding content compared with other nonrewarding imagery. These findings support a critical role for mOFC in the representation of rewarding goal states, even if hypothetical. PMID- 20200122 TI - Control of the firing patterns of vibrissa motoneurons by modulatory and phasic synaptic inputs: a modeling study. AB - Vibrissa motoneurons (vMNs) generate rhythmic firing that controls whisker movements, even without cortical, cerebellar, or sensory inputs. vMNs receive serotonergic modulation from brain stem areas, which mainly increases their persistent sodium conductance (g(NaP)) and, possibly, phasic input from a putative central pattern generator (CPG). In response to serotonergic modulation or just-suprathreshold current steps, vMNs fire at low rates, below the firing frequency of exploratory whisking. In response to periodic inputs, vMNs exhibit nonlinear suprathreshold resonance in frequency ranges of exploratory whisking. To determine how firing patterns of vMNs are determined by their 1) intrinsic ionic conductances and 2) responses to periodic input from a putative CPG and to serotonergic modulation, we construct and analyze a single-compartment, conductance-based model of vMNs. Low firing rates are supported in extended regimes by adaptation currents and the minimal firing rate decreases with g(NaP) and increases with M-potassium and h-cation conductances. Suprathreshold resonance results from the locking properties of vMN firing to stimuli and from reduction of firing rates at low frequencies by slow M and afterhyperpolarization potassium conductances. h conductance only slightly affects the suprathreshold resonance. When a vMN is subjected to a small periodic CPG input, serotonergically induced g(NaP) elevation may transfer the system from quiescence to a firing state that is highly locked to the CPG input. Thus we conclude that for vMNs, the CPG controls firing frequency and phase and enables bursting, whereas serotonergic modulation controls transitions from quiescence to firing unless the CPG input is sufficiently strong. PMID- 20200123 TI - Pulsed noise experience disrupts complex sound representations. AB - Cortical sound representations are adapted to the acoustic environment. Early exposure to exponential frequency-modulated (FM) sweeps results in more neurons selective to the experienced sounds. Here we examined the influence of pulsed noise experience on the development of sound representations in the primary auditory cortex (AI) of the rat. In naive animals, FM sweep direction selectivity depends on the characteristic frequency (CF) of the neuron--low CF neurons tend to select for upward sweeps and high CF neurons for downward sweeps. Such a CF dependence was not observed in animals that had received weeklong exposure to pulsed noise in periods from postnatal day 8 (P8) to P15 or from P24 to P39. In addition, AI tonotopicity, tuning bandwidth, intensity threshold, tone responsiveness, and sweep response magnitude were differentially affected by the noise experience depending on the exposure time windows. These results are consistent with previous findings of feature-dependent multiple sensitive periods. The different effects induced here by pulsed noise and previously by FM sweeps further indicate that plasticity in cortical complex sound representations is specific to the sensory input. PMID- 20200124 TI - MeCP2 is required for normal development of GABAergic circuits in the thalamus. AB - Methyl-CpG binding protein 2 (MeCP2) is highly expressed in neurons in the vertebrate brain, and mutations of the gene encoding MeCP2 cause the neurodevelopmental disorder Rett syndrome. This study examines the role of MeCP2 in the development and function of thalamic GABAergic circuits. Whole cell recordings were carried out in excitatory neurons of the ventrobasal complex (VB) of the thalamus and in inhibitory neurons of the reticular thalamic nucleus (RTN) in acute brain slices from mice aged P6 through P23. At P14-P16, the number of quantal GABAergic events was decreased in VB neurons but increased in RTN neurons of Mecp2-null mice, without any change in the amplitude or kinetics of quantal events. There was no difference between mutant and wild-type mice in paired-pulse ratios of evoked GABAergic responses in the VB or the RTN. On the other hand, unitary responses evoked by minimal stimulation were decreased in the VB but increased in the RTN of mutants. Similar changes in the frequency of quantal events were observed at P21-P23 in both the VB and RTN. At P6, however, quantal GABAergic transmission was altered only in the VB not the RTN. Immunostaining of vesicular GABA transporter showed opposite changes in the number of GABAergic synaptic terminals in the VB and RTN of Mecp2-null mice at P18-P20. The loss of MeCP2 had no significant effect on intrinsic properties of RTN neurons recorded at P15-P17. Our findings suggest that MeCP2 differentially regulates the development of GABAergic synapses in excitatory and inhibitory neurons in the thalamus. PMID- 20200125 TI - Cys-loop ligand-gated chloride channels in dorsal unpaired median neurons of Locusta migratoria. AB - In insects, inhibitory neurotransmission is generally associated with members of the cys-loop ligand-gated anion channels, such as the glutamate-gated chloride channel (GluCl), the GABA-gated chloride channels (GABACl), and the histamine gated chloride channels (HisCl). These ionotropic receptors are considered established target sites for the development of insecticides, and therefore it is necessary to obtain a better insight in their distribution, structure, and functional properties. Here, by combining electrophysiology and molecular biology techniques, we identified and characterized GluCl, GABACl, and HisCl in dorsal unpaired median (DUM) neurons of Locust migratoria. In whole cell patch-clamp recordings, application of glutamate, GABA, or histamine induced rapidly activating ionic currents. GluCls were sensitive to ibotenic acid and blocked by picrotoxin and fipronil. The pharmacological profile of the L. migratoria GABACl fitted neither the vertebrate GABA(A) nor GABA(C) receptor and was similar to the properties of the cloned Drosophila melanogaster GABA receptor subunit (Rdl). The expression of Rdl-like subunit-containing GABA receptors was shown at the molecular level using RT-PCR. Sequencing analysis indicated that the orthologous GABACl of D. melanogaster CG10357-A is expressed in DUM neurons of L. migratoria. Histamine-induced currents exhibited a fast onset and desensitized completely on continuous application of histamine. In conclusion, within the DUM neurons of L. migratoria, we identified three different cys-loop ligand-gated anion channels that use GABA, glutamate, or histamine as their neurotransmitter. PMID- 20200126 TI - Copy number changes of CNV regions in intersubspecific crosses of the house mouse. AB - Copy number variation (CNV) contributes significantly to natural genetic variation within and between populations. However, the mutational mechanisms leading to CNV, as well as the processes that control the size of CNV regions, are so far not well understood. Here, we have analyzed a gene family that forms CNV regions on the X and the Y chromosomes in Mus musculus. These CNV regions show copy number differences in two subspecies, M. musculus domesticus and M. musculus musculus. Assessment of copy numbers at these loci for individuals caught in a natural hybrid zone showed copy number increases and a large variance among individuals. Crosses of natural hybrid animals among each other produced even more extreme variants with major differences in copy number in the offspring from the same parents. To assess the inheritance pattern of the loci further, we have produced F1 and backcross hybrid animals from these subspecies. We found that copy number expansions can already be traced in F1 offspring and they became stronger in the backcross individuals. Specific analysis of hybrid male offspring indicated that neither meiotic recombination nor interchromosomal exchange was required for creating these changes because the X and Y chromosomes have no homologues in males. This suggests that intrachromosomal exchanges can drive CNV and that this can occur at an elevated frequency in interspecific crosses, even within an individual. Accordingly, we find copy number mosaicism in individuals, that is, DNA from different tissues of the same individual can have different copy numbers for the loci studied. A preliminary survey of autosomal loci suggests that these can also be subject to change in hybrids. Hence, we conclude that the effects we see are not only restricted to some specific loci but may also be caused by a general induction of replication-coupled repair processes. PMID- 20200127 TI - Intermittent access to sucrose increases sucrose-licking activity and attenuates restraint stress-induced activation of the lateral septum. AB - Intermittent access to palatable food can attenuate anorectic and hormonal responses to stress in rats. The neuronal mechanisms of modulation of stress response by diets are not fully understood. The present study was conducted to create rat models with intermittent access to sucrose that demonstrate resistance to stress-induced hypophagia, to study the pattern of sucrose consumption by these rat models, and to investigate in which brain structures intermittent sucrose regimens modify stress-induced neuronal activation. The obtained results demonstrate that 6-wk intermittent access to sucrose without food restriction (4 day/wk ad libitum access to sucrose in addition to chow, and following 3 day/wk exclusive feeding of chow; SIA rats) and combined with food restriction (4 day/wk access to chow and sucrose restricted to 2 h/day, and following 3 days/wk on unrestricted chow; SIR rats) increased sucrose-licking activity. The alterations in the rats' feeding behavior were accompanied by a resistance of their body weight gain and food intake to 1-h restraint stress applied once per week. The chronic intermittent sucrose consumption significantly lowered, in the SIA and SIR rats, the levels of expression of corticotropin-releasing factor type 2 receptor and restraint stress-induced expression of c-fos mRNA in the medioventral part of the lateral septum. Conversely, the levels of the corticotropin-releasing factor type 2 receptor transcript in the ventromedial hypothalamic nucleus were decreased only in the food-restricted SIR rats. The lower stress-induced neuronal activation in the medioventral part of the lateral septum may contribute to the attenuated anorectic stress response in the rats maintained on intermittent sucrose regimens. PMID- 20200128 TI - Maternal protein restriction leads to hyperresponsiveness to stress and salt sensitive hypertension in male offspring. AB - Low birth weight humans often exhibit hypertension during adulthood. Studying the offspring of rat dams fed a maternal low-protein diet is one model frequently used to study the mechanisms of low birth weight-related hypertension. It remains unclear whether this model replicates key clinical findings of hypertension and increased blood pressure responsiveness to stress or high-salt diet. We measured blood pressure via radiotelemetry in 13-wk-old male offspring of maternal normal- and low-protein dams. Neither group exhibited hypertension at baseline; however, 1 h of restraint was accompanied by a significantly greater blood pressure response in low-protein compared with normal-protein offspring. To enhance the effect of a high-salt diet on blood pressure, normal- and low-protein offspring underwent right uninephrectomy, while controls underwent sham surgery. After 5 weeks on a high-salt diet (4% NaCl), mean arterial pressure in the Low Protein+Sham offspring was elevated by 6 +/- 2 mmHg (P < 0.05 vs. baseline), while it remained unchanged in the normal-protein offspring. In the two uninephrectomized groups, blood pressure increased further, but was of similar magnitude. Glomerular filtration rate in the low-protein uninephrectomized offspring was 50% less than that in normal-protein offspring with intact kidneys. These data indicate that, while male low-protein offspring are not hypertensive during young adulthood, their blood pressure is hyperresponsive to restraint stress and is salt sensitive, and their glomerular filtration rate is more sensitive to hypertension-causing insults. Collectively, these may predispose for the development of hypertension later in life. PMID- 20200130 TI - Effect of maternal undernutrition on vascular expression of micro and messenger RNA in newborn and aging offspring. AB - The aim of this study was to test the hypothesis that maternal undernutrition (MUN) alters offspring vascular expression of micro-RNAs (miRNAs), which, in turn, could regulate the expression of a host of genes involved with angiogenesis and extracellular matrix remodeling. The expression of miRNA and mRNA in the same aortic specimens in 1-day-old (P1) and 12-mo-old offspring aortas of dams, which had 50% food restriction from gestation day 10 to term, was determined by specific rat miRNA and DNA arrays. MUN significantly downregulated the expression of miRNAs 29c, 183, and 422b in the P1 group and 200a, 129, 215, and 200b in the 12-mo group, and upregulated the expression of miRNA 189 in the P1 group and 337 in the 12-mo group. The predicted target genes of the miRNAs altered in the two age groups fell into the categories of: 1) structural genes, such as collagen, elastin, and enzymes involved in ECM remodeling; and 2) angiogenic factors. MUN primarily altered the expression of mRNAs in the functional category of cell cycle/mitosis in the P1 group and anatomic structure and apoptosis in the 12-mo age group. Several of the predicted target genes of miRNAs altered in response to MUN were identified by the DNA array including integrin-beta(1) in the P1 aortas and stearoyl-CoA desaturase-1 in the 12-mo age groups. These results are consistent with the hypothesis that MUN modulation of offspring gene expression may be mediated in part by a miRNA mechanism. PMID- 20200131 TI - Initiating treadmill training in late middle age offers modest adaptations in Ca2+ handling but enhances oxidative damage in senescent rat skeletal muscle. AB - Aging skeletal muscle shows an increased time to peak force and relaxation and a decreased specific force, all of which could relate to changes in muscle Ca(2+) handling. The purpose of this study was to determine if Ca(2+)-handling protein content and function are decreased in senescent gastrocnemius muscle and if initiating a training program in late middle age (LMA, 29 mo old) could improve function in senescent (34- to 36-mo-old) muscle. LMA male Fischer 344 x Brown Norway rats underwent 5-7 mo of treadmill training. Aging resulted in a decrease in maximal sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) activity and a decrease in Ca(2+) release rate but no change in Ca(2+) uptake rate. Efficiency of the Ca(2+) pump was increased with age, as was the content of SERCA2a. Training caused a further increase in SERCA2a content. Aging also caused an increase in protein carbonyl and reactive nitrogen species damage accumulation, and both further increased with training. Consistent with the increase in oxidative damage, heat shock protein 70 content was increased with age and further increased with training. Together, these results suggest that while initiating exercise training in LMA augments the age-related increase in expression of heat shock protein 70 and the more efficient SERCA2a isoform, it did not prevent the decrease in SERCA activity and exacerbated oxidative damage in senescent gastrocnemius muscle. PMID- 20200132 TI - Effects of bladder outlet obstruction on properties of Ca2+-activated K+ channels in rat bladder. AB - In this study, we investigated the effects of bladder outlet obstruction (BOO) on the expression and function of large conductance (BK) and small conductance (SK) Ca(2+)-activated K(+) channels in detrusor smooth muscle. The bladder from adult female Sprague-Dawley rats with 6-wk BOO were used. The mRNA expression of the BK channel alpha-subunit, beta1-, beta2-, and beta4-subunits and SK1, SK2, and SK3 channels were investigated using real-time RT-PCR. All subunits except for the BK beta2, SK2, and SK3 channels were predominantly expressed in the detrusor smooth muscle rather than in the mucosa. The mRNA expression of the BK channel alpha subunit was not significantly changed in obstructed bladders. However, the expression of the BK channel beta1-subunit and the SK3 channel was remarkably increased in obstructed bladders. On the other hand, the expression of the BK channel beta4-subunit was decreased as the severity of BOO-induced bladder overactivity progressed. In detrusor smooth muscle strips from obstructed bladders, blockade of BK channels by iberiotoxin (IbTx) or charybdotoxin (CTx) and blockade of SK channels by apamin increased the amplitude of spontaneous contractions. These blockers also increased the contractility and affinity of these strips for carbachol during cumulative applications. The facilitatory effects elicited by these K(+) channel blockers were larger in the strips from obstructed bladders compared with control bladders. These results suggest that long-term exposure to BOO for 6 wk enhances the function of both BK and SK types of Ca(2+)-activated K(+) channels in the detrusor smooth muscle to induce an inhibition of bladder contractility, which might be a compensatory mechanism to reduce BOO-induced bladder overactivity. PMID- 20200133 TI - Water deprivation-induced sodium appetite and differential expression of encephalic c-Fos immunoreactivity in the spontaneously hypertensive rat. AB - The spontaneously hypertensive rat (SHR) has an intense consumption of NaCl solution. Water deprivation (WD) followed by water intake to satiety induces partial rehydration (PR)-the WD-PR protocol-and sodium appetite. In the present work, WD produced similar water intake and no alterations in arterial pressure among spontaneously hypertensive rat (SHR), Wistar-Kyoto, and Holtzman strains. It also increased the number of cells with positive c-Fos immunoreactivity (Fos IR) in the lamina terminalis and in the hypothalamic supraoptic (SON) and paraventricular (parvocellular, PVNp) nucleus in these strains. The WD and WD-PR produced similar alterations in all strains in serum osmolality and protein, plasma renin activity, and sodium balance. The SHR ingested about 10 times more 0.3 M NaCl than normotensives strains in the sodium appetite test that follows WD PR. After WD-PR, the Fos-IR persisted, elevated in the lamina terminalis of all strains but notably in the subfornical organ of the SHR. The WD-PR reversed Fos IR in the SON of all strains and in the PVNp of SHR. It induced Fos-IR in the area postrema and in the nucleus of the solitary tract (NTS), dorsal raphe, parabrachial (PBN), pre-locus coeruleus (pre-LC), suprachiasmatic, and central amygdalar nucleus of all strains. This effect was bigger in the caudal-NTS, pre LC, and medial-PBN of SHRs. The results indicate that WD-PR increases cell activity in the forebrain and hindbrain areas that control sodium appetite in the rat. They also suggest that increased cell activity in facilitatory brain areas precedes the intense 0.3 M NaCl intake of the SHR in the sodium appetite test. PMID- 20200134 TI - Spinal interneurons and micturition reflexes: focus on "Characterization of a spinal, urine storage reflex, inhibitory center and its regulation by 5-HT1A receptors in female cats". PMID- 20200135 TI - A new approach for flow-through respirometry measurements in humans. AB - Indirect whole room calorimetry is commonly used in studies of human metabolism. These calorimeters can be configured as either push or pull systems. A major obstacle to accurately calculating gas exchange rates in a pull system is that the excurrent flow rate is increased above the incurrent flow rate, because the organism produces water vapor, which also dilutes the concentrations of respiratory gases in the excurrent sample. A common approach to this problem is to dry the excurrent gases prior to measurement, but if drying is incomplete, large errors in the calculated oxygen consumption will result. The other major potential source of error is fluctuations in the concentration of O(2) and CO(2) in the incurrent airstream. We describe a novel approach to measuring gas exchange using a pull-type whole room indirect calorimeter. Relative humidity and temperature of the incurrent and excurrent airstreams are measured continuously using high-precision, relative humidity and temperature sensors, permitting accurate measurement of water vapor pressure. The excurrent flow rates are then adjusted to eliminate the flow contribution from water vapor, and respiratory gas concentrations are adjusted to eliminate the effect of water vapor dilution. In addition, a novel switching approach is used that permits constant, uninterrupted measurement of the excurrent airstream while allowing frequent measurements of the incurrent airstream. To demonstrate the accuracy of this approach, we present the results of validation trials compared with our existing system and metabolic carts, as well as the results of standard propane combustion tests. PMID- 20200136 TI - Effects of photoperiod on daily locomotor activity, energy expenditure, and feeding behavior in a seasonal mammal. AB - The objective of this study was to determine whether the previously observed effects of photoperiod on body weight in Siberian hamsters were due to changes in the daily patterns of locomotor activity, energy expenditure, and/or feeding behavior. Adult males were monitored through a seasonal cycle using an automated comprehensive laboratory animal monitoring system (CLAMS). Exposure to a short day photoperiod (SD; 8:16-h light-dark cycle) induced a significant decline in body weight, and oxygen consumption (Vo(2)), carbon dioxide production (Vco(2)), and heat production all decreased reaching a nadir by 16 wk of SD. Clear daily rhythms in locomotor activity, Vo(2), and Vco(2) were observed at the start of the study, but these all progressively diminished after prolonged exposure to SD. Rhythms in feeding behavior were also detected initially, reflecting an increase in meal frequency but not duration during the dark phase. This rhythm was lost by 8 wk of SD exposure such that food intake was relatively constant across dark and light phases. After 18 wk in SD, hamsters were transferred to a long-day photoperiod (LD; 16:8-h light-dark cycle), which induced significant weight gain. This was associated with an increase in energy intake within 2 wk, while Vo(2), Vco(2), and heat production all increased back to basal levels. Rhythmicity was reestablished within 4 wk of reexposure to long days. These results demonstrate that photoperiod impacts on body weight via complex changes in locomotor activity, energy expenditure, and feeding behavior, with a striking loss of daily rhythms during SD exposure. PMID- 20200138 TI - Complementation, genetic conflict, and the evolution of sex and recombination. AB - The existence of sexual reproduction is difficult to explain because the 2-fold cost of meiosis requires a compensatory 2-fold advantage that is difficult to prove. Here, I show that asexual reproduction has a short-term disadvantage due to the loss of complementation of recessive deleterious mutations, which can overcome the 2-fold cost of meiosis in one or few generations. This complementation hypothesis can also explain why most asexual species are polyploid, why only certain types of asexual reproduction exist, why meiosis is not one-step, and the origin of amphimixis. I also show that the promotion of variation by recombination is not necessary to explain the evolution of amphimixis. Instead, recombination can be the result of an intragenomic conflict between alleles that induce the initiation of crossing over and alleles that evolve to resist that initiation. Thus recombination does not require any advantage at the individual or population level. PMID- 20200137 TI - Endothelial nitric oxide synthase is central to skeletal muscle metabolic regulation and enzymatic signaling during exercise in vivo. AB - Endothelial nitric oxide synthase (eNOS) is associated with a number of physiological functions involved in the regulation of metabolism; however, the functional role of eNOS is poorly understood. We tested the hypothesis that eNOS is critical to muscle cell signaling and fuel usage during exercise in vivo, using 16-wk-old catheterized (carotid artery and jugular vein) C57BL/6J mice with wild-type (WT), partial (+/-), or no expression (-/-) of eNOS. Quantitative reductions in eNOS expression ( approximately 40%) elicited many of the phenotypic effects observed in enos(-/-) mice under fasted, sedentary conditions, with expression of oxidative phosphorylation complexes I to V and ATP levels being decreased, and total NOS activity and Ca(2+)/CaM kinase II Thr(286) phosphorylation being increased in skeletal muscle. Despite these alterations, exercise tolerance was markedly impaired in enos(-/-) mice during an acute 30-min bout of exercise. An eNOS-dependent effect was observed with regard to AMP activated protein kinase signaling and muscle perfusion. Muscle glucose and long chain fatty acid uptake, and hepatic and skeletal muscle glycogenolysis during the exercise bout was markedly accelerated in enos(-/-) mice compared with enos(+/-) and WT mice. Correspondingly, enos(-/-) mice exhibited hypoglycemia during exercise. Thus, the ablation of eNOS alters a number of physiological processes that result in impaired exercise capacity in vivo. The finding that a partial reduction in eNOS expression is sufficient to induce many of the changes associated with ablation of eNOS has implications for chronic metabolic diseases, such as obesity and insulin resistance, which are associated with reduced eNOS expression. PMID- 20200139 TI - Extensive MHC class II B gene duplication in a passerine, the common Yellowthroat (Geothlypis trichas). AB - The major histocompatibility complex (MHC) is characterized by a birth and death model of evolution involving gene duplication, diversification, loss of function, and deletion. As a result, gene number varies across taxa. Birds have between one and 7 confirmed MHC class II B genes, and the greatest diversity appears to occur in passerines. We used multiple primer sets on both genomic DNA (gDNA) and complementary DNA (cDNA) to characterize the range of class II B genes present in a passerine, the common yellowthroat (Geothlypis trichas). We confirmed 39 exon 2 sequences from gDNA in a single individual, indicating the presence of at least 20 class II B loci. From a second individual, we recovered 16 cDNA sequences belonging to at least 8 transcribed loci. Phylogenetic analysis showed that common yellowthroat sequences fell into subgroups consisting of classical loci, as well as at least 4 different clusters of sequences with reduced sequence variability that may represent pseudogenes or nonclassical loci. Data from 2 additional common yellowthroats demonstrated high interindividual variability. Our results reveal that some passerines possess an extraordinary diversity of MHC gene duplications, including both classical and nonclassical loci. PMID- 20200140 TI - Experiments with digital organisms on the origin and maintenance of sex in changing environments. AB - Many theories have been proposed to explain the evolution of sex, but the question remains unsettled owing to a paucity of compelling empirical tests. The crux of the problem is to understand the prevalence of sexual reproduction in the natural world, despite obvious costs relative to asexual reproduction. Here we perform experiments with digital organisms (evolving computer programs) to test the hypothesis that sexual reproduction is advantageous in changing environments. We varied the frequency and magnitude of environmental change, while the digital organisms could evolve their mode of reproduction as well as the traits affecting their fitness (reproductive rate) under the various conditions. Sex became the dominant mode of reproduction only when the environment changed rapidly and substantially (with particular functions changing from maladaptive to adaptive and vice versa). Even under these conditions, it was easier to maintain sexual reproduction than for sex to invade a formerly asexual population, although sometimes sex did invade and spread despite the obstacles to becoming established. Several diverse properties of the ancestral genomes, including epistasis and modularity, had no effect on the subsequent evolution of reproductive mode. Our study provides some limited support for the importance of changing environments to the evolution of sex, while also reinforcing the difficulty of evolving and maintaining sexual reproduction. PMID- 20200141 TI - Correction of the Delta phe508 cystic fibrosis transmembrane conductance regulator trafficking defect by the bioavailable compound glafenine. AB - Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which encodes a cAMP-activated anion channel expressed in epithelial cells. The most common mutation Delta Phe508 leads to protein misfolding, retention by the endoplasmic reticulum, and degradation. One promising therapeutic approach is to identify drugs that have been developed for other indications but that also correct the CFTR trafficking defect, thereby exploiting their known safety and bioavailability in humans and reducing the time required for clinical development. We have screened approved, marketed, and off patent drugs with known safety and bioavailability using a Delta Phe508-CFTR trafficking assay. Among the confirmed hits was glafenine, an anthranilic acid derivative with analgesic properties. Its ability to correct the misprocessing of CFTR was confirmed by in vitro and in vivo studies using a concentration that is achieved clinically in plasma (10 microM). Glafenine increased the surface expression of Delta Phe508-CFTR in baby hamster kidney (BHK) cells to approximately 40% of that observed for wild-type CFTR, comparable with the known CFTR corrector 4-cyclohexyloxy-2-{1-[4-(4-methoxybenzensulfonyl)-piperazin-1-yl] ethyl}-quinazoline (VRT-325). Partial correction was confirmed by the appearance of mature CFTR in Western blots and by two assays of halide permeability in unpolarized BHK and human embryonic kidney cells. Incubating polarized CFBE41o(-) monolayers and intestines isolated from Delta Phe508-CFTR mice (treated ex vivo) with glafenine increased the short-circuit current (I(sc)) response to forskolin + genistein, and this effect was abolished by 10 microM CFTR(inh)172. In vivo treatment with glafenine also partially restored total salivary secretion. We conclude that the discovery of glafenine as a CFTR corrector validates the approach of investigating existing drugs for the treatment of CF, although localized delivery or further medicinal chemistry may be needed to reduce side effects. PMID- 20200142 TI - Adrenocortical development and cancer: focus on SF-1. AB - Steroidogenic factor-1 (SF-1/Ad4-binding protein; NR5A1) is an essential regulator of tissue-specific gene expression in steroidogenic cells and of adrenogonadal development. Here, I discuss recent data in the literature showing the implication of SF-1 and the importance of its dosage not only during development but also for adrenal cortex tumorigenesis in humans and mice. PMID- 20200143 TI - Why do people drink at home? AB - BACKGROUND: The past 30 years have seen a shift in the culture concerning the consumption of alcohol in the UK. One of these is the increasing trend for adults to consume alcohol "at home". To date this is a development that has received little research attention. Participants and Methods Four focus groups (FG) of current drinkers who drank at home and reflected the views of both genders, differing age bands and living arrangements were conducted. The setting for the study was an economically deprived seaside resort in the North-West of England. Each focus group had two facilators and was taped, transcribed and subject to thematic analysis. FG A: (n=15; 9 males, 6 females) young people aged 13-21. FG B (n=4, 1 male, 3 female) volunteers aged 30-50 some of whom had children and were in relationships. FG C (n=15, 6 males, 9 females) recruited from a residents association-aged 25-70. FG D (n=4, 1 male, 3 female), aged 20-30 recruited through a local Lesbian and Gay Group. RESULTS: The principal reasons for drinking at home concerned convenience, these included cost, safety, social occasions, fear of under age drinkers, child-care, relief of stress. Lesser themes such as the smoking ban also emerged. CONCLUSIONS: These findings provide data of import to researchers and public health professionals to allow them to produce and target public health messages that take into account that the majority of drinking now takes place "at home". PMID- 20200144 TI - A risky business? PMID- 20200145 TI - Using NSAIDs in cardiovascular disease. AB - The risk of unwanted cardiovascular effects associated with NSAIDs has been publicised in the UK in recent years by the Medicines and Healthcare products Regulatory Agency (MHRA) and the National Prescribing Centre (NPC). Here we consider the evidence on cardiovascular risk in the context of other unwanted effects of NSAIDs (particularly those relating to the gastrointestinal tract and the kidneys), and offer practical advice on the use of NSAIDs in patients with cardiovascular disease. PMID- 20200146 TI - Managing primary hyperparathyroidism in primary care. AB - Patients with calcium concentrations above 3 mmol/L typically start to develop symptoms of hypercalcaemia, which can include nausea, vomiting, thirst and polyuria, malaise, confusion, lowered pain threshold and coma. Milder hypercalcaemia (calcium concentrations <3 mmol/L) is often asymptomatic, and the problem is therefore usually discovered as an incidental finding on routine biochemical screening. Primary hyperparathyroidism is a common cause of hypercalcaemia. Here, we consider the recognition and further management of patients presenting with asymptomatic primary hyperparathyroidism in primary care. PMID- 20200147 TI - Body surface area for adjustment of drug dose. AB - For many drugs, it is important to adjust the dose for individual patients. To estimate the dose, a patient's body weight or body surface area (BSA) is often used. BSA is difficult to measure directly, but may be calculated using formulae involving the patient's weight and height. Here we discuss BSA and when it is used in practice, in particular, for calculating drug doses in children and for cancer chemotherapy. PMID- 20200148 TI - Identification of candidate surface antigens for non-invasive prenatal diagnosis by comparative global gene expression on human fetal mesenchymal stem cells. AB - Transplacental passage of circulating first-trimester fetal mesenchymal stem cells (fMSC) raises the prospect of harvesting fetal cells in maternal blood. Despite high sensitivity in model systems, negative selection and culture strategies yield fMSC only rarely in post-termination maternal blood. The different adhesion molecule profile of fMSC to competitor maternal cell types suggests that improved positive selection strategies may facilitate non-invasive prenatal diagnosis. We aimed to identify surface antigens specific to fMSC and not maternal peripheral blood lymphocytes (PBL), using genome-wide analysis of actively expressed transcripts. Maternal PBL and fMSC cultured from first trimester blood, liver and bone marrow were assessed for global gene expression by Affymetrix U133Plus2.0 arrays. Data were analysed using Affymetrix GCOS01.2. Transcripts present in all fMSC (n = 9) but absent in all PBL samples (n = 3) were selected for further analysis of cell-surface membrane molecules by RT-PCR and immunocytochemistry. Of 1544 genes expressed in fMSC and not maternal PBL, filtering for cell-surface molecules yielded 159 genes. Of these, 29 had a mean expression ratio of >300 (P < 0.001), which represented 18 unique genes, and their positive expression in all fMSC samples was confirmed by RT-PCR. Candidates for non-invasive prenatal diagnosis were chosen for further analysis by immunocytochemistry. Surface expression of OSMR and COL1 proteins on all fMSC, but no maternal PBL was confirmed. Identification of novel surface antigens on circulating human fMSC and not maternal PBL facilitates positive selection strategies for isolating fMSC for non-invasive prenatal diagnosis. PMID- 20200149 TI - Chronic kidney disease in the urban poor. AB - BACKGROUND AND OBJECTIVES: In the United States, relatively little is known about clinical outcomes of chronic kidney disease (CKD) in vulnerable populations utilizing public health systems. The primary study objectives were to describe patient characteristics, incident ESRD, and mortality in adults with nondialysis dependent CKD receiving care in the health care safety net. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Time to ESRD and time to death were examined among a cohort of 15,353 ambulatory adults with nondialysis-dependent CKD from the Community Health Network of San Francisco. RESULTS: The mean age of the CKD cohort was 59.0 +/- 13.8 years; 50% of the cohort was younger than 60 years and 26% was younger than 50 years. Most (72%) were members of nonwhite racial-ethnic groups, 73% were indigent (annual income <$15,000) and 18% were uninsured. In adjusted analyses, blacks [hazard ratio (95% confidence interval), 4.00 (2.99 to 5.35)], Hispanics [2.20 (1.46 to 3.30)], and Asians/Pacific Islanders [3.84 (2.73 to 5.40)] had higher risks of progression to ESRD than non-Hispanic whites. The higher risk of progression to ESRD among nonwhite compared with white persons with CKD was not explained by lower relative mortality. CONCLUSIONS: Adults with CKD stages 3 to 5 cared for within an urban public health system were relatively young and predominantly nonwhite-both factors associated with a higher risk of progression to ESRD. These findings call for targeted efforts to assess the burden and progression of CKD within other public and safety-net health systems in this country. PMID- 20200150 TI - Perception of the Arabidopsis danger signal peptide 1 involves the pattern recognition receptor AtPEPR1 and its close homologue AtPEPR2. AB - Plasma membrane-borne pattern recognition receptors, which recognize microbe associated molecular patterns and endogenous damage-associated molecular patterns, provide the first line of defense in innate immunity. In plants, leucine-rich repeat receptor kinases fulfill this role, as exemplified by FLS2 and EFR, the receptors for the microbe-associated molecular patterns flagellin and elongation factor Tu. Here we examined the perception of the damage associated molecular pattern peptide 1 (AtPep1), an endogenous peptide of Arabidopsis identified earlier and shown to be perceived by the leucine-rich repeat protein kinase PEPR1. Using seedling growth inhibition, elicitation of an oxidative burst and induction of ethylene biosynthesis, we show that wild type plants and the pepr1 and pepr2 mutants, affected in PEPR1 and in its homologue PEPR2, are sensitive to AtPep1, but that the double mutant pepr1/pepr2 is completely insensitive. As a central body of our study, we provide electrophysiological evidence that at the level of the plasma membrane, AtPep1 triggers a receptor-dependent transient depolarization through activation of plasma membrane anion channels, and that this effect is absent in the double mutant pepr1/pepr2. The double mutant also fails to respond to AtPep2 and AtPep3, two distant homologues of AtPep1 on the basis of homology screening, implying that the PEPR1 and PEPR2 are responsible for their perception too. Our findings provide a basic framework to study the biological role of AtPep1-related danger signals and their cognate receptors. PMID- 20200151 TI - Sodium-hydrogen exchanger regulatory factor 1 (NHERF-1) transduces signals that mediate dopamine inhibition of sodium-phosphate co-transport in mouse kidney. AB - Dopamine inhibited phosphate transport in isolated renal brush border membrane vesicles and in cultured renal proximal tubule cells from wild-type but not from NHERF-1 null mice. Co-immunoprecipitation experiments established that NHERF-1 associated with D1-like receptors. In wild-type mice, dopamine stimulated cAMP accumulation and protein kinase C (PKC) activity in renal proximal tubule cells, an effect that was abolished by SCH-23390, a D1-like receptor antagonist. In NHERF-1 null kidney tissue; however, dopamine failed to stimulate either cAMP accumulation or PKC activity. Infection of proximal tubule cells from NHERF-1 null mice with adenovirus-green fluorescent protein-NHERF-1 restored the ability of dopamine to stimulate cAMP and PKC. Finally, in (32)P-labeled wild-type proximal tubule cells and in opossum kidney cells, dopamine increased NHERF-1 phosphorylation at serine 77 of the PDZ I domain of NHERF-1, a site previously shown to attenuate binding of cellular targets including the Npt2a (sodium dependent phosphate transporter 2a). Together, these studies establish that NHERF 1 plays a key role in dopamine signaling and is also a downstream target of D1 like receptors in the mouse kidney. These studies suggest a novel role for the PDZ adapter protein NHERF-1 in coordinating dopamine signals that inhibit renal phosphate transport. PMID- 20200152 TI - A slow, tight binding inhibitor of InhA, the enoyl-acyl carrier protein reductase from Mycobacterium tuberculosis. AB - InhA, the enoyl-ACP reductase in Mycobacterium tuberculosis is an attractive target for the development of novel drugs against tuberculosis, a disease that kills more than two million people each year. InhA is the target of the current first line drug isoniazid for the treatment of tuberculosis infections. Compounds that directly target InhA and do not require activation by the mycobacterial catalase-peroxidase KatG are promising candidates for treating infections caused by isoniazid-resistant strains. Previously we reported the synthesis of several diphenyl ethers with nanomolar affinity for InhA. However, these compounds are rapid reversible inhibitors of the enzyme, and based on the knowledge that long drug target residence times are an important factor for in vivo drug activity, we set out to generate a slow onset inhibitor of InhA using structure-based drug design. 2-(o-Tolyloxy)-5-hexylphenol (PT70) is a slow, tight binding inhibitor of InhA with a K(1) value of 22 pm. PT70 binds preferentially to the InhA x NAD(+) complex and has a residence time of 24 min on the target, which is 14,000 times longer than that of the rapid reversible inhibitor from which it is derived. The 1.8 A crystal structure of the ternary complex between InhA, NAD(+), and PT70 reveals the molecular details of enzyme-inhibitor recognition and supports the hypothesis that slow onset inhibition is coupled to ordering of an active site loop, which leads to the closure of the substrate-binding pocket. PMID- 20200153 TI - The THAP-zinc finger protein THAP1 associates with coactivator HCF-1 and O-GlcNAc transferase: a link between DYT6 and DYT3 dystonias. AB - THAP1 is a sequence-specific DNA binding factor that regulates cell proliferation through modulation of target genes such as the cell cycle-specific gene RRM1. Mutations in the THAP1 DNA binding domain, an atypical zinc finger (THAP-zf), have recently been found to cause DYT6 dystonia, a neurological disease characterized by twisting movements and abnormal postures. In this study, we report that THAP1 shares sequence characteristics, in vivo expression patterns and protein partners with THAP3, another THAP-zf protein. Proteomic analyses identified HCF-1, a potent transcriptional coactivator and cell cycle regulator, and O-GlcNAc transferase (OGT), the enzyme that catalyzes the addition of O GlcNAc, as major cellular partners of THAP3. THAP3 interacts with HCF-1 through a consensus HCF-1-binding motif (HBM), a motif that is also present in THAP1. Accordingly, THAP1 was found to bind HCF-1 in vitro and to associate with HCF-1 and OGT in vivo. THAP1 and THAP3 belong to a large family of HCF-1 binding factors since seven other members of the human THAP-zf protein family were identified, which harbor evolutionary conserved HBMs and bind to HCF-1. Chromatin immunoprecipitation (ChIP) assays and RNA interference experiments showed that endogenous THAP1 mediates the recruitment of HCF-1 to the RRM1 promoter during endothelial cell proliferation and that HCF-1 is essential for transcriptional activation of RRM1. Together, our findings suggest HCF-1 is an important cofactor for THAP1. Interestingly, our results also provide an unexpected link between DYT6 and DYT3 (X-linked dystonia-parkinsonism) dystonias because the gene encoding the THAP1/DYT6 protein partner OGT maps within the DYT3 critical region on Xq13.1. PMID- 20200154 TI - Molecular dynamics simulations show that conformational selection governs the binding preferences of imatinib for several tyrosine kinases. AB - Tyrosine kinases transmit cellular signals through a complex mechanism, involving their phosphorylation and switching between inactive and active conformations. The cancer drug imatinib binds tightly to several homologous kinases, including Abl, but weakly to others, including Src. Imatinib specifically targets the inactive, so-called "DFG-out" conformation of Abl, which differs from the preferred, "DFG-in" conformation of Src in the orientation of a conserved Asp-Phe Gly (DFG) activation loop. However, recent x-ray structures showed that Src can also adopt the DFG-out conformation and uses it to bind imatinib. The Src/Abl binding free energy difference can thus be decomposed into two contributions. Contribution i measures the different protein-imatinib interactions when either kinase is in its DFG-out conformation. Contribution ii depends on the ability of imatinib to select or induce this conformation, i.e. on the relative stabilities of the DFG-out and DFG-in conformations of each kinase. Neither contribution has been measured experimentally. We use molecular dynamics simulations to show that contribution i is very small, 0.2 +/- 0.6 kcal/mol; imatinib interactions are very similar in the two kinases, including long range electrostatic interactions with the imatinib positive charge. Contribution ii, deduced using the experimental binding free energy difference, is much larger, 4.4 +/- 0.9 kcal/mol. Thus, conformational selection, easy in Abl, difficult in Src, underpins imatinib specificity. Contribution ii has a simple interpretation; it closely approximates the stability difference between the DFG-out and DFG-in conformations of apo-Src. Additional calculations show that conformational selection also governs the relative binding of imatinib to the kinases c-Kit and Lck. These results should help clarify the current framework for engineering kinase signaling. PMID- 20200155 TI - Analysis of a TIR-less splice variant of TRIF reveals an unexpected mechanism of TLR3-mediated signaling. AB - Recognition of viral RNA by Toll-like receptor 3 (TLR3) triggers activation of the transcription factors NF-kappaB and IRF3 and induction of type I interferons. TRIF is a Toll-interleukin 1 receptor (TIR) domain-containing adapter protein critically involved in TLR3-mediated signaling. It has been shown that TRIF interacts with TLR3 through their respective TIR domains. In this study, we identified a splice variant of TRIF lacking the TIR domain, which is designated as TRIS. Overexpression of TRIS activates NF-kappaB, interferon-stimulated response element (ISRE), and the interferon-beta promoter, whereas knockdown of TRIS inhibited TLR3-mediated signaling, suggesting that TRIS is involved in TLR3 mediated signaling. Furthermore, we identified an N-terminal TBK1-binding motif of TRIS or TRIF that was important for its interaction with TBK1 and ability to activate ISRE. Activation of ISRE by TRIS also needs its dimerization or oligomerization mediated by its C-terminal RIP homotypic interaction motif. Finally, we demonstrated that TRIS was associated with TRIF upon TLR3 activation by poly(I-C). These findings reveal an unexpected mechanism of TLR3-mediated signaling. PMID- 20200156 TI - Insights into regulated ligand binding sites from the structure of ZO-1 Src homology 3-guanylate kinase module. AB - Tight junctions are dynamic components of epithelial and endothelial cells that regulate the paracellular transport of ions, solutes, and immune cells. The assembly and permeability of these junctions is dependent on the zonula occludens (ZO) proteins, members of the membrane-associated guanylate kinase homolog (MAGUK) protein family, which are characterized by a core Src homology 3 (SH3) GUK module that coordinates multiple protein-protein interactions. The structure of the ZO-1 SH3-GUK domain confirms that the interdependent folding of the SH3 and GUK domains is a conserved feature of MAGUKs, but differences in the orientation of the GUK domains in three different MAGUKs reveal interdomain flexibility of the core unit. Using pull-down assays, we show that an effector loop, the U6 region in ZO-1, forms a novel intramolecular interaction with the core module. This interaction is divalent cation-dependent and overlaps with the binding site for the regulatory molecule calmodulin on the GUK domain. These findings provide insight into the previously observed ability of the U6 region to regulate TJ assembly in vivo and the structural basis for the complex protein interactions of the MAGUK family. PMID- 20200157 TI - NMR analysis of the structure, dynamics, and unique oligomerization properties of the chemokine CCL27. AB - Chemokines have two essential interactions in vivo, with G protein-coupled receptors, which activate intracellular signaling pathways, and with glycosaminoglycans (GAGs), which are involved in cell surface localization and transport. Although it has been shown that chemokines bind and activate their respective G protein-coupled receptors as monomers, many chemokines oligomerize upon GAG binding, and the ability to oligomerize and bind GAGs is required for in vivo function. In this study, we investigated the structure, dynamics, and oligomerization behavior of cutaneous T-cell-attracting chemokine (CTACK, also known as CCL27) by NMR. (15)N relaxation and translational self-diffusion rates indicate that CCL27 oligomerizes, but in contrast to many other chemokines that form relatively discrete oligomers, CCL27 transitions between monomer, dimer, and tetramer species over a relatively narrow concentration range. A three dimensional structure determination was pursued under conditions where CCL27 is primarily dimeric, revealing the standard motif for a chemokine monomer. Analysis of chemical shift perturbations of (1)H-(15)N HSQC spectra, relaxation-dispersion experiments, and filtered nuclear Overhauser effects suggest that CCL27 does not adopt a discrete CXC or CC dimer motif. Instead, CCL27 has uncommon oligomerization behavior, where several equilibria involving relatively low affinity interactions between different interfaces seem to be simultaneously at work. However, interaction with heparin avidly promotes oligomerization under conditions where CCL27 is monomeric by itself. We hypothesize that the plasticity in the oligomerization state may enable CCL27 to adopt different oligomeric structures, depending on the nature of the GAG binding partner, thereby providing a mechanism for increased diversity and specificity in GAG-binding and GAG related functions. PMID- 20200158 TI - Order and disorder in the domain organization of the plasmid partition protein KorB. AB - The plasmid partition protein KorB has a dual role: it is essential for the correct segregation of the low copy number broad host range RK2 plasmid while also being an important regulator of transcription. KorB belongs to the ParB family of proteins, and partitioning in RK2 has been studied as a simplified model of bacterial chromosome segregation. Structural information on full-length ParB proteins is limited, mainly due to the inability to grow crystals suitable for diffraction studies. We show, using CD and NMR, that KorB has regions of significant intrinsic disorder and hence it adopts a multiplicity of conformations in solution. The biophysical data are consistent with bioinformatic predictions based on the amino acid sequence that the N-terminal region and also the region between the central DNA-binding domain and the C-terminal dimerization domain are intrinsically disordered. We have used small angle x-ray scattering data to determine the ensemble of solution conformations for KorB and selected deletion mutants, based on models of the known domain structures. This conformational range of KorB is likely to be biologically required for DNA partitioning and for binding to a diverse set of partner proteins. PMID- 20200159 TI - The LAMMER kinase homolog, Lkh1, regulates Tup transcriptional repressors through phosphorylation in Schizosaccharomyces pombe. AB - Disruption of the fission yeast LAMMER kinase, Lkh1, gene resulted in diverse phenotypes, including adhesive filamentous growth and oxidative stress sensitivity, but an exact cellular function had not been assigned to Lkh1. Through an in vitro pull-down approach, a transcriptional repressor, Tup12, was identified as an Lkh1 binding partner. Interactions between Lkh1 and Tup11 or Tup12 were confirmed by in vitro and in vivo binding assays. Tup proteins were phosphorylated by Lkh1 in a LAMMER motif-dependent manner. The LAMMER motif was also necessary for substrate recognition in vitro and cellular function in vivo. Transcriptional activity assays using promoters negatively regulated by Tup11 and Tup12 showed 6 or 2 times higher activity in the Delta lkh1 mutant than the wild type, respectively. Northern analysis revealed derepressed expression of the fbp1(+) mRNA in Delta lkh1 and in Delta tup11 Delta tup12 mutant cells under repressed conditions. Delta lkh1 and Delta tup11 Delta tup12 mutant cells showed flocculation, which was reversed by co-expression of Tup11 and -12 with Ssn6. Here, we presented a new aspect of the LAMMER kinase by demonstrating that the activities of global transcriptional repressors, Tup11 and Tup12, were positively regulated by Lkh1-mediated phosphorylation. PMID- 20200161 TI - Stromal hyaluronan interaction with epithelial CD44 variants promotes prostate cancer invasiveness by augmenting expression and function of hepatocyte growth factor and androgen receptor. AB - The main aim of our study is to determine the significance of the stromal microenvironment in the malignant behavior of prostate cancer. The stroma-derived growth factors/cytokines and hyaluronan act in autocrine/paracrine ways with their receptors, including receptor-tyrosine kinases and CD44 variants (CD44v), to potentiate and support tumor epithelial cell survival. Overexpression of hyaluronan, CD44v9 variants, and stroma-derived growth factors/cytokines are specific features in many cancers, including prostate cancer. Androgen/androgen receptor interaction has a critical role in regulating prostate cancer growth. Our previous study showed that 1) that increased synthesis of hyaluronan in normal epithelial cells promotes expression of CD44 variants; 2) hyaluronan interaction with CD44v6-v9 promotes activation of receptor-tyrosine kinase, which stimulates phosphatidylinositol 3-kinase-induced cell survival pathways; and 3) CD44v6/short hairpin RNA reduces colon tumor growth in vivo (Misra, S., Hascall, V. C., De Giovanni, C., Markwald, R. R., and Ghatak, S. (2009) J. Biol. Chem. 284, 12432-12446). Our results now show that hepatocyte growth factor synthesized by myofibroblasts associated with prostate cancer cells induces activation of HGF receptor/cMet and stimulates hyaluronan/CD44v9 signaling. This, in turn, stabilizes the androgen receptor functions in prostate cancer cells. The stroma derived HGF induces a lipid raft-associated signaling complex that contains CD44v9, cMet/phosphatidylinositol 3-kinase, HSP90 and androgen receptor. CD44v9/short hairpin RNA reverses the assembly of these components in the complex and inhibits androgen receptor function. Our results provide new insight into the hyaluronan/CD44v9-regulated androgen receptor function and the consequent malignant activities in prostate cancer cells. The present study describes a physiologically relevant in vitro model for studying the molecular mechanisms by which stroma-derived HGF and hyaluronan influence androgen receptor and CD44 functions in the secretory epithelia during prostate carcinogenesis. PMID- 20200160 TI - Down-regulation of PROS1 gene expression by 17beta-estradiol via estrogen receptor alpha (ERalpha)-Sp1 interaction recruiting receptor-interacting protein 140 and the corepressor-HDAC3 complex. AB - Pregnant women show a low level of protein S (PS) in plasma, which is known to be a risk for deep venous thrombosis. 17Beta-estradiol (E(2)), an estrogen that increases in concentration in the late stages of pregnancy, regulates the expression of various genes via the estrogen receptor (ER). Here, we investigated the molecular mechanisms behind the reduction in PS levels caused by E(2) in HepG2-ERalpha cells, which stably express ERalpha, and also the genomic ER signaling pathway, which modulates the ligand-dependent repression of the PSalpha gene (PROS1). We observed that E(2) repressed the production of mRNA and antigen of PS. A luciferase reporter assay revealed that E(2) down-regulated PROS1 promoter activity and that this E(2)-dependent repression disappeared upon the deletion or mutation of two adjacent GC-rich motifs in the promoter. An electrophoretic mobility shift assay and DNA pulldown assay revealed that the GC rich motifs were associated with Sp1, Sp3, and ERalpha. In a chromatin immunoprecipitation assay, we found ERalpha-Sp protein-promoter interaction involved in the E(2)-dependent repression of PROS1 transcription. Furthermore, we demonstrated that E(2) treatment recruited RIP140 and the NCoR-SMRT-HDAC3 complex to the PROS1 promoter, which hypoacetylated chromatin. Taken together, this suggested that E(2) might repress PROS1 transcription depending upon ERalpha-Sp1 recruiting transcriptional repressors in HepG2-ERalpha cells and, consequently, that high levels of E(2) leading to reduced levels of plasma PS would be a risk for deep venous thrombosis in pregnant women. PMID- 20200162 TI - G alpha(q) acts as an adaptor protein in protein kinase C zeta (PKCzeta)-mediated ERK5 activation by G protein-coupled receptors (GPCR). AB - G(q)-coupled G protein-coupled receptors (GPCR) mediate the actions of a variety of messengers that are key regulators of different cellular functions. These receptors can regulate a highly interconnected network of biochemical routes that control the activity of several members of the mitogen-activated protein kinase (MAPK) family. The ERK5 MAPK has been shown to be activated by G(q)-coupled GPCR via unknown mechanisms. We find that the atypical protein kinase C (PKCzeta), previously reported to interact with the ERK5 activator MEK5 and to be involved in epidermal growth factor-mediated ERK5 stimulation, plays a crucial role in the activation of the ERK5 pathway by G(q)-coupled GPCR. Stimulation of ERK5 by G(q) coupled GPCR is abolished upon pharmacological inhibition of PKCzeta as well as in embryonic fibroblasts obtained from PKCzeta-deficient mice. Both PKCzeta and MEK5 associate to G alpha(q) upon activation of GPCR, thus forming a ternary complex that seems essential for the activation of ERK5. These data put forward a novel function of G alpha(q) as a scaffold protein involved in the modulation of the ERK5 cascade by GPCR that could be relevant in G(q)-mediated physiological functions. PMID- 20200164 TI - Vaccination: an option not to be ignored. PMID- 20200163 TI - Lysosomal degradation of alpha-synuclein in vivo. AB - Pathologic accumulation of alpha-synuclein is a feature of human parkinsonism and other neurodegenerative diseases. This accumulation may be counteracted by mechanisms of protein degradation that have been investigated in vitro but remain to be elucidated in animal models. In this study, lysosomal clearance of alpha synuclein in vivo was indicated by the detection of alpha-synuclein in the lumen of lysosomes isolated from the mouse midbrain. When neuronal alpha-synuclein expression was enhanced as a result of toxic injury (i.e. treatment of mice with the herbicide paraquat) or transgenic protein overexpression, the intralysosomal content of alpha-synuclein was also significantly increased. This effect was paralleled by a marked elevation of the lysosome-associated membrane protein type 2A (LAMP-2A) and the lysosomal heat shock cognate protein of 70 kDa (hsc70), two essential components of chaperone-mediated autophagy (CMA). Immunofluorescence microscopy revealed an increase in punctate (lysosomal) LAMP-2A staining that co localized with alpha-synuclein within nigral dopaminergic neurons of paraquat treated and alpha-synuclein-overexpressing animals. The data provide in vivo evidence of lysosomal degradation of alpha-synuclein under normal conditions and, quite importantly, under conditions of enhanced protein burden. In the latter, increased lysosomal clearance of alpha-synuclein was mediated, at least in part, by CMA induction. It is conceivable that these neuronal mechanisms of protein clearance play an important role in neurodegenerative processes characterized by abnormal alpha-synuclein buildup. PMID- 20200165 TI - Treating silent reflux disease does not improve poorly controlled asthma. AB - Many patients with asthma also have gastroesophageal reflux disease (GERD), and GERD can cause symptoms that mimic those of poorly controlled asthma. Patients with poorly controlled asthma are often treated empirically for GERD, whether or not they have symptomatic reflux. However, a randomized, placebo-controlled trial funded by the American Lung Association and the National Institutes of Health found that treating silent GERD does not improve asthma control. These results warrant a reevaluation of current guidelines and clinical practice. PMID- 20200167 TI - Stenting for atherosclerotic renal artery stenosis: one poorly designed trial after another. PMID- 20200168 TI - Stenting atherosclerotic renal arteries: time to be less aggressive. AB - Percutaneous intervention has become very popular for treating atherosclerotic renal artery stenosis, as the use of stents has boosted the rate of technical success and as more cases are being discovered incidentally during angiography of the coronary or other arteries. Yet randomized trials indicate that the procedure does little in terms of controlling blood pressure and may actually harm as many patients as it helps in terms of renal function. Needed are better ways to predict which patients will benefit and better ways to prevent adverse effects such as atheroembolism. PMID- 20200169 TI - Interpreting the JUPITER trial: statins can prevent VTE, but more study is needed. AB - Analysis of a secondary end point of the JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) found that a statin reduced the risk of venous thromboembolism (VTE) in apparently healthy people with high levels of C-reactive protein and normal levels of low density lipoprotein cholesterol (N Engl J Med 2009; 360:1851-1861). Still, pending more study, statins should not be substituted for proven prophylaxis and anticoagulation, especially for patients with recurrent deep venous thrombosis, hospitalized patients, postoperative patients, and other patients prone to VTE. PMID- 20200170 TI - When and how to evaluate mildly elevated liver enzymes in apparently healthy patients. AB - Because 1% to 9% of people without symptoms have elevated liver enzymes, extensive evaluation of all abnormal test results would expose many patients to undue risks and expenses. On the other hand, failure to evaluate minor liver enzyme elevations could mean missing the early diagnosis of potentially treatable disorders. This review discusses likely causes of elevated aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase levels and provides algorithms for evaluating high liver enzyme values in apparently healthy patients in the primary care setting. PMID- 20200171 TI - Palpable purpura. PMID- 20200172 TI - Measles: not just a childhood rash. AB - In recent years, the number of US measles cases has increased, and outbreaks in adults continue to be reported in communities with a high number of unvaccinated people. These trends underscore the need for high overall measles vaccination coverage, and for physicians to entertain the diagnosis of measles in adult patients with a febrile illness and rash. PMID- 20200173 TI - MMR, climate change, and orthopaedics: a bad month for peer review. PMID- 20200174 TI - Prevention of pandemic influenza after mass gatherings - learning from Hajj. PMID- 20200175 TI - All a matter of viewpoint. PMID- 20200176 TI - Evaluating memory clinics. PMID- 20200177 TI - Henry VIII's leg ulcers. PMID- 20200178 TI - Mental illness and the workplace: conceal or reveal? PMID- 20200179 TI - Richard Mead, Thomas Guy, the South Sea Bubble and the founding of Guy's Hospital. PMID- 20200180 TI - Medicolegal reports in asylum applications: a framework for addressing the practical and ethical challenges. AB - The clinical care of asylum-seekers may bring clinicians in contact with the immigration authorities. A request for a medicolegal report usually requires the responsible clinician to state their opinion on the risks involved in returning an applicant to their country of origin, taking into account their current condition, the treatments available in that country, and the risks involved in travel. This review draws on clinical experience and a review of the literature to describe the work involved in preparing a medical report requested by immigration authorities. Although the starting point chosen is the psychiatric report, the principles described apply to the preparation of immigration reports in any medical discipline. PMID- 20200182 TI - Falling in and out of consciousness: catatonia in a postoperative patient. PMID- 20200181 TI - Trends in the epidemiology of asthma in England: a national study of 333,294 patients. AB - BACKGROUND: Observations in the UK at the end of the last century found increasing trends of asthma prevalence over time. However, it has been reported that the number of new cases of asthma presenting to general practice has declined, especially among younger children. Aim To study national trends in the epidemiology of asthma. METHODS: A cross-sectional observation analysis was performed using the QRESEARCH database, which is one of the world's largest national aggregated health databases containing records from 422 English practices yielding 30 million patient-years of observation. Data was extracted on 333,294 individuals with a recorded diagnosis of asthma and calculated annual age sex standardized incidence, lifetime period prevalence and asthma-related prescribing rates for each year from 2001-2005. RESULTS: The incidence rate of asthma decreased in all patients (2001: 6.9 (95% confidence intervals [CI] 6.8 7.0); 2005: 5.2 (95% CI 5.1-5.3) per 1000 patient-years, p<0.001), but most particularly in children under 5 years of age (-38.4%) where a decrease in the lifetime prevalence of asthma (-34.3%) was also found. However, the lifetime prevalence rate of asthma for adults increased (15-44 years: 23.3%; 45-64 years: 27.7%; >65 years: 21.5%) with an estimated 5,658,900 (95% CI 5,639,700-5,678,200) or approximately one person in nine having being diagnosed with asthma in England. The number of asthma-related prescriptions also increased over the study period (17.1%), such that in 2005 an estimated 32,577,300 (95%CI 32,531,600 32,623,000) prescriptions were issued. CONCLUSIONS: This large national study reveals that the rate of new diagnoses of asthma appears to have passed its peak; however, the number of adults with a lifetime asthma diagnosis continues to rise. Whether these trends are genuine or are a result of the introduction of incentives and guidelines to improve identification and recording of asthma or changing diagnostic trends is a question with important public health implications and one, therefore, that warrants detailed further enquiry. PMID- 20200183 TI - Haematemesis and melaena [corrected] as the first presentation of duodenal varices. PMID- 20200184 TI - Isabella Leitch's contributions to the development of systematic reviews of research evidence. PMID- 20200185 TI - How our absentee landlord lost the hospital plot. PMID- 20200186 TI - Aggregation of Streptococcus pneumoniae by a pneumococcal capsular polysaccharide specific human monoclonal IgM correlates with antibody efficacy in vivo. AB - Acquired antibody immunity to Streptococcus pneumoniae (pneumococcus) has been linked to serotype (ST)-specific opsonic antibodies to the relevant pneumococcal capsular polysaccharide (PPS) that mediate protection by enhancing the bactericidal effect of host phagocytes. Despite the well-recognized role of opsonic IgG in host defense against pneumococcus, PPS-specific monoclonal antibodies (MAbs) that mediate protection against lethal challenge with ST3 pneumococcus in mice but do not promote phagocytic killing in vitro (nonopsonic antibodies) have been described. In this study, we sought to determine the biological activity of one such MAb, A7 (a human PPS3-specific IgM), and the mechanism by which it mediates protection. In vitro studies demonstrated that coincubation of A7 with ST3 in the absence of phagocytes or a complement source resulted in a reduction in CFU on blood agar plates that was largely reversible by sonication. A chromogenic cellular proliferation assay demonstrated that A7 did not affect replication of ST3 in liquid culture. The ability of A7 to induce aggregation of ST3 was confirmed by fluorescence microscopy and flow cytometry: A7 induced aggregation of ST3, and in the presence of a complement source, A7 promoted deposition of complement component 3 (C3) on aggregated bacteria in a dose-dependent fashion. Similarly, administration of preincubated mixtures of A7 and ST3 intraperitoneally to mice protected them from the lethality of ST3 in a dose-dependent fashion. These findings suggest that A7-mediated aggregation enhances resistance to ST3, most likely by enhancing C3 deposition on the ST3 capsule, thereby promoting host antipneumococcal activity in vivo. PMID- 20200187 TI - Quality monitoring of HIV-1-infected and uninfected peripheral blood mononuclear cell samples in a resource-limited setting. AB - Human immunodeficiency virus type 1 (HIV-1) vaccine and natural history studies are critically dependent on the ability to isolate, cryopreserve, and thaw peripheral blood mononuclear cell (PBMC) samples with a high level of quality and reproducibility. Here we characterize the yield, viability, phenotype, and function of PBMC from HIV-1-infected and uninfected Ugandans and describe measures to ascertain reproducibility and sample quality at the sites that perform cryopreservation. We have developed a comprehensive internal quality control program to monitor processing, including components of method validation. Quality indicators for real-time performance assessment included the time from venipuncture to cryopreservation, time for PBMC processing, yield of PBMC from whole blood, and viability of the PBMC before cryopreservation. Immune phenotype analysis indicated lowered B-cell frequencies following processing and cryopreservation for both HIV-1-infected and uninfected subjects (P < 0.007), but all other major lymphocyte subsets were unchanged. Long-term cryopreservation did not impact function, as unstimulated specimens exhibited low background and all specimens responded to staphylococcal enterotoxin B (SEB) by gamma interferon and interleukin-2 production, as measured by intracellular cytokine staining. Samples stored for more than 3 years did not decay with regard to yield or viability, regardless of HIV-1 infection status. These results demonstrate that it is possible to achieve the high level of quality necessary for vaccine trials and natural history studies in a resource-limited setting and provide strategies for laboratories to monitor PBMC processing performance. PMID- 20200189 TI - Vaccinia virus B5 protein affects the glycosylation, localization and stability of the A34 protein. AB - Vaccinia virus has two infectious forms, the intracellular mature virus, which has a single envelope, and the extracellular enveloped virus (EEV), which is surrounded by two lipid bilayers. The outer membrane of the EEV contains at least six viral proteins. Among them A34, a type II membrane glycoprotein, and B5, a type I membrane glycoprotein, form a complex and are involved in processes such as morphogenesis and EEV entry. A34 is required for normal incorporation of B5 into the EEV membrane. Here, we used a virus lacking B5 and viruses with mutations in the B5 membrane-proximal stalk region and looked at the effect of those modifications on A34. Data presented show that B5 is required for the correct glycosylation, trafficking and stability of A34, emphasizing the complex interactions and mutual dependence of these vaccinia EEV proteins. PMID- 20200188 TI - Glucose-based peritoneal dialysis fluids downregulate toll-like receptors and trigger hyporesponsiveness to pathogen-associated molecular patterns in human peritoneal mesothelial cells. AB - The objective of this study was to investigate the effects of glucose-based peritoneal dialysis (PD) fluids and icodextrin-based PD fluids on the expression of Toll-like receptor 2 (TLR2)/TLR4 and subsequent ligand-induced mitogen activated protein kinase (MAPK) and NF-kappaB signaling and tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta) mRNA expression in human peritoneal mesothelial cells (HPMCs). A human peritoneal mesothelial cell line (HMrSV5) was stimulated with glucose-based and icodextrin-based peritoneal dialysis fluids. Cell viability was assessed using MTT [3-(4,5-dimethylthiazolyl) 2,5-diphenyl-2H-tetrazolium bromide]. TLR2/TLR4 expression was determined by real time PCR, Western blotting, and an immunofluorescence assay. In addition, cells were pretreated with different PD solutions and then incubated with Pam3CSK4 or lipopolysaccharide (LPS), and the degrees of MAPK and NF-kappaB activation were reflected by detecting the phosphorylation levels of extracellular signal regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38, and p65, using a Western blot method. TNF-alpha and IL-1beta mRNA expression was measured by real-time PCR. Glucose-based peritoneal dialysis fluids suppressed the expression of TLR2 and TLR4 proteins in HPMCs. Challenge of cells with either Pam3CSK4 or LPS resulted in impaired TNF-alpha and IL-1beta production. Moreover, reduced TLR2 and TLR4 levels in glucose-based peritoneal dialysis solution-treated mesothelial cells were accompanied by reduced p42/44 (ERK1/2), JNK, p38 MAPK, and NF-kappaB p65 phosphorylation upon TLR ligand engagement. No significant changes in MAPK and NF-kappaB signaling and TNF-alpha and IL-1beta mRNA expression were observed in icodextrin-based PD solution-treated mesothelial cells. Glucose-based PD solution, but not icodextrin-based PD solution, downregulates expression of TLR2/TLR4 by human peritoneal mesothelial cells and triggers hyporesponsiveness to pathogen-associated molecular patterns. PMID- 20200190 TI - Rotavirus NSP5 orchestrates recruitment of viroplasmic proteins. AB - Rotavirus genome replication and the first steps of virus morphogenesis take place in cytoplasmic viral factories, called viroplasms, containing four structural (VP1, VP2, VP3 and VP6) and two non-structural (NSP2 and NSP5) proteins. NSP2 and NSP5 have been shown to be essential for viroplasm formation and, when co-expressed in uninfected cells, to form viroplasm-like structures (VLS). In the present work, VLS formation was shown upon co-expression of NSP5 with the core protein VP2 despite the absence of NSP2, indicating a central role for NSP5 in VLS assembly. Since VP2 and NSP2 also induce NSP5 hyperphosphorylation, the possible correlation between VLS formation and the NSP5 phosphorylation status was investigated without evidence of a direct link. In VLS induced by NSP2, the polymerase VP1 was recruited, while the middle layer protein VP6 was not, forming instead tubular structures. On the other hand, VLS induced by VP2 were able to recruit both VP1 and VP6. More importantly, in VLS formed when NSP5 was expressed with both inducers, all viroplasmic proteins were found co-localized, resembling their distribution in viroplasms. Our results suggest a key role for NSP5 in architectural assembly of viroplasms and in recruitment of viroplasmic proteins. A new role for VP2 as an inducer of viroplasms and of NSP5 hyperphosphorylation is also described. These data may contribute to the understanding of rotavirus morphogenesis. PMID- 20200191 TI - Implications of the release of high-mobility group box 1 protein from dying cells during human immunodeficiency virus type 1 infection in vitro. AB - Plasma levels of high-mobility group box 1 protein (HMGB1) are elevated during the course of human immunodeficiency virus type 1 (HIV-1) infection and the molecule has an impact on virus replication. This study investigated the mode of cell death and release of HMGB1 during HIV-1 infection in vitro. MT4 cells and primary CD4(+) T cells were infected with HIV-1 isolates, and HMGB1 release was monitored in relation to cytopathic effects (CPE) and apoptosis. HMGB1 release from cells was analysed by Western blotting. For MT4 cells, an enzyme-linked immunosorbent spot (ELISPOT) assay was adapted to measure the release during necrosis. Lactate dehydrogenase (LDH) activity was quantified using a commercial assay. Flow cytometry was used to determine the level of infection and apoptosis. MT4 cells were > or =90 % infected at 48 h post-infection (p.i.). CPE was first observed at 60 h and correlated with release of HMGB1, LDH activity and caspase-3 (C3) activation. HMGB1 spots were clearly detected by ELISPOT assay at 72 h p.i. Annexin V and C3 staining showed that apoptosis was substantially involved in HIV 1-related cell death. Addition of Z-VAD (a caspase inhibitor) in a single dose at 24 or 40 h p.i. decreased both the number of caspase-positive cells and the release of HMGB1. Infection of primary CD4(+) T cells showed a 22 % (median) infection rate at 96 h. Related CPE corresponded to LDH and HMGB1 release. Both necrosis and apoptosis contributed to HMGB1 liberation during HIV-1-induced cell death and the protein could induce tumour necrosis factor-alpha release from peripheral mononuclear blood cells. These data imply that passive HMGB1 release contributes to the excessive immune activation characteristic of HIV-1 pathogenesis. PMID- 20200192 TI - Analysis of genetic diversity and molecular evolution of human group B rotaviruses based on whole genome segments. AB - Group B rotavirus (GBR) is a rare enteric pathogen that causes severe diarrhoea, primarily in adults. Nearly full-length sequences of all 11 RNA segments were determined for human GBRs detected recently in India (IDH-084 in 2007, IC-008 in 2008), Bangladesh (Bang117 in 2003) and Myanmar (MMR-B1 in 2007), and analysed phylogenetically with the sequence data of GBRs reported previously. All RNA segments of GBR strains from India, Bangladesh and Myanmar showed >95 % nucleotide sequence identities. Among the 11 RNA segments, the VP6 and NSP2 genes showed the highest identities (>98 %), whilst the lowest identities were observed in the NSP4 gene (96.1 %), NSP5 gene (95.6 %) and VP8*-encoding region of the VP4 gene (95.9 %). Divergent or conserved regions in the deduced amino acid sequences of GBR VP1-VP4 and NSP1-NSP5 were similar to those in group A rotaviruses (GARs), and the functionally important motifs and structural characteristics in viral proteins known for GAR were conserved in all of the human GBRs. These findings suggest that, whilst the degree of genetic evolution may be dependent on each RNA segment, human GBR may have been evolving in a similar manner to GAR, associated with the similar functional roles of individual viral proteins. PMID- 20200193 TI - Residue 752 in DNA polymerase of equine herpesvirus type 1 is non-essential for virus growth in vitro. AB - A single amino acid variation in the equine herpesvirus type 1 (EHV-1) DNA polymerase (Pol) (D752/N752) determines its neuropathogenic potential. Here, an EHV-1 strain RacL11 mutant with a deletion of Pol residue 752 was constructed. The deletion virus was then repaired to encode D752 or N752, respectively. The Delta752 mutant virus replicated with kinetics indistinguishable from those of D752 and N752 viruses. In addition, we could demonstrate that the deletion mutant was significantly more resistant to aphidicolin, a drug targeting Pol, compared with the N752 but not the D752 variant. In equine peripheral blood mononuclear cells, no significant difference was detected between the mutants with respect to cellular tropism or virus replication. The results demonstrated that amino acid residue 752 in EHV-1 Pol is not required for virus growth, and that only the N752 mutation confers a drug-sensitive phenotype to the virus. PMID- 20200194 TI - Siblings' farewell to a stillborn sister or brother and parents' support to their older children: a questionnaire study from the parents' perspective. AB - This study aims to capture parental descriptions of how siblings take leave of and mourn a stillborn brother or sister and how their parents support them. Data were collected by questionnaires from 16 parents of siblings to a stillborn child one year after the stillbirth. Data were analysed numerically for the multiple choice questions and content analysis was used for parental comments and descriptions. The results describe siblings' farewell to a stillborn brother or sister and how their parents in the midst of their own grief were involved in supporting siblings' wellbeing, and observed their mourning reactions. Although the findings need to be interpreted with caution, they may provide insight that enables staff to become more sensitive to the whole family experience in the practice of their profession. Further research into siblings' grief and parental support after stillbirth is crucial so that further light may be shed on their situation. PMID- 20200195 TI - Protective effect of Thuja occidentalis against DMBA-induced breast cancer with reference to oxidative stress. AB - In vivo experiment has been conducted to observe the preventive role of Thuja occidentalis Linn (leaves) against 7, 12 dimethylbenz(a)anthracene (DMBA)-induced mammary cancer. Ethyl acetate (EtOAc) and methanolic (MeOH) extracts in two doses (5 and 10 mg/kg body weight) of the plant were tested for DMBA-induced Indian Cancer Research Centre (ICRC) mice mammary carcinoma in terms of tumor weight, volume, life span, histological variation and oxidative stress against the reference drug doxorubicin using standard animal protocol. EtOAc extract (10 mg/kg body weight) of the plant exhibits reduction of tumor weight (39%), tumor volume (50%), reduced glutathione (GSH) (83%) and malignant cells compared to cancerous control group while the increase in body weight and life span in comparison with cancerous control and doxorubicin-treated group. EtOAc extract being most potent extract has been subjected to detailed chromatographic separation. The most potent chromatographic fraction exhibits the presence of flavonoidal unit. Structural elucidation of bioactive principle is in progress. It is inferred that the plant T. occidentalis (leaves) possess significant potential for phytopreventive bioefficacy against DMBA-induced mammary carcinogenesis. PMID- 20200196 TI - Full recovery from a potentially lethal dose of orphenadrine ingestion using conservative treatment: a case report. AB - Intoxication by orphenadrine is uncommon. The clinical features consist of both central and peripheral anticholinergic effects. Ingestion of 2 to 3 g orphenadrine in an adult has been associated with fatality. A 46-year-old female was brought to our emergency department 1.5 hours after ingesting 40 tablets of 100 mg orphenadrine. She became stuporous 3 hours post-ingestion and developed generalized convulsions 1 hour later. Fifty-five hours post-ingestion, she had recovered and was found to have anterior shoulder dislocation. In addition, severe rhabdomyolysis and persistent nausea were observed. All of the above-noted toxic effects resolved with conservative treatment. Although orphenadrine intoxication can cause convulsions and hemodynamic instability, there is no available antidote and treatment remains supportive. PMID- 20200197 TI - Rapid benefits of a new formulation of subcutaneous interferon beta-1a in relapsing-remitting multiple sclerosis. AB - This study evaluated the efficacy of a new formulation of subcutaneous (sc) interferon (IFN)-beta1a in relapsing-remitting multiple sclerosis (RRMS). Patients (n = 180) were randomized (2 : 1) to IFN-beta1a or placebo for 16 weeks; all patients then received IFN-beta1a for 24 weeks. Monthly brain MRI was performed. At week 16, the mean number of combined unique active (CUA) lesions was lower with IFN-beta1a than with placebo (p < 0.001; 69% fewer lesions). The mean cumulative number of CUA lesions was already lower with IFN-beta1a by week 4 (post hoc analysis; p = 0.015). The new formulation of sc IFN-beta1a has rapid beneficial effects on MRI outcomes in RRMS. PMID- 20200199 TI - Combining longitudinal discriminant analysis and partial area under the ROC curve to predict non-response to treatment for hepatitis C virus. AB - A longitudinal discriminant analysis is applied to build predictive models based on repeated measurements of serum hepatitis C virus RNA. These models are evaluated through the partial area under the receiver operating curve index (PA index) and, the final selection of the best model is based on cross-validated estimates of the PA index. Models are compared by building 95% bootstrap confidence interval for the difference in PA index between two models. Data from a randomised trial, in which chronic HCV patients were enrolled, are used to illustrate the application of the proposed method to predict treatment outcome. PMID- 20200200 TI - The role of endothelial cells and their progenitors in intimal hyperplasia. AB - Intimal hyperplasia leading to restenosis is the major process that limits the success of cardiovascular intervention. The emergence of vascular progenitor cells and, in particular, endothelial progenitor cells has led to great interest in their potential therapeutic value in preventing intimal hyperplasia. We review the mechanism of intimal hyperplasia and highlight the important attenuating role played by a functional endothelium. The role of endothelial progenitor cells in maintaining endothelial function is reviewed and we describe how reduced progenitor cell number and function and reduced endothelial function lead to an increased risk of intimal hyperplasia. We review other potential sources of endothelial cells, including monocytes, mesenchymal stem cells and tissue resident stem cells. Endothelial progenitor cells have been used in clinical trials to reduce the risk of restenosis with varied success. Progenitor cells have huge therapeutic potential to prevent intimal hyperplasia but a more detailed understanding of vascular progenitor cell biology is necessary before further clinical trials are commenced. PMID- 20200201 TI - Beta-blockers and risk of all-cause mortality in non-cardiac surgery. AB - Myocardial ischemia is a frequent complication in patients undergoing non-cardiac surgery and beta-blockers may exert a protective effect. The main benefit of beta blockers in perioperative cardiovascular morbidity and mortality is believed to be linked to specific effects on myocardial oxygen supply and demand. beta blockers may exert anti-inflammatory and anti-arrhythmic effects. Randomized clinical trials which evaluated the effects of beta-blockers on all-cause mortality in patients undergoing non-cardiac surgery have yielded conflicting results. In 9 trials, 10,544 patients with non-cardiac surgery were randomized to beta-blockers (n = 5274) or placebo (n = 5270) and there were a total of 304 deaths. Patients randomized to beta-blockers group showed a 19% increased risk of all-cause mortality (odds ratio [OR] 1.19, 95% confidence interval (CI) 0.95 1.50; p = 0.135). However, trials included in the meta-analysis differed in several aspects, and a significant degree of heterogeneity (I( 2) = 46.5%) was noted. A recent analysis showed that the surgical risk category had a substantial influence on the overall estimate of the effect of beta-blockers. Compared with patients in the intermediate-high-surgical-risk category, those in the high-risk category showed a 73% reduction in the risk of total mortality with beta-blockers compared with placebo (OR 0.27, 95% CI 0.10-0.71, p = 0.016). These data suggest that perioperative beta-blockers confer a benefit which is mostly limited to patients undergoing high-risk surgery. PMID- 20200198 TI - Boosting endogenous neuroprotection in multiple sclerosis: the ASsociation of Inosine and Interferon beta in relapsing- remitting Multiple Sclerosis (ASIIMS) trial. AB - Anti-inflammatory drugs are effective on relapses, but neuroprotective agents to prevent disability are still unavailable. Uric acid has neuroprotective effects in experimental models including encephalomyelitis and appears to be involved in multiple sclerosis. Oral administration of inosine, a precursor of uric acid, increases serum uric acid levels and is well tolerated. Our objective was to test the possibility that a combination therapy associating an anti-inflammatory drug (interferon beta) and an endogenous neuroprotective molecule (uric acid) would be more effective than interferon beta alone on the accumulation of disability. Patients with relapsing-remitting multiple sclerosis on interferon beta for at least 6 months were randomized to interferon beta + inosine or interferon beta + placebo for 2 years. The dose of inosine was adjusted to maintain serum uric acid levels in the range of asymptomatic hyperuricaemia (> hamsters > monkeys >>> humans. The rate of glucuronidation by rat hepatic microsomes was 90-fold greater than that of human hepatic microsomes. Human intestinal microsomes converted BMP to BMP glucuronide at a rate even lower than that of human hepatic microsomes. Among the human UGT enzymes tested, only UGT2B7 had detectable glucuronidation activity for BMP. BMP monoglucuronide was the only metabolite formed when BMP was incubated with suspensions of freshly isolated hepatocytes from male F-344 rats or with cryopreserved human hepatocytes. Glucuronidation of BMP in human hepatocytes was extremely low. Overall, the results support in vivo studies in rats in which BMP glucuronide was the only metabolite found. The poor glucuronidation capacity of humans for BMP suggests that the pharmacokinetic profile of BMP in humans will be dramatically different from that of rodents. PMID- 20200233 TI - Sequential metabolism of secondary alkyl amines to metabolic-intermediate complexes: opposing roles for the secondary hydroxylamine and primary amine metabolites of desipramine, (s)-fluoxetine, and N-desmethyldiltiazem. AB - Three secondary amines desipramine (DES), (S)-fluoxetine [(S)-FLX], and N desmethyldiltiazem (MA) undergo N-hydroxylation to the corresponding secondary hydroxylamines [N-hydroxydesipramine, (S)-N-hydroxyfluoxetine, and N-hydroxy-N desmethyldiltiazem] by cytochromes P450 2C11, 2C19, and 3A4, respectively. The expected primary amine products, N-desmethyldesipramine, (S)-norfluoxetine, and N,N-didesmethyldiltiazem, are also observed. The formation of metabolic intermediate (MI) complexes from these substrates and metabolites was examined. In each example, the initial rates of MI complex accumulation followed the order secondary hydroxylamine > secondary amine >> primary amine, suggesting that the primary amine metabolites do not contribute to formation of MI complexes from these secondary amines. Furthermore, the primary amine metabolites, which accumulate in incubations of the secondary amines, inhibit MI complex formation. Mass balance studies provided estimates of the product ratios of N-dealkylation to N-hydroxylation. The ratios were 2.9 (DES-CYP2C11), 3.6 [(S)-FLX-CYP2C19], and 0.8 (MA-CYP3A4), indicating that secondary hydroxylamines are significant metabolites of the P450-mediated metabolism of secondary alkyl amines. Parallel studies with N-methyl-d(3)-desipramine and CYP2C11 demonstrated significant isotopically sensitive switching from N-demethylation to N-hydroxylation. These findings demonstrate that the major pathway to MI complex formation from these secondary amines arises from N-hydroxylation rather than N-dealkylation and that the primary amines are significant competitive inhibitors of MI complex formation. PMID- 20200234 TI - A role for the C terminus of Mopeia virus nucleoprotein in its incorporation into Z protein-induced virus-like particles. AB - Arenaviruses are enveloped, negative-strand RNA viruses. For several arenaviruses, virus-like particle (VLP) formation requires the viral matrix Z protein. However, the mechanism by which viral ribonucleoprotein complexes are incorporated into virions is poorly understood. Here, we show that the expression of the Z protein and nucleoprotein (NP) of Mopeia virus, a close relative of the pathogenic Lassa virus, resulted in the highly selective incorporation of the NP protein into Z protein-induced VLPs. Moreover, the Z protein promoted the association of NP with cellular membranes, suggesting that the association of NP, Z, and the cellular membranes may facilitate the efficient incorporation of NP into VLPs. By employing a series of NP deletion constructs and testing their VLP incorporation, we further demonstrated an important role for the C-terminal half of NP in its incorporation into VLPs. PMID- 20200235 TI - Analysis of apoptosis of memory T cells and dendritic cells during the early stages of viral infection or exposure to toll-like receptor agonists. AB - Profound type I interferon (IFN-I)-dependent attrition of memory CD8 and CD4 T cells occurs early during many infections. It is dramatic at 2 to 4 days following lymphocytic choriomeningitis virus (LCMV) infection of mice and can be elicited by the IFN-inducing Toll receptor agonist poly(I:C). We show that this attrition occurs in many organs, indicating that it is due to T cell loss rather than redistribution. This loss correlated with elevated intracellular staining of T cells ex vivo for activated caspases but with only low levels of ex vivo staining with annexin V, probably due to the rapid clearance of apoptotic cells in vivo. Instead, a high frequency of annexin V-reactive CD8alpha(+) dendritic cells (DCs), which are known to be highly phagocytic, accumulated in the spleen as the memory T cell populations disappeared. After short in vitro incubation, memory phenotype T cells isolated from LCMV-infected mice (day 3) or mice treated with poly(I:C) (12 h) displayed substantial DNA fragmentation, as detected by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assay, compared to T cells isolated from uninfected mice, indicating a role for apoptosis in the memory T cell attrition. This apoptosis of memory CD8 T cells early during LCMV infection was reduced in mice lacking the proapoptotic molecule Bim. Evidence is presented showing that high levels of T cell attrition, as found in young mice, correlate with reduced immunodomination by cross-reactive memory cells. PMID- 20200236 TI - Innate immune responses and permissiveness to ranavirus infection of peritoneal leukocytes in the frog Xenopus laevis. AB - Ranaviruses such as frog virus 3 ([FV3] family Iridoviridae) are increasingly prevalent pathogens that infect reptiles, amphibians, and fish worldwide. Whereas studies in the frog Xenopus laevis have revealed the critical involvement of CD8 T-cell and antibody responses in host resistance to FV3, little is known about the role played by innate immunity to infection with this virus. We have investigated the occurrence, composition, activation status, and permissiveness to infection of peritoneal leukocytes (PLs) in Xenopus adults during FV3 infection by microscopy, flow cytometry, and reverse transcription-PCR. The total number of PLs and the relative fraction of activated mononucleated macrophage like cells significantly increase as early as 1 day postinfection (dpi), followed by NK cells at 3 dpi, before the peak of the T-cell response at 6 dpi. FV3 infection also induces a rapid upregulation of proinflammatory genes including arginase 1, interleukin-1beta, and tumor necrosis factor alpha. Although PLs are susceptible to FV3 infection, as evidenced by apoptotic cells, active FV3 transcription, and the detection of viral particles by electron microscopy, the infection is weaker (fewer infectious particles), more transitory, and involves a smaller fraction (less than 1%) of PLs than the kidney, the main site of infection. However, viral DNA remains detectable in PLs for at least 3 weeks postinfection, past the point of viral clearance observed in the kidneys. This suggests that although PLs are actively involved in anti-FV3 immune responses, some of these cells can be permissive and harbor quiescent, asymptomatic FV3. PMID- 20200237 TI - Syncytial phenotype of C-terminally truncated herpes simplex virus type 1 gB is associated with diminished membrane interactions. AB - The cytoplasmic domain of glycoprotein B (gB) from herpes simplex virus type 1 (HSV-1) is an important regulator of membrane fusion. C-terminal truncations of the cytoplasmic domain lead to either hyperfusion or fusion-null phenotypes. Currently, neither the structure of the cytoplasmic domain nor its mechanism of fusion regulation is known. Here we show, for the first time, that the full length cytoplasmic domain of HSV-1 gB associates stably with lipid membranes, preferentially binding to membranes containing anionic head groups. This interaction involves a large increase in helical content. However, the truncated cytoplasmic domains associated with the hyperfusion phenotype show a small increase in helical structure and a diminished association with lipid membranes, whereas the one associated with the fusion-null phenotype shows no increase in helical structure and only a minimal association with lipid membranes. We hypothesize that stable binding to lipid membranes is an important part of the mechanism by which the cytoplasmic domain negatively regulates membrane fusion. Moreover, our experiments with truncated cytoplasmic domains point to two specific regions that are critical for membrane interactions. Taken together, our work provides several important new insights into the architecture of the cytoplasmic domain of HSV-1 gB and its interaction with lipid membranes. PMID- 20200238 TI - Gene expression profiling indicates the roles of host oxidative stress, apoptosis, lipid metabolism, and intracellular transport genes in the replication of hepatitis C virus. AB - Hepatitis C virus (HCV) is a leading cause of chronic liver disease. The identification and characterization of key host cellular factors that play a role in the HCV replication cycle are important for the understanding of disease pathogenesis and the identification of novel antiviral therapeutic targets. Gene expression profiling of JFH-1-infected Huh7 cells by microarray analysis was performed to identify host cellular genes that are transcriptionally regulated by infection. The expression of host genes involved in cellular defense mechanisms (apoptosis, proliferation, and antioxidant responses), cellular metabolism (lipid and protein metabolism), and intracellular transport (vesicle trafficking and cytoskeleton regulation) was significantly altered by HCV infection. The gene expression patterns identified provide insight into the potential mechanisms that contribute to HCV-associated pathogenesis. These include an increase in proinflammatory and proapoptotic signaling and a decrease in the antioxidant response pathways of the infected cell. To investigate whether any of the host genes regulated by infection were required by HCV during replication, small interfering RNA (siRNA) silencing of host gene expression in HCV-infected cells was performed. Decreasing the expression of host genes involved in lipid metabolism (TXNIP and CYP1A1 genes) and intracellular transport (RAB33b and ABLIM3 genes) reduced the replication and secretion of HCV, indicating that they may be important factors for the virus replication cycle. These results show that major changes in the expression of many different genes in target cells may be crucial in determining the outcome of HCV infection. PMID- 20200240 TI - Monocytes regulate T cell migration through the glia limitans during acute viral encephalitis. AB - Leukocyte access into the central nervous system (CNS) parenchyma is tightly regulated by the blood-brain barrier (BBB). Leukocyte migration through the endothelial cell wall into the perivascular space is well characterized; however, mechanisms regulating their penetration through the glia limitans into the parenchyma are less well studied, and the role of monocytes relative to neutrophils is poorly defined. Acute viral encephalitis was thus induced in CCL2 deficient (CCL2(-/-)) mice to specifically abrogate monocyte recruitment. Impaired monocyte recruitment prolonged T cell retention in the perivascular space, although no difference in overall CNS accumulation of CD4 or CD8 T cells was detected by flow cytometry. Delayed penetration to the CNS parenchyma was not associated with reduced or altered expression of either matrix metalloproteinases (MMP) or the T cell chemoattractants CXCL10 and CCL5. Nevertheless, decreased parenchymal leukocyte infiltration delayed T cell-mediated control of virus replication as well as clinical disease. These data are the first to demonstrate that the rapid monocyte recruitment into the CNS during viral encephalitis is dispensable for T cell migration across the blood vessel endothelium. However, monocytes facilitate penetration through the glia limitans. Thus, the rapid monocyte response to viral encephalitis constitutes an indirect antiviral pathway by aiding access of effector T cells to the site of viral infection. PMID- 20200241 TI - Investigation of the species origin of the St. Jude Porcine Lung epithelial cell line (SJPL) made available to researchers. PMID- 20200242 TI - Human cytomegalovirus IE2 86 and IE2 40 proteins differentially regulate UL84 protein expression posttranscriptionally in the absence of other viral gene products. AB - It has previously been demonstrated that, during human cytomegalovirus infection, the viral IE2 86 and IE2 40 proteins are both important for the expression of an early-late viral protein, UL84. Here, we show that expression of the UL84 protein is enhanced upon cotransfection with either IE2 86 or IE2 40, although IE2 40 appears to play a more important role. The UL84 protein levels are tightly linked to the amount of IE2 40 present, but this does not appear to be true for IE2 86. RNA remains constant for all corresponding proteins, indicating posttranscriptional regulation of UL84. The first 105 amino acids of UL84 are necessary and sufficient for this phenotype, and this region is also required for an interaction with IE2 86 and IE2 40. Treatment with proteasome inhibitors shows that UL84 exhibits some proteasome-dependent degradation, and UL84 is not protected against this degradation when coexpressed with IE2 86 or IE2 40. UL84 also exhibits an inhibitory effect on IE2 86 and IE2 40 protein levels in these cotransfection assays. Further, we show that the amino acid sequence of UL84 is important for the enhancement governed by IE2 40. These results indicate that IE2 86, IE2 40, and UL84 serve to regulate protein expression in a posttranscriptional fashion and that this regulation is independent of other viral proteins. PMID- 20200239 TI - Acceleration of hepatitis C virus envelope evolution in humans is consistent with progressive humoral immune selection during the transition from acute to chronic infection. AB - During the transition from acute to chronic infection in individuals persistently infected with hepatitis C virus (HCV), cellular responses initiate within the first 6 months of primary infection and collapse thereafter, whereas humoral responses activate later during the chronic phase. Whether and how this deviation of immune responses specifically influences HCV evolution are unknown. To determine the pattern of HCV evolution during this critical period, we conducted extensive sequence analysis on annual clonal hemigenomic sequences for up to 3 years in six well-characterized subjects, using statistical methods that accounted for repeated measures. Significantly different evolutionary rates were observed in envelope versus nonenvelope genes, with an increasing rate of nonsynonymous change (dN) in envelope genes and a stable dN in nonenvelope genes (P = 0.006). The ratio of the envelope to nonenvelope nonsynonymous rate increased from 2 in year 1 to 5 in years 2 and 3. Centripetal changes (reversions toward matching of the worldwide subtype 1a consensus sequence) were frequently observed during the 3-year transition from acute infection to chronicity, even in the presence of neutralizing antibody (NAb) pressure. Remarkably, sequences of hypervariable region 1 (HVR1) remained stable for up to 21 months in the absence of NAb pressure in one subject, followed by rapid changes that were temporally associated with the detection of NAb responses, which strongly suggests that HVR1 evolution is shaped by NAb pressure. These data provide the first systematic estimates of HCV evolutionary rates in multiple genes during early infection in vivo and provide additional evidence for deterministic, rather than random, evolution of HCV. PMID- 20200243 TI - Binding site on the transferrin receptor for the parvovirus capsid and effects of altered affinity on cell uptake and infection. AB - Canine parvovirus (CPV) and its relative feline panleukopenia virus (FPV) bind the transferrin receptor type 1 (TfR) to infect their host cells but show differences in the interactions with the feline and canine TfRs that determine viral host range and tissue tropism. We changed apical and protease-like domain residues by introducing point mutations and adding or removing glycosylation signals, and we then examined the interactions of those mutant TfRs with the capsids. Most substitutions had little effect on virus binding and uptake. However, mutations of several sites in the apical domain of the receptor either prevented binding to the capsids or reduced the affinity of receptor binding to various degrees. Glycans within the virus binding face of the apical domain also controlled capsid binding. CPV, but not the related feline parvovirus, could use receptors containing a canine TfR-specific glycosylation to mediate efficient infection, while addition of other N-linked glycosylation sites into the virus binding face of the feline apical domain reduced or eliminated both binding and infection. Replacement of critical feline TfR residue 221 with every amino acid had effects on binding and infection which were significantly associated with the biochemical properties of the residue replaced. Receptors with reduced affinities mostly showed proportional changes in their ability to mediate infection. Testing feline TfR variants for their binding and uptake patterns in cells showed that low-affinity versions bound fewer capsids and also differed in attachment to the cell surface and filopodia, but transport to the perinuclear endosome was similar. PMID- 20200244 TI - Measles virus-induced immunosuppression in SLAM knock-in mice. AB - Measles virus (MV) causes transient severe immunosuppression in patients, which may lead to secondary viral and bacterial infections, largely accounting for measles-related morbidity and mortality. MV is known to infect immune cells by using the human signaling lymphocyte activation molecule (SLAM; also called CD150) as a cellular receptor, but the mechanism by which MV causes immunosuppression is not well understood. We show that MV infection of SLAM knock in mice, in which the V domain of mouse SLAM was replaced by the V domain of human SLAM, crossed with alpha/beta-interferon receptor knockout mice, reproduced many immunological alterations observed in human patients. These included lymphopenia, inhibition of T-cell proliferation and antibody production, increased production of the Th2 cytokine interleukin-4 (IL-4) and the immunosuppressive cytokine IL-10, and suppression of contact hypersensitivity. Gross redistribution of lymphocytes among lymphoid tissues was not apparent in infected mice, nor was an increase of regulatory T cells. The numbers of lymphocytes in lymph nodes remained almost unchanged after MV infection, despite enhanced apoptosis, suggesting that lymph nodes were replenished with lymphocytes from the peripheral blood, which may have contributed to the observed lymphopenia in the spleen. Blocking of IL-10 by use of an anti-IL-10 receptor antibody ameliorated suppression of contact hypersensitivity in infected mice. These results indicate that SLAM knock-in mice lacking the expression of the alpha/beta interferon receptor serve as a useful small animal model with which to elucidate MV-induced immunosuppression. PMID- 20200245 TI - The de novo methyltransferases DNMT3a and DNMT3b target the murine gammaherpesvirus immediate-early gene 50 promoter during establishment of latency. AB - The role of epigenetic modifications in the regulation of gammaherpesvirus latency has been a subject of active study for more than 20 years. DNA methylation, associated with transcriptional silencing in mammalian genomes, has been shown to be an important mechanism in the transcriptional control of several key gammaherpesvirus genes. In particular, DNA methylation of the functionally conserved immediate-early replication and transcription activator (RTA) has been shown to regulate Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus Rta expression. Here we demonstrate that the murine gammaherpesvirus (MHV68) homolog, encoded by gene 50, is also subject to direct repression by DNA methylation, both in vitro and in vivo. We observed that the treatment of latently MHV68-infected B-cell lines with a methyltransferase inhibitor induced virus reactivation. In addition, we show that the methylation of the recently characterized distal gene 50 promoter represses activity in a murine macrophage cell line. To evaluate the role of de novo methyltransferases (DNMTs) in the establishment of these methylation marks, we infected mice in which conditional DNMT3a and DNMT3b alleles were selectively deleted in B lymphocytes. DNMT3a/DNMT3b-deficient B cells were phenotypically normal, displaying no obvious compromise in cell surface marker expression or antibody production either in naive mice or in the context of nonviral and viral immunogens. However, mice lacking functional DNMT3a and DNMT3b in B cells exhibited hallmarks of deregulated MHV68 lytic replication, including increased splenomegaly and the presence of infectious virus in the spleen at day 18 following infection. In addition, total gene 50 transcript levels were elevated in the spleens of these mice at day 18, which correlated with the hypomethylation of the distal gene 50 promoter. However, by day 42 postinfection, aberrant virus replication was resolved, and we observed wild-type frequencies of viral genome-positive splenocytes in mice lacking functional DNMT3a and DNMT3b in B lymphocytes. The latter correlated with increased CpG methylation in the distal gene 50 promoter, which was restored to levels similar to those of littermate controls harboring functional DNMT3a and DNMT3b alleles in B lymphocytes, suggesting the existence of an alternative mechanism for the de novo methylation of the MHV68 genome. Importantly, this DNMT3a/DNMT3b-independent methylation appeared to be targeted specifically to the gene 50 promoter, as we observed that the promoters for MHV68 gene 72 (v-cyclin) and M11 (v-bcl2) remained hypomethylated at day 42 postinfection. Taken together, these data provide the first evidence of the importance of DNA methylation in regulating gammaherpesvirus RTA/gene 50 transcription during virus infection in vivo and provide insight into the hierarchy of host machinery required to establish this modification. PMID- 20200246 TI - The first complete papillomavirus genome characterized from a marsupial host: a novel isolate from Bettongia penicillata. AB - The first fully sequenced papillomavirus (PV) of marsupials, tentatively named Bettongia penicillata papillomavirus type 1 (BpPV1), was detected in papillomas from a woylie (Bettongia penicillata ogilbyi). The circular, double-stranded DNA genome contains 7,737 bp and encodes 7 open reading frames (ORFs), E6, E7, E1, E2, E4, L2, and L1, in typical PV conformation. BpPV1 is a close-to-root PV with L1 and L2 ORFs most similar to European hedgehog PV and bandicoot papillomatosis carcinomatosis virus types 1 and 2 (BPCV1 and -2). It appears that the BPCVs arose by recombination between an ancient PV and an ancient polyomavirus more than 10 million years ago. PMID- 20200248 TI - Influenza H1N1 A/Solomon Island/3/06 virus receptor binding specificity correlates with virus pathogenicity, antigenicity, and immunogenicity in ferrets. AB - Influenza viruses attach to cells via a sialic acid moiety (sialic acid receptor) that is alpha2-3 linked or alpha2-6 linked to galactose (alpha2-3SAL or alpha2 6SAL); sialic acid acts as a receptor for the virus. Using lectin staining, we demonstrated that the alpha2-6SAL configuration is predominant in the respiratory tract of ferrets, including trachea, bronchus, and lung alveolus tissues. Recombinant wild-type (rWT) influenza A/Solomon Island/3/06 (SI06) (H1N1) viruses were constructed to assess the impact of the hemagglutinin (HA) variations (amino acids 190 or 226) identified in natural variants on virus replication in the upper and lower respiratory tract of ferrets, as well as virus antigenicity and immunogenicity. A single amino acid change at residue 226 (from Gln to Arg) in the HA of SI06 resulted in the complete loss of binding to alpha2-6SAL and a concomitant loss of the virus's ability to replicate in the lower respiratory tract of ferrets. In contrast, the virus with Gln226 in the HA protein has a receptor binding preference for alpha2-6SAL and replicates efficiently in the lungs. There was a good correlation between viral replication in the lungs of ferrets and disease symptoms. In addition, we also showed that the 190 and 226 residues affected viral antigenicity and immunogenicity. Our data emphasize the necessity of thoroughly assessing wild-type influenza viruses for their suitability as reference strains and for carefully selecting the HA antigen for vaccine production during annual influenza vaccine evaluation processes. PMID- 20200247 TI - Novel infectious cDNA clones of hepatitis C virus genotype 3a (strain S52) and 4a (strain ED43): genetic analyses and in vivo pathogenesis studies. AB - Previously, RNA transcripts of cDNA clones of hepatitis C virus (HCV) genotypes 1a (strains H77, HCV-1, and HC-TN), 1b (HC-J4, Con1, and HCV-N), and 2a (HC-J6 and JFH1) were found to be infectious in chimpanzees. However, only JFH1 was infectious in human hepatoma Huh7 cells. We performed genetic analysis of HCV genotype 3a (strain S52) and 4a (strain ED43) prototype strains and generated full-length consensus cDNA clones (pS52 and pED43). Transfection of Huh7.5 cells with RNA transcripts of these clones did not yield cells expressing HCV Core. However, intrahepatic transfection of chimpanzees resulted in robust infection with peak HCV RNA titers of approximately 5.5 log(10) international units (IU)/ml. Genomic consensus sequences recovered from serum at the times of peak viral titers were identical to the sequences of the parental plasmids. Both chimpanzees developed acute hepatitis with elevated liver enzymes and significant necroinflammatory liver changes coinciding with detection of gamma interferon secreting, intrahepatic T cells. However, the onset and broadness of intrahepatic T-cell responses varied greatly in the two animals, with an early (week 4) multispecific response in the ED43-infected animal (3 weeks before the first evidence of viral control) and a late (week 11) response with limited breadth in the S52-infected animal (without evidence of viral control). Autologous serum neutralizing antibodies were not detected during the acute infection in either animal. Both animals became persistently infected. In conclusion, we generated fully functional infectious cDNA clones of HCV genotypes 3a and 4a. Proof of functionality of all genes might further the development of recombinant cell culture systems for these important genotypes. PMID- 20200249 TI - Regulation of Epstein-Barr virus origin of plasmid replication (OriP) by the S phase checkpoint kinase Chk2. AB - The Epstein-Barr virus (EBV) origin of plasmid replication (OriP) is required for episome stability during latent infection. Telomere repeat factor 2 (TRF2) binds directly to OriP and facilitates DNA replication and plasmid maintenance. Recent studies have found that TRF2 interacts with the DNA damage checkpoint protein Chk2. We show here that Chk2 plays an important role in regulating OriP plasmid stability, chromatin modifications, and replication timing. The depletion of Chk2 by small interfering RNA (siRNA) leads to a reduction in DNA replication efficiency and a loss of OriP-dependent plasmid maintenance. This corresponds to a change in OriP replication timing and an increase in constitutive histone H3 acetylation. We show that Chk2 interacts with TRF2 in the early G(1)/S phase of the cell cycle. We also show that Chk2 can phosphorylate TRF2 in vitro at a consensus acceptor site in the amino-terminal basic domain of TRF2. TRF2 mutants with a serine-to-aspartic acid phosphomimetic substitution mutation were reduced in their ability to recruit the origin recognition complex (ORC) and stimulate OriP replication. We suggest that the Chk2 phosphorylation of TRF2 is important for coordinating ORC binding with chromatin remodeling during the early S phase and that a failure to execute these events leads to replication defects and plasmid instability. PMID- 20200250 TI - Phenotypic and functional profile of HIV-inhibitory CD8 T cells elicited by natural infection and heterologous prime/boost vaccination. AB - Control of HIV-1 replication following nonsterilizing HIV-1 vaccination could be achieved by vaccine-elicited CD8(+) T-cell-mediated antiviral activity. To date, neither the functional nor the phenotypic profiles of CD8(+) T cells capable of this activity are clearly understood; consequently, little is known regarding the ability of vaccine strategies to elicit them. We used multiparameter flow cytometry and viable cell sorts from phenotypically defined CD8(+) T-cell subsets in combination with a highly standardized virus inhibition assay to evaluate CD8(+) T-cell-mediated inhibition of viral replication. Here we show that vaccination against HIV-1 Env and Gag-Pol by DNA priming followed by recombinant adenovirus type 5 (rAd5) boosting elicited CD8(+) T-cell-mediated antiviral activity against several viruses with either lab-adapted or transmitted virus envelopes. As it did for chronically infected virus controllers, this activity correlated with HIV-1-specific CD107a or macrophage inflammatory protein 1beta (MIP-1beta) expression from HIV-1-specific T cells. Moreover, for vaccinees or virus controllers, purified memory CD8(+) T cells from a wide range of differentiation stages were capable of significantly inhibiting virus replication. Our data define attributes of an antiviral CD8(+) T-cell response that may be optimized in the search for an efficacious HIV-1 vaccine. PMID- 20200251 TI - Delivery of cytokines by recombinant virus in early life alters the immune response to adult lung infection. AB - Respiratory syncytial virus (RSV) is the main cause of bronchiolitis, the major cause of hospitalization of infants. An ideal RSV vaccine would be effective for neonates, but the immune responses of infants differ markedly from those of adults, often showing a bias toward T-helper 2 (Th2) responses and reduced gamma interferon (IFN-gamma) production. We previously developed recombinant RSV vectors expressing IFN-gamma and interleukin-4 (IL-4) that allow us to explore the role of these key Th1 and Th2 cytokines during infection. The aim of the current study was to explore whether an immunomodulation of infant responses could enhance protection. The expression of IFN-gamma by a recombinant RSV vector (RSV/IFN-gamma) attenuated primary viral replication in newborn mice without affecting the development of specific antibody or T-cell responses. Upon challenge, RSV/IFN-gamma mice were protected from the exacerbated disease observed for mice primed with wild-type RSV; however, antiviral immunity was not enhanced. Conversely, the expression of IL-4 by recombinant RSV did not affect virus replication in neonates but greatly enhanced Th2 immune responses upon challenge without affecting weight loss. These studies demonstrate that it is possible to manipulate infant immune responses by using cytokine-expressing recombinant viruses and that neonatal deficiency in IFN-gamma responses may lead to enhanced disease during secondary infection. PMID- 20200252 TI - A detrimental effect of interleukin-10 on protective pulmonary humoral immunity during primary influenza A virus infection. AB - Interleukin-10 (IL-10) is an important anti-inflammatory molecule that can cause immunosuppression and long-term pathogen persistence during chronic infection of mice with viruses such as lymphocytic choriomeningitis virus. However, its specific role in immunity to acute viral infections is not fully understood. We found that IL-10 plays a detrimental role in host responses to acute influenza A virus since IL-10(-/-) mice had improved viral clearance and survival after infection compared to wild-type mice. Enhanced viral clearance in IL-10(-/-) mice was not correlated with increased CD4(+) or CD8(+) T-cell recruitment into the lung but was correlated with increased pulmonary anti-influenza virus antibody titers, and this was dependent upon the presence of T cells, primarily CD4(+) T cells. In addition, virus-specific antibody produced during the early stages of infection in the respiratory tract of IL-10(-/-) but not wild-type mice was sufficient to mediate passive protection against viral challenge of naive mice. Complement was necessary for this antibody-mediated passive protection, but FcgammaR or neutrophil deficiency did not significantly influence viral clearance. Our results show that an absence of IL-10 at the time of primary infection leads to enhanced local virus-specific antibody production and, thus, increased protection against influenza A virus infection. PMID- 20200253 TI - ORF157 from the archaeal virus Acidianus filamentous virus 1 defines a new class of nuclease. AB - Acidianus filamentous virus 1 (AFV1) (Lipothrixviridae) is an enveloped filamentous virus that was characterized from a crenarchaeal host. It infects Acidianus species that thrive in the acidic hot springs (>85 degrees C and pH <3) of Yellowstone National Park, WY. The AFV1 20.8-kb, linear, double-stranded DNA genome encodes 40 putative open reading frames whose sequences generally show little similarity to other genes in the sequence databases. Because three dimensional structures are more conserved than sequences and hence are more effective at revealing function, we set out to determine protein structures from putative AFV1 open reading frames (ORF). The crystal structure of ORF157 reveals an alpha+beta protein with a novel fold that remotely resembles the nucleotidyltransferase topology. In vitro, AFV1-157 displays a nuclease activity on linear double-stranded DNA. Alanine substitution mutations demonstrated that E86 is essential to catalysis. AFV1-157 represents a novel class of nuclease, but its exact role in vivo remains to be determined. PMID- 20200255 TI - Do you need a supplement of docosahexaenoic acid or an n-3 long-chain polyunsaturated fatty acid? PMID- 20200254 TI - Zinc bioavailability and homeostasis. AB - Zinc has earned recognition recently as a micronutrient of outstanding and diverse biological, clinical, and global public health importance. Regulation of absorption by zinc transporters in the enterocyte, together with saturation kinetics of the absorption process into and across the enterocyte, are the principal means by which whole-body zinc homeostasis is maintained. Several physiologic factors, most notably the quantity of zinc ingested, determine the quantity of zinc absorbed and the efficiency of absorption. Other factors are age and the time over which zinc is ingested. Zinc from supplements has not been shown to be absorbed differently from that taken with meals that lack inhibitors of zinc absorption. The principal dietary factor known to impair zinc bioavailability is inositol hexa- (and penta-) phosphate or phytate. Modeling of zinc absorption as a function of dietary zinc and phytate accounts for >80% of the variability in the quantity of zinc absorbed. Fitting the model to new data has resulted in continual improvement in parameter estimates, which currently indicate a maximal absorption in adults of approximately 6 mg Zn/d and that the average estimated dietary requirement doubles with 1000 mg dietary phytate/d. Intestinal excretion of endogenous zinc is regulated in response to recent absorption and to zinc status. The quantitative relation of intestinal excretion of endogenous zinc to zinc absorption is currently considered to be of major importance in the determination of zinc requirements. The effects of phytate on intestinal losses of endogenous zinc merit further investigation but are probably not of the same magnitude as its inhibitory effects on absorption of exogenous zinc. PMID- 20200256 TI - Orange juice neutralizes the proinflammatory effect of a high-fat, high carbohydrate meal and prevents endotoxin increase and Toll-like receptor expression. AB - BACKGROUND: The intake of glucose or a high-fat, high-carbohydrate (HFHC) meal, but not orange juice, induces an increase in inflammation and oxidative stress in circulating mononuclear cells (MNCs) of normal-weight subjects. OBJECTIVE: We investigated the effect of orange juice on HFHC meal-induced inflammation and oxidative stress and the expression of plasma endotoxin and Toll-like receptors (TLRs). DESIGN: Three groups (10 subjects in each group) of normal, healthy subjects were asked to drink water or 300 kcal glucose or orange juice in combination with a 900-kcal HFHC meal. Blood samples were obtained before and 1, 3, and 5 h after the drinks and meal combinations were consumed. RESULTS: Protein expression of the NADPH oxidase subunit p47(phox), phosphorylated and total p38 mitogen-activated protein kinase, and suppressor of cytokine signaling-3; TLR2 and TLR4 messenger RNA (mRNA) and protein expression; mRNA expression of matrix metalloproteinase (MMP)-9 in MNCs; and plasma concentrations of endotoxin and MMP 9 increased significantly after glucose or water were consumed with the meal but not when orange juice was consumed with the meal. The generation of reactive oxygen species by polymorphonuclear cells was significantly lower when orange juice was added to the meal than when water or glucose was added to the meal. CONCLUSIONS: The combination of glucose or water and the HFHC meal induced oxidative and inflammatory stress and an increase in TLR expression and plasma endotoxin concentrations. In contrast, orange juice intake with the HFHC meal prevented meal-induced oxidative and inflammatory stress, including the increase in endotoxin and TLR expression. These observations may help explain the mechanisms underlying postprandial oxidative stress and inflammation, pathogenesis of insulin resistance, and atherosclerosis. PMID- 20200257 TI - Effect of conjugated linoleic acid on body fat accretion in overweight or obese children. AB - BACKGROUND: Conjugated linoleic acid (CLA) is a supplemental dietary fatty acid that decreases fat mass accretion in young animals. OBJECTIVE: The aim of this study was to determine CLA's efficacy with regard to change in fat and body mass index (BMI; in kg/m(2)) in children. DESIGN: We conducted a 7 +/- 0.5-mo randomized, double-blind, placebo-controlled trial of CLA in 62 prepubertal children aged 6-10 y who were overweight or obese but otherwise healthy. The subjects were randomly assigned to receive 3 g/d of 80% CLA (50:50 cis-9,trans-11 and trans-10,cis-12 isomers) or placebo in chocolate milk. RESULTS: Fifty-three subjects completed the trial (n = 28 in the CLA group, n = 25 in the placebo group). CLA attenuated the increase in BMI (0.5 +/- 0.8) compared with placebo (1.1 +/- 1.1) (P = 0.05). The percentage change in body fat measured by dual energy X-ray absorptiometry was smaller (P = 0.001) in the CLA group (-0.5 +/- 2.1%) than in the placebo group (1.3 +/- 1.8%). The change in abdominal body fat as a percentage of total body weight was smaller (P = 0.02) in the CLA group ( 0.09 +/- 0.9%) than in the placebo group (0.43 +/- 0.6%). There were no significant changes in plasma glucose, insulin, or LDL cholesterol between groups. Plasma HDL cholesterol decreased significantly more (P = 0.05) in the CLA group (-5.1 +/- 7.3 mg/dL) than in the placebo group (-0.7 +/- 8 mg/dL). Bone mineral accretion was lower (P = 0.04) in the CLA group (0.05 +/- 0.03 kg) than in the placebo group (0.07 +/- 0.03 kg). Reported gastrointestinal symptoms did not differ significantly between groups. CONCLUSIONS: CLA supplementation for 7 +/- 0.5 mo decreased body fatness in 6-10-y-old children who were overweight or obese but did not improve plasma lipids or glucose and decreased HDL more than in the placebo group. Long-term investigation of the safety and efficacy of CLA supplementation in children is recommended. PMID- 20200258 TI - The effect of home-delivered Dietary Approach to Stop Hypertension (DASH) meals on the diets of older adults with cardiovascular disease. AB - BACKGROUND: Many older adults with hyperlipidemia or hypertension participate in the Older Americans Act Nutrition Program, which serves meals in community settings and delivers meals to homes. However, there is little information regarding whether therapeutic meals designed around Dietary Approach to Stop Hypertension (DASH) principles have a beneficial effect on the diets of these older adults. OBJECTIVE: The objective of this study was to determine the degree to which dietary change is influenced by providing 7 home-delivered therapeutic meals weekly to adults aged > or = 60 y. DESIGN: We conducted a 1-y randomized controlled trial in 298 persons with hyperlipidemia or hypertension, in which 50% of participants received 7 therapeutic meals per week for 12 mo. Those in need of dietary change at baseline (n = 210) were examined. Changes in intermediate DASH accordance, DASH accordance, and the nutrients that make up the DASH diet were measured by using 24-h food recalls at baseline, 6 mo, and 12 mo. Chi-square tests, t tests, and multiple regression were used to examine the association between receipt of meals and dietary change over time. RESULTS: Participants who received meals were 20% (P = 0.001) more likely to reach intermediate DASH accordance at 6 mo and were 18% (P = 0.007) more likely to meet saturated fat accordance at 12 mo than were those who did not receive meals. When stratified by race and income, gains were marginally larger for whites and higher-income individuals. CONCLUSION: Delivery of 7 DASH meals per week was found to increase compliance with dietary recommendations among noncompliant older adults with cardiovascular disease. PMID- 20200260 TI - Setting Dietary Reference Intakes with the use of bioavailability data: calcium. AB - The determination of Dietary Reference Intakes (DRIs) for calcium, especially in children, has relied in significant part on the evaluation of the relation between calcium intake and calcium absorption and retention. At present, most of these studies are conducted with the use of dual-tracer stable isotope, although mass balance or other isotope methods are still used occasionally. Studies carried out to evaluate DRI values need to be conducted under the most controlled conditions possible. However, the achievement of such conditions can be difficult, especially in studies in small children, because strict, long-term dietary monitoring and sample collections are not well tolerated. Other dietary factors, which include vitamin D status and the presence of enhancers and inhibitors of calcium absorption, may have to be considered. However, for most healthy populations who do not have very low calcium intakes or serum 25 hydroxyvitamin D concentrations, other dietary factors will not be major determinants of the net calcium absorption or retention that will be used for the establishment of DRI values. Ultimately, DRI values must be chosen based on an attempt to achieve some targeted value for calcium absorption/retention or to maximize, within constraints, the overall calcium absorbed and retained. In children, it is important to use data obtained at the age and pubertal status being evaluated rather than to interpolate from data performed in other age groups. PMID- 20200259 TI - Dietary glycemic index and load in relation to risk of uterine leiomyomata in the Black Women's Health Study. AB - BACKGROUND: High dietary glycemic index (GI) and glycemic load (GL) may promote tumorigenesis by increasing endogenous concentrations of insulin-like growth factor I (IGF-I) or the bioavailability of estradiol. In vitro studies have shown that uterine leiomyoma (UL) cells proliferate in response to IGF-I and display increased IGF-I gene expression and protein synthesis. Previous epidemiologic studies suggest that a high GL is a risk factor for endometrial and ovarian cancers, which, like UL, are hormone-responsive tumors. OBJECTIVE: We investigated the relation of dietary GI and GL with UL risk in the Black Women's Health Study. DESIGN: In this prospective cohort study, we followed 21,861 premenopausal women for incident UL from 1997 to 2007. Diet was assessed in 1995 and 2001 with food-frequency questionnaires. We used Cox regression to estimate incidence rate ratios (IRRs) and 95% CIs, controlled for potential confounders. RESULTS: During 162,604 person-years of follow-up, there were 5800 cases of UL diagnosed by ultrasound or surgery. Dietary GI was weakly associated with UL risk overall (IRR for highest compared with lowest quintile: 1.09; 95% CI: 0.99, 1.19; P for trend = 0.04). Positive associations were observed between GL and UL in women aged <35 y (IRR for highest compared with lowest quintile: 1.18; 95% CI: 1.02, 1.37; P for trend = 0.15) and between GI and UL in college-educated women (IRR for highest compared with lowest quintile: 1.17; 95% CI: 1.03, 1.34; P for trend = 0.004). CONCLUSIONS: Our results suggest that high dietary GI and GL may be associated with an increased UL risk in some women. The observed associations warrant investigation in future studies. PMID- 20200261 TI - Micronutrient bioavailability: Dietary Reference Intakes and a future perspective. AB - This article provides a review of how the challenge of bioavailability was approached in establishing the Dietary Reference Intakes, with a special focus on folic acid, vitamin B-12, beta-carotene, iron, selenium, and zinc, the targeted micronutrients for this workshop. In a future perspective, the necessity of having a clear working definition of bioavailability is emphasized. The bioavailability of micronutrients should be considered, with advantage, under subheadings determined by the broad factors that affect bioavailability. Special emphasis is given to giving greater and specific attention to factors involved in the maintenance of homeostasis. These factors, it is argued, are best considered separately from even a broad definition of bioavailability and have the potential to provide new insights into some micronutrient requirements. PMID- 20200262 TI - Bioconversion of dietary provitamin A carotenoids to vitamin A in humans. AB - Recent progress in the measurement of the bioconversion of dietary provitamin A carotenoids to vitamin A is reviewed in this article. Methods to assess the bioavailability and bioconversion of provitamin A carotenoids have advanced significantly in the past 10 y, specifically through the use of stable isotope methodology, which includes the use of labeled plant foods. The effects of the food matrix on the bioconversion of provitamin A carotenoids to vitamin A, dietary fat effects, and the effect of genotype on the absorption and metabolism of beta-carotene have been reported recently. A summary of the major human studies that determined conversion factors for dietary beta-carotene to retinol is presented here, and these data show that the conversion efficiency of dietary beta-carotene to retinol is in the range of 3.6-28:1 by weight. There is a wide variation in conversion factors reported not only between different studies but also between individuals in a particular study. These findings show that the vitamin A value of individual plant foods rich in provitamin A carotenoids may vary significantly and need further investigation. PMID- 20200264 TI - Selenium bioavailability: current knowledge and future research requirements. AB - Information on selenium bioavailability is required to derive dietary recommendations and to evaluate and improve the quality of food products. The need for robust data is particularly important in light of recent suggestions of potential health benefits associated with different intakes of selenium. The issue is not straightforward, however, because of large variations in the selenium content of foods (determined by a combination of geologic/environmental factors and selenium supplementation of fertilizers and animal feedstuffs) and the chemical forms of the element, which are absorbed and metabolized differently. Although most dietary selenium is absorbed efficiently, the retention of organic forms is higher than that of inorganic forms. There are also complications in the assessment and quantification of selenium species within foodstuffs. Often, extraction is only partial, and the process can alter the form or forms present in the food. Efforts to improve, standardize, and make more widely available techniques for species quantification are required. Similarly, reliable and sensitive functional biomarkers of selenium status are required, together with improvements in current biomarker methods. This requirement is particularly important for the assessment of bioavailability, because some functional biomarkers respond differently to the various selenium species. The effect of genotype adds a potential further dimension to the process of deriving bioavailability estimates and underlines the need for further research to facilitate the process of deriving dietary recommendations in the future. PMID- 20200263 TI - Iron bioavailability and dietary reference values. AB - Iron differs from other minerals because iron balance in the human body is regulated by absorption only because there is no physiologic mechanism for excretion. On the basis of intake data and isotope studies, iron bioavailability has been estimated to be in the range of 14-18% for mixed diets and 5-12% for vegetarian diets in subjects with no iron stores, and these values have been used to generate dietary reference values for all population groups. Dietary factors that influence iron absorption, such as phytate, polyphenols, calcium, ascorbic acid, and muscle tissue, have been shown repeatedly to influence iron absorption in single-meal isotope studies, whereas in multimeal studies with a varied diet and multiple inhibitors and enhancers, the effect of single components has been, as expected, more modest. The importance of fortification iron and food additives such as erythorbic acid on iron bioavailability from a mixed diet needs clarification. The influence of vitamin A, carotenoids, and nondigestible carbohydrates on iron absorption and the nature of the "meat factor" remain unresolved. The iron status of the individual and other host factors, such as obesity, play a key role in iron bioavailability, and iron status generally has a greater effect than diet composition. It would therefore be timely to develop a range of iron bioavailability factors based not only on diet composition but also on subject characteristics, such as iron status and prevalence of obesity. PMID- 20200265 TI - L-arginine supplementation improves exercise capacity after a heart transplant. AB - BACKGROUND: Endothelial dysfunction is associated with the decreased exercise capacity observed in heart-transplant (HTx) recipients. L-arginine supplementation (LAS) stimulates the nitric oxide (NO) pathway and restores endothelial function. OBJECTIVE: We compared exercise capacity in healthy subjects and HTx patients and investigated whether chronic LAS might improve exercise capacity and NO/endothelin balance after an HTx. DESIGN: Clinical, echocardiographic, and exercise characteristics were measured in 11 control subjects and 22 HTx recipients. In a prospective, double-blind study, the 22 HTx recipients performed a 6-min exercise [6-min-walk test (6MWT)] and a maximal bicycle exercise test before and after a 6-wk period of placebo intake or LAS. Endothelial function was measured by analyzing blood NO metabolites, endothelin, and the resulting NO/endothelin balance. RESULTS: Exercise capacity decreased after transplantation. Unlike with the placebo intake, 6 wk of LAS improved quality of life in HTx recipients (mean +/- SEM Minnesota Score: from 15.3 +/- 1.3 to 10.6 +/- 1.1; P < 0.001) and their submaximal exercise capacity. The distance walked during the 6MWT increased (from 525 +/- 20 to 580 +/- 20 m; P = 0.002), and the ventilatory threshold during the incremental test was delayed by 1.2 min (P = 0.01). Central factors such as resting stroke volume, systolic pulmonary arterial pressure, cardiac systolodiastolic functions, and heart-rate reserve were not modified, but LAS significantly increased the NO:endothelin ratio (from 2.49 +/- 0.38 to 3.31 +/- 0.39; P = 0.03). CONCLUSION: Oral LAS may be a useful adjuvant therapeutic to improve quality of life and exercise tolerance in HTx recipients. PMID- 20200266 TI - Population reference intakes and micronutrient bioavailability: a European perspective. AB - The processes of setting population reference intakes in the European Union and elsewhere have highlighted the paucity of data for informing the assessments and the need to take the opportunity to establish transparent, physiologically based approaches to setting reference values for safe and adequate intakes, including considerations of excess exposures. The confusion arising from the European exercise contributed to a number of initiatives to rationalize approaches to setting reference levels and safe upper levels of intake. A biologically based approach to nutrient risk assessment, which has many features that could be extended advantageously to the creation of a similar approach to setting nutrient reference values, has been proposed. This approach has yet to be explored, but an additional product of the earlier confusion has been the development of proposals for the international harmonization of approaches to setting nutrient-based dietary standards that could lead to internationally agreed-upon standards for nutrient risk assessment and for setting key intake values. PMID- 20200267 TI - Micronutrient bioavailability research priorities. AB - A micronutrient bioavailability workshop, which involved international experts and members of the scientific community and the food industry, with interactive breakout sessions based on synectics principles, was organized by the International Life Sciences Institute Europe Addition of Nutrients to Food Task Force and the European Commission Network of Excellence European Micronutrient Recommendations Aligned. After presentations by experts, a series of "challenge statements" was discussed. The aim was to address topical issues, in particular those that linked bioavailability with the derivation of micronutrient requirements and dietary recommendations, to identify gaps in knowledge and to consider research priorities. Several generic research priorities were identified, including improving the quality of dietary surveys/food composition tables, the need for more metabolic studies that use stable isotopes and high quality longer-term interventions, and the development of multifactorial mathematical models. Among the common recurrent factors identified as important were polymorphisms/genotype, consideration of the whole diet, chemical form of the micronutrient, and the determination of physiologic requirements. The involvement of all participants in the structured discussions ensured a broad overview of current knowledge, state-of-the-art research, and consideration of priorities for future research. PMID- 20200268 TI - Multiple-dose pharmacokinetics and pharmacodynamics of sergliflozin etabonate, a novel inhibitor of glucose reabsorption, in healthy overweight and obese subjects: a randomized double-blind study. AB - Sergliflozin, the active entity of sergliflozin etabonate, is a selective inhibitor of the sodium-dependent glucose cotransporter-2 in the renal tubule. The pharmacokinetics and pharmacodynamics of sergliflozin were examined during administration of sergliflozin etabonate (500 or 1000 mg) or placebo 3 times daily (tid) for 14 days in healthy overweight or obese human volunteers (n = 18). At the doses tested, sergliflozin showed less than dose-proportional pharmacokinetic characteristics. Mean half-life of the active entity was approximately 2 hours; there was no evidence of drug accumulation. Sergliflozin etabonate produced rapid and sustained suppression of renal glucose reabsorption, resulting in a dose-related glucosuria, and a transient increase in urinary electrolyte and fluid loss; plasma glucose, insulin, and electrolyte levels were unchanged. Sergliflozin etabonate produced a rapid, dose-related reduction in body weight (mean changes of -0.09, -1.55, and -1.74 kg from baseline to day 15 with placebo, sergliflozin etabonate 500 mg, and sergliflozin etabonate 1000 mg, respectively), apparently through increased urinary calorie loss rather than through osmotic diuresis. Sergliflozin etabonate 500 or 1000 mg tid was generally well tolerated; no clinically significant adverse events were identified. Renal function (creatinine clearance) was not affected by sergliflozin etabonate, although urinary microalbumin, N-acetyl-beta-D-glucosaminidase, and beta(2) microglobulin levels tended to increase. PMID- 20200269 TI - Population pharmacokinetic analysis of istradefylline in healthy subjects and in patients with Parkinson's disease. AB - This model-based analysis quantifies the population pharmacokinetics (PK) of orally administered istradefylline, a selective adenosine A(2A) receptor antagonist, in healthy subjects and patients with Parkinson's disease, including the estimation of covariate effects on istradefylline PK parameters. Istradefylline plasma concentration data from 8 phase 1 and 8 phase 2/3 studies conducted in 1449 patients and normal, healthy volunteers aged from 18 to 87 years were best described by a 2-compartment model with first-order absorption parameterized in terms of apparent oral clearance (CL/F), apparent central volume of distribution (V2/F), apparent intercompartmental clearance (Q/F), apparent peripheral volume of distribution (V3/F) and a first-order absorption rate constant (Ka). The typical population PK parameters were CL/F (5.76 L/h), V2/F (198 L), Q (21.6 L/h), V3/F (307 L), and Ka (0.464 h(-1)) for a 70-kg, nonsmoking Caucasian who had 55.6 kg of lean body mass, no presence of CYP3A4 inhibitors, and unknown food status. Smoking and CYP3A4 inhibitors as concomitant medications were important predictors of istradefylline exposure. Istradefylline area under the concentration-time curve at steady-state increased 35% (95% confidence interval, 18%-55%) in the presence of CYP3A4 inhibitors and decreased 38% (95% confidence interval, 26%-50%) in smokers. The population PK model described the observed concentration data well and was deemed appropriate for further evaluation of the istradefylline exposure-response relationship in patients with Parkinson's disease. PMID- 20200270 TI - Critical role of IkappaB Kinase alpha in TLR7/9-induced type I IFN production by conventional dendritic cells. AB - A plasmacytoid dendritic cell (DC) can produce large amounts of type I IFNs after sensing nucleic acids through TLR7 and TLR9. IkappaB kinase alpha (IKKalpha) is critically involved in this type I IFN production through its interaction with IFN regulatory factor-7. In response to TLR7/9 signaling, conventional DCs can also produce IFN-beta but not IFN-alpha in a type I IFN-independent manner. In this study, we showed that IKKalpha was required for production of IFN-beta, but not of proinflammatory cytokines, by TLR7/9-stimulated conventional DCs. Importantly, IKKalpha was dispensable for IFN-beta gene upregulation by TLR4 signaling. Biochemical analyses indicated that IKKalpha exerted its effects through its interaction with IFN regulatory factor-1. Furthermore, IKKalpha was involved in TLR9-induced type I IFN-independent IFN-beta production in vivo. Our results show that IKKalpha is a unique molecule involved in TLR7/9-MyD88 dependent type I IFN production through DC subset-specific mechanisms. PMID- 20200271 TI - Identification of a unique population of tissue-memory CD4+ T cells in the airways after influenza infection that is dependent on the integrin VLA-1. AB - During the immune response to influenza infection, activated T cells are distributed to both lymphoid and extralymphoid tissues, including the infected airways where direct recognition of viral Ag-bearing cells takes place. The collagen-binding alpha(1)beta(1) integrin VLA-1 is essential for the development of memory CD8(+) T cells in the airways, and although expressed by some CD4(+) T cells, its significance has not been demonstrated. We investigated the role of VLA-1 on virus-specific CD4(+) T cells during and after primary or secondary influenza infection of mice. The proportion of CD4(+) cells expressing CD49a (alpha(1) integrin) was low in all tissues sampled during primary infection but increased in the airways after viral clearance. Furthermore, during the first 24 h of a secondary influenza challenge, the majority of IFN-gamma-secreting effector CD4(+) T cells from the airways was in the CD49a(+) population. Airway CD49a(+)CD4(+) cells also expressed reduced markers of apoptosis compared with CD49a(-) cells, and fewer memory or effector CD4(+) cells could be recovered from airways of alpha(1)(-/-) mice, although lymphoid tissues appeared unaffected. These data suggest VLA-1 expression defines a population of tissue memory CD4(+) T cells that act as rapid effectors upon reinfection, and VLA-1 expression is integral to their accumulation in the airways. PMID- 20200272 TI - Mast cells express IL-17A in rheumatoid arthritis synovium. AB - The proinflammatory cytokine IL-17A is considered a crucial player in rheumatoid arthritis (RA) pathogenesis. In experimental models of autoimmune arthritis, it has been suggested that the cellular source of IL-17A is CD4(+) T cells (Th17 cells). However, little is known about the source of IL-17 in human inflamed RA tissue. We explored the cellular sources of IL-17A in human RA synovium. Surprisingly, only a small proportion of IL-17-expressing cells were T cells, and these were CCR6 negative. Unexpectedly, the majority of IL-17A expression colocalized within mast cells. Furthermore, we demonstrated in vitro that mast cells produced RORC-dependent IL-17A upon stimulation with TNF-alpha, IgG complexes, C5a, and LPS. These data are consistent with a crucial role for IL-17A in RA pathogenesis but suggest that in addition to T cells innate immune pathways particularly mediated via mast cells may be an important component of the effector IL-17A response. PMID- 20200274 TI - CD22 x Siglec-G double-deficient mice have massively increased B1 cell numbers and develop systemic autoimmunity. AB - CD22 and Siglec-G are inhibitory coreceptors for BCR-mediated signaling. Although CD22-deficient mice show increased calcium signaling in their conventional B2 cells and a quite normal B cell maturation, Siglec-G-deficient mice have increased calcium mobilization just in B1 cells and show a large expansion of the B1 cell population. Neither CD22-deficient, nor Siglec-G-deficient mice on a pure C57BL/6 or BALB/c background, respectively, develop autoimmunity. Using Siglec-G x CD22 double-deficient mice, we addressed whether Siglec-G and CD22 have redundant functions. Siglec-G x CD22 double-deficient mice show elevated calcium responses in both B1 cells and B2 cells, increased serum IgM levels and an enlarged population of B1 cells. The enlargement of B1 cell numbers is even higher than in Siglecg(-/-) mice. This expansion seems to happen at the expense of B2 cells, which are reduced in absolute cell numbers, but show an activated phenotype. Furthermore, Siglec-G x CD22 double-deficient mice show a diminished immune response to both thymus-dependent and thymus-independent type II Ags. In contrast, B cells from Siglec-G x CD22 double-deficient mice exhibit a hyperproliferative response to stimulation with several TLR ligands. Aged Siglec G x CD22 double-deficient mice spontaneously develop anti-DNA and antinuclear autoantibodies. These resulted in a moderate form of immune complex glomerulonephritis. These results show that Siglec-G and CD22 have partly compensatory functions and together are crucial in maintaining the B cell tolerance. PMID- 20200273 TI - Febrile-range hyperthermia augments lipopolysaccharide-induced lung injury by a mechanism of enhanced alveolar epithelial apoptosis. AB - Fever is common in critically ill patients and is associated with worse clinical outcomes, including increased intensive care unit mortality. In animal models, febrile-range hyperthermia (FRH) worsens acute lung injury, but the mechanisms by which this occurs remain uncertain. We hypothesized that FRH augments the response of the alveolar epithelium to TNF-alpha receptor family signaling. We found that FRH augmented LPS-induced lung injury and increased LPS-induced mortality in mice. At 24 h, animals exposed to hyperthermia and LPS had significant increases in alveolar permeability without changes in inflammatory cells in bronchoalveolar lavage fluid or lung tissue as compared with animals exposed to LPS alone. The increase in alveolar permeability was associated with an increase in alveolar epithelial apoptosis and was attenuated by caspase inhibition with zVAD.fmk. At 48 h, the animals exposed to hyperthermia and LPS had an enhanced lung inflammatory response. In murine lung epithelial cell lines (MLE-15, LA-4) and in primary type II alveolar epithelial cells, FRH enhanced apoptosis in response to TNF-alpha but not Fas ligand. The increase in apoptosis was caspase-8 dependent and associated with suppression of NF-kappaB activity. The FRH-associated NF-kappaB suppression was not associated with persistence of IkappaB-alpha, suggesting that FRH-mediated suppression of NF-kappaB occurs by means other than alteration of IkappaB-alpha kinetics. These data show for the first time that FRH promotes lung injury in part by increasing lung epithelial apoptosis. The enhanced apoptotic response might relate to FRH-mediated suppression of NF-kappaB activity in the alveolar epithelium with a resultant increase in susceptibility to TNF-alpha-mediated cell death. PMID- 20200275 TI - Activation of tolerogenic dendritic cells in the tumor draining lymph nodes by CD8+ T cells engineered to express CD40 ligand. AB - Tolerogenic dendritic cells in the tumor microenvironment can inhibit the generation and maintenance of robust antitumor T cell responses. In this study, we investigated the effects of local delivery of CD40L by tumor-reactive CD8(+) T cells on dendritic cell activation and antitumor T cell responses in the TRAMP model. To increase the immunostimulatory signal, CD40L was engineered, by deleting the majority of the cytoplasmic domain, to increase its levels of expression and duration on the surface of CD8(+) T cells. Tumor-reactive CD8(+) T cells expressing the truncated form of CD40L stimulated maturation of dendritic cells in vitro and in the prostate draining lymph nodes in vivo. Following dendritic cell maturation, a significantly higher fraction of adoptively transferred, tumor-reactive (reporter) CD8(+) T cells was stimulated to express IFN-gamma and infiltrate the prostate tissue. The antitumor CD8(+) T cell response was further enhanced if TRAMP mice were also immunized with a tumor specific Ag. These findings demonstrate that augmented T cell responses can be achieved by engineering tumor-reactive T cells to deliver stimulatory signals to dendritic cells in the tumor microenvironment. PMID- 20200276 TI - Caspase-1 independent IL-1beta production is critical for host resistance to mycobacterium tuberculosis and does not require TLR signaling in vivo. AB - To investigate the respective contributions of TLR versus IL-1R mediated signals in MyD88 dependent control of Mycobacterium tuberculosis, we compared the outcome of M. tuberculosis infection in MyD88, TRIF/MyD88, IL-1R1, and IL-1beta-deficient mice. All four strains displayed acute mortality with highly increased pulmonary bacterial burden suggesting a major role for IL-1beta signaling in determining the MyD88 dependent phenotype. Unexpectedly, the infected MyD88 and TRIF/MyD88 deficient mice, rather than being defective in IL-1beta expression, displayed increased cytokine levels relative to wild-type animals. Similarly, infected mice deficient in caspase-1 and ASC, which have critical functions in inflammasome mediated IL-1beta maturation, showed unimpaired IL-1beta production and importantly, were considerably less susceptible to infection than IL-1beta deficient mice. Together our findings reveal a major role for IL-1beta in host resistance to M. tuberculosis and indicate that during this infection the cytokine can be generated by a mechanism that does not require TLR signaling or caspase-1. PMID- 20200278 TI - H-2Ld class I molecule protects an HIV N-extended epitope from in vitro trimming by endoplasmic reticulum aminopeptidase associated with antigen processing. AB - In the classical MHC class I Ag presentation pathway, antigenic peptides derived from viral proteins by multiple proteolytic cleavages are transported to the endoplasmic reticulum lumen and are then exposed to ami-nopeptidase activity. In the current study, a long MHC class I natural ligand recognized by cytotoxic T lymphocytes was used to study the kinetics of degradation by aminopeptidase. The in vitro data indicate that this N-extended peptide is efficiently trimmed to a 9 mer, unless its binding to the MHC molecules protects the full-length peptide. PMID- 20200277 TI - IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis. AB - Sepsis is a highly lethal disorder characterized by widespread apoptosis-induced depletion of immune cells and the development of a profound immunosuppressive state. IL-7 is a potent antiapoptotic cytokine that enhances immune effector cell function and is essential for lymphocyte survival. In this study, recombinant human IL-7 (rhIL-7) efficacy and potential mechanisms of action were tested in a murine peritonitis model. Studies at two independent laboratories showed that rhIL-7 markedly improved host survival, blocked apoptosis of CD4 and CD8 T cells, restored IFN-gamma production, and improved immune effector cell recruitment to the infected site. Importantly, rhIL-7 also prevented a hallmark of sepsis (i.e., the loss of delayed-type hypersensitivity), which is an IFN-gamma- and T cell dependent response. Mechanistically, rhIL-7 significantly increased the expression of the leukocyte adhesion markers LFA-1 and VLA-4, consistent with its ability to improve leukocyte function and trafficking to the infectious focus. rhIL-7 also increased the expression of CD8. The potent antiapoptotic effect of rhIL-7 was due to increased Bcl-2, as well as to a dramatic decrease in sepsis induced PUMA, a heretofore unreported effect of IL-7. If additional animal studies support its efficacy in sepsis and if current clinical trials continue to confirm its safety in diverse settings, rhIL-7 should be strongly considered for clinical trials in sepsis. PMID- 20200279 TI - Carbohydrate oxidation acidifies endosomes, regulating antigen processing and TLR9 signaling. AB - Phagocytes kill encapsulated microbes through oxidative cleavage of surface carbohydrates, releasing glycan fragments and microbial contents that serve as ligands for immune receptors, which tailor the immune response against the offending pathogen. The glycan fragments serve as MHC class II (MHC II) ligands and innate receptor agonists, whereas microbial proteins serve as substrates for proteolytic cleavage and MHC II presentation, and released nucleic acids activate innate pattern-recognition receptors (e.g., TLR9). In the current study, confocal microscopy of live macrophages and dendritic cells revealed that endocytosis of carbohydrates lead to vesicular acidification independent of proton pump activity. Acidification was dependent on NO-mediated oxidation in the presence of the ingested carbohydrate and was sufficient to negatively regulate T cell dependent polysaccharide Ag cleavage, promote acid-dependent protein Ag processing, and facilitate CpG-mediated TLR9 signaling. Our findings lead to a model in which oxidation of carbohydrates from encapsulated microbes facilitates adaptive immune responses against microbial protein and carbohydrate Ags through promoting Ag processing for MHC II-mediated presentation as well as innate responses against released microbial DNA via TLR9 signaling. PMID- 20200280 TI - A critical role for the g protein-coupled receptor mFPR2 in airway inflammation and immune responses. AB - The formylpeptide receptor-like 1, now officially termed FPR2, in human and its mouse homolog mFPR2 mediate leukocyte migration in response to agonists associated with inflammation and immune responses. To clarify the in vivo role of the receptor, we generated mice deficient in mFPR2. mFPR2(-/-) mice showed markedly reduced severity in OVA/alum-induced allergic airway inflammation. This was associated with diminished recruitment of CD11c(+) dendritic cells into the airway mucosa and secondary lymphoid organs, as well as reduced production of Type 2 cytokines and Igs. We also found that the bronchoalveolar lavage fluid from wild type mice with airway inflammation contained mFPR2 agonist activity. This study reveals a critical role for mFPR2 in the progression of allergic airway inflammation and immune responses. PMID- 20200281 TI - SHIP1 inhibition increases immunoregulatory capacity and triggers apoptosis of hematopoietic cancer cells. AB - Genetic studies revealed that SHIP1 limits blood cell production and immune regulatory cell numbers in vivo. We postulated that molecular targeting of SHIP1 might enhance blood cell production and increase immunoregulatory capacity. In this study, we report the identification of a chemical inhibitor of SHIP1, 3 alpha-aminocholestane (3AC). Treatment with 3AC significantly expands the myeloid immunoregulatory cell compartment and impairs the ability of peripheral lymphoid tissues to prime allogeneic T cell responses. In addition, 3AC treatment profoundly increases granulocyte production without triggering the myeloid associated lung consolidation observed in SHIP1(-/-) mice. Moreover, 3AC also enhances RBC, neutrophil, and platelet recovery in myelosuppressed hosts. Intriguingly, we also find that chemical inhibition of SHIP1 triggers apoptosis of blood cancer cells. Thus, SHIP1 inhibitors represent a novel class of small molecules that have the potential to enhance allogeneic transplantation, boost blood cell production, and improve the treatment of hematologic malignancies. PMID- 20200282 TI - Constitutive association of TGF-beta-activated kinase 1 with the IkappaB kinase complex in the nucleus and cytoplasm of human neutrophils and its impact on downstream processes. AB - Neutrophils influence innate and adaptative immunity by generating numerous mediators whose regulation largely depends on the IkappaB kinase (IKK)/IkappaB/NF kappaB signaling cascade. A singular feature of neutrophils is that they express several components of this pathway (namely, NF-kappaB/Rel proteins and IkappaB alpha) in both the nucleus and cytoplasm. We recently reported that the IKK complex of neutrophils is similarly expressed and activated in both cellular compartments. However, the upstream IKK kinase has not yet been identified. In this study, we report that neutrophils express the mitogen-activated protein 3 kinase, TGF-beta-activated kinase 1 (TAK1), as well as its associated partners, TAK1-binding protein (TAB) 1, TAB2, and TAB4, in both the cytoplasm and nucleus. Following cell stimulation by TNF-alpha or LPS, TAK1 becomes rapidly and transiently activated. Blocking TAK1 kinase activity with a highly selective inhibitor (5z-7-oxozeaenol) attenuated the phosphorylation of nuclear and cytoplasmic IKKalpha/beta, IkappaB-alpha, and RelA, and also impaired IkappaB alpha degradation and NF-kappaB DNA binding in activated neutrophils. Moreover, TAK1 was found to be involved in the activation of p38 MAPK and ERK, which also influence cytokine generation in neutrophils. As a result, inflammatory cytokine expression and release were profoundly impaired following TAK1 inhibition. Similarly, the delayed apoptosis observed in response to LPS or TNF-alpha was reversed by TAK1 inhibition. By contrast, IKKgamma phosphorylation and STAT1 activation were unaffected by TAK1 inhibition. Our data establish the central role of TAK1 in controlling nuclear and cytoplasmic signaling cascades in primary neutrophils, making it a promising target for therapeutic intervention in view of the foremost role of neutrophils in several chronic inflammatory conditions. PMID- 20200283 TI - Metabolic control, self-care behaviors, and parenting in adolescents with type 1 diabetes: a correlational study. AB - PURPOSE: The purpose of this pilot study was to explore relationships among metabolic control, self-care behaviors, and parenting in adolescents with type 1 diabetes. METHODS: Twenty-nine adolescents (mean age, 14.1 years) and their parents participated. Metabolic control was determined by an average of 4 A1C values taken prior to study enrollment; self-care behaviors were measured with a 12-item self-report questionnaire; parenting style was evaluated using the Parenting Practices Report. RESULTS: The mean for A1C values was 8.5%; the mean for overall self-care behaviors was 4.93 (5 = usually). Participants rated themselves highest on the self-care behaviors of giving insulin shots when indicated and adjusting insulin when eating a lot. They ranked themselves lowest on eating a low-fat diet and testing urine for ketones. Parents tended to be more authoritative in their approaches to parenting than either authoritarian or permissive. A significant relationship was found between authoritative mothering and adolescent self-care behaviors and metabolic control. Regression analyses controlling for age and length of time with diabetes confirmed the significance of these relationships. Authoritative fathering positively correlated with the self-care behaviors of monitoring blood glucose, taking insulin, and not skipping meals. A relationship was also noted between permissive parenting by mothers/fathers and poorer metabolic outcomes. However, the permissive parenting correlations did not remain significant when controlling for age and length of time with diabetes. CONCLUSIONS: Clinicians may help prevent declining participation in self-care behaviors and metabolic control in adolescents with type 1 diabetes by working with parents, particularly mothers, and encouraging authoritative parenting. PMID- 20200284 TI - 3-year follow-up of clinical and behavioral improvements following a multifaceted diabetes care intervention: results of a randomized controlled trial. AB - PURPOSE: The purpose of this study was to determine if improvements observed in clinical, behavioral, and psychosocial outcomes measured at 12 months following a multifaceted diabetes care intervention were sustained at 3-year follow-up. METHODS: This study was a multilevel, nonblinded, cluster design, randomized controlled trial that took place in an underserved suburb of Pittsburgh, Pennsylvania, between 1999 and 2005. Eleven primary care practices, and their patients, were randomly assigned to 3 groups: chronic care model (CCM) intervention (n = 30), provider education only (PROV) (n = 38), and usual care (UC) (n = 51). Subjects were followed for 3 years. RESULTS: Improvements observed at 12-month follow-up in glycemic (-0.5%) and blood pressure control (-4.8 mm Hg), and the proportion of participants who self-monitor their blood glucose (86.7%-100%), were sustained at 3-year follow-up in the CCM group. Additional improvements occurred in non-HDLc levels in all study groups and quality of well being scores in the CCM intervention group. All associations remained after controlling for medication treatment intensification. CONCLUSIONS: We have demonstrated that improvements in outcomes can be sustained over time following a multifaceted diabetes care intervention. Future research in this area is necessary to understand if improvements in outcomes can be sustained following diabetes self-management education (DSME) and what type of patient fares the best from multifaceted diabetes care interventions. PMID- 20200285 TI - T cell Ig and mucin domain proteins and immunity. AB - Proteins of the transmembrane (or T cell) Ig and mucin domain (TIM) family are expressed by multiple cell types within the immune systems of rodents and humans. Studies over the last several years have suggested that these proteins may be promising targets for therapeutic manipulation of immune responses. This review discusses the progress that has been made in understanding TIM protein function in the immune system, as well as some of the unresolved issues that remain on the road to eventually targeting TIM proteins for enhancing or inhibiting immunity. PMID- 20200286 TI - Cavitary pulmonary zygomycosis caused by Rhizopus homothallicus. AB - We report the first two proven cases of cavitary pulmonary zygomycosis caused by Rhizopus homothallicus. The diagnosis in each case was based on histology, culture of the causal agent, and the nucleotide sequence of the D1/D2 region of the 28S ribosomal DNA. PMID- 20200287 TI - MST (molecular serotyping tool): a program for computer-assisted molecular identification of Escherichia coli and Shigella O antigens. AB - Escherichia coli and Shigella O antigens can be inferred using the rfb restriction fragment length polymorphism (RFLP) molecular test. We present herein a dynamic programming algorithm-based software to compare the rfb-RFLP patterns of clinical isolates with those in a database containing the 171 previously published patterns corresponding to all known E. coli/Shigella O antigens. PMID- 20200288 TI - Longitudinal genotyping of Candida dubliniensis isolates reveals strain maintenance, microevolution, and the emergence of itraconazole resistance. AB - We investigated the population structure of 208 Candida dubliniensis isolates obtained from 29 patients (25 human immunodeficiency virus [HIV] positive and 4 HIV negative) as part of a longitudinal study. The isolates were identified as C. dubliniensis by arbitrarily primed PCR (AP-PCR) and then genotyped using the Cd25 probe specific for C. dubliniensis. The majority of the isolates (55 of 58) were unique to individual patients, and more than one genotype was recovered from 15 of 29 patients. A total of 21 HIV-positive patients were sampled on more than one occasion (2 to 36 times). Sequential isolates recovered from these patients were all closely related, as demonstrated by hybridization with Cd25 and genotyping by PCR. Six patients were colonized by the same genotype of C. dubliniensis on repeated sampling, while strains exhibiting altered genotypes were recovered from 15 of 21 patients. The majority of these isolates demonstrated minor genetic alterations, i.e., microevolution, while one patient acquired an unrelated strain. The C. dubliniensis strains could not be separated into genetically distinct groups based on patient viral load, CD4 cell count, or oropharyngeal candidosis. However, C. dubliniensis isolates obtained from HIV-positive patients were more closely related than those recovered from HIV-negative patients. Approximately 8% (16 of 194) of isolates exhibited itraconazole resistance. Cross resistance to fluconazole was only observed in one of these patients. Two patients harboring itraconazole-resistant isolates had not received any previous azole therapy. In conclusion, longitudinal genotyping of C. dubliniensis isolates from HIV-infected patients reveals that isolates from the same patient are generally closely related and may undergo microevolution. In addition, isolates may acquire itraconazole resistance, even in the absence of prior azole therapy. PMID- 20200289 TI - Association of recurrent furunculosis with Panton-Valentine leukocidin and the genetic background of Staphylococcus aureus. AB - Staphylococcus aureus is a major cause of skin and soft tissue infections, such as furuncles, carbuncles, and abscesses, but it also frequently colonizes the human skin and mucosa without causing clinical symptoms. Panton-Valentine leukocidin (PVL) is a pore-forming toxin that has been associated with soft tissue infections and necrotizing pneumonia. We have compared the genotypes, virulence gene repertoires, and phage patterns of 74 furunculosis isolates with those of 108 control strains from healthy nasal carriers. The large majority of furunculosis strains were methicillin sensitive. Clonal cluster (CC) 121 (CC121) and CC22 accounted for 70% of the furunculosis strains but for only 8% of the nasal isolates. The PVL-encoding genes luk-PV were detected in 85% of furunculosis strains, while their prevalence among colonizing S. aureus strains was below 1%. luk-PV genes were distributed over several lineages (CCs 5, 8, 22, 30, and 121 and sequence type 59). Even within the same lineages, luk-PV-positive phages characterized furunculosis strains, while their luk-PV-negative variants were frequent among nasal strains. The very tight epidemiological linkage between luk-PV and furunculosis, which could be separated from the genetic background of the S. aureus strain as well as from the gene makeup of the luk-PV-transducing phage, lends support to the notion of an important role for PVL in human furunculosis. These results make a case for the determination of luk-PV in recurrent soft tissue infections with methicillin-sensitive as well as methicillin-resistant S. aureus. PMID- 20200291 TI - Replacing reverse line blot hybridization spoligotyping of the Mycobacterium tuberculosis complex. AB - Spoligotyping is a tool for the molecular characterization/typing of Mycobacterium tuberculosis complex (MTBC) strains based on target sequences (spacers) in the direct repeat (DR) region (14). The standard spoligotyping assay involves the hybridization of amplified sample DNA to nylon membrane-immobilized oligonucleotides whose sequences are representative of 43 spacer regions. Variations in the number of spacers as a result of deletions of adjacent blocks of repetitive units allow the differentiation of clinical isolates. In the present study, we developed a new multiplexed primer extension-based spoligotyping assay using automated matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS) that improves the classical reverse line blot hybridization assay with respect to reproducibility, throughput, process flow, ease of use, and data analysis. Validation of the MALDI TOF MS-based spoligotyping assay with two sample sets with a total of 326 samples resulted in 96.6% concordance (315/326) when the full spoligotype patterns were compared with the results of standard spoligotyping and 99.9% concordance when the results were compared with those of individual primer extension assays. Ten strains (including two Mycobacterium canettii strains) showed discordant results with one or two spacer differences from the membrane-based spoligotyping result. Most discordant samples were identified to be the result of ambiguities in the interpretation of weak hybridization signals in the reverse line blot assay and sequence variations in the spacer regions. We established a new automated primer extension assay and successfully validated it for use for the routine typing of MTBC strains in the research and public health laboratory environments. The present multiplex levels of up to 30 are extendable and allow the additional incorporation of controls and antibiotic resistance markers. PMID- 20200290 TI - Comparison of self-collected and physician-collected vaginal swabs for microbiome analysis. AB - To our knowledge, no data are available on whether the microbial species composition and abundance sampled with self-collected vaginal swabs are comparable to those of swabs collected by clinicians. Twenty healthy women were recruited to the study during a routine gynecological visit. Eligible women were between 18 and 40 years old with regular menstrual cycles. Participants self collected a vaginal swab using a standardized protocol and then were examined by a physician, who collected an additional five swabs from the lateral wall of the mid-vagina. In this study, the self-collected and three physician-obtained swabs were analyzed and compared using terminal restriction fragment length polymorphism and sequence analyses of the 16S rRNA genes. Vaginal microbial community comparative statistical analyses of both T-RFLP and 16S rRNA gene sequence datasets revealed that self-collected vaginal swabs sampled the same microbial diversity as physician collected swabs of the mid-vagina. These findings enable large-scale, field-based studies of the vaginal microbiome. PMID- 20200292 TI - Comparison of the plating efficiencies and shelf lives of three different commercial buffered charcoal yeast extract media supplemented with alpha ketoglutaric acid. AB - The plating efficiencies and shelf lives of locally made buffered charcoal yeast extract medium supplemented with alpha-ketoglutaric acid (BCYEalpha) were compared to those of media made by BD, Hardy, and Remel. Lung homogenates from guinea pigs infected with Legionella pneumophila were plated monthly onto different medium lots. All media performed equally well and had shelf lives of at least 12 months. PMID- 20200293 TI - Evaluation of molecular tools for detection and drug susceptibility testing of Mycobacterium tuberculosis in stool specimens from patients with pulmonary tuberculosis. AB - Pulmonary tuberculosis diagnosis is difficult when patients cannot produce sputum. Most sputum is swallowed, and tuberculosis DNA can survive intestinal transit. We therefore evaluated molecular testing of stool specimens for detecting tuberculosis originating from the lungs. Paired stool and sputum samples (n=159) were collected from 89 patients with pulmonary tuberculosis. Control stool samples (n=47) were collected from patients without tuberculosis symptoms. Two techniques for DNA extraction from stool samples were compared, and the diagnostic accuracy of the PCR in stool was compared with the accuracy of sputum testing by PCR, microscopy, and culture. A heminested IS6110-PCR was used for tuberculosis detection, and IS6110-PCR-positive stool samples then underwent rifampin sensitivity testing by universal heteroduplex generator PCR (heteroduplex-PCR) assay. For newly diagnosed pulmonary tuberculosis patients, stool IS6110-PCR had 86% sensitivity and 100% specificity compared with results obtained by sputum culture, and stool PCR had similar sensitivities for HIV positive and HIV-negative patients (P=0.3). DNA extraction with commercially available spin columns yielded greater stool PCR sensitivity than DNA extraction with the in-house Chelex technique (P=0.007). Stool heteroduplex-PCR had 98% agreement with the sputum culture determinations of rifampin resistance and multidrug resistance. Tuberculosis detection and drug susceptibility testing by stool PCR took 1 to 2 days compared with an average of 9 weeks to obain those results by traditional culture-based testing. Stool PCR was more sensitive than sputum microscopy and remained positive for most patients for more than 1 week of treatment. In conclusion, stool PCR is a sensitive, specific, and rapid technique for the diagnosis and drug susceptibility testing of pulmonary tuberculosis and should be considered when sputum samples are unavailable. PMID- 20200295 TI - Detection of group B Streptococcus bacteria in LIM enrichment broth by peptide nucleic acid fluorescent in situ hybridization (PNA FISH) and rapid cycle PCR. AB - The sensitivity, specificity, and negative and positive predictive values for the detection of group B Streptococcus (GBS) in 206 LIM enrichment broths by the use of subculture, GBS peptide nucleic acid fluorescent in situ hybridization (PNA FISH), and GBS PCR were 96.9%, 100%, 98.6%, and 100%; 98.4%, 100%, 99.3%, and 100%; and 100%, 100%, 100%, and 100%, respectively. PMID- 20200294 TI - Lactobacilli are prominent in the initial stages of polymicrobial infection of dental pulp. AB - In earlier studies we used molecular methods to identify the major bacterial consortia associated with advanced dentin caries. These consortia are dominated by bacteria from the families Lactobacillaceae, Streptococcaceae, Veillonellaceae (formerly Acidaminococcaceae), Eubacteriaceae, and Lachnospiraceae from the phylum Firmicutes; Coriobacteriaceae, Bifidobacteriaceae, and Propionibacteriaceae from the phylum Actinobacteria; and Prevotellaceae from the phylum Bacteroidetes, as well as fusobacteria. The phases of infection of vital pulp tissue by dentin microorganisms remain obscure. In the present study, fluorescence in situ hybridization was performed on sections of tissue embedded in resin. Probes for 16S rRNA corresponding to the major taxa of bacteria in carious dentin were used to provide information on the characteristics of pulp infection. Lactobacilli were prominent in 7 of 8 pulps determined to be at a limited stage of infection. Established infection (6 pulps) showed a more complex profile, with lactobacilli persisting in all of the lesions and with invasion of the necrotic regions of tissue by Bacteroidetes, fusobacteria, Lachnospiraceae, and Coriobacteriaceae in particular. Advanced infections (7 pulps) were characterized by mixed anaerobic species, with a strong representation by Coriobacteriaceae and Lachnospiraceae. Lactobacilli were not represented at this stage. Typically, groups of organisms were spatially isolated within the pulp tissue. Analysis indicated that lactobacilli could invade vital pulp tissue to achieve a very high biomass that was not associated with a detectable local inflammatory infiltrate. The findings establish that invasion of the dental pulp can be associated with a pronounced selection from the complex microbial populations within carious dentin, suggesting specific pathogenicity. PMID- 20200296 TI - Clinical evaluation of TRCRapid M.TB for detection of Mycobacterium tuberculosis complex in respiratory and nonrespiratory specimens. AB - The rapid and accurate diagnosis of tuberculosis is crucial to providing optimal treatment and reducing the spread of infection. We evaluated respiratory and nonrespiratory clinical specimens using a new automated Mycobacterium tuberculosis complex (MTBC) rRNA detection kit (TRCRapid M.TB; Tosoh Bioscience, Tokyo, Japan), which is based on the transcription-reverse transcription concerted reaction (TRC). TRC enables the rapid and completely homogeneous real time monitoring of isothermal RNA sequence amplification without any postamplification procedures. The results were compared with those obtained by M. tuberculosis culture. A total of 1,155 respiratory specimens and 420 nonrespiratory specimens collected from 1,282 patients were investigated. Of the 45 specimens culture positive for MTBC, 42 were TRC positive, and of the 1,530 specimens culture negative for MTBC, 1,523 were TRC negative. Compared to the results of culture, the overall sensitivity and specificity of TRC were 96.6% and 99.9%, respectively, for respiratory specimens and 87.5% and 98.5%, respectively, for nonrespiratory specimens. The sensitivities of TRC were 100% for smear positive respiratory and nonrespiratory specimens, 88.9% for smear-negative respiratory specimens, and 80% for smear-negative nonrespiratory specimens. No significant differences in test performance between respiratory and nonrespiratory specimens were observed. The TRC method proved to be clinically useful for the rapid identification of MTBC in respiratory and nonrespiratory specimens and in both smear-positive and smear-negative samples. PMID- 20200297 TI - Genome rearrangements of completely sequenced strains of Yersinia pestis. AB - Yersinia pestis has caused three worldwide plagues in human history that have led to innumerable deaths. We have completely sequenced the genomes of two strains (D106004 and D182038) of Y. pestis isolated from Yunnan Province of China. The most striking finding of our study is that large amounts of genome rearrangement events exist between the genomes of two Yunnan strains despite being isolated from two foci only 50 kilometers apart. When we compared the genome sequences of the Yunnan strains with six strains (CO92, KIM, 91001, Antiqua, Nepal516, and Pestoides F) of Y. pestis sequenced previously, we found that the genomes of Y. pestis were divided into 61 relatively independent segments. Pairwise comparisons of all 61 segments among eight strains showed that the Yunnan strains were most closely related to strain CO92. We concluded that Y. pestis genomes consist of segments that can change their positions and directions within the genomes caused by genome rearrangements, and our study confirmed the inference that the third plague pandemic originated in Yunnan since the genome sequences of Yunnan strains were closest to the strain CO92 isolated from the United States. PMID- 20200298 TI - Outbreak of infection with Klebsiella pneumoniae sequence type 258 producing Klebsiella pneumoniae Carbapenemase 3 in an intensive care unit in Italy. PMID- 20200299 TI - Testosterone concentrations in diabetic and nondiabetic obese men. AB - OBJECTIVE: To determine the prevalence of subnormal testosterone concentrations in patients with obesity and with type 2 diabetes in a primary care clinic population. RESEARCH DESIGN AND METHODS: Free testosterone concentrations of 1,849 men (1,451 nondiabetic and 398 diabetic) in the Hypogonadism In Males (HIM) study were analyzed. The HIM study was a U.S.-based cross-sectional study designed to define the prevalence of hypogonadism in men aged >45 years. Free testosterone was measured by equilibrium dialysis. RESULTS: The prevalence of subnormal free testosterone concentrations in lean, overweight, and obese nondiabetic men was 26% (n = 275), 29% (n = 687), and 40% (n = 489), respectively (P < 0.001 for trend), and 44% (n = 36), 44% (n = 135), and 50% (n = 227), respectively, in diabetic men (P = 0.46 for trend within group and P < 0.05 compared with nondiabetic men). The mean free testosterone concentration of diabetic men was significantly lower than that of nondiabetic men. Free testosterone concentrations were negatively and significantly (P < 0.001) related to age (r = -0.37), BMI (r = -0.18), and sex hormone-binding globulin (r = -0.11) in multiple regression analysis. The average decline of free testosterone concentrations was 7.8 pg/ml per decade in nondiabetic men and 8.4 pg/ml per decade in diabetic men. CONCLUSIONS: Forty percent of obese nondiabetic men and 50% of obese diabetic men aged >or=45 years have subnormal free testosterone concentrations. In view of its high prevalence, obesity is probably the condition most frequently associated with subnormal free testosterone concentrations in males. The concomitant presence of diabetes is associated with an additional increase in the prevalence of subnormal free testosterone concentrations. PMID- 20200300 TI - Prognostic value of coronary computed tomographic angiography in diabetic patients without known coronary artery disease. AB - OBJECTIVE: Diabetic patients have a high prevalence of coronary artery disease (CAD), but timely diagnosis of CAD remains challenging. We assessed the ability of coronary computed tomography angiography (CCTA) to detect CAD in diabetic patients and to predict subsequent cardiac events. RESEARCH DESIGN AND METHODS: We analyzed 140 diabetic patients without known CAD undergoing CCTA; 1,782 patients without diabetes were used as a control group. Besides calcium scoring and the degree of the most severe stenosis, the atherosclerotic burden score counting the number of segments having either a nonstenotic plaque or a stenosis was recorded. The primary end point was a composite of hard cardiac events defined as all-cause death, nonfatal myocardial infarction, or unstable angina requiring hospitalization. RESULTS: During a mean follow-up of 33 months, there were seven events in the diabetic group and 24 events in the control group. The best predictor in diabetic patients was the atherosclerotic burden score: the annual event rate ranged from 0.5% for patients with <5 lesions to 9.6% for patients with >9 lesions, resulting in a hazard ratio (HR) of 1.3 (95% CI 1.1 1.7) for each additional lesion (P = 0.005). For comparison, in nondiabetic patients the annual event rate ranged from 0.3 to 2.2%, respectively, resulting in an HR of 1.2 (95% CI 1.1-1.3, P < 0.001). The atherosclerotic burden score improved the prognostic value of conventional risk factors significantly (P < 0.001). CONCLUSIONS: In diabetic patients without known CAD, CCTA can identify a patient group at particularly high risk for subsequent hard cardiac events. PMID- 20200301 TI - A 24-week, randomized, treat-to-target trial comparing initiation of insulin glargine once-daily with insulin detemir twice-daily in patients with type 2 diabetes inadequately controlled on oral glucose-lowering drugs. AB - OBJECTIVE: To determine whether glargine is noninferior to detemir regarding the percentage of patients reaching A1C <7% without symptomatic hypoglycemia 97 and >87 cm in men and women, respectively. With these cutoffs, there was substantial disagreement between the original American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLBI) and the recently updated MetS definition, particularly among men (kappa = 0.85). Subjects with MetS identified by the updated definition but not meeting the original AHA/NHLBI MetS criteria demonstrated significantly increased cIMT (P < 0.001) compared with subjects who did not meet the MetS criteria by either definition. CONCLUSIONS: Our findings support the use of ethnic-specific waist circumference cutoffs and the updated MetS definition in Andean adults. PMID- 20200304 TI - Long-term outcomes of diabetic patients with critical limb ischemia followed in a tertiary referral diabetic foot clinic. AB - OBJECTIVE: We describe the long-term outcomes of 510 diabetic patients with critical limb ischemia (CLI) and an active foot ulcer or gangrene, seen at the University Hospital of Rome Tor Vergata, a tertiary care clinic. RESEARCH DESIGN AND METHODS: These patients were seen between November 2002 and November 2007 (mean follow-up 20 +/- 13 months [range 1-66 months]). The Texas Wound Classification was used to grade these wounds that were either class C (ischemia) and D (ischemia+infection) and grade 2-3 (deep-very deep). This comprehensive treatment protocol includes rapid and extensive initial debridement, aggressive use of peripheral percutaneous angioplasty, empirical intravenous antibiotic therapy, and strict follow-up. RESULTS: The protocol was totally applied (with percutaneous angioplasty [PA+]) in 456 (89.4%) patients and partially (without percutaneous angioplasty [PA-]) in 54 (10.6%) patients. Outcomes for the whole group and PA+ and PA- patients are, respectively: healing, n = 310 (60.8%), n = 284 (62.3%), and n = 26 (48.1%); major amputation, n = 80 (15.7%), n = 67 (14.7%), and n = 13 (24.1%); death, n = 83 (16.25%), n = 68 (14.9%), and n = 15 (27.8%); and nonhealing, n = 37 (7.25%), n = 37 (8.1%), and n = 0 (0%) (chi(2) <0.0009). Predicting variables at multivariate analysis were the following: for healing, ulcer dimension, infection, and ischemic heart disease; and for major amputation, ulcer dimension, number of minor amputations, and age. Additional predicting variables for PA+ patients were the following: for healing, transcutaneous oxygen tension [DeltaTcPo(2)]; and for major amputation, basal TcPo(2), basal A1C, DeltaTcPo(2), and percutaneous angioplasty technical failure. CONCLUSIONS: Early diagnosis of CLI, aggressive treatment of infection, and extensive use of percutaneous angioplasty in ischemic affected ulcers offers improved outcome for many previously at-risk limbs. Ulcer size >5 cm(2) indicates a reduced chance of healing and increased risk of major amputation. It was thought that all ulcers warrant aggressive treatment including percutaneous angioplasty and that treatment should be considered even for small ischemic ulcers. PMID- 20200305 TI - Improved pancreatic beta-cell function in type 2 diabetic patients after lifestyle-induced weight loss is related to glucose-dependent insulinotropic polypeptide. AB - OBJECTIVE: Restoration of insulin secretion is critical for the treatment of type 2 diabetes. Exercise and diet can alter glucose-induced insulin responses, but whether this is due to changes in beta-cell function per se is not clear. The mechanisms by which lifestyle intervention may modify insulin secretion in type 2 diabetes have also not been examined but may involve the incretin axis. RESEARCH DESIGN AND METHODS: Twenty-nine older, obese (aged 65 +/- 1 years; BMI 33.6 +/- 1.0 kg/m(2)) subjects, including individuals with newly diagnosed type 2 diabetes (obese-type 2 diabetic) and individuals with normal glucose tolerance (obese NGT), underwent 3 months of nutritional counseling and exercise training. beta Cell function (oral glucose-induced insulin secretion corrected for insulin resistance assessed by hyperinsulinemic-euglycemic clamps) and the role of glucose-dependent insulinotropic polypeptide (GIP) were examined. RESULTS: After exercise and diet-induced weight loss (-5.0 +/- 0.7 kg), oral glucose-induced insulin secretion was increased in the obese-type 2 diabetic group and decreased in the obese-NGT group (both P < 0.05). When corrected for alterations in insulin resistance, the change in insulin secretion remained significant only in the obese-type 2 diabetic group (1.23 +/- 0.26 vs. 2.04 +/- 0.46 arbitrary units; P < 0.01). Changes in insulin secretion were directly related to the GIP responses to oral glucose (r = 0.64, P = 0.005), which were augmented in the obese-type 2 diabetic group and only moderately suppressed in the obese-NGT group. CONCLUSIONS: After lifestyle-induced weight loss, improvements in oral glucose induced insulin secretion in older, obese, nondiabetic subjects seem to be largely dependent on improved insulin sensitivity. However, in older obese diabetic patients, improved insulin secretion is a consequence of elevated beta cell function. We demonstrate for the first time that changes in insulin secretion after lifestyle intervention may be mediated via alterations in GIP secretion from intestinal K-cells. PMID- 20200306 TI - Prolonged nocturnal hypoglycemia is common during 12 months of continuous glucose monitoring in children and adults with type 1 diabetes. AB - OBJECTIVE: To characterize the amount of nocturnal hypoglycemia and evaluate factors associated with nocturnal hypoglycemia assessed with continuous glucose monitoring (CGM) in adults and children with type 1 diabetes who participated in the Juvenile Diabetes Research Foundation CGM randomized clinical trial. RESEARCH DESIGN AND METHODS: The analysis included 36,467 nights with >or=4 h of CGM glucose readings between 12 midnight and 6:00 a.m. from 176 subjects assigned to the CGM group of the trial. The percentage of nights in which hypoglycemia occurred (two consecutive CGM readings or=2 h on 23% of nights with hypoglycemia. In a multivariate model, a higher incidence of nocturnal hypoglycemia was associated with 1) lower baseline A1C levels (P < 0.001) and 2) the occurrence of hypoglycemia on one or more nights during baseline blinded CGM (P < 0.001). The hypoglycemia frequency was not associated with age or with insulin modality (pump versus multiple daily injections). CONCLUSIONS: Nocturnal hypoglycemia is frequent and often prolonged in adults and children with type 1 diabetes. Patients with low A1C levels are at an increased risk for its occurrence. One week of blinded CGM can identify patients who are at greater risk for nocturnal hypoglycemia. PMID- 20200307 TI - Prevention of nocturnal hypoglycemia using predictive alarm algorithms and insulin pump suspension. AB - OBJECTIVE: The aim of this study was to develop a partial closed-loop system to safely prevent nocturnal hypoglycemia by suspending insulin delivery when hypoglycemia is predicted in type 1 diabetes. RESEARCH DESIGN AND METHODS: Forty subjects with type 1 diabetes (age range 12-39 years) were studied overnight in the hospital. For the first 14 subjects, hypoglycemia (<60 mg/dl) was induced by gradually increasing the basal insulin infusion rate (without the use of pump shutoff algorithms). During the subsequent 26 patient studies, pump shutoff occurred when either three of five (n = 10) or two of five (n = 16) algorithms predicted hypoglycemia based on the glucose levels measured with the FreeStyle Navigator (Abbott Diabetes Care). RESULTS: The standardized protocol induced hypoglycemia on 13 (93%) of the 14 nights. With use of a voting scheme that required three algorithms to trigger insulin pump suspension, nocturnal hypoglycemia was prevented during 6 (60%) of 10 nights. When the voting scheme was changed to require only two algorithms to predict hypoglycemia to trigger pump suspension, hypoglycemia was prevented during 12 (75%) of 16 nights. In the latter study, there were 25 predictions of hypoglycemia because some subjects had multiple hypoglycemic events during a night, and hypoglycemia was prevented for 84% of these events. CONCLUSIONS: Using algorithms to shut off the insulin pump when hypoglycemia is predicted, it is possible to prevent hypoglycemia on 75% of nights (84% of events) when it would otherwise be predicted to occur. PMID- 20200308 TI - Insulin resistance predicts mortality in nondiabetic individuals in the U.S. AB - OBJECTIVE: Insulin resistance is a suspected causative factor in a wide variety of diseases. We aimed to determine whether insulin resistance, estimated by the homeostasis model assessment for insulin resistance (HOMA-IR), is associated with all-cause or disease-specific mortality among nondiabetic persons in the U.S. RESEARCH DESIGN AND METHODS: We determined the association between HOMA-IR and death certificate-based mortality among 5,511 nondiabetic, adult participants of the third U.S. National Health and Nutrition Examination Survey (1988-1994) during up to 12 years of follow-up, after adjustment for potential confounders (age, sex, BMI, waist-to-hip ratio, alcohol consumption, race/ethnicity, educational attainment, smoking status, physical activity, C-reactive protein, systolic and diastolic blood pressure, plasma total and HDL cholesterol, and triglycerides). RESULTS: HOMA-IR was significantly associated with all-cause mortality (adjusted hazard ratio 1.16 [95% CI 1.01-1.3], comparing successive quartiles of HOMA-IR in a linear model and 1.64 [1.1-2.5], comparing the top [HOMA-IR >2.8] to the bottom [HOMA-IR or=25.2 kg/m(2). Subjects in the second, third, and fourth quartile of HOMA-IR appeared to have higher cardiovascular mortality than subjects in the lowest quartile of HOMA-IR. HOMA-IR was not associated with cancer-related mortality. CONCLUSIONS: HOMA-IR is associated with all-cause mortality in the nondiabetic U.S. population but only among persons with normal BMI. HOMA-IR is a readily available measure that can be used in the future to predict mortality in clinical or epidemiological settings. PMID- 20200309 TI - Improvement of postprandial endothelial function after a single dose of exenatide in individuals with impaired glucose tolerance and recent-onset type 2 diabetes. AB - OBJECTIVE: Endothelial dysfunction is frequently present in individuals with insulin resistance or type 2 diabetes and can be induced by high-fat or high carbohydrate meals. Because exenatide reduces postprandial glucose and lipid excursions, we hypothesized that it may also improve postprandial endothelial function. RESEARCH DESIGN AND METHODS: In a double-blinded randomized crossover design, postprandial endothelial function was examined in 28 individuals with impaired glucose tolerance or recent-onset type 2 diabetes after a single injection of exenatide or placebo given just before a high-fat meal. Endothelial function was determined with peripheral arterial tonometry pre- and postprandially. RESULTS: Postprandial endothelial function was higher after exenatide compared with placebo (P = 0.0002). In the placebo phase, postprandial change in endothelial function was inversely associated with mean postprandial concentrations of triglycerides (r = -0.62, P = 0.0004). Changes in postprandial triglyceride concentrations explained 64% of exenatide's effect on postprandial endothelial function. CONCLUSIONS: Exenatide ameliorates postprandial endothelial dysfunction after a high-fat meal. PMID- 20200311 TI - Designing marine reserve networks for both conservation and fisheries management. AB - Marine protected areas (MPAs) that exclude fishing have been shown repeatedly to enhance the abundance, size, and diversity of species. These benefits, however, mean little to most marine species, because individual protected areas typically are small. To meet the larger-scale conservation challenges facing ocean ecosystems, several nations are expanding the benefits of individual protected areas by building networks of protected areas. Doing so successfully requires a detailed understanding of the ecological and physical characteristics of ocean ecosystems and the responses of humans to spatial closures. There has been enormous scientific interest in these topics, and frameworks for the design of MPA networks for meeting conservation and fishery management goals are emerging. Persistent in the literature is the perception of an inherent tradeoff between achieving conservation and fishery goals. Through a synthetic analysis across these conservation and bioeconomic studies, we construct guidelines for MPA network design that reduce or eliminate this tradeoff. We present size, spacing, location, and configuration guidelines for designing networks that simultaneously can enhance biological conservation and reduce fishery costs or even increase fishery yields and profits. Indeed, in some settings, a well-designed MPA network is critical to the optimal harvest strategy. When reserves benefit fisheries, the optimal area in reserves is moderately large (mode ~30%). Assessing network design principals is limited currently by the absence of empirical data from large-scale networks. Emerging networks will soon rectify this constraint. PMID- 20200310 TI - Suppressive effect of insulin infusion on chemokines and chemokine receptors. AB - OBJECTIVE: In view of the previously described anti-inflammatory effects of insulin, we investigated the potential suppressive effect of insulin on plasma concentrations and expression of the chemokines, monocyte chemoattractant protein 1 (MCP-1) and regulated on activation normal T-cell expressed and secreted (RANTES) and their receptors, chemokine receptor (CCR)-2 and CCR-5, in mononuclear cells (MNCs). We also investigated the effect of insulin on other chemokines. RESEARCH DESIGN AND METHODS: Ten obese type 2 diabetic patients were infused with insulin (2 units/h with 100 ml of 5% dextrose/h) for 4 h. Another 8 and 6 type 2 diabetic patients were infused with 100 ml of 5% dextrose/h or saline for 4 h, respectively, and served as control subjects. Blood samples were obtained at 0, 2, 4, and 6 h. RESULTS: Insulin infusion significantly suppressed the plasma concentrations of MCP-1, eotaxin, and RANTES and the expression of RANTES, macrophage inflammatory protein (MIP)-1beta, CCR-2, and CCR-5 in MNCs at 2 and 4 h. Dextrose and saline infusions did not alter these indexes. CONCLUSIONS: A low-dose infusion of insulin suppresses the plasma concentration of key chemokines, MCP-1, and RANTES, and the expression of their respective receptors, CCR-2 and CCR-5, in MNCs. Insulin also suppresses the expression of RANTES and MIP-1beta in MNCs. These actions probably contribute to the comprehensive anti-inflammatory effect of insulin. PMID- 20200312 TI - Imaging and manipulation of the competing electronic phases near the Mott metal insulator transition. AB - The complex interplay between the electron and lattice degrees of freedom produces multiple nearly degenerate electronic states in correlated electron materials. The competition between these degenerate electronic states largely determines the functionalities of the system, but the invoked mechanism remains in debate. By imaging phase domains with electron microscopy and interrogating individual domains in situ via electron transport spectroscopy in double-layered Sr(3)(Ru(1-x)Mn(x))(2)O(7) (x = 0 and 0.2), we show in real-space that the microscopic phase competition and the Mott-type metal-insulator transition are extremely sensitive to applied mechanical stress. The revealed dynamic phase evolution with applied stress provides the first direct evidence for the important role of strain effect in both phase separation and Mott metal-insulator transition due to strong electron-lattice coupling in correlated systems. PMID- 20200313 TI - In situ assembly of macromolecular complexes triggered by light. AB - Chemical biology aims for a perfect control of protein complexes in time and space by their site-specific labeling, manipulation, and structured organization. Here we developed a self-inactivated, lock-and-key recognition element whose binding to His-tagged proteins can be triggered by light from zero to nanomolar affinity. Activation is achieved by photocleavage of a tethered intramolecular ligand arming a multivalent chelator head for high-affinity protein interaction. We demonstrate site-specific, stable, and reversible binding in solution as well as at interfaces controlled by light with high temporal and spatial resolution. Multiplexed organization of protein complexes is realized by an iterative in situ writing and binding process via laser scanning microscopy. This light-triggered molecular recognition should allow for a spatiotemporal control of protein protein interactions and cellular processes by light-triggered protein clustering. PMID- 20200314 TI - Platelet tissue factor synthesis in type 2 diabetic patients is resistant to inhibition by insulin. AB - OBJECTIVE: Patients with type 2 diabetes have an increased risk of cardiovascular disease and show abnormalities in the coagulation cascade. We investigated whether increased synthesis of tissue factor (TF) by platelets could contribute to the hypercoagulant state. RESEARCH DESIGN AND METHODS: Platelets from type 2 diabetic patients and matched control subjects were adhered to different surface coated proteins, and TF premRNA splicing, TF protein, and TF procoagulant activity were measured. RESULTS: Different adhesive proteins induced different levels of TF synthesis. A mimetic of active clopidogrel metabolite (AR-C69931 MX) reduced TF synthesis by 56 +/- 10%, an aspirin-like inhibitor (indomethacin) by 82 +/- 9%, and the combination by 96 +/- 2%, indicating that ADP release and thromboxane A(2) production followed by activation of P2Y12 and thromboxane receptors mediate surface-induced TF synthesis. Interference with intracellular pathways revealed inhibition by agents that raise cAMP and interfere with phosphatidylinositol 3-kinase/protein kinase B. Insulin is known to raise cAMP in platelets and inhibited collagen III-induced TF premRNA splicing and reduced TF activity by 35 +/- 5 and 47 +/- 5% at 1 and 100 nmol/l. Inhibition by insulin was reduced in type 2 diabetes platelets resulting in an approximately 1.6-fold higher TF synthesis than in matched control subjects. CONCLUSIONS: We characterized the extra- and intracellular mechanisms that couple surface activation to TF synthesis in adhering platelets. In healthy individuals, TF synthesis is inhibited by insulin, but in patients with type 2 diabetes inhibition is impaired. This leads to the novel finding that platelets from type 2 diabetic patients produce more TF than platelets from matched control subjects. PMID- 20200315 TI - MTNR1B G24E variant associates With BMI and fasting plasma glucose in the general population in studies of 22,142 Europeans. AB - OBJECTIVE: Common variants in the melatonin receptor type 1B (MTNR1B) locus have been shown to increase fasting plasma glucose (FPG) and the risk of type 2 diabetes. The aims of this study were to evaluate whether nonsynonymous variants in MTNR1B associate with monogenic forms of hyperglycemia, type 2 diabetes, or related metabolic traits. RESEARCH DESIGN AND METHODS: MTNR1B was sequenced in 47 probands with clinical maturity-onset diabetes of the young (MODY), in 51 probands with early-onset familial type 2 diabetes, and in 94 control individuals. Six nonsynonymous variants (G24E, L60R, V124I, R138C, R231H, and K243R) were genotyped in up to 22,142 Europeans. Constitutive and melatonin induced signaling was characterized for the wild-type melatonin receptor type 1B (MT2) and the 24E, 60R, and 124I MT2 mutants in transfected COS-7 cells. RESULTS: No mutations in MTNR1B were MODY specific, and none of the investigated MTNR1B variants associated with type 2 diabetes. The common 24E variant associated with increased prevalence of obesity (odds ratio 1.20 [1.08-1.34]; P = 8.3 x 10(-4)) and increased BMI (beta = 0.5 kg/m(2); P = 1.2 x 10(-5)) and waist circumference (beta = 1.2 cm; P = 9 x 10(-6)) in combined Danish and French study samples. 24E also associated with decreased FPG (beta = -0.08 mmol/l; P = 9.2 x 10(-4)) in the Danish Inter99 population. Slightly decreased constitutive activity was observed for the MT2 24E mutant, while the 124I and 60R mutants displayed considerably decreased or completely disrupted signaling, respectively. CONCLUSIONS: Nonsynonymous mutations in MTNR1B are not a common cause of MODY or type 2 diabetes among Danes. MTNR1B 24E associates with increased body mass and decreased FPG. Decreased MT2 signaling does apparently not directly associate with FPG or type 2 diabetes. PMID- 20200316 TI - Local non-esterified fatty acids correlate with inflammation in atheroma plaques of patients with type 2 diabetes. AB - OBJECTIVE: Atherosclerosis is prevalent in diabetic patients, but there is little information on the localization of nonesterified fatty acids (NEFAs) within the plaque and their relationship with inflammation. We sought to characterize the NEFA composition and location in human diabetic atheroma plaques by metabolomic analysis and imaging and to address their relationship with inflammation activity. RESEARCH DESIGN AND METHODS: Time-of-flight secondary ion mass spectrometry (TOF-SIMS) was used for metabolomic analysis imaging of frozen carotid atheroma plaques. Carotid endarterectomy specimens were used for conventional immunohistochemistry, laser-capture microdissection quantitative PCR, and in situ Southwestern hybridization. Biological actions of linoleic acid were studied in cultured vascular smooth muscle cells (VSMCs). RESULTS: TOF-SIMS imaging evidenced a significant increase in the quantity of several NEFA in diabetic versus nondiabetic atheroma plaques. Higher levels of NEFA were also found in diabetic sera. The presence of LPL mRNA in NEFA-rich areas of the atheroma plaque, as well as the lack of correlation between serum and plaque NEFA, suggests a local origin for plaque NEFA. The pattern of distribution of plaque NEFA is similar to that of MCP-1, LPL, and activated NF-kappaB. Diabetic endarterectomy specimens showed higher numbers of infiltrating macrophages and T lymphocytes-a finding that associated with higher NEFA levels. Finally, linoleic acid activates NF-kappaB and upregulates NF-kappaB-mediated LPL and MCP-1 expression in cultured VSMC. DISCUSSION: There is an increased presence of NEFA in diabetic plaque neointima. NEFA levels are higher in diabetic atheroma plaques than in nondiabetic subjects. We hypothesize that NEFA may be produced locally and contribute to local inflammation. PMID- 20200317 TI - High-mobility group box-1 protein promotes angiogenesis after peripheral ischemia in diabetic mice through a VEGF-dependent mechanism. AB - OBJECTIVE: High-mobility group box-1 (HMGB1) protein is a nuclear DNA-binding protein released from necrotic cells, inducing inflammatory responses and promoting tissue repair and angiogenesis. Diabetic human and mouse tissues contain lower levels of HMGB1 than their normoglycemic counterparts. Deficient angiogenesis after ischemia contributes to worse outcomes of peripheral arterial disease in patients with diabetes. To test the hypothesis that HMGB1 enhances ischemia-induced angiogenesis in diabetes, we administered HMGB1 protein in a mouse hind limb ischemia model using diabetic mice. RESEARCH DESIGN AND METHODS: After the induction of diabetes by streptozotocin, we studied ischemia-induced neovascularization in the ischemic hind limb of normoglycemic, diabetic, and HMGB1-treated diabetic mice. RESULTS: We found that the perfusion recovery was significantly attenuated in diabetic mice compared with normoglycemic control mice. Interestingly, HMGB1 protein expression was lower in the ischemic tissue of diabetic mice than in normoglycemic mice. Furthermore, we observed that HMGB1 administration restored the blood flow recovery and capillary density in the ischemic muscle of diabetic mice, that this process was associated with the increased expression of vascular endothelial growth factor (VEGF), and that HMGB1 induced angiogenesis was significantly reduced by inhibiting VEGF activity. CONCLUSIONS: The results of this study show that endogenous HMGB1 is crucial for ischemia-induced angiogenesis in diabetic mice and that HMGB1 protein administration enhances collateral blood flow in the ischemic hind limbs of diabetic mice through a VEGF-dependent mechanism. PMID- 20200318 TI - PTEN inhibition improves muscle regeneration in mice fed a high-fat diet. AB - OBJECTIVE: Mechanisms impairing wound healing in diabetes are poorly understood. To identify mechanisms, we induced insulin resistance by chronically feeding mice a high-fat diet (HFD). We also examined the regulation of phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) during muscle regeneration because augmented IGF-1 signaling can improve muscle regeneration. RESEARCH DESIGN AND METHODS: Muscle regeneration was induced by cardiotoxin injury, and we evaluated satellite cell activation and muscle maturation in HFD-fed mice. We also measured PIP(3) and the enzymes regulating its level, IRS-1-associated phosphatidylinositol 3-kinase (PI3K) and PTEN. Using primary cultures of muscle, we examined how fatty acids affect PTEN expression and how PTEN knockout influences muscle growth. Mice with muscle-specific PTEN knockout were used to examine how the HFD changes muscle regeneration. RESULTS: The HFD raised circulating fatty acids and impaired the growth of regenerating myofibers while delaying myofiber maturation and increasing collagen deposition. These changes were independent of impaired proliferation of muscle progenitor or satellite cells but were principally related to increased expression of PTEN, which reduced PIP(3) in muscle. In cultured muscle cells, palmitate directly stimulated PTEN expression and reduced cell growth. Knocking out PTEN restored cell growth. In mice, muscle-specific PTEN knockout improved the defects in muscle repair induced by HFD. CONCLUSIONS: Insulin resistance impairs muscle regeneration by preventing myofiber maturation. The mechanism involves fatty acid-stimulated PTEN expression, which lowers muscle PIP(3). If similar pathways occur in diabetic patients, therapeutic strategies directed at improving the repair of damaged muscle could include suppression of PTEN activity. PMID- 20200319 TI - Glycerol-3-phosphate acyltransferase 1 deficiency in ob/ob mice diminishes hepatic steatosis but does not protect against insulin resistance or obesity. AB - OBJECTIVE: Hepatic steatosis is strongly associated with insulin resistance, but a causal role has not been established. In ob/ob mice, sterol regulatory element binding protein 1 (SREBP1) mediates the induction of steatosis by upregulating target genes, including glycerol-3-phosphate acyltransferase-1 (Gpat1), which catalyzes the first and committed step in the pathway of glycerolipid synthesis. We asked whether ob/ob mice lacking Gpat1 would have reduced hepatic steatosis and improved insulin sensitivity. RESEARCH DESIGN AND METHODS: Hepatic lipids, insulin sensitivity, and hepatic insulin signaling were compared in lean (Lep(+/?)), lean-Gpat1(-/-), ob/ob (Lep(ob/ob)), and ob/ob-Gpat1(-/-) mice. RESULTS Compared with ob/ob mice, the lack of Gpat1 in ob/ob mice reduced hepatic triacylglycerol (TAG) and diacylglycerol (DAG) content 59 and 74%, respectively, but increased acyl-CoA levels. Despite the reduction in hepatic lipids, fasting glucose and insulin concentrations did not improve, and insulin tolerance remained impaired. In both ob/ob and ob/ob-Gpat1(-/-) mice, insulin resistance was accompanied by elevated hepatic protein kinase C-epsilon activation and blunted insulin-stimulated Akt activation. CONCLUSIONS: These results suggest that decreasing hepatic steatosis alone does not improve insulin resistance, and that factors other than increased hepatic DAG and TAG contribute to hepatic insulin resistance in this genetically obese model. They also show that the SREBP1-mediated induction of hepatic steatosis in ob/ob mice requires Gpat1. PMID- 20200320 TI - Peroxisome proliferator-activated receptor-gamma coactivator-1alpha overexpression increases lipid oxidation in myocytes from extremely obese individuals. AB - OBJECTIVE: To determine whether the obesity-related decrement in fatty acid oxidation (FAO) in primary human skeletal muscle cells (HSkMC) is linked with lower mitochondrial content and whether this deficit could be corrected via overexpression of peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha). RESEARCH DESIGN AND METHODS: FAO was studied in HSkMC from lean (BMI 22.4 +/- 0.9 kg/m(2); N = 12) and extremely obese (45.3 +/- 1.4 kg/m(2); N = 9) subjects. Recombinant adenovirus was used to increase HSkMC PGC 1alpha expression (3.5- and 8.0-fold), followed by assessment of mitochondrial content (mtDNA and cytochrome C oxidase IV [COXIV]), complete ((14)CO(2) production from labeled oleate), and incomplete (acid soluble metabolites [ASM]) FAO, and glycerolipid synthesis. RESULTS: Obesity was associated with a 30% decrease (P < 0.05) in complete FAO, which was accompanied by higher relative rates of incomplete FAO ([(14)C]ASM production/(14)CO(2)), increased partitioning of fatty acid toward storage, and lower (P < 0.05) mtDNA (-27%), COXIV (-35%), and mitochondrial transcription factor (mtTFA) (-43%) protein levels. PGC-1alpha overexpression increased (P < 0.05) FAO, mtDNA, COXIV, mtTFA, and fatty acid incorporation into triacylglycerol in both lean and obese groups. Perturbations in FAO, triacylglycerol synthesis, mtDNA, COXIV, and mtTFA in obese compared with lean HSkMC persisted despite PGC-1alpha overexpression. When adjusted for mtDNA and COXIV content, FAO was equivalent between lean and obese groups. CONCLUSION: Reduced mitochondrial content is related to impaired FAO in HSkMC derived from obese individuals. Increasing PGC-1alpha protein levels did not correct the obesity-related absolute reduction in FAO or mtDNA content, implicating mechanisms other than PGC-1alpha abundance. PMID- 20200321 TI - Vascular safety during high tibial osteotomy: a cadaveric angiographic study. AB - BACKGROUND: High tibial osteotomy is technically demanding. Risks include injury to the popliteal neurovascular bundle. The present goal was to further define this risk. HYPOTHESIS: The distance from the posterior tibia to the popliteal artery increases with increasing knee flexion. A saw angle perpendicular to the coronal plane can injure the popliteal artery. STUDY DESIGN: Descriptive laboratory study. METHODS: Seven fresh-frozen cadaveric lower extremities were used. Lateral radiographs at knee flexion angles of 90 degrees , 60 degrees , 45 degrees , 30 degrees , and 0 degrees were taken to measure the distance from the anterior border of the popliteal artery to the posterior cortex of the tibia 5.0 mm and 2.0 cm below the joint line. After an opening wedge high tibial osteotomy was made, qualitative assessments were made of the depth of a saw blade inserted into the kerf and the relative encroachment of the saw blade on the popliteal artery. The interval through which the space anterior to the popliteus can be accessed was identified by gross dissection in all specimens. RESULTS: The distance from the posterior tibia to the popliteal artery increased with knee flexion. At 5.0 mm and 2.0 cm below the joint line, the mean distance at 90 degrees was significantly greater than at all other angles. The popliteal artery could be injured by the oscillating saw at angles greater than 30 degrees to the coronal plane. A protective device inserted anterior to the popliteus protects the neurovascular structures. CONCLUSION: The popliteal artery is farthest from the posterior tibia at 90 degrees of knee flexion. Saw angles greater than 30 degrees from the coronal plane put the popliteal neurovasculature at risk of injury. CLINICAL RELEVANCE: To perform a safe osteotomy, the knee should be positioned in 90 degrees of flexion with the saw angled less than 30 degrees from the coronal plane. A protective device deep to the popliteus may protect against popliteal injury. PMID- 20200322 TI - The distal triceps tendon footprint and a biomechanical analysis of 3 repair techniques. AB - BACKGROUND: Anatomic repair of tendon ruptures is an important goal of surgical treatment. There are limited data on the triceps brachii insertion, footprint, and anatomic reconstruction of the distal triceps tendon. HYPOTHESIS: An anatomic repair of distal triceps tendon ruptures more closely imitates the preinjury anatomy and may result in a more durable repair. STUDY DESIGN: Descriptive and controlled laboratory studies. METHODS: The triceps tendon footprint was measured in 27 cadaveric elbows, and a distal tendon rupture was created. Elbows were randomly assigned to 1 of 3 repair groups: cruciate repair group, suture anchor group, and anatomic repair group. Biomechanical measurement of load at yield and peak load were measured. Cyclic loading was performed for a total of 1500 cycles and displacement measured. RESULTS: The average bony footprint of the triceps tendon was 466 mm2. Cyclic loading of tendons from the 3 repair types demonstrated that the anatomic repair produced the least amount of displacement when compared with the other repair types (P < .05). Load at yield and peak load were similar for all repair types (P > .05). CONCLUSION: The triceps bony footprint is a large area on the olecranon that should be considered when repairing distal triceps tendon ruptures. Anatomic repair of triceps tendon ruptures demonstrated the most anatomic restoration of distal triceps ruptures and showed statistically significantly less repair-site motion when cyclically loaded. CLINICAL RELEVANCE: Anatomic repair better restores preinjury anatomy compared with other types of repairs and demonstrates less repair-site motion, which may play a role in early postoperative management. PMID- 20200323 TI - Influence of the anteromedial and posterolateral bundles of the anterior cruciate ligament on external and internal tibiofemoral rotation. AB - BACKGROUND: The influence of the anteromedial and posterolateral bundles of the anterior cruciate ligament on tibiofemoral rotation might be of great value to detect anterior cruciate ligament injuries and investigate the postoperative restoration of rotational stability. HYPOTHESIS: The anterior cruciate ligament and especially the posterolateral bundle will have a significant influence on isolated tibiofemoral rotation. STUDY DESIGN: Controlled laboratory study. METHODS: Tibiofemoral rotation was measured in 20 human cadaveric knees using a noninvasive external measurement device (Rotameter) and a knee navigation system. The measurements of the knees with the intact anterior cruciate ligament were compared with the measurements after isolated resection of the posterolateral bundle and after a complete resection of the anterior cruciate ligament at an applied torque of 5,10, and 15 N.m. Statistical analysis was made using analysis of variance and the post hoc Scheffe test. The Pearson coefficient was used to compare both measurement techniques. RESULTS: In comparison with knees with an intact anterior cruciate ligament, the knees after isolated resection of the posterolateral bundle showed significant increase of tibiofemoral rotation at almost all applied torques (P <.05). Total resection of the anterior cruciate ligament also produced significant increases compared with the intact anterior cruciate ligament at torques of 5, 10, and 15 N.m as measured by the Rotameter (P <.05). Total resection of the anterior cruciate ligament yielded increases in rotation compared with posterolateral bundle resection alone, but these differences were not significant. The results of the knee navigation system confirmed the measured results of the Rotameter. Comparison of the 2 measurement methods revealed a high correlation at all applied torques, with Pearson correlation coefficients ranging from .85 to .95. CONCLUSION: The anterior cruciate ligament and especially the posterolateral bundle of the anterior cruciate ligament have a significant effect on isolated tibiofemoral rotation. Therefore, the developed noninvasive device might be of great importance to investigate the status and the postoperative reconstruction of the anterior cruciate ligament in the clinical setting. CLINICAL RELEVANCE: Noninvasive measurement of tibiofemoral rotation might be useful to detect anterior cruciate ligament tears and to evaluate the restoration of rotational stability after anterior cruciate ligament surgery. PMID- 20200324 TI - Pannexin-I/P2X 7 purinergic receptor channels mediate the release of cardioprotectants induced by ischemic pre- and postconditioning. AB - Ischemic pre- and postconditioning protect ex vivo rat hearts from ischemia/reperfusion injury by promoting the release of cardioprotective agents by an unknown mechanism. Because P2X( 7) purinergic receptors are known to combine with pannexin-1 to form channels that allow adenosine triphosphate (ATP) release from cells, we hypothesized that these channels have a role in the release of multiple cardioprotectants during ischemic preconditioning (IPC). Addition of either a pannexin-1 hemichannel blocker (5 micromol/L carbenoxolone [CBX] or 0.4 micromol/L mefloquine [MF]) or a selective antagonist of the rat P2X(7) purinergic receptor (2 micromol/L brilliant blue G [BBG]) blocked IPC. These antagonists also blocked ischemic postconditioning. Preconditioning by exogenous addition of either sphingosine-1-phosphate or adenosine was not blocked by either CBX or BBG, indicating that they only affected the release of endogenous mediators, not any subsequent steps. To determine if only ATP release was mediated by pannexin-1/P2X(7) channels, we added an extra cycle of IPC to release sufficient quantities of additional cardioprotectants to eliminate the dependence on adenosine derivatives. This did not override the inhibition of IPC by CBX or MF, suggesting that the channel mediates the release of multiple cardioprotectants. Inhibitors of other P2X receptors, P2Y receptors, or connexins did not affect IPC. We conclude that a pannexin-1/P2X(7) channel is responsible for the release of cardioprotectants induced by ischemic pre- and postconditioning. PMID- 20200325 TI - Tegaserod and the risk of cardiovascular ischemic events: an observational cohort study. AB - OBJECTIVES: Tegaserod, a partial 5-HT(4) agonist previously approved for treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation, was suspended from US marketing in 2007, based on pooled clinical trial results which contained a signal suggesting increased risk of cardiovascular ischemic events (CVIEs). We sought to evaluate whether there was an association between tegaserod and CVIE in a setting of routine clinical practice. METHODS: This was a matched cohort study conducted within a large US health insurance database, involving 52 229 patients who initiated tegaserod and 52 229 patients with similar characteristics who did not initiate tegaserod. Participants were followed for up to 6 months for the occurrence of CVIE (myocardial infarction, acute coronary syndrome, coronary revascularization, and stroke). Outcomes were identified using insurance claims and were confirmed by review of medical records. We conducted as-matched analyses providing hazard ratios (HRs) along with 95% confidence intervals (95% CI) and as-treated analyses accounting for changes in dispensed therapy. RESULTS: There was no increased risk of CVIE associated with tegaserod treatment. The as-matched association between tegaserod and ischemic cardiovascular outcomes (HR = 0.95, 95% CI 0.73-1.23) and stroke (HR = 0.90, 95% CI 0.46-1.77) did not change substantially in the as treated analyses (cardiovascular relative risk [RR] = 1.14, 95% CI 0.83-1.56; stroke: RR = 1.09, 95% CI = 0.49-2.02). The results were largely unaffected by adjustment for characteristics or subgroup analyses. CONCLUSION: In this observational study of tegaserod use, we found no evidence for an increased risk of CVIE in tegaserod users. PMID- 20200326 TI - Effects of additional administration of low-dose indapamide on patients with hypertension treated with angiotensin II receptor blocker. AB - BACKGROUND: Low-dose thiazide or thiazide-like diuretics have proven useful for the management of blood pressure in patients older than 65 years (elderly group). However, there are few reports about the antihypertensive effects of antihypertensive diuretic agents in patients younger than 65 years (middle-aged group). So, we evaluated the efficacy of low-dose indapamide on blood pressure. METHODS: Indapamide(1 mg) was given daily for 3 months and was then given every other day for 3 months to patients whose hypertension was poorly controlled with angiotensin II receptor blocker (ARB)-based treatment. RESULTS: After daily administration of indapamide, blood pressure was significantly decreased in both the middle-aged and elderly groups. Blood pressure was not significantly changed by every-other-day administration compared with that observed after daily administration in either group. The rate of attainment of the target blood pressure was 90.3% and 85.7% in the middle-aged and elderly groups, respectively. The serum uric acid levels were reduced after every-other-day administration compared to daily administration but tended to be higher than the levels at the baseline in both groups. CONCLUSIONS: The addition of low-dose indapamide is a useful strategy for the management of hypertension, as it reduced blood pressure without marked side effects. PMID- 20200327 TI - Review article: epoxyeicosatrienoic acids: novel mediators of cardioprotection. AB - Recent evidence from a number of in vitro and in vivo studies in isolated cells and animal models has suggested that the cytochrome P450 (CYP450) pathway of arachidonic acid (AA) metabolism produces potent cardioprotective metabolites that markedly reduce reversible (myocardial stunning) and irreversible (infarct size [IS]) injury in the ischemic/reperfused heart. The major players in this protective response appear to be the AA metabolites including the regioisomers of 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs). The present review article will discuss the beneficial effects of the EETs on myocardial stunning and IS reduction and consider some of the signaling pathways and cellular mechanisms by which the EETs produce their beneficial effects and the possible therapeutic benefits that may result from activation of this pathway. The results discussed in this review are taken from experiments obtained from 3 diverse species in different laboratories: the mouse, rat, and dog, in which the results were nearly identical qualitatively and quantitatively, suggesting that these findings are likely to be extrapolated to man as well. PMID- 20200328 TI - Review article: effects of plant sterols and stanols beyond low-density lipoprotein cholesterol lowering. AB - Consumption of foods and supplements enriched with plant sterols/stanols (PS) may help reduce low-density lipoprotein cholesterol (LDL-C) levels. In this review, we consider the effects of PS beyond LDL-C lowering. Plant sterols/stanols exert beneficial effects on other lipid variables, such as apolipoprotein (apo) B/apoAI ratio and, in some studies, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG). Plant sterols/stanols may also affect inflammatory markers, coagulation parameters, as well as platelet and endothelial function. Evidence also exists about a beneficial effect on oxidative stress, but this does not seem to be of greater degree than that expected from the LDL-C lowering. Many of these effects have been demonstrated in vitro and animal models. Some in vitro effects cannot be seen in vivo or in humans at usual doses. The epidemiological studies that evaluated the association of plasma PS concentration with cardiovascular disease (CVD) risk do not provide a definitive answer. Long-term randomized placebo-controlled studies are required to clarify the effects of supplementation with PS on CVD risk and progression of atherosclerosis. PMID- 20200329 TI - Defining the optimal prognostic window for cardiopulmonary exercise testing in patients with heart failure. AB - BACKGROUND: Ventilatory efficiency (VE/VCO(2) slope) and peak oxygen consumption (VO) provide robust prognostic information in patients with heart failure undergoing cardiopulmonary exercise testing (CPX). The purpose of this study is to assess the change in prognostic characteristics of CPX at different time intervals. METHODS AND RESULTS: Seven hundred ninety-one subjects (74% male, mean age: 60.7+/-12.9 years, ejection fraction: 34.6+/-15.0%, ischemic etiology: 51%) underwent CPX and were tracked for major cardiac events over a 4-year period. All event-free subjects were tracked for at least 3 years. Mean VE/VCO(2) slope and peak VO(2) were 35.0+/-10.0 and 16.0+/-6.4 mL O(2) . kg(-1) . min(-1), respectively. There were a total of 263 major cardiac events (199 deaths, 45 transplants, and 19 left ventricular assist device implantations). Both continuous and dichotomous expressions of the VE/VCO(2) slope and peak VO(2) were prognostically significant up to 18 months post-CPX. Continuous and dichotomous expressions of the VE/VCO(2) slope remained prognostically significant up to 36 months post-CPX, whereas peak VO(2) was not predictive during the third and fourth year of follow-up. In a multivariate analysis, the VE/VCO(2) slope was consistently the superior prognostic marker, whereas peak VO(2) added predictive value and was retained in the regression up to 18 months post-CPX. CONCLUSIONS: These results indicate that commonly assessed CPX variables retain prognostic value for at least 2 years. The VE/VCO(2) slope is the superior predictor of adverse events throughout follow-up, although peak VO(2) provides additive prognostic information during the first 2 years of follow-up. PMID- 20200330 TI - Osteopontin expression in cardiomyocytes induces dilated cardiomyopathy. AB - BACKGROUND: Inflammatory processes play a critical role in myocarditis, dilated cardiomyopathy, and heart failure. The expression of the inflammatory chemokine osteopontin (OPN) is dramatically increased in cardiomyocytes and inflammatory cells during myocarditis and heart failure in human and animals. However, its role in the development of heart diseases is not known. METHODS AND RESULTS: To understand whether OPN is involved in cardiomyopathies, we generated a transgenic mouse (MHC-OPN) that specifically overexpresses OPN in cardiomyocytes with cardiac-specific promoter-directed OPN expression. Young MHC-OPN mice were phenotypically indistinguishable from their control littermates, but most of them died prematurely with a half-life of 12 weeks of age. Electrocardiography revealed conduction defects. Echocardiography showed left ventricular dilation and systolic dysfunction. Histological analysis revealed cardiomyocyte loss, severe fibrosis, and inflammatory cell infiltration. Most of these inflammatory cells were activated T cells with Th1 polarization and cytotoxic activity. Autoantibodies against OPN, cardiac myosin, or troponin I, were not found in the serum of MHC-OPN mice. CONCLUSIONS: These data show that OPN expression in the heart induces in vivo T-cell recruitment and activation leading to chronic myocarditis, the consequence of which is myocyte destruction and hence, dilated cardiomyopathy. Thus, OPN might therefore constitute a potential therapeutic target to limit heart failure. PMID- 20200331 TI - GATA-4 is an angiogenic survival factor of the infarcted heart. AB - BACKGROUND: Recent data suggest that GATA-4 is an antiapoptotic factor required for adaptive responses and a key regulator of hypertrophy and hypertrophy associated genes in the heart. As a leading cause of chronic heart failure, reversal of postinfarction left ventricular remodeling represents an important target for therapeutic interventions. Here, we studied the role of GATA-4 as a mediator of postinfarction remodeling in rats. METHODS AND RESULTS: Myocardial infarction, caused by ligating the left anterior descending coronary artery, significantly decreased the DNA binding activity of GATA-4 at day 1, whereas at 2 weeks the GATA-4 DNA binding was significantly upregulated. To determine the functional role of GATA-4, peri-infarct intramyocardial delivery of adenoviral vector expressing GATA-4 was done before left anterior descending coronary artery ligation. Hearts treated with GATA-4 gene transfer exhibited significantly increased ejection fraction and fractional shortening. Accordingly, infarct size was significantly reduced. To determine the cardioprotective mechanisms of GATA 4, myocardial angiogenesis, rate of apoptosis, c-kit+ cardiac stemlike cells, and genes regulated by GATA-4 were studied. The number of capillaries and stemlike cells was significantly increased, and decreased apoptosis was observed. CONCLUSION: These results indicate that the reversal of reduced GATA-4 activity prevents adverse postinfarction remodeling through myocardial angiogenesis, antiapoptosis, and stem cell recruitment. GATA-4-based gene transfer may represent a novel, efficient therapeutic approach for heart failure. PMID- 20200332 TI - Family-based analysis of candidate genes for polycystic ovary syndrome. AB - CONTEXT: Polycystic ovary syndrome (PCOS) is a complex disorder having both genetic and environmental components. A number of association studies based on candidate genes have reported significant association, but few have been replicated. D19S884, a polymorphic marker in fibrillin 3 (FBN3), is one of the few association findings that has been replicated in independent sets of families. OBJECTIVE: The aims of the study are: 1) to genotype single nucleotide polymorphisms (SNPs) in the region of D19S884; and 2) to follow up with an independent data set, published results reporting evidence for PCOS candidate gene associations. DESIGN: The transmission disequilibrium test (TDT) was used to analyze linkage and association between PCOS and SNPs in candidate genes previously reported by us and by others as significantly associated with PCOS. SETTING: The study was conducted at academic medical centers. PATIENTS OR OTHER PARTICIPANTS: A total of 453 families having a proband with PCOS participated in the study. Sisters with PCOS were also included. There was a total of 502 probands and sisters with PCOS. INTERVENTION(S): There were no interventions. MAIN OUTCOME MEASURE(S): The outcome measure was transmission frequency of SNP alleles. RESULTS: We identified a six-SNP haplotype block spanning a 6.7-kb region on chromosome 19p13.2 that includes D19S884. SNP haplotype allele-C alone and in combination with D19S884-allele 8 is significantly associated with PCOS: haplotype-C TDT chi(2) = 10.0 (P = 0.0016) and haplotype-C/A8 TDT chi(2) = 7.6 (P = 0.006). SNPs in four of the other 26 putative candidate genes that were tested using the TDT were nominally significant (ACVR2A, POMC, FEM1B, and SGTA). One SNP in POMC (rs12473543, chi(2) = 9.1; P(corrected) = 0.042) is significant after correction for multiple testing. CONCLUSIONS: A polymorphic variant, D19S884, in FBN3 is associated with risk of PCOS. POMC is also a candidate gene of interest. PMID- 20200333 TI - Changes in apolipoprotein B100-containing lipoprotein metabolism due to an estrogen plus progestin oral contraceptive: a stable isotope kinetic study. AB - CONTEXT: Oral contraceptives with estrogen plus progestin are likely to influence apolipoprotein B (apoB)-containing lipoprotein metabolism by changing the expression of different enzymes or receptors that play a major role in this metabolism. However, the precise changes in apoB kinetic parameters induced by oral contraceptives that are now currently used are unknown. OBJECTIVES: We studied the impact of Moneva, containing 30 microg ethinylestradiol and 75 microg gestodene, on the apoB production rate and fractional catabolic rate of very-low density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low density lipoprotein (LDL). DESIGN: Using a 16-h [(13)C]leucine infusion, we performed an apoB kinetic study in nine normolipidemic women before and 3 months after beginning Moneva. RESULTS: On Moneva, serum triglycerides increased moderately (+12%, P = 0.04) in the fed state, whereas serum LDL remained unchanged. LDL particles were richer in triglycerides in women on Moneva (7.5 +/- 1.5 vs. 4.3 +/- 1.0% of total LDL mass, P < 0.01). The apoB production rate of VLDL, IDL, and LDL increased by 49 (P = 0.04), 55 (P = 0.05), and 51% (P = 0.01), respectively. The fractional catabolic rate of apoB in LDL increased by 36% (P = 0.04). Consequently, the serum LDL apoB pool size remained unchanged (26.49 +/- 6.98 vs. 23.96 +/- 5.37 mg/kg). CONCLUSION: Oral contraception with ethinylestradiol plus gestodene induces an increase in the production rate of apoB-containing lipoproteins all along the VLDL-->IDL-->LDL cascade. The increased production rate of apoB in LDL is counterbalanced by a higher fractional catabolic rate of apoB in LDL, thus precluding an increase in the concentration of atherogenic LDL particles. PMID- 20200334 TI - Adrenocortical zonation in humans under normal and pathological conditions. AB - CONTEXT: Aldosterone synthase (CYP11B2) and steroid 11 beta-hydroxylase (CYP11B1) catalyze the terminal steps for aldosterone and cortisol syntheses, respectively, thereby determining the functional differentiation of human adrenocortical cells. Little is known, however, about how the cells expressing the enzymes are actually distributed in the adrenals under normal and pathological conditions. OBJECTIVE: The objective of the study was to determine the localization of CYP11B2 and -B1 in human adrenal specimens by using developed antibodies capable of distinguishing the two enzymes from each other. RESULTS: Under normal conditions, CYP11B2 was sporadically detected in the zona glomerulosa, whereas CYP11B1 was entirely detected in the zonae fasciculata-reticularis. Adrenocortical cells lacking both enzymes were observed in the outer cortical regions. In addition to conventional zonation, we found a variegated zonation consisting of a subcapsular cell cluster expressing CYP11B2, which we termed aldosterone-producing cell cluster, and a CYP11B1-expressing area. Aldosterone-producing adenomas differed in cell populations expressing CYP11B2 from one another, whereas CYP11B1 expressing and double-negative cells were also intermingled. Adenomas from patients with Cushing's syndrome expressed CYP11B1 entirely but not CYP11B2, resulting in atrophic nontumor glands. The nontumor portions of both types of adenomas bore frequently one or more aldosterone-producing cell clusters, which sustained CYP11B2 expression markedly under the conditions of the suppressed renin-angiotensin system. CONCLUSION: Immunohistochemistry of the human normal adrenal cortex for CYP11B2 and CYP11B1 revealed a variegated zonation with cell clusters constitutively expressing CYP11B2. This technique may provide a pathological confirmatory diagnosis of adrenocortical adenomas. PMID- 20200335 TI - The subcutaneous abdominal fat and not the intraabdominal fat compartment is associated with anovulation in women with obesity and infertility. AB - CONTEXT: Abdominal fat contributes to anovulation. OBJECTIVE: We compared body fat distribution measurements and their contribution to anovulation in obese ovulatory and anovulatory infertile women. DESIGN: Seventeen ovulatory and 40 anovulatory women (age, 30 +/- 4 yr; body mass index, 37.7 +/- 6.1 kg/m(2)) participated. Body fat distribution was measured by anthropometrics, dual-energy x-ray absorptiometry, and single-sliced abdominal computed tomography scan. Multiple logistic regression analysis was applied to determine which fat compartments significantly contributed to anovulation. RESULTS: Anovulatory women had a higher waist circumference (113 +/- 11 vs. 104 +/- 9 cm; P < 0.01) and significantly more trunk fat (23.0 +/- 5.3 vs. 19.1 +/- 4.2 kg; P < 0.01) and abdominal fat (4.4 +/- 1.3 kg vs. 3.5 +/- 0.9 kg; P < 0.05) on dual-energy x-ray absorptiometry scan than ovulatory women despite similar body mass index. The volume of intraabdominal fat on single-sliced abdominal computed tomography scan was not significantly different between the two groups (203 +/- 56 vs. 195 +/- 71 cm(3); P = 0.65), but anovulatory women had significantly more sc abdominal fat (SAF) (992 +/- 198 vs. 864 +/- 146 cm(3); P < 0.05). After multiple logistic regression analysis, only trunk fat, abdominal fat, and SAF were associated with anovulation. CONCLUSIONS: Abdominal fat is increased in anovulatory women due to a significant increase in SAF and not in intraabdominal fat. SAF and especially abdominal and trunk fat accumulation are associated with anovulation. PMID- 20200336 TI - A novel ultrapressure liquid chromatography tandem mass spectrometry method for the simultaneous determination of androstenedione, testosterone, and dihydrotestosterone in pediatric blood samples: age- and sex-specific reference data. AB - CONTEXT: Current immunoassays for analysis of plasma androgens in children have several limitations due to antibody-specific variations of data and normal ranges. Mass spectrometry-based methods are available for individual steroids but need complex sample preparation and report only fragmentary reference data for the pediatric population. OBJECTIVE: Our objective was to develop a state of the art sensitive and specific tandem mass spectrometry method for high-throughput simultaneous determination of plasma concentrations of androstenedione (A), testosterone (T), and dihydrotestosterone (DHT) and to report age-, sex-, and pubertal stage-specific reference levels for these steroids in children aged 0-18 yr. SUBJECTS AND METHODS: Plasma (100 microl) was mixed with internal standard and extracted by solid-phase extraction. Androgens were measured by ultrapressure liquid chromatography tandem mass spectrometry. Samples of 138 boys and 131 girls with neither signs of endocrine nor systemic disease were considered for the generation of reference data. The following age groups were used: less than 1 wk, 2 wk to 2 months, 3-5 months, 6-11 months, 1-3 yr, 4-6 yr, 7-9 yr, 10-12 yr, 13 15 yr, and over 16 yr. RESULTS: Lower quantification limit was 2.9 ng/dl (0.1 nmol/liter) for A, T, and DHT. No relevant interference with other steroids was detected. Reference data for A, T, and DHT are reported as functions of age, sex, pubertal maturation, and testicular volume. CONCLUSION: Simplicity, velocity, sensitivity, specificity, and the availability of pediatric reference data allow application of our new method in clinical routine as well as in research settings. PMID- 20200337 TI - Peroxisome proliferator-activated receptor-delta genotype influences metabolic phenotype and may influence lipid response to statin therapy in humans: a genetics of diabetes audit and research Tayside study. AB - CONTEXT: Previous studies have identified a single-nucleotide polymorphism in the gene encoding peroxisome proliferator-activated receptor-delta (PPARD), rs2016520, that is associated with changes in metabolic disease in some but not all studies, which suggests that PPARD agonists may have therapeutic benefits for the treatment of metabolic disorders, including dyslipidemia, type 2 diabetes, and obesity. OBJECTIVE: The objective of the study was to determine whether rs2016520 or other single-nucleotide polymorphism in the PPARD locus influenced the risk of developing various characteristics of metabolic disease. DESIGN: Haplotype tagging analysis across PPARD was performed in 11,074 individuals from the Welcome Trust U.K. Type 2 Diabetes Case Control Collection. RESULTS: In subjects with and without type 2 diabetes, rs2016520 was associated with body mass index, high-density lipoprotein cholesterol, leptin, and TNFalpha and was dependent on gender. CONCLUSION: The current results suggest differential effects of PPARdelta in males and females. PMID- 20200338 TI - Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant? AB - BACKGROUND: Ibudilast is a phosphodiesterase inhibitor influencing inflammation and neurodegeneration in multiple sclerosis (MS). This study evaluated the safety, tolerability, and effects on MRI parameters of 2 different doses of ibudilast in relapsing forms of MS. METHODS: In this multicenter, double-blind, phase 2 trial, patients with relapsing MS and gadolinium-enhancing lesions were randomly assigned 1:1:1 to receive 30 or 60 mg ibudilast or placebo every day for 12 months. The primary endpoint was the cumulative number of newly active lesions on bimonthly brain MRI over 12 months. Secondary endpoints included relapse rate, change in Expanded Disability Status Scale (EDSS) score, T2-hyperintense and T1 hypointense lesion volumes, and percent brain volume change (PBVC). RESULTS: A total of 297 patients were randomized in 19 centers. During the first 12 months, the mean number of active lesions and relapse rate did not differ between treatment arms. A reduction in PBVC (p = 0.04) was found in the 60-mg group (0.8%) compared with placebo (1.2%). Post hoc analysis showed a reduction in the proportion active lesions that evolved into persistent black holes for the 60-mg (0.14; p = 0.004) and 30-mg (0.17; p = 0.036) groups compared with the placebo group (0.24). Over 2 years, there were fewer patients (p = 0.026) with confirmed progression on the EDSS. Treatment with ibudilast was generally safe and well tolerated. CONCLUSION: Ibudilast showed no beneficial effect on the rate of newly active lesions and relapses. However, preliminary evidence suggests that ibudilast seems to act in a neuroprotective fashion as measured by 2 independent MRI outcomes, with a possible beneficial clinical effect on disability progression. CLASSIFICATION OF EVIDENCE: This interventional study provides Class III evidence on the effect of ibudilast on disease activity. PMID- 20200339 TI - Prevalence of subdiaphragmatic visceral infarction in cardioembolic stroke. AB - BACKGROUND: A substantial proportion of ischemic strokes have an embolic mechanism, but the source of embolism is not detected. Coexistence of subdiaphragmatic visceral infarction (SDVI; e.g., renal, splenic, hepatic, bowel infarction) may be a suggestion of a common source of embolism. One large autopsy study found SDVI in 21.5% of patients with fatal stroke. METHOD: We performed diffusion-weighted magnetic resonance abdominal imaging and subsequently performed it in consecutive patients with stroke or TIA and a history of nonvalvular atrial fibrillation. RESULTS: Among 27 patients, 6 had SDVI (3 recent renal, 1 recent splenic, and 3 old splenic infarction). The median time between onset of ischemic stroke and abdominal MRI was 8 days (interquartile range 3-15 days). No predictive factor of SDVI was found in this study population with respect to demographic or ultrasound characteristics. CONCLUSIONS: One in 5 patients with nonfatal cardioembolic stroke or TIA may be associated with subdiaphragmatic visceral infarction (SDVI). Further study should evaluate the frequency of SDVI in patients with stroke of unknown cause. PMID- 20200340 TI - Neurologic complications of 2009 influenza A (H1N1): heightened attention on an ongoing question. PMID- 20200341 TI - Primary neuroprotection: the Holy Grail of multiple sclerosis therapy. PMID- 20200342 TI - From C. Miller Fisher to MRI: Searching for stroke mechanisms. PMID- 20200343 TI - Severe encephalopathy with swine origin influenza A H1N1 infection in childhood: case reports. PMID- 20200344 TI - Brain reorganization in patients with spinal cord compression evaluated using fMRI. AB - OBJECTIVE: This prospective study characterizes the reorganization that occurs within the primary sensorimotor cortices following decompression of cervical spinal stenosis. METHODS: Twelve right-handed patients with cervical myelopathy underwent blood oxygenation level dependent functional MRI (fMRI) prior to decompression and 6 months following surgery. Ten right-handed controls also underwent fMRI. All subjects performed a finger-tapping paradigm with the right hand. Volume time course data were corrected for temporal serial correlation and % normalized before inclusion in the general linear model. Activation maps were created for each group using a threshold of p < 0.005 with Bonferroni correction. Between-group differences in left hemisphere volume of activation (VOA) were measured along the precentral gyrus (PrCG) and postcentral gyrus (PoCG). Each subject also completed clinical questionnaires. RESULTS: Prior to surgery, patients demonstrated a larger VOA (1.23 cm(3), t(max) = 11.8) in comparison to controls within the PrCG. This difference increased following surgery (2.99 cm(3), t(max) = 13.6). Within the PoCG, controls demonstrated a larger VOA (0.53 cm(3), t(max) = 8.28) than preoperative patients. This difference decreased by 0.12 cm(3) (t(max) = 7.05) following surgery. Preoperatively, patients had a 21.7 cm(3) VOA (t(max) = 29.4) within the sensorimotor cortex with the center of gravity located within Brodmann area (BA) 3. Following surgery, the VOA increased to 23.1 cm(3) (t(max) = 26.1) within BA 3. There were significant improvements in clinical outcomes following surgery. CONCLUSIONS: Spinal cord compression resulted in an increase in volume of activation (VOA) within the precentral gyrus (PrCG) and a loss of VOA within the postcentral gyrus (PoCG) in comparison to controls. Surgical decompression results in cortical reorganization with enlarging VOA within both the PrCG and PoCG. PMID- 20200345 TI - Clinical trial efforts in Alzheimer disease: why test statins? PMID- 20200347 TI - Does herpes zoster ophthalmicus increase the risk of stroke? PMID- 20200346 TI - Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. AB - BACKGROUND: There is some evidence that statins may have a protective and symptomatic benefit in Alzheimer disease (AD). The LEADe study is a randomized controlled trial (RCT) evaluating the efficacy and safety of atorvastatin in patients with mild to moderate AD. METHODS: This was an international, multicenter, double-blind, randomized, parallel-group study. Subjects had mild to moderate probable AD (Mini-Mental State Examination score 13-25), were aged 50-90 years, and were taking donepezil 10 mg daily for > or 3 months prior to screening. Entry low-density lipoprotein cholesterol levels (LDL-C) were > 95 and < 195 mg/dL. Patients were randomized to atorvastatin 80 mg/day or placebo for 72 weeks followed by a double-blind, 8-week atorvastatin withdrawal phase. Coprimary endpoints were changes in cognition (Alzheimer's Disease Assessment Scale Cognitive Subscale [ADAS-Cog]) and global function (Alzheimer's Disease Cooperative Study Clinical Global Impression of Change [ADCS-CGIC]) at 72 weeks. RESULTS: A total of 640 patients were randomized in the study. There were no significant differences in the coprimary endpoints of ADAS-cog or ADCS-CGIC or the secondary endpoints. Atorvastatin was generally well-tolerated. CONCLUSIONS: In this large-scale randomized controlled trial evaluating statin therapy as a treatment for mild to moderate Alzheimer disease, atorvastatin was not associated with significant clinical benefit over 72 weeks. This treatment was generally well-tolerated without unexpected adverse events. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that intensive lipid lowering with atorvastatin 80 mg/day in patients with mild to moderate probable Alzheimer disease (aged 50-90), taking donepezil, with low-density lipoprotein cholesterol levels between 95 and 195 mg/dL over 72 weeks does not benefit cognition (as measured by Alzheimer's Disease Assessment Scale-Cognitive Subscale) (p = 0.26) or global function (as measured by Alzheimer's Disease Cooperative Study Clinical Global Impression of Change) (p = 0.73) compared with placebo. PMID- 20200348 TI - Herpes zoster ophthalmicus and the risk of stroke: a population-based follow-up study. AB - OBJECTIVE: To investigate the risk of stroke development following a diagnosis of herpes zoster ophthalmicus (HZO). METHODS: Data were retrospectively collected from the Taiwan National Health Insurance Research Database. The study cohort comprised all patients with a diagnosis of HZO (ICD-9-CM code 053.2) in 2003 and 2004 (n = 658). The comparison cohort was comprised of randomly selected patients (3 for every HZO patient, n = 1974) matched with the study group in terms of age and gender. Patients were tracked from their index visits for 1 year. The Kaplan Meier method was utilized to compute the 1-year stroke-free survival rate. Cox proportional hazard regressions were carried out to compute the adjusted 1-year stroke-free survival rate after adjusting for possible confounding factors. RESULTS: Stroke developed in 8.1% of patients with HZO and 1.7% of patients in the comparison cohort during the 1-year follow-up period. HZO patients had significantly lower 1-year stroke-free survival rates than patients in the comparison cohort. After adjusting for patients' demographic characteristics, selected comorbidities, and medication habits, HZO patients were found to have a 4.52-fold (95% confidence interval 2.45-8.33) higher risk of stroke than the matched comparison cohort. There was no significant difference in the rate of stroke development between patients who had received systemic antiviral treatment and those who had not. CONCLUSIONS: Herpes zoster ophthalmicus may represent a marker of increased risk of stroke development during the 1-year follow-up period. PMID- 20200349 TI - Down-regulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis. AB - Iron-refractory, iron-deficiency anemia (IRIDA) is a familial disorder characterized by iron deficiency anemia unresponsive to oral iron treatment but partially responsive to intravenous iron therapy. Previously, we showed that IRIDA patients harbor loss-of-function mutations in TMPRSS6, a type II transmembrane serine protease primarily expressed by the liver. Both humans and mice with TMPRSS6 mutations show inappropriately elevated levels of the iron regulatory hormone hepcidin, suggesting that TMPRSS6 acts to negatively regulate hepcidin expression. Here we investigate the relationship between Tmprss6 and the bone morphogenetic protein (BMP)-Smad signaling pathway, a key pathway promoting hepcidin transcription in hepatocytes. We show that livers from mice deficient for Tmprss6 have decreased iron stores and decreased Bmp6 mRNA, but markedly increased mRNA for Id1, a target gene of Bmp6 signaling. In contrast, mice deficient for both Tmprss6 and hemojuvelin (Hjv), a BMP coreceptor that augments hepcidin expression in hepatocytes, showed markedly decreased hepatic levels of hepcidin and Id1 mRNA, markedly increased hepatic Bmp6 mRNA levels, and systemic iron overload similar to mice deficient for Hjv alone. These findings suggest that down-regulation of Bmp/Smad signaling by Tmprss6 is required for regulation of hepcidin expression and maintenance of systemic iron homeostasis. PMID- 20200350 TI - Mutation and ADAMTS13-dependent modulation of disease severity in a mouse model for von Willebrand disease type 2B. AB - Von Willebrand disease (VWD)-type 2B originates from a gain-of-function mutation in von Willebrand factor (VWF), resulting in enhanced platelet binding. Clinical manifestations include increased bleeding tendency, loss of large multimers, thrombocytopenia, and circulating platelet aggregates. We developed a mouse model to study phenotypic consequences of VWD-type 2B mutations in murine VWF: mVWF/R1306Q and mVWF/V1316M. Both mutations allow normal multimerization but are associated with enhanced ristocetin-induced platelet aggregation, typical for VWD type 2B. In vivo expression resulted in thrombocytopenia and circulating aggregates, both of which were more pronounced for mVWF/V1316M. Furthermore, both mutants did not support correction of bleeding time or arterial vessel occlusion in a thrombosis model. They further displayed a 2- to 3-fold reduced half-life and induced a 3- to 6-fold increase in number of giant platelets compared with wild-type VWF. Loss of large multimers was observed in 50% of the mice. The role of ADAMTS13 was investigated by expressing both mutants in VWF/ADAMTS13 double deficient mice. ADAMTS13 deficiency resulted in more and larger circulating platelet aggregates for both mutants, whereas the full multimer range remained present in all mice. Thus, we established a mouse model for VWD-type 2B and found that phenotype depends on mutation and ADAMTS13. PMID- 20200351 TI - Platelet interleukin-1alpha drives cerebrovascular inflammation. AB - White blood cell infiltration across an activated brain endothelium contributes to neurologic disease, including cerebral ischemia and multiple sclerosis. Identifying mechanisms of cerebrovascular activation is therefore critical to our understanding of brain disease. Platelet accumulation in microvessels of ischemic mouse brain was associated with endothelial activation in vivo. Mouse platelets expressed interleukin-1alpha (IL-1alpha), but not IL-1beta, induced endothelial cell adhesion molecule expression (ICAM-1 and VCAM-1), and enhanced the release of CXC chemokine CXCL1 when incubated with primary cultures of brain endothelial cells from wild-type or IL-1alpha/beta-deficient mice. A neutralizing antibody to IL-1alpha (but not IL-1beta) or application of IL-1 receptor antagonist inhibited platelet-induced endothelial activation by more than 90%. Platelets from IL 1alpha/beta-deficient mice did not induce expression of adhesion molecules in cerebrovascular endothelial cells and did not promote CXCL1 release in vitro. Conditioned medium from activated platelets induced an IL-1alpha-dependent activation of mouse brain endothelial cells and supported the transendothelial migration of neutrophils in vitro. Thus, we have identified platelets as a key source of IL-1alpha and propose that platelet activation of brain endothelium via IL-1alpha is a critical step for the entry of white blood cells, major contributors to inflammation-mediated injury in the brain. PMID- 20200352 TI - Human embryonic stem cells: a source of mast cells for the study of allergic and inflammatory diseases. AB - Human mast cells are tissue resident cells with a principal role in allergic disorders. Cross-linking of the high-affinity receptor for immunoglobulin E (FcepsilonRI) results in release of inflammatory mediators initiating the clinical symptoms of allergy and anaphylaxis. Much of our knowledge regarding the mechanisms of mast cell activation comes from studies of mouse bone marrow derived mast cells. However, clear differences have been identified between human and mouse mast cells. Studies of human mast cells are hampered by the limited sources available for their isolation, the resistance of these cells to genetic manipulation, and differences between cultures established from different persons. To address this limitation, we developed a simple coculture-free method for obtaining mast cells from human embryonic stem cells (hES). These hES-derived mast cells respond to antigen by releasing mast cell mediators. Moreover, the cells can be generated in numbers sufficient for studies of the pathways involved in their effector functions. Genetically modified mast cells, such as GFP expressing cells, can be obtained by introduction and selection for modification in hES cells before differentiation. This direct coculture-free differentiation of hES cells represents a new and unique model to analyze the function and development of human mast cells. PMID- 20200353 TI - The receptor tyrosine kinase c-Kit controls IL-33 receptor signaling in mast cells. AB - Members of the Toll/interleukin-1 receptor (TIR) family are of importance for host defense and inflammation. Here we report that the TIR-family member interleukin-33R (IL-33R) cross-activates the receptor tyrosine kinase c-Kit in human and murine mast cells. The IL-33R-induced activation of signal transducer and activator of transcription 3 (STAT3), extracellular signal-regulated kinase 1/2 (Erk1/2), protein kinase B (PKB), and Jun NH(2)-terminal kinase 1 (JNK1) depends on c-Kit and is required to elicit optimal effector functions. Costimulation with the c-Kit ligand stem cell factor (SCF) is necessary for IL-33 induced cytokine production in primary mast cells. The structural basis for this cross-activation is the complex formation between c-Kit, IL-33R, and IL-1R accessory protein (IL-1RAcP). We found that c-Kit and IL-1RAcP interact constitutively and that IL-33R joins this complex upon ligand binding. Our findings support a model in which signals from seemingly disparate receptors are integrated for full cellular responses. PMID- 20200354 TI - Enumeration of human antigen-specific naive CD8+ T cells reveals conserved precursor frequencies. AB - The number of antigen-specific naive CD8(+) T cells is believed to be important in the shaping of adaptive immune responses, and is predictive for the magnitude of priming responses in mouse models. Because of extremely low precursor frequencies, knowledge about these cells comes from indirect techniques and estimations. Here, we present a strategy based on the combination of tetramer staining, magnetic-bead enrichment, and multiparametric cytometry, which permitted direct detection and analysis of CD8(+) T cells reactive for 6 different naive epitopes (MART-1(26-35), HIV-1 Gag p17(77-85), hepatitis C virus [HCV] NS3(1406-1415), HCV Core(132-140), NY-ESO-1(157-165), and cytomegalovirus [CMV] pp65(495-503)). Interestingly, we detected higher than 100-fold differences in precursor frequency across these epitopes (from 0.6 x 10(-6) to 1.3 x 10(-4)), but conserved frequencies among humans. Development of a procedure for direct assessment of T-cell precursor frequency in humans has important implications, with particular relevance to vaccine development and monitoring of tumor and self reactive T cells. PMID- 20200355 TI - Occurrence of minimal change nephrotic syndrome in classical Hodgkin lymphoma is closely related to the induction of c-mip in Hodgkin-Reed Sternberg cells and podocytes. AB - It is currently considered that idiopathic minimal change nephrotic syndrome is an immune-mediated glomerular disease. Its association with classical Hodgkin lymphoma minimal change nephrotic syndrome (cHL-MCNS) suggests a molecular link, which remains to be elucidated. We analyzed the expression of cmaf inducing protein (c-mip) in lymphomatous tissues and kidney biopsy samples of patients with cHL-MCNS (n = 8) and in lymphomatous tissues of patients with isolated cHL (n = 9). Because c-mip affects the regulatory loop involving Fyn, we investigated possible structural defects in this signaling pathway, using laser capture microdissection, reverse transcription polymerase chain reaction, and Western blotting. We found that c-mip was selectively expressed in Hodgkin and Reed Sternberg (HRS) cells and podocytes of patients with cHL-MCNS but is undetectable in patients with isolated cHL. We demonstrated that c-mip was specifically involved in the negative regulation of early proximal signaling through its interaction with phosphoprotein associated with glycosphingolipid-enriched microdomains and Fyn. We showed that the up-regulation of c-mip in cHL-MCNS was associated with a possible Fyn defect in HRS cells and podocytes. Moreover, we showed that c-mip was up-regulated in Fyn-deficient podocytes. c-mip may be a useful marker of cHL-MCNS and its induction reflects the dysregulation of proximal signaling. PMID- 20200356 TI - Hematopoietic progenitor cell regulation by CD4+CD25+ T cells. AB - CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) possess the capacity to modulate both adaptive and innate immune responses. We hypothesized that Tregs could regulate hematopoiesis based on cytokine effector molecules they can produce. The studies here demonstrate that Tregs can affect the differentiation of myeloid progenitor cells. In vitro findings demonstrated the ability of Tregs to inhibit the differentiation of interleukin-3 (IL-3)/stem cell factor (colony-forming unit [CFU]-IL3)-driven progenitor cells. Inhibitory effects were mediated by a pathway requiring cell-cell contact, major histocompatibility complex class II expression on marrow cells, and transforming growth factor-beta. Importantly, depletion of Tregs in situ resulted in enhanced CFU-IL3 levels after bone marrow transplantation. Cotransplantation of CD4(+)FoxP3(+)(gfp) Tregs together with bone marrow was found to diminish CFU-IL3 responses after transplantation. To address the consequence of transplanted Tregs on differentiated progeny from these CFU 2 weeks after hematopoietic stem cell transplantation, peripheral blood complete blood counts were performed and examined for polymorphonuclear leukocyte content. Recipients of cotransplanted Tregs exhibited diminished neutrophil counts. Together, these findings illustrate that both recipient and donor Tregs can influence hematopoietic progenitor cell activity after transplantation and that these cells can alter responses outside the adaptive and innate immune systems. PMID- 20200357 TI - Palmitoylation of oncogenic NRAS is essential for leukemogenesis. AB - Activating mutations of NRAS are common in acute myeloid leukemia, chronic myelomonocytic leukemia, and myelodysplastic syndrome. Like all RAS proteins, NRAS must undergo a series of post-translational modifications for differential targeting to distinct membrane subdomains. Although farnesylation is the obligatory first step in post-translational modifications of RAS, to date, successes of therapies targeting farnesyl protein transferase are modest. Other RAS modifications, such as palmitoylation, are required for optimal plasma membrane association of RAS proteins. However, the relative importance of these latter modifications of RAS in leukemogenesis is not clear. We have previously shown that expression of oncogenic NRAS using a bone marrow transduction and transplantation model efficiently induces a chronic myelomonocytic leukemia- or acute myeloid leukemia-like disease in mice. Here we examined the role of palmitoylation in NRAS leukemogenesis using this model. We found that palmitoylation is essential for leukemogenesis by oncogenic NRAS. We also found that farnesylation is essential for NRAS leukemogenesis, yet through a different mechanism from that of palmitoylation deficiency. This study demonstrates, for the first time, that palmitoylation is an essential process for NRAS leukemogenesis and suggests that the development of therapies targeting RAS palmitoylation may be effective in treating oncogenic NRAS-associated malignancies. PMID- 20200358 TI - Bortezomib modulates surface CD20 in B-cell malignancies and affects rituximab mediated complement-dependent cytotoxicity. AB - Unresponsiveness to rituximab treatment develops in many patients prompting elucidation of underlying molecular pathways. It was recently observed that rituximab-resistant lymphoma cells exhibit up-regulation of components of the ubiquitin-proteasome system (UPS). Therefore, we investigated in more detail the role of this system in the regulation of CD20 levels and the influence of proteasome inhibitors on rituximab-mediated complement-dependent cytotoxicity (R CDC). We observed that incubation of Raji cells with rituximab leads to increased levels of ubiquitinated CD20. However, inhibition of the UPS was not associated with up-regulation of surface CD20 levels, although it significantly increased its ubiquitination. Short-term (24 hours) incubation of Raji cells with 10 or 20 nM bortezomib did not change surface CD20 levels, but sensitized CD20(+) lymphoma cells to R-CDC. Prolonged (48 hours) incubation with 20 nM bortezomib, or incubation with 50 nM bortezomib for 24 hours led to a significant decrease in surface CD20 levels as well as R-CDC. These effects were partly reversed by bafilomycin A1, an inhibitor of lysosomal/autophagosomal pathway of protein degradation. These studies indicate that CD20 levels are regulated by 2 proteolytic systems and that the use of proteasome inhibitors may be associated with unexpected negative influence on R-CDC. PMID- 20200359 TI - Haitian amputees--lessons learned from Sierra Leone. PMID- 20200360 TI - The Democrats' last ditch--reconciliation or bust. PMID- 20200361 TI - Ministry of touch--reflections on disaster work after the Haitian earthquake. PMID- 20200362 TI - The Israeli field hospital in Haiti--ethical dilemmas in early disaster response. PMID- 20200363 TI - Haiti--a view from the ship. PMID- 20200364 TI - Health care reform--where do we go from here? PMID- 20200365 TI - Aquaporin-1: new developments and perspectives for peritoneal dialysis. AB - Peritoneal dialysis involves diffusive and convective transport and osmosis through the highly vascularized peritoneal membrane. Several lines of evidence have demonstrated that the water channel aquaporin-1 (AQP1) corresponds to the ultrasmall pore predicted by the model of peritoneal transport. Proof-of principle studies have shown that upregulation of the expression of AQP1 in peritoneal capillaries results in increased water permeability and ultrafiltration, without affecting the osmotic gradient or small solute permeability. Conversely, studies in Aqp1 mice have shown that haplo insufficiency for AQP1 results in significant attenuation of water transport. Recent studies have demonstrated that AQP1 is involved in the migration of different cell types, including endothelial cells. In parallel, chemical screening has identified lead compounds that could act as antagonists or agonists of AQPs, with description of putative binding sites and potential mechanisms of gating the water channel. By modulating water transport, these pharmacological agents could have clinically relevant effects in targeting specific tissues or disease states. PMID- 20200366 TI - Intra-abdominal hypertension favors ascites. PMID- 20200367 TI - Biomarkers of EPS: can we go "back to the future"? PMID- 20200368 TI - Technique failure in peritoneal dialysis patients: insights and challenges. PMID- 20200369 TI - Encapsulating peritoneal sclerosis in a peritoneal dialysis patient using biocompatible fluids only: is Alport syndrome a risk factor? PMID- 20200370 TI - Two cases of ascending peritonitis in CAPD. PMID- 20200371 TI - Regular lactulose use is associated with lower peritonitis rates: an observational study. PMID- 20200372 TI - Pseudoachalasia of the esophagus caused by encapsulating peritoneal sclerosis. AB - Encapsulating peritoneal sclerosis is a severe complication of peritoneal dialysis. Progressive sclerotic thickening of the peritoneum results in tethering and cocooning of the bowel, leading to chronic bowel obstruction, malabsorption, malnutrition, and high mortality. Conservative treatment is often unsuccessful and a surgical enterolysis is required for management. Pseudoachalasia is a rare condition that mimics the clinical and radiological features of achalasia of the cardia. Pseudoachalasia is most commonly caused by infiltrating or metastasizing cancers. In this report, we present a case of pseudoachalasia associated with encapsulating peritoneal sclerosis. The clinical symptoms settled after peritonectomy and enterolysis. PMID- 20200373 TI - Intraperitoneal meropenem administration: a possible alternative to the intravenous route. PMID- 20200374 TI - Pulmonary hypertension in dialysis patients. PMID- 20200375 TI - Peritoneal dialysis-associated peritonitis due to Kytococcus sedentarius. PMID- 20200376 TI - Campylobacter fetus peritonitis in a patient with an unused embedded subcutaneous peritoneal catheter. PMID- 20200377 TI - An unusual organism for PD-related peritonitis: Hafnia alvei. PMID- 20200378 TI - Development of pilonidal sinus in an old exit site four years after removal of the Tenckhoff catheter. PMID- 20200379 TI - Abdominal wall skin pressure ulcer due to a peritoneal catheter. PMID- 20200380 TI - Images in clinical medicine. Neuropathic ulceration. PMID- 20200381 TI - Medicare's opportunity to encourage innovation in health care delivery. PMID- 20200382 TI - Comparison of dopamine and norepinephrine in the treatment of shock. AB - BACKGROUND: Both dopamine and norepinephrine are recommended as first-line vasopressor agents in the treatment of shock. There is a continuing controversy about whether one agent is superior to the other. METHODS: In this multicenter, randomized trial, we assigned patients with shock to receive either dopamine or norepinephrine as first-line vasopressor therapy to restore and maintain blood pressure. When blood pressure could not be maintained with a dose of 20 microg per kilogram of body weight per minute for dopamine or a dose of 0.19 microg per kilogram per minute for norepinephrine, open-label norepinephrine, epinephrine, or vasopressin could be added. The primary outcome was the rate of death at 28 days after randomization; secondary end points included the number of days without need for organ support and the occurrence of adverse events. RESULTS: The trial included 1679 patients, of whom 858 were assigned to dopamine and 821 to norepinephrine. The baseline characteristics of the groups were similar. There was no significant between-group difference in the rate of death at 28 days (52.5% in the dopamine group and 48.5% in the norepinephrine group; odds ratio with dopamine, 1.17; 95% confidence interval, 0.97 to 1.42; P=0.10). However, there were more arrhythmic events among the patients treated with dopamine than among those treated with norepinephrine (207 events [24.1%] vs. 102 events [12.4%], P<0.001). A subgroup analysis showed that dopamine, as compared with norepinephrine, was associated with an increased rate of death at 28 days among the 280 patients with cardiogenic shock but not among the 1044 patients with septic shock or the 263 with hypovolemic shock (P=0.03 for cardiogenic shock, P=0.19 for septic shock, and P=0.84 for hypovolemic shock, in Kaplan-Meier analyses). CONCLUSIONS: Although there was no significant difference in the rate of death between patients with shock who were treated with dopamine as the first line vasopressor agent and those who were treated with norepinephrine, the use of dopamine was associated with a greater number of adverse events. (ClinicalTrials.gov number, NCT00314704.) PMID- 20200384 TI - Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults. AB - BACKGROUND: Fasting glucose is the standard measure used to diagnose diabetes in the United States. Recently, glycated hemoglobin was also recommended for this purpose. METHODS: We compared the prognostic value of glycated hemoglobin and fasting glucose for identifying adults at risk for diabetes or cardiovascular disease. We measured glycated hemoglobin in whole-blood samples from 11,092 black or white adults who did not have a history of diabetes or cardiovascular disease and who attended the second visit (occurring in the 1990-1992 period) of the Atherosclerosis Risk in Communities (ARIC) study. RESULTS: The glycated hemoglobin value at baseline was associated with newly diagnosed diabetes and cardiovascular outcomes. For glycated hemoglobin values of less than 5.0%, 5.0 to less than 5.5%, 5.5 to less than 6.0%, 6.0 to less than 6.5%, and 6.5% or greater, the multivariable-adjusted hazard ratios (with 95% confidence intervals) for diagnosed diabetes were 0.52 (0.40 to 0.69), 1.00 (reference), 1.86 (1.67 to 2.08), 4.48 (3.92 to 5.13), and 16.47 (14.22 to 19.08), respectively. For coronary heart disease, the hazard ratios were 0.96 (0.74 to 1.24), 1.00 (reference), 1.23 (1.07 to 1.41), 1.78 (1.48 to 2.15), and 1.95 (1.53 to 2.48), respectively. The hazard ratios for stroke were similar. In contrast, glycated hemoglobin and death from any cause were found to have a J-shaped association curve. All these associations remained significant after adjustment for the baseline fasting glucose level. The association between the fasting glucose levels and the risk of cardiovascular disease or death from any cause was not significant in models with adjustment for all covariates as well as glycated hemoglobin. For coronary heart disease, measures of risk discrimination showed significant improvement when glycated hemoglobin was added to models including fasting glucose. CONCLUSIONS: In this community-based population of nondiabetic adults, glycated hemoglobin was similarly associated with a risk of diabetes and more strongly associated with risks of cardiovascular disease and death from any cause as compared with fasting glucose. These data add to the evidence supporting the use of glycated hemoglobin as a diagnostic test for diabetes. PMID- 20200387 TI - Images in clinical medicine. Congenital cytomegalovirus infection. PMID- 20200383 TI - Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. AB - BACKGROUND: Childhood absence epilepsy, the most common pediatric epilepsy syndrome, is usually treated with ethosuximide, valproic acid, or lamotrigine. The most efficacious and tolerable initial empirical treatment has not been defined. METHODS: In a double-blind, randomized, controlled clinical trial, we compared the efficacy, tolerability, and neuropsychological effects of ethosuximide, valproic acid, and lamotrigine in children with newly diagnosed childhood absence epilepsy. Drug doses were incrementally increased until the child was free of seizures, the maximal allowable or highest tolerable dose was reached, or a criterion indicating treatment failure was met. The primary outcome was freedom from treatment failure after 16 weeks of therapy; the secondary outcome was attentional dysfunction. Differential drug effects were determined by means of pairwise comparisons. RESULTS: The 453 children who were randomly assigned to treatment with ethosuximide (156), lamotrigine (149), or valproic acid (148) were similar with respect to their demographic characteristics. After 16 weeks of therapy, the freedom-from-failure rates for ethosuximide and valproic acid were similar (53% and 58%, respectively; odds ratio with valproic acid vs. ethosuximide, 1.26; 95% confidence interval [CI], 0.80 to 1.98; P=0.35) and were higher than the rate for lamotrigine (29%; odds ratio with ethosuximide vs. lamotrigine, 2.66; 95% CI, 1.65 to 4.28; odds ratio with valproic acid vs. lamotrigine, 3.34; 95% CI, 2.06 to 5.42; P<0.001 for both comparisons). There were no significant differences among the three drugs with regard to discontinuation because of adverse events. Attentional dysfunction was more common with valproic acid than with ethosuximide (in 49% of the children vs. 33%; odds ratio, 1.95; 95% CI, 1.12 to 3.41; P=0.03). CONCLUSIONS: Ethosuximide and valproic acid are more effective than lamotrigine in the treatment of childhood absence epilepsy. Ethosuximide is associated with fewer adverse attentional effects. (ClinicalTrials.gov number, NCT00088452.) PMID- 20200385 TI - A trial of a 7-valent pneumococcal conjugate vaccine in HIV-infected adults. AB - BACKGROUND: Streptococcus pneumoniae is a leading and serious coinfection in adults with human immunodeficiency virus (HIV) infection, particularly in Africa. Prevention of this disease by vaccination with the current 23-valent polysaccharide vaccine is suboptimal. Protein conjugate vaccines offer a further option for protection, but data on their clinical efficacy in adults are needed. METHODS: In this double-blind, randomized, placebo-controlled clinical efficacy trial, we studied the efficacy of a 7-valent conjugate pneumococcal vaccine in predominantly HIV-infected Malawian adolescents and adults who had recovered from documented invasive pneumococcal disease. Two doses of vaccine were given 4 weeks apart. The primary end point was a further episode of pneumococcal infection caused by vaccine serotypes or serotype 6A. RESULTS: From February 2003 through October 2007, we followed 496 patients (of whom 44% were male and 88% were HIV seropositive) for 798 person-years of observation. There were 67 episodes of pneumococcal disease in 52 patients, all in the HIV-infected subgroup. In 24 patients, there were 19 episodes that were caused by vaccine serotypes and 5 episodes that were caused by the 6A serotype. Of these episodes, 5 occurred in the vaccine group and 19 in the placebo group, for a vaccine efficacy of 74% (95% confidence interval [CI], 30 to 90). There were 73 deaths from any cause in the vaccine group and 63 in the placebo group (hazard ratio in the vaccine group, 1.18; 95% CI, 0.84 to 1.66). The number of serious adverse events within 14 days after vaccination was significantly lower in the vaccine group than in the placebo group (3 vs. 17, P=0.002), and the number of minor adverse events was significantly higher in the vaccine group (41 vs. 13, P=0.003). CONCLUSIONS: The 7-valent pneumococcal conjugate vaccine protected HIV-infected adults from recurrent pneumococcal infection caused by vaccine serotypes or serotype 6A. (Current Controlled Trials number, ISRCTN54494731.) PMID- 20200386 TI - Management of varices and variceal hemorrhage in cirrhosis. PMID- 20200388 TI - Clinical problem-solving. Stalking the diagnosis. PMID- 20200389 TI - Treating shock--old drugs, new ideas. PMID- 20200390 TI - Ethosuximide in childhood absence epilepsy--older and better. PMID- 20200391 TI - Collection of data on patients' race and ethnic group by physician practices. PMID- 20200392 TI - On-pump versus off-pump CABG. PMID- 20200393 TI - A controlled trial of initial antiviral regimens for HIV-1 infection. PMID- 20200394 TI - Effects of obesity and smoking on U.S. life expectancy. PMID- 20200395 TI - A crisis in late pregnancy. PMID- 20200396 TI - Repair of mitral-valve prolapse. PMID- 20200397 TI - Capecitabine and oxaliplatin for advanced esophagogastric cancer. PMID- 20200398 TI - Surveys of physicians and electronic health information. PMID- 20200399 TI - Human eosinophil granulocytes do not express the enzyme arginase. AB - Human polymorphonuclear PMN constitutively express the enzyme arginase I, which hydrolyzes arginine to ornithine and urea. This arginine consumption has been recognized as a key pathway of myeloid cell-mediated suppression of the adaptive immune system during inflammation, infection, and tumor growth. Eos granulocytes are crucial immunoregulatory and effector cells of allergic inflammation and infections with parasites and helminths and in a variety of tumors. Here, we analyzed if human Eos also express arginase with its potential immunosuppressive consequences. We show that human peripheral blood Eos do not express arginase I or II protein or arginase enzymatic activity. Correspondingly, no metabolism of arginine to ornithine can be detected in Eos-S. Neither Eos apoptosis nor cytokine-mediated cellular activation induces arginase in human Eos in vitro. Finally, we show that arginase activity and protein are also undetectable in Eos of allergic patients from peripheral blood or from BALF activated in vivo during allergic pulmonary inflammation. This work demonstrates a fundamental difference between neutrophil and Eos granulocytes. As Eos are not equipped with the immunosuppressive enzyme arginase, they cannot participate, via arginine limitation, in the suppression of the evolving adaptive immune response in allergy, infections, or tumor immunity. PMID- 20200400 TI - STAT1-dependent IgG cell-surface expression in a human B cell line derived from a STAT1-deficient patient. AB - STAT1 is a key effector of cytokines involved in the resistance to pathogens; its identified transcriptional targets mediate the innate immune response involved in the defense against viruses and bacteria. Little is known about the role of STAT1 in adaptive immunity, including its impact on BCR or surface Ig expression. Analysis of this point is difficult in humans, as STAT1 deficiency is extremely rare. SD patients die early in childhood from a severe immunodeficiency. Herein, a SD B cell line obtained from a SD patient was compared with a B cell line from a STAT1-proficient subject in search of differences in surface Ig expression. In this SD B cell line, a complete absence of surface IgG was noted. The mRNA encoding the surface form of IgG was detected only in STAT1-proficient B cells; the mRNAs encoding the secreted and the surface forms were detected in SD and STAT1-proficient B cells. Re-expression of STAT1 in SD B cells restored surface IgG expression and a functional BCR. Conversely, shRNA silencing of STAT1 in B cells reduced considerably the expression of the surface IgG. Although limited to one B cell line, these results suggest that STAT1 may play an essential role in surface IgG expression in human B cells. Possible mechanisms involve regulation of mRNA splicing, transcription, or both. These observations extend the role of STAT1 further in adaptive immunity, including the regulation of BCR expression. PMID- 20200402 TI - Apoptosis signal-regulating kinase 1 in peptidoglycan-induced COX-2 expression in macrophages. AB - In this study, we investigated the role of ASK1 in PGN-induced C/EBPbeta activation and COX-2 expression in RAW 264.7 macrophages. The PGN-induced COX-2 expression was attenuated by the DNs of ASK1, JNK1, JNK2, a JNK inhibitor (SP600125), and an AP-1 inhibitor (curcumin). PGN caused ASK1 dephosphorylation time-dependently at Ser967, dissociation from the ASK1-14-3-3 complex, and subsequent ASK1 activation. In addition, PGN activated PP2A and suppression of PP2A by okadaic acid markedly inhibited PGN-induced ASK1 Ser967 dephosphorylation and COX-2 expression. PGN induced the activation of the JNK-AP-1 signaling cascade downstream of ASK1. PGN-increased C/EBPbeta expression and DNA-binding activity were inhibited by the ASK1-JNK-AP-1 signaling blockade. COX-2 promoter luciferase activity induced by PGN was attenuated in cells transfected with the COX-2 reporter construct possessing the C/EBP-binding site mutation. In addition, the ASK1-JNK-AP-1-C/EBPbeta cascade was activated in human peripheral mononuclear cells exposure to PGN. The TLR2 agonist Pam(3)CSK(4) was also shown to induce ASK1 Ser967 dephosphorylation, JNK and c-jun phosphorylation, C/EBPbeta activation, and COX-2 expression in RAW 264.7 macrophages. PGN-induced COX-2 promoter luciferase activity was prevented by selective inhibition of TLR2 and c Jun in RAW 264.7 macrophages. Our data demonstrate that PGN might activate the TLR2-mediated PP2A-ASK1-JNK-AP-1-C/EBPbeta cascade and subsequent COX-2 expression in RAW 264.7 macrophages. PMID- 20200403 TI - MAPK-directed phosphatases preferentially regulate pro- and anti-inflammatory cytokines in experimental visceral leishmaniasis: involvement of distinct protein kinase C isoforms. AB - The role of phosphatases in the impairment of MAPK signaling, which is directly responsible for Leishmania-induced macrophage dysfunction, is still poorly understood. Gene expression profiling revealed that Leishmania donovani infection markedly up-regulated the expression of three phosphatases: MKP1, MKP3, and PP2A. Inhibition of these phosphatases prior to infection points toward preferential induction of the Th2 response through deactivation of p38 by MKP1. On the other hand, MKP3 and PP2A might play significant roles in the inhibition of iNOS expression through deactivation of ERK1/2. Among various PKC isoforms, PKCzeta was associated with induction of MKP3 and PP2A in infected macrophages, whereas PKCepsilon was correlated with MKP1 induction. Inhibition of phosphatases in L. donovani-infected BALB/c mice shifted the cytokine balance in favor of the host by inducing TNF-alpha and iNOS expression. This was validated by cystatin, an immunomodulator and curing agent for experimental visceral leishmaniasis, which showed that inhibition of MKPs and PP2A activity may be necessary for a favorable T cell response and suppression of organ parasite burden. This study, for the first time, suggests the possibility of the involvement of MAPK-directed phosphatases in the establishment of L. donovani infection. PMID- 20200401 TI - Clostridium difficile toxin B differentially affects GPCR-stimulated Ca2+ responses in macrophages: independent roles for Rho and PLA2. AB - Clostridium difficile toxins cause acute colitis by disrupting the enterocyte barrier and promoting inflammation. ToxB from C. difficile inactivates Rho family GTPases and causes release of cytokines and eicosanoids by macrophages. We studied the effects of ToxB on GPCR signaling in murine RAW264.7 macrophages and found that ToxB elevated Ca(2+) responses to Galphai-linked receptors, including the C5aR, but reduced responses to Galphaq-linked receptors, including the UDP receptors. Other Rho inhibitors also reduced UDP Ca(2+) responses, but they did not affect C5a responses, suggesting that ToxB inhibited UDP responses by inhibiting Rho but enhanced C5a responses by other mechanisms. By using PLCbeta isoform-deficient BMDM, we found that ToxB inhibited Ca(2+) signaling through PLCbeta4 but enhanced signaling through PLCbeta3. Effects of ToxB on GPCR Ca(2+) responses correlated with GPCR use of PLCbeta3 versus PLCbeta4. ToxB inhibited UDP Ca(2+) signaling without reducing InsP3 production or the sensitivity of cellular Ca(2+) stores to exogenous InsP3, suggesting that ToxB impairs UDP signaling at the level of InsP3/Ca(2+)coupling. In contrast, ToxB elevated InsP3 production by C5a, and the enhancement of Ca(2+) signaling by C5a was prevented by inhibition of PLA(2) or 5-LOX but not COX, implicating LTs but not prostanoids in the mechanism. In sum, ToxB has opposing, independently regulated effects on Ca(2+) signaling by different GPCR-linked PLCbeta isoforms in macrophages. PMID- 20200404 TI - The catalytic PI3K isoforms p110gamma and p110delta contribute to B cell development and maintenance, transformation, and proliferation. AB - Class I PI3K-dependent signaling regulates cell proliferation, differentiation, and survival. Analysis of gene-deficient mice revealed specific roles for the hematopoietically expressed PI3K catalytic subunits, p110gamma and p110delta, in development and function of T and B lymphocytes. However, the functional redundancy between these two PI3K isoforms in the B cell lineage remains unclear. Here, we demonstrate that p110delta and p110gamma are expressed in B cells at early developmental stages. Normal B cell differentiation requires both isoforms, as p110gamma/p110delta double deficiency causes an increased percentage of CD43(hi)/B220(+)/CD19(-) cells as compared with single deficiency. Interestingly, initial transformation efficiency of B cell precursors was strongly reduced in double-deficient cells following transformation by p185 bcr-abl or v-abl oncogenes as compared with single-deficient cells. The requirement of p110gamma and p110delta in B cell development is underlined by reduced splenic B cell numbers of p110gamma/p110delta double-deficient mice and of lethally irradiated wild-type mice reconstituted with double-deficient BM. Moreover, the peripheral maintenance of p110gamma/p110delta double-deficient T and B cells was highly impaired following adoptive transfer of double-deficient splenocytes into wild type mice. Functionally, LPS stimulation of splenocytes revealed proliferation defects resulting in decreased survival of p110gamma/p110delta double-deficient B cells, which correlated with impaired induction of D-type cyclins and Bcl-X(L). Surprisingly, this was not observed when purified B cells were analyzed, indicating a contribution of likely cell-extrinsic factor(s) to the impaired proliferation of double-deficient B cells. Thus, we provide novel evidence that p110gamma and p110delta have overlapping and cell-extrinsic roles in the development, peripheral maintenance, and function of B cells. PMID- 20200406 TI - Differential effects of selective HDAC inhibitors on macrophage inflammatory responses to the Toll-like receptor 4 agonist LPS. AB - Broad-spectrum inhibitors of HDACs are therapeutic in many inflammatory disease models but exacerbated disease in a mouse model of atherosclerosis. HDAC inhibitors have anti- and proinflammatory effects on macrophages in vitro. We report here that several broad-spectrum HDAC inhibitors, including TSA and SAHA, suppressed the LPS-induced mRNA expression of the proinflammatory mediators Edn 1, Ccl-7/MCP-3, and Il-12p40 but amplified the expression of the proatherogenic factors Cox-2 and Pai-1/serpine1 in primary mouse BMM. Similar effects were also apparent in LPS-stimulated TEPM and HMDM. The pro- and anti-inflammatory effects of TSA were separable over a concentration range, implying that individual HDACs have differential effects on macrophage inflammatory responses. The HDAC1 selective inhibitor, MS-275, retained proinflammatory effects (amplification of LPS-induced expression of Cox-2 and Pai-1 in BMM) but suppressed only some inflammatory responses. In contrast, 17a (a reportedly HDAC6-selective inhibitor) retained anti-inflammatory but not proinflammatory properties. Despite this, HDAC6(-/-) macrophages showed normal LPS-induced expression of HDAC-dependent inflammatory genes, arguing that the anti-inflammatory effects of 17a are not a result of inhibition of HDAC6 alone. Thus, 17a provides a tool to identify individual HDACs with proinflammatory properties. PMID- 20200405 TI - Leukocyte function in the aging immune system. AB - Aging is associated with a progressive dysregulation of immune responses. Whether these changes are solely responsible for the observed increased mortality and morbidity amongst the elderly is uncertain. Recent advances have highlighted the age-associated changes that occur beyond T and B lymphocytes. Additionally, multiple human and animal studies have identified a relationship between chronic low-grade inflammation and geriatric syndromes, such as frailty, suggesting that the phenomenon of "inflamm-aging" may provide a rationale for the increased vulnerability to chronic inflammatory diseases in older adults. In the present review, we broadly summarize our current understanding of age-dependent changes in leukocyte function and their contribution to aging-related disease processes. PMID- 20200407 TI - At the intersection of interpersonal violence, masculinity, and alcohol use: the experiences of heterosexual male perpetrators of intimate partner violence. AB - This article examines the relationship between violence, masculinity, and alcohol use among heterosexual, economically disadvantaged, and primarily Black men officially identified as batterers. Violence occurred against intimates and strangers. Alcohol use coupled with violence against intimates and violence against others (e.g., strangers) appeared to be used for masculinity construction. The use of alcohol before and during assaultive behavior combined with the use of violence symbolized dominance and control. This occurred in situations where markers of masculinity were largely absent (e.g., steady employment) in instances of both intimate partner violence and stranger violence. PMID- 20200408 TI - Normative misperceptions of abuse among perpetrators of intimate partner violence. AB - This research was designed to evaluate the applicability of social norms approaches to interventions with male perpetrators of intimate partner violence (IPV). Participants included 124 nonadjudicated IPV perpetrating men recruited from the general population who completed assessment of their own IPV behaviors via telephone interviews and estimated the prevalence of behaviors in other men. Results indicated that IPV perpetrators consistently overestimated the percentage of men who engaged in IPV and that their estimates were associated with violence toward their partner over the past 90 days. Findings provide preliminary support for incorporating social norms approaches into clinical applications. PMID- 20200409 TI - Gels containing MMP inhibitors prevent dental erosion in situ. AB - Matrix metalloproteinase (MMP) inhibition has been shown to reduce dentin caries progression, but its role in dental erosion has not yet been assessed. This study tested the hypothesis that gels containing MMP inhibitors (epigallocatechin gallate-EGCG and chlorhexidine) can prevent dental erosion. Volunteers (n = 10) wore palatal devices containing bovine dentin blocks (n = 10/group) treated for 1 min with EGCG at 10 (EGCG10) or 400 microM (EGCG400), chlorhexidine at 0.012%, F at 1.23% (NaF), and no vehicle (placebo). Erosion was performed with Coca-Cola (5 min) 4X/day during 5 days. The wear, assessed by profilometry (mean +/- SD, microm), was significantly reduced by the gels containing MMP inhibitors (0.05 +/ 0.02(a), 0.04 +/- 0.02(a), and 0.05 +/- 0.02(a) for EGCG10, EGCG400, and chlorhexidine, respectively) when compared with NaF (0.79 +/- 0.35(b)) and placebo gels (1.77 +/- 0.35(b)) (Friedman and Dunn's tests, p < 0.01). The use of gels delivering MMP inhibitors was shown to prevent erosion and opens a new perspective for protection against dental erosion. PMID- 20200410 TI - Threshold for detection of incisal forces is increased by jaw movement. AB - Current knowledge regarding the sensitivity of the teeth to forces is based on psychophysical experiments that measured touch detection thresholds under static jaw conditions. It is not known whether jaw movements alter the perception of forces applied to the teeth, but, based on limb movement studies, it is hypothesized that the perception of mechanoreceptor outputs will be downwardly modulated by jaw movements. We predicted that, compared with static jaw conditions, rhythmic jaw movements would be associated with significantly higher psychophysical thresholds for the detection of incisally applied forces. In eight participants, mechanical pulses were delivered to an incisor during static jaw holding or during cyclic jaw opening and closing. Analogous to findings in human limbs, the psychophysical salience of periodontal mechanoreceptor feedback was downwardly modulated by physiologically relevant movements; detection thresholds for mechanical pulses applied to a central incisor were significantly higher during jaw-closing movements than during static jaw positioning. PMID- 20200411 TI - N-acetyl cysteine alleviates cytotoxicity of bone substitute. AB - Lack of cytocompatibility in bone substitutes impairs healing in surrounding bone. Adverse biological events around biomaterials may be associated with oxidative stress. We hypothesized that a clinically used inorganic bone substitute is cytotoxic to osteoblasts due to oxidative stress and that N-acetyl cysteine (NAC), an antioxidant amino acid derivative, would detoxify such material. Only 20% of rat calvaria osteoblasts were viable when cultured on commercial deproteinized bovine bone particles for 24 hr, whereas this percentage doubled on bone substitute containing NAC. Intracellular ROS levels markedly increased on and under bone substitutes, which were reduced by prior addition of NAC to materials. NAC restored suppressed alkaline phosphatase activity in the bone substitute. Proinflammatory cytokine levels from human osteoblasts on the bone substitute decreased by one-third or more with addition of NAC. NAC alleviated cytotoxicity of the bone substitute to osteoblastic viability and function, implying enhanced bone regeneration around NAC-treated inorganic biomaterials. PMID- 20200412 TI - Indian hedgehog roles in post-natal TMJ development and organization. AB - Indian hedgehog (Ihh) is essential for embryonic mandibular condylar growth and disc primordium formation. To determine whether it regulates those processes during post-natal life, we ablated Ihh in cartilage of neonatal mice and assessed the consequences on temporomandibular joint (TMJ) growth and organization over age. Ihh deficiency caused condylar disorganization and growth retardation and reduced polymorphic cell layer proliferation. Expression of Sox9, Runx2, and Osterix was low, as was that of collagen II, collagen I, and aggrecan, thus altering the fibrocartilaginous nature of the condyle. Though a disc formed, it exhibited morphological defects, partial fusion with the glenoid bone surface, reduced synovial cavity space, and, unexpectedly, higher lubricin expression. Analysis of the data shows, for the first time, that continuous Ihh action is required for completion of post-natal TMJ growth and organization. Lubricin overexpression in mutants may represent a compensatory response to sustain TMJ movement and function. PMID- 20200413 TI - Graded structures for all-ceramic restorations. AB - One failure mode of all-ceramic restorations is radial cracking at the cementation surface, from occlusally induced flexure of the stiffer ceramic layer(s) on the softer dentin underlayer. We hypothesize that such failure may be substantially mitigated by an appropriate grading of elastic modulus through the ceramic thickness. In this study, we fabricated graded structures by infiltrating glass into zirconia plates, with resulting diminished modulus in the outer surfaces. The plates were then bonded to a polymeric base and subjected to flexure by contact loading until fracture. Comparison of infiltrated specimens with non-infiltrated controls showed a significant increase in the fracture loads, by a factor of nearly 2. Finite element analysis revealed the cause of increase in the load-bearing capacity to be diminished tensile stresses within the lower-modulus graded zone, corresponding to an increase in material strength. The results confirmed that suitably graded structures can be highly beneficial in the design of next-generation all-ceramic restorations. PMID- 20200415 TI - Different forms of DMP1 play distinct roles in mineralization. AB - Dentin matrix protein-1 (DMP1) is a major synthetic product of hypertrophic chondrocytes and osteocytes. Previous in vitro studies showed full-length DMP1 inhibits hydroxyapatite (HA) formation and growth, while its N-terminal fragment (37K) promotes HA formation. Since there are 3 fragments within the mineralized tissues [N-terminal, C-terminal (57K), and a chondroitin-sulfate-linked N terminal fragment (DMP1-PG)], we predicted that each would have a distinct effect on mineralization related to its interaction with HA. In a gelatin-gel system, 37K and 57K fragments were both promoters of HA formation and growth; DMP1-PG was an inhibitor. The secondary structures of the 3 fragments and the full-length protein in the presence and absence of Ca2+ and HA determined by FTIR showed that the full-length protein undergoes slight conformational changes on binding to HA, while 37K, 57K, and DMP1-PG do not change conformation. These findings indicate that distinct forms of DMP1 may work collectively in controlling the mineralization process. PMID- 20200416 TI - Osteocytes and WNT: the mechanical control of bone formation. AB - Mechanical loading is of pivotal importance in the maintenance of skeletal homeostasis, but the players involved in the transduction of mechanical stimuli to promote bone maintenance have long remained elusive. Osteocytes, the most abundant cells in bone, possess mechanosensing appendices stretching through a system of bone canaliculi. Mechanical stimulation plays an important role in osteocyte survival and hence in the preservation of bone mechanical properties, through the maintenance of bone hydratation. Osteocytes can also control the osteoblastic differentiation of mesenchymal precursors in response to mechanical loading by modulating WNT signaling pathways, essential regulators of cell fate and commitment, through the protein sclerostin. Mutations of Sost, the sclerostin encoding gene, have dramatic effects on the skeleton, indicating that osteocytes may act as master regulators of bone formation and localized bone remodeling. Moreover, the development of sclerostin inhibitors is opening new possibilities for bone regeneration in orthopedics and the dental field. PMID- 20200414 TI - Wnt/beta-catenin signaling in oral tissue development and disease. AB - The Wnt/beta-catenin signaling pathway is one of several key conserved intercellular signaling pathways in animals, and plays fundamental roles in the proliferation, regeneration, differentiation, and function of many cell and tissue types. This pathway is activated in a dynamic manner during the morphogenesis of oral organs, including teeth, taste papillae, and taste buds, and is essential for these processes to occur normally. Conversely, forced activation of Wnt/beta-catenin signaling promotes the formation of ectopic teeth and taste papillae. In this review, we discuss our current understanding of the roles of Wnt/beta-catenin signaling in oral tissue development and in related human diseases, and the potential of manipulating this pathway for therapeutic purposes. PMID- 20200417 TI - Killing of Treponema denticola by mouse peritoneal macrophages. AB - Treponema denticola has been identified as an important cause of periodontal disease and hypothesized to be involved in extra-oral infections. The objective of this study was to investigate the role of T. denticola cell length and motility during mouse peritoneal macrophages in vitro uptake. Macrophages, incubated under aerobic and anaerobic conditions, produced a similar amount of TNF-alpha when stimulated with Escherichia coli LPS. The uptake of FlgE- and CfpA deficient mutants of T. denticola was significantly increased compared with the wild-type strain, due to cell size or lack of motility. Opsonization with specific antibodies considerably improved the treponemes' uptake. These results suggest that macrophages, in addition to other phagocytes, could play an important role in the control of T. denticola infection, and that the raising of specific antibodies could improve the efficacy of the immune response toward T. denticola, either at an oral site or during dissemination. PMID- 20200418 TI - Aggregatibacter actinomycetemcomitans leukotoxin: from threat to therapy. AB - Aggregatibacter actinomycetemcomitans is a Gram-negative bacterium that colonizes the human oral cavity and is the causative agent for localized aggressive periodontitis (LAP), an aggressive form of periodontal disease that occurs in adolescents. A. actinomycetemcomitans secretes a protein toxin, leukotoxin (LtxA), which helps the bacterium evade the host immune response during infection. LtxA is a membrane-active toxin that specifically targets white blood cells (WBCs). In this review, we discuss recent developments in this field, including the identification and characterization of genes and proteins involved in secretion, regulation of LtxA, biosynthesis, newly described activities of LtxA, and how LtxA may be used as a therapy for the treatment of diseases. PMID- 20200419 TI - Implication of ethanol wet-bonding in hybrid layer remineralization. AB - During mineralization, unbound water within the collagen matrix is replaced by apatite. This study tested the null hypothesis that there is no difference in the status of in vitro biomimetic remineralization of hybrid layers, regardless of their moisture contents. Acid-etched dentin was bonded with One-Step with ethanol wet-bonding, water-wet-bonding, and water-overwet-bonding protocols. Composite dentin slabs were subjected to remineralization for 1-4 months in a medium containing dual biomimetic analogs, with set Portland cement as the calcium source and characterized by transmission electron microscopy. Remineralization was either non-existent or restricted to the intrafibrillar mode in ethanol-wet bonded specimens. Extensive intrafibrillar and interfibrillar remineralization was observed in water-wet-bonded specimens. Water-overwet specimens demonstrated partial remineralization of hybrid layers and precipitation of mineralized plates within water channels. The use of ethanol-wet-bonding substantiates that biomimetic remineralization is a progressive dehydration process that replaces residual water in hybrid layers with apatite crystallites. PMID- 20200420 TI - An all-in-one adhesive does not etch beyond hybrid layers. AB - Continuous etching of aggressive all-in-one adhesives occurs in wet dentin tubules after polymerization of the adhesives. This study challenged the hypothesis that unpolymerized acidic monomers from an aggressive all-in-one self etching adhesive continue to etch beyond dentin hybrid layers. Dentin surfaces bonded with Adper Prompt L-Pop were sectioned into 0.3-mm-thick slabs. Some of the slabs were stored in water (pH 6.8) or glycine buffer (pH 11.1) for six weeks and then examined by CLSM, SEM, and TEM. The rest were immersed in a biomimetic remineralizing medium for up to 4 months. Morphologic analysis indicated no difference in demineralization thickness between the two 6-week storage groups. However, increased permeability and loss of integrity occurred along the base of the hybrid layers in the glycine buffer group, but not in the water storage group. These findings were also confirmed by the results of biomimetic remineralization along the bases of those hybrid layers. PMID- 20200421 TI - Anti-NGF treatment reduces bone resorption in periodontitis. AB - Periodontitis is characterized by periodontal tissue destruction, including the alveolar bone. One of its critical components is the release of pro-inflammatory neuropeptides from sensory nerve endings innervating the periodontium. Since nerve growth factor (NGF) has been reported to up-regulate neuropeptides in sensory neurons, we hypothesized that it would be increased in ligature-induced periodontitis in rats, and that systemic NGF neutralization would reduce the periodontitis-associated alveolar bone resorption. Real-time PCR analysis disclosed a statistically significant time-dependent up-regulation of NGF mRNA in gingiva during 2 weeks of periodontitis. Interestingly, NGF up-regulation was also detected in the contralateral gingiva. In addition, immunohistochemistry of trigeminal ganglion neurons innervating the gingivomucosa demonstrated increased expression of TrkA receptor for NGF. Systemic anti-NGF treatment during periodontitis significantly reduced interleukin-1beta expression in gingiva and bilateral alveolar bone resorption. This suggests that NGF promotes periodontal inflammation and implicates a possible use of anti-NGF treatment in periodontitis. PMID- 20200422 TI - Association between cytokine gene polymorphisms and gastric precancerous lesions: systematic review and meta-analysis. AB - Polymorphisms within interleukin-1 (IL1) and tumor necrosis factor alpha (TNFA) gene clusters are associated with an increased risk of gastric cancer. However, their role in gastric precancerous lesions remains poorly understood. Our objective was to perform a meta-analysis of studies addressing the association between IL1B-511, IL1RN variable number of tandem repeat, and TNFA-308 gene polymorphisms and gastric precancerous lesions, including original data from Portugal and Mozambique. Published studies on the association between these cytokine gene polymorphisms and gastric precancerous lesions were identified by systematic review, and estimates of the association were combined using random effects meta-analysis taking into account new data obtained from Portuguese volunteer shipyard workers (n = 215) and Mozambican dyspeptic patients (n = 96) who underwent endoscopic and pathologic evaluation following the same protocol. Odds ratio (OR) estimates for intestinal metaplasia were 2.83 [95% confidence interval (95% CI), 1.15-6.96] for the IL1RN*22 genotype, 1.86 (95% CI, 1.03-3.36) for IL1B-511 T carriers, and 0.59 (95% CI, 0.12-3.04) for the TNFA-308*AA genotype in the Portuguese sample. All Mozambican subjects with intestinal metaplasia were T carriers for IL1B-511 and none had the 2 allele for IL1RN. In meta-analysis, IL1RN*22 genotype was associated with an increased risk of gastric precancerous lesions (22 versus LL: OR, 2.27; 95% CI, 1.40-3.70; I(2) = 26.4%; 12 studies). No such association was found for the IL1B-511 (TT versus CC: OR, 1.34; 95% CI, 0.87-2.07; I(2) = 65.7%; 13 studies) or TNFA-308 genotypes (AA versus GG: OR, 0.93; 95% CI, 0.35-2.43; I(2) = 0.0%; 7 studies). The IL1RN*22 genotype seems to consistently increase the risk of gastric precancerous lesions, supporting a role for this polymorphism in the early stages of gastric carcinogenesis. PMID- 20200423 TI - Randomized controlled trial of a psychosocial telephone counseling intervention in BRCA1 and BRCA2 mutation carriers. AB - BACKGROUND: Responses following BRCA1/2 genetic testing are relevant for the comprehension of risk status and may play a role in risk management decision making. The objective of this study was to evaluate a psychosocial telephone counseling (PTC) intervention delivered to BRCA1/2 mutation carriers following standard genetic counseling (SGC). We examined the effect of the intervention on distress and the concerns related to genetic testing. METHODS: This prospective randomized clinical trial included 90 BRCA1/2 mutation carriers. We measured anxiety, depression, and genetic testing distress outcomes at intervention baseline and 6 and 12 months following disclosure. We evaluated the effects of SGC versus SGC plus PTC on psychological outcomes using intention-to-treat analyses through generalized estimating equations. RESULTS: At 6 months, PTC reduced depressive symptoms (Z = -2.25, P = 0.02) and genetic testing distress (Z = 2.18, P = 0.02) compared with SGC. Furthermore, women in the intervention condition reported less clinically significant anxiety at 6 months (chi(2)(1) = 4.11, P = 0.04) than women who received SGC. We found no differences in outcomes between the intervention groups at the 12-month follow-up. CONCLUSIONS: As an adjunct to SGC, PTC delivered following disclosure of positive BRCA1/2 test results seems to offer modest short-term benefits for distress and anxiety. These results build upon a growing literature of psychosocial interventions for BRCA1/2 carriers and, given the potential impact of affect on risk management decision making, suggest that some carriers may derive benefits from adjuncts to traditional genetic counseling. PMID- 20200424 TI - A segregation analysis of Barrett's esophagus and associated adenocarcinomas. AB - Familial aggregation of esophageal adenocarcinomas, esophagogastric junction adenocarcinomas, and their precursor Barrett's esophagus (BE) has been termed familial BE (FBE). Numerous studies documenting increased familial risk for these diseases raise the hypothesis that there may be an inherited susceptibility to the development of BE and its associated cancers. In this study, using segregation analysis for a binary trait as implemented in S.A.G.E. 6.0.1, we analyzed data on 881 singly ascertained pedigrees to determine whether FBE is caused by a common environmental or genetic agent and, if genetic, to identify the mode of inheritance of FBE. The inheritance models were compared by likelihood ratio tests and Akaike's A Information Criterion. Results indicated that random environmental and/or multifactorial components were insufficient to fully explain the familial nature of FBE, but rather, there is segregation of a major type transmitted from one generation to the next (P < 10(-10)). An incompletely dominant inheritance model together with a polygenic component fits the data best. For this dominant model, the estimated penetrance of the dominant allele is 0.1005 [95% confidence interval (95% CI), 0.0587-0.1667] and the sporadic rate is 0.0012 (95% CI, 0.0004-0.0042), corresponding to a relative risk of 82.53 (95% CI, 28.70-237.35) or odds ratio of 91.63 (95% CI, 32.01-262.29). This segregation analysis provides epidemiologic evidence in support of one or more rare autosomally inherited dominant susceptibility allele(s) in FBE families and, hence, motivates linkage analyses. PMID- 20200425 TI - PTGER2 overexpression in colorectal cancer is associated with microsatellite instability, independent of CpG island methylator phenotype. AB - BACKGROUND: Prostaglandin-endoperoxide synthase 2 (PTGS2, the HUGO Gene Nomenclature Committee-approved official symbol for cycloxygenase-2, COX-2) and its enzymatic product prostaglandin E2 have critical roles in inflammation and carcinogenesis through the G protein-coupled receptor PTGER2 (EP2). The PTGS2 (COX-2) pathway is a promising target for cancer therapy and chemoprevention. PTGS2 (COX-2) expression in colon cancer has been inversely associated with survival as well as tumoral microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP). However, the prognostic significance of PTGER2 expression or its relationship with MSI, CIMP, LINE-1 hypomethylation, or PTGS2 (COX-2) remains uncertain. METHODS: Using the database of 516 colorectal cancers in two prospective cohort studies with clinical outcome data, we detected PTGER2 overexpression in 169 (33%) tumors by immunohistochemistry. We analyzed MSI using 10 microsatellite markers; CIMP by MethyLight (real-time methylation-specific PCR) on an eight-marker panel [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1]; BRAF, KRAS, PIK3CA, and methylation in LINE-1 by Pyrosequencing; and CTNNB1 (beta-catenin) and TP53 (p53) by immunohistochemistry. RESULTS: PTGER2 overexpression was positively associated with the mucinous component (P = 0.0016), signet ring cells (P = 0.0024), CIMP-high (P = 0.0023), and MSI-high (P < 0.0001). In multivariate analysis, the significant relationship between PTGER2 and MSI-high persisted (adjusted odds ratio, 2.82; 95% confidence interval, 1.69-4.72; P < 0.0001). PTGER2 was not significantly associated with PTGS2 (COX-2), TP53, or CTNNB1 expression, patient survival, or prognosis. CONCLUSION: PTGER2 overexpression is associated with MSI-high in colorectal cancer. IMPACT: Our data imply potential roles of inflammatory reaction by PTGER2 upregulation in carcinogenic process to MSI-high colorectal cancer. PMID- 20200427 TI - Adolescent diet in relation to breast cancer risk among premenopausal women. AB - BACKGROUND: Although the association between adult diet and breast cancer has been investigated extensively, large prospective studies have generally not shown a direct link between intakes of carbohydrate, fat, fiber, and other nutrients and risk of breast cancer. Adolescence may be a period of increased susceptibility to risk factors that predispose to breast cancer. Dietary risk factors could therefore be more important during early life than later in adulthood. METHODS: This is a prospective observational study of 39,268 premenopausal women in the Nurses' Health Study II who completed a 124-item food frequency questionnaire on their diet during high school (HS-FFQ) in 1998, at which time participants were 34 to 53 years of age. Cox proportional hazards regression was used to estimate relative risks and 95% CIs. RESULTS: Four hundred fifty-five incident cases of invasive breast cancer were diagnosed between 1998 and 2005. Compared with women in the lowest quintile of intake, the relative risk of breast cancer in the highest quintile of adolescent total fat consumption was 1.35 (95% confidence interval, 1.00-1.81). Adolescent consumption of saturated, monounsaturated, polyunsaturated, and trans fats was not significantly associated with breast cancer risk. Total dairy, milk, carbohydrate intake, glycemic index, glycemic load, and fiber consumed during adolescence were not significantly related to breast cancer incidence. CONCLUSION: Dietary fat consumed during adolescence may be associated with an elevated risk of breast cancer. Further studies to assess this relationship among postmenopausal women, and confirm these results in premenopausal women, are needed. PMID- 20200426 TI - Glutathione pathway genetic polymorphisms and lung cancer survival after platinum based chemotherapy. AB - BACKGROUND: Lung cancer is commonly treated with platinum compounds. The "glutathione pathway" participates in the metabolism of platinum compounds. We set out to test the hypotheses that single nucleotide polymorphisms (SNPs) or copy number polymorphisms for genes within the glutathione pathway might influence survival in lung cancer patients treated with these drugs. METHODS: Germline DNA samples from 973 lung cancer patients were genotyped for 290 glutathione pathway SNPs. GSTT1 copy number was also assayed. We determined the association of these polymorphisms with survival for lung cancer patients, followed by functional genomic validation. RESULTS: We observed suggestive associations between survival and GSTT1 copy number (P = 0.017), and GSTA5, GSTM4, and ABCC4 SNPs, adjusted for covariates (P = 0.018, 0.002, and 0.002, respectively) or not (P = 0.005, 0.011, and 0.002). One hundred lymphoblastoid cell lines were then treated with cisplatin, and IC(50) values were significantly associated with the GSTM4 SNP (P = 0.019). Furthermore, GSTM4, GSTT1, and ABCC4 overexpression significantly decreased cisplatin sensitivity in lung cancer and HEK293T cell lines. CONCLUSIONS: These results suggest that GSTM4 polymorphisms are biomarkers for the prediction of cisplatin response. ABCC4 polymorphisms, as well as GSTT1 copy number, may also help to predict cisplatin response, but further validation is required. These results represent a step toward the individualized chemotherapy of lung cancer. PMID- 20200428 TI - Impact of socioeconomic status on extent of lymph node dissection for colon cancer. AB - BACKGROUND: The pathologic identification of 12 or more lymph nodes (LN) after colectomy for colon cancer became a quality indicator for surgery in 2001. We investigated whether this new standard of care was differentially adopted across racial and socioeconomic lines. METHODS: We identified 111,339 stage I to III colon cancer patients identified as black or white in the Surveillance, Epidemiology, and End Results database from 1988 to 2004 who underwent colectomy. We did multivariable logistic regression to investigate the influence of race, area socioeconomic status (SES), and other clinical and demographic characteristics on the number of LNs examined. RESULTS: Between 1988 and 2004, white patients were more likely than black patients to have > or =12 LNs identified (odds ratio, 1.06; 95% confidence interval, 1.02-1.10) after adjustment for age, year of diagnosis, sex, marital status, tumor grade, stage, and subsite within the colon. After adjustment for SES, race was no longer significant (adjusted odds ratio, 1.00; 95% confidence interval, 0.96-1.04). There was, however, a significant positive trend between a patient's SES and having > or =12 LNs examined (P(trend) < 0.0001), with a 30% increased odds comparing the highest to the lowest quintiles of SES. We found that the association between SES and the dissection of > or =12 LNs was only present in individuals diagnosed after 1999. CONCLUSIONS: The association between high SES and the examination of > or =12 LNs was only apparent from 2000 onward, and coincides with its dissemination and acceptance as a new standard of care. This suggests that the emergence of LN dissection as a quality indicator may have been more rapidly disseminated into higher SES groups. PMID- 20200429 TI - Urinary 6-Sulphatoxymelatonin levels and risk of breast cancer in premenopausal women: the ORDET cohort. AB - BACKGROUND: Lower urinary melatonin levels are associated with a higher risk of breast cancer in postmenopausal women. Literature for premenopausal women is scant and inconsistent. METHODS: In a prospective case-control study, we measured the concentration of 6-sulphatoxymelatonin (aMT6s) in the 12-hour overnight urine of 180 premenopausal women with incident breast cancer and 683 matched controls. RESULTS: In logistic regression models, the multivariate odds ratio (OR) of invasive breast cancer for women in the highest quartile of total overnight aMT6s output compared with the lowest was 1.43 [95% confidence interval (CI), 0.83 2.45; P(trend) = 0.03]. Among current nonsmokers, no association was existent (OR, 1.00; 95% CI, 0.52-1.94; P(trend) = 0.29). We observed an OR of 0.68 between overnight urinary aMT6s level and breast cancer risk in women with invasive breast cancer diagnosed >2 years after urine collection and a significant inverse association in women with a breast cancer diagnosis >8 years after urine collection (OR, 0.17; 95% CI, 0.04-0.71; P(trend) = 0.01). There were no important variations in ORs by tumor stage or hormone receptor status of breast tumors. CONCLUSION: Overall, we observed a positive association between aMT6s and risk of breast cancer. However, there was some evidence to suggest that this might be driven by the influence of subclinical disease on melatonin levels, with a possible inverse association among women diagnosed further from recruitment. Thus, the influence of lag time on the association between melatonin and breast cancer risk needs to be evaluated in further studies. PMID- 20200431 TI - Long-term mortality from second malignant neoplasms in 5-year survivors of solid childhood tumors: temporal pattern of risk according to type of treatment. AB - BACKGROUND: The temporal pattern in mortality from late second malignant neoplasms in solid childhood cancer survivors, according to the type of treatment, has not been investigated in detail. METHODS: We studied 4,230 5-year survivors of solid childhood cancer diagnosed between 1942 and 1986 in France and the United Kingdom. Complete clinical, chemotherapy, and radiotherapy data were recorded and the integral radiation dose was estimated for 2,701 of the 2,948 patients who had received radiotherapy. RESULTS: After a median follow-up of 28 years, 134 fatal events were due to second malignancies, compared with the 13.3 expected from the general France-UK population rates. The standardized mortality ratio was of a similar magnitude after radiotherapy alone and chemotherapy alone and higher after both treatments. The standardized mortality ratio decreased with follow-up, whereas the absolute excess risk increased significantly over a period of at least 25 years after the first cancer. This temporal pattern was similar after chemotherapy alone, radiotherapy alone, or both treatments. We observed a similar long-term temporal pattern among survivors who had died of a second malignant neoplasm of the gastrointestinal tract and breast. Survivors who had received a higher integral radiation dose during radiotherapy were at a particularly high risk, as well as those who had received alkylating agents and epipodophyllotoxins. CONCLUSIONS: Five-year survivors of childhood cancer run a high long-term mortality risk for all types of second malignant neoplasms whatever the treatment received and require careful long-term screening well beyond 25 years after the diagnosis. PMID- 20200430 TI - TP53, MDM2, NQO1, and susceptibility to cervical cancer. AB - Host genetic variability modifies the risk of cervical cancer in women infected with oncogenic human papillomavirus (HPV). Studies have reported an association of the TP53 codon 72 arginine and cervical cancer, but the results are inconsistent. We examined the association of this single nucleotide polymorphism (SNP) in women with cervical cancer and cervical intraepithelial neoplasia grade 3, using a family-based association test. We further explored SNPs in two genes that regulate p53 stability: MDM2 (SNP309) and NQO1 (SNP609, SNP465). We also examined the relationship between host genotype and tumor HPV type. We genotyped 577 patients and their biological parents and/or siblings, using PCR-RFLP or Taqman assays. HPVs were typed by sequence-based methods. The transmission/disequilibrium test was used to detect disease-susceptibility alleles. The arginine peptide of TP53 codon 72 was overtransmitted in Caucasian families (P = 0.043), and the significance of this finding was enhanced in a subgroup of women infected with HPV16- and/or HPV18-related HPVs (P = 0.026). Allele C of NQO1 SNP609 was also overtransmitted in all cases (P = 0.026). We found no association between MDM2 SNP309 or NQO1 SNP465 and cervical cancer. Our results indicate that functional polymorphisms in TP53 codon 72 and NQO1 SNP609 associate with the risk of cervical cancer especially in women infected with type 16- and/or type 18-related HPVs. PMID- 20200432 TI - Antioxidant micronutrients and biomarkers of oxidative stress and inflammation in colorectal adenoma patients: results from a randomized, controlled clinical trial. AB - Previous epidemiologic observational and experimental studies investigated the potential of antioxidant micronutrients to modulate cancer risk, but these studies produced inconsistent results. In this pilot, randomized, double-blind, placebo-controlled clinical trial (n = 47), we assessed the effects of an antioxidant micronutrient combination (800 mg dl-alpha-tocopherol acetate, 24 mg beta-carotene, 1.0 g vitamin C, 200 microg l-selenomethionine, 7.2 mg riboflavin, 80 mg niacin, 60 mg zinc, 5 mg manganese) given daily over 4 months on oxidative and inflammatory biomarkers in patients with a history of sporadic colorectal adenoma. Plasma tumor necrosis factor-alpha (TNF-alpha), interleukin-6, and F2 isoprostane concentrations were measured using ELISAs, and cystine (CySS) was measured using high-performance liquid chromatography. Plasma TNF-alpha concentration decreased in the active treatment group by 37% relative to the placebo group (P = 0.002), and CySS decreased by 19% (P = 0.03); however, interleukin-6 and F2-isoprostane concentrations decreased in antioxidant-treated nonsmokers but increased in smokers, although these findings were not statistically significant. The decreases of TNF-alpha and CySS were more pronounced in nonsmokers. These data suggest that (a) an antioxidant micronutrient cocktail can modulate biomarkers of oxidative stress and inflammation in humans and (b) the effects of antioxidant micronutrient supplementation on biomarkers of inflammation and oxidative stress may differ according to smoking status. PMID- 20200433 TI - Mammography and women under 50: deja vu all over again? PMID- 20200434 TI - Saliva-derived DNA performs well in large-scale, high-density single-nucleotide polymorphism microarray studies. AB - As of June 2009, 361 genome-wide association studies (GWAS) had been referenced by the HuGE database. GWAS require DNA from many thousands of individuals, relying on suitable DNA collections. We recently performed a multiple sclerosis (MS) GWAS where a substantial component of the cases (24%) had DNA derived from saliva. Genotyping was done on the Illumina genotyping platform using the Infinium Hap370CNV DUO microarray. Additionally, we genotyped 10 individuals in duplicate using both saliva- and blood-derived DNA. The performance of blood- versus saliva-derived DNA was compared using genotyping call rate, which reflects both the quantity and quality of genotyping per sample and the "GCScore," an Illumina genotyping quality score, which is a measure of DNA quality. We also compared genotype calls and GCScores for the 10 sample pairs. Call rates were assessed for each sample individually. For the GWAS samples, we compared data according to source of DNA and center of origin. We observed high concordance in genotyping quality and quantity between the paired samples and minimal loss of quality and quantity of DNA in the saliva samples in the large GWAS sample, with the blood samples showing greater variation between centers of origin. This large data set highlights the usefulness of saliva DNA for genotyping, especially in high-density single-nucleotide polymorphism microarray studies such as GWAS. PMID- 20200436 TI - Misconceptions about breast lumps and delayed medical presentation in urban breast cancer patients. AB - BACKGROUND: Despite current recommendations for women to be screened for breast cancer with mammography every 1 to 2 years, less than half of all newly diagnosed breast cancers are initially detected through screening mammography. Prompt medical attention to a new breast symptom can result in earlier stage at diagnosis, yet many patients delay seeking medical care after becoming aware of a breast symptom. METHODS: In a population-based study of breast cancer, we examined factors potentially associated with patient delay in seeking health care for a breast symptom among 436 symptomatic urban breast cancer patients (146 white, 197 black, and 95 Hispanic). Race/ethnicity, socioeconomic status, health care access and utilization, and misconceptions about the meaning of breast lumps were the key independent variables. RESULTS: Sixteen percent of patients reported delaying more than 3 months before seeking medical advice about breast symptoms. Misconceptions about breast lumps and lacking a regular provider, health insurance, and recent preventive care were all associated with prolonged patient delay (P < 0.005 for all). Misconceptions were much more common among ethnic minorities and women of lower socioeconomic status. CONCLUSION: Reducing patient delay and disparities in delay will require educating women about the importance of getting breast lumps evaluated in a timely manner and providing greater access to regular health care. PMID- 20200437 TI - Podoplanin and ABCG2: malignant transformation risk markers for oral lichen planus. AB - BACKGROUND: Oral lichen planus (OLP) is a potentially malignant disorder associated with an increased risk for oral cancer. The purpose of this study was to determine protein expression of podoplanin and ATP-binding cassette, G2 subfamily (ABCG2) in patients with OLP and evaluate their use as biomarkers for OLP malignant transformation risk. METHODS: Podoplanin and ABCG2 expressions were determined in samples from 110 patients with untransformed OLP and 9 patients with malignant transformed OLP (mean follow-up of 5.1 years). We compared podoplanin expression, ABCG2 expression, and clinicopathologic parameters between the two groups. RESULTS: Podoplanin expression was observed in 48 of 110 (43.6%) cases of untransformed OLP and in 8 of 9 (88.9%) cases of transformed OLP. ABCG2 expression was found in 23 of 110 (20.9%) cases of untransformed OLP and in 6 of 9 (66.7%) cases of transformed OLP. Multivariate regression analysis revealed that podoplanin or ABCG2 expression was associated with 17.13-fold [95% confidence interval (95% CI), 1.71-171.22; P = 0.016] or 6.04-fold (95% CI, 1.20 30.36; P = 0.029) increased risk of malignant transformation, respectively. The risk of OLP malignant transformation was considerably higher with coexpression of podoplanin and ABCG2 than without coexpression of podoplanin and ABCG2 (odds ratio, 25.24; 95% CI, 4.48-142.27; P < 0.001). CONCLUSIONS: The expressions of podoplanin and ABCG2 in OLP were significantly associated with malignant transformation risk. IMPACT: Our data suggested that podoplanin and ABCG2 may be used as biomarkers for risk assessment of oral malignant transformation in patients with OLP. PMID- 20200435 TI - p53 autoantibodies as potential detection and prognostic biomarkers in serous ovarian cancer. AB - BACKGROUND: This study examined the value of serum p53 autoantibodies (p53-AAb) as detection and prognostic biomarkers in ovarian cancer. METHODS: p53-AAb were detected by ELISA in sera obtained preoperatively from women undergoing surgery for a pelvic mass. This group included women subsequently diagnosed with invasive serous ovarian cancer (n = 60), nonserous ovarian cancers (n = 30), and women with benign disease (n = 30). Age-matched controls were selected from the general population (n = 120). Receiver operating characteristic curves were constructed to compare the values of p53-AAb, CA 125, and HE4 as a screening biomarker. Kaplan-Meier curves and Cox proportional hazards modeling were used to assess its prognostic value on survival. RESULTS: p53-AAb were detected in 25 of 60 (41.7%) of serous cases, 4 of 30 (13.3%) nonserous cases, 3 of 30 (10%) benign disease cases, and 10 of 120 (8.3%) controls (combined P = 0.0002). p53-AAb did not significantly improve the detection of cases [area under the curve (AUC), 0.69] or the discrimination of benign versus malignant disease (AUC, 0.64) compared with CA 125 (AUC, 0.99) or HE4 (AUC, 0.98). In multivariate analysis among cases, p53-AAb correlated only with a family history of breast cancer (P = 0.01). Detectable p53 antibodies in pretreatment sera were correlated with improved overall survival (P = 0.04; hazard ratio, 0.57; 95% confidence interval, 0.33 0.97) in serous ovarian cancer. CONCLUSIONS: Antibodies to p53 are detected in the sera of 42% of patients with advanced serous ovarian cancer. IMPACT: Although their utility as a preoperative diagnostic biomarker, beyond CA 125 and HE4, is limited, p53-AAb are prognostic for improved overall survival. PMID- 20200438 TI - Smoking, gender, and ethnicity predict somatic BRAF mutations in colorectal cancer. AB - Approximately 5% to 15% of all colorectal cancers (CRC) have an activating BRAF somatic mutation, which may be associated with a distinct risk profile compared with tumors without BRAF mutations. Here, we measured the prevalence and epidemiologic correlates of the BRAF V600E somatic mutation in cases collected as a part of a population-based case-control study of CRC in northern Israel. The prevalence of BRAF V600E was 5.0% in this population, and the mutation was more likely to be found in tumors from cases who were of Ashkenazi Jewish descent [odds ratio (OR), 1.87; 95% confidence interval (95% CI), 1.01-3.47], female (OR, 1.97; P = 1.17-3.31), and older (73.8 years versus 70.3 years; P < 0.001). These results were similar when restricting to only tumors with microsatellite instability. Whether smoking was associated with a BRAF somatic mutation depended on gender. Although men were less likely to have a tumor with a BRAF somatic mutation, men who smoked were much more likely to have a tumor with a somatic BRAF mutation (OR(interaction), 4.95; 95% CI, 1.18-20.83) than women who never smoked. We note the strong heterogeneity in the reported prevalence of the BRAF V600E mutation in studies of different ethnicities, with a lower prevalence in Israel than other Western populations but a higher prevalence among Jewish than non-Jewish Israeli cases. Epidemiologic studies of CRC should incorporate somatic characteristics to fully appreciate risk factors for this disease. PMID- 20200440 TI - Lower risk of lung cancer after multiple pneumonia diagnoses. AB - BACKGROUND: Although pneumonia has been suggested as a risk factor for lung cancer, previous studies have not evaluated the influence of number of pneumonia diagnoses in relation to lung cancer risk. METHODS: The Environment And Genetics in Lung cancer Etiology (EAGLE) population-based study of 2,100 cases and 2,120 controls collected information on pneumonia more than 1 year before enrollment from 1,890 cases and 2,078 controls. RESULTS: After adjusting for study design variables, smoking, and chronic bronchitis, pneumonia was associated with decreased risk of lung cancer [odds ratio (OR), 0.79; 95% confidence interval (CI), 0.64-0.97], especially among individuals with three or more diagnoses versus none (OR, 0.35; 95% CI, 0.16-0.75). Adjustment for chronic bronchitis contributed to this inverse association. In comparison, pulmonary tuberculosis was not associated with lung cancer (OR, 0.96; 95% CI, 0.62-1.48). CONCLUSIONS: The apparent protective effect of pneumonia among individuals with multiple pneumonia diagnoses may reflect an underlying difference in immune response and requires further investigation and confirmation. Therefore, careful evaluation of the number of pneumonia episodes may shed light on lung cancer etiology. PMID- 20200439 TI - Androgen receptor CAG repeat length and risk of biliary tract cancer and stones. AB - Biliary tract cancers, encompassing cancers of the gallbladder, extrahepatic bile ducts, and ampulla of Vater, are rare but highly fatal. Gallstones represent the major risk factor for biliary tract cancer, and share with gallbladder cancer a female predominance and an association with reproductive factors and obesity. Although estrogens have been implicated in earlier studies of gallbladder cancer, there are no data on the role of androgens. Because intracellular androgen activity is mediated through the androgen receptor (AR), we examined associations between AR CAG repeat length [(CAG)(n)] and the risk of biliary tract cancers and stones in a population-based study of 331 incident cancer cases, 837 gallstone cases, and 750 controls from Shanghai, China, where the incidence rates for biliary tract cancer are rising sharply. Men with (CAG)(n) >24 had a significant 2-fold risk of gallbladder cancer [odds ratio (OR), 2.00; 95% confidence interval (CI), 1.07-3.73], relative to those with (CAG)(n) < or = 22. In contrast, women with (CAG)(n) >24 had reduced gallbladder cancer risk (OR, 0.69; 95% CI, 0.43 1.09) relative to those with (CAG)(n) < or = 22; P interaction sex = 0.01, which was most pronounced for women ages 68 to 74 (OR, 0.48; 95% CI, 0.25-0.93; P interaction age = 0.02). No associations were found for bile duct cancer or gallstones. Reasons for the heterogeneity of genetic effects by gender and age are unclear but may reflect an interplay between AR and the levels of androgen as well as estrogen in men and older women. Further studies are needed to confirm these findings and clarify the mechanisms involved. PMID- 20200441 TI - Is human papillomavirus viral load a clinically useful predictive marker? A longitudinal study. AB - BACKGROUND: It has been suggested that in women who test positive for high-risk human papillomavirus (HPV) types, viral load can distinguish women who are at increased risk of cervical neoplasia from those who are not. METHODS: Quantitative PCR (qPCR) was used to measure HPV copy number in serial samples taken from 60 and 58 young women previously found to have incident cervical HPV16 or HPV18 infections, respectively, using GP5+/GP6+ primers; women provided at least three samples for qPCR testing, at least one of which was positive. RESULTS: A 10-fold increase in HPV16 or HPV18 copy number was associated with a modestly increased risk of acquiring a cytologic abnormality [HPV16: hazards ratio, 1.76 (95% confidence interval, 1.38-2.25); HPV18: hazards ratio, 1.59 (95% confidence interval, 1.25-2.03)]. However, in most women, copy number increased during follow-up, before decreasing again. In women with a HPV16 infection, the median copy number per 1,000 cells was 7.7 in their first qPCR HPV-positive sample, 1,237 in the sample yielding the maximum copy number, and 7.8 in their last qPCR HPV-positive sample; corresponding copy numbers for women with HPV18 infection were 2.3, 87, and 2.4. Maximum HPV16 and HPV18 copy number did not differ significantly between women who acquired an incident cervical cytologic abnormality and those who did not. CONCLUSION: Whereas large relative increases in copy number are associated with an increased risk of abnormality, a single measurement of viral load made at an indeterminate point during the natural history of HPV infection does not reliably predict the risk of acquiring cervical neoplasia. Therefore, a single measure of HPV viral load cannot be considered a clinically useful biomarker. PMID- 20200442 TI - Sequence variants in the TLR4 and TLR6-1-10 genes and prostate cancer risk. Results based on pooled analysis from three independent studies. AB - BACKGROUND: Genetic variation in two members of the Toll-like receptor family, TLR4 and the gene cluster TLR6-1-10, has been implicated in prostate cancer in several studies but the associated alleles have not been consistent across reports. METHODS: We did a pooled analysis combining genotype data from three case-control studies, Cancer of the Prostate in Sweden, the Health Professionals Follow-up Study, and the Prostate, Lung, Colon and Ovarian Cancer Screening Trial, with data from 3,101 prostate cancer cases and 2,523 controls. We did imputation to obtain dense coverage of the genes and comparable genotype data for all cohorts. In total, 58 single nucleotide polymorphisms in TLR4 and 96 single nucleotide polymorphisms in TLR6-1-10 were genotyped or imputed and analyzed in the entire data set. We did a cohort-specific analysis as well as meta-analysis and pooled analysis. We also evaluated whether the analyses differed by age or disease severity. RESULTS: We observed no overall association between genetic variation at the TLR4 and TLR6-1-10 loci and risk of prostate cancer. CONCLUSIONS: Common germ line genetic variation in TLR4 and TLR6-1-10 did not seem to have a strong association with risk of prostate cancer. IMPACT: This study suggests that earlier associations between prostate cancer risk and TLR4 and TLR6-1-10 sequence variants were chance findings. To definitely assess the causal relationship between TLR sequence variants and prostate cancer risk, very large sample sizes are needed. PMID- 20200443 TI - A prospective, multicenter study to validate use of the PUSH in patients with diabetic, venous, and pressure ulcers. AB - Monitoring wound progress is essential for evaluating and documenting treatment outcomes. The Pressure Ulcer Scale for Healing (PUSH) was developed to track pressure ulcer (PU) progress but information about its utility for other types of chronic wounds is limited. A 10-month, descriptive, multicenter study was conducted to examine the responsiveness and concurrent validity of the PUSH when used to monitor wound changes in diabetic foot (DFU), venous leg (VLU), and PU. Using a convenience sample of participants (n = 98, mean age 60 [range 20 to 89] years, the majority [85%] male), PUSH score and acetate wound surface area tracings were obtained at baseline and approximately 4 weeks later from 47 Stage II to Stage IV PU, 23 VLU, and 28 patients with a DFU. After an average of 32 days, wound surface area, total PUSH scores, and individual PUSH component scores decreased significantly between baseline and follow-up (P = 0.000). The mean PUSH score change was significantly different between healing and nonhealing wounds (P = 0.000). A strong relationship (r = .66) was found between total PUSH score and surface area. Results suggest the PUSH tool is a valid, responsive, evaluative tool to monitor and document wound progress of PU, VLU, and DFU. Additional studies to assess use of this tool for DFU and to ascertain the predictive validity of the PUSH tool are warranted. PMID- 20200444 TI - A cross-sectional descriptive study of pressure ulcer prevalence in a teaching hospital in China. AB - Surveying pressure ulcer (PU) prevalence is a common practice in some western countries and has served as a tool to improve prevention policies and procedures. Although attention on PU prevention has increased in China, no PU prevalence baseline information is available to help guide care. To obtain this baseline information, a cross-sectional descriptive study was conducted in a 3,000-bed teaching hospital in Wuhan. On the morning of the study, trained clinicians audited the total hospital patient population (61 nursing units, 2,913 inpatients) using the PU survey tool designed by National Database of Nursing Quality Indicators. The majority of the patients (1,648, 56.6) were male, average patient age was 43.91 (+/-21.20) years, range 1 to 94 years. The overall PU prevalence rate was 1.8% (52 patients/79 ulcers). The hospital-acquired prevalence rate was 1.54% (0.82% when Stage I ulcers were excluded). Prevalence rates were highest in the ICU (45.5%) and most ulcers (53.2%) were located in the sacral-coccyx area. The results of this study suggest that overall PU prevalence rates are low compared to data from other countries. Differences in patient acuity, average patient length-of-stay, and prevention practices may explain these observations. The results of this study can guide hospital prevention efforts and serve as a benchmark for PU prevalence studies in China. PMID- 20200445 TI - Heel pressure ulcers in orthopedic patients: a prospective study of incidence and risk factors in an acute care hospital. AB - Heel pressure ulcers (PU) are a major concern in orthopedic patients. A prospective 6-month study was conducted in an acute care hospital in Canada to determine the incidence of heel PU in an orthopedic population, evaluate the effect of patient and care variables on heel PU incidence, and describe the natural history/sequelae of Stage I heel PU. One hundred and fifty (150) patients (average age 70.6 years) admitted for elective orthopedic surgery or treatment of a fractured hip participated in the study. A direct heel skin assessment was performed following admission and before discharge. Patients with a Stage I ulcer were assessed or contacted 1 week following discharge. The incidence of heel PU in this population was 13.3% CI (range 8% to 19%). Incidence was 16% in the hip fracture and 13% in the elective surgery group. PU incidence in the hip fracture group was significantly lower (P = 0.016) for patients receiving heel pressure relief measures (pillows, rolled sheets). In the elective surgery group, PU incidence rates were higher for patients with respiratory disease, lower hemoglobin, low pulse rate, and altered mental status (P <0.05). When both patient groups were combined, only the presence or absence of respiratory disease significantly affected PU incidence. Length of stay was an average of 3 days longer in all groups with a heel PU but the difference was not statistically significant. One week following discharge, 13 of the 17 (76%) Stage I heel PU had resolved, one remained unchanged, and two were assessed as deep tissue injury (11%) and one as Stage II. These incidence rates are similar to those reported in other countries and confirm that efforts to reduce heel PU incidence rates are needed. PMID- 20200446 TI - Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice. AB - Levels of the necessary nutrient vitamin C (ascorbate) are tightly regulated by intestinal absorption, tissue accumulation, and renal reabsorption and excretion. Ascorbate levels are controlled in part by regulation of transport through at least 2 sodium-dependent transporters: Slc23a1 and Slc23a2 (also known as Svct1 and Svct2, respectively). Previous work indicates that Slc23a2 is essential for viability in mice, but the roles of Slc23a1 for viability and in adult physiology have not been determined. To investigate the contributions of Slc23a1 to plasma and tissue ascorbate concentrations in vivo, we generated Slc23a1-/- mice. Compared with wild-type mice, Slc23a1-/- mice increased ascorbate fractional excretion up to 18-fold. Hepatic portal ascorbate accumulation was nearly abolished, whereas intestinal absorption was marginally affected. Both heterozygous and knockout pups born to Slc23a1-/- dams exhibited approximately 45% perinatal mortality, and this was associated with lower plasma ascorbate concentrations in dams and pups. Perinatal mortality of Slc23a1-/- pups born to Slc23a1-/- dams was prevented by ascorbate supplementation during pregnancy. Taken together, these data indicate that ascorbate provided by the dam influenced perinatal survival. Although Slc23a1-/- mice lost as much as 70% of their ascorbate body stores in urine daily, we observed an unanticipated compensatory increase in ascorbate synthesis. These findings indicate a key role for Slc23a1 in renal ascorbate absorption and perinatal survival and reveal regulation of vitamin C biosynthesis in mice. PMID- 20200447 TI - Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network. AB - Hereditary spastic paraplegias (HSPs; SPG1-45) are inherited neurological disorders characterized by lower extremity spastic weakness. More than half of HSP cases result from autosomal dominant mutations in atlastin-1 (also known as SPG3A), receptor expression enhancing protein 1 (REEP1; SPG31), or spastin (SPG4). The atlastin-1 GTPase interacts with spastin, a microtubule-severing ATPase, as well as with the DP1/Yop1p and reticulon families of ER-shaping proteins, and SPG3A caused by atlastin-1 mutations has been linked pathogenically to abnormal ER morphology. Here we investigated SPG31 by analyzing the distribution, interactions, and functions of REEP1. We determined that REEP1 is structurally related to the DP1/Yop1p family of ER-shaping proteins and localizes to the ER in cultured rat cerebral cortical neurons, where it colocalizes with spastin and atlastin-1. Upon overexpression in COS7 cells, REEP1 formed protein complexes with atlastin-1 and spastin within the tubular ER, and these interactions required hydrophobic hairpin domains in each of these proteins. REEP proteins were required for ER network formation in vitro, and REEP1 also bound microtubules and promoted ER alignment along the microtubule cytoskeleton in COS7 cells. A SPG31 mutant REEP1 lacking the C-terminal cytoplasmic region did not interact with microtubules and disrupted the ER network. These data indicate that the HSP proteins atlastin-1, spastin, and REEP1 interact within the tubularER membrane in corticospinal neurons to coordinate ER shaping and microtubule dynamics. Thus, defects in tubular ER shaping and network interactions with the microtubule cytoskeleton seem to be the predominant pathogenic mechanism of HSP. PMID- 20200448 TI - Targeted regulation of self-peptide presentation prevents type I diabetes in mice without disrupting general immunocompetence. AB - Peptide loading of MHC class II (MHCII) molecules is directly catalyzed by the MHCII-like molecule HLA-DM (DM). Another MHCII-like molecule, HLA-DO (DO), associates with DM, thereby modulating DM function. The biological role of DO mediated regulation of DM activity in vivo remains unknown; however, it has been postulated that DO expression dampens presentation of self antigens, thereby preventing inappropriate T cell activation that ultimately leads to autoimmunity. To test the idea that DO modulation of the MHCII self-peptide repertoire mediates self tolerance, we generated NOD mice that constitutively overexpressed DO in DCs (referred to herein as NOD.DO mice). NOD mice are a mouse model for type 1 diabetes, an autoimmune disease mediated by the destruction of insulin-secreting pancreatic beta cells. Our studies showed that diabetes development was completely blocked in NOD.DO mice. Similar to NOD mice, NOD.DO animals selected a diabetogenic T cell repertoire, and the numbers and function of Tregs were normal. Indeed, immune system function in NOD.DO mice was equivalent to that in NOD mice. NOD.DO DCs, however, presented an altered MHCII-bound self-peptide repertoire, thereby preventing the activation of diabetogenic T cells and subsequent diabetes development. These studies show that DO expression can shape the overall MHCII self-peptide repertoire to promote T cell tolerance. PMID- 20200451 TI - Activation of the shoulder musculature during pendulum exercises and light activities. AB - STUDY DESIGN: Prospective, single-group, repeated-measures design. OBJECTIVES: To evaluate electromyographic (EMG) signal amplitude in the supraspinatus, infraspinatus, and deltoid muscles during pendulum exercises and light activities in a group of healthy subjects. BACKGROUND: There are numerous rehabilitation protocols used after rotator cuff repair. One of the most commonly used exercises in these protocols is the pendulum. Patients can easily perform these exercises incorrectly, and may also perform light activities of daily living without knowing that they may be putting excessive stress on the repair. The effect of improperly performed pendulum exercises and light activities after rotator cuff repair is unknown. METHODS: Muscle activity was recorded in 13 subjects performing pendulum exercises incorrectly and correctly in both large (51-cm) and small (20-cm) diameters, and while typing, drinking, and brushing their teeth. RESULTS: Incorrect and correct large pendulums and drinking elicited more than 15% maximum voluntary isometric contraction in the supraspinatus and infraspinatus. The supraspinatus EMG signal amplitude was greater during large, incorrectly performed pendulums than during those performed correctly. Both correct and incorrect large pendulums resulted in statistically higher muscle activity in the supraspinatus than the small pendulums. CONCLUSION: Larger pendulums may require more force than is desirable early in rehabilitation after rotator cuff repair. PMID- 20200449 TI - Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. AB - Injury and loss of podocytes are leading factors of glomerular disease and renal failure. The postmitotic podocyte is the primary glomerular target for toxic, immune, metabolic, and oxidant stress, but little is known about how this cell type copes with stress. Recently, autophagy has been identified as a major pathway that delivers damaged proteins and organelles to lysosomes in order to maintain cellular homeostasis. Here we report that podocytes exhibit an unusually high level of constitutive autophagy. Podocyte-specific deletion of autophagy related 5 (Atg5) led to a glomerulopathy in aging mice that was accompanied by an accumulation of oxidized and ubiquitinated proteins, ER stress, and proteinuria. These changes resulted ultimately in podocyte loss and late-onset glomerulosclerosis. Analysis of pathophysiological conditions indicated that autophagy was substantially increased in glomeruli from mice with induced proteinuria and in glomeruli from patients with acquired proteinuric diseases. Further, mice lacking Atg5 in podocytes exhibited strongly increased susceptibility to models of glomerular disease. These findings highlight the importance of induced autophagy as a key homeostatic mechanism to maintain podocyte integrity. We postulate that constitutive and induced autophagy is a major protective mechanism against podocyte aging and glomerular injury, representing a putative target to ameliorate human glomerular disease and aging related loss of renal function. PMID- 20200452 TI - [The frequency of prosthesis-patient mismatch after mechanical mitral valve replacement and its effect on postoperative systolic pulmonary arterial pressure]. AB - OBJECTIVES: We investigated the frequency of prosthesis-patient mismatch (PPM) after mechanical mitral valve replacement (MVR), its effect on postoperative systolic pulmonary arterial pressure (PAP), and the relationship of indexed effective orifice area (EOA) with systolic PAP and hemodynamic variables of the prosthetic valve. STUDY DESIGN: The study included 100 patients (27 men, 73 women; mean age 51+/-11 years) with a normally functioning mechanical mitral valve prosthesis. Prosthetic mitral EOA, indexed EOA, and net atrioventricular compliance (Cn) were estimated by Doppler echocardiography. Prosthesis-patient mismatch was defined as an indexed EOA or=40 mmHg. RESULTS: The frequencies of PPM and postoperative persistent PHT were 33% and 31%, respectively. Postoperative persistent PHT was seen in 79% and 8% in patients with and without PPM, respectively (p<0.001). The frequency of low Cn was significantly higher in patients with PPM (60% vs. 31%; p<0.001). Postoperative systolic PAP was significantly higher in patients with PPM (42.0+/-6.6 mmHg vs. 29.9+/-6.0 mmHg, p<0.0001) and in 41 patients having a low Cn compared to 59 patients having a high Cn (37.2+/-8.8 mmHg vs. 31.6+/-7.4 mmHg, p<0.001). Postoperative systolic PAP was significantly correlated with indexed EOA (r= 0.535, p<0.001) and Cn (r=-0.422, p<0.001), whereas prosthetic valve size was not correlated with systolic PAP (r=0.022, p=0.829) and indexed EOA (r=0.008, p=0.93). In multivariate regression analysis, indexed EOA, age, mean transprosthetic gradient, and Cn were independent factors affecting systolic PAP. CONCLUSION: Prosthesis-patient mismatch after MVR is associated with persistent PHT. Use of a prosthetic valve that is compatible to the body surface area may significantly reduce the incidence of PPM, and thus the frequency of persistent PHT. PMID- 20200453 TI - [The efficiency and safety of balloon valvuloplasty in patients with mitral stenosis and a high echo score: mid- and short-term clinical and echocardiographic results]. AB - OBJECTIVES: We aimed to evaluate the success and safety of percutaneous mitral balloon valvuloplasty (PMBV) and its mid-term clinical and echocardiographic results in patients with symptomatic mitral stenosis, including those having a high echo score (9 to 11). STUDY DESIGN: This prospective study included 57 consecutive patients (9 men, 48 women; mean age 41+/-9 years) who underwent PMBV with the Inoue technique for symptomatic (NYHA class II-IV) mitral stenosis (valve area <1.5 cm2). The patients were divided into two groups according to the echo scores of 8 (group 2, n=32). Clinical and echocardiographic evaluations were performed before and after 24-48 hours of PMBV and during the follow-up period, including restenosis and major cardiovascular events. RESULTS: Patients in group 2 had significantly higher rates of atrial fibrillation (53.1% vs. 16%; p=0.006) and functional capacity of NYHA class III IV (90.7% vs. 56%; p=0.01). Procedural success rates were 96% (n=24) and 90.6% (n=29) in group 1 and 2, respectively. Failure occurred in one patient (4%) in group 1, and in three patients (9.4%) in group 2. One patient in group 1 developed severe mitral stenosis resulting in valve replacement. In group 2, two patients developed hemopericardium. After the procedure, there was a two-fold increase from 1.0+/-0.1 cm2 to 2.0+/-0.2 cm2 in the mean valve area, being more prominent in group 1 (group 1: from 1.1+/-0.1 cm2 to 2.1+/-0.1 cm2; group 2: from 0.9+/-0.1 cm2 to 1.8+/-0.1 cm2; p<0.001). In-hospital mortality or embolic events did not occur, nor did restenosis or major cardiovascular events during a mean follow-up of 21+/-13 months. CONCLUSION: Our results show that PMBV can be performed successfully in patients having a low (0.05). CONCLUSION: Similar QTc and JTc dispersion values detected in patients with and without ventricular extrasystoles may suggest that ventricular repolarization abnormalities occur in early life and may predispose to the development of ventricular arrhythmias in the long-term. PMID- 20200455 TI - [Adaptation of Myocardial Infarction Dimensional Assessment Scale to Turkish: a validity and reliability study]. AB - OBJECTIVES: It is well known that myocardial infarction (MI) adversely affects health-related quality of life. This study was designed to investigate the validity and reliability of the Turkish adaptation of the Myocardial Infarction Dimensional Assessment Scale (MIDAS) in patients admitted to hospital following their first MI. STUDY DESIGN: The study included 81 patients (13 women, 68 men; age or=50 years, and 34.7% and 12% in women and men, respectively. Compliance was significantly correlated with the delivery of information to the patients on the dose, the right time, and the properties of the drugs prescribed. Multivariate logistic regression analysis showed that age 90th percentile, n = 55) or low (<10th percentile, n = 53) warfarin dose requirements (after accounting for known genetic and nongenetic variables). One CALU variant, rs339097, was associated with high doses (P = 0.01). We validated this variant as a predictor of higher warfarin doses in two replication cohorts: (i) 496 patients of mixed ethnicity and (ii) 194 African American patients. The G allele of rs339097 (the allele frequency was 0.14 in African Americans and 0.002 in Caucasians) was associated with the requirement for a 14.5% (SD +/- 7%) higher therapeutic dose (P = 0.03) in the first replication cohort and a higher-than-predicted dose in the second replication cohort (allele frequency 0.14, one-sided P = 0.03). CALU rs339097 A>G is associated with higher warfarin dose requirements, independent of known genetic and nongenetic predictors of warfarin dose in African Americans. PMID- 20200518 TI - Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. AB - Innate immunity provides the first line of defence against invading pathogens and provides important cues for the development of adaptive immunity. Type-2 immunity responsible for protective immune responses to helminth parasites and the underlying cause of the pathogenesis of allergic asthma-consists of responses dominated by the cardinal type-2 cytokines interleukin (IL)4, IL5 and IL13 (ref. 5). T cells are an important source of these cytokines in adaptive immune responses, but the innate cell sources remain to be comprehensively determined. Here, through the use of novel Il13-eGFP reporter mice, we present the identification and functional characterization of a new innate type-2 immune effector leukocyte that we have named the nuocyte. Nuocytes expand in vivo in response to the type-2-inducing cytokines IL25 and IL33, and represent the predominant early source of IL13 during helminth infection with Nippostrongylus brasiliensis. In the combined absence of IL25 and IL33 signalling, nuocytes fail to expand, resulting in a severe defect in worm expulsion that is rescued by the adoptive transfer of in vitro cultured wild-type, but not IL13-deficient, nuocytes. Thus, nuocytes represent a critically important innate effector cell in type-2 immunity. PMID- 20200519 TI - Transcriptional control of preadipocyte determination by Zfp423. AB - The worldwide epidemic of obesity has increased the urgency to develop a deeper understanding of physiological systems related to energy balance and energy storage, including the mechanisms controlling the development of fat cells (adipocytes). The differentiation of committed preadipocytes to adipocytes is controlled by PPARgamma and several other transcription factors, but the molecular basis for preadipocyte determination is not understood. Using a new method for the quantitative analysis of transcriptional components, we identified the zinc-finger protein Zfp423 as a factor enriched in preadipose versus non preadipose fibroblasts. Ectopic expression of Zfp423 in non-adipogenic NIH 3T3 fibroblasts robustly activates expression of Pparg in undifferentiated cells and permits cells to undergo adipocyte differentiation under permissive conditions. Short hairpin RNA (shRNA)-mediated reduction of Zfp423 expression in 3T3-L1 cells blunts preadipocyte Pparg expression and diminishes the ability of these cells to differentiate. Furthermore, both brown and white adipocyte differentiation is markedly impaired in Zfp423-deficient mouse embryos. Zfp423 regulates Pparg expression, in part, through amplification of the BMP signalling pathway, an effect dependent on the SMAD-binding capacity of Zfp423. This study identifies Zfp423 as a transcriptional regulator of preadipocyte determination. PMID- 20200520 TI - IL25 elicits a multipotent progenitor cell population that promotes T(H)2 cytokine responses. AB - CD4(+) T helper 2 (T(H)2) cells secrete interleukin (IL)4, IL5 and IL13, and are required for immunity to gastrointestinal helminth infections. However, T(H)2 cells also promote chronic inflammation associated with asthma and allergic disorders. The non-haematopoietic-cell-derived cytokines thymic stromal lymphopoietin, IL33 and IL25 (also known as IL17E) have been implicated in inducing T(H)2 cell-dependent inflammation at mucosal sites, but how these cytokines influence innate immune responses remains poorly defined. Here we show that IL25, a member of the IL17 cytokine family, promotes the accumulation of a lineage-negative (Lin(-)) multipotent progenitor (MPP) cell population in the gut associated lymphoid tissue that promotes T(H)2 cytokine responses. The IL25 elicited cell population, termed MPP(type2) cells, was defined by the expression of Sca-1 (also known as Ly6a) and intermediate expression of c-Kit (c-Kit(int)), and exhibited multipotent capacity, giving rise to cells of monocyte/macrophage and granulocyte lineages both in vitro and in vivo. Progeny of MPP(type2) cells were competent antigen presenting cells, and adoptive transfer of MPP(type2) cells could promote T(H)2 cytokine responses and confer protective immunity to helminth infection in normally susceptible Il25(-/-) mice. The ability of IL25 to induce the emergence of an MPP(type2) cell population identifies a link between the IL17 cytokine family and extramedullary haematopoiesis, and suggests a previously unrecognized innate immune pathway that promotes T(H)2 cytokine responses at mucosal sites. PMID- 20200521 TI - Heteroplasmic mitochondrial DNA mutations in normal and tumour cells. AB - The presence of hundreds of copies of mitochondrial DNA (mtDNA) in each human cell poses a challenge for the complete characterization of mtDNA genomes by conventional sequencing technologies. Here we describe digital sequencing of mtDNA genomes with the use of massively parallel sequencing-by-synthesis approaches. Although the mtDNA of human cells is considered to be homogeneous, we found widespread heterogeneity (heteroplasmy) in the mtDNA of normal human cells. Moreover, the frequency of heteroplasmic variants varied considerably between different tissues in the same individual. In addition to the variants identified in normal tissues, cancer cells harboured further homoplasmic and heteroplasmic mutations that could also be detected in patient plasma. These studies provide insights into the nature and variability of mtDNA sequences and have implications for mitochondrial processes during embryogenesis, cancer biomarker development and forensic analysis. In particular, they demonstrate that individual humans are characterized by a complex mixture of related mitochondrial genotypes rather than a single genotype. PMID- 20200522 TI - Commentary: Understanding the origins of anger, contempt, and disgust in public health policy disputes: applying moral psychology to harm reduction debates. AB - Scientific disputes about public health issues can become emotional battlefields marked by strong emotions like anger, contempt, and disgust. Contemporary work in moral psychology demonstrates that each of these emotions is a reaction to a specific type of moral violation. Applying this work to harm reduction debates, specifically the use of smokeless tobacco to reduce harm from tobacco use, we attempt to explain why some public health disputes have been so heated. Public health ethics tend to emphasize social justice concerns to the exclusion of other moral perspectives that value scientific authority, professional loyalty, and bodily purity. An awareness of their different emotional reactions and underlying moral motivations might help public health professionals better understand each others' viewpoints, ultimately leading to more productive dialogue. PMID- 20200523 TI - Whistleblowing in the pharmaceutical industry in the United States, England, Canada, and Australia. AB - Fraud and abuse in the spending of public monies plague governments around the world. In the United States the False Claims Act encourages whistleblowing by private individuals to expose evidence of fraud. They are rewarded for their efforts with monetary compensation and protection from retaliation. Such is not the case in Canada, England, and Australia. Although some recent legislation has increased the protections afforded to whistleblowers, they are still likely to be viewed more as disloyal employees than courageous public servants, and there is little incentive to risk their jobs and reputation. Qui tam laws provide a police force of thousands in the effort to reduce rampant fraud, waste, and abuse, and would be an asset in any health-care system where pubic health policy requires conservation of resources. PMID- 20200524 TI - Growing inequalities and reproductive health in transitional countries: Kazakhstan and Belarus. AB - The present study examines how growing socio-economic inequalities in transitional countries that have followed different health policy paths affect women's access to reproductive health care. I conducted surveys in Kazakhstan and Belarus and used logistic regression analyses to determine accessibility to and satisfaction with reproductive health services, reproductive status, and reproductive history based on country of residence. By all measures, access to reproductive health services was most problematic for the low-income women in Kazakhstan but to a significantly lesser extent for economically disadvantaged respondents in Belarus. Differences in education had a significant effect on women's access to reproductive health services in Kazakhstan but were not present in Belarus. Household income was the most powerful predictor of self-perceived health in Kazakhstan, but not in Belarus. The unreformed health-care system in Belarus appears to be more accessible for all women than Kazakhstan's health-care system that underwent significant market-oriented reform. PMID- 20200525 TI - Smoking habits in Italian pregnant women: any changes after the ban? AB - A reduction in the prevalence of smoking and tobacco consumption was noted after the enactment in 2005 of new smoking regulations in Italy. To determine the impact of the smoking ban on pregnant women, we compared the results of two retrospective studies on two samples of 300 women, who recently delivered, conducted before and after the regulations went into effect. The comparison showed a marked drop in passive exposure to smoke in the workplace but not in the family environment; however, passive exposure and smoking were associated before and during pregnancy. Nearly all women agreed that the ban on smoking in public was reasonable and stated it had influenced their smoking habit or exposure. Despite this lip service, both studies highlighted that smoking in pregnancy remains a problem for many women, as about 10 per cent did not quit and over 50 per cent relapsed after delivery. PMID- 20200526 TI - Breakfast cereal industry pledges to self-regulate advertising to youth: will they improve the marketing landscape? AB - In 2007, the Council of Better Business Bureaus created the Children's Food and Beverage Advertising Initiative to improve the nutritional profile of products marketed to children in the United States. We provide quantitative baseline data describing (a) the amount of child-directed breakfast cereal advertising in 2007; (b) an assessment of the nutritional value for all cereals advertised on television; and (c) the relationship between nutrition quality and child exposure to television advertising for major cereal brands. In 2007, the average American child viewed 757 cereal ads, and 98 per cent of these ads promoted unhealthy cereals that would be prohibited from advertising to children in the United Kingdom. Healthy cereals were advertised in 2007 in the United States, but adults, not children, were predominantly exposed to these ads. These quantitative methods can be used in the future to evaluate the impact of industry self regulation efforts to improve the marketing landscape. PMID- 20200527 TI - Beyond idealism and realism: Canadian NGO/government relations during the negotiation of the FCTC. AB - The Framework Convention on Tobacco Control (FCTC) marks a unique point in the history of global health governance. This convention produced the first legally binding treaty under the auspices of the World Health Organization. Another first was the extent to which non-governmental organizations (NGOs) participated in the negotiation process. This article explores the relationship between one group of NGOs and their respective government during the negotiation of the FCTC. Documentary analyses and 18 individual in-depth interviews were conducted with both government and NGO representatives. In contrast to the polar perspectives of idealism (NGOs as unique and autonomous) and realism (NGOs as funded arms of the government), our findings suggest that neither opposition nor conformity on the part of the NGOs characterize the relationship between the NGOs and government. While specific to the case under study (the FCTC), our findings nonetheless indicate the need for a nuanced view of the relationship between governments and NGOs, at least during the process of multilateral health policy negotiations. PMID- 20200530 TI - Editorial: Global health initiatives and the new dichotomy in health systems. PMID- 20200531 TI - High-fat milk consumption in Iran: lessons from a recent policy affecting public health. PMID- 20200532 TI - Global health: will positive changes for Sierra Leone's health professionals mean the end of its Brain Drain? PMID- 20200533 TI - Senior safety zones: community built environment factors around senior wellness centers. PMID- 20200534 TI - Readiness and perceived barriers to removing artificial trans-fat from restaurant menus. PMID- 20200535 TI - Neuroanatomy and neurophysiology of sexual function after spinal cord lesion. PMID- 20200538 TI - Maternal serum and vaginal fluid C-reactive protein levels do not predict early onset neonatal infection in preterm premature rupture of membranes. AB - OBJECTIVE: The aim of this study was to evaluate the usefulness of maternal serum and vaginal fluid C-reactive protein (CRP) determinations in the prediction of neonatal congenital infection. STUDY DESIGN: Fifty women between 24 and 36 weeks gestation, complicated by preterm premature rupture of membranes (pPROM), were divided into two groups according to the presence (n=14) or absence (n=36) of early-onset newborns' infection. RESULT: Maternal serum and vaginal fluid CRP concentrations were comparable between both groups. Serum CRP levels >=10 and >=15 mg l(-1) predicted neonatal infection with a sensitivity of 47 and 47%, specificity of 63 and 76%, positive predictive value (PPV) of 38 and 47%, and negative predictive value (NPV) of 72 and 76%, respectively. The cutoff value of vaginal CRP >=2.4 mg l(-1) predicted infection with a sensitivity of 71%, specificity of 47%, PPV of 34%, and NPV of 81%. Receiver-operating characteristic curve analysis revealed that the predictive performance of CRP was poor. CONCLUSION: Maternal serum and vaginal fluid CRP determinations after pPROM are of poor predictive value in neonatal early-onset infection prediction. PMID- 20200539 TI - Incidence and clinicopathologic correlation of fetal vessel thrombosis in mono- and dichorionic twin placentas. AB - OBJECTIVE: To determine the incidence of fetal vessel thrombosis in monochorionic diamniotic and dichorionic-diamniotic twin placentas, and its association with intrauterine growth retardation (IUGR), hypertensive disorders of pregnancy, twin twin transfusion syndrome (TTTS), fetal vascular anastomoses, chorangiosis, and chorioamnionitis. STUDY DESIGN: Histologic slides from 80 pairs of monochorionic and 80 pairs of dichorionic twin placentas were reviewed for evidence of fetal vessel thrombosis (>=5 adjacent avascular terminal villi with upstream intravascular fibrin thrombi). Associations with clinical and other pathologic variables were analyzed by chi(2) tests. RESULT: Thrombosis occurred in 7.5% of monochorionic and 3.1% of dichorionic twin placentas (P=0.090). It was associated with IUGR among the monochorionic twins (P=<0.0001) and with hypertensive disorders of pregnancy among the dichorionic twins (P=0.018). Vascular anastomoses, TTTS, chorangiosis, and chorioamnionitis were not associated with fetal vessel thrombosis. CONCLUSION: Fetal vessel thrombosis was identified more frequently in monochorionic twins, but this difference was not statistically significant. It is associated with IUGR in monochorionic twins, but not with TTTS or fetal vascular anastomoses at the chorionic surface. PMID- 20200537 TI - PARP inhibition: PARP1 and beyond. AB - Recent findings have thrust poly(ADP-ribose) polymerases (PARPs) into the limelight as potential chemotherapeutic targets. To provide a framework for understanding these recent observations, we review what is known about the structures and functions of the family of PARP enzymes, and then outline a series of questions that should be addressed to guide the rational development of PARP inhibitors as anticancer agents. PMID- 20200540 TI - Randomized trial of enteral protein and energy supplementation in infants less than or equal to 1250 g at birth. AB - OBJECTIVE: To determine if enteral protein and energy supplementation would significantly improve weight gain as compared with energy supplementation alone in or=14 days, diet of >or=75% enteral nutrition (fortified human milk or formula) and either failure to regain BW or weight gain<15 g kg(-1) per days. Infants were randomized to a multinutrient supplement that provided increased protein and energy (P/E) intake or energy alone (medium chain triglyceride oil, MCT). Growth rates were compared at the end of the 4-week study period. RESULT: Of 30 eligible infants, 23 were enrolled, 12 received MCT (BW=862+/-252 g, mean+/-s.d.) and 11 received P/E (BW=879+/-241 g). Significantly higher protein intake (P/E=3.5+/-0.3 g kg(-1) per day, MCT=3.0+/-0.5 g kg(-1) per day) and better growth (P/E=17.0+/-2.4 g kg(-1) per day, MCT=11.5+/-4.8 g kg(-1) per day) were observed in the P/E group. CONCLUSION: These data are consistent with the importance of providing additional daily protein intake to achieve increased postnatal growth in very low birth weight infants experiencing slow growth. PMID- 20200541 TI - IKKbeta leads to an inflammatory skin disease resembling interface dermatitis. AB - IKKbeta is a subunit of the IkappaB kinase (IKK) complex required for NF-kappaB activation in response to pro-inflammatory signals. NF-kappaB regulates the expression of many genes involved in inflammation, immunity, and apoptosis, and also controls cell proliferation and differentiation in different tissues; however, its function in skin physiopathology remains controversial. In this study we report the alterations caused by increased IKKbeta activity in skin basal cells of transgenic mice. These animals suffered chronic inflammation with abundant macrophages and other CD45(+) infiltrating cells in the skin, which resulted in epidermal basal cell injury and degeneration of hair follicles. They showed histological features characteristic of interface dermatitis (ID). This phenotype is accompanied by an increased production of inflammatory cytokines by transgenic keratinocytes. Accordingly, transcriptome studies show upregulation of genes associated with inflammatory responses. The inflammatory phenotype observed as a consequence of IKKbeta overexpression is independent of T and B lymphocytes, as it also arises in mice lacking these cell types. In summary, our data indicate the importance of IKKbeta in the development of ID and in the homeostasis of stratified epithelia. Our results also support the idea that IKKbeta might be a valid therapeutic target for the treatment of skin inflammatory diseases. PMID- 20200542 TI - Distinct gene signature revealed in white blood cells, CD4(+) and CD8(+) T cells in (NZBx NZW) F1 lupus mice after tolerization with anti-DNA Ig peptide. AB - Tolerizing mice polygenically predisposed to lupus-like disease (NZB/NZW F1 females) with a peptide mimicking anti-DNA IgG sequences containing MHC class I and class II T cell determinants (pConsensus, pCons) results in protection from full-blown disease attributable in part to the induction of CD4(+)CD25(+)Foxp3+ and CD8(+)Foxp3+ regulatory T cells. We compared 45 000 murine genes in total white blood cells (WBC), CD4(+) T cells, and CD8(+) T cells from splenocytes of (NZBxNZW) F1 lupus-prone mice tolerized with pCons vs untreated naive mice and found two-fold or greater differential expression for 448 WBC, 174 CD4, and 60 CD8 genes. We identified differentially expressed genes that played roles in the immune response and apoptosis. Using real-time PCR, we validated differential expression of selected genes (IFI202B, Bcl2, Foxp3, Trp-53, CCR7 and IFNar1) in the CD8(+)T cell microarray and determined expression of selected highly upregulated genes in different immune cell subsets. We also determined Smads expression in different immune cell subsets, including CD4(+) T cells and CD8(+) T cells, to detect the effects of TGF-beta, known to be the major cytokine that accounts for the suppressive capacity of CD8(+) Treg in this system. Silencing of anti-apoptotic gene Bcl2 or interferon genes (IFI202b and IFNar1 in combination) in CD8(+) T cells from tolerized mice did not affect the expression of the other selected genes. However, silencing of Foxp3 reduced expression of Foxp3, Ifi202b and PD1-all of which are involved in the suppressive capacity of CD8(+) Treg in this model. PMID- 20200544 TI - Signatures of natural selection and coevolution between killer cell immunoglobulin-like receptors (KIR) and HLA class I genes. AB - Natural killer (NK) cells are lymphocytes of the innate immune system. In humans, NK cell activities are partly controlled by the diverse killer immunoglobulin like receptor (KIR) gene family. The importance of NK cells in both immunity to infection and reproduction makes KIR strong candidates for genes undergoing dynamic evolution in the human genome. Using high-resolution allelic typing, we investigated the potential role of natural selection in the diversification of KIR in the Irish population. Higher diversity than expected is observed at several loci, consistent with a history of balancing selection acting to maintain several allelic variants at high frequency in the population. KIR diversity is enhanced further at the haplotype level with functional polymorphisms at KIR2DL4, KIR3DL1 and KIR2DS4 defining nine 'core' haplotypes. Analysis of these core haplotypes in combination with human leukocyte antigen (HLA) class I ligands revealed several nonrandom associations. In particular, the KIR:HLA association for the core haplotype defined by KIR3DL1(*)01502 was female specific and a likely consequence of negative selection acting against KIR3DL1(*)01502 on an HLA C1/C1 background. Many of the associations between KIR and HLA in the Irish differ from those previously reported, which argues against universal selective pressures for specific KIR:HLA combinations in diverse human populations. PMID- 20200543 TI - STAT3 locus in inflammatory bowel disease and multiple sclerosis susceptibility. AB - STAT3 (signal transducer and activator of transcription 3) signaling is a critical component of Th17-dependent autoimmune processes. Genome-wide association studies (GWAS) have revealed the role of the STAT3 gene in inflammatory bowel disease (IBD) susceptibility, although confirmation in clinical subphenotypes is warranted. Mice with targeted deletion of Stat3 in T cells are resistant to experimental autoimmune encephalomyelitis, which is a multiple sclerosis (MS) model. Moreover, increased phosphorylated STAT3 was reported in T cells of patients evolving from clinically isolated syndrome to defined MS and in relapsing patients. These evidences led us to analyze the role of STAT3 in Crohn's disease (CD), ulcerative colitis (UC) and MS risk. Polymorphisms in the STAT3 region (rs3809758/rs744166/rs1026916/rs12948909) were genotyped and the inferred haplotypes were subsequently analyzed in 860 IBD and 1540 MS Spanish patients and 1720 ethnically matched controls. The haplotype conformed by the risk alleles of each polymorphism was significantly associated with both clinical phenotypes of IBD (CD: P=0.005, odds ratio 1.25, 95% confidence interval 1.06-1.46; and UC: P=0.002, odds ratio 1.19, 95% confidence interval 1.02-1.38). No evidence of association was detected for MS. The originally described association of IBD with STAT3 polymorphisms is corroborated for the two clinical phenotypes, CD and UC, in an independent population. A major role of this gene in MS seems unlikely. PMID- 20200545 TI - Inflammation in vivo is modulated by GPR83 isoform-4 but not GPR83 isoform-1 expression in regulatory T cells. AB - Most recently, we have described the G-protein coupled receptor 83 (GPR83), which is highly expressed by CD4(+)CD25(+) regulatory T cells (Tregs) to be involved in the induction of CD4(+)Foxp3(+) Tregs in the course of an ongoing immune response. Four GPR83 isoforms have been described. Here, we have shown that GPR83 isoform-4, which differs from GPR83 isoform-1 by 20 additional aminoacids in the second cytoplasmatic loop, is predominantly expressed by Tregs. Interestingly, GPR83 isoform-4 but not GPR83 isoform-1 retrovirally transduced T cells were able to interfere with inflammatory responses in vivo. Re-analysis of GPR83 transduced T cells revealed that this in vivo acquisition of suppressive activity was associated with the induction of Treg-associated molecules including Foxp3 in GPR83 isoform-4 but not GPR83 isoform-1 transduced CD4(+) T cells under inflammatory conditions. Our results suggest that the 20 additional aminoacids within GPR83 isoform-4 are involved in Treg induction during inflammatory immune responses. PMID- 20200546 TI - Finemapping of the arthritis QTL Pia7 reveals co-localization with Oia2 and the APLEC locus. AB - In this study, we sought to determine the effect of the quantitative trait locus Pia7 on arthritis severity. The regulatory locus derived from the arthritis resistant E3 rat strain was introgressed into the arthritis-susceptibility DA strain through continuous backcrossing. Congenic rats were studied for their susceptibility to experimental arthritis using pristane and adjuvant oil. In addition, cell number and function of various leukocyte populations were analyzed either under naive or stimulated conditions. We found that the minimal congenic fragment of DA.E3-Pia7 rats overlapped with the minimal fragment in DA.PVG-Oia2 congenic rats, which has been positionally cloned to the antigen-presenting lectin-like receptor complex (APLEC) genes. DA.E3-Pia7 congenic rats were protected from both PIA and OIA, but the protection was more pronounced in OIA. In adoptive transfer experiments we observed that the Pia7 locus controlled the priming of arthritogenic T cells and not the effector phase. In addition, Pia7 congenic rats had a significant higher frequency of B cells and granulocytes as well as TNFalpha production after stimulation, indicating a higher activation state of cells of the innate immune system. In conclusion, this study shows that the APLEC locus is a major locus regulating the severity of experimentally induced arthritis in rats. PMID- 20200548 TI - Regular slow-breathing exercise effects on blood pressure and breathing patterns at rest. AB - Previous studies reported that a device-guided slow-breathing (DGB) exercise decreases resting blood pressure (BP) in hypertensive patients. This study investigated the effects of daily practice of DGB on (a) 24-h BP and breathing patterns in the natural environment, as well as (b) BP and breathing pattern during clinic rest. Altogether, 40 participants with pre-hypertension or stage 1 hypertension were trained to decrease breathing rate through DGB or to passively attend to breathing (control, CTL) during daily 15-min sessions. The participants practiced their breathing exercise at home for 4 weeks. The DGB (but not the CTL) intervention decreased clinic resting BP, mid-day ambulatory systolic BP (in women only) and resting breathing rate, and increased resting tidal volume. However, 24-h BP level was not changed by DGB or CTL interventions, nor was overnight breathing pattern. These findings are consistent with the conclusion that a short-term, autonomic mechanism mediated the observed changes in resting BP, but provided no evidence that regular DGB affected factors involved in long term BP regulation. Additional research will be needed to determine whether 24-h BP can be lowered by a more prolonged intervention. PMID- 20200547 TI - Long-term efficacy of a combination of amlodipine and olmesartan medoxomil +/- hydrochlorothiazide in patients with hypertension stratified by age, race and diabetes status: a substudy of the COACH trial. AB - A prespecified subgroup analysis of a 44-week open-label extension study is presented. The efficacy and safety of the combination of amlodipine (AML) + olmesartan medoxomil (OM), with and without the addition of hydrochlorothiazide (HCTZ), were investigated in patients aged >=65 and <65 years, Blacks and non Blacks and patients with and without type 2 diabetes. After an 8-week double blind, placebo-controlled portion of the study, patients initiated therapy on AML 5 + OM 40 mg per day, were uptitrated stepwise to AML 10 + OM 40 mg per day, with the addition of HCTZ 12.5 mg, and 25 mg if blood pressure (BP) goal was not achieved (<140/90 or <130/80 mm Hg for patients with diabetes). Endpoints included the change from baseline in mean seated systolic BP, mean seated diastolic BP and achievement of BP goal. BP decreased from baseline for all treatments in each prespecified subgroup. By the end of the study, BP goal was achieved in 61.0% of patients aged >=65 years, 68.1% of patients aged <65 years, 63.3% of Blacks, 67.8% of non-Blacks, 26.9% of patients with diabetes and 72.9% of patients without diabetes. The combination of AML + OM +/- HCTZ was efficacious, safe and well tolerated by these subgroups. PMID- 20200549 TI - Long-term reproducibility of ambulatory blood pressure is superior to office blood pressure in the very elderly. AB - Although it is known that reproducibility of ambulatory blood pressure (BP) is superior to office BP in middle-aged subjects, little is known in older age groups. Hence, we compared the long-term reproducibility of ambulatory and office BP readings in subjects over the age of 75 years. A cohort of 72 subjects 75-90 years of age (mean, 82 years at baseline) had repeat office and ambulatory BPs 2 years apart under similar conditions. On the same day, patients underwent office BP measurements by a semi-automated device and then by ambulatory BP monitoring. Awake and sleep periods were divided according to a diary kept by each patient. The agreement between studies was assessed using the standard deviation of the differences (SDD) and Bland-Altman plots. There were minimal mean changes in office, 24-h, and awake and sleep mean BP values between baseline and 2 years later. The SDDs between visits were lower for 24-h BP compared with the office BP (11.7/5.9 mm Hg versus 17.8/9.0 mm Hg, P<0.01). The SDD for 24-h BP was also lower than the SDDs for the awake and sleep BP (P<0.05). Nocturnal BPs defined by absolute values were more reproducible than categories of dippers and non dippers. These data demonstrate that long-term reproducibility of 24-h BP is superior to office measurements for very elderly subjects. In a clinical trial involving this age group, far fewer subjects would be required if 24-h BP was the primary efficacy endpoint rather than the office BP. PMID- 20200550 TI - Efficacy, safety and tolerability of aliskiren, a direct renin inhibitor, in women with hypertension: a pooled analysis of eight studies. AB - Hypertension is a major risk factor for cardiovascular disease, which is the leading cause of mortality in women in developed countries. This pooled analysis assessed the antihypertensive efficacy, safety and tolerability of monotherapy with the direct renin inhibitor aliskiren (150 mg and 300 mg) over 8-12 weeks in women with mild-to-moderate hypertension (mean sitting diastolic blood pressure (msDBP) >=95 and <110 mm Hg) across eight randomized and double-blind trials. Safety and tolerability were assessed in the five placebo-controlled trials in the analysis. In the 1527 women enrolled in these studies, aliskiren 150 mg and 300 mg produced significantly greater blood pressure (BP) reductions (14.1/11.0 and 16.1/12.3 mm Hg, respectively) compared with placebo (7.2/7.6 mm Hg; P<0.0001). BP reductions with aliskiren monotherapy in women were similar to those observed in men, and consistent across subgroups of age, metabolic syndrome and obesity. The overall incidence of adverse events in women was similar with aliskiren treatment (150 mg, 42.3%; 300 mg, 46.0%) and placebo (39.0%); adverse events with aliskiren were more frequent in women than in men, consistent with previous studies of gender differences in drug tolerability. In conclusion, aliskiren monotherapy at 150 mg and 300 mg doses provided effective, dose dependent BP-lowering in women with mild-to-moderate hypertension, and it was well tolerated. PMID- 20200551 TI - Association of resistin and adiponectin with different clinical blood pressure phenotypes. AB - We investigated whether the resistin (Res) and adiponectin (Adp) levels are associated with different clinical blood pressure (BP) phenotypes. Among 465 consecutive never-treated white subjects, we excluded those with diabetes mellitus; impaired glucose metabolism; history of any cardiovascular disease or other concurrent medical condition; secondary hypertension; ongoing vasoactive treatment. Three separate clinic BP measurements and ambulatory BP monitoring were implemented to divide 328 subjects (aged 48+/-6 years; 172 males) into hypertensives (n=105), masked hypertensives (n=41), white-coat hypertensives (n=52) and normotensives (n=130). Participants underwent echocardiography and oral glucose tolerance testing, whereas, from fasting venous blood samples metabolic profile, plasma Res and Adp levels were assessed. Hypertensives and masked hypertensives showed higher log(10)(Res) and lower log(10)(Adp) levels compared with normotensives, whereas white-coat hypertensives had similar levels of these adipokines compared with normotensives. Common correlates for both of the adipokines were 24-h systolic BP, standing/sitting difference of both diastolic BP and heart rate, and waist circumference. Hypertensive and masked hypertensive compared with normotensive phenotype were independently associated with log(10)(Res) with odds ratios of 1.24 (1.08-1.44), and 1.16 (1.09-1.34) and log(10)(Adp) with 0.74 (0.65-0.87), and 0.81 (0.67-0.95), respectively. Increased Res and decreased Adp plasma levels are associated with out-of-clinic hypertension, whereas they did not determine white-coat hypertension. PMID- 20200552 TI - In times of crisis. PMID- 20200553 TI - Synaptotagmin-SNARE coupling enlightened. PMID- 20200554 TI - Channeling sperm activation. PMID- 20200556 TI - Hedgehog signaling pathway is activated in diffuse large B-cell lymphoma and contributes to tumor cell survival and proliferation. AB - Hedgehog (HH) signaling is important in the pathogenesis of several malignancies. Recently, we described that HH signaling proteins are commonly expressed in diffuse large B-cell lymphoma (DLBCL); however, the functional role of HH pathway in DLBCL has not been explored. Here, we assessed the possibility that HH pathway activation contributes to the survival of DLBCL. We found that HH signaling inhibition induces predominantly cell-cycle arrest in DLBCL cells of germinal center (GC) B-cell type, and apoptosis in DLBCL cells of activated B-cell (ABC) type. Apoptosis after HH signaling inhibition in DLBCL cells of ABC type was associated with downregulation of BCL2; however HH inhibition was not associated with BCL2 downregulation in DLBCL of GC type. Functional inhibition of BCL2 significantly increased apoptosis induced by HH inhibition in DLBCL cells of both types. We also showed that DLBCL cells synthesize, secrete and respond to endogenous HH ligands, providing support for the existence of an autocrine HH signaling loop. Our findings provide novel evidence that dysregulation of HH pathway is involved in the biology of DLBCL and have significant therapeutic implications as they identify HH signaling as a potential therapeutic target in DLBCL, in particular for those lymphomas expressing the HH receptor smoothened. PMID- 20200557 TI - Erucylphosphohomocholine, the first intravenously applicable alkylphosphocholine, is cytotoxic to acute myelogenous leukemia cells through JNK- and PP2A-dependent mechanisms. AB - Alkylphospholipids and alkylphosphocholines (APCs) are promising antitumor agents, which target the plasma membrane and affect multiple signal transduction networks. We investigated the therapeutic potential of erucylphosphohomocholine (ErPC3), the first intravenously applicable APC, in human acute myelogenous leukemia (AML) cells. ErPC3 was tested on AML cell lines, as well as AML primary cells. At short (6-12 h) incubation times, the drug blocked cells in G2/M phase of the cell cycle, whereas, at longer incubation times, it decreased survival and induced cell death by apoptosis. ErPC3 caused JNK 1/2 activation as well as ERK 1/2 dephosphorylation. Pharmacological inhibition of caspase-3 or a JNK 1/2 inhibitor peptide markedly reduced ErPC3 cytotoxicity. Protein phosphatase 2A downregulation by siRNA opposed ERK 1/2 dephosphorylation and blunted the cytotoxic effect of ErPC3. ErPC3 was cytotoxic to AML primary cells and reduced the clonogenic activity of CD34(+) leukemic cells. ErPC3 induced a significant apoptosis in the compartment (CD34(+) CD38(Low/Neg) CD123(+)) enriched in putative leukemia-initiating cells. This conclusion was supported by ErPC3 cytotoxicity on AML blasts showing high aldehyde dehydrogenase activity and on the side population of AML cell lines and blasts. These findings indicate that ErPC3 might be a promising therapeutic agent for the treatment of AML patients. PMID- 20200558 TI - Targeting PKC delta-mediated topoisomerase II beta overexpression subverts the differentiation block in a retinoic acid-resistant APL cell line. AB - Retinoic acid (RA) relieves the maturation block in t(15:17) acute promyelocytic leukemia (APL), leading to granulocytic differentiation. However, RA treatment alone invariably results in RA resistance, both in vivo and in vitro. RA resistant cell lines have been shown to serve as useful models for elucidation of mechanisms of resistance. Previously, we identified topoisomerase II beta (TOP2B) as a novel mediator of RA-resistance in APL cell lines. In this study, we show that both TOP2B protein stability and activity are regulated by a member of the protein kinase C (PRKC) family, PRKC delta (PRKCD). Co-treatment with a pharmacologic inhibitor of PRKCD and RA resulted in the induction of an RA responsive reporter construct, as well as the endogenous RA target genes, CEBPE, CYP26A1 and RIG-I. Furthermore, the co-treatment overcame the differentiation block in RA-resistant cells, as assessed by morphological analysis, restoration of promyelocytic leukemia nuclear bodies, induction of CD11c cell surface expression and an increase in nitro-blue-tetrazolium reduction. Cumulatively, our data suggest a model whereby inhibition of PRKCD decreases TOP2B protein levels, leading to a loss of TOP2B-mediated repressive effects on RA-induced transcription and granulocytic differentiation. PMID- 20200559 TI - The anti-apoptotic gene BCL2A1 is a novel transcriptional target of PU.1. PMID- 20200560 TI - Galectin-9 exhibits anti-myeloma activity through JNK and p38 MAP kinase pathways. AB - Galectins constitute a family of lectins that specifically exhibit the affinity for beta-galactosides and modulate various biological events. Galectin-9 is a tandem-repeat type galectin with two carbohydrate recognition domains and has recently been shown to have an anti-proliferative effect on cancer cells. We investigated the effect of recombinant protease-resistant galectin-9 (hGal9) on multiple myeloma (MM). In vitro, hGal9 inhibited the cell proliferation of five myeloma cell lines examined, including a bortezomib-resistant subcell line, with IC(50) between 75.1 and 280.0 nM, and this effect was mediated by the induction of apoptosis with the activation of caspase-8, -9, and -3. hGal9-activated Jun NH(2)-terminal kinase (JNK) and p38 MAPK signaling pathways followed by H2AX phosphorylation. Importantly, the inhibition of either JNK or p38 MAPK partly inhibited the anti-proliferative effect of hGal9, indicating the crucial role of these pathways in the anti-MM effect of hGal9. hGal9 also induced cell death in patient-derived myeloma cells, some with poor-risk factors, such as chromosomal deletion of 13q or translocation t(4;14)(p16;q32). Finally, hGal9 potently inhibited the growth of human myeloma cells xenografted in nude mice. These suggest that hGal9 is a new therapeutic target for MM that may overcome resistance to conventional chemotherapy. PMID- 20200561 TI - Role of BCR-ABL-Y177-mediated p27kip1 phosphorylation and cytoplasmic localization in enhanced proliferation of chronic myeloid leukemia progenitors. AB - In chronic myelogenous leukemia (CML), hematopoietic stem cell transformation leads to increased proliferation of malignant myeloid progenitors. The cyclin dependent kinase inhibitor p27kip1 (p27) is a critical negative regulator of hematopoietic progenitor proliferation and pool size that is deregulated in BCR ABL expressing cell lines. However, cell-context specific regulation of p27 in primary human CML progenitors and its contribution to CML progenitor expansion remain unclear. Here, we investigated p27 regulation and function in (1) CD34+ cells from CML patients and (2) human CD34+ cells ectopically expressing the BCR ABL gene following retrovirus transduction. We found that p27 levels are increased in CML CD34+ cells related to a BCR-ABL-dependent increase in p27 protein translation. However, p27 was relocated to the cytoplasm in CML progenitors and nuclear p27 levels were reduced, allowing increased cell cycling and expansion in culture. Cytoplasmic relocation of p27 in CML progenitors was related to signaling through BCR-ABL Y177, activation of the AKT kinase and phosphorylation of p27 on Thr-157 (T157). Expression of a mutant p27 that cannot be phosphorylated on T157 significantly inhibited CML progenitor proliferation. These studies show the importance of BCR-ABL-Y177-AKT-mediated p27 phosphorylation in altered p27 localization and enhanced proliferation and expansion of primary CML progenitors. PMID- 20200562 TI - Cutaneous vaccination using microneedles coated with hepatitis C DNA vaccine. AB - The skin is potentially an excellent organ for vaccine delivery because of accessibility and the presence of immune cells. However, no simple and inexpensive cutaneous vaccination method is available. Micron-scale needles coated with DNA were tested as a simple, inexpensive device for skin delivery. Vaccination with a plasmid encoding hepatitis C virus nonstructural 3/4A protein using microneedles effectively primed specific cytotoxic T lymphocytes (CTLs). Importantly, the minimally invasive microneedles were as efficient in priming CTLs as more complicated or invasive delivery techniques, such as gene gun and hypodermic needles. Thus, microneedles may offer a promising technology for DNA vaccination. PMID- 20200563 TI - Gene-modified T cells as immunotherapy for multiple myeloma and acute myeloid leukemia expressing the Lewis Y antigen. AB - We have evaluated the carbohydrate antigen Lewis(Y) (Le(Y)) as a potential target for T-cell immunotherapy of hematological neoplasias. Analysis of 81 primary bone marrow samples revealed moderate Le(Y) expression on plasma cells of myeloma patients and myeloblasts of patients with acute myeloid leukemia (AML) (52 and 46% of cases, respectively). We developed a retroviral vector construct encoding a chimeric T-cell receptor that recognizes the Le(Y) antigen in a major histocompatibility complex-independent manner and delivers co-stimulatory signals to achieve T-cell activation. We have shown efficient transduction of peripheral blood-derived T cells with this construct, resulting in antigen-restricted interferon-gamma secretion and cell lysis of Le(Y)-expressing tumor cells. In vivo activity of gene-modified T cells was demonstrated in the delayed growth of myeloma xenografts in NOD/SCID mice, which prolonged survival. Therefore, targeting Le(Y)-positive malignant cells with T cells expressing a chimeric receptor recognizing Le(Y) was effective both in vitro and in a myeloma mouse model. Consequently, we plan to use T cells manufactured under Good Manufacturing Practice conditions in a phase I immunotherapy study for patients with Le(Y) positive myeloma or AML. PMID- 20200564 TI - A dual promoter lentiviral vector for the in vivo evaluation of gene therapeutic approaches to axon regeneration after spinal cord injury. AB - The identification of axon growth-promoting genes, and overexpression of these genes in central nervous system (CNS) neurons projecting to the spinal cord, has emerged as one potential approach to enhancing CNS regeneration. Assessment of the regenerative potential of candidate genes usually requires axonal tracing of spinal projections, ideally limited to neurons that express the candidate gene. Alternatively, coexpression of a reporter gene such as enhanced green fluorescent protein (GFP) from an internal ribosomal entry site can be used to identify neurons expressing the candidate gene, but this strategy does not label corticospinal axons in the spinal cord. We therefore developed a dual promoter lentiviral vector in which a potentially therapeutic transgene is expressed from the cytomegalovirus-enhanced chicken beta-actin promoter and the fluorescent protein copGFP is expressed from the elongation factor-1alpha promoter. The vector was constructed to be compatible with the Gateway recombination system for efficient introduction of transgenes through entry shuttle vectors. We show both simultaneous expression of a candidate and reporter gene in corticospinal and red nucleus neurons, and efficient labeling of their axons after lesions in the cervical spinal cord. This expression system is therefore an accurate and efficient means of screening candidate genes in vivo for enhancement of axonal growth. PMID- 20200565 TI - Adeno-associated virus-mediated delivery of kringle 5 of human plasminogen inhibits orthotopic growth of ovarian cancer. AB - Kringle 5 (K5) of human plasminogen is a potent angiogenesis inhibitor. In this study, we investigated the effects of recombinant adeno-associated virus (AAV) mediated delivery of K5 in mouse models of human ovarian cancer. A single intramuscular injection of AAV-K5 resulted in sustained expression of K5 reaching a maximum serum level of 800 ng ml(-1). Gene therapy inhibited both vascular endothelial growth factor (VEGF)-induced and tumor cell-induced angiogenesis in matrigel plug assays. Furthermore, a single injection of AAV-K5 significantly inhibited both subcutaneous and intraperitoneal growth of human ovarian cancer cells. Immunofluorescence studies of residual tumors surgically resected from the treated animals showed reduced tumor burden, which correlated with the inhibition of tumor neovascularization. In addition, AAV-K5 gene therapy differentially affected the nascent vessels more than mature vasculature and induced apoptotic death of tumor cells. These data show that AAV-K5 can be effectively used to inhibit ovarian cancer. PMID- 20200566 TI - Progress and prospects: nuclear import of nonviral vectors. AB - The nuclear envelope represents a key barrier to successful nonviral transfection and gene therapy both in vitro and in vivo. Although the main purpose of the nuclear envelope is to partition the cell to maintain cytoplasmic components in the cytoplasm and nuclear components, most notably genomic DNA, in the nucleus, this function poses a problem for transfections in which exogenous DNA is delivered into the cytoplasm. After delivery to the cytoplasm, nucleic acids rapidly become complexed with cellular proteins that mediate interactions with the cellular machinery for trafficking. Thus, it is these proteins that, in essence, control the nuclear import of DNA, and we must also understand their activities in cells. In this review, we will discuss the principles of nuclear import of proteins and DNA-protein complexes, as well as the various approaches that investigators have used to improve nuclear targeting of plasmids. These approaches include complexation of plasmids with peptides, native and engineered proteins, ligands and polymers, as well as the inclusion of transcription factor binding sites for general and cell-specific delivery. KEYWORDS: nonviral gene transfermid R:plasmidmid R:nuclear pore complexmid R:importinmid R:nuclear localization signalmid R:karyopherin. PMID- 20200567 TI - Dating the cyanobacterial ancestor of the chloroplast. AB - Cyanobacteria have had a pivotal role in the history of life on Earth being the first organisms to perform oxygenic photosynthesis, which changed the atmospheric chemistry and allowed the evolution of aerobic Eukarya. Chloroplasts are the cellular organelles of photoautotrophic eukaryotes in which most portions of photosynthesis occur. Although the initial suggestion that cyanobacteria are the ancestors of chloroplasts was greeted with skepticism, the idea is now widely accepted. Here we attempt to resolve and date the cyanobacterial ancestry of the chloroplast using phylogenetic analysis and molecular clocks. We found that chloroplasts form a monophyletic lineage, are most closely related to subsection I, N(2)-fixing unicellular cyanobacteria (Order Chroococcales), and heterocyst forming Order Nostocales cyanobacteria are their sister group. Nostocales and Chroococcales appeared during the Paleoproterozoic and chloroplasts appeared in the mid-Proterozoic. The capability of N(2) fixation in cyanobacteria may have appeared only once during the late Archaean and early Proterozoic eons. Furthermore, we found that oxygen-evolving cyanobacteria could have appeared in the Archaean. Our results suggest that a free-living cyanobacterium with the capacity to store starch through oxygenic CO(2) fixation, and to fix atmospheric N(2), would be a very important intracellular acquisition, which, as can be recounted today from several lines of evidence, would have become the chloroplast by endosymbiosis. PMID- 20200568 TI - Mapping a quantitative trait locus for the concentration of beta-lactoglobulin in milk, and the effect of beta-lactoglobulin genetic variants on the composition of milk from Holstein-Friesian x Jersey crossbred cows. AB - AIM: To identify quantitative trait loci (QTL) affecting the concentration of beta-lactoglobulin in milk, and to evaluate the effect of beta-lactoglobulin genetic variants on the concentration of fat, protein and casein in bovine milk. METHODS: A herd of 850 F2 Holstein-Friesian x Jersey crossbred cows was produced through mating six Holstein-Friesian x Jersey F1 bulls of high genetic merit with F1 cows from the national herd. A total of 1,610 herd-test records from 556 second-parity crossbreds were analysed. The concentration of fat, protein and casein in milk was measured at peak, mid- and late lactation, during the production seasons of 2003-2004 and 2004-2005. Liveweight was measured daily. DNA from the F2 animals, their F1 dams and sires, and selected grandsires was genotyped across the genome, initially with 285 microsatellite markers, and subsequently with 6,634 single nucleotide polymorphisms (SNP). RESULTS: A highly significant QTL for the concentration of beta-lactoglobulin in milk was identified, which coincided with the position of the beta-lactoglobulin gene on bovine Chromosome 11. No other consistently significant QTL for the concentration of beta-lactoglobulin in milk were detected. Cows with the BB beta-lactoglobulin genotype produced milk with a 30% lower concentration of beta-lactoglobulin than cows with the AA genotype. The beta-lactoglobulin polymorphism also explained variation in the proportion of casein in total protein. In addition, the percentage of fat was higher for BB than AA animals, whereas the percentage of total protein, mean daily milk yield and liveweight did not differ between AA and BB animals. CONCLUSIONS: A significant QTL determining the concentration of beta lactoglobulin in milk was identified. Selection of animals for the beta lactoglobulin B-allele may enable the production of milk naturally enriched for casein, thus allowing a potential increase in the yield of cheese. There may be additional future value in production of bovine milk more like human milk, where decreasing the concentration of beta-lactoglobulin is desirable. PMID- 20200569 TI - Identification of Tritrichomonas foetus and Giardia spp. infection in pedigree show cats in New Zealand. AB - AIMS: To establish the presence of Tritrichomonas foetus, to investigate the prevalence of co-infection with Giardia spp., and determine risk factors for T. foetus infection in pedigree show cats in New Zealand. METHODS: Freshly voided faecal samples were collected from cats attending two regional pedigree cat shows in the North Island during 2006. The samples were subjected to ZnSO4 floatation; ELISA for Giardia spp.; culture for T. foetus; and DNA isolation, amplification, and sequencing. Owners were asked to complete a questionnaire concerning aspects of the cats' environment, previous medical history, and diet. RESULTS: Faecal samples were collected from 22 cats from 12 separate catteries. Giardia spp. were identified using ELISA or faecal floatation in seven samples, and Sarcocystis spp. were identified in four samples. Tritrichomonas foetus was cultured from three samples, but 18 samples were positive on PCR. Two were randomly selected for representative sequencing. Basic local alignment search tool (BLAST) analysis results indicated 100% homology to T. foetus internal transcribed spacer 1. Poor faecal quality was apparent in only 8/22 samples, all of which were positive for T. foetus, and five of the eight were from cats with a previous history of chronic intermittent diarrhoea. Five samples were positive for both T. foetus and Giardia spp. Numbers of participants were too low to assess risk factors or significant associations. CONCLUSIONS: This is the first report of the presence of T. foetus-infected cats in New Zealand, and the large proportion of PCR positive samples was much greater than previous surveys of pedigree cats in other countries. CLINICAL RELEVANCE: Tritrichomonas foetus infection is recognised as an important cause of chronic large-bowel diarrhoea in cats, and may be highly prevalent in pedigree show cats in New Zealand, with the potential for co infection with Giardia spp. Diagnosis is simple, and should involve PCR for the greatest sensitivity. PMID- 20200570 TI - An evaluation of plasma homocysteine in the assessment of vitamin B12 status of pasture-fed sheep. AB - AIM: To assess the diagnostic potential of concentrations of homocysteine (Hcy) in plasma in relation to those of methylmalonic acid (MMA) and vitamin B12, as predictors of responsiveness of young sheep to supplementation with vitamin B12. METHODS: Eighty-two ewes grazing ryegrass-white clover pasture were used, 39 of which had been supplemented with a Co bullet and 43 unsupplemented. Thirty days after commencement of parturition their lambs (n=53 and 59, respectively) were randomly allocated into one of two treatments, in a 2 x 2 factorial design. Half of the lambs from each group of ewes received an injection of vitamin B12, while the remainder were controls. The trial commenced 31 October 2001 (Day 0), and continued until 01 May 2002 (Day 182). All lambs were weighed, and blood samples taken from 16 identified animals from each treatment group, at approximately monthly intervals. Changes in concentrations of Hcy, vitamin B12 and MMA in plasma, and liveweight gain (LWG) of the treatment groups were evaluated during the suckling (Days 0-89) and post-weaning (Days 90-182) periods. RESULTS: Mean LWG was 40% greater in supplemented than unsupplemented lambs. The concentrations of vitamin B12 and MMA in plasma in the unsupplemented lambs were in the deficient reference ranges of <170 pmol/L and >16 mumol/L, respectively. Mean monthly concentrations of Hcy in plasma ranged from 1.5 to 4.5 mumol/L but showed no pattern of response to vitamin B12 deficiency or supplementation. CONCLUSIONS: Measurement of the concentration of Hcy in plasma as a metabolic indicator of reduced methylation capability of sheep on typical pastures in New Zealand appeared to have little value in detection of vitamin B12 responsiveness, and was less sensitive than the concentration of the vitamin itself or the indicator of adenosyl-cobalamin deficiency, MMA, in plasma. The possibility that concentrations of Hcy in plasma remain low due to re-methylation of Hcy to methionine via the alternative betaine-choline rather than the vitamin B12 dependent methyl-tetrahydrofolate metabolic pathway is rejected, but the possibility is raised that high rates of trans-sulphuration of Hcy to cysteine in the gastrointestinal tract of grazing sheep could be responsible. CLINICAL RELEVANCE: The propionate-succinate pathway appears to be the first rate-limiting pathway in vitamin B12 deficiency, and the product of disruption of this pathway, increased MMA, is the most reliable indicator of metabolic abnormality in predicting responsiveness to supplementation. PMID- 20200571 TI - Reproductive performance of pasture-fed dairy cows supplemented with monopropylene glycol. AB - AIM: To determine the effects of monopropylene glycol (MPG) on resumption of oestrous cycles and pregnancy rates in mixed-aged cows in commercial herds, when administered for 6 weeks before the planned start of mating (PSM). METHODS: A trial was conducted using 1,814 pasture-fed predominantly Holstein-Friesian cows on four spring-calving dairy farms in the Waikato region of New Zealand. Each farm contained >500 cows, >60% of which had a body condition score (BCS) < or =4.5 two weeks before the planned start of calving. Within each farm, cows that had calved but not been seen in oestrus were allocated at random to one of three treatment groups, viz Control cows receiving no MPG (n=580), a second group receiving a single dose of 200 ml MPG after the morning milking (n=622; MPGx1), and a third group receiving 200 ml MPG after each morning and afternoon milking (n=612; MPGx2). Administration of MPG commenced 6 weeks prior to the PSM. Observations for oestrous behaviour and removal of tail paint was carried out at least daily. One week prior to the PSM, all cows with no recorded oestrus were examined to determine whether they had ovulated or not, and anovulatory cows were treated to induce oestrus and ovulation. Cows were artificially inseminated ~6 weeks from the PSM, then bulls were introduced for up to 12 weeks. Pregnancy diagnosis was carried out using transrectal ultrasonography at 12 and 16 weeks after the PSM. Milk production was determined from one herd test during the treatment period, and a second 2-3 weeks after the end of the treatment. RESULTS: There were no effects of treatment with MPG on resumption of oestrous cycles. Pregnancy rates at 12 and 16 weeks after the PSM were greater for cows in the MPGx1 group compared with those in the MPGx2 and Control groups (p<0.05). The yield of milk protein at the fi rst herd test was greater in cows in the MPGx1 and MPGx2 groups than in Control cows (p=0.013). CONCLUSION: This study showed that MPG given to cows with a low BCS for 6 weeks prior to mating had limited benefits on reproductive outcomes. PMID- 20200572 TI - A serological survey of the prevalence of antibodies against enteroviruses in brushtail possums (Trichosurus vulpecula) in New Zealand: enteroviruses have a limited distribution in brushtail possums. AB - AIM: To establish an immunoassay to detect antibodies against enteroviruses in brushtail possums (Trichosurus vulpecula), and to determine the prevalence of seropositive samples of antibodies to enteroviruses in wild possums in New Zealand. METHODS: A sandwich ELISA was established to detect antibodies to enteroviruses in possums. The IgG fraction of guinea-pig polyclonal antibodies to enteroviruses of possums was used as the capture antibody to bind the enteroviral antigens prior to incubating with test sera from possums. The bound antibodies from the test sera were detected using a conjugate specific to possum immunoglobulins. An archival serum bank was surveyed for the prevalence of seropositive samples, from possums, to the virus. The sera were collected from possums from areas of Northland, Wanganui, Castlepoint, Paraparaumu, Shannon, Orongorongo, Nelson, Hokitika, Banks Peninsula, Riverton, Kawau Island, Chatham Island and Stewart Island, between 1993 and 1996. Possums were captured from farmland, forest margin, scrub, beech, exotic forest or native forest. RESULTS: Antibodies to the enteroviruses were detected in possums from Shannon (56/270; 21%), Wanganui (4/46; 9%), Kawau Island (3/44; 7%), and Orongorongo (1/43; 2%). The proportion of seropositive possums per area was similar for those found on the forest margin or pasture grazed by sheep and cattle compared with those in the forest. Seropositive possums were significantly older than those that were seronegative (p<0.01). CONCLUSIONS: The distribution of enteroviruses in possums was clustered in the Manawatu-Wanganui regions, where the viruses were originally isolated. The limited distribution was likely due to the lack of contact between possum populations due to natural barriers. If a recombinant enterovirus carrying a biocontrol agent against possums was released it would encounter little interference from field strains in the majority of the country, due to the limited distribution of these viruses in the field. PMID- 20200573 TI - Development of a vaccine to mitigate greenhouse gas emissions in agriculture: vaccination of sheep with methanogen fractions induces antibodies that block methane production in vitro. AB - AIM: To develop an understanding of the immune responses of ruminants to methanogens, and to provide proof of a concept that harnessing the immune system of ruminants is a potentially viable approach to mitigate greenhouse gas emissions from agriculture. METHODS: Four subcellular fractions, namely cytoplasmic, two cell-wall preparations, and cell wall-derived proteins were prepared from Methanobrevibacter ruminantium M1. Twenty sheep (10 months of age) were vaccinated with these fractions or with whole cells (n=4 per group). Sheep were re-vaccinated once after 3 weeks, and antibody responses to M. ruminantium M1 antigens in sera and saliva measured using ELISA at 2 weeks after the second vaccination. Antigens recognised by the antisera were visualised using Western blotting. The antisera were tested in vitro for their impact on M. ruminantium M1, measuring the effect on cell growth, methane production, and ability to induce agglutination. RESULTS: Basal levels (pre-vaccination) of antibodies against M. ruminantium M1 antigens were low. Vaccination with the antigenic fractions induced strong antibody responses in serum. Both IgG and IgA responses to methanogen antigens were detected in saliva following vaccination. Western blot analysis of the antisera indicated reactivity of antibodies, and a wide range of proteins was present in the different methanogen fractions. Antisera against the various fractions agglutinated methanogens in an in-vitro assay. In addition, these antisera decreased the growth of a pure culture of a methanogen and production of methane in vitro. CONCLUSIONS: Antigens from methanogens are immunogenic in ruminants, and antisera from sheep vaccinated with fractions of methanogens have a significant impact on these organisms, inducing cell agglutination, and decreasing growth of methanogens and production of methane. Only antisera to selected methanogen fractions were able to achieve these effects. The results demonstrate the feasibility of a vaccination strategy to mitigate emission of methane. PMID- 20200575 TI - A randomised, non-inferiority trial of a new cephalonium dry-cow therapy. AB - AIM: To test the non-inferiority of a novel cephalonium formulation of antibiotic dry-cow therapy (DCT) to a reference formulation, infused at the end of lactation, for cure of existing and prevention of new intramammary infections (IMI). METHODS: Cows with a maximum somatic cell count (SCC) of < or =150,000 cells/ml and with no history of clinical mastitis in the preceding lactation were blocked by herd and age, ranked on maximum SCC, and assigned to be treated with nothing (negative control; n=293 cows), infused in all four quarters with 250 mg of a novel cephalonium formulation (new treatment; n=299 cows), or infused in all four quarters with a reference cephalonium formulation (reference treatment; n=301 cows) at the end of lactation (prophylactic study). Cows with a maximum SCC >150,000 cells/ml and/or with a history of clinical mastitis were blocked as above, and assigned to the new treatment (n=389 cows), or the reference treatment (n=399 cows) in all four quarters (therapeutic study). Quarter-milk samples were collected for bacteriology and measurement of SCC at drying off, between 0 and 6 days, and between 3 and 12 days after calving. Non-inferiority was assessed by calculating the difference between the new and reference treatments, and constructing a 95% confidence around this difference. If the upper (or lower) 95% CI was below (or above) the pre-stated margin of non-inferiority the new treatment was declared non-inferior. The pre-stated margins were 3% and 10% for the prophylactic and therapeutic studies, respectively. RESULTS: There was no difference in the proportion of new IMI across the dry period, the hazard of clinical mastitis in the dry period or in the first 21 days of the subsequent lactation, or in the SCC at the quarter or cow level for cows treated with the novel or reference cephalonium formulations in the prophylactic study. Both formulations resulted in fewer new IMI, and lower hazard of clinical mastitis and SCC compared with the negative controls. The new treatment was non-inferior to the reference treatment (p<0.05). In the therapeutic study, the novel formulation resulted in a 2.7% lower percentage cured than the reference formation, but the new treatment was non-inferior to the reference treatment (p<0.05). CONCLUSION: The new treatment was non-inferior to the reference treatment in prevention of new IMI and in curing existing infections over the dry period. PMID- 20200574 TI - Tasks considered by veterinarians to cause them musculoskeletal discomfort, and suggested solutions. AB - AIM: To describe veterinarians' perceptions of the causes of, and reasons for, work-related musculoskeletal discomfort (MSD), and to summarise their suggestions for ways to reduce the risk of MSD. METHODS: A cross-sectional study administered online asked 2,112 veterinarians registered in New Zealand to indicate, using free-handed text, the three tasks that "will most likely lead to musculoskeletal aches and pains (MSD)", reasons "why are these tasks likely to be the most risky?", and "any solutions that you apply or know of ". RESULTS: Complete questionnaires were returned by 828 veterinarians, a response rate of 39%. The tasks considered by veterinarians most likely to lead to MSD were lifting, surgery, rectal palpations, and animal handling. The main reasons why tasks were perceived to be most likely to lead to MSD were awkward posture, repetitive activities, and physical activity. The solutions suggested by veterinarians included provision of appropriate assistance and/or adequate staff, attention to correct manual handling techniques, provision of facilities to allow work to be carried out at a comfortable height, and regular rotation of jobs. Of the 39 solution categories, 16 (41%) could be categorised as those requiring a change in design of the work environment, and 15 (38%) involved training. CONCLUSIONS: The results of this study indicate that veterinarians perceive the causes of work related MSD to be related to physical rather than psychosocial factors. We propose that the findings reported in this study provide a useful starting point for the application of a participatory ergonomics approach for addressing the problem of MSD amongst veterinarians in New Zealand. PMID- 20200576 TI - Nodular gill disease causing proliferative branchitis and mortality in Chinook salmon (Oncorhynchus tshawytscha). AB - CASE HISTORY: A period of escalating mortality occurred among Chinook salmon (1-5 g) held in freshwater raceways at a commercial culture facility. The mortality rate peaked at 1.5% of the population per day, water temperature was 9-10 degrees C, and water quality had recently deteriorated due to an influx of suspended solids. The affected fish did not respond to several chloramine-T bath treatments (10 ppm for 1 hour). CLINICAL FINDINGS: The dead fish did not exhibit flared opercula typical of infection with bacterial gill disease (BGD) nor did the remaining fish show obvious signs of respiratory distress. Clinical lesions were limited to the gills of the fish, and were consistent with a proliferative branchitis, including substantial hyperplasia and fusion of lamellae. DIAGNOSIS: Numerous angular amoebic organisms (approximately 10 x 8 microm), with a central, large vesicular nucleus and faintly acidophilic cytoplasm, visible on H&E-stained sections, were located on the hyperplastic epithelia of the lamellae, filaments, and remaining lining of the branchial cavity. Morphologically, the amoebae were similar to representatives of the genus Cochliopodia spp. described from North American salmonids, that presented similar lesions and clinical signs; consequently, the disease was diagnosed as nodular gill disease (NGD). CLINICAL RELEVANCE: Grossly, NGD can be mistaken for BGD; the distinction is important because chloramine-T, routinely used in the treatment of BGD, is ineffective for the treatment of NGD. Static formalin baths of 170 ppm (37% formaldehyde) for 1 hour, supplemented with oxygen, may reduce amoebic infections but should be used cautiously as treatment can precipitate mortality in fish with gill disease. Cues for the onset of NGD are not completely understood, although poor water quality and elevations in temperature are likely to exacerbate infections. Similarly, the prevalence of this disease is not accurately known, but it is possible that it may be more common among salmonids in New Zealand than is presently recognised. PMID- 20200577 TI - Disseminated Mortierella wolfii infection in a neonatal calf. PMID- 20200578 TI - Epidemiology of Chlamydophila caviae-like Chlamydia isolated from urethra and uterine cervix. AB - In 2000, chlamydial strains OK133 and OK135 were isolated from 2 female patients with cervicitis. These strains were unresponsive to commercially available PCR and LCR test kits for the diagnosis of Chlamydia trachomatis infection, and their phenotypic characteristics were very similar. The OK135 nucleotide sequence in MOMP-VD2 gene closely resembled that of Chlamydophila caviae GPIC. A similar strain was isolated in 2003 from a male patient OKM2 with urethritis, from which the strain SC10-6 was cloned by the plaque purification method. The nucleotide sequence of the entire MOMP gene of SC10-6 was exactly the same as that of OK135. Thus, the strains OK135 and SC10-6, together with OK133, have been called C. caviae-like Chlamydia. We designed primers for nested PCR assay, the product of which showed a single-band 311-bp fragment, to detect C. caviae-like Chlamydia. Of swab specimens obtained from 202 patients from 2003 to 2006 (119 male and 83 female patients), 18 specimens (8.9%) from 14 male and 4 female patients were positive, suggesting that C. caviae-like Chlamydia infection is rather common. Thus far, it has not been determined whether C. caviae-like Chlamydia is pathogenic for humans. PMID- 20200579 TI - Comparison of capillary architecture between slow and fast muscles in rats using a confocal laser scanning microscope. AB - The skeletal muscle is classified into 2 types, slow oxidative or fast glycolytic muscle. For further characterization, we investigated the capillary architecture in slow and fast muscles. The rat soleus and extensor digitorum longus (EDL) muscles were used as representatives of slow and fast muscles, respectively. To investigate capillary density, sections of both types of muscle were stained with alkaline phosphatase; the soleus muscle showed more intense reactivity, indicating that it had a denser capillary structure than the EDL muscle. We then injected fluorescent contrast medium into samples of both muscle types for light and confocal-laser microscopic evaluation. The capillary density and capillary-to fiber ratio were significantly higher, and the course of the capillaries was more tortuous, in the soleus muscle than in the EDL muscle. Capillary coursed more tortuously in the soleus than in the EDL muscle. Succinate dehydrogenase (SDH) activity, an indicator of mitochondrial oxidative capacity, and vascular endothelial growth factor (VEGF) expression were also significantly higher in the soleus muscle. Thus, we conclude that slow oxidative muscle possess a rich capillary structure to provide demanded oxygen, and VEGF might be involved in the formation and/or maintenance of this highly capillarized architecture. PMID- 20200580 TI - Irinotecan hydrochloride (CPT-11) in dialysis patients with gastrointestinal cancer. AB - We investigated changes in drug disposition and toxicities with CPT-11 in 15 dialysis patients with gastrointestinal cancers to clarify whether CPT-11 could be administered safely in such patients. For comparison, the same parameters were also investigated in 10 cancer patients not undergoing dialysis. Items investigated included (1) plasma concentrations of SN-38, SN-38G and CPT-11 at 0, 1, 12, 24, 36, 48 and 72 h after administration, together with a comparison of mean AUC values for 3 dose levels of CPT-11 (50, 60 and 70 mg/m2) in dialysis patients and controls; and (2) occurrence of adverse events. Several findings emerged from this study: (1) No significant difference was observed in the AUC for SN-38 or CPT-11 between the dialysis and control groups; (2) The AUC for SN 38G at each dose was significantly higher in dialysis patients; and (3) Grade 1-4 leucopenia was observed in 11 of the dialysis patients. One patient developed grade 4 leucopenia and died due to sepsis. Anorexia, diarrhea, nausea, alopecia and interstitial pneumonia occurred in 6 dialysis patients. We found changes in drug dispositions of CPT-11, SN-38 and SN-38G in dialysis patients, suggesting that hepatic excretion, especially that of SN-38G, was increased. No significant difference in occurrence of adverse events was observed between the 2 groups. This indicates that CPT-11 can be administered safely in patients on dialysis. PMID- 20200581 TI - Prognostic factors influencing survival after nephroureterectomy for transitional cell carcinoma of the upper urinary tract. AB - We analyzed the prognostic factors influencing survival after surgeries for upper urinary tract urothelial carcinoma (UUT-UC) with longer follow-up periods than in previous studies. Between January 2000 and December 2004, 386 patients underwent nephroureterectomy for UUT-UC. The data for the 221 patients with UUT-UC were retrospectively reviewed. Nine variables were evaluated for association with the survival outcomes of cause-specific survival. The prognostic significance was tested univariately with the log-rank test. The simultaneous effects of multiple prognostic factors were estimated by multiple regression analysis using the Cox proportional hazards model. The median follow-up was 38.4 months. The 5-year over all survival was 62.3%. Significant prognostic factors for disease-specific survival rate on univariate analysis were pathological stage (p < 0.0001), tumor grade (p = 0.0324), and venous invasion (p < 0.0001). Multivariate analysis revealed that only venous invasion was significant for disease-specific survival rate (p = 0.0205). Venous invasion was the only independent prognostic factor in pathologically localized UUT-UC. PMID- 20200583 TI - Influencing factors for dietary behaviors of patients with diabetic nephropathy. AB - The aim of this study was to clarify the factors influencing the dietary behavior of patients with diabetic nephropathy. One hundred twenty-two patients with type 2 diabetes were recruited from the outpatients of Okayama University Hospital in Okayama, Japan. We performed a cross-sectional study using a questionnaire including 206 items among 18 categories as follows: background factors, coping behavior (coping scale), degree of uncertainty in illness (uncertainty scale), and dietary behavior. The data were analyzed by correlation analysis, t-test, one way analysis of variance, Pearson correlation analysis, and multiple regression analysis. We found that those patients with microalbuminuria alone tended to recognize more mild about their kidney status than those with macroalbuminuria and chronic renal failure. We also found that common factors influencing the dietary behavior of diabetic patients with and without nephropathy are as follows: 1. coping with the problem (beta = 0.342, p < 0.01); 2. anxiety about prognosis (beta = -0.344, p < 0.01); 3. sex (beta = -0.234, p < 0.05); 4. uncertainty regarding treatment (beta = 0.377, p < 0.01); 5. negative coping (beta = -0.354, p< 0.01); and 6. employment status (beta = 0.367, p < 0.01). Coping and uncertainty in illness had a significant relation to positive support and lack of support. To maintain appropriate dietary behavior in diabetic patients, medical staff need to determine what the social supports are important for the patient, and also to ensure good communication among healthcare personnel as well as positive support for patients and families. PMID- 20200582 TI - Triplet chemotherapy with cisplatin, docetaxel, and irinotecan for patients with recurrent or refractory non-small cell lung cancer. AB - We examined the feasibility of triplet chemotherapy using cisplatin, docetaxel, and irinotecan for patients with recurrent or refractory non-small cell lung cancer (NSCLC), retrospectively. Twenty-five patients (21 men and 4 women) with NSCLC and good performance status who were < or = 70 years old were analyzed. The median age was 58 years. Most patients had performance status 1 (16/25), stage IV disease (18/25) and adenocarcinoma-histology (16/25). Cisplatin and docetaxel were given on day 1 and irinotecan on day 2; the cycle was repeated every 3 weeks. The objective response rate was 39.1% (95% confidence interval: 18.7 59.5%). The median survival time and actual 2-, 3-, and 5-year survival rates were 14.3 months, 32%, 20%, and 8%, respectively. Of note, only 6 patients were treated with gefitinib at the recurrence after triplet chemotherapy; of these, 4 (67%) achieved a partial response, which might result in favorable survival. Grade 3/4 toxicities consisted of neutropenia (100%), neutropenic fever (56%), nausea/vomiting (40%), and diarrhea (16%); no cases of treatment-related death occurred. Triplet chemotherapy showed impressive survival data in our clinical trial, but proved too toxic for use in treating patients with NSCLC in the clinical practice. PMID- 20200584 TI - The first case of a class I glucose-6-phosphate dehydrogenase deficiency, G6PD Santiago de Cuba (1339 G > A), in a Chinese population as found in a survey for G6PD deficiency in northeastern and central China. AB - In Liaoning Province in northeastern China, we found a G6PD-deficient patient at the age of 3. By the classification of the World Health Organization, this patient was categorized as class I (very severe G6PD deficiency). When we investigated the G6PD gene of the patient, we found that he had a replacement of G to A at nucleotide 1339. As a result, the amino acid at position 447 should change from Gly to Arg. This replacement is known as G6PD Santiago de Cuba, because it was first discovered in a Cuban boy who showed heavy chronic anemia. Today, 28 G6PD variants have been reported in the Chinese population, and all are categorized as class II (severe deficiency) or class III (mild deficiency); in class II or III deficiency, anemia is not present in daily life, but hemolytic attack can occur when the carrier ingests certain oxidative medicines or foods. This is the first report of a G6PD-deficient Chinese patient in the category of class I. We intended to find other G6PD-deficient cases in northeastern China and tested several hundred blood samples, but no cases of G6PD deficiency were found (0/414). In central China, where falciparum malaria was endemic from the 1950s to 1970s, we found two G6PD-deficient cases (2/27) and the other members from their families whose variant type was G6PD Kaiping (1388G > T), which is a common variant in the Chinese population. PMID- 20200585 TI - Differential response of heat-shock-induced p38 MAPK and JNK activity in PC12 mutant and PC12 parental cells for differentiation and apoptosis. AB - Among the 3 mitogen-activated protein kinases--ERK, p38 MAPK and JNK--JNK has been suggested to participate in apoptosis, whereas p38 MAPK is thought to be part of the differentiation response. There are many common inducers of JNK and p38 MAPK, but the mechanisms underlying the differential response to apoptosis and differentiation are poorly understood. We found that heatshock activated p38 MAPK at 3 min after exposure to a temperature of 44 degrees C in stress hypersensitive PC12m3 mutant cells, while it activated JNK at 20 min after the same heat treatment. However, heatshock activated p38 MAPK 5min after heat treatment and JNK 10 min after heat treatment in PC12 parental cells. The extent of phosphorylation of p38 MAPK induced by heat shock in PC12m3 cells was significantly greater than that in PC12 parental cells, and a high level of heat shock-induced neurite outgrowth was observed only in PC12m3 cells. On the other hand, heat-shock-induced JNK activation appeared more quickly and apoptosis started earlier in PC12 parental cells. These findings indicate that short stress induces p38 MAPK and longer stress induces JNK, and that the response of these kinases to heat shock differs depending on cell type. PMID- 20200586 TI - Poorly differentiated adenocarcinoma with signet-ring cell carcinoma of the extrahepatic bile duct in a 42-year-old Japanese female: a case report. AB - Poorly differentiated adenocarcinoma without papilla or tubule formation of the extrahepatic bile duct is rare. Here we present a case (a 42-year-old Japanese woman) without either pancreatobiliary maljunction or liver disease. The patient had obstructive jaundice. Imaging studies revealed a bile duct tumor obstructing the common bile duct and invading the surrounding tissues. Pathologic examination revealed a dense periductal growth of poorly differentiated adenocarcinoma containing signet-ring cells, but without papilla or tubule formation in the extrahepatic bile duct. The tumor cells directly invaded the pancreatic parenchyma and the portal vein. In the extrahepatic bile duct, poorly differentiated adenocarcinoma may be established as a distinct clinicopathologic entity if the tumors are characterized by: 1) the absence of papilla or tubule formation, 2) Asian preponderance, 3) occurrence at a younger age than is usual for patients with biliary cancers, and 4) an aggressive mural invasiveness. PMID- 20200587 TI - Effective management of an advanced gastric cancer patient by TS-1 combined chemotherapy using nasojejunal tube and successful transfer to home care after percutaneous transesophageal gastro-tubing (PTEG): a case report. AB - A 67-year-old woman with debilitation and massive ascites was admitted to our hospital and diagnosed with stage IV scirrhous gastric cancer with peritoneal dissemination. After successful nasojejunal tube feeding because of oral intake disability, TS-1 combined with paclitaxel chemotherapy was selected. TS-1 at 80mg/m2 was given daily via nasojejunal tube for 2 weeks, followed by a 1-week rest, and paclitaxel at 50mg/m2 was administered intravenously on day 1 and 8. There were no serious side effects. After 4 cycles, a partial response was observed and percutaneous transesophageal gastrotubing (PTEG) was placed. After the fifth cycle, she was transferred to her home and received chemotherapy in an outpatient clinic. After 7 cycles, the disease progressed, and TS-1 combined with low-dose cisplatin was administered for 3 cycles. However, the patient died 16 weeks after discharge. PTEG was useful not only for a route of TS-1 administration, but also for receiving chemotherapy at home to maintain her quality. PMID- 20200588 TI - Bilateral iliopsoas hematomas under sedation: a complication of postoperative therapy after coronary artery bypass grafting. AB - We report a case of bilateral iliopsoas hematomas that occurred during postoperative therapy after coronary artery bypass grafting (CABG). An 81-year old woman receiving anticoagulant and antiplatelet therapies under sedation after CABG developed sudden anemia and went into shock. Abdominal ultrasonography showed a right retroperitoneal hematoma. She improved gradually with conservative treatment. Many patients with an iliopsoas hematoma complain of low-abdominal pain or femoral neuropathy, but such local signs may be absent under sedation. In anticoagulant and antiplatelet therapies under sedation, when the cause of anemia and shock is not clear, we should suspect peritoneal hematoma and examine the peritoneal space. PMID- 20200590 TI - THE POLICY RESPONSE TO THE SMOKING AND LUNG CANCER CONNECTION IN THE 1950s AND 1960s. AB - A key current concern is how scientific knowledge may inform policy in relation to major environmental and health concerns. There are distinct schools of analysis about this relationship between science and policy. They stress rational relationships; denial and delay; or the role of networks. History is important in modifying such perspectives: smoking policy in the 1950s and 1960s is the case study here. The initial response in the 1950s to the link between smoking and lung cancer was in part conditioned by the role of the tobacco industry and the financial importance of tobacco: the British tobacco industry had closer relationships with government than the American one, and did not rely on public relations. Public health interests worked with the industry. But politicians were concerned also about the fluidity of the epidemiological evidence; the dangers of stirring up further pressure over air pollution; the financial and ideological implications of health education and its location; and the electoral dangers of intervening in a popular mass habit. In the 1960s the British and American medical reports stimulated the growth of a public health 'policy community'. The initial political considerations began to weaken and these years marked the beginning of a new style of public health. PMID- 20200591 TI - Synthesis and characterization of chitosan-carbon nanotube composites. AB - Acid functionalized single walled carbon nanotubes were covalently grafted to chitosan by first reacting the oxidized carbon nanotubes with thionyl chloride to form acyl-chlorinated carbon nanotubes which are subsequently dispersed in chitosan and covalently grated to form composite material, CNT-chitosan, 1, which was washed several times to remove un-reacted materials. This composite has been characterized by FTIR, 13C NMR, TGA, SEM and TEM and has been shown to exhibit enhanced thermal stability. The reaction of 1, with poly lactic acid has also been accomplished to yield CNTchitosan-g-poly(LA), 2 and fully characterized by the above techniques. Results showed covalent attachment of chitosan and chitosan poly lactic acid to the carbon nanotubes. PMID- 20200592 TI - Not Just Numbers: Creating a Partnership Climate to Improve Math Proficiency in Schools. AB - Although we know that family involvement is associated with stronger math performance, little is known about what educators are doing to effectively involve families and community members, and whether this measurably improves math achievement at their schools. This study used data from 39 schools to assess the effects of family and community involvement activities on school levels of math achievement. The study found that better implementation of math-related practices of family and community involvement predicted stronger support from parents for schools' partnership programs, which, in turn, helped estimate the percentage of students scoring proficient on math achievement tests. PMID- 20200593 TI - The Family Fluency Program. PMID- 20200594 TI - Role of CTLA-4, IL-18 and IL-10 on the Induction of Low Dose Oral Tolerance. AB - Oral Tolerance is the temporary loss of systemic immunological responsiveness to a specific soluble antigen after ingestion of that antigen. Results from our lab and others indicated that CTLA-4 and lack of IL-12 played a role in the induction of low dose oral tolerance at the Th1 cell level. Previous literature suggested that IL-18 also played a role in preventing oral tolerance induction while the cytokine IL-10 had been shown to be a factor contributing to suppressed immune responses. To determine the role of CTLA-4 in conjunction with either IL-18 or IL 10 in low dose oral tolerance induction, anti-CTLA-4 mAb and either IL-18 or anti IL-10 mAb were administered concurrently to mice fed either ovalbumin (OVA) or water. Results showed that the PLN cell proliferation of mice treated with anti CTLA-4 mAb and IL-18 remained significantly suppressed compared with water-fed controls, while a partial abrogation of suppressed IL-4 and IFN-gamma levels were observed. In contrast, mice treated with anti-CTLA-4 mAb and anti-IL-10 mAb exhibited a reversal of PLN cell proliferation and IL-4 suppression; however, IFN gamma levels remained suppressed. Results suggest that IL-10, IL-18 and CTLA-4 play roles in the induction of oral tolerance at the cell proliferation and cytokine level. PMID- 20200595 TI - Synthesis and Optical Properties of Cubic Gold Nanoframes. AB - This paper describes a facile method of preparing cubic Au nanoframes with open structures via the galvanic replacement reaction between Ag nanocubes and AuCl(2) (-). A mechanistic study of the reaction revealed that the formation of Au nanoframes relies on the diffusion of both Au and Ag atoms. The effect of the edge length and ridge thickness of the nanoframes on the localized surface plasmon resonance peak was explored by a combination of discrete dipole approximation calculations and single nanoparticle spectroscopy. With their hollow and open structures, the Au nanoframes represent a novel class of substrates for applications including surface plasmonics and surface-enhanced Raman scattering. PMID- 20200596 TI - Assessment of Protein Stability in Cerebrospinal Fluid Using Surface-Enhanced Laser Desorption/Ionization Time-of-Flight Mass Spectrometry Protein Profiling. AB - Recent studies have evaluated proper acquisition and storage procedures for the use of serum or plasma for mass spectrometry (MS)-based proteomics. The present study examines the proteome stability of human cerebrospinal fluid (CSF) over time at 23 degrees C (room temperature) and 4 degrees C using surface-enhanced laser desorption/ionization time-of-flight MS. Data analysis revealed that statistically significant differences in protein profiles are apparent within 4 h at 23 degrees C and between 6 and 8 h at 4 degrees C. Inclusion of protease and phosphatase inhibitor cocktails into the CSF samples failed to significantly reduce proteome alterations over time. We conclude that MS-based proteomic analysis of CSF requires careful assessment of sample collection procedures for rapid and optimal sample acquisition and storage. PMID- 20200597 TI - On the expectation and variance of the reversal distance. AB - We give a pair of well-matched lower and upper bounds for the expectation of reversal distance under the hypothesis of random gene order by investigating the expected number of cycles in the breakpoint graph of linear signed permutations. Sankoff and Haque [9] proved similar results for circular signed permutations based on approximations based on a slightly different model; while our approach is discrete. We also provide an near-tight upper bound for the variance of reversal distance, which gives information on the distribution of reversal distance. PMID- 20200598 TI - FAST MOLECULAR SOLVATION ENERGETICS AND FORCE COMPUTATION. AB - The total free energy of a molecule includes the classical molecular mechanical energy (which is understood as the free energy in vacuum) and the solvation energy which is caused by the change of the environment of the molecule (solute) from vacuum to solvent. The solvation energy is important to the study of the inter-molecular interactions. In this paper we develop a fast surface-based generalized Born method to compute the electrostatic solvation energy along with the energy derivatives for the solvation forces. The most time-consuming computation is the evaluation of the surface integrals over an algebraic spline molecular surface (ASMS) and the fast computation is achieved by the use of the nonequispaced fast Fourier transform (NFFT) algorithm. The main results of this paper involve (a) an efficient sampling of quadrature points over the molecular surface by using nonlinear patches, (b) fast linear time estimation of energy and inter-molecular forces, (c) error analysis, and (d) efficient implementation combining fast pairwise summation and the continuum integration using nonlinear patches. PMID- 20200599 TI - Time Controlled Protein Release from Layer-by-Layer Assembled Multilayer Functionalized Agarose Hydrogels. AB - Axons of the adult central nervous system exhibit an extremely limited ability to regenerate after spinal cord injury. Experimentally generated patterns of axon growth are typically disorganized and randomly oriented. Support of linear axonal growth into spinal cord lesion sites has been demonstrated using arrays of uniaxial channels, templated with agarose hydrogel, and containing genetically engineered cells that secrete brain-derived neurotrophic factor (BDNF). However, immobilizing neurotrophic factors secreting cells within a scaffold is relatively cumbersome, and alternative strategies are needed to provide sustained release of BDNF from templated agarose scaffolds. Existing methods of loading the drug or protein into hydrogels cannot provide sustained release from templated agarose hydrogels. Alternatively, here it is shown that pH-responsive H-bonded poly(ethylene glycol)(PEG)/poly(acrylic acid)(PAA)/protein hybrid layer-by-layer (LbL) thin films, when prepared over agarose, provided sustained release of protein under physiological conditions for more than four weeks. Lysozyme, a protein similar in size and isoelectric point to BDNF, is released from the multilayers on the agarose and is biologically active during the earlier time points, with decreasing activity at later time points. This is the first demonstration of month-long sustained protein release from an agarose hydrogel, whereby the drug/protein is loaded separately from the agarose hydrogel fabrication process. PMID- 20200600 TI - Cerebral Correlates of Amygdala Responses During Non-Conscious Perception of Facial Affect in Adolescent and Pre-Adolescent Children. AB - During nonconscious perception of facial affect, healthy adults commonly activate a right-lateralized pathway comprising the superior colliculus, pulvinar, and amygdala. Whether this system is fully developed prior to adulthood is unknown. Twenty-three healthy adolescents underwent functional magnetic resonance imaging (fMRI) while viewing fearful, angry, and happy faces, backward masked by neutral faces. Left amygdala activation differed among the three affects, showing reductions to masked anger and increases to masked fear and happy faces. During masked fear, left amygdala activation correlated positively with extrastriate cortex and temporal poles and negatively with precuneus and middle cingulate gyrus. Responses of the left amygdala to masked anger correlated positively with right parahippocampal gyrus and negatively with dorsal anterior cingulate. Amygdala responses to masked happy faces were uncorrelated with other brain regions. Contrary to the right-lateralized pathway seen in adults, adolescents show evidence of a predominantly left-lateralized extrastriate pathway during masked presentations of facial affect. PMID- 20200601 TI - Conscious and nonconscious memory effects are temporally dissociable. AB - Intentional (explicit) retrieval can reactivate sensory cortex, which is widely assumed to reflect conscious processing. In the present study, we used an explicit visual memory event-related potential paradigm to investigate whether such retrieval related sensory activity could be separated into conscious and nonconscious components. During study, abstract shapes were presented in the left or right visual field. During test, old and new shapes were presented centrally and participants classified each shape as "old-left", "old-right", or "new". Conscious activity was isolated by comparing accurate memory for shape and location (old-hits) with forgotten shapes (old-misses), and nonconscious activity was isolated by comparing old-left-misses with old-right-misses and vice versa. Conscious visual sensory activity had a late temporal onset (after 800 ms) while nonconscious visual sensory activity had an early temporal onset (before 800 ms). These results suggest explicit memory related sensory activity reflects both conscious and nonconscious processes that are temporally dissociable. PMID- 20200602 TI - Immersed finite element method and its applications to biological systems. AB - This paper summarizes the newly developed immersed finite element method (IFEM) and its applications to the modeling of biological systems. This work was inspired by the pioneering work of Professor T.J.R. Hughes in solving fluid structure interaction problems. In IFEM, a Lagrangian solid mesh moves on top of a background Eulerian fluid mesh which spans the entire computational domain. Hence, mesh generation is greatly simplified. Moreover, both fluid and solid domains are modeled with the finite element method and the continuity between the fluid and solid subdomains is enforced via the interpolation of the velocities and the distribution of the forces with the reproducing Kernel particle method (RKPM) delta function. The proposed method is used to study the fluid-structure interaction problems encountered in human cardiovascular systems. Currently, the heart modeling is being constructed and the deployment process of an angioplasty stent has been simulated. Some preliminary results on monocyte and platelet deposition are presented. Blood rheology, in particular, the shear-rate dependent de-aggregation of red blood cell (RBC) clusters and the transport of deformable cells, are modeled. Furthermore, IFEM is combined with electrokinetics to study the mechanisms of nano/bio filament assembly for the understanding of cell motility. PMID- 20200604 TI - Designing ARVs Patent Pool Up to Trade & Policy Evolutionary Dynamics. AB - Patent pools for second and third-line Fixed Dose Combination (FDC) antiretroviral drugs (ARVs) should not be delayed as they are instrumental to urgent public health needs in the under-served markets.Nonetheless, multinational originator companies still seem to perceive patent pooling for ARVs as a minefield that would offer the generic competitors lots of deeply exploitable opportunities, to the detriment of patent owner's rights.This paper analyses the brand industry concerns, while looking for a strategy up to a really equitable and free world market, without any discrimination between end-users in wealthy and resource-limited countries.This strategy would urge partnerships between originator companies first to make newer FDC ARVs quickly available and allow patent pool agreements with generic counterparts to be negotiated straight afterwards.The patent pool strategy highlighted in this paper would assert the primacy of health over for-profit policies, while aligning with the 61(st) WHO's Assembly recommendations and G7, G8 and World Trade Organisation's warnings and pledges against trade protectionism. PMID- 20200603 TI - Roles of retrotransposons in benign and malignant hematologic disease. AB - Nearly half of our genomes are repetitive sequences derived from retrotransposons. These repeats have accumulated by a 'copy-and-paste' mechanism whereby: (i.) a genomic template sequence is transcribed to RNA, (ii.) the RNA is reverse-transcribed, and (iii.) the DNA copy is inserted at a new location in the host genome. As we remain susceptible to new retrotransposition events, many of these insertions are highly polymorphic. Transposons are of interest since insertions into both coding and non-coding gene regions have been associated with a wide variety of functional sequelae and because transposable elements can be involved in genomic rearrangements in transformed cells. In this review, we highlight how expression of retrotransposons, de novo and polymorphic transposon insertions, and genomic rearrangements that these repeats potentiate contribute to both benign and neoplastic hematopoietic diseases. PMID- 20200606 TI - Implications of patent pools on innovation regarding antiretrovirals. AB - Patent pools have been promoted as an innovative means of promoting the production of fixed-dose combination antiretroviral medicines (ARVs), which can be particularly appropriate for resource-poor settings. An important question, however, is what are the implications of patent pools on innovation for creating new and improved antiretrovirals. Indeed, given the continuing mutation of HIV and growing resistance to existing treatments, continued innovation in ARV development is vital for addressing these challenges. Would patent pools be a hindrance or rather a stimulus for further innovation? This question is particularly relevant in light of UNITAID's initiative to create a patent pool for ARV development, focusing on pediatric formulations and new combinations, by the end of 2009. In this article, the author argues that a voluntary and well designed patent pool, involving both innovative and generic manufacturers, focused on developing fixed-dose combinations for resource-poor markets with the greatest need, could actually stimulate increased innovation to meet these needs. Indeed, by bringing together the major ARV producers worldwide to collaborate on developing products which will meet the needs of the poorest, an ARV patent pool could create significant public health benefits. UNITAID has taken the lead in designing and implementing such a pool and UNITAID's experience will have important lessons for policy-makers in the future. PMID- 20200605 TI - Cholesteryl ester transfer protein gene polymorphisms and longevity syndrome. AB - PURPOSE: High levels of high density lipoprotein (HDL) cholesterol are associated with a decreased risk of coronary heart disease (CHD). Subjects with high levels of HDL cholesterol (>70 mg/dl; 1.79 mmol/l) as well as high levels of low density lipoprotein (LDL) cholesterol, could represent a group with longevity syndrome (LS). Since HDL particles are influenced by cholesteryl ester transfer protein (CETP) activity, it is worth studying the CETP polymorphism. The aim of the study was to detect whether 2 genetic variants of the CETP are associated with the LS. SUBJECTS AND METHODS: The study population consisted of 136 unrelated men and women with no personal and family history of CHD; 69 met the criteria for LS and 67 did not meet these criteria and had "normal" HDL cholesterol (>40 and <70 mg/dl; >1.03 and <1.79 mmol/l). All patients were genotyped for the TaqIB and I405V polymorphisms. RESULTS: The B2 allele frequency of TaqIB polymorphism was higher in the LS in comparison with the non-LS group (p=0.03) whereas B1 allele frequency was higher in the non-LS group (p=0.03). CONCLUSIONS: Gene polymorphisms could help decide whether individuals who have increased levels of both LDL cholesterol and HDL cholesterol require treatment. Some of the prerequisites could include that subjects with LS should not only have very high levels of HDL cholesterol but also favorable gene polymorphisms. However, further investigations with a larger sample and including other gene polymorphisms, are needed. PMID- 20200607 TI - Patent pools: intellectual property rights and competition. AB - Patent pools do not correct all problems associated with patent thickets. In this respect, patent pools might not stop the outsider problem from striking pools. Moreover, patent pools can be expensive to negotiate, can exclude patent holders with smaller numbers of patents or enable a group of major players to form a cartel that excludes new competitors. For all the above reasons, patent pools are subject to regulatory clearance because they could result in a monopoly. The aim of this article is to present the relationship between patents and competition in a broad context. PMID- 20200608 TI - Mate for the heart: pulsatile or continuous? PMID- 20200609 TI - Measure twice, think three times, cut once. PMID- 20200610 TI - Cardiac surgery in patients irradiated for Hodgkin's lymphoma. AB - Background/Objectives. Therapy for Hodgkin's lymphoma is disease specific and cannot be compared with treatment for other diseases. It often includes more extensive radiotherapy on the mediastinum than for other malignancies. Cardiac morbidity is known to occur in patients previously irradiated. This study describes the postoperative course after cardiac surgery of patients previously irradiated for Hodgkin's lymphoma.Methods. From January 1990 until June 2008, 12 patients underwent cardiac surgery in the University Medical Center Utrecht after previous irradiation for Hodgkin's lymphoma. Data on radiotherapy, surgery and follow-up were collected retrospectively. The postoperative functional status was assessed by a telephone questionnaire.Results. Atrial fibrillation (33%) and pleural effusion (25%) were the most common postoperative complications. After a mean followup of 2.6+/-2.9 years four patients had died. The remaining patients were all in a favourable New York Heart Association and Canadian Cardiothoracic Society class. The estimated one-, two- and four-year survival rates were 83, 69 and 46% respectively.Conclusion. The early postoperative outcome of cardiac surgery in this population is reasonably good. The long-term results may prove to be disappointing, but the cohort is small. (Neth Heart J 2010;18:61-5.). PMID- 20200611 TI - An in vivo comparison of radiofrequency cardiac lesions formed by standard and magnetically steered 4 mm tip catheters. AB - Background. In vivo comparison of cardiac radiofrequency ablation lesions between standard and magnetically steered 4 mm tip catheters has never been reported.Methods. High and low right atrium (RA) free wall, isthmus, right ventricle (RV) free wall and outflow tract lesions were studied macroscopically and microscopically five days after lesion formation in seven pigs. Shape, size, thrombus formation, and ablation parameters were compared. The effect of minimal, medium and high wall contact was assessed by a contact measurement utility for magnetic catheters.Results. All 14 RA free wall lesions were transmural with a similar epicardial and endocardial surface area. In the RV, the epicardial area usually appeared to be smaller than the endocardial area with standard catheters. Isthmus lesions were difficult to assess transmurality. There was no difference in endocardial area: standard 39 mm(2) (range 16 to 82 mm(2)) vs. magnetic 36 mm(2) (range 23 to 111 mm(2)). If the catheter tip was perpendicular to the tissue, magnetic lesions were more often round or oval, while standard lesions were more often elongated (p<0.05). When the catheter tip was parallel to tissue, lesions always tended to be elongated. Microscopic characteristics were similar. The contact utility was not useful. Average impedance (p<0.0001) and energy delivered (p<0.05) were less with magnetic catheters.Conclusion. Lesions from magnetically steered catheters are transmural of similar size, but with less variability than standard catheter lesions when the tip is perpendicular to the tissue. Magnetic lesions are associated with lower impedance and energy delivery. This suggests a more stable tip-to-tissue contact. (Neth Heart J 2010;18:66-71.). PMID- 20200612 TI - Evaluation of global left ventricular function assessment of non-fluorescent electromechanical endocardial mapping compared with biplane left ventricular contrast angiography. AB - Background. Little is known about the diagnostic accuracy of global LV function assessment by electromechanical endocardial mapping (EEM). The aim of the present study was to determine the relationship between global left ventricular (LV) function measured by EEM and biplane left ventricular contrast angiography (LVA) after ST-elevation myocardial infarction (STEMI).Methods. Thirty-seven patients underwent LVA and EEM during routine coronary angiography four months after primary percutaneous intervention for STEMI. Global LV function parameters were available from both techniques in all patients. LVA was regarded as reference standard.Results. All procedures were carried out without adverse events. Average age was 55+/-10 years and 84% were male. EEM showed an overestimation of end diastolic volume (EDV) and end-systolic volume (ESV) of 6.5 ml and 25.5 ml, respectively. Correlation (r) was 0.84 (p<0.001) for EDV and 0.74 (p<0.001) for ESV. Average left ventricular ejection fraction (LVEF) measured by EEM was 17.2% point (+/-11.3% point) lower compared with LVA (r=0.69, p<0.001).Conclusion. Although global functional parameters by EEM correlated well with LVA, the relatively large differences in terms of absolute values for ventricular volumes and LVEF render the two techniques non-interchangeable for global LV-function data. (Neth Heart J 2010;18:72-77.). PMID- 20200613 TI - Measure twice, cut once: pitfalls in the diagnosis of supraventricular tachycardia. AB - In atrioventricular nodal and atrioventricular reentrant tachycardia, the relative timing of atrial and ventricular activation may sometimes be very similar, even during electrophysiological studies, and this may lead to an erroneous diagnosis and inappropriate treatment. As examples, we describe two cases that were recently referred to our hospital for a second opinion and treatment of paroxysmal supraventricular tachycardia. In both, the original diagnosis of the referring centres was commontype atrioventricular nodal reentrant tachycardia. Catheter ablation in those centres was unsuccessful. During our electrophysiological studies, however, an atrioventricular reentrant tachycardia was demonstrated, using a concealed accessory pathway for retrograde conduction in both patients. The accessory atrioventricular connection was successfully ablated and on follow-up both patients remained free of symptoms without medication. These findings illustrate the importance of complete electrophysiological analysis even for apparently simple supraventricular arrhythmias. (Neth Heart J 2010;18:78-84.). PMID- 20200614 TI - Recurrent and founder mutations in the Netherlands: Extensive clinical variability in Marfan syndrome patients with a single novel recurrent fibrillin-1 missense mutation. AB - Background/Methods. Marfan syndrome (MFS) is a heritable connective tissue disorder usually caused by a mutation in the fibrillin 1 (FBN1) gene. Typical characteristics of MFS that have been described include dolichostenomelia, ectopia lentis and aortic root dilatation. However, there is great clinical variability in the expression of the syndrome's manifestations, both between and within families. Here we discuss the clinical variability of MFS by describing a large fourgeneration Dutch family with MFS.Results. Nineteen individuals of one family with a single missense FBN1 mutation (c.7916A>G) were identified. The same mutation was found in one unrelated person. Clinical variability was extensive and not all mutation carriers fulfilled the diagnostic criteria for MFS. Some patients only expressed mild skeletal abnormalities, whereas aortic root dilation was present in eight patients, an acute type A aortic dissection was recorded in two other patients, and a mitral valve prolapse was present in eight patients. In some patients cardiac features were not present on initial screening, but did however develop over time.Conclusion. MFS is a clinically highly variable syndrome, which means a meticulous evaluation of suspected cases is crucial. Mutation carriers should be re-evaluated regularly as cardiovascular symptoms may develop over time. (Neth Heart J 2010;18:85-9.). PMID- 20200616 TI - Postural electrocardiographic abnormalities. AB - False-positive stress testing is a common problem in daily practice. We present a young male patient with pseudo-ischaemic ST-segment changes due to upright position. (Neth Heart J 2010;18:99-102.). PMID- 20200615 TI - Cardiac PET-CT: advanced hybrid imaging for the detection of coronary artery disease. AB - Hybrid imaging of positron emission tomography (PET) together with computed tomography (CT) is rapidly emerging. In cardiology, this new advanced hybrid imaging modality allows quantification of cardiac perfusion in combination with assessment of coronary anatomy within a single scanning session of less than 45 minutes. The near-simultaneous anatomical evaluation of coronary arteries using CT and corresponding functional status using PET provides a wealth of complementary information in patients who are being evaluated for (suspected) coronary artery disease, and could help guide clinical patient management in a novel manner. Clinical experience gained with this recently introduced advanced hybrid imaging tool, however, is still limited and its implementation into daily clinical practice remains largely unchartered territory. This review discusses principles of perfusion PET, its diagnostic accuracy, and potential clinical applications of cardiac PET-CT in patients with ischaemic heart disease. (Neth Heart J 2010;18:90-8.). PMID- 20200617 TI - Entrainment mapping of ventricular tachycardia. PMID- 20200620 TI - Texas Heart Institute Medal and The Ray C. Fish Award for Scientific Achievement in Cardiovascular Diseases. PMID- 20200618 TI - Galectin-1 and its involvement in hepatocellular carcinoma aggressiveness. AB - Hepatocellular carcinoma is one of the most common cancers worldwide. Despite several efforts to elucidate hepatocellular carcinoma molecular pathogenesis, it is still not fully understood. To acquire further insights into the molecular mechanisms of hepatocellular carcinoma, we performed a systematic functional genomic approach on human HuH-7 and JHH-6 cells. The subsequent analysis of the differentially expressed genes in human specimens revealed a molecular signature of 11 genes from which we selected the LGALS1 gene, which was overexpressed in hepatocellular carcinoma. The expression analysis in humans of Galectin-1 (Gal 1), the protein encoded by LGALS1, showed a Gal-1 preferential accumulation in the stromal tissue around hepatocellular carcinoma tumors. Moreover, a significant association between increased expression of Gal-1 in hepatocellular carcinoma and the presence of metastasis was observed. Interestingly, Gal-1 overexpression resulted in an increase of cell migration and invasion. In conclusion, this study provides a portfolio of targets useful for future investigations into molecular marker-discovery studies on a large number of patients and functional assays. In addition, our data provide evidence that Gal-1 plays a role in hepatocellular carcinoma cell migration and invasion, and we suggest that further studies should be conducted to fully establish the role of Gal-1 in hepatocellular carcinoma pathogenesis and evaluate Gal-1 as a potential molecular therapeutic target. PMID- 20200619 TI - The role of macrophage migration inhibitory factor in Alzheimer's disease. AB - Previous studies have shown that amyloid beta protein (Abeta ), the essential molecule for the formation of toxic oligomers and, subsequently, Alzheimer plaques, has been associated in vivo with the immune modulator, macrophage migration inhibitory factor (MIF) (17). To further investigate this association in vivo we used the APP transgenic mouse model. Serial brain sections of transgenic APP mice were stained for Abeta plaques and MIF and we observed MIF immunolabeling in microglial cells in association with Abeta plaques in the transgenic mouse brain sections. In addition, functional studies in murine and human neuronal cell lines revealed that Abeta-induced toxicity could be reversed significantly by a small molecule inhibitor of MIF (ISO-1). Finally, to elucidate the role of MIF in Alzheimer's Disease (AD) we measured MIF levels in the brain cytosol and cerebrospinal fluid (CSF) of AD patients and age-matched controls. Our results demonstrate a marked increase of MIF levels within the CSF of AD patients compared with controls. Combined, our results indicate a strong role for MIF in the pathogenesis of AD and furthermore suggest that inhibition of MIF may provide a valuable avenue of investigation for the prevention of disease onset, progression and/or severity. PMID- 20200621 TI - Is Jupiter also a god of primary prevention? PMID- 20200622 TI - Revascularization options in patients with chronic kidney disease. AB - Cardiovascular disease is the leading cause of death in patients who have chronic kidney disease or end-stage renal disease and are undergoing hemodialysis. Chronic kidney disease is a recognized risk factor for premature atherosclerosis. Unfortunately, most major randomized clinical trials that form the basis for evidence-based use of revascularization procedures exclude patients who have renal insufficiency. Retrospective, observational studies suggest that patients with end-stage renal disease and severe coronary occlusive disease have a lower risk of death if they undergo coronary revascularization rather than medical therapy alone. Due to a lack of prospective studies, however, the relative merits of percutaneous versus surgical revascularization are merely a matter of opinion. Several small, retrospective studies have shown that coronary artery bypass grafting is associated with higher procedural death but better long-term survival than is percutaneous coronary intervention. This difference appears to result from poor long-term results of percutaneous coronary intervention in patients who have chronic kidney disease or end-stage renal disease.Because randomized trials comparing percutaneous coronary intervention and coronary artery bypass grafting have included patients undergoing balloon angioplasty and placement of bare-metal stents, their conclusions are suspect in the era of drug-eluting stents. In this review, we discuss different revascularization options for patients with chronic kidney disease, the outcomes of revascularization procedures, and the risk factors for adverse outcomes. PMID- 20200623 TI - Endoluminal abdominal aortic aneurysm repair: the latest advances in prevention of distal endograft migration and type 1 endoleak. AB - Endovascular abdominal aortic aneurysm repair (EVAR) is an attractive alternative to open surgical repair. Distal endograft migration and type 1 endoleak are recognized to be the 2 main complications of EVAR. First-generation endografts had a stronger propensity for distal migration, modular component separation, thrombosis, and loss of structural integrity. Substantial progress has been made in recent years with 2nd- and 3rd-generation devices to prevent these complications. Some of the most common predictors of endograft failure are angulated and short infrarenal necks, large-diameter necks, and thrombus in the aneurysmal sac. The purpose of this study is to describe and review our experience in using innovative techniques and a newer generation of endografts to prevent distal migration and type 1 endoleak in patients with challenging infrarenal neck anatomy. The use of these innovative EVAR techniques and the new generation of endografts in patients with challenging infrarenal neck anatomy has yielded encouraging procedural and intermediate-term results. PMID- 20200624 TI - Lipoprotein-associated phospholipase A2 as a novel risk marker for cardiovascular disease: a systematic review of the literature. AB - We sought to critically assess the role of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) in the prediction of cardiovascular events in primary and secondary prevention settings. The inclusion criteria for our study included population-based epidemiologic studies and the presence of clinical outcomes of interest, including atherosclerotic disease, coronary events, stroke, and cardiovascular death. Studies that lacked clinical outcomes or that involved animals were excluded. We included primary and secondary prevention studies of subjects in all ethnic groups and of either sex, with no age limitation. We searched MEDLINE, Google Scholar, and the Cochrane Library for studies with publication dates from January 1970 through July 2009, and we searched major cardiology meeting abstracts from 2000 through 2009. From each study, we used predictive ability-including relative risk, hazard ratio, odds ratio, and prevalence of high Lp-PLA(2) levels, with adjustment-along with baseline population characteristics.Of 33 studies that met our inclusion criteria, 30 showed a significant association between Lp-PLA(2) and cardiovascular events. Most of the studies had been adjusted for major Framingham risk factors and other variables that might influence the effect under question. After multivariate adjustments in cohort and nested case-control studies, increased levels of Lp PLA(2) remained a significant predictor of cardiovascular events. The available body of evidence suggests that Lp-PLA(2) is a reliable marker of risk for cardiovascular events. PMID- 20200625 TI - Inflammation, high-sensitivity C-reactive protein, and vascular protection. PMID- 20200626 TI - Variation in high-sensitivity C-reactive protein levels over 24 hours in patients with stable coronary artery disease. AB - Limited, controversial data exist regarding changes in high-sensitivity C reactive protein (hs-CRP) levels over short times and the importance of detecting these changes in patients who have coronary artery disease (CAD). We investigated the variation of hs-CRP levels and their association with the severity of CAD in patients with stable CAD.We measured morning, midday, evening, and midnight hs CRP levels in 124 patients (94 with CAD, 30 with normal coronary arteries), who were evaluated via coronary angiography and Gensini scoring. Patients were divided into 3 groups (normal coronary arteries, mild CAD, or severe CAD) according to Gensini score.Temporal hs-CRP levels varied significantly--the highest mean concentrations were found in the morning, and the lowest concentrations at midday (P <0.001). All temporal hs-CRP measurements and the absolute increase in hs-CRP levels were significantly higher in patients with severe CAD (both P <0.001). The most significant predictors of CAD severity were age (P=0.005), midday hs-CRP level (P <0.001), and brain natriuretic peptide level (P=0.045). Receiver operating characteristic curve analysis showed that cutoff values of hs-CRP taken at different times predicted severe CAD with similar sensitivity and specificity. Different cutoff values for temporal hs-CRP levels correlated with the severity of CAD. Serum levels of hs-CRP varied over 24 hours, whether patients had CAD or normal coronary arteries. PMID- 20200627 TI - Impact of C-reactive protein on in-stent restenosis: a meta-analysis. AB - We sought to evaluate the impact of C-reactive protein (CRP) levels on in-stent restenosis after percutaneous coronary intervention.The plasma level of CRP is considered a risk predictor for cardiovascular diseases. However, the relationship between CRP and in-stent restenosis has been a matter of controversy. Meta-analysis reduces variability and better evaluates the correlation.We performed a systemic search for literature published in March 2008 and earlier, using MEDLINE(R), the Cochrane clinical trials database, and EMBASE(R). We also scanned relevant reference lists and hand-searched all review articles or abstracts from conference reports on this topic. Of the 245 studies that we initially searched, we chose 9 prospective observational studies (1,062 patients).Overall, CRP concentration was higher in patients who experienced in stent restenosis. The weighted mean difference in CRP levels between the patients with in-stent restenosis and those without was 1.67, and the Z-score for overall effect was 2.12 (P=0.03). Our subgroup analysis that compared patients with stable and unstable angina showed a weighted mean difference in the CRP levels of 2.22 between the patients with and without in-stent restenosis, and the Z-score for overall effect was 2.23 (P=0.03) in 5 studies of unstable-angina patients. There was no significance in 4 studies of stable-angina patients.In spite of significant heterogeneity across the studies, our meta-analysis suggests that preprocedurally elevated levels of CRP are associated with greater in-stent restenosis after stenting and that this impact appears more prominent in unstable angina patients. PMID- 20200628 TI - Non-gadolinium-enhanced 3-dimensional magnetic resonance angiography for the evaluation of thoracic aortic disease: a preliminary experience. AB - We compared image quality and diagnostic accuracy of a noncontrast 3-dimensional magnetic resonance angiography (NC-MRA) technique (balanced steady-state free precession sequence) to contrast-enhanced MRA (CE-MRA) for evaluation of thoracic aortic disease.The CE-MRA provides 3-dimensional high-resolution images of the thoracic aorta that are important in the evaluation of patients with aortic disease. However, recent concerns with the potential nephrotoxic effects of gadolinium contrast medium limit the application of CE-MRA for patients who have significant renal insufficiency.Twenty-one patients (mean age, 51 yr; 18 men) who underwent NC-MRA and CE-MRA for evaluation of thoracic aortic disease were retrospectively identified. Data sets were reviewed by 2 readers who were blinded to the patients' information. The thoracic aorta was divided into 5 segments. Image quality and reader confidence for diagnosis of aortic pathology were rated on 5-point scales. The Wilcoxon matched-pairs signed rank test and the Student t test were used for comparisons.The NC-MRA identified all pathologic findings with 100% diagnostic accuracy and similar reader confidence, when compared with CE MRA. Although overall image quality was not significantly different, superior image quality was observed at the aortic root (4.4 +/- 0.8 vs 3.2 +/- 0.9, P <0.0005) and ascending aorta (4.1 +/- 1 vs 3.7 +/- 0.9, P=0.05) respectively.In conclusion, NC-MRA is a useful alternative for evaluation and follow-up of thoracic aortic disease, especially for patients with poor intravenous access or contraindications to gadolinium use. PMID- 20200629 TI - Hypothyroidism and renal function in patients with systolic heart failure. AB - The extent to which hypothyroidism affects renal function in patients with heart failure remains incompletely explored, despite the known adverse prognostic implications of renal dysfunction in these patients.In a pilot retrospective study, we evaluated 75 patients (age, >or=18 yr) with left ventricular ejection fractions <0.40. Forty-five patients had normal thyroid function (thyroid stimulating hormone [TSH], 0.35-5.5 micro IU/mL) and 30 had hypothyroidism. The group with hypothyroidism was subdivided into 17 patients who had controlled hypothyroidism (TSH, 0.35-5.5 micro IU/mL) and 13 who had uncontrolled hypothyroidism (TSH, >5.5 micro IU/mL). Renal function, measured in terms of glomerular filtration rate, was analyzed once in each patient, and the populations were statistically compared, with P <0.05 conferring statistical significance.Baseline characteristics in all groups were similar. Mean glomerular filtration rate was better in patients with normal thyroid function than those with hypothyroidism (75.45 +/- 31.48 vs 63.95 +/- 21.43 mL/min/1.73 m2; P=0.032). There was no significant difference between patients with controlled hypothyroidism (66.89 +/- 24.18 mL/min/1.73 m2) and those with normal thyroid function (P=0.131). In patients with uncontrolled hypothyroidism, mean glomerular filtration rate (60.2 +/- 17.4 mL/min/1.73 m2) was significantly worse than in patients with normal thyroid function (P=0.015).We found that heart-failure patients with insufficiently treated hypothyroidism have worse renal function than do patients whose thyroid function is normal or whose hypothyroidism is effectively treated. Larger studies will be needed in order to evaluate this conclusion further. We recommend that hypothyroidism in heart-failure patients be strictly controlled, lest it affect prognosis adversely. PMID- 20200630 TI - Retroperitoneal approach via paramedian incision for aortoiliac occlusive disease. AB - Aortoiliac occlusive disease is a frequently encountered occlusive arterial disease. Different surgical approaches to the infrarenal abdominal aorta have been reported. We retrospectively studied the postoperative outcomes of patients who were treated for aortoiliac occlusive disease via a retroperitoneal versus a transperitoneal surgical approach.From January 2005 through May 2009, 47 patients underwent surgery at our hospital for the correction of aortoiliac occlusive disease: 30 via a paramedian incision and retroperitoneal approach, and 17 via a midline sternotomy and transperitoneal approach. In the retroperitoneal group, the surgical procedures involved iliofemoral bypass in 15 patients, aortofemoral bypass in 12, aortoiliac bypass in 2, and aortobifemoral bypass in 1. All 17 patients in the transperitoneal group underwent aortobifemoral bypass. The preoperative characteristics and perioperative data of the patients were analyzed. We believe that the retroperitoneal aortoiliac approach with a paramedian incision may be considered as a surgical option for aortoiliac revascularization. PMID- 20200631 TI - Myocardial protection during reoperative cardiac surgery: early experience with a new technique. AB - We recently introduced a new adjunct to myocardial preservation in patients with a patent left internal mammary artery graft who were undergoing reoperative cardiac surgery. The purpose of this study was to review our early experience with this technique.The technique consists of preoperative insertion of a suitably sized angioplasty balloon catheter into the proximal part of the graft under fluoroscopic guidance. Intraoperative inflation of the balloon results in occlusion of the graft during aortic cross-clamping. We have used this technique in 9 patients. The case records of these patients were retrospectively reviewed. There were 5 men and 4 women with a mean age of 71 +/- 11 years and a mean Euro SCORE of 10 +/- 3. The median time interval from previous cardiac operation to reoperation was 6 years (interquartile range, 2-11 yr). After the balloon catheter was inserted successfully into the left internal mammary artery graft, the balloon was inflated intraoperatively for successful occlusion of the graft in all patients. There was no in-hospital death, and no significant complications were observed.The early results of this technique seem favorable. A prospective randomized study is needed in order to evaluate the potential advantages of this method over other techniques of myocardial protection during cardiac reoperations. PMID- 20200632 TI - Valve-sparing aortic root replacement and tricuspidization in a patient with an asymmetric bicuspid aortic valve. AB - Aortic valve replacement is the standard surgical procedure for severe aortic regurgitation. Due to advances over the past decade, there have been substantial improvements in aortic root graft design, in aortic valve repair techniques, and in the understanding of valvular function in the remodeled aortic root. Herein, we describe the case of a dyspneic patient with an asymmetric bicuspid aortic valve who underwent valve-sparing aortic root replacement and tricuspidization. The patient subsequently resumed strenuous physical activity and was asymptomatic 2 years after the operation. PMID- 20200633 TI - Pericardial fat necrosis: a review and update. AB - A previously healthy middle-aged person presents with excruciating left-sided chest pain of 6 hours' duration. The pain has come on abruptly, without warning, and is located in the lower part of the chest anteriorly. It radiates to the neck and left shoulder and worsens on deep inspiration. The patient appears seriously ill, with tachypnea, tachycardia, and diaphoresis. Otherwise, the physical examination is unremarkable. The electrocardiogram shows sinus tachycardia. Results of conventional blood studies and the chest radiograph are within normal limits. Three days later, a follow-up chest radiograph shows a 3.5 x 4-cm mass adjacent to the left side of the heart near the diaphragm. PMID- 20200634 TI - Takotsubo cardiomyopathy: what is behind the octopus trap? PMID- 20200635 TI - Atypical transient stress-induced cardiomyopathies with an inverted Takotsubo pattern in sepsis and in the postpartal state. AB - Several cases of inverted Takotsubo cardiomyopathy--a variant form with hyperdynamic left ventricular apex and akinesia of the left ventricular base and mid-portion--have been reported recently, especially in association with cerebrovascular accidents and catecholamine cardiomyopathies. Herein, we describe 2 cases of inverted Takotsubo cardiomyopathy: one that occurred in a middle-aged woman who had a septic condition, and another in a young woman who was in the postpartal state. Such cases have not been reported previously. PMID- 20200636 TI - Use of an active-fixation coronary sinus lead to implant a biventricular pacemaker via the femoral vein. AB - Cardiac resynchronization therapy, which involves the placement of a pacing lead in the right atrium and in each ventricle, is effective in treating heart failure that is caused by left bundle branch block and cardiomyopathy. The left ventricular lead is usually placed into a lateral branch of the coronary sinus via the subclavian route. When the subclavian route is unavailable, insertion of a standard, passive-fixation coronary sinus lead via the femoral approach is feasible; however, the likelihood of subsequent dislodgment is high. Herein, we describe the placement of a novel, self-retaining, active-fixation coronary sinus lead--the Attain StarFix Model 4195 OTW Lead--in an elderly heart-failure patient, via the femoral approach. We believe that this is the 1st report of this procedure. PMID- 20200637 TI - Extrinsic compression of the left coronary ostium by the pulmonary trunk: management in a case of Eisenmenger syndrome. AB - Extrinsic compression of the left main coronary artery by a massively dilated pulmonary artery in patients who have severe pulmonary hypertension can lead to significant myocardial ischemia. A 58-year-old man with a large patent ductus arteriosus and Eisenmenger syndrome presented with angina at rest and worsening heart failure of 3 months' duration. The new symptoms were recognized to be secondary to extrinsic compression of the left main coronary artery ostium by a dilated main pulmonary artery and were successfully relieved by the placement of a metallic stent in the affected segment of the left main coronary artery. Multislice computed tomographic imaging after 6 months showed stent patency and the intimate relation of the stented vessel to the dilated main pulmonary trunk. We discuss diagnostic and management issues pertaining to this uncommon clinical entity. PMID- 20200638 TI - Pulmonary stenosis as a predisposing factor for infective endocarditis in a patient with Noonan syndrome. AB - Noonan syndrome is an autosomal dominant dysmorphic syndrome. Pulmonary stenosis is the most common cardiac anomaly in Noonan patients, with an incidence of 60%. A 9-year-old girl was referred to our institution with pericardial effusion. Transthoracic echocardiography indeed confirmed massive pericardial effusion and revealed, further, valvular and arterial pulmonary vegetations that accompanied a dysplastic tricuspid pulmonary valve. We decided to perform emergency pericardial tube drainage and to continue the anti-biotic regimen for 2 more weeks before undertaking open-heart surgery. After 2 weeks, the patient underwent an operation wherein the valvular vegetations were excised and a pulmonary valve commissurotomy was performed, yielding a competent pulmonary valve with 3 distinct but moderately dysplastic cusps. In addition to the pulmonary valve, the main, left, and right pulmonary arteries were filled with mobile vegetations, which were removed during the procedure. In this patient, a dysplastic and stenotic pulmonary valve may have contributed to the progression of endocarditis and to the growth of vegetations that occupied the pulmonary arteries. In conclusion, we hypothesize that although pulmonary stenosis is not considered a common predisposing factor for infective endocarditis, it can contribute to the progression of infective endocarditis in Noonan patients. PMID- 20200639 TI - Atrial septal hematoma: after minimally invasive aortic valve replacement. AB - Interatrial septal hematoma is a very rare complication after mitral valve surgery. Unusually, it is the result of aortic valve disease, including aortic dissection. We report a case wherein interatrial septal hematoma followed minimally invasive aortic valve replacement in a 68-year-old woman. The hematoma was recognized upon intraoperative transesophageal echocardiography, but there was no evidence of accompanying aortic dissection. The interatrial septal hematoma was at first drained by needle, but recurrence prompted reoperation and plication of the interatrial septum. Finally, the hematoma resolved after correction of the coagulopathy. Catheter injury to the coronary sinus exacerbated by the retrograde administration of cardioplegic solution is thought to have caused the origin of the interatrial septal dissection. PMID- 20200640 TI - Percutaneous balloon mitral valvulotomy and coexisting left atrial hemangioma: case report and long-term follow-up. AB - Hemangiomas of the heart are extremely rare. The prognosis is quite variable, because this benign tumor may grow, involute, or stop growing; therefore, resection is usually the treatment of choice. In patients with tumors of the left atrium, percutaneous balloon mitral valvulotomy is generally contraindicated. Yet for patients with moderate-to-severe mitral valve stenosis, balloon valvulotomy is an established therapy. Herein, we present the case of a 73-year-old woman who was referred to our department in 1995 with severe mitral valve stenosis. Echocardiography showed a valve orifice area of 0.9 cm2, according to Gorlin's formula, and a mean pressure gradient of 11 mmHg. Surgical therapy was declined by the patient. There were no signs of coronary artery disease. The injection of contrast medium into the left coronary artery showed a hemangioma at the posterior wall of the left atrium. Magnetic resonance imaging and transesophageal echocardiography confirmed the diagnosis. Despite the increased risk posed by the hemangioma, we performed successful percutaneous balloon mitral valvulotomy with an Inoue balloon. We saw the patient in 2001, and again in 2008 when she was 86 years of age. She was in excellent condition, with no signs of relevant dyspnea. Magnetic resonance imaging showed the size of the hemangioma to be stable. By use of echocardiography, we were able to confirm a good long-term result of the balloon valvulotomy. In this patient, a nonsurgical approach was adequate because of the lack of growth of the hemangioma in the left atrium. PMID- 20200641 TI - Vanishing platelets: rapid and extreme tirofiban-induced thrombocytopenia after percutaneous coronary intervention for acute myocardial infarction. AB - Glycoprotein IIb/IIIa inhibitors are established treatment for patients who develop acute coronary syndromes. Thrombocytopenia is known to occur following the administration of various drugs, including heparin and glycoprotein IIb/IIIa inhibitors. In the case of glycoprotein IIb/IIIa inhibitors, the mechanism is thought to be drug-dependent antibodies. In most cases, the thrombocytopenia is mild or moderate in severity. Severe thrombocytopenia (platelet count, <50 x 10(9)/L) is distinctly rare. Herein, we report a case of tirofiban-induced thrombocytopenia in which the overall platelet count dropped precipitously to <1 x 10(9)/L within 12 hours of administration; recovery was relatively prolonged, possibly owing to concomitant renal insufficiency. The severity and the rapidity of onset emphasize the need to routinely check platelet counts early after tirofiban administration, in order to prevent sequelae. PMID- 20200642 TI - Pre- and postoperative evaluation of partial anomalous pulmonary venous return: by 3-dimensional cardiovascular magnetic resonance imaging and cardiovascular computed tomography. AB - The pre- and postoperative evaluation of anomalous pulmonary venous return usually requires multiple invasive and noninvasive tests in order to obtain complete anatomic and functional data. Conversely, in a single setting, either cardiovascular magnetic resonance imaging or cardiovascular computed tomography can sufficiently reveal this information in adult patients. Herein, we present the cases of 2 patients with partial anomalous pulmonary venous return who underwent preoperative and postoperative evaluation by either method alone, and we discuss the benefits and limitations of each technique. PMID- 20200643 TI - Surgicel packing and an erroneous diagnosis of mediastinitis in a neonate. AB - Internal accumulation of the topical hemostatic agent Surgicel can mimic fluid collections that might be misdiagnosed as an abscess or a hematoma upon 3 common postoperative imaging methods. Herein, we report the unusual case of a neonate who underwent surgical repair of complex congenital heart conditions and then required early re-exploration, prompted by initial suspicion of mediastinitis on the basis of computed tomographic findings. During reoperation, it was determined that the mass on computed tomography was an accumulation of oxidized Surgicel. We discuss the capabilities and limitations of various imaging methods in the achievement of an accurate differential diagnosis. PMID- 20200644 TI - Papillary fibroelastoma of the interventricular septum: mimicking a cardiac myxoma. AB - Papillary fibroelastomas are benign cardiac tumors that involve cardiac valves. These tumors are usually asymptomatic and are found incidentally during cardiac surgery or during echocardiographic evaluation in a patient who exhibits cardiac symptoms. However, these tumors may cause major thromboembolic complications. Herein, we describe the surgical management of a patient who had an unusual appearance and location of a papillary fibroelastoma that was attached to the interventricular septum. PMID- 20200645 TI - Peripheral arteriovenous fistula after coronary stenting. PMID- 20200646 TI - Catastrophic right ventricular rupture prevented by coincident coronary artery bypass grafting: the pivotal role of cardiac magnetic resonance imaging. PMID- 20200647 TI - Left atrial myxoma as a cause of acute myocardial infarction. PMID- 20200648 TI - Bilateral coronary artery fistulae to main pulmonary artery: discovered incidentally upon multidetector-row computed tomography. PMID- 20200649 TI - Giant aneurysm of the left atrial appendage: detected by real-time 3-dimensional echocardiography. PMID- 20200650 TI - Spontaneous dissection of left anterior descending coronary artery in a young man. PMID- 20200651 TI - The twiddling Andersen. PMID- 20200652 TI - Interrupted aortic arch and aortic coarctation: two similar entities. PMID- 20200654 TI - Human intestinal spirochetosis--a review. AB - Human intestinal spirochetosis (IS) is a condition defined histologically by the presence of spirochetal microorganisms attached to the apical cell membrane of the colorectal epithelium. Intestinal spirochetes comprise a heterogeneous group of bacteria. In humans, Brachyspira aalborgi and Brachyspira pilosicoli predominate. Prevalence rates of IS are low where living standards are high, in contrast to poorly developed areas where IS is common. Homosexuals and HIV infected individuals are at high risk of being colonized. Clinical significance in individual cases has remained unclear up to now. A review of the literature assumes that invasion of spirochetes beyond the surface epithelium may be associated with gastrointestinal symptoms which respond to antibiotic treatment (metronidazole), whereas individuals lacking this feature may be mostly asymptomatic. Of unknown reason, homosexual and HIV-positive men as well as children are more likely to be symptomatic irrespective of invasion. Rare cases of spirochetemia and multiple organ failure have been reported in critically ill patients with IS. PMID- 20200656 TI - Total laparoscopic hysterectomy with obliterated anterior cul-de-sac. AB - Endometriosis may in severe cases lead to obliteration of the anterior and/or posterior cul-de-sacs in the female pelvis. The anterior cul-de-sac is generally less commonly affected. This type of cases usually presents a challenge for the operating surgeon, whether via open route or through laparoscopy. In this paper, we present an illustrative case and explain our technique for dealing with a scarred and totally obliterated anterior cul-de-sac because of endometriosis during total laparoscopic hysterectomy. PMID- 20200657 TI - Histopathological and cytological diagnostics: a view from Russia. AB - In the former Soviet Union, pathologists usually do not examine cytological specimens. Cytology belongs to another field of practice: laboratory medicine. Not all cytologists find enough time to compare their reports with histopathological ones, while histological and cytological specimens are hardly ever confronted; this opportunity of quality control is therefore lost. There are no nationwide programs of cervical cancer prevention. There are almost no laboratory technicians for screening of cytological smears. Overall, there are grounds for optimism: the improved economy makes it possible today to acquire modern equipment and literature, while broadening international co-operation is already attracting foreign expertise into the country. PMID- 20200658 TI - Age differences in alcohol drinking patterns among Norwegian and German hospital doctors--a study based on national samples. AB - AIMS: To describe and discuss the alcohol drinking patterns of the younger generation of hospital doctors in Norway and Germany - respectively the abstainers, frequent drinkers, episodic heavy drinkers and hazardous drinkers. METHODS: Data were collected in nationwide postal surveys among doctors in Norway (2000) and Germany (2006). A representative sample of 1898 German and 602 Norwegian hospital doctors aged 27-65 years were included in the analyses (N=2500). Alcohol drinking patterns were measured using the first three items of AUDIT in Norway and the AUDIT-C in Germany, scores of >or=5 (ranking from 0 to 12) indicating hazardous drinking. Episodic heavy drinking was defined by the intake of >or=60 g of ethanol, on one occasion, at least once a week. Frequent drinkers were who drank alcoholic beverages at least twice a week. Abstainers were persons who drank no alcohol. The analyses were performed separately for age groups (27-44 years versus 45-65 years) and genders. RESULTS: Compared to the age groups 45 to 65 years in the Norwegian and German samples, the younger age groups (27-44 years) tend to have higher rates of abstainers, higher rates of infrequent drinking of moderate amount of alcoholic drinks, lower rates of episodic heavy drinking and lower rates of hazardous drinking. CONCLUSION: The younger generation of hospital doctors in Norway and Germany showed tendencies to healthier drinking habits. Changes in professional life, and in the attitude towards alcohol consumption, may go some way towards explaining these findings. PMID- 20200659 TI - First experiences in the implementation of biometric technology to link data from Health and Demographic Surveillance Systems with health facility data. AB - BACKGROUND: In developing countries, Health and Demographic Surveillance Systems (HDSSs) provide a framework for tracking demographic and health dynamics over time in a defined geographical area. Many HDSSs co-exist with facility-based data sources in the form of Health Management Information Systems (HMIS). Integrating both data sources through reliable record linkage could provide both numerator and denominator populations to estimate disease prevalence and incidence rates in the population and enable determination of accurate health service coverage. OBJECTIVE: To measure the acceptability and performance of fingerprint biometrics to identify individuals in demographic surveillance populations and those attending health care facilities serving the surveillance populations. METHODOLOGY: Two HDSS sites used fingerprint biometrics for patient and/or surveillance population participant identification. The proportion of individuals for whom a fingerprint could be successfully enrolled were characterised in terms of age and sex. RESULTS: Adult (18-65 years) fingerprint enrolment rates varied between 94.1% (95% CI 93.6-94.5) for facility-based fingerprint data collection at the Africa Centre site to 96.7% (95% CI 95.9-97.6) for population-based fingerprint data collection at the Agincourt site. Fingerprint enrolment rates in children under 1 year old (Africa Centre site) were only 55.1% (95% CI 52.7 57.4). By age 5, child fingerprint enrolment rates were comparable to those of adults. CONCLUSION: This work demonstrates the feasibility of fingerprint-based individual identification for population-based research in developing countries. Record linkage between demographic surveillance population databases and health care facility data based on biometric identification systems would allow for a more comprehensive evaluation of population health, including the ability to study health service utilisation from a population perspective, rather than the more restrictive health service perspective. PMID- 20200660 TI - Violence against women in relation to literacy and area of residence in Ethiopia. AB - OBJECTIVE: This study explores violence against women in a low-income setting in relation to residency and literacy. SETTING: The study was conducted within the Butajira Rural Health Programme (a Health and Demographic Surveillance Site), which includes rural and semi-urban settings in south-central Ethiopia. DESIGN: This is a community-based cross-sectional study and is part of the WHO Women's Health and Life Events multi-country study. It included 1,994 randomly selected married women. METHODS: A standardised WHO questionnaire was used to measure physical violence, residency, literacy of the woman and her spouse, and attitudes of women about gender roles and violence. Analyses present prevalence with 95% confidence intervals and odds ratios derived from bivariate and multivariate logistic regression models. RESULTS: In urban and rural areas of the study area, the women were of varying ages, had varying levels of literacy and had spouses with varying levels of literacy. Women in the overall study area had beliefs and norms favouring violence against women, and women living in rural communities and illiterate women were more likely to accept such attitudes. In general, violence against women was more prevalent in rural communities. In particular, violence against rural literate women and rural women who married a literate spouse was more prevalent. Literate rural women who were married to an illiterate spouse had the highest odds (Adj. OR = 3.4; 95% CI: 1.7-6.9) of experiencing physical violence by an intimate partner. CONCLUSION: Semi-urban lifestyle and literacy promote changes in attitudes and norms against intimate partner violence; however, within the rural lifestyle, literate women married to illiterate husbands were exposed to the highest risks of violence. PMID- 20200655 TI - Evidence and consensus-based German guidelines for the management of analgesia, sedation and delirium in intensive care--short version. AB - Targeted monitoring of analgesia, sedation and delirium, as well as their appropriate management in critically ill patients is a standard of care in intensive care medicine. With the undisputed advantages of goal-oriented therapy established, there was a need to develop our own guidelines on analgesia and sedation in intensive care in Germany and these were published as 2(nd) Generation Guidelines in 2005. Through the dissemination of these guidelines in 2006, use of monitoring was shown to have improved from 8 to 51% and the use of protocol-based approaches increased to 46% (from 21%). Between 2006-2009, the existing guidelines from the DGAI (Deutsche Gesellschaft fur Anasthesiologie und Intensivmedizin) and DIVI (Deutsche Interdisziplinare Vereinigung fur Intensiv- und Notfallmedizin) were developed into 3(rd) Generation Guidelines for the securing and optimization of quality of analgesia, sedation and delirium management in the intensive care unit (ICU). In collaboration with another 10 professional societies, the literature has been reviewed using the criteria of the Oxford Center of Evidence Based Medicine. Using data from 671 reference works, text, diagrams and recommendations were drawn up. In the recommendations, Grade "A" (very strong recommendation), Grade "B" (strong recommendation) and Grade "0" (open recommendation) were agreed. As a result of this process we now have an interdisciplinary and consensus-based set of 3(rd) Generation Guidelines that take into account all critically illness patient populations. The use of protocols for analgesia, sedation and treatment of delirium are repeatedly demonstrated. These guidelines offer treatment recommendations for the ICU team. The implementation of scores and protocols into routine ICU practice is necessary for their success. PMID- 20200661 TI - Rehabilitation Programs for Cystic Fibrosis - View from a CF Center. AB - BACKGROUND: Rehabilitation programs are comprehensive interventions which effectively improve the health status and reduce costs in chronic respiratory illnesses. Because patients with cystic fibrosis have been discouraged to participate for concerns of microbial cross infection, the efficacy of systematic rehabilitation is unknown for this group. METHODS: We retrospectively studied 142 cystic fibrosis patients aged 2-46 years who participated in rehabilitation programs taking place in Germany/Switzerland and in Israel, focusing on changes in lung function and weight. RESULTS: During 172 stays in 97 patients in Israel and 68 stays in 45 patients rehabilitating in Germany/Switzerland, overall lung function and weight improved. Outcome did not differ between Israel and German/Swiss sites. Interestingly, lung function improved during the initial phase of the stay, whereas weight gain was sustained throughout. The study uncovered gaps in reporting sufficient individual outcome information back to the admitting centre. CONCLUSIONS: Rehabilitation programs specified for cystic fibrosis patients need to be assessed prospectively to optimize treatment of this life limiting condition. PMID- 20200662 TI - The influence of hand hygiene prior to insertion of peripheral venous catheters on the incidence of complications. AB - Using two studies of a simple design it has been possible to furnish proof of the influence of hand hygiene prior to insertion of peripheral venous catheters on the incidence of complications. In the first study detailed data were collected anonymously for each patient on the procedure used for catheter insertion or on any complications. Data were collected for around 64% of patients in one hospital. Evaluation of the questionnaires revealed that there was a significant increase in the incidence of complications in line with an increasing duration of the indwelling period of between 24 and 96 hours. The unexpected finding of this evaluation study was that in the case of catheters with an indwelling period of more than two days there were highly significantly lower complication rates in those cases in which hand disinfection was carried out or gloves donned before catheter placement. The second study, based on the former, documented the cases giving rise to complications. The proportion of peripheral venous catheters implicated in complications was 24%. Here, too, there was a sharp rise in the risk of complications in line with the duration of the indwelling period. Catheters placed in the OR during the patient's hospital stay showed a significantly lower risk of complications than those inserted on wards, or even in the outpatient department. Conductance of hygienic hand disinfection or the wearing of disposable gloves resulted in significantly lower complication rates compared to normal handwashing or omission of a hand hygiene measure. The most plausible explanation for this positive effect exerted by the wearing of disposable gloves or conductance of hygienic hand disinfection prior to catheter placement is that there was no recontamination during repalpation, as often seen, of the prepared venepuncture site. PMID- 20200663 TI - Evaluation of disinfectants - the past begets the future. AB - The efficacy of disinfectants is verified on the basis of the results of test methods that have undergone continuous change in line with new scientific insights. To begin with, the prime focus was on the relevance of practical measures: germ carriers were contaminated with, for example, the sputum of patients suffering from tuberculosis or with stools, while the data provided on the recoverable bacteria following exposure were very imprecise since they were based on subjective evaluation - using different methods for the various countries. With the development of the quantitative suspension test various factors of influence were analyzed for the first time and the concept of reduction factors with logarithmic units was introduced. Today, such insights are viewed as something to be taken for granted in all European and international standards. European standardization orchestrated by the European Commission received important impetus from one scientist: H. Reber. An important aspect here was that the European standards introduced and recognized in principle a separation of the methods into "in-vitro tests" and "tests conducted under everyday practice conditions". The increasingly more precise test methods have, on the other hand, soon revealed shortcomings in the disinfectant performance of even commonly used and hitherto accepted products. This gave rise to tests with a lower margin of error and with quantitative requirements. It is only by having a uniform overview that it is possible to detect and eliminate such shortcomings. The closure of several Hygiene Institutes at German and Austrian universities and the ongoing confinement of this discipline (infection control) to microbiology have additionally meant that already today there is a shortage of infection control experts who have a holistic view of matters and are able to spearhead further development of test methods. Without experts capable of taking a holistic view of matters, it will not be possible to create an atmosphere conducive to the development, and evaluation, of test methods, as needed for quality assurance. The less often disinfectants are evaluated by competent specialists, the greater is the risk that dangers are not recognized and countered. PMID- 20200664 TI - Food hygiene on the wards. AB - A PROBLEM THAT IS OFTEN OVERLOOKED OR SIMPLY NOT GIVEN ENOUGH ATTENTION: the food served to patients from the kitchen is not sterile. If food is allowed to stand at room temperature for a long time, both in the case of food cooked for lunch and of food intended for supper which has been previously chilled, there is the possibility of massive spore germination or of dangerous toxin formation. Therefore regulations on how to handle food and beverages (e.g. tea) must be set out in the infection control policy, and checks carried out to monitor compliance with the rules relating to temperature checks, duration and type of storage, need for reheating, etc. Making staff aware of the issues involved is of paramount importance. These include monitoring hygiene standards in the ward kitchen, formulation of a cleaning policy, periodic bacteriological checks (not only of workstations but also of the dishwasher results), whenever possible the use of disposable cloths for working surfaces and equipment, changing cleaning cloths at least once daily and hygienic hand disinfection before and after handing out food. Foodstuffs brought in by visitors represent a special hygienic and organizational problem because in many cases they already have a high baseline microbial count. Visitors must be made aware that, for example, slices of cake left in the patient's room and often eaten only hours later can pose a risk of infection.In summary, the following principles of food hygiene must be observed on the wards:Maintenance of the cold-hot chainNot only reheat food, but ensure it is well heated throughout Avoid situations giving rise to spore germination in foodstuffs brought in by visitorsCleanliness and minimal contamination of kitchen worktopsCleanliness of crockery and kitchen towels Do not allow food to stand at room temperature for a long time, in particular desserts and confectionery A standard policy must be enforced to define the hygienic status and organization for food distribution for ward kitchens too. PMID- 20200665 TI - Testing virucidal activity in Germany: an update. AB - Several chemical disinfectants have been tested in a quantitative suspension test for virucidal activity as per the test method devised by the German Society for Control of Viral Diseases (DVV) and the former German Federal Health Office (BGA, now the Robert Koch-Institute, RKI) drafted in 1982. The introduction of the term "limited virucidal activity" (effective against enveloped viruses) in addition to the existing term "virucidal activity" (effective against non-enveloped and enveloped viruses) by the Robert Koch Institute has led to enormous expansion of these tests. However, there are no definitions to determine when a disinfectant with virucidal activity as apposed to a disinfectant with limited virucidal activity is to be used. The 1982 guideline was recently revised, while bringing it into line to reflect the latest insights. The BSA challenge has been omitted, while other controls such as verification of the sustained effect and interference control with which cell susceptibility is verified have been incorporated. A new requirement is that all tests be conducted in at least two independent batches, followed by biometric evaluation of the test results with calculation of the 95% confidence interval. The new guideline differs from DIN EN 14476, which in the meantime has been published in Europe, in that it does not feature the statistics now required. This guideline has introduced the parvovirus for chemothermal inactivation as well as the Bovine Viral Diarrhea Virus (BVDV) as test virus for the limited virucidal activity (in addition to vaccinia virus which serves as a surrogate virus for hepatitis C virus - HCV). A second important example is Feline Calicivirus (FCV), which serves as a surrogate for noroviruses. In the USA efficacy testing of surface disinfectants against noroviruses is conducted with FCV in a carrier test (practice-related test). The third surrogate virus is the Duck Hepatitis B Virus (DHBV), used as a surrogate for hepatitis B virus (HBV). Today evaluation of the virus-inactivating properties is often conducted in parallel with bacteriological evaluation, so as to avoid any subsequent surprises in respect of viral efficacy. The DVV has failed over the past 24 years to formulate guidelines for practice-oriented tests. The future challenge is to define these as quickly as possible. Here similar approaches should be used for e.g. process challenge devices, challenge, exposure time as for bacteriological evaluation, so that the resultant application recommendations have equivalent status. The term "limited virucidal activity" should be expanded to disinfectant efficacy at European level. PMID- 20200666 TI - Prevention is in! Surveillance is out! AB - There has been a major change in the basic approach taken to hospital hygiene practices, and indeed to infection control within the hospital on the whole. Whereas as recently as the 1990s lectures on the topic of hand disinfection at international congresses were confined to "the periphery of the congress", today several keynote speakers address this issue with the full attention of the audience. This trend is also reflected in publications, and going beyond the domain of hand disinfection, has highlighted the important role of surface disinfection as well as of instrument disinfection in the prevention of nosocomial infections. The role of preventive as opposed to evidence-based hospital hygiene measures has for decades triggered lively discussions. The enormous rise in nosocomial infections due to antibiotic-resistant infections (MRSA, VRE, ESBL, etc.) will, no doubt, have made a significant contribution to bringing about a change in attitude. Even if of all the transmission channels implicated, the hands are the chief vehicles, there is in the meantime widespread evidence that contaminated instruments and surfaces can play a role in transmission. Surveillance is no doubt suitable for analyzing pathogenic transmission channels or shortcomings in infection control measures, but it is no substitute for the requisite preventive use of disinfection measures, since as a rule by the time the results of infectiology diagnostic measures are available, microbial spread will already have taken place. Prevention has had a long tradition in Germany and, in respect of infectious diseases, can be traced back to the 1880s (Robert Koch). It was therefore not surprising that it was Germany, where such efforts were initiated already in already in 1959, that began to formulate guidelines for efficacy testing of disinfection procedures. Since 1989 such guidelines have been compiled for the whole of Europe, thus assuring the preconditions for provision of high-quality disinfectants and, above all, for disinfection procedures whose efficacy has been verified. For the future it must be advocated that industry, on the one hand, will continue to develop more environmentally compatible disinfectants with broader spectra of action and that, on the other hand, the test methods for efficacy testing will be further improved in order to meet the requirements for efficacy testing of such agents. PMID- 20200667 TI - Reducing the health impact of infectious agents: the significance of preventive strategies. AB - Each year almost 15 million people die of infectious diseases and in all probability this figure is much higher, because in many cases infection is not at all recognized as being the cause of death or its contributory role is not known. There is an increase in the risks posed by infections; the belief in the omnipotence of drugs has not stood the test of time; rather, by adopting a counterstance we risk losing all that we accomplished during the last decades. After all, over the past 40 years we witnessed progress in the development of reliable and affordable anti-infectives and vaccines. As a result of this, today parents have their children vaccinated less often since they are no longer aware of the risks posed by lack of vaccination. This will give rise to the sudden reemergence of certain infectious diseases. And we overlook the fact that by observing basic rules of hygiene (hand hygiene; water decontamination; etc), we could save many lives on this earth. It is becoming increasingly more difficult to treat with antibiotics patients harboring resistant bacterial strains on their skin. Hospitals need surface disinfection to prevent microbes such as Clostridiium difficile or norovirus. The institutional use of alcohol-based hand disinfectants has by now become an accepted practice in North America. But some of these substances have dangerous side effects where humans and the environment are concerned. Our test methods are not always able to evaluate the actual extent of the risks posed.Prevention is accorded greater importance in view of the declining number of therapeutic measures available. But combating pathogenic microorganisms could, in turn, give rise to problems whose nature we cannot at all predict today. We need far greater knowledge of the pathogens and should be less naive when embracing new technologies, which only seem to solve problems. What will be the long-term implications if the increasing selective pressure exerted on these bacteria induces them to become more resistant?We need an effective combination of treatment and vaccination strategies, together with a consistent prevention policy. Unlike drugs and vaccinations, disinfectants can be used in a consistent manner; they can simultaneously eliminate a vast range of pathogenic microorganisms, without having any major side effects. PMID- 20200668 TI - "I wash my hands of it!?" - Trends in hand hygiene over the past decades. AB - Hand hygiene is the most important measure to protect against the spread of nosocomial infections. With the development of in vitro und in vivo test methods for evaluation of the effect of hand hygiene, there has been a sharp increase over the past 50 years in the body of knowledge relating to effective methods for removal from the hands or killing and inactivation of pathogens. In 1958 the German Society of Hygiene and Microbiology (DGHM) published a first "Guidelines for Testing Chemical Disinfectants" and included only those hand disinfection products on its "List of Tested Chemical Disinfectants Found To Be Effective" that had been tested as per the methods cited in the guidelines. The American Society of Testing and Materials (today: ASTM International) was next, with the first test protocols for hand disinfection products, which in 1974 were adopted by the US Food and Drug Agency as "Guidelines" in a "Tentative Final Monograph" (TFM) and in 1994, having revised it to incorporate new insights, it was published once again. Where the user is concerned, guidelines for hand disinfection containing information on indication and implementation are of course more important than methods dealing with efficacy testing of products. Such guidelines are compiled within the hospitals by the infection control teams set up during the 1970s. Written guidelines were also published by several healthcare institutions, scientific societies and associations. The guidelines formulated by the World Health Organisation (WHO), in an expert committee under the direction of Didier Pittet, proved to be the most successful of the attempts undertaken at global level to enhance hand hygiene. The most remarkable changes appear to be the efforts aimed at improving compliance among medical personnel and the increasing international acceptance of hand disinfection by using alcohols in the form of rubs; whether this will be with lotions or gels remains to be seen. PMID- 20200669 TI - Milestones in the testing of surface disinfectants: from Robert Koch to CEN TC 216. AB - The first publication on testing disinfection procedures dates back to 1881 and was compiled by Robert Koch. Although his conclusions were erroneous, we continue to use the "germ carrier test" right up to the present day even if preference is now given to the suspension test first devised by Geppert. Over the years many conceptual milestones had to be reached, and much knowledge and many insights were needed to develop this procedure further to ensure reproducible results. Today, the disinfectant effect is calculated in terms of logarithmic reduction factors for the microbial count: a reduction of 5 log levels has been agreed, i.e. an inactivation kinetics of 99.999%.Of paramount importance was, in particular, the insight that different methods had to be employed to test disinfectants, while doing so not only in the laboratory but also under everyday working conditions. This gave rise to a situation whereby each country developed its own test methods, producing significantly different results. It was only in 1970 that the parties concerned came together so as to reach a uniform solution in Europe. The achievements of the "International Colloquium" were later adopted and continued by the European Standardization Committee (CEN) in a special working group (TS 216). The most important accomplishment of this working group is, no doubt, the insight that it is not a testresult but rather a testsystem that will reveal the truth. The tests carried out in Phase 1 are quantitative suspension tests to elucidate the bactericidal, virucidal, tuberculocidal, fungicidal and sporicidal efficacy. Phase 2 defines the requisite concentration per exposure time. CEN was founded and is sponsored by industry, since the latter needs reliable standards. Time will tell whether this was not perhaps the greatest milestone in the development of test methods. However, the successes scored by CEN are ultimately only the logical consequence of the accomplishments already achieved by the "International Colloquium". In reality, most of the procedures that today have been accepted via TS 216 are based on the activities set in motion by the Colloquium. It is impossible to acknowledge just how pivotal was the role played by both legendary "International Colloquia" in 1970 and 1972 in Hamburg in the development of uniform test procedures. PMID- 20200670 TI - Forty years of control of healthcare-associated infections in Scandinavia. AB - In the early 60s the first specialists for hospital hygiene came on the scene in Scandinavia too. From the outset this new discipline was based on cooperation between doctors and nurses, with the support of hospital-based microbiology laboratories and of sterilization departments. Teaching programs were soon devised, with training being underpinned by manuals featuring working instructions. Automated washing facilities for bedpans, etc. or washing machines for medical instruments became widespread practice very quickly; these initially used hot water, and later steam, for disinfection. For many years now, this equipment is found not only in hospitals but in virtually all healthcare establishments too. This has considerably helped to reduce chemical disinfection of medical instruments. As regards disinfection of heat-sensitive instruments the Scandinavian countries adopted different approaches: Finland gave preference to ethylene oxide sterilization, while Sweden opted for lower temperatures and for formaldehyde (low-temperature, steam formaldehyde (LTSF) sterilization), a technique imported from England and further developed in Sweden. During the 70s there were several cases of hepatitis B infections contracted in hospitals, particularly in dialysis units and by hospital personnel. The requirement that gloves be worn when carrying out working procedures has resulted in a major decrease in the infection rate and has helped to prevent HIV (AIDS) infections. However, to date it has not been possible to offset the risk of bloodborne infection against latex intolerance. Infection statistics were introduced in the 80s and since the late 90s we, too, are waging battle (later than other countries) against resistant bacteria (MRSA, VRE, multi-resistant Gram-negative bacteria). For some years now we no longer use the term "hospital hygiene" either, using instead "infection in healthcare settings" in view of the extended fields of application. Whether our strategy has proved successful for prevention of infection? Who could give a clear answer to such a question? Cost pressures in the healthcare sector will have a negative effect on the infection rate despite the fact that the progress made by science should really bring about a reduction in this rate. This conjures up a situation analogous to that of a downward escalator that one is trying to ascend: it is as if one were not moving, not making any progress. PMID- 20200671 TI - Hygiene yesterday, today, tomorrow. AB - I began my career in 1945 by tracing the footsteps of the legendary Max von Pettenkofer and Robert Koch. At that time their influence was still discernible, and continues to be.The first major innovation was the introduction of antibiotics, which some people believed would now dispense with the need for disinfection and sterilization. The next major development was the introduction of hospital hygiene as a discipline in its own right, aimed at highlighting the growing risk of nosocomial infections, albeit also against the background of the, admittedly, brilliant but unceasingly innovative armamentarium of medical paraphernalia and fittings. As regards the pathogens, viruses were seen to play an increasingly more prominent role as nosocomial pathogens, giving rise to completely novel challenges and problems in the field of disinfection and sterilization. In 1956 at Prof. Pette's institute in Hamburg it generally took weeks to produce the results to diagnose poliomyelitis. Their value was immensely important for science - but their value to the doctor and patients was questionable. The introduction of inexpensive sterile disposable syringes and other disposable equipment represented, in my opinion, the next milestone. In the meantime, there was a dramatic increase in the overall constellation of problems caused by the continuing upsurge in antibiotic bacterial resistance. And with growing awareness of environmental issues, the late 60s set in motion a new avalanche where one had to strive not only to keep abreast of matters, but also to ensure that science continued to prevail as the highest instance. Today we are facing completely different, but in principle still similar problems in consolidating the status of disinfection and sterilization, e.g. when it comes to the ultra delicate devices that in some cases are heavily contaminated after routine clinical use. Hence we elderly infection control experts still have a task to accomplish: to issue warnings again and again against accepting as "fate" the unresolved problems, but instead to highlight the very core of the problem. Disinfection and sterilization is a topical issue and will always continue to be just that: to protect the population and patients, and to protect ourselves as well as personnel in hospitals, medical practice and research. PMID- 20200672 TI - Role of disinfection as infection prophylaxis over the course of time - anesthesia, intensive care and emergency medicine, pain therapy. AB - It is alarming that anesthetists, just as in earlier years, have been shown to be the specialists with the poorest rate of compliance with simple, basis everyday rules of hygiene. Unfortunately, infection prophylaxis is something to which the physician ascribes importance only when he sees the consequences of his actions, that is to say when he has to diagnose and treat infections in "his" patient as a result of his "failure" to adhere to infection control regulations. That infection control measures have not been taken at the bedside highlights the need for enlightenment and education of staff and serves as the basis for their involvement. Such measures can be taken much less easily in emergency medicine. The emergency physician / anesthetist is rarely confronted with the patient's outcome. Any errors in infection prophylaxis have no perceptible consequences. "The threat posed to vital functions does not allow any time," said the emergency doctor. "During the time elapsing from first administering the anesthetic until full narcosis is reached or in the case of intrasurgical bleeding, I'm feeling stressed and then have no time for hygiene" admits the anesthetist in the OR. To improve this situation, the root cause of ignorance and thoughtlessness as regards hygiene must be addressed. Apart from general training and continuing education for correct conductance of hygienic measures and regarding the consequences of failure to observe the guidelines, today the individual aspect of motivation must be addressed. Each professional administering treatment makes a difference for the patient through his individual approach to hygiene. Each head physician and medical director makes a difference to the behavior of future anesthetists by acting as a role model. And within the hospital system the factors "overburdened personnel and time pressure" as the cause of inappropriate infection control must be clarified. Today hygiene does not merely denote "clean working practices" and reduced patient morbidity. Today reduced infection rates mean reduced costs in the healthcare sector and hence reserves for the future care of the population. Today we know that hygienic practices when attending to the patient are not an onerous burden but that they pay off. We must "only" get around to implementing them. PMID- 20200673 TI - Disinfection for prevention and control of infections on the threshold of the 21 century for the critically ill patient. AB - In infectious diseases we can discern a cause and effect chain, which in particular offers the practicable perspectives of prophylaxis and treatment. However, to date we have not been able to control them. Apart from new epidemics, such as those caused by HIV and SARS, long-forgotten scourges like TB are enjoying a comeback. Furthermore, the advances made in clinical medicine mean that induced immunosuppression, for instance as a result of major surgery or organ transplantation, has become a serious problem in intensive care units. The body's natural barriers are breached through medical interventions while, on the other hand, immunocompromising therapeutic agents such as cytostacis and glucocorticoids ensure that invading microorganisms will be able to multiply. Drugs administered as stress ulcus prophylaxis give rise to a shift in the bacterial flora of the throat, thus laying the foundation for a lower respiratory tract infection. With regard to bacterial resistance, antibiotic therapy, especially when used as prophylaxis, results in the bacteria becoming less sensitive to the drugs, while reinforcing selective pressures. The hands of personnel as well as the therapeutic devices ranging from the respirator to the catheter are the chief sources of infection in intensive care units. Disinfection, antibiotic therapy and, possibly, extracorporeal elimination methods can be contemplated to selectively prevent the establishment and multiplication of microorganisms. However, only disinfectants are able to unleash their full destructive might against microbes, especially when used for medical devices that are not amenable to sterilization, even if their subsequent removal and, possibly, the issue of staff hand protection, can be a problem. While it is not easy to furnish proof of a direct link between efficient control and prevention methods and the incidence of infection, there is by now a consensus on the role of hand hygiene and of disinfection of the human body and of surfaces. In an age when medicine, in particular intensive care medicine, is at risk of becoming impaled on its own sword, disinfection could serve as a bulwark against rising infection rates. PMID- 20200674 TI - Role of disinfection in the Infection Prevention Multibarrier System. AB - The role of disinfection in infection prevention has been analyzed over the past 50 years both in the form of benefit-risk evaluations as well as in an epidemiological sense. This has served as the basis for not only national and international guidelines and recommendations, but has also created the legal and normative framework for regulation of infection control (and hence of disinfection) in numerous and acts and ordinances. Likewise, today the efficacy of disinfection measures, user safety and environmental compatibility in line with the state of the art are assured. Compliance as regards the conductance of disinfection measures has increased accordingly. The user is able to select and correctly employ the disinfectant most suited to the intended disinfection procedure. The quality of the apparatus used has vastly improved since the coming into force of the German Medical Devices Act (MPG). And finally the preconditions for conductance of disinfection have become so matter of fact that it is easy to forget just what progress has been made here. This applies e.g. to the facilities now available for hand hygiene, for decontamination of instruments, laundry and bedpans with washer-disinfectors as well as for surface disinfection and drinking water disinfection. But it is the human being who continues to pose the greatest risk. Risk awareness does not always result in proper action being taken: it is hard to really grasp something that one cannot experience. As such, hand disinfection is often dispensed with, and without any sense of having done something wrong, the debate about the evidence of the usefulness of floor disinfection continues, and often medical practitioners fail to resort to exclusive automated decontamination of medical devices because of the costs incurred. Hospitals, nursing homes and rehabilitation establishments are obliged to set up a quality management system, and to continue developing this. This calls for a quality assurance system regulating organizational procedures, responsibilities, workflow patterns for the entire domain of infection control within the hospital or medical practitioner's premises and outcome evaluation (microbiological monitoring, surveillance of nosocomial infections). An indispensable component of primary prevention is assurance of structural and process quality. In turn, disinfection is indispensable for assurance of process quality. PMID- 20200675 TI - A brief history of European harmonization of disinfectant testing - a Dutch view. AB - Since 1970 we know in Europe that, by engaging in intensive dialog and constructive cooperation it is possible to achieve a generally acceptable test procedure, despite the many divergent approaches taken by the different countries. When in 1966 I began my career as a microbiologist, different procedures were used in all countries to test the efficacy of disinfectants. The results of such tests did not at all lend themselves to comparison. One of the most important requirements to be addressed to a future, generally acceptable procedure was naturally that the results should be reproducible. To that effect, it was necessary to standardize all aspects of the test since even the slightest discrepancy could give rise to markedly different results. On the other hand, each specified detail had to be scientifically corroborated to prove acceptable to all parties. 1990 marked a major breakthrough towards harmonization of European disinfection test procedures with the founding of the "Chemical Disinfection and Antiseptics" (TC 216) working group within the framework of the "European Committee for Standardization (CEN). This served as a basis for Phase 1 (basic evaluation of the disinfectant effect or suspension tests under different conditions) and Phase 2 tests (tests on different surfaces under practice oriented conditions). The quantitative principle is now valid for both phases. Major investments were needed to bring about European harmonization. We Dutch, in particular, are well known for having our own opinions. But we, too, continued to engage in discussions and collaborations until we reached a consensus and learned to respect each other and even to become friends in some cases. TODAY, HARMONIZATION ENDEAVORS EXTEND WELL BEYOND EUROPE: with its biocide program, the OECD pesticides working group is working towards the development of a global test procedure for disinfectants. So we have not, by any means, reached the end of the road: there is still much to be accomplished by our successors: I am confident that we shall succeed, because no one - neither the manufacturers nor the authorities - can negate the knowledge base on which the European standards are founded. PMID- 20200676 TI - Hospital hygiene in an age of Diagnostic Related Groups (DRG), Protection against Infection Act (IfSG), Book V of the German Code of Social Law (SGB V) and administrative reforms - facts and visions from Bavaria. AB - Since 1 January 2001, German hospitals and establishments engaged in outpatient surgery are obliged to continually record and evaluate nosocomial infections and the emergence of nosocomial pathogens showing special resistance and multi resistance profiles. A survey conducted among 164 hospitals revealed that 79 % of establishments already carried out separate surveillance and evaluation of postoperative wound infections, while 77 % also recorded nosocomial infections and 91 % recorded pathogens with special resistance and multi-resistance profiles. However, only the larger hospitals had their own in-house infection control physician, while the smaller establishments generally consulted external infection control physicians. When asked how long such experts made their services available to the hospitals, no clear answer was given. Furthermore, only two-thirds of hospitals had their own infection control nurses (most of whom worked part time). These findings have induced the State Office for Health and Food Safety (LGL) in Bavaria to expand its advisory and information services and to formulate standards in consultation with partners at state level. The public health offices are legally obliged to supervise infection control policies in hospitals and medical establishments. These supervisory activities have not always been conducted in a uniform manner, thus engendering anxiety among the institutions to be supervised when it comes to discharging their prescribed duties. A concept devised to improve and standardize the monitoring of hospital hygiene is to be used to standardize supervision of infection control practices (by the statutory authorities). With the incorporation of the, hitherto, State Office for Occupational Safety, Occupational Medicine and Safety Engineering into the LGL, the specialist centers for public health and the Trade Supervisory Office will be united under one umbrella. The idea is to avail of the resulting improved cooperation possibilities, so as to avoid duplication of effort as regards the overlapping areas of medical and trade supervision and limit contradictory commentaries and avoid a situation whereby several public health officials have to pay visits to the various establishments. This will also reinforce partnerships between medical establishments and the public health authorities at local level. Some thirty years ago, while the present author could possibly dream of such an outcome when he took his first steps into the, at times arduous, terrain of hospital hygiene, he probably would not have dared to express it. PMID- 20200677 TI - Disinfection for infection prevention over the course of time. AB - In recent years and decades increasingly more emphasis has been placed on alcohol based solutions for hygienic and surgical hand disinfection. Traditional handwashing with soap and water has been largely replaced in the everyday clinical setting, as has the use of disinfectant soap-based solutions for surgical hand disinfection. It has been possible in recent years to reduce the exposure time for alcohol-based hand disinfection in surgery from 5 to 3 minutes, and there are plans to reduce this even further. The growing awareness of the tolerability issues has also given rise to favorable developments here. There have also been dramatic changes in preoperative skin disinfection. The non alcoholic solutions with a slow onset of action (e.g. iodophors) have been virtually replaced by alcohol-based solutions of demonstrated efficacy. Non alcoholic solutions continue to be used for disinfection of mucous membranes, but iodine-based products are being phased out here. The term "instrument disinfection" has been largely supplanted now by the expression "instrument reprocessing or medical device decontamination" (which is also underpinned by legislation) and it takes account of the trend towards thermal disinfection. Meticulous cleaning is thus an indispensable precondition for sterilization, which normally follows disinfection. The greatest lack of consensus at European level relates to surface disinfection. Routine, parallel cleaning and disinfection of all surfaces close to and remote from the patient is being increasingly replaced by selective disinfection, whenever warranted, of surfaces close to the patient. The problem here is that medical personnel continue to view cleaning and disinfection as interchangeable tasks. This situation is further compounded by the fact that hospitals are finding it increasingly more difficult to assure adequately successful cleaning and disinfection outcomes. To ensure effective infection control, cleaning and disinfection of surfaces in special situations must also be assured whenever warranted outside the regular working hours. Disinfection and decontamination of highly complex medical devices that pose special challenges (heat-sensitive devices with an intricate design and, correspondingly, with surfaces that are difficult to access, e.g. flexible endoscopes) will present the main challenge in the future. There is still much to be accomplished here to assure the hygienic safety of the patient. PMID- 20200678 TI - Testing and listing disinfectants - instrument and product of quality assurance. AB - In Germany, the Disinfectants Commission of the Association for Applied Hygiene (VAH) ensures that the user can avail of procedures that meet the stipulated quality requirements. These requirements are based on the tried and tested standard methods of the German Society of Hygiene and Microbiology (DGHM) as well as on European standards. They take account of the different requirements dictated by the various fields of application, reflecting the quality assurance system in a transparent manner. Special emphasis is increasingly placed on retesting the products already available on the market. In multi-center trials the inter- and intralaboratory fluctuations in the test results are ascertained, the quest for suitable standard substances intensified, culture conditions and detection procedures are standardized and the test procedures and potential influence factors analyzed in detail. The aim here is to devise test procedures that will yield a reproducible and reliable result independently of the test location, and meet the requirements of everyday practice. Attention must be paid to, inter alia, the prevailing microbial spectrum in quality and quantity, the prevailing organic and inorganic load as well as material and surface properties. The test procedures are gradually brought into line with the current stock of scientific knowledge, because such a task calls for conscientiousness, tenacity and patience as well as continuous dialog between research, industry and practice. Thanks to these joint efforts, we are increasingly better able to meet the demands made by intelligent and selective prophylactic disinfection. PMID- 20200680 TI - Divergent opinions on surface disinfection: myths or prevention? A review of the literature. AB - Virtually no prevention strategy in hospital hygiene has been the focus of such frequent controversial discussions as the role of surface disinfection. Set against that background, the Commission for Hospital Hygiene and Infection Prevention at the Robert Koch Institute founded a working group comprising members with divergent views of risk evaluation as regards the role of disinfection. This working group produced a most carefully drafted guideline on how to deal with various risk areas and also incorporated a new provision into the guideline, stating that: "Cleaning and disinfection procedures must be organized and implemented such that there is no increase in the microbial load or spread of facultatively pathogenic or pathogenic microorganisms on surfaces."Numerous studies have come to the conclusion that surface disinfection constitutes a basic infection control measure with which the spread of pathogens can be controlled. Conversely, when using only detergents such a form of control is not possible, something that must be taken into account in future when engaging in risk evaluation and formulating infection control measures. In view of the burgeoning trend in, for example, norovirus outbreaks, also in hospitals and nursing homes, such insights are of paramount importance and attest to the need for disinfection of surfaces and of areas with frequent hand and skin contacts. This discussion about the need for surface disinfection has, in addition to causing confusion among users, led to a decline in the willingness to accept hygienic practices, thus increasing the risk of occurrence of nosocomial infections as well as of antibiotic-resistant microorganisms. PMID- 20200679 TI - Virucidal agents in the eve of manorapid synergy. AB - Virucidal agents are chemical substances that attack and inactivate viral particles outside the cell (virions). In general this is accomplished by damaging their protein shells (capsid) or the substance penetrates the core itself, where it destroys the genetic material. Damage to the virion structure is also possible. These agents are used not only for traditional surface disinfection or sterilization of blood, blood products, and other medicinal products as well as in antiviral chemotherapy. They have also been used in recent times for inactivation of viruses in foodstuffs, detergents or cosmetics. Below is given an overview of the data currently available on the performance of these substances when used for the latter applications (cleaning and cosmetics). These include:hydrogen peroxide, hypochlorites, cupric and ferric ions, per acidsethanol, parachlorometaxylenol in a sodium C14-16 olefin sulfonate, glutaraldehyde, quaternary ammonium salts, chlorhexidine and chlorhexidine gluconate, curdline sulphate, glycerol, lipids, azodicarbonamide, cicloxolone sodium, dichlorisocyanuric acid (sodium salt), benzalkonium salts, disulfate benzamides and benzisothiazolones, congo red, ascorbic acid, nonoxynol-9, para aminobenzoic acid, bis(monosuccinamide) derivative of p,p'-bis(2-aminoethyl) diphenlyi-C60) (fullerene).merocyanine, benzoporphyrin derivative monoacid ring A, rose bengal, hypericin, hypocrellin A, anthraquinones extracted from plants, sulfonated anthraquinones and other anthraquinone derivativesGRAMICIDINE, GOSSYPOL, GARLIC (ALLIUM SATIVUM) EXTRACT AND ITS COMPONENTS: ajoene, diallyl thiosulfinate (allicin), allyl methyl thioulfinate, methyl allyl thiosulfinate, extracts of ledium, motherworth, celandine, black currant, coaberry and bilberry, extract of Cordia salicifolia, steam distillate from Houttuynia cordata (Saururaceae) and its component, 5,6,7-trimethoxyflavone from Calicarpa japonica, isoscullarein (5,7,8,4'-tetrahydroxyflavone) from Scutellaria baikalensis and isoscutellarein-8-methylether, alkaloids and phytosteryl ester compounds. PMID- 20200681 TI - EURIDIKI, a backward glance - or: how theory and practice came together. AB - The advent of intensive care medicine dates back some 40 years. The rising number of immunoincompetent patients who had to undergo intensive care treatment highlighted the need to focus on the serious problem of nosocomial infections. At that time not only did the majority of intensive care physicians have a lack of knowledge of the fundamentals of infectiology, but also there was also no behavioral guideline available. There were no recommendations available for infection prevention, or if they were they contradicted, in some cases to a considerable and confusing extent, existing guidelines.EURIDIKI, founded in 1979 by H.-J. Molitor in Vienna, was one of the first initiatives aimed at bringing together experts from the field of hospital hygiene and intensive care medicine. The declared goal was to formulate implementable behavioral rules for correct hygiene practices in intensive care units and to give doctors and nurses a sense of confidence when discharging their everyday duties. To assure effective prophylaxis against hospital infections, EURIDIKI believes that, based on its experiences, it is not only of clinical treatment principles that adequate knowledge is needed but also of the infection risks they pose. Doctors as well as assistant personnel must be conversant with disinfection and sterilization methods and indications. Likewise, experience is needed in diagnosis and differential diagnosis of infections, with associated immunological implications, microbiology, proper collection and transport of clinical samples (such as body secretions), including interpretation of microbiological and infection/immunological results. Of paramount importance is precise knowledge of antimicrobial chemotherapy, of dosages tailored to the respective case, of potential development of resistance and of other adverse side effects. On the other hand, the external infection control experts who are consulted by hospitals should be conversant with not only the priorities governing infection control rules, but must also know how to implement these. This means they must be familiar with the diagnostic and therapeutic principles and procedures underlying medical and nursing measures, bearing in mind the existing structural conditions and human resources availability. PMID- 20200682 TI - Infection control programs and nursing experts for hospital hygiene. AB - From the data he had collected, Ignaz Phillip Semmelweis drew the right conclusions and began using disinfectants for handwashing. And this at a time when it was not at all known that infections were caused by bacteria. While ridiculed by colleagues, the results achieved impressively attested to just how correct were his views: there was a demonstrable reduction in mortality rates among puerperae from some 20% to 3%, which was very low for that time. In the course of the 20(th) century "Surveillance" was introduced, entailing systematic recording, analysis and interpretation of nosocomial infection data, in several countries throughout the world. This helps identify infection problems and take appropriate preventive measures. But the ongoing trend of emergent infectious diseases and the development of antibiotic-resistant bacteria continue to pose new challenges for us: the microorganisms appear to be always one step ahead of us. During the 20(th) century the prevailing belief was that hand disinfection was the easiest, least expensive and most effective preventive measure to prevent the spread of microorganisms. In the 21(st) century compliance is the main focus of attention. We must devise novel motivational systems, tailored to the present day setting, to inculcate a sense of responsibility and ensure observance of hand hygiene regimens. Here, the infection control nurse plays a pivotal role. PMID- 20200683 TI - Infection control - delivering the message in the 21 century. AB - The experiences gleaned from new and suddenly emergent infectious diseases (e.g. SARS, avian influenza or diarrhea caused by Clostridium difficile) have highlighted how important it is, also for infection prophylaxis, to be able to find instruments for rapid and effective communication. Since 1990 online (E) learning has been used to train nursing staff and offers the advantage of being able to study at an individual pace as well as cut down on the time and financial resources needed. It serves to overcome geographic distances in respect of the teaching institution, can be used at any time of day according to individual needs and has proved suitable for presenting learning modules in infection prevention.No doubt, traditional didactic learning continues to be the most important approach, but new technologies such as "problem based learning" (PBL) are becoming more popular, and allow students to acquire knowledge in concrete situations. Translating knowledge into behavior calls for an ability to convert scientific theoretic knowledge quickly, efficiently and clearly into practical behavior. Hence E learning is an ideal way to ensure that the latter requirements are met. While it is obvious that knowledge can be easily imparted by this method, further research is needed to establish whether and to what extent it is possible to use this method to translate the acquired knowledge into altered behavior too. Experts believe that novel media technologies hold out several new prospects for accomplishing this. PMID- 20200684 TI - Antisepsis and genital hygiene in scrotal surgery: liability claims in the event of treatment errors. AB - Systematic observance of infection control principles in surgery, whether conducted on an inpatient or outpatient basis, is an indispensable precondition for quality management. In Germany, the introduction of the Protection against Infection Act (IfSG) on 1 January 2001 represented a milestone for regulation of the framework conditions in outpatient surgery. Once again, infection control issues were the main focus of attention. Section 36(1) IfSG stipulates that infection control policies specify in-house procedures for infection prophylaxis in agreement with quality assurance measures. On 1 January 2004 this was further reinforced, inter alia, by means of a new tripartite contract based on Section 115b of Book 5 of the German Code of Social Law (SGB V). Since experience shows that incidents are more likely to result in liability claims the smaller the operation and the more unexpected the complications from a lay person's perspective, surgery carried out on patients who spend the night before and after the operation outside the hospital or clinic is becoming a particularly liability prone area. In the event of a postoperative infection, often involving a protracted hospital stay and in some cases considerable permanent damage, the patient often cites an infection control error. This paper highlights by way of example some liability aspects whose observance as a matter of principle can reduce the liability risk for the physician. PMID- 20200685 TI - Adoption of alcohol hand disinfection in the United States: a personal perspective. AB - Even though alcohol-based hand disinfectants have been used for decades as a routine measure in Europe, in the USA until recently handwashing was the procedure of choice. Alcohol-based rub products were recommended only if no handwashing facility or running water was available. It was only during the late 80s and early 90s that the advantages of alcohol-based products began to elicit interest. In 1995 Larsen published new application guidelines for hand disinfection and in 1996 the CDC included alcohol-based hand disinfection in its "Isolation guideline". However, these recommendations were rarely implemented in practice. In 1996 Didier Pittet first gave me a demonstration of alcohol-based rub products at his Geneva hospital, and the following year experts at Lausanne University provided me with the products available at that time. In 1998 and 2000 I had the opportunity to exchange information and experiences with numerous European experts, including Dr. Molitor, who also gave me additional insights into the mechanism of action of such products. As a result of myriad scientific demonstrations, interest in these rub products now began to be expressed in the USA too. In 1999 an interdisciplinary working group for hand hygiene was set up, comprising representatives from CDC's Healthcare Infection Control Practices Advisory Committee (HICPAC), the Society for Healthcare Epidemiology of America, the Association for Professionals in Infection Control and the Infectious Diseases Society of America, whose intention was to formulate new guidelines for hand hygiene in the healthcare sector. The insights that I gained from Dr. Molitor and from other European experts were of enormous value and helped to weigh up the pros and cons of alcohol-based hand disinfection, both in respect of the different products available and on comparing them with hand washing. The new CDC guideline for hand hygiene was published in 20002 and for the first time in the USA it featured the requirement that alcohol-based rub products be used as the method of choice provided that the hands were not visibly soiled or contaminated with protein-based material. Unfortunately, we have no reliable data, but it is estimated that today up to 95% of doctors and nurses in American hospitals preferentially use alcohol-based rub products - thus reflecting a situation that has long been common practice in Europe. PMID- 20200686 TI - Importance of disinfection as a means of prevention in our changing world hygiene and the home. AB - Contrary to expectation, the risks of infection are growing rather than declining, even in everyday life. After all, who is able to make a distinction between cleanliness and hygiene? This situation is further compounded by the growing number of persons who are susceptible to infections. If one wants to combat infectious diseases in an economically feasible and consistent manner, public support must be sought. In turn, the public have a right to be informed in a proper and responsible manner. The difference between "dirt" and "contamination" must be highlighted once again.To create a forum for everyday hygiene, an international expert working group was set up (http://www.ifh homehygiene.org). The hallmark of this group is its holistic view of hygiene in the family setting, something that is not true in the case of most public health sectors. Based on the latest study results, the International Forum for Hygiene (IFH) has coined a new motto "Selective Hygiene", and evaluates the causes of infection so as to be able to react in an appropriate manner. The aim cannot be routine, daily repetitive decontamination of all potentially dangerous microbes that are found in a normal household, but rather selective reaction to important transmission processes, i.e. hands and foodstuffs, kitchen, bathroom and toilet. The motto can be summarized as follows: "Do the right thing at the right time". This, however, calls for an understanding of the risks and of effective procedures for microbial reduction. Depending on the respective circumstances, hands can be washed with running water or by using a hand disinfectant. Even experts must learn that hygiene in the home must be evaluated differently from that of the hospital setting. The comparatively lower risk is offset by markedly less awareness of the risks involved. These risks can be significantly increased by any members of the household who are ill. Hence in some cases it is advisable to use disinfectants in the home too - even if it is claimed in certain quarters that we have become "too clean", and have thus lower immunity. Study data demonstrate that disinfectants have become indispensable in the household in the context of "selective hygiene strategies" so as to prevent infectious diseases. PMID- 20200687 TI - From antiseptics to antibiotics - and back? AB - There is no straight line to trace the trajectory of antiseptics; rather, this has been manifested more as a fluctuating line, a backwards and forwards movement, seen in the wake of major discoveries but of colossal mistakes too. While today no one would allow their prophylactic policies to be guided by miasma or contagia, there continues to be some uncertainly about how to manage anti infectives effectively even today.When in 1941 the first human being was successfully treated with penicillin, interest in antiseptics gradually waned. From that time onwards, everything was treated with antibiotics, unleashing a race for the discovery of novel antibiotics, as witnessed decades earlier in the case of antiseptics. The significance of antiseptics declined to such an extent that among physicians they were associated merely with cleaning agents or sanitary disinfection. Today, at the beginning of the 21(st) century we know that the euphoria generated by antibiotics was just another station along the pathway of discoveries. Bacterial infections and new, hitherto unknown infectious diseases continue to play a major role. Several viral infections continue to be refractory to successful treatment and bacterial antibiotic resistance has become a problem worldwide. The most effective countermeasures no longer entail only the development of new antibiotics but above all responsible management of antibiotics and strict observance of infection control measures in the hospital setting. Set against that background, interest in antiseptics has been rekindled. In that spirit we can look eagerly forward over the coming years to further developments in antisepsis. PMID- 20200688 TI - "Maecenates voco!": laudation for Hans-Joachim Molitor. PMID- 20200689 TI - Description of project. PMID- 20200690 TI - Hospital Hygiene, looked at from a holistic perspective. PMID- 20200691 TI - Gabapentin enacarbil in restless legs syndrome. AB - Restless legs syndrome (RLS) is a sleep-related movement disorder with a high prevalence in the general population. Patients affected by a severe form of the disorder may develop comorbidities, such as psychological distress, cognitive dysfunction and cardiovascular diseases; these patients require pharmacotherapy. Dopamine agonists represent the first line treatment for RLS patients but, if adverse events such as compulsive behaviors and augmentation occur, the pharmacological approach should be modified. Gabapentin is a GABA analogue used in the treatment of seizures and pain syndromes. This drug has an unfavorable pharmacokinetic profile; the prodrug gabapentin enacarbil was developed to overcome this limitation. Unlike oral gabapentin, gabapentin enacarbil shows no evidence of saturation and exposure to gabapentin is dose proportional. The extended release formulation of gabapentin enacarbil has the characteristics of an optimal drug therapy. Doses from 1200 to 1800 mg/day of gabapentin enacarbil appear effective in treating RLS after only a few days of treatment. The most frequently reported adverse events associated with gabapentin enacarbil are dizziness and somnolence, which are transient and of mild intensity. Further studies are required to confirm the long term efficacy and safety of gabapentin enacarbil on the symptoms of RLS. PMID- 20200692 TI - Golimumab: A novel anti-TNF-alpha human monoclonal antibody for rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. AB - Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, has been implicated in the pathology of a variety of chronic autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. The introduction of TNF-alpha inhibitors represented a significant advance in the management of these diseases but the responses of individual patients to TNF alpha inhibitors are not homogeneous and more therapeutic tools are needed. Golimumab (CNTO-148) is a novel anti-TNF-alpha human monoclonal antibody that blocks both soluble and transmembrane TNF-alpha. It is indicated in the treatment of adults with moderately to severely active rheumatoid arthritis in combination with methotrexate, in adults with active and progressive psoriatic arthritis either alone or in combination with methotrexate, and in adult patients with active ankylosing spondylitis who have had an inadequate response to conventional therapies. Golimumab has generally been well tolerated in clinical trials with a safety profile comparable to other currently available TNF-alpha inhibitors. Its advantages are that it can be administered s.c. once monthly, it is labeled for patient self-administration and is suitable for both s.c. and i.v. administration. Golimumab is currently being investigated in other chronic inflammatory diseases. PMID- 20200693 TI - Eslicarbazepine acetate: A novel agent for the adjunctive treatment of epilepsy. AB - Eslicarbazepine acetate, a novel antiepileptic agent, has recently been marketed as an adjunctive therapy in adults with partial onset seizures with or without secondary generalization. Its mode of action is not fully elucidated but it is believed that it and its metabolites stabilize the inactivated state of voltage gated sodium channels, preventing their return to the inactivated state. Eslicarbazepine acetate is extensively converted to eslicarbazepine, its major active metabolite. Its pharmacokinetic profile is unaffected by food, gender, age or moderate hepatic impairment; clearance is dependent on renal function and dose reduction is recommended in patients with a creatinine clearance < 60 ml/min. Eslicarbazepine acetate does not induce its own metabolism or clearance. Clinical trials have demonstrated efficacy in short and long term studies (up to 1 year) together with improvements in quality of life outcomes and depressive symptoms where these existed at baseline. Most adverse events were mild to moderate in intensity and occurred early in treatment; the most frequently reported events were dizziness, somnolence and headache. Trials using eslicarbazepine acetate as monotherapy are ongoing. PMID- 20200694 TI - Minodronate for the treatment of osteoporosis. AB - Minodronate, a new nitrogen-containing bisphosphonate, was developed in Japan. It was the first drug to demonstrate significant prevention of vertebral fractures in Japanese patients with osteoporosis in a phase III doubleblind comparative study. As a result of positive data from clinical trials in Japan minodronate was granted a Japanese marketing approval for the treatment of osteoporosis on January 21, 2009. In vitro studies demonstrated that minodronate is one of the most potent inhibitors of bone resorption among currently available bisphosphonates. Preclinical studies demonstrated the inhibitory effect of minodronate on the decrease in the bone mineral density (BMD) in ovariectomized rats, dogs and monkeys. Daily oral minodronate was safe, well tolerated and effective in reducing vertebral fracture risk in postmenopausal women with established osteoporosis. The effects on lumbar and hip BMD and the safety profile of minodronate are comparable to those of alendronate. These data suggest that minodronate is a promising new potent bisphosphonate for the treatment of osteoporosis. PMID- 20200695 TI - Recent trends in the management of antiphospholipid syndrome (Hughes syndrome). AB - Antiphospholipid syndrome (Hughes syndrome) is characterized by the presence of arterial or venous thrombosis or recurrent miscarriages in a patient with positive laboratory tests for antiphospholipid antibodies (anticardiolipin antibodies and/or lupus anticoagulant and/or anti-beta(2) glycoprotein I). Despite the strong association between antiphospholipid antibodies, and thrombosis and obstetric morbidity, their pathogenic role in the development of these clinical features has not been fully elucidated. At present, patients with thrombosis are treated with long-term oral anticoagulation as standard. The approach for women with obstetric manifestations is based on the use of aspirin plus heparin. However, the knowledge of new pathogenic mechanisms might identify novel therapeutic targets and, therefore, may improve the management of these patients. PMID- 20200696 TI - Highlights from the 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). AB - The Rhine river was the scenario of this year's congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held in the Dusseldorf Messe right beside the river in September 9-12, 2009. The meeting contained a number of important new contributions with a direct impact in how patients are and can be treated in the current clinical setting. PMID- 20200699 TI - Rational design of diphosphorus ligands--a route to superior catalysts. AB - The development of catalytic chemical conversions owes its success to the procreation of ligand variety and parameter quantification. Rational ligand design can provide a powerful means to tune transition metal reactivity and reaction selectivity. In this review an attempt is made to describe the quantification of ligand parameters and to present examples of successful ligand design in several academically and industrially important catalytic systems. PMID- 20200700 TI - A zigzag tetranuclear iron(III) complex, [Fe4(bpaeO)2(CH3O)2(N3)8] coexisting both ferromagnetic and antiferromagnetic couplings (bpaeOH = N,N-bis(2 pyridylmethyl)-2-aminoethanol). AB - A zigzag tetranuclear [Fe(4)(bpaeO)(2)(CH(3)O)(2)(N(3))(8)] possesses two different high-spin ferric sites and both ferromagnetic and antiferromagnetic interactions exist within the iron(III) ions. PMID- 20200701 TI - The switch that wouldn't switch--unexpected luminescence from a ruthenium(II) dppz-complex in water. AB - The complex [(dmcb)(2)Ru(dppz)](PF(6))(2) shows unexpected luminescence in water implying fundamentally different excited state relaxation pathways than are typically observed for complexes of this kind. PMID- 20200702 TI - Issues surrounding standard cytotoxicity testing for assessing activity of non covalent DNA-binding metallo-drugs. AB - Investigating the methods commonly used to evaluate in vitro cytotoxicity of novel compounds, specifically non-covalent DNA binders, identifies that these methods may not be appropriate. The level of anticancer activity depends not only on the incubation time but also on the absolute amount (number of moles) of drug compound applied, rather than the concentration. PMID- 20200703 TI - Tailor made synthesis of amphiphilic azoaromatics via regioselective C-N bond fusion. Comparative studies of surface properties of the two positional isomers and cobalt complexes. AB - Tailor made synthesis of the isomeric azoaromatics, HL(1)-HL(4) [HL = (arylamino)phenylazopyridine] containing a single hydrophobic tail (C(n) = C(10) and C(12)) is described. The coordination induced C-N bond fusion synthetic protocol has been successfully used for the synthesis of the compounds, which are subsequently characterized using various spectroscopic techniques. The single crystal X-ray structure of compound HL(4) has revealed that the hydrophobic chain in it orients itself with all-trans conformation of alkyl groups. Studies of their surface properties clearly demonstrate that these behave as surfactants. Amphiphilic properties of the compounds are followed by the studies of compression isotherms and their surface morphologies are studied with the use of high resolution field emission scanning electron microscopy (FE-SEM) as well as atomic force microscopy (AFM). Distinct differences in surface properties in the two HL isomers are observed and disposition of the hydrophobic tail with respect to the head group is shown to play a significant role in the organization process of the molecules at the air-water interface. Transferred monolayers of the above two isomeric compounds show agglomerated nano-domain structures. This phenomenon has been explained considering hydrophobic tail-tail repulsive interaction within the adjacent molecules. Surface properties of the double tail complex, [Co(L(1))(2)]ClO(4) (1) along with that of the single tail complex, [Co(L(1))(L(5))]ClO(4) (3) are also reported. Amphiphilic behavior of the above azoaromatics are distinctly different than those in their metal free state. Notably, the double tail complex (1) favors bi-layer formation even at low surface pressure region (approximately 10 mN m(-1)). The single tail cobalt complex (3), on the other hand, forms a monolayer at high surface pressure region leading finally to the collapse at a very high pressure approximately 60 mN m( 1). PMID- 20200704 TI - Synthesis, structure, and magnetic properties of bis(monosubstituted pyrazine)dihalocopper(II). AB - The investigation into synthesizing new metal organic compounds with the general formula Cu(S-pyrazine)X(2) using monosubstituted pyrazines has led to the generation of a new family of compounds Cu(S-pyrazine)(2)X(2) with similar structure and magnetic properties. The bis(S-pyrazine)dihalocopper(II) compounds [where S = Cl, CN, OCH(3), and OCH(2)CH(3) and halide = Cl or Br] have been characterized by IR, powder X-ray diffraction, single-crystal X-ray diffraction, and temperature dependent magnetic susceptibility. The bis(chloropyrazine)dihalocopper(II) compounds crystallize in the monoclinic space group P2(1)/n while the methoxy and ethoxy analogues crystallize in the triclinic space group P1. This structurally related family of compounds exhibit antiferromagnetic interactions with exchange constants of approximately -25 K for the chloride analogues and -50 K for the bromide analogues. PMID- 20200705 TI - Cu(II) and Ni(II) dioxotetraamine complexes integrated with tetrathiafulvalene moiety; structures and solution chemistry. AB - A new bifunctional tetrathiafulvalene (TTF) derivative has been designed and synthesized, in which the TTF moiety (a redox functional group) is integrated with a dioxotetraamine (a coordination functional group) structure. Like other dioxotetraamine compounds, it is capable of acting as an ion leaving and accepting ligand for protons and Cu(II) and Ni(II) ions in solution. Experiments of pH titration have shown that the TTF unit adds new redox properties to the traditional ligand. Oxidation of the ligand increases the acidity of the imido group and the coordination of metal ions is also sensitive to the oxidation state of the ligand. The ligand forms either a square coordinated Ni(II) complex with two deprotonated imido groups and two amino groups, or a pentacoordinated Cu(II) complex with an additional solvent molecule. The compounds form a belt structure with strong N-H...O hydrogen bonds, which is a basic character for this type of compound in the crystalline form. PMID- 20200707 TI - Anticancer activity of osmium metalla-rectangles. AB - A series of cationic metalla-rectangles of the general formula [(p cymene)(4)Os(4)(OO[intersection]OO)(2)(N[intersection]N)(2)](4+) have been obtained in methanol from the dinuclear arene osmium precursors [(p cymene)(2)Os(2)(OO[intersection]OO)(2)Cl(2)] (OO[intersection]OO = 2,5-dioxydo 1,4-benzoquinonato (dhbq), 2,5-dichloro-1,4-benzoquinonato (dcbq)) by reaction with bipyridine linkers (N[intersection]N = 4,4'-bipyridine, 1,2-bis(4 pyridyl)ethylene) in the presence of AgCF(3)SO(3). All complexes were isolated as triflate salts and characterised by NMR, IR and UV-visible spectroscopy. The cytotoxicities of the dinuclear and tetranuclear osmium complexes were established using ovarian A2780 cancer cell lines. The most active metalla rectangle, [(p-cymene)(4)Os(4)(dhbq)(2)(4,4'-bipyridine)(2)](4+), shows an IC(50) value of 5.7 microM (comparable to cisplatin) against A2780 cancer cells and 7.5 microM against the cisplatin resistant A2780cisR cells. PMID- 20200708 TI - Synthesis and characterization of [Pb{Se2P(OiPr)2}2]n pseudo polymorphs: polymeric, single source precursor enabling preparation of shape-controlled lead selenide structures. AB - Novel lead pseudo polymorphs supported by diselenophosphate (dsep) ligands, [Pb{Se(2)P(O(i)Pr)(2)}(2)](n) (1alpha and 1beta), were synthesized and structurally characterized. The two structures differed in the binding modes of the dsep ligand. Each repeating unit in 1alpha was composed of a lead atom coordinated by two dsep ligands, one in a chelating mode and the other in a bridging-dangling mode. By contrast, the dsep ligands in 1beta adopted a bimetallic-biconnective (mu(1)-S, mu(1)-S) binding pattern. The bridging-dangling mode observed in 1alpha is the first example of this mode for the dsep ligand. [Pb{Se(2)P(O(i)Pr)(2)}(2)](n) could be successfully utilized as a single source precursor (SSP) for growing lead selenide (PbSe) nanostructures with different shapes via the solvothermal process. The morphologies of the as-grown PbSe structures were controlled by capping agents, poly(vinyl pyrrolidone) (PVP) and ethylenediamine, both bind on the {200} plane and enhance the growth rate of the <111> direction of the PbSe crystals, resulting in the formation of cubes and eight-horned rod dendrites, respectively. Raman spectroscopy was utilized to investigate the phonon vibration behaviour of the as-grown eight-horned rod dendrites. All peaks in the Raman spectra can be attributed to longitudinal (LO) and transverse (TO) optical phonon modes of the PbSe rod dendrites. PMID- 20200706 TI - New discrete and polymeric supramolecular architectures derived from dinuclear Co(II), Ni(II) and Cu(II) complexes of aryl-linked bis-beta-diketonato ligands and nitrogen bases: synthetic, structural and high pressure studies. AB - New examples of nitrogen base adducts of dinuclear Co(II), Ni(II) and Cu(II) complexes of the doubly deprotonated forms of 1,3-aryl linked bis-beta-diketones of type [RC(=O)CH(2)C(=O)C(6)H(4)C(=O)CH(2)C(=O)R] (L(1)H(2)) incorporating the mono- and difunctional amine bases pyridine (Py), 4-ethylpyridine (EtPy), piperidine (pipi), 1,4-piperazine (pip), N-methylmorpholine (mmorph), 1,4 dimethylpiperazine (dmpip) and N,N,N',N'-tetramethylethylenediamine (tmen) have been synthesised by reaction of the previously reported [Cu(2)(L(1))(2)].2.5THF (R = Me), [Cu(2)(L(1))(2)(THF)(2)] (R = t-Bu), [Ni(2)(L(1))(2)(Py)(4)] (R = t-Bu) and [Co(2)(L(1))(2)(Py)(4)] (R = t-Bu) complexes with individual bases of the above type. Comparative X-ray structural studies involving all ten base adduct derivatives have been obtained and reveal a range of interesting discrete and polymeric molecular architectures. The respective products have the following stoichiometries: [Cu(2)(L(1))(2)(Py)(2)].Py (R = Me), [Cu(2)(L(1))(2)(EtPy)(2)].2EtPy (R = t-Bu), [Cu(2)(L(1))(2)(pipi)(2)].2pipi (R = t-Bu), [Cu(2)(L(1))(2)(mmorph)(2)] (R = t-Bu), [Cu(2)(L(1))(2)(tmen)(2)] (R = t Bu) and {[Cu(2)(L(1))(2)(pip)].pip.2THF}(n), [Co(2)(L(1))(2)(tmen)(2)] (R = t Bu), [Ni(2)(L(1))(2)(Py)(4)].dmpip (R = t-Bu), [Ni(2)(L(1))(2)(pipi)(4)].pipi (R = t-Bu) and [Ni(2)(L(1))(2)(tmen)(2)] (R = t-Bu). The effect of pressure on the X ray structure of [Cu(2)(L(1))(2)(mmorph)(2)] has been investigated. An increase in pressure from ambient to 9.1 kbar resulted in modest changes to the unit cell parameters as well as a corresponding decrease of 6.7 percent in the unit cell volume. While a small 'shearing' motion occurs between adjacent molecular units throughout the lattice, no existing bonds are broken or new bonds formed. PMID- 20200709 TI - A hexadentate bis(thiosemicarbazonato) ligand: rhenium(V), iron(III) and cobalt(III) complexes. AB - A new 1,3-diaminopropane bridged bis(thiosemicarbazone) ligand (H(4)L) has been synthesised. The new hexadentate ligand is capable of forming six coordinate complexes with rhenium(V), iron(III) and cobalt(III). In the case of the iron(III) and cobalt(III) complexes the ligand doubly deprotonates to give the monocations [Fe(III)(H(2)L)](+) and [Co(III)(H(2)L)](+) in which the metal ion is in a distorted octahedral environment. In the rhenium(V) complex the ligand loses four protons by deprotonation of both secondary amine nitrogen atoms to give [Re(V)(L)](+) with the metal ion in a distorted trigonal prismatic coordination environment. [Re(V)(L)](+) represents a rare example of a rhenium(V) complex that does not contain one of the ReO(3+), ReN(2+) or Re(NPh)(2+) cores. The new ligand and metal complexes have been characterised by a combination of NMR spectroscopy, X-ray crystallography, mass spectrometry and microanalysis. The electrochemistry of [Fe(III)(H(2)L)](+), [Co(III)(H(2)L)](+) and [Re(V)(L)](+) has been investigated by cyclic voltammetry with each complex undergoing a single electron reduction event. It is possible to prepare the rhenium(V) complex from ReOCl(3)(PPh(3))(2) or directly from [ReO(4)](-) with the addition of a reductant, which suggests the new ligand may be of interest in the development of rhenium radiopharmaceuticals. PMID- 20200710 TI - Gas phase structures of chalcogen tetrahalides MX4 with M = S, Se, Te and X = F, Cl, Br, I. AB - Structural and conformational properties of the tetrahalides MX(4) with M = S, Se, Te and X = F, Cl, Br, I were studied with quantum chemical calculations (MP2/aug-cc-pVTZ and relativistic core potentials for heavy atoms). The pseudotrigonal bipyramidal geometries (C(2v) symmetry) of the three tetrafluorides and of TeCl(4), whose structures have been determined by gas electron diffraction, are very well reproduced with this computational method. No additional stable conformer with C(3v), C(S), C(4v) or T(d) symmetry is predicted for these four chalcogen tetrahalides. For all other MX(4) compounds, except SeI(4), the existence of two conformers with C(2v) and T(d) symmetry is predicted. The T(d) structure is favoured in the case of SI(4) and SeBr(4) and SeI(4) is predicted to exist only as T(d) conformer. PMID- 20200711 TI - Superparamagnetic gamma-Fe2O3@SiO2 nanoparticles: a novel support for the immobilization of [VO(acac)2]. AB - This work reports a detailed investigation about the physicochemical properties of superparamagnetic gamma-Fe(2)O(3) nanomaterial synthesized by the co precipitation method and coated with two silica shells, and its application as support for the immobilization of oxovanadium(IV) acetylacetonate ([VO(acac)(2)]). The influence of the silica coatings on the surface composition and physicochemical interactions of the core-shell nanocomposites is discussed based on the combination of several techniques: electron microscopy techniques (SEM and TEM with EDS), DLS, powder XRD, XPS, FTIR and magnetic characterization. The identity of the iron oxide, gamma-Fe(2)O(3), was confirmed by XPS, FTIR and by the Rietveld refinement of the PXRD pattern. The results obtained by electron microscopy techniques, XRD and magnetization indicated that the gamma-Fe(2)O(3) nanoparticles are superparamagnetic and present an average size of approximately 6.5 nm. The first silica coating leads to a core-shell nanomaterial with an average particle size of 21 nm and upon the second coating, the average size increases to 240 nm. Magnetic measurements revealed that the silica-coated nanomaterials maintain the superparamagnetic state at room temperature, although with an expected reduction of the magnetization saturation due to the increase of the silica shell thickness. Furthermore, a numerical fit of the temperature dependence of magnetization was performed to determine the core size distribution and the effect of the silica coatings on the dipolar magnetic interactions. [VO(acac)(2)] was covalently immobilized on the surface of the silica-coated magnetic nanoparticles functionalized with amine groups, as confirmed by chemical analysis and XPS. In a proof-of-principle experiment, we demonstrated the catalytic performance of the novel magnetic hybrid nanomaterial in the epoxidation of geraniol, which presented high selectivity towards the 2,3 epoxygeraniol product and easy recovery by magnetic separation. PMID- 20200712 TI - Sulfur-assisted synthesis of nitride nanocrystals. AB - A series of nitrides (TiN, ZrN, BN, AlN) were prepared by using the corresponding elements (Ti, Zr, B, Al), NaN(3) and sulfur as starting materials in a stainless steel autoclave at 250 degrees C. Sulfur was used to facilitate the exothermic reaction between NaN(3) and sulfur (at 250 degrees C) and the final formation of nitrides. The treatment temperature affected the growth of the nitride crystals, for example, diversified morphologies of TiN nanocrystals were formed in different temperature ranges: grain and truncated octahedron (250 degrees C), octahedron (>300 degrees C), and dendrite (>400 degrees C). Through similar processes, other nitrides (for example, TiN, AlN, Si(3)N(4)) could also be produced by employing NaNH(2) and additives (such as iodine or N-aminothiourea instead of sulfur) in low temperatures. PMID- 20200714 TI - Anionic zinc-trimesic acid MOFs with unusual topologies: reversible hydration studies. AB - The reaction of 1,3,5-benzenetricarboxylic acid (H(3)BTC) with ZnSO(4).6H(2)O in a DMF-water solution afforded two new metal-organic frameworks [Zn(6)(mu(3) OH)(2)(BTC)(4)(DMF)(2.5)(H(2)O)(2)].[Zn(H(2)O)(3)(DMF)(3)].3.1H(2)O (1) and Zn(2)(HBTC)(BTC)(H(2)O)(3)].DMA.3H(2)O (2). Both compounds are thermally stable and can be prepared reproducibly. Rehydration experiments on compound 2 demonstrate reversible dehydration and rehydration while 1 rehydrates to a different crystalline material. Network analysis revealed a binodal (3,6)-net for 1 and a (3,5)-net for 2, both rare topologies. PMID- 20200713 TI - Bismuth(III) complexes derived from non-steroidal anti-inflammatory drugs and their activity against Helicobacter pylori. AB - The formation of bismuth(III) complexes of carboxylates and benzoates derived from the 1 : 3 reaction of BiPh(3) with the common non-steroidal anti inflammatory drugs (NSAIDs) ketoprofen, naproxen, ibuprofen, mefenamic acid, diflunisal, 5-chlorosalicylic acid, fenbufen, sulindac, tolfenamic acid and flufenamic acid, has been achieved using both solvent-free and solvent-mediated methods. The thermochemical profiles of the solvent-free reactions were studied using DSC-TGA. All reactions produced the tris-substituted complexes of general formula [BiL(3)](n), with the complexes derived from ketoprofen and sulindac having an additional single bismuth bound H(2)O molecule in the inner coordination sphere. The complexes are stable in air over a period of six months, do not undergo significant decomposition when suspended overnight in water, but decompose in 1 M HCl solution to release the free acid form of the NSAID. All ten complexes show excellent in vitro activity against Helicobacter pylori with MIC values of > or = 6.25 microg mL(-1). PMID- 20200715 TI - The role of Glu498 in the dioxygen reactivity of CotA-laccase from Bacillus subtilis. AB - The multicopper oxidases couple the one-electron oxidation of four substrate molecules to the four electron reductive cleavage of the O-O bond of dioxygen. This reduction takes place at the trinuclear copper centre of the enzyme and the dioxygen approaches this centre through an entrance channel. In this channel, an acidic residue plays a key role in steering the dioxygen to the trinuclear copper site, providing protons for the catalytic reaction and giving overall stability to this site. In this study, the role of the Glu(498) residue, located within the entrance channel to the trinuclear copper centre, has been investigated in the binding and reduction of dioxygen by the CotA-laccase from Bacillus subtilis. The absence of an acidic group at the 498 residue, as in the E498T and E498L mutants, results in a severe catalytic impairment, higher than 99%, for the phenolic and non-phenolic substrates tested. The replacement of this glutamate by aspartate leads to an activity that is around 10% relative to that of the wild-type. Furthermore, while this latter mutant shows a similar K(m) value for dioxygen, the E498T and E498L mutants show a decreased affinity, when compared to the wild type. X-ray structural and spectroscopic analysis (UV-visible, electron paramagnetic resonance and resonance Raman) reveal perturbations of the structural properties of the catalytic centres in the Glu(498) mutants when compared to the wild-type protein. Overall, the results strongly suggest that Glu(498) plays a key role in the protonation events that occur at the trinuclear centre and in its stabilization, controlling therefore the binding of dioxygen and its further reduction. PMID- 20200716 TI - Facile synthesis of MOF-177 by a sonochemical method using 1-methyl-2 pyrrolidinone as a solvent. AB - High quality MOF-177 crystals in the size range of 5-20 microm were successfully synthesized via a sonochemical route in a substantially reduced synthesis time (40 min) in the presence of low-cost NMP (1-methyl-2-pyrrolidone) as a solvent. Microwave heating in NMP also produced MOF-177 under similar conditions (35 min, 5-50 microm) but exhibited inferior crystallinity. In comparison, a conventional solvothermal route in DEF (diethylformamide) took 48 h to produce MOF-177 crystals 0.5-1.5 mm in size. The BET surface areas of the MOF-177 samples decreased in the order of sonochemical (4898 m(2) g(-1)) > conventional (4833 m(2) g(-1)) > microwave route (4197 m(2) g(-1)). In line with this trend, MOF-177 prepared via the sonochemical route resulted in the highest CO(2) adsorption capacity, 1315 mg g(-1) at 30 bar and 298 K. The product yield of MOF-177 synthesized via the sonochemical route was 95.6%, and was significantly higher than the product yields of other methods. PMID- 20200717 TI - Characterization of a rhodium-sparteine complex, [((-)-sparteine)Rh(eta4-COD)]+: crystal structure and DNMR/DFT studies on ligand-rotation dynamics. AB - A cationic rhodium-sparteine complex, [((-)-sparteine)Rh(eta(4)-COD)](+) (1(+); COD = 1,5-cyclooctadiene) was obtained, isolated as its tetrafluoroborate salt (1BF(4)), and characterized using X-ray crystallography and multinuclear ((1)H, (13)C) NMR spectroscopy. This is the first structurally characterized sparteine complex of rhodium. The Rh-N bonds are unusually long (2.214(3) and 2.242(3) A), apparently due to steric repulsion between COD and sparteine. (1)H NMR exchange experiments (EXSY) demonstrate a dynamic process that results in an overall 180 degrees rotation of the COD methine protons in solution (CD(2)Cl(2)) with a first order rate constant of 460 s(-1) at the coalescence temperature (314 K) and interpolated rate constant of 150 s(-1) at 298 K. Temperature-dependent NMR studies yield DeltaH(++) = 13.0 +/- 0.3 kcal mol(-1), DeltaS(++) = -5 +/- 1 cal mol(-1) K(-1), such that DeltaG(298)(++) = 14.3 +/- 0.3 kcal mol(-1). DFT studies (B3LYP) indicate that the loosely bound (-)-sparteine ligand rotates through a pseudo-tetrahedral transition state where both ligands are rotated approximately 90 degrees relative to each other. While both ligands remain bound (eta(4)-COD, kappa(2)-sparteine), bonding to sparteine is weakened much more than bonding to COD in the transition state. DFT computed DeltaG(298)(++) and DeltaS(++) values (15.55 kcal mol(-1) and -2.67 cal mol(-1) K(-1), respectively) agree very well with the experimental values. Attempts to find alternative mechanisms involving partial dechelation of COD and (-)-sparteine yielded slightly higher barriers along with positive DeltaS values for intermediate formation. PMID- 20200718 TI - Single wall carbon nanotubes deposited on stainless steel sheet substrates as novel counter electrodes for ruthenium polypyridine based dye sensitized solar cells. AB - We report on the implementation of stainless steel foils coated with dispersed Single Wall Carbon Nanotubes as novel, low cost and highly efficient counter electrodes for dye sensitized solar cells (DSSCs). We use commercially available non purified nanotubes dispersed in water by ultrasonication and drop cast on stainless steel substrates. When implemented on a ruthenium based DSSC we obtain a high short circuit current density (J(sc)= 9.21 mA cm(-2)), a good open circuit voltage (V(oc) = 0.660 V) and a solar energy conversion efficiency of 3.92%. The above cited values are measured under a light flux of 100 mW cm(-2) generated by a solar simulator equipped with a filter AM 1.5. The obtained results are comparable to those attained using a stainless steel counter electrode sputtered with a 2 microm thick platinum film (J(sc) 10.92 mA cm(-2), V(max) = 0.66 V and eta = 4.5%, AM 1.5). PMID- 20200719 TI - Crystallographic elucidation of purely structural, thermal and light-induced spin transitions in an iron(II) binuclear complex. AB - The intricate phase diagram of the binuclear iron(II) spin-crossover complex [{Fe(3-bpp)(NCS)(2)}(2)(4,4'-bypiridine)].2CH(3)OH where 3-bpp is 2,6-bis(pyrazol 3-yl)pyridine has been investigated by variable temperature single crystal X-ray diffraction including a study into the effect of photo-irradiation. This sample is known to exhibit an incomplete spin transition at low temperature. At room temperature, in phase I, iron ions are all crystallographically equivalent, adopting the high spin state (HS). X-Ray structural investigation has revealed two phase transitions in the range (300-30 K). The first transition (T approximately 161 K) leading to phase II is of a purely structural nature and corresponds to a break in symmetry as a result of a twist of the two rings of 4,4'-bipyridine; the two iron sites of the binuclear unit becoming crystallographically independent but remaining all HS. The second structural transition corresponds to the spin crossover, one of the two Fe(II) ions of the binuclear complex being in the low spin state (LS) in phase III. The crystal structure shows an ordered HS-LS crystal packing where HS and LS sites are clearly identified and not randomly distributed in the metal ion sites as often observed. Moreover, light irradiation of single crystals in phase III at 30 K, leading to phase III*, induces a light-induced spin-state trapping (LIESST) effect corresponding to the full conversion of all the iron sites to HS. The crystal packing in phase III* is closer to that of phase III than to those observed in the other HS phases, I and II. This reveals an unusual differentiation between the thermal and light-induced HS states. A deeper analysis of the structural properties first demonstrates the key role of the bipyridine bridge in the peculiar preliminary pure structural transition shown by the title compound. Elsewhere, it also shows that the molecular packing is strongly dependent on the nature of the external perturbation contrary to the iron coordination sphere geometry that appears to be only dependent on the spin state. Moreover, in the HS phase II, the distortion of the iron sites that will subsequently undergo a spin crossover demonstrates some differences with the distortion of the iron sites that remain HS. The predominant role of the iron environment distortion in the spin crossover phenomenon is thus clearly evidenced. PMID- 20200720 TI - Organic-soluble optically pure anionic metal complexes PPh4[M(III)(S,S EDDS)].2H2O (M = Fe, Co, Cr). AB - The first organic-soluble, optically and diastereomerically pure EDDS metal complexes have been synthesised. A number of synthetic approaches were attempted, but finally the tetraphenylphosphonium series emerged as providing readily accessible compounds of trivalent Cr, Fe and Co in reasonable yields via the silver salts without the need to perform ion-exchange chromatography. The species PPh(4)[M(III)(S,S-EDDS)] are very soluble in methanol, acetonitrile and even THF but isolation was facilitated by addition of stoichiometric water giving the highly crystalline but still conveniently soluble title compounds. The structures of the three isomorphous crystals comprise H(2)O-bridged extended hydrogen bonded structures with large channels occupied by the counterion molecules. The magnetic properties and circular dichroism spectra are reported along with comparative data for water-soluble NH(4)[Fe(III)(S,S-EDDS)]. Phase purity (and hence diastereomeric purity) in the paramagnetic systems is assessed through powder XRD. The practical utility of this type of compound was confirmed by optical resolution of (+/-)-[Ru(II)(bpy)(3)]Cl(2). PMID- 20200721 TI - Luminescence quenching of Re(I) molecular rectangles by quinones. AB - The rhenium-based rectangles [{Re(CO)(3)(mu-bpy)Br}{Re(CO)(3)(mu-L)Br}](2) (I, L = 4,4'-dipyridylacetylene (dpa); II, L = 4,4'-dipyridylbutadiyne (dpb); III, L = 1,4-bis(4'-pyridylethynyl)benzene (bpeb); bpy = 4,4'-bipyridine) are emissive in solution at room temperature. The presence of extended pi conjugation leads to an increase in electron delocalization, which, in turn, results in improved luminescence and lower nuclear reorganization energy. These rectangles, upon electronic excitation, undergo facile electron transfer (ET) reactions with quinones and both the dynamic and static quenching contribute to the reaction. Spectral and electrochemical measurements show that quinone 7,7,8,8 tetracyanoquinodimethane (TCNQ) binds strongly to rectangle I. The driving force dependence of k(et), deduced from the luminescence quenching of rectangles with quinones, can be well accounted for within the context of the Marcus theory of electron transfer. PMID- 20200722 TI - Zwitterionic dicopper helicates: anion encapsulation and binding studies. AB - The synthesis and spectroscopic studies of a dicopper(II) double helicate capable of binding anions is described. X-Ray crystallographic analysis of three anion variations of the complex have shown that the helicate is capable of accommodating anions with an approximate volume of 0.09 nm(3) and smaller. ESI-MS revealed that the supramolecular complexes retain the 2 : 2 ligand : metal cluster in solution. Spectrometric analysis has shown the complex is capable of binding anions in a 1 : 1 ratio of helicate to anion, in the order SO(4)(2-) > HPO(4)(2-) > ClO(4)(-) approximately BF(4)(-) approximately NO(3)(-). We demonstrate that coordination to the metal centre, H-bonding and electrostatic interactions all play a role in encapsulating the anions. PMID- 20200723 TI - Construction of a monoanionic S,N,S-pincer ligand with a pyrrole core by sequential [1,2] phospho-Fries rearrangement. Characterization of palladium and silver coordination complexes. AB - The synthesis of an S,NH,S-pincer ligand possessing a pyrrole core and two O,O diethylthiophosphonyl groups to design P=S lateral coordination sites is reported. The synthetic procedure to produce this ligand makes use of the nitrogen atom of the pyrrole heterocycle to successively functionalize the ortho positions with the two O,O-diethylthiophosphonyl moieties. The ortho functionalization arises from a repetition of a [1,2] base-induced rearrangement allowing the transformation of O,O-diethyl-N-pyrollylthiophosphoramidate to ortho thiophosphonate. The coordination properties of this tridentate S,NH,S-ligand have been investigated with silver and palladium metals. Reaction of the monoanionic S,N,S-pincer ligand 4 (O,O,O,O-tetraethylpyrrol-2,5-yl dithiophosphonate) with PdCl(2)(MeCN)(2) at room temperature in the presence of triethylamine gives rise to the formation of the eta(3)-complex [Pd(eta(3)-4')Cl] 5. Ligand 4 also reacts with silver oxide in dichloromethane to produce complex which, in the solid state, exists as a tetramer involving an almost linear arrangement of four silver atoms. PMID- 20200727 TI - Rational synthesis and characterization of porous Cu(II) coordination polymers. AB - Porous coordination polymers or metal-organic frameworks constructed from metal ions and organic ligands have attracted much attention as next-generation porous materials due to their high designability, regularity, flexibility, and porosity. In particular, the Cu(II) ion with Jahn-Teller distortion can offer unique functions (coordination flexibility, Lewis acid property, and polarity) to porous frameworks. In this Perspective, we focus on porous Cu(II) coordination polymers; their unique characteristics and potential future applications are illustrated by recent experimental results. PMID- 20200728 TI - Orientation dependence in the four-atom reaction of OH + HBr using the single state oriented OH radical beam. AB - The orientation dependence for the Br atom formation in the reaction of the oriented OH radicals with HBr molecules at 0.26 eV collision energy has been observed for the first time using the hexapole electric field, and we found that the reaction cross-section for O-end attack is more favorable than that for H-end attack by a factor of 3.4 +/- 2.3. PMID- 20200729 TI - Ionic liquids assisted formation of an oil/water emulsion stabilised by a carbon nanotube/ionic liquid composite layer. AB - Assisted by ionic liquids, a facile way of preparing size controllable emulsions stabilised by a CNT/IL composite has been demonstrated. The functionally and structurally tunable CNT/IL composite layer will potentially enhance the application of emulsion in template synthesis, biphase catalysis and interface electron/charge transfer. PMID- 20200730 TI - Key role of the pore volume of zeolite for selective production of propylene from olefins. AB - A plausible reaction mechanism for propylene (C(3)H(6)) production from ethylene (C(2)H(4)) was investigated, based on the amounts of effluent hydrocarbons and hydrocarbons produced in the pores of SAPO-34. Propylene was produced via an oligomerization-cracking mechanism. On the basis of this mechanism, the conversions of C(2)H(4), pentenes, and hexenes were examined. The catalytic performance was compared, in order to investigate the role of the pore volume of zeolites with 8-, 10-, and 12-membered rings in the selective production of C(3)H(6). The selectivity for C(3)H(6) was crucially dependent upon the pore volume of the zeolite. Highly selective production of C(3)H(6) from olefins (C(2)H(4), pentenes, and hexenes) can be accomplished by employing a new concept: adjusting the pore volume of a zeolite to accommodate the volume of an olefin and/or its carbenium cations, as opposed to a conventional molecular sieve approach. For example, an unimolecular cracking of pentenes into C(3)H(6) and C(2)H(4) involving primary cations can be controlled by the pore volume of a zeolite. PMID- 20200731 TI - Ultrafast intramolecular charge transfer in tetrapyrazinoporphyrazines controls the quantum yields of fluorescence and singlet oxygen. AB - A series of octasubstituted zinc(II) tetrapyrazinoporphyrazines (TPyzPz), aza analogues of phthalocyanines, differing in the number of peripheral N,N diethylamino (n = 0-8) and tert-butylsulfanyl substituents (m = 8-n) has been synthesized. All possible congeners were characterized including adjacent and opposite isomers. Steady-state (UV-vis, fluorescence) and time-resolved (fluorescence, femtosecond transient absorption) spectroscopies, redox and photochemical (singlet oxygen formation) properties were investigated and compared. The peripheral tertiary amino substituents (donor) induce a new competitive relaxation pathway to fluorescence and intersystem crossing due to the mixing of the first excited state S(1) of the TPyzPz macrocycle with a nearby intramolecular charge transfer (ICT) state. The fluorescence quantum yield and fluorescence lifetime of 6Zn bearing one N,N-diethylamino substituent (n = 1, m = 7) decreased with increasing solvent polarity, while the same observables of 5Zn with no donor centre (n = 0, m = 8) were not affected. Protonation of the N,N diethylamino substituent in 6Zn led to a strong increase of the fluorescence intensity. The cyclic voltammetry data, the steady-state and time-resolved emission and transient absorption studies revealed strong electronic coupling between the TPyzPz moiety and N,N-diethylamino substituents. ICT is an extremely rapid process occurring with a time constant of 10 ps and 7 ps in 6Zn (n = 1, m = 7) and 11Zn (n = 8, m = 0) in pyridine, respectively. The ICT efficiency decreased in non-polar solvents. The presence of two N,N-diethylamino substituents in 7Zn (n = 2, m = 6) considerably quenched the S(1) states in pyridine (polar, coordinating), toluene (non-polar, non-coordinating) and toluene 1% pyridine (v/v) (non-polar, coordinating). The photophysical properties of compounds with more donor substituents on the periphery (n > 2, m < 6) were similar to those of 7Zn. PMID- 20200732 TI - Dipole tuning of charge transport in molecular junctions. AB - Molecules with different magnitude and direction of dipole moments are sandwiched between mercury (Hg) and p(+)-Si to form Hg-molecules-(p(+)) Si junctions. The importance of the dipole moment of molecules in controlling the symmetry of current-voltage curves is shown by carrying out charge transport measurements at these molecular junctions. Junction parameters are obtained by considering charge transport across the junction as a combination of tunneling and Schottky emission. An interesting effect due to dipole reversal resulting in rectification of junction curves in the opposite quadrants of the current-voltage axis is observed and analyzed. The junction curves also exhibit a different degree of rectification with increasing magnitude of the dipole moment of the sandwiched molecules. PMID- 20200733 TI - Experimental and theoretical study of neutral AlmCn and AlmCnHx clusters. AB - Neutral Al(m)C(n) and Al(m)C(n)H(x) clusters are investigated both experimentally and theoretically for the first time. Single photon ionization through 193, 118, and 46.9 nm lasers is used to detect neutral cluster distributions through time of flight mass spectrometry (TOFMS). Al(m)C(n) clusters are generated through laser ablation of a mixture of Al and C powders pressed into a disk. An oscillation of the vertical ionization energies (VIEs) of Al(m)C(n) clusters is observed in the experiments. The VIEs of Al(m)C(n) clusters change as a function of the numbers of Al and C atoms in the clusters. Al(m)C(n)H(x) clusters are generated through an Al ablation plasma-hydrocarbon reaction, an Al-C ablation plasma reacting with H(2) gas, or through cold Al(m)C(n) clusters reacting with H(2) gas in a fast flow reactor. The VIEs of Al(m)C(n)H(x) clusters are observed to vary as a function of the number of H atoms in the clusters. Density functional theory and ab initio calculations are carried out to explore the structures, ionization energies, and electronic structures of the Al(m)C(n) and Al(m)C(n)H(x) clusters. C=C bonds are favored for the lowest energy structures for Al(m)C(n) clusters. H atoms can be bonded to either Al or C atoms in forming Al(m)C(n)H(x) clusters, with little difference in energy. Electron density plots of the highest occupied molecular orbitals (HOMOs) for closed shell species and the singly occupied molecular orbitals (SOMOs) for open shell species of Al(m)C(n) and Al(m)C(n)H(x) clusters are presented and described to help understand the physical and chemical properties of the observed species. VIEs do not simply depend on open or closed shell valence electron configurations, but also depend on the electronic structure details of the clusters. The calculational results provide a good and consistent explanation for the experimental observations, and are in general agreement with them. All calculated clusters are found to have a number of low lying isomeric structures. PMID- 20200734 TI - Improved reliability from a plasma-assisted metal-insulator-metal capacitor comprising a high-k HfO2 film on a flexible polyimide substrate. AB - We have used a sol-gel spin-coating process to fabricate a new metal-insulator metal (MIM) capacitor comprising a 10 nm-thick high-k thin dielectric HfO(2) film on a flexible polyimide (PI) substrate. The surface morphology of this HfO(2) film was investigated using atomic force microscopy and scanning electron microscopy, which confirmed that continuous and crack-free film growth had occurred on the film surface. After oxygen (O(2)) plasma pretreatment and subsequent annealing at 250 degrees C, the film on the PI substrate exhibited a low leakage current density of 3.64 x 10(-9) A cm(-2) at 5 V and a maximum capacitance density of 10.35 fF microm(-2) at 1 MHz. The as-deposited sol-gel film was completely oxidized when employing O(2) plasma at a relatively low temperature (ca. 250 degrees C), thereby enhancing the electrical performance. We employed X-ray photoelectron spectroscopy (XPS) at both high and low resolution to examine the chemical composition of the film subjected to various treatment conditions. The shift of the XPS peaks towards higher binding energy, revealed that O(2) plasma treatment was the most effective process for the complete oxidation of hafnium atoms at low temperature. A study of the insulator properties indicated the excellent bendability of our MIM capacitor; the flexible PI substrate could be bent up to 10(5) times and folded to near 360 degrees without any deterioration in its electrical performance. PMID- 20200735 TI - Gas-phase fluorescence excitation and emission spectroscopy of mass-selected trapped molecular ions. AB - A flexible interface to perform optical spectroscopic measurements on gaseous ions stored in a modified commercial quadrupole ion trap (QIT) mass spectrometer is described. The modifications made to the mass spectrometer did not adversely affect its operating characteristics. Gas-phase ions are produced using electrospray ionization, mass isolated and stored in the trapping mass spectrometer. The ions are subsequently irradiated with visible light from a tunable laser and dispersed fluorescence spectra are recorded simultaneously. Mass spectra are recorded after the irradiation period. This set-up allows us to track a range of possible outcomes upon photoexcitation of selected ions including fluorescence, photofragmentation and photodetachment of electrons. The experimental set-up is characterized using rhodamine 590, which is a methyl ester variant of rhodamine 6G. Fluorescence excitation and emission spectra of gaseous rhodamine 590 are measured and compared with solution-phase spectra. Excitation and emission maxima for the gaseous ions are found to lie at higher energy than for the solvated rhodamine 590. In addition, the gas-phase Stokes shift is significantly smaller than the solution-phase Stokes shift. The effects of several experimental parameters on the observed fluorescence signal are investigated, including laser power, relative number of ions, q(z) trapping parameter and buffer gas pressure. In addition to its use for the photophysical characterization of the intrinsic properties of ionic chromophores, this set-up may be used to investigate the properties of mass-selected, dye-labeled biomolecules, both alone and in well-defined complexes and clusters. PMID- 20200736 TI - Weak forces at work in dye-loaded zeolite materials: spectroscopic investigation on cation-sulfur interactions. AB - The interaction between sulfur-containing chromophores and cationic species (K(+)) has been investigated in dye-loaded zeolite materials by means of photoluminescence spectroscopy. A red-shift in the emission spectra of the host guest compounds (HGCs) has been detected and unambiguously connected to the close proximity between a conjugated moiety and nearby free charges, suggesting a specific role played by sulfur lone pair electrons. Quantum-chemical calculations on model compounds have been performed to support this hypothesis. PMID- 20200737 TI - An ab initio/RRKM study of the reaction mechanism and product branching ratios of the reactions of ethynyl radical with allene and methylacetylene. AB - Ab initio CCSD(T)/cc-pVTZ//B3LYP/6-311G** calculations of the C(5)H(5) potential energy surface have been performed to investigate the reaction mechanism of ethynyl radical (C(2)H) with C(3)H(4) isomers, allene and methylacetylene. They were followed by RRKM calculations of reaction rate constants and product branching ratios under single-collision conditions. The results show that the C(2)H + CH(2)CCH(2) reaction in a case of statistical behavior is expected to produce 1,4-pentadiyne (56-63%), ethynylallene (22-24%), and pentatetraene (10 15%), with the most favorable pathways including H losses from the initial HCCCH(2)CCH(2) adduct leading to either 1,4-pentadiyne or ethynylallene, and a multistep route HCCC(CH(2))(2) --> four-member ring --> CH(2)CCCHCH(2) --> CH(2)CCCCH(2) + H featuring a formal insertion of C(2)H into a double bond of allene followed by H elimination giving rise to pentatetraene. On the contrary, the C(2)H + CH(3)CCH reaction produces diacetylene + methyl (21-61%) by CH(3) loss from the HCCC(CH)CH(3) initial adduct as well as methyldiacetylene + H (27 56%) and ethynylallene + H (11-22%) by H eliminations from CHCCHCCH(3). The calculated product branching ratios are in general agreement with the available experimental data, although some quantitative deviations from experiment and possible reasons for them are also discussed. The present calculations confirm that the C(2)H + C(3)H(4) reactions proceed without entrance barriers and lead, via intermediates and transition states residing lower in energy than the initial reactants, to the C(5)H(4) + H and C(4)H(2) + CH(3) products exothermic by 20-36 kcal mol(-1), with strong dependence of the product distribution on the reacting C(3)H(4) isomer, making these reactions fast under low-temperature conditions of Titan's atmosphere where they can serve as a source of more complex unsaturated hydrocarbons. PMID- 20200738 TI - Surface diffusion in porous catalysts. AB - This paper presents the application of pulsed field gradient (PFG) nuclear magnetic resonance (NMR) to observe surface diffusion of 1-octene in porous 1 wt% Pd/theta-Al(2)O(3) catalyst trilobes. We demonstrate for the first time the ability to identify diffusion on the pore surfaces unambiguously at ambient conditions in saturated porous media; this technique is applicable to microporous and mesoporous materials in general. At very short observation times, two distinct diffusion regimes are present. These are associated with the bulk pore and pore surface diffusion of 1-octene; using the model proposed by Karger for two site exchange we determined the diffusion coefficients of these regimes to be 1.3 x 10(-9) and 1.7 x 10(-11) m(2) s(-1), respectively, and the mean residence time of a molecule on the pore surface to be 150 ms. Treatment of the catalyst trilobes with a silane surface coating is seen to influence the surface such that a surface diffusion coefficient is no longer observed, supporting the interpretation that the molecular dynamics of surface diffusing species are influenced strongly by their interaction with hydroxyl groups on the alumina surface. This technique will enable further study and improved understanding of molecular transport in porous catalysts used in liquid-phase, heterogeneous catalytic processes. PMID- 20200739 TI - Rapid syntheses of a metal-organic framework material Cu3(BTC)2(H2O)3 under microwave: a quantitative analysis of accelerated syntheses. AB - A typical MOF material, Cu-BTC has been synthesized with microwave and conventional electric heating in various conditions to elucidate, for the first time, the quantitative acceleration in the synthesis of a MOF by microwaves. The acceleration by microwaves is mainly due to rapid nucleation rather than rapid crystal growth, even though both stages are accelerated. The acceleration in the nucleation stage by microwaves is due to the very large pre-exponential factor (about 1.4 x 10(10) times that of conventional synthesis) in the Arrhenius plot. However, the activation energy for the nucleation in the case of microwave synthesis is higher than the activation energy of conventional synthesis. The large acceleration in the nucleation, compared with that in the crystal growth, is observed once again by the syntheses in two-steps (changing heating methods from microwave into conventional heating or from conventional heating into microwave heating just after the nucleation is completed). The crystal size of Cu BTC obtained by microwave-nucleation is generally smaller than the Cu-BTC made by conventional-nucleation, probably due to rapid nucleation and the small size of nuclei with microwave-nucleation. PMID- 20200740 TI - Electro-optical study of chiral nematic liquid crystal/chiral ionic liquid composites with electrically controllable selective reflection characteristics. AB - A chiral nematic liquid crystal (N*-LC)/chiral ionic liquid (CIL) composite with unique electro-optical characteristics was prepared and filled into a planar treated cell. When an electric field was applied to the cell, the anions and the cations of CIL moved towards the anode and the cathode of the power supply, respectively, thus forming a density gradient of the chiral groups, which resulted in wideband reflection. By adjusting the intensity of the electric field, the reflection bandwidth can be controlled accurately and reversibly. Moreover, the electric field-induced states can be memorized after the applied electric field is turned off. The reflective properties of the composite are investigated in the visible and near-infrared region, respectively. Additionally, the changes of the reflection bandwidths with the intensity and the applied time of the electric field were also investigated. From scanning electron microscopy (SEM) investigations, the mechanism of the electrically controllable reflection was demonstrated. Potential applications of the composite are related to reflective, color electronic paper (E-paper) and smart reflective windows for the solar light management. PMID- 20200741 TI - Interaction of water, hydrogen and their mixtures with SnO2 based materials: the role of surface hydroxyl groups in detection mechanisms. AB - DRIFTS, TGA and resistance measurements have been used to study the mechanism of water and hydrogen interaction accompanied by a resistance change (sensor signal) of blank and Pd doped SnO(2). It was found that a highly hydroxylated surface of blank SnO(2) reacts with gases through bridging hydroxyl groups, whereas the Pd doped materials interact with hydrogen and water through bridging oxygen. In the case of blank SnO(2) the sensor signal maximum towards H(2) in dry air (R(0)/R(g)) is observed at approximately 345 degrees C, and towards water, at approximately 180 degrees C, which results in high selectivity to hydrogen in the presence of water vapors (minor humidity effect). In contrast, on doping with Pd the response to hydrogen in dry air and to water occurred in the same temperature region (ca. 140 degrees C) leading to low selectivity with a high effect of humidity. An increase in water concentration in the gas phase changes the hydrogen interaction mechanism of Pd doped materials, while that of blank SnO(2) is unchanged. The interaction of hydrogen with the catalyst doped SnO(2) occurs predominantly through hydroxyl groups when the volumetric concentration of water in the gas phase is higher than that of H(2) by a factor of 1000. PMID- 20200742 TI - Glancing-angle Raman spectroscopic probe for reaction kinetics at water surfaces. AB - We report glancing-angle Raman spectra acquired at the surface of aqueous dimethyl sulfoxide solutions and demonstrate that this technique can be used to measure the surface concentration of solutes. The presence of some solute molecules at the surface suppresses the intensity of the OH-stretching band of water there. We used this phenomenon to study the interfacial reaction of gas phase ozone with aqueous NaX solutions (X = Br, I) by monitoring the decrease in intensity of the OH-stretching band of water over time. UV-VIS analysis of the product solutions indicates that X(3)(-), formed from X(2) evolved in the ozonation reaction, is the species most likely responsible for the decrease in OH stretching intensity at the surface. The dependence of the rate of OH-Raman signal loss at the water surface on the bulk halide concentration is well described by a Langmuir-Hinshelwood kinetic model. The Langmuir-Hinshelwood parameters indicated that iodide has a approximately 50 times greater propensity for the surface compared to bromide. PMID- 20200743 TI - Dynamics of multi-channel dissociation of tetrahydrofuran photoexcited at 193 nm: distributions of kinetic energy, angular anisotropies and branching ratios. AB - We investigated the photodissociation dynamics of tetrahydrofuran (c-C(4)H(8)O) at 193.3 nm in a molecular-beam apparatus using photofragment-translational spectroscopy and direct vacuum-ultraviolet (VUV) photoionization. Five dissociation channels leading to products with m/z ratios appropriate for CH(2)CH(2)CH(2) + H(2)CO, CH(2)CHCH(2) + CH(2)OH, H + CH(2)CH(2) + CH(2)CHO, CH(2)CH(2) + CH(3) + HCO and CH(2)CH(2) + CH(2)CO + H(2) were identified; their branching ratios were determined to be 0.40, 0.25, 0.04 0.29 and 0.02, respectively. Secondary dissociations from nascent products CH(2)CH(2)CH(2)CHO to CH(2)CH(2) + CH(2)CHO and from CH(2)CH(2)O to CH(3) + HCO and likely to CH(2)CO + H(2) were observed. We measured distributions of product kinetic energy, average kinetic-energy release, and fractions in translation for each dissociation channel. The formation of CH(2)CHCH(2) + CH(2)OH indicates that hydrogen migration occurs before complete fragmentation. All photofragments have nearly isotropic angular distributions, with |beta| values less than 0.05. The photodissociation of tetrahydrofuran into five channels is proposed to proceed mainly on the ground state potential-energy surface following ring opening and efficient internal conversions. PMID- 20200744 TI - Theoretical investigation of hydrogen atom transfer in the adenine-thymine base pair and its coupling with the electronic rearrangement. Concerted vs. stepwise mechanism. AB - Two different mechanisms to obtain the imino-enol tautomer of the adenine-thymine base pair, a concerted hydrogen atom transfer and a stepwise process, have been studied and compared. The first mechanism includes both the concerted movement of two hydrogen atoms, in the bridges that bond the two bases, and an electronic reorganisation of the bonds. The stepwise mechanism is the simplest one where there is a correlation between the movement of the hydrogen atoms, but two or more steps can be identified. In this study, a different behaviour has been found when the first atom to move is the hydrogen in the N-N bridge or that in the N-O one. PMID- 20200745 TI - Reactivity of crotonaldehyde and propene over Au/Pd(111) surfaces. AB - The surface chemistry of crotonaldehyde and propene, primary and secondary reaction products in the aerobic selective oxidation of crotyl alcohol, has been studied by temperature-programmed reaction over Au/Pd(111) surface alloys. Gold strongly promotes desorption versus reaction at mole fractions > or = 0.3 (crotonaldehyde) and > or = 0.8 (C(3)H(6)); only approximately 5% of the chemisorbed aldehyde or alkene react over Au-rich alloys. Surprisingly, co adsorbed oxygen strongly suppresses crotonaldehyde decomposition over both clean Pd(111) and alloy surfaces, while C(3)H(6) combustion, an important undesired side-reaction over unpromoted Pd(111), is also moderated by Au. PMID- 20200746 TI - Carbon and proton shielding tensors in methyl halides. AB - The series of methyl halides, CH(3)X (X = F, Cl, Br, and I), is prototypic for demonstrating the s.c. normal halogen dependence of light-atom nuclear magnetic resonance shielding constants in the presence of halogen atoms of varying electronegativity. We report a systematic experimental and first-principles theoretical study of the (13)C and (1)H shielding tensors in this series. The experimental shielding constants were obtained from gas-phase NMR experiments and the anisotropies were determined using liquid crystal NMR spectroscopy. After taking into account rovibrational effects and solute-solvent interactions, this provided the currently best experimental estimates for the full shielding tensors. Quantum chemical calculations were carried out at ab initio and density functional theory levels, involving relativistic corrections taken into account at the leading-order Breit-Pauli perturbation level. Anharmonic and harmonic vibrational corrections were performed. The main trends of the shielding constants and anisotropies of the nearby light (13)C and (1)H nuclei as functions of the halogen mass, were confirmed to be mainly due to relativistic spin-orbit effects. For carbon, also the scalar relativistic effects are important for quantitative results. Thermal averaging at 300 K decreases the magnitude of all the parameters but exhibits partial cancellation between the nonrelativistic and smaller relativistic rovibrational averages. For the shielding anisotropy, the relativistic terms add to the negative rovibrational effect. Overall, the current experimental and theoretical results are in excellent agreement for all the shielding parameters, setting a standard for further investigations of normal halogen dependence. PMID- 20200747 TI - An investigation of slow charge separation in a tyrosine M210 to tryptophan mutant of the Rhodobacter sphaeroides reaction center by femtosecond mid-infrared spectroscopy. AB - Energy and electron transfer in a tyrosine M210 to tryptophan (YM210W) mutant of the Rhodobacter sphaeroides reaction center (RC) were investigated through time resolved visible pump/mid-infrared (mid-IR) probe spectroscopy at room temperature, with the aim to further characterize the primary charge separated states in the RC. This mutant is known to display slow and multi-exponential charge separation, and was used in earlier work to prove the existence of an alternative route for charge separation starting from the accessory bacteriochlorophyll in the active branch, B(L). The mutant RCs were excited at 860 nm (direct excitation of the primary donor (P) BChls (P(L)/P(M))), 600 nm (unselective excitation), 805 nm (direct excitation of both accessory bacteriochlorophyll cofactors B(L) and B(M)) and 795 nm (direct excitation of B(L)). Absorption changes associated with carbonyl (C=O) stretch vibrational modes of the cofactors and protein were recorded in the region between 1600 and 1775 cm(-1), and both a sequential analysis and simultaneous target analysis of the data were performed. The decay of P* in the YM210W mutant was multi exponential with lifetimes of 29 and 63.5 ps. The decay of P(+)B(L)(-) state was approximately 10 times longer in the YM210W RC than in the R-26 RC (approximately 7 ps vs. approximately 0.7 ps), and in the mid-IR difference absorption spectrum of P(+)B(L)(-) the stretching frequency of the 9-keto C=O group of B(L) in the ground state was located around 1675-1680 cm(-1), consistent with the presence of a hydrogen bond donated by an adjacent water molecule. Excitation at 795 nm produced a small amount of B(L)*-driven charge separation, as assessed from the excitation wavelength dependence of the raw difference spectra recorded during the first few ps after excitation. This process led to the formation of P(+)B(L)( ). Only the relaxed form of the P(+)H(L)(-) radical pair was observed in the YM210W mutant, and the mid-IR difference absorption spectra of P(+)H(L)(-) and P(+)B(L)(-) showed a change in the relative amplitude of the P(L)(+) and P(M)(+) bands when compared to equivalent spectra for the R-26 RC. This indicates that the YM210W mutation causes an increased localization of the electron hole on the P(M) half of the dimer. The absorbance difference spectrum of P(+)H(L)(-) in the R-26 RC contains a feature attributable to a Stark shift of one or more amide C=O oscillators. This feature was shifted to lower frequency by approximately 5 cm( 1) in the YM210W RC, and consideration of the limited structural changes in this RC indicates that this feature arises from an amide C=O group in the immediate vicinity of the M210 residue, most probably that of the adjacent M209 amino acid. PMID- 20200748 TI - Fast photo-processes in triazole-based push-pull systems. AB - Electron donor-acceptor compounds 1 (asymmetrical push-pull derivative) and 2 (symmetrical push-pull-push derivative) were studied in which one (push-pull) or two aniline units (push-pull-push) are connected to a biphenyl group via triazole linkers, made by "click" chemistry. Steady-state and time-resolved spectroscopies indicate that highly dipolar charge separated excited states are populated in moderately polar solvents. The very similar photophysical behavior of both compounds implies symmetry breaking in the excited state of 2. The polarity of the solvent determines the efficiency of formation of the charge separated state. While in toluene it is very low, it becomes very high in acetonitrile. The bis triazole substituted biphenyl unit in 2 behaves as a better electron acceptor than the mono-triazole substituted biphenyl in 1, which leads to a more facile charge separation in 2. Rates of charge separation are of the order of 10(11) 10(12) s(-1), and increase with solvent polarity. PMID- 20200749 TI - Ab initio study of the antiferromagnetic coupling in the wheel-shaped [Cu20Cl(OH)24(H2O)12(P8W48O184)]25- anion. AB - The most stable spin configuration in the Cu(20) unit embedded in the P(8)W(48)O(184) POM framework has been analyzed with ab initio computational methods. Because of the large size of the Cu(20) unit, a fragment approach has been adopted to compute the four possible magnetic interactions. Difference Dedicated Configuration Interaction results reveal that the magnetic coupling between unpaired copper electrons ranges from ferromagnetic (J = 14.8 cm(-1)) to antiferromagnetic (J = -72.6 cm(-1)). With the four calculated J-values we have performed a simulation of the magnetic susceptibility vs. temperature by using the Ising model and a Monte Carlo algorithm to sample the spin configurations. The most stable spin alignment, governed by the most intense antiferromagnetic interaction, features 12 up and 8 down spins. There is no full cancellation of spins that can comply with the magnetic interactions found for this molecule. PMID- 20200750 TI - Unraveling solvent effects on the electronic absorption spectra of TRITC fluorophore in solution: a theoretical TD-DFT/PCM study. AB - In this paper the equilibrium between the two ground state forms of TRITC in solvents of different polarity has been studied by means of state of the art DFT calculations using the polarizable continuum model (PCM) for including bulk solvent effects. TD-DFT/PCM calculations have been used to calculate vertical excitation energies and the UV-Vis spectra of TRITC has been interpreted in terms of the equilibrium between different forms, which is modulated by the microenvironment embedding the molecule. We show that the most intense absorption bands are sensitive to solute-solvent interactions and provide a distinctive signature of specific interactions. The good agreement with experimental data makes our approach suitable to study and monitor modifications of the chemical environment of fluorophores in different solutions as well as in interaction with biological systems and nanoparticles. PMID- 20200751 TI - Theoretical study of electronic structures of [(H2O)3(O-)Mn(mu-oxo)2Mn(OH2)4]q+ (q = 2 or 3) with Mn-O bond. AB - Molecular geometries and electronic structures of manganese binuclear complexes, [(H(2)O)(3)(O-)Mn(bis-mu-oxo-O(2))Mn(OH(2))(4)](q+) (q = 2 or 3), which are model complexes of the S(3) state in the Kok cycle of OEC, were examined using hybrid density functional theory and broken symmetry method. The complexes of q = 2 and 3, which have a Mn-O bond, correspond to those derived from Mn(2)(II,III) and Mn(2)(III,III) at the S(0) state of the Kok cycle. The conformers with the Mn-O bond axial to the Mn(2)O(2) core are lower in energy than those with the equatorial Mn-O bond. The equatorial Mn-O bonds are assigned as Mn(III)-O*(-) and Mn(IV)-O*(-) for M(2)(II,III) and M(2)(III,III) series, respectively. The axial Mn-O bonds are Mn(IV)=O(2-) for M(2)(II,III) and Mn(IV)-O*(-) for Mn(2)(III,III). The characters of Mn-O orbitals are pi-orbitals composed of d-p interactions. The conformer with the axial Mn(IV)=O(2-) derived from M(2)(II,III) at S(0) is thermochemically unstable, leading to proton transfer to give two OHs in the complex, while the axial Mn(IV)-O*(-) from Mn(2)(III,III) at S(0) is stable without the proton transfer. The magnetic interactions between two Mn ions and O were also examined by estimations of effective exchange integrals. PMID- 20200752 TI - A new battery-charging method suggested by molecular dynamics simulations. AB - Based on large-scale molecular dynamics simulations, we propose a new charging method that should be capable of charging a lithium-ion battery in a fraction of the time needed when using traditional methods. This charging method uses an additional applied oscillatory electric field. Our simulation results show that this charging method offers a great reduction in the average intercalation time for Li(+) ions, which dominates the charging time. The oscillating field not only increases the diffusion rate of Li(+) ions in the electrolyte but, more importantly, also enhances intercalation by lowering the corresponding overall energy barrier. PMID- 20200753 TI - Cyclohexane selective photocatalytic oxidation by anatase TiO2: influence of particle size and crystallinity. AB - A systematic study is presented on the effect of crystallite size of Anatase (Hombikat, Sachtleben), varied by calcination at different temperatures up to 800 degrees C, on photocatalytic activity in cyclohexane selective oxidation. Two different reactors were used to test the materials: a top illumination reactor and an in situ ATR-FTIR cell. Properties such as crystallinity and associated availability of holes and electrons for surface reactions, as well as the amount of surface OH-groups, are shown to have a significant influence on TiO(2) activity, (surface) selectivity, and stability. Upon increasing the crystallite size, productivity (g(-1)(catalyst)) decreases, while (i) the TOF (moles of cyclohexanone formed per minute per OH-site), (ii) the rate of cyclohexanone desorption, (iii) catalytic site stability, and (iv) the cyclohexanol/cyclohexanone ratio increase. The results are discussed on the basis of a reaction scheme, and a simple reaction rate equation. PMID- 20200754 TI - Calculation of absorption and emission spectra of [n]cycloparaphenylenes: the reason for the large Stokes shift. AB - The electronic absorption and emission spectra of the [n]cycloparaphenylenes with n = 6,7,...,11 ([n]CP) have been studied at the time-dependent density functional theory level. The calculations show that the optical gap increases with increasing size of the ring due to reduced ring strain in the larger carbon nanohoops, whereas the energy of the first bright state follows the opposite trend for the studied [n]CPs. For the excited-state structures, the C-C bonds between the phenylene groups have a significant double-bond character giving rise to a continuous electron delocalisation pathway around the ring. The torsion angles between the phenylene moieties are much smaller for the excited state than for the ground state suggesting that the excited state has a stronger electron delocalisation around the carbon nanohoop than for the ground state. The double bond character of the phenylene C-C bonds declines and the phenylene torsion angle increases with increasing ring size. The aromatic stabilisation of the excited state due to the continuous electron delocalisation pathway is probably the main reason for the large Stokes shift. The excited state of the larger [n]CPs are less aromatic than the smaller ones explaining why the Stokes shift decreases with increasing size of the ring. For large [n]CPs, the excitation energy spectrum forms bands making localisation of the excitons feasible. Localisation of the excitons probably leads to the observed ring-size independence of the electronic excitation spectra for large [n]CPs. PMID- 20200755 TI - Calibration of 57Fe isomer shift from ab initio calculations: can theory and experiment reach an agreement? AB - Using linear response approach to the Mossbauer isomer shift, the calibration constant alpha((57)Fe) was obtained from high level ab initio calculations carried out for a representative set of iron compounds. The importance of the effects of relativity and electron correlation for an accurate description of the (57)Fe isomer shift is demonstrated on the basis of the Hartree-Fock, coupled cluster with singles and doubles and of the double hybrid density functional calculations. A reliable value of the calibration constant (alpha((57)Fe) = 0.306 +/- 0.009 mm s(-1)) was obtained with the use of the B2-PLYP double hybrid density functional. This value is in good agreement with the experimentally estimated constant of -0.31 +/- 0.04 a(0)(3) mm s(-1) and can be recommended for theoretical modeling of (57)Fe isomer shifts. PMID- 20200757 TI - Maternal concentrations of perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) and duration of breastfeeding. AB - OBJECTIVE: Perfluorooctanoate (PFOA) has been associated with impaired lactation in mice. We examined whether maternal perfluorooctanesulfonate (PFOS) and PFOA concentrations correlated with duration of breastfeeding among women. METHODS: We randomly selected 1400 pregnant women from the Danish national birth cohort (1996 2002) and measured PFOS and PFOA concentrations in early pregnancy by using high performance liquid chromatography/tandem mass spectrometry. Self-reported data on the duration of any and exclusive breastfeeding were collected twice during telephone interviews around 6 and 18 months after the birth of the child. RESULTS: The duration of breastfeeding decreased with increasing concentrations of pregnancy PFOS and PFOA among multiparous women, for whom the adjusted odds ratios (OR) for weaning before 6 months of age were 1.20 (95% CI 1.06-1.37) per 10 ng/ml increase in PFOS concentrations and 1.23 (95% CI 1.13-1.33) per 1 ng/ml increase in PFOA concentrations. No consistent association was found for primiparous women. CONCLUSIONS: These findings suggest that PFOA and PFOS may reduce the ability to lactate, but could equally reflect reverse causation since no association was seen in primiparous women. PMID- 20200758 TI - Osteomyelitis of the scapula with secondary septic arthritis of the shoulder joint. AB - We report a delayed diagnosis of osteomyelitis of the scapula involving the inferior angle and extending to the glenoid, with secondary septic arthritis of the glenohumeral joint in a 7-month-old female infant. The patient was treated with arthrotomy of the shoulder joint, anterior drainage of pus and intravenous antibiotics. The diagnosis was delayed as the patient was found to have bilateral lung abscess and other foci of infection, for which she was treated in the neonatal intensive care unit, with all the medical efforts directed towards saving her life. The diagnosis of septic shoulder arthritis is uncommon and difficult, requiring a high index of suspicion, which was another reason for the delayed diagnosis. PMID- 20200759 TI - Neonatal intrahepatic cholestasis caused by citrin deficiency in two Malaysian siblings: outcome at one year of life. AB - We report two Malaysian siblings with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). The younger sibling, a six-month-old Chinese girl, presented with prolonged neonatal jaundice, and was investigated for biliary atresia. Urine metabolic screen showed the presence of urinary-reducing sugars, and she was treated with a lactose-free formula. NICCD was suspected based on the clinical history, examination and presence of urinary citrulline. Mutation study of the SLC25A13 gene showed the compound heterozygotes, 851del4 and IVS16ins3kb, which confirmed the diagnosis of NICCD in the patient and her three-year-old female sibling, who also had unexplained neonatal cholestasis. Long-term dietary advice, medical surveillance and genetic counselling were provided to the family. The diagnosis of NICCD should be considered in infants with unexplained prolonged jaundice. DNA-based genetic testing of the SLC25A13 gene may be performed to confirm the diagnosis retrospectively. An awareness of this condition may help in early diagnosis using appropriate metabolic and biochemical investigations, thus avoiding invasive investigations in infants with neonatal cholestasis caused by NICCD. PMID- 20200760 TI - Tubercular granuloma in the myocardium: an autopsy report. AB - Granulomatous myocarditis is a rare disorder of the myocardium, and is usually associated with various inflammatory and autoimmune conditions. We report granulomatous myocarditis in an apparently healthy 58-year-old Indian man, who developed sudden chest pain and died while being escorted to the hospital. At the autopsy, no gross distinct cardiac lesions were observed. The histopathological sections from the left ventricular apex revealed a granuloma comprising a central area of caseous necrosis surrounded by lymphocytes, and epithelioid, plasma and Langhans giant cells. Myocardial tuberculosis was suspected as the underlying aetiology based on the histological features of the granuloma. PMID- 20200761 TI - Severe Kikuchi's disease responsive to immune modulation. AB - Kikuchi's disease, although an uncommon entity, has been increasingly reported since it was first discovered in 1972. The most common manifestation of Kikuchi's disease, cervical lymphadenopathy, has no clinically distinguishable features. Therefore, a diagnosis of Kikuchi's disease has largely been based on clinical suspicion and histopathological confirmation. We present a 15-year-old Chinese girl with severe Kikuchi's disease, whose relapsing course was only responsive to highdose steroid and intravenous immunoglobulin therapy. PMID- 20200762 TI - Pulmonary artery thrombus seen as a solitary pulmonary nodule on chest radiograph. AB - Solitary pulmonary nodule (SPN) is a diagnostic challenge for both radiologists and physicians. There have been numerous common and uncommon causes of SPN. We report a 30-year-old Indian man with pulmonary thromboembolism, where the pulmonary thrombus was seen as a SPN on the chest radiograph. To the best of our knowledge, this observation has not been published in the literature. PMID- 20200763 TI - Vessels in femoral triangle in a rare relationship. AB - The femoral region of the thigh is utilised for various clinical procedures, both open and closed, particularly in respect to arterial and venous cannulations. A rare vascular pattern was observed during the dissection of the femoral region on both sides of the intact formaldehyde-preserved cadaver of a 42-year-old Indian man from West Bengal. The relationships and patterns found were contrary to the belief that the femoral vein is always medial to the artery, just below the inguinal ligament and the common femoral artery. The femoral artery crossed the vein just deep to the inguinal ligament so that the femoral vein was lying deep to the artery at the base of the femoral triangle. Just deep to the inguinal ligament, the profunda femoris artery (deep femoral artery) arose from the femoral artery, and the long saphenous vein drained into the femoral vein. The embryological and clinical correlations are discussed. PMID- 20200764 TI - Multiple variations of the hepatobiliary vasculature including a splenomesenteric trunk. AB - Anatomical variations of the origins and branching patterns of the hepatobiliary system may be encountered during both surgical and laparoscopic procedures. We report the rare finding of a splenomesenteric trunk with an absent coeliac trunk in a 74-year-old female cadaver. Due to the absence of the coeliac trunk, the common hepatic artery was found to originate from the splenic artery. Embryological considerations and possible clinical consequences are discussed. PMID- 20200765 TI - The first case of Silver-Russell syndrome accompanied by linea alba hernia in China. AB - A 10-month-old Chinese boy presented with delayed motor development for seven months. Blood and biochemistry investigations revealed no abnormalities. The physical examination showed poor postnatal growth (below -2 standard deviation from the mean at diagnosis), preservation of the occipitofrontal head circumference with delayed closure of the anterior fontanel, a classical triangular facial phenotype, asymmetry of the lower extremities and other characteristic features that fulfil the diagnostic criteria of Silver-Russell syndrome clinically. As PubMed and web searches revealed no similar findings, we believe that this may be the first case of Silver-Russell syndrome with linea alba hernia and pes varus reported in China, and possibly the world. The genetic deficit responsible for this case is still under investigation. PMID- 20200766 TI - Medicine in stamps. Ivan Petrovich Pavlov (1849-1936): conditioned reflexes. PMID- 20200768 TI - Diagnostic tests for food allergy. AB - The diagnosis of food allergy is still based primarily on a detailed medical history and comprehensive physical examination. Clinical or laboratory tests only serve as an add-on tool to confirm the diagnosis. The standard techniques include skin prick testing and in-vitro testing for specific IgE-antibodies, and oral food challenges. Properly done, oral food challenges continue to be the gold standard in the diagnostic workup. Recently, unconventional diagnostic methods are increasingly used. These include food specific IgG, antigen leucocyte antibody and sublingual/intradermal provocation tests, as well as cytotoxic food and applied kinesiology and electrodermal testings. These lack scientific rationale, standardisation and reproducibility. There have been no well-designed studies to support these tests, and in fact, several authors have disproved their utility. These tests, therefore, should not be advocated in the evaluation of patients with suspected food allergy because the results do not correlate with clinical allergy and may lead to misleading advice and treatment. PMID- 20200769 TI - Writing a case report. AB - A case report is a description of a single case with unique features. This includes a previously-unreported clinical condition, previously-unreported observation of a recognised disease, unique use of imaging or diagnostic test to reveal a disease, previously-unreported treatment in a recognised disease, or previously-unreported complication of a procedure. Case reports should be short and focused, with a limited number of figures and references. The structure of a case report usually comprises a short unstructured (or no) abstract, brief (or no) introduction, succinct but comprehensive report of the case, and to-the-point discussion. PMID- 20200770 TI - Egyptian ever-married women's attitude toward discontinuation of female genital cutting. AB - INTRODUCTION: This study aimed to examine Egyptian ever-married women's beliefs and attitude toward the discontinuation of female genital cutting (FGC). We also examined the significant sources of information which the women with positive attitude were exposed to the year prior to the survey. METHODS: In a national representative community-based sample of 15,573 ever-married Egyptian women, the intention to continue the practice of FGC and other sociodemographical variables were collected from the 2000 Egypt Demographic and Health Survey data. A secondary in-depth analysis was conducted on the data in order to investigate the women's attitude and its associated factors. RESULTS: Only 12.4 percent of the sample intended to discontinue the practice. The logistic regression models showed that women with a positive attitude to discontinue the practice believed that FGC was not an important part of religious traditions, that husbands did not prefer a cut wife, and that FGC reduced sexual desire. The most significant sources of information related to a positive attitude to discontinue the practice were community discussions, the mosques or churches and the newspapers. CONCLUSION: The aforementioned sources of information are related to the social and religious aspects of women in the Egyptian community. In order to change women's attitude toward the discontinuation of this unhealthy practice, communication rather than passive learning is needed. PMID- 20200771 TI - Antiepileptic drug utilisation and seizure outcome among paediatric patients in a Malaysian public hospital. AB - INTRODUCTION: The primary purpose of this study was to evaluate the utilisation pattern and seizure outcome of newer and older antiepileptic drugs in paediatric clinical practice in a Malaysian hospital setting. METHODS: Over a two-month period, all paediatric epilepsy patients from Penang General Hospital, Malaysia who were diagnosed according to the classification of the International League Against Epilepsy were followed up prospectively, and the patients' information was gathered with the help of a validated data collection form. This included demographic characteristics, monotherapy and polytherapy of antiepileptic drugs, as well as the number of seizures experienced. RESULTS: Partial seizures, including complex and simple partial seizures (47.2 percent), followed by generalised seizures (40 percent), were the most common seizure types found in this study. An average of 1.51 antiepileptic drugs per patient was prescribed, with 54.3 percent of the patients on monotherapy and 45.7 percent on polytherapy. Overall, sodium valproate was the most frequently prescribed antiepileptic drug (36.8 percent), followed by carbamazepine (30.2 percent) and lamotrigine (10.4 percent). Carbamazepine was the most frequently prescribed monotherapy (28.6 percent), followed by sodium valproate (17.1 percent). The newer antiepileptic drugs were also found to be used as monotherapy in 7.2 percent of the cases. Moreover, a significant difference was observed between the older and newer antiepileptic drugs in terms of the number of seizures experienced (p=0.027). Most (75 percent) of the seizure-free patients were on carbamazepine monotherapy. CONCLUSION: Monotherapy was the most frequently used remedy in all forms of epilepsy. Overall, sodium valproate was the most commonly used drug, while carbamazepine was found to be more frequently used as monotherapy. There was a significant difference found between the older and newer antiepileptic drugs, with 87.5 percent of seizure-free patients on older antiepileptic drugs. PMID- 20200772 TI - Drug utilisation among older inpatients in a teaching hospital in Western Nepal. AB - INTRODUCTION: The proportion of the elderly population in Nepal, though low, is steadily increasing. Studies on drug utilisation among geriatric patients in Western Nepal, a region with the highest proportion of the elderly in all of Nepal, are lacking. The present study was carried out at the Manipal Teaching Hospital, a 700-bed teaching hospital in Pokhara, Western Nepal. METHODS: The study was carried out from June 1, 2005 to May 31, 2006 using case records of discharged patients aged 60 years and older. This was an observational study that utilised a retrospective case notes review methodology. The microorganisms isolated on culture and their antibiotic sensitivity patterns were studied. Drug consumption was measured by the defined daily dose (DDD) per 100 bed-days. The mean cost of the drugs was calculated. The percentage of drugs prescribed by generic name and the percentages of fixed-dose combinations used were noted. The basic demographic information of older inpatients, drug utilisation patterns, drug consumption using DDD, organisms isolated and their antibiotic sensitivity patterns, and the mean cost of the drugs were studied. RESULTS: A total of 548 patients were admitted. Hypertension, acute exacerbation of chronic obstructive pulmonary disease and cancer were the most common illnesses among the patients. The mean number of drugs consumed by each patient was 7.73. Escherichia coli and Pseudomonas aeruginosa were the most common microorganisms isolated. Ranitidine, multivitamins, amlodipine, ipratropium and dextrose normal saline were most commonly prescribed. The DDD per 100 bed-days of ranitidine and omeprazole (highest values) was 33.48 and 3.51, respectively. The mean cost of drugs was USD26.6, and antibiotics accounted for around 40 percent of the cost. CONCLUSION: The use of a high number of drugs, and of parenteral drugs and intravenous fluids, is a common problem. The prescription of generic drugs is low. Guidelines for the use of drugs in the elderly are required and further studies are needed on this issue. PMID- 20200773 TI - Ruptured uterus in rural Uganda: prevalence, predisposing factors and outcomes. AB - INTRODUCTION: A ruptured uterus is a life-threatening obstetric complication that remains a major public health concern in low-income countries, particularly in Africa. It is a significant cause of maternal and perinatal morbidity and mortality. In Uganda, the prevalence remains high largely because most women do not deliver in health facilities. Further review of this problem may be helpful in the development of appropriate preventive strategies. METHODS: A five-year retrospective review of all cases of ruptured uterus admitted to Mityana Hospital, Uganda from January 1, 2003 to December 31, 2007 was conducted. RESULTS: Out of 14,656 deliveries, 73 cases of ruptured uterus were recorded, resulting in a ratio of 1 in 200. The highest incidence was in patients aged 20 24 years old, of parity 1-4 and residing in the Kassanda sub-county. Other predisposing factors included not attending antenatal care (67.1 percent), which was associated with rupture at home or with traditional birth attendants (TBAs) (Odds Ratio [OR] 6.29; 95 percent confidence interval [CI] 2.01-19.67), obstructed or prolonged labour (68.5 percent), which increased the likelihood of rupture before admission (OR 3.28; 95 percent CI 1.05-10.26), residing more than 10 kilometres from the hospital (64.4 percent), which increased the likelihood of rupture before admission (OR 3.62; 95 percent CI 1.16-11.32) and the existence of previous scars (19.2 percent), which decreased the likelihood of rupture before admission (OR 0.24; 95 percent CI 0.07-0.81). All the women had surgery, of which 14 percent had a total hysterectomy, 22 percent had a subtotal hysterectomy, 25 percent had a repair and bilateral tubal ligation, and 39 percent had a repair only. Eight percent of the women died, while seven percent of the babies were born alive. CONCLUSIONS: Uterine rupture is a disturbing problem in Uganda. There is a need to put in place a functional referral system for pregnant women that links the community and TBAs to the hospital, and a need to intensify information, education and communication programmes to encourage women and their partners to use the reproductive health services that are available to them. In addition, greater accessibility to equipped health facilities, the use of a partogram to monitor labour and timely interventions will go a long way to reducing uterine rupture. PMID- 20200774 TI - Leptin levels and antihypertensive treatment in preeclampsia. AB - INTRODUCTION: This study was carried out to investigate changes in the plasma leptin concentrations during preeclampsia treatment and to determine whether antihypertensive treatments, aimed at decreasing leptin levels, would improve foetal outcomes. METHODS: A prospective study was undertaken in 57 pregnant women with preeclampsia (37 with mild and 20 with severe preeclampsia) and 46 normal pregnant women who were matched in maternal and gestational age and body mass index. The mild preeclampsia group was treated with alpha-methyldopa, while the severe preeclampsia group was treated with a combination of alpha-methyldopa and nifedipine. RESULTS: The severe preeclampsia group had significantly lower platelet counts, higher systolic and diastolic blood pressures and elevated serum uric acid concentrations. Pre-treatment plasma leptin levels were significantly increased in the severe preeclampsia group (range 18.3-49.5) compared to the the mild preeclampsia group (range 20.7-45.4) and normal controls (range 8.6-19.2). Post-treatment plasma leptin levels in both the mild and severe preeclampsia groups (range 10.2-23.5 and 11.3-24.4, respectively) were statistically similar to those of the control group (range 9.1-20.7). Estimated foetal weight, intrauterine growth retardation and demise were statistically similar in the three study groups. CONCLUSION: Plasma leptin concentrations were found to be elevated in women diagnosed with severe preeclampsia. However, the exact mechanism underlying the increased plasma leptin levels in preeclampsia and the functional role of leptin in the development of hypertension need to be further clarified. Leptin has a promising future as a valuable marker to identity women with a high risk for preeclampsia. PMID- 20200775 TI - The safety of simultaneous bilateral versus unilateral total knee arthroplasty: the experience in a Korean hospital. AB - INTRODUCTION: The safety of simultaneous bilateral total knee arthroplasty (SBTKA) remains controversial. This study aimed to compare the postoperative outcomes of SBTKA versus unilateral total knee arthroplasty (UTKA) performed by a single surgeon at a tertiary teaching hospital in Korea. METHODS: 629 female patients with total knee arthroplasty (308 patients for SBTKA and 321 for UTKA) performed under combined spinal epidural anaesthesia (CSE) were selected, and their medical records during admission and follow-up visits for a duration of six months after discharge were reviewed. RESULTS: Although significantly higher incidences of postoperative confusion and hypoxia during hospitalisation and a longer hospital stay were demonstrated in the SBTKA group, the rates of serious postoperative complications, such as myocardial infarction and deep venous thrombosis, were not different between the groups during the hospital stay and six months afterwards. No death associated with the surgery was encountered in both groups. CONCLUSION: It was concluded that SBTKA under CSE may be considered to be relatively safe in Korean female patients. PMID- 20200776 TI - Relationship between apoptotic markers (Bax and Bcl-2) and biochemical markers in type 2 diabetes mellitus. AB - INTRODUCTION: Bax is essential for apoptosis in normal cells. However, overexpression of Bcl-2 enhances cell survival by suppressing apoptosis in cells subjected to apoptosis-inducing stimuli. The aim of this study was to examine the expression of apoptotic (Bax and Bcl-2) and biochemical markers in type 2 diabetics mellitus. METHODS: A test group comprising 41 type 2 diabetes mellitus patients and a control group comprising 36 non-diabetic patients were enrolled in this study. Skin biopsy tissue samples were stained immunohistochemically for Bcl 2 and Bax expressions. Fasting plasma glucose (FPG), triglycerides, total cholesterol (TC), high-density lipoprotein cholesterol (HDLC) and glycosylated haemoglobin A1c (A1C) were analysed. Low-density lipoprotein cholesterol (LDLC) was calculated. RESULTS: Bcl-2 expression was significantly higher (p-value is less than 0.001) in the control group. Bax expression was significantly higher (p value is 0.018) in the diabetic group. Positive Bcl-2 expression was observed in 18 of 36 (50 percent) controls. Positive Bcl-2 expression was found in 5 of 41 (12.2 percent) diabetics. There was a significant difference (p-value is less than 0.001) between the two groups for mean FPG, HDLC and A1C. There was no significant difference for TC, LDLC and triglycerides between the two groups. Positive Bax expression was found in 11 of 35 (31.4 percent) controls. The odds of developing Bcl-2 among non-diabetics were 12.67 times compared to diabetics (p value is less than 0.001). CONCLUSION: Prolonged hyperglycaemia induces apoptosis in the endothelial cells of diabetic ulcers, which aggravates microvasculopathy and delays tissue healing and regeneration. PMID- 20200778 TI - Sleep-disordered breathing in patients with Parkinson's disease. AB - INTRODUCTION: There are limited studies reporting the frequency of sleep disordered breathing (SDB) in Parkinson's disease (PD), and the figures quoted are variable, ranging from 2.5 to 66 percent. This study aimed to determine the prevalence and types of SBD in PD patients attending the Universiti Kebangsaan Malaysia Medical Centre neurology clinic, and the correlation between the subjective sleep symptoms using the Parkinson's disease sleep scale (PDSS) and the objective measurements using polysomnography (PSG). METHODS: This was a cross sectional study involving 46 PD patients over a period of six months. The patients' demographic data, Hoehn and Yahr staging and PDSS scores were collected. The patients were then subjected to overnight PSG using the Somnomedic system. RESULTS: There were 27 male and 19 female patients with a mean age of 64.0+/-9.7 years. 29 were Chinese, 15 Malay and 2 Indian. The mean duration of illness was 5.8+/-4.3 years. The mean PDSS score was 120.3+/-13.5. SDB was found in 54.6 percent of the patients (apnoeahypopnoea index [AHI] 5 and above), with 27.3 percent having moderate and severe SDB (AHI 15 and above). The median AHI was 6.7 (range 0-40.4). The prevalence of SDB in PD patients based on the AHI cutoffs were 27.3 percent for mild, 18.2 percent for moderate and 9.1 percent for severe. There were statistically significant positive correlations between the AHI and the neck circumference and between the AHI and the waist-hip ratio. There was no significant correlation between the AHI and PDSS, or the AHI and disease severity. CONCLUSION: There was a high prevalence of SBD in our PD patients, which was comparable to other studies. Obstructive sleep apnoea was the dominant type of SBD. There was no correlation between the subjective sleep symptoms using the PDSS and the objective measurements using PSG. PMID- 20200777 TI - Diabetic retinopathy in a Nigerian community. AB - INTRODUCTION: This study was designed to determine the prevalence of diabetic retinopathy among diabetic patients attending the medical outpatient department of the Federal Medical Centre, Owo, Ondo State, Nigeria. METHODS: This study was conducted between November 2007 and February 2008. Ethical clearance was obtained from the ethical committee of the hospital prior to carrying out the study. 100 diabetic patients selected by simple random sampling were interviewed with the aid of a semi-structured questionnaire. All the respondents had fundoscopy conducted at the eye clinic with the aid of a direct ophthalmoscope. The data was collated and analysed. RESULTS: The majority of the respondents (85 percent) had type 2 diabetes mellitus, while the rest (15 percent) had type 1 diabetes mellitus. 15 percent of the respondents had varying degrees of diabetic retinopathy. The duration of diabetes mellitus was significantly associated with the development of diabetic retinopathy at a p-value of 0.002. CONCLUSION: A few of the respondents had diabetic retinopathy. There is a need to create awareness among diabetic patients on the need for routine ocular examinations. PMID- 20200779 TI - Percutaneous transcatheter aortic valve replacement: first transapical implant in Asia. AB - Percutaneous transcatheter implantation of the aortic valve has been demonstrated as an alternative to open heart surgery in high-risk patients with symptomatic severe aortic stenosis (AS) who are not suitable for open surgery. The majority of these new devices are delivered via the transfemoral approach. However, due to the current size of delivery sheaths, the small and tortuous iliofemoral anatomy makes this approach challenging. The transapical approach provides a viable option for this patient subgroup. The first-in-Asia transcatheter aortic valve implantation via the transapical route is described. A 79-year-old Chinese woman with symptomatic severe AS and peripheral arterial disease, who was at high surgical risk, was successfully treated, and had good functional and haemodynamic results at the three-month follow-up. PMID- 20200780 TI - Giant cell (temporal) arteritis in Singapore: an occult case and the rationale of treatment. AB - Further observations in respect of giant cell arteritis (GCA) as encountered in a local neuro-ophthalmology service established in Singapore ten years earlier are reported. The rarely seen occult form of the disease is described along with an illustrative case report concerning an 80-year-old woman. The overall management of GCA is discussed in respect of four clinical scenarios and their treatment. PMID- 20200781 TI - Fingertip injuries. AB - Fingertip injuries are commonly seen by family and emergency physicians. Many of the cases are simple to treat and do not need specialised treatment by a hand surgeon. However, there are certain conditions where early intervention by a hand surgeon is warranted for better functional and aesthetic outcomes. Common injuries include mallet finger injury, crush injuries to the fingertip with resultant subungual haematoma, nail bed laceration, partial or complete amputation of the fingertips, pulp amputations and fractures of the distal phalanges. PMID- 20200782 TI - Amikacin in neonates: dosing recommendations should be based on both pharmacokinetics and dynamics. PMID- 20200785 TI - Non Omnis Moriar: In memoriam of Professor Kazimierz Jaskiewicz (1942-2009). PMID- 20200786 TI - Oncogenic osteomalacia associated with phosphaturic mesenchymal tumour, mixed connective tissue type of the knee. AB - One of the most unusual and uncommon types of osteomalacia is the oncogenic osteomalacia that is predominantly caused by a soft tissue or bone tumour, mostly by a phosphaturic mesenchymal tumour, mixed connective tissue type (PMTMCT). We report a case of a 27-year-old male presented with complaints of progressive and generalized muscle weakness, bone pains and multiple fractures. Intra-articular PMTMCT of the knee was diagnosed and surgically removed. We describe histopathological features of PMTMCT and review the most recent studies concerning this diagnostic problem. PMID- 20200787 TI - Shortage of child and adolescent psychiatrists in Texas. AB - This study was conducted to determine how the current shortage of Texas child and adolescent psychiatrists (CAPs) impacts the delivery of mental health care services to indigent Texas youth. First, Texas Medical Board data detailed how many counties had CAPs and how many did not. Second, statewide Medicaid data revealed the number of prescriptions for psychotropics written for Medicaid youth by CAPs and non-CAPs. Third, Local Mental Health Authority (LMHA) encounter data of youth seen by a CAP were analyzed. Fourth, state census data gave the location and characteristics of youth by county. Eighty percent of counties in Texas, predominantly rural, do not have a CAP. Non-CAPs wrote 66% of psychotropic medication prescriptions written for Medicaid youth. Those in nonmetropolitan areas were more likely to see a non-CAP than were Medicaid youth in metropolitan areas. For youth seen by an LMHA, those in rural poor counties were less likely to see a CAP than were those in urban counties. The shortage of CAPs in Texas results in an unequal distribution of psychiatric care for those receiving Medicaid prescriptions or services through LMHAs, especially in rural areas. Suggestions to correct this shortage are made. PMID- 20200788 TI - Electronic medicine: TMB leery of treating patients online. PMID- 20200789 TI - Free advice: specialists say Medicare consultation code rule undervalues their work. PMID- 20200790 TI - The long wait: TMA practice consulting eases pain of credentialing. PMID- 20200791 TI - Vaccinator-in-chief: Houston physician Becomes chair of ACIP. PMID- 20200792 TI - DOs vs. Dos: proposed medical school creates rift between osteopathic physicians, UNT. PMID- 20200793 TI - A taxing situation: comptroller offers waiver on unpaid sales and use taxes. PMID- 20200794 TI - Positive development of the processing time--time span between acceptance and publication of papers in the IJSM from 2008 to 2010. PMID- 20200795 TI - Analytical variability in athletes haematological testing. PMID- 20200797 TI - [Pneumology - modern, with tradition]. PMID- 20200798 TI - [The position of respiratory medicine in Germany: status quo and future outlook]. PMID- 20200799 TI - [Sport activities of patients with severe COPD in an outpatient setting - only possible with self-guidance?]. PMID- 20200801 TI - Thigh muscles' responses caused by a single combined aerobic and resistance training session in healthy young men. AB - The aim of this study was to understand the amplitude and localization of neuromuscular response induced by a training session combining an aerobic and a resistance component. Ten healthy men completed a single session of combined (aerobic and resistance) and aerobic only training, in a randomized order. Surface electromyographic activity and torque obtained during maximal voluntary and electrically evoked contractions of the knee extensor muscles were analyzed to distinguish peripheral from central adaptations. The isometric torque developed by the knee extensor muscles during maximal voluntary contraction decreased significantly following a single session of both combined (-9.2%, p=0.043) and aerobic (-9.6%, p=0.005) training. This was accompanied by a decrease in central activation of the knee extensor muscles after each training session (respectively 2.9, p=0.005 and 1.8% p=0.040) as indicated by twitch interpolation technique. After the combined training protocol, the peak torque of the twitch significantly increased by 6.8% (p=0.046), whereas it decreased by 17.3% (p=0.016) after the aerobic training protocol. The present study demonstrates that the decrease in torque production is similar after a single combined training session or after an aerobic training session of the same duration. Both central and peripheral mechanisms could explain the decrease of torque. PMID- 20200802 TI - Influence of cardiopulmonary exercise testing protocol and resting VO(2) assessment on %HR(max), %HRR, %VO(2max) and %VO(2)R relationships. AB - The findings of previous studies investigating the strength of the relationships between the percentages of maximal heart rate (%HR(max)), heart rate reserve (%HRR), maximal oxygen uptake (%VO(2max)), and oxygen uptake reserve (%VO(2)R) have been equivocal. This inconsistency between studies could largely be due to differences in methodology. The purpose of this study was therefore to determine whether different VO(2max) test protocols and resting VO(2) assessment influence the relationships between the %HR(max), %HRR, %VO(2max), and %VO(2)R. Thirty three young men performed maximal treadmill protocols (ramp, Bruce) to assess HR(max) and VO(2max). Resting VO(2) was assessed as follows: a) resting VO(2standard), using strict criteria (24 h exercise abstention, alcohol, soft drinks, or caffeine; 8 h fasting; 30 min assessment); b) resting VO(2sitting) and; c) resting VO(2standing) (both 5 min before exercise testing). The %HRR was closer to %VO(2max) than to %VO(2)R, especially in the ramp protocol (p<0.001). In the Bruce protocol, relationships were closer to the identity line, and there was no significant difference between %HRR and %VO(2max), or %VO(2)R. The VO(2max) was significantly higher in the ramp protocol compared to the Bruce protocol (p<0.001). In both protocols resting VO(2) assessment produced no significant difference in the intercepts and slopes of the %HRR-%VO(2)R relationships obtained from individual regression models. The %VO(2)R calculated using resting VO(2standard) was closer to %HRR compared to VO(2sitting) and VO(2standing). The premise that %HRR is more strongly related to %VO(2)R than to %VO(2max) was not confirmed. Methodological differences should be considered when interpreting previous studies investigating %HR(max), %HRR, %VO(2max), and %VO(2)R relationships. PMID- 20200803 TI - Exercise effects on methylation of ASC gene. AB - Chronic moderate exercise has been reported to reduce pro-inflammatory cytokines. To analyze the molecular mechanisms by which training exerts these effects, the epigenetic influences of age and exercise on the ASC gene, which is responsible for IL-1beta and IL-18 secretion, were investigated by ASC gene methylation. Further, the relationship between carcinogenesis and exercise, and methylation of the P15 tumor suppressive gene was also analyzed. High-intensity interval walking exercise, consisting of 3 min low-intensity walking at 40% of peak aerobic capacity followed by a 3 min high-intensity walking period above 70% of peak aerobic capacity, was continued for 6 months. Peripheral blood DNA extracts from young control (n=34), older control (n=153), and older exercise (n=230) groups were then analyzed by pyrosequencing for DNA methylation. Methylation of ASC decreased significantly with age (young control vs. older control, p<0.01), which is indicative of an age-dependent increase in ASC expression. Compared to the older control group, the degree of ASC methylation was higher in the older exercise group (older control vs. older exercise: p<0.01), and presumably lower ASC expression. Neither exercise nor age affected the methylation of the P15. In summary, chronic moderate exercise appears to attenuate the age-dependent decrease in ASC methylation, implying suppression of excess pro-inflammatory cytokines through reduction of ASC expression. PMID- 20200804 TI - [The German version of the Childhood Trauma Questionnaire (CTQ): preliminary psychometric properties]. AB - Given the relevance of child maltreatment for the development and treatment of many mental disorders, the objective of our study was the psychometric evaluation of the German version of the Childhood Trauma Questionnaire (CTQ). In a sample of psychiatric patients (N=1 524) the established factor structure (i.e. sexual, physical and emotional abuse as well as physical and emotional neglect) was replicated by means of confirmatory factor analysis. The internal consistency of all scales (apart from physical neglect) was high (Cronbachs alpha >= 0.89). Correlations between the CTQ and self-report measures for posttraumatic stress, dissociation and general psychopathology were low to moderate. The psychometric properties of the German version of the CTQ were similar to the American original; it proved to be a reliable and valid screen for the retrospective assessment of child maltreatment. PMID- 20200805 TI - [Improved diagnostics of trauma-related disease through the application of the Life-Stressor Checklist]. AB - The study examines the effectiveness of applying the Life-Stressor Checklist (LSC R) in diagnosing trauma-related disease. The validity of a quantitative analysis of the checklist is evaluated in consideration of the dose-response effect between the number of different traumatic stressor expositions and the degree of trauma-related symptoms. The trauma checklist LSC-R was applied to 130 patients. Data on psychological symptoms was collected with the help of IES-R (PTSD symptoms) and SCL-90-R, the relevance of traumatic experiences for the genesis of disorders was assessed by expert evaluation. The dose effect replicated clearly with r=0.714 and a cut-off of >=6 yielded a 75% agreement with the expert evaluation. The total value of the trauma checklist showed a differentiation within high-risk groups and also agreement with the severity of the traumatization. The quantitative analysis of the trauma checklist permits an effective screening for identifying trauma-related disease. PMID- 20200806 TI - Upper respiratory tract infection during pregnancy: is it associated with adverse perinatal outcome? AB - We sought to determine whether there is an association between upper respiratory tract infection (URTI) requiring hospitalization during pregnancy and adverse perinatal complications. A retrospective population-based study comparing all singleton pregnancies of patients with and without URTI requiring hospitalization was performed. Multiple logistic regression models were performed to control for confounders. Data were collected from the computerized perinatal database. Out of 186,373 deliveries, 0.13% ( N = 246) required hospitalization due to URTI during pregnancy. URTI was significantly associated with preterm deliveries (PTD; 15.9% versus 7.9%; P < 0.001), lower birth weight (3082 +/- 624 versus 3183 +/- 546 g; P < 0.001), and higher rate of cesarean deliveries (CD; 20.3% versus 13.2%; P < 0.001) as compared with the comparison group. Even after controlling for possible confounders using multivariable analyses, the significant association between URTI and PTD (weighted odds ratio [OR] = 2.2; 95% confidence interval [CI] 1.6 to 3.1; P < 0.001) and CD (weighted OR = 1.5; 95% CI 1.1 to 2.2; P = 0.020) persisted. In contrast, no significant association was documented between URTI and premature rapture of membranes (4.9% versus 6.9%; P = 0.212), low Apgar scores (< 7) at 5 minutes (0.4% versus 0.6%; P = 0.761), and perinatal mortality (0 to 4% versus 1.3%; P = 0.223). Maternal URTI requiring hospitalization is an independent risk factor for PTD and CD. PMID- 20200807 TI - Predictors of fetal growth in maternal HIV disease. AB - We sought to determine predictors of fetal growth restriction in maternal HIV disease. Pregnant HIV-positive women on antiretroviral therapy were monitored with serial viral load and CD4 counts. Individualized growth potential (GP) percentile was calculated for birth weight (BW). BW <10th GP percentile defined fetal growth restriction (FGR). Multiple medical and social factors, CD4 count, viral load, and antiretroviral therapy were tested for impact on fetal growth using chi-square and multiple regression analysis. Two hundred eleven women were studied. CD4 count <200 in the first trimester was strongly associated with FGR (odds ratio 8.75, 95% confidence interval 2.88 to 26.52). Maternal age ( P = 0.02) and smoking ( P = 0.03) were independent cofactors for FGR (Nagelkerke R(2) = 0.33). No other factors demonstrated an independent effect. Severity of maternal HIV disease as indicated by the CD4 count, rather than placental exposure to viral load, predicts FGR. Smoking has an independent detrimental effect on fetal growth. PMID- 20200808 TI - Endoscopic sutured closure of a gastric natural orifice transluminal endoscopic surgery access gastrotomy compared with open surgical closure in a porcine model. A randomized, multicenter controlled trial. AB - BACKGROUND AND STUDY AIMS: In natural orifice transluminal endoscopic surgery (NOTES) procedures it is essential to be able to perform secure closure of the access perforation. The aim of this study was to compare endoscopically sutured closure of a gastric access gastrotomy using the tissue apposition system (TAS), with closure via laparotomy in a randomized multicenter study. METHODS: A total of 32 pigs (18 - 42 kg) were used in this study. The gastric NOTES access was created using a needle knife and a 20-mm balloon. Following transgastric pelvic peritoneoscopy, the endoscope was withdrawn into the stomach. The animals were then randomized to endoscopic closure or laparotomy with surgical closure. Procedure time, recovery time, and weight gain were measured. At necropsy, adhesions, abscesses or peritonitis were recorded. RESULTS: Of the 32 pigs, 29 survived 14 days without complications. All endoscopic and all open surgical closures were secure at postmortem. On average two suture pairs were used for endoscopic closure. Surgical closure was quicker (12.5 vs. 20.1 minutes). Recovery time and postoperative weight gain were similar for both groups. Two pigs in the endoscopic group died: one of gastric dilatation, without leakage from the gastrotomy; another was euthanized due to rectal prolapse. In the laparotomy group one pig was euthanized after 7 days due to abdominal wound dehiscence. At necropsy there were significantly more intra-abdominal adhesions in the laparotomized group. CONCLUSION: This randomized controlled study of endoscopic and surgical closure of a gastrotomy made for transperitoneal access for NOTES procedures suggests that both techniques are comparable in technical closure rates, postoperative recovery, and prevention of peritonitis. There were fewer adhesions in the endoscopic group. PMID- 20200809 TI - Narrow band imaging for characterization of high grade dysplasia and specialized intestinal metaplasia in Barrett's esophagus: a meta-analysis. AB - BACKGROUND AND STUDY AIM: Narrow band imaging (NBI), a novel endoscopic technique that highlights mucosal surface structures and microvasculature is increasingly advocated as a tool to detect and characterize neoplasia and intestinal metaplasia in patients with Barrett's esophagus. We aimed to assess the diagnostic accuracy of NBI with magnification for the diagnosis of high grade dysplasia (HGD) and specialized intestinal metaplasia (SIM) in patients with Barrett's esophagus. METHODS: We performed a meta-analysis of studies which compared NBI-based diagnosis of HGD and SIM with histopathology as the gold standard. RESULTS: Eight studies including 446 patients with 2194 lesions met the inclusion criteria. For diagnosing HGD, the pooled sensitivity, specificity, diagnostic odds ratio (DOR), and area under the curve (AUC) were 0.96 (95 % confidence interval [CI] 0.93-0.99), 0.94 (95 %CI 0.84-1.0), 342.49 (95 %CI 40.49 - 2896.89) and 0.99 (SE 0.01) on a per-lesion analysis with similar results on per-patient analysis.. For the characterization of SIM, the pooled sensitivity, specificity, DOR, and AUC were 0.95 (95 %CI 0.87-1.0), 0.65 (95 %CI 0.52-0.78), 37.53 (95 %CI 6.50-217.62) and 0.88 (SE 0.08) on a per-lesion analysis. CONCLUSION: NBI with magnification is accurate with high diagnostic precision for diagnosis of HGD in Barrett's esophagus on the basis of irregular mucosal pit patterns and/or irregular microvasculature. NBI has high sensitivity but poor specificity for characterizing SIM. PMID- 20200810 TI - Upregulated NADPH oxidase contributes to diabetic testicular complication and is relieved by strontium fructose 1,6-diphosphate. AB - Diabetes is frequently associated with declining sexual function resulting from oxidative damage. NADPH oxidase is a major resource of reactive oxygen species (ROS) in the testes and is likely related to an activated endothelin-1 (ET-1) system. An activation of NADPH oxidase-ET-1 pathway was hypothesized in diabetic testopathy. We verified the hypothesis and tested if strontium fructose 1,6 diphosphate (FDP-Sr) could relieve these changes in diabetic testis as compared to testosterone propionate (TP) and sildenafil. Diabetes was produced in male Sprague-Dawley rats 8 weeks after a single injection of streptozotocin (STZ), and interventions with testosterone propionate (TP), sildenafil and FDP-Sr were conducted in the last 4 weeks. Blood glucose, testosterone, follicle stimulating hormone (FSH) , luteinizing hormone (LH) and expressions of NADPH oxidase subunits and the ET system were measured. Decreased insulin, FSH, LH and testosterone in serum were found associating with testicular oxidative stress in STZ-injected rats. Additionally, over-expressions of NADPH oxidase p22, p47, p67 subunits and the ET pathway were significant in the diabetic testis relative to normal and were completely abolished by FDP-Sr. Both TP and sildenafil were not beneficial to diabetic testopathy except serum androgen raised by TP. Activated NADPH oxidase and ET system are significant contributing to testis injury and are responded to FDP-Sr only, against both TP and sildenafil, by restoring the testis function and the hypothalamus-pituitary-testis axis. It is due to its extra energy supply and an antioxidant activity of FDP-Sr. PMID- 20200811 TI - Association of antidiabetic therapies to glycemic control and to body weight in type 2 diabetes: a German multicenter analysis on 9294 patients. AB - Glycemic and body weight control are two outstanding goals in the treatment of patients with type 2 diabetes that often are not appropriately achieved. This observational study evaluates whether treatment by quality controlled diabetes centers generates an improvement in this regard and focuses on associations with different therapies. Data of 9.294 type 2 diabetic patients (mean age 66.9+/-11.6 years, mean diabetes duration 12.4+/-9.2 years) from 103 German diabetes centers were assessed by a standardized, prospective, computer-based diabetes care and outcome documentation system (DPV-Wiss-database). Therapeutic concepts included lifestyle intervention (n=1.813), oral antidiabetics (OAD, n=1.536), insulin (n=4.504) and insulin plus OAD (n=1.441). HbA1c and body weight were compared before and after a stable therapeutical period of 1.07+/-0.3 years. Change in HbA1c (%): all patients 7.4+/-1.6-7.0+/-1.3, lifestyle intervention 7.5+/-1.9 6.9+/-1.5, OAD 6.7+/-1.1-6.5+/-1.0, insulin 7.6+/-1.6-7.2+/-1.4, insulin plus OAD 7.5+/-1.5-7.2+/-1.3; each p<=0.05. Change in body weight (kg): all patients +0.08+/-0.07, n. s.; lifestyle intervention -0.28+/-0.20, OAD -0.56+/-0.13, each p<0.05 [metfomin -0.77+/-0.21, sulfonylurea drugs -0.75+/-0.34, each p<0.05; glitazones +0.62+/-0.70, alpha-glucosidase inhibitors -0.22+/-0.76, each n. s.], insulin +0.27+/-0.10, insulin plus OAD +0.63+/-0.14, each n. s. In summary, lifestyle, metformin or sulfonylurea drug treatment resulted in HbA1c-values below 7.0% plus a significant weight reduction. Insulin treatment-associated concepts resulted in HbA1c-values slightly above 7.0% without body weight alterations. These "real life" data underline that a specialised and quality controlled diabetes care is able to achieve significant treatment results even in patients with disease progression and a high proportion of insulin therapies. PMID- 20200812 TI - Weight reducing and metabolic effects of topiramate in patients with migraine--an observational study. AB - Topiramate is an anticonvulsant agent effective in the prophylaxis of migraine, which also induces weight reduction by an unknown mechanism. We investigated the effect of topiramate on metabolic and endocrine parameters in patients with migraine independently of any intention to lose body weight. Six patients (26-61 years old, body mass indices [BMI] 20.9-32.1 kg/m(2)) with migraine were treated with an average dose of 100 mg topiramate/day over a period of 20 weeks. The following parameters were measured every 4-8 weeks: BMI, body fat proportion, waist and hip circumference, HOMA insulin resistance, fasting serum-/plasma concentrations of adiponectin, leptin, ghrelin, vascular endothelial growth factor (VEGF), cortisol, interleukin-6 and tumor necrosis factor (TNF)-alpha. Profound metabolic changes were observed for the whole treatment period. Compared with the baseline value, 20 weeks of treatment reduced the BMI by 7.2+/-1.4%, body fat proportion by 11.6+/-3.6%, waist circumference by 4.2+/-1.2%, leptin by 39.2+/-6.5% and HOMA insulin resistance by 37.3+/-5%, while adiponectin was increased by 69.9+/-17.3% (P<0.05, respectively). VEGF concentrations increased during the week 2-4 by 177.4+/-39.4% (P<0.05) followed by a continuous decrease. There were trends for a reduction in ghrelin concentration, whereas cortisol, interleukin-6 and TNF-alpha values were unchanged. In summary, in this small sample of migraine patients topiramate treatment was associated with increased insulin sensitivity, increased adiponectin concentration and a reduction of body fat in all treated patients. The role of increased VEGF concentrations prior to these metabolic changes is not clear and might, hypothetically, involve a centrally mediated effect of topiramate on body weight regulation. PMID- 20200813 TI - Associations of estrogen receptor alpha and beta gene polymorphisms with sex steroid levels and body fat content in men. AB - OBJECTIVE: Estrogens play an important role in male physiology. We investigated the possible association of four single nucleotide polymorphisms in Estrogen Receptor alpha ( ESR1) and Estrogen Receptor beta ( ESR2) genes with circulating levels of sex steroids and Sex Hormone Binding Globulin (SHBG) in men. DESIGN AND METHODS: SHBG, total and calculated free testosterone (TT and cal FT), estradiol (E2) and free Estradiol (FE2) were determined in a population-based cohort of 170 apparently healthy Greek men. Body mass index (BMI), waist circumference (WC) and percentage of body fat (%fat) content were measured in all participants. Genotyping for the PVU II and XBA I polymorphisms of the ESR1 gene and for the RSA I and ALU I polymorphisms of the ESR2 gene was performed. RESULTS: PVU II showed an association with E2 levels [median (IQR) pp 58.5 (42.1-73.4) pg/ml vs. Pp 48.8 (42.9-60.1) and PP 57.7 (44-70.5), p=0.032], and with %fat [mean+/-SD pp 24.6+/-5.3 vs. Pp 22.4+/-5.2 and PP 21.2+/-6.7, p=0.044], after adjustment for age and WC. Furthermore, the effect of PVU II on E2 was independent of %fat (p=0.038). A synergistic effect of the two ESR1 polymorphisms on E2 (p=0.023), FE2 (p=0.03) and %fat (p=0.004) was present. Finally, a synergistic effect of the ESR1 and ESR2 genes on TT (p=0.009), independent of age, WC and %fat also emerged. CONCLUSIONS: Genetic variation in ESR1 is associated with serum estradiol levels and body fat content regulation in men. Furthermore, a synergistic effect of ESR1 and ESR2 genes is exerted on serum testosterone levels. PMID- 20200814 TI - Two patients with an identical novel mutation in the AAAS gene and similar phenotype of triple A (Allgrove) syndrome. AB - BACKGROUND: Triple A syndrome, also known as Allgrove syndrome, is a rare autosomal recessive disorder characterized by three cardinal symptoms: adrenal insufficiency due to ACTH insensitivity, achalasia and alacrima. Various progressive neurological abnormalities and skin changes have been described in association with the syndrome. The disease is caused by mutation in the AAAS gene on chromosome 12q13. AAAS encodes a protein named ALADIN which is part of the nuclear pore complex (NPC). The mislocalization of mutated ALADIN proteins in the cytoplasm and/or the nucleus results in an impaired protein function. Phenotypes of previously reported patients with triple A syndrome varied within and between affected families so that no genotype-phenotype could be established. METHODS: Genetic analysis was performed in two unrelated patients, their parents and one sister. AAAS coding sequences including exon-intron boundaries were amplified and sequenced using an ABI 3100 sequencing machine. PATIENTS: We present two unrelated Swiss patients with triple A syndrome demonstrating similar phenotypic characteristics. Both showed a progression of the disease presenting with adrenal insufficiency and alacrima in early childhood. At the age between 30-40 years they developed symptomatic achalasia. The pattern and severity of progressive neurological and autonomic dysfunction was comparable. In both patients molecular genetic analysis revealed an identical novel homozygous mutation (c.618delC, p.Ser207fs) in the AAAS gene. CONCLUSION: Recent genotype/phenotype studies showed a marked inter- and intrafamiliar variability in triple A syndrome. Here we present a rather tight genotype/phenotype correlation in two unrelated patients carrying the identical novel p.Ser207fs mutation in the AAAS gene. PMID- 20200815 TI - Diagnosis of diabetic neuropathy using simple somatic and a new autonomic (neuropad) tests in the clinical practice. AB - AIM: The global spread of diabetes (DM) and the importance of early therapeutic intervention determine the need of simple, inexpensive and sensitive methods for diagnosis of diabetic complications in the general practice. The aim of this study was to assess a new instrument - the plaster Neuropad in diagnosing the sudomotor diabetic dysfunction and to investigate the correlates of Neuropad data with diabetic complications. PATIENTS AND METHODS: In this cross-sectional study participated 264 inpatients (M/F=126/138) with DM type 1/2 (61/203), mean age 55.4+/-12.0 and DM duration of 9.3+/-7.1 years. According to hospital records were registered: anthropometric data; fasting plasma glucose and HbA1c; presence of micro-(retino-, nephro-, neuropathy), and macrovascular (arterial hypertension, coronary artery disease and/or brain vascular disease) complications, and neuropathic symptoms were evaluated. For investigation of somatic DN a modified Neuropathy Disability Score (NDS) and for sudomotor autonomic DN - Neuropad were used. RESULTS: Neuropad showed the highest between feet correlation of 0.91 compared to all other individual tests and the NDS. Neuropad was able to separate patients in groups with different general risk profile, including age, duration of DM, presence of coronary and/or brain vascular disease, nephropathy, and retinopathy. Moreover, Neuropad differentiated patient groups by their stage of DN, evaluated by symptoms, diagnosis, the individual somatic tests and with the highest significance - by NDS. Most sensitive for detecting DN was NDS > or = 3, followed by Achilles reflexes, vibration perception (128 Hz tuning fork) and Neuropad. A borderline or abnormal result of Neuropad showed sensitivity=76.3/79.3, specificity=56.1/42.9, positive=86.3/62.8 and negative=39.5/63.0 predictive values, and diagnostic accuracy 72.2/62.9%, compared to the indices for presence of somatic DN (NDS > or = 3)/foot at risk (NDS > or = 6) respectively. CONCLUSIONS: Screening for DN must cover somatic and autonomic disturbances. Neuropad is a new sensitive and appropriate for everyday clinical use test for detecting sudomotor DN and identification of patients at higher risk for chronic diabetes complications. PMID- 20200817 TI - [Conservative treatment and rehabilitation in peripheral facial palsy]. AB - Facial paralysis may be treated by physical therapies with different therapeutic strategies and devices. Exercise therapy, electrotherapy, massage, lymph drainage, biofeedback therapy are applied. Therapeutic strategies are based on the course of disease. It may be assumed that paralysis in moderate and moderate to severe courses of disease in acute lesions, moreover in chronic partial lesions and after gracilis muscle transplantation will benefit best from physical therapies. Course of disease depends on the degree of lesion, low-grade lesion will improve earlier and prognosis of motor recovery is good. To predict the course of disease in idiopathic facial paralysis nerve conduction studies can render valuable information by measuring the amplitude of the motor evoked potential in side to side comparison. In regard to scientific studies there is limited evidence that exercise therapy and biofeedback therapy improve the course of disease, motor performance recovers earlier and motor synkinesis are decreased. There is no evidence for electrotherapy to improve the course of disease nor to have any adverse effects. There is no relevant literature for massage and lymph-drainage in regard to facial paralysis. Every patient with facial paralysis--regardless to the degree of lesion--should receive a brochure with mimic exercises and instructions to support facial symmetry as basic intervention. PMID- 20200816 TI - Acute hyperhomocysteinemia impairs endothelium function in subjects with type 2 diabetes mellitus. AB - The objective of the present study was to examine the effect of acute, methionine induced hyperhomocysteinemia (HHCY) on endothelial function and indices of arterial stiffness in subjects with type 2 diabetes mellitus (T2DM). A total of 30 subjects with T2DM, free of macrovascular disease were examined in a crossover study. L-methionine (M) (0.1 g/kg) and water (W) load were given in random order with an interval of about 1 week in between. Endothelial function was assessed by flow-mediated vasodilation (FMD). Arterial stiffness was assessed by determination of augmentation index (AI). Measurements were performed in the fasting state, 1, 2 and 3 h after the M or the W load. Total plasma homocysteine (HCY) levels did not change after W administration, while M administration resulted in a significant increase in HCY concentrations at 3 h. FMD throughout the experiment expressed as area under the curve (AUC) was significantly lower after the M than after the W load. Consistent with impairment in endothelial function, the AUC of AI was significantly higher after the M than after the W administration. Acute HHCY impairs endothelial function and increases arterial stiffness in patients with T2DM. This effect is probably mediated by a reduction of nitric oxide bioavailability in endothelium. PMID- 20200818 TI - [Quality evaluation in colorectal surgery in dependence on health-care categories of hospitals - minor differences in outcome with room for improvement in process quality]. AB - BACKGROUND: In the present study, different variables focusing on quality of colorectal surgery were investigated with respect to hospital categories: university hospital - U; hospital with maximum care responsibility (with a full spectrum of medical disciplines) - M; secondary care hospital with central regional responsibility (6-9 departments) - S; primary care hospital with local responsibility (2-5 departments) - G; The primary goal of this study was to analyse the current standard of care in patients with colorectal carcinoma in Germany. METHODS: From 2000-2004, data of 47 435 patients with colorectal cancer were evaluated, using data compiled in the German multi-centred observational study "Colon/Rectal Carcinoma". Analysis was performed for all variables with respect to hospital categories. Due to the remarkable number of patients, differences between the groups were to be regarded as significant if p<0.01. RESULTS: Preoperative colonoscopy (U: 70.1% M: 70.4% S: 67.9% G: 67.2) and preoperative determination of serum tumour markers (U: 83.8% M: 80.1% S: 81.9% G: 77.1) mainly indicate the quality of gastroenterological work-up before surgical intervention. In general, standards established by the "German Cancer Association" were not met and showed significantly lower rates for primary and secondary care hospitals. In contrast, variables indicating quality of perioperative course and outcome: rate of anastomotic leak (U: 2.1% M: 2.8% S: 2.1% G: 3.1%), rate of surgical intervention (U: 4.3% M: 3.1% S: 3.5% G: 3.1%) and mortality rate (U: 4.4% M: 2.2% S: 3.5% G: 4.1%) were in accordance with the requirements and did not differ significantly between all groups. However, an analysis of surgical and histopathological process quality (complete histology: U: 96.3% M: 93.6% S: 91.9% G: 90.9%) revealed significant differences with results being significantly lower for primary care hospitals. CONCLUSION: There is in principle no necessity to centre colorectal surgery in tertiary care hospitals as quality parameters focusing on results and outcome are comparable. However, in primary care hospitals, there are deficits with regards to process quality. Therefore, all measures aiming to enhance in particular process quality, i. e., hospital certification or participation with quality assurance studies, are highly desirable to further improve patient care. PMID- 20200819 TI - ["Teilhabe" (social participation) of patients in health care research: relations to similar concepts and overview of assessment instruments]. AB - The great significance of the concept of participation in health care policy is in contrast with the comparatively low resonance that the participation construct ("Teilhabe" in German) has found in scientific circles. It can be argued that this is due in part to the insufficient specification of the term in the ICF ("International Classification of Functioning, Disability and Health") and the lack of suitable measuring instruments. This article deals with the question of what approaches to defining participation currently exist and what methods are conceivable for facilitating the integration of the construct in health services research. Based on a review of German and international literature on participation, the construct is differentiated from related concepts such as "social capital," "social network," "social support," and "community integration". It is recommended that participation should be understood as "social role participation". The possibility this entails of referring to existing research traditions and available studies leads to the necessity that a comprehensive measurement of participation should include five dimensions of this construct: performance, capability, importance, context factors, and satisfaction. A review of the available instruments for measuring participation shows that most of them cover the ICF domains that are important in this context to a sufficient extent. However, there are the following areas for improvement: a) No measuring instrument includes all five relevant dimensions of participation, b) None of the instruments take non-health-related obstacles to participation (context factors) into consideration, c) The possibility of a version with parallel content for proxy assessment is rarely used, d) The published methods available to German-speaking users cover participation only globally or are older and do not incorporate experience with the ICF. In view of the significance of the participation construct in the German health care system, studies on new or ongoing developments of assessment instruments that meet these challenges would be welcomed. PMID- 20200820 TI - [Effect of written patient information on knowledge and function of patients with acute uncomplicated back pain (PIK Study)]. AB - BACKGROUND: If patients return early in the course of acute, uncomplicated back pain to their normal activities, their symptoms improve more quickly. Written detailed patient information can have a positive effect on knowledge and can increase physical activity. In this study the effect of a short evidence-based back pain leaflet on knowledge, function and patients' beliefs was investigated. METHODS: A randomised controlled trial was carried out in 12 primary care practices. Patients with acute, uncomplicated back pain received either the back pain specific information (intervention) or a leaflet without content regarding back pain (control). Participants' data were inquired before consultation of the general practitioner, as well as 1 week and 3 months later. Outcome measures were SF-36, FABQ-D, FFbH-R, knowledge concerning back pain, frequency of use of the leaflet, usefulness of the information and change of behaviour. RESULTS: The included patients totaled 174. The response rates were 74.7% (1 week) and 67% (3 months). Patients receiving the intervention leaflet showed better knowledge at 1 week and greater improvement in function scores at 3 months. There was no effect on patients' beliefs. Patients of the intervention group reported more activity in everyday life. CONCLUSION: Short written information may have small, in total possibly positive effects on knowledge, support of activity and function in patients with acute, uncomplicated back pain. PMID- 20200823 TI - [Open access--you have a choice with OpenMind]. PMID- 20200822 TI - [Diabetic nephropathy--manage now!]. PMID- 20200824 TI - [Adolescent violence and gun rampage]. PMID- 20200825 TI - [Nonsuicidal self-injury in adolescence]. AB - Nonsuicidal self-injury (NSSI) usually starts in adolescence. International studies report prevalence rates between 3 and 37% (for Germany between 15 and 26%) in adolescents. From a neurobiological perspective, there is evidence that primarily the serotonergic system is involved in the origin and maintenance of this behaviour. NSSI is often used by adolescents to influence aversive affective states, but sometimes serves other functions as well, such as self-punishment or anti-dissociation. To date there are many assessment instruments, some of which are available in a German translation. Regarding psychotherapeutic interventions there is evidence for a good efficacy of dialectical behavioral therapy for adolescents (DBT-A). There is little evidence for psychopharmacological interventions in childhood and adolescence; thus treatment should focus on psychotherapeutic interventions. PMID- 20200826 TI - [Psychopathy, temperament and antisocial behaviour in girls]. AB - OBJECTIVE: This study addresses the question whether temperament and character differ between antisocial incarcerated girls with and without psychopathy. Furthermore, it enquires whether this model discriminates between groups with varied psychopathy symptoms. METHOD: 170 incarcerated girls aged 14 to 17 years were examined using the German version of the Junior Temperament and Character Inventory (JTCI 12-18) and the Psychopathy Checklist Youth Version (PCL:YV). On the basis of the PCL:YV scores the girls were divided into three high-scoring psychopathy groups and compared to a group without psychopathy. RESULTS: Three quarters of the juvenile criminals did not show psychopathy; the percentage of those scoring high on the psychopathy core dimensions was only 7%. With the aid of Cloninger's model of personality, differences in the psychopathy groups as compared to the nonpsychopathy group were identified regarding the dimensions novelty seeking, reward dependence, cooperativeness and self-transcendence. However, specific relationships between individual psychopathy dimensions and the JTCI-factors could not be identified. CONCLUSIONS: The results confirm the existence of the psychopathy construct in female delinquents, though the percentage of girls with core psychopathy dimensions is very small. The differentiating temperament factors found among girls scoring high on psychopathy dimensions as opposed to girls without psychopathy indicate that psychopathy is a valid construct that can identify a specific subgroup of antisocial girls with core psychopathy symptoms. PMID- 20200827 TI - [Does the Fragmented Images Test measure locally oriented visual processing in autism spectrum disorders?]. AB - OBJECTIVE: The cognitive phenotype of autism spectrum disorders (ASD) is characterized among other things by local processing (weak central coherence). It was examined whether a test that measures identification of fragmented pictures (FBT) is able to seize this preference for local processing. METHOD: The FBT performance of 15 patients with ASD, 16 with depression, 16 with schizophrenia and of 16 control subjects was compared. In addition, two tests well known to be sensitive to local processing were assessed, namely the Embedded Figures Test (EFT) and the Block Design Test (BDT). RESULTS: ASD patients demonstrated a preference for local processing. Difficulties in global processing, or more specifically in gestalt perception (FBT), were accompanied by good performance on the EFT and BDT as expected. Controlling for age and nonverbal intelligence (ANCOVA) reduced differences to trends. However, the calculation of difference scores (i.e., subtraction of FBT from EFT performance) resulted in significant differences between ASD and control groups even after controlling for of age and intelligence. CONCLUSIONS: The FBT is a suitable exploratory test of local visual processing in ASD. In particular, a difference criterion can be generated (FBT vs. EFT) that discriminates between ASD and clinical as well as healthy control groups. PMID- 20200828 TI - [Assessment of intelligence of 6-year-old children--practical comparability of HAWIVA-III and HAWIK-IV]. AB - OBJECTIVE: The present study focuses on the practical comparability of HAWIVA-III and HAWIK-IV test results. METHOD: HAWIVA-III and HAWIK-IV were administered in counterbalanced order to N=45 6-year-old children. The study presents means, standard deviations, and uncorrected and corrected correlations, as well as standard differences. Regression analysis was used to predict IQ values. RESULTS: There is a significant positive correlation between indices of HAWIVA-III and HAWIK-IV (VT/SV: r=.81; HT/WLD: r=.86; VG/VG: r=.77) and between the two Full Scale IQs (r=.91). Predicted WISC-IV values based on WPPSI-III indices are reported. CONCLUSION: The results of this study indicate that there is a close relation between HAWIVA-III and HAWIK-IV. Therefore, HAWIK-IV-results can be compared with diagnostic findings assessed by HAWIVA-III. PMID- 20200829 TI - [Bipolar disorders as co-morbidity in childhood and adolescence--underdiagnosed or overinterpreted? Therapy of a 14-year-old boy with hyperkinetic conduct disorder and hypomania]. AB - OBJECTIVE: Considerable debate exists regarding differing prevalence rates of co morbid bipolar disorder in children and adolescents with ADHD in Germany as compared to the US. METHODS: Described in this case report are the assessment of and treatment procedure for a 14-year old boy with hyperkinetic conduct disorder and co-morbid hypomanic episode, as well as different possible interpretations of symptoms. CONCLUSIONS: Further studies of children and adolescents with ADHD and coexisting impulsive-aggressive behaviour are needed. Important in practice is a precise differentiation of symptoms with regard to co-morbid bipolar disorder. PMID- 20200830 TI - [Management of children, adolescents and adults with attention deficit/hyperactivity disorder (ADHD) in Germany. Position of the central adhd network for 2009 special expert assessment by the medical expert on evaluation of development in public health]. PMID- 20200834 TI - [Presentation]. PMID- 20200835 TI - [Genetic factors in the development of language]. AB - AIM: To review selectively the status of the genetic research in the field of speech and language disorders. DEVELOPMENT: Major contributions to the field are selected, presented, and discussed. Twin and family studies have demonstrated that most cognitive traits including language are moderately to highly heritable. Rare mutations affecting the FOXP2 transcription factor cause a monogenic speech and language disorder. The results of association studies of FOXP2 with several language disorders are controversial, probably due to the problem of phenotype definition. CONCLUSIONS: Common forms of disorders of speech and language are mostly likely associated with variability in the function of multiple genes. Longitudinal studies looking at gene environmental interaction might be important in order to understand the mechanism of language development. PMID- 20200836 TI - [Understanding questions: a specific difficulty in children with pragmatic communication and language disorders]. AB - INTRODUCTION: The question-answer schema is the basis for communicative interaction and is therefore a fundamental aim of the work carried out with children with severe communication and language impairment. DEVELOPMENT: Answering questions requires basic skills that enable the listener to identify intonation and facial expression, as well as skills in interpreting intentions and in understanding linguistic content. Some questions can rest on contextual social keys and others may be based on lexical or structural keys. Some questions, however, call for a more complex understanding, such as 'what' and 'who' questions. Here, we propose an analysis of the skills involved in understanding questions and the consequences on intervention strategies. CONCLUSIONS: Intervention in understanding questions should combine different approaches (cognitive, social, linguistic) depending on the type of question, the specific difficulties the child has and the context. PMID- 20200837 TI - [Early cognitive functioning in twins with birth weight discordance]. AB - INTRODUCTION: The neuroconstructivist approach studies early childhood comparative development from an interdisciplinary and neuropsychological perspective in order to relate neurological architecture to cognitive functioning. AIM: Logical development and resistance to interference as a component of executive functions are studied comparatively in typical babies and twins born with weight discordance to analyze its effects on development, learning and behaviour control. SUBJECTS AND METHODS: The task's resolution is registered when babies are 18, 21 and 24 months of age. Microgenetic and multivariate analysis compares, on the one hand, 48 typical babies to growth discordant twins and, on the other, 32 twins to one another. RESULTS: Intergroup task resolution is similar with regard to logical development in both groups under analysis but resistance to interference is lower in growth discordant twins than in typical babies and, when twins are compared to one another, twins with lower weight show more difficulties regarding logical resolution. CONCLUSION: Twin babies show less resistance to interference than typical babies and similar but delayed in time logical functioning. PMID- 20200838 TI - [Textual pragmatics in adolescents with attention deficit hyperactivity disorder: argument]. AB - INTRODUCTION: Clinical linguistics involves a study of linguistic deficits which focuses on a series of aspects that range from strictly formal, grammatical points to the effective and contextualised use of language. Thus, it is also inevitably concerned with the cognitive, i.e. mental, correlate of such language use, whose basic textual dimensions are narration and argument. AIMS: To describe the argumentative skills in adolescents with attention deficit hyperactivity disorder (ADHD) and to examine their relationship with academic achievement and sociability. MATERIALS AND METHODS: We analysed 79 argumentative texts written by adolescents with ADHD, using a methodology from cognitive linguistics and from theories of argumentation with a dialogical foundation. RESULTS AND CONCLUSIONS: Adolescents with ADHD provided a greater number of arguments than those in the control group, but with a higher predominance of emotional and negative sanction strategies compared with a greater use of fallacious or circular arguments in those in the control group; the difference between the use of rational arguments in the two groups is not significant. PMID- 20200839 TI - [Population-based diagnostic study to compare the DSM-IV and the Questionnaire for screening Latin American schoolchildren and adolescents for attention deficit hyperactivity disorder]. AB - AIM: To detect attention deficit hyperactivity disorder (ADHD) in children between 4 and 14 years of age by means of the Questionnaire for screening Latin American schoolchildren and adolescents for ADHD (QLSA-ADHD) and the criteria of the Diagnostic and statistical manual of mental disorders, fourth edition, ADHD version (DSM-IV ADHD). PATIENTS AND METHODS: A prospective, cross-sectional, analytical study was conducted to detect ADHD in the child population that visited the outpatient department at the Rodolfo Nieto Padron Children's Hospital. These children were administered two surveys: the DSM-IV ADHD and the QLSA-ADHD. The results were analysed using graphs and test statistics from the SPSS package, such as the correlation coefficient and chi squared. RESULTS: The questionnaires were analysed by finding the overall sum of the criteria of the 200 children included in the DSM-IV ADHD and the average score values were found to be 64 'yes' (32%) and 137 'no' (68%). The QLSA-ADHD was evaluated in the same way and the average was 50 'yes' (25%) and 149 'no' (75%). The chi squared test was then performed for the two, the result being 1.762, with 1 degree of freedom and p > 0.05; that is to say, there was no significant difference between the scores obtained in both surveys. With the QLSA-ADHD, 25% of children with ADHD were detected, whereas the figure rose slightly to 25.5% (51 patients) with the DSM-IV. The chi squared test was conducted between the results from the two surveys, the value being 3.405, with 1 degree of freedom and p > 0.05. CONCLUSIONS: Our findings show that, in our population, there is no difference between the QLSA-ADHD and the DSM-IV for detecting ADHD. PMID- 20200840 TI - [Neuroimaging in attention deficit hyperactivity disorder]. AB - INTRODUCTION: Advances in neuroimaging in the last decade have allowed a number of new findings about attention deficit hyperactivity disorder (ADHD) to be obtained. Quickly developing technology, together with the progress being made in genetics and neurochemical research, suggests a dysfunction of the fronto striatal circuit that involves the prefrontal cortex and its relationship with the basal, thalamic and cerebellar nuclei as the pathophysiological foundation of this disorder. On the other hand, neuroimaging in the future may complement clinical evaluation, which will favour more accurate diagnoses and allow the subtypes and even the mode of treatment and its monitoring to be identified. AIMS AND DEVELOPMENT: The aim of this study was to review the more significant literature on neuroimaging and ADHD and to discuss the usefulness and drawbacks of the different modes of neuroimaging techniques that can be applied with a view to gaining an improved and deeper knowledge of ADHD in the future. CONCLUSIONS: Although the development of neuroimaging in ADHD is a promising area, at the present time its diagnostic value is very restricted. One of the greatest difficulties in this respect concerns the clinical, genetic and pathophysiological heterogeneity of the disorder. Hence, given the inexistence of a specific marker, future studies will have to search for several markers that have a suitable value in the diagnosis, prognosis and/or treatment of the different subtypes of ADHD. PMID- 20200842 TI - [Attention deficit disorder and hyperactivity: a pattern of evolution?]. AB - INTRODUCTION: When the frequency of a gene in the general population exceeds 1%, is not considered a random mutation but a mutation that has been positively selected during evolution. The high prevalence of attention deficit/hyperactivity disorder (ADHD) from 5-10% and its association with the seven-repeat allele of DRD4, which is positively selected in evolution, raising the possibility that ADHD increases the reproductive fitness of the individual and/or group. One of the main characteristics of ADHD is its diversity and is a well recognized fact that diversity confers many benefits to a population (eg. immunity). DEVELOPMENT: This article discusses the various studies that support this hypothesis and offers further explanations on the prevalence, age distribution and sex distribution of the severity and heterogeneity of ADHD. CONCLUSION: It is possible that the presence of altered gene combinations, as in ADHD, can bring concrete benefits to society but are detrimental to the individual. PMID- 20200841 TI - [Reading comprehension of students with attention deficit hyperactivity disorder: what is the role of executive functions?]. AB - INTRODUCTION: Deficits in reading comprehension of children with attention deficit hyperactivity disorder (ADHD) have received scarce attention. However, to establish the underlying cognitive processes of ADHD and deficits in reading comprehension association could be essential for deeply understanding neurobiological bases of reading comprehension. AIM: To examine the contribution of verbal fluency, reading fluency, and executive functions (working memory, attention and suppression mechanism) in predicting mental processes of texts comprehension. PATIENTS AND METHODS: The participants in the study were 42 students, 12 to 16 year old, with a clinical diagnosis of ADHD. A battery of tests was administered to measure cognitive processes and reading processes. RESULTS AND CONCLUSIONS: Stepwise regression analysis carried out showed that the score in verbal fluency was the best single predictor of reading comprehension. Furthermore executive functions, but not reading fluency, made a significant contribution to reading comprehension. These findings underline the need for consideration of the role of executive functions in assessment and treatment of reading comprehension deficits of students with ADHD. PMID- 20200843 TI - [Brain neuroplasticity in occipital areas in blind teenagers]. AB - INTRODUCTION AND DEVELOPMENT: Neuroplasticity is a process by which neurons increase their connectivity with other neurons in a stable fashion as a consequence of experience, learning and both sensitive and cognitive stimulation. Different authors have shown a huge process of brain plasticity in blind subjects towards other sensorial areas, mainly auditive and visual ones. From an anatomical standpoint many data show significant differences in blind subjects brains, mainly in visual pathways and structures as a result of lack of activity on those areas. This brings a lesser neuroplasticity and, therefore, a decrease in structural volumes. They have also found differences in subcortical structures volumes related to vision, such as splenium or corpus callosum istmus. METHODOLOGY: An adolescent was administered passive tactile stimulation with an 1,500 taxels stimulator. This was carried out daily for an hour, for three months, and stimulation consisted of vertical, horizontal and oblique lines. The results obtained in an adolescent indicate a clear progression of EEG activity from tactile sensory parietal areas to visual occipital ones as stimulation progresses. CONCLUSION: Therefore one can speculate if systematic and organized repetition of tactile stimuli in blind subjects leads to a greater neuroplasticity which expands towards occipital areas, largely responsible for human vision. PMID- 20200844 TI - [Epilepsy: classification for a diagnostic approach based on aetiology and complexities]. AB - INTRODUCTION: In our teaching experience we have had to resort to certain tools that allow the student, physician and specialist to carry out a timely diagnosis in order to be able to establish the most accurate treatment possible, with a view to offering the patient a better prognosis. DEVELOPMENT: Hence, based on the different classifications elaborated by the International League against Epilepsy since the sixties, we have designed a system of classification according to the patient record and the symptomatology of the seizures that enables us to distinguish primary epilepsies from secondary ones. Accordingly, we can focus on epileptic syndromes versus neurological syndromes with epilepsy, grouping them together in four subgroups, depending on their complexity: primary (I: age; II: not age) and secondary (III: sequelae; IV: surgical and medical diseases). The clinical presentation (divided into mild, moderate, severe and catastrophic symptoms) is then added, without neglecting the genetic substrate in all cases, to be able to differentiate the naming of the nosology. CONCLUSIONS: On behalf of the Bogota Central League against Epilepsy, we outline this tool so that it can be applied in teaching and in medical practice for this group of patients. PMID- 20200845 TI - [The reticular paradigm of cortical memory]. AB - INTRODUCTION: Recent advances in cognitive neuroscience oblige us to change radically the traditional model of representation of memory in the cerebral cortex. The old -modular- model postulates a separate area for each form of memory (working memory, episodic memory, visual memory, auditory memory, tactile memory, etc.). In the new -reticular- paradigm, memories and items of knowledge are made of widely distributed networks of neuron populations synaptically connected by experience. DEVELOPMENT: Memory networks overlap and interact profusely; a neuron or group of neurons can be part of many networks, thus many memories or items of knowledge. After birth and throughout life, each new experience is etched in the form of those networks or cognits by synaptic associative processes that course from area to area along phylogenetic, ontogenetic, and connective gradients, from sensory and motor areas into associative areas. By self-organization, new cognits distribute themselves within two cortical hierarchies with a sensory and motor base, respectively. The perceptual hierarchy, in posterior cortex, houses cognits defined by sensory parameters in sensory areas and perceptual memories in associative areas. The executive hierarchy, on the other hand, represents concrete movements in frontal motor areas and more complex actions (e.g., plans) in prefrontal cortex. CONCLUSIONS: The reticular memory paradigm has important implications with regard to the cognitive development of the individual, cortical clinical syndromes, and cognitive rehabilitation. PMID- 20200846 TI - [Variability of cognitive development in different types of epilepsy in children]. AB - INTRODUCTION: Children with epilepsy have a higher risk of suffering from cognitive and behavioural disorders, the intensity and repercussions of which may be more or less important. AIM: To examine the different factors, dependent on epilepsy, its cause or the treatment, which can affect the cognitive development of children with epilepsy. DEVELOPMENT: To this end, a review was carried out of the studies that have provided data about the causes of cognitive disorders in children with epilepsy, and we suggest which children with epilepsy are at greater risk of suffering cognitive disorders and how they must be treated. CONCLUSIONS: Children with epilepsy often experience cognitive and behavioural difficulties for the rest of their lives. Sometimes these problems can be avoided, or at least improved. Being familiar with them, together with their early detection and treatment must be priorities for neuropaediatricians who treat children with epilepsy. PMID- 20200847 TI - [Neurocognitive dysfunction in electrical status epilepticus during slow-wave sleep syndrome: Can the natural course of the syndrome be modified with early pharmacological treatment?]. AB - INTRODUCTION: Epileptic syndromes with continuous spike wave in slow-wave sleep (CSWS), including electrical status epilepticus in sleep (ESES) and Landau Kleffner syndrome, are true epileptic encephalopathies where sustained epileptic activity is related to cognitive and behavioural decline. AIMS: To review the natural course of ESES, to define the general principles of treatment of epileptic syndromes with CSWS, to delineate the different options that are currently available for treating these epileptic encephalopathies, and to analyze the prognostic factors linked to pharmacological treatment of ESES. DEVELOPMENT: Epileptic syndromes with CSWS are initially treated with a pharmacologic intervention with polytherapy of antiepileptic drugs in most cases. However, due to the poor response that CSWS often have to antiepileptic drugs, non pharmacologic treatment options are an important part of a comprehensive treatment plan for this group of children. This article discusses the use of corticosteroids, intravenous immunoglobulins, ketogenic diet, vagus nerve stimulation, and epilepsy surgery in the treatment of patients with epileptic syndromes with CSWS. CONCLUSIONS: Treatment of ESES extends beyond just control of the seizures; amelioration of the continuous epileptiform discharge must occur to improve neuropsychological outcome. There is a significant correlation between the length of the ESES period and the extent of residual intellectual deficit at follow-up. According to this knowledge, there is a well defined therapeutic interval where our different strategies of treatment may be useful, and the upper limits of this time frame to a critical period of 12-18 months. PMID- 20200848 TI - [Presurgery neuropsychological evaluation in pediatric focal epilepsies]. AB - INTRODUCTION: Neuropsychological assessment is included in the protocols for evaluation of epilepsy surgery candidates, providing information about the patient's cognitive dysfunctions, allowing for prediction of possible cognitive deficits derived from surgery and yielding objective measures of any post surgical changes. Neuropsychological disturbances constitute an important co morbidity of medically intractable epilepsy. An early epilepsy onset in infancy may lead to cognitive dysfunctions that are atypical in terms of brain localization, due to the inherent plasticity and reorganization processes of the immature brain. The analysis of the neuropsychological profiles of paediatric focal epilepsies is much more complex than in the adult population. DEVELOPMENT AND CONCLUSIONS: In this paper, we review the neuropsychological disturbances associated to focal epilepsies (posterior cortex, temporal and frontal epilepsies), stressing the point that there is a considerable lack of rigorous studies on the topic in the literature, in spite of this being an essential part of the presurgical work-up in epilepsy patients. PMID- 20200849 TI - [Predictive variables for mental retardation in a Pediatric Epilepsy Monitoring Unit. Neuropsychological assessment]. AB - AIM: We sought to describe the epidemiological and clinical data from our patients in the Pediatric Epilepsy Monitoring Unit (PEMU) of the Sant Joan de Deu Hospital of Barcelona, and determine the variables of risk for mental retardation. PATIENTS AND METHODS: A retrospective review of PEMU reports and hospital discharge summaries from March 2005 to December 2008 was conducted. The data from patients with intelligence quotient (IQ) estimated, older than 3 years of age and with epileptic electroencephalography (EEG) activity was analyzed in 158 patients (8.8 +/- 5.2 years; 55.1% boys). Of those pediatric patients, 63 had IQ less than 70 and 47 an IQ greater than or equal to 70. Intractable epilepsy was present in all of them. RESULTS: The percentage of the patients with mental retardation is significantly higher in patients with onset of epilepsy before 24 months (68.3%) than patients with later onset (27.7%). Onset of seizures, EEG findings and epilepsy etiology are significant risk factors for mental retardation. CONCLUSIONS: Early age at seizure, multifocal epilepsy and cryptogenic etiology are factors of worse prognosis to normal development of cognitive functions in pediatric intractable epilepsy. PMID- 20200850 TI - [Neurolinguistic aspects in autism spectrum disorders. Neuroanatomical and functional relations]. AB - INTRODUCTION AND DEVELOPMENT: Impairments in language and communication are a defining feature of autism spectrum disorders. There is significant variability in linguistic abilities in autism spectrum disorders. They have difficulties with certain aspects of language such as semantics functions, syntax, prosody and phonology, although the most evident language deficits concern to pragmatics functioning. These language difficulties can cause serious problems in social interaction. CONCLUSIONS: The neural bases underlying this failure to develop language are unknown. Several functional and structural imaging studies have identified irregularities in language-related regions in autism spectrum disorders, such as morphometric differences in Broca's area and Wernicke's area, and patterns of reduced or reversed laterality in frontal and temporal cortex. There is also decreased functional connectivity between anterior and posterior language regions. PMID- 20200851 TI - [Models of intervention in children with autism]. AB - INTRODUCTION: Autism spectrum disorders make up a group of neurodevelopmental disorders that globally affect different higher brain functions in the individual, such as intelligence, the capacity to use language and social interaction. Today, although there is still no curative treatment for autism, there are a number of non pharmacological interventions that can modify the poor prognosis that is generally associated to this type of disorders. AIM: To briefly review the different approaches to the neuro rehabilitation of patients suffering from autism spectrum disorders, which are usually known as methods of intervention. DEVELOPMENT: From the categorical point of view, three types of methods of intervention can be distinguished, depending on whether the orientation is psychodynamic, biomedical or psycho educational. It is difficult to compare the results of the different methods of intervention, but researchers have identified several common elements that they should have if they are to be effective. At present, the psycho educational methods are preferred, since they are the only ones that, to date, have proved to be effective in research studies. CONCLUSIONS: Early intervention by diagnostic and early care centres, with the use of mixed models of psycho educational intervention that nevertheless also include an important percentage of behavioural elements, has proved to be capable of modifying the course of patients with autism spectrum disorders and is currently the most suitable approach. PMID- 20200852 TI - [Alexithymia and Asperger syndrome]. AB - INTRODUCTION: The study starts with the hypothesis that the difficulty to identify and describe emotions and feelings, and to differentiate the feelings of bodily sensations that accompany them, are a common denominator of the construct of alexithymia and Asperger syndrome (AS). PATIENTS AND METHODS: The study evaluates the levels of alexithymia in nine adult male subjects with AS. RESULTS: The results are classified according to whether the source of information is the subject itself with SA (significant alexithymia level in 2/3 parts of the subjects surveyed) or if the source is a relative (the final score in relation to the presence of the alexithymia is the double than in neurotypical population). CONCLUSION: It's confirmed a significant comorbidity between alexithymia and SA leading to the question of whether alexithymia is a idiosyncratic trait of individuals with SA. PMID- 20200853 TI - [Autism and vaccinations: the end?]. AB - INTRODUCTION: Of the different theories explaining the aetiology of autism, one that has achieved widespread popularity among the general public is the involvement of the MMR vaccine as the causation of autism. The connection between vaccines and autism rests upon two theories. On the one hand, the anti-measles fraction of the vaccine is attributed with the development of an enteropathy due to malabsorption, which would facilitate the absorption of toxic neuropeptides and the effects of this process on the brain would favour the appearance of autism. The other theory involves thimerosal (a combination of ethylmercury and thiosalicylate), which is used as a preservative in some vaccines, including the MMR. The data in favour of these hypotheses have led to a great amount of social alarm, especially in certain areas that are more inclined to accept 'alternative' therapies and hypotheses. DEVELOPMENT AND CONCLUSIONS: This article analyses the data on which the involvement of the MMR vaccine in autism is based. It also underlines the weakness of the anti-vaccine arguments, as well as the forceful, convincing response, based on experimental and epidemiological work, that has been generated following the notable social unrest. Running parallel to the scientific debate, there has also been a legal discussion, which has arisen as a consequence of the more than 5,000 lawsuits filed in the United States, and in which the claims for financial compensation together amount to two thousand million dollars. On 12th February 2009, following a court hearing in which the specific case of a girl called Michelle Cedillo was taken as an example, the court ruled that the overall weight of the evidence was overwhelmingly opposed to the theories put forward by the plaintiffs. PMID- 20200854 TI - Isolation of amniotic mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) have the ability to differentiate into osteocytes, chondrocytes, and adipocytes and possess immunomodulatory properties. Amniotic membrane from human term placenta is a potential source of multipotent MSCs that could be useful for regenerative medicine. This unit describes a detailed and simple protocol for the isolation of amniotic mesenchymal cells. We also introduce a simple density separation technique for the purification of this cell type from possible contamination with amniotic epithelial cells. PMID- 20200855 TI - Derivation of vasculature from embryonic stem cells. AB - The formation of the multicellular vascular system is critical to the growth, development, and viability of an organism, and many embryonic lethal mouse knockouts are due to vascular defects. Unfortunately, the complex nature, and many cell types involved in vasculogenesis and angiogenesis has stymied in vitro models of vascular formation. This unit describes a system that allows human embryonic stem cells to differentiate and spontaneously form vascular networks via both vasculogenesis and angiogenesis in the context of the three germ layers. PMID- 20200856 TI - Outlook and adaptation in advanced cancer: a systematic review. AB - 'Fighting spirit' in early-stage cancer comprises optimism about prognosis, a belief that the disease and/or its effects are controllable, and a determination to cope with the situation using various active coping methods. It is associated with better adjustment. In advanced cancer, the usefulness of this coping style is contentious. This systematic review identified eight studies that investigated these qualities in advanced cancer. They provided some evidence that positive attitude and self-efficacy may be associated with better emotional adjustment; active, problem-focused coping appears to be adaptive and avoidant coping maladaptive. However, major methodological flaws make any conclusions highly speculative. Further research in this area using larger samples and longitudinal design is required. PMID- 20200857 TI - Knowledge of genomic testing among early-stage breast cancer patients. AB - BACKGROUND: Genomic recurrence risk test results now inform clinical decisions about adjuvant treatment for women with early-stage breast cancer. We sought to understand patients' knowledge of these tests and correlates of their knowledge. METHODS: Participants in this cross-sectional study were 78 women, treated for early-stage, estrogen receptor-positive breast cancer with 0-3 positive lymph nodes, whose medical records indicated they received Oncotype DX testing earlier. We mailed a questionnaire that assessed knowledge of genomic recurrence risk testing (13 item scale, alpha=0.83) and reviewed medical charts of consenting patients. RESULTS: Knowledge about genomic recurrence risk testing was low (mean knowledge score=67%, SD=0.23). Low knowledge scores were more commonly due to responses of 'don't know' than incorrect answers. Most women (91%) clearly understood that test results can aid decisions about chemotherapy, and few (22%) understood that the test's estimate of the chance of metastasis assumes the patient is receiving hormone therapy. Higher knowledge about genomic recurrence risk testing was associated with higher education, reading ability, and numeracy. Knowledge was higher among women who recalled receiving both verbal and printed information about the test and among women who had active roles in deciding about their treatments. Higher knowledge was also associated with having fewer concerns about genomic testing. DISCUSSION: Among early-stage breast cancer patients who received Oncotype DX, we found low knowledge about many aspects of genomic recurrence risk testing. Research is needed to understand testing information provided to patients and best practices for patient education. PMID- 20200859 TI - Get involved and reap the rewards. PMID- 20200861 TI - System develops 'Mercy Alerts' to share RCAs. PMID- 20200862 TI - Collaborating to manage vendor interactions and protect quality of care in the OR. AB - A culture that provides for safe patient environments demands that health care risk managers address all barriers to safe care, sometimes in extraordinary ways. For example, the operating room is one environment that has gained attention with policies on performing "time outs" before beginning a case and strong emphasis on correct site, correct patient and correct procedure surgery. However, a common hospital practice that has been generally accepted is to invite, allow and encourage sales representatives, or vendors, into the operating room to help surgeons use new equipment or devices. This article will describe how risk managers - partnering with their facility's sourcing and materials management departments - were able to influence a network-wide shift in vendor interactions in the operating room to create safer places for patient care. PMID- 20200863 TI - Critical issues for homeland security and health care sector readiness. AB - The "war on terrorism" and the nation's response to associated terrorist threats has created a significant challenge for health care risk management professionals. The Department of Homeland Security and initiation of the National Response Plan have set in motion a series of national requirements and obligations designed to protect and prepare the country to meet terrorist threats. These requirements and obligations have an impact on the health care industry with its ownership of critical infrastructure/key resources requiring protection from all-hazards events. Health care risk management professionals should be aware that the consequences of not meeting expectations during a future attack are significant. PMID- 20200864 TI - Prescribers hold key to systemic reduction of medication error occurrences. AB - The medication use process is a complex system made up of interlocking component subsystems. These include the prescribing, dispensing and administration systems. Although great emphasis has been placed on preventing errors in the administration process, the prescribing process can be a common source of error. Physicians and other practitioners need to be aware of the sources of error in this subsystem and need to be receptive to ideas and suggestions for reducing prescribing errors, because only the prescribers themselves can fix this part of the system. PMID- 20200865 TI - Managing corporate governance risks in a nonprofit health care organization. AB - Triggered by corporate scandals, there is increased oversight by governmental bodies and in part by the Sarbanes-Oxley Act of 2002. Corporations are developing corporate governance compliance initiatives to respond to the scrutiny of regulators, legislators, the general public and constituency groups such as investors. Due to state attorney general initiatives, new legislation and heightened oversight from the Internal Revenue Service, nonprofit entities are starting to share the media spotlight with their for-profit counterparts. These developments are changing nonprofit health care organizations as well as the traditional role of the risk manager. No longer is the risk manager focused solely on patients' welfare and safe passage through a complex delivery system. The risk manager must be aware of corporate practices within the organization that could allow the personal objectives of a few individuals to override the greater good of the community in which the nonprofit organization serves. PMID- 20200868 TI - Moving toward the ERM concept. PMID- 20200869 TI - Advancing ERM participation through staff patient safety initiatives. PMID- 20200870 TI - Enterprise risk management. Part one: defining the concept, recognizing its value. PMID- 20200871 TI - Enterprise risk management. Part two: getting an ERM program started. PMID- 20200872 TI - Enterprise risk management. Part three: the role of the chief risk officer (CRO). PMID- 20200873 TI - Information technology in health care: addressing promises and pitfalls. AB - Health information technology (HIT) and electronic medical records systems are receiving much attention in health care though only a relatively small number of health care organizations and providers have embraced the technology. This article introduces important concepts and definitions and provides the risk manager with key elements to consider when incorporating HIT principles into a proactive risk management program. A checklist is offered to assist in the assessment of electronic records systems. PMID- 20200874 TI - Strategies for risks presented by obese patients in the ED. AB - Regardless of whether bariatric services or surgeries are offered at a health care facility, it is important to evaluate every emergency department's capability to appropriately assess, monitor and treat extremely obese patients. As the general population is growing in numbers as well as weight, having the appropriate equipment as well as understanding the special needs of the bariatric, or extremely obese, patient will go along way to avoiding unnecessary frustrations and possibly jeopardizing patient care. This article will assist in identifying possible risks in an ED for patients and suggest strategies for facing these risks. PMID- 20200875 TI - Case law update. Surgery center only has duty to warn not to drive after procedure. Young v. The Gastro-Intestinal Center, Inc._ Ark. _,_S.W. 3d _, No. 04 595 (Ark. March 24, 2005). PMID- 20200876 TI - Leading the way to professional success. AB - One of the goals contained in the ASHRM Strategic Plan for 2007-2009 is to develop the risk management professional in a changing healthcare environment. The goal is tremendously important to all of us. PMID- 20200877 TI - Different roles, same goal: risk and quality management partnering for patient safety. By the ASHRM Monographs Task Force. PMID- 20200878 TI - Including patients in root cause and system failure analysis: legal and psychological implications. AB - The act of open disclosure of an adverse event alone may not be enough for patients or their families. Patients and patient advocates are asking for increased transparency and a greater role in the process of change. When properly handled, involving patients in post-event analysis allows risk management professionals to further improve their organization's systems analysis process while empowering patients to be part of the solution. This article examines the legal and psychological considerations surrounding the involvement of patients in system failure analysis and provides tools for selecting patients who are able to benefit from this process and for adequately preparing patients and caregivers for what lies ahead. PMID- 20200879 TI - Avoiding pitfalls of anticoagulation therapy. AB - Antithrombotic therapy poses a significant risk of litigation owing to the risk of devastating outcomes from both the condition for which the therapy is necessary and the therapy itself. Using a case-based approach, this article illustrates how evidence-based guidelines, documentation, and patient communication can potentially reduce the likelihood of errors associated with antithrombotic therapy. PMID- 20200880 TI - PURE conversations: enhancing communication and teamwork. AB - Communications failures have been identified as a significant cause of adverse outcomes in obstetrics. Following the lead of some high reliability organizations, healthcare has introduced structured communication such as SBAR as a way to make sure communications between professionals are direct, complete and effective. The authors have observed, however, that structured communication in healthcare often requires a cultural change in the way that professionals relate to each other; PURE conversations (Purposeful/prepared/productive, Unambiguous, Respectful and Effective) can facilitate this cultural shift. PURE conversations stress the mental processes necessary to conduct and monitor structured communications in real time by taking into account the context and relationships that exist among professionals. This article describes the elements of a multidisciplinary workshop based on clinical scenarios incorporating the PURE concept to improve the effectiveness and adoption of structured communication by the perinatal team. PMID- 20200881 TI - Uninjured, non-medicare beneficiary has no standing to bring MSP claim. Brockovich v. Sharp Healthcare, No. 06-CV-1628 (S.D. Cal. Nov. 7, 2007); Brockovich v. Community Medical Centers, No. CV-F-06-1609 (E.D. Cal. March 6, 2007). PMID- 20200882 TI - Engaging 'levers' to guage success. AB - In 2007, as part of its annual strategic planning process, the ASHRM board was fortunate to have the assistance of Rick Foster, an internationally known management consultant and author. Those of you who have participated in the AHA's Patient Safety Leadership Fellowship program have had the opportunity to work with Rick as he showed you what your Myers Briggs personality assessment results really mean, and how to understand different behavioral tendencies predicted by those assessments. PMID- 20200883 TI - Using Web-based simulation learning to deal with shoulder dystocia. AB - Simulation-based learning can provide education and training to individuals in a variety of industries. The military, aviation and nuclear power industries have seen demonstrable improvement in critical event handling through the use of this type of learning when coupled with crew resource management techniques. Simulation training is also emerging in the healthcare field as an effective patient safety and risk management tool. In the area of obstetrics, healthcare risk managers can have an impact on injury and claim reduction rates related to shoulder dystocia by advocating for and implementing simulation training for obstetrical providers. This article will describe a shoulder dystocia simulation training program that uses a high-fidelity mannequin, and illustrate the impact that the healthcare risk manager can have in reducing injuries due to shoulder dystocia. PMID- 20200884 TI - The timing of early resolution: working at the patient's pace. AB - In recent years, risk managers have been charged with educating providers who need to know how to communicate to a patient that an unanticipated or adverse event has occurred. Much has been written about the elements that should be part of a disclosure conversation: who should be involved, what should be said and when it should be said. Patients have acknowledged their desire to have early, and complete, information where possible. However, what is lacking is an understanding of what happens after the initial disclosure conversation, when the time comes to discuss accommodation or compensation with the patient or family. This article will look at the post-disclosure status of the patient or family, the steps of the grieving process, and the mechanisms for both the risk manager and the provider to successfully bring closure to the event. PMID- 20200885 TI - The Five A's: what do patients want after an adverse event? AB - After an adverse event, Five A's: Acknowledgment, Apology, All the Facts, Assurance and Appropriate Compensation, serve to meet the essential needs of patients and their families. This simple mnemonic creates a clear framework of understanding for the actions health professionals need to take to manage errors and adverse events in an empathic and patient-oriented fashion. While not all patients demand or need compensation, most need at least the first four A's. Patient-centered communication using this simple framework following an adverse event will foster a climate of understanding and frank discussion, addressing the emotional and physical needs of the whole patient and family. PMID- 20200886 TI - Vicarious liability: Attending physician may be liable for the orders of resident physicians. Thomas v. VanTuinen, No. 263613 (Ct. App. Mich. February 20, 2007). PMID- 20200887 TI - Risk management issues in assessing suicidal and homicidal patients. PMID- 20200888 TI - Facing challenges, from new technology to inertia. PMID- 20200889 TI - Cyber risk and privacy liability: a click in the right direction? AB - Cyber risk and privacy exposure exert an impact upon virtually every aspect of a healthcare organization (HCO)--assets, clinical operations, finances and reputation. Exposure is enterprise-wide and includes risk to both physical and non-physical assets in increasing degrees. The consequences of a cyber attack or privacy breach could be operationally and financially catastrophic, so an HCO's move toward an enterprise-wide approach at identifying and minimizing risk, cyber and privacy liability should be on the radar screen for risk managers and leadership. PMID- 20200890 TI - When systems fail: improving care through technology can create risk. AB - Emerging medical technology is transforming the care of the modern-day patient. Hospital performance and patient safety is improving, lowering professional liability and medical malpractice costs. This advanced technology affects not only diagnosis and treatment but also hospital productivity and revenue. However, it also exposes hospitals and medical personnel to a number of unforeseeable risks. This article examines ongoing efforts to improve patient safety through the use of technology, automation and complex systems operations. It discusses the importance of skilled negotiation when vying for technology contracts and the value of maintaining a reliable data center to support it. Technology risk exposure is now a reality. A hospital needs to know how to protect itself from cyber liability, business interruption, and data loss and theft by ensuring that there is adequate coverage. PMID- 20200891 TI - Technological iatrogenesis: new risks force heightened management awareness. AB - Iatrogenesis is a term typically reserved to express the state of ill health or the adverse outcome resulting from a medical intervention, or lack thereof. Three types of iatrogenesis are described in the literature: clinical, social and cultural. This paper introduces a fourth type, technological iatrogenesis, or emerging errors stimulated by the infusion of technological innovations into complex healthcare systems. While health information technologies (HIT) have helped to make healthcare safer, this has also produced contemporary varieties of iatrogenic errors and events. The potential pitfalls of technological innovations and risk management solutions to address these concerns are discussed. Specifically, failure mode effect analysis and root cause analysis are discussed as opportunities for risk managers to prevent problems and avert errors from becoming sentinel events. PMID- 20200892 TI - Partnering with technology to reduce OB losses. AB - Following a catastrophic birth injury that occurred as a result of deviations from the expected standards of care, the OB Risk Reduction Task Force of a healthcare network identified criteria to transform care at the bedside from theory to practice: 1) protocol-driven, real-time alerts to help healthcare providers meet clinical guidelines; and 2) the ability to produce reliable data to monitor and measure adherence to accepted standards of care. The group selected a technological solution to achieve that end. This case study illustrates how a strong partnership model between healthcare and technology solution providers can achieve much when both parties are focused on the same goals of performance improvement and active risk reduction. PMID- 20200893 TI - Online learning as a staff risk management education option. AB - As clinicians face growing responsibilities to keep up with continuing medical education offerings, they have less time to learn fundamental risk management knowledge to practice safely. To meet their clinicians' needs and time constraints, the authors developed, implemented and assessed 15 lessons in three online risk management courses for resident physicians in an academic center. This report demonstrates that Internet-based learning can provide a practical alternative to formal classroom teaching of a risk management curriculum to busy resident physicians and potentially to other healthcare professionals. PMID- 20200894 TI - Modernization of patient safety event reporting: surveillance and benchmarking. PMID- 20200895 TI - Negligent credentialing: Minnesota recognizes the tort of negligent credentialing. Larson v. Wasemiller, No. A05-1698 and A05-1791 (Minn. August 16, 2007). PMID- 20200896 TI - Viewing the candidates as risk managers. AB - After one of the most chaotic political primary seasons that we've seen in many years, election season began early this time around. It promises to be one of the most entertaining in decades as we head towards the respective national conventions in late summer. The candidates are touting "change" as one of the central themes for their campaigns, but I must say that a more appropriate word might be "choice." I doubt that there has ever been a more diverse field of candidates. PMID- 20200898 TI - Tackling patient safety taxonomy: a must for risk managers. PMID- 20200899 TI - Considerations for implementing pre-dispute arbitration agreements in provider contracts. AB - Due in part to the historical increase in large compensatory awards and punitive damages in jury verdicts in medical malpractice/long-term care cases and the concomitant increase in the costs of defending these claims, healthcare providers have sought to reduce litigation costs and avoid exposure to runaway jury verdicts in medical malpractice trials by implementing arbitration agreements in healthcare admission contracts. Risk managers should be aware of the evolving law in this area and recognize that a successful arbitration program requires a commitment to ensuring that the program is administered in accordance with evolving laws. PMID- 20200900 TI - Minimizing the legal risk with 'curbside' consultation. AB - "Curbside consultations"--in which a physician obtains insights on a medical case from another physician who has not seen the patient or reviewed the record--can yield advantages to the requesting physician. However, shortcomings are inherent in this common type of exchange and pose legal risk to the curbside consultant. This article provides background and practical tips that might help avoid being caught up in a lawsuit by surprise, or if named as a party, avoid being held culpable when the only involvement was a brief conversation with a colleague. PMID- 20200901 TI - Addressing risk in the design of new healthcare services: a step-by-step methodology. AB - New service design can be done effectively through enterprise risk management (ERM) by identifying the clinical and administrative risks within the new service design. This article proposes a 10-step process describing the business team's tasks and integrating risk management, quality management and patient safety concepts. PMID- 20200902 TI - Failure to deliver products of conception should be a critical finding. Lakeland Medical Center v. Taylor, _____ So. 2d _____, No. 2007-CA-0642 (Ct. App. La. November 28, 2007). PMID- 20200903 TI - From the end of the world to the top of the world. AB - I've been on the road a bit this summer. Because of the kind generosity of my London broker, Lloyd and Partners, Ltd., I've been allowed the unique opportunity to have an insider's view of the London market. I observed an interesting renewal situation and sat with underwriters in their boxes amid the hallowed (at least to us insurance geeks) trappings of Lloyd's. I spent several lovely days in Hanover with my long-time lead reinsurer, Hanover Re, while trying desperately to keep up with my own work back home. It's been stimulating and thought-provoking, and I know I won't ever view the purchase of insurance in the same way. PMID- 20200905 TI - Data for safety: turning lessons learned into actionable knowledge. PMID- 20200906 TI - Integrating disclosure, patient safety and risk management activities. AB - National Quality Forum safe-practice guidelines encourage hospitals to integrate disclosure, patient safety and risk management activities. Combining collaborative law with a patient safety program in a parallel process makes it possible to achieve this integration. This combination provides for physician-led guidance in determining whether disclosure is required - and, if so, provides mentor assistance with actual disclosure. It offers proactive error prevention by offering a means to quickly utilize information to make safety changes. Additionally, the combination provides an opportunity to access collaborative law at a time when it is still possible to resolve issues without resort to litigation. PMID- 20200907 TI - The ECG dilemma: guidelines on improving interpretation. AB - The "ECG Dilemma" was recognized by the American College of Cardiology (ACC) and the American Heart Association more than 10 years ago. Estimates put the number of patients suffering from significant ECG interpretation errors every year in the same range as deaths from diabetes. Missed MI ranks in the top tier of malpractice dollars lost. Guidelines have been put forth to reduce these losses and improve patient safety and quality of care. These guidelines, and suggestions towards implementing them, are discussed. PMID- 20200908 TI - Preventing and responding to medical identity theft. AB - Medical identity theft is a crime with two victims: patients and providers. It is easy to commit and lucrative because healthcare record keeping and business interactions are complex and mainly electronic. Patients whose identity has been stolen are vulnerable to both medical error and financial loss. Providers may suffer both reputation loss and financial loss. There are steps to help prevent and to respond appropriately to medical identity theft. PMID- 20200909 TI - Hospitals under no duty to disclose negative information unless asked. Medical staff affairs.Kadlec Medical Center v. Lakeview Anesthesia Associates, F. 3d, No. 06-30745 (5th Cir. May 8, 2008). PMID- 20200910 TI - Life: coming to grips with the balancing act. PMID- 20200912 TI - Basic considerations and potential benefits. PMID- 20200913 TI - Feasibility: the process and the people. PMID- 20200914 TI - Implications of owning a captive insurance company. PMID- 20200915 TI - Selecting a third-party administrator through an RFP. PMID- 20200916 TI - Creating a better captive meeting agenda. PMID- 20200918 TI - Medical malpractice: Hospital may be liable for failing to provide stat echocardiogram. Columbia Medical Center of Las Colinas v. Hogue, 51 Tex. Sup. J. 1220 (Tex. 2008). PMID- 20200919 TI - 'Make a new plan, Stan'. PMID- 20200921 TI - Torts to contract? Moving from informed consent to shared decision-making. AB - Many claims of medical malpractice arise from a breakdown in communication between physician and patient. As a result, medical decision-making may change from an informed consent model to a shared decision-making strategy. Shared decision-making, a contract derivative, will trigger contract obligations and change the face of medical malpractice from tort to contract. PMID- 20200922 TI - Implications of the Inpatient Prospective Payment System final rules. AB - This article was prepared in response to the Centers for Medicare & Medicaid Services (CMS) publication of the Inpatient Prospective Payment System (IPPS) Final Rules for FY 2008 and 2009 which placed additional requirements on hospitals for certain hospital-acquired conditions. This article addresses these rulings and the implications for healthcare facilities, including strategies for dealing with challenges created by the rulings. PMID- 20200923 TI - Communication plays key role in OB patient expectations. AB - Obstetrics is a medical specialty with high profesional liability exposure. Every aspect of an adverse OB outcome has become an opportunity for a legal review. Common root causes in adverse outcomes include communication failure, poor teamwork, and system failures. Indeed, poor communication is a significant factor in OB-related malpractice claims. This excerpt from the booklet Risk Management Pearls for Obstetrics highlights those causes (particularly poor communications) and provides strategies to address them. PMID- 20200924 TI - Diagnosis of emergency condition not necessary for EMTALA claim. Thomas v. St. Joseph Healthcare Inc., No. 2007-CA-001192-MR, No. 2007-CA-001244-MR (Ct. App. Ky. Dec. 5, 2008). PMID- 20200925 TI - Infrared spectroscopy indicates altered bone turnover and remodeling activity in renal osteodystrophy. AB - Renal osteodystrophy alters metabolic activity and remodeling rate of bone and also may lead to different bone composition. The objective of this study was to characterize the composition of bone in high-turnover renal osteodystrophy patients by means of Fourier transform infrared spectroscopic imaging (FTIRI). Iliac crest biopsies from healthy bone (n = 11) and patients with renal osteodystrophy (ROD, n = 11) were used in this study. The ROD samples were from patients with hyperparathyroid disease. By using FTIRI, phosphate-to-amide I ratio (mineral-to-matrix ratio), carbonate-to-phosphate ratio, and carbonate-to amide I ratio (turnover rate/remodeling activity), as well as the collagen cross link ratio (collagen maturity), were quantified. Histomorphometric analyses were conducted for comparison. The ROD samples showed significantly lower carbonate-to phosphate (p < .01) and carbonate-to-amide I (p < .001) ratios. The spatial variation across the trabeculae highlighted a significantly lower degree of mineralization (p < .05) at the edges of the trabeculae in the ROD samples than in normal bone. Statistically significant linear correlations were found between histomorphometric parameters related to bone-remodeling activity and number of bone cells and FTIRI-calculated parameters based on carbonate-to-phosphate and carbonate-to-amide I ratios. Hence the results suggested that FTIRI parameters related to carbonate may be indicative of turnover and remodeling rate of bone. PMID- 20200927 TI - Fracture risk prediction using BMD and clinical risk factors in early postmenopausal women: sensitivity of the WHO FRAX tool. AB - The aim of this prospective study was (1) to identify significant and independent clinical risk factors (CRFs) for major osteoporotic (OP) fracture among peri- and early postmenopausal women, (2) to assess, in this population, the discriminatory capacity of FRAX and bone mineral density (BMD) for the identification of women at high risk of fracture, and (3) to assess whether adding risk factors to either FRAX or BMD would improve discriminatory capacity. The study population included 2651 peri- and early postmenopausal women [mean age (+/- SD): 54 +/- 4 years] with a mean follow-up period of 13.4 years (+/-1.4 years). At baseline, a large set of CRFs was recorded, and vertebral BMD was measured (Lunar, DPX) in all women. Femoral neck BMD also was measured in 1399 women in addition to spine BMD. Women with current or past OP treatment for more than 3 months at baseline (n = 454) were excluded from the analyses. Over the follow-up period, 415 women sustained a first low-energy fracture, including 145 major OP fractures (108 wrist, 44 spine, 20 proximal humerus, and 13 hip). In Cox multivariate regression models, only 3 CRFs were significant predictors of a major OP fracture independent of BMD and age: a personal history of fracture, three or more pregnancies, and current postmenopausal hormone therapy. In the subsample of women who had a hip BMD measurement and who were not receiving OP therapy (including hormone-replacement therapy) at baseline, mean FRAX value was 3.8% (+/ 2.4%). The overall discriminative value for fracture, as measured by the area under the Receiver Operating Characteristic (ROC) curve (AUC), was equal to 0.63 [95% confidence interval (CI) 0.56-0.69] and 0.66 (95% CI 0.60-0.73), respectively, for FRAX and hip BMD. Sensitivity of both tools was low (ie, around 50% for 30% of the women classified as the highest risk). Adding parity to the predictive model including FRAX or using a simple risk score based on the best predictive model in our population did not significantly improve the discriminatory capacity over BMD alone. Only a limited number of clinical risk factors were found associated with the risk of major OP fracture in peri- and early postmenopausal women. In this population, the FRAX tool, like other risk scores combining CRFs to either BMD or FRAX, had a poor sensitivity for fracture prediction and did not significantly improve the discriminatory value of hip BMD alone. PMID- 20200926 TI - Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: the FLEX trial. AB - In the Fracture Intervention Trial (FIT) Long Term Extension (FLEX) Trial, 10 years of alendronate (ALN) did not significantly reduce the risk of nonvertebral fractures (NVFs) compared with 5 years of ALN. Continuing ALN reduced the risk of clinical but not morphometric vertebral fractures regardless of baseline vertebral fracture status. In previous studies, ALN efficacy for NVF prevention in women without prevalent vertebral fracture was limited to those with femoral neck (FN) T-scores of -2.5 or less. To determine whether the effect of long-term ALN on fracture differs by vertebral fracture status and femoral neck (FN) T score, we performed a post hoc analysis using FLEX data, a randomized, double blind, placebo-controlled trial among 1099 postmenopausal women originally randomized to ALN in the FIT with mean ALN use of 5 years. In the FLEX Trial, women were randomized to placebo (40%) or ALN 5 mg/day (30%) or ALN 10 mg/day (30%) for an additional 5 years. Among women without vertebral fracture at FLEX baseline (n = 720), continuation of ALN reduced NVF in women with FLEX baseline FN T-scores of -2.5 or less [relative risk (RR) = 0.50, 95% confidence interval (CI) 0.26-0.96] but not with T-scores of greater than -2.5 and -2 or less (RR 0.79, 95% CI 0.37-1.66) or with T-scores of greater than -2 (RR 1.41, 95% CI 0.75 2.66; p for interaction = .019). Continuing ALN for 10 years instead of stopping after 5 years reduces NVF risk in women without prevalent vertebral fracture whose FN T-scores, achieved after 5 years of ALN, are -2.5 or less but does not reduce risk of NVF in women whose T-scores are greater than -2. PMID- 20200928 TI - Men with metabolic syndrome have lower bone mineral density but lower fracture risk--the MINOS study. AB - Data on the association of the metabolic syndrome (MetS) with bone mineral density (BMD) and fracture risk in men are inconsistent. We studied the association between MetS and bone status in 762 older men followed up for 10 years. After adjustment for age, body mass index, height, physical activity, smoking, alcohol intake, and serum 25-hydroxycholecalciferol D and 17beta estradiol levels, men with MetS had lower BMD at the hip, whole body, and distal forearm (2.2% to 3.2%, 0.24 to 0.27 SD, p < .05 to .005). This difference was related to abdominal obesity (assessed by waist circumference, waist-hip ratio, or central fat mass) but not other MetS components. Men with MetS had lower bone mineral content (3.1% to 4.5%, 0.22 to 0.29 SD, p < .05 to 0.001), whereas differences in bone size were milder. Men with MetS had a lower incidence of vertebral and peripheral fractures (6.7% versus 12.0%, p < .05). After adjustment for confounders, MetS was associated with a lower fracture incidence [odds ratio (OR) = 0.33, 95% confidence interval (CI) 0.15-0.76, p < .01]. Among the MetS components, hypertriglyceridemia was most predictive of the lower fracture risk (OR = 0.25, 95%CI 0.10-0.62, p < .005). Lower fracture risk in men with MetS cannot be explained by differences in bone size, rate of bone turnover rate and bone loss, or history of falls or fractures. Thus older men with MetS have a lower BMD related to the abdominal obesity and a lower risk of fracture related to hypertriglyceridemia. MetS probably is not a meaningful concept in the context of bone metabolism. Analysis of its association with bone-related variables may obscure the pathophysiologic links of its components with bone status. PMID- 20200929 TI - Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength. AB - The development of bone-rebuilding anabolic agents for treating bone-related conditions has been a long-standing goal. Genetic studies in humans and mice have shown that the secreted protein sclerostin is a key negative regulator of bone formation. More recently, administration of sclerostin-neutralizing monoclonal antibodies in rodent studies has shown that pharmacologic inhibition of sclerostin results in increased bone formation, bone mass, and bone strength. To explore the effects of sclerostin inhibition in primates, we administered a humanized sclerostin-neutralizing monoclonal antibody (Scl-AbIV) to gonad-intact female cynomolgus monkeys. Two once-monthly subcutaneous injections of Scl-AbIV were administered at three dose levels (3, 10, and 30 mg/kg), with study termination at 2 months. Scl-AbIV treatment had clear anabolic effects, with marked dose-dependent increases in bone formation on trabecular, periosteal, endocortical, and intracortical surfaces. Bone densitometry showed that the increases in bone formation with Scl-AbIV treatment resulted in significant increases in bone mineral content (BMC) and/or bone mineral density (BMD) at several skeletal sites (ie, femoral neck, radial metaphysis, and tibial metaphysis). These increases, expressed as percent changes from baseline were 11 to 29 percentage points higher than those found in the vehicle-treated group. Additionally, significant increases in trabecular thickness and bone strength were found at the lumbar vertebrae in the highest-dose group. Taken together, the marked bone-building effects achieved in this short-term monkey study suggest that sclerostin inhibition represents a promising new therapeutic approach for medical conditions where increases in bone formation might be desirable, such as in fracture healing and osteoporosis. PMID- 20200930 TI - A nonsecosteroidal vitamin D receptor ligand with improved therapeutic window of bone efficacy over hypercalcemia. AB - Vitamin D(3) analogues were shown to be beneficial for osteoporosis and other indications, but their narrow therapeutic window between efficacy and hypercalcemia has limited their clinical utility. A nonsecosteroidal, tissue selective, orally bioavailable, vitamin D receptor (VDR) ligand was ascertained to be efficacious in bone while having modest calcemic effects in vivo. This compound (VDRM2) potently induced Retinoid X Receptor alpha (RXR)-VDR heterodimerization (EC(50) = 7.1 +/- 1.6 nM) and induced osteocalcin promoter activity (EC(50) = 1.9 +/- 1.6 nM). VDRM2 was less potent in inducing Ca(2+) channel transient receptor potential cation channel, subfamily V, member 6 (TRPV6) expression (EC(50) = 37 +/- 12 nM). VDRM2 then was evaluated in osteopenic ovariectomized (OVX) rats and shown to dose-dependently restore vertebral bone mineral density (BMD) from OVX to sham levels at 0.08 microg/kg per day. Hypercalcemia was observed at a dose of 4.6 microg/kg per day of VDRM2, suggesting a safety margin of 57 [90% confidence interval (CI) 35-91]. 1alpha,25 dihydroxyvitamin D(3) [1alpha,25(OH)(2)D], ED71, and alfacalcidol restored BMD at 0.030, 0.0055, and 0.046 microg/kg per day, respectively, whereas hypercalcemia was observed at 0.22, 0.027, and 0.23 microg/kg per day, indicating a safety margin of 7.3, 4.9, and 5.0, respectively (90% CIs 4.1-13, 3.2-7.7, and 3.5-6.7, respectively). Histomorphometry showed that VDRM2 increased cortical bone area and stimulated the periosteal bone-formation rate relative to OVX at doses below the hypercalcemic dose. By contrast, ED71 increased the periosteal bone-formation rate only above the hypercalcemic dose. VDRM2 suppressed eroded surface on trabecular bone surfaces at normal serum calcium dosage levels, suggesting dual anabolic and antiresorptive activity. In summary, vitamin D analogues were more potent than VDRM2, but VDRM2 had a greater safety margin, suggesting possible therapeutic potential. PMID- 20200932 TI - Prevalent fractures are related to cortical bone geometry in young healthy men at age of peak bone mass. AB - Low areal bone mass is a risk factor for fractures in men. Limited data are available on fractures and bone geometry in men, and the relation with sex steroids is incompletely understood. We investigated prevalent fractures in relation to peak bone mass, bone geometry, and sex steroids in healthy young men. Healthy male siblings (n = 677) at the age of peak bone mass (25 to 45 years) were recruited in a cross-sectional population-based study. Trabecular and cortical bone parameters of the radius and cortical bone parameters of the tibia were assessed using peripheral quantitative computed tomography (pQCT). Areal bone mineral density (aBMD) was determined using dual-energy X-ray absorptiometry (DXA). Sex steroids were determined using immunoassays, and fracture prevalence was assessed using questionnaires. Fractures in young men were associated with a longer limb length, shorter trunk, lower trabecular BMD, smaller cortical bone area, and smaller cortical thickness (p < .005) but not with bone-size-adjusted volumetic BMD (vBMD). With decreasing cortical thickness [odds ratio (OR) 1.4/SD, p 300 microg/g of creatinine). Even in the absence of renal tubular dysfunction, occupational exposure to cadmium is associated in men with lower BMD values, a higher risk of having osteoporosis, and a higher urinary calcium excretion, suggesting a direct osteotoxic effect of cadmium. PMID- 20200938 TI - Increased prevalence of bisphosphonate-related osteonecrosis of the jaw with vitamin D deficiency in rats. AB - Necrotic bone exposure in the oral cavity has recently been reported in patients treated with nitrogen-containing bisphosphonates as part of their therapeutic regimen for multiple myeloma or metastatic cancers to bone. It has been postulated that systemic conditions associated with cancer patients combined with tooth extraction may increase the risk of osteonecrosis of the jaw (ONJ). The objective of this study was to establish an animal model of bisphosphonate related ONJ by testing the combination of these risk factors. The generation of ONJ lesions in rats resembling human disease was achieved under the confluence of intravenous injection of zoledronate (ZOL; 35 microg/kg every 2 weeks), maxillary molar extraction, and vitamin D deficiency [VitD(-)]. The prevalence of ONJ in the VitD(-)/ZOL group was 66.7%, which was significantly higher (p < .05, Fisher exact test) than the control (0%), VitD(-) (0%), and ZOL alone (14.3%) groups. Similar to human patients, rat ONJ lesions prolonged the oral exposure of necrotic bone sequestra and were uniquely associated with pseudoepitheliomatous hyperplasia. The number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end label-positive (TUNEL(+)) osteoclasts significantly increased on the surface of post-tooth extraction alveolar bone of the VitD(-)/ZOL group, where sustained inflammation was depicted by [(18)F]fluorodeoxyglucose micro-positron emission tomography (microPET). ONJ lesions were found to be associated with dense accumulation of mixed inflammatory/immune cells. These cells, composed of neutrophils and lymphocytes, appeared to juxtapose apoptotic osteoclasts. It is suggested that the pathophysiologic mechanism(s) underpinning ONJ may involve the interaction between bisphosphonates and compromised vitamin D functions in the realm of skeletal homeostasis and innate immunity. PMID- 20200939 TI - Timing of ibuprofen use and bone mineral density adaptations to exercise training. AB - Prostaglandins (PGs) are essential signaling factors in bone mechanotransduction. In animals, inhibition of the enzyme responsible for PG synthesis (cyclooxygenase) by nonsteroidal anti-inflammatory drugs (NSAIDs) blocks the bone formation response to loading when administered before, but not immediately after, loading. The aim of this proof-of-concept study was to determine whether the timing of NSAID use influences bone mineral density (BMD) adaptations to exercise in humans. Healthy premenopausal women (n = 73) aged 21 to 40 years completed a supervised 9-month weight-bearing exercise training program. They were randomized to take (1) ibuprofen (400 mg) before exercise, placebo after (IBUP/PLAC), (2) placebo before, ibuprofen after (PLAC/IBUP), or (3) placebo before and after (PLAC/PLAC) exercise. Relative changes in hip and lumbar spine BMD from before to after exercise training were assessed using a Hologic Delphi-W dual-energy X-ray absorptiometry (DXA) instrument. Because this was the first study to evaluate whether ibuprofen use affects skeletal adaptations to exercise, only women who were compliant with exercise were included in the primary analyses (IBUP/PLAC, n = 17; PLAC/PLAC, n = 23; and PLAC/IBUP, n = 14). There was a significant effect of drug treatment, adjusted for baseline BMD, on the BMD response to exercise for regions of the hip (total, p < .001; neck, p = .026; trochanter, p = .040; shaft, p = .019) but not the spine (p = .242). The largest increases in BMD occurred in the group that took ibuprofen after exercise. Total hip BMD changes averaged -0.2% +/- 1.3%, 0.4% +/- 1.8%, and 2.1% +/- 1.7% in the IBUP/PLAC, PLAC/PLAC, and PLAC/IBUP groups, respectively. This preliminary study suggests that taking NSAIDs after exercise enhances the adaptive response of BMD to exercise, whereas taking NSAIDs before may impair the adaptive response. PMID- 20200940 TI - Dramatic increase in cortical thickness induced by femoral marrow ablation followed by a 3-month treatment with PTH in rats. AB - We previously reported that following mechanical ablation of the marrow from the midshaft of rat femurs, there is a rapid and abundant but transient growth of bone, and this growth is enhanced and maintained over a 3-week period by the bone anabolic hormone parathyroid hormone (PTH). Here, we asked whether further treatment with PTH or bisphosphonates can extend the half-life of the new bone formed in lieu of marrow. We subjected the left femur of rats to mechanical marrow ablation and treated the animals 5 days a week with PTH for 3 weeks (or with vehicle as a control) to replace the marrow by bone. Some rats were euthanized and used as positive controls or treated with vehicle, PTH, or the bisphosphonate alendronate for a further 9 weeks. We subjected both femurs from each rat to soft X-ray, peripheral quantitative computed tomography (pQCT), micro computed tomography (microCT), dynamic histomorphometry analysis, and biomechanical testing. We also determined the concentrations of serum osteocalcin to confirm the efficacy of PTH. Treatment with PTH for 3 months dramatically enhanced endosteal and periosteal bone formation, leading to a 30% increase in cortical thickness. In contrast, alendronate protected the bone that had formed in the femoral marrow cavity after marrow ablation and 3 weeks of treatment with PTH but failed to promote endosteal bone growth or to improve the biomechanical properties of ablated femurs. We further asked whether calcium-phosphate cements could potentiate the formation of bone after marrow ablation. Marrow cavities from ablated femurs were filled with one of two calcium-phosphate cements, and rats were treated with PTH or PBS for 84 days. Both cements helped to protect the new bone formed after ablation. To some extent, they promoted the formation of bone after ablation, even in the absence of any anabolic hormone. Our data therefore expand the role of PTH in bone engineering and open new avenues of investigation to the field of regenerative medicine and tissue engineering. Local bone marrow aspiration in conjunction with an anabolic agent, a bisphosphonate, or a calcium-phosphate cement might provide a new platform for rapid preferential site-directed bone growth in areas of high bone loss. PMID- 20200941 TI - The type 2 deiodinase Thr92Ala polymorphism is associated with increased bone turnover and decreased femoral neck bone mineral density. AB - The role of type 2 deiodinase (D2) in the human skeleton remains unclear. The D2 polymorphism Thr92Ala has been associated with lower enzymatic activity, which could result in lower local triiodothyronine (T(3)) availability in bone. We therefore hypothesized that the D2 Thr92Ala polymorphism may influence bone mineral density (BMD) and bone turnover. We studied 154 patients (29 men, 125 women: 79 estrogen-replete, 46 estrogen-deficient) with cured differentiated thyroid carcinoma. BMD and bone turnover markers [bone-specific alkaline phosphatase (BAP), cross-linking terminal C-telopeptide of type I collagen (CTX), procollagen type 1 amino-terminal propeptide (P1NP), and cross-linked N telopeptide of type I collagen (NTX)] were measured. Effects of the D2 Thr92Ala polymorphism on BMD and bone turnover markers were assessed by a linear regression model, with age, gender, estrogen state, body mass index (BMI), serum calcium, 25-hydroxyvitamin D, parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), and free triiodothyroxine (T(4)) as covariables. Sixty patients were wild type (Thr/Thr), 66 were heterozygous (Thr/Ala), and 28 were homozygous (Ala/Ala) for the D2 polymorphism. There were no significant differences in any covariables between the three genotypes. Subjects carrying the D2 Thr92Ala polymorphism had consistently lower femoral neck and total hip densities than wild-type subjects (p = .028), and this was accompanied by significantly higher serum P1NP and CTX and urinary NTX/creatinine levels. We conclude that in patients with cured differentiated thyroid carcinoma, the D2 Thr92Ala polymorphism is associated with a decreased femoral neck BMD and higher bone turnover independent of serum thyroid hormone levels, which points to a potential functional role for D2 in bone. PMID- 20200942 TI - Smurf1 inhibits mesenchymal stem cell proliferation and differentiation into osteoblasts through JunB degradation. AB - Ubiquitin ligase Smurf1-deficient mice develop an increased-bone-mass phenotype in an age-dependent manner. It was reported that such a bone-mass increase is related to enhanced activities of differentiated osteoblasts. Although osteoblasts are of mesenchymal stem cell (MSC) origin and MSC proliferation and differentiation can have significant impacts on bone formation, it remains largely unknown whether regulation of MSCs plays a role in the bone-mass increase of Smurf1-deficient mice. In this study we found that bone marrow mesenchymal progenitor cells from Smurf1(-/-) mice form significantly increased alkaline phosphatase-positive colonies, indicating roles of MSC proliferation and differentiation in bone-mass accrual of Smurf1(-/-) mice. Interestingly, Smurf1( /-) cells have an elevated protein level of AP-1 transcription factor JunB. Biochemical experiments demonstrate that Smurf1 interacts with JunB through the PY motif and targets JunB protein for ubiquitination and proteasomal degradation. Indeed, Smurf1-deficient MSCs have higher proliferation rates, consistent with the facts that cyclin D1 mRNA and protein both are increased in Smurf1(-/-) cells and JunB can induce cyclinD1 promoter. Moreover, JunB overexpression induces osteoblast differentiation, shown by higher expression of osteoblast markers, and JunB knock-down not only decreases osteoblast differentiation but also restores the osteogenic potential to wild-type level in Smurf1(-/-) cells. In conclusion, our results suggest that Smurf1 negatively regulates MSC proliferation and differentiation by controlling JunB turnover through an ubiquitin-proteasome pathway. PMID- 20200943 TI - rBMP represses Wnt signaling and influences skeletal progenitor cell fate specification during bone repair. AB - Bone morphogenetic proteins (BMPs) participate in multiple stages of the fetal skeletogenic program from promoting cell condensation to regulating chondrogenesis and bone formation through endochondral ossification. Here, we show that these pleiotropic functions are recapitulated when recombinant BMPs are used to augment skeletal tissue repair. In addition to their well-documented ability to stimulate chondrogenesis in a skeletal injury, we show that recombinant BMPs (rBMPs) simultaneously suppress the differentiation of skeletal progenitor cells in the endosteum and bone marrow cavity to an osteoblast lineage. Both the prochondrogenic and antiosteogenic effects are achieved because rBMP inhibits endogenous beta-catenin-dependent Wnt signaling. In the injured periosteum, this repression of Wnt activity results in sox9 upregulation; consequently, cells in the injured periosteum adopt a chondrogenic fate. In the injured endosteum, rBMP also inhibits Wnt signaling, which results in the runx2 and collagen type I downregulation; consequently, cells in this region fail to differentiate into osteoblasts. In muscle surrounding the skeletal injury site, rBMP treatment induces Smad phosphorylation followed by exuberant cell proliferation, an increase in alkaline phosphatase activity, and chondrogenic differentiation. Thus different populations of adult skeletal progenitor cells interpret the same rBMP stimulus in unique ways, and these responses mirror the pleiotropic effects of BMPs during fetal skeletogenesis. These mechanistic insights may be particularly useful for optimizing the reparative potential of rBMPs while simultaneously minimizing their adverse outcomes. PMID- 20200944 TI - Gs G protein-coupled receptor signaling in osteoblasts elicits age-dependent effects on bone formation. AB - Age-dependent changes in skeletal growth are important for regulating skeletal expansion and determining peak bone mass. However, how G protein-coupled receptors (GPCRs) regulate these changes is poorly understood. Previously, we described a mouse model expressing Rs1, an engineered receptor with high basal G(s) activity. Rs1 expression in osteoblasts induced a dramatic age-dependent increase in trabecular bone with features resembling fibrous dysplasia. To further investigate how activation of the G(s)-GPCR pathway affects bone formation at different ages, we used the tetracycline-inducible system in the ColI(2.3)(+)/Rs1(+) mouse model to control the timing of Rs1 expression. We found that the Rs1 phenotype developed rapidly between postnatal days 4 and 6, that delayed Rs1 expression resulted in attenuation of the Rs1 phenotype, and that the Rs1-induced bone growth and deformities were markedly reversed when Rs1 expression was suppressed in adult mice. These findings suggest a distinct window of increased osteoblast responsiveness to G(s) signaling during the early postnatal period. In addition, adult bones encode information about their normal shape and structure independently from mechanisms regulating bone expansion. Finally, our model provides a powerful tool for investigating the effects of continuous G(s)-GPCR signaling on dynamic bone growth and remodeling. PMID- 20200945 TI - Sorting of growth plate chondrocytes allows the isolation and characterization of cells of a defined differentiation status. AB - Axial growth of long bones occurs through a coordinated process of growth plate chondrocyte proliferation and differentiation. This maturation of chondrocytes is reflected in a zonal change in gene expression and cell morphology from resting to proliferative, prehypertrophic, and hypertrophic chondrocytes of the growth plate followed by ossification. A major experimental limitation in understanding growth plate biology and pathophysiology is the lack of a robust technique to isolate cells from the different zones, particularly from small animals. Here, we report on a new strategy for separating distinct chondrocyte populations from mouse growth plates. By transcriptome profiling of microdissected zones of growth plates, we identified novel, zone-specific cell surface markers and used these for flow cytometry and immunomagnetic cell separation to quantify, enrich, and characterize chondrocytes populations with respect to their differentiation status. This approach provides a novel platform to study cartilage development and characterize mouse growth plate chondrocytes to reveal unique cellular phenotypes of the distinct subpopulations within the growth plate. PMID- 20200946 TI - SQSTM1 gene analysis and gene-environment interaction in Paget's disease of bone. AB - Even though SQSTM1 gene mutations have been identified in a consistent number of patients, the etiology of Paget's disease of bone (PDB) remains in part unknown. In this study we analyzed SQSTM1 mutations in 533 of 608 consecutive PDB patients from several regions, including the high-prevalence area of Campania (also characterized by increased severity of PDB, higher number of familial cases, and peculiar phenotypic characteristics as giant cell tumor). Eleven different mutations (Y383X, P387L, P392L, E396X, M401V, M404V, G411S, D423X, G425E, G425R, and A427D) were observed in 34 of 92 (37%) and 43 of 441 (10%) of familial and sporadic PDB patients, respectively. All five patients with giant cell tumor complicating familial PDB were negative for SQSTM1 mutations. An increased heterogeneity and a different distribution of mutations were observed in southern Italy (showing 9 of the 11 mutations) than in central and northern Italy. Genotype-phenotype analysis showed only a modest reduction in age at diagnosis in patients with truncating versus missense mutations, whereas the number of affected skeletal sites did not differ significantly. Patients from Campania had the highest prevalence of animal contacts (i.e., working or living on a farm or pet ownership) without any difference between patients with or without mutation. However, when familial cases from Campania were considered, animal contacts were observed in 90% of families without mutations. Interestingly, a progressive age related decrease in the prevalence of animal contacts, as well as a parallel increase in the prevalence of SQSTM1 mutations, was observed in most regions except in the subgroup of patients from Campania. Moreover, patients reporting animal contacts showed an increased number of affected sites (2.54 +/- 2.0 versus 2.19 +/- 1.9, p < .05) over patients without animal contacts. This difference also was evidenced in the subgroup of patients with SQSTM1 mutations (3.84 +/- 2.5 versus 2.76 +/- 2.2, p < .05). Overall, these data suggest that animal related factors may be important in the etiology of PDB and may interact with SQSTM1 mutations in influencing disease severity. PMID- 20200947 TI - Osteocalcin gene polymorphisms influence concentration of serum osteocalcin and enhance fracture identification. AB - Osteoporosis is a major health problem affecting more than 75 million people throughout Europe, the United States, and Japan. Epidemiologic studies have determined that both genetic and environmental factors contribute to the pathogenesis of osteoporosis. We have investigated the association between polymorphisms at the osteocalcin locus and variables linked to bone health. Osteocalcin provides a link between bone and energy metabolism, hence its potential importance as an osteoporosis candidate gene. In this study, we included a total of 996 women (all aged 75 years) from the Osteoporosis Prospective Risk Assessment (OPRA) cohort. We sequenced the osteocalcin gene along with flanking regions to search for novel coding polymorphisms. We also analyzed four polymorphisms selected from within and flanking regions of the osteocalcin gene to study their association with serum total osteocalcin levels (S-TotalOC), total-body (TB) bone mineral density (BMD), fracture, TB fat mass, and body mass index (BMI). The promoter polymorphism rs1800247 was significantly associated with S-TotalOC (p = .012) after controlling for BMI and TB BMD. The polymorphism rs1543297 was significantly associated with prospectively occurring fractures (p = .008). In a model taking into account rs1543297 and rs1800247, along with TB BMD, BMI, smoking, and S-TotalOC, the polymorphisms together were able to identify an additional 6% of women who sustained a fracture (p = .02). We found no association between the polymorphisms and TB BMD, BMI, or TB fat mass. In conclusion, polymorphisms in and around the osteocalcin locus are significantly associated with S-TotalOC and fracture. Genotyping at the osteocalcin locus could add valuable information in the identification of women at risk of osteoporosis. PMID- 20200949 TI - Enhanced differentiation of human embryonic stem cells to mesenchymal progenitors by inhibition of TGF-beta/activin/nodal signaling using SB-431542. AB - Directing differentiation of human embryonic stem cells (hESCs) into specific cell types using an easy and reproducible protocol is a prerequisite for the clinical use of hESCs in regenerative-medicine procedures. Here, we report a protocol for directing the differentiation of hESCs into mesenchymal progenitor cells. We demonstrate that inhibition of transforming growth factor beta (TGF beta)/activin/nodal signaling during embryoid body (EB) formation using SB-431542 (SB) in serum-free medium markedly upregulated paraxial mesodermal markers (TBX6, TBX5) and several myogenic developmental markers, including early myogenic transcriptional factors (Myf5, Pax7), as well as myocyte-committed markers [NCAM, CD34, desmin, MHC (fast), alpha-smooth muscle actin, Nkx2.5, cTNT]. Continuous inhibition of TGF-beta signaling in EB outgrowth cultures (SB-OG) enriched for myocyte progenitor cells; markers were PAX7(+) (25%), MYOD1(+) (52%), and NCAM(+) (CD56) (73%). DNA microarray analysis revealed differential upregulation of 117 genes (>2-fold compared with control cells) annotated to myogenic development and function. Moreover, these cells showed the ability to contract (80% of the population) and formed myofibers when implanted intramuscularly in vivo. Interestingly, SB-OG cells cultured in 10% fetal bovine serum (FBS) developed into a homogeneous population of mesenchymal progenitors that expressed CD markers characteristic of mesenchymal stem cells (MSCs): CD44(+) (100%), CD73(+) (98%), CD146(+) (96%), and CD166(+) (88%) with the ability to differentiate into osteoblasts, adipocytes, and chondrocytes in vitro and in vivo. Furthermore, microarray analysis of these cells revealed downregulation of genes related to myogenesis: MYH3 (-167.9-fold), ACTA1 (-161-fold), MYBPH (-139-fold), ACTC ( 100.3-fold), MYH8 (-45.5-fold), and MYOT (-41.8-fold) and marked upregulation of genes related to mesoderm-derived cell lineages. In conclusion, our data provides a simple and versatile protocol for directing the differentiation of hESCs into a myogenic lineage and then further into mesenchymal progenitors by blocking the TGF-beta signaling pathway. PMID- 20200948 TI - Mechanical implications of estrogen supplementation in early postmenopausal women. AB - Whereas the structural implications of drug intervention are well established, there are few data on the possible mechanical consequences of treatment. In this work we examined the changes in elastic and shear moduli (EM and SM) in a region of trabecular bone in the distal radius and distal tibia of early postmenopausal women on the basis of MRI-based micro-finite-element (microFE) analysis. Whole section axial stiffness (AS) encompassing both trabecular and cortical compartments was evaluated as well. The study was conducted on previously acquired high-resolution images at the two anatomic sites. Images were processed to yield a 3D voxel array of bone-volume fraction (BVF), which was converted to a microFE model of hexahedral elements in which tissue modulus was set proportional to voxel BVF. The study comprised 65 early postmenopausal women (age range 45 to 55 years), of whom 32 had chosen estrogen supplementation (estradiol group); the remainder had not (control group). Subjects had been scanned at baseline and 12 and 24 months thereafter. At the distal tibia, EM and SM were reduced by 2.9% to 5.5% in the control group (p < .05 to <.005), but there was no change in the estradiol subjects. AS decreased 3.9% (4.0%) in controls (p < .005) and increased by 5.8% (6.2%) in estradiol group subjects (p < .05) at 12 (24) months. At the distal radius, EM and SM changes from baseline were not significant, but at both time points AS was increased in estradiol group subjects and decreased in controls (p < .005 to <.05), albeit by a smaller margin than at the tibia. EM and SM were strongly correlated with BV/TV (r(2) = 0.44 to 0.92) as well as with topologic parameters expressing the ratio of plates to rods (r(2) = 0.45 to 0.82), jointly explaining up to 96% of the variation in the mechanical parameters. Finally, baseline AS was strongly correlated between the two anatomic sites (r(2) = 0.58), suggesting that intersubject variations in the bone's mechanical competence follows similar mechanisms. In conclusion, the results demonstrate that micro-MRI-based microFE models are suited for the study of the mechanical implications of antiresorptive treatment. The data further highlight the anabolic effect of short-term estrogen supplementation. PMID- 20200950 TI - Time since prior fracture is a risk modifier for 10-year osteoporotic fractures. AB - The objective of this study was to assess the importance of time since prior fracture as a risk factor for future osteoporotic fractures and how it affects 10 year fracture rates. We identified 39,991 women 45 years of age or older undergoing baseline bone mineral density (BMD) testing (1990-2007) from a regional database that contains dual-energy X-ray absorptiometry (DXA) results for Manitoba, Canada. Health service records were used to identify nontrauma ICD 9-CM fracture codes preceding DXA, grouped as "major" fractures (n = 5178; hip, spine, forearm, and humerus) or "minor" fractures (n = 3479; ribs, sternum, pelvis, trunk, clavicle, scapula, patella, tibia/fibula, and ankle). Time since prior fracture was coded in years as less than 1, 1 to 5, 5 to 10, and more than 10. Incident fractures (ie, hip, spine, forearm, and humerus) after BMD testing were identified (mean follow-up 4.2 years, maximum 10 years) and studied in Cox proportional-hazards models adjusted for age, BMD T-score, and other covariates. After BMD testing, n = 1749 (4.4%) women experienced an incident fracture. Prior major fracture was a strong risk factor for incident fracture, greatest risk in the first year [hazard ratio (HR) 1.90, 95% confidence interval (CI) 1.60-2.25], declining by more than 10 years (HR 1.62, 95% CI 1.25-2.10). Prior minor fracture was a weaker risk factor, greatest in the first year (HR 1.45, 95% CI 1.13-1.87) and no longer significant by 1 to 5 years. Major and minor fractures both showed a time-dependent decline in importance as risk factors. In conclusion, time since prior fracture modifies future fracture risk, but prior fractures of the hip, spine, forearm, and humerus remain strong risk factors even 10 years later. Fracture risk assessment should emphasize the importance of prior fractures at these sites. PMID- 20200951 TI - Pathway-based genome-wide association analysis identified the importance of regulation-of-autophagy pathway for ultradistal radius BMD. AB - Wrist fracture is not only one of the most common osteoporotic fractures but also a predictor of future fractures at other sites. Wrist bone mineral density (BMD) is an important determinant of wrist fracture risk, with high heritability. Specific genes underlying wrist BMD variation are largely unknown. Most published genome-wide association studies (GWASs) have focused only on a few top-ranking single-nucleotide polymorphisms (SNPs)/genes and considered each of the identified SNPs/genes independently. To identify biologic pathways important to wrist BMD variation, we used a novel pathway-based analysis approach in our GWAS of wrist ultradistal radius (UD) BMD, examining approximately 500,000 SNPs genome wide from 984 unrelated whites. A total of 963 biologic pathways/gene sets were analyzed. We identified the regulation-of-autophagy (ROA) pathway that achieved the most significant result (p = .005, q(fdr) = 0.043, p(fwer) = 0.016) for association with UD BMD. The ROA pathway also showed significant association with arm BMD in the Framingham Heart Study sample containing 2187 subjects, which further confirmed our findings in the discovery cohort. Earlier studies indicated that during endochondral ossification, autophagy occurs prior to apoptosis of hypertrophic chondrocytes, and it also has been shown that some genes in the ROA pathway (e.g., INFG) may play important roles in osteoblastogenesis or osteoclastogenesis. Our study supports the potential role of the ROA pathway in human wrist BMD variation and osteoporosis. Further functional evaluation of this pathway to determine the mechanism by which it regulates wrist BMD should be pursued to provide new insights into the pathogenesis of wrist osteoporosis. PMID- 20200952 TI - Cell-based immunotherapy with mesenchymal stem cells cures bisphosphonate-related osteonecrosis of the jaw-like disease in mice. AB - Patients on high-dose bisphosphonate and immunosuppressive therapy have an increased risk of bisphosphonate-related osteonecrosis of the jaw (BRONJ); despite the disease severity, its pathophysiology remains unknown, and appropriate therapy is not established. Here we have developed a mouse model of BRONJ-like disease that recapitulates major clinical and radiographic manifestations of the human disease, including characteristic features of an open alveolar socket, exposed necrotic bone or sequestra, increased inflammatory infiltrates, osseous sclerosis, and radiopaque alveolar bone. We show that administration of zoledronate, a potent aminobisphosphonate, and dexamethasone, an immunosuppressant drug, causes BRONJ-like disease in mice in part by suppressing the adaptive regulatory T cells, Tregs, and activating the inflammatory T-helper-producing interleukin 17 cells, Th17. Most interestingly, we demonstrate that systemic infusion with mesenchymal stem cells (MSCs) prevents and cures BRONJ-like disease possibly via induction of peripheral tolerance, shown as an inhibition of Th17 and increase in Treg cells. The suppressed Tregs/Th17 ratio in zoledronate- and dexamethasone-treated mice is restored in mice undergoing salvage therapy with Tregs. These findings provide evidence of an immunity-based mechanism of BRONJ-like disease and support the rationale for in vivo immunomodulatory therapy using Tregs or MSCs to treat BRONJ. PMID- 20200953 TI - Genome-wide pleiotropy of osteoporosis-related phenotypes: the Framingham Study. AB - Genome-wide association studies offer an unbiased approach to identify new candidate genes for osteoporosis. We examined the Affymetrix 500K + 50K SNP GeneChip marker sets for associations with multiple osteoporosis-related traits at various skeletal sites, including bone mineral density (BMD, hip and spine), heel ultrasound, and hip geometric indices in the Framingham Osteoporosis Study. We evaluated 433,510 single-nucleotide polymorphisms (SNPs) in 2073 women (mean age 65 years), members of two-generational families. Variance components analysis was performed to estimate phenotypic, genetic, and environmental correlations (rho(P), rho(G), and rho(E)) among bone traits. Linear mixed-effects models were used to test associations between SNPs and multivariable-adjusted trait values. We evaluated the proportion of SNPs associated with pairs of the traits at a nominal significance threshold alpha = 0.01. We found substantial correlation between the proportion of associated SNPs and the rho(P) and rho(G) (r = 0.91 and 0.84, respectively) but much lower with rho(E) (r = 0.38). Thus, for example, hip and spine BMD had 6.8% associated SNPs in common, corresponding to rho(P) = 0.55 and rho(G) = 0.66 between them. Fewer SNPs were associated with both BMD and any of the hip geometric traits (eg, femoral neck and shaft width, section moduli, neck shaft angle, and neck length); rho(G) between BMD and geometric traits ranged from -0.24 to +0.40. In conclusion, we examined relationships between osteoporosis-related traits based on genome-wide associations. Most of the similarity between the quantitative bone phenotypes may be attributed to pleiotropic effects of genes. This knowledge may prove helpful in defining the best phenotypes to be used in genetic studies of osteoporosis. PMID- 20200954 TI - Similarities and discrepancies in subchondral bone structure in two differently induced canine models of osteoarthritis. AB - In osteoarthritis (OA), cartilage degradation is accompanied by subchondral bone changes. The pathogenesis and physiology of bone changes in OA are still unclear. The changes in subchondral bone architecture and cartilage damage were compared in differently induced experimental models of OA. Experimental OA was induced bilaterally by anterior cruciate ligament transection (ACLT) or by cartilage trauma (Groove model); bilateral sham surgery served as control. Lysylpyridinoline (LP, bone resorption) and C-telopeptide of type II collagen (CTX-II, cartilage breakdown) were measured over time. At 20 weeks after surgery, the subchondral cortical plate and trabecular bone of the tibia were analyzed by micro-computed tomography (microCT) and cartilage degeneration was analyzed histologically and biochemically. In both models, cartilage degeneration and cortical subchondral plate thinning were present. CTX-II levels were elevated over time in both models. Subchondral trabecular bone changes were observed only in the ACLT model, not in the Groove model. Correspondingly, LP levels were elevated over time in the ACLT model and not in the Groove model. Interestingly, the trabecular bone changes in the ACLT model were extended to the metaphyseal area. The early decrease in plate thickness, present in both models, as was cartilage damage, suggests that plate thinning is a phenomenon that is intrinsic to the process of OA independent of the cause/induction of OA. On the other hand, trabecular changes in subchondral and metaphyseal bone are not part of a common pathway of OA development and may be induced biomechanically in the destabilized and less loaded ACLT joint. PMID- 20200955 TI - IKKbeta activation is sufficient for RANK-independent osteoclast differentiation and osteolysis. AB - Monocytes differentiate into osteoclasts through stimulation of receptor activator of NF-kappaB (RANK). Many downstream effectors of RANK play a positive role in osteoclastogenesis, but their relative importance in osteoclast differentiation is unclear. We report the discovery that activation of a single pathway downstream of RANK is sufficient for osteoclast differentiation. In this regard, introduction of constitutively activated IKKbeta (IKKbeta(SSEE)) but not wild-type IKKbeta into monocytes stimulates differentiation of bona fide osteoclasts in the absence of RANK ligand (RANKL). This phenomenon is independent of upstream signals because IKKbeta(SSEE) induced the development of bone resorbing osteoclasts from RANK and IKKalpha knockout monocytes and in conditions in which NEMO-IKKbeta association was inhibited. NF-kappaB p100 and p105, but not RelB, were critical mediators of this effect. Inflammatory autocrine signaling by tumor necrosis factor alpha (TNF-alpha) and interleukin 1 (IL-1) were dispensable for the spontaneous osteoclastogenesis driven by IKKbeta(SSEE). More important, adenoviral gene transfer of IKKbeta(SSEE) induced osteoclasts and osteolysis in calvariae and knees of mice. Our data establish the sufficiency of IKKbeta activation for osteolysis and suggest that IKKbeta hyperactivation may play a role in conditions of pathologic bone destruction refractory to RANK/RANKL proximal therapeutic interventions. PMID- 20200956 TI - Percent fat mass is inversely associated with bone mass and hip geometry in rural Chinese adolescents. AB - This study was an attempt to examine the phenotypic, genetic, and environmental correlations between percent fat mass (PFM) and bone parameters, especially hip geometry, among 786 males and 618 females aged 13 to 21 years from a Chinese twin cohort. PFM, bone area (BA), bone mineral content (BMC), cross-sectional area (CSA), and section modulus (SM) were obtained by dual-energy X-ray absorptiometry. Multiple linear regression models were used to assess the PFM bone relationships. A structural equation model for twin design was used to estimate genetic/environmental influences on individual phenotype and phenotypic correlations. After controlling for body weight and other pertinent covariates, we observed inverse associations between PFM and bone parameters: Compared with the lowest age- and gender-specific tertile of PFM, males in the highest tertile of PFM had lower measures of whole-body-less-head BA (WB-BA), lumbar spine BA (L(2)-L(4)-BA), total-hip BA (TH-BA), total-hip BMC, CSA, and SM (p < .005 for all, adjusted p < .05). Similar inverse associations were observed in females for all the preceding parameters except WB-BA and L2-L(4)-BA. These associations did not vary significantly by Tanner stages. In both genders, the estimated heritabilities were 80% to 86% for BMC, 67% to 80% for BA, 74% to 77% for CSA, and 64% for SM. Both shared genetics and environmental factors contributed to the inverse PFM-bone correlations. We conclude that in this sample of relatively lean Chinese adolescents, at a given body weight, PFM is inversely associated with BA, BMC, and hip geometry in both genders, and such associations are attributed to both shared genetic and environmental factors. PMID- 20200957 TI - Genetically determined phenotype covariation networks control bone strength. AB - To identify genes affecting bone strength, we studied how genetic variants regulate components of a phenotypic covariation network that was previously shown to accurately characterize the compensatory trait interactions involved in functional adaptation during growth. Quantitative trait loci (QTLs) regulating femoral robustness, morphologic compensation, and mineralization (tissue quality) were mapped at three ages during growth using AXB/BXA Recombinant Inbred (RI) mouse strains and adult B6-i(A) Chromosome Substitution Strains (CSS). QTLs for robustness were identified on chromosomes 8, 12, 18, and 19 and confirmed at all three ages, indicating that genetic variants established robustness postnatally without further modification. A QTL for morphologic compensation, which was measured as the relationship between cortical area and body weight, was identified on chromosome 8. This QTL limited the amount of bone formed during growth and thus acted as a setpoint for diaphyseal bone mass. Additional QTLs were identified from the CSS analysis. QTLs for robustness and morphologic compensation regulated bone structure independently (ie, in a nonpleiotropic manner), indicating that each trait may be targeted separately to individualize treatments aiming to improve strength. Multiple regression analyses showed that variation in morphologic compensation and tissue quality, not bone size, determined femoral strength relative to body weight. Thus an individual inheriting slender bones will not necessarily inherit weak bones unless the individual also inherits a gene that impairs compensation. This systems genetic analysis showed that genetically determined phenotype covariation networks control bone strength, suggesting that incorporating functional adaptation into genetic analyses will advance our understanding of the genetic basis of bone strength. PMID- 20200958 TI - Local low-dose lovastatin delivery improves the bone-healing defect caused by Nf1 loss of function in osteoblasts. AB - Postfracture tibial nonunion (pseudoarthrosis) leads to lifelong disability in patients with neurofibromatosis type I (NF1), a disorder caused by mutations in the NF1 gene. To determine the contribution of NF1 in bone healing, we assessed bone healing in the Nf1(ob) (-/-) conditional mouse model lacking Nf1 specifically in osteoblasts. A closed distal tibia fracture protocol and a longitudinal study design were used. During the 21- to 28-day postfracture period, callus volume, as expected, decreased in wild-type but not in Nf1(ob) (-/ ) mice, suggesting delayed healing. At these two time points, bone volume (BV/TV) and volumetric bone mineral density (vBMD) measured by 3D micro-computed tomography were decreased in Nf1(ob) (-/-) callus-bridging cortices and trabecular compartments compared with wild-type controls. Histomorphometric analyses revealed the presence of cartilaginous remnants, a high amount of osteoid, and increased osteoclast surfaces in Nf1(ob) (-/-) calluses 21 days after fracture, which was accompanied by increased expression of osteopontin, Rankl, and Tgfbeta. Callus strength measured by three-point bending 28 days after fracture was reduced in Nf1(ob) (-/-) versus wild-type calluses. Importantly, from a clinical point of view, this defect of callus maturation and strength could be ameliorated by local delivery of low-dose lovastatin microparticles, which successfully decreased osteoid volume and cartilaginous remnant number and increased callus BV/TV and strength in mutant mice. These results thus indicate that the dysfunctions caused by loss of Nf1 in osteoblasts impair callus maturation and weaken callus mechanical properties and suggest that local delivery of low-dose lovastatin may improve bone healing in NF1 patients. PMID- 20200960 TI - Patients with high-bone-mass phenotype owing to Lrp5-T253I mutation have low plasma levels of serotonin. AB - The Lrp5 gene is a major determinant of bone mass accrual. It has been demonstrated recently to achieve this function by hampering the synthesis of gut derived serotonin, which is a powerful inhibitor of bone formation. In this study we analyzed plasma serotonin levels in patients with a high-bone-mass (HBM) phenotype owing to gain-of-function mutation of Lrp5 (T253I). A total of 9 HBM patients were compared with 18 sex- and age-matched controls. In HBM patients, the serotonin concentrations in platelet-poor plasma were significantly lower than in the controls (mean +/- SEM: 2.16 +/- 0.28 ng/mL versus 3.51 +/- 0.49 ng/mL, respectively, p < .05). Our data support the hypothesis that circulating serotonin levels mediate the increased bone mass resulting from gain-of-function mutations in Lrp5 in humans. PMID- 20200959 TI - Velocities of bone mineral accrual in black and white American children. AB - Black adults have higher bone mass than whites in the United States, but it is not clear when black children gain bone mineral faster than white children. We performed a cohort study to compare the growth velocity of total-body bone mineral content (TBMC) between black and white children of the same sex at different ages and stages of sexual maturity. TBMC and total-body area were measured in a cohort of 188 black and white boys and girls aged 5 to 15 years annually for up to 4 years. Rates of change in TBMC and area were found to vary with age and with Tanner stage. For both TBMC and area, growth velocities between black and white children differed significantly across Tanner stages. Age specific velocities were higher in black children during prepuberty and initial entry into puberty but reversed in subsequent Tanner stages. Despite earlier entry into each Tanner stage, black children spent only an average of only 0.2 year longer in Tanner stages II through IV, and total gain in TBMC from age 5 to 15 was not higher in whites. In conclusion, the higher bone mass in black adults compared with whites cannot be attributed to faster accrual during puberty. It is due to black children's higher rate of bone mineral accrual in prepuberty and plausibly in postpuberty. Most of the racial difference in TBMC velocity can be explained by growth in size. PMID- 20200961 TI - Familial resemblance and diversity in bone mass and strength in the population are established during the first year of postnatal life. AB - Familial resemblance and diversity in bone structure and strength in adulthood are determined in part during growth. Whether these characteristics are established during gestation or shortly after birth is not known. Total-body, lumbar spine, and femoral neck size and mass and indices of tibial bending strength and distal radial compressive strength were measured using bone densitometry and quantitative computed tomography in 236 girls at 18.5 years of age. Among them, 219, 141, and 105 girls had crown-heel length (CHL) and weight recorded at birth and at 6 and 12 months of age, and then height and weight were recorded at 3, 5, 10, 13, and 15 years of age in 181, 176, 127, 111, and 228 girls, respectively. Of these girls, 101 and 93 girls also had bone structure assessed at 11 and 13 years of age, respectively. Similar bone measurements were made once in 78 mother-father pairs. CHL and weight at birth did not correlate or did so weakly with bone traits in girls at 18 years of age. By contrast, CHL at 6 months correlated with the height, bone traits, and strength at puberty and at 18 years of age (r = 0.24-0.56, p < .001) in girls and with their parents' height and bone traits (r = 0.15-0.37, p < .05). When the girls' CHL at 6 months was stratified into quartiles, the absolute and relative differences in bone traits observed at puberty (approximately 11.5 years) were maintained as these traits tracked during the ensuing 7 years. Similarly, weight at 6 months correlated with the girls' bone traits at puberty and 18 years of age (r = 0.22-0.55, p < .05). During puberty and at 18 years of age, the girls' bone traits correlated with the corresponding traits in their parents (r = 0.32-0.43, p < .01). It is concluded that familial resemblance in bone structural strength and the position of an individual's bone traits relative to others in adulthood are likely to be established during the first year of life. Thus susceptibility to bone fragility late in life has its antecedents established early in life. PMID- 20200962 TI - Rapid growth produces transient cortical weakness: a risk factor for metaphyseal fractures during puberty. AB - Fractures of the distal radius in children have a similar incidence to that found in postmenopausal women but occur more commonly in boys than in girls. Fractures of the distal tibia are uncommon in children and show no sex specificity. About 90% of lengthening of the radius but only 30% of lengthening of the tibia during puberty occur at the distal growth plate. We speculated that more rapid modeling at the distal radial metaphysis results in a greater dissociation between growth and mineral accrual than observed at the distal tibia. We measured the macro- and microarchitecture of the distal radial and tibial metaphysis using high resolution peripheral quantitative computed tomography in a cross-sectional study of 69 healthy boys and 60 healthy girls aged from 5 to 18 years. Bone diameters were larger but total volumetric bone mineral density (vBMD) was lower at the distal radius (not at the distal tibia) by 20% in boys and by 15% in girls at Tanner stage III than in children of the same sex at Tanner stage I (both p < .05). In boys at Tanner stage III, total vBMD was lower because the larger radial total cross-sectional area (CSA) had a thinner cortex with lower vBMD than in boys at Tanner stage I. In girls at Tanner stage III, the larger total radial CSA was not associated with a difference in cortical thickness or cortical vBMD relative to girls in Tanner stage I. Cortical thickness and density at both sites in both sexes after Tanner stage III were greater than in younger children. Trabecular bone volume fraction (BV/TV) was higher in boys than in girls at both sites and more so after puberty because trabeculae were thicker in more mature boys but not in girls. There was no sex- or age-related differences in trabecular number at either site. We infer that longitudinal growth outpaces mineral accrual in both sexes at the distal radius, where bone grows rapidly. The dissociation produces transitory low cortical thickness and vBMD in boys but not in girls. These structural features in part may account for the site and sex specificity of metaphyseal fractures during growth. PMID- 20200963 TI - A key role for membrane transporter NKCC1 in mediating chondrocyte volume increase in the mammalian growth plate. AB - The mechanisms that underlie growth plate chondrocyte volume increase and hence bone lengthening are poorly understood. Many cell types activate the Na-K-Cl cotransporter (NKCC) to bring about volume increase. We hypothesised that NKCC may be responsible for the volume expansion of hypertrophic chondrocytes. Metatarsals/metacarpals from 16 rat pups (P(7)) were incubated in the presence/absence of the specific NKCC inhibitor bumetanide and measurement of whole-bone lengths and histologic analysis of the growth plate were done after 24 hours. Fluorescent NKCC immunohistochemistry was visualised using a confocal laser scanning microscopy on seven rat tibial growth plates (P(7)). Microarray analysis was performed on mRNA isolated from proliferative and hypertrophic zone cells of tibial growth plates from five rats of each of three ages (P(49/53/58)). Exposure to bumetanide resulted in approximately 35% reduction (paired Student's t test, p < .05) of bone growth in a dose-dependent manner; histologic analysis showed that a reduction in hypertrophic zone height was responsible. Quantification of fluorescence immunohistochemistry revealed a significant (paired Student's t test, p < .05) change in NKCC from the intracellular space of proliferative cells to the cytosolic membrane of hypertrophic zone cells. Further, microarray analysis illustrated an increase in NKCC1 mRNA between proliferative and hypertrophic cells. The increase in NKCC1 mRNA in hypertrophic zone cells, its cellular localization, and reduced bone growth in the presence of the NKCC inhibitor bumetanide implicate NKCC in growth plate hypertrophic chondrocyte volume increase. Further investigation is warranted to determine the regulatory control of NKCC in the mammalian growth plate and the possible detrimental effect on bone growth with chronic exposure to loop diuretics. PMID- 20200964 TI - Effect of vitamin D(3) and calcium on fracture risk in 65- to 71-year-old women: a population-based 3-year randomized, controlled trial--the OSTPRE-FPS. AB - Antifracture efficacy of high-dose vitamin D (800 IU) and calcium (1000 mg) remains controversial. To determine whether daily 800 IU of vitamin D and 1000 mg of calcium supplementation prevents fractures, we randomized 3432 women of the population-based Osteoporosis Risk Factor and Prevention (OSTPRE) Study cohort (ages 65 to 71 years) living in the region of northern Savonia, Finland (latitude 62 degrees to 64 degrees N) for 3 years to receive 800 IU of cholecalciferol and 1000 mg of calcium as calcium carbonate or to a control group that did not receive placebo. The main outcome measure was incident fractures. Fracture data were collected in telephone interviews and validated. Data on 3195 women, 1586 in the intervention group and 1609 in the control group, were available for analysis. In adjusted Cox proportional hazards models, the risk of any fracture decreased in the vitamin D and calcium group by 17% [adjusted hazard ratio (aHR) = 0.83; 95% confidence interval (CI) 0.61-1.12], and the risk of any nonvertebral fracture decreased by 13% (aHR = 0.87; 95% CI 0.63-1.19). The risk of distal forearm fractures decreased by 30% (aHR = 0.70; 95% CI 0.41-1.20), and the risk of any upper extremity fractures decreased by 25% (aHR = 0.75; 95% CI 0.49-1.16), whereas the risk of lower extremity fractures remained essentially equal (aHR = 1.02; 95% CI 0.58-1.80). None of these effects reached statistical significance. In conclusion, this study did not produce statistically significant evidence that vitamin D and calcium supplementation prevents fractures in a 65- to 71-year-old general population of postmenopausal women. PMID- 20200966 TI - Thyroid hormone-mediated growth and differentiation of growth plate chondrocytes involves IGF-1 modulation of beta-catenin signaling. AB - Thyroid hormone regulates terminal differentiation of growth plate chondrocytes in part through modulation of the Wnt/beta-catenin signaling pathway. Insulin like growth factor 1 (IGF-1) has been described as a stabilizer of beta-catenin, and thyroid hormone is a known stimulator of IGF-1 receptor expression. The purpose of this study was to test the hypothesis that IGF-1 signaling is involved in the interaction between the thyroid hormone and the Wnt/beta-catenin signaling pathways in regulating growth plate chondrocyte proliferation and differentiation. The results show that IGF-1 and the IGF- receptor (IGF1R) stimulate Wnt-4 expression and beta-catenin activation in growth plate chondrocytes. The positive effects of IGF-1/IGF1R on chondrocyte proliferation and terminal differentiation are partially inhibited by the Wnt antagonists sFRP3 and Dkk1. T(3) activates IGF-1/IGF1R signaling and IGF-1-dependent PI3K/Akt/GSK 3beta signaling in growth plate chondrocytes undergoing proliferation and differentiation to prehypertrophy. T(3)-mediated Wnt-4 expression, beta-catenin activation, cell proliferation, and terminal differentiation of growth plate chondrocytes are partially prevented by the IGF1R inhibitor picropodophyllin as well as by the PI3K/Akt signaling inhibitors LY294002 and Akti1/2. These data indicate that the interactions between thyroid hormone and beta-catenin signaling in regulating growth plate chondrocyte proliferation and terminal differentiation are modulated by IGF-1/IGF1R signaling through both the Wnt and PI3K/Akt signaling pathways. While chondrocyte proliferation may be triggered by the IGF 1/IGF1R-mediated PI3K/Akt/GSK3beta pathway, cell hypertrophy is likely due to activation of Wnt/beta-catenin signaling, which is at least in part initiated by IGF-1 signaling or the IGF-1-activated PI3K/Akt signaling pathway. PMID- 20200965 TI - The role of mast cells in parathyroid bone disease. AB - Chronic hyperparathyroidism (HPT) is a common cause of metabolic bone disease. These studies investigated the underlying cellular and molecular mechanisms responsible for the detrimental actions of elevated parathyroid hormone (PTH) on the skeleton. Bone biopsies from hyperparathyroid patients revealed an association between parathyroid bone disease and increased numbers of bone marrow mast cells. We therefore evaluated the role of mast cells in the etiology of parathyroid bone disease in a rat model for chronic HPT. In rats, mature mast cells were preferentially located at sites undergoing bone turnover, and the number of mast cells at the bone-bone marrow interface was greatly increased following treatment with PTH. Time-course studies and studies employing parathyroid hormone-related peptide (PTHrP), as well as inhibitors of platelet derived growth factor-A (PDGF-A, trapidil), kit (gleevec), and PI3K (wortmannin) signaling revealed that mature mast cell redistribution from bone marrow to bone surfaces precedes and is associated with osteitis fibrosa, a hallmark of parathyroid bone disease. Importantly, mature mast cells were not observed in the bone marrow of mice. Mice, in turn, were resistant to the development of PTH induced bone marrow fibrosis. These findings suggest that the mast cell may be a novel target for treatment of metabolic bone disease. PMID- 20200967 TI - Individual trabeculae segmentation (ITS)-based morphological analysis of high resolution peripheral quantitative computed tomography images detects abnormal trabecular plate and rod microarchitecture in premenopausal women with idiopathic osteoporosis. AB - Idiopathic osteoporosis (IOP) in premenopausal women is a poorly understood entity in which otherwise healthy women have low-trauma fracture or very low bone mineral density (BMD). In this study, we applied individual trabeculae segmentation (ITS)-based morphological analysis to high-resolution peripheral quantitative computed tomography (HR-pQCT) images of the distal radius and distal tibia to gain greater insight into skeletal microarchitecture in premenopausal women with IOP. HR-pQCT scans were performed for 26 normal control individuals and 31 women with IOP. A cubic subvolume was extracted from the trabecular bone compartment and subjected to ITS-based analysis. Three Young's moduli and three shear moduli were calculated by micro-finite element (microFE) analysis. ITS based morphological analysis of HR-pQCT images detected significantly decreased trabecular plate and rod bone volume fraction and number, decreased axial bone volume fraction in the longitudinal axis, increased rod length, and decreased rod to-rod, plate-to-rod, and plate-to-plate junction densities at the distal radius and distal tibia in women with IOP. However, trabecular plate and rod thickness did not differ. A more rod-like trabecular microstructure was found in the distal radius, but not in the distal tibia. Most ITS measurements contributed significantly to the elastic moduli of trabecular bone independent of bone volume fraction (BV/TV). At a fixed BV/TV, plate-like trabeculae contributed positively to the mechanical properties of trabecular bone. The results suggest that ITS based morphological analysis of HR-pQCT images is a sensitive and promising clinical tool for the investigation of trabecular bone microstructure in human studies of osteoporosis. PMID- 20200968 TI - Hypercalcemia and soft tissue calcification owing to sarcoidosis: the sunlight cola connection. AB - Hypercalcemia occurs in sarcoidosis because of 1,25-dihydroxyvitamin D production by pulmonary alveolar macrophages. Long-standing hypercalcemia and hypercalciuria may cause such complications as nephrocalcinosis, nephrolithiasis, and soft tissue calcification, which can be at least partially reversible with treatment. Here we present a 43-year-old African-American man with diffuse soft tissue calcifications and acute kidney injury owing to sarcoidosis-induced hypercalcemia, probably exacerbated by sun exposure and phosphorus intake in the form of dietary cola drinks. Soft tissue calcifications resolved and kidney function improved significantly with hydration and glucocorticoid therapy. We discuss the pathophysiology of the hypercalcemia of sarcoidosis and current treatment options. PMID- 20200969 TI - TNF-alpha's effects on proliferation and apoptosis in human mesenchymal stem cells depend on RUNX2 expression. AB - RUNX2 is a bone-specific transcription factor that plays a critical role in prenatal bone formation and postnatal bone development. It regulates the expression of genes that are important in committing cells into the osteoblast lineage. There is increasing evidence that RUNX2 is involved in osteoblast proliferation. RUNX2 expression increases during osteoblast differentiation, and recent data even suggest that it acts as a proapoptotic factor. The cytokine tumor necrosis factor alpha (TNF-alpha) is known to modulate osteoblast functions in a manner that depends on the differentiation stage. TNF-alpha affects the rate at which mesenchymal precursor cells differentiate into osteoblasts and induces apoptosis in mature osteoblasts. Thus we sought to establish whether or not the effects of TNF-alpha and fetal calf serum on proliferation and apoptosis in human mesenchymal stem cells (hMSCs) were dependent on RUNX2 level and activity. We transfected hMSCs with small interfering RNAs (siRNAs) directed against RUNX2 and found that they proliferated more quickly than control hMSCs transfected with a nonspecific siRNA. This increase in proliferation was accompanied by a rise in cyclin A1, B1, and E1 expression and a decrease in levels of the cyclin inhibitor p21. Moreover, we observed that RUNX2 silencing protected hMSCs from TNF-alpha's antiproliferative and apoptotic effects. This protection was accompanied by the inhibition of caspase-3 activity and Bax expression. Our results confirmed that RUNX2 is a critical link between cell fate, proliferation, and growth control. This study also suggested that, depending on the osteoblasts' differentiation stage, RUNX2 may control cell growth by regulating the expression of elements involved in hormone and cytokine sensitivity. PMID- 20200970 TI - Bone resorption is not driven by formation in adult skeleton. PMID- 20200971 TI - Estimates of the proportion of older white men who would be recommended for pharmacologic treatment by the new US National Osteoporosis Foundation guidelines. AB - The new US National Osteoporosis Foundation's (NOF's) Clinician's Guide to Prevention and Treatment of Osteoporosis includes criteria for recommending pharmacologic treatment based on history of hip or vertebral fracture, femoral neck or spine bone mineral density (BMD) T-scores of -2.5 or less, and presence of low bone mass at the femoral neck or spine plus a 10-year risk of hip fracture of 3% or greater or of major osteoporotic fracture of 20% or greater. The proportion of men who would be recommended for treatment by these guidelines is not known. We applied the NOF criteria for treatment to men participating in the Osteoporotic Fractures in Men Study (MrOS). To determine how the MrOS population differs from the general US population of Caucasian men aged 65 years and older, we compared men in MrOS with men who participated in the National Health and Nutrition Examination Survey (NHANES) III on criteria included in the NOF treatment guidelines that were common to both cohorts. Compared with NHANES III, men in MrOS had higher femoral neck BMD values. Application of NOF guidelines to MrOS data estimated that at least 34% of US white men aged 65 years and older and 49% of those aged 75 years and older would be recommended for drug treatment. Application of the new NOF guidelines would result in recommending a very large proportion of white men in the United States for pharmacologic treatment of osteoporosis, for many of whom the efficacy of treatment is unknown. PMID- 20200972 TI - Vertebral morphology in aromatase inhibitor-treated males with idiopathic short stature or constitutional delay of puberty. AB - Aromatase inhibitors (AIs), blockers of estrogen biosynthesis, delay bone maturation and therefore are used increasingly to promote growth in children and adolescents with growth disorders. The effects of treatment on skeletal health are largely unknown. Since estrogen deficiency is associated with various detrimental skeletal effects, we evaluated in this cross-sectional posttreatment study vertebral body morphology, dimensions and endplates, and intervertebral disks by the use of magnetic resonance imaging (MRI) in two cohorts of males previously treated with the AI letrozole or placebo. Males with idiopathic short stature received treatment with letrozole or placebo for 2 years during prepuberty or early puberty; males with constitutional delay of puberty received letrozole or placebo in combination with low-dose testosterone for 1 year during early or midpuberty. In males with idiopathic short stature, mild vertebral body deformities were found in 5 of 11 (45%) letrozole-treated subjects, whereas in the placebo group no deformities were detected (p = .01). In the cohort of males with constitutional delay of puberty, a high prevalence of endplate and intervertebral disk abnormalities was observed in both the letrozole- and the placebo-treated groups. We conclude that AI therapy during prepuberty or early puberty may predispose to vertebral deformities, which probably reflect impaired vertebral body growth rather than impaired bone quality and compression fractures. If AIs are used in growth indications, follow-up of vertebral morphology is indicated. PMID- 20200973 TI - The calcium-sensing receptor and 25-hydroxyvitamin D-1alpha-hydroxylase interact to modulate skeletal growth and bone turnover. AB - We examined parathyroid and skeletal function in 3-month-old mice expressing the null mutation for 25-hydroxyvitamin D-1alpha-hydroxylase [1alpha(OH)ase(-/-)] and in mice expressing the null mutation for both the 1alpha(OH)ase and the calcium sensing receptor [Casr(-/-)1alpha(OH)ase(-/-)] genes. On a normal diet, all mice were hypocalcemic, with markedly increased parathyroid hormone (PTH), increased trabecular bone volume, increased osteoblast activity, poorly mineralized bone, enlarged and distorted cartilaginous growth plates, and marked growth retardation, especially in the compound mutants. Osteoclast numbers were reduced in the Casr(-/-)1alpha(OH)ase(-/-) mice. On a high-lactose, high-calcium, high phosphorus "rescue" diet, serum calcium and PTH were normal in the 1alpha(OH)ase( /-) mice but increased in the Casr(-/-)1alpha(OH)ase(-/-) mice with reduced serum phosphorus. Growth plate architecture and mineralization were improved in both mutants, but linear growth of the double mutants remained abnormal. Mineralization of bone improved in all mice, but osteoblast activity and trabecular bone volume remained elevated in the Casr(-/-)1alpha(OH)ase(-/-) mice. These studies support a role for calcium-stimulated maturation of the cartilaginous growth plate and mineralization of the growth plate and bone and calcium-stimulated CaSR-mediated effects on bone resorption. PTH-mediated bone resorption may require calcium-stimulated CaSR-mediated enhancement of osteoclastic activity. (c) 2010 American Society for Bone and Mineral Research. PMID- 20200974 TI - TNF-alpha mediates diabetes-enhanced chondrocyte apoptosis during fracture healing and stimulates chondrocyte apoptosis through FOXO1. AB - To gain insight into the effect of diabetes on fracture healing, experiments were carried out focusing on chondrocyte apoptosis during the transition from cartilage to bone. Type 1 diabetes was induced in mice by multiple low-dose streptozotocin injections, and simple transverse fractures of the tibia or femur was carried out. Large-scale transcriptional profiling and gene set enrichment analysis were performed to examine apoptotic pathways on total RNA isolated from fracture calluses on days 12, 16, and 22, a period of endochondral bone formation when cartilage is resorbed and chondrocyte numbers decrease. Tumor necrosis factor alpha (TNF-alpha) protein levels were assessed by ELISA and caspase-3 by bioactivity assay. The role of TNF was examined by treating mice with the TNF specific inhibitor pegsunercept. In vitro studies investigated the proapoptotic transcription factor FOXO1 in regulating TNF-induced apoptosis of chondrogenic ATDC5 and C3H10T1/2 cells as representative of differentiated chondrocytes, which are important during endochondral ossification. mRNA profiling revealed an upregulation of gene sets related to apoptosis in the diabetic group on day 16 when cartilage resorption is active but not day 12 or day 22. This coincided with elevated TNF-alpha protein levels, chondrocyte apoptosis, enhanced caspase-3 activity, and increased FOXO1 nuclear translocation (p < .05). Inhibition of TNF significantly reduced these parameters in the diabetic mice but not in normoglycemic control mice (p < .05). Silencing FOXO1 using siRNA in vitro significantly reduced TNF-induced apoptosis and caspase activity in differentiated chondrocytes. The mRNA levels of the proapoptotic genes caspase-3, caspase-8, caspase-9, and TRAIL were significantly reduced with silencing of FOXO1 in chondrocytic cells. Inhibiting caspase-8 and caspase-9 significantly reduced TNF-induced apoptosis in chondrogenic cells. These results suggest that diabetes causes an upregulation of proapoptotic genes during the transition from cartilage to bone in fracture healing. Diabetes increased chondrocyte apoptosis through a mechanism that involved enhanced production of TNF-alpha, which stimulates chondrocyte apoptosis and upregulates mRNA levels of apoptotic genes through FOXO1 activation. PMID- 20200976 TI - Progressive ankylosis protein (ANK) in osteoblasts and osteoclasts controls bone formation and bone remodeling. AB - The progressive ankylosis gene (ank) encodes a transmembrane protein that transports intracellular inorganic pyrophosphate (PP(i)) to the extracellular milieu. ank/ank mice, which express a truncated nonfunctional ANK, showed a markedly reduced bone mass, bone-formation rate, and number of tartrate-resistant acid phosphatase-positive (TRAP(+)) multinucleated osteoclasts. ANK function deficiency suppressed osteoblastic differentiation of ank/ank bone marrow stromal cells, as indicated by the decrease in the expression of bone marker genes, including osterix, reduced alkaline phosphatase activity, and mineralization. Runx2 gene expression levels were not altered. Conversely, overexpression of ANK in the preosteoblastic cell line MC3T3-E1 resulted in increased expression of bone marker genes, including osterix. Whereas runx2 expression was not altered in ANK-overexpressing MC3T3-E1 cells, runx2 transcriptional activity was increased. Extracellular PP(i) or P(i) stimulated osteoblastogenic differentiation of MC3T3 E1 cells or partially rescued delayed osteoblastogenic differentiation of ank/ank bone marrow stromal cells. A loss of PP(i) transport function ANK mutation also stimulated osteoblastogenic differentiation of MC3T3-E1 cells. Furthermore, ANK function deficiency suppressed the formation of multinucleated osteoclasts from ank/ank bone marrow cells cultured in the presence of macrophage colony stimulating factor and receptor activator of nuclear factor-kappaB ligand. In conclusion, ANK is a positive regulator of osteoblastic and osteoclastic differentiation events toward a mature osteoblastic and osteoclastic phenotype. PMID- 20200977 TI - Critical role for Y1 receptors in mesenchymal progenitor cell differentiation and osteoblast activity. AB - The neuropeptide Y (NPY) system has been implicated in the regulation of bone homeostasis and osteoblast activity, but the mechanism behind this is unclear. Here we show that Y1 receptor signaling is directly involved in the differentiation of mesenchymal progenitor cells isolated from bone tissue, as well as the activity of mature osteoblasts. Importantly, the mRNA levels of two key osteogenic transcription factors, runx2 and osterix, as well as the adipogenic transcription factor PPAR-gamma, were increased in long bones of Y1(-/ ) mice compared with wild-type mice. In vitro, bone marrow stromal cells (BMSCs) isolated from Y1(-/-) mice formed a greater number of mineralized nodules under osteogenic conditions and a greater number of adipocytes under adipogenic conditions than controls. In addition, both the number and size of fibroblast colony-forming units formed in vitro by purified osteoprogenitor cells were increased in the absence of the Y1 receptors, suggestive of enhanced proliferation and osteogenesis. Furthermore, the ability of two specific populations of mesenchymal progenitor cells isolated from bone tissue, an immature mesenchymal stem cell population and a more committed osteoprogenitor cell population, to differentiate into osteoblasts and adipocytes in vitro was enhanced in the absence of Y1 receptor signaling. Finally, Y1 receptor deletion also enhanced the mineral-producing ability of mature osteoblasts, as shown by increased in vitro mineralization by BMSCs isolated from osteoblast-specific Y1( /-) mice. Together these data demonstrate that the NPY system, via the Y1 receptor, directly inhibits the differentiation of mesenchymal progenitor cells as well as the activity of mature osteoblasts, constituting a likely mechanism for the high-bone-mass phenotype evident in Y1(-/-) mice. PMID- 20200975 TI - Correlates of trabecular and cortical volumetric bone mineral density of the radius and tibia in older men: the Osteoporotic Fractures in Men Study. AB - Quantitative computed tomography (QCT) can estimate volumetric bone mineral density (vBMD) and distinguish trabecular from cortical bone. Few comprehensive studies have examined correlates of vBMD in older men. This study evaluated the impact of demographic, anthropometric, lifestyle, and medical factors on vBMD in 1172 men aged 69 to 97 years and enrolled in the Osteoporotic Fractures in Men Study (MrOS). Peripheral quantitative computed tomography (pQCT) was used to measure vBMD of the radius and tibia. The multivariable linear regression models explained up to 10% of the variance in trabecular vBMD and up to 9% of the variance in cortical vBMD. Age was not correlated with radial trabecular vBMD. Correlates associated with both cortical and trabecular vBMD were age (-), caffeine intake (-), total calcium intake (+), nontrauma fracture (-), and hypertension (+). Higher body weight was related to greater trabecular vBMD and lower cortical vBMD. Height (-), education (+), diabetes with thiazolidinedione (TZD) use (+), rheumatoid arthritis (+), using arms to stand from a chair (-), and antiandrogen use (-) were associated only with trabecular vBMD. Factors associated only with cortical vBMD included clinic site (-), androgen use (+), grip strength (+), past smoker (-), and time to complete five chair stands (-). Certain correlates of trabecular and cortical vBMD differed among older men. An ascertainment of potential risk factors associated with trabecular and cortical vBMD may lead to better understanding and preventive efforts for osteoporosis in men. PMID- 20200978 TI - Replication of previous genome-wide association studies of bone mineral density in premenopausal American women. AB - Bone mineral density (BMD) achieved during young adulthood (peak BMD) is one of the major determinants of osteoporotic fracture in later life. Genetic variants associated with BMD have been identified by three recent genome-wide association studies. The most significant single-nucleotide polymorphisms (SNPs) from these studies were genotyped to test whether they were associated with peak BMD in premenopausal American women. Femoral neck and lumbar spine BMD were determined by dual-energy X-ray absorptiometry in two groups of premenopausal women: 1524 white women and 512 black women. In premenopausal white women, two SNPs in the C6orf97/ESR1 region were significantly associated with BMD (p < 4.8 x 10(-4)), with suggestive evidence for CTNNBL1 and LRP5 (p < .01). Evidence of association with one of the two SNPs in the C6orf97/ESR1 region also was observed in premenopausal black women. Furthermore, SNPs in SP7 and a chromosome 4 intergenic region showed suggestive association with BMD in black women. Detailed analyses of additional SNPs in the C6orf97/ESR1 region revealed multiple genomic blocks independently associated with femoral neck and lumbar spine BMD. Findings in the three published genome-wide association studies were replicated in independent samples of premenopausal American women, suggesting that genetic variants in these genes or regions contribute to peak BMD in healthy women in various populations. PMID- 20200979 TI - Cross-sectional evidence of suppressed bone mineral accrual among female adolescent runners. AB - We aimed to evaluate patterns of bone mineral accrual among a cross-sectional sample of female adolescent runners and girls participating in a nonendurance running sport. One-hundred and eighty-three interscholastic competitive female athletes (age 16.0 +/- 0.1 years), 93 endurance runners and 90 nonrunners, completed a menstrual and sports history questionnaire, had their height and weight measured, and underwent a dual-energy X-ray absorptiometry scan for the measurements of body composition and bone mass. For the majority of analyses, the girls were separated into four groups according to their age (13 to 14 years, 15 years, 16 years, and 17 to 18 years). Runners' height, weight, body mass index (BMI), percent body fat, lean tissue mass, number of menstrual cycles in the past year, and months of participation in a non-lean-build/variable-impact-loading sport were significantly lower than mean values for nonrunners. Although bone mass rose at all sites in the nonrunners between the ages of 13 to 14 years and 17 to 18 years, no such increase was noted in the runners. Runners compared with nonrunners exhibited significantly lower body weight and height-adjusted total body and lumbar spine bone mineral content (BMC) values and lower bone mineral density (BMD) Z-score values among the older (16 years and/or 17 to 18 years) but not younger (13 to 14 years and/or 15 years) age groups. These findings suggest that the runners, in contrast to the nonrunners, exhibited a suppressed bone mineral accrual pattern, which supports the notion that female adolescent endurance runners may be at risk for inadequate bone mass gains and thus a low peak BMD. PMID- 20200980 TI - Archaeological skeletons support a northwest European origin for Paget's disease of bone. AB - The strong genetic component in the etiology of Paget's disease of bone (PDB), together with marked geographic variation in its prevalence, with high frequencies in British populations, has led some to suggest that the disease originated in Britain and spread around the world in recent times by the migration and admixture of British populations. This study aims to investigate this hypothesis by studying the world geographic distribution of PDB cases identified in ancient skeletons excavated from archaeological sites. The methodology is a review of PDB cases described in the literature. There were 109 cases that met modern diagnostic criteria. All came from Western Europe, 94% from England. These data support the hypothesis that PDB originated in this geographic region. PMID- 20200982 TI - Near-infrared fluorescent probe traces bisphosphonate delivery and retention in vivo. AB - Bisphosphonate use has expanded beyond traditional applications to include treatment of a variety of low-bone-mass conditions. Complications associated with long-term bisphosphonate treatment have been noted, generating a critical need for information describing the local bisphosphonate-cell interactions responsible for these observations. This study demonstrates that a fluorescent bisphosphonate analogue, far-red fluorescent pamidronate (FRFP), is an accurate biomarker of bisphosphonate deposition and retention in vivo and can be used to monitor site specific local drug concentration. In vitro, FRFP is competitively inhibited from the surface of homogenized rat cortical bone by traditional bisphosphonates. In vivo, FRFP delivery to the skeleton is rapid, with fluorescence linearly correlated with bone surface area. Limb fluorescence increases linearly with injected dose of FRFP; injected FRFP does not interfere with binding of standard bisphosphonates at the doses used in this study. Long-term FRFP retention studies demonstrated that FRFP fluorescence decreases in conditions of normal bone turnover, whereas fluorescence was retained in conditions of reduced bone turnover, demonstrating preservation of local FRFP concentration. In the mandible, FRFP localized to the alveolar bone and bone surrounding the periodontal ligament and molar roots, consistent with findings of osteonecrosis of the jaw. These findings support a role for FRFP as an effective in vivo marker for bisphosphonate site-specific deposition, turnover, and long-term retention in the skeleton. PMID- 20200981 TI - Leptin stimulates fibroblast growth factor 23 expression in bone and suppresses renal 1alpha,25-dihydroxyvitamin D3 synthesis in leptin-deficient mice. AB - Leptin is the LEP (ob) gene product secreted by adipocytes. We previously reported that leptin decreases renal expression of the 25-hydroxyvitamin D(3) 1alpha-hydroxylase (CYP27B1) gene through the leptin receptor (ObRb) by indirectly acting on the proximal tubules. This study focused on bone-derived fibroblast growth factor 23 (FGF-23) as a mediator of the influence of leptin on renal 1alpha-hydroxylase mRNA expression in leptin-deficient ob/ob mice. Exposure to leptin (200 ng/mL) for 24 hours stimulated FGF-23 expression by primary cultured rat osteoblasts. Administration of leptin (4 mg/kg i.p. at 12-hour intervals for 2 days) to ob/ob mice markedly increased the serum FGF-23 concentration while significantly reducing the serum levels of calcium, phosphate, and 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)]. Administration of FGF-23 (5 microg i.p. at 12-hour intervals for 2 days) to ob/ob mice suppressed renal 1alpha-hydroxylase mRNA expression. The main site of FGF-23 mRNA expression was the bone, and leptin markedly increased the FGF-23 mRNA level in ob/ob mice. In addition, leptin significantly reduced 1alpha-hydroxylase and sodium-phosphate cotransporters (NaP(i)-IIa and NaP(i)-IIc) mRNA levels but did not affect Klotho mRNA expression in the kidneys of ob/ob mice. Furthermore, the serum FGF-23 level and renal expression of 1alpha-hydroxylase mRNA were not influenced by administration of leptin to leptin receptor-deficient (db/db) mice. These results indicate that leptin directly stimulates FGF-23 synthesis by bone cells in ob/ob mice, suggesting that inhibition of renal 1,25(OH)(2)D(3) synthesis in these mice is at least partly due to elevated bone production of FGF 23. PMID- 20200983 TI - Taking vitamin D with the largest meal improves absorption and results in higher serum levels of 25-hydroxyvitamin D. AB - Many patients treated for vitamin D deficiency fail to achieve an adequate serum level of 25-hydroxyvitamin D [25(OH)D] despite high doses of ergo- or cholecalciferol. The objective of this study was to determine whether administration of vitamin D supplement with the largest meal of the day would improve absorption and increase serum levels of 25(OH)D. This was a prospective cohort study in an ambulatory tertiary-care referral center. Patients seen at the Cleveland Clinic Foundation Bone Clinic for the treatment of vitamin D deficiency who were not responding to treatment make up the study group. Subjects were instructed to take their usual vitamin D supplement with the largest meal of the day. The main outcome measure was the serum 259(OH)D level after 2 to 3 months. Seventeen patients were analyzed. The mean age (+/-SD) and sex (F/M) ratio were 64.5 +/- 11.0 years and 13 females and 4 males, respectively. The dose of 25(OH)D ranged from 1000 to 50,000 IU daily. The mean baseline serum 25(OH)D level (+/ SD) was 30.5 +/- 4.7 ng/mL (range 21.6 to 38.8 ng/mL). The mean serum 25(OH)D level after diet modification (+/-SD) was 47.2 +/- 10.9 ng/mL (range 34.7 to 74.0 ng/mL, p < .01). Overall, the average serum 25(OH)D level increased by 56.7% +/- 36.7%. A subgroup analysis based on the weekly dose of vitamin D was performed, and a similar trend was observed.Thus it is concluded that taking vitamin D with the largest meal improves absorption and results in about a 50% increase in serum levels of 25(OH)D levels achieved. Similar increases were observed in a wide range of vitamin D doses taken for a variety of medical conditions. PMID- 20200984 TI - Of mice and (wo)men: mouse models of breast cancer metastasis to bone. PMID- 20200985 TI - ASARM mineralization hypothesis: a bridge too far? PMID- 20200986 TI - A role for ethanol-induced oxidative stress in controlling lineage commitment of mesenchymal stromal cells through inhibition of Wnt/beta-catenin signaling. AB - The mechanisms by which chronic ethanol intake induces bone loss remain unclear. In females, the skeletal response to ethanol varies depending on physiologic status (e.g., cycling, pregnancy, or lactation). Ethanol-induced oxidative stress appears to be a key event leading to skeletal toxicity. In this study, ethanol containing liquid diets were fed to postlactational female Sprague-Dawley rats intragastrically for 4 weeks beginning at weaning. Ethanol consumption decreased bone mineral density (BMD) compared with control animals during this period of bone rebuilding following the end of lactation. Coadministration of the antioxidant N-acetylcysteine (NAC) was able to block bone loss and downregulation of the bone-formation markers alkaline phosphatase and osteocalcin in serum and gene expression in bone. Real-time array analysis of total RNA isolated from bone tissue revealed that the majority of Wnt signaling components were downregulated by chronic ethanol infusion. Real-time PCR confirmed downregulated gene expression in a subset of the Wnt signaling components by ethanol. However, the Wnt antagonist DKK1 was upregulated by ethanol. The key canonical Wnt signaling molecule beta-catenin protein expression was inhibited, while glycogen synthase kinase-3-beta was dephosphorylated by ethanol in bone and preosteoblastic cells. These actions of ethanol were blocked by NAC. Ethanol treatment inactivated TCF/LEF gene transcription, eliminated beta-catenin nuclear translocation in osteoblasts, and reciprocally suppressed osteoblastogenesis and enhanced adipogenesis. These effects of ethanol on lineage commitment of mesenchymal stem cells were eliminated by NAC pretreatment. These observations are consistent with the hypothesis that ethanol inhibits bone formation through stimulation of oxidative stress to suppress Wnt signaling. PMID- 20200987 TI - Sclerostin and the regulation of bone formation: Effects in hip osteoarthritis and femoral neck fracture. AB - Remodeling imbalance in the elderly femoral neck can result in thin cortices and porosity predisposing to hip fracture. Hip osteoarthritis protects against intracapsular hip fracture. By secreting sclerostin, osteocytes may inhibit Wnt signaling and reduce bone formation by osteoblasts. We hypothesised that differences in osteocytic sclerostin expression might account for differences in osteonal bone-formation activity between controls and subjects with hip fracture or hip osteoarthritis. Using specific antibody staining, we determined the osteocytic expression of sclerostin within osteons of the femoral neck cortex in bone removed from subjects undergoing surgery for hip osteoarthritis (hOA: 5 males, 5 females, 49 to 92 years of age) or hip fracture fixation (FNF: 5 males, 5 females, 73 to 87 years of age) and controls (C: 5 males, 6 females, 61 to 90 years of age). Sclerostin expression and distances of each osteocyte to the canal surface and cement line were assessed for all osteonal osteocytes in 636 unremodeled osteons chosen from fields ( approximately 0.5 mm in diameter) with at least one canal staining for alkaline phosphatase (ALP), a marker of bone formation. In adjacent sections, ALP staining was used to classify basic multicellular unit (BMUs) as quiescent or actively forming bone (ALP(+)). The areal densities of scl(-) and scl(+) osteocytes (number of cells per unit area) in the BMU were inversely correlated and were strong determinants of ALP status in the BMU. In controls and hip fracture patients only, sclerostin-negative osteocytes were closer to osteonal surfaces than positively stained cells. Osteon maturity (progress to closure) was strongly associated with the proportion of osteonal osteocytes expressing sclerostin, and sclerostin expression was the chief determinant of ALP status. hOA patients had 18% fewer osteocytes per unit bone area than controls, fewer osteocytes expressed sclerostin on average than in controls, but wide variation was seen between subjects. Thus, in most hOA patients, there was increased osteonal ALP staining and reduced sclerostin staining of osteocytes. In FNF patients, newly forming osteons were similar in this respect to hOA osteons, but with closure, there was a much sharper reduction in ALP staining that was only partly accounted for by the increased proportions of osteonal osteocytes staining positive for sclerostin. There was no evidence for a greater effect on ALP expression by osteocytes near the osteonal canal. In line with data from blocking antibody experiments, osteonal sclerostin appears to be a strong determinant of whether osteoblasts actively produce bone. In hOA, reduced sclerostin expression likely mediates increased osteoblastic activity in the intracapsular cortex. In FNF, full osteonal closure is postponed, with increased porosity, in part because the proportion of osteocytes expressing sclerostin increases sharply with osteonal maturation. PMID- 20200989 TI - Preventing metastases to bone: denosumab or bisphosphonates? PMID- 20200991 TI - Microindentation for in vivo measurement of bone tissue mechanical properties in humans. AB - Bone tissue mechanical properties are deemed a key component of bone strength, but their assessment requires invasive procedures. Here we validate a new instrument, a reference point indentation (RPI) instrument, for measuring these tissue properties in vivo. The RPI instrument performs bone microindentation testing (BMT) by inserting a probe assembly through the skin covering the tibia and, after displacing periosteum, applying 20 indentation cycles at 2 Hz each with a maximum force of 11 N. We assessed 27 women with osteoporosis-related fractures and 8 controls of comparable ages. Measured total indentation distance (46.0 +/- 14 versus 31.7 +/- 3.3 microm, p = .008) and indentation distance increase (18.1 +/- 5.6 versus 12.3 +/- 2.9 microm, p = .008) were significantly greater in fracture patients than in controls. Areas under the receiver operating characteristic (ROC) curve for the two measurements were 93.1% (95% confidence interval [CI] 83.1-100) and 90.3% (95% CI 73.2-100), respectively. Interobserver coefficient of variation ranged from 8.7% to 15.5%, and the procedure was well tolerated. In a separate study of cadaveric human bone samples (n = 5), crack growth toughness and indentation distance increase correlated (r = -0.9036, p = .018), and scanning electron microscope images of cracks induced by indentation and by experimental fractures were similar. We conclude that BMT, by inducing microscopic fractures, directly measures bone mechanical properties at the tissue level. The technique is feasible for use in clinics with good reproducibility. It discriminates precisely between patients with and without fragility fracture and may provide clinicians and researchers with a direct in vivo measurement of bone tissue resistance to fracture. PMID- 20200990 TI - Mouse BMD quantitative trait loci show improved concordance with human genome wide association loci when recalculated on a new, common mouse genetic map. AB - Bone mineral density (BMD) is a heritable trait, and in mice, over 100 quantitative trait loci (QTLs) have been reported, but candidate genes have been identified for only a small percentage. Persistent errors in the mouse genetic map have negatively affected QTL localization, spurring the development of a new, corrected map. In this study, QTLs for BMD were remapped in 11 archival mouse data sets using this new genetic map. Since these QTLs all were mapped in a comparable way, direct comparisons of QTLs for concordance would be valid. We then compared human genome-wide association study (GWAS) BMD loci with the mouse QTLs. We found that 26 of the 28 human GWAS loci examined were located within the confidence interval of a mouse QTL. Furthermore, 14 of the GWAS loci mapped to within 3 cM of a mouse QTL peak. Lastly, we demonstrated that these newly remapped mouse QTLs can substantiate a candidate gene for a human GWAS locus, for which the peak single-nucleotide polymorphism (SNP) fell in an intergenic region. Specifically, we suggest that MEF2C (human chromosome 5, mouse chromosome 13) should be considered a candidate gene for the genetic regulation of BMD. In conclusion, use of the new mouse genetic map has improved the localization of mouse BMD QTLs, and these remapped QTLs show high concordance with human GWAS loci. We believe that this is an opportune time for a renewed effort by the genetics community to identify the causal variants regulating BMD using a synergistic mouse-human approach. PMID- 20200992 TI - Microfluidic enhancement of intramedullary pressure increases interstitial fluid flow and inhibits bone loss in hindlimb suspended mice. AB - Interstitial fluid flow (IFF) has been widely hypothesized to mediate skeletal adaptation to mechanical loading. Although a large body of in vitro evidence has demonstrated that fluid flow stimulates osteogenic and antiresorptive responses in bone cells, there is much less in vivo evidence that IFF mediates loading induced skeletal adaptation. This is due in large part to the challenges associated with decoupling IFF from matrix strain. In this study we describe a novel microfluidic system for generating dynamic intramedullary pressure (ImP) and IFF within the femurs of alert mice. By quantifying fluorescence recovery after photobleaching (FRAP) within individual lacunae, we show that microfluidic generation of dynamic ImP significantly increases IFF within the lacunocanalicular system. In addition, we demonstrate that dynamic pressure loading of the intramedullary compartment for 3 minutes per day significantly eliminates losses in trabecular and cortical bone mineral density in hindlimb suspended mice, enhances trabecular and cortical structural integrity, and increases endosteal bone formation rate. Unlike previously developed modalities for enhancing IFF in vivo, this is the first model that allows direct and dynamic modulation of ImP and skeletal IFF within mice. Given the large number of genetic tools for manipulating the mouse genome, this model is expected to serve as a powerful investigative tool in elucidating the role of IFF in skeletal adaptation to mechanical loading and molecular mechanisms mediating this process. PMID- 20200993 TI - Increased trabecular bone formation in mice lacking the growth factor midkine. AB - Midkine (Mdk) and pleiotrophin (Ptn) comprise a family of heparin-binding growth factors known primarily for their effects on neuronal cells. Since transgenic mice overexpressing Ptn have been reported to display increased bone density, we have previously analyzed Ptn-deficient mice but failed to detect any abnormality of skeletal development and remodeling. Together with the finding that Mdk expression increases in the course of primary osteoblast differentiation, we reasoned that Mdk, rather than Ptn, could play a physiologic role in bone formation. Here, we show that Mdk-deficient mice display an increased trabecular bone volume at 12 and 18 months of age, accompanied by cortical porosity. Histomorphometric quantification demonstrated an increased bone-formation rate compared with wild-type littermates, whereas bone resorption was differentially affected in trabecular and cortical bone of Mdk-deficient mice. To understand the effect of Mdk on bone formation at the molecular level, we performed a genome wide expression analysis of primary osteoblasts and identified Ank and Enpp1 as Mdk-induced genes whose decreased expression in Mdk-deficient osteoblasts may explain, at least in part, the observed skeletal phenotype. Finally, we performed ovariectomy and observed bone loss only in wild-type but not in Mdk-deficient animals. Taken together, our data demonstrate that Mdk deficiency, at least in mice, results in an increased trabecular bone formation, thereby raising the possibility that Mdk-specific antagonists might prove beneficial in osteoporosis therapy. PMID- 20200998 TI - Mechanical stretching induces osteoprotegerin in differentiating C2C12 precursor cells through noncanonical Wnt pathways. AB - Mechanical loading is known to be important for maintaining the formation and resorption rates of bone. To study the mechanisms by which mechanical loading regulates osteogenesis, we investigated the role of the Wnt pathway in C2C12 cells committed to osteogenic differentiation in response to cyclic mechanical stretching. Osteoprotegerin (OPG) acts as a decoy receptor for RANKL to inhibit osteoclastogenesis and resorption of bone. Our results demonstrate that stretching leads to a sustained increase in OPG expression in C2C12 cells. The expression of osteogenic marker genes, such as osteocalcin and alkaline phosphatase, was transiently decreased by stretching at 24 hours and returned to control levels at 48 hours. The addition of inhibitors of the canonical Wnt/beta catenin pathways, such as the secreted FZD-related peptide sRFP2, as well as siRNA-mediated knockdown, did not inhibit the effect of stretching on OPG expression. In contrast, treatment with inhibitors of noncanonical Wnt signaling, including KN93, and siRNA for Nemo-like kinase (NLK) blocked most of the mechanical inductive effect on OPG. Furthermore, stretching-induced OPG production in the culture medium was able to inhibit the osteoclast formation of bone marrow macrophages. These results suggest that mechanical stretching may play an important role in bone remodeling through the upregulation of OPG and that the mechanical signaling leading to OPG induction involves the noncanonical Wnt pathway. PMID- 20200994 TI - Identification of genes influencing skeletal phenotypes in congenic P/NP rats. AB - We previously showed that alcohol-preferring (P) rats have higher bone density than alcohol-nonpreferring (NP) rats. Genetic mapping in P and NP rats identified a major quantitative trait locus (QTL) between 4q22 and 4q34 for alcohol preference. At the same location, several QTLs linked to bone density and structure were detected in Fischer 344 (F344) and Lewis (LEW) rats, suggesting that bone mass and strength genes might cosegregate with genes that regulate alcohol preference. The aim of this study was to identify the genes segregating for skeletal phenotypes in congenic P and NP rats. Transfer of the NP chromosome 4 QTL into the P background (P.NP) significantly decreased areal bone mineral density (aBMD) and volumetric bone mineral density (vBMD) at several skeletal sites, whereas transfer of the P chromosome 4 QTL into the NP background (NP.P) significantly increased bone mineral content (BMC) and aBMD in the same skeletal sites. Microarray analysis from the femurs using Affymetrix Rat Genome arrays revealed 53 genes that were differentially expressed among the rat strains with a false discovery rate (FDR) of less than 10%. Nine candidate genes were found to be strongly correlated (r(2) > 0.50) with bone mass at multiple skeletal sites. The top three candidate genes, neuropeptide Y (Npy), alpha synuclein (Snca), and sepiapterin reductase (Spr), were confirmed using real-time quantitative PCR (qPCR). Ingenuity pathway analysis revealed relationships among the candidate genes related to bone metabolism involving beta-estradiol, interferon-gamma, and a voltage-gated calcium channel. We identified several candidate genes, including some novel genes on chromosome 4 segregating for skeletal phenotypes in reciprocal congenic P and NP rats. PMID- 20201000 TI - The effect of prior bisphosphonate therapy on the subsequent BMD and bone turnover response to strontium ranelate. AB - Strontium ranelate is an effective treatment for osteoporosis in treatment-naive women. In the United Kingdom, bisphosphonates are often used first line. Prior bisphosphonate use may blunt the bone mineral density (BMD) response to strontium ranelate by reducing strontium uptake into the bone. Sixty bisphosphonate-naive women and 60 women discontinuing bisphosphonates were recruited. All women commenced strontium ranelate and calcium/vitamin D. BMD and bone turnover markers were recorded for 12 months. After 12 months, the bisphosphonate-naive group's BMD increased by 5.6% (p < .001) at the spine, 3.4% (p < .001) at the total hip, and 4.0% (p < .001) at the heel. By comparison, the prior bisphosphonate group had a 2.1% (p = .002) increase at the spine but no change at the hip or heel. At all time points, BMD was significantly greater in the bisphosphonate-naive group. In the prior bisphosphonate group, there was no significant change in BMD during the first 6 months at the spine, but between months 6 and 12 there was a parallel gain in BMD (0.027 versus 0.020 g/cm(2), p = .40). The baseline difference in bone markers was no longer significant by 3 months for bone-specific alkaline phosphatase (BSAP) and 6 months for procollagen type 1 amino-terminal propeptide (P1NP) and carboxy-terminal cross-linking telopeptide of type I collagen (CTX). More women in the prior bisphosphonate group suffered a vertebral fracture (2 versus 8 women, p = .047). After bisphosphonates, bone turnover remains suppressed for up to 6 months, with blunting of the BMD response to strontium ranelate during this time. After 6 months, BMD increases in the spine but not at the hip or heel. PMID- 20200999 TI - Serum 25-hydroxyvitamin D levels modulate the acute-phase response associated with the first nitrogen-containing bisphosphonate infusion. AB - The acute-phase response (APR) is the most frequent side effect after the first dose of intravenous nitrogen-containing bisphosphonates (N-BPs). It has been demonstrated in vitro that N-BPs stimulate gammadelta T-cell proliferation and production of cytokines and that vitamin D is able to modulate them. Therefore, we have studied the relationship between bone metabolism parameters, particularly for 25-hydroxyvitamin D [25(OH)D], and APR in patients treated with 5 mg zoledronic acid intravenously. Ninety N-BP-naive osteoporotic women (63.7 +/- 10.6 years of age) were stratified for the occurrence of APR (APR(+)) or not (APR(-)) and quantified by body temperature and C-reactive protein (CRP). The APR(+) women had significantly lower 25(OH)D levels than the APR(-) women. Levels of 25(OH)D were normal (>30 ng/mL) in 31% of APR(+) women and in 76% of APR(-) women. The odds ratio (OR) to have APR in 25(OH)D-depleted women was 5.8 [95% confidence interval (CI) 5.30-6.29; p < .0002] unadjusted and 2.38 (95% CI 1.85 2.81; p < .028) after multiple adjustments (for age, body mass index, CRP, calcium, parathyroid hormone, and C-telopeptide of type I collagen). Levels of 25(OH)D were negatively correlated with postdose body temperature (r = -0.64, p < .0001) and CRP (r = -0.79, p < .001). An exponential increase in fever and CRP has been found with 25(OH)D levels lower than 30 ng/mL and body temperature less than 37 degrees C, whereas normal CRP was associated with 25(OH)D levels above 40 ng/mL. The association between post-N-BPs APR and 25(OH)D suggests an interesting interplay among N-BPs, 25(OH)D, and the immune system, but a causal role of 25(OH)D in APR has to be proven by a randomized, controlled trial. However, if confirmed, it should have some practical implications in preventing APR. PMID- 20201001 TI - A single amino acid substitution in the SdhB protein of succinate dehydrogenase determines resistance to amicarthiazol in Xanthomonas oryzae pv. oryzae. AB - BACKGROUND: Xanthomonas oryzae pv. Oryzae Ishiyama, a causal agent of rice bacterial leaf blight, was found to be sensitive in vitro to the systemic fungicide amicarthiazol (2-amino-4-methylthiazole -5-carboxanilide), which is a potent inhibitor of succinate dehydrogenase (SDH, EC 1.3.99.1). This paper aimed to determine the molecular resistance mechanism of X. oryzae pv. oryzae to amicarthiazol. RESULTS: UV-induced resistant mutants of X. oryzae pv. oryzae to amicarthiazol were isolated. The activity of SDH in wild-type X. oryzae pv. oryzae was strongly inhibited by amicarthiazol, while that in resistant mutants was insensitive, although their SDH activity was decreased compared with the wild type sensitive strain without amicarthiazol. A mutation of Histidine(229) (CAC) to Tyrosine(229) (TAC) was identified in sdhB, which encoded the iron-sulfur protein subunit of SDH. The sdhB from the mutant was ligated into a cosmid, pUFR034, to generate pUFR034RAX, which conferred resistance to amicarthiazol when transformed into the wild-type sensitive strain. CONCLUSION: A mutation of His(229) (CAC) to Tyr(229) (TAC) in SdhB was responsible for determining amicarthiazol resistance. . PMID- 20201003 TI - Hyperintensity in the basis pontis: atypical neuroradiological findings in a woman with FXTAS. PMID- 20201004 TI - Rehabilitation in Parkinson's disease: assessing the outcome using objective metabolic measurements. AB - Objective measurements to assess the efficacy of rehabilitation treatment in Parkinson's disease, suitable to be carried out routinely in the clinical setting, are lacking. Metabolic parameters, reflecting the recruitment and co ordination of muscle fibers, might be simple instrumental measurements suitable for use as outcome markers. Twenty parkinsonian patients underwent a 4-week rehabilitation treatment. Functional evaluation was based on Unified Parkinson's Disease Rating Scale Motor Section (UPDRS III), Berg's scale, 6-minute walking test (6MWT), and the metabolic data recorded during the 6MWT namely the active energy expenditure (AEE), the kinetics of the energy consumption curve, and the peak value of energy consumption. Both rating scales and gait improved significantly (UPDRS III decreased by 32%, Berg increased by 21% and the 6MWT increased by 17%). We observed significant improvements also in metabolic measurements (35, 18, and 15 improvement in the kinetics of the energy consumption, AEE, and peak value of energy consumption, respectively). Hence, the rehabilitation protocol improved functional characteristics of the patients and these improvements were clearly reflected also by the metabolic measurements. The improvement in clinical scores corresponded with an increase in energy consumption during the 6MWT, indicating greater speed in the recruitment of motor units and of a capacity to maintain this recruitment over time. PMID- 20201005 TI - Carisbamate in essential tremor: brief report of a proof of concept study. AB - The efficacy and safety of carisbamate, an investigational neuromodulator currently in development for epilepsy, were examined in a multicenter, randomized, double-blind, cross-over, placebo-controlled study of essential tremor. Sixty-two patients (intent-to-treat analysis set; mean age 64 years; 66% men) received carisbamate 400 mg/day or matching placebo in a crossover study design with two 21-day treatment periods. The Fahn-Tolosa-Marin Tremor Rating Scale (TRS) was the primary assessment tool. Carisbamate and placebo treatment did not differ in their effect on the TRS (P = 0.94) or on measures of affect, mood, or quality of life. Carisbamate was generally well tolerated and had an adverse event profile comparable to that of placebo. PMID- 20201007 TI - NLR-containing inflammasomes: central mediators of host defense and inflammation. PMID- 20201008 TI - IL-1: discoveries, controversies and future directions. AB - Although there has been a great amount of progress in the 25 years since the first reporting of the cDNA for IL-1alpha and IL-1beta, the history of IL-1 goes back to the early 1940s. In fact, the entire field of inflammatory cytokines, TLR and the innate immune response can be found in the story of IL-1. This Viewpoint follows the steps from the identification of the fever-inducing activities of "soluble factors" produced by endotoxin-stimulated leukocytes through to the discovery of cryopyrin and the caspase-1 inflammasome and on to the clinical benefits of anti-IL-1beta-based therapeutics. It also discusses some of the current controversies regarding the activation of the inflammasome. The future of novel anti-inflammatory agents to combat chronic inflammation is based, in part, on the diseases that are uniquely responsive to anti-IL-1beta, which is surely a reason to celebrate the 25th anniversary of the cloning of IL-1alpha and IL 1beta. PMID- 20201011 TI - Women advancing science. PMID- 20201012 TI - Sterile inflammatory responses mediated by the NLRP3 inflammasome. AB - Through pattern recognition receptors the innate immune system detects disruption of the normal function of the organism and initiates responses directed at correcting these derangements. Cellular damage from microbial or non-microbial insults causes the activation of nucleotide-binding domain leucine-rich repeat containing receptors in multiprotein complexes called inflammasomes. Here we discuss the role of the NLRP3 inflammasome in the recognition of cellular damage and the initiation of sterile inflammatory responses. PMID- 20201013 TI - Inflammasomes as microbial sensors. AB - Members of the Nod-like receptor family and the adaptor ASC assemble into multiprotein platforms, termed inflammasomes, to mediate the activation of caspase-1 and subsequent secretion of IL-1beta and IL-18. Recent studies have identified microbial and endogenous molecules as well as possible mechanisms involved in inflammasome activation. PMID- 20201014 TI - Signaling by ROS drives inflammasome activation. AB - Inflammasomes are innate immune signaling pathways that sense pathogens and injury to direct the proteolytic maturation of inflammatory cytokines such as IL 1beta and IL-18. Among inflammasomes, the NLRP3/NALP3 inflammasome is the most studied. However, little is known on the molecular mechanisms that mediate its assembly and activation. Recent findings suggest that ROS are produced by NLRP3/NALP3 activators and are essential secondary messengers signaling NLRP3/NALP3 inflammasome activation. PMID- 20201015 TI - Critical functions of priming and lysosomal damage for NLRP3 activation. AB - Inflammasomes are cytosolic multi-protein complexes that form in response to infectious or injurious challenges. Inflammasomes control the activity of caspase 1, which is essential for the maturation and release of IL-1beta family cytokines. The NLRP1, IPAF and AIM2 inflammasomes recognize specific substances, while the NLRP3 inflammasome responds to many structurally and chemically diverse triggers. Here, we discuss the critical roles of priming and lysosomal damage in NLRP3 inflammasome activation. PMID- 20201017 TI - Pyroptosis - a cell death modality of its kind? AB - The term "pyroptosis" was originally introduced to describe a particular form of cell death in macrophages, which is induced by bacterial infection, is accompanied by caspase-1 activation and hence leads to the release of pyrogenic interleukins; however, it is still controversial whether pyroptosis - which can also be triggered by non-bacterial pathological stimuli - truly represents a cell death modality on its own or whether it constitutes a special case of apoptosis or necrosis. PMID- 20201016 TI - NOD-like receptor (NLR) signaling beyond the inflammasome. AB - Recent years have witnessed a marked progress in our knowledge of NOD-like receptors (NLR), intracellular sensors with central roles in innate and adaptive immunity. A majority of the research has focused on caspase-1 inflammasomes. However, several members of the mammalian NLR family exert important roles in immunity beyond inflammasome signaling. Here we highlight the emerging roles of several of these NLR. PMID- 20201018 TI - The NLRP3 inflammasome, a target for therapy in diverse disease states. AB - A role for NLRP3 inflammasome in recurrent and chronic inflammation was initially described in a group of rare autoinflammatory conditions, termed cryopyrin associated periodic syndrome. Subsequently, inflammasomes have been implicated in the pathology of many common diseases, including cancer, gout and diabetes. Despite diverse pathologies, the central role of the inflammasome in innate defences and tumour elimination suggests common therapeutic approaches to reduce inflammation where appropriate. PMID- 20201019 TI - The role of inflammasomes in the immunostimulatory effects of particulate vaccine adjuvants. AB - Adjuvants are essential for enhancing and directing immunity to vaccine antigens. Most adjuvants in clinical use are particulates, but how they drive innate and adaptive immune responses is unclear. A major recent advance was the demonstration that particulate adjuvants promote activation of the NLRP3 inflammasome. The mechanisms underlying this activation have been partly resolved and the role of NLRP3 in particulate adjuvant-induced adaptive immunity is currently the subject of intense interest. PMID- 20201020 TI - The controversial relationship between NLRP3, alum, danger signals and the next generation adjuvants. AB - Alum has been the only adjuvant licensed for human vaccines for decades and is still widely used, but its mechanism of action remains obscure. Recently, the NLRP3 inflammasome has been linked to the immunostimulatory properties of alum and other particulate adjuvants, although it is disputed to what degree NLRP3 is genuinely essential in vivo. Meanwhile, researchers are testing adjuvants harnessing both the infectious/non-infectious-discriminating TLR and the danger sensing NLRP3 inflammasome pathways. Could this be the basis of a long-needed rationale in the design of adjuvants? PMID- 20201021 TI - Genetics of inflammasome-associated disorders: a lesson in the guiding principals of inflammasome function. AB - Human genetics research has had a great impact on the genesis of the inflammasome field and the treatment of certain inflammasomopathies. The identification of mutations causing rare autoinflammatory syndromes, reproductive wastage disorders and of single nucleotide polymorphisms influencing susceptibility to complex diseases such as vitiligo, sepsis, and Crohn's disease has not only led to the characterization of novel proteins involved in NOD-like receptor-coupled inflammatory signaling pathways but also to greater insights into pathogenic mechanisms. PMID- 20201022 TI - New insights into the nature of autoinflammatory diseases from mice with Nlrp3 mutations. AB - Mutations in the Nlrp3 (CIAS1, cryopyrin) gene are associated with cryopyrin associated periodic syndrome, autoinflammatory diseases characterized by excessive IL-1 production and neutrophilia in blood and tissues. Recent studies with gene-targeted mice expressing mutations homologous to those found in cryopyrin-associated periodic syndrome patients have advanced the understanding of NLRP3-associated autoinflammation. In this Viewpoint, we will discuss the mechanisms of NLRP3 inflammasome activation and its induction of Th17-cell dominant immunologic responses. PMID- 20201024 TI - Does age make a difference in caregiver strain? Comparison of young versus older caregivers in early-stage Parkinson's disease. AB - Family care research has identified negative outcomes of providing care to a spouse with Parkinson's disease (PD), such as declining physical and mental health. Research has also identified protective variables that decrease negative outcomes such as high mutuality and rewards of meaning. It is important for clinicians to identify "at risk" family caregivers and provide earlier interventions. Despite the importance of age and developmental stage there is a paucity of research comparing young versus older spouse caregivers. This study compared the difference in negative aspects of strain and modulators of strain in young and older PD spouse caregivers. A series of hierarchical multiple regressions were used to examine the contribution of age on both positive and negative aspects of the care situation for 65 (37 young, 28 old) PD spouse caregivers. Negative variables included 3 dimensions of strain; strain from lack of personal resources, strain from worry, and global strain. Positive or protective variables included mutuality, preparedness, and rewards of meaning. Even in early stage disease before significant care is required, young spouses (40-55) were found to be at greater risk for negative consequences of the care situation reporting significantly more strain from lack of personal resources, and lower levels of mutuality and rewards of meaning than older (greater than 70) spouses. As expected, young spouses were more likely to be working, caring for children in the home, and in better physical health than older spouses. Clinicians are well-situated to identify the unique needs of young spouses and intervene early in the caregiving trajectory. These findings provide ideas for targeted interventions. Future larger studies that compare young and older spouses should include later stage disease to more fully understand the developmental differences raised by the present findings. PMID- 20201025 TI - Mortality in Parkinson's disease, a 20-year follow-up study. PMID- 20201026 TI - Study of the release of gallic acid from (-)-epigallocatechin gallate in old oolong tea by mass spectrometry. AB - Liquid chromatography combined with multiple-stage mass spectrometry (LC/MS(n)) was used to study the pathway of the release of gallic acid (GA) from epigallocatechin gallate (EGCG) in infusion of old oolong tea. The possibility of releasing GA from EGCG in old tea preparations was supported by an in vitro observation of GA degraded from EGCG under heating conditions mimicking the drying process. Negative electrospray ionization with the data-dependent mode of MS(n) was used to study the formation pathway of GA in old oolong tea. The MS(n) data show that GA was released from the dimer of EGCG, not directly degraded from EGCG. PMID- 20201027 TI - Overview of formation of G-quadruplex structures. AB - There are many structures that can be adopted by nucleic acids other than the Watson-Crick duplex. In particular, a noncanonical four-stranded topology, called a G-quadruplex, is of great interest because of its roles in key biological processes such as the maintenance of telomeres and regulation of gene transcription. This review describes the condition for forming the G-quadruplex structure, G-quadruplex-forming sequences, and methods for studying the structures. PMID- 20201028 TI - In vitro selection of RNA aptamers to a protein target by filter immobilization. AB - This unit describes the selection of aptamers from a pool of single-stranded RNA by binding to a protein target. Aptamers generated from this selection experiment can potentially act as protein function inhibitors, and may find applications as therapeutic or diagnostic reagents. A pool of dsDNA is used to generate an ssRNA pool, which is mixed with the protein target. Bound complexes are separated from unbound reagents by filtration, and the RNA:protein complexes are amplified by a combination of reverse transcription, PCR, and in vitro transcription. PMID- 20201029 TI - In vitro selection of RNA aptamers to a small molecule target. AB - This unit describes the selection of aptamers from a single-stranded RNA pool that bind to small molecule targets. Aptamers generated by this type of selection experiment can potentially function as receptors for small molecules in numerous applications, including medical diagnostics, therapeutics, and environmental monitoring. This unit describes two modes of selection, one by column filtration and one by batch selection. PMID- 20201030 TI - The continuous evolution in vitro technique. AB - In vitro experimentation techniques were developed in response to the necessity of exploring new molecular structures and functions and to better understand evolutionary phenomena that shape organismal and molecular populations. The advancement of these techniques has allowed further exploration of more complicated evolutionary dynamics. One such technique is the continuous evolution in vitro (CE) method, to which this unit is devoted. The CE method is characterized by continuous cycles of amplification of RNA molecules that occur without much participation of the researcher. This feature allows us to evolve lineages in which the evolutionary phenomena occurring at the molecular level more closely mimic what happens in organismal populations in the present, or what may have happened in RNA populations during the RNA world stage of life. PMID- 20201032 TI - Stat5 is indispensable for the maintenance of bcr/abl-positive leukaemia. AB - Tumourigenesis caused by the Bcr/Abl oncoprotein is a multi-step process proceeding from initial to tumour-maintaining events and finally results in a complex tumour-supporting network. A key to successful cancer therapy is the identification of critical functional nodes in an oncogenic network required for disease maintenance. So far, the transcription factors Stat3 and Stat5a/b have been implicated in bcr/abl-induced initial transformation. However, to qualify as a potential drug target, a signalling pathway must be required for the maintenance of the leukaemic state. Data on the roles of Stat3 or Stat5a/b in leukaemia maintenance are elusive. Here, we show that both, Stat3 and Stat5 are necessary for initial transformation. However, Stat5- but not Stat3-deletion induces G(0)/G(1) cell cycle arrest and apoptosis of imatinib-sensitive and imatinib-resistant stable leukaemic cells in vitro. Accordingly, Stat5-abrogation led to effective elimination of myeloid and lymphoid leukaemia maintenance in vivo. Hence, we identified Stat5 as a vulnerable point in the oncogenic network downstream of Bcr/Abl representing a case of non-oncogene addiction (NOA). PMID- 20201033 TI - An injection method for measuring the carbon isotope content of soil carbon dioxide and soil respiration with a tunable diode laser absorption spectrometer. AB - We present a novel technique in which the carbon isotope ratio (delta(13)C) of soil CO(2) is measured from small gas samples (<5 mL) injected into a stream of CO(2)-free air flowing into a tunable diode laser absorption spectrometer (TDL). This new method extends the dynamic range of the TDL to measure CO(2) mole fractions ranging from ambient to pure CO(2), reduces the volume of sample required to a few mL, and does not require field deployment of the instrument. The measurement precision of samples stored for up to 60 days was 0.23 per thousand. The new TDL method was applied with a simple gas well sampling technique to obtain and measure gas samples from shallow soil depth increments for CO(2) mole fraction and delta(13)C analysis, and subsequent determination of the delta(13)C of soil-respired CO(2). The method was tested using an artificial soil system containing a controlled CO(2) source and compared with an independent method using the TDL and an open soil chamber. The profile and chamber estimates of delta(13)C of an artificially produced CO(2) flux were consistent and converged to the delta(13)C of the CO(2) source at steady state, indicating the accuracy of both methods under controlled conditions. The new TDL method, in which a small pulse of sample is measured on a carrier gas stream, is analogous for the TDL technique to the development of continuous-flow configurations for isotope ratio mass spectrometry. While the applications presented here are focused on soil CO(2), this new TDL method could be applied in a number of situations requiring measurement of delta(13)C of CO(2) in small gas samples with ambient to high CO(2) mole fractions. PMID- 20201034 TI - Evaluation of the biocontrol potential of various Metarhizium isolates against green peach aphid Myzus persicae (Homoptera: Aphididae). AB - BACKGROUND: Twenty-three isolates of Metarhizium anisopliae (Metschnikof) Sorokin and M. acridum (Driver & Milner) JF Bischoff, Rehner & Humber from non-aphid host insects around the globe were evaluated for their aphid biocontrol potential, which is not well known. RESULTS: The apterous adults of green peach aphid Myzus persicae (Sulzer) were exposed to the fungal sprays of 11.5, 99 and 1179 conidia mm(-2) and blank control in three leaf-dish bioassays. All the tested isolates except one were proven to be infective to the aphid species at 21 +/- 1 degrees C and 14:10 h light:dark photoperiod, causing corrected mortalities of 10.1-95.3% at the high spore concentration. The data from ten isolates causing > 50% mortality at the high concentration were found to fit a time-concentration mortality model well, yielding parameters for the estimates of their LC(50) and LT(50) that vary with post-spray time and spore concentration respectively. Four isolates of M. anisopliae (ARSEF 759, 4132, 2080 and 576) had LC(50) values of 44 80 conidia mm(-2) on day 8 and LT(50) values of 4.9-6.8 days at 100 conidia mm( 2), with 91-98% of the killed aphids being well mycotised after death. CONCLUSION: The Metarhizium infectivity to M. persicae differs greatly among the tested isolates. The four mentioned isolates with desired virulence and sporulation potential are excellent candidates for microbial control of aphids. PMID- 20201031 TI - A systems biology approach to understanding atherosclerosis. AB - Atherosclerosis, a chronic inflammatory disease of the vascular system, presents significant challenges to developing effective molecular diagnostics and novel therapies. A systems biology approach integrating data from large-scale measurements (e.g. transcriptomics, proteomics and genomics) is successfully contributing to deciphering regulatory networks underlying the response of many different cellular systems to perturbations. Such a network analysis strategy using pathway information and data from multiple measurement platforms, tissues and species is a promising approach to elucidate the mechanistic underpinnings of complex diseases. Here, we present our views on the contributions that a systems approach can bring to the study of atherosclerosis, propose ways to tackle the complexity of the disease in a systems manner and review recent systems-level studies of the disease. PMID- 20201035 TI - Zinc signals promote IL-2-dependent proliferation of T cells. AB - Zinc signals, i.e. a change of the intracellular concentration of free zinc ions in response to receptor stimulation, are involved in signal transduction in several immune cells. Here, the role of zinc signals in T-cell activation by IL-2 was investigated in the murine cytotoxic T-cell line CTLL-2 and in primary human T cells. Measurements with the fluorescent dyes FluoZin-3 and Zinquin showed that zinc is released from lysosomes into the cytosol in response to stimulation of the IL-2-receptor. Activation of the ERK-pathway was blocked by chelation of free zinc with N,N,N',N'-tetrakis-2(pyridyl-methyl)ethylenediamine, whereas zinc was not required for STAT5 phosphorylation. In addition, the key signaling molecules MEK and ERK were activated in response to elevated free intracellular zinc, induced by incubation with zinc and the ionophore pyrithione. Downstream of ERK activation, ERK-specific gene expression of c-fos and IL-2-induced proliferation was found to depend on zinc. Further experiments indicated that inhibition of MEK and ERK-dephosphorylating protein phosphatases is the molecular mechanism for the influence of zinc on this pathway. In conclusion, an increase of cytoplasmic free zinc is required for IL-2-induced ERK signaling and proliferation of T cells. PMID- 20201036 TI - NTPDase1 governs P2X7-dependent functions in murine macrophages. AB - P2X7 receptor is an adenosine triphosphate (ATP)-gated ion channel within the multiprotein inflammasome complex. Until now, little is known about regulation of P2X7 effector functions in macrophages. In this study, we show that nucleoside triphosphate diphosphohydrolase 1 (NTPDase1)/CD39 is the dominant ectonucleotidase expressed by murine peritoneal macrophages and that it regulates P2X7-dependent responses in these cells. Macrophages isolated from NTPDase1-null mice (Entpd1(-/-)) were devoid of all ADPase and most ATPase activities when compared with WT macrophages (Entpd1(+/+)). Entpd1(-/-) macrophages exposed to millimolar concentrations of ATP were more susceptible to cell death, released more IL-1beta and IL-18 after TLR2 or TLR4 priming, and incorporated the fluorescent dye Yo-Pro-1 more efficiently (suggestive of increased pore formation) than Entpd1(+/+) cells. Consistent with these observations, NTPDase1 regulated P2X7-associated IL-1beta release after synthesis, and this process occurred independently of, and prior to, cytokine maturation by caspase-1. NTPDase1 also inhibited IL-1beta release in vivo in the air pouch inflammatory model. Exudates of LPS-injected Entpd1(-/-) mice had significantly higher IL 1beta levels when compared with Entpd1(+/+) mice. Altogether, our studies suggest that NTPDase1/CD39 plays a key role in the control of P2X7-dependent macrophage responses. PMID- 20201037 TI - The NK receptor KLRG1 is dispensable for virus-induced NK and CD8+ T-cell differentiation and function in vivo. AB - The killer cell lectin-like receptor G1 (KLRG1) is expressed by NK and T-cell subsets and recognizes members of the classical cadherin family. KLRG1 is widely used as a lymphocyte differentiation marker in both humans and mice but the physiological role of KLRG1 in vivo is still unclear. Here, we generated KLRG1 deficient mice by homologous recombination and used several infection models for their characterization. The results revealed that KLRG1 deficiency did not affect development and function of NK cells examined under various conditions. KLRG1 was also dispensable for normal CD8+ T-cell differentiation and function after viral infections. Thus, KLRG1 is a marker for distinct NK and T-cell differentiation stages but it does not play a deterministic role in the generation and functional characteristics of these lymphocyte subsets. In addition, we demonstrate that E cadherin expressed by K562 target cells inhibited NK-cell reactivity in transgenic mice over-expressing KLRG1 but not in KLRG1-deficient or WT mice. Hence, the inhibitory potential of KLRG1 in mice is rather weak and strong activation signals during viral infections may override the inhibitory signal in vivo. PMID- 20201038 TI - Influence of human cytomegalovirus infection on the NK cell receptor repertoire in children. AB - Human cytomegalovirus (hCMV) infection is usually asymptomatic but may cause disease in immunocompromised hosts. It has been reported that hCMV infection may shape the NK cell receptor (NKR) repertoire in adult individuals, promoting a variable expansion of the CD94/NKG2C+ NK cell subset. We explored the possible relationship between this viral infection and the expression pattern of different NKR including CD94/NKG2C, CD94/NKG2A, immunoglobulin-like transcript 2 (ILT2, CD85j), KIR2DL1/2DS1, KIR3DL1, and CD161 in peripheral blood lymphocytes from healthy children, seropositive (n=21) and seronegative (n=20) for hCMV. Consistent with previous observations in adults, a positive serology for hCMV was associated with increased numbers of NKG2C+ NK and T cells as well as with ILT2+ T lymphocytes. Moreover, the proportions of CD161+ and NKG2C+CD56-CD3- NK cells also tended to be increased in hCMV+ individuals. Excretion of the virus was associated with higher proportions of NKG2C+ NK cells. Altogether, these data reveal that hCMV may have a profound influence on the NKR repertoire in early childhood. PMID- 20201039 TI - CCL21 is sufficient to mediate DC migration, maturation and function in the absence of CCL19. AB - Mice deficient in CCR7 signals show severe defects in lymphoid tissue architecture and immune response. These defects are due to impaired attraction of CCR7+ DC and CCR7+ T cells into the T zones of secondary lymphoid organs and altered DC maturation. It is currently unclear which CCR7 ligand mediates these processes in vivo as CCL19 and CCL21 show an overlapping expression pattern and blocking experiments have given contradictory results. In this study, we addressed this question using CCL19-deficient mice expressing various levels of CCL21. Complete deficiency of CCL19 and CCL21 but not CCL19 alone was found to be associated with abnormal frequencies and localization of DC in naive LN. Similarly, CCL19 was not required for DC migration from the skin, full DC maturation and efficient T-cell priming. Our findings suggest that CCL21 is the critical CCR7 ligand regulating DC homeostasis and function in vivo with CCL19 being redundant for these processes. PMID- 20201040 TI - Interleukin-4 downregulates CD127 expression and activity on human thymocytes and mature CD8+ T cells. AB - Signaling via the IL-7 receptor complex (IL-7Ralpha/CD127 and IL-2Rgamma/CD132) is required for T-cell development and survival. Decreased CD127 expression has been associated with persistent viral infections (e.g. HIV, HCV) and cancer. Many IL-2Rgamma-sharing (gammaC) cytokines decrease CD127 expression on CD4+ and CD8+ T cells in mice (IL-2, IL-4, IL-7, IL-15) and in humans (IL-2, IL-7), suggesting a common function. IL-4 is of particular interest as it is upregulated in HIV infection and in thyroid and colon cancers. The role of IL-4 in regulating CD127 expression and IL-7 activity in human thymocytes and mature CD8+ T cells is unknown and was therefore investigated. IL-4 decreased CD127 expression on all thymocyte subsets tested and only on naive (CD45RA+) CD8+ T cells, without altering membrane-bound CD127 mRNA expression. Pre-treatment of thymocytes or CD8+ T cells with IL-4 inhibited IL-7-mediated phosphorylation of STAT5 and decreased proliferation of CD8+ T cells. By downregulating CD127 expression and signaling on developing thymocytes and CD8+ T cells, IL-4 is a potential contributor to impaired CD8+ T-cell function in some anti-viral and anti-tumor responses. These findings are of particular consequence to diseases such as HIV, HCV, RSV, measles and cancer, in which CD127 expression is decreased, IL-7 activity is impaired and IL-4 concentrations are elevated. PMID- 20201041 TI - Isolation of intact genomic DNA from FOXP3-sorted human regulatory T cells for epigenetic analyses. PMID- 20201044 TI - Separation of alpha- from beta-arylalanines by nickel nitrilotriacetate chromatography. AB - A method is described to separate alpha- from beta-arylalanines by ligand exchange chromatography on a nickel nitrilotriacetate agarose column with UV monitoring of the effluent. Separate mixtures containing an alpha- and beta arylalanine pair (1 mg of each) were individually loaded onto the nickel resin pre-equilibrated with the mobile phase at room temperature, and the amino acids were eluted from the column with a gradient from pH 12.0-8.0. The beta arylalanines eluted first, followed by the alpha-isomers. The four alpha/beta amino acid pairs tested were well separated with baseline resolution. An aliquot of each fraction was chemically treated to derivatize the amino acids to their N acyl methyl ester analogs, and their identities were confirmed by GC/MS analysis. The sample recovery was quantitative (>98%), and the column matrix was very resilient, as demonstrated by consistent separation of the solutes after approximately 100 preparative cycles. PMID- 20201045 TI - Retention behavior of estrogen metabolites on hydrophilic interaction chromatography stationary phases. AB - Estrogens and estrogen metabolites are important biological mediators of the endocrine system. They have also been implicated in detrimental carcinogenesis and beneficial neuroprotective processes. The retention behavior of estrogen metabolites was investigated on five polar stationary phases, used for hydrophilic interaction chromatography, and coupled with ESI-MS. Data were fit to partitioning and surface adsorption models. Retention of the compounds, especially estrogen glucuronides, on the amide- and diol-bonded stationary phases, could be best described by the surface adsorption model; however, mixed modes of retention were observed on most stationary phases. Retention time increased while the peak efficiency decreased proportional to the number of hydroxyl groups in the analytes. The effects of salt concentration and salt type were also investigated. The presence of solvated salt ions, which interact with the stationary phase and the analyte, enhanced retention of the analytes. This was believed to be due to two effects. The increased ionic strength reduced the contribution of secondary electrostatic interactions (mixed-mode effects). It also enhanced hydrogen-bonding and partitioning (hydrophilic interaction) between the analyte and the stationary phase, likely facilitated by the associated solvated salt ions. PMID- 20201042 TI - The Drosophila PRR GNBP3 assembles effector complexes involved in antifungal defenses independently of its Toll-pathway activation function. AB - The Drosophila Toll-signaling pathway controls the systemic antifungal host response. Gram-negative binding protein 3 (GNBP3), a member of the beta-glucan recognition protein family senses fungal infections and activates this pathway. A second detection system perceives the activity of proteolytic fungal virulence factors and redundantly activates Toll. GNBP3(hades) mutant flies succumb more rapidly to Candida albicans and to entomopathogenic fungal infections than WT flies, despite normal triggering of the Toll pathway via the virulence detection system. These observations suggest that GNBP3 triggers antifungal defenses that are not dependent on activation of the Toll pathway. Here, we show that GNBP3 agglutinates fungal cells. Furthermore, it can activate melanization in a Toll independent manner. Melanization is likely to be an essential defense against some fungal infections given that the entomopathogenic fungus Beauveria bassiana inhibits the activity of the main melanization enzymes, the phenol oxidases. Finally, we show that GNBP3 assembles "attack complexes", which comprise phenoloxidase and the necrotic serpin. We propose that Drosophila GNBP3 targets fungi immediately at the inception of the infection by bringing effector molecules in direct contact with the invading microorganisms. PMID- 20201043 TI - Loss of DNAM-1 contributes to CD8+ T-cell exhaustion in chronic HIV-1 infection. AB - The hallmark of chronic viral infections is a progressive exhaustion of antigen specific CD8(+) T cells that leads to persisting viral replication. It is generally believed that exhaustion is a consequence of the accumulation of multiple inhibitory receptors on CD8(+) T cells that makes them dysfunctional. Here, we show that during human chronic HIV-1 infection, a CD8(+) T-cell positive costimulatory pathway mediated by DNAX-activating molecule-1 is also disrupted. Thus, DNAX-activating molecule-1 downregulation on CD8(+) T cells aggravates the impairment of CTL effector function in chronic HIV-1 infection. PMID- 20201046 TI - Preparative separation and purification of bufadienolides from Chinese traditional medicine of ChanSu using high-speed counter-current chromatography. AB - A preparative high-speed counter-current chromatography method for isolation and purification of bufadienolides from ChanSu was developed by using a stepwise elution with two-phase solvent system composed of n-hexane/ethyl acetate/methanol/water at the ratios of 4:6:2:4 v/v, 4:6:2.5:4 v/v and 4:6:3.2:4 v/v. A total of 3.8 mg of gamabufotalin (1), 7.2 mg of arenobufagin (2), 3.4 mg of telocinobufagin (3), 5.3 mg of bufotalin (4), 8.5 mg of cinobufotalin (5) and 8 mg of bufalin (6) were obtained in one-step separation from 80 mg of the crude extract with purity of 92.7, 96.7, 87.2, 97.3, 94.9 and 99.4%, respectively. Their chemical structures were identified on the basis of (1)H-NMR and (13)C-NMR technology. PMID- 20201047 TI - Molecularly imprinted silica as a selective SPE sorbent for triazine herbicides. AB - A molecularly imprinted organically modified silica was prepared through a simple sol-gel procedure and evaluated as a specific sorbent for SPE of triazine herbicides. The material proved to be highly selective for the template molecule, atrazine, as well as for other structurally related species such as simazine and propazine. The performance of this material was shown to be comparable with commercial acrylate-based molecularly imprinted polymers. The molecularly imprinted silica was applied for the determination of trace levels of the target triazine analytes in sugar cane juice (locally called "garapa"). PMID- 20201048 TI - Comparison of HPLC enantioseparation of substituted binaphthyls on CD-, polysaccharide- and synthetic polymer-based chiral stationary phases. AB - Retention and enantioseparation behavior of ten 2,2'-disubstituted or 2,3,2' trisubstituted 1,1'-binaphthyls and 8,3'-disubstituted 1,2'-binaphthyls, which are used as catalysts in asymmetric synthesis, was investigated on eight chiral stationary phases (CSPs) based on beta-CD, polysaccharides (tris(3,5 dimethylphenylcarbamate) cellulose or amylose CSPs) and new synthetic polymers (trans-1,2-diamino-cyclohexane, trans-1,2-diphenylethylenediamine and trans-9,10 dihydro-9,10-ethanoanthracene-(11S,12S)-11,12-dicarboxylic acid CSPs). Normal-, reversed-phase and polar-organic separation modes were employed. The effect of the mobile phase composition was examined. The enantiomeric separation of binaphthyl derivatives, which possess quite similar structures, was possible in different enantioselective environments. The substituents and their positions on the binaphthyl skeleton affect their properties and, as a consequence, the separation system suitable for their enantioseparation. In general, the presence of ionizable groups on the binaphthyl skeleton, substitution with non-identical groups and a chiral axis in the 1,2' position had the greatest impact on the enantiomeric discrimination. The 8,3'-disubstituted 1,2'-binaphthyl derivatives were the most easily separated compounds in several separation systems. From all the chiral stationary phases tested, cellulose-based columns were shown to be the most convenient for enantioseparation of the studied analytes. However, the polymeric CSPs with their complementary behavior provided good enantioselective environments for some derivatives that could be hardly separated in any other chromatographic system. PMID- 20201049 TI - Development of single-drop microextraction and simultaneous derivatization followed by GC-MS for the determination of aliphatic amines in tobacco. AB - In this work, for the first time, headspace (HS) single-drop microextraction and simultaneous derivatization followed by GC-MS was developed to determine the aliphatic amines in tobacco samples. In the HS extraction procedure, the mixture of derivatization reagent and organic solvent was employed as the extraction solvent for HS single-drop microextraction and in situ derivatization of aliphatic amine in the samples. Fast extraction and simultaneous derivatization of the analytes were performed in a single step, and the obtained derivatives in the microdrop extraction solvent were analyzed by GC-MS. The optimized experiment conditions were: sample preparation temperature of 80 degrees C and time of 30 min, HS extraction solvent (the mixture of benzyl alcohol and 2,3,4,5,6 pentafluorobenzaldehyde) volume of 2.0 microL, extraction time of 90 s. With the optimal conditions, the method validations were also studied. The method has good linearity (R(2) more than 0.99), accepted precision (RSD less than 13%), good recovery (98-104%) and low limit of detection (0.11-0.97 microg/g). Finally, the proposed technique was successfully applied to the analyses of aliphatic amines in tobacco samples of seven different brands. It was further demonstrated that the proposed method offered a simple, low-cost and reliable approach to determine aliphatic amines in tobacco samples. PMID- 20201052 TI - Assessing suturing techniques using a virtual reality surgical simulator. AB - Advantages of virtual-reality simulators surgical skill assessment and training include more training time, no risk to patient, repeatable difficulty level, reliable feedback, without the resource demands, and ethical issues of animal based training. We tested this for a key subtask and showed a strong link between skill in the simulator and in reality. Suturing performance was assessed for four groups of participants, including experienced surgeons and naive subjects, on a custom-made virtual-reality simulator. Each subject tried the experiment 30 times using five different types of needles to perform a standardized suture placement task. Traditional metrics of performance as well as new metrics enabled by our system were proposed, and the data indicate difference between trained and untrained performance. In all traditional parameters such as time, number of attempts, and motion quantity, the medical surgeons outperformed the other three groups, though differences were not significant. However, motion smoothness, penetration and exit angles, tear size areas, and orientation change were statistically significant in the trained group when compared with untrained group. This suggests that these parameters can be used in virtual microsurgery training. PMID- 20201053 TI - Effects of hydrostatic pressure, agitation and CO2 stress on Phytophthora nicotianae zoospore survival. AB - BACKGROUND: Phytophthora nicotianae Breda de Haan is a common pathogen of ornamental plants in recycled irrigation systems. In a previous study, annual vinca (Catharanthus roseus Don) inoculated with zoospore suspensions using a CO(2)-pressurized sprayer had less foliage blight than plants inoculated using a hand sprayer. Here, the impact of hydrostatic pressure, agitation and aeration with CO(2) on the survival of P. nicotianae zoospores was examined. RESULTS: Exposure of zoospores to 840 kPa hydrostatic pressure for 8 min or agitation at a mixing intensity (G) of 6483 s(-1) for 4 min at 22-23 degrees C did not kill zoospores, but resulted in viable cysts. Motile and forcefully encysted zoospores of P. nicotianae were equally infectious on vinca or lupine (Lupinus polyphylus Lindl.). Bubbling CO(2) into zoospore-infested water at 110.4 mL (0.2 g) min(-1) for 5 min caused 81% reduction in the number of germinated zoospores. Pressure at 630 kPa (16.3 g CO(2)) or 70 kPa (3.85 g CO(2)) facilitated CO(2) injection and shortened the zoospore inactivation time to 30 s. When air was bubbled through the suspension, germination was similar to the control. CONCLUSIONS: Exposure to CO(2) killed P. nicotianae zoospores in water. Neither pressure nor agitation had an effect on zoospore viability or infectivity. Based on results of this study, the authors designed a recycling CO(2) water treatment system that is currently under evaluation. PMID- 20201054 TI - Effects of organic-farming-compatible insecticides on four aphid natural enemy species. AB - BACKGROUND: The toxicities of pyrethrins + rapeseed oil, pyrethrins + piperonyl butoxide (PBO), potassium salts of fatty acids and linseed oil were assessed in the laboratory on the parasitic wasp Aphidius rhopalosiphi (Destefani-Perez), the ladybird Adalia bipunctata (L.), the rove beetle Aleochara bilineata (Gyll.) and the carabid beetle Bembidion lampros (Herbst.). The methods selected were residual contact toxicity tests on inert and natural substrates. RESULTS: Both the pyrethrin products led to 100% mortality in the adult parasitic wasps and ladybird larvae on glass plates and plants. The pyrethrins + PBO formulation was toxic for B. lampros on sand and natural soil, but the pyrethrins + rapeseed oil formulation was harmless for this species. Insecticidal soaps were harmless for all these beneficial species. None of the tested products significantly affected the parasitism of the onion fly pupae by A. bilineata. CONCLUSION: The results indicated the potentially high toxicity of natural pyrethrins for beneficial arthropods. Although this toxicity needs to be confirmed in field conditions, the toxicity levels obtained in the laboratory were similar to or higher than those of several synthetic insecticides known to be toxic in the field. Insecticidal soaps could be considered as an alternative for aphid control in organic farming in terms of selectivity. PMID- 20201055 TI - Modulation of antigen expression in B-cell precursor acute lymphoblastic leukemia during induction therapy is partly transient: evidence for a drug-induced regulatory phenomenon. Results of the AIEOP-BFM-ALL-FLOW-MRD-Study Group. AB - BACKGROUND: Changes of antigen expression on residual blast cells of acute lymphoblastic leukemia (ALL) occur during induction treatment. Many markers used for phenotyping and minimal residual disease (MRD) monitoring are affected. Glucocorticoid (GC)-induced expression modulation has been causally suspected, however, subclone selection may also cause the phenomenon. METHODS: We investigated this by following the phenotypic evolution of leukemic cells with flow cytometry from diagnosis to four time points during and after GC containing chemotherapy in the 20 (of 360 consecutive) B-cell precursor patients with ALL who had persistent MRD throughout. RESULTS: The early expression changes of CD10 and CD34 were reversible after stop of GC containing chemotherapy. Modulation of CD20 and CD45 occurred mostly during the GC phase, whereas CD11a also changed later on. Blast cells at diagnosis falling into gates designed according to "shifted" phenotypes from follow-up did not form clusters and were frequently less numerous than later on. CONCLUSIONS: Our data support the idea that drug induced modulation rather than selection causes the phenomenon. The good message for MRD assessment is that modulation is transient in at least two (CD10 and CD34) of the five prominent antigens investigated and reverts to initial aberrant patterns after stop of GC therapy, whereas CD20 expression gains new aberrations exploitable for MRD detection. PMID- 20201058 TI - Acute blepharospasm and torticollis associated with an ependymoma of the lateral ventricle. PMID- 20201059 TI - Immunocytochemical studies of adhesion molecules on mouse UNK cells and their extracellular matrix ligands during mouse pregnancy. AB - Uterine natural killer (uNK) cells are the dominant lymphocytes of pregnant mammals' uterus. Studies have identified four differentiation stage of mouse uNK cells based on Dolichos biflorus lectin cytochemistry, and their distribution showed preferential domain in the uterus through out the pregnancy. This work was done to investigate the expression of alpha5, alpha6, and beta7 integrins on uNK cells and their ligands distribution. Section of mouse uterus from sixth to seventeenth gestational days were submitted to immunocytochemistry and positive reactions for alpha5, alpha6, and beta7 integrins were found on uNK from eighth to tenth gestational days but not after twelfth gestational days. Fibronectin reactions were seemed from sixth to tenth gestational days around uNK from the myometrium and endometrium close to the myometrium. No reaction for fibronectin was seen in the decidualized and nondecidualized endometrium near the placenta. Laminin reaction was seen just in the antimesometrial side. beta7 integrin seems to be the active receptor to bind with VCAM-1 or MAdCAM-1 of endothelial cells, promoting the uNK cross through the vessels. The absence of laminin in an uNK domain suggests these cells are not dependent of laminin and alpha6 integrin for their establishment. However, fibronectin seems to support uNK migration, proliferation, differentiation, and survival in the uterus by binding with alpha5 integrin. The loss of alpha5 integrin ligation by the down regulation of fibronectin could inhibits these events and further studies are need to investigate whether unligated alpha5 can actively and initiate apoptosis, maybe in a caspase 8-dependent way that has been called integrin-mediated death. PMID- 20201061 TI - Dynamic transcriptional changes of TIEG1 and TIEG2 during mouse tissue development. AB - TGF-beta-inducible early-response gene (TIEG) is a family of primary response genes induced by TGF-beta, which are well recognized in regulating cellular proliferation and apoptosis. However, their expression profile has never been investigated during embryogenesis in different organs. In this study, we aimed to investigate the transcriptional level of both TIEG1 and TIEG2 during development in various mice organs, including the brain cortex, cerebellum and stem, brain striatum, muscle, heart, liver, kidney, and lung. Quantitative real-time PCR was used to profile the change of transcriptional level of the two TIEG members in the mice tissues at six developmental stages. Taken together, the expression of TIEG1 and TIEG2 was specific in different organs yet varied with different developmental time points. Their dynamic changes were moderately consistent in most organs including the brain cortex, striatum, liver, kidney, and lung. However, their mRNA expression in both the heart and muscle was significantly different at all developmental stages, which might propose a compensation of functions in the TIEG family. Nevertheless, our data indicate that both the TIEG genes are essential in regulating the normal organ development and functioning in murine model, as their expressions were ubiquitous and tissue specific at various developmental stages. PMID- 20201062 TI - Nuclear transfer-derived epiblast stem cells are transcriptionally and epigenetically distinguishable from their fertilized-derived counterparts. AB - Mouse embryonic pluripotent stem cells can be obtained from the inner cell mass at the blastocyst stage (embryonic stem cells, ESCs) or from the late epiblast of postimplantation embryos (epiblast stem cells, EpiSCs). During normal development, the transition between these two stages is marked by major epigenetic and transcriptional changes including DNA de novo methylation. These modifications represent an epigenetic mark conserved in ESCs and EpiSCs. Pluripotent ESCs derived from blastocysts generated by nuclear transfer (NT) have been shown to be correctly reprogrammed. However, NT embryos frequently undergo abnormal development. In the present study, we have examined whether pluripotent cells could be derived from the epiblast of postimplantation NT embryos and whether the reprogramming process would affect the epigenetic changes occurring at this stage, which could explain abnormal development of NT embryos. We showed that EpiSCs could be derived with the same efficiency from NT embryos and from their fertilized counterparts. However, gene expression profile analyses showed divergence between fertilized- and nuclear transfer-EpiSCs with a surprising bias in the distribution of the differentially expressed genes, 30% of them being localized on chromosome 11. A majority of these genes were downregulated in NT EpiSCs and imprinted genes represented a significant fraction of them. Notably, analysis of the epigenetic status of a downregulated imprinted gene in NT-EpiSCs revealed complete methylation of the two alleles. Therefore, EpiSCs derived from NT embryos appear to be incorrectly reprogrammed, indicating that abnormal epigenetic marks are imposed on cells in NT embryos during the transition from early to late epiblast. PMID- 20201060 TI - Architectonic subdivisions of neocortex in the Galago (Otolemur garnetti). AB - In the present study, galago brains were sectioned in the coronal, sagittal, or horizontal planes, and sections were processed with several different histochemical and immunohistochemical procedures to reveal the architectonic characteristics of the various cortical areas. The histochemical methods used included the traditional Nissl, cytochrome oxidase, and myelin stains, as well as a zinc stain, which reveals free ionic zinc in the axon terminals of neurons. Immunohistochemical methods include parvalbumin (PV) and calbindin (CB), both calcium-binding proteins, and the vesicle glutamate transporter 2 (VGluT2). These different procedures revealed similar boundaries between areas, which suggests that functionally relevant borders were being detected. These results allowed a more precise demarcation of previously identified areas. As thalamocortical terminations lack free ionic zinc, primary cortical areas were most clearly revealed by the zinc stain, because of the poor zinc staining of layer 4. Area 17 was especially prominent, as the broad layer 4 was nearly free of zinc stain. However, this feature was less pronounced in the primary auditory and somatosensory cortex. As VGluT2 is expressed in thalamocortical terminations, layer 4 of primary sensory areas was darkly stained for VGluT2. Primary motor cortex had reduced VGluT2 staining, and increased zinc-enriched terminations in the poorly developed granular layer 4 compared to the adjacent primary somatosensory area. The middle temporal visual (MT) showed increased PV and VGluT2 staining compared to the surrounding cortical areas. The resulting architectonic maps of cortical areas in galagos can usefully guide future studies of cortical organizations and functions. PMID- 20201063 TI - Bone marrow-derived mesenchymal stem cells prevent the loss of Niemann-Pick type C mouse Purkinje neurons by correcting sphingolipid metabolism and increasing sphingosine-1-phosphate. AB - Niemann-Pick type C (NP-C) disease exhibits neuronal sphingolipid storage and cerebellar Purkinje neuron (PN) loss. Although it is clear that PNs are compromised in this disorder, it remains to be defined how neuronal lipid storage causes the PN loss. Our previous studies have shown that bone marrow-derived mesenchymal stem cells (BM-MSCs) transplantation prevent PN loss in NP-C mice. The aim of the present study was therefore to examine the neuroprotective mechanism of BM-MSCs on PNs. We found that NP-C PNs exhibit abnormal sphingolipid metabolism and defective lysosomal calcium store compared to wild-type mice PNs. BM-MSCs promote the survival of NP-C PNs by correction of the altered calcium homeostasis, restoration of the sphingolipid imbalance, as evidenced by increased sphingosine-1-phosphate levels and decreased sphingosine, and ultimately, inhibition of apoptosis pathways. These effects suggest that BM-MSCs modulate sphingolipid metabolism of endogenous NP-C PNs, resulting in their survival and improved clinical outcome in mice. PMID- 20201064 TI - Butyrate greatly enhances derivation of human induced pluripotent stem cells by promoting epigenetic remodeling and the expression of pluripotency-associated genes. AB - We report here that butyrate, a naturally occurring fatty acid commonly used as a nutritional supplement and differentiation agent, greatly enhances the efficiency of induced pluripotent stem (iPS) cell derivation from human adult or fetal fibroblasts. After transient butyrate treatment, the iPS cell derivation efficiency is enhanced by 15- to 51-fold using either retroviral or piggyBac transposon vectors expressing 4 to 5 reprogramming genes. Butyrate stimulation is more remarkable (>100- to 200-fold) on reprogramming in the absence of either KLF4 or MYC transgene. Butyrate treatment did not negatively affect properties of iPS cell lines established by either 3 or 4 retroviral vectors or a single piggyBac DNA transposon vector. These characterized iPS cell lines, including those derived from an adult patient with sickle cell disease by either the piggyBac or retroviral vectors, show normal karyotypes and pluripotency. To gain insights into the underlying mechanisms of butyrate stimulation, we conducted genome-wide gene expression and promoter DNA methylation microarrays and other epigenetic analyses on established iPS cells and cells from intermediate stages of the reprogramming process. By days 6 to 12 during reprogramming, butyrate treatment enhanced histone H3 acetylation, promoter DNA demethylation, and the expression of endogenous pluripotency-associated genes, including DPPA2, whose overexpression partially substitutes for butyrate stimulation. Thus, butyrate as a cell permeable small molecule provides a simple tool to further investigate molecular mechanisms of cellular reprogramming. Moreover, butyrate stimulation provides an efficient method for reprogramming various human adult somatic cells, including cells from patients that are more refractory to reprogramming. PMID- 20201065 TI - Epidermal growth factor and perlecan fragments produced by apoptotic endothelial cells co-ordinately activate ERK1/2-dependent antiapoptotic pathways in mesenchymal stem cells. AB - Mounting evidence indicates that mesenchymal stem cells (MSC) are pivotal to vascular repair and neointima formation in various forms of vascular disease. Yet, the mechanisms that allow MSC to resist apoptosis at sites where other cell types, such as endothelial cells (EC), are dying are not well defined. In the present work, we demonstrate that apoptotic EC actively release paracrine mediators which, in turn, inhibit apoptosis of MSC. Serum-free medium conditioned by apoptotic EC increases extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation and inhibits apoptosis (evaluated by Bcl-xL protein levels and poly (ADP-ribose) polymerase cleavage) of human MSC. A C-terminal fragment of perlecan (LG3) released by apoptotic EC is one of the mediators activating this antiapoptotic response in MSC. LG3 interacts with beta1-integrins, which triggers downstream ERK1/2 activation in MSC, albeit to a lesser degree than medium conditioned by apoptotic EC. Hence, other mediators released by apoptotic EC are probably required for induction of the full antiapoptotic phenotype in MSC. Adopting a comparative proteomic strategy, we identified epidermal growth factor (EGF) as a novel mediator of the paracrine component of the endothelial apoptotic program. LG3 and EGF cooperate in triggering beta1-integrin and EGF receptor dependent antiapoptotic signals in MSC centering on ERK1/2 activation. The present work, providing novel insights into the mechanisms facilitating the survival of MSC in a hostile environment, identifies EGF and LG3 released by apoptotic EC as central antiapoptotic mediators involved in this paracrine response. PMID- 20201066 TI - The senescence-related mitochondrial/oxidative stress pathway is repressed in human induced pluripotent stem cells. AB - The ability of stem cells to propagate indefinitely is believed to occur via the fine modulation of pathways commonly involved in cellular senescence, including the telomerase, the p53, and the mitochondrial/oxidative stress pathways. Induced pluripotent stem cells (iPSCs) are a novel stem cell population obtained from somatic cells through forced expression of a set of genes normally expressed in embryonic stem cells (ESCs). These reprogrammed cells acquire self-renewal properties and appear almost undistinguishable from ESCs in terms of morphology, gene expression, and differentiation potential. Accordingly, iPSCs exhibit alterations of the senescence-related telomerase and p53 signaling pathways. However, although treatments with antioxidants have been recently shown to enhance cellular reprogramming, detailed information regarding the state of the mitochondrial/oxidative stress pathway in iPSCs is still lacking. Mitochondria undergo specific changes during organismal development and aging. Thus, addressing whether somatic mitochondria within iPSCs acquire ESC-like features or retain the phenotype of the parental cell is an unanswered but relevant question. Herein, we demonstrate that somatic mitochondria within human iPSCs revert to an immature ESC-like state with respect to organelle morphology and distribution, expression of nuclear factors involved in mitochondrial biogenesis, content of mitochondrial DNA, intracellular ATP level, oxidative damage, and lactate generation. Upon differentiation, mitochondria within iPSCs and ESCs exhibited analogous maturation and anaerobic-to-aerobic metabolic modifications. Overall, the data highlight that human iPSCs and ESCs, although not identical, share similar mitochondrial properties and suggest that cellular reprogramming can modulate the mitochondrial/oxidative stress pathway, thus inducing a rejuvenated state capable of escaping cellular senescence. PMID- 20201067 TI - Thermodynamic resolution: how do errors in modeled protein structures affect binding affinity predictions? AB - The present study addresses the effect of structural distortion, caused by protein modeling errors, on calculated binding affinities toward small molecules. The binding affinities to a total of 300 distorted structures based on five different protein-ligand complexes were evaluated to establish a broadly applicable relationship between errors in protein structure and errors in calculated binding affinities. Relatively accurate protein models (less than 2 A RMSD within the binding site) demonstrate a 14.78 (+/-7.5)% deviation in binding affinity from that calculated by using the corresponding crystal structure. For structures of 2-3 A, 3-4 A, and >4 A RMSD within the binding site, the error in calculated binding affinity increases to 20.8 (+/-5.98), 22.79 (+/-11.3), and 29.43 (+/-11.47)%, respectively. The results described here may be used in combination with other tools to evaluate the utility of modeled protein structures for drug development or other ligand-binding studies. PMID- 20201069 TI - Scientist honored for role in discovering telomerase. PMID- 20201073 TI - T-loop phosphorylated Cdk9 localizes to nuclear speckle domains which may serve as sites of active P-TEFb function and exchange between the Brd4 and 7SK/HEXIM1 regulatory complexes. AB - P-TEFb functions to induce the elongation step of RNA polymerase II transcription by phosphorylating the carboxyl-terminal domain of the largest subunit of RNA polymerase II. Core P-TEFb is comprised of Cdk9 and a cyclin regulatory subunit, with Cyclin T1 being the predominant Cdk9-associated cyclin. The kinase activity of P-TEFb is dependent on phosphorylation of the Thr186 residue located within the T-loop domain of the Cdk9 subunit. Here, we used immunofluorescence deconvolution microscopy to examine the subcellular distribution of phospho Thr186 Cdk9/Cyclin T1 P-TEFb heterodimers. We found that phospho-Thr186 Cdk9 displays a punctate distribution throughout the non-nucleolar nucleoplasm and it co-localizes with Cyclin T1 almost exclusively within nuclear speckle domains. Phospho-Thr186 Cdk9 predominantly co-localized with the hyperphosphorylated forms of RNA polymerase II. Transient expression of kinase-defective Cdk9 mutants revealed that neither is Thr186 phosphorylation or kinase activity required for Cdk9 speckle localization. Lastly, both the Brd4 and HEXIM1 proteins interact with P-TEFb at or very near speckle domains and treatment of cells with the Cdk9 inhibitor flavopiridol alters this distribution. These results indicate that the active form of P-TEFb resides in nuclear speckles and raises the possibility that speckles are sites of P-TEFb function and exchange between negative and positive P-TEFb regulatory complexes. PMID- 20201074 TI - The proinflammatory activity of recombinant serum amyloid A is not shared by the endogenous protein in the circulation. AB - OBJECTIVE: Elevated serum levels of the acute-phase protein serum amyloid A (SAA) are a marker for active rheumatoid arthritis (RA), and SAA can also be found in the tissues of patients with active RA. Based on a number of studies with recombinant SAA (rSAA), the protein has been suggested to be a potent proinflammatory mediator that activates human neutrophils, but whether endogenous SAA shares these proinflammatory activities has not been directly addressed. The present study was undertaken to investigate whether SAA in the plasma of patients with RA possesses proinflammatory properties and activates neutrophils in a manner similar to that of the recombinant protein. METHODS: Neutrophil activation was monitored by flow cytometry, based on L-selectin shedding from cell surfaces. Whole blood samples from healthy subjects and from RA patients with highly elevated SAA levels were studied before and after stimulation with rSAA as well as purified endogenous SAA. RESULTS: Recombinant SAA potently induced cleavage of L-selectin from neutrophils and in whole blood samples. Despite highly elevated SAA levels, L-selectin was not down-regulated on RA patient neutrophils as compared with neutrophils from healthy controls. Spiking SAA-rich whole blood samples from RA patients with rSAA, however, resulted in L-selectin shedding. In addition, SAA purified from human plasma was completely devoid of neutrophil- or macrophage-activating capacity. CONCLUSION: The present findings show that rSAA is proinflammatory but that this activity is not shared by endogenous SAA, either when present in the circulation of RA patients or when purified from plasma during an acute-phase response. PMID- 20201075 TI - META060 inhibits osteoclastogenesis and matrix metalloproteinases in vitro and reduces bone and cartilage degradation in a mouse model of rheumatoid arthritis. AB - OBJECTIVE: The multikinase inhibitor META060 has been shown to inhibit NF-kappaB activation and expression of markers of inflammation. This study was undertaken to investigate the effect of META060 on biomarkers associated with bone and cartilage degradation in vitro and its antiinflammatory efficacy in vivo in both acute and chronic inflammation models. METHODS: Glycogen synthase kinase 3beta (GSK3beta)-dependent beta-catenin phosphorylation was evaluated in RAW 264.7 macrophages to assess kinase inhibition. The inhibition of osteoclastogenesis and tartrate-resistant acid phosphatase (TRAP) activity was evaluated in RANKL treated RAW 264.7 cells. The inhibition of interleukin-1beta (IL-1beta)-mediated markers of inflammation was analyzed in human rheumatoid arthritis synovial fibroblasts (RASFs). Mice with carrageenan-induced acute inflammation and collagen-induced arthritis (CIA) were used to assess efficacy. RESULTS: META060 inhibited the activity of kinases (spleen tyrosine kinase [Syk], Bruton's tyrosine kinase [Btk], phosphatidylinositol 3-kinase [PI 3-kinase], and GSK3) associated with RA and inhibited beta-catenin phosphorylation. META060 inhibited osteoclastogenesis, as indicated by decreased transformation of RAW 264.7 cells to osteoclasts and reduced TRAP activity, and inhibited IL-1beta-activated prostaglandin E(2), matrix metalloproteinase 3, IL-6, IL-8, and monocyte chemotactic protein 1 in RASFs. In mice with acute inflammation, oral administration of META060 reduced paw swelling similar to the effect of aspirin. In mice with CIA, META060 significantly reduced the arthritis index and decreased bone, joint, and cartilage degradation. Serum IL-6 concentrations in these mice were inhibited in a dose-dependent manner. CONCLUSION: Our findings indicate that META060 reduces swelling in a model of acute inflammation and inhibits bone and cartilage destruction in a model of chronic inflammation. Its efficacy is associated with the inhibition of multiple protein kinases, including Syk, Btk, PI 3-kinase, and GSK3. These results warrant further clinical testing of META060 for its therapeutic potential in the treatment of inflammatory diseases. PMID- 20201077 TI - MicroRNA-29, a key regulator of collagen expression in systemic sclerosis. AB - OBJECTIVE: To investigate the role of microRNA (miRNA) as posttranscriptional regulators of profibrotic genes in systemic sclerosis (SSc). METHODS: MicroRNA, which target collagens, were identified by in silico analysis. Expression of miRNA-29 (miR-29) was determined by TaqMan real-time polymerase chain reaction analysis of skin biopsy and fibroblast samples from SSc patients and healthy controls as well as in the mouse model of bleomycin-induced skin fibrosis. Cells were transfected with precursor miRNA (pre-miRNA)/anti-miRNA of miR-29 using Lipofectamine. Collagen gene expression was also studied in luciferase reporter gene assays. For stimulation, recombinant transforming growth factor beta (TGFbeta), platelet-derived growth factor B (PDGF-B), or interleukin-4 (IL-4) was used. The effects of inhibiting PDGF-B and TGFbeta signaling on the levels of miR 29 were studied in vitro and in the bleomycin model. RESULTS: We found that miR 29a was strongly down-regulated in SSc fibroblasts and skin sections as compared with the healthy controls. Overexpression in SSc fibroblasts significantly decreased, and accordingly, knockdown in normal fibroblasts increased, the levels of messenger RNA and protein for type I and type III collagen. In the reporter gene assay, cotransfection with pre-miR-29a significantly decreased the relative luciferase activity, which suggests a direct regulation of collagen by miR-29a. TGFbeta, PDGF-B, or IL-4 reduced the levels of miR-29a in normal fibroblasts to those seen in SSc fibroblasts. Similar to human SSc, the expression of miR-29a was reduced in the bleomycin model of skin fibrosis. Inhibition of PDGF-B and TGFbeta pathways by treatment with imatinib restored the levels of miR-29a in vitro and in the bleomycin model in vivo. CONCLUSION: These data add the posttranscriptional regulation of collagens by miR-29a as a novel aspect to the fibrogenesis of SSc and suggest miR-29a as a potential therapeutic target. PMID- 20201078 TI - Effect of oleocanthal and its derivatives on inflammatory response induced by lipopolysaccharide in a murine chondrocyte cell line. AB - OBJECTIVE: In joint diseases, cartilage homeostasis is disrupted by mechanisms that are driven by combinations of biologic factors that vary according to the disease process. In osteoarthritis (OA), biomechanical stimuli predominate, with up-regulation of both catabolic and anabolic factors. Likewise, OA progression is characterized by increased nitric oxide (NO) production, which has been associated with cartilage degradation. Given the relevance of cartilage degenerative diseases in our society, the development of a novel pharmacologic intervention is a critically important public health goal. Recently, oleocanthal isolated from extra virgin olive oil was found to display nonsteroidal antiinflammatory drug activity similar to that of ibuprofen, a drug widely used in the therapeutic management of joint inflammatory diseases. We undertook this study to evaluate the effect of oleocanthal and its derivatives on the modulation of NO production in chondrocytes. METHODS: Cultured ATDC-5 chondrocytes were tested with different doses of oleocanthal and its derivatives. Cell viability was evaluated using the MTT assay. Nitrite accumulation was determined in culture supernatant using the Griess reaction. Inducible NO synthase (NOS2) protein expression was examined using Western blotting analysis. RESULTS: Oleocanthal and its derivatives decreased lipopolysaccharide-induced NOS2 synthesis in chondrocytes without significantly affecting cell viability at lower concentrations. Among the derivatives we examined, derivative 231 was the most interesting, since its inhibitory effect on NOS2 was devoid of cytotoxicity even at higher concentrations. CONCLUSION: This class of molecules shows potential as a therapeutic weapon for the treatment of inflammatory degenerative joint diseases. PMID- 20201076 TI - Markers of oxidative and nitrosative stress in systemic lupus erythematosus: correlation with disease activity. AB - OBJECTIVE: Free radical-mediated reactions have been implicated as contributors in a number of autoimmune diseases, including systemic lupus erythematosus (SLE). However, the potential for oxidative/nitrosative stress to elicit an autoimmune response or to contribute to disease pathogenesis, and thus be useful when determining a prognosis, remains largely unexplored in humans. This study was undertaken to investigate the status and contribution of oxidative/nitrosative stress in patients with SLE. METHODS: Sera from 72 SLE patients with varying levels of disease activity according to the SLE Disease Activity Index (SLEDAI) and 36 age- and sex-matched healthy controls were evaluated for serum levels of oxidative/nitrosative stress markers, including antibodies to malondialdehyde (anti-MDA) protein adducts and to 4-hydroxynonenal (anti-HNE) protein adducts, MDA/HNE protein adducts, superoxide dismutase (SOD), nitrotyrosine (NT), and inducible nitric oxide synthase (iNOS). RESULTS: Serum analysis showed significantly higher levels of both anti-MDA/anti-HNE protein adduct antibodies and MDA/HNE protein adducts in SLE patients compared with healthy controls. Interestingly, not only was there an increased number of subjects positive for anti-MDA or anti-HNE antibodies, but also the levels of both of these antibodies were statistically significantly higher among SLE patients whose SLEDAI scores were > or = 6 as compared with SLE patients with lower SLEDAI scores (SLEDAI score <6). In addition, a significant correlation was observed between the levels of anti-MDA or anti-HNE antibodies and the SLEDAI score (r = 0.734 and r = 0.647, respectively), suggesting a possible causal relationship between these antibodies and SLE. Furthermore, sera from SLE patients had lower levels of SOD and higher levels of iNOS and NT compared with healthy control sera. CONCLUSION: These findings support an association between oxidative/nitrosative stress and SLE. The stronger response observed in serum samples from patients with higher SLEDAI scores suggests that markers of oxidative/nitrosative stress may be useful in evaluating the progression of SLE and in elucidating the mechanisms of disease pathogenesis. PMID- 20201079 TI - Genetic deficiency of Syk protects mice from autoantibody-induced arthritis. AB - OBJECTIVE: The Syk tyrosine kinase plays an important role in diverse functions in hematopoietic lineage cells. Although previous in vitro and pharmacologic analyses suggested Syk to be a possible player in the development of autoimmune arthritis, no in vivo genetic studies addressing that issue have yet been reported. The aim of the present study was to test whether genetic deficiency of Syk affects autoantibody-induced experimental arthritis in the K/BxN serum transfer model. METHODS: Syk(-/-) bone marrow chimeras carrying a Syk-deficient hematopoietic system were generated by transplanting Syk(-/-) fetal liver cells into lethally irradiated wild-type recipients. After complete repopulation of the hematopoietic compartment, autoantibody-mediated arthritis was induced by injection of arthritogenic K/BxN serum. Arthritis development was monitored by macroscopic and microscopic observation of the ankle joints, micro-computed tomography of bone morphology, as well as a joint function assay. RESULTS: Genetic deficiency of Syk in the hematopoietic compartment completely blocked the development of all macroscopic and microscopic signs of arthritis. The Syk(-/-) mutation also prevented the appearance of periarticular bone erosions. Finally, Syk(-/-) bone marrow chimeras were completely protected from arthritis-induced loss of articular function. CONCLUSION: Our results indicate that Syk is critically involved in the development of all clinically relevant aspects of autoantibody-mediated K/BxN serum-transfer arthritis in experimental mice. These results provide the first in vivo genetic evidence of the role of Syk in the development of autoimmune arthritis. PMID- 20201080 TI - Autocitrullination of human peptidyl arginine deiminase type 4 regulates protein citrullination during cell activation. AB - OBJECTIVE: To address mechanisms that control the activity of human peptidyl arginine deiminase type 4 (PAD-4). METHODS: PAD-4 autocitrullination was determined by anti-modified citrulline immunoblotting, using purified recombinant and endogenous PAD-4 from activated human primary neutrophils and cell lines expressing PAD-4. The citrullination sites in PAD-4 were determined by mass spectrometry. Mechanisms of autocitrullination-induced inactivation and the functional consequences of autocitrullination in PAD-4 polymorphic variants were addressed using purified components and cell lines expressing PAD-4 wild-type, PAD-4 mutant, and PAD-4 polymorphic variants relevant to rheumatoid arthritis (RA). RESULTS: PAD-4 is autocitrullinated in vitro and during activation of primary cells and cell lines expressing PAD-4. Interestingly, this modification inactivated the function of the enzyme. The efficiency of inactivation differed among genetically defined PAD-4 variants relevant to RA. PAD-4 was citrullinated at 10 sites, which are clustered into 3 distinct regions, including a cluster of arginines around the active site cleft where Arg-372 and -374 were identified as the potential autocitrullination targets that inactivate the enzyme. Autocitrullination also modified the structure of PAD-4, abrogating its recognition by multiple rabbit antibodies, but augmenting its recognition by human anti-PAD-4 autoantibodies. CONCLUSION: Our findings suggest that autocitrullination regulates the production of citrullinated proteins during cell activation, and that this is affected by structural polymorphisms in PAD-4. Autocitrullination also influences PAD-4 structure and immune response. PMID- 20201081 TI - Schistocytes in megaloblastic anemia. PMID- 20201082 TI - Neutrophil dysplasia induced by granulocyte colony-stimulating factor. PMID- 20201087 TI - Moving toward hematological predictors of disease severity in malaria: going with the flow. PMID- 20201088 TI - Dose-intensified treatment of Burkitt lymphoma and B-cell lymphoma unclassifiable, (with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma) in young adults (<50 years): a comparison of two adapted BFM protocols. AB - The chemotherapy dose-intensity in two adapted German BFM paediatric protocols (BFM 90 and NHL 86) was compared in contemporaneously treated adults <50 years with Burkitt lymphoma and B-cell lymphoma unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (collectively referred to as BL). In BFM 90, primary prophylaxis with Granulocyte colony-stimulating factor was used, postinduction treatment was started at granulocytes > or =0.5 x 10(9)/L (> or =1.0 x 10(9)/L in NHL 86) with a higher mean methotrexate dose (2.9 g/m(2)/cycle, n = 23; 1.6 g/m(2)/cycle in NHL 86, n = 22, P < 0.001). Intervals between consecutive treatment-cycles were shorter in BFM 90 (P < 0.001) with no additional toxicity. However, the two-year failure free survival with BFM 90 (82%) was similar to that achieved with NHL 86 (72%, P = 0.33). We conclude that BFM 90 enables safe intensification of therapy in young adults with BL compared to NHL 86, but registry-based studies are required to further evaluate the antineoplastic effects and cost-effectiveness of the two therapeutic approaches. PMID- 20201089 TI - FDA report: Ferumoxytol for intravenous iron therapy in adult patients with chronic kidney disease. AB - On June 30, 2009, the United States Food and Drug Administration (FDA) approved ferumoxytol (Feraheme injection, AMAG Pharmaceuticals), an iron-containing product for intravenous (IV) administration, for the treatment of iron deficiency anemia in adult patients with chronic kidney disease (CKD). The safety and efficacy of ferumoxytol were assessed in three randomized, open-label, controlled clinical trials. Two trials evaluated patients with nondialysis dependent CKD and a third trial assessed patients undergoing hemodialysis. Randomization was either to ferumoxytol or oral iron. Ferumoxytol was administered as two 510 mg IV injections, separated by 3-8 days. Oral iron, Ferro-Sequels, was administered at a dose of 100 mg twice daily for 21 days. In all three clinical trials, ferumoxytol administration increased the mean blood hemoglobin (Hgb) concentrations by approximately 1.0 g/dL over the 35 day period, a mean increase that was greater than what was observed in patients receiving oral iron. Patients receiving ferumoxytol also had increases in blood transferrin saturation (TSAT) and ferritin values. For the proposed ferumoxytol dosing regimen, 4.9% of patients had serum ferritin >or=800 ng/mL and TSAT >or=50% post-treatment. The most important ferumoxytol safety concerns were hypersensitivity reactions and/or hypotension. Anaphylaxis or anaphylactoid reactions were reported in 0.2% of subjects, and other adverse reactions potentially associated with hypersensitivity (e.g., pruritus, rash, urticaria, or wheezing) were reported in 3.7%. Hypotension was observed in 1.9%, including three patients with serious hypotensive reactions. Ferumoxytol administration may transiently affect the diagnostic ability of magnetic resonance imaging and the drug label provides further information regarding this effect. PMID- 20201096 TI - Therapeutic use of human alpha-fetoprotein in clinical patients: is a cancer risk involved? PMID- 20201099 TI - Cellular and molecular mechanisms involved in hepatocellular carcinoma gender disparity. AB - Hepatocellular carcinoma (HCC) represents the most common primary liver cancer and one of the most fatal human cancers. Besides alcoholic liver disease as well as genetic and environmental factors, hepatitis B and C viral infections also represent the most important risk factors for onset and development of the disease. In fact, HCC worldwide prevalence varies widely and mirrors the geographical distribution of chronic viral hepatitis. Interestingly, a gender difference was described for this disease: in almost all populations, a male/female ratio averaging between 2:1 and 4:1 was reported. Here, we analyze the implication of cytokines and sex hormones in this issue. Exploiting the emerging knowledge on the possible differential role of hepatitis viruses B and C, we discuss the role of reactive oxygen species and apoptosis dysregulation in the characterization of the molecular mechanisms of gender disparity in the development of HCC. PMID- 20201101 TI - Comparison of two nitroxide labile esters for delivering electron paramagnetic resonance probes into mouse brain. AB - In vivo quantitation of O(2) in brain has been hindered by a lack of suitable imaging modalities. Development of low-frequency electron paramagnetic resonance (EPR) spectrometers that can detect free radicals in animals in real time makes it feasible to image paramagnetic oximetry probes such as nitroxides in brain tissue. We have shown that masking the carboxyl group of 3-carboxy-2,2,5,5 tetramethyl-1-pyrrolidinyloxyl (nitroxide 1) as an esterase-labile acetoxymethyl ester yields 3-acetoxymethoxycarbonyl-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl (nitroxide 2). Nitroxide 2 can cross the blood-brain barrier and is then hydrolyzed in situ by esterases to regenerate nitroxide 1, which becomes entrapped in brain tissue. Seeking to improve the loading of nitroxides into brain, we synthesized the more lipophilic pentanoyloxymethyl ester, 3 pentanoyloxymethoxycarbonyl-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl (nitroxide 3). We report that the higher lipophilicity of nitroxide 3 does not significantly increase its ability to generate EPR signals in the mouse brain. Therefore, irrespective of whether nitroxide 2 or 3 was injected, similar levels of nitroxide were entrapped in brain tissue. These findings suggest that nitroxides 2 and 3 perform comparably well as proimaging agents for measuring O(2) distribution in brain. PMID- 20201102 TI - Carotid artery stenting in high surgical risk patients using the FiberNet embolic protection system: the EPIC trial results. AB - OBJECTIVE: The multicenter EPIC (FiberNet Embolic Protection System in Carotid Artery Stenting Trial) single-arm trial evaluated the 30-day outcomes of a new design concept for embolic protection during carotid artery stenting (CAS). BACKGROUND: Embolic protection filters available for use during CAS include fixed and over-the-wire systems that rely on embolic material capture within a "basket" structure. The FiberNet Embolic Protection System (EPS), which features a very low crossing profile, consists of a three-dimensional fiber-based filter distally mounted on a 0.014 inch guidewire with integrated aspiration during filter retrieval. METHODS: The trial enrolled 237 patients from 26 centers. Demographics, clinical and lesion characteristics, as well as adverse events through a 30-day follow-up were recorded. The mean age of the patients was 74 years, 64% were male and 20% had symptomatic carotid artery disease. RESULTS: The combined major adverse event (MAE) rate at 30 days for all death, stroke, and myocardial infarction was 3.0%. There were three major strokes (two ischemic and one hemorrhagic) and two minor strokes (both ischemic) for a 2.1% 30-day stroke rate. The procedural technical success rate was 97.5% and macroscopic evidence of debris was reported in 90.9% of the procedures. CONCLUSIONS: The FiberNet EPS, used with commercially available stents, produced low stroke rates following CAS in high surgical risk patients presenting with carotid artery disease. The unique filter design including aspiration during retrieval may have contributed to the low 30-day stroke rate reported during CAS in patients considered at high risk for complications following carotid endarterectomy (CEA). PMID- 20201104 TI - Differential time course of FSH/FSH receptor complex endocytosis within sertoli and germ cells during rat testis development. AB - Follicle-stimulating hormone (FSH) is required for initiation and maintenance of spermatogenesis, a dynamic process of cell proliferation and maturation. By using FSH-gold particles and pulse-chase experiments, we analyzed the kinetics of FSH endocytosis in Sertoli and germ cells during development. Ultrastructural time dependent analysis demonstrates that FSH was first located on plasma membrane, before being accumulated within the endosomal compartment, in the early endosomes, identified by morphological criteria and Rab-5 colocalization. Thereafter, FSH-gold was routed to the degradation pathway. The FSH endocytosis kinetic was similar in Sertoli cells, spermatogonia and spermatocytes. However, quantitative analysis of gold particles revealed differences in the dynamic of FSH accumulation in the endosomes between immature and mature rats. This age dependent kinetic of FSH endocytosis, mostly detectable by ultrastructural analysis associated with quantitative data, argues for a potential new regulatory mechanism of the FSH signalling pathway that could occur during maturation of testicular cells. PMID- 20201103 TI - Notch and delta mRNAs in early-stage and mid-stage drosophila embryos exhibit complementary patterns of protein-producing potentials. AB - Notch and Delta proteins generate Notch signaling that specifies cell fates during animal development. There is an intriguing phenomenon in Drosophila embryogenesis that has not received much attention and whose significance to embryogenesis is unknown. Notch and Delta mRNAs expressed in early-stage embryos are shorter than their counterparts in mid-stage embryos. We show here that the difference in sizes is due to mRNA 3' processing at alternate polyadenylation sites. While the early-stage Notch mRNA has a lower protein-producing potential than the mid-stage Notch mRNA, the early-stage Delta mRNA has a higher protein producing potential than the mid-stage Delta mRNA. Our data can explain the complementary patterns of Notch and Delta protein levels in early- and mid-stage embryos. Our data also raise the possibility that the manner and regulation of Notch signaling change in the course of embryogenesis and that this change is effected by 3' UTR and mRNA 3' processing factors. PMID- 20201105 TI - Long-term consequences of Sox9 depletion on inner ear development. AB - The transcription factor Sox9 has been implicated in inner ear formation in several species. To investigate the long-term consequences of Sox9 depletion on inner ear development we analyzed the inner ear architecture of Sox9-depleted Xenopus tadpoles generated by injection of increasing amounts of Sox9 morpholino antisense oligonucleotides. We found that Sox9-depletion resulted in major defects in the development of vestibular structures, semicircular canals and utricle, while the ventrally located saccule was less severely affected in these embryos. Consistent with this phenotype, we observed a specific loss of the dorsal expression of Wnt3a expression in the otic vesicle of Sox9 morphants, associated with an increase in cell death and a reduction in cell proliferation in the region of the presumptive otic epithelium. We propose that, in addition to its early role in placode specification, Sox9 is also required for the maintenance of progenitors in the otic epithelium. PMID- 20201106 TI - Identification of a distant cis-regulatory element controlling pharyngeal arch specific expression of zebrafish gdf6a/radar. AB - Skeletal formation is an essential and intricately regulated part of vertebrate development. Humans and mice deficient in growth and differentiation factor 6 (Gdf6) have numerous skeletal abnormalities, including joint fusions and cartilage reductions. The expression of Gdf6 is dynamic and in part regulated by distant evolutionarily conserved cis-regulatory elements. radar/gdf6a is a zebrafish ortholog of Gdf6 and has an essential role in embryonic patterning. Here, we show that radar is transcribed in the cells surrounding and between the developing cartilages of the ventral pharyngeal arches, similar to mouse Gdf6. A 312 bp evolutionarily conserved region (ECR5), 122 kilobases downstream, drives expression in a pharyngeal arch-specific manner similar to endogenous radar/gdf6a. Deletion analysis identified a 78 bp region within ECR5 that is essential for transgene activity. This work illustrates that radar is regulated in the pharyngeal arches by a distant conserved element and suggests radar has similar functions in skeletal development in fish and mammals. PMID- 20201107 TI - Sodium nitroprusside induces autophagic cell death in glutathione-depleted osteoblasts. AB - Previous studies reported that high levels of nitric oxide (NO) induce apoptotic cell death in osteoblasts. We examined molecular mechanisms of cytotoxic injury induced by sodium nitroprusside (SNP), a NO donor, in both glutathione (GSH) depleted and control U2-OS osteoblasts. Cell viability was reduced by much lower effective concentrations of SNP in GSH-depleted cells compared to normal cells. The data suggest that the level of intracellular GSH is critical in SNP-induced cell death processes of osteoblasts. The level of oxidative stress due to SNP treatments doubled in GSH-depleted cells when measured with fluorochrome H2DCFDA. Pretreatment with the NO scavenger PTIO preserved the viability of cells treated with SNP. Viability of cells treated with SNP was recovered by pretreatment with Wortmannin, an autophagy inhibitor, but not by pretreatment with zVAD-fmk, a pan specific caspase inhibitor. Large increases of LC3-II were shown by immunoblot analysis of the SNP-treated cells, and the increase was blocked by pretreatment with PTIO or Wortmannin; this implies that under GSH-depleted conditions SNP induces different molecular signaling that lead to autophagic cell death. The ultrastructural morphology of SNP-treated cells in transmission electron microscopy showed numerous autophagic vacuoles. These data suggest NO produces oxidative stress and cellular damage that culminate in autophagic cell death of GSH-depleted osteoblasts. PMID- 20201109 TI - Nanoparticle detection of respiratory infection. AB - Respiratory viruses are a constant concern for all demographics. Examples include established viruses such as respiratory syncytial virus (RSV), the leading cause of respiratory infection in infants and young children, and emerging viruses such as severe acute respiratory syndrome (SARS), which reached near pandemic levels in 2003, or H1N1 (swine) influenza. Despite this prevalence, traditional methods of virus detection are typically labor intensive and require several days to successfully confirm infection. Recently, however, nanoparticle-based detection strategies have been employed in an effort to develop detection assays that are both sensitive and expedient. Each of these platforms capitalizes on the unique properties of nanoparticles for the detection of respiratory viruses. In this article, several nanoparticle-based scaffolds are discussed. Gold nanoparticles (AuNPs) have been functionalized with virus specific antibodies or oligonucleotides. In each of these constructs, AuNPs act as both an easily conjugated scaffolding system for biological molecules and a powerful fluorescence quencher. AuNPs have also been immobilized and used as electrochemical transducers. They efficiently serve as a conducting interface of electrocatalyic activity making them a powerful tool in this application. Quantum dots (QDs) posses unique fluorescence properties that have also been explored for their application to virus detection when combined with direct antibody conjugation or streptavidin-biotin binding systems. QDs have an advantage over many traditional fluorophores because their fluorescence properties can be finely tuned and they are resistant to photobleaching. The development of these nanoparticle-based detection strategies holds the potential to be a powerful method to quickly and easily confirm respiratory virus infection. PMID- 20201108 TI - Different pathways lead to mitochondrial fragmentation during apoptotic and excitotoxic cell death in primary neurons. AB - Mitochondrial fragmentation is recognized to be an important event during the onset of apoptosis. In this current study, we have used single cell imaging to investigate the role of the mitochondrial fission protein DRP-1 on mitochondrial morphology and mitochondrial fragmentation in primary hippocampal neurons undergoing necrotic or apoptotic cell death. Treatment of neurons with 500 nM staurosporine (apoptosis) or 30 MUM glutamate (l-Glu; excitotoxic necrosis) produced a fragmentation and condensation of mitochondria, which although occurred over markedly different time frames appeared broadly similar in appearance. In neurons exposed to an apoptotic stimuli, inhibiting DRP-1 activity using overexpression of the dominant negative DRP-1(K38A) slowed the rate of mitochondrial fragmentation and decreased total cell death when compared to overexpression of wild-type DRP-1. In contrast, responses to l-Glu appeared DRP-1 independent. Similarly, alterations in the fission/fusion state of the mitochondrial network did not alter mitochondrial Ca(2+) uptake or the ability of l-Glu to stimulate excitotoxic Ca(2+) overload. Finally, apoptosis-induced mitochondrial fragmentation was observed concurrent with recruitment of Bax to the mitochondrial membrane. In contrast, during glutamate excitotoxicity, Bax remained in the cytosolic compartment. We conclude that different pathways lead to the appearance of fragmented mitochondria during necrotic and apoptotic neuronal cell death. PMID- 20201110 TI - Applications of mass spectrometry to the study of siRNA. AB - RNA interference (RNAi) has quickly become a well-established laboratory tool for regulating gene expression and is currently being explored for its therapeutic potential. The design and use of double-stranded RNA oligonucleotides as therapeutics to trigger the RNAi mechanism and a greater effort to understand the RNAi pathway itself is driving the development of analytical techniques that can characterize these oligonucleotides. Electrospray (ESI) and MALDI have been used routinely to analyze oligonucleotides and their ability to provide mass and sequence information has made them ideal for this application. Reviewed here is the work done to date on the use of ESI and MALDI for the study of RNAi oligonucleotides as well as the strategies and issues associated with siRNA analysis by mass spectrometry. While there is not a large body of literature on the specific application of mass spectrometry to RNAi, the work done in this area is a good demonstration of the range of experiments that can be conducted and the value that ESI and MALDI can provide to the RNAi field. PMID- 20201111 TI - Outcomes in a cohort of patients with Stage I twin-to-twin transfusion syndrome. AB - OBJECTIVE: To determine pregnancy outcomes of patients who present with Stage I twin-to-twin transfusion syndrome (TTTS). METHODS: This was a retrospective review of all patients with TTTS referred to our institution between January 2005 and December 2006. Quintero criteria were used for staging. Laser ablation was not offered to patients with Stage I disease. RESULTS: A total of 155 twin pregnancies were evaluated for TTTS during this period. Forty-two met the criteria for Stage I and were included in the analysis. The overall survival to discharge was 82%. The mean gestational age at the time of consultation was 20.9 +/- 0.4 weeks. A total of 23 cases (54.8%) underwent amnioreduction. Progression of TTTS requiring invasive therapy occurred in four cases. The mean gestational age at delivery was 32.5 +/- 0.62 weeks. When divided according to use of amnioreduction, there were no statistically significant differences between the groups for gestational age at delivery or for birth weight. Those Stage I cases with a CHOP cardiovascular score of 5 or higher delivered almost 3 weeks earlier than the remainder of the cohort. CONCLUSIONS: Progression of TTTS beyond Stage I occurred in only 9.5% of the cohort. Mean gestational age at delivery and survival to discharge did not differ between Stage I patients and those treated with placental laser ablation for more advanced stages of TTTS. PMID- 20201112 TI - Real-time three-dimensional ultrasound with Live xPlane imaging assists first trimester acquisition of a true midsagittal section. AB - OBJECTIVE: To determine whether real-time three-dimensional (3D) ultrasound with Live xPlane imaging, which enables the simultaneous display of two real-time high quality image planes, can assist both operators certified by The Fetal Medicine Foundation (FMF) and non-FMF-certified operators in acquiring a true midsagittal plane in the first trimester. METHODS: Eight operators, four of them FMF certified (FMF group) and the other four not (non-FMF group), were asked to acquire a fetal image that they believed to represent the true midsagittal plane using real-time 3D ultrasound with Live xPlane imaging as guidance. Each operator was asked to obtain such an image five times from each of five patients. A total of 200 images from 40 patients were obtained and stored for subsequent analysis. All pregnancies were between 11 + 0 and 13 + 6 weeks of gestation. The angle between the falx cerebri and vertical axis (angle of deviation) was then measured by a single operator. A true midsagittal section was defined as an angle of deviation equal to 0 degrees. The angle of deviation and the time taken to acquire each image were compared between FMF and non-FMF groups. RESULTS: The median angle of deviation for each operator ranged from 1.2 degrees to 3.4 degrees. There was no significant difference in this angle between those who were FMF certified and those who were not (2.0 degrees vs. 2.2 degrees, P = 0.463). The interquartile range of the angle of deviation was also similar between the FMF- and non-FMF-certified operators. Although the time taken for image acquisition was longer among the non-FMF-certified operators (median, 45.5 s vs. 32.0 s), this difference did not reach statistical significance (P = 0.107). CONCLUSION: Live xPlane imaging can provide a tool to assist the acquisition of a true midsagittal plane and to determine how true a 'midsagittal' plane really is. PMID- 20201113 TI - Effect of antihypertensive therapy with alpha-methyldopa on uterine artery Doppler in pregnancies with hypertensive disorders. AB - OBJECTIVES: Antihypertensive drugs lower blood pressure by direct vascular effects or central vasodilatory mechanisms. Their effect on uterine artery Doppler resistance indices in hypertensive disorders of pregnancy is uncertain. This study aimed to evaluate the impact of antihypertensive therapy with alpha methyldopa on maternal uterine artery Doppler pulsatility index (PI) and resistance index (RI) in women presenting with hypertensive disorders of pregnancy. METHODS: This was a cross-sectional study of 51 women with pre eclampsia, 29 with gestational hypertension and 80 matched normotensive controls. Uterine artery PI and RI were measured at recruitment (between 24 and 40 weeks' gestation) and, in the hypertensive groups, 24-48 h after starting alpha methyldopa. Differences between mild and severe, and between early- and late onset pre-eclampsia were compared using the Mann-Whitney test. The Wilcoxon rank sum test was used to compare measurements before and after treatment. RESULTS: Prior to treatment, uterine artery PI and RI were significantly higher in women with pre-eclampsia compared with those with gestational hypertension and controls (P < 0.0001). The median uterine artery PI multiple of the median (MoM) was significantly higher (P < 0.0001) in early-onset than in late-onset pre-eclampsia (1.83 (range, 0.88-3.65) vs. 1.19 (range, 0.91-1.72)) and in severe compared with mild disease (2.26 (range, 2.02-3.65) vs. 1.29 (range, 0.88-2.9)). Uterine artery PI- and RI-MoMs in both pre-eclampsia and gestational hypertension, before and after 34 weeks' gestation, were not affected by alpha-methyldopa treatment. CONCLUSIONS: Antihypertensive therapy using alpha-methyldopa in women presenting with hypertensive disorders of pregnancy has no significant effect on uterine artery resistance to blood flow, suggesting that it does not impair uteroplacental circulation in these cases. PMID- 20201114 TI - Expectant management of ultrasonically diagnosed ovarian dermoid cysts: is it possible to predict outcome? AB - OBJECTIVE: The aim of this study was to assess the natural history of ultrasonically diagnosed ovarian dermoid cysts in a large group of women who were managed expectantly, and to assess the factors that were associated with failure of expectant management. METHODS: Our database was searched for dermoid cysts diagnosed on ultrasonography by a single expert operator between 2001 and 2007 in this retrospective study. In women who opted for expectant management, demographic data including age, gravidity and parity were recorded. Indications for scan, site of cysts, dimensions and the outcomes of expectant management were also recorded. RESULTS: Two hundred and eighty-nine women were diagnosed with a total of 323 dermoid cysts by a single expert ultrasound operator. 93/289 (32.2%; 95% CI, 26.8-37.6%) women with 105/323 (32.5%; 95% CI, 27.4-37.6%) ovarian dermoid cysts were managed expectantly for longer than 3 months. The mean age at diagnosis was 33.8 (range, 13-79) years and the median duration of follow up was 12.6 (interquartile range, 7.6-29.3) months. The mean growth rate of dermoid cysts during follow up was 1.67 mm/year. There were no demographic or morphological features that could be used to predict the growth rate of dermoid cysts. After a period of expectant management, 24/93 (25.8%; 95% CI, 16.9-34.7%) women had surgical intervention. The risk of surgical intervention was significantly increased in younger women, those of parity > or = 2 and in women with bilateral cysts or larger-diameter cysts, and reduced in women with a past history of ovarian cyst. CONCLUSIONS: The success rate of expectant management of dermoid cysts is high and this approach should be considered as a viable alternative to surgical management. PMID- 20201115 TI - Objective burden, resources, and other stressors among informal cancer caregivers: a hidden quality issue? AB - A great deal of clinical cancer care is delivered in the home by informal caregivers (e.g. family, friends), who are often untrained. Caregivers' context varies widely, with many providing care despite low levels of resources and high levels of additional demands. BACKGROUND: Changes in health care have shifted much cancer care to the home, with limited data to inform this transition. We studied the characteristics, care tasks, and needs of informal caregivers of cancer patients. METHODS: Caregivers of seven geographically and institutionally defined cohorts of newly diagnosed colorectal and lung cancer patients completed self-administered questionnaires (n = 677). We combined this information with patient survey and chart abstraction data and focused on caregivers who reported providing, unpaid, at least 50% of the patient's informal cancer care. RESULTS: Over half of caregivers (55%) cared for a patient with metastatic disease, severe comorbidity, or undergoing current treatment. Besides assisting with activities of daily living, caregivers provided cancer-specific care such as watching for treatment side effects (68%), helping manage pain, nausea or fatigue (47%), administering medicine (34%), deciding whether to call a doctor (30%), deciding whether medicine was needed (29%), and changing bandages (19%). However, half of caregivers reported not getting training perceived as necessary. In addition, 49% of caregivers worked for pay, 21% reported poor or fair health, and 21% provided unpaid care for other individuals. One in four reported low confidence in the quality of the care they provided. CONCLUSIONS: Much assistance for cancer patients is delivered in the home by informal caregivers, often without desired training, with a significant minority having limited resources and high additional demands. Future research should explore the potentially high yield of addressing caregiver needs in improving quality of cancer care and both survivors' and caregivers' outcomes. PMID- 20201116 TI - Comparison of inter- and intraobserver agreement and reliability between three different types of placental volume measurement technique (XI VOCAL, VOCAL and multiplanar) and validity in the in-vitro setting. AB - OBJECTIVES: To compare XI VOCAL (eXtended Imaging Virtual Organ Computer-aided AnaLysis) for three-dimensional (3D) ultrasound volumetry of the placenta and of phantom objects with a rotational method using VOCAL and with the multiplanar method. METHODS: We acquired 3D volume datasets from 32 fetuses at 11-14 weeks' gestation. Placental volume was calculated twice by each of two observers using XI VOCAL (with 5, 10, 15 and 20 slices), multiplanar (1-mm interval) and VOCAL (with 12 degrees, 18 degrees and 30 degrees rotation) methods. In addition, validity was assessed using the in-vitro setting with three phantom objects of known volume. RESULTS: Both inter- and intraobserver reliabilities were very high for all three methods. There was no systematic bias between any two methods except between XI VOCAL (10 slices) and the multiplanar (1-mm interval) method, with a smaller volume using the former method. The limits of agreement were wide between any two of the three methods. In the in-vitro setting, there was a trend towards less valid measurements with the XI VOCAL technique and fewer slices. With the same number of steps, measurements made with VOCAL (12 degrees and 18 degrees) were more valid than were those made with XI VOCAL (15 and 10 slices, respectively). CONCLUSION: XI VOCAL cannot be used interchangeably with VOCAL or multiplanar techniques in measuring placental volume at 11-14 weeks' gestation. PMID- 20201117 TI - Rare case of postpartum hemorrhage caused by rupture of a uterine artery pseudoaneurysm 3 months after Cesarean delivery. PMID- 20201118 TI - Reproducibility of regional placental vascularity/perfusion measurement using 3D power Doppler. AB - OBJECTIVES: To assess reproducibility and regional variability of placental perfusion measurement using three-dimensional (3D) power Doppler VOCAL() (Virtual Organ Computer-aided AnaLysis). METHODS: Twenty pregnant women at 26-34 weeks' gestation with normally grown, biophysically normal, singleton pregnancies with anterior placentae had placental power Doppler mapping data stored digitally from each of the four placental quadrants. Each was imaged by two investigators, with two datasets stored per investigator per quadrant. 5760 data values from the 320 datasets were evaluated by the same two investigators. Power Doppler imaging of the placental cord insertion was performed to generate a value for standardization as 'fractional moving blood volume' if appropriate. The vascularization index (VI), flow index (FI) and vascularization flow index (VFI) were calculated from spherical regions-of-interest to assess reproducibility within and between quadrants and between investigators for both acquisition and analysis. RESULTS: We found extensive variability for all readings. For repeated measurements within the same dataset the intra-analyzer intraclass correlation coefficient (ICC) range was: 0.24-0.57 for VI, 0.33-0.78 for FI and 0.12-0.48 for VFI. The corresponding interanalyzer ICC range was: 0.38-0.92 for VI, 0.40-0.85 for FI and 0.10-0.92 for VFI. The intra-acquirer variability (paired t-test) mean differences range was: - 3.91 to 4.71 for VI, - 2.68 to 3.31 for FI and - 2.23 to 2.78 for VFI; the corresponding interacquirer variability (paired t-test) range was: - 1.92 to 5.18 for VI, - 3.06 to 2.04 for FI and - 1.69 to 2.60 for VFI. The regional variability range (coefficient of variation) was: 6.28-126.34% for VI, 2.26-49.01% for FI and 6.09-151.55% for VFI. For all analyzed data, FI showed least variability and cord values for VI were consistently 100% (mean VFI, 98.4 and 98.8 between observers). CONCLUSIONS: There is insufficient evidence to support the meaning, reliability or reproducibility of VOCAL (VI, FI or VFI) as a tool to quantify placental perfusion, despite its use in multiple publications and journal submissions. There is poor reproducibility at the most fundamental level. Further investigation into the reproducibility of placental perfusion and quantification using VOCAL is required before development and application as a clinically useful tool. PMID- 20201119 TI - Jacquelin Perry special issue: stepping forward with gait rehabilitation. PMID- 20201120 TI - Proceedings from Genetic Analysis Workshop 14: Microsatellite and single nucleotide polymorphism, Noordwijkerhout, The Netherlands. 7-10 September 2004. PMID- 20201121 TI - Proceedings from the 16th Heparin Symposium, 2008, Loveno, Italy. PMID- 20201122 TI - Proceedings from the Fifth International Conference on Pediatric Mechanical Circulatory Support Systems & Pediatric Cardiopulmonary Perfusion, Dallas, Texas, USA, May 27-30, 2009. PMID- 20201123 TI - Initial ventilation through laryngeal tube instead of face mask in out-of hospital cardiopulmonary arrest is effective and safe. AB - INTRODUCTION: Bag-valve-mask ventilation is recommended as the initial airway management option for paramedics during cardiopulmonary resuscitation, although this technique requires considerable skill and is associated with the risk of stomach insufflation, regurgitation, and aspiration. The present two-phase study investigated the efficacy and safety of the laryngeal tube (LT-D) used by paramedics as the sole technique for ventilation in out-of-hospital cardiac arrest. METHODS: Paramedics staffing the emergency services' ambulances were selected for the study and trained in the use of the LT-D (phase I). They were then requested to use the device in patients requiring out-of-hospital cardiopulmonary resuscitation without prior bag-valve-mask ventilation. Patients were evaluated with regard to successful placement and effective ventilation using the airway. On arrival at the scene, the emergency physician replaced the LT-D with an endotracheal tube and assessed the incidence of regurgitation and injuries to the airways (phase II). RESULTS: Forty patients were enrolled into this study. One was excluded from analysis because of protocol violation. Insertion of the LT-D was successful and ventilation was effective in 33 patients (85%). Ventilation was not possible in six patients (15%) because of cuff rupture (n = 3) or massive regurgitation and aspiration before LT-D insertion (n = 3). No patient regurgitated after tube placement. No airway injuries were observed. The participants rated ventilation using the LT-D as effective. CONCLUSION: The LT-D is feasible and effective for airway management and ventilation when used by paramedics in out-of-hospital cardiopulmonary resuscitation and can be recommended as the sole technique in such situations. PMID- 20201124 TI - Update on emerging infections: news from the Centers for Disease Control and Prevention. Bartonella quintana in body lice and head lice from homeless persons, San Francisco, California, USA. PMID- 20201125 TI - Contrast enhancement and histopathological findings in vestibular schwannoma. AB - Changes of contrast uptake are considered to indicate the efficacy of therapy in irradiated vestibular schwannomas. We present a case of a large vestibular schwannoma with heterogeneous contrast uptake on MRI. Using neuronavigation, histological samples were obtained during surgery from an area with homogeneous contrast uptake and from a central tumor portion without contrast enhancement on MRI. Intraoperative investigation found no evidence of necrotic tumor, and histopathological examination revealed an active tumor in both sections, with no central necrosis. This finding illustrates the surgical experience that " necrotic tumor areas " on MRI may not be consistent with intraoperative findings. Lack of contrast uptake in previously irradiated schwannomas may not be indicative of effective radiotherapy. PMID- 20201126 TI - Formation of two consecutive intrathecal catheter tip granulomas within nine months. AB - The formation of catheter tip granulomas is an increasingly observed serious complication of intrathecally administered medication. This complication, which is frequently associated with neurological disturbances, has previously been attributed to high dosages and high concentrations of intrathecal morphine. Much less commonly, intrathecal hydromorphone and intrathecal baclofen have also been associated with intrathecal granuloma formation. In the current case, we report a patient who developed her fi rst catheter tip granuloma after 20 months of intrathecal morphine. After surgical granuloma removal and installation of a new catheter, the patient received intrathecal ziconitide for an interim period of six months. Because of a progressive inefficacy, ziconitide was replaced by hydromorphone. One month later, only nine months after the fi rst operative granuloma removal, a new catheter tip granuloma required a further surgical intervention. This case report highlights the potential of intrathecal morphine and hydromorphone to form consecutive inflammatory granulomas within the same patient. To the best of our knowledge, this is the fi rst report of a patient developing two consecutive catheter tip granulomas within nine months. PMID- 20201127 TI - Extended extra- and intracerebral ulceration and brain abscess following self mutilation in an auto-aggressive 51-year-old woman: case report. AB - In neurosurgical practice, the operative treatment of deep or infected wounds caused by auto-mutilation is quite rare, especially in the neurocranium. We present an extraordinary case of an auto-aggressive 51-year-old female suffering from a deeply ulcerated wound on the right frontal skull with consecutive brain abscess, caused manually with needles and forceps over a period of 8 months. The clinical course is present ed together with a description of the conservative and surgical regimen and is illustrated with photographs and CT and MRI images. PMID- 20201129 TI - Proceedings from the 14th Annual Meeting of the Japanese Society for Hemodiafiltration, Nagoya, Japan, February 14-16, 2009. PMID- 20201128 TI - Hypokalemic periodic paralysis: a case series, review of the literature and update of management. AB - The objective of this study was to present a case series of patients with hypokalemic periodic paralysis. We described all patients with diagnosis of hypokalemic periodic paralysis admitted to the Al Ain Hospital (UAE) during the year 2006. Seventeen patients, all males and mostly Asians, were presented to the Al Ain Hospital over a 12-month period. The majority were admitted during the summer months. Four were thyrotoxic. All of the 17 patients received oral potassium supplements and recovered well without any major complications. In conclusion, clinicians should have a high index of suspicion, especially among Asians presenting with flaccid paralysis and hypokalemia. The main steps in the management include exclusion of other causes of hypokalemia, potassium replacement, hydration and close monitoring of the cardiac rhythm and serum potassium levels. When possible, the underlying cause must be adequately addressed to prevent the persistence or recurrence of paralysis. PMID- 20201130 TI - Subtle BBB alterations in brain edema associated with acute liver failure. AB - Vasogenic mechanism of brain edema in acute liver failure (ALF) remains poorly understood. Recent work demonstrates that matrix metalloproteinase-9 (MMP-9) contributes to the development of brain edema in experimental ALF (J Hepatol 44:1105, 2006). Importantly, MMP-9 blockage with specific monoclonal antibodies and/or synthetic inhibitor, the edema is attenuated. Specifically, utrastructural evaluations demonstrate intact blood-brain barrier and its tight junction. These results suggest that subtle alterations in BBB are likely to involve in the brain edema associated with ALF. PMID- 20201131 TI - Proceedings of the conference New Paths: Health and Safety in Western Agriculture. PMID- 20201132 TI - China boosts medical research. PMID- 20201133 TI - Reforms on the horizon for Australia's health system. PMID- 20201134 TI - Institute to investigate cancer hotspot in Czech Republic. PMID- 20201135 TI - Atherosclerosis and diet in ancient Egypt. PMID- 20201136 TI - Metabolism of mono- and dichloro-dibenzo-p-dioxins by Phanerochaete chrysosporium cytochromes P450. AB - The white-rot fungus Phanerochaete chrysosporium possesses biodegradative capabilities of polychlorinated dibenzo-p-dioxins (PCDDs). One hundred twenty yeast clones expressing individual P450s of P. chrysosporum (PcCYPs), generated in our previous efforts, were screened for transformation of dioxin, and 40 positive clones were obtained. Of these clones, six clones showed metabolism of 2 chloro-dibenzo-p-dioxin, and a microsomal PcCYP designated as PcCYP11a3 showed much higher activity than any other PcCYPs. The turnover numbers of hydroxylation activities of PcCYP11a3 toward 1-MCDD (58 min(-1)) and 2-MCDD (13 min(-1)) are more than 200 times higher than those of previously reported PcCYP65a2. In addition, PcCYP11a3 catalyzes hydroxylation of 2,3-dichlorodibenzo-p-dioxin. To our best knowledge, PcCYP11a3 has the highest activity toward PCDDs among the known CYPs derived from microorganisms. Although PcCYP11a3 showed no detectable activity toward 2,7-dichloro-dibenzop-dioxin and 2,3,7-trichloro-dibenzo-p dioxin, PcCYP11a3 is promising as a template whose activity would be enhanced by site-directed mutagenesis. PMID- 20201137 TI - What determines movement across health care plans? PMID- 20201138 TI - When individuals buy in their own services. PMID- 20201139 TI - Mental health treatment in hospitals' emergency departments. PMID- 20201140 TI - Let's get personal. PMID- 20201141 TI - The American way. PMID- 20201142 TI - Give peace a chance. PMID- 20201143 TI - A beacon of help. PMID- 20201144 TI - Recent debate about the term 'schizophrenia'. PMID- 20201145 TI - Self-harm and mental health. PMID- 20201146 TI - The assessment criteria for employment and support allowance. PMID- 20201147 TI - Making personalisation a reality. PMID- 20201148 TI - Time to care. PMID- 20201149 TI - Going beyond the boundaries. PMID- 20201150 TI - Upon reflection. PMID- 20201151 TI - The new Mental Health Act statistics reveal some interesting, if inconvenient, truths. PMID- 20201152 TI - Progress at the National Survivor User Network. PMID- 20201153 TI - Looking at ordinary people's tales of living with their mental illness. Interview by Alita Howe. PMID- 20201154 TI - ["Expressing the essence of nursing care to elderly persons". Interview by Sylvie Warnet]. PMID- 20201157 TI - Modest and uneven: physician efforts to reduce racial and ethnic disparities. AB - While nearly half of U. S. physicians identify language or cultural communication barriers as obstacles to providing high-quality care, physician adoption of practices to overcome such barriers is modest and uneven, according to a new national study by the Center for Studying Health System Change (HSC). Despite broad consensus among the medical community about how physicians can help to address and, ultimately, reduce racial and ethnic disparities, physician adoption of several recommended practices to improve care for minority patients ranges from 7 percent reporting they have the capability to track patients' preferred language to 40 percent reporting they have received training in minority health issues to slightly more than half reporting their practices provide some interpreter services. The challenges physicians face in providing quality health care to all of their patients will keep mounting as the U.S. population continues to diversify and the minority population increases PMID- 20201158 TI - The good apprentice in medical education. AB - This paper targets both current apprentices and their supervisors drawing on current research to answer the following questions. What is apprenticeship and what are the key elements? What is a good apprentice and what can an intern or registrar do to assist their own learning and development? It takes a pragmatic approach and seeks to assist apprentices and their supervisors by attending closely to what is practicable, realistic, expedient and convenient; articulating this and laying it out as clearly as possible. PMID- 20201159 TI - Effectiveness of holistic physiotherapy for low back pain. AB - BACKGROUND: Low back pain is a term used to designate a wide and complete assemblage of symptoms that has become a cause of disability in the 21th century man. Until recently, it was believed that low back pain caused by intervertebral disc disease and degenerative progresses. At present, an increasing number of studies are linking the condition to conditions of osteoarticular and musculoligamentous structures in the spine and the associated statics of the pelvis. MATERIAL AND METHODS: The study compared the outcomes of two different plysiotherapeutic approaches to treatment of low pack pain in group of 60 female patients. In the experimental group, a customised programme of treatment was based on postisometric relaxation of muscles and ligaments, active mobilisation of the spine, Kibler Fold mobilisation, Kinesiology Taping and Maigne's relaxing exercises. the control group underwent electrotherapy procedures and performed a set of exercises usually recommended for low back pain. Intensity of pain and difficulty in performing daily activities were evaluated at baseline and on completion of the treatment: the measurements included mobility of the spine, static balance of the pelvis, tenderness and tension of muscles and ligaments and presence of cell-pain zones. Statistics analysis used basic statistics concerning the distribution of the examined characteristics and a comparison of means in independent groups using the Mann-Whitney U test. RESULTS: As a result of the treatment, low back pain was reduced in about 90% of patients in the experimental group, while static balance of the pelvis, tone of the muscles and ligaments and spinal mobility improved in approximately 80% of these patients. In the control group, radiating pain decreased and ligaments in 25% of participants, white the other parameters did not change significantly. The results were statistically significant at < 0.05. CONCLUSION: These results confirm a high holistic physiotherapy including elements of osteopathy such as post-isometric muscle relaxation, active mobilisation, Kibler Fold mobilisation, customised self therapy and Kinesiology Taping. PMID- 20201160 TI - Diabetic kidney disease: act now or pay later. PMID- 20201161 TI - Protocell research and its implications. AB - If and when protocells exist, they will exhibit three requisites for life: regeneration, replication, and evolution. Based on a recent collection of articles, this essay examines two major questions: (1) should research on development of protocells continue, and (2) what are the implications of this research for our understanding of "life."On the first question, I agree with contributors that the research should continue if there are adequate and ongoing safeguards against its misuse. On the second, I believe that creation of protocells is highly likely to escalate, rather than settle, controversies about the meaning and value of life, especially human life. PMID- 20201163 TI - [Proceedings and abstracts of the XIII Argentine Congress of Hepatology. June 10 13, 2005. Buenos Aires, Argentina]. PMID- 20201162 TI - Understanding obesity by asking the right questions. AB - Obesity, once considered a sign of wealth and high stature in the community, is now a global health problem and one of the leading causes of morbidity and mortality. Although weight gain occurs when energy intake exceeds energy expenditure, the causes and treatment are more complex than the simple energy balance equation would suggest. A new text on the subject challenges us to think out of the box for answers and solutions. PMID- 20201164 TI - [Psoriasis: a complex disease. Special issue from satellite symposium during the 18th Congress of European Academy of Dermatology and Venereology. Berlin, Germany, October 7-11, 2009]. PMID- 20201165 TI - Abstracts from the 9th International Symposium on Lysosomal Storage Diseases, April 2009, Frankfurt, Germany. PMID- 20201166 TI - Rehabilitation professionals are forced to be very efficient in treating and assessing stroke patients due to the economic demands. Foreword. PMID- 20201167 TI - Trauma registry--needs and challenges in developing countries. PMID- 20201168 TI - Does clinical experience affect knowledge regarding hepatitis-B among male medical students at a private university? AB - OBJECTIVE: To assess the knowledge of male medical students about Hepatitis-B in their preclinical and clinical years and to investigate the self reported vaccination status of these students. METHODS: In the year of 2007, 187 male students of Isra University Hyderabad Sindh Pakistan were selected by convenient sampling and surveyed with a self reported questionnaire comprising of questions regarding knowledge about hepatitis B. Data gathered was analyzed by SPSS V. 16. Knowledge between preclinical and clinical students were compared by Pearson's coefficient chi square test, p value < 0.005 was considered significant. RESULTS: Out of 187 students interviewed, 73 (39%) and 114 (61%) were from preclinical and clinical years respectively. Significant difference was found in clinical and preclinical students regarding basic knowledge about hepatitis B. and mode of transmission of disease (P = 0.004) and (P = < 0.001) respectively. CONCLUSION: Significant difference was found in the knowledge of both preclinical and clinical male medical students. PMID- 20201169 TI - Retained placenta still a continuing cause of maternal morbidity and mortality. AB - OBJECTIVE: To determine the frequency, causes and outcome of patients with retained placenta. METHODS: Descriptive case series. This study was carried out at Liaquat University Hospital, Gynae Unit-I, from January 2005 to December 2007. Two years retrospective and one year prospective analysis of patients was done according to age, parity, causes, place of delivery, person who conducted the delivery, conservative and surgical procedures, maternal morbidity and mortality. Patients were examined and appropriate investigations were done. The patients who came with or developed retained placenta at Liaquat University Hospital were included in the study. The patients having retained placenta due to uterine abnormalities were excluded from the study. All the information was collected on a predesigned proforma and analyzed on SPSS version 10.0. RESULTS: About 8782 patients were admitted during the specified period. Ninety patients had retained placenta. Frequency of retained placenta was 37.7% in women of age group 26 to 30 years, 26.6% upto age of 35 years, 22.2% in age 20-25 years, it was low between 36-40 years of age, while the frequency was high in women of low parity (44.4%). Causes included augmentation by oxytocics in 38.8%, manipulation 38.8%, inertia 14.4% and tumour (fibroid) 7.7%. Majority of patients (60%) had a home delivery. Delivery by Dai was done in 72.2%. The commonest complication was anaemia 48.8%, followed by puerperal pyrexia 24.4%, hypovolaemic shock 22.2%, acute renal failure 3.3% and hepatic failure in 1.1% respectively. CONCLUSION: Retained placenta is a frequent cause of maternal morbidity in Pakistan. PMID- 20201170 TI - Prevalence of selected disorders of inborn errors of metabolism in suspected cases at a tertiary care hospital in Karachi. AB - OBJECTIVE: To study the prevalence of selected disorders of inborn errors of metabolism at a tertiary care hospital in Karachi by performing selective screening of high risk clinically suspected individuals. METHODS: Cross sectional comparative study, was done at the Paediatric Endocrine Unit 2 of National Institute of Child Health Karachi in collaboration with Sapporo City Institute of Public Health, Japan. Sixty-two children age < 1 month-10 years meeting the inclusion criteria (Undiagnosed family history of similar illness or deaths, history of recurrent episodes of severe or persistent vomiting for which no infection or surgical cause was found and history of undiagnosed neurological symptoms and developmental delay) were enrolled in the study. Routine workup of inborn errors of metabolism was done in each child and their dried blood samples (DBS) and dried urine samples (DUS) were send to IEM Selective Screening Unit Japan. SPSS version 10 was used to derive results and p-value of < 0.05 was taken as statistically significant. RESULTS: Out of 62 children, sixteen children (9 boys and 7 girls) were positive for inborn errors of metabolism (IEM). Respiratory distress (p = 0.042) and developmental delay (p = 0.048) were found to be the most common clinical presentations in our children. Out of 16 children with positive results, 14 children had history of death of siblings with similar complaints (p = 0.027). Consanguineous marriage was reported in 13 children. Among children with positive results 10 (62.5%) had organic acidemias, 1 (6.2%) had Ornithine Transcarbamylase (OTC) deficiency (Urea cycle defect) and 5 (31.2%) had congenital lactic acidemias. CONCLUSION: Significant number of positive cases were seen in our series of patients, establishing the fact that IEM is prevalent in our population, though undiagnosed. Further such studies are needed on our side in future to determine incidence of metabolic disorders in Pakistan, which can be achieved by developing local facilities, neonatal screening programmes and collaboration with other countries who are actively working in this field. PMID- 20201171 TI - Admission creatine kinase as a prognostic marker in acute myocardial infarction. AB - OBJECTIVES: To investigate the prognostic significance of creatine kinase (CK) in Pakistani patients suffering from acute myocardial infarction (AMI) and to find out if CK combined with troponin T (TnT) could be a better predictor for long term adverse cardiac event. METHODS: One hundred and eighty six consecutive patients with AMI who were eligible for streptokinase (SK) treatment were included in this prospective cohort study. The relationship between their serum/plasma CK and TnT levels at the time of admission and clinical outcome was investigated over a mean follow up of 24.12 +/- 3.75 months. RESULTS: Admission CK was found to be associated with subsequent cardiac event and mortality (P < 0.01 and P < 0.04 respectively). Admission CK was also mildly associated with time interval between onset of symptoms to SK treatment (correlation coefficient 'r' = 0.23). Odds of encountering a cardiac event in AMI patients with above normal CK levels (adjusted for gender) were 3.46 times higher than the odds in patients with normal CK levels. Similarly, odds of mortality in patients with positive TnT were 4.6 times the odds in patients with negative TnT. The two biochemical markers, CK and TnT, together did not provide any further information about prognosis of the disease. CONCLUSION: Admission CK is a better prognostic marker for a subsequent cardiac event, while TnT is a better predictor of mortality over a mean follow up of nearly 2 years. Together, they do not improve predictability of an adverse cardiac event. PMID- 20201172 TI - Association of herpes simplex virus infection and Bell's palsy. AB - OBJECTIVE: To determine the association of the Herpes Simplex virus Type-1 infection and Bell's palsy in patients treated at the outpatient department of a tertiary care center. METHODS: A prospective, observational study was carried out at the outpatient department of Medical and ENT units of Abbasi Shaheed Hospital, Karachi. Fifty patients were enrolled in the study with their informed and written consent, between 2006-2007. All were >12 years of age. They were diagnosed as having Bell's palsy and were investigated for serologic evidence of Herpes simplex virus (HSV). The IgG and IgM antibodies for HSV were identified in the blood samples at the Aga Khan University hospitals laboratory. RESULT: Of the 50 patients enrolled, 35 (70%) patients were IgG/IgM positive for the HSV stressing the etiological association of HSV with Bell's palsy. CONCLUSION: The study suggests that a relationship exists between HSV infection and Bell's palsy. The information might prove helpful in hastening the recovery by modifying management guidelines in view of the results of this study. PMID- 20201173 TI - Standards for labelling and storage of anaesthetic medications--an audit. AB - OBJECTIVE: To check compliance of anaesthetist to current policies set for the use of medication within operation room and for induction room floor stock. METHODS: The initial audit was conducted from 1st October to 31st November 2006 and reaudit after dissemination and sharing of results within the department repeated in July-August 2007. In each audit four operating rooms were visited twice a week. Syringes were checked for standard drug labelling for narcotic and non narcotic preparations. Drug trolley was checked for any expired drugs and whether the trolley was locked in case of operating room (OR) where list was ended or was on hold. Any unattended drug was noted and Induction room was checked twice weekly for accurate drug inventory and for standard drug storage recommendations. RESULTS: Labels were according to standard in non narcotic drugs on 25% syringes in first audit and 63% in second audit, likewise, narcotics labels were according to standards in 41% in first and 57% in second audit. Unattended drugs were present once in first and twice in second audit. There was 100% compliance in other drug storage policy parameters in both audits. CONCLUSION: Poor compliance of drug labelling standards for both narcotic and non narcotic drugs was present. However, second audit revealed improvement in all areas of drug handling. Dissemination of policies and reminders are important for continuing improvement in use of medication within operation room and within induction room floor stock. PMID- 20201174 TI - Chickenpox: presentation and complications in adults. AB - OBJECTIVE: To describe the clinical manifestations laboratory findings and frequency of complications in adult chickenpox patients admitted in the hospital. METHODS: This was a hospital based descriptive study, conducted at the Infectious Diseases Unit, Rashid Hospital Dubai, UAE, from March 2005 to February 2008. The study was designed to include demographics (age, sex, nationality); clinical information, radiological and biochemical changes observed in each patient and data was entered into the proforma separately. Full blood count, urea, electrolytes and blood sugar were done for all the patients, whereas, other tests were carried out when and where it was indicated. Patients were treated according to the standard protocol for the management of Chickenpox and its complications. RESULTS: A total of 102 adult patients were entered into the study. The main presenting symptoms were itchy skin rash, fever, cough, sputum, breathlessness, throat pain, vomiting, abdominal pain, confusion and headache. Whereas, the most common complications observed were raised Alanine aminotransferases (ALT) levels (51.9%) and the levels were greater than 10-folds of normal value in 4.9%, thrombocytopenia (42.1%), varicella pneumonia (28.4%), skin infection (25.4%), septicaemia (10.7%), Encephalitis/Meningitis (8.8%), Acute Respiratory Distress Syndrome (ARDS) (6.8%), acute renal failure (2.9%) and acute hepatic failure (1.9%). The frequency of varicella pneumonia was noted to be higher in males, older age group (p < .005), smokers (p < .002) and patients with respiratory symptoms (p < .0001). Total five (4.9%) patients expired, whereas, mortality rate was 17.2% in varicella pneumonia patients and 45.5% in mechanically ventilated patients. CONCLUSION: Chickenpox in adults causes severe systemic manifestations leading to high frequency of complications with increased mortality rate, particularly in the older age group and in smokers who develops varicella pneumonia and require mechanical ventilation. PMID- 20201175 TI - Liver histology in hepatitis C virus positive patients with normal and elevated alanine amino transferase levels. AB - OBJECTIVE: To compare liver histology in HCV RNA positive patients with normal and elevated Alanine Aminotransferase Level (AST). METHODS: This Cohort (prospective) study was conducted at Civil Hospital Karachi from Jan 2007 to July 2007. Forty patients with positive HCV RNA were included. Their liver function tests were followed for three months. Those having normal ALT on three occasions were taken as controls and those having elevated ALT were taken as cases. Liver biopsy was performed, Specimens were reviewed by single pathologist. Scheuer's scoring for grading of inflammation and staging of fibrosis of chronic hepatitis was used. RESULTS: Out of Forty patients having positive HCV RNA, 14 (35%) were male and 26 (65%) were female. Mean ALT in control group was 27.3 +/- 6.1 u/l, mean ALT in cases was 91.7 +/- 39.95 u/l. Mean age in controls was 34.2 +/- 10.75 years and in cases was 33.6 +/- 9.40 years. On histopathology, the mean grade of inflammation in controls was 1.40 +/- 0.681 while in cases was 1.20 +/- 0.834, which was not statistically significantly different in the two groups (p = 0.411). Similarly mean staging of fibrosis in controls was 1.20 +/- 0.768 and in cases was 1.35 +/- 1.348 which was also not statistically different in the two groups (p = 0.668). Stage 3 and 4 fibrosis was seen only in raised ALT group and not in the controls. CONCLUSION: Patients with persistently normal ALT and elevated ALT, although had similar grading of inflammation but the fibrosis score was more in elevated ALT group. None of the patients with normal ALT had normal histology, so decision for antiviral treatment should be individualized in this group also. PMID- 20201176 TI - Breast carcinoma over three decades in northern Pakistan--are we getting anywhere? AB - OBJECTIVE: To compare the histological prognostic markers in breast carcinoma over three decades in Northern Pakistani population and analyse for any change in trends in terms of prognostic markers. METHODS: Cross-sectional descriptive study was carried out from January 2004 to December 2006 at AFIP, Rawalpindi on 822 cases of female breast carcinoma. Assessment of tumour size on gross examination followed by microscopic evaluation of tumour type, tumour grade, lymph node metastasis and skin involvement was done. The results of the present data were compared with studies of Wahid et al (January 1994 to December 1997) and Malik et al (January 1984 to December 1986) from the same institute. RESULTS: Total 822 cases of breast cancer were diagnosed with 541 (64.9%) cases of mastectomy. The mean age was 48 +/- 12 years with a mean tumour size of 4.6 +/- 2 cm. Atumour size of >5 cm was seen in 30.6% cases and only 18.8% cases had a size <2 cm. Infiltrating ductal carcinoma was the commonest subtype in 674 (81%) cases with histological grade II in 533 (64%) cases. Lymph node metastasis was present in 74.6% cases and skin involvement in 36% cases. The comparison of the results of the present study with those over the past two decades in Pakistan show that the mean age at diagnosis remains around 48 years. There is statistically significant increase in the tumours of <5 cm at presentation and a higher frequency of tumours with dermal invasion. No significant change is seen in frequency of lymph node metastasis at operation and tumour grade. CONCLUSION: The comparison of results of other studies done over the past three decades in the region are not very encouraging. The age of presentation remains younger as compared to the West. A positive note is seen in terms of a decreasing tumour size but lack of DCIS cases in our material underlines the need of mammography and launching of effective screening programmes at the national level. Early detection of cases will help in treatment and subsequently improve prognosis in these patients as advocated by the West. PMID- 20201177 TI - Etiology, functional status and short term outcome of patients with pituitary lesions. An experience from a developing country. AB - OBJECTIVE: To describe the etiology, functional status and short term outcome of patients with pituitary lesions (PL). METHODS: Brain or pituitary MRI reports of 3753 patients were analyzed for PL over the period of 2000 to 2007, done at the Aga Khan University Hospital (AKUH), Karachi, Pakistan. MRIs with reported PL and all those ordered by Endocrinologists with or without pituitary abnormalities, were included in the analysis. This made a total of 338 (9%) MRI reports. PL were defined as pituitary tumors, cysts, haemorrhage, hypoplasia; and empty sella. Patients with these PL, were analyzed for symptoms, hormonal profile and short term outcome in the hospital retrospectively. RESULTS: In the analysis of 338 MRI reports, 23% had normal pituitary gland on MRI examination. Hypogonadotrophic hypogonadism was the commonest (38.5%) endocrine abnormality seen with normal pituitary MRI, followed by hypopituitarism (5.1%). Most common PL identified were macroadenoma (38.7%), empty sella (16.5%) and microadenoma (12.7%). Patients with macroadenoma had 58% of non-functional tumours while 19.1% had hypopituitrism, 17.6% had acromegaly and 17.5% had prolactinoma. Majority of these lesions were causing headache and visual symptoms (42.7%) and were treated with surgery (75.5%). Patients with microadenoma included 39.5% prolactinomas, 18.6% cushing disease, 14% acromegaly, 4.7% hypogonadotrophic hypogonadism and 2.3% hypopituitrism. Majority of these lesions were treated with drugs and 37.3% were treated with surgery. In empty sella patients, 32% patients had endocrine abnormalities among which 21.4% had hypopituitrism, 2% had hypogonadotrophic hypogonadism, and only 6% patients had normal endocrine workup. A significant number of patients (62.5%) never had endocrine hormonal checkup. CONCLUSION: Although PL are less common entities (9% in 3,753 reports) but they are associated with significant endocrinal abnormalities and need prompt treatment. Empty sella, which is not considered as a distinct abnormality, is also associated with significant endocrine deficiencies. PMID- 20201178 TI - Management of stone disease: 17 years experience of a stone clinic in a developing country. AB - OBJECTIVE: To review 17 years experience of the stone clinic with incorporating the changes in practice over the years and to report the benefits of stone clinic in a developing country. METHODS: The SIUT Stone clinic was established in 1990 with installation of HM4 Lithotriptor. This clinic is run jointly by a Urologist, Dietitian, Nephrologist, Biochemist and Radiologist. From 1990 - 2007, about 38,749 stone patients received treatment with ESWL (55%), PCNL (6.0%), URS (15.5%), litholopaxy 4.0% and open surgery 19.7%. These patients after treatment were followed in the stone clinic with stone analysis and 24 hours urine metabolic studies where indicated. Dietary and oral hydration programme combined with medical therapy was also instituted. Recurrence rate was noted in those patients who were advised diet modification, oral hydration and medical treatment. Complications of stone disease were documented during the follow-up period. RESULTS: In ESWL group 8226 patients were followed in the stone clinic for 5 years. In this group, 185 (2.2%) had recurrence of renal calculi. In PCNL group 1306 patients were followed, and 16 (1.1%) had recurrence. In the open surgery group of 1294 patients, 17 (1.3%) had recurrence of renal calculi. The complications of stone disease noted were renal failure and infections in 162 (1.5%) patients, during the follow-up period. CONCLUSION: This study shows the beneficial effect of a stone clinic in a developing country and positive effect on the reduction of recurrence and complications of stone disease. Our experience promotes the need to open more specialized stone clinics in areas where stone disease is highly prevalent. PMID- 20201180 TI - The 'molar tooth sign' in Joubert syndrome. AB - The molar tooth sign is seen in very few conditions and is a very rare paediatric central nervous system congenital anomaly. Molar tooth sign is the result of cerebellar vermis hypoplasia, thick and maloriented superior cerebellar peduncles, and an abnormally deep interpeduncular fossa. In Joubert syndrome this is seen in about 85% of patients. We present a case of 13 months old baby boy with recurrent episodes of fits and hyperpnoea, regression of milestones and developmental delay. MRI examination showed the characteristic molar tooth sign with apposition of cerebellar hemispheres, batwing-shaped fourth ventricle communicating through a thin fissure with foramen of Magendie, cerebellar vermis agenesis and deep interpeduncular fossa consistent with diagnosis of Joubert syndrome. PMID- 20201179 TI - To asses the effects of rocuronium pretreatment on succinylcholine induced fasciculations and postoperative myalgias. AB - OBJECTIVE: To asses the effects of Rocuronium pretreatment on Succinylcholine induced Fasciculations and postoperative Myalgias. METHODS: A randomized double blind case control study was conducted in Department of Anaesthesia and Surgical Intensive Care Unit, Liaquat National Hospital, Karachi from October 2003 - April 2004. Sixty adults ASA I or II patients who presented for elective general surgical procedures were included in the study. The patients were divided in two groups of thirty each by a simple lottery method. Group "A" received placebo and group "B" received Rocuronium 0.1 mg/kg, one minute prior to induction with Pentothal Sodium 5 mg/kg, Suxamethonium, 1.5 mg/kg and Nalbuphine 10 mg / 70 kg. Fasciculations and intubation condition was assessed immediately after the induction of anaesthesia while post operative myalgias were assessed 6, 12 and 24 hours after surgery. RESULTS: Fasciculations were noticed in group "A" as 100% (mild to severe) and in group "B" 13.3% (mild). Post operative myalgias at 6 and 12 hours after surgery were 76.66 % in group "A" and 16.66 in groups "B". After 24 hours in group "A' post operative myalgias were 93.33% and group "B" 23.33%. CONCLUSION: It is concluded that pretreatment with Rocuronium reduced the incidence of myalgias, fasciculations and produced rapid precurarization in one minute thereby saving time on busy operating lists. They also allowed the early ambulation of patients in minor surgeries. PMID- 20201181 TI - Wegener's granulomatosis: a diagnostic challenge. AB - Wegener's Granulomatosis (WG) is a necrotizing granulomatous vasculitis that primarily involves small vessels in the body. Patient usually presents in the fourth to fifth decade. The clinical presentation is variable; however, majority of patients (90%) seek medical attention for nasal and sinus symptoms with or without lower respiratory symptoms of cough, dyspnoea and haemoptysis. The typical form of WG tends to involve the triad of upper and lower respiratory tract and the kidneys; while involvement of other organs like ocular, cutaneous, rheumatological, neural, gastrointestinal and lower genito-urinary tract is occasionally seen. A "limited" form with clinical findings isolated to the upper respiratory tract or lungs, occur in approximately one-fourth of cases. We present a case of Wegener's Gmnulomatosis in an eighty five year old lady who presented with an acute pneumonia-like illness. She underwent an extensive work up to reach a definitive diagnosis. PMID- 20201182 TI - Superior gluteal artery aneurysm. AB - To report the successful coil embolization of a rare gluteal artery aneurysm and review therapeutic options for this rare condition. We report a case of pseudo aneurysm of superior gluteal artery initially diagnosed as gluteal abscess. They can be diagnosed by Doppler ultrasound, computed tomography or magnetic resonance imaging. Mainstay of the diagnosis is by angiography and the preferred management with good clinical results is with angiographic embolization. This report reviews the literature and addresses the incidence, aetiology, and treatment of gluteal artery aneurysms. PMID- 20201183 TI - YMDD mutation in Pakistani patients. The comparison of Eastern response with the Western response. AB - Lamivudine exhibits potent antiviral activity in chronic hepatitis B. YMDD mutations in west is around 32% (5 years) but reports from East are scarce. To evaluate frequency of lamivudine resistance and compare the results with the West, a total of 100 chronic hepatitis B patients were given Lamivudine 100 mg before breakfast. Out of 81 patients (19 no follow up), (85%) males and (15%) females. Wild type were 69 (85%) and 12 (14.8%) pre-core mutants. At 1 year 25/69 wild type (36.2%) lost their HBeAg and 18 (26%) seroconverted. At 2 years 30 (43.4%) became HBeAg negative and 22(31.8%) had positive anti-HBe. At 3 years 33 (47.8%) became HBeAg negative and 25 (36.2%) sero-converted. Of 12 precore mutants 8 (66.6%) lost HBV DNA within 24 weeks of therapy. At 36 months 44.4% showed sero-conversion with a YMDD mutation rate of 6% which is in contrast to 32% reported from the West. PMID- 20201184 TI - Crisis response in mental health: do we have a protocol? PMID- 20201185 TI - Knowledge and practices among the general practitioners of Karachi regarding dog bite management. AB - OBJECTIVE: To find out the knowledge and practices among the general practitioners (GPs) of Karachi regarding dog bite management. METHODS: This cross sectional study was carried out in private and public Qlinics of Karachi using a pre-tested self-administered questionnaire. The study population was composed of 151 GPs with MBBS degree. Data was analyzed on SPSS version 12.0. RESULTS: Out of total 151 general practitioners, 124 were male and 27/female doctors. The majority (77.5%) of GPs knew the cause of rabies, but only 51.7% knew about the incubation period. Only 19.4% GPs had appropriate knowledge about the first line treatment. Almost all GPs (98%) had no knowledge about the types of anti-rabies vaccine and only 19.2% knew about anti-rabies serum. CONCLUSION: There is an apparent lack of awareness among GPs regarding appropriate animal wound management and vaccine administration. Reorientation programmes and continued medical education (CME) for GPs are required to highlight WHO guidelines regarding treatment of animal bite. PMID- 20201186 TI - Role of omega-3 fatty acids in improving health. PMID- 20201187 TI - Observation at a medical store in Karachi, Pakistan. PMID- 20201188 TI - Cardiac revascularization: CABG vs. PTCA. PMID- 20201189 TI - Social and political involvement of the American Speech and Hearing Association. PMID- 20201190 TI - The role of ASHA in social, political, and moral activities. PMID- 20201191 TI - Philosophies and goals of the ASHA Black Caucus. PMID- 20201192 TI - American Speech and Hearing Association. PMID- 20201193 TI - [The nursing staff]. PMID- 20201194 TI - [Are blood gas tests valid in smokers?]. AB - The authors analyze the influence of smoking on the validity of measurements of arterial saturation using percutaneous oxygen-hemoglobin blood gas tests. The authors conclude that these methods can yield elevated oxygen saturation values in smokers. PMID- 20201195 TI - [Nursing staff and patient results: systematic review about the existing relationship]. AB - OBJECTIVE: Review the evidence about the relationship between nursing staff characteristics and patient care results. METHODS: Systematic Review Research at CENTRAL, the Cochrane Plus library MEDLINE CINAHL, EMBASE and PsycINFO until June 2009. Original studies on adult patients checked into hospitals in acute care sections of whatever design have been included, these studies were published either in Spanish or English. Two independent reviewers evaluated the quality of these studies under the GRDAE system and extracted data. RESULTS: 55 studies were included. Patient-nurse ratio has repercussions on costs, mortality and the appearance of complications. Controversy on the repercussion regarding care quality. The relationship of nursing hours per patient has repercussions on satisfaction, infection, cardiac alterations, bleeding, average hospital stay net costs, sepsis, and ulcers. Controversy on repercussions regarding falls, medication errors and life quality decreases the complications, and promotes self care. Nurses-emotional states bears an influence on falls and medication errors. CONCLUSION: There is a relationship between the nursing staff and patient care results. This review's results have to be considered with caution and evaluated as a tendency since quality conditions their interpretation. Nursing staffs acquire a special relevance in the Spanish health system context due to changes produced in the population and type of patient, the deficit of professionals, and the modification of nursing study plans. PMID- 20201196 TI - ["Dextra" school nurse: community nurse]. PMID- 20201197 TI - [Viewing veins with AccuVein AV300]. AB - In spite of the major advances which have occurred in medicine and biotechnology over these last years, regarding intravenous therapy the greatest advances have occurred, on the one hand, in bio-compatible and throw away catheters and, on the other hand, in security devices which avoid accidental punctures. Advances to locate veins have been very limited, having been developed on occasion by devices which are not easily transported and which require fungible material when they make contact with a patient's skin. The AccuVein AV300 device is a portable manual use instrument which enables nurses to locate certain peripheral veins. This device does not substitute a nurse's traditional skill in locating veins by visual or feeling means, but rather this device supplements their skills and enhances them. This device is lightweight, intuitive, and does not require previous training for its use and hygiene since it never enters into contact with a patient's skin as it emits an infrared light on the skin which reflects veins drawing them on the surface of the skin. PMID- 20201198 TI - [A new section on pharmacology updating]. PMID- 20201199 TI - [Pharmacology general concepts]. AB - It is very important to have basic knowledge, a sufficient critical attitude and an adequate methodology so that a prescription becomes a rational decision and not a purely reflex action. Dispensing pharmaceuticals requires that health professionals have adequate professional development and information since from a health-social-economic perspective therapeutic errors and iatrogenic medicine lead to a very important resource expenditure. PMID- 20201200 TI - [Efficiency and cost-effectiveness for a safety device]. AB - When dealing with preventive measures, it is necessary to evaluate their effectiveness and to analyze the costs involved in implementing those measures. Therefore, the authors carried out a before-after intervention study on the use of a safe intravenous peripheral catheter in emergency ward services; this study included the participation by workers in selecting material by means of a Likert questionnaire. The effectiveness of a safe intravenous peripheral catheter was calculated comparing skin accidents caused by this device 40 months before and after its implantation. An economic analysis was calculated by means of a cost effectiveness index fined as a "Euros spent for accident prevented" index. Workers who participated chose a passive safe intravenous peripheral catheter (p < 0.05). During the pre-intervention period, 17 intravenous peripheral catheter expositions were declared, during the post-intervention period, none were declared. The total net cost per intervention came to 36.606 Euro. The cost effectiveness index was 2.579,3 Euro for accident prevented. PMID- 20201201 TI - [Hypothermia]. AB - A deep understanding about the causes and situations which predispose a patient to hypothermia can prevent its progression and the emergence of complications which present life-threatening risks and can lead to irreversible organ deterioration. The distinct degrees of hypothermia require a diagnosis and a distinct therapeutic treatment which share common pillars based on: the need to employ general measures which counterarrest the deterioration of those organs caused by heat loss; and the use of internal or external reheating methods which vary due to the degree of hypothermia and the hemodynamic stability of the patient. In moderate or severe cases, a nurse's role, as one who collaborates in patient treatment, requires paying special attention to strict monitoring of vital constants, neurological, metabolic and cardio-respiratory signs, as well as collaborating in various therapeutic procedures. As a nursing diagnosis, hypothermia refers to those situations in which a nurse's professional competence capacitates he/she to carry out actions which resolve that prejudicial situation a patient faces. PMID- 20201202 TI - [Vascular ulcers: arterial and venous]. PMID- 20201204 TI - [In Process Citation]. PMID- 20201203 TI - [In Process Citation]. PMID- 20201205 TI - [In Process Citation]. PMID- 20201206 TI - [In Process Citation]. PMID- 20201207 TI - [In Process Citation]. PMID- 20201209 TI - [In Process Citation]. PMID- 20201208 TI - [In Process Citation]. PMID- 20201210 TI - [In Process Citation]. PMID- 20201211 TI - [In Process Citation]. PMID- 20201212 TI - [In Process Citation]. PMID- 20201213 TI - [Successes in early detection of cancer. More and more curable colorectal carcinomas]. PMID- 20201214 TI - [Screening for colorectal malignancies]. PMID- 20201215 TI - [Endoscopic diagnosis of early cancers in the upper gastrointestinal tract]. PMID- 20201216 TI - [The role of genetic predisposition in early detection of cancer]. PMID- 20201217 TI - [Polymyalgia rheumatica]. PMID- 20201218 TI - [Diabetic neuropathies (Part 1): diagnosis and therapy]. PMID- 20201220 TI - [In Process Citation]. PMID- 20201219 TI - [General practitioner's medical records for preoperative anesthetic visit]. AB - General practitioners' medical records could deliver important information for pre-anesthesia evaluation. However, sometimes after hospital admission tests- already done by the general practitioner--have to be repeated for preoperative assessment due to incomplete information or more technical issues.These time spending double examinations cause additional costs for the health system and discomfort for the patient. Here, we focus on important medical records patient could easily get from his general practitioner for the preoperative visit. PMID- 20201221 TI - [In Process Citation]. PMID- 20201222 TI - A special issue on nano- and micro-technologies for biological targeting, tracking, imaging and sensing. PMID- 20201223 TI - Long-acting, multi-targeted nanomedicine: addressing unmet medical need in acute lung injury. AB - Acute lung injury (ALI) associated with sepsis and acute respiratory distress syndrome (ARDS) is a leading cause of death of critically ill patients in U.S. Our understanding of the pathobiology and mechanisms underlying ALI is increasing as a result of basic research and advances in molecular biology. Unfortunately, morbidity and mortality from ALI and ARDS still remains unacceptably high (30 40%). The major reason underlying lag in improvement in outcome is the lack of novel and specific therapies for ALI and ARDS. To begin to address this issue, we developed novel long-acting biocompatible and biodegradable phospholipid micelles (size, approximately 15 nm) to inhibit triggering receptor expressed on myeloid cells 1 (TREM-1), reactive oxygen species and Hsp90, key effectors thought to underlie ALI, in vivo. Realizing short half-life of peptide drugs (minutes) hampers their clinical use, we invented micellar TREM-1 peptide and glucagon-like peptide-1(7-36) amide (GLP-1) where each peptide drug is stabilized in its active form (alpha-helix) and its bioactivity is prolonged for hours in vivo. Likewise, water-insolubility of 17-allylamino-17-demethoxygeldanamycin (17-AAG), a selective Hps90 inhibitor, constrains its use in humans. Accordingly, self association of 17-AAG with these micelles overcomes this limitation while at the same time increasing its stability and bioavailability. These long-acting micellar nanomedicines provide significant advancement in the treatment of experimental of ALI which could then be extended to critically ill patients. PMID- 20201224 TI - Implications of intracellular distribution of nanovesicles for bioimaging studies. AB - An ever increasing number of diverse nanomaterials for biopharmaceutical applications is emerging, ranging from liposomes, niosomes, micelles, nanoemulsions, dendrimers, nanocells, cell ghosts, lipoproteins to solid nanoparticles and quantum dots. Several of these nanomaterials have been brought from the bench into the clinic over the last three decades giving raise to "Nanomedicine", a term implying the application of nanotechnology for therapy and diagnosis. Though pharmaceutical nanoparticular carriers have been successfully established as devices for enhancing the therapeutic index of clinically approved and experimental drugs, their utilization for imaging and monitoring biological functions has just began to materialize. The development of the effective carrier mechanism does not only mean the execution of delivery, but also the positive confirmation of the correct and specific delivery the cargo. Consequently, the ability to track and image the fate of any nanomedicine starting from the systemic down to the sub-cellular level becomes essential. In unison, the importance of monitoring any desired or undesired cellular and subcellular morphological and functional alterations subsequent to or indicative of therapeutic delivery is gaining increasingly attention. Focusing on selected pharmaceutical nanomaterials, this review tries to illustrate the interconnectivity between therapeutic applications of nanocarriers and their use for imaging and monitoring cellular and subcellular functions. PMID- 20201225 TI - Tracking cell-nanoparticle interactions. AB - Nanoparticles are highly attractive tools for future biomedical applications. Essential steps towards using nanoparticles in living organisms include the development of strategies for a defined nanoparticle uptake by the cell, the availability of appropriate particle tracking methods and the design of nanoparticles with low cytotoxicity. Optical tweezers are versatile tools to study the interaction between particles and cells with nanometre, piconewton and microsecond resolution and they have proven capable of trapping and tracking individual nanoparticles in three dimensions. This minireview presents recent achievements for the usage of nanoparticles in in vivo studies and discusses how optical tweezers can be employed to quantify cell-nanoparticle interactions at the single particle level. PMID- 20201226 TI - Nanoparticles as tools for evaluation of cellular redox state. AB - Signaling pathways in living cells which regulate cell cycle and activate defense mechanisms against environmental stresses are mainly controlled through cell redox potential status. The main cellular redox buffer is constituted by oxidized/reduced glutathione system (GSSG/2GSH). Physiological functions and pathological situations resulting from oxidative stress are driven by glutathione homeostasis and its dysfunction, respectively. Many methodologies devoted to the investigation of cellular redox potential relying on the determination of reduced and oxidized glutathione concentrations measured in various cellular compartments, tissues and organs have been reported. Most of them are till now based on separative and non-separative techniques and include extractive step from biological samples. They are time-consuming and tedious in order to preserve reduced to oxidized glutathione ratio, thus introducing bias in its evaluation. New trends are focused on in situ evaluation of redox state especially through the monitoring of glutathione pool. This review reports recent developments in fluorescence imaging of cellular redox state, especially those involving nanotechnologies. PMID- 20201227 TI - Using polymers to make up magnetic nanoparticles for biomedicine. AB - The use of magnetic nanoparitilces for biological and biomedical applications such as protein separation, targeted drug delivery, hyperthermia treatment, use as contrast agents of magnetic resonance imaging, biosensing, magnetic fluids environmental remediation is one of the most attractive fields of nanotechnology today because of their unique magnetic properties and the potential to function at cellular and molecular level of biological interactions. To apply them in biological fluids or aqueous environment it is essential to modulate the chemical nature of magnetic nanoparticle surfaces to increase their water solubility and colloidal stability in aqueous medium. By employing different coating technologies they cannot only be rendered longterm stable in biological fluids but also functionalized to fulfill different tasks, like molecular targeting or linking of therapeutic agents. To achieve this goal different polymeric coatings are applied to provide solubility and stability in aqueous solution and additional functional groups for attachment. Taken together the versatile modifications described in this review improved the ability to specifically tailor the features and properties of magnetic nanoparticles for biomedical applications. PMID- 20201228 TI - Application of the quartz crystal microbalance to nanomedicine. AB - The quartz crystal microbalance (QCM) is a highly sensitive instrument which determines the nature of binding interactions in real time within a label free environment. Current advances in this technology have afforded increased stability, sensitivity, parallel control availability, high throughput capacity and an increased range of experimental configurations. QCM is ideally suited to the study of nanomedicine where investigation of nanovehicle performance in the biological milieu has become of increased clinical significance. Primary issues include activation of the complement system and induction of apoptosis. It is the aim of this review to discuss the opportunities afforded by the QCM in the mechanistic understanding of interaction in the biological environment and how this can be applied to improved nanoconstruct design to attain performance enhancement. PMID- 20201229 TI - Polymeric nanosensors for measuring the full dynamic pH range of endosomes and lysosomes in mammalian cells. AB - Polymer nanoparticle sensors have been constructed for studying pH in the endocytic pathway in mammalian cells. The pH sensors for fluorescence ratiometric measurements were prepared using inverse microemulsion polymerization with rhodamine as reference fluorophor and fluorescein and oregon green as pH sensitive dyes, which gave a dynamic pH measurement range from 4.1-7.5. Thus, the sensors cover the pH range of almost all intracellular compartments in mammalian cells. Both neutral and cationic polyacrylamide particles were synthesized where (3-acrylamidopropyl) trimethylammonium chloride was used to introduce a net positive charge in the cationic particles. It was found that the positively charged particle sensors were internalized spontaneously by HepG2 cancer cells. These new pH nanosensors are potential tools in time resolved quantification of pH in the endocytic pathway of living cells. PMID- 20201230 TI - P53 detection by fluorescence lifetime on a hybrid fluorescein isothiocyanate gold nanosensor. AB - p53 is a tumor suppressor whose detection in the body is highly valuable as marker for early cancer diagnosis and prognosis. In this report we have studied constructs based on gold nanoparticles (NPs) functionalized with specific anti p53 antibodies and with a fluoresceine derivative, FITC. The interaction of surface plasmons on gold NPs few nm in size, with fluorophores bound within few nanometers from the surface, induces changes in the fluorophore excited state lifetime. This parameter follows linearly the p53 concentration in solutions up to 200-400 pM, depending on the size of the NP, with an uncertainty approximatley =25 pM. We have evaluated the specificity of the nanosensor for p53 by testing it against bovine serum albumin, beta-lactoglobulin and lysozyme solutions. The titration of total cell extracts from p53 positive or p53-null cells with the anti-p53 antibody decorated gold NPs indicates that this construct is promising for possible applications to in vivo screening. PMID- 20201231 TI - Nucleic acid delivery to magnetically-labeled cells in a 2D array and at the luminal surface of cell culture tube and their detection by MRI. AB - The magnetic labeling of living cells has become of major interest in the areas of cell therapy and tissue engineering. Magnetically labeled cells have been reported to allow increased and controlled seeding, tracking, and targeting of cells. In this work, we comprehensively characterize magnetic nanoparticles (MNPs) possessing a magnetite core of about 11 nm, and which are coated with the fluorinated surfactant F(CF2)nCH2CH2SCH2CH2C(O)OLi and 1,9-nonandithiol (NDT) for the nonspecific labeling of human pulmonary epithelial (H441) cells. We achieved a non-specific cell loading of 38 pg Fe/cell. In this work we combine magnetic cell labeling with subsequent genetic modification of the cells with non-viral transfection complexes associated with PEI-Mag2 magnetic nanoparticles upon gradient magnetic field application called magnetofection. The magnetic responsiveness and magnetic moment of the MNP-labeled cells and the magnetic transfection complexes were evaluated by measuring changes in the turbidity of prepared cells suspensions and complexes in a defined magnetic gradient field. The magnetic responsiveness of cells that were loaded with NDT-Mag1 MNPs (20-38 pg Fe/cell) was sufficient to engraft these labeled cells magnetically onto the luminal surface of a culture tube. This was achieved using a solenoid electromagnet that produced a radial magnetic field of 20-30 mT at the seeding area and an axial gradient field of approx. 4 T/m. The MNP-labeled cells were magnetofected in 2D arrays (well plates) and at the luminal surface of cell culture tube. The optimized magnetic pre-labeling of cells did not interfere with, or even increased, the efficiency of magnetofection in both culture systems without causing cell toxicity. Cell loading of 38 pg Fe/cell of NDT-Mag1 MNPs resulted in high transverse relaxivities r2*, thus allowing the MRI detection of cell concentrations that were equivalent to (or higher than) 1.2 microg Fe/ml. Multi-echo gradient echo imaging and R2* mapping detected as few as 1533 MNP labeled H441 cells localized within a 50 microl fibrin clot and MNP-labeled cell monolayers that were engrafted on the luminal surface of a cell culture tube. Further loading of cells with MNPs did not increase either the magnetic responsiveness of the cells or the sensitivity of MR imaging. In summary, the NDT Mag1 magnetic nanoparticles provided a high cell-loading efficiency, resulting in strong cell magnetic moments and a high sensitivity to MRI detection. The transfection ability of the labeled cells was also maintained, thereby increasing the magnetofection efficiency. PMID- 20201232 TI - Development of a novel magnetic resonance imaging contrast agent for pressure measurements using lipid-coated microbubbles. AB - The aim of this study was to prepare gas-filled lipid-coated microbubbles as potential MRI contrast agents for imaging of fluid pressure. Air-filled microbubbles were produced with phospholipid 1,2-distearoyl-sn-glycero-3 phosphocholine (DSPC) in the presence or absence of cholesterol and/or polyethylene-glycol distearate (PEG-distearate). Microbubbles were also prepared containing a fluorinated phospholipid, perfluoroalkylated glycerol phosphatidylcholine, F-GPC shells encompassing perfluorohexane-saturated nitrogen gas. These microbubbles were evaluated in terms of physico-chemical characteristics such as size and stability. In parallel to these studies, DSPC microbubbles were also formulated containing nitrogen (N2) gas and compared to air-filled microbubbles. By preventing advection, signal drifts were used to assess their stability. DSPC microbubbles were found to have a drift of 20% signal change per bar of applied pressure in contrast to the F-GPC microbubbles which are considerably more stable with a lower drift of 5% signal change per bar of applied pressure. By increasing the pressure of the system and monitoring the MR signal intensity, the point at which the majority of the microbubbles have been damaged was determined. For the DSPC microbubbles this occurs at 1.3 bar whilst the F-GPC microbubbles withstand pressures up to 2.6 bar. For the comparison between air-filled and N2-filled microbubbles, the MRI sensitivity is assessed by cycling the pressure of the system and monitoring the MR signal intensity. It was found that the sensitivity exhibited by the N2-filled microbubbles remained constant, whilst the air-filled microbubbles demonstrated a continuous drop in sensitivity due to continuous bubble damage. PMID- 20201233 TI - Characterization of a new scaffold formed of polyelectrolyte complexes using atomic force and ultrasonic force microscopy. AB - Poly(acryloxyethyl-trimethylammonium chloride-co-2-hydroxyethyl methacrylate) [poly(Q-co-H)]/ sodium alginate gel (Ca2+) [AlgNa]/poly-l-lysine [PLL] films have been prepared on a mica surface. The structural arrangement and elasticity of the polyelectrolyte complexes have been studied with nanoscale resolution using Atomic Force Microscopy (AFM) and Ultrasonic Force Microscopy (UFM). The elastic contrast on the AlgNa surface is indicative of the formation of a biopolymer network. On the AlgNa film, the surface morphology is mostly characterized by areas with rounded beads (approximately =150 nm in diameter) and polymer strands. Flatter, more homogenous surface regions are also present, presumably related to outdiffused PLL. Incorporation of the poly(Q-co-H) layer results in an increased compactness of the film, and an enhancement of the previous AlgNa topographic features. The unique subsurface sensitivity provided by UFM allows us to resolve the elastic bonding distribution in the buried biopolymer network by imaging from the poly(Q-co-H) overlayer. Provided the biocompatibility of the resulting polyelectrolyte complex film, we propose this system as a novel scaffold for bioengineering applications. The results we present demonstrate the potential of UFM to get insight in the elastic behavior of encapsulated bionetworks. PMID- 20201234 TI - A novel coumarin fluorescent sensor to probe polarity around biomolecules. AB - Polarity-sensitive (solvatochromic) probes are useful tools to investigate on subtle biochemical processes which occur at membrane and subcellular level (e.g., the uptake and cell targeting of a functionalized nanoparticle). In this paper, we describe the development of a new solvatochromic biosensor. The probe is structured as a "push-pull" system, bearing an electron-rich naphtyl ring and an electron poor benzothiazene group, conjugated to a central coumarin core. These features confer interesting spectroscopic and solvatochromic properties to the fluorophore. The dye was derivatized with a versatile sulfonyl chloride functional group. We also demonstrated that solvatochromic properties are nearly maintained when the fluorophore is covalently linked to proteins usually employed for nanoparticle coatings (bovine serum albumin or streptavidin). Finally, we proved the efficiency of our polarity-sensitive probe by obtaining a statistically significant difference between the fluorescence signals of fluorophore-labeled streptavidin before and after addition of BSA-labeled biotin. PMID- 20201235 TI - Trafficking in human organs--dark facet of globalization. PMID- 20201236 TI - [Controversies regarding intraperitoneal chemotherapy for advanced ovarian cancer]. AB - Ovarian cancer is unique among solid tumors in its propensity to remain localized in the peritoneal cavity for much of its natural history. There is now a growing body of clinical data demonstrating a survival advantage for patients with advanced stages of ovarian cancer treated by intraperitoneal (i.p.) chemotherapy compared with standard intravenous (i.v.) treatment route. Cytotoxic agents administered directly into the peritoneal cavity, however, have limited potential for penetrating bulky tumor masses. On the basis of the results of three randomized, phase III clinical trials, i.p. chemotherapy has now been shown to be superior to standard i.v. chemotherapy in the primary setting of chemotherapeutic management of advanced epithelial ovarian cancer, with small residual volume after surgery. Despite the fact that i.p. chemotherapy has been shown to determine an improvement in survival, many investigators feel that the formidable toxicity, complexity, and quality of life alterations associated with i.p. therapy make it mandatory that it should be compared prospectively to a less toxic and more convenient regimen of i.v. carboplatin/paclitaxel. The barriers to implementing this treatment into clinical practice appear to be toxicity concerns, and a lack of technical expertise with the peritoneal infusion devices. It is critically important to state that a large body of exiting data revels this is a management approach that can be administered safely, but not in routine oncology practice, outside the setting of a clinical trial or tertiary medical center. PMID- 20201237 TI - [Pulmonary manifestations in childhood obesity]. AB - Obesity has an increasing incidence throughout the world, inducing a complex and multisystemic pathology. The respiratory manifestations are: restrictive respiratory physiology, reduced respiratory compliance, altered ventilation/perfusion index, bronchial hyperresponsiveness. Increases in body mass index (BMI) are associated with increases in prevalence, incidence and severity of bronchial asthma. The mechanic effects of obesity remain important, but the adipocites have many influences by the hormones, leptines, cytokines and other proinflammatory agents. PMID- 20201238 TI - [HIV infection associated cognitive disorders]. AB - The most frequent neuropsychiatric complication of the human immunodefienciency virus infection is cognitive impairment, wich may range in severity from a mild cognitive disorder to a severe dementing illness. HIV-associated dementia is known to be a poor indicator in patients with HIV. Caring for a person who develops cognitive impairment or even stable dementia is exhausting emotionally, psysically and financially. The most important difference between HIV-associated dementia and HIV associated minor cognitive disorder is the severity of impairment in activities of daily living. The purpose of this articol is to distinguish the most common symptomatology of this complication of HIV infection in order to prevent and treat cognitive deficits from the early stages if is possible. PMID- 20201239 TI - [The fever of international travel]. AB - Between 20 and 70 percent of the 50 million people who travel from the industrialized world to the developing world each year report some illness associated with their travel. Although most illness reported by travellers are mild, 20-70% of travellers become ill enough to seek medical attention, either during or immediately after travel. The full spectrum of health complaints is unknown. Nevertheless the usual presentation of a returned traveller is a particular syndrome-fever, respiratory infection, diarrhoea, eosinophilia, or skin and soft tissue infection- or screening for asymptomatic infection. The most common diseases diagnosed in returning travellers are more often of cosmopolitan than exotic origin. However, fever in returned travelers always should raise suspicion for a severe or potentially life-threatening tropical infection. Therefore, fever in a returned traveller requires prompt investigation focused on infections that are life-threatening, treatable or transmissible. Careful assessment of the travel history, likely incubation period, exposure history, associated signs and symptoms, duration of fever, immunization status, use or non use of antimalarial chemoprophylaxis and degree of compliance with the prescribed regimen, if used, helps to establish the diagnosis. Determining an approximate incubation period can be particularly helpful in ruling out possible causes of fever. Malaria is the most important cause of fever in the returned traveller. While most travel-related infections present within 6 months of return, some infections with long latent periods or potential for lifetime persistence might be seen in those who have lived abroad. PMID- 20201240 TI - [Cross-sectional study of leptospirosis cases admitted to the Iasi Clinic of Infectious Diseases over a 5-years period]. AB - Leptospirosis is a zooantroponosis manifested as an infection with a severe evolution, with liver and renal failure and haemoragic manifestation. The aim of the study was to present the epidemiologic, clinic and therapeutical aspects of 100 cases of leptospirosis admitted in the clinic of Infectious Diseases of Iasi, during 5 years (2002-2006). MATERIAL AND METHOD: The diagnostic was based on the clinical-biologic study and risk factors with febrile syndrome, mialgic syndrome, headache, meningial, liver and renal failure and hematological syndromes, with the serologic evidence of serotypes of leptospirosis. RESULTS: All the patients were serologic confirmed with leptospirosis. Leptospirosis is an emergent disease with the possibility of severe evolution in some forms, with lever and renal failure. PMID- 20201241 TI - [Retroprospective epidemiological study of toxocariasis cases hospitalized between 2005-2008]. AB - The authors presents the results of a retroprospective epidemiological study on toxocariasis cases admitted in the Paediatric Diseases Clinic of Iasi, between January 2005 - June 2008. MATERIAL AND METHOD: The study included a number of 228 children. RESULTS: The age distribution highlighted a predominance of 3-7 years of age group (46.9%); sex distribution, a significant predominance in males (53.5%) and a small advance the rural areas (54.3%) given the urban areas (45.6%). The present study lead to a spring-autumn seasonality. A high risk for infection is the dog (41.2%). The distribution of toxocariasis in children patients in Moldavia, Romania, highlighted a predominance in Iasi county (45.6%). PMID- 20201242 TI - [Clinical, computerized tomography and pathological findings of lesions in the parapharyngeal space]. AB - We present the clinical, computer tomografic and patological findings of current lesion of the parapharyngial space. MATERIAL AND METHOD: We retrospectivly analised the clinical, cross-sectional imaging files and the patological results for 33 patients explored during January 2006-March 2008 by a medical team at the "Prof. Dr. N. Oblu" Clinical Hospital. RESULTS: In our study we didn't find primitive lesions in the parapharyngial space but, we explored 33 lesions extended in the parapharyngial space with origins around the parapharyngial space. The most frequent hystological types of tumor were represented by squamous cell carcinoma of nasopharyngs (n = 22), followed by primitive lesions in to the infratemporal phosa (n = 5). We had also 2 tumoral cases of the parotyd gland, one of the skull base and 3 facial fractures with involvement in to the parapharyngial space. CONCLUSION: The infiltrations of parapharyngial space by different lesions require Computer tomographic exams for a precise evaluation of the extension of the lesions, evenetual lymph node metastasis, the presence of tumoral recidive and the orientation to a imagistic diagnosis which will be confirmated by a patological exam. The multidisciplinary approach of these lesions will permit a proper terapeutical management to each case. PMID- 20201243 TI - [Metabolic syndrome and breast cancer risk in post-menopausal women]. AB - Lipid metabolism disorders--breast cancer risk association in postmenopausal women was searched in many studies; the HDL-cholesterol value triggered most of controversies. Some authors plead for increased breast cancer risk in overweight/obese postmenopausal women if HDL is higher while others plead for higher risk if HDL is lower then in general population. MATERIAL AND METHOD: We studied a 110 subjects female population aged between 41 and 69, and determined height, weight, body mass index (BMI), abdominal perimeter (AP), lipid parameters (total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides). All women performed mammography and breast echography. Imagery divided the subjects in three groups: 30 breast cancer patients (first diagnosis)--group 1, 50 breast dysplasia women--group 2, and normal breast patients--group 3. RESULTS: HDL cholesterol proved significantly higher in group 2 compared to group 3 (control group), by the third and the fourth quartile; the same when it came to overweight/obese post-menopausal women. Nevertheless, more lipid disorders clustered in group 1 obese/overweight postmenopausal women. CONCLUSIONS: High HDL in breast dysplasia women is reported in international studies too. High menopause prevalence in group 3, implying abdominal obesity and lipid disorders may explain the small difference between group 1 (breast cancer patients) and group 3 (control group). High clustering in group 1 pleads for increased breast cancer risk in metabolic syndrome postmenopausal women. Comparing HDL values and the clustering phenomenon in group 1 to the other two groups considered as a control population (as done in international published studies), we can conclude that low HDL--abdominal obesity association increases breast cancer risk after the menopausal age. PMID- 20201244 TI - [Bone turnover markers evaluation in psoriatic arthritis]. AB - The aim of this study was to investigate the blood level of bone turnover markers: osteoprotegerin (OPG), bone alkaline phosphatase (Bone-ALP), and receptor activator of NF-kappa B ligand (RANKL) of patients with psoriatic arthritis. METHODS: Twenty-four patients with psoriatic arthritis (CASPAR classification criteria) and twenty healthy controls were included. The OPG, Bone ALP and RANKL levels were quantified by using ELISA method. RESULTS: Peripheral blood levels of bone turnover markers were higher in psoriatic arthritis than martors and there was a strong negative correlation between OPG-RANKL and Bone ALP- RANKL. CONCLUSION: The OPG and Bone-ALP serum level is strongly negative related to the increase in RANKL serum level in patients with psoriatic arthritis. The increase in OPG and Bone-ALP serum level induces the production of bone matrix parallel to the bone destruction mediated by RANKL. Follow up of patients with psoriatic arthritis, by use of early determination of RANKL, OPG and Bone-ALP serum levels, and also of bone metabolism markers (they have specific role in bone remodeling), allows a precise evaluation of disease activity and, in future, could be a criteria for the initiation of specific, targeting treatment. PMID- 20201245 TI - [Effect of memantine treatment on patients with moderate-to-severe Alzheimer's disease treated with donepezil]. AB - OBJECTIVE: Investigating the behavioral and cognitive effect of memantine in moderate to severe patients with Alzheimer's disease receiving donepezil. MATERIAL AND METHOD: 43 patients were enrolled in this prospective, randomized, parallel group study. There were no significant imbalances between the treatment groups in demographic and baseline clinical characteristics. Cognitive and global measures were collected at baseline and at the end of weeks 4, 8, 12 and 24. Behavioral measures were collected at baseline, at the end of week 12 and at week 24. RESULTS: Memantine--treated patients showed significantly less deterioration in their functionality. Of patients who exhibited agitation/aggression at baseline, those treated with memantine and donepezil showed significant reduction of symptoms compared with donepezil--treated patients. CONCLUSIONS: Treatment with memantine was well tolerated and reduced agitation/aggression, irritability, and appetite eating disturbances in patients who were agitated at baseline and delazed its emergence in those who were free of agitation at baseline. PMID- 20201246 TI - [Chilblain lupus in an adolescent]. AB - Chilblain lupus or lupus pernio is a particular clinical type of cutaneous chronic lupus erythematosus, more frequently met in adults and difficult do diagnose without specific lesions at the level of the face and/or the scalp. The patient B.A., female, aged 16 is hospitalized in the Dermatological Clinic Iasi for some red-to-violaceous plaques, infiltrated, slightly scaling located around the nails and on the hands and legs finger sides. The lesions come up at the age of 13 become even more serious and painful in cold weather, getting better in the warm season when they become slightly pruriginous and are accompanied by a discrete facial erythema in "vespertilio", completely neglected by the patient. The general status was very good during this time, without general manifestations or visceral touches. The clinical diagnosis that was initially suggested, pernio, was afterwards denied by a detailed anamnesis, by laboratory testes (positive antinuclear antibodies, positive anti-double-stranded DNA antibodies) and by the histopathological examination of the biopsy from cutaneous lesions. The introduction of the antimalarial drugs (Plaquenil 200 mg/ day) associated with photoprotective creams, led to cure of cutaneous lesions. PMID- 20201247 TI - [A severe case of infectious mononucleosis associated with ciprofloxacin and salazopyrin administration]. AB - We report a case of rash probably induced by ciprofloxacin and/or salazopyrin administration in a patient with infectious mononucleosis. A 22 year woman developed a maculopapular and petechial eruption in the 3-rd day of ciprofloxacin (given for a genital tract infection) and the 32-nd day of salazopyrin (for a spondylodiscitis). Subsequently she developed a severe hepatitis, shock, and very severe leucocytosis (88 000/mmc) that occasioned haematological investigations for a lymphoproliferative syndrome. PMID- 20201248 TI - [General principles of clinical and therapeutic management in postoperative external enteral fistulas]. AB - Postoperative enterocutaneous fistulas represent a frequent complication in the emergency or cancerous digestive surgery. As to the high level of mortality and morbidity caused by this type of postoperative complication (4%), efforts are made to establish the principles of therapeutic management, on the purpose of decreasing these indicators and thus lowering the prolonged hospitalisation afferent costs. PMID- 20201249 TI - [Natural history of alcoholic chronic pancreatitis in north-western Romania]. AB - AIM: To describe the natural history of alcoholic chronic pancreatitis (ACP) patients form north-western Romania. METHODS: We performed a retrospective analysis and a subsequent prospective follow-up (mean = 7.3 years) of 99 patients with ACP. Average duration of ACP was 15.6 years. RESULTS: Patients were mostly men (93%), with a mean age of 42.9 years at the time of operation and 35.7 years at the disease onset. Indications for surgery were: intractable pain (12%), complications (83%) and suspicion of malignancy (5%). During the evolution, 35 patients needed two to four surgical procedures. Calcifications developed in 63.6% of patients, steatorrhea in 41.4% and secondary diabetes in 43.4%. CONCLUSION: ACP in north-western Romania is characterized by early onset of the disease and a severe evolution with multiple complications needing repeated surgery. The "burnout" of the disease, with calcifications, secondary diabetes and marked exocrine insufficiency leads to lasting pain relief. PMID- 20201250 TI - [Laparoscopic cholecystectomy in pacients with child's class A cirrhosis of the liver and acute cholecystitis due to cholelithiasis]. AB - Cholecystectomy in cirrhotic patients has been reserved for patients with severe biliary disease, because of the high morbidity and mortality in cirrhotic patients undergoing this procedure. Laparoscopic cholecystectomy (LC) was originally contraindicated in cirrhotic patients because of the associated portal hypertension and coagulopathy. MATERIAL AND METHOD: This study examined the safety of LC in Child's class A patients and acute cholecystitis due to cholelithiasis in patients from "Sf. Ioan" Emergency Hospital Iasi. The studied period was January 2001 - December 2005. Ten patients with cirrhosis had their gallbladder removed laparoscopically during that time period. All patients were Child's class A. RESULTS: The average age was 62,5 (range, 56-68). The operative indication was acute cholecystitis. Three patients were previously diagnosed with cirrhosis, and 7 were diagnosed intraoperatively. None of the patients required a blood transfusion. No intraoperative or postoperative complications occurred. No deaths occurred. Postoperative stay was 5.8 days. These results compare favorably to other published studies from international literature. CONCLUSION: Based on our findings, we believe LC can be performed safely in patients with class A cirrhosis. PMID- 20201251 TI - [Intraoperative injuries of the biliary tract]. AB - Statistically speaking, the intraoperative lesions of common bile duct are rare clinical cases, but they have a high gravity potential. Our study was made on a lot of 11 operated pacients during 1995-2007 in our Clinic and it shows the tactical and technical approach used in solving these complications. The study also shows the high level of difficulty of these cases, as immediate recognition of this type of intraoperative lesions is needed. The successful evolution of these cases depends on how quickly the lesions are found and solved. PMID- 20201252 TI - [Celioscopic exploration in polytrauma with neurosurgical component]. AB - Caelioscopic surgery has been introduced in the medical practice for only two decades and imposed as a method due to its multiple advantages, expanding its application to therapy and exploration. If, initially the traumatic pathology of the abdomen has been used, this paper proposes the expansion of this method in polytraumatisms with neuralsurgical components, and not only. MATERIAL AND METHOD: This paper presents a study made on 67 cases with the Emergency Hospital of Piatra Neamt, of which 22 patients (33%) after the caelioscopic exploration requested surgical intervention. RESULTS: In 26 cases we have limited to caelioscopic exploration and eventually, peritoneal drainage, and 19 cases have only been monitored. Thus it is covered a segment of pathology to which paraclinical exploration, respectively abdominal echography and CT, does not provide a certain diagnosis in post-traumatic abdominal lesions. This method is relatively easy for a general surgeon and can be successfully applied in neural surgical lesion associations, within a good cooperation of guard teams and much better within a polytraumatic centre. This is how morbidity and even mortality can be significantly reduces. PMID- 20201253 TI - [Surgical treatment of lung hydatid cysts]. AB - Lungs represent the econd most common localization of hydatidosis, after liver. The current treatment for pulmonary hydatid cyst (PHC) is complete excision with maximum preservation of lung tissue. The authors emphasize the particularities of diagnosis and surgical treatment of PHC. MATERIAL AND METHOD: A clinical retrospective study was carried out on a series of 247 cases with PHC, admitted in the Thoracic Surgery Department of Pneumology Hospital of Iasi between 1999 and 2007. Data regarding the clinical picture, imagistical findings and surgical treatment were collected from the medical files and reviewed. RESULTS: There were 162 men and 85 women, aged between 11 and 78 years. Of these, 134 patients had uncomplicated cysts and 113 had complicated forms. The cysts were located in the right lung in 115 cases (46.5%), the left lung in 98 cases (39.5%) and bilaterally in 34 cases (14%). Liver cysts were associated in 28 cases (11.3%) cases. The surgical procedures employed were: Dor in 118(47.5%) cases, Posadas in 64 (26%) cases, Geroulanos in 5 cases and ideal cystectomy in 14 cases. Pulmonary resection was used in 46 cases (18.5%), including 16 wedge resections, 27 lobectomies and 3 pneumonectomies. Medical parasiticide (Albendazole, 800 mg per day) was used postoperatively. The outcome was fatal in one patient (0.41%), mainly due to associated pathology. In our series, the overall incidence of complications was 7.7%, these consisting of: anaphyfilaxis (3 cases), hemothorax (2 cases), pneumothorax (2 cases), prolonged air leak in 5 cases (including a bronchial stump insufficiency) and atelectasis (5 cases). CONCLUSION: Surgery is the mainstay of the treatment of PHC and the operative technique must be adapted to each individual case. PMID- 20201254 TI - [Unusual forms of liver abscesses]. AB - Liver abscess is a rare disease. In this paper we present five unusual cases of liver absceses. These cases represents 5.68% from all patients with liver abscesses treated in the First Surgical Clinic Iasi, from 1977 to 2007. The ethiology of the abscesses was different: intrahepatic biliary duct migration of Ascaris lumbricoides, migration of a foreign body (toothpick) from stomach into the liver, infected hydatid cyst with a large biliary leak and cholangitis and, residual cavities after surgical treatment of hepatic hydatid cyst associated with foreign bodies. Another case was a patient with a very large, multilocular liver abscess (2000 mL) with biliary ethiology. In all cases a surgical drainage was performed. In the cases with hydatid cysts and biliary leakage, ERCP procedures were performed. The postoperative course was uneventful. CONCLUSIONS: Surgical treatment remains a valuable option in the treatment of pyogenic hepatic abscesses especially in unusual form. PMID- 20201255 TI - [Isolated retroperitoneal Castleman's disease]. AB - Castleman's disease is a rare disorder characterized by proliferation of the lymphoid tissue. Castleman's disease affects both males and females, and may occur at any age. Little is known about how often Castleman's disease actually occurs, other than it is rare, or what causes the disease. The most frequent location of the disease is the mediastinum. The location of the disease in the retroperitoneum is rare and it is usually associated with the generalized form of the disease. We report a case of a 34-year old man with isolated retroperitoneum Castleman's disease of the hyaline-vascular type, which presented as a palpable abdominal mass. The final diagnosis was reached after exploratory laparotomy and resection of the tumor. PMID- 20201256 TI - Septal myomectomy and coronary artery bypass in one case of hypertrophic obstructive cardiomyopathy. AB - Surgery of the hypertrophic cardiomyopathy remains controversial. The safest procedure and the simples procedure is the mitral valve replacement. Septal myomectomy is difficult because of the poor surgical exposure and complications: incomplete resection, complete heart block, ventricular septal defect. CASE PRESENTATION: A 56 years old man with hypertrophic cardiomyopathy, double coronary stenosis and grade II mitral regurgitation by systolic anterior motion was long time stable under treatment with b-blockers. He developed angina and the circumflex and the left anterior descending arteries were stented. Re-stenosis developed in the left anterior descending stent and the patient was referred to surgery. The intraventricular gradient was 80 mmHg and the maximal septal thickness 28 mm. He was successfully treated by septal myomectomy and bypass on the left anterior descending artery with the left internal thoracic artery. Perioperative transesophageal echography was used to establish the limits of the surgical resection and to control the remnant gradient. The patient is asymptomatic 6 months after the procedure, he has a 30 mmHg remnant gradient and a grade I mitral regurgitation. CONCLUSION: Septal myomectomy is a safe alternative to mitral valve replacement for hypertrophic cardiomyopathy. This procedure must be guided by perioperative transesophageal echography to avoid incomplete resection. PMID- 20201257 TI - [True posttraumatic femoral artery aneurysm: a rare clinical entity]. AB - Traumatic etiology in aneurysms is very rare. After arterial trauma we usually find pseudo aneurysms. True aneurysms are due to deterioration of the arterial wall in small and long-term repetitive trauma. Pseudo aneurysms are usually described on radial and cubital artery in patients who work with vibrating tools ("hypothenar and thenar hammer syndrome") and on axilar artery in those who use axilar crutches. We present a case of a woman with a true aneurysm of the femoral artery developed due to repetitive trauma of the femoral region at the work place. The patient presented as an emergency, with ruptured aneurysm and she underwent an emergency operation. The diagnosis was established late by histopathological examination. This is the first case of posttraumatic true aneurysm with this location. True aneurysms should be considered in repetitive trauma regardless of anatomical region. PMID- 20201258 TI - [New approaches in coronary microcirculation]. AB - The last decades, coronary microcirculation has become a very important territory because of its role in coronary circulation physiology and pathophysiology. Only its implication in coronary artery disease was known at the beginning, but subsequently its role in many others diseases was shown. The nontraditional pathophysiological construct sustains that myocardial microcirculatory dysfunction is the primary event, and the atherosclerotic plaque rupture or erosion is the secondary event. In some instances, the coronary microvascular dysfunction may be an epiphenomena, an important marker of risk or even a cause, thus becoming therapeutic target. PMID- 20201260 TI - Modulatory role of bivalent cations on reward system. AB - Bivalent cations (Ca, Mg, Zn, Mn etc.) modulate activity of reward system (RS). At physiologic levels they may influence all components of RS. There are influenced behavioral reactions at physiological stimuli and all essential elements of drug dependence (compulsive intake of substance, craving, reinforcement, withdrawal syndrom, relapse and reinstatement of intake) The fact that some cations (e.g. calcium) enhance some of the aspects of drug dependence and others (e.g. magnesium, zinc) decrease intensity of this process show that ratio between intra- and extracellular in the brain of these cations is important for the function of RS. Among actions of different cations at the level of RS there are important differences. Their mecahanism of action are common in part and specific in other. It is important the fact that modulatory action appear at physiologic cation concentrations (that could be reached at therapeutic doses). Modulatory action is related to ratio between concetrations of different bivalent cations and is exerted both in normal or pathologic conditions. PMID- 20201259 TI - Adipokines involvement in lung function. AB - The last two decades brings many data about white adipose tissue capacity to secrete hormones, named adipokines, which could mediate the relationship between obesity and lung diseases. In this paper we presented some data about adipokines involvement on pulmonary function, with special emphasis on leptin, adiponectin, tumor necrosis factor alpha, vascular endothelial growth factor, resistin, hepatocyte growth factor, interleukin-6, angiotensinogen and apelin. PMID- 20201261 TI - [Scintigraphic visualization of Pgp protein: a non-invasive method to evaluate the MDR cellular character]. AB - The MDR character is a major factor that influence the effectiveness of cancer chemotherapy. This feature can be noninvasively evaluated through 99mTc isonitrils (MIBI, Tetrofosmin) scintigraphy, because these radiotracers cellular efflux is mediated by the Pgp membranar active transport system, the same that mediate chemotherapy drugs cellular efflux. The Pgp glycoprotein overexpression in the case of the MDR positive tumoral cells will determine both the chemotherapic drug and the isonitrile radiotracer quickly efflux from the cell. This paper present, based both on the literature and personal authors research work, the principle of the method, radiotracers structural characteristics and cellular uptake mechanism, practical protocol details from the acquisition untill the qualitative and quantitative image processing and results interpretation. Quantification indexes are proposed for the radiotracer cellular uptake quantitative evaluation on the scintigraphic image. The results could bring the possibility to make MDR positive patient diagnosis and further selection for the MDR modulators drug therapy. PMID- 20201262 TI - [Immunohistochemical evaluation of topoisomerase IIalpha as proliferation factor in gastric lymphoma]. AB - Topoisomerase IIalpha is a nuclear enzyme essential for DNA replication, with presumed prognostic value in various tumors. MATERIAL AND METHODS: Study group included 34 gastric lymphomas. Tissue samples, formalin-fixed, paraffin-embedded, were investigated by immunhistochemistry using monoclonal antibodies anti Ki67 and anti topoisomerase IIalpha. RESULTS: The 34 gastric lymphomas were previously diagnosed as follows: 14 MALT lymphoma and 20 aggressive lymphoma (17 diffuse large B-cell lymphoma, 2 diffuse large B-cell lymphoma with minor MALT component and 1 peripheral T-cell lymphoma). Both markers (Ki67 and topoisomerase IIalpha) were positive in 2-31% of tumor cells in MALT lymphoma, while in aggressive lymphoma up to 46-98% of tumor cells showed a positive expression. CONCLUSION: Similar expression of Ki67 and topoisomerase IIalpha recommends the utilization of topoisomerase IIalpha in determining the proliferation fraction in gastric lymphomas. In addition, we suggest that it might be possible to use topoisomerase II inhibitor agents in high grade gastric lymphomas. PMID- 20201263 TI - [Matrix metalloproteinase 9 presence in adhesive intraperitoneal processes]. AB - Matrix metalloproteinases (MMP) represents a zinc-dependent proteolytic enzyme multigenic family, directly involved in embryogenesis, some physiological and pathological processes, occurring in the adult organism. For physiological processes, MMP play roles in proliferation, tissue remodeling, wound healing, angiogenesis. AIM: The aim of the study was to analyze the MMP9 presence in chronic peritoneal adherences, following the correlation between the presence of this metalloproteinase and the evolution of the connective tissue remodeling process from intraperitoneal adherences. MATERIAL AND METHODS: 6 women formed the study group: 5 operated for gynecological pathologies (with harvested tissue fragments from the adherences) and one patient with harvested tissue from normal peritoneum. Fragments were fixed in 10% formalin and processed for the microscopic exam in routine staining and immunohistochemistry, using anti-MMP9 antibodies and a technique based on peroxidaze-antiperoxidase system. The immunohistochemical reaction was quantified by using image analysis software. RESULTS: The morphological structure of the adherences was mainly represented by fibrous tissue, sometimes associated with elements of muscle and adipose tissues. For the fibrous connective tissue, the collagen component was characterized by a fascicular organization with different orientations and with fibrillar aspect. Semiquantitative analysis showed increased levels for MMP9 in adherences by comparison with normal peritoneum (mean ration for the MMP9-positive area: 26.5% for the adherences versus 15.93% normal peritoneum). CONCLUSION: The intraperitoneal adherences with more than 1 year of evolution show an extension of the remodeling processes that can lead to the possible resolution. PMID- 20201264 TI - The influence of leukotriene receptors' antagonists on experimentally induced ulcer in rats. AB - AIM: Gastric mucosal cells synthesize a large number of eicosanoids (including leukotrienes) which are distinctively involved in ulcerogenesis. This experimental study investigated the effect of 4 leukotriene receptors' antagonists on indomethacin(IND)-induced ulcer in rats. MATERIAL AND METHODS: Animals were divided into six groups (of 8 rats each) which received as follows: group I (control)--saline; group II--IND 20 mg/kg p.o.; group III--montelukast sodium 10 mg/kg p.o. and IND 20 mg/kg p.o.; group IV-- a quinolinic derivative (19363) 20 rM/kg p.o. and IND 20 mg/kg p.o.; group V--a phenethylamido derivative (20599) 20 microM/kg p.o. and IND 20 mg/ kg p.o.; group VI--a resatophenone derivative (19072) 20 microM/kg p.o. and IND 20 mg/kg p.o. Animals were sacrificed eight hours after the last administration. The gastric index (UI), gastric pH and histopathological exam were performed on the removed stomachs. RESULTS: UI was 25.8 +/- 6.3 in group II, 10.20 +/- 2.3 in group III (p < 0.05), 21.60 +/- 2.8 in group IV, 13.40 +/- 2.4 in group V (p < 0.05) and 20.80 +/- 3.9 in group VI. pH values were 2.2 +/- 0.3 in group II, 3.4 +/- 0.9 in group III (p < 0.05), 2.6 +/- 0.8 in group IV, 2.9 +/- 0.7 in group V and 2.5 +/- 0.6 in group VI. The histopathological exam revealed: (i) typical lesions for ulcer in groups II, IV and VI, the most severe being in group II; (ii) only superficial non hemorrhagic erosions in group V; (iii) small erosion areas alternating with large zones of normal mucosa in group III. The obtained data demonstrated different degrees of gastro-protective activity for the studied leukotriene receptor antagonists. CONCLUSION: Especially montelukast but also phenethylamido derivative (20599) exhibited a partial gastro-protective effect on IND-induced ulcer in rats. PMID- 20201265 TI - [New polyphenolic extracts for oxidative stress treatment in experimental diabetes]. AB - The paper focuses on the extraction and purification by chromatographic and spectral methods of certain natural polyphenolic extracts from Aronia melanocarpa and common elder (Sambuccus nigra) fruit, and also on their effects in hypoinsulinemic diabetes mellitus. MATERIAL AND METHOD: The research was made upon Wistar rats, which were divided into 4 groups: group I--control group; group II--with polyphenols in a dose of 0.034 g/body-kg; group III--with diabetes mellitus, induced by 55 mg/body-kg of streptozotocyne; group IV--to whom was administered a solution of polyphenols, 12 weeks, after the onset of diabetes mellitus. RESULTS: Glycosylated hemoglobin values are much higher in the diabetic group and they are significantly lower in the group protected by polyphenols. The serous activity of glutathione-peroxidase and superoxide-dismutase has significantly lower values in the diabetic group as compared to the group protected by polyphenols. The serous concentration of malondialdehyde in the diabetic group undergoing polyphenols treatment is lower as compared to the diabetic group, which means a significant decrease of lipid peroxides in the serum. The results demonstrate the hypoglycemic, hypolipemic and antioxidant effects of Aronia melanocarpa and Sambucus nigra extracts in streptozocin-induced diabetes. PMID- 20201266 TI - [Investigation of statistic data evolution with social impact]. AB - Usually statistical analysis of medical and social data consists the final product of the research activity, the mean values, percentages, deviations etc. being an important information to share with other researchers. This paper shows the alternate possibility, using the statistical analysis to discover conclusions not so obvious from the available data. We use this method to analyze couples evolution towards marriage or towards divorce. Age influenced tendency is determined from official referendum and statistical data regarding both married and cohabiting couples. PMID- 20201267 TI - [New trends for the occupational health in accordance with the European program]. AB - The development of the European schedule of the occupational diseases has the aim to harmonize the data from all Member States. For this purpose European Agency for Safety and Health at work recommends for all the Member States to progressively make their statistics concerning occupational diseases, compatible with European schedule, in order to evaluate the incidence of the recognised occupational diseases and to define quantified criteria for the recognising each occupational disease. The presented data allude to the incidence of the recognised occupational diseases for the first time in 2001, supposed reference year, and to the deaths due to occupational diseases. The used indicators were the number and incidence rate of occupational diseases by sex, age, economic activity, occupation and causative agents, workplaces, exposed professions. PMID- 20201268 TI - [Cross-sectional epidemiological research on genital and breast cancers in the North-East region of Romania]. AB - The genitals and breast cancers takes an important place in the women's pathology, either through the increase numbers of cases and also through the mortality induced by these cases. AIM: The descriptive evaluation of the genitals and breast cancers and there risk factors to women from North-Eastern region of Romania. MATERIAL AND METHOD: We have been included in the study 105 women (age range 23-77 years, mean 53,77) diagnosed with breast cancer, ovarian cancer, endometrial cancer and cervical cancer at the hospital admission, residency in the "Cuza Voda" Iasi Hospital--Obstetrics and Gynecology Clinic (I, II, and IV Gynecologic Clinics) and "Elena Doamna" Iasi Hospital--Obstetrics and Gynecology Clinic (III Gynecologic Clinics) within 11 months. We have used a special questionnaire for the evaluation of the risk factors. Trained interviewers identified and questioned cases. The following parameters were assessed: marital status, educational level, age at menarche, age at the first sexual contact, age at first birth, parity, spontaneous abortions, period of breast-feeding, menopausal status, age at menopause, family history of cancers, personal history of gynecologic diseases, body mass index, oral contraceptive use, hormone replacement therapy use, environmental exposures, Pap test. After data collection, these have been codified and included in a MS Excel Database, in order to be processed with SPSS 13 and EpiInfo 3.4.3. (2007) softwares. RESULTS: The following cases' repartition on diagnostic types was observed: breast cancer (41 cases), cervical cancer (24 cases), endometrial cancer (12 cases) and ovarian cancer (7 cases). The cases mean of age was 56.22 years for breast cancer, 46.29 for cervical cancer, 59.75 for endometrial cancer and 54.86 for ovarian cancer. In our study, the most affected range of age was 50-59 years for breast cancer (p = 0,00033), 40-49 years for cervical cancer (p = 0,00257), 60-69 years for endometrial cancer (p = 0,211) and 50-59 years for ovarian cancer (p = 0.032). A significant correlation was observed between types of neoplasia and obesity (division by 2 = 25.277, p = 0.046), HPV infection (chi2 = 47.49, p = 0,022), stage (chi = 88.27, p = 0,010) and between age and diagnostic (chi2 = 252.15, p = 0.00017). From 84 cases, 10 have presented ASCUS lesions, 7 HGSIL, 4 carcinoma, 3 LGSIL and 1 AGCUS lesions. CONCLUSION: The diagnostic, educational level, age at first birth over 30 years was directly correlated with histological types. In our study, the mains factors correlated with types of neoplasia were obesity, HPV infections, stage and age. PMID- 20201269 TI - [In vitro susceptibility of staphylococci to ciprofloxacin]. AB - OBJECTIVE: To evaluate the in vitro activity of ciprofloxacin against communitary and hospital staphylococcal strains isolated during 2006-2008 in Eastern region of Romania. MATERIAL AND METHODS: We have tested 1022 staphylococci strains, identified by conventional laboratory methods. Minimum inhibitory concentrations (MICs) were determined by agar dilution method, according to NCCLS. RESULTS: For both hospital and communitary isolates, MIC 90 was 0.25 mg/L (4 fold less than breakpoint for sensitivity). Resistance was absent or reduced (1.7%) for coagulase- positive staphylococci, both communitary and hospital. For coagulase negative staphylococci, resistance for clinical strains is increased (6%) compared to comunitary strains (0.3%). In conclusion, ciprofloxacin is highly effective against staphylococci representing a therapeutic option for multiresistant strains. Our data shown the necessity of adequate antibiotic use in the hospital and community. PMID- 20201270 TI - [Anaerobic Gram-negative bacilli involved in the etiopathogeny of the abscesses of superficial fascial spaces of the face and neck]. AB - The aim of this study was to isolate and identify at species level the strains of anaerobic Gram-negative bacilli (GNB) from pus samples collected in patients with abscesses of fascial spaces of the face and neck. Microscopy of Gram-stained smears and cultures were performed in each specimen. The strictly anaerobic GNB strains were identified using the conventional methods of diagnosis and the Rapid ID 32 A system. In addition, the other strains isolated in association with these bacteria were identified at least to genus level. The 28 anaerobic GNB isolates belonged to: Fusobacterium nucleatum and different species of Prevotella (4 species) and Bacteroides (3 species). CONCLUSIONS: The anaerobic GBN strains were recovered--either alone or in association with other migroorganisms--in more than half of all investigated samples and represented about 40% of all isolates. The most frequently isolated species were P> melaninogenica and B. ureolyticus. PMID- 20201271 TI - [Nutritional behaviour at persons between 55-70 years of age from different activity domains]. AB - In the present work we decided to find out more about nutritional behaviour at persons between 55-70 years from the four activity domains, representative for the professional background of the Dolj county (agriculture, education, industry and health), using the following hypothesis of work: the grade of medical culture specific for some groups of population induces decisive changes in the nutritional behaviour and, after that, in the health state and professional performance. MATERIAL AND METHOD: 129 subjects were included in the research, with the age between 55 and 70 years, selected from the recalled activity sectors. With the aim of knowing the nutritional behaviour, we have done a nutritional inquiry, each subject completed thee kinds of questionnairies. RESULTS: The farmers and the subjects from industry preferred to eat cheese, eggs, vegetable concentrated lipids and cereal products which were consumed in excess; on the oher hand, they ate few meat and meat products, fish, animal concentrated lipids, vegetables and fruits, sugar and sweets. The educators preferred more various food: meat products, cheese, eggs, vegetable concentrated lipids, cereal products, bread, dried vegetables, sugar and sweets, but they consumed few milk, meat, vegetables and fruit. The food preffered by the persons coming from health was: meat and meat products, cheese, eggs, vegetable concentrated lipids, cereal products, dried vegetables but some of them were eaten in excess. Any proteins were consumed in excess by the subjects coming from agriculture, education and health, and almost normally by the persons coming from industry. Sweets were deficiently used by the persons coming from agriculture and industry and in excess by those ones coming from education and health. Lower caloric values were observed in patients belonging to the second age group coming from health and education. Mineral and vitamins consumption was in deficit in all the subjects we studied. CONCLUSION: We could identify two kinds of nutritional behaviour: one common for the persons from agriculture and industry and the other very resembling for the persons from educational and medical sector. PMID- 20201272 TI - [Food intake and colorectal cancers; an ecological study in Romania]. AB - The aim of the present study performed in a Romanian population was to identify the food which can be either associated with or protect against colorectal carcinoma. MATERIAL AND METHOD: Correlation and regression analysis were used to examine the association between dietary intake and the rate of incidence for colon, rectum and anus cancers, in study groups from 7 regions of Romania. RESULTS: A strong and positive association was observed for colonic cancer and the intake of coffee, tea and cocoa (r = 0.77, p = 0.042) whereas statistical significance of borderline value was found for margarine (r = 0.73, p = 0.06) and sweets (r = 0.74, p = 0.066) intake. A potential protective effect can be attributed to wine consumption ( r = -0.75, p = 0.03). The malignancies of the rectum and anus showed both a strong positive correlation with the intake of red meat ( r = 0.76, p = 0.048), sausages ( r = 0.87, p = 0.012), margarine (r = 0.97, p = 0.0004), butter ( r = 0.76, p = 0.049), sweets ( r = 0.93, p = 0.003), beverages (r = 0.97, p = 0.0003), coffee, tea, cocoa ( r = 0.94, p = 0.002). Negative correlations were reported for the recto-anal cancer and the consumption of: fish (r = -0.8, p = 0.032), cheese (r = -0.9, p = 0.006), wine (r = -0.85, p = 0.015). CONCLUSION: The need for reducing the dietary intake of margarine, red meat, sausages and sweets while the beneficial effects of wine consumption have been also confirmed. PMID- 20201273 TI - Investigation of dental-plaque formers biofilms by optic and confocal laser scanning microscopy and microbiological tools. AB - The aim of the present study was to investigate the dental plaque formed on natural teeth surfaces by optic and confocal laser scanning microscopy (CLSM), to quantify the microbial density by viable cell counts, to identify the recovered microbial strains, the antibiotic susceptibility testing and their pathogenicity features (i.e. adherence and invasion capacity on HeLa cells, adherence on prostetic substrata used in oral medicine by original experimental models, production of extracellular enzymes and exotoxins). results: The CLSM revealed a very complex and highly organized architecture of dental plaque. The direct optic examination of Gram-stained smears revealed a great diversity of morphological types (82.5% of cases), with comparative levels of microbial densities. 50% of recovered microbial strains exhibited ability to adhere to three different polimeric inert substrata used in oral medicine, but reduced adherence and invasion capacity of HeLa cells and scared expression of soluble enzymatic factors. PMID- 20201274 TI - [Evaluation of children's emotional profile for ambulatory dental and oral surgery]. AB - Oral surgery interventions are for a child patient a stressfull moment, full of strangers, with large mental load and neuro-vegetative dystonia. MATERIAL AND METHOD: 236 patients with oral surgery problems treated in the Maxilo-facial Surgery Clinic in the 1.10.2006 - 1.01. 2008 were investigated for emotional items based on assessment scales. RESULTS: Perception surgical act is associated by the small patients in 100% with painful phenomenon. Dental anxiety is associated mainly with a negativist behavior and its primary source is a pain or fear of pain, pain being an experience that every person--adult or child, living a more or less frequently, with greater or lesser intensity. Moreover, intensely anxious patients are most sensitive to pain. PMID- 20201275 TI - [Experimental study regarding the involvement of vitamins in the development of the dentomaxilar system]. AB - The severe deficiencies of maternal nutrition in vitamins, both before and during pregnancy, might induce severe alterations of developing teeth in embryos and very young rats. Thus, the morphologic analysis of embryonic preparations revealed blood vessels slightly widen out, without turgescence, increased cellular density with oedema of the conjunctive tissue, foamy aspect of cells from mesenchyma. The adult preparations presented decreased cellular density with important fibrosis and presence of foamy cells, lack of dentine formation with small and diffuse proteinic accumulations, rarefied blood vessels, lack of enamel formation. PMID- 20201276 TI - Clinical and pathological aspects of epithelial hyperplasia. AB - In many cases, the oral health status indicates the general status of the body. 90% of the disorders of the body also manifest at the level of the oral cavity, which means that the dentist can draw the attention of a certain health problem. Diabetes mellitus is associated with a high prevalence of the lesions of the oral mucous, especially lichen planus, recurrent aphthous stomatitis or oral candidiasis. We present here a case of diabetes mellitus with hyperplasic lesion at the level of the inferior vestibule, extended to the right jugal mucosa. The lesion appeared pursuant to the application of removable prosthetics. The biopsy specimen was examined using normal and special staining (HE Hematoxiline - eosine, Van Gieson VG) and immunohistochemistry (IHC). In the HE stain, an epithelial hyperplasia was noticed as a result of the proliferation of the basal cells, associated with hyperkeratosis (parakeratosis or orthokeratosis). A moderated inflammatory limphoplasmocitary infiltrate, composed by lymphocytes and plasma cells, was present within the hyperplasic chorion. The immunohistochemical reactions revealed Ki-67 positive nuclei in the basal and suprabasal strata (indicating an increased proliferating activity); rare p53 positive nuclei in the basal stratum (indicating a suppressive action on the cell proliferation); CD3/CD8 positive cells in the inflammatory infiltrate (indicating an important number of T suppressor lymphocytes in the inflammatory infiltrate). In conclusion, diabetes mellitus is a disease which frequently determines major modifications at the level of the oral cavity. Interdisciplinary collaboration between the pathologist and the dentist is necessary for adequate diagnosis and successful treatment. PMID- 20201277 TI - In vitro antimicrobial activity and chemical composition of the essential oil of Foeniculum vulgare Mill. AB - In our study, four samples of volatile oil from Foeniculum vulgare, cultivated in different pedoclimatic conditions, were investigated for their antimicrobial activity and chemical composition. MATERIAL AND METHODS: Organisms. Staphylococcus aureus ATCC 25923, Bacillus cereus, Pseudomonas aeruginosa, Escherichia coli ATCC 25922, Candida albicans were included in the report. Antimicrobial susceptibility tests. The comparative inhibitory activity of volatile oil samples with other antimicrobial agents was quantitative determined by minimum inhibitory concentration (MIC). Oil samples are the volatile oils extracted by steam distillation, from two ecological vegetative populations of Foeniculum vulgare. Gas chromatography coupled to mass spectrometry (GC-MS) was used to determine the chemical composition of the essential oils. RESULTS: All oil samples have a good activity against E. coli and S. aureus at low concentrations. Against B. cereus and P. aeruginosa these oil samples are less active. The oil samples were generally bactericidal at a concentration up to twofold or fourfold higher than the MIC value. Significantly synergic activity with amoxicillin or tetracycline showed all fennel samples against E. coli, Sarcina lutea and B. subtilis strains. Fennel oil samples have shown high activity against Candida albicans. CONCLUSION: No significant antimicrobial activity variations were observed for Foeniculum vulgare volatile oil samples obtained after two or three years cultivation period. The most important identified compounds in all samples of fennel volatile oils were trans-anethole, estragole, fenchone, limonene, alpha-pinene and gamma-terpinene. PMID- 20201279 TI - Chemical composition and in vitro antimicrobial activity of essential oil of Melissa officinalis L. from Romania. AB - Melissa officinalis L. (lemon balm) is used in traditional medicine to treat insomnia, anxiety, gastric conditions, psychiatric conditions, migraines, hypertension and bronchial conditions. Natural essential oils (mixtures of fragrant chemical) obtained from various parts of plants are efficient active antimicrobial agents. The widespread use of antimicrobial agents selects resistant bacterial strains, which seriously compromise the effectiveness of antibiotic treatment. The use of herbal medicines might be a precautionary measure to prevent the development of lack of susceptibility to synthetic antibiotics that is associated with therapeutic failures. MATERIAL AND METHODS: In this work, the chemical composition and the antimicrobial properties of essential oil from romanian Melissa officinalis were determined. Therefore, the purpose of this study was to evaluate in vitro antimicrobial activity of lemon balm oil by comparison with lavender essential oil, which is also utilised for its antimicrobial properties in folk medicine. RESULTS: The most important identified compounds, well known for their antimicrobial effects were citral (neral and geranial) (16.10%), citronellal (3.76%) and trans-caryophyllene (3.57%).The lemon balm oil sample exhibited a higher degree antibacterial activity than did Lavandula oil against Gram-positive strains. The both oil samples tested has shown a high activity against Candida albicans. The gram negative bacteria were not affected by the lemon balm oil. PMID- 20201278 TI - New method for determination of dydrogesterone in human plasma for therapeutic drug monitoring in gynecological disorders. AB - A new simple, sensitive and selective liquid chromatography coupled with mass spectrometry (LC/MS) method for quantification of dydrogesterone in human plasma was validated. MATERIAL AND METHOD: The analytes was eluted in 1.3 minutes on a reversed phase column (Zorbax SB-C18, 100 mm x 3.0 mm I.D., 3.5 microm) under isocratic conditions using a mobile phase of a 20 : 80 (v/v) mixture of ammonium acetate 1 mM and acetonitrile. The flow rate was 1 mL/min at the column temperature of 35 degrees C. The detection of the analyte was in MS/ MS mode using an atmospheric pressure chemical ionization source (APCI+, m/z 313 > m/z 295). The sample preparation was very simple and rapid and consisted in plasma protein precipitation from 0.2 mL plasma using 0.6 mL methanol. RESULTS: Calibration curves were generated over the range of 5-150 ng/mL with values for coefficient of determination greater than 0.997 and by using a weighted (1/y) linear regression. The values of precision and accuracy were less than 12.5% and 7.5%, respectively, both for within- and between-run analysis. The mean recovery of the analyte was 99.8%. This is the first reported method for analysis dydrogesterone in human plasma that uses protein precipitation as sample processing procedure. The validated LC/MS method could be applied for determination of dydrogesterone in human plasma for therapeutic drug monitoring in gynecological disorders. PMID- 20201280 TI - [Stability of some medicinal solutions with captopril]. AB - The aim of the study was to investigate the stability of some oral liquid formulations containing 1 mg/ml captopril. MATERIAL AND METHOD: The oral solutions were prepared using captopril substance, keeping the formulation as simple as possible to avoid potentially undesirable excipients. Samples were stored for 39 days below 8 degrees C and at 22 +/- 3 degrees C and analysed for physical, chemical and microbiological stability. RESULTS: The formulations with ascorbic acid are stable for seven days either at 8 and 22 degrees C and could be prepared in hospital pharmacy as a more safely alternative to children terapy with tablets powders. PMID- 20201281 TI - [Analytical application of phosphotungstic acid complexes. Fabrication and characterisation of membrane selective electrodes for some H2 antihistaminics]. AB - PVC matrix membrane selective electrodes for ranitidine, nizatidine and famotidine, based on sparingly soluble complexes, were prepared and characterized. The optimum functional pH range, response time, selectivity and lifetime were determined for each of the built electrodes. The linear range, precision and accuracy of each method were obtained by statistical interpretation of experimental results, while the limit of detection and thelimit of quantification were determined by a graphical method. All these electrodes were applied for the direct quantitative potentiometric determination of ranitidine hydrochloride, nizatidine and famotidine in pharmaceutical formulations. PMID- 20201283 TI - [Violations of trofologic status and methods of their determination in patients with diseases of digestive organs]. AB - Nutrition support is a major life-saving technique. Therefore the indication for enteral and parenteral nutrition must be clear in each case before treatment is started, whereby the aim is to return to normal food intake as soon as possible. We tried to describe the methods of examination of nutritional status and the indications for nutritional support, using either the enteral or parenteral route, in patients with digestive disease. PMID- 20201282 TI - Synthesis and antituberculosis action of some new pyruvic acid derivatives. AB - The present paper studies the synthesis and activity of 12 new azoic derivatives against Mycobacterium tuberculosis. MATERIAL AND METHOD: In order to obtain new antituberculosis substances, we studied 6 thiadiazolic derivatives and 6 triazolic derivatives of pyruvic acid and we observed the influence of the different radical groups inserted in the molecule on their antituberculosis activity. For this study we developed a simple method to obtain the new derivatives. The first stage of the experiment was the synthesis of the thyosemicarbazide derivatives. In order to obtain the thiadiazolic derivatives we treated the thyosemicarbazides with concentrated sulfuric acid. The triazolic derivatives were obtained after treating the thiosemicarbazide derivatives with a diluted NaOH solution at boiling. RESULTS: The structure of the substances was furthermore confirmed by IR and quantitative elemental analysis. The newly obtained substances were tested on the Mycobacterium tuberculosis complex, 6 concentrations for each substance. Early tests on Mycobacterium tuberculosis indicate that 2 of the tested substances have clear antituberculosis activity in vitro for the tested concentrations. For the other tested substances further research is needed since the CMI hasn't been reached in their cas. CONCLUSIONS: We synthesised 12 new thiadiazolic and triazolic derivatives in order to obtain new possible antituberculosis agents. Early tests on Mycobacterium tuberculosis indicate that 2 of the tested substances have clear antituberculosis activity in vitro for the tested concentrations. PMID- 20201284 TI - [Correction of protein metabolism violations in patients with malabsorption syndrome]. AB - It is established that a heightened nitrogen balance is defined by a dysabsorbtion syndrom. Proved that the optimal quota of protein at albuminous insufficiency is about 135 g/day. Parenteral introduction of aminoacidic mixes (Infesol) led to clinical improvement, normalization of an aminoacidic spectrum of blood. Use of mixes for an enteral nutrition (Nutridrink) provides a reduction of symptoms of albuminous deficiency. PMID- 20201285 TI - [Metabolic activity of intestinal microflora and its role in determination of nutritional support tactic after gastrectomy]. AB - Nutrition recommendations in symptoms of postgastrectomy syndroms is very different. The calculation of regimen using the parenteral and enteral alimentation may be established in the control test of definition of fecal short chain fatty acids and microflora in such patients. Probiotics attach to the intestinal wall and protect it from the attacks of pathologic microorganisms. Probiotics are especially useful in the complex treatment of postgastrectomy syndroms. PMID- 20201286 TI - [Influence of honey, royal jelly and propolis on accelerating acetate healing of experimental gastric ulcers in rats]. AB - This study examines gastric acetic ulcer healing in the rat after administration of honey, royal jelly and propolis into the stomach. Chronic gastric ulcers were induced in male Wistar rats by the application of 100% acetic acid to the serosal surface of the stomach on 60 sec. Bee-keeping products were administrated into the stomach from 2nd to 7th day after acetic ulcer induction. On 7th day animals were killed, and ulcer area was measured in mm2. In gastric juice pH and activity of pepsin were measured. The healing of acetic ulcers is accelerated with the administration of honey, royal jelly or propolis during six days. The largest healing effect was demonstrated with propolis and royal jelly, smaller one with the honey. It was revealed decrease of stomach acid secretion in the rats, which have received bee-keeping products versus the rats of control group. PMID- 20201287 TI - [Experimental study of the structuring role and other chyme characteristics in some functionality gastrointestinal truct at enteral nutrition]. AB - The structure of hymus of gastrointestinal tract and mechanisms of its formation were studied on representatives of three classes of vertebrates (fishes, birds, mammal). Established that enteral hymus is in homeostasis and spatially structured in all animals. On weight hymus consists about 80-95% of hydrated cavitary mucus and 5-20% of food particles. [Russian characters: see text] plays a key role in formation of hymus structure and it is the basic endogenous formation for cavitary hydrolysis and providing the directed movement of nutrients to apical surfaces of enterocytes. PMID- 20201288 TI - [Role of nutritional support in intensive patients care with acute pancreatitis]. AB - THE AIM: study on the efficacy of methods of nutritional support in intensive therapy of patients with acute pancreatitis. 70 of a patients was divided into 3 groups: the nutritional support didn't take place (20 patients), the parenteral nutrition (26 patients) has been carried out only, parenteral-enteral nutritional support (24 patients) has been carried out. More faster reduction of total protein and albumin of blood (on 4 days), the time reduction of finding in section of reanimation (on 2 days) and the total duration of hospitalization (on 11 days) in group of a patients, receiving combined parenteral-enteral nutritional support is mounted. PMID- 20201289 TI - [Early postoperative enteral immunocorrection using modified pectin containing drugs in peritonitis]. AB - Surgical endotoxicosis entails dysfunction of all organs and systems including immune system that considerably aggravates severity of current disease and slows down a recovery in the postoperative period. Searching of various ways of immunocorrection in peritonitis of various etiology is the actual commitment of the contemporary surgery. The complex method of simultaneous enterosorbtion and immunocorrection with the modified pectin contained specimen in patients with a peritonitis is offered. In study the role natural enteral sorbents in optimization of the immune answer due to restoration of microbiocenosis sorbtion and immunocorrection modified with the modified pectin contained intestines is proved. Entero specimen provide decreasing of medium molecular weight substances' level to 89.0% in reactive stage of a peritonitis and to 69.0%--in toxic stage during 3 days. By 5th day of treatment the level of medium molecular weight substances and leucocyte intoxication index were already reached to the normal parameters. It allows us to recommend this introducted method in a complex of medical treatment in postoperation period in peritonitis. PMID- 20201290 TI - [Syndrome of excessive bacterial growth and disruption of the digestive and absorption: pathogenetic nutritional therapy]. AB - The colon contains literally billions of bacteria. These bacteria protect us from pathogenic microorganisms such as bacteria, viruses and fungi that might otherwise penetrate the mucosal membrane. The bacteria of the colon are also known as intestinal flora. Also they are very impotent when we try to use enteral nutrition. Diagnosis of bacterial overgrowth of the bowel may be recognized by special methods of definition of fecal short-chain fatty acids, which are the pathology biomarkers of the gut failure. PMID- 20201291 TI - [Parenteral nutrition in treatment of patients with syndrome of short bowel]. AB - If the gut is too short parenteral feeding becomes the only option. As clinicians interested in this field, we must continue to inform others about what standarts may be set in different patients. Nowadays the enteral nutrition is also used in the scheem of the treatment such patients. We discuss about haw, where and in what compositions and regimens it may be recommended the nutritional support. PMID- 20201292 TI - [Evaluation of inclusion of specialized carbohydrate-protein product with vitamins and mineral substances in the diet therapy of gastrointestinal and osteopenia diseases]. AB - It has been shown that inclusion of the specialized product containing 50% from recommended daily consumption of calcium, 20%--of protein, 17-60%--of 11 mineral substances and 11 vitamins in the diet of patients suffering from diseases of gastroenteric tract and osteopenia within 6 months lead to increasing of bone mineral density while it has not liquidated the existing vitamin B2 and vitamin D deficiency. The data obtained confirm the expediency of the development of specialized products of the set chemical composition intended for a concrete category of patients, and their inclusion in the diet. PMID- 20201293 TI - [Features of immune status among native population of Yamal in the conditions of Europeanization of traditional food]. AB - The destruction of nutrition traditional structure and imbalance of food allowance by the basic kinds of plastic and energy materials impose a negative mark on efficiency of immune protection of north Aboriginals. PMID- 20201294 TI - [Effectiveness of Ultop 10 mg using at treatment of functional (nonulcer) dyspepsia syndrome]. PMID- 20201295 TI - [Chronic stomach erosion: new opportunities of pathogenetic treatment]. PMID- 20201296 TI - [Molecular-genetic typing of Helicobacter pylori: applied aspects of diagnosis and treatment of duodenal ulcer]. AB - In this article genetic features of Helicobacter pylori in duodenal ulcer patients are studied, also a comparative estimation of this microorganism's genetic features is made in various Helicobacter pylori-positive conditions. In the article necessity of carrying out genetic typing of Helicobacter pylori for revealing potential microorganism virulence, strain resistance to claritromycin is proved that allows to define a forecast of a current of disease and to carry out individual selection of a therapy. PMID- 20201297 TI - [Possibilities of pharmacological hepatopathy and correction of fat metabolism violations in diabetes mellitus type 1]. AB - The purpose of the research has been the study of possibilities for the pharmacological correction of the morphological changes in liver and lipid metabolism disorders in experimental type 1 diabetes. Simvastatin, new compound from the group of antioxidants--3-hydroxipyridine derivate under the code HP-5, and also the combination of simvastatin and HP-5 have been used for the pharmacological correction in this research. It was revealed that the using of HP 5 and the combination of simvastatin and HP-5 attenuate the order of expression of diabetic hepatopathia as the result of the histological study and hinder from the development of dislipidemia in rates with type 1 diabetes which is more expressed in comparison with the monotherapy by simvastatin. These changes also are followed with the diminishing of the free radical lipid oxidation activity by the specific antioxidant effect of the investigated 3-hydroxipyridine derivate. PMID- 20201298 TI - [Recommendations for the regional and federal rosters of celiac disease]. PMID- 20201299 TI - [Respiratory function in patients with chronic inflammatory bowel diseases]. AB - Article presents results of the study pulmonary function tests (PFT) in 58 inflammatory bowel disease (IBD) patients (mean age 40,3 yr): 12 with Crohn's disease and 46 with ulcerative colitis by spirometry. A pulmonary function abnormality was present in 30 (51,7%) of the 58 symptom free patients and normal radiological results. Pulmonary function abnormalities was present of small airway disease. Influence of smoking on functional infringements has appeared statistically insignificant. PMID- 20201300 TI - [Response of immunocompetent cells and structural changes of colon mucosa in patients with diverticulum disease]. AB - It was established the activisation of macrophages and plasma cells with raise their adhesion in diverticular disease. The express of immune response depends on unit or plural diverticuls. Epithelial cells proliferation is on the increase in the cript and mouth region of diverticul. The small undifferential epithelial cells migrated from depth to top of cripts. These cells formed some fields of cells connected by means of branches. Therefore the chronic inflammation and local disturbance of epithelium regeneration were established in diverticular disease. PMID- 20201301 TI - [Structural and functional disorders of erythrocyte cell membrane in patients with Crohn's disease]. AB - Investigation of erythrocyte membrane in patients with Crohn's disease detected the changes in asymmetry of its molecular components, abnormalities in normal functioning of membrane-associated enzymes and energy-dependent processes in the cell. The mechanism of damaging effect on the cell membrane was caused by the excessive blood accumulation of a composite complex of low-molecular substances, compounds of quinone and carbohydrate nature, peptides, modified forms of nucleotides. The revealed changes make it possible to assess the severity of endogenous intoxication and cell membrane disorder, which take place not only in the course of the disease acute attack, but also retain during the period of incomplete clinical and endoscopic remission. PMID- 20201302 TI - [Intestinal digestion in patients with chronic pancreatitis]. AB - Clinical signs of a lesion of a small bowel at a chronic pancreatitis are caused by disturbance first of all a membranous stage of intestinal digestion, observed at early stages of disease and progress in process of augmentation of duration of disease. Expression of enzymatic disorders correlated with a lesion of elements of a brush border. PMID- 20201303 TI - [Age bowels bradyarrhythmia as risk factor colorectal cancer]. AB - We studied constipation risk and risk of colorectal cancer for people between 20 and 80 years. It has been shown that risk of constipation occurs 10 years earlier than risk of colon cancer. The maximum occurrence of constipation observed in 40 49 years and colorectal cancer--in 70-80 years. Maximum detection of organic pathology of colon cancer occurs almost 30 years later than functional. Circadian regularity is rhythm of bowel healthy aging and it can help to prevent constipation and reduce risk of colon cancer. PMID- 20201304 TI - [Specific immune response in diagnosis of celiac disease with chronic diarrhea]. AB - High concentration of Ab Gl, Ab tTG, Ab Em and Ab Rt and increased amount of immunocompetent cells in the SIM in coeliac disease is an index of the developing specific immune response to gliadin and tissue antigens. High specificity and sensitivity of Ab tTG and Ab Em were determined in celiac disease. PMID- 20201306 TI - [Linear form compression device for formation of colon anastomosis in experiment]. AB - The possibility of compressive intestine anastomosis formation with the help of linear form nikelid-titan implant was carried out in experiment (12 dogs). It is stat that linear form nikelid-titan implant migrates from a zone of anastomosis and leaves an organism of an experimental animal in the natural way in 5th - 6th day. Average pressure of break developed anastomosis using pneumatic pressure makes 193 +/- 8,6 mm mercury. PMID- 20201305 TI - [Experimental substantiation of use of sodium hypochlorite and ozone at a formation of intestinal anastomosis in conditions of acute intestinal obstruction and peritonitis]. AB - Presented are the results of experimental research on 144 animals (the rats Wistar), on whom was carried out resection of a part of large intestine and a intestinal anastamosis was formed in the presents of acute intestinal obstruction and peritonitis. The sanitation of abdominal cavity in the basic group of animals (74) was performed using sodium hypochlorite solution and dissolved ozone. The intestinal lavage was carried out by dissolved ozone with the subsequent introduction of ozonized oil Ozonide in the area of intestinal anastamosis. The combined application of ozone and sodium produces an expressed samative effect which leads to healing of intestinal anastamosis and decreases unstability of intestinal sutures and mortality. PMID- 20201307 TI - [Infliksimab in therapy of inflammatory bowels diseases]. AB - In last decade there were an increase in patients with inflammatory bowel disease (IBD) - Crohn's disease (CD) and ulcerative colitis (UC). To achieve remission of IBD usually was used various combinations of 5-ASK drugs, glucocorticoids and cytostatics, but positive dynamics of the patients cannot achieve. In this regard some prospects assigned to infliksimabom therapy. You can find results of Remikeyd therapy in patients with Crohn's disease and ulcerative colitis. We showed that all cases achieved positive dynamics within the IBD, which allowed him to recommend as an effective tool in the form of monotherapy for one year. PMID- 20201308 TI - [Helicobacter pylori infection as additional risk factor of the development of NSAID-gastropatia effects at the patients with osteoarthritis]. AB - Prevalence of osteoartrosis disease is high among the population. The main places in treatment of this pathology occupy NSAID. Intake of NSAID is lead to the development of NSAID-gastropatia. During last years H. pylori infection was numbered with risk factors of the NSAID-gastropatia development. In this review considered researches which are devoted to studying ties between H. pylori and NSAID. Data of the using eradication therapy with purpose of prevention and treatment of NSAID-gastropatia associated with H. pylori are shown in this review. PMID- 20201309 TI - [Epidemiological research of Helicobacter pylori resistance to clarithromycin at inhabitants of Sankt of Petersburg with a stomach ulcer]. PMID- 20201310 TI - [The experience of usage of alginate contain medication in complex therapy at children with GERD disease]. AB - GERD Therapy at children is complicated task because of Physiological features of a children's body, which reflects on the processes of acid production, motility in upper gastro-intestinal tract and on the metabolism of pharmaceutical products. Some of these medications have age usage limitations due to lack of investigation of side effects in treatment of children. Usage of alginate contain medication in complex therapy of such pathological condition brings to not only fast and effective relief of such symptoms as heartburn, eructation and in positive endoscopy dynamics. PMID- 20201311 TI - [Syndrome of excessive bacterial growth in small intestine: etiology, pathogenesis, clinical manifestations]. AB - In survey presented literature data about etiology, pathogenesis and clinical course of the syndrome of excess intestinal bacterial growth. Is produced information about intestinal microflora and its unfavorable changes in various environmental influences. Is showed that main clinical findings of the syndrome are formed by influence of disturbances of motility, intestinal digestion and absorption. PMID- 20201312 TI - [Diagnosis and treatment of hydropic-ascitic syndrome in patients with bowel pathology]. AB - The lecture outlines the pathogenesis, clinic characteristics, diagnosis and treatment of hydropic-ascitic syndrome (HAS) associated with the violation of absorption and exudation of protein in the small intestine. At absorption violation in patients we can find not only HAS also we can find there chronic diarrhea, violation of trophics. Increased exudation of plasma protein in bowel lumen develops at inherent violation of patency of lymph vessels (limfangiektase), blockade of lymphatic apparatus of the intestines, with tuberculosis, amyloidosis, sarcoidosis, retroperitonealnom fibrosis, endometriosis, Uippl disease and tumor infiltration of lymphatic system and mesentery. Secondary enteropatiya with protein loss (EPL) is possible in patients with constrictiv perikardite and right ventricular failure of various etiology. Establishment of correct diagnosis with the help of HAS enterogene biopsy of small intestine mucosa, coloring amyloid in biopsy sampling and PAS-positive inclusions, immunological tests for celiac disease and heavy chains - alpha. In patients with chronic diarrhea and malabsorption symptoms most likely cause of the HAS is celiac. In the absence of data for celiac disease should be kept in mind the small bowel disease chronic lymphoproliferative diseases. Treatment depends on basic disease. Good effect of providing enteral nutrition. Disorders of water-electrolyte exchange eliminates intravenous glucose-electrolyte solutions. The main method of removing gipoproteinemy when EPL was prolonged intravenous proteincontents solutions and temporary use of corticosteroids. PMID- 20201313 TI - [Characteristics of diagnostic of cyst esophagus]. AB - The paper present a clinical diagnosis of cysts of the esophagus surveillance, identified the patient in adulthood, as a review of the literature, reflecting the questions of clinic, diagnosis and the treatment of esophageal cysts. PMID- 20201314 TI - [Polyps esophageal cardio-conversion in children: causes, clinical picture, management and prognosis of tactics]. AB - 105 children with polyps of esophago-gastric junction region, detected by gastroscopy, were under follow up during 1-9 years. 55 children with polyp size less than 5 mm were followed up without endoscopic polypectomy (EP) and 50 children with polyp size more than 5 mm and another indications underwent EP. Polyps were more frequently encountered in males aged 7-15 years without specific clinical symptoms; histologically, there were hyperplastic polyps. The majority of children (94.5%) treated conservatively were found to have absence of growth or polyp regression. Risk factors of reappearing of polyps after EP were progress of esophagitis and abnormal gastroesophageal flap valve. According to results of 24-hour pH monitoring of esophagus, alkaline gastroesophageal reflux was diagnosed only in patients with polyps in comparison with children without polyps with chronic diseases of upper floor of digestive tract (p = 0.04). PMID- 20201315 TI - [Correction of portal hypertension and renal dysfunction with help of nebivolol and lizinopril in patients with hepatic cirrhosis]. AB - The effect of nebevolol, beta-blocker on the portal hypertension and renal blood flow and the safety of its use versus lisinopril, an angiotensin-converting enzyme inhibitor were examined in the patients with cirrhosis. 72 patients were examined (39 patients with cirrhosis of the liver without ascites - the 1st group and 32 patients with cirrhosis of the liver with ascites - the 2nd group. Trustworthy decrease of portal hypertension parameters (the decrease of portovenosis gradient of pressure (PPG) by 19,3% (p = 0,048) in the patients with liver cirrhosis of class A on Child-Pugh without ascites with nebevolol was revealed. The trust worthy changes of portal blood flow was not revealed in all examined patients with lisinopril. But these patients without ascites have demonstrated the improvement of the renal hemodynamic (renal functional reserve (RFR) by 56%, effective renal plasma flow (ERPF) by 17,3%). The lisinopril intake 5 mg a day declines PPG by 18,1%. The tendency of the reduction of the functional index due to the expressed hypotensive effect of nebevolol and lisinopril was revealed in all examined patients with liver cirrhosis. So it was demonstrated that for the management of the portal hypertension in the patients with liver cirrhosis is necessary to examine of functional renal condition to prevent the development of hepatorenal syndrome. PMID- 20201316 TI - [The technology of liver puncture biopsy]. PMID- 20201317 TI - [At the 13th International Symposium on Celiac Disease (Amsterdam, 5-8 April, 2009)]. PMID- 20201318 TI - [Analysis of serotypes distribution of group B streptococci origin from pregnant carriage using multiplex PCR]. AB - The aim of study was to evaluate the applicability of the PCR multiplex method for the identification of Streptococcus agalactiae (group B streptococci; GBS) serotypes and to indicate the participation of serotypes in the group of pregnant women. 1178 pregnant women at 35-37 weeks of pregnancy were studied between 2007 2009. Vaginal and rectal swabs collected from these women were tested for the presence of GBS. S. agalactiae identification was done basing on the culture method according to the CDC recommendations. For all isolated GBS strains the surface polysaccharides which conditioning serotypes were determined using commercially available serological latex kit and multiplex PCR method with two sets of specific primers. The frequency of GBS carriage among 1176 pregnant women was 30% (353 cases). Simultaneous colonization of the vagina and anus was demonstrated in 80% women, whereas GBS carriage only in the vagina or only in the anus was indicated in 9% and 11% cases, respectively. In pregnant women colonized by GBS serotype III (35%) dominated. The other serotypes were detected with the following frequency: Ia (20%), V (17%), II (15%), Ib (8%) and IV (5%). In the analyzed women population, GBS strains belonging to the VI, VII, VIII serotypes were not found. The results of our study show a great diagnostic usefulness of multiplex PCR method for identification of genes encoding GBS surface polysaccharides that are typical for individual serotypes. PMID- 20201319 TI - [Application of multiplex pcr for identification of MRSA and MRCNS strains in medium of automatic blood culture system]. AB - Rapid detection and identification ofmethicillin-resistant staphylococci in patient's blood is essential for the prompt antimicrobial therapy of infection. Molecular-based diagnosis, in comparison to conventional methods, allows to increase sensitivity and to reduce time necessary to achieve positive results and also enable to test susceptibility. The aim of the study was the use of multiplex PCR to detect region of the 16S rRNA that is unique to staphylococci, the S. aureus-specific clfA gene and the mecA gene which is a determinant of methicillin resistance, in a medium of the BACTEC blood culture system. Three different extraction methods were examined in order to ascertain the most suitable method to isolate staphylococcal DNA. The only method which removed PCR inhibitors contained in BACTEC blood culture material use Triton X-100 and lysostaphyin to lysis bacterial cells. The use of High Template Preparation Kit failed to yield a positive result in all investigated probes. Third of the methods, based on alkali lysis, resulted in DNA which could be amplified by PCR only in case of S. aureus blood culture. The findings of our study suggest that not all DNA extraction methods are appropriate because some of them may not remove potent amplification inhibitors found in blood and medium of system BACTEC. PMID- 20201320 TI - [Antimicrobial susceptibility of Yersinia enterocolitica and Yersinia pseudotuberculosis strains isolated from humans in Poland during 2004-2009]. AB - The number of yersiniosis has increased in the last few years in Poland, especially an increase of Yersinia enterocolitica bioserotype 1B/O:8 infections was observed. From 2004 to 2009 265 of Y. enterocolitica 4/O:3, 108 of Y. enterocolitica 1B/O:8, 8 of Y. enterocolitica 2/O:9 and 4 of Y. pseudotuberculosis clinical isolates were collected. To obtain basic data for resistance monitoring purpose 385 Yersinia strains were tested by standard disc diffusion method for their susceptibilities to 12 antimicrobial agents. In addition beta-lactamase (enzyme A) inhibition assays were undertaken with ticarcillin and clavulanic acid and beta-lactamase (enzyme B) induction tests were perfonned with imipenem as the inducer for 135 strains. The present study demonstrated a high susceptibility of clinical strains to most of the tested antibiotics with the exception of ampicillin, ticarcillin and streptomycin. No strains were resistant to third-generation cephalosporins, fluoroquinolones, gentamicin and tetracyclin. Less than 10% isolates were resistant to amoxicillin with clavulanic acid (except--all Y. enterocolitica 2/O:9 strains were resistant), sulfonamide, trimetoprim/sulfamethoxazole and chloramphenicol. Four isolates of Y. enterocolitica 4/O:3 and one Y. enterocolitica 2/O:9 was multidrug resistant (MDR). Detection of enzyme A by disc diffusion in all tested strains, with the exception of the three Y. pseudotubeculosis I isolates, was highly reliable but results of enzyme B detection by the disc diffusion test were, especially for Y. enterocolitica 1B/O:8, faced with the difficulties. PMID- 20201321 TI - [Susceptibility of Enterobacteriaceae rods to selected tetracyclines]. AB - The aim of this study was to evaluated the susceptibility of Enterobacteriaceae rods to tigecycline, tetracycline and doxycycline. We analysed 121 strains belonged to species as follows: Escherichia coli (40 strains), Proteus mirabilis (22), Enterobacter cloacae (19), Klebsiellapneumoniae (18), Morganella morgannii (13), Serratia marcescens (4), Klebsiella oxytoca (3) i Proteus vulgaris (2). All strains of E. coli, K. oxytoca, S. marcescens and P. vulgaris were susceptible to tigecycline. Twenty five of analysed strains produced extended-spectrum beta lactamases. Among of ESBL-positive strains 22 (88.0%) were susceptible to tigecycline and 13 (52.0%) to tetracycline and doxycycline. PMID- 20201322 TI - [Influence of culture conditions on adhesion Escherichia coli strains to polystyrene]. AB - The aim of this study was evaluation of influence of culture conditions (nutrient availability, pH, temperature) on adhesion E. coli strains to polystyrene. This study included 74 of E. coli strains isolated from urine and blood samples. All of these strains were isolated in the Clinical Microbiology Department of Dr. A. Jurasz University Hospital in 2003-2006. Analyzed strains most often adhered to polystyrene after incubation in high-nutrient medium, at pH values between 5.0 and 7.0, at 37 degrees C. PMID- 20201323 TI - [Adhesion of Escherichia coli rods to urological catheters]. AB - The aim of this study was evaluation of adhesion of E. coli rods to urological catheters made of different synthetic materials. This study included 74 of E. coli strains isolated from urine and blood samples. All of these strains were isolated in the Clinical Microbiology Department of dr A. Jurasz University Hospital in 2003-2006. Analized strains significantly more often adhered to latex catheters than latex catheters covered by silicon and significantly more often adhered to PCV catheters than latex catheters covered by silicon. Four strains were characterized by a strong adhesion to all kinds used urological catheters, used in this study. Among E. coli strains isolated from the blood a higher percentage of strains demonstated adhesion to latex and PCV catheters than in the group of E. coli strains isolated from urine samples (79.3% vs. 68.9% and 69.0% vs. 55.6%, respectively). Out of strains demonstrating the adhesion to urological catheters, the most came from the patients from Clinic of the Nephrology, of Arterial Hypertension and Internal Diseases with the Station of Dialyses. All of lactose-negative E. coli strains adhered weakly to urological catheters. PMID- 20201324 TI - [Urinary system as a primary source of bloodstream infection]. AB - The aim of this study was the determinantion of the appearance of urosepsis in patients in the Department of Nephrology Hypertension and internal Diseases, Dialysis Unit, Department of General, Oncologic and Pediatric Urology and Department of Transplantology and Surgery of University Hospital nr 1 of dr. A. Jurasza in Bydgoszcz. In the period of 2006-2008, total 233 isolates were obtained from positive blood culture and 28.8% of these was also related to urinary tract infection. The majority of cases of urosepsis was observed in urologic and transplantologic wards. Among investigated strains, the most frequency isolated species was E. coli. All Enterobacteriaceae strains examined in our study were susceptible to imipenem, the highest rate of resistance was found for ampicillin, six isolates was producing extended-spectrum beta lactamases and four-AmpC beta-lactamases. Among P. aeruginosa strains there was no resistance to netilmicin and one or two isolates was producing AmpC beta lactamases or ES L, respectively. PMID- 20201325 TI - [Vancomycin-resistant Enterococcus spp. strains]. AB - The aim of our study was to evaluate a frequency of isolation and susceptibility to antibiotics of vancomycin-resistant enterococci isolated between 2005 and the first half of the 2009 from patients of University Hospital of Dr. A. Jurasz Collegium Medicum of L. Rydygier in Bydgoszcz Nicolaus Copernicus University in Toruli. Study shows increasing frequency of VRE isolation from two in 2005, 8 in 2006, 30 in 2007 to 79 in 2008 and 40 in the first half of 2009 year. Among all isolated VRE strains E. faecium definitely predominated (75.0-90.0% in 2006 2009). The majority of strains were obtained from patients of the Pediatrics, Hematology and Oncology Clinic (43,4%) and Pediatric Surgery Clinic (41.5%). VRE strains were mainly isolated from digestive tract (79,9%). The isolates demonstrated frequently resistance to penicillin, ampicillin, ciprofloxacin, rifampicin and chloramphenicol. Percentage of VRE strain resistant to aminoglycosides decreased during the last four years of study. Over 56% of VRE isolates showed resistance to teicoplanin. Linezolid and quinupristin dalfopristin were the only drugs presenting activity against isolated VRE strains. PMID- 20201326 TI - [Influence of contact with hospital environment on sensitivity to antibiotics of lipophilic strains of Corynebacterium residing on human skin]. AB - Sensitivity of two groups of lipophilic corynebacteria strains of different species, which form stable residential flora on human skin, to therapeutically significant groups of antibiotic was compared. Strains were isolated from people who did not have any contact with hospital environment, and from doctors closely connected with hospital. It was shown that strains isolated from doctors, which were in fact not under antibiotic pressure, were five times more multiresistant whilst at the same time being resistant to antibiotics used only in hospital treatment. PMID- 20201327 TI - [Activity of doripenem against Pseudomonas spp. and Acinetobacter spp. rods]. AB - Doripenem, the newest carbapenem was approved in 2008 by the European Medicines Agency for the treatment of complicated intra-abdominal infections and complicated urinary tract infections. Its spectrum of activity is similar to that of meropenem and imipenem/cilastatin. The aim of this study was to compare in vitro activity of doripenem against nonfermentative Gram-negative rods. A total of 235 strains of Pseudomonas spp. (74.9%) and Acinetobacter spp. (25.1%) were included into the study. Strains were isolated in The Department of Clinical Microbiology of the University Hospital No 1 in Bydgoszcz and identified using ID GN tests (bioMerieux). To determine susceptibility to doripenem and other carbapenems disc-diffusion method was applied. Percentage of doripenem resistant strains reached 28.4% and 39.0% for Pseudomonas spp. and Acinetobacter spp, respectively. All doripenem sensitive or intermediate Acinetobacter spp. strains were simultaneously sensitive to imipenem and meropenem. Activity of imipenem and meropenem among doripenem resistant Acinetobacter spp. were represented by 60.9% and 56.5% strains, respectively. Activity of imipenem and meropenem among doripenem resistant Pseudomonas spp. strains were represented by 12.0% and 18.0%, respectively. Occurence of one doripenem sensitive Pseudomonas spp. strain simultaneously resistant to imipenem and meropenem was observed. PMID- 20201328 TI - [Subclass distribution of human IgG antibodies to Mycoplasma pneumoniae in the course of mycoplasmosis]. AB - The prevalence of human IgG1-IgG4 to sonicated antigen of M. pneumoniae in the 138 sera obtained from patients with mycoplasmosis was analysed. Antibodies of IgG1 were diagnosed in 47 (34.1%), IgG2 in 42 (30.4%) and IgG3 subclass in 58 (42.0%) serum samples. The concentration of IgG4 was below detection level. Generally, the frequency of occurrence of IgG2 antibodies increased with age reaching its peak among adults. On the other hand IgG1 and IgG3 for M. pneumoniae were diagnosed more often in serum samples obtained from children than from adults. We did not find any essential changes in the pattern of IgG subclass during the course of infection however it seems that the level of IgG3 antibodies decreased faster than IgG1 which may be caused by the fact that the IgG3 antibodies have a much shorter half-life in comparison to the IgG1. PMID- 20201329 TI - [Scorpio TS prosthesis in severe deformity and revision knee arthroplasty- preliminary report]. AB - Authors present early results of Scorpio TS prosthesis in primary and revision total knee arthoplasty due to aseptic and septic loosening. 26 arthroplasties were performed on 25 patients. There were 19 women and 6 men of age from 37 to 80 (average 68.4 years). 11 patients from this group were operated because of septic loosening. The follow up from 2 to 22 months (average 11 months). Early results were access according to Clinical Rating System of The Knee Society: 19 patients had very good and good (73%) including primaries, 1 satisfactory (4%) and 6 poor (23%) results. The satisfactory and poor results were obtained in 7 cases with septic loosening who had had four or more previous operations on the knee. Four of them had instability of prosthesis and we changed it for MRH type. In one case due to reinfection and sepsis amputation above the knee was performed. In another patient tibia fracture below stem and loosening of tibial component occurs after 6 months of revision. ORIF gave fracture union after 8 months and exchange Scorpio TS to MRH was performed. In two cases the wound problems occurred and was solved. There were no reinfection and aseptic loosening in another cases. We didn't notice any thrombosis complications. PMID- 20201330 TI - [Total hip arthroplasty after previous support proximal femoral osteotomy]. AB - Clinical outcome and technical difficulties observed after total hip arthroplasty (THA) subsequent to support proximal femur osteotomy were studied in 6 total hip arthroplasties. 6 patients were follow up at an average 6.2 years after THA. The average Harris hip score before THA was 57 and after 83.6. The average leg abbreviation after THA was 1.2 cm. In one case femur perforation made impossible to stem implantation. Support proximal femoral osteotomy may make routine insertion of a femoral prosthesis difficult and jeopardize the clinical and radiological outcome of future THA. PMID- 20201331 TI - [Hemiarthroplasty for treatment of comminuted trochanteric fractures in elderly patients]. AB - Successful operative stabilization of the comminuted, trochanteric fractures in elderly patients is problematic due to advanced osteoporosis and poor physical activity excluding the cooperation in the postoperative rehabilitation. Stable fixation with dynamic hip screw or gamma nail, or flexible Ender nailing requires relieve of load during forthcoming several postoperative weeks needed for bone union, that reduced their usefulness in elderly patients. The aim of study was to analyze the usefulness of the cemented hemiartrhoplasty for the treatment of patients with comminuted trochanteric fractures. We analyzed 18 patients (16 women and 2 men, aged 69- 93-years-old (mean 83.3 years) treated in our Department in 2007 with cemented hemiathroplasty due to comminuted trochanteric fractures. Patients were intensively rehabilitated bearing their body weights from 3rd-5th, and consequently discharged on 9th-12th postoperative day. Due to the possibility of almost immediate mobilization in the postoperative period, cemented hemiathroplasty could be a method of choice for the treatment of the comminuted trochanteric fractures in elderly patients. PMID- 20201332 TI - [Distant functional outcomes of treatment and physiotherapy of tibial eminence fractures in adults]. AB - Authors of paper present distant functional outcomes of treatment and physiotherapy of tibial eminence fractures basing on clinical material covering years from 1998 to 2006, that make up 15 patients, 7 women (46.7%) and 8 men (53.3%), aged between 18 and 57 years, on average 37.5-years-old. Subject fractures ware classified basing on Meyers i McKeever criteria, however obtained outcomes basing on IKDC (International Knee Documentation Committee) system. Obtained outcomes persuade authors to standpoint, that inoperative treatment of fractures type I leads to good functional outcomes, operative treatment of fracture type II leads to good functional outcomes too and operative treatment of fracture type III and III+ leads to sufficient outcomes. PMID- 20201333 TI - [Physical activity and quality of life following total uncemented hip replacement and hip resurfacing]. AB - INTRODUCTION: The influence of physical activity on the survival of total hip replacement remains not fully recognized. It is unclear which activities are beneficient for patients following THR. MATERIAL: The study was conducted on group of 87 patients (94 hips) following uncemented THR with ABGII/Trident and 45 patients (51 hips) following hip resurfacing. The follow-up period was 6-30 months for THR group and 6-42 months for resurfacing group. METHODS: The patients answered a questionnaire based on WOMAC and SF-36 score, UCLA activity scale with additional questions concerning patients physical activity, working and place of living. RESULTS: In WOMAC, physical domains of SF-36 and UCLA activity score patients following hip resurfacing showed better results. The most preferred activity in both groups was exercise walking and biking. The last one was particularly preferred by patients living in rural areas. CONCLUSION: The vast majority of patients restricted their activity to disciplines with a safe range of hip weight bearing. PMID- 20201334 TI - [Postural control strategy in patients with anterior cruciate ligament deficiency]. AB - Dysfunction of the knee joint caused by injury of the anterior cruciate ligament is associated not only with mechanical joint destabilization but also damage of receptors in the ligament responsible for joint proprioception. Sensory disorders associated with damage of receptors in the ligaments may produce abnormalities in the posture control. The study aimed at evaluating postural control strategy in patients with chronic anterior cruciate ligament deficiency and determining a relationship between clinical assessment, subjective evaluation of knee joint functioning, and type of postural control. MATERIAL AND METHODS: Postural control with dynamic and static Riva test in one-legged position was assessed in 46 patients (6 women and 40 men), aged between 15 and 52 years (mean 32 years), in whom damage of the anterior cruciate ligament was diagnosed clinically and/or radiologically. Diagnosis was confirmed arthroscopically in all cases. Clinical evaluation was made with the aid of two subjective scales of knee ailments: Lysholm knee scale and subjective knee evaluation form IKDC 2000. Arthrometer Rolimeter by Aircast was used to measure the difference between lower limbs in anterior knee laxity during "anterior drawer" test and Lachman's test. The way of visual proprioceptive control was assessed with both dynamic (DRT) and static (SRT) Riva tests in monopodalic stance. Tests were performed with the DELOS Postural Proprioceptive System (DELOS s.r.l., Corso Lecce, Torino, Italy) in the biomechanical evaluation laboratory at Rehasport Clinic in Poznan. CONCLUSIONS: Strategy of the postural control in both dynamic and static Riva test does not allow differentiating ACL deficient leg from the mechanically stable leg. The obtained results of postural control in dynamic and static Riva test confirm significant value of knee joint mechanical stability for preservation its functional stability. Knee joint extension (hyperextension) may be one of mechanisms maintaining functional knee joint stability. PMID- 20201335 TI - [Assess of patients' functional condition with rheumatoid arthritis before and after physical therapy treatment]. AB - The aim of this study was to assess the impact of duration of disease and age on the functional condition of patients and also healing effectiveness in different duration of disease and age. MATERIAL AND METHODS: The study involved 31 patients with rheumatoid arthritis aged 40-70 years, with duration of disease 5-20 years. In this group was used following physical therapy technique: cryotherapy, ultrasound therapy, laser therapy, electrical stimulation TENS, iontophoresis, diadynamic and magnetic therapy. Before and after the treatment motor capacity was estimated using Health Assessment Questionnaire (HAQ). RESULTS: The presented results indicate improvement of measured parameters and increasement of patients independence after therapy, especially with duration of disease 5-10 years aged 60-70 years. CONCLUSIONS: Susceptibility of anti pain treatment using physical therapy increase with increasing duration of disease. Therapy influence on functional condition of patient decreasing with duration of disease. PMID- 20201336 TI - [Tender points and trigger points--differences and similarities]. AB - Two main types of myalgia that are not inflammatory are fibromyalgia (FB) and myofasical pain (MFP). In both of them during diagnosing tender points (characteristic for fibromyalgia) and trigger points (MTrP--characteristic for myofasical pain) are of key importance. A great degree of similarity together with the inability to differentiate between those points result in wrong diagnosis and, as a consequence, failure of therapy. Additional difficulties are caused by the lack of unity in nomenclature, as in literature the term tender point and trigger point are used interchangeably. Moreover, some centres question the existence of fibromyalgia and myofascial pain as separate pain entities. PMID- 20201337 TI - [Report on the course of the shoulder arthroplasty in Sports-Clinic in Zory]. PMID- 20201338 TI - Penetration of screw into the wall of thoracic aorta after stabilization of thoracic spine--case report. AB - In our research we have discussed a rare case of penetration of screw into the thoracic aorta after stabilization of thoracic spine due to compressive fracture of IV thoracic vertebra. We have focused on existence of potential danger of damage of aorta during stabilization of the posterior part of thoracic spine. We have emphasized the meaning of prophylactic implantation of stent-graft into the site of potential damage of aorta before the restabilization of the vertebral column. PMID- 20201339 TI - Tracheal tube cuff pressure depends on the anaesthesiologist's experience. A follow-up study. AB - BACKGROUND: Excessive tracheal tube cuff pressure can cause ischemia of the tracheal mucosa, and possible serious complications, such as tracheal stenosis, formation of tracheo-oesophageal fistula or even life-threatening haemorrhage. Inadequate cuff pressure increases the risk of aspiration of gastric contents. METHODS: The cuff pressures were analysed on the basis of the anaesthesiologists' experience. The results were compared to those obtained during the previous study which had been conducted seven years earlier (2002). The physicians were divided into three groups, according to their experience: group I - less than 2 years of practice; group II--2 to 10 years of practice; and group III--over 10 years of practice. High-volume, low-pressure tubes were used for intubation. The anaesthesiologists were not informed of the planned audit. RESULTS: Statistical analysis demonstrated significant differences between cuff pressure readings in the respective study groups. Cuff pressures in group II (p < 0.05) and group III (p < 0.0005) were greater than those in group I. In 2002, no statistically significant differences had been observed between the three groups (p = 0.1156). When comparing results from 2002 and present one differences were observed inside individual groups, concerning group II (p < 0.05) and group III (p < 0.0005). CONCLUSION: There is a tendency to overinflation of endotracheal tube cuffs in all groups. This problem is more common in the group of highly experienced anaesthesiologists, and is more more prevalent at present than in 2002. PMID- 20201340 TI - [Effects of cervical plexus block on lung ventilation]. AB - BACKGROUND: Carotid endarterectomy is a preventative operation to reduce the incidence of embolic stroke. The prime concern during surgery is the protection of the brain during carotid artery cross-clamping. Since blood flow to the brain is provided via the non-affected carotid artery and collateral circulation, it is essential to maintain consciousness in the patient during surgery, in order to assess the effects of cross-clamping. Regional anaesthesia has therefore been regarded as the method of choice for this kind of surgery. Cervical plexus analgesia can be achieved at two levels: superficial--when skin branches of the plexus are blocked, and deep--when short and long nerves are blocked. Successful block of the cervical plexus depends of effective analgesia achieved at both levels. This can be achieved by a single injection as described by Winnie, or multiple injection at C2, C3 and C4 as described by Moore. Among possible complications, the most common is transient phrenic nerve block with diaphragm dysfunction. METHODS: We have compared the effects of cervical plexus block performed according to Winnie (group W), or Moore (group M) on spirometry, arterial oxygen saturation and carbon dioxide tension, in seventy-five patients scheduled for endarterectomy. RESULTS: Group W consisted of 44 patients, and group M--of 31 patients. VC, FVC, FEV1 and PIF decreased in all patients. There were no statistically significant differences between the groups. Transient paralysis of the diaphragm, confirmed by chest x-ray, occurred in 8 (19.5%) patients of group W, and in 4 (14.3%) patients of group M. Gas exchange remained unchanged. CONCLUSIONS: We proved that cervical plexus block is associated with moderate depression of respiratory function without impairment of gas exchange. The block may be complicated by transient unilateral diaphragm paralysis. PMID- 20201341 TI - [Regional analgesia for trauma patients]. AB - BACKGROUND: We retrospectively assessed the effects and usefulness of regional techniques, performed at the time of admission to the emergency department, in patients with lower limb trauma. METHODS: A fascia iliaca compartment block using "three in one" method, and the sciatic nerve block from the lateral approach in the popliteal fossa were used.The effectiveness of blocks were assessed according to the Numerical Rating Scale. RESULTS: A fascia iliaca compartment block was performed in 12 cases, and sciatic nerve block in 13 cases. Various doses and drugs combination were used depending on parients needs.The "three in one" technique was satisfactory in 11 cases and popliteal technique in 10. No anaesthesia-related side effects or complications were observed. CONCLUSIONS: Regional techniques may be useful in the emergency department, for patients with lower limb trauma but they require expertise and skills. PMID- 20201342 TI - Improving the quality of acute pain services: experiences of treatment of 5212 patients. AB - BACKGROUND: In a retrospective, non-randomized, observational study, we compared methods of postoperative analgesia in 5212 cases treated in 2003 and 2004. METHODS: Patients were allocated to two groups: Group A included 2,796 patients treated in 2004; Group B included 2,419 treated in 2003.The acute pain team was staffed by anaesthesiologists who performed daily visits to patients receiving the APS. They dealt with complaints and complications, evaluated the effectiveness of analgesia, and kept records. The visiting anaesthesiologists rotated weekly in group A, and daily in group B. RESULTS: Analgesic effects, VAS, patient satisfaction, and the incidence of complications were compared between the two groups. The number of patients with an analgesic effect evaluated as "bad" was significantly lower in group A than in group B (p < 0.05). The proportion of patients in whom satisfaction was evaluated as"good"was significantly higher in group A compared to group B (p < 0.05);"moderate" and "bad"satisfaction scores were significantly lower in group A than in group B (p < 0.05). There was no significant difference in the incidence of complications between the two groups (p > 0.05).The number of cases in which analgesia was no longer required was lower in group A than in group B (p < 0.05). CONCLUSION: During postoperative management of analgesia by an acute pain service, a weekly rotation of anaesthesiologist staffing is more effective in improving patient satisfaction than a daily rotation. PMID- 20201343 TI - [Ventilator-associated pneumonia after cardiac surgery]. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) is a common complication in intensive care patients. Patients are most likely to be affected after abdominal and thoracic surgery. METHODS: The aim of the study was to analyze the epidemiology and aetiology of ventilator-associated pneumonia (VAP) following coronary artery surgery. Suspected cases were detected by the hospital Infection Control Team, in cooperation with ward personnel, and in accordance with CDC definitions. RESULTS: Fifty-three VAP cases were detected among 2,170 cardiac surgery patients. The ventilator utilization rate was 52%.The total cumulative VAP incidence was 2.2%, and the ventilator-associated pneumonia rate was 18.3/1,000 ventilator days, with a mortality of 1.9%.The most common isolates were Gram negative bacteria (P aeruginosa--10.4%, E. coli--12.5%, Klebsiella pneumoniae--16.7%) and Candida albicans. CONCLUSIONS: The incidence of VAP was similar to those reported in NHSN and KISS programs, however the data on the epidemiology of VAP were different. There were also differences in both the epidemiology and microbiology of VAP in this hospital, compared with results reported from other cardiac centres. This indicates the necessity of introducing an effective detection system for hospital acquired pneumonia after cardiac surgery. PMID- 20201344 TI - [A modified technique of retrograde intubation using gastric tube--a manikin study]. AB - BACKGROUND: Airway management is a critical skill that must be mastered by all emergency physicians. Retrograde intubation was first described in 1960, and since then it has been used as an alternative method when the classical approach to establish an artificial airway fails. Although it may be difficult due to anatomical and/or technical reasons, it requires limited equipment, is easy to learn, and has few contraindications METHODS: The author presents their own modification of the standard technique of retrograde intubation, using a gastric tube as a guide. After puncture of the cricothyroid membrane and passage of a guide wire (epidural catheter), a gastric tube is passed over the guide wire in a retrograde direction, through the previously dilated cricothyroid membrane, instead of via mouth. An endotracheal tube is then advanced over the gastric tube and inserted into the trachea. RESULTS: The method was tested and compared with a standard one on a manikin model by 38 anaesthesiologists and anaesthesia residents. The success rate was 96% for the modified method, and 65% for the standard method. CONCLUSION: The retrograde passage of a guide catheter (e.g., gastric tube) through the cricothyroid membrane may be more effective than the routine method, when it is introduced though the mouth. PMID- 20201345 TI - [Medical personnel in a paediatric hospital do not possess adequate cardiopulmonary resuscitation skills]. AB - BACKGROUND: The main changes to the European Resuscitation Guidelines in 2005 were relate to the tidal volume of artificial breaths, the position and depth of chest compressions, and th number of resuscitation cycles. To find out if these guidelines were widely known, we assessed the knowledge and skills of physicians and nurses working in a paediatric hospital. METHODS: During practical sessions, the skills of 118 employees (64 physicians and 54 nurses) were assessed when performing resuscitation on adult, child and infant AMBU manikins. Additionally, all participants completed self-assessment questionnaires. RESULTS: The main fault was the inadequate checking of the airway in adults. Only 53.6% of physicians and 71.9% of nurses could properly open the airway, and 85.7% of physicians and 50.0% of nurses correctly placed their heads above the victim's face when observing chest movements. Nearly 45% of nurses, and 100% of physicians delivered the correct tidal volume to adults, however it was frequently associated with marked gastric distension, in both adults and infants. The participants usually positioned their hands or fingers correctly on the manikin's chest, but delivered slow and shallow compressions. Almost 50% of participants graded their skills as inadequate. CONCLUSION: Despite continuous education, the resuscitation skills of physicians and nurses from a paediatric hospital were far from satisfactory. The results indicate an urgent need for regular training. PMID- 20201346 TI - [Regional citrate anticoagulation for continuous haemodiafiltration in the postoperative period]. AB - BACKGROUND: Continuous renal replacement therapy (CRRT) is commonly used for the treatment of acute renal failure in haemodynamically unstable patients after cardiac surgery. The main problem associated with CRRT is the need for systemic anticoagulation that may lead to bleeding complications. As an alternative to heparins, and to avoid systemic anticoagulation, the use of regional citrate infusion has been proposed for patients with a high risk of bleeding. CASE REPORTS: We present the clinical course of three patients with a high risk of bleeding after cardiac surgery in which CRRT, based on regional citrate anticoagulation, was conducted safely. Circuit survival times were over 80 hours and filters were changed on schedule, without any signs of dysfunction. Metabolic alkalosis was observed in one patient, who was treated by reducing the circuit blood flow and increasing the dialisate flow. One patient required chronic dialysis, the other two recovering after short-term CRRT. CONCLUSION: Regional citrate anticoagulation during CRRT should be used as a method of choice in patients with a high risk of haemorrhage in the postoperative period. PMID- 20201347 TI - [Cefepim in empiric therapy of ventilator-associated pneumonia]. AB - BACKGROUND: The most common infection following surgical treatment, when mechanical ventilation and tracheal intubation are used, is ventilator-associated pneumonia (VAP) induced by Gram-negative and Gram-positive bacteria. Its treatment is difficult due to increasingly high antimicrobial drug resistance observed recently. CASE REPORT: A 73-year-old patient was admitted to undergo coronary artery bypass grafting and cardiac aneurysm excision. Additionally, chronic circulatory insufficiency (NYHA 2) with ejection fraction of 30% together with hypertension and type 2 diabetes were diagnosed. After extracorporeal circulation, she was given adrenaline/noradrenaline and intra-aortic balloon pump. Postoperatively, elevated levels of CRP (70 mg L(-1)) and of procalcitonin (22.4 ng mL(-1)) were detected. Empiric therapy with cefepime 1 g x 2 iv was started. X-ray revealed atelectasis in the middle left lung lobe and Enterobacter cloacae was isolated from the bronchial tree. Patient was intubated and mechanically ventilated. Antibiotic therapy with cefepime was continued for 10 days and resulted in improvement of patient's general condition. On postoperative day 7, she was transferred from ITU to the cardiac surgery ward. CONCLUSION: Cefepime applied empirically to a VAP patient can effectively treat the lung infection and improve his/her general condition. PMID- 20201348 TI - [The protocol for multi organ donor management]. AB - Identification and preparation of a potential organ donor requires careful and meticulous intensive care, so that the organs may be harvested in the best possible condition for transplantation. The protocol consists of three key elements: (1) monitoring and haemodynamicstabilisation, (2) hormonal therapy, and (3) adequate mechanical ventilation and nosocomial pneumonia prophylaxis. Standard haemodynamic monitoring should consist of a 12 lead EGG, and direct monitoring of arterial and central venous pressures. Pulmonary artery catheterisation is indicated in donors with a left ventricular ejection fraction (LVEF) below 45%. PCWP should be kept at around 12 mm Hg, Cl at greater than 2.4 L m(-2), and SVR between 800 and 1200 dyn s(-1) cm(-5). When a vasopressor is necessary, vasopressin should be used as the drug of choice. If vasopressin is not available, noradrenaline or adrenaline may be used. Haemoglobin concentration should be maintained between 5.5-6.2 mmol L(-1). In a potential heart donor, troponin concentration should be checked daily. Neutral thermal conditions should be maintained using a warm air blower. A brain dead patient cannot maintain adequate pituitary function, therefore hormone replacement therapy with methylprednisolone, thyroxin and desmopressin is indicated. Glucose concentrations should be kept within the normal range, using insulin if necessary. The lung harvesting protocol should be similarto ARDS treatment guidelines (optimal PEEP, low tidal volumes). Lung recruitment manoeuvres, and aggressive prevention and treatment of nosocomial infection are essential. PMID- 20201349 TI - [Protocol of extracorporeal membrane oxygenation for acute respiratory failure treatment]. PMID- 20201350 TI - [aaRS--the etiological factor and the attractive target of many disorders]. AB - Aminoacyl-tRNA synthetases (aaRS) are essential proteins of all living organisms. It is known that they ensure the fidelity of transfer of genetic information from the DNA into the protein. Not far away it occurred that their role is not confined to catalyze the attachment of amino acids to transfer RNAs and thereby establish the rules of genetic code by virtue of matching the nucleotide triplet of anticodon with cognate amino acid. aaRSs are also engaged in the other crucial cellular processes. So the disturbance of function of any of them often causes serious disorders. Therefore this proteins could be an attractive target of drugs, not only against the mentioned illnesses but also against bacterial, fungal and parasitic infections. Constant progress on this field makes aaRSs still an interesting object of researches. PMID- 20201351 TI - [The important role of GLUT2 in intestinal sugar transport and absorption]. AB - The classical model of sugar absorption indicates that Na+ -glucose cotransporter, SGLT1 transports glucose from intestinal lumen to cytosol and GLUT2 transports glucose from cytosol to the blood. Recent evidence indicates that GLUT 2 is rapidly inserted into the apical membrane after a meal. Intestinal glucose absorption by the apical GLUT2 pathway can be 3 to 5-times greater then by SGLT1 et the high concentration of sugar. Apical GLUT2 insertion is regulated by pathway of calcium absorption through L-type channel Ca(v)1.3, activation of sweet taste receptors (T1R2/F1R3) and endocrine and paracrine hormones (especially insulin and GLP-2). PMID- 20201352 TI - [Endomorphins--endogenous ligands of the mu-opioid receptor]. AB - Two endogenous opioid peptides with extremely high mu-opioid receptor affinity and selectivity, endomorphin-1 and endomorphin-2, were: discovered and isolated from the mammalian brain in 1997. Endomorphins are amidated tetrapeptides, structurally different from so called typical opioids: enkephalins, dynorphins and endorphins. A protein precursor of endomorphins and a gene encoding their sequence remain unknown. Endomorphins are unable to cross the blood-brain barrier because of their low hydrophobicity. In animal models, these peptides turned out to be very potent in relieving neuropathic and inflammatory pain. In comparison with morphine, a prototype opioid receptor ligand, endomorphins produces less undesired side effects. In this article we describe the discovery of endomorphins, their cellular localization and functions in the organism, as well as their structure-activity relationships and biodegradation pathways. PMID- 20201353 TI - [Cysteinyl leukotrienes and their receptors]. AB - Cysteinyl leukotrienes (LTC4, LTD4, LTE4) have a proinflamation effect, such as contraction of blood vessels smooth muscle and the respiratory tract, chemotaxis of proinflammatory cells increased endothelium cells permeability and mucus secretion. They are lipid mediators playing an important part in the pathophysiology of bronchial asthma, allergic rhinitis, atopic dermatitis, urticaria, cardiovascular system disorders and tumors. They act through at least four receptors from the rhodopsin gene family, lying in the area of GPCR genes superfamily--CYSLTR1, CYSLTR2, GPR17 and receptor for LTE4 (CYSLT(E)R). Their location, apart from small exceptions, is differentiated and typical for tissues. The highest CYSLTR1 expression was stated in the spleen, peripheral blood leucocytes, interstitial lung macrophage and smooth muscle cells. CYSLTR2 shows highest expression in the hearth, adrenal glands, placenta, spleen and peripheral blood leucocytes, and somewhat smaller in the brain. Biochemical and pharmacological study and the analysis of sequences have shown that all three types of receptors belong to the group of 7-transmembrane receptors--GPCR. The CYSLTR1 excitation power is distributed: LTD4>LTC4>LTF4, and CYSLTR2 LTC4=LTD4>LTE4. Cysteinyl leukotrienes receptors are coupled with the G(q/11) proteins and signal path leading to phosphatidylinositol hydrolysis (PI) and mobilization of intracellular calcium. These receptors are in vivo coupled with the PTX-sensitive G(q/11) protein or both G proteins. CYSLTR1 increases the metabolism of PI and intracellular calcium, activates MAPK kinases, induces differentiation and proliferation of cells, chemotaxis, actin reorganization, release of inflammation mediators and regulation of hematopoietic stem cells. CYSLTR2 also increases the concentration of intracellular calcium, stimulates the release of IL-8 and increases expression of early genes. It is connected to thrombosis, vessel damage, inflammation process and cell death. The existence of new, nuclear, localization of CYSLTR and coexistence with other membrane receptors is postulated. It is probable that they can crate homo- or heterodimers. This indicates the existence of new, previously not know actions of, cysteinyl leukotrienes and their receptors. PMID- 20201354 TI - [Calreticulin--the structure, cell localizations and functions in animals and plants]. AB - Calreticulin (CRT) is an ubiquitously expressed Ca2+ binding protein in endoplasmic reticulum (ER) of eukaryotic cells. A highly conserved structure between CRTs from different species of animals and plants confirms an important role of the protein in living cells. CRT has been found in different cellular compartments, suggesting to play a role in many cellular processes both inside and outside the ER. Although, the basic CRT functions like regulation of Ca2 homeostasis and molecular chaperoning in ER might be the key to explain the multi process property of the protein. The plant CRT sequence shares the same structural domain features identified for animal CRT and seems to have similar properties. However, the current knowledge about CRT expression and physiological role in plants is still very limited. Therefore in this work, we focus on these less-well-characterized functions of CRT in plants. PMID- 20201355 TI - [Endoplasmic reticulum chaperons]. AB - The induction of chaperon proteins, belonging to GRPs (glucose-regulated proteins) family, is a mechanism which protects the cells against the endoplasmic reticulum stress. The genes that code synthesis of these proteins as well as some factors and mechanisms which regulate their expression were described. The explanation of GRPs function and regulation of their synthesis create new therapeutic possibilities in neoplasm diseases and those induced by endoplasmic reticulum stress. PMID- 20201356 TI - [Transformations of erythrocytes shape and its regulation]. AB - Erythrocytes can occur in many different shapes. Most of them are pathological and can be involved in diseases such a hemolytic anemia's and sickle cell anemia. Only three kinds of red blood cells are no pathological. Echinocytes, stomatocytes and discocytes can occure in blood stream of healthy organism. The echinocyte-dyscocyte-stomatocyte transformation protects red blood cells from lysis caused by echinocytogenic agents (hypertonic saline, basic pH, vanadate, anionic amphiphiles, ATP depletion etc.) or stomatocytogenic agents (hypotonic saline, acidic pH, cationic amphiphiles etc.). Mechanisms of these transformations can be classified in three group: redistribution of bilayer's lipid, modification Donnan's equilibrium and interaction of band 3 protein with different type of external factors. PMID- 20201357 TI - [Fluorescence lifetime imaging microscopy (FLIM) in biological and medical research]. AB - Fluorescence lifetime imaging microscopy (FLIM) is a powerful tool for producing an image based on the differences in the exponential decay rate of the fluorescence from a fluorescent sample. This technique can provide information, not only concerning the localization of specific fluorophores, but also about the local fluorophore environment. It can be used in scanning confocal, multi-photon microscopes, or in wide-field microscopes and endoscopes. FLIM systems can be implemented both in the frequency domain, using sinusoidally modulated excitation light and in the time domain, using pulsed excitation sources. The power of this technique lies in the fact that the measured fluorescent lifetime of a fluorophore is sensitive to the molecular environment of that fluorophore. Due to this phenomenon FLIM has recently found use in several applications: in the analysis of protein-protein interactions with high spatial and temporal specificity, in ion concentration imaging as well as in measuring of oxygen concentration and in medical applications. PMID- 20201358 TI - [Starch metabolism in potato tubers]. AB - Sucrose is a substrate for starch biosynthesis, unloaded symplastically into the developing potato tubers. Sucrose is converted to glucose-6-phosphate in the cytosol and exported into the amyloplasts. Starch may be degraded either hydrolytically or phosphorolytically. Glucose and maltose are products of hydrolytic starch breakdown in the sprouting tubers. Glucose phosphates are products of the phosphorolytic activity, metabolized to glucose and fructose in cold-stored tubers. Development of molecular tools for assaying potato gene function provide opportunities to receive genetic progress in the sugar-starch potato breeding. PMID- 20201359 TI - [Mobilization of storage proteins in cereal grains]. AB - Mobilization of seed reserves is a gradual process leading to the total degradation of accumulated biopolymers. In cereals cysteine endopeptidases and serine carboxypeptidases play essential role in hydrolysis of storage proteins. Peptidases of other catalytic groups seem to take part in regulatory processes or various processes that are not directly connected with storage proteins breakdown in the endosperm of germinating grains. The rate of the hydrolysis depends on the presence of biologically active gibberellins in the grain tissues. The presence of gibberellins determines peptidases synthesis in the aleurone layer, and acidification of starchy endosperm where the process occurs. Although the researches are highly advanced the functions of many peptidases in the storage proteins degradation are still not identified. PMID- 20201360 TI - [BD flow cytometry]. PMID- 20201361 TI - [Selecting reagents for multicolor BD flow cytometry]. PMID- 20201362 TI - [Medical-economical reasoning of volumes of financing of medicamental aid in the Armed Forces]. AB - The article presents the observe of methodological approaches to determination of necessity of financing the guarantee military-treatment institutes by medicaments in conditions of delivery of dispensary-polyclinic aid, of stationary treatment; organization of buying of medicaments, volumes of financing of medical service of the Armed Forces. PMID- 20201363 TI - [Several aspects of using of telemedical technologies in dermatology]. AB - There was effectuated an analyze of introduction of telemedical technologies in Russia and abroad. Was shown that the USA Armed Forces are one of active developers of telemedical technologies and user of them. It was marked that in dermatology, in contrast to other medical sciences, the diagnosis is made by dint of eyes, that's why it's very important to presents photos of evidence of dermatosis and histologic specimen. That's why program Teledermatopatologist is examining already in civil medicine. For television consulting on the forefront stages of medical aid (including military) it's enough to have a notebook, integrated modem and digital camera, and a corresponding soft and data base. PMID- 20201364 TI - [Main directions of growth of specialized medical aid in the Armed Forces]. AB - Systemic and process approaches permit to present a specialized medical aid (SMA) as opened, complicated, hierarchical, self-organizing system. The main tendencies of development of SMA in military and civil health care are differentiation and integration of medical specialties, standardization of types of SMA, multilevelness of SMA, development of microsurgical, endovideosurgical techniques. PMID- 20201365 TI - [Plasmapheresis intensive therapy of progressing stage of psoriatic disease]. AB - There were examined 124 medical histories of patients with psoriatic disease in progressing stage. It's found that including of hardware-generated filtrational membrane plasmapheresis, providing a middle-volume exfusion of plasma and following compensation of missing volume by water-electrolytic balanced solution at the beginning of intensive therapy of acute stage of disease is pathogenesisly proved and effective. Advancing using of plasmapheresis is shown on examples of patients with PASI more then 18 points, tending to decreasing of duration of acute form and severity of pathological process. PMID- 20201366 TI - [Results of psychophysiological testing of Kirov region's persons, who are under service call]. AB - There was effectuated a testing of 500 recruits of Kirov region for purposes of detecting cognitive power, level of neuro-psychic resistance, evidence of dividual professionally important qualities. It was shown, that 11,8% of recruits are characterized by modesty and unsociability, 34,9%--are more opened for contact. According to intelligence quotient level 12,3% had bad marks, 62,3%- normal level, 25,4%--high level. Phenomena of psychic disadaptation had 23,6%, more then 70% had different negative psychological characteristics. There was effectuated a counter conditioning of recruits according to their psychological peculiarities, was shown necessity and importance of individual approach to them. PMID- 20201367 TI - [Capabilities of telemedicine for solving tasks of psycho-prophylactic work among military servicemen of Air Force command posts]. AB - The article is devoted to using of telecommunicational technologies for prophylaxis, diagnostics and treatment of psychic disorders by military servicemen of specialbuildings of command post of Air Force. Were defined main tasks of using telecomunicational net for improvement of psychic reliability of military operators during a combat duty. Was proposed a scheme of using forces and facilities of medical service in organization of psycho-prophylactic work with using telemedical technologies, was proved necessity of creation of coordination counsel in telemedicine. PMID- 20201368 TI - [Peculiarities of psychophysiological status of flying staff of fighter aircraft of land basing]. AB - It was investigated the influence of professional activity on psychophysiological peculiarities of fighter pilot of different types of aircraft of land basing and afloat aircraft. As a result of investigation, it was determined that on base of social parameters they are equal. Airmen of the aviation of land basing have a similar personality profile, but different types of interpersonal relations. Station of depletion among airmen of the aviation of land basing was absent. Among airmen of afloat aircraft every third had a forming stage of depletion, characterized by emotional deficit, personal suspension, psychosomatic and psychovegetative disorders. PMID- 20201369 TI - [First-string native neurohistologist and histopathologist (to the 130th anniversary of Doynikov B.S.)]. AB - The article presents a biographic sketch, devoted to one of founders of histopathology of peripheral nervous system--Doynikov B.S. (1879-1948) - professor of Military-medical academy, author of fundamental monographies "General histology and histopathology of peripheral somatic nervous system" and "General histology and histopathology of peripheral vegetative nervous system". PMID- 20201371 TI - [The 80th anniversary of Central Military Clinical Sanatorium Sochi]. AB - The history of Central Military Clinical Sanatorium Sochi begins the 31st May 1929, when according to the order No 137 by Revmilitarysoviet of the Republic and National commissar of health care of Russian Soviet Federative Socialist Republic was founded a Military sanitarium station in Sochi. The now-days CMCS Sochi has modern treatment-diagnostics base and everything that is necessary for high qualified treatment. There are different modern diagnostic methods: laboratories, roentgenologic; functional: reovasographics, veloergometry, electrocardiogram, ultrasonic dopplerographia, USI of internal and etc. PMID- 20201370 TI - [The 265th anniversary of Orenburg military hospital]. AB - Orenburg military hospital, founded according to decree of empress Anna Ioanovna one year later after grounding of fortress Orenburg, started it's work in June 1744. To the beginning of the Great Patriotic War 1941-1945 the hospital was a big military treatment institute. In 1946-1958 the hospital was a regional hospital of South-Ural military region, and then--regional hospital of Baikal military region. Hospital takes an active party in life of the Armed Forces in general, it's staff comprises veterans of Afgan war, of other flash points, military servicemen and civil staff taken part in peacemaking operations. PMID- 20201372 TI - [Development of a set of diagnostic test systems for analysis of expression of C myc, mad1, max, p53, and E2F1 gene oncomarkers by the reverse transcription reaction-polymerase chain reaction alignment technique]. AB - Based on the performed studies, the authors developed test systems to analyze the expression of mRNA of the p53, C-myc, mad1, max, and E2F1 genes. These test systems could reveal a statistically significant difference between follicular adenoma and carcinoma of the thyroid in their expression of p53 mRNA. It should be noted that the use of our developed test systems is promising when searching for the diagnostic and prognostic markers of cancer, analyzing, and creating the genetic networks characterizing this or that cancer. PMID- 20201373 TI - [Comparative analysis of erythrocytic indices in patients with gynecological diseases and gynecological neoplasms]. AB - The study enrolled 177 women with gynecological cancer and 132 with gynecological disease. Hemoglobin (Hb), mean corpuscular hemoglobin (MCH), red blood cells (RBC), and erythrocyte sedimentation rate (ESR) were analyzed. The gynecological patients with anemia showed a correlation between Hb and MCH (p < 0,05), which is indicative of iron deficiency. In the gynecological cancer patients, the correlation between Hb and MCH was significant (p < 0,01), that between Hb and RBC was strong (p < 0,001), suggesting the reductions in both erythropoiesis and Hb synthesis in the erythrokaryocytes. In these patients, anemia results from chronic diseases. The gynecological cancer patients were found to have higher ESR and lower Hb, RBC, and MCH than the gynecological patients. PMID- 20201374 TI - [Techniques for experimental and clinical studies of erythrocyte deformability]. AB - Deformability is an important property of red blood cells and ensures the efficiency of their transport in the microcirculatory vascular system, as well as tissue oxygenation. A study of erythrocyte deformability uses different methods: filtration through about 5.0-microm pores, laser difractometry techniques and a focus of attention has recently been on a procedure for measuring the deformability of erythrocytes in a flow microchamber. The authors have developed a procedure for the recording of erythrocyte deformability and for the computer aided treatment of an obtained image to have an accurate quantitative assessment of this important microrheological property of the cells. Comparison of the suspension viscosity of erythrocytes at high shift rates and the erythrocyte lengthening index (ELI) in the flow microchamber yielded a high correlation (p = 0.917; p < 0.01). That of ELI in the fractions of young and old cells also supported the high sensitivity of the procedure. Analysis of changes in the degree of erythrocyte deformability (in accordance with ELI), by applying three values of shift strain, revealed an almost linear relationship of the lengthening of fixed cells to the applied shift pressure. The known rheomodulator pentoxiphylline caused a significant erythrocyte deformability increase that was recorded by both methods (in the flow microchamber and at viscosimetry of erythrocyte suspensions with the hematocrit being equal to 40%). Thus, findings suggest that the method for the recording of erythrocyte deformability in the flow microchamber with the computer-aided analysis of images allows one to adequately measure this property of red blood cells. PMID- 20201375 TI - [Cytomorphological diagnosis in the primary central nervous system lymphoma]. AB - The paper provides a retrospective analysis of cases of the cytological diagnosis of the rare abnormality--primary central nervous system (CNS) lymphomas. It shows the specific features of each nosological entity and the importance of assessing clinical and X-ray data. The capabilities, advantages, and disadvantages of diagnosis of both cytological and histological diagnosis of CNS lymphomas are estimated. PMID- 20201376 TI - [Interpretation of thromboelastography data in cardiosurgical patients]. PMID- 20201378 TI - [Comparative significance of the biochemical markers of cell-mediated immunity in the diagnosis of tuberculous pleurisy]. AB - The authors have compared the informative value of the tests determining the activity of adenosine deaminase (ADA) and the levels of interferon-gamma (INF gamma) and neopterin in the diagnosis of pleural effusions of tuberculous (n = 67) and nontuberculous (n = 30) origin. The equally high diagnostic value has been found in the study of the activities of ADA (94.8%) and INF-gamma, which are markers of lymphocytic cellular immunity. There are great differences in the sensitivity of the neopterin test depending whether tuberculosis is isolated or complicates the course of tuberculosis of the lung or intrathoracic lymph nodes, which may be regarded as a reflection of the different status of macrophageal cellular immunity. PMID- 20201377 TI - [Immune status parameters in patients with allergic airway diseases with bacterial sensitization]. AB - In-depth analysis was made to study immunological parameters in 188 patients with allergic airway diseases (AAD) and bacterial sensitization and in 40 healthy individuals. No substantial changes were found in the count of CD3+, CD4+, CD20+, and CD8+ cells. However, it was ascertained that the patients with AAD showed a significant reduction in the peripheral blood levels of natural killer and CD95+ cells, at the same time there was an increase in CD25+-activated lymphocytes and in the absolute count of CD8+ cells and total IgE. As compared with the healthy individuals, the patients with ADD had elevated interleukin (IL)-1 and IL-4 and decreased interferon-gamma in cytokine immunoregulation. Thus, the study conducted leads one to believe that AAD with bacterial sensitization is an immunopathological process with a predominance of a Th2-dependent immune response. PMID- 20201379 TI - [Development and use of a domestic test system for diagnosis of tuberculous infection on the basis of quantitative analysis of interferon-gamma induction in whole blood samples in vitro, by using specific recombinant antigens]. AB - A test system was developed to detect tuberculous infection by qualitative analysis of interferon-gamma (IFN-gamma) in the plasma samples after 20-24-hour incubation of whole blood samples in the presence of Mycobacterium tuberculosis (MBT) antigens: tuberculin PPD and a mixture of the MBT-specific recombinant antigens ESAT-6 and CFP-10. The analysis used 3 test tubes each containing 1 ml of heparinized venous blood, one of which served as a control; the other two test tubes were employed to measure antigen-induced IFN-gamma production. Whether this test system might be used to determine primary tuberculous infection was studied in 277 children and adolescents. The threshold diagnostic IFN-gamma induction level determined in the test tube containing a mixture of the antigens ESAT-6 and CFP-10 was ascertained. Postvaccine allergy was detectable if there was IFN-gamma induction in the test tube containing tuberculin and if there was no diagnostic IFN-gamma level in that containing the antigens ESAT-6 and CFP-10. The diagnostic sensitivity of detection of primary tuberculous infection was 97.6% with 94.4% specificity, which enabled this condition to be differentiated from postvaccine allergy. The level of antigen-induced IFN-gamma may be lower in relatively disseminated forms of pulmonary tuberculosis. PMID- 20201380 TI - [Determination of the optical characteristics of a highly dispersive biological medium using an updated diffusion model of radiation transfer]. PMID- 20201381 TI - [Spectral analysis of electrocardiographic signals based on wavelet-packet processing]. PMID- 20201382 TI - [A corrective couch for functional recovery of the spine and prophylaxis and treatment of osteochondrosis]. PMID- 20201383 TI - [Effects of uncoupling proteins on nitric oxide synthesis and oxidative stress development in ishemia-reperfusion of old rat hearts]. AB - Genipin is aglycone of geniposide, one of the active compounds of Gardenia gasminoides Ellis. The gardenia fruit extract has been used in traditional Chinese medicine to relieve the symptoms of type 2 diabetes that is accompanied with extensive oxidative stress and endothelial dysfunction of NO production. Besides, genipin was shown to inhibit UCP-depended proton leak through the inner mitochondrial membrane that leads to increased membrane potential and ATP production. We studied the effects of genipin at ischemia/reperfusion-induced oxidative stress and activity of NOS isozymes using Langendorfperfused old rat heart model. Ischemia/reperfusion is well-known oxidative agent, and showed significant increasing of superoxide radical, hydrogen peroxide and hydroxyl radical. Genipin application in doze 10-5 mol/L for 15 min before prolonged ischemia exerted powerful antiradical and antilipoperoxidative effects. Heart ischemia/reperfusion was supported with peroxynitrite generation and nitrozative stress. We demonstrated the inhibitory property of genipin on INOS expression that possibly occurs via protein kinase A inhibition and stabilization of I kappaB-NF-kappaB complex. Genipin stimulated cNOS activity seemingly activating PI3K/Akt signaling pathway. Although, post-ischemic recovery ofcardiodynamic parameters of old rat hearts were depressed due to "switching off" the NO production by inducible NOS which is important in early period of reperfusion. Thus, we conclude that genipin is powerfull antioxidant and posses insulin-like activity due to its property of managing the NO production at intracellular signal transduction cascade level. PMID- 20201384 TI - [Cardioprotective effects of activation of ATP-sensitive potassium channels in experiments in vivo: influence on blood biochemical parameters following ischemia reperfusion of the myocardium]. AB - In experiments on the anaesthetized dogs with modeling of experimental ischemia (90 min) and reperfusion (180 min), the participation of biochemical processes in the cardioprotective effect of the preischemic activation of ATP-sensitive potassium (KATP) channels caused by intravenous introduction of flokalin, a new fluorine-containing opener of these channels was shown. Flokalin was introduced in a dose 0.1 mg/kg of animal body weight which practically did not change the parameters of hemodynamic in normoxia. Thus, the experiments investigating the influence offlokalin on changes of biochemical parameters of arterial blood during ischemia-reperfusion of myocardium showed certain features of ischemia reperfusion syndrome development during stimulation of K(ATP) channels. The analysis of biochemical parameters of blood showed that flokalin suppressed free radical reactions and had antioxidant properties: reduced quantity of H2O2 and NO3- (the last can interpreted as a reduction in peroxynitrites formation), prevented the decline of catalase and superoxide dismutase activity. Practically constant content of low-molecular nitrosothiols in blood during all duration of experiment and increase of NO2-level during reperfusion may indicate on intact functions of the NO system and protective influence of flokalin during ischemia reperfusion of myocardium. Practically unchanged content of inorganic phosphorus and uric acid in blood during ischemia- reperfusion under conditions of preischemic introduction of flokalin indicates the prevention of ATP degradation and fomation of both superoxide anion by xanthinoxidase and peroxynitrite by it interaction with nitric oxide. All mentioned properties of flokalin related to the changes of biochemical parameters of arterial blood, together with the changes of parameters of hemodynamics, result in diminishment of infarct size of myocardium after ischemia-reperfusion by 37% versus control experiments. K(ATP) channels, flokalin, ischemia-reperfusion, free radikaly, NO system. PMID- 20201385 TI - [Effects of RNA on blood circulation and its adrenergic and cholinergic regulation]. AB - Experimental investigations of the impacts of microRNA agent nucleks on heart function, coronary and systemic circulation as well as on adrenergic and cholinergic mechanisms of cardiohaemodynamics regulation were performed on anaesthetized dogs. Bolus injection (0.1-100.0 mg) or prolonged infusion (2.5 mg/min) of nucleks into perfusion coronary artery blood stream induced coronary dilatation. Under the intracoronary infusion of nucleks we observed more pronounced coronary vasodilatation and left ventricle pressure elevation in response to adrenergic heart receptors stimulation by norepinephrine (0.05-5.0 mkg, intracoronary). Besides that the drug infusion into coronary blood stream promoted the acceleration of recovery processes of the studied cardiohaemnodynamic parameters after norepinephrine injection. After intracoronary infusion of nucleks the sensitivity of cholinergic receptors to the stimulation by acetylcholine (0.001-1.0 mkg, intracoronary) increased significantly. After NO-synthase blockade (L-NAME, infusion 2.0 mg/min, intracoronary) nucleks did not cause any effect on coronary vessels tone and heart activity both it did not change their adrenergic and cholinergic reactivity. PMID- 20201386 TI - [Modulation of the smooth muscle contractions of the rat vas deferens by TRPM8 channel agonist menthol]. AB - TRPM8 is nonselective, Ca2- permeable cationic channel, which is activated by innocuous cold and by chemical drugs imitators of cooling, menthol, icilin and cucalyptol. TRPM8 expression was detected in the smooth muscle cells of the rat vas deference with preferential localization of the TRPM8 protein to the membrane of sarcoplasmic reticulum (SR). In the present work we have studied the effects of TRPM8 channel agonist, menthol, on the contractions of the smooth muscle strips of the epididimal and prostatic portions of the rat vas deferens evoked by potassium rich (KCl) Krebs solution and by muscarinic or adrenergic agonists carbachol (CCh) or noradrenalin (Nor). Menthol (0.1-1 mmol/l) per se virtually unaffected the basal tone, but inhibited in a dose-dependent manner KCl-, CCh- and Nor-evoked contractions of both parts of the vas deference by 30-50%. Blockade of the Ca2+ -ATPase of the SR with cyclopiazonic acid (CPA, 10 micromol/l) enhanced inhibitory action of menthol on KCl-induced contractions, but slightly decreased inhibition by menthol of agonist-induced ones. Nonspecific TRPM8 blocker, capsazepine (10 micromol/l), did not eliminate, but augmented inhibitory action of menthol on all types of contractions. Our data propose that menthol inhibits contractions via two mechanisms: partial blockade of Ca2+ entry via the voltage-gated, L-type calcium channels and a decrease of the calcium storage capacity of the SR. The latter mechanism at least in part is mediated by the SR-resident TRPM8 channel, which by activation of menthol leads to the enhancement of passive leak of Ca2+ from the SR and reduction in the amount of the releasable calcium during activation of contractions. PMID- 20201387 TI - [Histological and hormonal characteristic of microencapsulated human parathyroid tissue in long-term culture]. AB - Microencapsulated human parathyroid tissue preserves the viability and high ability to secrete parathormone in long-term culture that indicates on perspective to further study the efficiency of using this tissue in the presence of compensated hypofunctional state of parathyroid system in experimental animals. PMID- 20201388 TI - [Characteristics of behavioral manifestations of somatic and visceral pain during short-term immobilization stress]. AB - In experiments on mice with behavior registration, we investigated the influence of short (30 min) immobilization stress on the development of somatic (the formalin test) and visceral (the acetic test) pain. It is shown that during somatic pain short immobilization prolongs the duration of the initial sharp and the remote phases of painful reaction. This is accompanied by an increase in motion activity and reduction of sleep duration. When visceral pain was evoked, such stress causes occurrence of the period of temporal hyperalgesia together with activation of mobility of animals. PMID- 20201389 TI - [The effect of desmopressin on changes of bile acids specter in rats]. AB - We studied the effect of the synthetic analogue of antidiuretic hormone desmopressin on the level of choleresis and the bile acids spectrum in acute experiments in bile duct-cannulated rats. It is shown that desmopressin increases bile flow and concentration of taurin-conjugated bile acids. In this situation, the concentration ofglycocholates practically is not changed, and concentration of free bile acids is diminished, which results in increase in the conjugation coefficient. Blockade of V(1a) vasopressin receptors decreases the efficiency of desmopressin regulatory effect on certain aspects of bile secretion. Indexes of choleresis volume velocity were less than those obtained following peptide introduction. The changes in concentration of conjugated and free bile acids had opposite dynamics. Concentration of tauro- and glycocholates was diminished, while concentration of free bile acids was increased, which resulted in a decrease in conjugation coefficient. The data obtained indicate that desmopressin affects both the synthesis and in a higher degree the conjugation process of bile acids with amino acids through V(1a) vasopressin receptors. PMID- 20201390 TI - [Hypoxic pulmonary hypertension: the role of phosphatidylcholine-specific phospholipase C]. AB - The aim of the study was to investigate the role of phosphatidylcholine-specific phospholipase C (PC-PLC) in the development of hypoxic pulmonary hypertension. Induction of hypoxic hypoxia in rats resulted in a biphasic increase in systolic right ventricular pressure (RVP). The first phase was transient (5.4 +/- 0.9 min), while the second phase was sustained and persisted during the whole time course of hypoxia (120 min). An inhibition of cNOS with L-NAME (25 mg/kg; i.v.) did not cause any change in the nature of the hypoxic reaction, despite the RVP values were significantly higher in normoxia and hypoxia. These results demonstrate that NO synthase is not substantially involved in the hypoxic pulmonary vasoconstriction. Injection of PKC inhibitor chelerythrine (0.5 mg/kg; i.v.) prevented the development of the first phase of the RVP increase and reduced the second phase by 40%. An inhibition of PC-PLC with D609 (5 mg/kg; i.v.) completely abolished pulmonary hypertension. The results obtained suggest that PC-PLC possibly plays a key role in the development and maintenance of hypoxic pulmonary hypertension. PMID- 20201391 TI - [Effects of cardioelectrostimulation and chemical preparations on autonomic nervous regulation of heart rate]. AB - The aim of the study was to evaluate the peculiarities of heart rate variability and autonomic nervous system regulation and to predict the changes in sinus rhythm after successful medical or electrical correction. 72 patients with atrial fibrillation before and after its correction have been monitored. Atrial fibrillation during the first month after cardioversion occurred in 26.3% of patients. Data analysis using computerized heart rhythm analysis showed a decreased heart rate variability in patients during atrial fibrillation and increased heart rate variability. These parameters are the markers which characterize the sinus rhythm maintenance. PMID- 20201392 TI - Influence of supplementary vitamins and minerals on lipid peroxidation and redox state in heart, kidney and liver of rats exposed to fluoride. AB - The effect of fluoride (F) and supplementary vitamins and minerals on lipid peroxidation (LPO) and redox state (RS) in heart, kidney and liver of 40 (4 groups of 10) male Wistar rats were studied. One group of rats was left untreated as control, group 1 was received 5 mg/l NaF in their drinking water, group 2 was received 5 mg/l NaF in their drinking water plus vitamins (A, C, and D) in their diet, and group 3 was received 5 mg/l NaF in their drinking water plus vitamins (A, C, and D) and minerals (Mg-, Mn-, Zn-sulfate, and Na-citrate) in their diet. In comparison with the group 2, 3 and controls, elevated malondialdehyde (MDA) content in the group 1 indicated an increase in LPO product. In addition, unsteady ratios of oxidized to reduced nicotinamide adenine dinucleotide (NAD+/NADH) reflected significant alterations in the RS status. These results demonstrate that the combination of vitamins and minerals supplementation proved to restore MDA content and establish steady RS status that has not been previously reported. PMID- 20201393 TI - [Gender difference in physical development and functional state of the cardiac vascular system in children of 12 years old]. AB - It was shown that physical development in the girls of 12 years old somewhat forestall the physical development in the boys of the same age. Average values of the height and massa in the girls of 12 years old are following: 1.57 m +/- 0.15 m and 45.8kg +/- 0.16 kg against 1.55 m +/- 0.04 m and 44.53 kg 0.13 kg in the boys. Average values of heart rate, end diastolic pressure and workability of the left ventriculus in the children of 12 years old are similar in boys and girls, and the average value of stroke volume and power of the left ventriculus in the boys are more. The conclusion was made that the effectivenes of the heart activity in the boys of 12 years old is more than in the girls of the same age. PMID- 20201394 TI - [Mechanism of apoptosis in the thyroid cells in thyroid pathology]. AB - The literature data and the results of own examinations concerning the changes in programmed cell death processes of goiter alterated thyroid tissue in patients with euthyroid or toxic goiter and also the extranodular tissue of the gland in the presence of pathological changes in it (the pronounced hyperplastic process, sclerotic and/or dystrophic changes, lymphoid infiltration, chronic or autoimmune thyroiditis) were analyzed. It has been shown that the significant changes in the processes ofmitochondria and postmitochondria regulation and apoptosis realization are occurred under thyroid pathology. The character and the degree of disorders in the apoptosis mitochondria mechanisms and the activity of destructive processes in the patient thyroid cells are dependent on many factors such as the type of pathology, the severity of its occurrence, the peculiarities of tissue follicular structure and the patient sex. Obtained resistance of the apoptosis mitochondria mechanisms can play an important role in the pathogenesis of thyroid nodular pathology or in the development of inflammatory and autoimmune processes. PMID- 20201395 TI - [Organisms producing hypolipidemic compounds with antioxidant activity]. AB - Complex compounds produced by fungal cultures of Lecanicilium and Beauveria with both high hypolipidemic and antioxydant activities were screened. Two fractions of the hypolipipidemic compounds with antioxidant activity of 95 and 75% in a dose of 25 mcg/ml were isolated. PMID- 20201396 TI - [Rapid bioluminescent antibiotic susceptibility assay]. AB - Rapid testing of pathogen susceptibility to antibiotics is of great practical value for rational chemotherapy of pyoinflammatory deseases and postoperative complications of microbial etiology. The standard microbiological methods, i.e., the disk diffusion method and the method of serial dilutions are labour- and time consuming (not less than 18-36 hours). The method of the authors is based on measuring bioluminescence resulting from interaction of adenosine-5'-triphosphate (ATP) and ATP reagent, a standard reaction mixture of firefly luciferase (an enzyme) and luciferin. The bioluminescence intensity is proportional to the ATP concentration in the reaction mixture and the ATP concentration is proportional to the number of the pathogen viable cells in the sample. The bioluminescence intensity value in the pathogen suspension aliquots with and without (control) the antibiotic were compared after the incubation for 5 hours and the coefficient of the microbial cell growth inhibition was calculated. Satisfactory correlation (R2 > 88%) of the results of the bioluminescent assay and the assay with the disk diffusion method and the method of serial dilutions was observed. PMID- 20201397 TI - [In vitro investigation of Ingavirin efficacy against influenza B virus]. AB - The experimental investigation of Ingavirin activity against influenza B virus showed that in concentrations 100 and 200 mcg/ml it was efficient in inhibition of the virus reproduction: the cytopathic effect was lowered by 75%, the level of the pathogen accumulation in the MDCK cell culture was decreased by more than 2.0 lg and the formation of the virus specific hemagglutinin was inhibited by more than 90%. PMID- 20201398 TI - [In vitro Ingavirin efficacy against adenoviral infection pathogen]. AB - The experimental investigation of the Ingavirin antiviral effect showed that in concentrations of 200 and 100 mcg/ml it totally protected the cells from the cytopathic action of the virus, when added before the inoculation of the HeLa cell culture. After a tenfold decrease of the infective dose (up to 0.001 CPD50/cell), the inhibition of the virus cytopathic effect by Ingavirin amounted to 100% in all the tested concentrations (including the low ones) added either before or after the culture contamination. Ingavirin was efficient in inhibition of the adenovirus type 5 reproduction in the HeLa cell culture. PMID- 20201399 TI - [In vitro antibiotic susceptibility compliance with efficacy of chemotherapy in infections due to pathogenic Burkholderias]. AB - Among the known species of Burkholderia only two are obligate pathogens, i.e., B. mallei and B. pseudomallei, causative agents of glanders and melioidosis respectively. The other species are saprophytes as natural inhabitants of water reservoirs and soil, still capable of causing opportunistic infections in humans and animals under definite conditions. All the species of Burkholderia are characterized by high resistance to antibacterials, including antibiotics. By the MICs, the most efficient chemotherapeutics against pathogenic burkholderias are tetracyclines, fluoroquinolones, penems and combined sulfanilamides. In the treatment of experimental glanders and melioidosis the set of the effective drugs had the inverse variation dependence on the infection severity and the desease process rate. Co-trimoxasole showed the best results, then followed doxicycline, ciprofioxacin and ceftazidime in the diminishing succession. The modification of the method for determination of antibiotic susceptibility with addition of native blood to the medium and the subculture under the atmosphere of 5% CO2 was shown useful in estimation of the prospects of the use of chemotherapeutics for the treatment of Burkholderia infections. PMID- 20201400 TI - [Comparative analysis of the use of antimicrobials with systemic action in outpatients in the Russian Federation, Ukraine and Kazakhstan]. PMID- 20201401 TI - [Cycloferon, as an agent in the therapy and urgent prophylaxis of influenza and acute respiratory tract viral infection (multicentre randomized controlled comparative study)]. AB - Data on the study of the efficacy of the tablets of cycloferon, an early inductor of types 1 and 2 interferon, in the treatment of influenza and acute respiratory tract viral infections in adults are presented. The study enrolled 522 patients with moderate influenza of type A (H1N1) verified in 61% of the patients and type A (H3N2) verified in 7.5% of the cases. The patients were randomized with the envelope procedure. In the patients treated with cycloferon the intensity and period of the fever were stopped earlier and averaged from 1.8 to 3 days vs. 5 days in the reference group (symptomatic therapy). The improvement signs in the general state of the patients treated with cycloferon were noted on the 2nd day. The influenza complication as pneumonia was recorded in 2.2% of the patients treated with cycloferon, whereas in the patients under the symptomatic therapy the complications as bronchitis, pneumonia, angina were stated in 21.4% of the cases. For urgent prophylaxis of the influenza and respiratory tract viral infections (epidemiologic study) a group of 3717 subjects randomized with the table of random numbers was observed. 2080 patients were treated with cycloferon and 1637 patients were under the symptomatic therapy. The results were evaluated by the efficacy index and the protection estimate (T. A. Semenenko, 1991). The total efficacy index and the protection estimate in all the patients of the group were 4.9 and 79.8% respectively. The complicated forms of the disease were recorded in 1.5% of the patients treated with cycloferon and in 10.5 and 11.3% of the patients not treated with cycloferon. PMID- 20201402 TI - [Determination of cefixime blood plasma levels by HPLC]. AB - For comparative study of the pharmacokinetics of Cemidexor (capsules of 100 mg) and Suprax (capsules of 400 mg), a method of HPLC with quantitative determination of cefixime (the active substance in the drugs) in the blood plasma of patients with UV detection was developed. The data teproducibility with an account of the admissibility criterion was observed within the interval of all the concentrations (0.06-10 mcg/ml). The accuracy and correctness of the method also corresponded to the admissibility criteria. The lower limit of the quantitative determimation of the cefexime blood plasma levels was 0.06 mcg/ml. The pharmacokinetics was studied with the open crossed randomized method. The results were used for calculation of the pharmacokinetic parameters required for estimation of the bioequivalence of the drugs. The statistical analysis of the pharmacokinetic parameters showed that Cemidoxor and Suprax were bioequivalent. PMID- 20201403 TI - [Estrogen receptor expression in tumors different from breast cancer]. AB - A review of the literature data on expression of estrogen receptor alpha and beta (ERalpha and ERbeta) in tumors different from breast cancer. The results regarding the ERalpha and ERbeta expression frequency in non-small cell and small cell lung cancer, colorectal cancer, esophageal, ovarian, prostate and brain tumors are presented. High frequency of estrogen receptor expression (in up to 50 and more per cent of cases) in various types of tumors, differences between ERalpha and ERbeta in expression frequency, prognostic significance and prediction of the neoplastic process aggressiveness as well as in biological implications of interaction with antiestrogens (antagonistic and/or agonistic effect) are shown. The data on comparative evaluation of ERalpha and ERbeta expression in lung, ovarian, prostate tumor cells and corresponding nonneoplastic tissues are reported. Authors consider necessary to include the ERalpha and ERbeta detection into the routine clinical practice not only in breast cancer but in other tumors as well. Prospects of the clinical application of antiestrogens, in particular tamoxifen, in adjuvant therapy of different tumors with positive ER status are discussed. PMID- 20201404 TI - [Type 1 interferons: induction and mechanisms of antiviral action]. PMID- 20201405 TI - [Inhibitor-protected aminopenicillins. Pharmacological characterization and role in community-acquired infections]. PMID- 20201406 TI - Chitinase 3-like protein 2 (CHI3L2, YKL-39) activates phosphorylation of extracellular signal-regulated kinases ERK1/ERK2 in human embryonic kidney (HEK293) and human glioblastoma (U87 MG) cells. AB - Human cartilage chitinase 3-like protein 2 (CHI3L2, YKL-39) is secreted by articular chondrocytes, also synoviocytes, lung, and heart. Increased levels of YKL-39 have been demonstrated in synovial fluids of patients with rheumatoid or osteoarthritis as well as in some other pathologies and in malignant tumors, particularly in glioblastomas. It belongs to glycosyl hydrolase family 18 and the most closely related to human cartilage glycoprotein 39 (HC gp-39 or chitinase 3 like protein 1, CHI3L1 or YKL-40), which as it was shown previously, promotes the growth of human synovial cells as well as skin and fetal lung fibroblasts. Dose dependent growth stimulation was observed when the fibroblastic cell line was exposed to YKL-40 in a concentration range from 0.1 to 2 nM, which is similar to the effective dose of the well characterized mitogen, insulin-like growth factor 1. The use of selective inhibitors of the mitogen-activated protein kinase (MAP kinase) signaling pathway indicates that both, YKL-40 and IGF-I are involved in phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/ERK2). Thus YKL-40 initiates a signaling cascade which leads to increased cell proliferation, suggesting that this protein could play some role in the inhibition of apoptosis. We report here that YKL-39, which as YKL-40 has significantly increased expression in glioblastomas, also activates signal regulated kinases ERK1/ERK2 in human embryonic kidney (HEK293) and human glioblastoma (U87 MG) cells. PMID- 20201408 TI - [Characteristics of the cytomixis channel formation in Nicotiana tabacum L. pollen mother cells]. AB - The cytomictic channels in pollen mother cells of tobacco can be formed by two distinct ways: on the basis of plasmodesmata and de novo without any relation to ones. Cytomictic channels formation it was shown to be possible on the basis of single plasmodesma. It is not unlikely that special electron-dense bodies involve de novo formation of the channels. Also the role of cytomictic channels in the pollen development regulation is discussed. PMID- 20201407 TI - [Polypurine/polypyrimidine sequences with potential of forming triplexes in the proviral DNA of bovine retroviruses]. AB - Perfect interstranded triplexes that can potentially arise in the proviral DNA of wide-spread bovine retroviruses like as bovine leukemia virus (BLV) and bovine immunodeficiency virus (BIV) have been determined. In the BLV and BIV genomes 2 and 5 fragments respectively were found to form triple helixes under acidic conditions. One of those fragments that is localized on the BLV gag gene can exist as cruciform structure too. Experimentally the existence of triplexes is confirmed by atomic force microscopic visualization of supercoiled pGEMEX DNA for which genome 6 fragments are found with mirror symmetry that is necessary for intramolecular triplex formation. The diagrams of triplexes (one of the elements of signaling genome function) localization on the genome of bovine retroviruses are obtained. PMID- 20201409 TI - Formation of multicellular aggregates under different conditions of microenvironment. AB - Multicellular aggregates (spheroids) represent an intermittent level between monolayer growing cells and tissue culture. Spheroids are rather objective model of the three-dimensional growth and organization, the cell-to-cell interactions and influence of microenvironmental conditions on tumour microaggregates. In our work formation and growth of spheroids depends on concentration of CMC and FCS. Conditions of microenvironment influence on intensiveness of proliferation as well as on cells adhesiveness and formation of microaggregates. PMID- 20201410 TI - [Adaptibility of wheat alloplasmic lines in hybridization]. AB - The adaptability of alloplasmatic lines of wheat and their hybrids with wheat alien amphyploid and wheat was studied. The influence of nuclear genome and interaction of nuclear and cytoplasm genomes on adaptability of wheat and its hybrids has been established. For an estimation of adaptability it is necessary to use a complex of attributes (morphological, cytogenetic, resistance to abiotic and biotic factors of environment). PMID- 20201411 TI - [Genetic polymorphism of clones and their seed progeny in the scotch pine clone plantation]. AB - Genetic variation at 12 allozyme loci (10 of them being polymorphic ones) has been studied in the archive-clone plantation of 23 Pinus sylvestris plus-trees and their seed progeny in the south-east of Ukraine. More than a half of clones had 4-8 heterozygous loci, whereas their seed progeny was marked by a lower variation than maternal trees. Seed progeny was obtained at a high outcrossing rate (t(m) = 95%). The clone progeny was characterized by a high percentage of abnormal allele segregation in megagametophytes. There was also a high frequency of significant deviation in distribution of seed embryo genotypes from the theoretically expected one according to the Hardy-Weinberg law. PMID- 20201412 TI - [Evaluation of enzyme multiple forms spectra using the index of system diversity level]. AB - Comparative estimation of the most widely used indexes of the system diversity has been carried out using model electrophoretic spectra. The basic requirements to the diversity index of electrophoretic spectra are formulated. A formula for the estimation of the level of spectra diversity of multiple forms on the basis of synthesis of the Ashby complication of the system index and the Simpson index is offered. PMID- 20201413 TI - [Genoprotective effect of sodium humate in conditions of induced oxidative stress]. AB - It was shown that sodium humate in a range of concentration of 50-1000 mg/l reduces a level of clastogenic effects induced with dioxidin (20 mg/l), a prooxidant mutagene. The greatest effect was observed at concentration of 300 mg/l. Direct doze-effect dependence under the influence of sodium humate was not revealed. Possible antioxydative and desmutagenic mechanisms of sodium humate protective action are discussed. PMID- 20201414 TI - [Study of genetic determination of base clinical components of metabolic syndrome]. AB - Genetic analysis was carried out on the material including clinic and genealogical data about 510 patients with type 2 Diabetes Mellitus, 445 Essential Hypertension individuals, 239 abdominal obesity persons and their 1st degree relatives. It has been shown that the Essential Hypertension and abdominal obesity distribution in the population and families can be described by means of a variants polygene model with essential influence of the major genes. Gene complexes of predisposition to obesity, Essential Hypertension and Type 2 Diabetes Mellitus are independent, however, their liabilities are covered. PMID- 20201415 TI - Recent advances in plant biotechnology and genetic engineering for production of secondary metabolites. AB - For a long time people are using plants not only as crop cultures but also for obtaining of various chemicals. Currently plants remain one of the most important and essential sources of biologically active compounds in spite of progress in chemical or microbial synthesis. In our review we compare potentials and perspectives of modern genetic engineering approaches for pharmaceutical biotechnology and give examples of actual biotechnological systems used for production of several promising natural compounds: artemisinin, paclitaxel and scopolamine. PMID- 20201416 TI - [Gene therapy based on human mesenchymal stem cells: strategies and methods]. AB - Major technologies of transient and stable transgene expression in hMSC are reviewed. Properties and efficiencies of recombinant lentiviruses, adenoviruses, AAV and baculoviruses used for hMSC transduction are compared. The aims oftransgenesis include directed differentiation of hMSC, function improvement, correction of pathology factors and proliferatrion control, as well as many basic research challenges. PMID- 20201417 TI - Curcumin loaded pH-sensitive nanoparticles for the treatment of colon cancer. AB - The investigation was aimed at designing pH-sensitive, polymeric nanoparticles of curcumin, a natural anti-cancer agent, for the treatment of colon cancer. The objective was to enhance the bioavailability of curcumin, simultaneously reducing the required dose through selective targeting to colon. Eudragit S100 was chosen to aid targeting since the polymer dissolves at colonic pH to result in selective colonic release of the entrapped drug. Solvent emulsion-evaporation technique was employed to formulate the nanoparticles. Various process parameters were optimized and the optimized formulation was evaluated for particle size distribution and encapsulation efficiency before subjecting to freeze-drying. The freeze dried product was characterized for particle size, drug content, DSC studies, particle morphology. Anti-cancer potential of the formulation was demonstrated by MTT assay in HT-29 cell line. Nanometric, homogeneous, spherical particles were obtained with encapsulation efficiency of 72%. Freeze-dried nanoparticles exhibited a negative surface charge, drug content of > 99% and presence of drug in amorphous form which may result in possible enhanced absorption. MTT assay demonstrated almost double inhibition of the cancerous cells by nanoparticles, as compared to curcumin alone, at the concentrations tested. Enhanced action may be attributed to size influenced improved cellular uptake, and may result in reduction of overall dose requirement. Results indicate the potential for in vivo studies to establish the clinical application of the formulation. PMID- 20201418 TI - Interfacially assembled carbohydrate nanocapsules: a hydrophilic macromolecule delivery platform. AB - A prospective approach was used to synthesize carbohydrate nanocapsules with a macromolecule payload and suitable interfacial properties for in vivo systemic circulation. Spatially directed carbohydrate assembly and polymerization resulted in structured hydrophilic vesicles with diameters of 200-300 nm. Mononucleated dispersions with monodisperse distributions were demonstrated in aqueous vehicles. The effects of pH, buffer capacity and reaction time on the molar degree of substitution of terephthaloyl chloride, trimesoyl chloride, and diethylmalonyl chloride were evaluated. The delivery of a test protein, lysozyme showed continuous release for 7 days. Immobilization of lysozyme caused by co polymerization was 20% based on asymptotic recovery of released lysozyme. A theoretical shell thickness of 9.5 nm was estimated from a relative core volume of 80% and the average vesicle size. PMID- 20201419 TI - Poly(D,L-lactic-co-glycolic acid) nanoencapsulation reduces Erlotinib-induced subacute toxicity in rat. AB - Erlotinib-HCl is a quinazoline derivative used as a drug in the therapy of non small-cell lung cancer. The present study was conducted to compare the subacute toxicity induced by Erlotinib-HCl delivered to rats as nanoparticles and as free drug. Wistar rats were orally administered with a daily dosage of 200 mg kg(-1) Erlotinib-HCl either as free drug or as Poly(D,L-lactic-co-glycolic acid) (PLGA) encapsulated nanoparticles. After four weeks of treatment, the animals were analyzed for toxicological changes. Although nanoparticulate form of the drug did not induce any toxicity, free drug significantly reduced the levels of white blood cells (WBC), red blood cells (RBC) and haemoglobin, while increasing the levels of neutrophils and corpuscular haemoglobin. Moreover, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were significantly increased in the animals administered with free drug. Histopathological studies confirmed significant damage to the internal organs of animals treated with free drug. Whereas, the internal organs of animals treated with the drug encapsulated in PLGA nanoparticles were more or less similar to the healthy organs. Our results show that Erlotinib-HCl delivered in the form of nanoparticles has less toxic effect than the free drug in experimental rats. PMID- 20201420 TI - Identification of nanofibers in the Chinese herbal medicine: Yunnan Baiyao. AB - Yunnan Baiyao is a traditional Chinese herbal medicine that has been used to treat wounds for over 100 years. Here, we use Atomic Force Microscopy (AFM) to determine nano-scale structures of the Yunnan Baiyao. AFM images revealed uniform nanofibers present in relatively high abundance in a solution of this medicine. Fibers were typically 25.1 nm in diameter and ranged in length from 86-726 nm due to processing. Due to the unique adhesive and structural properties of nanofibers, we concluded that these fibers may play a role in platelet aggregation, leading to clotting, and the sealing of wounds. PMID- 20201421 TI - The accuracy of Amplex Red assay for hydrogen peroxide in the presence of nanoparticles. AB - We have shown the ability of different types of oxide nanoparticles, CeO2, Fe2O3, TiO2 and SnO2 to skew the accuracy of detection of H2O2 using the widely applied Amplex Red assay. These oxide materials are commonly employed in electronics manufacture, industrial catalysis, and in the manufacture of consumer products, and their toxicological profiles are not well understood. All four oxide nanoparticles demonstrated intrinsic capability of converting Amplex Red molecules to fluorescent resorufin, even in the absence of H2O2, in aqueous solution as well as cell culture media. Kinetic parameters were calculated and a simulated time dependent concentration profile was generated to better understand this complicated system. The results show that care is needed for interpreting the result of seemly robust bioassays in the presence of nanoparticles. PMID- 20201422 TI - Preparation and agglutination of immuno-nanolatex for malaria diagnosis. AB - This is the first systematic study on the adsorption of malaria antigen onto latex particles to elaborate immuno-latex for diagnostic purpose. Immuno-latex was prepared from adsorption of malaria antigen onto polystyrene (PS) or poly(styrene-co-acrylic acid) (St/AA) latex particles and was used for detection of antibody to P. Falciparum based on agglutination test. Adsorption behavior of the malaria antigen onto polymer particles as a function of incubation time, antigen concentration, pH and concentration of the medium was studied. The prepared immuno-latexes were characterized in terms of immuno-agglutination and specific bridging using patient's plasma with P. Falciparum infection. This evaluation was performed using photon correlation spectroscopy. PMID- 20201423 TI - Pyrene excimer nucleic acid probes for biomolecule signaling. AB - Pyrene excimer nucleic acid probes are novel molecular probes that integrate the unique optical properties of pyrene excimer with excellent recognition capability of nucleic acids. Pyrene has the property of forming excimer that has a large Stokes shift and long fluorescence lifetime. Nucleic acid probes, like aptamers and molecular beacons, can directly bind to target molecules with a high selectivity and affinity. Possessing these outstanding characteristics of pyrene excimer and nucleic acid probes, pyrene excimer nucleic acid probes can be effectively used in detection of biomolecules, study of protein-DNA interactions, and investigation of enzymatic processes in complex biological systems. In this review, we will discuss the optical properties of pyrene excimer and summarize recent progresses on pyrene excimer signaling nucleic acid probes for the signaling of biomolecules and their interactions in complex biological samples. PMID- 20201424 TI - Preparation of SiO2/polymethyl methacrylate/Fe3O4 nanoparticles and its application in detecting E. coli O157:H7 using chemiluminescent immunological method. AB - This paper described that Fe3O4 nanoparticles were encapsulated with methyl methacrylate (MMA) using linolenic acid (LA) as a crosslinking agent, after which the resulting polymethyl methacrylate (PMMA) embed Fe3O4 nanoparticles (PMMA/Fe3O4) were coated with silica, forming SiO2/ (PMMA/Fe3O4) core-shell structure particles. Then these magnetic nanoparticles (MNPs) were applied in the developed system of chemiluminescent magnetic enzyme-linked immunoassay. E. coli O157:H7 was sandwiched between rabbits anti-E. coli O157:H7 polyclonal antibody coated magnetite nanoparticles (immunomagnetic nanoparticles or IMNPs) and mouse anti-E. coli O157:H7 monoclonal antibody (E. coli O157-McAb). Commercial alkaline phosphatase conjugated horse anti-mouse immunoglobulin (ALP-Ab) was used to bond with the monoclonal antibody, finally the chemiluminescent signals were detected by adding 3-(2'-spiroadamantane)-4-methoxy-4-(3"-phosphoryloxy)phenyl-1,2 dioxetane (AMPPD) which was the substrate reagent of ALP. The specificity and sensitivity of this system for detecting E. coli O157:H7 were researched. The results indicated that this method was of good specificity when using E. coli Top 10F' and Vibrio cholera as negative controls. The detection limit was 10(3) cells mL(-1) when the antigen solution was 1 mL, and the procedure duration was about 3 h. PMID- 20201425 TI - An automated MagStation for high-throughput single nucleotide polymorphism genotyping and the dual-color hybridization. AB - We designed a novel automated MagStation for high-throughput single nucleotide polymorphism (SNP) discrimination using dual-color hybridization. Magnetic particles (MPs) were used as target DNA carriers. The principle for SNP discrimination in this study was allele specific hybridization using dual-color fluorescent (Cy3, Cy5) probes. The MagStation is equipped with a 96-well automated magnetic separation unit which collects MPs on the side of the tubes as it moves to separation positions. The MagStation equips a heating block, where hybridization at different optimized temperature can be performed. This MagStation permits heating and magnetic separation of 96 samples per assay. The methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism of 96 different samples was semi-automated integrated using this automated MagStation. PMID- 20201426 TI - Assembly and simple demonstration of a micropump installing PDMS-based thin membranes as flexible micro check valves. AB - Integration of chemical or biochemical systems creates extremely efficient devices exploiting the advantages of microspaces. Recently, various microfluidic devices have been developed to make micro chemical processes more sophisticated. On the other hand, we demonstrated the concept of a cardiomyocyte pump using only chemical energy input to cells as a driver (Tanaka et al. Lab Chip 6(3), pp. 362 368). However, its flow rate was too poor to be applied for practical applications of micro chemical systems mainly because of the inefficiency of the check valves made of polyimide. As cardiomyocytes' force is weak, more flexible materials must be used. In this report, a more flexible material, poly(dimethylsiloxane) (PDMS) check valves were designed and fabricated, and then, the check valve function was demonstrated by pumping fluid in an assembled micropump incorporating the PDMS check valves. Water was dropped on an inlet of the microchannel, and a diaphragm of the micropump was oscillated using a pair of tweezers to prove the function of the valves. From the result, pumping volume per stroke was calculated as 1.7 micro/stroke. The developed valves are not only usable for our cardiomyocyte pumps but also applicable to general micro and nano fluidic devices for biomedical fields such as immune assay systems owning to easy and inexpensive fabrication method of the valves. PMID- 20201427 TI - TiO2 nanopowder co-doped with iodine and boron to enhance visible-light photocatalytic activity. AB - An iodine and boron co-doped TiO2 photocatalyst was prepared by the hydrolyzation precipitation method. X-ray diffraction (XRD), ultraviolet-visible diffuse reflectance spectroscopy (UV-Vis DRS), and X-ray photoelectron spectroscopy (XPS) were applied to characterize the crystalline structure, light absorbing ability, and the chemical state of iodine and boron in the photocatalysts. The results of photocatalytic degradation of methyl orange demonstrated that the I-B-TiO2 catalyst prepared at 400 degrees C for 3 h exhibited the highest photocatalytic activity with a methyl orange degradation ratio of 61% under visible-light (lambda > or = 420 nm) irradiation for 120 min. The characterization results revealed that I-B-TiO2 is in conformity with the anatase TiO2 and that the doping of iodine and boron ions could efficiently inhibit the grain growth. Doped iodine was present in the multivalent forms of 17+, I- and I5+. Doped boron was present as B3+ in an as-prepared sample, forming a possible chemical environment such as B-O-Ti. Overall, the doping of I and B enhanced the ability of TiO2 to absorb visible-light, and it was observed that the photocatalytic activity of I-B-TiO2 was enhanced by the synergistic effect of I and B. PMID- 20201428 TI - Cell membrane injury induced by silica nanoparticles in mouse macrophage. AB - Studies on the cytotoxic mechanism of SiO2 nanoparticles is of vital importance for estimating the potential risk of overexposure and cytotoxicity amelioration and safety precautions of SiO2 nanoparticles. The cell membrane injury induced by 20-nm silica nanoparticles was investigated by measuring reactive oxygen species (ROS), membrane fluidity and free Ca2+ content ([Ca2+]i) in cells with laser scanning confocal microscope (LSCM). The 20-nm SiO2 nanoparticles at different concentrations of 31.25, 125, and 500 microg/ml were respectively incubated with RAW264.7 cells for 24 h to determine oxidative stress responses, membrane fluidity, intracellular [Ca2+]i concentration. Exposure to SiO2 nanoparticles at 125 and 500 microg/ml increased ROS levels and intracellular [Ca2+]i, reduced membrane fluidity levels. The decrease of the membrane fluidity indicated membrane damage. Increases of ROS generation and intracellular [Ca2+]i played a role in cytotoxicity. Results showed that mechanisms of cytotoxicity induced by SiO2 nanoparticles was closely correlated to increase oxidative stress, decrease membrane fluidity and perturbation of intracellular calcium homeostasis. PMID- 20201429 TI - Towards aqueous gold nanoparticles with buffer resistance and high concentration. AB - High-concentration gold nanoparticles stabilized by poly(vinylpyrrolindone) (PVP) are prepared through modified citrate-reduction method. The modified approach possesses all the advantages of the popular citrate reduction method. With PVP as weak ligands as well as spatial effects for the metal nanoparticles, the control of the size and size distribution of the gold nanoparticles in the size range between 10 and 30 nm was achieved via maintaining balanced nucleation and growth by tuning the feed ratios of the metal precursors and reducing reagents. As a modified procedure to gold nanoparticles, PVP-stabilized gold nanoparticles are more stable in a broad range of pH and different buffers than conventional gold colloids. Because only PVP are employed in the new synthetic schemes, surface modification and functionalization of the resulting gold nanoparticles through small molecular ligands can be readily carried out. PMID- 20201430 TI - Polyacrylamide gel-based microarray: a novel method applied to the association Study between the polymorphisms of BDNF gene and autism. AB - Single nucleotide polymorphisms (SNPs) are important markers which can be used in the association study for searching for associated genes of complex diseases. High-throughput methods in a large number of samples are needed for SNP genotyping. In this study, we applied polyacrylamide gel-based microarray combined with universal dual-color hybridization for trios-based associative study of BDNF polymorphisms with autism in Chinese. All four SNPs in both patients and their parents could be analyzed quickly and correctly. In single SNP TDT analysis, C270T showed preferential transmission of the T allele compared to the C allele (TDT p < 0.001) in autism. In haplotype TDT analysis, C270T polymorphism also existed in the haplotype combination which showed significant association (TDT p < 0.05). These results suggest a potential association between BDNF and autism in the Chinese population. The study also show that the polyacrylamide gel-based microarray combined with universal dual-color detectors is a rapid, simple, high-throughput method for SNPs genotyping, and can be very effective and cost effective in association study of susceptible gene with disorders in large samples. PMID- 20201431 TI - Improvement on synthesis of different alkyl-phenylboronic acid. AB - Various alkyl-phenylboronic acids have been widely used in the fields of electronics, chemistry, medicine and biology, especially in glucose sensors and intermediates of medicines. In this paper, the syntheses of two or three different alkyl-phenylboronic acids and the improvement on synthesis processes were studied with Grignard reagent method in detail. The influencing factors such as temperature, reaction time, reactant molar ratio were analyzed with the orthogonal experiment; optimized processes for the preparation of different alkyl phenylboronic acids were thus obtained using different alkylborates as original materials. Based on the analysis of the experiment results, a "one-pot" method was proposed and checked to synthesize several different alkyl-phenylboronic acids. It was shown that 2,6-dimethylphenylboronic acid could be synthesized with "one-pot" method while para-alkyl-phenylboronic acid could not. An optimized process for the synthesis of 2,6-dimethylphenylboronic acid was obtained by investigating the influence of the boronation reagent, reactant proportion and solvent on the yield. Meanwhile, the preliminary synthesis of 2-ethylphenylboric acid was investigated with "one-pot" method too. Each product was identified by mass spectrum, 1HNMR, IR and HPLC. PMID- 20201432 TI - A novel methotrexate delivery system based on chitosan-methotrexate covalently conjugated nanoparticles. AB - In this paper, a chitosan-methotrexate covalently conjugated nanoparticles (CS MTX-TPP NPs) has been developed as a potential delivery system for methotrexate (MTX). MTX was first conjugated to CS by using glutaraldehyde as cross-linked agent, and followed by the process of ionic gelation between MTX-conjugated CS and sodium tripolyphosphate (TPP) to form CS-MTX-TPP NPs at mild reaction conditions. The hydrodynamic diameter of CS-MTX-TPP NPs and the encapsulation efficiency of MTX were affected by the weight ratio of MTX/CS. At the ratio of 1/11, the mean hydrodynamic diameter of CS-MTX-TPP NPs was the lowest (187.9 +/- 9.0 nm) and the nanoparticles presented the encapsulation efficiency of MTX with 53.0 +/- 3.2%. The characterizations by atomic force microscopy (AFM) and photon correlation spectroscopy (PCS) showed the CS-MTX-TPP NPs had a spherical shape and good dispersion with diameter of sub-200-nm and zeta potential of 30 mV. Additionally, in vitro release test revealed that the stable covalent bonding of CS and MTX was beneficial for providing slow release for MTX. Especially, cellular toxicity study in MCF-7 cancer cells further demonstrated the effective anticancer efficacy of this new type of delivery for MTX. PMID- 20201433 TI - Single molecule fluorescence imaging of DNA at agarose surfaces by total internal reflection fluorescence microscopy. AB - We performed single molecule fluorescence detection of YOYO-1 labeled lambda-DNA molecules adsorbed on a solid substrate after treatment with different concentrations of agarose by total internal reflection fluorescence microscopy (TIRFM). At agarose-modified surfaces, we found that molecular adsorption behaviors were dependent on agarose concentration, pH and ionic strength. We further revealed the subtle differences among adsorptive forces. Both electrostatic interaction and hydrophobic interaction were the major driving force for adsorption of DNA molecules on agarose surfaces. We also found that surface topography plays a role to a certain extent in the adsorption dynamics. The characteristics of agarose surfaces were further assessed using contact angle (CA) measurements. PMID- 20201434 TI - Real-time monitoring and scale-up synthesis of concentrated gold nanorods. AB - The control and monitoring of gold nanorod growth are critical for maintaining the quality of gold nanorods. Through in situ spectroscopic determination of gold nanorod growth in cuvettes, we found that this growth correlates with the evolution of extinction spectra and solution colors. This spectroscopy provides a universal method for in situ observation of the chemical evolution of nano materials using cuvettes as small reactors at ambient temperature. Synthesis of gold nanorods with high concentrations and high yields is scaled up by simply increasing the solute concentration of the growth solution. Under optimal synthetic conditions, a yield of up to 0.1 g of gold nanorods is obtained, and spectrum monitoring indicates the formation of few spherical gold nanoparticles. PMID- 20201436 TI - Nanoreactor of Fe3O4@SiO2 core-shell structure with nanochannels for efficient catalysis. AB - We introduced a new nanoreactor system consisting of nanochannel-filled Fe3O4 core and SiO2 shell. Different morphologies of Fe3O4@SiO2 core-shell nanostructures could be obtained through simple HCl etching of the magnetic cores. The outer silica shells were permeable and the Fe3O4 cores were accessible to the reactants. Therefore, the present nanoreactor system was applied to catalyze the reduction of H2O2, and it showed outstanding catalytic activity compared with bare Fe3O4 or Fe3O4@SiO2 core-shell nanoparticles. PMID- 20201435 TI - Time-resolved luminescence-based assay for thyroglobulin. AB - We have demonstrated a time-resolved luminescence (TRL) assay for the sensitive and selective detection of thyroglobulin (Tg), a thyroid cancer marker, in homogeneous solution using water-soluble alpha-D-mannose-conjugated Au nanodots (Man-Au NDs). The Man-Au NDs (1.7 nm in diameter) were prepared from the reaction between Au nanoparticles (2.9 nm in diameter) with 11-mercapto-3,6,9 trioxaundecyl-alpha-D-mannopyranoside (Man-RSH; 0-10 mM). We have found that the luminescence intensity and lifetimes of Man-Au NDs separately become stronger and longer, respectively, upon increasing the concentration of Man-RSH. The Man-Au NDs possess several interesting optical properties, including long luminescence lifetime (> 500 ns) and large Stokes' shift (> 150 nm). The TRL assay is based on the competition between Tg and Man-Au NDs for interacting with concanavalin A (Con A). The fluorescence intensities integrated over the region of 50-400 ns increase upon increasing the concentration of Tg over the range 0.1-2.5 nM. The Con A/Man-Au NDs system in a label-free manner allows the detection of Tg at concentrations as low as 90 pM in the presence of BSA at 50 microM by TRL. With its advantages of rapid and specificity, this present approach holds great potential for diagnosis of cancers. PMID- 20201437 TI - Chitosan/sodium tripolyphosphate nanoparticles: preparation, characterization and application as drug carrier. AB - With the existence of amino groups, chitosan (CS) possesses positive charge, so it can self-assemble with tripolyphotspate (TPP) possessing negative charge via ionic gelation. We here synthesized CS/TPP nanoparticles, and then characterized it with the infrared spectra (IR) and scanning electron microscope (SEM) and transmission electron microscopy (TEM) and used bovine serum albumin (BSA) as a model drug to investigate sustained-release properties of CS/TPP nanoparticles. Infrared spectrum of CS/TPP nanoparticles indicated that CS was cross-linked with TPP. A homogeneous size distribution and good dispersion and micro-porous surface of CS/TPP nanoparticles were observed. The highest encapsulation efficiency (EE) of the BSA in CS/TPP nanoparticles prepared in different concentration of CS reached 79.74%, while BSA continually and smoothly released up to one week. PMID- 20201438 TI - Preparation of SiO2/(PMMA/Fe3O4) from monolayer linolenic acid modified Fe3O4 nanoparticles via miniemulsion polymerization. AB - SiO2/(PMMA/Fe3O4) composite particles were prepared from linolenic acid (LA) instead of oleic acid (OA) modified Fe3O4 nanoparticles by miniemulsion polymerization. LA has three unsaturated double bonds with which it can polymerizate more easily than OA. And coating Fe3O4 with polymethyl methacrylate (PMMA) polymer beforehand can prevent magnetic nanoparticles from the aggregation that usually comes from the increasing of ionic strength during the hydrolyzation of tetraethoxysilane (TEOS) by the steric hindrance. Finally, the resulting PMMA/Fe3O4 nanoparticles were coated with silica, forming SiO2/(PMMA/Fe3O4) core shell structure particles. The sizes of nanoparticles with core-shell structure were in the range from 300 to 600 nm. The nanoparticles were spherical particles and had consistent size. The result of magnetic measurement showed that the composite particles had superparamagnetic property. PMID- 20201439 TI - Determination of GPTMS and epoxy groups on GPTMS doped nanosilica composite by spectrofluorimetric analysis. AB - A spectrofluorimetric method was established for the quantitative determination of 3-glycidoxypropyltrimethoxysilane (GPTMS), based on the quantitative reaction between dihydroxyl of hydrated epoxy groups and potassium periodate generating formaldehyde and the reaction of the formaldehyde with acetylacetone in the presence of ammonium ions generating a new compound having yellow green fluorescence. The established method was then used to determine the purity of a commercially obtained GPTMS sample and the amount of epoxy groups on GPTMS doped nanosilica composite (GPTMS/nano-SiO2). The conditions such as the concentrations of ammonium salts and acetylacetone, pH value, coloring temperature, and coloring time were investigated in detail with respect to their effects on the fluorescence intensity. It was found that the established method is simple in terms of operation and can be used to practically determine the purity of GPTMS and the amount of epoxy groups on GPTMS/nano-SiO2 with good accuracy and reproducibility. PMID- 20201440 TI - Determination of paracetamol with porous electrochemical sensor. AB - A novel and sensitive electrochemical sensor based on porous pseudo-carbon paste electrode (PPCPE) for paracetamol detection is described. It was demonstrated that PPCPE exhibits a high selectivity and sensitivity toward paracetamol in comparison with polypyrrole modified carbon paste electrode (PCPE), carbon nanotube modified carbon paste electrode (CNTPE) and carbon paste electrode (CPE), and a detection limit as low as 0.005 mM was obtained. PMID- 20201441 TI - [The taboo must fall]. PMID- 20201442 TI - [Nursing care is the pivotal and anchor point in pain management]. PMID- 20201443 TI - [Pain measurement in infants and young children. Children connect pain with what bothers them]. PMID- 20201444 TI - [Clinical assessment in bachelor education. Professional competence for assessment of nursing situations]. PMID- 20201445 TI - [Nursing education as example for reform]. PMID- 20201446 TI - [Nursing and midwifery practice at the Basal University Hospital. Portfolio for general practice development achieved]. PMID- 20201447 TI - [Hybrid simulation in nursing education. Between "hightec" and "hightouch"]. PMID- 20201448 TI - [In health competence lies great potential (interview by Margrit Bachl)]. PMID- 20201449 TI - [First protest against SRK control]. PMID- 20201450 TI - [Malnutrition also on surgical units? Nutrition status should be assessed]. PMID- 20201451 TI - [The art of speaking, the art of understanding]. PMID- 20201452 TI - [Imparting bad news, ou: the art of speaking]. PMID- 20201453 TI - [Ten years of volunteering at CHUV. When health care teams appreciate their volunteers]. PMID- 20201454 TI - [The psycho-physical approaches in crisis psychiatry. Touching the body to heal the soul]. PMID- 20201455 TI - [Stress in emergencies. From the hospital... to Tribunal]. PMID- 20201456 TI - [Pain: unnecessary suffering]. PMID- 20201457 TI - [Cooperation, from experimentation to realization]. PMID- 20201458 TI - [Improvement of medical and nursing practices, in new hypotheses of employment]. PMID- 20201459 TI - [Re-evaluation of the status of nurses, current advances and negotiations]. PMID- 20201460 TI - [Creativity and innovations for pain treatment]. PMID- 20201461 TI - [Consultation of announcement and therapeutic education in urology]. PMID- 20201462 TI - [Practice of excision in France, an un-edited national investigation]. PMID- 20201463 TI - [The nurse, an actor of first resort]. PMID- 20201464 TI - [From health to public health]. PMID- 20201465 TI - [Place for implantable catheters, results of an audit of knowledge of private homecare nurses]. PMID- 20201466 TI - [Antibiotics and wounds. Scientific evidence and everyday practice]. PMID- 20201467 TI - [Antibiotic agents in the treatment of wounds, a review of the literature]. PMID- 20201468 TI - [Local antibiotics available for the care of wounds]. PMID- 20201469 TI - [Topical antibiotics for the treatment of burns]. PMID- 20201470 TI - [Antibiotics in cancerous wounds and in the patient treated with antineoplastic agents]. PMID- 20201471 TI - [Antibiotics in the treatment of wounds in the diabetic foot]. PMID- 20201472 TI - [Antibiotics in the treatment of foot ulcers and scabs]. PMID- 20201473 TI - [Use of antibiotics in surgical and traumatic wounds]. PMID- 20201474 TI - [From the clinic to research]. PMID- 20201475 TI - [Bibliographic elements. Antibiotics and wounds]. PMID- 20201476 TI - [1/10 The concept of clinical reasoning]. PMID- 20201477 TI - [3/5 Mistreatment, what assessment has there been since the plans of good treatment/mistreatment?]. PMID- 20201478 TI - Unanswered questions, unmet needs in venous thromboprophylaxis. AB - Although significant progress has been made over the past 25 years in preventing thromboembolic disease in patients undergoing total hip and total knee arthroplasty, important questions remain unanswered. Few would debate the need to seek a balance between maximal antithrombotic efficacy and minimal bleeding in choosing a thromboprophylactic strategy, but there is less agreement as to how efficacy should be defined, and whether efficacy and safety (however each is defined) are intrinsic to the thromboprophylactic agent chosen or depend as well on exogenous factors, ranging from the timing of drug administration to surgical technique. Differences between recent guidelines from the American Academy of Orthopaedic Surgeons (AAOS) and the American College of Chest Physicians (ACCP) illustrate these unanswered questions. The AAOS guidelines focus solely on preventing symptomatic pulmonary embolism and ignores the importance of other acute and chronic manifestations of venous thromboembolic disease. The ACCP, on the other hand, does consider these other manifestations of venous thromboembolic disease, and thus reaches very different conclusions about what constitutes effective thromboprophylaxis. Despite these questions and uncertainties, there are fundamental truths: (1) venous thromboembolism (VTE) is a known and serious complication of total joint arthroplasty, and (2) evidence-based thromboprophylaxis works. Gaps between guideline-recommended and actual orthopedic practice must be reduced. PMID- 20201479 TI - The ACCP guidelines for thromboprophylaxis in total hip and knee arthroplasty. AB - The 1986 National Institutes of Health consensus conference Prevention of Venous Thrombosis and Pulmonary Embolism emphasized the high rates of venous thromboembolic disease (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), associated with orthopedic surgery of the lower extremity when performed without thromboprophylaxis. Total joint arthroplasty patients treated with placebo or as controls have, based on studies conducted between 1908 and 2002, a total DVT prevalence of 41% to 85% and a proximal DVT prevalence of 5% to 36% when examined by venography at 7 to 14 days. Prevalence of PE is less certain, but clinical studies have reported a range of 0.9% to 28% for all PE and 0.1% to 2% for fatal PE in control or placebo patients. As the number of total joint arthroplasties in the United States has grown - nearing 1,000,000 annually and expected to increase significantly over the next 20 years as the population ages - so too has interest in appropriate thromboprophylaxis. Methods of preventing VTE are either pharmacologic or mechanical. Guidelines from the American College of Chest Physicians make evidence-based recommendations for both pharmacologic and nonpharmacologic prophylaxis in the settings of total hip and total knee arthroplasty. These recommendations and their underlying rationale are discussed herein. PMID- 20201480 TI - Comparison of ACCP and AAOS guidelines for VTE prophylaxis after total hip and total knee arthroplasty. AB - Orthopedists have expressed concerns regarding the utility for and applicability to their practices of guidelines from the American College of Chest Physicians (ACCP) for thromboprophylaxis in the settings of total hip and total knee arthroplasty (THA and TKA, respectively). These concerns include the acceptance by the ACCP of venographically assessed asymptomatic deep venous thrombosis as a meaningful clinical trial endpoint and a potential underestimation by the ACCP of the true risk of major bleeding and wound complication in unselected patient populations outside carefully controlled clinical trials. Because symptomatic pulmonary embolism is rare after THA and TKA, the American Academy of Orthopaedic Surgeons has developed a clinical practice guideline focused on preventing this complication while minimizing the risk of bleeding due to pharmacologic prophylaxis. These guidelines are reviewed here. PMID- 20201481 TI - New oral anticoagulants for thromboprophylaxis after total hip or knee arthroplasty. AB - Patients undergoing total hip or knee arthroplasty are at increased risk of venous thromboembolism (VTE). The long-term sequelae of VTE, such as post thrombotic syndrome or pulmonary hypertension, can be debilitating with severe morbidity. Conventional anticoagulants have several short-comings: for example, warfarin requires regular coagulation monitoring and low-molecular-weight heparins are inconvenient to use because they require subcutaneous administration. The development of new anticoagulants has focused on 2 classes of compounds: direct thrombin inhibitors and direct factor Xa inhibitors. These new oral agents have shown efficacy in large randomized clinical trials and offer new, more convenient options for anticoagulation. PMID- 20201483 TI - Thermal sensitive microgels with stable and reversible photoluminescence based on covalently bonded quantum dots. AB - In this study, thermal sensitive microgels functionalized with carboxyl groups were synthesized directly from hydroxypropyl cellulose (HPC) and acrylic acid (AA) without using any organic solvent. Furthermore, covalently bonded hybrid microgels with novel thermosensitivity in terms of size and fluorescence were fabricated from these HPC-PAA microgels and cysteamine-capped CdTe quantum dots (QDs). The composition of the hybrid microgels were characterized by thermal thermogravimetric analysis (TGA) and coulometric titration. It was verified that the weight percent of CdTe QDs was ca. 40%, and the percent of poly(acrylic acid) varied between 9.0% and 13.6%. Through a systematic study, it was found that both the size and the fluorescent intensity of the microgels decreased as the temperature increased from below the lower critical solution temperature (LCST) to above the LCST of the HPC. Different from most reported cases, it was found that the thermal sensitive alteration of the current hybrid microgels' size and fluorescent intensity are reversible. The novel fluorescent properties are deduced to be related to the structural characteristics of the microgels, i.e., the QDs are covalently bonded to the microgels and the dispersion of QDs in the microgels is spatially homogeneous. As a consequence of this special structure, the refractive indexes of the microgels were changed and the surface defects of the QDs were reduced, and therefore affected the fluorescent properties of the resulting hybrid microgels. PMID- 20201484 TI - Electroless growth of silver nanoparticles into mesostructured silica block copolymer films. AB - Silver nanoparticles and silver nanowires have been grown inside mesostructured silica films obtained from block copolymers using two successive reduction steps: the first one involves a sodium borohydride reduction or a photoreduction of silver nitrate contained in the film, and the second one consists of a silver deposit on the primary nanoparticles, carried out by silver ion solution reduction with hydroxylamine chloride. We have demonstrated that the F127 block copolymer ((PEO)(106)(PPO)(70)(PEO)(106)), "F type", mesostructured silica film is a suitable "soft" template for the fabrication of spherical silver nanoparticles arrays. Silver spheres grow from 7 to 11 nm upon the second reduction step. As a consequence, a red shift of the surface plasmon resonance associated with metallic silver has been observed and attributed to plasmonic coupling between particles. Using a P123 block copolymer ((PEO)(20)(PPO)(70)(PEO)(20)), "P type", mesostructured silica film, we have obtained silver nanowires with typical dimension of 10 nm x 100 nm. The corresponding surface plasmon resonance is blue-shifted. The hydroxylamine chloride treatment appears to be efficient only when a previous chemical reduction is performed, assuming that the first sodium borohydride reduction induces a high concentration of silver nuclei in the first layer of the porous silica (film/air interface), which explains their reactivity for further growth. PMID- 20201482 TI - Nitric oxide, oxygen, and superoxide formation and consumption in macrophages and colonic epithelial cells. AB - Knowledge of the rates at which macrophages and epithelial cells synthesize NO is critical for predicting the concentrations of NO and other reactive nitrogen species in colonic crypts during inflammation, and elucidating the linkage between inflammatory bowel disease, NO, and cancer. Macrophage-like RAW264.7 cells, primary bone marrow-derived macrophages (BMDM), and HCT116 colonic epithelial cells were subjected to simulated inflammatory conditions, and rates of formation and consumption were determined for NO, O(2), and O(2)(-). Production rates of NO were determined in either of two ways: continuous monitoring of NO concentrations in a closed chamber with corrections for autoxidation, or NO(2)(-) accumulation measurements in an open system with corrections for diffusional losses of NO. The results obtained using the two methods were in excellent agreement. Rates of NO synthesis (2.3 +/- 0.6 pmol s( 1) 10(6) cells(-1)), NO consumption (1.3 +/- 0.3 s(-1)), and O(2) consumption (59 +/- 17 pmol s(-1) 10(6) cells(-1) when NO is negligible) for activated BMDM were indistinguishable from those of activated RAW264.7 cells. NO production rates calculated from NO(2)(-) accumulation data for HCT116 cells infected with Helicobacter cinaedi (3.9 +/- 0.1 pmol s(-1) 10(6) cells(-1)) were somewhat greater than those of RAW264.7 macrophages infected under similar conditions (2.6 +/- 0.1 pmol s(-1) 10(6) cells(-1)). Thus, RAW264.7 cells have NO kinetics nearly identical to those of primary macrophages, and stimulated epithelial cells are capable of synthesizing NO at rates comparable to those of macrophages. Using these cellular kinetic parameters, simulations of NO diffusion and reaction in a colonic crypt during inflammation predict maximum NO concentrations of about 0.2 microM at the base of a crypt. PMID- 20201485 TI - Synthesis of the natural products 3-hydroxymollugin and 3-methoxymollugin. AB - 3-Hydroxymollugin 2 and 3-methoxymollugin 3 are cytotoxic compounds isolated as minor compounds from Pentas longiflora and Rubia cordifolia. Syntheses of 3 hydroxymollugin 2 and 3-methoxymollugin 3 were developed starting from easily available 3-bromomollugin 6. Surprisingly, it was found that the reaction of 3 bromomollugin 6 with sodium methoxide in methanol resulted in the formation of 3 methoxymollugin 3 and the ring-contracted methyl isopropenylfuromollugin 7. A mechanism for this ring contraction is proposed on the basis of a pericyclic retro oxa-6pi ring-opening reaction. A second synthesis of 3-hydroxymollugin 2 was based on epoxidation of methyl 3-(3-methylbut-2-enyl)-1,4-naphthoquinone-2 carboxylate 17 and subsequent reduction of the quinone moiety, ring transformation, and DDQ oxidation. The latter oxidation process results in 3 hydroxymollugin 2 along with the rearranged furomollugin 4, which is a ring contracted analogue of the natural product mollugin 1. PMID- 20201487 TI - Recognition of anions and neutral guests by dicationic pyridine-2,6-dicarboxamide receptors. AB - Dicationic N-methylated at pyridyl or quinolyl moieties derivatives of three isomers of N,N'-bis(pyridyl)pyridine-2,6-dicarboxamide (o-, m-, and p-1) and of N,N'-bis(3-quinolyl)pyridine-2,6-dicarboxamide (4) strongly bind anions in MeCN (log K in the range 3.5-6.5) with pronounced selectivity for Cl(-) and also bind neutral urea and amide guests with log K in the range 1.1-2.8. Crystal structures of the triflate salts of m-1, p-1, and 4 show that amide NH and pyridinium o-CH groups are directed inside the receptor cleft with their four protons forming a circle of radius ca. 2.35 A optimal for inclusion of Cl(-). The binding of anions to these protons is evident from the crystal structure of a mixed triflate/chloride salt of p-1, calculated (DFT/B3LYP 6-31G**) structures of 1:1 complexes of all receptors with Cl(-), and results of (1)H NMR titrations. In the crystal structure of o-1 pyridinium N-Me(+) groups are directed inside the receptor cleft impeding the anion complexation, but calculations demonstrate that simple rotation of pyridinium rings in opposite directions by ca. 30 degrees creates a cavity to which the Cl(-) ion can fit forming 4 hydrogen bonds to amide NH and aliphatic CH groups of N-Me(+). The results of (1)H NMR titrations confirm this type of binding in solution. Anions quench the intense fluorescence of 4, which allows their fluorescent sensing in the muM range. A new methodology for determination of anion binding constants to strongly acidic receptors by inhibitory effects of anions on the receptor deprotonation by an external base has been developed. High affinity and selectivity of anion complexation by dicationic pyridine-2,6-dicarboxamides is attributed to the rigid preorganized structure of receptors, the high acidity of NH and CH groups, and the electrostatic charge effect. PMID- 20201486 TI - Folding-based electrochemical biosensors: the case for responsive nucleic acid architectures. AB - Biomolecular recognition is versatile, specific, and high affinity, qualities that have motivated decades of research aimed at adapting biomolecules into a general platform for molecular sensing. Despite significant effort, however, so called "biosensors" have almost entirely failed to achieve their potential as reagentless, real-time analytical devices; the only quantitative, reagentless biosensor to achieve commercial success so far is the home glucose monitor, employed by millions of diabetics. The fundamental stumbling block that has precluded more widespread success of biosensors is the failure of most biomolecules to produce an easily measured signal upon target binding. Antibodies, for example, do not change their shape or dynamics when they bind their recognition partners, nor do they emit light or electrons upon binding. It has thus proven difficult to transduce biomolecular binding events into a measurable output signal, particularly one that is not readily spoofed by the binding of any of the many potentially interfering species in typical biological samples. Analytical approaches based on biomolecular recognition are therefore mostly cumbersome, multistep processes relying on analyte separation and isolation (such as Western blots, ELISA, and other immunochemical methods); these techniques have proven enormously useful, but are limited almost exclusively to laboratory settings. In this Account, we describe how we have refined a potentially general solution to the problem of signal detection in biosensors, one that is based on the binding-induced "folding" of electrode-bound DNA probes. That is, we have developed a broad new class of biosensors that employ electrochemistry to monitor binding-induced changes in the rigidity of a redox tagged probe DNA that has been site-specifically attached to an interrogating electrode. These folding-based sensors, which have been generalized to a wide range of specific protein, nucleic acid, and small-molecule targets, are rapid (responding in seconds to minutes), sensitive (detecting sub-picomolar to micromolar concentrations), and reagentless. They are also greater than 99% reusable, are supported on micrometer-scale electrodes, and are readily fabricated into densely packed sensor arrays. Finally, and critically, their signaling is linked to a binding-specific change in the physics of the probe DNA, and not simply to adsorption of the target onto the sensor head. Accordingly, they are selective enough to be employed directly in blood, crude soil extracts, cell lysates, and other grossly contaminated clinical and environmental samples. Indeed, we have recently demonstrated the ability to quantitatively monitor a specific small molecule in real-time directly in microliters of flowing, unmodified blood serum. Because of their sensitivity, substantial background suppression, and operational convenience, these folding-based biosensors appear potentially well suited for electronic, on-chip applications in pathogen detection, proteomics, metabolomics, and drug discovery. PMID- 20201488 TI - In situ growth of side-chain PEG polymers from functionalized human growth hormone-a new technique for preparation of enhanced protein-polymer conjugates. AB - The application of atom transfer radical polymerization (ATRP) for preparation of a novel class of protein-polymer bioconjugates is described, exemplified by the synthesis of a recombinant human growth hormone (rh-GH) poly(ethylene glycol) methyl ether methacrylate (PEGMA) hybrid. The rh-GH protein was activated via a bromo-ester functionalized linker and used as a macroinitiator to polymerize the hydrophilic monomer PEGMA under solely aqueous conditions at 4 degrees C. ATRP conditions resulted in controlled polymer growth from rh-GH with low polydispersity polyPEGMA chains. The rh-GH PEGMA product exhibited properties consistent with the presence of attached hydrophilic polymer chains, namely, high stability to denaturation and proteolysis. The polymerization conditions and conjugation proceeded with retention of the biological activity of the hormone. The rh-GH PEGMA was administered subcutaneously to rats and the activity compared to native rh-GH. The rh-GH PEGMA exhibited similar activity as the native rh-GH in vivo when a daily dose of 40 microg was administered. However, when a higher dose of 120 microg was administered with 3 days between injections the bioavailability of the rh-GH PEGMA was significantly better than that of the native. The results therefore demonstrate that ATRP can be successfully used as a general alternative approach to direct polymer conjugation, namely, PEGylation, to produce PEG-like protein conjugates. This technique can be exploited to design and synthesize protein-polymer derivatives with tailored therapeutic properties. PMID- 20201489 TI - Molecular architecture of electroactive and biodegradable copolymers composed of polylactide and carboxyl-capped aniline trimer. AB - Two-, four-, and six-armed branched copolymers with electroactive and biodegradable properties were synthesized by coupling reactions between poly(l lactides) (PLLAs) with different architecture and carboxyl-capped aniline trimer (CCAT). The aniline oligomer CCAT was prepared from amino-capped aniline trimer and succinic anhydride. FT-IR, NMR, and SEC analyses confirmed the structure of the branched copolymers. UV-vis spectra and cyclic voltammetry of CCAT and copolymer solution showed good electroactive properties, similar to those of polyaniline. The water contact angle of the PLLAs was the highest, followed by the undoped copolymer and the doped copolymers. The values of doped four-armed copolymers were 54-63 degrees . Thermal properties of the polymers were studied by DSC and TGA. The copolymers had better thermal stability than the pure PLLAs, and the T(g) between 48-58 degrees C and T(m) between 146-177 degrees C of the copolymers were lower than those of the pure PLLA counterparts. This kind of electroactive and biodegradable copolymer has a great potential for applications in cardiovascular or neuronal tissue engineering. PMID- 20201490 TI - Aminated linear and star-shape poly(glycerol methacrylate)s: synthesis and self assembling properties. AB - Over the past 10 years, polyglycerols and their structurally related analogs have received considerable attention in the biomedical field. Poly(glycidyl methacrylate) (PGMA) is a versatile polymer because its pendant epoxide groups can be opened with different functional groups to generate poly(glycerol methacrylate)s (PGOHMA) derivatives. In this work, linear and star-shape PGMAs were synthesized by atom transfer radical polymerization and then functionalized with four different amines by ring-opening addition. This resulted in the formation of polyglycerol-like polymers having both hydroxyl and amine moieties and different water-solubility. The water-insoluble polymers could form pH sensitive nanoassemblies, while the soluble derivatives efficiently complexed a short strand polynucleotide. The aminated polyglycerol interacted more avidly with the oligonucleotide than the control poly(ethyleneimine), and high transfection efficacy could be obtained with the linear derivative. Such polymers could find practical applications for the delivery of drugs and nucleic acids. PMID- 20201491 TI - Effective tolerance to serum proteins of head-tail type polycation vectors by PEGylation at the periphery of the head block. AB - To improve the stability of a head-tail type polycation (PAMAM dendron-PLL), which is composed of a polyamidoamine (PAMAM) dendron head and poly(l-lysine) (PLL) tail blocks, as a gene vector against serum proteins, the PEGylation of the PAMAM dendron head was examined using physicochemical and transfection experiments. The PEGylation of the PAMAM dendron-PLL polyplexes neutralized the zeta-potential, indicating that the PEG brushes surround the surface of the polyplexes. The PEGylated PAMAM dendron-PLL polyplexes had higher tolerance against incubation with serum proteins when compared with non-PEGylated PAMAM dendron-PLL polyplexes. In addition, the transfection efficiency of the PEGylated PAMAM dendron-PLL polyplexes increased with increasing incubation periods, leading to an increase in the amount of pDNA uptaked by HeLa cells. Furthermore, effective stabilization of the PAMAM dendron-PLL polyplexes through PEGylation of the PAMAM dendron block was confirmed by the transfection experiments after preincubation with serum proteins and the PEGylated PAMAM dendron-PLL polyplexes showed a comparable level of transfection efficiency with polyethyleneimine polyplexes. PMID- 20201492 TI - Tunable bioadhesive copolymer hydrogels of thermoresponsive poly(N-isopropyl acrylamide) containing zwitterionic polysulfobetaine. AB - This work describes a novel tunable bioadhesive hydrogel of thermoresponsive N isopropylacrylamide (NIPAAm) containing zwitterionic sulfobetaine methacrylate (SBMA). This novel hydrogel highly regulates general bioadhesive foulants through the adsorption of plasma proteins, the adhesion of human platelets and cells, and the attachment of bacteria. In this investigation, nonionic hydrogels of polyNIPAAm, zwitterionic hydrogels of polySBMA, and three copolymeric hydrogels of NIPAAm and SBMA (poly(NIPAAm-co-SBMA)) were prepared. The copolymeric hydrogels exhibited controllable temperature-dependent swelling behaviors and showed stimuli-responsive phase characteristics in the presence of salts. The interactions of these hydrogels with biomolecules and microorganisms were demonstrated by protein adsorption, cell adhesion, and bacterial attachment, which allowed us to evaluate their bioadhesive properties. An enzyme-linked immunosorbent assay (ELISA) with monoclonal antibodies was used to measure different plasma protein adsorptions on the prepared hydrogel surfaces. At a physiological temperature, the high content of the nonionic polyNIPAAm in poly(NIPAAm-co-SBMA) hydrogel exhibits a high protein adsorption due to the interfacial exposure of polyNIPAAm-rich hydrophobic domains. A relatively high content of polySBMA in poly(NIPAAm-co-SBMA) hydrogel exhibits reduced amounts of protein adsorption due to the interfacial hydration of polySBMA-rich hydrophilic segments. The attachment of platelets and the spreading of cells were only observed on polyNIPAAm-rich hydrogel surfaces. Interestingly, the incorporation of zwitterionic SBMA units into the polyNIPAAm gels was found to accelerate the hydration of the cell-cultured surfaces and resulted in more rapid cell detachment. Such copolymer gel surface was shown to be potentially useful for triggered cell detachment. In addition, the interactions of hydrogels with bacteria were also evaluated. The polySBMA-rich hydrogels exhibited evident antimicrobial properties when they were incubated with Gram-positive bacteria ( S. epidermidis ) and Gram-negative bacteria ( E. coli ). This work shows that the bioadhesive properties of poly(NIPAAm-co-SBMA) hydrogels can be effectively controlled via regulated nonionic and zwitterionic molar mass ratios. The tunable bioadhesive behavior of temperature-sensitive poly(NIPAAm-co-SBMA) makes this biocompatible hydrogel appropriate for biomedical applications. PMID- 20201493 TI - Polylactide stereocomplexation leads to higher hydrolytic stability but more acidic hydrolysis product pattern. AB - Poly-l-lactide/poly-d-lactide (PLLA/PDLA) stereocomplex had much higher hydrolytic stability compared to plain PLLA, but at the same time shorter and more acidic degradation products were formed. Both materials were subjected to hydrolytic degradation in water and in phosphate buffer at 37 and 60 degrees C, and the degradation processes were monitored by following mass loss, water uptake, thermal properties, surface changes, and pH of the aging medium. The degradation product patterns were determined by electrospray ionization-mass spectrometry (ESI-MS). The high crystallinity and strong secondary interactions in the stereocomplex prevented water uptake and resulted in lower mass loss and degradation rate. However, somewhat surprisingly, the pH of the aging medium decreased much faster in the case of PLLA/PDLA stereocomplex. In accordance, the ESI-MS results showed that hydrolysis of PLLA/PDLA resulted in shorter and more acidic degradation products. This could be explained by the increased intermolecular crystallization due to stereocomplexation, which results in an increased number of tie chains. Because mainly these short tie chains are susceptible to hydrolysis this leads to formation of shorter oligomers compared to hydrolysis of regular PLLA. PMID- 20201494 TI - A concise synthesis of substituted thiourea derivatives in aqueous medium. AB - An efficient method for the synthesis of symmetrical and unsymmetrical substituted thiourea derivatives by means of simple condensation between available building blocks such as amines and carbon disulfide in aqueous medium is presented. This protocol works smoothly with aliphatic primary amines to afford various di- and trisubstituted thiourea derivatives. The present method is also useful in synthesizing various substituted 2-mercapto imidazole heterocycles. This method proceeds through a xanthate (amino dithiol deivative) intermediate, unlike isothiocyanate as in an earlier known method. PMID- 20201495 TI - Novel steroid-sensing model and characterization of protein interactions based on fluorescence anisotropy decay. AB - Intramolecular binding of a ligand with an alkyl link, (-CH(2))(3), covalently bound to a residue near the active site of the protein forms a novel steroid sensing model. A genetically engineered big up tri, open(5)-3-ketosteroid isomerase (KSI) was designed to conjugate uniquely with this ligand at its Cys-86 through the formation of a disulfide bond. The steady-state protein-ligand binding, mediated by hydrophobic interactions, was confirmed with fluorescence spectra, and the fluorophore-labeled peptide sequence was identified with tandem mass spectra. A comparison of steady-state fluorescence spectra of various fluorophore-labeled KSI mutants reveals that the emission characteristics vary with environmental factors. An evaluation of the decay of the fluorescence anisotropy of the fluorophore indicates the existence of an intramolecular protein-ligand binding interaction. The measurement of time-resolved fluorescence anisotropy of various protein-ligand complexes yielded values of anisotropy decay representing the degrees of freedom of the fluorophore related to its location, inside or outside the steroid-binding domain. When 19-norandrostenedione (19-NA) was added to this protein-ligand system, competitive binding between the ligand and the steroid was observed; this finding confirms the feasibility of the design of steroid detection with engineered KSI. On integration of this protein-ligand system with a silicon-based nanodevice (a p-type field-effect transistor with an ultrathin body), a noncharged steroid, 19-NA, became detectable at a micromolar level ( Biosens. Bioelectron. 2008 , 23 , 1883 ). PMID- 20201497 TI - Prediction of hydration structures around hydrophilic surfaces of proteins by using the empirical hydration distribution functions from a database analysis. AB - We developed a knowledge-based program to predict hydration structures around hydrophilic surfaces of proteins as probability density. In the program, we assume that the three-dimensional distribution of hydration water molecules on a hydrophilic surface is reconstructed by summing up the empirical hydration distribution function of each solvent-exposed polar atom composing the surface. The probability functions of polar atoms in the CO, NH(n) (n = 1,3), and OH groups were calculated from the 17 984 protein structures solved by X-ray crystallography better than resolutions of 2.2 A (Matsuoka, D.; Nakasako, M. J. Phys. Chem. B 2009, 113, 11274-11292). The program was first tested for human lysozyme. The predicted probability density enveloped more than 85% of crystal water sites found in the crystal structure refined at a resolution of 0.95 A, and the density peaks suggested as hydration sites were located within 1.5 A from more than 75% of the crystal water sites. The density reproduced the hydration structure in a solvent accessible narrow channel from the surface to the lysozyme interior. We also tested the feasibility of the program to predict the water clusters existing in the transmembrane channels of bacteriorhodopsin and aquaporin. In bacteriorhodopsin, the distributions were distinct between the ground state and the photoreaction intermediate indispensable for its function. The program reproduced the interfacial hydration in Per-Arnt-Sim-related protein protein complex and the hydration of metastable conformations in domain motion of glutamate dehydrogenase. Taking the results for the various types of protein hydration, the present program may be a useful tool to characterize the surface properties of proteins and discuss the relevance of hydration structures to the biological functions of proteins. In addition, it will be used to predict hydration structures of proteins available at resolutions insufficient to identify water molecules. PMID- 20201498 TI - NMR studies of carbosilane dendrimer with terminal mesogenic groups. AB - The 4-generation carbosilane dendrimer with terminal cyanobiphenyl mesogenic groups in dilute solution of CDCl(3) was investigated using (1)H NMR technique. The spectrum was obtained and the relaxation time, T(1), was measured in the temperature range 320-225 K. For the first time, the extrema of T(1) values were achieved for majority of the dendrimer functional groups. The values of activation energies of the dendrimer functional groups were obtained. The relaxation data for outer and inner methyl groups show that the dendrimer investigated has dense corona and hollow core. This structure is formed because the mesogenic groups do not allow terminal segments to penetrate into the dendrimer, that is, the backfolding effect is absent. The NMR spectral and relaxation data give evidence for changing conformation of the dendrimer internal segments with decreasing temperature. This reorganization is most likely connected with a change of dendrimer size. We suppose that our experimental results will provide additional information for understanding principles of dendrimer nanocontainer operation. NMR can possibly be a tool for indicating the encapsulation effect as well as the dendrimer effective size. PMID- 20201500 TI - Cellulose nanocrystals: chemistry, self-assembly, and applications. PMID- 20201499 TI - Structure of the 1,N(2)-etheno-2'-deoxyguanosine lesion in the 3'-G(epsilon dG)T 5' sequence opposite a one-base deletion. AB - The structure of the 1,N(2)-ethenodeoxyguanosine lesion (1,N(2)-epsilondG) has been characterized in 5'-d(CGCATXGAATCC)-3'.5'-d(GGATTCATGCG)-3' (X = 1,N(2) epsilondG), in which there is no dC opposite the lesion. This duplex (named the 1 BD duplex) models the product of translesion bypass of 1,N(2)-epsilondG by Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4) [Zang, H., Goodenough, A. K., Choi, J. Y., Irimia, A., Loukachevitch, L. V., Kozekov, I. D., Angel, K. C., Rizzo, C. J., Egli, M., and Guengerich, F. P. (2005) J. Biol. Chem. 280, 29750 29764], leading to a one-base deletion. The T(m) of this duplex is 6 degrees C higher than that of the duplex in which dC is present opposite the 1,N(2) epsilondG lesion and 8 degrees C higher than that of the unmodified 1-BD duplex. Analysis of NOEs between the 1,N(2)-epsilondG imidazole and deoxyribose H1' protons and between the 1,N(2)-epsilondG etheno H6 and H7 protons and DNA protons establishes that 1,N(2)-epsilondG adopts the anti conformation about the glycosyl bond and that the etheno moiety is accommodated within the helix. The resonances of the 1,N(2)-epsilondG H6 and H7 etheno protons shift upfield relative to the monomer 1,N(2)-epsilondG, attributed to ring current shielding, consistent with their intrahelical location. NMR data reveal that Watson-Crick base pairing is maintained at both the 5' and 3' neighbor base pairs. The structure of the 1-BD duplex has been refined using molecular dynamics calculations restrained by NMR derived distance and dihedral angle restraints. The increased stability of the 1,N(2)-epsilondG lesion in the absence of the complementary dC correlates with the one-base deletion extension product observed during the bypass of the 1,N(2) epsilondG lesion by the Dpo4 polymerase, suggesting that stabilization of this bulged intermediate may be significant with regard to the biological processing of the lesion. PMID- 20201501 TI - Interaction of an antimicrobial peptide with membranes: experiments and simulations with NKCS. AB - We used Monte Carlo simulations and biophysical measurements to study the interaction of NKCS, a derivative of the antimicrobial peptide NK-2, with a 1 palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE) membrane. The simulations showed that NKCS adsorbed on the membrane surface and the dominant conformation featured two amphipathic helices connected by a hinge region. We designed two mutants in the hinge to investigate the interplay between helicity and membrane affinity. Simulations with a Leu-to-Pro substitution showed that the helicity and membrane affinity of the mutant (NKCS-[LP]) decreased. Two Ala residues were added to NKCS to produce a sequence that is compatible with a continuous amphipathic helix structure (NKCS-[AA]), and the simulations showed that the mutant adsorbed on the membrane surface with a particularly high affinity. The circular dichroism spectra of the three peptides also showed that NKCS-[LP] is the least helical and NKCS-[AA] is the most. However, the activity of the peptides, determined in terms of their antimicrobial potency and influence on the temperature of the transition of the lipid to hexagonal phase, displayed a complex behavior: NKCS-[LP] was the least potent and had the smallest influence on the transition temperature, and NKCS was the most potent and had the largest effect on the temperature. PMID- 20201503 TI - A theoretical study of the reaction of beta-carotene with the nitrogen dioxide radical in solution. AB - A theoretical study of the reaction of beta-carotene (BC) with the nitrogen dioxide radical (NO2*) in solution is carried out using the density functional theory (DFT) at the B3LYP/6-31G(d) level, to optimize the molecular geometries, and the polarizable continuum model (PCM), to account for solvent effects. The three most important reaction mechanisms--electron transfer from beta-carotene to the radical, hydrogen abstraction by the radical, and radical addition to form an adduct--are studied in detail. Three solvents with different polarities--heptane, methanol, and water--are employed to investigate the effect of the environment on the reaction mechanisms. Our results show that electron transfer is thermodynamically favored only in the polar solvents, the abstraction reactions are spontaneous in the three solvents, although faster in the polar ones, and the addition reactions are all endergonic and, therefore, unlikely to occur in any of the solvents. In both the abstraction and addition mechanisms, the attack of the radical takes place preferentially at the beta-ionone rings, in particular at positions H4 and C5, respectively. The higher stability of the reaction products in these cases is explained in terms of their molecular geometries and electronic structures. PMID- 20201502 TI - Sensitive immunosensor for cancer biomarker based on dual signal amplification strategy of graphene sheets and multienzyme functionalized carbon nanospheres. AB - A novel electrochemical immunosensor for sensitive detection of cancer biomarker alpha-fetoprotein (AFP) is described that uses a graphene sheet sensor platform and functionalized carbon nanospheres (CNSs) labeled with horseradish peroxidase secondary antibodies (HRP-Ab2). Greatly enhanced sensitivity for the cancer biomarker is based on a dual signal amplification strategy: first, the synthesized CNSs yielded a homogeneous and narrow size distribution, which allowed several binding events of HRP-Ab2 on each nanosphere. Enhanced sensitivity was achieved by introducing the multibioconjugates of HRP-Ab2-CNSs onto the electrode surface through "sandwich" immunoreactions. Second, functionalized graphene sheets used for the biosensor platform increased the surface area to capture a large amount of primary antibodies (Ab1), thus amplifying the detection response. On the basis of the dual signal amplification strategy of graphene sheets and the multienzyme labeling, the developed immunosensor showed a 7-fold increase in detection signal compared to the immunosensor without graphene modification and CNSs labeling. The proposed method could respond to 0.02 ng mL(-1) AFP with a linear calibration range from 0.05 to 6 ng mL(-1). This amplification strategy is a promising platform for clinical screening of cancer biomarkers and point-of-care diagnostics. PMID- 20201504 TI - An RNA-aptamer-based assay for the detection and analysis of malachite green and leucomalachite green residues in fish tissue. AB - A robust screening assay employing solid phase extraction (SPE) followed by a novel aptamer-based procedure is presented for the rapid detection and semiquantitation of the triphenylmethane dye, Malachite Green (MG) and its primary metabolite Leucomalachite Green (LMG) in fish tissue. To the authors' knowledge, this is the first reported use of an RNA aptamer for the development of a diagnostic assay for the detection of chemical residues in food. The aptamer based screening assay is found to be highly specific for MG; but has negligible affinity for the LMG metabolite. However, because the LMG metabolite is lipophilic and known to be highly persistent in tissues, an oxidation step has been incorporated within the sample cleanup procedure to ensure that all LMG residues are converted to MG prior to measurement. This article provides evidence that an oligonucleotide aptamer can be used as an alternative recognition element to conventional antibodies with application to the detection of residues in food. Furthermore, this finding has the future potential to reduce the number of animals currently being used in the production of antibodies for immunodiagnostic kits. PMID- 20201505 TI - Influence of the linear aromatic density on methylene blue aggregation around polyanions containing sulfonate groups. AB - The aggregation of methylene blue around different polyelectrolytes is studied by diafiltration, UV-vis, and (1)H NMR spectroscopies. Poly(sodium acrylate-co sodium maleate) induces the formation of higher-order aggregates, showing a typical polyelectrolyte behavior dominated by long-range electrostatic interactions with the dye which are highly dependent on the ionic strength. Poly(sodium 4-styrenesulfonate) presents a high dispersant ability of methylene blue, showing what we can call a typical polyaromatic-anion behavior characterized by the presence of short-range aromatic-aromatic interactions with the dye which are less dependent on the ionic strength. An intermediate behavior is found for the copolymers poly(sodium 4-styrenesulfonate-co-sodium maleate) at two different comonomer compositions, related to a different probability of the polymers to form and stabilize ion pairs in hydrophobic environments. Their behavior is a function of the linear aromatic density, which is related to the comonomeric structure. PMID- 20201506 TI - Gold nanoparticle extraction followed by capillary electrophoresis to determine the total, free, and protein-bound aminothiols in plasma. AB - This study describes the use of Tween 20-capped gold nanoparticles (Tween 20 AuNPs) for the selective extraction and enrichment of five aminothiols, including glutathione, gamma-glutamylcysteine, cysteine, homocysteine, and cysteineglycine, prior to analysis by capillary electrophoresis with UV detection. Tween 20-AuNPs are capable of extracting aminothiols from a complicated matrix because a Tween 20 capping layer can inhibit effectively the nonspecific adsorption. Moreover, Tween 20-AuNPs had better aminothiol loading compared to Zonyl FSN-100- and Triton X-100-capped AuNPs. The extraction efficiency of aminothiols was highly dependent on the number of Tween 20-AuNPs, the concentration of dithiothreitol, and the type of surfactant (i.e., capping agent). Under optimal extraction conditions, the limits of detection at a signal-to-noise ratio of 3 for five aminothiols were down to 10-65 nM. Total and free aminothiols in plasma were determined by varying the order of disulfide reduction with tris(2 carboxyethyl)phosphine. Efficient separation of total and free aminothiols with baseline resolution was successfully achieved by the addition of cationic polyelectrolyte, poly(diallyldimethylammonium chloride), to the background electrolyte. Because this extraction method provided no matrix effect, the concentrations of total and free aminothiols in plasma can be quantified with an external calibration method. On the basis of the advantages of simplicity, high selectivity, high sensitivity, and good reproducibility, this proposed method may have great potential for disease diagnosis. PMID- 20201507 TI - Effects of an applied electric field on the vapor-liquid equilibria of water, methanol, and dimethyl ether. AB - Gibbs ensemble Monte Carlo simulations are employed to examine the influence of moderately strong electric fields on the vapor-liquid coexistence curves and on structural and energetic properties of the saturated phases of water, methanol, and dimethyl ether. The application of an electric field of 0.1 V/A increases the critical temperature and normal boiling point by approximately 3% compared to the zero field case for all three compounds, whereas the critical density is found to decrease by 1% for methanol and dimethly ether and by 3% for water. For the special case of an electric field applied in only the liquid phase, these effects are magnified with a 4% increase in T(C) and a 13% decrease in rho(C). For the case of an electric field in only the vapor phase, the opposite effect is seen with a 4% decrease in T(C) and a 12% increase in rho(C). Structural analysis shows very little change in the radial distribution functions, but greatly increased orientational ordering with the application of an electric field. The orientational ordering effect is stronger in the liquid phase than in the vapor phase. An examination of the energetics reveals that, in the presence of an electric field, the interactions with the first and second solvation shells become less favorable but these are outweighed by a larger increase in the favorable long-range interactions with more distant molecules and the field. PMID- 20201508 TI - Estimation and congener-specific characterization of polychlorinated naphthalene emissions from secondary nonferrous metallurgical facilities in China. AB - Secondary nonferrous production is addressed as one of the potential sources of the unintentionally produced persistent organic pollutants (UP-POPs) due to the impurity of raw material. Although there are inventories of dioxin emissions from secondary nonferrous metallurgical facilities, release inventories of polychlorinated naphthalenes (PCNs) are scarce. This study selected typical secondary copper, aluminum, zinc, and lead plants to investigate the emissions of PCNs in secondary nonferrous production in China. The toxic equivalency (TEQ) emission factor for PCNs released to the environment is highest for secondary copper production, at 428.4 ng TEQ t(-1), followed by secondary aluminum, zinc, and lead production, at 142.8, 125.7, and 20.1 ng TEQ t(-1), respectively. PCNs released in secondary copper, aluminum, lead, and zinc production in China are estimated to be 0.86, 0.39, 0.009, and 0.01 g TEQ a(-1), respectively. Analysis of stack gas emission from secondary nonferrous production revealed that less chlorinated PCNs are the dominant homologues, with mono- to tri-CNs making the most important contributions to the concentration. However, for fly ash, the more highly chlorinated PCNs such as octa-CN are the dominant homologues. PMID- 20201509 TI - Assessing pathogen risk to swimmers at non-sewage impacted recreational beaches. AB - The risk of gastrointestinal illness to swimmers from fresh sewage and non-sewage fecal sources at recreational beaches was predicted using quantitative microbial risk assessment (QMRA). The QMRA estimated the probability of illness for accidental ingestion of recreational water with a specific concentration of fecal indicator bacteria, here the geometric mean enterococci limit of 35 cfu 100 mL( 1), from either a mixture of sources or an individual source. Using seagulls as an example non-sewage fecal source, the predicted median probability of illness was less than the illness benchmark of 0.01. When the fecal source was changed to poorly treated sewage, a relativity small difference between the median probability of illness and the illness benchmark was predicted. For waters impacted by a mixture of seagull and sewage waste, the dominant source of fecal indicator was not always the predicted dominant source of risk. PMID- 20201510 TI - Solution-phase synthesis of SnSe nanocrystals for use in solar cells. AB - Nanocrystals of phase-pure tin(II) selenide (SnSe) were synthesized via a solution-phase route employing stoichiometric amounts of di-tert-butyl diselenide as a novel and facile selenium source. The direct band gap of the resulting nanocrystals (E(g) = 1.71 eV) is significantly blue-shifted relative to the bulk value (E(g) = 1.30 eV), a likely consequence of quantum confinement resulting from the relatively small average diameter of the nanocrystals (mu(D) < 20 nm). Preliminary solar cell devices incorporating SnSe nanocrystals into a poly[2 methoxy-5-(3',7'-dimethyloctyloxy)-1,4-phenylenevinylene] matrix demonstrate a significant enhancement in quantum efficiency and short-circuit current density, suggesting that this earth-abundant material could be a valuable component in future photovoltaic devices. PMID- 20201513 TI - Photoelectrochemical water oxidation by cobalt catalyst ("Co-Pi")/alpha-Fe(2)O(3) composite photoanodes: oxygen evolution and resolution of a kinetic bottleneck. AB - A cobalt-phosphate water oxidation catalyst ("Co-Pi") has been electrodeposited onto mesostructured alpha-Fe(2)O(3) photoanodes. The photoelectrochemical properties of the resulting composite photoanodes were optimized for solar water oxidation under frontside illumination in pH 8 electrolytes. A kinetic bottleneck limiting the performance of such photoanodes was identified and shown to be largely overcome by more sparse deposition of Co-Pi onto the alpha-Fe(2)O(3). Relative to alpha-Fe(2)O(3) photoanodes, a sustained 5-fold enhancement in the photocurrent density and O(2) evolution rate was observed at +1.0 V vs RHE with the Co-Pi/alpha-Fe(2)O(3) composite photoanodes. These results demonstrate that integration of this promising water oxidation catalyst with a photon-absorbing substrate can provide a substantial reduction in the external power needed to drive the catalyst's electrolysis chemistry. PMID- 20201512 TI - Ester to amide switch peptides provide a simple method for preparing monomeric islet amyloid polypeptide under physiologically relevant conditions and facilitate investigations of amyloid formation. AB - A major issue in studies of amyloid formation is the difficulty of preparing the polypeptide of interest in an initially monomeric state under physiologically relevant conditions. This is particularly problematic for polypeptides which are natively unfolded in their unaggregated state, and perhaps the most challenging such system is islet amyloid polypeptide (Amylin), the causative agent of amyloid formation in type-2 diabetes. Preparation of islet amyloid polypeptide with the Ser-19 Ser-20 amide bond replaced by an ester circumvents these problems. The modified peptide is unstructured and monomeric at slightly acidic pH's as judged by analytical ultracentrifugation, gel filtration, dynamic light scattering, and CD. A rapid pH jump leads to deprotonation of the Ser-20 amide group, and a subsequent rapid O to N acyl shift regenerates normal human islet amyloid polypeptide. The half time, t(1/2), for the conversion to normal islet amyloid polypeptide is 70 s at pH 7.4. The amyloid fibrils which are formed by the regenerated islet amyloid polypeptide are indistinguishable from those formed by the wild type polypeptide. The approach allows studies of amyloid formation by islet amyloid polypeptide to be carried out from a well-defined, physiologically relevant starting state in the absence of denaturants or organic cosolvents. PMID- 20201514 TI - Continuous symmetry breaking induced by ion pairing effect in heptamethine cyanine dyes: beyond the cyanine limit. AB - The association of heptamethine cyanine cation 1(+) with various counterions A (A = Br(-), I(-), PF(6)(-), SbF(6)(-), B(C(6)F(5))(4)(-), TRISPHAT) was realized. The six different ion pairs have been characterized by X-ray diffraction, and their absorption properties were studied in polar (DCM) and apolar (toluene) solvents. A small, hard anion (Br(-)) is able to strongly polarize the polymethine chain, resulting in the stabilization of an asymmetric dipolar-like structure in the crystal and in nondissociating solvents. On the contrary, in more polar solvents or when it is associated with a bulky soft anion (TRISPHAT or B(C(6)F(5))(4)(-)), the same cyanine dye adopts preferentially the ideal polymethine state. The solid-state and solution absorption properties of heptamethine dyes are therefore strongly correlated to the nature of the counterion. PMID- 20201515 TI - Synthesis of monodisperse mesoporous titania beads with controllable diameter, high surface areas, and variable pore diameters (14-23 nm). AB - Monodisperse mesoporous anatase titania beads with high surface areas and tunable pore size and grain diameter have been prepared through a combined sol-gel and solvothermal process in the presence of hexadecylamine (HDA) as a structure directing agent. The monodispersity of the resultant titania beads, along with the spherical shape, can be controlled by varying the amount of structure directing agent involved in the sol-gel process. The diameter of the titania beads is tunable from approximately 320 to 1150 nm by altering the hydrolysis and condensation rates of the titanium alkoxide. The crystallite size, specific surface area (from 89 to 120 m(2)/g), and pore size distribution (from 14 to 23 nm) of the resultant materials can be varied through a mild solvothermal treatment in the presence of varied amounts of ammonia. On the basis of the results of small-angle XRD, high-resolution SEM/TEM, and gas sorption characterization, a mechanism for the formation of the monodisperse precursor beads has been proposed to illustrate the role of HDA in determining the morphology and monodispersity during the sol-gel synthesis. The approach presented in this study demonstrates that simultaneous control of the physical properties, including specific surface area, mesoporosity, crystallinity, morphology, and monodispersity, of the titania materials can be achieved by a facile sol-gel synthesis and solvothermal process. PMID- 20201516 TI - Comparison of batch mode and dynamic physiologically based bioaccessibility tests for PAHs in soil samples. AB - A fed state in vitro methodology capable of use in commercial testing laboratories has been developed for measuring the human ingestion bioaccessibility of polyaromatic hydrocarbons (PAHs) in soil (Fed ORganic Estimation human Simulation Test- FOREhST). The protocol for measuring PAHs in the simulated gastro-intestinal fluids used methanolic KOH saponification followed by a combination of polymeric sorbent solid phase extraction and silica sorbent cartridges for sample cleanup and preconcentration. The analysis was carried out using high pressure liquid chromatography with fluorescence detection. The repeatability of the method, assessed by the measurement of the bioaccessibility of 6 PAHs (benz[a]anthracene, benzo[b]fluoranthene, benzo[k]fluoranthene, benzo[a]pyrene, dibenz[ah]anthracene, and indeno[1,2,3 c,d]pyrene) in eleven gas works soils, was approximately 10% RSD. The method compared well with the results from an independent dynamic human simulation reactor comprising of the stomach, duodenal and colon compartments tested on the same soils. The measured bioaccessible fraction of the soils varied from 10-60% for soils containing 10-300 mg kg(-1) PAH (the sum of the six studied) with total organic carbon concentrations in the soils ranging from 1-13%. A multiple regression model showed that the PAH bioaccessible fraction could be explained using the PAH compound, the soil type and the total PAH to soil organic carbon content. The method described here has potential for site specific detailed quantitative risk assessment either to modify the risk estimation or to contribute to the risk evaluation. PMID- 20201517 TI - Simple detection of protein soft structure changes. AB - We present a rapid method for protein tertiary structure analysis which avoids the need for techniques such as circular dichroism and differential scanning calorimetry. Small changes to a protein's noncovalent "soft" structure are detected by exploiting differences in thermal stability and fluorescent reporter binding. It can detect subtle stability differences using micrograms of protein in 2 microL volumes within minutes. PMID- 20201518 TI - A guest-responsive fluorescent 3D microporous metal-organic framework derived from a long-lifetime pyrene core. AB - The carboxylate ligand 1,3,6,8-tetrakis(p-benzoic acid)pyrene (TBAPy)-based on the strongly fluorescent long-lifetime pyrene core-affords a permanently microporous fluorescent metal-organic framework, [In(2)(OH)(2)(TBAPy)].(guests) (1), displaying 54% total accessible volume and excellent thermal stability. Fluorescence studies reveal that both 1 and TBAPy display strong emission bands at 471 and 529 nm, respectively, upon excitation at 390 nm, with framework coordination of the TBAPy ligands significantly increasing the emission lifetime from 0.089 to 0.110 ms. Upon desolvation, the emission band for the framework is shifted to lower energy: however, upon re-exposure to DMF the as-made material is regenerated with reversible fluorescence behavior. Together with the lifetime, the emission intensity is strongly enhanced by spatial separation of the optically active ligand molecules within the MOF structure and is found to be dependent on the amount and chemical nature of the guest species in the pores. The quantum yield of the material is found to be 6.7% and, coupled with the fluorescence lifetime on the millisecond time scale, begins to approach the values observed for Eu(III)-cryptate-derived commercial sensors. PMID- 20201519 TI - Adsorption of pharmaceutical antibiotics on template-synthesized ordered micro- and mesoporous carbons. AB - The presence of pharmaceutical antibiotics in aquatic environments poses potential human health and ecological risks. We synthesized ordered micro- and mesoporous carbons, and further conducted batch experiments to systematically examine their adsorption properties toward three antibiotics, sulfamethoxazole, tetracycline, and tylosin, in aqueous solution. In comparison, nonporous graphite, single-walled carbon nanotubes, and two commercial microporous activated carbons were included as additional adsorbents. Adsorption of low-sized sulfamethoxazole was stronger on the activated carbons than on other carbonaceous adsorbents resulting from the pore-filling effect; in contrast, due to the size exclusion effect adsorption of bulky tetracycline and tylosin was much lower on the activated carbons, especially for the more microporous one, than on the synthesized carbons. After normalizing for adsorbent surface area, adsorption of tetracycline and tylosin on the synthesized carbons was similar to that on nonporous graphite, reflecting complete accessibility of the adsorbent surface area in adsorption. Additionally, compared with other porous adsorbents the synthesized carbons showed faster adsorption kinetics of tetracycline and tylosin, which was attributed to their regular-shaped, open and interconnected three-dimensional pore structure. The findings indicate that template-synthesized micro- and mesoporous carbons are promising adsorbents for the removal of antibiotics, particularly, the bulky and flexible-structured compounds, from aqueous solution. PMID- 20201520 TI - In situ synthesis of magnetic multiwalled carbon nanotube composites for the clean-up of (fluoro)quinolones from human plasma prior to ultrahigh pressure liquid chromatography analysis. AB - Magnetic nanoparticles (MNPs) were deposited onto multiwalled carbon nanotubes (MWCNTs) by in situ high-temperature decomposition of the magnetic precursor [iron(III)] and MWCNTs, in ethylene glycol. This one-step synthetic method was applied to commercially available carbon nanotubes (CNTs). Scanning electron micrographs of the resulting products revealed that MNPs decorated the surface of the MWCNTs. The hybrid nanoparticles thus obtained were used for sampling and cleanup in the determination of eight fluoroquinolones (FQs) and two quinolones (Qs) at trace levels by ultra performance liquid chromatography (UPLC). A systematic study of analyte adsorption and desorption was conducted with MNPs and MWCNTs separately. Although both solid phases adsorbed the analytes to some extent, the much higher recoveries were obtained by using the MNP-MWCNT composite which was thus selected to treat plasma samples containing FQs and Qs. Lower accuracies were determined at spiked plasma compared to the standard solution caused by the complexation affinity of the analytes with proteins because high recoveries were observed when deproteinization was performed before treating the sample with the magnetic MWCNTs. The performance characteristics of the optimized method were determined, and the method was applied to the analysis of plasma samples from antibiotic-treated patients. On the basis of the results, the use of an in situ synthesized MWCNT-MNP composite allows the simple, expeditious sampling and treatment of such complex biological samples for the subsequent determination of FQs and Qs present at free form. PMID- 20201521 TI - Probing the phosphoproteome of HeLa cells using nanocast metal oxide microspheres for phosphopeptide enrichment. AB - Metal oxide affinity chromatography (MOAC) has become a prominent method to enrich phosphopeptides prior to their analysis by liquid chromatography-mass spectrometry. To overcome limitations in material design, we have previously reported the use of nanocasting as a means to generate metal oxide spheres with tailored properties. Here, we report on the application of two oxides, tin dioxide (stannia) and titanium dioxide (titania), for the analysis of the HeLa phosphoproteome. In combination with nanoflow LC-MS/MS analysis on a linear ion trap-Fourier transform ion cyclotron resonance instrument, we identified 619 phosphopeptides using the new stannia material, and 896 phosphopeptides using titania prepared in house. We also compared the newly developed materials to commercial titania material using an established enrichment protocol. Both titania materials yielded a comparable total number of phosphopeptides, but the overlap of the two data sets was less than one-third. Although fewer peptides were identified using stannia, the complementarity of SnO(2)-based MOAC could be shown as more than 140 phosphopeptides were exclusively identified by this material. PMID- 20201522 TI - Cascade resulting in the reductive ethynylation of aldehydes: dissection of its components. AB - A mild and efficient two-carbon homologation of aldehydes exploiting multiple modes of KOt-Bu was developed. This process involves a sequential Peterson allenylation/allene-alkyne isomerization/protodesilylation in a single-flask operation. The differential roles played by the various elements of the process were demonstrated through dissection experiments. PMID- 20201523 TI - Freezing of dynamics of a methyl group in a protein hydrophobic core at cryogenic temperatures by deuteron NMR spectroscopy. AB - Methyl groups are thought to dominate the dynamics of proteins after slow collective modes of motion freeze out in a glass-transition process. In this work we investigate methyl group dynamics of a key hydrophobic core leucine residue in chicken villin headpiece subdomain protein at 140-4 K using deuteron NMR longitudinal relaxation measurements. A distinct increase in the apparent activation energy is observed at approximately 95 K, indicating an abrupt freezing of methyl group dynamics. Relaxation times at temperatures below 60 K are dominated by the deuteron tunneling mechanism. PMID- 20201525 TI - Highly resolved spectra of gas-phase gramicidin s: a benchmark for peptide structure calculations. AB - We have measured a vibrationally resolved UV spectrum of doubly protonated gramicidin S (GS) in the gas phase and, subsequently, a highly resolved, conformer-specific IR spectrum in the 6 mum fingerprint region, using a cold ion trap in combination with table-top lasers. The study has revealed at least three conformational states of GS populated under our experimental conditions, with the major one showing evidence of a symmetric three-dimensional structure similar to that in the condensed phase. The derived qualitative constraints, along with the measured vibrational frequencies, serve as a benchmark for computations of peptide structure. PMID- 20201526 TI - Bisabolyl-derived sesquiterpenes from tobacco 5-epi-aristolochene synthase catalyzed cyclization of (2Z,6E)-farnesyl diphosphate. AB - We report the structures and stereochemistry of seven bisabolyl-derived sesquiterpenes arising from an unprecedented 1,6-cyclization (cisoid pathway) efficiently catalyzed by tobacco 5-epi-aristolochene synthase (TEAS). The use of (2Z,6E)-farnesyl diphosphate as an alternate substrate for recombinant TEAS resulted in a robust enzymatic cyclization to an array of products derived exclusively (>/=99.5%) from the cisoid pathway, whereas these same products account for ca. 2.5% of the total hydrocarbons obtained using (2E,6E)-farnesyl diphosphate. Chromatographic fractionations of extracts from preparative incubations with the 2Z,6E substrate afforded, in addition to the acyclic allylic alcohols (2Z,6E)-farnesol (6.7%) and nerolidol (3.6%), five cyclic sesquiterpene hydrocarbons and two cyclic sesquiterpene alcohols: (+)-2-epi-prezizaene (44%), ( )-alpha-cedrene (21.5%), (R)-(-)-beta-curcumene (15.5%), alpha-acoradiene (3.9%), 4-epi-alpha-acoradiene (1.3%), and equal amounts of alpha-bisabolol (1.8%) and epi-alpha-bisalolol (1.8%). The structures, stereochemistry, and enantiopurities were established by comprehensive spectroscopic analyses, optical rotations, chemical correlations with known sesquiterpenes, comparisons with literature data, and GC analyses. The major product, (+)-2-epi-prezizaene, is structurally related to the naturally occurring tricyclic alcohol, jinkohol (2-epi-prezizaan 7beta-ol). Cisoid cyclization pathways are proposed by which all five sesquiterpene hydrocarbons are derived from a common (7R)-beta bisabolyl(+)/pyrophosphate(-) ion pair intermediate. The implications of the "cisoid" catalytic activity of TEAS are discussed. PMID- 20201527 TI - Flow induced dispersion analysis quantifies noncovalent interactions in nanoliter samples. AB - Flow Induced Dispersion Analysis (FIDA) is presented as a new approach to characterize noncovalent interactions. The new method only requires nanoliter samples, is easy to implement, and also provides diffusivities of the free analyte and the formed complex. The technique is based on signal analysis of temporal variances obtained for pressure driven flows in micrometer sized fused silica capillaries. PMID- 20201529 TI - Epoxidations catalyzed by manganese(V) oxo and imido complexes: role of the oxidant-Mn-oxo (imido) intermediate. AB - The manganese(V) oxo complex (TBP(8)Cz)Mn(V)(O) (1) is shown to catalyze the epoxidation of alkenes with a series of iodosylarenes (ArIO) as oxidants. Competition experiments reveal that the identity of ArIO influences the product ratios, implicating an unusual coordinated oxo-metal-ArIO intermediate (1-OIAr) as the active catalytic species. The isoelectronic manganese(V) imido complex (TBP(8)Cz)Mn(V)(NMes) (2) does not participate in NR transfer but does catalyze epoxidations with ArIO as the O-atom source, suggesting a mechanism similar to that seen for 1. Direct evidence (ESIMS) is obtained for 1-OIMes. PMID- 20201528 TI - Organelle-targetable fluorescent probes for imaging hydrogen peroxide in living cells via SNAP-Tag protein labeling. AB - Hydrogen peroxide (H(2)O(2)) is a potent small-molecule oxidant that can exert a diverse array of physiological and/or pathological effects within living systems depending on the timing and location of its production, accumulation, trafficking, and consumption. To help study the chemistry and biology of this reactive oxygen species (ROS) in its native cellular context, we now present a new method for monitoring local, subcellular changes in H(2)O(2) levels by fluorescence imaging. Specifically, we have exploited the versatility of the SNAP tag technology for site-specific protein labeling with small molecules on the surface or interior of living cells with the use of boronate-capped dyes to selectively visualize H(2)O(2). The resulting SNAP-Peroxy-Green (SNAP-PG) probes consist of appropriately derivatized boronates bioconjugated to SNAP-tag fusion proteins. Spectroscopic measurements of the SNAP-PG constructs confirm their ability to detect H(2)O(2) with specificity over other biologically relevant ROS. Moreover, these hybrid small-molecule/protein reporters can be used in live mammalian cells expressing SNAP-tag fusion proteins directed to the plasma membrane, nucleus, mitochondria, and endoplasmic reticulum. Imaging experiments using scanning confocal microscopy establish organelle-specific localization of the SNAP-tag probes and their fluorescence turn-on in response to changes in local H(2)O(2) levels. This work provides a general molecular imaging platform for assaying H(2)O(2) chemistry in living cells with subcellular resolution. PMID- 20201531 TI - Si-H bond activation of alkynylsilanes by group 4 metallocene complexes. AB - The reactivity of variously substituted alkynylsilanes toward selected group 4 metallocene complexes was investigated. Reactions of the alkynylsilanes R(1)C(2)SiR(2)(2)H (R(1) = SiMe(3), R(2) = Me, 1; R(1) = SiMe(3), R(2) = Ph, 2; R(1) = SiMe(2)H, R(2) = Me, 5) with Cp(2)TiMe(2) (Cp = eta(5)-cyclopentadienyl) resulted, upon methyl group transfer to the silyl group, in the previously described titanocene alkyne complexes Cp(2)Ti(R(1)C(2)SiR(2)(2)R(3)) (R(1) = Me(3)Si, R(2) = R(3) = Me, 3; R(1) = HMe(2)Si, R(2) = R(3) = Me, 6) or the unreported complex 4 (R(1) = Me(3)Si, R(2) = Ph, R(3) = Me). The Cp(2)TiCl(2)/n BuLi system yielded alkyne complexes 6 and 7 (R(1) = HMe(2)Si, R(2) = Me, R(3) = H); no alkyl group transfer was detected. On the other hand, reactions utilizing the Cp(2)ZrCl(2)/n-BuLi system afforded inseparable mixtures; however, complexes of the type Cp(2)Zr[R(1)C(2)SiMe(2)(n-Bu)] (R(1) = Me(3)Si, 8; R(1) = HMe(2)Si, 9) were detected. Cp(2)Hf(n-Bu)(2) reacted with the alkynylsilanes in a diverse way, depending on the substituents of the alkyne substrate. The reaction with an excess of alkyne 1 (R(1) = Me(3)Si, R(2) = Me) afforded only an intractable mixture, which contained Me(3)SiC(2)SiMe(2)(n-Bu) (10). Hafnacyclopentadienes 13 15 as precedented product types were obtained when alkyne 12 (R(1) = Ph, R(2) = Me) was used. In sharp contrast, the symmetrically substituted alkynes 5 (R(1) = HMe(2)Si, R(2) = Me) and H(2)PhSiC(2)SiPhH(2) (18) yielded the hitherto unknown Si-containing metallacycles 16 and 19. A reaction mechanism leading to these products was proposed and subsequently supported by DFT calculations. In addition, the reduction of Cp(2)HfCl(2) with magnesium in THF in the presence of alkynylsilanes was shown to be an alternative route to compounds 14-16 and 19. Presumably due to steric reasons, alkyne 1 could not form any of the product types described above. Nevertheless, it was utilized for the preparation of the PMe(3)-stabilized hafnocene alkyne complex 11. PMID- 20201530 TI - Magnetic glyco-nanoparticles: a tool to detect, differentiate, and unlock the glyco-codes of cancer via magnetic resonance imaging. AB - Within cancer, there is a large wealth of diversity, complexity, and information that nature has engineered rendering it challenging to identify reliable detection methods. Therefore, the development of simple and effective techniques to delineate the fine characteristics of cancer cells can have great potential impacts on cancer diagnosis and treatment. Herein, we report a magnetic glyco nanoparticle (MGNP) based nanosensor system bearing carbohydrates as the ligands, not only to detect and differentiate cancer cells but also to quantitatively profile their carbohydrate binding abilities by magnetic resonance imaging (MRI). Using an array of MGNPs, a range of cells including closely related isogenic tumor cells, cells with different metastatic potential and malignant vs normal cells can be readily distinguished based on their respective "MRI signatures". Furthermore, the information obtained from such studies helped guide the establishment of strongly binding MGNPs as antiadhesive agents against tumors. As the interactions between glyco-conjugates and endogenous lectins present on cancer cell surface are crucial for cancer development and metastasis, the ability to characterize and unlock the glyco-code of individual cell lines can facilitate both the understanding of the roles of carbohydrates as well as the expansion of diagnostic and therapeutic tools for cancer. PMID- 20201532 TI - Hydrogen scrambling in [(C(5)R(5))(L)M(H)(C(2)H(4))](+) (M = Co, Rh). Relation of experimental kinetic data to the barriers of the elementary reaction steps. AB - The energetics of hydrogen scrambling in the ethylene hydride complexes of two late transition metals [(C(5)R(5))(L)M(H)(C(2)H(4))](+) (R = H, Me; L = P(OMe)(3), PMe(3); M = Co, Rh) were studied using density functional theory. Four potential nuclear (C/H) scrambling processes in these complexes are discussed; the computed energy barriers for three of them compare very well with activation energies from previous NMR studies, while the fourth process appears to be inactive for energetic reasons. The observed trends for the different metals M, ligands L, and substituents R are reproduced; the activation barriers are insensitive toward L, but somewhat higher for R = H than R = Me. The connection of these elementary processes (or lack thereof) to the beta-migratory insertion reaction in these complexes is discussed; the reported data from NMR experiments are not directly related to the elementary steps of the insertion/elimination reaction. Furthermore, for rhodium complexes with L = C(2)H(4), the observed shift of the global energy minimum is correctly reproduced by our calculations. PMID- 20201533 TI - Direct extraction of photosynthetic electrons from single algal cells by nanoprobing system. AB - There are numerous sources of bioenergy that are generated by photosynthetic processes, for example, lipids, alcohols, hydrogen, and polysaccharides. However, generally only a small fraction of solar energy absorbed by photosynthetic organisms is converted to a form of energy that can be readily exploited. To more efficiently use the solar energy harvested by photosynthetic organisms, we evaluated the feasibility of generating bioelectricity by directly extracting electrons from the photosynthetic electron transport chain before they are used to fix CO(2) into sugars and polysaccharides. From a living algal cell, Chlamydomonas reinhardtii, photosynthetic electrons (1.2 pA at 6000 mA/m(2)) were directly extracted without a mediator electron carrier by inserting a nanoelectrode into the algal chloroplast and applying an overvoltage. This result may represent an initial step in generating "high efficiency" bioelectricity by directly harvesting high energy photosynthetic electrons. PMID- 20201534 TI - Persistent spectral hole-burning in the R(1) line of Cr(3+)-doped NaMg[Al(oxalate)(3)].9(H(2)O/D(2)O) induced by resonant energy transfer. AB - In the 3D network [Rh(bpy)(3)][NaCr(ox)(3)]ClO(4) (ox = oxalate, bpy = 2,2' bipyridine) phonon-assisted as well as resonant energy migration within the R(1) line of the (4)A(2) --> (2)E transition of Cr(3+) has been identified. The latter is dominant below 4.2 K, and in a fluorescence line narrowing spectrum, it manifests itself in a multiline pattern across the inhomogeneous line width with spacings corresponding to the zero-field splitting of the (4)A(2) ground state (Milos, M.; Kairouani, S.; Rabaste, S.; Hauser, A. Coord. Chem. Rev. 2008, 252, 2540). H. Riesen demonstrated efficient spectral hole burning within the R(1) line of Cr(3+) doped at low concentrations into partially deuterated NaMg[Al(ox)(3)].9H(2)O (Riesen, H. Coord. Chem. Rev. 2006 250, 1737). Here we show that at higher Cr(3+) concentrations in the same host, both phenomena can be observed simultaneously, the resonant energy migration thus creating an additional series of persistent side holes. PMID- 20201535 TI - Quantum chemical characterization of low-lying excited states of an aryl peroxycarbonate: mechanistic implications for photodissociation. AB - Recent experiments have revealed the existence of an excited state dissociative mechanism for certain peroxycarbonates, with the demonstration that the lifetime of the excited state matches the picosecond time scale for appearance of nascent carbon dioxide product. The data infer that the photoreaction proceeds via an effectively concerted three-body dissociation within the lifetime of the singlet excited state. Many other arylperoxides decay sequentially via [(aryloxy)carbonyl]oxy radical intermediates on nanosecond-microsecond time scales. Uncertainty as to the lifetime of the excited state relates to the character and the relative energetic ordering of states of the parent molecule, since the spectra and photochemistry imply that low-lying states may exist on each of the aryl, carbonate, and peroxide chemical functionalities. We employ many-body electronic structure calculations to determine the energies and characters of the low-lying valence states of a minimal aryl peroxycarbonate model germane to the above-mentioned experiments, methyl phenyl peroxycarbonate (MPC). Our results indicate that the lowest-lying state is an intrinsically nondissociative aryl pipi* excited state. We identify additional low-lying states that are expected to be dissociative in nature and propose that the time scales observed for the dissociation reaction may correspond to the time scale for transfer of excited state population to these states. PMID- 20201536 TI - Density functional investigations on the charge distribution, vibrational spectra, and NMR chemical shifts in cucurbit[n]uril (n = 5-12) hosts. AB - Electronic structure, charge distribution, and vibrational frequencies of cucurbit[n]uril, CB[n] (n = 5-12), hosts have been derived using the density functional methods. CB[n] conformers with different orientations of methylene group connecting glycouril units have been investigated. The conformers that possess uniform CB[n] cavity turn out to be of lowest energy, and molecular electrostatic potential (MESP) herein engender shallow minima near ureido oxygens along the series. MESP topography has been utilized to estimate the cavity height and diameter; the ratio of which governs the shape (circular or elliptical) of the cavity. When this ratio is larger than unity (for CB[n] with n >or= 8), an elliptical host cavity is noticed. Calculated vibrational spectra reveal that carbonyl stretching frequency shift in successive CB[n] homologue decreases steadily from 1760 cm(-1) in CB[5] to 1742 cm(-1) in CB[12]. An increase in glycouril units along the CB[n] series influences significantly the intensity profile of C horizontal lineO and C-N stretching vibrations in the calculated infrared spectra. Furthermore, calculated (1)H chemical shifts predict that one of methylene protons directing outside the host cavity are deshielded, whereas the remaining proton near the carbonyl group exhibits downshifted signal in the NMR spectra. PMID- 20201537 TI - Density functional theory based studies on the nature of Raman and resonance Raman scattering of nerve agent bound to gold and oxide-supported gold clusters: a plausible way of detection. AB - A detailed theoretical investigation has been carried out at the density functional level of theories to investigate the nature of Raman intensities of the -P=O stretching mode of a model nerve agent DFP (diisopropylfluorophosphate) when bound to different gold (Au(8), Au(20)) and oxide-supported gold (MgO...Au(4), CaO...Au(4), TiO(2)...Au(4), Al(2)O(3)...Au(4), M(16)O(16)...Au(8), and [M(16)O(15)...Au(8)](2+), M = Ca, Mg) clusters. All of these clusters and the DFP-bound clusters are fully optimized, and the computed energetics shows that DFP attaches itself weakly to these clusters. The normal Raman spectra calculations on these clusters show that there is substantial enhancement of the P=O stretching mode of DFP compared to the isolated species. This enhancement has been found to be due to the polarization of the -P=O bond of DFP when bound to the clusters. Significant enhancement in intensity has been observed in the case of Au(n)...DFP (n = 8, 20), M(16)O(16)...Au(8)...DFP, and [M(16)O(15)...Au(8)](2+)...DFP (M = Ca, Mg) clusters. The resonance Raman calculations on the Au(n)...DFP (n = 8, 20) reveals that this enhancement could be made quite large and selective, which is a feature that is unique to the nerve agents and could be used as a property for detecting them. PMID- 20201538 TI - Lower-defect graphene oxide nanoribbons from multiwalled carbon nanotubes. AB - An improved method is described for the production of graphene oxide nanoribbons (GONRs) via longitudinal unzipping of multiwalled carbon nanotubes. The method produces GONRs with fewer defects and/or holes on the basal plane, maintains narrow ribbons <100 nm wide, and maximizes the high aspect ratio. Changes in the reaction conditions such as acid content, time, and temperature were investigated. The new, optimized method which introduces a second, weaker acid into the system, improves the selectivity of the oxidative unzipping presumably by in situ protection of the vicinal diols formed on the basal plane of graphene during the oxidation, and thereby prevents their overoxidation and subsequent hole generation. The optimized GONRs exhibit increased electrical conductivity over those chemically reduced nanoribbons produced by previously reported procedures. PMID- 20201539 TI - Efficient photoinduced electron transfer in a porphyrin tripod-fullerene supramolecular complex via pi-pi interactions in nonpolar media. AB - A novel porphyrin tripod (TPZn(3)) was synthesized via "click chemistry". Three porphyrin moieties of TPZn(3) are geometrically close and linked by a flexible linker. The electron-transfer oxidation of TPZn(3) results in intramolecular pi dimer formation between porphyrin moieties as indicated by electrochemical, vis NIR, and ESR measurements. The cyclic voltammogram of TPZn(3) exhibited stepwise one-electron oxidation processes of three porphyrin moieties in the range from 0.58 to 0.73 V (vs SCE in CH(2)Cl(2)). When TPZn(3) was oxidized by tris(2,2' bipyridyl)-ruthenium(III) ([Ru(bpy)(3)](3+)), the oxidized species (TPZn(3))(n+) (0 < n 84%) with Dgui and have the same specificity toward glucose/mannose but had no effect on the fungus. Fluorescence microscopy showed that both Dgui and ConM bind to C. gloeosporioides ungerminated conidia. However, Dgui did not bind to C. gloeosporioides germinated conidia and germ tubes and was not inhibitory to mycelial growth. Because only Dgui inhibited germination of the fungus, C. gloeosporioides conidia might have surface-specific germination targets recognized by Dgui but not by its homologues, ConM and ConA. Therefore, Dgui is a candidate for biotechnological approaches for improving the resistance of various nutritionally and commercially important crops that are affected by C. gloeosporioides. PMID- 20201550 TI - Tumor targeting chitosan nanoparticles for dual-modality optical/MR cancer imaging. AB - We report tumor targeting nanoparticles for optical/MR dual imaging based on self assembled glycol chitosan to be a potential multimodal imaging probe. To develop an optical/MR dual imaging probe, biocompatible and water-soluble glycol chitosan (M(w) = 50 kDa) were chemically modified with 5beta-cholanic acid (CA), resulting in amphiphilic glycol chitosan-5beta-cholanic acid conjugates (GC-CA). For optical imaging near-infrared fluorescence (NIRF) dye, Cy5.5, was conjugated to GC-CA resulting in Cy5-labeled GC-CA conjugates (Cy5.5-GC-CA). Moreover, in order to chelate gadolinium (Gd(III)) in the Cy5.5-GC-CA conjugates, 1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was directly conjugated in Cy5.5-GC-CA. Finally, the excess GdCl(3) was added to DOTA modified Cy5.5-GC-CA conjugates in distilled water (pH 5.5). The freshly prepared Gd(III) encapsulated Cy5.5-GC-CA conjugates were spontaneously self-assembled into stable Cy5.5 labeled and Gd(III) encapsulated chitosan nanoparticles (Cy5.5-CNP-Gd(III)). The Cy5.5-CNP-Gd(III) was spherical in shape and approximately 350 nm in size. From the cellular experiment, it was demonstrated that Cy5.5-CNP-Gd(III) were efficiently taken up and distributed in cytoplasm (NIRF filter; red). When the Cy5.5-GC-Gd(III) were systemically administrated into the tail vein of tumor bearing mice, large amounts of nanoparticles were successfully localized within the tumor, which was confirmed by noninvasive near-infrared fluorescence and MR imaging system simultaneously. These results revealed that the dual-modal imaging probe of Cy5.5-CNP-Gd(III) has the potential to be used as an optical/MR dual imaging agent for cancer treatment. PMID- 20201551 TI - Degradation of rutin and polyphenols during the preparation of tartary buckwheat bread. AB - The impact of bread making and baking procedure on rutin, quercetin and polyphenol concentration and antioxidant activity of tartary buckwheat (Fagopyrum tataricum) bread and breads made of mixtures of tartary buckwheat and wheat flour was studied. A decrease in polyphenol concentration through baking was observed in all samples. The high DPPH (2,2-diphenyl-1-picrylhydrazyl) scavenging capacity in mixed breads (32-56%) and in tartary buckwheat bread (85-90%) decreased slightly through the bread making process, while an increase of antioxidant activity in bread made of 100% wheat flour during bread making was observed. With the addition of water to mixtures containing tartary buckwheat during the preparation of the dough, rutin concentration decreased, while quercetin concentration increased. The rutin concentration continued to decrease during the bread baking process, while the concentration of quercetin remained stable. After baking, rutin (0.47 mg/g) was present only in bread made of 100% tartary buckwheat flour along with quercetin (4.83 mg/g). PMID- 20201552 TI - Functional properties of select edible oilseed proteins. AB - Borate saline buffer (0.1 M, pH 8.45) solubilized proteins from almond, Brazil nut, cashew nut, hazelnut, macadamia, pine nut, pistachio, Spanish peanut, Virginia peanut, and soybean seeds were prepared from the corresponding defatted flour. The yield was in the range from 10.6% (macadamia) to 27.4% (almond). The protein content, on a dry weight basis, of the lyophilized preparations ranged from 69.23% (pine nut) to 94.80% (soybean). Isolated proteins from Brazil nut had the lightest and hazelnut the darkest color. Isolated proteins exhibited good solubility in aqueous media. Foaming capacity (<40% overrun) and stability (<1 h) of the isolated proteins were poor to fair. Almond proteins had the highest viscosity among the tested proteins. Oil-holding capacity of the isolated proteins ranged from 2.8 (macadamia) to 7 (soybean) g of oil/g of protein. Least gelation concentrations (% w/v) for almond, Brazil nut, cashew, hazelnut, macadamia, pine nut, pistachio, Spanish peanut, Virginia peanut, and soybean were, respectively, 6, 8, 8, 12, 20, 12, 10, 14, 14, and 16. PMID- 20201553 TI - Widespread occurrence of the mycotoxin fumonisin b(2) in wine. AB - Fumonisins are important mycotoxins because they are suspected to cause human and animal toxicoses by the consumption of contaminated corn-based food and feeds. However, with the discovery of fumonisin production in grapes by Aspergillus niger , wine may also be a fumonisin-containing commodity. In the present study, we have developed a simple and quantitative cation-exchange-based purification method for the subsequent isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) determination of fumonisins in wine. A comparative study of seven different solid-phase extraction (SPE) columns showed that polymeric mixed-mode reversed-phase (RP) cation-exchange columns were superior to classic silica-based cation and mixed-mode cation-exchange columns. A total of 77 wine samples from 13 countries were subsequently tested, and surprisingly, 18 (23%) were found to contain fumonisin B(2) in the range of 1-25 microg/L. These findings were further confirmed by immunoaffinity purification and re-analysis of the positive cation-exchanged extracts. PMID- 20201554 TI - Dietary black raspberry anthocyanins do not alter development of obesity in mice fed an obesogenic high-fat diet. AB - Anthocyanins (ACNs) from various foods have been shown to minimize the development of obesity in some animal models. The objective of the current study was to compare the effects of feeding purified black raspberry (BRB) ACNs or the freeze-dried whole BRB on the development of obesity. Male C57BL/6J mice (25 days of age) were assigned at random to treatments (7/treatment; 3/cage). The treatments included (1) control low-fat diet (10% calories from fat) (LF); (2) LF plus BRB juice in place of drinking water; (3) LF diet plus purified BRB ACNs in drinking water (1.25 mg/mL); (4) control high-fat diet (60% calories from fat) (HF60); (5) HF60 diet + BRB juice in place of drinking water; (6) HF60 diet + ACNs in drinking water (1.25 mg/mL); and (7) HF60 + freeze-dried whole BRB powder (21.7 g/kg of diet). Body weight gains in mice fed HF60 diet plus purified BRB ACNs tended to be lower after 56, 63, and 70 days than in mice fed HF60 alone. Body weights were increased at time of sacrifice, but heart, liver, and kidney weights as a percentage of body weight were decreased in mice fed HF60 diet compared to LF fed mice. Weights (g or g/body weight) of epididymal and retroperitoneal fat were increased in the HF60 fed mice compared to LF fed mice. Fasting serum glucose, leptin, and insulin levels as well as homeostasis assessment of insulin resistance (HOMA-IR) were elevated in mice fed the HF60 diet relative to LF-fed controls. Serum cholesterol, triglycerides, and monocyte chemoattractant protein-1 (MCP-1) were not altered by diet. Serum levels of resistin were increased in mice fed the HF60 diet compared to mice fed the LF diet. None of the responses measured were altered by whole BRB powder included in the diet relative to the HF60 control diet. Cyanidin containing di- or triglycosides in BRB was ineffective in altering the development of obesity in contrast to cyanidin-monoglycosides, which have been shown to be effective. The sugar moiety on the anthocyanidins may be an important factor in determining the response in the development of obesity. PMID- 20201555 TI - Nanoparticle-mediated cytoplasmic delivery of proteins to target cellular machinery. AB - Despite recent advances in nanomaterial-based delivery systems, their applicability as carriers of cargo, especially proteins for targeting cellular components and manipulating cell function, is not well-understood. Herein, we demonstrate the ability of hydrophobic silica nanoparticles to deliver proteins, including enzymes and antibodies, to a diverse set of mammalian cells, including human cancer cells and rat stem cells, while preserving the activity of the biomolecule post-delivery. Specifically, we have explored the delivery and cytosolic activity of hydrophobically functionalized silica nanoparticle-protein conjugates in a human breast cancer cell line (MCF-7) and rat neural stem cells (NSCs) and elucidated the mechanism of cytosolic transport. Importantly, the proteins were delivered to the cytosol without extended entrapment in the endosomes, which facilitated the retention of biological activity of the delivered proteins. As a result, delivery of ribonuclease A (RNase A) and the antibody to phospho-Akt (pAkt) resulted in the initiation of cell death. Delivery of control protein conjugates (e.g., those containing green fluorescent protein or goat antirabbit IgG) resulted in minimal cell death, indicating that the carrier-mediated toxicity was low. The results presented here provide insight into the design of nanomaterials as protein carriers that enable control of cell function. PMID- 20201556 TI - Sulfonamide linked neoglycoconjugates--a new class of inhibitors for cancer associated carbonic anhydrases. AB - The contribution of membrane-bound carbonic anhydrases (CAs) to hypoxic tumor growth and progression in cancer implicates cancer-associated CAs as a promising drug target for oncology. In this paper, we present a new class of sulfonamide linked neoglycoconjugate that was designed to selectively target and inhibit the extracellular domains of the cancer-relevant CA isozymes. We describe the application of novel, yet straightforward, chemistry toward the synthesis of inhibitors that comprise both S-glycosyl sulfenamides and S-glycosyl sulfonamides. We also present the CA inhibition profile of our new neoglycoconjugates, more specifically a library of 30 compounds (3-32) that were designed to optimize both SAR (structure-activity relationship) and SPR (structure-property relationship) characteristics. We show that our approach produces neutral, water-soluble, and potent inhibitors (K(i)s in the low nanomolar range) that target cancer-associated CAs. PMID- 20201557 TI - Competitive adsorption of naphthalene with 2,4-dichlorophenol and 4-chloroaniline on multiwalled carbon nanotubes. AB - Competitive adsorption between nonpolar organic compounds and polar ionic organic compounds (IOCs) on carbon nanotubes (CNTs) is essential for application of CNTs as superior sorbents and for environmental risk assessment of both CNTs and organic contaminants. It was observed in this study that adsorption of neutral and dissociated species of polar 2,4-dichlorophenol (DCP) and 4-chloroaniline (PCAN) on a multiwalled CNT sample (MWCNT15) can be suppressed by nonpolar naphthalene. Naphthalene adsorption can also be suppressed by neutral DCP/PCAN, but not dissociated DCP/PCAN. Moreover, competition of naphthalene decreased the adsorption affinity of neutral DCP/PCAN, but not their adsorption capacity because of the formation of solute bilayer on MWCNT15. For dissociated DCP/PCAN, naphthalene not only decreased their adsorption affinity but also their adsorption capacity because no solute bilayer was formed. Neutral DCP/PCAN also decreased the adsorption affinity and adsorption capacity of naphthalene. These observations indicate that competitive adsorption of naphthalene with DCP/PCAN depends on the dissociation of DCP/PCAN, as interpreted by (i) the different sites on CNTs for adsorption of organic chemicals (i.e., naphthalene, and the neutral and dissociated species of DCP/PCAN), (ii) the interactions between organic chemicals, and (iii) the interactions of organic chemicals with CNT surface. PMID- 20201558 TI - Chemical vapor deposition synthesis of N-, P-, and Si-doped single-walled carbon nanotubes. AB - Here we report the synthesis of single-walled carbon nanotube bundles by chemical vapor deposition in the presence of electron donor elements (N, P, and Si). In order to introduce each dopant into the graphitic carbon lattice, different precursors containing the doping elements (benzylamine, pyrazine, triphenylphosphine, and methoxytrimethylsilane) were added at various concentrations into ethanol/ferrocene solutions. The synthesized nanotubes and byproduct were characterized by electron microscopy and Raman spectroscopy. Our results reveal intrinsic structural and electronic differences for the N-, P-, and Si- doped nanotubes. These tubes can now be tested for the fabrication of electronic nanodevices, and their performance can be observed. PMID- 20201559 TI - Contribution of extracellular polymeric substances on representative gram negative and gram positive bacterial deposition in porous media. AB - The significance of extracellular polymeric substances (EPS) on cell transport and retained bacteria profiles in packed porous media (quartz sand) was examined by direct comparison of the overall deposition kinetics and retained profiles of untreated bacteria (with EPS) versus those of treated cells (without EPS) from the same cell type. Four representative cell types, Pseudomonas sp. QG6 (gram negative, motile), mutant Escherichia coli BL21 (gram-negative, nonmotile), Bacillus subtilis (gram-positive, motile), and Rhodococcus sp. QL2 (gram positive, nonmotile), were employed to systematically determine the influence of EPS on cell transport and deposition behavior. Packed column experiments were conducted for the untreated and treated cells in both NaCl (four ionic strength ranging from 2.5 mM to 20 mM) and CaCl(2) (5 mM) solutions at pH 6.0. The breakthrough plateaus of untreated bacteria were lower than those of treated bacteria for all four cell types under all examined conditions (in both NaCl and CaCl(2) solutions), indicating that the presence of EPS on cell surfaces enhanced cell deposition in porous media regardless of cell type and motility. Retained profiles of both untreated and treated cells for all four cell types deviated from classic filtration theory (log-linear decreases). However, the degree of deviation was greater for all four untreated cells, indicating that the presence of EPS on cell surfaces increased the deviation of retained profiles from classic filtration theory. Elution experiments demonstrated that neither untreated nor treated cells preferentially deposited in secondary energy minima. Furthermore, the release of previously deposited cells in the secondary energy minima did not change the shape of retained cell profiles, indicating that deposition in secondary energy minima did not produce the observed deviations of retained profiles from classic filtration theory. PMID- 20201560 TI - Ultrasonic-assisted nanodimensional self-assembly of poly-3-hexylthiophene for organic photovoltaic cells. AB - We have demonstrated ultrasonic-assisted nanodimensional self-assembly of a conjugated polymer, P3HT, depending on its regioregularity, on solvent polarity, and on light irradiation. The resulting P3HT nanowires were investigated by means of AFM, UV-vis, and XRD and compared with films made by a conventional thermal annealing method. Obtained results indicate that ultrasonic agitation effectively generates P3HT nanowires, exemplifying a quick route to nanoscale morphology control which contributes to better organic photovoltaic cell performance. PMID- 20201561 TI - Efficient, enantioselective iminium catalysis with an immobilized, recyclable diarylprolinol silyl ether catalyst. AB - A highly efficient approach for the synthesis, application, and recycling of immobilized diarylprolinol silyl ethers was developed. The MeOPEG-supported Jorgensen-Hayashi catalyst provides unchanged reactivity and selectivity as compared to the homogeneous catalyst, as demonstrated for the Michael addition of nitromethane to alpha,beta-unsaturated aldehydes via iminium activation. In addition, the immobilization allows for a simple, column-free isolation of pure, sensitive aldehyde products and therefore may be useful for application in more complicated syntheses. PMID- 20201562 TI - Identification of novel interacting protein partners of SMN using tandem affinity purification. AB - Mutations in the survival motor neuron (SMN) gene cause spinal muscular atrophy (SMA), a neuromuscular disease associated with muscle weakness that progresses to paralysis, respiratory distress, and ultimately death. Both neurons and muscle are severely affected in this disease. Tandem affinity purification (TAP) has emerged as a useful tool for studying protein complexes in vitro. We have used this purification system to discover novel SMN interacting partners in C2C12 muscle and PC12 neuronal cells. To do so, we fused a TAP-tag, consisting of a HIS hexamer and FLAG epitope separated by the tobacco etch virus (TEV) protease cleavage site, to either the N- or C-terminal region of SMN. Interestingly, the profile of SMN interacting proteins varies depending on the cell type and stage. We have identified a number of novel SMN interacting proteins in both C2C12 and PC12 cells, and from among these we have validated Annexin II and myosin regulatory light chain (MRLC). The discovery of these proteins will lead to a better understanding of the mechanisms underlying the pathophysiology of SMA. PMID- 20201563 TI - Role of surface cobalt silicate in single-walled carbon nanotube synthesis from silica-supported cobalt catalysts. AB - A silica-supported cobalt catalyst has been developed via incipient wetness impregnation for high-yield synthesis of single-walled carbon nanotubes (SWNTs). Co/SiO2-impregnated catalysts have not been observed to be efficient for SWNT synthesis. Using an appropriately chosen precursor, we show that effective catalysts can be obtained for SWNT synthesis with yields up to 75 wt %. Detailed characterization indicates that the active sites for SWNT synthesis are small cobalt particles resulting from the reduction of a highly dispersed surface cobalt silicate species. The SWNTs produced by this catalyst are of high quality and easy to purify, and the process is simple and scalable. PMID- 20201564 TI - Catalytic asymmetric conjugate addition of alpha-cyanoketones for the construction of a quaternary stereogenic center. AB - The catalytic asymmetric conjugate addition of alpha-cyanoketone pronucleophiles to vinyl ketones promoted by a Y/1 catalyst is described. High enantioselectivity was observed for a range of aromatic vinyl ketones, providing 1,5-dicarbonyl compounds bearing an all-carbon quaternary stereogenic center. The product was successfully converted to a spiro-piperidine entity and a bicyclo[3.3.0]octane framework through either the reduction of nitrile or intramolecular pinacol coupling. PMID- 20201566 TI - Single-file diffusion of confined water inside SWNTs: an NMR study. AB - We report a nuclear magnetic resonance (NMR) study of confined water inside approximately 1.4 nm diameter single-walled carbon nanotubes (SWNTs). We show that the confined water does not freeze even up to 223 K. A pulse field gradient (PFG) NMR method is used to determine the mean squared displacement (MSD) of the water molecules inside the nanotubes at temperatures below 273 K, where the bulk water outside the nanotubes freezes and hence does not contribute to the proton NMR signal. We show that the mean squared displacement varies as the square root of time, predicted for single-file diffusion in a one-dimensional channel. We propose a qualitative understanding of our results based on available molecular dynamics simulations. PMID- 20201565 TI - Coordination modes of multidentate ligands in fac [Re(CO)(3)(polyaminocarboxylate)] analogues of (99m)Tc radiopharmaceuticals. dependence on aqueous solution reaction conditions. AB - We study Re analogues of (99m)Tc renal agents to interpret previous results at the (99m)Tc tracer level. The relative propensities of amine donors versus carboxylate oxygen donors of four L = polyaminocarboxylate ligands to coordinate in fac-[Re(I)(CO)(3)L](n) complexes were assessed by examining the reaction of fac-[Re(I)(CO)(3)(H(2)O)(3)](+) under conditions differing in acidity and temperature. All four L [N,N-bis-(2-aminoethyl)glycine (DTGH), N,N ethylenediaminediacetic acid, diethylenetriamine-N-malonic acid, and diethylenetriamine-N-acetic acid] can coordinate as tridentate ligands while creating a dangling chain terminated in a carboxyl group. Dangling carboxyl groups facilitate renal clearance in fac-[(99m)Tc(I)(CO)(3)L](n) agents. Under neutral conditions, the four ligands each gave two fac-[Re(I)(CO)(3)L](n) products with HPLC traces correlating well with known traces of the fac [(99m)Tc(I)(CO)(3)L](n) mixtures. Such mixtures are common in renal agents because the needed dangling carboxyl group can compete for a coordination site. However, the HPLC separations needed to assess the biodistribution of a single tracer are impractical in a clinical setting. One goal in investigating this Re chemistry is to identify conditions for avoiding this problem of mixtures in preparations of fac-[(99m)Tc(I)(CO)(3)L](n) renal tracers. After separation and isolation of the fac-[Re(I)(CO)(3)L](n) products, NMR analysis of all products and single crystal X-ray crystallographic analysis of both DTGH products, as well as one product each from the other L, allowed us to establish coordination mode unambiguously. The product favored in acidic conditions has a dangling amine chain and more bound oxygen. The product favored in basic conditions has a dangling carboxyl chain and more bound nitrogen. At the elevated temperatures used for simulating tracer preparation, equilibration was facile (ca. 1 h or less), allowing selective formation of one product by utilizing acidic or basic conditions. The results of this fundamental study offer protocols and guidance useful for the design and preparation of fac-[(99m)Tc(I)(CO)(3)L](n) agents consisting of a single tracer. PMID- 20201567 TI - Bioinspired silica surfaces with near-infrared improved transmittance and superhydrophobicity by colloidal lithography. AB - In this paper, we report a kind of bioinspired high performance near-infrared improved transmittance silica surfaces with superhydrophobic properties by colloidal lithography, with transmittance about 99% from 1300 to 2000 nm. Meanwhile, the optical properties of such surfaces can be controlled by the antireflective structure morphologies resulting from the different reactive ion etching conditions. Using proper microspheres as mask, the high-performance near infrared telecommunication optics can be achieved. Besides, the antireflective surfaces possess superhydrophobic properties after modified by fluorosilane. Such antireflective surfaces are promising for fabrication of highly light transmissive, antireflective, and superhydrophobic near-infrared optical materials to be used in many important fields. PMID- 20201568 TI - Adsorption in periodically ordered mesoporous organosilica materials studied by in situ small-angle X-ray scattering and small-angle neutron scattering. AB - Modified periodically ordered mesoporous organosilica materials were prepared starting from a recently introduced type of sol-gel precursor, containing both organic moieties and hydrolyzable Si-OR groups. In order to thoroughly characterize the mesoporosity and its accessibility, different probe gases were used in conventional gas adsorption experiments. Furthermore, in situ small-angle X-ray scattering (SAXS) and small-angle neutron scattering (SANS) were applied to study the mesoporosity and the sorption processes, taking advantage of scattering contrast matching conditions. Thereby, the materials were characterized not only by different probe molecules but also at different temperatures (nitrogen at 77 K, dibromomethane at 290 K and perfluoropentane at 276 K). The comparison between the standard and in situ SAXS/SANS adsorption experiments revealed valuable information about the porosity and microstructure of the materials. It is demonstrated that the organic moieties are homogeneously distributed; that is, they do not phase-separate from silica on the nanometer scale. PMID- 20201569 TI - "Zero-length" dimers of ribonuclease A: further characterization and no evidence of cytotoxicity. AB - "Zero-length" dimers of ribonuclease A, a novel type of dimers formed by two RNase A molecules bound to each other through a zero-length amide bond [Simons, B. L., et al. (2007) Proteins 66, 183-195], were further characterized and tested for their possible in vitro cytotoxic activity. Results obtained are the following. Besides dimers, also trimers and higher oligomers could be identified among the products of the covalently linking reaction, and the "zero-length" dimers prepared by us appear not to be a unique species. The product was indeed heterogeneous, and results obtained with two RNase A mutants, E9A and K66A, indicated that amino and carboxyl groups others than those belonging to Lys66 and Glu9 are involved in the amide bond. As for their functional properties, the "zero-length" dimers degrade poly(A).poly(U) (dsRNA) with an activity that increases with the increase of the oligomer's basicity and yeast RNA (ssRNA) with an activity that instead decreases with the increase of oligomer's basicity, which is in agreement with previous data. No cytotoxicity of the RNase A "zero length" dimers could be evidenced in assays performed with various tumor cells lines; the dimers, instead, become cytotoxic if cationized by conjugation with polyethylenimine (PEI) [Futami et al. (2005) J. Biosci. Bioengin. 99, 95-103]. However, PEI derivatives of RNase A "zero-length" dimers and PEI derivatives of native RNase A resulted to be equally cytotoxic. In other words, protein "dimericity" does not play any role in this case. Moreover, the acquired cytotoxicity does not seem to be specific for tumor cells: PEI-cationized native RNase A was also cytotoxic toward human monocytes. PMID- 20201570 TI - Enzyme catalysis in an aqueous/organic segment flow microreactor: ways to stabilize enzyme activity. AB - Multiphase flow microreactors benefit from rapid mixing and high mass transfer rates, yet their application in enzymatic catalysis is limited due to the fast inactivation of enzymes used as biocatalysts. Enzyme inactivation during segment flow is due to the large interfacial area between aqueous and organic phases. The Peclet number of the system points to strong convective forces within the segments, and this results in rapid deactivation of the enzyme depending on segment length and flow rate. Addition of surfactant to the aqueous phase or enzyme immobilization prevents the biocatalyst from direct contact with the interface and thus stabilizes the enzyme activity. Almost 100% enzyme activity can be recovered compared to 45% without any enzyme or medium modification. Drop tensiometry measurements point to a mixed enzyme-surfactant interfacial adsorption, and above a certain concentration, the surfactant forms a protective layer between the interface and the biocatalyst in the aqueous compartments. Theoretical models were used to compare adsorption kinetics of the protein to the interface in the segment flow microreactor and in the drop tensiometry measurements. This study is the basis for the development of segment flow microreactors as a tool to perform productive enzymatic catalysis. PMID- 20201571 TI - Improvement of (31)P NMR spectral resolution by 8-hydroxyquinoline precipitation of paramagnetic Fe and Mn in environmental samples. AB - Solution (31)P nuclear magnetic resonance (NMR) spectroscopy is currently the main method for the characterization of phosphorus (P) forms in environment samples. However, identification and quantification of P compounds may be hampered by poor resolution of spectra caused by paramagnetic Fe and Mn. In this study, a novel technique was developed to improve spectral resolution by removing paramagnetic Fe and Mn from alkaline extracts via 8-hydroxyquinoline (8-HOQ) precipitation. Batch experiments showed that both Fe and Mn were effectively removed by the precipitation at pH 9.0, with the removal efficiencies of 83-91% for Fe and 67-78% for Mn from the extracts of five different environmental samples, while little effect was found on concentration of total P. The (31)P NMR analysis of a model P solution showed that addition of 8-HOQ and its precipitation with metal ions did not alter P forms. Further analyses of the five extracts with (31)P NMR spectroscopy demonstrated that the 8-HOQ precipitation was an ideal method compared with the present postextraction techniques, such as bicarbonate dithionate (BD), EDTA and Chelex-100 treatments, by improving spectral resolution to a large extent with no detrimental effects on P forms. PMID- 20201572 TI - Addition-elimination reactions across the M-C bond of metal N-heterocyclic carbenes. AB - Silyl, phosphinyl, stannyl, and boryl reagents can be added across the neutral metal-carbon dative bond in d(0) f-block metal N-heterocyclic carbene complexes in a reversible manner, allowing additional functional groups to be incorporated into redox-inactive organo-f-block compounds. PMID- 20201573 TI - Expanding the chemistry of DNA for in vitro selection. AB - Six new 5-position modified dUTP derivatives connected by a unique amide linkage were synthesized and tested for compatibility with the enzymatic steps of in vitro selection. Six commercially available DNA polymerases were tested for their ability to efficiently incorporate each of these dUTP derivatives during PCR. It was not possible to perform PCR under standard conditions using any of the modified dUTP derivatives studied. In contrast, primer extension reactions of random templates, as well as defined sequence templates, were successful. KOD XL and D. Vent DNA polymerases were found to be the most efficient at synthesizing full-length primer extension product, with all of the dUTP derivatives tested giving yields similar to those obtained with TTP. Several of these modified dUTPs were then used in an in vitro selection experiment comparing the use of modified dUTP derivatives with TTP for selecting aptamers to a protein target (necrosis factor receptor superfamily member 9, TNFRSF9) that had previously been found to be refractory to in vitro selection using DNA. Remarkably, selections employing modified DNA libraries resulted in the first successful isolation of DNA aptamers able to bind TNFRSF9 with high affinity. PMID- 20201575 TI - Crystallization control of thermal stability and morphology of hen egg white lysozyme crystals by ionic liquids. AB - Ionic liquids (ILs) exhibit a variety of properties that make them attractive additives for biomaterials. 1-Butyl-3-methylimidazolium tetrafluoroborate ([C(4)mim]BF(4)), 1-butyl-3-methylimidazolium chloride ([C(4)mim]Cl), 1-butyl-3 methylimidazolium bromide ([C(4)mim]Br), and 1,3-dimethylimidazolium iodine([bmim]I), as additives during lysozyme crystallization, were tested for their effects on the thermal stability and morphology of lysozyme crystals obtained. [C(4)mim]Cl was chosen to evaluate the effect of IL addition concentration on the thermal stability of lysozyme. It is shown that the characteristic peak temperature and endothermic enthalpy values (DeltaH) for denaturation increase with increasing addition concentration. As for the degradation, peak temperatures decrease, whereas endothermic enthalpy values markedly increase with the rise of [C(4)mim]Cl addition concentration. In the case of adding [C(4)mim]BF(4), [C(4)mim]Br, and [bmim]I, similar thermal behaviors of lysozyme crystals were observed. The effect of ILs on thermal behaviors of lysozyme can be attributed to enhancing crystal contacts, changing conformational stability, or interaction among molecules, as evidenced by difference in crystal growth morphology. This study is especially helpful in controlling the thermal stability of lysozyme crystals and in gaining initial insight into potential crystallization conditions for prescreening ILs that stabilize the protein and other macromolecule crystals. PMID- 20201574 TI - Fluorophore labeling of the glycine-rich loop as a method of identifying inhibitors that bind to active and inactive kinase conformations. AB - Targeting protein kinases with small organic molecules is a promising strategy to regulate unwanted kinase activity in both chemical biology and medicinal chemistry research. Traditionally, kinase inhibitors are identified in activity based screening assays using enzymatically active kinase preparations to measure the perturbation of substrate phosphorylation, often resulting in the enrichment of classical ATP competitive (Type I) inhibitors. However, addressing enzymatically incompetent kinase conformations offers new opportunities for targeted therapies and is moving to the forefront of kinase inhibitor research. Here we report the development of a new FLiK (Fluorescent Labels in Kinases) binding assay to detect small molecules that induce changes in the conformation of the glycine-rich loop. Due to cross-talk between the glycine-rich loop and the activation loop in kinases, this alternative labeling approach can also detect ligands that stabilize inactive kinase conformations, including slow-binding Type II and Type III kinase inhibitors. Protein X-ray crystallography validated the assay results and identified a novel DFG-out binding mode for a quinazoline-based inhibitor in p38alpha kinase. We also detected the high-affinity binding of a clinically relevant and specific VEGFR2 inhibitor, and we provide structural details of its binding mode in p38alpha, in which it stabilizes the DFG-out conformation. Last, we demonstrate the power of this new FLiK labeling strategy to detect the binding of Type I ligands that induce conformational changes in the glycine-rich loop as a means of gaining affinity for the target kinase. This approach may be a useful alternative to develop direct binding assays for kinases that do not adopt the DFG-out conformation while also avoiding the use of expensive kits, detection reagents, or radioactivity frequently employed with activity-based assays. PMID- 20201576 TI - Surfactant-synthesized ormosils with application to stone restoration. AB - A challenging objective in monumental stone restoration is to synthesize crack free silica materials for application as consolidants. Hydrophobicity is also a valuable property for such products; it is important to prevent the penetration of water because water is the main vehicle by which the agents of decay enter the pore structure of the stone. We report the development of a hydrophobic crack free nanomaterial with application to stone restoration. Specifically, organically modified silicate (ormosil) has been synthesized by the co condensation of tetraethoxysilane (TEOS) and hydroxyl-terminated polydimethylsiloxane (PDMS) in the presence of a nonionic surfactant (n octylamine). The role played by the surfactant in the assembly of the organic inorganic hybrid silica gel was investigated. We also prepared a crack-free material using the same synthesis but without adding PDMS to the starting sol. Finally, the effectiveness of the nanomaterials synthesized as a consolidant and hydrophobic protective treatment was evaluated on a particular widely used monumental stone. The high hydrophobicity of the organic-inorganic hybrid product synthesized in our laboratory is discussed as a function of the surface roughness of the material. PMID- 20201577 TI - Interpolyelectrolyte complexation in chloroform. AB - Interpolyelectrolyte complexes (IPECs) were formed in chloroform from complementary polyelectrolyte-surfactant complexes (PESCs), i.e., linear polyelectrolytes whose counterions were substituted by surfactants to dissolve them in the low-polarity organic solvent. The interaction between such complementary PESCs was followed by turbidimetry, (1)H NMR, and dynamic light scattering. The experimental results, together with those from transmission electron microscopy and scanning force microscopy, provide evidence on the formation IPECs in the system. This process is apparently driven by the entropically favorable release of the pairs of the oppositely charged surfactant ions. If the mixing base-molar ratio between the complementary PESCs, Z, is below a certain threshold value, their chloroform mixtures are colloidally stable, containing relatively large aggregates. These aggregates are attributed to particles of the formed IPECs stabilized by the fragments of the excess polymeric component. Otherwise, the mixtures of the PESCs undergo phase separation (most pronounced at Z = 1) with the formation of an insoluble top phase (attributed to insoluble IPEC) and a clear bottom phase enriched with the surfactant counterions. Electron and scanning force micrographs indicate a rather broad size distribution of the soluble macromolecular coassemblies with a close to spherical shape. PMID- 20201578 TI - Fabrication of centimeter-sized single-domain two-dimensional colloidal crystals in a wedge-shaped cell under capillary forces. AB - Self-assembly of colloidal spheres confined within cells of different shapes formed with two slides under capillary forces are studied. It is found that by controlling the shape of the cell the curvature of the drying front can result in a significant effect on the self-organization process. A curved drying front formed within parallel slides is always associated with growth of colloidal crystal structures with a high density of disorder. We demonstrate that single domain two-dimensional colloidal crystals with centimeter size can be grown under capillary forces under a straight drying front formed in a wedge-shaped cell. These findings are demonstrated by laser diffraction, microscopy imaging methods and off-normal optical transmission measurements. The present growth method should be of importance in expanding colloidal crystal applications in angle resolved nanosphere lithography, as well as in preparation of high-quality quasi three-dimensional plasmonic crystals. PMID- 20201579 TI - Conformational flexibility of c8-phenoxyl-2'-deoxyguanosine nucleotide adducts. AB - Previous computational work suggests that isolated C8-phenoxyl-2'-deoxyguanosine nucleoside adducts preferentially adopt a syn orientation about the glycosidic bond, which is the first step in the mechanism by which many bulky C8 adducts exert their mutagenic effects. Since it is not clear whether these results can be directly extrapolated to the preferred conformation in DNA helices, approaches that more accurately reflect the physiological environment were used in the present study to understand the anti/syn preference of the ortho and para C8 phenoxyl-2'-deoxyguanosine adducts. Using nucleoside models and methods (B3LYP) similar to those previously implemented, we determine that the syn conformer is less stable than previously predicted when geometries relevant to B-DNA are considered. This indicates that the conformational energy trend is model dependent and stresses the importance of considering models that better mimic the DNA environment when determining the conformational preference of damaged bases. Therefore, we expanded our computational model to include the 5'-monophosphate group. Since the correct anti/syn energy trend for 2'-deoxyguanosine (dG) 5' monophosphate has only been found using very specific computational models and prior knowledge of the biologically relevant nucleotide conformation, which is unavailable for most damaged systems, we initially benchmark our computational approach by studying the natural nucleotide. Despite the wide use of gas-phase optimizations in the current literature, only through the implementation of solvation-phase optimizations, as well as the use of a counterion model for the phosphate backbone, is the correct anti/syn energy trend predicted. Indeed, this is the first time in the literature that a biologically relevant syn structure is characterized for dG using methods suitable for studying bulky DNA adducts. Subsequently, our newly identified approach for DNA lesions was used to study C8 phenoxyl DNA adducts. In contrast to previously published results, we predict that the ortho and para adducts may adopt both the anti and syn conformations in DNA helices. These results have implications for the base-pairing properties and mutagenicity of these adducts, which must be further considered in future work. PMID- 20201580 TI - Ascorbate-assisted growth of hierarchical ZnO nanostructures: sphere, spindle, and flower and their catalytic properties. AB - A simple solution-based method to prepare mainly flowerlike zinc oxide (ZnO) nanostructures using the ascorbate ion as a shape-directing/capping agent at relatively low temperature (ca. 30 and 60 degrees C) was described. However, we observed that different shapes of hierarchical ZnO nanostructures such as flowerlike, spindlelike, and spherical could be obtained with an increase in the synthesis temperature from 60 to 90 degrees C. The effects of other organic capping agents on the shape of hierarchical ZnO nanostructures were also studied. FTIR, FESEM, and XRD characterization were performed on the formed ZnO nanostructures to understand the role of ascorbate in the growth of flowerlike morphology. The nucleation and growth process can regulate by changing the metal precursor and ascorbate ion concentrations. We were able to identify intermediate nanostructures such as spherical/quasi-spherical and spindle that are very much on the pathway of formation of large, flowerlike ZnO nanostructures. Electron microscopy results indicated that these spherical/quasi-spherical ZnO nanoparticles might aggregate through oriented attachment to produce spindlelike and flowerlike nanostructures. On the basis of these results, a possible growth mechanism for the formation of flowerlike ZnO nanostructures was described. The optical properties of these differently shaped ZnO nanostructures were also described. The catalytic activities of the as-synthesized spherical and flowerlike ZnO nanostructures were tested in the Friedel-Crafts acylation reaction of anthracene with benzoyl chloride. The catalysis results indicated that the catalytic activity of flowerlike ZnO nanostructures is slightly higher than the spherical counterpart. PMID- 20201581 TI - Adsorbents with high selectivity for uremic middle molecular peptides containing the Asp-Phe-Leu-Ala-Glu sequence. AB - Asp-Phe-Leu-Ala-Glu (DE5) is a frequent sequence of many toxic middle molecular peptides that accumulate in uremic patients. To eliminate these peptides by hemoperfusion, three adsorbents (CP1-Zn(2+), CP2-Zn(2+), and CP3-Zn(2+)) were designed on the basis of coordination and hydrophobic interactions. Adsorption experiments indicated that CP2-Zn(2+) had the highest affinity for DE5 among these three adsorbents. Also, the adsorption capacity of CP2-Zn(2+) in DE5 and DE5-containing peptides was about 2-6 times higher than that of peptides without the DE5 sequence. Linear polymers bearing the same functional groups of the adsorbents were used as models to study the adsorption mechanism via isothermal titration calorimetry (ITC) and computer-aided analyses. The results indicated that coordination and hydrophobic interactions played the most important roles in their affinity. When two carboxyl moieties on Asp and Glu residues coordinated to CP2-Zn(2+), the hydrophobic interaction took place by the aggregation of the hydrophobic amino acid residues with phenyl group on CP2-Zn(2+). The optimal collaboration of these interactions led to the tight binding and selective adsorption of DE5-containing peptides onto CP2-Zn(2+). These results may provide new insight into the design of affinity adsorbents for peptides containing DE5 like sequences. PMID- 20201582 TI - Axle length effect on photoinduced electron transfer in triad rotaxane with porphyrin, [60]fullerene, and triphenylamine. AB - Photoinduced multiple electron-transfer processes of a newly synthesized rotaxane with one acceptor and two donors are studied with the time-resolved fluorescence and absorption methods. In this rotaxane, zinc porphyrin (ZnP) with a crown-ether necklace is employed as a photosensitized electron donor; through the crown ether, a short axle with C(60) and triphenylamine (TPA) at both terminals is penetrating as an electron acceptor and a hole-shift, respectively (abbreviated as (ZnP;C(60)-(A(S))-TPA)(Rot)). The time-resolved fluorescence and transient absorption measurements reveal that the through-space electron-transfer processes take place via the excited states of the ZnP unit to the spatially arranged C(60) moiety, giving the radical ion pair (ZnP(*+);C(60)(*-)-(A(S))-TPA)(Rot) in polar solvents. Consecutively, (ZnP;C(60)(*-)-(A(S))-TPA(*+))(Rot) is also generated by the through-space hole-shift between ZnP and TPA, in addition to the through-bond charge separation via the excited state of the C(60) moiety. Both radial ion pairs have lifetimes of 320-420 ns, which are longer than those of the previously reported similar rotaxane with cationic longer axle (150-170 ns). PMID- 20201583 TI - Structures and heats of formation of simple alkali metal compounds: hydrides, chlorides, fluorides, hydroxides, and oxides for Li, Na, and K. AB - Geometry parameters, frequencies, heats of formation, and bond dissociation energies are predicted for simple alkali metal compounds (hydrides, chlorides, fluorides, hydroxides and oxides) of Li, Na, and K from coupled cluster theory [CCSD(T)] calculations including core-valence correlation with the aug-cc-pwCVnZ basis set (n = D, T, Q, and 5). To accurately calculate the heats of formation, the following additional correction were included: scalar relativistic effects, atomic spin-orbit effects, and vibrational zero-point energies. For calibration purposes, the properties of some of the lithium compounds were predicted with iterative triple and quadruple excitations via CCSDT and CCSDTQ. The calculated geometry parameters, frequencies, heats of formation, and bond dissociation energies were compared with all available experimental measurements and are in excellent agreement with high-quality experimental data. High-level calculations are required to correctly predict that K(2)O is linear and that the ground state of KO is (2)Sigma(+), not (2)Pi, as in LiO and NaO. This reliable and consistent set of calculated thermodynamic data is appropriate for use in combustion and atmospheric simulations. PMID- 20201584 TI - Molecular dynamics and DFT study on HIV-1 nucleocapsid protein-7 in complex with viral genome. AB - The HIV-1 nucleocapsid protein-7 (NCp7) is a highly basic, small zinc-binding protein involved in both deoxyribonucleic (DNA) and ribonucleic (RNA) acids annealing and in viral particle maturation including genome encapsidation, with an additional chaperoning activity toward reverse transcriptase by promoting the two obligatory strand transfers during reverse transcription. Because of its interaction with highly conserved sequences of the HIV-1 genome, NCp7 is being considered a new potential drug target, resistant to mutation, for antiviral activity. The high flexibility of this protein has, however, limited the identification of structural determinants involved in the interaction with stranded sequences of DNA and RNA. Here, we provide a quantum mechanics (density functional theory) study of the zinc-binding motifs and a molecular dynamics simulation of the protein in complex with RNA and DNA, starting from available nuclear magnetic resonance (NMR) structures. Results show that the interaction between the NCp7 and the viral genome is probably based on electrostatic interactions due to a cluster of basic residues, which is reinforced by the exploitation of nonelectrostatic contacts that further stabilize the complexes. Moreover, a possible mechanism for DNA destabilization that involves amino acids T24 and R26 is also hypothesized. Finally, a network of hydrophobic and hydrogen bond interactions for the stabilization of complexes with DNA and, especially, with RNA is described here for the first time. The complexes between NCp7 and both DNA and RNA, resulting from computer simulations, showed structural properties that are in agreement with most of the currently available molecular biology evidence and could be considered as reliable models (better than NMR structures currently available) for subsequent structure-based ligand design approaches. PMID- 20201585 TI - Probing DNA binding, DNA opening, and assembly of a downstream clamp/jaw in Escherichia coli RNA polymerase-lambdaP(R) promoter complexes using salt and the physiological anion glutamate. AB - Transcription by all RNA polymerases (RNAPs) requires a series of large-scale conformational changes to form the transcriptionally competent open complex RP(o). At the lambdaP(R) promoter, Escherichia coli sigma(70) RNAP first forms a wrapped, closed 100 bp complex I(1). The subsequent step opens the entire DNA bubble, creating the relatively unstable (open) complex I(2). Additional conformational changes convert I(2) to the stable RP(o). Here we probe these events by dissecting the effects of Na(+) salts of Glu(-), F(-), and Cl(-) on each step in this critical process. Rapid mixing and nitrocellulose filter binding reveal that the binding constant for I(1) at 25 degrees C is approximately 30-fold larger in Glu(-) than in Cl(-) at the same Na(+) concentration, with the same log-log salt concentration dependence for both anions. In contrast, both the rate constant and equilibrium constant for DNA opening (I(1) to I(2)) are only weakly dependent on salt concentration, and the opening rate constant is insensitive to replacement of Cl(-) with Glu(-). These very small effects of salt concentration on a process (DNA opening) that is strongly dependent on salt concentration in solution may indicate that the backbones of both DNA strands interact with polymerase throughout the process and/or that compensation is present between ion uptake and release. Replacement of Cl(-) with Glu(-) or F(-) at 25 degrees C greatly increases the lifetime of RP(o) and greatly reduces its salt concentration dependence. By analogy to Hofmeister salt effects on protein folding, we propose that the excluded anions Glu(-) and F(-) drive the folding and assembly of the RNAP clamp/jaw domains in the conversion of I(2) to RP(o), while Cl(-) does not. Because the Hofmeister effect of Glu(-) or F(-) largely compensates for the destabilizing Coulombic effect of any salt on the binding of this assembly to downstream promoter DNA, RP(o) remains long-lived even at 0.5 M Na(+) in Glu(-) or F(-) salts. The observation that Esigma(70) RP(o) complexes are exceedingly long-lived at moderate to high Glu(-) concentrations argues that Esigma(70) RNAP does not dissociate from strong promoters in vivo when the cytoplasmic glutamate concentration increases during osmotic stress. PMID- 20201587 TI - Pd-catalyzed decarboxylative arylation of thiazole, benzoxazole, and polyfluorobenzene with substituted benzoic acids. AB - A Pd-catalyzed decarboxylative coupling of thiazoles and benzoxazole with various substituted benzoic acids is developed. The reaction is compatible with both electron-rich and electron-poor benzoic acids. It can also be extended to the synthesis of polyfluoro-substituted biaryls using polyfluorobenzenes as the starting materials. PMID- 20201586 TI - Simultaneous single-molecule fluorescence and conductivity studies reveal distinct classes of Abeta species on lipid bilayers. AB - The extracellular senile plaques prevalent in brain tissue in Alzheimer's disease (AD) are composed of amyloid fibrils formed by the Abeta peptide. These fibrils have been traditionally believed to be featured in neurotoxicity; however, numerous recent studies provide evidence that cytotoxicity in AD may be associated with low-molecular weight oligomers of Abeta that associate with neuronal membranes and may lead to membrane permeabilization and disruption of the ion balance in the cell. The underlying mechanism leading to disruption of the membrane is the subject of many recent studies. Here we report the application of single-molecule optical detection, using fluorescently labeled human Alphabeta40, combined with membrane conductivity measurements, to monitor the interaction of single-oligomeric peptide structures with model planar black lipid membranes (BLMs). In a qualitative study, we show that the binding of Alphabeta to the membrane can be described by three distinctly different behaviors, depending on the Alphabeta monomer concentration. For concentrations much below 10 nM, there is uniform binding of monomers over the surface of the membrane with no evidence of oligomer formation or membrane permeabilization. Between 10 nM and a few hundred nanomolar, the uniform monomer binding is accompanied by the presence of peptide species ranging from dimers to small oligomers. The dimers are not found to permeabilize the membrane, but the larger oligomers lead to permeabilization with individual oligomers producing ion conductances of <10 pS/pore. At higher concentrations, perhaps beyond physiologically relevant concentrations, larger extended and dynamic structures are found with large conductances (hundreds of picosiemens), suggesting a major disruption of the membrane. PMID- 20201588 TI - A novel role of malonyl-ACP in lipid homeostasis. AB - The FapR protein of Bacillus subtilis has been shown to play an important role in membrane lipid homeostasis. FapR acts as a repressor of many genes involved in fatty acid and phospholipid metabolism (the fap regulon). FapR binding to DNA is antagonized by malonyl-CoA, and thus FapR acts as a sensor of the status of fatty acid biosynthesis. However, malonyl-CoA is utilized for fatty acid synthesis only following its conversion to malonyl-ACP, which plays a central role in the initiation and elongation cycles carried out by the type II fatty acid synthase. Using in vitro transcription studies and isothermal titration calorimetry, we show here that malonyl-ACP binds FapR, disrupting the repressor-operator complex with an affinity similar to that of its precursor malonyl-CoA. NMR experiments reveal that there is no protein-protein recognition between ACP and FapR. These findings are consistent with the crystal structure of malonyl-ACP, which shows that the malonyl-phosphopantetheine moiety protrudes away from the protein core and thus can act as an effector ligand. Therefore, FapR regulates the expression of the fap regulon in response to the composition of the malonyl phosphopantetheine pool. This mechanism ensures that fatty acid biosynthesis in B. subtilis is finely regulated at the transcriptional level by sensing the concentrations of the two first intermediates (malonyl-CoA and malonyl-ACP) in order to balance the production of membrane phospholipids. PMID- 20201589 TI - Optimal de novo design of MRM experiments for rapid assay development in targeted proteomics. AB - Targeted proteomic approaches such as multiple reaction monitoring (MRM) overcome problems associated with classical shotgun mass spectrometry experiments. Developing MRM quantitation assays can be time consuming, because relevant peptide representatives of the proteins must be found and their retention time and the product ions must be determined. Given the transitions, hundreds to thousands of them can be scheduled into one experiment run. However, it is difficult to select which of the transitions should be included into a measurement. We present a novel algorithm that allows the construction of MRM assays from the sequence of the targeted proteins alone. This enables the rapid development of targeted MRM experiments without large libraries of transitions or peptide spectra. The approach relies on combinatorial optimization in combination with machine learning techniques to predict proteotypicity, retention time, and fragmentation of peptides. The resulting potential transitions are scheduled optimally by solving an integer linear program. We demonstrate that fully automated construction of MRM experiments from protein sequences alone is possible and over 80% coverage of the targeted proteins can be achieved without further optimization of the assay. PMID- 20201590 TI - A regularized method for peptide quantification. AB - Peptide abundance estimation is generally the first step in protein quantification. In peptide abundance estimation, peptide overlapping and peak intensity variation are two challenges. The main objective of this paper is to estimate peptide abundance by taking advantage of peptide isotopic distribution and smoothness of peptide elution profile. Our method proposes to solve the peptide overlapping problem and provides a way to control the variance of estimation. We compare our method with a commonly used method on simulated data sets and two real data sets of standard protein mixtures. The results show that our method achieves more accurate estimation of peptide abundance on different samples. In our method, there is a variance-related parameter. Considering the well-known trade-off between the variance and the bias of estimation, we should not only focus on reducing the variance in real applications. A suggestion about parameter selection is given based on the discussion of variance and bias. Matlab source codes and detailed experimental results are available at http://bioinformatics.ust.hk/PeptideQuant/peptidequant.htm. PMID- 20201591 TI - Volume-based thermoelasticity: compressibility of inorganic solids. AB - Thermodynamic properties such as entropy, among others, have been shown to correlate well with formula volume, thus permitting prediction of these properties on the basis of chemical formula and density alone, with no structural detail required. We here extend these studies to the thermoelastic property of isothermal compressibility, beta. We show that compressibility is strongly linearly correlated with formula volume per atom pair, V(pr), for binary solids, with the alkali halides having a proportionality constant of 0.908 GPa(-1) V(pr)( 1) while 1:1 monoxides, monochalcogenides, monopnictides, and chalcopyrites (ABX(2), which may be considered as AX plus BX) have a common compressibility proportionality constant of 0.317 GPa(-1) V(pr)(-1). Oxides with closely packed oxygen lattices (such as Al(2)O(3)), garnets (such as Y(3)Fe(5)O(12) = 4M(2)O(3)), spinels (MgAl(2)O(4) = MgO.Al(2)O(3)), and other oxides (e.g., FeTiO(3) = FeO.TiO(2)) have compressibilities which are only slightly dependent on volume, at about 0.108 GPa(-1) V(pr)(-1) + 0.003 GPa(-1). PMID- 20201592 TI - Screening kinase inhibitors with a microarray-based fluorescent and resonance light scattering assay. AB - In this technical note, a microarray-based spectroscopic assay with two readout principles, fluorescence and resonance light scattering (RLS), for screening kinase inhibitors has been reported. In this assay, the phosphorylation and inhibition events are marked by biotinylated antiphosphoserinen/antiphosphotyrosine antibodies, and gold nanoparticles are attached to the antibodies by standard avidin-biotin chemistry followed by silver deposition for RLS signal enhancement. The avidin conjugated fluorescein is used as a fluorescent probe. Assays for both serine kinase, the alpha-catalytic subunit of cyclic adenosine 5'-monophosphate (cAMP) dependent protein kinase (PKA), and tyrosine kinase, leukocyte-specific protein tyrosine kinase (LCK), have been developed. The utility of this assay to high-throughput screening was demonstrated with a commercial inhibitor library, a collection of 80 kinase inhibitors, and satisfactory results were obtained. In addition, quantitative determination of binding strength and the inhibiting type (type I) of these inhibitors are also demonstrated by the adenosine 5'-triphosphate (ATP) competing assays. PMID- 20201593 TI - A facile asymmetric synthesis of either enantiomer of 2-substituted pyrrolidines. AB - A new and general method for asymmetric synthesis of either enantiomer of 2 substituted pyrrolidines from a single starting material is described. Reductive cyclization of (S(S))-gamma-chloro-N-tert-butanesulfinyl ketimines with LiBHEt(3) in THF at -78 to 23 degrees C afforded (S(S),R)-N-tert-butanesulfinyl-2 substituted pyrrolidines in excellent yields (88-98%) and with high diastereoselectivity (99:1). The diastereoselectivity is controlled effectively by the choice of reducing agent. Thus, the corresponding epimers of (S(S),S)-2 substituted pyrrolidines were synthesized in good yields (87-98%) and with high diastereoslectivity (1:99) by simply switching the reducing agent from LiBHEt(3) to DIBAL-H/LiHMDS. Deprotection of N-tert-butanesulfinyl-2-substituted pyrrolidines using 4 N HCl in dioxane and MeOH gave the corresponding enantiomers of 2-substituted pyrrolidines in quantative yield. This method was found to be effective for a variety of substrates including aromatic, heteroaromatic, and aliphatic substituents. Extension of this methodology to the formation of 2 substituted piperidines is also illustrated. Reductive cyclization of (S(S)) delta-chloro-N-tert-butanesulfinyl ketimine with LiBHEt(3) in THF at -78 to 23 degrees C or DIBAL-H/LiHMDS in toluene at -78 to 0 degrees C afforded the (S(S),R)-N-tert-butanesulfinyl-2-substituted piperidines in excellent yield (98%) and with high diastereoselectivity (99:1) or (S(S),S)-N-tert-butanesulfinyl-2 substituted piperidines in good yield (98%) and with high diastereoselectivity (1:99), respectively. PMID- 20201594 TI - In situ surface plasmon resonance investigation of the assembly process of multiwalled carbon nanotubes on an alkanethiol self-assembled monolayer for efficient protein immobilization and detection. AB - In situ surface plasmon resonance (SPR) was used to study the assembly process of multiwalled carbon nanotubes (MWCNTs) quantitatively on an alkanethiol self assembled monolayer (SAM) surface, showing that MWCNTs can follow the Langmuir adsorption kinetics to assemble spontaneously whereas the assembly temperature has an essential influence on the assembly kinetics and the surface distribution of MWCNTs. To further in situ investigate protein attachment on the MWCNT surface and its sensing application quantitatively, goat IgG was immobilized by three strategies: direct adsorption, covalent binding, and 1-pyrenebutanoic acid, succinimidyl ester (PBSE)-assisted attachment, of which the covalent binding approach provides the best protein loading capacity. The SPR label-free detection of anti-goat IgG demonstrates excellent performance with high sensitivity, good specificity, and rapid response in comparison to that with a plain substrate without MWCNT assembly reported in our previous work. This is contributed by the 3D MWCNT assembly matrix providing a high probe immobilization capability and superb accessibility for the target to enhance its sensing performance significantly. PMID- 20201595 TI - Highlighting a variety of unusual characteristics of adsorption and diffusion in microporous materials induced by clustering of guest molecules. AB - In this work, we highlight several unusual characteristics of adsorption and diffusion of a variety of guest molecules, such as linear and branched alkanes with a number of C atoms in the 1-6 range, CO(2), and Ar in microporous structures such as zeolites (FAU, NaY) and metal organic frameworks (IRMOF-1, CuBTC, MIL-47, MIL-53 (Cr)-lp, PCN-6') that have channel or cavity sizes larger than about 0.75 nm. Clustering of guest molecules is found to manifest at temperatures below the critical temperature, T(c), of the guest species. The degree of clustering is increased as the temperature, T, is reduced increasingly below T(c). For linear alkanes, T(c) increases with chain length and, consequently, at a given T the degree of clustering increases with increasing chain length. For C4, C5, and C6 alkane isomers, the linear isomer shows a higher degree of clustering than the corresponding branched isomers. Mixture adsorption characteristics are significantly influenced by clustering; specifically, the separation selectivity is found to increased significantly with lowering T. We also discuss the interesting possibility of separating alkane isomer mixtures by exploiting the differences in the degrees of clustering, induced by differences in T(c) of constituent species. An important characteristic of clustering is that the inverse thermodynamic factor 1/Gamma(i) identical with (d ln c(i))/(d ln f(i)) exceeds unity for a range of molar concentrations c(i) within the micropores. For the concentration ranges for which 1/Gamma(i) >1, the Fick diffusivity, D(i), for unary diffusion is often lower than both the Maxwell Stefan, D(i), and the self-diffusivity, D(i,self). Correlation effects in diffusion are significantly lowered as a consequence of clustering; this reduction in correlation effects is found to have a significant influence on the mixture diffusion characteristics. The diffusion selectivity is significantly affected with increased clustering. PMID- 20201596 TI - Photoluminescent properties of chalcobromide-capped octahedral hexarhenium(III) complexes [{Re(6)Q(8-n)Br(n)}Br(6)](n-4) (Q = Se, n = 1-3; Q = S, n = 1, 2). AB - Photoluminescent properties of chalcobromide-capped octahedral hexarhenium(III) complexes with terminal bromide ligands [{Re(6)Q(8-n)Br(n)}Br(6)](n-4) (Q = Se, n = 1 ([1-Se](3-)), n = 2 ([2a-Se](2-) and [2b-Se](2-)), and n = 3 ([3-Se](-)); Q = S, n = 1 ([1-S](3-)), n = 2 ([2a-S](2-), [2b-S](2-), and [2c-S](2-)) were studied. The Q(7)Br capped complex [{Re(6)Q(7)Br}Br(6)](3-) and Q(6)Br(2) [{Re(6)Q(6)Br(2)}Br(6)](2-) (both D(3d) and C(2v) symmetric geometrical isomers) were successfully separated by column chromatography. All of the chalcobromide capped complexes studied showed photoluminescence in both crystalline and solution phases. The emission maximum wavelength of the complexes at 296 K spans 853-915 or 868-968 nm in the crystalline phase or in acetonitrile, respectively. The selenobromide-capped complexes showed more intense emission as compared with the thiobromide analogues. The emission quantum yield (Phi(em)) and emission lifetime (tau(em)) became smaller and shorter, respectively, with an increase in the number of a capping bromide ligand in [{Re(6)Q(8-n)Br(n)}Br(6)](n-4). In the crystalline phase at 80 K, the emission maximum of the chalcobromide-capped complex shifted to the longer wavelength relative to that at 296 K. The emissive excited-state of the chalcobromide-capped hexarhenium(III) complexes was concluded to originate from the {Re(6)Q(8-n)Br(n)}(n+2) core with a spin-triplet type. The Phi(em) and tau(em) values of the {Re(6)Q(8-n)Br(n)}(n+2) complex were dependent significantly on the symmetry of the hexarhenium core, showing more intense emission for the complex with the higher symmetric core. A linear correlation between natural logarithm of the nonradiative decay rate constant and the emission maximum energy was observed for [{Re(6)Q(6)Br(2)}Br(6)](2-). PMID- 20201597 TI - Optimal decharging and clustering of charge ladders generated in ESI-MS. AB - In electrospray ionization mass spectrometry (ESI-MS), peptide and protein ions are usually observed in multiple charge states. Moreover, adduction of the multiply charged species with other ions frequently results in quite complex signal patterns for a single analyte, which significantly complicates the derivation of quantitative information from the mass spectra. Labeling strategies targeting the MS1 level further aggravate this situation, as multiple biological states such as healthy or diseased must be represented simultaneously. We developed an integer linear programming (ILP) approach, which can cluster signals belonging to the same peptide or protein. The algorithm is general in that it models all possible shifts of signals along the m/z axis. These shifts can be induced by different charge states of the compound, the presence of adducts (e.g., potassium or sodium), and/or a fixed mass label (e.g., from ICAT or nicotinic acid labeling), or any combination of the above. We show that our approach can be used to infer more features in labeled data sets, correct wrong charge assignments even in high-resolution MS, improve mass precision, and cluster charged species in different charge states and several adduct types. PMID- 20201598 TI - Absolute configuration assignment of norcamphor-derived furyl hydroperoxide using density functional theory calculations of optical rotation and vibrational circular dichroism. AB - Density functional theory (DFT) calculations of sodium d line specific rotation and of vibrational circular dichroism (VCD) have been used to assign the absolute configuration of a recently prepared (1S,4R)-norcamphor-derived furyl hydroperoxide, (+)-3, introduced as a stereoselective oxidant. Both approaches give the same absolute configuration to the newly generated stereogenic carbon at position 2, i.e., (1S,2S,4R)-(+)-3, thus providing a confident assignment in a case made difficult by the large conformational flexibility and the small difference between the computed optical rotations of the two possible diastereoisomers. Although the computed IR absorption spectra of (1S,2S,4R)-3 and (1S,2R,4R)-3 are practically indistinguishable, a number of significant differences in the VCD spectra of these two nonmirror-image isomers can be observed, which allows the structural identification of the synthesized compound. This is clearly shown here for the first time. PMID- 20201599 TI - Hopping enables a DNA repair glycosylase to search both strands and bypass a bound protein. AB - Spontaneous DNA damage occurs throughout the genome, requiring that DNA repair enzymes search each nucleotide every cell cycle. This search is postulated to be more efficient if the enzyme can diffuse along the DNA, but our understanding of this process is incomplete. A key distinction between mechanisms of diffusion is whether the protein maintains continuous contact (sliding) or whether it undergoes microscopic dissociation (hopping). We describe a simple chemical assay to detect the ability of a DNA modifying enzyme to hop and have applied it to human alkyladenine DNA glycosylase (AAG), a monomeric enzyme that initiates repair of alkylated and deaminated purine bases. Our results indicate that AAG uses hopping to effectively search both strands of a DNA duplex in a single binding encounter. This raised the possibility that AAG might be capable of circumnavigating blocks such as tightly bound proteins. We tested this hypothesis by binding an EcoRI endonuclease dimer between two sites of DNA damage and measuring the ability of AAG to act at both damaged sites in a single binding encounter. Remarkably, AAG bypasses this roadblock in approximately 50% of the binding events. We infer that AAG makes significant excursions from the surface of the DNA, allowing reorientation between strands and the bypass of a bound protein. This has important biological implications for the search for DNA damage because eukaryotic DNA is replete with proteins and only transiently accessible. PMID- 20201600 TI - Synthesis and application of lactosylated, 99mTc chelating albumin for measurement of liver function. AB - Neogalactosylated and neolactosylated albumins are currently used as radiopharmaceutical agents for imaging the liver asialoglycoprotein receptors, which allows the quantification of hepatic liver function in various diseases and also in healthy liver transplant donors. We developed an original process for synthesizing a chelating neolactosylated human albumin using maleimidopropyl lactose and maleimidopropyl-diethylene triamine pentaacetic acid (DTPA) derivatives. The lactosylated protein (LACTAL) conjugate showed excellent liver uptake compared to nonlactosylated protein and a very high signal-to-noise ratio, based on functional assessment of biodistribution in mice using (99m)Tc scintigraphy. PMID- 20201601 TI - Two-dimensional separation in laser ionization orthogonal time-of-flight mass spectrometry. AB - The capabilities of two-dimensional separation using a high irradiance laser ionization orthogonal time-of-flight mass spectrometer (LI-O-TOFMS) were demonstrated in this paper. Ions were separated via their initial kinetic energy in one dimension and their mass-to-charge ratios in the other dimension. Investigation of the transient ion profiles after laser pulses revealed that the separation of analyte ions from multiply charged ions and gas species ions was achieved. Comparison of mass spectra in the normal accumulation mode and in the two-dimensional separation mode indicated that the relative sensitivity coefficients are stable and close to their true values in the two-dimensional separation mode, especially for trace elements that are prone to interference. PMID- 20201602 TI - Water transport with a carbon nanotube pump. AB - Transportation of water molecules in a carbon nanotube based on an energy pump concept is investigated by molecular dynamics simulations. A small portion of the initially twisted wall of a carbon nanotube is employed to function as an energy pump for possible smooth transportation of water molecules. The momentum and resultant force on a water molecule and the corresponding displacement and velocity of the molecule are particularly studied to disclose the transportation process. The efficiency of the transportation is found to be dependent on the size of the energy pump. Once the process for the transportation of one molecule is elucidated, transportations of 20 water molecules are simulated to investigate the effect of the environmental temperature and fluctuations in the nanotube channel on the transportation. It is revealed that the accelerated period of multiple water molecules is longer than that in the transportation of a single water molecule. In addition, the fluctuations in the nanotube wall due to the buckling propagation and a higher environmental temperature will all lead to obvious decreases in the water velocity and hence retard the transportation process. PMID- 20201603 TI - Ligand metalation in the reactivity of a tetravalent uranium amides. AB - The reactions of organolithium reagents with the tetravalent UCl(2)[N(SiMe(3))(2)](2) and its DME solvate have been examined. Treatment of both compounds with methyl-lithium in diethyl ether resulted in one electron reduction of the metal center and gamma-deprotonation of one of the ligands. The dimeric {U[(mu-CH(2)-SiMe(2))N(SiMe(3))](2)[mu-Li(DME)]}(2) (1) was isolated from the reaction mixture regardless of the amount of MeLi employed. The employment of LiCH(2)SiMe(3) in DME led instead to multiple gamma-deprotonation events at the same carbon atom with formation of the trimetallic {U[(mu-CH(2) SiMe(2))N(SiMe(3))][N(SiMe(3))(2)]}(2){U[(mu(3)-C SiMe(2))N(SiMe(3))][N(SiMe(3))(2)]}{mu-OMe} (2) cluster centered on a fully deprotonated carbon atom. Crystallographic analysis revealed the presence of mu OCH(3) units in the cluster as generated by DME solvent cleavage. A similar reaction carried out in the absence of DME led to the isolation of a closely related trimetallic {U[mu-(CH(2)-SiMe(2))N(SiMe(3))][N(SiMe(3))(2)]}(2){U[(mu(3) C-SiMe(2))N(SiMe(3))][(mu-CH(2)-SiMe(2))N(SiMe(3))]} (3). One additional gamma deprotonated fragment replacing the bridging methoxy group of 2 was present in this case. The presence of a fully deprotonated carbon atom bridging three metal centers and of one silicon atom was confirmed by both X-ray structures and NMR data. An attempt to reduce UCl(2)[N(SiMe(3))(2)](2) with KC(8) in a coordinating solvent resulted in ligand scrambling with the formation of two products. The first is a trimeric U(III) cluster formulated as {U-mu Cl[N(SiMe(3))(2)][DME]}(2){U-mu-Cl[N(SiMe(3))(2)](2)}{mu(3)-Cl}(2) (4). The second was U[N(SiMe(3))(2)](3). A similar reduction reaction carried out in noncoordinating toluene resulted instead in an attack on the ligand affording the dimeric {U-mu-Cl[N(SiMe(3))(2)](2)[ horizontal lineN(SiMe(3))]}(2) (5). Alkylation of UCl(2)[N(SiMe(3))(2)](2) with n-butyl-lithium in hexane surprisingly yielded the pentavalent U[(mu-CH(2) SiMe(2))N(SiMe(3))](2)[N(SiMe(3))(2)] (6). The acquisition of one additional ligand during the reaction hinted at the presence of other products in the reaction mixture. PMID- 20201604 TI - Retention of latex colloids on calcite as a function of surface roughness and topography. AB - Adhesion of colloidal particles to mineral and rock surfaces is important for environmental and technological processes. Surface topography variations of mineral and rock surfaces at the submicrometer scale may play a significant role in colloid retention in the environment. Here, we present colloid deposition data on calcite as a function of submicrometer surface roughness based on surface data over a field of view of several square millimeters, sufficient to trace the pattern of common inhomogeneities on mineral surfaces. A freshly cleaved calcite crystal was reacted to produce a well-defined etch pit density of approximately 3.4 +/- 1.2 to 8.3 +/- 1.6 [10(-3) microm(-2)] and etch pit depth ranging from approximately 4 to 50 nm. This surface was exposed at the point of zero charge (PZC) of calcite to a colloidal suspension. We used a bimodal particle size distribution of nonfunctionalized polystyrene latex spheres with average diameters of 499 and 903 nm. Vertical scanning interferometry (VSI) was applied to quantify calcite surface topography variations as well as the retention of latex colloids. For both particle sizes, the experiments showed a positive correlation between the surface roughness (Rq) and the number of adsorbed particles. Etch pits were preferred sites for colloidal deposition in contrast to surface steps. The majority of adsorbed particles were trapped at etch pit walls compared to etch pit bottoms. Increasing pit density (D) and depth (d) resulted in an increase of colloidal retention. Deposition of smaller particles exceeded that of the larger-sized fraction of the bimodal system investigated here. Our results show that colloidal deposition at rough mineral and rock surfaces is an important geochemical process. The results about surface roughness dependent particle adsorption will foster the understanding and predictability of colloidal retention for a multitude of natural and technical processes. PMID- 20201605 TI - Generation of dual patterns of metal oxide nanomaterials based on seed-mediated selective growth. AB - A facile route for the generation of the dual patterns of metal oxide nanomaterials, for example, ZnO and CuO, has been developed by printing the oxide seeds through a combination of microcontact printing (microCP) and microfluidic (microF) techniques, followed by the simultaneous growth of the two metal oxide nanomaterials in a one-step solution reaction based on hydrothermal, seed mediated selective growth. The obtained dual patterns of ZnO nanorods and CuO nanoneedles show a sharp boundary between them, indicating well-defined dual pattern generation. Also, the simultaneous growth of metal oxide nanomaterials is highly material-selective for the specific seeds prepatterned on substrates, resulting in the selective growth of ZnO nanorods and CuO nanoneedles on the ZnO and CuO seeds, respectively. Moreover, the generation of high-quality dual patterns has been similarly realized on a flexible poly(ethylene terephthalate) (PET) wafer. This study demonstrates the well-controlled hydrothermal growth of different metal oxide nanomaterials in the same reaction solution on the preprinted oxide seeds on the target substrates. It opens up an avenue to develop multifunctional devices of different metal oxides with the combination of microCP and microF techniques. PMID- 20201606 TI - Spontaneous formation of hierarchically structured curly films of nickel carbonate hydrate through drying. AB - Novel curly nickel carbonate hydrate film superstructures can be prepared for the first time via a facile drying process of the films formed on air/solution interface in the presence of double hydrophilic copolymer or polyelectrolyte additives. As-prepared curly film patches with average edge sizes of several hundred micrometers display adjustable curly features along different orientation. The coiling up degree of the film edges is strongly dependent on the polymer concentration in bulk solution. Most of these curly structures have a relatively smooth outer surface; however, the microstructures of the outer surface of curly films formed show porous network-like features. In addition, using different kinds of nickel salts can produce distinct curly film samples. A possible formation mechanism of the curly film structure has been proposed. The multiple interaction modes between nickel salt precursors and polymer can favor the self-organization of the film formed at the air/solution interface. This approach is expected to be extended for producing a variety of curly hierarchical structures. PMID- 20201607 TI - Public option and private profits: what do markets expect? AB - BACKGROUND: The debate on US healthcare reform has largely focused on the introduction of a public health plan option. While supporters stress various beneficial effects that would arise from increased competition in the health insurance market, opponents often contend that a public plan would drive insurers out of the market and potentially lead to the 'collapse' of the private health insurance industry. OBJECTIVE: To contribute to the US healthcare reform debate by inferring, from financial market data, the effect that the public option is likely to have on the private health insurance market. METHODS: The study utilized daily data on the price of a security that was traded in a prediction market from June 2009 and whose pay-off was tied to the event that a federal government-run healthcare plan - the 'public option' - would be approved by 31 December 2009 (100 daily observations). These data were combined with data on stock returns of health insurance companies (1500 observations from 100 trading days and 15 companies) to evaluate the expected effect of the public option on private health insurers. The impact on hospital companies (1000 observations) was also estimated. RESULTS: The results suggested that daily stock returns of health insurance companies significantly responded to the changing probability regarding the public option. A 10% increase in the probability that the public option would pass, on average, reduced the stock returns of health insurance companies by 1.28% (p < 0.001). Hospital company stock returns were also affected (0.9% reduction; p < 0.001). CONCLUSIONS: The results reveal the market expectation of a negative effect of the public option on the value of health insurance companies. The magnitude of the effect suggests a downward adjustment in the expected profits of health insurers of around 13%, but it does not support more calamitous scenarios. PMID- 20201608 TI - Efficacy and safety of the combined oral contraceptive ethinylestradiol/drospirenone (Yasmin) in healthy Chinese women: a randomized, open-label, controlled, multicentre trial. AB - To evaluate and compare the contraceptive efficacy, bleeding pattern, side effects and other positive effects of a combined oral contraceptive (COC) containing drospirenone (DRSP) [Yasmin] with those of a COC containing desogestrel (DSG) in healthy Chinese women. This was a randomized, open-label, controlled, multicentre study of 768 healthy Chinese women requiring contraception. The subjects were randomized to ethinylestradiol (EE) 30 microg/DRSP 3 mg (n = 573) or EE 30 microg/ DSG 150 microg (n = 195), at a ratio of 3 : 1. Each individual was treated for 13 cycles. Further visits were required at cycle 4, cycle 7, cycle 10 and cycle 13 of treatment. Weight, height and body mass index were evaluated at each visit. The Menstrual Distress Questionnaire (MDQ) was administered at baseline, visit 3 (cycle 7) and visit 5 (after cycle 13). Baseline characteristics were similar between the two groups (p > 0.05). The Pearl Index (method failure) for EE/DRSP was 0.208 per 100 women-years, which was lower than that for EE/DSG (0.601 per 100 women-years). There were no significant differences between the treatment groups with regard to bleeding patterns. According to the MDQ subscale, improvements in water retention and increases in appetite during the intermenstrual period and in water retention and general well being during the menstrual period in the EE/DRSP group (-0.297, -0.057, 0.033 and 0.150, respectively) were significantly improved compared with the EE/DSG group ( 0.108, 0.023, 0.231 and -0.023, respectively) [all p < 0.05]. Other values that improved in both groups, particularly improvement in breast pain and tenderness and skin condition, were more evident in the EE/DRSP group (18.0%, 89/494; 12.6%, 62/494) than in the EE/DSG group (11.3%, 19/168; 5.4%, 9/168). Mean weight increased in the EE/DSG group (0.57 kg) while there was a significant decrease in mean weight (-0.28 kg) in the EE/DRSP group (p < 0.01). Both EE/DRSP and EE/DSG have good contraceptive efficacy and a comparable bleeding pattern. EE/DRSP had a more favourable effect on weight and premenstrual symptoms than EE/DSG. PMID- 20201609 TI - Trends in development of the influenza vaccine with broader cross-protection. AB - Influenza A viruses cause in humans acute respiratory infections, which spread yearly in the form of epidemics or pandemics. A high variability and broad host specificity of influenza A viruses are the main reasons of repeated influenza infections. Therefore, no effective prevention against influenza is available today. The main problem of insufficient protection efficacy is that virus neutralizing antibodies induced by current vaccines are closely strain-specific and the vaccines need to be updated each year. Therefore, various novel approaches to vaccine preparation have been developed with the aim to widen the spectrum of their efficacy. These approaches comprise using new adjuvants as components of the inactivated vaccines, new techniques of live attenuated vaccine preparation (reverse genetics), and new vaccine design focused on the conserved antigens of influenza A viruses inducing protective immunity not only against the influenza viruses antigenically similar (homologous) to vaccine strains, but also against heterologous viruses, even of different subtypes. In this review examples of new approaches to the induction of intersubtype immunity against influenza and their utilization in vaccine preparation are described. PMID- 20201610 TI - Malvastrum yellow vein Yunnan virus is amonopartite begomovirus. AB - Nine samples of diseased Malvastrum coromandelianum plants collected from the fields in Yunnan province of China were found to be infected with Malvastrum yellow vein Yunnan virus (MYVYNV), when tested by PCR using specific primers. The results of PCR and Southern blot analysis showed that only 4 samples out of 9 were associated with the satellite DNAb molecules. Their sequence analysis indicated that DNAb molecules share 97.8%-99.4% of nucleotide sequence identities with DNAb associated with MYVYNV isolate Y160 and less than 82.0% with those associated with other begomoviruses. Two infectious clones of MYVYNV (isolates Y160 and Y277) produced yellow vein, vein thickening and upward leaf curl symptoms in Nicotiana benthamiana plants. In the presence of its cognate DNAb, the symptoms changed to downward leaf curl and crinkle. Southern blot analysis showed that DNAb could increase accumulation of its cognate virus in the infected N. benthamiana plants. The above results indicated that MYVYNV is a monopartite begomovirus and its association with DNAb is not necessary for the infection of plants, but is able to intensify symptoms specific for the disease. PMID- 20201611 TI - Monosodium luminol upregulates the expression of Bcl-2 and VEGF in retrovirus infected mice through downregulation of corresponding miRNAs. AB - The retrovirus ts1 is a mutant of Moloney murine leukemia virus (MoMuLV) that causes neurodegeneration (ND) in susceptible mice. Our previous studies showed that the antioxidant drug monosodium luminol (GVT) prevented the development of ND in ts1-infected mice. In this study, we analyzed effect of GVT on the expression of B-cell lymphoma-2 protein (Bcl-2) and vascular endothelial growth factor (VEGF) in central nervous system (CNS) tissues of these animals. Our data showed that GVT treatment of ts1-infected mice significantly increased their expression of Bcl-2 and VEGF in brainstem compared with ts1-infected untreated mice. We also studied the expression of specific microRNAs (miRNAs) such as miRNA 15 and -16 (targeting Bcl-2), and miRNA-20 (targeting VEGF). We found that the expression of miRNAs inversely correlated with the upregulation of their target proteins in ts1-infected untreated as well as in GVT-treated-ts1-infected mice. The data showed that GVT treatment prevented ts1-induced ND at least in part by upregulating Bcl-2 and VEGF expression, what likely occurred as a consequence of downregulation of their corresponding miRNAs. PMID- 20201612 TI - Fusion of HSP70 gene of Mycobacterium tuberculosis to hemagglutinin (H5) gene of avian influenza virus in DNA vaccine enhances its potency. AB - A series of plasmids containing the HSP70 gene of Mycobacterium tuberculosis fused to the hemagglutinin (H5) gene of H5N1 avian influenza virus (AIV) (H5 HSP70 (heat shock protein 70) vaccine) or individual H5 gene (H5 vaccine) or HSP70 gene (HSP70 vaccine) were constructed based on the plasmid pcDNA3.1. Expression of H5 gene in Vero cells in vitro and in chickens in vivo was confirmed following their transfection and immunization with H5 or H5-HSP70 vaccines. Controls consisted of HSP70 vaccine, empty plasmid pcDNA3.1 and co administered H5 and HSP70 vaccines. H5-HSP70 vaccine produced in chicken higher hemagglutination inhibition (HI) antibody titer than H5 vaccine. However, the increase was not statistically significant. We have demonstrated for the first time that the H5 DNA vaccine with fused HSP70 gene may produce an enhanced induction of humoral immune response to AIV in chickens. PMID- 20201613 TI - Contribution of rearranged actin structures to the spread of Ectromelia virus infection in vitro. AB - We describe here a contribution of virus-induced actin tails and filopodia in transmission of Ectromelia virus (ECTV) infection in permissive cells detected by the immunofluorescence and confocal microscopy. Immunoblot analysis revealed profoundly decreased beta-actin levels during ECTV replicative cycle in the infected cells 24 hrs post infection (p.i.). These results provided a basis for the further analysis of ECTV motion in the infected cells as well as for impact of ECTV infection on the cytoskeletal proteins. PMID- 20201614 TI - Protein interaction matrix of Papaya ringspot virus type P based on a yeast two hybrid system. AB - Comprehensive analysis of the interactions between 10 mature proteins of Papaya ringspot virus type P (PRSV-P) was carried out based on a yeast two-hybrid system assay (YTHS). We detected 6 interactions between different viral proteins (VPg P1, VPg-P3, VPg-CI, VPg-CP, NIaPro-CI, and NIb-P3) and 4 self-interactions (HC Pro, VPg, NIaPro, and CP). These interactions did not show the same directionality as corresponding interactions detected in other potyviruses and consequently, a protein interaction matrix displayed different patterns. This initial map of the protein interactions of PRSV-P allows further study of various viral proteins in order to develop anew strategy to control PRSV-P infection. PMID- 20201615 TI - Tumors induced by Murine herpesvirus 60 or by cell line NB-78 derived from a tumor induced by Murine herpesvirus 78 show presence of the inducing viruses. AB - Murine herpesviruses 60 and 78 (MHV-60, MHV-78), closely related to Mouse herpesvirus strain 68 (MHV-68), are oncogenic lymphotropic gammaherpesviruses, which may serve as models for study of human oncogenic gammaherpesviruses such as Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV). In this work, we attempted to detect an analog of the MHV-68 ORF73 gene in tumors induced in mice either directly by MHV-60 or indirectly by MHV-78 via inoculation of NB-78 cells derived from a tumor induced by MHV-78. Besides the ORF73 gene, viral antigen and infectious virus were searched for. We succeeded in inducing lymphomas in mice by NB-78 cells and thus confirmed their transformed character. Importantly, we showed that the tumors induced by either MHV-60 or NB-78 cells were positive for the ORF73 gene, viral antigen and infectious virus. These results confirmed the generally accepted hypothesis about the connection between reactivation of latent gammaherpesviruses and malignant tumorigenesis. PMID- 20201616 TI - Analysis of the gene 3 region sequences of Chinese field strains of Transmissible gastroenteritis virus. AB - The genome of Transmissible gastroenteritis virus (TGEV) displays genetic diversity especially in gene 3 region. Sequence and comparative analysis of 3a and 3b genes of eight Chinese field strains with reference TGEV strains indicated that these strains shared 87.0-100% and 51.5%-100% identities at the nucleotide level, respectively, and 86.1%-100% and 66.2%-100% identities at the amino acid level, respectively. Moreover, in one of the strains (CH/SDQ/08), a 51 nt deletion in the gene 3 region was found. Phylogenetic analysis showed that the eight Chinese strains were more closely related to TGEV strains H165, H16, Miller M6, Miller M60, TS, and CHV than to other reference strains. In addition, this study indicated the presence of different TGEV strains within the same pig herds in China. PMID- 20201617 TI - Expression of microRNA-155 precursor in peripheral blood mononuclear cells from Hepatitis C patients after antiviral treatment. AB - Chronic hepatitis caused by Hepatitis C virus (HCV) is the main source of liver cirrhosis, hepatocellular carcinoma, and extra-hepatic diseases. After treatment induced resolution of hepatitis C, the persistence of HCV RNA in serum and peripheral blood mononuclear cells (PBMCs) is often observed. An expression of the precursor of microRNA-155 (miR-155) called BIC can be the factor responsible for a course of HCV infection. Therefore, we assessed the relationship between BIC expression and HCV RNA status in sera and PBMCs samples of 64 hepatitis C patients treated with interferon alpha(IFN-alpha)+ribavirin. High expression of BIC in PBMCs was determined in 100% of patients that harbored HCV RNA in serum and PBMCs. Further, we found that 83% of PBMCs samples were BIC-positive in a group of patients that eliminated HCV RNA only from serum. The lowest expression of BIC was found in patients that eliminated HCV RNA from both serum and PBMCs. PMID- 20201618 TI - 5'-UTR-based phylogenetic analysis of Classical swine fever virus isolates from India. AB - Classical swine fever (CSF) caused by Classical swine fever virus (CSFV) is a globally significant disease of pigs. Genetic typing of CSFV isolates can help in understanding the epidemiology of disease and trace down the source of outbreak. 5'-UTR sequence analysis and subsequent genetic classification of nine CSFV field isolates from India indicated that 3 isolates belonged to genotype 2.1 and were closely related to European CSFV strains. The remaining 6 isolates belonged to genotype 1 that contained old and new strains. However, the genotype 2.1 group consisted of recent field isolates only. The study showed circulation of both genotypes 1 and 2.1 in north-eastern part of India. PMID- 20201619 TI - Mechanisms of paediatric trauma at a rural hospital in Uganda. PMID- 20201620 TI - Course of choledochal cysts according to the type of treatment. AB - OBJECTIVE: To compare natural course and treatment results of various types of choledochal cysts. MATERIAL AND METHODS: Complication rate in treated (T) and natural course in not treated (NT) patients with choledochal cysts were compared. The level of bilioenteric anastomosis after cyst resection was categorized and their post-procedure courses were analyzed. RESULTS: A total of 204 patients (T, 174; NT, 30) were included. Patients with initial malignancies were excluded from the outcome analysis (n = 13). Of the remaining 191 patients, the mean follow-up time was 35.9 months (range 6-310.7 months). Biliary stricture was the most troublesome post-operative complication, and occurred in 10 patients (6.1%). It occurred significantly more frequently in the above hilar anastomosis group than in at or below (p-trend = 0.017), and also with older age (p-trend = 0.019). Common bile duct stone was the most frequent adverse event among NT (42.9%). Overall, there were fewer complications among treated patients (T, 17.2%; NT, 67.9%; p < 0.001). Anomalous pancreaticobiliary union (APBU) was present in 69 patients (37.5%), which was associated with higher prevalence of carcinoma (APBU present, 13%; APBU-absent, 3.5%; p = 0.019). No malignancy developed in both T and NT groups during follow-up. CONCLUSIONS: This study suggests, that even asymptomatic choledochal cysts should be treated, not only for prevention of malignancies, but also to lower the future adverse events. Bilioenteric anastomosis at larger caliber duct is recommended for prevention of post operative biliary strictures. PMID- 20201621 TI - Increased CD8+ intraepithelial lymphocyte infiltration and reduced surface area to volume ratio in the duodenum of patients with ulcerative colitis. AB - OBJECTIVE: Recent evidence suggests the involvement of the upper gastrointestinal tract in ulcerative colitis (UC). By conducting a prospective controlled study, we explored the immunological abnormalities in the duodenal mucosa of UC patients. METHODS: Duodenal and colonic biopsies were collected from 24 corticosteroid-free UC patients and 21 controls. Colonization by Helicobacter pylori and positivity for anti-endomysial antibodies was an exclusion criteria. The severity of duodenal and colonic inflammation was determined by endoscopic and histologic scores. Morphometry was performed to measure the surface area to volume ratio (SV). Duodenal CD3(+) and CD8(+) intraepithelial lymphocytes (IELs) and lamina propria mononuclear cells (LPMCs) were detected by immunohistochemistry. RESULTS: Fifteen UC patients and 14 controls were Helicobacter pylori and anti-endomysial antibody negative and were thus included in the study. Microscopic duodenitis was reported in 4 of the 15 UC patients (26.6%), and in none of the controls. A significantly higher number of CD3(+) and CD8(+) IELs and LPMCs was found in UC patients than in controls. A significant positive correlation between the percentage of both CD3(+) and CD8(+) IELs and disease activity was found in UC patients. SV was significantly reduced in UC patients compared to controls, and inversely correlated with the percentage of CD8(+) IELs. CONCLUSIONS: The duodenum of UC patients is infiltrated by a higher number of CD8(+) IELs which correlates with the degree of villous flattening and disease activity, but not with extent of the colonic lesions. Further studies are needed to clarify whether the duodenum is a target organ in UC. PMID- 20201622 TI - Prostate surgery to improve sleep quality: the key to success? (Related to: Hernandez C. et al. Nocturia in Spanish patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH). Curr Med Res Opin 2008 Apr;24(4):1033-8). PMID- 20201623 TI - Gastrointestinal side effects in postmenopausal women using osteoporosis therapy: 1-year findings in the POSSIBLE US study. AB - OBJECTIVE: To characterize gastrointestinal side effects (GI SEs) and its associations with medication discontinuation, health-related quality of life (HRQoL), and treatment) satisfaction in postmenopausal women prescribed osteoporosis (OP) therapies. METHODS: Prospective Observational Scientific Study Investigating Bone Loss Experience (POSSIBLE US*) participants enrolled October 27, 2004 - January 25, 2007 and complete questionnaires for up to 3 years. GI SEs for women new to or stable on therapy at entry were characterized at 6 and 12 months. Adjusted odds of experiencing GI SEs; mean HRQoL and treatment satisfaction scores; and risk of discontinuing therapy for bisphosphonate (BP) versus non-BP users were compared with logistic and generalized linear models. RESULTS: About 20% of women reported >or=1 GI SE at entry. GI SEs at month 6 were more common in BP than non-BP users (new: OR = 1.5, 95% CI: 1.2-2.0; stable: OR = 1.7, 95% CI: 1.3-2.1). Women new to OP therapy with GI SEs at month 6 had lower LS Mean HRQoL (OPAQ-SV Emotional Status: 72.3 vs. 78.2, p = 0.005) and treatment satisfaction scores (SEs: 71.4 vs. 82.9; EFFICACY: 58.6 vs. 65.6; Global: 55.0 vs. 64.4; all p 85 years old) with mean age of 90.2 years, and 120 young control subjects (range from 20 to 50 years) with mean age of 32.0 years. No significant differences were detected in the genotype and allele frequencies of examined gene variants between the two groups (p > 0.05). However, when gender was considered, genotypes and alleles frequencies of rs1501299 SNP in ADIPOQ gene and rs7799039 in LEP gene were significantly associated with longevity in men (p < 0.02) but not in women (p > 0.05). Thus, ADIPOQ and LEP genes polymorphisms might play a gender-specific role in the pathway to men's longevity. PMID- 20201643 TI - The impact of physical health and socioeconomic factors on sexual activity in middle-aged and elderly Taiwanese men. AB - Sexual activity in older people has become a topic of growing interest. The aim of this study is to investigate the effect of physical health and socioeconomic factors on the sexual activity of middle-aged and elderly Taiwanese men. From August 2007 to April 2008, 744 men older than 40 years were enrolled from a free health screening in Kaohsiung, Taiwan. All participants received detailed physical examination and answered questionnaires that collected demographic and lifestyle information, and medical history as well as answered items from the International Prostate Symptoms Score and five-item version of the International Index of Erectile Function (IIEF-5). Overall, 100 (13.4%) participants reported to be sexually inactive in previous 6 months. Older age, lower education levels, loss of a partner, erectile dysfunction, and increased number of comorbidities were found to be independent predictors for sexual inactivity. In conclusion, most middle-aged and elderly Taiwanese men remain sexually active. In addition to erectile dysfunction and loss of a partner, lower education levels and increased number of comorbidities were found to be predictors for sexual inactivity. Further research would need to elucidate whether improvement of those factors could help to preserve sexual activity. PMID- 20201644 TI - Lack of association between CYP21 V281L variant and polycystic ovary syndrome in Italian women. AB - AIM: To investigate the association between V281L CYP21 polymorphism and the hyperandrogenic phenotype of polycystic ovary syndrome (PCOS), in a cohort of 110 Italian women. METHODS: The CYP21 genotype distribution was evaluated in 50 women with PCOS and 60 control subjects. Genotypes were detected using restriction fragment length polymorphism (RFLP) analysis performed on polymerase chain reaction templates from genomic DNA. Genotypes distribution was compared between groups and we considered a p-value less than 0.05 as statistically significant. RESULTS: The frequency of VV, VL and LL was in agreement with other populations. Nevertheless no significant association was observed between CYP21 polymorphism and the presence of PCOS in an Italian cohort of women. CONCLUSION: Although CYP21 gene, involved in steroidogenesis, is a candidate gene for pathogenesis of PCOS, our data suggest that V281L polymorphism is not associated with PCOS in Italian women; a larger study is needed to confirm this result. PMID- 20201645 TI - The subplate and early cortical circuits. AB - The developing mammalian cerebral cortex contains a distinct class of cells, subplate neurons (SPns), that play an important role during early development. SPns are the first neurons to be generated in the cerebral cortex, they reside in the cortical white matter, and they are the first to mature physiologically. SPns receive thalamic and neuromodulatory inputs and project into the developing cortical plate, mostly to layer 4. Thus SPns form one of the first functional cortical circuits and are required to relay early oscillatory activity into the developing cortical plate. Pathophysiological impairment or removal of SPns profoundly affects functional cortical development. SPn removal in visual cortex prevents the maturation of thalamocortical synapses, the maturation of inhibition in layer 4, the development of orientation selective responses and the formation of ocular dominance columns. SPn removal also alters ocular dominance plasticity during the critical period. Therefore, SPns are a key regulator of cortical development and plasticity. SPns are vulnerable to injury during prenatal stages and might provide a crucial link between brain injury in development and later cognitive malfunction. PMID- 20201646 TI - Impact of UV-B radiation on the digestive enzymes and immune system of larvae of Indian major carp Catla catla. AB - PURPOSE: Ultraviolet radiation is a potent threat to the aquatic animals. Exposure to such stressor affects metabolic and immunological processes. The present investigation aims to study the effect of UV-B radiation on digestive enzymes and immunity of larvae of Catla catla. MATERIALS AND METHODS: Larvae were exposed to ultraviolet-B (UV-B, 280-320 nm) radiation (145 microW/cm(2)) for three different exposure times of 5, 10 and 15 min on every other day. After 55 days, important digestive enzymes were assayed. For immunological study, lysozyme, glutamate oxaloacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT) levels were measured. Then the fish were kept for one month without radiation and lysozyme level was measured. RESULTS: Protein concentration varied directly with the duration of exposure and was highest among fish that had received the 15 min UV-B irradiation. Significantly higher amylase, protease, trypsin and chymotrypsin activities were found in 5 min exposed fish compared to others. Lysozyme level was significantly higher in control group compared to the UV-B treated fish. The lysozyme level decreased with the increasing duration of UV-B radiation. When fish were kept without UV-B radiation for one month, lysozyme level was brought to the normal level in all treatments, except 15 min exposed fish. The GOT and GPT levels were significantly higher in the 15 min exposed group than others. CONCLUSIONS: The effects of UV-B radiation on the digestive physiology and immune system of catla have been clearly observed in the present study. The decreased enzyme activities in UV-B radiated fish results into improper digestion and poor growth. PMID- 20201647 TI - Effect of ultraviolet C irradiation on human sperm motility and lipid peroxidation. AB - PURPOSE: Ultraviolet C (UVC) irradiation of aqueous solutions is known to be a good source of reactive oxygen species (ROS). The aim of this study is to examine the effect of increasing doses of UVC irradiation, in the presence and absence of the antioxidant butylated hydroxytoluene (BHT), on human sperm motility and lipid peroxidation of its membranes. MATERIALS AND METHODS: Human sperm samples were irradiated with UVC light (254 nm) for different periods of time. A computer assisted semen analysis of sperm motility was carried out after UV irradiation. The percentage of motile sperm (%MOT), progressive motility, straight line velocity (VSL), curvilinear velocity (VCL) and the percentage of linearity (%LIN) were evaluated. The level of lipid peroxidation of sperm membranes was estimated by measurement of the thiobarbituric acid reactive substances (TBARS). RESULTS: UVC irradiation of human spermatozoa produced a diminution of the sperm motility (%MOT, progressive motility, VSL, VCL, %LIN), viability and, concomitantly, an increase of the level of lipid peroxidation of the sperm membranes. The observed effects of the UVC irradiation were prevented by addition of the antioxidant BHT, indicating that the effects of UVC on the tested sperm parameters are mediated by an important rise in lipid peroxidation of the sperm membrane. CONCLUSION: Lipid peroxidation of the human sperm plasma membrane leads to a decrease in the sperm motility (%MOT, progressive motility, VSL, VCL, %LIN) and viability. The protective effect of BHT on the UVC-irradiated sperm cells indicates the effects of ROS on sperm function. PMID- 20201648 TI - DNA damage intensity in fibroblasts in a 3-dimensional collagen matrix correlates with the Bragg curve energy distribution of a high LET particle. AB - PURPOSE: The DNA double-strand break (DSB) damage response induced by high energy charged particles on lung fibroblast cells embedded in a 3-dimensional (3-D) collagen tissue equivalents was investigated using antibodies to the DNA damage response proteins gamma-histone 2AX (gamma-H2AX) and phosphorylated DNA-PKcs (p DNA-PKcs). MATERIALS AND METHODS: 3-D tissue equivalents were irradiated in positions across the linear distribution of the Bragg curve profiles of 307.7 MeV/nucleon, 556.9 MeV/nucleon, or 967.0 MeV/nucleon (56)Fe ions at a dose of 0.30 Gy. RESULTS: Patterns of discrete DNA damage streaks across nuclei or saturated nuclear damage were observed, with saturated nuclear damage being more predominant as samples were positioned closer to the physical Bragg peak. Quantification of the DNA damage signal intensities at each distance for each of the examined energies revealed a biological Bragg curve profile with a pattern of DNA damage intensity similar to the physical Bragg curve for the particular energy. Deconvolution microscopy of nuclei with streaked or saturated nuclear damage pattern revealed more details of the damage, with evidence of double strand breaks radially distributed from the main particle track as well as multiple discrete tracks within saturated damage nuclei. CONCLUSIONS: These 3-D culture systems can be used as a biological substrate to better understand the interaction of heavy charged particles of different energies with tissue and could serve as a basis to model space-radiation-induced cancer initiation and progression. PMID- 20201649 TI - Double-strand break induction and repair in V79-4 hamster cells: the role of core ionisations, as probed by ultrasoft X-rays. AB - PURPOSE: To compare the induction of double-strand breaks (DSB) in cells irradiated by 250 and 350 eV ultrasoft X-rays and assess the residual yield of breaks 2 hours post irradiation in order to unravel the correlation between the sharp increase in cell-killing efficiency of ultrasoft X-rays above versus below the carbon-K threshold (284 eV) and the induction of core events in DNA atoms. MATERIALS AND METHODS: V79-4 hamster cells were irradiated with synchrotron ultrasoft X-rays at isoattenuating energies of 250 eV and 350 eV. DSB were quantified using pulse field gel electrophoresis. RESULTS: A significant increase in DSB induction was observed for 350 eV ultrasoft X-rays above the carbon-K threshold, compared to 250 eV below the threshold, per unit dose to the cell. The DSB induced by the 350 eV ultrasoft X-rays were less repaired 2 h after irradiation. CONCLUSION: The increased DSB induction at 350 eV is attributed to the increase in the relative proportion of photon interactions in DNA resulting in significant dose inhomogeneity across the cell with a local increase in dose to DNA. It results from an increase in carbon-K shell interactions and the short range of the electrons produced. Core ionisations in DNA, through core-hole relaxation in conjunction with localised effects of spatially correlated low energy photo- and Auger-electrons lead to an increase in number and the complexity of DSB. PMID- 20201651 TI - Human bone marrow mesenchymal stem cells expressing SDF-1 promote hematopoietic stem cell function of human mobilised peripheral blood CD34+ cells in vivo and in vitro. AB - PURPOSE: There is mounting evidence demonstrating that stromal cell derived factor-1 (SDF-1) plays an important role in homing of hematopoietic progenitor cells to bone marrow. This study was aimed to assess whether bone marrow mesenchymal stem cells overexpressing exogenous SDF-1 could synergistically promote the homing of CD34(+) (Cluster of Differentiation [CD]) cells to bone marrow of lethally irradiated severe combined immunodeficiency (SCID) mice. METHODS: Human SDF-1 complementary Deoxyribonucleic acid (cDNA) was transfected into bone marrow-derived mesenchymal stem cells with recombinant lentiviral vector. The expression of SDF-1 was detected by real-time Polymerase Chain Reaction (PCR) and Enzyme-Linked Immunosorbent Assay (ELISA), and the ex vivo chemotaxis function on CD34(+) cells was measured by coculture system and Transwell system. SDF-1 gene-modified mesenchymal stem cell (MSC) and CD34(+) cells were infused into lethally irradiated SCID mice and the hematopoietic reconstitution in the recipient mice was examined. RESULTS: Messenger ribonucleic acid (mRNA) and protein of SDF-1 in infected MSC were significantly higher than that of the non-infected control MSC (p < 0.05). The infected MSC have significant chemotaxis effect on CD34(+) cells in vitro and promote hematopoietic reconstitution after CD34(+) cell transplantation in vivo. CONCLUSION: MSC with high-level expression of SDF-1 can synergistically promote hematopoietic reconstitution after CD34(+) cell transplantation in lethally irradiated SCID mice. PMID- 20201650 TI - Evaluation of continuous low dose rate versus acute single high dose rate radiation combined with oncolytic viral therapy for prostate cancer. AB - PURPOSE: Conditionally Replicative Adenovirus (CRAd) has been previously demonstrated to augment the activity of radiation, resulting in synergy of cell kill. However, previous models combining radiation with CRAd have not focused on the methods of radiation delivery. MATERIALS AND METHODS: We model the combination of a novel prostate-specific CRAd, Ad5 PSE/PBN E1A-AR (Ad5: adenovirus 5; PSE: prostate-specific enhancer; PBN: rat probasin promoter; E1A: early region 1A; AR: androgen receptor), with radiation delivered both acutely and continuously, in an effort to better mimic the potential clinical modes of prostate cancer radiotherapy. RESULTS: We demonstrate that pre-treatment of cells with acute single high dose rate (HDR) radiation 24 hours prior to viral infection results in significantly enhanced viral replication and virus-mediated cell death. In addition, this combination causes increased level of gamma-H2AX (Phosphorylated histone protein H2AX on serine 139), a marker of double-stranded DNA damage and an indirect measure of nuclear fragmentation. In contrast, continuous low dose rate (LDR) radiation immediately following infection of the same CRAd results in no enhancement of viral replication, and only additive effects in virus-mediated cell death. CONCLUSIONS: These data provide the first direct assessment of the real-time impact of radiation on viral replication and the first comparison of the effect of radiation delivery on the efficacy of CRAd virotherapy. Our data demonstrate substantial differences in CRAd efficacy based on the mode of radiation delivery. PMID- 20201652 TI - The effect of ionising radiation on testosterone binding globulin characteristics: correction of the protein' parameters by lipid polyene complexes of fungus Laetiporus sulfureus. AB - PURPOSE: The aims of this work were: (i) To compare the effects of ionising radiation (IR) on testosterone binding globulin (TeBG) characteristics (serum concentration, cooperativity of androgen binding and affinity for hormone) in divergent mammalian species; (ii) to couple radiation effects with probable TeBG parameter changes; and (iii) to investigate the prevention of these changes by fungal preparations (in particular - by lipid polyene complexes of Laetiporus sulphureus). MATERIALS AND METHODS: Characteristics of TeBG were investigated in microaliquots of rat and human serum samples using [(3)H]-5 alpha dihydrotestosterone ([(3)H]-DHT) radioligand assays after in vivo exposures to IR (external gamma-sources, incorporation of (131)I-, (137)Cs-radionuclides) at experimental and post-Chernobyl radioecological conditions (doses 0.25-2.2 Gy). RESULTS: Species-specific changes of TeBG parameters were found depending on the type of IR, dose and time after irradiation. Specifically children living in radionuclide contaminated regions (near Chernobyl) were found to have a decrease of positive cooperativity for the TeBG-androgen binding, a drop of TeBG levels, and a decline in hormone affinity. Screening of natural substances (from phanerogams and fungi) detected that lipid polyene complexes of the basidiomycete L. sulphureus allowed recovery of the standard features of TeBG. CONCLUSIONS: IR induced a depletion of TeBG from blood simultaneously with species-specific changes of TeBG, which depend on the type of radiation, the dose of radiation (from 0.25 up to 2.2 Gy), and the time after radiation. The Hill coefficient of TeBG (indicating the degree of molecular cooperativity when hormone binding) appeared to be the most radiosensitive marker of the glycoprotein activity because of it is inversely to radiation dose. There are pharmacological possibilities to restore IR-induced "declines" of TeBG's affinity and cooperativity for androgen ligand binding. PMID- 20201653 TI - Molecular radiobiology meets clinical radiation oncology. AB - BACKGROUND: The 2nd Langendorff Congress in Freiburg in Breisgau (Germany) gathered basic and translational scientists as well as clinicians interested in recent developments in molecular and clinical radiobiology. The topics ranged from the most recent insight into the organisation of the DNA damage response and radiotherapeutically relevant cell death mechanisms to biological imaging for treatment planning and advances in the understanding of the molecular biological effects of particle beams. Clinical aspects of stem cell and tumour stem cell biology as well as of angiogenesis and hypoxia, the search for novel molecular radiosensitisers and potential strategies for exploitation of the immune system to further improve tumour radiotherapy were also discussed. RESULTS AND CONCLUSION: This report surveys the presentations at the meeting, considering their significance in light of the literature, and documents the increasing importance of molecular radiobiology for clinical radiooncology. PMID- 20201655 TI - Current and future perspectives in cardiogenic shock, reperfusion strategies and hemodynamic inotropic support for acute heart failure. PMID- 20201654 TI - Plasma disc decompression compared with fluoroscopy-guided transforaminal epidural steroid injections for symptomatic contained lumbar disc herniation: a prospective, randomized, controlled trial. AB - OBJECT: Patients with radiculopathy, with or without back pain, often do not respond to conservative care and may be considered for epidural steroid injection therapy or a disc decompression procedure. Plasma disc decompression (PDD) using the Coblation SpineWand device is a percutaneous, minimally invasive interventional procedure. The purpose of this study was to evaluate clinical outcomes with PDD as compared with standard care using fluoroscopy-guided transforaminal epidural steroid injection (TFESI) over the course of 2 years. METHODS: This was a multicenter randomized controlled clinical study. Ninety patients (18-66 years old) who had sciatica (visual analog scale score > or = 50) associated with a single-level lumbar contained disc herniation were enrolled. In all cases, their condition was refractory to initial conservative care and 1 epidural steroid injection had failed. Participants were randomly assigned to receive either PDD (46 patients) or TFESI (44 patients, up to 2 injections). RESULTS: The patients in the PDD Group had significantly greater reduction in leg pain scores and significantly improved Oswestry Disability Index and 36-Item Short Form Health Survey ([SF-36], physical function, bodily pain, social function, and physical components summary) scores than those in the TFESI Group. During the 2-year follow-up, 25 (56%) of the patients in the PDD Group and 11 (28%) of those in the TFESI Group remained free from having a secondary procedure following the study procedure (log-rank p = 0.02). A significantly higher percentage of patients in the PDD Group showed minimum clinically important change in scores for leg and back pain and SF-36 scores that exceeded literature based minimum clinically important changes. Procedure-related adverse events, including injection site pain, increased leg or back pain, weakness, and lightheadedness, were observed in 5 patients in the PDD Group (7 events) and 7 in the TFESI Group (14 events). CONCLUSIONS: In study patients who had radicular pain associated with a contained lumbar disc herniation, those patients treated with PDD had significantly reduced pain and better quality of life scores than those treated using repeated TFESI. In addition, significantly more PDD patients than TFESI patients avoided having to undergo a secondary procedure during the 2 year study follow-up. PMID- 20201656 TI - Predictors and in-hospital outcomes of cardiogenic shock on admission in patients with acute coronary syndromes admitted to hospitals without on-site invasive facilities. AB - BACKGROUND: The purpose was to identify predictors of cardiogenic shock (CS) on admission and to asses associations between CS and real-life management patterns and outcomes in unselected cohort of acute coronary syndrome (ACS) patients admitted to hospitals without onsite invasive facilities. METHODS: Data concerning in-hospital management and mortality of 56 (4.3%) patients with and 1257 (95.7%) without CS on hospital admission was assessed. RESULTS: Prior myocardial infarction, prior heart failure symptoms, age, and diabetes mellitus were independently associated with increased risk of CS on admission. A total of 23.8% patients were transferred for invasive treatment during index hospital stay and the frequency of transfer was similar among patients with and without CS on admission (21.4% versus 23.9%; P = 0.75), but in the STEMI subgroup, patients with shock were transported less frequently (21.4% versus 43.8%; P = 0.0027). CS patients were less likely to receive guideline-recommended therapies including antiplatelet drugs, statins, and beta-blockers. In-hospital mortality was lower in non-shock patients (6.2% versus 63.6%; P < 0.001) and CS on admission was an independent predictor of in-hospital death. CONCLUSIONS: CS on admission is an important determinant of treatment strategy selection and is associated with unfavorable prognosis of ACS patients admitted to hospitals without on-site invasive facilities. PMID- 20201657 TI - Early treatment with abciximab in patients with ST elevation myocardial infarction results in a high rate of normal or near normal blood flow in the infarct related artery. AB - There is debate whether early treatment with GpIIb/IIIa inhibitors is of clinical benefit in primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI). This study explored the effects of early given abciximab on coronary blood flow and major adverse cardiac events (MACE) in patients with STEMI treated with primary PCI and adjunctive abciximab. We studied all consecutive patients from our catchment area with STEMI undergoing acute angiography with the intention of primary PCI during 2005. Abciximab was given as early pre-treatment before, (n = 133) or at the cath. lab. after a diagnostic angiography (n = 109). Pre-procedural TIMI 2-3 flow was observed in 45.9 % of patients in the early group versus 20.2 % in the cath. lab. group, P = 0.0001. Mortality rates were 3.8 % versus 3.7% inhospital and 8.3 % versus 7.3% at one year in the early respectively the cath. lab. group, both P = NS. The MACE rate (death, non fatal myocardial infarction, unplanned revascularization) at one year was 19.5 % (early group) and 26.6 % (cath. lab. group), P = 0.19. CONCLUSION: In this single centre registry study of unselected patients with STEMI early given abciximab was associated with a significantly higher rate of TIMI 2-3 flow compared to abciximab given after the acute angiography. PMID- 20201658 TI - From multimarker approach to multiplex assays in acute coronary syndromes: what are we searching for? AB - In the setting of acute coronary syndrome (ACS) the enhancement of analytical performances for several biomarkers improved the understanding of complex ACS pathogenesis highlighting the potential targets of treatment. The introduction of multiplex arrays, developed on ELISA methodology, measuring simultaneously multiple proteins in one assay, allowed the chance to obtain patient multimarker profiles. Aim of this commentary is to clarify the clinical reliability and usefulness of multiplex arrays, in ACS context, referring to available recent methodological and translational research literature. We reported that a certain number of clinical studies in ACS considered these methods but provided poor evidence, since their lack of standardization. The main drawback of multiplex arrays lies in the cross-reactions between the array antibodies with the reagents of co-detected analytes and with the sample matrix proteins. This cross reactivity rises as the increasing number of markers assayed in the same plate. We have shown that these multiplex arrays were employed to screen markers potentially involved in the disease, among a wide spectrum of proteins, without a preliminary robust biological hypothesis. The need of up-to-date biostatistical approaches is stressed. Researchers should address their efforts to build up and standardize sub-microarrays measuring a lower number of markers than multiplex one, selected on a clear link with ACS evolution. PMID- 20201659 TI - Acute eosinophilic myocarditis: diagnosis and treatment. AB - Hypereosinophilic syndrome (HES) is a rare disorder of unregulated eosinophilia, which if untreated, may lead to systemic tissue infiltration and inflammation. Cardiac involvement is a common and serious associated complication. We describe a case of HES associated myocarditis mimicking a non-ST elevation MI (NSTEMI). Unlike myocarditis in general, our patient responded well to high dose methylprednisone, the standard of care in HES. We review the clinical presentation, pathophysiology, pathology and treatment of eosinophilic myocarditis related to HES. PMID- 20201660 TI - Pure retroperitoneoscopic surgery versus minimal incision-assisted retroperitoneoscopic surgery for upper urinary tract diseases. AB - OBJECTIVES: We developed minimal incision-assisted retroperitoneoscopic surgery (MARP) in an attempt to pursue optimized patient-related benefits. We evaluated the clinical value of MARP for upper urinary tract diseases compared with pure retroperitoneoscopic surgery (PRPS). PATIENTS AND METHODS: Between January 2003 and September 2008, PRPS and MARP were carried out in 338 and 85 patients, respectively. The upper urinary tract surgical procedures were defined as simple and complex procedures. We defined our experience from January 2003 to December 2005 as our early stage of PRPS learning curve. Our experience from January 2006 to September 2008 was defined as our late stage of PRPS learning curve. Patients' perioperative details were compared. RESULTS: MARP was associated with shorter operative time for each complex procedure and with less frequent conversion to open surgery (2.4% vs. 11.3%, p = 0.023). A significantly greater proportion of MARP patients underwent complex procedures (81.2% vs. 49.1%, p < 0.001), and a significantly greater proportion of MARP were carried out at the early stage of PRPS learning curve (62.4% vs. 44.1%, p = 0.003). Estimated blood loss, hospital stay, the amount of analgesic use (diclofenac sodium suppository), and intraoperative and postoperative complications were comparable. CONCLUSIONS: MARP maintains the patient-related benefits of PRPS while allowing surgeons to perform more complex cases of upper urinary tract diseases and shortening the relevant operative time. It can be useful for cases in which the specimen is going to be extracted intact, when starting out learning retroperitoneoscopy, or when unable to progress the case using laparoscopic techniques. PMID- 20201661 TI - Comparison of neodymium-doped yttrium aluminum garnet laser treatment with cold knife endoscopic incision of urethral strictures in male patients. AB - OBJECTIVE: To assess the effectiveness of visual laser ablation treatment with neodymium-doped yttrium aluminum garnet (Nd:YAG) laser in male patients with urethral strictures and to compare the effects with those obtained in patients treated with Sachse's optical urethrotomy. MATERIALS AND METHODS: Fifty patients aged 22 to 83 (mean age 61.8) with primary (n = 26, 52%) and recurrent (n = 24, 48%) urethral strictures 0.3 to 2.4 cm long qualified for the study. The patients were randomized into two groups: 30 men treated using visual laser ablation of urethral strictures (VLASU) with Nd:YAGlaser and 20 men treated by correction of urethral strictures using Sachse's optical urethrotomy. RESULTS: At 12-month follow-up, seven (35%) patients who underwent optical urethrotomy and 21 (70%) in the VLASU group did not require repetition of the procedure. The choice of VLASU as a method of treatment significantly decreased the probability of therapeutic failure and recurrence of urethral strictures (p = 0.02). CONCLUSION: VLASU can be used as a method of treatment of this disorder. It is an effective, modern, low-invasive, and repeatable technique and is technically simple and easy to master. It can be used in cases in which introduction of a 22 Char optical urethrotome into the stricture site is impossible, as well as for treatment of multiple strictures during one procedure. PMID- 20201662 TI - Thermal effects from modified endodontic laser tips used in the apical third of root canals with erbium-doped yttrium aluminium garnet and erbium, chromium-doped yttrium scandium gallium garnet lasers. AB - OBJECTIVE: To evaluate the temperature changes occurring on the apical third of root surfaces when erbium-doped yttrium aluminium garnet (Er:YAG) and erbium, chromium-doped yttrium scandium gallium garnet (Er,Cr:YSGG) laser energy was delivered with a tube etched, laterally emitting conical tip and a conventional bare design optical fiber tip. BACKGROUND DATA: Thermal effects of root canal laser treatments on periodontal ligament cells and alveolar bone are of concern in terms of safety. MATERIALS AND METHODS: A total of 64 single-rooted extracted teeth were prepared 1 mm short of the working length using rotary nickel-titanium Pro-Taper files to an apical size corresponding to a F5 Pro-Taper instrument. A thermocouple located 2 mm from the apex was used to record temperature changes arising from delivery of laser energy through laterally emitting conical tips or plain tips, using an Er:YAG or Er,Cr:YSGG laser. RESULTS: For the Er:YAG and Er,Cr:YSGG systems, conical fibers showed greater lateral emissions (452 + 69% and 443 + 64%) and corresponding lower forward emissions (48 + 5% and 49 + 5%) than conventional plain-fiber tips. All four combinations of laser system and fiber design elicited temperature increases less than 2.5 degrees C during lasing. The use of water irrigation attenuated completely the thermal effects of individual lasing cycles. CONCLUSIONS: Laterally emitting conical fiber tips can be used safely under defined conditions for intracanal irradiation without harmful thermal effects on the periodontal apparatus. PMID- 20201663 TI - Ultra-structural changes at the apical stop irradiated with CO2 laser. AB - OBJECTIVE: This study evaluated ultra-structural dentine changes at the apical stop after CO(2) laser irradiation used during biomechanical preparation. BACKGROUND: Most studies evaluating the sealing efficiency of CO(2) lasers have been carried out after apical root canal resections and retro-filling procedures. METHODS: Sixty human canines were prepared with #1 to #6 Largo burs. The apical stops were established at 1 mm (n = 30) and 2 mm (n = 30) from the apex. Final irrigation was performed with 1% NaOCl and 15% EDTA followed by 20 ml of distilled and deionized water. Specimens were subdivided into three subgroups (n = 10 for each stop distance): GI- no radiation (n = 20); GII- 3W potency (n = 20), GIII- 5W potency (n = 20). After preparation, specimens were evaluated by scanning electron microscopy, with ultra-structural changes classified according to a scoring system based on six qualitatively different outcomes. RESULTS: Statistical analysis using the Mann-Whitney test confirmed more intense results for the specimens irradiated at 5 W potency than at 3 W (p < 0.0001). The Kruskal Wallis test indicated that when using the same potencies (3 or 5 W) at 1 and 2 mm from the apex, there were no statistically significant differences in ultra structural changes. CONCLUSIONS: Our results showed that ultra-structural changes ranged from smear layer removal to dentine fusion. As laser potency was increased from 3 to 5 W, ultra-structural changes included extensive fused lava-like areas sealing the apical foramen. PMID- 20201664 TI - Effect of GaAlAs laser irradiation on the epiphyseal cartilage of rats. AB - OBJECTIVE: To study the effect of an 830-nm gallium-aluminum-arsenic (GaAlAs) diode laser at two different energy densities (5 and 15 J/cm(2)) on the epiphyseal cartilage of rats by evaluating bone length and the number of chondrocytes and thickness of each zone of the epiphyseal cartilage. BACKGROUND DATA: Few studies have been conducted on the effects of low-level laser therapy on the epiphyseal cartilage at different irradiation doses. MATERIALS AND METHODS: A total of 30 male Wistar rats with 23 days of age and weighing 90 g on average were randomly divided into 3 groups: control group (CG, no stimulation), G5 group (energy density, 5 J/cm(2)), and G15 group (energy density, 15 J/cm(2)). Laser treatment sessions were administered every other day for a total of 10 sessions. The animals were killed 24 h after the last treatment session. Histological slides of the epiphyseal cartilage were stained with hematoxylin eosin (HE), photographed with a Zeiss photomicroscope, and subjected to histometric and histological analyses. Statistical analysis was performed using one-way analysis of variance followed by Tukey's post hoc test. All statistical tests were performed at a significance level of 0.05. RESULTS: Histological analysis and x-ray radiographs revealed an increase in thickness of the epiphyseal cartilage and in the number of chondrocytes in the G5 and G15 groups. CONCLUSION: The 830-nm GaAlAs diode laser, within the parameters used in this study, induced changes in the thickness of the epiphyseal cartilage and increased the number of chondrocytes, but this was not sufficient to induce changes in bone length. PMID- 20201665 TI - Can anti-infective drugs improve the infection-related symptoms of patients with cancer during the terminal stages of their lives? AB - BACKGROUND: Appropriate use of anti-infective drugs is essential in clinical practice. No evidence-based guidelines or protocols have been published on the appropriate use of anti-infective drugs in patients receiving palliative care as yet. METHODS: The medical records, which included the demographic data of patients, anti-infective drug use, bacteriologic findings, symptoms, and hematologic findings were reviewed retrospectively to determine the potential factors that contribute to symptom improvement of patients in terminal phase. RESULTS: Seventy-one patients (64%) who received anti-infective drugs and had a total of 326 episodes of infection were assessed. Symptom improvement was seen in 33.1%. A total of 22.6% of episodes were started on anti-infective drugs during the last week of life and the symptom improvement in these episodes was 9.2%. Symptom improvement was hardly observed when the anti-infective drug was administered during the last week of life. The association between the decrease in the C-reactive protein (CRP) levels, the decrease of the leukocyte count, reduction of fever, and symptom improvement was determined. The decrease of CRP levels was 42.4%; leukocyte, 56.7%; and reduction of fever was 28.4%. The symptom improvement of individual treatment history was also investigated. The symptom improvement of the group who took positive treatment such as chemotherapy, radiotherapy, surgery, and catheter placement was significantly lower than that of no-treatment group. CONCLUSIONS: Active cancer treatment probably induces the symptoms related to infection and the use of anti-infective drugs. Unnecessary and excessive treatment should be avoided, and the symptoms should be managed with consideration of the patient's state of mind in order to improve the quality of life of terminally ill patients. PMID- 20201666 TI - Improving residents' end-of-life communication skills with a short retreat: a randomized controlled trial. AB - BACKGROUND: Internal medicine residents are largely unprepared to carry out end of-life (EOL) conversations. There is evidence that these skills can be taught, but data from randomized controlled trials are lacking. PURPOSE: We studied whether a day-long communication skills training retreat would lead to enhanced performance of and confidence with specific EOL conversations. We also studied the effect of the retreat on residents' ability to respond to patient emotions. METHODS: PGY-2 resident volunteers were randomly assigned to a retreat group or a control group. The retreat involved a combination of teaching styles and skills practice with standardized patients. All participants completed questionnaires and were evaluated carrying out two types of conversations (breaking bad news or discussing direction of care) with a standardized patient before (T1) and after (T2) the intervention phase. Conversations were audio-taped and later rated by a researcher blinded to group assignment and time of assessment. RESULTS: Forty nine residents agreed to randomization (88%) with 23 residents randomized to the retreat group and 26 to the control group. Compared to controls, retreat participants demonstrated higher T2 scores for breaking bad news, discussing direction of care, and responding to emotion. Comparing T2 to T1, the retreat group's improvement in responding to emotion was statistically significant. The retreat group's confidence improved significantly only for the breaking bad news construct. CONCLUSIONS: A short course for residents can significantly improve specific elements of resident EOL conversation performance, including the ability to respond to emotional cues. PMID- 20201667 TI - Advance care planning and hospice enrollment: who really makes the decision to enroll? AB - PURPOSE: The purpose of this study was to assess patient participation in advance care planning (ACP) and the decision to enroll in hospice. METHODS: One hundred sixty-five family members of patients who died in hospice between January 2004 and September 2004 returned an anonymous survey (165/380; 43% response rate). RESULTS: Forty-nine percent of family members reported that the patient was not involved in the hospice enrollment decision. The majority of respondents (78%) reported one or more people helped make the decision to enroll in hospice. For patients reported as being involved in the decision to enroll in hospice (either independently or in a shared capacity) they were more likely to have cancer (odds ratio [OR] = 2.3, p = 0.02), die at home (OR = 3.3, p = 0.006), have a length of stay in hospice greater than 7 days (OR = 2.1, p = 0.03), and less likely to have dementia (OR = 0.43, p = 0.001). White respondents were more likely to report having ACP discussions with the patient about: feeding tubes (OR = 4.7; p = 0.001), cardiopulmonary resuscitation (CPR; OR = 3.9; p = 0.002), or mechanical ventilation (OR = 2.7; p = 0.02) than non-white respondents. White respondents were more likely than non-white respondents to report that the patient had a written advance directive (OR = 4.2, p = 0.001). DISCUSSION: These data indicate that some patients are not actively involved in the decision to enroll in hospice and that others, often physicians and family members, are making these decisions for the patient collaboratively. These data support the need for early education and interventions that assist patients and families in discussing ACP preferences and the need for greater understanding of how involved patients want to be with the decision to enroll in hospice. PMID- 20201669 TI - Large infiltrated erythematous and scaly plaque on the cheek and thickened earlobe. PMID- 20201668 TI - Whole-brain proton MR spectroscopic imaging of mild-to-moderate traumatic brain injury and correlation with neuropsychological deficits. AB - Changes in the distribution of the magnetic resonance (MR)-observable brain metabolites N-acetyl aspartate (NAA), total choline (Cho), and total creatine (Cre), following mild-to-moderate closed-head traumatic brain injury (mTBI) were evaluated using volumetric proton MR spectroscopic imaging (MRSI). Studies were carried out during the subacute time period following injury, and associations of metabolite indices with neuropsychological test (NPT) results were evaluated. Twenty-nine subjects with mTBI and Glasgow Coma Scale (GCS) scores of 10-15 were included. Differences in individual metabolite and metabolite ratio distributions relative to those of age-matched control subjects were evaluated, as well as analyses by hemispheric lobes and tissue types. Primary findings included a widespread decrease of NAA and NAA/Cre, and increases of Cho and Cho/NAA, within all lobes of the TBI subject group, and with the largest differences seen in white matter. Examination of the association between all of the metabolite measures and the NPT scores found the strongest negative correlations to occur in the frontal lobe and for Cho/NAA. No significant correlations were found between any of the MRSI or NPT measures and the GCS. These results demonstrate that significant and widespread alterations of brain metabolites occur as a result of mild-to-moderate TBI, and that these measures correlate with measures of cognitive performance. PMID- 20201671 TI - Bronchoalveolar lavage fluid galactomannan for diagnosis of invasive pulmonary aspergillosis. PMID- 20201672 TI - Galactomannan detection and diagnosis of invasive aspergillosis. PMID- 20201674 TI - The endangered white coat. PMID- 20201675 TI - Mixed cryoglobulinemia: a role for parvovirus b19 infection. PMID- 20201680 TI - The fate of carbon in growing fish: an experimental study of isotopic routing. AB - The application of stable isotope analysis to ecology requires estimating the contribution of different isotopic sources to the isotopic signatures of an animal's tissues using mixing models. These models make the physiologically unrealistic assumption that assimilated nutrients are disassembled into their elemental components and that these atoms are then reassembled into biomolecules. We quantified the extent to which mixing models yield erroneous results with an experiment using Nile tilapia (Oreochromis niloticus). The tilapia were fed synthetic diets that varied in protein content and in which the carbon isotopic composition of protein differed widely from that of carbohydrates and lipids. We predicted that dietary protein would contribute disproportionately to the carbon in muscle, whereas the nonprotein components of diet would contribute disproportionately to lipids. Our experiment also allowed us to test the conjecture of a positive correlation between the (15)N enrichment in tissues and protein intake. As predicted, the contribution of protein carbon to muscle was higher than that expected by the assumptions of isotopic mixing in all treatments except that with the lowest dietary protein content. We hypothesized that the unexpectedly high contribution of nonprotein carbon to muscle was the result of assimilating both dispensable and indispensable amino acids synthesized by the fishes' gut microbiota. Although we expected the contribution of carbon in nonprotein dietary ingredients to be higher than expected from a mixing model, we found that protein contributed more than expected, probably as a result of differences in amino acid composition between diet and tissues, which led to excess carbon used for lipid synthesis. Finally, our results verified the positive relationship between dietary protein content and the enrichment in tissue (15)N. Assuming perfect mixing in field isotopic studies can lead to erroneous inferences about the relative contributions of different sources to an animal's diet. PMID- 20201681 TI - Undifferentiated propagation of the human embryonic stem cell lines, H1 and HSF6, on human placenta-derived feeder cells without basic fibroblast growth factor supplementation. AB - In order for human embryonic stem cells (hESCs) to be cultured on mouse embryonic fibroblast (MEFs) feeder cells, continuous basic fibroblast growth factor (bFGF) supplementation is required. However, the role of bFGF in a culture system using human-derived feeder cells has not been evaluated until now. In this study, we propagated the widely used hESC lines, H1 and HSF6, on human placenta-derived feeder cells (HPCs) without exogenous bFGF supplementation, and were able to propagate hESCs on HPC feeders up to 50 passages. The absence of bFGF in culture media did not interrupt the undifferentiated propagation and the expression of pluripotent stem cell markers ALP, SSEA-4, TRA-60, Oct-4, Nanog, and Rex-1, as well as the formation of embryoid bodies (EBs) and their differentiation potential. In contrast, hESCs cocultured with MEF feeders could not propagate and form EBs without exogenous bFGF supplementation. Expression of bFGF and the activation of the ERK1/2-c-Fos/c-Jun pathway, which is known as the signaling pathway of bFGF, were identifiable not only in hESCs cultured in bFGF-containing media regardless of feeder cell type, but also in hESCs cocultured with HPC feeder cells in media without bFGF. These findings may support the hypothesis that HPC feeder cells enhance endogenous bFGF production and activation of the ERK1/2-c-Fos/c-Jun pathway, which suggests that HPCs have an additional advantage in their hESC propagation compared with MEF. PMID- 20201683 TI - Preliminary face and construct validation study of a virtual basic laparoscopic skill trainer. AB - BACKGROUND: The Virtual Basic Laparoscopic Skill Trainer (VBLaST) is a developing virtual-reality-based surgical skill training system that incorporates several of the tasks of the Fundamentals of Laparoscopic Surgery (FLS) training system. This study aimed to evaluate the face and construct validity of the VBLaST system. MATERIALS AND METHODS: Thirty-nine subjects were voluntarily recruited at the Beth Israel Deaconess Medical Center (Boston, MA) and classified into two groups: experts (PGY 5, fellow and practicing surgeons) and novice (PGY 1-4). They were then asked to perform three FLS tasks, consisting of peg transfer, pattern cutting, and endoloop, on both the VBLaST and FLS systems. The VBLaST performance scores were automatically computed, while the FLS scores were rated by a trained evaluator. Face validity was assessed using a 5-point Likert scale, varying from not realistic/useful (1) to very realistic/useful (5). RESULTS: Face-validity scores showed that the VBLaST system was significantly realistic in portraying the three FLS tasks (3.95 +/- 0.909), as well as the reality in trocar placement and tool movements (3.67 +/- 0.874). Construct-validity results show that VBLaST was able to differentiate between the expert and novice group (P = 0.015). However, of the two tasks used for evaluating VBLaST, only the peg-transfer task showed a significant difference between the expert and novice groups (P = 0.003). Spearman correlation coefficient analysis between the two scores showed significant correlation for the peg-transfer task (Spearman coefficient 0.364; P = 0.023). CONCLUSIONS: VBLaST demonstrated significant face and construct validity. A further set of studies, involving improvement to the current VBLaST system, is needed to thoroughly demonstrate face and construct validity for all the tasks. PMID- 20201684 TI - Robot-assisted laparoscopic middle pancreatectomy. AB - BACKGROUND: Middle pancreatectomy has been accepted as a valid surgical alternative to more extensive standard resections for the treatment of benign central pancreatic tumors. In this article, we describe a new minimally invasive approach to this procedure, using a robot-assisted laparoscopic technique. MATERIALS AND METHODS: From May 2004 to October 2005, 3 patients (2 female and 1 male), with a mean age of 52 years (range, 44-68), underwent robot-assisted laparoscopic middle pancreatectomies at the Department of General Surgery of Misericordia Hospital in Grosseto, Italy. Two of the patients had symptomatic serous cystadenomas, and 1 patient had a mucinous cystadenoma, which was discovered incidentally. The da Vinci((R)) Surgical System (Intuitive Surgical, Sunnyvale, CA) was used to perform the main steps of the intervention. All patients underwent a pancreaticogastrostomy for pancreaticoenteric reconstruction to the distal stump. RESULTS: The mean operative time was 320 minutes (range, 270 380). Mean blood loss was 233 mL (range, 100-400). There were no mortalities. One patient developed a postoperative pancreatic fistula, which was managed conservatively. The postoperative hospital stay was 9 days for 2 patients and 27 days for the third patient. No endocrine or exocrine deficiencies were observed in the patients during a mean follow-up of 44 months (range, 38-48). CONCLUSIONS: Robot-assisted laparoscopic middle pancreatectomy presents an interesting, less invasive option for resection of benign tumors of the neck and proximal body of the pancreas. In benign disease, it allows for the preservation of functional pancreatic parenchyma and, subsequently, reduced operative trauma. PMID- 20201685 TI - Robot-assisted laparoscopic extended right hepatectomy with biliary reconstruction. AB - Robotic surgery represents one of the most advanced developments in the field of minimally invasive surgery. In this article, we describe the case of an extended right hepatectomy with a left hepaticojejunostomy performed for radical resection of a hilar cholangiocarcinoma. This operation was performed by using the da Vinci Robotic Surgical System (Intuitive Surgical, Sunnyvale, CA). In this case, the operative time was 540 minutes, with an intraoperative blood loss of 800 mL. The postoperative course was uneventful, and the patient was discharged at postoperative day 11. This report confirms the technical feasibility and safety of robot-assisted extended hepatic resections with biliary reconstruction. Further experience and a long follow-up are required to validate this initial report. PMID- 20201686 TI - Postoperative patient attitudes and perceptions of transvaginal cholecystectomy. AB - A survey was conducted in order to dispel misconceptions about natural orifice transvaginal cholecystectomy. Forty-two patients were surveyed after having undergone that procedure. Those patients were asked questions related to 1) patient satisfaction, 2) whether they would recommend the procedure to others, and 3) dyspaurenia. The survey was done after a sexual abstinence period that varied from 30 to 40 days. We encountered no complications, and all patients liked the procedure and would recommend it to family and friends. No patient developed dyspaurenia. The postoperative responses were unanimous and positive for all questions. The result of this postoperative transvaginal cholecystectomy survey will help patients and surgeons ease their fears and social taboos and better communicate, and this will help patients to become aware of the option of transvaginal peritoneoscopy. PMID- 20201687 TI - Outcome of a strategy to reduce surgical site infection in a tertiary-care hospital. AB - BACKGROUND: Surgical site infection (SSI) is a preventable complication. Achieving a zero SSI rate for all clean operations should be the goal of all surgeons. AIM: We aimed to reduce our SSI rate by 50% for patients undergoing elective gastrointestinal and hernia operations. METHODS: The study was conducted in a tertiary-care hospital department of surgery from January 2006 to December 2007 for all clean and clean-contaminated elective gastrointestinal and hernia operations. Four interventions targeted at reducing SSI were implemented in January 2006: Use of clippers instead of shavers for surgical site hair removal; standardized prophylactic antibiotic regimen and antibiotic administration within 30 min before incision; standardized glucose monitoring for diabetics; and maintenance of postoperative normothermia. Prospective data were collected and compared with historical data from January to December 2005. RESULTS: A total of 2,408 patients underwent elective gastrointestinal and hernia operations from January 2006 to December 2007. After implementation, we were able to achieve 91%, 87%, 89%, and 76% overall compliance with the respective interventions, but postoperative normothermia was achieved in only 44% of our patients. With the bundle of interventions, our overall SSI rate was reduced from 3.1% to 0.5% (p < 0.001), an 84% reduction within two years. The incidence of SSI was 1.7% in colorectal operations, 1.2% in upper gastrointestinal operations, 0.3% in hepatopancreaticobiliary operations, and zero in inguinal and ventral hernia operations. The estimated cost saving for both the patients and the hospital was S$208,562 (US$147,967). CONCLUSIONS: Surgical site infections could be reduced with the bundle of interventions. With these encouraging results, the good practices should be sustained and promulgated. Such a SSI prevention program must be embedded in the work processes for all surgical disciplines. PMID- 20201688 TI - Bacteremia increases the risk of death among patients with soft-tissue infections. AB - BACKGROUND: Soft-tissue infections traditionally have been viewed as carrying a lower risk of death than other types of infection such as pneumonia, blood stream, and intra-abdominal. The influence of secondary bacteremia on the outcomes of patients with soft-tissue infections is not well described. OBJECTIVES: To describe the risk factors for bacteremia among patients admitted to an urban medical center with soft-tissue infections and the influence of bacteremia on outcomes. METHODS: A retrospective cohort study of 717 patients with culture-positive non-necrotizing soft-tissue infections admitted between April 1, 2005, and December 31, 2007. RESULTS: Bacteremia was present in 52% of the patients. Increasing age, previous hospitalization, decubitus or lower extremity ulcers, device-related soft-tissue infection, and polymicrobial infection were independent predictors of bacteremia. Intensive care unit admission (adjusted odds ratio [AOR] 3.57; 95% confidence interval [CI] 2.17, 5.86), lower-extremity ulcer (AOR 3.43; 95% CI 2.07, 5.70), and bacteremia (AOR 6.37; 95% CI 3.34, 12.12) were independent predictors of in-hospital death. When patients with device-related soft-tissue infections were excluded, the rate of secondary bacteremia was 37.6% (201/535), and it remained an independent predictor of in-hospital death. CONCLUSIONS: The occurrence of bacteremia in soft tissue infections is associated with a greater risk of death. Health care providers should be aware of the risk factors for bacteremia in patients with soft-tissue infections in order to provide more appropriate initial antimicrobial therapy and to ascertain its presence as a prognostic indicator. PMID- 20201689 TI - Design of the silent cerebral infarct transfusion (SIT) trial. AB - BACKGROUND: Silent cerebral infarct (SCI) is the most common cause of serious neurological disease in sickle cell anemia (SCA), affecting approximately 22% of children. The goal of this trial is to determine whether blood transfusion therapy will reduce further neurological morbidity in children with SCI, and if so, the magnitude of this benefit. PROCEDURE: The Silent Cerebral Infarct Transfusion (SIT) Trial includes 29 clinical sites and 3 subsites, a Clinical Coordinating Center, and a Statistical and Data Coordinating Center, to test the following hypothesis: prophylactic blood transfusion therapy in children with SCI will result in at least an 86% reduction in the rate of subsequent overt strokes or new or progressive cerebral infarcts as defined by magnetic resonance imaging (MRI) of the brain. The intervention is blood transfusion versus observation. Two hundred and four participants (102 in each treatment assignment) will ensure 85% power to detect the effect necessary to recommend transfusion therapy (86% reduction), after accounting for 10% drop out and 19% crossover rates. MRI examination of the brain is done at screening, immediately before randomization and study exit. Each randomly assigned participant receives a cognitive test battery at study entry, 12-18 months later, and study exit and an annual neurological examination. Blood is obtained from all screened participants for a biologic repository containing serum and a renewable source of DNA. CONCLUSION: The SIT Trial could lead to a change in standard care practices for children affected with SCA and SCI, with a consequent reduction in neurological morbidity. PMID- 20201690 TI - Central nervous system (CNS) tumors in the first six months of life: the Children's Hospital Los Angeles experience, 1979-2005. AB - BACKGROUND: The authors report the experience at the Children's Hospital Los Angeles with brain tumors diagnosed before 6 months of age, describing the characteristics of the patients, their tumors, treatment strategies, and prognostic factors. METHODS: Thirty-three children who were identified between 1979 and 2005 were included. Twelve were female (36%). There were 11 gliomas, 9 choroid plexus tumors, 8 medulloblastomas and supratentorial primitive neuroectodermal tumors (PNET), 2 atypical teratoid/rhabdoid tumors (ATRT), and 1 each of ependymoma, craniopharyngioma, and immature teratoma. Locations of primary tumors included 21 supratentorial (64%) and 7 posterior fossa, and 5 tumors involved both compartments. The treatment strategies included 5 patients with biopsy only, 18 less than gross total resections (or=3 ppm). Pretransfusion ETCOc levels significantly correlated with pretransfusion reticulocyte count (r = .96, P <.001), but not with pretransfusion hemoglobin (r = .44, P = .16) or pretransfusion soluble transferrin receptors (sTfR, r = .52, P = .10). In conclusion, we found that patients with hemoglobinopathies have ETCOc values above the range for healthy controls and ETCOc measurements can be used as an adjunct to hemoglobin measurements to determine the proper timing of transfusions. PMID- 20201693 TI - Allogeneic hematopoietic stem cell transplantation is superior to immunosuppressive therapy in Indian children with aplastic anemia--a single center analysis of 100 patients. AB - The authors compared the outcome in 100 children (61 boys, 39 girls; median age of 10.1 +/- 3.4 years) with aplastic anemia who underwent either immunosuppressive therapy (IST; n = 70) or hematopoietic stem cell transplantation (HSCT; n = 30) between 1998 and 2007. Conditioning regimes for HSCT were a combination of either cyclophosphamide (Cy) with antilymphocyte globulin (ALG) or fludarabine (Flu) with Cy or busulfan (Bu) +/- antithymocyte globulin (ATG). Stem cell source was bone marrow in 20 and peripheral blood stem cells (PBSCs) in 10. Patients undergoing IST received either equine ALG or ATG in combination with steroids and cyclosporine. Primary engraftment was seen in 25 children (83.3%), with acute graft-versus-host disease (aGvHD) in 5 (16.6%). The day 100 transplant-related mortality (TRM) was 30% and at a median follow up of 36 months (range: 6-197), the overall and disease-free survival is 70%. Among children who received IST, 60 children received ALG while 10 received ATGAM. Responses were seen in 27 children (43.5%), which was complete (CR) in 12 and partial (PR) in 15. At a median follow up of 38 months (range: 1-84), the overall survival is 37.1%, with 81.4% survival among responders and <10% survival among non-responders. HSCT would be the treatment of choice in children with severe aplastic anemia who have a human leukocyte antigen (HLA)-matched related donor and is superior to IST in this series from India. PMID- 20201694 TI - Deciduoid mesothelioma of the pleura in an adolescent boy. AB - Deciduoid mesothelioma is an extremely rare variant of malignant epithelioid mesothelioma. This report presents the case of a 13-year-old boy with this type of tumor in his pleura, whose initial main symptoms were chest pains and progressive scoliosis. Ensuing chemotherapy, which comprised pemetrexed and cisplatin, yielded good response after 5 cycles. Subsequent radical surgery was carried out and another 3 cycles of chemotherapy were given. The patient has been doing well 2 years after completion of this regime of treatment. PMID- 20201695 TI - Successful mobilization with AMD3100 and filgrastim with engraftment of autologous peripheral blood stem cells in a heavily pretreated pediatric patient with recurrent Burkitt lymphoma. AB - The authors report a case of a 13-year-old female with recurrent Burkitt lymphoma who was heavily pretreated with chemotherapy. During chemotherapy for relapse, she developed serious aspergillus infection of the palate and sinuses. Despite 10 microg/kg of filgrastim for 5 days, peripheral blood CD34(+) cells remained or=40 years were enrolled in 1991. The follow-up evaluation was conducted in 1999-2000, with a response rate of 92.9%. RESULTS: A total of 829 CHD events (fatal and nonfatal) were observed among the participants who were free of cardiovascular diseases (CVD) at baseline. Higher SBP was significantly associated with more risk of CHD in both nonsmokers and current smokers (all p < 0.0001 for linear trends). Comparing with never smoking, both low and high levels of cigarettes smoked per day (1-7, and >or=8 cigarettes per day) and pack-years (<10, and >or=10 pack-years) were associated with increased risk of CHD in those with normal and high SBP. The multivariate adjusted relative risks (RRs) of CHD were 2.54 (95% confidence interval [CI] 2.00-3.23), 1.28 (1.01 1.63), and 1.57 (1.33-1.86) for current smokers with high SBP, current smokers with normal SBP, and nonsmokers with high SBP, respectively, compared with nonsmokers with normal SBP. The present study identified a statistically significant additive interaction between these two factors on CHD. CONCLUSIONS: Our study indicated that the combined effects of cigarette smoking and high SBP could be expected to have extra adverse effects on CHD in women, which highlights the importance of multifactorial interventions to decrease the risk of CHD, for example, quitting smoking and treatment of high blood pressure in Chinese women. PMID- 20201702 TI - Prevalence and factors associated with colorectal cancer screening in Canadian women. AB - AIMS: This representative study investigated the prevalence and factors associated with women's use of colorectal cancer (CRC) screening. METHODS: Women aged 50-74 were selected from the Ontario subsample of the 2005 Canadian Community Health Survey. Women who had never screened for CRC (n = 3676) were compared with women who had ever had CRC screening (n = 2105). Andersen's Behavioral Model of Health Service Use of predisposing, need, and enabling factors guided chi-square and logistic regression analyses. RESULTS: Fully 38% of women reported ever having CRC screening. Predisposing factors (older age, higher education, white race, currently having cancer [not CRC], and use of other screening tests), need factors (nonsmoking and physical activity level), and enabling factors (urban location, having a family doctor, more than five doctor visits annually, and greater sense of belonging), were each associated with higher odds of screening. Lower household income seemed to be associated with lower odds of screening. CONCLUSIONS: Despite CRC guidelines published before and during 2004, only 38% of women reported ever having CRC screening by 2005. Enabling factors contributed significantly to screening rates after adjustment for need factors, which provides some evidence that access to CRC screening by women was inequitable despite Canada's publicly funded healthcare system. Research findings can help develop female-specific strategies to increase rates of CRC screening. PMID- 20201703 TI - Frequency of cervical cancer and breast cancer screening in HIV-infected women in a county-based HIV clinic in the Western United States. AB - BACKGROUND: Women's primary-care services are frequently dispensed to HIV infected women through HIV specialty clinics. Our objective was to evaluate cervical cancer and breast cancer screening practices in a county-based HIV clinic in San Mateo, California. METHODS: This was a retrospective cohort study of medical records of HIV-infected women obtaining HIV care at this site. RESULTS: Between January 1, 2002 and December 31, 2006, 69 women were documented to have at least 12 months of medical care at the clinic. Median followup time was 51 months. Over 253 person-years of followup, there were 656 pap smears performed per 1,000 person-years; 77.9% of women had at least one Pap smear during the study time period. A total of 59.5% (47/79) of normal pap smears had a followup pap smear within 18 months; 62.0% of abnormal pap smears had a followup pap smear within 12 months. A CD4 count of less than 200 cells/mm(3) was associated with not receiving a pap smear in multivariable analysis. Mammogram screening was performed on 64.7% of women aged 40 or older. CONCLUSIONS: Based on the results of this study, the majority of HIV-infected women at this clinic received cervical and breast cancer screening at some point during their care. Only two-thirds of abnormal pap smear results had followup pap smear screening within a year. With the increased risk of cervical cancer in HIV-infected women, efforts should be made to promote cervical cancer screening, particularly in high risk women. PMID- 20201704 TI - Are all bisphosphonates the same? Potential reasons for clinical differences: a perspective. AB - Bisphosphonates are first-line treatment for postmenopausal osteoporosis and women with low bone mass and risk factors for fracture. These agents are often perceived as having equivalent effectiveness and safety and are even used interchangeably by some practitioners. Research suggests, however, that differences between them are meaningful to the patient and clinician. Data from randomized controlled trials and observational database studies have demonstrated variations between bisphosphonates in the scope of fracture protection, such as vertebral and nonvertebral, as well as the speed of onset of this antifracture effect. It has been proposed that unique properties of each compound related to their mechanisms of action could explain, at least in part, differences observed in clinical outcomes. Although the bisphosphonates share a similar core structure, they also contain two side chains or groups, R1 and R2, attached to the central carbon atom. All bisphosphonates approved by the FDA for postmenopausal osteoporosis contain a hydroxyl side group at position R1, increasing their binding to bone and distinguishing them from earlier bisphosphonates not approved for this clinical use. Differences in the physicochemical and biological properties of the approved bisphosphonates are due to differences in the R2 side group. The presence of nitrogen and its orientation within the R2 side chain can influence each bisphosphonate's overall potency. For the physician to optimally determine the bisphosphonate that best suits an individual patient, it is important that they are aware of the differences between them. PMID- 20201705 TI - Perceptions of HIV risk among monogamous wives of alcoholic men in South India: a qualitative study. AB - OBJECTIVE: To understand women's perceptions of their own HIV risk and to determine the feasibility of conducting an HIV prevention study. METHODS: Two focus groups were conducted in November 2004 with wives of heavy drinkers admitted to the Deaddiction Unit at the National Institute of Mental Health and Neurosciences (NIMHANS) in Bangalore, India. Data were analyzed using content analysis. RESULTS: Results focused on (1) awareness of the women regarding HIV/AIDS and condom use, (2) perception of personal risk for HIV/AIDS and the risk of their spouses, and (3) the feasibility of a future community-based HIV prevention study. Focus group findings indicated that although the majority of the women were aware of HIV/AIDS, there were important misconceptions about the mode of transmission. Women acknowledged the potential risk for HIV associated with their spouse's drinking, as well as their extramarital sexual activities, but expressed an inability to negotiate safer sex behaviors, such as condom use, within the context of marriage. This was often expressed as fear of being physically abused for attempting such negotiations. All women agreed that the HIV prevention study we proposed, originally developed in the West, would be acceptable if tailored to specific local needs. The women provided valuable suggestions for the effective implementation of the study. CONCLUSIONS: The findings of this study indicate a critical need to develop culturally relevant HIV prevention programs directly targeted to wives that equip them with effective skills to negotiate safer sex behaviors with their spouses. PMID- 20201706 TI - Progress and priorities in the health of women and girls: a decade of advances and challenges. AB - OBJECTIVE: Following the initial wave of federal support to address women's health, there is a need to assess successes and determine the next priorities to advance the health of women. The objective of this study was to systematically collect expert opinion on the major advances in women's health in the past decade and priorities for women's health research and service in the coming decade. METHODS: We utilized a Delphi method to query the leadership from academic and community Centers of Excellence in Women's Health, as designated by the Department of Health and Human Services. Leaders from 36 of the 48 centers responded to a series of questions about the major advances and critical indicators to evaluate future needs in women's health. We utilized a social ecology model framework to organize the responses to each question. RESULTS: The experts identified increased health education for women and increased empowerment of women across multiple spheres as the major advances positively impacting the health of women. The experts selected the following areas as the most important indicators to measure the status of the health of women in the future: health education and promotion, rates and impact of interpersonal violence against women, and access to healthcare. The major advances and measures of the health of women did not focus on specific changes to individual women in illness management, clinical care, or individual behavioral change. CONCLUSIONS: As we move to address health reform, we must be able to recognize and incorporate a broad perspective on public health and policy initiatives critical to the health and wellness of women and girls and, therefore, central to the well-being of the nation. PMID- 20201707 TI - Effect of baseline glomerular filtration rate on renal function following stenting for atherosclerotic renal artery stenosis. AB - OBJECTIVE: Percutaneous transluminal renal artery angioplasty and stenting (PTRAS) is one treatment option for atherosclerotic renal artery stenosis (ARAS). However, factors predicting the outcome remain controversial. This study investigated the effect of the baseline glomerular filtration rate (GFR) on renal function after PTRAS in patients with ARAS. MATERIAL AND METHODS: Patients who underwent PTRAS due to significant ARAS (luminal narrowing > or = 60%) were enrolled. The patients were divided into control (n = 57; estimated GFR (eGFR) > or = 60 ml/min/1.73 m(2)) and chronic renal failure (CRF) groups (n = 53; eGFR < 60 ml/min/1.73 m(2)), according to the baseline eGFR. RESULTS: The mean age at the time of PTRAS was 62 +/- 9 years, and the mean duration of follow-up was 50 +/- 26 months. There was a significant decrease in eGFR after PTRAS in the control group, whereas the CRF group showed no significant change in eGFR. The percentage change in eGFR was negatively correlated with the baseline eGFR (r = 0.274, p = 0.004). Multivariate linear regression revealed that only baseline eGFR predicted the change in eGFR (p = 0.032). CONCLUSIONS: PTRAS was more effective at preserving renal function in patients with moderately impaired renal function. Thus, baseline GFR may indicate the expected renal function outcome after PTRAS. PMID- 20201708 TI - Darbepoetin alfa in anemia of myelodysplastic syndromes: present and beyond. AB - IMPORTANCE OF THE FIELD: Anemia is the leading clinical manifestation in myelodysplastic syndromes (MDS), significantly altering quality of life. Darbepoetin alfa has recently been added to the armentarium of erythropoiesis stimulating agents (ESAs) for the treatment of anemia in MDS. AREAS COVERED IN THIS REVIEW: We review here the efficacy and safety data on the use of darbepoetin alfa in the management of anemia in MDS patients. Published reports covering the period from 2005 till today were reviewed, as well as updated guidelines on the use of ESAs. WHAT THE READER WILL GAIN: Darbepoetin alfa administered, during correction phase, once a week or at longer intervals, yielded erythroid response rates comparing favourably with those obtained with recombinant human erythropoietin (rHuEPO) in lower-risk MDS. During maintenance phase, intervals between injections can be further increased in many responders. Quality of life was consistently improved in responders and the drug was overall well tolerated. TAKE HOME MESSAGE: Those results, together with recent studies showing improved long-term outcomes in responders, support the use of darbepoetin, among other ESAs, for the treatment of anemia of lower-risk MDS, as recommended by international guidelines. PMID- 20201709 TI - Enhanced T cell receptor gene therapy for cancer. AB - IMPORTANCE OF THE FIELD: Adoptive therapy with T cell receptor- (TCR-) redirected T cells has shown efficacy in mouse tumor models and first responses in cancer patients. One prerequisite to elicit effective anti-tumor reactivity is the transfer of high-avidity T cells. Their generation, however, faces several technical difficulties. Target antigens are often expressed at low levels and their recognition requires the use of high-affine receptors. Yet, mainly low affinity TCRs have been isolated from tumor-infiltrating lymphocytes. Furthermore, upon transfer into a T cell the introduced receptor has to compete with the endogenous TCR. AREAS COVERED IN THIS REVIEW: This review discusses how the functional avidity of TCR-modified T cells can be enhanced by i) increasing the amount of introduced TCR heterodimers on the cell surface; and ii) generating receptors with high affinity. Risks of TCR gene therapy and possible safety mechanisms are discussed. WHAT THE READER WILL GAIN: The reader will gain an overview of the technical developments in TCR and T cell engineering. TAKE HOME MESSAGE: Despite technical obstacles, many advances have been made in the generation of high-avidity T cells expressing enhanced TCRs. Mouse studies and clinical trials will evaluate the effect of these improvements. PMID- 20201710 TI - Differences in development among children and adolescents in eastern and western China. AB - BACKGROUND: There are wide-ranging differences in human growth, not only between ethnic groups but also between regions. China covers a vast area and has a very large population. However, no studies on the differences in development among children and adolescents in eastern and western China have been reported. AIM: This study assessed the differences in stature and body weight in children and adolescents in eastern and western China. SUBJECTS AND METHODS: Using data derived from two national surveys on students' constitution and health carried out by the Chinese government in 1985 and 2005, the average stature and body weight for children and adolescents aged 7-18 years in eastern and western China were calculated. The differences of mean values between eastern and western China were compared. RESULTS: Boys and girls in eastern China were taller and heavier than their counterparts in western China in all age groups (7-18 years) in 2005, the average differences being 3.56 cm, 4.56 kg (urban boys), 3.05 cm, 2.92 kg (urban girls), 4.04 cm, 4.19 kg (rural boys) and 3.48 cm, 2.96 kg (rural girls). In 18-year-old groups, the differences in the stature and body weight between eastern and western China were 2.82 cm, 5.17 kg for urban boys, 1.86 cm, 2.11 kg for urban girls, 2.26 cm, 3.38 kg for rural boys and 1.96 cm, 1.38 kg for rural girls, respectively. From 1985 to 2005, differences in stature and body weight of children and adolescents between eastern and western China have continuously expanded. CONCLUSION: There have been obvious regional variations in development in children and adolescents in China, the variations in development in children and adolescents between eastern and western China being related to regional economic status and living standards of residents. PMID- 20201711 TI - Bone loss associated with use of antiepileptic drugs. AB - IMPORTANCE OF THE FIELD: Epilepsy is a neurological disorder associated with several comorbidities, one of them being reduced bone health. As the bone loss most often is insidious and asymptomatic, they are usually not recognized, and thus untreated. The key message of this paper is to make clinicians aware of the problem. AREAS COVERED IN THIS REVIEW: This article reviews data from basic and clinical studies of bone loss associated with usage of antiepileptic drugs (AEDs) within the last 4 decades. WHAT THE READER WILL GAIN: The reader will learn that there is accumulating evidence of biochemical abnormalities indicating a disturbed bone metabolism, a decreased bone density and a 2 - 6 times increased risk of fractures among those with epilepsy compared to the general population. These findings most likely have many causes, both internal and external, but long term use of AEDs seems to play an important role. Enzyme-inducing drugs, such as phenytoin, phenobarbital and carbamazepine, but also the enzyme inhibitor valproate, appear to have bone-depleting properties. Reduced bone density may be detected during the first 1 - 5 years of treatment. Although many theories have been launched, the exact mechanisms by which the the drugs affect bone architecture are not fully understood. TAKE HOME MESSAGE: We recommend clinicians to promote osteoprotective behavior among their epilepsy patients; that is, sunlight exposure and weight-bearing exercise as well as avoidance of risk factors such as bone-depleting drugs other than AEDs, smoking and heavy alcohol consumption. Enzyme inducing drugs should be avoided, if possible. Bone mineral density screening should be assessed on an individual basis, taking risk factors for bone loss into account. All patients taking AEDs on long-term basis ought to have adequate amounts of dietary calcium and vitamin D, and those who have developed bone loss should in addition be given specific antiosteoporotic treatment. PMID- 20201713 TI - Microemulsions as drug delivery systems to improve the solubility and the bioavailability of poorly water-soluble drugs. AB - IMPORTANCE OF THE FIELD: Microemulsions have been studied extensively as potential drug delivery vehicles for poorly water-soluble drugs. An understanding of the physicochemical and biopharmaceutical characteristics of the microemulsions according to administration routes will provide guidance for designing the formulations of microemulsions. AREAS COVERED IN THIS REVIEW: In this paper, the use and the characteristics of microemulsions as drug delivery vehicles are reviewed. As the formulations of the microemulsion always include a great amount of surfactant and co-surfactant, which may cause hemolysis or histopathological alterations of the tissue, the potential toxicity or the irritancy of microemulsions is also discussed in this paper. WHAT THE READER WILL GAIN: Developments of microemulsions for poorly water-soluble drugs in recent years are included in this review. Several factors limiting the commercial or clinical use of microemulsions are also discussed. TAKE HOME MESSAGE: Considering the potential in enhanced drug uptake/permeation and facing the limitations, their unique properties make microemulsions a promising vehicle for poorly water soluble drugs. PMID- 20201712 TI - Electrostatic surface modifications to improve gene delivery. AB - IMPORTANCE OF THE FIELD: Gene therapy has the potential to treat a wide variety of diseases, including genetic diseases and cancer. AREAS COVERED IN THIS REVIEW: This review introduces biomaterials used for gene delivery and then focuses on the use of electrostatic surface modifications to improve gene delivery materials. These modifications have been used to stabilize therapeutics in vivo, add cell-specific targeting ligands, and promote controlled release. Coatings of nanoparticles and microparticles as well as non-particulate surface coatings are covered in this review. Electrostatic principles are crucial for the development of multilayer delivery structures fabricated by the layer-by-layer method. WHAT THE READER WILL GAIN: The reader will gain knowledge about the composition of biomaterials used for surface modifications and how these coatings and multilayers can be utilized to improve spatial control and efficiency of delivery. Examples are shown for the delivery of nucleic acids, including DNA and siRNA, to in vitro and in vivo systems. TAKE HOME MESSAGE: The versatile and powerful approach of electrostatic coatings and multilayers will lead to the development of enhanced gene therapies. PMID- 20201714 TI - Cytochrome P450 2D6 polymorphism and drug utilization in patients with oral lichen planus. AB - OBJECTIVE: Oral lichen planus (OLP) is one of the commonest diseases of the oral mucosa. The etiology of the disease is unknown. Our goal was to determine frequencies of functionally important alleles which determine the metabolic rate (phenotype) of individuals with OLP and to compare drug utilization, with focus on CYP2D6, with that of a control group. MATERIAL AND METHODS: The study population consisted of 46 patients with OLP, 60 sex- and age-matched control subjects for drug utilization evaluation and 223 healthy non-medicated controls for genotype comparison. DNA analysis was done using polymerase chain reaction and restriction fragment length polymorphism. The gene CYP2D6 was analyzed for the alleles CYP2D6*3,*4,*5,*6 and gene duplication. Drug utilization was evaluated according to Anatomical Therapeutic Chemical code, liver drug metabolism pathway and mono- or polytherapy. RESULTS: Intake of drugs was significantly higher in the group of OLP patients in comparison with control subjects. The use of CYP2D6 substrates, inhibitors or inducers did not differ between OLP patients and controls. Predicted phenotype frequencies in OLP patients and healthy controls, respectively were as follows: ultrarapid metabolizers 2% and 5.8%, extensive metabolizers 52% and 49.8%, intermediate metabolizers 39% and 37.7% and poor metabolizers 7% and 6.7%. CONCLUSIONS: We did not find a statistically significant difference in the frequency of CYP2D6 alleles between OLP patients and healthy controls. OLP patients used more medication than age- and sex-matched controls. PMID- 20201715 TI - The effects of oxidative DNA damage and mutations in the p53 protein on cells of the colonic mucosa with and without the fecal stream: an experimental study in rats. AB - OBJECTIVE: The aim of this study was to investigate the levels of oxidative DNA damage and p53 mutations in an experimental model of diversion colitis. MATERIAL AND METHODS: Sixty rats were divided into three groups with 20 animals in accordance with the sacrifice was carried out 6, 12 and 18 weeks. For each group, 15 animals were subjected to diversion of the fecal stream through colostomy in the left proximal colon and distal mucous fistula (experimental group), and five to a laparotomy without deviation of the fecal stream (control group). The presence of colitis was evaluated by inflammatory grading scale. Mutations in the p53 protein were evaluated by immunohistochemistry with primary antibody with cross-reactivity for rats. The oxidative DNA damage was measured using the comet assay. To statistical analysis were used the Student's t, Mann-Whitney and Kruskal-Wallis test adopting a significance level of 5% (p < 0.05). RESULTS: Colon segments without fecal stream showed greater degree of inflammation when compared to animals with preserved fecal stream (p = 0.01). The levels of oxidative stress were significantly higher in segments without fecal stream (p < 0.0001) and increased with the time of fecal diversion (p = 0.007). The levels of oxidative DNA damage are directly related to tissue degree of inflammation. There were no mutations in the p53 protein in the segments without fecal stream regardless of time of exclusion considered. CONCLUSION: Despite higher levels of oxidative damage to nuclear DNA on segments without fecal stream that developed colitis mutations in the p53 protein were not detected. PMID- 20201716 TI - Iron deficiency anemia in Helicobacter pylori infection: meta-analysis of randomized controlled trials. AB - BACKGROUND: Helicobacter pylori (H. pylori) infection and iron deficiency anemia are prevalent in disadvantaged populations worldwide. The benefit of H. pylori eradiation for iron deficiency anemia has been extensively studied, but data are still equivocal. METHODS: A search in The Cochrane Library, PUBMED, EMBASE, EBM Review databases, Science Citation Index Expanded, and CMB (Chinese Biomedical Literature Database) was performed. Randomized controlled trials (RCTs) comparing anti-H. pylori plus oral iron to oral iron alone for the iron deficiency patients in whom H. pylori was positive were selected for meta-analysis. Reviev Manager 5.0 software was used for the performance of meta-analysis. RESULTS: Sixteen randomized controlled trials totaling 956 patients were included. The meta analysis showed that the difference from baseline to endpoint of hemoglobin (Hb), serum iron (SI), and serum ferritin (SF) was statistically significantly different between anti-H. pylori treatment plus oral iron and oral iron alone (SMD, Hb 1.48; 95% CI, 0.96, 2.00; p < 0.00001; SI 1.15; 95% CI, 0.87, 1.43; p < 0.00001; SF 1.84; 95% CI, 1.20, 2.48; p < 0.00001, respectively). CONCLUSIONS: Our study suggests that treatment of H. pylori infection could be effective in improving anemia and iron statue in IDA patients infected by H. pylori, particularly in patients with moderate or severe anemia. PMID- 20201717 TI - Fecal fat determination with a modified titration method. AB - OBJECTIVE: Intestinal malabsorption is a serious condition which unfortunately may remain unrecognized due to methodological problems. The old titration method of van de Kamer is still the gold standard. We present a modification of the method, pointing out practical improvements and pitfalls. MATERIAL AND METHODS: Our method uses less than one tenth of the amount of feces originally described, which implies proper mixing and homogenization of all feces collected over 72 hrs. Validation is performed by measuring fat concentration in commercial milk products. RESULTS: Reproducibility and validity were satisfactory. Concentration and output of fecal fat was poorly correlated, indicating that fecal output is required for diagnosing intestinal malabsorption. Our experiments also highlight the importance of using a non-polar extraction agent because polar agents take up water-soluble short chain fatty acids which are derived from fermentation of carbohydrates and give erroneous results. CONCLUSION: The modified method is reliable and robust and minimizes the aesthetical problems associated with fecal fat determination. PMID- 20201728 TI - Time-lapse, single cell based confocal imaging analysis of caspase activation and phosphatidylserine flipping during cellular apoptosis. AB - Apoptosis is an important phenomenon for investigating the efficacy of anti cancer drug candidates. The conventional assays for cellular apoptosis, such as enzyme-linked immunosorbent assay, absorbance monitoring for the activity of caspase, and flow cytometric assay, have focused only on biochemical events. We investigated the staurosporine (STS)-induced apoptosis of the murine macrophage RAW-264.7 cell using a cell based bioimaging technique. Using time-lapse confocal microscopy, we monitored caspase-3 activation during apoptosis by imaging the translocation of green fluorescent protein from the cytosol to the nuclei. Five hours after 1 MUM STS treatment, caspase-3 was observed to be activated and membrane blebbing was observed simultaneously. Also, the loss of phosphatidylserine (PS) asymmetry in the phospholipid bilayer of plasma membrane during early apoptosis was monitored by imaging annexin-V labeled with fluorescein isocyanate binding to the externalized PS at various concentrations of STS. Moreover, disintegration of the plasma membrane during late apoptosis was confirmed using a nuclear dye, propidium iodide. The single cell based bioimaging data agreed well with those of the biochemical assays for caspase activation and morphological observation for membrane integrity. PMID- 20201729 TI - Pharmacoeconomics of voriconazole. AB - IMPORTANCE OF THE FIELD: The recent increase in the use of antineoplastic and immune suppressive agents and the use of broad-spectrum antibiotics, prosthetic interventions, organ transplants and more aggressive surgery have been related to a greater prevalence of invasive fungal infections (IFI). Over the past few years, several new antifungal therapies have become available for these patients. Pharmacoeconomic data can play a useful role in comparing the relative benefits of treatment. AREAS COVERED IN THIS REVIEW: This review summarizes all the available evidence regarding the pharmacoeconomics of voriconazole. A systematic review of pharmacoeconomic analyses through a non-restricted literature search was conducted (until May 2009). WHAT THE READER WILL GAIN: The reader will gain a greater understanding of the pharmacoeconomics role of voriconazole. TAKE HOME MESSAGE: The majority of economic analyses have shown that voriconazole is a more cost-effective alternative in the treatment of invasive fungal infections than the antifungal drugs with which it was compared. PMID- 20201730 TI - Treatment modalities for bacterial rhinosinusitis. AB - IMPORTANCE OF THE FIELD: Rhinosinusitis is a common illness that represents a substantial economic burden. The vast majority of cases resolve spontaneously but a small proportion develops a secondary bacterial infection. Accurate diagnosis of rhinosinusitis depends upon clinical assessment. Isolation of the causative agents must be considered in cases failing initial treatment. AREAS COVERED IN THIS REVIEW: This up-to-date review defines the anatomy, pathogenesis, phases of rhinosinusitis, the unique microbiology of each type of rhinosnusitis (acute and chronic, acute exacerbation, nosocomial, rhinosinusitis in immunocompromised host, and rhinosinusitis of ododental origin), clinical features, diagnosis, and treatment. WHAT THE READER WILL GAIN: The reader will gain understanding of the above issues and logic for choosing the appropriate treatment for each condition of rhinosinusitis. TAKE HOME MESSAGE: The proper choice of antibiotic therapy depends on the probable infecting pathogens, bacterial antibiotic resistance and antibiotics' pharmacologic profiles. In addition to antibiotics, adjuvant therapies and surgery are used in the management of bacterial sinusitis. Accurate diagnosis and careful consideration when choosing therapy for rhinosinusitis will optimize the chances of achieving an early recovery and avoiding complications. PMID- 20201731 TI - Triple inhaled therapy in stable chronic obstructive pulmonary disease: the earlier, the better? Evaluation of Welte T, Miravitlles M, Hernandez P, et al. Efficacy and tolerability of budesonide/formoterol added to tiotropium in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2009;180:741-50. PMID- 20201732 TI - Treatment of viral hepatitis B in children. AB - IMPORTANCE OF THE FIELD: Treatment of chronic hepatitis B (CHB) in children is aimed at reducing viral replication and at minimizing liver injury and related consequences in children with chronic active viral liver infection. AREAS COVERED IN THIS REVIEW: In this review, treatment options available for both adults and children are summarized, together with suggestions from our own experience. The most relevant works published between 1982 and 2009 on PubMed/Medline database search were used. WHAT THE READER WILL GAIN: At present, standardized treatment is available in only a few therapeutic options, such as IFN-alpha and lamivudine; it is hoped that these will be complemented in the future by new, encouraging drugs still under study in pediatric age patients. Moreover, current treatment approaches have their limitations: although IFN-alpha has been shown to be effective in patients with non-vertically-transmitted infection, HBeAg clearance while on treatment is similar to spontaneous seroconversion after long-term follow-up. IFN-alpha-induced side effects are frequent rarely severe in children. Lamivudine achieves similar results in children with active viral replication. However, despite good compliance to oral administration, this treatment can lead to the development of drug-resistant mutations. TAKE HOME MESSAGE: In conclusion, the decision to treat CHB in children demands that the possibility of favorable spontaneous viral clearance has been considered and must be made on the bases of the extent of liver damage. PMID- 20201733 TI - New evidence on pitavastatin: efficacy and safety in clinical studies. AB - IMPORTANCE OF THE FIELD: Many clinical trials of pitavastatin have been done since its launch. New insights on pitavastatin from these trials are summarized and evaluated. AREAS COVERED IN THIS REVIEW: The results of clinical studies using pitavastatin, from 2008 to 2009, the LIVES study, the JAPAN-ACS study, the CHIBA study, the PIAT study and Phase III clinical trials in the West are reviewed. WHAT THE READER WILL GAIN: In the LIVES study, pitavastatin showed significant and continuous elevation of high-density lipoprotein cholesterol (HDL C), estimated glomerular filtration rate (eGFR), as well as potential decrease in low-density lipoprotein cholesterol (LDL-C), in addition to long-term safety. Non inferiority of pitavastatin against atorvastatin in the percentage change in plaque volume was proved in the JAPAN-ACS study. Also, comparable effects on LDL C reduction rate of pitavastatin versus atorvastatin were confirmed in the CHIBA study and Phase III clinical trials in the West, and a greater increase in HDL-C was observed than with atorvastatin in the PIAT study. TAKE HOME MESSAGE: Pitavastatin is a useful potent stain in raising HDL-C as well as in lowering of LDL-C, though a large-scale, clinical trial to confirm prevention of cardiovascular events is needed in the future. PMID- 20201734 TI - Identifying pancreatic cancer patients for targeted treatment: the challenges and limitations of the current selection process and vision for the future. AB - Recent preclinical data have demonstrated that pancreatic adenocarcinoma (PDA) cells with defects in the Fanconi anemia/BRCA2 pathway are hypersensitive to interstrand crosslinking agents. The challenge is to efficiently identify patients who will benefit from these therapies. Patients were chosen for this study by evaluating personal history, ethnic background and family history of pancreatic malignancy. Molecular assays were performed on tissue samples. Patient A developed PDA in the context of a known BRCA2 frameshift mutation (2157delG), suspected because of her personal and multigenerational family history of breast cancer. She was treated with surgical resection, and targeted chemotherapy. Patient A continues to be disease free 32 months after her diagnosis and treatment. Patient B developed PDA in the context of a strong family history of PDA and Ashkenazi Jewish heritage. Genetic analysis on critical DNA repair genes revealed no alterations. This patient did not receive a tailored treatment regimen. This study highlights the challenge of treating PDA patients and selecting those eligible for targeted therapy. The current targeted treatment options for PDA are reviewed. A new multidisciplinary approach for stratifying PDA patients for promising targeted adjuvant therapy and familial risk counseling is proposed. PMID- 20201736 TI - Computational methods to predict the reactivity of nanoparticles through structure-property relationships. AB - IMPORTANCE OF THE FIELD: Innovative biomedical techniques operational at the nanoscale level are being developed in therapeutics, including advanced drug delivery systems and targeted nanotherapy. Given the large number of nanoparticles that are being developed for possible biomedical use, the use of computational methods in the assessment of their properties is of key importance. AREAS COVERED IN THIS REVIEW: Among the in silico methods, quantum mechanics is still used rarely in the study of nanostructured particles. This review provides an overview of some of the main quantum mechanics methods that are already used in the assessment of chemicals. Furthermore, classical tools used in the chemistry field are described, to show their potential also in the pharmacological field. WHAT THE READER WILL GAIN: The current status of computational methods in terms of availability and applicability to nanoparticles, and recommendations for further research are highlighted. TAKE HOME MESSAGE: The in silico modelling of nanoparticles can assist in targeting and filling gaps in knowledge on the effects of these particular particles. Computational models of the behaviour of nanoparticles in biological systems, including simulation models for predicting intermolecular interactions and harmful side effects, can be highly valuable in screening candidate particles for potential biomedical use in diagnostics, imaging and drug delivery. PMID- 20201735 TI - Central nervous system delivery of large molecules: challenges and new frontiers for intrathecally administered therapeutics. AB - IMPORTANCE OF THE FIELD: Therapeutic proteins and DNA constructs offer promise for the treatment of central nervous system disorders, yet significant biological barriers limit the ability of these molecules to reach the central nervous system from the bloodstream. Direct administrations to the cerebrospinal fluid (intrathecal administration) comprise an emerging field to facilitate the efficient delivery of these biological macromolecules to central nervous system tissues. AREAS COVERED IN THIS REVIEW: Previous reports from 1990 to the present time describing the interactions and turnover of the cerebrospinal fluid within the intrathecal space, characterizations of the effects that therapeutic proteins and DNA have shown after intrathecal delivery through a lumbar route, and reports of emerging technologies to address the limitations of intrathecally administered macromolecules are reviewed. WHAT THE READER WILL GAIN: This review provides an overview of the limitations that must be overcome for intrathecally administered biological macromolecules and the recent advances and promising approaches for surmounting these limitations. TAKE HOME MESSAGE: Emerging approaches that stabilize and sustain the delivery of intrathecally administered biological macromolecules may enhance substantially the clinical relevance of promising therapeutic proteins and DNA constructs for the treatment of various central nervous system disorders. PMID- 20201738 TI - Self-assembled filamentous nanostructures for drug/gene delivery applications. AB - IMPORTANCE OF THE FIELD: Among many nanostructural shapes, filamentous shapes can have unique advantages over the others, including longer persistence in the bloodstream. With the advent of nanotechnology in recent years, a variety of shape-controlled nanostructures has been fabricated. As a wide variety of building blocks can self-assemble into filamentous nanostructures, there are many options available for biomaterial developments with filamentous nanostructures. Similarly to conventional spherical micelles, most filamentous nanostructures have hydrophobic cores where hydrophobic guest molecules can be encapsulated, which enable them to be used in drug delivery applications. Moreover, on suitable molecular design and self-assembly process control, filamentous nanostructures can also be made to deliver nucleic acids or even both drugs and nucleic acids simultaneously. AREAS COVERED IN THIS REVIEW: This review describes the self assembly process, current developments, and prospects of filamentous nanostructures in drug and gene delivery applications. WHAT THE READER WILL GAIN: This review should be helpful in gaining insight into the self-assembly process and nanostructural shape control, the advantages of constructing filamentous nanostructures, and the design of more advanced nanobiomaterials. TAKE HOME MESSAGE: At present, the development of multifunctional nanostructures is one of the main focuses in nanobiomaterial developments. In this regard, filamentous nanostructures can be good initial targets for tailor-made nanostructure developments because they have more structural variables, as compared with spherical micelles. PMID- 20201737 TI - Endosomal disruptors in non-viral gene delivery. AB - IMPORTANCE OF THE FIELD: Non-viral gene delivery for the treatment of genetic and non-genetic diseases has been under investigation for several decades, but there has been very little application in patients because of poor gene expression and toxicity. AREAS COVERED IN THIS REVIEW: As gene delivery almost invariably involves endocytosis, many of its limitations are related to compartmentalisation of the transgene within the endosomes. Gene expression enhancers have become an essential part of manipulating endosomal release, as well as protecting transgene from intracellular degradation. However, disruption of the endosomes can also release proteases that have been shown to activate apoptotic pathways. WHAT THE READER WILL GAIN: An understanding of the role that endosomal release plays in the toxicity of gene delivery vehicles will help identify new approaches to minimise adverse effects while enhancing non-viral gene expression. TAKE HOME MESSAGE: The future of non-viral gene therapy needs to identify new approaches that limit endosome-induced toxicity while enhancing expression so that a pharmacological response can be reliably observed in vivo. PMID- 20201739 TI - From conventional towards new - natural surfactants in drug delivery systems design: current status and perspectives. AB - IMPORTANCE OF THE FIELD: Surfactants play an important role in the development of both conventional and advanced (colloidal) drug delivery systems. There are several commercial surfactants, but a proportionally small group of them is approved as pharmaceutical excipients, recognized in various pharmacopoeias and therefore widely accepted by the pharmaceutical industry. AREAS COVERED IN THIS REVIEW: The review covers some of the main categories of natural, sugar-based surfactants (alkyl polyglucosides and sugar esters) as prospective pharmaceutical excipients. It provides analysis of the physicochemical characteristics of sugar based surfactants and their possible roles in the design of conventional or advanced drug delivery systems for different routes of administration. WHAT THE READER WILL GAIN: Summary and analysis of recent data on functionality, applied concentrations and formulation improvements produced by alkyl polyglucosides and sugar esters in different conventional and advanced delivery systems could be of interest to researchers dealing with drug formulation. TAKE HOME MESSAGE: Recent FDA certification of an alkyl polyglucoside surfactant for topical formulation presents a significant step in the process of recognition of this relatively new group of surfactants. This could trigger further research into the potential benefits of naturally derived materials in both conventional and new drug delivery systems. PMID- 20201740 TI - Drug delivery strategies for therapy of visceral leishmaniasis. AB - IMPORTANCE OF THE FIELD: Visceral leishmaniasis (VL) is the most overwhelming type of leishmaniasis associated with the poverty of developing countries and usually mortal if untreated. Most of the conventionally used dosage forms offer us the shortcomings of toxic side effects and emergence of drug resistance. Several efforts have been made to overcome the barriers involved in the treatment of VL. Colloidal carriers extensively represent the drug delivery systems (DDSs) for intracellular localization of antileishmanial compounds in macrophage-rich organs such as liver, spleen and bone marrow. These DDSs offer superior therapeutic efficacy over the conventional treatment in terms of site-specific drug delivery with reduced side effects. However, after 35 years of research in the field, AmBisome (Amphotericin B liposome for injection, Astellas Pharma US, Inc.) is the only DDS used against the VL. AREAS COVERED IN THIS REVIEW: A literature search was performed (for drugs and DDSs against VL) on PubMed and through Google. WHAT THE READER WILL GAIN: This review aims to describe the pathophysiology of VL and its current conventional treatment with special reference to DDSs designed against VL. TAKE HOME MESSAGE: On reviewing the conventional drugs and DDSs developed against VL, it is concluded that advances in the field of targeted drug delivery can result in more efficient strategies for the therapy of VL. PMID- 20201742 TI - Listeriolysin O enhances cytoplasmic delivery by Her-2 targeting liposomes. AB - To enhance cytoplasmic delivery of liposomal contents to breast cancer cells, the authors have attached the pore-forming protein, listeriolysin O (LLO), to thermosensitive liposomes. The antibody trastuzumab (Herceptin) was also conjugated with the outer surface of the liposomes, resulting in highly specific binding and internalization into mammary epithelial cells that overexpress the human epidermal growth factor receptor 2 (Her-2). The liposomes were preloaded with a marker fluorescent dye, and the effect of LLO on the distribution of dye within the cells was monitored using fluorescence microscopy. Owing to the thermosensitive nature of the liposomes, hyperthermia at 42 degrees C triggered the release of the encapsulated fluorescent calcein from the endocytosed liposomes into the interior of the endosomes. LLO, when conjugated to these liposomes, subsequently formed pores in the endosomal membrane, allowing calcein to flow out of the endosomal compartment into the cytoplasm. Her-2-targeted liposomes bearing LLO delivered a 22-fold greater concentration of calcein to mammary epithelial cells that overexpress Her-2 compared to cells with normal Her 2 expression. Thus, the addition of LLO to preformed liposomes offers a method for significantly enhancing delivery of liposomal contents to the cytoplasm of targeted cells. PMID- 20201741 TI - Substance P antagonist CP-96345 blocks lung vascular leakage and inflammation more effectively than its stereoisomer CP-96344 in a mouse model of smoke inhalation and burn injury. AB - The recently developed murine model of smoke inhalation and burn (SB) injury was used to study the effect of the substance-P antagonist CP96345. C57BL/6 mice were pre-treated with an i.v. dose of a specific NK-1 receptor antagonist, CP9635, or its inactive enantiomer, CP96344, (10 mg/Kg) 1 h prior to SB injury per protocol (n = 5). Mice were anesthetized and exposed to cooled cotton smoke, 2X 30 s, followed by a 40% total body surface area flame burn per protocol. At 48 h after SB injury Evans Blue (EB) dye and myeloperoxidase (MPO) were measured in lung after vascular perfusion. Lungs were also analyzed for hemoglobin (Hb) and wet/dry weight ratio. In the current study, CP96345 pre-treatment caused a significant decrease in wet/dry weight ratio (23%, p = 0.048), EB (31%, p = 0.047), Hb (46%, p = 0.002), and MPO (54%, p = 0.037) levels following SB injury compared to animals with SB injury alone. CP-96344 pre-treatment caused an insignificant decrease in wet/dry weight ratio (14%, p = 0.18), EB (16%, p = 0.134), Hb (9%, p = 0.39), and an insignificant increase in MPO (4%, p = 0.79) as compared to mice that received SB injury alone. As expected, levels of EB, Hb, MPO, and wet/dry weight ratios were all significantly (p < 0.05) increased 48 h following SB injury alone compared to respective sham animals. In conclusion, the current study indicates that pre-treatment with a specific NK-1R antagonist CP 96345 attenuates the lung injury and inflammation induced by SB injury in mice. PMID- 20201743 TI - Positive predictive value of serological diagnostic measures in celiac disease. AB - BACKGROUND: Celiac disease (CD) antibodies, immunoglobulin A (IgA) anti-tissue transglutaminase (anti-tTG), IgA endomysium antibody (EMA), IgA and IgG anti gliadin antibodies (IgA and IgG AGA) are first-line diagnostic tools used in selecting patients for duodenal biopsy. The goal of this study was to evaluate the diagnostic quality of serological testing for CD. METHODS: CD serological tests (IgA and IgG AGA, anti-tTG and EMA) from 11,915 individuals were measured. Data were combined with clinical data and results of duodenal biopsy using a unique Danish personal identification number. RESULTS: The positive predictive value (PPV) varied according to different combinations of positive CD antibodies, being highest when all antibodies were positive (97.6%). The anti-tTG concentration correlated strongly with EMA positivity, number of additional positive antibodies, and higher PPV. A logistic regression model predicted the probability of later biopsy-proven CD in relation to concentrations of IgA AGA and anti-tTG at initial serological screening. CONCLUSIONS: The anti-tTG concentration at initial serological CD screening was highly informative in relation to EMA positivity, number of additional CD specific antibodies and PPV. Furthermore, in the high-risk group of patients investigated, the concentrations of anti-tTG and IgA AGA at initial serological screening could accurately predict the probability of future biopsy-proven CD. PMID- 20201744 TI - Inter-laboratory variation in cerebrospinal fluid biomarkers for Alzheimer's disease: united we stand, divided we fall. AB - Abstract Several drug candidates for Alzheimer's disease are being evaluated in clinical trials, with the goal of finding a drug with disease-modifying effects. When such a drug finally reaches the market, there will be a demand for accurate diagnostic tools useful for early detection of disease and for monitoring biochemical effects. The core cerebrospinal fluid (CSF) biomarkers amyloid peptides (Abeta42), total-tau and phospo-tau are promising in this respect. However, inter-center variation (caused by pre-analytical, analytical and post analytical factors), and inter-laboratory variation (caused by analytical factors), particularly for CSF Abeta42, lowers their utility in multicenter studies. Here, we discuss the causes of these variations, and present a global quality control program to overcome them. PMID- 20201745 TI - Recommendations for the implementation of international standardization of glycated hemoglobin in Italy. AB - This document is issued by the Italian Society of Clinical Biochemistry and Clinical Molecular Biology (SIBioC) and a number of other National Scientific Societies and Associations in order to promote a coordinated plan for implementing the standardization of glycated hemoglobin (HbA(1c)) measurement in Italy according to the recommendations by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). Changes in reporting HbA(1c) results, new units, how to relate old and new units, a timeline for changes and definition of the analytical goals are the main issues discussed. PMID- 20201746 TI - Development and applications of alternative methods of segmentation for Mandarin Hearing in Noise Test in normal-hearing listeners and cochlear implant users. AB - CONCLUSION: The study demonstrates that two methods of segmentation, i.e. word and character segmentations, produce equivalent results in the Mandarin Hearing in Noise Test (MHINT). Potentially, both methods of segmentation can be used clinically. A majority of the Mandarin-speaking cochlear implant subjects could complete MHINT - with the more relaxed adaptive rules. The results make it possible to compare the performance of cochlear implant users across languages. OBJECTIVES: The primary purpose of the present study was to evaluate the modified adaptive scoring rules and to develop alternative methods of segmentations in MHINT that are suitable for the Chinese language. METHODS: Thirty Mandarin speaking normal-hearing adults were tested with MHINT using three adaptive rules based on character and/or word segmentation of the sentences. Twenty-three Mandarin-speaking post-lingually deafened cochlear implant patients were also recruited to participate in the testing. RESULTS: There were no significant differences in the reception threshold for sentences and speech recognition scores obtained with either method of segmentation (p > 0.05). Fifteen of the 23 cochlear implant subjects (65%) could be tested with the modified adaptive scoring rules. The performance-intensity functions of the cochlear implant subjects were shifted at least 8-10 dB to higher signal-to-noise ratios as compared with those of the normal-hearing subjects. PMID- 20201747 TI - Emerging drugs for chronic myeloid leukemia. AB - IMPORTANCE OF THE FIELD: The deregulated tyrosine kinase activity of BCR-ABL has been demonstrated to be necessary and sufficient to maintain leukemia phenotype of chronic myeloid leukemia (CML) which, therefore, represents a unique model for the development of molecular targeted therapy and the first disease in which the tyrosine kinase inhibitors (TKIs) completely changed the therapeutical approach. The impressive results of TKIs in this model have been overshadowed by the development of clinical resistance. AREAS COVERED IN THIS REVIEW: This review focuses on clinical results with imatinib therapy and second generation TKIs. Furthermore, a summary of the guidelines for the management of TKI resistant patients is provided together with a description of the new drugs in clinical or preclinical phases which are developing to overcome resistance. WHAT THE READER WILL GAIN: Future perspective for the 'cure' of CML patients and new drugs designed for this purpose are suggested. TAKE HOME MESSAGE: CML therapy has dramatically changed in the last few years due to the introduction of targeted therapy. Studies on new drugs targeting different pathways other than BCR-ABL are ongoing to improve the clinical results. PMID- 20201748 TI - A role for CYP in the drug-hormone crosstalk of the brain. AB - IMPORTANCE OF THE FIELD: Libido disorders, menstruation problems, perception and cognition deficiencies are potentially undesired, but clinically emerging, side effects after long-term therapy with antiepileptic drugs or chemotherapeutic agents. These disorders were shown to occur predominantly in patients who had taken drugs interacting with the CYP system of the brain, particularly in the hippocampus, the hypothalamus, the cerebellum or in the amygdala. CYPs present and active in these regions usually inactivate steroid hormones such as testosterone. AREAS COVERED IN THIS REVIEW: The present review focuses on recent concepts of brain CYP function, gives an outlook on neuroactive drug use in therapy and self-medication, and highlights the endocrine side effects after drug therapy in neurological diseases and brain tumors. WHAT THE READER WILL GAIN: The reader is introduced to a CYP mediated drug-hormone crosstalk as a possible mechanism to explain these side effects. TAKE HOME MESSAGE: The drug-hormone crosstalk may be of considerable importance in the assessment of neuroactive drugs and future drug design. PMID- 20201750 TI - Clearance after vasectomy: has the time come to modify the current practice? AB - OBJECTIVE: Vasectomy is a simple, reliable and effective form of permanent contraception. Clearance after vasectomy has been the subject of much debate among urologists. Poor compliance with postvasectomy semen analysis is well recognized, with rates as low as 36%. This can leave the partner at risk of an unplanned pregnancy and, consequently, the surgeon at risk of litigation. Although there is no consensus about the requirements for postvasectomy clearance, urologists usually tend to request at least two azoospermic postvasectomy semen samples (PVSSs) before labelling patients as sterile. This study investigated whether simplifying the criteria for postvasectomy clearance can result in improved compliance. MATERIAL AND METHODS: Medline, Embase and Cochrane databases were searched for studies on postvasectomy clearance. The main focus of the search was on the timing and number of PVSSs, their impact on patients' compliance and the significance of the rare non-motile sperm (RNMS). RESULTS: It has been found that patients' compliance decreases when more than one PVSS is requested. One azoospermic PVSS can be as indicative of sterility as two azoospermic samples. There have been calls for a uniform protocol recommending only one routine sperm sample taken 16 weeks postoperatively. This period will allow the vasa and seminal vesicles to become clear of spermatozoa. A significant proportion of men will have RNMS in their semen after vasectomy; only 1% will ultimately fail. Therefore, RNMS samples can, for practical purposes, be considered azoospermic and one PVSS, even if containing RNMS, should be considered sufficient for clearance. CONCLUSIONS: Provided that patients are adequately warned about the risk of vasectomy failure and appropriate consent is obtained, a single azoospermic PVSS at 16 weeks is sufficient for clearance. Patients with RNMS should be practically considered azoospermic and further sampling should be abandoned. This approach should improve patients' compliance. Evaluation in a prospective setting will be required to validate this conclusion. PMID- 20201749 TI - Comparison of the influence of angiotensin-converting enzyme inhibitor lisinopril and angiotensin II receptor antagonist losartan in patients with idiopathic membranous nephropathy and nephrotic syndrome. AB - OBJECTIVE: In this prospective study, the effects of an angiotensin-converting enzyme inhibitor [lisinopril (LIS)] and an angiotensin II receptor antagonist [losartan (LOS)] were compared in nephrotic patients with idiopathic membranous nephropathy. MATERIAL AND METHODS: Twenty-seven patients (13 males, mean age +/- SD 51.3 +/- 15.4 years) were treated with LIS (13 patients, six males, mean age 52.1 +/- 15.3 years) or LOS (14 patients, seven males, mean age 50.5 +/- 15.5 years) for 12 months. At baseline and after the treatment period, serum albumin, total cholesterol, estimated glomerular filtration rate (GFR), 24 h proteinuria and mean arterial pressure were determined. RESULTS: Proteinuria (g/24 h) was significantly reduced in both groups (LIS from 4.82 +/- 1.26 to 1.75 +/- 0.64, p < 0.0001; LOS from 4.55 +/- 1.09 to 2.54 +/- 1.94, p = 0.002) (all results +/- SD). Serum albumin levels (g/dl) increased significantly in both groups (LIS 2.27 +/- 0.41 to 3.17 +/- 0.63, p < 0.0001; LOS 2.93 +/- 0.40 to 3.55 +/- 0.44, p < 0.0001). GFR (ml/min x 1.73 m(2)) did not change significantly in either group (LIS 55 +/- 17 to 56 +/- 17, p = 0.65; LOS 64 +/- 18 to 59 +/- 16, p = 0.13). Total cholesterol (mg/dl) was significantly reduced only in the lisinopril group (LIS 347 +/- 81 to 266 +/- 64, p < 0.0001; LOS 306 +/- 58 to 263 +/- 77, p = 0.138). Mean arterial pressure (mmHg) was reduced in both groups (LIS 107 +/- 12 to 95 +/- 6, p < 0.0001; LOS 104 +/- 10 to 96 +/- 5, p = 0.003). In the comparison between the two groups, serum albumin levels were higher in the losartan group at baseline (p < 0.0001) and after 12 months (p = 0.029). There were no significant differences between the baseline and end-of-study values for the rest of the studied parameters. CONCLUSION: Treatment with lisinopril and losartan in nephrotic patients with idiopathic membranous nephropathy results in similar (and significant) effects on renal function, hypoalbuminaemia, proteinuria and blood pressure. PMID- 20201751 TI - Ureteral injuries during photoselective vaporization of the prostate. AB - Photoselective vaporization of the prostate is a relatively new surgical modality for male lower urinary tract symptoms. The method has a risk of tissue damage if laser pulses miss the prostatic adenoma and travel through the irrigation fluid in the bladder. Five cases of damage to the ureteral orifices are described, with hidden orifices, intravesical prostatic adenomas and prior prostatectomy as risk factors for laser-related injuries to ureteral orifices. A laser-coagulated ureteral orifice does not seem to regain patency spontaneously, so rapid nephrostomy and subsequent DJ stenting is recommended. PMID- 20201752 TI - Intraprostatic botulinum toxin type A injection for the treatment of benign prostatic hyperplasia: Initial experience with Dysport. AB - OBJECTIVE: To evaluate the effect of intraprostatic botulinum toxin type A (BoNTA, Dysport) injection on lower urinary tract symptoms, prostate-specific antigen (PSA), prostate volume (PV), peak urine flow rate (Q(max)) and postvoiding residue (PVR), and to evaluate the role of PV in the treatment outcome. MATERIAL AND METHODS: Seventy-two men with PSA < 4 ng/ml, International Prostate Symptom Score (IPSS) > or = 8, Q(max) < 12 ml/s and PV < 60 ml were enrolled. A total of 300-600 U Dysport was injected transperineally under transrectal ultrasound guidance. Initial IPSS, quality of life (QoL) score, Q(max) and PVR were compared with their measures at 1, 6 and 12 months after the injection. Initial PSA and PV were compared with their values after 6 months. Parameters were also compared between patients with PV < or = 30 ml and those with PV > 30 ml. RESULTS: The mean age of participants was 63.5 years. At follow up sessions, IPSS and QoL score were significantly decreased (p < 0.001). PVR reduced significantly and Q(max) increased considerably (p < 0.001). PSA and PV substantially decreased after 6 months (p < 0.001). No serious complications were reported. Similar to patients with larger prostates, IPSS and QoL score decreased statistically significantly after 12 months in those with PV < or = 30 ml; however, changes in PV, PSA, PVR and Q(max) did not persist during 12 months' follow-up. CONCLUSIONS: The procedure is safe and efficacious and the results are comparable to previous experiences with Botox. It seems that the toxin efficacy depends directly on PV in prostates < 60 ml. PMID- 20201753 TI - Effects of different dose of FTY720 on lymphocyte cell cycle arrest in cardiac transplantation model of rats. AB - PURPOSES: To probe into immunosuppressive effect and cell cycle arrest effect of different dose of FTY720. METHOD: we study immunosuppressive effect and cell cycle arrest effect of different dose of FTY720 and time and dose dependence of FTY720 with control and random method in vivo, respectively. RESULTS: (i) survival time of graft in rat cardiac transplantation model is prolonged in group treated with FTY720. It is longer in group treated with FTY720 10 mg/kg than that in group treated with FTY720 2 mg/kg. (ii) The mean sum of lymphocyte in periphery blood decrease obviously 2 h after administration, reaches its peak 4 h after administration, and then maintain at low level stably. The mean sum of lymphocyte shows a linear relationship with dose of FTY720 and decrease with increasing of dose of FTY720. (iii) The percent of cell in G1-G0 increased in group treated with FTY720, not only in thymus but also in lymph node; this is more prevalent in the group treated with FTY720 10 mg/kg than that in group treated with FTY720 2 mg/kg. Similarly, the percent of cell in S and G2-M decreased in group treated with FTY720, not only in thymus but also in lymph node, and this decrease is more associated with group treated with FTY720 10 mg/kg than the one treated with FTY720 2 mg/kg. CONCLUSION: FTY720 is an effective immunosuppressant and immunosuppressive effect of FTY720 show a tendency of time and dose dependent. Effect of cell cycle arrest of FTY720 is related to dose of this new immunosuppressant. PMID- 20201754 TI - Highlights from the March 2010 issue of DNA and Cell Biology. PMID- 20201755 TI - Clinical-quality registries: their role in quality improvement. PMID- 20201756 TI - Troponin measurement and the new assays: how low can we go? PMID- 20201757 TI - The prevalence of trachoma in Australia: the National Indigenous Eye Health Survey. AB - OBJECTIVE: To determine the prevalence of trachoma among Indigenous Australians. DESIGN, SETTING AND PARTICIPANTS: A national, stratified, random cluster sample survey of Indigenous children (5-15 years) and adults (>or= 40 years) in 30 communities across Australia. Data collection was undertaken in 2008. MAIN OUTCOME MEASURES: Results based on a standardised protocol that included trachoma grading and double grading of photographs of the tarsus. RESULTS: 1694 Indigenous children and 1189 Indigenous adults were examined. Recruitment rates were 84% for children and 72% for adults. The overall rate of follicular trachomatous inflammation among children was 3.8%, ranging from 0.6% in major cities to 7.3% in very remote areas; 50% of communities in very remote areas had endemic rates (> 5%). Trachomatous scarring (TS) occurred among 15.7% of adults, trachomatous trichiasis (TT) among 1.4% and corneal opacity (CO) among 0.3%. TS was found in all regions and TT in all except major cities and inner regional areas. The highest community rates for TS were 58.3%; for TT, 14.6%; and for CO, 3.3%. CONCLUSION: Blinding endemic trachoma remains a major public health problem in many Aboriginal and Torres Strait Islander communities. Although active trachoma is predominantly seen in very remote communities, scarring and blinding sequelae occur among Indigenous people across the country. The Australian Government's recent commitment to eliminate blinding trachoma is welcomed and much needed. PMID- 20201758 TI - Cardiovascular risk perception and evidence--practice gaps in Australian general practice (the AusHEART study). AB - OBJECTIVE: To examine the perception and management of cardiovascular disease (CVD) risk in Australian primary care. DESIGN, SETTING AND PARTICIPANTS: The Australian Hypertension and Absolute Risk Study (AusHEART) was a nationally representative, cluster-stratified, cross-sectional survey of 322 general practitioners. Each GP was asked to collect data on CVD risk factors and their management in 15-20 consecutive patients aged >or= 55 years who presented between April and June 2008, and to estimate each patient's absolute risk of a cardiovascular event in the next 5 years. MAIN OUTCOME MEASURES: Estimated 5-year risk of a cardiovascular event, proportion of patients receiving appropriate treatment. RESULTS: Among 5293 patients, 29% (1548) had established CVD. A further 22% (1145), when categorised according to the 2009 National Vascular Disease Prevention Alliance guideline, to 42% (2211), when categorised according to National Heart Foundation (NHF) 2004 guideline, had a high (>or= 15%) 5-year risk of a cardiovascular event. Of the 1548 patients with established CVD, 50% were prescribed a combination of a blood pressure (BP)-lowering medication, a statin and an antiplatelet agent, and 9% were prescribed a BP-lowering medication and a statin but not an antiplatelet agent. Among high-risk patients without established CVD, categorised using NHF 2004 adjustments, 34% were prescribed a combination of a BP-lowering medication and a statin. GPs estimated 60% of patients with established CVD as having a risk of less than 15%. The GPs' estimates of risk among patients without established CVD agreed with the centrally calculated estimate (according to the NHF 2004 guideline) in 48% of instances (Kappa = 0.21). CONCLUSIONS: These data confirm substantial undertreatment of patients who are at high risk of a cardiovascular event. We recommend that GPs assess absolute risk for older patients and ensure that high risk patients receive evidence-based pharmacotherapy. PMID- 20201759 TI - The cost of overweight and obesity in Australia. AB - OBJECTIVE: To assess and compare health care costs for normal-weight, overweight and obese Australians. DESIGN, SETTING AND PARTICIPANTS: Analysis of 5-year follow-up data from the Australian Diabetes, Obesity and Lifestyle study, collected in 2004-2005. Data were available for 6140 participants aged >or= 25 years at baseline. MAIN OUTCOME MEASURES: Direct health care cost, direct non health care cost and government subsidies associated with overweight and obesity, defined by both body mass index (BMI) and waist circumference (WC). RESULTS: The annual total direct cost (health care and non-health care) per person increased from $1472 (95% CI, $1204-$1740) for those of normal weight to $2788 (95% CI, $2542-$3035) for the obese, however defined (by BMI, WC or both). In 2005, the total direct cost for Australians aged >or= 30 years was $6.5 billion (95% CI, $5.8-$7.3 billion) for overweight and $14.5 billion (95% CI, $13.2-$15.7 billion) for obesity. The total excess annual direct cost due to overweight and obesity (above the cost for normal-weight individuals) was $10.7 billion. Overweight and obese individuals also received $35.6 billion (95% CI, $33.4-$38.0 billion) in government subsidies. Comparing costs by weight change since 1999-2000, those who remained obese in 2004-2005 had the highest annual total direct cost. Cost was lower in overweight or obese people who lost weight or reduced WC compared with those who progressed to becoming, or remained, obese. CONCLUSION: The total annual direct cost of overweight and obesity in Australia in 2005 was $21 billion, substantially higher than previous estimates. There is financial incentive at both individual and societal levels for overweight and obese people to lose weight and/or reduce WC. PMID- 20201760 TI - CICADA: Cough in Children and Adults: Diagnosis and Assessment. Australian cough guidelines summary statement. AB - Cough is a common and distressing symptom that results in significant health care costs from medical consultations and medication use. Cough is a reflex activity with elements of voluntary control that forms part of the somatosensory system involving visceral sensation, a reflex motor response and associated behavioural responses. At the initial assessment for chronic cough, the clinician should elicit any alarm symptoms that might indicate a serious underlying disease and identify whether there is a specific disease present that is associated with chronic cough. If the examination, chest x-ray and spirometry are normal, the most common diagnoses in ADULTS are asthma, rhinitis or gastro-oesophageal reflux disease (GORD). The most common diagnoses in CHILDREN are asthma and protracted bronchitis. Management of chronic cough involves addressing the common issues of environmental exposures and patient or parental concerns, then instituting specific therapy. In ADULTS, conditions that are associated with removable causes or respond well to specific treatment include protracted bacterial bronchitis, angiotensin-converting enzyme inhibitor use, asthma, GORD, obstructive sleep apnoea and eosinophilic bronchitis. In CHILDREN, diagnoses that are associated with removable causes or respond well to treatment are exposure to environmental tobacco smoke, protracted bronchitis, asthma, motor tic, habit and psychogenic cough. In ADULTS, refractory cough that persists after therapy is managed by empirical inhaled corticosteroid therapy and speech pathology techniques. PMID- 20201761 TI - Diabetic kidney disease: act now or pay later. AB - The 21st century has the most diabetogenic environment in human history with the number of people with diabetes worldwide increasing to 380 million by 2025. The fastest rate of increase will be in developing countries. Diabetes is now the major cause of end-stage kidney disease globally; 20%-40% of people on dialysis are diabetic. In Australia, the number of people with type 2 diabetes starting dialysis increased fivefold between 1993 and 2007. We must act now at local, national and international levels to prevent type 2 diabetes; screen for early diabetic kidney disease; increase public awareness of kidney disease; treat with medications proven to reduce kidney disease progression; and promote research into and trialling of new therapies. The problem is global yet requires local action. World Kidney Day on 11 March 2010 is a time to intensify action on diabetic kidney disease and to continue to do so until this huge but largely preventable health burden is controlled. PMID- 20201762 TI - Ethics review of multisite studies: the difficult case of community-based indigenous health research. AB - Researchers have longstanding concerns about the logistical and administrative burdens posed by ethics review of multisite studies involving human participants. Centralised ethics review, in which approval by one committee has authority across multiple sites, is widely touted as a strategy for streamlining the process. The Harmonisation of Multi-centre Ethical Review (HoMER) project is currently developing such a system for Australia. It is unclear how centralised review will work for multisite Indigenous health research, where the views of local stakeholders are important and community consultation is mandatory. Our recent experience in conducting the National Indigenous Eye Health Survey (NIEHS) shows how elaborate the current ethics approval and community consultation processes can be, and points to several lessons and ideas to guide pending reforms. PMID- 20201763 TI - Hyperhaemolysis in sickle cell disease--an unusual and potentially life threatening complication. AB - As sickle cell disease is increasing in Australia, paediatricians and other health care providers need to be aware of the broad range of complications that can occur in this condition. Although the complications of splenic sequestration and chest crises are well recognised, the infrequent but equally dramatic complication of hyperhaemolysis is less well appreciated. Here, we report a case of hyperhaemolysis in a Victorian paediatric patient. PMID- 20201764 TI - Fit for the future--a regional governance structure for a new age. AB - Australia's health care system is at a crossroads. It is recognised that the fragmentation of health services, largely caused by the split between Commonwealth and state government funding responsibilities, is undermining patient care. The National Health and Hospitals Reform Commission (NHHRC) has advanced two models of health-system governance to redress this situation - neither incorporating the regional approach so prominent in submissions to the NHHRC and included in Option B of the NHHRC interim report. A regional governance framework such as that described in this paper could keep faith with the importance widely given to local engagement during the consultation process; sit neatly within the NHHRC's Healthy Australia Accord option; make regions responsible for funding allocation and service delivery; eliminate major weaknesses in our current system; and provide stability to the system at a time of significant reform. PMID- 20201765 TI - Motives for migration of South African doctors to Australia since 1948. AB - OBJECTIVE: To determine why more than 2000 doctors have migrated from South Africa to Australia since 1948. DESIGN, SETTING AND PARTICIPANTS: South African trained doctors living in Australia and the spouses or adult children of deceased practitioners who had emigrated from South Africa were contacted by email between August 2008 and February 2009. The sample of doctors was gathered and expanded by an email "snowball" technique and through advertising in alumni and professional journals and newsletters. A questionnaire was emailed to 653 contacts. MAIN OUTCOME MEASURE: Primary reason given for migration. RESULTS: Responses were received from 469 of the 653 email contacts (72%), from a population of about 2200 South African doctors in Australia. Of the 469 respondents, 434 (93%) had been motivated to emigrate by a wish to leave South Africa, rather than by Australian inducements. The primary reason for emigration before 1990 was opposition to apartheid (142/205 [69%]); the primary reason for emigration after 1990 was the level of violent crime (including "safety" issues) (116/264 [44%]). CONCLUSION: Most South African doctors who migrated to Australia were impelled to emigrate by South African issues, rather than attracted by Australia. PMID- 20201766 TI - A case study evaluation of ethics review systems for multicentre clinical trials. PMID- 20201767 TI - National registration legislative proposals need more work and more time. PMID- 20201768 TI - Winds of change: growing demands for transparency in the relationship between doctors and the pharmaceutical industry. PMID- 20201769 TI - Making cars and making health care: a critical review. PMID- 20201771 TI - Robotic brachytherapy of the prostate. AB - Recent applications of robotics in the field of prostate brachytherapy are seeding the future and could potentially lead to a fully automated prostate brachytherapy surgery. Currently, a typical prostate brachytherapy surgery involves the implantation of upwards of 100 radioactive I-125 seeds by a surgeon. This review supplies background information on prostate biology, brachytherapy of the prostate, robotic brachytherapy, and transrectal ultrasound. Subsequently, it examines the physics involved in ultrasound, radiation from an I-125 source, dosimetry, and robotics. A current semi-automated robotic brachytherapy system is examined in detail and a discussion on future improvements is outlined. Finally, future work to improve prostate brachytherapy is postulated, most notably, phantom optimization using polyvinyl alcohol cryogel. The future of robotic brachytherapy lies in the advent of more sophisticated robotics. This review will give the reader a superior understanding of brachytherapy and its recent robotic advancements. Hopefully, this review will generate new ideas needed to advance prostate brachytherapy procedures leading to more accurate dosimetry, faster procedure time, less ionizing radiation received by surgery staff, more rapid patient recovery, and an overall safer procedure. PMID- 20201772 TI - Monitoring brain oxygenation in head-injury patients. AB - Over the last few decades, many methods have been developed to try to monitor the oxygenation status of the brain tissue. These methods have been the subject of a large body of research attempting to understand and interpret the measurements, thus producing clinically useful indicators to guide clinical interventions with the ultimate aim of improving patient outcome. Many techniques have remained in the research domain or have simply been abandoned, but some have generated substantial interest and have been developed into commercially available products in widespread use around the world. This review gives an overview of the management of head-injury patients and discusses the most widely used modalities for monitoring cerebral oxygenation and other variables such as intracranial pressure and cerebral blood flow. PMID- 20201773 TI - Muscle characteristics and fatigue properties after spinal cord injury. AB - Spinal cord injury (SCI) results in a myriad of changes in paralyzed skeletal muscle. Many of these changes stem from the disruption in nerve activation and lead to a loss of muscle mass and the transformation of muscle fiber types to a predominance of type II fast-twitch fibers. Changes to muscle contractile properties are also commonly reported, however, the results are not yet conclusive and appear to vary with the muscle examined. The presence or absence of spasticity also appears to be a significant variable, acting to preserve some muscle characteristics following paralysis. The purpose of this review is to summarize the current literature examining changes in skeletal muscle after SCI, with a particular focus on the effect on fatigue resistance. Mechanisms of fatigue in able-bodied muscle are discussed in the context of their potential to explain the decreased fatigue resistance observed after SCI. PMID- 20201774 TI - Exercise therapy after spinal cord injury: the effects on heath and function. AB - Individuals with spinal cord injury (SCI) are susceptible to an array of secondary health complications. Some of these health concerns are attributable to the SCI per se, but many are secondary to the resulting immobility. For example, the incidence of pressure ulcers, type 2 diabetes, and cardiovascular disease are greatly increased in this population. Despite the need for exercise training as a means to reverse these health risks, individuals with SCI have traditionally been one of the most inactive segments of society. Physical activity programs and information about how activity can promote health are two of the services most desired but least available to people with SCI. Recently, efforts have been made to increase exercise options for individuals with SCI and to study the health benefits of exercise in this population. Accessible resistance and aerobic exercise training, functional electrically stimulated exercise, and body weight supported treadmill training have all shown promise as ways to reverse some of the physiological consequences of SCI. Future research will determine whether these physiological adaptations actually translate to a long-term reduction in disease and mortality. PMID- 20201775 TI - Effect of black seed on dextromethorphan O- and N-demethylation in human liver microsomes and healthy human subjects. AB - OBJECTIVE: To investigate the effects of black seed on the metabolic activities of CYP3A4 and CYP2D6 in human liver microsomes and in human subjects using dextromethorphan as a probe drug. METHODS: CYP2D6-mediated O-demethylation and CYP3A4-mediated N-demethylation of dextromethorphan (DEX) to dextrorphan (DOR) and 3-methoxymorphinan (3-MM), respectively, were utilized to assess the metabolic activities of the two enzymatic pathways. In the in vitro experiments, DEX was incubated with microsomes and NADPH in absence or presence of black seed extract (10-100 microg/ml) and the formation of the metabolites were measured by HPLC. In the clinical study, four healthy volunteers received a single oral dose of DEX 30 mg alone in phase I, and along with last dose of black seed (2.5 g twice daily for seven days) in phase II. Activities of the two enzymes were evaluated based on the urinary metabolic ratios (MRs), which were calculated from eight-hour urine collections. DEX and its metabolites were assayed in urine samples by HPLC following a liquid-liquid extraction. RESULTS: Black seed extracts significantly inhibited the formation of both metabolites in microsomes. The maximum inhibition was observed at the highest extract concentration (i.e., 100 microg/ml), which was about 80% and 60% for DOR and 3-MM, respectively. In the clinical study, the urinary MRs of DEX/DOR and DEX/3-MM increased by factors of 127 and 1.6-fold, respectively, after consumption of black seed. CONCLUSION: Black seed significantly inhibited CYP2D6 and CYP3A4 mediated metabolism of DEX in human liver microsomes and healthy human volunteers indicating that it has the potential to interact with CYP2D6 and CYP3A4 substrates. PMID- 20201770 TI - The role of tissue engineering in articular cartilage repair and regeneration. AB - Articular cartilage repair and regeneration continue to be largely intractable because of the poor regenerative properties of this tissue. The field of articular cartilage tissue engineering, which aims to repair, regenerate, and/or improve injured or diseased articular cartilage functionality, has evoked intense interest and holds great potential for improving articular cartilage therapy. This review provides an overall description of the current state of and progress in articular cartilage repair and regeneration. Traditional therapies and related problems are introduced. More importantly, a variety of promising cell sources, biocompatible tissue engineered scaffolds, scaffoldless techniques, growth factors, and mechanical stimuli used in current articular cartilage tissue engineering are reviewed. Finally, the technical and regulatory challenges of articular cartilage tissue engineering and possible future directions are also discussed. PMID- 20201776 TI - Impact of ritonavir, atazanavir and their combination on the CYP3A4 induction potential of efavirenz in primary human hepatocytes. AB - Currently used combinations of anti-HIV drugs, known as Highly Active Antiretroviral Therapy (HAART), have considerably reduced the mortality in patients with AIDS. However, HAART medications such as efavirenz (EFV), atazanavir (ATV) and ritonavir (RTV) often cause adverse drug-drug interactions (DDIs) that result from changes in the expression and activity of drug metabolizing enzymes. Since EFV is most commonly used with ATV and RTV, the known CYP inhibitors, we evaluated the effects of combinations of these agents on the CYP3A4 induction by EFV. We determined the induction of CYP3A4 by EFV, RTV, ATV, EFV+RTV, EFV+ATV, EFV+RTV+ATV and rifampicin (RIF) employing primary human hepatocytes from 3 donors. Also, concentration dependent activation of human Pregnane X-receptor (hPXR) which is key transcriptional regulator of CYP3A4 by EFV, RIF and RTV was estimated in transiently transfected LS180 cells. CYP3A4 activity (testosterone-6beta-hydroxylation) was induced by EFV (3 fold) and RIF (4 fold), but was significantly suppressed in the presence of RTV and ATV. All treatments significantly induced the CYP3A4 transcripts (3-25 fold) as quantitated by RT-PCR. hPXR activation data in LS180 cells were consistent with the induction of transcripts and the estimated EC(50) values were 0.87 microM, 0.44 microM and 3.7 microM for RIF, RTV and EFV, respectively. However, in primary hepatocytes the net effect was suppression of EFV mediated CYP3A4 induction by RTV and ATV. This observation corresponds to the clinical observations of attenuated CYP3A4 induction by EFV induction in the presence of RTV and other protease inhibitors (PIs). Our results underscore the limitation of transcriptional activation assays in predicting the net outcome for compounds that exhibit complex interactions resulting from induction and inhibition of CYP enzymes. PMID- 20201777 TI - P-Glycoprotein is not a key target for the chemosensitizing effect of 1-phenyl-2 decanoylamino-3-morpholino-1-propanol in HepG2 cells exposed to doxorubicin. AB - Chemosensitization of HepG2 cells to doxorubicin by 1-phenyl-2-decanoylamino-3 morpholino-1-propanol neither impinged on downregulation of P-glycoprotein expression nor on severe impairment of its activity. Moreover, differently from verapamil, a potent P-glycoprotein inhibitor, 1-phenyl-2-decanoylamino-3 morpholino-1-propanol chemosensitized HepG2 cells in a fashion that was insensitive to the pancaspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone. At concentrations exceeding the one employed for chemosensitization, 1-phenyl-2-decanoylamino-3-morpholino-1-propanol was by itself strongly toxic to HepG2 cells, and also this effect was insensitive to the pancaspase inhibitor. These results suggest that 1-phenyl-2-decanoylamino-3 morpholino-1-propanol, at subtoxic concentrations, might synergize with scarcely toxic doxorubicin doses to propagate a caspase-independent cytotoxic response, such that P-glycoprotein-dependent drug resistance is circumvented. PMID- 20201778 TI - Development of a UGT1A1 reporter gene assay for induction studies: correlation between reporter gene data and regulation of UGT1A1 in human hepatocytes. AB - The present manuscript describes the development of a cell-based reporter transcriptional activation assay for evaluating induction of UGT1A1. A reporter construct (pGL-UGT1A1-Luc) encompassing the proximal promoter (nucleotide -254 to +38) and distal enhancer (-3483 to -3194) regions of the human UGT1A1 gene was generated by PCR cloning, and co-transfected with a previously generated PXR construct (pSG5-PXR) into HepG2 cells. The system was then validated using known ligands of PXR, rifampicin (RIF), clotrimazole (CLOT) sulfinpyrazone (SPZ) and phenobarbital (PB), which produced dose dependent induction of UGT1A1 luciferase activity by 4.4, 5.3, 4.7 and 3.7 fold, respectively, relative to the vehicle control, 0.1 % dimethylsulfoxide (DMSO). Aryl hydrocarbon receptor (AhR) ligands a-naphthoflavone (a-Naph), b-naphthoflavone (b-Naph) and 3-methylchloranthene (3 MC) increased UGT1A1 luciferase activity in a concentration dependent manner resulting in 17.2, 11.3 and 6.1 fold, respectively, at their highest concentrations, suggesting that endogenous AhR is also involved in the regulation of the UGT1A1 reporter construct in HepG2 cells. For comparison with transcriptional regulation of endogenous UGT1A1, 10 mM RIF, 50 mM SPZ, 10 mM CLOT, 4 mM 3-MC, 10 mM b-Naph and 25 mM a-Naph also induced UGT1A1 mRNA in human primary hepatocytes by 2.5, 2.8, 3.2, 3.7, 3.9 and 4.3 fold, respectively. In summary, by co-transfecting the UGT1A1 reporter and PXR constructs into HepG2 cells, we have developed a cellular model for evaluating induction of UGT1A1. Data from the reporter gene assay correlated with that generated in human primary hepatocytes. Based on these data, we suggest that this reporter gene assay can be used as a screening tool in the early stages of drug discovery, to evaluate potential induction of UGT1A1 by new chemical entities and to aid in lead selection and optimization. PMID- 20201779 TI - An evaluation of ondansetron binding interactions with human cytochrome P450 enzymes CYP3A4 and CYP2D6. AB - The results of an evaluation study of ondansetron binding to human cytochromes P450 CYP3A4 and CYP2D6 is reported. The methodology includes NMR spectroscopic measurements of substrate to heme iron distances together with molecular modelling of the enzyme-substrate interactions. It is shown that there is a generally good agreement between the experimental and calculated binding affinities for ondansetron towards CYP2D6 and CYP3A4 enzymes, based on interactive docking studies. Moreover, the modelled binding orientations for ondansetron in CYP2D6 and CYP3A4 are largely consistent with the NMR data and with the known routes for P450-mediated metabolism of this compound. PMID- 20201781 TI - Assessment of the inactivation potential of desethylamiodarone on human CYP1A1. AB - Desethylamiodarone was reported to inactivate human CYP1A1. To assess this, two protocols were implemented employing dilution and non-dilution of the preincubation mixture. Inactivation studies performed with diluted preincubation mixtures showed no inactivation of CYP1A1 by desethylamiodarone. However there was evidence for a mixed competitive inhibition (competitive and the uncompetitive inhibition constants of 2.1 microM and 9.6 microM, respectively) of CYP1A1 by desethylamiodarone. NADPH addition and/or replenishment were found to be important factors in determining the control activity in inactivation studies. PMID- 20201780 TI - Pharmacokinetic interaction between verapamil and methylxanthine derivatives in mice. AB - The aim of this study was to assess the impact of a P-glycoprotein and CYP3A inhibitor, verapamil on the pharmacokinetics of two methylxanthines, pentoxifylline and lisofylline in male CD-1 mice. To differentiate the effects of verapamil, both methylxanthines were also given to male CF-1 mdr1a (-/-) and mdr1a (+/+) mice. CD-1 mice received a single dose (50 mg/kg) of pentoxifylline or lisofylline intravenously, whereas mutant animals were given the same dose of both compounds intravenously and orally. Blood and tissue samples were collected at different time points following drug administration and concentrations of pentoxifylline and lisofylline were measured by a chiral HPLC method. Verapamil significantly increased concentrations of both methylxanthines in murine serum and tissues. In contrast to lisofylline, pentoxifylline concentrations were also significantly higher in mutant mice 30 min following intravenous administration. Due to the fact that pentoxifylline is not a good P-glycoprotein substrate, a possible mechanism of this interaction might be that in the presence of verapamil, pentoxifylline elimination is inhibited by its metabolites that are normally eliminated through P-glycoprotein-mediated transport. This hypothesis was supported by the outcomes of pharmacokinetic analysis. In conclusion, the interaction between verapamil and pentoxifylline is, at least partially, P glycoprotein-mediated, whereas alterations in lisofylline pharmacokinetics are caused by inhibition of drug metabolising enzymes. PMID- 20201782 TI - Toxicokinetic interaction between quetiapine and antiretroviral therapy following quetiapine overdose. AB - A 47-year-old woman ingested an overdose of 8000 mg quetiapine. The treatment had been initiated 3 weeks before. The current medications were lamuvidine, ritonavir, atazanavir and tenofovir for an HIV infection. The patient presented a deep coma and sustained hypotension as main complications. The toxicokinetic data revealed a markedly prolonged elimination half-life for quetiapine (62.4 hours) and the relationship with antiretroviral therapy is discussed. PMID- 20201785 TI - Inhibitors of HDACs--effective drugs against cancer? AB - Alterations in genomic and non-genomic mechanisms can disturb homeostasis and cause severe human diseases. Histone deacetylases (HDACs) are epigenetic regulators which catalyze the removal of acetyl moieties from histones and non histone proteins. Aberrant histone deacetylation, due to increased HDAC activity and expression, often correlates with pathological gene repression and neoplastic transformation. Therefore, intense efforts have been made to find small molecule inhibitors of HDACs (HDACIs). Such compounds indeed alter cellular signaling networks relevant for tumorigenesis, and several HDACIs are currently tested in clinical trials against different types of cancer. Although HDACs share a conserved deacetylase domain and an at least similar mechanism of catalysis, isoenzyme-specific HDACIs could be identified and certain HDACIs even evoke degradation of HDACs. Here, we summarize molecular actions of HDACs and of different classes of HDACIs. In addition, we review data obtained in clinical studies involving HDACIs and we discuss how such agents might be beneficial for the treatment of cancer. PMID- 20201784 TI - The biology of the sodium iodide symporter and its potential for targeted gene delivery. AB - The sodium iodide symporter (NIS) is responsible for thyroidal, salivary, gastric, intestinal and mammary iodide uptake. It was first cloned from the rat in 1996 and shortly thereafter from human and mouse tissue. In the intervening years, we have learned a great deal about the biology of NIS. Detailed knowledge of its genomic structure, transcriptional and post-transcriptional regulation and pharmacological modulation has underpinned the selection of NIS as an exciting approach for targeted gene delivery. A number of in vitro and in vivo studies have demonstrated the potential of using NIS gene therapy as a means of delivering highly conformal radiation doses selectively to tumours. This strategy is particularly attractive because it can be used with both diagnostic (99mTc, 125I, 124I)) and therapeutic (131I, 186Re, 188Re, 211At) radioisotopes and it lends itself to incorporation with standard treatment modalities, such as radiotherapy or chemoradiotherapy. In this article, we review the biology of NIS and discuss its development for gene therapy. PMID- 20201786 TI - Anti-GD2 antibody therapy for GD2-expressing tumors. AB - In the development of novel immune therapies for high-risk cancers, one goal is to find tumor targets that are not widely shared by normal cells. One such target is the surface disialoganglioside GD2. This antigen is expressed on the surface of a variety of tumors for which no curative therapies exist for patients with advanced disease. In childhood, the most common GD2-expressing tumor is neuroblastoma. GD2 is also expressed on several other high-risk tumors, including those of neuroectodermal or epithelial origin, virtually all melanomas, and approximately 50% of tumor samples from osteosarcoma and soft-tissue sarcomas. Because of the tumor-selective expression of this molecule, it is an attractive target for tumor-specific therapies such as antibody therapy. Over the last 2 decades, several anti-GD2 antibodies have been developed. To reduce both the toxicity of the antibody and the development of human anti-mouse antibodies (HAMA), research efforts have primarily focused on exploring anti-GD2 antibodies that have progressively more human elements while at the same time reducing the mouse components. This review will examine antibodies currently undergoing clinical testing as well as the most recent advances to improve antibody therapy for patients with GD2-expressing tumors. PMID- 20201787 TI - Antitumor effect of butanoylated heparin with low anticoagulant activity on lung cancer growth in mice and rats. AB - Whole unfractionated heparin can modestly decrease tumor growth, but the dose of heparin is limited by its anticoagulant properties. To overcome this limitation, we modified the chemical structure of heparin and have prepared a heparin derivative by O-acylating low molecular weight heparin with butyric anhydride, producing a more potent antiproliferative compound, which is only weakly anticoagulant so that the dose may be escalated without threat of hemorrhage. In this study, we investigated the effect of this chemically modified heparin, butanoylated heparin, on the growth of lung cancer in vitro and in vivo. We found that butanoylated heparin a) significantly inhibited lung cancer cell proliferation in vitro and lung cancer growth in mice and rats; b) had very low anticoagulant effect; c) had no significant toxicity on heart, liver, kidney and lung; d) significantly although modestly induced apoptosis and decreased expression of the cell proliferation pathway consisting of mutant p53, phospho-Rb and E2F1 expression in the tumor tissues. We also found that butanoylated heparin significantly inhibited CXCL12 and CXCR4 expression, suggesting that CXCL12/CXCR4 axis may be involved in regulation of tumor growth inhibition by heparin. We concluded that chemically modified butanoylated heparin has potent antiproliferative activity against lung cancer and may represent a new chemical therapeutic agent for cancer patients. PMID- 20201788 TI - Exploring the potential of NO-independent stimulators and activators of soluble guanylate cyclase for the medical treatment of erectile dysfunction. AB - Nitric oxide (NO)-sensitive soluble guanylyl cyclase (sGC) is the receptor that catalyzes the formation of the intracellular messenger cyclic guanosine monophosphate (cGMP). Binding of the physiological activator, NO, to the reduced heme moiety of sGC increases the conversion of guanosine triphosphate (GTP) to cyclic GMP (cGMP) and engages crucial effector systems such as protein kinases, phosphodiesterases, and ion channels. The development of compounds that activate sGC independent of NO release has therapeutic implications. Recent studies have demonstrated the potential use of heme-dependent sGC stimulators (e.g. YC-1, BAY 41-2272, BAY 41-8543, BAY 63-2521, CFM-1571 and A-350619) and heme-independent sGC activators (e.g. BAY 58-2667, HMR-1766, S-3448, A-778935) in the treatment of cardiovascular diseases. Erectile dysfunction (ED) affects millions of men. Phosphodiesterase (PDE)-5 inhibitors, produce an NO-dependent increase in intracellular cGMP concentration, have been a successful approach in the treatment of ED. However, >30% of men with ED do not respond to PDE-5 inhibitor therapy, implying that endogenous NO production may be impaired to such an extent that inhibition of cGMP degradation produces no significant therapeutic advantage. Endogenous NO released from nitrergic nerves in the corpora cavernosa is significantly decreased in various conditions (e.g. diabetes, aging, and hypertension) and have reduced activation of the NO-sGC-cGMP pathway. It is conceivable that sGC stimulators and/or activators may be more effective than PDE5 inhibitors in the treatment of ED in such circumstances by improving NO-sGC cGMP signaling and erectile function. This novel drug therapy approach for the treatment of ED shows promise. PMID- 20201789 TI - Peak treadmill exercise echocardiography. AB - Stress echocardiography is a useful tool for the clinical decision making process, given its accuracy and demonstrated prognostic value. Among available stress echocardiography techniques, exercise is safer and more physiologic, therefore must be considered the first choice for patients able to exercise. Peak exercise echocardiography has greater sensitivity than post-exercise imaging. Image quality of apical views at peak exercise is similar than that of images acquired during the immediate post-exercise period. Although more demanding than post-exercise treadmill imaging, the successfulness of peak treadmill exercise imaging may be improved with some skills. The role of new technology is promising for exercise echo. Doppler tissue and speckle imaging can assess myocardial velocities and deformation. However, although Doppler tissue imaging increases the agreement and accuracy among novel readers, it has not been demonstrated to be better than visual assessment when the latter is performed by experienced observers. Speckle imaging can easily measure myocardial torsion, which has been found to be altered under ischemic conditions. Finally, 3-dimensional echocardiography can also be used during exercise since a full volume of the entire myocardium can be obtained in a few cardiac cycles. PMID- 20201791 TI - Recent applications of chemiluminescence assays in clinical immunology. AB - Chemiluminescence has traditionally been used to study the nature of the oxidative bactericidal mechanisms of neutrophils and monocytes, the intrinsic defects of abnormally functioning neutrophils or monocytes and cell activation. During the last ten years Chemiluminescence has been applied in a wide variety of techniques including: immunoassays, protein blotting, toxicological and pharmacological tests (e.g. after exposure to antibiotic or immunomodulators agents such as adjuvants and cytotoxic drugs). In this review, we discuss some promising clinical applications of Chemiluminescence in clinical immunology for the study of autoimmune diseases, inflammatory responses, endocrine disorders, immunodeficiency's states, mucosal immune response against drugs and pathogens and host responses against tumors and infections. Further, we review numerous advantages showed by Chemiluminescence-based methods over other methods to assay the same endpoints, which facilitate their uses in the current practice of clinical immunology. PMID- 20201795 TI - Medical applications of implantable drug delivery microdevices based on MEMS (Micro-Electro-Mechanical-Systems). AB - Drug delivery microdevices based on MEMS (Micro-Electro-Mechanical-Systems) represent the next generation of active implantable drug delivery systems. MEMS technology has enabled the scaling down of current delivery modalities to the micrometer and millimeter size. The complementary use of biocompatible materials makes this technology potentially viable for a wide variety of clinical applications. Conditions such as brain tumors, chronic pain syndromes, and infectious abscess represent specialized clinical diseases that will likely benefit most from such drug delivery microdevices. Designing MEMS microdevices poses considerable technical and clinical challenges as devices need to be constructed from biocompatible materials that are harmless to human tissue. Devices must also be miniaturized and capable of delivering adequate pharmacologic payload. Balancing these competing needs will likely lead to the successful application of MEMS drug delivery devices to various medical conditions. This work reviews the various factors that must be considered in optimizing MEMS microdevices for their appropriate and successful application to medical disease. PMID- 20201796 TI - Multidimensional targeting: using physical and chemical forces in unison. AB - Targeted drug delivery has traditionally relied on finding highly specific biochemical markers at a target location. However, recent developments in this area have shown that purely physical and physicochemical factors are as important and can be used to aid in the targeting process. Here, we review the physicochemical factors affecting the targeting and delivery process and their relation to established biochemical markers. We refer to this combined approach as multidimensional targeting (MDT). More specifically, we examine the role of MDT factors across different length scales of relevance to the drug delivery pathway. Finally, we conclude with our perspective on the future of this burgeoning area. PMID- 20201797 TI - Pulmonary rehabilitation as evaluated by clinical trials: an overview. AB - During the 80' and the 90's, the role of pulmonary rehabilitation (PR) was still not clearly demonstrated. The following development of PR was mainly due to the increasing number of clinical studies providing proofs of its effectiveness, and convincing physicians, institutions, and regulatory agencies about its additional value to conventional pharmacological therapies. In the later years, PR has become an evidence-based non pharmacological treatment, designed for patients suffering from chronic obstructive lung disease (COPD). In the pulmonary rehabilitation programs (PRPs), exercise is essential for improving muscular tone and thus reducing disability. This later is due to chronic breathlessness, fatigue, and impairment of daily activities, that cause a reduction in functional performance and quality of life (QoL) in COPD patients. PRPs include also educational, psychosocial and nutritional interventions, so that it becomes a multifaceted approach. Despite the existing consciousness that PR results in improvement of exercise tolerance, dyspnea, and QoL, it is under prescribed by most health professionals, and only about 2% of COPD patients undergo PRPs. An appropriate consideration of the PR is essential to ensure optimal management of COPD, in particular when patients have respiratory symptoms that lead to a decrease in physical activity. PMID- 20201792 TI - The Vpu protein: new concepts in virus release and CD4 down-modulation. AB - Human immunodeficiency virus type 1 (HIV-1) and several simian immunodeficiency viruses (SIV) encode for a transmembrane protein known as Vpu (viral protein U). While one of the smallest of the HIV-1 proteins, it has two important functions within virus-infected cells. The first of these functions is the down-regulation of the CD4 receptor to prevent its interaction with the HIV-1 envelope glycoprotein. Vpu interacts with the CD4 receptor in the rough endoplasmic reticulum (RER), resulting in its re-translocation across the RER and subsequent degradation via the proteasomal pathway. The second major function of the Vpu protein is to facilitate release of virus from infected cells. Previous studies have shown that virus release is cell type specific, suggesting that certain cells may express a restriction factor that inhibits virus release in the absence of Vpu. Recently, bone marrow stromal antigen 2 (BST-2/HM1.24/CD317/tetherin) has been identified as this factor. This review will focus on new findings within the last four years on the role of Vpu in CD4 down-regulation and the restriction of virus release from cells. We will relate these findings to virus pathogenesis and propose questions regarding BST-2 as a restriction factor. PMID- 20201798 TI - Prevalence of diabetes among immigrants in the Nordic countries. AB - Some immigrant groups in Europe show an increased prevalence of diabetes, e.g. South Asians in the UK and Moroccans and Turks in the Netherlands. This study aimed at reviewing the literature among immigrants in the Nordic countries. Search was performed primarily of Medline through PubMed, and secondarily of other databases and by using information from reference lists. Terms used were: "Diabetes Mellitus", "Immigrant", and "Nordic countries" or "Scandinavia" or "Denmark", "Finland", "Iceland", "Norway" or "Sweden". Altogether 17 articles on diabetes were found. Excess risk of diabetes was found in non-European immigrant groups, especially from the Middle East and South Asian regions, in some cases 10 times the risk of the indigenous population, with the highest relative risks among women. No excess risk was found among European immigrants, with the possible exception of Finnish women. Conflicting results were found in studies with a low number of diabetic cases, with a failure to show statistically significant excess risks among non-European groups. There were also some other methodological problems, e.g. low participation rate in population based clinical studies, and probable underestimation of known diabetes by self-report. A genetic sensitivity seems likely in the Middle East and South Asian groups, combined with lifestyle factors. PMID- 20201799 TI - Biomaterials and mesenchymal stem cells for regenerative medicine. AB - The reconstruction of hard and soft tissues is a major challenge in regenerative medicine, since diseases or traumas are causing increasing numbers of tissue defects due to the aging of the population. Modern tissue engineering is increasingly using three-dimensional structured biomaterials in combination with stem cells as cell source, since mature cells are often not available in sufficient amounts or quality. Biomaterial scaffolds are developed that not only serve as cell carriers providing mechanical support, but actively influence cellular responses including cell attachment and proliferation. Chemical modifications such as the incorporation of chemotactic factors or cell adhesion molecules are examined for their ability to enhance tissue development successfully. E.g. growth factors have been investigated extensively as substances able to support cell growth, differentiation and angiogenesis. Thus, continuously new patents and studies are published, which are investigating the advantages and disadvantages of different biomaterials or cell types for the regeneration of specific tissues. This review focuses on biomaterials, including natural and synthetic polymers, ceramics and corresponding composites used as scaffold materials to support cell proliferation and differentiation for hard and soft tissues regeneration. In addition, the local delivery of drugs by scaffold biomaterials is discussed. PMID- 20201800 TI - Secretory production of recombinant proteins in Escherichia coli. AB - Extracellular production of heterologous proteins using the Escherichia coli cell factory offers several advantages over intracellular production and mammalian culture. Properly folded proteins can be rapidly accumulated in the culture media, and downstream processes for isolation and purification can be much simplified. Efforts to enhance the secretory production of target proteins can be largely classified as selection and modification of the signal peptide, co expression of proteins to assist translocation and folding, improvement of periplasmic release, and protection of target proteins from degradation and contamination. Here, we review recent patents on the secretory production of recombinant proteins in E. coli. PMID- 20201801 TI - Five years patenting time frame concerning enzymatic preparation of glycosides. AB - Carbohydrates are important molecules in various technological fields. The regio- and stereoselective synthesis of oligosaccharides for food and pharmaceutical molecular design and the selective glycosylation of peptides, proteins and drugs, as well as the selective hydrolysis of natural abundant saccharidic materials affording low molecular weight high value- added products, can be all considered significant aspects. Advance in the chemical synthesis of glycosidic bond represents one of the most successful topic in organic synthetic chemistry in the last half century for the intrinsic difficulties chemists have to face dealing with carbohydrates: yields and selectivity. Biocatalytic strategies selected for high-yield and stereospecific construction of glycosidic bonds are based principally on the action of two classes of enzymes, namely glycoside hydrolases (endo- and exo-glycosidases) and glycosyltransferases although only enzymes of the second class are devoted to synthetic action in nature. Reviewing patents on the preparation of glycosides is hard to manage, here a five years time frame for this review is set, considering it a suitable compromise in terms of amount of innovation and numbers of patents to analyze. Interest of researchers for the natural sources of biocatalysts, with particular emphasis on modified enzymes and lists of the most innovative patents in cosmetic, fine chemicals and food fields will be commented. Biomolecular asset of selected patents related to glycosides will be expressly considered. Large number of enzymes will be required in future in order to realize more sustainable new enzymatic processes to answer human needs. PMID- 20201802 TI - A review of recent patents on macroorganisms as biological control agents. AB - The indiscriminate use of synthetic pesticides has brought undesired problems to human health, agriculture, and the environment. Integrated Pest Management (IPM) and Biological Control (BC) programs, which are based on minimum use of pesticides, are seen as alternative, more ecological solutions to the unintended problems associated with pesticide use. These programs combine the introduction, augmentation, and/or conservation of pest natural enemies, with other protection tools. Although patents and the process of commercialization of microorganisms has been the subject of various reviews, macroorganisms used for pest and disease control have stimulated less comprehensive analyses. From our review of patents, there has been an enormous increase in the number of macroorganism-related patents registered in the last two decades. Private companies own 65% of all these patents. Rearing methods and crop protection strategies are the main intellectual property patented, with parasitoid wasps and predatory mites being the primary Biological Control Agent (BCA) focus of patents. Among countries, Japan was the first country with these types of patents, followed by the United States, Canada and China. Increasing concern for pesticide risks by governments and the public is seen as the main impetus for change in "traditional" crop protection practices and for investment in other more ecological products like BCAs. PMID- 20201803 TI - Membrane bio reactors (MBR) in waste water treatment: a review of the recent patents. AB - Effluent standards have become more and more stringent due to an increase in awareness about environmental impacts on both continuous and intermittent polluting discharge. For that, a high efficient waste water treatment plants are needed to be designed. Membrane bioreactor (MBR) can be good solution to cope with such issues. MBR systems respects the conventional activated sludge process which use microorganisms for degradation of organic pollutants and requires aeration as well as reduced foot print and sludge production through maintaining a high biomass concentration in the bio reactor. The present work elucidates the recent patents and critically reviews the advancement in MBR process, which can be helpful to designer. It was found that the behavior of aeration device, mixed liquor suspended solids (MLSS) concentration, flux enhancer and handling of sludge plays an important role in the performance of MBR process. PMID- 20201804 TI - The use of beneficial microbial endophytes for plant biomass and stress tolerance improvement. AB - Endophytes are microorganisms that live within host plants for at least part of their life and do not cause apparent symptoms of diseases. In general, beneficial endophytes promote host plant growth, increase plant nutrient uptake, inhibit plant pathogen growth, reduce disease severity, and enhance tolerance to environmental stresses. As sustainable and renewable agricultural production (including current biofuel and bioenergy crops) increases in prominence, endophytic microorganisms will play important roles and offer environmentally friendly methods to increase productivity while reducing chemical inputs. This review discusses various aspects of beneficial fungal and bacterial endophyte interactions with plants, including the physiological and molecular mechanisms by which they benefit plant performance. We also discuss the potential for genetic modification of endophytes with useful genes, which could be used to impart additional traits following inoculation with the genetically engineered endophytes. Finally, we review US-issued patents over the past decade which relate to the use of fungal and bacterial endophytes for plant growth and stress tolerance improvement. PMID- 20201805 TI - Hemoglobin and cooperativity: Experiments and theories. AB - Cooperative interactions within biological macromolecules are of fundamental physiological relevance and have been studied in great detail. Yet, even in the best investigated case of oxygen binding by hemoglobin, our understanding of the structural and thermodynamic bases of cooperativity is far from satisfactory. Several theoretical models have been proposed to explain cooperative O2 binding to hemoglobin, among which the two-state model by Monod, Wyman and Changeux, has been the most successful and the most thoroughly tested. This model explains the functional properties of hemoglobin as resulting from the equilibrium of two quaternary conformations, named R and T, characterized by different ligand affinity, and is capable of very accurate (but not always exact) predictions. This review focuses on the experiments carried out to test the models of cooperativity, and especially the two-state model, and identifies two major deviations, or groups of deviations, between the predictions of this model and the actual experimental results, namely (i) the changes in the behaviour of the T and R-state due to solvent components; (ii) the appearance of R-like reactivity under experimental conditions in which the T-state should be largely prevalent. Modern models of cooperativity, devised to account for these discrepancies while maintaining the basic two-state hypothesis of Monod, Wyman and Changeux, are also reviewed. PMID- 20201806 TI - Recent progress in research on ribosome inactivating proteins. AB - The intent of this article is to review recent literature on ribosome inactivating proteins (RIPs) including isolation and characterization of new RIPs, studies on the crystal structures and mechanisms of actions of RIPs, the use of saporin-based neurotoxins to selectively lesion cholinergic neurons in neuroscience research, and the use of RIP-based conjugates and immunotoxins in anticancer therapy. PMID- 20201807 TI - Conformations and biological activities of amyloid beta peptide 25-35. AB - Amyloid-beta (Abeta) peptide is commonly found in human Alzheimer's disease (AD) brain and is the main component of Alzheimer amyloid plaques. The predominant forms of Abeta in the human brain are Abeta(1-40) and Abeta(1-42), but Abeta(25 35) fragment, physiologically present in elderly people, is the more toxic region and has been recently found to play a relevant role in AD, due to its peculiar aggregation properties. In this work, we review the current understanding on the conformations and biological activity of Abeta(25-35) exploring aggregation, cytotoxic and neurodegenerative properties of this fundamental Abeta fragment, in order to provide an effective starting point to better approach a pathology spread and problematic as AD. PMID- 20201808 TI - Evolution of mannose 6-phosphate receptors (MPR300 and 46): lysosomal enzyme sorting proteins. AB - Lysosomal enzymes undergo phosphorylation on their mannose residues in the Golgi apparatus and are recognized by two distinct type I transmembrane glycoproteins designated as the mannose 6-phosphate receptors; MPR300, (Mr 300 kDa) and MPR46, (Mr 46 kDa) that internally transport them to the lysosomes. In humans, absence of this recognition system leads to severe lysosomal storage disease, emphasizing their essential role in the biogenesis of lysosomes. Among the two receptors only MPR46 shows an absolute requirement for divalent metal ions. Only MPR300 is known to be a multifunctional protein that also binds many other ligands such as the human IGF-II, thyroglobulin, retinoic acid, granzyme A and B. In mammals, the extracytoplasmic domain of MPR300 protein is comprised of 15 repetitive cassettes which share significant similarity with each other and also with the single cassette that constitutes the extracytoplasmic domain of MPR46. Therefore it became necessary to understand the evolution of these receptors. Homologous proteins were affinity purified from different non-mammalian vertebrates such as birds, reptiles, amphibians, fish and also from the invertebrates, echinodermates (starfish) and molluscs (unio). Cloning and sequencing of both receptors from different mammals, chicken, fish and MPR46 from starfish revealed that these proteins exhibit similar structural domains as the mammalian receptors. alpha fucosidase characterized from the molluscs exhibits specific interaction with the putative MPR300 protein from the same species. Available evidence suggests evolutionary conservation of both receptors from molluscs, as below these species no receptors that bind phosphomannan have been identified. PMID- 20201809 TI - Random mutagenesis methods for in vitro directed enzyme evolution. AB - Random mutagenesis is a powerful tool for generating enzymes, proteins, entire metabolic pathways, or even entire genomes with desired or improved properties. This technology is used to evolve genes in vitro through an iterative process consisting of recombinant generation. Coupled with the development of powerful high-throughput screening or selection methods, this technique has been successfully used to solve problems in protein engineering. There are many methods to generate genetic diversity by random mutagenesis and to create combinatorial libraries. This can be achieved by treating DNA or whole bacteria with various chemical mutagens, by passing cloned genes through mutator strains, by "error-prone" PCR mutagenesis, by rolling circle error-prone PCR, or by saturation mutagenesis. The next sections of this review article focus on recent advances in techniques and methods used for in vitro directed evolution of enzymes using random mutagenesis. Selected examples, highlighting successful applications of these methods, are also presented and discussed. PMID- 20201810 TI - Disulfiram: an old therapeutic with new applications. AB - Disulfiram treatment, despite its limitations, remains a viable option as a treatment for alcohol dependence and has shown recent promise in treating (1) those with co-morbid alcohol dependence and post-traumatic stress disorder, (2) those with co-morbid cocaine- and alcohol-dependence, and (3) those with cocaine dependence alone. Although disulfiram's mechanism of action in alcohol dependence was long thought to be its effects as a psychological deterrent, more recent studies have uncovered potential anti-craving effects as well as direct effects of disulfiram on cocaine abuse, highlighting a few of the many potential and unique benefits disulfiram may have through its inhibition of dopamine beta hydroxylase. This article will review the major clinical trials of disulfiram spanning nearly 60 years. We will discuss the pharmacodynamics and pharmacokinetics of disulfiram, indications and limitations of its use, suggestions for appropriate patient populations, and monitoring for compliance and adverse effects. We will also review recent literature on newer potential applications for disulfiram use via its unique action on dopamine beta hydroxylase. PMID- 20201811 TI - Naltrexone for the treatment of alcoholism: clinical findings, mechanisms of action, and pharmacogenetics. AB - Naltrexone is an opioid receptor antagonist with established efficacy, albeit moderate, for the treatment of alcohol dependence. This manuscript provides a critical review of the literature on naltrexone as a pharmacotherapy for alcoholism by covering the following areas: (a) clinical findings from treatment studies; (b) pharmacokinetics and safety data; (c) medication compliance and persistence; and (d) neurobiological and biobehavioral mechanisms of action of naltrexone for the indication of alcohol dependence. This review will then focus on the emerging literature on naltrexone pharmacogenetics, which has the potential to identify responders on the basis of genetic variation and to use genetic tools to individualize the use of this medication. Limitations and future directions in the research and practice of naltrexone for alcoholism are also outlined. PMID- 20201812 TI - Acamprosate: a prototypic neuromodulator in the treatment of alcohol dependence. AB - Alcoholism is one of the most prevalent substance dependence disorders in the world. Advances in research in the neurobiological mechanisms underlying alcohol dependence have identified specific neurotransmitter targets for the development of pharmacological treatments. Acamprosate, marketed under the brand name Campral, is an orally administered drug available by prescription in the U.S. and throughout much of the world for treating alcohol dependence. Its safety and efficacy have been demonstrated in numerous clinical trials worldwide. Here we provide an overview of acamprosate in the context of the neurobiological underpinnings of alcohol dependence. We propose that unlike previously available pharmacotherapies, acamprosate represents a prototypical neuromodulatory approach in the treatment of alcohol dependence. A neuromodulatory approach seeks to restore the disrupted changes in neurobiology resulting from chronic alcohol intake. We believe that a neuromodulatory approach will provide a heuristic framework for developing more effective pharmacotherapies for alcohol dependence. PMID- 20201813 TI - Effectiveness and safety of baclofen in the treatment of alcohol dependent patients. AB - Both preclinical and clinical research studies have shown the GABA(B) receptor agonist baclofen represents a promising treatment for alcohol dependence. Preliminary clinical studies indicate that baclofen is able to suppress withdrawal symptoms in alcohol-dependent patients affected by the alcohol withdrawal syndrome. Moreover, baclofen has shown efficacy and safety in promoting alcohol abstinence in alcohol dependent patients in two placebo controlled trials including one in alcohol-dependent patients with liver cirrhosis. These trials also demonstrated that baclofen was associated with reductions in withdrawal-related anxiety and alcohol craving. However, more work is needed to clearly demonstrate the efficacy of baclofen and to ascertain whether efficacy is limited to certain subtypes of alcoholic patients. For example, a recent US trial failed to demonstrate a robust effect of baclofen in treating alcohol-dependent patients though the relative moderate severity of alcohol-dependence in that trial has been suggested as one factor that may have contributed to the finding. In the present review, the authors will summarize the published clinical studies on the role of baclofen in alcohol dependence and will also present some unpublished secondary analyses. Finally, the authors will discuss possible future directions to further investigate the role of baclofen in alcohol dependence (e.g., baclofen's biobehavioral mechanisms, different baclofen doses, differences in severity and in alcoholic subtypes, different formulations of baclofen, possible combination of baclofen with other medications). PMID- 20201814 TI - The role of topiramate and other anticonvulsants in the treatment of alcohol dependence: a clinical review. AB - Alcohol dependence is a major health problem worldwide. Various pharmacological agents have been used in the management of alcohol dependence. This review looks at the role of topiramate and other anticonvulsants in the management of alcohol dependence. Topiramate is the most widely used anticonvulsant in the treatment of alcohol dependence. The literature on topiramate is reviewed and critically analyzed, along with its proposed mechanism of action in alcohol dependence. A review of data available on other anticonvulsants like carbamazepine, oxcarbazepine, sodium valproate, gabapentin and levetiracetam are presented and their potential in the treatment of alcohol dependence is considered, together with future research directions. PMID- 20201815 TI - Aripiprazole: a drug with a novel mechanism of action and possible efficacy for alcohol dependence. AB - Alcohol dependence is a costly and socially devastating illness. The dopamine system has received increased attention due to the consensus that dopaminergic dysfunction is at the core of the addiction process. Agents that modulate this system might be beneficial in reducing craving, reward, and relapse. Aripiprazole is a 3(rd) generation atypical antipsychotic U.S. Food and Drug Administration approved for the treatment of schizophrenia, bipolar disorder, and treatment resistant major depression. Its principal mechanism of action appears to be associated with partial agonism at the D2 dopamine receptor. Nevertheless, relatively recent pre-clinical data shows that aripiprazole might exert its action by way of agonism, partial agonism, and antagonism at both dopamine and serotonin receptors. In animal models of alcoholism aripiprazole produced an overall decrease in drinking behavior. Clinical trials with aripiprazole in alcoholics have shown some positive, but inconsistent, results. Given aripiprazole's putative activity on frontal-subcortical circuits subserving reward/craving and impulsive behavior, it might prove to be beneficial for neuropsychiatric conditions in which dysregulation of reward and impulsivity, among them alcoholism, are at the core of the syndrome. This article proposes a potential role for aripiprazole in alcoholism treatment, and suggests that more randomized controlled trials should be designed at appropriate doses to better understand aripiprazole's potential role as a treatment option. More options are needed to treat alcoholics that fall into different subgroups (e.g., those with impulsive disorders), or non-responsive to available treatments. Early results with aripiprazole are promising and warrant further exploration. PMID- 20201816 TI - Blockade of the cannabinoid CB1 receptor and alcohol dependence: preclinical evidence and preliminary clinical data. AB - The present paper summarizes the results of a number of pharmacological studies implicating the cannabinoid CB(1) receptor in the neural circuitry regulating different alcohol-related behaviors in rodents. Specifically, cannabinoid CB(1) receptor antagonists--including the prototype, rimonabant--have been reported to suppress: (a) acquisition and maintenance of alcohol drinking behavior under the 2-bottle "alcohol vs water" choice regimen; (b) the increase in alcohol intake occurring after a period of alcohol abstinence (an experimental model of alcohol relapse); (c) alcohol's reinforcing and motivational properties measured in rats trained to perform a specific task (e.g., lever-pressing) to access alcohol; (d) reinstatement of extinguished alcohol-seeking behavior triggered in rats by a nicotine challenge or presentation of cues previously associated to alcohol availability (another model of alcohol relapse). Additional data indicate that the opioid receptor antagonists, naloxone and naltrexone, synergistically potentiate the suppressing effect of rimonabant on alcohol intake and alcohol's motivational properties in rats. Conversely, the two clinical studies conducted to date (one in alcohol-dependent individuals and one in nontreatment-seeking heavy alcohol drinkers) yielded less conclusive results. Unfortunately, the recent discontinuation--due to the occurrence of some psychiatric adverse effects -of all trials with cannabinoid CB(1) receptor antagonists apparently hinders further investigations on the potential of rimonabant in the treatment of alcohol dependence. PMID- 20201819 TI - The nociceptin/orphanin FQ system as a target for treating alcoholism. AB - Nociceptin (known also as orphanin FQ) is the most recently discovered member of the endogenous opioid peptide family, albeit nearly 15 years ago. Nociceptin renders or influences many behavioral, psychological and neurobiological processes, including memory, anxiety, stress and reward. Since its discovery, results of a steady stream of studies have suggested that endogenous nociceptin might be involved in responses to addictive drugs, and that targeting the nociceptin system may be beneficial in treating addictions. The current review summarizes and critically appraises those studies, particularly those that point to an application in treating alcoholism. Overall, most, studies suggest that the endogenous nociceptin system has a physiological role in mediating or regulating behavioral responses to alcohol, and that activating nociceptin receptors suppresses ongoing alcohol consumption or reinstatement of responding for alcohol. These findings encourage the development of therapies targeted at the nociceptin system for the treatment of alcoholism in humans, though a minor number of studies showing continuous activation of the nociceptin receptor can produce increased, rather than reduced, alcohol consumption emphasize the necessity of further investigation. PMID- 20201818 TI - Pre-clinical evidence that corticotropin-releasing factor (CRF) receptor antagonists are promising targets for pharmacological treatment of alcoholism. AB - Alcoholism is a chronic disorder characterized by cycling periods of excessive ethanol consumption, withdrawal, abstinence and relapse, which is associated with progressive changes in central corticotropin-releasing factor (CRF) receptor signaling. CRF and urocortin peptides act by binding to the CRF type 1 (CRF1R) or the CRF type 2 (CRF2R) receptors, both of which have been implicated in the regulation of neurobiological responses to ethanol. The current review provides a comprehensive overview of preclinical evidence from studies involving rodents that when viewed together, suggest a promising role for CRFR antagonists in the treatment of alcohol abuse disorders. CRFR antagonists protect against excessive ethanol intake resulting from ethanol dependence without influencing ethanol intake in non-dependent animals. Similarly, CRFR antagonists block excessive binge-like ethanol drinking in non-dependent mice but do not alter ethanol intake in mice drinking moderate amounts of ethanol. CRFR antagonists also protect against increased ethanol intake and relapse-like behaviors precipitated by exposure to a stressful event. Additionally, CRFR antagonists attenuate the negative emotional responses associated with ethanol withdrawal. The protective effects of CRFR antagonists are modulated by CRF1R. Finally, recent evidence has emerged suggesting that CRF2R agonists may also be useful for treating alcohol abuse disorders. PMID- 20201821 TI - Mitochondrial metabolism modulation: a new therapeutic approach for Parkinson's disease. AB - Mitochondrial metabolism is a highly orchestrated phenomenon in which many enzyme systems cooperate in a variety of pathways to dictate cellular fate. As well as its vital role in cellular energy metabolism (ATP production), mitochondria are powerful organelles that regulate reactive oxygen species production, NAD+/NADH ratio and programmed cell death. In addition, mitochondrial abnormalities have been well recognized to contribute to degenerative diseases, like Parkinson's disease (PD). Particularly a deficiency in the mitochondrial respiratory chain complex I and cristae disruption have been consistently described in PD. Moreover, the products of PD-familial genes, including alpha-synuclein, Parkin, PINK1, DJ-1, LRRK2 and HTR2A, were shown to localize to the mitochondria under certain conditions. It seems that PD has a mitochondrial component so events that would modulate normal mitochondrial functions may compromise neuronal survival. However, it remains an open question whether alterations of these pathways lead to different aspects of PD or whether they converge at a point that is the common denominator of PD pathogenesis. In this review we will focus on mitochondrial metabolic control and its implications on sirtuins activation, microtubule dynamics and autophagic-lysosomal pathway. We will address mitochondrial metabolism modulation as a new promising therapeutic tool for PD. PMID- 20201817 TI - Neuronal nicotinic acetylcholine receptors as pharmacotherapeutic targets for the treatment of alcohol use disorders. AB - Alcohol use disorders (AUDs) are complex, and developing effective treatments will require the combination of novel medications and cognitive behavioral therapy approaches. Epidemiological studies have shown there is a high correlation between alcohol consumption and tobacco use, and the prevalence of smoking in alcoholics is as high as 80% compared to about 30% for the general population. Both preclinical and clinical data provide evidence that nicotine administration increases alcohol intake and non-specific nicotinic receptor antagonists reduce alcohol-mediated behaviors. As nicotine interacts specifically with the neuronal nicotinic acetylcholine receptor (nAChR) system, this suggests that nAChRs play an important role in the behavioral effects of alcohol. In this review, we discuss the importance of nAChRs for the treatment of AUDs and argue that the use of FDA approved nAChR ligands, such as varenicline and mecamylamine, approved as smoking cessation aids may prove to be valuable treatments for AUDs. We also address the importance of combining effective medications with behavioral therapy for the treatment of alcohol dependent individuals. PMID- 20201822 TI - Raf inhibitors as therapeutic agents against neurodegenerative diseases. AB - The active form of the serine/threonine kinase cRaf-1 is upregulated postmortem in the brains of Alzheimer's disease (AD) patients and in transgenic mouse models of AD pathology. The persistent activation of cRaf-1 can activate the proinflammatory factor NFkappaB and consequently, upregulate the expression of several of its downstream factors such as the amyloid precursor protein (APP), Cox-2 and iNOS. These factors have been found upregulated in numerous neurodegenerative conditions including AD, epilepsy, brain trauma, and psychological stress. The Raf kinase inhibitors, GW5074 and ZM336372, are neuroprotective against many different neurotoxic insults in vitro, including the Abeta peptide, glutamate and glutathione depletion. Recently, we have reported that the multi-kinase and potent Raf inhibitor sorafenib reversed memory impairment and reduced the expression of APP, Cox-2, and iNOS in the brain of the transgenic mouse model of AD, APPswe. Similar improvement of behavioral outcome was attained after acute treatment with GW5074 in a mouse model of Huntington's disease. Several Raf inhibitors have been developed to treat aggressive forms of cancer showing an upregulation of Raf kinases. These Raf inhibitors offer a great promise as therapeutic tools against neurological disorders. The negative and positive aspects of these inhibitors as anti-neurodegenerative agents are discussed. PMID- 20201820 TI - TRPC channels and their implication in neurological diseases. AB - Calcium is an essential intracellular messenger and serves critical cellular functions in both excitable and non-excitable cells. Most of the physiological functions in these cells are uniquely regulated by changes in cytosolic Ca2+ levels ([Ca2+](i)), which are achieved via various mechanisms. One of these mechanism(s) is activated by the release of Ca2+ from the endoplasmic reticulum (ER), followed by Ca2+ influx across the plasma membrane (PM). Activation of PM Ca2+ channel is essential for not only refilling of the ER Ca2+ stores, but is also critical for maintaining [Ca2+](i) that regulates biological functions, such as neurosecretion, sensation, long term potentiation, synaptic plasticity, gene regulation, as well as cellular growth and differentiation. Alterations in Ca2+ homeostasis have been suggested in the onset/progression of neurological diseases, such as Parkinson's, Alzheimer's, bipolar disorder, and Huntington's. Available data on transient receptor potential conical (TRPC) protein indicate that these proteins initiate Ca2+ entry pathways and are essential in maintaining cytosolic, ER, and mitochondrial Ca2+ levels. A number of biological functions have been assigned to these TRPC proteins. Silencing of TRPC1 and TRPC3 has been shown to inhibit neuronal proliferation and loss of TRPC1 is implicated in neurodegeneration. Thus, TRPC channels not only contribute towards normal physiological processes, but are also implicated in several human pathological conditions. Overall, it is suggested that these channels could be used as potential therapeutic targets for many of these neurological diseases. Thus, in this review we have focused on the functional implication of TRPC channels in neuronal cells along with the elucidation of their role in neurodegeneration. PMID- 20201823 TI - A universal, fully automated high throughput screening assay for pyrophosphate and phosphate release from enzymatic reactions. AB - The malachite green assay is often used for measuring the presence of inorganic mono-phosphate concentrations. Some studies have adapted this assay for use in monitoring enzymatic reactions and have suggested its potential use in high throughput screening (HTS). With the increasing availability of laboratory automation, some studies are starting to explore the possibility of conducting limited, semi-automated versions of the assay. Here we report the optimization and complete adaptation of the malachite green assay to a fully automated, HTS platform that can be performed unattended with standard, commercially available, automated liquid-handling systems. The assay is universal for the majority of enzymes that release phosphate or pyrophosphate. Moreover, the assay is fully scalable from smaller drug screening efforts ( approximately 20,000 wells per day) to ultra-high throughput environments ( approximately 200,000 wells per day). The assay uses cost-effective, commercially available reagents, and can be used to perform automated IC50 value and kinetic parameter determination. Finally, we demonstrate the utility of the assay via the initial, primary screening of 100,080 compounds against two target enzymes from Bacillus anthracis, O-succinylbenzoyl-CoA synthetase and nicotinate mononucleotide adenylyltransferase. PMID- 20201824 TI - Prediction of critical micelle concentration of nonionic surfactants by a quantitative structure - property relationship. AB - A quantitative structure - property relationship (QSPR) was used to predict the critical micelle concentration (cmc) of nonionic surfactants. The relation was developed for a diverse set of 23 nonionic surfactants (r = 0.99, F-test = 1042.5) employing the connectivity and valence connectivity indices only. The molecular connectivity indices were calculated for the whole molecule which was a simple and general approach. PMID- 20201825 TI - High-throughput synthesis and screening of new catalytic materials for the direct epoxidation of propylene. AB - Nanoparticles of 35 individual metals as well as their binary combinations were synthesized using High Throughput pulsed laser ablation (PLA), and collected on Al(2)O(3), CeO(2), SiO(2), TiO(2), and ZrO(2) pellets. These materials were then screened for their catalytic activities and selectivities for the partial oxidation of propylene, in particular for propylene oxide (PO), using array channel microreactors. Reaction conditions were the following: 1 atm pressure, gas hourly space velocity (GHSV) of 20,000 h-1, temperature 300 degrees C, 333 degrees C, and 367 degrees C, and feed gas composition 20 vol% O(2), 20 vol% C(3)H(6) and balance He. Initial screening experiments resulted in the discovery of SiO(2) supported Cr, Mn, Cu, Ru, Pd, Ag, Sn, and Ir as the most promising leads for PO synthesis. Subsequent experiments pointed to bimetallic Cu-on Mn/SiO(2), for which the PO yields increased several fold over single metal catalysts. For multimetallic materials, the sequence of deposition of the active metals was shown to have a significant effect on the resulting catalytic activity and selectivity. PMID- 20201826 TI - The chemical defensive system in the pathobiology of idiopathic environment associated diseases. AB - Chemical defensive system consisting of bio-sensoring, transmitting, and responsive elements has been evolved to protect multi-cellular organisms against environmental chemical insults (xenobiotics) and to maintain homeostasis of endogenous low molecular weight metabolites (endobiotics). Both genetic and epigenetic defects of the system in association with carcinogenesis and individual sensitivity to anti-tumor therapies have been intensely studied. Recently, several non-tumor human pathologies with evident environmental components such as rather rare functional syndromes (multiple chemical sensitivity, chronic fatigue, Persian Gulf, and fibromyalgia now collectively labeled as idiopathic environmental intolerances) and common diseases (vitiligo and systemic lupus erythematosus) have become subjects of the research on the impaired metabolism and detoxification of xenobiotics and endogenous toxins. Here, we collected and critically reviewed epidemiological, genetic, and biochemical data on the involvement and possible role of cytochrome P450 super family enzymes, glutathione-S-transferase isozymes, catechol-O-methyl transferase, UDP-glucuronosyl transferases, and proteins detoxifying inorganic and organic peroxides (catalase, glutathione peroxidase, and peroxiredoxin) in the above pathologies. Genetic predisposition assessed mainly by single nucleotide polymorphism and gene expression analyses revealed correlations between defects in genes encoding xenobiotic-metabolizing and/or detoxifying enzymes and risk/severity of these syndromes/diseases. Proteome analysis identified abnormal expression of the enzymes. Their functions were affected epigenetically leading to metabolic impairment and, as a consequence, to the negative health outcomes shared by some of these pathologies. Data obtained so far suggest that distinct components of the chemical defensive system could be suitable molecular targets for future pathogenic therapies. PMID- 20201827 TI - Regulation of drug metabolism and transporters. AB - Drug metabolizing enzymes (DME) play a central role in the intestinal absorption/permeability, metabolism, elimination and detoxification of endogenous and exogenous compounds. DME include phase I and II metabolizing enzymes. The hydroxylation activity of phase I DME increases the hydrophilicity of the molecules. The electrophilicity of phase I DME-derived products is reduced via conjugation with endogenous ligands, such as glutathione and glucuronic acid, and facilitates their inactivation and excretion in the bile and/or the urine. The transport system is involved in the cellular input/output of molecules and drugs. Numerous endogenous and exogenous compounds, being the substrates of DME, regulate the expression of DME genes through the activation of a number of nuclear receptors. These nuclear receptors directly or indirectly target different regulatory sequences present in the promoter region of the DME genes. The review describes the activation process of nuclear receptors, as well as their interactions to elucidate the extended cross-talk between them in the regulation of DME. PMID- 20201828 TI - Cyclic mechanical strain promotes transforming-growth-factor-beta1-mediated cardiomyogenic marker expression in bone-marrow-derived mesenchymal stem cells in vitro. AB - Cardiomyocytes in the heart reside in mechanically dynamic environments, such as those subject to cyclic mechanical strain. TGF-beta1 (transforming growth factor beta1) stimulates cardiomyogenic marker expression of BMMSCs (bone-marrow-derived mesenchymal stem cells). In the present study, we tested the hypothesis that cyclic mechanical strain promotes TGF-beta1-mediated cardiomyogenic marker expression in BMMSCs in vitro. The mRNA expression of cardiac-specific genes was more up-regulated in BMMSCs cultured with a TGF-beta1 supplement and subjected to cyclic strain for 1 week than in BMMSCs cultured statically with a TGF-beta1 supplement. Immunocytochemical analyses and flow cytometric analysis showed that the proportions of cardiac troponin-I-positive cells and cardiac MHC (myosin heavy chain)-positive cells and the proportions of cells expressing tropomyosin respectively were increased to a greater extent by TGF-beta1with cyclic strain than by TGF-beta1 alone. These results showed that cyclic strain promotes TGF beta1mediated cardiomyogenic marker expression in BMMSCs in vitro. PMID- 20201829 TI - Failure of bacille Calmette-Guerin in patients with high risk non-muscle-invasive bladder cancer unsuitable for radical cystectomy: an update of available treatment options. AB - Although the accepted standard upon failing intravesical bacille Calmette-Guerin (BCG) in patients with high-risk non-muscle-invasive bladder cancer (NMIBC) is radical cystectomy, there are some patients for whom this is not an option. We critically reviewed previous reports on the treatment possibilities available in such a clinical scenario. The options available can be categorized as chemotherapy, immunotherapy, device-assisted therapy and combined therapy. Combining new with established intravesical treatments seems to hold the most promise. Maintenance thermo-chemotherapy gives a reported 2-year disease-free survival rate of 50% and in small early-phase studies of intravesical gemcitabine administered in combination with mitomycin-C, tolerance and efficacy data would suggest the need for larger trials, given the early encouraging results. Electromotive mitomycin-C given sequentially with BCG might not only reduce the recurrence rate but also reduce progression and disease-specific mortality, although currently there is no trial in a specific population with 'BCG failure'. PMID- 20201830 TI - Relationship between prostate cancer mortality and number of unfavourable risk factors in men treated with definitive brachytherapy. AB - OBJECTIVE: To explore whether the number of unfavourable pretreatment risk factors predicts cause-specific mortality in men treated with prostate brachytherapy. PATIENTS AND METHODS: Between April 1995 and March 2006, 739 patients were treated who had at least one of the following adverse risk factors: pretreatment prostate-specific antigen (PSA) level of >10 ng/mL, a Gleason score of > or =7, clinical stage > or =T2b, or a PSA velocity (PSAV) of >2 ng/mL/year. Supplemental external beam radiotherapy (EBRT) was delivered to 464 (62.8%) men and 301 (40.7%) received androgen deprivation therapy (ADT). Of men with more than two risk factors, 87% received EBRT and 62% received ADT. RESULTS: The biochemical progression-free survival (bPFS), cause-specific survival (CSS) and overall survival for all patients were 95.0%, 97.9% and 70.0% at 12 years. Men with three or four risk factors had a prostate cancer-specific mortality (PCSM) at 12 years of 5.3%, vs 1.7% for men with one or two risk factors (P= 0.006). When 'percentage of positive biopsy cores >50%' replaced PSAV as a risk factor, men with two or more risk factors had a PCSM of 8.9%, vs 1.0% for men with one or two risk factors (P= 0.001). There was no difference in all-cause mortality between the groups in either analysis. CONCLUSION: Multimodal brachytherapy results in high rates of bPFS and CSS, even for men with several unfavourable risk factors. Men with two or more unfavourable risk factors had a slightly greater risk of PCSM and no difference in all-cause mortality. The presence of three or four unfavourable intermediate-risk factors does not appear to clearly identify a group that requires further treatment intensification, although the percentage of positive cores might be more predictive than PSAV. PMID- 20201832 TI - Cytotoxicity and apoptosis by survivin small interfering RNA in bladder cancer cells. AB - OBJECTIVE: To investigate the effects of survivin gene RNA interference on cell growth and the cell cycle in the human bladder cancer cell line T24. MATERIALS AND METHODS: A small interfering RNA (siRNA) targeting survivin was transfected into T24 cells using a liposome approach. Reverse transcription-polymerase chain reaction and Western blot analysis were used to examine survivin gene expression in T24 cells. Cells densities were determined by haematocytometer counts and flow cytometry was used for cell cycle analysis. Caspase-3 activity was quantified. RESULTS: After treatment with survivin siRNA, the survivin gene expression in T24 cells was almost completely absent. The survivin siRNA treatment caused a profound decrease in survivin protein, which was correlated with a decrease in cell growth, G2/M arrest, and an increase in the fraction of cells undergoing apoptosis. The inhibition of survivin expression increased caspase-3 activity in T24 cells, which led to apoptosis. CONCLUSIONS: RNA interference can efficiently suppress survivin expression in T24 cells. Targeting survivin by siRNA may be a promising approach to block proliferation of bladder cancer cells and may provide a suitable adjuvant therapy for treatment of bladder cancer. PMID- 20201833 TI - Osteoporosis in patients with prostate cancer on long-term androgen deprivation therapy: an increasing, but under-recognized problem. PMID- 20201831 TI - The effect of long-term hormonal treatment on voiding patterns during filling cystometry and on urethral histology in a postpartum, ovariectomized female rat. AB - OBJECTIVE: To study whether long-term treatment with oestrogen (E(2) ), selective E(2) receptor modulators (SERMs), or growth hormone (GH) can prevent the development of abnormal voiding patterns during filling cystometry (CMG) in a postpartum, ovariectomized (Ovx) female rat. MATERIALS AND METHODS: Immediately after spontaneous delivery, 60 primiparous Sprague-Dawley rats were randomly divided into six equal groups. One group served as uninjured sham controls and five groups underwent intravaginal balloon dilatation. On day seven, previously dilated rats underwent bilateral Ovx and implantation of a subcutaneous hormone delivery pump. The five treatment groups received normal saline (control), E(2) , raloxifene, levormeloxifene, or GH for 7 weeks. Conscious CMG was performed 7 weeks after Ovx. Urethral sphincter tissue was harvested for elastin immunohistochemistry and real-time polymerase chain reaction of alpha(1A) adrenoceptor mRNA. RESULTS: No abnormal voiding patterns were detected in the group treated with GH. The E(2) , raloxifene and levormeloxifene groups had greater detrusor overactivity and urethral relaxation incontinence than control rats. The raloxifene group had a significantly lower baseline bladder pressure and opening pressure. GH-treated rats had higher elastin content in the urethra. Urethral alpha(1A) -adrenoceptor mRNA concentration was significantly lower in the SERM-treated rats compared with controls. CONCLUSIONS: GH prevents the development of abnormal voiding patterns during filling CMG in a rat model of parturition-induced incontinence; E(2) and SERMs may worsen voiding patterns. PMID- 20201834 TI - Total urethral construction with the radial artery-based forearm free flap in the transsexual. AB - OBJECTIVE: to report our experience of using a radial artery-based forearm free flap urethroplasty (RAFFFU) inside a pre-fashioned pedicled pubic phalloplasty for female-to-male gender reassignment. PATIENTS AND METHODS: a neourethra based on the RAFFF was incorporated into a previously constructed phalloplasty in 27 patients. Surgical outcome, patients' satisfaction and voiding sensation of the neourethra were subjectively and prospectively assessed by direct questioning during the follow-up. RESULTS: after a median follow-up of 9.2 months, all patients who completed the two stages of the procedure were able to void from the tip of the phallus while standing. Donor-site morbidity was minimal, with all patients reporting a complete recovery of forearm sensation and mobility. The overall satisfaction rate was 92%. CONCLUSIONS: the RAFFFU is the best technique of total urethral construction in female-to-male transsexuals who opt not to undergo a RAFFF phalloplasty. PMID- 20201835 TI - Circulating endothelial cells and progenitors: potential biomarkers of renal cell carcinoma. AB - OBJECTIVE: To compare the levels of circulating endothelial cells (CECs) and progenitors (CEPs) between tumour-bearing mice and healthy controls, in human renal cell carcinoma (RCC) xenograft models. The secondary objective was to correlate CEC and CEP levels with tumour variables such as tumour volume, weight and vascularity, indicators of disease severity. MATERIALS AND METHODS: Two human RCC xenograft models were used. Tumour cells were inoculated either subcutaneously or beneath the renal subcapsule (orthotopic). Tumour dimensions were recorded and blood samples were taken throughout the experiment, as well as at the end of the experiment, upon which tumours were excised and prepared for histological examination. All blood samples were analysed by flow cytometry. RESULTS: CEC and CEP levels were significantly elevated in tumour-bearing mice compared with healthy controls. In particular, there was a divergence in CEC levels between RCC-bearing mice and controls during early phases in disease, whereas CEP levels were only elevated towards the end. Additionally, CEC levels correlated with tumour variables such as tumour volume, when tumour volume was <200 mm3 and with tumour vascularity in certain models. CEP levels did not correlate significantly with most tumour variables examined. CONCLUSION: In human RCC xenograft models, CEC levels showed promise as an adjuvant biomarker in evaluating disease burden. RESULTS from correlating CEC levels with tumour variables such as tumour volume, weight and vascularity suggested that CEC levels were a better prognostic indicator during early phases of tumour growth. CEP levels were elevated in tumour-bearing mice compared with controls; however, enumerated numbers were small and require further validation in future studies. PMID- 20201836 TI - Radical prostatectomy in older men: survival outcomes in septuagenarians and octogenarians. AB - OBJECTIVE: To examine the survival outcomes of septuagenarians and octogenarians (aged > or =80 years) who underwent radical prostatectomy (RP) at our institution, as the US Preventive Services Task Force recently released recommendations that men aged > or =75 years should not be screened for prostate cancer. PATIENTS AND METHODS: Our institutional RP database (1982-2008) was queried for men aged > or =70 years at the time of surgery to evaluate actuarial survival after RP; 386 aged 70-81 years (median 71) underwent RP. The median (range) follow-up was 6.5 (1-22) years. Clinicopathological characteristics and mortality data were evaluated; mortality data were gathered through Social Security Administration Death Index and causes of death were confirmed with the Center for Disease Control National Death Index information. Kaplan-Meier analysis was used to evaluate cause-specific survival. RESULTS: Ten patients (2.6%) had clinical stage T1a-b, 213 (55.3%) had T1c, and 143 (37.1%) had T2 prostate cancer. The median (range) preoperative prostate-specific antigen (PSA) level was 6.2 (0.2-49.9) ng/mL, and the biopsy and pathological Gleason sum was 6 (3-9) and 7 (4-9), respectively. Causes of death included prostate cancer (17), other malignancies (14), cardiovascular causes (14), neurological disease (four), pneumonia (two) and accident (one). The prostate cancer-specific survival rate was 97.6%, 94.0% and 90.2% at 5, 10 and 15 years after RP, respectively; the respective cardiovascular survival rate was 99.5%, 97.6% and 92.5%, and the overall survival rate was 93.1%, 82.5% and 68.9%, respectively. CONCLUSIONS: If appropriately selected, older men have excellent overall and prostate-cancer specific survival after RP. The benefits of surgery should be weighed against the increased risks of surgical and anaesthetic complications. PMID- 20201837 TI - Immunohistochemical expression of somatostatin receptor subtypes in prostate tissue from cystoprostatectomies with incidental prostate cancer. AB - OBJECTIVE: To examine immunohistochemically the expression of the five somatostatin receptors (SSTRs) in cystoprostatectomies (CyPs) with incidental prostate cancer. MATERIALS AND METHODS: The five SSTRs (SSTR1-5) were evaluated in 'normal-looking' epithelium (NEp), high-grade prostatic intraepithelial neoplasia (HGPIN) and pT2a Gleason score 6 adenocarcinoma in 20 CyP specimens with incidental prostate cancer and 20 radical prostatectomy (RP) specimens with clinically detected prostate cancer. RESULTS: For cytoplasm expression, the mean percentage of positive secretory cells with strong cytoplasmic staining increased from NEp to HGPIN and prostate cancer, being slightly lower in the CyP than in the RP specimens. Both in the CyP and RP specimens SSTR4 was found in the highest percentage of cells. There was membrane staining in the secretory cells for SSTR3 and SSTR4. There was nuclear staining in the secretory cells for SSTR4 and SSTR5. For SSTR1 and SSTR3 the mean proportions of positive basal cells were higher than for the other three subtypes, and greater in NEp than in HGPIN. There were positive smooth muscle and endothelial cells for all five SSTR subtypes, the highest proportions being SSTR1 and the lowest SSTR5. CONCLUSIONS: This immunohistochemical study expands our knowledge of the expression and localization of SSTRs in the various tissue components in the prostate with incidental cancer, compared with clinically detected cancer. Such information might be useful in developing further non-invasive strategies for the prevention and treatment of pre-neoplastic and neoplastic lesions of the prostate. PMID- 20201838 TI - Corticotropin-releasing hormone-receptor 2 is required for acute stress-induced bladder vascular permeability and release of vascular endothelial growth factor. AB - OBJECTIVE: To investigate the corticotropin-releasing hormone (CRH) receptor (CRH R) requirement for the effect of acute stress on bladder vascular permeability and release of vascular endothelial growth factor (VEGF), as increasing evidence indicates that acute stress worsens certain inflammatory disorders, including interstitial cystitis/painful bladder syndrome (IC/PBlS), which is characterized by pain, variable bladder inflammation, increased expression of bladder vascular endothelial growth factor (VEGF), and many detrusor mast cells. MATERIALS AND METHODS: Bladders of normal C57BL/6, and C57BL/6- derived CRH-R1, CRH-R2 or double CRH-R1 + 2 knockout (-/-) female mice (10-12 weeks old) were catheterized under anaesthesia. After emptying the urine, normal saline was instilled with or without intravesical CRH-R antagonists in C57BL/6 mice before they were stressed by placing them in a restrainer for 30 min. Evans blue was injected in the tail vein before stress for the permeability experiments. The bladders from C57BL/6 or CRH-R -/- mice were then removed, minced into 1 mm(2) pieces and cultured overnight. Culture media were collected 24 h later for VEGF assay. C57BL/6 bladder was processed for CRH-R immunohistochemistry. RESULTS: Acute stress increased bladder vascular permeability in control C57BL/6 and CRH-R1 -/- mice, but not CRH-R2 -/- or CRH-R1+2 -/- mice. The CRH-R2 antagonist Astressin 2B, but not the CRH-R1 antagonist Antalarmin, inhibited stress-induced VEGF release from C57BL/6 mouse bladder explants. Stress could not induce a VEGF increase from bladder explants of CRH-R2 -/- or CRH-R1+2 -/- mice, but did so in CRH-R1 -/- mice. Bladder CRH-R2 immunoreactivity was detected in C57BL/6 bladders. CONCLUSIONS: Acute stress induces bladder vascular permeability and VEGF release that is dependent on CRH-R2. These findings suggest that CRH and VEGF might participate in the pathogenesis of IC/PBlS and provide for new therapeutic targets. PMID- 20201839 TI - Long-term efficacy of the bone-anchored male sling for moderate and severe stress urinary incontinence. AB - OBJECTIVE: To present a prospective long-term evaluation of the bone-anchored male sling (InVanceTM, American Medical Systems, Minnetonka, MN, USA) for patients with moderate to severe stress urinary incontinence (SUI) after prostate surgery PATIENTS AND METHODS: Forty-five patients had a male sling implanted for SUI after prostate surgery. The evaluation before and after surgery included a complete history and physical examination, various questionnaires (American Urological Association Symptom Score, University of California Los Angeles/RAND prostate index), cysto-urethroscopy, International Continence Society (ICS) 1-h pad test and a urodynamic study. The follow-up assessments were at 2, 6 and 12 months after surgery, and yearly thereafter. The success rate was defined as the percentage of patients 'dry' and 'improved'. RESULTS: The median (range) follow up was 36 (2-64) months. Twelve patients (27%) had previous adjuvant radiotherapy. Eighteen patients (40%) had moderate SUI (two or three pads/day) and 27 (60%) had severe SUI (more than three pads/day). All preoperative ICS 1-h pad tests were positive. The success rate was 76%; 16 patients were dry (36%), 18 were improved (one or two pads/day, 40%) and in 11 the sling was a failure (24%); 76% of ICS 1-h pad tests were negative after surgery. The postoperative urodynamic study showed no signs of bladder outlet obstruction. In all, 72% of patients were satisfied/very satisfied with the surgery and 86% considered themselves cured/almost cured. The success rate was not affected by the presence of previous radiotherapy or the severity of SUI. Ten patients had perineal numbness, but in all it resolved within 1-3 months. There was one mesh infection which required its removal. There was no urethral erosion. CONCLUSION: Compared to previous studies, the InVance male sling had a good success rate for moderate and severe SUI, with a median follow-up of 36 months. The results did not differ for moderate or severe SUI or with the presence of previous radiotherapy. PMID- 20201840 TI - Raman spectral imaging of prostate cancer: can Raman molecular imaging be used to augment standard histopathology? AB - OBJECTIVE: To evaluate whether Raman molecular imaging (RMI, which combines digital imaging and analytical spectroscopy to evaluate the biochemical composition of interrogated material) can be used to identify biochemical differences in patients with Gleason 7 prostate cancer who progress to metastatic disease and die from prostate cancer. PATIENTS AND METHODS: We identified 38 patients who had a radical prostatectomy for Gleason 7 adenocarcinoma of the prostate. Half progressed to metastatic disease and half had no evidence of disease after treatment. Patients were matched for preoperative prostate-specific antigen level, surgical margin status, pathological stage, tumour volume, age at surgery, year of surgery and DNA ploidy. Sequential 5 microm sections were obtained from paraffin-embedded tissue and one genitourinary pathologist selected areas of tumour for study. Principal component analysis was used to investigate the correlation between spectral response and clinical outcome. RESULTS: The analysis was able to distinguish between those with progressive disease and those with no evidence of disease, most notably within the Gleason 3 regions when evaluating the epithelium and stroma as separate histological elements. A two sample t-test gave P < 0.01 for both the Gleason 3 and 4 epithelium and stroma classes. CONCLUSIONS: RMI is a novel technique that shows promise for identifying patients at risk of progression by visualizing molecular information not seen using other current methods. In Gleason 7 disease, RMI shows distinctive chemical differences in patients who progress to metastatic disease in both Gleason pattern 3 and 4 regions. This preliminary work lays the foundation for the further study of RMI for evaluating prostate tissue. PMID- 20201841 TI - The recovery of urinary continence after radical retropubic prostatectomy: a randomized trial comparing the effect of physiotherapist-guided pelvic floor muscle exercises with guidance by an instruction folder only. AB - OBJECTIVE: To compare the effect on the recovery of incontinence after retropubic radical prostatectomy (RRP) of intensive physiotherapist-guided pelvic floor muscle exercises (PG-PFME) in addition to an information folder, with PFME explained to patients by an information folder only (F-PFME), and to determine independent predictors of failure to regain continence after RRP. PATIENTS AND METHODS: We postulated that a 10% increase in the proportion of men who regained continence at 6 months with PG-PFME compared with men treated with F-PFME only would constitute a clinically relevant effect. To show statistical significance of this difference with a power of 80%, 96 men should be randomized to each of the two arms. One day before operation, all patients received verbal instruction and an information folder on PFME. Patients randomized to the F-PFME arm received no further physiotherapist guidance, whereas those in the PG-PFME arm received a maximum of nine sessions with the physiotherapist. The men underwent a 1-h pad test at 1, 12 and 26 weeks, and a 24-h pad-test at 1, 4, 8, 12 and 26 weeks after catheter removal. We defined 'continence' as urine loss of <1 g at the 1-h and <4 g at the 24-h pad-test. RESULTS: During the 2-year recruitment period, the number of patients randomized fell short of the target determined by the sample size calculation, because of limitations of resources and unexpected changes in treatment preferences. Despite this, we analysed the data. Of the 82 randomized patients, 70 completed the study. Of these, 34 and 36 men had been assigned to the PG-PFME and the F-PFME group, respectively. At 6 months after RRP, 10 (30%) and nine (27%) men were completely dry on both the 1-h and 24-h pad-test in the PG-PFME and the F-PFME group, respectively (difference not significant). In a multivariate analysis the amount of urine loss at 1 week after catheter removal seemed to be an independent prognostic factor for failure to regain continence. CONCLUSION: PG-PFME seems to have no beneficial effect on the recovery of continence within the first 6 months after RRP, over an instruction folder-guided approach. However, due to under-powering there is a high risk of type II error. Nevertheless, these findings add to the knowledge base for availability in meta analyses and can serve as a starting point for the design of new randomized studies. PMID- 20201842 TI - Transurethral endoscopic treatment of patients with upper tract urothelial carcinomas using neodymium-YAG and/or holmium-YAG laser ablation. AB - OBJECTIVE: To report our experience of treating patients with original and recurrent upper tract urothelial carcinomas (UC) using endoscopic lasers, with holmium-YAG and/or neodymium-YAG laser ablation, and for whom tumour stage and grade were obtained by endoscopic biopsy. PATIENTS AND METHODS: From March 2003 to March 2007, 15 patients with upper tract UC were treated with endoscopic laser ablation as the primary management. Patients were followed up by intravenous urography, computed tomography, urine cytology and/or ureteroscopic surveillance at 3- to 12-month intervals. The median (range) follow-up was 25.5 (13-51) months. RESULTS: Of the 15 patients, five had an upper tract recurrence during the follow-up. Three of these were treated with total nephroureterectomy and two had a progression in tumour stage or grade. Three patients had residual tumours; they were treated with repeated endoscopic laser treatments and had no recurrence over a median (range) of 24 (13-26) months. The renal preservation rate was 12/15 and the local recurrence rate was six/15 after the initial endoscopy. The median operative duration and tumour size were 60 min and 10 mm, respectively. CONCLUSION: Patients with low-grade and -stage disease and normal contralateral kidneys also benefit from this approach, if there is an adequate endoscopic biopsy. As the operative duration tended to be associated with the maximum tumour size, this treatment is potentially available for a maximum tumour size of <4 cm; if the tumour is <4 cm surgery will require <120 min. PMID- 20201843 TI - Introduction to Addiction Reviews 2. PMID- 20201845 TI - Current perspectives on selective dopamine D(3) receptor antagonists as pharmacotherapeutics for addictions and related disorders. AB - Repeated exposure to drugs of abuse produces long-term molecular and neurochemical changes that may explain the core features of addiction, such as the compulsive seeking and taking of the drug, as well as the risk of relapse. A growing number of new molecular and cellular targets of addictive drugs have been identified, and rapid advances are being made in relating those targets to specific behavioral phenotypes in animal models of addiction. In this context, the pattern of expression of the dopamine (DA) D(3) receptor in the rodent and human brain and changes in this pattern in response to drugs of abuse have contributed primarily to direct research efforts toward the development of selective DA D(3) receptor antagonists. Growing preclinical evidence indicates that these compounds may actually regulate the motivation to self-administer drugs and disrupt drug-associated cue-induced craving. This report will be divided into three parts. First, preclinical evidence in support of the efficacy of selective DA D(3) receptor antagonists in animal models of drug addiction will be reviewed. The effects of mixed DA D(2)/D(3) receptor antagonists will not be discussed here because most of these compounds have low selectivity at the D(3) versus D(2) receptor, and their efficacy profile is related primarily to functional antagonism at D(2) receptors and possibly interactions with other neurotransmitter systems. Second, major advances in medicinal chemistry for the identification and optimization of selective DA D(3) receptor antagonists and partial agonists will be analyzed. Third, translational research from preclinical efficacy studies to so-called proof-of-concept studies for drug addiction indications will be discussed. PMID- 20201847 TI - Agonist-like pharmacotherapy for stimulant dependence: preclinical, human laboratory, and clinical studies. AB - A variety of natural and synthetic agents have long been used for stimulant properties, with nontherapeutic use producing multiple waves of stimulant abuse and dependence. The multitude of effects of stimulants exist on continua, and accordingly, here we characterize stimulant abuse/dependence and candidate pharmacotherapies in this manner. Behavioral therapy and medications have been investigated for treatment of stimulant abuse/dependence. Effectiveness of some behavioral interventions has been demonstrated. Most medications studied have been found to lack efficacy. However, an expanding literature supports use of agonist-like medications to treat stimulant abuse/dependence, a strategy effective for nicotine and opiate dependence. The agonist-like conceptualization for stimulant dependence posits that medications with properties similar to that of the abused drug, but possessing lesser abuse liability, will normalize neurochemistry and stabilize behavior, thus reducing drug use. Data suggest use of a range of medications, from l-dopa/carbidopa to amphetamine preparations, depending on the severity of use. This report reviews preclinical, human laboratory, and clinical trial data supporting the agonist-like approach, including risks and benefits. Future directions for development of agonist-like medications are also discussed. PMID- 20201849 TI - Human immunodeficiency virus-associated neurocognitive disorder: pathophysiology in relation to drug addiction. AB - Human immunodeficiency virus (HIV) infection in the United States and increasingly in other parts of the world is now being driven by drug-abusing populations. Both HIV infection and drugs of abuse affect the basal ganglia, hippocampal structures, and the prefrontal cortex. Understanding the interactions between the two and their combined effects is critical. In vitro studies show that opiates, methamphetamine, and cocaine can potentiate HIV replication and can enhance or synergize with HIV proteins to cause glial cell activation, neurotoxicity, and breakdown of the blood-brain barrier. Many of these studies have been confirmed in vivo by using rodent models. However, the complexities of polydrug addiction and drug withdrawal have yet to be examined in simian models of HIV-associated neurocognitive disorder. Clinical studies in substance-abusing, HIV-positive patients pose multiple challenges whether aimed at studying disease pathogenesis or conducting clinical trials. This review examines the literature to date, lists the experimental challenges faced by researchers studying effects of drug addiction on HIV neuropathogenesis, and suggests future directions for research. PMID- 20201851 TI - Electrophysiological correlates of abused drugs: relation to natural rewards. AB - The addictive consequences of abused substances depend upon activation of neurons in reward centers of the brain. Investigations aimed at determining the underlying basis for substance abuse have resulted in breakthroughs related to drug actions on normal neural processes; for example, the singular role of dopamine as the basis for drug addiction has been revised to include effects that, with other transmitter systems, produce changes in target neuronal firing that are different from those previously assumed, including "reward value" at the neuronal and systems levels and changes in the significance of pursued stimuli as a function of motivational state, context, effort, salience, and cognitive demand. Studies comparing these factors directly show differences between the actions of abused substances and less potent food-related rewards. Characterization of the change in reward-encoding processes for drug and natural rewards has provided insight into how abused substances gain control over behavior. This report explores how abused drugs alter neuron firing in reward sensitive brain regions and how those alterations effect drug-seeking activity in animals and humans. PMID- 20201850 TI - Synaptic plasticity in the mesolimbic system: therapeutic implications for substance abuse. AB - In an ever-changing environment, animals must learn new behavioral strategies for the successful procurement of food, sex, and other needs. Synaptic plasticity within the mesolimbic system, a key reward circuit, affords an animal the ability to adapt and perform essential goal-directed behaviors. Ironically, drugs of abuse can also induce synaptic changes within the mesolimbic system, and such changes are hypothesized to promote deleterious drug-seeking behaviors in lieu of healthy, adaptive behaviors. In this review, we will discuss drug-induced neuroadaptations in excitatory transmission in the ventral tegmental area and the nucleus accumbens, two critical regions of the mesolimbic system, and the possible role of dopamine receptors in the development of these neuroadaptations. In particular, we will focus our discussion on recent studies showing changes in AMPA receptor function as a common molecular target of addictive drugs, and the possible behavioral consequences of such neuroadaptations. PMID- 20201848 TI - Amphetamine toxicities: classical and emerging mechanisms. AB - The drugs of abuse, methamphetamine and MDMA, produce long-term decreases in markers of biogenic amine neurotransmission. These decreases have been traditionally linked to nerve terminals and are evident in a variety of species, including rodents, nonhuman primates, and humans. Recent studies indicate that the damage produced by these drugs may be more widespread than originally believed. Changes indicative of damage to cell bodies of biogenic and nonbiogenic amine-containing neurons in several brain areas and endothelial cells that make up the blood-brain barrier have been reported. The processes that mediate this damage involve not only oxidative stress but also include excitotoxic mechanisms, neuroinflammation, the ubiquitin proteasome system, as well as mitochondrial and neurotrophic factor dysfunction. These mechanisms also underlie the toxicity associated with chronic stress and human immunodeficiency virus (HIV) infection, both of which have been shown to augment the toxicity to methamphetamine. Overall, multiple mechanisms are involved and interact to promote neurotoxicity to methamphetamine and MDMA. Moreover, the high coincidence of substituted amphetamine abuse by humans with HIV and/or chronic stress exposure suggests a potential enhanced vulnerability of these individuals to the neurotoxic actions of the amphetamines. PMID- 20201846 TI - Cocaine-induced neuroadaptations in glutamate transmission: potential therapeutic targets for craving and addiction. AB - A growing body of evidence indicates that repeated exposure to cocaine leads to profound changes in glutamate transmission in limbic nuclei, particularly the nucleus accumbens. This review focuses on preclinical studies of cocaine-induced behavioral plasticity, including behavioral sensitization, self-administration, and the reinstatement of cocaine seeking. Behavioral, pharmacological, neurochemical, electrophysiological, biochemical, and molecular biological changes associated with cocaine-induced plasticity in glutamate systems are reviewed. The ultimate goal of these lines of research is to identify novel targets for the development of therapies for cocaine craving and addiction. Therefore, we also outline the progress and prospects of glutamate modulators for the treatment of cocaine addiction. PMID- 20201852 TI - Neurochemistry of drug action: insights from proton magnetic resonance spectroscopic imaging and their relevance to addiction. AB - Proton magnetic resonance spectroscopy ((1)H MRS) is a noninvasive imaging technique that permits measurement of particular compounds or metabolites within the tissue of interest. In the brain, (1)H MRS provides a snapshot of the neurochemical environment within a defined volume of interest. A search of the literature demonstrates the widespread utility of this technique for characterizing tumors, tracking the progress of neurodegenerative disease, and for understanding the neurobiological basis of psychiatric disorders. As of relatively recently, (1)H MRS has found its way into substance abuse research, and it is beginning to become recognized as a valuable complement in the brain imaging toolbox that also contains positron emission tomography, single-photon emission computed tomography, and functional magnetic resonance imaging. Drug abuse studies using (1)H MRS have identified several biochemical changes in the brain. The most consistent alterations across drug class were reductions in N acetylaspartate and elevations in myo-inositol, whereas changes in choline, creatine, and amino acid transmitters also were abundant. Together, the studies discussed herein provide evidence that drugs of abuse may have a profound effect on neuronal health, energy metabolism and maintenance, inflammatory processes, cell membrane turnover, and neurotransmission, and these biochemical changes may underlie the neuropathology within brain tissue that subsequently gives rise to the cognitive and behavioral impairments associated with drug addiction. PMID- 20201853 TI - Cocaine addiction in mothers: potential effects on maternal care and infant development. AB - Maternal cocaine addiction is a significant public health issue particularly affecting children, with high rates of reported abuse, neglect, and foster care placement. This review examines both preclinical and clinical evidence for how cocaine abuse may affect maternal care and infant development, exploring brain, behavioral, and neuroendocrine mechanisms. There is evidence that cocaine affects infant development both directly, via in utero exposure, and indirectly via alterations in maternal care. Two neural systems known to play an important role in both maternal care and cocaine addiction are the oxytocin and dopamine systems, mediating social and reward-related behaviors and stress reactivity. These same neural mechanisms may also be involved in the infant's development of vulnerability to addiction. Understanding the neuroendocrine pathways involved in maternal behavior and addiction may help facilitate earlier, more effective interventions to help substance-abusing mothers provide adequate care for their infant and perhaps prevent the intergenerational transmission of risk. PMID- 20201855 TI - Addictions and their familiality in Iceland. AB - Here, we provide an overview of previous family studies of addiction and present a new family study based on clinical data for more than 19,000 individuals who have been treated for addiction in Iceland over the last three decades. Coupled with the extensive Icelandic genealogy information, this population-based sample provides a unique opportunity for family studies. The relative risk (RR) was determined for up to fifth-degree relatives of probands diagnosed with alcohol, cannabis, sedative, and amphetamine dependence. We observe highly significant RR values for all substances ranging from 2.27 for alcohol to 7.3 for amphetamine, for first-degree relatives, and RRs significantly above 1 for distant relations, where the effect of shared environmental factors is minimized. The magnitude of risk in psychostimulant dependence is particularly striking. These findings emphasize the role of genetics in the etiology of addiction and highlight the importance of substance-specific effects. PMID- 20201856 TI - Transgenic mice in the study of drug addiction and the effects of psychostimulant drugs. AB - The first transgenic models used to study addiction were based upon a priori assumptions about the importance of particular genes in addiction, including the main target molecules of morphine, amphetamine, and cocaine. This consequently emphasized the importance of monoamine transporters, opioid receptors, and monoamine receptors in addiction. Although the effects of opiates were largely eliminated by mu opioid receptor gene knockout, the case for psychostimulants was much more complex. Research using transgenic models supported the idea of a polygenic basis for psychostimulant effects and has associated particular genes with different behavioral consequences of psychostimulants. Phenotypic analysis of transgenic mice, especially gene knockout mice, has been instrumental in identifying the role of specific molecular targets of addictive drugs in their actions. In this article, we summarize studies that have provided insight into the polygenic determination of drug addiction phenotypes in ways that are not possible with other methods, emphasizing research into the effects of psychostimulant drugs in gene knockouts of the monoamine transporters and monoamine receptors. PMID- 20201857 TI - Conditioned taste aversion learning: implications for animal models of drug abuse. AB - Drugs of abuse are typically discussed in terms of their rewarding effects and how these effects mediate drug taking. However, these drugs produce aversive effects that could have an important role in the overall acceptability of a drug and its likelihood of being self-administered. Rewarding and aversive effects, then, could be interpreted as separate behavioral effects, with the balance of the two determining overall drug acceptability. Interestingly, the role of aversive effects on drug acceptability in the self-administration preparation has received limited attention in this context. This chapter examines the aversive effects of drugs and discusses their role in drug taking. If these aversive effects serve a protective function, manipulations that alter or decrease these effects could have implications for drug taking. Several factors have been reported to alter conditioned taste aversion (CTA) learning, a preparation used in the assessment of the aversive effects of drugs in general. Two of these factors, drug history and strain, are reviewed here. By reviewing these, we intend to demonstrate the protective nature of aversive effects in the initiation and escalation of drug taking and to provide evidence that reductions in aversive effects could produce changes in patterns of drug self-administration that could lead to an increased vulnerability to abuse drugs by altering the reward-aversion balance. The aim of this chapter is not to question the importance of rewarding effects in self-administration but rather to provide evidence that aversive effects are an important factor that needs to be considered in discussions of drug-taking behavior. PMID- 20201854 TI - Search for genetic markers and functional variants involved in the development of opiate and cocaine addiction and treatment. AB - Addiction to opiates and illicit use of psychostimulants is a chronic, relapsing brain disease that, if left untreated, can cause major medical, social, and economic problems. This article reviews recent progress in studies of association of gene variants with vulnerability to develop opiate and cocaine addictions, focusing primarily on genes of the opioid and monoaminergic systems. In addition, we provide the first evidence of a cis-acting polymorphism and a functional haplotype in the PDYN gene, of significantly higher DNA methylation rate of the OPRM1 gene in the lymphocytes of heroin addicts, and significant differences in genotype frequencies of three single-nucleotide polymorphisms of the P glycoprotein gene (ABCB1) between "higher" and "lower" methadone doses in methadone-maintained patients. In genomewide and multigene association studies, we found association of several new genes and new variants of known genes with heroin addiction. Finally, we describe the development and application of a novel technique: molecular haplotyping for studies in genetics of drug addiction. PMID- 20201858 TI - The strong relationship between bipolar and substance-use disorder. AB - Bipolar disorder and substance-use disorders commonly occur in the same individual. In fact, bipolar disorder has a higher prevalence of substance-use disorders than any other psychiatric illness. Individuals with both disorders have a more severe course of bipolar disorder, including earlier onset, more frequent episodes, and more complications, including anxiety- and stress-related disorders, aggressive behavior, legal problems, and suicide. Bipolar and substance-use disorders share common mechanisms, including impulsivity, poor modulation of motivation and responses to rewarding stimuli, and susceptibility to behavioral sensitization. Studies of potential treatments for bipolar substance-use disorder have paid scant attention to the combined disorders. The most promising treatment strategies are those that address their shared mechanisms. PMID- 20201860 TI - Regulation of the dopamine transporter: aspects relevant to psychostimulant drugs of abuse. AB - Dopaminergic signaling in the brain is primarily modulated by dopamine transporters (DATs), which actively translocate extraneuronal dopamine back into dopaminergic neurons. Transporter proteins are highly dynamic, continuously trafficking between plasmalemmal and endosomal membranes. Changes in DAT membrane trafficking kinetics can rapidly regulate dopaminergic tone by altering the number of transporters present at the cell surface. Various psychostimulant DAT ligands-acting either as amphetamine-like substrates or cocaine-like nontranslocated inhibitors-affect transporter trafficking, triggering rapid insertion or removal of plasmalemmal DATs. In this review, we focus on the effects of psychostimulants of addiction (particularly D-methamphetamine and cocaine) on DAT regulation and membrane trafficking, with an emphasis on how these drugs may influence intracellular signaling cascades and transporter associated scaffolding proteins to affect DAT regulation. In addition, we consider involvement of presynaptic receptors for dopamine and other ligands in DAT regulation. Finally, we discuss possible implications of transporter regulation to the putative toxicity of several substituted amphetamine derivatives commonly used as recreational drugs, as well as to the design of therapeutics for cocaine addiction. PMID- 20201861 TI - Regulator of G protein-signaling proteins and addictive drugs. AB - Regulator of G protein-signaling (RGS) proteins are a family of more than 30 intracellular proteins that negatively modulate intracellular signaling of receptors in the G protein-coupled receptor family. This family includes receptors for opioids, cannabinoids, and dopamine that mediate the acute effects of addictive drugs or behaviors and chronic effects leading to the development of addictive disease. Members of the RGS protein family, by negatively modulating receptor signaling, influence the intracellular processes that lead to addiction. In turn, addictive drugs control the expression levels of several RGS proteins. This review will consider the distribution and mechanisms of action of RGS proteins, particularly the R4 and R7 families that have been implicated in the actions of addictive drugs, how knowledge of these proteins is contributing to an understanding of addictive processes, and whether specific RGS proteins could provide targets for the development of medications to manage and/or treat addiction. PMID- 20201863 TI - Office of National Drug Control Policy: a scientist in drug policy in Washington, DC. AB - This essay describes how a basic scientist was thrust into the epicenter, the political cauldron of our national drug control policy, and how the experience altered her professional trajectory and perspective. PMID- 20201862 TI - Novel phenotype issues raised in cross-national epidemiological research on drug dependence. AB - Stage-transition models based on the American Diagnostic and Statistical Manual (DSM) generally are applied in epidemiology and genetics research on drug dependence syndromes associated with cannabis, cocaine, and other internationally regulated drugs (IRDs). Difficulties with DSM stage-transition models have surfaced during cross-national research intended to provide a truly global perspective, such as the work of the World Mental Health Surveys Consortium. Alternative simpler dependence-related phenotypes are possible, including population-level count process models for steps early and before coalescence of clinical features into a coherent syndrome (e.g., zero-inflated Poisson [ZIP] regression). Selected findings are reviewed, based on ZIP modeling of alcohol, tobacco, and IRD count processes, with an illustration that may stimulate new research on genetic susceptibility traits. The annual National Surveys on Drug Use and Health (NSDUH) can be readily modified for this purpose, along the lines of a truly anonymous research approach that can help make NSDUH-type cross national epidemiological surveys more useful in the context of subsequent genomewide association (GWAS) research and post-GWAS investigations with a truly global health perspective. PMID- 20201859 TI - Shared brain vulnerabilities open the way for nonsubstance addictions: carving addiction at a new joint? AB - For more than half a century, since the beginning of formal diagnostics, our psychiatric nosology has compartmentalized the compulsive pursuit of substance (e.g., alcohol, cocaine, heroin, nicotine) from nonsubstance (e.g., gambling, food, sex) rewards. Emerging brain, behavioral, and genetic findings challenge this diagnostic boundary, pointing to shared vulnerabilities underlying the pathological pursuit of substance and nonsubstance rewards. Working groups for the fifth revision of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-V), are thus considering whether the nosologic boundaries of addiction should be redrawn to include nonsubstance disorders, such as gambling. This review discusses how neurobiological data from problem gambling, obesity, and "normal" states of attachment (romantic infatuation, sexual attraction, maternal bonds) may help us in the task of carving addictions "at a new joint." Diagnostic recarving may have a positive effect on addiction research, stimulating discovery of "crossover" pharmacotherapies with benefit for both substance and nonsubstance addictions. PMID- 20201864 TI - Preface to the biology of disadvantage: socioeconomic status and health. PMID- 20201865 TI - Health disparities across the lifespan: meaning, methods, and mechanisms. AB - Over the past two decades, exponential growth of empirical research has fueled markedly increased concern about health disparities. In this paper, we show the progression of research on socioeconomic status (SES) and health through several eras. The first era reflected an implicit threshold model of the association of poverty and health. The second era produced evidence for a graded association between SES and health where each improvement in education, income, occupation, or wealth is associated with better health outcomes. Moving from description of the association to exploration of pathways, the third era focused on mechanisms linking SES and health, whereas the fourth era expanded on mechanisms to consider multilevel influences, and a fifth era added a focus on interactions among factors, not just their main effects or contributions as mediators. Questions from earlier eras remain active areas of research, while later eras add depth and complexity. PMID- 20201866 TI - Socioeconomic gradients in health in international and historical context. AB - This article places socioeconomic gradients in health into a broader international and historical context. The data we present supports the conclusion that current socioeconomic gradients in health within the United States are neither inevitable nor immutable. This literature reveals periods in the United States with substantially smaller gradients, and identifies many examples of other countries whose different social policy choices appear to have led to superior health levels and equity even with fewer aggregate resources. The article also sheds light on the potential importance of various hypothesized mechanisms in driving major shifts in U.S. population health patterns. While it is essential to carefully examine individual mechanisms contributing to health patterns, it is also illuminating to take a more holistic view of the set of factors changing in conjunction with major shifts in population health. In this article, we do so by focusing on the period of the 1980s, during which U.S. life expectancy gains slowed markedly relative to other developed countries, and U.S. health disparities substantially increased. A comparison with Canada suggests that exploring broad social policy differences, such as the weaker social safety net in the United States, may be a promising area for future investigation. PMID- 20201867 TI - Childhood socioeconomic status and adult health. AB - Socioeconomic status (SES) exposures during childhood are powerful predictors of adult cardiovascular morbidity, cardiovascular mortality, all-cause mortality, and mortality due to a range of specific causes. However, we still know little about when childhood SES exposures matter most, how long they need to last, what behavioral, psychological, or physiological pathways link the childhood SES experience to adult health, and which specific adult health outcomes are vulnerable to childhood SES exposures. Here, we discuss the evidence supporting the link between childhood and adolescent SES and adult health, and explore different environmental, behavioral, and physiological pathways that might explain how early SES would influence adult health. We also address the ages when SES exposures matter most for setting adult health trajectories as well as the role of exposure duration in SES influences on later health. While early childhood exposures seem to be potent predictors of a range of health outcomes, we emphasize that later childhood and adolescent exposures are risks for other health outcomes. PMID- 20201868 TI - Money, schooling, and health: Mechanisms and causal evidence. AB - An association between higher educational attainment and better health status has been repeatedly reported in the literature. Similarly, thousands of studies have found a relationship between higher income and better health. However, whether these repeated observations amount to causality remains a challenge, not least because of the practical limitations of randomizing people to receive different amounts of money or schooling. In this essay, we review the potential causal mechanisms linking schooling and income to health, and discuss the twin challenges to causal inference in observational studies, in other words, reverse causation and omitted variable bias. We provide a survey of the empirical attempts to identify the causal effects of schooling and income on health, including natural experiments. There is evidence to suggest that schooling is causally related to improvements in health outcomes. Evidence also suggests that raising the incomes of the poor leads to improvement in their health outcomes. Much remains unknown beyond these crude findings, however; for example, what type of education matters for health, or whether there is a difference between the health impacts of temporary income shocks versus changes in long-term income. PMID- 20201869 TI - Race, socioeconomic status, and health: complexities, ongoing challenges, and research opportunities. AB - This paper provides an overview of racial variations in health and shows that differences in socioeconomic status (SES) across racial groups are a major contributor to racial disparities in health. However, race reflects multiple dimensions of social inequality and individual and household indicators of SES capture relevant but limited aspects of this phenomenon. Research is needed that will comprehensively characterize the critical pathogenic features of social environments and identify how they combine with each other to affect health over the life course. Migration history and status are also important predictors of health and research is needed that will enhance understanding of the complex ways in which race, SES, and immigrant status combine to affect health. Fully capturing the role of race in health also requires rigorous examination of the conditions under which medical care and genetic factors can contribute to racial and SES differences in health. The paper identifies research priorities in all of these areas. PMID- 20201871 TI - Neighborhoods and health. AB - Features of neighborhoods or residential environments may affect health and contribute to social and race/ethnic inequalities in health. The study of neighborhood health effects has grown exponentially over the past 15 years. This chapter summarizes key work in this area with a particular focus on chronic disease outcomes (specifically obesity and related risk factors) and mental health (specifically depression and depressive symptoms). Empirical work is classified into two main eras: studies that use census proxies and studies that directly measure neighborhood attributes using a variety of approaches. Key conceptual and methodological challenges in studying neighborhood health effects are reviewed. Existing gaps in knowledge and promising new directions in the field are highlighted. PMID- 20201872 TI - Are psychosocial factors mediators of socioeconomic status and health connections? A progress report and blueprint for the future. AB - The association between socioeconomic status (SES) and physical health is robust. Yet, the psychosocial mediators of SES-health association have been studied in relatively few investigations. In this chapter, we summarize and critique the recent literature regarding negative emotions and cognitions, psychological stress, and resources as potential pathways connecting SES and physical health. We discuss the psychosocial origins of the SES-health links and outline how psychosocial factors may lead to persistently low SES. We conclude that psychosocial resources may play a critical mediating role, and the origins of the SES-health connection are apparent in childhood. We offer a blueprint for future research, which we hope contributes to a better understanding of how SES gets under the skin across the life span. PMID- 20201870 TI - Work and its role in shaping the social gradient in health. AB - Adults with better jobs enjoy better health: job title was, in fact, the social gradient metric first used to study the relationship between social class and chronic disease etiology, a core finding now replicated in most developed countries. What has been less well proved is whether this correlation is causal, and if so, through what mechanisms. During the past decade, much research has been directed at these issues. Best evidence in 2009 suggests that occupation does affect health. Most recent research on the relationship has been directed at disentangling the pathways through which lower-status work leads to adverse health outcomes. This review focuses on six areas of recent progress: (1) the role of status in a hierarchical occupational system; (2) the roles of psychosocial job stressors; (3) effects of workplace physical and chemical hazard exposures; (4) evidence that work organization matters as a contextual factor; (5) implications for the gradient of new forms of nonstandard or "precarious" employment such as contract and shift work; and (6) emerging evidence that women may be impacted differently by adverse working conditions, and possibly more strongly, than men. PMID- 20201873 TI - Multiple risk exposure as a potential explanatory mechanism for the socioeconomic status-health gradient. AB - The social patterning of disease and mortality provokes a search for explanation. One potential underlying explanation for socioeconomic status (SES) gradients in health is exposure to multiple risk factors. Income and class tend to sort individuals into different settings that are often accompanied by systematic differences in environmental quality. Housing and neighborhood quality, pollutants and toxins, crowding and congestion, and noise exposure all vary with SES. Persons lower in SES also experience more adverse interpersonal relationships with family members, friends, supervisors, and community members. Furthermore, exposure to these multiple risk factors is associated with worse health outcomes. Thus, the convergence of exposure to multiple physical and psychosocial risk factors accompanying disadvantage may account for a portion of SES gradients in health in both childhood and adulthood. PMID- 20201875 TI - Socio-economic differentials in peripheral biology: cumulative allostatic load. AB - This chapter focuses on evidence linking socio-economic status (SES) to "downstream" peripheral biology. Drawing on the concept of allostatic load, we examine evidence linking lower SES with greater cumulative physiological toll on multiple major biological regulatory systems over the life course. We begin by reviewing evidence linking lower SES to poorer trajectories of aging in multiple, individual physiological systems, followed by evidence of the resulting cumulative, overall burdens of physiological dysregulation seen among those of lower SES. The role of cumulative physiological dysregulation in mediating SES gradients in morbidity and mortality is then examined. We conclude with discussion of the question of interactions between SES (and other such environmental factors) and genetic endowment, and their potential consequences for patterns of physiological activity--an area of research that appears poised to contribute significantly to our understanding of how social conditions "get under the skin" to affect health and aging. PMID- 20201876 TI - Evaluating the evidence base: policies and interventions to address socioeconomic status gradients in health. AB - This chapter discusses the current evidence base for policies that could address socioeconomic status (SES) health gradients in the United States. The present volume has documented an enormous amount of research on the linkages between SES and health, but there are still relatively few studies that rigorously establish the effectiveness of particular policies or interventions in reducing those gradients. Given the difficulty in developing randomized evidence for many types of interventions related to social determinants of health, we argue for conducting policy analysis from a Bayesian perspective. This Bayesian approach combines information on best available theory and evidence regarding probable health benefits and costs of an intervention, providing a framework that also incorporates the probable costs of inaction. The second half of the chapter adopts a ladder metaphor to classify policies and interventions that could reduce SES gradients in population health. Using this framework, we consider the evidence base for various types of policies, focusing primarily on the social determinants of health, under the rubric that "all policy is health policy." We conclude by discussing promising strategies for future strengthening of the evidence base for policy, including the role of health impact assessment. PMID- 20201877 TI - Using team science to address health disparities: MacArthur network as case example. AB - In this paper, the director and the administrator of the MacArthur Network on Socioeconomic Status and Health reflect on the evolution of the network. Against the backdrop of the science of "team science," they describe the history and process of the network including the forging of a group agenda, the development of a creative, productive group working style, and the outcomes arising from these processes. PMID- 20201878 TI - Professor Sam Sideman: a tribute. PMID- 20201879 TI - Introduction to analysis of cardiac development: from embryo to old age. PMID- 20201874 TI - Central role of the brain in stress and adaptation: links to socioeconomic status, health, and disease. AB - The brain is the key organ of stress reactivity, coping, and recovery processes. Within the brain, a distributed neural circuitry determines what is threatening and thus stressful to the individual. Instrumental brain systems of this circuitry include the hippocampus, amygdala, and areas of the prefrontal cortex. Together, these systems regulate physiological and behavioral stress processes, which can be adaptive in the short-term and maladaptive in the long-term. Importantly, such stress processes arise from bidirectional patterns of communication between the brain and the autonomic, cardiovascular, and immune systems via neural and endocrine mechanisms underpinning cognition, experience, and behavior. In one respect, these bidirectional stress mechanisms are protective in that they promote short-term adaptation (allostasis). In another respect, however, these stress mechanisms can lead to a long-term dysregulation of allostasis in that they promote maladaptive wear-and-tear on the body and brain under chronically stressful conditions (allostatic load), compromising stress resiliency and health. This review focuses specifically on the links between stress-related processes embedded within the social environment and embodied within the brain, which is viewed as the central mediator and target of allostasis and allostatic load. PMID- 20201881 TI - The formation of the embryonic mouse heart: heart fields and myocardial cell lineages. AB - During cardiogenesis in the mouse, the second heart field (SHF) is the source of the myocardium of the outflow tract and it contributes to other regions of the heart with the exception of the primitive left ventricle. This contribution corresponds with that of the second myocardial cell lineage, identified by retrospective clonal analysis. Gene regulatory networks, signaling pathways, and heterogeneity within the SHF are discussed, together with the question of regulation of myocardial progenitor cells within the first heart field. The extension of the SHF into the mesodermal core of the arches also gives rise to endothelial cells of the pharyngeal arch arteries. Knowledge about the origin and genetic regulation of cells that contribute to the heart and associated vasculature is important for the diagnosis and treatment of congenital heart malformations. PMID- 20201880 TI - The integrative aspects of cardiac physiology and their implications for cell based therapy. AB - Cardiac development is characterized by a complex interplay of chemical, mechanical, and electrical forces, which together contribute to the proper formation of the heart muscle. In adult myocardium, cardiomyocytes are elongated, well-coupled by gap junctions, and organized in spatially well-defined muscle fibers. This specific tissue architecture affects electromechanical activation and global cardiac function. Since the adult heart has only limited capacity for repair after injury, a significant loss of myocardial tissue often leads to impaired cardiac function. Recent efforts to transplant autologous cells to counteract this cardiomyocyte loss have resulted in marginal functional improvement and no evidence of myocyte regeneration. In order to achieve durable therapeutic efficiency, the transplanted cells will need to not only be cardiomyogenic, but also functionally integrate with host myocardial tissue and thereby contribute to both structural and functional restoration. PMID- 20201882 TI - The effect of mechanical loads in the differentiation of precursor cells into mature cells. AB - Stem cell differentiation, both in vivo and in vitro, is regulated by a variety of signals. These signals can be of biochemical origin, such as those from growth factors and cytokines, or from different mechanical loads, such as fluid shear stress and matrix elasticity. The mechanisms by which the mechanical loads affect precursor cell differentiation are not entirely understood, but their role in regenerative medicine and cell therapy could be of vast importance. This paper reviews the role of mechanical loads on the differentiation of precursor cells. PMID- 20201883 TI - Cell and gene therapy strategies for the treatment of postmyocardial infarction ventricular arrhythmias. AB - Ventricular arrhythmias in the setting of a healed myocardial infarction represent a major cause of morbidity and mortality. The underlying mechanism is the presence of slow conduction tissue within the infarct border zone. In the current review we describe experimental gene and cell therapy approaches targeting the electrophysiologic substrate of the border zone, with the aim of preventing postinfarction ventricular arrhythmias. These include strategies that aim to prevent reentry by improving conduction velocity or by prolonging refractoriness. Attempts to augment conduction velocity include cardiomyocyte transplantation to regenerate the infarct, overexpression of unique sodium channels (to improve excitability), and methods to improve cell-to-cell coupling. Strategies to prolong refractoriness include gene therapy to prolong action potential duration or cell therapy using engineered cell grafts transfected ex vivo to express unique potassium channels. Finally, we will also discuss the potential advantages and drawbacks of these strategies as well as a road map for future clinical use. PMID- 20201884 TI - PI3K kinase and scaffold functions in heart. AB - Signal transduction events are key modulators of cellular function and, in the cardiovascular system, an emerging role is played by phosphoinositide 3-kinases (PI3Ks), a family of enzymes containing a 3-phosphorylated phosphoinositide that produce lipid second messengers. In the heart, multiple PI3K isoforms are expressed, but play potentially distinct roles. Among cardiac PI3Ks, PI3Kalpha is triggered by tyrosine kinase receptors and plays a role in adaptive hypertrophy, while PI3Kgamma is triggered by G protein-coupled receptors and is involved in maladaptive heart remodeling. This view has been recently complicated by the finding that PI3Ks can also be involved in protein-protein interactions and affect signaling independently of their kinase activity. This review will thus focus on the effects of these multiple signaling events, with particular emphasis on their involvement in cardiac hypertrophy and failure. PMID- 20201885 TI - Vascularization shaping the heart. AB - Myocardial infarction can lead to irreversible heart failure. In an attempt to restore function in the failing heart, tissue-engineered cardiac constructs can be applied to repopulate scar tissue with a new pool of contractile cells. Effective engineering of viable thick complex tissue-constructs requires intense vascularization. Furthermore, endothelial-cardiomyocyte crosstalk plays a key role in mutually enhancing tissue functionality, which can further improve construct survival. The ability to generate an engineered, vascularized muscle tissue was demonstrated by us using the skeletal and the cardiac muscle models. In the skeletal model, we showed that prevascularization of the construct promoted perfusion of the graft. More recently, we successfully generated a beating human cardiac muscle-construct, containing an endothelial network, by co culturing human embryonic stem cell-derived-cardiomyocytes, fibroblasts, and endothelial cells within biodegradable scaffolds. Such muscle-constructs could contribute significantly to the emerging discipline of cardiovascular regenerative medicine as well as to the study of the important role of tissue vascularization. PMID- 20201886 TI - Inhibition of ROCK improves survival of human embryonic stem cell-derived cardiomyocytes after dissociation. AB - In recent years the differentiation efficiency of human embryonic stem cells (hESCs) to cardiomyocytes has improved considerably. In general, hESC-derived cardiomyocytes are formed in aggregates, which require dissociation for follow-up experimental analyses and (clinical) applications. Here, we show that inhibition of the Rho-associated kinase (ROCK) by Y-27632 improved survival of dissociated hESC-derived differentiated cells. A maximum effect on cell survival was already observed within the first 24 hours. Hereafter, no further differences in the percentage of apoptotic and proliferating cells were observed with or without ROCK-inhibitor treatment. Improved survival was observed in both cardiomyocyte as well as non-cardiomyocyte cell populations. Viable cardiomyocytes were indicated by the appearance of beating, sarcomeric organization of cardiac-specific proteins, and fluorescence of a mitochondrion-selective dye. These results facilitate development of applications of hESC-derived cardiomyocytes in multiple research areas. Furthermore, these findings may be applied to other cell types differentiated from hESCs or other stem cells. PMID- 20201887 TI - Molecular mechanisms in evolutionary cardiology failure. AB - Integration of the relevant evolutionary paradigm in cardiology has not yet been fully achieved: In the past, heart failure (HF) was mainly ascribed to infections, and the origins of cardiac hypertrophy (CH) were regarded as mechanical. Recent changes in lifestyle have both reduced the incidence of infections and increased lifespan, and HF is now seen as a complex disease--one that is still caused by mechanical disorder, but also associated with ischemia and senescence. The long-held view that CH serves to restore myocardial economy back to normal is still valid. The adaptive process is characterized by a quantitative and a qualitative fetal gene reprogramming, which is now being confirmed by recent advances in microRNA research. It underscores the fact CH is the physiologic reaction of the heart to a pathologic stimulus. The goal for therapy is economic, not inotropic. Another major issue is myocardial fibrosis, a major determinant of diastolic function and arrhythmias. Recent changes in lifestyle have crucially modified the context in which HF occurs. PMID- 20201888 TI - Human embryonic stem cell-derived cardiomyocytes can mobilize 1,4,5-inositol trisphosphate-operated [Ca2+]i stores: the functionality of angiotensin II/endothelin-1 signaling pathways. AB - Because previous findings showed that in human embryonic stem cell-derived cardiomyocytes (hESC-CM) the machinery for Ca2+-induced release of calcium is immature, we tested the hypothesis that hESC-CM contain functional 1,4,5-inositol triphosphate (IP3)-operated intracellular Ca2+ ([Ca2+]i) stores. We investigated the effects of angiotensin II (AT-II) and endothelin 1 (ET-1), which activate the 1,4,5-IP3 pathway, on [Ca2+]i transients and contractions in hESC-CM. Our major findings were that in hESC-CM, both AT-II (10(-9)-10(-7) M) and ET-1 (10(-9)-10( 7) M) exert inotropic and lusitropic effects. The involvement of 1,4,5-IP3 dependent intracellular Ca2+ release in AT-I-induced effects was supported by these findings: the effects of AT-II were blocked by 2-aminoethoxyphenyl borate (2-APB, a 1,4,5-IP3 receptor blocker) and U73122 (a phosopholipase C blocker); and hESC-CM express AT-II type 1 and IP3 type I and II receptors as determined by fluorescence immunostaining. In conclusion, hESC-CM exhibit functional AT-II and ET-1 signaling pathways, as well as 1,4,5-IP3-operated releasable Ca2+ stores. PMID- 20201889 TI - Atrial-selective sodium channel block as a novel strategy for the management of atrial fibrillation. AB - Safe and effective pharmacologic management of atrial fibrillation (AF) is one of the greatest challenges facing an aging society. Currently available pharmacologic strategies for rhythm control of AF are associated with ventricular arrhythmias and in some cases multi-organ toxicity. Consequently, drug development has focused on atrial-selective agents such as IKur blockers. Recent studies suggest that IKur block alone may be ineffective for suppression of AF and may promote AF in healthy hearts. Recent experimental studies have demonstrated other important electrophysiologic differences between atrial and ventricular cells, particularly with respect to sodium channel function, and have identified sodium channel blockers that exploit these electrophysiologic distinctions. Atrial-selective sodium channel blockers, such as ranolazine and amiodarone, effectively suppress and/or prevent the induction of AF in experimental models, while producing little to no effect on ventricular myocardium. These findings suggest that atrial-selective sodium channel block may be a fruitful new strategy for the management of AF. PMID- 20201890 TI - The involvement of ZnT-1, a new modulator of cardiac L-type calcium channels, in [corrected] atrial tachycardia remodeling. [corrected]. AB - Atrial fibrillation (AF), the highest occurring cardiac arrhythmia in the Western world, is associated with substantial morbidity and increased mortality. In spite of extensive research, the cause of atrial electrical remodeling, a major factor in the self-perpetuating nature of AF, is still unknown. Downregulation of L-type Ca2+ channel (LTCC) activity is the hallmark of atrial electrical remodeling. ZnT 1 is a ubiquitous membrane protein that was recently suggested to inhibit the LTCC. We have studied and shown that ZnT-1 expression inhibits LTCC function in an oocyte expression system as well as in isolated cardiomyocytes. Our data also show that rapid electrical pacing can augment ZnT-1 expression in culture as well as in the atria of rats in vivo. Finally, in a pilot study, ZnT-1 expression was found to be augmented in the atria of AF patients. These findings position ZnT-1 as a probable missing link in the mechanism underlying atrial tachycardia remodeling. PMID- 20201891 TI - Extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in cardiac hypertrophy. AB - Cardiac hypertrophy results from increased mechanical load on the heart and through the action of neurohumoral mediators. ERK1/2 are known to be activated in response to almost every stress- and agonist-induced hypertrophic stimulus examined to date, suggesting the straightforward hypothesis that these kinases are required for promoting the cardiac growth response. However, recent data from genetically modified mouse models suggest a more complicated picture. For example, inducible expression of dual-specificity phosphatase 6, an ERK1/2 inactivating phosphatase, eliminated ERK1/2 phosphorylation in transgenic mice, but it did not diminish the hypertrophic response to pressure overload. Similarly, Erk1-/- and Erk2+/- mice showed no reduction in stimulus-induced cardiac growth in vivo. However, blockade or deletion of cardiac ERK1/2 did predispose the heart to decompensation and failure after long-term pressure overload. Thus, ERK1/2 signaling is not to be absolutely necessary for mediating cardiac hypertrophy, although it does appear to provide critical protective effects/signals during stress-stimulation. PMID- 20201892 TI - The role of mechanical forces in the torsional component of cardiac looping. AB - During early development, the initially straight heart tube (HT) bends and twists (loops) into a curved tube to lay out the basic plan of the mature heart. The physical mechanisms that drive and regulate looping are not yet completely understood. This paper reviews our recent studies of the mechanics of cardiac torsion during the first phase of looping (c-looping). Experiments and computational modeling show that torsion is primarily caused by forces exerted on the HT by the primitive atria and the splanchnopleure, a membrane that presses against the ventral surface of the heart. Experimental and numerical results are described and integrated to propose a hypothesis for cardiac torsion, and key aspects of our hypothesis are tested using experiments that perturb normal looping. For each perturbation, the models predict the correct qualitative response. These studies provide new insight into the mechanisms that drive and regulate cardiac looping. PMID- 20201893 TI - Multiscale modeling of metabolism, flows, and exchanges in heterogeneous organs. AB - Large-scale models accounting for the processes supporting metabolism and function in an organ or tissue with a marked heterogeneity of flows and metabolic rates are computationally complex and tedious to compute. Their use in the analysis of data from positron emission tomography (PET) and magnetic resonance imaging (MRI) requires model reduction since the data are composed of concentration-time curves from hundreds of regions of interest (ROI) within the organ. Within each ROI, one must account for blood flow, intracapillary gradients in concentrations, transmembrane transport, and intracellular reactions. Using modular design, we configured a whole organ model, GENTEX, to allow adaptive usage for multiple reacting molecular species while omitting computation of unused components. The temporal and spatial resolution and the number of species are adaptable and the numerical accuracy and computational speed is adjustable during optimization runs, which increases accuracy and spatial resolution as convergence approaches. An application to the interpretation of PET image sequences after intravenous injection of 13NH3 provides functional image maps of regional myocardial blood flows. PMID- 20201894 TI - Cardiac myocyte force development during differentiation and maturation. AB - The maturation of cardiac myocytes during the immediate prenatal period coincides with changes in the mechanical properties of the extracellular matrix. We investigated the effects of extracellular stiffness on cardiomyocyte maturation in neonatal rat ventricular myocytes grown on collagen-coated gels. Cells on 10 kPa substrates developed aligned sarcomeres, while cells on stiffer substrates had unaligned sarcomeres and stress fibers. Cells generated greater mechanical force on gels with stiffness similar to that of the native myocardium than on stiffer or softer substrates. To investigate the differentiation of myocyte progenitors, we used clonal expansion of engineered human embryonic stem cells. Puromycin-selected cardiomyocytes exhibited a gene expression profile similar to that of adult human cardiomyocytes and generated force and action potentials consistent with normal fetal cardiomyocytes. These results suggest that extracellular stiffness significantly affects maturation and differentiation of immature ventricular myocytes. PMID- 20201895 TI - Increase in endocardial rotation during doxorubicin treatment. AB - Treatment of cardiomyopathy, when detected early, may slow myocardial deterioration and even reverse its course. However, no efficient, noninvasive measure of cardiac function is yet able to detect the early signs of cardiomyopathy. The aim of this study was to determine whether ultrasound speckle tracking analysis is a more sensitive measure of early changes of cardiac function than standard echocardiographic parameters. Eight Wistar rats were injected with doxorubicin and scanned weekly by ultrasound in order to follow the early stages of cardiomyopathy. Apical short-axis scans were analyzed by a novel speckle tracking imaging program, enabling layer-specific assessment of myocardial function. Only four of eight rats survived the full treatment. They showed a significant elevation of endocardial apical rotation (P<0.006) after 4 weeks of treatment (25.1+/-3.7 deg) versus baseline values (8.0+/-2.8 deg), while ejection fraction remained normal (78.5+/-3.5%). Thus, in the rat model, layer specific assessment of myocardial function may detect cardiomyopathy at its early stages. PMID- 20201896 TI - Matching ATP supply and demand in mammalian heart: in vivo, in vitro, and in silico perspectives. AB - Although the heart rapidly adapts cardiac output to match the body's circulatory demands, the regulatory mechanisms ensuring that sufficient ATP is available to perform the required cardiac work are not completely understood. Two mechanisms have been suggested to serve as key regulators: (1) ADP and Pi concentrations- ATP utilization/hydrolysis in the cytosol increases ADP and Pi fluxes to mitochondria and hence the amount of available substrates for ATP production increases; and (2) Ca2+ concentration--ATP utilization/hydrolysis is coupled to changes in free cytosolic calcium and mitochondrial calcium, the latter controlling Ca2+-dependent activation of mitochondrial enzymes taking part in ATP production. Here we discuss the evolving perspectives of each of the putative regulatory mechanisms and the precise molecular targets (dehydrogenase enzymes, ATP synthase) based on existing experimental and theoretical evidence. The data synthesis can generate novel hypotheses and experimental designs to solve the ongoing enigma of energy supply-demand matching in the heart. PMID- 20201897 TI - The dynamics of fibroblast-myocyte-capillary interactions in the heart. AB - In the heart, electrical, mechanical, and chemical signals create an environment essential for normal cellular responses to developmental and pathologic cues. Communication between fibroblasts, myocytes, and endothelial cells, as well as the extracellular matrix, are critical to fluctuations in heart composition and function during normal development and pathology. Recent evidence suggests that cytokines play a role in cell-cell signaling in the heart. Indeed, we find that interactions between myocytes and cardiac fibroblasts results in increased interleukin-6 and tumor necrosis factor-alpha secretion. We also used confocal and transmission electron microscopy to observe close relationships and possible direct communication between these cells in vivo. Our results highlight the importance of direct cell-cell communication in the heart, and indicate that interactions between fibroblasts, myocytes, and capillary endothelium results in differential cytokine expression. Studying these cell-cell interactions has many implications for the process of cardiac remodeling and overall heart function during development and cardiopathology. PMID- 20201899 TI - Epigenetics in heart failure. AB - Heart failure is one of the main causes of mortality in developed countries and is frequently associated with cardiac hypertrophy. Gene expression reprogramming in cardiac myocytes is a key feature of heart hypertrophy and failure and is characterized by upregulation of fetal genes and decreased expression of some subsets of adult ones. The full picture of signaling events underlying gene transcription in these pathophysiologic states is not completely understood, but recent evidence suggests a major role for epigenetics. This report provides an overview of the mechanisms of epigenetics and how they affect myocardial gene expression during hypertrophy and failure. PMID- 20201898 TI - L-type calcium channel as a cardiac oxygen sensor. AB - Acute oxygen sensing in the heart is thought to occur through redox regulation and phosphorylation of membrane channels. Here we report a novel O2-sensing mechanism involving the C-terminus of the L-type Ca2+ channel and regulated by PKA phosphorylation. In patch-clamped myocytes, oxygen deprivation decreased ICa within 40 s. The suppressive effect of anoxia was relieved by PKA-mediated phosphorylation only when Ca2+ was the charge carrier, whereas phosphorylated IBa remained sensitive to O2 withdrawal. Suppression of Ca2+ release by thapsigargin did not alter the response of ICa to anoxia, suggesting a mandatory role for Ca2+ influx and not Ca2+-induced Ca2+ release (CICR) in O2 regulation of the channel. Consistent with this idea, mutation of 80 amino acids in the Ca2+/CaM-binding domain of the recombinant alpha1C subunit that removes Ca2+ dependent inactivation (CDI) abolished O2 sensitivity of the channel. Our findings suggest that the Ca2+/CaM binding domain of the L-type Ca2+ may represent a molecular site for O2 sensing of the heart. PMID- 20201900 TI - Nonuniform activation and the mechanics of myocardial trabeculae with fast or slow myosin. AB - Left ventricular (LV) wall motion abnormalities reflect regional nonuniform contraction which may be arrhythmogenic. We studied sarcomere mechanics and force development (F) in uniform and nonuniform trabeculae using a model in which half of the muscle can be rendered weak by exposure to low [Ca2+]o. Stretch allowed the weak muscle segment to generate a force that was four-fold higher than force when the whole muscle was exposed to low [Ca2+]o. The sarcomere force-velocity relationships (FSVR) and the force-sarcomere-length relationships (FSLR) explained the force increase in the weak segment and the decrease of force in the strong segment such that both carried the same force. Correction for muscle stiffness converted the FSVR into a [Ca2+]o-independent linear FVRXB for "the single cross-bridge (XB)." Stretch increased XB force<10% above FXB-max, but recruited more XBs by feedback of V to the rate of XB, weakening (g=g0+g1V). The g1 here was indistinguishable from g1 of XBs in slow myosin of aged animals. The mechanics of nonuniform muscle can be explained by a linear FVRXB combined with the effect of V on the XB weakening rate. PMID- 20201901 TI - Developmental basis of adult cardiovascular diseases: valvular heart diseases. AB - In this chapter, we review the working hypothesis that the roots of adult valvular heart disease (VHD) lie in embryonic development. Valvulogenesis is a complex process in which growth factors signal the process of endocardium-to mesenchyme transformation (EMT) resulting in formation of prevalvular "cushions." The post-EMT processes, whereby cushions are morphogenetically remolded into valve leaflets, are less well understood, but they require periostin. Mice with targeted deletion of periostin develop degenerative changes similar to human forms of VHD. Mitral valves are also abnormally elongated in hypertrophic cardiomyopathy (HCM), which plays an important role in clinical disease expression. However, the mechanism for this is unclear, but correlates with enhanced expression of periostin in a specific population of ventricular cells derived from the embryonic proepicardial organ, which accumulate at sites where valvular endocardial EMT is reactivated. Collectively, these findings suggest that developmental mechanisms underlie adult valve responses to genetic mutations in degenerative VHD and HCM. PMID- 20201902 TI - Notch and cardiac outflow tract development. AB - Congenital heart disease represents the most common form of human birth defect, occurring in nearly 1 in 100 live births. An increasing number of patients with these defects are surviving infancy. Approximately one-third of congenital heart defects involve malformations of the outflow tract. Related defects are found in isolation and as part of common human syndromes. Our laboratory has investigated mechanisms of cardiac morphogenesis with particular attention to outflow tract formation. During cardiogenesis, neural crest cells interact with second heart field myocardium and endocardial cushion mesenchyme. Our recent work demonstrates that Jagged1/Notch signaling within the second heart field initiates a signaling cascade involving Fgf8, Bmp4, and downstream effectors that modulate outflow tract development and aortic arch artery patterning. Hence, complex tissue-tissue interactions and integration of multiple pathways converge to orchestrate proper patterning of the outflow region. The role of Notch signaling in adult cardiac homeostasis and disease is an area of active investigation. PMID- 20201904 TI - Heat acclimation-mediated cross-tolerance in cardioprotection: do HSP70 and HIF 1alpha play a role? AB - Heat acclimation (AC) is an evolutionarily conserved feature allowing adjustment to persistent changes in ambient temperature. The mechanisms underlying acclimation involve a continuum of physiologic changes, determined by temperature adaptive shifts in gene expression. The AC heart generates greater pressure at lower O2 consumption, but at the expense of contractile velocity, and renders cytoprotection to a wide range of stressors (cross-tolerance) via greater cytoprotective protein reserves, faster post-injury molecular dynamic response, and post-translational modifications. A greater abundance of HSP70 and HIF-1alpha and its metabolic targeted genes (both nuclear and mitochondrial) are among the cytoprotective changes that occur. The cytoprotection profile provides a dual protective strategy--a constitutive availability of cytoprotective proteins without a need for de novo protein synthesis, together with an "alerted system" responding rapidly upon insult. Hence, cross-tolerance is achieved via activation of "on-call" constitutive cytoprotection shared by all stressors, together with organ-specific functional remodeling and stress-specific cross-talk. PMID- 20201905 TI - Navigation within the heart and vessels in clinical practice. AB - The field of interventional cardiology has developed at an unprecedented pace on account of the visual and imaging power provided by constantly improving biomedical technologies. Transcatheter-based technology is now routinely used for coronary revascularization and noncoronary interventions using balloon angioplasty, stents, and many other devices. In the early days of interventional practice, the operating physician had to manually navigate catheters and devices under fluoroscopic imaging and was exposed to radiation, with its comcomitant necessity for wearing heavy lead aprons for protection. Until recently, very little has changed in the way procedures have been carried out in the catheterization laboratory. The technological capacity to remotely manipulate devices, using robotic arms and computational tools, has been developed for surgery and other medical procedures. This has brought to practice the powerful combination of the abilities afforded by imaging, navigational tools, and remote control manipulation. This review covers recent developments in navigational tools for catheter positioning, electromagnetic mapping, magnetic resonance imaging (MRI)-based cardiac electrophysiological interventions, and navigation tools through coronary arteries. PMID- 20201903 TI - Return to the fetal gene program: a suggested metabolic link to gene expression in the heart. AB - A hallmark of cardiac metabolism before birth is the predominance of carbohydrate use for energy provision. After birth, energy substrate metabolism rapidly switches to the oxidation of fatty acids. This switch accompanies the expression of "adult" isoforms of metabolic enzymes and other proteins. However, in a variety of pathophysiologic conditions, including hypoxia, ischemia, hypertrophy, atrophy, diabetes, and hypothyroidism, the postnatal heart returns to the "fetal" gene program. These adaptive mechanisms are also a feature of the failing heart muscle, where at a certain point this fetal-like reprogramming no longer suffices to support cardiac structure and function. We advance the hypothesis that in the postnatal heart, metabolic remodeling triggers the process through glycosylation of transcription factors, potentially protecting the stressed heart from irreversible functional impairment and programmed cell death. In other words, we propose a metabolic link to gene expression in the heart. PMID- 20201906 TI - Noninvasive imaging of cardiac electrophysiology and arrhythmia. AB - Cardiac arrhythmias are a major cause of death and disability. Despite the clinical need and the importance of studying arrhythmia mechanisms in humans, a noninvasive imaging modality for cardiac electrophysiology is not yet available for routine application. Here we describe such a noninvasive imaging modality, electrocardiographic imaging (ECGI), and provide examples of its application in various (normal and abnormal) cardiac rhythms. PMID- 20201907 TI - Theory of cardiac sarcomere contraction and the adaptive control of cardiac function to changes in demands. AB - This chapter explores the adaptive control of cardiac function by the loading conditions and relates the observed phenomena to our theory of the sarcomeric control of contraction. Our theory includes two feedback mechanisms: cooperativity-regulated cross-bridge recruitment and energy consumption, and mechanical feedback that determines the interplay between the external work and the force-time integral. The latter also suggests that cardiac efficiency is load independent. This paper explores the regulation of cardiac function by loading conditions, and the role of afterload in adult sheep in situ (n=8). Different afterloads were imposed by partial aortic occlusions. Transient inferior vena cava occlusions (IVCOs) were pre-formed at each steady afterload. A novel, highly linear relationship was found between the external work and pressure-time integral during each transient IVCO at constant afterload. Of interest, the slope of this relationship was afterload-dependent also during fast transient changes in the afterload. These observations are congruent with the suggested adaptive sarcomeric control of contraction, and may provide a powerful tool for quantifying cardiac function. PMID- 20201910 TI - A new year, a new era, a new page. PMID- 20201911 TI - Women, serious mental illness and recidivism: A gender-based analysis of recidivism risk for women with SMI released from prison. AB - Two groups now constitute the fastest growing segment of the U.S. prison population: women and persons with mental illness. Few large-scale studies have explored associations among serious mental illness (SMI), gender, and recidivism, or compared factors such as illness severity and clinical history as these construct notably different situations for incarcerated women and men. We report on our recent study comparing prison recidivism rates, severity of mental illness, and clinical history for women and men released from Utah State Prison 1998-2002. IMPLICATIONS: While women generally have better recidivism outcomes than men, we find that SMI related factors have a greater negative effect on the trajectories of women in this sample as compared with the men. This suggests that programs and policies focused on the SMI-specific risks and needs of women could significantly reduce prison recidivism and increase community tenure for this group, with far-reaching effects for families and communities. PMID- 20201912 TI - A narrative review of the effectiveness of aggression management training programs for psychiatric hospital staff. AB - Workplace violence, including patient-perpetrated violence in healthcare settings, is increasingly being recognized as preventable. Staff training has been identified as a necessary component of any initiative aimed at preventing or reducing incidents of aggression and violence in the workplace. This narrative review of the literature evaluates the effectiveness of staff training programs designed to prevent and manage violence and aggression in psychiatric hospitals. An exhaustive review of the literature was performed on all articles published in English between January 1, 1990 and April 1, 2007 that evaluate an aggression management training program. Twenty-nine studies met the inclusion criteria for a full review and were summarized using a qualitative narrative approach. Aggression management training has been proven effective in some areas, such as reducing the use of restraints and other coercive control devices, but more methodologically rigorous research is needed to firmly establish whether it is effective in reducing aggression and staff injuries. IMPLICATIONS: The findings of this study suggest that relying too heavily on aggression management staff training will have limited effect on addressing the range of issues related to patient-perpetrated violence in psychiatric hospitals. Mental healthcare organizations must look beyond staff training if they are to achieve meaningful reductions in aggressive incidents and staff injuries. PMID- 20201913 TI - A forensic nursing protocol for initiating human immunodeficiency virus post exposure prophylaxis following sexual assault. AB - The use of human immunodeficiency virus post-exposure prophylaxis (HIV PEP) should be considered in the care of sexual assault patient populations. In order to effectively implement HIV PEP following sexual assault, healthcare providers need to have a working knowledge of HIV transmission risk factors following a sexual exposure and protocols for initiating HIV PEP. Being able to implement evidence-based practices that address each of these factors is paramount to successful prevention of HIV transmission following a sexual assault exposure. Most healthcare practitioners, however, lack the specialized knowledge needed to address these issues in the expeditious manner necessitated by a potential HIV exposure. IMPLICATIONS: This paper is designed to provide healthcare providers with a basic understanding of HIV transmission risk factors and the knowledge and skills needed to effectively implement HIV PEP following a sexual assault exposure. PMID- 20201914 TI - Chronic traumatic encephalopathy (CTE) in a National Football League Player: Case report and emerging medicolegal practice questions. AB - We present a case of chronic traumatic encephalopathy (CTE) in a retired National Football League (NFL) Player with autopsy findings, apolipoprotein E genotype, and brain tissue evidence of chronic brain damage. This 44-year-old retired NFL player manifested a premortem history of cognitive and neuropsychiatric impairment, which included in part, chronic depression, suicide attempts, insomnia, paranoia, and impaired memory before he finally committed suicide. A full autopsy was performed with Polymerase Chain Reaction-based analyses of his blood to determine the apolipoprotein genotype. Histochemical and immunohistochemical analyses were performed on topographical gross sections of the brain. Autopsy confirmed a fatal gunshot wound of the head. The apolipoprotein E genotype was E3/E3 and the brain tissue revealed diffuse cerebral taupathy (Neurofibrillary Tangles and Neuritic Threads). This will be the third case of CTE in a national football player, which has been reported in the medical literature. Omalu et al., reported the first two cases in 2005 and 2006. This case series manifested similar premortem history of neuropsychiatric impairment with autopsy evidence of cerebral taupathy without any neuritic amyloidopathy. For a definitive diagnosis of CTE to be made, and for medicolegal purposes, a full autopsy must be performed with histochemical and immunohistochemical analyses of the brain to identify the presence of Neurofibrillary Tangles (NFTs) and Neuritic Threads (NTs). IMPLICATIONS: Further longitudinal prospective studies are required to confirm the common denominators and epidemiology of CTE in professional American football players, which have been identified by this case series. PMID- 20201915 TI - Expanding evidence collection time: Is it time to move beyond the 72-hour rule? How do we decide? PMID- 20201916 TI - Does femur length affect the stride length? Forensic implications. AB - All the long bones in the human body have a linear and positive relationship with stature. This principle has been used by forensic scientists and anthropologists to estimate stature in many kinds of medico-legal and forensic examinations. The present proposition states that the femur length may have a positive relationship with stride length. This relationship can help the forensic scientist to estimate stride length from the length of the femur and vice versa which can further be extended to formulate opinion in person's gait, biomechanics, movement, and posture analysis of the suspects in forensic case work. This can further be used to give opinion while handling certain evidences like closed-circuit television footage and video surveillance system in crime scene investigation. PMID- 20201918 TI - Foresight in medicine: current challenges with Haemophilus influenzae type b conjugate vaccines. AB - An effective vaccine to prevent invasive infections caused by Haemophilus influenzae type b (Hib) bacteria has been available for more than 20 years. Hib conjugate vaccine is safe, efficacious and easy to use, and its cost-benefit ratio is high both in industrialized as well as in developing countries. In spite of this, WHO estimates that every year approximately 8 million children contract life-threatening Haemophilus infections, especially meningitis or severe pneumonia. If we want to take seriously the Millenium Development Goal of reducing the mortality of under 5-year-old children by two-thirds before the year 2015, an effective means to contribute to this would be more efficient use of Hib vaccines. PMID- 20201919 TI - Prophylactic human papillomavirus vaccines: will they do their job? AB - The prophylactic HPV L1 virus like particle vaccines are highly efficacious preventing >98% of HPV 16/18 caused high grade cervical intra-epithelial neoplasia (CIN2/3) according to protocol group in phase III randomized clinical trials over approximately 4 years. Data from the trials together with postvaccine surveillance indicates that they have a good safety profile. As the current HPV vaccines include only two of the 15 oncogenic HPVs, they will not eliminate cervical cancer or the other HPV associated ano-genital diseases but could reduce, for example, the incidence of cervix cancer by up to 70-80%, if effectively delivered to adolescent females. PMID- 20201921 TI - Plasma soluble transferrin receptor assay when screening for iron-deficiency in an unselected population of elderly anaemic patients. PMID- 20201920 TI - CD20-depleting therapy in autoimmune diseases: from basic research to the clinic. AB - The B lymphocyte-associated antigen CD20 is becoming an important immunotherapy target for autoimmune diseases, although its biological function has not been defined. Besides rheumatoid arthritis, growing experience with B cell-depleting therapy indicates that it may be effective in Sjogren's syndrome, dermatomyositis polymyositis, systemic lupus erythematosus and some types of vasculitides. However, controlled clinical trials are still lacking for some of these indications. Infection has not been seen as a major limitation to this therapy, but reports of progressive multifocal leukoencephalopathy in an extremely small number of patients are of concern. Here, we review the therapeutic actions of anti-CD20 antibodies, and the recent and ongoing clinical trials with CD20 depleting therapy in autoimmune diseases. PMID- 20201922 TI - A paradigm shift is also required in treatment goals and in performance indicators. PMID- 20201925 TI - Influence of dissolved oxygen concentration on the pharmacokinetics of alcohol in humans. AB - BACKGROUND: Ethanol oxidation by the microsomal ethanol oxidizing system requires oxygen for alcohol metabolism, and a higher oxygen uptake increases the rate of ethanol oxidation. We investigated the effect of dissolved oxygen on the pharmacokinetics of alcohol in healthy humans (n = 49). The concentrations of dissolved oxygen were 8, 20, and 25 ppm in alcoholic drinks of 240 and 360 ml (19.5% v/v). METHODS: Blood alcohol concentrations (BACs) were determined by converting breath alcohol concentrations. Breath samples were collected every 30 min when the BAC was higher than 0.015%, 20 min at BAC < or =0.015%, 10 min at BAC < or =0.010%, and 5 min at BAC < or =0.006%. RESULTS: The high dissolved oxygen groups (20, 25 ppm) descended to 0.000% and 0.050% BAC faster than the normal dissolved oxygen groups (8 ppm; p < 0.05). In analyzing pharmacokinetic parameters, AUC(inf) and K(el) of the high oxygen groups were lower than in the normal oxygen group, while C(max) and T(max) were not significantly affected. In a Monte Carlo simulation, the lognormal distribution of mean values of AUC(inf) and t(1/2) was expected to be reduced in the high oxygen group compared to the normal oxygen group. CONCLUSIONS: In conclusion, elevated dissolved oxygen concentrations in alcoholic drinks accelerate the metabolism and elimination of alcohol. Thus, enhanced dissolved oxygen concentrations in alcohol may have a role to play in reducing alcohol-related side effects and accidents. PMID- 20201926 TI - Human variation in alcohol response is influenced by variation in neuronal signaling genes. AB - BACKGROUND: Alcohol use disorders (AUD) exhibit the properties shared by common conditions and diseases classified as genetically complex. The etiology of AUDs is heterogeneous involving mostly unknown interactions of environmental and heritable factors. A person's level of response (LR) to alcohol is inversely correlated with a family history and the development of AUDs. As an AUD endophenotype, alcohol LR is hypothesized to be less genetically complex and closer to the primary etiology of AUDs. METHODS: A genome wide association study (GWAS) was performed on subjects characterized for alcohol LR phenotypes. Gene Set Enrichment Analysis (GSEA) of the GWAS data was performed to determine whether, as a group, genes that participate in a common biological function (a gene set) demonstrate greater genetic association than would be randomly expected. RESULTS: The GSEA analysis implicated variation in neuronal signaling genes, especially glutamate signaling, as being involved in alcohol LR variability in the human population. CONCLUSIONS: These data, coupled with cell and animal model data implicating neuronal signaling in alcohol response, support the conclusion that neuronal signaling is mechanistically involved in alcohol's cellular and behavioral effects. Further, these data suggest that genetic variation in these signaling pathways contribute to human variation in alcohol response. Finally, this concordance of the cell, animal, and human findings supports neuronal signaling, particularly glutamate signaling, as a prime target for translational studies to understand and eventually modulate alcohol's effects. PMID- 20201927 TI - Increased activation of the ACC during a spatial working memory task in alcohol dependence versus heavy social drinking. AB - BACKGROUND: Activation of the anterior cingulate cortex (ACC) in a spatial working memory task has been associated with risk factors for alcohol use disorders such as low alcohol effects and positive alcohol expectations in adolescents. To transfer these results into adults, we used the same task in adults. METHODS: During functional magnetic resonance imaging, 12 light social, 7 heavy social, and 11 non-abstinent-dependent alcohol drinkers performed a spatial working memory task and completed measures of automatic alcohol-related thoughts and behavior (Obsessive-Compulsive Drinking Scale-OCDS), alcohol use of the last 90 days, and general intelligence. RESULTS: Behavioral performance in the spatial working memory task was not significantly different in all 3 groups. Controlling for differences in general intelligence alcohol-dependent participants showed a higher task-related activation of the dorsal ACC (dACC) in comparison with light and heavy social drinkers. Measures of the OCDS were positively correlated with the activation in the left hippocampus and right thalamus in all participants. CONCLUSIONS: Our results support the findings of increased dACC activation during a spatial working memory task as a risk factor for alcohol dependence. Increased task-related activation in the dACC was only observed in alcohol-dependent participants and not in heavy social drinkers with comparable alcohol consumption. Furthermore, the absence of behavioral performance differences between groups as well as an association between dACC activation and working memory performance indicates subtle working memory deficits. Low capacity of working memory has been linked to more automatic and less self-regulated behavior in studies on natural reward processing. Therefore, additional neural activation during performance of the non-alcohol-related working memory task in participants with higher OCDS values in the left hippocampus and the right thalamus may be a consequence of decreased neural capacity because of distracting alcohol-related thoughts. PMID- 20201924 TI - Genome-wide association study of alcohol dependence implicates a region on chromosome 11. AB - BACKGROUND: Alcohol dependence is a complex disease, and although linkage and candidate gene studies have identified several genes associated with the risk for alcoholism, these explain only a portion of the risk. METHODS: We carried out a genome-wide association study (GWAS) on a case-control sample drawn from the families in the Collaborative Study on the Genetics of Alcoholism. The cases all met diagnostic criteria for alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition; controls all consumed alcohol but were not dependent on alcohol or illicit drugs. To prioritize among the strongest candidates, we genotyped most of the top 199 single nucleotide polymorphisms (SNPs) (p < or = 2.1 x 10(-4)) in a sample of alcohol-dependent families and performed pedigree-based association analysis. We also examined whether the genes harboring the top SNPs were expressed in human brain or were differentially expressed in the presence of ethanol in lymphoblastoid cells. RESULTS: Although no single SNP met genome-wide criteria for significance, there were several clusters of SNPs that provided mutual support. Combining evidence from the case-control study, the follow-up in families, and gene expression provided strongest support for the association of a cluster of genes on chromosome 11 (SLC22A18, PHLDA2, NAP1L4, SNORA54, CARS, and OSBPL5) with alcohol dependence. Several SNPs nominated as candidates in earlier GWAS studies replicated in ours, including CPE, DNASE2B, SLC10A2, ARL6IP5, ID4, GATA4, SYNE1, and ADCY3. CONCLUSIONS: We have identified several promising associations that warrant further examination in independent samples. PMID- 20201928 TI - Ethanol enhances the interaction of breast cancer cells over-expressing ErbB2 with fibronectin. AB - BACKGROUND: Ethanol is a tumor promoter and may enhance the metastasis of breast cancer. However, the underlying cellular/molecular mechanisms remain unknown. Amplification of ErbB2 or HER2, a receptor tyrosine kinase of the ErbB family, is found in 20 to 30% of patients with breast cancer. We have previously demonstrated that the effect of ethanol on the migration/invasion of breast cancer cells positively correlated with the expression levels of ErbB2. Adhesion to the extracellular matrix (ECM) is an important initial step for cancer cell invasion and metastasis. In this study, we investigated the effects of ethanol on the adhesion of MCF7 breast cancer cells over-expressing ErbB2 (MCF7(ErbB2)) to human plasma fibronectin. METHODS: To test the hypothesis that ethanol may enhance the attachment of human breast cancer cells to fibronectin, an important component of the ECM, we evaluated the effect of ethanol on the expression of focal adhesions, cell attachment, and ErbB2 signaling in cultured MCF7(ErbB2) cells. RESULTS: Exposure to ethanol drastically enhanced the adhesion of MCF(ErbB2) cells to fibronectin and increased the expression of focal adhesions. Ethanol induced phosphorylation of ErbB2 at Tyr1248, FAK at Tyr861, and cSrc at Try216. Ethanol promoted the interaction among ErbB2, FAK, and cSrc, and the formation of a focal complex. AG825, a selective ErbB2 inhibitor, attenuated the ethanol-induced phosphorylation of ErbB2 and its association with FAK. Furthermore, AG825 blocked ethanol-promoted cell/fibronectin adhesion as well as the expression of focal adhesions. CONCLUSIONS: Our results suggest that ethanol enhances the adhesion of breast cancer cells to fibronectin in an ErbB2-dependent manner, and the FAK pathway plays an important role in ethanol-induced formation of a focal complex. PMID- 20201929 TI - Verbal and nonverbal memory in adults prenatally exposed to alcohol. AB - BACKGROUND: Neurocognitive effects of prenatal alcohol exposure in adulthood are not well documented. Questions persist regarding the extent to which there are specific, measurable effects beyond those associated with global ability deficits, whether individuals without the full fetal alcohol syndrome (FAS) demonstrate alcohol-related cognitive impairments, and whether observed memory effects are specific to a particular modality, i.e., verbal vs. visual/spatial domains. METHODS: In this study, verbal and nonverbal selective reminding paradigms were used to assess memory function in 234 young adults (M age: 22.78, SD: 1.79). Alcohol exposure was quantified prenatally. Alcohol groups included: Individuals with physical effects of alcohol exposure (Dysmorphic group, n = 47); Exposed individuals without such effects (n = 74). Contrast groups included: Controls (n = 59) matched for ethnicity, socioeconomic status, and hospital of birth; Special Education contrast group (n = 54) included to control for disability status. Memory outcomes entailed total recall, delayed recall, and measures of encoding and retrieval, and learning over trials as indexed by slope. RESULTS: Results indicated that Dysmorphic individuals were significantly less efficient in memory performance than Controls on all of the outcomes measured, but they did not differ from those in the Special Education contrast group. The nondysmorphic, alcohol-exposed group was intermediate in their performance, suggesting a continuum of effects of prenatal exposure. Evaluation of the encoding and retrieval aspects of memory performance indicated that learning rather than forgetting accounted for the deficits associated with prenatal alcohol exposure. Finally, no interaction was found between modality of presentation (verbal and nonverbal) and effects of alcohol exposure on memory performance. CONCLUSION: These findings indicate that prenatal alcohol exposure is associated with persistent and specific effects on memory performance, and these problems result from less efficient encoding of information across both verbal and nonverbal modalities. Education and training efforts with this clinical group should take these characteristics into account. PMID- 20201930 TI - Chronic alcohol consumption is associated with an increased cytotoxic profile of circulating lymphocytes that may be related with the development of liver injury. AB - BACKGROUND: Apoptosis has recently emerged as a key component of acute and chronic liver diseases and it could be related to alcoholic liver disease. In the present study, we attempted to analyze the cytotoxic profile of circulating lymphocytes in chronic alcoholic patients grouped according to ethanol intake status and presence of liver disease. METHODS: We investigate the phenotypic and functional behavior of different compartments of peripheral blood (PB) cytotoxic T and natural killer (NK) cells in chronic alcoholic patients without liver disease and active ethanol intake (AWLD group; n = 22), and in subjects with alcohol liver cirrhosis (ALC group; n = 22). RESULTS: AWLD patients showed an expansion of both CD4+/CD8+ cytotoxic T cells and NK/T cells, in association with an enhanced cytolytic activity against K562 cells and a higher ability to induce in vitro expression of the pro-apoptotic protein APO2.7 in HepG2 cells. Conversely, ethanol intake in ALC patients was associated with decreased NK cell numbers, a reduced cytotoxic activity against K562 cells without significant changes in the expression of APO2.7, and a pro-fibrotic profile of cytokine secretion. CONCLUSIONS: Overall, our results suggest that alcoholic patients display different phenotypical and functional changes in circulating PB cytotoxic lymphocytes according to the presence of alcoholic liver disease, which could be related to the development and progress of liver injury. PMID- 20201931 TI - Comparing structural equation models that use different measures of the level of response to alcohol. AB - BACKGROUND: The two measures of a low level of response (LR) to alcohol, an alcohol challenge and the retrospective Self-Report of the Effects of Alcohol questionnaire (SRE), each identify individuals at high risk for heavy drinking and alcohol problems. These measures also perform similarly in identifying subjects with unique functional brain imaging characteristics. However, few data are available regarding whether alcohol challenge-based and SRE-based LRs operate similarly in structural equation models (SEMs) that search for characteristics, which help to mediate how LR impacts alcohol outcomes. METHODS: Two hundred and ninety-four men from the San Diego Prospective Study were evaluated for their LR to alcohol using alcohol challenges at approximately age 20. At approximately age 35, the same subjects filled out the SRE regarding the number of drinks needed for effects 15 to 20 years earlier. The two different LR scores for these men were used in SEM analyses evaluating how LR relates to future heavy drinking and to drinking in peers (PEER), alcohol expectancies (EXPECT), and drinking to cope (COPE) as potential mediators of the LR to drinking pattern (ALCOUT) relationships. RESULTS: While the 2 LR measures that were determined 15 years apart related to each other at a modest level (r = 0.17, p < 0.01), the SEM results were similar regardless of the LR source. In both alcohol challenge-based and SRE-based LR models, LR related directly to ALCOUT, with partial mediation from PEER and COPE, but not through EXPECT in these 35-year-old men. CONCLUSIONS: Consistent with the >60% overlap in prediction of outcomes for the 2 LR measures, and with results from functional brain imaging, alcohol challenge- and SRE-based LR values operated similarly in SEM models in these men. PMID- 20201932 TI - Induction of innate immune gene expression cascades in brain slice cultures by ethanol: key role of NF-kappaB and proinflammatory cytokines. AB - BACKGROUND: Postmortem human alcoholic brain has increased expression of proinflammatory cytokines (He and Crews, 2007). Nuclear factor kappaB (NF-kappaB) is a transcription factor known to induce proinflammatory cytokine expression. Ethanol exposure increases NF-kappaB-DNA binding in rat brain (Crews et al., 2006) and in brain slice cultures in vitro (Zou and Crews, 2006). Using hippocampal-entorhinal cortex (HEC) brain slice cultures, we explored the effect of ethanol on NF-kappaB-DNA binding, proinflammatory gene expression, and sensitivity to glutamate neurotoxicity. METHODS: The HEC brain slice cultures are prepared from rats on P7 and used after 2 weeks in culture. NF-kappaB-DNA binding is determined by EMSA, NF-kappaB subunit-DNA binding by ELISA and mRNA by RT-PCR. Multiple antibody immunohistochemistry and confocal microscopy are used to characterize cell types expressing ethanol-induced genes. RESULTS: Ethanol treatment results in a progressive increase in NF-kappaB-DNA binding that includes large increases in NF-kappaB subunit p50 protein-DNA binding. The expression of NF-kappaB proinflammatory target genes progressively increased with time of ethanol treatment. Ethanol induces proinflammatory cytokines TNFalpha, MCP-1, and IL-1beta, proinflammatory proteases TACE, and tissue plasminogen activator (tPA) as well as inducible nitric oxide synthase. Blockade of NF-kappaB by using NF-kappaB p65 siRNA and BHT reduces ethanol induction of proinflammatory genes. Neutralizing antibody to proinflammatory cytokine TNFalpha reduces ethanol induction of proinflammatory genes, suggesting cytokine propagation of proinflammatory gene induction. Furthermore, neutralizing antibodies to proinflammatory cytokines and protease tPA inhibitors blunt ethanol sensitization to glutamate neurotoxicity. CONCLUSIONS: These findings indicate that ethanol treatment increases NF-kappaB-DNA binding and proinflammatory gene expression in brain slices. Ethanol-induced innate immune proinflammatory gene induction alters neurotransmission and likely contributes to alcoholic neurodegeneration. PMID- 20201934 TI - Assessing the severity of hazardous drinking and related consequences among incarcerated women. AB - BACKGROUND: Recent epidemiological efforts have demonstrated the utility of measuring individual differences in the severity of alcohol use along a single severity continuum marked by alcohol-related problems, symptoms of alcohol dependence, and the social consequences of drinking. Translation of this utility to specialized clinical populations is not assured. The expected inter relationships among problems, symptoms and consequences, and enhanced sensitivity of combined assessments require confirmation in applied clinical settings. METHOD: Subjects were 245 incarcerated women who met Alcohol Use Disorders Identification Test criteria for hazardous use of alcohol. Participants were recruited from a statewide adult correctional facility for an ongoing clinical trial testing the effectiveness of brief motivational interviewing on alcohol use and HIV risk behaviors. Participants ranged in age from 18 to 56 (M = 34.1, SD = 8.9), 71.4% were Caucasian, and 65.7% reported <12 years of education. RESULTS: Analyses suggested that the 6 problems of alcohol abuse, 7 symptoms for alcohol dependence, and 14 alcohol-related social consequences loaded to a single factor (0.38 to 0.85) that formed a continuum of alcohol severity. Contrary to epidemiological studies, physical fights and being arrested were the most prevalent consequences and were associated with lower alcohol severity in this population. Three of the five items that discriminated best between higher and lower alcohol severity were related to familial and relationship consequences. CONCLUSIONS: Consistent with epidemiological studies, alcohol severity can be measured among incarcerated hazardously drinking women on a single continuum that includes alcohol problems, symptoms, and social consequences. Replication of the expected alignment of problems and symptoms supports the construct validity of the continuum and further challenges the proposed hierarchical structure of abuse/dependence distinction. Large differences in rates of specific consequences and observed effectiveness of tailored social consequence items suggest the benefits of cross-sample validation to improve evaluation of clinical outcomes. PMID- 20201933 TI - Ethanol impairs activation of retinoic acid receptors in cerebellar granule cells in a rodent model of fetal alcohol spectrum disorders. AB - BACKGROUND: Ethanol is the main addictive and neurotoxic constituent of alcohol. Ethanol exposure during embryonic development causes dysfunction of the central nervous system (CNS) and leads to fetal alcohol spectrum disorders. The cerebellum is one of the CNS regions that are particularly vulnerable to ethanol toxic effects. Retinoic acid (RA) is a physiologically active metabolite of vitamin A that is locally synthesized in the cerebellum. Studies have shown that RA is required for neuronal development, but it remains unknown if ethanol impairs RA signaling and thus induces neuronal malformations. In this study, we tested the hypothesis that ethanol impairs the expression and activation of RA receptors in cerebellum and in cerebellar granule cells. METHODS: The cerebellum of ethanol unexposed and exposed pups was used to study the expression of retinoic acid receptors (RARs or RXRs) by immunohistochemistry and by Western blot analysis. We also studied the effect of ethanol on expression of RA receptors in the cerebellar granule cells. Activation of RA receptors (DNA binding activities) in response to high-dose ethanol was determined by electrophoretic mobility shift and supershift assays. RESULTS: Findings from these studies demonstrated that ethanol exposure reduced the expression of RARalpha/gamma while it increased the expression of RXRalpha/gamma in the cerebellum and in cerebellar granule neurons. Immuno-histological studies further strengthened the expression pattern of RA receptors in response to ethanol. The DNA-binding activity of RARs was reduced, while DNA-binding activity of RXRs was increased in response to ethanol exposure. CONCLUSION: For the first time, our studies have demonstrated that high-dose ethanol affects the expression and activation of RA receptors, which could impair the signaling events and induce harmful effects on the survival and differentiation of cerebellar granule cells. Taken together, these findings could provide insight into the treatment options for brain defects caused by excessive ethanol exposure, such as in Fetal Alcohol Spectrum Disorders. PMID- 20201935 TI - MAOA alters the effects of heavy drinking and childhood physical abuse on risk for severe impulsive acts of violence among alcoholic violent offenders. AB - BACKGROUND: A polymorphism in the promoter region of the monoamine oxidase A gene (MAOA) has been shown to alter the effect of persistent drinking and childhood maltreatment on the risk for violent and antisocial behaviors. These findings indicate that MAOA could contribute to inter-individual differences in stress resiliency. METHODS: Recidivism in severe violent crimes was assessed after 8 years of nonincarcerated follow-up in a male sample of 174 impulsive Finnish alcoholic violent offenders, the majority of whom exhibited antisocial (ASPD) or borderline personality disorder (BPD) or both. We examined whether MAOA genotype alters the effects of heavy drinking and childhood physical abuse (CPA) on the risk for committing impulsive recidivistic violent crimes. RESULTS: Logistic regression analyses showed that both heavy drinking and CPA were significant independent predictors of recidivism in violent behavior (OR 5.2, p = 0.004 and OR 5.3, p = 0.003) among offenders having the high MAOA activity genotype (MAOA H), but these predictors showed no effect among offenders carrying the low MAOA activity genotype (MAOA-L). CONCLUSION: Carriers of the MAOA-H allele have a high risk to commit severe recidivistic impulsive violent crimes after exposure to heavy drinking and CPA. PMID- 20201937 TI - Common susceptibility variants examined for association with dilated cardiomyopathy. AB - Rare mutations in more than 20 genes have been suggested to cause dilated cardiomyopathy (DCM), but explain only a small percentage of cases, mainly in familial forms. We hypothesised that more common variants may also play a role in increasing genetic susceptibility to DCM, similar to that observed in other common complex disorders. To test this hypothesis, we performed case-control analyses on all DNA polymorphic variation identified in a resequencing study of six candidate DCM genes (CSRP3, LDB3, MYH7, SCN5A, TCAP, and TNNT2) conducted in 289 unrelated white probands with DCM of unknown cause and 188 unrelated white controls. In univariate analyses, we identified associated common variants at LDB3 site 10779, LDB3 site 57877, MYH7 sites 16384 and 17404, and TCAP sites 140 and 1735. Multivariate analyses to examine the joint effects of multiple gene variants confirmed univariate results for MYH7 and TCAP and identified a block of nine variants in MYH7 that was strongly associated with DCM. Common variants in genes known to be causative of DCM may play a role in genetic susceptibility to DCM. Our results suggest that examination of common genetic variants may be warranted in future studies of DCM and other Mendelian-like disorders. PMID- 20201936 TI - GJB2 mutations in Mongolia: complex alleles, low frequency, and reduced fitness of the deaf. AB - We screened the GJB2 gene for mutations in 534 (108 multiplex and 426 simplex) probands with non-syndromic sensorineural deafness, who were ascertained through the only residential school for the deaf in Mongolia, and in 217 hearing controls. Twenty different alleles, including four novel changes, were identified. Biallelic GJB2 mutations were found in 4.5% of the deaf probands (8.3% in multiplex, 3.5% in simplex). The most common mutations were c.IVS1 + 1G > A (c.-3201G > A) and c.235delC with allele frequencies of 3.5% and 1.5%, respectively. The c.IVS1 + 1G > A mutation appears to have diverse origins based on associated multiple haplotypes. The p.V27I and p.E114G variants were frequently detected in both deaf probands and hearing controls. The p.E114G variant was always in cis with the p.V27I variant. Although in vitro experiments using Xenopus oocytes have suggested that p.[V27I;E114G] disturbs the gap junction function of Cx26, the equal distribution of this complex allele in both deaf probands and hearing controls makes it a less likely cause of profound congenital deafness. We found a lower frequency of assortative mating (37.5%) and decreased genetic fitness (62%) of the deaf in Mongolia as compared to the western populations, which provides an explanation for lower frequency of GJB2 deafness in Mongolia. PMID- 20201938 TI - Heritability of obesity-related phenotypes and association with adiponectin gene polymorphisms in the Chinese national twin registry. AB - The purpose of this study was to estimate the heritability of obesity-related phenotypes and investigate the association of adiponectin gene polymorphisms +45T>G and +276G>T with these measures in Chinese twins. 1260 twin pairs were recruited from two cities through the Chinese National Twin Registry System from 2001 to 2005. Two SNPs at the adiponectin locus (+45T>G and +276G>T) were genotyped. Structural equation modeling (SEM) was used to estimate heritability and the best-fitting variance component model. The regular association among all twins was analysed with generalised estimating equations (GEE). Sib transmission/disequilibrium test (TDT) within dizygotic (DZ) twin pairs discordant for their genotype was performed using SEM. Additive genetic, common and unique environmental (ACE) model-based heritability of body mass index (BMI) was 61%, while additive genetic and unique environmental (AE)-model-based heritability of waist circumference (WC) and waist-hip ratio (WHR) were 75% and 61%, respectively. There was no association of adiponectin gene +45T>G and +276G>T genotypes with obesity-related phenotypes in all twins or discordant DZ twins. Our twins data did not support that there was an association between adiponectin gene polymorphisms +45T>G and +276G>T and the obesity-related phenotypes. Further studies are required to better understand the role of adiponectin gene polymorphisms in obesity. PMID- 20201939 TI - Limited distribution of a cardiomyopathy-associated variant in India. AB - Heart failure is a leading cause of death of people in South Asia, and cardiomyopathy is a major cause of heart failure. Myosin binding protein C (MYBPC3) is expressed in the heart muscle, where it regulates the cardiac response to adrenergic stimulation and is important for the structural integrity of the sarcomere. Mutations in the MYBPC3 gene are associated with hypertrophic or dilated cardiomyopathies. A 25-base-pair deletion in intron 32 causes skipping of the downstream exon and is associated with familial cardiomyopathy. To date, this deletion is found primarily in India and South Asia, although it is also found at low frequency in Southeast Asia. In order to better characterise the distribution of this variant, we determined its frequency in 447 individuals from 19 populations, including 10 populations from India and neighbouring populations from Pakistan and Nepal. The deletion frequency is over 8% in some of our Indian samples, and it is not present in any of the populations we sampled outside of India. The differences in the deletion frequencies among populations in India are consistent with patterns of variation previously reported and with patterns we observed among Indian populations based on high-density SNP chip data. Our results indicate that the MYBPC3 deletion is primarily found among Indian populations and that its distribution is consistent with genome-wide patterns of variation in India. PMID- 20201940 TI - Unexpected detection of monoclonal B-cell lymphocytosis in a HLA-matched sibling donor on the day of allogeneic stem cell transplantation for a patient with chronic lymphocytic leukaemia: clinical outcome. PMID- 20201941 TI - The novel inhibitor of histone deacetylase resminostat (RAS2410) inhibits proliferation and induces apoptosis in multiple myeloma (MM) cells. AB - Inhibition of histone deacetylase (HDAC) is a promising mechanism for novel, anti myeloma agents. We investigated the effects of the novel HDAC inhibitor resminostat on multiple myeloma (MM) cells in vitro. Resminostat is a potent inhibitor of HDACs 1, 3 and 6 [50% inhibitory concentration (IC50)=43-72 nmol/l] representing HDAC classes I and II and induces hyperacetylation of histone H4 in MM cells. Low micromolar concentrations of resminostat abrogated cell growth and strongly induced apoptosis (IC50=2.5-3 micromol/l in 3 out of 4 MM cell lines) in MM cell lines as well as primary MM cells. At 1 micromol/l, resminostat inhibited proliferation and induced G0/G1 cell cycle arrest in 3 out of 4 MM cell lines accompanied with decreased levels of cyclin D1, cdc25a, Cdk4 and pRb as well as upregulation of p21. Resminostat decreased phosphorylation of 4E-BP1 and p70S6k indicating an interference with Akt pathway signalling. Treatment with resminostat resulted in increased protein levels of Bim and Bax and decreased levels of Bcl-xL. Caspases 3, 8 and 9 were activated by resminostat. Furthermore, synergistic effects were observed for combinations of resminostat with melphalan and the proteasome inhibitors bortezomib and S-2209. In conclusion, we have identified potent anti-myeloma activity for this novel HDAC inhibitor. PMID- 20201942 TI - Emergent T-helper 2 profile with high interleukin-6 levels correlates with the appearance of bortezomib-induced neuropathic pain. PMID- 20201943 TI - Reticulocytes and erythroid precursors in haemolysis vasculopathy. PMID- 20201944 TI - Stem cell transplantation after alemtuzumab in T-cell prolymphocytic leukaemia results in longer survival than after alemtuzumab alone: a multicentre retrospective study. PMID- 20201945 TI - Asparaginase-related venous thrombosis in UKALL 2003- re-exposure to asparaginase is feasible and safe. AB - We report the incidence and outcome of venous thrombosis (VT) in the UK acute lymphoblastic leukaemia (ALL) 2003 trial. VT occurred in 59/1824 (3.2%) patients recruited over 5 years with 90% occurring during a period of Asparagine depletion. Pegylated Escherichia Coli Asparaginase (Peg-ASP) 1000 units/m(2) was used throughout. Thirty-four children received further Peg-ASP, most with concurrent heparin prophylaxis. There were no episodes of bleeding or recurrent thrombosis. Optimal Asparagine depletion is central to success of modern regimes for treatment of ALL. This report confirms a significant risk of thrombosis with such therapy, but demonstrates that re-exposure to Asparaginase is feasible and safe. PMID- 20201946 TI - High immunohistochemical expression of p-AKT predicts inferior survival in patients with diffuse large B-cell lymphoma treated with immunochemotherapy. AB - Chemotherapy and rituximab (R) is current standard therapy in diffuse large B cell lymphoma (DLBCL), but a substantial proportion of patients still fail to reach sustained remission. In vitro studies have indicated that rituximab resistance could be accompanied by dysregulated apoptotic pathways, such as the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway, which can be constitutively activated in DLBCL. In this retrospective, immunohistochemical study on 106 patients treated with R-CHO(E)P (cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab [+etoposide]), we investigated the prognostic role of proteins involved in different apoptotic pathways; phosphorylated AKT (p AKT), bcl-2, MCL1, bcl-xL, Bax and Bak. High p-AKT expression (>108 cells/mm2, highest quartile, n=27) predicted worse progression-free (PFS) (P=0.02) and overall (OS) (P=0.01) survival, independent of International Prognostic Index and sex. Also bcl-2+ (cut-off 50%) predicted worse PFS (P=0.005) and OS (P=0.05) but after adjustment for clinical factors only the influence on PFS (P=0.03) remained significant. The prognostic impact of p-AKT overexpression was independent of bcl 2 status. MCL1, bcl-xL, Bax and Bak expression did not add any prognostic information. Our results suggest that high p-AKT expression predicts worse outcome, possibly indicating that inhibition of the activated PI3K/AKT pathway could be of clinical interest in DLBCL patients. In addition, bcl-2 status could have prognostic importance also in the era of immunochemotherapy. PMID- 20201947 TI - Review of phenotypic markers used in flow cytometric analysis of MGUS and MM, and applicability of flow cytometry in other plasma cell disorders. AB - Flow cytometric immunophenotyping is considered an indispensable tool for the diagnosis, classification and monitoring of disease in monoclonal gammopathies. The clinical sensitivity of flow cytometry is comparable with advanced molecular methods. Clinical application of flow cytometry in monoclonal gammopathies has various dimensions, such as differential diagnosis of malignant plasma cell disorder from reactive plasmacytosis, identifying the progression risk in monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic multiple myeloma (MM), and minimal residual disease detection. Flow cytometry based clonality assessment with immunophenotyping encourages and enables the most stringent method of diagnosis and follow-up. The objective of this review is to update the malignant plasma cells phenotypic profile of MGUS and MM. The most comprehensive antigens, such as CD19, CD27, CD28, CD45, CD56 and CD117, play a significant role in the characterization of normal and malignant plasma cells. Several research groups described the putative phenotype of myeloma cell progenitors, but no remarkable suggestion could be made because of disparity. This review also focuses on the association of malignant phenotypic markers and chromosomal aberrations that identify the specific prognostic features in monoclonal gammopathies. PMID- 20201949 TI - Final analysis of the UKLG LY02 trial comparing 6-8 cycles of CHOP with 3 cycles of CHOP followed by a BEAM autograft in patients <65 years with poor prognosis histologically aggressive NHL. AB - This trial involved 457 patients and sought to assess the value of early intensification with autologous transplantation in patients with poor prognosis histologically aggressive non-Hodgkin lymphoma (NHL) showing a response to initial CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy. Randomization was made at the time of diagnosis with 223 assigned to continuing CHOP and 234 to 3 cycles of CHOP followed by a BEAM (carmustine, etoposide, cytarabine, melphalan) autograft. Analysis was on an intention to treat basis. After the initial three cycles of CHOP 19% of the whole group were in complete response (CR) and 53% in partial remission (PR). At the end of treatment 86% of patients in the CHOP arm had responded with 58% in CR. In the high-dose therapy arm the overall response rate was 83% with 64% in CR (difference between arms not significant). The progression-free survival (PFS) and overall survival at 5 years for the continuing CHOP arm were 38% and 50% respectively, and for the autograft arm were 44% and 50% (differences not significant). Of the patients who attained CR and subsequently relapsed, there were no long-term survivors in the autograft recipients compared to 46% of the continuing CHOP recipients (P = 0.0008). In conclusion, no survival benefit was demonstrated for an early autograft in first response. PMID- 20201950 TI - Indirect markers for detecting growth hormone abuse by athletes. PMID- 20201951 TI - Mycophenolic acid trough level monitoring: relevance in acute and chronic graft versus host disease and its relation with albumin. AB - Mycophenolate mofetil (MMF) is used to treat acute and chronic graft versus host disease (GvHD). There is scant evidence in the literature about mycophenolic acid (MPA) trough level monitoring in GvHD. We therefore reviewed 32 patients treated with MMF for acute (n = 19) or chronic GvHD (n = 13). Twelve (63%) of 19 patients with acute GvHD and nine (69%) of 13 with chronic GvHD showed a good response. In all 21 patients who responded to MMF, their mean total MPA levels were therapeutic (1-3.5 mg/L), whereas five of 11 patients who did not respond had sub therapeutic mean MPA levels (p = 0.002). Sixteen (66%) of 24 steroid refractory or dependent patients responded to MMF. Associations between the mean total MPA level for each patient and the corresponding mean serum albumin concentration showed therapeutic mean total MPA levels for all 23 patients with mean albumin >= 31 g/L but sub-therapeutic mean total MPA levels in five of nine patients with mean albumin <31 g/L (p = 0.0006). In conclusion, MMF is efficacious in steroid refractory and dependent acute or chronic GvHD with statistically significant correlation between therapeutic plasma total MPA trough levels and clinical response. Serum albumin levels should be taken into account when considering MMF dose adjustments. PMID- 20201952 TI - Short-term kidney transplant outcomes among African American recipients do not predict long-term outcomes: donor pair analysis. AB - African American (AA) renal transplant recipients have poorer graft survival compared to other racial and ethic groups. This study was undertaken to determine whether pre-transplant factors and events occurring in the first six months post transplant were predictive of the poorer long-term outcomes in AA recipients. To control for kidney quality, a paired analysis of deceased donor kidneys in which one donor kidney was transplanted into an adult AA recipient and the other was transplanted into an adult Caucasian was undertaken. Cox proportional hazard modeling was used to determine the impact of outcome variables at six months. Outcomes at six months among the paired recipients were very similar for graft and patient survival, and estimated glomerular filtration rate (GFR). Less than 10% of difference in long-term outcomes was explained by differences in the pre transplant covariates and events in the first six months. Causes of graft failure after six months revealed a two to three times higher rate of chronic allograft nephropathy (CAN) and late acute rejection among AA. In conclusion, early outcomes after kidney transplant did not predict the poor long-term graft survival among AA, and AA recipients appear to be more prone to graft loss because of CAN and late acute rejection. PMID- 20201948 TI - Advances in the understanding of haemoglobin switching. AB - The study of haemoglobin switching has represented a focus in haematology due in large part to the clinical relevance of the fetal to adult haemoglobin switch for developing targeted approaches to ameliorate the severity of the beta haemoglobinopathies. Additionally, the process by which this switch occurs represents an important paradigm for developmental gene regulation. In this review, we provide an overview of both the embryonic primitive to definitive switch in haemoglobin expression, as well as the fetal to adult switch that is unique to humans and old world monkeys. We discuss the nature of these switches and models of their regulation. The factors that have been suggested to regulate this process are then discussed. With the increased understanding and discovery of molecular regulators of haemoglobin switching, such as BCL11A, new avenues of research may lead ultimately to novel therapeutic, mechanism-based approaches to fetal haemoglobin reactivation in patients. PMID- 20201954 TI - "Transcription physiology" of pigment formation in melanocytes: central role of MITF. AB - Melanin production is the primary mechanism protecting human skin against the UV light-induced damage. The polymeric compound melanin is synthesized within melanocytes in the specialized subcellular organelles, termed melanosomes, which are then transferred to surrounding keratinocytes. The genes for melanin synthesis and deposition are coordinately expressed in melanocytes. The transcription factor MITF, which has been reported to activate more than 25 genes in pigment cells, has emerged as an essential regulator not only for melanocyte development, proliferation and survival, but also for the expression of enzymes and structural proteins ensuring the production of melanin. MITF is a transcriptional activator of several genes which encode melanosome-localized proteins involved both in melanin synthesis and in melanosome biogenesis and transport, including genes whose mutations are associated with human oculocutaneous and ocular forms of albinism. Here, we outline the mechanisms of transcriptional regulation of genes associated with the biosynthesis of melanin in melanocytes and melanoma cells. MITF is crucial in this process, while several other factors seem to have only an auxiliary role to play under specific circumstances. PMID- 20201955 TI - Exploration of the functional hierarchy of the basal layer of human epidermis at the single-cell level using parallel clonal microcultures of keratinocytes. AB - The basal layer of human epidermis contains both stem cells and keratinocyte progenitors. Because of this cellular heterogeneity, the development of methods suitable for investigations at a clonal level is dramatically needed. Here, we describe a new method that allows multi-parallel clonal cultures of basal keratinocytes. Immediately after extraction from tissue samples, cells are sorted by flow cytometry based on their high integrin-alpha 6 expression and plated individually in microculture wells. This automated cell deposition process enables large-scale characterization of primary clonogenic capacities. The resulting clonal growth profile provided a precise assessment of basal keratinocyte hierarchy, as the size distribution of 14-day-old clones ranged from abortive to highly proliferative clones containing 1.7 x 10(5) keratinocytes (17.4 cell doublings). Importantly, these 14-day-old primary clones could be used to generate three-dimensional reconstructed epidermis with the progeny of a single cell. In long-term cultures, a fraction of highly proliferative clones could sustain extensive expansion of >100 population doublings over 14 weeks and exhibited long-term epidermis reconstruction potency, thus fulfilling candidate stem cell functional criteria. In summary, parallel clonal microcultures provide a relevant model for single-cell studies on interfollicular keratinocytes, which could be also used in other epithelial models, including hair follicle and cornea. The data obtained using this system support the hierarchical model of basal keratinocyte organization in human interfollicular epidermis. PMID- 20201953 TI - Akt inhibition up-regulates MMP1 through a CCN2-dependent pathway in human dermal fibroblasts. AB - Akt is a key signalling molecule that was found to be down-regulated in chronic wounds. Akt blockade has dual antifibrotic effects in human dermal fibroblasts, by up-regulating matrix metalloproteinase 1 (MMP1) and down-regulating collagen gene expression (J Invest Dermatol 2008: 128: 1906). The aim of this study was to gain additional insights into the mechanism of MMP1 up-regulation following Akt blockade. As previous studies showed that CCN2 can be a positive regulator of MMP1, we examined the effects of Akt inhibition on CCN2 expression. Akt blockade using a specific pharmacological inhibitor and Akt siRNA resulted in a significant up-regulation of CCN2, which correlated with the increase in MMP1. The MMP1 up-regulation following Akt blockade was partially suppressed by CCN2 siRNA, suggesting that CCN2 is contributing to this effect. Additional experiments showed that CCN2 induces phosphorylation of ERK1/2, Ets1 and c-Jun. Consistent with the stimulatory role of ERK1/2/Ets1 in the expression of MMP1, the ERK1/2 inhibitor UO126 prevented the phosphorylation of ERK1/2 and Ets1 and completely abrogated the induction of MMP1 after CCN2 overexpression, while having no effect on c-Jun activation. Taken together these results establish CCN2 as a key regulator of MMP1 induction via activation of the ERK1/2/Ets1 pathway. Down-regulation of Akt signalling leads to inappropriate activation of the CCN2/MMP1 pathway that may contribute to the pathogenesis of chronic wounds. Coordinate expression of CCN2, Akt and MMP1 could be important for normal wound healing to occur. Thus, targeting these specific proteins may represent a promising approach to the therapy of dysregulated wound healing. PMID- 20201956 TI - Confirmation of a disease model of pemphigus vulgaris: characterization and correlation between disease parameters in 90 mice. AB - Pemphigus vulgaris (PV) is a chronic autoimmune bullous disease associated with immunoglobulin G (IgG) autoantibodies against desmoglein 3 (Dsg3). Previously, a mouse model of PV was established by adoptive transfer of naive splenocytes from Dsg3(-/-) mice to Rag2(-/-) mice. The model is unique as Dsg3-specific naive lymphocytes from Dsg3(-/-) mice can be primed and activated by the endogenous Dsg3 in recipient mice, resulting in pathogenic anti-Dsg3 IgG without any active immunization. Here, we show that PV occurs after both intravenous (i.v.) and intraperitoneal (i.p.) transfer of naive splenocytes. We evaluated the robustness of the model by comparing engraftment as well as PV phenotype using several disease parameters. While engraftment of spleen cells was significantly better after i.p. transfer, anti-Dsg3 IgG antibody production, IgG deposition and disease score were comparable after both i.v. and i.p. cell transfer. Thus, transferred cells can be primed, activated and gain effector function. However, we detected heterogeneity in disease development, as only 46% of the mice developed hair loss, whereas 76% of the mice developed anti-Dsg3 IgG. We also tested cyclophosphamide in the model, as this drug is reported to be beneficial to PV patients. Cyclophosphamide significantly inhibited disease development in a preventive setting, and mice were free of symptoms 35 days after discontinuing the treatment. We have successfully confirmed the induction of PV after both i.v. and i.p. transfer. In addition, we have shown that this model can be used for evaluation of immunosuppressive drugs. PMID- 20201957 TI - Anti-inflammatory effects of the GABA(B) receptor agonist baclofen in allergic contact dermatitis. AB - The gamma amino butyric acid B (GABA(B)) receptor is a G protein-coupled receptor (GPCR) involved in synaptic transmission. Recent data indicate it to be also expressed on immune cells, along with chemokine receptors, which are also GPCRs. As GPCRs can undergo heterologous desensitization, we have examined the ability of baclofen, a GABA(B) receptor selective agonist, to interfere with the function of pro-inflammatory chemokine receptors known to be upregulated in cutaneous inflammation. In vitro, baclofen reduces chemotaxis of human peripheral blood mononuclear cells towards CCL2, CCL5, CXCL10, CXCL2 and CX3CL1 in a dose dependant manner. Protein kinase C inhibitors calphostin C and G0 6976 could reverse this effect, pointing towards the involvement of both calcium-dependent and -independent protein kinase C in baclofen-induced inhibition of chemokine receptors. In an in vivo model of contact hypersensitivity in C57BL/6 mice, intraperitoneal injection of baclofen markedly alleviated signs of inflammation as well as recruitment of neutrophils, monocytes and lymphocytes into the skin. This study demonstrates a new role for the GABA(B) receptor in inflammation, making it a potential new therapeutic target to treat inflammatory skin diseases. PMID- 20201958 TI - The mouse frizzy (fr) and rat 'hairless' (frCR) mutations are natural variants of protease serine S1 family member 8 (Prss8). AB - Please cite this paper as: The mouse frizzy (fr) and rat 'hairless' (fr(CR)) mutations are natural variants of protease serine S1 family member 8 (Prss8). Experimental Dermatology 2010; 19: 527-532. Abstract: We have previously suggested (based on genetic mapping analysis) that the allelic 'fuzzy' and 'hairless' mutations in the rat are likely orthologues of the mouse frizzy mutation (fr). Here, we analysed three large intraspecific backcross panels that segregated for mouse fr to restrict this locus to a 0.6-Mb region that includes fewer than 30 genes. DNA sequencing of one of these candidates known to be expressed in skin, protease serine S1 family member 8 (Prss8), revealed a T to A transversion associated with the fr allele that would result in a valine to aspartate substitution at residue 170 in the gene product. To test whether this missense mutation might be the molecular basis of this frizzy variant, we crossed fr/fr mice with mice that carried a recessive perinatal lethal mutation in Prss8. Hybrid offspring that inherited both fr and the Prss8 null allele displayed abnormal hair and skin, showing that these two mutations are allelic, and suggesting strongly that the T to A mutation in Prss8 is responsible for the mutant frizzy phenotype. Sequence analysis of all Prss8 coding regions in the 'hairless' rat identified a 12-bp deletion in the third exon, indicating that mouse fr and the rat 'hairless' mutations are indeed orthologues. However, this analysis failed to detect any alterations to Prss8 coding sequences in the allelic 'fuzzy' rat variant. PMID- 20201959 TI - Effectiveness of cross polarized light and fluorescence diagnosis for detection of sub-clinical and clinical actinic keratosis during imiquimod treatment. AB - BACKGROUND: During treatment of actinic keratosis (AK) lesions with imiquimod sub clinical lesions often become visible. It is, however, unclear whether these sub clinical lesions would be detectable beforehand. OBJECTIVE: The aim of this pilot study was to compare two techniques, cross polarized light photography (CPL) and fluorescence diagnosis (FD) using methyllevulinic acid and illumination with Wood's lamp for their ability to detect sub-clinical lesions. These findings were also compared with biopsy results taken before and after treatment with imiquimod 5% cream or vehicle. METHODOLOGY: Twelve patients with at least five clinically visible AK lesions in a single contiguous 20 cm(2) area on the head were recruited. Patient eligibility was determined at the screening visit, when they were randomized to treatment. The randomization was 3:1, active to vehicle (nine treated with imiquimod, three with vehicle cream) for a total duration of 24 weeks (six clinic visits). Patients were assessed for baseline AK lesion counts (clinical and sub-clinical) at the screening visit and final counts at week 20. RESULTS: The number of clinically observed AK lesions was significantly lower at week 12 and week 20 compared with baseline following imiquimod treatment versus vehicle. The number of counted lesions were significantly higher using the CPL method compared with clinical counting with imiquimod treatment at baseline (8.3 +/- 3.4 vs 5.8 +/- 1.3; P = 0.027) and week 20 (4.8 +/- 2.4 vs 3.0 +/- 1.7; P = 0.02) but not in the vehicle group. The FD lesion counting method did not show a significant increase in the number of detected lesions compared with clinical analysis in the imiquimod and placebo groups but when comparisons were performed using pooled data (treatments and visits combined) the results were significant. CONCLUSION: The number of sub-clinical and clinical AK lesions detected during treatment with imiquimod can be better demonstrated using the methods of CPL and FD, but statistical significance was reached only using the CPL method. This is only a preliminary study with a small number of patients and as a result it is difficult to conclude both statistical and clinical significance. However, results were encouraging and indicate that larger studies are needed to demonstrate the relevance of these two new methods for improved detection of clinical and especially sub-clinical AK lesions. PMID- 20201960 TI - Enzymes involved in the conversion of arachidonic acid to eicosanoids in the skin of atopic dogs. AB - Canine atopic dermatitis (AD), a chronic inflammatory skin disease, shares characteristics with its human counterpart. To get insight into the role of enzymes involved in production of prostaglandin E(2) (PGE2) and leukotriene B(4) (LTB(4)), potent inflammatory mediators originating from membrane-derived arachidonic acid (AA), expression of genes encoding these enzymes and receptors was quantified by qPCR in non-lesional and lesional skin from atopic dogs and in healthy skin. Significantly higher mRNA expression of the key enzymes 5 lipoxygenase (5-LO), 5-LO activating protein (FLAP), leukotriene A(4) hydrolase (LTA(4)H) and prostaglandin E synthase 1 (mPGES-1) and their receptors (PGE receptors 2 and 3) were observed. Being responsible for elevated levels of metabolites of the 3-series prostaglandins and the 5-series leukotrienes these enzymes may be interesting targets for therapy that should result in amelioration of clinical signs in canine atopic dermatitis. PMID- 20201961 TI - Reproducible pattern of microRNA in normal human skin. AB - MicroRNAs (miRNAs) regulate cell growth, differentiation and apoptosis via specific targeting of messenger RNA (mRNA). Aberrant mRNA expression contributes to pathological processes such as carcinogenesis. To take advantage of miRNA profiling in skin disease it is essential to investigate miRNA expression pattern in normal human skin. Here we investigated miRNA expression profiles from skin biopsies of 8 healthy volunteers taken from sun protected and mildly photo damaged skin using the modified protocol for miRNA extraction. We were able to show a constant pattern of miRNA expression between different individuals. We did not find any significant differences in miRNA expression between sun protected and mildly photodamaged skin. These results may be valuable for future design of studies on miRNA expression in skin disease. PMID- 20201962 TI - Pseudoaneurysm in association with a knee endoprothesis operation in an inhibitor positive haemophilia A patient - treatment with local thrombin. PMID- 20201963 TI - Birth defects caused by mutations in human GLI3 and mouse Gli3 genes. AB - ABSTRACT GLI3 is the gene responsible for Greig cephalopolysyndactyly syndrome (GCPS), Pallister-Hall syndrome (PHS) and Postaxial polydactyly type-A (PAP-A). Genetic polydactyly mice such as Pdn/Pdn (Polydactyly Nagoya), Xt(H)/Xt(H) (Extra toes) and Xt(J)/Xt(J) (Extra toes Jackson) are the mouse homolog of GCPS, and Gli3(tmlUrtt)/Gli3(tmlUrt) is produced as the mouse homolog of PHS. In the present review, relationships between mutation points of GLI3 and Gli3, and resulting phenotypes in humans and mice are described. It has been confirmed that mutation in the upstream or within the zinc finger domain of the GLI3 gene induces GCPS; that in the post-zinc finger region including the protease cleavage site induces PHS; and that in the downstream of the GLI3 gene induces PAP-A. A mimicking phenomenon was observed in the mouse homolog. Therefore, human GLI3 and mouse Gli3 genes have a common structure, and it is suggested here that mutations in the same functional regions produce similar phenotypes in human and mice. The most important issue might be that GCPS and PHS exhibit an autosomal dominant trait, but mouse homologs, such as Pdn/Pdn, Xt(H)/Xt(H), Xt(J)/Xt(J) and Gli3(tmlUrt)/Gli3(tmlUrt), are autosomal recessive traits in the manifestation of similar phenotypes to human diseases. It is discussed here how the reduced amounts of the GLI3 protein, or truncated mutant GLI3 protein, disrupt development of the limbs, head and face. PMID- 20201964 TI - No association between severe constipation with related drug treatment in pregnant women and congenital abnormalities in their offspring: A population based case-control study. AB - Constipation is a common pathological condition in pregnant women; nevertheless, its possible association with structural birth defects (i.e. congenital abnormalities [CA]) in their offspring has not been studied in controlled epidemiological studies. We evaluated the possible association between severe constipation with laxative treatment in pregnant women and congenital abnormalities in their offspring. The dataset of the population-based Hungarian Case-Control Surveillance System of Congenital Abnormalities (HCCSCA) 1980-1996 contained 22 843 cases with CA and 38 151 matched controls without CA. Only pregnant women with prospectively and medically recorded constipation were included in the study and 13 CA groups were compared in cases and all their matched controls. A total of 78 (0.34%) cases had mothers with severe constipation and treatment during pregnancy compared to 144 (0.38%) controls (adjusted OR with 95% CI = 1.0, 0.7-1.3). Specified groups of CA were also assessed versus controls, but a higher occurrence of pregnant women with severe constipation and related treatment was not found in any CA group. Among laxative drugs, senna has no teratogenic potential; thus, if severe constipation requires laxative drug treatment in pregnant women, senna is not contraindicated. A higher rate of CA was not found in the offspring of pregnant women with severe constipation and related senna treatment. PMID- 20201965 TI - Biochemical alterations in the palatal processes in fetuses of biotin-deficient mice. AB - To clarify the role of biotin in palatal formation, we investigated the effects of biotin deficiency on the development of palatal processes in mouse fetuses at midgestation. We also investigated protein expressions in the palatal processes. Pregnant mice were given either a biotin-deficient diet or a biotin-supplemented (control) diet from day 0 of gestation (dg 0). Some dams in the biotin-deficient group were changed to a biotin-supplemented diet on dg 12, 13 or 14. On dg 15, the palatal processes were dissected from these fetuses and their peptides were characterized using two-dimensional electrophoresis and liquid chromatography/tandem mass spectrometry (LC-MS/MS) system. Regarding Trasler's stage for the growth of the palatal processes in mouse fetuses on dg 15, the average stage of palatal development was 5.83 +/- 0.39 in the biotin-supplemented group, 5.39 +/- 0.66 in the dg 13-supplemented group, and 4.64 +/- 0.90 in the biotin-deficient group. The development of the palatal processes significantly increased in relation to the earlier day of biotin supplementation. In a protein analysis of palatal processes by isoelectro focusing (IEF) and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), a 19-kDa spot was confirmed around position at pI 6-7 in the biotin-supplemented group, but this protein was not present in either the biotin-deficient group or the dg 13 supplemented group. From the MS/MS database of peptides, adenosine diphosphate (ADP)-ribosylation factor 2 (arf2) and alpha-crystallin were detected in the mesenchyme of the palatal processes. It is suggested that the expression of these proteins may be downregulated by biotin deficiency, inducing the inhibited development of palatal processes. PMID- 20201966 TI - Gender-dependent differences in the incidence of ochratoxin A-induced neural tube defects in the Pdn/Pdn mouse. AB - Genetic polydactyly/arhinencephaly mouse embryo, Pdn/Pdn, exhibits suppression of Gli3 gene expression. Ochratoxin A (OTA) is a teratogen that causes neural tube defects (NTD) in mice. We investigated gender-dependent differences in the incidence of NTD induced by OTA in the Pdn/Pdn mouse. After administering 2 mg/kg OTA to Pdn/+ female mice, mated with Pdn/+ males, on day 7.5 of gestation, we examined the genotypes, sex and NTD of fetuses on day 18. Non-treated Pdn/Pdn had a 15.8% risk of NTD, and all NTD fetuses were female. When Pdn/Pdn embryos were exposed to OTA, the incidence of NTD increased to 16 (51.6%) of 31 Pdn/Pdn fetuses, and 10 (71.4%) of 14 male Pdn/Pdn fetuses exhibited NTD. From these results, it was speculated that NTD in OTA-treated male Pdn/Pdn were due to the synergistic effect between depressed Gli3 and altered sex-correlated gene expression from OTA treatment. After treatment with OTA, the embryos were recovered on day 9 and gene expressions, which were correlated with Gli3, telencephalic morphogenesis, formation of gonadal anlage, and gender-dependent differentiation were investigated. From real-time polymerase chain reaction analysis results, it was suggested that the manifestation of NTD in the male OTA treated Pdn/Pdn might be due to the complicated altered gene expressions among Gli3, Wnt7b, Wnt8b, Fez1, Barx1, Lim1, Dmrt1, Igf1, Fog2, Dax1 and Sox9, and in particular, upregulation and gender-dependent difference in Barx1 and gender dependent difference in Sox9 gene expressions might be noteworthy findings. PMID- 20201967 TI - Global gene profiling and comprehensive bioinformatics analysis of a 46,XY female with pericentric inversion of the Y chromosome. AB - XY females are rare individuals who carry a Y chromosome but are phenotypically female. In approximately 80-90% of these cases, there are no mutations in the SRY gene, a testis-determining gene on the short arm of the Y chromosome, and the pathophysiology of XY females without SRY mutation remains unclear. In the present study, we used a molecular data mining technique to analyze the pathophysiology of an XY female with functional SRY and pericentric inversion of the Y chromosome, and compared the results with those of a normal male. Interestingly, upregulations of numerous genes included in the development category of the Biological Process ontology, including genes associated with sex determination and organ morphogenesis, were seen in the patient. Additionally, the transforming growth factor-beta (TGF-beta) signaling pathway and Wnt signaling pathway, in which most cell-cell interactions during embryonic development are involved, were altered. Alterations in the expression of numerous genes at the developmental stage, including alterations at both the gene and pathway levels, may persist as a vestige of anomalies of sex differentiation that presumably began in the fetal period. The present study indicates that a data mining technique using bioinformatics contributes to identification of not only genes responsible for birth defects, but also disorders of sex development (DSD) specific pathways, and that this kind of analysis is an important tool for clarifying the pathophysiology of human idiopathic XY gonadal dysgenesis. Our findings could serve as one of the basic datasets which will be used for future follow-up investigations. PMID- 20201968 TI - New method for detecting antiandrogenic effects through the measurement of external genitalia in rabbits. AB - The aim of the present study was to develop a quantitative evaluation method for detecting antiandrogenic activity of chemicals in rabbits that are regularly used for developmental toxicity studies. Kbl: New Zealand White rabbits (n = 8-9) were injected intramuscularly with an antiandrogen, cyproterone acetate (CA; 10 mg/kg body weight [BW]/day), on gestation days (GD) 13-24. On GD 29, live fetuses were obtained by cesarean section and sexed by examination of the internal genitalia. The external genitalia were evaluated in cross-section measurements of the phallus by both diameter and width of the ventral gap of the preputial lamella with a micrometer under a stereoscopic microscope. The diameters of the preputial lamella were 1015 +/- 83.5, 856 +/- 64.0, and 865 +/- 72.6 microm in control males, control females, and CA-treated males, respectively. The ventral gaps of the preputial lamella were 26 +/- 8.2, 437 +/- 72.3, and 318 +/- 59.4 microm in the control males, control females, and CA-treated males, respectively. There were statistically significant differences in both parameters between control males and control females or CA-treated males. The lower fetal BW in CA-treated males did not disturb the detection of the feminization of the ventral gap of the preputial lamella; however, the diameter of the preputial lamella might be influenced by fetal BW because no difference in the relative diameter of the preputial lamella was found between control males and CA-treated males. These results demonstrated that this approach could detect the antiandrogen activity of CA quantitatively by feminization of male external genitalia in rabbit fetuses. PMID- 20201969 TI - Improved learning in microencephalic rats. AB - ABSTRACT Environmental enrichment (EE) facilitates recovery from behavioral abnormalities and spatial memory disabilities in several neurological disease models. Exposure to EE improves spatial memory acquisition and enhances the survival of newly generated cells in the dentate gyri of adult rodents. However, the effects of EE on spatial learning and neurogenesis in the methylazoxymethanol acetate-induced microencephalic rat have not been investigated. Depletion of serotonin in the rat hippocampus is known to influence spatial memory and adult neurogenesis, suggesting a role for serotonin in these processes. To confirm this hypothesis, male methylazoxymethanol acetate-induced microencephalic rats were exposed to EE or conventional housing after weaning; half of these rats further received intracisternal 5,7-dihydroxytryptamine on postnatal day 3, to induce long-lasting depletion of serotonin. As adults, these microencephalic rats were observed using the Morris water maze test and examined for hippocampal neurogenesis. EE alleviated the impairment of spatial memory acquisition and enhanced neurogenesis in the dentate gyri of adult microencephalic rats. Injection of 5,7-dihydroxytryptamine during the neonatal period caused pronounced reductions in hippocampal serotonin levels in these rats. Long-lasting depletion of serotonin eliminated the EE-induced alleviation of spatial memory acquisition and neurogenesis impairment in microencephalic rats. The present results suggest that EE alleviates spatial memory performance deficits in microencephalic rats and further indicate that serotonin might be involved in the underlying mechanisms through increased hippocampal neurogenesis. These data provide new insights into therapeutic interventions for individuals with human migration disorders associated with learning disabilities. PMID- 20201970 TI - Congenital polymicrogyria including the perisylvian region in early childhood. AB - Six pediatric cases including four infants with congenital polymicrogyria including the perisylvian region are presented herein. Their clinical features were analyzed and compared with patients suffering from congenital bilateral perisylvian syndrome (CBPS). Two specific abnormalities were diagnosed as accompanying disorders in two cases, namely Kabuki syndrome and Peters' anomaly. In the other four cases, the pathogenetic etiology was not elucidated. Subtle symptoms, such as choking and drooling became detectable in one case each, and expressive language development was delayed in two patients. A developmental delay became apparent in five cases during the follow-up period, and epilepsy was observed in one patient with onset at 12 years of age. Our results indicate that the presence of perisylvian polymicrogyria may not always result in the development of oropharyngoglossal dysfunction or dysarthria, although most patients tend to gradually show the onset of developmental disorders. To support cognitive and psychosocial development, an early integrated approach, including not only conventional speech and language therapy, but also various communication methods is essential for patients with congenital polymicrogyria including the perisylvian region. PMID- 20201971 TI - Longstanding malformation of right sided pinna in an elderly man. AB - The pinna is the second most common site for external ear vascular malformation in the head and neck. These malformations are relatively uncommon in adults and can pose difficult therapeutic challenges. We hereby present a case of a 69-year old man with a congenital lesion in the right pinna consistent with an arteriovenous malformation. The lesion was complicated by ulceration and bleeding for 6 months prior to presentation. Resection of pinna was carried out, and satisfactory functional and esthetic results were obtained. There was no recurrence at 22 months of regular follow up. PMID- 20201972 TI - Bilateral absence of patella. AB - A 20-year-old man with bilateral absence of patella, thinness of the left femoral neck, femoral and tibial shaft was reported. This clinical presentation has not been reported in the English language literature. We propose that the unusual association observed in our patient may represent a distinguishing clinical presentation from previously reported aplastic patella syndromes. PMID- 20201973 TI - Fetal Eagle-Barrett syndrome and pulmonary atresia with intact ventricular septum. PMID- 20201974 TI - To what extent do children with cerebral palsy participate in everyday life situations? AB - The aims of the study are to describe participation of children with cerebral palsy in everyday life situations, to investigate the relationship between participation (primary outcome variable) with child and parent characteristics (independent variables) and to compare the frequency of participation (secondary outcome variable) of children with cerebral palsy with children without disabilities. A cross-sectional survey of parents of children with cerebral palsy in Northern Ireland was undertaken in families' homes using standard questionnaires. Children with cerebral palsy born between 31/8/1991 and 1/4/1997 were identified from a case register of people with the condition. A total of 102 parents opted in (51% response rate). Questionnaires included the Life Habits Questionnaire (Life-H) to measure difficulties in participation and The Frequency of Participation Questionnaire (FPQ), to measure frequency of participation with comparative data for children without disability. Overall, children with cerebral palsy participated less often than their non-disabled peers across a number of lifestyle and cultural pursuits. Among the 102 children with cerebral palsy, participation in 'relationships' was the least disrupted area of everyday life and aspects of 'school', 'personal care' and 'mobility' were the most disrupted. Children with cerebral palsy and severe co-impairments were significantly less likely to experience higher levels of participation in most areas of everyday life when compared to children with cerebral palsy and no severe co-impairments. Child physical and psychological well-being did not influence participation although higher parenting stress was significantly related to lower child participation in 'community activities'. Participation is an important health outcome for children with cerebral palsy and should be incorporated in routine clinical practice. Professionals have a role to play both at the level of addressing individual child and family needs as well as influencing legislation and policy to ensure improved access to services and local communities. PMID- 20201976 TI - Sexually transmitted infections and infectiousness beliefs among people living with HIV/AIDS: implications for HIV treatment as prevention. AB - OBJECTIVES: Sexually transmitted infections (STIs) significantly impact the health of people living with HIV/AIDS, increasing HIV infectiousness and therefore transmissibility. The current study examined STIs in a community sample of 490 HIV-positive men and women. METHODS: Assessments were performed using confidential computerized interviews in a community research setting. RESULTS: Fourteen per cent of the people living with HIV/AIDS in this study had been diagnosed with a new STI in a 6-month period. Individuals with a new STI had significantly more sexual partners in that time period, including non-HIV positive partners. Participants who had contracted an STI were significantly more likely to have detectable viral loads and were less likely to know their viral load than participants who did not contract an STI. Multivariate analysis showed that believing an undetectable viral load leads to lower infectiousness was associated with contracting a new STI. CONCLUSIONS: Individuals who believed that having an undetectable viral load reduces HIV transmission risks were more likely to be infectious because of STI coinfection. Programmes that aim to use HIV treatment for HIV prevention must address infectiousness beliefs and aggressively control STIs among people living with HIV/AIDS. PMID- 20201978 TI - Two novel Salp15-like immunosuppressant genes from salivary glands of Ixodes persulcatus Schulze tick. AB - Salp15, a 15-kDa tick salivary gland protein, is known for several suppressive activities against host immunity and critical functions for the transmission of Lyme borrelia in Ixodes scapularis and Ixodes ricinus, the major vectors found in North America and Western Europe. Salp15 inhibits the activation of cluster of differentiation (CD)4(+)T-cells through the repression of T-cell receptor (TCR) triggered calcium fluxes and interleukin (IL)-2 production. Furthermore, Salp15 adheres to the spirochaeta and specifically interacts with its outer surface protein C. The binding of Salp15 to Borrelia burgdorferi protects it from antibody-mediated killing in vitro. The aim of this study is to identify the Salp15 genes in Ixodes persulcatus Schulze, the specific vector for human Lyme borreliosis in Japan. Two cDNA clones encoding the Salp15-like sequence were obtained from salivary glands of fed female ticks. These genes encode 135- and 132-amino acid proteins, designated Salp15 Iper-1 and Salp15 Iper-2, respectively, both having signal peptide sequences and predicted to be secretory proteins. Salp15 Iper-1 and -2 showed 51.8 and 68.2% similarity to I. scapularis Salp15, respectively. Reverse transcriptase PCR analysis showed that Salp15 Iper genes were expressed specifically in the salivary glands throughout life cycle stages of the ticks and were up-regulated by blood feeding. In the I. persulcatus derived sequences, the C-terminal part, which is the binding domain to the CD4 molecule of T-cells in I. scapularis Salp15, was well conserved. In the future, it will be necessary to analyse immunosuppressive functions of I. persulcatus Salp15 and their interaction with Borrelia spp. in Japan. PMID- 20201977 TI - T-cell exhaustion: characteristics, causes and conversion. AB - T-cell exhaustion is characterized by the stepwise and progressive loss of T-cell functions and can culminate in the physical deletion of the responding cells. Exhaustion is well-defined during chronic lymphocytic choriomeningitis virus infection and commonly develops under conditions of antigen-persistence, which occur following many chronic infections that are of significant public health concern including hepatitis B virus, hepatitis C virus and human immunodeficiency virus infections, as well as during tumour outgrowth. Exhaustion is not a uniformly disabled setting as a gradation of phenotypic and functional defects can manifest, and these cells are distinct from prototypic effector, memory and also anergic T cells. We are gaining insights into the extrinsic and intrinsic factors that determine the severity of exhaustion. These include the duration and magnitude of antigenic activation, availability of CD4 T-cell help, the levels of stimulatory and suppressive cytokines, as well as the expression of activatory and inhibitory receptors. More information is now becoming available regarding the molecular mechanisms that attenuate the responsiveness of exhausted T cells. As the parameters that dictate exhaustion are more thoroughly defined, this is fostering the development of methods that prevent and rejuvenate functionally inferior responses. In this article we discuss our current understanding of the properties of exhausted T cells and the mechanisms that promote and maintain this state. PMID- 20201975 TI - History of viral suppression on combination antiretroviral therapy as a predictor of virological failure after a treatment change. AB - OBJECTIVES: HIV-infected persons experience different patterns of viral suppression after initiating combination antiretroviral therapy (cART). The relationship between such differences and risk of virological failure after starting a new antiretroviral could help with patient monitoring strategies. METHODS: A total of 1827 patients on cART starting at least one new antiretroviral from 1 January 2000 while maintaining a suppressed viral load were included in the analysis. Poisson regression analysis identified factors predictive of virological failure after baseline in addition to traditional demographic variables. Baseline was defined as the date of starting new antiretrovirals. RESULTS: Four hundred and fifty-one patients (24.7%) experienced virological failure, with an incidence rate (IR) of 7.3 per 100 person-years of follow-up (PYFU) [95% confidence interval (CI) 6.7-8.0]. After adjustment, patients who had rebounded in the year prior to baseline had a 2.4-times higher rate of virological failure after baseline (95% CI 1.77-3.26; P<.0001), while there was no increased incidence in patients whose last viral rebound was >3 years prior to baseline [Incidence rate ratio (IRR) 1.06; 95% CI 0.75-1.50; P=0.73] compared with patients who had never virally rebounded. Patients had an 86% (95% CI 1.36-2.55; P<.0001), 53% (95% CI 1.06-2.04; P=0.02) and 5% (95% CI 0.80-1.38; P=0.72) higher virological failure rate after baseline if they were virally suppressed <50%, 50-70% and 70-90% of the time they were on cART prior to baseline, respectively, compared with those virally suppressed >90% of the time. DISCUSSION: Intensive monitoring after a treatment switch is required in patients who have rebounded recently or have a low percentage of time suppressed while on cART. Consideration should be given to increasing the provision of adherence counselling. PMID- 20201979 TI - Comparative analysis of Bombyx mori nucleopolyhedrovirus responsive genes in fat body and haemocyte of B. mori resistant and susceptible strains. AB - The infection profiles of the Bombyx mori nucleopolyhedrovirus (BmNPV) in B. mori larvae revealed that the virus invaded the fat body and haemocyte of both KN and 306 strains, which are highly resistant and susceptible, respectively, to BmNPV infection. However, viral proliferation was notably slowed in the resistant B. mori strain. Using suppression subtractive hybridization, two fat body cDNA libraries were constructed to compare BmNPV responsive gene expression levels between the two silkworm lines. In total, 96 differentially expressed genes were obtained. Real-time quantitative PCR (qPCR) analysis confirmed that eight genes were significantly up-regulated in the fat body and haemocyte of the KN strain following BmNPV injection. Our results suggest that these genes may have potential roles in B. mori antiviral infection mechanisms. PMID- 20201980 TI - An expansion of the genome size dataset for the insect order Hymenoptera, with a first test of parasitism and eusociality as possible constraints. AB - Although the Hymenoptera represent a remarkably diverse and socioeconomically important group that is of considerable interest in genome biology, they remain understudied in terms of genome size. This study reports new genome size estimates for 89 species of ants, bees and wasps, representing 17 families and four superfamilies. These are used in a test of the hypothesis that genome sizes are constrained by traits associated with parasitism or eusociality. Not all parasitoid wasps exhibit small genomes, though a relationship based on specific types of parasitism may still occur; by contrast, there was no convincing evidence of a constraint relating to eusociality. The data provided here can be used to guide future research aimed at understanding the evolution of large-scale genomic properties in this order. PMID- 20201981 TI - cDNA cloning, homology modelling and evolutionary insights into novel endogenous cellulases of the borer beetle Oncideres albomarginata chamela (Cerambycidae). AB - Novel endogenous cDNAs of beta-1, 4-endoglucanases (Oa-EGase I and Oa-EGase II) were cloned from the cerambycid beetle Oncideres albomarginata chamela. Oa-EGase I- and Oa-EGase II-deduced proteins and three-dimensional structures possess all features, including general architecture, signature motifs and catalytic domains, of glycosyl hydrolase families 5 and 45 (GHF5 and GHF45) and also share high levels of homology with other beetle cellulases. Total carboxymethylcellulase activity of O. a. chamela was 208.13 U/g of larvae. Phylogenetic analyses suggest that insect GHF5 and GHF45 are very ancient gene families and indicate, at least in the case of GHF5, that this family likely evolved from a common ancestor rather than, as is often reported, via horizontal gene transfer. Beetle GHF45 cellulases did not cluster with other metazoan cellulases. However, the presence of GHF45 cellulases in ancient molluscan taxa puts into question the hypothesis of horizontal gene transfer for the evolution of cellulases in animals. PMID- 20201982 TI - RET gene mutations are not involved in the origin of human testicular seminoma. AB - Testicular germ cell cancers are the most common solid malignancies in young men, but their pathogenesis remains undetermined although some epidemiological data have implicated both environmental and genetic factors. Glial cell-derived neurotrophic factor (GDNF) is secreted by Sertoli cells, and promotes germ stem cell proliferation by activating RET, a tyrosine kinase receptor. Over-expression of GDNF in adult transgenic mice induces the development of testicular tumours that mimic human seminoma, the most frequent testicular germ cell tumour. Activating mutations of RET were previously reported in several types of cancer, including thyroid, pituitary, adrenal and melanoma cancer. Both mouse experimental model and clinical studies suggested that mutations or selective polymorphisms of RET might be associated with human seminoma. To verify this hypothesis, we conducted this study in a French University Hospital and carried out an association study using tissue samples from 66 paraffin-embedded seminoma tumours. The most frequently mutated exons of the RET proto-oncogene were sequenced to identify mutations or selective polymorphisms. No somatic mutations were identified. The polymorphic variants frequencies did not differ from those in a control Caucasian population. Human classical seminoma that occurs in young men does not appear to be linked with mutations or relevant polymorphisms of RET. PMID- 20201983 TI - Polyclonal expansion of cervical cytobrush-derived T cells to investigate HIV specific responses in the female genital tract. AB - Human immunodeficiency virus (HIV) -specific T-cell responses are detectable in the female genital tract of HIV-infected women but little is known about their frequency or the factors that influence their detection. We investigated the feasibility of polyclonal in vitro expansion of cervical cytobrush-derived T cells to investigate HIV-specific responses in the female genital tract in HIV infected women. Cytobrush-derived cervical cells were isolated from 22 HIV infected women and expanded with anti-CD3 and recombinant interleukin-2. Cervical T-cell lines were investigated for Gag-specific responses by interferon-gamma ELISPOT and compared with those detected in matched blood samples. Cervical T cell lines were established from 16/22 (72.7%) participants. Although the absolute number of CD3(+/-) cells recovered after expansion was positively associated with the number of cells isolated ex vivo (P = 0.01; R = 0.62), we observed a significant negative correlation between fold expansion and ex vivo cell number (P = 0.004; R = -0.68). We show that both the magnitude (P = 0.002; R = 0.7) and specific Gag regions targeted by cervical T-cell lines (P < 0.0001; R = 0.5) correlated significantly with those detected in blood. With one exception, cervical interferon-gamma T-cell responses to Gag were detected only in HIV infected women with blood Gag-specific response > 1000 spot-forming units/10(6) cells. We conclude that cervical Gag-specific T-cell responses in expanded lines are most easily detectable in women who have corresponding high-magnitude Gag specific T-cell responses in blood. PMID- 20201984 TI - T-cell receptor revision: friend or foe? AB - T-cell receptor (TCR) revision is a process of tolerance induction by which peripheral T cells lose surface expression of an autoreactive TCR, reinduce expression of the recombinase machinery, rearrange genes encoding extrathymically generated TCRs for antigen, and express these new receptors on the cell surface. We discuss the evidence for this controversial tolerance mechanism below. Despite the apparent heresy of post-thymic gene rearrangement, we argue here that TCR revision follows the rules obeyed by maturing thymocytes undergoing gene recombination. Expression of the recombinase is carefully controlled both spatially and temporally, and may be initiated by loss of signals through surface TCRs. The resulting TCR repertoire is characterized by its diversity, self major histocompatibility complex restriction, self tolerance, and ability to mount productive immune responses specific for foreign antigens. Hence, TCR revision is a carefully regulated process of tolerance induction that can contribute to the protection of the individual against invading pathogens while preserving the integrity of self tissue. PMID- 20201985 TI - Chronic rejection of a lung transplant is characterized by a profile of specific autoantibodies. AB - SUMMARY: Obliterative bronchiolitis (OB) continues to be the major limitation to long-term survival after lung transplantation. The specific aetiology and pathogenesis of OB are not well understood. To explore the role of autoreactivity in OB, we spotted 751 different self molecules onto glass slides, and used these antigen microarrays to profile 48 human serum samples for immunoglobulin G (IgG) and IgM autoantibodies; 27 patients showed no or mild bronchiolitis obliterans syndrome (BOS; a clinical correlate of OB) and 15 patients showed medium to severe BOS. We now report that these BOS grades could be differentiated by a profile of autoantibodies binding to 28 proteins or their peptides. The informative autoantibody profile included down-regulation as well as up regulation of both IgM and IgG specific reactivities. This profile was evaluated for robustness using a panel of six independent test patients. Analysis of the functions of the 28 informative self antigens showed that eight of them are connected in an interaction network involved in apoptosis and protein metabolism. Thus, a profile of autoantibodies may reflect pathological processes in the lung allograft, suggesting a role for autoimmunity in chronic rejection leading to OB. PMID- 20201986 TI - An antibody profile of systemic lupus erythematosus detected by antigen microarray. AB - SUMMARY: Patients with systemic lupus erythematosus (SLE) produce antibodies to many different self-antigens. Here, we investigated antibodies in SLE sera using an antigen microarray containing many hundreds of antigens, mostly self-antigens. The aim was to detect sets of antibody reactivities characteristic of SLE patients in each of various clinical states--SLE patients with acute lupus nephritis, SLE patients in renal remission, and SLE patients who had never had renal involvement. The analysis produced two novel findings: (i) an SLE antibody profile persists independently of disease activity and despite long-term clinical remission, and (ii) this SLE antibody profile includes increases in four specific immunoglobulin G (IgG) reactivities to double-stranded DNA (dsDNA), single stranded DNA (ssDNA), Epstein-Barr virus (EBV) and hyaluronic acid; the profile also includes decreases in specific IgM reactivities to myeloperoxidase (MPO), CD99, collagen III, insulin-like growth factor binding protein 1 (IGFBP1) and cardiolipin. The reactivities together showed high sensitivity (> 93%) and high specificity for SLE (> 88%). A healthy control subject who had the SLE antibody profile was later found to develop clinical SLE. The present study did not detect antibody reactivities that differentiated among the various subgroups of SLE subjects with statistical significance. Thus, SLE is characterized by an enduring antibody profile irrespective of clinical state. The association of SLE with decreased IgM natural autoantibodies suggests that these autoantibodies might enhance resistance to SLE. PMID- 20201987 TI - Salmonella pathogenicity island 1 differentially modulates bacterial entry to dendritic and non-phagocytic cells. AB - Salmonella enterica serovar Typhimurium can enter non-phagocytic cells, such as intestinal epithelial cells, by virtue of a Type Three Secretion System (TTSS) encoded in the Salmonella Pathogenicity Island 1 (SPI-1), which translocates bacterial effector molecules into the host cell. Salmonella can also be taken up by dendritic cells (DCs). Although the role of SPI-1 in non-phagocytic cell invasion is well established, its contribution to invasion of phagocytic cells has not been evaluated. Here, we have tested the invasive capacity of a S. Typhimurium strain lacking a key component of its TTSS-1 (DeltaInvC) leading to defective translocation of SPI-1-encoded effectors. Whereas this mutant Salmonella strain was impaired for invasion of non-phagocytic cells, it was taken up by DCs at a significantly higher rate than wild-type Salmonella. Similar to wild-type Salmonella, the DeltaInvC mutant strain retained the capacity to avoid antigen presentation to T cells. However, mice infected with the DeltaInvC mutant strain showed higher survival rate and reduced organ colonization. Our data suggest that, besides promoting phagocytosis by non-phagocytic cells, SPI-1 modulates the number of bacteria that enters DCs. The SPI-1 could be considered not only as an inducer of epithelial cell invasion but as a controller of DC entry. PMID- 20201988 TI - Enhancement of humoral and cellular immunity with an anti-glucocorticoid-induced tumour necrosis factor receptor monoclonal antibody. AB - Adjuvants, including antibodies to tumour necrosis factor receptor superfamily members, augment immune responses. One member of this family, glucocorticoid induced tumour necrosis factor receptor (GITR), is expressed at low levels on naive/resting T cells, B cells and macrophages, but at higher levels on T regulatory cells. The aim of this study was to determine the ability of a rat anti-mouse GITR monoclonal antibody, 2F8, to stimulate murine humoral and cellular immunity in a prime boost model with particular attention to posology and antigen-specific effects. 2F8 enhanced the humoral immune response to ovalbumin and haemagglutinin (HA) compared with controls and this enhancement was equal to or greater than that obtained in mice dosed with standard adjuvants. 2F8 F(ab')(2) fragments were as effective as intact antibody in boosting humoral immunity, indicating that FcR-mediated cross-linking of 2F8 is not required for efficacy. Moreover, the enhanced response was durable and antigen specific. Administration of 2F8 shifted the immune response towards a T helper type 1 response with significant enhancement of immunoglobulin G2a- and G2b-specific anti-HA antibodies, as well as enhanced cellular immunity as measured by ELISPOT. 2F8-treated mice also generated significantly more neutralizing antibodies to HA than control mice. Our findings show that anti-GITR is a robust, versatile adjuvant that, unlike commonly used adjuvants that primarily enhance humoral immunity, enhances both humoral and cellular immunity. These results support the continued development of anti-GITR for such indications as haematological and solid tumours, chronic viral infections, and as a vaccine adjuvant. PMID- 20201989 TI - Optimal stimulation for CD70 induction on human monocyte-derived dendritic cells and the importance of CD70 in naive CD4(+) T-cell differentiation. AB - Studies in mice have shown that CD70 on dendritic cells (DCs) is sufficient to convert T-cell tolerance into immunity and hence induce anti-tumour immune responses. Therefore, it is important to investigate (i) optimal stimuli to induce CD70 on human monocyte-derived DCs (MoDCs), which are widely used for tumour immunotherapy, and (ii) the role of CD70 in functional differentiation of naive CD4(+) and CD8(+) T cells stimulated with MoDCs. We show that interferon alpha (IFN-alpha) is a key cytokine to differentiate monocytes into DCs with the capacity to express CD70 upon maturation. CD70 expression on IFN-alpha-induced MoDCs was elicited by different categories of maturation-inducing factors (Toll like receptor ligands, CD40 ligand and pro-inflammatory mediators), among which prostaglandin E(2) was most effective. Naive T cells stimulated with MoDCs also expressed CD70. Stimulation with MoDCs promoted naive CD4(+) T cells to acquire the ability to produce T helper type 1 and 2 cytokines in a CD70-dependent manner. In contrast, the CD70-CD27 interaction diminished the production of an immunoregulatory cytokine IL-10. The CD27 signal did not play a dominant role in the induction of effector molecules in naive CD8(+) T cells during the stimulation with MoDCs. This study adds a novel function to the versatile cytokines, type I IFNs, that is, the induction of CD70 on MoDCs. CD70 promotes naive CD4(+) T cells to acquire immunostimulatory activity through the DC-T-cell and T-cell-T-cell interactions during the stimulation with MoDCs. Hence, the CD70 CD27 interaction may play an important role in inducing effective immune responses in DC-based immunotherapy. PMID- 20201991 TI - Iloperidone redux: a dissection of the Drug Approval Package for this newly commercialised second-generation antipsychotic. AB - OBJECTIVE: To describe the contents of a Drug Approval Package and to describe the efficacy and safety of iloperidone for the treatment of schizophrenia. DATA SOURCES: Drug Approval Package from the US Food and Drug Administration available at http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022192s000TOC.cfm. DATA SYNTHESIS: The Drug Approval Package contains several different sections that describe both the preclinical (animal) and the clinical (human) studies conducted that led to the approval of iloperidone, a second-generation antipsychotic medication. Most of this information has not been published in the peer-reviewed literature and much of it had not been previously publicly available. Iloperidone's indication for the acute treatment of schizophrenia in adults is supported by two of the four principal registration studies completed by the manufacturer. The documents made available reveal that there was disagreement between the Food and Drug Administration (FDA) and the manufacturer as to which study was considered 'positive' for iloperidone. There was additional controversy surrounding the appropriateness of combining patients with schizophrenia and schizoaffective disorder in the same study. Questions were also raised by the FDA about the relative efficacy of iloperidone vs. other antipsychotics; the need for an initial titration period was offered as a possible explanation as to why risperidone appeared to have superior efficacy. Moreover, there was disagreement as to what constitutes an appropriate study to test the long-term efficacy of an antipsychotic. Additional information is made available regarding the safety and tolerability of iloperidone, with the FDA acknowledging an overall attractive profile that includes less akathisia and extrapyramidal symptoms than other agents in its class. Of potential clinical utility are the results from FDA analyses of patients where clinical variables shifted from the normal to abnormal range. CONCLUSIONS: Iloperidone is efficacious and reasonably tolerable. The information made publicly available in the Drug Approval Package from the US FDA allows a closer examination as to how the medication was approved and allows for outside clinicians and researchers to appraise the data more carefully. Safety signals generated by FDA analyses of outliers can provide the impetus for the conduct of additional studies and post hoc analyses of registration study data already collected. PMID- 20201990 TI - Mycobacterium tuberculosis conserved hypothetical protein rRv2626c modulates macrophage effector functions. AB - Secretory proteins of Mycobacterium tuberculosis are the major immunomodulators of the host immune response. Open reading frame (ORF) Rv2626c, encoding a conserved hypothetical protein eliciting a strong humoral immune response in patients with tuberculosis (TB), was shown to be up-regulated upon infection in mice under hypoxic conditions. We now show that recombinant Rv2626c protein (rRv2626c) can bind to the surface of murine macrophages and elicit the type-1 immune response, as manifested by nitric oxide (NO) secretion and expression of inducible nitric oxide synthase (iNOS). Significant induction of pro-inflammatory cytokines [interleukin (IL)-12 and tumour necrosis factor (TNF)-alpha] was evident upon stimulation of murine macrophages, as well as peripheral blood mononuclear cells (PBMCs) isolated from patients with active TB disease, with rRv2626c. Stimulation with rRv2626c also enhanced the expression of costimulatory molecules such as B7-1, B7-2 and CD40 on murine macrophages. We further show that the production of NO and pro-inflammatory cytokines in response to rRv2626c is mediated by the transcription factor nuclear factor (NF)-kappaB, and this was further confirmed using pyrrolidine dithiocarbamate (PDTC), a specific pharmacological inhibitor of NF-kappaB. Rv2626c therefore appears to modulate macrophage effector functions by eliciting both innate and adaptive immune responses, suggesting its possible use as a vaccine candidate. PMID- 20201992 TI - Long-term safety, tolerability and efficacy of fesoterodine treatment in subjects with overactive bladder symptoms. AB - AIMS: The aim of this study was to assess the long-term safety, tolerability and efficacy of fesoterodine treatment in subjects with overactive bladder (OAB) symptoms. METHODS: This was an open-label extension study of a 12-week, double blind fesoterodine study. During open-label treatment, all subjects received fesoterodine 8 mg for an initial 4 weeks, after which subjects could elect dose reduction to 4 mg or subsequent reescalation to 8 mg during clinic visits (dose reduction and reescalation each permitted once annually). The maximum allowable duration of open-label fesoterodine treatment ranged from 24 to 32 months across study sites. Safety and tolerability were evaluated via discontinuations, fesoterodine exposure, treatment-emergent adverse events (TEAEs) and subject reported treatment tolerance. Three-day bladder diaries and other patient reported outcomes (PROs) were assessed during the first 24 months of open-label treatment. PROs included evaluations of health-related quality of life [HRQL; King's Health Questionnaire (KHQ), and International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF)], severity of bladder-related problems and treatment satisfaction. Subjects completed 3-day diaries before open-label baseline and months 1, 4, 8, 12 and 24; the ICIQ-SF and measures of bladder related problems and treatment satisfaction at open-label baseline and months 4, 12 and 24; and the KHQ at open-label baseline and months 12 and 24. RESULTS: Of the 417 eligible subjects who enrolled in the open-label extension, 61% continued fesoterodine treatment for > or = 24 months and 71% elected to maintain the fesoterodine 8-mg dose throughout treatment. No unexpected safety signals were observed. Most subjects rated treatment tolerance as at least 'good' throughout the study (> or = 88%). Dry mouth was the most commonly reported TEAE (34%) during open-label treatment, resulting in discontinuation in 2% of subjects (n = 8). Improvements from open-label baseline in OAB symptoms, HRQL and bladder related problems were statistically significant at the earliest point measured and maintained through month 24. Treatment satisfaction rates were high throughout the study (> or = 84%). CONCLUSIONS: Long-term fesoterodine treatment was well tolerated and associated with sustained improvements in OAB symptoms and HRQL. PMID- 20201993 TI - Insulin analogues and cancer risk: cause for concern or cause celebre? AB - People with diabetes, particularly those with type 2 diabetes, may be at an increased risk of cancer. Furthermore, their cancer risk may be modified by treatment choices. In this respect, metformin may be protective, whereas insulin and insulin analogues can function as growth factors and therefore have theoretical potential to promote tumour proliferation. Analogues causing inappropriate prolonged stimulation of the insulin receptor, or excess stimulation of the IGF-1 receptor, are the most likely to show mitogenic properties in laboratory studies. Some recent epidemiological studies appear to be consistent with these experimental findings, suggesting that there could be different relative risks for cancer associated with different insulins, although these studies have attracted some methodological criticism. However, it is biologically plausible that hormonal factors that influence neoplasia could begin to manifest their effects in surprisingly short timescales (within 2 years) and hence these epidemiological studies justify further research. Even if future research were to document an increase in cancer risk among insulin users, this would be unlikely to significantly diminish the favourable benefit-risk ratio for patients requiring insulin therapy. There is a need for further population studies and for the development of new laboratory models that are more sophisticated than previous experimental methods employed to assess potential tumour growth-promoting properties of insulins. PMID- 20201994 TI - Association between the neutrophil myeloperoxidase index and subsets of bacterial infections. AB - The mean myeloperoxidase index (MPXI) is calculated during the routine complete blood count performed using the autoanalyzer ADVIA120/2120. The pattern of changes in the neutrophil myeloperoxidase levels in patients with specific infectious diseases was analyzed by assessing the MPXI levels. In patients with bacterial sepsis, identified by positive blood-culture tests, with (n = 29) and without (n = 51) systemic inflammatory response syndrome, the mean MPXI significantly reduced to -3.18 and -2.06, respectively. In contrast, among patients with nontuberculous nonseptic bacterial infections (n = 40), the mean MPXI significantly elevated to 5.51, while tuberculosis patients (n = 37) and patients with viral infection (n = 60) showed an unchanged MPXI (mean values, 0.46 and -1.06, respectively). Among the parameters of inflammation, only the C reactive protein values showed a weak correlation with the MPXI levels. [Conclusion] These results indicate that MPXI is correlated with some specific infectious states, i.e. MPXI is low in bacterial sepsis and high in nontuberculous nonseptic bacterial infections. MPXI appears to be an independent and useful biomarker for the diagnosis and follow-up of infectious diseases, especially when the MPXI values are obtained at regular intervals during the disease courses of the patients. PMID- 20201996 TI - Prognostic value of serum CA125 levels in diffuse large B-cell lymphoma: potential role of a new sex- and age-adjusted reference value. AB - CA125, a tumor marker normally used to follow the clinical course of ovarian cancer, also may have a role in lymphoma. All available series were analyzed using the standard reference value 35 U/ml, but age and sex may influence serum CA125 (sCA125) levels. We aim to study the prognostic value of serum CA125 (sCA125) levels in diffuse large B-cell lymphoma (DLBCL), considering the influence of age and sex on sCA125 levels. We investigated the relationship between sCA125 and clinical outcome after treatment in 42 patients with DLBCL, comparing both the standard (35 U/ml) and a new age and sex adjusted (sex/age adjusted) reference value proposed by our group. We found that patients with elevated sCA125 levels had significantly more adverse prognostic factors at diagnosis, lower CR rates, higher relapse rates and worse survival. In the low risk IPI categories, the presence of elevated sCA125 defined a particularly high risk subgroup with poorer 3-year PFS when compared with patients with normal sCA125 levels. The use of a sex/age-adjusted reference value for sCA125 may increase the sensitivity to identify those patients with elevated sCA125 levels truly related to DLBCL activity. PMID- 20201998 TI - Characterisation and relevance of CD138-negative plasma cells in plasma cell myeloma. AB - INTRODUCTION: The use of CD138 to isolate CD138(+) plasma cells (PCs) from plasma cell myeloma (PCM) patients' bone marrow samples has been used extensively in myeloma research. We sought to highlight the problem with this selection process, by demonstrating that a subpopulation of CD138- plasma cells exists which is not included in these analyses. METHODS: Retrospective analysis of a patient database was carried out on all PCM patient bone marrow biopsies taken between 4/9/07 and 18/2/09 (n = 218). CD138(+) and CD138- cell populations were separated using flow cytometry cell sorter then analyzed for percentage of cells in S phase using plasma cell labeling index as an indicator of proliferation. RESULTS: Database results indicated a CD138- PC population in all PCM patient samples which also had a significantly increased (r = 0.53; P < 0.0001) CD45 expression, an indicator or immaturity. Flow cytometric analysis demonstrated the presence of a more immature, higher proliferating CD138- PC population through a significantly (t = 3.26; P < 0.02) higher number of CD138- PCs in S phase compared with the CD138(+) cells. CONCLUSION: We have characterised the CD138- PCs as more immature and with a significantly higher proliferative potential. The current trend to ignore this more immature and proliferative subpopulation of malignant PCs may have serious implications when determining gene expression, classifications and drug sensitivity of the malignancy. PMID- 20201999 TI - Serum myeloperoxidase levels and platelet activation parameters as diagnostic and prognostic markers in the course of coronary disease. AB - Early prediction of coronary artery disease complications is vital for the prevention and effective treatment of patients with coronary cardiac disease. It has been reported that inflammatory markers play a key role in the progression of cardiovascular diseases. Platelet count and platelet morphological parameters were analyzed on a fully-automated hematological analyzer ADVIA 2120 (Siemens). Serum myeloperoxidase (MPO) level was determined with an enzyme immunoassay (BioCheck). The measuring range of this assay is between 0 and 40 ng/ml. We demonstrate that serum MPO concentration and platelet activation increase systematically with the advancement of coronary artery disease. Moreover, MPO level is significantly higher in patients with unstable coronary artery disease and myocardial infarction compared with healthy subjects and patients with stable angina. The diagnostic sensitivity of these parameters was higher than of TnI (cardiac troponin I), CK-MB (creatine kinase-heart type), CRP (C-reactive protein), and fibrinogen and DD (D-dimers). MPO, L-PLT (large platelet), MPV (mean platelet volume), and MPC (mean platelet component concentration) may serve as attractive diagnostic and prognostic markers in the assessment of the risk for unstable atheroma in the course of coronary artery disease. PMID- 20202000 TI - Male infertility in cancer patients: Review of the literature. AB - The number of men surviving cancer at a young age has increased dramatically in the past 20 years as a result of early detection and improved cancer treatment protocols; more than 75% of young cancer patients nowadays are long-term survivors. Quality of life has become an important issue in childhood and adult cancer patients. The commonest cancers in patients of reproductive age are leukaemia, Hodgkin's lymphomas and testicular germ cell tumors. Fertility is often impaired after chemotherapy and radiation therapy. Cryopreservation of semen before cancer treatment starts is currently the only method to preserve future male fertility. In some malignancies, especially in germ cell tumors, sperm quality is already abnormal at the time of diagnosis. In approximately 12% of men, no viable spermatozoa are present for cryopreservation before the start of chemotherapy. Cytotoxic therapy influences spermatogenesis at least temporarily and in some cases permanently. The amount of damage inflicted by chemotherapy on spermatogenesis depends on the combination of drugs used and on the cumulative dose given for cancer treatment. Alkylating agents, such as cyclophosphamide and procarbazine, are most detrimental to germ cells. Radiation therapy, especially whole-body irradiation, is also associated with the risk of permanent sterility. Besides the cancer treatment, tumor type and pretreatment fertility are of prognostic value for future fertility in male cancer survivors. After cancer treatment, many men need artificial reproductive techniques to achieve fatherhood; usually in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) is indicated for successful treatment. About 15% of men will use their cryopreserved semen because of persistent azoospermia after cancer treatment. Treatment results with cryopreserved semen are generally good and comparable to general IVF and ICSI results. So far, no studies have reported an increased rate of congenital abnormalities or malignancies in children born from fathers who had cancer treatment is the past, but close follow up is warranted, especially in children born after IVF/ICSI. PMID- 20202001 TI - Tension-free vaginal mesh procedure for pelvic organ prolapse: a single-center experience of 310 cases with 1-year follow up. AB - OBJECTIVE: To prospectively evaluate the efficacy of a tension-free vaginal mesh (TVM) procedure for pelvic organ prolapse (POP). METHODS: Between December 2005 and April 2008, 310 female patients (mean age 67.2 years, range 42-84) with POP underwent TVM procedures at our institute. Fifty-six individuals were qualified as stage 2 according to the POP quantification system and 162 and 92 were stage 3 and 4, respectively. One hundred ninety-one patients underwent anterior TVM, and seven underwent posterior TVM. One hundred twelve cases underwent both anterior and posterior TVM procedures. Each patient was systematically assessed at 1, 3, 6 and 12 months after surgery. Quality of life (QOL) was also assessed by using the Short Form-36 and the prolapse-QOL questionnaires. RESULTS: Perioperative complications were the following: five bladder injuries (1.6%), no rectal injuries and three hemorrhages greater than 400 mL (1.0%). The anatomical cure rate (% stage 0 cases) at 3, 6 and 12 months after surgery were 94.1%, 93.5%, and 92.3%, respectively. Short Form-36 and prolapse-QOL parameters were significantly improved, and maintained during the follow-up period. Postoperative complications were the following: five pelvic hematomas (1.6%), one wound infection (0.3%), 10 vaginal mesh extrusions (3.2%), and three cases of pelvic pain (1.0%). Complications concerning lower urinary tract function were: eight cases of postoperative stress urinary incontinence (2.6%), three cases of transient urinary retention (1.0%), and two cases of de novo overactive bladder (0.6%). CONCLUSIONS: The TVM procedure provides a good outcome at 1 year with a low incidence of surgical complications and recurrence. Further evaluation with a longer follow up is needed. PMID- 20202002 TI - Efficacy of low dose tamsulosin in medical expulsive therapy for ureteral stones in Japanese male patients: a randomized controlled study. AB - OBJECTIVE: To evaluate the efficacy of low dose tamsulosin for facilitating spontaneous passage of ureteral stones in Japanese male patients. METHODS: A total of 71 patients with symptomatic ureteral stones, 10 mm or smaller in size, were randomly allocated into groups 1 and 2. Group 1 received tamsulosin (0.2 mg/day) for a maximum of 4 weeks and group 2 received no medication. The primary endpoint was the stone expulsion rate and the secondary endpoints were stone expulsion time and analgesic use. RESULTS: There were no significant differences between the groups in terms of age, stone size and location. The stone expulsion rate was significantly higher in group 1 than in group 2 (77% vs 50%, P = 0.002). No significant differences were noted in the stone expulsion time and analgesic use between the groups. CONCLUSION: Low dose tamsulosin can significantly facilitate spontaneous passage of ureteral stones without significant side effects in Japanese male patients. PMID- 20202003 TI - Autologous bone-marrow-derived mesenchymal stem cell transplantation into injured rat urethral sphincter. AB - OBJECTIVES: To evaluate the functional and histological recovery by autologous bone-marrow-derived mesenchymal stem cell (BMSC) transplantation into injured rat urethral sphincters. METHODS: BMSC were harvested from female Sprague-Dawley retired breeder rats for later transplantation. The cells were cultured, and transfected with the green fluorescence protein gene. The urethral sphincters were injured by combined urethrolysis and cardiotoxin injection. One week after injury, the cultured BMSC were injected autologously into the periurethral tissues. Controls included sham-operated rats and injured rats injected with cell free medium (CFM). Abdominal leak point pressures (LPP) were measured before and after surgery during the following 13 weeks. The urethras were then retrieved for histological evaluation. The presence of green-fluorescence-protein-labeled cells and the regeneration of skeletal muscles, smooth muscles, and peripheral nerves were evaluated by immunohistochemical staining. RESULTS: LPP was significantly reduced in the injured rats. It increased gradually after transplantation, but there was no significant difference between the BMSC and CFM groups. In the BMSC group, transplanted cells survived and differentiated into striated muscle cells and peripheral nerve cells. The proportions of skeletal muscle cells and peripheral nerves in the urethra were significantly greater in the BMSC group compared to the CFM group. CONCLUSIONS: Despite a clear trend towards recovery of LPP in BMSC-transplanted urethras, no significant effect was detected. Further study is required for clinical applications for the treatment of stress urinary incontinence. PMID- 20202004 TI - Skeletal-related events in urological cancer patients with bone metastasis: a multicenter study in Japan. AB - OBJECTIVE: To investigate the incidence of skeletal-related events (SRE) in urological cancer patients with bone metastases in Japan. METHODS: Five hundred eleven patients with urological cancer and documented bone metastases treated from January 2003 to April 2008 in ten Japanese institutions were included in a retrospective analysis. Type and incidence of SRE (fracture, radiotherapy, spinal cord compression, surgery, hypercalcemia, and bone pain) were determined from patient medical records. RESULTS: The overall incidence of SRE, including 'pain', was 61%. The most common event was radiotherapy for bone metastases, with an incidence of 31%. The overall incidence of events seemed to be similar among Japanese and Western patients with prostate cancer and renal cell carcinoma when comparing data with previously published reports. Nevertheless, a much lower incidence of fracture (19.1%) was observed in Japanese renal cell carcinoma patients. CONCLUSIONS: The overall incidence of SRE in Japanese urological cancer patients with bone metastasis was similar to that in Western patients, but the incidence of fracture was lower in Japanese renal cancer patients. PMID- 20202005 TI - Rensch's rule inverted--female-driven gigantism in nine-spined stickleback Pungitius pungitius. AB - 1. Allometric scaling of sexual size dimorphism (SSD) with body size is a commonplace occurrence in intraspecific or interspecific comparisons. Typically, SSD increases with body size when males, and decreases when females are the larger sex--a pattern known as Rensch's rule. Intraspecific studies of Rensch's rule in vertebrates are extremely scarce. 2. In an allometric SSD-body size relationship, the sex with the larger body size variation is the driver of size divergence whereas the other sex is following it owing to correlational selection. Hence, one can test which sex is responsible for the observed body size divergence within this framework. 3. Nine-spined stickleback (Pungitius pungitius) provides an excellent model to study intraspecific variation in SSD owing to the large interpopulation variation in mean body size. Using data on body size variation in 11 nine-spined stickleback populations covering the full known size range of the species, we investigated: (i) whether variation in SSD scales allometrically with mean body size across the populations; (ii) which sex is driving the allometric relationship and (iii) whether the observed pattern is likely to have a genetic component. In addition, we analysed the size dependency of female reproductive output. 4. We found strong support for an inverse of Rensch's rule: level of female-biased SSD increased with increasing mean size while females were the more variable sex. Results from a common garden experiment supported the pattern found in the wild. Females from giant populations had 2-3 times larger reproductive output than normal-sized females. 5. The fact that females were the more variable sex indicates that the evolution of gigantism in nine-spined sticklebacks is driven by females, and the 2-3 times larger reproductive output per clutch of giant vs. normal-sized females suggests fecundity selection to have an important role in it. Our results oppose the commonly held view that males drive the evolution of SSD as a result of sexual selection favouring larger males. PMID- 20202006 TI - Cohort variation in offspring growth and survival: prenatal and postnatal factors in a late-maturing viviparous snake. AB - 1. Recruitment to adulthood plays an important role in the population dynamics of late-maturing organisms as it is usually variable. Compared to birds and mammals, few studies assessing the contributions to this variation of environmental factors, offspring traits and maternal traits have been carried out for late maturing snakes. 2. Cohort variation in recruitment through offspring growth and survival in the meadow viper (Vipera ursinii ursinii) was evaluated from 13 years of mark-recapture data collected at Mont Ventoux, France. In this species, females are mature at the age of 4-6 years and adult survival and fecundity rates are high and constant over time. 3. Offspring were difficult to catch during the first 3 years of their lives, but their mean annual probability of survival was reasonably high (0.48 +/- 0.11 SE). Mass and body condition at birth (mass residuals) varied significantly between years, decreased with litter size, and increased with maternal length. 4. Cohorts of offspring in better condition at birth grew faster, but offspring growth was not affected by sex, habitat or maternal traits. 5. Survival varied considerably between birth cohorts, some cohorts having a high-survival rate and others having essentially no survivors. No difference in mass or body condition at birth was found between cohorts with 'no survival' and 'good survival'. However, offspring survival in cohorts with good survival was positively correlated with mass at birth and negatively correlated with body condition at birth. 6. Thus, variation in offspring performance was influenced by direct environmental effects on survival and indirect environmental effects on growth, mediated by body condition at birth. Effects of maternal traits were entirely channelled through offspring traits. PMID- 20202007 TI - Explaining abundance-occupancy relationships in specialists and generalists: a case study on aquatic macroinvertebrates in standing waters. AB - 1. A positive interspecific abundance-occupancy relationship is one of the most robust patterns in macroecology. Yet, the mechanisms driving this pattern are poorly understood. Here, we use biological traits of freshwater macroinvertebrates to gain a mechanistic understanding and disentangle the various explanations. We ask whether mechanisms underlying the abundance occupancy relationship differ between species, and whether information on individual species can be used to explain their contribution to the interspecific relationship. 2. We test the hypothesis that the importance of metapopulation dynamics or niche differences in explaining the relationship differs between species, varying in relation to their habitat breadth. In addition, we analyse how a species' biological traits shape its habitat breadth and its abundance and occupancy. 3. The abundance and occupancy of the 234 different aquatic macroinvertebrate species were strongly and positively related. Marked differences were found between habitat specialists and habitat generalists in the goodness-of-fit of abundance-occupancy relationships. The occupancy-frequency distribution was bimodal for habitat generalists, allowing 'satellite species' to be distinguished from 'core species'. 4. Habitat generalists appeared to be more widespread but less abundant than habitat specialists, suggesting that the jack of-all-trades may be master-of-none. Species traits (trophic position and other life-history traits) explained a significant part of the variation around the general relationship. Among habitat specialists, more species showed synchronized life cycles, a low dispersal capacity or clustered oviposition, being better adapted to predictable habitats. Among habitat generalists, more species had long lived adults, spreading reproductive effort in time and space, and were strong dispersers, being better adapted to unpredictable habitats. 5. Interspecific abundance-occupancy relationships can be best understood by examining the contribution of individual species. For habitat specialists, the interplay between niche differences (diet and habitat use) and the underlying spatial distribution of environmental conditions result in competitive displacement and differences in species' success. For habitat generalists, differences in colonization and extinction rates between species are more important. Therefore, both metapopulation dynamics and niche differences can operate simultaneously but apply to different species, thus constituting different endpoints of the same continuum. PMID- 20202008 TI - Parent age, lifespan and offspring survival: structured variation in life history in a wild population. AB - 1. Understanding the degree to which reproductive success varies with an individual's age and lifespan, and the degree to which population-level variation mirrors individual-level variation, is central to understanding life-history evolution and the dynamics of age-structured populations. We quantified variation in the survival probability of offspring, one key component of reproductive success and fitness, in relation to parent age and lifespan in a wild population of red-billed choughs (Pyrrhocorax pyrrhocorax). 2. On average across the study population, the first-year survival probability of offspring decreased with increasing parent age and lifespan; offspring of old parents were less likely to survive than offspring of young parents, and offspring of long-lived parents were less likely to survive than offspring of short-lived parents. 3. However, survival did not vary with parent age across offspring produced by groups of parents that ultimately had similar lifespans. 4. Rather, across offspring produced by young parents, offspring survival decreased with increasing parent lifespan; parents that ultimately had long lifespans produced offspring that survived poorly, even when these parents were breeding at young ages. 5. The average decrease in offspring survival with increasing parent age observed across the population therefore reflected the gradual disappearance of short-lived parents that produced offspring that survived well, not age-specific variation in offspring survival within individual parents. 6. The negative correlation between offspring survival and maternal lifespan was strongest when environmental conditions meant that offspring survival was low across the population. 7. These data suggest an environment-dependent trade-off between parent and offspring survival, show consistent individual variation in the resolution of this trade off that is set early in a parent's life, and demonstrate that such structured life-history variation can generate spurious evidence of senescence in key fitness components when measured across a population. PMID- 20202009 TI - Personality, space use and tick load in an introduced population of Siberian chipmunks Tamias sibiricus. AB - 1. Although behaviours can contribute to the heterogeneity in parasite load among hosts, links between consistent individual differences in behaviour and parasitic infection have received little attention. We investigated the role of host activity and exploration on hard tick infestations of marked individuals in a population of Siberian chipmunks Tamias sibiricus introduced in a suburban French forest over 3 years. 2. Individual activity-exploration profiles were assessed from 106 hole-board tests on 73 individuals, and chipmunks' trappability and trap diversity were used respectively as indices of their activity-exploration and space use on a sub-sample of 60 individuals. At each capture, we counted the total number of ticks per head of chipmunk. 3. We found significant and consistent individual differences in activity-exploration, trappability, trap diversity and tick load, and could estimate individual indices for these four variables, corrected for confounding effects of year, season, body mass and sex. 4. Using a path analysis, we found an indirect effect of activity-exploration on tick load: tick load increased with space use, which in turn was positively affected by trappability in the field. Trappability was itself positively related to activity-exploration in the hole board. Habitat type affected tick load, independently of behavioural traits. A second path model revealed a lack of either direct or indirect influence of tick loads on chipmunks' personality and trappability. 5. Our results show that host personality-related patterns in space use can lead to a non-random parasite distribution among hosts. PMID- 20202010 TI - Mixed conditional logistic regression for habitat selection studies. AB - 1. Resource selection functions (RSFs) are becoming a dominant tool in habitat selection studies. RSF coefficients can be estimated with unconditional (standard) and conditional logistic regressions. While the advantage of mixed effects models is recognized for standard logistic regression, mixed conditional logistic regression remains largely overlooked in ecological studies. 2. We demonstrate the significance of mixed conditional logistic regression for habitat selection studies. First, we use spatially explicit models to illustrate how mixed-effects RSFs can be useful in the presence of inter-individual heterogeneity in selection and when the assumption of independence from irrelevant alternatives (IIA) is violated. The IIA hypothesis states that the strength of preference for habitat type A over habitat type B does not depend on the other habitat types also available. Secondly, we demonstrate the significance of mixed-effects models to evaluate habitat selection of free-ranging bison Bison bison. 3. When movement rules were homogeneous among individuals and the IIA assumption was respected, fixed-effects RSFs adequately described habitat selection by simulated animals. In situations violating the inter-individual homogeneity and IIA assumptions, however, RSFs were best estimated with mixed effects regressions, and fixed-effects models could even provide faulty conclusions. 4. Mixed-effects models indicate that bison did not select farmlands, but exhibited strong inter-individual variations in their response to farmlands. Less than half of the bison preferred farmlands over forests. Conversely, the fixed-effect model simply suggested an overall selection for farmlands. 5. Conditional logistic regression is recognized as a powerful approach to evaluate habitat selection when resource availability changes. This regression is increasingly used in ecological studies, but almost exclusively in the context of fixed-effects models. Fitness maximization can imply differences in trade-offs among individuals, which can yield inter-individual differences in selection and lead to departure from IIA. These situations are best modelled with mixed-effects models. Mixed-effects conditional logistic regression should become a valuable tool for ecological research. PMID- 20202011 TI - Adrenal androgen levels as predictors of outcome in castration-resistant prostate cancer patients treated with combined androgen blockade using flutamide as a second-line anti-androgen. AB - OBJECTIVES: To analyze the clinical effects of flutamide as a second-line anti androgen for combined androgen blockade in patients with castration-resistant prostate cancer (CRPC) initially treated with bicalutamide as a first-line anti androgen. METHODS: Our study population consisted of 16 patients with CRPC who were treated with flutamide (375 mg daily) as second-line hormonal therapy. Dehydroepiandrosterone (DHEA), androstenedione, androstenediol, testosterone and dihydrotestosterone were measured to investigate the relationship between plasma androgens and outcome following treatment. Furthermore, adrenal androgen levels in a medium of adrenal cancer cell line were also measured. RESULTS: Second-line hormonal therapy using flutamide resulted in a reduction of the prostate-specific antigen (PSA) level in 14 (87.5%) of 16 patients. A PSA decline greater than 50% was observed in 8 (50%) of the 16 patients. The duration of median responsiveness was 6.25 months. PSA elevation of baseline androstenediol level was a predictive factor of PSA responsiveness. The lower DHEA group improved the duration of responsiveness to flutamide. In vitro, 3 micromol/L flutamide suppressed DHEA, androstenedione and androstenediol synthesis compared with bicalutamide in a medium of adrenal cancer cell line. CONCLUSIONS: Our data show that flutamide suppresses the adrenal androgens in comparison with bicalutamide. The responsiveness and response duration of flutamide can be predicted in patients with a higher baseline androstenediol level and a lower DHEA level. Metabolites from adrenal androgens contribute to the progression of prostate cancer. PMID- 20202012 TI - Impact of tension-free vaginal tape procedure on dysfunctional voiding in women with stress urinary incontinence. AB - OBJECTIVES: To determine the prevalence of dysfunctional voiding (DV) in female stress urinary incontinence (SUI) and its modification after tension-free vaginal tape (TVT) procedure. METHODS: Three hundred and sixty women with SUI were enrolled and underwent urodynamics from 2002 to 2008. DV was determined when non neurogenic detrusor-sphincter dyssynergia occurred during voluntary voiding. It was further quantitatively analyzed using the tense/loose value, a parameter derived from external anal sphincter electromyogram. The distribution of other urodynamic variables was also evaluated. One hundred and fifty patients underwent the TVT procedure and forty of them were studied with urodynamics after surgery during follow up. RESULTS: Overall, DV was diagnosed in ninety-nine patients, with a prevalence of 27.5%. The functional profile length in SUI women with DV was significantly shorter than that in SUI women without DV (3.13 +/- 0.76 vs 3.32 +/- 0.65, P = 0.017). After the TVT procedure, the recovery of SUI between cases with and without DV showed no significant difference. The rate of DV state change after the surgery, namely from with to without DV or from without to with DV, significantly differed between the female patients with and without DV (66.7% vs 3.6%, P < 0.05) during follow up. The DV improved after the surgery in SUI women with DV. CONCLUSIONS: DV might represent a coexistent finding in women with SUI. The main difference of women with SUI and DV, as compared with those without DV, is a shortened functional profile length. In such cases, TVT procedure can improve DV along with the treatment of SUI. PMID- 20202013 TI - Climate change affects the duration of the reproductive season in birds. AB - 1. The duration of the reproductive season may depend on the duration of the growing season, with recent amelioration in spring temperatures allowing earlier start of reproduction. Earlier start of reproduction may allow a longer breeding season because of more broods a longer interval between broods for multi-brooded species. 2. We analysed extensive long-term data sets on timing of breeding in 20 species of birds from Denmark, based on records of over 100 000 individual offspring, showing considerable heterogeneity among species in temporal change in duration of the breeding season. 3. Multi-brooded species increased the duration of their breeding season by 0.43 days year(-1) while single-brooded species decreased the duration of their breeding season by 0.44 days year(-1). This implies that recent climate change has allowed more broods or better temporal spacing of broods in multi-brooded species, while the time window for reproduction has become narrower in single-brooded species. 4. The single-most important predictor of change in duration of the breeding season was change in the date breeding started; there was no change in the date of end of breeding. Species advancing their breeding date the most also expanded the duration of the breeding season. In contrast, long-distance migration and generation time did not predict change in duration of the breeding season. PMID- 20202014 TI - Effect of plant species loss on aphid-parasitoid communities. AB - 1. The consequences of species loss on ecosystem functioning within a single trophic level have been extensively studied. However, the loss of basal species is likely to have profound impacts on the abundance, richness and ecosystem functioning of species at higher trophic levels. 2. Here, we used experimentally established plant communities with a species richness gradient to study the effects of plant species loss on a multi-trophic insect community in the field. We measured densities and species richness of aphids and parasitic wasps (primary, secondary and facultative tertiary parasitoids of aphids) that naturally colonized the grassland plots. 3. Furthermore, we calculated two ecosystem functions: aphid load (the number of aphid individuals per host plant biomass used as a proxy for herbivory) and parasitism rate. We used structural equation models to explore pathways of direct and indirect effects of plant species richness on higher trophic levels. 4. We found that the densities and richness of species at all trophic levels were influenced by changes in plant species richness. The effects were rarely direct, but instead mediated by the abundance and species richness of aphid host plants and subsequent trophic levels. 5. The herbivore and primary parasitoid levels were most directly affected by changes in plant species richness, with highest insect densities and species richness occurring at intermediate plant species richness. The densities and species richness of secondary parasitoids declined linearly with plant species richness owing to sparser resources, resulting in shorter food chains in communities with the highest plant species richness. 6. Aphid load was highest at intermediate plant species richness and negatively affected by both host plant biomass and host plant species richness. Parasitism rate was mostly affected indirectly via aphid density and overall only weakly negatively related to plant species richness. 7. Our results demonstrate that plant species richness can have strong cascading effects up to high trophic levels. However, their direction may differ at the lower and higher ends of the plant species richness spectrum, cautioning against simplifying consequences of plant species loss for specialist food webs that may become limited by sparse resources at high plant richness. PMID- 20202015 TI - Modelling the interactions between Pseudomonas putida and Escherichia coli O157:H7 in fish-burgers: use of the lag-exponential model and of a combined interaction index. AB - AIMS: The objective of the current study was to examine the interactions between Pseudomonas putida and Escherichia coli O157:H7 in coculture studies on fish burgers packed in air and under different modified atmospheres (30 : 40 : 30 O(2) : CO(2) : N(2), 5 : 95 O(2) : CO(2) and 50 : 50 O(2) : CO(2)), throughout the storage at 8 degrees C. METHODS AND RESULTS: The lag-exponential model was applied to describe the microbial growth. To give a quantitative measure of the occurring microbial interactions, two simple parameters were developed: the combined interaction index (CII) and the partial interaction index (PII). Under air, the interaction was significant (P < 0.05) only within the exponential growth phase (CII, 1.72), whereas under the modified atmospheres, the interactions were highly significant (P < 0.001) and occurred both in the exponential and in the stationary phase (CII ranged from 0.33 to 1.18). PII values for E. coli O157:H7 were lower than those calculated for Ps. putida. CONCLUSIONS: The interactions occurring into the system affected both E. coli O157:H7 and pseudomonads subpopulations. The packaging atmosphere resulted in a key element. SIGNIFICANCE AND IMPACT OF THE STUDY: The article provides some useful information on the interactions occurring between E. coli O157:H7 and Ps. putida on fish-burgers. The proposed index describes successfully the competitive growth of both micro-organisms, giving also a quantitative measure of a qualitative phenomenon. PMID- 20202016 TI - A practical random mutagenesis system for probiotic Lactobacillus casei using Tn5 transposition complexes. AB - AIMS: Despite the fact that the entire genome sequence of probiotic Lactobacillus casei has recently been available, their mechanisms of beneficial effects are poorly clarified, probably because of the lack of an efficient mutagenesis system. The aim of this study was to establish a practical random mutagenesis system of L. casei using the Tn5 transposome complexes. METHODS AND RESULTS: We optimized the conditions for transformation using a plasmid pUCYIT356-1-Not2 and then transposition reaction using Tn5 transposome system for L. casei ATCC 27139. Tn5 insertion library of this strain being consisted of 9408 mutants was constructed by repeating the mutagenesis procedure. To examine the utility of this mutagenesis system, we screened a panel of insertion mutants for nutrient requirements. Six auxotrophic mutants were isolated and their Tn5 insertion sites were determined by inverse PCR, which demonstrated that insertions occur randomly throughout the whole bacterial genome. CONCLUSIONS: Tn5 transposome system functioned efficiently to generate transposon insertion mutants of L. casei and enabled to construct useful L. casei Tn5 insertion library at optimized conditions for transformation and transposition. SIGNIFICANCE AND IMPACT OF THE STUDY: The availability of this system facilitates the study of the mechanisms of beneficial effects of L. casei for human health. PMID- 20202017 TI - Bacterial diversity of the digestive gland of Sydney rock oysters, Saccostrea glomerata infected with the paramyxean parasite, Marteilia sydneyi. AB - AIMS: To determine whether the infestation by the protozoan paramyxean parasite, Marteilia sydneyi, changes the bacterial community of the digestive gland of Sydney rock oysters, Saccostrea glomerata. METHODS AND RESULTS: Six 16S rDNA clone libraries were established from three M. sydneyi-infected and three un infected oysters. Restriction enzyme analysis followed by sequencing representative clones revealed a total of 23 different operational taxonomic units (OTUs) in un-infected oysters, comprising the major phyla: Firmicutes, Proteobacteria, Cyanobacteria and Spirocheates, where the clone distribution was 44, 36, 7 and 5%, respectively. Close to half of the OTUs are not closely related to any other hitherto determined sequence. In contrast, S. glomerata infected by M. sydneyi had only one OTU present in the digestive gland. Phylogenetic analysis of the 16S rDNA sequence reveals that this dominant OTU, belonging to the alpha Proteobacteria, is closely related to a Rickettsiales-like prokaryote (RLP). CONCLUSIONS: The microbiota of the digestive gland of Sydney rock oysters is changed by infection by M. sydneyi, becoming dominated by a RLP, and generally less diverse. The bacterial community of un-infected S. glomerata differs from previous studies in that we identified the dominant taxa as Firmicutes and alpha Proteobacteria, rather than heterotrophic gamma-Proteobacteria. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first culture-independent study of the microbiota of the digestive glands of edible oysters to the species level. The commercial viability of the Sydney rock oyster industry in Australia is currently threatened by Queensland Unknown disease and the changes in the bacterial community of S. glomerata corresponding with infection by M. sydneyi sheds further light on the link between parasite infection and mortality in this economically damaging disease. PMID- 20202018 TI - Changes in biochemical constituents of paddy straw during degradation by white rot fungi and its impact on in vitro digestibility. AB - AIMS: To improve the digestibility of paddy straw to be used as animal feed by means of selective delignification using white rot fungi. METHODS AND RESULTS: Solid state fermentation of paddy straw was carried out with some white rot fungi for 60 days. Different biochemical analyses, e.g. total organic matter (TOM) loss, hemicellulose loss, cellulose loss, lignin loss and in vitro digestibility, were carried out along with laccase, xylanase and carboxymethyl cellulase activity. The results were compared with that of a widely studied fungus Phanerochaete chrysosporium, which degraded 464 g kg(-1) TOM and enhanced the in vitro digestibility from 185 to 254 g kg(-1) after 60 days of incubation. Straw inoculated with Phlebia brevispora possessed maximum crude protein. CONCLUSIONS: All the tested white rot fungi efficiently degraded the lignin and enhanced the in vitro digestibility of paddy straw. Phlebia brevispora, Phlebia radiata and P. chrysosporium enhanced the in vitro digestibility almost to similar levels, while the loss in TOM was much lesser in P. brevispora and P. radiata when compared to P. chrysosporium. SIGNIFICANCE AND IMPACT OF THE STUDY: The study reflects the potential of P. brevispora and P. radiata as suitable choices for practical use in terms of availability of organic matter with higher protein value, selective ligninolysis and better digestibility. PMID- 20202019 TI - Evaluation of positively charged alumina nanofibre cartridge filters for the primary concentration of noroviruses, adenoviruses and male-specific coliphages from seawater. AB - AIM: To evaluate the electropositive, alumina nanofibre (NanoCeram) cartridge filter as a primary concentration method for recovering adenovirus, norovirus and male-specific coliphages from natural seawater. METHODS AND RESULTS: Viruses were concentrated from 40 l of natural seawater using a NanoCeram cartridge filter and eluted from the filter either by soaking the filter in eluent or by recirculating the eluent continuously through the filter using a peristaltic pump. The elution solution consisted of 3% beef extract and 0.1 mol l(-1) of glycine. The method using a peristaltic pump was more effective in removing the viruses from the filter. High recoveries of norovirus and male-specific coliphages (>96%) but not adenovirus (<3%) were observed from seawater. High adsorption to the filter was observed for adenovirus and male-specific coliphages (>98%). The adsorption and recovery of adenovirus and male-specific coliphages were also determined for fresh finished water and source water. CONCLUSION: The NanoCeram cartridge filter was an effective primary concentration method for the concentration of norovirus and male-specific coliphages from natural seawater, but not for adenovirus, in spite of the high adsorption of adenovirus to the filter. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrates that NanoCeram cartridge filter is an effective primary method for concentrating noroviruses and male-specific coliphages from seawater, thereby simplifying collection and processing of water samples for virus recovery. PMID- 20202020 TI - Taxonomic and functional diversity of atrazine-degrading bacterial communities enriched from agrochemical factory soil. AB - AIMS: To characterize atrazine-degrading potential of bacterial communities enriched from agrochemical factory soil by analysing diversity and organization of catabolic genes. METHODS AND RESULTS: The bacterial communities enriched from three different sites of varying atrazine contamination mineralized 65-80% of (14) C ring-labelled atrazine. The presence of trzN-atzBC-trzD, trzN-atzABC-trzD and trzN-atzABCDEF-trzD gene combinations was determined by PCR. In all enriched communities, trzN-atzBC genes were located on a 165-kb plasmid, while atzBC or atzC genes were located on separated plasmids. Quantitative PCR revealed that catabolic genes were present in up to 4% of the community. Restriction analysis of 16S rDNA clone libraries of the three enrichments revealed marked differences in microbial community structure and diversity. Sequencing of selected clones identified members belonging to Proteobacteria (alpha-, beta- and gamma subclasses), the Actinobacteria, Bacteroidetes and TM7 division. Several 16S rRNA gene sequences were closely related to atrazine-degrading community members previously isolated from the same contaminated site. CONCLUSIONS: The enriched communities represent a complex and diverse bacterial associations displaying heterogeneity of catabolic genes and their functional redundancies at the first steps of the upper and lower atrazine-catabolic pathway. The presence of catabolic genes in small proportion suggests that only a subset of the community has the capacity to catabolize atrazine. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides insights into the genetic specificity and the repertoire of catabolic genes within bacterial communities originating from soils exposed to long-term contamination by s-triazine compounds. PMID- 20202021 TI - Characterization of an enrichment culture debrominating tetrabromobisphenol A and optimization of its activity under anaerobic conditions. AB - AIM: To study the effects of incubation conditions on the microbial community structure and activity of a TBBPA-debrominating enrichment culture composed of bacterial and archaeal species. METHODS AND RESULTS: The effects of the methanogen inhibitor 2-bromoethanesulfonate (BES), of the antibiotic ampicillin, of substrate (tetrabromobisphenol A, TBBPA) omission and availability of different electron donors on microbial community structure and activity were examined under anaerobic conditions. Debromination of TBBPA was blocked in the presence of ampicillin, while long-term incubation with BES resulted in delayed debromination activity. The results suggest that the bacterial species responsible for the debromination of TBBPA, while archaeal species involved in electron donor metabolism. The enrichment culture lost its debromination activity after cultivation for 9 months without TBBPA, concomitantly with the disappearance of two DNA bands in a denaturing gradient gel electrophoresis (DGGE) analysis of 16S rRNA gene fragments corresponding to Pelobacter carbinolicus and Sphaerochaeta sp. TQ1 that were present in the original culture. When butyrate was used as an electron donor, TBBPA debromination activity was attenuated. When acetate was used as the electron donor, no debromination was observed and in addition, there was a decrease in the abundance of the mcrA gene. CONCLUSIONS: The results indicate that to maintain a high rate of TBBPA debromination activity, it is essential to preserve the microbial community structure (bacterial and archaeal members) of this culture and supply an electron donor that produces high amounts of hydrogen when fermented. SIGNIFICANCE AND IMPACT OF THE STUDY: The study provides important information for the management of cultures to be used in bioremediation of TBBPA contaminated sites. PMID- 20202022 TI - Influence of long-term land application of Class B biosolids on soil bacterial diversity. AB - AIM: To evaluate the effect of long-term annual land applications of Class B biosolids on soil bacterial diversity at University of Arizona Marana Agricultural Field Center, Tucson, Arizona. METHODS AND RESULTS: Following the final of 20 consecutive years of application of Class B biosolids in March 2005, followed by cotton growth from April to November 2005 surface soil samples (0-30 cm) were collected from control (unamended) and biosolid-amended plots. Total bacterial community DNA was extracted, amplified using 16S rRNA primers, cloned, and sequenced. All 16S rRNA sequences were identified by 16S rRNA sequence analysis and comparison to known sequences in GenBank (NCBI BlastN and Ribosomal Database Project II, RDP). Results showed that the number of known genera (identifiable > 96%) increased in the high rate biosolid plots compared to control plots. Biosolids-amended soils had a broad phylogenetic diversity comprising more than four major phyla: Proteobacteria (32%), Acidobacteria (21%), Actinobacteria (16%), Firmicutes (7%), and Bacteroidetes (6%) which were typical to bacterial diversity found in the unamended arid southwestern soils. CONCLUSION: Bacterial diversity was either enhanced or was not negatively impacted following 20 years of land application of Class B biosolids. SIGNIFICANCE AND IMPACT OF THE STUDY: This study illustrates that long-term land application of biosolids to arid southwestern desert soils has no deleterious effect on soil microbial diversity. PMID- 20202023 TI - Control of postharvest decay on cherry tomatoes by marine yeast Rhodosporidium paludigenum and calcium chloride. AB - AIMS: In this study, the potential of calcium chloride (CaCl(2)) application to improve the efficacy of the marine antagonist Rhodosporidium paludigenum in controlling postharvest diseases of cherry tomatoes was assessed. METHODS AND RESULTS: CaCl(2) alone was found not to have any direct influence on the population growth of R. paludigenum in NYDB cultures or in cherry tomato wounds. However, the combined treatments with 1 x 10(8) cells ml(-1)R. paludigenum and CaCl(2) at the concentration from 0.5 to 2% showed high activities to reduce black rot caused by Alternaria alternata in cherry tomato wounds, significantly higher than those of R. paludigenum or CaCl(2) alone. Meanwhile, 0.5% CaCl(2) in combination with 1 x 10(8) cells ml(-1)R. paludigenum greatly inhibited the natural decay of cherry tomatoes in 21 days' storage at 25 degrees C. CONCLUSIONS: The combination of R. paludigenum and CaCl(2) enhances the inhibition of black rot and natural decay of postharvest cherry tomatoes. The results from this study provide a new way to improve the efficiency of R. paludigenum in maintaining the quality of postharvest fruits and vegetables. SIGNIFICANCE AND IMPACT OF THE STUDY: The marine yeast R. paludigenum combined with CaCl(2) has greatly potential use as an alternative to chemical fungicides in inhibiting postharvest decay on cherry tomatoes. PMID- 20202025 TI - Beating heart mitral valve surgery: innovation or back to the past? PMID- 20202026 TI - Are ventricular assist devices underutilized? AB - A dramatic shift in the durability and reliability of ventricular assist device (VAD) therapy is taking hold due to the newer generations of continuous flow VADs that are either in clinical trials or under consideration by the Food and Drug Administration (FDA) for commercial approval. To expand the pool of potential mechanical circulatory support (MCS) patients, device reliability will need to prove to be greatly enhanced over previous generations of VADs and functional capacity and quality of life will need to improve substantially over baseline. Improved patient selection should have the simultaneously beneficial effects of improving outcomes while expanding the MCS patient population. The critical factors determining the likelihood of expansion of the MCS field include, but are not limited to, improvements in technology and its reliability, training and education of all advanced heart failure caregivers, improving availability of MCS geographically, and a shift in patient selection to a population more likely to benefit from MCS therapy. PMID- 20202027 TI - Resternotomy using hypothermic arrest. AB - BACKGROUND: Resternotomy during closed chest cardiopulmonary bypass in hypothermia with or without circulatory arrest has been the preferred method for cardiac reoperations with adherent structures to the sternum. Here, we report our experience with this method and the effects of omitting ventricular decompression during the cooling procedure. METHODS: Twenty reoperations were performed in 19 patients. In half (n = 10) of the procedures aortic regurgitation was present. Cardiopulmonary bypass was instituted in all patients before resternotomy, and the re-entry into the chest was performed either under hypothermic low-flow cardiopulmonary bypass or circulatory arrest. The reason for this choice of technique was adherent structures to the sternum posing a substantial risk for rupture during resternotomy in all patients. RESULTS: Rupture upon re-entry into the chest occurred in five operations. No patient died due to re-entry injury. The overall hospital mortality was 15%. No differences in postoperative outcomes including heart failure, biochemical markers indicating myocardial damage, and three-month follow-up assessment of cardiac function were found between patients with aortic regurgitation and patients without aortic regurgitation. CONCLUSIONS: Based on our experience, omitting ventricular decompression in resternotomy in hypothermia and arrested circulation or low-flow cardiopulmonary bypass can be safely used, and the presence of aortic regurgitation does not seem to influence the outcome. PMID- 20202028 TI - Early pulmonary embolectomy for acute pulmonary embolus: an operation whose time has come. PMID- 20202029 TI - Acute aortic valve rupture secondary to blunt chest trauma. AB - Cardiac valve injury after blunt chest trauma is rare. We present a case of blunt chest trauma resulting in an isolated aortic valve rupture treated with aortic valve replacement. PMID- 20202030 TI - Acute cor pulmonale and repeated pulmonary embolism in a patient with a "worm like" transit thrombus crossing a patent foramen ovale. PMID- 20202031 TI - Left ventricular myxoma accompanied with congenital atrial septal defect. PMID- 20202032 TI - Endocardial fibroelastosis of the right ventricle and tricuspid valve in a young adult with Behcet's disease. AB - Endocardial fibroelastosis is characterized by massive proliferation of collagenous and elastic tissue, in which the pathological process is restricted to the endocardium. In this report, we present the case of a 20-year-old man with Behcet's disease and endocardial fibroelastosis of the right ventricle involving tricuspid valve resulting in a tumor mass that was resected along with tricuspid valve replacement. The clinical and pathological features of this rare entity are reviewed. PMID- 20202033 TI - Bridge to transplantation: current outcomes. AB - The use of implantable ventricular assist devices for the treatment of advanced, decompensated heart failure as a bridge to heart transplantation has experienced considerable evolution over the past decade. Improvements in the management and prevention of serious adverse events, and introduction of new continuous-flow rotary pumps that are smaller, more durable, and associated with fewer serious adverse advents has expanded the use of this therapy to a larger population of patients for bridge to transplant indication. PMID- 20202034 TI - Delayed presentation of iatrogenic left ventricular pseudoaneurysm. AB - Occurrence of left ventricular aneurysm outside the realm of ischemic heart disease is uncommon and one following an iatrogenic trauma is very rare. We describe one such case of left ventricular pseudoaneurysm developing following pericardiocentesis and presenting one year after the procedure, and its successful surgical management. PMID- 20202035 TI - Beating heart valve surgery in patients with low left ventricular ejection fraction. AB - BACKGROUND: Patients with very low left ventricular ejection fraction (LVEF) are at high risk for valve surgery. We herein present our experience with beating heart valve surgery in such patients. METHODS: From May 2000 to October 2006, 346 consecutive patients underwent beating heart valve surgery. Of these, 50 patients had LVEF <30%: 7 had LVEF 21 to 29%, 34 had LVEF <20%, and 9 had LVEF <10%. Mean age was 57.44 +/- 12.45 years (range 28 to 85 years). There were 40 males (80%) and 10 females (20%). RESULTS: Isolated mitral valve (MV) and aortic valve replacements were performed in 11 (22%) and 10 (20%) of patients, respectively. Fourteen (28%) patients underwent combined coronary artery bypass grafting and valve replacements. MV repairs were performed; 13 (26%) patients and 2 (4%) patients had combined MV replacements and tricuspid repairs. Mean hospital stay was 15.37 +/- 13.12 days (range 3 to 55 days). Overall early mortality (<30 days) was 6% (three patients) and one patient (2%) died late (>30 days). CONCLUSIONS: Beating heart valve surgery in patients with poor LVEF yields results similar to conventional surgery using cardioplegia. Additional studies are needed to fully evaluate the potential benefits of this method of myocardial perfusion for this high-risk group of patients. PMID- 20202036 TI - Aortic root replacement using a biovalsalva prosthesis in comparison to a "handsewn" composite bioprosthesis. AB - BACKGROUND: The Biovalsalva aortic root prosthesis incorporates an Elan porcine stentless biological aortic valve suspended within a triple-layered vascular conduit with preformed aortic sinuses of Valsalva. This study compared implantation of the Biovalsalva prosthesis with a "handsewn" composite bioprosthetic graft (CE Perimount bovine bioprosthesis anastomosed to a gelatin impregnated gelweave Dacron graft). METHODS: Between December 2004 and January 2009, 39 patients underwent elective or urgent aortic root replacement (modified Bentall procedure with coronary button reimplantation) using a Biovalsalva (n = 21) or a handsewn bioprosthesis (n = 18) for aortic root dilatation. RESULTS: There was no significant difference in the preoperative variables between the two study groups including age (70.7 +/- 1.7 vs. 67.6 +/- 2.9 years, p > 0.05). There was no in-hospital mortality. Three patients in each group underwent concomitant aortic hemi-arch replacement. Patients who underwent Biovalsalva implantation had a reduced need for transfusion of blood (1.25 +/- 0.32 vs. 3.17 +/- 0.71 units, p < 0.05) and fresh frozen plasma (2.78 +/- 0.39 vs. 1.85 +/- 0.31, p < 0.05), and reduced mediastinal blood loss (416 +/- 52 vs. 583 +/- 74 mL, p < 0.05) compared to those with a handsewn bioprosthesis. Cardiopulmonary bypass time (141 +/- 6 vs. 170 +/- 17 minutes, p = NS) and aortic cross-clamp time (113 +/- 6 vs. 115 +/ 7 minutes, p = NS) were similar. Postoperative echocardiography demonstrated excellent hemodynamic function of the Biovalsalva prosthesis (mean size 25.1 +/- 0.4 mm valved conduit) with a peak pressure gradient of 26.2 +/- 1.9 mmHg and no or trivial valvular regurgitation. CONCLUSIONS: The Biovalsalva prosthesis should be considered for patients requiring a biological aortic root replacement. It offers an "off-the-shelf" preassembled composite biological valve conduit with excellent hemostatic and hemodynamic properties. PMID- 20202037 TI - Ultrasonic scalpel for hemostasis in pacemaker-dependent patients during open heart surgery. AB - We successfully used the ultrasonically activated scalpel to secure hemostasis in a temporary pacemaker-dependent patient following repair of Ebstein's anomaly. The advantages of using this modality are briefly discussed. PMID- 20202038 TI - Primary cardiac synovial sarcoma. AB - Synovial sarcomas are rare tumors and account for only 3% of cardiac malignancies. In this report, we present a case of a primary synovial sarcoma of the left ventricle. PMID- 20202039 TI - Transient global amnesia as the presenting feature of heparin-induced thrombocytopenia. AB - A 57-year-old man developed transient global amnesia within an hour of bolus unfractionated heparin administration on day 4 post-mitral valve replacement. Both immunoglobulin G-specific enzyme-linked immunosorbent assay and serotonin release assay were strongly positive for the antibodies that cause heparin induced thrombocytopenia. The patient's cognitive functions returned to normal following discontinuation of unfractionated heparin and warfarin and commencement of lepirudin infusion. PMID- 20202040 TI - Does childhood anxiety evoke maternal control? A genetically informed study. AB - BACKGROUND: Despite theoretical and empirical support for an association between maternal control and child anxiety, few studies have examined the origins of this association. Furthermore, none use observer-ratings of maternal control within a genetically informative design. This study addressed three questions: 1) do children who experience maternal control report higher anxiety levels than those who do not?; 2) to what extent do genetic and environmental factors influence maternal control and child anxiety?; 3) to what extent do genetic and environmental factors influence the associations between child anxiety and maternal control? METHOD: Five hundred and thirty 8-year-old children (from 265 twin pairs) and their mothers were observed participating in an 'etch-a-sketch' task from which maternal control was rated. Children rated their anxiety using the Screen for Child Anxiety Related Emotional Disorders. RESULTS: Children who experienced maternal behaviour rated as 'extreme control' reported higher anxiety levels than those who did not. Maternal control was highly heritable (A = .63), high self-rated anxiety less so (h(2)(g) = .36). The overlap between high child anxiety and maternal control was primarily due to shared genetic factors. CONCLUSIONS: These results suggest that maternal control is likely to have been elicited by children with high levels of anxiety. PMID- 20202042 TI - Xanthogranulomatous reaction to a ruptured galactocele. AB - We describe a case of a 34-year-old, healthy, lactating female with a 2-month history of breast pain and an enlarging, tender mass on her right nipple. Her right breast was firm and mildly engorged without mass, warmth or erythema. A tender, yellow nodule was located on the superior aspect of the nipple, obstructing the flow of milk from this portion of the nipple. A biopsy showed epidermal erosion, sheets of cells with massively distended, foamy cytoplasm in the dermis, and a hypertrophied and occluded glandular duct, consistent with reactive squamous metaplasia. Immunostaining for CD68 confirmed the foamy cells were macrophages, and anti-human milk fat globulin-1 (HMFG1) labeled the substance within the macrophages consistent with human breast milk. Therefore, the lesion could be identified as a xanthogranulomatous reaction to a ruptured galactocele. PMID- 20202044 TI - Bilateral areolar and periareolar pityriasis versicolor. AB - An adolescent boy presented with isolated, symmetrical, bilateral areolar and periareolar pityriasis versicolor. This extremely rare condition should be considered in the differential diagnosis of light brown patches on the areolae. PMID- 20202045 TI - Cutaneous macroglobulinosis deposits in a patient with IgM paraproteinemia/incipient Waldenstrom macroglobulinemia. AB - A 43-year-old healthy patient developed disseminated flat skin-colored to red brown papules over a few months. These papules were the result of cutaneous IgM deposits representing the first symptom of a hitherto undiagnosed IgM paraproteinemia. This extremely rare skin manifestation of IgM paraproteinemia e. g. possibly incipient Waldenstrom macroglobulinemia should be included in the histopathological differential of eosinophilic dermal deposits. PMID- 20202041 TI - Prodromal symptoms and atypical affectivity as predictors of major depression in juveniles: implications for prevention. AB - BACKGROUND: Given the long-term morbidity of juvenile-onset major depressive disorder (MDD), it is timely to consider whether more effort should be dedicated to its primary and secondary prevention. METHODS: We reviewed studies of prodromal symptoms that may herald a first episode pediatric MDD and considered whether that literature has made an impact on secondary prevention (efforts to prevent progression from symptoms to full disorder). We also reviewed studies of children at familial risk for MDD that addressed atypical affectivity and the regulation of sad, dysphoric affect (mood repair) and related physiological systems, and considered whether research in those areas has made an impact on primary prevention of pediatric MDD (efforts to prevent the disorder). RESULTS: A compelling body of literature indicates that depressive symptoms in youngsters predict subsequent MDD across the juvenile (and early adult) years and that any combination of several symptoms for at least one week is informative in that regard. These findings are echoed in the case selection criteria used by many secondary prevention programs. Convergent findings also indicate that (compared to typical peers) young offspring at familial risk for depression manifest low positive affectivity and compromised mood repair, along with signs of dysfunction in three intertwined physiological systems that contribute to affectivity and mood repair (the hypothalamic-pituitary-adrenal (HPA) axis, cerebral hemispheric asymmetry, and cardiac vagal control). While all these affect-related parameters are suitable for case selection and as intervention targets, they have not yet made an impact on primary prevention programs. CONCLUSIONS: According to recent meta-analyses, attempts to prevent pediatric depression have not lived up to expectations. Based on our review, possible reasons for this include: (a) the use of case selection criteria that yield samples heterogeneous with regard to whether the symptoms are truly prodromal to an episode of MDD or are trait-like (which could affect response to the intervention), (b) failure to fully capitalize on the broad-ranging literature on vulnerability to pediatric MDD, as evidenced by the infrequent use of family history of depression (a robust index of vulnerability) or combined indices of vulnerability for case selection, and (c) lack of synchrony between dimensions of vulnerability and the content of the prevention program, as indicated by the overwhelming use of cognitive-behavioral interventions, irrespective of subjects' age, developmental readiness, and whether or not they evidenced the relevant cognitive vulnerability. Prevention trials of pediatric MDD could benefit from new approaches to case selection that combine various indices of vulnerability, more effective use of existing findings, and new or modified interventions that are developmentally sensitive. PMID- 20202046 TI - Pityriasis rubra pilaris--a retrospective single center analysis over eight years. AB - BACKGROUND: Pityriasis rubra pilaris (PRP) is a rare papulosquamous dermatosis. We evaluated evaluate co-morbidities, complications, and outcome of treatment regimens. PATIENTS AND METHODS: This is a retrospective study at an academic teaching hospital. We analyzed all patients with the definite diagnosis of PRP seen since 2001. Epidemiologic data, co-morbidities, response to and course during treatment were investigated. RESULTS: We identified 10 PRP-patients (6 men, 4 women), mean age 56.4 years, with type I (n = 9) and type IV (n = 1). Three patients had internal co-morbidities (atrial fibrillation with cardiac insufficiency, dilated cardiomyopathy, diabetes mellitus). Two patients needed psychiatric treatment because of depression. PRP caused ectropium (2 x), diffuse effluvium (1 x), and stenosis of the outer ear canal (1 x). We did not observe a spontaneous remission. Among 9 patients with PRP type I, five were treated with acitretin (two of them as Re-PUVA), and two with methotrexate (in one patient combined with fumaric acids). Systemic corticosteroids were not effective. One patient was treated with infliximab i.v., 5 mg/kg body weight. Starting with the first application, inflammatory activity decreased and erythema got paler. The treatment was well tolerated. CONCLUSIONS: PRP type I is a severe, chronic inflammatory dermatosis responding hesitantly to classic systemic therapies. Tumor necrosis factor-alpha antagonists are an effective treatment option for difficult cases. PMID- 20202047 TI - Epidemiology of vitiligo, associated autoimmune diseases and audiological abnormalities: Ankara study of 80 patients in Turkey. AB - BACKGROUND: Recent clinical studies suggest that the pathogenetic mechanisms of vitiligo could be of systemic origin as vitiligo is associated with auditory abnormalities as well as other autoimmune disorders. OBJECTIVES: To investigate clinical, genetic characteristics and laboratory findings of vitiligo as well as auditory abnormalities and the association of the disease with the other autoimmune disorders. MATERIALS AND METHODS: From January to December 2008, we collected-data from 80 vitiligo patients to establish the clinical and epidemiological profile of vitiligo in Turkey. RESULTS: Thirty patients were men and 50 were women, with a mean age of 37 years and a mean onset age of 10 years. Vitiligo vulgaris was the most common type, followed by focal, acrofacial, segmental and universal types. Forty-four (55%) patients had an associated autoimmune disease. These associated diseases were Hashimoto thyroiditis in 25, alopecia areata in 10, pernicious anaemia in seven and diabetes mellitus in two patients. Statistically significant changes in human leukocyte antigen in patients with vitiligo were HLA A24,-30, B63, CW6, DR15, DR51, DQ5,-6. Auditory problems were observed in 37.7% patients. Nine of the 20 patients showed unilateral minimal hearing loss (>30 dB), while the other 11 demonstrated bilateral hearing loss (>30 dB) over a large range of frequencies (2000-8000 Hz). CONCLUSION: Our study demonstrates that vitiligo is a part of systemic autoimmune process. Audiological examination should be performed in all patients for auditory problems which are commonly presented as hypoacusis. PMID- 20202049 TI - Teledermatology integrated in the Dutch national healthcare system. PMID- 20202050 TI - Dermoscopic features of a collision tumour composed of a pigmented basal cell carcinoma and a melanoma. PMID- 20202051 TI - Aggravating factors for melasma: a prospective study in 197 Tunisian patients. AB - BACKGROUND: Melasma is a frequent cause of consultations at dermatology departments by dark-skinned patients in Tunisia. OBJECTIVE: To investigate factors that influence melasma severity in a large Tunisian population. METHODS: A total of 197 patients (188 women and 9 men), who attended Tunis Military Hospital for a consultation were included prospectively from August 2005 to August 2006. Disease severity was estimated using the Melasma Area and Severity Index (MASI). Aggravating factors were investigated using multiple logistic regressions. RESULTS: Of the women included, 14% presented phototype III, 45% phototype IV and 41% phototype V; 76% presented a centrofacial melasma phenotype, 23% a malar and 1% a mandibular phenotype. About 60% developed melasma before thirty. Sun exposure was reported as a triggering factor by 51% of women and as an aggravating factor by 84%. Pregnancy was reported as an aggravating factor by 51% of women who had been pregnant, and oral contraceptive use reported by 38% of women exposed to oral contraceptives. The risk of severe melasma was about three times higher for women with age at onset under 30, phototype V and major lifetime sun exposure and about 8 times higher for women exposed to oral contraceptives. CONCLUSION: This study identifies a number of factors associated with the severity of melasma. Further epidemiological studies in this type of population, in particular, to investigate triggering factors, are justified by the aesthetic damage caused by melasma in dark-skinned patients, lack of efficacy of existing treatments, non-compliance with photoprotection recommendations and the challenge of treatment. PMID- 20202052 TI - Thyroid peroxidase antibodies in patients with telogen effluvium. PMID- 20202053 TI - Psoriatic disease: concepts and implications. PMID- 20202054 TI - Prevalence and prognostic value of cutaneous manifestations in patients with myelodysplastic syndrome. AB - BACKGROUND: Skin manifestations associated with myelodysplastic syndrome (MDS) may reveal bone marrow transformation into acute myeloid leukaemia. OBJECTIVE: The objective of this study was to assess the prevalence of skin manifestations associated with MDS. In addition, we evaluated the risk of acute myeloid leukaemia transformation associated with skin manifestations. METHODS: We studied a cohort of 157 patients with primary MDS followed up prospectively for a median of 44 months. Skin lesions were prospectively assessed as part of medical examination every 6 months by a board certified dermatologist. Survival analyses were performed to assess the association between the presence of skin lesions and the risk of acute myeloid leukaemia. RESULTS: Fifteen patients (9.55%) experienced skin lesions previously reported as associated with MDS. These were neutrophilic dermatosis (7, 4.46%), specific lesions (5, 3.18%), cutaneous vasculitis (2, 1.27%) and Behcet disease (1, 0.63%). Survival analysis showed that the risk of transformation into acute myeloid leukaemia was slightly but not significantly increased in patients with skin lesions as compared with patients without skin lesions with a relative risk of 2.08 (95% CI 0.92-4.67). CONCLUSION: The prevalence of skin lesions, mostly neutrophilic dermatosis and specific lesions, is relatively high in patients with MDS. There is a trend for a higher risk of transformation into acute myeloid leukaemia in patients with skin lesions. PMID- 20202055 TI - Intralesional immunotherapy of common warts: successful treatment with mumps, measles and rubella vaccine. AB - BACKGROUND: Despite numerous therapeutic modalities reported in the literature, treatment of common warts remains a continuing challenge and there is no universal consensus about optimal treatment. Recently, intralesional immunotherapy by different antigens has proved efficacy in the treatment of different types of warts. OBJECTIVE: To evaluate the efficacy and safety of intralesional mumps, measles and rubella (MMR) vaccine in the treatment of common warts. METHODS: The study included 135 patients with single or multiple recalcitrant or non-recalcitrant common warts. They were randomly assigned to two groups; the first group (85 patients) received intralesional MMR vaccine, and the second group (50 patients) received intralesional saline as a control group. Both treatments were injected into single lesions or largest wart in case of multiple lesions at 2-week intervals until complete clearance or for a maximum of five treatments. Follow-up was made every 2 months for 6 months to detect any recurrence. RESULTS: A highly significant difference was found between the therapeutic response of common warts to MMR vaccine and saline control group (P < 0.001). In the MMR group, complete response was achieved in 80% and 84.6% of patients presenting with recalcitrant and multiple warts respectively. No recurrence was observed in the MMR group and side effects included pain during injection and flu-like symptoms. CONCLUSIONS: Intralesional immunotherapy by MMR vaccine is a promising effective and safe treatment modality for common warts, particularly the multiple ones. PMID- 20202056 TI - A case of multiple benign fibrous histiocytoma with indeterminate cells and eosinophils. PMID- 20202057 TI - Subcutaneous zygomycosis: report of 10 cases from two institutions in North India. AB - BACKGROUND: Subcutaneous zygomycosis is an uncommon condition observed in tropics. Few series have been published, particularly from the northern regions of India. OBJECTIVES: The aim of this study was to describe clinical, investigative and therapeutic details in subcutaneous zygomycosis observed in two teaching hospitals in Delhi. PATIENTS AND METHODS: Ten patients seen over a period of 10 years (1999-2009) form the material for this report. RESULTS: There were four children and six adults. In four children, the presentation was a subcutaneous localized mass or gradually spreading plaque. In the others, it was observed over nasal region of face, spreading inward into mucosal sites and paranasal sinuses, and outward to the contiguous areas. Regional lymphadenopathy was present in two with facial lesions. Majority showed a granulomatous infiltrate with admixture of other cells, mainly eosinophils. Aseptate or poorly septate hyphae were observed in seven. In one patient in whom no hyphae were observed, there was dense perivascular inflammation. Organisms were cultured from four patients, Basidiobolus ranarum in two and Syncephalastrum racemosum in two. The main therapy used was a saturated solution of potassium iodide (KI). Four received only KI of which two attained cure after 3 months and 9 months respectively, and the other two showed signs of regression. In one boy subsidence was associated with reduced circumference of thigh. Ketoconazole or itraconazole was given with KI to hasten regression when response was slow or there were side effects to KI. CONCLUSION: Awareness and early recognition will prevent disfigurement produced by advanced disease, misdiagnosis and unnecessary surgical intervention. PMID- 20202058 TI - Pemphigus, analysis of 155 patients. AB - BACKGROUND: Pemphigus vulgaris is a chronic autoimmune mucocutaneous blistering disease. In the last 20 years, immunomodulatory agents have been added to the therapeutic armamentarium. Only few recent studies have evaluated the long-term outcome of pemphigus and possible prognostic parameters in a large group of patients. The aim of this study was to evaluate and analyse the course and prognostic factors of pemphigus in patients followed from 1976 to 2004. PATIENTS AND METHODS: The study group consisted of 155 patients attending the pemphigus clinic of a major tertiary-care medical centre. Background, clinical and treatment data were derived from the patient files and telephone contact. Statistical analysis was performed with Pearson correlation, Fisher exact test, and univariate and multivariate logistic regression models. RESULTS: Age < 40 years at disease onset, Sephardic Jewish origin, and mucosal involvement at diagnosis and high number of relapses were found to be independent prognostic factors of poor outcome. A long (> 1 year) primary remission was a good prognostic factor. During the 26-year study period, 16 patients died. None of the deaths was directly related to either the disease or a complication of treatment. CONCLUSIONS: The course and outcome of pemphigus are worse in patients who are young at diagnosis (< 40 years) or of Sephardic Jewish origin. Mucosal involvement at diagnosis and poor response to treatment also predict poor outcome. The mortality rate of pemphigus is apparently lower than reported in the literature, perhaps because of the contemporary use of adjuvant immunomodulatory therapeutic agents. PMID- 20202059 TI - Role of Synchrotron infra red microspectroscopy in studying epidermotropism of cutaneous T-cell lymphoma. AB - BACKGROUND: The molecular mechanisms of epidermotropism in mycosis fungoides (MF) are not well understood to date. OBJECTIVES: The aim of this study was to differentiate between epidermal and dermal lymphocytes within the skin of MF patients. METHODS: This study was done on 10 MF patients with a mean age of 50 years diagnosed clinically in the Department of Dermatology, Cairo University, Egypt. A 6 mm biopsy was taken from each patient in order to confirm the diagnosis. Skin biopsies were cut, put on low e-slides and then stained with H&E. Further examination with Synchrotron infrared (IR) microspectroscopy was done in National Synchrotron Light Source--Brookhaven National Laboratory, New York, USA. Immunophenotyping using antibodies CD3, CD4, CD8, CD20 and CD30 was also done. Statistical analysis was done by Student's t-test and cluster analysis. RESULTS: Both epidermal and dermal lymphocytes were clustered separately. Also, Amide I and RNA and DNA within the lymphocytes were significantly different between the epidermis and the dermis. CONCLUSIONS: The biochemical analysis of protein, RNA and DNA with Synchrotron IR microspectroscopy is a promising tool for studying epidermotropism in cutaneous T-cell lymphoma. PMID- 20202060 TI - The high rate of familial lichen sclerosus suggests a genetic contribution: an observational cohort study. AB - BACKGROUND: Familial lichen sclerosus (LS) has been described in only 37 families. We feel that the association is under-reported. OBJECTIVES: To determine the percentage of patients with LS who have a positive family history. METHOD: A large observational-cohort study of a total of 1052 females at vulval clinics within a University Hospital with a diagnosis of LS of the vulva (clinical diagnosis was confirmed in 80% of cases by histology). Patients were questioned as to family history of LS or balanitis xerotica obliterans; male circumcision for medical reasons; vulval cancer; and routine medical and family history. The outcome was the presence or absence of personal or family history of LS, autoimmune disorder or vulval cancer. RESULTS: In total 1052 patients were investigated. Of these, 126 (12%) had a positive family history of LS. These patients belonged to 95 families. Vulval cancer was significantly increased in those with a family history of LS compared with those without (4.1% vs. 1.2%, P < 0.05). There was more associated autoimmune disease in familial LS than in sporadic LS, although this was not statistically significant. (7% vs. 5%, P > 0.2). CONCLUSION: Our data from a large cohort of patients with LS provide evidence of an increased risk for family members to develop LS. This indicates a likely genetic component in the aetiology of LS. PMID- 20202061 TI - A fatal leopard attack. AB - A rare case of a big cat fatal attack is presented. A male leopard that had escaped from its unlocked cage attacked a 26-year-old male zoo worker. The man sustained penetrating injuries to the neck with consequent external bleeding. The man died while being transported to the hospital as a result of the injuries sustained. The wounds discovered on the victim's body corresponded with the known methods of leopard attacks and with findings on the carcasses of animals killed by leopards in the wild. The conclusion of the medicolegal investigation was that the underlying cause of death was a bite wound to the neck which lacerated the left internal jugular vein, the two main branches of the left external carotid artery, and the cervical spine. The cause of death was massive external bleeding. Special attention is paid to the general pattern of injuries sustained from big cat attacks. PMID- 20202062 TI - An autopsy case of sudden unexplained death caused by malaria. AB - Sudden unexplained deaths, especially those unwitnessed can lead to forensic issues and would necessitate the need for a meticulous and complete postmortem examination including ancillary investigations to discover the cause of death. We herein report a case of sudden unexplained death caused by malaria in an apparently healthy individual. This fatal case is presented to remind the forensic pathologist of the possibility of malaria as a cause of sudden unexplained death in malaria-endemic regions. In the present case, histopathological examination demonstrated the presence of parasitized red blood cells with malarial pigment in the blood capillaries in the brain, myocardium, pericardium, lungs, kidneys, liver, and the spleen. Cerebral malaria with acute renal insufficiency or pulmonary edema with an acute respiratory distress syndrome might have been the cause of death. PMID- 20202063 TI - Detection of gunshot residue in blowfly larvae and decomposing porcine tissue using inductively coupled plasma mass spectrometry (ICP-MS). AB - Blowfly larvae and porcine tissue contaminated with gunshot residue (GSR) were collected during summer and winter months, over a 37-day and a 60-day sampling period, respectively. Wound samples were microwave-digested and analyzed by inductively coupled plasma mass spectrometry (ICP-MS) for the detection of antimony, barium, and lead. During summer, the 37-day sampling period encompassed all stages of decomposition, except skeletonization. The three elements were detected in larvae only on days 3 and 4 after death but were detected at significant levels in tissue samples throughout the entire sampling period. In winter, no significant decomposition was observed throughout the 60-day sampling. Although temperatures were too low for blowfly activity, the three elements were detected in the tissue samples at relatively constant, significant levels. Hence, GSR determination in tissue was more dependent on decomposition stage rather than time since death. PMID- 20202064 TI - Shooting through clothing in firearm suicides. AB - There is a longstanding empirical rule that people who commit suicide rarely shoot through their clothing, but rather put it aside to expose the nude skin. Signs of shots through clothing have always been considered suspicious, raising presumptions of the presence of an abettor. Our report, based on a retrospective study of fatal suicidal firearm injuries from the years 1980 to 2007, points out that suicide victims only rarely remove clothing from the site of the future entry wound. The report covered 43 cases with fatal gunshot wounds in the area of the thorax, with only four persons (9%) removing the clothing present in the area of the subsequent self-inflicted wound. Defects present on the clothing of a victim cannot, therefore, be understood as an absolute criterion for disproving the possibility of suicide, and nor do they necessarily indicate an unfortunate accident or homicide. If, however, the suicide victim removes the clothing from the area of the future wound, then this is almost always an indication of suicide. PMID- 20202065 TI - Evaluation of Tamm-Horsfall protein and uroplakin III for forensic identification of urine. AB - In this study, Tamm-Horsfall protein (THP), a major component of urinary protein, and uroplakin III (UPIII), a transmembrane protein widely regarded as a urothelium-specific marker, were evaluated for forensic identification of urine by ELISA and/or immunohistochemistry. THP was detected in urine, but not in plasma, saliva, semen, vaginal fluid, or sweat by the simple ELISA method developed in this study. In addition, most aged urine stains showed positive results. The urine specificity of THP was confirmed by gene expression analysis. Therefore, as reported previously, ELISA detection of THP can be used as a presumptive test for urine identification. UPIII was specific for immunohistochemical staining of cells in centrifuged precipitate of urine. However, ELISA and RT-PCR for UPIII were not specific for urine. UPIII may be applicable for forensic urine identification by immunohistochemistry. PMID- 20202066 TI - Age estimation by racemization method in teeth: application of aspartic acid, glutamate, and alanine. AB - Here, we report on an experimental approach of simultaneous determination of various amino acids racemization (AAR) rates in teeth. We evaluated the measurements of aspartic acid (Asp), glutamate (Glu), and alanine (Ala) isolated from dentin. Asx D/L rates from total amino acid fraction, generally used for age estimation, showed high correlation (r = 0.98) with age. As Glx and Ala showed very slow racemization kinetics in TA, we performed further analysis of the acid soluble protein (SP) fraction. The results supported improved correlation between age and D/L rates for Glu (r = 0.84) and Ala (r = 0.85), as well as for Asp (r = 0.98). By providing further elucidation on dentin protein racemization, the technique offers a considerable opportunity to involve other amino acids in age estimation studies. As the process does not require additional separation steps, the method can be easily adapted to existing protocols. PMID- 20202067 TI - DETECHIP: a sensor for drugs of abuse. AB - The design and preliminary characterization of a novel sensor for drugs of abuse, DETECHIP, is described in this proof-of-concept note. Combining both colorimetric and fluorimetric assays, DETECHIP is suitable for lab and field use. More than a conventional spot test which provides a single "yes or no" answer, DETECHIP provides twenty responses for a more complete characterization of suspect material. This is accomplished by visually noting colorimetric and fluorescent changes of carefully selected dyes upon the addition of test analytes, including drugs of abuse, with respect to controls. Color and fluorescence changes are recorded numerically so that a 20 digit identification code can be constructed for comparison of test analytes and known compounds. DETECHIP is applicable to a variety of drugs, both plant-derived and synthetic, addressing the need to use several different spot tests simultaneously for a single sample. PMID- 20202068 TI - Multiple self-inflicted stab wounds to neck, chest and abdomen as a unique manner of suicide. AB - This is a case report of a 30-year-old man found dead in his flat lying on the floor with multiple stab wounds over the body, surrounded by an extensive volume of blood. Examination of the scene of death showed a secure flat, locked from inside. A blood-stained knife was present close to the body and two unstained notes left on the sofa at the locus. A small plastic bag containing white powder (which following toxicological examinations appeared to be cocaine) and an almost full bottle of beer were present on a table. Autopsy revealed more than 40 stab wounds to neck, chest, and abdomen arranged in isolated groups within which the wounds showed similar directions and had a transverse orientation. Together with hesitation marks located on the neck and wrists these characteristics allowed to interpret this case as a suicide. PMID- 20202069 TI - Alterations of length heteroplasmy in mitochondrial DNA under various amplification conditions. AB - There are several areas within mitochondrial DNA that show length heteroplasmy. If the heteroplasmy pattern is unique and consistent for each person, it may be used to support an interpretation of exclusion in identity testing. We investigated whether the length heteroplasmy pattern would be consistent under different amplification conditions. We also determined whether various amplification parameters would affect the homopolymeric cytosine stretches (C stretch) in HV1. Monoclonal samples tended to be heteroplasmic after amplification. After several repetitions, C-stretch patterns of all samples were inconsistent even under the same amplification conditions. Increased PCR cycles and high template concentrations resulted in a more frequent heteroplasmic tendency. These amplification parameters seem to have little effect if samples are not long enough in C-stretch or total length of the segment from nt 16180 to nt 16193. It is suggested that the pattern of length heteroplasmy cannot be used as an additional polymorphic marker. PMID- 20202070 TI - Accidental hanging deaths in children in Konya, Turkey between 1998 and 2007. AB - In general, hanging cases are the result of suicide, and accidental and homicidal hanging cases are rarely seen. This study retrospectively investigated 4571 death examinations and autopsies that were performed at The Konya Branch of the Forensic Medicine Council (Turkey) between 1998 and 2007; hanging was involved in 201 (6.5%) of the cases. There were a total of 13 accidental hanging cases, where 12 of these involved children. In seven of the cases, the accidental hanging involved a scarf that wraps around swing-like cradles and is intended to prevent infants from falling down. It was concluded that accidental hanging deaths can be reduced by replacing swing-like cradles with cribs that are designed for children, removing ropes in and around the house, and preventing children from reaching and/or playing with rope-like objects. PMID- 20202071 TI - Environmental pollen trapped by tobacco leaf as indicators of the provenance of counterfeit cigarette products: a preliminary investigation and test of concept. AB - The global trade in counterfeit tobacco products is increasingly taking market share from legal brands in many parts of the developed world, with attendant adverse economic, health, criminal, and other societal impacts. Knowing the geographical source is central to developing new strategies for curbing this illicit trade, and here, the potential of environmental pollen extracted from manufactured cigarettes is examined. Two samples representing U.S. and Chinese brands were investigated for their pollen content. Results indicate that tobacco leaf very efficiently captures environmental pollen (about 1800 and 12,600 grains per cigarette, respectively) with no detectable self-contamination by the tobacco plant. In both cases, the flora is typical of open space environments, but pollen type counts indicate very different distributions of species. This preliminary investigation indicates that palynology has the potential to constrain geographical source(s) of tobacco, particularly if regionally localized species can be recognized among the pollen. PMID- 20202072 TI - Evaluation of the ability of people with intellectual disabilities to 'weigh up' information in two tests of financial reasoning. AB - BACKGROUND: An assessment of mental capacity includes an evaluation of the ability to 'weigh up' information, but how to do this is uncertain. We have previously used a laboratory decision-making task, temporal discounting, which involves a trade-off between the value and the delay of expected rewards. Participants with intellectual disabilities (ID) showed very little evidence of 'weighing up' of information: only a third of participants showed consistent temporal discounting performance, and when present, consistent performance was usually impulsive; and the ability to perform consistently was more strongly related to executive functioning than to IQ. The aim of the present study was to replicate these observations and extend them to a more realistic financial decision-making task. METHODS: We administered a temporal discounting task and a financial decision-making task, as well as tests of executive functioning and IQ, to 20 participants who attended day services for people with learning disabilities (mean Full-Scale IQ = 59), and to 10 staff members. RESULTS: Performance in both decision-making tasks was related more strongly to executive functioning than to IQ. In both tasks, decisions by service users were made largely on the basis of a single item of information: there was very little evidence in either task that information from two sources was being 'weighed'. CONCLUSIONS: The results suggest that difficulty in 'weighing up' information may be a general problem for people with ID, pointing to a need for psycho educational remediation strategies to address this issue. The importance of executive functioning in decision-making by people with ID is not recognized in the legal test for mental capacity, which in practice includes a possibly irrelevant IQ criterion. PMID- 20202073 TI - Theoretical exploration of the neural bases of behavioural disinhibition, apathy and executive dysfunction in preclinical Alzheimer's disease in people with Down's syndrome: potential involvement of multiple frontal-subcortical neuronal circuits. AB - BACKGROUND: Recent research has suggested a specific impairment in frontal-lobe functioning in the preclinical stages of Alzheimer's disease (AD) in people with Down's syndrome (DS), characterised by prominent changes in personality or behaviour. The aim of the current paper is to explore whether particular kinds of change (namely executive dysfunction (EDF), disinhibition and apathy), associated in the literature with disruption of different underlying frontal-subcortical circuits, are a) more or less frequently reported than others and b) related to poor performance on tasks involving different cognitive processes. METHOD: Seventy-eight participants (mean age 47 years, range 36-72) with DS and mild to moderate intellectual disability (based on ICD-10 criteria), without a diagnosis of dementia of Alzheimer's type (DAT) or other psychiatric disorders, were selected from a larger sample of older adults with DS (n = 122). Dementia diagnosis was based on the CAMDEX informant interview, conducted with each participant's main carer. Informant-reported changes in personality/behaviour and memory were recorded. Participants were scored based on symptoms falling into three behavioural domains and completed five executive function (EF) tasks, six memory tasks (two of which also had a strong executive component) and the BPVS (as a measure of general intellectual ability). Multiple regression analyses were conducted to determine the degree to which the behavioural variables of 'EDF', 'disinhibition' and 'apathy', along with informant-reported memory decline and antidepressant medication use, predicted performance on the cognitive tasks (whilst controlling for the effects of age and general intellectual ability). RESULTS: Strikingly, disinhibited behaviour was reported for 95.7% of participants with one or more behavioural change (n = 47) compared to 57.4% with reported apathy and 36.2% with reported EDF. 'Disinhibition' score significantly predicted performance on three EF tasks (designed to measure planning, response inhibition and working memory) and an object memory task, (also thought to place high demands on working memory), while 'apathy' score significantly predicted performance on two different tasks, those measuring spatial reversal and prospective memory (p < 0.05). Informant reported memory decline was associated only with performance on a delayed recall task while antidepressant medication use was associated with better performance on a working memory task (p < 0.05). CONCLUSION: Observed dissociation between performance on cognitive tasks associated with reported apathy and disinhibition is in keeping with proposed differences underlying neural circuitry and supports the involvement of multiple frontal-subcortical circuits in the early stages of DAT in DS. However, the prominence of disinhibition in the behavioural profile (which more closely resembles that of disinhibited subtype of DFT than that of AD in the general population) leads us to postulate that the serotonergically mediated orbitofrontal circuit may be disproportionately affected. A speculative theory is developed regarding the biological basis for observed changes and discussion is focused on how this understanding may aid us in the development of treatments directly targeting underlying abnormalities. PMID- 20202074 TI - Executive function in adolescents with Down Syndrome. AB - BACKGROUND: The present work is aimed at analysing executive function (EF) in adolescents with Down Syndrome (DS). So far, EF has been analysed mainly in adults with DS, showing a pattern of impairment. However, less is known about children and adolescents with this syndrome. Studying adolescents with DS might help us better understand whether performances on EF tasks of individuals with DS are determined by age or by Alzheimer disease, as some studies suggest, or whether their performances are directly related to DS cognitive profile. METHOD: A battery of EF tasks assessing set shifting, planning/problem-solving, working memory, inhibition/perseveration and fluency, as well as a tasks assessing sustained attention has been administered to a group of 15 adolescents with DS and 15 typically developing children matched for mental age. All EF tasks were selected from previous studies with individuals with intellectual disabilities or from developmental literature and are thought to be useful for the samples considered. RESULTS: The present results revealed that the group of individuals with DS performed at a significantly lower level on tasks assessing set shifting, planning/problem-solving, working memory and inhibition/perseveration, but not on the tasks assessing fluency. In addition, individuals with DS demonstrated a greater number of errors and less strategy use for the sustained attention task. CONCLUSIONS: The results suggest a broad impairment in EF in adolescents with DS, and are consistent with several similar studies conducted with adults with DS. We assume that EF deficit is a characteristic of DS. PMID- 20202075 TI - Experience with a naphthylmedetomidine-ketamine-hyaluronidase combination in inducing immobilization in anthropoid apes. AB - BACKGROUND: The aim of the study was to compare the effect of naphthylmedetomidine to medetomidine on the behavior of orangutans and chimpanzees. METHODS: The immobilization was performed as part of a medical examination in five chimpanzees and three orangutans. Following pre-medication with midazolam (0.70-1.20 mg/kg p.o.), naphthylmedetomidine (50-70 microg/kg), or medetomidine (20-30 microg/kg) was given with ketamine (3 mg/kg) and hyaluronidase (150 M.U.) into musculus deltoideus. RESULTS: We observed the distinct anti-aggressive effect of naphthylmedetomidine. The immobilization with naphthylmedetomidine was shallower and the influence on cardiac frequency less substantial compared to medetomidine. The overall sedative effect of naphthylmedetomidine lasted for less time, and its effect was incompletely antagonized with atipamezole in comparison to medetomidine. CONCLUSIONS: Naphthylmedetomidine could replace medetomidine for inducing immobilization and sedation. A combination of naphthylmedetomidine-ketamine is suitable for relocating animals to other cages or for painless medical examinations. PMID- 20202076 TI - Indication of higher salivary alpha-amylase expression in hamadryas baboons and geladas compared to chimpanzees and humans. AB - BACKGROUND: Little is known about salivary alpha-amylase expression in primates. METHODS: We compared saliva of gelada and hamadryas baboons, chimpanzees and humans using SDS-PAGE and immunoblotting. RESULTS AND CONCLUSIONS: Amylase expression was increased in hamadryas baboons (P = 0.0376) compared to humans and might indicate dietary starch use in Cercopithecines. PMID- 20202077 TI - Airborne Mycobacterium avium infection in a group of red-shanked douc langurs (Pygathrix nemaeus nemaeus). AB - BACKGROUND: This report describes an airborne Mycobacterium avium (MA)-infection in two red-shanked douc langurs (Pygathrix nemaeus nemaeus) from Cologne zoo. METHODS: The two individuals and their tissues were investigated clinically (including x-rays), in pathology, in pathohistology, in classical bacteriology and by polymerase chain reaction (PCR). RESULTS: Clinically, one individual displayed emaciation and a positive reaction in an intrapalpebral testing for M. bovis/MA. The other individual was without any symptoms and did not show any reaction in the intrapalpebral test. In x-ray photos of the lungs, calcified nodules were detected. In pathology, calcified and necrotic nodules were observed within the lungs and the bronchial lymph nodes. In pathohistology, both classical tuberculous granulomas, and few acid fast rods were seen in Ziehl-Neelsen-stain. However, classical bacteriology could not demonstrate mycobacteria. In PCR, MA infection could be confirmed in one individual using the bronchial lymph nodes. CONCLUSIONS: It was an airborne infection; however, the definite source of infection in these cases remained unclear. Animals in contact to the langurs (house sparrows and mice) as well as water used in the building are the most promising candidates. The risk for a zoonotic transmission in these cases has been calculated to be low. PMID- 20202078 TI - Epizootic fatal amebiasis in an outdoor group of Old World monkeys. AB - BACKGROUND: Entamoeba (E.) histolytica is an obligate parasite of humans and non human primates. METHODS: This report describes the pathomorphological, immunohistological, and microbiological findings of fatal E. histolytica infection in two mantled guerezas (Colobus guereza) and one Hanuman langur (Semnopithecus entellus) from an epizootic outbreak of amebiasis in an open-range recreation park. RESULTS: Pathomorphological examination revealed multifocal necrotizing and granulomatous hepatitis with intralesional protozoan trophozoites in all three cases. In addition, necrotizing and ulcerative gastritis was detected in both mantled guerezas. Furthermore, oligofocal acute pulmonary embolization was detected in one of these cases. No extra-hepatic lesions were observed in the Hanuman langur. Immunohistological examination confirmed the etiologic diagnosis of E. histolytica-induced lesions. CONCLUSIONS: Although E. histolytica is a rarely diagnosed pathogen in Western European countries, veterinarians and animal keepers involved in handling and care taking of non human primates should be aware of the potential threat caused by this zoonotic parasite. PMID- 20202079 TI - Eph receptor tyrosine kinases regulate astrocyte cytoskeletal rearrangement and focal adhesion formation. AB - EphA4 null mice have impaired astrocytic gliosis following spinal cord injury. This may be because of altered cytoskeletal regulation and is examined herein using cultured astrocytes from wildtype and EphA4 null mice. Under basal conditions EphA4 null astrocytes appeared relatively normal but following stimuli resulting in cytoskeletal rearrangement, EphA4 null cells responded more slowly. When F-actin stress fibers were collapsed using the Rho kinase inhibitor HA1077, fewer EphA4 null cells showed stress fiber collapse in response to HA1077 and recovered stress fibers more slowly following HA1077 removal. EphA4 null astrocytes were less adherent and had smaller focal adhesions, while activation of Eph receptors with ephrin-A5-Fc increased the numbers of focal adhesions in both wildtype and knockout astrocytes following serum starvation. Using scratch wound assays, EphA4 null astrocytes invading the scratch showed impaired glial fibrillary acidic protein expression, particularly in proliferative cells. Astrocytes did not express Ephexin, a major Eph-interacting Rho guanine exchange factor, but they expressed Vav proteins, with lower levels of phospho-Vav in EphA4 null compared to wildtype astrocytes. This may contribute to the slower cytoskeletal responses generally observed in the EphA4 null astrocytes. Eph receptor signaling therefore regulates astrocyte reactivity through modulation of cytoskeletal responses. PMID- 20202080 TI - Nicotine self-administration differentially modulates glutamate and GABA transmission in hypothalamic paraventricular nucleus to enhance the hypothalamic pituitary-adrenal response to stress. AB - The mechanisms by which chronic nicotine self-administration augments hypothalamo pituitary-adrenal (HPA) responses to stress are only partially understood. Nicotine self-administration alters neuropeptide expression in corticotropin releasing factor (CRF) neurons within paraventricular nucleus (PVN) and increases PVN responsiveness to norepinephrine during mild footshock stress. Glutamate and GABA also modulate CRF neurons, but their roles in enhanced HPA responsiveness to footshock during chronic self-administration are unknown. We show that nicotine self-administration augmented footshock-induced PVN glutamate release, but further decreased GABA release. In these rats, intra-PVN kynurenic acid, a glutamate receptor antagonist, blocked enhanced adrenocorticotropic hormone and corticosterone responses to footshock. In contrast, peri-PVN kynurenic acid, which decreases activity of GABA afferents to PVN, enhanced footshock-induced corticosterone secretion only in control rats self-administering saline. Additionally, in rats self-administering nicotine, footshock-induced elevation of corticosterone was significantly less than in controls after intra-PVN saclofen (GABA-B receptor antagonist). Therefore, the exaggerated reduction in GABA release by footshock during nicotine self-administration disinhibits CRF neurons. This disinhibition combined with enhanced glutamate input provides a new mechanism for HPA sensitization to stress by chronic nicotine self administration. This mechanism, which does not preserve homeostatic plasticity, supports the concept that smoking functions as a chronic stressor that sensitizes the HPA to stress. PMID- 20202081 TI - Hemopressins and other hemoglobin-derived peptides in mouse brain: comparison between brain, blood, and heart peptidome and regulation in Cpefat/fat mice. AB - Many hemoglobin-derived peptides are present in mouse brain, and several of these have bioactive properties including the hemopressins, a related series of peptides that bind to cannabinoid CB1 receptors. Although hemoglobin is a major component of red blood cells, it is also present in neurons and glia. To examine whether the hemoglobin-derived peptides in brain are similar to those present in blood and heart, we used a peptidomics approach involving mass spectrometry. Many hemoglobin-derived peptides are found only in brain and not in blood, whereas all hemoglobin-derived peptides found in heart were also seen in blood. Thus, it is likely that the majority of the hemoglobin-derived peptides detected in brain are produced from brain hemoglobin and not erythrocytes. We also examined if the hemopressins and other major hemoglobin-derived peptides were regulated in the Cpe(fat/fat) mouse; previously these mice were reported to have elevated levels of several hemoglobin-derived peptides. Many, but not all of the hemoglobin derived peptides were elevated in several brain regions of the Cpe(fat/fat) mouse. Taken together, these findings suggest that the post-translational processing of alpha and beta hemoglobin into the hemopressins, as well as other peptides, is up-regulated in some but not all Cpe(fat/fat) mouse brain regions. PMID- 20202082 TI - The hematopoietic factor granulocyte-colony stimulating factor improves outcome in experimental spinal cord injury. AB - Granulocyte-colony stimulating factor (G-CSF) is a potent hematopoietic factor that drives differentiation of neutrophilic granulocytes. We have recently shown that G-CSF also acts as a neuronal growth factor, protects neurons in vitro and in vivo, and has regenerative potential in various neurological disease models. Spinal cord injury (SCI) following trauma or secondary to skeletal instability is a terrible condition with no effective therapies available at present. In this study, we show that the G-CSF receptor is up-regulated upon experimental SCI and that G-CSF improves functional outcome in a partial dissection model of SCI. G CSF significantly decreases apoptosis in an experimental partial spinal transsection model in the mouse and increases expression of the anti-apoptotic G CSF target gene Bcl-X(L). In vitro, G-CSF enhances neurite outgrowth and branching capacity of hippocampal neurons. In vivo, G-CSF treatment results in improved functional connectivity of the injured spinal cord as measured by Mn(2+) enhanced MRI. G-CSF also increased length of the dorsal corticospinal tract and density of serotonergic fibers cranial to the lesion center. Mice treated systemically with G-CSF as well as transgenic mice over-expressing G-CSF in the CNS exhibit a strong improvement in functional outcome as measured by the BBB score and gridwalk analysis. We show that G-CSF improves outcome after experimental SCI by counteracting apoptosis, and enhancing connectivity in the injured spinal cord. We conclude that G-CSF constitutes a promising and feasible new therapy option for SCI. PMID- 20202083 TI - DJ-1 forms complexes with mutant SOD1 and ameliorates its toxicity. AB - Mutations in Cu/Zn superoxide dismutase (SOD1) gene cause familial amyotrophic lateral sclerosis (ALS), which could be attributed to the toxic properties of the misfolded protein, oxidative stress, and mitochondrial dysfunction. DJ-1 - a causative agent of familial Parkinson's disease PARK7 - is responsible for inducing antioxidative reaction. In this study, we showed the up-regulation of DJ 1 protein levels in mutant SOD1 transgenic mice through the lifespan were observed in the motor neurons. We demonstrated biochemically DJ-1 formed complexes with mutant SOD1 in the cell lysates. Furthermore, DJ-1 over-expression resulted in increased cell viability and reduced cell toxicity in mutant SOD1 transfected neuronal cells, because of improvement in apoptotic pathway and reduction in oxidative stress levels. We also evaluated DJ-1 levels in CSF collected from sporadic ALS patients and controls subjects. The CSF DJ-1 levels were significantly higher in patients with sporadic ALS than in control subjects. These results show that DJ-1 may be associated with sporadic and familial ALS pathogenesis. Therefore, insight into the effects of DJ-1 on mutant SOD1-mediated toxicity may provide a therapeutic advance for the treatment of motor neuron degeneration in ALS. PMID- 20202084 TI - Quantal release of acetylcholine in mice with reduced levels of the vesicular acetylcholine transporter. AB - Mammalian motor nerve terminals contain hundreds of thousands of synaptic vesicles, but only a fraction of these vesicles is immediately available for release, the remainder forming a reserve pool. The supply of vesicles is replenished through endocytosis, and newly formed vesicles are refilled with acetylcholine through a process that depends on the vesicular acetylcholine transporter (VAChT). During expression of short-term plasticity, quantal release can be increased, but it is unknown whether this reflects enhanced recruitment of vesicles from the reserve pool or rapid recycling. We examined spontaneous and evoked release of acetylcholine at endplates from genetically modified VAChT KD(HOM) mice that express approximately 30% of the normal level of VAChT to determine steps rate-limited by synaptic vesicle filling. Quantal content and quantal size were reduced in VAChT KD(HOM) mice compared with wild-type controls. Although high-frequency stimulation did not reduce quantal size further, the post tetanic increase in end-plate potential amplitude or MEPP frequency was significantly smaller in VAChT KD(HOM) mice. This was the case even when tetanic depression was eliminated using an extracellular solution containing reduced Ca(2+) and raised Mg(2+). These results reveal the dependence of short-term plasticity on the level of VAChT expression and efficient synaptic vesicle filling. PMID- 20202085 TI - Prolonged activation of ERK triggers glutamate-induced apoptosis of astrocytes: neuroprotective effect of FK506. AB - Although, astrocytes are more resistant than neurons to ischemic injury, astrocyte death has been demonstrated in animal models of brain ischemia. Astrocytes death after ischemia/reperfusion may strongly affect neuronal survival because of the absence of their trophic and metabolic support to neurons, and astrocytic glutamate uptake. Early signals involved in astrocytes death are poorly understood. We demonstrated enhanced and mostly cytoplasmic activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) during glutamate-induced apoptosis of cultured astrocytes. Treatment with UO126, inhibitor of MEK1, threo beta-benzyloxyaspartic acid, glutamate transporter inhibitor, and FK506, a cytoprotective drug prevented ERK activation and glutamate-induced apoptosis. Over-expression of ERK dual specificity phosphatases 5 and 6 reduced apoptosis in transfected astrocytes. Prolonged ERK1/2 activation was observed in ischemic brain: in the nucleus and cytoplasm of astrocytes in the cerebral cortex, and exclusively in the cytoplasm of astrocytes in the striatum. Global gene expression profiling in the cortex revealed that FK506 blocks middle cerebral artery occlusion-induced expression of numerous genes associated with ERK signaling pathway and apoptosis. The results demonstrate a pro-apoptotic role of sustained activation of ERK1/2 signaling in glutamate-induced death of astrocytes and the ability of FK506 to block both ERK activation and astrocytic cell death in vitro and in ischemic brains. PMID- 20202086 TI - The effect of lathyrism on dentin structure of the rat incisors: a morphometric and scanning electron microscopic investigation. AB - BACKGROUND: The present study was designed to study the effect of beta aminopropionitrile (beta-APN), present in Lathyrus sativus grass pea consumed in drought prone areas, on dentin of the continuously erupting rat incisors. METHODS: Eighteen adult male rats were used. In the experimental group (18 rats), lathyrism was induced by a once daily subcutaneous administration of beta-APN for 40 days. The maxillary and mandibular incisors were examined ultrastructurally and morphometrically. RESULTS: The mean number of patent tubules, the mean area, perimeter and the area percent of the tubules were analyzed. Ultrastructurally, the dentinal tubules of both coronal and radicular dentin in the lathyritic group were narrower or even obliterated compared with those in the control. The coronal and radicular dentin of the lathyritic group exhibited an irregular lattice of non-mineralized small branching collagen fibrils obliterating the dentinal tubules. The mean number of patent tubules in the control and lathyritic groups revealed an insignificant difference. The mean area of the tubules showed a statistically significant difference in lathyritic radicular dentin (P = 0.0353). The percentage of the total surface area of the dentinal tubules significantly decreased in the radicular dentin of the lathyritic group (P = 0.024). CONCLUSIONS: These findings indicated a deleterious effect of lathyrism on dentin, with a possible negative impact on developing teeth integrity. PMID- 20202087 TI - EGFR and Ki-67 expression in oral squamous cell carcinoma using tissue microarray technology. AB - OBJECTIVE: Our aim was to validate the use of tissue microarrays (TMA) in oral squamous cell carcinomas (OSCC) to analyse epidermal growth factor receptor (EGFR) and Ki-67 expression. We also analysed the relationship that the expression of these markers may have with clinical, pathological and survival variables. PATIENTS AND METHODS: The study sample comprised 39 unselected patients diagnosed and treated for OSCC. We analysed Ki-67 and EGFR expression by immunohistochemistry on formalin-fixed, paraffin-embedded surgical specimens. Whole sections (WS) were compared with double 1.5 mm core-tissue microarrays. RESULTS: High EGFR expression was observed both on TMA (in 98% of the cases) and WS (in 100% of the cases) with substantial agreement kappa value (0.720). EGFR expression was not significantly associated with clinical, pathological and survival variables on TMA and WS. Ki-67 analysis showed a Spearman correlation of 0.741 with a Ki-67 mean labelling index of 45% in TMA and 56.8% in WS. We found a significant relationship between gender and Ki-67 labelling index on WS (P = 0.022) and TMA (P = 0.002). Clinical stage was the only parameter in multivariate analysis that had a significant predictive value. CONCLUSION: We demonstrate that dual 1.5 mm core TMA is a valid, rapid, economical and tissue-saving way to study OSCC biopsies and that it presents strong correlation with the WS. EGFR overexpression in OSCC suggests that these tumours may be a candidate for therapy investigation directed to EGFR. PMID- 20202088 TI - Quantitative analysis of argyrophilic nuclear organizer regions in giant cell lesions of jaws. AB - BACKGROUND: Giant cell lesions of the jaws are considerably similar according to histopathologic characteristics yet show different clinical behaviors. These lesions include central giant cell granuloma (CGCG), aneurysmal bone cyst, Cherubism, and Brown tumor associated with hyperparathyroidism. The present study aimed to investigate AgNORs count in these lesions as a proliferative marker and to determine whether it can be used to discriminate between them or not. METHODS: Forty-one cases of giant cell lesions of jaws were retrived from Oral Pathology Department (1987-2007). They included 21 cases of CGCG, eight cases of aneurysmal bone cyst (ABC), six cases of Cherubism, six cases of Brown tumor. The mean AgNORs count was calculated for all cases. To compare mean AgNORs in groups of lesions, ANOVA test was performed. RESULTS: Mean AgNOR counts were: (0/85 +/- 0/29) in CGCG, (0/76 +/- 0/32) in ABC (0/87 +/- 0/10) in Cherubism and (0/82 +/- 0/16) in Brown tumor. A significant difference was not observed in AgNOR counts among these groups of lesions. CONCLUSIONS: Jaws giant cell containing lesions have no acceptable differences in mean AgNORs. PMID- 20202089 TI - Effects of long-term use of HAART on oral health status of HIV-infected subjects. AB - BACKGROUND: The aim of this study was to determine the effects of long-term use of highly active antiretroviral therapy (HAART) on oral health status of HIV infected subjects. METHODS: Oral examination and measurement of saliva flow rate of both unstimulated and wax-stimulated whole saliva were performed in HIV infected subjects with and without HAART, and in non-HIV individuals. The following data were recorded; duration and risk of HIV infection, type and duration of HAART, CD4 cell count, viral load, presence of orofacial pain, oral dryness, oral burning sensation, oral lesions, cervical caries, and periodontal pocket. Multiple logistic regression analysis was performed to determine the effects of long-term use of HAART on oral health status of HIV-infected subjects. RESULTS: One hundred and fifty-seven HIV-infected subjects - 99 on HAART (age range 23-57 years, mean 39 years) and 58 not on HAART (age range 20-59 years, mean 34 years) - and 50 non-HIV controls (age range 19-59 years, mean 36 years) were enrolled. The most common HAART regimen was 2 NRTI + 2 NNRTI. HIV-infected subjects without HAART showed greater risks of having orofacial pain, oral dryness, oral lesions, and periodontal pockets than those with short-term HAART (P < 0.01). The subjects with long-term HAART were found to have a greater risk of having oral lesions than those with short-term HAART (P < 0.05). The unstimulated and stimulated salivary flow rates of the subjects with HAART were significantly lower than in those without HAART (P < 0.05). CONCLUSION: We conclude that long-term HAART has adverse effects on oral health status of HIV infected subjects. PMID- 20202090 TI - Celecoxib enhances the inhibitory effect of cisplatin on Tca8113 cells in human tongue squamous cell carcinoma in vivo and in vitro. AB - BACKGROUND: Overexpression of cyclooxygenase-2 (COX-2) is associated with carcinogenesis, invasiveness, and metastasis of malignant tumors. Inhibition of COX-2 is one hot topic of research in prevention and treatment of malignant tumors. Because of the selective and specific inhibition on the activity of COX 2, the roles of celecoxib in prevention and treatment of tumors have attracted broad attention in recent years. In this study, we investigated the inhibitory effect of celecoxib combined with cisplatin on the proliferation of human tongue squamous cell carcinoma cell line Tca8113 in vivo and in vitro. METHODS: Human tongue squamous cell carcinoma tumor cells Tca8113 and a mouse model with Tca8113 cells were used to study the growth inhibition of cisplatin enhanced by celecoxib. Drug treatment of Tca8113 in vitro and mice bearing xenografts in vivo were used. The level of COX-2 expression was detected by Western blotting. Sensitivity of cells to drug treatment was analyzed by MTT assay. RESULTS: Treatment of Tca8113 cells with cisplatin (CDDP) had less effect on the expression of COX-2, whereas the COX-2 expression was significantly down regulated after treatment with celecoxib alone or in combination with CDDP for 24 h. In addition, the combination of celecoxib with CDDP was also able to inhibit the Tca8113 line heterotransplanted in Balb/c nude mice. CONCLUSIONS: Those findings indicate that a low dose of celecoxib could augment CDDP-induced growth inhibition of Tca8113 cells and its xenograft in Balb/c nude mice. PMID- 20202091 TI - A novel animal model to study non-spontaneous bisphosphonates osteonecrosis of jaw. AB - The aim of this study was to evaluate a novel animal model of bisphosphonates associated osteonecrosis, which realistically recapitulates the same pathological human condition. Five Wistar rats were given intravenous zoledronic acid 0.04 mg once a week for 5 weeks. After 2 weeks, the animals underwent the extraction of an upper molar, producing a 4 mm-diameter bone defect on the same site. After 7 weeks from the extraction, the animals were clinically examined and a bone scintigraphy was carried out. After an additional week, the rats were killed and both Computerized Tomography and histological analysis were performed. Five rats, not treated with zoledronic acid and exposed to the same surgical treatment, were used as controls. At 7 weeks after the extraction, all the rats treated with zoledronic acid showed expansion of the defect and bone exposure. These features were confirmed by bone scintigraphy. The rats of the control group demonstrated epithelialization of the bone defect and a normal uptake of the contrast medium during the scan. The Computerized Tomography scan disclosed irregularity of the cortical margin and bone destruction, which were not evident in the control group. On microscopy, the samples showed necrotic bone, loss of osteocytes and peripheral resorption without inflammatory infiltrate, while the controls showed normal bone healing. The rat treated with zoledronic acid can be considered a novel, reliable and reproducible animal model to understand better the pathophysiology of osteonecrosis of the jaw and to develop a therapeutic approach. PMID- 20202092 TI - Oral complaints and stimulated salivary flow rate in 1188 adults. AB - BACKGROUND: Recently, oral sensory complaints (OSC) were proposed as a disease entity to represent idiopathic sensory disturbances of dry mouth, burning mouth, and taste disturbance, even though neither the status of OSC in the general population nor its underlying mechanism has yet been elucidated. Moreover, these three OSC-related complaints have not been assessed in combination by means of a visual analog scale (VAS) in a large-scale, community-dwelling population of a broad age range. METHODS: In a 1188-member community-dwelling adult population, comprised of 373 males and 815 females, aged 20-90 years, the three OSC-related complaints and stimulated salivary flow rate (SSFR) were assessed by means of a VAS and modified Saxon test, respectively. Association of each complaint with age, gender, SSFR, and other complaints was analyzed. RESULTS: Increases in both prevalence and intensity of subjective dry mouth and burning mouth were associated closely with decreasing SSFR. Even for taste disturbance, which may be affected less significantly by salivation status than the other two complaints, a significant association was suggested between decreasing SSFR and especially severe taste disturbance. However, these oral complaints were found in considerable prevalence even in the individuals with high SSFR. Often overlapping presentation of these complaints and a close association in intensity between the complaints to each other were also found. CONCLUSIONS: Hyposalivation may be a significant and common etiology for the three oral complaints, although the considerable prevalence of complaints without hyposalivation suggests other etiologies, including those related to the OSC. PMID- 20202093 TI - Expectations and final evaluation of complete dentures by patients, dentist and dental technician. AB - There is a poor association between the dentist's evaluation of denture quality and patients' satisfaction with their dentures. Possible differences between dental professionals and patients' expectations might help explain differences in outcome evaluations. This study compared scores given by a dentist, a dental technician and patients for their expectations before and their final evaluation after complete dentures treatment. Twenty completely edentulous patients, a prosthodontist and a dental technician provided scores for the expected aesthetic and functional results of their dentures based on a visual analogue scale at baseline. Post-treatment completion ratings were given after adjustments, by dentist and patients. The dental technician provided post-treatment completion ratings after completing the dentures. The patients had higher expectations than the dental technician and the dentist perceived for both aesthetic and function (P < 0.001). The patients also presented higher post-treatment completion ratings than the dental professionals perceived for final aesthetics (P = 0.016, Kendall's W = 0.207) and function (P = 0.002, Kendall's W = 0.303). Only the dentist presented a statistically significant difference between expectations (lower) and final (higher) outcomes for aesthetics (P = 0.017) and function (P = 0.003). There was no correlation between expectations and post-treatment completion ratings according to the patients' age. There was also no correlation between the patients' gender and expectation scores. Patients presented higher expectations regarding their dentures than dental professionals. The dentist believed that dentures would bring fewer benefits than patients did, but his perception of denture benefits post-treatment was significantly higher than his expectations. PMID- 20202094 TI - Does the presence of antagonist remaining teeth affect implant overdenture success? A systematic review. AB - Many patients who need implant overdentures are not completely edentulous; they still have antagonist natural teeth or implant fixed prostheses. In such cases, however, little is known about whether existing natural teeth affect the success of implant overdentures positively or act as a complicating factor. This systematic review attempts to clarify the correlation between existing remaining teeth and the survival/success rate of maxillary and mandibular implant overdentures. An assessment of available relevant articles published in English from 1990 to 2009 was performed using an online database and a manual search in libraries. Although the opposing natural dentition was not sufficiently described in the literature, 10 articles about the mandible and 10 articles about the maxilla were selected. As there was no controlled study on the natural teeth opposing implant overdentures, this review could not reach a clear conclusion. The review did reveal a remarkably high success/survival rate for mandibular implant overdentures; maxillary implant overdentures showed a lower rate. The presence of antagonist teeth hardly seems to be a risk factor for success for mandibular implant overdentures. For maxillary implant overdentures, the existence of antagonist teeth might act negatively for implant survival, but they are certainly not a contraindication. Although a few articles stated this relationship, we could not find an apparent correlation between the remaining antagonist teeth and the success of the implant overdentures. A detailed description of the opposing dentate status and results of randomized controlled clinical trials would be required to characterize this evidence-based implant overdenture treatment. PMID- 20202095 TI - Randomized controlled trial to investigate how acrylic-based resilient liner affects on masticatory ability of complete denture wearers. AB - The aim of this study was to determine the effects of an acrylic-based resilient liner (ARL) on masticatory ability by verifying the null hypothesis that masticatory performance and mandibular movements do not differ between people who wear mandibular complete dentures with ARL and those who wear complete dentures with conventional acrylic resin (CAR). From April 2004 to July 2006, we conducted a randomized controlled trial study at two centres. After written informed consent was obtained from 74 edentulous patients, they were randomly allocated to either the ARL group or CAR group. Masticatory performance and mandibular movement at the lower incisal point during chewing were measured as the outcomes. We did not observe significant differences in both outcomes between the groups. The chewing cycles were significantly different during the initial, middle, and final phases of mastication. Within the limitations of the current study, the results indicate that the acrylic-based resilient denture liners used have no clinical impact on the masticatory ability of complete denture wearers. PMID- 20202096 TI - Investigating filler morphology and mechanical properties of new low-shrinkage resin composite types. AB - Three types of low-shrinkage composites are today commercially available: Ormocers, cationic ring-opening curing systems and highly filled methacrylate based materials, which cure via free-radical polymerization mechanisms. The aim of this study was to characterize the inorganic fraction of materials belonging to each type and to compare their mechanical properties. Two Ormocers (Admira and an experimental Ormocer V35694), one ring-opening composite (Filtek Silorane) and five methacrylate-based composites [Filtek Supreme XT, Tetric EvoCeram, Grandio, Synergy D6 (Coltene-Whaledent, Langenau, Germany) and an experimental material, V34930] were tested. Inorganic fillers were quantified by thermogravimetric analysis and morphologically characterized by scanning electron microscopy. Dynamic modulus was determined by an impulse excitation technique, static elastic moduli and flexural strength by a three-point bending method. The results were analyzed using ANOVA tests (P < 0.05) and linear correlations. Grandio, V34930 and V35694 exhibited significantly higher filler mass fractions. Both dynamic and static moduli of Grandio and V34930 were significantly higher than the other materials (P < 0.05), although no significant difference in flexural strength was observed between material type (P > 0.05). From the present findings, it was suggested that V35694 and Filtek Silorane exhibit comparable properties to conventional methacrylate-based composites, although clinically the cavity type and location must guide material choice. Under high occlusal load, the use of Grandio and V34930 might be favoured. For small cavities, alternative technologies could be preferred as the need for mechanical resistance is lower and the potential for stress generation is greater. PMID- 20202097 TI - Eighteen-month clinical evaluation of microhybrid, packable and nanofilled resin composites in Class I restorations. AB - The aim of this article was to report the results of an 18-month longitudinal randomized clinical trial that evaluated the clinical performance of microhybrid, packable and nanofilled resin composite restorations placed in Class I cavities of molar teeth. Three Class I resin composite restorations were placed in each of 35 patients. Each patient received one microhybrid ('Point 4'; Kerr, Orange, CA, USA), one packable ('Packable Premise'; Kerr, Orange, CA, USA) and one nanofilled ('Nanofilled Premise'; Kerr, Orange, CA, USA) resin composite restoration. Clinical evaluation was performed at baseline (2 weeks after placement), and after 6, 12 and 18 months after placement using modified Ryge criteria. No patients were lost from the study. At the final appointment (after 18 months), 95.4%, 93.7% and 96.2% respectively of the microhybrid ('Point 4'), packable ('Packable Premise' and nanofilled ('Nanofilled Premise') resin composite restorations received Alfa ratings. Regardless of the type of restorative material, no significant changes were observed in the modified Ryge criteria at the baseline and 18-month recalls (P 0.05). CONCLUSIONS: After NVB, adhesive luting to dentin is recommended after 7 days if sodium ascorbate has been applied prior to dentin hybridization. PMID- 20202104 TI - Bonding to zirconia using a new surface treatment. AB - PURPOSE: Selective infiltration etching (SIE) is a newly developed surface treatment used to modify the surface of zirconia-based materials, rendering them ready for bonding to resin cements. The aim of this study was to evaluate the zirconia/resin bond strength and durability using the proposed technique. MATERIALS AND METHODS: Fifty-four zirconia discs were fabricated and divided into three groups (n = 18) according to their surface treatment: as-sintered surface (control group), airborne-particle abrasion (50-mum aluminum oxide), and SIE group. The zirconia discs were bonded to preaged composite resin discs using a light-polymerized adhesive resin (Panavia F 2.0). The zirconia/resin bond strength was evaluated using microtensile bond strength test (MTBS), and the test was repeated after each of the following intervals of accelerated artificial aging (AA): thermocycling (10,000 cycles between 5 and 55 degrees C), 4 weeks of water storage (37 degrees C), and finally 26 weeks of water storage (37 degrees C). Silver nitrate nanoleakage analysis was used to assess the quality of zirconia/resin interface. A repeated measures ANOVA and Bonferroni post hoc test were used to analyze the data (n = 18, alpha= 0.05) RESULTS: There were significant differences in the MTBS values between the three test groups at each of the test intervals (p < 0.001). AA resulted in reduction in the bond strength of the as-sintered and the particle-abraded groups (5.9 MPa and 27.4, MPa, respectively). Reduction in the bond strength of these groups was explained by the observed nanoleakage across the zirconia/resin interface. The bond strength of the SIE specimens was stable after completion of AA (51.9 MPa), which also demonstrated a good seal against silver nitrate penetration across the zirconia/resin interface. CONCLUSION: SIE established a strong, stable, and durable bond to zirconia substrates. Conservative resin-bonded zirconia restorations are now possible using this new technique. PMID- 20202105 TI - Efficacy of phosphodiesterase type 5 inhibitor treatment in men with erectile dysfunction and dyslipidemia: a post hoc analysis of the vardenafil statin study. AB - INTRODUCTION: Dyslipidemia occurs often in subjects with erectile dysfunction (ED), but there is little information about how this condition affects ED treatment responses. AIM: To determine whether low-density lipoprotein cholesterol (LDL-C) levels, total cholesterol (TC)/high-density lipoprotein cholesterol (HDL-C) ratio; or the presence of metabolic syndrome influenced efficacy of vardenafil in men with ED and dyslipidemia. METHODS: Post hoc subgroup analysis of a 12-week study of the influence of lipid levels and presence of metabolic syndrome on the efficacy of vardenafil as measured by International Index of Erectile Function-Erectile Function (IIEF-EF) domain score, responses to Sexual Encounter Profile (SEP) SEP2 and SEP3 questions, duration of erection leading to successful intercourse, and erection duration regardless of the answer to SEP3. Lipid values were obtained at study start, after patients had received at least 3 months of therapy with a statin. MAIN OUTCOME MEASURES: Outcomes in subjects with LDL-C < 100, > or = 100 to < 130, or > or = 130 mg/dL [< 2.59, > or = 2.59 to < 3.36, or > or = 3.36 mmol/L]; TC/HDL-C ratio < 3.5 vs. > or = 3.5, and presence or absence of metabolic syndrome. RESULTS: Vardenafil improved all endpoints evaluated compared with placebo in all subgroups, however, nominally significant treatment by subgroup interaction terms did not follow a distinct pattern. Increasing LDL-C (P = 0.033), but not TC/HDL-C ratio or metabolic syndrome, was associated with an increase in treatment response measured by the IIEF-EF domain score. Responses to SEP3 were nominally influenced by LDL-C levels (P = 0.019), but were not significantly influenced by TC/HDL-C ratio, or the metabolic syndrome. Only higher TC/HDL-C ratios (> or = 3.5) were associated with larger treatment differences in duration of erection leading to successful intercourse (P = 0.028). CONCLUSIONS: Vardenafil was effective in men with dyslipidemia regardless of LDL-C levels, TC/HDL-C ratio, and/or presence of metabolic syndrome. Despite the known presence of ED and dyslipidemia, other cardiovascular risk factors were apparently not aggressively managed. PMID- 20202106 TI - Prevalence of dilated cardiomyopathy in Doberman Pinschers in various age groups. AB - BACKGROUND: Dilated cardiomyopathy (DCM) in Doberman Pinschers is an autosomal dominant inherited disease. The prevalence of DCM in Doberman Pinschers of various age groups in Europe is currently unknown, but this information would be important to develop recommendations for screening programs. OBJECTIVES: To evaluate the prevalence of cardiomyopathy in various age groups of Dobermans. ANIMALS: Seven hundred and seventy-five examinations in 412 Doberman Pinschers. METHODS: Dogs were included in a prospective longitudinal cohort study. Each examination included echocardiography and 24-hour ECG (Holter) examination. A cut off value of >100 ventricular premature contractions (VPCs) per 24 hours on Holter examination or abnormal echocardiography was considered diagnostic for cardiomyopathy. The cumulative prevalence included all dogs with DCM and healthy dogs >7 years of age. RESULTS: DCM prevalence in various age groups was as follows: age group 1 (1 to <2 years) 3.3%, age group 2 (2 to <4 years) 9.9%, age group 3 (4 to <6 years) 12.5%, age group 4 (6 to <8 years) 43.6%, and age group 5 (>8 years) 44.1%. The cumulative prevalence of Doberman Pinscher cardiomyopathy was 58.2%. There was an equal sex distribution, but male dogs showed earlier echocardiographic changes than did female dogs, which had significantly more VPCs. CONCLUSIONS AND CLINICAL IMPORTANCE: The prevalence of Doberman cardiomyopathy is very high in Europe. Disease manifestation and progression are different between male and female dogs. Yearly screening for DCM by Holter examination and echocardiography is recommended, starting at 2 years of age. PMID- 20202107 TI - Cranioencephalic malformation with atlanto-occipital luxation in an Andalusian neonate foal. PMID- 20202108 TI - Comparison of traps for the control of sheep blowfly in the U.K. AB - The ability of three commercially available trap types to catch Lucilia (Diptera: Calliphoridae) blowflies was assessed on three sheep farms in southwest England in 2008. The aim was to evaluate their relative value for the control of ovine cutaneous myiasis (sheep blowfly strike) on farms. There was a highly significant difference between the total number of female Lucilia caught per day by the traps, with an Agrilure Trap (Agrimin Ltd, Brigg, U.K.) catching more than the other trap types (Rescue Disposable Fly Trap, Sterling International, Spokane, U.S.A.; Redtop Trap, Miller Methods, Johannesburg, South Africa). However, there was no significant difference between the traps in the numbers of female Lucilia sericata (Meigen) caught. Nevertheless, consideration of the rate at which female L. sericata were caught over time showed that the Agrilure trap did not begin catching until about 30 days after its initial deployment. It subsequently caught L. sericata at a faster rate than the other two traps. The data suggest that the freeze-dried liver bait used in the Agrilure trap required a period of about 30 days to become fully rehydrated and decompose to the degree required to attract and catch L. sericata. Once the bait was attractive, however, the trap outperformed the other two traps in terms of the rate of L. sericata capture. The Agrilure trap would appear to be the most effective of the designs tested for use against sheep blowfly and blowfly strike in the U.K., but care would be needed to ensure that the traps were deployed in advance of the blowfly season so that the bait was suitably aged when trapping was required. PMID- 20202109 TI - Fecundity, nymphal development and longevity of field-collected tropical bedbugs, Cimex hemipterus. AB - This study examined the fecundity, oviposition, nymphal development and longevity of field-collected samples of the tropical bedbug, Cimex hemipterus (Fabricius) (Hemiptera: Cimicidae). Under environmental conditions of 26+/-2 degrees C, 70 +/ 5% relative humidity and a 12-h photoperiod, with bloodmeals provided by a human host, six strains of tropical bedbug had a fecundity of up to 50 eggs per lifetime, over 11-14 oviposition cycles. Increased feeding frequency improved fecundity. After feeding and mating, adult females normally took 2-3 days to produce a first batch of eggs. The oviposition period lasted 2-7 days before cessation of the oviposition cycle. The egg incubation period usually lasted 5-7 days before the emergence of first instars. The nymphs underwent five stadia (the first four of which each took 3-4 days, whereas the last took 4-5 days) before becoming adults at a sex ratio of 1 : 1. More than five bloodmeals were required by the nymphs to ensure a successful moult. Unmated adults lived significantly longer than mated adults (P < 0.05). Unmated females lived up to almost 7 months, but the longevity of mated males and females did not differ significantly (P > 0.05). PMID- 20202110 TI - Retrospective evaluation of caspofungin therapy in invasive aspergillosis (RECAM IA). AB - To evaluate caspofungin in high-risk invasive aspergillosis (IA) patient, a retrospective review of patient characteristics, antifungal therapies and clinical outcomes on hospitalised patients at sites in Russia, Canada, Germany, and Thailand was performed. Fifty-five patients were included, six with proven and 49 with probable aspergillosis; 76.4% had haematological diseases, 80% were on immunosuppressive drugs, 32.7% were neutropenic at caspofungin initiation. Median duration of prior antifungal therapy was 9 days (range 1-232). Reasons for initiating caspofungin included: disease refractory to first-line antifungal (49.1%) and toxicities with prior antifungals (18.2%). Median caspofungin therapy duration was 14 days (range 2-62), with a median of 13 days (range 1-62) as monotherapy. Favourable responses were observed in 45.5% of the patients, complete responses in 40% and partial responses in 5.5%; 74.5% survived 7 days after completion of caspofungin therapy with 69.1% having been successfully discharged from the hospital. Few patients (14.6%) on caspofungin switched because of suspected resistance, lack of response or adverse events. There were no increases in hospital stay as a result of adverse events or drug-drug interactions related to caspofungin; 7.3% of patients had a mean value of 13 (+/- 14.11) days of increased stay attributable to treatment failure. Caspofungin was well-tolerated. It exhibited effectiveness and high survival in treating severe IA patients. PMID- 20202111 TI - Cytological analysis of the epithelial cells in patients with oral candidiasis. AB - The aim of this study was to evaluate oral epithelial cells of the oral mucosa infected by Candida albicans using exfoliative cytology. Oral smears were collected from clinically normal-appearing mucosa by liquid-based exfoliative cytology of 60 individuals (30 patients with oral candidiasis and 30 healthy controls matched for age and gender) and analysed for morphologic and cytomorphometric technique. Morphologically, candida-infected epithelial cells exhibited nuclear enlargement, perinuclear rings, discrete orangeophilia, and cytoplasmic vacuoles. The cytomorphometric analysis demonstrated that the cytoplasmic area (CA) of the epithelial cells was diminished in patients undergoing candidiasis as compared to the non-infected controls. In addition, there was an augmentation in nuclear area (NA) and NA/CA area ratio. This study revealed that oral mucosa of patients undergoing candidal infection exhibited significant changes in the size and shape of the oral epithelial cells. PMID- 20202112 TI - Classification of invasive fungal disease in patients with acute myeloid leukaemia. AB - Invasive fungal diseases (IFD) are a major cause of morbidity and mortality in patients with acute myeloid leukaemia (AML). Their incidence has risen dramatically in recent years. The diagnosis of IFDs remains difficult, even if the European Organisation for the Research and Treatment of Cancer (EORTC)/Mycosis Study Group (MSG) criteria are applied for study purposes to classify the likelihood of these infections. These criteria have been developed for clinical trials, and their relevance in clinical settings outside a clinical trial remains unknown. We evaluated the impact of the EORTC/MSG criteria and a modification thereof for clinical purposes in patients with AML. We retro spectively analysed 100 AML patients for the occurrence of IFD. First, EORTC/MSG criteria were applied to classify the patients. Second, a modified version of these criteria already used in clinical trials was used to re-classify the patients. Fifty-seven patients developed an invasive fungal infection. Following the original criteria, 43% were classified as 'possible' IFD, whereas 7% each were classified as 'probable' and 'proven' IFD. After application of the modified criteria, only 9% of the patients remained 'possible' IFD, whereas 41% were 'probable'. The occurrence of 'proven' cases was not altered by the modification and thus remained 7%. The application of modified criteria for the classification of IFD in AML patients leads to a considerable shift from 'possible' IFD (according to conventional EORTC criteria) towards 'probable' IFD. Nevertheless, neither the old EORTC criteria nor their modification was designed for use in clinical practice. As this study underscores the uncertainty in the diagnosis of IFD, the need for a clinically applicable classification is obvious. PMID- 20202113 TI - Adherence ability of Candida africana: a comparative study with Candida albicans and Candida dubliniensis. AB - In this study, we compared the adherence ability to human Hela cells and biofilm formation of three closely related Candida yeast. In our experiments, Candida africana showed poor adhesion ability to human Hela cells and the absence of biofilm formation on polyvinyl chloride strips. Conversely, Candida albicans and Candida dubliniensis formed mature biofilms and stable attachment to Hela cells. To our knowledge, this is the first comparative study reporting data on biofilm formation and adherence to human Hela cells by C. africana. PMID- 20202114 TI - Differentially expressed genes associated with tryptophan-dependent pigment synthesis in Malassezia furfur--a comparison with the recently published genome of Malassezia globosa. AB - Malassezia (M.) furfur, a commensal organism found on the human skin, produces a wide range of pigments and fluorochromes when cultured with tryptophan as a sole nitrogen source. Some compounds of this pigment metabolism may provide an explanation for clinical characteristics of pityriasis versicolor (PV), a frequent skin disease in humans characterised by long-lasting pigmentary changes. Malassezia globosa is currently regarded as the causative agent of PV, but tryptophan-dependent pigment production has not yet been demonstrated in this species. In a previous study, we identified M. furfur genes that were differentially expressed 3 and 5 h, respectively, after induction of tryptophan dependent pigment production. The recent publication of the genome of M. globosa prompted us to check the M. furfur sequences for homologues in M. globosa. The 3 h pool contained 79 sequences and the 5-h pool contained 91 sequences. A translated vs. translated BLAST search resulted in 62 sequences (78%) of the 3-h pool and 61 sequences (67%) of the 5-h pool showing similarity to a sequence from M. globosa. It appears that M. globosa possesses homologues to most of the genes that are differentially expressed during pigment production in M. furfur. PMID- 20202115 TI - Novel presentation of immune reconstitution inflammatory syndrome: folliculitis secondary to Malassezia spp. AB - Folliculitis, as a manifestation of immune reconstitution inflammatory syndrome (IRIS) during antiretroviral therapy, has only been described in its aseptic form. Here, we describe folliculitis associated with Malassezia spp. as a distinct manifestation of IRIS. The distinction between these two types of IRIS folliculitis is relevant for treatment. PMID- 20202116 TI - Intraocular caspofungin: in vitro safety profile for human ocular cells. AB - Endogenous Candida endophthalmitis is sight-threatening, difficult to treat and sometimes leads to loss of the eye. Only a few therapeutic agents are available for its treatment. Caspofungin is the first of a new class of antifungal drugs (echinocandins) with a high activity against Candida species, the most common pathogens found in endogenous endophthalmitis. This study investigates the safety profile of caspofungin for intraocular application in a cell-culture model. Endothelial toxicity of caspofungin was evaluated in cultured human corneas. Possible toxic effects of caspofungin (5-300 MUg ml(-1)) in corneal endothelial cells (CEC), primary human trabecular meshwork cells (TMC) and primary human retinal pigment epithelium (RPE) cells were evaluated after 24 h and under conditions of inflammatory stress by treatment with tumour necrosis factor-alpha (TNF-alpha), lipopolysaccharides (LPS) or interleukin-6 (IL-6) and hydrogen peroxide (H(2)O(2)). Toxicity was evaluated by tetrazolium dye-reduction assay; cell viability was quantified by a microscopic live-dead assay. No corneal endothelial toxicity could be detected after 30 days of treatment with 75 MUg ml( 1) of caspofungin. Concentrations up to 75 MUg ml(-1) had no influence on CEC, TMC or RPE cell proliferation, or on cell viability when administered for 24 h. Exposure to H(2)O(2) did not increase cellular toxicity of caspofungin at concentrations of 5-50 MUg ml(-1). After preincubation with TNF-alpha, LPS or IL 6 for 24 h followed by treatment with caspofungin for 24 h, no significant decrease in cell proliferation or viability was observed. This study showed no significant toxicity for caspofungin on CEC, TMC or RPE cells, or human corneal endothelium when administered in therapeutic concentrations up to 50 MUg ml(-1). PMID- 20202117 TI - Quantitative analysis of the effects of antimycotic agents on the hyphal growth of Trichophyton rubrum: a preliminary study. AB - The thallus diameter is commonly used as a quantitative parameter to evaluate hyphal growth. However, a different parameter is required to evaluate hyphal growth more precisely. The hyphal growth of Trichophyton rubrum in the presence of antimycotic agents was evaluated using the number of hyphal crossings as a quantitative parameter. Continuous video images of hyphal growth were taken for 48 h. Culture medium contained 0.4 MUg ml(-1) of terbinafine (TBF) and itraconazole (ITCZ). Image analyses were performed every 6 h using a 50 MUm square grid. The mean density of the hyphal crossings in each sampling frame was used as a parameter of hyphal growth. The mean ratio of hyphal crossings on distressed hyphae to total hyphal crossings was used as a parameter representing the antimycotic effects of TBF and ITCZ. The mean density of total hyphal crossings in the TBF group was significantly lower than in the control and ITCZ groups. The ratio of distressed hyphae significantly increased during the 48-h time course in the TBF group, but not in the ITCZ group. Counting the number of hyphal crossings provides a new method for assessing hyphal growth and antimycotic activity quantitatively. PMID- 20202118 TI - O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation is significantly less frequent in ependymal tumours as compared to malignant astrocytic gliomas. PMID- 20202119 TI - Review: the ubiquitin-proteasome system: contributions to cell death or survival in neurodegeneration. AB - The significance of the accumulation of ubiquitin-positive intraneuronal inclusions in the brains of those affected with different neurodegenerative diseases is currently unclear. While one interpretation is that the disease mechanism(s) involves dysfunction of an ubiquitin-mediated process, such as the ubiquitin-proteasome system, the inclusions are also found in surviving neurones, suggesting a possible neuroprotective role. Here we review recent evidence in support of these seemingly opposing notions gleaned from cell and animal models as well as investigations of patient samples, with particular emphasis on studies relevant to Parkinson's disease. PMID- 20202121 TI - Review: neuromuscular synaptic vulnerability in motor neurone disease: amyotrophic lateral sclerosis and spinal muscular atrophy. AB - Amid the great diversity of neurodegenerative conditions, there is a growing body of evidence that non-somatic (that is, synaptic and distal axonal) compartments of neurones are early and important subcellular sites of pathological change. In this review we discuss experimental data from human patients, animal models and in vitro systems showing that neuromuscular synapses are targeted in different forms of motor neurone disease (MND), including amyotrophic lateral sclerosis and spinal muscular atrophy. We highlight important developments revealing the heterogeneous nature of vulnerability in populations of lower motor units in MND and examine how progress in our understanding of the molecular pathways underlying MND may provide insights into the regulation of synaptic vulnerability and pathology. We conclude that future experiments developing therapeutic approaches specifically targeting neuromuscular synaptic vulnerability are likely to be required to prevent or delay disease onset and progression in human MND patients. PMID- 20202120 TI - Review: autophagy and neurodegeneration: survival at a cost? AB - Protein aggregation, mitochondrial impairment and oxidative stress are common to multiple neurodegenerative diseases. Homeostasis is regulated by a balanced set of anabolic and catabolic responses, which govern removal and repair of damaged proteins and organelles. Macroautophagy is an evolutionarily conserved pathway for the degradation of long-lived proteins, effete organelles and protein aggregates. Aberrations in macroautophagy have been observed in Alzheimer, Huntington, Parkinson, motor neuron and prion diseases. In this review, we will discuss the divergent roles of macroautophagy in neurodegenerative diseases and suggest a potential regulatory mechanism that could determine cell death or survival outcomes. We also highlight emerging data on neurite morphology and synaptic remodelling that indicate the possibility of detrimental functional trade-offs in the face of neuronal cell survival, particularly if the need for elevated macroautophagy is sustained. PMID- 20202123 TI - Aberrant microRNA expression in the brains of neurodegenerative diseases: miR-29a decreased in Alzheimer disease brains targets neurone navigator 3. AB - AIMS: MicroRNAs (miRNAs) are small non-coding RNAs that regulate translational repression of target mRNAs. Accumulating evidence indicates that various miRNAs, expressed in a spatially and temporally controlled that manner in the brain plays a key role in neuronal development. However, at present, the pathological implication of aberrant miRNA expression in neurodegenerative events remains largely unknown. To identify miRNAs closely associated with neurodegeneration, we performed miRNA expression profiling of brain tissues of various neurodegenerative diseases. METHODS: We initially studied the frontal cortex derived from three amyotrophic lateral sclerosis patients by using a microarray of 723 human miRNAs. This was followed by enlargement of study population with quantitative RT-PCR analysis (n = 21). RESULTS: By microarray analysis, we identified up-regulation of miR-29a, miR-29b and miR-338-3p in amyotrophic lateral sclerosis brains, but due to a great interindividual variation, we could not validate these results by quantitative RT-PCR. However, we found significant down-regulation of miR-29a in Alzheimer disease (AD) brains. The database search on TargetScan, PicTar and miRBase Target identified neurone navigator 3 (NAV3), a regulator of axon guidance, as a principal target of miR-29a, and actually NAV3 mRNA levels were elevated in AD brains. MiR-29a-mediated down-regulation of NAV3 was verified by the luciferase reporter assay. By immunohistochemistry, NAV3 expression was most evidently enhanced in degenerating pyramidal neurones in the cerebral cortex of AD. CONCLUSIONS: These observations suggest the hypothesis that underexpression of miR-29a affects neurodegenerative processes by enhancing neuronal NAV3 expression in AD brains. PMID- 20202122 TI - Review: transactive response DNA-binding protein 43 (TDP-43): mechanisms of neurodegeneration. AB - Since the identification of phosphorylated and truncated transactive response DNA binding protein 43 (TDP-43) as a primary component of ubiquitinated inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions, and the discovery that mutations in the TDP-43 gene cause ALS, much effort has been directed towards establishing how TDP-43 contributes to the development of neurodegeneration. Although few in vivo models are presently available, findings thus far strongly support the involvement of abnormally modified TDP-43 in promoting TDP-43 aggregation and cellular mislocalization. Therefore, TDP-43-mediated neurotoxicity is likely to result from a combination of toxic gains of function conferred by TDP-43 inclusions as well as from the loss of normal TDP-43 function. Nonetheless, the exact neurotoxic TDP-43 species remain unclear, as do the mechanism(s) by which they cause neuronal death. Moreover, little is currently known about the roles of TDP 43, both in the nucleus and the cytoplasm, making it difficult to truly appreciate the detrimental consequences of aberrant TDP-43 function. This review will summarize what is currently understood regarding normal TDP-43 function and the involvement of TDP-43 in neurodegeneration, and will also highlight some of the many remaining questions in need of further investigation. PMID- 20202124 TI - HtrA2/Omi-immunoreactive intraneuronal inclusions in the anterior horn of patients with sporadic and Cu/Zn superoxide dismutase (SOD1) mutant amyotrophic lateral sclerosis. AB - AIMS: HtrA2/Omi is a mitochondrial serine protease that promotes the apoptotic processes, but the relationship between HtrA2/Omi and amyotrophic lateral sclerosis (ALS) is still unknown. The purpose of the present study was to determine whether abnormal expression of HtrA2/Omi occurs in patients with ALS. METHODS: We prepared autopsied spinal cord tissues from 7 control subjects, 11 patients with sporadic ALS (SALS) and 4 patients with Cu/Zn superoxide dismutase (SOD1)-related familial ALS (FALS). We then performed immunohistochemical studies on HtrA2/Omi using formalin-fixed, paraffin-embedded sections from all of the cases. RESULTS: In the control subjects, the anterior horn cells were mildly to moderately immunostained with HtrA2/Omi. In the patients with SALS, strong HtrA2/Omi immunoreactivity was found in some skein-like inclusions and round hyaline inclusions as well as many spheroids, but Bunina bodies were immunonegative for HtrA2/Omi. In the patients with SOD1-related FALS, Lewy body like hyaline inclusions were observed in three cases and conglomerate inclusions were observed in the remaining case, and both types of inclusions were intensely immunopositive for HtrA2/Omi. CONCLUSIONS: These results suggest that abnormal accumulations of HtrA2/Omi may occur in several types of motor neuronal inclusions in the anterior horn from SALS and SOD1-linked FALS cases, and that HtrA2/Omi may be associated with the pathogenesis of both types of ALS. PMID- 20202125 TI - KIAA0510, the 3'-untranslated region of the tenascin-R gene, and tenascin-R are overexpressed in pilocytic astrocytomas. AB - AIMS: Studying the molecules and signalling pathways regulating glioma invasiveness is a major challenge because these processes determine malignancy, progression, relapse and prognosis. We took advantage of our previous study focused on genes that were critical in tumour invasion to further study here an unknown sequence, referred to as KIAA0510, the chromosomal location of which was 1q25, described as a 5596-bp long mRNA and that we found to be significantly overexpressed in pilocytic astrocytomas compared with glioblastomas. METHODS AND RESULTS: Using in silico analysis as well as Polymerase chain reaction techniques, we decipher the full genomic characterization of the KIAA0510 sequence and demonstrate that KIAA0510 constitutes the 3'-untranslated region of tenascin-R gene. We have clearly confirmed the overexpression of tenascin-R in pilocytic astrocytomas vs. glioblastomas at mRNA and protein levels. We also analysed a large series of various brain tumours and found that in the group of astrocytic tumours, tenascin-R expression decreased with malignancy, whereas oligodendrogliomas sometimes retained a high level of tenascin-R even in high grade tumours. Gangliogliomas strongly expressed tenascin-R too. In contrast, ependymomas and meningiomas were negative. In normal brain, tenascin-R was exclusively expressed by normal oligodendrocytes and subsets of neurones during post-natal development and in adulthood, where it could differentially affect cellular adhesiveness and/or differentiation. CONCLUSION: KIAA0510, the 3' untranslated region of the tenascin-R gene, and tenascin-R are overexpressed in pilocytic astrocytomas. Gangliogliomas shared with pilocytic astrocytomas strong tenascin-R expression. Whether tenascin-R overexpression negatively influences brain invasion remains to be determined. PMID- 20202128 TI - Reconciling species-level vs plastic responses of evergreen leaf structure to light gradients: shade leaves punch above their weight. AB - *When grown in a common light environment, the leaves of shade-tolerant evergreen trees have a larger leaf mass per unit area (LMA) than their light-demanding counterparts, associated with differences in lifespan. Yet plastic responses of LMA run counter to this pattern: shade leaves have smaller LMA than sun leaves, despite often living longer. *We measured LMA and cell wall content, and conducted punch and shear tests, on sun and shade leaves of 13 rainforest evergreens of differing shade tolerance, in order to understand adaptation vs plastic responses of leaf structure and biomechanics to shade. *Species shade tolerance and leaf mechanical properties correlated better with cell wall mass per unit area than with LMA. Growth light environment had less effect on leaf mechanics than on LMA: shade leaves had, on average, 40% lower LMA than sun leaves, but differences in work-to-shear, and especially force-to-punch, were smaller. This was associated with a slightly larger cell wall fraction in shade leaves. *The persistence of shade leaves might reflect unattractiveness to herbivores because they yield smaller benefits (cell contents per area) per unit fracture force than sun leaves. In forest trees, cell wall fraction and force-to punch are more robust correlates of species light requirements than LMA. PMID- 20202127 TI - A long antisense RNA in plant chloroplasts. AB - Based on computational prediction of RNA secondary structures, a long antisense RNA (asRNA) was found in chloroplasts of Arabidopsis, Nicotiana tabacum and poplar, which occurs in two to three major transcripts. Mapping of primary 5' ends, northern hybridizations and quantitative real-time reverse transcription polymerase chain reaction (qPCR) experiments demonstrated that these transcripts originate from a promoter that is typical for the plastid-encoded RNA polymerase and are over their full length in antisense orientation to the gene ndhB and therefore were designated asRNA_ndhB. The asRNA_ndhB transcripts predominantly accumulate in young leaves and at physiological growth temperatures. Two nucleotide positions in the mRNA that are subject to C-to-U RNA editing and which were previously found to be sensitive to elevated temperatures are covered by asRNA_ndhB. Nevertheless, the correlation between the accumulation of asRNA_ndhB and RNA editing appeared weak in a temperature shift experiment. With asRNA_ndhB, we describe the first asRNA of plant chloroplasts that covers RNA editing sites, as well as a group II intron splice acceptor site, and that is under developmental control, raising the possibility that long asRNAs could be involved in RNA maturation or the control of RNA stability. PMID- 20202129 TI - Expression analysis and functional characterization of the monosaccharide transporters, OsTMTs, involving vacuolar sugar transport in rice (Oryza sativa). AB - In Arabidopsis, the compartmentation of sugars into vacuoles is known to be facilitated by sugar transporters. However, vacuolar sugar transporters have not been studied in detail in other plant species. To characterize the rice (Oryza sativa) tonoplast monosaccharide transporters, OsTMT1 and OsTMT2, we analysed their subcellular localization using green fluorescent protein (GFP) and expression patterns using reverse-transcription polymerase chain reaction (RT PCR), performed histochemical beta-glucuronidase (GUS) assay and in situ hybridization analysis, and assessed sugar transport ability using isolated vacuoles. Expression of OsTMT-GFP fusion protein in rice and Arabidopsis revealed that the OsTMTs localize at the tonoplast. Analyses of OsTMT promoter-GUS transgenic rice indicated that OsTMT1 and OsTMT2 are highly expressed in bundle sheath cells, and in vascular parenchyma and companion cells in leaves, respectively. Both genes were found to be preferentially expressed in the vascular tissues of roots, the palea/lemma of spikelets, and in the main vascular tissues and nucellar projections on the dorsal side of the seed coats. Glucose uptake studies using vacuoles isolated from transgenic mutant Arabidopsis (tmt1-2 3) expressing OsTMT1 demonstrated that OsTMTs are capable of transporting glucose into vacuoles. Based on expression analysis and functional characterization, our present findings suggest that the OsTMTs play a role in vacuolar glucose storage in rice. PMID- 20202131 TI - The evolutionary ecology of clonally propagated domesticated plants. AB - While seed-propagated crops have contributed many evolutionary insights, evolutionary biologists have often neglected clonally propagated crops. We argue that widespread notions about their evolution under domestication are oversimplified, and that they offer rich material for evolutionary studies. The diversity of their wild ancestors, the diverse ecologies of the crop populations themselves, and the intricate mix of selection pressures, acting not only on the parts harvested but also on the parts used by humans to make clonal propagules, result in complex and diverse evolutionary trajectories under domestication. We examine why farmers propagate some plants clonally, and discuss the evolutionary dynamics of sexual reproduction in clonal crops. We explore how their mixed clonal/sexual reproductive systems function, based on the sole example studied in detail, cassava (Manihot esculenta). Biotechnology is now expanding the number of clonal crops, continuing the 10 000-yr-old trend to increase crop yields by propagating elite genotypes. In an era of rapid global change, it is more important than ever to understand how the adaptive potential of clonal crops can be maintained. A key component of strategies for preserving this adaptive potential is the maintenance of mixed clonal/sexual systems, which can be achieved by encouraging and valuing farmer knowledge about the sexual reproductive biology of their clonal crops. PMID- 20202130 TI - The transcriptome of Populus in elevated CO reveals increased anthocyanin biosynthesis during delayed autumnal senescence. AB - *The delay in autumnal senescence that has occurred in recent decades has been linked to rising temperatures. Here, we suggest that increasing atmospheric CO2 may partly account for delayed autumnal senescence and for the first time, through transcriptome analysis, identify gene expression changes associated with this delay. *Using a plantation of Populus x euramericana grown in elevated [CO2] (e[CO2]) with free-air CO2 enrichment (FACE) technology, we investigated the molecular and biochemical basis of this response. A Populus cDNA microarray was used to identify genes representing multiple biochemical pathways influenced by e[CO2] during senescence. Gene expression changes were confirmed through real time quantitative PCR, and leaf biochemical assays. *Pathways for secondary metabolism and glycolysis were significantly up-regulated by e[CO2] during senescence, in particular, those related to anthocyanin biosynthesis. Expressed sequence tags (ESTs) representing the two most significantly up-regulated transcripts in e[CO2], LDOX (leucoanthocyanidin dioxgenase) and DFR (dihydroflavonol reductase), gave (e[CO2]/ambient CO(2) (a[CO2])) expression ratios of 39.6 and 19.3, respectively. *We showed that in e[CO2] there was increased autumnal leaf sugar accumulation and up-regulation of genes determining anthocyanin biosynthesis which, we propose, prolongs leaf longevity during natural autumnal senescence. PMID- 20202132 TI - Spatial and temporal ecology of Scots pine ectomycorrhizas. AB - Spatial analysis was used to explore the distribution of individual species in an ectomycorrhizal (ECM) fungal community to address: whether mycorrhizas of individual ECM fungal species were patchily distributed, and at what scale; and what the causes of this patchiness might be. Ectomycorrhizas were extracted from spatially explicit samples of the surface organic horizons of a pine plantation. The number of mycorrhizas of each ECM fungal species was recorded using morphotyping combined with internal transcribed spacer (ITS) sequencing. Semivariograms, kriging and cluster analyses were used to determine both the extent and scale of spatial autocorrelation in species abundances, potential interactions between species, and change over time. The mycorrhizas of some, but not all, ECM fungal species were patchily distributed and the size of patches differed between species. The relative abundance of individual ECM fungal species and the position of patches of ectomycorrhizas changed between years. Spatial and temporal analysis revealed a dynamic ECM fungal community with many interspecific interactions taking place, despite the homogeneity of the host community. The spatial pattern of mycorrhizas was influenced by the underlying distribution of fine roots, but local root density was in turn influenced by the presence of specific fungal species. PMID- 20202133 TI - Prevalence of obesity and overweight among adults in Iran. AB - The prevalence of overweight and obesity in most developed and developing countries have been increasing markedly over the past two decades. This increase includes all ages, genders, racial and ethnic groups, income, and educational levels. This study examined the prevalence of overweight and obesity among adults aged 25-55 years in Shiraz (Southern Iran). The data are based on a random multistage sample survey of 2282 married adults (1141 pairs) living is Shiraz, whose heights and weights were measured in the 2002-2003 academic year. The prevalence of overweight or obesity (body mass index > or = 25) was 49.7% in men and 63.9% in women. The prevalence of obesity (body mass index > or = 30) was 10.5% and 22.5% in men and women, respectively, which shows an increased secular change of 5.8% in men and 17.4% in women during a 14-year period. Overweight and obesity are common in Iran. Obesity and overweight were significantly more common among women than among men (P-valve = 0.000). There is a need to establish programmes for prevention and treatment of obesity especially Iranian's women. PMID- 20202134 TI - Interventions to promote healthy eating habits: evaluation and recommendations. AB - Although in several EU Member States many public interventions have been running for the prevention and/or management of obesity and other nutrition-related health conditions, few have yet been formally evaluated. The multidisciplinary team of the EATWELL project will gather benchmark data on healthy eating interventions in EU Member States and review existing information on the effectiveness of interventions using a three-stage procedure (i) Assessment of the intervention's impact on consumer attitudes, consumer behaviour and diets; (ii) The impact of the change in diets on obesity and health and (iii) The value attached by society to these changes, measured in life years gained, cost savings and quality-adjusted life years. Where evaluations have been inadequate, EATWELL will gather secondary data and analyse them with a multidisciplinary approach incorporating models from the psychology and economics disciplines. Particular attention will be paid to lessons that can be learned from private sector that are transferable to the healthy eating campaigns in the public sector. Through consumer surveys and workshops with other stakeholders, EATWELL will assess the acceptability of the range of potential interventions. Armed with scientific quantitative evaluations of policy interventions and their acceptability to stakeholders, EATWELL expects to recommend more appropriate interventions for Member States and the EU, providing a one-stop guide to methods and measures in interventions evaluation, and outline data collection priorities for the future. PMID- 20202135 TI - The influence of geographic life environments on cardiometabolic risk factors: a systematic review, a methodological assessment and a research agenda. AB - Recent environmental changes play a role in the dramatic increase in the prevalence of cardiometabolic risk factors (CMRFs) such as obesity, hypertension, type 2 diabetes, dyslipidemias and the metabolic syndrome in industrialized countries. Therefore, identifying environmental characteristics that are associated with risk factors is critical to develop more effective public health interventions. We conducted a systematic review of the literature investigating relationships between characteristics of geographic life environments and CMRFs (131 articles). Most studies were published after 2006, relied on cross-sectional designs, and examined whether sociodemographic and physical environmental characteristics, and more recently service environment characteristics, were associated with obesity or, to a lesser extent, hypertension. Only 14 longitudinal studies were retrieved; diabetes, dyslipidemias and the metabolic syndrome were rarely analysed; and aspects of social interactions in the neighbourhood were critically underinvestigated. Environmental characteristics that were consistently associated with either obesity or hypertension include low area socioeconomic position; low urbanization degree; low street intersection, service availability and residential density; high noise pollution; low accessibility to supermarkets and high density of convenience stores; and low social cohesion. Intermediate mechanisms between environmental characteristics and CMRFs have received little attention. We propose a research agenda based on the assessment of underinvestigated areas of research and methodological limitations of current literature. PMID- 20202136 TI - Perioperative management of anticoagulation in patients undergoing cardiac rhythm device procedures: a bridge to nowhere? PMID- 20202137 TI - Use of the wearable external cardiac defibrillator in children. AB - BACKGROUND: The wearable cardiac defibrillator (WCD) is an alternative to the implantation of cardioverter defibrillator (ICD) for patients at risk for sudden death who do not fulfill standard criteria for ICD implantation or in whom the risk:benefit ratio is equivocal. Published data pertaining to the WCD in children is sparse. We describe the utility of the WCD in children at a single tertiary care center. METHODS: We retrospectively identified all patients aged birth to 18 years of age who were prescribed a WCD between January 1, 2007, and June 30, 2009. Patient information regarding diagnosis, clinical history, electrocardiograms, rhythm reports, and outcome at last follow-up was reviewed. Information regarding the WCD was obtained including indication for use, patient compliance, and accuracy of rhythm determination, inappropriate and appropriate shock events, and other complications. RESULTS: Since 2007, four patients age less than or equal to 18 years have been prescribed the WCD at our institution. None of the patients had an inappropriate shock. Two patients had documented noncompliance with wear, which resulted in failure to detect and treat a life threatening arrhythmia in one. Two patients required downsizing of the WCD during use in order to improve electrode contact and rhythm detection. CONCLUSIONS: The WCD is an option for children of appropriate size who are at increased risk for sudden cardiac death, but in whom the risk of ICD implantation outweighs the benefit. Careful patient selection and education is important to ensure safety, as noncompliance with wear was common in this series of children. PMID- 20202138 TI - Response to cardiac resynchronization therapy in patients with heart failure and renal insufficiency. AB - BACKGROUND: Renal insufficiency (RI) adversely impacts prognosis in heart failure (HF) patients, partly because renal and cardiac dysfunction are intertwined, yet few cardiac resynchronization therapy (CRT) studies have examined patients with moderate-to-severe RI. METHODS: We analyzed 787 CRT-defibrillator (CRT-D) recipients with a glomerular filtration rate (GFR) measured prior to implant. Patients were grouped by GFR (in mL/min/1.73 m(2)): >or=60 (n = 376), 30-59 (n = 347), and <30 (n = 64). Overall survival, changes in left ventricular (LV) ejection fraction and LV end-systolic diameter, and GFR change at 3-6 months were compared among CRT-D groups and with a control cohort (n = 88), also stratified by GFR, in whom LV lead implant was unsuccessful and a standard defibrillator (SD) was placed. All patients met clinical criteria for CRT-D. RESULTS: Among CRT D recipients, overall survival improved incrementally with higher baseline GFR (for each 10 mL/min/1.73 m(2) increase, corrected hazard ratio [HR] 1.21, 95% confidence interval [CI] 1.13-1.30, P < 0.0001). Survival among SD and CRT-D patients within GFR < 30 and GFR >or= 60 groups was similar, whereas CRT-D recipients with GFR 30-59 had significantly better survival compared to SD counterparts (HR 2.23, 95% CI 1.34-3.70; P = 0.002). This survival benefit was associated with improved renal and cardiac function. CRT recipients with GFR >or= 60 derived significant echocardiographic benefit but experienced a GFR decline, whereas those with GFR < 30 had no echocardiographic benefit but did improve GFR. CONCLUSIONS: CRT may provide the largest survival benefit in HF patients with moderate RI, perhaps by improving GFR and LV function. Severe baseline RI predicts poor survival and limited echocardiographic improvement despite a modest GFR increase, such that CRT may not benefit those with GFR < 30 mL/min/1.73 m(2). CRT recipients with normal renal function derive echocardiographic benefit but no overall survival advantage. PMID- 20202139 TI - Preliminary study of the plasma and cerebrospinal fluid concentrations of IL-6 and IL-10 in patients with chronic pain receiving intrathecal opioid infusions by chronically implanted pump for pain management. AB - OBJECTIVE: This preliminary study assessed possible relationships between plasma and/or cerebrospinal fluid (CSF) concentrations of the pleiotropic cytokine, interleukin (IL)-6, the anti-inflammatory cytokine, IL-10, and levels of pain reported by patients receiving intrathecal (i.t.) opioids. DESIGN: A prospective study quantifying IL-6 and IL-10 concentrations using enzyme-linked immunoassays in samples of plasma and CSF as well as assessment of pain scores in patients receiving intrathecal opioids for management of chronic noncancer pain. SETTING: Outpatient pain clinics. PATIENTS: Patients with chronic pain receiving intrathecal morphine or hydromorphone alone or in combination with local anesthetics. INTERVENTIONS: Two groups of patients were studied. The first group (n = 50) had been receiving long-term i.t. opioids by chronically implanted pump for approximately 5 years; paired samples of plasma and CSF were collected at the time of i.t. pump refill. For the second patient group (n = 10), possible temporal changes in the plasma and/or CSF concentrations of IL-6 and IL-10 were investigated for 3 months after initiation of i.t. opioid infusions. RESULTS: For patients receiving long-term i.t. opioid infusions, there were significant inverse correlations (P < or = 0.05) between pain intensity and the plasma (but not CSF) IL-10 and IL-6 concentrations. Despite the considerable inter-patient variability in the CSF concentrations of IL-6 in the long-term cohort, the mean CSF IL-6 concentration was approximately fivefold higher in patients receiving long-term i.t. opioids relative to those receiving i.t. opioids for only 3 months. CONCLUSIONS: The significant inverse correlations observed between pain intensity and the plasma IL-6 and IL-10 concentrations in patients receiving longterm i.t. opioids for chronic pain management, suggests that these cytokines are worthy of further investigation as possible biomarkers of persistent pain. PMID- 20202140 TI - Thoracoscopic sympathectomy at the T2 or T3 level facilitates bradykinin-induced protein extravasation in human forearm skin. AB - BACKGROUND: The endogenous peptide bradykinin (BK) is an inflammatory mediator that induces nociceptor activation and sensitization as well as protein extravasation and vasodilation. OBJECTIVE: To test the hypothesis if sympathectomy affects BK-induced inflammation in humans. METHODS: Dermal microdialysis was employed on the volar forearm in 10 patients (21-41 years) with regional hyperhidrosis before and three months after preganglionic endoscopic transthoracic sympathetic clipping (ETSC) at the T2 or T3 level and in 10 healthy volunteers (22-36 years). After 60 minutes perfusion with Ringer's solution microdialysis fibers were perfused with BK 10(-7) M and 10(-5) M for 30 minutes followed by 30 minutes Ringer's solution again. To assess protein extravasation dialysate protein content was measured photometrically and Laser-Doppler imaging was used to quantify axonreflex vasodilation. RESULTS: Baseline flux values after ETSC were higher as compared with controls and preoperative values (anova, Bonferroni post hoc test, P < 0.05), but neither BK 10(-7) M nor 10(-5) M led to significant vasodilation. Baseline dialysate protein did not significantly differ between groups. BK 10(-5) M induced protein extravasation while BK 10(-7) M was ineffective, and BK 10(-5) M induced protein extravasation was significantly enhanced after ETSC (P < 0.001). CONCLUSIONS: Forearm skin perfusion is increased after ETSC on the T2 or T3 level indicating decreased sympathetic activity while BK-induced protein extravasation was increased. These results show that preganglionic sympathectomy does not diminish bradykinin-induced protein extravasation as found for postganglionic sympathectomy in rats. PMID- 20202142 TI - Evaluation of the acceptability and usability of a decision support system to encourage safe and effective use of opioid therapy for chronic, noncancer pain by primary care providers. AB - OBJECTIVE: To develop and evaluate a clinical decision support system (CDSS) named Assessment and Treatment in Healthcare: Evidenced-Based Automation (ATHENA) Opioid Therapy, which encourages safe and effective use of opioid therapy for chronic, noncancer pain. DESIGN: CDSS development and iterative evaluation using the analysis, design, development, implementation, and evaluation process including simulation-based and in-clinic assessments of usability for providers followed by targeted system revisions. RESULTS: Volunteers provided detailed feedback to guide improvements in the graphical user interface, and content and design changes to increase clinical usefulness, understandability, clinical workflow fit, and ease of completing guideline recommended practices. Revisions based on feedback increased CDSS usability ratings over time. Practice concerns outside the scope of the CDSS were also identified. CONCLUSIONS: Usability testing optimized the CDSS to better address barriers such as lack of provider education, confusion in dosing calculations and titration schedules, access to relevant patient information, provider discontinuity, documentation, and access to validated assessment tools. It also highlighted barriers to good clinical practice that are difficult to address with CDSS technology in its current conceptualization. For example, clinicians indicated that constraints on time and competing priorities in primary care, discomfort in patient-provider communications, and lack of evidence to guide opioid prescribing decisions impeded their ability to provide effective, guideline-adherent pain management. Iterative testing was essential for designing a highly usable and acceptable CDSS; however, identified barriers may limit the impact of the ATHENA-Opioid Therapy system and other CDSS on clinical practices and outcomes unless CDSS are paired with parallel initiatives to address these issues. PMID- 20202141 TI - Nonimmersive virtual reality mirror visual feedback therapy and its application for the treatment of complex regional pain syndrome: an open-label pilot study. AB - OBJECTIVE: Chronic pain conditions such as phantom limb pain and complex regional pain syndrome are difficult to treat, and traditional pharmacological treatment and invasive neural block are not always effective. Plasticity in the central nervous system occurs in these conditions and may be associated with pain. Mirror visual feedback therapy aims to restore normal cortical organization and is applied in the treatment of chronic pain conditions. However, not all patients benefit from this treatment. Virtual reality technology is increasingly attracting attention for medical application, including as an analgesic modality. An advanced mirror visual feedback system with virtual reality technology may have increased analgesic efficacy and benefit a wider patient population. In this preliminary work, we developed a virtual reality mirror visual feedback system and applied it to the treatment of complex regional pain syndrome. DESIGN: A small open-label case series. Five patients with complex regional pain syndrome received virtual reality mirror visual feedback therapy once a week for five to eight sessions on an outpatient basis. Patients were monitored for continued medication use and pain intensity. RESULTS: Four of the five patients showed >50% reduction in pain intensity. Two of these patients ended their visits to our pain clinic after five sessions. CONCLUSION: Our results indicate that virtual reality mirror visual feedback therapy is a promising alternative treatment for complex regional pain syndrome. Further studies are necessary before concluding that analgesia provided from virtual reality mirror visual feedback therapy is the result of reversing maladaptive changes in pain perception. PMID- 20202143 TI - A survey of patients' use of the internet for chronic pain-related information. AB - OBJECTIVE: To investigate the use of the Internet as a pain information seeking tool among a population of patients attending a chronic pain clinic. METHODS: A bespoke self-completing questionnaire was given to 150 patients attending 17 consecutive chronic pain clinics at The Royal Perth Hospital during August and September 2007. RESULTS: One hundred twenty-two completed surveys were received, a response rate of 81%. Only 23.8% of the patients had used the Internet to access pain-related health care information. There was no gender difference between those who did and did not access the Internet for information. Age group, highest educational level attained, and the availability of Internet access were all significantly associated with the use of the Internet to search for pain related information. 41.4% described the information they found as useful, 6.9% found it frightening and 10.3% found it confusing. Forty-four percent wanted more information to be available on the Internet while only 6.9% planned to discuss their findings with their doctor. CONCLUSIONS: When compared with other studies about patient information-seeking behavior, a smaller than expected percentage of patients attending chronic pain clinics in Perth used the Internet to search for information about pain. There are a variety of reasons for this that would suggest that health care professionals should not be complacent but seek to maximize the potential of the Internet to inform our patients by advising them how and where to look for relevant information. PMID- 20202144 TI - Evolution of the scientific literature on pain from 1976 to 2007. AB - OBJECTIVE: This study traces the evolution of the scientific literature on pain published during the last 30+ years (1976-2007). METHODS: Using the Web of Science, pain-focused journal articles from the Science Citation Index Expanded published in 1977, 1987, 1997, and 2007 were retrieved and analyzed. RESULTS: The number of pain-related publications rose from 1,562 articles for 1976-77 to 9,159 PubMed for 2006-2007, with slow growth for the period 1976-1995, and rapid increases from 1995-2007. The analysis of contributing countries showed two major players, the United States and the UK; the doubling of the number of countries involved in pain research from 40 in 1977 to 82 in 2007; and the appearance in 2007 of The Netherlands, Turkey, China, and Brazil among the top-15 most prolific contributors. During the 30-year period, the number of journals publishing pain related research increased nearly 2.5-fold (363 journals in 1977 vs 972 in 2007), including 14 new, international pain-focused journals since 2000. Additionally, while there were only two pain journals (Pain and Headache) in 1977, 15 pain focused journals were indexed in 2007 with the result that 17 of the top-20 pain focused journals in 2007 did not exist in 1977. CONCLUSION: The rapid evolution and explosion of pain research in the last 30+ years was reflected in substantial changes in the landscape of the contributing countries and in the scientific journals targeted by pain researchers. PMID- 20202145 TI - A survey of selected physician views on acupuncture in pain management. AB - OBJECTIVES: To collect information on the role of acupuncture in pain management from pain physicians and referral physicians who manage clinical pain conditions. METHODS: The survey was conducted between 2007 and 2008 through nationwide direct mail or e-mail to 1083 physicians who are currently practicing in the United States. We divided our 16 survey questions into five categories: 1) physician's attitude toward acupuncture as a modality of pain management; 2) physician's preference or belief with regard to the type of pain condition suitable for acupuncture referrals; 3) timing for making acupuncture referrals (e.g., acupuncture as a first line pain treatment option or a last approach after failed conventional pain management); 4) clinical assessment criteria for the effectiveness of acupuncture therapy; and 5) barriers to making acupuncture referrals (e.g., physician's personal view, insurance issues, patient refusal, etc.). The survey results were calculated and interpreted as the percentage rate of response. RESULT: The results indicate that an overwhelming majority of survey responders have a positive attitude and favorable experience with using acupuncture as an alternative modality for chronic pain management. However, our survey responders are mostly from teaching hospitals, suggesting a possible gap between teaching hospitals and other medical facilities (private practice and community hospitals) in utilizing acupuncture for pain management. The lack of insurance coverage and facility for acupuncture treatment are two primary barriers to making acupuncture referrals. CONCLUSIONS: The survey results indicate that acupuncture is considered by many physicians to be a useful alternative modality for chronic pain management. PMID- 20202146 TI - Single CT-guided chemodenervation of the anterior scalene muscle with botulinum toxin for neurogenic thoracic outlet syndrome. AB - OBJECTIVE: To examine pain relief in patients with neurogenic thoracic outlet syndrome (NTOS) after a single, low dose injection of botulinum toxin A (Botox) into the anterior scalene muscle (ASM) under computed tomographic (CT) guidance. DESIGN: Prospective longitudinal study. SETTING: Academic medical institution. PATIENTS: Patients 18 years of age and older were evaluated for potential scalenectomy and first rib resection using the transaxillary approach at the study institution between 2005 and 2008. All patients had failed physical therapy. A total of 29 procedures on 27 participants were studied. INTERVENTIONS: A single, 20-unit injection of Botox into the ASM under CT-guidance. OUTCOME MEASURES: Short-form McGill Pain Questionnaire (SF-MPQ) prior to and at 1, 2, and 3 months post-Botox toxin injection. RESULTS: There was a decline in pain during the 3 months subsequent to Botox injection as noted by the following components of the SF-MPQ: sensory (P = 0.02), total (P = 0.05), visual analog scale (VAS [P = 0.04]), and present pain intensity (PPI) score (P = 0.06). The proportion of patients reporting more intense pain scores did not return to the pre intervention level at 3 months post-Botox injection. CONCLUSION: Patients experienced substantial pain relief in months 1 and 2 following a single Botox injection into the ASM under CT guidance. Significant pain reduction was noted for 3 months after Botox injection with respect to both sensory and VAS scores, and the total and PPI scores approximated statistical significance. After 3 months, patients experienced a 29% decrease in the sensory component of their pain as well as an approximate 15% reduction in their VAS score. A single, CT guided Botox injection into the ASM may offer an effective, minimally invasive treatment for NTOS. PMID- 20202147 TI - Effect of inhaled steroid and montelukast on clinical symptoms in children with newly diagnosed asthma: a pilot study. AB - There is a lack of evidence for treatment of newly diagnosed asthma, and they are based mainly on expert opinion. This pilot study was aimed at evaluating the effects of inhaled corticosteroid (ICS) in two different doses and montelukast sodium on clinical symptoms and lung function in children with newly diagnosed asthma. This was a randomized, double-blind, parallel-group, 12-month pilot trial, studying the effects of budesonide 800 mcg/day and 400 mcg/day and montelukast 5 or 10 mg tablet according to age on clinical symptoms and lung function in 60 children with newly diagnosed asthma. After 6 months of treatment with different doses of inhaled budesonide and montelukast sodium, asthma control and lung function significantly improved in all three groups of treatment; there were no differences between groups. We found significant correlation between time of enrollment and individual answer to the treatment in montelukast group only; children enrolled later (at the end of heating season) responded better to treatment. The answer to both ICS doses was independent from time of enrollment. The results of the present pilot study suggest that natural exposure, even to perennial allergens, should be considered in choosing the initial asthma treatment. We showed that montelukast may be used as initial asthma therapy in children allergic to house-dust mites preferably at the end of the heating season. Therefore, ICS could be a better choice as initial asthma therapy during maximum allergen exposure. PMID- 20202148 TI - Wolcott-Rallison syndrome due to the same mutation (W522X) in EIF2AK3 in two unrelated families and review of the literature. AB - Wolcott-Rallison syndrome (WRS) is a rare autosomal recessive disorder characterized by an early-infancy-onset diabetes mellitus associated with a variety of multisystemic clinical manifestations. Here, we present six patients with WRS, carrying the same homozygous mutation (EIF2AK3-W522X), from two unrelated Turkish families. This is the largest series of patients with the same mutation for this rare syndrome. In this communication we compare clinical features of these six patients with the other 34 patients who have been reported to date, and review the clinical features of WRS. All WRS patients presented first with symptoms of insulin dependent diabetes mellitus, with a mean age at onset of 2 months. All patients had skeletal dysplasia or early signs of it, and growth retardation. Many of the patients with WRS have been reported to have developmental delay, mental retardation, and learning difficulties; in contrast, none of our patients showed abnormal development at age up to 30 months. Acute attacks of hepatic failure were reported in 23 cases out of 37 patients; in 15 of those 23 cases an acute attack of renal failure accompanied the liver failure. Exocrine pancreatic deficiency has been reported in only four cases other than our four patients. Central hypothyroidism was observed in six of 28 cases. We propose that central hypothyroidism is not a component of WRS, but rather a reflection of euthyroid sick syndrome. Four of our patients experienced severe neutropenia, compared to only five of the 27 other cases, suggesting that the W522X mutation may be specifically associated with neutropenia. Other than the consistent features of diabetes mellitus and epiphyseal dysplasia, WRS patients are otherwise characterized by extensive phenotypic variability that correlates poorly to genotype. PMID- 20202149 TI - Oral glucose tolerance testing in children with cystic fibrosis. AB - BACKGROUND: Cystic fibrosis (CF) related diabetes is the most common comorbidity in persons with CF. International Society for Pediatric and Adolescent Diabetes (ISPAD) guidelines recommend annual oral glucose tolerance testing (OGTT) screening starting at age 10. The OGTT might be recommended in younger children if, as in adults, it provided clinically relevant prognostic information. A database review was performed to determine whether OGTT findings in children with CF predict subsequent clinical course. METHODS: A retrospective matched-pair cohort study was based on OGTTs performed during 1998-2003. Children aged 6-9 were classified as having normal glucose tolerance (NGT) or abnormal glucose tolerance (AGT). Children with AGT were matched by age and gender to those with NGT. Clinical status was assessed at baseline and 5 yr later. In a separate investigation, diabetes and prior AGT status of children aged 10-18 were used to assess predictions derived from the cohort study. RESULTS: In 1998-2003, 39 of 94 children had AGT. Of these, 31 had sufficient follow-up data to be included. Both at baseline and 5 yr later there was no significant difference in height, weight, body mass index (BMI) or lung function between AGT and NGT. Diabetes developed in 13 AGT (42%) and one NGT (3%) [odds ratio (OR) 11, p = 0.0009]. Age of diabetes onset was 12 +/- 1 yr in boys and 11 +/- 1 yr in girls, compared to approximately 23 yr in the general CF population. Fifteen current children age 10-18 who had AGT before age 10 have diabetes, close to the prediction of 19. CONCLUSIONS: AGT in children with CF age 6-9 yr identifies those at high risk for progression to early onset diabetes. PMID- 20202150 TI - Renal Doppler indices in diabetic children with insulin resistance syndrome. AB - End-stage renal failure is still a leading cause of mortality among type 1 diabetes patients. Insulin resistance plays a larger role in type 1 diabetes disease process than is commonly recognized. Detection of diabetic nephropathy as early as possible currently offers the best chance of delaying or possibly preventing progression to end-stage disease. Renal resistive index (RI) and pulsatility index (PI), measured using renal Doppler ultrasonography, reflect intrarenal vascular resistance. The present work aimed at examining renal Doppler indices (RI and PI) in type 1 diabetic children and their relation to features of insulin resistance and other established parameters of early diabetic nephropathy as microalbuminuria. One hundred diabetic children with a mean age of 13.4 +/- 2.9 yr and an average diabetes duration of (7.2 +/- 2.5 yr) were included. Thirty healthy children served as controls. All renal Doppler indices were significantly higher in children with type 1 diabetes mellitus (p <= 0.01). The worst parameters were observed in children diagnosed with insulin resistance syndrome (IRS) (38%), hypertensive (12%), and obese (4%) children. Resistive index showed a significant correlation to blood pressure (r = 0.2, p = 0.04), waist-hip ratio (r = 0.5, p = 0.02), insulin dose (r = 0.2, p = 0.02) and estimated glucose disposal rate (r = -0.5, p = 0.01). No correlation was noted to microalbuminuria, HbA1c, or duration of diabetes. The present work concluded that renal Doppler indices are worse in diabetic children and particularly those with IRS. These children appear to be at graver risk for diabetic nephropathy. In these patients adding renal Doppler assessment to their work up, might diagnose diabetic nephropathy at a prealbuminuric stage. PMID- 20202151 TI - Eleven-year study of causes of neonatal bacterial meningitis in Ahvaz, Iran. AB - BACKGROUND: Bacterial meningitis is a devastating infection with a high mortality rate, especially in neonates. The aim of this study was to determine the causative agents that cause bacterial meningitis in Khuzestan province in the south-western region of Iran. METHODS: A descriptive, cross-sectional study was carried out from 1997 to 2007 at the neonatal ward of a university teaching hospital (Emam Khomeini hospital) in Ahvaz. All infants younger than 29 days old who suffered from meningitis were included. Laboratory tests included Gram stain, culture, and biochemical tests. Cases were defined as meningitis if the cerebrospinal fluid culture was positive. RESULTS: Based on cerebrospinal fluid culture, 31 infants were identified as having bacterial meningitis. Eleven (35.5%) of these cases were caused by Klebsiella pneumoniae, nine (29%) were caused by Enterobacter spp., three (9.6%) were caused by Escherichia coli, three (9.6%) were caused by Enterococcus spp., two (6.4%) were caused by Acinetobacter, and one case each (3.2%) was caused by Staphylococcus aureus, Pseudomonas aeruginosa and nontypeable Haemophilus influenzae. The male-to-female ratio was 2 : 1 (67.7% were male). The birthweights of 20 (64.5%) patients were under 2500 g and 11 (35.4%) patients had normal birthweights. Thirteen (42%) were early-onset cases and 18 (58%) were late-onset cases. More than half of the cases (54.8%) acquired the infection from the hospital. Blood cultures were positive for 18 (58%) patients. Thirty-two percent of cases died in spite of treatment. CONCLUSIONS: Klebsiella pneumoniae and Enterobacter spp. were the two main causative agents that caused neonatal bacterial meningitis, and nosocomial meningitis was the most common type in our ward. PMID- 20202152 TI - Evolution in pediatric health care. AB - BACKGROUND: There is disturbing evidence of escalating chronic disease among children--a phenomenon that is extracting a heavy toll from individuals, families, and health-care systems. METHODS: This review was prepared by assessing medical and scientific literature available from Medline, as well as by reviewing numerous books, conference proceedings, and government publications. RESULTS: Knowledge translation in medical science, the process whereby new research is incorporated into clinical practice, remains lethargic. Nutritional and environmental factors have recently been recognized as common determinants of modern illness, and various diagnostic techniques in molecular medicine are now available to facilitate diagnosis of disease etiology. CONCLUSIONS: A re evaluation of the current pediatric clinical paradigm is required in light of emerging research from fields such as epigenetics, molecular medicine and environmental health. Education about these branches of medical science should be integrated into pediatric medical education, and important research information from these disciplines should be incorporated into public health care and clinical practice relating to children. PMID- 20202153 TI - A systematic review and meta-analysis of tumor necrosis factor alpha-308 polymorphism and Kawasaki disease. AB - BACKGROUND: There have been genetic studies assessing the association between tumor necrosis factor (TNF)-alpha-308 and Kawasaki disease (KD) but the results have been conflicting due to lack of power. Therefore, a systematic review and meta-analysis was conducted to increase the power for identifying the association between the TNF-alpha-308 polymorphism and KD. METHOD: Studies were identified from MEDLINE and EMBASE databases and were included if the subjects were children and the frequencies between TNF-alpha-308 and KD were reported. Data were pooled using a random effect model if heterogeneity between studies was present. RESULTS: Thirteen studies were identified however only six studies were included. The pooled prevalence of minor A allele was 5.2% (95% confidence interval [CI]: 0.1%-9.5%). Gene effect was assessed using per-allele and per-genotype approaches. The pooled odds ratio of G versus A with the random effect model was 1.13 (95%CI: 0.34-3.27). The genotype effects for GG versus GA+AA was estimated and the pooled odds ratio was 1.08 (95%CI: 0.42-2.92). CONCLUSION: This review suggests a trend of association between the TNF-alpha-308 G-allele and KD. However, the gene effects are heterogeneous and assessing sources of heterogeneity are limited. An updated meta-analysis is needed if more studies are published. PMID- 20202155 TI - Clinical management of short children with low serum immunoglobulin but no immunodeficiency features. AB - BACKGROUND: In children of different ages investigated for failure to thrive, low (below the cut-off for age) immunoglobulin (Ig) values can be detected, without any clinical evidence of humoral immunodeficiencies. To better characterize infants presenting with diminished immunoglobulin levels, we studied IgG subclasses, in vitro Ig production and B cell subpopulation. METHODS: We monitored 17 children (12 boys and five girls, age range 1-18 years) with low serum levels of one or more Ig isotypes but without any clinical or laboratory features of immunodeficiency. RESULTS: Low IgM levels were frequent (52.9%). During the follow up, six of 17 cases (35.3%) normalized their immunoglobulin levels. Frequently, in the observed patients, low levels of immunoglobulins were not limited to the period of infancy. In all patients, in vitro Ig production and B lymphocyte subpopulations were within normal ranges. CONCLUSIONS: We suggest a quantification of serum Ig levels in children who fail to thrive in order to identify patients with low Ig levels. These children should be monitored until Ig levels normalize to exclude any immunodeficiency status. Early recognition of children with persistent hypogammaglobulinemia would allow prompt and appropriate clinical interventions. PMID- 20202154 TI - Impact of sustained neuromuscular blockade on outcome of mechanically ventilated children. AB - BACKGROUND: Neuromuscular blocking agents (NMBA) are commonly administered to critically ill children in pediatric intensive care units (PICU) in the USA and Europe. Although NMBA are frequently used in PICU patients, their role in the PICU setting has not yet been clearly defined. The aim of this study was to describe the sustained administration of NMBA and its impact on outcome of PICU patients. METHODS: A 3-year retrospective cohort study was conducted to compare mechanically-ventilated patients who received NMBA for at least 12 h with patients who did not (control group). RESULTS: A total of 317 consecutive patients were ventilated over 3473 days. Patients were similar in age, weight and severity scores. Thirty-four children (10.7%) received NMBA. Compared with controls, the neuromuscular blockade (NMB) group had a longer duration of mechanical ventilation (13.7 vs 5.5 days, P= 0.000), longer PICU stay (20 vs 11 days, P= 0.000) and increased occurrence of ventilator-associated pneumonia (6.6 vs 4.1/1000 ventilator days, P= 0.010). The NMB use was not associated with higher mortality (8.8% vs 17.6%, P= 0.287) or longer hospital stay (30.5 vs 23 days, P= 0.117). CONCLUSION: Although the use of NMBA was not associated with greater mortality, we found that sustained use of NMBA is associated with prolonged mechanical ventilation, longer PICU stay and higher incidence of ventilator-associated pneumonia when compared with controls. Larger studies are necessary to confirm these findings. PMID- 20202156 TI - Construct validity of the Comprehensive Developmental Inventory for Infants and Toddlers. AB - BACKGROUND: The aim of this study was to investigate the construct validity of the diagnostic test, the Comprehensive Developmental Inventory for Infants and Toddlers (CDIIT). METHODS: A total of 1085 children in four age groups (infant, 1 year-old, 2-year-old, preschool age) were enrolled. The Developmental Quotient of each subdomain of the five CDIIT subtests (Cognition, Language, Motor, Social, and Self-help) was used as the basic unit for factor analysis with the iterative principle factor method and promax rotation. RESULTS: The two-factor solution in two younger age groups and 2- or 3-factor solutions in the 2-year-old and preschool groups provided superior factor structure in terms of interpretability and compatibility with existing child development theories. CONCLUSION: Although five constructs were proposed in the original manual of CDIIT, two to three constructs were revealed in this empirical study. PMID- 20202157 TI - Long-term stability of thyroid hormones and DNA in blood spots kept under varying storage conditions. AB - BACKGROUND: Congenital hypothyroidism is screened using blood spotted on filter paper that may be transported from remote areas to central testing facilities. However, storage conditions and transportation may affect sample quality. METHODS: We examined long-term stability of thyroid-stimulating hormone (TSH) and thyroxin (TT4) in blood spotted on filter paper, which was stored at room temperature (RT), 4 degrees C and -20 degrees C under continuous or intermittent power supply (six hours on and six hours off around the clock.) Hormone levels in the discs were measured periodically for up to ten years. Extraction of DNA from blood spots and polymerase chain reaction were performed. RESULTS: Our results showed that TT4 was stable for up to 6.1, 5.34 and 5.16 years when stored at -20 degrees C, 4 degrees C and RT, respectively. TSH was stable for up to 2.7 years at RT, and for up to 6.5 and 4.1 years when stored at -20 degrees C and 4 degrees C, respectively, under continuous power supply. However, under intermittent power supply, TSH was stable for up to 3.8 and 2.5 years when stored at 4 degrees C and -20 degrees C, respectively. Mitochondrial cytochrome oxidase and sex-determining region of Y chromosome genes were successfully amplified from DNA extracted from the blood spots. CONCLUSION: Our data indicate that TT4 and TSH are most stable in blood spots stored at -20 degrees C under continuous power supply. However, they can be stored at RT or at 4 degrees C and -20 degrees C under interrupted power supply for at least 2.5 years. Moreover, the DNA extracted from the blood spots was intact and suitable for genetic studies. PMID- 20202158 TI - Ghrelin and adiponectin levels in colostrum, cord blood and maternal serum. AB - BACKGROUND: Ghrelin and adiponectin, which are considered to take part in the regulation of energy metabolism, have been found in breast milk and cord blood. The aims of this study were to determine ghrelin and adiponectin levels in colostrum, cord blood and maternal serum and to investigate the correlations between colostrum and cord blood levels of these peptides and the anthropometry of newborn infants and their mothers. METHODS: Total ghrelin (TGHR), free ghrelin (FGHR) and adiponectin levels were studied in colostrum and the serum samples of 25 healthy lactating women and the cord blood of their healthy full-term infants. RESULTS: No significant differences could be found among TGHR and adiponectin levels in colostrum, cord blood and maternal serum. The median FGHR level in colostrum was significantly higher than that of maternal serum and cord blood. The colostrum TGHR was negatively correlated with body mass index (BMI) and weight of the infants at birth. TGHR and FGHR levels in colostrum were found to be positively correlated with those of maternal TGHR and FGHR concentrations, respectively. Adiponectin levels in colostrum were not correlated with BMI or birthweight of the infants or BMI of the mothers. CONCLUSION: These findings suggest that the source of ghrelin in breast milk is probably both breast tissue itself and the serum of the mother. Ghrelin in colostrum seems to be related to the anthropometry of infants even at birth, unlike adiponectin. PMID- 20202159 TI - Photosensitizing effect of hematoporphyrin IX on immature stages of Ceratitis capitata (Diptera: Tephritidae). AB - Immature stages of Ceratitis capitata were tested as a model for hematoporphyrin IX (HP IX) phototoxicity. The lethal concentration 50 (LC(50)) of HP IX in the food was determined during postembryonic development until adult emergence as 0.173 mm (95% CI: 0.138-0.209). The corresponding HP IX LC(50) during the dispersal period alone was 0.536 mm (95% CI: 0.450-0.633). HP IX toxicity was compared against Phloxine B (PhB) (0.5 mm). HP IX elicited a mortality of 90.87%, which was mainly concentrated during prepupal and early pupal stages. PhB mortality was much lower (56.88%) and occurred mainly during the adult pharate stage. A direct correlation between light-dependent HP IX mortality, evidence of reactive oxygen species (ROS) and lipid peroxidation (conjugated dienes and thiobarbituric acid reactive substances) was established in C. capitata larvae. ROS were found to be very significant in both the brain and in the gut. PMID- 20202160 TI - Synergistic effect of ultrasound and thiazone-PEG 400 on human skin optical clearing in vivo. AB - In this paper, we propose a new physical method in combination with mixed solution of thiazone and polyethylene glycol 400 (thiazone PEG 400 solution) penetration into tissue to assess the skin optical clearing. Four treatments were performed: (1) control group (C); (2) polyethylene glycol 400 (PEG400); (3) 0.25% thiazone (0.25%T); (4) 0.25% thiazone and 5-min ultrasound (0.25%T/SP). The diffuse reflectance spectra and imaging depth of human skin in vivo at different times were measured by spectroscopy and optical coherence tomography (OCT). The optical clearing efficacy of skin was qualitatively and quantitatively analyzed. The results showed that the diffuse reflectance at 540 nm of samples at 10 min after being treated by 0.25%T/SP decreased by approximately 15.51%, whereas, 0.46%, 4.73% and 5.75% were received in C, PEG400 and 0.25%T, respectively. And at 60 min, the decrease in diffuse reflectance of samples in 0.25%T/SP is about 2.22-fold, 1.20-fold compared with that of the samples in PEG 400 and 0.25%T, at 540 nm, respectively. Simultaneously, 0.25%T/SP results in 41.33% increase in OCT 1/e light penetration depth after 60 min. There was a significant difference in the optical clearing effect on skin between ultrasound-mixed solution of thiazone in combination with PEG 400 and the mixed solution (P < 0.05). PMID- 20202161 TI - Use of UV-A energy for photosynthesis in the red macroalga Gracilaria lemaneiformis. AB - UV radiation is known to inhibit photosynthetically active radiation (PAR)-driven photosynthesis; however, moderate levels of UV-A have been shown to enhance photosynthesis and growth rates of some algae. Here, we have shown that UV-A alone could drive photosynthetic utilization of bicarbonate in the red alga Gracilaria lemaneiformis as evidenced in either O(2) evolution or carbon fixation as well as pH drift. Addition of UV-B inhibited the apparent photosynthetic efficiency, raised the photosynthetic compensation point and photosynthesis saturating irradiance level, but did not significantly affect the maximal rate of photosynthetic O(2) evolution. The electron transport inhibitor, DCMU, inhibited the photosynthesis completely, reflecting that energy of UV-A was transferred in the same way as that of PAR. Inorganic carbon acquisition for photosynthesis under UV alone was inhibited by the inhibitors of carbonic anhydrase. The results provided the evidence that G. lemaneiformis can use UV-A efficiently to drive photosynthesis based on the utilization of bicarbonate, which could contribute significantly to the enhanced photosynthesis in the presence of UV-A observed under reduced levels of solar radiation. PMID- 20202162 TI - Physiological responses of Scenedesmus quadricauda (Chlorophyceae) to UV-A and UV C light. AB - Despite intensive research focused on the effects of UV-B, deeper metabolic responses to UV-A and UV-C are still scarce. Besides, especially microalgal species had to develop efficient protective features in comparison with tissue structure of vascular plants. We exposed axenic cultures of Scenedesmus quadricauda (Chlorophyceae) to UV-A (366 nm) and UV-C (254 nm) light over 1 h. Both wavelengths stimulated increase in soluble proteins, superoxide radical and hydrogen peroxide, but had a nonsignificant effect on cell viability. Within 17 detected free amino acids, five (including proline) increased in response to UV-A while only aspartic acid and histidine increased in UV-C treatment. Total soluble phenols and flavonoids were influenced neither by UV-A nor by UV-C while selected flavonols (quercetin and kaempferol) decreased in UV-A and were not detected in UV-C treatment. Benzoic acid derivatives increased preferentially after UV-A illumination (vanillic acid and vanillin) while cinnamic derivatives (caffeic, chlorogenic and p-coumaric acids) decreased in both UV-A and UV-C. It is concluded that UV light stimulated oxidative stress while exposure time was not sufficient to stimulate larger changes in phenolic metabolites. Present findings in the context of available data and with emphasis on phenolics in algae are discussed. PMID- 20202163 TI - Association of acenaphthoporphyrins with liposomes for the photodynamic treatment of leishmaniasis. AB - Acenaphthoporphyrins are potential photosensitizers for photodynamic therapy, but their hydrophobicity limits their potential. Liposomes have been widely investigated as delivery vehicles that can transport hydrophobic drugs in biological systems. Here we study the association of acenaphthoporphyrins with liposomes made up of dimyristoyl phosphatidylcholine (DMPC), and to liposomes made up of a mixture of DMPC, cholesterol (Chol) and distearoyl phosphatidylglycerol (DSPG) in a 2:1:0.8 molar ratio to evaluate how liposome composition affects association constants. In liposomes consisting only of DMPC, the smaller monoacenaphthoporphyrin had the largest association constant of 5.5 x 10(4) m(-1) while the larger adj-diacenaphthoporphyrin and opp diacenaphthoporphyrin (ODP) had smaller association constants at 1.8 x 10(4) and 1.5 x 10(4) m(-1), respectively. The addition of liposomal Chol and DSPG has little effect on the magnitudes of the association constants. Polarization studies show that the acenaphthoporphyrins are driven far into the lipid bilayer to minimize polar-nonpolar interactions. Confocal microscopy confirms that the DMPC liposomes transport the porphyrins into promastigotes of Leishmania tarentolae. The compounds associated with DMPC:Chol:DSPG liposomes are effective in vitro against axenic and intracellular amastigotes of the pathogenic Leishmania panamensis. The effectiveness of the compounds is enhanced upon exposure of cultures to visible light. PMID- 20202164 TI - A plant-specific histone H3 lysine 4 demethylase represses the floral transition in Arabidopsis. AB - Histone demethylation regulates chromatin structure and gene expression, and is catalyzed by various histone demethylases. Trimethylation of histone H3 at lysine 4 (H3K4) is coupled to active gene expression; trimethyl H3K4 is demethylated by Jumonj C (JmjC) domain-containing demethylases in mammals. Here we report that a plant-specific JmjC domain-containing protein known as PKDM7B (At4g20400) demethylates trimethyl H3K4. PKDM7B mediates H3K4 demethylation in a key floral promoter, FLOWERING LOCUS T (FT), and an FT homolog, TWIN SISTER OF FT (TSF), and represses their expression to inhibit the floral transition in Arabidopsis. Our findings suggest that there are at least two distinct sub-families of JmjC domain containing demethylases that demethylate the active trimethyl H3K4 mark in eukaryotic genes, and reveal a plant-specific JmjC domain enzyme capable of H3K4 demethylation. PMID- 20202165 TI - Fasciclin-like arabinogalactan proteins: specialization for stem biomechanics and cell wall architecture in Arabidopsis and Eucalyptus. AB - The ancient cell adhesion fasciclin (FAS) domain is found in bacteria, fungi, algae, insects and animals, and occurs in a large family of fasciclin-like arabinogalactan proteins (FLAs) in higher plants. Functional roles for FAS containing proteins have been determined for insects, algae and vertebrates; however, the biological functions of the various higher-plant FLAs are not clear. Expression of some FLAs has been correlated with the onset of secondary-wall cellulose synthesis in Arabidopsis stems, and also with wood formation in the stems and branches of trees, suggesting a biological role in plant stems. We examined whether FLAs contribute to plant stem biomechanics. Using phylogenetic, transcript abundance and promoter-GUS fusion analyses, we identified a conserved subset of single FAS domain FLAs (group A FLAs) in Eucalyptus and Arabidopsis that have specific and high transcript abundance in stems, particularly in stem cells undergoing secondary-wall deposition, and that the phylogenetic conservation appears to extend to other dicots and monocots. Gene-function analyses revealed that Arabidopsis T-DNA knockout double mutant stems had altered stem biomechanics with reduced tensile strength and a reduced tensile modulus of elasticity, as well as altered cell-wall architecture and composition, with increased cellulose microfibril angle and reduced arabinose, galactose and cellulose content. Using materials engineering concepts, we relate the effects of these FLAs on cell-wall composition with stem biomechanics. Our results suggest that a subset of single FAS domain FLAs contributes to plant stem strength by affecting cellulose deposition, and to the stem modulus of elasticity by affecting the integrity of the cell-wall matrix. PMID- 20202166 TI - Role of the phytochrome and cryptochrome signaling pathways in hypocotyl phototropism. AB - Unilateral blue-light irradiation activates phototropin (phot) photoreceptors, resulting in asymmetric distribution of the phytohormone auxin and induction of a phototropic response in higher plants. Other photoreceptors, including phytochrome (phy) and cryptochrome (cry), have been proposed as modulators of phototropic responses. We show here that either phy or cry is required for hypocotyl phototropism in Arabidopsis thaliana under high fluence rates of blue light, and that constitutive expression of ROOT PHOTOTROPISM 2 (RPT2) and treatment with the phytohormone gibberellin (GA) biosynthesis inhibitor paclobutrazol partially and independently complement the non-phototropic hypocotyl phenotype of the phyA cry1 cry2 mutant under high fluence rates of blue light. Our results indicate that induction of RPT2 and reduction in the GA are crucial for hypocotyl phototropic regulation by phy and cry. We also show that GA suppresses hypocotyl bending via destabilization of DELLA transcriptional regulators under darkness, but does not suppress the phototropic response in the presence of either phyA or cryptochromes, suggesting that these photoreceptors control not only the GA content but also the GA sensing and/or signaling that affects hypocotyl phototropism. The metabolic and signaling regulation of not only auxin but also GA by photoreceptors therefore appears to determine the hypocotyl growth pattern, including phototropic and gravitropic responses and inhibition of hypocotyl elongation, for adaptation to various light environments. PMID- 20202167 TI - Cytosolic pyruvate,orthophosphate dikinase functions in nitrogen remobilization during leaf senescence and limits individual seed growth and nitrogen content. AB - The protein content of seeds determines their nutritive value, downstream processing properties and market value. Up to 95% of seed protein is derived from amino acids that are exported to the seed after degradation of existing protein in leaves, but the pathways responsible for this nitrogen metabolism are poorly defined. The enzyme pyruvate,orthophosphate dikinase (PPDK) interconverts pyruvate and phosphoenolpyruvate, and is found in both plastids and the cytosol in plants. PPDK plays a cardinal role in C(4) photosynthesis, but its role in the leaves of C(3) species has remained unclear. We demonstrate that both the cytosolic and chloroplastic isoforms of PPDK are up-regulated in naturally senescing leaves. Cytosolic PPDK accumulates preferentially in the veins, while chloroplastic PPDK also accumulates in mesophyll cells. Analysis of microarrays and labelling patterns after feeding (13)C-labelled pyruvate indicated that PPDK functions in a pathway that generates the transport amino acid glutamine, which is then loaded into the phloem. In Arabidopsis thaliana, over-expression of PPDK during senescence can significantly accelerate nitrogen remobilization from leaves, and thereby increase rosette growth rate and the weight and nitrogen content of seeds. This indicates an important role for cytosolic PPDK in the leaves of C(3) plants, and allows us to propose a metabolic pathway that is responsible for production of transport amino acids during natural leaf senescence. Given that increased seed size and nitrogen content are desirable agronomic traits, and that efficient remobilization of nitrogen within the plant reduces the demand for fertiliser applications, PPDK and the pathway in which it operates are targets for crop improvement. PMID- 20202168 TI - A functional genomics screen identifies diverse transcription factors that regulate alkaloid biosynthesis in Nicotiana benthamiana. AB - Biosynthesis of the alkaloid nicotine in Nicotiana species is induced by insect damage and jasmonate application. To probe the transcriptional regulation of the nicotine pathway, we constructed two subtracted cDNA libraries from methyl jasmonate (MeJA)-treated Nicotiana benthamiana roots directly in a viral vector suitable for virus-induced gene silencing (VIGS). Sequencing of cDNA inserts produced a data set of 3271 expressed sequence tags (ESTs; 1898 unigenes), which were enriched in jasmonate-responsive genes, and included 69 putative transcription factors (TFs). After a VIGS screen to determine their effect on nicotine metabolism, six TFs from three different TF families altered constitutive and MeJA-induced leaf nicotine levels. VIGS of a basic helix-loop helix (bHLH) TF, NbbHLH3, and an auxin response factor TF, NbARF1, increased nicotine content compared with control plants; silencing the bHLH family members, NbbHLH1 and NbbHLH2, an ethylene response factor TF, NbERF1, and a homeobox domain-like TF, NbHB1, reduced nicotine levels. Transgenic N. benthamiana plants overexpressing NbbHLH1 or NbbHLH2 showed increased leaf nicotine levels compared with vector controls. RNAi silencing led to both reduced nicotine and decreased levels of transcript encoding of enzymes of the nicotine pathway. Electrophoretic mobility shift assays showed that recombinant NbbHLH1 and NbbHLH2 directly bind G box elements identified from the putrescine N-methyltransferase promoter. We conclude that NbbHLH1 and NbbHLH2 function as positive regulators in the jasmonate activation of nicotine biosynthesis. PMID- 20202169 TI - Populus CEN/TFL1 regulates first onset of flowering, axillary meristem identity and dormancy release in Populus. AB - Members of the CENTRORADIALIS (CEN)/TERMINAL FLOWER 1 (TFL1) subfamily control shoot meristem identity, and loss-of-function mutations in both monopodial and sympodial herbaceous plants result in dramatic changes in plant architecture. We studied the degree of conservation between herbaceous and woody perennial plants in shoot system regulation by overexpression and RNA interference (RNAi)-mediated suppression of poplar orthologs of CEN, and the related gene MOTHER OF FT AND TFL 1 (MFT). Field study of transgenic poplars (Populus spp.) for over 6 years showed that downregulation of PopCEN1 and its close paralog, PopCEN2, accelerated the onset of mature tree characteristics, including age of first flowering, number of inflorescences and proportion of short shoots. Surprisingly, terminal vegetative meristems remained indeterminate in PopCEN1-RNAi trees, suggesting the possibility that florigen signals are transported to axillary mersitems rather than the shoot apex. However, the axillary inflorescences (catkins) of PopCEN1 RNAi trees contained fewer flowers than did wild-type catkins, suggesting a possible role in maintaining the indeterminacy of the inflorescence apex. Expression of PopCEN1 was significantly correlated with delayed spring bud flush in multiple years, and in controlled environment experiments, 35S::PopCEN1 and RNAi transgenics required different chilling times to release dormancy. Considered together, these results indicate that PopCEN1/PopCEN2 help to integrate shoot developmental transitions that recur during each seasonal cycle with the age-related changes that occur over years of growth. PMID- 20202170 TI - SQUAMOSA-PROMOTER BINDING PROTEIN 1 initiates flowering in Antirrhinum majus through the activation of meristem identity genes. AB - The degree to which developmental genetic pathways are conserved across distantly related organisms is a major question in biology. In Arabidopsis thaliana (L.) Heynh., inflorescence development is initiated in response to a combination of external and internal floral inductive signals that are perceived across the whole plant, but are integrated within the shoot apical meristem. Recently, it was demonstrated that SQUAMOSA-PROMOTER BINDING PROTEIN (SBP)-box proteins regulate A. thaliana flowering time by mediating signals from the autonomous and photoperiod pathways, and by directly activating key genes involved in inflorescence and floral meristem identity, including FRUITFULL (FUL), APETALA1 (AP1) and LEAFY (LFY). In the distantly related core eudicot species Antirrhinum majus L., paralogous SBP-box proteins SBP1 and SBP2 have likewise been implicated in regulating the AP1 ortholog SQUAMOSA (SQUA). To test the hypothesis that SBP box genes are also involved in the floral induction of A. majus, we used a reverse genetic approach to silence SBP1. SBP1-silenced lines are late to nonflowering, and show reduced apical dominance. Furthermore, expression and sequence analyses suggest that the SBP1-mediated transition to flowering occurs through the positive regulation of FUL/LFY homologs. Together, these data outline the utility of virus-induced gene silencing in A. majus, and provide new insight into the conservation of flowering time genetic pathways across core eudicots. PMID- 20202171 TI - ZEBRA-NECROSIS, a thylakoid-bound protein, is critical for the photoprotection of developing chloroplasts during early leaf development. AB - The zebra-necrosis (zn) mutant of rice (Oryza sativa) produces transversely green/yellow-striped leaves. The mutant phenotype is formed by unequal impairment of chloroplast biogenesis before emergence from the leaf sheath under alternate light/dark or high/low temperatures (restrictive), but not under constant light and temperature (permissive) conditions. Map-based cloning revealed that ZN encodes a thylakoid-bound protein of unknown function. Virus-induced gene silencing of a ZN homolog in Nicotiana benthamiana causes leaf variegation with sporadic green/yellow sectors, indicating that ZN is essential for chloroplast biogenesis during early leaf development. Necrotic lesions often occur in the yellow sectors as a result of an excessive accumulation of reactive oxygen species (ROS). The phenotypic severity (leaf variegation and necrosis) and ROS levels are positively correlated with an increase in light intensity under restrictive conditions. In the mutant leaves, chlorophyll (Chl) metabolism, ROS scavenging activities, maximum quantum yield of photosystem II (PSII), and structures and functions of the photosynthetic complexes are normal in the Chl containing cells, suggesting that ROS are mainly generated from the defective plastids of the Chl-free cells. The PSII activity of normal chloroplasts is hypersensitive to photoinhibition because the recovery rates of PSII are much slower. In the PSII repair, the degradation of damaged D1 is not impaired, suggesting a reduced activity of new D1 synthesis, possibly because of higher levels of ROS generated from the Chl-free cells by excess light. Together, we propose that ZN is required for protecting developing chloroplasts, especially during the assembly of thylakoid protein complexes, from incidental light after darkness. PMID- 20202172 TI - Arabidopsis has a cytosolic fumarase required for the massive allocation of photosynthate into fumaric acid and for rapid plant growth on high nitrogen. AB - The Arabidopsis genome has two fumarase genes, one of which encodes a protein with mitochondrial targeting information (FUM1) while the other (FUM2) does not. We show that a FUM1-green fluorescent protein fusion is directed to mitochondria while FUM2-red fluorescent protein remains in the cytosol. While mitochondrial FUM1 is an essential gene, cytosolic FUM2 is not required for plant growth. However FUM2 is required for the massive accumulation of carbon into fumarate that occurs in Arabidopsis leaves during the day. In fum2 knock-out mutants, fumarate levels remain low while malate increases, and these changes can be reversed with a FUM2 transgene. The fum2 mutant has lower levels of many amino acids in leaves during the day compared with the wild type, but higher levels at night, consistent with a link between fumarate and amino acid metabolism. To further test this relationship we grew plants in the absence or presence of nitrogen fertilizer. The amount of fumarate in leaves increased several fold in response to nitrogen in wild-type plants, but not in fum2. Malate increased to a small extent in the wild type but to a greater extent in fum2. Growth of fum2 plants was similar to that of the wild type in low nitrogen but much slower in the presence of high nitrogen. Activities of key enzymes of nitrogen assimilation were similar in both genotypes. We conclude that FUM2 is required for the accumulation of fumarate in leaves, which is in turn required for rapid nitrogen assimilation and growth on high nitrogen. PMID- 20202173 TI - Identification and genetic analysis of the APOSPORY locus in Hypericum perforatum L. AB - The introduction of apomixis - seed formation without fertilization - into crop plants is a long-held goal of breeding research, since it would allow for the ready fixation of heterozygosity. The genetic basis of apomixis, whether of the aposporous or the diplosporous type, is still only poorly understood. Hypericum perforatum (St John's wort), a plant with a small genome and a short generation time, can be aposporous and/or parthenogenetic, and so represents an interesting model dicot for apomixis research. Here we describe a genetic analysis which first defined and then isolated a locus (designated HAPPY for Hypericum APOSPORY) associated with apospory. Amplified fragment length polymorphism (AFLP) profiling was used to generate a cleaved amplified polymorphic sequence (CAPS) marker for HAPPY which co-segregated with apospory but not with parthenogenesis, showing that these two components of apomixis are independently controlled. Apospory was inherited as a dominant simplex gene at the tetraploid level. Part of the HAPPY sequence is homologous to the Arabidopsis thaliana gene ARI7 encoding the ring finger protein ARIADNE7. This protein is predicted to be involved in various regulatory processes, including ubiquitin-mediated protein degradation. While the aposporous and sexual alleles of the HAPPY component HpARI were co-expressed in many parts of the plant, the gene product of the apomict's allele is truncated. Cloning HpARI represents the first step towards the full characterization of HAPPY and the elucidation of the molecular mechanisms underlying apomixis in H. perforatum. PMID- 20202174 TI - Transcriptome-wide identification of microRNA targets in rice. AB - MicroRNA (miRNA)-guided target RNA expression is vital for a wide variety of biological processes in eukaryotes. Currently, miRBase (version 13) lists 142 and 353 miRNAs from Arabidopsis and rice (Oryza sativa), respectively. The integration of miRNAs in diverse biological networks relies upon the confirmation of their RNA targets. In contrast with the well-characterized miRNA targets that are cleaved in Arabidopsis, only a few such targets have been confirmed in rice. To identify small RNA targets in rice, we applied the 'degradome sequencing' approach, which globally identifies the remnants of small RNA-directed target cleavage by sequencing the 5' ends of uncapped RNAs. One hundred and sixty targets of 53 miRNA families (24 conserved and 29 rice-specific) and five targets of TAS3-small interfering RNAs (siRNAs) were identified. Surprisingly, an additional conserved target for miR398, which has not been reported so far, has been validated. Besides conserved homologous transcripts, 23 non-conserved genes for nine conserved miRNAs and 56 genes for 29 rice-specific miRNAs were also identified as targets. Besides miRNA targets, the rice degradome contained fragments derived from MIRNA precursors. A closer inspection of these fragments revealed a unique pattern distinct from siRNA-producing loci. This attribute can serve as one of the ancillary criteria for separating miRNAs from siRNAs in plants. PMID- 20202175 TI - Haemorrhagic diathesis in neonatal calves: an emerging syndrome in Europe. AB - In 2008 and 2009 a large number of cases of haemorrhagic diathesis (HD) in neonatal calves were reported in different European countries. In Flanders, 84 cases of neonatal HD in 30 herds were reported in this period. The disease typically affects calves younger than 1 month old from different breed and gender. Prominent clinical signs are cutaneous bleeding, petechiae on all mucosae, melena and often high fever. Early in the disease, the mental state of the animals is uncompromised. The typical haematological finding is pancytopenia, with severe to complete thrombocytopenia being the cause of the increased susceptibility to bleeding. In seven of the affected herds blood samples of calves of the same age group as the clinical case were collected and on six of those farms at least one subclinical case could be identified. Necropsy findings were generalized petechiae, ecchymoses or haemorrhages and variable lymphadenopathy. Histopathology of haemorrhagic lesions revealed multifocal extravasation of red blood cells (haemorrhage) with preservation of tissue architecture and absence of other abnormalities. Total bone marrow aplasia and depletion of all lymphoid tissue was the most prominent finding on histology. Activated macrophages and haemophagocytosis were seen on bone marrow cytology from two live calves. Polymerase chain reaction for bovine viral diarrhoea virus, bluetongue and epizootic haemorrhagic disease virus was negative. Several attempts to isolate a viral agent were unsuccessful. PMID- 20202176 TI - Systematic review of surveillance systems for emerging zoonoses. AB - Evaluations of emerging zoonoses surveillance systems are rarely found in the published literature, making it difficult for decision-makers to choose the best surveillance initiatives. PMID- 20202177 TI - Clinical and radiological features of invasive pulmonary aspergillosis in transplant recipients and neutropenic patients. AB - Invasive pulmonary aspergillosis (IPA) is an important cause of mortality in transplant recipients and in patients with neutropenia. Although IPA has been studied extensively in neutropenic patients, there are limited data on IPA in recipients of solid organ transplants (SOTs). We compared the clinical features and radiologic findings of 27 SOT recipients with IPA with those of 35 neutropenic patients with IPA. The SOT recipients were more likely than neutropenic patients to show peribronchial consolidation (31% vs. 7%; P=0.03) or ground-glass opacity (38% vs. 7%; P=0.007) and less likely to have fever (22% vs. 80%; P<0.001), macro-nodules (35% vs. 67%; P=0.02), mass-like consolidation (27% vs. 67%; P=0.004), halo signs (8% vs. 56%; P<0.001), or air-crescent signs (0% vs. 22%; P=0.01). PMID- 20202178 TI - Multi-institutional randomized control study of haemolysis in stored red cell units prepared manually or by an automated system. AB - BACKGROUND: The haemolysis level at the end of storage is a performance parameter for RBC preparations. In the evaluation of new devices or new processes for processing blood, it is relevant to evaluate whether the haemolysis is linked to (1) specific characteristics of the blood donor, or (2) the nature of the blood processing methodologies. MATERIALS AND METHODS: As part of the validation of a new automated whole blood processing system compared to the current manual methods, randomized, paired crossover studies were conducted evaluating measures of blood component quality, including RBC haemolysis over 42 days of storage. RESULTS: The association between haemolysis and the individual subject was evaluated by modelling haemolysis with independent predictors of treatment (control and test processing) and leucocyte reduction as fixed factors with donor and laboratory as random effects in a mixed-effects ANOVA model. It was found that the day 42 haemolysis values were strongly dependent on the donor subject, with an intraclass correlation coefficient of 0.81. CONCLUSIONS: The data reported in this study suggest a link between the specific whole blood donor and the haemolysis levels observed in red-blood-cell units stored refrigerated for 42 days. Additional research to identify possible donor characteristics associated with haemolysis during storage is warranted. PMID- 20202179 TI - The PROTON study: profiles of blood product transfusion recipients in the Netherlands. AB - BACKGROUND: Transfusion recipient data are needed for correct estimation of cost effectiveness in terms of recipient outcomes after transfusion. Also, such data are essential for monitoring blood use, estimation of future blood use and benchmarking. STUDY DESIGN AND METHODS: A sample of 20 of 93 Dutch hospitals was selected. Datasets containing all blood product transfusions between 1996 and 2006 were extracted from hospital blood bank computer systems, containing transfusion date, blood product type and recipient characteristics such as gender, address, date of birth. The datasets were appended and matched to national hospitalization datasets including primary discharge diagnoses (ICD-9). Using these data, we estimated distributions of blood recipient characteristics in the Netherlands. RESULTS: The dataset contains information on 290,043 patients who received 2,405,012 blood products (1,720,075 RBC, 443,697 FFP, 241,240 PLT) from 1996 to 2006. This is 28% of total blood use in the Netherlands during this period. Comparable diagnosis and age distributions of all hospitalizations indicate included hospitals to be representative, per hospital category, for the Netherlands. Of all red blood cells (RBC), fresh-frozen plasma (FFP) and platelets (PLT), respectively 1.7%, 2.5% and 4.5% were transfused to neonates. Recipients of 65 years or older received 57.6% of RBC, 41.4% of FFP and 29.0% of PLT. Most of the blood products were transfused to patients with diseases of the circulary system (25.1%) or neoplasms (22.0%). CONCLUSION: Transfusion data from a limited sample of hospitals can be used to estimate national distributions of blood recipient characteristics. PMID- 20202180 TI - Current concepts for quality assured long-distance transport of temperature sensitive red blood cell concentrates. AB - BACKGROUND AND OBJECTIVES: The German Armed Forces Blood Service in Koblenz supplies red blood cell concentrates (RBCs) to military and civilian institutions at home and to field hospitals during peacekeeping operations abroad. During long distance transport, blood products can be exposed to extreme environmental conditions or inappropriate handling, which may compromise product quality. MATERIALS AND METHODS: Different active and passive cooling systems, cooling elements, packaging material and data loggers were examined in a climate chamber. A number of techniques for measuring temperature were investigated in order to preserve the blood products' quality during transport, including some field tests with multiparametric data recording. RESULTS: Any kind of active cooling systems, conventional cooling elements and customary packaging material, as well as temperature-sensitive labels, minimum-maximum thermometers and intra-product measurement were found to be unsuitable for military requirement. The best results were obtained when the passively cooling RCB 25 transport box (Dometic) was used together with latent heat/cold storage elements (deltaT) and Junior data loggers (Escort). CONCLUSION: The elaborated protocol allows temperatures to be maintained between 2 and 6 degrees C as required by European guidelines for at least 36 h each and between 1 and 10 degrees C as required by German guidelines for at least 48 or 64 h at ambient temperatures between -10 and 40 degrees C. Preliminary results indicate that care must be taken concerning additional factors such as air pressure variation or vibration. PMID- 20202181 TI - When and why is blood crossmatched? A prospective survey of transfusion laboratory practice in two regions in the north of England. AB - BACKGROUND AND OBJECTIVES: This study was undertaken to provide data relating to the timing of laboratory crossmatch procedures, and the source of requests for out of hours crossmatch, to support interpretation of error reports originating in the transfusion laboratory, received by the Serious Hazards of Transfusion haemovigilance scheme. MATERIALS AND METHODS: Data on the timing, origin and urgency of all crossmatch requests were collected in 34 hospitals in northern England over a 7-day period in 2008. Additional data on clinical urgency were collected on crossmatches that were performed out of hours. RESULTS: Data were obtained on 2423 crossmatches, including 610 (25.2%) performed outside core hours. 30.3% of out of hours crossmatch requests were for transfusions that were set up outside 4 h of completion of the crossmatch. CONCLUSION: 2008 Serious Hazards of Transfusion data showed that 29/39 (74%) of laboratory errors resulting in 'wrong blood' occurred out of hours whilst our audit shows that only 25% of crossmatch requests are made in that time period, suggesting that crossmatching performed outside core hours carries increased risks. The reason for increased risk of error needs further research, but 25 laboratories had only one member of staff working out of hours, often combining blood transfusion, haematology and coagulation work. A total of 25% of out of hours requests were not clinically urgent. Hospitals should develop policies to define indications for out of hours transfusion testing, empower laboratory staff to challenge inappropriate requests and ensure that staffing and expertise is appropriate for the workload at all times. PMID- 20202182 TI - Calibration of the second International Standard for hepatitis B immunoglobulin in an international collaborative study. AB - BACKGROUND AND OBJECTIVES: The International Standard for hepatitis B immunoglobulin is used in the standardization of the anti-HBs content of immunoglobulins for prophylactic and therapeutic use and also in the standardization and calibration of quantitative diagnostic anti-HBs assay kits. A collaborative study was undertaken to assess the suitability of a candidate Second International Standard (2nd IS), and to calibrate it in International Units (IU). MATERIALS AND METHODS: The candidate 2nd IS was prepared from a bulk of 5% hepatitis B immunoglobulin (NIBSC code 07/164). Twenty-two participants from 12 countries assayed the first IS, the candidate 2nd IS, a freeze-dried pool of plasma containing anti-HBs and a plasma from a blood donor. These samples were assayed with 19 different assay kits. RESULTS: Data from 102 assays were received. The mean potencies of two coded samples of the candidate 2nd IS were 100.7 and 101.4 IU/ml (combined potency 101.0 IU/ml). The geometric coefficients of variation for these samples were both 13%. The predicted long-term stability of 07/164 was assessed by assaying samples stored at elevated temperatures for a period of 6 months. 07/164 was predicted to be stable at -20 degrees C with the estimated % loss per year of below 0.2%. CONCLUSION: 07/164 was established as the 2nd IS for hepatitis B immunoglobulin with an assigned potency of 100 IU/ampoule by the WHO Expert Committee on Biological Standardisation. The United States Food and Drug Administration has adopted the same standard as the new Reference for Hepatitis B Immunoglobulin, Lot 3. PMID- 20202183 TI - Psychological and behavioural impacts of the 2008 China earthquake on blood donors. AB - BACKGROUND AND OBJECTIVES: On May 12, 2008, a severe earthquake hit Sichuan province in China. A post-earthquake survey was conducted to study the earthquake's effect on blood donor behaviour and stress at three blood centres at varying distances from the epicentre. MATERIALS AND METHODS: A questionnaire was developed to assess donor post-traumatic stress disorders (PTSD) and attitudes toward giving blood. Responses were compared by centre and donor characteristics using multivariate logistic regression techniques. RESULTS: Of all 17 456 donors, the overall prevalence of PTSD was 13.2%. Donors who knew someone killed or injured by the earthquake were 2.1 times more likely to have PTSD than others (95% CI: 1.8-2.4). 85.2% of donors cited the earthquake as their reason for donating. 16.1% of donors felt it acceptable to be less honest about one's health history in an emergency. After adjusting for PTSD, geographic and demographic characteristics, the donors knowing someone killed or injured by the earthquake were 1.4 times (95% CI: 1.2-1.7) more likely to cite the earthquake as reason for donating, and 1.8 times (95% CI: 1.5-2.1) more likely to accept being less honest about one's health history in case of national emergency. CONCLUSIONS: The psychological and behavioural impacts of the earthquake on blood donors extended far from the epicentre. After a disaster, it is important to emphasize that donors must be truthful on the donor questionnaire as some donors appear willing to be less than honest when they perceive an increased need for blood products. PMID- 20202184 TI - Perceptions of risk and optimistic bias for acute gastrointestinal illness: a population survey. AB - Optimistic bias refers to the tendency of individuals to believe that they are less likely to experience negative events compared with other people. Individuals who perceive their risk of an adverse health event to be low may not be as receptive to informational messages aimed at disease prevention. Our objective was to estimate the magnitude of optimistic bias for acute gastrointestinal illness, and to describe demographic associations with, and reasons for, individuals' perception of personal risk. Data were obtained by a retrospective, cross-sectional telephone survey of 2057 randomly selected English-speaking residents of Ontario, Canada conducted between May 2005 and April 2006. Data were collected on the occurrence of acute gastrointestinal illness during the 28 days prior to the survey, demographics, respondents' perception of their personal risk of acute gastrointestinal illness compared with the average person, and the reasons for this perception. Associations with perception of illness were evaluated using ordinal logistic regression and reasons for perception of risk were explored qualitatively. Optimistic bias was present among all respondents, but was not statistically significant within the group that had experienced acute gastrointestinal illness in the previous 28 days. Rural residency and not having experienced acute gastrointestinal illness in the previous 28 days were associated with a lower perception of risk compared with the average person. Proportionally fewer individuals who had not completed secondary education saw themselves as at less than average risk. The most common reason given for the perception of lower risk was that the respondent was healthier than the average person, although personal lifestyle choices also were provided as reasons. The presence of optimistic bias may negatively impact compliance with public health initiatives to reduce acute gastrointestinal illness. Therefore, recognizing the demographic characteristics associated with a perception of lower risk and understanding the reasons for this perception may help with targeting effective preventive messaging. PMID- 20202185 TI - The role of exposures to animals and other risk factors in sporadic, non typhoidal Salmonella infections in Michigan children. AB - Salmonellosis is largely a major foodborne disease. However, contact with animals particularly reptiles, has been increasingly recognized as a risk factor for Salmonella infection among children. The major risk factors for salmonellosis in Michigan children have not been assessed. Therefore, we have evaluated the association between Salmonella infections and contact with animals among Michigan children aged <= 10 years by conducting a population-based case-control study. A total of 123 children with laboratory-confirmed Salmonella infections and 139 control children, who had not experienced symptoms of gastrointestinal illness during the month prior to the interviews, were enrolled. A multivariable analysis matched on age group revealed that children with Salmonella infections had reported more commonly than controls contact with reptiles [adjusted matched odds ratio (MOR) = 7.90, 95% confidence interval (CI): 1.52-41.01] and cats (MOR = 2.53, 95% CI: 1.14-5.88). Results of this study suggest an association between salmonellosis and contact with cats and reptiles in Michigan children. Additional efforts are needed to educate caretakers of young children about the risk of Salmonella transmission through animal contact. PMID- 20202186 TI - Risk factors associated with detection of Salmonella in broiler litter at the time of new flock placement. AB - In this study, we investigated risk factors associated with the probability to detect Salmonella in samples of litter collected within 2 h prior to new flock placement in 76 grow-out houses on 38 conventional broiler farms located in the US states of Mississippi, Alabama and Texas. We evaluated characteristics of location and layout of the farm; area adjacent to and surrounding the house; house construction; condition and type of equipment in the house; litter management and other production, sanitation, visitation and biosecurity practices; non-broiler animal species on the farm; and weather conditions on the 3 days leading up to flock placement. Logistic regression was used to model the relationships between probability to detect Salmonella in litter and potential risk factors. In the screening process, each risk factor was evaluated as a single fixed effects factor in a multilevel model that accounted for variability among the sampled farms and their production complexes and companies. Of almost 370 risk factors screened, 24 were associated with the probability to detect Salmonella in litter. These were characteristics of the surroundings of the house, house construction and conditions, litter management, length of downtimes between flocks in the house, biosecurity and farm location. After investigation of collinearity between these variables and building of models for important risk factor categories, the list of candidate variables for the final model was refined to eight factors. The final model demonstrated that a higher probability of detecting Salmonella in litter was strongly associated with the use of wood to construct the base of the walls or to cover the inside of the broiler house foundation, and with the use of fresh wood shavings to top-dress or completely replace the litter between flocks. PMID- 20202187 TI - Scientometric analysis of the world-wide research efforts concerning Leishmaniasis. AB - ABSTRACT: BACKGROUND: Leishmaniasis is a chronic disease that is found in various countries of the world. The aim of the current study was to investigate the impact of leishmaniasis on the world's research output. The present study assessed benchmarking of research output for the period between 1957 and 2006. Using large database analyses, research in the field of leishmaniasis was evaluated. Furthermore, cooperation between different countries was identified. RESULTS: The number of publications increased with time. Most publications came from Western countries such as the US, UK or Germany. Interestingly, countries like Brazil and India had a high research output. We found a substantial amount of cooperation between countries. CONCLUSION: Although leishmaniasis is of limited geographic distribution it attracts a wide research interest. The central hub of research cooperation is the USA. PMID- 20202188 TI - Molecular characterization of resistance to Rifampicin in an emerging hospital associated Methicillin-resistant Staphylococcus aureus clone ST228, Spain. AB - BACKGROUND: Methicillin-resistant S. aureus (MRSA) has been endemic in Hospital Universitari de Bellvitge, Barcelona, since 1990. During the 1990-95 period the Iberian clone (ST-247; SCCmec-I) was dominant. Isolates of clonal complex 5 (ST 125; SCCmec-IV) gradually replaced the Iberian clone from 1996 to 2003. A new multiresistant MRSA phenotype showing rifampicin resistance emerged in 2004 and rapidly increased from 25% in 2004 to 45% in 2006. The aims of this study were i) the molecular characterisation of rifampicin resistant MRSA isolates, ii) the study of the rifampicin resistance expression by disk diffusion, microdilution and E-test, and iii) the analysis of the rpoB gene mutations involved in rifampicin resistance. RESULTS: A sample of representative 108 rifampicin resistant MRSA isolates belonged to a single PFGE genotype, ST-228, SCCmec type I and spa type t041. Of 108 isolates, 104 (96%) had a low-level rifampicin resistance (MICs, 2 to 4 mg/L) and 4 a high-level rifampicin resistance (MICs, 128 - > or = 256 mg/L). Disk diffusion and E-test methods failed to identify a low-level rifampicin resistance in 20 and 12 isolates, respectively. A low-level rifampicin resistance was associated with amino acid substitution 481His/Asn in the beta-subunit of RNA polymerase. Isolates with a high-level rifampicin resistance carried additional mutations in the rpoB gene. CONCLUSIONS: The emergence of MRSA clone ST228-SCCmecI, related to the Southern Germany clone, involved a therapeutical challenge for treating serious MRSA infections. Decreased susceptibility to rifampicin in MRSA strains of ST228-SCCmecI was associated with one or two specific mutations in the rpoB gene. One fifth of isolates with low-level rifampicin-resistance were missed by the diffusion methods. PMID- 20202189 TI - Promiscuity of enhancer, coding and non-coding transcription functions in ultraconserved elements. AB - BACKGROUND: Ultraconserved elements (UCEs) are highly constrained elements of mammalian genomes, whose functional role has not been completely elucidated yet. Previous studies have shown that some of them act as enhancers in mouse, while some others are expressed in both normal and cancer-derived human tissues. Only one UCE element so far was shown to present these two functions concomitantly, as had been observed in other isolated instances of single, non ultraconserved enhancer elements. RESULTS: We used a custom microarray to assess the levels of UCE transcription during mouse development and integrated these data with published microarray and next-generation sequencing datasets as well as with newly produced PCR validation experiments. We show that a large fraction of non exonic UCEs is transcribed across all developmental stages examined from only one DNA strand. Although the nature of these transcripts remains a mistery, our meta analysis of RNA-Seq datasets indicates that they are unlikely to be short RNAs and that some of them might encode nuclear transcripts. In the majority of cases this function overlaps with the already established enhancer function of these elements during mouse development. Utilizing several next-generation sequencing datasets, we were further able to show that the level of expression observed in non-exonic UCEs is significantly higher than in random regions of the genome and that this is also seen in other regions which act as enhancers. CONCLUSION: Our data shows that the concurrent presence of enhancer and transcript function in non-exonic UCE elements is more widespread than previously shown. Moreover through our own experiments as well as the use of next-generation sequencing datasets, we were able to show that the RNAs encoded by non-exonic UCEs are likely to be long RNAs transcribed from only one DNA strand. PMID- 20202190 TI - Origin of measles virus: divergence from rinderpest virus between the 11th and 12th centuries. AB - Measles, caused by measles virus (MeV), is a common infection in children. MeV is a member of the genus Morbillivirus and is most closely related to rinderpest virus (RPV), which is a pathogen of cattle. MeV is thought to have evolved in an environment where cattle and humans lived in close proximity. Understanding the evolutionary history of MeV could answer questions related to divergence times of MeV and RPV. We investigated divergence times using relaxed clock Bayesian phylogenetics. Our estimates reveal that MeV had an evolutionary rate of 6.0-6.5 x 10(-4) substitutions/site/year. It was concluded that the divergence time of the most recent common ancestor of current MeV was the early 20th century. And, divergence between MeV and RPV occurred around the 11th to 12th centuries. The result was unexpected because emergence of MeV was previously considered to have occurred in the prehistoric age. MeV may have originated from virus of non-human species and caused emerging infectious diseases around the 11th to 12th centuries. In such cases, investigating measles would give important information about the course of emerging infectious diseases. PMID- 20202191 TI - Genome dynamics of Bartonella grahamii in micro-populations of woodland rodents. AB - BACKGROUND: Rodents represent a high-risk reservoir for the emergence of new human pathogens. The recent completion of the 2.3 Mb genome of Bartonella grahamii, one of the most prevalent blood-borne bacteria in wild rodents, revealed a higher abundance of genes for host-cell interaction systems than in the genomes of closely related human pathogens. The sequence variability within the global B. grahamii population was recently investigated by multi locus sequence typing, but no study on the variability of putative host-cell interaction systems has been performed. RESULTS: To study the population dynamics of B. grahamii, we analyzed the genomic diversity on a whole-genome scale of 27 B. grahamii strains isolated from four different species of wild rodents in three geographic locations separated by less than 30 km. Even using highly variable spacer regions, only 3 sequence types were identified. This low sequence diversity contrasted with a high variability in genome content. Microarray comparative genome hybridizations identified genes for outer surface proteins, including a repeated region containing the fha gene for filamentous hemaggluttinin and a plasmid that encodes a type IV secretion system, as the most variable. The estimated generation times in liquid culture medium for a subset of strains ranged from 5 to 22 hours, but did not correlate with sequence type or presence/absence patterns of the fha gene or the plasmid. CONCLUSION: Our study has revealed a geographic microstructure of B. grahamii in wild rodents. Despite near-identity in nucleotide sequence, major differences were observed in gene presence/absence patterns that did not segregate with host species. This suggests that genetically similar strains can infect a range of different hosts. PMID- 20202192 TI - Monitoring the regulation of gene expression in a growing organ using a fluid mechanics formalism. AB - BACKGROUND: Technological advances have enabled the accurate quantification of gene expression, even within single cell types. While transcriptome analyses are routinely performed, most experimental designs only provide snapshots of gene expression. Molecular mechanisms underlying cell fate or positional signalling have been revealed through these discontinuous datasets. However, in developing multicellular structures, temporal and spatial cues, known to directly influence transcriptional networks, get entangled as the cells are displaced and expand. Access to an unbiased view of the spatiotemporal regulation of gene expression occurring during development requires a specific framework that properly quantifies the rate of change of a property in a moving and expanding element, such as a cell or an organ segment. RESULTS: We show how the rate of change in gene expression can be quantified by combining kinematics and real-time polymerase chain reaction data in a mechanistic model which considers any organ as a continuum. This framework was applied in order to assess the developmental regulation of the two reference genes Actin11 and Elongation Factor 1-beta in the apex of poplar root. The growth field was determined by time-lapse photography and transcript density was obtained at high spatial resolution. The net accumulation rates of the transcripts of the two genes were found to display highly contrasted developmental profiles. Actin11 showed pulses of up and down regulation in the accelerating and decelerating parts of the growth zone while the dynamic of EF1beta were much slower. This framework provides key information about gene regulation in a developing organ, such as the location, the duration and the intensity of gene induction/repression. CONCLUSIONS: We demonstrated that gene expression patterns can be monitored using the continuity equation without using mutants or reporter constructions. Given the rise of imaging technologies, this framework in our view opens a new way to dissect the molecular basis of growth regulation, even in non-model species or complex structures. PMID- 20202193 TI - Obituary of Dr. Angelo di George. PMID- 20202194 TI - Doxorubicin-induced ovarian toxicity. AB - BACKGROUND: Young cancer patients may occasionally face infertility and premature gonadal failure. Apart from its direct effect on follicles and oocytes, chemotherapy may induce ovarian toxicity via an impact on the entire ovary. The role of doxorubicin in potential ovarian failure remains obscure. Our intention was to elucidate doxorubicin-related toxicity within ovaries. METHODS: Female mice were injected intraperitoneally with 7.5 or 10 mg/kg doxorubicin and their ovaries were visualized in vivo by high resolution MRI, one day and one month following treatment. Ovaries of other treated mice were excised and weighed at the same post-treatment intervals. Ovarian histological sections were stained for TUNEL or active caspase-3 and follicles were counted and categorized. Ovulation rates were evaluated in superovulated female mice treated with doxorubicin. RESULTS: A single injection of doxorubicin resulted in a major reduction in both ovarian size and weight that lasted even one month post treatment. A dramatic reduction in ovulation rate was observed one week after treatment, followed by a partial recovery at one month. Histological examination revealed positive staining of TUNEL and active caspase-3. We observed a significant reduction in the population of secondary and primordial follicles one month following treatment. CONCLUSIONS: Our results may imply a mechanism of chemotherapy-induced ovarian toxicity, manifested by reduced ovulation and accompanied by a reduction in ovarian size, caused probably by an acute insult to the ovary. PMID- 20202195 TI - Histone deacetylase inhibitor vorinostat suppresses the growth of uterine sarcomas in vitro and in vivo. AB - BACKGROUND: Uterine sarcomas are very rare malignancies with no approved chemotherapy protocols. Histone deacetylase (HDAC) inhibitors belong to the most promising groups of compounds for molecular targeting therapy. Here, we described the antitumor effects of suberoylanilide hydroxamic acid (SAHA; vorinostat) on MES-SA uterine sarcoma cells in vitro and in vivo. We investigated effects of vorinostat on growth and colony forming ability by using uterine sarcoma MES-SA cells. We analyzed the influence of vorinostat on expression of different HDACs, p21(WAF1) and activation of apoptosis. Finally, we examined the antitumor effects of vorinostat on uterine sarcoma in vivo. RESULTS: Vorinostat efficiently suppressed MES-SA cell growth at a low dosage (3 microM) already after 24 hours treatment. Decrease of cell survival was even more pronounced after prolonged treatment and reached 9% and 2% after 48 and 72 hours of treatment, respectively. Colony forming capability of MES-SA cells treated with 3 microM vorinostat for 24 and 48 hours was significantly diminished and blocked after 72 hours. HDACs class I (HDAC2 and 3) as well as class II (HDAC7) were preferentially affected by this treatment. Vorinostat significantly increased p21(WAF1) expression and apoptosis. Nude mice injected with 5 x 106 MES-SA cells were treated for 21 days with vorinostat (50 mg/kg/day) and, in comparison to placebo group, a tumor growth reduction of more than 50% was observed. Results obtained by light- and electron microscopy suggested pronounced activation of apoptosis in tumors isolated from vorinostat-treated mice. CONCLUSIONS: Our data strongly indicate the high therapeutic potential of vorinostat in uterine sarcomas. PMID- 20202196 TI - Morphologic characterization of osteosarcoma growth on the chick chorioallantoic membrane. AB - BACKGROUND: The chick chorio-allantoic membrane (CAM) assay is a commonly used method for studying angiogenic or anti-angiogenic activities in vivo. The ease of access allows direct monitoring of tumour growth by biomicroscopy and the possibility to screen many samples in an inexpensive way. The CAM model provides a powerful tool to study effects of molecules, which interfere with physiological angiogenesis, or experimental tumours derived from cancer cell lines. We therefore screened eight osteosarcoma cell lines for their ability to form vascularized tumours on the CAM. FINDINGS: We implanted 3-5 million cells of human osteosarcoma lines (HOS, MG63, MNNG-HOS, OST, SAOS, SJSA1, U2OS, ZK58) on the CAM at day 10 of embryonic development. Tumour growth was monitored by in vivo biomicroscopy at different time points and tumours were fixed in paraformaldehyde seven days after cell grafting. The tissue was observed, photographed and selected cases were further analyzed using standard histology.From the eight cell lines the MNNG-HOS, U2OS and SAOS were able to form solid tumours when grafted on the CAM. The MNNG-HOS tumours showed the most reliable and consistent growth and were able to penetrate the chorionic epithelium, grow in the CAM stroma and induce a strong angiogenic response. CONCLUSIONS: Our results show that the CAM assay is a useful tool for studying osteosarcoma growth. The model provides an excellent alternative to current rodent models and could serve as a preclinical screening assay for anticancer molecules. It might increase the speed and efficacy of the development of new drugs for the treatment of osteosarcoma. PMID- 20202197 TI - Improvement of the design and generation of highly specific plant knockdown lines using primary synthetic microRNAs (pri-smiRNAs). AB - BACKGROUND: microRNAs (miRNAs) are endogenous small non-coding RNAs that post transcriptionally regulate gene expression. In plants, they typically show high complementarity to a single sequence motif within their target mRNAs and act by catalyzing specific mRNA cleavage and degradation. miRNAs are processed from much longer primary transcripts via precursor miRNAs containing fold-back structures. Leaving these secondary structures intact, miRNAs can be re-designed experimentally to target mRNAs of choice. RESULTS: We designed primary synthetic miRNAs (pri-smiRNAs) on the basis of the primary transcript of the Arabidopsis MIR159A gene by replacing the original miR159a and the corresponding miR159a* with novel sequences, keeping the overall secondary structure as predicted by the program RNAfold. We used the program RNAhybrid to optimize smiRNA design and to screen the complete Arabidopsis transcriptome for potential off-targets. To improve the molecular cloning of the pri-smiRNA we inserted restriction sites in the original MIR159A primary transcript to easily accommodate the smiRNA/smiRNA* DNA fragment. As a proof-of-concept, we targeted the single gene encoding chalcone synthase (CHS) in Arabidopsis. We demonstrate smiRNA(CHS) expression and CHS mRNA cleavage in different transgenic lines. Phenotypic changes in these lines were observed for seed color and flavonol derivatives, and quantified with respect to anthocyanin content. We also tested the effect of mismatches and excess G:U base pairs on knockdown efficiency. CONCLUSIONS: RNAhybrid-assisted design of smiRNAs and generation of pri-smiRNAs using a novel vector containing restriction sites greatly improves specificity and speed of the generation of stable knockdown lines for functional analyses in plants. PMID- 20202198 TI - Probability distributed time delays: integrating spatial effects into temporal models. AB - BACKGROUND: In order to provide insights into the complex biochemical processes inside a cell, modelling approaches must find a balance between achieving an adequate representation of the physical phenomena and keeping the associated computational cost within reasonable limits. This issue is particularly stressed when spatial inhomogeneities have a significant effect on system's behaviour. In such cases, a spatially-resolved stochastic method can better portray the biological reality, but the corresponding computer simulations can in turn be prohibitively expensive. RESULTS: We present a method that incorporates spatial information by means of tailored, probability distributed time-delays. These distributions can be directly obtained by single in silico or a suitable set of in vitro experiments and are subsequently fed into a delay stochastic simulation algorithm (DSSA), achieving a good compromise between computational costs and a much more accurate representation of spatial processes such as molecular diffusion and translocation between cell compartments. Additionally, we present a novel alternative approach based on delay differential equations (DDE) that can be used in scenarios of high molecular concentrations and low noise propagation. CONCLUSIONS: Our proposed methodologies accurately capture and incorporate certain spatial processes into temporal stochastic and deterministic simulations, increasing their accuracy at low computational costs. This is of particular importance given that time spans of cellular processes are generally larger (possibly by several orders of magnitude) than those achievable by current spatially-resolved stochastic simulators. Hence, our methodology allows users to explore cellular scenarios under the effects of diffusion and stochasticity in time spans that were, until now, simply unfeasible. Our methodologies are supported by theoretical considerations on the different modelling regimes, i.e. spatial vs. delay-temporal, as indicated by the corresponding Master Equations and presented elsewhere. PMID- 20202199 TI - Distribution of the main malaria vectors in Kenya. AB - BACKGROUND: A detailed knowledge of the distribution of the main Anopheles malaria vectors in Kenya should guide national vector control strategies. However, contemporary spatial distributions of the locally dominant Anopheles vectors including Anopheles gambiae, Anopheles arabiensis, Anopheles merus, Anopheles funestus, Anopheles pharoensis and Anopheles nili are lacking. The methods and approaches used to assemble contemporary available data on the present distribution of the dominant malaria vectors in Kenya are presented here. METHOD: Primary empirical data from published and unpublished sources were identified for the period 1990 to 2009. Details recorded for each source included the first author, year of publication, report type, survey location name, month and year of survey, the main Anopheles species reported as present and the sampling and identification methods used. Survey locations were geo-positioned using national digital place name archives and on-line geo-referencing resources. The geo-located species-presence data were displayed and described administratively, using first-level administrative units (province), and biologically, based on the predicted spatial margins of Plasmodium falciparum transmission intensity in Kenya for the year 2009. Each geo-located survey site was assigned an urban or rural classification and attributed an altitude value. RESULTS: A total of 498 spatially unique descriptions of Anopheles vector species across Kenya sampled between 1990 and 2009 were identified, 53% were obtained from published sources and further communications with authors. More than half (54%) of the sites surveyed were investigated since 2005. A total of 174 sites reported the presence of An. gambiae complex without identification of sibling species. Anopheles arabiensis and An. funestus were the most widely reported at 244 and 265 spatially unique sites respectively with the former showing the most ubiquitous distribution nationally. Anopheles gambiae, An. arabiensis, An. funestus and An. pharoensis were reported at sites located in all the transmission intensity classes with more reports of An. gambiae in the highest transmission intensity areas than the very low transmission areas. CONCLUSION: A contemporary, spatially defined database of the main malaria vectors in Kenya provides a baseline for future compilations of data and helps identify areas where information is currently lacking. The data collated here are published alongside this paper where it may help guide future sampling location decisions, help with the planning of vector control suites nationally and encourage broader research inquiry into vector species niche modeling. PMID- 20202200 TI - Subarachnoidal Neurocysticercosis non-responsive to cysticidal drugs: a case series. AB - BACKGROUND: Neurocysticercosis (NC) is one of the most frequent parasitic diseases of the central nervous system. Cysticidal drugs, albendazole and praziquantel, are generally effective when parasites localize in the parenchyma. In contrast, parasites lodged in the subarachnoid basal cisterns are less responsive to treatment. CASE PRESENTATION: The clinical and radiological pictures of six Mexican patients non-respondent to cysticidal treatment are presented. CONCLUSIONS: The possible factors involved in the cysticidal non response are discussed and hints are provided of potentially useful changes to therapeutic protocols. PMID- 20202201 TI - Chemogenomic and transcriptome analysis identifies mode of action of the chemosensitizing agent CTBT (7-chlorotetrazolo[5,1-c]benzo[1,2,4]triazine). AB - BACKGROUND: CTBT (7-chlorotetrazolo [5,1-c]benzo[1,2,4]triazine) increases efficacy of commonly used antifungal agents by an unknown mechanism. It increases the susceptibility of Saccharomyces cerevisiae, Candida albicans and Candida glabrata cells to cycloheximide, 5-fluorocytosine and azole antimycotic drugs. Here we elucidate CTBT mode of action with a combination of systematic genetic and transcriptome analysis. RESULTS: To identify the cellular processes affected by CTBT, we screened the systematic haploid deletion mutant collection for CTBT sensitive mutants. We identified 169 hypersensitive deletion mutants. The deleted genes encode proteins mainly involved in mitochondrial functions, DNA repair, transcription and chromatin remodeling, and oxidative stress response. We found that the susceptibility of yeast cells to CTBT depends on molecular oxygen. Transcriptome analysis of the immediate early response to CTBT revealed rapid induction of oxidant and stress response defense genes. Many of these genes depend on the transcription factors Yap1 and Cin5. Yap1 accumulates rapidly in the nucleus in CTBT treated cells suggesting acute oxidative stress. Moreover, molecular calculations supported a superoxide generating activity of CTBT. Superoxide production in vivo by CTBT was found associated to mitochondria as indicated by oxidation of MitoSOX Red. CONCLUSION: We conclude that CTBT causes intracellular superoxide production and oxidative stress in fungal cells and is thus enhancing antimycotic drug effects by a secondary stress. PMID- 20202202 TI - Dynamics of peptidergic secretory granule transport are regulated by neuronal stimulation. AB - BACKGROUND: Peptidergic neurons store and secrete the contents of large dense core vesicles (LDCVs) from axon terminals and from dendrites. Secretion of peptides requires a highly regulated exocytotic mechanism, plus coordinated synthesis and transport of LDCVs to their sites of release. Although these trafficking events are critical to function, little is known regarding the dynamic behavior of LDCVs and the mechanisms by which their transport is regulated. Sensory neurons also package opiate receptors in peptide-containing LDCVs, which is thought to be important in pain sensation. Since peptide granules cannot be refilled locally after their contents are secreted, it is particularly important to understand how neurons support regulated release of peptides. RESULTS: A vector encoding soluble peptidylglycine alpha-hydroxylating monooxygenase fused to green fluorescent protein was constructed to address these questions in cultured primary peptidergic neurons of the trigeminal ganglion using time lapse confocal microscopy. The time course of release differs with secretagogue; the secretory response to depolarization with K+ is rapid and terminates within 15 minutes, while phorbol ester stimulation of secretion is maintained over a longer period. The data demonstrate fundamental differences between LDCV dynamics in axons and growth cones under basal conditions. CONCLUSIONS: Under basal conditions, LDCVs move faster away from the soma than toward the soma, but fewer LDCVs travel anterograde than retrograde. Stimulation decreased average anterograde velocity and increases granule pausing. Data from antibody uptake, quantification of enzyme secretion and appearance of pHluorin fluorescence demonstrate distributed release of peptides all along the axon, not just at terminals. PMID- 20202203 TI - Deep brain stimulation for obsessive-compulsive disorder and treatment-resistant depression: systematic review. AB - BACKGROUND: In spite of advances in psychotherapy and pharmacotherapy, there are still a significant number of patients with depression and obsessive-compulsive disorder that are not aided by either intervention. Although still in the experimental stage, deep brain stimulation (DBS) offers many advantages over other physically-invasive procedures as a treatment for these psychiatric disorders. The purpose of this study is to systematically review reports on clinical trials of DBS for obsessive-compulsive disorder (OCD) and treatment resistant depression (TRD). Locations for stimulation, success rates and effects of the stimulation on brain metabolism are noted when available. The first observation of the effects of DBS on OCD and TRD came in the course of using DBS to treat movement disorders. Reports of changes in OCD and depression during such studies are reviewed with particular attention to electrode locations and associated adverse events; although these reports were adventitious observations rather than planned. Subsequent studies have been guided by more precise theories of structures involved in DBS and OICD. This study suggests stimulation sites and prognostic indicators for DBS. We also briefly review tractography, a relatively new procedure that holds great promise for the further development of DBS. METHODS: Articles were retrieved from MEDLINE via PubMed. Relevant references in retrieved articles were followed up. We included all articles reporting on studies of patients selected for having OCD or TRD. Adequacy of the selected studies was evaluated by the Jadad scale. Evaluation criteria included: number of patients, use of recognized psychiatric rating scales, and use of brain blood flow measurements. Success rates classified as "improved" or "recovered" were recorded. Studies of DBS for movement disorders were included if they reported coincidental relief of depression or reduction in OCD. Most of the studies involved small numbers of subjects so individual studies were reviewed. RESULTS: While the number of cases was small, these were extremely treatment-resistant patients. While not everyone responded, about half the patients did show dramatic improvement. Associated adverse events were generally trivial in younger psychiatric patients but often severe in older movement disorder patients. The procedures differed from study to study, and the numbers of patients was usually too small to do meaningful statistics or make valid inferences as to who will respond to treatment. CONCLUSIONS: DBS is considered a promising technique for OCD and TRD. Outstanding questions about patient selection and electrode placement can probably be resolved by (a) larger studies, (b) genetic studies and (c) imaging studies (MRI, fMRI, PET, and tractography). PMID- 20202204 TI - Gram-negative bacteremia induces greater magnitude of inflammatory response than Gram-positive bacteremia. AB - INTRODUCTION: Bacteremia is recognized as a critical condition that influences the outcome of sepsis. Although large-scale surveillance studies of bacterial species causing bacteremia have been published, the pathophysiological differences in bacteremias with different causative bacterial species remain unclear. The objective of the present study is to investigate the differences in pathophysiology and the clinical course of bacteremia caused by different bacterial species. METHODS: We reviewed the medical records of all consecutive patients admitted to the general intensive care unit (ICU) of a university teaching hospital during the eight-year period since introduction of a rapid assay for interleukin (IL)-6 blood level to routine ICU practice in May 2000. White blood cell count, C-reactive protein (CRP), IL-6 blood level, and clinical course were compared among different pathogenic bacterial species. RESULTS: The 259 eligible patients, as well as 515 eligible culture-positive blood samples collected from them, were included in this study. CRP, IL-6 blood level, and mortality were significantly higher in the septic shock group (n = 57) than in the sepsis group (n = 127) (P < 0.001). The 515 eligible culture-positive blood samples harbored a total of 593 isolates of microorganisms (Gram-positive, 407; Gram-negative, 176; fungi, 10). The incidence of Gram-negative bacteremia was significantly higher in the septic shock group than in the sepsis group (P < 0.001) and in the severe sepsis group (n = 75, P < 0.01). CRP and IL-6 blood level were significantly higher in Gram-negative bacteremia (n = 176) than in Gram-positive bacteremia (n = 407) (P < 0.001, <0.0005, respectively). CONCLUSIONS: The incidence of Gram-negative bacteremia was significantly higher in bacteremic ICU patients with septic shock than in those with sepsis or severe sepsis. Furthermore, CRP and IL-6 levels were significantly higher in Gram negative bacteremia than in Gram-positive bacteremia. These findings suggest that differences in host responses and virulence mechanisms of different pathogenic microorganisms should be considered in treatment of bacteremic patients, and that new countermeasures beyond conventional antimicrobial medications are urgently needed. PMID- 20202205 TI - Monitoring of clinical signs in goats with transmissible spongiform encephalopathies. AB - BACKGROUND: As there is limited information about the clinical signs of BSE and scrapie in goats, studies were conducted to describe the clinical progression of scrapie and BSE in goats and to evaluate a short clinical protocol for its use in detecting scrapie-affected goats in two herds with previously confirmed scrapie cases. Clinical assessments were carried out in five goats intracerebrally infected with the BSE agent as well as five reported scrapie suspects and 346 goats subject to cull from the two herds, 24 of which were retained for further monitoring. The brain and selected lymphoid tissue were examined by postmortem tests for disease confirmation. RESULTS: The sensitivity and specificity of the short clinical protocol in detecting a scrapie case in the scrapie-affected herds was 3.9% and 99.6%, respectively, based on the presence of tremor, positive scratch test, extensive hair loss, ataxia and absent menace response. All BSE- and scrapie-affected goats displayed abnormalities in sensation (over-reactivity to external stimuli, startle responses, pruritus, absent menace response) and movement (ataxia, tremor, postural deficits) at an advanced clinical stage but the first detectable sign associated with scrapie or BSE could vary between animals. Signs of pruritus were not always present despite similar prion protein genotypes. Clinical signs of scrapie were also displayed by two scrapie cases that presented with detectable disease-associated prion protein only in lymphoid tissues. CONCLUSIONS: BSE and scrapie may present as pruritic and non-pruritic forms in goats. Signs assessed for the clinical diagnosis of scrapie or BSE in goats should include postural and gait abnormalities, pruritus and visual impairment. However, many scrapie cases will be missed if detection is solely based on the display of clinical signs. PrPd accumulation in the brain appeared to be related to the severity of clinical disease but not to the display of individual neurological signs. PMID- 20202206 TI - GASdb: a large-scale and comparative exploration database of glycosyl hydrolysis systems. AB - BACKGROUND: The genomes of numerous cellulolytic organisms have been recently sequenced or in the pipeline of being sequenced. Analyses of these genomes as well as the recently sequenced metagenomes in a systematic manner could possibly lead to discoveries of novel biomass-degradation systems in nature. DESCRIPTION: We have identified 4,679 and 49,099 free acting glycosyl hydrolases with or without carbohydrate binding domains, respectively, by scanning through all the proteins in the UniProt Knowledgebase and the JGI Metagenome database. Cellulosome components were observed only in bacterial genomes, and 166 cellulosome-dependent glycosyl hydrolases were identified. We observed, from our analysis data, unexpected wide distributions of two less well-studied bacterial glycosyl hydrolysis systems in which glycosyl hydrolases may bind to the cell surface directly rather than through linking to surface anchoring proteins, or cellulosome complexes may bind to the cell surface by novel mechanisms other than the other used SLH domains. In addition, we found that animal-gut metagenomes are substantially enriched with novel glycosyl hydrolases. CONCLUSIONS: The identified biomass degradation systems through our large-scale search are organized into an easy-to-use database GASdb at http://csbl.bmb.uga.edu/~ffzhou/GASdb/, which should be useful to both experimental and computational biofuel researchers. PMID- 20202207 TI - Angiomyofibroblastoma of the spermatic cord: a case report. AB - INTRODUCTION: Angiomyofibroblastoma is a benign soft tissue tumor with tendency to arise in the vulva. CASE PRESENTATION: We report a 36-year-old Greek Caucasian man presenting with a left inguinal painless mass. This is the second case of angiomyofibroblastoma of the spermatic cord. At operation, a 4.5 cm well circumscribed solid tumor was found adherent to the spermatic cord. The tumor consisted of spindle-shaped cells proliferating in short fascicles between numerous medium-sized blood vessels with thin and hyalinized walls. Neoplastic cells had eosinophilic cytoplasm with neither mitotic figures nor nuclear atypia. The stroma included abundant mast cells and few mature lypocytes. Immunostaining showed positivity for vimentin, CD34, desmin and smooth muscle actin. Our patient was treated by simple excision and was followed up for five years with clinical examination and ultrasonography, revealing no evidence of local recurrence or metastasis. CONCLUSION: This unusual neoplasm should be distinguished from aggressive angiomyxoma and other myxoid malignant tumors with widespread metastatic potential. PMID- 20202208 TI - Prevalence of the pathogenic chytrid fungus, Batrachochytrium dendrobatidis, in an endangered population of northern leopard frogs, Rana pipiens. AB - BACKGROUND: Emerging infectious diseases threaten naive host populations with extinction. Chytridiomycosis, an emerging infectious disease of amphibians, is caused by the pathogenic fungus Batrachochytrium dendrobatidis (Bd) and has been linked to global declines in amphibians. RESULTS: We monitored the prevalence of Bd for four years in the Northern leopard frog, Rana pipiens, which is critically imperiled in British Columbia (BC), Canada. The prevalence of Bd initially increased and then remained constant over the last three years of the study. Young of the year emerging from breeding ponds in summer were rarely infected with Bd. Some individuals cleared their Bd infections and the return rate between infected and uninfected individuals was not significantly different. CONCLUSIONS: The BC population of R. pipiens appears to have evolved a level of resistance that allows it to co-exist with Bd. However, this small population of R. pipiens remains vulnerable to extinction. PMID- 20202209 TI - Home care utilization and outcomes among Asian and other Canadian patients with heart failure. AB - BACKGROUND: Heart failure (HF) is a major cause of hospitalization and death in the aging population around the world. Home care utilization is associated with improved survival for the patients with HF, and varies by ethno-culture. The purpose of this study was to investigate the difference in hospital readmission rate and mortality between Asian and other Canadian HF patients. METHODS: HF patients were identified using hospital discharge abstracts from March 31, 2000 to April 1, 2006 in Calgary Health Region. Readmission and one-year mortality for HF were determined by linking hospital discharge and vital statistics data. Stratified by home care services use, readmission and mortality rates were compared between the Asians and other Canadians while controlling for age, sex, comorbidities, and household income. RESULTS: Of 26,171 HF patients discharged from hospital, 56.6% of Asians and 58.0% of other Canadians used home care services [adjusted odds ratio (OR) for Asian: 0.84, 95% confidence interval (CI): 0.74-0.89]. The hospital readmission rate was similar between Asians and other Canadians regardless of home care services use. Mortality was similar between those who used home care services (adjusted OR for Asian: 0.96, 95% CI: 0.81 1.13). For patients who did not use home care services, Asians had significantly lower mortality than other Canadians (adjusted OR for Asian: 0.76, 95% CI: 0.60 0.86). CONCLUSION: Mortality was similar between Asian and other Canadian patients when home care services were utilized. However, among those without home care, Asian patients had a significantly lower mortality than other Canadian patients. PMID- 20202210 TI - Increased hematogones in an infant with bicytopenia and leucocytosis:a case report. AB - Hematogones are the normal bone marrow constituents of bone marrow in children and their number decreases with age. As hematogones can resemble malignant lymphoblasts by their morphologic features and by expression of an immature B cell phenotype, an accurate distinction of hematogone-rich lymphoid regeneration from leukemic lymphoblasts is critical for patient care. The increased number of hematogones had been reported in the bone marrow of children recovering from chemotherapy, aplastic conditions, other forms of bone marrow injury, infections like Cytomegalovirus, HIV and immune thrombocytopenia disorders. We describe here a case of one and half month old male infant with bicytopenia and leucocytosis associated with increased hematogones in the bone marrow due to an unknown probable viral infection. PMID- 20202211 TI - Membrane attack complex inhibitor CD59a protects against focal cerebral ischemia in mice. AB - BACKGROUND: The complement system is a crucial mediator of inflammation and cell lysis after cerebral ischemia. However, there is little information about the exact contribution of the membrane attack complex (MAC) and its inhibitor-protein CD59. METHODS: Transient focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) in young male and female CD59a knockout and wild-type mice. Two models of MCAO were applied: 60 min MCAO and 48 h reperfusion, as well as 30 min MCAO and 72 h reperfusion. CD59a knockout animals were compared to wild type animals in terms of infarct size, edema, neurological deficit, and cell death. RESULTS AND DISCUSSION: CD59a-deficiency in male mice caused significantly increased infarct volumes and brain swelling when compared to wild-type mice at 72 h after 30 min-occlusion time, whereas no significant difference was observed after 1 h-MCAO. Moreover, CD59a-deficient mice had impaired neurological function when compared to wild-type mice after 30 min MCAO. CONCLUSION: We conclude that CD59a protects against ischemic brain damage, but depending on the gender and the stroke model used. PMID- 20202212 TI - Bromocriptine treatment associated with recovery from peripartum cardiomyopathy in siblings: two case reports. AB - INTRODUCTION: Peripartum cardiomyopathy is a rare form of cardiomyopathy, with heterogeneous presentation occurring in women between one-month antepartum and six months postpartum. It carries a poor prognosis and a high risk of mortality. CASE PRESENTATION: We report the development of peripartum cardiomyopathy in two sisters, 27- and 35-year-old African women, one of whom presented with a large left ventricular thrombus. Subsequently, both patients were treated with bromocriptine, heparin and standard therapy for heart failure (angiotensin converting enzyme inhibitors, beta-blockers and diuretics). During follow-up, the left ventricular thrombus observed in one patient degraded. Neither patient experienced a thrombotic event, and both experienced continuous improvements in cardiac function and New York Heart Association stage. CONCLUSION: The development of peripartum cardiomyopathy in two sisters indicates that there may be a genetic basis for this type of cardiomyopathy, and that women with a positive family history for peripartum cardiomyopathy may have an increased risk of developing the disease. This is also the first report of a patient experiencing degradation of a large left ventricular thrombus under standard therapy for heart failure with bromocriptine. It suggests that the use of bromocriptine in association with adequate anti-coagulation and heart failure therapy may be beneficial and safe. PMID- 20202213 TI - Statistical modeling of volume of alcohol exposure for epidemiological studies of population health: the US example. AB - BACKGROUND: Alcohol consumption is a major risk factor in the global burden of disease, with overall volume of exposure as the principal underlying dimension. Two main sources of data on volume of alcohol exposure are available: surveys and per capita consumption derived from routine statistics such as taxation. As both sources have significant problems, this paper presents an approach that triangulates information from both sources into disaggregated estimates in line with the overall level of per capita consumption. METHODS: A modeling approach was applied to the US using data from a large and representative survey, the National Epidemiologic Survey on Alcohol and Related Conditions. Different distributions (log-normal, gamma, Weibull) were used to model consumption among drinkers in subgroups defined by sex, age, and ethnicity. The gamma distribution was used to shift the fitted distributions in line with the overall volume as derived from per capita estimates. Implications for alcohol-attributable fractions were presented, using liver cirrhosis as an example. RESULTS: The triangulation of survey data with aggregated per capita consumption data proved feasible and allowed for modeling of alcohol exposure disaggregated by sex, age, and ethnicity. These models can be used in combination with risk relations for burden of disease calculations. Sensitivity analyses showed that the gamma distribution chosen yielded very similar results in terms of fit and alcohol attributable mortality as the other tested distributions. CONCLUSIONS: Modeling alcohol consumption via the gamma distribution was feasible. To further refine this approach, research should focus on the main assumptions underlying the approach to explore differences between volume estimates derived from surveys and per capita consumption figures. PMID- 20202214 TI - Immunohistochemical expression of mitochondrial membrane complexes (MMCs) I, III, IV and V in malignant and benign periampullary epithelium: a potential target for drug therapy of periampullary cancer? AB - BACKGROUND: Mitochondrial membrane complexes (MMCs) are key mediators of cellular oxidative phosphorylation, and inhibiting them could lead to cell death. No published data are available on the relative abundance of MMCs in different periampullary cancers. Therefore, we studied the expression profile of MMCs I, III, IV and V in periampullary cancers, reactive pancreatitis, normal pancreas and chronic pancreatitis. METHODS: This was a retrospective study on tissue microarrays constructed from formalin-fixed paraffin-embedded tissue from 126 consecutive patients (cancer = 104, chronic pancreatitis = 22) undergoing pancreatic resections between June 2001 and June 2006. 78 specimens of chronic pancreatitis tissue were obtained adjacent to areas of cancer. Normal pancreatic tissue was obtained from the resection specimens in a total of 30 patients. Metastatic tumours in 61 regional lymph nodes from 61 patients were also studied. RESULTS: MMCs I, III, IV and V were highly expressed (p < 0.05) in all primary periampullary cancers compared with metastatic lymph nodes and adjacent benign pancreas. MMCs III, IV and V were highly expressed in all cancers regardless of type compared with chronic pancreatitis (p < 0.05). Higher expression of MMCs I and V was associated with better survival and may, in part, relate to lower expression of these MMCs in poorly differentiated tumours compared with well and moderately differentiated tumours. CONCLUSIONS: Differential expression of MMCs III, IV and V in primary periampullary cancers compared with adjacent benign periampullary tissue and chronic pancreatitis is a novel finding, which may render them attractive anticancer targets. PMID- 20202215 TI - ABCtoolbox: a versatile toolkit for approximate Bayesian computations. AB - BACKGROUND: The estimation of demographic parameters from genetic data often requires the computation of likelihoods. However, the likelihood function is computationally intractable for many realistic evolutionary models, and the use of Bayesian inference has therefore been limited to very simple models. The situation changed recently with the advent of Approximate Bayesian Computation (ABC) algorithms allowing one to obtain parameter posterior distributions based on simulations not requiring likelihood computations. RESULTS: Here we present ABCtoolbox, a series of open source programs to perform Approximate Bayesian Computations (ABC). It implements various ABC algorithms including rejection sampling, MCMC without likelihood, a Particle-based sampler and ABC-GLM. ABCtoolbox is bundled with, but not limited to, a program that allows parameter inference in a population genetics context and the simultaneous use of different types of markers with different ploidy levels. In addition, ABCtoolbox can also interact with most simulation and summary statistics computation programs. The usability of the ABCtoolbox is demonstrated by inferring the evolutionary history of two evolutionary lineages of Microtus arvalis. Using nuclear microsatellites and mitochondrial sequence data in the same estimation procedure enabled us to infer sex-specific population sizes and migration rates and to find that males show smaller population sizes but much higher levels of migration than females. CONCLUSION: ABCtoolbox allows a user to perform all the necessary steps of a full ABC analysis, from parameter sampling from prior distributions, data simulations, computation of summary statistics, estimation of posterior distributions, model choice, validation of the estimation procedure, and visualization of the results. PMID- 20202216 TI - The hidden cost of chronic fatigue to patients and their families. AB - BACKGROUND: Nearly 1 in 10 in the population experience fatigue of more than six months at any one time. Chronic fatigue is a common reason for consulting a general practitioner, and some patients report their symptoms are not taken seriously enough. A gap in perceptions may occur because doctors underestimate the impact of fatigue on patients' lives. The main aim of the study is to explore the economic impact of chronic fatigue in patients seeking help from general practitioners and to identify characteristics that explain variations in costs. METHODS: The design of study was a survey of patients presenting to general practitioners with unexplained chronic fatigue. The setting were 29 general practice surgeries located in the London and South Thames regions of the English National Health Service. Use of services over a six month period was measured and lost employment recorded. Regression models were used to identify factors that explained variations in these costs. RESULTS: The mean total cost of services and lost employment across the sample of 222 patients was 3878 pounds for the six month period. Formal services accounted for 13% of this figure, while lost employment accounted for 61% and informal care for 26%. The variation in the total costs was significantly related to factors linked to the severity of the condition and social functioning. CONCLUSIONS: The economic costs generated by chronic fatigue are high and mostly borne by patients and their families. Enquiry about the functional consequences of fatigue on the social and occupational lives of patients may help doctors understand the impact of fatigue, and make patients feel better understood. PMID- 20202218 TI - AutoSOME: a clustering method for identifying gene expression modules without prior knowledge of cluster number. AB - BACKGROUND: Clustering the information content of large high-dimensional gene expression datasets has widespread application in "omics" biology. Unfortunately, the underlying structure of these natural datasets is often fuzzy, and the computational identification of data clusters generally requires knowledge about cluster number and geometry. RESULTS: We integrated strategies from machine learning, cartography, and graph theory into a new informatics method for automatically clustering self-organizing map ensembles of high-dimensional data. Our new method, called AutoSOME, readily identifies discrete and fuzzy data clusters without prior knowledge of cluster number or structure in diverse datasets including whole genome microarray data. Visualization of AutoSOME output using network diagrams and differential heat maps reveals unexpected variation among well-characterized cancer cell lines. Co-expression analysis of data from human embryonic and induced pluripotent stem cells using AutoSOME identifies >3400 up-regulated genes associated with pluripotency, and indicates that a recently identified protein-protein interaction network characterizing pluripotency was underestimated by a factor of four. CONCLUSIONS: By effectively extracting important information from high-dimensional microarray data without prior knowledge or the need for data filtration, AutoSOME can yield systems-level insights from whole genome microarray expression studies. Due to its generality, this new method should also have practical utility for a variety of data intensive applications, including the results of deep sequencing experiments. AutoSOME is available for download at http://jimcooperlab.mcdb.ucsb.edu/autosome webcite. PMID- 20202217 TI - Cell cycle-dependent regulation of the bi-directional overlapping promoter of human BRCA2/ZAR2 genes in breast cancer cells. AB - BACKGROUND: BRCA2 gene expression is tightly regulated during the cell cycle in human breast cells. The expression of BRCA2 gene is silenced at the G0/G1 phase of cell growth and is de-silenced at the S/G2 phase. While studying the activity of BRCA2 gene promoter in breast cancer cells, we discovered that this promoter has bi-directional activity and the product of the reverse activity (a ZAR1-like protein, we named ZAR2) silences the forward promoter at the G0/G1 phase of the cell. Standard techniques like cell synchronization by serum starvation, flow cytometry, N-terminal or C-terminal FLAG epitope-tagged protein expression, immunofluorescence confocal microscopy, dual luciferase assay for promoter evaluation, and chromatin immunoprecipitation assay were employed during this study. RESULTS: Human BRCA2 gene promoter is active in both the forward and the reverse orientations. This promoter is 8-20 fold more active in the reverse orientation than in the forward orientation when the cells are in the non dividing stage (G0/G1). When the cells are in the dividing state (S/G2), the forward activity of the promoter is 5-8 folds higher than the reverse activity. The reverse activity transcribes the ZAR2 mRNA with 966 nt coding sequence which codes for a 321 amino acid protein. ZAR2 has two C4 type zinc fingers at the carboxyl terminus. In the G0/G1 growth phase ZAR2 is predominantly located inside the nucleus of the breast cells, binds to the BRCA2 promoter and inhibits the expression of BRCA2. In the dividing cells, ZAR2 is trapped in the cytoplasm. CONCLUSIONS: BRCA2 gene promoter has bi-directional activity, expressing BRCA2 and a novel C4-type zinc finger containing transcription factor ZAR2. Subcellular location of ZAR2 and its expression from the reverse promoter of the BRCA2 gene are stringently regulated in a cell cycle dependent manner. ZAR2 binds to BRCA2/ZAR2 bi-directional promoter in vivo and is responsible, at least in part, for the silencing of BRCA2 gene expression in the G0/G1 phase in human breast cells. PMID- 20202219 TI - An enhanced method for sequence walking and paralog mining: TOPO(R) Vector Ligation PCR. AB - BACKGROUND: Although technological advances allow for the economical acquisition of whole genome sequences, many organisms' genomes remain unsequenced, and fully sequenced genomes may contain gaps. Researchers reliant upon partial genomic or heterologous sequence information require methods for obtaining unknown sequences from loci of interest. Various PCR based techniques are available for sequence walking - i.e., the acquisition of unknown DNA sequence adjacent to known sequence. Many such methods require rigid, elaborate protocols and/or impose narrowly confined options in the choice of restriction enzymes for necessary genomic digests. We describe a new method, TOPO(R) Vector-Ligation PCR (or TVL PCR) that innovatively integrates available tools and familiar concepts to offer advantages as a means of both targeted sequence walking and paralog mining. FINDINGS: TVL-PCR exploits the ligation efficiency of the pCR(R)4-TOPO(R) (Invitrogen, Carlsbad, California) vector system to capture fragments of unknown sequence by creating chimeric molecules containing defined priming sites at both ends. Initially, restriction enzyme-digested genomic DNA is end-repaired to create 3' adenosine overhangs and is then ligated to pCR4-TOPO vectors. The ligation product pool is used directly as a template for nested PCR, using specific primers to target orthologous sequences, or degenerate primers to enable capture of paralogous gene family members. We demonstrated the efficacy of this method by capturing entire coding and partial promoter sequences of several strawberry Superman-like genes. CONCLUSIONS: TVL-PCR is a convenient and efficient method for DNA sequence walking and paralog mining that is applicable to any organism for which relevant DNA sequence is available as a basis for primer design. PMID- 20202220 TI - Strategies of Nitrosomonas europaea 19718 to counter low dissolved oxygen and high nitrite concentrations. AB - BACKGROUND: Nitrosomonas europaea is a widely studied chemolithoautotrophic ammonia oxidizing bacterium. While significant work exists on the ammonia oxidation pathway of N. europaea, its responses to factors such as dissolved oxygen limitation or sufficiency or exposure to high nitrite concentrations, particularly at the functional gene transcription level are relatively sparse. The principal goal of this study was to investigate responses at the whole-cell activity and gene transcript levels in N. europaea 19718 batch cultures, which were cultivated at different dissolved oxygen and nitrite concentrations. Transcription of genes coding for principal metabolic pathways including ammonia oxidation (amoA), hydroxylamine oxidation (hao), nitrite reduction (nirK) and nitric oxide reduction (norB) were quantitatively measured during batch growth, at a range of DO concentrations (0.5, 1.5 and 3.0 mg O2/L). Measurements were also conducted during growth at 1.5 mg O2/L in the presence of 280 mg-N/L of externally added nitrite. RESULTS: Several wide ranging responses to DO limitation and nitrite toxicity were observed in N. europaea batch cultures. In contrast to our initial hypothesis, exponential phase mRNA concentrations of both amoA and hao increased with decreasing DO concentrations, suggesting a mechanism to metabolize ammonia and hydroxylamine more effectively under DO limitation. Batch growth in the presence of 280 mg nitrite-N/L resulted in elevated exponential phase nirK and norB mRNA concentrations, potentially to promote utilization of nitrite as an electron acceptor and to detoxify nitrite. This response was in keeping with our initial hypothesis and congruent with similar responses in heterotrophic denitrifying bacteria. Stationary phase responses were distinct from exponential phase responses in most cases, suggesting a strong impact of ammonia availability and metabolism on responses to DO limitation and nitrite toxicity. In general, whole-cell responses to DO limitation or nitrite toxicity, such as sOUR or nitrite reduction to nitric oxide (NO) did not parallel the corresponding mRNA (nirK) profiles, suggesting differences between the gene transcription and enzyme translation or activity levels. CONCLUSIONS: The results of this study show that N. europaea possesses specific mechanisms to cope with growth under low DO concentrations and high nitrite concentrations. These mechanisms are additionally influenced by the physiological growth state of N. europaea cultures and are possibly geared to enable more efficient substrate utilization or nitrite detoxification. PMID- 20202221 TI - Medical marijuana users in substance abuse treatment. AB - BACKGROUND: The rise of authorized marijuana use in the U.S. means that many individuals are using cannabis as they concurrently engage in other forms of treatment, such as substance abuse counseling and psychotherapy. Clinical and legal decisions may be influenced by findings that suggest marijuana use during treatment serves as an obstacle to treatment success, compromises treatment integrity, or increases the prevalence or severity of relapse. In this paper, the author reviews the relationship between authorized marijuana use and substance abuse treatment utilizing data from a preliminary pilot study that, for the first time, uses a systematic methodology to collect data examining possible effects on treatment. METHODS: Data from the California Outcomes Measurement System (CalOMS) were compared for medical (authorized) marijuana users and non-marijuana users who were admitted to a public substance abuse treatment program in California. Behavioral and social treatment outcomes recorded by clinical staff at discharge and reported to the California Department of Alcohol and Drug Programs were assessed for both groups, which included a sample of 18 reported medical marijuana users. RESULTS: While the findings described here are preliminary and very limited due to the small sample size, the study demonstrates that questions about the relationship between medical marijuana use and involvement in drug treatment can be systematically evaluated. In this small sample, cannabis use did not seem to compromise substance abuse treatment amongst the medical marijuana using group, who (based on these preliminary data) fared equal to or better than non-medical marijuana users in several important outcome categories (e.g., treatment completion, criminal justice involvement, medical concerns). CONCLUSIONS: This exploratory study suggests that medical marijuana is consistent with participation in other forms of drug treatment and may not adversely affect positive treatment outcomes. These findings call for more extensive sampling in future research to allow for more rigorous research on the growing population of medical marijuana users and non-marijuana users who are engaged in substance abuse treatment. PMID- 20202222 TI - Postnatal ontogenesis of clock genes in mouse suprachiasmatic nucleus and heart. AB - BACKGROUND: The master clock within the hypothalamic suprachiasmatic nucleus (SCN) synchronizing clocks in peripheral tissues is entrained by the environmental condition, such as the light-dark (LD) cycle. The mechanisms of circadian clockwork are similar in both SCN and peripheral tissues. The aim of the present work was to observe the profiles of clock genes expression in mouse central and peripheral tissues within postnatal day 5 (P5). The daily expression of four clock genes mRNA (Bmal1, Per2, Cry1 and Rev-erb alpha) in mouse SCN and heart was measured at P1, P3 and P5 by real-time PCR. RESULTS: All the studied mice clock genes began to express in a circadian rhythms manner in heart and SCN at P3 and P5 respectively. Interestingly, the daily rhythmic phase of some clock genes shifted during the postnatal days. Moreover, the expressions of clock genes in heart were not synchronized with those in SCN until at P5. CONCLUSION: The data showed the gradual development of clock genes in SCN and a peripheral tissue, and suggested that development of clock genes differed between in the SCN and the heart. Judging from the mRNA expression, it was possible that the central clock synchronized the peripheral clock as early as P5. PMID- 20202223 TI - Different DNA methylation patterns detected by the Amplified Methylation Polymorphism Polymerase Chain Reaction (AMP PCR) technique among various cell types of bulls. AB - BACKGROUND: The purpose of this study was to apply an arbitrarily primed methylation sensitive polymerase chain reaction (PCR) assay called Amplified Methylation Polymorphism Polymerase Chain Reaction (AMP PCR) to investigate the methylation profiles of somatic and germ cells obtained from Holstein bulls. METHODS: Genomic DNA was extracted from sperm, leukocytes and fibroblasts obtained from three bulls and digested with a methylation sensitive endonuclease (HpaII). The native genomic and enzyme treated DNA samples were used as templates in an arbitrarily primed-PCR assay with 30 sets of single short oligonucleotide primer. The PCR products were separated on silver stained denaturing polyacrylamide gels. Three types of PCR markers; digestion resistant-, digestion sensitive-, and digestion dependent markers, were analyzed based on the presence/absence polymorphism of the markers between the two templates. RESULTS: Approximately 1,000 PCR markers per sample were produced from 27 sets of primer and most of them (>90%) were digestion resistant markers. The highest percentage of digestion resistant markers was found in leukocytic DNA (94.8%) and the lowest in fibroblastic DNA (92.3%, P < or = 0.05). Spermatozoa contained a higher number of digestion sensitive markers when compared with the others (3.6% vs. 2.2% and 2.6% in leukocytes and fibroblasts respectively, P < or = 0.05). CONCLUSIONS: The powerfulness of the AMP PCR assay was the generation of methylation-associated markers without any prior knowledge of the genomic sequence. The data obtained from different primers provided an overview of genome wide DNA methylation content in different cell types. By using this technique, we found that DNA methylation profile is tissue-specific. Male germ cells were hypomethylated at the HpaII locations when compared with somatic cells, while the chromatin of the well-characterized somatic cells was heavily methylated when compared with that of the versatile somatic cells. PMID- 20202224 TI - Cyclic stretch enhances the expression of toll-like receptor 4 gene in cultured cardiomyocytes via p38 MAP kinase and NF-kappaB pathway. AB - BACKGROUND: Toll-like receptor 4 (TLR4) plays an important role in innate immunity. The role of TLR4 in stretched cardiomyocytes is not known. We sought to investigate whether mechanical stretch could regulate TLR4 expression, as well as the possible molecular mechanisms and signal pathways mediating the expression of TLR4 by cyclic mechanical stretch in cardiomyocytes. METHODS: Neonatal Wistar rat cardiomyocytes grown on a flexible membrane base were stretched by vacuum to 20% of maximum elongation at 60 cycles/min. Western blot, real-time polymerase chain reaction, and promoter activity assay were performed. In vitro monocyte adhesion to stretched myocyte was detected. RESULTS: Cyclic stretch significantly increased TLR4 protein and mRNA expression after 2 h to 24 h of stretch. Addition of SB203580, TNF-alpha antibody, and p38alpha MAP kinase siRNA 30 min before stretch inhibited the induction of TLR4 protein. Cyclic stretch increased, while SB203580 abolished the phosphorylated p38 protein. Gel shifting assay showed significant increase of DNA-protein binding activity of NF-kappaB after stretch and SB203580 abolished the DNA-protein binding activity induced by cyclic stretch. DNA-binding complexes induced by cyclic stretch could be supershifted by p65 monoclonal antibody. Cyclic stretch increased TLR4 promoter activity while SB203580 and NF-kappaB siRNA decreased TLR4 promoter activity. Cyclic stretch increased adhesion of monocyte to cardiomyocytes while SB203580, TNF-alpha antibody, and TLR4 siRNA attenuated the adherence of monocyte. TNF-alpha and Ang II significantly increased TLR4 protein expression. Addition of losartan, TNF alpha antibody, or p38alpha siRNA 30 min before Ang II and TNF-alpha stimulation significantly blocked the increase of TLR4 protein by AngII and TNF-alpha. CONCLUSIONS: Cyclic mechanical stretch enhances TLR4 expression in cultured rat neonatal cardiomyocytes. The stretch-induced TLR4 is mediated through activation of p38 MAP kinase and NF-kappaB pathways. TLR4 up-regulation by cyclic stretch increases monocyte adherence. PMID- 20202227 TI - Abstracts of the 30th International Symposium on Intensive Care and Emergency Medicine. Brussels, Belgium. March 9-12, 2010. PMID- 20202226 TI - Influence of Factor V Leiden on susceptibility to and outcome from critical illness: a genetic association study. AB - INTRODUCTION: Disturbance of the pro-coagulatant and anti-coagulant balance is associated with a poor outcome from critical illness. The objective of this study is to determine whether the Factor V Leiden (FVL) mutation is associated with susceptibility to or death from critical illness. METHODS: A genetic association study involving four case cohorts comprising two Gram negative sepsis, one invasive pneumococcal disease and one intensive care unit cohort with a total of 1,249 patients. Controls were derived from a population-based cohort study (N = 8,147). DNA from patients and controls was genotyped for the FVL mutation. RESULTS: When all patients were investigated together no significant difference in the frequency of FVL mutation was observed compared with controls (odds ratio (OR), 1.03; 95% confidence interval (CI), 0.83 to 1.29). However, when stratified among patients admitted to intensive care (N = 237), susceptibility and the likelihood of long-term death was influenced by the FVL mutation. In adjusted logistic regression analysis, FVL carriers had an increased risk of ICU admission compared to non-carriers (OR 1.62; 95% CI, 1.08 to 2.42). In adjusted Cox regression analysis, FVL carriers were at increased risk of long-term death compared to non-carriers (relative risk 1.78; 95% CI, 1.13 to 2.81). FVL carrier status did not predict either susceptibility to or outcome from Gram negative, Escherichia coli or Streptococcus pneumoniae sepsis. CONCLUSIONS: Overall, the FVL mutation did not appear to increase the risk of admission due to severe invasive infections. Nevertheless, in the subgroup of patients admitted to intensive care an increased risk and a poorer long-term outcome for individuals with critical illness were observed for FVL mutation carriers. PMID- 20202225 TI - A two-year survey of the oseltamivir-resistant influenza A(H1N1) virus in Yamagata, Japan and the clinical effectiveness of oseltamivir and zanamivir. AB - BACKGROUND: Oseltamivir is the preferred antiviral drug for influenza, but oseltamivir-resistant A(H1N1) viruses have circulated worldwide since the 2007 2008 influenza season. We aimed to determine the rate of oseltamivir resistance among A(H1N1) isolates from Yamagata, Japan, to compare the virological characteristics between isolates from the 2007-2008 and 2008-2009 seasons, and to evaluate the clinical effectiveness of oseltamivir. RESULTS: Oseltamivir resistance, determined by detecting the H275Y mutation in the neuraminidase (NA) gene, was observed in 2.5% (2 of 79) and 100% (77 of 77) of isolates from the 2007-2008 and 2008-2009 seasons, respectively. Antigenic analysis suggested that antigenically different variants of A(H1N1) viruses circulated in the 2008-2009 season. Growth testing demonstrated that the ability of the 2008-2009 isolates to replicate in MDCK cells was similar to those of the oseltamivir-susceptible isolates from the 2007-2008 season. A phylogenetic analysis revealed that two oseltamivir-resistant viruses isolated in the 2007-2008 season were closely related to other oseltamivir-susceptible viruses in Yamagata but were different from oseltamivir-resistant viruses isolated in Europe and North America in the 2007-2008 season. The oseltamivir-resistant viruses isolated in Japan in the 2008 2009 season were phylogenetically similar to oseltamivir-resistant isolates from Europe and North America during the 2007-2008 season. Furthermore, the median duration of fever after the start of oseltamivir treatment was significantly longer in oseltamivir-resistant cases (2 days; range 1-6 days) than in oseltamivir-susceptible cases (1.5 days: range 1-2 days) (P = 0.0356). CONCLUSION: Oseltamivir-resistant A(H1N1) isolates from Yamagata in the 2007-2008 season might have acquired resistance through the use of oseltamivir, and the 2008-2009 oseltamivir-resistant isolates might have been introduced into Japan and circulated throughout the country. Influenza surveillance to monitor oseltamivir-resistance would aid clinicians in determining an effective antiviral treatment strategy. PMID- 20202228 TI - Cigarette smoking impairs sperm bioenergetics. PMID- 20202229 TI - Current diagnosis and management of syringocele: a review. AB - Cowper's syringocele is a rare but an under-diagnosed cystic dilation of the Cowper's ducts and is increasingly being recognized in the adult population. Recent literature suggests that syringoceles be classified based on the configuration of the duct's orifice to the urethra, either open or closed, as this also allows the clinical presentations of 2 syringoceles to be divided, albeit with some overlap. Usually post-void dribbling, hematuria, or urethral discharge indicates open syringocele, while obstructive symptoms are associated with closed syringoceles. As these symptoms are shared by many serious conditions, a working differential diagnosis is critical. Ultrasonography coupled with retro and ante grade urethrography usually suffices to diagnose syringocele, but supplementary procedures - such as cystourethroscopy, computed tomography scan, and magnetic resonance imaging - can prove useful. Conservative observation is first recommended, but persistent symptoms are usually treated with endoscopic marsupialization unless contraindicated. Upon reviewing the literature, this paper addresses the clinical anatomy, classification, presentation, diagnosis, and treatment of syringoceles in further detail. PMID- 20202231 TI - Diffusion weighted imaging in the detection of upper urinary tract urothelial tumors. AB - PURPOSE: Diffusion-weighted (DW) magnetic resonance imaging (MRI) provides information about the biophysical properties of tissues such as cell organization and density. DW imaging (DWI) is becoming important in the assessment of malignant tumors. The purpose of our study was to evaluate the capability and reliability of DWI in the evaluation of upper urinary tract urothelial tumors. MATERIALS AND METHODS: DWI was performed in seventeen patients with upper urinary tract urothelial tumor, previously diagnosed by either CT or retrograde pyelography. An histological evaluation was performed after surgical resection. Each MRI was carried out using a 1.5T superconductive magnet MRI system. DWI images were obtained with b value of 1000 s/mm(2) under normal breathing. The apparent diffusion coefficient (ADC) values were measured. RESULTS: In nine patients with renal pelvis tumors and seven patients with ureteral tumors, the lesions were shown as high-signal intensity in the corresponding region on DWI. In one patient with carcinoma in situ (CIS) of the ureter, the lesion was not depicted with DWI. The mean ADC value of the tumor was 1.125 + or - 0.217 x 10( 3) mm(2)/s and was significantly lower than those of the renal parenchyma (1.984 + or - 0.238 x 10(-3) mm(2)/s, p < 0.01) and the urine (2.941 + or - 0.315 x 10( 3) mm(2)/s, p < 0.01). CONCLUSIONS: In our study, the renal pelvic and ureteral tumors except CIS were shown clearly with DWI. Although further studies are required, DWI may take the place of invasive retrograde urography for detecting tumors of the upper urinary tract. PMID- 20202230 TI - Laparoscopic nephropexy exposes a possible underlying pathogenic mechanism and allows successful treatment with tissue gluing of the kidney and fixation of the colon to the lateral abdominal wall. AB - OBJECTIVES: Surgical treatment of "Ren Mobilis" has historically been associated with poor results and fairly high morbidity. We have used a transperitoneal laparoscopic approach in order to minimize morbidity. The goal of this study was to evaluate the success rate and to discuss the possible pathogenic mechanism, which has implications for the surgical strategy. MATERIALS AND METHODS: Seven women with a right mobile kidney were examined by intravenous pyelogram and CT scans. Symptoms were judged to emanate from the mobile kidney. Transperitoneal laparoscopic nephropexy was performed. The surgical treatment consisted of fixing the kidney to the dorsal abdominal wall using tissue glue (Tisseel) after diathermy coagulation of the surfaces to induce fibrosis. The right colon was fixed with clips to the lateral abdominal wall, trapping the kidney in place. RESULTS: In 6 of the cases, there was an incomplete rotation of the ascending colon to the right side, allowing the kidney to move freely. In one case, the kidney moved into a retroperitoneal pocket of the mesocolon. The 6 cases with a lateral passage for the kidney were symptom-free at follow-up (30-80 months), but in the 7th case the patient's kidney quickly loosened and she underwent an open reoperation, after which she was symptom-free. CONCLUSION: Our series demonstrates that good results can be achieved with a transperitoneal laparoscopic approach, but also indicates that there is a common pathogenic mechanism with incomplete rotation of the ascending colon that can be corrected during surgery, which might contribute to the good results. PMID- 20202232 TI - What is the best drainage method for a perinephric abscess? AB - PURPOSE: To compare the results of percutaneous and open drainage for perinephric abscess. MATERIALS AND METHODS: The files of 86 patients who underwent drainage for perinephric abscesses from April 2001 through March 2008 were evaluated. The method of drainage for each patient was performed according to the clinical decision of the treating physician. Percutaneous tube drain (PCD) was used for drainage of the abscess in 43 patients (group 1), while the other 43 patients were managed with open drainage (group 2). Cure was defined as complete obliteration of the abscess cavity. The cure rates, complications, and hospital stay were compared between both groups. RESULTS: The study included 50 males and 36 females with mean age 44.2 + or - 17.3. The most common predisposing factors were diabetes mellitus and/or stones. Open drainage of perinephric abscesses resulted in a statistically significant higher cure rate (98% versus 69%, p < 0.001) and shorter hospital stay than PCD (3.6 versus 6 days, p < 0.001). Failure of complete drainage of multilocular abscess was observed in 8 of 13 cases (61.5%) in group 1 and one of 38 cases (2.6%) in group 2 (P < 0.001). Complications were observed in 7% of group 1 and 11.5% in group 2 (P = 0.45). After mean follow-up of 19 months, 9 of 46 patients (19.6%) had recurrence; 7 of them were in group 1. CONCLUSION: Percutaneous drainage of perinephric abscess is an effective minimally invasive treatment. However, PCD is not the optimal method for drainage of multilocular abscess because open surgical drainage provided higher cure rates and shorter hospitalization than PCD. PMID- 20202233 TI - Laparoscopic ureteral reimplant for ureteral stricture. AB - PURPOSE: Evaluate the initial experience of laparoscopic ureteral reimplant for ureteral stenosis. MATERIALS AND METHODS: From January 2004 to June 2008, 10 patients underwent 11 laparoscopic reconstruction surgeries for ureteral stenosis. Seven cases of stenosis of the distal ureter, two at the level of iliac vessels, a case of bilateral distal stenosis and one in the medium third. Eight ureteroneocystotomies were performed by extravesical technique with anti-reflux mechanism, two cases of vesical reimplant with Boari technique and one case using the psoas hitch technique. RESULTS: The average surgical time was 166 minutes (115-245 min), mean blood loss was 162 mL (100-210 mL) and the average hospital stay was 2.9 days (2-4 days). There were two complications: a lesion of the sigmoid colon identified peroperatively and treated with laparoscopic sutures with good evolution, and a case of ureteral stone obstruction at the 30th day postoperative, treated by laser ureterolitotripsy. All patients had resolution of the stenosis at an average follow-up period of 18 months (3-54 months). CONCLUSION: Laparoscopic surgery represents a feasible, safe and low morbidity technique for ureteral reimplant in ureteral stenosis. PMID- 20202234 TI - Outcomes following negative prostate biopsy for patients with persistent disease after radiotherapy for prostate cancer. AB - PURPOSE: When faced with biochemical recurrence after definitive radiotherapy for prostate cancer, clinicians must determine whether the recurrence is local or systemic. Post radiotherapy prostate biopsies to detect persistent local disease are difficult to interpret histopathologically and are subject to sampling error. Our study examines outcomes for patients with a negative prostate biopsy performed for rising prostate-specific antigen (PSA) levels after prostate radiation. MATERIALS AND METHODS: We performed a retrospective review of 238 prostate cancer patients with a negative biopsy following definitive radiotherapy. Seventy-five of these patients had biochemical recurrence at the time of biopsy. A negative biopsy was defined as the absence of prostate cancer without radiation-treatment effect in the specimen. RESULTS: Patients underwent biopsy at a mean of 41 months after the completion of radiation. They had a mean PSA of 6. Patients were followed for an average of 63 months. Thirty-two patients (43%) developed metastasis, and 11 (15%) died of prostate cancer despite a negative post-radiation biopsy. Five of nine patients (56%) with sequential biopsies had a positive second biopsy. CONCLUSIONS: Patients with PSA recurrence and a negative post-radiation biopsy have a high chance of persistent local disease, progression, and death from prostate cancer. Furthermore, an initial negative biopsy does not rule-out local recurrence. Patients with biochemical recurrence after radiotherapy for prostate cancer need to be evaluated earlier for local recurrence. PMID- 20202235 TI - Analgesic efficacy and safety of nonsteroidal anti-inflammatory drugs after transurethral resection of prostate. AB - OBJECTIVES: The aim of this study was to assess the analgesic efficacy and safety of nonsteroidal anti-inflammatory drugs (NSAIDs), administered as intramuscular diclofenac in comparison with intravenous paracetamol after transurethral resection of the prostate (TURP). MATERIALS AND METHODS: Fifty men, aged 55 to 75 years, undergoing TURP at our hospital were included in this study. Patients were divided randomly and prospectively into two groups (25 patients in each group). Group I (NSAID) received 75 mg of diclofenac i.m. at the end of the operation followed by 75 mg of diclofenac i.m. for 24 hours (75 mg x 2 once a day = 150 mg/24 h) postoperatively. The other group (Group II) consisted of patients who received 1g/100 mL i.v. paracetamol 15 minutes twice daily as postoperative analgesia. Postoperative pain scores were evaluated at 30 minutes, 1, 2, 4 and 6 hours after administration of each analgesic, using a visual analogue scale (VAS). Furthermore, preoperative and postoperative hemoglobin (Hb) levels and hemostatic variables (bleeding time, prothrombine time and the international normalized ratio, i.e. the ratio of a patient's prothrombin time to a normal [control] sample) were recorded in all patients. RESULTS: The pain score changes during a 4 hour period between the two groups was similar (p = 0.162). Thirty minutes after surgery, pain scores were high (> 3 cm) in both groups and without differences between groups (p = 0.11) but 6 hours after surgery, pain scores were significantly higher with paracetamol compared to diclofenac (p < 0.05). No significant difference was observed between the groups regarding the amount of resected tissue, operating time, preoperative-postoperative Hb levels and hemostatic variables. In the both groups, no patient required blood transfusion postoperatively. CONCLUSIONS: NSAIDs are not a contraindication to TURP and should be used for the control of postoperative pain if indicated. PMID- 20202236 TI - Duration of preoperative scrotal pain may predict the success of microsurgical varicocelectomy. AB - PURPOSE: Varicocelectomy is used in the treatment of scrotal pain. We report our results with microsurgical subinguinal varicocele ligation to treat pain. MATERIALS AND METHODS: A total of 284 men underwent subinguinal microsurgical varicocele ligation for scrotal pain. All patients were asked to return for a follow-up evaluation 3 months after surgery, which included a physical examination, as well as questions on pain severity, number of days required before their return to work and development of any postoperative complications. RESULTS: Median patient age at the time of varicocele ligation was 23.7 years (range 16-38 years). The average duration of pain before presentation was 11.2 months (range 1 month to 40 months). In 85.6% patients there was complete resolution of pain and 6.3% had partial resolution. Pain persisted postoperatively in 19 cases (8.1%). There were statistically non-significant differences in the characteristics of the pain and grade of varicocele between postoperative groups. A significant difference was observed in postoperative success between patients who had long period and those who had short period of pain. CONCLUSIONS: Sub-inguinal microsurgical varicocele ligation is an effective treatment for painful varicocele. The duration of pain preoperatively may predict outcomes in selected patients. PMID- 20202237 TI - Cigarette smoking impairs sperm bioenergetics. AB - OBJECTIVE: The growing consensus on the negative impact of cigarette smoking on fertility prompted us to compare the rate of sperm respiration in smokers and non smokers. MATERIALS AND METHODS: Semen samples from 20 smokers and 58 non-smokers consulting at the andrology laboratory for fertility evaluation were used. Smoking was defined as consumption of at least a half a pack per day. A phosphorescence analyzer that measures O(2) concentration in sperm suspensions as function of time was used to determine the rate of respiration. In a sealed vial, the rate of sperm respiration (k) was defined as -d[O(2)]/dt; where [O(2)] was obtained from the phosphorescence decay rate of a palladium phosphor. [O(2)] in solutions containing sperm and glucose declined linearly with time, showing the kinetics of O(2) consumption was zero-order. Inhibition of O(2) consumption by cyanide confirmed the oxidations that occurred in the sperm mitochondrial respiratory chain. RESULTS: There were no differences (p > 0.28) between smokers and non-smokers for ejaculate volume, motility, concentration, normal morphology, viability and hypo-osmotic swelling test. The rate (mean + or - SD, in microM O(2)/min/10(8) sperm) of sperm mitochondrial O(2) consumption in the smokers was 0.96 + or - 0.58 and in the non-smokers 1.39 + or - 0.67 (p = 0.004). CONCLUSIONS: The rate of sperm respiration was significantly lower in smokers. This negative impact of cigarette smoking on sperm aerobic metabolism may, in part, explain the lower rate of fertility in smokers. PMID- 20202238 TI - Experience with different botulinum toxins for the treatment of refractory neurogenic detrusor overactivity. AB - PURPOSE: To report our experience with the use of the botulinum toxin-A (BoNT/A) formulations Botox and Prosigne in the treatment of neurogenic detrusor overactivity (NDO). MATERIALS AND METHODS: At a single institution, 45 consecutive patients with refractory urinary incontinence due to NDO received a single intradetrusor (excluding the trigone) treatment with botulinum toxin type A 200 or 300 units. Botox was used for the first 22 patients, and Prosigne for the subsequent 23 patients. Evaluations at baseline and week 12 included assessment of continence and urodynamics. Safety evaluations included monitoring of vital signs, hematuria during the procedure, hospital stay, and spontaneous adverse event reports. RESULTS: A total of 42 patients were evaluated (74% male; mean age, 34.8 years). Significant improvements from baseline in maximum cystometric capacity (MCC), maximum detrusor pressure during bladder contraction, and compliance were observed in both groups (P < 0.05). Improvement in MCC was significantly greater with Botox versus Prosigne (+103.3% vs. +42.2%; P = 0.019). Continence was achieved by week 12 in 16 Botox recipients (76.2%) and 10 Prosigne recipients (47.6%; P = 0.057). No severe adverse events were observed. Mild adverse events included 2 cases of transient hematuria on the first postoperative day (no specific treatment required), and 3 cases of afebrile urinary tract infection. CONCLUSIONS: Botox and Prosigne produce distinct effects in patients with NDO, with a greater increase in MCC with Botox. Further evaluation will be required to assess differences between these formulations. PMID- 20202239 TI - To circ or not to circ: clinical and pharmacoeconomic outcomes of a prospective trial of topical steroid versus primary circumcision. AB - PURPOSE: To compare the efficacy and costs of circumcision versus topical treatment using a prospective pharmacoeconomic protocol. MATERIALS AND METHODS: We treated 59 patients (3-10 years of age) randomized into two groups: 29 underwent an 8-week course of topical treatment with 0.2% betamethasone hyaluronidase cream twice a day; and 30 underwent circumcision. Topical treatment success was defined as complete exposure of the glans. In cases of treatment failure, circumcision was performed and its cost imputed to that of the initial treatment. The pharmacoeconomic aspects were defined according to the Brazilian National Public Health System database and the Brazilian Community Pharmacies Index. RESULTS: The two groups were statistically similar for all clinical parameters evaluated. Topical treatment resulted in complete exposure of the glans in 52% of the patients. Topical treatment was associated with preputial pain and hyperemia. However, treatment suspension was unnecessary. Minor complications were observed in 16.6% of the surgical group patients. The mean cost per patient was US$ 53.70 and US$ 125.20, respectively, for topical steroid treatment (including the costs related to treatment failure) and circumcision. The total costs were US$ 2,825.32 and US$ 3,885.73 for topical treatment and circumcision, respectively. CONCLUSIONS: Topical treatment of phimosis can reduce costs by 27.3% in comparison with circumcision. Therefore, topical treatment of phimosis should be considered prior to the decision to perform surgery. PMID- 20202240 TI - The effect of alpha-blocker treatment on bladder hypoxia inducible factor-1 alpha regulation during lower urinary tract obstruction. AB - AIMS: To determine whether alpha1-blocker treatment, in chronic bladder outlet obstruction (BOO), influences bladder tissue ischemia. MATERIALS AND METHODS: This prospective study included 60 patients with BOO, of which 40 were under alpha1-blocker medication and 20 without treatment. Patients underwent transurethral resection of the prostate (TURP) or suprapubic prostatectomy (SPP). Ten patients with non-muscle invasive bladder cancer underwent transurethral resection of the bladder tumor and served as the control group. Tissue specimens were immunohistochemically stained for hypoxia inducible factor-1alpha (HIF 1alpha). RESULTS: Bladder tissue from obstructed subjects showed high immunoreactivity to HIF-1alpha. The specimens from the control group, showed no or weak, mainly cytoplasmic immunoreactivity to HIF-1alpha. Patients under alpha blocker treatment did not differ in the number of HIF-1alpha positive cells compared to subjects with no treatment (median number 86.8 [20-150] and 88.6 [0 175], respectively) (p > 0.05). The lowest bladder pressure at which HIF-1alpha was up regulated, was detected at detrusor pressure Qmax (PdetQmax) = 60 cm H2O. CONCLUSIONS: Treatment with alpha-blockers in obstructed patients considered as non-responders, does not result in HIF-1alpha down regulation, thus bladder continues to be under chronic stress. PMID- 20202262 TI - Chronic health conditions: changing prevalence in an aging population and some implications for the delivery of health care services. AB - Since the prevalence of many chronic health conditions increases with age, we might anticipate that as the population ages the proportion with one or more such conditions, and the cost of treatment, would rise. How much would the overall prevalence of chronic conditions increase in a quarter century if age-specific rates of prevalence did not change? How much would the requirements for health care resources increase? How much difference would it make to those requirements if people had fewer chronic conditions? The overall prevalence rates for almost all conditions associated mostly with old age would rise by more than 25 per cent, and health care requirements would grow more rapidly than the population - more than twice as rapidly in the case of hospital stays - if the rates for each age group remained constant. Even modest reductions in the average number of conditions at each age could result in substantial savings. PMID- 20202263 TI - Does geography matter? The health service use and unmet health care needs of older Canadians. AB - The rising cost of health care and changing demographic profiles have resulted in the relocation and redistribution of funding and services between rural and urban areas. Most econometric analyses of Canada's health service use include broad controls by province and rural/urban status, but relatively little econometric work has focused on geographical variation in health service use. Using the Canadian Community Health Survey 2.1, we examined determinants of various measures of health services use by Canadians aged 55 or older across a range of urban and rural areas of residence. Our regression analysis showed that older residents in rural areas made fewer visits to a general practitioner, to a specialist, and to a dentist relative to urban residents. All else being equal, there are no significant differences in hospital nights or in unmet healthcare needs. These differences are significant after controlling for demographic characteristics, socioeconomic status, private health insurance, and health status. PMID- 20202264 TI - The Canadian elder standard - pricing the cost of basic needs for the Canadian elderly. AB - We determined the after-tax income required to finance basic needs for Canadian elders living with different circumstances in terms of age, gender, city of residence, household size, homeowner or renter status, means of transportation, and health status. Using 2001 as our base year, we priced the typical expenses for food, shelter, medical, transportation, miscellaneous basic living items and home-based long-term care for elders living in five Canadian cities. This is the first Canadian study of basic living expenses tailored to elders instead of adults in general, prepared on an absolute rather than a relative basis. We also accounted for an individual's unique life circumstances and established the varying effect that they have on the cost of basic expenses, particularly for home care. We found that the maximum Guaranteed Income Supplement and Old Age Security benefit did not meet the cost of basic needs for an elder living in poor circumstances. PMID- 20202265 TI - What will the family composition of older persons be like tomorrow? A comparison of Canada and France. AB - Western societies are experiencing a dramatic growth in the population aged 75 and older. Changes in family composition raise questions about who will care for those who need assistance. We compared population projections to the year 2030 of those families aged 75 and older in Canada and France. Over the next 25 years, the pool of potential family carers, (i.e., spouses and children), will broaden from the effect of the baby boom and increased proportion of women with spouses. The populations most dependent on formal care, with no potential support from a child or a spouse, will increase more sharply in Canada (123%) than in France (34%) but at a slower rate than the total population. Policy and programs in both countries will need to prepare for a greater number of elderly spouses providing care and in Canada, at least, a significant increase in the number that will need to rely on formal services. PMID- 20202266 TI - Sons who care: examining the experience and meaning of filial caregiving for married and never-married sons. AB - In filial caregiving, women typically provide more care than men. The numerical predominance of female caregivers has been explained such that diversity among male caregivers has been overlooked. That is, "internalist" explanations, which emphasize the differing socialization experience of females and males, tend to homogenize each gender's caregiving experience. "Externalist" explanations, which emphasize various factors that push or pull women and men into caregiving, reduce the actors involved to passive agents whose subjective understanding of caregiving over time is ignored. Both explanations divert attention from the diversity in male caregiving. This article presents qualitative data derived from interviews with 48 caregiving sons to provide evidence of that diversity. Some themes are common to both married and never-married male caregivers, yet there are also systematic differences between the two groups of caregivers. For example, caregiving for married sons was more limited; caregiving for never married sons was a more central element in their lives. PMID- 20202267 TI - Of the family tree: congruence on filial obligation between older parents and adult children in Japanese Canadian families. AB - Drawing on the intergenerational stake hypothesis (Bengtson and Kuypers, 1971), this article explores intergenerational congruence and incongruence on filial obligation, and implications for social support, between older nisei (second generation) parents and adult sansei (third generation) children in Japanese Canadian families. Using data from semi-structured interviews with 100 parent child dyads in British Columbia, congruence on close-ended responses to value statements (degree congruence) and the content congruence of open-ended responses are examined. The findings show the majority of parent-child dyads indicate overall (both degree and content) congruence in filial obligation, especially when a parent is female, widowed, and/or has poor/fair health status. We conclude that despite markedly different historical life course experiences and acculturation processes, both generations continue to regard filial obligation as important. These findings are discussed with respect to implications for social support exchanges given a continued valuation of filial obligation in Asian post immigrant (North American-born) and immigrant families. PMID- 20202268 TI - Strategies used by home support workers in the delivery of care to elderly clients. AB - An estimated 36,000 home support workers assist older Canadians annually with daily activities, such as bathing, dressing, grooming, and light housework, yet home support workers' day-to-day experiences are not well understood. Mahmood and Martin-Matthews (2008) have developed a model that locates the home support worker, elderly client, and family member at the intersection of the public and private spheres framed by their social, spatial, temporal, and organizational features. This study, funded by the Canadian Institutes of Health Research, examines and refines that model through an analysis of in-depth interviews with home support workers in British Columbia. Home support workers identify key issues in service delivery and discuss a range of creative solutions to complete their daily tasks efficiently, effectively, and respectfully. The study's findings inform our understanding of home support workers' job experiences; they also highlight those qualities that characterize exceptional workers in navigating the various domains of home support. PMID- 20202269 TI - Relations between immigrant care workers and older persons in home and long-term care. AB - Immigrant care workers play an increasingly important role in home and long-term care in Canada, yet the full extent of their relations with older persons in those settings is relatively unknown. This article examines the role of immigrant care workers in both home and long-term care sectors, with a focus on relations with older clients and implications for quality of care. The data are derived from interviews with workers, employers, and older clients conducted in various home and long-term care services for older adults across three Canadian provinces: Ontario, British Columbia, and Quebec. Factors stemming from immigrant care workers' ethnic/racial background, language barriers, and contextual factors such as staff shortage in different care settings for older adults complicate the relationship between immigrant care workers and their clients. In some cases, these factors diminish the quality of care. We point to some policy alternatives that our findings suggest should be considered. PMID- 20202270 TI - A cross-sectional study of the prevalence, correlates, and costs of falls in older home care clients 'at risk' for falling. AB - This study examined the six-month prevalence, risk factors, and costs of falls in older people using home support services who are at risk of falling. Of the 109 participants, 70.6 per cent reported >or= one fall in the previous six months, and 27.5 per cent experienced multiple falls. Although there was no statistically significant difference in any fall-related risk factor between fallers (1+ falls) and non-fallers (0 falls), fallers had clinically important trends towards lower levels of physical, social, and psychological functioning. There was no statistically significant difference between fallers and non-fallers in the total per-person costs of use of health services in the previous six months; however, there were significant differences between groups in specific types of health services. The multivariate analysis revealed the presence of five risk factors for falls: neurological disorder (e.g., cognitive impairment, Parkinson's disease), age >or= 85 years, environmental hazards, previous slip or trip, and visual impairment. PMID- 20202271 TI - The effects and costs of a multifactorial and interdisciplinary team approach to falls prevention for older home care clients 'at risk' for falling: a randomized controlled trial. AB - This study determined the effects and costs of a multifactorial, interdisciplinary team approach to falls prevention. Randomized controlled trial of 109 older adults who are at risk for falls. This was a six-month multifactorial and evidence-based prevention strategy involving an interdisciplinary team. The primary outcome was number of falls during the six month follow-up. At six months, no difference in the mean number of falls between groups. Subgroup analyses showed that the intervention effectively reduced falls in men (75-84 years old) with a fear of falling or negative fall history. Number of slips and trips was greatly reduced; and emotional health had a greater improvement in role functioning related to emotional health in the intervention group. Quality of life was improved, slips and trips were reduced, as were falls among males (75-84 years old) with a fear of falling or negative fall history. PMID- 20202272 TI - Intra- and inter-household differences in antenatal care, delivery practices and postnatal care between last neonatal deaths and last surviving children in a peri urban area of India. AB - Nearly a quarter of the world's neonatal deaths take place in India. The state of Uttar Pradesh alone accounts for one-quarter of all neonatal deaths in the country. In this study 892 married women aged less than 50 years living in a peri urban area of Kanpur city in Uttar Pradesh were interviewed. In all, 109 women reported neonatal deaths. Characteristics of the last neonatal deaths of these 109 women were compared with those of the last surviving children. Also, characteristics of women who had a neonatal death were compared with those of 783 women who had no neonatal death. It was found that as compared with neonatal deaths, the last surviving children of the 109 women had: (a) significantly better antenatal tests during pregnancy, intake of iron/folic acid tablets and higher percentage of tetanus toxoid immunization; (b) safer delivery practices such as a higher percentage of institutional delivery, sterilization of instruments and application of antiseptic after removal of umbilical cord; (c) postnatal care, such as application of antiseptic to the navel and postnatal checkups; and (d) higher maternal age and greater birth spacing. Likewise, better antenatal care and safer delivery practices and postnatal care were observed among the 783 women with no neonatal deaths, when compared with women who had experienced neonatal death. The complexities of inter- and intra-household differences in health care are discussed. The paper concludes that to improve child survival general education and awareness regarding safe delivery should be increased. Continuing cultural stigmas and misconceptions about birth practices before, during and after childbirth should be an important part of the awareness campaigns. PMID- 20202273 TI - Desire for more children, contraceptive use and unmet need for family planning in a remote area of Bali, Indonesia. AB - Exploring fertility preferences in relation to contraceptive use can increase the understanding of future reproductive behaviour and unmet family planning needs. This knowledge can help assist women in meeting their reproductive goals. The influences on the desire for more children and current contraceptive use were examined among 1528 married women of reproductive age in an isolated community in Bali, Indonesia, using multivariate logistic regression analysis. Women who were younger, had fewer living children, had given birth in the past year and had regular access to health services were more likely to desire children. Being older, having fewer living children, not having regular access to health services, having given birth in the past year and having the desire for more children were associated with a lower likelihood of using contraception. Women with regular access to health care are more likely to desire more children, probably because they are confident in their ability to have successful birth outcomes. However, specialized clinics or family planning outreach workers may be required to reduce barriers to service utilization among some groups. The findings of this study identify key target populations for family planning, including older women and postpartum women--groups that may not perceive themselves to be at risk for unintended pregnancy. Meeting unmet need for family planning among these groups could help women meet their fertility goals, as well as reduce maternal morbidity and mortality. PMID- 20202274 TI - Consistency in reporting condom use between husbands and wives in Bangladesh. AB - Consistency in reporting contraceptive use between spouses is little understood, especially in developing settings. This research challenges the accuracy of measuring contraceptive prevalence rate, which is traditionally calculated based on women's responses. Multinomial logistic regression techniques are employed on a couple dataset from the 1999-2000 Bangladesh Demographic and Health Survey (DHS) to investigate the consistency in reporting condom use between husbands and wives. The level of inconsistency in reporting condom use was about 46%, of which about 32% was explained by husbands reporting condom use while wives did not, and 14% by wives reporting condom use while husbands did not. Regression analysis showed that couple education and age difference between the spouses are significant determinants of inconsistent reporting behaviour. The findings suggest the need for alternative approaches (questions) in the DHS to ensure consistency in the collection of data related to use of family planning methods. PMID- 20202275 TI - Cavernous sinus thrombosis secondary to contralateral sphenoid sinusitis: a diagnostic challenge. AB - OBJECTIVE: To report what we believe to be the first case in the English language literature of unilateral cavernous sinus thrombosis complicating contralateral sphenoid sinusitis. CASE REPORT: A 62-year-old man presented to his general practitioner with a severe, right-sided, temporal headache. He was diagnosed with temporal arteritis and treated with systemic steroids. After five days, he developed right proptosis, ophthalmoplegia and ptosis. He was referred to the neurologists. After an urgent computed tomography head scan and computed tomography angiogram, a diagnosis of carotido-cavernous fistula was made. However, this was subsequently excluded after a negative cerebral angiogram. A review of the scans enabled diagnosis of right cavernous sinus thrombosis secondary to left sphenoiditis. The patient was referred to the otolaryngology team. After an urgent endoscopic sphenoidotomy and medical treatment, all symptoms and signs improved dramatically. CONCLUSIONS: Sphenoiditis can lead to contralateral cavernous sinus thrombosis. Urgent surgical sphenoidotomy, with appropriate medical treatment, can be successful in this life-threatening complication. PMID- 20202276 TI - Cochlear implant patients' speech understanding in background noise: effect of mismatch between electrode assigned frequencies and perceived pitch. AB - OBJECTIVE: To assess the electrode pitch function in a series of adults with postlingually implanted cochlear implants and with contralateral residual hearing, in order to investigate the correlation between the degree of frequency map mismatch and the subjects' speech understanding in quiet and noisy conditions. DESIGN: Case series. SUBJECTS: Seven postlingually deafened adults with cochlear implants, all with detectable contralateral residual hearing. Subjects' electrode pitch function was assessed by means of a pitch-matching test, in which they were asked to match an acoustic pitch (pure tones delivered to the non-implanted ear by an audiometer) to a perceived 'pitch' elicited by stimulation of the cochlear implant electrodes. A mismatch score was calculated for each subject. Speech recognition was tested using lists of sentences presented in quiet conditions and at +10, 0 and 5 dB HL signal-to-noise ratio levels (i.e. noise 10 dB HL lower than signal, noise as loud as signal and noise 5 dB HL higher than signal, respectively). Correlations were assessed using a linear regression model, with significance set at p < 0.05. RESULTS: All patients presented some degree of mismatch between the acoustic frequencies assigned to their implant electrodes and the pitch elicited by stimulation of the same electrode, with high between-individual variability. A significant correlation (p < 0.005) was found between mismatch and speech recognition scores at +10 and 0 dB HL signal-to-noise ratio levels (r2 = 0.91 and 0.89, respectively). CONCLUSION: The mismatch between frequencies allocated to electrodes and the pitch perceived on stimulation of the same electrodes could partially account for our subjects' difficulties with speech understanding in noisy conditions. We suggest that these subjects could benefit from mismatch correction, through a procedure allowing individualised reallocation of frequency bands to electrodes. PMID- 20202277 TI - The ongoing dilemma of residual cholesteatoma detection: are current magnetic resonance imaging techniques good enough? AB - INTRODUCTION: There is a clear clinical need to reliably detect residual cholesteatoma after canal wall up mastoid surgery. Ideally, this would be achieved through non-invasive radiological means rather than second-look surgery, thus preventing morbidity in those patients in whom no residual disease is found. CASE REPORT: We describe a case in which non-echo-planar, diffusion-weighted magnetic resonance imaging sequences were used pre-operatively, and compared with subsequent surgical findings. This case highlights both the potential of this increasingly popular magnetic resonance technique and also its current limitations. DISCUSSION: Various magnetic resonance sequencing types have been employed to try to reliably detect residual cholesteatoma, each with varying success. Non-echo-planar, fast-spin echo, diffusion-weighted sequences currently appear to be the most reliable at detecting even the smallest pearl of cholesteatoma, down to 2 mm in diameter. In our unit, a propeller, diffusion weighted image sequence is employed on a GE Signa scanner. However, both this case study and other reports show that the accuracy of the technique is not 100 per cent. This begs the question of how much one can rely on the findings of such techniques when deciding whether second-look surgery is indicated. Scan-negative patients will require continued follow up as, at the time of imaging, residual disease may not have reached a detectable size. PMID- 20202278 TI - Management of obesity in Scotland: development of the latest evidence-based recommendations. AB - The problem of obesity in Scotland has reached epidemic proportions and this reality is recognised at Scottish Government level. The financial impact of treating obesity and obesity-related disease is substantial and in Scotland the cost was estimated at pound171 x 10(6) in 2001 but only a small proportion of this estimate included weight-loss interventions. The Scottish Intercollegiate Guidelines Network (SIGN) define clinical guidelines as 'systematically developed statements to help practitioner and patient decisions' that 'provide recommendations for effective practice in the management of clinical conditions where variations in practice are known to occur and where effective care may be known not to occur'. The evidence base for successful interventions has progressed since the publication by SIGN of Obesity in Scotland: Integrating Prevention with Weight Management in 1996 and Management of Obesity in Children and Young People in 2003. In 2007 SIGN commissioned a review of these two publications. In 2006 the National Institute for Health and Clinical Excellence (NICE) published a comprehensive obesity guideline and to avoid duplication of effort SIGN used the ADAPTE guideline adaptation framework to utilise and update evidence tables produced by NICE (where appropriate) as a basis for considered judgement. The new SIGN guideline is due for publication in 2010 and addresses children, young people (<18 years old) and adults. It will provide evidence-based recommendations on primary prevention of obesity (defined as intervention when individuals are at a healthy weight and/or overweight to prevent or delay the onset of obesity) within the clinical setting and treatment by lifestyle measures, drugs and surgery. PMID- 20202279 TI - Nutritional developmental epigenomics: immediate and long-lasting effects. AB - The phenotype of an individual is the result of complex interactions between genome, epigenome and current, past and ancestral environment leading to a lifelong remodelling of the epigenomes. The genetic information expression contained in the genome is controlled by labile chromatin-associated epigenetic marks. Epigenetic misprogramming during development is widely thought to have a persistent effect on the health of the offspring and may even be transmitted to the next generation. The epigenome serves as an interface between the environment and the genome. Dietary factors, including folate involved in C1 metabolism, and other social and lifestyle exposures have a profound effect on many aspects of health including ageing and do so, at least partly, through interactions with the genome, which result in altered gene expression with consequences for cell function and health throughout the life course. Depending on the nature and intensity of the environmental insult, the critical spatiotemporal windows and developmental or lifelong processes involved, epigenetic alterations can lead to permanent changes in tissue and organ structure and function or to phenotypic changes that can (or cannot) be reversed using appropriate epigenetic tools. Moreover, the flexibility of epigenetic marks may make it possible for environmental, nutritional and hormonal factors or endocrine disruptors to alter, during a particular spatiotemporal window in a sex-specific manner, the sex specific methylation or demethylation of specific CpG and/or histone modifications underlying sex-specific expression of a substantial proportion of genes. Moreover, genetic factors, the environment and stochastic events change the epigenetic landscape during the lifetime of an individual. Epigenetic alterations leading to gene expression dysregulation accumulate during ageing and are important in tumorigenesis and age-related diseases. Several encouraging trials suggest that prevention and therapy of age- and lifestyle-related diseases by individualised tailoring to optimal epigenetic diets or drugs are conceivable. However, these interventions will require intense efforts to unravel the complexity of these epigenetic, genetic and environment interactions and to evaluate their potential reversibility with minimal side effects. PMID- 20202280 TI - Nutrition, intestinal defence and the microbiome. AB - The interaction between nutrition and infection was the subject of important work by several groups in the 1960s. The explosion of knowledge in immunology, including innate immunity, has led to increased understanding of the impact of nutrition on host defence, but much more work needs to be done in this area. In the last decade an increasing volume of work has opened up the previously obscure world of human endogenous flora. This work suggests that the microbiome, the total genetic pool of the microbiota, contributes to the already complex interaction between nutrition and infectious disease. The established concept that nutritional status, host defence and infection all impact on each other now has to be expanded into a multiple interaction, with the microbiota interacting with all three other elements. There is good evidence that the microbiome programmes host defence and drives a metabolome that impacts on energy balance, and indeed on some micronutrients. In turn, host defence shapes the microbiome, and nutritional status, particularly micronutrient status, helps determine several elements of host defence. While interventions in this area are in their infancy, the understanding of interactions that already have an enormous impact on global health is now at a threshold. The present review explores the evidence for these interactions with a view to putting potential interventions into the context of a conceptual framework. PMID- 20202281 TI - Investigation of Pontiac-like illness in office workers during an outbreak of Legionnaires' disease, 2008. AB - In July 2008, office workers in Dublin complained of influenza-like illness preceding and interspersing two cases of notified Legionnaires' disease. Legionella pneumophila serogroup 1 was identified in both cooling towers supplying the office. A retrospective cohort study was undertaken to investigate possible Pontiac fever (PF). Forty-seven employees (23%) met the clinical case definition for PF but confirmatory testing was negative. Exposure to the smoking area situated beside the cooling towers was associated with an increased risk of PF (RR 2.4, 95% CI 1.5-3.8). The diagnosis of PF should be considered when many persons exposed to a possible reservoir of Legionella spp. present with flu-like symptoms. More sensitive microbiological tests would allow better confirmation and more comprehensive reporting of PF. Early detection is vital to prevent potentially severe illness and outbreaks of PF or Legionnaires' disease. PMID- 20202282 TI - Evaluation of VcA VNTR as a strain-typing and phylogeny study method of Vibrio cholerae strains. AB - This study attempted to examine the relatedness between RAPD-PCR, PFGE and VcA VNTR results with those of conventional phage typing of V. cholerae strains and to evaluate VcA VNTR as an indispensable molecular-typing tool that accomplishes the urgent need for effective epidemiological surveillance. All the O1 El Tor strains were predominantly clustered into phage type T27 with the new phage typing scheme. Using RAPD-PCR, a total of 69 O1 El Tor strains were grouped under 16 different electrophoretic patterns. A total of 33 pulsotypes were identified in these strains by PFGE. VcA VNTR revealed high VcA polymorphism in all V. cholerae strains incorporated in this study. Our results underline the considerable potential of VcA VNTR analysis as a tool for molecular typing of V. cholerae. PMID- 20202283 TI - Molecular characterization of Staphylococcus aureus in Lebanon. AB - Staphylococcus aureus is an important human pathogen and is a growing public health concern. In this study, 130 S. aureus, 93 methicillin-resistant S. aureus (MRSA) and 37 methicillin-sensitive S. aureus (MSSA), clinical isolates recovered from Lebanon were typed by protein A gene (spa) sequencing and multi-locus sequence typing (MLST). Forty-eight different spa types were identified and clustered into 30 different groups. MLST revealed 10 sequence types (STs) among the isolates. There were eight major MRSA clones defined as isolates with the same ST and the same SCCmec type. The majority of the PVL-positive isolates (53%) were ST80-MRSA-IVc. Systematic surveillance of both hospital and community isolates in Lebanon together with measures designed to limit the spread are required. PMID- 20202284 TI - Community-associated methicillin-resistant Staphylococcus aureus is prevalent in wounds of community-based injection drug users. AB - Injection drug users (IDUs) have an elevated risk for carriage of Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA). Cutaneous injection related infections are common in IDUs but detailed studies are few. Based on a subsample of 218 individuals from a community-recruited cohort of IDUs at a supervised injection facility, we investigated the microbiology and related antibiotic susceptibility profiles of isolates from 59 wounds. Twenty-seven percent of subjects had at least one wound and 25 (43%) were culture positive for S. aureus alone [14 MRSA and 11 (19%) methicillin-susceptible (MSSA) isolates]. Sixteen of 18 MRSA isolates were classified as community associated (CA) by the presence of genes encoding for PVL. MRSA and MSSA occurred in mixed infection with other organisms on three and six occasions, respectively. All CA-MRSA isolates were susceptible to tetracycline, vancomycin and linezolid but only 13% were susceptible to clindamycin compared to 63% of MSSA isolates. The frequency of CA-MRSA is a cause for concern in wound infection in the IDU setting. PMID- 20202285 TI - Viral hepatitis B, C and HIV infection in Croatian prisons. AB - Incarcerated persons comprise about 0.4% of the Croatian population, of whom 25 30% misuse drugs. We attempted to determine the structure of the prison population, prevalence of HBV, HCV, HIV markers, co-infections with HBV, HCV and HIV and acute HBV, HCV and HIV infection. In total, 25.9% of prisoners were positive for some markers for viral hepatitis (HBV 11.3%, HCV 8.3%, HBV/HCV 6.3%). Prevalence of HBV infection in intravenous drug users (IDUs) was 26.2% (highly promiscuous group 20.4%, individuals with psychiatric diseases and personality disorders 16.0%). HCV infection in IDUs was 52.0% and 4.9% in the highly promiscuous group. HBV/HCV co-infection was registered in 34.9% of prisoners positive for HBV markers (203/582). Acute HBV infection was detected in 0.5%, and HCV in 1.2%. Only 0.15% (5/3348) of prisoners were anti-HIV positive. It appears that individuals with psychiatric diseases and personality disorders could be an additional risk population for these viral infections. PMID- 20202286 TI - Spatio-temporal epidemiology of Campylobacter jejuni enteritis, in an area of Northwest England, 2000-2002. AB - A total of 969 isolates of Campylobacter jejuni originating in the Preston, Lancashire postcode district over a 3-year period were characterized using multi locus sequence typing. Recently developed statistical methods and a genetic model were used to investigate temporal, spatial, spatio-temporal and genetic variation in human C. jejuni infections. The analysis of the data showed statistically significant seasonal variation, spatial clustering, small-scale spatio-temporal clustering and spatio-temporal interaction in the overall pattern of incidence, and spatial segregation in cases classified according to their most likely species-of-origin. PMID- 20202287 TI - The development of oral fluid-based diagnostics and applications in veterinary medicine. AB - The purpose of this review was to discuss the history of the development and implementation of oral fluid diagnostics for infectious diseases of humans and domestic animals. The use of oral fluid for the assessment of health and diagnosis of disease in humans and animals has a surprisingly long history. As early as 1909, Pollaci and Ceraulo reported sensitive and specific agglutination of 'Micrococcus melitensis' (Brucella melitensis) by oral fluid from patients diagnosed with Malta Fever. A 1986 report of the detection of antibodies against human immunodeficiency virus (HIV) in oral fluid from patients with acquired immunodeficiency syndrome (AIDS) marked the start of a remarkably rapid series of developments in oral fluid-based assays. Cumulatively, the literature strongly supports implementation of oral fluid-based diagnostics in veterinary diagnostic medicine. Pathogen-specific IgA, IgM and IgG antibodies have all been demonstrated in oral fluid collected from diverse domestic animal species in response to infection. A variety of infectious agents, both local and systemic, are shed in oral fluid, including some of the most economically significant pathogens of production animals (e.g. foot-and-mouth disease virus, classical swine fever virus and porcine reproductive and respiratory syndrome virus) Ultimately, point-of-care rapid assays (i.e. cow-side, sow-side or pen-side tests) and access to real-time infectious disease data will revolutionize our delivery of health management services. PMID- 20202288 TI - Peripheral inflammation augments gap junction-mediated coupling among satellite glial cells in mouse sympathetic ganglia. AB - Intercellular coupling by gap junctions is one of the main features of glial cells, but very little is known about this aspect of satellite glial cells (SGCs) in sympathetic ganglia. We used the dye coupling method to address this question in both a prevertebral ganglion (superior mesenteric) and a paravertebral ganglion (superior cervical) of mice. We found that in control ganglia, the incidence of dye coupling among SGCs that form the envelope around a given neuron was 10-20%, and coupling between SGCs around different envelopes was rare (1.5 3%). The dye injections also provided novel information on the structure of SGCs. Following peripheral inflammation, both types of coupling were increased, but most striking was the augmentation of coupling between SGCs forming envelopes around different neurons, which rose by 8-14.6-fold. This effect appeared to be non-systemic, and was blocked by the gap junction blocker carbenoxolone. These changes in SGCs may affect signal transmission and processing in sympathetic ganglia. PMID- 20202289 TI - The input ambiguity hypothesis and case blindness: an account of cross-linguistic and intra-linguistic differences in case errors. AB - English-acquiring children frequently make pronoun case errors, while German acquiring children rarely do. Nonetheless, German-acquiring children frequently make article case errors. It is proposed that when child-directed speech contains a high percentage of case-ambiguous forms, case errors are common in child language; when percentages are low, case errors are rare. Input to English and German children was analyzed for percentage of case-ambiguous personal pronouns on adult tiers of corpora from 24 English-acquiring and 24 German-acquiring children. Also analyzed for German was the percentage of case-ambiguous articles. Case-ambiguous pronouns averaged 63.3% in English, compared with 7.6% in German. The percentage of case-ambiguous articles in German was 77.0%. These percentages align with the children's errors reported in the literature. It appears children may be sensitive to levels of ambiguity such that low ambiguity may aid error free acquisition, while high ambiguity may blind children to case distinctions, resulting in errors. PMID- 20202290 TI - Dietary fat modifications and blood pressure in subjects with the metabolic syndrome in the LIPGENE dietary intervention study. AB - Hypertension is a key feature of the metabolic syndrome. Lifestyle and dietary changes may affect blood pressure (BP), but the knowledge of the effects of dietary fat modification in subjects with the metabolic syndrome is limited. The objective of the present study was to investigate the effect of an isoenergetic change in the quantity and quality of dietary fat on BP in subjects with the metabolic syndrome. In a 12-week European multi-centre, parallel, randomised controlled dietary intervention trial (LIPGENE), 486 subjects were assigned to one of the four diets distinct in fat quantity and quality: two high-fat diets rich in saturated fat or monounsaturated fat and two low-fat, high-complex carbohydrate diets with or without 1.2 g/d of very long-chain n-3 PUFA supplementation. There were no overall differences in systolic BP (SBP), diastolic BP or pulse pressure (PP) between the dietary groups after the intervention. The high-fat diet rich in saturated fat had minor unfavourable effects on SBP and PP in males. PMID- 20202291 TI - Community-based management of multidrug-resistant tuberculosis in South Africa. PMID- 20202292 TI - What is the role of clinical trials for the treatment of tuberculosis and what are the alternatives? PMID- 20202293 TI - Multidrug-resistant tuberculosis: epidemiology, risk factors and case finding. AB - Although the multidrug-resistant tuberculosis (MDR-TB) epidemic is a very recent problem, many studies have attempted to understand it. We now have good estimates of the current burden (approximately 500 000 MDR-TB cases worldwide), and following the introduction of potential MDR-TB control strategies projections of these figures are being estimated. The projected trends in tuberculosis (TB) and MDR-TB incidence vary. Risk factors for resistance can be divided into two categories: 1) those facilitating the selection of resistance in the community and 2) the specific conditions that appear to increase some patients' vulnerability to resistance. The epidemiological situation varies greatly across countries, principally due to poor treatment practices and poor implementation of control programmes in the past-and even today, to a lesser degree-and recent data have suggested that national TB programmes that use existing drugs efficiently can postpone and even reverse the MDR-TB epidemic. Other factors that have also contributed to this epidemic situation are analysed in this article. The recognition of factors leading to the epidemic in some regions and the identification of populations at risk will assist in focusing case-finding efforts. From an individual perspective, treatment failures with first-line rifampicin-containing regimens and contacts of MDR-TB cases have the highest rates of resistance. Patients previously treated for TB and the other risk factors analysed in this article should be prioritised in case finding. PMID- 20202294 TI - The structure and function of the lung. PMID- 20202295 TI - Merrill Wallace Chase and cellular immunology. PMID- 20202296 TI - Predictors of uptake of human immunodeficiency virus testing by tuberculosis patients in Free State Province, South Africa. AB - SETTING: Two districts of the Free State Province in South Africa. OBJECTIVE: To determine the predictors of human immunodeficiency virus (HIV) test uptake by tuberculosis (TB) patients. DESIGN: A cross-sectional survey was conducted among 600 TB patients in 61 primary health care facilities. Probability proportional-to size sampling was used to determine the number of patients recruited at each facility. Structured exit interviews were conducted with convenience samples of patients at these facilities. Descriptive and logistic regression analyses were performed on the data. RESULTS: The average age of the recruited TB patients was 38.4 years. The majority were female (n = 310, 51.7%), unmarried (n = 439, 73.3%), unemployed (n = 513, 85.5%) and had undertaken HIV testing (n = 405, 67.5%). In multivariate analysis, having received information on the relationship between TB and HIV (OR 5.4, 95%CI 3.1-9.5) was the strongest predictor of HIV test uptake among unmarried patients. Other associated factors included knowing/having lost someone ill with HIV/AIDS (acquired immune-deficiency syndrome; OR 3.6, 95%CI 2.2-5.8), female sex (OR 2.3, 95%CI 1.4-3.7), unemployment (OR 2.2, 95%CI 1.2-4.1) and undergoing retreatment for TB (OR 2.0, 95%CI 1.2-3.2). CONCLUSION: HIV test scale-up efforts should aim to increase TB patients' awareness of the relationship between TB and HIV/AIDS and consider the impact of socio-demographic factors. PMID- 20202297 TI - Changing prevalence of tuberculosis infection with increasing age in high-burden townships in South Africa. AB - SETTING: Crowded townships of Cape Town, South Africa, where human immunodeficiency virus (HIV) prevalence and tuberculosis (TB) notification rates are among the highest in the world. OBJECTIVES: To determine age-specific prevalence rates of latent tuberculosis infection (LTBI) among HIV-negative individuals, and the annual risk and force of infection during childhood and adolescence. DESIGN: A cross-sectional survey using a standardised tuberculin skin test (TST) in HIV-negative individuals aged 5-40 years. A TST diameter of > or =10 mm was defined as indicative of LTBI. RESULTS: Among 1061 individuals, only 4.7% had low-grade TST responses of 1-9 mm. However, the proportions of individuals with TST > or =10 mm increased from 28.0% in the 5-10 year age stratum to 88.0% in the 31-35 year age stratum. The mean annual risk of infection was 3.9% up to 5 years of age. The estimated force of infection (the rate of acquisition of LTBI among the residual pool of non-infected individuals) increased throughout childhood to a maximum of 7.9% per year at age 15 years. CONCLUSIONS: Extremely high rates of infection in childhood and adolescence result in very high LTBI prevalence rates in young adults who are most at risk of acquiring HIV infection. This may be an important factor fuelling the high rates of HIV-associated TB in southern Africa. PMID- 20202298 TI - High treatment failure and default rates for patients with multidrug-resistant tuberculosis in KwaZulu-Natal, South Africa, 2000-2003. AB - SETTING: Multidrug-resistant tuberculosis (MDR-TB) has emerged as a significant public health threat in South Africa. OBJECTIVE: To describe treatment outcomes and determine risk factors associated with unfavorable outcomes among MDR-TB patients admitted to the provincial TB referral hospital in KwaZulu-Natal Province, South Africa. DESIGN: Retrospective observational study of MDR-TB patients admitted from 2000 to 2003. RESULTS: Of 1209 MDR-TB patients with documented treatment outcomes, 491 (41%) were cured, 35 (3%) completed treatment, 208 (17%) failed treatment, 223 (18%) died and 252 (21%) defaulted. Of the total number of patients with known human immunodeficiency virus (HIV) status, 52% were HIV-infected. Treatment failure, death and default each differed in their risk factors. Greater baseline resistance (aOR 2.3-3.0), prior TB (aOR 1.7), and diagnosis in 2001, 2002 or 2003 (aOR 1.9-2.3) were independent risk factors for treatment failure. HIV co-infection was a risk factor for death (aOR 5.6), and both HIV (aOR 2.0) and male sex (aOR 1.9) were risk factors for treatment default. CONCLUSION: MDR-TB treatment outcomes in KwaZulu-Natal were substantially worse than those published from other MDR-TB cohorts. Interventions such as concurrent antiretroviral therapy and decentralized MDR-TB treatment should be considered to improve MDR-TB outcomes in this high HIV prevalence setting. PMID- 20202299 TI - Community-based treatment for multidrug-resistant tuberculosis in rural KwaZulu Natal, South Africa. AB - SETTING: Hlabisa health sub-district, KwaZulu-Natal, South Africa. OBJECTIVE: To describe the establishment of a community-based multidrug-resistant tuberculosis (MDR-TB) treatment programme embedded in the district TB control programme and to evaluate whether early outcomes are comparable to those in the traditional hospital-based model of care. DESIGN: Cases who initiated community-based MDR-TB treatment (CM) between March and December 2008 were compared with patients who initiated MDR-TB treatment under the traditional hospital-based model of care (TM) between January 2001 and February 2008. Time to initiation of treatment and time to sputum smear and culture conversion were compared for the two groups in Kaplan-Meier survival curves using the Mantel-Cox log-rank test. RESULTS: Overall, 50 CM cases and 57 TM cases were included; 39 of the 50 CM cases (78.0%) were human immunodeficiency virus positive. The median time to initiation of treatment was 84 days for CM and 106.5 days for TM (P = 0.002). Median time to sputum smear conversion was shorter for CM than TM (59 vs. 92 days, P = 0.055), as was time to sputum culture conversion (85 vs. 119 days, P = 0.002). CONCLUSION: Community-based treatment for MDR-TB can be implemented within the existing TB control programme in rural South Africa and should be scaled up where resources allow. PMID- 20202300 TI - Recent nosocomial transmission and genotypes of multidrug-resistant Mycobacterium tuberculosis. AB - SETTING: Multidrug-resistant tuberculosis (MDR-TB) is a serious health problem in Eastern European countries, including Latvia. OBJECTIVE: To investigate the proportion of tuberculosis, including MDR-TB cases, attributable to recent transmission and risk factors associated with clustering. DESIGN: Retrospective nested case-control study. The data set incorporated a wide spectrum of social features, as well as genotypes of Mycobacterium tuberculosis isolates determined by insertion sequence 6110 restriction fragment length polymorphism analysis of PvuII cleaved genomic DNA and spoligotyping. RESULTS: In comparison with non clustered M. tuberculosis, the Beijing genotype (OR 12.15) and multidrug resistance (OR 5.61, P < 0.01) were associated with clustering. In comparison with clustered drug-susceptible M. tuberculosis, clustering of MDR M. tuberculosis was associated with Beijing genotype (OR 41.67), previous hospitalisation (OR 18.33) and previous TB treatment (OR 17.68, P < 0.05). Direct epidemiological links in hospitals were found for almost one third (32%) of MDR Beijing cases. CONCLUSIONS: MDR cases were more likely to be found in clusters than drug-susceptible cases (74.0% vs. 33.6%). Recent nosocomial transmission of MDR-TB is an important risk factor for the spread of multiresistance, and is associated with the Beijing genotype. Special attention should be paid to infection control measures in hospitals and ambulatory treatment should be enforced. PMID- 20202301 TI - Are the statistical data from Benin's National Tuberculosis Programme reliable? AB - SETTING: The National Tuberculosis Programme (NTP) of Benin, West Africa. OBJECTIVE: To verify the accuracy of the data published by the NTP in terms of notified cases and treatment results. DESIGN: Purposeful selection of nine basic management units (BMUs) that had declared zero tuberculosis (TB) patients lost to follow-up in the first three quarters of 2006. Retrospective onsite survey by independent teams based on the documents kept at the BMUs, on the data transmitted to and compiled at the central level and on home interviews with patients who had been declared treatment successes. RESULTS: Of the 446 cases evaluated, there was excellent agreement between the TB register and the TB treatment card, between the TB register and the quarterly reports and between the TB register and the laboratory register. Home interviews with 32 patients all confirmed the information contained in the treatment cards and the TB register. CONCLUSION: The results published by the NTP of Benin are remarkably reliable. PMID- 20202302 TI - Socio-economic factors affecting the success of tuberculosis treatment in six counties of Shandong Province, China. AB - SETTING: Tuberculosis (TB) control in rural China is of high priority in health policy making. OBJECTIVE: To investigate treatment success among rural TB patients and the determinants of patient and case management and to explore the current status of DOTS implementation in rural China. METHODS: A patient-based study was conducted in six counties of Shandong Province, China. Study sites were selected by multi-stage random sampling. Subjects were rural smear-positive pulmonary TB patients registered with the county TB dispensaries at study sites who completed treatment during the period October 2006 to September 2007. RESULTS: This study observed a success rate of 74.5% among 501 participants. The cure rate, of 50.5%, was much lower than the national level. There was a difference in treatment success rates across counties. Factors independently affecting treatment success were patient income, study site, and home visits and supervision by town and village health workers. CONCLUSIONS: Enhancing financial resources for TB control and effective involvement of human resources are crucial to achieving success with the DOTS strategy in rural China. PMID- 20202303 TI - Recurrent tuberculosis in Denmark: relapse vs. re-infection. AB - SETTING: Denmark, a country with a low-incidence of tuberculosis (TB). OBJECTIVE: To analyse the proportion of relapse vs. re-infection and to compare selected characteristics between the two subgroups. DESIGN: A population-based cohort study. All 4154 Mycobacterium tuberculosis isolates from patients in Denmark genotyped by insertion sequence 6110 restriction fragment length polymorphism were followed for recurrent TB over 13.5 years. Recurrent cases were classified as relapse or re-infection by genotype patterns in initial and serial disease episodes. RESULTS: Recurrent TB was found in 73 (1.8%) cases. Identical M. tuberculosis genotypes in initial and serial episodes were found in 54 (1.3%), indicating relapse, whereas different genotypes, representing re-infection, were found in 19 (0.5%) cases. Cavitary TB in the initial episode was significantly associated with relapse (OR 4.6, 95%CI 1.1-26.9) compared to re-infection. CONCLUSION: The rate of recurrent TB is low in Denmark. Comparing selected characteristics between the relapse and re-infection subgroups revealed that only the presence of cavitary disease was associated with relapse. Although recurrent TB was rarely due to re-infection, the risk of re-infection increased with time. PMID- 20202304 TI - Predictors and mortality associated with treatment default in pulmonary tuberculosis. AB - OBJECTIVE: To identify risk factors for default from pulmonary tuberculosis (TB) treatment and to assess mortality associated with default in Estonia. DESIGN: All patients with culture-confirmed pulmonary TB who started treatment during 2003 2005 were included in a retrospective cohort study. RESULTS: In 1107 eligible patients, the treatment success rate was 81.5% and the default rate 9.4% (respectively 60.4% and 17.0% in multidrug-resistant TB [MDR-TB]). Independent predictors of treatment default were alcohol abuse (OR 3.22, 95%CI 1.93-5.38), unemployment (OR 3.05, 95%CI 1.84-5.03), MDR-TB (OR 2.17, 95%CI 1.35-3.50), urban residence (OR 1.85, 95%CI 1.00-3.42) and previous incarceration (OR 1.78, 95%CI 1.05-3.03). Of the defaulters, 29.4% died during follow-up (median survival 342.0 days). Cox regression analysis revealed that unemployment was associated with all cause and TB-related mortality among defaulters (respectively HR 4.58, 95%CI 1.05 20.1 and HR 11.2, 95%CI 1.58-80.2). HIV infection (HR 51.2, 95%CI 6.06-432), sputum smear positivity (HR 9.59, 95%CI 1.79-51.4), MDR-TB (HR 8.56, 95%CI 1.81 40.4) and previous TB (HR 5.15, 95%CI 1.64-16.2) were predictors of TB-related mortality. CONCLUSION: The main risk factors for treatment default can be influenced. Interventions to reduce default should therefore concentrate on socially disadvantaged patients and prevention of alcohol abuse, with special attention given to MDR-TB patients. PMID- 20202305 TI - Tuberculosis testing in correctional officers: a national random survey of jails in the United States. AB - SETTING: The correctional system in the United States is large and growing. The Centers for Disease Control and Prevention recommend baseline and annual testing of employees in correctional facilities for latent tuberculosis infection (LTBI). OBJECTIVE: To describe the extent of and factors associated with LTBI testing practices for jail correctional officers. DESIGN: A national survey of 1760 randomly selected jails was conducted. We used multivariable logistic regression models to examine factors associated with testing officers in a guideline concordant manner and having a written policy. RESULTS: A total of 1174 (67%) surveys were returned. Only 52% of jails had a written policy on LTBI testing of officers, and 51% screened officers at least annually (guideline concordance). Large jails (OR 2.41, 95%CI 1.67-3.49) and jails in states with a high tuberculosis incidence (OR 1.67, 95%CI 1.17-2.38) and in the Midwest (OR 1.58, 95%CI 1.07-2.33) were more likely to screen in a guideline-concordant manner. CONCLUSION: Screening for LTBI among correctional officers in the United States was inconsistent. Strategies to improve LTBI testing among correctional officers are needed. PMID- 20202306 TI - Cost-effectiveness of QuantiFERON-TB test vs. tuberculin skin test in the diagnosis of latent tuberculosis infection. AB - OBJECTIVE: To evaluate the cost-effectiveness of the tuberculin skin test (TST), the QuantiFERON-TB Gold test (QFT) and a combination of TST and QFT (TST+QFT) for diagnosing latent tuberculosis infection (LTBI) in France in a bacille Calmette Guerin (BCG) vaccinated population. METHODS: A decision analysis model evaluated three strategies among simulated adults in close contact with tuberculosis (TB). We calculated direct lifetime medical costs, life expectancies and incremental cost-effectiveness ratios (ICERs). RESULTS: The discounted direct medical costs of care per patient of no testing, TST, QFT and TST+QFT were respectively euro417, euro476, euro443 and euro435, while discounted life expectancies were respectively 25.030, 25.071, 25.073 and 25.062 years. TST had higher costs and lower efficacy than QFT; TST+QFT was associated with an ICER of euro560 per year of life gained (YLG) compared to no testing, and QFT was associated with an ICER of euro730/YLG compared to TST+QFT. The only scenario where QFT was associated with an ICER of >euro75 000/YLG was when the prevalence of LTBI around TB was low (<5%) and TST specificity high (>90%). CONCLUSIONS: In France, for the diagnosis of LTBI after close contact with TB, the TST is more expensive and less effective than QFT. Although it is more expensive, QFT is more effective and cost-effective than TST+QFT under a wide range of realistic test performance scenarios. PMID- 20202307 TI - Diagnostic accuracy of the microscopic observation drug susceptibility assay: a pilot study from India. AB - SETTING: The microscopic observation drug susceptibility (MODS) assay is a rapid, sensitive, low-cost liquid culture technique. OBJECTIVE: To establish the accuracy of MODS for the detection of active pulmonary tuberculosis (TB), and to document the costs and challenges of setting up this assay in a low-income setting. DESIGN: Prospective blinded pilot study of 200 adult TB suspects at a tertiary referral hospital in India. Reference standard included culture (Lowenstein-Jensen and automated liquid culture) and clinical diagnosis. RESULTS: Patients were mostly male (n = 122, 61.1%) and out-patients (n = 184, 92.0%), with a mean age of 40.4 years (standard deviation 16.2). Seventeen (8.5%) were human immunodeficiency virus infected and 47 (23.5%) were reference culture positive. Compared to reference culture, MODS was 78.9% sensitive (95%CI 62.2 90.0) and 96.7% specific (95%CI 92.0-98.8). Clinical assessment suggested that MODS was false-negative in 3/8 reference culture-positive MODS-negatives and true positive in 4/6 reference culture-negative MODS-positives. MODS was faster than solid (P < 0.001) and liquid culture (P = 0.088), and cheaper than both. CONCLUSION: MODS may be a good alternative to automated liquid culture, but there were several challenges in setting up the assay. Prior training and validation, setup costs and inability to rule out cross-contamination need to be taken into account before the test can be established. PMID- 20202308 TI - Species-specific antigenic Mycobacterium tuberculosis proteins tested by delayed type hypersensitivity response. AB - OBJECTIVE: To investigate the diagnostic potential of four Mycobacterium tuberculosis antigens encoded by M. tuberculosis-specific region of difference 1 (RD1) region genes (PE35, PPE68, culture filtrate protein 10 [CFP-10], early secreted antigenic target-6 [ESAT-6]) and RD9 region gene Rv3619c, for delayed type hypersensitivity (DTH) responses in guinea pigs. DESIGN: Recombinant M. tuberculosis proteins were expressed in Escherichia coli and purified to homogeneity by affinity chromatography. Guinea pigs were injected with heat killed M. tuberculosis and live bacille Calmette-Guerin (BCG), M. avium and M. vaccae. Two to four weeks later, the guinea pigs were challenged intradermally in the flank region with mycobacterial sonicates and purified recombinant proteins. The DTH responses were quantitated by measuring erythema at injection sites after 24 h. RESULTS: All mycobacterial sonicates induced positive DTH responses in guinea pigs injected with M. tuberculosis, M. bovis BCG, M. avium and M. vaccae. Purified proteins PE35, PPE68, CFP10 and ESAT-6 elicited positive DTH responses in the M. tuberculosis-injected group but not in BCG-, M. avium- and M. vaccae injected guinea pigs, whereas Rv3619c elicited positive DTH responses in the M. tuberculosis- and BCG-injected groups, but not in the M. avium- and M. vaccae injected guinea pigs. CONCLUSION: The recombinant RD1 antigens induced M. tuberculosis-specific DTH responses. These antigens may therefore be useful in the diagnosis of tuberculosis. PMID- 20202309 TI - Macrolides versus quinolones in Legionella pneumonia: results from the Community Acquired Pneumonia Organization international study. AB - BACKGROUND: Data supporting a quinolone or a macrolide as preferred therapy for community-acquired pneumonia (CAP) due to Legionella pneumophila are not firmly established. Some literature suggests a benefit of quinolones over macrolides. OBJECTIVE: To compare time to clinical stability (TCS) and length of hospital stay (LOS) in patients with Legionella pneumonia who were treated with levofloxacin (LVX) compared to those treated with newer macrolides. DESIGN: An analysis of patients with Legionnaires' disease from the Community-Acquired Pneumonia Organization database was performed. Patients were diagnosed with CAP using radiographic and clinical criteria, while Legionella was detected by urinary antigen or sputum culture. All patients received a macrolide (azithromycin or clarithromycin) or LVX. TCS was defined as the time from hospital admission to candidacy for switch to oral therapy. RESULTS: A total of 39 patients were included for analysis. The mean TCS for the macrolide group was 5.1 days vs. 4.3 days for the LVX group (P = 0.43). The mean LOS for the macrolide group was 12.7 days vs. 8.9 days for the quinolone group (P = 0.10). CONCLUSION: LOS and TCS were not statistically different between the macrolide and the LVX groups in treating CAP due to Legionella, despite trends in both outcomes favoring LVX. PMID- 20202310 TI - Subjective global assessment of nutritional status of chronic obstructive pulmonary disease patients on admission. AB - BACKGROUND: Identifying chronic obstructive pulmonary disease (COPD) patients with malnutrition is important to prevent associated mortality due to poor pulmonary function. There is currently no consensus regarding the application of the subjective global assessment (SGA) tool in Indian patients. OBJECTIVE: To assess nutritional status using the SGA method in Indian COPD patients. METHODS: A total of 106 hospitalised patients with COPD were included (mean age 55.58 +/- 7.82, male/female = 92/14). Pulmonary function tests, anthropometric measurements and biochemical tests were conducted in all subjects. The association of SGA scores (A, B or C) and body mass index (BMI) groups with other biochemical parameters were tested for statistical significance. RESULTS: Of the 106 patients, 83% were malnourished (BMI < 20 kg/m(2)). According to SGA scores, 17.0% were well nourished, 59.5% were moderately malnourished and 23.5% were severely malnourished. SGA scores correlated positively with pulmonary function parameters and negatively with anthropometric parameters. However, there was no correlation for biochemical parameters. CONCLUSION: The SGA is a simple screening tool for the assessment of the nutritional status of COPD patients in India. PMID- 20202311 TI - Assessing allergic rhinitis in developing countries. AB - BACKGROUND: Allergic rhinitis (AR) affects 5% to 40% of the general population. In developing countries, AR is poorly documented and tracked due to a lack of appropriate diagnostic tools. OBJECTIVE: 1) To validate a questionnaire standardised in industrialised countries to ascertain AR, the Score For Allergic Rhinitis (SFAR), in developing countries; 2) to better understand AR prevalence previously reported from developing countries by comparing results from the SFAR and the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaires. METHODS: Six African countries were selected for their climates. In each country, 70 individuals with and 30 without nasal symptoms filled out the SFAR and the ISAAC questionnaires. Skin prick tests (SPTs) for allergens were performed by the physician if necessary. RESULTS: The SFAR presented a close match with the gold standard (the physician's diagnosis of AR backed up by SPT where necessary) in terms of various performance parameters. In particular, it showed high sensitivity (0.84) and specificity (0.81). Compared to the ISAAC questionnaire, the SFAR had greater sensitivity and equal specificity. CONCLUSIONS: In the absence of a medical visit, the SFAR is a useful standardised screening instrument for the collection of information needed for the identification of AR in developing countries. PMID- 20202313 TI - Who teaches what in teaching the present and future primary care workforce? PMID- 20202312 TI - Association between breastfeeding and allergic disorders in Japanese children. AB - SETTING: Data on the association between breastfeeding and allergies are conflicting. OBJECTIVE: To investigate the relationship between the duration and exclusivity of breastfeeding and the prevalence of wheeze, asthma and eczema in young Japanese children. DESIGN: Study subjects were 1957 children aged 3 years. Data on breastfeeding, allergic symptoms and potential confounders were collected using a questionnaire. Outcomes were defined according to the criteria of the International Study of Asthma and Allergies in Childhood. Adjustment was made for sex, number of siblings, household smoking, paternal and maternal history of asthma, atopic eczema and allergic rhinitis, and paternal and maternal educational levels. RESULTS: The prevalence values of symptoms of wheeze, asthma and eczema in the previous 12 months were respectively 22.1%, 8.9% and 17.3%. Exclusive breastfeeding for > or =4 months vs. <4 months was associated with a lower prevalence of asthma. The duration of breastfeeding, regardless of exclusivity, for > or =6 months tended to be associated with a lower prevalence of asthma. There was no appreciable association between breastfeeding and wheeze or eczema. CONCLUSIONS: Data from this study indicate that breastfeeding may be associated with a lower prevalence of asthma among young Japanese children. PMID- 20202314 TI - The United Kingdom Conference of Educational Advisers (UKCEA) workforce surveys. PMID- 20202315 TI - The importance of usability testing to allow e-learning to reach its potential for medical education. PMID- 20202316 TI - Using emotional intelligence to facilitate strengthened appraiser development. AB - This paper describes a new approach to developing strengthened medical appraiser skills prior to the introduction of medical revalidation. We describe how we extended previous skills-based models and competency checklists to produce a behavioural model of effective appraiser performance. Development centre (DC) methods were used to produce a one-day workshop to encourage appraisers to reflect on their current level of ability and to identify and address additional required skills through observation, practice and feedback. In describing the DC, we discuss the impact of using the concept of emotional intelligence (EI) to develop appraiser skills and improve self-awareness. This aimed to support appraisers to effectively influence appraisees' continual professional development (CPD) and review appraisee practice through audit, significant events and patient and colleague feedback, with the ultimate aim of improving patient care. Finally, we provide initial evaluation data for our DC approach. PMID- 20202317 TI - A survey of general practitioners' opinions and perceived competencies in teaching undergraduate psychiatry. AB - INTRODUCTION: There have been increasing numbers of suggestions that general practitioners (GPs) should be more involved in undergraduate teaching. This study looks at GPs' opinions regarding those best placed to deliver undergraduate psychiatry teaching and what areas of the curriculum GPs feel competent to teach. The study aims to inform decisions about the contribution of GPs to the delivery of undergraduate teaching in psychiatry. METHOD: A questionnaire asked GPs about teaching undergraduate psychiatry in both general and specialist areas. RESULTS: The response rate was 61%. Over a third of GPs felt competent to teach psychiatry to undergraduates in a general practice setting, and the vast majority thought psychiatry should be taught by a combination of GPs and psychiatrists. GPs felt least confident about teaching child psychiatry and addiction. CONCLUSIONS: Many GPs would like to be involved in teaching psychiatry and would welcome further training. The study suggests that there is capacity for increasing teaching in collaboration with GPs. PMID- 20202318 TI - A review of further training for GP appraisers in Scotland. AB - A one-day further intensive skills (FIS) course has been developed to provide additional training for existing general practitioner (GP) appraisers in Scotland. The course focuses on skills in developing the appraisee's personal development portfolio (PDP) and skills in responding to significant issues (with emotional content) presented by appraisees - both key areas for effective appraisals. The course is briefly described. An initial pilot of the course led to some changes being made to the content, as it was discovered that the inclusion of training on Summary Form completion in the pilot made the course too dense and distracted from the experiential elements of the training. Two subsequent course deliveries were evaluated by conducting semi-structured interviews with over 40% of the participants from these two courses. The main purpose of the evaluation was to discover to what extent the participants felt they had benefited from the training and whether they felt the training had led to any changes in their practice as appraisers. Secondary aims were to discover the acceptability of the use of video recording as a training technique and views regarding a reaccreditation process for appraisers. Key findings were that almost all participants found this training beneficial and judged it to have led to positive changes in their practice, as well as reassuring them that their skills were up to scratch. Some appraisers felt that it had encouraged a slightly more challenging approach. The acceptability of the use of video recording during the training, as a means of allowing participants to gain further benefit from the work undertaken after the course was finished, was tested. This technique received a mixed response, with opinion divided as to whether it added value. Opinion amongst the participants was also mixed regarding whether this training should contribute towards their reaccreditation as appraisers. However, a number of participants felt this could be a valid element in an appraiser reaccreditation process. PMID- 20202319 TI - Undergraduate medical student attitudes to the peer assessment of professional behaviours in two medical schools. AB - The objective of this study was to investigate medical school student views on the peer assessment of professional behaviours. Focus groups were held with students at two northern England medical schools which were using peer assessment. The study showed that preparing students to give and receive feedback was a key aspect in the successful delivery of peer assessment. Medical school students are generally positive about the peer assessment of professional behaviours. However, they expressed mixed views about anonymity and how information was to be used. The results imply that peer assessment could offer valuable feedback for formative learning. PMID- 20202320 TI - Acknowledging learning styles: a practical approach to planning and delivering teaching sessions. PMID- 20202321 TI - Practical tips and strategies for designing and implementing interprofessional curricula. PMID- 20202322 TI - How to . . . design an effective powerpoint presentation. PMID- 20202323 TI - Undergraduate learning: never mind the quality, feel the width! Medical student teaching in general practice. PMID- 20202324 TI - Occurrence of Campylobacter in commercially broken liquid egg in Japan. AB - Samples of unpasteurized liquid egg (whole egg, egg yolk, and egg white) and pasteurized liquid whole egg were collected from egg-breaking facilities in Japan and were tested for the presence of Campylobacter. Isolates recovered were tested for freeze-thaw response, sensitivity to antimicrobials, and heat resistance. Campylobacter was isolated from 27.9% of unpasteurized liquid whole egg samples and 36.0% of unpasteurized liquid egg yolk samples. No Campylobacter was isolated from unpasteurized liquid egg white or pasteurized liquid whole egg samples. The contamination levels of Campylobacter ranged from <3 to 240/100 ml. Freeze-thaw response was tested by freezing and thawing liquid whole egg and egg yolk to examine whether those conditions influenced the survival rate. It was shown that freezing and thawing reduced Campylobacter counts. Sensitivity to all antimicrobials used in this study was observed in 47.6% of the isolates. The most predominant antibiotic resistance profile was similar to that of isolates from chicken. D(55 degrees C)-values of 0.16 to 0.38 min and 0.47 to 0.84 min were determined for Campylobacter isolates in liquid whole egg and egg yolk, respectively. These values were lower than those reported for Salmonella. The very weak heat tolerance of Campylobacter indicated that it could be eliminated at the current legal pasteurization condition. There is no safety concern for commercially broken pasteurized liquid egg pertaining to Campylobacter contamination. PMID- 20202326 TI - Growth of Listeria spp. in shredded cabbage is enhanced by a mild heat treatment. AB - Mild thermal processing can enhance the shelf life of cut fruits and vegetables by delaying the onset of spoilage and preserving the organoleptic properties of shredded cabbage. However, food safety issues related to this process have not been fully investigated. Therefore, the survival and growth of Listeria spp. on cabbage treated in this manner was examined. Experimentally, 24 strains of Listeria spp. (including L. monocytogenes) were inoculated onto cut and intact cabbage tissues and stored at 5 degrees C. All strains on intact tissues exhibited a moderate decline in numbers (up to 1.0 log CFU/cm(2)) over the 28-day storage period. Conversely, cut tissue supported growth of most strains during the first 7 to 14 days of incubation with maximum increases of 1.2 log CFU/cm(2). Subsequently, the survival or growth on heat-treated (50 degrees C for 3 min) and untreated shredded cabbage of four L. monocytogenes and four nonpathogenic Listeria spp. strains were compared during storage for 21 days at 5 degrees C. Growth on untreated shred for all strains was similar to the results observed on cut tissue with a maximum increase of approximately 1.0 log CFU/g. However, in the heat-treated cabbage shred all strains displayed a rapid increase in growth (up to 2.5 log CFU/g) during the first 7 days of incubation, which may be indicative of the destruction of an endogenous growth-inhibiting compound within the cabbage. In conclusion, this study shows that mild thermal treatments of cut cabbage may promote pathogen growth if other inimical barriers are not implemented downstream of the thermal treatment. PMID- 20202325 TI - Fate of Escherichia coli O157:H7 and Salmonella on fresh and frozen cut pineapples. AB - Pineapples have been associated with outbreaks of Escherichia coli and Salmonella. Little is known about the behavior of E. coli O157:H7 and Salmonella on cut pineapple. The objectives of this study were to evaluate the fate of E. coli O157:H7 and Salmonella on fresh and frozen cut pineapples and the influence of acid adaptation on Salmonella survival on fresh cut pineapple at ambient storage (23 degrees C). Cut pineapples were spot inoculated with a four-strain cocktail of E. coli O157:H7 or a five-strain cocktail of Salmonella. Inoculated samples were air dried, placed in containers, and stored at 4, 12, 23, and -20 degrees C. Samples were stomached and then enumerated on nonselective and selective media at days 0, 1, 3, 5, 7, 10, 14, 21, and 28 (4 and 12 degrees C); 0, 1, 3, 5, and 7 (23 degrees C); and 0, 7, 14, 21, 28, 60, 90, 120, 150, and 180 (-20 degrees C). E. coli O157:H7 and Salmonella inoculated onto pineapple did not grow but survived for the shelf life at each temperature, with improved survival at lower temperatures. E. coli O157:H7 and Salmonella can survive on frozen cut pineapples for at least 180 days. Acid adaptation of Salmonella did not allow growth and did not increase survival. Fresh and frozen cut pineapples are potential vectors for E. coli O157:H7 and Salmonella transmission and preventive procedures should be implemented during production and postharvest processing. PMID- 20202327 TI - Survival and growth of Salmonella in salsa and related ingredients. AB - A large outbreak of Salmonella Saintpaul associated with raw jalapeno peppers, serrano peppers, and possibly tomatoes was reported in the United States in 2008. During the outbreak, two clusters of illness investigated among restaurant patrons were significantly associated with eating salsa. Experiments were performed to determine the survival and growth characteristics of Salmonella in salsa and related major ingredients, i.e., tomatoes, jalapeno peppers, and cilantro. Intact and chopped vegetables and different formulations of salsas were inoculated with a five-strain mixture of Salmonella and then stored at 4, 12, and 21 degrees C for up to 7 days. Salmonella populations were monitored during storage. Salmonella did not grow, but survived on intact tomatoes and jalapeno peppers, whereas significant growth at 12 and 21 degrees C was observed on intact cilantro. In general, growth of Salmonella occurred in all chopped vegetables when stored at 12 and 21 degrees C, with chopped jalapeno peppers being the most supportive of Salmonella growth. Regardless of differences in salsa formulation, no growth of Salmonella (initial inoculation ca. 3 log CFU/g) was observed in salsa held at 4 degrees C; however, rapid or gradual decreases in Salmonella populations were only observed in formulations that contained both fresh garlic and lime juice. Salmonella grew at 12 and 21 degrees C in salsas, except for those formulations that contained both fresh garlic and lime juice, in which salmonellae were rapidly or gradually inactivated, depending on salsa formulation. These results highlight the importance of preharvest pathogen contamination control of fresh produce and proper formulation and storage of salsa. PMID- 20202328 TI - Evaluation of antimicrobial resistance phenotypes for predicting multidrug resistant Salmonella recovered from retail meats and humans in the United States. AB - Although multidrug-resistant (MDR) non-Typhi Salmonella (NTS) strains are a concern in food production, determining resistance to multiple antimicrobial agents at slaughter or processing may be impractical. Single antimicrobial resistance results for predicting multidrug resistance are desirable. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value were used to determine each antimicrobial agent's ability to predict MDR phenotypes of human health significance: ACSSuT (resistance to at least ampicillin, chloramphenicol, streptomycin, sulfamethoxazole, tetracycline) in NTS isolates, and MDR-AmpC-SN (resistance to ACSSuT, additional resistance to amoxicillin-clavulanate and to ceftiofur, and decreased susceptibility [MIC >= 2 microg/ml] to ceftriaxone) in NTS serotype Newport. The U.S. National Antimicrobial Resistance Monitoring System determined MICs to 15 or more antimicrobial agents for 9,955 NTS isolates from humans from 1999 to 2004 and 689 NTS isolates from retail meat from 2002 to 2004. A total of 847 (8.5%) human and 26 (3.8%) retail NTS isolates were ACSSuT; 995 (10.0%) human and 16 (2.3%) retail isolates were serotype Newport. Among Salmonella Newport, 204 (20.5%) human and 9 (56.3%) retail isolates were MDR-AmpC-SN. Chloramphenicol resistance provided the highest PPVs for ACSSuT among human (90.5%; 95% confidence interval, 88.4 to 92.3) and retail NTS isolates (96.3%; 95% confidence interval, 81.0 to 99.9). Resistance to ceftiofur and to amoxicillin-clavulanate and decreased susceptibility to ceftriaxone provided the highest PPVs (97.1, 98.1, and 98.6%, respectively) for MDR-AmpC-SN from humans. High PPVs for these agents applied to retail meat MDR-AmpC-SN, but isolate numbers were lower. Variations in MIC results may complicate ceftriaxone's predictive utility. Selecting specific antimicrobial resistance offers practical alternatives for predicting MDR phenotypes. Chloramphenicol resistance works best for ACSSuT-NTS, and resistance to ceftiofur, amoxicillin-clavulanate, or chloramphenicol works best for MDR-AmpC SN. PMID- 20202329 TI - Probiotics down-regulate genes in Salmonella enterica serovar typhimurium pathogenicity islands 1 and 2. AB - Salmonella Typhimurium pathogenesis relies mainly on the expression of genes of two pathogenicity islands, Salmonella pathogenicity islands 1 and 2 (SPI1 and SPI2). Each island has its own pattern of expression and regulation. Success in suppression of the responsible key activator of each island would be an effective way of controlling Salmonella, especially with the emerging problem of antibiotic resistant strains. Probiotics have been shown to inhibit several foodborne pathogens, and their mode of action may partly involve down-regulation of virulence genes. To investigate whether probiotics played a role in the regulation of the pathogenicity islands SPI1 and SPI2 in Salmonella, two reporter strains were constructed in which the general regulator of SPI1, hilA, and the response regulator of SPI2, ssrB, were fused with luxCDABE genes. These constructs were used to screen the effect of probiotics on the expression of each gene. Molecules secreted by Bifidobacterium bifidum were able to down-regulate both genes. PMID- 20202330 TI - Inactivation of Escherichia coli O157:H7 in nonintact beefsteaks of different thicknesses cooked by pan broiling, double pan broiling, or roasting by using five types of cooking appliances. AB - This study compared thermal inactivation of Escherichia coli O157:H7 in nonintact beefsteaks of different thicknesses by different cooking methods and appliances. Coarsely ground beef was inoculated with rifampin-resistant E. coli O157:H7 (eight-strain composite, 6 to 7 log CFU/g) and then mixed with sodium chloride (0.45%) plus sodium tripolyphosphate (0.23%); the total water added was 10%. The meat was stuffed into bags (10-cm diameter), semifrozen (-20 degrees C, 6 h), and cut into 1.5-, 2.5-, and 4.0-cm-thick steaks. Samples were then individually vacuum packaged, frozen (-20 degrees C, 42 h), and tempered (4 degrees C, 2.5 h) before cooking. Partially thawed (-2 +/- 1 degrees C) steaks were pan broiled (Presto electric skillet and Sanyo grill), double pan broiled (George Foreman grill), or roasted (Oster toaster oven and Magic Chef standard kitchen oven) to a geometric center temperature of 65 degrees C. Extent of pathogen inactivation decreased in order of roasting (2.0 to 4.2 log CFU/g) > pan broiling (1.6 to 2.8 log CFU/g) >/= double pan broiling (1.1 to 2.3 log CFU/g). Cooking of 4.0-cm thick steaks required a longer time (19.8 to 65.0 min; variation was due to different cooking appliances), and caused greater reductions in counts (2.3 to 4.2 log CFU/g) than it did in thinner samples (1.1 to 2.9 log CFU/g). The time to reach the target temperature increased in order of George Foreman grill (3.9 to 19.8 min) < Oster toaster oven (11.3 to 45.0 min) < Presto electric skillet (16.3 to 55.0 min) < Sanyo grill (14.3 to 65.0 min) < standard kitchen oven (20.0 to 63.0 min); variation was due to steak thickness. Results indicated that increased steak thickness allowed greater inactivation of E. coli O157:H7, as time to reach the target internal temperature increased. Roasting in a kitchen oven was most effective for pathogen inactivation. PMID- 20202331 TI - Inhibition of Clostridium perfringens spore germination and outgrowth by buffered vinegar and lemon juice concentrate during chilling of ground turkey roast containing minimal ingredients. AB - Inhibition of Clostridium perfringens spore germination and outgrowth in ground turkey roast containing minimal ingredients (salt and sugar), by buffered vinegar (MOstatin V) and a blend (buffered) of lemon juice concentrate and vinegar (MOstatin LV) was evaluated. Ground turkey roast was formulated to contain sea salt (1.5%), turbinado sugar (0.5%), and various concentrations of MOstatin V (0.75, 1.25, or 2.5%) or MOstatin LV (1.5, 2.5, or 3.5%), along with a control (without MOstatins). The product was inoculated with a three-strain spore cocktail of C. perfringens to obtain initial spore levels of ca. 2.0 to 0.5 log CFU/g. Inoculated products were vacuum packaged, heat shocked for 20 min at 75 degrees C, and cooled exponentially from 54.4 to 4.0 degrees C in 6.5, 9, 12, 15, 18, or 21 h. In control samples without MOstatin V or MOstatin LV, C. perfringens populations reached 2.98, 4.50, 5.78, 7.05, 7.88, and 8.19 log CFU/g (corresponding increases of 0.51, 2.29, 3.51, 4.79, 5.55, and 5.93 log CFU/g) in 6.5, 9, 12, 15, 18, and 21 h of chilling, respectively. MOstatin V (2.5%) and MOstatin LV (3.5%) were effective in inhibiting C. perfringens spore germination and outgrowth in ground turkey roast to <1.0 log CFU/g during abusive chilling of the product within 21 h. Buffered vinegar and a blend (buffered) of lemon juice concentrate and vinegar were effective in controlling germination and outgrowth of C. perfringens spores in turkey roast containing minimal ingredients. PMID- 20202332 TI - Reduction of Campylobacter jejuni and Campylobacter coli in poultry skin by fruit extracts. AB - Campylobacter spp. are a major cause of foodborne bacterial gastroenteritis in humans, and current methods to control Campylobacter contamination in foods are not completely successful. Plants are a promising source of antimicrobial agents, particularly given the growing interest in "all natural" foods. In this study, the antimicrobial activity of extracts from 28 edible plants against Campylobacter jejuni and Campylobacter coli was evaluated in vitro and in a poultry skin model. Nine of 28 extracts exhibited antimicrobial activity in a diffusion assay, and MBCs were determined for the three most active extracts, i.e., lime, plum, and sour orange peel (MBCs of 2 to 3 mg/ml). Mixtures of the lime, plum, and sour orange peel extracts were applied to chicken skin inoculated with 10(5) CFU of Campylobacter to test for synergistic or antagonist effects. After incubation (48 h at 4 degrees C) with any extract mixture, no Campylobacter CFUs were detectable. A panel of tasters determined that the mixture of lime and plum gave the best flavor to chicken wings. These active extracts from edible fruits are simple to prepare and are alternatives to reduce or eliminate Campylobacter contamination of chicken products. PMID- 20202333 TI - Inhibition of microbial growth and enrichment of gamma-aminobutyric acid during germination of brown rice by electrolyzed oxidizing water. AB - Electrolyzed oxidizing water (EOW) has been regarded as a potential environmentally friendly broad spectrum microbial decontaminant. EOW with a pH of 3.0 and oxidation reduction potential of 1,079.0 mV were generated by the electrolysis of a dilute NaCl solution (20 mM) in an electrochemical cell. The effects of EOW, 1% NaClO solution, and alkaline electrolyzed water on controlling microbial growth, germination ratio, and enrichment of gamma-aminobutyric acid in germinated brown rice (GBR) were evaluated in this study. Results show that EOW was the most effective at inhibiting microbial growth during germination. Rinsing the rice grains with EOW at 12-h intervals resulted in aerobic plate count reductions of 4.82 log CFU/g, while soaking resulted in bacterial count reductions of 5.38 log CFU/g after 72 h of germination. Moreover, EOW significantly enriched gamma-aminobutyric acid content in GBR (P < 0.05); content was increased 1.6 times in grain rinsed with EOW and 1.8 times in grain soaked in EOW. The findings indicate that EOW is a feasible disinfectant for industrial GBR production. PMID- 20202334 TI - Zoonoses action plan Salmonella monitoring programme: an investigation of the sampling protocol. AB - The Zoonoses Action Plan (ZAP) Salmonella Programme was established by the British Pig Executive to monitor Salmonella prevalence in quality-assured British pigs at slaughter by testing a sample of pigs with a meat juice enzyme-linked immunosorbent assay for antibodies against group B and C(1) Salmonella. Farms were assigned a ZAP level (1 to 3) depending on the monitored prevalence, and ZAP 2 or 3 farms were required to act to reduce the prevalence. The ultimate goal was to reduce the risk of human salmonellosis attributable to British pork. A mathematical model has been developed to describe the ZAP sampling protocol. Results show that the probability of assigning a farm the correct ZAP level was high, except for farms that had a seroprevalence close to the cutoff points between different ZAP levels. Sensitivity analyses identified that the probability of assigning a farm to the correct ZAP level was dependent on the sensitivity and specificity of the test, the number of batches taken to slaughter each quarter, and the number of samples taken per batch. The variability of the predicted seroprevalence was reduced as the number of batches or samples increased and, away from the cutoff points, the probability of being assigned the correct ZAP level increased as the number of batches or samples increased. In summary, the model described here provided invaluable insight into the ZAP sampling protocol. Further work is required to understand the impact of the program for Salmonella infection in British pig farms and therefore on human health. PMID- 20202335 TI - Efficacy of a biopesticide for control of aflatoxins in corn. AB - A 2-year study was carried out to determine the efficacy of a biopesticide in reducing aflatoxin contamination in corn. The biopesticide, afla-guard, delivers a nontoxigenic strain of Aspergillus flavus to the field where it competes with naturally occurring toxigenic strains of the fungus. Afla-guard was applied to entire fields in two areas of Texas at either 11.2 or 22.4 kg/ha. Specific nontreated fields in close proximity to treated fields were designated as controls. Samples of corn were collected at harvest and analyzed for aflatoxins and density of toxigenic and nontoxigenic isolates of A. flavus. Aflatoxin concentrations were generally quite low in 2007, but the mean concentration in treated samples (0.5 ppb) was reduced by 85% compared with controls (3.4 ppb). In 2008, samples from treated and control fields averaged 1.5 and 12.4 ppb, respectively, an 88% reduction. There were no significant differences between the two afla-guard application rates. In conjunction with the reductions in aflatoxin contamination, treatments produced significant reductions in the incidence of toxigenic isolates of A. flavus in corn. PMID- 20202336 TI - Infrequent internalization of Escherichia coli O157:H7 into field-grown leafy greens. AB - Several sources of contamination of fresh produce by Escherichia coli O157:H7 (O157) have been identified and include contaminated irrigation water and improperly composted animal waste; however, field studies evaluating the potential for internalization of O157 into leafy greens from these sources have not been conducted. Irrigation water inoculated with green fluorescent plasmid labeled Shiga toxin-negative strains (50 ml of 10(2), 10(4), or 10(6) CFU of O157 per ml) was applied to soil at the base of spinach plants of different maturities in one field trial. In a second trial, contaminated compost (1.8 kg of 10(3) or 10(5) CFU of O157 per g) was applied to field plots (0.25 by 3.0 m) prior to transplantation of spinach, lettuce, or parsley plants. E. coli O157:H7 persisted in the soil up to harvest (day 76 posttransplantation) following application of contaminated irrigation water; however, internalized O157 was not detected in any spinach leaves or in roots exposed to O157 during the early or late growing season. Internalized O157 was detected in root samples collected 7 days after plants were contaminated in mid-season, with 5 of 30 samples testing positive for O157 by enrichment; however, O157 was not detected by enrichment in surface disinfected roots on days 14 or 22. Roots and leaves from transplanted spinach, lettuce, and parsley did not internalize O157 for up to 50 days in the second trial. These results indicate that internalization of O157 via plant roots in the field is rare and when it does occur, O157 does not persist 7 days later. PMID- 20202337 TI - Real-time reverse transcriptase PCR for the rapid and sensitive detection of Salmonella typhimurium from pork. AB - Reverse transcriptase PCR (RT-PCR) detects the presence of mRNA and has a greater potential for detecting viable pathogens than do DNA-based PCR assays, with improved speed and sensitivity compared with traditional methods. Our objective was to rapidly and sensitively detect Salmonella Typhimurium from pork within two 8-h work shifts using a SYBR Green I real-time RT-PCR (rt-RT-PCR) assay. Pork chop and sausage samples (25 g) were inoculated with 10(8) to 10(0) CFU of Salmonella Typhimurium and stomached in 225 ml of tetrathionate broth. Serial dilutions were spread plated on xylose lysine Tergitol 4 agar either immediately or after 10 h of selective preenrichment or preenrichment followed by 12 h of selective enrichment (for stressed cells) at 37 degrees C for standard cultural enumeration. RNA was extracted using the TRIzol method. The rt-RT-PCR assay was carried out in a Bio-Rad iCycler using a SYBR Green I one-step RT-PCR kit and Salmonella specific invA gene primers with an internal amplification control (IAC). The PCR was followed by melting temperature (T(m)) analysis to determine specific Salmonella invA (T(m) = 87.5 degrees C) and IAC (T(m) = 82 degrees C) products. Improved Salmonella detection up to 10(1) CFU/25 g of pork and 10(0) CFU/25 g of sausages was obtained after 10 h of enrichment within approximately 24 h. Even without enrichment, Salmonella could be detected from both pork chop and sausage at 10(6) CFU/25 g within 1 day. This robust rt-RT-PCR detects and confirms Salmonella in pork within approximately 24 h and thus is significantly faster than traditional methods that take >/=1 week. This assay shows promise for routine testing and monitoring of Salmonella by the pork industry. PMID- 20202338 TI - Modeling the efficacy of triplet antimicrobial combinations: yeast suppression by lauric arginate, cinnamic acid, and sodium benzoate or potassium sorbate as a case study. AB - The growth of four spoilage yeasts, Saccharomyces cerevisiae, Zygosaccharomyces bailii, Brettanomyces bruxellensis, and Brettanomyces naardenensis, was inhibited with three-agent (triplet) combinations of lauric arginate, cinnamic acid, and sodium benzoate or potassium sorbate. The inhibition efficacy was determined by monitoring the optical density of yeast cultures grown in microtiter plates for 7 days. The relationship between the optical density and the sodium benzoate and potassium sorbate concentrations followed a single-term exponential decay model. The critical effective concentration was defined as the concentration at which the optical density was 0.05, which became an efficacy criterion for the mixtures. Critical concentrations of sodium benzoate or potassium sorbate as a function of the lauric arginate and cinnamic acid concentrations were then fitted with an empirical model that mapped three-agent combinations of equal efficacy. The contours of this function are presented in tabulated form and as two- and three-dimensional plots. Triplet combinations were highly effective against all four spoilage yeasts at three practical pH levels, especially at pH 3.0. The triplet combinations were particularly effective for inhibiting growth of Z. bailii, and combinations containing potassium sorbate had synergistic activities. The equal efficacy concentration model also allowed tabulation of the cost of the various combinations of agents and identification of those most economically feasible. PMID- 20202339 TI - Distribution of aminogenic activity among potential autochthonous starter cultures for dry fermented sausages. AB - Any bacterial strain to be used as starter culture should have suitable characteristics, including a lack of amino acid decarboxylase activity. In this study, the decarboxylase activity of 76 bacterial strains, including lactic acid bacteria and gram-positive, catalase-positive cocci, was investigated. These strains were previously isolated from European traditional fermented sausages to develop autochthonous starter cultures. Of all the strains tested, 48% of the lactic acid bacteria strains and 13% of gram-positive, catalase-positive cocci decarboxylated one or more amino acids. Aminogenic potential was strain dependent, although some species had a higher proportion of aminogenic strains than did others. Thus, all Lactobacillus curvatus strains and 70% of Lactobacillus brevis strains had the capacity to produce tyramine and beta phenylethylamine. Some strains also produced other aromatic amines, such as tryptamine and the diamines putrescine and cadaverine. All the enterococcal strains tested were decarboxylase positive, producing high amounts of tyramine and considerable amounts of beta-phenylethylamine. None of the staphylococcal strains had tyrosine-decarboxylase activity, but some produced other amines. From the aminogenic point of view, Lactobacillus plantarum, Lactobacillus sakei, and Staphylococcus xylosus strains would be the most suitable for use as autochthonous starter cultures for traditional fermented sausages. PMID- 20202340 TI - Lessons learned from the management of a national outbreak of Salmonella ohio linked to pork meat processing and distribution. AB - During the summer of 2005, an increase in reports of human cases of Salmonella enterica serovar Ohio infection was observed in Belgium. During 11 weeks, between 1 July and 13 September, 60 cases of laboratory-confirmed Salmonella Ohio infection were reported to the National Reference Centre for Salmonella, with a peak onset of symptoms in the third week of July. All clinical isolates caused self-limiting gastroenteritis; both genders (32 males and 28 females) and all age groups (three children <5 years of age, three children 5 to 14 years of age, 32 adults 15 to 64 years of age, and 22 adults >65 years of age) were affected. The isolates were distributed throughout Belgium but a cluster of several cases was observed around Brussels. At the same time, an increase in the incidence of this serovar was observed in the Salmonella isolates originating from the official surveillance campaign conducted by the Federal Agency for the Safety of the Food Chain, which identified pork as a likely source of the outbreak strain. Pulsed field gel electrophoresis typing confirmed the clonal relationship between the human isolates, the isolates from samples collected in the cutting plants, and the isolates from pork meat in distribution. Further epidemiological investigations indicated that one particular slaughterhouse was involved. In that slaughterhouse, the carcasses were contaminated during the evisceration process because of contaminated equipment and uncontrolled environmental conditions. This study highlights the importance of a centralized surveillance laboratory in the management of outbreaks and the need of strict implementation of hygienic rules to avoid this type of outbreak. PMID- 20202341 TI - Incidence and contamination level of Listeria monocytogenes and other Listeria spp. in ready-to-eat meat products in Jordan. AB - The objective of the present study was to investigate the incidence and contamination levels of different Listeria monocytogenes serovars in ready-to-eat meat products (RTE-MP) collected from different outlets and processing plants in Jordan in order (i) to provide information to Jordanian health authorities on the incidence of L. monocytogenes in RTE-MP sold and consumed in Jordan and (ii) to ascertain the risks of these products for consumers. Two hundred forty RTE-MP samples, 120 beef and 120 poultry, were analyzed. European International Organization for Standardization (EN ISO) 11290-1 and -2 standard protocols were used for detection and enumeration of L. monocytogenes. The identity of suspected L. monocytogenes was confirmed using PCR. Three Listeria spp., L. monocytogenes, L. innocua, and L. welshimeri, were isolated. L. innocua and L. welshimeri were the most and least frequently isolated with 56 and 36 samples, respectively. L. monocytogenes was isolated from 41 samples (17.1%): 23 from beef and 18 from poultry samples. The contamination levels of L. monocytogenes were 100 CFU/g was found. The L. monocytogenes strains isolated fell into two serotypes (1 and 4) and four different serovars (1/2a, 1/2b, 1/2c, and 4b). PMID- 20202342 TI - Level of chemical and microbiological contaminations in chili bo (paste). AB - The objective of this study was to determine the level of preservatives and microbiological loads in various brands of commercially available chili bo (paste). Fifteen different brands of chili bo obtained from the local market and hypermarkets were analyzed for pH, moisture and benzoic acid content, microbiological loads (aerobic, anaerobic, aerobic spores, and fungi), and thermophilic microorganisms. Results showed that both moisture content and pH vary among samples. The concentrations of benzoic acid detected in chili bo were found to be in the range of 537 to 5,435 mg/kg. Nine of fifteen brands were found to exceed the maximum level permitted by the Malaysian Food Law in accordance with the Codex Alimentarius (1,000 mg/kg for benzoic acid). An apparent correlation between benzoic acid concentration and microbiological loads present in the chili bo was observed. The microbiological loads were found to be relatively low in the end products containing high amounts of benzoic acid. The heat-resistant (70 to 80 degrees C) microorganisms present in chili bo were identified as Ochrobacterum tritici, Stenotrophomonas rhizophila, Microbacterium maritypicum, Roseomonas spp., CDC group II-E subgroup A, Flavimonas oryzihabitans, and Pseudomonas aeruginosa, with M. maritypicum being the most frequently found (in 9 of 15 samples) microorganism. Most of these identified microorganisms were not known to cause foodborne illnesses. PMID- 20202343 TI - Inactivation of Escherichia coli O157:H7 on lettuce, using low-energy X-ray irradiation. AB - Low-energy X-ray irradiation was assessed as a means of eliminating Escherichia coli O157:H7 on lettuce. Round-cut iceberg lettuce samples (2.54-cm diameter) were dip or spot inoculated with a three-strain cocktail of E. coli O157:H7, stored for 24 h at 4 degrees C, and then irradiated at four dose levels up to 0.25 kGy using a prototype low-energy (70 kV) X-ray irradiator. E. coli O157:H7 survivors were quantified by plating on sorbitol MacConkey agar containing cefixime and tellurite. Dip inoculation yielded a D(10)-value of 0.040 +/- 0.001 kGy, which is 3.4 times lower than a previously reported value of 0.136 kGy using gamma radiation. The D(10)-value for E. coli O157:H7 on spot-inoculated samples was 0.078 +/- 0.008 kGy, which is about twice that of dip-inoculated samples. When 10 stacked leaves were irradiated from both sides, a dose of 0.2 kGy was achieved at the center of the stack with a surface dose of 1 kGy, corresponding to a approximately 5-log reduction of E. coli O157:H7 at the center of the stack. Based on these findings, low-energy X-ray irradiation appears to be a promising microbial inactivation strategy for leafy greens and potentially for other types of fresh produce. PMID- 20202344 TI - Control of Listeria monocytogenes on cooked cured ham by formulation with a lactate-diacetate blend and surface treatment with lauric arginate. AB - Ready-to-eat (RTE) meat products have been identified as a significant source of listeriosis in humans in the United States. Meat processors in the United States are required to use one of three alternatives to control L. monocytogenes in RTE meats: (i) a postlethality inactivation treatment along with a L. monocytogenes growth inhibitor; (ii) a postlethality inactivation treatment or a growth inhibitor; or (iii) sanitation measures and intensive testing. Lauric arginate (LAE) has been proposed as an effective postlethality inactivation treatment. The present study was conducted to investigate the antimicrobial effect of a lactate diacetate blend in the formulation combined with surface application of LAE on cooked cured ham inoculated with L. monocytogenes, vacuum packaged, and stored at 4 degrees C for up to 90 days. The treatments evaluated were (i) control ham with no added antimicrobials (control); (ii) ham formulated with 1.68% potassium lactate and 0.12% sodium diacetate (PLSD); (iii) control ham with 0.07% LAE as a surface treatment (LAE); and (iv) ham formulated with PLSD and LAE surface treatment (sprayed in bag and distributed across meat surface during vacuum packing) (PLSD + LAE). Use of only LAE as a surface treatment resulted in an initial 1-log CFU/g reduction in levels of L. monocytogenes on ham; however, this reduction only delayed the growth of the pathogen to 8 log CFU/g by 12 days when compared with the control ham without added antimicrobials. Use of PLSD in the formulation of ham resulted in a complete inhibition of L. monocytogenes throughout storage. The combination of PLSD in the formulation and a surface treatment with LAE resulted in an initial 0.7-log CFU/g reduction of the pathogen on ham and complete inhibition of the pathogen at the reduced level throughout storage. Formulation of ham with a lactate-diacetate blend combined with lauric arginate as a surface treatment will allow RTE meat processors to effectively achieve alternative 1 status, as designated by the U.S. Department of Agriculture Food Safety and Inspection Service, in their facilities. PMID- 20202345 TI - Synergistic effects of ethanol and UV radiation to reduce levels of selected foodborne pathogenic bacteria. AB - The purpose of this study was to determine whether combined treatments would produce synergistic disinfection effects on food products during food processing compared with single treatments. We investigated the bactericidal effects of a commercial chemical disinfectant (ethanol) and of UV radiation on Bacillus cereus F4810/72, Cronobacter sakazakii KCTC 2949, Staphylococcus aureus ATCC 35556, Escherichia coli ATCC 10536, and Salmonella enterica Typhimurium NO/NA in vitro. Various concentrations of ethanol (10, 30, 40, and 50%) were tested with various exposure doses of UV radiation (6, 96, 216, 360, and 504 mWs/cm(2)) with a UV lamp. The combined ethanol-UV treatments resulted in greater reductions in bacterial counts than did either treatment alone. The synergistic effect values for B. cereus, C. sakazakii, S. aureus, S. enterica Typhimurium NO/NA, and E. coli were 0.40 to 1.52, 0.52 to 1.74, 0.20 to 2.32, 0.07 to 1.14, and 0.02 to 1.75 log CFU/ml, respectively. The results of this study suggest that a significant synergistic benefit results from combining ethanol and UV treatments against foodborne pathogens in vitro. PMID- 20202346 TI - Serotype, genotype, and antimicrobial susceptibility profiles of Salmonella from chicken farms in Shanghai. AB - Five hundred fifty samples were collected from five chicken farms in Shanghai during March 2005 to October 2006. Twenty-five samples tested positive for Salmonella from a total of 550 samples, of which 500 were obtained from feces of healthy chickens and 50 were obtained from diseased chicks. The 25 presumptive Salmonella isolates were confirmed by the API 20E identification kit. Serotyping of these isolates by agglutination tests with antiserum displayed seven serovars; genotyping of these isolates with multilocus sequence typing demonstrated six sequence type (ST) patterns (i.e., ST-11, ST-19, ST-92, ST-96, ST-290, and ST 367). The multilocus sequence typing data revealed that some of these strains, isolated from different farms, might have the same ST and might come from the same source. The susceptibilities of these strains to 14 antimicrobials were determined; most of the isolates (13 of 25) were resistant to doxycycline and tetracycline, and two isolates were resistant to cefotaxime and ceftazidime, but none was resistant to gentamicin or kanamycin. PMID- 20202347 TI - Survival of Enterococcus faecalis OG1RF:pCF10 in poultry and cattle feed: vector competence of the red flour beetle, Tribolium castaneum (Herbst). AB - Laboratory experiments were designed to determine the survival of Enterococcus faecalis OG1RF:pCF10 in poultry and cattle feed and its acquisition and transmission by adults of the red flour beetle, Tribolium castaneum (Herbst), to sterile feed. Adult T. castaneum beetles were introduced into poultry and cattle feed inoculated with E. faecalis OG1RF:pCF10 and incubated at 28 degrees C with 65% relative humidity for 7 days in a growth chamber. E. faecalis survived in both poultry and cattle feed during the 7-day test period. There was a logarithmic decrease in E. faecalis concentration in poultry and cattle feed and in and on the insects. E. faecalis persisted on the surface and within T. castaneum adults for 7 days when adults were released on E. faecalis-inoculated poultry feed and for only 5 days on E. faecalis-inoculated cattle feed. The concentration of E. faecalis decreased more slowly on poultry feed than on cattle feed, and this may explain why adult T. castaneum insects were more successful in acquiring and transferring E. faecalis from inoculated poultry feed to sterile poultry feed during the 7-day test period. However, T. castaneum adults reared on inoculated cattle feed were unable to contaminate sterile cattle feed on day 7. To our knowledge, this is the first report documenting T. castaneum to successfully acquire antibiotic-resistant enterococci from animal feed and transfer them to sterile feed. Management of T. castaneum through effective integrated pest management program is therefore important to prevent the spread of antibiotic-resistant and virulent enterococci in animal feed and feed manufacturing environments. PMID- 20202348 TI - Pooling raw shell eggs: Salmonella contamination and high risk practices in the United Kingdom food service sector. AB - Salmonella contamination of pooled raw shelled egg mix (RSEM) used as an ingredient in lightly cooked or uncooked foods and high-risk kitchen hygiene practices in United Kingdom food service establishments using RSEM were investigated. Samples were collected from 934 premises. Salmonella was found in 1 (0.13%) of 764 RSEM samples, 2 (0.3%) of 726 samples from surfaces where ready-to eat foods were prepared, and 7 (1.3%) of 550 cleaning cloths. Poor RSEM storage and handling practices were highlighted. Workers in 40% of the premises sampled failed to use designated utensils when RSEM was added to other ingredients, workers in 17% of the premises did not clean surfaces and utensils thoroughly after use with RSEM and before preparing other foods, only 42% of workers washed and dried their hands after handling eggs or RSEM, workers in 41% of the premises did not store RSEM at refrigeration temperature before use, and workers in 8% of the premises added RSEM to cooked rice at the end of cooking when preparing egg fried rice. Take-away premises, especially those serving Chinese cuisine, were least likely to have a documented food safety management system and awareness of the key food safety points concerning the use of RSEM compared with other food service premises (P < 0.0001). Food service businesses using RSEM must be aware of the continuing hazard from Salmonella, must adopt appropriate control measures, and must follow advice provided by national food agencies to reduce the risk of Salmonella infection. PMID- 20202349 TI - The REFLECT statement: reporting guidelines for randomized controlled trials in livestock and food safety: explanation and elaboration. AB - Concerns about the completeness and accuracy of reporting of randomized clinical trials (RCTs) and the impact of poor reporting on decision-making have been documented in the medical field over the past several decades. Experience from RCTs in human medicine would suggest that failure to report critical trial features can be associated with biased estimated effect measures, and there is evidence to suggest similar biases occur in RCTs conducted in livestock populations. In response to these concerns, standardized guidelines for reporting RCTs were developed and implemented in human medicine. The Consolidated Standards of Reporting Trials (CONSORT) statement was first published in 1996 with a revised edition published in 2001. The CONSORT statement consists of a 22-item checklist for reporting a RCT and a flow diagram to follow the number of participants at each stage of a trial. An explanation and elaboration document not only defines and discusses the importance of each of the items, but also provides examples of how this information could be supplied in a publication. Differences between human and livestock populations necessitate modifications to the CONSORT statement to maximize its usefulness for RCTs involving livestock. These have been addressed in an extension of the CONSORT statement titled the REFLECT statement: Methods and processes of creating reporting guidelines for randomized control trials for livestock and food safety. The modifications made for livestock trials specifically addressed the common use of group housing and group allocation to intervention in livestock studies, the use of a deliberate challenge model in some trials, and common use of non-clinical outcomes, such as contamination with a foodborne pathogen. In addition, the REFLECT statement for RCTs in livestock populations proposed specific terms or further clarified terms as they pertained to livestock studies. PMID- 20202350 TI - Streamline triage and manage user expectations: lessons from a qualitative study of GP out-of-hours services. AB - BACKGROUND: Several models of GP out-of-hours provision exist in the UK but there is little detail about their effectiveness to meet users' needs and expectations. AIM: To explore users' needs, expectations, and experiences of out-of-hours care, and to identify proposals for service redesign. SETTING: Service providers in urban (GP cooperative), mixed (hospital based), rural (private) locations in Wales. PARTICIPANTS: Sixty recent service users or carers (20 in each location). METHOD: Semi-structured telephone interviews; thematic analysis. RESULTS: Users' concerns were generally consistent across the three different services. Efficiency was a major concern, with repetitive triage procedures and long time delays at various stages in the process being problematic. Access to a doctor when required was also important to users, who perceived an obstructive gatekeeping function of preliminary contacts. Expectations moderated the relationship between user concerns and satisfaction. Where expectations of outcome were unfulfilled, participants reported greater likelihood of reconsulting with the same or alternative services for the same illness episode. Accurate expectations concerning contacts with the next administrative, nursing, or medical staff professional were managed by appropriate information provision. CONCLUSION: Users require more streamlined and flexible triage systems. Their expectations need to be understood and incorporated into how services advise and provide services for users, and actively managed to meet the aims of both enhancing satisfaction and enabling users to cope with their condition. Better information and education about services are needed if users are to derive the greatest benefit and satisfaction. This may influence choices about using the most appropriate forms of care. PMID- 20202351 TI - Patient satisfaction with point-of-care testing in general practice. AB - BACKGROUND: Point-of-care testing is increasingly being used in general practice to assist GPs in their management of patients with chronic disease. However, patient satisfaction and acceptability of point-of-care testing in general practice has not been widely studied. AIM: To determine if patients are more satisfied with point-of-care testing than with pathology laboratory testing for three chronic conditions. DESIGN OF STUDY: As part of a large multicentre, randomised, controlled trial assessing the use of point-of-care testing in Australian general practice, satisfaction was measured for patients having pathology testing performed by point-of-care testing devices or pathology laboratories. Patients in the trial were managed by GPs for diabetes, hyperlipidaemia, and/or anticoagulant therapy. METHOD: Patient satisfaction was measured using level of agreement with a variety of statements at the end of the study with a patient satisfaction questionnaire for both the intervention and control groups. Analysis was performed using a mixed model analysis of variance (ANOVA) with allowance for clustering at the practice level following Box-Cox transformations of the data to achieve normality. RESULTS: Overall, intervention patients reported that they were satisfied with point-of-care testing. In comparison with the control group, the intervention group had a higher level of agreement than control patients with statements relating to their satisfaction with the collection process (P<0.001) and confidence in the process (P<0.001). They also viewed point-of-care testing as strengthening their relationship with their GP (P = 0.010) and motivational in terms of better managing their condition (P<0.001). CONCLUSION: The results from this trial support patient satisfaction and acceptability of point-of-care testing in a general practice setting. PMID- 20202352 TI - Mortality and cancer in patients with new musculoskeletal episodes: a cohort study. AB - BACKGROUND: The risk of serious outcome in persons presenting to primary care with common regional musculoskeletal problems is unknown. AIM: To determine the risk of mortality and cancer in older patients presenting with new musculoskeletal problems. DESIGN OF STUDY: Cohort study. SETTING: One hundred and seventy-nine general practices contributing to the General Practice Research Database. METHOD: Cases were 48,206 people aged > or =50 years, with a recorded musculoskeletal problem in 1996 but none during the previous 2 years. Cases were allocated to groups based on problem location (for example, the back). A total of 40,254 controls had no musculoskeletal consultation during 1996 or during the previous 2 years. Outcome measures were mortality and recorded malignant and pre malignant neoplasms 1 and 10 years after baseline consultation. RESULTS: Mortality rates in the first year of follow-up were higher for cases (373 per 10,000 person-years) than controls (244). The hip (standardised mortality ratio 2.36; 95% confidence interval [CI] = 1.99 to 2.77 compared to controls) and back (2.07; 95% CI = 1.87 to 2.28) groups had the highest 1-year rates. Ten-year mortality rates were closer between groups. Higher cancer rates were found for the back, hip, and neck groups. The first-year excess mortality in cases was only partly explained by cancer and other comorbidity (hip hazard ratio 1.72; 95% CI = 1.43 to 2.07; back 1.68; 95% CI = 1.49 to 1.90). CONCLUSION: New consulting episodes of musculoskeletal problems in the back or hip are associated with higher subsequent cancer rates and increased mortality risk in older people. Unexpected cancer and death in these patients remains rare but the ability of clinical signs and symptoms to identify persons at risk needs to be confirmed. PMID- 20202353 TI - Commentary: This pain is killing me. PMID- 20202354 TI - Factors associated with immunisation coverage and timeliness in New Zealand. AB - BACKGROUND: Immunisation coverage in New Zealand is lower than what is necessary to prevent large epidemics of pertussis. Primary care is where most immunisation delivery occurs. General practices vary in their structure and organisation, both in a general sense and specifically with respect to immunisation delivery. AIM: To identify the structural and organisational characteristics of general practices associated with higher immunisation coverage and more timely immunisation delivery. DESIGN OF STUDY: A random sample of practices during 2005 and 2006. SETTING: General practices in the Auckland and Midland regions, with over-sampling of indigenous Maori governance practices. METHOD: Practice immunisation coverage and timeliness were measured. Primary care practice characteristics relevant to immunisation delivery by the practice were described. Associations of these practice characteristics with higher practice immunisation coverage and more timely immunisation delivery were determined. RESULTS: A total of 124 (61%) of 205 eligible practices were recruited. A median (25th to 75th centile) of 71% (57-77%) of registered children at each practice were fully immunised, and 56% (40-64%) had no immunisation delay. In multivariate analyses, both practice immunisation coverage (P<0.001) and timeliness (P<0.001) decreased with increased social deprivation. After adjustment for socioeconomic deprivation, region, and governance, immunisation coverage and timeliness were better at practices that enrolled children at a younger age (coverage: P = 0.002; timeliness P = 0.007), used one of the four available practice management systems (coverage: P<0.001; timeliness: P = 0.006), and had no staff shortages (coverage: P = 0.027; timeliness: P = 0.021). CONCLUSION: Practice immunisation coverage and timeliness vary widely in New Zealand. General organisational and structural aspects of general practices are key determinants of general practice immunisation delivery. PMID- 20202355 TI - Trends in the epidemiology of smoking recorded in UK general practice. AB - BACKGROUND: Smoking represents the most important cause of avoidable morbidity and mortality in the economically developed world. The UK has recently introduced a range of initiatives aiming to reduce smoking prevalence and smoking-related health inequalities. AIM: To investigate the epidemiology of smoking in UK general practice. DESIGN OF STUDY: Cross-sectional study. SETTING: A total of 525 general practices contributing to the QRESEARCH database. METHOD: A dataset was extracted on 2.7 million patients around each financial year for the period 2001 2007, including, age, sex, deprivation, and smoking status. For patients newly recorded as smoking, data were extracted on receipt of smoking cessation advice and referral to stop-smoking services. RESULTS: Over the study period, the proportion of people with smoking status recorded increased by 32.9% (2001/2002: 46.6% to 2006/2007: 79.5%). A large overall increase in the provision of smoking cessation advice (2001/2002: 43.6% to 2006/2007: 84.0%) and referral to stop smoking services (2001/2002: 1.0% to 2006/2007: 6.6%) was also observed. The proportion of people who smoked (with a recorded smoking status) reduced by 6.0% (2001/2002: 28.4% to 2006/2007: 22.4%). This decrease was greatest among patients in the most deprived areas (7.2%) and the youngest patients (16-25 years: 7.1%). In 2006/2007, more than twice as many patients in deprived areas smoked as those in affluent areas (most deprived: 33.8%; most affluent: 14.1%). CONCLUSION: A significant and important reduction in the number of UK smokers occurred between April 2001 and April 2007. However, although this is an improvement, comparatively high rates of smoking remain among younger adults and those who are the most socioeconomically deprived. PMID- 20202356 TI - Validity of diagnostic coding within the General Practice Research Database: a systematic review. AB - BACKGROUND: The UK-based General Practice Research Database (GPRD) is a valuable source of longitudinal primary care records and is increasingly used for epidemiological research. AIM: To conduct a systematic review of the literature on accuracy and completeness of diagnostic coding in the GPRD. DESIGN OF STUDY: Systematic review. METHOD: Six electronic databases were searched using search terms relating to the GPRD, in association with terms synonymous with validity, accuracy, concordance, and recording. A positive predictive value was calculated for each diagnosis that considered a comparison with a gold standard. Studies were also considered that compared the GPRD with other databases and national statistics. RESULTS: A total of 49 papers are included in this review. Forty papers conducted validation of a clinical diagnosis in the GPRD. When assessed against a gold standard (validation using GP questionnaire, primary care medical records, or hospital correspondence), most of the diagnoses were accurately recorded in the patient electronic record. Acute conditions were not as well recorded, with positive predictive values lower than 50%. Twelve papers compared prevalence or consultation rates in the GPRD against other primary care databases or national statistics. Generally, there was good agreement between disease prevalence and consultation rates between the GPRD and other datasets; however, rates of diabetes and musculoskeletal conditions were underestimated in the GPRD. CONCLUSION: Most of the diagnoses coded in the GPRD are well recorded. Researchers using the GPRD may want to consider how well the disease of interest is recorded before planning research, and consider how to optimise the identification of clinical events. PMID- 20202358 TI - Out-of-hours care: do we? PMID- 20202359 TI - Near-patient testing in primary care. PMID- 20202360 TI - Tailoring treatment to risk in type 2 diabetes. PMID- 20202361 TI - Case validation in research using large databases. PMID- 20202362 TI - Health in a cold climate. PMID- 20202363 TI - The relationship between glycaemic control and mortality in patients with type 2 diabetes in general practice (ZODIAC-11). AB - BACKGROUND: The relationship between the degree of glycaemic control and mortality remains an important topic of discussion. AIM: This study aimed to investigate this relationship. DESIGN OF STUDY: Prospective cohort study. SETTING: Primary care. METHOD: A total of 1145 patients with type 2 diabetes were enrolled in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) in 1998. Their survival status was recorded in September 2004. Mortality ratios were calculated using standardised mortality ratios (SMRs). Associations between haemoglobin A(1c) (HbA(1c)) levels and mortality were studied with a Cox proportional hazard model. HbA(1c) levels were studied as continuous and as categorical variables. RESULTS: A total of 335 patients died after a median follow-up period of 5.8 years. The SMR (95% confidence interval [CI]) for total mortality was 1.86 (95% CI = 1.66 to 2.06) and 2.24 (95% CI = 1.91 to 2.61) for cardiovascular mortality. For each 1% increase in HbA(1c) there was a 21% increase in the hazard ratio for total mortality. When compared with the target HbA(1c) group (HbA(1c) 6.5-7%), the group with very poor glycaemic control (HbA1c >9%) had a hazard ratio of 2.21 (95% CI = 1.42 to 3.42) for total mortality. The group with normal glycaemic control (HbA(1c) <6.5%) had a hazard ratio of 1.00 (95% CI = 0.46 to 2.19) for total mortality. CONCLUSION: HbA(1c) level was associated with mortality and this effect seemed largely attributable to patients who were in really poor glycaemic control. The absence of differences in mortality in the groups with lower HbA(1c) levels supports the position that there is no basis for continually decreasing the therapeutic target HbA(1c) level in patients with type 2 diabetes mellitus. PMID- 20202364 TI - National Dementia Strategy: well intentioned--but how well founded and how well directed? AB - The National Dementia Strategy was published in February 2009. It was eagerly anticipated and has generated a good deal of sustained media interest, widened awareness, and heightened expectation of better help for people with dementia. The three ambitions of the strategy--to raise awareness, facilitate assessment, and improve services--are unquestionably correct; but the assumptions, emphases, and economic predictions are questionable. Encouraging reliance on referral to secondary care centres, and exaggerated claims for the effectiveness of interventions to achieve clinical improvement and cost savings, may lead to disappointment and frustration. The infrastructure of care and treatment of people throughout the course of dementia will be better informed and delivered by a collaborative model which respects the knowledge and commitment contained within families and primary care. Better services will require substantial redirection of resources. PMID- 20202365 TI - Commentary. PMID- 20202366 TI - Family practice: meanings for modern times. PMID- 20202367 TI - Community pharmacists and the helpful GP prescriber. PMID- 20202368 TI - Circumcision. PMID- 20202369 TI - Circumcision. PMID- 20202370 TI - Nurse-led management of hypertension. PMID- 20202371 TI - Circumcision. PMID- 20202385 TI - Robotic-assisted laparoscopic gynecologic procedures in a fellowship training program. AB - BACKGROUND AND OBJECTIVE: The robotic surgical platform is an alternative technique to traditional laparoscopy and requires the development of new surgical skills for both the experienced surgeon and trainee. Our goal was to perform an early evaluation of the feasibility of training fellows in robotic-assisted gynecologic procedures at the outset of our incorporation of this technology into clinical practice. METHODS: A systematic approach to fellow training included (1) didactic and hands-on training with the robotic system, (2) instructional videos, (3) assistance at the operating table, and (4) performance of segments of gynecologic procedures in tandem with the attending physician. Time to complete the entire procedure, individual segments, rate of conversion to laparotomy, and complications were recorded. RESULTS: Twenty-one robotic-assisted gynecologic procedures were performed from April 2006 to January 2007. Fellows participated as the console surgeon in 14/21 cases. Thirteen patients (62%) had prior abdominal surgery. Median values with ranges were age 51 years (range, 33 to 90); BMI 28 (range, 19.4 to 43.8); EBL 25 mL (range, 25 to 250); and hospital stay 1 day (range, 1 to 4). No significant difference existed between fellow and attending mean total operative and individual segment times. One conversion to laparotomy was necessary. No major surgical complications occurred. CONCLUSION: These data suggest that it is feasible to incorporate a systematic approach to robotic-assisted laparoscopic training for trainees at the outset of incorporation of this technology into current practice. PMID- 20202386 TI - Perceived proficiency in minimally invasive surgery among senior OB/GYN residents. AB - BACKGROUND AND OBJECTIVES: To assess self-perceived proficiency in minimally invasive surgical procedures among fourth-year Ob/Gyn residents in the United States and to evaluate trends in self-perceived proficiencies by comparing the current survey to a similar survey distributed in 2001. METHODS: A Web-based survey was sent out to all fourth-year residents in accredited obstetrics and gynecology programs in the United States. The residents completed the online survey regarding their perceived proficiency in performing minimally invasive procedures. These results were compared with the results from a similar survey performed in 2001. The residents were also asked about teaching methods and the importance of minimally invasive surgery training during residency. RESULTS: We received responses from 248 senior residents. Of these, 65.1% thought emphasis on laparoscopic surgery training should be increased or greatly increased, and 97.1% thought laparoscopic skills were important for building a successful practice. Perceived proficiencies in advanced laparoscopic procedures, such as total laparoscopic hysterectomy and supracervical hysterectomy, were significantly higher compared with our results in 2001. Residents also seemed to feel more comfortable performing basic and advanced hysteroscopic procedures. Of respondents, 56.8% felt that a fellowship in minimally invasive surgery would be beneficial to them following graduation. CONCLUSION: Senior Ob/Gyn residents seem to feel more comfortable performing advanced laparoscopic procedures at graduation than they did 7 years ago. The majority feels that the emphasis on training in minimally invasive surgery should be increased. PMID- 20202387 TI - Use of neutral argon plasma in the laparoscopic treatment of endometriosis. AB - BACKGROUND AND OBJECTIVES: To report the feasibility and safety of the use of a novel energy source that uses an electrically neutral beam of pure argon plasma for the laparoscopic management of endometriosis. METHODS: In this prospective pilot study, 20 patients undergoing laparoscopic treatment of endometriosis were included. Characteristic endometriotic lesions throughout the pelvis were vaporized or resected using neutral argon plasma. Specimens were evaluated for the presence of endometriosis and thermal effects on tissue. The bases of the treated lesions were biopsied to determine whether residual endometriosis was present. RESULTS: Neutral argon plasma was used in 18 of the 20 patients for laparoscopic treatment of pelvic endometriosis. All biopsies confirmed complete vaporization or resection with no residual endometriosis at the base. Endometriosis was identified on pathology in all lesions excised. Thermal effects did not interfere with histologic analysis in any of the lesions. No complications occurred. CONCLUSION: Neutral argon plasma can be utilized as a multi-functional device that has vaporization, coagulation, and superficial cutting capacities with minimal thermal spread and acceptable outcomes. The use of neutral argon plasma appears to be efficacious and safe for the complete treatment of endometriotic implants. PMID- 20202388 TI - Hand-assist laparoscopic surgery for the gynecologic surgeon. AB - BACKGROUND: Hand assist laparoscopy (HALS) is a minimally invasive technique which allows for the placement of the surgeon's non-dominant hand through a hand port device while maintaining pneumoperitoneum. There is no standardization of this procedure and it is rarely used in gynecology. METHODS: The multidisciplinary team of authors, with experience in minimally invasive pelvic surgery, has developed a practical approach performing HALS over several years. Here we present our technique. CONCLUSIONS: There are several roles for HALS in the world of gynecology and pelvic surgery. Further experience will help improve upon a standard technique. PMID- 20202389 TI - Feasibility, safety, and cost outcomes of laparoscopic management of early endometrial and cervical malignancy. AB - BACKGROUND: The role of laparoscopy in the management of early stage endometrial and cervical cancer is continuously validated by many reports throughout the world. Interestingly, such data are still unavailable in many European countries, as it is in Greece. In this prospective study, we report on initial feasibility, safety, and cost outcomes of laparoscopic management of early stage endometrial and cervical cancer, recently introduced in our country. MATERIALS AND METHODS: This was a prospective pilot study comprising a case series. Patients referred to a tertiary referral medical center with a recent diagnosis of endometrial or cervical cancer were evaluated, and those meeting inclusion criteria were offered laparoscopic surgical staging. RESULTS: Out of 64 patients evaluated, 17 with early clinical stage endometrial cancer and 8 with early clinical stage cervical cancer underwent successful laparoscopic staging. Mean patient age was 61.6 and 39.2 years, mean BMI was 32.3 and 24.1kg/m(2), mean operative time was 243 and 284 minutes, mean estimated blood loss was 190mL and 270mL, mean lymph node count was 27.2 and 29.1, and mean hospital stay was 2 and 3 days for endometrial and cervical cancer cases, respectively. The overall costs for the procedures performed were not greater than their laparotomy counterpart. One intraoperative complication was managed laparoscopically, and 2 cases occurred of postoperative lymphocyst formation. CONCLUSION: To our knowledge, this is the first study of laparoscopic management of early endometrial and cervical cancer in Greece. Our preliminary data support the feasibility, safety, and cost effectiveness of laparoscopic management of early endometrial and cervical cancer in our country and are in accordance with series reported in the international literature. PMID- 20202390 TI - Laparoscopic excision of endometriosis may require unilateral parametrectomy. AB - OBJECTIVE: We investigated the effects of laparoscopic excision of endometriosis with unilateral parametrectomy on bladder, rectal, and sexual function as well as patient satisfaction. METHODS: Women who underwent this procedure between February 1, 2006 and November 15, 2007 were enrolled. Patient characteristics, pre- and postoperative findings, and follow-up data were retrospectively collected from a computerized database. RESULTS: Twelve patients were enrolled in the study. All of the symptoms except dysuria improved after surgery, worsening long after the operation. It seems that all parameters including sexuality, micturition, and defecation are equally important in regards to the final judgement of satisfaction, with a trend towards amelioration long after the operation. CONCLUSIONS: Unilateral parametrectomy may offer successful results in terms of patient satisfaction despite some impairment in bladder, bowel, and sexual function. The risk of permanent functional impairment is high; therefore, surgeons need to maintain the integrity of the contralateral nerve pathway. This is highly important, because pain relief seems to be partially involved in the final judgement of postoperation satisfaction. PMID- 20202391 TI - Videolaparoscopic radical hysterectomy approach: a ten-year experience. AB - BACKGROUND: Because of the advancements in surgical techniques and laparoscopic instruments, total laparoscopic radical hysterectomy can now be performed for the treatment of uterine cervical carcinoma. We assessed the feasibility, complications, and survival rates of patients who underwent total laparoscopic radical hysterectomy with pelvic lymphadenectomy. METHODS: We retrospectively collected data from the medical charts of 29 patients who had undergone surgery between 1998 and 2008. The following data were assessed: age, staging, histological type, number of lymph nodes retrieved, parametrial measures, operative time, length of hospital stay, surgical complications, and disease-free time. RESULTS: The mean patient age was 37.07+/-10.45 years. Forty percent of the patients had previously undergone abdominal or pelvic surgeries. Mean operative time was 228.96+/-60.41 minutes, and mean retrieved lymph nodes was 16.9+/-8.12. All patients had free margins. No conversions to laparotomy were necessary. Median time until hospital dismissal was 6.5 days (range 3-38 days). Four patients had intraoperative complications: 2 lacerations of the rectum, 1 laceration of the bladder, and 1 lesion of the ureter. Three patients developed bladder or ureteral fistulas postoperatively that were successfully corrected surgically. CONCLUSION: Laparoscopic radical hysterectomy is feasible and has acceptable complications. The radicalism of the surgery must be considered, bearing in mind the parametrial measures and the number of lymph nodes retrieved. PMID- 20202392 TI - Risk stratification and early oncologic outcomes following robotic prostatectomy. AB - BACKGROUND AND OBJECTIVES: Although the popularity of robotic-assisted laparoscopic prostatectomy is assured, little is known about the oncologic outcomes following the procedure. METHODS: We performed a retrospective cohort study including consecutive patients who underwent the surgery between 2003 and 2007 with at least 6 months of follow-up (n=464). Patients were stratified into low-, intermediate-, and high-risk groups according to D'Amico criteria. Biochemical failure was defined as a PSA > or =0.2 ng/mL. RESULTS: Of study patients, 256 (55%), 171 (37%), and 37 (8%) were classified as low-, intermediate , and high-risk, respectively. Over a mean follow-up of 14.1 months (range, 6.0 to 55.3), 7.3% experienced biochemical failure. Biochemical disease-free survival at 30 months was 94%, 79%, and 73% among patients in the low-, intermediate-, and high-risk groups, respectively, (P<0.001). Preoperative risk stratification was strongly associated with biochemical failure, with hazard ratios of 5.04 (95%: 1.52 to 16.7; P<0.001) and 7.04 (95%: 1.39 to 35.6; P < 0.001) for intermediate- and high- over low-risk groups, respectively. The ability of risk stratification to predict biochemical failure had an area under the receiver operator characteristic curve of 0.74. CONCLUSION: Robotic prostatectomy provides excellent cancer control outcomes for clinically localized disease. PMID- 20202393 TI - Endoscopic total thyroidectomy. AB - BACKGROUND AND OBJECTIVE: Endoscopic neck surgery for the thyroid and parathyroid is being tested as an alternative to open thyroidectomy. The aim of this study was to determine the safety and feasibility of endoscopic transaxillary total thyroidectomy (ETTT). METHODS AND RESULTS: Twenty-two consecutive patients from January 2006 to September 2008 underwent ETTT. No conversions to open were necessary. Mean age was 49.3+/-12.9 years, 20 were female, and 2 were male. Mean operating time was 238 minutes+/-72.7. Mean blood loss was 40mL+/-28.3mL. Mean weight of the gland was 137.05g+/-129.21g. The recurrent laryngeal nerve was identified with no permanent injury. Six patients developed hoarseness of the voice for a mean of 15.1+/-8.01 days. No patient developed tetany or hypocalcemia requiring treatment. Six patients experienced transient numbness in the anterior chest wall lasting 2 weeks in 5 patients and 2 months in one. All patients were discharged within 24 hours of admission. CONCLUSION: ETTT requires additional operative time compared with the open approach, but is cosmetically favorable. Visualization of the nerve and parathyroid is much better. Although the learning curve is steep, with experience the operative time will decrease. ETTT is different but safe and feasible. PMID- 20202394 TI - Single port access (SPA) cholecystectomy: two year follow-up. AB - INTRODUCTION: Laparoscopy is a constantly evolving field of surgery. New technology, applications, and benefits prompt continual improvement. We have developed a Single Port Access (SPA) surgical technique that allows for the entire cholecystectomy to be performed through a single incision within the umbilicus while maintaining safe standard dissection and retraction techniques of currently performed multiport laparoscopic cholecystectomy. METHODS: Fifteen consecutive patients underwent SPA cholecystectomy. Indications were cholelithiasis, cholecystitis, CBD stones, and biliary akinesia. The entire procedure was performed through a single umbilical incision measuring <1.8 cm within the umbilicus. Three trocars and a rigid grasper were inserted through separate fascial sites within the same skin incision. The cholecystectomy procedures are then performed in the standard fashion described in multi-port cholecystectomy. RESULTS: Fifteen patients successfully underwent Single Port Access cholecystectomy. One patient required a second 5-mm port site secondary to difficulty with retraction of a large liver. Operative times averaged 107 minutes. Blood loss, patient recovery, and outcomes have been comparable to those of standard multi-port procedures. No umbilical hernias have been seen at 2 years of follow-up. CONCLUSION: We present the SPA cholecystectomy as an alternative to multi-port cholecystectomy. In the first 2 years, SPA surgery has evolved into a technique easily taught and performed without the restrictions of new equipment or added cost. PMID- 20202395 TI - Zero leaks with minimally invasive esophagectomy: a team-based approach. AB - INTRODUCTION: Minimally invasive surgery has been applied in several ways to esophagectomy. Newer techniques have improved patient outcomes while maintaining oncological principles; however, mortality still exists. Most series have reported mortality rates ranging from 2% to 25%. The aim of this study was to determine the efficacy of minimally invasive esophagectomies (MIE) in a non university tertiary care center. METHODS: MIE in the form of a combined thoracoscopic and laparoscopic technique was performed cooperatively by 2 surgeons. Records of patients who underwent MIE between September 2005 and August 2008 were retrospectively reviewed. RESULTS: Thirty-four patients underwent MIE over a 3-year period. There was a male predominance. Mean age at presentation was 62.6 years. Comorbidities were documented in 79% of the patients. Most patients (68%) presented with dysphagia. Two patients had end-stage achalasia, 1 had corrosive esophageal stricture, and 31 had esophageal malignancies. No mortalities were reported. No anastomotic leaks were observed. Eighteen (58%) patients with malignancy received preoperative chemoradiotherapy. Six (33%) patients had a pathological response (CR) on final histopathology. The mean operating time was 294 minutes. The mean blood loss was 302 mL. CONCLUSIONS: Minimally invasive esophagectomy can be performed with results that meet and exceed reported benchmarks. A team-based approach greatly impacts the outcome of the surgery. This surgical technique must be standardized to achieve this outcome. PMID- 20202396 TI - Comparison of closure of gastric perforation ulcers with biodegradable lactide glycolide-caprolactone or omental patches. AB - BACKGROUND: The current treatment of perforated peptic ulcers is primary closure, supported by the application of an omental patch. It is difficult and time consuming to perform this procedure by laparoscopic surgery, largely because of the required suturing. It was our aim to develop and test a new method of closure for gastric perforation that is similar in efficacy and safety to a traditional repair. This technique could have utility in laparoscopic repair, as it does not require sutures or mobilization of the omentum. METHOD: The new method, called the "stamp" method consists of closure of the perforation by gluing a biodegradable patch made of lactide-glycolide-caprolacton (LGC, Polyganics, B.V. Groningen, The Netherlands) on the outside of the stomach. It was compared with the omental patch procedure. Perforations were made in the stomach of 20 rats and closed by either method (10 rats in each group). The rats were followed for 10 weeks. RESULTS: No complications were seen in any of the rats. In both groups, histological degradation of the patch by giant cells started at week 2. No signs of inflammation existed in either group. Signs of closure of the mucosa were seen after 2 weeks, and the muscular layer started to regenerate after 8 weeks in both groups. CONCLUSION: Results of both methods were similar, which means that treatment of a gastric perforation through the application of a biodegradable patch to the outside of the stomach is a feasible option and might even be an interesting technique for closure of other perforations in the digestive tract. PMID- 20202397 TI - Laparoscopic surgery for colorectal polyps. AB - BACKGROUND: Size, location, and type of colonic polyps may prevent colonoscopic polypectomy. Laparoscopic colectomy may serve as an optimal alternative in these patients. We assessed the perioperative outcome and the risk for cancer in patients operated on laparoscopically for colonic polyps not amenable to colonoscopic resection. METHODS: An evaluation was conducted of our prospective accumulated data of a consecutive series of patients operated on for colonic polyps. RESULTS: Sixty-four patients underwent laparoscopic resection for colonic polyps during a 6-year period. This group comprised 18% of all our laparoscopic colorectal procedures. Forty-six percent were males, mean age was 71. Most of the polyps (66%) were located on the right side. No deaths occurred. Conversion was necessary in 3 patients (4.6%). Significant complications occurred in 3 patients (4.6%). Nine patients (14%) were found to have malignancy. Three of them had lymph-node involvement. No difference existed in polyp size between malignant and nonmalignant lesions. CONCLUSIONS: Laparoscopic colectomy for endoscopic nonresectable colonic polyps is a safe, simple procedure as reflected by the low rate of conversions and complications. However, invasive cancer may be found in the final pathology following surgery. This mandates a strict adherence to surgical oncological principles. Polyp size cannot predict the risk of malignancy. PMID- 20202398 TI - Staged second-look laparoscopy to evaluate ischemic bowel. AB - BACKGROUND AND OBJECTIVES: An open, second-look laparotomy often is required to assess ischemic bowel after extensive mesenteric lymphadenectomy to cytoreduce midgut carcinoids. Aggressive resection of tumor at the base of the mesentery may compromise the integrity of the blood supply to the involved segment of intestine. Long segments of bowel that initially appear ischemic are sometimes created. The surgeon is faced with the decision to perform a resection or to close the abdomen temporarily knowing that this patient will require a second look laparotomy. METHODS: Segments of bowel showing signs of possible ischemia were preserved based on signs of perfusion. A side-side anastomosis was performed in the standard fashion. A Jackson Pratt drain was placed in an area adjacent to the anastomosis and brought out through the abdominal wall, and the incision was closed. Forty-eight hours later, a laparoscopic second-look operation was performed. A pneumoperitoneum was established using the drain tubing as the CO(2) inflation port. The drain was removed, and a 5-mm trocar was inserted into the abdomen via its tract. Segments of previously questionable dusky bowel and the anastomosis were inspected with a laparoscope. RESULTS: Our 3 second-look operations were completed in approximately 5 minutes, and the patients recovered without complication or prolonged hospital course. Our fourth patient progressed extremely well postoperatively and was able to avoid the planned second-look laparoscopy. CONCLUSIONS: This technique provides an easy solution for the intraoperative finding of questionable blood supply in the intestines. PMID- 20202399 TI - Evaluations of laparoscopic proctocolectomy versus traditional technique in patients with rectal cancer. AB - BACKGROUND: This was a retrospective study that evaluated the surgical outcomes of laparoscopic surgery (LS) for rectal cancer, in comparison with a case control series of open surgery (OS), during an 8-year period. METHODOLOGY: Between October 1998 and December 2006, 203 patients with rectal malignancies underwent colectomy; 146 of them had colectomy with the traditional technique (OS), while 57 underwent resection of rectal cancer laparoscopically (LS). The LS group was compared with 60 patients from the OS group (selected from the 146 OS group patients), matched by size, sex, age, anatomical location of the tumor, type, extent of resection, and pathological stage. Data were obtained from patients' medical records. Statistical analysis was performed with the t test and chi square test. All data are expressed as mean +/- standard error of the mean (SEM). RESULTS: Mean age of the LS group was 63.7+/-12 years versus 69+/-12 years in the OS group. There were more men than women in both the laparoscopic (33 males, 24 females) and OS groups (35 men, 25 women). The mean follow-up period was 38 months and 78 months for LS and OS groups, respectively. The procedure included low anterior resection (43 in LS and 45 in OS), and 13 patients in both groups underwent abdominoperineal resection and 3 transanal resections (2 in OS and 1 in LS). Mean tumor size was 4.2+/-2.12cm in the LS versus 5.2+/-2.02cm in the OS group. Conversion to an open procedure occurred in 4 patients (6.7%), all in the first 20 cases. Postoperative complications developed in 28 patients (11.7%), 13 in the LS group and 15 in the OS group. Median operative time was longer, but median blood loss was significantly lower in the LS group. The length of hospital stay was significantly shorter for the LS group. CONCLUSION: Laparoscopic surgery is feasible and safe for patients with rectal cancer and provides benefits during the postoperative period without increased morbidity or mortality. PMID- 20202400 TI - Clinical outcomes of laparoscopic versus open appendectomy. AB - BACKGROUND: Appendectomy, being the most common surgical procedure performed in general surgery, is still being performed by both open and laparoscopic methods due to a lack of consensus as to which is the most appropriate method. Because further trials are necessary and few such studies have been performed in developing countries, we decided to evaluate the outcomes of the 2 procedures to share our experience with the international community. METHODS: Consecutive patients with suspected acute appendicitis who underwent laparoscopic (LA) (n=48) and open (n=52) appendectomy (OA) over a period of 3 years were studied. Clinical outcomes were compared between the 2 groups in relation to operative time, analgesia used, length of hospital stay, return to work, resumption of a regular diet, and postoperative complications. RESULTS: Mean age of patients was 25.8 years in the laparoscopic and 25.5 years in the open group. Patient demographics were similar in both groups (P>0.05). There was significantly less need for analgesia (1.0+/-0.5 in LA and 1.5+/-0.6 doses in OA), a short hospital stay (1.4+/-0.7 in LA and 3.4+/-1.0 days in OA), early return to work (12.6+/-3.3 in LA and 19.1+/-3.1 days in OA), and less time needed to return to a regular diet (20.1+/-2.9 in LA and 22.0+/-4.7, P<0.05 in OA) in the laparoscopic appendectomy group. Operative time was significantly shorter (54.9+/-14.7 in LA and 13.6+/ 12.6 minutes in OA) in the open group. Total number of complications was less in the laparoscopic group; however, there was no statistically significant difference. CONCLUSION: The laparoscopic technique is a safe and clinically beneficial operative procedure. It provides certain advantages over open appendectomy, including short hospital stay, decreased requirement of postoperative analgesia, early food tolerance, and earlier return to normal activities. Where feasible, laparoscopy should be undertaken as the initial procedure of choice for most cases of suspected appendicitis. PMID- 20202402 TI - Laparoscopic cholecystectomy in elderly patients. AB - BACKGROUND AND OBJECTIVE: In this study, we investigated whether laparoscopic cholecystectomy, a minimally invasive procedure, is advantageous in elderly patients. METHODS: Data from 595 patients who underwent laparoscopic cholecystectomy between January 2003 and December 2007 were prospectively collected in a database. The patients were separated into 2 groups; patients >70 years of age (group A), and patients <70 years of age (group B). Group A was further divided into 3 subgroups, ages 70 to 74, 75 to 79, and 80 and above. Comparison between the groups was made with Mann-Whitney U and chi-square tests where appropriate. RESULTS: ASA scores increased in conjunction with increased age (P<0.001). Of patients with an operative time longer than one hour, 26 patients aged 70 or older, and 152 patients aged 69 or younger had no difference with respect to PaCO2 and pH measurements (P>0.05). In patients aged 80 or older, the rates of acute cholecystitis, conversion to open surgery, and postoperative complications were significantly higher than in other groups (P>0.05). CONCLUSION: We believe that in elderly patients, laparoscopic surgery can be applied safely without further increasing the surgical risks. The complications can be minimized by carefully selecting the patients aged 80 or older and by experienced teams with high technical capabilities operating on such patients. PMID- 20202401 TI - Factors influencing the successful completion of laparoscopic cholecystectomy. AB - OBJECTIVE: To analyze the preoperative factors contributing to the decision to convert laparoscopic to open cholecystectomy. METHODS: Retrospective identification of 324 consecutive patients undergoing laparoscopic cholecystectomy, with univariate and multivariate analysis of the following parameters: age, gender, obesity, previous abdominal surgery, presentation with acute cholecystitis, pancreatitis or obstructive jaundice, gallbladder wall thickening, gallbladder or common bile duct stones. RESULTS: Thirty-nine patients (12%) underwent conversion to open cholecystectomy. Patients aged over 65 years were four times more likely to require conversion than patients under 50 years of age. Under 50 years of age, males had equal conversion rates to females, and above this age there was a non-significant increased conversion rate in males. Obese patients had higher conversion rates than non-obese patients (23% versus 9%, P < 0.003). Thirty-eight percent of patients with choledocholithiasis required conversion. Age, acute cholecystitis and choledocholithiasis independently predicted conversion. A patient aged less than fifty years with neither acute cholecystitis nor choledocholithiasis had a conversion rate of just 2%, while almost 60% of those over 65 years of age with acute cholecystitis or choledocholithiasis required conversion. CONCLUSION: The parameters of age, acute cholecystitis and choledocholithiasis must be considered in the clinical decision making process when planning laparoscopic cholecystectomy. PMID- 20202403 TI - Laparoscopic cholecystectomy in cirrhotic patients. AB - BACKGROUND AND OBJECTIVES: Gallstones are twice as common in cirrhotic patients as in the general population. Although laparoscopic cholecystectomy (LC) has become the gold standard for symptomatic gallstones, cirrhosis has been considered an absolute or relative contraindication. Many authors have reported on the safety of LC in cirrhotic patients. We reviewed our patients retrospectively and assessed the safety of LC in cirrhotic patients at a tertiary care hospital in Pakistan. METHODS: From January 2003 to December 2005, a retrospective study was conducted at SU IV, Liaquat University of Medical & Health Sciences Jamshoro. All the cirrhotic patients with Child-Pugh class A and B cirrhosis undergoing LC were included in the study. Cirrhosis was diagnosed based on clinical, biochemical, ultrasonography, and intraoperative findings of the nodular liver and histopathological study. RESULTS: Of 250 patients undergoing laparoscopic cholecystectomy, 20 (12.5%) were cirrhotic. Of these 20, 12 (60%) were Childs group A and 8 (40%) were group B. Thirty percent were hepatitis B positive, and 70% were hepatitis C positive. Preoperative diagnosis of cirrhosis was possible in 80% of cases, and 20% were diagnosed during surgery. Morbidity rate was 15% and mortality rate was 0%. Two patients developed postoperative ascites, and mean hospital stay was 2.8+/-0.1 days. Of the 20 cases, 2 (10%) were converted to open cholecystectomy. The mean operation time was 70.2+/-32.54 minutes. CONCLUSION: Laparoscopic cholecystectomy is an effective and safe treatment for symptomatic gallstone disease in select patients with Child-Pugh A and B cirrhosis. The advantages over open cholecystectomy are the lower morbidity rate and reduced hospital stay. PMID- 20202404 TI - Laparoscopic removal of a large gastric trichobezoar in a 4-year-old girl. AB - BACKGROUND: Standard treatment of large gastric bezoars not amenable to medical or endoscopic management is surgical removal. The optimal operative approach, laparotomy versus laparoscopy, is a contested subject. Though laparoscopic removal has been described, it remains a relatively new technique for surgical management with outcome literature limited to case reports. In addition, currently described laparoscopic techniques often involve limited midline laparotomy incisions or >3 cm extensions of port sites. METHODS: The following describes the case of a 4-year-old girl with a large gastric trichobezoar. RESULTS: The gastric trichobezoar was successfully removed through a 12-mm left lower quadrant trocar incision cosmetically hidden within a skin crease. CONCLUSION: This case, along with accumulating literature, supports the use of laparoscopy to treat large gastric bezoars. PMID- 20202405 TI - Cecal volvulus following laparoscopic nephrectomy and renal transplantation. AB - Cecal volvulus is a rare cause of bowel obstruction that carries a high mortality. Recent surgery is known to be a risk factor for the development of cecal volvulus. We present a case of cecal volvulus following laparoscopic nephrectomy and renal transplantation. PMID- 20202406 TI - Splenic injury after elective colonoscopy. AB - Splenic injury is a rare but serious complication of colonoscopy. Since the mid 1970s, 68 splenic injuries during colonoscopy including our 2 cases have been described. With the increasing use of colonoscopy, endoscopists, surgeons, and radiologists are more likely to encounter this unusual complication. Any cause of increased splenocolic adhesions, splenomegaly, or underlying splenic disease might be a predisposing factor for splenic injury during colonoscopy. However, it can occur in patients without significant adhesions or underlying splenic pathology. The diagnosis is often described in the literature as delayed, because many physicians are not aware of this complication of colonoscopy. Although computerized tomography is highly sensitive, knowledge of this complication is the best tool to aid in early diagnosis. Patients with abdominal pain, hypotension, and a drop in hematocrit without rectal bleeding after colonoscopy should be suspected of having splenic injury. Early recognition and interdisciplinary management are required to assure successful management of this potentially life-threatening injury. Patients with hemodynamic instability most often undergo surgery. We present 2 cases of splenic injury secondary to colonoscopy that required splenectomy. PMID- 20202407 TI - Laparoscopic morcellation of didelphic uterus with cervical and renal aplasia. AB - This is a case report (and review of the literature) of a 12-year and 10-month old girl with a rare congenital anomaly of uterus didelphys, unilateral cervix aplasia, and ipsilateral renal aplasia. She had severe dysmenorrhea from the first menses. In an effort to preserve fertility, a cervical fistula was made that closed over. A laparoscopic hemi-hysterectomy was done successfully and rapidly with laparoscopic morcellation. Because no ureter was present, it was not necessary to trace it. For this congenital anomaly, laparoscopic morcellation of the obstructed hemiuterus is the preferred treatment either as a primary procedure or as a secondary procedure following failure of a surgical cervical fistula for the young patient. PMID- 20202408 TI - Abdominal drain causing early small bowel obstruction after laparoscopic colectomy. AB - We report a rare drain-related complication leading to small bowel obstruction after laparoscopic colectomy. An 82-year-old man developed small bowel obstruction on the second day after laparoscopic anterior resection. Emergency relaparoscopy found herniation of the small bowel mesentery into the side holes of the silicon intraabdominal drain, which led to a 90-degree acute turn of the small bowel and mechanical obstruction. The herniation was reduced, and the drain was removed laparoscopically. PMID- 20202409 TI - Preparing a community hospital to manage work-related exposures to infectious agents in BioSafety level 3 and 4 laboratories. AB - Construction of new BioSafety Level (BSL) 3 and 4 laboratories has raised concerns regarding provision of care to exposed workers because of healthcare worker (HCW) unfamiliarity with precautions required. When the National Institutes of Health began construction of a new BSL-4 laboratory in Hamilton, Montana, USA, in 2005, they contracted with St. Patrick Hospital in Missoula, Montana, for care of those exposed. A care and isolation unit is described. We developed a training program for HCWs that emphasized the optimal use of barrier precautions and used pathogen-specific modules and simulations with mannequins and fluorescent liquids that represented infectious body fluids. The facility and training led to increased willingness among HCWs to care for patients with all types of communicable diseases. This model may be useful for other hospitals, whether they support a BSL-4 facility, are in the proximity of a BSL-3 facility, or are interested in upgrading their facilities to prepare for exotic and novel infectious diseases. PMID- 20202410 TI - Bartonella spp. transmission by ticks not established. AB - Bartonella spp. infect humans and many animal species. Mainly because PCR studies have demonstrated Bartonella DNA in ticks, some healthcare providers believe that these microorganisms are transmitted by ticks. B. henselae, in particular, is regarded as being present in and transmissible by the Ixodes scapularis tick. The presence of a microbial agent within a tick, however, does not imply that the tick might transmit it during the course of blood feeding and does not confer epidemiologic importance. After a critical review of the evidence for and against tick transmission, we conclude that transmission of any Bartonella spp. by ticks, to animals or humans, has not been established. We are unaware of any well documented case of B. henselae transmission by I. scapularis ticks. PMID- 20202411 TI - Potential for tick-borne bartonelloses. AB - As worldwide vectors of human infectious diseases, ticks are considered to be second only to mosquitoes. Each tick species has preferred environmental conditions and biotopes that determine its geographic distribution, the pathogens it vectors, and the areas that pose risk for tick-borne diseases. Researchers have identified an increasing number of bacterial pathogens that are transmitted by ticks, including Anaplasma, Borrelia, Ehrlichia, and Rickettsia spp. Recent reports involving humans and canines suggest that ticks should be considered as potential vectors of Bartonella spp. To strengthen this suggestion, numerous molecular surveys to detect Bartonella DNA in ticks have been conducted. However, there is little evidence that Bartonella spp. can replicate within ticks and no definitive evidence of transmission by a tick to a vertebrate host. PMID- 20202412 TI - Serologic markers for detecting malaria in areas of low endemicity, Somalia, 2008. AB - Areas in which malaria is not highly endemic are suitable for malaria elimination, but assessing transmission is difficult because of lack of sensitivity of commonly used methods. We evaluated serologic markers for detecting variation in malaria exposure in Somalia. Plasmodium falciparum or P. vivax was not detected by microscopy in cross-sectional surveys of samples from persons during the dry (0/1,178) and wet (0/1,128) seasons. Antibody responses against P. falciparum or P. vivax were detected in 17.9% (179/1,001) and 19.3% (202/1,044) of persons tested. Reactivity against P. falciparum was significantly different between 3 villages (p<0.001); clusters of seroreactivity were present. Distance to the nearest seasonal river was negatively associated with P. falciparum (p = 0.028) and P. vivax seroreactivity (p = 0.016). Serologic markers are a promising tool for detecting spatial variation in malaria exposure and evaluating malaria control efforts in areas where transmission has decreased to levels below the detection limit of microscopy. PMID- 20202413 TI - Infection of kissing bugs with Trypanosoma cruzi, Tucson, Arizona, USA. AB - Triatomine insects (Hemiptera: Reduviidae), commonly known as kissing bugs, are a potential health problem in the southwestern United States as possible vectors of Trypanosoma cruzi, the causative agent of Chagas disease. Although this disease has been traditionally restricted to Latin America, a small number of vector transmitted autochthonous US cases have been reported. Because triatomine bugs and infected mammalian reservoirs are plentiful in southern Arizona, we collected triatomines inside or around human houses in Tucson and analyzed the insects using molecular techniques to determine whether they were infected with T. cruzi. We found that 41.5% of collected bugs (n = 164) were infected with T. cruzi, and that 63% of the collection sites (n = 22) yielded >or=1 infected specimens. Although many factors may contribute to the lack of reported cases in Arizona, these results indicate that the risk for infection in this region may be higher than previously thought. PMID- 20202414 TI - Surveillance for West Nile virus in American white pelicans, Montana, USA, 2006 2007. AB - West Nile virus (WNV)-associated deaths of American white pelican (Pelecanus erythrorhynchos) chicks have been recognized at various nesting colonies in the United States since 2002. We evaluated American white pelican nesting colonies in Sheridan County, Montana, USA, for an association between WNV-positive pelican carcasses and human West Nile neuroinvasive disease. Persons in counties hosting affected colonies had a 5x higher risk for disease than those in counties with unaffected colonies. We also investigated WNV infection and blood meal source among mosquitoes and pelican tissue type for greatest WNV detection efficacy in carcasses. WNV-infected Culex tarsalis mosquitoes were detected and blood engorged Cx. tarsalis contained pelican DNA. Viral loads and detection consistency among pelican tissues were greatest in feather pulp, brain, heart, and skin. Given the risks posed to wildlife and human health, coordinated efforts among wildlife and public health authorities to monitor these pelican colonies for WNV activity are potentially useful. PMID- 20202415 TI - Murine typhus in Austin, Texas, USA, 2008. AB - In August 2008, Texas authorities and the Centers for Disease Control and Prevention investigated reports of increased numbers of febrile rash illnesses in Austin to confirm the causative agent as Rickettsia typhi, to assess the outbreak magnitude and illness severity, and to identify potential animal reservoirs and peridomestic factors that may have contributed to disease emergence. Thirty-three human cases of confirmed murine typhus were identified. Illness onset was reported from March to October. No patients died, but 23 (70%) were hospitalized. The case-patients clustered geographically in central Austin; 12 (36%) resided in a single ZIP code area. Specimens from wildlife and domestic animals near case patient homes were assessed; 18% of cats, 44% of dogs, and 71% of opossums had antibodies reactive to R. typhi. No evidence of R. typhi was detected in the whole blood, tissue, or arthropod specimens tested. These findings suggest that an R. typhi cycle involving opossums and domestic animals may be present in Austin. PMID- 20202416 TI - Chikungunya virus infection during pregnancy, Reunion, France, 2006. AB - Mother-to-child transmission of chikungunya virus was reported during the 2005 2006 outbreak on Reunion Island, France. To determine the effects of this virus on pregnancy outcomes, we conducted a study of pregnant women in Reunion in 2006. The study population was composed of 1,400 pregnant women (628 uninfected, 658 infected during pregnancy, 27 infected before pregnancy, and 87 infected on unknown dates). We compared pregnancy outcomes for 655 (628 + 27) women not infected during pregnancy with 658 who were infected during pregnancy. Infection occurred during the first trimester for 15% of the infected women, the second for 59%, and the third for 26%. Only hospital admission during pregnancy differed between infected and uninfected women (40% vs. 29%). Other outcomes (cesarean deliveries, obstetric hemorrhaging, preterm births, stillbirths after 22 weeks, birthweight, congenital malformations, and newborn admissions) were similar. This virus had no observable effect on pregnancy outcomes. PMID- 20202417 TI - Effects of mumps outbreak in hospital, Chicago, Illinois, USA, 2006. AB - In 2006, nearly 6,000 mumps cases were reported in the United States, 795 of which occurred in Illinois. In Chicago, 1 healthcare institution experienced ongoing transmission for 4 weeks. This study examines the outbreak epidemiology and quantifies the financial affect on this organization. This retrospective cohort study was conducted through case and exposure identification, interviews, medical record reviews, and immunologic testing of blood specimens. Nine mumps cases resulted in 339 exposures, 325 (98%) among employees. During initial investigation, 186 (57%) of the exposed employees had evidence of mumps immunity. Physicians made up the largest group of noncompliers (55%) with mumps immunity testing. The cost to the institution was $262,788 or $29,199 per mumps case. The outbreak resulted in substantial staffing and financial challenges for the institution that may have been minimized with readily accessible electronic employee vaccination records and adherence to infection control recommendations. PMID- 20202418 TI - Blood meal analysis to identify reservoir hosts for Amblyomma americanum ticks. AB - Efforts to identify wildlife reservoirs for tick-borne pathogens are frequently limited by poor understanding of tick-host interactions and potentially transient infectivity of hosts under natural conditions. To identify reservoir hosts for lone star tick (Amblyomma americanum)-associated pathogens, we used a novel technology. In field-collected ticks, we used PCR to amplify a portion of the 18S rRNA gene in remnant blood meal DNA. Reverse line blot hybridization with host specific probes was then used to subsequently detect and identify amplified DNA. Although several other taxa of wildlife hosts contribute to tick infection rates, our results confirm that the white-tailed deer (Odocoileus virginianus) is a reservoir host for several A. americanum-associated pathogens. Identification of host blood meal frequency and reservoir competence can help in determining human infection rates caused by these pathogens. PMID- 20202419 TI - Borrelia, Ehrlichia, and Rickettsia spp. in ticks removed from persons, Texas, USA. AB - Data regarding the type, frequency, and distribution of tick-borne pathogens and bacterial agents are not widely available for many tick species that parasitize persons in the southern United States. We therefore analyzed the frequency and identity of pathogens and bacterial agents in ticks removed from humans and subsequently submitted to the Texas Department of State Health Services, Zoonosis Control Program, from October 1, 2004, through September 30, 2008. The data showed associations of bacterial agents and potential vectors. Tick-related illnesses may pose unidentified health risks in areas such as Texas, where incidence of human disease related to tick bites is low but well above zero and where ticks are not routinely suspected as the cause of disease. Cause, treatment, and prevention strategies can be better addressed through collecting sufficient data to establish baseline assessments of risk. PMID- 20202420 TI - New endemic Legionella pneumophila serogroup I clones, Ontario, Canada. AB - The water-borne pathogen Legionella pneumophila serogroup 1 (Lp1) is the most commonly reported etiologic agent of legionellosis. To examine the genetic diversity, the long-term epidemiology, and the molecular evolution of Lp1 clinical isolates, we conducted sequence-based typing on a collection of clinical isolates representing 3 decades of culture-confirmed legionellosis in Ontario, Canada. Analysis showed that the population of Lp1 in Ontario is highly diverse and combines lineages identified worldwide with local strains. Identical types were identified in sporadic and outbreak-associated strains. In the past 15 years, the incidence of some lineages distributed worldwide has tended to decrease, and local endemic clones and lineages have emerged. Comparative geographic distribution analysis suggests that some lineages are specific to eastern North America. These findings have general clinical implications for the study of Lp1 molecular evolution and for the identification of Lp1 circulating strains in North America. PMID- 20202422 TI - Vaccine preventability of meningococcal clone, Greater Aachen Region, Germany. AB - Emergence of serogroup B meningococci of clonal complex sequence type (ST) 41/44 can cause high levels of disease, as exemplified by a recent epidemic in New Zealand. Multiplication of annual incidence rates (3.1 cases/100,000 population) of meningococcal disease in a defined German region, the city of Aachen and 3 neighboring countries (Greater Aachen) prompted us to investigate and determine the source and nature of this outbreak. Using molecular typing and geographic mapping, we analyzed 1,143 strains belonging to ST41/44 complex, isolated from persons with invasive meningococcal disease over 6 years (2001-2006) from 2 German federal states (total population 26 million) and the Netherlands. A spatially slowly moving clone with multiple-locus variable-number tandem repeat analysis type 19, ST42, and antigenic profile B:P1.7-2,4:F1-5 was responsible for the outbreak. Bactericidal activity in serum samples from the New Zealand MeNZB vaccination campaign confirmed vaccine preventability. Because this globally distributed epidemic strain spreads slowly, vaccination efforts could possibly eliminate meningococcal disease in this area. PMID- 20202421 TI - Invasive Haemophilus influenzae Disease, Europe, 1996-2006. AB - An international collaboration was established in 1996 to monitor the impact of routine Haemophilus influenzae type b (Hib) vaccination on invasive H. influenzae disease; 14 countries routinely serotype all clinical isolates. Of the 10,081 invasive H. influenzae infections reported during 1996-2006, 4,466 (44%, incidence 0.28 infections/100,000 population) were due to noncapsulated H. influenzae (ncHi); 2,836 (28%, 0.15/100,000), to Hib; and 690 (7%, 0.036/100,000), to non-b encapsulated H. influenzae. Invasive ncHi infections occurred in older persons more often than Hib (median age 58 years vs. 5 years, p<0.0001) and were associated with higher case-fatality ratios (12% vs. 4%, p<0.0001), particularly in infants (17% vs. 3%, p<0.0001). Among non-b encapsulated H. influenzae, types f (72%) and e (21%) were responsible for almost all cases; the overall case-fatality rate was 9%. Thus, the incidence of invasive non-type b H. influenzae is now higher than that of Hib and is associated with higher case fatality. PMID- 20202424 TI - Economic cost analysis of West Nile virus outbreak, Sacramento County, California, USA, 2005. AB - In 2005, an outbreak of West Nile virus (WNV) disease occurred in Sacramento County, California; 163 human cases were reported. In response to WNV surveillance indicating increased WNV activity, the Sacramento-Yolo Mosquito and Vector Control District conducted an emergency aerial spray. We determined the economic impact of the outbreak, including the vector control event and the medical cost to treat WNV disease. WNV disease in Sacramento County cost approximately $2.28 million for medical treatment and patients' productivity loss for both West Nile fever and West Nile neuroinvasive disease. Vector control cost approximately $701,790, including spray procedures and overtime hours. The total economic impact of WNV was $2.98 million. A cost-benefit analysis indicated that only 15 cases of West Nile neuroinvasive disease would need to be prevented to make the emergency spray cost-effective. PMID- 20202423 TI - Use of avian bornavirus isolates to induce proventricular dilatation disease in conures. AB - Avian bornavirus (ABV) is a newly discovered member of the family Bornaviridae that has been associated with the development of a lethal neurologic syndrome in birds, termed proventricular dilatation disease (PDD). We successfully isolated and characterized ABV from the brains of 8 birds with confirmed PDD. One isolate was passed 6 times in duck embryo fibroblasts, and the infected cells were then injected intramuscularly into 2 healthy Patagonian conures (Cyanoliseus patagonis). Clinical PDD developed in both birds by 66 days postinfection. PDD was confirmed by necropsy and histopathologic examination. Reverse transcription PCR showed that the inoculated ABV was in the brains of the 2 infected birds. A control bird that received uninfected tissue culture cells remained healthy until it was euthanized at 77 days. Necropsy and histopathologic examinations showed no abnormalities; PCR did not indicate ABV in its brain tissues. PMID- 20202426 TI - Rickettsia helvetica in patient with meningitis, Sweden, 2006. AB - Pathogenicity of Rickettsia helvetica is relatively unknown. We isolated a spotted fever group rickettsial organism from a patient with subacute meningitis. Nucleotide sequences of the 16S rRNA, ompB, and 17kDa genes identified the isolate as R. helvetica. This organism may be associated with serious infections such as central nervous system disorders. PMID- 20202425 TI - Paenibacillus larvae Bacteremia in injection drug users. AB - Paenibacillus larvae causes American foulbrood in honey bees. We describe P. larvae bacteremia in 5 injection drug users who had self-injected honey-prepared methadone proven to contain P. larvae spores. That such preparations may be contaminated with spores of this organism is not well known among pharmacists, physicians, and addicts. PMID- 20202427 TI - Rare influenza A (H3N2) variants with reduced sensitivity to antiviral drugs. AB - In 2007 and 2008 in Myanmar, we detected influenza viruses A (H3N2) that exhibited reduced sensitivity to both zanamivir and amantadine. These rare and naturally occurring viruses harbored a novel Q136K mutation in neuraminidase and S31N mutation in M2. PMID- 20202428 TI - Etymologia: yersinia. PMID- 20202429 TI - Sarcocystis species lethal for domestic pigeons. AB - A large number of Sarcocystis spp. infect birds as intermediate hosts, but pigeons are rarely affected. We identified a novel Sarcocystis sp. that causes lethal neurologic disease in domestic pigeons in Germany. Experimental infections indicated transmission by northern goshawks, and sequence analyses indicated transnational distribution. Worldwide spread is possible. PMID- 20202430 TI - Candidatus Bartonella mayotimonensis and endocarditis. AB - We describe a new Bartonella species for which we propose the name Candidatus Bartonella mayotimonensis. It was isolated from native aortic valve tissue of a person with infective endocarditis. The new species was identified by using PCR amplification and sequencing of 5 genes (16S rRNA gene, ftsZ, rpoB, gltA, and internal transcribed spacer region). PMID- 20202431 TI - Surveillance lessons from first-wave pandemic (H1N1) 2009, Northern California, USA. AB - After the appearance of pandemic (H1N1) 2009 in April 2009, influenza activity was monitored within the Kaiser Permanente Northern California division by using laboratory, pharmacy, telephone calls, and utilization (services patients received) data. A combination of testing and utilization data showed a pattern of disease activity, but this pattern may have been affected by public perception of the epidemic. PMID- 20202432 TI - Experimental infection of squirrel monkeys with nipah virus. AB - We infected squirrel monkeys (Saimiri sciureus) with Nipah virus to determine the monkeys' suitability for use as primate models in preclinical testing of preventive and therapeutic treatments. Infection of squirrel monkeys through intravenous injection was followed by high death rates associated with acute neurologic and respiratory illness and viral RNA and antigen production. PMID- 20202433 TI - Q fever in Greenland. AB - We report a patient with Q fever endocarditis in a settlement in eastern Greenland (Isortoq, Ammassalik area). Likely animal sources include sled dogs and seals. Q fever may be underdiagnosed in Arctic areas but may also represent an emerging infection. PMID- 20202434 TI - Banna virus, China, 1987-2007. AB - Banna viruses (BAVs) have been isolated from pigs, cattle, ticks, mosquitoes, and human encephalitis patients. We isolated and analyzed 20 BAVs newly isolated in China; this finding extends the distribution of BAVs from tropical zone to north temperate climates and demonstrate regional variations in BAV phylogeny and mosquito species possibly involved in BAV transmission. PMID- 20202435 TI - Bluetongue virus serotypes 1 and 4 in red deer, Spain. AB - We studied the potential of red deer as bluetongue maintenance hosts and sentinels. Deer maintained detectable bluetongue virus (BTV) serotype 4 RNA for 1 year after the virus was cleared from livestock. However, the virus was not transmitted to yearlings. BTV serotype 1 RNA was detected in red deer immediately after its first detection in cattle. PMID- 20202436 TI - Novel spotted fever group rickettsiosis, Brazil. AB - We report a clinical case of spotted fever group rickettsiosis acquired in Sao Paulo, Brazil. Definitive diagnosis was supported by seroconversion between acute phase and convalescent-phase serum samples. Molecular analysis of skin samples indicated the agent was a novel spotted fever group strain closely related to Rickettsia africae, R. parkeri, and R. sibirica. PMID- 20202437 TI - Climate warming and tick-borne encephalitis, Slovakia. AB - Increased tick-borne encephalitis (TBE) cases have been reported in central Europe. To investigate temporal trends in the altitude at which TBE cases occur in Slovakia, we analyzed the number of TBE cases during 1961-2004. Since 1980, TBE cases moved from lowlands to submountainous areas, most likely because of rising temperature. PMID- 20202438 TI - Terrestrial rabies and human postexposure prophylaxis, New York, USA. AB - During 1993-2002, cats accounted for 2.7% of rabid terrestrial animals in New York but for one third of human exposure incidents and treatments. Nonbite exposures and animals of undetermined rabies status accounted for 54% and 56%, respectively, of persons receiving rabies treatments. PMID- 20202439 TI - Increasing skin infections and Staphylococcus aureus complications in children, England, 1997-2006. AB - During 1997-2006, general practitioner consultations for skin conditions for children <18 years of age in England increased 19%, from 128.5 to 152.9/1,000 child-years, and antistaphylococcal drug prescription rates increased 64%, from 17.8 to 29.1/1,000 child-years. During the same time period, hospital admissions for Staphylococcus aureus infections rose 49% from 53.4 to 79.3/100,000 child years. PMID- 20202441 TI - School closure and mitigation of pandemic (H1N1) 2009, Hong Kong. AB - In Hong Kong, kindergartens and primary schools were closed when local transmission of pandemic (H1N1) 2009 was identified. Secondary schools closed for summer vacation shortly afterwards. By fitting a model of reporting and transmission to case data, we estimated that transmission was reduced approximately 25% when secondary schools closed. PMID- 20202440 TI - Influenza A pandemic (H1N1) 2009 virus infection in domestic cat. AB - Influenza A pandemic (H1N1) 2009 virus continues to rapidly spread worldwide. In 2009, pandemic (H1N1) 2009 infection in a domestic cat from Iowa was diagnosed by a novel PCR assay that distinguishes between Eurasian and North American pandemic (H1N1) 2009 virus matrix genes. Human-to-cat transmission is presumed. PMID- 20202442 TI - Global Origin of Mycobacterium tuberculosis in the Midlands, UK. AB - DNA fingerprinting data for 4,207 Mycobacterium tuberculosis isolates were combined with data from a computer program (Origins). Largest population groups were from England (n = 1,031) and India (n = 912), and most prevalent strains were the Euro-American (45%) and East African-Indian (34%) lineages. Combining geographic and molecular data can enhance cluster investigation. PMID- 20202443 TI - Quinine-resistant malaria in traveler returning from Senegal, 2007. AB - We describe clinical and parasitologic features of in vivo and in vitro Plasmodium falciparum resistance to quinine in a nonimmune traveler who returned to France from Senegal in 2007 with severe imported malaria. Clinical quinine failure was associated with a 50% inhibitory concentration of 829 nmol/L. Increased vigilance is required during treatment follow-up. PMID- 20202444 TI - Putative new lineage of west nile virus, Spain. AB - To ascertain the presence of West Nile virus (WNV), we sampled mosquitoes in 2006 in locations in southern Spain where humans had been infected. WNV genomic RNA was detected in 1 pool from unfed female Culex pipiens mosquitoes. Phylogenetic analysis demonstrated that this sequence cannot be assigned to previously described lineages of WNV. PMID- 20202445 TI - Venezuelan equine encephalitis and 2 human deaths, Peru. AB - Studies have suggested that enzootic strains of Venezuelan equine encephalitis (VEE) subtype ID in the Amazon region, Peru, may be less pathogenic to humans than are epizootic variants. Deaths of 2 persons with evidence of acute VEE virus infection indicate that fatal VEEV infection in Peru is likely. Cases may remain underreported. PMID- 20202446 TI - Extensively drug-resistant Mycobacterium tuberculosis from aspirates, Rural South Africa. AB - The yield from aspirating lymph nodes and pleural fluid for diagnosing extensively drug-resistant (XDR) tuberculosis is unknown. Mycobacterium tuberculosis was cultured from lymph node or pleural fluid aspirates of 21 patients; 7 (33%) cultures grew XDR M. tuberculosis. Additive diagnostic yield for XDR M. tuberculosis was found in parallel culture of sputum and fluid aspirate. PMID- 20202447 TI - Parvovirus 4-like virus in blood products. AB - Porcine plasma and factor VIII preparations were screened for parvovirus 4 (PARV) like viruses. Although the prevalence of PARV4-like viruses in plasma samples was relatively low, viruses appeared to be concentrated during manufacture of factor VIII. PARV4-like viruses from human and porcine origins coevolved likewise with their hosts. PMID- 20202448 TI - Rhabdomyolysis and pandemic (H1N1) 2009 pneumonia in adult. PMID- 20202449 TI - Yersinia pseudotuberculosis and Y. enterocolitica infections, FoodNet, 1996-2007. PMID- 20202450 TI - Measles outbreak, the Netherlands, 2008. PMID- 20202451 TI - Neurologic manifestations of pandemic (H1N1) 2009 virus infection. PMID- 20202452 TI - Rickettsia felis, West Indies. PMID- 20202453 TI - Rickettsia africae, Western Africa. PMID- 20202454 TI - Transmission of West Nile virus during horse autopsy. PMID- 20202455 TI - Breeding sites of bluetongue virus vectors, belgium. PMID- 20202456 TI - Two lineages of dengue virus type 2, Brazil. PMID- 20202457 TI - Yersinia species isolated from bats, Germany. PMID- 20202458 TI - Human herpesvirus 8, Southern Siberia. PMID- 20202459 TI - A flea Has smaller fleas that on him prey; and these have smaller still to bite 'em, and so proceed ad infinitum. PMID- 20202460 TI - Personalizing medicine through personalized communication: individuality of the patient across borders and cultures. PMID- 20202461 TI - Does adjuvant bisphosphonate in early breast cancer modify the natural course of the disease? A meta-analysis of randomized controlled trials. AB - To address whether the use of bisphosphonates in the adjuvant setting of breast cancer might have any effect on the natural course of the disease, a meta analysis was conducted of published and unpublished randomized controlled trials found in PubMed, the Cochrane Central Register of Controlled Trials, the ISI Web of Knowledge, and abstracts of major international conferences up to January 2009. All trials that randomized patients with primary breast cancer to undergo adjuvant treatment with any bisphosphonate versus non-use were considered eligible. Analysis included data from 13 eligible trials involving 6886 patients randomized to treatment with bisphosphonates (n = 3414) or either placebo or no treatment (n = 3472). Compared with no use, adjuvant breast cancer treatment with bisphosphonates did not reduce the overall number of deaths (odds ratio [OR], 0.708; 95% CI, 0.482-1.041; P = .079), bone metastases (OR, 0.925; 95% CI, 0.768 1.114; P = .413), overall disease recurrences (OR, 0.843; 95% CI, 0.602-1.181; P = .321), distant relapse (OR, 0.896; 95% CI, 0.674-1.192; P = .453), visceral recurrences (OR, 1.051; 95% CI, 0.686-1.609; P = .820), or local relapses (OR, 1.056; 95% CI, 0.750-1.487; P = .756). No significant heterogeneity was observed among the trials except for estimates of deaths and disease recurrences (P = .034 and P = .016, respectively). In subgroup analyses, use of zoledronic acid was associated with a statistically significant lower risk for disease recurrence (OR, 0.675; 95% CI, 0.479-0.952; P = .025). However, these results should be interpreted with caution because the statistical significance for this association was weak and might be attributed to chance from multi-test analyses. Use of zoledronic acid was not associated with any significant difference in death (OR, 0.642; 95% CI, 0.388-1.063) and bone metastasis rates (OR, 0.661; 95% CI, 0.379-1.151). Currently available evidence does not support the hypothesis that use of bisphosphonates in adjuvant treatment of early breast cancer will alter the natural course of the disease. Nonetheless, a nonsignificant trend seems to exist for better outcomes in patients undergoing bisphosphonate treatment. Until further evidence from new clinical trials becomes available, adjuvant bisphosphonates should not be recommended routinely. PMID- 20202462 TI - NCCN Clinical Practice Guidelines in Oncology: non-Hodgkin's lymphomas. PMID- 20202463 TI - The role of hematopoietic stem cell transplant in follicular lymphoma. AB - Substantial progress has been made in the clinical management of patients with follicular lymphoma over the past 2 decades. However, the role of autologous and allogeneic stem cell transplantation in these patients remains controversial. Myeloablative chemotherapy or radioimmunotherapy supported by autologous hematopoietic cell transplantation has been shown to lead to a longer progression free survival and, in some studies, improved survival over standard therapy. However, in the era of rituximab-based therapies used as part of induction or salvage, these historical trials may not be representative. Allogeneic stem cell transplantation offers the advantages of a tumor-free graft and some immunologic graft-versus-lymphoma effects. However, fully myeloablative transplants have high morbidity and mortality rates. Dose-reduced conditioning regimens followed by allogeneic hematopoietic cell transplantation have substantially reduced treatment-related mortality and perhaps will produce better outcomes long-term. This article outlines some historical information regarding stem cell transplantation for follicular lymphoma and discusses recent modifications that may improve outcomes, such as adding radioimmunotherapy to autologous stem cell transplantation or using alternative dose-reduced regimens that could benefit patients with reduced toxicities. PMID- 20202464 TI - An update on the role of interim restaging FDG-PET in patients with diffuse large B-cell lymphoma and Hodgkin lymphoma. AB - A significant amount of literature is available on treatment monitoring and response assessment in lymphoma using FDG-PET, yet confusion exists concerning the potential and limitations of FDG-PET for determining the presence of residual disease during chemotherapy (interim FDG-PET). This article reviews the role of interim FDG-PET in 3 important scenarios: untreated diffuse large B-cell lymphoma, untreated Hodgkin lymphoma, and relapsed or refractory aggressive lymphoma in transplant-eligible patients, and provides recommendations on the use of this imaging modality in these settings. PMID- 20202465 TI - Genomic analysis of lymphoma: potential for clinical application. AB - The application of gene expression profiling to the study of lymphomas will significantly influence the way these tumors are diagnosed and treated. Diffuse large B-cell lymphoma is now known to consist of several different genetic entities with different clinical presentations and therapeutic outcomes. In both follicular and diffuse large B-cell lymphoma, these studies have shown that host tumor interactions have a major impact on the clinical course. Findings of gene expression profiling in diffuse large B-cell lymphoma has indicated the frequent up-regulation of the nuclear factor-kappaB and B-cell receptor signaling pathways in the activated B-cell type. Drugs targeting these pathways may be effective in the treatment of these cases and clinical trials have been initiated based on these findings. Gene expression profiling may assist in the selection of treatments based on specific metabolic pathways shown to be active in a particular lymphoma. These techniques offer the promise of truly personalized medicine for patients with lymphoma. PMID- 20202466 TI - Time sequence of auditory nerve and spiral ganglion cell degeneration following chronic kanamycin-induced deafness in the guinea pig. AB - We investigated the time sequence of morphological changes of the spiral ganglion cell (SGC) and auditory nerve (AN) following chronic kanamycin-induced deafness. Guinea pigs were treated with kanamycin by subcutaneous injection at 500 mg/kg per day for 7 days. Histological changes in hair cells, SGCs, Schwann cells and the area of the cross-sectional of the AN with vestibular ganglion (VG) in the internal acoustic meatus were quantified at 1, 7, 14, 28, 56 and 70 days after kanamycin treatment. Outer hair cells decreased at 7 and 14 days. Loss of inner hair cells occurred at 14 and 28 days. The cross-sectional area of the AN with VG increased at 1 day and decreased shortly following loss of SGCs and Schwann cells at 7, 14 and 28 days after deafening. There was a similar time course of morphological changes in the overall cochlea and the basal turn. Thus, the effects of kanamycin on hair cells, spiral ganglion and Schwann cells are progressive. Early degeneration of SGC and Schwann cell mainly results from the direct toxic effect of kanamycin. However, multiple factors such as loss of hair cell, degeneration of Schwann cell and the progressive damage of kanamycin, may participate in the late degeneration process of SGCs. The molecular mechanism of the degeneration of SGC and Schwann cell should be investigated in the future. Moreover, there is a different time sequence of cell degeneration between acute and chronic deafness by kanamycin. PMID- 20202467 TI - Role of thromboxane TP and angiotensin AT1 receptors in lipopolysaccharide induced arterial dysfunction in the rabbit: an in vivo study. AB - Inflammation plays a major role in pathological conditions leading to cardiovascular events. Administration of lipopolysaccharide to animals decreases arterial blood flow, in contrast to the dilatations that occur in microvessels. The purpose of the present study was to determine whether or not lipopolysaccharide, in vivo, evokes arterial constriction and if so the underlying mechanisms. Rabbits were anaesthetized, blood pressure monitored and femoral artery diameter continuously recorded with an echotracking device. Lipopolysaccharide induced leucopenia, thrombocytopenia, acidosis and a progressive hypotension with a decrease in femoral artery diameter (-30.7+/-2.4% after 3 h) and an increase in arterial rigidity. Three hours after lipopolysaccharide administration, the arterial dilatations to acetylcholine, arachidonic acid and iloprost were inhibited while that to sodium nitroprusside was not altered; the constrictions to norepinephrine, angiotensin II, U46619 (thromboxane analog) and serotonin were not modified. Under control conditions endothelin-1 produced an endothelin ET(B) dependent dilatation, reversed after lipopolysaccharide to an endothelin ETA dependent constriction. The thromboxane TP receptor antagonist S 18886 partially blocked the constriction; the angiotensin AT1 receptor antagonist candesartan prevented it. S 18886 normalized the impaired dilatations to acetylcholine, antagonists of 5-HT-receptors partially restored them while candesartan was ineffective. Antagonists of the endothelin or the histamine receptors had no effect. The present data show that lipopolysaccharide-induced inflammation causes 1) a strong constriction of the femoral artery in which activation of both thromboxane and angiotensin AT1 receptors is involved 2) a reduction of the endothelium-dependent dilatation to acetylcholine attributed to the activation of thromboxane TP receptors. PMID- 20202468 TI - Erythropoietin suppresses epithelial to mesenchymal transition and intercepts Smad signal transduction through a MEK-dependent mechanism in pig kidney (LLC PK1) cell lines. AB - PURPOSE: Tumor growth factor-beta1 (TGF-beta1) plays a pivotal role in processes like kidney epithelial-mesenchymal transition (EMT) and interstitial fibrosis, which correlate well with progression of renal disease. Little is known about underlying mechanisms that regulate EMT. Based on the anatomical relationship between erythropoietin (EPO)-producing interstitial fibroblasts and adjacent tubular cells, we investigated the role of EPO in TGF-beta1-mediated EMT and fibrosis in kidney injury. METHODS: We examined apoptosis and EMT in TGF-beta1 treated LLC-PK1 cells in the presence or absence of EPO. We examined the effect of EPO on TGF-beta1-mediated Smad signaling. Apoptosis and cell proliferation were assessed with flow cytometry and hemocytometry. We used Western blotting and indirect immunofluorescence to evaluate expression levels of TGF-beta1 signal pathway proteins and EMT markers. RESULTS: We demonstrated that ZVAD-FMK (a caspase inhibitor) inhibited TGF-beta1-induced apoptosis but did not inhibit EMT. In contrast, EPO reversed TGF-beta1-mediated apoptosis and also partially inhibited TGF-beta1-mediated EMT. We showed that EPO treatment suppressed TGF beta1-mediated signaling by inhibiting the phosphorylation and nuclear translocation of Smad 3. Inhibition of mitogen-activated protein kinase kinase 1 (MEK 1) either directly with PD98059 or with MEK 1 siRNA resulted in inhibition of EPO-mediated suppression of EMT and Smad signal transduction in TGF-beta1 treated cells. CONCLUSIONS: EPO inhibited apoptosis and EMT in TGF-beta1-treated LLC-PK1 cells. This effect of EPO was partially mediated by a mitogen-activated protein kinase-dependent inhibition of Smad signal transduction. PMID- 20202469 TI - Development of an immunoassay for the detection of cystatin C dimers. AB - Human cystatin C (CysC) is a reversible cysteine protease inhibitor, which is abundantly secreted to body fluids. It is a potential marker of kidney dysfunction, but has been suggested to be of diagnostic importance in a number of neurodegenerative diseases, as well. The amyloid formation by a L68Q variant CysC accounts for the hereditary CysC amyloid angiopathy (HCCAA). Also, the wild type CysC forms inactive dimers at partly denaturing conditions through a domain swapping mechanism. Here, we have developed an immunoassay for the detection of dimeric CysC consisting of either a full length or an N-terminally truncated form. A codon optimized gene encoding a full length CysC was expressed in Escherichia coli, where the product was directed to the periplasmic space. Two different forms of CysC were isolated, a full length product and a form proteolytically truncated by 8 N-terminal amino acid residues. In vitro dimerization experiments were conducted in order to enable the selection of monoclonal antibodies for the construction of an immunoassay being able to primarily recognize the dimers. The analytical detection limit of the assay was 0.043 microg/l, with assay imprecision below 16%. The assay was linear in the range of 5-100 microg/l (R(2)=0.997). The dimer assay was employed for the measurement of serum and cerebrospinal fluid (CSF) sample panel of 20 multiple sclerosis (MS) and 22 non-MS patients. A dimer signal was observed in both serum and CSF samples. The dimer signals from CSF were approximately 2-22 times higher (average 13) than the corresponding signals from serum samples. However, the measured signal levels between the different patient groups showed no statistically significant difference in serum or in CSF (P=0.07 and P=0.98 respectively). In conclusion, the immunoassay provides direct means for detecting CysC dimers in serum and CSF in respect to the amount of total CysC. PMID- 20202470 TI - 2-Methoxyestradiol induce the conversion of human peripheral blood memory B lymphocytes into plasma cells. AB - 2-Methoxyestradiol (2ME), an end-metabolite of 17beta-estradiol, is an antiproliferative agent that is currently being tested in clinical trials for cancer treatment. We hereby report that sub-cytotoxic concentrations of 2ME influence the in vitro proliferation of human peripheral blood B lymphocytes. More surprisingly, we have observed that 2ME induces the conversion of CD138(-) B lymphocytes into CD138(+) cells of phenotype similar to immunoglobulin (Ig) secreting plasma cells. Normal human B lymphocytes expressing CD138 increased in response to 2ME in a dose-dependent fashion, from 2% at baseline up to 31% in cells cultured in the presence of 0.75 microM 2ME. Moreover, most of the converted cells were also CD27(+) and secreted high levels of IgG (151 microg/10(6)cells/24h). IEF studies revealed that conversion occurred in a polyclonal manner. We then exploited this effect of 2ME to gain further insights into the molecular mechanisms that govern changes in transcription factors involved in plasma cells differentiation. Plasma cells generated by 2ME treatment of normal human B lymphocytes expressed elevated levels of IRF4 and reduced levels of Pax5 and Bcl-6. Similarly, levels of XBP-1 and Blimp-1 transcripts were increased. Our results suggest that the differentiation of peripheral blood B lymphocytes into plasma cells requires a similar modulation of transcription factors expression that for tonsil and bone marrow B lymphocytes. PMID- 20202471 TI - New syntax to describe local continuous structure-sequence information for recognizing new pre-miRNAs. AB - As an important complement to experimental identification of pre-miRNA, computational prediction methods are attracting more and more attention. Features extracted from pre-miRNA are the key to computational prediction. Among the features, local continuous structure-sequence information is usually employed by existing computational methods. As more and more species-specific miRNAs have been identified, a new syntax is required to describe pre-miRNA local continuous structure-sequence features. Therefore, we proposed here the use of couplet syntax to describe pre-miRNA intrinsic features. When tested on a dataset from miRBase12.0 with the use of features extracted by couplet syntax, the SVM classifier achieves a sensitivity of 81.98% and specificity of 87.16% on a human test set and a sensitivity of 86.71% on all other species. The obtained results indicate that the proposed couplet syntax can describe the intrinsic features of pre-miRNA better than traditional methods. By means of describing pre-miRNA secondary structure more precisely and masking frequently mutated nucleotides, couplet syntax provides a powerful feature-describing method that can be applied to many computational prediction methods. PMID- 20202472 TI - Helix-helix interactions and their impact on protein motifs and assemblies. AB - Protein secondary structure elements are arranged in distinct structural motifs such as four-alpha-helix bundle, 8alpha/8beta TIM-barrel, Rossmann dinucleotide binding fold, assembly of a helical rod. Each structural motif is characterized by a particular type of helix-helix interactions. A unique pattern of contacts is formed by interacting helices of the structural motif. In each type of fold, edges of the helix surface, which participate in the formation of helix-helix contacts with preceding and following helices, differ. This work shows that circular arrangements of the four, eight, and sixteen alpha-helices, which are found in the four-alpha-helical motif, TIM-barrel 8alpha/8beta fold, and helical rod of 16.3 helices per turn correspondingly, can be associated with the mutual positioning of the edges of the helix surfaces. Edges (i, i+1)-(i+1, i+2) of the helix surface are central for the interhelical contacts in a four-alpha-helix bundle. Edges (i, i+1)-(i+2, i+3) are involved in the assembly of four-alpha helix subunits into helical rod of a tobacco mosaic virus and a three-helix fragment of a Rossmann fold. In 8alpha/8beta TIM-barrel fold, edges (i, i+1) (i+5, i+6) are involved in the octagon arrangement. Approximation of a cross section of each motif with a polygon (n-gon, n=4, 8, 16) shows that a good correlation exists between polygon interior angles and angles formed by the edges of helix surfaces. PMID- 20202473 TI - Development of a weak-base docetaxel derivative that can be loaded into lipid nanoparticles. AB - Hydrophobic uncharged drugs such as docetaxel are difficult to encapsulate and retain in liposomal nanoparticles (LNP). In this work we show that a weak base derivative of docetaxel can be actively loaded into LNP using pH gradient loading techniques to achieve stable drug encapsulation and controlled release properties. Docetaxel was derivatized at the hydroxyl group in the C-2' position to form an N-methyl-piperazinyl butanoic acid ester. The free hydroxyl group in this position is essential for anticancer activity and the prodrug has, therefore, to be converted into the parent drug (docetaxel) to restore activity. Cytotoxicity testing against a panel of cancer cell lines (breast, prostate and ovarian cancer) demonstrated that the prodrug is readily converted into active drug; the derivative was found to be as active as the parent drug in vitro. The docetaxel derivative can be efficiently loaded at high drug-to-lipid ratios (up to 0.4 mg/mg) into LNP using pH loading techniques. Pharmacokinetic, tolerability and efficacy studies in mice demonstrate that the LNP-encapsulated prodrug has the long drug circulation half-life required for efficient tumor accumulation (50 100 times higher drug plasma levels compared with free derivative and Taxotere, the commercial docetaxel formulation), is active in a xenograft model of breast cancer (MDA-MB-435/LCC6), and is well tolerated at i.v. doses of 3 times higher than the maximum tolerated dose (MTD) of the parent drug. This is the first demonstration that a therapeutically active, remote-loaded, controlled-release LNP formulation of a taxane can be achieved. The approach reported here has broad applicability to other approved drugs as well as new chemical entities. PMID- 20202475 TI - Higher serum tropomyosin-related kinase B protein level in major depression. AB - Accumulating evidence suggests that the brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) are molecules involved in the pathophysiology of major depressive disorder and response of antidepressants. To examine both BDNF and TrkB protein levels and their relationship with psychopathology in patients with major depressive disorder, 55 physically healthy patients with major depressive disorder were compared with 53 healthy controls. The severity of major depression was assessed by the 17-item Hamilton Depression Rating Scale (HDRS). Serum BDNF and TrkB protein levels were measured with Enzyme linked immunosorbent assay (ELISA) kits. After using the analysis of covariance (ANCOVA) with age adjustment, the results of this work showed that BDNF presented no significant difference (F((1,107))=0.149, p=0.701) but the TrkB protein level was significantly higher in depressive patients than in healthy controls (F((1,107))=4.043, p=0.047). These findings suggest that the serum TrkB protein level may play an important role in the psychopathology of major depression. PMID- 20202474 TI - Ultrasound-enhanced delivery of targeted echogenic liposomes in a novel ex vivo mouse aorta model. AB - The goal of this study was to determine whether targeted, Rhodamine-labeled echogenic liposomes (Rh-ELIP) containing nanobubbles could be delivered to the arterial wall, and whether 1-MHz continuous wave ultrasound would enhance this delivery profile. Aortae excised from apolipoprotein-E-deficient (n=8) and wild type (n=8) mice were mounted in a pulsatile flow system through which Rh-ELIP were delivered in a stream of bovine serum albumin. Half the aortae from each group were treated with 1-MHz continuous wave ultrasound at 0.49 MPa peak-to-peak pressure, and half underwent sham exposure. Ultrasound parameters were chosen to promote stable cavitation and avoid inertial cavitation. A broadband hydrophone was used to monitor cavitation activity. After treatment, aortic sections were prepared for histology and analyzed by an individual blinded to treatment conditions. Delivery of Rh-ELIP to the vascular endothelium was observed, and sub endothelial penetration of Rh-ELIP was present in five of five ultrasound-treated aortae and was absent in those not exposed to ultrasound. However, the degree of penetration in the ultrasound-exposed aortae was variable. There was no evidence of ultrasound-mediated tissue damage in any specimen. Ultrasound-enhanced delivery within the arterial wall was demonstrated in this novel model, which allows quantitative evaluation of therapeutic delivery. PMID- 20202476 TI - Activation of apoptosis signal-regulating kinase 1 is a key factor in paraquat induced cell death: modulation by the Nrf2/Trx axis. AB - Although oxidative stress is fundamental to the etiopathology of Parkinson disease, the signaling molecules involved in transduction after oxidant exposure to cell death are ill-defined, thus making it difficult to identify molecular targets of therapeutic relevance. We have addressed this question in human dopaminergic neuroblastoma SH-SY5Y cells exposed to the parkinsonian toxin paraquat (PQ). This toxin elicited a dose-dependent increase in reactive oxygen species and cell death that correlated with activation of ASK1 and the stress kinases p38 and JNK. The relevance of these kinases in channeling PQ neurotoxicity was demonstrated with the use of interference RNA for ASK1 and two well-established pharmaceutical inhibitors for JNK and p38. The toxic effect of PQ was substantially attenuated by preincubation with vitamin E, blocking ASK1 pathways and preventing oxidative stress and cell death. In a search for a physiological pathway that might counterbalance PQ-induced ASK1 activation, we analyzed the role of the transcription factor Nrf2, master regulator of redox homeostasis, and its target thioredoxin (Trx), which binds and inhibits ASK1. Trx levels were undetectable in Nrf2-deficient mouse embryo fibroblasts (MEFs), whereas they were constitutively high in Keap1-deficient MEFs as well as in SH SY5Y cells treated with sulforaphane (SFN). Consistent with these data, Nrf2 deficient MEFs were more sensitive and Keap1-deficient MEFs and SH-SY5Y cells incubated with SFN were more resistant to PQ-induced cell death. This study identifies ASK1/JNK and ASK1/p38 as two critical pathways involved in the activation of cell death under oxidative stress conditions and identifies the Nrf2/Trx axis as a new target to block these pathways and protect from oxidant exposure such as that found in Parkinson and other neurodegenerative diseases. PMID- 20202477 TI - Cloning and tissue expressions of seven chitinase family genes in Litopenaeus vannamei. AB - GH18 chitinase is a multi-gene family. The family plays important physiological roles in Crustacea, e.g. ecdysis and defense against pathogen. However, data about GH18 family are rather limited in Crustacea. In the study, different cloning strategies were adopted to clone chitinase genes of Litopenaeus vannamei, which is the most widely cultured shrimp. Seven chitinase family members were identified. Analysis of domain architectures showed the repeated CBM18 modules and catalytic domain of enzymatically inactive chitolectin in Crustacea for the first time. Comparing to the three known groups of crustacean chitinase, four of the seven members are located on new evolutionary clades thus enriched the chitinase family of Crustacea. Tissue expression profiles were investigated in eight tissues. Expression of CHT5 and CHID1 were both detected in the hemocyte by which the innate immunity activity was carried out. The domain architectures, evolutionary relationships and tissue expression patterns all provide reasonable explanation for the existence of multiple genes in crustacean chitinase family. PMID- 20202478 TI - Molecular cloning of sea bass (Dicentrarchus labrax L.) caspase-8 gene and its involvement in Photobacterium damselae ssp. piscicida triggered apoptosis. AB - Caspase-8 is an initiator caspase that plays a crucial role in some cases of apoptosis by extrinsic and intrinsic pathways. Caspase-8 structure and function have been extensively studied in mammals, but in fish the characterization of that initiator caspase is still scarce. In this work, the sea bass counterpart of mammalian caspase-8 was sequenced and characterized, and its involvement in the apoptogenic activity of a toxin from a fish pathogen was assessed. A 2472 bp cDNA of sea bass caspase-8 was obtained, consisting of 1455 bp open reading frame coding for 484 amino acids and with a predicted molecular weight of 55.2 kDa. The sea bass caspase-8 gene has 6639 bp and is organized in 11 introns and 12 exons. Several distinctive features of sea bass caspase-8 were identified, which include two death effector domains, the caspase family domains p20 and p10, the caspase-8 active-site pentapeptide and potential aspartic acid cleavage sites. The sea bass caspase-8 sequence revealed a significant degree of similarity to corresponding sequences from several vertebrate taxonomic groups. A low expression of sea bass caspase-8 was detected in various tissues of non-stimulated sea bass. Furthermore, it is shown that stimulation of sea bass with mid-exponential phase culture supernatants from Photobacterium damselae ssp. piscicida (Phdp), known to induce selective apoptosis of macrophages and neutrophils, resulted in an increased expression of caspase-8 in the spleen, one of the main affected organs by Phdp infection. PMID- 20202479 TI - The Marsupenaeus japonicus voltage-dependent anion channel (MjVDAC) protein is involved in white spot syndrome virus (WSSV) pathogenesis. AB - Voltage-dependent anion channel (VDAC) proteins abound in the outer membrane of mitochondria. They play an important role in mitochondrial membrane permeabilization (MMP), which can lead to stress-induced cellular apoptosis and necrosis. Several pathogens regulate this MMP in their host cells to benefit their replication cycle, while in other cases, the host can use the same mechanism to combat pathogenesis. In this study, the first shrimp VDAC gene was identified and characterized from Marsupenaeus japonicus (MjVDAC). Its open reading frame (ORF) contained 849 bp encoding 282 amino acids. The deduced MjVDAC protein includes the 4-element eukaryotic porin signature motif, the conserved ATP binding motif (the GLK motif) and a VKAKV-like sequence known in other organisms to be involved in the protein's incorporation in the mitochondrial outer membrane. Tissue tropism analysis indicated that MjVDAC is abundant in the heart, muscle, stomach and pleopod. MjVDAC proteins colocalized with mitochondria in transiently transfected Sf9 cells and in shrimp hemocytes. dsRNA silencing of shrimp VDAC delayed white spot syndrome virus (WSSV) infection by 1 day in different shrimp organs. Taken together, these findings suggest that MjVDAC is likely to be involved in WSSV pathogenesis. PMID- 20202481 TI - Wiener-Granger causality: a well established methodology. AB - For decades, the main ways to study the effect of one part of the nervous system upon another have been either to stimulate or lesion the first part and investigate the outcome in the second. This article describes a fundamentally different approach to identifying causal connectivity in neuroscience: a focus on the predictability of ongoing activity in one part from that in another. This approach was made possible by a new method that comes from the pioneering work of Wiener (1956) and Granger (1969). The Wiener-Granger method, unlike stimulation and ablation, does not require direct intervention in the nervous system. Rather, it relies on the estimation of causal statistical influences between simultaneously recorded neural time series data, either in the absence of identifiable behavioral events or in the context of task performance. Causality in the Wiener-Granger sense is based on the statistical predictability of one time series that derives from knowledge of one or more others. This article defines Wiener-Granger Causality, discusses its merits and limitations in neuroscience, and outlines recent developments in its implementation. PMID- 20202480 TI - Twelve-month metabolic declines in probable Alzheimer's disease and amnestic mild cognitive impairment assessed using an empirically pre-defined statistical region of-interest: findings from the Alzheimer's Disease Neuroimaging Initiative. AB - Alzheimer's disease (AD) is characterized by specific and progressive reductions in fluorodeoxyglucose positron emission tomography (FDG PET) measurements of the cerebral metabolic rate for glucose (CMRgl), some of which may precede the onset of symptoms. In this report, we describe twelve-month CMRgl declines in 69 probable AD patients, 154 amnestic mild cognitive impairment (MCI) patients, and 79 cognitively normal controls (NCs) from the AD Neuroimaging Initiative (ADNI) using statistical parametric mapping (SPM). We introduce the use of an empirically pre-defined statistical region-of-interest (sROI) to characterize CMRgl declines with optimal power and freedom from multiple comparisons, and we estimate the number of patients needed to characterize AD-slowing treatment effects in multi-center randomized clinical trials (RCTs). The AD and MCI groups each had significant twelve-month CMRgl declines bilaterally in posterior cingulate, medial and lateral parietal, medial and lateral temporal, frontal and occipital cortex, which were significantly greater than those in the NC group and correlated with measures of clinical decline. Using sROIs defined based on training sets of baseline and follow-up images to assess CMRgl declines in independent test sets from each patient group, we estimate the need for 66 AD patients or 217 MCI patients per treatment group to detect a 25% AD-slowing treatment effect in a twelve-month, multi-center RCT with 80% power and two tailed alpha=0.05, roughly one-tenth the number of the patients needed to study MCI patients using clinical endpoints. Our findings support the use of FDG PET, brain-mapping algorithms and empirically pre-defined sROIs in RCTs of AD-slowing treatments. PMID- 20202482 TI - Introduction to the reports from the National Cancer Institute First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation. PMID- 20202483 TI - Crohn's disease is a risk factor for preterm birth. AB - BACKGROUND & AIMS: Women with Crohn's disease (CD) are considered to be at increased risk for adverse outcomes of pregnancy. However, the few studies assessing this risk have had small sample sizes and limitations. We examined outcomes of pregnancy among a large cohort of primiparous women with CD. METHODS: Our population-based prevalence study utilized data from medical birth registries in Sweden and Denmark between 1994 and 2006. Linking birth registry data with national patient registries, we identified 2377 women with a hospital diagnosis of CD prior to delivery and 869,202 women with no diagnosis of CD. Using logistic regression analysis, we estimated relative risks with 95% confidence intervals (CI) for pre-eclampsia, preterm birth, 5-minute Apgar scores below 7, cesarean section, small for gestational age (SGA), stillbirth, and congenital malformations. RESULTS: Maternal CD was associated with increased risk of moderately and very preterm birth (prevalence odds ratio [POR], 1.76; 95% CI, 1.51-2.05; and POR, 1.86; 95% CI, 1.38-2.52, respectively). Maternal CD was also associated with increased risk for cesarean section (POR, 1.93; 95% CI, 1.76 2.12). The strongest associations with CD were observed for prelabor cesarean section and induced preterm delivery. Risk of small size for gestational age birth was slightly increased among women with CD, especially during the time period of 2002-2006 (POR, 1.43; 95% CI, 1.09-1.89). We found no increased risks for pre-eclampsia, low 5-minute Apgar score, stillbirth, or congenital malformations. CONCLUSIONS: Maternal CD is a risk factor for preterm birth, but not birth defects. PMID- 20202484 TI - Complications with pneumatic dilation. PMID- 20202485 TI - Administered CpG oligodeoxynucleotide induces mRNA expression of CXC and CC chemokines at the intestinal mucosa and PBMCs in piglets. AB - Oligonucleotides containing CpG motifs (CpG ODN) are known to be potent stimulators of the innate immune system in vitro and in vivo. We therefore investigated if intranasal (IN)-mucosal or intramuscular (IM)-systemic administration of CpG ODN could enhance innate immunity in the intestinal mucosa and peripheral blood mononuclear cells (PBMCs) in piglets. Repeated IN or IM administration of CpG ODN significantly increased local/systemic mRNA expression of the CC chemokines macrophage inflammatory protein 1beta (MIP-1beta) and monocyte chemoattractant protein-1 (MCP-1) and CXC chemokine gamma interferon inducible protein 10 (IP-10) and percentages of macrophages and cDCs in the intestine (jejunum, caecum and colon) and PBMCs by different kinetics. IN delivery of CpG ODN induced much stronger chemokine responses than IM delivery at intestinal mucosas, whereas IN delivery of CpG ODN induced some weaker chemokine responses than IM delivery in PBMCs. These findings suggest that IN administration of 100mug/kg-CpG ODN without antigen codelivery may represent a valuable strategy for induction of innate immunity against infection. PMID- 20202487 TI - Dynamic loading enhances integrative meniscal repair in the presence of interleukin-1. AB - OBJECTIVE: Meniscal tears are a common knee injury and increased levels of interleukin-1 (IL-1) have been measured in injured and degenerated joints. Studies have shown that IL-1 decreases the shear strength, cell accumulation, and tissue formation in meniscal repair interfaces. While mechanical stress and IL-1 modulate meniscal biosynthesis and degradation, the effects of dynamic loading on meniscal repair are unknown. The purpose of this study was to determine the effects of mechanical compression on meniscal repair under normal and inflammatory conditions. EXPERIMENTAL DESIGN: Explants were harvested from porcine medial menisci. To simulate a full-thickness defect, a central core was removed and reinserted. Explants were loaded for 4h/day at 1 Hz and 0%-26% strain for 14 days in the presence of 0 or 100 pg/mL of IL-1. Media were assessed for matrix metalloproteinase (MMP) activity, aggrecanase activity, sulfated glycosaminoglycan (S-GAG) release, and nitric oxide (NO) production. After 14 days, biomechanical testing and histological analyses were performed. RESULTS: IL 1 increased MMP activity, S-GAG release, and NO production, while decreasing the shear strength and tissue repair in the interface. Dynamic loading antagonized IL 1-mediated inhibition of repair at all strain amplitudes. Neither IL-1 treatment nor strain altered aggrecanase activity. Additionally, strain alone did not alter meniscal healing, except at the highest strain magnitude (26%), a level that enhanced the strength of repair. CONCLUSIONS: Dynamic loading blocked the catabolic effects of IL-1 on meniscal repair, suggesting that joint loading through physical therapy may be beneficial in promoting healing of meniscal lesions under inflammatory conditions. PMID- 20202486 TI - Modulation of transcription factor function by O-GlcNAc modification. AB - O-linked beta-N-acetylglucosamine (O-GlcNAc) modification of nuclear and cytoplasmic proteins is important for many cellular processes, and the number of proteins that contain this modification is steadily increasing. This modification is dynamic and reversible, and in some cases competes for phosphorylation of the same residues. O-GlcNAc modification of proteins is regulated by cell cycle, nutrient metabolism, and other extracellular signals. Compared to protein phosphorylation, which is mediated by a large number of kinases, O-GlcNAc modification is catalyzed only by one enzyme called O-linked N-acetylglucosaminyl transferase or OGT. Removal of O-GlcNAc from proteins is catalyzed by the enzyme beta-N-acetylglucosaminidase (O-GlcNAcase or OGA). Altered O-linked GlcNAc modification levels contribute to the establishment of many diseases, such as cancer, diabetes, cardiovascular disease, and neurodegeneration. Many transcription factors have been shown to be modified by O-linked GlcNAc modification, which can influence their transcriptional activity, DNA binding, localization, stability, and interaction with other co-factors. This review focuses on modulation of transcription factor function by O-linked GlcNAc modification. PMID- 20202489 TI - Efficacy and safety of naproxcinod in the treatment of patients with osteoarthritis of the knee: a 13-week prospective, randomized, multicenter study. AB - OBJECTIVE: To evaluate the efficacy and safety of the cyclooxygenase-inhibiting nitric-oxide donator, naproxcinod, compared with naproxen and placebo in patients with osteoarthritis (OA) of the knee. METHOD: 918 eligible patients were randomly assigned to double-blind treatment with either naproxcinod 375 mg, naproxcinod 750 mg, naproxen 500 mg or placebo, twice daily for 13 weeks. The primary objective was to show superiority of naproxcinod compared to placebo. Main efficacy criteria were assessment of pain and physical function using the Western Ontario and MacMaster Universities Osteoarthritis Index (WOMAC) and patients' overall rating of disease status (Likert scale). The main secondary objectives were to show that naproxcinod was non-inferior to naproxen 500 mg and to evaluate overall safety. RESULTS: Both doses of naproxcinod were statistically and clinically superior to placebo in relieving signs and symptoms of OA of the knee after 13 weeks of treatment, as demonstrated by all three co-primary endpoints (P< or =0.0003). The evaluation of the other secondary efficacy measures was consistent with the primary endpoint results. Naproxcinod 750 mg was non-inferior to equimolar doses of naproxen 500 mg in the Intent-to-Treat (ITT) population. 24.5% of patients discontinued prematurely, with a higher incidence in the placebo group (18.6%) than the active groups (4.3-7.1%) discontinuing due to lack of efficacy. Both doses of naproxcinod were well-tolerated, with most adverse events being mild or moderate. Compared to placebo, naproxcinod 750 mg and 375 mg showed a similar blood pressure (BP) profile in contrast to naproxen which increased BP. CONCLUSIONS: These results demonstrated the clinical efficacy and safety of naproxcinod in the management of the signs and symptoms of OA. Naproxcinod was well-tolerated, with BP effects similar to placebo and different from naproxen. Clinical Trials.gov identifier: NCT00542555. PMID- 20202491 TI - Weakened implantable cardioverter-defibrillator header bond: abnormality not limited to subpectoral implants. PMID- 20202488 TI - Subjects with higher physical activity levels have more severe focal knee lesions diagnosed with 3T MRI: analysis of a non-symptomatic cohort of the osteoarthritis initiative. AB - PURPOSE: To study the prevalence of focal knee abnormalities using 3 Tesla (T) magnetic resonance (MR) studies in relation to physical activity levels in asymptomatic, middle-aged subjects from the osteoarthritis initiative (OAI). MATERIAL AND METHODS: We analyzed baseline data from 236, 45-55 years old individuals (136 women, 100 men) without knee pain (based on Western Ontario and McMaster University scores) and a body mass index (BMI) of 19-27 kg/m(2). Physical activity levels were determined in all subjects using the Physical Activity Scale for the Elderly (PASE). MR imaging (MRI) at 3T was performed using coronal intermediate-weighted (IW) 2D fast spin-echo (FSE), sagittal 3D dual-echo in steady state (DESS) and 2D IW fat-suppressed (fs) FSE sequences of the right knee. All images were analyzed by two musculoskeletal radiologists identifying and grading cartilage, meniscal, ligamentous and other knee abnormalities using the whole-organ MR imaging score (WORMS) MRI OA scoring method. Statistical significances between subjects with different activity levels were determined using one-way analysis of variance (ANOVA), chi-square tests and a multi-variate regression model adjusted for gender, age, BMI, Kellgren-Lawrence (KL) score and osteoarthritis (OA) risk factors. RESULTS: Meniscal lesions were found in 47% of the 236 subjects, cartilage lesions in 74.6%, bone marrow edema pattern (BMEP) in 40.3% and ligament lesions in 17%. Stratification of subjects by physical activity resulted in an increasing incidence of cartilage, meniscus and ligament abnormalities, BMEP and joint effusion according to activity levels (PASE). The severity grade of cartilage lesions was also associated with PASE levels and presence of other knee abnormalities was also significantly associated with cartilage defects. CONCLUSION: Asymptomatic middle-aged individuals from the OAI incidence cohort had a high prevalence of knee abnormalities; more physically active individuals had significantly more and more severe knee abnormalities independently of gender, age, BMI, KL score and OA risk factors. These data therefore also suggest that subjects with higher physical activity levels may be at greater risk for cartilage, meniscus and ligament abnormalities, but the analysis of the longitudinal data will show whether these subjects will demonstrate accelerated progress. PMID- 20202492 TI - "Locked-in" sensitivity in the managed ventricular pacing mode. AB - Two cases of "locked-in" sensitivity in the managed ventricular pacing mode are reported. Patient A was a 22-year-old man with a history of hypertrophic obstructive cardiomyopathy and a prophylactic dual-chamber automatic implantable cardioverter-defibrillator who manifested paradoxic T-wave oversensing on the ventricular lead at a sensitivity setting of 1.2 mV but not earlier when the sensitivity had been set to 0.9 mV. Patient B was a 74-year-old patient with ischemic cardiomyopathy and a dual-chamber defibrillator who presented with persistent paradoxic undersensing of the P wave on the atrial lead even at the maximal sensitivity of 0.15 mV, although P-wave sensing was normal earlier when sensitivity was set to 0.3 mV. The phenomenon and the mechanism for its behavior are described. PMID- 20202493 TI - Mapping of atrial tachycardias after catheter ablation for atrial fibrillation: use of bi-atrial activation patterns to facilitate recognition of origin. AB - BACKGROUND: Mapping and ablation of atrial tachycardias (ATs) secondary to catheter ablation of atrial fibrillation (AF) is often challenging due to the complex atrial substrate, different AT mechanisms, and potential origin not only in the left atrium (LA) but also from the right atrium (RA) and the adjacent thoracic veins. OBJECTIVE: This study sought to develop an algorithm to facilitate localization of successful ablation regions based on limited activation data from simultaneous RA and coronary sinus (CS) recordings acquired from a single 20-pole catheter. METHODS: Simultaneous lateral RA and CS atrial activation patterns (AAPs) from a 20-electrode catheter were analyzed for 155 successfully ablated ATs in 133 patients (age 58 +/- 9.6 years; 104 male [78.2%]) with prior ablation for AF. The first 125 ATs in 109 patients were analyzed retrospectively to define specific AAPs related to the location of critical AT sites as defined by effective ablation in 1 of 3 atrial regions. A classification algorithm was developed and tested retrospectively in a second blinded evaluation of the 125 previously analyzed ATs. The accuracy of the algorithm was then prospectively tested in 30 ATs in 24 patients. RESULTS: Seven different lateral RA-CS activation patterns were identified as indicating AT origin from the left lateral atrium, septum, roof, or RA, with the pattern for some regions dependent on whether conduction block was present in common atrial flutter isthmuses. The algorithm derived identified the region of effective ablation with a sensitivity of 93%, a specificity of 97%, and a positive predictive value of 80% in the blinded analysis. In the prospective series, overall accuracy was 96%. CONCLUSION: Simultaneous assessment of RA and CS activation patterns from a single RA catheter suggests the likely region of origin of ATs that emerge after AF ablation, and may therefore facilitate ablation of these complex arrhythmias. PMID- 20202494 TI - Expression of beta-1,4-galactosyltransferase-I affects cellular adhesion in human peripheral blood CD4+ T cells. AB - beta-1,4-galactosyltransferase-I (beta-1,4-GalT-I) has two isoforms that differ only in the length of their cytoplasmic domains. In this study, we found that both the long and short isoforms of beta-1,4-GalT-I were expressed in human CD4(+) T lymphocytes, and localized in the cytoplasm and on the plasma membrane. The expression level of beta-1,4-GalT-I was increased in CD4(+) T cells after stimulation with interleukin (IL)-2, and was further increased after stimulation with IL-2+IL-12, but decreased after stimulation with IL-2+IL-4 when compared to stimulation with IL-2 alone. We also demonstrated that the cellular adhesion of CD4(+) T cells was significantly increased upon cytokine stimulation, and was inhibited by alpha-lactalbumin, indicating that the increase in adhesion was positively correlated with the expression and activity of long beta-1,4-GalT-I. Collectively, the data suggest that beta-1,4-GalT-I plays a role in the cellular adhesion of CD4(+) T cells. PMID- 20202495 TI - Practice management in neurology. Preface. PMID- 20202496 TI - Physician compensation: approach and models in neurological practice. AB - Compensation methodology has always challenged physician groups. The highly complex system of reimbursement for the physician's services in the rapidly changing environment of health care makes the choice of a compensation model even more problematic. Any methodology chosen should reflect the underlying philosophy and culture of a group , and have the flexibility to accommodate the variability of interests, expertise, energy levels, and practice styles of its members. Further, compensation models must strike a balance between the financial viability of the practice and fair compensation for all physicians. This article describes the most common compensation structures and addresses the strengths and weaknesses of each. PMID- 20202497 TI - Negotiating with payers. AB - Negotiating with payers for better reimbursement, contract language, support for practice enhancement, or changes in policies and procedures is a critical function that may greatly enhance a practice's success over time. This article discusses keys to successful negotiating and several specific areas beyond reimbursement that deserve the reader's attention. PMID- 20202498 TI - Benchmarking the neurology practice. AB - A medical practice, whether operated by a solo physician or by a group, is a business. For a neurology practice to be successful, it must meet performance measures that ensure its viability. The best method of doing this is to benchmark the practice, both against itself over time and against other practices. Crucial medical practice metrics that should be measured are financial performance, staffing efficiency, physician productivity, and patient access. Such measures assist a physician or practice in achieving the goals and objectives that each determines are important to providing quality health care to patients. PMID- 20202499 TI - Neurology on the internet. AB - Since the Internet's inception in 1969, neurologists have witnessed a continuous parade of innovative phases. There is tremendous potential for near-instantaneous dissemination of the latest developments in neurologic knowledge, although their value is dependent on the degree of awareness of neurologists and is limited by the reluctance of some sources to make information readily accessible. The encyclopedic nature of the Internet, with its vast resources of online information, may be diminished by issues of access, variable quality and reliability, and a lack of intelligent retrieval systems. A major hindrance, for example, is seen with restrictions on archival, but proprietary, neurologic literature. Neurologic patients and their caregivers use the Internet heavily, but for somewhat different reasons. It is important for neurologists to understand these differences. The emergence of the online Personal Health Record will become increasingly valuable as these sites evolve and more medical providers incorporate electronic applications and medical records into their practices. Online groups for neurologists with similar interests, often referred to as "networks," have the potential to catalyze the natural organizing tendencies among those seeking solutions to shared problems. Networking can function well for neurologists, neurologic patients, and for focused efforts in an area such as advocacy. These considerations are discussed in this article. PMID- 20202500 TI - Mobile phones to improve the practice of neurology. AB - Smartphones make mobile computing at point of care practical. Smartphones can think, sync, and link. Built-in and user-installed applications facilitate communications between neurologists and their medical colleagues and patients and augment data acquisition and processing in the core medical information domains of patient data, clinical decision support, and practice management. Mobile telemedicine is becoming practical in certain scenarios. Smartphones can improve neurologic diagnosis and treatment, teaching, and research. Patients can benefit from smartphone technology. In addition to enhanced communication, patient education, and social networking, these devices can promote healthy lifestyles, preventive medicine, and compliance and even serve as monitoring and prosthetic devices. PMID- 20202501 TI - Health information technology and electronic health records in neurologic practice. AB - The tipping point for electronic health records (EHR) has been reached and universal adoption in the United States is now inevitable. Neurologists will want to choose their electronic health record prudently. Careful selection, contracting, planning, and training are essential to successful implementation. Neurologists need to examine their workflow carefully and make adjustments to ensure that efficiency is increased. Neurologists will want to achieve a significant return on investment and qualify for all applicable financial incentives from payers, including CMS. EHRs are not just record-keeping tools but play an important role in quality improvement, evidence-based medicine, pay for performance, patient education, bio-surveillance, data warehousing, and data exchange. PMID- 20202502 TI - Hot topics in risk management in neurologic practice. AB - Caring for patients with neurologic disease requires an understanding of certain aspects of civil law, especially in selected types of interaction between physicians and neurologic patients. This article provides a brief survey of the areas of obtaining informed consent, treatment of acute stroke with tissue plasminogen activator, reporting drivers with dementia or epilepsy, and assessing the capacity to vote for those with dementia. PMID- 20202503 TI - Neurological malpractice and nonmalpractice liability. AB - This article provides an overview of the current neurological malpractice trends, and outlines management strategies for several common recurring claims involving headache, stroke, and epilepsy. Selected nonmalpractice liability issues are reviewed, focusing on the unique risks engendered by the forensic expert. PMID- 20202504 TI - Consent issues in neurology. AB - The requirement that doctors obtain valid consent from patients before providing medical treatment has long been ingrained in both legal doctrine and medical ethics. We summarize the foundations of the informed consent doctrine and discuss the recent evolution in thinking about consent and medical decision making. We show how consent has evolved from physicians merely providing patients information to shared decision making between patients and physicians. We then address three specific examples of situations common in neurological practice that pose challenges in obtaining valid consent: the administration of intravenous tPA following ischemic stroke, consideration of carotid endarterectomy for carotid artery stenosis, and implementation of do-not resuscitate orders. PMID- 20202505 TI - Neurology education: current and emerging concepts in residency and fellowship training. AB - This article discusses the current and future state of neurology training. A priority is to attract sufficient numbers of qualified candidates for the existing residency programs. A majority of neurology residents elects additional training in a neurologic subspecialty, and programs will have to be accredited accordingly. Attempts are being made to standardize and strengthen the existing general residency and subspecialty programs through cooperative efforts. Ultimately, residency programs must comply with the increasing requirements and try to adapt these requirements to the unique demands and realities of neurology training. An effort is underway to establish consistent competency-testing methods. PMID- 20202506 TI - Using evidence-based medicine in neurology. AB - Given the rising costs of health care, the rational use of resources is a necessity. Evidence-based medicine assists physicians in providing the right care to the right patient at the right time. Familiarity with scientific literature and clinical experience are also important in decision making. This article covers the basics of critical appraisal and an introduction to statistics that will help clinicians, patients, and policymakers make sense of scientific evidence. PMID- 20202507 TI - Pay for performance and the physicians quality reporting initiative in neurologic practice. AB - Pay-for-performance (P4P) initiatives are receiving significant attention in the media and throughout all parts of health care. To improve quality, hundreds of private payers have initiated P4P programs over the past decade. Recently, the federal government has followed suit with its Physicians Quality Reporting Initiative (PQRI). These programs have several potential shortcomings, and questions arise as to their value in truly improving health outcomes. Nevertheless, momentum continues to gather in both the public and private sectors for P4P to serve as a catalyst for health care reform. PMID- 20202508 TI - Patient education in neurology. AB - Patient education is an important component of quality patient care and offers many potential benefits. Health care providers are responsible for giving patients the education they want and need to optimize their health and make health decisions. This review provides a definition of patient education; examines the potential benefits and effectiveness of patient education; builds a general framework for approaching patient education as it pertains to patient knowledge, behaviors, attitudes, and skills; and summarizes representative studies of patient education in selected neurologic conditions. PMID- 20202509 TI - The future of neurology. AB - For the past 200 years, neurology has been deeply rooted in the history and neurologic examination, but 21st century advances in neurosurgery, endovascular techniques, and neuropathology, and an explosion in basic neuroscience research and neuroimaging have added exciting new dimensions to the field. Neurology residency training programs face intense governmental regulatory changes and economic pressures, making it difficult to predict the number of neurology residents being trained for the future. The future job outlook for neurologists in the United States, based on recent survey and trends, suggests an increased demand because of the prevalence of neurologic diseases within the aging population, particularly in underserved urban and rural areas. Telemedicine and "teleconsultation" offer a potential solution to bringing virtual subspecialists to underserved areas. The future for neurology and neuroscience research in the United States remains a high priority according to the National Institute of Neurologic Diseases and Stroke, but this may be affected in the long run by budgetary constraints and a growing deficit. PMID- 20202510 TI - A giant crystal ball in the heart. PMID- 20202511 TI - The present state of coronary computed tomography angiography a process in evolution. AB - In the past 5 years since the introduction of 64-detector row cardiac computed tomography angiography (CCTA), there has been an exponential growth in the quantity of scientific evidence to support the feasibility of its use in the clinical evaluation of individuals with suspected coronary artery disease (CAD). Since then, there has been considerable debate as to where CCTA precisely fits in the algorithm of evaluation of individuals with suspected CAD. Proponents of CCTA contend that the quality and scope of the available evidence to date support the replacement of conventional methods of CAD evaluation by CCTA, whereas critics assert that clinical use of CCTA is not yet adequately proven and should be restricted, if used at all. Coincident with the scientific debate underlying the clinical utility of CCTA, there has developed a perception by many that the rate of growth in cardiac imaging is disproportionately high and unsustainable. In this respect, all noninvasive imaging modalities and, in particular, more newly introduced ones, have undergone a higher level of scrutiny for demonstration of clinical and economic effectiveness. We herein describe the latest available published evidence supporting the potential clinical and cost efficiency of CCTA, drawing attention not only to the significance but also the limitations of such studies. These points may trigger discussion as to what future studies will be both necessary and feasible for determining the exact role of CCTA in the workup of patients with suspected CAD. PMID- 20202512 TI - Report of a National Heart, Lung, And Blood Institute Workshop: heterogeneity in cardiometabolic risk in Asian Americans In the U.S. Opportunities for research. AB - The Asian and Pacific Islander population (Asian Americans) in the U.S. has increased dramatically in the last few decades. Yet, data on cardiovascular disease (CVD) in this population are scarce. The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health conducted an Expert Workshop to: 1) assess the importance of studying CVD in Asian Americans in the U.S.; and 2) consider strategic options for further investigations of CVD in this population. There is considerable geographical, ethnic, cultural, and genetic diversity within this population. Limited data also suggest striking differences in the risk of CVD, obesity, type 2 diabetes mellitus, and other CVD risk factors across the Asian-American population. The Asian-American population is a new diverse pool with less contemporary genetic and cultural admixture relative to groups that have lived in the U.S. for generations, plus it is diverse in lifestyle including culture, diet, and family structure. This diversity provides a window of opportunity for research on genes and gene-environment interactions and also to investigate how acculturation/assimilation to U.S. lifestyles affects health and CVD risk among relatively homogenous groups of recent immigrants. Given the heterogeneity in body weight, body size, and CVD risk, the Asian American population in the U.S. offers a unique model to study the interaction and relationships between visceral adiposity and adipose tissue distribution and beta cell function, insulin resistance, and atherosclerosis. PMID- 20202513 TI - Asian Americans and cardiometabolic risk why and how to study them. PMID- 20202515 TI - Plaque burden with composition? That is the next question. PMID- 20202514 TI - Impact of olmesartan on progression of coronary atherosclerosis a serial volumetric intravascular ultrasound analysis from the OLIVUS (impact of OLmesarten on progression of coronary atherosclerosis: evaluation by intravascular ultrasound) trial. AB - OBJECTIVES: The aim of this study was to evaluate the impact of olmesartan on progression of coronary atherosclerosis. BACKGROUND: Prior intravascular ultrasound (IVUS) trial results suggest slowing of coronary atheroma progression with some medicines but have not shown convincing evidence of regression with angiotension-II receptor blocking agents. METHODS: A prospective, randomized, multicenter trial-OLIVUS (Impact of OLmesartan on progression of coronary atherosclerosis: evaluation by IntraVascular UltraSound)-was performed in 247 stable angina pectoris patients with native coronary artery disease. When these patients underwent percutaneous coronary intervention for culprit lesions, IVUS was performed in their nonculprit vessels (without angiographically documented coronary stenosis [<50%]). Patients were randomly assigned to receive 10 to 40 mg of olmesartan or control and treated with a combination of beta-blockers, calcium channel blockers, diuretics, nitrates, glycemic control agents, and/or statins per physician's guidance. Serial IVUS examinations (baseline and 14-month follow up) were performed to assess coronary atheroma volume. Volumetric IVUS analyses included lumen, plaque, vessel volume, percent atheroma volume (PAV), percent change in total atheroma volume (TAV) and PAV. RESULTS: Patient characteristics and blood pressure control were identical between the 2 groups. However, follow up IVUS showed significantly decreased TAV and percent change in PAV in the olmesartan group (5.4% vs. 0.6 % for TAV and 3.1% vs. -0.7% for percent change in PAV, control vs. olmesartan, p < 0.05 for all). CONCLUSIONS: These observations suggest a positive role in a potentially lower rate of coronary atheroma progression through the administration of olmesartan, an angiotension-II receptor blocking agent, for patients with stable angina pectoris. PMID- 20202516 TI - Rosuvastatin prevents conduit artery endothelial dysfunction induced by ischemia and reperfusion by a cyclooxygenase-2-dependent mechanism. AB - OBJECTIVES: The purpose of this study was to determine whether single-dose rosuvastatin (40 mg) protects against ischemia and reperfusion (IR)-induced endothelial dysfunction in humans and whether this effect is cyclooxygenase (COX) 2 dependent. BACKGROUND: Animal studies have demonstrated that rosuvastatin can limit damage and improve recovery after IR. METHODS: In a double-blind, parallel design, 20 volunteers were randomized to a single dose of oral rosuvastatin (40 mg) or placebo. Twenty-four hours later, endothelium-dependent, flow-mediated dilation (FMD) of the radial artery was measured before and after IR (15 min of upper arm ischemia followed by 15 min of reperfusion). In a separate protocol, 18 volunteers received the COX-2 inhibitor celecoxib (200 mg orally twice daily) for 5 days. On day 4, subjects were randomized to single-dose rosuvastatin (40 mg) or placebo and 24 h later underwent the same protocol as described. RESULTS: Pre-IR FMD was similar between groups (p = NS). IR significantly blunted FMD in the placebo group (FMD pre-IR: 6.4 +/- 1.4%; FMD post-IR: 1.1 +/- 3.8%, [p = 0.002]). Rosuvastatin prevented this impairment (FMD pre-IR: 7.5 +/- 3.1%; FMD post-IR: 6.2 +/- 3.9%, [p = NS] vs. rosuvastatin pre-IR, [p = 0.03] vs. placebo). Pre treatment with celecoxib completely abolished rosuvastatin's protective effect (FMD pre-IR: 8.0 +/- 2.2%; FMD post-IR: 1.4 +/- 2.0%, [p < 0.001] compared with pre-IR, [p = NS] vs. placebo, [p = 0.002] vs. rosuvastatin alone). CONCLUSIONS: Rosuvastatin pharmacologically prevents the development of IR-induced conduit artery endothelial dysfunction. This beneficial effect of rosuvastatin is mediated by a COX-2-dependent mechanism, evidence that may also provide potential mechanistic insight into the reported cardiotoxic effects of COX-2 inhibitors. PMID- 20202517 TI - Disparate evolution of right and left atrial rate during ablation of long-lasting persistent atrial fibrillation. AB - OBJECTIVES: The purpose of this study was to assess whether additional ablation in the right atrium (RA) improves termination rate in long-lasting persistent atrial fibrillation (PsAF). BACKGROUND: Prolongation of atrial fibrillation (AF) cycle length (CL) measured from the left atrial appendage predicts favorable outcome during catheter ablation of PsAF. However, in some patients, despite prolongation of AF CL in the left atrium (LA) with ablation, AF persists. We hypothesized that this persistence is due to RA drivers, and that these patients may benefit from RA ablation. METHODS: In all, 148 consecutive patients undergoing catheter ablation of PsAF (duration 25 +/- 32 months) were studied. AF CL was monitored in both atria during stepwise ablation commencing in the LA. Ablation was performed in the RA when all LA sources in AF had been ablated and an RA-LA gradient existed. The procedural end point was AF termination. RESULTS: Two distinct patterns of AF CL change emerged during LA ablation. In 104 patients (70%), there was parallel increase of AF CL in LA and RA culminating in AF termination (baseline: LA 153 ms [range 140 to 170 ms], RA 155 ms [range 143 to 171 ms]; after ablation: LA 181 ms [range 170 to 200 ms], RA 186 ms [range 175 to 202 ms]). In 24 patients (19%), RA AF CL did not prolong, creating a right-to left frequency gradient (baseline: LA 142 ms [range 143 to 153 ms], RA 145 ms [range 139 to 162 ms]; after ablation: LA 177 ms [range 165 to 185 ms], RA 152 ms [range 147 to 175 ms]). These patients had a longer AF history (23 months vs. 12 months, p = 0.001), and larger RA diameter (42 mm vs. 39 mm, p = 0.005), and RA ablation terminated AF in 55%. In the remaining 20 patients, biatrial ablation failed to terminate AF. CONCLUSIONS: A divergent pattern of AF CL prolongation after LA ablation resulted in a right-to-left gradient, demonstrating that the right atrium is driving AF in approximately 20% of PsAF. PMID- 20202518 TI - Prognostic value of 64-slice cardiac computed tomography severity of coronary artery disease, coronary atherosclerosis, and left ventricular ejection fraction. AB - OBJECTIVES: We sought to determine the prognostic and incremental value of coronary artery disease (CAD) severity, coronary atherosclerosis, and left ventricular ejection fraction (LVEF) measured with cardiac computed tomography angiography (CTA). BACKGROUND: CTA is an emerging tool used for the detection of obstructive CAD. However, there are limited data supporting the prognostic value of 64-slice CTA and its ability to predict all-cause mortality and major adverse cardiac events such as cardiac death and nonfatal myocardial infarction. METHODS: Consecutive patients (without history of revascularization, heart transplantation, and congenital heart disease) were prospectively enrolled. Each CTA was evaluated for CAD severity, total plaque score, and LVEF. Patients were followed, and all events were confirmed with death certificates or hospital or physician records and reviewed by a clinical events committee. RESULTS: Between February 2006 and February 2008, 2,076 consecutive patients were prospectively enrolled and followed for a mean of 16 +/- 8 months. At follow-up, a total of 31 (1.5%) patients had cardiac death or nonfatal myocardial infarction and 47 (2.3%) had all-cause mortality or nonfatal myocardial infarction. Multivariate analysis showed that CAD severity (hazard ratio [HR]: 3.02; 95% confidence interval [CI]: 1.89 to 4.83) was a predictor of major adverse cardiac events and that LVEF (HR: 1.47; 95% CI: 1.17 to 1.86) had incremental value over CAD severity. Total plaque score had incremental value over CAD severity and LVEF for all-cause mortality and nonfatal myocardial infarction (HR: 1.17; 95% CI: 1.06 to 1.29). CONCLUSIONS: Using CTA, CAD severity, LVEF, and total plaque score seems to have prognostic and incremental value over routine clinical predictors. Cardiac CTA seems to be a promising noninvasive modality with prognostic value. PMID- 20202519 TI - Cardiac computed tomographic angiography what's the prognosis? PMID- 20202520 TI - Pulse pressure amplification a mechanical biomarker of cardiovascular risk. AB - OBJECTIVES: The aim of this study was to determine whether the carotid/brachial (C/B) ratio is an independent predictor of cardiovascular (CV) risk. BACKGROUND: Brachial and carotid pulse pressure (PP) are independent predictors of CV risk, mainly in elderly patients. Because PP is physiologically lower at the brachial than at the carotid arterial site, PP amplification is represented by the C/B ratio and could independently predict CV risk. METHODS: In a Paris population (n = 834), brachial and carotid PP were measured from sphygmomanometry and pulse wave analysis. With stepwise multiple regression, carotid PP was calculated from a nomogram including age, sex, body height, brachial PP, and plasma glucose. This model was applied to 125,151 subjects, followed for 12 years, during which 3,997 deaths occurred (735 of CV origin). With Cox regression analysis, multi-adjusted hazard ratios (HRs) were calculated for 1 SD increase of brachial PP, calculated carotid PP, and C/B ratio. RESULTS: Brachial PP was significantly associated with both CV and all-cause mortality (HR: 1.16, 95% confidence interval [CI]: 1.13 to 1.19, and HR: 1.13, 95% CI: 1.10 to 1.17, respectively). Calculated carotid PP predicted a similar risk (HR: 1.21, 95% CI: 1.15 to 1.28, and HR: 1.18, 95% CI: 1.12 to 1.25, respectively). Finally, the C/B ratio was a strong risk predictor (HR: 1.22, 95% CI: 1.12 to 1.32, and HR: 1.41, 95% CI: 1.14 to 1.73, respectively). Addition of drug treatment and other confounding variables did not statistically modify the results. CONCLUSIONS: Brachial PP, calculated carotid PP, and C/B PP amplification all predict CV mortality. In contrast to brachial and carotid PP, the C/B ratio is less dependent on blood pressure calibration and thus can be directly applicable to large population studies. PMID- 20202521 TI - What to anticipate from pulse pressure amplification. PMID- 20202523 TI - Balloon pulmonary valvuloplasty, pulmonary regurgitation, and exercise capacity the good, the bad, and the not yet clear. PMID- 20202522 TI - Long-term pulmonary regurgitation following balloon valvuloplasty for pulmonary stenosis risk factors and relationship to exercise capacity and ventricular volume and function. AB - OBJECTIVES: This study sought to examine the prevalence and predictors of pulmonary regurgitation (PR) following balloon dilation (BD) for pulmonary stenosis (PS) and to investigate its impact on ventricular volume and function, and exercise tolerance. BACKGROUND: Balloon pulmonary valvuloplasty relieves PS but can cause late PR. The sequelae of isolated PR are not well understood. METHODS: Patients were at least 7 years of age and 5 years removed from BD, and had no other form of congenital heart disease or significant residual PS. Cardiac magnetic resonance imaging and exercise testing were performed prospectively to quantify PR fraction, ventricular volumes and function, and exercise capacity. RESULTS: Forty-one patients underwent testing a median of 13.1 years after BD. The median PR fraction was 10%; 14 patients (34%) had PR fraction >15%; 7 (17%) had PR >30%. PR fraction was associated with age at dilation (ln-transformed, R = -0.47, p = 0.002) and balloon:annulus ratio (R = 0.57, p < 0.001). The mean right ventricular (RV) end-diastolic volume z-score was 1.8 +/- 1.9; RV dilation (z score > or =2) was present in 14/35 patients (40%). PR fraction correlated closely with indexed RV end-diastolic volume (R = 0.79, p < 0.001) and modestly with RV ejection fraction (R = 0.50, p < 0.001). Overall, peak oxygen consumption (Vo(2)) (% predicted) was below average (92 +/- 17%, p = 0.006). Patients with PR fraction >15% had significantly lower peak Vo(2) than those with less PR (85 +/- 17% vs. 96 +/- 16%, p = 0.03). CONCLUSIONS: Mild PR and RV dilation are common in the long term following BD. A PR fraction >15% is associated with lower peak Vo(2), suggesting that isolated PR and consequent RV dilation are related to impaired exercise cardiopulmonary function. PMID- 20202524 TI - Atrial fibrillation degenerates into ventricular fibrillation. PMID- 20202525 TI - Comparative efficacy of dronedarone and amiodarone for the maintenance of sinus rhythm in patients with atrial fibrillation. PMID- 20202527 TI - Dronedarone is superior to placebo the case for optimism. PMID- 20202528 TI - Cardiac rehabilitation for patients with ventricular assist devices an offer to improve strong collaborative relationships. PMID- 20202530 TI - Negative dysphotopsia following cataract surgery. PMID- 20202531 TI - Scleral fixation of intraocular lenses combined with penetrating keratoplasty. AB - I describe a technique for transscleral fixation of a posterior chamber intraocular lens (PC IOL) combined with penetrating keratoplasty. Partial thickness trephination of the cornea is followed by full-thickness penetration of the anterior chamber at 12 o'clock and 6 o'clock through 5.5 and 2.0mm incisions, respectively. Scleral fixation of a PC IOL is performed through the incisions under a closed chamber followed by replacement of the diseased graft with a donor button. The results in 5 eyes of 5 patients with aphakic bullous keratopathy and lack of capsule support are reported. PMID- 20202532 TI - Hydroimplantation: foldable intraocular lens implantation without an ophthalmic viscosurgical device. AB - I describe a technique for implantation of a 1-piece acrylic foldable intraocular lens (IOL) using an irrigation cannula of the phaco machine without using an ophthalmic viscosurgical device (OVD). The irrigating cannula introduced through a side port provides excellent stability and positioning to the eye; if required, the cannula tip is used to guide the leading haptic of the IOL into the capsular bag. The fluid coming from the side port via a bimanual irrigation cannula maintains adequate formation of the capsular bag and anterior chamber while the foldable IOL is inserted. The hydroimplantation technique has the advantage of increased efficiency, reduced surgical time and cost, no need for OVD removal from behind the IOL or for additional instrumentation, no OVD-induced intraocular pressure elevation postoperatively, and no risk of early capsular bag distension syndrome. PMID- 20202533 TI - Functional assessment of accommodating intraocular lenses versus monofocal intraocular lenses in cataract surgery: metaanalysis. AB - PURPOSE: To compare accommodating intraocular lens (IOLs) and monofocal IOLs in restoring accommodation in cataract surgery. SETTING: Dartmouth Medical School and Department of Ophthalmology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA. METHODS: In this metaanalysis, 2 researchers independently extracted data, assessed trial quality, and contacted authors for missing information. Because of measurement-scale variations, outcomes were pooled for distance-corrected near visual acuity (DCNVA) as standardized mean differences with 95% confidence intervals [CIs] and anterior displacement of the lens as weighted mean differences (95% CI). RESULTS: The metaanalysis comprised 12 randomized controlled studies of 727 eyes. Based on 10 studies that compared DCNVA, accommodating IOLs were favored but failed the test of heterogeneity (I(2) = 94%). Pooling the 6 homogeneous trials (I(2) = 43%) showed no difference (standardized mean difference, -0.16; 95% CI, -0.56 to 0.25). Heterogeneity could not be explained by any characteristic of the study population or methodology. Based on 4 studies that evaluated pilocarpine-induced IOL shift, there was a significant anterior compared with the control (weighted mean difference, 95% CI, -0.36 - 0.47 to -0.24]), although the studies were heterogeneous (I(2) = 58%). Three of 5 studies mentioning posterior capsule opacification (PCO) reported increased rates in the accommodating IOL group postoperatively. CONCLUSIONS: There was no clear evidence of near acuity improvement despite statistically significant pilocarpine-induced anterior lens displacement. Further randomized controlled studies with standardized methods evaluating adverse effects (eg, PCO) are needed to clarify the tradeoffs. PMID- 20202534 TI - Color discrimination by patients with different types of light-filtering intraocular lenses. AB - PURPOSE: To evaluate photopic and mesopic color discrimination in patients with different types of light-filtering intraocular lenses (IOLs). SETTING: Peking University Third Hospital, Peking University Eye Center, Beijing, China. METHODS: Cataract patients with different types of IOLs were enrolled 3 months postoperatively. Overall and partial color discrimination under photopic (1000 lux) and mesopic (40 lux) conditions were evaluated with the Farnsworth-Munsell (FM) 100-hue test. Corrected distance visual acuity (CDVA) was tested under both conditions. Subjective visual quality was assessed with the 25-item National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25). RESULTS: The study evaluated 43 patients with a blue light-filtering IOL (15 photochromic, 13 yellow tinted) or an IOL filtering ultraviolet light only (n = 15). The difference in the FM 100-hue total error scores under photopic or mesopic conditions was not statistically significant between groups. There were no statistically significant differences in partial error scores in the 10 bands of the FM 100-hue color circle under photopic conditions. Under mesopic condition, there were statistically significant differences in partial error scores in the green to blue-green band (color caps 36 to 46) and the blue-green to blue band (color caps 46 to 54) (P = .005 and P = .030, respectively). There were no statistically significant differences in mean overall or subheading NEI VFQ-25 scores. CONCLUSIONS: Filtering blue lights under mesopic conditions seemed to modify color discrimination in the green-to-blue bands postoperatively. The modification did not disturb overall color discrimination or cause subjective discomfort. PMID- 20202535 TI - Optical aberrations in professional baseball players. AB - PURPOSE: To determine the presence, type, and size of optical higher-order aberrations (HOAs) in professional athletes with superior visual acuity and to compare them with those in an age-matched population of nonathletes. SETTING: Vero Beach and Fort Myers, Florida, USA. METHODS: Players from 2 professional baseball teams were studied. Each player's optical aberrations were measured with a naturally dilated 4.0 mm pupil using a Z-Wave aberrometer and a LADARWave aberrometer. RESULTS: One hundred sixty-two players (316 eyes) were evaluated. The HOAs were less than 0.026 mum in all cases. Spherical aberration C(4,0) was the largest aberration with both aberrometers. There were small but statistically significant differences between the aberrometers in mean values for trefoil C(3,3) and C(3,-3) and secondary astigmatism C(4,2). Although statistically significant, the differences were clinically insignificant, being similar at approximately 0.031 diopter (D) of spherical power. A statistically significant difference was found between the professional baseball players and the control population in trefoil C(3,-3). These differences were clinically insignificant, similar to 0.071 D of spherical power. CONCLUSIONS: Professional baseball players have small higher-order optical aberrations when tested with naturally dilated pupils. No clinically significant differences were found between the 2 aberrometers. Statistically significant differences in trefoil were found between the players and the control population; however, the difference was clinically insignificant. It seems as though the visual system of professional baseball players is limited by lower-order aberrations and that the smaller HOAs do not enhance visual function over that in a control population. PMID- 20202536 TI - Oral acetaminophen (paracetamol) for additional analgesia in phacoemulsification cataract surgery performed using topical anesthesia Randomized double-masked placebo-controlled trial. AB - PURPOSE: To evaluate the clinical analgesic efficacy of 1.0 g oral acetaminophen (paracetamol) given in addition to topical anesthesia before phacoemulsification cataract surgery. SETTING: Inpatient and outpatient ophthalmology clinics, Bydgoszcz, Poland. METHODS: Consecutive patients with age-related cataract having phacoemulsification under topical anesthesia (tetracaine 0.5%) were enrolled in a prospective double-blind randomized placebo-controlled study. Patients were randomly assigned to preoperative oral administration of a placebo medication or to oral administration of 1.0 g acetaminophen. The main outcome measure was intensity of pain during and after surgery. Pain intensity was measured using a 10 cm baseline visual analog scale and a discrete 5-category verbal rating scale. RESULTS: The study comprised 160 consecutive patients (80 in each group). Intraoperatively, the mean visual analog scale pain intensity score was 2.17 +/- 1.81 in the placebo group and 1.45 +/- 1.17 in the acetaminophen group and the mean verbal rating scale score, 1.11 +/- 0.73 and 0.67 +/- 0.66, respectively (P<.01). Postoperatively, the mean visual analog scale score for pain was 1.47 +/ 1.39 in the placebo group and 0.56 +/- 0.61 in the acetaminophen group and the mean verbal rating scale score, 0.94 +/- 0.79 and 0.28 +/- 0.41, respectively (P<.01). There was no significant difference in patient behavior during surgery and no significant adverse effects of acetaminophen use. CONCLUSION: Preoperative oral administration of acetaminophen 1.0 g was effective, convenient, safe, and cost effective in reducing intraoperative and postoperative pain in phacoemulsification performed using topical anesthesia. PMID- 20202537 TI - Phacoemulsification versus phacoemulsification with micro-bypass stent implantation in primary open-angle glaucoma: randomized double-masked clinical trial. AB - PURPOSE: To compare phacoemulsification alone and phacoemulsification with micro bypass stent implantation in eyes with primary open-angle glaucoma. SETTING: Instituto di Fisiopatologia Clinica, Clinica Oculistica, Universita' di Torino, Torino, Italy. METHODS: In this prospective double-masked randomized clinical trial, patients had phacoemulsification alone (control group) or phacoemulsification with iStent implantation (combined group). Primary outcomes were intraocular pressure (IOP) and reduction in medication use over 15 months and IOP after a 1-month washout of ocular hypotensive agents (ie, 16 months postoperatively). RESULTS: The baseline IOP was similar between groups (combined group: 17.9 mm Hg +/- 2.6 [SD]; control group: 17.3 +/- 3.0 mm Hg) (P = .512). Three patients in the control group were lost to follow-up. The mean IOP was 14.8 +/- 1.2 mm Hg in the combined group and 15.7 +/- 1.1 mm Hg in the control group at 15 months and 16.6 +/- 3.1 mm Hg and 19.2 +/- 3.5 mm Hg, respectively, after washout; the IOP was statistically significantly lower in the combined group than in the control group at both time points (P = .031 and P = .042, respectively). At 15 months, the mean number of medications was lower in the combined group than in the control group (0.4 +/- 0.7 and 1.3 +/- 1.0, respectively; P = .007), as was the proportion of patients on ocular hypotensive medication (33% and 76%, respectively). CONCLUSIONS: Phacoemulsification with stent implantation was more effective in controlling IOP than phacoemulsification alone; the safety profiles were similar. PMID- 20202538 TI - Surgically induced astigmatism after phacoemulsification with and without correction for posture-related ocular cyclotorsion: randomized controlled study. AB - PURPOSE: To report the impact of posture-related ocular cyclotorsion on one surgeon's surgically induced astigmatism (SIA) results and the variance in SIA. SETTING: Institute of Eye Surgery, Whitfield Clinic, Waterford, Ireland. METHODS: This prospective randomized controlled study included eyes that had phacoemulsification with intraocular lens implantation. Eyes were randomly assigned to have (intervention group) or not have (control group) correction for posture-related ocular cyclotorsion. In the intervention group, the clear corneal incision was placed precisely at the 120-degree meridian with instruments designed to correct posture-related ocular cyclotorsion. In the control group, the surgeon endeavored to place the incision at the 120-degree meridian, but without markings. RESULTS: The intervention group comprised 41 eyes and the control group, 61 eyes. The mean absolute SIA was 0.74 diopters (D) in the intervention group and 0.78 D in the control group; the difference between groups was not statistically significant (P>.5, unpaired 2-tailed Student t test). The variance in SIA was 0.29 D(2) and 0.31 D(2), respectively; the difference between groups was not statistically significant (P>.5, unpaired F test). CONCLUSIONS: Attempts to correct for posture-related ocular cyclotorsion did not influence SIA or its variance in a single-surgeon series. These results should be interpreted with full appreciation of the limitations of currently available techniques to correct for posture-related ocular cyclotorsion in the clinical setting. PMID- 20202539 TI - Intraocular lens exchange in patients with negative dysphotopsia symptoms. AB - PURPOSE: to evaluate the results of intraocular lens (IOL) exchange in cases of severe negative dysphotopsia and to measure the distance between the iris and the IOL optic using ultrasound biomicroscopy (UBM). SETTING: Szent Rokus Hospital and Eye Clinic, Semmelweis University, Budapest, Hungary. METHODS: Data of patients with major negative dysphotopsia symptoms after phacoemulsification with IOL implantation were reviewed retrospectively. In cases in which IOL exchange was performed to diminish the symptoms, the distance between the iris and the anterior surface of the IOL optic was measured by UBM and compared with that in a group of nonsymptomatic pseudophakic patients (control group). RESULTS: in 3806 cataract procedures, 5 eyes (4 patients) had severe negative dysphotopsia symptoms. Intraocular lens exchange was performed in 3 cases. In 1 case, the secondary IOL was implanted in the reopened capsular bag and the symptoms persisted. In 2 cases, the secondary IOL was implanted in the ciliary sulcus and the symptoms resolved. On UBM, the mean iris-optic distance was 0.45 mm +/- 0.07 (SD) in the symptomatic group, 0.59 +/- 0.29 mm in the control group (n = 21) (P = .353), and 0.00 mm in the sulcus-fixated group. CONCLUSIONS: The iris-optic distance was not statistically significantly different between eyes with severe negative dysphotopsia symptoms and nonsymptomatic eyes. However, when IOL exchange reduced the iris-IOL distance, the severe negative dysphotopsia symptoms resolved. PMID- 20202540 TI - Repeatability of corneal power and wavefront aberration measurements with a dual Scheimpflug Placido corneal topographer. AB - PURPOSE: To evaluate the repeatability of the Galilei dual-Scheimpflug analyzer in measuring corneal curvature, wavefront aberrations, pachymetry, and anterior chamber depth (ACD). SETTING: Cullen Eye Institute, Baylor College of Medicine, Houston, Texas, USA. METHODS: Three consecutive measurements were performed in 1 eye of each subject. The following were evaluated: (1) mean total corneal power at the central, paracentral, and peripheral zones (0.0 to 4.0 mm, 4.0 to 7.0 mm, and 7.0 to 8.0 mm, respectively) and posterior corneal power (K(avg)); (2) corneal higher-order wavefront aberrations (6.0 mm pupil); (3) mean pachymetry at the central, paracentral, and peripheral zones; and (4) ACD. Repeatability was assessed by calculating the within-subject standard deviation (SD), coefficient of variation (COV), and intraclass correlation coefficient (ICC). RESULTS: The study enrolled 20 subjects. The SD was 0.09 diopter (D), 0.05 D, and 0.19 D for central, paracentral, and peripheral total corneal power, respectively, and 0.03 D for posterior K(avg). The COV ranged from 0.10% to 0.35%, and the ICC was 0.996 or more (P<.001). For 3rd-order coma and trefoil, the SD was 0.08 mum and 0.09 mum, respectively. For 4th-order spherical aberration, astigmatism, and tetrafoil, the SDs were lower (0.02 mum, 0.04 mum, and 0.09 mum, respectively). The SD was 1.68 mum, 1.98 mum, and 2.82 mum for central, paracentral, and peripheral pachymetry, respectively, and 0.04 mm for ACD. CONCLUSION: Dual Scheimpflug measurements of corneal power, pachymetry, ACD, and corneal aberrations for Zernike terms in the middle of the Zernike tree showed excellent repeatability. PMID- 20202541 TI - Manual limbal markings versus iris-registration software for correction of myopic astigmatism by laser in situ keratomileusis. AB - PURPOSE: To compare the efficacy and safety of manual limbal markings and wavefront-guided treatment with iris-registration software in laser in situ keratomileusis (LASIK) for myopic astigmatism. SETTING: National Taiwan University Hospital, Taipei, Taiwan. METHODS: Eyes with myopic astigmatism had LASIK with a Technolas 217z laser. Eyes in the limbal-marking group had conventional LASIK (PlanoScan or Zyoptix tissue-saving algorithm) with manual cyclotorsional-error adjustments according to 2 limbal marks. Eyes in the iris registration group had wavefront-guided ablation (Zyoptix) in which cyclotorsional errors were automatically detected and adjusted. Refraction, corneal topography, and visual acuity data were compared between groups. Vector analysis was by the Alpins method. RESULTS: The mean preoperative spherical equivalent (SE) was -6.64 diopters (D) +/- 1.99 (SD) in the limbal-marking group and -6.72 +/- 1.86 D in the iris-registration group (P = .92). At 6 months, the mean SE was -0.42 +/- 0.63 D and -0.47 +/- 0.62 D, respectively (P = .08). There was no statistically significant difference between groups in the astigmatism correction, success, or flattening index values using 6-month postoperative refractive data. The angle of error was within +/-10 degrees in 73% of eyes in the limbal-marking group and 75% of eyes in the iris-registration group. CONCLUSION: Manual limbal markings and iris-registration software were equally effective and safe in LASIK for myopic astigmatism, showing that checking cyclotorsion by manual limbal markings is a safe alternative when automated systems are not available. PMID- 20202542 TI - Visual acuity and higher-order aberrations with wavefront-guided and wavefront optimized laser in situ keratomileusis. AB - PURPOSE: To compare visual acuity and higher-order aberrations (HOAs) after wavefront-guided and wavefront-optimized laser in situ keratomileusis (LASIK). METHODS: This retrospective study comprised refraction-matched myopic eyes that had wavefront-guided (Visx Star S4 laser) or wavefront-optimized (WaveLight Allegretto Wave laser) LASIK targeted for emmetropia. Preoperative and postoperative manifest refraction spherical equivalent (MRSE), uncorrected (UDVA) and corrected (CDVA) distance visual acuities, and preoperative and postoperative HOAs were compared. RESULTS: Preoperatively, there were no significant differences between the wavefront-guided and wavefront-optimized groups in age, sex, corneal thickness, MRSE, or HOAs (all P>.05). The mean MRSE was -2.88 diopters (D) +/- 2.6 (SD) and -2.96 +/- 2.6 D, respectively, preoperatively and 0.01 +/- 0.25 D and -0.02 +/- 0.33 D, respectively, postoperatively; 96% of all eyes were within +/-0.50 D of emmetropia postoperatively. There were no differences in UDVA, CDVA, MRSE, or HOAs between groups (all P>.05). The UDVA was 20/20 or better in 85% of eyes in the wavefront-guided group and 86% of eyes in the wavefront-optimized group. All eyes had 20/25 or better CDVA postoperatively; no eye lost 2 lines of CDVA. Fourteen eyes were converted from wavefront-guided to wavefront-optimized treatment because of poor limbal ring alignment (8 eyes), a wave scan not consistent with the manifest refraction (5 eyes), and no iris registration (1 eye). CONCLUSIONS: Wavefront-guided LASIK and wavefront-optimized LASIK produced equivalent visual outcomes and no differences in HOAs. Wavefront guided treatment could not be performed in many eyes because of difficulties during wavefront measurement. PMID- 20202543 TI - Efficacy, safety, and flap dimensions of a new femtosecond laser for laser in situ keratomileusis. AB - PURPOSE: To evaluate the clinical results of a preproduction femtosecond laser for flap creation in laser in situ keratomileusis (LASIK). SETTING: Private practice, Brussels, Belgium. METHODS: This study comprised myopic eyes with a plano target refraction and a target flap thickness of 110 microm. The LASIK flap was created with a Ziemer LDV femtosecond laser. Prospective evaluation included flap dimensions, intraoperative and postoperative complications, and visual outcomes. RESULTS: Sixty-three patients (111 eyes; mean age 37.2 years) were evaluated. Preoperatively, the mean corrected distance visual acuity (CDVA) was 1.34 (Snellen) and the mean manifest refraction spherical equivalent (MRSE), 4.91 diopters (D) +/- 2.45 (SD). Six months postoperatively, the mean CDVA was 1.33; the mean MRSE, -0.05 +/- 0.3 D; and the mean uncorrected distance visual acuity (UDVA), 1.27. The UDVA was 20/25 or better in 98.2% of eyes and 20/20 or better in 94.6% of eyes. The MRSE was within +/-0.50 D in 95.5% of eyes and within +/-1.00 D in 99.1% of eyes. The cylinder was 0.50 D or less in 99.1% of eyes. The mean flap thickness was 106.6 +/- 12.6 microm. The most frequent complications were epithelial sloughing (10.8%), a decentered cut (4.5%), flap adhesions (5.4%), a slightly irregular flap border (5.4%), and microstriae (5.4%); all were mild. CONCLUSIONS: Overall, the flap dimensions and refractive results were predictable and the complication rate was acceptable after LASIK using the new femtosecond laser for flap creation. PMID- 20202544 TI - First clinical results of epithelial laser in situ keratomileusis with a 1000 Hz excimer laser. AB - PURPOSE: To evaluate the safety, stability, and efficacy of the first clinical cases of epithelial laser in situ keratomileusis (epi-LASIK) performed using a 1000 Hz excimer laser system. SETTING: Klinikum Rechts der Isar, Munich, Germany. METHODS: The epi-LASIK procedure was performed using an EpiLift microkeratome and a WaveLight Concept System 1000 laser. Preoperatively and 1, 3, and 6 months postoperatively, a complete ophthalmic examination was performed. The examination included objective and subjective refraction, uncorrected and corrected distance visual acuities, and topography. RESULTS: The study comprised 30 eyes of 17 patients. The mean spherical equivalent was -4.36 diopters (D) +/-1.77 (SD) preoperatively, 0.07 +/- 0.38 D 1 month postoperatively, -0.06 D +/- 0.25 D at 3 months, and -0.05 +/- 0.24 D at 6 months. Six months postoperatively, 90% of patients were within +/-0.50 D of the intended correction and all were within +/ 1.00 D. At 3 months, 25 eyes had a clear cornea and 5 eyes had trace haze. CONCLUSIONS: In this pilot series, the use of the 1000 Hz excimer laser did not lead to the clinical side effects that are potentially associated with the use of a high repetition rate. The safety, stability, and efficacy of the laser were high although no adjustments to the nomogram were made. PMID- 20202545 TI - Limbal relaxing incisions at the time of apodized diffractive multifocal intraocular lens implantation to reduce astigmatism with or without subsequent laser in situ keratomileusis. AB - PURPOSE: To evaluate the visual and refractive outcomes of limbal relaxing incisions (LRIs) to reduce astigmatism at the time of apodized diffractive multifocal intraocular lens (IOL) implantation. SETTING: University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA. METHODS: This retrospective review comprised consecutive patients who had LRIs at the time of lens extraction and AcrySof ReSTOR IOL implantation. A subgroup of patients had subsequent laser in situ keratomileusis (LASIK) for residual refractive error correction. RESULTS: The study evaluated 73 eyes (59 patients); 21 eyes (28.7%) of 59 patients had further LASIK (LRI+LASIK). The mean follow-up was 13.2 months +/- 6.4 (SD). The mean keratometric astigmatism decreased from 1.49 +/- 0.71 diopters (D) preoperatively to 0.56 +/- 0.57 D at the last follow-up (P<.001). Although the LRI+LASIK group had significantly greater corneal astigmatism than the LRI-only group preoperatively (P = .005) and 1 month (P = .030) and 6-months (P = .014) postoperatively, there was no statistically significant difference between the 2 groups at the last follow-up (P = .528). At the last follow-up, the uncorrected distance visual acuity was 20/25 or better and the uncorrected near visual acuity was J1 or better in 32 (76%) of 42 eyes in the LRI-only group and in 17 (81%) of 21 eyes in the LRI+LASIK group. CONCLUSION: Limbal relaxing incisions at the time of apodized diffractive multifocal IOL implantation, with or without subsequent LASIK, were effective and safe in reducing astigmatism. PMID- 20202547 TI - Keratorefractive effect of microwave keratoplasty on human corneas. AB - PURPOSE: To determine the change in dioptric power on excised human corneoscleral buttons after microwave keratoplasty application and to determine the qualitative effect on the cornea using histology and scanning electron microscopy. SETTING: Department of Academic Ophthalmology, Rayne Institute, St. Thomas' Hospital, London, United Kingdom. METHODS: Excised human corneoscleral buttons were treated with a prototype microwave keratoplasty ring applicator. A 28.12 W, 1-second application was performed on the corneas using a 6.0 mm diameter inner conductor and an 8.4 mm diameter outer conductor. Videokeratography was performed with a topographic modeling system (TMS-1) before and after microwave keratoplasty. The induced change in corneal curvature was calculated using the mean dioptric power of rings situated 2.0 to 6.0 mm from the geometrical apex of the corneas. Scanning electron microscopy and toluidine-blue light microscopy were performed to determine the effect on the corneal stroma. RESULTS: Six excised corneoscleral buttons from 6 donors were used. The mean reduction in curvature after microwave keratoplasty application was 3.07 diopters +/- 2.62 (SD). Scanning and light microscopy showed microwave-induced shrinkage of corneal stromal collagen with little disturbance to the overlying epithelium. CONCLUSION: Microwave keratoplasty reduced corneal curvature and has therapeutic potential as a noninvasive alternative to excimer laser surgical correction of myopia and as a treatment for corneal ectasia. PMID- 20202546 TI - Straylight measurements in laser in situ keratomileusis and laser-assisted subepithelial keratectomy for myopia. AB - PURPOSE: To compare straylight values before and 3 months after laser in situ keratomileusis (LASIK) and laser-assisted subepithelial keratectomy (LASEK) and to analyze the causes of any change. SETTING: Private refractive surgery clinic, Driebergen, The Netherlands. METHODS: Straylight was measured before and after LASIK or LASEK with a C-Quant straylight meter; values were recorded as the straylight parameter log(s). Main outcome measures were the difference between postoperative and preoperative straylight values and factors causing a difference between the values. RESULTS: The study evaluated 102 eyes having LASIK and 137 eyes having LASEK. On average, there was significant improvement in straylight values postoperatively in both groups. The mean decrease was -0.016 log(s) in the LASIK group and -0.026 log(s) in the LASEK group. Nonparametric testing (sign test) showed that the improvement in straylight was statistically significant in more than 50% of eyes in both groups. Straylight improved in 62 eyes in the LASIK group (P<.001) and 78 eyes in the LASEK group (P<.02) and deteriorated in 35 eyes and 58 eyes, respectively. There was an increase in straylight in 17 eyes (7.1%). Clinical correlations were found in some eyes that had increased postoperative straylight values. CONCLUSION: On average, straylight values 3 months after LASIK and LASEK were slightly decreased from baseline values. PMID- 20202548 TI - Comparison of real-time intraocular pressure during laser in situ keratomileusis and epithelial laser in situ keratomileusis in porcine eyes. AB - PURPOSE: To compare real-time intraocular pressure (IOP) between laser in situ keratomileusis (LASIK) and epithelial LASIK (epi-LASIK) in porcine eyes during flap creation using a microkeratome or an epikeratome, respectively. SETTING: Vissum Madrid, Madrid, Spain. METHODS: In this prospective study, a Moria microkeratome was used in 1 eye (LASIK group) and an Epi-K epikeratome in the other eye (epi-LASIK group) to create a lamellar corneal flap and an epithelial flap, respectively, in freshly enucleated porcine eyes. The IOP changes during the procedures were recorded by direct cannulation using a reusable blood pressure transducer connected to the anterior chamber. RESULTS: Each group comprised 17 eyes. In the LASIK group, the mean IOP was 113.65 mm Hg +/- 10.78 (SD) during suctioning and 112.35 +/- 11.51 mm Hg during cutting phases. The mean duration of the phases was 9.00 +/- 1.46 seconds and 6.06 +/- 1.14 seconds, respectively. In the epi-LASIK group, the mean IOP was 92.57 +/- 20.86 mm Hg during suctioning, 82.09 +/- 20 mm Hg during cutting, and 67.28 +/- 13.49 during low vacuum. The mean duration of the phases was 25.88 +/- 1.96 seconds, 33.82 +/- 2.81 seconds, and 29.71 +/- 3.29 seconds, respectively. The IOP values were significantly different between the 2 groups (all comparisons P<.05). CONCLUSION: Real-time IOP measured during suctioning and flap creation by direct cannulation of the anterior chamber in freshly enucleated porcine eyes showed a significant increase in IOP during LASIK and epi-LASIK; the increase was lower in the epi LASIK group. PMID- 20202549 TI - Acrylic intraocular lens damage after folding using a forceps insertion technique. AB - PURPOSE: To analyze intraocular lens (IOL) surface abnormalities seen after folding using a forceps insertion technique. SETTING: Mayo Clinic, Rochester, Minnesota, USA. METHODS: Acrylic AcrySof MA60AC IOLs were examined using an Axio Imager microscope before and after they were folded using a forceps insertion technique. Differential interference contrast, brightfield reflected light, and darkfield reflected light imaging techniques were used as necessary. The effects of temperature, time, and ophthalmic viscosurgical device (OVD) on optic surface abnormalities after folding were studied. RESULTS: All 17 IOLs examined had smooth, defect-free optic surfaces before folding. After folding, anterior optic surface depressions were observed in all IOLs; the depressions corresponded to the contact area of the titanium insertion forceps. Surface depressions were present up to 72 hours after folding, were more pronounced when an insertion forceps with a high degree of wear was used, and were greater when the IOL was warmed to 98 degrees F before folding. Coating the IOL surface with OVD before grasping it with the insertion forceps prevented formation of depressions. CONCLUSIONS: The anterior optic surface of the acrylic IOL was vulnerable to forceps-induced surface depressions. Surface abnormalities were prevented by coating the anterior optic surface with OVD before grasping it with a metal insertion forceps. PMID- 20202550 TI - Ocular penetration of topically applied linezolid in a rabbit model. AB - PURPOSE: To evaluate ocular penetration of topically applied linezolid, a new antibiotic agent targeted against gram-positive organisms. SETTING: Laboratory of Pharmacology, University Hospital of Strasbourg, Strasbourg, France. METHODS: New Zealand White rabbits were divided into 3 equal groups. One drop of 50 microL (2 mg/mL) linezolid was administrated in Group 1. In Group 2, eyes were dosed in accordance with a keratitis protocol (1 drop of 2 mg/mL every 15 minutes for 1 hour). Aqueous humor was sampled 6 times from immediately after to 3 hours after drop delivery. In Group 3, a keratitis protocol was implemented before the animals were humanely killed. Conjunctiva, cornea, vitreous, and blood samples were collected 1 hour and 2 hours after the last drop. Linezolid concentrations were measured by high-performance liquid chromatography. RESULTS: Each group comprised 8 rabbits. In Group 1 and Group 2, the peak linezolid concentration in the aqueous humor (mean 0.87 mg/L +/- 0.16 [SD] and 2.17 +/- 0.4 mg/L, respectively) was 45 minutes after the last drop delivery. In Group 3, the concentrations 1 hour and 2 hours after the last drop were higher than 3 microg/g in the conjunctiva samples and higher than 4 microg/g in the cornea samples. The linezolid concentration in the vitreous and serum was negligible. CONCLUSIONS: Linezolid levels in the aqueous humor, conjunctiva, and cornea exceeded the minimum inhibitory concentration of most gram-positive organisms that cause bacterial keratitis and endophthalmitis. Linezolid could be a valuable alternative in cases of increased resistance to vancomycin. PMID- 20202551 TI - Effect of varying microkeratome parameters on laser in situ keratomileusis interface surfaces. AB - PURPOSE: To evaluate the effect of altering microkeratome parameters (oscillation rates and head-advance speeds) and repeated blade use on human and porcine laser in situ keratomileusis interface surface quality and to evaluate correlations between human and porcine interface surface quality. SETTING: Emory Vision, Atlanta, Georgia, USA. METHODS: Corneal flaps were created in porcine eyes and human cadaver eyes with an Amadeus I microkeratome using varying head-advance speeds and oscillation rates. Microkeratome blades were used once in 18 porcine eyes, twice in 18 human eyes (simulating clinical use), and 5 times in 15 porcine eyes. The interface surface was imaged with electron microscopy, with overall bed quality and surface smoothness graded from 1 to 5 (smoothest to roughest) by 5 masked corneal specialists using the same grading criteria for porcine eyes and human eyes. RESULTS: Neither oscillation rates nor head-advance speeds consistently influenced bed smoothness in any group. There were no differences in bed quality between first cuts and second cuts in human eyes or between porcine eyes with multiple blade use. Porcine eyes had statistically significantly smoother stromal beds than human eyes (P<.01); there was no correlation between porcine eye scores and human eye scores (r = -0.1). CONCLUSIONS: Neither alterations in microkeratome parameters nor repeated blade use consistently influenced stromal bed quality in human or porcine eyes. No subjective correlation existed between stromal bed qualities of porcine corneas and human corneas; therefore, future studies evaluating corneal stromal bed quality should be performed in human corneas only. PMID- 20202552 TI - Pseudophakic eye with obliquely crossed piggyback toric intraocular lenses. AB - A 72-year-old man presented with high astigmatism (2.25 -5.0 x 45) induced by long-term rotation of a toric intraocular lens (IOL). Corneal astigmatism was 3.78 diopters (D). The corrected distance visual acuity (CDVA) was 20/32. Because of the risk of repositioning, a secondary toric IOL of -3.0/6.0 D especially designed for sulcus implantation was piggybacked through 3.5 mm sutureless clear corneal incision with a cylindrical axis obliquely crossed with that of the primary IOL. Eight months postoperatively, the corneal astigmatism was 5.04 D. The CDVA was 20/25 with a refraction of 1.0 -2.5 x 70. No interlenticular opacification or significant rotation or decentration of the secondary toric IOL was observed. The refractive properties of this pseudophakic eye were analyzed using a mathematical approach. The calculated postoperative refraction was 0.84 1.7 x 47. A piggyback toric IOL can be implanted in an obliquely crossed style that allows a secondary toric IOL to correct astigmatism induced by long-term toric IOL rotation. PMID- 20202553 TI - Immunohistochemical observation of anterior subcapsular cataract in eye with spontaneously regressed retinoblastoma. AB - We report the histological findings of secondary cataract in an eye with a spontaneously regressed retinoblastoma to obtain keys to clarify the mechanism of this phenomenon. During phacoemulsification, opacified anterior capsule was obtained, fixed in formalin, and embedded in paraffin. Paraffin sections of the specimen were histologically observed. Hematoxylin-eosin staining showed extracellular matrix accumulation in the extracted fibrous anterior subcapsular opacification. Immunohistochemistry revealed the presence of fibrous collagen types and cellular fibronectin. Presumed lens cells amid matrix were positively labeled for vimentin, alpha-smooth muscle actin, and phospho-Smad2. Histology of the fibrous anterior subcapsular opacification tissue showed the possibility of epithelial-mesenchymal transition of the lens epithelial cells in the secondary cataract following a spontaneously regressed retinoblastoma. PMID- 20202554 TI - Bilateral Descemet membrane detachment after canaloplasty. AB - We report a case of bilateral Descemet membrane detachment (DMD) after canaloplasty in a 70-year-old Portuguese man with primary open-angle glaucoma. The patient developed bilateral DMD immediately following consecutive (1 week apart) canaloplasty surgery in both eyes. Slitlamp biomicroscopy, gonioscopy, and Fourier-domain optical coherence tomography (FD-OCT) findings are described. On postoperative day 1, in both cases, slitlamp biomicroscopy revealed an unscrolled inferonasal DMD and a clear cornea with deep and quiet anterior chambers. Gonioscopy showed an intact, lightly pigmented, and distended trabecular meshwork with no evidence of suture extrusion. High-resolution FD-OCT revealed a widely dilated canal of Schlemm, trabecular distention, and a retrocorneal hyperreflective membrane corresponding to a DMD. At 3 months, the DMD resolved spontaneously in both eyes. Although DMD is a known complication of canaloplasty, the occurrence of bilateral symmetrically located DMDs in our case suggests a possible anatomical predisposition in addition to factors induced by the surgical technique. PMID- 20202555 TI - Long-term pathological follow-up of obsolete design: Pannu universal intraocular lens. AB - We studied an enucleated postmortem eye from an 82-year-old white donor who had been implanted with a Pannu "universal" intraocular lens (IOL) in the anterior chamber approximately 20 years earlier. This IOL has design features characteristic of a 1-piece, C-loop posterior chamber IOL. Magnetic resonance imaging showed a relatively well-centered IOL in the anterior chamber with haptics impinging on the iris. Gross and light microscopic analyses of the eye and the IOL showed peripheral anterior synechiae enclaving one haptic, areas of angle widening, significant attenuation of the corneal endothelium, multiple areas of iris trauma secondary to optic and haptic iris abrasion, large areas of pigment dispersion in the angle, diffuse pigment accumulation within the anterior chamber, and attenuation of the ganglion cell layer. The histopathological findings were consistent with glaucoma and chronic inflammation. PMID- 20202556 TI - Pseudomonas keratitis after collagen crosslinking for keratoconus: case report and review of literature. AB - A 19-year-old woman presented with a 3-day history of pain, redness, and diminution of vision occurring one day after collagen crosslinking (CXL) with riboflavin and ultraviolet-A had been performed for keratoconus in the right eye. On presentation, severe keratitis with a 7.0mm x 6.0mm central infiltrate was present. Culture results from the patient's contact lens and corneal scrapings were positive for Pseudomonas aeruginosa. Keratitis can occur following CXL because of the presence of an epithelial defect, use of a soft bandage contact lens, and topical corticosteroids in the immediate postoperative period, and patients should be counseled about it. PMID- 20202557 TI - Efficacy of topical anesthesia for foldable phakic intraocular lens implantation for the correction of myopia. PMID- 20202558 TI - Partial retraction of Malyugin pupil expansion device to improve safety during ring removal. PMID- 20202559 TI - Epi-Shugarcaine with plain balanced salt solution for prophylaxis of intraoperative floppy-iris syndrome. PMID- 20202560 TI - Consultation section. Refractive surgical problem. PMID- 20202563 TI - Factors affecting stromal hydration of clear corneal incision architecture. PMID- 20202564 TI - Letter to the editor on Calladine et al. PMID- 20202567 TI - Benefits of stromal hydration. PMID- 20202568 TI - Variation of cross-chop technique. PMID- 20202569 TI - Intraocular lens calculation in extreme myopia. PMID- 20202572 TI - Limitations of Fourier-domain OCT. PMID- 20202573 TI - Preface. Gastroenterologic issues in the obese patient. PMID- 20202574 TI - The epidemiology of obesity. AB - Obesity has received considerable attention as a major health hazard because of the increase in the prevalence of obesity not only in the United States but also in several other countries worldwide. Obesity is caused by an interaction of environmental factors, genetic predisposition, and human behavior, and is associated with an increased risk of numerous chronic diseases, from diabetes and cancers to many digestive diseases. The obesity epidemic exerts a heavy toll on the economy with its massive health care costs. This article describes some of the epidemiologic features of obesity, including global prevalence, secular trends, risk factors, and burden of illness related to obesity with special emphasis on obesity trends in the United States. PMID- 20202575 TI - Prevalence and epidemiology of gastrointestinal symptoms among normal weight, overweight, obese and extremely obese individuals. AB - Until recently, the epidemiology of gastrointestinal (GI) symptoms had not been adequately studied in relation to increasing body mass index. To date there are only a few studies in the literature, and thus the relationship between obesity and specific GI symptoms is poorly understood. Future studies that incorporate different ethnicities from varied geographic locations are urgently required. A greater understanding of how GI symptoms are related to obesity and the physiology will be important in the clinical management of these patients. PMID- 20202576 TI - Gastrointestinal symptoms and diseases related to obesity: an overview. AB - Obesity is a leading cause of illness and death worldwide. It is a risk factor for many common gastrointestinal symptoms and digestive disorders, including many cancers. Disruption of mechanisms that regulate appetite and satiety are fundamental to the development of obesity. Knowledge of these issues that are discussed in this article will provide the basis to develop health strategies to prevent obesity-related diseases. PMID- 20202577 TI - Gastroesophageal reflux disease and obesity. AB - Gastroesophageal reflux disease (GERD) is a common condition, with multifactorial pathogenesis, affecting up to 40% of the population. Obesity is also common. Obesity and GERD are clearly related, both from a prevalence and causality association. GERD symptoms increase in severity when people gain weight. Obese patients tend to have more severe erosive esophagitis and obesity is a risk factor for the development of Barrett's esophagus and adenocarcinoma of the esophagus. Patients report improvement in GERD when they lose weight and there are several reports suggesting a decrease in GERD symptoms after bariatric surgery. At present, there is little evidence that obesity has any effect on the efficacy of antisecretory therapy, with conflicting data on surgical outcomes. This review attempts to put in perspective the relationship of these two common entities. PMID- 20202578 TI - Colonic complications of obesity. AB - Obesity is a risk factor for colorectal cancer and adenomatous polyps. The increased prevalence of neoplasia coupled with the observation that obesity may be associated with a suboptimal bowel preparation may diminish the adequate detection of adenomas for obese who undergo colonoscopy. The colonic complications of obesity are reviewed in this article. PMID- 20202579 TI - Hepatic complications of obesity. AB - Obesity is associated with a spectrum of chronic liver disease. Because obesity increases the risk for advanced forms of liver disease (ie, cirrhosis and liver cancer), the obesity epidemic is emerging as a major factor underlying the burden of liver disease in the United States and many other countries. This article reviews mechanisms that mediate the pathogenesis of obesity-related liver disease, summarizes clinical evidence that demonstrates obesity-related liver disease can be life-threatening, and discusses whether or not treatments for obesity or related comorbidities impact liver disease outcomes. PMID- 20202580 TI - Pharmacologic therapies for obesity. AB - This article examines the transitions in pharmacological therapy for obesity. It reviews the current options approved by the Food and Drug Administration and several drugs approved for other indications that can be used to treat obesity as well. Because weight regulation is complex and redundant systems protect against perceived starvation, optimal treatment of obesity in individual patients will likely require different combinations of behavioral, nutritional, pharmacologic, endoscopic, and surgical therapies. PMID- 20202581 TI - Preoperative gastrointestinal assessment before bariatric surgery. AB - Obesity is a major health problem throughout the world. Bariatric surgery is frequently considered among the treatment options for the severely overweight, and surgically induced weight loss has become the best treatment for many morbidly obese people. A preoperative assessment to evaluate the suitability of a patient for a given operation and to clarify factors that may affect the outcome of a planned procedure should be carried out before the surgery. Preoperative evaluation of the gastrointestinal tract by a gastroenterologist before bariatric surgery yields important information that can lead to changes in planned treatments. This article discusses the factors that a gastroenterologist should assess before the surgery. PMID- 20202582 TI - Endoscopy in the obese patient. AB - Obese patients present many unique challenges to the endoscopist. Special consideration should be given to these patients, and endoscopists need to be aware of the additional challenges that may be present while performing endoscopic procedures on obese patients. This article reviews the special risks that obese patients face while undergoing endoscopy, endoscopic management of patients postbariatric surgery, and future role of endoscopy in the management of obese patients. PMID- 20202583 TI - Endoscopic retrograde cholangiopancreatography in patients with Roux-en-Y anatomy. AB - Bariatric surgery has been increasingly performed in response to the obesity pandemic. During the last decade, Roux-en-Y gastric bypass (RYGB) has become the preferred surgical approach. It is also commonly performed after pylorus preserving pancreaticoduodenectomy and other biliary tract surgeries. This article discusses the different options available for endoscopists who are faced with the need to perform endoscopic retrograde cholangiopancreatography in patients after Roux-en-Y reconstruction, with special emphasis on those after RYGB. PMID- 20202584 TI - Postoperative metabolic and nutritional complications of bariatric surgery. AB - Bariatric surgery has become an increasingly important method for management of medically complicated obesity. In patients who have undergone bariatric surgery, up to 87% with type 2 diabetes mellitus develop improvement or resolution of their disease postoperatively. Bariatric surgery can reduce the number of absorbed calories through performance of either a restrictive or a malabsorptive procedure. Patients who have undergone bariatric surgery require indefinite, regular follow-up care by physicians who need to follow laboratory parameters of macronutrient as well as micronutrient malnutrition. Physicians who care for patients after bariatric surgery need to be familiar with common postoperative syndromes that result from specific nutrient deficiencies. PMID- 20202585 TI - The surgical treatment of metabolic disease and morbid obesity. AB - The disease of obesity has continued to increase in the United States. Obesity is defined as a body mass index (BMI) greater than 30 kg/m(2). In 1991, the National Institute of Health Consensus Panel on Gastric Surgery for Severe Obesity defined the population who would most likely benefit from bariatric surgery. These same criteria continue to be used today to determine which patients should undergo metabolic and weight loss surgery. These recommendations include patients who have a BMI greater than 35 kg/m(2) with significant comorbid conditions such as diabetes, hypertension, or obstructive sleep apnea; and patients who have a BMI greater than 40 kg/m(2) with or without any significant comorbid conditions because they have a significant increased risk for developing these conditions. PMID- 20202586 TI - Short- and long-term surgical follow-up of the postbariatric surgery patient. AB - Follow-up of the large numbers of patients undergoing bariatric surgery poses problems for surgical programs and for internists who care for morbidly obese patients. Early surgical follow up is concentrated on the perioperative period to ensure healing and care for any surgical complications. It is especially important to treat persistent vomiting to avoid thiamine deficiency. Subsequently, monitoring weight loss and resolution of comorbidities assumes more importance. Identification and management of nutritional deficiencies and other unwanted consequences of surgery may become the responsibility of internists if the patient no longer attends the office of the operating surgeon. The long-term goal is to avoid weight regain and deficiencies, especially of protein, iron and vitamin B12, and calcium and vitamin D. Abdominal pain and gastrointestinal dysfunction should be investigated promptly to exclude or confirm such conditions as small bowel obstruction or gallstones. Good communication between bariatric surgeons and internal medicine specialists is essential for early and accurate identification of problems arising from bariatric surgery. PMID- 20202587 TI - Systemic lupus erythematosus. Preface. PMID- 20202588 TI - Changing worldwide epidemiology of systemic lupus erythematosus. AB - Developed countries have better systemic lupus erythematosus survival rates than developing countries, or countries with lower economic performance. This is in part because of a higher human development index, defined by standard of living (a marker for gross domestic product), literacy rates, and life expectancy, with contribution from ethnic variations within individual countries, and unique environmental factors. PMID- 20202589 TI - Health-related quality of life and employment among persons with systemic lupus erythematosus. AB - This article assesses the effect of systemic lupus erythematosus (SLE) on the shealth-related quality of life (HRQOL) and employment of persons with this condition. Far more than impaired health status can affect an individual's quality of life. The term "health-related quality of life" is used to connote the decrement in an individual's quality of life specifically attributable to a decrease in health status. The article presents evidence on employment because this plays a crucial role in determining the quality of life of most Americans of normal working age. However, evidence is also presented with respect to other domains of activity, because most people work to live but not many live to work. PMID- 20202590 TI - Cutaneous lupus and the Cutaneous Lupus Erythematosus Disease Area and Severity Index instrument. AB - This article provides an overview of cutaneous lupus erythematosus, including classification schemes, disease subtypes, and therapy. It also describes the Cutaneous Lupus Erythematosus Disease Area and Severity Index, a novel clinical outcome instrument that quantifies cutaneous activity and damage in cutaneous lupus erythematosus. PMID- 20202592 TI - The metabolic syndrome in systemic lupus erythematosus. AB - The metabolic syndrome (MetS) is a recently defined clustering of cardiovascular risk factors associated with increased insulin resistance and a high risk of developing type II diabetes mellitus. Systemic lupus erythematosus (SLE) is associated with an increased prevalence of the MetS and patients also show evidence of increased insulin resistance. Controversy remains, however, regarding the precise definition of the MetS and its exact role in predicting long-term coronary heart disease risk both in SLE and in the general population. The major benefit of identifying the MetS in patients with SLE is likely to be from highlighting patients for focused lifestyle interventions and helping to guide individualized therapeutic regimes that take into account cardiovascular risk. PMID- 20202593 TI - Gonadal failure with cyclophosphamide therapy for lupus nephritis: advances in fertility preservation. AB - Intravenous cyclophosphamide remains an important therapy for patients with severe systemic lupus erythematosus--including lupus nephritis, which primarily affects women in their reproductive years. As prognosis improves, the chronic toxicity of this therapy assumes greater importance. This article reviews cyclophosphamide use, its effect on gonadal function, and protection of gonadal reserve during therapy. Egg, embryo, or gonadal tissue cryopreservation and alternative therapeutic strategies are considered. PMID- 20202591 TI - Pediatric lupus--are there differences in presentation, genetics, response to therapy, and damage accrual compared with adult lupus? AB - Some complement deficiencies predispose to systemic lupus erythematosus (SLE) early in life. Currently, there are no known unique physiologic or genetic pathways that can explain the variability in disease phenotypes. Children present with more acute illness and have more frequent renal, hematologic, and central nervous system involvement compared to adults with SLE. Almost all children require corticosteroids during the course of their disease; many are treated with immunosuppressive drugs. Mortality rates remain higher with pediatric SLE. Children and adolescents accrue more damage, especially in the renal, ocular and musculoskeletal organ systems. Conversely, cardiovascular mortality is more prevalent in adults with SLE. PMID- 20202594 TI - B-cell biology and related therapies in systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a complex disease characterized by numerous autoantibodies and clinical involvement in multiple organ systems. The immunologic events triggering the onset and progression of clinical manifestations have not yet been fully defined, but a central role for B cells in the pathogenesis has been brought to the fore in the last several years. The breakdown of B-cell tolerance is likely a defining and early event in the disease process and may occur by multiple pathways, including alterations in factors that affect B-cell activation thresholds, B-cell longevity, and apoptotic cell processing. Antibody-dependent and -independent mechanisms of B cells are important in SLE. Thus, autoantibodies contribute to autoimmunity by multiple mechanisms including immune complex mediated type III hypersensitivity reactions, type II antibody-dependent cytotoxicity, and by instructing innate immune cells to produce pathogenic cytokines including interferon alpha, tumor necrosis factor, and interleukin 1. Recent data have highlighted the critical role of toll like receptors as a link between the innate and adaptive immune system in SLE immunopathogenesis. Given the large body of evidence implicating abnormalities in the B-cell compartment in SLE, there has been a therapeutic focus on developing interventions that target the B-cell compartment. Several different approaches to targeting B cells have been used, including B-cell depletion with monoclonal antibodies against B-cell-specific molecules, induction of negative signaling in B cells, and blocking B-cell survival and activation factors. Overall, therapies targeting B cells are beginning to show promise in the treatment of SLE and continue to elucidate the diverse roles of B cells in this complex disease. PMID- 20202595 TI - Biomarkers in lupus nephritis. AB - Biomarkers have the potential to be useful tools for noninvasively evaluating and managing patients with lupus nephritis. Many candidate biomarkers have been identified, but they require validation in larger cohorts. It is likely that combinations or biomarker profiles, rather than individual markers, will emerge to help better predict the severity of inflammation, the extent of fibrosis, degree of drug responsiveness, and other variables. This approach has the potential to reduce the use of the renal biopsy, improve therapeutic efficacy, and limit toxicity. We predict algorithms based on genotype and biomarkers combined with clinical presentation will emerge to help guide physicians in management. Assays that show the most potential include serum erythrocyte bound complement C4d, interleukin 17, interleukin 23, interferon score/chemokine score ratio, and anti-C1q antibodies. Such urinary biomarkers as fractional excretion of endothelial-1, monocyte chemoattractant protein-1, vascular cell adhesion molecule-1, and TWEAK (tumor necrosis factor-like weak inducer of apoptosis) may also be useful but require validations. PMID- 20202596 TI - Endothelial function and its implications for cardiovascular and renal disease in systemic lupus erythematosus. AB - Vascular manifestations associated with systemic lupus erythematosus (SLE) span a broad range, including vasculopathy. An understudied pathway of this morbidity is a repair component. Recent studies have elevated the anti-injury biomarkers, adiponectin and membrane endothelial protein C receptor (EPCR), for consideration with roles to antagonize premature atherosclerosis and SLE nephritis, respectively. For example, adiponectin was found to serve as an independent predictor of carotid plaque, and its elevations were persistent over more than one visit. Unexpectedly, this biomarker was present despite clinical quiescence. In vasculopathy as a comorbidity to SLE nephritis, the persistent expression of membrane EPCR at peritubular capillaries may represent a response to the local cues of a deficit of active protein C. Under conditions of unresolved morbidity, higher levels of adiponectin and membrane EPCR may represent a physiologic attempt to limit further endothelial damage, and the observed increase in plaque and progression of SLE nephritis represent an overwhelming of this reparative process by disease-provoking stimuli. PMID- 20202597 TI - Cell-bound complement biomarkers for systemic lupus erythematosus: from benchtop to bedside. AB - Systemic lupus erythematosus is arguably the most clinically and serologically diverse autoimmune disease. This article highlights the biomarkers helpful in diagnosing this disease. The authors' own research is presented. PMID- 20202598 TI - Interferon-alpha: a therapeutic target in systemic lupus erythematosus. AB - The long history of elevated interferon (IFN)-alpha in association with disease activity in patients who have systemic lupus erythematosus (SLE) has assumed high significance in the past decade, with accumulating data strongly supporting broad activation of the type I IFN pathway in cells of patients who have lupus, and association of IFN pathway activation with significant clinical manifestations of SLE and increased disease activity based on validated measures. In addition, a convincing association of IFN pathway activation with the presence of autoantibodies specific for RNA-binding proteins has contributed to delineation of an important role for Toll-like receptor activation by RNA-containing immune complexes in amplifying innate immune system activation and IFN pathway activation. Although the primary triggers of SLE and the IFN pathway remain undefined, rapid progress in lupus genetics is helping define lupus-associated genetic variants with a functional relationship to IFN production or response in patients. Together, the explosion of data and understanding related to the IFN pathway in SLE have readied the lupus community for translation of those insights to improved patient care. Patience will be needed to allow collection of clinical data and biologic specimens across multiple clinical centers required to support testing of IFN activity, IFN-inducible gene expression and chemokine gene products as candidate biomarkers. Meanwhile, promising clinical trials are moving forward to test the safety and efficacy of monoclonal antibody inhibitors of IFN alpha. Other therapeutic approaches to target the IFN pathway may follow close behind. PMID- 20202600 TI - Transbronchial human interleukin-10 gene transfer reduces acute inflammation associated with allograft rejection and intragraft interleukin-2 and tumor necrosis factor-alpha gene expression in a rat model of lung transplantation. AB - BACKGROUND: The ability to express genes with potential immunoregulatory capacity could reduce allograft rejection (AR). This study examined the effect of ex vivo lipid-mediated transbronchial human interleukin-10 (hIL-10) gene transfer on AR and the intragraft cytokine profile in a rat model of lung transplantation. METHODS: Left single lung transplants were performed between a highly histoincompatible combination of inbred rats. The donor left lung was extracted and intrabronchially instilled with a plasmid encoding hIL-10 (IL-10 group) or Escherichia coli beta-galactosidase (control group), mixed with a cationic lipid. At 3 and 6 days after transplantation, the degree of AR was graded histologically (stage 1-4) and several pathologic categories of inflammation were scored on a scale of 0 to 4 according to the percentage of involvement. Intragraft cytokine profile was examined by real-time reverse transcription polymerase chain reaction. RESULTS: The stage of AR (3.1 +/- 0.4 vs 3.8 +/- 0.4) and the pathologic scores for edema (2.3 +/- 0.8 vs 3.2 +/- 0.4), intraalveolar hemorrhage (0.3 +/- 0.5 vs 2.2 +/- 0.8), and necrosis (0.3 +/- 0.5 vs 1.2 +/- 0.4) in the IL-10 group were significantly decreased compared with the control group at Day 6. IL-2 and tumor necrosis factor-alpha messenger RNA expression levels on Day 3 were significantly decreased in the IL-10 group. CONCLUSIONS: Ex vivo lipid-mediated transbronchial hIL-10 gene transfer attenuated acute inflammation associated with AR, which was related to decreased levels of proinflammatory cytokine gene expression in a rat model of lung transplantation. PMID- 20202599 TI - Glutamate receptor biology and its clinical significance in neuropsychiatric systemic lupus erythematosus. AB - The recent appreciation that a subset of anti-DNA antibodies cross-reacts with the N-methyl-d-aspartate receptor encourages a renewed examination of antibrain reactivity in systemic lupus erythematosus (SLE) autoantibodies. Moreover, investigations of their autospecificity present a paradigm for studies of antibrain reactivity and show that (1) serum antibodies access brain tissue only after a compromise of blood-brain barrier integrity, (2) the same antibodies have differential effects on brain function depending on the region of brain exposed to the antibodies, and (3) insults to the blood-brain barrier are regional rather than diffuse. These studies suggest that an anatomic classification scheme for neuropsychiatric SLE may facilitate research on etiopathogenesis and the design of clinical trials. PMID- 20202601 TI - New hope for advanced gastric cancer. PMID- 20202602 TI - Neoadjuvant chemotherapy in MRI-staged rectal cancer. PMID- 20202603 TI - Doubling back on centromere 17 in early breast cancer. PMID- 20202604 TI - Taxanes and anthracyclines in early breast cancer: which first? PMID- 20202605 TI - Neurocognitive function after WBRT plus SRS or SRS alone. PMID- 20202606 TI - Whole-brain irradiation for patients with brain metastases: still the standard of care. PMID- 20202607 TI - Adjuvant neck dissection after chemoradiotherapy. PMID- 20202609 TI - Neck dissection and chemoradiation in head and neck cancer. PMID- 20202610 TI - HER2 as a cancer stem-cell target. PMID- 20202611 TI - The power of positive thinking. PMID- 20202612 TI - Minimally invasive surgery for head and neck cancer. AB - Minimally invasive surgery has been adopted in many areas of surgery to reduce patient morbidity during surgical resection. To achieve this, endoscopic instrumentation coupled with improved imaging and localisation techniques have been developed, to enable adequate resection of tumours with minimum damage to surrounding tissues. We review two emerging technologies, robotic assisted surgery and intraoperative imaging. We also discuss two fields of head and neck surgery, skull-base tumour resection and thyroidectomy, where the application of minimally invasive endoscopic techniques has been widely applied, and review their results. PMID- 20202613 TI - Optimising the therapeutic ratio in head and neck cancer. AB - The intensity of contemporary treatment for locally advanced head and neck cancer is at the upper limit of human tolerance of acute toxicities. While impressive gains in locoregional control have been achieved, improvements in overall survival have been more modest. We hypothesise that unrecognised sequelae of highly toxic contemporary treatments substantially contribute to patient mortality. This possibility provides motivation to investigate reducing treatment intensity in selected patients with locally advanced head and neck cancer. With the demonstration of a good prognosis among subgroups of patients with head and neck cancer, major improvements in the technical delivery of radiotherapy, and further research into relevant factors in survivorship, we may be able to improve overall survival of patients with locally advanced disease without further increasing, and possibly reducing, treatment intensity. PMID- 20202614 TI - Nerve-sparing and individually tailored surgery for cervical cancer. AB - Cancer of the cervix is the second most common cancer in women worldwide, with about 500,000 new cases and 273,000 deaths reported annually. Ideal surgical management of cervical cancer should reduce early and late morbidity without compromising oncological disease control. Type of surgical radicality in early cervical cancer should be a consequence of exact preoperative and intraoperative assessments of risk factors. During the past 15 years, substantial progress has been made in understanding the neuroanatomy of the autonomic pelvic plexus. This progress has resulted in individually tailored surgery for cervical cancer. The concept of preservation of autonomic nerves during radical hysterectomy has become standard in many oncogynaecological centres. Nerve-sparing radical hysterectomy and individually tailored surgery, in comparison with standard radical hysterectomy, have led to a much improved quality of life. Since 2008, there has been a new classification of radical hysterectomy, which includes nerve sparing techniques. 5-year survival in early stage cervical cancer is 88-97% and more than 50% of women are younger than 50 years of age. Thus, we must take into consideration the quality of life of these patients. In this Review, we focus on the neuroanatomy of the pelvis and the possible damage of autonomic nerves, and suggest options for the sparing of these nerves during surgery for cervical cancer. PMID- 20202615 TI - The first reported localisation and resection of a brain tumour. PMID- 20202617 TI - Critical comparison of molecular mixing and interaction models for liquids, solutions and mixtures. AB - Surface properties of condensed matter, in particular solids are frequently characterized with probe liquids. The liquids are assigned physico-chemical parameters, such as solubility parameters, surface/interfacial tensions and Hamaker constants. Each parameter has been subdivided into two-to-five van der Waals (London, Debye and Keesom) and Lewis contributions. A critical comparison reveals that each contribution varies considerably distorting the balance between them. Despite this scatter each set of parameters representing a particular molecular interaction shows similar trends. Experimental verification of these multi-parameter contributions in multi-components systems remain, however uncertain. Three models involving solubility parameters, surface/interfacial tensions and Hamaker constants were compared for internal and mutual conceptual consistency. It is shown that Fowkes definition of work of adhesion as interfacial tension contradicts Dupre's definition as work process of adhesion. The exchange energy density (EED) process differs from the work of adhesion process by a factor two for the interfacial average term and for three-component systems the models differ substantially. The processes which are represented by Hamaker constants are in accord with the EED process for two-component systems, but assumed equal to work process of adhesion for three-component systems. Although the process representation is common for all models, it is shown that they represent only a fraction of the total energy balance. PMID- 20202618 TI - Structure-function correlations using scanning laser polarimetry in primary angle closure glaucoma and primary open-angle glaucoma. AB - PURPOSE: To assess the correlations between retinal nerve fiber layer (RNFL) thickness measured with scanning laser polarimetry and visual field (VF) sensitivity in primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG). DESIGN: Prospective, comparative, observational cases series. METHODS: Fifty patients with POAG and 56 patients with PACG were examined using scanning laser polarimetry with variable corneal compensation (GDx VCC; Laser Diagnostic Technologies, Inc.) and Humphrey VF analyzer (Carl Zeiss Meditec, Inc.) between August 2005 and July 2006 at Taipei Veterans General Hospital. Correlations between RNFL thickness and VF sensitivity, expressed as mean sensitivity in both decibel and 1/Lambert scales, were estimated by the Spearman rank correlation coefficient (r(s)) and multivariate median regression models (pseudo R(2)). The correlations were determined globally and for 6 RNFL sectors and their corresponding VF regions. RESULTS: The correlation between RNFL thickness and mean sensitivity (in decibels) was weaker in the PACG group (r(s) = 0.38; P = .004; pseudo R(2) = 0.17) than in the POAG group (r(s) = 0.51; P < .001; pseudo R(2) = .31), but the difference in the magnitude of correlation was not significant (P = .42). With Bonferroni correction, the structure-function correlation was significant in the superotemporal (r(s) = 0.62), superonasal (r(s) = 0.56), inferonasal (r(s) = 0.53), and inferotemporal (r(s) = 0.50) sectors in the POAG group (all P < .001), whereas it was significant only in the superotemporal (r(s) = 0.53) and inferotemporal (r(s) = 0.48) sectors in the PACG group (both P < .001). The results were similar when mean sensitivity was expressed as 1/Lambert scale. CONCLUSIONS: Both POAG and PACG eyes had moderate structure-function correlations using scanning laser polarimetry. Compared with eyes with POAG, fewer RNFL sectors have significant structure-function correlations in eyes with PACG. PMID- 20202619 TI - Thermal comparison of Infiniti OZil and Signature Ellips phacoemulsification systems. AB - PURPOSE: To determine thermal characteristics of Signature Ellips (Abbott Medical Optics) and Infiniti OZil (Alcon, Inc.) transverse ultrasound and compare both with longitudinal ultrasound in clinically relevant scenarios. DESIGN: Laboratory investigation. METHODS: Temperature increase over baseline after 60 seconds was measured in water at positions in 90-degree increments around the sleeve near the proximal needle shaft in an artificial chamber for Ellips and OZil on continuous ultrasound with aspiration blocked and unblocked. This was also done with Signature using longitudinal ultrasound, with and without micropulse (6 ms on, 12 ms off), with aspiration blocked and unblocked, and at the OZil sleeve tip on continuous transverse mode with aspiration unblocked. RESULTS: OZil (8.1 +/- 0.3 C) had greater temperature increase than Ellips (5.2 +/- 0.3 C; P < .0001) with aspiration unblocked and blocked (29.3 +/- 1.0 C vs 12.2 +/- 0.7 C; P < .0001). OZil had uneven distribution of heat around the shaft (30.1 +/- 0.5 C vs 28.5 +/- 0.6 C; P < .0001), whereas Ellips did not (P = .57). OZil was cooler at the tip (6.6 +/- 0.2 C; P < .0001). Friction in a cadaver eye incision only increased these numbers by 10% (OZil, irrigation blocked). CONCLUSIONS: Metal stress probably creates heat at the proximal needle junction for both transverse methods. Heat generation differences between OZil and Ellips result from the manner in which they create needle motion. Incision burns may occur, especially for OZil, under nonpulsed settings during fragment removal with occlusion when reaching across the anterior chamber such that the proximal needle shaft came near the wound. PMID- 20202620 TI - Sealants after axillary lymph node dissection. PMID- 20202621 TI - Reliable preparation of the gastric tube for cervical esophagogastrostomy after esophagectomy for esophageal cancer. AB - Maintaining sufficient blood flow to the gastric tube is essential to avoid anastomotic leakage after esophageal reconstruction for esophageal cancer. We were able to obtain sufficient blood flow to the tip of the gastric tube by separating the inferior polar branches of the splenic vessels at their origin. By using this procedure, we were able to preserve the junction between the left gastroepiploic vessels and the inferior short gastric vessels without splenectomy. The entire greater omentum also was preserved to use the network between the right and left gastroepiploic vessels. Finally, the anastomotic site was wrapped with the omentum. By using these techniques, the anastomotic site of the gastric tube was well nourished in all patients who underwent esophageal reconstruction for esophageal cancer; anastomotic leakage did not occur. PMID- 20202622 TI - Clinical images. Classic presentation of a type II obturator hernia. AB - A type II obturator hernia is a rare clinical entity that may be found on imaging and at surgery, as seen in this case of a 91-year-old woman who presented to our emergency department. Images are presented with treatment choices and a brief discussion on different types of obturator hernias. PMID- 20202624 TI - The course of neuropsychological performance and functional capacity in older patients with schizophrenia: influences of previous history of long-term institutional stay. AB - BACKGROUND: Chronically institutionalized patients with schizophrenia have been reported to manifest cognitive and functional decline. Previous studies were limited by the fact that current environment could not be separated from lifetime illness course. The present study examined older outpatients who varied in their lifetime history of long-term psychiatric inpatient stay. METHODS: Community dwelling patients with schizophrenia (n = 111) and healthy comparison subjects (n = 76) were followed up to 45 months and examined two or more times with a neuropsychological battery and performance-based measures of everyday living skills (University of California San Diego Performance-Based Skills Assessment Battery [UPSA]) and social competence. A mixed-effects model repeated-measures method was used to examine changes. RESULTS: There was a significant effect of institutional stay on the course of the UPSA. When the schizophrenia patients who completed all three assessments were divided on the basis of length of institutional stay and compared with healthy comparison subjects, patients with longer stays worsened on the UPSA and social competence, while patients with shorter stays improved. For neuropsychological performance, both patient samples worsened slightly, while the healthy comparison group manifested a practice effect. Reliable change index analyses showed that worsening on the UPSA for longer stay patients was definitely nonrandom. CONCLUSIONS: Lifetime history of institutional stay was associated with worsening on measures of social and everyday living skills. Neuropsychological performance in schizophrenia did not evidence the practice effect seen in the healthy comparison sample. These data suggest that schizophrenia patients with a history of long institutional stay may worsen even if they are no longer institutionalized. PMID- 20202623 TI - Improving cardiac surgical care: a work systems approach. AB - Over the past 50 years, significant improvements in cardiac surgical care have been achieved. Nevertheless, surgical errors that significantly impact patient safety continue to occur. In order to further improve surgical outcomes, patient safety programs must focus on rectifying work system factors in the operating room (OR) that negatively impact the delivery of reliable surgical care. The goal of this paper is to provide an integrative review of specific work system factors in the OR that may directly impact surgical care processes, as well as the subsequent recommendations that have been put forth to improve surgical outcomes and patient safety. The important role that surgeons can play in facilitating work system changes in the OR is also discussed. The paper concludes with a discussion of the challenges involved in assessing the impact that interventions have on improving surgical care. Opportunities for future research are also highlighted throughout the paper. PMID- 20202626 TI - Childhood maltreatment and hypothalamic-pituitary-adrenal axis reactivity. PMID- 20202625 TI - Acute effects of alcohol on intrusive memory development and viewpoint dependence in spatial memory support a dual representation model. AB - BACKGROUND: A dual representation model of intrusive memory proposes that personally experienced events give rise to two types of representation: an image based, egocentric representation based on sensory-perceptual features; and a more abstract, allocentric representation that incorporates spatiotemporal context. The model proposes that intrusions reflect involuntary reactivation of egocentric representations in the absence of a corresponding allocentric representation. We tested the model by investigating the effect of alcohol on intrusive memories and, concurrently, on egocentric and allocentric spatial memory. METHODS: With a double-blind independent group design participants were administered alcohol (.4 or .8 g/kg) or placebo. A virtual environment was used to present objects and test recognition memory from the same viewpoint as presentation (tapping egocentric memory) or a shifted viewpoint (tapping allocentric memory). Participants were also exposed to a trauma video and required to detail intrusive memories for 7 days, after which explicit memory was assessed. RESULTS: There was a selective impairment of shifted-view recognition after the low dose of alcohol, whereas the high dose induced a global impairment in same-view and shifted-view conditions. Alcohol showed a dose-dependent inverted "U"-shaped effect on intrusions, with only the low dose increasing the number of intrusions, replicating previous work. When same-view recognition was intact, decrements in shifted-view recognition were associated with increases in intrusions. CONCLUSIONS: The differential effect of alcohol on intrusive memories and on same/shifted-view recognition support a dual representation model in which intrusions might reflect an imbalance between two types of memory representation. These findings highlight important clinical implications, given alcohol's involvement in real-life trauma. PMID- 20202627 TI - [Difficulty in the diagnosis of an abscessed Spigelian hernia]. PMID- 20202628 TI - [Prosthetic material in incisional hernia surgery]. AB - There are different designs of prosthesis for use in the repair of incisional hernia, and it is often difficult to choose the most appropriate. The biological behaviour of the material must be a key part in the selection, although this behaviour will vary depending on what materials are available. A proper understanding of the relationship of the material with the abdominal wall dynamics is another important factor in this selection. Finally we need a stable repair without long term side effects. This paper analyses the prostheses more commonly available for incisional hernia surgery in the non-emergency situation. PMID- 20202629 TI - [Infected urachal cyst as an unusual differential diagnosis of acute appendicitis]. PMID- 20202630 TI - [Pulmonary hypoplasia in the adult]. PMID- 20202631 TI - Retinal vessel extraction by matched filter with first-order derivative of Gaussian. AB - Accurate extraction of retinal blood vessels is an important task in computer aided diagnosis of retinopathy. The matched filter (MF) is a simple yet effective method for vessel extraction. However, a MF will respond not only to vessels but also to non-vessel edges. This will lead to frequent false vessel detection. In this paper we propose a novel extension of the MF approach, namely the MF-FDOG, to detect retinal blood vessels. The proposed MF-FDOG is composed of the original MF, which is a zero-mean Gaussian function, and the first-order derivative of Gaussian (FDOG). The vessels are detected by thresholding the retinal image's response to the MF, while the threshold is adjusted by the image's response to the FDOG. The proposed MF-FDOG method is very simple; however, it reduces significantly the false detections produced by the original MF and detects many fine vessels that are missed by the MF. It achieves competitive vessel detection results as compared with those state-of-the-art schemes but with much lower complexity. In addition, it performs well at extracting vessels from pathological retinal images. PMID- 20202633 TI - The effect of the SAFE or SORRY? programme on patient safety knowledge of nurses in hospitals and nursing homes: a cluster randomised trial. AB - BACKGROUND: Patients in hospitals and nursing homes are at risk for the development of often preventable adverse events. Guidelines for the prevention of many types of adverse events are available, however compliance with these guidelines appears to be lacking. As a result many patients do not receive appropriate care. We developed a patient safety program that allows organisations to implement multiple guidelines simultaneously and therefore facilitates guideline use to improve patient safety. This program was developed for three frequently occurring nursing care related adverse events: pressure ulcers, urinary tract infections and falls. For the implementation of this program we developed educational activities for nurses as a main implementation strategy. OBJECTIVES: The aim of this study is to describe the effect of interactive and tailored education on the knowledge levels of nurses. DESIGN: A cluster randomised trial was conducted between September 2006 and July 2008. SETTINGS: Ten hospital wards and ten nursing home wards participated in this study. Prior to baseline, randomisation of the wards to an intervention or control group was stratified for centre and type of ward. PARTICIPANTS: All nurses from participating wards. METHODS: A knowledge test measured nurses' knowledge on the prevention of pressure ulcers, urinary tract infections and falls, during baseline en follow-up. The results were analysed for hospitals and nursing homes separately. RESULTS: After correction for baseline, the mean difference between the intervention and the control group on hospital nurses' knowledge on the prevention of the three adverse events was 0.19 points on a zero to ten scale (95% CI: -0.03 to 0.42), in favour of the intervention group. There was a statistically significant effect on knowledge of pressure ulcers, with an improved mean mark of 0.45 points (95% CI: 0.10-0.81). For the other two topics there was no statistically significant effect. Nursing home nurses' knowledge did neither improve (0 points, CI: -0.35 to 0.35) overall, nor for the separate subjects. CONCLUSION: The educational intervention improved hospital nurses' knowledge on the prevention of pressure ulcers only. More research on long term improvement of knowledge is needed. PMID- 20202634 TI - What is the natural history of 18F-FDG uptake in arterial atheroma on PET/CT? Implications for imaging the vulnerable plaque. AB - PURPOSE: Increased uptake of 18F-fluorodeoxyglucose (18F-FDG) in atherosclerotic plaque on Positron Emission Tomography (PET), predicts vulnerability. Recent studies have shown that the PET signal is reproducible over a 2-week period and as a result drug trials are underway. However, the natural history of these lesions is unknown. The aim of this study is determine the natural history of increased vascular wall uptake of 18F-fluorodeoxyglucose (18F-FDG). METHODS: Following institutional ethics committee approval, we retrospectively examined PET/CT images of patients from our Institution that had at least 4 examinations in the last 5 years. This represented 205 studies in total, from 50 patients (29 men, 21 women, mean age 49.4+/-12.1 years, mean 5.1+/-1.7 studies/patient). The mean follow-up was 27.2+/-11.8 months. The carotids and the aorta were evaluated for increased 18F-FDG uptake with a maximum Standardized Uptake Value (SUVmax)>2.5, and >3.0, and calcification. Plots of SUVmax and Hounsfield units (HU) were made versus time. RESULTS: The initial prevalence of increased focal arterial 18F-FDG uptake was 17/50 patients and of arterial calcification 19/50. 132 sites of 18F-FDG uptake in total were observed longitudinally. 18F-FDG vascular uptake did not persist with time. There was no correlation between 18F FDG uptake and HU. No calcifications developed at sites of focal increased 18F FDG uptake. CONCLUSIONS: Arterial lesions with increased 18F-FDG uptake represent transient phenomena. This data is important for the interpretation of findings of clinical trials using arterial 18F-FDG uptake as an imaging biomarker to monitor pharmacological intervention. PMID- 20202635 TI - Impact of HDL on adipose tissue metabolism and adiponectin expression. AB - OBJECTIVE: The objective of the current study was to investigate the hypothesis that high-density lipoprotein (HDL) influences adipocyte metabolism and adiponectin expression. Therefore, HDL was increased in vivo via apolipoprotein (apo) A-I gene transfer and in vitro via supplementation of HDL to partly differentiated adipocytes, in the presence or absence of lipopolysaccharide (LPS), known to decrease HDL cholesterol and adiponectin levels in vivo. METHODS AND RESULTS: Apo A-I transfer resulted in a significant increase of HDL cholesterol in control and LPS-injected C57BL/6 mice, which was paralleled by an increase in plasma adiponectin levels and adiponectin expression in abdominal fat. Triglyceride and free fatty acids levels after LPS administration were 2.2 fold (p<0.05) and 1.3-fold (p<0.05) lower, respectively, in Ad.hapoA-I-LPS than in Ad.Null-LPS mice. In parallel, the LPS-induced mRNA expression of hormone sensitive lipase was 3.5-fold (p=0.05) decreased in the Ad.hapoA-I-LPS group. On the other hand, apo A-I transfer abrogated the LPS-mediated reduction in lipin-1 and CD36 mRNA expression by 8.2-fold (p<0.05) and 18-fold (p<0.05), respectively. Concomitantly, the phosphorylation state of Akt was 2.0-fold (p<0.05) increased in the Ad.hapoA-I-LPS compared to the Ad.Null-LPS group. Pre-incubation of partly differentiated adipocytes with HDL (50 microg protein/ml) increased adiponectin expression by 1.5-fold under basal conditions (p<0.05) and could abrogate LPS induced down-regulation of adiponectin, both in a phosphatidylinositol-3-kinase dependent manner. CONCLUSIONS: HDL affects adipocyte metabolism and adiponectin expression. PMID- 20202636 TI - Mycophenolate mofetil attenuates plaque inflammation in patients with symptomatic carotid artery stenosis. AB - Atherosclerosis as well as the subsequent progression towards cardiovascular events are considered to, at least partially, be a consequence of chronic inflammatory activity. Therefore, we decided to evaluate the impact of short-term immunosuppressive treatment on plaque characteristics in patients with symptomatic carotid artery stenosis. Twenty-one patients were randomized to receive either 1000 mg. Mycophenolate mofetil (MMF) BD or placebo for at least 2 weeks prior to undergoing carotid endarterectomy (CEA). The serial sections of the CEA specimens were immunostained for activated T-cells (CD3+CD69+), regulatory T-cells (CD3+FOXP3+) and macrophages (CD68). In addition, gene expression profiling was performed by Illumina gene-array. Immunostaining revealed a reduction of activated T-cells in nine MMF-treated patients compared to 11 placebo-treated control patients (19.7% vs. 28.1%; p<0.05) as well as an increase of regulatory T-cells (3.8% vs. 1.8%; p=0.05). Microarray analyses confirmed beneficial changes to plaque phenotype, showing reduced expression of pro-inflammatory genes. Significantly reduced expression of metalloproteinases and osteopontin was observed in three out of nine MMF-treated patients compared to nil out of 11 in the placebo group. In the present study we show that immunosuppressive treatment for two-and-a-half weeks prior to CEA elicits changes in the plaque phenotype of symptomatic patients. These changes include reduced inflammatory cell presence with a concomitant decrease in pro-inflammatory gene expression. PMID- 20202637 TI - FDG-PET imaging of atherosclerosis: Do we know what we see? AB - Imaging atherosclerosis may help to identify subjects harboring rupture-prone atherosclerotic plaques who may benefit from preventive interventions. Potential of plaques to rupture depends on their structural changes and metabolic activation, which are difficult to assess using anatomic imaging modalities. Recent studies suggested that functional imaging with positron emission tomography (PET) utilizing fluorine-18-labeled 2-deoxy-d-glucose (FDG) has the potential to assess plaque metabolism and add to prediction of vascular risk. Aortic, iliac, and carotid plaques can be detected with FDG-PET, even though not all plaques exhibit high FDG uptake. Detection of coronary artery plaques is more cumbersome due to technical limitations of PET and fast movement of these vessels during cardiac and respiratory cycles. Studies on substrate accumulating FDG in plaques are contradictory and mostly do not extend beyond correlation analyses. Vascular FDG uptake has an excellent short-term stability, but larger fluctuations of uptake long-term, which may complicate interpretation of such changes in therapeutic trials. FDG uptake in major arteries correlates with some cardiovascular risk factors and atherosclerosis markers, but clinical utility of such correlations is unclear. What is more important is that recently reported studies in cancer patients showed correlation between higher baseline FDG uptake and subsequent cardiovascular mortality. Anti-atherogenic therapy and therapeutic lifestyle changes seem to decrease vascular FDG uptake but it is not clear whether the latter predicts subsequent lower morbidity and mortality. These initial findings suggest that vascular FDG-PET may in the future find some utility in management of patients with atherosclerosis, but a number of important issues need to be addressed first. We need to: (1) determine optimal standard ways of performing imaging and quantifying vascular FDG uptake; (2) understand molecular mechanisms governing FDG accumulation in plaques; (3) perform studies prospectively linking vascular FDG uptake to cardiovascular events in non-cancer patients. As of today, vascular FDG-PET is not ready for its prime time in clinical practice. PMID- 20202638 TI - The in vivo assessment of mechanical loadings on pectoral pacemaker implants. AB - Reduced sizes of implantable cardiac pacemakers and clinical advances have led to a higher feasibility of using such devices in younger patients including children. Increased structural demands deriving from reduced device size and more active recipients require detailed knowledge of in vivo mechanical conditions to ensure device reliability. Objective of this study was the proof of feasibility of a system for the measurement of in vivo mechanical loadings on pacemaker implants. The system comprised the following: implantable instrumented pacemaker (IPM) with six force sensors, accelerometer and radio-frequency (RF) transceiver; RF data logging system and video capture system. Three Chacma baboons (20.6+/ 1.15 kg) received one pectoral sub-muscular IPM implant. After wound healing, forces were measured during physical activities. Forces during range of motion of the arm were assessed on the anaesthetized animals prior to device explantation. Mass, volume and dimensions of the excised Pectoralis major muscles were determined after device explantation. Remote IPM activation and data acquisition were reliable in the indoor cage environment with transceiver distances of up to 3m. Sampling rates of up to 1,000 Hz proved sufficient to capture dynamic in vivo loadings. Compressive forces on the IPM in conscious animals reached a maximum of 77.2+/-54.6N during physical activity and were 22.2+/-7.3N at rest, compared with 34.6+/-15.7 N maximum during range of motion and 13.4+/-3.3N at rest in anaesthetized animals. The study demonstrated the feasibility of the developed system for the assessment of in vivo mechanical loading conditions of implantable pacemakers with potential for use for other implantable therapeutic devices. PMID- 20202639 TI - Load transfer along the bone-dental implant interface. AB - In this paper the variation of normal and shear stresses along a path defined on the bone-dental implant interface is investigated. In particular, the effects of implant diameter, collar length and slope, body length, and the effects of four different types of external threads on the interfacial stress distribution are studied. The geometry of the bone is digitized from a CT scan of a mandibular incisor and the surrounding bone. The bone and the implant are assumed to be perfectly bonded. The finite element method with 2D plane strain assumption is used to compute interfacial stresses. Highest continuous interfacial stresses are encountered in the region where the implant collar engages the cortical region, and near the apex of the implant in the subcortical region. Stress concentrations in the interfacial stresses occur near the geometric discontinuities on the implant contour, and jumps in stress values occur where the elastic modulus of the bone transitions between the cortical and trabecular bone values. Among the six contour parameters, the slope and the length of the implant collar, and the implant diameter influence the interfacial stress levels the most, and the effects of changing these parameters are significantly noticed only in the cortical bone (alveolar ridge) area. External threads cause significant stress concentrations in interfacial stresses in otherwise smoothly varying regions. This work shows that the presence of external threads could cause significant variations in both normal and shear stresses along the bone-implant interface, but not reduction in shear stress as previously thought. PMID- 20202640 TI - Development and validation of a fast high pressure liquid chromatography method for the analysis of lignocellulosic biomass hydrolysis and fermentation products. AB - A simple, precise, and accurate 10-min high pressure liquid chromatography (HPLC) method was developed and validated for the analysis of organic acids, alcohols, and furans from processing biomass into renewable fuels. The method uses an H(+) form cation-exchange resin stationary phase that has a five-fold shorter analysis time versus that in the traditional method. The new method was used for the analysis of acetic acid, ethanol, 5-hydroxymethyl furfural, and furfural. Results were compared with a legacy method that has historically has been used to analyze the same compounds but with a 55 min run time. Linearity was acceptable on the new method with r(2)>0.999 for all compounds using refractive index detection. Limits of detection were between 0.003 and 0.03 g/L and limits of quantification were between 0.1 and 0.01 g/L. The relative standard deviations for precision were less than 0.4% and recoveries ranged from 92% to 114% for all compounds. PMID- 20202641 TI - Comparison of electrospray ionization and atmospheric pressure chemical ionization for multi-residue analysis of biocides, UV-filters and benzothiazoles in aqueous matrices and activated sludge by liquid chromatography-tandem mass spectrometry. AB - This paper describes the development of a multi-residue method for the determination of 36 emerging organic pollutants (26 biocides, 5 UV-filters and 5 benzothiazoles) in raw and treated wastewater, activated sludge and surface water using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The target analytes were enriched from water samples adjusted to pH 6 by solid-phase extraction (SPE) on Oasis HLB 200mg cartridges and eluted with a mixture of methanol and acetone (60/40, v/v). Extraction of freeze-dried sludge samples was accomplished by pressurized liquid extraction (PLE) using a mixture of methanol and water (50/50, v/v) as extraction solvent followed by SPE. LC-tandem MS detection was compared using electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) in positive and negative ionization mode. ESI exhibited strong ion suppression for most target analytes, while APCI was generally less susceptible to ion suppression but partially leading to ion enhancement of up to a factor of 10. In general, matrix effects could be compensated using stable isotope-labeled surrogate standards, indicated by relative recoveries ranging from 70% to 130%. In wastewater, activated sludge and surface water up to 33 analytes were detected. Maximum concentrations up to 5.1 and 3.9mugL(-1) were found in raw wastewater for the water-soluble UV-filters benzophenone-4 (BZP-4) and phenylbenz-imidazole sulfonic acid (PBSA), respectively. For the first time, the anti-dandruff climbazole was detected in raw wastewater and in activated sludge with concentrations as high as 1.4 microg L(-1) and 1.2 microg gTSS(-1), respectively. Activated sludge is obviously a sink for four benzothiazoles and two isothiazolones, as concentrations were detected in activated sludge between 120 ng gTSS(-1) (2-n-octyl-4-isothiazolin-3-one, OIT) to 330 ng gTSS(-1) (benzothiazole-2-sulfonic acid, BTSA). PMID- 20202642 TI - Preparation and characterization of coverage-controlled CaCO3 nanoparticles. AB - CaCO(3) nanoparticles were coated with stearate through a salt-exchange procedure. Their coverage had been successfully controlled by extraction in a Soxhlet apparatus, based on which a series of CaCO(3) nanoparticles were obtained with different surface coverages. They were characterized with thermogravimetric analysis, X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy. It was found that free stearate, intercalated stearate and chemically-bonded alkyl chains could be extracted sequentially with the Soxhlet apparatus. Thus, the coverages of CaCO(3) nanoparticles could be adjusted through carefully extracting the stearates from the CaCO(3) nanoparticles with multi layer coverage. Spectroscopic results revealed that the alkyl chains tended to adopt an extended-chain conformation in the monolayer coverage as well as the bi layer coverage, but less ordered conformation in partially-coated coverage and random orientation at the outmost surface of the coated nanoparticles. PMID- 20202643 TI - A master curve for the onset of shear induced restructuring of fractal colloidal aggregates. AB - Colloidal aggregates exposed to shear flow exhibit a size-dependent qualitative behavior [Becker et al. JCIS, 339, 362-372, 2009]. Under the same flow conditions small aggregates rotate like rigid bodies, whereas larger aggregates change their structure and even bigger aggregates break. In this study the transition from the rotational regime to the restructuring regime is investigated by DEM simulations. We applied a model for tangential interaction, capable of supporting bond-bending moments and torsional torques [Becker, Briesen, Phys. Rev. E, 78, 2008, 061404]. The probability for an aggregate to be affected by restructuring changes with the number of primary particle from zero to one in a small interval. The probability becomes a master curve being independent of the shear flow and the interparticle interactions if it is represented as a function of the relative deviation from the critical particles number, i.e. the number of primary particle where the probability of restructuring is equal to 0.5. Investigating the dependency of the critical particle number on the shear rates reveals power law relations which adequately represents the data. The exponents in the power law relations can particularly obtained from a fractal scaling argument. PMID- 20202644 TI - Spontaneous growth of self-relief wrinkles in freely floating lipid-based nanomembranes, formed on a reactive bath of polyoxometalate aqueous solution. AB - Wetting and capillarity have appeared over the last decadesas potential tools for the guided actuation, self-assembly and nanostructuration, and most recently as powerful "tool-free" techniques of micro-, and nano-fabrication, in the field of nanotechnology. The present work deals with such a use of wetting, achieving for the first time the spontaneous growth of composite (lipid-capped polyoxometalate) nanomembranes, using the reactive spreading film formed by the droplets of a lipid solution, on an aqueous foundation hosting the polyoxometalate ions. Moreover, we show that the internal stress produced by the reactive wetting, and the resulting self-movements of the drop could be accumulated within the drying spreading film, driving the spontaneous occurrence of wrinkles, in the freely floating nanomembranes that are thus formed. Finally, we showed that gravity driven scaling relations for buckling instabilities apply to these spontaneously occurring wrinkles, allowing the in situ characterization of the physical properties of the nanomembranes. This approach that allowed producing floating nanomembranes of "lipid-capped Keggin ions" that were collectable as freestanding nanosheets may constitute a potential route for the fabrication of a wide range of functional (copolymers/metal nanoparticles) nanocomposite membranes. PMID- 20202645 TI - Geometrical determination of the lacunarity of agglomerates with integer fractal dimension. AB - Different agglomerates composed by a variable number of spherical primary particles corresponding to extreme and intermediate values of fractal dimension (D(f)=1, D(f)=2 and D(f)=3) are analysed in this work. In each case, the moment of inertia, diameter of gyration and prefactor of the power-law relationship are determined as a function of the number of composing primary particles. The obtained results constitute the geometrical data base for the development of a method for the determination of the fractal dimension of individual agglomerates from their planar projections, although it is not the aim of this paper to describe the method itself. As a result of these calculations, the prefactor of the power-law relationship was shown not to be a constant parameter, but to tend asymptotically to a limit value with increasing number of primary particles. This limit value is closely related with the compactness of the initial geometrical arrangement in the agglomerate, this justifying the historical association of this parameter with the lacunarity of the agglomerate. A correlation for the determination of the prefactor as a function of the fractal dimension and the number of elementary structures is proposed and compared with other methods proposed in the literature. PMID- 20202646 TI - Silica coated magnetite particles for magnetic removal of Hg2+ from water. AB - The magnetic removal of Hg(2+) from water has been assessed using silica coated magnetite particles. The magnetite particles were first prepared by hydrolysis of FeSO(4) and their surfaces were modified with amorphous silica shells that were then functionalized with organic moieties containing terminal dithiocarbamate groups. Under the experimental conditions used, the materials reported here displayed high efficiency for Hg(2+) uptake (74%) even at contaminant levels as low as 50 MUg l(-1). Therefore these eco-nanomagnets show great potential for the removal of heavy metal ions of polluted water, via magnetic separation. PMID- 20202647 TI - Binding of dicamba to soluble and bound extracellular polymeric substances (EPS) from aerobic activated sludge: a fluorescence quenching study. AB - Binding of dicamba to soluble EPS (SEPS) and bound EPS (BEPS) from aerobic activated sludge was investigated using fluorescence spectroscopy. Two protein like fluorescence peaks (peak A with Ex/Em=225 nm/342-344 nm and peak B with Ex/Em=275/340-344 nm) were identified in SEPS and BEPS. Humic-like fluorescence peak C (Ex/Em=270-275 nm/450-460 nm) was only found in BEPS. Fluorescence of the peaks A and B for SEPS and peak A for BEPS were markedly quenched by dicamba at all temperatures whereas fluorescence of peaks B and C for BEPS was quenched only at 298 K. A dynamic process dominated the fluorescence quenching of peak A of both SEPS and BEPS. Fluorescence quenching of peak B and C was governed a static process. The effective quenching constants (logK(a)) were 4.725-5.293 for protein like fluorophores of SEPS and 4.23-5.190 for protein-like fluorophores of BEPS, respectively. LogK(a) for humic-like substances was 3.85. Generally, SEPS had greater binding capacity for dicamba than BEPS, and protein-like substances bound dicamba more strongly than humic-like substances. Binding of dicamba to SEPS and BEPS was spontaneous and exothermic. Electrostatic force and hydrophobic interaction forces play a crucial role in binding of dicamba to EPS. PMID- 20202648 TI - Disease-associated prion protein in the dental tissue of mice infected with scrapie. AB - Transmissible spongiform encephalopathies (TSEs) induce fatal neurodegenerative diseases in man and animals. The present study demonstrates immunohistochemically the presence of disease-associated prion protein (PrP(Sc)) in the epithelial cell rests of Malassez (ERM) of mice experimentally infected with ME7 scrapie by the intracerebral route. Mouse bioassay of scrapie-infected dental tissue revealed prolonged incubation periods, suggesting that there are relatively low amounts of infectious agent in dental tissue compared with the brain. These findings indicate that PrP(Sc) may spread from the brain to the ERM along the cranial nerves via the trigeminal ganglion that innervates the dental tissues. Dental tissue might therefore be a potential source of PrP(Sc) for horizontal transmission of TSEs. PMID- 20202649 TI - Children's intergroup empathic processing: the roles of novel ingroup identification, situational distress, and social anxiety. AB - Individuals often feel more empathy toward members of their own social groups than toward members of other social groups. However, individual factors contributing to this empathy bias remain largely unexplored among children. This study examined intergroup empathic processing among 94 children (mean age=8.74years, SD=1.76) assigned to novel color groups. After 1week in their group, children were interviewed to assess their ingroup identification and trait levels of social anxiety. Subsequently, a social threat was simulated, and children's feelings of situational distress and empathy bias for others who experienced the same threat were assessed. Findings indicated that, among children who reported more social anxiety and situational distress, those with a stronger ingroup identity displayed more empathy bias favoring their ingroup. Given that empathy is an important contributor to prosocial behavior, implications for children's intergroup relations are discussed. PMID- 20202650 TI - Poor recovery after the first two attacks of multiple sclerosis is associated with poor outcome five years later. AB - OBJECTIVE: Examine the relative importance of several risk factors for progression, in a large sample of MS patients. METHODS: Using a retrospective design in a single university-based MS treatment center, we studied 207 patients with relapsing remitting MS diagnosed, treated at our center, evaluated within one year of their second attack, and at least 2 years after their first attack. Risk factors were: 1) age greater than 40 at first attack; 2) more than 2 attacks in the 2 years from onset; 3) EDSS >1.5 after second attack (poor recovery); 4) male gender; and 5) motor symptoms at onset. Groups were defined as having a few (0 to 2) or many (3 to 5) risk factors. RESULTS: Two hundred seven patients were followed for an average of 94 months (SD=44). 30% were over 40 years of age at onset, 38% had more than 2 attacks in 2 years, 28% had an EDSS >1.5 after the second attack (i.e., had poor recovery), 24% were male, and 58% had motor symptoms at onset. Regression analysis and Kaplan-Meier survival curves that suggested poor recovery after the first two attacks were the best individual predictors of progression at 5 years after initial diagnosis. In addition, having many individual risk factors was associated with having a higher risk of progression (p<.001 by Mann Whitney U, sustained final EDSS at an average disease duration of 9.7 years). CONCLUSIONS: This study suggests a paramount importance of recovery from early attacks, as well as an additive effect of individual risk factors for progression of MS in the first several years after diagnosis. PMID- 20202651 TI - Factors associated with delay to medical recognition in two Canadian multiple sclerosis cohorts. AB - Long referral and diagnostic delays can impact both the opportunity for early therapeutic intervention and estimates of MS incidence and prevalence. We investigated factors associated with diagnostic or referral delays within two geographically distinct MS Canadian cohorts and the association between referral delay and disability at first clinic visit. Adult-onset MS patients were selected from the population-based British Columbian MS (BCMS) (n=5705) and the clinic based Hopital Notre-Dame, Quebec (CHUM) (n=1489) databases. Referral delay (BCMS) and diagnostic delay (CHUM) were examined by sex, onset age, disease course (primary progressive (PPMS) vs. relapsing at onset), onset symptoms (BCMS only) and year of first clinic visit/diagnosis. Cohorts were analyzed separately by stratified analyses and multivariable linear modeling. The relationship between referral delay and initial disability was examined by multiple ordinal regression in the BCMS cohort. Younger at onset patients or those with PPMS exhibited significantly longer delays (p<0.001). Delays decreased over the 20+ year period, but reductions varied by clinical course, onset age and sex. Long referral delays were associated with greater disability at first clinic visit (p<0.001). If early intervention at mild disability levels is warranted in MS, then the extended delays to medical recognition for young adult-onset and PPMS patients must be addressed. PMID- 20202652 TI - [Prognostic value of glomerular filtrate in acute coronary syndrome: Cockcroft's index or MDRD equation?]. AB - BACKGROUND AND OBJECTIVES: One third of patients with a coronary event show kidney failure. Our aim is to establish the relationship between kidney failure and mortality in patients diagnosed of acute coronary syndrome (ACS) through Cockcroft Index (C-G) and MDRD-4 equation, analyzing which of them is better for prognostic stratification. PATIENTS AND METHOD: Prospective study of 445 patients admitted consecutively between 2006 and 2007 with a high risk of ACS, dividing the sample depending on his kidney function at admission in < 60 mL/min/1.73 m(2) and > or =60 mL/min/1.73 m(2) through C-G and Modification of Diet in Renal Disease study group 4 (MDRD-4) and other variables. We performed a multivariate logistic regression for both of them, analysing the relationship with mortality in the following six months after admission. RESULTS: Renal failure was present in 27.9% (creatinine < 1.1mg/dl); 30.5% (C-G) and 22.6% (MDRD-4). Glomerular filtration (GF) was 81.6+/-35.2 mL/min (C-G) and 77.2+/-26.1 mL/min/1.73 m(2) (MDRD-4). Patients with GF < 60 mL/min showed high mortality, Odds ratio 2.652; p=0.024 (IC 95%, 1.140-6.166) for C-G and 3.372; p=0.001 (IC 95%, 1.637-6.954) for MDRD-4. CONCLUSION: Renal failure increases the risk to die in the following six months after an ACS. The estimation through Cockcroft Index and/or MDRD-4 equation depends on the population characteristics and is indifferent with GF between 60 and 80 mL/min. PMID- 20202653 TI - [2009 pandemic influenza A (H1N1), six months experience]. PMID- 20202654 TI - [Home intravenous antibiotic therapy of hepatic abscess: Safety, efficacy and predictive factor of hospital readmission]. AB - BACKGROUND AND OBJECTIVE: Few data exists in the literature about intravenous antibiotic treatment of hepatic abscess in hospital based care units. Our objectives were to analyze the efficacy and safety of intravenous antibiotic therapy and the predictors of hospital readmission. PATIENTS AND METHODS: The study included all the patients admitted in our home care unit for intravenous antibiotic treatment of hepatic abscess from March 2006 to June 2009. RESULTS: We included 30 patients in the study. Five patients (16,6%) had phlebitis during treatment and none presented a major secondary effect. Mean size reduction of abscess during admission in our home care unit was 49,3% (36,6%). Nine (30%) patients were readmitted, 6 (20%) during admission at home and 3 (10%) along the year after. Four (13.3%) patients died along follow-up. Patients readmitted had a higher mean size of abscess at discharge from our home care unit as compared to the non readmitted ones (4,5 vs 1,5 cms P=0,001), besides a minor percentage of reduction of size (19% vs 64% P=0,001). Female patients were readmitted more frequently than male ones (77,8% vs 28,6% P=0,02), but they had minor scores of Barthel scale (75 vs. 92 P=0,01). CONCLUSIONS: Home intravenous antibiotic treatment of hepatic abscess seems to be a safe and effective alternative in most patients. The size and reduction of abscess at patient discharge, the female gender and dependence degree constituted the principal predictors of readmission. PMID- 20202655 TI - Prevalence of same-sex intimate partner violence in Hong Kong. PMID- 20202656 TI - Pharmacokinetics and bioavailability of moxifloxacin in buffalo calves. AB - The pharmacokinetics of moxifloxacin were investigated in buffalo calves following a single intravenous and intramuscular administration of moxifloxacin (5 mg kg(-1) body wt.). Moxifloxacin concentrations in plasma and urine were determined by microbiological assay. Pharmacokinetic analysis of disposition data indicated that intravenous administration data were best described by a two compartment open model, whereas intramuscular administration data were best described by a one compartment open model. Following intravenous administration, the elimination half life (t(1/2beta)), volume of distribution (Vd(area)) and total body clearance were 2.69+/-0.14 h, 1.43+/-0.08 L kg(-1) and 371.2+/-11.2 ml kg(-1)h(-1), respectively. Following intramuscular administration, the absorption half life (t(1/2ka)) was 0.83+/-0.20 h. The systemic bioavailability (F) of moxifloxacin in buffalo calves was 80.0+/-4.08%. Urinary excretion of moxifloxacin was less than 14% after 24h of administration of drug. In vitro binding of moxifloxacin to plasma proteins of buffalo calves was 28.4+/-3.77%. From the data of surrogate markers (AUC/MIC, C(max)/MIC), it was determined in the buffalo calves that when administered by intravenous or intramuscular route at 5 mg kg(-1), moxifloxacin is likely to be effective against bacterial isolates with MIC< or =0.1 microg ml(-1). PMID- 20202657 TI - DHEA and testosterone therapies in Trypanosoma cruzi-infected rats are associated with thymic changes. AB - The ability of the gonadal hormones to influence diverse immunological functions during the course of several infections has been extensively studied in the latest decades. Testosterone has a suppressive effect on immune response of vertebrates and increases susceptibility toward numerous parasitic diseases. Dehydroepiandrosterone is an abundant steroid hormone secreted by the human adrenal cortex and it is considered potent immune-activator. In this paper, it was examined the effects of DHEA and testosterone supplementation in the thymic atrophy in rats infected with Trypanosoma cruzi, by comparing blood parasitism, thymocyte proliferation, TNF-alpha and IL-12 levels. Our data point in the direction that DHEA treatment triggered enhanced thymocyte proliferation as compared to its infected counterparts and reduced production of TNF-alpha during the acute phase of infection. Oppositely, the lowest values for cells proliferation and IL-12 concentrations were reached in testosterone-supplied animals. The combined treatment testosterone and DHEA improves the effectiveness of the host's immune response, reducing blood parasites and the immunosuppressive effects of male androgens besides increasing IL-12 concentrations and decreasing TNF-alpha levels. PMID- 20202658 TI - Postnatal autonomic activity in the preterm lamb. AB - BACKGROUND: Early postnatal abnormalities of autonomic nervous system (ANS) activity, including at baseline and following cardiorespiratory challenge, are involved in apneas-bradycardias of prematurity, apparent life-threatening events of infancy and sudden infant death syndrome. Literature data suggest that baseline ANS activity does not mature normally after premature birth. OBJECTIVES: This study performed in preterm lambs was aimed at assessing ANS maturation at baseline and following laryngeal chemoreflexes (LCR), a group of reflexes triggered by the contact of liquids with the laryngeal mucosa. METHODS: Heart rate variability (HRV) and baroreflex sensitivity (BRs) were measured at baseline and after LCR during polysomnographic recordings performed in five non-sedated lambs born 15 days prematurely. Laryngeal chemoreflexes were induced by distilled water or acid (pH 2) during sleep and wakefulness on postnatal days 7 (D7) and 14 (D14, full-term equivalence). RESULTS: While the life-threatening cardiorespiratory events of the LCR observed at D7 were no longer present at D14, baseline and post-LCR HRV and BRs indices were significantly lower at D14 compared to D7 (up to p<0.001). These results suggest that an initial autonomic overactivity was present at D7 and normalized at D14. CONCLUSION: The autonomic cardiac and baroreflex control appears to follow a specific evolution in the preterm compared to the full-term newborn lamb, with an important initial autonomic stress, which normalizes at an age equivalent to full-term. Potential relevance of these findings in relation to anomalies of cardiac control in the early postnatal period, such as apneas-bradycardias of prematurity, apparent life threatening events of infancy and sudden infant death syndrome, awaits further studies. PMID- 20202659 TI - Validation of an immunoturbidimetric method for determination of porcine serum C reactive protein. AB - Measurement of porcine C-reactive protein (CRP) in serum is an important tool for monitoring health and welfare in pigs. In this study, an immunoturbidimetric method from Olympus System Reagent (OSR 6147) used to measure human CRP in serum that employ a human traceable calibrator has been evaluated in porcine serum samples. Intra- and inter-assay imprecision were lower than that obtained with the porcine-specific commercially available ELISA. The expected difference in serum CRP between healthy and non-healthy pigs was detected. CRP values measured by the immunoturbidimetric method showed a good correlation with those obtained by ELISA, although differences in absolute CRP values were observed. When an in house porcine standard was used a better agreement was obtained. In conclusion, the immunoturbidimetric method of Olympus can be used with porcine samples. The easier use of this method should facilitate the implementation of CRP serum determination for diagnostic and prognostic purposes in swine medicine. The results emphasize the need to establish species-specific standard and methods to decrease inter-laboratory discrepancies. PMID- 20202660 TI - Influence of gas law on ultrasonic behaviour of porous media under pressure. AB - This paper deals with the influence of gas law on ultrasonic behaviour of porous media when the saturating fluid is high pressured. Previous works have demonstrated that ultrasonic transmission through a porous sample with variations of the static pressure (up to 18 bars) of the saturating fluid allows the characterization of high damping materials. In these studies, the perfect gas law was used to link static pressure and density, which is disputable for high pressures. This paper compares the effects of real and perfect gas laws on modeled transmission coefficient for porous foams at these pressures. Direct simulations and a mechanical parameters estimation from minimization show that results are very similar in both cases. The real gas law is thus not necessary to describe the acoustic behaviour of porous media at low ultrasonic frequencies (100 kHz) up to 20 bars. PMID- 20202661 TI - Group-specific structural features of the 5'-proximal sequences of coronavirus genomic RNAs. AB - Global predictions of the secondary structure of coronavirus (CoV) 5' untranslated regions and adjacent coding sequences revealed the presence of conserved structural elements. Stem loops (SL) 1, 2, 4, and 5 were predicted in all CoVs, while the core leader transcription-regulating sequence (L-TRS) forms SL3 in only some CoVs. SL5 in group I and II CoVs, with the exception of group IIa CoVs, is characterized by the presence of a large sequence insertion capable of forming hairpins with the conserved 5'-UUYCGU-3' loop sequence. Structure probing confirmed the existence of these hairpins in the group I Human coronavirus-229E and the group II Severe acute respiratory syndrome coronavirus (SARS-CoV). In general, the pattern of the 5' cis-acting elements is highly related to the lineage of CoVs, including features of the conserved hairpins in SL5. The function of these conserved hairpins as a putative packaging signal is discussed. PMID- 20202663 TI - The influence of aeration intensity on predation and EPS production in membrane bioreactors. AB - Shear, in the form of vigorous aeration, is used to control fouling in membrane bioreactor (MBR) systems. However, shear also influences the physicochemical and biological properties of MBR biomass. The current study examines the relationship between the aeration intensity and extracellular polymeric substance (EPS) production in MBRs. Two identical submerged MBRs were operated in parallel but the aeration rate was three times greater in one of the MBRs. The concentrations of floc-associated and soluble EPS were monitored for the duration of the experiment. Microscopic images and floc-size measurements were also collected regularly. The membrane fouling potential of the biomass was quantified using the flux-step method. Increased aeration did not have a direct effect on soluble or floc-associated EPS production in the microfiltration MBRs. However, aeration intensity had a significant effect on predatory organisms. Large aquatic earthworms, Aeolosoma hemprichi, proliferated under lower shear conditions but were never observed in the high shear reactor. Predation by A. hemprichi resulted in increased floc-associated and soluble EPS production. Thus, the mixing conditions in the low shear MBR indirectly resulted in increased soluble EPS concentrations and higher fouling potential. This research suggests that predation can have a significant impact on the production rates of floc associated and soluble EPS--key parameters driving membrane fouling in MBRs. PMID- 20202662 TI - Ebola virus uses clathrin-mediated endocytosis as an entry pathway. AB - Ebola virus (EBOV) infects several cell types and while viral entry is known to be pH-dependent, the exact entry pathway(s) remains unknown. To gain insights into EBOV entry, the role of several inhibitors of clathrin-mediated endocytosis in blocking infection mediated by HIV pseudotyped with the EBOV envelope glycoprotein (EbGP) was examined. Wild type HIV and envelope-minus HIV pseudotyped with Vesicular Stomatitis Virus glycoprotein (VSVg) were used as controls to assess cell viability after inhibiting clathrin pathway. Inhibition of clathrin pathway using dominant-negative Eps15, siRNA-mediated knockdown of clathrin heavy chain, chlorpromazine and sucrose blocked EbGP pseudotyped HIV infection. Also, both chlorpromazine and Bafilomycin A1 inhibited entry of infectious EBOV. Sensitivity of EbGP pseudotyped HIV as well as infectious EBOV to inhibitors of clathrin suggests that EBOV uses clathrin-mediated endocytosis as an entry pathway. Furthermore, since chlorpromazine inhibits EBOV infection, novel therapeutic modalities could be designed based on this lead compound. PMID- 20202664 TI - Exploring the relationship between viscous bulking and ammonia-oxidiser abundance in activated sludge: A comparison of conventional and IFAS systems. AB - This study investigated the nature of viscous sludge bulking within a molasses fed integrated fixed-film activated sludge (IFAS) and conventional activated sludge (AS) plant by routinely measuring the total carbohydrate and protein fractions of the mixed liquor (ML). The impacts of sludge settleability and plant performance on the relative abundance of ammonia-oxidising bacteria (AOB) (Nitrosomonas oligotropha-cluster) were also investigated using quantitative polymerase chain reaction (qPCR). Results showed that sludge volume index (SVI) correlated positively with the amount of ML total carbohydrate in both the IFAS and traditional AS plants, highlighting the influential role that ML polysaccharide concentration plays on sludge settleability in these reactors. Results also revealed a negative relationship between the AOB/total Bacteria ratio and SVI, demonstrating that a poor settling sludge generally coincided with periods of relatively low AOB abundance. The existence of these relationships suggests that readily available organic carbon (molasses) was likely to have been present in excess in these systems. Our qPCR results also showed that concentrations of both AOB and total Bacteria genomic copies detected within the ML of the IFAS and conventional AS plants were remarkably similar. For the IFAS system, results showed that the ML supported an equivalent number of AOB (per gram of biomass) to that detected on the plastic IFAS media carriers, suggesting that the suspended biomass fraction plays an equally important role in the overall nitrification performance of these systems. Interestingly, large observed variations in AOB and AOB/total Bacteria ratio measured within both the ML and IFAS media carriers had no measurable impact on the apparent nitrification performance of these systems; indicating the presence of some excess or 'reserve' nitrifying capacity above that which is required for effective plant performance. Results presented here also constitute the first known side-by-side comparison of the distribution of AOB in IFAS and conventional racetrack-like AS plants at the full-scale level. PMID- 20202665 TI - High-rate anaerobic treatment of Fischer-Tropsch wastewater in a packed-bed biofilm reactor. AB - This study investigates the anaerobic treatment of an industrial wastewater from a Fischer-Tropsch (FT) process in a continuous-flow packed-bed biofilm reactor operated under mesophilic conditions (35 degrees C). The considered synthetic wastewater has an overall chemical oxygen demand (COD) concentration of around 28g/L, mainly due to alcohols. A gradual increase of the organic load rate (OLR), from 3.4gCOD/L/d up to 20gCOD/L/d, was adopted in order to overcome potential inhibitory effects due to long-chain alcohols (>C6). At the highest applied OLR (i.e., 20gCOD/L/d) and a hydraulic retention time of 1.4d, the COD removal was 96% with nearly complete conversion of the removed COD into methane. By considering a potential of 200tCOD/d to be treated, this would correspond to a net production of electric energy of about 8x10(7)kWh/year. During stable reactor operation, a COD balance and batch tests showed that about 80% of the converted COD was directly metabolized through H(2)(-) and acetate-releasing reactions, which proceeded in close syntrophic cooperation with hydrogenotrophic and acetoclastic methanogenesis (contributing to about 33% and 54% of overall methane production, respectively). Finally, energetic considerations indicated that propionic acid oxidation was the metabolic conversion step most dependent on the syntrophic partnership of hydrogenotrophic methanogens and accordingly the most susceptible to variations of the applied OLR or toxicity effects. PMID- 20202666 TI - 5-Hydroxy-1,4-naphthoquinone (juglone) and 2-hydroxy-1,4-naphthoquinone (lawsone) influence on jack bean urease activity: Elucidation of the difference in inhibition activity. AB - The aim of this study was elucidation of the difference in inhibition influence of 5-hydroxy-1,4-naphthoquinone (juglone) and 2-hydroxy-1,4-naphthoquinone (lawsone) on jack bean urease activity. It was found that juglone acted as a strong, time and concentration dependent inactivator of urease. On the contrary, lawsone showed an inconsiderable inhibition influence. The reactivation of juglone modified urease showed the participation of reversible and irreversible contribution in the inactivation. In the presence of an excess of DTT, urease inactivated by juglone regained 70% of its activity. The reversible inactivation was attributed to oxidation of the essential urease thiols by reactive oxygen species (ROS) realizing during reduction of juglone to seminaphthoquinone. Presence of hydrogen peroxide in the incubation system was proved by direct determination and by application of catalase. The irreversible contribution in the inhibition was assumed as an arylation of urease thiol groups by juglone. The insignificant urease inhibition by lawsone was concluded as an effect of a low hydrogen peroxide generation and lawsone resistance for reaction with protein thiols. It was found that lawsone well reacted with l-cysteine, poorly with glutathione and hardly with urease thiols. The observed sequence was arranged according the rule the more complex thiol the less susceptible for reaction with lawsone. On the other hand, juglone displayed an excellent reactivity towards both thiols and urease. Thus, this indicated a significance of a steric hindrance which appeared when the hydroxyl group changing position from 5 in juglone (5 hydroxy-1,4-naphthoquinone) to 2 in lawsone (2-hydroxy-1,4-naphthoquinone). PMID- 20202667 TI - Effect of cattle slurry pre-treatment by separation and addition of nitrification inhibitors on gaseous emissions and N dynamics: a laboratory study. AB - The application of untreated or treated animal manure to soils can result in increased N and C gaseous emissions contributing to ecosystem change and global warming. In the present study, dairy cattle slurry (liquid manure) was subjected first to pre-treatment by separation using a screw press to obtain a liquid (LF) and a solid fraction (SF). Then, the different fractions and the whole slurry (WS) were combined with two nitrification inhibitors (NI), dicyandiamide (DCD) or 3,4-dimethylpyrazole phosphate (DMPP), were applied to soil to assess the effect of slurry treatment by separation and NI addition on soil N dynamics and CH4, CO2, NH3, NO and N2O emissions. The WS and the two slurry fractions, combined or not with DCD or DMPP, were applied to soil at an equivalent field dosage of 120 kg total N ha(-1). Controls including a soil only, soil-DCD and soil-DMPP treatments were also included. The mixtures were incubated for 93-d at 20 degrees C. Results obtained show that NI inhibited nitrification between 16 and 30-d in WS and LF, with DMPP having a longer effect over time compared to DCD. There was no significant effect of NI on nitrification for the SF treatment. Nitrification inhibitors did not significantly affect (P>0.05) the CH4, CO2 and N2O emissions, but significantly decreased (P<0.05) NO emissions. Furthermore, the two NIs had a similar effect on gaseous emissions. Throughout the entire experiment, the greatest amount of NO was released from the LF treatment (without NI), while the greatest amount of N2O was released from the SF treatment. Slurry separation had no impact on N emissions, while the combination of this process with one of the two NI led to a small reduction in total N emissions. PMID- 20202668 TI - Detoxification and degradation of microcystin-LR and -RR by ozonation. AB - In the present study, two Microsystins (MCs) of Microcystin-LR and Microcystin-RR were degraded with different dosages of ozone (O(3)). The possible degradation pathways were elucidated by analyzing their intermediates and end-products with liquid chromatography-mass spectrometry (LC-MS) method. The toxicity of the MCs ozonation products was also evaluated by assaying the protein phosphatase inhibition in vitro and acute toxicity in vivo. Results demonstrated that ozonation was a promising technology for removal and detoxification of the cyanotoxins. The MCs destruction was mainly involved in the attack of ozone on Adda side chain. First, the conjugated diene structure of Adda moiety was attacked by hydroxyl radical (OH()) to produce dihydroxylated products, then the hydroxylated 4-5 and/or 6-7 bond of Adda was cleaved into aldehyde or ketone peptide residues, and finally the residues were oxidized into the corresponding carboxylic acids. The fragmentation of the Mdha-Ala peptide bond of MCs also contributed positively to the oxidation process. Additionally, the attack on the benzene ring of Adda side chain was exclusively observed during MC-RR degradation. The toxicity evaluation of MCs ozonation products revealed that those end-products had no adverse effects in vivo and in vitro ozonation that could completely remove the MCs' toxicity. PMID- 20202669 TI - Effects of tributyltin (TBT) on Xenopus tropicalis embryos at environmentally relevant concentrations. AB - Tributyltin (TBT) has been widely used as a biocide in antifouling paints and is a known endocrine disrupting chemical. In this paper, we exposed embryos of Xenopus tropicalis to 50-400ngL(-1) tributyltin chloride. TBT significantly decreased the survival rate, reduced the body length and retarded the development of embryos after 24, 36 and 48h of exposure. These effects of TBT were concentration- and time-dependent. Embryos treated with TBT showed multiple malformations. The most obvious alterations were abnormal eyes, enlarged proctodaeum, narrow fins, and skin hypopigmentation. Enlarged proctodaeum and narrow fins were mainly observed after 36 and 48h of exposure. The loss of eye pigmentation or the absence of external eyes occurred after 24 and 36h of exposure, while extended lenses or edemas of eyes were more commonly observed after 48h of exposure. Additional malformations included: small anterior region of heads, pericardial edemas, enlarged trunks, and bent tails. These results suggested that TBT is very toxic to X. tropicalis embryos at environmentally relevant concentrations. PMID- 20202670 TI - Multi-biomarker approach to investigate the state of contamination of the R. Lambro/R. Po confluence (Italy) by zebra mussel (Dreissena polymorpha). AB - This study assesses the response of the zebra mussel (Dreissena polymorpha) to chemical pollution derived from the R. Lambro/R. Po confluence, which is one of the most polluted aquatic environments in Europe. The mussels were tested under laboratory conditions to water sampled in the spring and fall at three sites located upstream or downstream of the confluence or directly in R. Lambro alone. We performed on mussel specimens a biomarker battery composed by eight different assays: single cell gel electrophoresis, apoptosis determination, the micronucleus test and Neutral Red retention, as well as catalase, superoxide dismutase, glutathione peroxidase and glutathione transferase activities. We also evaluated the bioaccumulation of several organic pollutants (PAHs, PCBs, DDTs, HCHs and HCB) to characterize the sampling sites. Significant increases in DNA strand breaks, apoptosis and micronuclei were observed, with no significant seasonal differences. We observed a clear induction of the enzyme activities measured in the spring, but the enzymatic activity trend in the fall was very complex, with several enzymes returning to baseline levels of activity, suggesting a possible seasonal change in chemical mixture characteristics. PMID- 20202671 TI - Characterization of an abundant and novel methyl- and methoxy-substituted brominated diphenyl ether isolated from whale blubber. AB - A previously unidentified yet abundant substituted polybrominated diphenyl ether (PBDE) was isolated from a northern bottlenose whale (Hyperoodon ampullatus) found dead in the Skagerrak, North Sea. A combination of gas chromatography, high and low resolution mass spectrometry and nuclear magnetic resonance spectroscopy (NMR) ((1)H, (1)H-(1)H and (1)H-(13)C) after isolation with preparative capillary gas chromatography (PCGC) lead to the identification of the unknown substance as 6-MeO-5-Me-2,2',3,4'-tetrabromo diphenyl ether (6-MeO-5-Me-BDE42). To our knowledge this is only the second time PCGC has been used to isolate individual organohalogen compounds present in trace amounts for identification with NMR. The concentration of this novel bioaccumulated compound was estimated to be about 100 ng g(-1) lipid, which was 2.5 times higher compared with the most abundant MeO PBDE congeners. PMID- 20202672 TI - Generic parameterization for a pharmacokinetic model to predict Cd concentrations in several tissues of different fish species. AB - In the present work, a set of generic parameters was proposed for a pharmacokinetic model, with the objective of predicting Cd concentration in the tissues of diverse fish species under different environmental conditions. Cd concentrations in a number of tissues of Oncorhynchus mykiss and Cyprinus carpio were estimated by a structurally identifiable multicompartmental model (unique solution). The 13 generic parameters of the model comprised exchange rates, tissue-blood partition coefficients, and weight-corrected elimination rate constants accounting for the routes of water respiration, excretion and egestion. On the other hand, absorption efficiencies from water and food were considered to be condition-specific and estimated for each experiment. These two parameters reflected the differences in fish exposure to diet (food type and metal concentration) or water (water chemistry and bioavailable metal concentration). A data set of 27 experiments of Cd bioaccumulation in fish tissues was compiled for model calibration. The selected dynamics on trout and carp were performed under very different experimental conditions, involving water and/or food exposure, different fish weights and exposure concentrations and the presence/absence of depuration periods. Model predicted, for most compartments and experiments, the tendency of Cd dynamics. However, accumulation in liver and kidney was underestimated in approximately a half of the experiments, due mainly to a rapid metallothionein (MT) sequestration phenomena and subsequent saturation on liver and kidney produced under high exposure concentrations. On the other hand, both generic and condition-specific parameter values were in accordance with the values reported in literature when available. Therefore, the results obtained in this work are an initial step indicating that a generic global input parameter set could be applied to physiology-based pharmacokinetic (PBPK) models for estimating Cd accumulation in fish in different types of scenarios. PMID- 20202673 TI - Pregnant ewes exposed to multiple endocrine disrupting pollutants through sewage sludge-fertilized pasture show an anti-estrogenic effect in their trabecular bone. AB - Pregnant ewes were maintained on pastures fertilized, twice yearly, with either sewage sludge (2.25tonnes dry matter/ha; Treated; T) or inorganic fertilizer containing equivalent amounts of nitrogen (Control; C), to determine effects on maternal and fetal bone structures, density and mechanical properties of exposure to environmental concentrations of multiple endocrine disrupting compounds (EDCs) and heavy metal pollutants. The ewes were maintained on the respective pastures from the age of about 8months until they were 4-6years of age and they were slaughtered at 110d gestation. Metaphyseal parts of adult ewe femurs exhibited a significantly reduced mean, total cross sectional area (CSA, -4%; p<0.05), lower trabecular bone mineral content (BMC, mg/mm; -18%; p<0.05), trabecular bone mineral density (BMD, mg/cm(3), -8.0%; p<0.05) and trabecular CSA, mm(2), -11.1%; p<0.05) in T compared with C animals. Femurs of T ewes were stronger than those of C ewes but this may reflect greater body weights. At the mid-diaphyseal part of the fetal bones, there was a reduction in endosteal circumference (-6.7%, p<0.05) and marrow cavity area (-13.8%, p<0.05) in the female T fetuses compared with female C fetuses. In the male fetuses the mid-diaphyseal part total bone mineral content was higher (+3.0%, p<0.05) in T than in C animals. No treatment difference in biomechanical bending was detected in the fetuses. It is concluded that ewes grazing pasture fertilized with sewage sludge exhibited an anti estrogenic effect on their trabecular bone in the form of reduced mineral content and density, despite increased body weight. It is suggested that human exposure to low levels of multiple EDCs may have implications for bone structure and human health. PMID- 20202674 TI - Recovery of mare oocytes on a fixed biweekly schedule, and resulting blastocyst formation after intracytoplasmic sperm injection. AB - Oocytes may be collected from live mares from either the stimulated preovulatory follicle or from all visible immature follicles. We evaluated the yield of mature oocytes, and of blastocysts after intracytoplasmic sperm injection (ICSI), for both follicle types. In Experiment 1, mares were assigned to Progesterone (1.2g biorelease progesterone weekly) or Control treatments. Transvaginal aspiration of all follicles was performed every 14 d. Overall, 596 follicles were aspirated, with a 54% oocyte recovery rate. There was no difference between treatments in number of follicles punctured (9.0 to 9.1) or oocytes recovered (4.8 to 5.0) per mare per aspiration session. Of 314 oocytes recovered, 180 (57%) matured in culture. Thirty-six mature oocytes were subjected to ICSI; 33% formed blastocysts (63% per mare per aspiration session). In Experiment 2, the preovulatory follicle was aspirated every 14 d for three to four cycles. Prostaglandin F(2 alpha) was given on Days 6 and 7 after aspiration. A follicle >or=25 mm in diameter was present on Day 13, the day of deslorelin administration, in 23 of 24 cycles, and ovulatory response (granulosa expansion) was seen in 24 of 25 follicles aspirated. Blastocyst development after ICSI was 41% per injected oocyte, or an estimated 33% per mare per aspiration session. We concluded that both aspiration of immature follicles and aspiration of the preovulatory follicle can be performed effectively every 14 d without monitoring ovarian follicular growth. As performed in these separate experiments, aspiration of immature follicles provided more blastocysts per aspiration session. PMID- 20202675 TI - TEM characterization of a silorane composite bonded to enamel/dentin. AB - OBJECTIVES: The low-shrinking composite composed of combined siloxane-oxirane technology (Filtek Silorane, 3M ESPE, Seefeld, Germany) required the development of a specific adhesive (Silorane System Adhesive, 3M ESPE), in particular because of the high hydrophobicity of the silorane composite. The purpose of this study was to characterize the interfacial ultra-structure at enamel and dentin using transmission electron microscopy (TEM). METHODS: Non-demineralized/demineralized 70-90 nm sections were prepared following common TEM specimen processing procedures. RESULTS: TEM revealed a typical twofold build-up of the adhesive resin, resulting in a total adhesive layer thickness of 10-20 microm. At bur-cut enamel, a tight interface without distinct dissolution of hydroxyapatite was observed. At bur-cut dentin, a relatively thin hybrid layer of maximum a few hundreds of nanometer was formed without clear surface demineralization. No clear resin tags were formed. At fractured dentin, the interaction appeared very superficial (100-200 nm). Distinct resin tags were formed due to the absence of smear plugs. Silver-nitrate infiltration showed a varying pattern of both spot- and cluster-like appearance of nano-leakage. Traces of Ag were typically detected along some part of the enamel-adhesive interface and/or between the two adhesive resin layers. Substantially more Ag-infiltration was observed along the dentin adhesive interface of bur-cut dentin, as compared to that of fractured dentin. CONCLUSIONS: The nano-interaction of Silorane System Adhesive should be attributed to its relatively high pH of 2.7. The obtained tight interface at both enamel and dentin indicates that the two-step self-etch adhesive effectively bridged the hydrophilic tooth substrate with the hydrophobic silorane composite. PMID- 20202676 TI - Distribution of 14C-bisphenol A in pregnant and newborn mice. AB - OBJECTIVES: The purpose of the present investigation was to trace the fate of bisphenol A injected into pregnant mice, focusing on its potential accumulation in the fetus and the brain, critical targets of hormonal chemicals, using whole body autoradiography. METHODS: Pregnant mice were injected intraperitoneally with 0.46MBq of (14)C-BPA and then killed at 1h or 1, 3, or 5 days after injection. Sections for autoradiography were prepared in a cryomicrotome and the exposed imaging plate was processed using a fluorescent/radioisotope image analyzer. RESULTS: Intraperitoneally injected (14)C-BPA was distributed throughout the body, including the fetus and the brain, within 1h. Radioactivity faded gradually from the whole body by the fifth day, and no accumulation in any specific organ was found. However, although (14)C was detected in the fetuses immediately after injection, the transfer of BPA from mother to newborn was not observed. SIGNIFICANCE: The routes of rapid BPA discharge were confirmed, and BPA neither accumulated in the body nor was it transferred to newborn mice. No evidence was observed to suggest the existence of a blood-placenta or blood-brain barrier for BPA. This information should be taken into consideration when assessing the risks of using dental materials that contain BPA. PMID- 20202677 TI - Is low empathy related to bullying after controlling for individual and social background variables? AB - This paper examines the relationship between low empathy and bullying while also controlling for the impact of a number of other individual and social background variables linked with bullying. This included the relationship to the prevalence of bullying, but also to the frequency and type of bullying. Questionnaires were completed by 720 adolescents (344 females, 376 males) aged 13-17 in three secondary schools in England. The results suggested that low affective empathy was independently related to bullying by males, but not females. There was no evidence that low cognitive empathy was independently related to bullying, but high impulsivity was related to all forms of male bullying and to female bullying. The implications of the findings for research and practice are discussed. PMID- 20202678 TI - Bystander CPR for paediatric out-of-hospital cardiac arrest. PMID- 20202679 TI - Conventional and chest-compression-only cardiopulmonary resuscitation by bystanders for children who have out-of-hospital cardiac arrests: a prospective, nationwide, population-based cohort study. AB - BACKGROUND: The American Heart Association recommends cardiopulmonary resuscitation (CPR) by bystanders with chest compression only for adults who have cardiac arrests, but not for children. We assessed the effect of CPR (conventional with rescue breathing or chest compression only) by bystanders on outcomes after out-of-hospital cardiac arrests in children. METHODS: In a nationwide, prospective, population-based, observational study, we enrolled 5170 children aged 17 years and younger who had an out-of-hospital cardiac arrest from Jan 1, 2005, to Dec 31, 2007. Data collected included age, cause, and presence and type of CPR by bystander. The primary endpoint was favourable neurological outcome 1 month after an out-of-hospital cardiac arrest, defined as Glasgow Pittsburgh cerebral performance category 1 or 2. FINDINGS: 3675 (71%) children had arrests of non-cardiac causes and 1495 (29%) cardiac causes. 1551 (30%) received conventional CPR and 888 (17%) compression-only CPR. Data for type of CPR by bystander were not available for 12 children. Children who were given CPR by a bystander had a significantly higher rate of favourable neurological outcome than did those not given CPR (4.5% [110/2439] vs 1.9% [53/2719]; adjusted odds ratio [OR] 2.59, 95% CI 1.81-3.71). In children aged 1-17 years who had arrests of non-cardiac causes, favourable neurological outcome was more common after bystander CPR than no CPR (5.1% [51/1004] vs 1.5% [20/1293]; OR 4.17, 2.37-7.32). However, conventional CPR produced more favourable neurological outcome than did compression-only CPR (7.2% [45/624] vs 1.6% [six of 380]; OR 5.54, 2.52-16.99). In children aged 1-17 years who had arrests of cardiac causes, favourable neurological outcome was more common after bystander CPR than no CPR (9.5% [42/440] vs 4.1% [14/339]; OR 2.21, 1.08-4.54), and did not differ between conventional and compression-only CPR (9.9% [28/282] vs 8.9% [14/158]; OR 1.20, 0.55-2.66). In infants (aged <1 year), outcomes were uniformly poor (1.7% [36/2082] with favourable neurological outcome). INTERPRETATION: For children who have out-of-hospital cardiac arrests from non-cardiac causes, conventional CPR (with rescue breathing) by bystander is the preferable approach to resuscitation. For arrests of cardiac causes, either conventional or compression-only CPR is similarly effective. FUNDING: Fire and Disaster Management Agency and the Ministry of Education, Culture, Sports, Science and Technology (Japan). PMID- 20202680 TI - Raman microspectrometry as a powerful tool for a quick screening of thiotrophy: an application on mangrove swamp meiofauna of Guadeloupe (F.W.I.). AB - The mangrove swamp environment constitutes a sulphide rich habitat harbouring some thioautotrophic organisms. The ciliate Zoothamnium niveum and the nematode Eubostrichus dianae, both known to live associated with bacterial sulphide oxidizing ectosymbionts, were analysed as positive controls by Raman microspectrometry. The detection of the 3 Raman bands characteristic of elemental sulphur (S(8)) allows us to define a positive model of sulphide-oxidizing symbiotic invertebrates and by extrapolation, of thioautotrophic organisms. A fast screening using this tool was carried out on eukaryotic organisms such as hydrozoan, nematodes, annelids, copepods, and ciliate (Pseudovorticella sp.) and on free-living filamentous bacteria found on decomposing leaves in order to detect thioautotrophic organisms. The Raman microspectrometry permits us: (i) to reveal thioautotrophic metabolism of free-living bacteria (Beggiatoa sp.) and even for Archaea and (ii) to detect sulphide-oxidizing endosymbiotic and ectosymbiotic bacteria associated with the Bivalve Lucina pectinata and Pseudovorticella sp., respectively. Raman microspectrometry represents a fast, easy and non destructive technique which can be used on living organisms without constraints of sample size. The Raman analysis can also be completed by ultrastructural analysis (SEM, TEM) on the same sample. PMID- 20202681 TI - Direct differentiation of human embryonic stem cells into selective neurons on nanoscale ridge/groove pattern arrays. AB - Human embryonic stem cells (hESCs) are pluripotent cells that have the potential to be used for tissue engineering and regenerative medicine. Repairing nerve injury by differentiating hESCs into a neuronal lineage is one important application of hESCs. Biochemical and biological agents are widely used to induce hESC differentiation. However, it would be better if we could induce differentiation of hESCs without such agents because these factors are expensive and it is difficult to control the optimal concentrations for efficient differentiation with reduced side effects. Moreover, the mechanism of differentiation induced by these factors is still not fully understood. In this study, we present evidence that nanoscale ridge/groove pattern arrays alone can effectively and rapidly induce the differentiation of hESCs into a neuronal lineage without the use any differentiation-inducing agents. Using UV-assisted capillary force lithography, we constructed nanoscale ridge/groove pattern arrays with a dimension and alignment that were finely controlled over a large area. Human embryonic stem cells seeded onto the 350-nm ridge/groove pattern arrays differentiated into neuronal lineage after five days, in the absence differentiation-inducing agents. This nanoscale technique could be used for a new neuronal differentiation protocol of hESCs and may also be useful for nanostructured scaffolding for nerve injury repair. PMID- 20202682 TI - Poly(ethylene glycol)-grafted poly(propylene fumarate) networks and parabolic dependence of MC3T3 cell behavior on the network composition. AB - We present a method to modify poly(propylene fumarate) (PPF), an injectable biomaterial for bone-tissue-engineering applications, by photo-crosslinking it with methoxy poly(ethylene glycol) monoacrylate (mPEGA) at various mPEGA compositions of 0-30%. The bulk properties such as thermal and rheological properties of uncrosslinked mPEGA/PPF blends and the mechanical properties of photo-crosslinked mPEGA/PPF blends were also investigated and correlated with surface characteristics to elaborate on the modulation of mouse MC3T3 cell adhesion, spreading, proliferation and differentiation through controlled physicochemical properties. Unlike PPF crosslinked with PEG dimethacrylate, mPEGA chains tethered on the surface of crosslinked PPF did not influence the swelling ratio in water while increased surface hydrophilicity greatly. Meanwhile, surface frictional coefficient and the capability of adsorbing proteins from cell culture medium decreased continuously with increasing the mPEGA composition in mPEGA/PPF networks. Demonstrating cell repulsive effect at the mPEGA compositions higher than 7%, the modified surfaces improved MC3T3 cell attachment, proliferation and differentiation, which reached maxima at the mPEGA composition of 5-7%. Besides revealing that mPEGA pendant chains could enhance cell responses by increasing hydrophilicity when their fraction on the hydrophobic surface was small, the present study also offered a new method of improving the wettability and performance of the scaffolds made from PPF for bone repair. PMID- 20202683 TI - Reduced proliferation of non-megakaryocytic acute myelogenous leukemia and other leukemia and lymphoma cell lines in response to eltrombopag. AB - Leukemia cell lines were treated with eltrombopag or thrombopoietin and their proliferative response was determined. Eltrombopag did not increase proliferation of cell lines that did not express high levels of megakaryocyte markers. Instead, treatment with eltrombopag alone inhibited proliferation of many cell lines (IC(50) range=0.56-21 microg/mL). The addition of other cytokines, such as G-CSF, Epo or Tpo, did not affect the decrease in proliferation. The decrease in proliferation appears to be through a TpoR-independent, nonapoptotic mechanism. These findings suggest that eltrombopag does not enhance, but rather inhibits, proliferation of leukemia cell lines in vitro. PMID- 20202684 TI - Sustained ocular delivery of fluocinolone acetonide by an intravitreal insert. AB - PURPOSE: To compare Iluvien intravitreal inserts that release 0.2 or 0.5 microg/day of fluocinolone acetonide (FA) in patients with diabetic macular edema (DME). DESIGN: Prospective, randomized, interventional, multicenter clinical trial. PARTICIPANTS: We included 37 patients with DME. METHODS: Subjects with persistent DME despite > or = 1 focal/grid laser therapy were randomized 1:1 to receive an intravitreal insertion of a 0.2- or a 0.5-microg/day insert. MAIN OUTCOME MEASURES: The primary end point was aqueous levels of FA throughout the study with an important secondary outcome of the change from baseline in best corrected visual acuity (BCVA) at month 12. RESULTS: The mean aqueous level of FA peaked at 3.8 ng/ml at 1 week and 1 month after administration of a 0.5 microg/day insert and was 3.4 and 2.7 ng/ml 1 week and 1 month after administration of a 0.2-microg/day insert. For both inserts, FA levels decreased slowly thereafter and were approximately 1.5 ng/ml for each at month 12. The mean change from baseline in BCVA was 7.5, 6.9, and 5.7 letters at months 3, 6, and 12, respectively, after administration of a 0.5 microg/day-insert and was 5.1, 2.7, and 1.3 letters at months 3, 6, and 12, respectively, after administration of a 0.2-microg/day insert. There was a mild increase in mean intraocular pressure after administration of 0.5-microg/day inserts, but not after administration of 0.2-microg/day inserts. CONCLUSIONS: The FA intravitreal inserts provide excellent sustained intraocular release of FA for > or = 1 year. Although the number of patients in this trial was small, the data suggest that the inserts provide reduction of edema and improvement in BCVA in patients with DME with mild effects on intraocular pressure over the span of 1 year. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 20202685 TI - Identification of genome-wide copy number variations and a family-based association study of Avellino corneal dystrophy. AB - OBJECTIVE: To determine the association of identified copy number variations (CNVs) in whole genome with the risk of Avellino corneal dystrophy (ACD) in a Korean population. DESIGN: Case-control study. PARTICIPANTS: A total of 146 patients with ACD and 226 control subjects. METHODS: A total of 193 trios were genotyped by the Illumina HumanHapCNV370-Duo BeadChip (370,404 markers) (Illumina, Inc., San Diego, CA). The intensity signal (log R ratio) and allelic intensity ratio (B allele frequency) of each marker in all individuals were obtained by Illumina BeadStudio software (Illumina, Inc.). To obtain authentic CNVs in this study, we performed a family-based CNV validation and family-based boundary mapping using the PennCNV algorithm, which incorporates multiple factors, including total log R ratio, B allele frequency, and family information, based on an integrated hidden Markov model. MAIN OUTCOME MEASURES: Statistical comparison and identification of CNVs between case and control using family information. RESULTS: We identified 27,267 individual trio CNVs with a median size of 16.2 kb, aggregated in 2245 CNV regions. Most of the identified trio CNVs in this study showed well-defined CNV boundaries and overlapped with those in the Database of Genomic Variants (DGV) (83.4% in number and 79.2% in length). With the common CNV regions (264 CNV regions >5%), we performed a family-based association test with the risk of ACD. CONCLUSIONS: Two CNV regions (chr6:29978470-29987783 and chr14:59896944-59916129) were significantly associated with the risk of ACD (P=0.05-0.003 and P=0.008, respectively). This study describes the first results of a genome-wide association analysis of individual CNVs with the risk of ACD and shows that 2 novel CNV loci may be involved in the risk of ACD. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 20202686 TI - Accidental macular injury from prolonged viewing of a plasma flash produced by a femtosecond laser. AB - OBJECTIVE: To report a case of macular injury caused by prolonged exposure to a flash from the plasma formed at the focus of a femtosecond laser. DESIGN: Interventional case report. PARTICIPANT: A patient with macular injury caused by sustained observation of the plasma flash produced by a femtosecond laser. INTERVENTION: The patient was examined with complete ophthalmologic evaluation (including Amsler grid test, funduscopy, fluorescein angiography, and optical coherence tomography [OCT]) at 3 hours, 1 month, and 6 months after injury. The injured right eye received a retrobulbar injection of 40 mg triamcinolone acetonide (TransTon), at 4 hours and at 10 days after injury, respectively. MAIN OUTCOME MEASURES: Visual acuity, ophthalmoscopic, and OCT findings. RESULTS: Three hours after injury, the best-corrected visual acuity of the right eye was 20/30 with a very small relative scotoma nasal to fixation. Funduscopy disclosed a well-circumscribed, yellow-white spot lesion located immediately temporal to the foveal center. As time passed, the patient's vision returned to 20/20 and the scotoma and retinal abnormalities had become less prominent, but were still present. In the acute stage, OCT showed a hyperreflective lesion involved all foveal retinal layers. At 1 and 6 months of follow-up, OCT revealed abnormal reflectivity located within the outer foveal retina. CONCLUSIONS: Prolonged viewing of a plasma flash induced by a focused femtosecond laser in the air without eye protection may produce persistent damage to the retina. The observed macular injury was probably the result of a combination of thermal and photochemical damage. PMID- 20202687 TI - Synthesis and characterization of the ligand based on benzoxazole and its transition metal complexes: DNA-binding and antitumor activity. AB - A new ligand 2-((2-((benzo[d]oxazol-2-yl)methoxy)phenoxy)methyl)benzoxazole (L) and its four transition metal complexes M(NO(3))(2)L (M=Cu, Co, Ni, Zn), have been synthesized and investigated. The single crystal structures of the complexes show that all of them have similar molecular structure and the ligand exhibits good coplanarity after coordination with the metal ions. Further investigation of DNA binding indicates that both the ligand L and the complexes can bond to DNA by intercalation mode, and the latter possesses much stronger binding affinity. Antitumor activity of these compounds tested on the four cancer cell lines, follows the order: Cu-L>Ni-L approximately Co-L>Zn-L>>L, which are thought to be related with their DNA-binding affinity. PMID- 20202688 TI - Is successful electroconvulsive therapy related to stimulation of the vagal system? AB - BACKGROUND: Electroconvulsive therapy (ECT) has been shown to exhibit strong beneficial effects in the treatment of major depressive disorder (MDD). While the exact underlying mechanisms are under debate, a role for the sympathetic response upon ECT has been suggested. When assessing patients with MDD for autonomic function, however, a loss of vagal function is prominent. OBJECTIVE: Here, we aimed to assess the immediate effects of ECT on vagal activity and to test the hypothesis that surrogates of the latter correlate with therapeutic outcome. METHODS: Twenty patients with MDD who underwent ECT treatment were assessed regarding their vagal function using electrophysiological measures and determination of pancreatic polypeptide (PP), which is known to be released upon vagal stimulation. Parameters were correlated to the improvement of disease severity upon ECT treatment. RESULTS: Patients showed a significant increase of PP shortly after ECT which correlated with clinical improvement. Furthermore, the described association with the sympathetic phase after ECT could be verified. CONCLUSION: ECT increases vagal activity which might be associated with the beneficial effect seen following this treatment. PP elevation after administration of ECT might be a useful parameter to estimate the degree of such vagal stimulation after treatment. PMID- 20202690 TI - Psychomotor performance and fitness to drive: the influence of psychiatric disease and its pharmacological treatment. AB - Both psychiatric disorders and psychiatric drug treatments produce changes of psychomotor performance which can disturb and/or interfere with the ability to drive safely. We studied the influence of current psychiatric drug treatments on psychomotor functions and on driving performance of 77 consecutive psychiatric outpatients in two different clinical situations: at admission, when patients are destabilized and their mental disorders untreated, and after 6 weeks of pertinent psychotropic treatment. Fitness to drive and psychomotor performance were assessed using the electronic LNDETER 100 battery. Treatment effects on global functioning were assessed using the Clinical Global Impression of Change (CGIC) scale. One-way repeated measures analysis of variance and post hoc comparisons with the Bonferroni correction were performed. At the time of diagnosis, 90% of the patients failed to achieve scores sufficient to renew their driving licenses. After 6 weeks of adequate treatment, 83% improved their mental condition, and 17% either remained unchanged or deteriorated. Of those who improved, 25% had scores sufficiently high for them to drive legally, and the rest improved their performance from baseline assessment. Three of the four sub-tests were able to discriminate between patients with different clinical conditions. The study clearly suggests that medical treatment of psychiatric problems has a positive effect on driving tests. PMID- 20202689 TI - Functional significance of preserved affect recognition in schizophrenia. AB - Affect recognition (AR) is a core component of social information processing; thus, it may be critical to understanding social behavior and functioning in broader aspects of daily living. Deficits in AR are well documented in schizophrenia, but there is also evidence that many individuals with schizophrenia perform AR tasks at near-normal levels. In the current study, we sought to evaluate the functional significance of AR deficits in schizophrenia by comparing subgroups with normal-range and impaired AR performance on proxy and interviewer-rated measures of real-world functioning. Schizophrenia outpatients were classified as normal-range (N=17) and impaired (N=31) based on a logistic cut point in the sample distribution of Bell-Lysaker Emotion Recognition Task (BLERT) scores, referenced to a normative sample of healthy control subjects (N=56). The derived schizophrenia subgroups were then compared on proxy [University of California San Diego Performance-Based Skill Assessment (UPSA), Social Skills Performance Assessment (SSPA), Medication Management Ability Assessment (MMAA)] and interviewer-rated [Quality of Life Scale (QLS), Independent Living Skills Survey (ILSS)] measures of functioning, as well as a battery of neurocognitive tests. Initial analyses indicated superior MMAA and QLS performance in the near-normal AR subgroup. Covariate analyses indicated that group differences in neurocognition fully mediated the observed associations between AR and MMAA, and attenuated the observed relationships between AR classification and QLS. These results support three main conclusions. First, AR, like many other domains of psychopathology studied in schizophrenia, is preserved in select subgroups. Second, there is a positive relationship between AR performance and functional outcome measures. Third, neurocognition appears to mediate the relationship between AR and measures of functioning. PMID- 20202691 TI - Cortical motor neurophysiology of patients with schizophrenia: a study using transcranial magnetic stimulation. AB - Trancranial magnetic stimulation (TMS) provides a non-invasive means for exploring physiological alterations of central motor control in a variety of neuropsychiatric diseases. The present study aimed to assess the neurophysiological profile of muscle evoked responses to a standard TMS procedure in 51 medicated patients with schizophrenia and 51 age- and sex-matched healthy subjects. Motor evoked potentials (MEPs) from the abductor pollicis brevis muscle were elicited by stimulation of the contralateral motor cortex with a circular coil. The hot spot was marked, and the resting motor threshold (RMTh), the stimulus intensity for maximum MEP (SI-max), the post-stimulus silent period of voluntary muscle activity, and MEP latency and amplitude were measured. The main findings were the significantly higher than normal values for RMTh and SI-max, which are both indices of neuronal excitability. In particular, patients who had ziprasidone in their therapeutic regimen demonstrated the highest SI-max for both hemispheres, and the highest RMTh for the left hemisphere, patients receiving olanzapine demonstrated the lowest RMTh for the left hemisphere, and those on quetiapine showed intermediate values. The silent period was longer in the patients than in the controls when a RMTh-related SI was used and did not differ between the two groups when a fixed SI was used. We concluded that the observed TMS changes could be interpreted as primary alterations of intracortical motor excitability followed by defects of cortical inhibition and should be attributed to schizophrenia, antipsychotic medication or the interaction between the two factors. PMID- 20202692 TI - Systemic minocycline differentially influences changes in spinal microglial markers following formalin-induced nociception. AB - In the present study, intraperitoneal administration of minocycline attenuated enhancing nociceptive behaviors in those rats receiving dual formalin injections (5% formalin followed at 7 days later by 1% formalin). The minocycline treatment did not prevent the increase in OX-42 and MHC class I labeling and morphological changes, but significantly attenuated upregulation of phospho-p38 in activated microglia. These results suggest that the later days of microglial activation with upregulated immune markers in the spinal cord contributes to enhancing long term pain response by a pathway of p38 activation in microglia. PMID- 20202693 TI - TNF-alpha, IL-1beta, IL-6, and cinc-1 levels in rat brain after meningitis induced by Streptococcus pneumoniae. AB - Bacterial meningitis caused by Streptococcus pneumoniae is associated with a significant mortality rate and persisting neurologic sequelae, including sensory motor deficits, seizures, and impairment of learning and memory. The presence of proliferating bacteria within the subarachnoid and ventricular space compartments triggers an intense inflammatory host response at killing the invading microorganism. Proinflammatory mediators released in the process, including tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6, were shown to contribute to the development of brain injury in bacterial meningitis. Thus, the aim of this study was to verify the levels of the TNF-alpha, IL-1beta, IL-6, and CINC-1 in the rat brain after pneumococcal meningitis. The animals underwent a magna cistern tap receiving either 10 microL of sterile saline as a placebo or an equivalent volume of a S. pneumoniae suspension at the concentration of 5x10(9) cfu/mL. The placebo group was killed immediately after the induction and the meningitis group at 0, 6, 12, 24, 48, and 96h after induction. The brains were removed followed by the isolation of the hippocampus and prefrontal cortex for determining TNF-alpha, IL-1beta, IL-6, and CINC-1 levels. In the hippocampus we found increased levels of the TNF-alpha only at 6h (p<0.01; F=3.777); CINC-1 levels increased at 6 and 24h (p<0.001; p<0.05; F=15.05); and IL-6 and IL-1beta levels were not altered. In the prefrontal cortex, the TNF-alpha levels were found to be increased only at 6h (p<0.05; F=4.921); IL-6 (p<0.05; F=11.69) and IL 1beta (p<0.001; F=132.0) levels were found to be increased only at 24h after meningitis induction; and CINC-1 levels were found to be increased at 6, 12, and 24h (p<0.01; p<0.01; p<0.01; F=16.86) after meningitis induction. Our data suggest that cytokine/chemokine levels can be putative biomarkers of brain damage in the first hours of the pneumococcal meningitis. PMID- 20202694 TI - Childhood apraxia of speech and multiple phonological disorders in Cairo-Egyptian Arabic speaking children: language, speech, and oro-motor differences. AB - Childhood apraxia of speech is a neurological childhood speech-sound disorder in which the precision and consistency of movements underlying speech are impaired in the absence of neuromuscular deficits. Children with childhood apraxia of speech and those with multiple phonological disorder share some common phonological errors that can be misleading in diagnosis. This study posed a question about a possible significant difference in language, speech and non speech oral performances between children with childhood apraxia of speech, multiple phonological disorder and normal children that can be used for a differential diagnostic purpose. 30 pre-school children between the ages of 4 and 6 years served as participants. Each of these children represented one of 3 possible subject-groups: Group 1: multiple phonological disorder; Group 2: suspected cases of childhood apraxia of speech; Group 3: control group with no communication disorder. Assessment procedures included: parent interviews; testing of non-speech oral motor skills and testing of speech skills. Data showed that children with suspected childhood apraxia of speech showed significantly lower language score only in their expressive abilities. Non-speech tasks did not identify significant differences between childhood apraxia of speech and multiple phonological disorder groups except for those which required two sequential motor performances. In speech tasks, both consonant and vowel accuracy were significantly lower and inconsistent in childhood apraxia of speech group than in the multiple phonological disorder group. Syllable number, shape and sequence accuracy differed significantly in the childhood apraxia of speech group than the other two groups. In addition, children with childhood apraxia of speech showed greater difficulty in processing prosodic features indicating a clear need to address these variables for differential diagnosis and treatment of children with childhood apraxia of speech. PMID- 20202695 TI - Expressive language skills in Chinese Singaporean preschoolers with nonsyndromic cleft lip and/or palate. AB - OBJECTIVE: The main objective of the present study was to examine THE EXPRESSIVE LANGUAGE SKILLS and obtain a prevalence estimate of expressive language IMPAIRMENT (not skills) in Chinese Singaporean preschoolers with nonsyndromic cleft lip and/or palate (CLP). METHODS: A group of 43 Chinese Singaporean preschoolers aged 3 to 6 years with a diagnosis of nonsyndromic CLP was assessed using the Singapore English Action Picture Test (SEAPT). The SEAPT is an English Language screening tool standardised on typically developing English-Mandarin Chinese Singaporean preschoolers that assesses expressive vocabulary and grammatical usage. A grammar and/or information score below the 20(th) percentile on the SEAPT is indicative of an expressive language impairment. In addition, the medical records of this cohort were examined retrospectively for documentation of surgical timings, audiological history, articulation and resonance. RESULTS: Based on the results of the SEAPT, 33% of the preschoolers with CLP were identified as having a-possible expressive language impairment. Hence, the likelihood that a child with CLP with normal cognitive functioning will have an expressive language impairment is between 3.9 to 12.7 times more likely than in the general population. There was no statistical significance when comparisons were made between dominant language groups or CLP groups on SEAPT measures of information and grammar content. Significantly more males than females were identified with language difficulties, relative to the sex ratio in the sample. No significance was found for the other participant variables. CONCLUSIONS: The findings of this study suggest that Chinese Singaporean preschoolers with CLP have more difficulty in the expressive use of grammar and vocabulary than their peers of typical development, with significantly more males affected than females. As language performance was not related to hearing, articulation or resonance; these early results suggest that a comprehensive investigation of cognition, literacy and family aggregation of communication disorders is urgently warranted to study other possible aetiologies for language impairment in children with CLP in Singapore. PMID- 20202696 TI - Genotyping sex in the amphibian, Xenopus (Silurana) tropicalis, for endocrine disruptor bioassays. AB - Endocrine disrupting compounds have been shown to alter gonad differentiation in both male and female individuals in amphibian, avian, fish, invertebrate, and reptile species. In some cases, these affected individuals are completely sex reversed and are morphologically indistinguishable from normal individuals of the opposite sex. Detecting shifts in sex ratios following chemical exposure often requires large numbers of organisms to achieve the necessary statistical power, especially in those species with genetic sex determination and homomorphic sex chromosomes (such as amphibians and many fish). The ability to assess the genetic sex of individuals would allow for detection of sex reversal (genotype-phenotype mismatches) that have greater statistical power compared to examining changes in sex ratios. Utilizing amplified fragment length polymorphisms (AFLPs), we developed a method for genotyping sex in the amphibian, Xenopus (Silurana) tropicalis, that can be incorporated into endocrine disruptor screening assays that examine the effects of chemicals on gonad differentiation. AFLPs from 512 primer pairs were assessed in one spawn of X. tropicalis. Each primer pair yielded, on average, 100 fragments. In total 17 sex-linked AFLPs were identified, isolated, and sequenced. A recombination map of these AFLPs was generated using over 300 individuals with four AFLPs having a recombination rate of 0% with regard to sex. A BLASTn search of the X. tropicalis genome using these AFLP sequences resulted in identification of sex-linked scaffolds. Areas of these scaffolds were searched for additional polymorphisms that could be utilized for genotyping sex. Retrospective and prospective strategies for incorporating genotyping sex in endocrine disruptor bioassays with X. tropicalis were developed. A Monte Carlo simulation comparing analyzing data as sex ratio shifts versus assessment of sex reversal using genotyping demonstrates the increase in statistical power that can be obtained by genotyping sex in studies dealing with altered gonad differentiation. This approach to identifying sex-linked markers and developing sex genotyping methods is applicable to other species with genetic sex determination. PMID- 20202697 TI - The relationship between the stipulated tempo step test, daily activity ability and gait time in elderly. AB - This study is aimed at examining the relationship between stipulated tempo step tests, daily activity ability, and gait time. One hundred and thirty healthy elderly women performed the step test in which they stepped in place for 20s while matching a metronome beat to tempos of 40, 60, and 120 bpm, respectively. The evaluation parameter was the time difference between the metronome sound and the time when subject's foot hit the ground. The subjects were divided into four groups according to (1) whether they had experienced a fall and (2) activity level. The time difference showed significantly greater variance in the order of 40, 60 and 120 bpm in both groups of high activity and low activity. A significant time difference between groups was found only in the 40 bpm tempo where the low activity group's value was higher. The correlations between the time difference and gait time were significant in all tempos of both groups (r=0.24-0.41). The time differences in 40 and 60 bpm step tests showed significant and moderate correlations (r=0.52-0.60) with gait time in the low activity group, but low correlations (r=0.29-0.30) in the high activity group. In conclusion, the stipulated step test can evaluate the level of daily activity ability in the elderly at home and it is effective in evaluating their balance ability. PMID- 20202698 TI - Is age or the body mass index (BMI) more determinant of the bone mineral density (BMD) in geriatric women and men? AB - The objective was to determine the effect of the body mass index (BMI) and age on the bone mineral density (BMD) in geriatric women and men. 900 geriatric patients were included in the study. BMD was measured in the right femoral neck and the antero-posterior lumbar region. All geriatric patients were classified in 1 of 4 categories on the basis of their BMI, as underweight, ideal weight, overweight, and obese. They were separated into three groups, 65-74, 75-84 and 85 and older, according to age groups. While a significant relationship was only determined between the femoral BMD measurements and the BMI in men; significant relationship was shown between both the lumbar and the femoral BMD measurements and the BMI in women. Significant relationship was also determined between the femoral BMD measurements and the BMI and age among women. While the BMDs of those aged 65-74 years group were found to be high compared to those aged 75-84 years and those aged 85 years and older groups, no difference was found between the two groups. This study confirms the effect of a high BMI on femoral neck and L2-L4 BMD among older men and women, but the effect of age was not shown above 75 years of age. PMID- 20202699 TI - Mortality and bloodstream infections in geriatrics units. AB - The purpose of this retrospective study was to evaluate risk factors of mortality in bloodstream infections in old and very old people in a French geriatric unit (Paul Brousse Hospital, APHP). 167 older patients with bloodstream infections were included and two groups were compared according to age (60-85 years and >=85 years). Information was collected for each patient: age, sex, diseases, urinary catheter, temperature, signs of severe sepsis, biological examinations, bacteria and antibiotic treatments. All bacteremias were nosocomial. There was no difference between groups for pathogen, source or prognosis. Mortality rate at 60 days was 32.3%. The risk factors for mortality were: low albumin rate (p<0.001), high C-reactive protein (CRP) (p=0.02) and moderate fever (p=0.006). Multivariate logistic regression showed that these three parameters were significantly associated with a risk of mortality. The parameter with the highest risk was a low albumin rate <30 g/l. Malnutrition may be a more long-term risk factor. A moderate fever probably results in a more frequent delay in diagnosis in this population. Our work supports that age is not a risk factor of mortality for bloodstream infections. However management of bacteremia has to be adapted to elderly. PMID- 20202700 TI - The geriatric patient: use of acute geriatrics units in the emergency care of elderly patients in France. AB - We studied the factors influencing the choice of admission to Geriatrics units, instead of other acute hospital units after an emergency visit. We report the results from a cohort of 1283 randomly selected patients aged >75 years hospitalized in emergency and representative of the French University hospital system. All patients underwent geriatric assessment. Baseline characteristics of patients admitted to Geriatrics and other units were compared. A center effect influencing the use of Geriatrics units during emergencies was also investigated. Admission to a Geriatrics unit during the acute care episode occurred in 499 cases (40.3%). By multivariate analysis, 4 factors were related to admission to a Geriatrics unit: cognitive disorder: odds ratio (OR)=1.79 (1.38-2.32) (95% confidence interval=95% CI); "failure to thrive" syndrome OR=1.54 (1.01-2.35), depression: OR=1.42 (1.12-1.83) or loss of Activities of Daily Living (ADL): OR=1.35 (1.04-1.75). The emergency volume of the hospital was inversely related to the use of Geriatrics units, with high variation that could be explained by other unstudied factors. In the French University Emergency Healthcare system, the "geriatrics patient" is defined by the existence of cognitive disorder, psychological symptoms or installed loss of autonomy. Nevertheless, considerable nation-wide variation was observed underlining the need to clarify and reinforce this discipline in the emergency healthcare system. PMID- 20202701 TI - Incidence of dementia and cause of death in elderly Japanese emigrants to Brazil before World War II. AB - In 1997 we examined the prevalence of dementia among the Japanese elderly immigrants living in the Sao Paulo metropolitan area (n=166). Herein, we followed up on these subjects for causes of death and dementia incidence. We were able to contact 108 subjects: 54 were already dead. The most common cause of death was cardiac disease. For dementia, 31.6% of the dead subjects were found to have developed dementia before they died, and 20.8 % of the living subjects were demented. As for the baseline the clinical dementia rating (CDR), 20.8 % of CDR 0 and 50.0 % of CDR 0.5 subjects developed dementia in the dead group; whereas in the living group, 23.9 % of CDR 0 and 52.6 % of CDR 0.5 developed dementia. As a whole, the incidence was 34.2 0/00 per 1000 person-years. Cardiac disease as the most common cause of death was probably due to the higher prevalence of diabetes mellitus. Compared with the previous study, the lower incidence of dementia from the CDR 0.5 group may have been due to a higher mortality rate. This is the first study on the incidence of dementia in elderly Japanese immigrants in Brazil. PMID- 20202702 TI - Influence of history of smoking on the physical capacity of older people. AB - Among the elderly, smoking is related to death and it contributes to disability associated with chronic diseases. This study aims to verify the influence of a history of smoking on the physical capacity of elderly people, and its relationship with the gender. Elderly people beginning to practice physical activity reported questions about their smoking history and underwent a physical evaluation, consisted by hemodynamic data (blood pressure, heart rate and maximum oxygen consumption), body mass index (BMI), muscular strength, flexibility and balance. Mann-Whitney test and Spearman's test was used to data analysis. The sample consisted of 127 subjects, among whom 26.8% were ex-smokers. There were a higher number of nonsmoking women (p<0.001) than others, and women smoked fewer packets per day (p=0.047). Among the women, those ex-smokers were younger and more flexible in comparison with those nonsmokers (p<0.05). Among the men, the ex smokers were older and walked more slowly than nonsmokers (p<0.05). There was a correlation between the BMI and duration of smoking time. Smoking cessation benefits the elderly, since the physical variables showed no long-term harm associated with the history of smoking when compared with those of elderly without this habit. PMID- 20202703 TI - Gender differences in rehabilitation outcomes among older Chinese patients. AB - Although gender differences have been demonstrated in cardiac and stroke rehabilitation, it remains unclear whether there are gender differences in geriatric rehabilitation. The purpose of this study is to investigate the relationship between gender and rehabilitation outcomes. We studied 1795 patients in two convalescence hospitals in Hong Kong. We defined absolute functional and motor gains as Barthel Index (BI) efficacy and Elderly Mobility Scale (EMS) efficacy while BI and EMS efficiency were efficacy divided by the length of stay. Satisfactory motor and functional outcomes were defined as discharge EMS >= 15 and BI >= 75. Compared with men, women had higher BI but lower EMS on admission and discharge. EMS and BI efficacy and efficiency were similar in both sexes. Female gender was a significant negative predictor for satisfactory motor outcome (p=0.0002) but a positive predictor for functional outcome (p=0.0007). Other predictors for satisfactory motor outcome were: age (p<0.001); urinary incontinence (p=0.0049); living at home (p=0.0056); admission EMS (p<0.001); admission BI (p=0.044). Other predictors for satisfactory functional outcome were: age (p=0.009); infection other than chest (p=0.047); urinary incontinence (p<0.001); Mini Mental State Examination (MMSE) (p=0.0004); admission EMS (p=0.005); BI (p<0.001). Women achieved a better functional outcome but a poorer motor outcome on discharge. Female gender was a positive predictor for functional outcome but a negative factor for motor outcome. PMID- 20202704 TI - Defects in myoglobin oxygenation in K(ATP)-deficient mouse hearts under normal and stress conditions characterized by near infrared spectroscopy and imaging. AB - BACKGROUND: Disruption of ATP-sensitive potassium (K(ATP)) channel activity results in the development of dilated cardiomyopathy in response to different forms of stress, likely due to the underlying metabolic defects. To further understand the role of Kir6.2-containing channels in the development of cardiac disease, we analysed the left ventricular (LV) wall oxygenation and the physiologic responses induced by acute stress in non-dilated Kir6.2(-/-) hearts. METHODS: Control (C57BL6) and Kir6.2(-/-) mouse hearts were perfused in constant flow Langendorff mode with Krebs-Henseleit buffer. Myocardial oxygenation was evaluated using a newly developed technique, near infrared spectroscopic imaging (NIRSI) of the myoglobin (Mb) oxygen saturation parameter (OSP, ratio of oxy- to total Mb). RESULTS: 2,4-dinitrophenol (DNP, 50-uM) and isoproterenol (0.1-uM) failed to produce a transient vasodilatory response and caused a significant diastolic pressure increase in Kir6.2(-/-) hearts. DNP strongly suppressed contractile function in both groups and induced severe mean OSP decreases in Kir6.2(-/-) hearts. Isoproterenol-induced decreases in OSP were similar despite the lack of contractile function stimulation in the Kir6.2(-/-) group. The index of OSP spatial heterogeneity (relative dispersion, RD) was lower by 15% in the Kir6.2(-/-) group at the baseline conditions. Recovery after stress caused reduction of RD values by 20% (DNP) and 8% (isoproterenol) in controls; however, these values did not change in the Kir6.2(-/-) group. CONCLUSIONS: 1) NIRSI can be used to analyse 2-D dynamics of LV oxygenation in rodent models of cardiomyopathy; 2) Kir6.2-containing K(ATP) channels play an important role in maintaining myocardial oxygenation balance under acute stress conditions and in post-stress recovery. PMID- 20202706 TI - Gender differences in variables related to B-natriuretic peptide, left ventricular ejection fraction and mass, and peak oxygen consumption, in patients with heart failure. AB - AIM AND METHODS: We assessed gender differences in variables related to B natriuretic peptide (BNP), left ventricular ejection fraction (LVEF), peak oxygen consumption (peak-VO2), and LV mass (LVM), among patients recently hospitalized for suspected heart failure (HF). RESULTS: Of 930 consecutive patients, 409 accepted follow-up after discharge, 221 of these had definite HF (90 women, mean age 74.5 [9.8]years). In 141 HF patients (61 women) with BNP data, women had lower BNP than men (43.9 [38.1] versus 76.3 [88.9]pmol/L, P=0.0193). LVEF (all HF patients) was higher in women (49.8 [13.4] versus 42.4 [13.9]%, P=0.0004). Peak VO2 (147 HF patients, 48 women) was lower in women (13.9 [4.3] versus 16.3 [4.2]mL/kg/min, P=0.0093). LVM index (200 HF patients, 78 women) was lower in women (130.4 [46.5] versus 171.7 [57.6]g/m(2), P<0.0001). Among HF patients, variables independently related to BNP were body mass index (BMI) and peak-VO2 exclusively among men, mitral regurgitation, respiratory disease and angiotensin receptor blocker treatment only among women. Variables independently related to LVEF were resting heart rate, acetylic salicylic acid use and BNP exclusively among men. No variable was exclusive for women. Variables independently related to peak-VO2 were right ventricular size, BNP, resting and peak heart rate solely among men, BMI and stable angina pectoris exclusively among women. Variables independently related to LVM were left atrial diameter only among men, BMI exclusively among women. CONCLUSION: Among elderly HF patients, there were some important gender differences in BNP, LVEF, peak-VO2 and LVM, and in variables independently related to these factors. PMID- 20202707 TI - Bundle branch block patterns and long-term outcomes in heart failure. AB - BACKGROUND: The prognostic value of left and right bundle branch blocks (LBBB and RBBB) in hospitalized heart failure (HF) patients is unclear. We sought to determine the prognostic value of bundle branch blocks in patients hospitalized with heart failure. METHODS: The associations of BBB type with death, HF hospitalizations or cardiovascular hospitalizations over a five year follow-up were examined within the EFFECT study of hospitalized patients fulfilling the Framingham criteria for acute heart failure. Multinomial logistic regression was used to determine associations with BBB type, and survival was assessed using multiple Cox regression analysis. RESULTS: Among 9082 patients (16.3% with LBBB; 7.2% with RBBB), LBBB was independently associated with lower systolic pressure, tachycardia and hyponatremia (odds ratio [OR] of 0.93 per 10 mmHg, 1.04 per 10 beats/min, and 0.84 per 10 mmol/L, respectively). Men and diabetics (OR of 2.11 and 1.35, respectively) had greater odds of RBBB. After multiple covariate adjustment (n=7319), patients with LBBB had increased risk of HF hospitalization with adjusted hazard ratio [HR] of 1.32 (95% CI; 1.20-1.46, p<0.001) and cardiovascular hospitalization with HR of 1.13 (95% CI; 1.04-1.23, p=0.003). LBBB was associated with increased mortality with adjusted HR of 1.10 (95% CI, 1.02 1.18; p=0.011) in 7910 analysed patients. RBBB did not predict significantly increased risk of either death or hospitalization. CONCLUSIONS: Heart failure patients presenting with LBBB had greater clinical severity of heart failure at presentation and greater risk of death and hospitalization for heart failure or cardiovascular disease than those without BBB. In contrast, RBBB did not independently predict worse outcomes. PMID- 20202708 TI - Left ventricular mass and risk of cardiovascular events and all-cause death among ethnic Chinese--the Chin-Shan Community Cardiovascular Cohort study. AB - BACKGROUND: We conducted this cohort study involving ethnic Chinese population to explore the association between left ventricular mass and cardiovascular events and all-cause death, and to define the cutoff value of left ventricular mass for risk stratification. METHODS: We evaluated 2604 participants aged >=35years in the Chin-Shan Community Cardiovascular Cohort (CCCC) study who had received echocardiography without previous cardiovascular events. Left ventricular mass was divided by body surface area to obtain left ventricular mass index (LVMI). The end-points were all-cause death and incident cardiovascular events including coronary heart disease and stroke over a median follow-up of 14.4years. RESULTS: By multivariate Cox regression analyses, a linear relationship between LVMI and cardiovascular events was found (adjusted hazard ratio 2.01, 95% CI, 1.11 to 3.63, for the highest quintile of LVMI compared with the lowest quintile, p for trend=0.001). A J-shape relationship between LVMI and all-cause death was observed, with the test for a linear relationship being rejected (p=0.003). The adjusted hazard ratios of all-cause death were significantly lower in the second quintile (0.58, 95% CI, 0.40 to 0.84) and in the third quintile (0.68, 95% CI, 0.47 to 0.96) of LVMI compared with the lowest quintile. The proposed cut-off value of LVMI was 105g/m(2) for prediction of cardiovascular events. CONCLUSION: A linear relationship between LVMI and cardiovascular events, and a J-shape relationship between LVMI and all-cause death were found. The cut-off value derived from our Chinese population was lower than the frequently applied value derived from Caucasian population. PMID- 20202709 TI - Epicardial application of an amiodarone-releasing hydrogel to suppress atrial tachyarrhythmias. AB - BACKGROUND: Amiodarone is currently the most effective antiarrhythmic drug for sinus rhythm maintenance. However, due to serious extracardiac adverse effects, prophylactic amiodarone therapy is only appropriate for patients at high risk for postoperative atrial fibrillation (AF). We hypothesized that epicardial application of an amiodarone-releasing hydrogel would produce therapeutic myocardial drug concentrations, while systemic levels would remain low. METHODS: Goats were fitted with right atrial epicardial patch electrodes. A poly(ethylene glycol)-based hydrogel with amiodarone (1mg/kg bw) (n=10) or without drug (n=6) was applied to the right atrial epicardium. Atrial effective refractory period (AERP), conduction time and atrial response to burst pacing (rapid atrial response, RAR) were assessed up to 28days in awake goats. Myocardial, plasma and extracardiac tissue amiodarone concentrations were analysed by high-performance liquid chromatography. RESULTS: The amiodarone-loaded hydrogel produced therapeutic drug concentrations in the right atrium up to 21days after application. In this period, AERP and conduction time were prolonged, while RAR inducibility was reduced (P<0.05) compared to animals treated with drug-free hydrogel. Mean amiodarone concentrations in the right atrium were 1 order of magnitude higher than in other heart chambers and 2 orders of magnitude higher than in extracardiac tissues. Plasma amiodarone levels remained below the detection limit (<10ng/mL) during the 28-day follow-up. CONCLUSIONS: Epicardial application of an amiodarone-releasing hydrogel reduces atrial vulnerability to tachyarrhythmias up to 3weeks, while extracardiac drug levels remain low. Therefore, amiodarone-releasing hydrogel could be applied during cardiac surgery to prevent postoperative AF at minimal risk for extracardiac adverse side effects. PMID- 20202710 TI - Risk-prediction models for mortality after coronary artery bypass surgery: application to individual patients. AB - INTRODUCTION: We derived a risk-assessment model for predicting mortality after coronary artery bypass surgery from patient data from the 1990s and examined the model's accuracy in predicting early mortality in more contemporary patients. We also examined the accuracy of a completely new model and an older model recalibrated with newer data. MATERIALS AND METHODS: Three mortality-prediction models were derived: an "old" model from 8959 patients treated during 1993-1999, a "new" model from 5281 patients treated during 2000-2004, and a version of the old model "recalibrated" with the 2000-2004 data. Each model's discriminatory ability was assessed by computing area under receiver-operator characteristic (ROC) curves, and precision was estimated by comparing observed and predicted mortality rates. To test the temporal applicability of the old model, we applied it to the 2000-2004 data and to data from 1879 patients operated on during 2005 2007. To compare the recalibration and remodeling strategies, the new and recalibrated models were applied to the 2005-2007 data. RESULTS: The old model showed good discrimination (ROC, 0.80) and concordance between observed and predicted mortality for the 2000-2004 patients but overpredicted mortality for the 2005-2007 patients. The new and recalibrated models had good discriminatory ability (ROC, 0.81 and 0.79) and showed similarly good concordance between observed and predicted mortality when applied to the 2005-2007 data. CONCLUSIONS: Predictive models for mortality after cardiac surgery lose precision within a few years after development. Recalibrating old models and creating new models (i.e., remodeling) are equally good strategies for predicting outcomes in contemporary patient cohorts. PMID- 20202711 TI - Assessment of ischemia-modified albumin levels for emergency room diagnosis of acute coronary syndrome. AB - BACKGROUND: The aim of this study was to retrospectively evaluate the utility of assessing ischemia-modified albumin (IMA) levels for diagnosing acute coronary syndrome (ACS) in patients presenting to the emergency room (ER) with chest pain. METHODS: The records of patients admitted to the ER with chest pain between August 2006 and December 2008 were examined. Those subsequently diagnosed with ACS were included in the study. Serum IMA and cardiac troponin I (cTnI) concentrations were determined in blood samples obtained from patients within 3h of ER admission and on days 1, 3, 7 and 14. IMA and cTnI cut-off values for diagnosis of ACS were employed and the successful diagnosis rates were compared. RESULTS: Of the patients diagnosed with ACS following ER presentation with acute chest pain, the correct diagnosis rate was significantly higher as determined by assessment of IMA vs. cTnI concentrations within 3h of ER presentation (81.02% vs. 42.34%, P<0.01). Thereafter there were no between marker differences in rates of successful diagnosis. CONCLUSIONS: These findings support the notion that IMA may be a useful biochemical marker for the early diagnosis of ACS, particularly in patients presenting to the ER with acute chest pain. PMID- 20202712 TI - Trichothecene chemotypes of Fusarium culmorum infecting wheat in Tunisia. AB - Fusarium culmorum is a major pathogen associated with Fusarium head blight (FHB) of wheat in Tunisia. It may cause yield loss or produce mycotoxins in the grain. The objectives of the present study were threefold: to evaluate by PCR assays the type of mycotoxins produced by 100 F. culmorum isolates recovered from different regions in Northern Tunisia, to determine the amount of mycotoxin production by HPLC analysis, and to analyse for correlations between the amount of mycotoxin produced and the aggressiveness of isolates. PCR assays of Tri5, Tri7, Tri13, and Tri3 were used to predict whether these isolates could produce nivalenol, 3 acetyl-deoxynivalenol, or 15-acetyl-deoxynivalenol. Two of the isolates were predicted to produce NIV, whereas the others were predicted to produce 3-AcDON. Trichothecene production was confirmed and quantified by high pressure liquid chromatography (HPLC) in 28 isolates, after growth on wheat grains, and in a liquid Mycotoxin Synthetic medium (MS). All strains produced DON/3-AcDON at detectable levels ranging from 21 microg/g to 11.000 microg/g of dry biomass on MS medium and from 10 microg/g to 610 microg/g on wheat grain. The evaluation of the relationship between 3-AcDON production and aggressiveness of 17 strains revealed a significant difference in aggressiveness among the isolates. Moreover, only a significant correlation was revealed between aggressiveness and the amount of 3-AcDON produced on MS medium (r=0.36). Chemotyping of F. culmorum isolates is reported for the first time for isolates from Tunisia, and highlights the important potential of F. culmorum to contaminate wheat with 3-AcDON trichothecenes. PMID- 20202713 TI - Estimating distributions out of qualitative and (semi)quantitative microbiological contamination data for use in risk assessment. AB - A framework using maximum likelihood estimation (MLE) is used to fit a probability distribution to a set of qualitative (e.g., absence in 25 g), semi quantitative (e.g., presence in 25 g and absence in 1g) and/or quantitative test results (e.g., 10 CFU/g). Uncertainty about the parameters of the variability distribution is characterized through a non-parametric bootstrapping method. The resulting distribution function can be used as an input for a second order Monte Carlo simulation in quantitative risk assessment. As an illustration, the method is applied to two sets of in silico generated data. It is demonstrated that correct interpretation of data results in an accurate representation of the contamination level distribution. Subsequently, two case studies are analyzed, namely (i) quantitative analyses of Campylobacter spp. in food samples with nondetects, and (ii) combined quantitative, qualitative, semiquantitative analyses and nondetects of Listeria monocytogenes in smoked fish samples. The first of these case studies is also used to illustrate what the influence is of the limit of quantification, measurement error, and the number of samples included in the data set. Application of these techniques offers a way for meta analysis of the many relevant yet diverse data sets that are available in literature and (inter)national reports of surveillance or baseline surveys, therefore increases the information input of a risk assessment and, by consequence, the correctness of the outcome of the risk assessment. PMID- 20202714 TI - Determinants of childhood burns in rural Bangladesh: A nested case-control study. AB - BACKGROUND: Burn is one of the major causes of childhood illnesses in Bangladesh and is the third leading cause of illness of 1- to 4-year-old children. Rural children are more at risk compared to urban-dwelling children. OBJECTIVE: The study was designed to identify the risk factors of childhood burn in rural Bangladesh. METHODS: This nested case-control study was conducted in rural Bangladesh. The study population was children of less than 10 years old in three sub-districts of Bangladesh. RESULTS: Children of families who did not have a household with a separate kitchen, a common occurrence in rural areas, were at significantly higher risk of burn (OR 1.65; 95% CI 1.22-2.24). A kitchen without a door was also found to create a more hazardous environment compared to a kitchen with a door. The traditional kerosene lamp (kupi bati) was found to be one of the major determinants of childhood burn in rural Bangladesh (OR 3.16; 95% CI 1.58-6.35). No use or restricted use of kupi bati significantly reduces the risk of childhood burn. Children of nuclear families were at significantly higher risk of burn compared to combined families. CONCLUSION: Cooking in an open place and use of the traditional kerosene lamp are the major determinants of childhood burn in rural Bangladesh. A combined family environment reduces the risk of childhood burn. Childhood burn can be reduced by prohibiting use of kupi bati and limiting children's access to the cooking area. Promoting combined family could be an initiative of childhood burn prevention program. PMID- 20202715 TI - Comparison of lactate, formate, and propionate as hydrogen donors for the reductive dehalogenation of trichloroethene in a continuous-flow column. AB - A continuous-flow column study was conducted to analyze the reductive dehalogenation of trichloroethene (TCE) with aquifer material with high content of iron oxides. The column was bioaugmented with the Point Mugu (PM) culture, which is a mixed microbial enrichment culture capable of completely transforming TCE to ethene (ETH). We determined whether lactate, formate, or propionate fermentation resulted in more effective dehalogenation. Reductive dehalogenation, fermentation, and sulfate, Fe(III), and Mn(IV) reduction were all exhibited within the column. Different steady-states of dehalogenation were achieved based on the concentration of substrates added, with effective transformation to ETH obtained when ample electron donor equivalents were provided. Most of the metabolic reducing equivalents were channeled to sulfate, Fe(III), and Mn(IV) reduction. When similar electron reducing equivalents were added, the most effective dehalogenation was achieved with formate, with 14% of the electron equivalents going towards dehalogenation reactions, compared to 6.5% for lactate and 9.6% for propionate. Effective dehalogenation was maintained over 1000 days of column operation. Over 90% of electron equivalents added could be accounted for by the different electron accepting processes in the column, with 50% associated with soluble and precipitated Fe(II) and Mn(II). Bulk Fe(III) and Mn(IV) reduction was rather associated with lactate and propionate addition than formate addition. Sulfate reduction was a competing electron acceptor reaction with all three electron donors. DNA was extracted from solid coupon samples obtained during the course of the experiment and analyzed using 16S rRNA gene clone libraries and quantitative PCR. Lactate and propionate addition resulted in a significant increase in Geobacter, Spirochaetes, and Desulfitobacterium phylotypes relative to "Dehalococcoides" when compared to formate addition. Results from the molecular biological analyses support chemical observations that a greater percentage of the electron donor addition was channeled to Fe(III) reduction when lactate and propionate were added compared to formate, and formate was more effective than lactate in supporting dehalogenation. The results demonstrate the importance of electron donor selection and competing electron acceptor reactions when implementing reductive dehalogenation remediation technologies. PMID- 20202716 TI - [Intraocular lens and bacterial adhesion: influence of the environmental factors, the characteristics of the bacteria, and the target material surface]. AB - Adhesion of bacteria to intraocular lenses is an important step in the pathogenesis of postoperative endophthalmitis. It can be described as a two-phase process including an initial, instantaneous, and reversible phase followed by a time-dependant and irreversible molecular and cellular phase. The binding of bacteria is affected by many factors including environmental factors such as medium composition, presence of proteins and flow conditions, the bacterial cell surface characteristics, and the material's surface properties. This article reviews all these factors affecting the adhesion of bacteria to intraocular lenses. A better understanding of these mechanisms would make it possible to reduce the bacterial adhesion process and thus could help decrease the incidence of postoperative endophthalmitis. PMID- 20202717 TI - Short course antibiotic therapy for Gram-negative hospital-acquired pneumonia in the critically ill. AB - Hospital-acquired pneumonia (HAP) is a common cause of morbidity and mortality in the critically ill, yet the optimal duration of antibiotic therapy is unknown. Too short a course may lead to treatment failure, whereas too long a course may lead to increased antibiotic resistance, antibiotic-related morbidity and increased costs. Standard duration of antibiotic therapy for Gram-negative (GN )HAP at our institution is 5 days, significantly shorter than advocated in many current guidelines. We performed a retrospective review of all cases of GN-HAP on our critical care unit fulfilling clinical and microbiological criteria to investigate recurrence rate and mortality following short course antibiotic therapy. Seventy-nine eligible patients with GN-HAP were identified. Of these, 79% were receiving mechanical respiratory support at diagnosis; 42% had GN-HAP due to non-fermenting Gram-negative bacilli (NF-GNB) and 72% were treated with the recommended 5 day course of antibiotics. Two patients had clear evidence of non-resolution of pneumonia after 5 days of therapy. Overall recurrence rate was 14%, with relapse rates significantly higher among patients with NF-GNB when compared to patients with other Gram-negative organisms (17% vs 2%; P=0.03). The overall recurrence rate was no higher than rates reported in earlier studies (17 41%). Critical care mortality (34.2%) was also not in excess of previously reported values (18-57%). In this limited study, use of a 5 day course of appropriate antibiotics for GN-HAP does not appear to increase risk of recurrence or mortality when pneumonia resolution has been achieved prior to the cessation of therapy. PMID- 20202718 TI - Evidence-based emergency medicine: clinical synopsis. Do antiviral medications improve recovery in patients with Bell's palsy? PMID- 20202719 TI - Cell phone cardiopulmonary resuscitation: audio instructions when needed by lay rescuers: a randomized, controlled trial. AB - STUDY OBJECTIVE: Given the ubiquitous presence of cellular telephones, we seek to evaluate the extent to which prerecorded audio cardiopulmonary resuscitation (CPR) instructions delivered by a cell telephone will improve the quality of CPR provided by untrained and trained lay rescuers. METHODS: We randomly assigned both previously CPR trained and untrained volunteers to perform CPR on a manikin for 3 minutes with or without audio assistance from a cell telephone programmed to provide CPR instructions. We measured CPR quality metrics-pauses (ie, no flow time), compression rate (minute), depth (millimeters), and hand placement (percentage correct)-across the 4 groups defined by being either CPR trained or untrained and receiving or not receiving cell telephone CPR instructions. RESULTS: There was no difference in CPR measures for participants who had or had not received previous CPR training. Participants using the cell telephone aid performed better compression rate (100/minute [95% confidence interval (CI) 97 to 103/minute] versus 44/minute [95% CI 38 to 50/minute]), compression depth (41 mm [95% CI 38 to 44 mm] versus 31 mm [95% CI 28 to 34 mm]), hand placement (97% [95% CI 94% to 100%] versus 75% [95% CI 68% to 83%] correct), and fewer pauses (74 seconds [95% CI 72 to 76 seconds] versus 89 seconds [95% CI 80 to 98 seconds]) compared with participants without the cell telephone aid. CONCLUSION: A simple audio program that can be made available for cell telephones increases the quality of bystander CPR in a manikin simulation. PMID- 20202720 TI - Improved glottic exposure with the Video Macintosh Laryngoscope in adult emergency department tracheal intubations. AB - STUDY OBJECTIVE: Glottic visualization with video is superior to direct laryngoscopy in controlled operating room studies. However, glottic exposure with video laryngoscopy has not been evaluated in the emergency department (ED) setting, where blood, secretions, poor patient positioning, and physiologic derangement can complicate laryngoscopy. We measure the difference in glottic visualization with video versus direct laryngoscopy. METHODS: We prospectively studied a convenience sample of tracheal intubations at 2 academic EDs. We performed laryngoscopy with the Karl Storz Video Macintosh Laryngoscope, which can be used for conventional direct laryngoscopy, as well as video laryngoscopy. We rated glottic visualization with the Cormack-Lehane (C-L) Scale, defining "good" visualization as C-L I or II and "poor" visualization as C-L III or IV. We compared glottic exposure between direct and video laryngoscopy, determining the proportion of poor direct visualizations improved to good visualization with video laryngoscopy. We also determined the proportion of good direct visualizations worsened to poor visualization by video laryngoscopy. RESULTS: We report data on 198 patients, including 146 (74%) medical, 51 (26%) trauma, and 1 (0.51%) unknown indications. All were tracheally intubated by emergency physicians. Postgraduate year 3 or 4 residents performed 102 (52.3%) of the laryngoscopies, postgraduate year 2 residents performed 60 (30.8%), interns performed 20 (10.3%), attending physicians performed 9 (4.6%), and operator experience and specialty were not reported in 4. Overall, good visualization (C-L grade I or II) was attained in 158 direct (80%) versus 185 video laryngoscopies (93%; McNemar's P<.0001). Of the 40 patients with poor glottic exposure on direct laryngoscopy, video laryngoscopy improved the view in 31 (78%; 95% confidence interval 62% to 89%). Of the 158 patients with good glottic view on direct laryngoscopy, video laryngoscopy worsened the view in 4 (3%; 95% confidence interval 0.7% to 6%). CONCLUSION: Video laryngoscopy affords more grade I and II views than direct laryngoscopy and improves glottic exposure in most patients with poor direct glottic visualization. In a small proportion of cases, glottic exposure is worse with video than direct laryngoscopy. PMID- 20202721 TI - [Recommendations of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) on the prevention of invasive fungal infection due to filamentous fungi]. AB - Invasive fungal infections (IFI) due to filamentous fungi still have high rates of mortality associated with the difficulties of early detection of the infection and their therapeutic limitations. Consequently, a useful approach is to prevent patients at risk of fungal infection from getting in contact with conidia of Aspergillus and other mould species. This document describes the recommendations to prevent IFI due to filamentous fungi, prepared by Spanish experts from different medical and professional fields. The paper reviews the incidence of the IFI in different risk populations and the questions related to environmental measures of prevention, control of hospital infections, additional procedures for prevention, prevention of IFI outside hospitals, as well as antifungal prophylaxis. PMID- 20202722 TI - Carbonic anhydrase inhibitors: synthesis and inhibition of the human cytosolic isozymes I and II and transmembrane isozymes IX, XII (cancer-associated) and XIV with 4-substituted 3-pyridinesulfonamides. AB - A series of novel 4-substituted-3-pyridinesulfonamides (2-27 and 31-33) have been synthesized and investigated as inhibitors of five isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), that is, the cytosolic, ubiquitous isozymes CA I and II, and transmembrane isozymes CA IX, XII (cancer-associated) and XIV. Against the human isozymes hCA I, the new compounds showed inhibition constants in the range of 0.078-11.7 microM, against hCA II in the range of 9.9-140 nM, against hCA IX in the range of 4.6-313 nM, against hCA XII in the range of 3.4 21.6 nM, and against hCA XIV in the range of 50.9-160 nM, respectively. Compounds 4, 6, 7, 9, 11-14, 19, 20, 22-24, 26, 27, 31 and 32 showed excellent hCA IX inhibitory efficacy, with inhibition constants of 4.6-12.0 nM, being much more effective as compared to the clinically used sulfonamides AAZ, MZA, EZA, DCP and IND. 4-[N'-(6-chloro-7-cyano-1,1-dioxo-1,4,2-benzodithiazin-3-yl)hydrazino]-3 pyridinesulfonamide (31) is the prominent of the compounds due to its remarkable inhibitory activity toward hCA I (KIs=0.078 microM), hCA IX (KIs=7.2 nM) and hCA XII (KIs=3.4 nM). PMID- 20202723 TI - Synthesis and evaluation of 9-benzylideneamino derivatives of homocamptothecin as potent inhibitors of DNA topoisomerase I. AB - A series of novel 9-benzylideneamino derivatives of homocamptothecin were synthesized via Friedlaender cyclization from our obtained intermediate 5. All the compounds were evaluated for in vitro cytotoxicity against three cancer cell lines (A549, LOVO and MDA-MB-435). Most of these derivatives possessed potent growth inhibitory effect on all the tested cell lines and four compounds (6d, 6f, 6i, 6k) showed higher inhibitory activities with the IC50 values of 2.3 nM-9.8 nM against breast cancer cell than topotecan. As compared to CPT, compound 6f revealed higher topoisomerase I inhibitory activity. PMID- 20202724 TI - Novel bis-phenanthridine derivatives with easily tunable linkers, study of their interactions with DNA and screening of antiproliferative activity. AB - Series of novel peptide-bridged bis-phenanthridine derivatives as well as corresponding monomers were prepared by solid phase peptide synthesis, which allowed easy and fast tuning of compound properties. Interactions of new derivatives with double stranded DNA were strongly structure-dependent, among which the most interesting is bis-phenanthridine derivative forming intramolecular excimer, with specific fluorescence band sensitive to the pH as well as on the interactions with ds-DNA. Moreover, at variance to commonly high cytotoxic effects of phenanthridine derivatives, here studied monomeric as well as bis-phenanthridine derivatives exhibited negligible antiproliferative activity on a panel of human cell lines, which makes them promising lead compounds for development of new spectrophotometric markers. PMID- 20202725 TI - Europe's forgotten cancer, what is OMF surgery's role? AB - We outline the principles of management of skin cancers, and highlight the role of oral and maxillofacial surgery. PMID- 20202726 TI - Ridge augmentation with the coronoid-temporalis muscle pedicled flap. PMID- 20202727 TI - Low accessibility and chemical activity of PAHs restrict bioremediation and risk of exposure in a manufactured gas plant soil. AB - Composting of manufactured gas plant soil by a commercial enterprise had removed most of its polycyclic aromatic hydrocarbons (PAHs), but concentrations remained above regulatory threshold levels. Several amendments and treatments were first tested to restart the PAH degradation, albeit with little success. The working hypothesis was then that PAHs were "stuck" due to strong sorption to black carbon. Accessibility was measured with cyclodextrin extractions and on average only 4% of the PAHs were accessible. Chemical activity of the PAHs was measured by equilibrium sampling, which confirmed a low exposure level. These results are consistent with strong sorption to black carbon (BC), which constituted 59% of the total organic carbon. Composting failed to remove the PAHs, but it succeeded to minimize PAH accessibility and chemical activity. This adds to accumulating evidence that current regulatory thresholds based on bulk concentrations are questionable and alternative approaches probing actual risk should be considered. PMID- 20202728 TI - Hemoglobin A(1c) and fructosamine for assessing glycemic control in diabetic patients with CKD stages 3 and 4. AB - BACKGROUND: Hemoglobin A(1c) (HbA(1c)) and fructosamine can be used to monitor glycemic control in diabetic patients with normal kidney function, but their validity in patients with chronic kidney disease (CKD) has not been evaluated. In this study, we evaluated the correlation and accuracy of these 2 measures of glycemic control in type 2 diabetic patients with CKD stages 3-4. STUDY DESIGN: Diagnostic test study. SETTING & PARTICIPANTS: Type 2 diabetic patients with normal (n = 30) and abnormal kidney function (n = 30) were recruited in Taipei Veterans General Hospital, Taiwan. INDEX TESTS: HbA(1c) and fructosamine. REFERENCE TEST: Self-monitoring of blood glucose levels. MEASUREMENTS: Blood glucose measurements consisted of 6 preprandial, 6 postprandial, and 2 bedtime assessments in a week with a cycle of 4-week intervals for 12 weeks. RESULTS: Correlation coefficients between HbA(1c) level or fructosamine-albumin ratio and mean blood glucose levels were 0.836 and 0.645 in participants with normal kidney function and 0.813 and 0.649 in participants with CKD stages 3-4, respectively. In patients with CKD stages 3-4, mean blood glucose levels in weeks 1-12 were 21.9 mg/dL (95% CI, 11.6-32.5) higher than estimated average glucose (eAG) levels calculated from HbA(1c) levels in participants with normal kidney function. In patients with CKD stages 3-4, mean blood glucose levels in weeks 10-12 were 15.5 mg/dL (95% CI, 5.2-30.5) higher than eAG levels calculated from fructosamine levels in participants with normal kidney function, but without statistical significance when eAG calculated from fructosamine level was corrected for serum albumin level (difference of 5.6 mg/dL; 95% CI, -8.6 to 19.8). LIMITATIONS: Relatively small number of participants with limited amount of blood glucose measurement data. CONCLUSION: Our data show that eAG calculated from HbA(1c) and fructosamine levels might underestimate mean blood glucose levels in patients with CKD stages 3-4. References ranges may need to be modified when interpreting results of measurements of glycemic control in type 2 diabetic patients with CKD. PMID- 20202729 TI - Pulse cyclophosphamide therapy and clinical remission in atypical hemolytic uremic syndrome with anti-complement factor H autoantibodies. AB - We report 3 children with atypical hemolytic uremic syndrome associated with anti complement factor H (CFH) autoantibodies who presented with sustained remission with low antibody titers and normal kidney function after plasma exchanges (PEs) and cyclophosphamide pulses. The 3 children initially presented with acute vomiting, fatigue, gross hematuria, hypertension, hemolytic anemia, thrombocytopenia, nephrotic syndrome, and acute kidney injury. C3 levels were normal in patients 1 and 3 and low in patient 2 (0.376 mg/mL [0.376 g/L]). CFH antibody titers were increased (15,000 to > 32,000 arbitrary units [AU]). Patient 1, an 11-year-old boy, was treated with 12 PEs, leading to a decrease in CFH antibody titer (to 800 AU). A first relapse 1 month later was treated with 6 PEs and 4 rituximab infusions. A second relapse 3 months later required 5 PEs, and the patient received oral steroids (0.5 mg/d/kg body weight) and 5 cyclophosphamide pulses (1 g/1.73 m(2)), leading to sustained remission with normal kidney function (estimated glomerular filtration rate [eGFR], 120 mL/min/1.73 m(2) [2.0 mL/s/1.73 m(2)]) and a stable decrease in CFH antibody titer (to 2,000 AU) 3 years later. Patient 2, a 5-year-old boy, required dialysis therapy for 2 weeks. He received 3 plasma infusions without remission. Six PEs associated with 2 cyclophosphamide pulses (0.5 g/1.73 m(2)) and steroids (1 mg/d/kg body weight) led to rapid remission, with eGFR of 107 mL/min/1.73 m(2) [1.78 mL/s/1.73 m(2)] and a prolonged decrease in CFH antibody titer after 15 months (1,300 AU). Patient 3, a 16-month-old boy, was treated with oral steroids (1 mg/d/kg body weight), 2 PEs, and 2 cyclophosphamide pulses (0.5 g/1.73 m(2)), resulting in a stable decrease in CFH antibody titer to 276 AU. Kidney function quickly normalized (eGFR, 110 mL/min/1.73 m(2) [1.83 mL/s/1.73 m(2)]) and has remained normal after 14 months. All 3 patients show a homozygous deletion mutation of the CFHR1 and CFHR3 genes. Cyclophosphamide pulses with PE may lead to a prolonged decrease in CFH antibody titers and a favorable outcome of atypical hemolytic uremic syndrome and kidney function. PMID- 20202730 TI - "He's a good-looking chap aint he?": narrative and visualisations of self in body dysmorphic disorder. AB - Body Dysmorphic Disorder (BDD) is a condition marked by a distressing preoccupation with an imaginary or minor defect in a facial feature or a localised part of the body. However, the link between such excessive preoccupation and perceptions of self throughout the life course has rarely been examined. The aim of this study was to examine narrative accounts of the self across different life-time periods. Eleven participants diagnosed with BDD in England were recruited from the National Obsessive Compulsive Disorder (OCD) clinic and a BDD self-help group. In the context of a semi-structured interview participants presented photographs of themselves across a variety of time periods and drew a self-portrait to prompt memory and generate discussion. Transcribed interviews were analysed using Michele Crossley's (2000) narrative analytic approach. The findings suggest that the majority of participants perceived their past self as excessively attractive. Rather than believing that the alteration of their current appearance would rid them of BDD, participants indicated that a return to their former infantile and pure self that was devoid of blemish, defects and emotional responsibility would provide comfort. These findings indicate that the difficulties associated with appearance are less to do with beauty per se, but are more likely associated with narratives of loss, aging and decline and death. PMID- 20202731 TI - Prospective risk analysis prior to retrospective incident reporting and analysis as a means to enhance incident reporting behaviour: a quasi-experimental field study. AB - Hospitals can apply prospective and retrospective methods to reduce the large number of medical errors. Retrospective methods are used to identify errors after they occur and to facilitate learning. Prospective methods aim to determine, assess and minimise risks before incidents happen. This paper questions whether the order of implementation of those two methods influences the resultant impact on incident reporting behaviour. From November 2007 until June 2008, twelve wards of two Dutch general hospitals participated in a quasi-experimental reversed treatment non-equivalent control group design. The six units of Hospital 1 first conducted a prospective analysis, after which a sophisticated incident reporting and analysis system was implemented. On the six units of Hospital 2 the two methods were implemented in reverse order. Data from the incident reporting and analysis system and from a questionnaire were used to assess between-hospital differences regarding the number of reported incidents, the spectrum of reported incident types, and the profession of reporters. The results show that carrying out a prospective analysis first can improve incident reporting behaviour in terms of a wider spectrum of reported incident types and a larger proportion of incidents reported by doctors. However, the proposed order does not necessarily yield a larger number of reported incidents. This study fills an important gap in safety management research regarding the order of the implementation of prospective and retrospective methods, and contributes to literature on incident reporting. This research also builds on the network theory of social contagion. The results might indicate that health care employees can disseminate their risk perceptions through communication with their direct colleagues. PMID- 20202732 TI - Hydrodynamic ultrasonic sinus floor elevation--an experimental study in sheep. AB - PURPOSE: The aim of the present study was to evaluate the pressure forces appearing to elevate the sinus membrane by comparing the hydraulic and pneumatic pressure. Also, the relation between the time and volume of the applied liquid and the achieved lift-volume were determined. MATERIALS AND METHODS: A total of 190 fresh, half sheep heads were used for the present investigation. An ultrasound surgical device (Piezotome; Acteon, Bordeaux, France) was tested to evaluate the pressure increase at different flow rates. The elevation volume at different flow rates and activation times of the ultrasound hand piece were measured. RESULTS: To detach the sinus membrane pneumatically from the sinus floor, a mean average pressure of 29.54 millibars was required. Using the hydraulic technique, a mean average pressure of 19.8 millibars was determined. Comparing the different flow rates, the elevated volume increased to 0.52 mL when a flow of 60 mL/minute was used. Using an activation time of 20 seconds, a lifted volume of 3.92 mL could be measured on average. If the flow was set to a maximum of 60 mL/minute, the created volume increased to 5.58 mL. A comparison using the chi(2) test showed a significant correlation (P = .03) between the application time and the created sinus lift volume. Even at high flow rates of 60 mL/minute of the activated Piezotome for a 20-second period, no rupture of the sinus membrane of the sheep heads occurred in 190 experiments. CONCLUSION: From these results, we have concluded that hydrodynamic ultrasound could be used as an alternative method for sinus floor elevations of any size and volume with a mere 3-mm-diameter transcrestal approach, if findings from clinical investigations confirm the results of the present animal study. PMID- 20202733 TI - Bell's palsy and dental infection: a case report and possible etiology. PMID- 20202734 TI - Cell response of titanium implant with a roughened surface containing titanium hydride: an in vitro study. AB - PURPOSE: The purpose of this study was to investigate the effect of surface chemistry of a sandblasted and acid-etched implant (with and without titanium hydride [TiH(2)]) on cell attachment, proliferation, and differentiation of preosteoblasts (MC3T3-E1). MATERIALS AND METHODS: Sandblasted and dual acid etched titanium discs comprised the test group, whereas sandblasted, acid-etched, and heat-treated discs comprised the control group. Both groups' discs were sent for surface characterization. MC3T3-E1 cells were cultured on these 2 groups' discs, and then cell attachment, cell proliferation, and cell differentiation were analyzed. RESULTS: Scanning electron microscope analysis showed that the titanium discs in the 2 groups shared the same surface topography; however, x-ray diffraction examination showed that the TiH(2) diffractions only appeared in the test group. Cell attachment and cell proliferation were much better in the test group than in the control group at all time points investigated (P < .05). The expressions of alkaline phosphatase and osteocalcin were significantly higher in the test group than in the control group for both protein and transcription level at every time point (P < .05 or P < .01). CONCLUSIONS: These results suggested that surface chemistry played a significant role in cell response to the sandblasted and acid-etched surface and the presence of TiH(2) might promote the attachment, proliferation, and differentiation of preosteoblasts. PMID- 20202735 TI - Change of lip cant after bimaxillary orthognathic surgery. AB - PURPOSE: The purpose of the present study was to investigate the correlations between lip cant change after bimaxillary orthognathic surgery and the ratio of lip cant change and occlusal cant change after surgery. PATIENTS AND METHODS: The subjects for the present study were obtained from a group of 25 patients who underwent bimaxillary orthognathic surgery for occlusal cant correction at the Department of Oral and Maxillofacial Surgery, Samsung Medical Center (Seoul, South Korea) from January 2000 to December 2005. To be included, a patient's chart had to contain a resting frontal facial photograph in the natural head position and a corresponding posteroanterior cephalogram in occlusion on the same day before surgery and postoperatively 6 months later. The lip cant change was assessed by the angle of each labial commissure and the bi-pupillary reference line. The occlusal canting change in the frontal plane was assessed with the angle between each maxillary first molar occlusal surface and the bi frontozygomatic suture reference line. RESULTS: With the angular measurement, the average occlusal cant change was 3.09 degrees (standard deviation [SD] 1.05 degrees), and the average lip cant change was 1.56 degrees (SD 1.05 degrees). With the linear measurement, the average occlusal cant change was 2.41 mm (SD 2.75), and the average lip cant change was 1.18 mm (SD 0.43). The lip cant correction ratio to occlusal cant correction was 51.5% +/- 8.4% in the angular measurement and 48.8% +/- 9.1% in the linear measurement. With Pearson's correlation analysis, the Pearson correlation coefficient was 0.869 for the angular measurement and 0.887 for the linear measurement. A high correlation was shown between the occlusal cant change and lip cant change. CONCLUSIONS: Bimaxillary orthognathic surgery can correct lip cant and occlusal cant. The average amount of lip cant correction and occlusal cant correction in our study was 51.5% +/- 8.4% and 48.8% +/- 9.1%, respectively. PMID- 20202736 TI - Self-association of Zn-insulin at neutral pH: investigation by concentration gradient--static and dynamic light scattering. AB - Equilibrium self-association of Zn-insulin at pH 7.0 was characterized over the range 0.3-5mg/mL by simultaneous measurement of static and dynamic light scattering. Analysis of static light scattering yielded a concentration-dependent weight-average molecular weight, and analysis of dynamic light scattering yielded a concentration-dependent intensity-average diffusion coefficient. The concentration dependence of both quantities may be accounted for to within experimental precision by a simple model, according to which the basic structural unit of Zn-insulin at concentrations exceeding 0.3mg/mL is a hexamer H. With increasing total protein concentration, hexameric protomers may self-associate in accordance with an isodesmic scheme in which a protomer may add to any prexisting oligomer H(n) to form H(n+1) with an invariant stepwise equilibrium association constant. PMID- 20202737 TI - pH-dependent self-association of zinc-free insulin characterized by concentration gradient static light scattering. AB - Insulin self-association at pH 1.85, 1.95, 3.0, 7.2, 8.0 and 10 was studied via composition gradient light scattering (CG-SLS). At pH 1.95 in acetic acid, insulin was found to exist as a monomer, and in pH 1.85 HCl as a dimer. At pH values of 3.0-8.0, the dependence of scattering intensity upon total insulin concentration at concentrations of up to 1.5mg/mL may be quantitatively accounted for by a simple isodesmic association equilibrium scheme requiring only a single association constant for addition of monomer to monomer or any oligomer. At pH 10, the association constant for addition of monomer to monomer was found to be smaller than the association constant for addition of monomer to all higher oligomers by a factor of approximately five. The isodesmic association scheme was also found to quantitatively account for the concentration dependence of the weight-average molecular weight derived from previously published sedimentation equilibrium measurements made at pH 7.0, and the best-fit value of the stepwise equilibrium constant obtained therefrom was in excellent agreement with that obtained from analysis of the light scattering data obtained at pH 7.2. PMID- 20202739 TI - Assessment of the predictive quality of simple indicator approaches for nitrate leaching from agricultural fields. AB - Diffuse N losses from agriculture are a major cause of excessive nitrate concentrations in surface and groundwaters. Leaching through the soil is the main pathway of nitrate loss. For environmental management, an anticipatory assessment and monitoring of nitrate leaching risk by indicator (index) approaches is increasingly being used. Although complex Nitrogen Loss Indicator (NLI) approaches may provide more information, relatively simple NLIs may have advantages in many practical situations, for instance, when data availability is restricted. In this study, we tested four simple NLIs to assess their predictive properties: 1. N balance (Nbal); 2. Exchange frequency of soil solution (EF); 3. Potential nitrate concentration in leachate (PNCL); 4. A composite NLI (balance exchange frequency product, BEP). Field data of nitrate leaching from two sites in northeast Germany along with published data from several sites in Germany, Scotland and the USA were utilized. Nbal proved to be a relatively poor indicator of Nloss for the time frame of one year, whereas its prediction accuracy improved for longterm-averaged data. Correlation between calculated EF and experimental data was high for single-year data, whereas it was lower for longterm-averaged data. PNCL gave no significant correlations with measured data and high deviations. The results for BEP were intermediate between those for Nbal and EF. The results suggest that the use of EF is appropriate for assessing N leaching loss for single-year data and specific sites with comparable N input and management practices, whereas for longterm-averaged data, Nbal is better suited. BEP is an appropriate NLI both for single year and longterm data which accounts for source and transport factors and thus is more flexible than source-based Nbal and transport-based EF. However, such simplified NLIs have limitations: 1. The N cycle is not covered completely; 2. Processes in the vadose zone and the aquifer are neglected, 3. Assessment of management factors is restricted. PMID- 20202738 TI - Spectroscopic study on the binding of porphyrins to (G(4)T(4)G(4))4 parallel G quadruplex. AB - The binding mode and stoichiometry of the cationic porphyrin TMPyP4 to G quadruplex structure are still controversial to date, mainly due to the intricate polymorphism of G-rich sequences in the different conditions of solution. Here in the presence of the molecular crowding agent PEG, the binding interaction of TMPyP4 and another porphyrin derivative TPrPyP4 with four-stranded parallel (G(4)T(4)G(4))4 G-quadruplex was studied systematically using circular dichroism, visible absorption titration, and steady-state and time-resolved fluorescence spectroscopies. The results show that each (G(4)T(4)G(4))4 molecule is able to bind four TMPyP4 or TPrPyP4 molecules. Two types of independent and nonequivalent binding sites with the higher and lower binding affinity are confirmed, and the stronger and weaker binding constants are 2.74 x 10(8) and 8.21 x 10(5)M(-1) for (G(4)T(4)G(4))4-TMPyP4, 2.05 x 10(8) and 1.05 x 10(6)M(-1) for (G(4)T(4)G(4))4 TPrPyP4, respectively. The two porphyrin molecules stack on the two ends of G quadruplex with the higher binding affinity, another two porphyrins bind weakly to the two external grooves. PMID- 20202740 TI - Novel anti-CD20 antibody TGLA with enhanced antibody-dependent cell-mediated cytotoxicity mediates potent anti-lymphoma activity. AB - Rituximab is the first anti-cancer antibody approved by the FDA for the treatment of B-cell lymphoma. However, its efficacy remains variable and often modest. Some patients are initially unresponsive to rituximab or later develop resistance to it, and require alternative therapies. Rituximab activity has been thought to involve antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and apoptosis. Present studies suggest that the patients unresponsive to rituximab may be helped with other CD20 antibodies with enhanced activities. In this study, we characterized a novel anti-CD20 chimeric antibody, TGLA, which binds to various B-cell lines specially and shares an epitope with rituximab. TGLA shows equal activities with rituximab, such as CDC, cell growth arrest and so on. Interestingly, TGLA also shows significant ADCC activity. Immunotherapeutic studies further show that TGLA is far more effective in delaying tumor growth than rituximab. These findings suggest that the ADCC enhanced anti-CD20 antibody TGLA might be an alternative therapeutic agent for B cell lymphoma. PMID- 20202741 TI - Inhibition of EGFR signaling augments oridonin-induced apoptosis in human laryngeal cancer cells via enhancing oxidative stress coincident with activation of both the intrinsic and extrinsic apoptotic pathways. AB - Oridonin, a bioactive diterpenoid isolated from Rabdosia rubescens, has been reported to have anti-tumor effects, while the epidermal growth factor receptor (EGFR) signal pathway has been reported to play a vital role in the biological progression of several tumors and to be a target for therapeutic intervention. In this work, we show that inhibition of EGFR with tyrphostin AG1478 enhances oridonin-induced cell death in human laryngeal cancer cells HEp-2, a cell line characterized by EGFR gene amplification. The enhanced apoptotic effect correlates with high expression and activation of Bax, FADD, caspase-8 as well as caspase-3 and decreased protein levels of Bcl(2) and SIRT1, suggesting that both the extrinsic and intrinsic apoptosis pathways are involved in the apoptotic processes. However, treatment with oridonin and AG1478 greatly enhances nuclear translocation of apoptosis inducing factor (AIF) without caspase-9 activation, indicating that the apoptosis occurs via a caspase-9-independent mitochondrial pathway. Here, it is the active form of caspase-8 but not caspase-9 that activates downstream effector caspase-3, resulting in the cleavage of critical cellular proteins and apoptosis. Furthermore, the combined use of AG1478 and oridonin augments the production of reactive oxygen species (ROS). Incubation of cells with N-Acetylcysteine (NAC) attenuates the apoptosis and the mitochondrial membrane potential (Deltapsim) disruption induced by the combination of oridonin and AG1478, which indicates that ROS plays a pivotal role in cell death. In conclusion, targeting EGFR combined with other conventional pro-apoptotic drugs should be a potentially very effective anti-neoplastic therapy for laryngeal cancer. PMID- 20202742 TI - Extracellular ATP enhances in vitro invasion of prostate cancer cells by activating Rho GTPase and upregulating MMPs expression. AB - We previously found that in addition to anti-proliferation function, extracellular ATP had a pro-invasion effect on prostate cancer cells, and probably serves as an important regulator of invasion in local microenvironment. However, the underlying mechanism remains unclear. In this study, we demonstrated that ATP increased the motility of prostate cancer cells, and promoted formation of lamellipodia and filopodia. We also found that ATP induced activation of Rac1 and Cdc42, and promoted expression of MMP-3 and MMP-13. These data suggest that extracellular ATP enhances the invasion of prostate cancer cells by activating Rho GTPases Rac1 and Cdc42 and upregulating MMPs expression. PMID- 20202743 TI - Alcohol consumption promotes mammary tumor growth and insulin sensitivity. AB - Epidemiological data show that in women, alcohol has a beneficial effect by increasing insulin sensitivity but also a deleterious effect by increasing breast cancer risk. These effects have not been shown concurrently in an animal model of breast cancer. Our objective is to identify a mouse model of breast cancer whereby alcohol increases insulin sensitivity and promotes mammary tumorigenesis. Our results from the glucose tolerance test and the homeostasis model assessment show that alcohol consumption improved insulin sensitivity. However, alcohol consuming mice developed larger mammary tumors and developed them earlier than water-consuming mice. In vitro results showed that alcohol exposure increased the invasiveness of breast cancer cells in a dose-dependent manner. Thus, this animal model, an in vitro model of breast cancer, may be used to elucidate the mechanism(s) by which alcohol affects breast cancer. PMID- 20202745 TI - Overexpression of LAPTM4B-35 promotes growth and metastasis of hepatocellular carcinoma in vitro and in vivo. AB - LAPTM4B-35, encoded by Lysosomal protein transmembrane 4 beta (LAPTM4B) is over expressed in more than 71% of hepatocellular carcinomas (HCCs) and associated with prognosis of the patients. But the exact role and molecular mechanism in HCC have not been determined. In this study, we explored the effects and mechanisms of LAPTM4B-35 on tumor growth and metastasis in vitro and in vivo by overexpression and depletion of LAPTM4B in HCC HepG2 and Bel7402 cells. These findings suggest that overexpression of LAPTM4B-35 plays a critical role in the growth and metastasis of HCC, and LAPTM4B-35 may therefore be a therapeutic target for HCC. PMID- 20202744 TI - Therapeutic effect of MIP-1alpha-recruited dendritic cells on preestablished solid and metastatic tumors. AB - We previously found that dendritic cell (DC) precursors could be recruited into the peripheral blood of B6 mice by administration of macrophage inflammatory protein (MIP)-1alpha. These MIP-1alpha-recruited DCs could induce anti-tumor protective immunity when pulsed with tumor cell lysate. In this study, MIP-1alpha recruited DCs could not effectively suppress preestablished tumor when pulsed with B16 tumor cell lysate. However, inoculation with these DCs expressing MAGE-1 induced an anti-tumor immunity against preestablished solid and metastatic tumor from B16-MAGE-1 cells. These MIP-1alpha-recruited DCs expressed higher level of CCR7 and displayed a more significant chemotactic response toward secondary lymphoid tissue. Therefore, they are superior in the induction of cytotoxic T lymphocytes and the inhibition of tumor development and metastasis than bone marrow-derived DCs. This study established a novel approach to the treatment of preestablished solid and metastatic tumors using MIP-1alpha-recruited DCs transduced with tumor antigen gene. PMID- 20202746 TI - A characterization of the antioxidant enzyme activity and reproductive toxicity in male rats following sub-chronic exposure to areca nut extracts. AB - In the present study, areca nut extracts (ANE) administered to male rats by gavage at a dose of 100mg/kg/day for a period of 15, 30, or 45 days resulted in signs of reproductive toxicity. ANE administration resulted in a significant decline (30-57% in epididymal sperm count and 27-61% in sperm motility) as well as substantial abnormalities in sperm morphology. Significant variances in activities of antioxidant enzymes were also observed. Malondialdehyde (MDA) levels, which represent the level of lipid peroxidation, increased by 16-188% and levels of sialic acid decreased by 2-46% compared with that in controls. These results indicate that ANE induced spermatogenic damage, as indicated by a decrease in sperm counts and sperm motility as well as the activity of antioxidant enzymes, an increase in sperm abnormalities, and alterations in sialic acid and MDA levels. Such effects reflect that ANE administration resulted in reactive oxygen species (ROS)-induced oxidative stress in the testis, cauda epididymis, and sperm of male rats. PMID- 20202747 TI - Kinetics and mechanism studies of p-nitroaniline adsorption on activated carbon fibers prepared from cotton stalk by NH4H2PO4 activation and subsequent gasification with steam. AB - Activated carbon fibers (ACFs) were prepared for the removal of p-nitroaniline (PNA) from cotton stalk by chemical activation with NH(4)H(2)PO(4) and subsequent physical activation with steam. Surface properties of the prepared ACFs were performed using nitrogen adsorption, FTIR spectroscopy and SEM. The influence of contact time, solution temperature and surface property on PNA adsorption onto the prepared ACFs was investigated by conducting a series of batch adsorption experiments. The kinetic rates at different temperatures were modeled by using the Lagergren-first-order, pseudo-second-order, Morris's intraparticle diffusion and Boyd's film-diffusion models, respectively. It was found that the maximum adsorption of PNA on the ACFs was more than 510 mg/L, and over 60% adsorption occurred in first 25 min. The effect of temperature on the adsorption was related to the contacting time and the micropore structure of the adsorbents. And the increase of micropore surface area favored the adsorption process. Kinetic rates fitted the pseudo-second-order model very well. The pore diffusion played an important role in the entire adsorption period, and intraparticle diffusion was the rate-limiting step in the beginning 20 min. The Freundlich model provided a better data fitting as compared with the Langmuir model. The surface micrograph of the ACF after adsorption showed a distinct roughness with oval patterns. The results revealed that the adsorption was in part with multimolecular layers of coverage. PMID- 20202748 TI - Excess copper induces production of hydrogen peroxide in the leaf of Elsholtzia haichowensis through apoplastic and symplastic CuZn-superoxide dismutase. AB - The effects of excess copper (Cu) on the production of reactive oxygen species (ROS) and antioxidant enzyme activities in leaves of the Cu-accumulator Elsholtzia haichowensis Sun were investigated. The addition of 100 microM of copper significantly increased the accumulation of hydrogen peroxide (H(2)O(2)) and the activities of superoxide dismutase (SOD) and other antioxidant enzymes. The increase in SOD activity was attributable to an increase in apoplastic and symplastic copper-zinc superoxide dismutase (CuZn-SOD) activity. Induction of CuZn-SOD proteins was demonstrated by immunoblot analysis. This study also provides the first cytochemical evidence of an accumulation of superoxide anion in the chloroplasts of mesophyll cells, and H(2)O(2) in the mesophyll cell walls and extracellular space, as a consequence of Cu treatment. Experiments with diphenyleneiodonium as an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and N-N-diethyldithiocarbamate as an inhibitor of SOD showed that the source of H(2)O(2) in the cell wall could be, in part, NADPH oxidase. Apoplastic guaiacol peroxidase (POD) and symplastic ascorbate peroxidase (APX) activities were induced in leaves of E. haichowensis with 100 microM Cu, suggesting that apoplastic POD and symplastic APX may be important in avoiding the buildup of toxic H(2)O(2) concentrations. PMID- 20202749 TI - Growth of nanoscale nickel ferrite on carbonaceous matrix--A novel method of turning harmful particulates into a functional nanocomposite: An XAFS study. AB - Particulate matter (PM) emission from residual oil combustion typically consists of carbonaceous material accompanied by inorganic matter notably transition metal sulfates. Often a minor sulfide form is found in the coarse fraction while an oxide form is more common in the fine and ultrafine fractions. A composite comprising of nanoscale nickel ferrite dispersed on carbonaceous matrix has been obtained following liberation of metal sulfates from the fine PM--a novel method of turning harmful particulates into a functional nanocomposite without the need for elaborate preparation using expensive precursors. The nickel ferrite content in the composite varies with the Fe/Ni ratio in particulate, fuel type, and combustion condition. Such variation may lead to the composite exhibiting diverse physical behaviors. Detailed structure and cation distribution in dispersed ferrite have been studied using Fe and Ni K-edges XAFS spectroscopy. Peaks are identified in the radial structure function with specific atom pair correlations within the spinel ferrite from which the relative occupancy of the cations in the octahedral and tetrahedral sites can be discerned. The results show that Ni(II) has strong preference for the octahedral site, while Fe(III) prefers both sites which is consistent with that of an inverted spinel ferrite. PMID- 20202750 TI - Biosorption of nickel and total chromium from aqueous solution by gum kondagogu (Cochlospermum gossypium): A carbohydrate biopolymer. AB - Gum kondagogu (Cochlospermum gossypium), an exudates tree gum from India was explored for its potential to decontaminate toxic metal ions in aqueous solution. The toxic metal ions nickel and total chromium biosorption capacity of the gum kondagogu were studied in the batch experimental mode. The optimum conditions of biosorption were determined by investigating pH, contact time, and initial metal ion and biosorbent concentrations. The Freundlich and Langmuir adsorption models were used for the mathematical description of biosorption equilibrium and the data were analyzed on the basis of pseudo-second-order kinetic model. The maximum biosorption capacity of gum kondagogu as calculated by Langmuir model were found to be 50.5 mg g(-1) for nickel at pH 5.0+/-0.1 and 129.8 mg g(-1) for total chromium at pH 2.0+/-0.1, respectively. FTIR, SEM-EDXA and XPS analysis were used to evaluate the binding characteristics of gum kondagogu with metals. The experimental results demonstrate that the metal-ion interaction occurs through ion-exchange, adsorption and precipitation mechanisms. PMID- 20202751 TI - Optimization of solvent bar microextraction combined with gas chromatography for the analysis of aliphatic amines in water samples. AB - Solvent bar microextraction (SBME) combined with gas chromatography-flame ionization detector (GC-FID), was used for preconcentration and determination of some aliphatic amines in waste water samples. The effect of different variables on the extraction efficiency was studied simultaneously using an experimental design. The variables of interest in the SBME were ionic strength, organic additive effect, sodium hydroxide concentration, stirring rate and extraction time and temperature. A Plackett-Burman design was performed for screening in order to determine the significant variables affecting the extraction efficiency. Then, the significant factors were optimized by a Box-Behnken design (BBD) and the response surface equations were derived. The optimum experimental conditions were sodium chloride concentration, 20% (w/v); sodium hydroxide concentration, 1 mol L(-1); stirring rate, 700 rpm; extraction temperature, 45 degrees C; extraction time, 30 min, and without addition of acetone. Under the optimum conditions, the preconcentration factors were between 260 and 1130. The limit of detections (LODs) ranged from 0.01 microg L(-1) (for dibutylamine) to 0.06 microg L(-1) (for N-ethyldiisopropylamine). The linear dynamic ranges (LDRs) of 0.05-800 and 0.1-600 microg L(-1) were obtained for most of the analytes. The performance of the method was evaluated for extraction and determination of aliphatic amines in waste water samples in the range of microgram per liter and satisfactory results were obtained (RSDs<13.6%). PMID- 20202752 TI - Pain's policy on the spinal administration of drugs. PMID- 20202753 TI - Placebo and treatment group responses in postherpetic neuralgia vs. painful diabetic peripheral neuropathy clinical trials in the REPORT database. PMID- 20202755 TI - Novel operation mode for eliminating influence of inclination angle and friction in atomic force microscopy. AB - The accuracy of topography imaging in contact force mode of atomic force microscopy (AFM) depends on the one-to-one corresponding relationship between the cantilever deflection and the tip-sample distance, whereas such a relationship cannot be always achieved in the presence of friction and incline angle of sample surface. Recently, we have developed a novel operation mode in which we keep the van der Waals force as constant instead of the applied normal force, to eliminate the effect of inclination angle and friction on topography imaging in the contact force mode. We have improved our AFM to enable the new operation mode for validation. Comparative experiments have been performed and the results have shown that the effect of friction and inclination angle on topography imaging in contact mode of AFM can be eliminated or at least decreased effectively by working in the new operation mode we present. PMID- 20202756 TI - Higher order structure of short immunostimulatory oligonucleotides studied by atomic force microscopy. AB - Immunostimulatory CpG-DNA activates the innate immune system by binding to Toll like receptor 9. Structurally different CpG-containing oligonucleotides trigger a different type of immune response while activating the same receptor. We therefore investigated the higher order structure of two different classes of immunostimulatory CpG-DNA. Class A, which contains a partly self-complementary sequence and poly-G ends, forms duplexes and nanoparticles in salt solution, while class B, which does not contain these features and is purely linear, does not form a duplex or nanoparticles. Results obtained here by high-resolution atomic force microscopy of classes A and B CpG-DNA, reflect these differences in secondary structure. Detailed structural analysis of the atomic force microscopy topographs is presented for two different sample preparation methods. PMID- 20202754 TI - Peripheral inflammation induces tumor necrosis factor dependent AMPA receptor trafficking and Akt phosphorylation in spinal cord in addition to pain behavior. AB - In the present study, intraplantar carrageenan induced increased mechanical allodynia, phosphorylation of PKB/Akt and GluR1 ser 845 (PKA site) as well as GluR1, but not GluR2 movement into neuronal membranes. This change in membrane GluR1/GluR2 ratio is indicative of Ca(2+) permeable AMPA receptor insertion. Pain behavior was reduced and biochemical changes blocked by spinal pretreatment, but not post-treatment, with a tumor necrosis factor (TNF) antagonist, Etanercept (100microg). Pain behavior was also reduced by spinal inhibition of phosphatidylinositol 3-kinase (PI-3K) (wortmannin; 1 and 5microg) and LY294002; 50 and 100microg) and Akt (Akt inhibitor IV; 3microg). Phosphorylated Akt was found exclusively in neurons in grey matter and in oligodendrocytes in white matter. Interestingly, this increase was seen first in superficial dorsal horn and alpha-motor neurons (peak 45min) and later (peak 2h post-injection) in deep dorsal horn neurons. Akt and GluR1 phosphorylation, AMPA receptor trafficking and mechanical allodynia were all TNF dependent. Whether phosphorylation of Akt and of GluR1 are in series or in parallel or upstream of pain behavior remains to be determined. Certainly, TNF-mediated GluR1 trafficking appears to play a major role in inflammatory pain and TNF-mediated effects such as these could represent a path by which glia contribute to neuronal sensitization (spinal LTP) and pathological pain. PMID- 20202757 TI - Drift study of SU8 cantilevers in liquid and gaseous environments. AB - We present a study of the drift, in terms of cantilever deflections without probe/target interactions, of polymeric SU8 cantilevers. The drift is measured in PBS buffer (pH 7.4) and under vacuum (1mbar) conditions. We see that the cantilevers display a large drift in both environments. We believe this is because the polymer matrix absorbs liquid in one situation whereas it is being degassed in the other. An inhomogeneous expansion/contraction of the cantilever is seen because one surface of the cantilever may still have remains of the release layer from the fabrication. To further study the effect, we coat the cantilevers with a hydrophobic coating, perfluorodecyltrichlorosilane (FDTS). Fully encapsulating the SU8 cantilever greatly reduces the drift in liquid whereas a less significant change is seen in vacuum. PMID- 20202758 TI - Scanning probe microscope based Deep-Level Spectroscopy of semiconductor films. AB - Deep-Level Spectroscopy, based on transformation and analysis of capacitance or charge transients, following the excitation of the sample by voltage pulses, yields information on electrically active defects in semiconductors, hardly obtainable by other methods. Our microscope performs Isothermal Charge-Transient Spectroscopy (IQTS). It samples the transients from 2micros to tens of ms and beyond with a resolution of hundreds of electrons. By means of a small heated stage the temperature of the sample can be varied between room temperature and about 200 degrees C. From the shift of IQTS peak maxima with temperature, the activation energy and capture cross-section of defects can be obtained. We have shown that quantitative determination of concentration is possible but it requires careful analysis and simulation, since the analysed volume depends besides on the experimental conditions also on the properties of the analysed structure. PMID- 20202759 TI - The unique contribution of attitudes toward non-alcoholic drinks to the prediction of adolescents' and young adults' alcohol consumption. AB - Attitudes toward alternative behaviors, such as drinking soda instead of alcohol, might contribute to the prediction of young people's drinking behavior. The current study explored the associations between late adolescents' and young adults' attitudes toward alcoholic and non-alcoholic drinks and their alcohol consumption, and whether these associations were moderated by participants' sex, age and education level. Cross-sectional data were collected among 1012 15 to 25 year-olds. Participants completed an online questionnaire on attitudes toward alcoholic and non-alcoholic drinks, binge drinking and monthly alcohol consumption. Data were analyzed by employing structural equation modeling in Mplus. After controlling for the shared variance in both attitudes, attitudes toward alcoholic drinks were positively related and attitudes toward non alcoholic drinks were negatively related to participants' monthly alcohol use and binge drinking. Relations between attitudes towards alcoholic drinks and monthly alcohol consumption were stronger for boys than for girls and stronger for participants with intermediate education background. Relations between both attitudes and binge drinking were strongest for high educated participants. According to our data, non-alcohol attitudes provide a unique contribution to the prediction of alcohol use. PMID- 20202760 TI - Self-injury in autism as an alternate sign of catatonia: implications for electroconvulsive therapy. AB - Multiple reports show the efficacious usage of ECT for catatonia in individuals with autism. There are also a few reports showing that ECT improves self-injury in people with and without autism. In this hypothesis, self-injury in autism and other developmental disorders may be an alternate sign of catatonia, and as such an indication for electroconvulsive therapy. The issue is important because self injury occurs at an increased rate in autistic and intellectually disabled individuals, but is poorly understood and often difficult to treat with psychological and pharmacological means. Self-injury may be considered a type of stereotypy, a classic symptom of catatonia that is exquisitely responsive to electroconvulsive therapy (ECT). Historical and modern reports further support the association of self-injury, tics and catatonia. Central gamma-aminobutyric acid (GABA) dysfunction may provide an important explanatory link between autism, catatonia and self-injury. Therefore, people with autism and other developmental disorders who develop severe self-injury (with or without concomitant tics) should be assessed for catatonia, and ECT should be considered as a treatment option. Further studies of the utility of ECT as an accepted treatment for catatonia are warranted in the study of self-injury in autism. PMID- 20202761 TI - Do 5-alpha reductase inhibitors influence the severity of brain injury in men after a stroke? PMID- 20202762 TI - Rotational fluoroscopy assists in detection of intra-articular screw penetration during volar plating of the distal radius. AB - PURPOSE: Intra-articular screw penetration is one complication of volar plate fixation of distal radius fractures. This study was designed to determine the most commonly used imaging techniques and views during volar plating of distal radius fractures and to evaluate surgeons' ability to detect intra-articular screw placement on static fluoroscopic images and rotational fluoroscopy. METHODS: Active members of the American Society for Surgery of the Hand were polled regarding preferred imaging techniques (fluoroscopic vs cassette radiographs) and views (rotational fluoroscopy or static orthogonal/anatomic tilt/semipronated imaging) during volar plating of distal radius fractures. After the survey, volar locking plates were applied to 30 cadaveric distal radiuses. We intentionally penetrated a single screw into the radiocarpal joint in half of the specimens (15 arms) and intentionally did not penetrate the radiocarpal joint in the other half. Imaging (standard posteroanterior [PA] and lateral views, 11 degrees tilt PA and 22 degrees tilt lateral views, and two 360 degrees fluoroscopy movies) was performed using a custom jig. Five surgeons blinded to results reviewed randomized image sets evaluating for intra-articular screw placement. Receiver operating characteristic curves were constructed to compare the reliability of each fluoroscopic projection or movie. RESULTS: Among 696 survey respondents, 606 exclusively used fluoroscopic imaging (without cassette radiographs) and over 450 preferred either tilt images or rotational fluoroscopy to detect intra-articular screw penetration. In our cadaveric model, rotational fluoroscopy provided the highest sensitivity (93%) and specificity (96%) for the detection of intra-articular screw penetration. Rotational fluoroscopy was significantly more reliable (p<.01) than most images (standard lateral, 11 degrees PA, 22 degrees lateral, paired PA/lateral) and trended strongly toward better reliability for all remaining images (standard PA [p=.07], paired 11 degrees PA/22 degrees lateral [p=.08], and 22 degrees tilt fluoroscopy movie [p=.11]). CONCLUSIONS: Rotational fluoroscopy improves the surgeon's ability to detect intra-articular screw penetration during volar plating of the distal radius. No combination of imaging allowed detection of all intra-articular screws. A high level of suspicion for intra-articular screw penetration should be maintained during volar plating of distal radial fractures. PMID- 20202763 TI - Yersinia ruckeri genes that attenuate survival in rainbow trout (Oncorhynchus mykiss) are identified using signature-tagged mutants. AB - To identify genes that enable the enteric redmouth disease bacterium, Yersinia ruckeri, to persist in salmonid fish, 1056 signature-tagged mini-Tn5Km2 transposon mutants of a serotype 1 strain of Y. ruckeri, RS1154, were screened in rainbow trout by immersion infection. Two rounds of screening in fish identified 25 mutants that were not re-isolated from the kidney, 7 days post-infection. Six mutants were tested a third time in fish, in 1:1 competitive challenges with the parent strain; 4 failed to establish in kidney and 2 were present at low levels compared to the parent. Sequence analyses from the single transposon insertion sites in each of the 25 mutants identified genes with sequence homologies to genes for ZnuA, a periplasmic zinc-binding protein of ZnuABC transporter; the UvrY response regulator of BarA-UvrY two-component system; a PtrA protease of the insulin-degrading enzyme family; the RcpA protein of type IV bundle-forming pili; the ParA ATPase of a ParAB DNA-partitioning system; a Wzy polymerase; a polysaccharide deacetylase; a transporter belonging to the major facilitator superfamily and 7 hypothetical proteins of unknown function. The products of 5 of these mutated genes have predicted functions associated with cell surfaces or membranes, which could be important for survival of Y. ruckeri in rainbow trout, while other putative gene products could contribute to infection and invasion processes. PMID- 20202764 TI - Pathogenic potential of equine alphaherpesviruses: the importance of the mononuclear cell compartment in disease outcome. AB - Equid herpesviruses types 1 and 4 (EHV-1 and EHV-4) are closely related pathogens of horses. While both viruses can infect the upper respiratory tract, EHV-1 regularly causes systemic infection, which is only rarely observed in the case of EHV-4. Little is known about the molecular basis for this striking difference in pathogenic potential. Recently, we have started a systematic analysis of differences in the amino acid sequences of proteins involved in virus replication, more specifically entry and egress, as well as proteins involved in immune evasion. Here, we summarize our findings relevant to glycoproteins D and G (gD and gG), which share a high degree of similarity between the viruses, yet exhibit important differences. We found that both these glycoproteins appear to be involved in the conquest of the mononuclear cell compartment. While gD is involved in infection of peripheral blood mononuclear cells through an RSD motif present in EHV-1 but not EHV-4, gG is implicated in thwarting innate responses by sequestration of chemokines. Again, the activity is only present in EHV-1, more specifically in a short stretch of variable amino acids in the extracellular domain of gG. The differences in the two glycoproteins of EHV-1 and EHV-4 are discussed, as is their role in pathogenesis. In addition, hypotheses are proposed related to the other equid respiratory alphaherpesviruses, EHV-8 and EHV-9, based on the amino acid sequences of gD and gG. PMID- 20202765 TI - Sex steroids to maintain cognitive function in women after the menopause: a meta analyses of treatment trials. AB - It is still debated whether estrogen treatment after the menopause could result in improved cognitive function in women. This debate is based on many animal and cell culture data showing that estrogens can positively affect the aging brain. Observational data also show a halved risk of dementia in women who took estrogens around the age of menopause. However, large treatment trials have shown negative effects of long-term treatment with estrogens in older women. The present meta-analyses included 36 randomised treatment trials and tested various hypotheses which have been developed to attempt to explain discrepant data. Results indicated that, contrary to expectations, age of women and duration of time elapsed when treatment was initiated since menopause ('window of opportunity' hypothesis) did not significantly affect treatment outcome, nor did it matter whether women were symptomatic or not. It was not clear whether bilateral oophorectomy affected the outcome, as this effect was based on only a few studies from the same group and some observational studies show negative effects on cognition in surgical menopausal women treated with hormones for more than 10 years. Duration of treatment overall significantly affected outcome. More negative effects were seen in longer studies, where positive effects were mainly seen in short term studies (<4 months). Treatment with combined estrogens and progestagens also negatively affected the outcome. Whether women with symptoms should be treated for a couple of months or using other (intermittent) modes of treatment and whether this could have long-term positive consequences remains to be investigated. PMID- 20202766 TI - Stab or throw? Biomechanical studies on the injuring potential of glass fragments. AB - During a Christmas party, two male guests started fighting. The perpetrator was allegedly pushed onto a glass table by the victim or fell into the table together with that man so that the glass top broke and caused a cut wound on the perpetrator's back. According to his statement he then threw a fragment of the broken glass table in the direction of the other man hitting him accidentally in a way so that the subclavian artery was severed and he died from exsanguination. Tests on the breaking characteristics of the glass table, the flying behaviour and the kinetics of thrown glass fragments conducted on various models supported the conclusion that the fatal injury on the victim's neck could not have been caused by a thrown glass fragment. It was much more likely that a stab with a blade-shaped glass fragment was the cause of the fatal injuries. PMID- 20202767 TI - Two UK suicides using nicotine extracted from tobacco employing instructions available on the Internet. AB - Tobacco is one of the most easily accessible and commonly abused drugs world wide. Nicotine, one of its principal constituents, can cause serious or fatal overdoses. Whilst the deliberate ingestion of this substance appears to be relatively rare, often the important signs of its consumption are not recognised, sometimes with fatal results. Here we describe two cases of intentional fatal ingestion of nicotine. The nicotine was extracted from tobacco using instructions available on the Internet. The first case involved a male aged 19 who died in 2008. The post-mortem blood and urine levels of nicotine were 5.5mg/l and >80 mg/l respectively; the blood level is in line with the generally recognised fatal level of >5mg/l. The levels of nicotine's main metabolite, cotinine, for this case were 2.5mg/l and 7.9 mg/l for blood and urine respectively. A comparative case in 1999 involved a 32 year-old male. The level of post-mortem nicotine in his blood was 1.0mg/l. These are believed to be the first UK suicides by nicotine using instructions from the Internet reported in the literature. Information that nicotine was the agent responsible only became apparent some time after death. There may be more deaths due to this cause that go unrecognised because quantification of nicotine and cotinine levels is not often conducted, due to the wide prevalence of smoking. It is important that all evidence at the scene of a sudden and unexplained death is carefully evaluated, including potential clues on PCs and lap-tops. PMID- 20202768 TI - The Ala54Thr polymorphism in the fatty acid-binding protein 2 (FABP2) gene is associated with hearing impairment: a preliminary report. AB - OBJECTIVE: The fatty acid-binding protein 2 (FABP2) is involved in the transport and metabolism of fatty acids. The FABP2 gene has been proposed as a candidate gene for diabetes and obesity. This study evaluates the hearing impairment risk in the Ala54Thr polymorphism of FABP2 in middle-aged and elderly Japanese. METHODS: Our sample population comprised 1428 community-dwelling Japanese aged 40 86 years (mean+/-standard deviation [SD]: 63.1+/-9.8) who participated in the Study of Aging between 2004 and 2006. An average hearing threshold level greater than 25 dB in the better ear for frequencies 500, 1000, 2000 and 4000 Hz was defined as hearing impairment. Data were analyzed by means of a multiple logistic regression with adjustment for potential confounders. RESULTS: The per-allele odds ratio for hearing impairment risk was 1.262 (95% confidence interval [CI]: 1.012-1.574) in model 1, adjusting for age, sex, history of ear disease, and history of occupational noise exposure; and 1.259 (CI: 1.009-1.571) in model 2, which adjusted for diabetes, body mass index and the histories of heart disease and hypertension, as well as the moderators in model 1. A significant adverse effect of the Thr54 variant on hearing was observed and the effect was independent of both diabetes and obesity in the present analyses. CONCLUSIONS: This study demonstrated that the Ala54Thr polymorphism of FABP2 was associated with a risk of hearing impairment in middle-aged and elderly people. The results might support caloric restriction theory indirectly, but additional researches are desired. PMID- 20202769 TI - Acute encephalopathy/encephalitis in childhood: a relatively common and potentially devastating clinical syndrome. PMID- 20202770 TI - Clinical presentation and management of intrahepatic cholangiocarcinoma. PMID- 20202771 TI - Cholangiocarcinoma: descriptive epidemiology and risk factors. AB - In theory, the term of cholangiocarcinoma is reserved for the tumours originating from the intrahepatic bile ducts. The problems of classification of the most frequent hilar tumours and the absence of histopathological confirmation in a large percentage of cases in cancer registries from many countries show the difficulty of establishing the specific epidemiologic behaviour of intrahepatic cholangiocarcinoma (ICC). There are clearly two types of ICC: the first one is the consequence of the recurrent infection of the biliary ducts by the parasites Opisthorchis viverrini and Clonorchis sinensis, and is only seen in the areas of Southeast Asia where liver flukes are endemic. In these areas, incidence and mortality rates of ICC are extremely high. Both parasites have been classified class I carcinogens by the International Agency for Research on Cancer. The other type of ICC is a cancer much rarer but present in the whole world. Some risk factors have been well-established (chronic inflammation of biliary ducts, hepatitis, thorotrast, etc) but many patients do not have any of these factors. An increase in incidence and mortality of this second type of ICC has been seen in recent years, mostly in developed countries. There is an ongoing discussion in the literature about its authenticity and potential causes. PMID- 20202772 TI - Intrahepatic cholangiocarcinoma. PMID- 20202773 TI - [Peripheric cholangiocarcinoma: radiopathologic correlations]. PMID- 20202774 TI - Emergency department radiology: reality or luxury? An international comparison. AB - Changes in society and developments within emergency care affect imaging in the emergency department. It is clear that radiologists have to be pro-active to even survive. High quality service is the goal, and if we are to add value to the diagnostic (and therapeutic) chain of healthcare, sub-specialization is the key, and, although specifically patient-oriented and not organ-based, emergency and trauma imaging is well suited for that. The development of emergency radiology in Europe and the United States is compared with emphasis on how different healthcare systems and medical cultures affect the utilization of Acute Care imaging. PMID- 20202775 TI - Parenchymal lymphoma of the brain on initial MR imaging: a comparative study between primary and secondary brain lymphoma. AB - BACKGROUND AND PURPOSE: Parenchymal lymphomatous brain masses have not been investigated considering if they are primary or as a part of systemic lymphoma (secondary) on imaging studies previously. We aimed to determine characteristics of the secondary parenchymal lymphomatous involvement of the brain and to find if there is any radiologic feature to help discrimination of untreated primary and secondary central nervous system lymphoma on patients' initial magnetic resonance imaging. MATERIALS AND METHODS: We evaluated MR images of 18 patients with the diagnosis of primary (n=12) and secondary central nervous system lymphoma (n=6). We considered the number, localization, enhancement pattern, signal characteristics, diffusion properties, presence of hemorrhage and presence of butterfly pattern on MR imaging at initial presentation. RESULTS: Secondary central nervous system lymphomas predominantly presented as multiple (n=4, 66.7%) lesions. Homogenous nodular enhancement and supratentorial white matter involvement were present in all patients with butterfly pattern and infiltrative/perivenular enhancement in half (n=3) of the patients. Deep gray matter (n=1, 16.7%) and infratentorial involvement (n=1, 16.7%) were scarce and no ring enhancement was observed. There was no statistically significant difference in any of the investigated MR features between the two groups. CONCLUSION: Statistical analyses revealed no significant distinctive radiologic characteristics between primary and secondary lymphoma of the brain parenchyma. PMID- 20202777 TI - Hydrophobicity/hydrophilicity descriptors obtained from extrapolated chromatographic retention data as modeling tools for biological distribution: application to some oxime-type acetylcholinesterase reactivators. AB - Chromatographic retention data obtained from interactions between some oxime-type compounds and different stationary phases (involving hydrophobic interaction, ion pairing formation availability, pi-pi, H-bonding, dipole-dipole, ion-dipole, electrostatic interaction and glycoprotein binding ability) have been studied. The logarithms of the capacity factors extrapolated at 0% or 100% organic solvent, resulting from the functional dependencies between retention and mobile phase composition, were used for estimation of different kind of hydrophobicity or hydrophilicity descriptors (HHDs) of these compounds. The conditions of the chromatographic separation were chosen as close as possible to in-vivo conditions (the aqueous component of the mobile phase has a pH in the physiologic interval 6.8-7.2, 0.9% sodium chloride was added to reproduce ionic strength and isotonic character, and the temperature was set at 37 degrees C). These descriptors characterizing the partition between stationary/mobile phases through specific interactions may be directly used for correlation to biological distribution processes, such as penetration of the blood/brain barrier. Oxime-type compounds used as acetylcholinesterase (AChE, E.C.3.1.1.7) reactivators have been considered for the retention study. The choice is supported by their use in the therapy of acute intoxication with organophosphorus AChE inhibitors (OPIs, especially nerve agents and pesticides), a rather complicated chemistry in solution and a relative lack of data about computational molecular descriptors used for modeling biological partition/distribution. Some correlations between the determined descriptors and computational values have also been discussed. PMID- 20202778 TI - Effectiveness of self-management interventions on mortality, hospital readmissions, chronic heart failure hospitalization rate and quality of life in patients with chronic heart failure: a systematic review. AB - OBJECTIVE: This review examined the effectiveness of self-management interventions compared to usual care on mortality, all-cause hospital readmissions, chronic heart failure hospitalization rate and quality of life in patients with chronic heart failure. METHODS: A systematic review was performed. MEDLINE, EMBASE, CINAHL and the Cochrane Library were searched between 1996 and 2009. Randomized controlled trials were selected evaluating self-management interventions designed for patients with chronic heart failure. Outcomes of interest are mortality, all-cause hospital readmissions, chronic heart failure hospitalization rate and quality of life. RESULTS: Nineteen randomized controlled trials were identified. The effectiveness of heart failure management programs initiating self-management interventions in patients with chronic heart failure indicate a positive effect, although not always significant, on reduction of numbers of all-cause hospital readmitted patients and due to chronic heart failure, decrease in mortality and increasing quality of life. CONCLUSION: This systematic review found that current available published studies show methodological shortcomings impairing validation of the effectiveness of self management interventions on mortality, all-cause hospital readmissions, chronic heart failure hospitalization rate and quality of life in patients with chronic heart failure. PRACTICE IMPLICATIONS: Further research should determine independent effects of self-management interventions and different combinations of interventions on clinical and patient reported outcomes. PMID- 20202779 TI - New directions in eHealth communication: opportunities and challenges. AB - OBJECTIVE: This article reviews key communication issues involved in the design of effective and humane eHealth applications to help guide strategic development and implementation of health information technologies. BACKGROUND: There is a communication revolution brewing in the delivery of health care and the promotion of health fueled by the growth of powerful new health information technologies. CONCLUSION: The development, adoption, and implementation of a broad range of new eHealth applications (such as online health information websites, interactive electronic health records, health decision support programs, tailored health education programs, health care system portals, mobile health communication programs, and advanced telehealth applications) holds tremendous promise to increase consumer and provider access to relevant health information, enhance the quality of care, reduce health care errors, increase collaboration, and encourage the adoption of healthy behaviors. PRACTICE IMPLICATIONS: With the growth of new and exciting health information technology opportunities, however, comes the daunting responsibility to design interoperable, easy to use, engaging, and accessible eHealth applications that communicate the right information needed to guide health care and health promotion for diverse audiences. PMID- 20202780 TI - From patient education to patient engagement: implications for the field of patient education. AB - OBJECTIVE: Advances in health care require that individuals participate knowledgeably and actively in their health care to realize its full benefit. Implications of these changes for the behavior of individuals and for the practice of patient education are described. METHODS: An "engagement behavior framework" (EBF) was compiled from literature reviews and key informant interviews. To assess the focus of research and interventions on the identified engagement behaviors, the EBF was used to code scientific sessions in professional conferences relevant to patient education in the US in 2006-2007. RESULTS: Many specific behaviors constitute engagement. Professional conferences on patient education show only modest attention to the full range of relevant behaviors. CONCLUSION: People must make informed choices about insurance and clinicians, coordinate communications among providers and manage complex treatments on their own. Not doing so risks preventable illness, suboptimal outcomes and wasted resources. PRACTICE IMPLICATIONS: Increased responsibilities of individuals, sick and well, to find and actively participate in high quality health care provides an opportunity for patient education researchers and clinicians to improve health outcomes by developing innovative strategies to support all individuals to effectively participate in their care to the extent possible. PMID- 20202781 TI - [Neurological and heart failure following an accidental intoxication by hydrogen sulphide: a case report]. AB - We report the case of a patient who was victim of a hydrogen sulphide poisoning. This poisoning took place following a fall in sewers. The initial clinical presentation was dominated by an acute respiratory failure caused by an acute pulmonary oedema. In this context, non cardiogenic pulmonary oedema is usually evoked in the literature. Our observation supports a left ventricular systolic dysfunction as a possible cause of this cardiorespiratory complication. The initial presentation was also marked by a coma which is often associated with severe poisonings by hydrogen sulphide. Evolution was favourable under symptomatic treatment. We discuss the mechanism of heart and neurological failure. PMID- 20202776 TI - Seasonal and regional diversity of maple sap microbiota revealed using community PCR fingerprinting and 16S rRNA gene clone libraries. AB - An arbitrary primed community PCR fingerprinting technique based on capillary electrophoresis was developed to study maple sap microbial community characteristics among 19 production sites in Quebec over the tapping season. Presumptive fragment identification was made with corresponding fingerprint profiles of bacterial isolate cultures. Maple sap microbial communities were subsequently compared using a representative subset of 13 16S rRNA gene clone libraries followed by gene sequence analysis. Results from both methods indicated that all maple sap production sites and flow periods shared common microbiota members, but distinctive features also existed. Changes over the season in relative abundance of predominant populations showed evidence of a common pattern. Pseudomonas (64%) and Rahnella (8%) were the most abundantly and frequently represented genera of the 2239 sequences analyzed. Janthinobacterium, Leuconostoc, Lactococcus, Weissella, Epilithonimonas and Sphingomonas were revealed as occasional contaminants in maple sap. Maple sap microbiota showed a low level of deep diversity along with a high variation of similar 16S rRNA gene sequences within the Pseudomonas genus. Predominance of Pseudomonas is suggested as a typical feature of maple sap microbiota across geographical regions, production sites, and sap flow periods. PMID- 20202782 TI - [Noninvasive mechanical ventilation in paediatric intensive care units: which indications in 2010?]. AB - Noninvasive ventilation (NVI) is increasingly used in paediatrics, although there is a high variety of practices and a paucity of published data in paediatrics. The last French consensus conference recognized a specific role of NVI for infants suffering from acute bronchiolitis with apnoea, and acute respiratory failure due to laryngotracheomalacia and cystic fibrosis. NVI is feasible and can be beneficial in paediatric acute respiratory failure during neuromuscular diseases. Like in adults, its place in other diseases such as acute bronchoalveolitis without apnoea, acute respiratory failure during neuromuscular diseases, status asthmaticus, acute respiratory distress syndrome (ARDS) and postextubation respiratory failure is growing, even though not always defined. All these adult recommendations have not been validated in the pediatric setting, and, thus, taking the paediatric characteristics into account is essential. In 2010, NVI had an important place in PICU, and must be managed by a trained team whose practice is regularly evaluated. PMID- 20202783 TI - [Monolobar Caroli disease]. PMID- 20202784 TI - Aerobic capacity in patients with chronic liver disease: Very modest effect of liver transplantation. AB - INTRODUCTION: Aerobic capacity is commonly impaired in patients with liver cirrhosis, as demonstrated by their low oxygen consumption at peak exercise (peak VO(2)). This impairment is correlated with the severity of the liver disease. We investigated the effect of orthotopic liver transplantation (OLT) alone on exercise capacity in this prospective study of patients with liver cirrhosis. METHOD: Twenty liver transplant candidates, aged 27 to 61years, underwent resting pulmonary function tests, echocardiography, and incremental cardiopulmonary exercise testing (CPET) before OLT and 16.3 + or - 1.6months after OLT. RESULTS: Following OLT, peak VO(2) increased by a mean of only 7.7% (from 63.4 to 71.1% of predicted value), and decreased in one-quarter of the patients. Cardiac function was normal before OLT and no changes in respiratory indicators followed OLT. Change in peak VO(2) after OLT (Delta peak VO(2)) was related to changes in hemoglobin level (r(2)=0.45, p=0.04), the stopping of beta-blocker therapy, and muscle impairment, as suggested by the correlation between Delta peak VO(2) and peak lactate concentration before OLT (r(2)=0.64, p<0.01). DISCUSSION: Our study provides evidence of a very modest and inconsistent increase in aerobic capacity in liver transplant candidates after liver transplantation alone. This persistent impairment of exercise tolerance was principally of peripheral origin but anemia and beta-blocker treatment should be considered as major aggravating factors. Rehabilitation programs before and after transplantation may increase its benefits to these deconditioned liver transplant recipients in their daily lives. PMID- 20202785 TI - Quality of life, self-perceived dysphonia, and diagnosed dysphonia through clinical tests in teachers. AB - OBJECTIVES: To examine the impact of voice on the quality of life of teachers and to assess whether the degree of dysphonia and otorhinolaryngologists' (ORL) diagnostics are correlated with the quality of life. METHODS: Eighty-eight female teachers from the municipal schools of Belo Horizonte who were in speech therapy at the Speech Therapy Clinic of the Hospital das Clinicas of Minas Gerais participated in the study. The variables studied were age, ORL diagnosis, perceptual-hearing assessment of voice through GRBAS scale, and vocal activities and participation profile (VAPP) protocol. Statistical analysis was performed through the descriptive analysis of the data and the Spearman coefficient of correlation. RESULTS: The average age of the participants was 38 years. Vocal deviation: degree 1-56 teachers (63.6%); degree 2-27 teachers (30.6%); and without vocal deviation-five teachers (5.6%). It was found that 57.9% of the teachers presented combined ORL diagnosis. No statistically significant relationship was observed among the ORL diagnosis, the degree of dysphonia, and the parameter values of quality of life assessed by VAPP. CONCLUSIONS: The examined participants of this study presented light degree of vocal deviation and ORL combined diagnosis. According to the figures obtained by VAPP, there was negative impact of voice on the quality of life of female teachers, but these impacts were not correlated with ORL diagnosis and grade of dysphonia. PMID- 20202786 TI - A comparison of rating scales used in the diagnosis of extraesophageal reflux. AB - OBJECTIVE: To evaluate the level of agreement between reflux area index scores, the reflux symptom index (RSI), and the reflux finding score (RFS). Inter- and intrarater reliability of the RFS was assessed. A criterion of pH 5 was used to evaluate its effects on agreement. STUDY DESIGN: Adult participants were enrolled in this prospective study. METHODS: Eighty-two participants (72 patients and 10 controls) completed the RSI, videoendoscopy, and 24-hour pH probe monitoring. The reflux area index for extraesophageal reflux (EER) events was calculated at pH 4 and 5. Two speech-language pathologists and one otolaryngologist independently rated 36 endoscopic examinations using the RFS through a web-based system. A repeated rating of six examinations was completed. RESULTS: Chi-square revealed poor agreement between the diagnostic tools, regardless of which pH criterion was used. Intraclass correlation coefficients revealed fair interrater reliability of the RFS and moderate intrarater reliability. Independent-sample t tests for the RFS and reflux area index (RAI) scores failed to identify patients from normal controls. CONCLUSIONS: The results of this study highlight the lack of agreement among the current available diagnostic tools for EER. Raters were not in agreement regarding the presence and severity of physical findings of EER. Results support the need for greater consensus among the clinical tools used in the diagnosis of EER. Physical rating scales may overidentify patients and would benefit from uniform scales and training. Assessing EER occurring at pH 5 may also yield important diagnostic information. Further research is needed to verify normative RAI cutpoints. PMID- 20202787 TI - Voice- and health-related quality of life in the elderly. AB - OBJECTIVE: Restrictions of verbal communication and high prevalence of voice disorders in the elderly are suspected to influence the quality of life. For assessment, both voice-specific and unspecific methods are already established and fundamental components of clinical diagnostics, but the question of correlation between voice-related and general health-related quality of life is still open in this subpopulation. METHODS: One hundred and seven socially active persons aged 65+ years were recruited and asked to complete Voice-Related Quality of Life (V-RQOL) and Short Form (SF)-36 questionnaires. RESULTS: There was a mild correlation between V-RQOL score and both of the SF-36 subscores (r(s)=0.28 for the physical subscore and r(s)=0.27 for the mental subscore). CONCLUSION: As correlation of voice- and health-related quality of life in elderly persons is only mild, both voice-specific and unspecific assessment methods are required for clinical diagnostics. PMID- 20202788 TI - A new simple method to estimate pulmonary regurgitation by echocardiography in operated fallot: comparison with magnetic resonance imaging and performance test evaluation. AB - BACKGROUND: The aim of this study was to assess a novel transthoracic echocardiographic method to estimate the severity of pulmonary regurgitation (PR) in patients with surgically repaired tetralogy of Fallot. METHOD: In 63 patients with operated tetralogy of Fallot, PR was evaluated by vena contracta width, jet deceleration, PR index, pressure half-time, and a new index, referred to as Pulmonary Regurgitation Index by M-mode echocardiography (PRIME), which is the systolic-to-diastolic variation in right pulmonary artery diameter. The results were matched to PR fraction (PRF) assessed by cardiovascular magnetic resonance imaging. PRIME cutoff values for selecting patients with mild, moderate, and severe PR were identified by maximizing PRIME sensitivity and specificity. Nonlinear regression by 3-parameter logistic function was used to estimate PRF by PRIME. RESULTS: The sensitivity and specificity of PRIME were high for all diagnostic targets: PRF > or =15% versus <15%, PRF > or =25% versus <25%, and PRF >40% versus < or =40%. The nonlinear regression model showed a good correlation between PRF and PRIME (R(2) = 0.95). CONCLUSION: PRIME is a simple and accurate method to estimate PR by transthoracic echocardiography in patients with operated tetralogy of Fallot. PMID- 20202789 TI - Can isovolumic acceleration be used in clinical practice to estimate ventricular contractile function? Reproducibility and regional variation of a new noninvasive index. AB - BACKGROUND: Myocardial acceleration during isovolumic contraction (IVA) has been validated as a relatively load-insensitive noninvasive index of contractility. Its feasibility, reproducibility, and variation between segments have not been studied in detail, and thus its utility in clinical practice has not been established. METHODS: We analyzed myocardial velocity loops (median frame rate 182 s(-1)) from 20 young volunteers (10 men, aged 25.7 +/- 2.9 years), 20 patients with type 2 diabetes (14 men, aged 64.1 +/- 8.5 years), and 20 patients with heart failure (17 men, aged 64.6 +/- 7.7 years). Long-axis IVA was measured in all walls at the annulus and in basal and mid-ventricular segments. Intraobserver reproducibility for 1 observer in all subjects and interobserver reproducibility among 3 observers in 10 subjects from each group were assessed. RESULTS: In control subjects, subjects with diabetes, and subjects with heart failure, the feasibility of measuring IVA was 97%, 89%, and 82%, respectively; intraobserver reproducibility was 12%, 18%, and 30%, respectively (pooled coefficients of variation); and mean interobserver reproducibility was 23%, 21%, and 28%, respectively. IVA was lower in the mid-ventricular segments by 24% to 43% compared with the annulus, and IVA was higher in the right than the left ventricle (P < .001). IVA of the medial mitral annulus discriminated those with heart failure from those with diabetes and controls, and had acceptable intraobserver reproducibility across groups (mean coefficient of variation 13%). CONCLUSION: IVA may be used as a research tool if it is measured at the medial mitral annulus, but its clinical applicability is hampered by low reproducibility, especially in patients with impaired left ventricular function in whom it would otherwise be most useful. PMID- 20202790 TI - Recovery of function after acute myocardial infarction evaluated by tissue Doppler strain and strain rate. AB - BACKGROUND: The aim of this study was to investigate the changes and time course of recovery of regional myocardial function within the first week following successful primary coronary intervention in patients with first-time ST-segment elevation myocardial infarctions using myocardial deformation analysis, which is more quantitative and thus more objective than the wall motion score. METHODS: Thirty-one consecutive patients admitted with ST-segment elevation myocardial infarctions were studied on days 1, 2, 3, and 7 using strain and strain rate tissue Doppler echocardiography. RESULTS: The mean peak troponin T level was 7.0 microg/L, and 15 patients had anterior and 16 had inferior infarct localization. Peak systolic strain rate and end-systolic strain increased significantly on day 2, both in segments with moderately reduced function (-0.6 to -1.0 s(-1) vs -8% to -15%, P < .001) and in severely reduced function (-0.2 to -1.0 s(-1) vs 1% to 12%, P < .001), but there were no further changes. Mean wall motion score in infarct related segments decreased significantly from day 1 to day 2 (2.7 to 2.4, P = .001) and from day 3 to day 7 (2.3 to 2.2, P = .001). CONCLUSIONS: Recovery of regional function after ST-segment elevation myocardial infarction occurred within 2 days and could be detected by wall motion score, strain rate, and strain. However, strain and strain rate were better discriminative parameters for the changes in function as well as being better to assess near normalization on day 2. This could have a clinical impact on early management in patients who undergo percutaneous coronary intervention. PMID- 20202791 TI - Dislocation of Amplatzer septal occluder device after closure of secundum atrial septal defect. AB - Atrial septal defect transcatheter occlusion techniques have become an alternative to surgical procedures. With the increasing use of this new technology, several complications have been identified. The authors present the case of a patient who was admitted to the hospital for primary percutaneous closure of a secundum atrial septal defect. On routine follow-up examination 24 hours after implantation, transthoracic echocardiography revealed a partial dislocation of the occluder into the right atrium. The patient was referred for cardiosurgical treatment. Strict selection criteria and the choice of the device may help reduce the incidence of complications such as dislocation of the occluder into the right atrium following the percutaneous device closure of an atrial septal defect. PMID- 20202792 TI - Predicting heart failure hospitalization and mortality by quantitative echocardiography: is body surface area the indexing method of choice? The Heart and Soul Study. AB - BACKGROUND: Echocardiographic measurements of left ventricular (LV) mass, left atrial (LA) volume, and LV end-systolic volume (ESV) predict heart failure (HF) hospitalization and mortality. Indexing measurements by body size is thought to establish limits of normality among individuals varying in body habitus. The American Society of Echocardiography recommends dividing measurements by body surface area (BSA), but others have advocated alternative indexing methods. METHODS: Echocardiographic measurements were collected in 1024 ambulatory adults with coronary artery disease. LV mass, LA volume, and LV ESV were calculated using truncated ellipse method and biplane method of disk formulae. Comparison between raw measurements and measurements divided by indexing parameters was made by hazard ratios per standard deviation increase in variable and c-statistics for BSA, BSA(0.43), BSA(1.5), height, height(0.25), height(2), height(2.7), body weight (BW), BW(0.26), body mass index (BMI), and BMI(0.27). RESULTS: Mean LV mass was 192 +/- 57 g, mean LA volume was 65 +/- 24 mL, and mean LV ESV was 41 +/ 26 mL. Average height was 171 +/- 9 cm, average BSA was 1.94 +/- 0.22 m(2), and average BMI was 28.4 +/- 5.3 kg/m(2). At an average follow-up of 5.6 +/- 1.8 years, there were 148 HF hospitalizations, 71 cardiovascular (CV) deaths, and 269 all-cause deaths. There was excellent correlation between raw measurements and those indexed by height (r = 0.98-0.99), and moderate correlation between raw measurements and those indexed by BW (r = 0.73-0.94). C-statistics and hazard ratios per standard deviation increase in indexed variables were similar for HF hospitalization, CV mortality, and all-cause mortality. There were no significant differences among indexing methods in ability to predict outcomes. CONCLUSION: The choice of indexing method by parameters of BSA, height, BW, and BMI does not affect the clinical usefulness of LV mass, LA volume, and LV ESV in predicting HF hospitalization, CV mortality, or all-cause mortality among ambulatory adults with coronary artery disease. Continued use of BSA to index measurements of LV mass, LA volume, and LV ESV is acceptable. PMID- 20202793 TI - Automated border detection for assessing the mechanical properties of the carotid arteries: comparison with carotid intima-media thickness. AB - BACKGROUND: Although carotid intima-media thickness (CIMT) assesses the structural properties of the carotid artery, it does not assess the mechanical properties of the vessel. METHODS: The carotid arteries of 71 adult patients were evaluated with CIMT, and automated border detection computed vessel stiffness, compliance, elasticity, and distensibility. RESULTS: CIMT and mechanical properties were differentially affected by traditional cardiac risk factors, with age dominating for CIMT, and age, diabetes, and smoking dominating for mechanical variables. There was a moderate linear correlation between CIMT and the distensibility coefficient (r = -0.54), but there were weak associations with other parameters of dynamic vessel function. When patients were separated into risk groups, the mechanical vascular parameters' classification frequently differed from the CIMT classification. This was particularly notable for patients with intermediate CIMT values, who were reclassified as low or high risk by mechanical parameters 45% of the time. CONCLUSION: We found that it is feasible to assess the cross-sectional area of the carotid artery using automatic border detection, which allows a novel method of determining carotid mechanical properties. These functional characteristics are often discordant with CIMT, suggesting that mechanical properties may be an important adjunct to the CIMT when evaluating the carotid artery. PMID- 20202794 TI - Neurosensory function following mandibular nerve lateralization for placement of implants. AB - This prospective cohort study investigates the types and duration of neurosensory disturbances (NDs) related to mandibular nerve (MN) lateralization for placement of implants. From March 2001 to March 2007, 87 patients underwent implant placement surgery with MN lateralization. All patients had panoramic radiograph and CT scans taken preoperatively. Patients completed questionnaires to report NDs 1 week after surgery, and at the end of each month within the year after surgery. All 87 patients (110 posterior segments, 23 bilateral and 64 unilateral) participated in the study. All patients reported NDs in the first week: anaesthesia in 81 sites, hypoesthesia in nine sites, burning in nine sites, pain in eight sites, pinching in two sites, and tickling in one site. The sites with NDs decreased to 29 sites (26%) at the end of first month, and to three sites (3%) at the end of the sixth month with no changes to the end of the year. 82 patients were satisfied with the result of nerve lateralization after 1 year. The mean time for full recovery of MN was 37+/-15 days. These findings indicate that concerning NDs, MN lateralization is a useful method for placing implants in the atrophic posterior mandible. PMID- 20202795 TI - Is perseveration uniquely characteristic of schizophrenia? AB - Evidence for the existence of categorically distinct disorders such as schizophrenia, bipolar disorder, and major depression is mixed: neuropsychological impairments may be similar in schizophrenia and bipolar disorder; schizophrenia and major depression show similar neuropsychological and frontal lobe disturbances; and overlap in biochemical anomalies among the disorders has also been reported. Interestingly, there are very few studies that directly compare all diagnoses. The present study compares cognitive perseveration in these three diagnostic groups using the Wisconsin Card Sorting Task (WCST) to examine performance across patients with schizophrenia (n=143), bipolar disorder (n=25) and major depression (n=21). Individuals used in this sample were 18-45 years old at time of testing to eliminate confounds of aging. Sex ratios within each diagnostic group are comparable to those of the national population. Univariate analyses examining diagnostic group and percent perseverative error revealed no significant differences in WCST performance across the diagnostic groups. Examination of clinical variables in the sample of individuals with schizophrenia revealed that perseveration is related to negative symptoms and depressive symptoms in young adults. PMID- 20202796 TI - Minocycline versus doxycycline for meticillin-resistant Staphylococcus aureus (MRSA): in vitro susceptibility versus in vivo effectiveness. PMID- 20202797 TI - In vitro combined activity of amphotericin B, caspofungin and voriconazole against clinical isolates of Trichosporon asahii. AB - Disseminated infections caused by Trichosporon asahii are difficult to resolve. Combination regimens with synergistic drugs could provide additional options for treating trichosporonosis. The aim of this study was to evaluate the antifungal activities of voriconazole (VCZ), caspofungin (CAS) and amphotericin B (AMB) alone or in combination in vitro against clinical isolates of T. asahii. The combined antifungal activities of VCZ, CAS and AMB against 18 clinical isolates were assessed by a chequerboard microdilution method. CAS combined with AMB showed the highest percentage of synergistic effects (89%), much higher than those of the other two combinations (AMB/VCZ and CAS/VCZ both 17%). No antagonistic effect was observed in any case. This study demonstrates that the activity of two combined antifungals, especially the combination of CAS and AMB, against T. asahii is more effective than that of a drug alone against this fungus, suggesting that combined antifungal therapy may be a potential strategy for treating disseminated trichosporonosis. PMID- 20202798 TI - Resistance to oral antibiotics in urinary coliform strains isolated between 2000 and 2008 in Sonderborg area, Denmark. PMID- 20202799 TI - First description of Klebsiella pneumoniae clinical isolates carrying both qnrA and qnrB genes in Portugal. AB - In the present study, 21 multidrug-resistant Klebsiella pneumoniae isolates were recovered from patients hospitalised in the Intensive Care Unit of Hospital Infante D. Pedro in Aveiro, Portugal. Fifteen isolates carried qnr genes. Four strains harboured the quinolone resistance genes qnrA and qnrB, both located on a large plasmid in two strains (KP4 and KP10) and on different plasmids in two strains (KP5 and KP6). These findings indicate an extremely high prevalence of qnr genes associated with various mobile elements such as ISCR1 and class 1 integrons. PMID- 20202801 TI - Production of a new glycolipid biosurfactant from marine Nocardiopsis lucentensis MSA04 in solid-state cultivation. AB - Considering the need of potential biosurfactant producers and economic production processes using industrial waste, the present study aims to develop solid-state culture (SSC) of a marine actinobacterium for biosurfactant production. A potential biosurfactant producer Nocardiopsis lucentensis MSA04 was isolated from the marine sponge Dendrilla nigra. Among the substrates screened, wheat bran increased the production significantly (E(24) 25%) followed by oil seed cake and industrial waste such as tannery pretreated sludge, treated molasses (distillery waste) and pretreated molasses. Enhanced biosurfactant production was achieved under SSC conditions using kerosene as carbon source, beef extract as nitrogen source and wheat bran as substrate. The maximum production of biosurfactant by MSA04 occurred at a C/N ratio of 0.5 envisaging that a higher amount of nitrogen source is required by the strain compared to that of the carbon source. The kerosene and beef extract interactively increase the production and a stable production was attained with the influence of both factors independently. A significant interactive influence of secondary control factors such as copper sulfate and inoculum size was validated in response surface methods-based experiments. The surface active compound produced by MSA04 was characterized as glycolipid with a hydrophobic non-polar hydrocarbon chain (nonanoic acid methyl ester) and hydrophilic sugar, 3-acetyl 2,5 dimethyl furan. In conclusion, the strain N. lucentensis MSA04 was a potential source of glycolipid biosurfactant, could be used for the development of bioremediation processes in the marine environment. PMID- 20202802 TI - [Skull fracture or bipartite parietal bone]. AB - We describe the case of a male newborn born at 37 weeks of gestation. Complete radiological assessment because of suspected skull fracture revealed the diagnosis of a bipartite parietal bone. A brief review of the literature shows the exceptional character of this anatomical variant, whose origin is unclear at the present time. PMID- 20202800 TI - Drug attitude as predictor for effectiveness in first-episode schizophrenia: Results of an open randomized trial (EUFEST). AB - Effectiveness has become more and more important as a comprehensive outcome measure for (long-term) treatment in schizophrenia. Early predictors to identify patients at a high risk for not succeeding the initiated treatment would be very useful. Discontinuation of the initiated treatment was used as criterion for effectiveness and patients' drug attitude was shown to be predictive for non adherence or discontinuation of long-term treatment in schizophrenia. Accordingly, the predictive validity of the Drug Attitude Inventory (DAI) for effectiveness should be evaluated. Based on a sub-sample of patients from the EUFEST study for whom DAI assessments were available significant predictors for effectiveness as measured by discontinuation of initiated treatment were identified based on a logistic and a Cox-regression analysis. A Receiver Operating Characteristic- (ROC-) analysis was conducted for the DAI, prognostic / diagnostic parameters (sensitivity, specificity) were calculated and a cut-off value suggested. In a sample of 228 first-episode patients, the DAI score was the most powerful predictor for effectiveness (p<0.001) besides two other significant predictors (PANSS-positive score and sexual side effects). The ROC-analysis revealed an area under the curve of 0.64 (p<0.001). The suggested cut-off point of about 20 yielded a sensitivity of 70-75% and a specificity of 40-45%. Study results indicate that the Drug Attitude Inventory, filled in by patients early in treatment seems to be a valid predictor for effectiveness as measured by discontinuation of the initiated treatment. DAI scores could also serve as an (differential) indicator for the need of enhanced treatment monitoring. These findings have to be validated in other (first-episode) samples. PMID- 20202803 TI - Cutaneous application of an accessory-gland secretion after sperm exchange in a terrestrial slug (Mollusca: Pulmonata). AB - Competition for fertilisation in hermaphroditic animals seems to have led to many odd behaviours and complex morphologies involved in the transfer of accessory gland products to the partner. Terrestrial slugs of the genus Deroceras show remarkably elaborate and interspecifically diverse penis morphologies and mating behaviours. Most species have an appending penial gland, which in Deroceras panormitanum consists of a few long fingers that are everted after sperm exchange and laid onto the partner's back. To investigate whether this gland transfers a secretion onto the partner's skin, we killed slugs at different mating stages and studied their penial glands and skin histologically. Two types of secretion granules appeared at a very early stage of courtship, and the penial gland was already filled 15min into the courtship. At copulation, the gland everted this secretion onto the partner's body, where it remained for at least 50min. No lysis of skin tissue or other effects on the skin were observed. The slugs tried to lick the received secretion off their own body, and some droplets were observed to be shed with the body mucus. Our results indicate the external application of a glandular substance that could function as either a pheromone or allohormone. The behaviours of the recipients suggest sexual conflict, although mutual interest cannot be ruled out. PMID- 20202805 TI - Fatty acid-genotype interactions and cardiovascular risk. AB - Cardiovascular disease (CVD) risk and rate of progression is determined by genetic, environmental and behavioural factors. Majority of genotype-diet-CVD phenotype research till date has focussed on the interactive impact of single nucleotide polymorphisms (SNP) and dietary fat composition, on blood lipids levels, with strong evidence of the existence of hypo- and hyper-responders. However, a recognised concern in the field of nutrigenetics is a lack of consistency between findings of different studies. This apparent lack of consistency is likely to be attributable to the impact of factors such as ethnicity and gender on the 'size' of nutrigenetic interactions, a clear understanding of which needs to be gained. Although not yet ready for widespread use, in the future a greater use of genetic profiling is likely to enhance current strategies of CVD prediction, and improve the design of more personalised approaches to minimise risk in the individual. PMID- 20202804 TI - Omega-3 fatty acids in dry eye and corneal nerve regeneration after refractive surgery. AB - Dry eye (DE) is a multifactorial condition that affects the surface of the eye and induces an inflammatory response. Corneal nerves play an important role in the maintenance of a healthy ocular surface. Here we review corneal structure, nerve architecture, DE conditions, and nerve regeneration following corneal surgery and discuss how n-3 fatty acids affect the health of the cornea. Animal studies show that resolvins, compounds derived from eicosapentaenoic acid (EPA), increase tear volume and decrease inflammation induced by DE. After corneal surgery in rabbits, treatment with nerve growth factor (NGF) or pigment epithelial derived factor (PEDF) in conjunction with docosahexaenoic acid (DHA) increase nerve density and corneal epithelial cell proliferation. Increased synthesis of the novel docosanoid, neuroprotectin D1 (NPD1), was found in corneas after the animals were treated with PEDF and DHA. Topical application of these lipids derived from n-3 fatty acids could be useful in treating DE and prevent clinical complications such as cornea erosion and ulcerations. PMID- 20202806 TI - Point-of-care Arkansas method for measuring adherence to treatment with isoniazid. AB - We evaluated the accuracy of a point-of-care test designed to measure adherence to isoniazid (INH) preventive therapy in a hospital setting in Rio de Janeiro, Brazil. Patients on treatment with daily INH and patients not receiving INH were included. Sensitivity and specificity of the test were 84%/98% at the first minute, and 95%/98% at the fifth minute, respectively. Among smokers, sensitivity and specificity was reduced (80%/89% at the fifth minute, respectively), but only 17% smoked. This test accurately detected INH metabolites 24h following directly observed INH intake, though sensitivity and specificity may be compromised by tobacco smoke exposure. PMID- 20202807 TI - Right ventricular dilation on CT pulmonary angiogram independently predicts mortality in pulmonary embolism. AB - BACKGROUND: The aim of this study was to determine the prognostic significance of right ventricular dilation on CT pulmonary angiogram in acute pulmonary embolism and to distinguish if this feature predicts mortality independently of the Pulmonary Embolism Severity Index, an established admission severity score. METHODS: A retrospective study of patients admitted with pulmonary embolism confirmed by CT pulmonary angiogram to three teaching hospitals in East Scotland between January 2005 and July 2007. Two radiologists judged presence of right ventricular dilation on CT pulmonary angiogram independently. The outcome of interest was 30 day mortality. Multivariable logistic regression was used to compare this outcome in patients with right ventricular dilation compared to those without right ventricular dilation, adjusting for Pulmonary Embolism Severity Index score. RESULTS: There were 585 patients included and 30.4% had right ventricular dilation on CT pulmonary angiogram. Patients with right ventricular dilation had increased 30 day mortality rates compared to patients without right ventricular dilation (12.4% vs. 5.4%; p=0.006). Survival analysis showed that a significantly greater proportion of deaths in the right ventricular dilation group occurred within the first 48h after admission compared to the group without right ventricular dilation (45.5% deaths vs. 9.1%; p=0.016). On multivariable analysis, adjusting for Pulmonary Embolism Severity Index score, right ventricular dilation was independently associated with increased 30 day mortality (OR 2.98; 95% CI 1.54-5.75; p=0.001). CONCLUSION: Right ventricular dilation on CT pulmonary angiogram is an independent predictor of 30 day mortality in acute pulmonary embolism. PMID- 20202808 TI - Autophagy for the avoidance of degenerative, inflammatory, infectious, and neoplastic disease. PMID- 20202809 TI - Impact of MSW landfill on the environmental contamination of phthalate esters. AB - This study aims to investigate the impact of MSW landfill on the contamination of phthalate esters (PAEs) in nearby environment. Landfill leachate, surface water, groundwater and soil profile samples were collected from a MSW landfill area in Wuhan, China. Contents of 16 PAEs were detected for each sample using gas chromatography method. Results showed that landfill had an obvious effect on the contamination of PAEs in groundwater, whereas showed no tremendous effect on the PAEs contamination in surface water and topsoil. Seven possible transportation processes of PAEs in landfill area were put forward. However, the especially important processes are the invasion of PAEs into aquifer through weathered crevice, horizontal transportation in aquifer and upward infiltration with groundwater. It is suggested that the whole landfill area should be engineered with seepage-proof membrane and clay so as to prevent landfill leachate from flowing out of the filling area. On the other hand, no weathering crevice is permitted in the landfill area as it will affect groundwater seriously. PMID- 20202810 TI - Waste and building materials: what type of articles should be submitted to Waste Management? PMID- 20202811 TI - Valuable processes and products from marine intertidal microbial communities. AB - Microbial communities are ubiquitous in marine intertidal environments. These communities, which grow preferentially as biofilms on natural and artificial surfaces, carry out key processes contributing to the functioning of coastal environments and providing valuable services to human society, including carbon cycling, primary productivity, trophic linkage, and transfer and removal of pollutants. In addition, their surface-associated life style greatly influences the integrity and performance of marine infrastructure and archaeological heritage materials. The fluctuating conditions of the intertidal zone make it an extreme environment to which intertidal biofilm organisms must adapt at varying levels. This requirement has probably favored the development and spread of specific microorganisms with particular physiological and metabolic processes. These organisms may have potential biotechnological utility, in that they may provide novel secondary metabolites, biopolymers, lipids, and enzymes and even processes for the production of energy in a sustainable manner. PMID- 20202812 TI - Recent advances in single-molecule sequencing. AB - Recent advances in sequencing technologies exhibit a tendency towards single molecule sequencing, which eventually will lead to the commercial implementation of such platforms. For this purpose dye labelling is currently the foundation of most approaches and an overview is provided on the latest developments. For label free sequencing the detection of conductivity changes using nanopores or nano edges will be discussed as well as another promising method that is based on Raman spectroscopy. Here the most recent advance aims to utilize the high lateral resolution of tip-enhanced Raman scattering. For this sequencing procedure Raman spectra must be collected along the DNA or RNA strand, while the difference spectra will provide a direct sequence reading without prior labelling. PMID- 20202813 TI - A comparison between electronic portal imaging device and cone beam CT in radiotherapy verification of nasopharyngeal carcinoma. AB - The demand of greater accuracy in intensity-modulated radiotherapy (IMRT) has driven the development of more advanced verification systems. The purpose of this study is to investigate the differences in verification accuracy in terms of the position error detected between cone-beam computed tomography (CBCT) and electronic portal imaging device (EPID) in the IMRT of nasopharyngeal carcinoma (NPC). Two groups of NPC patients (n = 22 and n = 28) verified by CBCT (G1-CB), EPID (G1-EP), and EPID (G2-EP) only, respectively, were recruited. The positional errors between the G1-CB group and the G2-EP group were compared. In addition, the magnitudes of the position errors of EPID taken in the same session of the CBCT, but after necessary corrections (G1-EP), were analyzed. In the CBCT group, 455 CBCT images (G1-CB) and 206 EPID images (G1-EP) were collected, whereas 319 EPID images (G2-EP) for the EPID group, were recorded. The median position errors detected in CBCT were between 0.80 and 0.90 mm in the antero-posterior (A-P), left-right (L-R), and supero-inferior (S-I) directions, whereas those of the EPID were all 0.50 mm. The magnitude of position deviation detected by the CBCT was higher than that of the EPID and their differences were extremely significant (p < 0.001). The frequencies in the G2-EP group with position errors greater than the tolerance (2 mm) were 32, 42, and 27 in the A-P, L-R, and S-I directions, respectively, which accounted for 16.5%, 21.6%, and 13.9% of the total number of EPID. There was difference in verification capability between the CBCT and EPID when applied to IMRT of NPC patients. Because an average of 1 of 6 verifications in EPID was inferior to that of the CBCT, verification by CBCT is recommended. PMID- 20202814 TI - Factors affecting prostate volume estimation in computed tomography images. AB - The aim of this study was to investigate how apex-localizing methods and the computed tomography (CT) slice thickness affected the CT-based prostate volume estimation. Twenty-eight volunteers underwent evaluations of prostate volume by CT, where the contour segmentations were performed by three observers. The bottom of ischial tuberosities (ITs) and the bulb of the penis were used as reference positions to locate the apex, and the distances to the apex were recorded as 1.3 and 2.0 cm, respectively. Interobserver variations to locate ITs and the bulb of the penis were, on average, 0.10 cm (range 0.03-0.38 cm) and 0.30 cm (range 0.00 0.98 cm), respectively. The range of CT slice thickness varied from 0.08-0.48 cm and was adopted to examine the influence of the variation on volume estimation. The volume deviation from the reference case (0.08 cm), which increases in tandem with the slice thickness, was within +/- 3 cm(3), regardless of the adopted apex locating reference positions. In addition, the maximum error of apex identification was 1.5 times of slice thickness. Finally, based on the precise CT films and the methods of apex identification, there were strong positive correlation coefficients for the estimated prostate volume by CT and the transabdominal ultrasonography, as found in the present study (r > 0.87; p < 0.0001), and this was confirmed by Bland-Altman analysis. These results will help to identify factors that affect prostate volume calculation and to contribute to the improved estimation of the prostate volume based on CT images. PMID- 20202815 TI - Dose sparing of brainstem and spinal cord for re-irradiating recurrent head and neck cancer with intensity-modulated radiotherapy. AB - Because of the dose limit for critical structures such as brainstem and spinal cord, administering a dose of 60 Gy to patients with recurrent head and neck cancer is challenging for those who received a previous dose of 60-70 Gy. Specifically, previously irradiated head and neck patients may have received doses close to the tolerance limit to their brainstem and spinal cord. In this study, a reproducible intensity-modulated radiation therapy (IMRT) treatment design is presented to spare the doses to brainstem and spinal cord, with no compromise of prescribed dose delivery. Between July and November 2008, 7 patients with previously irradiated, recurrent head and neck cancers were treated with IMRT. The jaws of each field were set fixed with the goal of shielding the brainstem and spinal cord at the sacrifice of partial coverage of the planning target volume (PTV) from any particular beam orientation. Beam geometry was arranged to have sufficient coverage of the PTV and ensure that the constraints of spinal cord <10 Gy and brainstem <15 Gy were met. The mean maximum dose to the brainstem was 12.1 Gy (range 6.1-17.3 Gy), and the corresponding mean maximum dose to spinal cord was 10.4 Gy (range 8.2-14.1 Gy). For most cases, 97% of the PTV volume was fully covered by the 95% isodose volume. We found empirically that if the angle of cervical spine curvature (Cobb's angle) was less than ~30 degrees , patients could be treated by 18 fields. Six patients met these criteria and were treated in 25 minutes per fraction. One patient exceeded a 30 degrees Cobb's angle and was treated by 31 fields in 45 minutes per fraction. We have demonstrated a new technique for retreatment of head and neck cancers. The angle of cervical spine curvature plays an important role in the efficiency and effectiveness of our approach. PMID- 20202816 TI - Neuraxial anesthesia in obstetric patients receiving anticoagulant and antithrombotic drugs. PMID- 20202817 TI - All parturients receiving neuraxial morphine should be monitored with continuous pulse oximetry. PMID- 20202818 TI - Prospective observational study of serial cardiac output by transthoracic echocardiography in healthy pregnant women undergoing elective caesarean delivery. AB - BACKGROUND: An understanding of cardiovascular changes in parturients is crucial for their anaesthetic management, but few studies have examined the effect of posture on cardiac output in the peripartum period. METHOD: Cardiac output was measured in four different positions by transthoracic echocardiography (Doppler) in 30 term women undergoing elective caesarean delivery. These positions were left lateral level (P1), left lateral with 20 degrees head up (P2), left lateral with 10 degrees head down (P3) measured preoperatively and supine (P4) measured postoperatively. RESULTS: Mean +/- SD cardiac output was 4407+/-1109 mL/min (P1), 4182+/-825 mL/min (P2), 4031+/-798 mL/min (P3) and 4641+/-1064 mL/min (P4). Cardiac output was significantly less in P3 than in P1 (P = 0.049) due to a lower P3 velocity time integral compared with P1 (P = 0.020). Postoperatively, in the supine position, there was no difference in cardiac output, although there was a lower heart rate (P = <0.001) and increased velocity time integral (P = <0.001) compared with P1. The mean differences in interobserver measurements were 0.02 cm (left ventricular outflow tract) and -1.06 cm (velocity time integral). The mean differences in intraobserver measurements were 0.00 cm (left ventricular outflow tract) and -0.22 cm (velocity time integral). Echocardiography was well accepted by all women. Eight women found the left lateral 10 degrees head-down position (P3) uncomfortable due to dizziness, headache, or increased abdominal pressure. CONCLUSIONS: Cardiac output showed large variability and was lower than previously reported. Cardiac output decreased with the left lateral 10 degrees head-down position due to a reduction in stroke volume that has not previously been reported. The transthoracic examination was acceptable to all women. PMID- 20202819 TI - Side effects of the addition of clonidine 75 microg or sufentanil 5 microg to 0.2% ropivacaine for labour epidural analgesia. AB - BACKGROUND: Sufentanil 5 microg and clonidine 75 microg produce a similar reduction in minimum local anaesthetic concentration of ropivacaine. The aim of the present study was to compare the side effects of two equianalgesic solutions by combining 0.2% ropivacaine with either sufentanil 5 microg or clonidine 75 microg for labour epidural analgesia. METHODS: In a prospective double-blind study, 60 women at 5 cm cervical dilatation were randomly allocated to receive 0.2% ropivacaine with either sufentanil 5 microg or clonidine 75 microg to initiate labour analgesia. The analgesic efficacy and side effects of the two mixtures were compared. RESULTS: Onset, duration and quality of analgesia and subsequent ropivacaine consumption were similar in the two groups. Hypotension was significantly more frequent and severe with clonidine than with sufentanil (systolic blood pressure <100 mmHg: 17/26 vs. 6/24, P <0.05; systolic blood pressure <90 mmHg: 5/26 vs. 0/24, P <0.05) resulting in more frequent ephedrine administration (11/26 vs. 2/24, P <0.05) and larger fluid requirements (1696 +/- 583 mL vs. 1264 +/- 407 mL, P < 0.05). Conversely, pruritus was more frequent with sufentanil than with clonidine (6/26 vs. 1/24, P <0.05). CONCLUSIONS: Hypotension occurs more frequently when clonidine is added to epidural ropivacaine instead of an equianalgesic dose of sufentanil. Therefore, clonidine cannot be recommended for routine administration for labour epidural analgesia. PMID- 20202820 TI - All parturients receiving neuraxial morphine should be monitored with continuous pulse oximetry. PMID- 20202821 TI - Multisensory systems integration for high-performance motor control in flies. AB - Engineered tracking systems 'fuse' data from disparate sensor platforms, such as radar and video, to synthesize information that is more reliable than any single input. The mammalian brain registers visual and auditory inputs to directionally localize an interesting environmental feature. For a fly, sensory perception is challenged by the extreme performance demands of high speed flight. Yet even a fruit fly can robustly track a fragmented odor plume through varying visual environments, outperforming any human engineered robot. Flies integrate disparate modalities, such as vision and olfaction, which are neither related by spatiotemporal spectra nor processed by registered neural tissue maps. Thus, the fly is motivating new conceptual frameworks for how low-level multisensory circuits and functional algorithms produce high-performance motor control. PMID- 20202822 TI - Cisplatin-induced apoptosis involves a Fas-ROCK-ezrin-dependent actin remodelling in human colon cancer cells. AB - In human colon cancer cells, cisplatin-induced apoptosis involves the Fas death receptor pathway independent of Fas ligand. The present study explores the role of ezrin and actin cytoskeleton in relation with Fas receptor in this cell death pathway. In response to cisplatin treatment, a rapid and transient actin reorganisation is observed at the cell membrane by fluorescence microscopy after Phalloidin-FITC staining. This event is dependent on the membrane fluidification studied by electron paramagnetic resonance and necessary for apoptosis induction. Moreover, early after the onset of cisplatin treatment, ezrin co-localised with Fas at the cell membrane was visualised by membrane microscopy and was redistributed with Fas, FADD and procaspase-8 into membrane lipid rafts as shown on Western blots. In fact, cisplatin exposure results in an early small GTPase RhoA activation demonstrated by RhoA-GTP pull down, Rho kinase (ROCK)-dependent ezrin phosphorylation and actin microfilaments remodelling. Pretreatment with latrunculin A, an inhibitor of actin polymerisation, or specific extinction of ezrin or ROCK by RNA interference prevents both cisplatin-induced actin reorganisation and apoptosis. Interestingly, specific extinction of Fas receptor by RNA interference abrogates cisplatin-induced ROCK-dependent ezrin phosphorylation, actin reorganisation and apoptosis suggesting that Fas is a key regulator of cisplatin-induced actin remodelling and is indispensable for apoptosis. Thus, these findings show for the first time that phosphorylation of ezrin by ROCK via Fas receptor is involved in the early steps of cisplatin induced apoptosis. PMID- 20202823 TI - Hepatitis B virus-associated intrahepatic cholangiocarcinoma and hepatocellular carcinoma may hold common disease process for carcinogenesis. AB - AIMS: To evaluate potential risk factors for intrahepatic cholangiocarcinoma (ICC) and analyse clinicopathologic characteristics of ICC patients with seropositive hepatitis B surface antigen (HBsAg). METHODS: A retrospective case control study was conducted. Cases were 317 ICC patients referred to the Eastern Hepatobiliary Surgery Hospital in China between 2003 and 2006. Controls were 634 healthy individuals. Adjusted odds ratios (ORs) were calculated in logistic regression analysis. Among 317 consecutively enrolled ICC patients, 154 patients were seropositive HBsAg (48.6%). We compared clinicopathologic characteristics of these patients (group I) with ICC patients seronegative for HBsAg (group II; n=163) and compared the age and sex distributions of patients in group I with randomly selected hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) (group III; n=1,140). RESULTS: Compared with the controls, ICC patients had a high prevalence of seropositive HBsAg, cirrhosis, hepatolithiasis and hepatic schistosomiasis. Compared with seronegative-HBsAg ICC patients, seropositive HBsAg ICC patients were younger, more frequently male and had a higher proportion of abnormal aminotransferase and serum alpha-fetoprotein (AFP) level, histological inflammation and cirrhosis, right-lobe focus, poor tumour differentiation, tumour encapsulation and microvascular invasion; had a lower proportion of abnormal serum carbohydrate antigen 19-9 (CA19-9) level and lymphatic metastasis. The age and sex distribution profiles were nearly identical between seropositive-HBsAg ICC patients and HBV-associated HCC patients. CONCLUSIONS: The HBV infection, cirrhosis, hepatolithiasis and hepatic schistosomiasis may be potential risk factors for ICC. HBV-associated ICC shares many clinicopathological similarities with HBV-associated HCC. The result indicated HBV-associated ICC and HBV-associated HCC may hold common disease process for carcinogenesis. PMID- 20202824 TI - Serum biomarkers of cell death for monitoring therapy response of gastrointestinal carcinomas. AB - PURPOSE: Antitumour treatments are thought to exert their therapeutic efficacy mainly by induction of apoptosis in tumour cells. In epithelial cells, caspases, the key enzymes of apoptosis, cleave the intermediate filament protein cytokeratin (CK)-18 into specific fragments that are released into circulating blood and can be detected by a specific ELISA. EXPERIMENTAL DESIGN: To investigate the use of CK-18 fragments as a potential biomarker for the treatment response, we examined the association of serum CK-18 levels and clinical response in 35 patients with gastrointestinal cancers. RESULTS: While both cleaved and total CK-18 levels were intrinsically elevated in tumour patients, they were further increased during 5-fluorouracil (5-FU)-based therapy. Importantly, the increased levels of CK-18 could discriminate between patients with different clinical response. Cancer patients with a partial response or stable disease revealed a significantly higher increase of cleaved CK-18 during chemotherapy as compared to patients with progressive disease. CONCLUSIONS: Our results suggest that detection of circulating caspase-cleaved CK-18 might be a useful serum biomarker for monitoring treatment response and should merit further evaluation in larger patient groups. PMID- 20202825 TI - Adsorptive removal of Cd(II) from aqueous solution using natural and modified rice husk. AB - In this study, the natural and modified rice husk were tested to remove Cd(II) ions from water. The modified rice husk was prepared by being treated with alkali. The results showed the Cd(II) adsorption capacity was 73.96, 125.94 mg/g, respectively, for the natural and modified rice husk. The modified rice husk had faster kinetics and higher adsorption capacities than the natural rice husk, which can be attributed to the surface structural changes of the material. Equilibrium adsorption data are more consistent with the Langmuir isotherm equation than with the Freundlich equation. The Cd(II) adsorption on the two adsorbents tends to increase with the increase of pH. The optimum pH for Cd(II) adsorption is 6.5. Both pseudo-first-order and pseudo-second-order equations were able to describe properly the kinetics of Cd(II) adsorption. The desorbability of Cd(II) is about 95.8-99.1% by 0.1M HCl solution. PMID- 20202826 TI - Enhanced bio-hydrogen production by the combination of dark- and photo fermentation in batch culture. AB - In this study, some key factors, for example, diluted ratio of effluents, the ratio of dark-photo bacteria, light intensity and light/dark cycle influencing hydrogen production by combining Clostridium butyricum and immobilized Rhodopseudomonas faecalis RLD-53 in batch culture, were investigated. Experimental results showed the photo-hydrogen yield decreased when increasing diluted ratio from 1:0.5 to 1:3, and it reached the maximum value of 4368 ml H(2)/l-effluents at the ratio of 1:0.5. When the ratio of dark-photo bacteria was at 1:2, the hydrogen yield reached highest value of 4.946 mol-H(2)/mol-glucose and cumulative hydrogen volume was 5357 ml-H(2)/l-culture during the combination process. When the light intensity was at 10.25 W/m(2), the hydrogen volume of photo-fermentation and the combination process reached maximum value of 4260 ml H(2)/l-effluents and 5892 ml-H(2)/l-culture, respectively. During the combination process, maximum total hydrogen yield was 5.374 mol-H(2)/mol-glucose. Meanwhile, hydrogen production under light/dark cycle was evaluated. PMID- 20202827 TI - Effects of different nitrogen and phosphorus concentrations on the growth, nutrient uptake, and lipid accumulation of a freshwater microalga Scenedesmus sp. AB - Microalgae have high potential to remove inorganic nutrients from wastewater and to produce biodiesel. Effects of nitrogen and phosphorus concentrations on growth, nutrient uptake, and lipid accumulation of a freshwater microalga Scenedesmus sp. LX1 were studied. Scenedesmus sp. LX1's growth was in accordance with the Monod model. The following Monod parameters were obtained: the N- and P saturated maximum growth rate was 2.21 x 10(6) cells m L(-1)d(-1), and the half saturation constants of N and P uptake were 12.1 mg L(-1) and 0.27 mg L(-1), respectively. In the nitrogen/phosphorus ratio of 5:1-12:1, 83-99% nitrogen and 99% phosphorus could be removed. In conditions of nitrogen (2.5 mg L(-1)) or phosphorus (0.1 mg L(-1)) limitation, Scenedesmus sp. LX1 could accumulate lipids to as high as 30% and 53%, respectively, of its algal biomass. The lipid productivity/unit volume of culture, however, was not enhanced. Further research should be made on how to enhance both lipid content and lipid productivity. PMID- 20202828 TI - Supercritical fluid extraction of peach (Prunus persica) almond oil: process yield and extract composition. AB - Peach kernels are industrial residues from the peach processing, contain oil with important therapeutic properties and attractive nutritional aspects because of the high concentration of oleic and linoleic acids. The extraction method used to obtain natural compounds from raw matter is critical for product quality definition. Thus, the aim of this work was to compare peach almond extraction yields obtained by different procedures: soxhlet extractions (Sox) with different solvents; hydrodistillation (HD); ethanolic maceration (Mac) followed by fractionation with various solvents, and supercritical fluid extraction (SFE) at 30, 40 and 50 degrees C and at 100, 200 and 300bar, performed with pure CO(2) and with a co-solvent. The extracts were evaluated with respect to fatty acid composition (FAC), fractionated chemical profile (FCP) and total phenolic content (TPC). The Sox total yields were generally higher than those obtained by SFE. The crossover pressure for SFE was between 260 and 280bar. The FAC results show oleic and linoleic acids as main components, especially for Sox and SFE extracts. The FCP for samples obtained by Sox and Mac indicated the presence of benzaldehyde and benzyl alcohol, components responsible for almond flavor and with important industrial uses, whereas the SFE extracts present a high content of a possible flavonoid. The higher TPC values were obtained by Sox and Mac with ethanol. In general, the maximum pressure in SFE produced the highest yield, TPC and oleic acid content. The use of ethanol at 5% as co-solvent in SFE did not result in a significant effect on any evaluated parameter. The production of peach almond oil through all techniques is substantially adequate and SFE presented advantages, with respect to the quality of the extracts due to the high oleic acid content, as presented by some Sox samples. PMID- 20202829 TI - Nitrate removal by microbial enhancement in a riparian wetland. AB - A riparian wetland (RW) was constructed in a river bend to study the effect of the addition of Bacillus subtilis FY99-01 on nitrate removal. Nitrate was removed more efficiently in the summer than in the winter owing to integrated hydraulic, microbial and environmental effects. The maximal nitrate removal and the mean nitrate loss rate in the RW were 36.1% and 50.5 g/m(2)/yr, respectively. Statistic analyses indicated that the redox potential was very significant to denitrification while organic matter in the outflow, temperature and nitrate in the inflow significantly affected nitrate removal. These results suggest that an RW can be a cost-effective approach to enhance microbial nitrate removal and can potentially be extended to similar river bends. PMID- 20202830 TI - Heterotrophic nitrogen removal by a newly isolated Acinetobacter calcoaceticus HNR. AB - Strain HNR, isolated from a Membrane Bioreactor (MBR), demonstrates a surprising ability to convert ammonium to nitrogen gas under aerobic conditions while growing heterotrophically. On the basis of phylogenetic analysis of the 16S rRNA gene sequence, strain HNR was related to Acinetobacter calcoaceticus (98.9% identity). Nitrogen balance during heterotrophic growth with 120mg/l of NH(4)(+) N showed that 40.2% of NH(4)(+)-N was in the form of N(2) and 52.1% was found in biomass. Only a trace production was either nitrite or nitrate. Further tests demonstrated that nitrite and nitrate were not reduced by strain HNR under aerobic conditions. Neither nitrate reductase (NR) nor nitrite reductase (NiR) activity was detectable in the aerobic reaction mixtures. However, a 0.051 U activity of hydroxylamine oxidase (HAO) was observed. The nitrogen removal was speculated to be via a hydroxylamine intermediate instead of nitrite, which was different from the conventional nitrogen removal pathway. PMID- 20202831 TI - Biological treatment of waste gas containing mixture of monochlorobenzene (MCB) and benzene in a bench scale biofilter. AB - The paper outlines treatment of waste gas containing monochlorobenzene (MCB) and benzene in a mixture using biofilter packed with compost and woodchips seeded with Acinetobacter calcoaceticus. The biofilter could treat waste gas containing MCB and benzene effectively with an efficiency of (99+/-5%) and (97+/-6%) at optimal empty bed contact time (EBCT) of 3 min with a loading of 57 g/m(3)/h of MCB and 2g/m(3)/h of benzene. At optimum loading of MCB and benzene, the biofilter showed total bacterial count of 13 x 10(5)CFU/g of compost, while the MCB and benzene degrading bacterial count was 71 x 10(4)CFU/g and 5 x 10(4)CFU/g compost respectively. The experimental removal efficiency of MCB and benzene were in good agreement with the model predicted value. PMID- 20202832 TI - High flux and antifouling filtration membrane based on non-woven fabric with chitosan coating for membrane bioreactors. AB - To prepare a high flux and antifouling filtration membrane used for submerged membrane bioreactors, non-woven fabric (NWF) was modified by coating chitosan (CS) on both internal and outer surface. Chemical structural and morphological changes were characterized. The changes of surface free energy were monitored by dynamic contact angle, which showed an increase after modification. The CS/NWF composite membranes were found to be with high flux, high effluent quality and excellent antifouling property. The results of fouling resistance distribution indicated that irreversible fouling resistance was decreased by coating CS. Especially, there were fewer gel layers existing on the outer surface. The adsorption of EPS on the NWF membrane internal surface decreased after being coated with CS. Modification improved filtration performance, and made fouling less troublesome and membrane regeneration efficient. PMID- 20202833 TI - Influence of biodynamic preparations on compost development and resultant compost extracts on wheat seedling growth. AB - Biodynamic (BD) agriculture, a form of organic agriculture, includes the use of specially fermented preparations, but peer-reviewed studies on their efficacy are rare. Composting of a grape pomace and manure mixture was studied in two years (2002 and 2005) with and without the BD compost preparations. Water extracts of finished composts were then used to fertigate wheat seedlings, with and without added inorganic fertilizer. BD-treated mixtures had significantly greater dehydrogenase activity than did untreated (control) mixtures during composting, suggesting greater microbial activity in BD-treated compost. In both years there was a distinct compost effect on wheat shoot and root biomass irrespective of supplemental fertilizer. Shoot biomass was highest in all treatments receiving 1% compost extract. Wheat seedlings that received 1% compost extract in 2005 grew similar root and shoot biomass as fertilized seedlings, despite only containing 30% as much nitrogen as the fertilizer treatment. In both years seedlings that received fertilizer plus 1% compost extract produced 22-61% more shoot biomass and 40-66% more root biomass than seedlings that received fertilizer alone, even at higher rates. In 2002 a 1% extract of BD compost grew 7% taller wheat seedlings than did 1% extract of untreated compost. At 0.1% only BD extract grew taller plants than water, but in 2002 only. No effect on shoot or root biomass was seen at 0.1%. Our results support the use of compost extracts as fertilizer substitutes or supplements, testimonial reports on the growth promoting effects of compost extracts, and the occasional superiority of BD compost to untreated compost. PMID- 20202834 TI - Optimizing on-farm pretreatment of perennial grasses for fuel ethanol production. AB - Switchgrass (Panicum virgatum L.) and reed canarygrass (Phalaris arundinacea L.) were pretreated under ambient temperature and pressure with sulfuric acid and calcium hydroxide in separate experiments. Chemical loadings from 0 to 100g (kg DM)(-1) and durations of anaerobic storage from 0 to 180days were investigated by way of a central composite design at two moisture contents (40% or 60% w.b.). Pretreated and untreated samples were fermented to ethanol by Saccharomyces cerevisiae D5A in the presence of a commercially available cellulase (Celluclast 1.5L) and beta-glucosidase (Novozyme 188). Xylose levels were also measured following fermentation because xylose is not metabolized by S. cerevisiae. After sulfuric acid pretreatment and anaerobic storage, conversion of cell wall glucose to ethanol for reed canarygrass ranged from 22% to 83% whereas switchgrass conversions ranged from 16% to 46%. Pretreatment duration had a positive effect on conversion but was mitigated with increased chemical loadings. Conversions after calcium hydroxide pretreatment and anaerobic storage ranged from 21% to 55% and 18% to 54% for reed canarygrass and switchgrass, respectively. The efficacy of lime pretreatment was found to be highly dependent on moisture content. Moreover, pretreatment duration was only found to be significant for reed canarygrass. Although significant levels of acetate and lactate were observed in the biomass after storage, S. cerevisiae was not found to be inhibited at a 10% solids loading. PMID- 20202835 TI - Synergistic effects of chitosan-guanidine complexes on enhancing antimicrobial activity and wet-strength of paper. AB - Chitosan-guanidine complexes were prepared by reacting chitosan and polyhexamethylene guanidine hydrochloride or crosslinked polyhexamethylene guanidine hydrochloride in the presence of sodium tripolyphosphate as a crosslinking agent. The complexes, used as functional additives for paper, synergistically improved wet-strength and antimicrobial activities. In comparison with the control sample, the wet/dry strength ratio of hand-sheets treated with the complexes was increased from 2.65% up to 23.3%. The MIC values of the chitosan-PHGH and chitosan-PHGHE complexes against Escherichia coli were 15.6 and 31.2 microg mL(-1), respectively, thus demonstrating excellent antimicrobial activity. Hand-sheets treated with the complexes exhibited antibacterial activity against E. coli and Staphylococcus aureus. The release of the guanidine polymers included in the complexes was dynamically monitored using UV and the results showed the amount released exceeded 80%. Atomic force microscopy images indicated that the antimicrobial mechanism of the complexes was likely due to membrane damage. PMID- 20202836 TI - New inhibitors for expression of IgE receptor on human mast cell. AB - Exploration for inhibitors against expression of IgE receptor (Fc epsilonRI) on human mast cell, a significant trigger to acute and chronic allergic symptoms, disclosed epigallocatechin gallate (EGCG), epicatechin gallate, and gallocatechin gallate as active principles. Additionally, the anthocyanidin, delphinidin, and the flavone, tricetinidin, possessing a pyrogallol function were also revealed to suppress expression of Fc epsilonRI. Structure-activity relationship analysis among catechins, anthocyanidins, and flavones revealed the pyrogallol moiety to be crucial for biological potency. Furthermore, EGCG was clarified to reduce generation of gamma-chain subunit to suppress expression of Fc epsilonRI on human mast cells. PMID- 20202837 TI - The identification a novel, selective, non-steroidal, functional glucocorticoid receptor antagonist. AB - The identification of novel, potent, non-steroidal/small molecule functional GR antagonist GSK1564023A selective over PR is described. Associated structure activity relationships and the process of optimisation of an initial HTS hit are also described. PMID- 20202838 TI - Identification of pyridazino[4,5-b]indolizines as selective PDE4B inhibitors. AB - Substituted pyridazino[4,5-b]indolizines were identified as potent and selective PDE4B inhibitors. We describe the structure-activity relationships generated around an HTS hit that led to a series of compounds with low nanomolar affinity for PDE4B and high selectivity over the PDE4D subtype. PMID- 20202839 TI - Synthesis and biological evaluation of N-difluoromethyl-1,2-dihydropyrid-2-one acetic acid regioisomers: dual inhibitors of cyclooxygenases and 5-lipoxygenase. AB - A new group of acetic acid (7a-c, R(1) = H), and propionic acid (7d-f, R(1) = Me), regioisomers wherein a N-difluoromethyl-1,2-dihydropyrid-2-one moiety is attached via its C-3, C-4, and C-5 position was synthesized. This group of compounds exhibited a more potent inhibition, and hence selectivity, for the cyclooxygenase-2 (COX-2) relative to the COX-1 isozyme. Attachment of the N difluoromethyl-1,2-dihydropyrid-2-one ring system to an acetic acid, or propionic acid, moiety confers potent 5-LOX inhibitory activity, that is, absent in traditional arylacetic acid NSAIDs. 2-(1-Difluoromethyl-2-oxo-1,2-dihydropyridin 5-yl)acetic acid (7c) exhibited the best combination of dual COX-2 and 5-LOX inhibitory activities. Molecular modeling (docking) studies showed that the highly electronegative CHF(2) substituent present in 7c, that showed a modest selectivity for the COX-2 isozyme, is oriented within the secondary pocket (Val523) present in COX-2 similar to the sulfonamide (SO(2)NH(2)) COX-2 pharmacophore present in celecoxib, and that the N-difluoromethyl-1,2 dihydropyrid-2-one pharmacophore is oriented close to the region containing the LOX enzyme catalytic iron (His361, His366, and His545). Accordingly, the N difluoromethyl-1,2-dihyrdopyrid-2-one moiety possesses properties suitable for the design of dual COX-2/5-LOX inhibitory drugs. PMID- 20202840 TI - Discovery of a synthetic dual inhibitor of HIV and HCV infection based on a tetrabutoxy-calix[4]arene scaffold. AB - A potential anti-HIV and HCV drug candidate is highly desirable as coinfection has become a worldwide public health challenge. A potent compound based on a tetrabutoxy-calix[4]arene scaffold that possesses dual inhibition for both HIV and HCV is described. Structural activity relationship studies demonstrate the effects of lower-rim alkylation in maintaining cone conformation and upper-rim interacting head groups on the calix[4]arene play key roles for its potent dual antiviral activities. PMID- 20202841 TI - Synthesis and SAR of N-(4-(4-alklylpiperazin-1-yl)phenyl)benzamides as muscarinic acetylcholine receptor subtype 1 (M1) anatgonists. AB - This Letter describes the synthesis and SAR, developed through an iterative analog library approach, of a novel series of selective M(1) mAChR antagonists, based on an N-(4-(4-alkylpiperazin-1-yl)phenyl)benzamide scaffold for the potential treatment of Parkinson's disease, dystonia and other movement disorders. Compounds in this series possess M(1) antagonist IC(50)s in the 350 nM to >10 microM range with varying degrees of functional selectivity versus M(2) M(5). PMID- 20202842 TI - Pyridinyl aminohydantoins as small molecule BACE1 inhibitors. AB - A novel class of pyridinyl aminohydantoins was designed and prepared as highly potent BACE1 inhibitors. Compound (S)-4g showed excellent potency with IC(50) of 20 nM for BACE1. X-ray crystallography indicated that the interaction between pyridine nitrogen and the tryptophan Trp76 was a key feature in the S2' region of the enzyme that contributed to increased potency. PMID- 20202843 TI - Orally active and brain permeable proline amides as highly selective 5HT2c agonists for the treatment of obesity. AB - Brain-penetrable proline amides were developed as 5HT2c agonists with more than 1000-fold binding selectivity against 5HT2b receptor. After medicinal chemistry optimization and SAR studies, orally active proline amides with robust efficacy in a rodent food intake inhibition model were uncovered. PMID- 20202844 TI - Correlations of the Gait Profile Score and the Movement Analysis Profile relative to clinical judgments. AB - The Gait Profile Score (GPS) is a single index measure that summarises the overall deviation of kinematic gait data relative to normative data. The GPS can be decomposed to provide Gait Variable Scores (GVS) of nine key component kinematic gait variables, which are presented as a Movement Analysis Profile (MAP). The purpose of this study was to investigate the validity of the GPS and MAP relative to clinician judgments. Kinematic data were selected from 60 children and inspected by 17 experienced clinicians. The degree of abnormality of the overall unilateral gait pattern and the nine kinematic variables was rated according to a 0-10 point scale. Strong, significant, positive correlations were found between the GPS and MAP component scores, and clinicians' ratings of kinematic gait deviation, with Spearman correlations ranging from 0.84 to 0.97. These high correlations provide evidence that the GPS and the MAP have criterion related validity relative to clinician judgments. We propose that the GPS and particularly its MAP decomposition may be useful in clinical practice and education as an adjunct to the traditional presentation of complex kinematic data. PMID- 20202845 TI - Gaining ground: assays for therapeutics against botulinum neurotoxin. AB - Owing in part to recently heightened concern over bioterrorism, interest in the mechanism of action of botulinum neurotoxin (BoNT) and development of effective therapeutic strategies has dramatically increased. The emergence of BoNT as an effective treatment for a variety of neurological disorders and its growing use in the cosmetic industry have also increased interest in developing effective countermeasures. Although recent attempts to create effective vaccines appear promising, the multitude of clinical and cosmetic uses of BoNT make mass vaccination against the toxin undesirable and impractical, leading to intensified efforts to develop effective therapeutics to combat large-scale intoxications. In this review, we examine the relevant and available in vitro cell-based assays and in vivo assays for drug discovery and development, especially with regard to the potential for medium- to high-throughput automation and its use in identifying physiologically relevant inhibitors. PMID- 20202846 TI - When metagenomics meets stable-isotope probing: progress and perspectives. AB - The application of metagenomics, the culture-independent capture and subsequent analysis of genomic DNA from the environment, has greatly expanded our knowledge of the diversity of microbes and microbial protein families; however, the metabolic functions of many microorganisms remain largely unknown. DNA stable isotope probing (DNA-SIP) is a recently developed method in which the incorporation of stable isotope from a labelled substrate is used to identify the function of microorganisms in the environment. The technique has now been used in conjunction with metagenomics to establish links between microbial identity and particular metabolic functions. The combination of DNA-SIP and metagenomics not only permits the detection of rare low-abundance species from metagenomic libraries but also facilitates the detection of novel enzymes and bioactive compounds. PMID- 20202847 TI - Regulatory roles of the bacterial nitrogen-related phosphotransferase system. AB - In addition to the sugar phosphotransferase system (sugar PTS) dedicated to carbohydrate uptake, many Gram-negative bacteria possess a so-called nitrogen PTS (PTS(Ntr)). Although fulfilling very different functions, both systems can communicate with each other by phosphate exchange. PTS(Ntr) regulates diverse processes implicated in metabolism of nitrogen and carbon, and is essential for virulence in some bacteria. Additionally, it plays a role in potassium homeostasis by regulating the expression and activity of a high- and a low affinity K(+) transporter, respectively. In this article, we review recent advances in the understanding of the regulatory roles of PTS(Ntr) in various organisms. PMID- 20202848 TI - Prevalence of mood-altering and opioid medication use among spine surgery candidates and relationship with hospital cost. AB - Depression is the most common psychiatric illness in the USA and is commonly diagnosed in patients with chronic back pain. We investigated the use of mood altering medications among spine surgery candidates and the relationship with opioid use and cost of care. We retrospectively reviewed the charts of 578 spine surgery patients who underwent surgery during 2005 to 2007 and their hospital charges. Patients were divided by type of spine surgery as follows: 154 lumbar microdiscectomies (LMD), 297 anterior cervical decompression and fusions (ACDF) and 127 lumbar decompression and fusions (LDF). We found that 25.4% of spine surgery candidates were on antidepressants, 9.3% on anxiolytics, and 41.3% on opioids were. More precisely, 26.6% of LMD, 24.6% of ACDF and 26% of LDF patients were on antidepressants; 9.1% of LMD, 7.1% of ACDF, and 15% of LDF patients were on anxiolytics; and 47.4% of LMD, 36% of ACDF, and 46.5% of LDF patients were on opioids. Of all patients, 16.8% were on two or three types of these medications. Significantly more antidepressants were used by females in the ACDF and LDF groups and more opioids were used by African Americans in the LDF group. There were significant differences (p<0.05) in the length of stay and hospital cost between patients on antidepressants and those not on antidepressants in the LDF group, especially among females. Opioids are the most commonly used psychoactive drugs among chronic back pain and spine surgery candidates followed by antidepressants and anxiolytics. Screening for antidepressant use among spine surgery patients seems reasonable on the preoperative visit. This would help adjust antidepressant medications following surgery as depression might resolve in response to pain improvement. If antidepressant medications were initially prescribed to treat pain; they also might need to be tapered off postoperatively to correspond with new pain levels. The relationship of antidepressants with increased hospital charges in this category of patients requires further investigation. PMID- 20202849 TI - Intracranial mucosa-associated lymphoid tissue (MALT) lymphoma. AB - Primary central nervous system lymphomas are a rare lymphoid tumor. A small proportion of these lymphomas are low-grade B-cell lymphoma of the mucosa associated lymphoid tissue (MALT) subgroup. A primary MALT-lymphoma of the dura is very rare, with only a few reports. These low-grade tumors respond favorably to a combination of surgery and post-operative regional external beam radiotherapy. Differentiating these lesions from primary lymphomas or other dural based lesions is therefore critical to determine clinical management and future prognosis. We report a 29-year-old patient with visual loss and dural-based MALT lymphoma and discuss the pertinent findings as well as the clinical management of patients with this unusual lesion. PMID- 20202850 TI - Single versus double burr hole drainage of chronic subdural hematomas. A study of 267 cases. AB - A spectrum of surgical techniques has been used in the management of chronic subdural hematomas. Single burr hole and double burr hole drainage are among the commonest techniques. A retrospective analysis of 267 patients with chronic subdural hematomas treated surgically by either single or double burr holes was performed. Recurrence rates of subdural hematomas treated either with single or double burr holes were not significantly different (chi 2; p > 0.05). Thus, the number of burr holes does not affect the post-operative recurrence rate of chronic subdural hematomas. Both techniques are equally effective treatments. PMID- 20202852 TI - Intraoperatively-made cement-on-cement antibiotic-loaded articulating spacer for infected total knee arthroplasty. AB - Cement articulating spacers have been used for the treatment of TKA infection. The disadvantages of commercially available pre-made mobile spacers include limitations in implant size and antibiotic dose, often allowing delivery of only a single antibiotic agent. Hand-made mobile spacers fail to provide a well-shaped and congruently articular surface and have difficulties in maintaining stability. We present a method of intraoperatively-made cement-on-cement antibiotic-loaded articulating spacer for infected total knee arthroplasty. A custom mold was made intraoperatively with bone cement and the standard posterior stabilized TKA provisional components which were of the same size as the original prosthesis. Fabrication of the spacers did not increase the overall surgical time. From 2004 to 2007, 17 infected total knee arthroplasties were treated with two-stage reimplantation. The average length of follow-up was 31 months. One patient required an above-knee amputation for persistent infection. A knee arthrodesis was performed in one case. Ten patients received reimplantation with Nexgen LCCK knee implants. Articulating spacers were retained in situ in five patients. This articulating spacer can help improve knee mobility and function during the interval between stages. PMID- 20202851 TI - Structure, biological functions and applications of the AB5 toxins. AB - AB(5) toxins are important virulence factors for several major bacterial pathogens, including Bordetella pertussis, Vibrio cholerae, Shigella dysenteriae and at least two distinct pathotypes of Escherichia coli. The AB(5) toxins are so named because they comprise a catalytic A-subunit, which is responsible for disruption of essential host functions, and a pentameric B-subunit that binds to specific glycan receptors on the target cell surface. The molecular mechanisms by which the AB(5) toxins cause disease have been largely unravelled, including recent insights into a novel AB(5) toxin family, subtilase cytotoxin (SubAB). Furthermore, AB(5) toxins have become a valuable tool for studying fundamental cellular functions, and are now being investigated for potential applications in the clinical treatment of human diseases. PMID- 20202853 TI - Synthesis of theophylline derivatives and study of their activity as antagonists at adenosine receptors. AB - The synthesis of oligo(ethylene glycol)-alkene substituted theophyllines in positions 7 and/or 8 is described. The binding activity at adenosine receptors of selected derivatives was studied. Compound 2 showed high affinity for human A(2B) receptor (K(i) = 4.16 nM) with a selectivity K(iA2A)/K(iA2B) of 24.1, and a solubility in water of 1 mM. The alkenyl substituent in some of the theophylline derivatives allows for covalent attachment of them onto hydrogen-terminated silicon substrate surfaces via hydrosilylation. Alternatively, an azido group was incorporated to an oligo(ethylene glycol)theophylline derivative as an anchor for tethering the molecules on ethynyl presenting surfaces via click reaction. PMID- 20202855 TI - Image quality of microns-thick specimens in the ultra-high voltage electron microscope. AB - Image quality of MeV transmission electrons is an important factor for both observation and electron tomography of microns-thick specimens with the high voltage electron microscope (HVEM) and the ultra-HVEM. In this work, we have investigated image quality of a tilted thick specimen by experiment and analysis. In a 3 MV ultra-HVEM, we obtained transmission electron images in amplitude contrast of 100 nm gold particles on the top surface of a tilted 5 microm thick amorphous epoxy-resin film. From line profiles of the images, we then measured and evaluated image blurring, contrast, and the signal-to-noise ratio (SNR) under different effective thicknesses of the tilted specimen and accelerating voltages of electrons. The variation of imaging blurring was consistent with the analysis based on multiple elastic scattering. When the effective thickness almost tripled, image blurring increased from approximately 3 to approximately 20 nm at the accelerating voltage of 3 MV. For the increase of accelerating voltage from 1 to 3 MV in the condition of the 14.6 microm effective thickness, due to the reduction of multiple scattering effects, image blurring decreased from approximately 54 to approximately 20 nm, and image contrast and SNR were both obviously enhanced by a factor of approximately 3 to preferable values. The specimen thickness was shown to influence image quality more than the accelerating voltage. Moreover, improvement on image quality of thick specimens due to increasing the accelerating voltage would become less when it was further increased from 2 to 3 MV in this work. PMID- 20202854 TI - Structural basis for the design of novel Schiff base metal chelate inhibitors of trypsin. AB - The crystal structures of the complexes of bovine trypsin with m guanidinosalicylidene-l-alaninato(aqua)copper(II) hydrochloride (inhibitor 1), [N,N'-bis(m-guanidinosalicylidene)ethylenediaminato]copper(II) (inhibitor 2), and [N,N'-bis(m-amidinosalicylidene)ethylenediaminato]copper(II) (inhibitor 4) have been determined. The guanidine-containing trypsin-inhibitors (1 and 2) bind to the trypsin active site in a manner similar to that previously reported for amidine-containing inhibitors, for example, m-amidinosalicylidene-l alaninato(aqua)copper(II) hydrochloride (inhibitor 3). However, the binding mode of the guanidino groups of inhibitors 1 and 2 to Asp189 in the S1 pocket of trypsin was found to be markedly different from that of the amidino group of inhibitor 3. The present X-ray analyses revealed that the interactions of the metal ion of the inhibitors with the active site residues of trypsin play a crucial role in the binding affinity to the trypsin molecule. These structural information and inhibitory activity data for amidine- and guanidine-containing Schiff base metal chelate inhibitors provide new avenues for designing novel inhibitors against physiologically important trypsin-like serine proteases. PMID- 20202856 TI - Molecular and ultrastructural profiles of the symbionts in Cephalotes ants. AB - The molecular and ultrastructural profiles of the symbionts found in the midgut and ileum of Cephalotes atratus, Cephalotes clypeatus, and Cephalotes pusillus were determined using the V3 region of the bacterial 16S rDNA gene and transmission electron microscopy (T.E.M.). Two samples of C. atratus, three of C. clypeatus, and six of C. pusillus were analyzed. The coefficients of similarity ranged from 80% to 94% for the samples of symbionts from C. clypeatus and C. atratus, despite being collected in geographically distant sites. The variability within symbionts found in the samples of C. pusillus varied from 29% to 55%, in samples geographically close as well as distant. PCR-DGGE was effective for the purpose of this study and can be considered a versatile tool to analyze gut microbiota. Details of the ultrastructural aspect of these bacteria are presented. PMID- 20202857 TI - Argon laser phototherapy could eliminate the damage effects induced by the ionizing radiation "gamma radiation" in irradiated rabbits. AB - The ionizing radiations could be taken in considerate as an integral part in our life, since, living organisms are actually exposed to a constant shower of ionizing radiations whether from the natural or artificial resources. The radio protective efficiency of several chemicals has been confirmed in animal trails, whereas, due to their accumulative toxicity, their clinical utility is limited. Therefore, we aimed in the present work to investigate the possibility of using argon laser to recuperate the damaged tissues due to exposing to the ionizing radiation. The rabbits were used in this study, and they were designed as control, gamma irradiated, laser, and gamma plus laser groups. Lipid peroxidation, reduced glutathione (GSH), glutathione peroxidase (GSH-Px) and glucose-6-phosphate dehydrogenase (G-6-PD) in blood and liver were evaluated. As well as, the level of protein thiol was evaluated in the plasma among each group. Results of this study revealed the potential therapeutic performance of the treatment by laser argon to decline the damaging effect of the ionized radiation whether at systematic or local levels. In conclusion, argon laser therapy appears propitious protective effect against the hazard effects of gamma radiation. PMID- 20202858 TI - Neuropeptide Y and sex hormone interactions in humoral and neuronal regulation of bone and fat. AB - The hypothalamus regulates the skeleton and adipose tissue via endocrine mechanisms. Changes in sex steroid levels in menopause and aging are central to the associated changes in bone mass and adiposity. Whereas many of these effects occur via direct actions on osteoblasts or adipocytes, sex hormones can also mediate effects on bone and adipose tissue via interaction with neuronal pathways. A key hypothalamic regulator of bone and adipose tissue is neuropeptide Y (NPY), which coordinately influences these tissues via effects on neuroendocrine and sympathetic nervous output. Better understanding of the interaction between NPY and sex steroids in regulating skeletal and energy homeostasis could lead to more effective treatments for osteoporosis and obesity. PMID- 20202859 TI - The impacts of continuous veno-venous hemofiltration on plasma cytokines and monocyte human leukocyte antigen-DR expression in septic patients. AB - The aim of this study was to investigate the impacts of continuous veno-venous hemofiltration (CVVH) on plasma cytokines and monocyte human leukocyte antigen-DR (HLA-DR) expression and to evaluate the relationship between them during CVVH treatment in septic patients. Forty septic patients were enrolled in this study. They were randomly divided into control group (who received conventional treatment, n=20) and CVVH group (who received conventional treatment and CVVH treatment, n=20). The blood samples were taken to measure the changes of plasma cytokines (IFN-gamma, TNF-alpha, IL-1, IL-2, IL-4, IL-6, IL-10 and IL-13) and HLA DR expression on monocytes. After CVVH treatment, the plasma levels of IFN-gamma, IL-1, IL-2, IL-4, IL-10 and IL-13 in septic patients were markedly decreased (P<0.05), while the levels of TNF-alpha and IL-6 were only lowered to some extent without significant difference (P>0.05). HLA-DR expression on monocytes improved in CVVH treated patients (P<0.05). No matter pre-treatment or post-treatment of CVVH, there was a negative correlation between plasma IL-10 and monocyte HLA-DR expression (P<0.05). In contrast, no obvious change was shown in control patients. Our findings suggest that CVVH is effective in removal of many plasma cytokines and in improvement of monocyte HLA-DR expression in septic patients. PMID- 20202860 TI - Vascular endothelial growth factor, basic fibroblast growth factor, insulin-like growth factor-I and platelet-derived growth factor levels in human milk of mothers with term and preterm neonates. AB - Human milk is a complex biological fluid. It contains many nutrients, anti infectious and biologically active substance. Human milk also contains many angiogenic polypeptides. We have determined four of these: Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (b-FGF), insulin-like growth factor- I (IGF-I) and platelet-derived growth factor (PDGF). The aim of this study was to compare the concentrations of VEGF, b-FGF, IGF-I and PDGF in human milk collected from mothers with preterm and term neonates. Human milk samples were collected from 29 mothers of preterm (<37 weeks) and from 29 mothers of term (38>weeks) infants at days 3, 7 and 28 postpartum. Milk samples were analyzed for VEGF, b-FGF and PDGF by enzyme-linked immunosorbent assay and IGF-I was measured by radioimmunoassay method. Human milk levels of VEGF, IGF-I and b-FGF were significantly higher (p<0.001). Furthermore, within-preterm group concentrations of VEGF, IGF-I and PDGF significantly differed during postpartum days 3-7-28 (p<0.001, p<0.05, p<0.001, respectively), but did not do so for b-FGF concentrations. In term groups, concentrations of IGF-I and VEGF significantly differed (p<0.05, p<0.001, respectively), but did not do so for concentrations of b-FGF and PDGF. This is the first report of simultaneous measurements of four major angiogenic factors in human milk collected from mothers with preterm and term. Our results suggest that three of four angiogenic factors, VEGF, b-FGF and IGF-I, are higher concentration in human milk which collected from preterm mothers than those of terms. PMID- 20202861 TI - Collective mass spectrometry approaches reveal broad and combinatorial modification of high mobility group protein A1a. AB - Transcriptional states are formed and maintained by the interaction and post translational modification (PTM) of several chromatin proteins, such as histones and high mobility group (HMG) proteins. Among these, HMGA1a, a small heterochromatin-associated nuclear protein has been shown to be post translationally modified, and some of these PTMs have been linked to apoptosis and cancer. In cancerous cells, HMGA1a PTMs differ between metastatic and nonmetastatic cells, suggesting the existence of an HMGA1a PTM code analogous to the "histone code." In this study, we expand on current knowledge by comprehensively characterizing PTMs on HMGA1a purified from human cells using both nanoflow liquid chromatography collision activated dissociation mediated Bottom Up and electron-transfer dissociation facilitated middle and Top Down mass spectrometry (MS). We find HMGA1a to be pervasively modified with many types of modifications such as methylation, acetylation, and phosphorylation, including finding novel sites. While Bottom Up MS identified lower level modification sites, Top and Middle Down MS were utilized to identify the most commonly occurring combinatorially modified forms. Remarkably, although we identify several individual modification sites through our Bottom Up and Middle Down MS analyses, we find relatively few combinatorially modified forms dominate the population through Top Down proteomics. The main combinatorial PTMs we find through the Top Down approach are N-terminal acetylation, Arg25 methylation along with phosphorylation of the three most C-terminal serine residues in primarily a diphosphorylated form. This report presents one of the most detailed analyses of HMGA1a to date and illustrates the strength of using a combined MS effort. PMID- 20202862 TI - Analytical strategy for the molecular weight determination of random copolymers of poly(methyl methacrylate) and poly(methacrylic acid). AB - Molecular weight characterization of random amphiphilic copolymers currently represents an analytical challenge. In particular, molecules composed of methacrylic acid (MAA) and methyl methacrylate (MMA) as the repeat units raise issues in commonly used techniques. The present study shows that when random copolymers cannot be properly ionized by MALDI, and hence detected and measured in MS, one possible analytical strategy is to transform them into homopolymers, which are more amenable to this ionization technique. Then, by combining the molecular weight of the so-obtained homopolymers, as measured by MS, with the relative molar proportion of the MMA and MMA units, as given by (1)H NMR spectrum, one can straightforwardly estimate the molecular weight of the initial copolymer. A methylation reaction was performed to transform MAA-MMA copolymer samples into PMMA homopolymers, using trimethylsilyldiazomethane as a derivatization agent. Weight average molecular weight (M(w)) parameters of the MAA-MMA copolymers could then be derived from M(w) values obtained for the methylated MAA-MMA molecules by MALDI, which were also validated by pulsed gradient spin echo (PGSE) NMR. An alkene function in one of the studied copolymer end-groups was also shown to react with the methylation agent, giving rise to MMA like polymeric by-products characterized by tandem mass spectrometry and which could be avoided by adjusting the amount of the trimethylsilyldiazomethane in the reaction medium. PMID- 20202863 TI - Muscle fibre conduction velocity and cardiorespiratory response during incremental cycling exercise in young and older individuals with different training status. AB - We investigated the effect of ageing and training on muscle fibre conduction velocity (MFCV) and cardiorespiratory response during incremental cycling exercise. Eight young (YT; 24+/-5 yrs) and eight older (OT; 64+/-3 yrs) cyclists, together with eight young (YU; 27+/-4 yrs) and eight older (OU; 63+/-2 yrs) untrained individuals underwent to an incremental maximal test on a cycle ergometer. Ventilatory threshold (VT), respiratory compensation point (RCP) and maximal oxygen uptake (VO(2)max) were identified and MFCV recorded from the vastus lateralis muscle using surface electromyography with linear arrays electrodes. In YT MFCV increased with the exercise intensity, reaching a peak of 4.99+/-1.02 [m/s] at VT. Thereafter, and up to VO(2)max, MFCV declined. In YU MFCV showed a similar trend although the peak [4.55+/-0.53m/s] was observed, at 75% of VO(2)max an intensity higher than VT (66% of VO(2)max). In both YT and YU MFCV did not decline until RPC, which occurred at 78% VO(2)max in YU and at 92% VO(2)max (P<0.01) in YT. Differently from young individuals, MFCV in older subjects did not increase with exercise intensity. Moreover, maximal MFCV in OU was significantly lower [3.53+/-0.40 m/s;] than that of YT (P<0.005) and YU (P<0.05). The present study shows that, especially in young individuals, MFCV reflects cardiorespiratory response during incremental dynamic cyclic exercise and hence can be used to investigate motor unit recruitment strategies. PMID- 20202865 TI - Relationship between prolonged QTc interval, cardiac allograft dysfunction and elevated molecular gene expression profiling test score after heart transplantation. PMID- 20202864 TI - Reversal of impaired myocardial beta-adrenergic receptor signaling by continuous flow left ventricular assist device support. AB - BACKGROUND: Myocardial beta-adrenergic receptor (beta-AR) signaling is severely impaired in chronic heart failure (HF). This study was conducted to determine if left ventricular (LV) beta-AR signaling could be restored after continuous-flow LV assist device (LVAD) support. METHODS: Twelve patients received LVADs as a bridge to transplant. Paired LV biopsy specimens were obtained at the time of LVAD implant (HF group) and transplant (LVAD group). The mean duration of LVAD support was 152 +/- 34 days. Myocardial beta-AR signaling was assessed by measuring adenylyl cyclase (AC) activity, total beta-AR density (B(max)), and G protein-coupled receptor kinase-2 (GRK2) expression and activity. LV specimens from 8 non-failing hearts (NF) were used as controls. RESULTS: Basal and isoproterenol-stimulated AC activity was significantly lower in HF vs NF, indicative of beta-AR uncoupling. Continuous-flow LVAD support restored basal and isoproterenol-stimulated AC activity to levels similar to NF. B(max) was decreased in HF vs NF and increased to nearly normal in the LVAD group. GRK2 expression was increased 2.6-fold in HF vs NF and was similar to NF after LVAD support. GRK2 activity was 3.2-fold greater in HF vs NF and decreased to NF levels in the LVAD group. CONCLUSIONS: Myocardial beta-AR signaling can be restored to nearly normal after continuous-flow LVAD support. This is similar to previous data for volume-displacement pulsatile LVADs. Decreased GRK2 activity is an important mechanism and indicates that normalization of the neurohormonal milieu associated with HF is similar between continuous-flow and pulsatile LVADs. This may have important implications for myocardial recovery. PMID- 20202866 TI - Post-traumatic seizures-A prospective study from a tertiary level trauma center in a developing country. AB - RATIONALE: No large studies till date are available from India on post-traumatic seizures (PTS). METHODS: This is a prospective observational study of 520 patients with traumatic brain injury (TBI) (July 2007-2008). Patients admitted after 24h of injury, with Glasgow coma scale (GCS) or =5.7 microg/mL), the likelihood ratio of diabetes was 2.54 in those with central obesity and hypoadiponectinaemia. CONCLUSION: The combined use of low adiponectin levels and large WC measures has greater discriminative power than using either index alone to identify subjects at particular risk of glucose intolerance and clustering of risk factors. PMID- 20202880 TI - The metabolic syndrome: prevalence, main characteristics and association with socio-economic status in adults living in Great Tunis. AB - AIMS: This study aimed to determine the prevalence of the metabolic syndrome (MetS) and its association with socio-economic status in the population of Great Tunis. METHODS: The study included 2712 subjects (1228 men and 1484 women), aged 35-70 years and living in the Great Tunis region, all of whom were recruited between March 2004 and June 2005. The sample was weighted by using the inverse of the response rate according to governorate, district and gender. The MetS was defined according to the National Cholesterol Education Program-Adult Treatment Panel III. RESULTS: In the studied population, the overall prevalence of the MetS was 31.2%, and it was significantly more frequently seen in women than in men (37.3% vs 23.9%, respectively; P<0.001), as were abdominal obesity (69% vs 21.6%, respectively; P<0.001), high blood pressure (50.3% vs 43.1%, respectively; P<0.001) and low HDL cholesterol (40.6% vs 33.6%, respectively; P<0.001), the most common characteristics of the MetS. Also, the prevalence of the MetS increased with age in both genders, but more so in women. In those aged greater than 55 years, the prevalence of MetS was 56.7% in women and 30.7% in men. An inverse relationship was observed between level of education and prevalence of the MetS in women, with the highest prevalence being in illiterate women and the lowest in those who were university graduates. CONCLUSION: The prevalence of the MetS is markedly high within the population of Great Tunis and especially in women. As these findings predict future increases in cardiovascular disease in these populations, substantial efforts need to be made to fight against obesity and sedentary lifestyles to ameliorate the expected poor health outcomes. PMID- 20202881 TI - [Conservative treatment for breast cancer: optimization of the tumor bed localization]. AB - PURPOSE: The main objective was to assess contributions and limits of surgical clips combined with computed tomography to define the tumor bed after conservative treatment of breast cancer. This retrospective observational study enrolled 16 patients treated by lumpectomy with surgical clips placed in the tumor bed. PATIENTS AND METHODS: We assessed the difficulties in localizing the tumour bed based on collected data (i.e. clinical description, mammography, ultrasound examination, surgical procedure and pathology data). The clip's number and localization, and the volumes of the boost were also analyzed. RESULTS: There was no preoperative occurrence of localization in 57 % of cases for palpable tumours, and in 13 % of cases where the lesion was subclinical. The collected data did not allow establishing a precise localization. The mean number of surgical clips per patient was 4 (range 1-9), and the delineation of the target volumes by radiation oncologists was not standardized. Oncoplastic techniques may produce difficulties in the localization of tumour bed. CONCLUSION: The placement of surgical clips by the surgeon is helpful, primarily when oncoplastic techniques are used. In many situations, these clips may cause problems of interpretation. In order to optimize the delineation of the boost, we propose a multidisciplinary approach and methodology to be used at the Henri Becquerel Cancer Centre. PMID- 20202882 TI - Merkel cell carcinoma of the hand: case report and literature review. AB - We are reporting on a 72-year-old male who was diagnosed with Merkel cell carcinoma on the dorsal aspect of his left index finger. This rare highly aggressive malignancy of the skin has only exceptionally been described on the finger or hand. This case report helps review important findings associated with this rare malignancy and reviews the pertinent literature. PMID- 20202883 TI - Ultrasound-assisted preparation of alkaline graphite intercalation compounds. AB - Alkaline graphite intercalation compounds were prepared by flake graphite, potassium dichromate, concentrated sulfur acid and sodium hydroxide under ultrasound irradiation and characterized by scanning electron microscopy and X ray diffraction. The influences of solution alkalinity, bath temperature and reaction time on the expansion volume were also investigated. The results show that alkaline graphite intercalation compounds were prepared when SO(4)(2-) and OH(-) ions were inserted into the spaces between the graphene planes, producing a flake morphology and multilevel structure. At the same time that the interlayer volume expanded, the oxidizing ability of the solid increased. When the bath temperature, the reaction time and the solution alkalinity were at 33-36 degrees C, at 60 min and for pH=13, the top expansion volume was 35 mL g(-1). PMID- 20202884 TI - Ultrasonic pretreatment of corn slurry for saccharification: a comparison of batch and continuous systems. AB - The effects of ultrasound on corn slurry saccharification yield and particle size distribution was studied in both batch and continuous-flow ultrasonic systems operating at a frequency of 20 kHz. Ground corn slurry (28%w/v) was prepared and sonicated in batches at various amplitudes (192-320 microm(peak-to-peak (p-p))) for 20 or 40s using a catenoidal horn. Continuous flow experiments were conducted by pumping corn slurry at various flow rates (10-28 l/min) through an ultrasonic reactor at constant amplitude of 12 microm(p-p). The reactor was equipped with a donut shaped horn. After ultrasonic treatment, commercial alpha- and gluco amylases (STARGEN 001) were added to the samples, and liquefaction and saccharification proceeded for 3h. The sonicated samples were found to yield 2-3 times more reducing sugars than unsonicated controls. Although the continuous flow treatments released less reducing sugar compared to the batch systems, the continuous flow process was more energy efficient. The reduction of particle size due to sonication was approximately proportional to the dissipated ultrasonic energy regardless of the type of system used. Scanning electron microscopy (SEM) images were also used to observe the disruption of corn particles after sonication. Overall, the study suggests that both batch and continuous ultrasonication enhanced saccharification yields and reduced the particle size of corn slurry. However, due to the large volume involve in full scale processes, an ultrasonic continuous system is recommended. PMID- 20202885 TI - Influence of the frequency of the external mechanical stimulus on bone healing: a computational study. AB - The mechanical environment considerably affects the evolution of the bone healing process. However, the effect of an external cyclic stimulation on the process has not yet been fully clarified. The aim of the present work is to evaluate the distribution of different mechanical variables in the fracture callus when an external cyclic stimulation is applied at different frequencies, in order to investigate those stimuli most likely to regulate bone healing. To perform this analysis an axisymmetric poroelastic finite element model of a sheep metatarsus fracture has been developed and several mechanical variables quantified within the callus: deviatoric strain, octahedral strain, pore pressure and fluid flow velocity. The applied mechanical stimulus corresponds to a compression displacement of 0.02 mm at frequencies of 1, 50 and 100Hz. The fluid flow velocity experiences considerable variations in amplitude and peak value when the frequency of the external stimulus changes, while the rest of the mechanical variables are not significatively modified. We conclude that the change in the frequency of the external mechanical stimulus directly affects the interstitial fluid flow velocity in the fracture callus. This change in the fluid flow velocity may induce movement of wastes, feeds or growth factors, as well as stimulating cellular differentiation and proliferation by means of changes in the mechanical environment of the callus. In addition, the results of this work suggest that, to obtain a more significant effect of cyclic stimulation, higher frequencies with lower amplitude than those normally used in previous experimental works are needed. PMID- 20202886 TI - Kleptomania, an unusual impulsive control disorder in Parkinson's disease? PMID- 20202887 TI - Sleep in Parkinson's disease: a comparison of actigraphy and subjective measures. AB - Sleep disturbances are common in Parkinson's disease (PD). Actigraphy has emerged as an alternative to polysomnography to measure sleep, raising the question of its ability to capture sleep quality in PD patients. Our aim was to compare self report data with actigraphic data. Thirty non-demented individuals with PD and 14 normal control participants (NC) were included. Sleep was measured using 24-h wrist actigraphy over a seven day period, during which time participants kept a sleep diary. Subjective sleep and arousal questionnaires included the Parkinson's Disease Sleep Scale and Epworth Sleepiness Scale. Patients with PD presented with more sleep problems than NC. In NC, none of the actigraphic sleep variables were related to any of the self-report measures of sleep. In PD, scores on subjective sleep measures correlated with actigraphy-derived estimates of sleep quality. Our results suggest that actigraphy is an appropriate method of measuring sleep quality in PD. PMID- 20202888 TI - Factors related to extended hospital stays following deep brain stimulation for Parkinson's disease. AB - OBJECTIVE: Patients with Parkinson's disease (PD) are typically discharged from the hospital the day following deep brain stimulation (DBS) surgery; however, factors extending hospital stay are largely unknown. This study examined potential factors that might have corresponded to increased post-operative stays following unilateral DBS surgery. METHODS: A retrospective review was performed on 115 unilateral PD DBS patients. Age, gender, number of microelectrode passes, duration and severity of illness, and pre-operative neuropsychological scores were considered as possible contributors to length of stay. RESULTS: Most patients (79%) had a hospital stay of one day following surgery. The most frequent reasons for delayed discharge (>1 day) included mental status change (N = 6) and hemorrhage (N = 5). Those with delayed discharge had significantly lower pre-surgical cognitive screening scores (Mini-Mental State Evaluation; MMSE), higher pre-surgical "on" medication motor score, and more microelectrode passes than those with immediate discharge. In correlation analyses, increasing length of hospital stay was significantly associated with more microelectrode passes, higher pre-surgical "on" medication motor scores, and decreasing MMSE scores. When the significant variables from the preliminary analyses were entered into a Poisson regression model, a greater number of microelectrode passes as well as lower MMSE scores remained significant predictors of increased length of stay. CONCLUSIONS: The number of microelectrode passes utilized for DBS surgery as well as a patient's general cognitive status may be important factors related to extended hospital stay. UPDRS "on" medication motor score may also provide some predictive power for immediate post-operative morbidity in unilateral DBS patients. PMID- 20202889 TI - Death proteases: alive and kicking. AB - Two recent discoveries significantly add to our understanding of plant programmed cell death (PCD). Hatsugai et al. showed that cell death is dependent on proper proteasome functioning. Sundstrom et al. showed that the in vivo substrate of a type II metacaspase is associated with cell viability. Both findings are major breakthroughs within the plant PCD field and highlight that the plant cell death machinery apparently employs a wide range of structurally unrelated proteases that, surprisingly, show a caspase-like preference for specific (evolutionarily conserved) substrates. PMID- 20202890 TI - Clinical performance of different care systems with silicone hydrogel contact lenses. AB - PURPOSE: To assess the clinical and subjective performance of a one-step hydrogen peroxide (H2O2) lens care system compared to a multi-purpose disinfecting system (MPDS) when used with silicone hydrogel (SiH) lenses. METHODS: This was an eight week, contralateral (lens type) clinical trial with a randomized, cross-over (care system) design. The H2O2 system was Clear Care ((AO Sept Plus) CIBA VISION) and the MPDS was OPTI-FREE RepleniSH (Alcon) and the SiH materials were lotrafilcon B (Air Optix; CIBA VISION) and senofilcon A (Acuvue OASYS, Johnson & Johnson Vision Care). Investigators and subjects were masked to lens care and lens type, respectively. Clinical variables and ocular health assessments were conducted at a baseline, two-week and four-week visit for each cross-over phase. Comfort, dryness and vision were rated on 0-100 scales. Wearing times and comfortable wearing times were also recorded. RESULTS: Twenty-six subjects were enrolled: nine male, 17 female, mean age (+/-standard deviation) 31+/-12 years (range 17-59 years) and 24 subjects completed the study. Clinical variables showed no difference between solutions (all p > 0.05), however one subject exhibited solution-induced corneal staining with both lens materials and the MPDS. There was no difference between solutions in subjective overall ratings of comfort, dryness or vision (p > 0.05). The H2O2 resulted in longer reported comfortable wearing times than the MPDS (10.93 +/- 1.71 vs 9.84 +/- 1.47 h; repeated measures ANOVA, p < 0.01). CONCLUSIONS: While both lens care systems performed well with the SiH lenses used, the H2O2 resulted in a longer reported comfortable wearing time then the MPDS. PMID- 20202891 TI - Tear film dynamics and lipid layer characteristics--effect of age and gender. AB - PURPOSE: Dry eye disease is significantly more prevalent in older subjects and among them more marked in women than men. Further, it is established that the tear film dynamics of dry eye sufferers is different to that of normal. It is therefore postulated that the greater prevalence of dry eye problems with advancing age is at least in part related to poorer tear film dynamics. METHODS: Tear film dynamics (non-invasive break up time) and lipid characteristics (lipid layer thickness and contamination) were assessed using the Tearscope lighting system. RESULTS: 160 Subjects less than 45 years old and 58 subjects aged 45 years or more formed the study populations. The tear film stability was mostly influenced by age; the break up time was statistically significantly shorter for the older age group (p < 0.001). The lipid layer was also significantly thinner (p = 0.013) for the subjects aged 45 years or older with a very marked synergic effect of age and gender. The lipid layer of older women was significantly thinner and more contaminated than that of younger women (p = 0.002 and < 0.001) and of older men (p = 0.034 and 0.004). CONCLUSIONS: Aging of the tear film is characterised by its destabilisation associated with significant changes in the tear lipid layer producing less protection from evaporation in the older population; the observed changes are more marked in women than in men. The findings have significant implications for the management of presbyopic dry eye sufferers, for whom decreasing evaporative problems is essential. PMID- 20202892 TI - Expanding the range of 'druggable' targets with natural product-based libraries: an academic perspective. AB - Existing drugs address a relatively narrow range of biological targets. As a result, libraries of drug-like molecules have proven ineffective against a variety of challenging targets, such as protein-protein interactions, nucleic acid complexes, and antibacterial modalities. In contrast, natural products are known to be effective at modulating such targets, and new libraries are being developed based on underrepresented scaffolds and regions of chemical space associated with natural products. This has led to several recent successes in identifying new chemical probes that address these challenging targets. PMID- 20202893 TI - Study on the enhanced fluorescent spectrum of ciprofloxacin+Al(III)+La(III)+cetyltrimethylammonium bromide system and its application. AB - The fluorescence of ciprofloxacin (CIP) in HAc-NaAc buffer solution and the presence of cetyltrimethylammonium bromide (CTMAB) enhanced visibly with adding Al(III) and La(III). This enhanced fluorescence spectra were studied, and a new co-luminescence system of CIP+Al(III)+La(III)+CTMAB was discovered. There was a linear relationship between the enhanced fluorescence intensity and the concentration of CIP in the range of 0.50-80.2microgl(-1) under the optimized condition. A novel enhanced fluorescence method for the determination of trace CIP was established by using this co-luminescence system. The detection limit of the proposed method was 0.17microgl(-1) for CIP. This method is simple, rapid and sensitive. The CIP in milk samples were analyzed by the proposed method with satisfactory results. The relative standard deviation and the recovery were in ranges of 3.21-4.34% and 97.1-100.1%, respectively. The mechanism of the co luminescence reaction and the reasons for fluorescence enhancement has been discussed. PMID- 20202894 TI - A comparison study on the interaction of hyperoside and bovine serum albumin with Tachiya model and Stern-Volmer equation. AB - The interaction between hyperoside and bovine serum albumin (BSA) was examined by fluorescence spectroscopy at 298, 304, and 310K. The spectroscopic data were analyzed using Tachiya model and Stern-Volmer equation to determine the binding sites and apparent binding constant between hyperoside and BSA. For Tachiya model, both binding sites and apparent binding constants increased with the increasing of temperature, whereas for Stern-Volmer equation, the corresponding binding constants decreased as temperature increasing and the binding sites were independent of temperature. The positive sign of enthalpy change (DeltaH) and entropy change (DeltaS) suggested that hydrophobic forces played a major role in the interaction. Synchronous fluorescence spectra indicated that the conformation of protein was perturbed by the interaction of hyperoside with BSA. Moreover, the presence of metal ion affected the hyperoside-BSA binding. PMID- 20202895 TI - The influence of text characteristics on perceived and actual difficulty of health information. AB - PURPOSE: Willingness and ability to learn from health information in text are crucial for people to be informed and make better medical decisions. These two user characteristics are influenced by the perceived and actual difficulty of text. Our goal is to find text features that are indicative of perceived and actual difficulty so that barriers to reading can be lowered and understanding of information increased. METHODS: We systematically manipulated three text characteristics, - overall sentence structure (active, passive, extraposed subject, or sentential-subject), noun phrases complexity (simple or complex), and function word density (high or low), - which are more fine-grained metrics to evaluate text than the commonly used readability formulas. We measured perceived difficulty with individual sentences by asking consumers to choose the easiest and most difficult version of a sentence. We measured actual difficulty with entire paragraphs by posing multiple-choice questions to measure understanding and retention of information in easy and difficult versions of the paragraphs. RESULTS: Based on a study with 86 participants, we found that low noun phrase complexity and high function words density lead to sentences being perceived as simpler. In the sentences with passive, sentential-subject, or extraposed-subject sentences, both main and interaction effects were significant (all p<.05). In active sentences, only noun phrase complexity mattered (p<.001). For the same group of participants, simplification of entire paragraphs based on these three linguistic features had only a small effect on understanding (p=.99) and no effect on retention of information. CONCLUSIONS: Using grammatical text features, we could measure and improve the perceived difficulty of text. In contrast to expectations based on readability formulas, these grammatical manipulations had limited effects on actual difficulty and so were insufficient to simplify the text and improve understanding. Future work will include semantic measures and overall text composition and their effects on perceived and actual difficulty. LIMITATIONS: These results are limited to grammatical features of text. The studies also used only one task, a question-answering task, to measure understanding of information. PMID- 20202896 TI - The origin of the ocular vestibular evoked myogenic potential (OVEMP). PMID- 20202897 TI - Brainstem representation of vestibular evoked myogenic potentials. AB - OBJECTIVE: Vestibular evoked myogenic potentials (VEMPs) are caused by a short latency reflex recorded from averaged electromyography from the sternocleidomastoid muscle evoked by intense auditory clicks. Besides peripheral vestibulopathy, abnormal VEMPs can be caused by lesions of the brainstem. The aim of this study was to analyze the topology of ischemic brain lesions generating pathological VEMPs. METHODS: Twenty-nine patients with brainstem infarcts were prospectively studied using VEMPs and MR imaging to evaluate the brainstem representation of the VEMP reflex. Individual brainstem lesions were projected to a standard MR-dataset for normalization. Probabilistic lesion maps were calculated. A digital brainstem atlas was fitted to the lesion maps. RESULTS: Twelve patients showed unilaterally abnormal VEMPs, 10 patients had normal VEMPs. Seven patients with bilaterally absent VEMPs were not analyzed. Most lesions were located in the lateral medulla oblongata involving the spinal accessory nerve. Most lesions in the pons were associated to anterolateral parts of pyramidal tract fibers. In a few cases, lesions were located in the tegmental area of the pons, including the vestibular nuclei. CONCLUSIONS: Abnormal VEMPs may be produced not only by peripheral vestibulopathy but also by brainstem lesions. VEMPs may be influenced by effects caused by lesions located above the level of the vestibular nuclei. SIGNIFICANCE: This study adds to the knowledge of anatomical brainstem representation of VEMP. PMID- 20202898 TI - The continuing problem of diagnosing unresponsive patients: searching for neurophysiological correlates of consciousness. PMID- 20202899 TI - Event-related potentials (MMN and novelty P3) in permanent vegetative or minimally conscious states. AB - OBJECTIVE: To assess markers of cognition, if any, in patients in a permanent vegetative state (PVS). METHODS: Event-related potential (ERP) mapping was performed on 27 patients in permanent (4-261 months after coma onset) vegetative (PVS, n=16) or minimally conscious states (MCS, n=11) due to anoxia (n=18) or other aetiologies (n=9). Mismatch negativity (MMN) to duration-deviant tones and novelty P3 (nP3) to the subject's own name were recorded according to a paradigm previously validated in healthy volunteers and comatose patients. SEPs, MLAEPs and BAEPs were also recorded. RESULTS: MMN was present in 5/27 and nP3 in 7/27 patients. ERPs were not related to the time from coma onset and not different in MCS and in PVS. Normal SEPs and MLAEPs, and present nP3s were less frequent in anoxia than in other aetiologies. CONCLUSIONS: Irrespective of their clinical assessment, a few patients are likely to process sound deviance (MMN) or novelty (nP3), mainly when their state is not due to anoxia. SIGNIFICANCE: Some PVS patients may be able to put certain awareness marker processes to work. The diagnostic criteria for PVS or MCS, currently based on mere behaviour, should also include functional brain investigations, such as ERPs, related to the aetiology. PMID- 20202900 TI - Extended surround inhibition in idiopathic paroxysmal kinesigenic dyskinesia. AB - OBJECTIVE: Paroxysmal kinesigenic dyskinesia (PKD) is characterized by recurrent attacks of dyskinesia, in which movement of one body part produces involuntary movements of other body parts. Surround inhibition (SI), a mechanism for suppression of unwanted movements, could be deficient in these patients. To test this idea, we performed a transcranial magnetic stimulation (TMS) study in drug naive patients with PKD. METHODS: TMS was set to be triggered by self-initiated flexion of the index finger at different intervals. Average motor evoked potential (MEP) amplitudes obtained from self-triggered TMS were normalized to average MEPs of the control TMS at rest. Normalized MEP amplitudes of the patients' self-triggered TMS sessions at different intervals were compared to those of the controls. RESULTS: During index finger flexion, MEP amplitudes from the little finger muscle were unchanged in both the patients and normal subjects, however, post-movement MEP enhancement observed in the normal subjects was absent in patients with PKD. These results suggest that the functional operation of SI is itself preserved, but that post-movement excitation of surrounding muscles is deficient in PKD. CONCLUSIONS: This finding may represent that the operation of SI is extended to the post-movement period, perhaps as a compensatory mechanism for preventing unwanted movement in surrounding muscles. SIGNIFICANCE: While many types of impaired inhibition have been described previously in PKD, this is the first possible example of increased inhibition. PMID- 20202901 TI - Ocular and cervical vestibular-evoked myogenic potentials to bone conducted vibration in Meniere's disease during quiescence vs during acute attacks. AB - OBJECTIVE: Two indicators of otolithic function were used to measure dynamic otolith function in the same patients both during an acute attack of Meniere's disease (MD) and in the quiescent period between attacks. METHODS: The early negative component (n10) of the ocular vestibular-evoked myogenic potential (the oVEMP) to brief 500 Hz bone conducted vibration (BCV) stimulation of the forehead, in the midline at the hairline (Fz) was recorded by surface EMG electrodes just beneath both eyes while the patient looked up. It has been proposed that the n10 component of the oVEMP to 500 Hz Fz BCV indicates utricular function. It has been proposed that the early positive component (p13) of the cervical vestibular-evoked myogenic potential (the cVEMP) recorded by surface electrodes on both tensed SCM neck muscles to 500 Hz Fz BCV indicates saccular function. RESULTS: Sixteen healthy control subjects tested on two occasions showed no detectable change in the symmetry of oVEMPs or cVEMPs to 500 Hz Fz BCV. In response to 500 Hz Fz BCV 15 early MD patients tested at both attack and quiescent phases showed a dissociation: there was a significant increase in contralesional of n10 of the oVEMP during the attack compared to quiescence but a significant decrease in the ipsilesional p13 of the cVEMP during the attack compared to quiescence. CONCLUSIONS: During an MD attack, dynamic utricular function in the affected ear as measured by the n10 of the oVEMP to 500 Hz Fz BCV is enhanced, whereas dynamic saccular function in the affected ear as measured by the p13 of the cVEMP to 500 Hz Fz BCV is not similarly affected. SIGNIFICANCE: The MD attack appears to affect different otolithic regions differentially. PMID- 20202902 TI - Sleep quality and cognitive performance in 8-year-old children. AB - OBJECTIVE: The present study examined how sleep duration and sleep quality are associated with cognitive performance in 8-year-old children using standardized neurocognitive tests. METHODS: Two hundred ninety children aged 7.4-8.8years participated in the study. Sleep duration and quality were measured using actigraphs and the Sleep Disturbance Scale for Parents. Cognitive performance was measured using four subtests of the Wechsler Intelligence Scale for Children III, the Beery Developmental Test of Visual-Motor Integration (VMI), and the Narrative memory subtest of the Developmental Neuropsychological Assessment for Children. RESULTS: When adjusting for age, sex, and maternal education, shorter sleep duration, but not sleep quality, was associated with lower visuospatial abilities (p-values 0.043). Sleep duration and quality were not associated with verbal abilities (p-values0.18). With regard to the individual test results, shorter sleep duration was associated with worse performance in Visual-Motor Integration (p=0.028), and when excluding children with high depression scores the same was also true with Block Design (p-values0.047). Moreover, poor sleep efficiency was associated with worse performance in Similarities (p=0.004). CONCLUSIONS: In a community sample of 8-year-old children, those who slept less or had poorer sleep quality had lower test scores in cognitive tasks, particularly those pertaining to visuospatial performance, although the association was not very strong. PMID- 20202903 TI - Pharmacology of glucocorticoids in rheumatoid arthritis. AB - Glucocorticoids (GCs) provide one of the most effective treatments for rheumatoid arthritis (RA); however, their long-term use is marred by undesired side effects. Increased understanding of the mechanisms of glucocorticoid action enables the development of novel drugs, such as SEGRAs or liposomal glucococorticoids, trying to improve their benefit/risk ratio. But also trying to optimise the use of conventional glucocorticoids is a sensible approach. One example is a new modified release prednisone tablet formulation that has been recently shown to be clinically and significantly better than the conventional immediate-release preparation with respect to reducing morning stiffness of the joints. The 'old spear' can also be sharpened by collecting clear-cut evidence on the efficacy and safety of conventional glucocorticoid therapy and deriving from that reliable evidence-based recommendations. This short review summarises the current knowledge in this regard, with particular emphasis on recently published articles. PMID- 20202904 TI - Cardiovascular pharmacology in the post-blockbuster era. PMID- 20202905 TI - How can tsetse population genetics contribute to African trypanosomiasis control? AB - In sub-Saharan Africa, tsetse transmitted Trypanosomiases have an enormous impact on human health and economic development. Both the World Health Organisation and African countries through the Pan African Tsetse and Trypanosomiasis Eradication Campaign (PATTEC) have recently asserted their determination to rid the sub continent of these diseases, and it is increasingly recognised that vector control should play an important role. This review mainly focuses on population genetics of tsetse of the palpalis group, the main vectors of sleeping sickness, and reports recent results on tsetse population structure and on measures of gene flow between populations. Implications of these studies for large-scale tsetse control programmes being undertaken in West Africa are important, particularly regarding control strategies (suppression or eradication). PMID- 20202907 TI - Toxoplasma gondii: epidemiology, feline clinical aspects, and prevention. AB - Toxoplasma gondii is a parasite of birds and mammals. Cats are the only definitive host and thus the only source of infective oocysts, but other mammals and birds can develop tissue cysts. Although feline infections are typically asymptomatic, infection during human pregnancy can cause severe disease in the fetus. Cat owners can reduce their pets' exposure risk by keeping all cats indoors and not feeding them raw meat. Humans usually become infected through ingestion of oocyst-contaminated soil and water, tissue cysts in undercooked meat, or congenitally. Because of their fastidious nature, the passing of non infective oocysts, and the short duration of oocyst shedding, direct contact with cats is not thought to be a primary risk for human infection. PMID- 20202906 TI - Giardiasis in dogs and cats: update on epidemiology and public health significance. AB - Molecular data have defined seven genetic Assemblages of Giardia duodenalis, named A-G. Humans are infected with Assemblages A and B, dogs primarily with C and D, and cats with F. Assemblage A has been subclassified into subtypes A-I to A-IV: A-I has been reported in humans and animals, A-II in humans, and A-III and IV exclusively in animals. Assemblage B has broad host specificity infecting humans and animals. Recently, small numbers of dogs and cats have been reported to also carry Assemblages A-I or B. Because these genotypes are found primarily in humans, and no comprehensive studies to address zoonotic transmission of G. duodenalis are yet available, the potential role of dogs and cats cannot be conclusively excluded. PMID- 20202908 TI - Using the Benner intuitive-humanistic decision-making model in action: a case study. AB - Nurse educators make decisions that affect students in profound ways. This decision-making process may follow an intuitive-humanistic decision-making model. The author most connected with developing the intuitive model and the distinction between theoretical knowledge and experiential knowledge in the discipline of nursing is Patricia Benner (Thompson, 1999). Educators use intuition in forming judgments regarding educational planning. The educator may not be aware of subtleties that influence the decision but rely on a 'gut' instinct as they determine the appropriate action. Utilizing six key concepts identified by Dreyfus and Dreyfus (Benner and Tanner, 1987) this process utilizes what is known to the educator from previous situations to determine a course of action appropriate for the given situation. This paper describes a method one nursing educator used and identifies outcomes that could impact the career path for the student when determining if they were safe to continue in a practice based course. PMID- 20202909 TI - A focus group study of the use of video-recorded simulated objective structured clinical examinations in nurse practitioner education. AB - The objective structured clinical examination (OSCE) is a common method of clinical skills assessment used for advanced nurse practitioner students across the United Kingdom. The purpose of an advanced nursing OSCE is to assess a nurse practitioner student's competence and safety in the performance of commonly used advanced clinical practice skills. Students often feel nervous when preparing for and participating in an OSCE. Consideration of these identified anxieties led to the development of an alternative method of meeting students' OSCE learning and preparation needs; namely video-recorded simulated OSCEs. Video-recording was appealing for the following reasons: it provides a flexible usage of staff resources and time; OSCE performance mistakes can be rectified; it is possible to use the same video-recordings with multiple cohorts of students, and the recordings can be made conveniently available for students with video streaming on internet-based video-sharing sites or virtual learning environments. The aim of the study was to explore the value of using such recordings amongst nurse practitioner students, via online and face-to-face focus groups, to see if they are a suitable OSCE educational preparation technique. The study findings indicate that simulated OSCE video-recordings are an effective method for supporting nurse practitioner educational development. PMID- 20202910 TI - (W)riting across and within: Providing a vehicle for sharing local nursing and midwifery projects and innovation. AB - INTRODUCTION: This paper describes the development and outcomes of a locally based journal that is contributed to and managed by nurses, midwives and academics within an area health service (AHS) in NSW, Australia. BACKGROUND: Nurses and midwives are often engaged in scholarly and rigorous activities aimed at improving practice and patient outcomes. However, often these endeavours remain unreported, unpublished and hence not shared for the benefit of others. Reasons given for nurses' and midwives' persistent reluctance to publish are well documented in the literature. Lack of expertise and understanding of the publication process, together with lack of confidence and opportunity are the reasons most often cited. To overcome these barriers we developed a local journal called Handover that provides a non-threatening, supportive opportunity for nurses and midwives to develop skills in writing and reviewing articles for publication. Handover was established and is managed by editorial committee members from the area health service and the two local universities. Each institution agreed to co-fund the journal which is published twice yearly. Two editions of the journal have been published with wide ranging content and contributions from across the AHS. Writing mentorship and support systems have been established. Reviewers workshop have been conducted and novice reviewers mentored by experienced reviewers. CONCLUSION: Our experience indicates that a locally based and owned journal can motivate and support novice writers and offers one solution to many of the barriers to publication identified in the literature. PMID- 20202911 TI - Embryo culture: can we perform better than nature? AB - Culture of preimplantation-stage embryos has always been a key element of laboratory embryology and has contributed substantially to the success of many assisted reproduction procedures. During the past decade, its importance has increased as extended in-vitro embryo culture and single blastocyst transfer have become indispensable parts of the approach to decreasing the chance of multiple pregnancy while preserving the overall efficiency of the treatment. However, in spite of the scientific and commercial challenge stimulating research worldwide to optimize embryo culture conditions, a consensus is missing even in the basic principles, including composition and exchange of media, the required physical and biological environment and even the temperature of incubation. This review attempts to summarize the controversies, demonstrate the fragility of some widely accepted dogmas and generate an open-minded debate towards rapid and efficient optimization. New approaches expanding the traditional frames of mammalian embryo culture are also discussed. Although some researchers suppose that the efficiency of the presently applied in-vitro culture systems have already approached the biological limits, authors are confident that substantial improvement may be achieved that may expand considerably the possibilities of future assisted reproduction in humans. PMID- 20202912 TI - Nurse-led interventions in heart failure care: patient and nurse perspectives. AB - BACKGROUND: Perspectives of nurses and patients on the intensity and content of disease management programmes (DMPs) in heart failure are seldom addressed but are important in optimizing these programmes. AIM: To describe the perspectives of patients and nurses on delivered care in two DMPs. METHODS: In total 442 patients (62% male; age 68+/-12years; LVEF 33%+/-14), assigned to the intervention groups of the Coordinating Study Evaluating Outcomes of Advising and Counselling in HF (COACH), and 32 registered nurses, completed questionnaires on satisfaction with the intensity and components of the DMPs. RESULTS: In spite of large differences in intensity and components, patients were satisfied with the content of both DMPs. In patients (NYHA III-IV), treatment and educational goals were more often achieved in those who received intensive support, compared to patients who received basic support (85% vs. 70%). Patients and nurses perceived that most home visits were adding significant value to the HF care, while 12% of the home visits were perceived as unnecessary by the nurses. CONCLUSION: Patients and nurses did not perceive the intense DMP as an emotional and physical burden for themselves. Patients with severe HF might be in need of more support to achieve optimal treatment and educational goals. PMID- 20202913 TI - Endoscopic ablation of longitudinal vaginal septa in prepubertal girls: a minimally invasive alternative to open resection. AB - INTRODUCTION: Vaginal septation is a congenital defect seen in patients with persistent cloaca, urogenital sinus and disorders of Mullerian duct aplasia. Rarely, these patients present with symptoms in infancy and childhood with the exception of hydrocolpos. Treatment traditionally consists of surgical excision of the vaginal septum. We present our experience with minimally invasive endoscopic ablation of vaginal septa. MATERIALS AND METHODS: We reviewed retrospectively the management of four patients with vaginal septae: Herlyn Werner-Wunderlich syndrome (1), cloacal malformations (2), and urogenital sinus (1). All were prepubertal (aged 2-9 years). The first patient presented with hydrocolpos. The others were asymptomatic and identified during definitive reconstruction. All four underwent endoscopic ablation in <=30 min, using a pediatric resectoscope. RESULTS: One of the cloacal patients developed a postoperative perineal/vestibular infection leading to urethral stenosis and currently requires intermittent catheterization. There were no other complications. Endoscopic examination under anesthesia at 6 months in all patients revealed no septal scarring or vaginal stenosis. CONCLUSION: The advantage of endoscopic ablation over traditional open repair is that it is minimally invasive and can be easily performed as an outpatient procedure or at the time of definitive reconstruction. Our results suggest that endoscopic ablation should be considered as the primary approach for correction of vaginal septa. PMID- 20202915 TI - Functions of base selection step in human DNA polymerase alpha. AB - Recent studies have revealed that the base selection step of DNA polymerases (pol) plays a role in prevention of DNA replication errors. We investigated whether base selection is required for the DNA replication fidelity of pol alpha and genomic stability in human cells. We introduced an Leu864 to Phe substitution (L864F) into human pol alpha and performed an in vitro LacZ alpha forward mutation assay. Our results showed that the overall mutation rate was increased by 180-fold as compared to that of the wild-type. Furthermore, steady state kinetics analyses consistently showed that L864F pol alpha had a decreased discrimination ability between correct and incorrect nucleotide incorporation, as well as between matched and mismatched primer termini. L864F pol alpha also exhibited increased translesion activity over the abasic, etheno-A, O(4)-methyl T, and O(6)-methyl-G sites. In addition, our steady state kinetics analyses supported the finding of increased translesion activity of L864F pol alpha over O(6)-methyl-G. We also established stable clones transfected with pola1L864F utilizing the human cancer cell line HCT116. Using the HPRT gene as a reporter, the spontaneous mutation rate of pola1L864F cells was determined to be 2.4-fold greater than that of wild-type cells. Mutation assays were also carried out using cells transiently transfected with the wild-type or pola1L864F, and increased mutant frequencies were observed in pola1L864F cells under both spontaneous and methyl methanesulfonate-induced conditions. Together, our results indicate that the base selection step in human pol alpha functions to prevent DNA replication errors and maintain genomic integrity in HCT116 cells. PMID- 20202916 TI - Biological monitoring of bisphenol A with HLPC/FLD and LC/MS/MS assays. AB - Biological monitoring is a necessary process for risk assessment of endocrine disrupting chemicals (EDCs), particularly, bisphenol A (BPA), in breast milk, because its human risks are not clear yet, and infants, who feed on breast milk, are highly susceptible for EDCs. Concerning biological monitoring of BPA, the HPLC/FLD has been widely used before the LC/MS/MS. However, there was no report, which simultaneously evaluated the two methods in real analyses. Therefore, we analyzed BPA with LC/MS/MS and HPLC/FLD in human breast milk and conducted comparison of two methods in analyzed BPA levels. After establishing optimal condition, e.g. linearity, recovery, reproducibility and free BPA system, we analyzed BPA levels in human breast milk samples (N=100). The LOQs were similar in the two methods, i.e. 1.8 and 1.3 ng/mL for the HPLC/FLD and LC/MS/MS assays, respectively. There were strong associations between total BPA levels with the two methods (R(2)=0.40, p<0.01), however, only 11% of them were analyzed as similar levels with 15% CVs. In addition, the detection range of BPA was broader in the HPLC method than the LC/MS/MS method. However, the BPA levels in the HPLC/FLD analysis were lower than those in the LC/MS/MS analysis (p<0.01). Thus, the differences in BPA levels between the two methods may come from mainly over estimation with the LC/MS/MS method in low BPA samples and some of poor resolution with the HPLC/FLD in high BPA samples. PMID- 20202917 TI - Necrotizing pyoderma gangrenosum: an unusual differential diagnosis of necrotizing fasciitis. PMID- 20202918 TI - [Paediatric mesothelioma: is there the such a disease?]. AB - Paediatric mesothelioma is a very rare entity. We report here epidemiologic data from 489 cases reported in international medical literature. A better knowledge about this entity is mandatory to improve its management. PMID- 20202919 TI - [Proteomics and breast cancer: a search for novel diagnostic and theragnostic biomarkers]. AB - A major challenge of breast cancer research is the identification of accurate biomarkers that improve screening, early diagnosis, prediction of aggressiveness and prediction of therapeutic response or toxicity as well as the identification of novel molecular therapeutic targets. Following the sequencing of the human genome and pioneer developments of transcriptomics, analysis of the proteome (the repertoire of proteins expressed in a biological samples) was recently introduced as a promising tool in the study of biology of human cancers. In spite of their current limitations, proteomics, either array-based (such as tissue microarrays, antibody arrays or reverse phase protein microarrays) or mass spectrometry-based, make possible to envision major improvements in the molecular knowledge of breast cancer and for the identification of tissue-based or circulating diagnostic and theragnostic biomarkers relevant to this disease. The current techniques applied to clinical samples of breast cancer and the most important results obtained are summarized in this review. PMID- 20202920 TI - Hyperthermic intraperitoneal chemotherapy with oxaliplatin and without adjuvant chemotherapy in stage IIIC ovarian cancer. AB - OBJECTIVE: To assess the feasibility and efficacy of cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) without adjuvant chemotherapy for relapsed or persistent advanced ovarian cancer. METHODS: This observational study included stage IIIC ovarian cancer patients due to undergo CRS (interval debulking or recurrent surgery) followed by HIPEC with oxaliplatin (460 mg/m2) for 30 min. RESULTS: Twenty-two patients (12 interval debulking procedures and 10 recurrence procedures) were enrolled between September 2003 and September 2007. HIPEC was not performed in four patients because of operative findings. No patient received adjuvant chemotherapy after HIPEC. Patients were followed up routinely until recurrence or death. Median peritoneal cancer index at surgery was 6 (range: 1-18). Before HIPEC, all patients had completeness of cytoreduction scores of 0 or 1. Median length of hospital stay was 21 days (range 13-65). Ten patients (55.6%) had CTCAE grade 3-4 toxicity, including three patients (16.7%) requiring reoperation. No postoperative mortality was observed. With a median follow-up of 38 months (CI 95% 23.8-39.2), median overall survival was not reached. The 3-year overall survival rate was 83% (CI 95% 54-95). Median disease-free survival was, respectively, 16.9 months (CI 95% 10.2-23.2) and 10 months (CI 95% 4.5-11.3) for patients undergoing interval debulking or recurrence surgery. CONCLUSION: HIPEC without adjuvant chemotherapy is both feasible and safe, but with a high rate of grade 3-5 toxicity. Survival results are encouraging but should be confirmed in a randomized trial. PMID- 20202921 TI - Evidence for a functional sidedness to the alphabetaTCR. AB - The T cell receptor (TCR) and associated CD3gammaepsilon, deltaepsilon, and zetazeta signaling dimers allow T cells to discriminate between different antigens and respond accordingly, but our knowledge of how these parts fit and work together is incomplete. In this study, we provide additional evidence that the CD3 heterodimers congregate on one side of the TCR in both the alphabeta and gammadeltaTCR-CD3 complexes. We also report that the other side of the alphabetaTCR mediates homotypic alphabetaTCR interactions and signaling. Specifically, an erythropoietin receptor-based dimerization assay was used to show that, upon complex assembly, the CD3epsilon chains of two CD3 heterodimers are arranged side-by-side in both the alphabeta and gammadeltaTCR-CD3 complexes. This system was also used to show that alphabetaTCRs can dimerize in the cell membrane and that mutating the unusual outer strands of the Calpha domain impairs this dimerization. Finally, we present data showing that, for CD4 T cells, the mutations that impair alphabetaTCR dimerization also alter ligand-induced calcium mobilization, TCR accumulation at the site of pMHC contact, and polarization toward the site of antigen contact. These data reveal a "functional-sidedness" to the alphabetaTCR constant region, with dimerization occurring on the side of the TCR opposite from where the CD3 heterodimers are located. PMID- 20202922 TI - Sensitivity of MRI resonance frequency to the orientation of brain tissue microstructure. AB - Recent advances in high-field (>or=7 T) MRI have made it possible to study the fine structure of the human brain at the level of fiber bundles and cortical layers. In particular, techniques aimed at detecting MRI resonance frequency shifts originating from local variation in magnetic susceptibility and other sources have greatly improved the visualization of these structures. A recent theoretical study [He X, Yablonskiy DA (2009) Proc Natl Acad Sci USA 106:13558 13563] suggests that MRI resonance frequency may report not only on tissue composition, but also on microscopic compartmentalization of susceptibility inclusions and their orientation relative to the magnetic field. The proposed sensitivity to tissue structure may greatly expand the information available with conventional MRI techniques. To investigate this possibility, we studied postmortem tissue samples from human corpus callosum with an experimental design that allowed separation of microstructural effects from confounding macrostructural effects. The results show that MRI resonance frequency does depend on microstructural orientation. Furthermore, the spatial distribution of the resonance frequency shift suggests an origin related to anisotropic susceptibility effects rather than microscopic compartmentalization. This anisotropy, which has been shown to depend on molecular ordering, may provide valuable information about tissue molecular structure. PMID- 20202925 TI - How to avoid phenotypic misclassification in using joint destruction as an outcome measure for rheumatoid arthritis? AB - Joint destruction is a measure for RA severity that is accurate, sensitive and reflective of the cumulative disease burden. Risk factors for this outcome measure may be used to arrive at individualized treatment strategies. Currently, relatively few risk factors for joint destruction are known. New risk factors, genetic risk factors in particular, may have relatively small effects on the rate of joint destruction. A sensitive determination of joint damage is then crucial in order to identify these risk factors and will reduce the risk on type 2 errors. The present article addresses the question how the rate of joint destruction is ideally measured. Different methods are discussed and suggestions for corrections of factors that affect the natural course of joint destruction, such as applied treatment strategies, are made. It is concluded that a precise estimation of the rate of radiological joint destruction is obtained by using quantitative and validated scoring methods as well as repetitive measurements over time in order to reduce within patient variation. PMID- 20202923 TI - A genome-wide association study of alcohol dependence. AB - Excessive alcohol consumption is one of the leading causes of preventable death in the United States. Approximately 14% of those who use alcohol meet criteria during their lifetime for alcohol dependence, which is characterized by tolerance, withdrawal, inability to stop drinking, and continued drinking despite serious psychological or physiological problems. We explored genetic influences on alcohol dependence among 1,897 European-American and African-American subjects with alcohol dependence compared with 1,932 unrelated, alcohol-exposed, nondependent controls. Constitutional DNA of each subject was genotyped using the Illumina 1M beadchip. Fifteen SNPs yielded P < 10(-5), but in two independent replication series, no SNP passed a replication threshold of P < 0.05. Candidate gene GABRA2, which encodes the GABA receptor alpha2 subunit, was evaluated independently. Five SNPs at GABRA2 yielded nominal (uncorrected) P < 0.05, with odds ratios between 1.11 and 1.16. Further dissection of the alcoholism phenotype, to disentangle the influence of comorbid substance-use disorders, will be a next step in identifying genetic variants associated with alcohol dependence. PMID- 20202926 TI - Assessment of tissue fibrosis in skin biopsies from patients with systemic sclerosis employing confocal laser scanning microscopy: an objective outcome measure for clinical trials? AB - OBJECTIVES: To obtain an objective, unbiased assessment of skin fibrosis in patients with SSc for use in clinical trials of SSc disease-modifying therapeutics. METHODS: Skin biopsies from the dorsal forearm of six patients with diffuse SSc and six healthy controls, and skin biopsies from the forearm of one patient with diffuse SSc before and following 1 year treatment with mycophenolate mofetil were analysed by confocal laser scanning microscopy (CLSM) with specific antibodies against collagen types I and III or fibronectin. The integrated density of fluorescence (IDF) was calculated employing National Institutes of Health-ImageJ software in at least four different fields per biopsy spanning the full dermal thickness. RESULTS: The intensities of collagen types I and III and fibronectin IDF were 174, 147 and 139% higher in SSc skin than in normal skin, respectively. All differences were statistically significant. The sum of the IDF values obtained for the three proteins yielded a comprehensive fibrosis score. The average fibrosis score for the six SSc samples was 28.3 x 10(6) compared with 18.6 x 10(6) for the six normal skin samples (P < 0.0001). Comparison of skin biopsies obtained from the same SSc patient before treatment and after 12 months of treatment with mycophenolate mofetil showed a reduction of 39% in total fibrosis score after treatment. CONCLUSIONS: CLSM followed by quantitative image analysis provides an objective and unbiased assessment of skin fibrosis in SSc and could be a useful end-point for clinical trials with disease-modifying agents to monitor the response or progression of the disease. PMID- 20202928 TI - Inflammation, oxidative stress and lipids: the risk triad for atherosclerosis in gout. AB - For many years, the relationship between cardiovascular disease risk and gout, though strong and consistent, was suspected of being coincidental rather than causative. In recent years, compelling epidemiological and clinical data have increasingly favoured an aetiological connection. However, that connection is notably complex, involving a multifaceted model that includes interactions between inflammatory processes, oxidative stress and potential genetic influences, as well as cardiovascular and renal components that remain only partly explained. Urate appears to be able to activate the immune response, and in that context has a mediating role in the inflammatory process via the inflammasome. This interaction of urate and inflammation is central to the inflammatory cascade associated with gout flares. In the arena of oxidative stress, urate has both antioxidant and pro-oxidant properties, and while potentially beneficial in scavenging free radicals, it can also impair endothelial function and thereby give rise to atherosclerotic risk. Human and animal studies have revealed associations between hyperuricaemia and a host of atherosclerotic risk factors, whereas a reduction in urate levels is frequently associated with improvement or even resolution of such risk factors. The degree to which reduction of serum urate can reliably improve cardiovascular risk remains uncertain. It is hoped that the introduction of newer urate-lowering agents may help to clarify this picture and improve treatment options for both gout and atherosclerosis. PMID- 20202927 TI - Evidence for the efficacy of complementary and alternative medicines in the management of fibromyalgia: a systematic review. AB - OBJECTIVE: To critically evaluate the evidence regarding complementary and alternative medicines (CAMs) taken orally or applied topically for the treatment of FM. METHODS: Randomized controlled trials of FM using CAMs, in comparison with other treatments or placebo, published in English up to March 2009, were eligible for inclusion. They were identified using systematic searches of bibliographic databases and manual searching of reference lists. Information was extracted on outcomes, and statistical significance, in comparison with alternative treatment or placebo, and side effects were reported. The methodological quality of the primary studies was determined. RESULTS: Single studies on four CAMs, and three on different approaches to homeopathic care were identified. Their methodological quality was moderate. The homeopathy studies were small, but each reported an improvement in pain. The effects of anthocyanidins, capsaicin and S adenosylmethionine each showed at least one statistically significant improved outcome compared with placebo. However, the studies of anthocyanidins and capsaicin only demonstrated an improvement in a single outcome, sleep disturbance and tenderness, respectively, of several outcomes considered. No evidence of efficacy was found regarding Soy in a single study. Most of these CAMs were free of major adverse effects and usually associated with only minor adverse effects such as dizziness, nausea and stomach upsets. CONCLUSION: There is insufficient evidence on any CAM, taken orally or applied topically, for FM. The small number of positive studies lack replication. Further high-quality trials are necessary to determine whether these initial findings can be supported by a larger evidence base. PMID- 20202929 TI - An adequacy evaluation of a 10-year, four-country nutrition and health programme. AB - BACKGROUND: Evaluations of large-scale health and nutrition programmes in developing countries are needed for determining the effectiveness of interventions. This article critically analyses a non-governmental organization (NGO)-led large-scale, multi-country, 10-year micronutrient and health (MICAH) programme with an 'adequacy evaluation', that is, a documentation of time trends in the expected direction. METHODS: MICAH was implemented from 1996 to 2005 in selected areas of Ethiopia, Ghana, Malawi and Tanzania, reaching >6 million people with numerous health and nutrition interventions. Coverage and impact were monitored through surveys at baseline, midpoint and end of funding. The data were subjected to post-hoc methods of quality determination, and, if of suitable quality, included in the adequacy evaluation. RESULTS: Most collected data were of moderate or high quality and therefore included in the adequacy evaluation. There were moderate to large improvements in vitamin A status in Ethiopian school age children, children <5 years of age in Tanzania and Ghana and mothers in Ghana. Iodine status improved in Malawi and Tanzania. Anaemia rates and malaria prevalence decreased in women, pregnant women and pre-school children in Ghana, Malawi and Tanzania, but anaemia increased in Ethiopian women. Large increases were reported for rates of exclusive breastfeeding and immunization. Child growth improved to the maximum that would be predicted with the given interventions. CONCLUSIONS: Numerous nutrition and health impacts were observed in the intervention areas, often of a magnitude equal to or larger than observed in controlled interventions or trials. These results show the value of integrated long-term interventions. PMID- 20202924 TI - Population genetics of ecological communities with DNA barcodes: an example from New Guinea Lepidoptera. AB - Comparative population genetics of ecological guilds can reveal generalities in patterns of differentiation bearing on hypotheses regarding the origin and maintenance of community diversity. Contradictory estimates of host specificity and beta diversity in tropical Lepidoptera (moths and butterflies) from New Guinea and the Americas have sparked debate on the role of host-associated divergence and geographic isolation in explaining latitudinal diversity gradients. We sampled haplotypes of mitochondrial cytochrome c oxidase I from 28 Lepidoptera species and 1,359 individuals across four host plant genera and eight sites in New Guinea to estimate population divergence in relation to host specificity and geography. Analyses of molecular variance and haplotype networks indicate varying patterns of genetic structure among ecologically similar sympatric species. One-quarter lacked evidence of isolation by distance or host associated differentiation, whereas 21% exhibited both. Fourteen percent of the species exhibited host-associated differentiation without geographic isolation, 18% showed the opposite, and 21% were equivocal, insofar as analyses of molecular variance and haplotype networks yielded incongruent patterns. Variation in dietary breadth among community members suggests that speciation by specialization is an important, but not universal, mechanism for diversification of tropical Lepidoptera. Geographically widespread haplotypes challenge predictions of vicariance biogeography. Dispersal is important, and Lepidoptera communities appear to be highly dynamic according to the various phylogeographic histories of component species. Population genetic comparisons among herbivores of major tropical and temperate regions are needed to test predictions of ecological theory and evaluate global patterns of biodiversity. PMID- 20202930 TI - Mapping of domains on HIV envelope protein mediating association with calnexin and protein-disulfide isomerase. AB - The cell catalysts calnexin (CNX) and protein-disulfide isomerase (PDI) cooperate in establishing the disulfide bonding of the HIV envelope (Env) glycoprotein. Following HIV binding to lymphocytes, cell-surface PDI also reduces Env to induce the fusogenic conformation. We sought to define the contact points between Env and these catalysts to illustrate their potential as therapeutic targets. In lysates of Env-expressing cells, 15% of the gp160 precursor, but not gp120, coprecipitated with CNX, whereas only 0.25% of gp160 and gp120 coprecipitated with PDI. Under in vitro conditions, which mimic the Env/PDI interaction during virus/cell contact, PDI readily associated with Env. The domains of Env interacting in cellulo with CNX or in vitro with PDI were then determined using anti-Env antibodies whose binding site was occluded by CNX or PDI. Antibodies against domains V1/V2, C2, and the C terminus of V3 did not bind CNX-associated Env, whereas those against C1, V1/V2, and the CD4-binding domain did not react with PDI-associated Env. In addition, a mixture of the latter antibodies interfered with PDI-mediated Env reduction. Thus, Env interacts with intracellular CNX and extracellular PDI via discrete, largely nonoverlapping, regions. The sites of interaction explain the mode of action of compounds that target these two catalysts and may enable the design of further new competitive agents. PMID- 20202931 TI - Communication between tandem cAMP binding domains in the regulatory subunit of protein kinase A-Ialpha as revealed by domain-silencing mutations. AB - Protein kinase A (PKA) is the main receptor for the universal cAMP second messenger. PKA is a tetramer with two catalytic (C) and two regulatory (R) subunits, each including two tandem cAMP binding domains, i.e. CBD-A and -B. Structural investigations of RIalpha have revealed that although CBD-A plays a pivotal role in the cAMP-dependent inhibition of C, the main function of CBD-B is to regulate the access of cAMP to site A. To further understand the mechanism underlying the cross-talk between CBD-A and -B, we report here the NMR investigation of a construct of R, RIalpha-(119-379), which unlike previous fragments characterized by NMR, spans in full both CBDs. Our NMR studies were also extended to two mutants, R209K and the corresponding R333K, which severely reduce the affinity of cAMP for CBD-A and -B, respectively. The comparative NMR analysis of wild-type RIalpha-(119-379) and of the two domain silencing mutations has led to the definition at an unprecedented level of detail of both intra- and interdomain allosteric networks, revealing several striking differences between the two CBDs. First, the two domains, although homologous in sequence and structure, exhibit remarkably different responses to the R/K mutations especially at the beta2-3 allosteric "hot spot." Second, although the two CBDs are reciprocally coupled at the level of local unfolding of the hinge, the A-to-B and B-to-A pathways are dramatically asymmetrical at the level of global unfolding. Such an asymmetric interdomain cross-talk ensures efficiency and robustness in both the activation and de-activation of PKA. PMID- 20202932 TI - An intersubunit interaction between S4-S5 linker and S6 is responsible for the slow off-gating component in Shaker K+ channels. AB - Voltage-gated ion channels are controlled by the membrane potential, which is sensed by peripheral, positively charged voltage sensors. The movement of the charged residues in the voltage sensor may be detected as gating currents. In Shaker K(+) channels, the gating currents are asymmetric; although the on-gating currents are fast, the off-gating currents contain a slow component. This slow component is caused by a stabilization of the activated state of the voltage sensor and has been suggested to be linked to ion permeation or C-type inactivation. The molecular determinants responsible for the stabilization, however, remain unknown. Here, we identified an interaction between Arg-394, Glu 395, and Leu-398 on the C termini of the S4-S5 linker and Tyr-485 on the S6 of the neighboring subunit, which is responsible for the development of the slow off gating component. Mutation of residues involved in this intersubunit interaction modulated the strength of the associated interaction. Impairment of the interaction still led to pore opening but did not exhibit slow gating kinetics. Development of this interaction occurs under physiological ion conduction and is correlated with pore opening. We, thus, suggest that the above residues stabilize the channel in the open state. PMID- 20202933 TI - Novel mode of phosphorylation-triggered reorganization of the nuclear lamina during nuclear egress of human cytomegalovirus. AB - The nucleocytoplasmic egress of viral capsids is a rate-limiting step in the replication of the human cytomegalovirus (HCMV). As reported recently, an HCMV specific nuclear egress complex is composed of viral and cellular proteins, in particular protein kinases with the capacity to induce destabilization of the nuclear lamina. Viral protein kinase pUL97 and cellular protein kinase C (PKC) play important roles by phosphorylating several types of nuclear lamins. Using pUL97 mutants, we show that the lamin-phosphorylating activity of pUL97 is associated with a reorganization of nuclear lamin A/C. Either pUL97 or PKC has the potential to induce distinct punctate lamina-depleted areas at the periphery of the nuclear envelope, which were detectable in transiently transfected and HCMV-infected cells. Using recombinant HCMV, which produces green fluorescent protein-labeled viral capsids, the direct transition of viral capsids through these areas could be visualized. This process was sensitive to an inhibitor of pUL97/PKC activity. The pUL97-mediated phosphorylation of lamin A/C at Ser(22) generated a novel binding motif for the peptidyl-prolyl cis/trans-isomerase Pin1. In HCMV-infected fibroblasts, the physiological localization of Pin1 was altered, leading to recruitment of Pin1 to viral replication centers and to the nuclear lamina. The local increase in Pin1 peptidyl-prolyl cis/trans-isomerase activity may promote conformational modulation of lamins. Thus, we postulate a novel phosphorylation-triggered mechanism for the reorganization of the nuclear lamina in HCMV-infected cells. PMID- 20202934 TI - Formation of heteromeric Kv2 channels in mammalian brain neurons. AB - The formation of heteromeric tetramers is a common feature of voltage-gated potassium (Kv) channels. This results in the generation of a variety of tetrameric Kv channels that exhibit distinct biophysical and biochemical characteristics. Kv2 delayed rectifier channels are, however, unique exceptions. It has been previously shown that mammalian Kv2.1 and Kv2.2 are localized in distinct domains of neuronal membranes and are not capable of forming heteromeric channels with each other (Hwang, P. M., Glatt, C. E., Bredt, D. S., Yellen, G., and Snyder, S. H. (1992) Neuron 8, 473-481). In this study, we report a novel form of rat Kv2.2, Kv2.2(long), which has not been previously recognized. Our data indicate that Kv2.2(long) is the predominant form of Kv2.2 expressed in cortical pyramidal neurons. In contrast to the previous findings, we also found that rat Kv2.1 and Kv2.2(long) are colocalized in the somata and proximal dendrites of cortical pyramidal neurons and are capable of forming functional heteromeric delayed rectifier channels. Our results suggest that the delayed rectifier currents, which regulate action potential firing, are encoded by heteromeric Kv2 channels in cortical neurons. PMID- 20202935 TI - Tight coupling of partial reactions in the acetyl-CoA decarbonylase/synthase (ACDS) multienzyme complex from Methanosarcina thermophila: acetyl C-C bond fragmentation at the a cluster promoted by protein conformational changes. AB - Direct synthesis and cleavage of acetyl-CoA are carried out by the bifunctional CO dehydrogenase/acetyl-CoA synthase enzyme in anaerobic bacteria and by the acetyl-CoA decarbonylase/synthase (ACDS) multienzyme complex in Archaea. In both systems, a nickel- and Fe/S-containing active site metal center, the A cluster, catalyzes acetyl C-C bond formation/breakdown. Carbonyl group exchange of [1 (14)C]acetyl-CoA with unlabeled CO, a hallmark of CODH/ACS, is weakly active in ACDS, and exchange with CO(2) was up to 350 times faster, indicating tight coupling of CO release at the A cluster to CO oxidation to CO(2) at the C cluster in CO dehydrogenase. The basis for tight coupling was investigated by analysis of three recombinant A cluster proteins, ACDS beta subunit from Methanosarcina thermophila, acetyl-CoA synthase of Carboxydothermus hydrogenoformans (ACS(Ch)), and truncated ACS(Ch) lacking its 317-amino acid N-terminal domain. A comparison of acetyl-CoA synthesis kinetics, CO exchange, acetyltransferase, and A cluster Ni(+)-CO EPR characteristics demonstrated a direct role of the ACS N-terminal domain in promoting acetyl C-C bond fragmentation. Protein conformational changes, related to "open/closed" states previously identified crystallographically, were indicated to have direct effects on the coordination geometry and stability of the A cluster Ni(2+)-acetyl intermediate, controlling Ni(2+)-acetyl fragmentation and Ni(2+)(CO)(CH(3)) condensation. EPR spectral changes likely reflect variations in the Ni(+)-CO equatorial coordination environment in closed buried hydrophobic and open solvent-exposed states. The involvement of subunit-subunit interactions in ACDS, versus interdomain contacts in ACS, ensures that CO is not released from the ACDS beta subunit in the absence of appropriate interactions with the alpha(2)epsilon(2) CO dehydrogenase component. The resultant high efficiency CO transfer explains the low rate of CO exchange relative to CO(2). PMID- 20202936 TI - Functional and kinetic analysis of the phosphotransferase CapP conferring selective self-resistance to capuramycin antibiotics. AB - Capuramycin-related compounds, including A-500359s and A-503083s, are nucleoside antibiotics that inhibit the enzyme bacterial translocase I involved in peptidoglycan cell wall biosynthesis. Within the biosynthetic gene cluster for the A-500359s exists a gene encoding a putative aminoglycoside 3 phosphotransferase that was previously demonstrated to be highly expressed during the production of A-500359s and confers selective resistance to capuramycins when expressed in heterologous hosts. A similar gene (capP) was identified within the biosynthetic gene cluster for the A-503083s, and CapP is now shown to similarly confer selective resistance to capuramycins. Recombinant CapP was produced and purified from Escherichia coli, and the function of CapP is established as an ATP dependent capuramycin phosphotransferase that regio-specifically transfers the gamma-phosphate to the 3''-hydroxyl of the unsaturated hexuronic acid moiety of A 503083 B. Kinetic analysis with the three major A-503083 congeners suggests that CapP preferentially phosphorylates A-503083s containing an aminocaprolactam moiety attached to the hexuronic acid, and bi-substrate kinetic analysis was consistent with CapP employing a sequential kinetic mechanism similar to most known aminoglycoside 3-phosphotransferases. The purified CapP product lost its antibiotic activity against Mycobacterium smegmatis, and this loss in bioactivity is primarily due to a 272-fold increase in the IC(50) in the bacterial translocase I-catalyzed reaction. The results establish CapP-mediated phosphorylation as a mechanism of resistance to capuramycins and now set the stage to explore this strategy of resistance as a potential mechanism inherent to pathogens and provide the impetus for preparing second generation analogues as a preemptive strike to such resistance strategies. PMID- 20202937 TI - On the relevance of the Met-turn methionine in metzincins. AB - The metzincins are a clan of metallopeptidases consisting of families that share a series of structural elements. Among them is the Met-turn, a tight 1,4-turn found directly below the zinc-binding site, which is structurally and spatially conserved and invariantly shows a methionine at position 3 in all metzincins identified. The reason for this conservation has been a matter of debate since its discovery. We have studied this structural element in Methanosarcina acetivorans ulilysin, the structural prototype of the pappalysin family, by generating 10 mutants that replaced methionine with proteogenic amino acids. We compared recombinant overexpression yields, autolytic and tryptic activation, proteolytic activity, thermal stability, and three-dimensional structure with those of the wild type. All forms were soluble and could be purified, although with varying yields, and three variants underwent autolysis, could be activated by trypsin, and displayed significant proteolytic activity. All variants were analyzed for the thermal stability of their zymogens. None of the mutants analyzed proved more stable or active than the wild type. Both bulky and small side chains, as well as hydrophilic ones, showed diminished thermal stability. Two mutants, leucine and cysteine, crystallized and showed three-dimensional structures that were indistinguishable from the wild type. These studies reveal that the Met-turn acts as a plug that snugly inserts laterally into a core structure created by the protein segment engaged in zinc binding and thus contributes to its structural integrity, which is indispensable for function. Replacement of the methionine with residues that deviate in size, side-chain conformation, and chemical properties impairs the plug-core interaction and prejudices molecular stability and activity. PMID- 20202938 TI - Proenzyme structure and activation of astacin metallopeptidase. AB - Proteolysis is regulated by inactive (latent) zymogens, with a prosegment preventing access of substrates to the active-site cleft of the enzyme. How latency is maintained often depends on the catalytic mechanism of the protease. For example, in several families of the metzincin metallopeptidases, a "cysteine switch" mechanism involves a conserved prosegment motif with a cysteine residue that coordinates the catalytic zinc ion. Another family of metzincins, the astacins, do not possess a cysteine switch, so latency is maintained by other means. We have solved the high resolution crystal structure of proastacin from the European crayfish, Astacus astacus. Its prosegment is the shortest structurally reported for a metallopeptidase, and it has a unique structure. It runs through the active-site cleft in reverse orientation to a genuine substrate. Moreover, a conserved aspartate, projected by a wide loop of the prosegment, coordinates the zinc ion instead of the catalytic solvent molecule found in the mature enzyme. Activation occurs through two-step limited proteolysis and entails major rearrangement of a flexible activation domain, which becomes rigid and creates the base of the substrate-binding cleft. Maturation also requires the newly formed N terminus to be precisely trimmed so that it can participate in a buried solvent-mediated hydrogen-bonding network, which includes an invariant active-site residue. We describe a novel mechanism for latency and activation, which shares some common features both with other metallopeptidases and with serine peptidases. PMID- 20202939 TI - Characterization and structure determination of the Cdt1 binding domain of human minichromosome maintenance (Mcm) 6. AB - The minichromosome maintenance (Mcm) 2-7 complex is the replicative helicase in eukaryotic species, and it plays essential roles in the initiation and elongation phases of DNA replication. During late M and early G(1), the Mcm2-7 complex is loaded onto chromatin to form prereplicative complex in a Cdt1-dependent manner. However, the detailed molecular mechanism of this loading process is still elusive. In this study, we demonstrate that the previously uncharacterized C terminal domain of human Mcm6 is the Cdt1 binding domain (CBD) and present its high resolution NMR structure. The structure of CBD exhibits a typical "winged helix" fold that is generally involved in protein-nucleic acid interaction. Nevertheless, the CBD failed to interact with DNA in our studies, indicating that it is specific for protein-protein interaction. The CBD-Cdt1 interaction involves the helix-turn-helix motif of CBD. The results reported here provide insight into the molecular mechanism of Mcm2-7 chromatin loading and prereplicative complex assembly. PMID- 20202940 TI - Functional oligomerization of the Saccharomyces cerevisiae isoprenylcysteine carboxyl methyltransferase, Ste14p. AB - The isoprenylcysteine carboxyl methyltransferase (Icmt) from Saccharomyces cerevisiae, also designated Ste14p, is a 26-kDa integral membrane protein that contains six transmembrane spanning segments. This protein is localized to the endoplasmic reticulum membrane where it performs the methylation step of the CAAX post-translational processing pathway. Sequence analysis reveals a putative GXXXG dimerization motif located in transmembrane 1 of Ste14p, but it is not known whether Ste14p forms or functions as a dimer or higher order oligomer. We determined that Ste14p predominantly formed a homodimer in the presence of the cross-linking agent, bis-sulfosuccinimidyl suberate. Wild-type untagged Ste14p also co-immunoprecipitated and co-purified with N-terminal-tagged His(10)-myc(3) Ste14p (His-Ste14p). Furthermore, enzymatically inactive His-Ste14p variants L81F and E213Q both exerted a dominant-negative effect on methyltransferase activity when co-expressed and co-purified with untagged wild-type Ste14p. Together, these data, although indirect, suggest that Ste14p forms and functions as a homodimer or perhaps a higher oligomeric species. PMID- 20202941 TI - Upper limb exercises using varied workloads and their association with dynamic hyperinflation in patients with COPD. AB - BACKGROUND: Increased ventilation during upper limb exercises (ULE) in patients with COPD is associated with dynamic hyperinflation (DH) and a decrease in inspiratory capacity (IC). The best level of ULE load training is still unknown. Our objective was to evaluate the dynamic hyperinflation development during ULE using three constant workloads. METHODS: This was a prospective, randomized protocol involving 24 patients with severe COPD (FEV(1) < 50%) performing an endurance symptom-limited arm exercise of up to 20 min in an arm cycloergometer with different workloads (50%, 65%, and 80% of the maximal load). Ventilation, metabolic, and lung function variables (static IC pre-exercise and postexercise) were measured. RESULTS: DH was observed during exercises with 65% (-0.23 L) and 80% (-0.29 L) workloads (P < .0001). Total time of exercise with 80% workload (7.6 min) was shorter than with 50% (12.5 min) (P < .0005) and with 65% (10.1 min; not significant). Oxygen consumption percent predicted (VO(2)) (P < .01) was lower with 50% workload than with 80%. Eighty percent workload showed lower work efficiency (VO(2) [mL/kg]/exercise time) than the other two workloads (P < .0001). CONCLUSION: Different workloads during upper limb exercises showed a direct influence over dynamic hyperinflation and the endurance exercise duration. PMID- 20202942 TI - Affective descriptors of the sensation of breathlessness are more highly associated with severity of impairment than physical descriptors in people with COPD. AB - BACKGROUND: Previous studies of the qualitative sensation of breathlessness have suggested that greater sensory discomfort is reported as airflow obstruction increases. This study investigated relationships between the language of breathlessness and severity of impairment in subjects with COPD. METHODS: Using a prospective, observational approach, subjects completed a structured interview in which they volunteered words to describe their sensation of breathlessness and endorsed statements from a preexisting descriptor list. Global impairment was assessed by the BMI, airflow obstruction, dyspnea, and exercise capacity (BODE) index. Independent t tests and logistic regression analyses (odds ratios) were used to assess relationships between language categories and severity of impairment. RESULTS: In this group of 91 people (47 men, 70 +/- 10 years of age, percent predicted FEV(1) 54 +/- 23), subjects volunteering extreme affective descriptors (frightening, awful, worried) had greater impairment (BODE index, perceived respiratory disability, functional exercise capacity, and airways obstruction), and this language category was significantly associated with increasing BODE index scores (odds ratio [OR] = 1.49; 95% CI, 1.18 to 1.86; P = .001). Descriptors denoting heavy, rapid, more, shallow, or does not go in or out all the way were significantly less likely to be selected as BODE index scored increased (OR = 0.75; 95% CI, 0.16 to 0.93). CONCLUSIONS: Affective descriptors or the emotional response to the sensation of breathlessness have a significant relationship with severity of COPD impairments. Affective descriptors may reflect the degree of threat imposed by the sensation and predict the likelihood of long term behavioral changes. PMID- 20202943 TI - A. Jay Block: the legend and his legacy. PMID- 20202944 TI - Swallowing complications after endotracheal extubation: moving from "whether" to "how". PMID- 20202945 TI - Coronary collateral circulation in sleep apnea: a cardioprotective mechanism? PMID- 20202946 TI - Death to the garden hose? PMID- 20202948 TI - The incidence of dysphagia following endotracheal intubation: a systematic review. AB - Hospitalized patients are often at increased risk for oropharyngeal dysphagia following prolonged endotracheal intubation. Although reported incidence can be high, it varies widely. We conducted a systematic review to determine: (1) the incidence of dysphagia following endotracheal intubation, (2) the association between dysphagia and intubation time, and (3) patient characteristics associated with dysphagia. Fourteen electronic databases were searched, using keywords dysphagia, deglutition disorders, and intubation, along with manual searching of journals and grey literature. Two reviewers, blinded to each other, selected and reviewed articles at all stages according to our inclusion criteria: adult participants who underwent intubation and clinical assessment for dysphagia. Exclusion criteria were case series (n < 10), dysphagia determined by patient report, patients with tracheostomies, esophageal dysphagia, and/or diagnoses known to cause dysphagia. Critical appraisal used the Cochrane risk of bias assessment and Grading of Recommendations, Assessment, Development and Evaluation tools. A total of 1,489 citations were identified, of which 288 articles were reviewed and 14 met inclusion criteria. The studies were heterogeneous in design, swallowing assessment, and study outcome; therefore, we present findings descriptively. Dysphagia frequency ranged from 3% to 62% and intubation duration from 124.8 to 346.6 mean hours. The highest dysphagia frequencies (62%, 56%, and 51%) occurred following prolonged intubation and included patients across all diagnostic subtypes. All studies were limited by design and risk of bias. Overall quality of the evidence was very low. This review highlights the poor available evidence for dysphagia following intubation and hence the need for high-quality prospective trials. PMID- 20202949 TI - American College of Chest Physicians consensus statement on the management of dyspnea in patients with advanced lung or heart disease. AB - BACKGROUND: This consensus statement was developed based on the understanding that patients with advanced lung or heart disease are not being treated consistently and effectively for relief of dyspnea. METHODS: A panel of experts was convened. After a literature review, the panel developed 23 statements covering five domains that were considered relevant to the topic condition. Endorsement of these statements was assessed by levels of agreement or disagreement on a five-point Likert scale using two rounds of the Delphi method. RESULTS: The panel defined the topic condition as "dyspnea that persists at rest or with minimal activity and is distressful despite optimal therapy of advanced lung or heart disease." The five domains were: measurement of patient-reported dyspnea, oxygen therapy, other therapies, opioid medications, and ethical issues. In the second round of the Delphi method, 34 of 56 individuals (61%) responded, and agreement of at least 70% was achieved for 20 of the 23 statements. CONCLUSIONS: For patients with advanced lung or heart disease, we suggest that: health-care professionals are ethically obligated to treat dyspnea, patients should be asked to rate the intensity of their breathlessness as part of a comprehensive care plan, opioids should be dosed and titrated for relief of dyspnea in the individual patient, both the patient and clinician should reassess whether specific treatments are serving the goal of palliating dyspnea without causing adverse effects, and it is important for clinicians to communicate about palliative and end-of-life care with their patients. PMID- 20202951 TI - Bundled babies and bundled billing: how to properly use the new pediatric critical care codes. AB - CMS introduced new pediatric critical care codes and renumbered neonatal and pediatric critical care Current Procedural Terminology (CPT) codes in January 2009. Unlike the time-based critical care codes used for adult care, services for many children use bundled codes for all critical care services by a single physician during a calendar day. New codes have been added for 24- to 60-month old children. CPT codes for critical care of neonates and children 28 days to 24 months were renumbered. This article discusses the changes and the impact on physicians providing critical care services. PMID- 20202952 TI - Hemothorax due to rupture of pulmonary arteriovenous malformation: an interventional emergency. AB - Spontaneous hemothorax as a result of a ruptured pulmonary arteriovenous malformation (PAVM) is a life-threatening event and requires immediate interventional therapy. We present two patients who survived following emergent embolization. Definitive thoracentesis was delayed until embolization was performed. The tamponade provided by the hemothorax may have prevented exsanguination, suggesting to us that drainage of blood from the pleural space should be delayed until the PAVM has been treated. Hemorrhage from a PAVM may be the first manifestation of hereditary hemorrhagic telangiectasia. Genetic testing and screening for other family members should be considered. PMID- 20202950 TI - The Master Settlement Agreement and its impact on tobacco use 10 years later: lessons for physicians about health policy making. AB - The issue of tobacco industry responsibility for population health problems and compensation for their treatment has been growing since the 1960s. In 1999, the state attorneys general collectively launched the largest class action lawsuit in US history and sued the tobacco industry to recover the costs of caring for smokers. In what became known as the Master Settlement Agreement (MSA), states were rewarded billions of dollars and won concessions regarding how cigarettes could be advertised and targeted to minors. Ten years after this settlement, much is known about how MSA monies were distributed and how states have used the money. There is some understanding about how much of the money went toward offsetting the health-care costs attributable to smoking and whether resources were allocated to efforts to reduce smoking in a particular state. However, there are few data on what effect, if any, the MSA had on tobacco control locally and nationally. This commentary explores these issues, as well as how the tobacco industry has evolved to offset the losses incurred by the settlement. Finally, an analysis of the complexities of current tobacco policy making is provided so that physicians and other health-care advocacy groups can more completely understand the present-day political dynamics and be more effective in shaping tobacco control policy in the future. PMID- 20202953 TI - Exacerbation of obstructive sleep apnea by oral indomethacin. AB - Patients with obstructive sleep apnea (OSA) are predisposed to instability in central ventilatory control during sleep. Increased instability, as reflected in an enhanced expired volume in per unit time loop gain, has been associated with a greater predisposition to upper airway collapse. Here, in an otherwise healthy patient with untreated mild OSA, we describe the further exacerbation of OSA after oral indomethacin administration. The subject was a control subject in part of a study to investigate the effects of altering cerebral blood flow (CBF) on ventilatory responses and sleep. He was administered either placebo or 100 mg of indomethacin orally with 20 mL of antacid 2.5 h before sleep on different days. He was studied overnight by polysomnography, arterial blood gases, and transcranial Doppler ultrasound. Administration of 100 mg of oral indomethacin prior to sleep resulted in an almost doubling of the apnea-hypopnea index (14 to 24/h), compared with placebo. This was due to an increase in apneas, rather than hypopneas. Following the indomethacin, changes in arterial blood gases were unremarkable, but both CBF as indexed using transcranial Doppler ultrasound and CBF reactivity to a steady-state change in CO(2) (CBF-CO(2)) reactivity were reduced, and the ventilatory response to CO(2) was elevated. CBF was also further reduced during nonrapid eye movement sleep following the indomethacin when compared with the control night. Indomethacin-induced reductions in CBF and CBF CO(2) reactivity and related increases in ventilatory instability may lead to a greater predisposition to upper airway collapse and related apnea; these factors may partly explain the exacerbation of OSA. PMID- 20202955 TI - A 59-year-old woman with chronic cough and multiple pulmonary nodules. PMID- 20202956 TI - A 27-year-old woman with acute, severe asthma who developed respiratory failure. PMID- 20202954 TI - Interactions between obesity and obstructive sleep apnea: implications for treatment. AB - Obstructive sleep apnea (OSA) adversely affects multiple organs and systems, with particular relevance to cardiovascular disease. Several conditions associated with OSA, such as high BP, insulin resistance, systemic inflammation, visceral fat deposition, and dyslipidemia, are also present in other conditions closely related to OSA, such as obesity and reduced sleep duration. Weight loss has been accompanied by improvement in characteristics related not only to obesity but to OSA as well, suggesting that weight loss might be a cornerstone of the treatment of both conditions. This review seeks to explore recent developments in understanding the interactions between body weight and OSA. Weight loss helps reduce OSA severity and attenuates the cardiometabolic abnormalities common to both diseases. Nevertheless, weight loss has been hard to achieve and maintain using conservative strategies. Since bariatric surgery has emerged as an alternative treatment of severe or complicated obesity, impressive results have often been seen with respect to sleep apnea severity and cardiometabolic disturbances. However, OSA is a complex condition, and treatment cannot be limited to any single symptom or feature of the disease. Rather, a multidisciplinary and integrated strategy is required to achieve effective and long-lasting therapeutic success. PMID- 20202957 TI - A 21-year-old male with dyspnea at rest, dry cough, and swelling of his right anterior chest. PMID- 20202962 TI - Risk factors for isoniazid hepatotoxicity in children with latent TB and TB: difference from adults. PMID- 20202963 TI - Recruitment maneuvers in ARDS ... More questions than answers. PMID- 20202964 TI - Use of antisialogogues in bronchoscopy. PMID- 20202965 TI - Pleurodesis practice in South and Central American countries. PMID- 20202966 TI - Operating characteristics of pulmonary capillary wedge pressure for pulmonary arterial hypertension. PMID- 20202967 TI - The plea for rigorous studies on cough in children. PMID- 20202968 TI - Statins, vitamin D, and COPD. PMID- 20202969 TI - Genetic diversity for grain nutrients in wild emmer wheat: potential for wheat improvement. AB - BACKGROUND AND AIMS: Micronutrient malnutrition, particularly zinc and iron deficiency, afflicts over three billion people worldwide due to low dietary intake. In the current study, wild emmer wheat (Triticum turgidum ssp. dicoccoides), the progenitor of domesticated wheat, was tested for (1) genetic diversity in grain nutrient concentrations, (2) associations among grain nutrients and their relationships with plant productivity, and (3) the association of grain nutrients with the eco-geographical origin of wild emmer accessions. METHODS: A total of 154 genotypes, including wild emmer accessions from across the Near Eastern Fertile Crescent and diverse wheat cultivars, were characterized in this 2-year field study for grain protein, micronutrient (zinc, iron, copper and manganese) and macronutrient (calcium, magnesium, potassium, phosphorus and sulphur) concentrations. KEY RESULTS: Wide genetic diversity was found among the wild emmer accessions for all grain nutrients. The concentrations of grain zinc, iron and protein in wild accessions were about two-fold greater than in the domesticated genotypes. Concentrations of these compounds were positively correlated with one another, with no clear association with plant productivity, suggesting that all three nutrients can be improved concurrently with no yield penalty. A subset of 12 populations revealed significant genetic variation between and within populations for all minerals. Association between soil characteristics at the site of collection and grain nutrient concentrations showed negative associations between soil clay content and grain protein and between soil-extractable zinc and grain zinc, the latter suggesting that the greatest potential for grain nutrient minerals lies in populations from micronutrient-deficient soils. CONCLUSIONS: Wild emmer wheat germplasm offers unique opportunities to exploit favourable alleles for grain nutrient properties that were excluded from the domesticated wheat gene pool. PMID- 20202970 TI - Kinship between parents reduces offspring fitness in a natural population of Rhododendron brachycarpum. AB - BACKGROUND AND AIMS: A reduction in offspring fitness resulting from mating between neighbours is interpreted as biparental inbreeding depression. However, little is known about the relationship between the parents' genetic relatedness and biparental inbreeding depression in their progeny in natural populations. This study assesses the effect of kinship between parents on the fitness of their progeny and the extent of spatial genetic structure in a natural population of Rhododendron brachycarpum. METHODS: Kinship coefficients between 11,858 pairs of plants among a natural population of 154 R. brachycarpum plants were estimated a priori using six microsatellite markers. Plants were genotyped, and pairs were selected from among 60 plants to vary the kinship from full-sib to unrelated. After a hand-pollination experiment among the 60 plants, offspring fitness was measured at the stages of seed maturation (i.e. ripening) under natural conditions, and seed germination and seedling survival under greenhouse conditions. In addition, spatial autocorrelation was used to assess the population's genetic structure. KEY RESULTS: Offspring fitness decreased significantly with increasing kinship between parents. However, the magnitude and timing of this effect differed among the life-cycle stages. Measures of inbreeding depression were 0.891 at seed maturation, 0.122 (but not significant) at seed germination and 0.506 at seedling survival. The local population spatial structure was significant, and the physical distance between parents mediated the level of inbreeding between them. CONCLUSIONS: The level of inbreeding between individuals determines offspring fitness in R. brachycarpum, especially during seed maturation. Genetic relatedness between parents caused inbreeding depression in their progeny. Therefore, biparental inbreeding contributes little to reproduction and instead acts as a selection force that promotes outcrossing, as offspring of more distant (less related) parents survive better. PMID- 20202971 TI - Combination therapy with bosentan and sildenafil in Eisenmenger syndrome: a randomized, placebo-controlled, double-blinded trial. AB - AIMS: To evaluate the efficacy of combining the dual endothelin receptor antagonist, bosentan, and the phosfodiesterase-5-inhibitor, sildenafil, in patients with Eisenmenger syndrome. METHODS AND RESULTS: The study was a randomized, placebo-controlled, double-blinded, cross-over design. Patients with Eisenmenger syndrome (n = 21) were treated open label with bosentan for 9 months. After 3 months, sildenafil/placebo was added for 3 months, and a cross-over was performed for the last 3 months. At baseline and after 3, 6, and 9 months, patients were examined with 6 min walk test, oxygen saturations, N-terminal pro brain natriuretic peptide, New York Heart Association (NYHA) classification, cardiac catheterization, and magnetic resonance imaging. The primary endpoint was changed in 6 min walk distance (MWD). Bosentan improved the 6 MWD (377 vs. 414 m, P = 0.001), pulmonary vascular resistance (PVR) (28 vs. 22 wood, P = 0.01), and pulmonary blood flow (2.6 vs. 3.5 L/min, P = 0.01). Adding sildenafil to bosentan did not improve the 6 MWD significantly (21 vs. 8 m, P = 0.48), but increased saturation at rest (2.9 vs. -1.8%, P < 0.01). CONCLUSION: In Eisenmenger syndrome, treatment with bosentan significantly improved walking distance, pulmonary blood flow, and PVR. Adding sildenafil to bosentan did not significantly improve walking distance but did increase saturation at rest. http://www.ClinicalTrial.gov: NCT00303004. PMID- 20202972 TI - Cardiovascular flashlight. Phaeochromocytoma: delayed diagnosis with severe consequences. PMID- 20202973 TI - Statistical expression deconvolution from mixed tissue samples. AB - MOTIVATION: Global expression patterns within cells are used for purposes ranging from the identification of disease biomarkers to basic understanding of cellular processes. Unfortunately, tissue samples used in cancer studies are usually composed of multiple cell types and the non-cancerous portions can significantly affect expression profiles. This severely limits the conclusions that can be made about the specificity of gene expression in the cell-type of interest. However, statistical analysis can be used to identify differentially expressed genes that are related to the biological question being studied. RESULTS: We propose a statistical approach to expression deconvolution from mixed tissue samples in which the proportion of each component cell type is unknown. Our method estimates the proportion of each component in a mixed tissue sample; this estimate can be used to provide estimates of gene expression from each component. We demonstrate our technique on xenograft samples from breast cancer research and publicly available experimental datasets found in the National Center for Biotechnology Information Gene Expression Omnibus repository. AVAILABILITY: R code (http://www.r-project.org/) for estimating sample proportions is freely available to non-commercial users and available at http://www.med.miami.edu/medicine/x2691.xml. PMID- 20202974 TI - An extended IUPAC nomenclature code for polymorphic nucleic acids. AB - The International Union of Pure and Applied Chemistry (IUPAC) code specified nearly 25 years ago provides a nomenclature for incompletely specified nucleic acids. However, no system currently exists that allows for the informatics representation of the relative abundance at polymorphic nucleic acids (e.g. single nucleotide polymorphisms) in a single specified character, or a string of characters. Here, I propose such an information code as a natural extension to the IUPAC nomenclature code, and present some potential uses and limitations to such a code. The primary anticipated use of this extended nomenclature code is to assist in the representation of the rapidly growing space of information in human genetic variation. CONTACT: johnsonad2@nhlbi.nih.gov SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 20202975 TI - The nuclear factor-kappaB-interleukin-6 signalling pathway mediating vascular inflammation. AB - Vascular inflammation is a common pathophysiological response to diverse cardiovascular disease processes, including atherosclerosis, myocardial infarction, congestive heart failure, and aortic aneurysms/dissection. Inflammation is an ordered process initiated by vascular injury that produces enhanced leucocyte adherence, chemotaxis, and finally activation in situ. This process is coordinated by local secretion of adhesion molecules, chemotactic factors, and cytokines whose expression is the result of vascular injury-induced signal transduction networks. A wide variety of mediators of the vascular injury response have been identified; these factors include vasoactive peptides (angiotensin II, Ang II), CD40 ligands, oxidized cholesterol, and advanced glycation end-products. Downstream, the nuclear factor-kappaB (NF-kappaB) transcription factor performs an important signal integration step, responding to mediators of vascular injury in a stimulus-dependent and cell type-specific manner. The ultimate consequence of NF-kappaB signalling is the activation of inflammatory genes including adhesion molecules and chemotaxins. However, clinically, the hallmark of vascular NF-kappaB activation is the production of interleukin-6 (IL-6), whose local role in vascular inflammation is relatively unknown. The recent elucidation for the role of the IL-6 signalling pathway in Ang II-induced vascular inflammation as one that controls monocyte activation as well as its diverse signalling mechanism will be reviewed. These new discoveries further our understanding for the important role of the NF-kappaB-IL-6 signalling pathway in the process of vascular inflammation. PMID- 20202976 TI - cAMP/PKA antagonizes thrombin-induced inactivation of endothelial myosin light chain phosphatase: role of CPI-17. AB - AIMS: Activation of cAMP signalling abrogates thrombin-induced hyperpermeability. One of the mechanisms underlying this protective effect is the inactivation of endothelial contractile machinery, one of the major determinants of endothelial barrier function, mainly via the activation of myosin light chain phosphatase (MLCP). To date, the mechanisms of cAMP-mediated MLCP activation are only partially understood. Here the contribution of two cAMP effectors, PKA and Epac, in the regulation of endothelial contractile machinery and barrier function was studied. METHODS AND RESULTS: Endothelial contractile machinery and barrier function were analysed in cultured human umbilical vein endothelial cells (HUVEC). The cAMP analogues 8-CPT-cAMP and 6-Bnz-cAMP were used to activate Epac and PKA, respectively, and forskolin (FSK) was used to activate adenylyl cyclase. The cells were challenged by thrombin to inhibit MLCP via the RhoA/Rock pathway. Activation of either PKA or Epac partially blocked thrombin-induced hyperpermeability. Simultaneous activation of PKA and Epac had additive effects that were comparable to that of FSK. Activation of PKA but not Epac inhibited thrombin-induced phosphorylation of MLC and the MLCP regulatory subunit MYPT1, partly via inhibition of the RhoA/Rock pathway. FSK activated the MLCP catalytic subunit PP1 via dephosphorylation and dissociation of the PP1 inhibitory protein CPI-17. FSK blunted thrombin-induced CPI-17 phosphorylation, CPI-17/PP1 complex formation, and PP1 inactivation. Down-regulation of CPI-17 attenuated thrombin induced hyperpermeability and abolished the antagonistic effect of the PKA activator, whereas the Epac activator retained its antagonistic effect. CONCLUSION: cAMP/PKA regulates the endothelial barrier via inhibition of the contractile machinery, mainly by the activation of MLCP via inhibition of CPI-17 and RhoA/Rock. The permeability-lowering effect of the cAMP/Epac pathway is independent of CPI-17. PMID- 20202977 TI - Influence of p53 in the transition of myotrophin-induced cardiac hypertrophy to heart failure. AB - AIMS: Cardiac-specific overexpression of myotrophin (myo) protein in transgenic (myo-Tg) mice results in hypertrophy at 4 weeks that progresses to heart failure (HF) by 36 weeks. Gene profiling showed that p53 expression increases as hypertrophy worsens to HF, suggesting that p53 may influence myo-induced HF. We aimed to define how the p53 signalling cascade affects the spectrum of cardiac hypertrophy (CH)/HF. METHODS AND RESULTS: Immunoblot analysis showed that in myo Tg mice (Mus musculus), upregulation of p53 occurs only when hypertrophy transitions to HF (16 weeks onward). To elucidate the role of p53, a double-Tg mouse line (p53(-/-)/myo(+/+)) was developed by crossing myo-Tg mice with p53 null mice. A significant reduction in cardiac mass with improved cardiac function was observed in p53(-/-)/myo(+/+) mice, suggesting that absence of p53 prevents hypertrophy from turning into HF. Analysis via real-time reverse-transcription PCR revealed changes in transcripts of the p53 pathway in p53(-/-)/myo(+/+) mice. Ingenuity Pathway Analysis indicated that cross-talk among several key nodal molecules (e.g. cyclin-dependent kinase inhibitor 1A, caspase-3, nuclear factor kappa-light-chain enhancer of activated B cells etc.) may play a regulatory role in the transition of CH to HF. CONCLUSION: Our data provide evidence, for the first time, that the coherence of p53 with myo plays an active role during the transition of CH to HF in a model of HF induced by myo overexpression. Transition from CH to HF can be prevented in the absence of p53 in myo-induced hypertrophy. Therefore, deletion/inhibition of p53 could be a therapeutic strategy to prevent CH from transitioning to HF. PMID- 20202978 TI - Caveolae, caveolins, and cavins: complex control of cellular signalling and inflammation. AB - Caveolae are specialized lipid rafts that form flask-shaped invaginations of the plasma membrane. They are involved in cell signalling and transport and have been shown critically regulate vascular reactivity and blood pressure. The organization and functions of caveolae are mediated by coat proteins (caveolins) and support or adapter proteins (cavins). The caveolins, caveolin-1, -2, and -3, form the structural backbone of caveolae. These proteins are also highly integrated into caveolae function and have their own activity independent of caveolae. The cavins, cavins 1-4, are involved in regulation of caveolae and modulate the function of caveolins by promoting the membrane remodelling and trafficking of caveolin-derived structures. The relationships between these different proteins are complex and intersect with many aspects of cell function. Caveolae have also been implicated in chronic inflammatory conditions and other pathologies including atherosclerosis, inflammatory bowel disease, muscular dystrophy, and generalized dyslipidaemia. The pathogenic role of the caveolins is an emerging area, however, the roles of cavins in disease is just beginning to be explored. This review will examine the relationship between caveolins and cavins and explore the role of caveolae in inflammatory signalling mechanisms. PMID- 20202979 TI - English language proficiency and lifetime mental health service utilization in a national representative sample of Asian Americans in the USA. AB - BACKGROUND: US Department of Health and Human Services reported that the lack of English language proficiency and the shortage of providers who possessed appropriate language skills were identified as major barriers to mental health service use for approximately half of the population of Asians and Pacific Islanders. The aim of this study was to examine the predictors of lifetime mental health service use in relation to English language proficiency among Asian Americans. METHODS: Data from 2095 Asian participants from the National Latino and Asian American Study were analyzed using logistic regression. RESULTS: Respondents with better English language proficiency and with a mental health diagnosis were more inclined to use mental health services. Participants who were born in the USA, who were widowed, separated or divorced, who sought comfort from religion, who reported worse physical and mental health self-ratings were more likely to use mental health services. The lack of health insurance coverage was not a significant predictor. CONCLUSIONS: The public health implications for behavioral health include the need to educate health-care providers working with Asian Americans regarding the benefits derived from seeking services and making interpreter services available in a culturally sensitive environment. PMID- 20202980 TI - Geographical access to healthcare in Northern England and post-mortem diagnosis of cancer. AB - BACKGROUND: There is some previous evidence that diagnosis of cancer at death, recorded as registry death certificate only records, is associated with problems of access to care. METHODS: Records from the Northern and Yorkshire Cancer Registry for patients registered with breast, colorectal, lung, ovarian or prostate cancer between 1994 and 2002 were supplemented with measures of travel time to general practitioner and hospital services, and social deprivation. Logistic regression was used to identify predictors of records where diagnosis was at death. RESULTS: There was no association between the odds diagnosis at death and access to primary care. For all sites except breast, the highest odds of being a cancer diagnosed at death fell among those living in the highest quartile of hospital travel time, although it was only statistically significant for colorectal and ovary tumours. Those in the most deprived and furthest travel time to hospital quartile were 2.6 times more likely to be a diagnosis at death case compared with those in the most affluent and proximal areas. CONCLUSIONS: There is some evidence that poorer geographical access to tertiary care, in particular when coupled with social disadvantages, may be associated with increased odds of diagnosis at death. PMID- 20202981 TI - Cancer in the London prison population, 1986-2005. AB - BACKGROUND: Little research has investigated cancer care in UK prisons. We wished to identify the number of new cases and the most common cancer diagnoses occurring each year in London prisoners, and the place of death for those who died from their disease. METHODS: Using the database of the Thames Cancer Registry, we identified cancer diagnoses in residents of seven London prisons from 1986 to 2005 and the place of death of patients dying from their disease between 1996 and 2005. RESULTS: On average, 31 patients were recorded as diagnosed with cancer while in prison within each 5-year period. In women, 83% (85/102) of diagnoses were in situ carcinoma of the cervix, and in men, 19% (11/57) were of lung cancer. None of the 25 patients recorded as dying from their disease died in prison. Most died in hospitals (48%, 12/25) or in hospices (28%, 7/25). CONCLUSIONS: London prisons contribute a small number of patients each year who require NHS cancer care, including those with advanced cancer who are released before death. Future studies should investigate cancer incidence for the national prison population, methods for improving screening coverage and follow up, the timeliness of access to cancer treatments and end-of-life care, and prisoners' and health professionals' experiences of care. PMID- 20202982 TI - Intracardiac thrombus: a good indication of ultrasound image integration system (Cartosound) for radiofrequency ablation. AB - We describe the case of a young man suffering from incessant ventricular tachycardia and a chronic apical left ventricular thrombus. We performed radiofrequency ablation of this tachycardia emerging from the border zone of the septoapical anevrism, near the apical thrombus. We used Cartosound system to avoid manipulation of catheter in the thrombus. We demonstrate, in this case, that the technique is feasible and safe. PMID- 20202983 TI - Rate-dependent measures of repolarization predict inducibility of ventricular arrhythmias. AB - OBJECTIVE: The aim of this study was to compare the rate-dependent measures of repolarization in patients with and without inducible ventricular arrhythmias, and so to assess the potential arrhythmogenic role of rate-dependent heterogeneities in cardiac repolarization. METHODS: Two groups of patients were studied during invasive electrophysiological procedures for standard clinical indications. A normal group (n = 17) with supraventricular tachycardia, structurally normal hearts and no inducible ventricular arrhythmias (PES-) and an inducible group (n = 13) with inducible ventricular arrhythmias (PES+). In each patient, we delivered a series of S1-S2 pacing sequences with a baseline S2 of 500 ms, which was progressively reduced. At the same time, a 12-lead electrocardiogram (ECG) was recorded. T-waves were extracted from each ECG recording, and 12 different T-wave measures were obtained from each patient across a range of coupling intervals. These included conventional measures, and those obtained from principal component analysis (PCA) of repolarization waveforms. RESULTS: At baseline S2, there was no significant difference between the PES- and PES+ using conventional T-wave measures. There were significant differences at baseline S2 between groups using PCA-derived measures. These differences showed rate dependence and were larger at shorter coupling intervals. Two dynamic ECG measurements identified subjects who were inducible during PES; maximum relative T-wave residuum >0.10 (odds ratio: 38.5, 95% CI: 4.7-318.5; P < 0.001) and maximum T-wave shape index <0.007 (odds ratio: 180.0, 95% CI: 10.2 3167.0; P < 0.001). CONCLUSION: T-wave shape index is rate dependent and discriminates between PES- and PES+ patients. We propose that patients with inducible arrhythmias have rate-dependent heterogeneity of repolarization which could be a useful tool for risk stratification. PMID- 20202984 TI - Culprit artery in evolving inferior wall acute myocardial infarction: RCA vs LCx. PMID- 20202986 TI - Reduced processing speed in rugby union players reporting three or more previous concussions. AB - The issue pertaining to the effect of multiple self-reported sports-related concussions on cognitive function is controversial. Although this topic has received increased attention in the literature recently, the issue remains unresolved. Evidence supporting a detrimental cognitive effect has been reported at a sub-concussive level and following one, two, and three or more previous concussions. However, numerous studies have been unable to replicate these findings. Additionally, discrepancies between neuropsychological testing formats have been identified, where studies utilizing traditional tests tend to support the notion of detrimental cognitive effects whereas studies with computerized tests have tended to demonstrate no effect. The present study sought to examine possible detrimental cognitive effects in a sample of adult male rugby union players who reported a history of three or more concussions (n = 34) compared with those who reported no previous concussions (n = 39). A computerized neuropsychological battery and a traditional neuropsychological measure of processing speed were administered for this purpose. Findings revealed that there were differences between groups on two processing speed measures from both traditional and computerized tests. Athletes with a history of multiple concussions performed significantly lower on these measures than those with no history of concussion. These results provide further evidence to suggest that a history of three or more self-reported concussions in active athletes may have a detrimental effect on cognitive function. Future research may focus on identifying moderating factors in an attempt to resolve some of the conflicting findings and identify potential athletes at risk for sustaining cognitive deficits. PMID- 20202987 TI - Candidaemia in adult cancer patients: risks for fluconazole-resistant isolates and death. AB - BACKGROUND: Candidaemia in cancer patients is associated with increasing fluconazole resistance. Models for predicting such isolates and their clinical impact are required. METHODS: Clinical, treatment and outcome data from a population-based candidaemia survey (2001-2004) were collected at 5 and 30 days after diagnosis. Speciation and antifungal susceptibility testing was performed. RESULTS: There were 138 candidaemia episodes (33% Candida albicans) in adults with haematological malignancies and 150 (51% C. albicans) in adults with solid organ malignancies. Thirty-nine isolates had fluconazole MICs of >or=64 mg/L and 40 had MICs of 16-32 mg/L (predominantly Candida glabrata and Candida krusei). By multivariate analysis, triazole therapy, gastrointestinal tract (GIT) surgery in the 30 days before candidaemia and age >65 years were predictive of fluconazole resistant candidaemia. Thirty day crude mortality was 40% in haematology patients and 45% in oncology patients. Fluconazole-resistant isolates were associated with increased risk of mortality by univariate (P = 0.04) and Kaplan-Meier survival analyses. By Cox proportional hazards modelling, the strongest predictors of mortality at onset of candidaemia were invasive ventilation, elevated creatinine, intensive care unit (ICU) admission and receipt of systemic triazoles or corticosteroids in the previous 30 days. Removal of a central venous access device (CVAD) at or within 5 days of onset was associated with decreased mortality. CONCLUSIONS: Risk factors for fluconazole-resistant candidaemia in adults with cancer include fluconazole/triazole exposure and GIT surgery. ICU admission, invasive ventilation, renal impairment, age >65 years and prior exposure to corticosteroids and triazoles are risk factors for death. CVAD removal reduced mortality. These findings should be integrated into surveillance and treatment algorithms. PMID- 20202988 TI - Daily dosing of tacrolimus in patients treated with HIV-1 therapy containing a ritonavir-boosted protease inhibitor or raltegravir. AB - OBJECTIVES: The number of HIV-infected patients receiving orthotopic liver transplantation (OLTX) is increasing. One major challenge is the severe drug-drug interactions between immunosuppressive drugs such as tacrolimus and ritonavir boosted HIV-1 protease inhibitors (PIs). The introduction of raltegravir, which is not metabolized by the cytochrome system, may allow concomitant treatment without dose adaptation. PATIENTS AND METHODS: We conducted a retrospective analysis of HIV-1-infected patients receiving tacrolimus concomitantly with different HIV therapies, including 12 h pharmacokinetic assessment of drug levels. RESULTS: Three OLTX patients received a ritonavir-boosted PI therapy when tacrolimus was added at very low doses of 0.06, 0.03 and 0.08 mg daily. Median tacrolimus blood levels were 6.6, 3.0 and 7.9 ng/mL over a follow-up period of 8, 22 and 33 months, respectively. In two other patients (one after OLTX and one with Crohn's disease), a raltegravir-based HIV therapy was started while patients received 1 or 2 mg of tacrolimus twice daily. No tacrolimus dose adjustment was necessary and drug levels remained unchanged. CONCLUSIONS: Decreasing the dose of tacrolimus to 0.03-0.08 mg daily in patients with concomitant boosted PI therapy resulted in stable tacrolimus blood levels without alteration of PI drug levels. Concomitant use of raltegravir and tacrolimus revealed no clinically relevant drug interaction. PMID- 20202989 TI - Microbiological aspects of the UK National Institute for Health and Clinical Excellence (NICE) guidance on urinary tract infection in children. AB - The publication in August 2007 of the UK National Institute for Health and Clinical Excellence (NICE) guidance on urinary tract infection in children provided a fresh and useful review of the management of this condition. However, it has also resulted in some controversy. In particular, the advice to use urgent microscopy for rapid screening of urine in children >or=3 months but <3 years of age has presented practical problems for some laboratories in staffing this service out of hours. Further discussion between microbiologists, paediatricians and primary care doctors regarding this recommendation is required. In addition, the abandoning of routine antibiotic prophylaxis following a first-time urine infection has caused some debate. The evidence around these issues is reviewed, as well as the differences in the laboratory processing and interpretation of paediatric urines compared with urine specimens from adults. General measures to reduce the risk of recurrence are also discussed. As mentioned in the NICE guidance, microbiologists should continue to emphasize the basic principles, particularly the importance of obtaining an accurate diagnosis from a well collected and well-transported urine specimen. PMID- 20202990 TI - A comparison of HER2/neu gene amplification and its protein overexpression between primary breast cancer and metastatic lymph nodes. AB - OBJECTIVE: Breast cancer is a heterogeneous disease. The aim of this prospective study, in which fluorescence in situ hybridization was used to determine human epidermal growth factor receptor 2 status in primary breast cancers and in the lymph node metastases, was to verify the stability of human epidermal growth factor receptor 2 status in the following steps of neoplastic progression of breast cancer, which is fundamental for an appropriate therapeutic approach. METHODS: From patients with primary breast cancer, for whom, after January 2003, surgery was performed and involved metastatic lymph nodes were found, we randomly selected four groups of 15 patients, whose human epidermal growth factor receptor 2 score by immunohistochemistry was either 0, 1+, 2+ or 3+, respectively, totaling to 60. For each of those patients, their primary tumors and all of the metastatic lymph nodes were examined. Primary tumors and metastatic lymph nodes in each patient were examined by fluorescence in situ hybridization. RESULTS: Of 18 patients with fluorescence in situ hybridization-positive primary tumors, 15 (83.3%) were fluorescence in situ hybridization-positive and 2 (11.1%) were fluorescence in situ hybridization-negative in all of their metastatic lymph nodes, and 1 (5.5%) patient had mixed (fluorescence in situ hybridization positive or -negative) metastatic lymph nodes. Of 42 patients with fluorescence in situ hybridization-negative primary tumors, 40 (95%) were fluorescence in situ hybridization-negative and 2 (5%) fluorescence in situ hybridization-positive in all of their metastatic lymph nodes. CONCLUSIONS: This study revealed that fluorescence in situ hybridization resulted in a high concordance of 83.3% between the human epidermal growth factor receptor 2 manifestation (fluorescence in situ hybridization-positive status) in primary tumors and that in metastatic lymph nodes, demonstrating that it is appropriate to determine whether and how to apply treatment by trastuzumab based on the results of evaluation of human epidermal growth factor receptor 2 expression. PMID- 20202991 TI - Clinical results of iridium-192 high dose rate brachytherapy with external beam radiotherapy. AB - OBJECTIVE: Here, we report the clinical results of iridium-192 high dose rate brachytherapy at Kanazawa University Hospital. METHODS: The study population consisted of 166 patients diagnosed with T1c-T3bN0M0 prostate cancer treated with high dose rate brachytherapy and external beam radiotherapy and followed up for 6 months or longer. Treatment consisted of external beam radiotherapy to the prostate at 44 Gy/22 fractions and high dose rate brachytherapy at 18 Gy/3 fractions. RESULTS: Median follow-up interval was 31.5 months (range 6.2-88.7). The overall 5-year biological recurrence-free survival rate was 93.0%. The 5-year biological recurrence-free survival rates for the patients in low-, intermediate- and high-risk groups according to the D'Amico risk classification criteria were 96.1%, 89.0% and 91.6%, respectively. When limited to the group that did not receive adjuvant hormonal therapy, the 5-year biological recurrence-free survival rates for the patients in low-, intermediate- and high-risk groups were 96.0%, 96.3% and 82.9%, respectively. Grade 3 or greater adverse effects were rare. Urethral stricture was observed in only 1.0% of the patients. Eighty percent of patients retained erectile function after high dose rate brachytherapy and reported satisfaction with sexual function. CONCLUSIONS: High dose rate brachytherapy is considered a good form of treatment for localized prostate cancer, although longer follow-up is necessary. PMID- 20202992 TI - Impact of global left ventricular afterload on left ventricular function in asymptomatic severe aortic stenosis: a two-dimensional speckle-tracking study. AB - AIMS: The present study sought to assess the effect of global left ventricular (LV) afterload on LV myocardial systolic function in patients with aortic stenosis (AS) and preserved LV ejection fraction. METHODS AND RESULTS: We prospectively examined the LV myocardial deformation (i.e. longitudinal, radial, and circumferential) by two-dimensional speckle tracking in 173 patients with asymptomatic severe AS. Thirty-eight patients (22%) had low flow as determined by a low stroke volume index (or=5 mmHg mL/m(2)). Systemic arterial compliance (P = 0.001), circumferential myocardial deformation (P = 0.024), and left atrial area index (P = 0.04) were independently associated with increased global LV load in multivariable analysis. Of note, LV ejection fraction was not identified as a determinant of low flow or increased afterload. CONCLUSION: In asymptomatic patients with severe AS, LV ejection fraction markedly underestimates the extent of myocardial systolic impairment. Intrinsic myocardial dysfunction is particularly common in patients with increased global LV afterload, and especially in the subset of patients with low-flow AS. PMID- 20202993 TI - Integration of mutation and chromosomal damage endpoints into 28-day repeat dose toxicology studies. AB - Two endpoints of genetic toxicity, mutation at the X-linked Pig-a gene and chromosomal damage in the form of micronucleated reticulocytes (MN-RETs), were evaluated in blood samples obtained from 28-day repeat-dosing studies typical of those employed in toxicity evaluations. Male Wistar Han rats were treated at 24-h intervals on days 1 through 28 with one of five prototypical genotoxicants: N ethyl-N-nitrosourea, 7,12-dimethyl-12-benz[a]anthracene, 4-nitroquinoline-1-oxide (4NQO), benzo(a)pyrene, and N-methyl-N-nitrosourea. Flow cytometric scoring of CD59-negative erythrocytes (indicative of glycosylphosphatidylinositol anchor deficiency and hence Pig-a mutation) was performed using blood specimens obtained on days -1, 15, 29, and 56. Blood specimens collected on days 4 and 29 were evaluated for MN-RET frequency using flow cytometry-based MicroFlow Kits. With the exception of 4NQO, each chemical induced significant increases in the frequency of MN-RETs on days 4 and 29. All five agents increased the frequency of mutant phenotype (CD59 negative) reticulocytes (RETs) and erythrocytes. Mutation responses in RETs occurred earlier than in erythrocytes and tended to peak, or nearly peak, at day 29. In contrast, the mutant phenotype erythrocyte responses were modest on day 29 and required additional time to reach their maximal value. The observed kinetics were expected based on the known turnover of RETs and erythrocytes. The data show that RETs can serve as an appropriate indicator cell population for 28-day studies. Collectively, these data suggest that blood-based genotoxicity endpoints can be effectively incorporated into routine toxicology studies, a strategy that would reduce animal usage while providing valuable genetic toxicity information within the context of other toxicological endpoints. PMID- 20202994 TI - An artificial solar spectrum substantially alters plant development compared with usual climate room irradiance spectra. AB - Plant responses to the light spectrum under which plants are grown affect their developmental characteristics in a complicated manner. Lamps widely used to provide growth irradiance emit spectra which are very different from natural daylight spectra. Whereas specific responses of plants to a spectrum differing from natural daylight may sometimes be predictable, the overall plant response is generally difficult to predict due to the complicated interaction of the many different responses. So far studies on plant responses to spectra either use no daylight control or, if a natural daylight control is used, it will fluctuate in intensity and spectrum. An artificial solar (AS) spectrum which closely resembles a sunlight spectrum has been engineered, and growth, morphogenesis, and photosynthetic characteristics of cucumber plants grown for 13 d under this spectrum have been compared with their performance under fluorescent tubes (FTs) and a high pressure sodium lamp (HPS). The total dry weight of the AS-grown plants was 2.3 and 1.6 times greater than that of the FT and HPS plants, respectively, and the height of the AS plants was 4-5 times greater. This striking difference appeared to be related to a more efficient light interception by the AS plants, characterized by longer petioles, a greater leaf unfolding rate, and a lower investment in leaf mass relative to leaf area. Photosynthesis per leaf area was not greater for the AS plants. The extreme differences in plant response to the AS spectrum compared with the widely used protected cultivation light sources tested highlights the importance of a more natural spectrum, such as the AS spectrum, if the aim is to produce plants representative of field conditions. PMID- 20202995 TI - Association between winter anthocyanin production and drought stress in angiosperm evergreen species. AB - Leaves of many evergreen angiosperm species turn red under high light during winter due to the production of anthocyanin pigments, while leaves of other species remain green. There is currently no explanation for why some evergreen species exhibit winter reddening while others do not. Conditions associated with low leaf water potentials (Psi) have been shown to induce reddening in many plant species. Because evergreen species differ in susceptibility to water stress during winter, it is hypothesized that species which undergo winter colour change correspond with those that experience/tolerate the most severe daily declines in leaf Psi during winter. Six angiosperm evergreen species which synthesize anthocyanin in leaves under high light during winter and five species which do not were studied. Field Psi, pressure/volume curves, and gas exchange measurements were derived in summer (before leaf colour change had occurred) and winter. Consistent with the hypothesis, red-leafed species as a group had significantly lower midday Psi in winter than green-leafed species, but not during the summer when all the leaves were green. However, some red-leafed species showed midday declines similar to those of green-leafed species, suggesting that low Psi alone may not induce reddening. Pressure-volume curves also provided some evidence of acclimation to more negative water potentials by red-leafed species during winter (e.g. greater osmotic adjustment and cell wall hardening on average). However, much overlap in these physiological parameters was observed as well between red and green-leafed species, and some of the least drought-acclimated species were red-leafed. No difference was observed in transpiration (E) during winter between red and green-leaved species. When data were combined, only three of the six red-leafed species examined appeared physiologically acclimated to prolonged drought stress, compared to one of the five green-leafed species. This suggests that drought stress alone is not sufficient to explain winter reddening in evergreen angiosperms. PMID- 20202996 TI - Metabolic networking in Brunfelsia calycina petals after flower opening. AB - Brunfelsia calycina flowers change colour from purple to white due to anthocyanin degradation, parallel to an increase in fragrance and petal size. Here it was tested whether the production of the fragrant benzenoids is dependent on induction of the shikimate pathway, or if they are formed from the anthocyanin degradation products. An extensive characterization of the events taking place in Brunfelsia flowers is presented. Anthocyanin characterization was performed using ultraperfomance liquid chromatography-quadrupole time of flight-tandem mass specrometry (UPLC-QTOF-MS/MS). Volatiles emitted were identified by headspace solid phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS). Accumulated proteins were identified by 2D gel electrophoresis. Transcription profiles were characterized by cross-species hybridization of Brunfelsia cDNAs to potato cDNA microarrays. Identification of accumulated metabolites was performed by UPLC-QTOF-MS non-targeted metabolite analysis. The results include characterization of the nine main anthocyanins in Brunfelsia flowers. In addition, 146 up-regulated genes, 19 volatiles, seven proteins, and 17 metabolites that increased during anthocyanin degradation were identified. A multilevel analysis suggests induction of the shikimate pathway. This pathway is the most probable source of the phenolic acids, which in turn are precursors of both the benzenoid and lignin production pathways. The knowledge obtained is valuable for future studies on degradation of anthocyanins, formation of volatiles, and the network of secondary metabolism in Brunfelsia and related species. PMID- 20202997 TI - Agrobacterium-mediated transformation of durum wheat (Triticum turgidum L. var. durum cv Stewart) with improved efficiency. AB - An efficient Agrobacterium-mediated durum wheat transformation system has been developed for the production of 121 independent transgenic lines. This improved system used Agrobacterium strain AGL1 containing the superbinary pGreen/pSoup vector system and durum wheat cv Stewart as the recipient plant. Acetosyringone at 400 microM was added to both the inoculation and cultivation medium, and picloram at 10 mg l(-1) and 2 mg l(-1) was used in the cultivation and induction medium, respectively. Compared with 200 microM in the inoculation and cultivation media, the increased acetosyringone concentration led to significantly higher GUS (beta-glucuronidase) transient expression and T-DNA delivery efficiency. However, no evident effects of acetosyringone concentration on regeneration frequency were observed. The higher acetosyringone concentration led to an improvement in average final transformation efficiency from 4.7% to 6.3%. Furthermore, the concentration of picloram in the co-cultivation medium had significant effects on callus induction and regeneration. Compared with 2 mg l(-1) picloram in the co cultivation medium, increasing the concentration to 10 mg l(-1) picloram resulted in improved final transformation frequency from 2.8% to 6.3%, with the highest frequency of 12.3% reached in one particular experiment, although statistical analysis showed that this difference in final transformation efficiency had a low level of significance. Stable integration of foreign genes, their expression, and inheritance were confirmed by Southern blot analyses, GUS assay, and genetic analysis. Analysis of T(1) progeny showed that, of the 31 transgenic lines randomly selected, nearly one-third had a segregation ratio of 3:1, while the remainder had ratios typical of two or three independently segregating loci. PMID- 20202998 TI - Terrestrial plant production and climate change. AB - The likely future increase in atmospheric CO(2) and associated changes in climate will affect global patterns of plant production. Models integrate understanding of the influence of the environment on plant physiological processes and so enable estimates of future changes to be made. Moreover, they allow us to assess the consequences of different assumptions for predictions and so stimulate further research. This paper is a review of the sensitivities of one such model, Hybrid6.5, a detailed mechanistic model of terrestrial primary production. This model is typical of its type, and the sensitivities of the global distribution of predicted production to model assumptions and possible future CO(2) levels and climate are assessed. Sensitivity tests show that leaf phenology has large effects on mean C(3) crop and needleleaved cold deciduous tree production, reducing potential net primary production (NPP) from that obtained using constant maximum annual leaf area index by 32.9% and 41.6%, respectively. Generalized Plant Type (GPT) specific parameterizations, particularly photosynthetic capacity per unit leaf N, affect mean predicted NPP of higher C(3) plants by -22.3% to 27.9%, depending on the GPT, compared to NPP predictions obtained using mean parameter values. An increase in atmospheric CO(2) concentrations from current values to 720 ppm by the end of this century, with associated effects on climate from a typical climate model, is predicted to increase global NPP by 37.3%. Mean increases range from 43.9-52.9% across different C(3) GPTs, whereas the mean NPP of C(4) grass and crop increases by 5.9%. Significant uncertainties concern the extent to which acclimative processes may reduce any potential future increase in primary production and the degree to which any gains are transferred to durable, and especially edible, biomass. Experimentalists and modellers need to work closely together to reduce these uncertainties. A number of research priorities are suggested. 'The green leaf or, to be more precise, the microscopic green grain of chlorophyll, is the focus, the point in the world to which solar energy flows on one side while all the manifestations of life on earth take their source on the other side.' Kliment Arkadievich Timiryazev The conclusions of a century of plant physiology, speech at Moscow University, 12 January 1901. PMID- 20202999 TI - Regulation of two germin-like protein genes during plum fruit development. AB - Germin-like proteins (GLPs) have several proposed roles in plant development and defence. Two novel genes (Ps-GLP1 and 2) encoding germin-like protein were isolated from plum (Prunus salicina). Their regulation was studied throughout fruit development and during ripening of early and late cultivars. These two genes exhibited similar expression patterns throughout the various stages of fruit development excluding two important stages, pit hardening (S2) and fruit ripening (S4). During fruit development until the ripening phase, the accumulation of both Ps-GLPs is related to the evolution of auxin. However, during the S2 stage only Ps-GLP1 is induced and this could putatively be in a H(2)O(2)-dependent manner. On the other hand, the diversity in the Ps-GLPs accumulation profile during the ripening process seems to be putatively due to the variability of endogenous auxin levels among the two plum cultivars, which consequently change the levels of autocatalytic ethylene available for the fruit to co-ordinate ripening. The effect of auxin on stimulating ethylene production and in regulating Ps-GLPs transcripts was also investigated. These data, supported by their localization in the extracellular matrix, suggest that auxin is somehow involved in the regulation of both transcripts throughout fruit development and ripening. PMID- 20203000 TI - SeqSharp: A general approach for improving cycle-sequencing that facilitates a robust one-step combined amplification and sequencing method. AB - Sequencing a specific DNA element within a genome or a complex mixture of DNA by the Sanger sequencing method generally involves PCR-mediated amplification of target DNA with forward and reverse primers, followed by a sequencing reaction directed from a single primer. To minimize the contribution of fluorescent signal due to the extension products originating from primers carried over from the amplification step, an intermediate step is routinely incorporated to remove the excess primers before proceeding to the sequencing reaction. We have developed a method called SeqSharp that removes noise in the sequencing data by enzymatically removing chain termination products originating from one or both of the amplification primers. This method substantially improves the quality of sequence information even without an intermediate primer removal step. Importantly, we show that SeqSharp significantly improves the sequence quality from a combined (one-step) amplification/sequencing protocol and provides a more robust method that, unlike previously described one-step sequencing methods, yields high quality sequence data from a single reaction by using equimolar primer concentrations. One-step SeqSharp is generally applicable and produced excellent sequence data from bacterial, fungal, and human DNA. PMID- 20203001 TI - Rare sequence variation in the genome flanking a short tandem repeat locus can lead to a question of "nonmaternity". AB - Typing of STR (short tandem repeat) alleles is used in a variety of applications in clinical molecular pathology, including evaluations for maternal cell contamination. Using a commercially available STR typing assay for maternal cell contamination performed in conjunction with prenatal diagnostic testing, we were posed with apparent nonmaternity when the two fetal samples did not demonstrate the expected maternal allele at one locus. By designing primers external to the region amplified by the primers from the commercial assay and by performing direct sequencing of the resulting amplicon, we were able to determine that a guanine to adenine sequence variation led to primer mismatch and allele dropout. This explained the apparent null allele shared between the maternal and fetal samples. Therefore, although rare, allele dropout must be considered whenever unexplained homozygosity at an STR locus is observed. PMID- 20203002 TI - Rapid and reliable detection of glucose-6-phosphate dehydrogenase (G6PD) gene mutations in Han Chinese using high-resolution melting analysis. AB - Glucose-6-phosphate dehydrogenase (G6PD) deficiency, an X-linked inherited disease, is one of the most common enzymopathies and affects over 400 million people worldwide. In China at least 21 distinct point mutations have been identified so far. In this study high-resolution melting (HRM) analysis was used to screen for G6PD mutations in 260 unrelated Han Chinese individuals, and the rapidity and reliability of this method was investigated. The mutants were readily differentiated by using HRM analysis, which produced distinct melting curves for each tested mutation. Interestingly, G1388A and G1376T, the two most common variants accounting for 50% to 60% of G6PD deficiency mutations in the Chinese population, could be differentiated in a single reaction. Further, two G6PD mutations not previously reported in the Chinese population were identified in this study. One of these mutations, designated "G6PD Jiangxi G1340T," involved a G1340T substitution in exon 11, predicting a Gly447Val change in the protein. The other mutation involved a C406T substitution in exon 5. The frequencies of the common polymorphism site C1311T/IVS (intervening sequence) XI t93c between patients with G6PD and healthy volunteers were not significantly different. Thus, HRM analysis will be a useful alternative for screening G6PD mutations. PMID- 20203003 TI - A commercial real-time PCR kit provides greater sensitivity than direct sequencing to detect KRAS mutations: a morphology-based approach in colorectal carcinoma. AB - KRAS mutation testing has become a standard procedure in the management of patients with carcinomas. The most frequently used method for KRAS testing is direct sequencing of PCR products. The development of commercial real-time quantitative PCR kits offers a useful alternative since they are in theory much more sensitive than direct sequencing and they avoid post- PCR handling. We present our experience as a reference center for the study of KRAS mutations, comparing direct sequencing and the use of a commercial real-time quantitative PCR kit, as well as determining the sensitivity of both procedures in clinical practice. The TheraScreen K-RAS Mutation Kit identified mutations in 75 (44%) of the 170 tumors. Three cases were tested positive using TheraScreen K-RAS Mutation Kit and negative by direct sequencing. We then compared the sensitivity of the kit and that of direct sequencing using 74 mutant tumors. The kit was able to detect the presence of a mutation in a 1% dilution of the total DNA in 13.5% of the tumors and, in 84%, KRAS mutation was identified at a dilution of 5%. Sequencing was able to detect KRAS mutations when the mutant DNA represented 10% of the total DNA in 20/74 (27%) of the tumors. When the mutant DNA represented 30% of the total DNA, sequencing could detect mutations in 56/74 (76%). PMID- 20203004 TI - Detection of exon 12 Mutations in the JAK2 gene: enhanced analytical sensitivity using clamped PCR and nucleotide sequencing. AB - JAK2 V617F is the most frequently found somatic mutation in polycythemia vera (PV). Among the cases negative for V617F, a significant fraction have a mutation in exon 12 of the JAK2 gene. Several groups have reported that the exon 12 mutations are present in only a small fraction of the blood cells in some patients. We have developed an assay to detect these mutations with an analytical sensitivity of 0.1% by using a "PCR clamp" to inhibit amplification of the normal sequence and enhance amplification of DNA containing a mutation in the clamp target sequence. The products of this reaction were analyzed by capillary electrophoresis to detect deletions, which are the most frequent type of exon 12 mutations, or by nucleotide sequencing to detect all of the mutations. In a survey of 34 specimens from patients with PV or idiopathic erythrocytosis who did not have a JAK2 V617F mutation, we found four with a mutation in exon 12, 3 of 10 with PV, and 1 of 24 with idiopathic erythrocytosis. In two cases the mutation was present in a small fraction of the cells and difficult to detect without the use of the clamp. The use of an assay with increased analytical sensitivity enhances the ability to identify patients with mutations in exon 12 of the JAK2 gene. PMID- 20203005 TI - Combined use of PCR-based TCRG and TCRB clonality tests on paraffin-embedded skin tissue in the differential diagnosis of mycosis fungoides and inflammatory dermatoses. AB - The distinction between mycosis fungoides (MF) and inflammatory dermatoses (ID) by clinicopathologic criteria can be challenging. There is limited information regarding the performance characteristics and utility of TCRG and TCRB clonality assays in diagnosis of MF and ID from paraffin-embedded tissue sections. In this study, PCR tests were performed with both TCRG and TCRB BIOMED-2 clonality methods followed by capillary electrophoresis and Genescan analysis using DNA samples from 35 MF and 96 ID patients with 69 and 133 paraffin-embedded specimens, respectively. Performance characteristics were determined for each test individually and in combination. TCRG and TCRB tests demonstrated identical sensitivity (64%) and specificity (84%) when analyzed as individual assays. The positive predictive value, negative predictive value, and change of posttest MF probability over a range of MF pretest probabilities were obtained. These data were used to construct an algorithm for sequential use of TCRG and TCRB. As single tests, commercially available BIOMED-2 PCR-based TCRG and TCRB clonality tests on paraffin-embedded tissue have no significant difference in terms of sensitivity and specificity. Combined use of the two tests in patients with intermediate pretest probabilities as proposed in the algorithm could improve test utility. PMID- 20203006 TI - Simultaneous genotyping of GSTT1 and GSTM1 null polymorphisms by melting curve analysis in presence of SYBR Green I. AB - Due to their ability to metabolize xenobiotics, glutathione S-transferases (GSTs) play an important role in cellular protection. GST family members mu (GSTM1) and theta (GSTT1) exhibit a common polymorphism that results in the complete deletion of the gene (null allele). Homozygous deletions, which result in the absence of the enzyme, are considered a risk factor for several diseases, including cancer. We report a simple, low cost, and high throughput assay for the simultaneous analysis of the GSTM1 and GSTT1 null polymorphisms in a single step. The assay is based on multiplex real-time PCR in the presence of SYBR Green I and genotype discrimination by melting curve analysis in a LightCycler. We have genotyped 792 samples to compare this new approach with conventional PCR followed by gel electrophoresis. Comparison of the methods gave a good agreement, with kappa values of 0.88 for GSTM1 and 0.64 for GSTT1. Reanalysis of discrepant samples indicated that absence of amplification of the larger GSTT1 fragment by conventional PCR accounted for most of the discrepancies. Moreover, the improved amplification efficiency of the real-time PCR results in a significant reduction of missing values. Due to its simplicity and low cost, this assay is well suited for the rapid analysis of GST-null genotypes in studies that involve large number of samples. PMID- 20203007 TI - DNA as a universal substrate for chemical kinetics. AB - Molecular programming aims to systematically engineer molecular and chemical systems of autonomous function and ever-increasing complexity. A key goal is to develop embedded control circuitry within a chemical system to direct molecular events. Here we show that systems of DNA molecules can be constructed that closely approximate the dynamic behavior of arbitrary systems of coupled chemical reactions. By using strand displacement reactions as a primitive, we construct reaction cascades with effectively unimolecular and bimolecular kinetics. Our construction allows individual reactions to be coupled in arbitrary ways such that reactants can participate in multiple reactions simultaneously, reproducing the desired dynamical properties. Thus arbitrary systems of chemical equations can be compiled into real chemical systems. We illustrate our method on the Lotka Volterra oscillator, a limit-cycle oscillator, a chaotic system, and systems implementing feedback digital logic and algorithmic behavior. PMID- 20203008 TI - Self-organization of grafted polyelectrolyte layers via the coupling of chemical equilibrium and physical interactions. AB - The competition between chemical equilibrium, for example protonation, and physical interactions determines the molecular organization and functionality of biological and synthetic systems. Charge regulation by displacement of acid-base equilibrium induced by changes in the local environment provides a feedback mechanism that controls the balance between electrostatic, van der Waals, steric interactions and molecular organization. Which strategies do responsive systems follow to globally optimize chemical equilibrium and physical interactions? We address this question by theoretically studying model layers of end-grafted polyacids. These layers spontaneously form self-assembled aggregates, presenting domains of controlled local pH and whose morphologies can be manipulated by the composition of the solution in contact with the film. Charge regulation stabilizes micellar domains over a wide range of pH by reducing the local charge in the aggregate at the cost of chemical free energy and gaining in hydrophobic interactions. This balance determines the boundaries between different aggregate morphologies. We show that a qualitatively new form of organization arises from the coupling between physical interactions and protonation equilibrium. This optimization strategy presents itself with polyelectrolytes coexisting in two different and well-defined protonation states. Our results underline the need of considering the coupling between chemical equilibrium and physical interactions due to their highly nonadditive behavior. The predictions provide guidelines for the creation of responsive polymer layers presenting self-organized patterns with functional properties and they give insights for the understanding of competing interactions in highly inhomogeneous and constrained environments such as those relevant in nanotechnology and those responsible for biological cells function. PMID- 20203009 TI - Hydrophobically stabilized open state for the lateral gate of the Sec translocon. AB - The Sec translocon is a central component of cellular pathways for protein translocation and membrane integration. Using both atomistic and coarse-grained molecular simulations, we investigate the conformational landscape of the translocon and explore the role of peptide substrates in the regulation of the translocation and integration pathways. Inclusion of a hydrophobic peptide substrate in the translocon stabilizes the opening of the lateral gate for membrane integration, whereas a hydrophilic peptide substrate favors the closed lateral gate conformation. The relative orientation of the plug moiety and a peptide substrate within the translocon channel is similarly dependent on whether the substrate is hydrophobic or hydrophilic in character, and the energetics of the translocon lateral gate opening in the presence of a peptide substrate is governed by the energetics of the peptide interface with the membrane. Implications of these results for the regulation of Sec-mediated pathways for protein translocation vs. membrane integration are discussed. PMID- 20203010 TI - Characterization of the two-protein complex in Escherichia coli responsible for lipopolysaccharide assembly at the outer membrane. AB - Lipopolysaccharide (LPS) is the major glycolipid that is present in the outer membranes (OMs) of most Gram-negative bacteria. LPS molecules are assembled with divalent metal cations in the outer leaflet of the OM to form an impervious layer that prevents toxic compounds from entering the cell. For most Gram-negative bacteria, LPS is essential for growth. In Escherichia coli, eight essential proteins have been identified to function in the proper assembly of LPS following its biosynthesis. This assembly process involves release of LPS from the inner membrane (IM), transport across the periplasm, and insertion into the outer leaflet of the OM. Here, we describe the biochemical characterization of the two protein complex consisting of LptD and LptE that is responsible for the assembly of LPS at the cell surface. We can overexpress and purify LptD and LptE as a stable complex in a 1:1 stoichiometry. LptD contains a soluble N-terminal domain and a C-terminal transmembrane domain. LptE stabilizes LptD by interacting strongly with the C-terminal domain of LptD. We also demonstrate that LptE binds LPS specifically and may serve as a substrate recognition site at the OM. PMID- 20203012 TI - Cryptic sex-ratio bias provides indirect genetic benefits despite sexual conflict. AB - When selection favors sexual dimorphism, high-fitness parents often produce low fitness progeny of the opposite sex. This sexual conflict is thought to overwhelm the genetic benefits of mate choice because preferred males incur a cost through the production of low-fitness daughters. We provide a counterpoint in a lizard (Anolis sagrei) that exhibits sexual conflict over body size. By using mate choice experiments, we show that female brown anoles produce more sons than daughters via large sires but more daughters than sons via small sires. Measures of progeny fitness in the wild suggest that maximal fitness payoffs can be achieved by shifting offspring production from daughters to sons as sire size increases. These results illustrate how the resolution of sexual conflict can restore the genetic benefits of mate choice. PMID- 20203013 TI - Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. AB - Metabolic syndrome is a group of obesity-related metabolic abnormalities that increase an individual's risk of developing type 2 diabetes and cardiovascular disease. Here, we show that mice genetically deficient in Toll-like receptor 5 (TLR5), a component of the innate immune system that is expressed in the gut mucosa and that helps defend against infection, exhibit hyperphagia and develop hallmark features of metabolic syndrome, including hyperlipidemia, hypertension, insulin resistance, and increased adiposity. These metabolic changes correlated with changes in the composition of the gut microbiota, and transfer of the gut microbiota from TLR5-deficient mice to wild-type germ-free mice conferred many features of metabolic syndrome to the recipients. Food restriction prevented obesity, but not insulin resistance, in the TLR5-deficient mice. These results support the emerging view that the gut microbiota contributes to metabolic disease and suggest that malfunction of the innate immune system may promote the development of metabolic syndrome. PMID- 20203011 TI - Observation of an antimatter hypernucleus. AB - Nuclear collisions recreate conditions in the universe microseconds after the Big Bang. Only a very small fraction of the emitted fragments are light nuclei, but these states are of fundamental interest. We report the observation of antihypertritons--comprising an antiproton, an antineutron, and an antilambda hyperon--produced by colliding gold nuclei at high energy. Our analysis yields 70 +/- 17 antihypertritons ((Lambda)(3)-H) and 157 +/- 30 hypertritons (Lambda3H). The measured yields of Lambda3H ((Lambda)(3)-H) and 3He (3He) are similar, suggesting an equilibrium in coordinate and momentum space populations of up, down, and strange quarks and antiquarks, unlike the pattern observed at lower collision energies. The production and properties of antinuclei, and of nuclei containing strange quarks, have implications spanning nuclear and particle physics, astrophysics, and cosmology. PMID- 20203015 TI - Solvent-mediated electron hopping: long-range charge transfer in IBr-(CO2) photodissociation. AB - Chemical bond breaking involves coupled electronic and nuclear dynamics that can take place on multiple electronic surfaces. Here we report a time-resolved experimental and theoretical investigation of nonadiabatic dynamics during photodissociation of a complex of iodine monobromide anion with carbon dioxide [IBr-(CO2)] on the second excited (A') electronic state. Previous experimental work showed that the dissociation of bare IBr- yields only I- + Br products. However, in IBr-(CO2), time-resolved photoelectron spectroscopy reveals that a subset of the dissociating molecules undergoes an electron transfer from iodine to bromine 350 femtoseconds after the initial excitation. Ab initio calculations and molecular dynamics simulations elucidate the mechanism for this charge hop and highlight the crucial role of the carbon dioxide molecule. The charge transfer between two recoiling atoms, assisted by a single solvent-like molecule, provides a notable limiting case of solvent-driven electron transfer over a distance of 7 angstroms. PMID- 20203014 TI - Iron-clad fibers: a metal-based biological strategy for hard flexible coatings. AB - The extensible byssal threads of marine mussels are shielded from abrasion in wave-swept habitats by an outer cuticle that is largely proteinaceous and approximately fivefold harder than the thread core. Threads from several species exhibit granular cuticles containing a protein that is rich in the catecholic amino acid 3,4-dihydroxyphenylalanine (dopa) as well as inorganic ions, notably Fe3+. Granular cuticles exhibit a remarkable combination of high hardness and high extensibility. We explored byssus cuticle chemistry by means of in situ resonance Raman spectroscopy and demonstrated that the cuticle is a polymeric scaffold stabilized by catecholato-iron chelate complexes having an unusual clustered distribution. Consistent with byssal cuticle chemistry and mechanics, we present a model in which dense cross-linking in the granules provides hardness, whereas the less cross-linked matrix provides extensibility. PMID- 20203016 TI - Biodiversity is our life. PMID- 20203017 TI - Seismology. Two years later, new rumblings over origins of Sichuan quake. PMID- 20203018 TI - Pharmacology. Growth hormone test finally nabs first doper. PMID- 20203019 TI - Paleoclimatology. Snowball Earth has melted back to a profound wintry mix. PMID- 20203021 TI - Archaeology. Of two minds about Toba's impact. PMID- 20203023 TI - Nutrition science. European food watchdog slashes dubious health claims. PMID- 20203024 TI - Genomics. Semiconductors inspire new sequencing technologies. PMID- 20203025 TI - Stem cells. Reprogrammed cells come up short, for now. PMID- 20203026 TI - Psychiatry. Anything but child's play. PMID- 20203027 TI - Astronomy. Unwinding the Milky Way. PMID- 20203028 TI - 17th Conference on Retroviruses and Opportunistic Infections, 16-19 February, San Francisco, CA. Treatment as prevention. PMID- 20203029 TI - 17th Conference on Retroviruses and Opportunistic Infections, 16-19 February, San Francisco, CA. The ins and outs of HIV. PMID- 20203030 TI - 17th Conference on Retroviruses and Opportunistic Infections, 16-19 February, San Francisco, CA. Limits of success. PMID- 20203031 TI - Bioenergy: counting on incentives. PMID- 20203032 TI - A greener future for China's cities. PMID- 20203033 TI - Comment on "Movement intention after parietal cortex stimulation in humans". AB - Desmurget et al. (Reports, 8 May 2009, p. 811) applied direct electrical stimulation (DES) to the human cortex to study the origin of movement intention. Their interpretation assumed that DES causes cortical activation, whereas it is possible that it actually evokes deactivation. The lack of certain knowledge about the true effects of DES limits its use for validation of cognitive models. PMID- 20203035 TI - Energy. Behavior and energy policy. PMID- 20203036 TI - Astronomy. Sunscreen for the young Earth. PMID- 20203037 TI - Ecology. The Seven Ages of Pan. PMID- 20203038 TI - Physics. Controlling implosion symmetry around a deuterium-tritium target. PMID- 20203039 TI - Cell biology. Burn out or fade away? PMID- 20203040 TI - Climate change. How stable is the methane cycle? PMID- 20203041 TI - Neuroscience. Questionable calcium. PMID- 20203042 TI - The Chicxulub asteroid impact and mass extinction at the Cretaceous-Paleogene boundary. AB - The Cretaceous-Paleogene boundary approximately 65.5 million years ago marks one of the three largest mass extinctions in the past 500 million years. The extinction event coincided with a large asteroid impact at Chicxulub, Mexico, and occurred within the time of Deccan flood basalt volcanism in India. Here, we synthesize records of the global stratigraphy across this boundary to assess the proposed causes of the mass extinction. Notably, a single ejecta-rich deposit compositionally linked to the Chicxulub impact is globally distributed at the Cretaceous-Paleogene boundary. The temporal match between the ejecta layer and the onset of the extinctions and the agreement of ecological patterns in the fossil record with modeled environmental perturbations (for example, darkness and cooling) lead us to conclude that the Chicxulub impact triggered the mass extinction. PMID- 20203044 TI - Geodynamo, solar wind, and magnetopause 3.4 to 3.45 billion years ago. AB - Stellar wind standoff by a planetary magnetic field prevents atmospheric erosion and water loss. Although the early Earth retained its water and atmosphere, and thus evolved as a habitable planet, little is known about Earth's magnetic field strength during that time. We report paleointensity results from single silicate crystals bearing magnetic inclusions that record a geodynamo 3.4 to 3.45 billion years ago. The measured field strength is approximately 50 to 70% that of the present-day field. When combined with a greater Paleoarchean solar wind pressure, the paleofield strength data suggest steady-state magnetopause standoff distances of < or = 5 Earth radii, similar to values observed during recent coronal mass ejection events. The data also suggest lower-latitude aurora and increases in polar cap area, as well as heating, expansion, and volatile loss from the exosphere that would have affected long-term atmospheric composition. PMID- 20203043 TI - Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies. AB - Sestrins are conserved proteins that accumulate in cells exposed to stress, potentiate adenosine monophosphate-activated protein kinase (AMPK), and inhibit activation of target of rapamycin (TOR). We show that the abundance of Drosophila sestrin (dSesn) is increased upon chronic TOR activation through accumulation of reactive oxygen species that cause activation of c-Jun amino-terminal kinase and transcription factor Forkhead box O (FoxO). Loss of dSesn resulted in age associated pathologies including triglyceride accumulation, mitochondrial dysfunction, muscle degeneration, and cardiac malfunction, which were prevented by pharmacological activation of AMPK or inhibition of TOR. Hence, dSesn appears to be a negative feedback regulator of TOR that integrates metabolic and stress inputs and prevents pathologies caused by chronic TOR activation that may result from diminished autophagic clearance of damaged mitochondria, protein aggregates, or lipids. PMID- 20203045 TI - Calibrating the Cryogenian. AB - The Neoproterozoic was an era of great environmental and biological change, but a paucity of direct and precise age constraints on strata from this time has prevented the complete integration of these records. We present four high precision U-Pb ages for Neoproterozoic rocks in northwestern Canada that constrain large perturbations in the carbon cycle, a major diversification and depletion in the microfossil record, and the onset of the Sturtian glaciation. A volcanic tuff interbedded with Sturtian glacial deposits, dated at 716.5 million years ago, is synchronous with the age of the Franklin large igneous province and paleomagnetic poles that pin Laurentia to an equatorial position. Ice was therefore grounded below sea level at very low paleolatitudes, which implies that the Sturtian glaciation was global in extent. PMID- 20203046 TI - The role of sulfuric acid in atmospheric nucleation. AB - Nucleation is a fundamental step in atmospheric new-particle formation. However, laboratory experiments on nucleation have systematically failed to demonstrate sulfuric acid particle formation rates as high as those necessary to account for ambient atmospheric concentrations, and the role of sulfuric acid in atmospheric nucleation has remained a mystery. Here, we report measurements of new particles (with diameters of approximately 1.5 nanometers) observed immediately after their formation at atmospherically relevant sulfuric acid concentrations. Furthermore, we show that correlations between measured nucleation rates and sulfuric acid concentrations suggest that freshly formed particles contain one to two sulfuric acid molecules, a number consistent with assumptions that are based on atmospheric observations. Incorporation of these findings into global models should improve the understanding of the impact of secondary particle formation on climate. PMID- 20203047 TI - Extensive methane venting to the atmosphere from sediments of the East Siberian Arctic Shelf. AB - Remobilization to the atmosphere of only a small fraction of the methane held in East Siberian Arctic Shelf (ESAS) sediments could trigger abrupt climate warming, yet it is believed that sub-sea permafrost acts as a lid to keep this shallow methane reservoir in place. Here, we show that more than 5000 at-sea observations of dissolved methane demonstrates that greater than 80% of ESAS bottom waters and greater than 50% of surface waters are supersaturated with methane regarding to the atmosphere. The current atmospheric venting flux, which is composed of a diffusive component and a gradual ebullition component, is on par with previous estimates of methane venting from the entire World Ocean. Leakage of methane through shallow ESAS waters needs to be considered in interactions between the biogeosphere and a warming Arctic climate. PMID- 20203048 TI - Hippocampal short- and long-term plasticity are not modulated by astrocyte Ca2+ signaling. AB - The concept that astrocytes release neuroactive molecules (gliotransmitters) to affect synaptic transmission has been a paradigm shift in neuroscience research over the past decade. This concept suggests that astrocytes, together with pre- and postsynaptic neuronal elements, make up a functional synapse. Astrocyte release of gliotransmitters (for example, glutamate and adenosine triphosphate) is generally accepted to be a Ca2+-dependent process. We used two mouse lines to either selectively increase or obliterate astrocytic Gq G protein-coupled receptor Ca2+ signaling to further test the hypothesis that astrocytes release gliotransmitters in a Ca2+-dependent manner to affect synaptic transmission. Neither increasing nor obliterating astrocytic Ca2+ fluxes affects spontaneous and evoked excitatory synaptic transmission or synaptic plasticity. Our findings suggest that, at least in the hippocampus, the mechanisms of gliotransmission need to be reconsidered. PMID- 20203049 TI - RTEL-1 enforces meiotic crossover interference and homeostasis. AB - Meiotic crossovers (COs) are tightly regulated to ensure that COs on the same chromosome are distributed far apart (crossover interference, COI) and that at least one CO is formed per homolog pair (CO homeostasis). CO formation is controlled in part during meiotic double-strand break (DSB) creation in Caenorhabditis elegans, but a second level of control must also exist because meiotic DSBs outnumber COs. We show that the antirecombinase RTEL-1 is required to prevent excess meiotic COs, probably by promoting meiotic synthesis-dependent strand annealing. Two distinct classes of meiotic COs are increased in rtel-1 mutants, and COI and homeostasis are compromised. We propose that RTEL-1 implements the second level of CO control by promoting noncrossovers. PMID- 20203050 TI - Spatially ordered dynamics of the bacterial carbon fixation machinery. AB - Cyanobacterial carbon fixation is a major component of the global carbon cycle. This process requires the carboxysome, an organelle-like proteinaceous microcompartment that sequesters the enzymes of carbon fixation from the cytoplasm. Here, fluorescently tagged carboxysomes were found to be spatially ordered in a linear fashion. As a consequence, cells undergoing division evenly segregated carboxysomes in a nonrandom process. Mutation of the cytoskeletal protein ParA specifically disrupted carboxysome order, promoted random carboxysome segregation during cell division, and impaired carbon fixation after disparate partitioning. Thus, cyanobacteria use the cytoskeleton to control the spatial arrangement of carboxysomes and to optimize the metabolic process of carbon fixation. PMID- 20203052 TI - Tuning the flagellar motor. AB - Many bacteria are motile by means of flagella, semi-rigid helical filaments rotated at the filament's base and energized by proton or sodium-ion gradients. Torque is created between the two major components of the flagellar motor: the rotating switch complex and the cell-wall-associated stators, which are arranged in a dynamic ring-like structure. Being motile provides a survival advantage to many bacteria, and thus the flagellar motor should work optimally under a wide range of environmental conditions. Recent studies have demonstrated that numerous species possess a single flagellar system but have two or more individual stator systems that contribute differentially to flagellar rotation. This review describes recent findings on rotor-stator interactions, on the role of different stators, and on how stator selection could be regulated. An emerging model suggests that bacterial flagellar motors are dynamic and can be tuned by stator swapping in response to different environmental conditions. PMID- 20203053 TI - A sulphite-inducible form of the sulphite efflux gene SSU1 in a Saccharomyces cerevisiae wine yeast. AB - Sulphite is widely used as a preservative in foods and beverages for its antimicrobial and antioxidant activities, particularly in winemaking where SO(2) is frequently added. Thus, sulphite resistance mechanisms have been extensively studied in the fermenting yeast Saccharomyces cerevisiae. Sulphite detoxification, involving a plasma membrane protein encoded by the SSU1 gene, is the most efficient resistance mechanism in S. cerevisiae. In this study, we characterized the unusual expression pattern of SSU1 in the wine strain 71B. We provide, for the first time, evidence of SSU1 induction by sulphite. The study of SSU1 expression during fermentation and in different growth conditions showed that sulphite is the main regulator of SSU1 expression, explaining its specific pattern. Combining analyses of gene expression and growth behaviour in response to sulphite, we found that 71B displayed unique behavioural patterns in response to sulphite pre-adaptation that may be explained by changes in SSU1 expression. Examination of the genomic organization of the SSU1 locus and sequencing of the region revealed three different alleles in 71B, two of which corresponded to translocated VIII-XVI forms. The lack of differences between promoter regions suggests that this inducible SSU1 expression pattern is due to modification of regulatory/signalling pathways. PMID- 20203054 TI - Stereospecific recognition of pyochelin and enantio-pyochelin by the PchR proteins in fluorescent pseudomonads. AB - The siderophore pyochelin of Pseudomonas aeruginosa promotes growth under iron limitation and induces the expression of its biosynthesis genes via the transcriptional AraC/XylS-type regulator PchR. Pseudomonas fluorescens strain CHA0 makes the optical antipode of pyochelin termed enantio-pyochelin, which also promotes growth and induces the expression of its biosynthesis genes when iron is scarce. Growth promotion and signalling by pyochelin and enantio-pyochelin are highly stereospecific and are known to involve the pyochelin and enantio pyochelin outer-membrane receptors FptA and FetA, respectively. Here we show that stereospecificity in signalling is also based on the stereospecificity of the homologous PchR proteins of P. aeruginosa and P. fluorescens towards their respective siderophore effectors. We found that PchR functioned in the heterologous species only if supplied with its native ligand and that the FptA and FetA receptors enhanced the efficiency of signalling. By constructing and expressing hybrid and truncated PchR regulators we showed that the weakly conserved N-terminal domain of PchR is responsible for siderophore specificity. Thus, both uptake and transcriptional regulation confer stereospecificity to pyochelin and enantio-pyochelin biosynthesis. PMID- 20203055 TI - Regulation of flagellar, motility and chemotaxis genes in Rhizobium leguminosarum by the VisN/R-Rem cascade. AB - In this paper, we describe the regulatory roles of VisN, VisR and Rem in the expression of flagellar, motility and chemotaxis genes in Rhizobium leguminosarum biovar viciae strains VF39SM and 3841. Individual mutations in the genes encoding these proteins resulted in a loss of motility and an absence of flagella, indicating that these regulatory genes are essential for flagellar synthesis and function. Transcriptional experiments involving gusA-gene fusions in wild-type and mutant backgrounds were performed to identify the genes under VisN/R and Rem regulation. Results showed that the chemotaxis and motility genes of R. leguminosarum could be separated into two groups: one group under VisN/R-Rem regulation and another group that is independent of this regulation. VisN and VisR regulate the expression of rem, while Rem positively regulates the expression of flaA, flaB, flaC, flaD, motA, motB, che1 and mcpD. All of these genes except mcpD are located within the main motility and chemotaxis gene cluster of R. leguminosarum. Other chemotaxis and motility genes, which are found outside of the main motility gene cluster (che2 operon, flaH for VF39SM, and flaG) or are plasmid-borne (flaE and mcpC), are not part of the VisN/R-Rem regulatory cascade. In addition, all genes exhibited the same regulation pattern in 3841 and in VF39SM, except flaE and flaH. flaE is not regulated by VisN/R-Rem in 3841 but it is repressed by Rem in VF39SM. flaH is under VisN/R-Rem regulation in 3841, but not in VF39SM. A kinetics experiment demonstrated that a subset of the flagellar genes is continuously expressed in all growth phases, indicating the importance of continuous motility for R. leguminosarum under free-living conditions. On the other hand, motility is repressed under symbiotic conditions. Nodulation experiments showed that the transcriptional activators VisN and Rem are dramatically downregulated in the nodules, suggesting that the symbiotic downregulation of motility-related genes could be mediated by repressing the expression of VisN/R and Rem. PMID- 20203056 TI - Structure analysis of the two-peptide bacteriocin lactococcin G by introducing D amino acid residues. AB - The importance of 3D structuring in the N- and C-terminal ends of the two peptides (39-mer LcnG-alpha and 35-mer LcnG-beta) that constitute the two-peptide bacteriocin lactococcin G was analysed by replacing residues in the end regions with the corresponding D-isomeric residues. When assayed for antibacterial activity in combination with the complementary wild-type peptide, LcnG-alpha with four D-residues in its C-terminal region and LcnG-beta with four d-residues in either its N- or its C-terminal region were relatively active (two- to 20-fold reduction in activity). 3D structuring of the C-terminal region in LcnG-alpha and the C- and N-terminal regions in LcnG-beta is thus not particularly critical for retaining antibacterial activity, indicating that the 3D structure of these regions is not vital for interpeptide interactions or for interactions between the peptides and cellular components. The 3D structure of the N-terminal region in LcnG-alpha may be more important, as LcnG-alpha with four N-terminal D residues was the least active of these four peptides (10- to 100-fold reduction in activity). The results are consistent with a proposed structural model of lactococcin G in which LcnG-alpha and -beta form a transmembrane parallel helix helix structure involving approximately 20 residues in each peptide, starting near the N terminus of LcnG-alpha and at about residue 13 in LcnG-beta. Upon expressing the lactococcin G immunity protein, sensitive target cells became resistant to all of these D-residue-containing peptides. The end regions of the two lactococcin G peptides are consequently not involved in essential structure dependent interactions with the immunity protein. The relatively high activity of most of the D-residue-containing peptides suggests that bacteriocins with increased resistance to exopeptidases may be generated by replacing their N- and C-terminal residues with d-residues. PMID- 20203057 TI - Genomic structure of an economically important cyanobacterium, Arthrospira (Spirulina) platensis NIES-39. AB - A filamentous non-N(2)-fixing cyanobacterium, Arthrospira (Spirulina) platensis, is an important organism for industrial applications and as a food supply. Almost the complete genome of A. platensis NIES-39 was determined in this study. The genome structure of A. platensis is estimated to be a single, circular chromosome of 6.8 Mb, based on optical mapping. Annotation of this 6.7 Mb sequence yielded 6630 protein-coding genes as well as two sets of rRNA genes and 40 tRNA genes. Of the protein-coding genes, 78% are similar to those of other organisms; the remaining 22% are currently unknown. A total 612 kb of the genome comprise group II introns, insertion sequences and some repetitive elements. Group I introns are located in a protein-coding region. Abundant restriction-modification systems were determined. Unique features in the gene composition were noted, particularly in a large number of genes for adenylate cyclase and haemolysin-like Ca(2+) binding proteins and in chemotaxis proteins. Filament-specific genes were highlighted by comparative genomic analysis. PMID- 20203058 TI - T-type Ca(2+) channel modulation by otilonium bromide. AB - Antispasmodics are used clinically to treat a variety of gastrointestinal disorders by inhibition of smooth muscle contraction. The main pathway for smooth muscle Ca(2+) entry is through L-type channels; however, there is increasing evidence that T-type Ca(2+) channels also play a role in regulating contractility. Otilonium bromide, an antispasmodic, has previously been shown to inhibit L-type Ca(2+) channels and colonic contractile activity. The objective of this study was to determine whether otilonium bromide also inhibits T-type Ca(2+) channels. Whole cell currents were recorded by patch-clamp technique from HEK293 cells transfected with cDNAs encoding the T-type Ca(2+) channels, Ca(V)3.1 (alpha1G), Ca(V)3.2 (alpha1H), or Ca(V)3.3 (alpha1I) alpha subunits. Extracellular solution was exchanged with otilonium bromide (10(-8) to 10(-5) M). Otilonium bromide reversibly blocked all T-type Ca(2+) channels with a significantly greater affinity for Ca(V)3.3 than Ca(V)3.1 or Ca(V)3.2. Additionally, the drug slowed inactivation in Ca(V)3.1 and Ca(V)3.3. Inhibition of T-type Ca(2+) channels may contribute to inhibition of contractility by otilonium bromide. This may represent a new mechanism of action for antispasmodics and may contribute to the observed increased clinical effectiveness of antispasmodics compared with selective L-type Ca(2+) channel blockers. PMID- 20203059 TI - Cyclic AMP stimulates Mrp2 translocation by activating p38{alpha} MAPK in hepatic cells. AB - Cyclic AMP (cAMP) induces translocation of multidrug resistant protein 2 (Mrp2) to the canalicular membrane and activates p38 MAPK in rat hepatocytes. In this study, we tested the hypothesis that cAMP-induced Mrp2 translocation may be mediated via p38 MAPK. Studies were conducted in rat hepatocytes and in a human hepatoma cell line, HuH-7. In rat hepatocytes, cAMP increased Mrp2 translocation and p38 MAPK activity. These effects of cAMP were inhibited by SB203580, an inhibitor of p38 MAPK. Wortmannin, a specific inhibitor of phosphoinositide-3 kinase (PI3K), did not inhibit cAMP induced activation of p38 MAPK, indicating PI3K-independent activation of p38 MAPK by cAMP. To further define the role of p38 MAPK, molecular approaches were used to up- or downregulate p38 MAPK activity in HuH-7 cells using constitutively active (CA) and dominant-negative (DN) MAPK kinase 3 and 6 (MKK3/6). MKK3/6 are upstream kinases responsible for the activation of p38 MAPK. Cells transfected with CAMKK6 showed increased p38 MAPK activity and MRP2 translocation compared with empty vector. cAMP-induced activation of p38 MAPK was inhibited in cells transfected with DNMKK3/6 and DNMKK3, but not with DNMKK6. DNMKK3/6 and DNMKK3 also inhibited cAMP-induced MRP2 translocation. cAMP selectively activated p38alpha MAPK in HuH-7 cells. Knockdown of p38alpha MAPK by short heterodimer RNA resulted in decreased level of p38 MAPK and failure of cAMP to stimulate MRP2 translocation. Taken together, these results suggest that cAMP-induced MRP2 translocation in hepatic cells is mediated via PI3K-independent and MKK3-mediated activation of p38alpha MAPK. PMID- 20203061 TI - Betaine improved adipose tissue function in mice fed a high-fat diet: a mechanism for hepatoprotective effect of betaine in nonalcoholic fatty liver disease. AB - Adipose tissue dysfunction, featured by insulin resistance and/or dysregulated adipokine production, plays a central role not only in disease initiation but also in the progression to nonalcoholic steatohepatitis and cirrhosis. Promising beneficial effects of betaine supplementation on nonalcoholic fatty liver disease (NAFLD) have been reported in both clinical investigations and experimental studies; however, data related to betaine therapy in NAFLD are still limited. In this study, we examined the effects of betaine supplementation on hepatic fat accumulation and injury in mice fed a high-fat diet and evaluated mechanisms underlying its hepatoprotective effects. Male C57BL/6 mice weighing 25 +/- 0.5 (SE) g were divided into four groups (8 mice/group) and started on one of four treatments: control diet, control diet supplemented with betaine, high-fat diet, and high-fat diet supplemented with betaine. Betaine was supplemented in the drinking water at a concentration of 1% (wt/vol) (anhydrous). Our results showed that long-term high-fat feeding caused NAFLD in mice, which was manifested by excessive neutral fat accumulation in the liver and elevated plasma alanine aminotransferase levels. Betaine supplementation alleviated hepatic pathological changes, which were concomitant with attenuated insulin resistance as shown by improved homeostasis model assessment of basal insulin resistance values and glucose tolerance test, and corrected abnormal adipokine (adiponectin, resistin, and leptin) productions. Specifically, betaine supplementation enhanced insulin sensitivity in adipose tissue as shown by improved extracellular signal-regulated kinases 1/2 and protein kinase B activations. In adipocytes freshly isolated from mice fed a high-fat diet, pretreatment of betaine enhanced the insulin signaling pathway and improved adipokine productions. Further investigation using whole liver tissues revealed that betaine supplementation alleviated the high-fat diet induced endoplasmic reticulum stress response in adipose tissue as shown by attenuated glucose-regulated protein 78/C/EBP homologous protein (CHOP) protein abundance and c-Jun NH(2)-terminal kinase activation. Our findings suggest that betaine might serve as a safe and efficacious therapeutic tool for NAFLD by improving adipose tissue function. PMID- 20203060 TI - Noninvasive stool-based detection of infant gastrointestinal development using gene expression profiles from exfoliated epithelial cells. AB - We have developed a novel molecular methodology that utilizes stool samples containing intact sloughed epithelial cells to quantify intestinal gene expression profiles in the developing human neonate. Since nutrition exerts a major role in regulating neonatal intestinal development and function, our goal was to identify gene sets (combinations) that are differentially regulated in response to infant feeding. For this purpose, fecal mRNA was isolated from exclusively breast-fed (n = 12) and formula-fed (n = 10) infants at 3 mo of age. Linear discriminant analysis was successfully used to identify the single genes and the two- to three-gene combinations that best distinguish the feeding groups. In addition, putative "master" regulatory genes were identified using coefficient of determination analysis. These results support our premise that mRNA isolated from stool has value in terms of characterizing the epigenetic mechanisms underlying the developmentally regulated transcriptional activation/repression of genes known to modulate gastrointestinal function. As larger data sets become available, this methodology can be extended to validation and, ultimately, identification of the main nutritional components that modulate intestinal maturation and function. PMID- 20203062 TI - PAI-1 plays a protective role in CCl4-induced hepatic fibrosis in mice: role of hepatocyte division. AB - Plasminogen activator inhibitor-1 (PAI-1) is an acute phase protein that has been shown to play a role in experimental fibrosis caused by bile duct ligation (BDL) in mice. However, its role in more severe models of hepatic fibrosis (e.g., carbon tetrachloride; CCl(4)) has not been determined and is important for extrapolation to human disease. Wild-type or PAI-1 knockout mice were administered CCl(4) (1 ml/kg body wt ip) 2x/wk for 4 wk. Plasma (e.g., transaminase activity) and histological (e.g., Sirius red staining) indexes of liver damage and fibrosis were evaluated. Proliferation and apoptosis were assessed by PCNA and TdT-mediated dUTP nick-end labeling (TUNEL) staining, respectively, as well as by indexes of cell cycle (e.g., p53, cyclin D1). In contrast to previous studies with BDL, hepatic fibrosis was enhanced in PAI-1(-/ ) mice after chronic CCl(4) administration. Indeed, all indexes of liver damage were elevated in PAI-1(-/-) mice compared with wild-type mice. This enhanced liver damage correlated with impaired hepatocyte proliferation. A similar effect on proliferation was observed after one bolus dose of CCl(4), without concomitant increases in liver damage. Under these conditions, a decrease in phospho-p38, coupled with elevated p53 protein, was observed; these results suggest impaired proliferation and a potential G(1)/S cell cycle arrest in PAI-1(-/-) mice. These data suggest that PAI-1 may play multiple roles in chronic liver diseases, both protective and damaging, the latter mediated by its influence on inflammation and fibrosis and the former via helping maintain hepatocyte division after an injury. PMID- 20203063 TI - Effect of indomethacin on bile acid-phospholipid interactions: implication for small intestinal injury induced by nonsteroidal anti-inflammatory drugs. AB - The injurious effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in the small intestine was not appreciated until the widespread use of capsule endoscopy. Animal studies found that NSAID-induced small intestinal injury depends on the ability of these drugs to be secreted into the bile. Because the individual toxicity of amphiphilic bile acids and NSAIDs directly correlates with their interactions with phospholipid membranes, we propose that the presence of both NSAIDs and bile acids alters their individual physicochemical properties and enhances the disruptive effect on cell membranes and overall cytotoxicity. We utilized in vitro gastric AGS and intestinal IEC-6 cells and found that combinations of bile acid, deoxycholic acid (DC), taurodeoxycholic acid, glycodeoxycholic acid, and the NSAID indomethacin (Indo) significantly increased cell plasma membrane permeability and became more cytotoxic than these agents alone. We confirmed this finding by measuring liposome permeability and intramembrane packing in synthetic model membranes exposed to DC, Indo, or combinations of both agents. By measuring physicochemical parameters, such as fluorescence resonance energy transfer and membrane surface charge, we found that Indo associated with phosphatidylcholine and promoted the molecular aggregation of DC and potential formation of larger and isolated bile acid complexes within either biomembranes or bile acid-lipid mixed micelles, which leads to membrane disruption. In this study, we demonstrated increased cytotoxicity of combinations of bile acid and NSAID and provided a molecular mechanism for the observed toxicity. This mechanism potentially contributes to the NSAID-induced injury in the small bowel. PMID- 20203064 TI - Apical leptin induces chloride secretion by intestinal epithelial cells and in a rat model of acute chemotherapy-induced colitis. AB - The purpose of this study was to investigate whether luminal leptin alters ion transport properties of the intestinal epithelium under acute inflammatory conditions. Monolayers of human intestinal T(84) epithelial cells and a rat model of chemotherapy-induced enterocolitis were used. Cells were treated with leptin and mounted in Ussing chambers to measure basal and secretagogue-induced changes in transepithelial short-circuit current (I(sc)). Furthermore, the role of MAPK and phosphatidylinositol 3-kinase (PI3K) signaling pathways in mediating responses to leptin was investigated. Acute colitis in Sprague-Dawley rats was induced by intraperitoneal injection of 40 mg/kg methotrexate. Leptin (100 ng/ml) induced a time-dependent increase in basal I(sc) in T(84) intestinal epithelial cells (P < 0.01). Moreover, pretreatment of T(84) cells with leptin for up to 1 h significantly potentiated carbachol- and forskolin-induced increases in I(sc). Pretreatment with an inhibitor of MAPK abolished the effect of leptin on basal, carbachol- and forskolin-induced chloride secretion (P < 0.05). However, the PI3K inhibitor, wortmannin, only blunted the effect of leptin on forskolin-induced increases in I(sc). Furthermore, leptin treatment evoked both ERK1/2 and Akt1 phosphorylation in T(84) cells. In the rat model, luminal leptin induced significant increases in I(sc) across segments of proximal and, to a lesser extent, distal colon (P < 0.05). We conclude that luminal leptin is likely an intestinal chloride secretagogue, particularly when present at elevated concentrations and/or in the setting of inflammation. Our findings may provide a mechanistic explanation, at least in part, for the clinical condition of secretory diarrhea both in hyperleptinemic obese patients and in patients with chemotherapy-induced intestinal inflammation. PMID- 20203065 TI - Local hindlimb antioxidant infusion does not affect muscle glucose uptake during in situ contractions in rat. AB - There is evidence that reactive oxygen species (ROS) contribute to the regulation of skeletal muscle glucose uptake during highly fatiguing ex vivo contraction conditions via AMP-activated protein kinase (AMPK). In this study we investigated the role of ROS in the regulation of glucose uptake and AMPK signaling during low moderate intensity in situ hindlimb muscle contractions in rats, which is a more physiological protocol and preparation. Male hooded Wistar rats were anesthetized, and then N-acetylcysteine (NAC) was infused into the epigastric artery (125 mg.kg(-1).h(-1)) of one hindlimb (contracted leg) for 15 min before this leg was electrically stimulated (0.1-ms impulse at 2 Hz and 35 V) to contract at a low-moderate intensity for 15 min. The contralateral leg did not receive stimulation or local NAC infusion (rest leg). NAC infusion increased (P<0.05) plasma cysteine and cystine (by approximately 360- and 1.4-fold, respectively) and muscle cysteine (by 1.5-fold, P=0.001). Although contraction did not significantly alter muscle tyrosine nitration, reduced (GSH) or oxidized glutathione (GSSG) content, S-glutathionylation of protein bands at approximately 250 and 150 kDa was increased (P<0.05) approximately 1.7-fold by contraction, and this increase was prevented by NAC. Contraction increased (P<0.05) skeletal muscle glucose uptake 20-fold, AMPK phosphorylation 6-fold, ACCbeta phosphorylation 10-fold, and p38 MAPK phosphorylation 60-fold, and the muscle fatigued by approximately 30% during contraction and NAC infusion had no significant effect on any of these responses. This was despite NAC preventing increases in S-glutathionylation with contraction. In conclusion, unlike during highly fatiguing ex vivo contractions, local NAC infusion during in situ low moderate intensity hindlimb contractions in rats, a more physiological preparation, does not attenuate increases in skeletal muscle glucose uptake or AMPK signaling. PMID- 20203066 TI - Changes in ventricular twist and untwisting with orthostatic stress: endurance athletes versus normally active individuals. AB - Endurance-trained individuals exhibit larger reductions in left ventricular (LV) end-diastolic volume in response to lower body negative pressure (LBNP) compared with normally active individuals. However, the relationship between LV torsion and untwisting and the LV volume response to LBNP in endurance athletes is unknown. Eight endurance-trained athletes [maximal oxygen consumption (VO2max): 66.4+/-7.2 ml.kg(-1).min(-1)] and eight normally active individuals (VO2max: 41.9+/-9.0 ml.kg(-1).min(-1)) (all men) underwent two cardiac magnetic resonance imaging (MRI) assessments, the first during supine rest and the second during -30 mmHg LBNP. Right ventricular (RV) and LV volumes were assessed, myocardial tagging was applied in order to quantify LV peak torsion and peak untwisting rate, and filling rates were measured with phase-contrast MRI. In response to LBNP, endurance-trained individuals had greater reductions in RV and LV end diastolic volume and stroke volume (P<0.05). Endurance athletes had reduced untwisting rates (20.3+/-8.7 degrees/s), while normally active individuals had increased untwisting rates (-16.2+/-32.1 degrees/s) in response to LBNP (P<0.05). Changes in peak untwisting rate were significantly correlated with change in peak torsion (R=-0.87, P<0.05), with the change in early filling rate and VO2max, but not with changes in end-diastolic or end-systolic volume (P>0.05). We conclude that increased untwisting rates in normally active subjects may mitigate the drop in early filling rate with LBNP and thus may be a compensatory mechanism for the reduction in stroke volume with volume unloading. The opposite response in athletes, who showed a decreased untwisting rate, may contribute to their larger reductions in LV end-diastolic and stroke volumes with volume unloading and their orthostatic intolerance. PMID- 20203067 TI - High-resolution spatial measurements of ventilation-perfusion heterogeneity in rats. AB - This study was designed to validate a high-resolution method to measure regional ventilation (VA) in small laboratory animals, and to compare regional Va and perfusion (Q) before and after methacholine-induced bronchoconstriction. A mixture of two different colors of 0.04-microm fluorescent microspheres (FMS) was aerosolized and administered to five anesthetized, mechanically ventilated rats. Those rats also received an intravenous injection of a mixture of two different colors of 15-microm FMS to measure regional blood flow (Q). Five additional rats were labeled with aerosol and intravenous FMS, injected with intravenous methacholine, and then relabeled with a second pair of aerosol and intravenous FMS colors. After death, the lungs were reinflated, frozen, and sequentially sliced in 16-microm intervals on an imaging cryomicrotome set to acquire signal for each of the FMS colors. The reconstructed lung images were sampled using randomly placed 3-mm radius spheres. Va within each sphere was estimated from the aerosol fluorescence signal, and Q was estimated from the number of 15-microm FMS within each sphere. Method error ranged from 6 to 8% for Q and 0.5 to 4.0% for Va. The mean coefficient of variation for Q was 17%, and for Va was 34%. The administration of methacholine altered the distribution of both VA and Q within lung regions, with a change in Va distribution nearly twice as large as that seen for Q. The methacholine-induced changes in Va were not associated with compensatory shifts in Q. Cryomicrotome images of FMS markers provide a high resolution, anatomically specific means of measuring regional VA/Q responses in the rat. PMID- 20203068 TI - A new method to study in vivo protein synthesis in slow- and fast-twitch muscle fibers and initial measurements in humans. AB - The aim of this study was to develop an approach to directly assess protein fractional synthesis rate (FSR) in isolated human muscle fibers in a fiber type specific fashion. Individual muscle fibers were isolated from biopsies of the vastus lateralis (VL) and soleus (SOL) obtained from eight young men during a primed, continuous infusion of [5,5,5-(2)H3]leucine performed under basal conditions. To determine mixed protein FSR, a portion of each fiber was used to identify fiber type, fibers of the same type were pooled, and the [5,5,5 (2)H3]leucine enrichment was determined via GC-MS. Processing isolated slow twitch [myosin heavy chain (MHC) I] and fast-twitch (MHC IIa) fibers for mixed protein bound [5,5,5-(2)H3]leucine enrichment yielded mass ion chromatographic peaks that were similar in shape, abundance, and measurement reliability as tissue homogenates. In the VL, MHC I fibers exhibited a 33% faster (P<0.05) mixed protein FSR compared with MHC IIa fibers (0.068+/-0.006 vs. 0.051+/-0.003%/h). MHC I fibers from the SOL (0.060+/-0.005%/h) and MHC I fibers from the VL displayed similar (P>0.05) mixed protein FSR. Feasibility of processing isolated human muscle fibers for analysis of myofibrillar protein [5,5,5-(2)H3]leucine enrichment was also confirmed in non-fiber-typed pooled fibers from the VL. These methods can be applied to the study of fiber type-specific responses in human skeletal muscle. The need for this level of investigation is underscored by the different contributions of each fiber type to whole muscle function and the numerous distinct adaptive functional and metabolic changes in MHC I and MHC II fibers originating from the same muscle. PMID- 20203069 TI - EGCG protects against oxidized LDL-induced endothelial dysfunction by inhibiting LOX-1-mediated signaling. AB - Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), originally identified as the major receptor for oxidized low-density lipoprotein (oxLDL) in endothelial cells, plays a major role in the pathology of vascular diseases. Green tea consumption is associated with reduced cardiovascular mortality in some epidemiological studies. In the present study, we hypothesized that the most abundant polyphenolic compound in tea, epigallocatechin-3-gallate (EGCG), can downregulate parameters of endothelial dysfunction by modulating LOX-1-regulated cell signaling. In cultured human umbilical vein endothelial cells (HUVECs), exposure to oxLDL (130 microg/ml), which led to an increase in LOX-1 expression at the RNA and protein levels, was abrogated by addition of EGCG or DPI, a well known inhibitor of flavoproteins, suggesting the involvement of NADPH oxidase. Furthermore, oxLDL rapidly activated the membrane translocation of Rac-1 and p47phox and the subsequent induction of ROS generation, which was suppressed markedly by pretreatment with EGCG or anti-LOX-1 monoclonal antibody. OxLDL also increased p38 MAPK phosphorylation and decreased phosphorylation of the amino terminal region of Akt, with maximal induction at about 30 min, and NF-kappaB phosphorylation within 1 h, resulting in redox-sensitive signaling. In addition, oxLDL diminished the expression of endothelial nitric oxide synthase (eNOS), enhanced the expression of endothelin-1 and adhesion molecules (ICAM, E-selectin, and monocyte chemoattractant protein-1), and increased the adherence of monocytic THP-1 cells to HUVECs. Pretreatment with EGCG, however, exerted significant cytoprotective effects in all events. These data suggest that EGCG inhibits the oxLDL-induced LOX-1-mediated signaling pathway, at least in part, by inhibiting NADPH oxidase and consequent ROS-enhanced LOX-1 expression, which contributes to further ROS generation and the subsequent activation of NF-kappaB via the p38 MAPK pathway. Results from this study may provide insight into a possible molecular mechanism by which EGCG suppresses oxLDL-mediated vascular endothelial dysfunction. PMID- 20203070 TI - Depression, psychological stress, vascular dysfunction, and cardiovascular disease: thinking outside the barrel. PMID- 20203071 TI - Expiratory flow limitation during exercise in prepubescent boys and girls: prevalence and implications. AB - The purpose of this study was to compare the prevalence and implications of expiratory flow limitation (EFL) during exercise in boys and girls. Forty healthy, prepubescent boys (B; n=20) and girls (G; n=20) were tested. Subjects completed pulmonary function tests and an incremental cycle maximal oxygen uptake (VO2max) test. EFL was recorded at the end of each exercise stage using the % tidal volume overlap method. Ventilatory and metabolic data were recorded throughout exercise. Arterial oxygen saturation (SpO2) was determined via pulse oximetry. Body composition was determined using dual-energy X-ray absorptiometry. There were no differences (P>0.05) in height, weight, or body composition between boys and girls. At rest, boys had significantly higher lung volumes (total lung capacity, B=2.6+/-0.5 liters, G=2.1+/-0.5 liters) and peak expiratory flow rates (B=3.6+/-0.6 l/s; G=1.6+/-0.3 l/s). Boys also had significantly higher VO2max (B=46.9+/-5.9 ml.kg lean body mass(-1).min(-1), G=41.7+/-6.6 ml.kg lean body mass(-1).min(-1)) and maximal ventilation (B=49.8+/-8.8 l/min, G=41.2+/-8.3 l/min) compared with girls. There were no sex differences (P>0.05) at VO2max in VE /VCO2, end-tidal PCO2, heart rate, respiratory exchange ratio, or SpO2. The prevalence (B=19/20 vs. G=18/20) and severity (B=58+/-7% vs. G=43+/-8% tidal volume) of EFL was not significantly different in boys compared with girls at VO2max. A significant relationship existed between % EFL at VO2max and the change in end-expiratory lung volume from rest to maximal exercise in boys (r=0.77) and girls (r=0.75). In summary, our data suggests that EFL is highly and equally prevalent in prepubescent boys and girls during heavy exercise, which led to an increased end-expiratory lung volume but not to decreases in arterial oxygen saturation. PMID- 20203072 TI - Oxidative stress is required for mechanical ventilation-induced protease activation in the diaphragm. AB - Prolonged mechanical ventilation (MV) results in diaphragmatic weakness due to fiber atrophy and contractile dysfunction. Recent work reveals that activation of the proteases calpain and caspase-3 is required for MV-induced diaphragmatic atrophy and contractile dysfunction. However, the mechanism(s) responsible for activation of these proteases remains unknown. To address this issue, we tested the hypothesis that oxidative stress is essential for the activation of calpain and caspase-3 in the diaphragm during MV. Cause-and-effect was established by prevention of MV-induced diaphragmatic oxidative stress using the antioxidant Trolox. Treatment of animals with Trolox prevented MV-induced protein oxidation and lipid peroxidation in the diaphragm. Importantly, the Trolox-mediated protection from MV-induced oxidative stress prevented the activation of calpain and caspase-3 in the diaphragm during MV. Furthermore, the avoidance of MV induced oxidative stress not only averted the activation of these proteases but also rescued the diaphragm from MV-induced diaphragmatic myofiber atrophy and contractile dysfunction. Collectively, these findings support the prediction that oxidative stress is required for MV-induced activation of calpain and caspase-3 in the diaphragm and are consistent with the concept that antioxidant therapy can retard MV-induced diaphragmatic weakness. PMID- 20203074 TI - Ensemble learning algorithms for classification of mtDNA into haplogroups. AB - Classification of mitochondrial DNA (mtDNA) into their respective haplogroups allows the addressing of various anthropologic and forensic issues. Unique to mtDNA is its abundance and non-recombining uni-parental mode of inheritance; consequently, mutations are the only changes observed in the genetic material. These individual mutations are classified into their cladistic haplogroups allowing the tracing of different genetic branch points in human (and other organisms) evolution. Due to the large number of samples, it becomes necessary to automate the classification process. Using 5-fold cross-validation, we investigated two classification techniques on the consented database of 21 141 samples published by the Genographic project. The support vector machines (SVM) algorithm achieved a macro-accuracy of 88.06% and micro-accuracy of 96.59%, while the random forest (RF) algorithm achieved a macro-accuracy of 87.35% and micro accuracy of 96.19%. In addition to being faster and more memory-economic in making predictions, SVM and RF are better than or comparable to the nearest neighbor method employed by the Genographic project in terms of prediction accuracy. PMID- 20203073 TI - Epigenetics and cancer. AB - Epigenetic modifications are central to many human diseases, including cancer. Traditionally, cancer has been viewed as a genetic disease, and it is now becoming apparent that the onset of cancer is preceded by epigenetic abnormalities. Investigators in the rapidly expanding field of epigenetics have documented extensive genomic reprogramming in cancer cells, including methylation of DNA, chemical modification of the histone proteins, and RNA-dependent regulation. Recognizing that carcinogenesis involves both genetic and epigenetic alterations has led to a better understanding of the molecular pathways that govern the development of cancer and to improvements in diagnosing and predicting the outcome of various types of cancer. Studies of the mechanism(s) of epigenetic regulation and its reversibility have resulted in the identification of novel targets that may be useful in developing new strategies for the prevention and treatment of cancer. PMID- 20203075 TI - Pressure mounts for global moratorium on use of the death penalty by 2015. PMID- 20203076 TI - Dopa responsive dystonia. PMID- 20203077 TI - GPs' income fell for the second year in a row in 2007-8. PMID- 20203078 TI - US doctors urge a more cautious approach to screening for prostate cancer. PMID- 20203080 TI - The NHS as an insurer. AB - The National Health Service (NHS) in England is not only a commissioner and provider of health care to the sick, but also offers certainty and peace of mind to all citizens--even those who do not use the health service in any year. However, due to the recent dominance of cost-effectiveness and cost-utility analysis as the central factors determining resource allocation decisions in the NHS, this second role--which we term its 'insurance value'--has increasingly become neglected. In this paper, we argue that this inattention is detrimental to the population at large. We explore some implications to the NHS of maximizing insurance value. These include requiring commissioners to take explicit account of how denial of service undermines peace of mind; requiring the National Institute for Health and Clinical Excellence (NICE) to calculate not just the health benefits, but also the peace of mind benefits of health technologies; and establishing a formal NHS 'insurance regulator' analogous to the Financial Ombudsman Service. Insurance value should be a guiding principle for NHS decision makers. PMID- 20203081 TI - The emotional experience of patient care: a case for innovation in health care design. AB - This paper considers recent developments in health care facility design and in the psychology literature that support a case for increased design sensitivity to the emotional experience of patient care. The author discusses several examples of innovative patient-centred health care design interventions. These generally resulted in improvements in the patient and staff experience of care, at less cost than major infrastructural interventions. The paper relates these developments in practice with recent neuroscience research, illustrating that the design of the built environment influences patient emotional stress. In turn, patient emotional stress appears to influence patient satisfaction, and in some instances, patient outcomes. This paper highlights the need for further research in this area. PMID- 20203082 TI - Determinants of self-reported medicine underuse due to cost: a comparison of seven countries. AB - OBJECTIVES: To compare the predictors of self-reported medicine underuse due to cost across countries with different pharmaceutical subsidy systems and co payments. METHODS: We analysed data from a 2007 survey of adults in Australia, Canada, Germany, the Netherlands, New Zealand (NZ), the United Kingdom (UK) and the United States (US). The predictors of underuse were calculated separately for each country using multivariate poisson regression. RESULTS: Reports of underuse due to cost varied from 3% in the Netherlands to 20% in the US. In Australia, Canada, NZ, the UK and the US, cost-related underuse was predicted by high out-of pocket costs (RR range 2.0-4.6), below average income (RR range 1.9-3.1), and younger age (RR range 3.9-16.4). In all countries except Australia and the UK, history of depression was associated with cost-related underuse (RR range 1.2 4.1). In Australia, Canada, Germany, the UK and the US lack of patient involvement in treatment decisions was associated with cost-related underuse (RR range 1.2-1.4). In Australia, Canada and NZ, indigenous persons more commonly reported underuse due to cost (RR range 2.1-2.9). CONCLUSIONS: Cost-related underuse of medicines was least commonly reported in countries with the lowest out-of-pocket costs, the Netherlands and the UK. Countries with reduced co payments or cost ceilings for low income patients showed the least disparity in rates of underuse between income groups. Despite differences in health insurance systems in these countries, age, ethnicity, depression, and involvement with treatment decisions were consistently predictive of underuse. There are opportunities for policy makers and clinicians to support medicine use in vulnerable groups. PMID- 20203083 TI - The impact of intragenic CpG content on gene expression. AB - The development of vaccine components or recombinant therapeutics critically depends on sustained expression of the corresponding transgene. This study aimed to determine the contribution of intragenic CpG content to expression efficiency in transiently and stably transfected mammalian cells. Based upon a humanized version of green fluorescent protein (GFP) containing 60 CpGs within its coding sequence, a CpG-depleted variant of the GFP reporter was established by carefully modulating the codon usage. Interestingly, GFP reporter activity and detectable protein amounts in stably transfected CHO and 293 cells were significantly decreased upon CpG depletion and independent from promoter usage (CMV, EF1 alpha). The reduction in protein expression associated with CpG depletion was likewise observed for other unrelated reporter genes and was clearly reflected by a decline in mRNA copy numbers rather than translational efficiency. Moreover, decreased mRNA levels were neither due to nuclear export restrictions nor alternative splicing or mRNA instability. Rather, the intragenic CpG content influenced de novo transcriptional activity thus implying a common transcription based mechanism of gene regulation via CpGs. Increased high CpG transcription correlated with changed nucleosomal positions in vitro albeit histone density at the two genes did not change in vivo as monitored by ChIP. PMID- 20203085 TI - Vision screening in a primary care setting. PMID- 20203084 TI - The crystal structure of unmodified tRNAPhe from Escherichia coli. AB - Post-transcriptional nucleoside modifications fine-tune the biophysical and biochemical properties of transfer RNA (tRNA) so that it is optimized for participation in cellular processes. Here we report the crystal structure of unmodified tRNA(Phe) from Escherichia coli at a resolution of 3 A. We show that in the absence of modifications the overall fold of the tRNA is essentially the same as that of mature tRNA. However, there are a number of significant structural differences, such as rearrangements in a triplet base pair and a widened angle between the acceptor and anticodon stems. Contrary to previous observations, the anticodon adopts the same conformation as seen in mature tRNA. PMID- 20203086 TI - SUMO modification regulates the transcriptional activity of MAML1. AB - The Mastermindlike (MAML) family, comprising human MAML1, MAML2, and MAML3, are transcriptional regulators in Notch signaling. MAML proteins contain two consensus sites for SUMOylation at Lysine217 and Lysine299 that are conserved in humans, mice, and Xenopus. In this report, we show that MAML1 is SUMOylated at both sites. The E2-conjugating enzyme UBC9 is essential for MAML1 SUMOylation, and the E3 ligase PIAS1 stimulates this activity. Mutation of the lysines abolishes SUMOylation of MAML1 and strongly increases MAML1-activated transcription in cell culture assays. The protease SENP1 reverses SUMOylation of MAML1 and potentiates the transcription factor activity of MAML1. Furthermore, SUMOylation enhances MAML1 interaction with HDAC7, which decreases MAML1 transcriptional activity. Taken together, our data indicate that SUMOylation of MAML1 is a mechanism for repressing MAML1 activity by influencing its interaction with HDAC7. PMID- 20203087 TI - Macrophage migration inhibitory factor is a therapeutic target in treatment of non-insulin-dependent diabetes mellitus. AB - Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine involved in the pathogenesis of a variety of autoimmune inflammatory diseases. Here, we investigated the role of MIF in the pathogenesis of non-insulin dependent diabetes mellitus (NIDDM) using MIF(-/-) mice and a mouse model of streptozotocin (STZ)-induced NIDDM. Following single injection of STZ, MIF(+/+) BALB/c mice showed a significant increase in blood glucose levels, developed polyuria, and succumbed to disease. In contrast, no such increase in blood glucose was observed in MIF(-/-) BALB/c mice treated with STZ. These mice produced significantly less inflammatory cytokines and resistin as compared with MIF(+/+) mice and failed to develop clinical disease. Finally, oral administration of a small-molecule MIF antagonist, CPSI-1306, to outbred ICR mice following induction of NIDDM significantly lowered blood glucose levels in the majority of animals, which was also associated with a significant reduction in the levels of the proinflammatory cytokines IL-6 and TNF-alpha in the sera. Taken together, these results demonstrate that MIF is involved in the pathogenesis of NIDDM and is a therapeutic target to treat this disease. PMID- 20203088 TI - Tumor-specific gene transfer with receptor-mediated nanocomplexes modified by polyethylene glycol shielding and endosomally cleavable lipid and peptide linkers. AB - Synthetic nanoparticle formulations have the potential for tumor-targeted gene delivery. Receptor-targeted nanocomplex (RTN) formulations comprise mixtures of cationic liposomes and targeting peptides that self-assemble on mixing with nucleic acids. RTN formulations were prepared containing different polyethylene glycol (PEG)ylated lipids with esterase-cleavable linkers (e.g., ME42) to promote intracellular PEG detachment and nanoparticle disassembly. In addition, integrin targeting peptides (peptide ME27) were tested with endosomal furin- and cathepsin B-cleavable peptide linkers located between the integrin-binding ligand and the K(16) nucleic acid-binding domain to promote intracellular disengagement from the receptor. ME42/ME27 RTNs formed stable particles of <200 nm in isotonic salt buffers, compared with 4-microm particles formed by un-PEGylated RTNs. Transfection efficiency by PEG-modified, cleavable RTNs improved approximately 2 fold in 4 different cell lines, with 80% efficiency in murine neuroblastoma cells. In an in vivo model of neuroblastoma, ME42/ME27 RTNs delivering luciferase genes were tumor specific, with little expression in other organs tested. PEGylation of the RTNs enhanced luciferase transfection 5-fold over non-PEG formulations, whereas the cleavability of the peptide ME27 enhanced transfection 4-fold over that of RTNs with noncleavable peptides. Cleavability of the lipid for in vivo transfections had no effect. PEGylated, cleavable RTN formulations offer prospects for tumor-specific therapeutic gene transfer. PMID- 20203089 TI - Selective estrogen receptor-alpha agonist provides widespread heart and vascular protection with enhanced endothelial progenitor cell mobilization in the absence of uterotrophic action. AB - The beneficial effects of estrogens on the cardiovascular system are associated with adverse effects on reproductive tissues. On the basis of previous work indicating a major role for estrogen receptor (ER)-alpha in maintaining cardiovascular health, we evaluated the tissue selectivity of the ER alpha selective agonist propyl pyrazole triol (PPT) compared with 17beta-estradiol (E2) in vivo. Four weeks postovariectomy, equimolar doses of PPT and E2 were administered to rats in subcutaneous implants for 5 d. Both treatments restored rapid vasorelaxation of aortic tissue to estrogenic agents and prevented coronary hyperresponsiveness to angiotensin II in isolated heart preparations. Accordingly, multiple endpoints of myocardial ischemia-reperfusion injury exacerbated by ovariectomy returned to baseline following treatment. These protective effects were linked to increased in vivo levels of endothelial progenitor cells (EPCs). Human EPC function was enhanced in vitro after PPT treatment. In sharp contrast to E2, PPT treatment had no effect on uterine weight and histomorphology except for vessel density, and failed to up-regulate classic estrogen target genes. Dissection of the effects on vascular reactivity and uterine morphology was also observed following increased exposure to PPT at a higher dose for longer time. These data provide the first in vivo evidence for tissue-specific ER alpha activation. By conferring cardiovascular protection dissected from unwanted uterotrophic effects, ER alpha-selective agonists may represent a potential safer alternative to natural hormones. PMID- 20203090 TI - Crucial role of the small GTPase Rac1 in insulin-stimulated translocation of glucose transporter 4 to the mouse skeletal muscle sarcolemma. AB - The Rho family GTPase Rac1 has been implicated in the regulation of glucose uptake in myoblast cell lines. However, no evidence for the role of Rac1 has been provided by a mouse model. The purpose of this study is to test the involvement of Rac1 in insulin action in mouse skeletal muscle. Intravenous administration of insulin indeed elicited Rac1 activation in gastrocnemius muscle, suggesting the involvement of Rac1 in this signaling pathway. We then examined whether insulin stimulated translocation of the facilitative glucose transporter GLUT4 from its storage sites to the skeletal muscle sarcolemma depends on Rac1. We show that ectopic expression of constitutively activated Rac1, as well as intravenous administration of insulin, caused translocation of GLUT4 to the gastrocnemius muscle sarcolemma, as revealed by immunofluorescent staining of a transiently expressed exofacial epitope-tagged GLUT4 reporter. Of particular note, insulin dependent, but not constitutively activated Rac1-induced, GLUT4 translocation was markedly suppressed in skeletal muscle-specific rac1-knockout mice compared to control mice. Immunogold electron microscopic analysis of endogenous GLUT4 gave similar results. Collectively, we propose a critical role of Rac1 in insulin dependent GLUT4 translocation to the skeletal muscle sarcolemma, which has heretofore been predicted solely by cell culture studies. PMID- 20203091 TI - Effects of a 6-week, individualized, supervised exercise program for people with bleeding disorders and hemophilic arthritis. AB - BACKGROUND: People with bleeding disorders may develop severe arthritis due to joint hemorrhages. Exercise is recommended for people with bleeding disorders, but guidelines are vague and few studies document efficacy. In this study, 65% of people with bleeding disorders surveyed reported participating in minimal exercise, and 50% indicated a fear of exercise-induced bleeding, pain, or physical impairment. OBJECTIVE: The purpose of this study was to examine the feasibility, safety, and efficacy of a professionally designed, individualized, supervised exercise program for people with bleeding disorders. DESIGN: A single group, pretest-posttest clinical design was used. METHODS: Thirty-three patients (3 female, 30 male; 7-57 years of age) with mild to severe bleeding disorders were enrolled in the study. Twelve patients had co-existing illnesses, including HIV/AIDS, hepatitis, diabetes, fibromyalgia, neurofibromatosis, osteopenia, osteogenesis imperfecta, or cancer. Pre- and post-program measures included upper and lower-extremity strength (force-generating capacity), joint range of motion, joint and extremity circumference, and distance walked in 6 minutes. Each patient was prescribed a 6-week, twice-weekly, individualized, supervised exercise program. Twenty participants (61%) completed the program. RESULTS: Pre- and post program data were analyzed by paired t tests for all participants who completed the program. No exercise-induced injuries, pain, edema, or bleeding episodes were reported. Significant improvements occurred in joint motion, strength, and distance walked in 6 minutes, with no change in joint circumference. The greatest gains were among the individuals with the most severe joint damage and coexisting illness. LIMITATIONS: Limitations included a small sample size with concomitant disease, which is common to the population, and a nonblinded examiner. CONCLUSIONS: A professionally designed and supervised, individualized exercise program is feasible, safe, and beneficial for people with bleeding disorders, even in the presence of concomitant disease. A longitudinal study with a larger sample size, a blinded examiner, and a control group is needed to confirm the results. PMID- 20203092 TI - Effect of intensive outpatient physical training on gait performance and cardiovascular health in people with hemiparesis after stroke. AB - BACKGROUND: Stroke can result in severe motor deficits, and many people who have survived a stroke have poor cardiovascular fitness, with potentially disabling effects on daily life. OBJECTIVE: The objective of this study was to evaluate the impact of intensive physical training on gait performance and cardiovascular health parameters in people with stroke in the chronic stage. DESIGN: This was a single-group, pretest-posttest experimental study. METHODS: Fourteen people with hemiparesis after cerebrovascular injury (mean age=58.4 years, mean time since injury=25 months) participated in a 12-week training intervention, 5 times per week for 1.5 hours per session. The intervention consisted of high-intensity, body-weight-supported treadmill training; progressive resistance strength training; and aerobic exercise. The main outcome measures were gait performance (Six-Minute Walk Test, 10-Meter Walk Test, and aerobic capacity) and parameters of cardiovascular health (systolic and diastolic blood pressures, body mass index, and resting heart rate). RESULTS: Significant improvements in all main outcome parameters were observed in response to the intervention. Gait speed during the Six-Minute Walk Test increased 62%, and systolic and diastolic blood pressures decreased 10% and 11%, respectively. Weekly testing of walking speed showed that most of the increase in the walking speed occurred in the first 8 weeks of training. Correlation analyses showed that improvements were unrelated to age, chronicity, or level of functioning. CONCLUSIONS: High-intensity physical training for people with stroke in the chronic stage increased walking speed regardless of chronicity, age, or level of functioning. Further studies should investigate the intervention duration needed to reach the full potential of gait recovery. PMID- 20203093 TI - Qualitative research ethics: enhancing evidence-based practice in physical therapy. AB - BACKGROUND: Increasing challenges to health care systems and the prominence of patient-centered care and evidence-based practice have fostered the application of qualitative approaches in health care settings, prompting discussions of associated ethical issues in a range of disciplines. OBJECTIVES: The purposes of this work were to identify and describe the application and value of qualitative health research for physical therapy and to identify ethical considerations in a qualitative research study. DESIGN: This was a qualitative interview study with telephone follow-ups. METHODS: Forty-six participants were interviewed about their early experiences with rheumatoid arthritis. They also were asked what motivated them to volunteer for the study. To inform the discussion of ethics in qualitative health research, this study drew on the in-depth interviews, took a descriptive approach to the data, and applied the traditional ethical principles of autonomy, justice, and beneficence to the study process. RESULTS: Ethical issues emerged in this qualitative health research study that were both similar to and different from those that exist in a positivist paradigm (eg, clinical research). With flexibility and latitude, the traditional principle approach can be applied usefully to qualitative health research. CONCLUSIONS: These findings build on previous research and discussion in physical therapy and other disciplines that urge a flexible approach to qualitative research ethics and recognize that ethics are embedded in an unfolding research process involving the role of the subjective researcher and an active participant. We suggest reflexivity as a way to recognize ethical moments throughout qualitative research and to help build methodological and ethical rigor in research relevant to physical therapist practice. PMID- 20203094 TI - A simple clinical scale to stratify risk of recurrent falls in community-dwelling adults aged 65 years and older. AB - BACKGROUND: Correct identification of people at risk for recurrent falls facilitates the establishment of preventive and rehabilitative strategies in older adults. OBJECTIVE: The purposes of this study were: (1) to develop and validate a simple clinical scale to stratify risk for recurrent falls in community-dwelling elderly people based on easily obtained social and clinical items and (2) to evaluate the added value of 3 clinical balance tests in predicting this risk. DESIGN: This was a prospective measurement study. METHODS: A population of 1,618 community-dwelling people over 65 years of age underwent a health checkup, including performance of 3 clinical balance tests: the One-Leg Balance Test, the Timed "Up & Go" Test, and the Five-Times-Sit-to-Stand Test. Falls were recorded using a self-administered questionnaire that was completed a mean (SD) of 25+/-5 months after the visit. Participants were randomly divided into either group A (n=999), which was used to develop the scale, or group B (n=619), which was used to prospectively validate the scale. RESULTS: Logistic regression analysis identified 4 variables that independently predicted recurrent falls in group A: history of falls, living alone, taking >or=4 medications per day, and female sex. Thereafter, 3 risk categories of recurrent falls (low, moderate, and high) were determined. Predicted probability of recurrent falls increased from 4.1% to 30.1% between the first and third categories. This scale subsequently was validated with great accuracy in group B. Only the Five-Times Sit-to-Stand Test provided added value in the estimation of risk for recurrent falls, especially for the participants who were at moderate risk, in whom failure on the test (duration of >15 seconds) doubled the risk. LIMITATIONS: Falls were assessed only once, and length of follow-up was heterogeneous (18-36 months). CONCLUSIONS: Clinicians could easily classify older patients in low-, moderate-, or high-risk groups of recurrent falls by using 4 easy-to-obtain items. The Five Times-Sit-to-Stand Test provides added value to stratify risk for falls in people at moderate risk. PMID- 20203095 TI - Continuing professional development is associated with increasing physical therapists' roles in arthritis management in Canada and the Netherlands. AB - BACKGROUND AND OBJECTIVE: This study explored the relationships among the roles assumed by physical therapists in arthritis care and their previous participation in arthritis courses for continuing professional development (CPD). DESIGN: A cross-sectional mail survey was conducted. METHOD: A total of 600 Canadian physical therapists and 461 Dutch physical therapists practicing in orthopedics were randomly selected to participate in a mail survey. The questionnaire covered areas related to their clinical practice, previous participation in arthritis related CPD courses, and roles in the management of osteoarthritis (OA) and rheumatoid arthritis (RA). Poisson regression was used to explore the associations between physical therapists' participation in arthritis-related CPD courses and the number of roles they assumed in OA and RA care, after adjusting for personal characteristics, arthritis caseload, and country of practice. RESULTS: The survey response rates were 47.7% in Canada and 50.5% in the Netherlands. A total of 424 participants (Canada=224, the Netherlands=200) had treated patients with OA in the previous month, and 259 participants (Canada=68, Netherlands=191) had treated patients with RA in the previous month. The most common roles reported by participants were providing traditional physical therapy interventions and providing postsurgical care. Arthritis-related CPD courses significantly increased (ie, multiplied) the expected number of roles assumed by physical therapists by a factor of 1.32 (95% confidence interval=1.11, 1.56) in OA management and 1.69 (95% confidence interval=1.34, 2.13) in RA management. LIMITATIONS: Physical therapists' roles in arthritis management were obtained through self-reporting, which might differ from their actual clinical practice. CONCLUSIONS: This exploratory analysis highlights the association between participation in arthritis-related CPD courses and the roles assumed by physical therapists in OA and RA management. Further research is needed to understand the effects of CPD activities on other areas of physical therapist practice and on patients' outcomes. PMID- 20203096 TI - Differential benefits of memory training for minority older adults in the SeniorWISE study. AB - PURPOSE: Cognitive training improves mental abilities in older adults, but the benefit to minority elders is unclear. We conducted a subgroup analysis of subjects in the SeniorWISE (Wisdom Is Simply Exploration) trial to examine this issue. DESIGN AND METHODS: SeniorWISE was a Phase 3 randomized trial that enrolled 265 nondemented community-dwelling older adults aged 65 years and older between 2001 and 2006. Participants were randomly assigned to 12 hr of either memory or health training. RESULTS: The sample was 79% female, 71% Caucasian, 17% Hispanic, and 12% African American. On the Rivermead Behavioural Memory Test (RBMT), 28% of the sample scored normal, 47% scored poor, and 25% impaired. Memory performance changed differently over time depending on the demographic characteristics of participants. Both Hispanics and Blacks performed better than Whites on visual memory, and Blacks performed better over time on instrumental activities of daily living. On all performance measures, lower pretest scores were associated with relatively greater improvements over time. IMPLICATIONS: Our analyses suggested that minority participants received differential benefits from the memory training; however, this remains speculative because the 3 ethnic groups in the sample were not equivalent in size. The question of why Black and Hispanic participants often made greater improvements needs further exploration. PMID- 20203097 TI - Plasma Pentraxin 3, but not high-sensitivity C-reactive protein, is a useful inflammatory biomarker for predicting cognitive impairment in elderly hypertensive patients. AB - BACKGROUND: Due to the increasing longevity of human populations worldwide, there is need of a useful biomarker for the early detection of cognitive impairment in elderly persons. Both high blood pressure (BP) and inflammatory processes have been reported to be involved in cognitive impairment via cerebrovascular atherosclerosis or neuronal cell damage. METHODS: In this cross-sectional study of 210 ambulatory elderly hypertensive patients without clinically evident dementia (mean age: 74 years; 44% men), we measured 24-hour BP, circulatory pentraxin 3 (PTX3) and high-sensitivity C-reactive protein (hs-CRP) levels, and cognitive function (Mini-Mental State Examination [MMSE]). RESULTS: A high plasma PTX3 level was observed in lean subjects, especially in those whose current body weight was lower than that measured 5 years earlier, whereas a high hs-CRP level was associated with obesity (all p < .05). Both PTX3 and hs-CRP levels were significantly associated with the MMSE score (r = -.248, p<0.001 and r = -.153, p<0.05, respectively); however, in multiple regression analysis, the PTX3 level, but not the hs-CRP level, was inversely associated with the MMSE score independently of patient demographics, glucose and lipid metabolic parameters, 24 hour systolic BP (SBP) level, and the atherosclerotic burden (all p < .05). Moreover, there was a significant interaction between the PTX3 and 24-hour SBP levels in the determinants of MMSE score (p < .05). CONCLUSIONS: A high plasma PTX3 level in elderly hypertensive patients, particularly in those with a high 24 hour BP level, could be a significant predictor of cognitive impairment. A high PTX3 level may be a marker of frailty in elderly hypertensive patients. PMID- 20203098 TI - CD28 expression redefines thymocyte development during the pre-T to DP transition. AB - CD27 and CD28 have emerged as indicators demarcating the transition of thymocytes through beta-selection. We found that CD28 exhibits a greater dynamic range of expression during this phase, thus it was employed to further parse the DN/CD44( ) compartment in order to assess IL-7 signaling during the beta-selection process. Plotting CD28 versus CD25 expression revealed six DN/CD44(-) populations. OP9-DL1 stromal cell co-culture was used to demonstrate a developmental linkage from DN3a (CD25(+)CD28(-/lo)) to DN3b (CD25(+)CD28(+)) to DN3c (CD25(int)CD28(+)) to DN4a (CD25(-)CD28(+)) to double positive (DP) and showed the DN4b (CD25(-)CD28(hi)) and DN4c (CD25(-)CD28(-/lo)) populations to be inefficient in producing DP cells. Using CD69 as an additional marker to further parse the DN4a population, we found the pre-DP cells to be the CD44(-)CD25( )CD28(int)CD69(-)CD4(-/lo)CD8(-/lo) subset. Using this refined developmental scheme, IL-7R alpha expression was found to be transiently up-regulated post-beta selection in the DN3b and DN3c subsets; however, this increase did not confer enhanced responsiveness over that observed in the DN3a population. CD28 messenger RNA expression was up-regulated in post-beta-selected cells, whereas transcripts for CD27, IL-7R alpha and Bcl-2 were lower than that observed in the DN3a population. This study refines the current thymocyte differentiation scheme to allow for more detailed evaluation of events controlling early T-cell development, specifically surrounding the beta-selection checkpoint. PMID- 20203100 TI - Structural basis for hydroxycholesterols as natural ligands of orphan nuclear receptor RORgamma. AB - The retinoic acid-related orphan receptor gamma (RORgamma) has important roles in development and metabolic homeostasis. Although the biological functions of RORgamma have been studied extensively, no ligands for RORgamma have been identified, and no structure of RORgamma has been reported. In this study, we showed that hydroxycholesterols promote the recruitment of coactivators by RORgamma using biochemical assays. We also report the crystal structures of the RORgamma ligand-binding domain bound with hydroxycholesterols. The structures reveal the binding modes of various hydroxycholesterols in the RORgamma pocket, with the receptors all adopting the canonical active conformation. Mutations that disrupt the binding of hydroxycholesterols abolish the constitutive activity of RORgamma. Our observations suggest an important role for the endogenous hydroxycholesterols in modulating RORgamma-dependent biological processes. PMID- 20203099 TI - Minireview: steroidogenic factor 1: its roles in differentiation, development, and disease. AB - The orphan nuclear receptor steroidogenic factor 1 (SF-1, also called Ad4BP, encoded by the NR5A1 gene) is an essential regulator of endocrine development and function. Initially identified as a tissue-specific transcriptional regulator of cytochrome P450 steroid hydroxylases, studies of both global and tissue-specific knockout mice have demonstrated that SF-1 is required for the development of the adrenal glands, gonads, and ventromedial hypothalamus and for the proper functioning of pituitary gonadotropes. Many genes are transcriptionally regulated by SF-1, and many proteins, in turn, interact with SF-1 and modulate its activity. Whereas mice with heterozygous mutations that disrupt SF-1 function have only subtle abnormalities, humans with heterozygous SF-1 mutations can present with XY sex reversal (i.e. testicular failure), ovarian failure, and occasionally adrenal insufficiency; dysregulation of SF-1 has been linked to diseases such as endometriosis and adrenocortical carcinoma. The current state of knowledge of this important transcription factor will be reviewed with a particular emphasis on the pioneering work on SF-1 by the late Keith Parker. PMID- 20203101 TI - Induction of Galphas contributes to the paradoxical stimulation of cytosolic phospholipase A2alpha expression by cortisol in human amnion fibroblasts. AB - Cytosolic phospholipase A (cPLA(2alpha)) catalyzes the formation of arachidonic acid in prostaglandin synthesis. In contrast to the well-described down regulation of cPLA(2alpha), up-regulation of cPLA(2alpha) by glucocorticoids has been reported in human amnion fibroblasts, which may play a key role in parturition. The mechanisms underlying this paradoxical induction of cPLA(2alpha) by glucocorticoids remain largely unknown. Using cultured human amnion fibroblasts, we found that the induction of cPLA(2alpha) by cortisol required ongoing transcription and synthesis of at least one other protein. The induction of cPLA(2alpha) by cortisol was abolished by mutagenesis of a glucocorticoid response element (GRE) in the promoter. The same GRE was found mediating the classical inhibition of cPLA(2alpha) expression by cortisol in human fetal lung fibroblasts (HFL-1). Cortisol increased Galpha(s) expression in amnion fibroblasts but not in HFL-1 cells. Inhibition of Galpha(s) with NF449 attenuated the phosphorylation of cAMP response element-binding protein-1 (CREB-1) and the induction of cPLA(2alpha) by cortisol in amnion fibroblasts. Both glucocorticoid receptor (GR) and CREB-1 were found bound to the GRE upon cortisol stimulation of amnion fibroblasts. The induction of cPLA(2alpha) by cortisol was blocked by GR antagonist RU486 or protein kinase A inhibitor H89 or dominant-negative CREB-1. In conclusion, cortisol activates the cAMP/protein kinase A/CREB-1 pathway via Galpha(s) induction, and the phosphorylated CREB-1 interacts with GR at the GRE to promote cPLA(2alpha) expression in amnion fibroblasts. PMID- 20203102 TI - Chronic inhibition of the mTORC1/S6K1 pathway increases insulin-induced PI3K activity but inhibits Akt2 and glucose transport stimulation in 3T3-L1 adipocytes. AB - The mammalian target of rapamycin complex 1 (mTORC)1 pathway has emerged as a critical signaling component in the modulation of insulin's metabolic action. This effect is triggered by a nutrient- and insulin-mediated negative feedback loop in which mTOR and S6 kinase (S6K)1 phosphorylate insulin receptor substrate (IRS)-1 on serine residues, which blunts phosphatidylinositol 3-kinase (PI3K) activation. Acute inhibition of mTORC1/S6K1 by rapamycin increases insulin signaling and glucose uptake in myocytes and adipocytes, but whether these effects can be maintained under chronic inhibition of mTORC1 or S6K1 remains unclear. Here, we analyzed the effect of chronic rapamycin inhibition or small interfering RNA-based down-regulation of specific elements of the mTORC1/S6K1 pathway on insulin signaling and glucose transport in adipocytes. Both chronic inhibition of mTORC1 by rapamycin or knockdown of either mTOR, raptor, or S6K1 reduced inhibitory serine phosphorylation of IRS-1, while increasing its insulin stimulated tyrosine phosphorylation and associated PI3K activity. However, knockdown of either mTOR or raptor selectively blunted IRS-1 phosphorylation on Ser636/639, whereas only S6K1 knockdown was found to reduce phosphorylation of IRS-1 on Ser1101. Unexpectedly, insulin-induced activation of Akt2 and glucose transporter 4 expression were reduced after chronic disruption of the mTORC1/S6K1 pathway, impairing insulin-mediated glucose uptake despite increased PI3K activation. In conclusion, these data indicate that both mTORC1 and S6K1 are key elements of the negative feedback loop but inhibit insulin-induced PI3K activity through phosphorylation of specific serine residues in IRS-1. However, this study also shows that chronic inhibition of the mTORC1/S6K1 pathway uncouples IRS 1/PI3K signaling from insulin-induced glucose transport due to impaired activation of Akt2 and blunted glucose transporter 4 expression. PMID- 20203104 TI - Measuring the HIV/AIDS epidemic: approaches and challenges. AB - In this article, the author reviews current approaches and methods for measuring the scope of the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) epidemic and their strengths and weaknesses. In recent years, various public health agencies have revised statistical estimates of the scope of the HIV/AIDS pandemic. The author considers the reasons underlying these revisions. New sources of data for estimating HIV prevalence have become available, such as nationally representative probability-based surveys. New technologies such as biomarkers that indicate when persons became infected are now used to determine HIV incidence rates. The author summarizes the main sources of errors and problems with these and other approaches and discusses opportunities for improving their reliability. Changing methods and data sources present new challenges, because incidence and prevalence estimates produced at different points in time are not directly comparable with each other, which complicates assessment of time trends. The methodological changes help explain the changes in global statistics. As methods and data sources continue to improve, the development of statistical tools for better assessing the extent to which changes in HIV/AIDS statistics can be attributed to changes in methodology versus real changes in the underlying epidemic is an important challenge. PMID- 20203103 TI - Activation of Rac1 is closely related to androgen-independent cell proliferation of prostate cancer cells both in vitro and in vivo. AB - We and others previously showed that signaling through cSrc or atypical protein kinase C (aPKC) pathway regulates the proliferation of prostate cancer cells and is associated with their progression to castrate-resistance in vivo. However, the interrelation of these two kinases has been largely unexplored. In the present study, we show that androgen-induced activation of cSrc regulates the activity of aPKC through the small molecular weight G protein Rac1 in androgen-dependent LNCaP cells. Knockdown of cSrc in those cells reduces the phosphorylation of aPKC and the abundance of activated form of Rac1. Additionally, the treatment of those cells with Rac1 inhibitor repressed cell cycle progression at G(1)/S transition. In fact, forced expression of a constitutively active Rac1 mutant in LNCaP cells promoted cell proliferation under androgen-depleted conditions both in vitro and in vivo. Moreover, LNCaP C4-2 and AILNCaP cells, the syngeneic androgen independent sublines from LNCaP cells, harbored abundant Rac1-GTP. Importantly, the inhibition of Rac1 suppressed cell proliferation and induced apoptotic cell death in all prostate cancer cell lines tested irrespective of their androgen dependence. In immunohistochemical evaluation of tumor specimens from prostate cancer patients, Rac1 pathway appeared to be activated in the majority of castrate-resistant diseases. Collectively, our present results both in vitro and in vivo highly implicate that Rac1 can be a potential therapeutic target for patients with advanced prostate cancer, especially those with castrate-resistant status. PMID- 20203105 TI - Verbal autopsy: methods in transition. AB - Understanding of global health and changing morbidity and mortality is limited by inadequate measurement of population health. With fewer than one-third of deaths worldwide being assigned a cause, this long-standing dearth of information, almost exclusively in the world's poorest countries, hinders understanding of population health and limits opportunities for planning, monitoring, and evaluating interventions. In the absence of routine death registration, verbal autopsy (VA) methods are used to derive probable causes of death. Much effort has been put into refining the approach for specific purposes; however, there has been a lack of harmony regarding such efforts. Subsequently, a variety of methods and principles have been developed, often focusing on a single aspect of VA, and the resulting literature provides an inconsistent picture. By reviewing methodological and conceptual issues in VA, it is evident that VA cannot be reduced to a single one-size-fits-all tool. VA must be contextualized; given the lack of "gold standards," methodological developments should not be considered in terms of absolute validity but rather in terms of consistency, comparability, and adequacy for the intended purpose. There is an urgent need for clarified thinking about the overall objectives of population-level cause-of-death measurement and harmonized efforts in empirical methodological research. PMID- 20203106 TI - Role of basic residues within or near the predicted transmembrane helix 2 of the human breast cancer resistance protein in drug transport. AB - The human breast cancer resistance protein (BCRP/ABCG2) mediates efflux of drugs and xenobiotics out of cells. In this study, we investigated the role of five basic residues within or near transmembrane (TM) 2 of BCRP in transport activity. Lys(452), Lys(453), His(457), Arg(465), and Lys(473) were replaced with Ala or Asp. K452A, K453D, H457A, R465A, and K473A were stably expressed in human embryonic kidney (HEK) cells, and their plasma membrane expression and transport activities were examined. All of the mutants were expressed predominantly on the plasma membrane of HEK cells. After normalization to BCRP levels, the activities of K452A and H457A in effluxing mitoxantrone, boron-dipyrromethene-prazosin, and Hoechst33342 were increased approximately 2- to 6-fold compared with those of wild-type BCRP, whereas the activities of K453D and R465A were decreased by 40 to 60%. Likewise, K452A and H457A conferred increased resistance to mitoxantrone and 7-ethyl-10-hydroxy-camptothecin (SN-38), and K453D and R465A exhibited lower resistance. The transport activities and drug-resistance profiles of K473A were not changed. These mutations also differentially affected BCRP ATPase activities with a 2- to 4-fold increase in V(max)/K(m) for K452A and H457A and a 40 to 70% decrease for K453D and R465A. These mutations may induce conformational changes as manifested by the altered binding of the 5D3 antibody to BCRP in the presence of prazosin and altered trypsin digestion. Molecular modeling and docking calculations indicated that His(457) and Arg(465) might be directly involved in substrate binding. In conclusion, we have identified several basic residues within or near TM2 that may be important for interaction of substrates with BCRP. PMID- 20203107 TI - Passive immunization against nicotine attenuates somatic nicotine withdrawal syndrome in the rat. AB - INTRODUCTION: Nicotine immunization is under consideration as an intervention for smoking cessation. Therefore, it was of interest to evaluate the effects of nicotine antibodies on the withdrawal syndrome following termination of chronic nicotine administration. METHODS: Experiment 1 determined whether passive immunization following continuous nicotine infusion would alter the intensity of nicotine withdrawal syndrome in the rat. Fourteen rats were rendered nicotine dependent by 7 days of subcutaneous nicotine bitartrate infusion. On the final day, seven rats received 150 mg intraperitoneal (i.p.) of immune gamma globulin (IgG) raised against 3'-aminomethylnicotine-recombinant Pseudomonas aeruginosa exoprotein A (NicVAX, Nabi Biopharmaceuticals, Rockville, MD) and seven rats received normal IgG. Rats were observed under blind conditions for somatically expressed nicotine abstinence signs immediately prior to drug termination and at 12, 24, and 36 hr afterward. In Experiment 2, similarly treated rats were observed at 6- and 72-hr postwithdrawal, to test the possibility that immunization altered the time course rather than the intensity of withdrawal syndrome. Experiment 3 tested whether immunized rats were still nicotine dependent. Without pump removal, each rat was challenged by 1/mg/kg mecamylamine HCl and observed for precipitated withdrawal syndrome. RESULTS: In Experiment 1, there was no premature withdrawal syndrome during nicotine infusion. After termination, the immunized group had significantly fewer withdrawal signs than controls. Experiment 2 showed that immunization did not simply alter the timing of the nicotine abstinence syndrome since immunization did not increase signs before or after the usual withdrawal timeframe. In Experiment 3, rats immunized on the final day of infusion were still nicotine dependent since they exhibited a vigorous mecamylamine-precipitated withdrawal syndrome. DISCUSSION: Nicotine antibodies did not precipitate a withdrawal syndrome, and they markedly reduced the severity of spontaneous nicotine withdrawal. The present data suggests that this may be most readily explained by their reported delay of nicotine clearance. PMID- 20203109 TI - Selection of alternative CYP3A4 probe substrates for clinical drug interaction studies using in vitro data and in vivo simulation. AB - Understanding the potential for cytochrome P450-mediated drug-drug interactions (DDIs) is a critical step in the drug discovery process. DDIs of CYP3A4 are of particular importance because of the number of marketed drugs that are cleared by this enzyme. In response to studies that suggested the presence of several binding regions within the CYP3A4 active site, multiple probe substrates are often used for in vitro CYP3A4 DDI studies, including midazolam (the clinical standard), felodipine/nifedipine, and testosterone. However, the design of clinical CYP3A4 DDI studies may be confounded for cases such as 1-(2-hydroxy-2 methylpropyl)-N-[5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl]-5-methyl-3-oxo-2 phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG 458), with which testosterone is predicted to exhibit a clinically relevant DDI whereas midazolam and felodipine/nifedipine are not. To develop an appropriate path forward for such clinical DDI studies, the inhibition potency of 20 known inhibitors of CYP3A4 were measured in vitro using 8 clinically relevant CYP3A4 probe substrates and testosterone. Hierarchical clustering suggested four probe substrate clusters: testosterone; felodipine; midazolam, buspirone, quinidine, and sildenafil; and simvastatin, budesonide, and fluticasone. The in vivo sensitivities of six clinically relevant CYP3A4 probe substrates (buspirone, cyclosporine, nifedipine, quinidine, sildenafil, and simvastatin) were determined in relation to midazolam from literature DDI data. Buspirone, sildenafil, and simvastatin exhibited similar or greater sensitivity than midazolam to CYP3A4 inhibition in vivo. Finally, Simcyp was used to predict the in vivo magnitude of CYP3A4 DDIs caused by AMG 458 using midazolam, sildenafil, simvastatin, and testosterone as probe substrates. PMID- 20203110 TI - Editor's nitpicking. PMID- 20203108 TI - Differences between intermittent and light daily smokers in a population of U.S. military recruits. AB - INTRODUCTION: Few studies have assessed differences between intermittent and light smokers, particularly among young adults. Exploring these differences promotes a systematic approach to research and treatment in low-level smokers. This study explored demographic, tobacco-related, and psychosocial predictors of intermittent nondaily smoking relative to light smoking among basic military training (BMT) recruits. The impact of smoking status on abstinence rates at follow-up was also assessed. METHODS: Participants were 5,603 U.S. Air Force BMT intermittent nondaily (n = 3,134) or light daily (n = 2,469) smoking recruits participating in a population-based group randomized trial targeting tobacco use prevention and cessation (Klesges et al., 2006, Efficacy of a tailored tobacco control program on long-term use in a population of U.S. military troops. Journal of Consulting and Clinical Psychology, 74, 295-306.). Participants completed baseline measures assessing demographics; tobacco use and history; and common social, attitudinal, and behavioral risk factors for tobacco use. Flights of recruits were randomly assigned to a tobacco use intervention or health education control intervention. At the 1-year follow-up, participants reported 7-day point prevalence and continuous abstinence. RESULTS: Intermittent nondaily smoking relative to light daily smoking was associated with lesser perceived addiction, intermittent and daily use of smokeless tobacco, nonsmoking male and female heads of household, lesser likelihood of smoking while stressed or while bored, and higher likelihood of intentions to quit smoking. Intermittent smokers were significantly more likely than light daily smokers to report abstinence at follow up. DISCUSSION: Intermittent and daily light smokers differ on several tobacco related and psychosocial variables. Attending to these factors in prevention and cessation programs may enhance abstinence in both groups. PMID- 20203111 TI - Lumbosacral transitional vertebrae: classification, imaging findings, and clinical relevance. AB - SUMMARY: LSTVs are common within the spine, and their association with low back pain has been debated in the literature for nearly a century. LSTVs include sacralization of the lowest lumbar vertebral body and lumbarization of the uppermost sacral segment. These vertebral bodies demonstrate varying morphology, ranging from broadened transverse processes to complete fusion. Low back pain associated with an LSTV may arise from the level above the transition, the contralateral facet when unilateral, and/or the anomalous articulation when present. Although this association is still somewhat controversial, beyond dispute is the importance of identifying an LSTV in patients in whom a surgical or interventional procedure is planned. This is essential to avoid an intervention or surgery at an incorrect level. In this article, each of these issues will be addressed with attention to identifying and correctly numbering LSTVs as well as detecting imaging findings related to the genesis of low back pain. PMID- 20203112 TI - Maintenance of certification: update on attitudes of members of the American Society of Neuroradiology. AB - BACKGROUND AND PURPOSE: Neuroradiology is in the fifth year of subspecialty recertification. New requirements for the MOC process include a PQI initiative. The purpose of this report was to survey compliance of ASNR members with the MOC process. MATERIALS AND METHODS: A 12-question Internet-based survey was sent to the 2864 members of the ASNR through e-mail addresses. The survey asked questions regarding compliance with cognitive testing, SAMs, CME credits, and PQI. Multiple reminders were sent and open comments graded for attitudes toward the MOC process. RESULTS: While most respondents were engaged in the MOC process (878/1074 [81.8%]) and were aware of CME and SAMs, (736/1067 [69%]) and cognitive testing requirements of the recertification, the PQI initiative had limited participation and many questions about the component. Of the 1057 respondents, 687 (490 not started, 87 registered but not started, 110 unaware of PQI) or 65% had not started a PQI project at the time of the survey. The ASNR was asked to help with the cognitive examination by 25 (4.4%), CME offerings by 53 (9.4%), SAM modules by 88 (14.0%), and PQI projects by 205 (36.2%) respondents. Open comments were generally unfavorable toward the MOC-PQI process by a 3:1 ratio. CONCLUSIONS: Compliance with the MOC process has improved since a prior survey 3 years ago; however, confusion over the PQI process remains the primary concern of ASNR members. PMID- 20203113 TI - Accuracy and reproducibility of phase-contrast MR imaging measurements for CSF flow. AB - BACKGROUND AND PURPOSE: PCMR, widely used for the evaluation of blood flow, has been adopted for the assessment of cerebrospinal fluid flow in a variety of disorders. The purpose of this study was to evaluate the accuracy and reproducibility of 2 fast PCMR techniques for measuring CSF flow. MATERIALS AND METHODS: Velocities were calculated from RPC and CPC images of fluid flowing in a tube at a constant velocity. Error and the COV were computed for average and peak velocities. Additionally, measurements of sinusoidally fluctuating flow and of CSF flow in 5 healthy volunteers were acquired with the RPC and CPC acquisitions. RESULTS: For constant velocity experiments, error for the RPC and CPC acquisitions averaged +1.15% and +8.91% and COVs averaged 1.29% and 3.01%, respectively. For peak velocities of >or=12.6 cm/s, error with RPC or CPC ranged from -33.3% to -36.9% and COVs were 0%-4% for RPC and 1%-7% for CPC. For peak velocities of 250%. For fluctuating flow, both acquisitions showed similar flow patterns. In volunteer studies, peak systolic and diastolic velocities were not significantly different. CONCLUSIONS: The RPC and CPC sequences measure velocities on the order of CSF flow with an average error of >or=9%. The 2 techniques significantly overestimate peak velocities <6.4 cm/s, with maximum errors of 209% and 276% and maximum COVs of 100% and 73% for the RPC and CPC sequences, respectively. Measurements of CSF velocities in human volunteers and of sinusoidally fluctuating phantom velocities did not differ significantly between the 2 techniques. PMID- 20203114 TI - Diffusion tensor imaging of commissural and projection white matter in tuberous sclerosis complex and correlation with tuber load. AB - BACKGROUND AND PURPOSE: Cortical and white matter changes have been identified outside the MR imaging-visible cortical/subcortical tubers in the tuberous sclerosis complex. The aim of this study was to evaluate DTI changes in the corpus callosum and internal capsules and to correlate the DTI changes with cortical/subcortical tuber load. MATERIALS AND METHODS: Twelve TSC patients and 23 controls underwent MR imaging including DTI. FA, trace, D( ||), and D() of genu and splenium of corpus callosum and right and left internal capsules were assessed. The number and volume of cortical/subcortical tubers were correlated with DTI indices of corpus callosum and internal capsules. RESULTS: In the genu and splenium, FA was lower and trace (P < .01) and D() were higher (P < .01), and in the internal capsules, trace was higher (P = .04) in TSC patients compared with controls. The total tuber volume correlated positively with trace of genu (r = 0.77, P < .01) and splenium (r = 0.69, P = .01) and with D() of splenium (r = 0.68, P = .01), and negatively with FA of splenium (r = -0.60, P = .04) of corpus callosum. The left and right hemispheric tuber volume correlated positively with trace of left (r = 0.56, P = .05) and right (r = 0.67, P = .02) internal capsules. CONCLUSIONS: Our findings of reduced FA, elevated trace, and elevated D() in the corpus callosum and internal capsules may be related to abnormalities in myelin. The correlations between tuber volume and DTI indices in corpus callosum and internal capsules suggested that more extensive malformation as demonstrated by larger tuber load was more likely to be associated with more severe DTI changes in the commissural and projection white matter. PMID- 20203115 TI - Osteoid osteoma invading the posterior labyrinth of the petrous bone. AB - We report a painless osteoid osteoma of the inner ear in an elderly woman presenting with hearing loss, tinnitus, and vertigo. CT showed a heterogeneous mass containing calcifications involving the posterior labyrinth, which heterogeneously enhanced on postcontrast MR images. Osteoid osteoma should be included in the differential diagnosis of an osteolytic petrous bone lesion with central calcification and enhancement. PMID- 20203116 TI - Correlation of automated volumetric analysis of brain MR imaging with cognitive impairment in a natural history study of mucopolysaccharidosis II. AB - BACKGROUND AND PURPOSE: Reliable markers for predicting neurologic outcome in patients with MPS II are lacking. The purpose of this study is to explore whether quantitative volumetric measurements of brain MR imaging can be used to differentiate between MPS II patients with and without cognitive impairment. This MR imaging study is the first in MPS II patients to use automated/semi-automated methods to quantify brain volumes in a longitudinal design. MATERIALS AND METHODS: Sixteen male patients with MPS II in a natural history study had annual brain MR imaging and detailed neurodevelopmental assessment over 2 years. Automated and semi-automated methods were used to determine brain volumes. Linear mixed regression models adjusting for age were used to assess the correlation between the volumetric parameters and cognition. RESULTS: Among the 16 MPS II patients, 10 (22 MR imaging studies) had cognitive impairment whereas the other 6 (11 MR imaging studies) had normal cognition. A decreased brain tissue/ICV ratio (-5%; P < .001) and an increased lateral ventricle/ICV ratio (+4%; P = .029) were found in patients with cognitive impairment compared with patients with normal cognition. These changes were apparent in patients as young as 7 years of age in addition to older patients. CONCLUSIONS: Quantitative volumetric measurements of brain MR imaging in MPS II patients can be obtained by using automated and semi automated segmentation methods. MPS II patients with cognitive impairment have decreased brain tissue volumes, but longer studies with more subjects are required to confirm these results. PMID- 20203117 TI - White matter characteristics and cognition in prenatally opiate- and polysubstance-exposed children: a diffusion tensor imaging study. AB - BACKGROUND AND PURPOSE: Prenatal drug exposure may influence the developing brain. Our aim was to study WM characteristics with DTI in children with prenatal opiate and polysubstance exposure and in controls. We assessed whether group differences in FA, DA, and DR could be found and related to cognitive function. MATERIALS AND METHODS: The study was approved by a committee for medical research ethics. Parents signed an informed consent; children gave spoken consent. Our sample included 14 prenatally substance-exposed adopted children (5 girls; age range, 8.6-13.9 years; mean, 11.3 +/- 1.7 years) and 14 control children (7 girls; age range, 9.0-10.2 years; mean, 9.8 +/- 0.3 years). Tract-based spatial statistics were used to define a common WM skeleton for the sample, and FA was compared between groups throughout the skeleton, controlling for age and sex. Clusters of significant group differences >or=100 voxels (P <. 05) were identified. FA, DA, and DR within clusters were correlated with cognitive function. RESULTS: Ten clusters of FA group differences, mostly in central, posterior, and inferior parts of the brain, were identified (P <. 05), showing lower FA in substance-exposed children. FA and DA correlated positively and DR, negatively with cognitive function across groups. CONCLUSIONS: Prenatally substance-exposed children exhibited lower FA in restricted areas of WM, mostly relatively central, inferior, and posterior, where myelination occurs early in development. Myelin in these areas may be particularly vulnerable to prenatal substance exposure. FA and DR related moderately to cognitive function. Potential confounding factors existed and were considered. PMID- 20203118 TI - A transition to plug-in hybrid electric vehicles (PHEVs): why public health professionals must care. PMID- 20203119 TI - Candidate gene-environment interactions. PMID- 20203120 TI - Inconsistent epidemiological findings on fish consumption may be indirect evidence of harmful contaminants in fish. PMID- 20203121 TI - Barriers for the prevention of chemical exposures in pregnant and breast-feeding workers? PMID- 20203122 TI - Yesterday once more? Unemployment and health in the 21st century. AB - The relationship between economic recession, higher unemployment and poorer health is well established in the medical and social science research literature. Much of this research resulted from the last major economic recessions of the early 1980s and 1990s. Many parallels are being made between then and now. Therefore, this paper revisits this literature to ascertain what the unemployment consequences of the economic recession may mean for public health and health services. However, this research agenda paper also outlines key differences between then and now focussing on the structure of the welfare system and the organisation and experience of work. Therefore, it is not simply a case of 'yesterday once more' and public health research, policy and practice needs to be sensitive and responsive to these changes. PMID- 20203123 TI - Solar simulated radiation induced cell death depends on spectral distribution and irradiance but not output delivery. AB - Photo-biological investigations are dependent on calibration and characterisation to determine the relevance of an artificial irradiator to the study at hand. The importance of this has been voiced in the literature. However, the importance of output delivery is relatively unknown. The biological relevance of a high-energy, rapidly pulsing solar simulator was investigated using the clonogenic assay and was found to be reciprocity law compliant despite an exaggerated ultraviolet (UV) irradiance in excess of 1600 W m(-2) delivered per pulse. In fact, it was found to be the least cytotoxic irradiator compared with a second solar simulator and a UVB fluorescent lamp with continuous UV irradiances of 55 and 6.4 W m(-2), respectively. The reduced survival observed with the continuous irradiators is attributed to differences in spectral irradiance and distribution, particularly in the UVB, which in the absence of thorough calibration and characterisation may have resulted in erroneous conclusions. PMID- 20203124 TI - Selection of the most appropriate two-dosemeter algorithm for estimating effective dose equivalent during maintenance periods in Korean nuclear power plants. AB - The application of a two-dosemeter system with its algorithm, as well as a test of its use in an inhomogeneous high-radiation field, is described in this study. The goal was to improve the method for estimating the effective dose equivalent during maintenance periods at Korean Nuclear Power Plants (NPPs). The use of this method in Korean and international NPPs, including those NPPs in the USA and Canada, was also investigated. The algorithms used by the the American National Standards Institute, Lakshmanan, the National Council on Radiation Protection and Measurements (NCRP), the Electric Power Research Institute and Kim were extensively analysed as two-dosemeter algorithms. Their possible application to NPPs was evaluated using data for each algorithm from two-dosemeter results that were obtained from an inhomogeneous high-radiation field during maintenance periods at Korean NPPs. The NCRP algorithm (55:50) was selected as an optimal two dosemeter algorithm for Korean NPPs by taking into account the field test results and the convenience of wearing two dosemeters. PMID- 20203125 TI - A Monte Carlo-based model for simulation of digital chest tomosynthesis. AB - The aim of this work was to calculate synthetic digital chest tomosynthesis projections using a computer simulation model based on the Monte Carlo method. An anthropomorphic chest phantom was scanned in a computed tomography scanner, segmented and included in the computer model to allow for simulation of realistic high-resolution X-ray images. The input parameters to the model were adapted to correspond to the VolumeRAD chest tomosynthesis system from GE Healthcare. Sixty tomosynthesis projections were calculated with projection angles ranging from +15 to -15 degrees. The images from primary photons were calculated using an analytical model of the anti-scatter grid and a pre-calculated detector response function. The contributions from scattered photons were calculated using an in house Monte Carlo-based model employing a number of variance reduction techniques such as the collision density estimator. Tomographic section images were reconstructed by transferring the simulated projections into the VolumeRAD system. The reconstruction was performed for three types of images using: (i) noise-free primary projections, (ii) primary projections including contributions from scattered photons and (iii) projections as in (ii) with added correlated noise. The simulated section images were compared with corresponding section images from projections taken with the real, anthropomorphic phantom from which the digital voxel phantom was originally created. The present article describes a work in progress aiming towards developing a model intended for optimisation of chest tomosynthesis, allowing for simulation of both existing and future chest tomosynthesis systems. PMID- 20203126 TI - Automatic landmarking of cephalograms using active appearance models. AB - There have been many attempts to further improve and automate cephalometric analysis in order to increase accuracy, reduce errors due to subjectivity, and to provide more efficient use of clinicians' time. The aim of this research was to evaluate an automated system for landmarking of cephalograms based on the use of an active appearance model (AAM) that contains a statistical model of shape and grey-level appearance of an object of interest and represents both shape and texture variations of the region covered by the model. Multi-resolution implementation was used, in which the AAM iterate to convergence at each level before projecting the current solution to the next level of the model. The AAM system was trained using 60 randomly selected, hand-annotated digital cephalograms of subjects between 7.2 and 25.6 years of age, and tested with a leave-five-out method that enabled testing not only of the accuracy of the AAM system but also the accuracy of each AAM. Differences between methods were examined using the non-parametric Wilcoxon signed rank test. An average accuracy of 1.68 mm was obtained, with 61 per cent of landmarks detected within 2 mm and 95 per cent of landmarks detected within 5 mm precision. A noticeable increase in overall precision and detection of low-contrast cephalometric landmarks was achieved compared with other automated systems. These results suggest that the AAM approach can adequately represent the average shape and texture variations of craniofacial structures on digital radiographs. As such it can successfully be implemented for automatic localization of cephalometric landmarks. PMID- 20203127 TI - Do GnRH analogues directly affect human endometrial epithelial cell gene expression? AB - We examined whether Gonadotrophin-releasing hormone (GnRH) analogues [leuprolide acetate (LA) and ganirelix acetate (GA)] modulate gene expression in Ishikawa cells used as surrogate for human endometrial epithelial cells in vitro. The specific aims were: (i) to study the modulatory effect of GnRH analogues by RT PCR [in the absence and presence of E(2) and P4, and cyclic adenosine monophosphate (cAMP)] on mRNA expression of genes modulated during the window of implantation in GnRH analogues/rFSH-treated assisted reproductive technology cycles including OPTINEURIN (OPTN), CHROMATIN MODIFYING PROTEIN (CHMP1A), PROSAPOSIN (PSAP), IGFBP-5 and SORTING NEXIN 7 (SNX7), and (ii) to analyze the 5' flanking regions of such genes for the presence of putative steroid-response elements [estrogen-response elements (EREs) and P4-response element (PREs)]. Ishikawa cells were cytokeratin+/vimentin- and expressed ERalpha, ERbeta, PR and GnRH-R proteins. At 6 and 24 h, neither LA nor GA alone had an effect on gene expression. GnRH analogues alone or following E(2) and/or P4 co-incubation for 24 h also had no effect on gene expression, but P4 significantly increased expression of CHMP1A. E(2) + P4 treatment for 4 days, alone or followed by GA, had no effect, but E(2) + P4 treatment followed by LA significantly decreased IGFBP-5 expression. The addition of 8-Br cAMP did not modify gene expression, with the exception of IGFBP-5 that was significantly increased. The GnRH analogues did not modify intracellular cAMP levels. We identified conserved EREs for OPN, CHMP1A, SNX7 and PSAP and PREs for SNX7. We conclude that GnRH analogues appear not to have major direct effects on gene expression of human endometrial epithelial cells in vitro. PMID- 20203128 TI - Activin promotes follicular integrity and oogenesis in cultured pre-antral bovine follicles. AB - The aim of this study was to determine the individual and combined effect of activin and follicle stimulating hormone (FSH) on somatic and germ cell development in cultured pre-antral follicles. Pre-antral bovine follicles (mean diameter 157 +/- 3, range 132-199 microm) were cultured for 8 days in serum-free medium in the presence of either 100 ng/ml of recombinant human activin A (rhAct A), 100 ng/ml rhAct A combined with a high (100 ng/ml) or low (50 ng/ml) concentration of recombinant FSH (rFSH) or 50 ng/ml rFSH alone. Intrafollicular connexin 43 expression and actin-based cell adhesion were assessed on Day 2 and 4 of culture. Steroidogenesis was evaluated after Day 4 and 8. Follicles exposed to 100 ng/ml activin maintained expression of connexin 43 at the follicular periphery. In the presence of activin, with or without 100 ng/ml or 50 ng/ml FSH, follicles were steroidogenic undergoing significant growth (P < 0.01), granulosa cell proliferation (P < 0.01) and antral cavity formation (P < 0.05) compared with cultured controls. Maximum oocyte growth occurred in the presence of 100 ng/ml activin alone with a significant percentage of these oocytes maintaining normal morphology over controls (P < 0.05). These results are consistent with a role for activin in maintaining oocyte granulosa cell interactions due to increased peripheral granulosa cell adhesion to the basement membrane and retention of adhesion at the surface of the zona pellucida. Thus, the polarized expression of cell contact interactions promoted by activin supports ongoing folliculogenesis. PMID- 20203129 TI - GEN1/Yen1 and the SLX4 complex: Solutions to the problem of Holliday junction resolution. AB - Chromosomal double-strand breaks (DSBs) are considered to be among the most deleterious DNA lesions found in eukaryotic cells due to their propensity to promote genome instability. DSBs occur as a result of exogenous or endogenous DNA damage, and also occur during meiotic recombination. DSBs are often repaired through a process called homologous recombination (HR), which employs the sister chromatid in mitotic cells or the homologous chromosome in meiotic cells, as a template for repair. HR frequently involves the formation and resolution of four way DNA structures referred to as the Holliday junction (HJ). Despite extensive study, the machinery and mechanisms used to process these structures in eukaryotes have remained poorly understood. Recent work has identified XPG and UvrC/GIY domain-containing structure-specific endonucleases that can symmetrically cleave HJs in vitro in a manner that allows for religation without additional processing, properties that are reminiscent of the classical RuvC HJ resolvase in bacteria. Genetic studies reveal potential roles for these HJ resolvases in repair after DNA damage and during meiosis. The stage is now set for a more comprehensive understanding of the specific roles these enzymes play in the response of cells to DSBs, collapsed replication forks, telomere dysfunction, and meiotic recombination. PMID- 20203131 TI - Bradycardia and hypotension in mianserin intoxication. AB - Cardiotoxicity is an important adverse effect of tricyclic antidepressants. But cardiac side effects after intoxication with the tetracyclic mianserin are rare. In this paper, we describe a case in which bradycardia and hypotension occured due to mianserin overdose. A 37-year-old woman was admitted to the medical intensive care unit for self-poisoning with 30 tablets of 10 mg mianserin 2 hours before her admission. The patient denied taking any other drugs. Four hours after her admission, bradycardia and hypotension occurred and she began to suffer from giddiness. Atropine and theophylline were given. On the second and third day, her heart rate and blood pressure were normal. Based on this case, we estimate the probability of bradycardia and hypotension in mianserin intoxication and the significance of closely monitoring the patient. PMID- 20203130 TI - Linking H3K79 trimethylation to Wnt signaling through a novel Dot1-containing complex (DotCom). AB - Epigenetic modifications of chromatin play an important role in the regulation of gene expression. KMT4/Dot1 is a conserved histone methyltransferase capable of methylating chromatin on Lys79 of histone H3 (H3K79). Here we report the identification of a multisubunit Dot1 complex (DotCom), which includes several of the mixed lineage leukemia (MLL) partners in leukemia such as ENL, AF9/MLLT3, AF17/MLLT6, and AF10/MLLT10, as well as the known Wnt pathway modifiers TRRAP, Skp1, and beta-catenin. We demonstrated that the human DotCom is indeed capable of trimethylating H3K79 and, given the association of beta-catenin, Skp1, and TRRAP, we investigated, and found, a role for Dot1 in Wnt/Wingless signaling in an in vivo model system. Knockdown of Dot1 in Drosophila results in decreased expression of a subset of Wingless target genes. Furthermore, the loss of expression for the Drosophila homologs of the Dot1-associated proteins involved in the regulation of H3K79 shows a similar reduction in expression of these Wingless targets. From yeast to human, specific trimethylation of H3K79 by Dot1 requires the monoubiquitination of histone H2B by the Rad6/Bre1 complex. Here, we demonstrate that depletion of Bre1, the E3 ligase required for H2B monoubiquitination, leads specifically to reduced bulk H3K79 trimethylation levels and a reduction in expression of many Wingless targets. Overall, our study describes for the first time the components of DotCom and links the specific regulation of H3K79 trimethylation by Dot1 and its associated factors to the Wnt/Wingless signaling pathway. PMID- 20203132 TI - Lactational hexavalent chromium exposure-induced oxidative stress in rat uterus is associated with delayed puberty and impaired gonadotropin levels. AB - Hexavalent chromium (CrVI) is a transition element utilized in many fields of modern industries. CrVI is a reproductive metal toxicant that can traverse the placental barrier and cause a wide range of fetal effects. Therefore, the present study was carried out to determine the CrVI-induced utero-toxicity. In the present study, lactating rats received drinking water containing CrVI (50 mg/L and 200 mg/L) from postnatal days (PND) 1-21. During PND 1-21, the pups received CrVI via the mother's milk. Pups from both control and treatment groups were continued on regular diet and water from PND-21 onwards and euthanized on PND-45 and -65. Specific activities antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST) were estimated. Hydrogen peroxide (H2O2), lipid peroxidation (LPO) and serum gonadotropins viz. Luteinizing hormone (LH) and follicle stimulating hormone (FSH) were also assayed. Specific activities of SOD, CAT, GPX, GR and GST and serum testosterone and progesterone were significantly decreased, while H2O2, LPO and serum FSH was increased in 50-parts per million (ppm) and 200 ppm-treated rats in an age-dependent manner. These results suggest that lactational CrVI exposure induces oxidative stress in rat uterus by decreasing antioxidant enzymes, which were associated with delayed puberty and altered steroids and gonadotrophin levels. PMID- 20203133 TI - Poisoning severity score, Glasgow coma scale, corrected QT interval in acute organophosphate poisoning. AB - The aim of this study was to investigate effectiveness of the poisoning severity score (PSS), Glasgow coma scale (GCS), and corrected QT (QTc) interval in predicting outcomes in acute organophosphates (OP) poisoning. Over a period of 2 years, 62 patients with OP poisoning were admitted to emergency department (ED) of Erciyes University Medical School Hospital. The age, sex, cause of contact, compound involved, time elapsed between exposure and admission to the ED, duration of hospital stay, and cardiac manifestations at the time of presentation were recorded. GCS and poisoning severity score (PSS) was calculated for each patient. Electrocardiogram (ECG) analysis included the rate, rhythm, ST-T abnormalities, conduction defects, and measurement of PR and QT intervals. Sixty two patients with OP poisoning presented to our ED from January 2007 to December 2008 from which 54 patients were included in the study. The mean age was 34.1 +/- 14.8 years. Of the cases, 53.7% were female. Twenty-six patients had a prolonged QTc interval. Mean PSS of men and women was 1.8 +/- 1.0. No statistically significant correlation was found between the PSS and QTc intervals of the cases. A significant correlation was determined between the GCS and PSS of grade 3 and grade 4 cases. GCS is a parameter that helps clinician to identify advanced grade OP poisoning patients in the initial assessment in the ED. However, ECG findings, such as prolonged QTc interval, are not effective in determination of short-term prognosis and show no relationship with PSS. PMID- 20203134 TI - Parents' and children's perceptions of active video games: a focus group study. AB - Energy expenditure studies have shown that playing Active Video Games (AVGs) is positively associated with increases in heart rate and oxygen consumption. It is proposed that playing AVGs may be a useful means of addressing inactivity and obesity in children. This study explored children's and parents' perceptions of AVGs and the likely facilitators and barriers to sustained use of AVGs. Data were gathered using focus group interviews: seven with children, four with adults. Both children and parents reported that AVGs offered a way to increase activity and improve fitness. Barriers to sustained engagement, according to parents, were the cost of AVGs and lack of space in the home to play the games. According to children, the likelihood of long-term engagement with AVGs depended on game content and child age, with AVGs being seen as more appropriate for younger children than teenagers. It would appear that there is potential for AVGs to reduce inactivity in young people. However, barriers to widespread, sustainable adoption would need to be addressed if this potential is to be realized. PMID- 20203135 TI - Biological safety of neutral-pH hydrogen-enriched electrolyzed water upon mutagenicity, genotoxicity and subchronic oral toxicity. AB - Hydrogen-dissolved water has been suggested to be effective for alleviating the oxidative stress. In the present study, neutral-pH hydrogen-enriched electrolyzed water (NHE-water; dissolved hydrogen: 0.90-1.14 parts per million [ppm]; oxido reduced potential: -150 approximately -80 mV), which was prepared with a water electrolysis apparatus equipped with a non-diaphragm cell and a highly compressed activated-carbon block, was evaluated for the mutagenic and genotoxic potentials, at concentrations up to 100% dose/plate, and for the subchronic toxicity. NHE water did not induce reverse mutations in Salmonella typhimurium strains TA100, TA1535, TA98 and TA1537, and Escherichia coli strain WP2uvrA, in either the absence or presence of rat liver S9 for exogenous metabolic activation. Similarly, NHE-water did not induce chromosome aberrations in Chinese hamster lung fibroblast cells (CHL/IU), in short-term (6-hour) tests, with or without rat liver S9, or in a continuous treatment (24-hour) test. To evaluate the subchronic toxicity, Crj:CD(SD) specific pathogen free (SPF)-rats were administered with NHE water at a dose of 20 mL/kg/day for 28 days via intragastric infusion. NHE-water related toxic changes were not seen in terms of any items such as clinical symptoms, body weight, food consumption, urinalysis, hematology, blood chemistry, necropsy, each organ weight and histopathology. Thus, the no-observable-adverse effect level (NOAEL) for NHE-water was estimated to be greater than 20 mL/kg/day under the conditions examined, demonstrating the consistency with the expected safety for a human with a body weight of 60 kg to drink the NHE-water up to at least 1.2 L/day. PMID- 20203136 TI - Cadmium transport in blood serum. AB - The binding of Cd(2+) to human serum transferrin in 0.1 M N-(2-hydroxyethyl) piperazine-N( ')-2-ethanesulfonic acid and 5 mM sodium bicarbonate at pH 7.4 has been studied by difference ultraviolet spectrophotometry. The apparent association constants were found to be 2.61 x 10(5) M( -1) and 8.51 x 10(4)M(- 1), respectively. These association constants are pH-dependent, reducing with both increasing and decreasing pH. The apparent pK(a) values were found to be 4.93 and 5.42. Competitive assays of binding of Cd(2+) to transferrin in the presence of citrate and human serum albumin at molar ratios corresponding to those found in normal plasma showed that a considerable amount of Cd(2+) was not bound to transferrin. The competitive binding assays indicate that approximately 50% of Cd(2+) is bound to transferrin, approximately 37% to albumin and reminder to citrate. These results therefore suggest that, although transferrin at pH 7.4 is the major Cd( 2+)-binding component of plasma, an appreciable amount of Cd(2+) may be bound to albumin. PMID- 20203137 TI - A new method for early assessment of effects of exposing two non-target crustacean species, Asellus aquaticus and Gammarus fossarum, to pesticides, a laboratory study. AB - A reliable method is needed for assessing the condition of aquatic animals and their resistance to toxic pollutants. The physiological responses of two freshwater crustaceans, Asellus aquaticus and Gammarus fossarum, following in vitro exposure to two pesticides (atrazine and imidacloprid), were measured by a combination of electron transport system (ETS) activity and respiration (R). Short-term exposure concentrations were selected according to standard toxicity tests and ranged from 0.01 mg L(-1) to 10 mg L(-1). When pesticide concentration was greater than 1 mg l(- 1) (which is below the LC(50) [48 hours] determined for both species), A. aquaticus and G. fossarum responded to short-term exposure with elevated levels of R and/or lower levels of ETS activity. One hour exposure to concentrations of up to 10 mg L(-1) showed an effect in both test species. Laboratory tests confirmed that G. fossarum is more sensitive to short-term pesticide exposure than A. aquaticus. The combination of these two methods provides a useful and effective tool for assessing the general condition of aquatic animals. It also enables to determine toxic effects on freshwater biota of specific or combined pollutants. ETS/R ratio may be used as a quick predictor of effects on organisms exposed to pesticides and other stress factors such as changes in temperature, light, salinity, oxygen concentration and food. PMID- 20203139 TI - The trait of sensory processing sensitivity and neural responses to changes in visual scenes. AB - This exploratory study examined the extent to which individual differences in sensory processing sensitivity (SPS), a temperament/personality trait characterized by social, emotional and physical sensitivity, are associated with neural response in visual areas in response to subtle changes in visual scenes. Sixteen participants completed the Highly Sensitive Person questionnaire, a standard measure of SPS. Subsequently, they were tested on a change detection task while undergoing functional magnetic resonance imaging (fMRI). SPS was associated with significantly greater activation in brain areas involved in high order visual processing (i.e. right claustrum, left occipitotemporal, bilateral temporal and medial and posterior parietal regions) as well as in the right cerebellum, when detecting minor (vs major) changes in stimuli. These findings remained strong and significant after controlling for neuroticism and introversion, traits that are often correlated with SPS. These results provide the first evidence of neural differences associated with SPS, the first direct support for the sensory aspect of this trait that has been studied primarily for its social and affective implications, and preliminary evidence for heightened sensory processing in individuals high in SPS. PMID- 20203141 TI - Globalisation and women's health in Sub-Saharan Africa. PMID- 20203142 TI - Review article: Globalisation and women's health in Sub-Saharan Africa: would paying attention to women's occupational roles improve nutritional outcomes? AB - AIM: This paper explores, through a review of literature, the link between globalisation and nutritional outcomes in Sub-Saharan Africa, focusing on the pathways of women's occupational roles on the food produced, consumed, and secured for households. METHODS: Following a framework linking globalisation and health, we drew evidence from peer reviewed, cross-national or large scale studies, official sources, reviews, online scientific databases, and case studies, published between 1990 and 2009. RESULTS: Publications cite improved technology, information, know how, normative commitments to and resources for human development, returns from access to investment in agriculture for low income women producers, and urban employment opportunities reducing social discrimination and improving opportunities for household food security, particularly if access to these benefits is reinforced by national policy. However, many more publications cite negative consequences, including in falling national and local food self-sufficiency, livelihood and nutritional losses, widening inequalities, and in declining or insecure access to production inputs, markets, incomes, local foods, and healthcare. These effects are documented to increase time and resource burdens for women, with negative consequences for their own and their families' health and nutrition. CONCLUSIONS: The evidence suggests that globalisation-related economic and trade policies have, on balance, been associated with shifts in women's occupational roles and resources that contribute to documented poor nutritional outcomes in Africa. These trends call for public policies that address such positive and negative effects for women and for improved monitoring of such gender and socio-economic trends, especially at the household and community level, in the tracking of the Millennium Development Goals. PMID- 20203140 TI - Gender-specific expression of the DRD4 gene on adolescent delinquency, anger and thrill seeking. AB - The present study investigated gender differences in the associations between the DRD4 variable number tandem repeat (VNTR) polymorphism and adolescent delinquency, short temper and thrill seeking. We also explored whether the gender specific expression of the DRD4 can be explained by gender differences in the exposure to psychosocial risks, such as poor parent-child relationship. Participants were 263 14- to 17-year olds (50% males) living in Russia. DNA was extracted from saliva samples and the VNTR DRD4 polymorphisms were genotyped using polymerase chain reaction. Participants reported on the extent of their delinquent behaviour, short temper, thrill seeking and exposure to psychosocial risk (i.e. poor parental monitoring of adolescent behaviour, exposure to violence and peer delinquency). Compared to individuals with the 4/4 genotype, males, but not females, with the 7-repeat allele (7R) had significantly higher delinquency, short temper and thrill seeking. This interaction effect, however, was completely explained by males' higher exposure to psychosocial risk factors. When parental monitoring of youths' activities and youth exposure to violence were included in the model, the 7R * gender interaction was no longer significant. Thus, social context plays an important role in explaining gender-specific phenotypic expression of the DRD4 gene. PMID- 20203143 TI - Can the Millennium Development Goals database be used to measure the effects of globalisation on women's health in Sub-Saharan Africa? A critical analysis. AB - BACKGROUND: Africa has had poor returns from integration with world markets in globalisation, has experienced worsening poverty and malnutrition and has high burdens of HIV and communicable disease, with particular burdens on women. It is therefore essential to describe the impact of globalisation on women's health. Indicators such as the Millennium Development Goals (MDGs) are presented as having a major role in measuring this impact, but an assessment of the adequacy of aggregate national indicators used in monitoring the MDGs for this purpose is lacking. METHODS: The Millennium Development Goals' panel database 2000 to 2006 was used to investigate the association between globalisation and women's health in Sub-Saharan Africa based on various determinants of heath. Out of the 148 countries classified as developing countries, 48 were in Sub-Saharan Africa. RESULTS: Results suggest that developing countries are becoming more integrated with world markets through some lowering of trade barriers. At the same time, women's occupational roles are changing, which could affect their health status. However, it is difficult to measure the impact of globalisation on women's health from the MDG database. First, data on trade liberalization is aggregated at the regional level and does not hold any information on individual countries. Second, too few indicators in the MDG database are disaggregated by sex, making it difficult to separate the effects on women from those on men. CONCLUSIONS: The MDG database is not adequate to assess the effects of globalisation on women's health in Sub-Saharan Africa. We recommend that researchers aim to address this research question to find other data sources or turn to case studies. We hope that results from this study will stimulate research on globalisation and health using reliable sources. PMID- 20203146 TI - Cerebrospinal fluid neurofilament: the biomarker that will resuscitate the 'Spinal Tap'. PMID- 20203147 TI - Glucocorticoid effects on endothelial barrier function in the murine brain endothelial cell line cEND incubated with sera from patients with multiple sclerosis. AB - Compromised blood-brain barrier integrity is a major hallmark of active multiple sclerosis (MS). Alterations in brain endothelial tight junction protein and gene expression occur early during neuroinflammation but there is little known about the underlying mechanisms. In this study, we analysed barrier compromising effects of sera from MS patients and barrier restoring effects of glucocorticoids on blood-brain barrier integrity in vitro. cEND murine brain microvascular endothelial cell monolayers were incubated with sera from patients in active phase of disease or in relapse. Data were compared with effects of the glucocorticoid dexamethasone alone or in combination with MS sera on barrier integrity. Tight junction protein levels and gene expression were evaluated concomitant with barrier integrity. We reveal downregulation of claudin-5 and occludin protein and mRNA and an accompanying upregulation in expression of matrix metalloproteinase MMP-9 after incubation with serum from active disease and remission and also a minor reconstitution of barrier functions related to dexamethasone treatment. Moreover, we for the first time describe downregulation of claudin-5 and occludin protein after incubation of cEND cells with sera from patients in remission phase of MS. Our findings reveal direct and differential effects of MS sera on blood-brain barrier integrity. PMID- 20203148 TI - Lesion enhancement diminishes with time in primary progressive multiple sclerosis. AB - Fewer gadolinium-enhancing lesions are seen in established primary progressive multiple sclerosis (PPMS) compared with other subtypes. Previously, we found unexpectedly high enhancement levels in early PPMS (42%), suggesting an early inflammatory phase. The objective of this study was to investigate whether this level of enhancement was maintained, and whether it influenced clinical progression, over 5 years. Forty-five patients with PPMS, within 5 years of onset, were scored on the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC) and its subtests (including the timed walk test [TWT]) 6-monthly for 3 years, and at 5 years. T1-weighted brain and spinal cord images after triple dose gadolinium-DTPA, and T2-weighted brain sequences were also acquired. A mixed effect logistic model evaluated change in the percentage of patients with enhancing lesions. Ordinal logistic and multiple linear regression models identified predictors of progression, adjusted for T2 lesion load. The percentage of patients with enhancing lesions in the brain and spinal cord declined over 5 years (p = 0.03). Among patients with enhancement, more enhancing lesions at baseline predicted greater decline in mobility on the TWT over 5 years (p = 0.02). In conclusion, a proportion of patients with PPMS may undergo an early inflammatory phase, which has some impact on subsequent mobility. PMID- 20203149 TI - Antiviral immune response in patients with multiple sclerosis and healthy siblings. AB - The objective of this study was to determine the immune responses to candidate viral triggers of multiple sclerosis in patients and healthy siblings raised in the same family household. Virus antigen-specific IgG responses to Epstein-Barr virus-derived gene products as well as to human herpersvirus-6, human cytomegalovirus, and measles virus were evaluated in 25 multiple sclerosis patients and compared with 49 healthy full-siblings. IgG responses to the latent Epstein-Barr virus-encoded nuclear antigen-1 (EBNA1) were selectively increased in individuals with multiple sclerosis compared with their unaffected siblings. We conclude that elevated IgG responses towards EBNA1 are associated with the development of multiple sclerosis. PMID- 20203150 TI - Oropharyngeal dysphagia in multiple sclerosis. AB - Swallowing disorders are commonly observed in multiple sclerosis (MS) patients. The complications of dysphagia are common causes of morbidity and death in late stages of MS. However, dysphagia in MS usually receives limited attention. The purpose of this study was to determine the prevalence of different kinds of swallowing disorders in MS patients with mild to moderate disability; and to identify possible associations between clinical and demographic features of patients and the presence of dysphagia. The swallowing functions of 101 consecutive MS patients were screened by the Northwestern Dysphagia Patient Check Sheet. This is a screening test which identifies patients with pharyngeal stage disorders, aspiration, oral stage disorders and/or pharyngeal delay. 'Dysphagia' was defined as having at least one of the above mentioned four disorders. Among 101 MS patients, 32 (31.7%) were classified as having dysphagia. Pharyngeal stage disorders were the most common observed impairment (28.7%) and aspiration, oral stage disorders, and pharyngeal delay were observed in 6.9%, 5%, and 1% of patients, respectively. Dysphagic patients had a significantly longer disease duration (p = 0.031) and more neurological impairment in cerebellar functional system (p = 0.04) when compared with non-dysphagic patients. Moreover, dysphagia was significantly more prevalent in patients with more neurological disability as measured by Expanded Disability Status Scale (EDSS) scores (p = 0.04). These results emphasize the importance of assessment and management of swallowing function in MS patients, particularly in patients with a high EDSS score; more severe cerebellar dysfunction, and long disease duration. PMID- 20203152 TI - Helicobacter pylori with or without its neutrophil-activating protein may be the common denominator associated with multiple sclerosis and neuromyelitis optica. PMID- 20203153 TI - Reduced activity and expression of mitochondrial citrate carrier in streptozotocin-induced diabetic rats. AB - Citrate carrier (CiC), an integral protein of the mitochondrial inner membrane, plays an important role in hepatic intermediary metabolism, supplying the cytosol with acetyl-coenzyme A for fatty acid and cholesterol synthesis. Here, the effect of streptozotocin-induced diabetes on CiC activity and expression in rat liver was investigated. The rate of citrate transport was reduced by about 35% in mitochondria from diabetic vs. control rats. Kinetic studies in mitochondria from diabetic rats showed a reduction in maximum velocity and almost unchanged Michaelis-Menten constant of the CiC protein. Mitochondrial phospholipid amount was not significantly affected, whereas an increase in the cholesterol content and in the cholesterol/phospholipid ratio was observed. To thoroughly investigate the mechanism responsible for the reduced CiC activity in the diabetic state, molecular studies were performed. Ribonuclease protection assays and Western blotting analysis indicated that both hepatic CiC mRNA accumulation and protein level decreased similarly to the CiC activity. The reduced mRNA level and the lower content of the mitochondrial CiC protein, might account for the decline of CiC activity in diabetic animals. To discriminate between the role played by hyperglycemia from that of hypoinsulinemia in the reduction of CiC activity and expression, studies were conducted administrating phlorizin or insulin to streptozotocin-diabetic rats. Our data indicated that both insulin and glucose affect CiC activity and expression in diabetic rats, although they act at different regulatory steps. PMID- 20203154 TI - Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. AB - Liraglutide is a glucagon-like peptide-1 (GLP-1) analog developed for type 2 diabetes. Long-term liraglutide exposure in rodents was associated with thyroid C cell hyperplasia and tumors. Here, we report data supporting a GLP-1 receptor mediated mechanism for these changes in rodents. The GLP-1 receptor was localized to rodent C-cells. GLP-1 receptor agonists stimulated calcitonin release, up regulation of calcitonin gene expression, and subsequently C-cell hyperplasia in rats and, to a lesser extent, in mice. In contrast, humans and/or cynomolgus monkeys had low GLP-1 receptor expression in thyroid C-cells, and GLP-1 receptor agonists did not activate adenylate cyclase or generate calcitonin release in primates. Moreover, 20 months of liraglutide treatment (at >60 times human exposure levels) did not lead to C-cell hyperplasia in monkeys. Mean calcitonin levels in patients exposed to liraglutide for 2 yr remained at the lower end of the normal range, and there was no difference in the proportion of patients with calcitonin levels increasing above the clinically relevant cutoff level of 20 pg/ml. Our findings delineate important species-specific differences in GLP-1 receptor expression and action in the thyroid. Nevertheless, the long-term consequences of sustained GLP-1 receptor activation in the human thyroid remain unknown and merit further investigation. PMID- 20203155 TI - The lipoprivic control of feeding is governed by fat metabolism, not by leptin or adipose depletion. AB - A lipoprivic control of feeding has been proposed based on the finding that appetite is stimulated by drugs such as beta-mercaptoacetate (MA) that reduce fatty acid oxidation. The adipose-derived hormone, leptin, has effects on feeding and fat oxidation that are opposite those produced by MA. However, effects of this hormone on MA-induced feeding are not known. Here we examined the effects of endogenous leptin levels and of acute central and peripheral leptin administration on MA-induced feeding. We also examined leptin-induced changes in feeding, body weight, and plasma fuels after capsaicin-induced deletion of the lipoprivic control. MA-induced feeding was not altered under any of these conditions, and leptin's effects were not altered by capsaicin. We then examined MA-induced feeding during chronic leptin treatment. Because chronic leptin produces several distinct metabolic states as body adiposity is reduced, we tested MA before, during, and after leptin treatment at times that coincided with these states. MA-induced feeding was unchanged on d 3 of leptin treatment when rats were in a lipolytic state and rapidly metabolizing body fat stores but reduced on d 10 when they were adipose deplete and their level of fat oxidation was reduced. Together results suggest that the lipoprivic control is normally less active in the fat deplete state than during states associated with fat availability. If so, its insensitivity to leptin would enable the lipoprivic control to operate when dietary fat, adiposity, and leptin levels are elevated. The role played by the lipoprivic control under such conditions remains uncertain. PMID- 20203156 TI - B cells limit repair after ischemic acute kidney injury. AB - There is no established modality to repair kidney damage resulting from ischemia reperfusion injury (IRI). Early responses to IRI involve lymphocytes, but the role of B cells in tissue repair after IRI is unknown. Here, we examined B cell trafficking into postischemic mouse kidneys and compared the repair response between control (wild-type) and muMT (B cell-deficient) mice with and without adoptive transfer of B cells. B cells infiltrated postischemic kidneys and subsequently activated and differentiated to plasma cells during the repair phase. Plasma cells expressing CD126 increased and B-1 B cells trafficked into postischemic kidneys with distinct kinetics. An increase in B lymphocyte chemoattractant in the kidney preceded B cell trafficking. Postischemic kidneys of muMT mice expressed higher IL-10 and vascular endothelial growth factor and exhibited more tubular proliferation and less tubular atrophy. Adoptive transfer of B cells into muMT mice reduced tubular proliferation and increased tubular atrophy. Treatment with anti-CD126 antibody increased tubular proliferation and reduced tubular atrophy in the late repair phase. These results demonstrate that B cells may limit the repair process after kidney IRI. Targeting B cells could have therapeutic potential to improve repair after IRI. PMID- 20203157 TI - Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations. AB - In contrast to pregnancy-associated thrombotic thrombocytopenic purpura, the pathogenesis and presentation of pregnancy-associated atypical hemolytic uremic syndrome (P-aHUS) remain ill-defined. We conducted a retrospective study to assess the presentation and outcomes of patients presenting with P-aHUS and the prevalence of alternative C3 convertase dysregulation. P-aHUS occurred in 21 of the 100 adult female patients with atypical HUS, with 79% presenting postpartum. We detected complement abnormalities in 18 of the 21 patients. The outcomes were poor: 62% reached ESRD by 1 month and 76% by last follow-up. The risk for P-aHUS was highest during a second pregnancy. Thirty-five women, 26 (74%) of whom had complement abnormalities, had at least one pregnancy before the onset of a non pregnancy-related aHUS. Outcomes did not differ between patients with pregnancy related and non-pregnancy-related aHUS. Mutations in the SCR19-20 domains of factor H were less frequent in P-aHUS patients compared with non-pregnancy related aHUS. Pregnancies in female patients with complement abnormalities (n = 44) were complicated by fetal loss and preeclampsia in 4.8% and 7.7%, respectively. Better understanding of complement dysregulation in pregnancy complications is essential, especially to guide development of pharmacologic agents to modulate this system. PMID- 20203158 TI - siRNA-based therapy ameliorates glomerulonephritis. AB - RNA interference by short interfering RNAs (siRNAs) holds promise as a therapeutic strategy, but use of siRNAs in vivo remains limited. Here, we developed a system to target delivery of siRNAs to glomeruli via poly(ethylene glycol)-poly(l-lysine)-based vehicles. The siRNA/nanocarrier complex was approximately 10 to 20 nm in diameter, a size that would allow it to move across the fenestrated endothelium to access to the mesangium. After intraperitoneal injection of fluorescence-labeled siRNA/nanocarrier complexes, we detected siRNAs in the blood circulation for a prolonged time. Repeated intraperitoneal administration of a mitogen-activated protein kinase 1 (MAPK1) siRNA/nanocarrier complex suppressed glomerular MAPK1 mRNA and protein expression in a mouse model of glomerulonephritis; this improved kidney function, reduced proteinuria, and ameliorated glomerular sclerosis. Furthermore, this therapy reduced the expression of the profibrotic markers TGF-beta1, plasminogen activator inhibitor 1, and fibronectin. In conclusion, we successfully silenced intraglomerular genes with siRNA using nanocarriers. This technique could aid the investigation of molecular mechanisms of renal disease and has potential as a molecular therapy of glomerular diseases. PMID- 20203159 TI - Ultrastructural analysis of vascular calcifications in uremia. AB - Accelerated intimal and medial calcification and sclerosis accompany the increased cardiovascular mortality of dialysis patients, but the pathomechanisms initiating microcalcifications of the media are largely unknown. In this study, we systematically investigated the ultrastructural properties of medial calcifications from patients with uremia. We collected iliac artery segments from 30 dialysis patients before kidney transplantation and studied them by radiography, microcomputed tomography, light microscopy, and transmission electron microscopy including electron energy loss spectrometry, energy dispersive spectroscopy, and electron diffraction. In addition, we performed synchrotron x-ray analyses and immunogold labeling to detect inhibitors of calcification. Von Kossa staining revealed calcification of 53% of the arteries. The diameter of these microcalcifications ranged from 20 to 500 nm, with a core shell structure consisting of up to three layers (subshells). Many of the calcifications consisted of 2- to 10-nm nanocrystals and showed a hydroxyapatite and whitlockite crystalline structure and mineral phase. Immunogold labeling of calcification foci revealed the calcification inhibitors fetuin-A, osteopontin, and matrix gla protein. These observations suggest that uremic microcalcifications originate from nanocrystals, are chemically diverse, and intimately associate with proteinaceous inhibitors of calcification. Furthermore, considering the core-shell structure of the calcifications, apoptotic bodies or matrix vesicles may serve as a calcification nidus. PMID- 20203160 TI - Prolonged CD4 T cell lymphopenia increases morbidity and mortality after renal transplantation. AB - Prolonged CD4 T cell lymphopenia after administration of polyclonal anti thymocyte globulins increases the rate of posttransplantation morbidity, but whether impaired immune reconstitution affects survival is unknown. We studied the effect of CD4 T cell lymphopenia on survival in 302 consecutive prevalent renal transplant recipients and the role of thymic function in CD4 T cell reconstitution and posttransplantation outcomes in 100 consecutive incident renal transplant recipients. We followed the prevalent cohort for a mean duration of 92 months. Of these 302 patients, 81 (27%) had persistent CD4 T cell counts <300/mm3 and 36 (12%) died during follow-up. We observed a higher death rate in patients with CD4 T cell lymphopenia persisting for >1 year (24.1 versus 7.6%; P < 0.001). Furthermore, in Cox regression analysis, CD4 T cell lymphopenia associated with a nearly five-fold risk for death (adjusted hazard ratio [HR] 4.63; 95% confidence interval [CI] 1.91 to 10.65; P = 0.001). In the incident cohort, we estimated thymic function by T cell receptor excision circles (TRECs) per 150,000 CD3+ cells, which predicted efficient CD4 T cell reconstitution. Higher pretransplantation TREC values associated with lower risks for cancer (adjusted HR 0.39; 95% CI 0.15 to 0.97; P = 0.046) and infection (HR 0.29; 95% CI 0.11 to 0.78; P = 0.013). In summary, prolonged polyclonal anti-thymocyte globulin induced CD4 T cell lymphopenia is an independent risk factor for death. Determination of pretransplantation thymic function may identify patients at higher risk for CD4 T cell lymphopenia and posttransplantation morbidity, including cancer and infections. PMID- 20203161 TI - Direct effect of methylprednisolone on renal sodium and water transport via the principal cells in the kidney. AB - BACKGROUND: Glucocorticoids influence renal concentrating and diluting ability. We tested the hypothesis that methylprednisolone treatment increased renal water and sodium absorption by increased absorption via the aquaporin-2 (AQP2) water channels and the epithelial sodium channels (ENaCs) respectively. METHODS: The effect of methylprednisolone was measured during fasting in a randomized, placebo controlled, single-blinded cross-over study of 15 healthy humans. The subjects received a standardized diet on day 1, fasted on day 2, and received 500 mg methylprednisolone intravenously on day 3. The effect variables were urinary excretions of AQP2 (u-AQP2), urinary excretion of the beta-fraction of the ENaC (u-ENaC(beta)), cAMP (u-cAMP), prostaglandin E(2) (u-PGE(2)), free water clearance (C(H2O)), and fractional excretion of sodium (FE(Na)), and plasma vasopressin (p-AVP), angiotensin II (p-Ang II), aldosterone (p-Aldo), atrial natriuretic peptide (p-ANP), and brain natriuretic peptide (p-BNP). RESULTS: Methylprednisolone treatment increased u-AQP2, u-ENaC(beta), and p-AVP significantly, but did not change u-cAMP, c(H2O), and FE(Na). P-ANP increased during methylprednisolone treatment, but after the increase in u-AQP2 and u ENaC(beta). U-PGE(2), p-Ang II, and p-BNP were unchanged. Heart rate increased and diastolic blood pressure fell. CONCLUSIONS: Methylprednisolone increased u AQP2 and u-ENaC. Neither the AVP-cAMP axis nor changes in the renin-angiotensin Aldo system, or the natriuretic peptide system seems to bear a causal relationship with the increase in either u-AQP2 or u-ENaC. Most probably, the effect is mediated via a direct effect of methylprednisolone on the principal cells. The lack of decrease in urinary output and sodium reabsorption most likely can be attributed to the diuretic and natriuretic properties of the increased secretion of ANP. PMID- 20203162 TI - Kidney transplantation and HIV: does recipient privacy outweigh the donor's right to information? AB - BACKGROUND AND OBJECTIVES: There exists an inherent conflict between a kidney donor's right to know key aspects of a recipient's medical history and specific disease, such as HIV, where federal and state statues protect this information. The authors of the live organ donor consensus group expressly stated the principal of a donor's right to recipient information. This information includes the risks and benefits of not only the donation procedure, but also the risks, benefits, and alternative treatment options of the recipient. In this paper, a case will be presented highlighting this conflict and the ethical and legal reasoning used to resolve it. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A 22 year-old woman came forward as a directed kidney donor for an HIV-positive individual. The donor and recipient were medically appropriate for kidney donation and transplantation. During the donor advocacy panel review, there was disagreement regarding whether or not the potential donor had the right to know about the HIV status of the potential recipient. RESULTS: In living kidney transplantation to HIV-positive individuals, the recipient's right to privacy of information outweighs the donor's right to know. CONCLUSIONS: Although protecting the recipient's right to privacy is paramount, the donor is still entitled to consider factors a priori that could alter their decision to donate. This can be accomplished by informing the donor that they are not entitled to protected health information of the recipient and that their decision to donate should be based on knowing the recipient is medically appropriate for kidney transplantation. PMID- 20203163 TI - Cholecalciferol supplementation in hemodialysis patients: effects on mineral metabolism, inflammation, and cardiac dimension parameters. AB - BACKGROUND AND OBJECTIVES: Vitamin D deficiency is highly prevalent in chronic kidney disease. The aim of this study was to evaluate the effects of oral cholecalciferol supplementation on mineral metabolism, inflammation, and cardiac dimension parameters in long-term hemodialysis (HD) patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This 1-year prospective study included 158 HD patients. Serum levels of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)(2)D], intact parathyroid hormone, and plasma brain natriuretic peptide as well as circulating bone metabolism and inflammation parameters were measured before and after supplementation. Baseline 25(OH)D and 1,25(OH)(2)D levels were measured twice (end of winter and of summer, respectively). Therapy with paricalcitol, sevelamer, and darbepoietin was evaluated. RESULTS: There was an increase in serum 25(OH)D and 1,25(OH)(2)D levels after supplementation. Conversely, serum calcium, phosphorus, and intact parathyroid hormone were decreased. There was a reduction in the dosage and in the number of patients who were treated with paricalcitol and sevelamer. Darbepoietin use was also reduced, with no modification of hemoglobin values. Serum albumin increased and C-reactive protein decreased during the study. Brain natriuretic peptide levels and left ventricular mass index were significantly reduced at the end of the supplementation. CONCLUSIONS: Oral cholecalciferol supplementation in HD patients seems to be an easy and cost-effective therapeutic measure. It allows reduction of vitamin D deficiency, better control of mineral metabolism with less use of active vitamin D, attenuation of inflammation, reduced dosing of erythropoiesis stimulating agents, and possibly improvement of cardiac dysfunction. PMID- 20203164 TI - Treatment with IFN-{alpha}, -{beta}, or -{gamma} is associated with collapsing focal segmental glomerulosclerosis. AB - BACKGROUND AND OBJECTIVES: Treatment with IFN is rarely associated with nephrotic syndrome and renal biopsy findings of minimal-change disease or FSGS. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We report 11 cases of collapsing FSGS that developed during treatment with IFN and improved after discontinuation of therapy. RESULTS: The cohort consists of seven women and four men with a mean age of 48.2 yr. Ten of the 11 patients were black. Six patients were receiving IFN alpha for hepatitis C virus infection (n = 5) or malignant melanoma (n = 1), three were receiving IFN-beta for multiple sclerosis, and two were treated with IFN-gamma for idiopathic pulmonary fibrosis. After a median and mean [corrected] duration of therapy of 4.0 and 12.6 months, respectively, patients presented with acute renal failure (mean creatinine 3.5 mg/dl) and nephrotic-range proteinuria (mean 24-hour urine protein 9.7 g). Renal biopsy revealed collapsing FSGS with extensive foot process effacement and many endothelial tubuloreticular inclusions. Follow-up was available for 10 patients, all of whom discontinued IFN. At a mean of 23.6 months, nine of 10 patients had improvement in renal function, including one with complete remission and two with partial remission. Among the seven patients with available data, mean proteinuria declined from 9.9 to 3.0 g/d. Four of the seven patients were treated with immunosuppression, and there was no detectable benefit. CONCLUSIONS: Collapsing FSGS may occur after treatment with IFN-alpha, -beta, or -gamma and is typically accompanied by the ultrastructural finding of endothelial tubuloreticular inclusions. Optimal therapy includes discontinuation of IFN. PMID- 20203165 TI - Effect of membrane permeability on inflammation and arterial stiffness: a randomized trial. AB - BACKGROUND AND OBJECTIVES: Both larger molecule removal and dialyzer biocompatibility have been implicated in the high-flux hemodialysis (HD) associated favorable outcome. In an attempt to delineate the effect of membrane permeability, we performed a randomized, crossover study to compare the inflammatory biomarkers, lipid profile, and aortic pulse wave velocity (PWV) of two dialyzers that are composed of identical membranes but with different flux characteristics. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Stable patients who had anuria and were on low-flux polysulfone membrane were randomly allocated either to HD with high-flux polyamide membrane (group A; 22 patients) or to HD with low-flux polyamide membrane (group B; 24 patients) for 24 weeks, then they were started on 24 weeks of the alternative HD treatment. Apart from the dialyzer, the dialysis prescription remained unchanged. RESULTS: Nineteen patients from group A and 23 patients from group B completed the study. Predialysis beta(2)-microglobulin levels decreased significantly when using the high-flux polyamide membrane. No difference between membranes was observed for serum albumin, high-sensitivity C-reactive protein, fibrinogen, IL-6, triglycerides, HDL cholesterol, LDL cholesterol, and lipoprotein(a) during the study. A significant increase in aortic PWV, a marker of aortic stiffness, was noted after patients switched from high-flux to low-flux polyamide membranes. Similarly, the rate of change in aortic PWV was significantly decreased with the use of the high-flux polyamide membrane. CONCLUSIONS: Our findings suggest that dialysis with polyamide membranes with different flux characteristics did not modify the inflammatory indices and lipid profile in stable HD patients; however, a seemingly beneficial effect on aortic stiffness was noted for patients who were maintained on high-flux polyamide membrane. PMID- 20203166 TI - The FDA's perspective on the risk for rapid rise in hemoglobin in treating CKD anemia: Quo Vadis. PMID- 20203167 TI - Serum potassium and outcomes in CKD: insights from the RRI-CKD cohort study. AB - BACKGROUND AND OBJECTIVES: The relationship between serum potassium (S(K)) and mortality in chronic kidney disease (CKD) has not been systematically investigated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We examined the predictors and mortality association of S(K) in the Renal Research Institute CKD Study cohort, wherein 820 patients with CKD were prospectively followed at four US centers for an average of 2.6 years. Predictors of S(K) were investigated using linear and repeated measures regression models. Associations between S(K) and mortality, the outcomes of ESRD, and cardiovascular events in time-dependent Cox models were examined. RESULTS: The mean age was 60.5 years, 80% were white, 90% had hypertension, 36% had diabetes, the average estimated GFR was 25.4 ml/min per 1.73 m(2), and mean baseline S(K) was 4.6 mmol/L. Higher S(K) was associated with male gender, lower estimated GFR and serum bicarbonate, absence of diuretic and calcium channel blocker use, diabetes, and use of angiotensin-converting enzyme inhibitors and/or statins. A U-shaped relationship between S(K) and mortality was observed, with mortality risk significantly greater at S(K) < or = 4.0 mmol/L compared with 4.0 to 5.5 mmol/L. Risk for ESRD was elevated at S(K) < or = 4 mmol/L in S(K) categorical models. Only the composite of cardiovascular events or death as an outcome was associated with higher S(K) (> or = 5.5). CONCLUSIONS: Although clinical practice usually emphasizes greater attention to elevated S(K) in the setting of CKD, our results suggest that patients who have CKD and low or even low-normal S(K) are at higher risk for dying than those with mild to moderate hyperkalemia. PMID- 20203170 TI - Widespread enzymatic correction of CNS tissues by a single intracerebral injection of therapeutic lentiviral vector in leukodystrophy mouse models. AB - Leukodystrophies are rare diseases caused by defects in the genes coding for lysosomal enzymes that degrade several glycosphingolipids. Gene therapy for leukodystrophies requires efficient distribution of the missing enzymes in CNS tissues to prevent demyelination and neurodegeneration. In this work, we targeted the external capsule (EC), a white matter region enriched in neuronal projections, with the aim of obtaining maximal protein distribution from a single injection site. We used bidirectional (bd) lentiviral vectors (LV) (bdLV) to ensure coordinate expression of a therapeutic gene (beta-galactocerebrosidase, GALC; arylsulfatase A, ARSA) and of a reporter gene, thus monitoring simultaneously transgene distribution and enzyme reconstitution. A single EC injection of bdLV.GALC in early symptomatic twitcher mice (a murine model of globoid cell leukodystrophy) resulted in rapid and robust expression of a functional GALC protein in the telencephalon, cerebellum, brainstem and spinal cord. This led to global rescue of enzymatic activity, significant reduction of tissue storage and decrease of activated astroglia and microglia. Widespread protein distribution and complete metabolic correction were also observed after EC injection of bdLV.ARSA in a mouse model of metachromatic leukodystrophy. Our data indicated axonal transport, distribution through cerebrospinal fluid flow and cross-correction as the mechanisms contributing to widespread bioavailability of GALC and ARSA proteins in CNS tissues. LV-mediated gene delivery of lysosomal enzymes by targeting highly interconnected CNS regions is a potentially effective strategy that, combined with a treatment able to target the PNS and peripheral organs, may provide significant therapeutic benefit to patients affected by leukodystrophies. PMID- 20203171 TI - Elevated expression of MeCP2 in cardiac and skeletal tissues is detrimental for normal development. AB - MeCP2 plays a critical role in interpreting epigenetic signatures that command chromatin conformation and regulation of gene transcription. In spite of MeCP2's ubiquitous expression, its functions have always been considered in the context of brain physiology. In this study, we demonstrate that alterations of the normal pattern of expression of MeCP2 in cardiac and skeletal tissues are detrimental for normal development. Overexpression of MeCP2 in the mouse heart leads to embryonic lethality with cardiac septum hypertrophy and dysregulated expression of MeCP2 in skeletal tissue produces severe malformations. We further show that MeCP2's expression in the heart is developmentally regulated; further suggesting that it plays a key role in regulating transcriptional programs in non-neural tissues. PMID- 20203172 TI - Chemoradiation in pancreatic adenocarcinoma: a literature review. AB - Adenocarcinoma of the exocrine pancreas has an annual incidence of 7,400 cases in the U.K. In comparison with other common cancers of solid organs, namely, breast, colorectal, and prostate cancer, pancreatic cancer has a high morbidity and mortality. Radical resection is possible in only 15%-20% of patients, and only 3% 4% of all patients presenting with this condition achieve long-term control and cure. Various strategies in the form of neoadjuvant and adjuvant treatment have been employed over the years to improve outcome, with limited success. Systemic chemotherapy remains the gold standard in the metastatic setting in good performance status patients, and adjuvant chemotherapy after resection of localized and locally advanced cancer has been found to improve outcome. The role of radiotherapy, however, remains controversial and is an area that merits further investigation in well-conducted multicenter trials at various stages of the disease in combination with systemic agents and exploiting recent advances in the delivery of radiotherapy. In this article, we review the published literature on the use of chemoradiation as a modality in various stages of pancreatic adenocarcinoma and highlight areas that future trials in this field should target for a way forward in this malignancy. PMID- 20203173 TI - Continuous Sunitinib treatment in patients with advanced hepatocellular carcinoma: a Swiss Group for Clinical Cancer Research (SAKK) and Swiss Association for the Study of the Liver (SASL) multicenter phase II trial (SAKK 77/06). AB - BACKGROUND: Sunitinib (SU) is a multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activity. The objective of this trial was to demonstrate antitumor activity of continuous SU treatment in patients with hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Key eligibility criteria included unresectable or metastatic HCC, no prior systemic anticancer treatment, measurable disease, and Child-Pugh class A or mild Child-Pugh class B liver dysfunction. Patients received 37.5 mg SU daily until progression or unacceptable toxicity. The primary endpoint was progression-free survival at 12 weeks (PFS12). RESULTS: Forty-five patients were enrolled. The median age was 63 years; 89% had Child-Pugh class A disease and 47% had distant metastases. PFS12 was rated successful in 15 patients (33%; 95% confidence interval, 20%-47%). Over the whole trial period, one complete response and a 40% rate of stable disease as the best response were achieved. The median PFS duration, disease stabilization duration, time to progression, and overall survival time were 1.5, 2.9, 1.5, and 9.3 months, respectively. Grade 3 and 4 adverse events were infrequent. None of the 33 deaths were considered drug related. CONCLUSION: Continuous SU treatment with 37.5 mg daily is feasible and has moderate activity in patients with advanced HCC and mild to moderately impaired liver dysfunction. Under this trial design (>13 PFS12 successes), the therapy is considered promising. This is the first trial describing the clinical effects of continuous dosing of SU in HCC patients on a schedule that is used in an ongoing, randomized, phase III trial in comparison with the current treatment standard, sorafenib (ClinicalTrials.gov identifier, NCT00699374). PMID- 20203174 TI - Predicting response to treatment in gastroesophageal junction adenocarcinomas: combining clinical, imaging, and molecular biomarkers. AB - The incidence of adenocarcinomas of the gastroesophageal junction (GEJ) is rapidly rising, and even in early-stage locoregional confined disease the 5-year survival rate rarely exceeds 25%-35%. Randomized trials and meta-analyses have demonstrated a benefit with neoadjuvant or perioperative chemotherapy and with neoadjuvant chemoradiotherapy. However, the optimal approach in individual patients is not clear and remains controversial. A consistent finding is that patients who have a histopathological response to neoadjuvant therapy are more likely to receive a survival benefit. These clinical data provide a strong argument for the urgent development of methods to predict histopathological response to neoadjuvant therapies for GEJ adenocarcinoma. Published data demonstrate that clinicopathological features (tumor location), imaging (fluorodeoxyglucose-positron emission tomography "metabolic response"), and tissue/molecular biomarkers may all have a predictive value for neoadjuvant therapies. However, it is uncertain from published data whether or not they will be useful for clinical decision making in individual patients. Existing candidate biomarkers need to be properly qualified and validated and novel biomarkers are required; and an optimal approach should involve the combination and integration of clinical, imaging, and molecular biomarkers. This review presents the evidence base and discusses novel experimental approaches for the combination of biomarker modalities to allow optimization of an individualized treatment approach in GEJ adenocarcinoma patients that may be relevant to other tumor types as well. PMID- 20203175 TI - Ubiquitination acutely regulates presynaptic neurotransmitter release in mammalian neurons. AB - The ubiquitin proteasome system (UPS) plays a crucial role in modulating synaptic physiology both presynaptically and postsynaptically, but the regulatory mechanisms remain obscure. To determine acute effects of proteasome inhibition on neurotransmission, we performed whole-cell voltage-clamp recordings from cultured rodent hippocampal neurons. We find that proteasome inhibitors induce a strikingly fast, severalfold increase in the frequency of both miniature (mini) and spontaneous synaptic currents at excitatory and inhibitory synapses. The lack of change in mini amplitude and kinetics indicates a presynaptic site of action. This effect does not depend on increased levels of presynaptic proteins, previously suggested as proteasomal targets. Furthermore, blockade of the UPS using E1-activating enzyme inhibitors also increases mini frequency, demonstrating that accumulation of ubiquitinated proteins is not required. Overall, these data suggest that the UPS not only orchestrates protein turnover, but also dynamically regulates the activity state of presynaptic proteins, thus crucially shaping synaptic transmission. PMID- 20203176 TI - Striatal activity during intentional switching depends on pattern stability. AB - The theoretical framework of coordination dynamics posits complementary neural mechanisms to maintain complex behavioral patterns under circumstances that may render them unstable and to voluntarily switch between behaviors if changing internal or external conditions so demand. A candidate neural structure known to play a role in both the selection and maintenance of intentional behavior is the basal ganglia. Here, we use functional magnetic resonance imaging to explore the role of basal ganglia in intentional switching between bimanual coordination patterns that are known to differ in their stability as a function of movement rate. Key measures of pattern dynamics and switching were used to map behavior onto the associated neural circuitry to determine the relation between specific behavioral variables and activated brain areas. Results show that putamen activity is highly sensitive to pattern stability: greater activity was observed in bilateral putamen when subjects were required to switch from a more to a less stable pattern than vice versa. Since putamen activity correlated with pattern stability both before and during the switching process, its role may be to select desired actions and inhibit competing ones through parametric modulation of the intrinsic dynamics. Though compatible with recent computational models of basal ganglia function, our results further suggest that pattern stability determines how the basal ganglia efficiently and successfully select among response alternatives. PMID- 20203177 TI - Calcium and cyclic AMP promote axonal regeneration in Caenorhabditis elegans and require DLK-1 kinase. AB - Axons of adult Caenorhabditis elegans neurons undergo robust regenerative growth after laser axotomy. Here we show that axotomy of PLM sensory neurons triggers axonal calcium waves whose amplitude correlates with the extent of regeneration. Genetic elevation of Ca(2+) or cAMP accelerates formation of a growth cone from the injured axon. Elevated Ca(2+) or cAMP also facilitates apparent fusion of axonal fragments and promotes branching to postsynaptic targets. Conversely, inhibition of voltage-gated calcium channels or calcium release from internal stores reduces regenerative growth. We identify the fusogen EFF-1 as critical for axon fragment fusion and the basic leucine zipper domain (bZip) protein CREB (cAMP response element-binding protein) as a key effector for branching. The effects of elevated Ca(2+) or cAMP on regrowth require the MAPKKK (mitogen activated protein kinase kinase kinase) DLK-1. Increased cAMP signaling can partly bypass the requirement for the bZip protein CEBP-1, a downstream factor of the DLK-1 kinase cascade. These findings reveal the relationship between Ca(2+)/cAMP signaling and the DLK-1 MAPK (mitogen-activated protein kinase) cascade in regeneration. PMID- 20203178 TI - Phosphorylation at S87 is enhanced in synucleinopathies, inhibits alpha-synuclein oligomerization, and influences synuclein-membrane interactions. AB - Increasing evidence suggests that phosphorylation may play an important role in the oligomerization, fibrillogenesis, Lewy body (LB) formation, and neurotoxicity of alpha-synuclein (alpha-syn) in Parkinson disease. Herein we demonstrate that alpha-syn is phosphorylated at S87 in vivo and within LBs. The levels of S87-P are increased in brains of transgenic (TG) models of synucleinopathies and human brains from Alzheimer disease (AD), LB disease (LBD), and multiple system atrophy (MSA) patients. Using antibodies against phosphorylated alpha-syn (S129-P and S87 P), a significant amount of immunoreactivity was detected in the membrane in the LBD, MSA, and AD cases but not in normal controls. In brain homogenates from diseased human brains and TG animals, the majority of S87-P alpha-syn was detected in the membrane fractions. A battery of biophysical methods were used to dissect the effect of S87 phosphorylation on the structure, aggregation, and membrane-binding properties of monomeric alpha-syn. These studies demonstrated that phosphorylation at S87 expands the structure of alpha-syn, increases its conformational flexibility, and blocks its fibrillization in vitro. Furthermore, phosphorylation at S87, but not S129, results in significant reduction of alpha syn binding to membranes. Together, our findings provide novel mechanistic insight into the role of phosphorylation at S87 and S129 in the pathogenesis of synucleinopathies and potential roles of phosphorylation in alpha-syn normal biology. PMID- 20203179 TI - Variability of visual responses of superior colliculus neurons depends on stimulus velocity. AB - Visually responding neurons in the superficial, retinorecipient layers of the cat superior colliculus receive input from two primarily parallel information processing channels, Y and W, which is reflected in their velocity response profiles. We quantified the time-dependent variability of responses of these neurons to stimuli moving with different velocities by Fano factor (FF) calculated in discrete time windows. The FF for cells responding to low-velocity stimuli, thus receiving W inputs, increased with the increase in the firing rate. In contrast, the dynamics of activity of the cells responding to fast moving stimuli, processed by Y pathway, correlated negatively with FF whether the response was excitatory or suppressive. These observations were tested against several types of surrogate data. Whereas Poisson description failed to reproduce the variability of all collicular responses, the inclusion of secondary structure to the generating point process recovered most of the observed features of responses to fast moving stimuli. Neither model could reproduce the variability of low-velocity responses, which suggests that, in this case, more complex time dependencies need to be taken into account. Our results indicate that Y and W channels may differ in reliability of responses to visual stimulation. Apart from previously reported morphological and physiological differences of the cells belonging to Y and W channels, this is a new feature distinguishing these two pathways. PMID- 20203181 TI - Fenretinide promotes functional recovery and tissue protection after spinal cord contusion injury in mice. AB - The inflammatory response is thought to contribute to secondary damage after spinal cord injury (SCI). Polyunsaturated fatty acids (PUFAs) play an important role in the onset and resolution of inflammation. Arachidonic acid (AA), an omega 6 PUFA, contributes to the initiation of inflammatory responses, whereas docosahexaenoic acid (DHA), an omega-3 PUFA, has antiinflammatory effects. Therefore, decreasing AA and increasing DHA levels after SCI might be expected to attenuate inflammation after SCI and promote tissue protection and functional recovery. We show here that daily oral administration of fenretinide after spinal cord contusion injury led to a significant decrease in AA and an increase in DHA levels in plasma and injured spinal cord tissue. This was accompanied by a significant reduction in tissue damage and improvement in locomotor recovery. Fenretinide also reduced the expression of proinflammatory genes and the levels of oxidative stress markers after SCI. In addition, in vitro studies demonstrated that fenretinide reduced TNF-alpha (tumor necrosis factor-alpha) expression by reactive microglia. These results demonstrate that fenretinide treatment after SCI can reduce inflammation and tissue damage in the spinal cord and improve locomotor recovery. These beneficial effects may be mediated via the ability of fenretinide to modulate PUFA homeostasis. Since fenretinide is currently in clinical trials for the treatment of cancers, this drug might be a good candidate for the treatment of acute SCI in humans. PMID- 20203180 TI - Striatal prediction error modulates cortical coupling. AB - Both perceptual inference and motor responses are shaped by learned probabilities. For example, stimulus-induced responses in sensory cortices and preparatory activity in premotor cortex reflect how (un)expected a stimulus is. This is in accordance with predictive coding accounts of brain function, which posit a fundamental role of prediction errors for learning and adaptive behavior. We used functional magnetic resonance imaging and recent advances in computational modeling to investigate how (failures of) learned predictions about visual stimuli influence subsequent motor responses. Healthy volunteers discriminated visual stimuli that were differentially predicted by auditory cues. Critically, the predictive strengths of cues varied over time, requiring subjects to continuously update estimates of stimulus probabilities. This online inference, modeled using a hierarchical Bayesian learner, was reflected behaviorally: speed and accuracy of motor responses increased significantly with predictability of the stimuli. We used nonlinear dynamic causal modeling to demonstrate that striatal prediction errors are used to tune functional coupling in cortical networks during learning. Specifically, the degree of striatal trial by-trial prediction error activity controls the efficacy of visuomotor connections and thus the influence of surprising stimuli on premotor activity. This finding substantially advances our understanding of striatal function and provides direct empirical evidence for formal learning theories that posit a central role for prediction error-dependent plasticity. PMID- 20203182 TI - Cooperation and competition among frontal eye field neurons during visual target selection. AB - The role of spike rate versus timing codes in visual target selection is unclear. We simultaneously recorded activity from multiple frontal eye field neurons and asked whether they interacted to select targets from distractors during visual search. When both neurons in a pair selected the target and had overlapping receptive fields (RFs), they cooperated more than when one or neither neuron in the pair selected the target, measured by positive spike timing correlations using joint peristimulus time histogram analysis. The amount of cooperation depended on the location of the search target: it was higher when the target was inside both neurons' RFs than when it was inside one RF but not the other, or outside both RFs. Elevated spike timing coincidences occurred at the time of attentional selection of the target as measured by average modulation of discharge rates. We observed competition among neurons with spatially non overlapping RFs, measured by negative spike timing correlations. Thus, we provide evidence for dynamic and task-dependent cooperation and competition among frontal eye field neurons during visual target selection. PMID- 20203183 TI - Phosducin regulates transmission at the photoreceptor-to-ON-bipolar cell synapse. AB - The rate of synaptic transmission between photoreceptors and bipolar cells has been long known to depend on conditions of ambient illumination. However, the molecular mechanisms that mediate and regulate transmission at this ribbon synapse are poorly understood. We conducted electroretinographic recordings from dark- and light-adapted mice lacking the abundant photoreceptor-specific protein phosducin and found that the ON-bipolar cell responses in these animals have a reduced light sensitivity in the dark-adapted state. Additional desensitization of their responses, normally caused by steady background illumination, was also diminished compared with wild-type animals. This effect was observed in both rod- and cone-driven pathways, with the latter affected to a larger degree. The underlying mechanism is likely to be photoreceptor specific because phosducin is not expressed in other retina neurons and transgenic expression of phosducin in rods of phosducin knock-out mice rescued the rod-specific phenotype. The underlying mechanism functions downstream from the phototransduction cascade, as evident from the sensitivity of phototransduction in phosducin knock-out rods being affected to a much lesser degree than b-wave responses. These data indicate that a major regulatory component responsible for setting the sensitivity of signal transmission between photoreceptors and ON-bipolar cells is confined to photoreceptors and that phosducin participates in the underlying molecular mechanism. PMID- 20203184 TI - MicroRNA-183 family members regulate sensorineural fates in the inner ear. AB - Members of the microRNA (miRNA) 183 family (miR-183, miR-96, and miR-182) are expressed abundantly in specific sensory cell types in the eye, nose, and inner ear. In the inner ear, expression is robust in the mechanosensory hair cells and weak in the associated statoacoustic ganglion (SAG) neurons; both cell types can share a common lineage during development. Recently, dominant-progressive hearing loss in humans and mice was linked to mutations in the seed region of miR-96, with associated defects in both development and maintenance of hair cells in the mutant mice. To understand how the entire triplet functions in the development of mechanosensory hair cells and neurons of the inner ear, we manipulated the levels of these miRNAs in zebrafish embryos using synthesized miRNAs and antisense morpholino oligonucleotides (MOs). Overexpression of miR-96 or miR-182 induces duplicated otocysts, ectopic or expanded sensory patches, and extra hair cells, whereas morphogenesis of the SAG is adversely affected to different degrees. In contrast, knockdown of miR-183, miR-96, and miR-182 causes reduced numbers of hair cells in the inner ear, smaller SAGs, defects in semicircular canals, and abnormal neuromasts on the posterior lateral line. However, the prosensory region of the posterior macula, where the number of hair cells is reduced by approximately 50%, is not significantly impaired. Our findings suggest both distinct and common roles for the three miRNAs in cell-fate determination in the inner ear, and these principles might apply to development of other sensory organs. PMID- 20203185 TI - Opposing effects of contextual surround in human early visual cortex revealed by functional magnetic resonance imaging with continuously modulated visual stimuli. AB - Spatial context in vision has profound effects on neural responses and perception. Recent animal studies suggest that the effect of surround on a central stimulus can dramatically change its character depending on the contrast of the center stimulus, but such a drastic change has not been demonstrated in the human visual cortex. To examine the dependency of the surround effect on the contrast of the center stimulus, we conducted an functional magnetic resonance imaging experiment by using a low or a high contrast in the center region while the surround contrast was sinusoidally modulated between the two contrasts. We found that the blood oxygen level-dependent response in human V1 corresponding to the center region was differentially modulated by the surround contrast, depending crucially on the center contrast: whereas a suppressive effect was observed in conditions in which the center contrast was high, a facilitative effect was seen in conditions where the center contrast was low. PMID- 20203186 TI - Nurture versus nature: long-term impact of forced right-handedness on structure of pericentral cortex and basal ganglia. AB - Does a conflict between inborn motor preferences and educational standards during childhood impact the structure of the adult human brain? To examine this issue, we acquired high-resolution T1-weighted magnetic resonance scans of the whole brain in adult "converted" left-handers who had been forced as children to become dextral writers. Analysis of sulcal surfaces revealed that consistent right- and left-handers showed an interhemispheric asymmetry in the surface area of the central sulcus with a greater surface contralateral to the dominant hand. This pattern was reversed in the converted group who showed a larger surface of the central sulcus in their left, nondominant hemisphere, indicating plasticity of the primary sensorimotor cortex caused by forced use of the nondominant hand. Voxel-based morphometry showed a reduction of gray matter volume in the middle part of the left putamen in converted left-handers relative to both consistently handed groups. A similar trend was found in the right putamen. Converted subjects with at least one left-handed first-degree relative showed a correlation between the acquired right-hand advantage for writing and the structural changes in putamen and pericentral cortex. Our results show that a specific environmental challenge during childhood can shape the macroscopic structure of the human basal ganglia. The smaller than normal putaminal volume differs markedly from previously reported enlargement of cortical gray matter associated with skill acquisition. This indicates a differential response of the basal ganglia to early environmental challenges, possibly related to processes of pruning during motor development. PMID- 20203187 TI - micro-Opioid receptor endocytosis prevents adaptations in ventral tegmental area GABA transmission induced during naloxone-precipitated morphine withdrawal. AB - Chronic morphine drives adaptations in synaptic transmission thought to underlie opiate dependence. Here we examine the role of micro-opioid receptor (MOR) trafficking in one of these adaptations, specifically, changes in GABA transmission in the ventral tegmental area (VTA). To address this question, we used a knock-in mouse, RMOR (for recycling MOR), in which genetic change in the MOR promotes morphine-induced receptor desensitization and endocytosis in GABA interneurons of the VTA. In wild-type mice (postnatal days 23-28) chronic morphine (10 mg/kg, s.c., twice daily for 5 d), induced a cAMP-dependent increase in the probability of GABA release onto VTA dopamine neurons. The increased GABA release frequency correlated with physical dependence on morphine measured by counting somatic signs of morphine withdrawal, such as, tremors, jumps, rears, wet-dog shakes, and grooming behavior precipitated by subcutaneous administration of naloxone (NLX) (2 mg/kg). This adaptation in GABA release was prevented in RMOR mice given the same morphine treatment, implicating MOR trafficking in this morphine-induced change in plasticity. Importantly, treatment with the cAMP activity inhibitor rp-cAMPS [(R)-adenosine, cyclic 3',5' (hydrogenphosphorothioate) triethylammonium] (50 ng/0.5 microl), directly to the VTA, attenuated somatic withdrawal signs to systemic morphine produced by intra VTA NLX (500 ng/0.5 microl), directly tying enhanced cAMP-driven GABA release to naloxone-precipitated morphine withdrawal in the VTA. PMID- 20203188 TI - Temporal sequence of attentional modulation in the lateral intraparietal area and middle temporal area during rapid covert shifts of attention. AB - In the visual system, spatial attention enhances sensory responses to stimuli at attended locations relative to unattended locations. Which brain structures direct the locus of attention, and how is attentional modulation delivered to structures in the visual system? We trained monkeys on an attention-switch task designed to precisely measure the onset of attentional modulation during rapid shifts of spatial attention. Here we show that attentional modulation appears substantially earlier in the lateral intraparietal area (LIP) than in an anatomically connected lower visual area, the middle temporal area. This temporal sequence of attentional latencies demonstrates that endogenous changes of state can occur in higher visual areas before lower visual areas and satisfies a critical prediction of the hypothesis that LIP is a source of top-down attentional signals to early visual cortex. PMID- 20203189 TI - Training of working memory impacts structural connectivity. AB - Working memory is the limited capacity storage system involved in the maintenance and manipulation of information over short periods of time. Individual capacity of working memory is associated with the integrity of white matter in the frontoparietal regions. It is unknown to what extent the integrity of white matter underlying the working memory system is plastic. Using voxel-based analysis (VBA) of fractional anisotropy (FA) measures of fiber tracts, we investigated the effect of working memory training on structural connectivity in an interventional study. The amount of working memory training correlated with increased FA in the white matter regions adjacent to the intraparietal sulcus and the anterior part of the body of the corpus callosum after training. These results showed training-induced plasticity in regions that are thought to be critical in working memory. As changes in myelination lead to FA changes in diffusion tensor imaging, a possible mechanism for the observed FA change is increased myelination after training. Observed structural changes may underlie previously reported improvement of working memory capacity, improvement of other cognitive functions, and altered functional activity following working memory training. PMID- 20203190 TI - Critical period for inhibitory plasticity in rodent binocular V1. AB - Postnatal cortical circuit development is characterized by windows of heightened plasticity that contribute to the acquisition of mature connectivity and function. What drives the transition between different critical plasticity windows is not known. Here we show that a switch in sign of inhibitory plasticity correlates with the reported transition between the precritical period (pre-CP) and the critical period (CP) for ocular dominance plasticity (ODP). In layer 4 of binocular visual cortex (V1b), depression of inhibitory synapses onto pyramidal neurons is induced when rats are monocularly deprived for 2 d at the end of the third postnatal week (pre-CP), whereas potentiation is induced if the monocular deprivation is started in the fourth postnatal week (CP). The magnitude of potentiation increases with deprivations started close to the peak of the CP for ODP. The direction of inhibitory plasticity depends on the differential manipulation of circuits activated by the two eyes. During development, these two forms of plasticity shift the balance between excitation and inhibition of the circuit in opposite directions, whereas the excitatory synaptic drive remains unaffected. Inhibitory plasticity is thus fundamental in modulating cortical circuit refinement and might be one of the mechanisms promoting ocular dominance shifts. PMID- 20203191 TI - Functional organization of vestibular commissural connections in frog. AB - Central vestibular neurons receive substantial inputs from the contralateral labyrinth through inhibitory and excitatory brainstem commissural pathways. The functional organization of these pathways was studied by a multi-methodological approach in isolated frog whole brains. Retrogradely labeled vestibular commissural neurons were primarily located in the superior vestibular nucleus in rhombomeres 2/3 and the medial and descending vestibular nucleus in rhombomeres 5 7. Restricted projections to contralateral vestibular areas, without collaterals to other classical vestibular targets, indicate that vestibular commissural neurons form a feedforward push-pull circuitry. Electrical stimulation of the contralateral coplanar semicircular canal nerve evoked in canal-related second order vestibular neurons (2 degrees VN) commissural IPSPs (approximately 70%) and EPSPs (approximately 30%) with mainly (approximately 70%) disynaptic onset latencies. The dynamics of commissural responses to electrical pulse trains suggests mediation predominantly by tonic vestibular neurons that activate in all tonic 2 degrees VN large-amplitude IPSPs with a reversal potential of -74 mV. In contrast, phasic 2 degrees VN exhibited either nonreversible, small-amplitude IPSPs (approximately 40%) of likely dendritic origin or large-amplitude commissural EPSPs (approximately 60%). IPSPs with disynaptic onset latencies were exclusively GABAergic (mainly GABA(A) receptor-mediated) but not glycinergic, compatible with the presence of GABA-immunopositive (approximately 20%) and the absence of glycine-immunopositive vestibular commissural neurons. In contrast, IPSPs with longer, oligosynaptic onset latencies were GABAergic and glycinergic, indicating that both pharmacological types of local inhibitory neurons were activated by excitatory commissural fibers. Conservation of major morpho physiological and pharmacological features of the vestibular commissural pathway suggests that this phylogenetically old circuitry plays an essential role for the processing of bilateral angular head acceleration signals in vertebrates. PMID- 20203192 TI - Amyloid-beta aggregates cause alterations of astrocytic metabolic phenotype: impact on neuronal viability. AB - Amyloid-beta (Abeta) peptides play a key role in the pathogenesis of Alzheimer's disease and exert various toxic effects on neurons; however, relatively little is known about their influence on glial cells. Astrocytes play a pivotal role in brain homeostasis, contributing to the regulation of local energy metabolism and oxidative stress defense, two aspects of importance for neuronal viability and function. In the present study, we explored the effects of Abeta peptides on glucose metabolism in cultured astrocytes. Following Abeta(25-35) exposure, we observed an increase in glucose uptake and its various metabolic fates, i.e., glycolysis (coupled to lactate release), tricarboxylic acid cycle, pentose phosphate pathway, and incorporation into glycogen. Abeta increased hydrogen peroxide production as well as glutathione release into the extracellular space without affecting intracellular glutathione content. A causal link between the effects of Abeta on glucose metabolism and its aggregation and internalization into astrocytes through binding to members of the class A scavenger receptor family could be demonstrated. Using astrocyte-neuron cocultures, we observed that the overall modifications of astrocyte metabolism induced by Abeta impair neuronal viability. The effects of the Abeta(25-35) fragment were reproduced by Abeta(1-42) but not by Abeta(1-40). Finally, the phosphoinositide 3-kinase (PI3 kinase) pathway appears to be crucial in these events since both the changes in glucose utilization and the decrease in neuronal viability are prevented by LY294002, a PI3-kinase inhibitor. This set of observations indicates that Abeta aggregation and internalization into astrocytes profoundly alter their metabolic phenotype with deleterious consequences for neuronal viability. PMID- 20203193 TI - Neurons in anterior cingulate cortex multiplex information about reward and action. AB - The dorsal anterior cingulate cortex (dACC) is thought to play a critical role in forming associations between rewards and actions. Currently available physiological data, however, remain inconclusive regarding the question of whether dACC neurons carry information linking particular actions to reward or, instead, encode abstract reward information independent of specific actions. Here we show that firing rates of a majority of dACC neurons in a population studied in an eight-option variably rewarded choice task were sensitive to both saccade direction and reward value. Furthermore, the influences of reward and saccade direction on neuronal activity were approximately equal in magnitude over the range of rewards tested and were statistically independent. Our results indicate that dACC neurons multiplex information about both reward and action, endorsing the idea that this area links motivational outcomes to behavior and undermining the notion that its neurons solely contribute to reward processing in the abstract. PMID- 20203194 TI - Type 3 deiodinase, a thyroid-hormone-inactivating enzyme, controls survival and maturation of cone photoreceptors. AB - Maturation of the mammalian nervous system requires adequate provision of thyroid hormone and mechanisms that enhance tissue responses to the hormone. Here, we report that the development of cones, the photoreceptors for daylight and color vision, requires protection from thyroid hormone by type 3 deiodinase, a thyroid hormone-inactivating enzyme. Type 3 deiodinase, encoded by Dio3, is expressed in the immature mouse retina. In Dio3(-/-) mice, approximately 80% of cones are lost through neonatal cell death. Cones that express opsin photopigments for response to both short (S) and medium-long (M) wavelength light are lost. Rod photoreceptors, which mediate dim light vision, remain essentially intact. Excessive thyroid hormone in wild-type pups also eliminates cones. Cone loss is mediated by cone-specific thyroid hormone receptor beta2 (TRbeta2) as deletion of TRbeta2 rescues cones in Dio3(-/-) mice. However, rescued cones respond to short but not longer wavelength light because TRbeta2 under moderate hormonal stimulation normally induces M opsin and controls the patterning of M and S opsins over the retina. The results suggest that type 3 deiodinase limits hormonal exposure of the cone to levels that safeguard both cone survival and the patterning of opsins that is required for cone function. PMID- 20203195 TI - Differential plasticity of the GABAergic and glycinergic synaptic transmission to rat lumbar motoneurons after spinal cord injury. AB - Maturation of inhibitory postsynaptic transmission onto motoneurons in the rat occurs during the perinatal period, a time window during which pathways arising from the brainstem reach the lumbar enlargement of the spinal cord. There is a developmental switch in miniature IPSCs (mIPSCs) from predominantly long-duration GABAergic to short-duration glycinergic events. We investigated the effects of a complete neonatal [postnatal day 0 (P0)] spinal cord transection (SCT) on the expression of Glycine and GABA(A) receptor subunits (GlyR and GABA(A)R subunits) in lumbar motoneurons. In control rats, the density of GlyR increased from P1 to P7 to reach a plateau, whereas that of GABA(A)R subunits dropped during the same period. In P7 animals with neonatal SCT (SCT-P7), the GlyR densities were unchanged compared with controls of the same age, while the developmental downregulation of GABA(A)R was prevented. Whole-cell patch-clamp recordings of mIPSCs performed in lumbar motoneurons at P7 revealed that the decay time constant of miniature IPSCs and the proportion of GABAergic events significantly increased after SCT. After daily injections of the 5-HT(2)R agonist DOI, GABA(A)R immunolabeling on SCT-P7 motoneurons dropped down to values reported in control P7, while GlyR labeling remained stable. A SCT made at P5 significantly upregulated the expression of GABA(A)R 1 week later with little, if any, influence on GlyR. We conclude that the plasticity of GlyR is independent of supraspinal influences whereas that of GABA(A)R is markedly influenced by descending pathways, in particular serotoninergic projections. PMID- 20203196 TI - Audiovisual functional magnetic resonance imaging adaptation reveals multisensory integration effects in object-related sensory cortices. AB - Information integration across different sensory modalities contributes to object recognition, the generation of associations and long-term memory representations. Here, we used functional magnetic resonance imaging adaptation to investigate the presence of sensory integrative effects at cortical levels as early as nonprimary auditory and extrastriate visual cortices, which are implicated in intermediate stages of object processing. Stimulation consisted of an adapting audiovisual stimulus S(1) and a subsequent stimulus S(2) from the same basic-level category (e.g., cat). The stimuli were carefully balanced with respect to stimulus complexity and semantic congruency and presented in four experimental conditions: (1) the same image and vocalization for S(1) and S(2), (2) the same image and a different vocalization, (3) different images and the same vocalization, or (4) different images and vocalizations. This two-by-two factorial design allowed us to assess the contributions of auditory and visual stimulus repetitions and changes in a statistically orthogonal manner. Responses in visual regions of right fusiform gyrus and right lateral occipital cortex were reduced for repeated visual stimuli (repetition suppression). Surprisingly, left lateral occipital cortex showed stronger responses to repeated auditory stimuli (repetition enhancement). Similarly, auditory regions of interest of the right middle superior temporal gyrus and sulcus exhibited repetition suppression to auditory repetitions and repetition enhancement to visual repetitions. Our findings of crossmodal repetition-related effects in cortices of the respective other sensory modality add to the emerging view that in human subjects sensory integrative mechanisms operate on earlier cortical processing levels than previously assumed. PMID- 20203197 TI - Neuropeptide Y suppresses anorexigenic output from the ventromedial nucleus of the hypothalamus. AB - Output from the hypothalamic ventromedial nucleus (VMN) is anorexigenic and is supported by the excitatory actions of leptin. The VMN is also highly sensitive to the orexigenic actions of Neuropeptide Y (NPY). We report that NPY robustly inhibits VMN neurons by hyperpolarizing them and decreasing their ability to fire action potentials. This action was mediated by Y(1) receptors coupled to the activation of GIRKs (G-protein-coupled inwardly rectifying potassium channels). Approximately 80% of VMN neurons expressing leptin receptors were sensitive to the actions of NPY, whereas 75% of NPY-sensitive neurons in VMN also responded to glucose by being uniformly inhibited by elevations in glucose. Interestingly, only approximately 36% of NPY-sensitive, leptin receptor b-expressing neurons were also glucosensitive. We suggest that NPY inhibits VMN neurons that are excited by leptin, thereby arresting the anorexigenic tone exerted by VMN neurons. The results further suggest a dynamic interplay between anorexigenic and orexigenic neuromodulators within the VMN to directly affect energy balance. PMID- 20203198 TI - A nonlinear relationship between cerebral serotonin transporter and 5-HT(2A) receptor binding: an in vivo molecular imaging study in humans. AB - Serotonergic neurotransmission is involved in the regulation of physiological functions such as mood, sleep, memory, and appetite. Within the serotonin transmitter system, both the postsynaptically located serotonin 2A (5-HT(2A)) receptor and the presynaptic serotonin transporter (SERT) are sensitive to chronic changes in cerebral 5-HT levels. Additionally, experimental studies suggest that alterations in either the 5-HT(2A) receptor or SERT level can affect the protein level of the counterpart. The aim of this study was to explore the covariation between cerebral 5-HT(2A) receptor and SERT in vivo in the same healthy human subjects. Fifty-six healthy human subjects with a mean age of 36 +/ 19 years were investigated. The SERT binding was imaged with [(11)C]3-amino-4-(2 dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB) and 5-HT(2A) receptor binding with [(18)F]altanserin using positron emission tomography. Within each individual, a regional intercorrelation for the various brain regions was seen with both markers, most notably for 5-HT(2A) receptor binding. An inverted U shaped relationship between the 5-HT(2A) receptor and the SERT binding was identified. The observed regional intercorrelation for both the 5-HT(2A) receptor and the SERT cerebral binding suggests that, within the single individual, each marker has a set point adjusted through a common regulator. A quadratic relationship between the two markers is consistent with data from experimental studies of the effect on SERT and 5-HT(2A) receptor binding of chronic changes in 5-HT levels. That is, the observed association between the 5-HT(2A) receptor and SERT binding could be driven by the projection output from the raphe nuclei, but other explanations are also at hand. PMID- 20203199 TI - Striatal muscarinic receptors promote activity dependence of dopamine transmission via distinct receptor subtypes on cholinergic interneurons in ventral versus dorsal striatum. AB - Striatal dopamine (DA) and acetylcholine (ACh) regulate motivated behaviors and striatal plasticity. Interactions between these neurotransmitters may be important, through synchronous changes in parent neuron activities and reciprocal presynaptic regulation of release. How DA signaling is regulated by striatal muscarinic receptors (mAChRs) is unresolved; contradictory reports indicate suppression or facilitation, implicating several mAChR subtypes on various neurons. We investigated whether mAChR regulation of DA signaling varies with presynaptic activity and identified the mAChRs responsible in sensorimotor- versus limbic-associated striatum. We detected DA in real time at carbon fiber microelectrodes in mouse striatal slices. Broad-spectrum mAChR agonists [oxotremorine-M, APET (arecaidine propargyl ester tosylate)] decreased DA release evoked by low-frequency stimuli (1-10 Hz, four pulses) but increased the sensitivity of DA release to presynaptic activity, even enhancing release by high frequencies (e.g., >25 Hz for four pulses). These bidirectional effects depended on ACh input to striatal nicotinic receptors (nAChRs) on DA axons but not GABA or glutamate input. In caudate-putamen (CPu), knock-out of M(2)- or M(4)-mAChRs (not M(5)) prevented mAChR control of DA, indicating that M(2)- and M(4)-mAChRs are required. In nucleus accumbens (NAc) core or shell, mAChR function was prevented in M(4)-knock-outs, but not M(2)- or M(5)-knock-outs. These data indicate that striatal mAChRs, by inhibiting ACh release from cholinergic interneurons and thus modifying nAChR activity, offer variable control of DA release probability that promotes how DA release reflects activation of dopaminergic axons. Furthermore, different coupling of striatal M(2)/M(4)-mAChRs to the control of DA release in CPu versus NAc suggests targets to influence DA/ACh function differentially between striatal domains. PMID- 20203200 TI - Distinct region-specific alpha-synuclein oligomers in A53T transgenic mice: implications for neurodegeneration. AB - Aggregation of alpha-synuclein (alpha-syn), a process that generates oligomeric intermediates, is a common pathological feature of several neurodegenerative disorders. Despite the potential importance of the oligomeric alpha-syn intermediates in neuron function, their biochemical properties and pathobiological functions in vivo remain vastly unknown. Here we used two dimensional analytical separation and an array of biochemical and cell-based assays to characterize alpha-syn oligomers that are present in the nervous system of A53T alpha-syn transgenic mice. The most prominent species identified were 53 A detergent-soluble oligomers, which preceded neurological symptom onset, and were found at equivalent amounts in regions containing alpha-syn inclusions as well as histologically unaffected regions. These oligomers were resistant to SDS, heat, and urea but were sensitive to proteinase-K digestion. Although the oligomers shared similar basic biochemical properties, those obtained from inclusion-bearing regions were prominently reactive to antibodies that recognize oxidized alpha-syn oligomers, significantly accelerated aggregation of alpha-syn in vitro, and caused primary cortical neuron degeneration. In contrast, oligomers obtained from non-inclusion-bearing regions were not toxic and delayed the in vitro formation of alpha-syn fibrils. These data indicate that specific conformations of alpha-syn oligomers are present in distinct brain regions of A53T alpha-syn transgenic mice. The contribution of these oligomers to the development of neuron dysfunction appears to be independent of their absolute quantities and basic biochemical properties but is dictated by the composition and conformation of the intermediates as well as unrecognized brain-region specific intrinsic factors. PMID- 20203201 TI - Impact of actin filament stabilization on adult hippocampal and olfactory bulb neurogenesis. AB - Rearrangement of the actin cytoskeleton is essential for dynamic cellular processes. Decreased actin turnover and rigidity of cytoskeletal structures have been associated with aging and cell death. Gelsolin is a Ca(2+)-activated actin severing protein that is widely expressed throughout the adult mammalian brain. Here, we used gelsolin-deficient (Gsn(-/-)) mice as a model system for actin filament stabilization. In Gsn(-/-) mice, emigration of newly generated cells from the subventricular zone into the olfactory bulb was slowed. In vitro, gelsolin deficiency did not affect proliferation or neuronal differentiation of adult neural progenitors cells (NPCs) but resulted in retarded migration. Surprisingly, hippocampal neurogenesis was robustly induced by gelsolin deficiency. The ability of NPCs to intrinsically sense excitatory activity and thereby implement coupling between network activity and neurogenesis has recently been established. Depolarization-induced [Ca(2+)](i) increases and exocytotic neurotransmitter release were enhanced in Gsn(-/-) synaptosomes. Importantly, treatment of Gsn(-/-) synaptosomes with mycotoxin cytochalasin D, which, like gelsolin, produces actin disassembly, decreased enhanced Ca(2+) influx and subsequent exocytotic norepinephrine release to wild-type levels. Similarly, depolarization-induced glutamate release from Gsn(-/-) brain slices was increased. Furthermore, increased hippocampal neurogenesis in Gsn(-/-) mice was associated with a special microenvironment characterized by enhanced density of perfused vessels, increased regional cerebral blood flow, and increased endothelial nitric oxide synthase (NOS-III) expression in hippocampus. Together, reduced filamentous actin turnover in presynaptic terminals causes increased Ca(2+) influx and, subsequently, elevated exocytotic neurotransmitter release acting on neural progenitors. Increased neurogenesis in Gsn(-/-) hippocampus is associated with a special vascular niche for neurogenesis. PMID- 20203202 TI - Reconstructing three-dimensional hand movements from noninvasive electroencephalographic signals. AB - It is generally thought that the signal-to-noise ratio, the bandwidth, and the information content of neural data acquired via noninvasive scalp electroencephalography (EEG) are insufficient to extract detailed information about natural, multijoint movements of the upper limb. Here, we challenge this assumption by continuously decoding three-dimensional (3D) hand velocity from neural data acquired from the scalp with 55-channel EEG during a 3D center-out reaching task. To preserve ecological validity, five subjects self-initiated reaches and self-selected targets. Eye movements were controlled so they would not confound the interpretation of the results. With only 34 sensors, the correlation between measured and reconstructed velocity profiles compared reasonably well to that reported by studies that decoded hand kinematics from neural activity acquired intracranially. We subsequently examined the individual contributions of EEG sensors to decoding to find substantial involvement of scalp areas over the sensorimotor cortex contralateral to the reaching hand. Using standardized low-resolution brain electromagnetic tomography (sLORETA), we identified distributed current density sources related to hand velocity in the contralateral precentral gyrus, postcentral gyrus, and inferior parietal lobule. Furthermore, we discovered that movement variability negatively correlated with decoding accuracy, a finding to consider during the development of brain-computer interface systems. Overall, the ability to continuously decode 3D hand velocity from EEG during natural, center-out reaching holds promise for the furtherance of noninvasive neuromotor prostheses for movement-impaired individuals. PMID- 20203203 TI - Neocortical activation of the hippocampus during sleep in infant rats. AB - We recently reported that the majority of hippocampal neurons in newborn rats increase their activity in association with myoclonic twitches, which are indicative of active sleep. Because spindle bursts in the developing somatosensory neocortex occur in response to sensory feedback from myoclonic twitching, we hypothesized that the state-dependent activity of the newborn hippocampus arises from sensory feedback that sequentially activates the neocortex and then hippocampus, constituting an early form of neocortical hippocampal communication. Here, in unanesthetized 5- to 6-d-old rats, we test this hypothesis by recording simultaneously from forelimb and barrel regions of somatosensory neocortex and dorsal hippocampus during periods of spontaneous sleep and wakefulness and in response to peripheral stimulation. Myoclonic twitches were consistently followed by neocortical spindle bursts, which were in turn consistently followed by bursts of hippocampal unit activity; moreover, spindle burst power was positively correlated with hippocampal unit activity. In addition, exogenous stimulation consistently evoked this neocortical-to hippocampal sequence of activation. Finally, parahippocampal lesions that disrupted functional connections between the neocortex and hippocampus effectively disrupted the transmission of both spontaneous and evoked neocortical activity to the hippocampus. These findings suggest that sleep-related motor activity contributes to the development of neocortical and hippocampal circuits and provides a foundation on which coordinated activity between these two forebrain structures develops. PMID- 20203204 TI - Control of rhodopsin's active lifetime by arrestin-1 expression in mammalian rods. AB - In rod photoreceptors, deactivation of the light-activated G-protein-coupled receptor rhodopsin (R*) is initiated by phosphorylation and completed through subsequent binding of visual arrestin (Arr1). The in vivo kinetics of these individual interactions have proven difficult to determine with precision since R* lifetime is much shorter than the lifetimes of downstream G-protein and effector molecules. Here, we have used a transgenic mouse line with accelerated downstream deactivation kinetics to reveal the contribution of Arr1 binding to the overall time course of rhodopsin deactivation. Photoresponses revealed that the lifetime of R* is significantly increased in rods that express half of the normal amount of Arr1, in a manner consistent with a twofold decrease in the rate of Arr1 binding across a wide range of flash strengths. A basic model of photoresponse deactivation consistent with established photoreceptor biochemistry shows that R* phosphorylation and Arr1 binding occur with a time constant of approximately 40 ms in wild-type mouse rods, much faster than previous estimates. PMID- 20203205 TI - Endogenous neuromagnetic activity for mental hierarchy of timing. AB - The frontal-striatal circuits, the cerebellum, and motor cortices play crucial roles in processing timing information on second to millisecond scales. However, little is known about the physiological mechanism underlying human's preference to robustly encode a sequence of time intervals into a mental hierarchy of temporal units called meter. This is especially salient in music: temporal patterns are typically interpreted as integer multiples of a basic unit (i.e., the beat) and accommodated into a global context such as march or waltz. With magnetoencephalography and spatial-filtering source analysis, we demonstrated that the time courses of neural activities index a subjectively induced meter context. Auditory evoked responses from hippocampus, basal ganglia, and auditory and association cortices showed a significant contrast between march and waltz metric conditions during listening to identical click stimuli. Specifically, the right hippocampus was activated differentially at 80 ms to the march downbeat (the count one) and approximately 250 ms to the waltz downbeat. In contrast, basal ganglia showed a larger 80 ms peak for march downbeat than waltz. The metric contrast was also expressed in long-latency responses in the right temporal lobe. These findings suggest that anticipatory processes in the hippocampal memory system and temporal computation mechanism in the basal ganglia circuits facilitate endogenous activities in auditory and association cortices through feedback loops. The close interaction of auditory, motor, and limbic systems suggests a distributed network for metric organization in temporal processing and its relevance for musical behavior. PMID- 20203206 TI - Error effects in anterior cingulate cortex reverse when error likelihood is high. AB - Strong error-related activity in medial prefrontal cortex (mPFC) has been shown repeatedly with neuroimaging and event-related potential studies for the last several decades. Multiple theories have been proposed to account for error effects, including comparator models and conflict detection models, but the neural mechanisms that generate error signals remain in dispute. Typical studies use relatively low error rates, confounding the expectedness and the desirability of an error. Here we show with a gambling task and functional magnetic resonance imaging that when losses are more frequent than wins, the mPFC error effect disappears, and moreover, exhibits the opposite pattern by responding more strongly to unexpected wins than losses. These findings provide perspective on recent ERP studies and suggest that mPFC error effects result from a comparison between actual and expected outcomes. PMID- 20203207 TI - Cisplatin ototoxicity blocks sensory regeneration in the avian inner ear. AB - Cisplatin is a chemotherapeutic agent that is widely used in the treatment of solid tumors. Ototoxicity is a common side effect of cisplatin therapy and often leads to permanent hearing loss. The sensory organs of the avian ear are able to regenerate hair cells after aminoglycoside ototoxicity. This regenerative response is mediated by supporting cells, which serve as precursors to replacement hair cells. Given the antimitotic properties of cisplatin, we examined whether the avian ear was also capable of regeneration after cisplatin ototoxicity. Using cell and organ cultures of the chick cochlea and utricle, we found that cisplatin treatment caused apoptosis of both auditory and vestibular hair cells. Hair cell death in the cochlea occurred in a unique pattern, progressing from the low-frequency (distal) region toward the high-frequency (proximal) region. We also found that cisplatin caused a dose-dependent reduction in the proliferation of cultured supporting cells as well as increased apoptosis in those cells. As a result, we observed no recovery of hair cells after ototoxic injury caused by cisplatin. Finally, we explored the potential for nonmitotic hair cell recovery via activation of Notch pathway signaling. Treatment with the gamma-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester failed to promote the direct transdifferentiation of supporting cells into hair cells in cisplatin-treated utricles. Taken together, our data show that cisplatin treatment causes maintained changes to inner ear supporting cells and severely impairs the ability of the avian ear to regenerate either via proliferation or by direct transdifferentiation. PMID- 20203208 TI - Alleviation of neurotoxicity by microglial human Siglec-11. AB - Sialic acid-binding Ig superfamily lectins (Siglecs) are members of the Ig superfamily that recognize sialic acid residues of glycoproteins. Siglec-11 is a recently identified human-specific CD33-related Siglec that binds to alpha2,8 linked polysialic acids and is expressed on microglia, the brain resident innate immune cells. Polysialylated neuronal cell adhesion molecule (PSA-NCAM) is a putative ligand of Siglec-11. We observed gene transcription and protein expression of Siglec-11 splice variant 2 in human brain tissue samples by RT-PCR and Western blot analysis. Siglec-11 was detected on microglia in human brain tissue by immunohistochemistry. Human Siglec-11 splice variant 2 was ectopically expressed by a lentiviral vector system in cultured murine microglial cells. Stimulation of Siglec-11 by cross-linking suppressed the lipopolysaccharides (LPS)-induced gene transcription of the proinflammatory mediators interleukin 1beta and nitric oxide synthase-2 in microglia. Furthermore, phagocytosis of apoptotic neuronal material was reduced in Siglec-11 transduced microglia. Expression of PSA-NCAM was detected on microglia and neurons by immunohistochemistry and RT-PCR. Coculture of microglia transduced with Siglec-11 and neurons demonstrated neuroprotective function of Siglec-11. The neuroprotective effect of Siglec-11 was dependent on polysialic acid (PSA) residues on neurons, but independent on PSA on microglia. Thus, data demonstrate that human Siglec-11 ectopically expressed on murine microglia interacts with PSA on neurons, reduces LPS-induced gene transcription of proinflammatory mediators, impairs phagocytosis and alleviates microglial neurotoxicity. PMID- 20203209 TI - Essential roles of Notch signaling in maintenance of neural stem cells in developing and adult brains. AB - Activation of Notch signaling induces the expression of transcriptional repressor genes such as Hes1, leading to repression of proneural gene expression and maintenance of neural stem/progenitor cells. However, a requirement for Notch signaling in the telencephalon was not clear, because in Hes1;Hes3;Hes5 triple mutant mice, neural stem/progenitor cells are depleted in most regions of the developing CNS, but not in the telencephalon. Here, we investigated a role for Notch signaling in the telencephalon by generating tamoxifen-inducible conditional knock-out mice that lack Rbpj, an intracellular signal mediator of all Notch receptors. When Rbpj was deleted in the embryonic brain, almost all telencephalic neural stem/progenitor cells prematurely differentiated into neurons and were depleted. When Rbpj was deleted in the adult brain, all neural stem cells differentiated into transit-amplifying cells and neurons. As a result, neurogenesis increased transiently, but 3 months later all neural stem cells were depleted and neurogenesis was totally lost. These results indicated an absolute requirement of Notch signaling for the maintenance of neural stem cells and a proper control of neurogenesis in both embryonic and adult brains. PMID- 20203210 TI - Dynamics of synaptic transmission between fast-spiking interneurons and striatal projection neurons of the direct and indirect pathways. AB - The intrastriatal microcircuit is a predominantly inhibitory GABAergic network comprised of a majority of projection neurons [medium spiny neurons (MSNs)] and a minority of interneurons. The connectivity within this microcircuit is divided into two main categories: lateral connectivity between MSNs, and inhibition mediated by interneurons, in particular fast spiking (FS) cells. To understand the operation of striatum, it is essential to have a good description of the dynamic properties of these respective pathways and how they affect different types of striatal projection neurons. We recorded from neuronal pairs, triplets, and quadruplets in slices of rat and mouse striatum and analyzed the dynamics of synaptic transmission between MSNs and FS cells. Retrograde fluorescent labeling and transgenic EGFP (enhanced green fluorescent protein) mice were used to distinguish between MSNs of the direct (striatonigral) and indirect (striatopallidal) pathways. Presynaptic neurons were stimulated with trains of action potentials, and activity-dependent depression and facilitation of synaptic efficacy was recorded from postsynaptic neurons. We found that FS cells provide a strong and homogeneously depressing inhibition of both striatonigral and striatopallidal MSN types. Moreover, individual FS cells are connected to MSNs of both types. In contrast, both MSN types receive sparse and variable, depressing and facilitating synaptic transmission from nearby MSNs. The connection probability was higher for pairs with presynaptic striatopallidal MSNs; however, the variability in synaptic dynamics did not depend on the types of interconnected MSNs. The differences between the two inhibitory pathways were clear in both species and at different developmental stages. Our findings show that the two intrastriatal inhibitory pathways have fundamentally different dynamic properties that are, however, similarly applied to both direct and indirect striatal projections. PMID- 20203211 TI - A role for RhoB in synaptic plasticity and the regulation of neuronal morphology. AB - Actin-rich dendritic spines are the locus of excitatory synaptic transmission and plastic events such as long-term potentiation (LTP). Morphological plasticity of spines accompanies activity-dependent changes in synaptic strength. Several Rho GTPase family members are implicated in regulating neuronal and, in particular, spine structure via actin and the actin-binding protein cofilin. However, despite expression in hippocampus and cortex, its ability to modulate actin-regulatory proteins, and its induction during aging, RhoB has been relatively neglected. We previously demonstrated that LTP is associated with specific RhoB activation. Here, we further examined its role in synaptic function using mice with genetic deletion of the RhoB GTPase (RhoB(-/-) mice). Normal basal synaptic transmission accompanied reduced paired-pulse facilitation and post-tetanic potentiation in the hippocampus of RhoB(-/-) mice. Early phase LTP was significantly reduced in RhoB(-/-) animals, whereas the later phase was unaffected. In wild-type mice (RhoB(+/+)), Western blot analysis of potentiated hippocampus showed significant increases in phosphorylated cofilin relative to nonpotentiated slices, which were dramatically impaired in RhoB(-/-) slices. There was also a deficit in phosphorylated Lim kinase levels in the hippocampus from RhoB(-/-) mice. Morphological analysis suggested that lack of RhoB resulted in increased dendritic branching and decreased spine number. Furthermore, an increase in the proportion of stubby relative to thin spines was observed. Moreover, spines demonstrated increased length along with increased head and neck widths. These data implicate RhoB in cofilin regulation and dendritic and spine morphology, highlighting its importance in synaptic plasticity at a structural and functional level. PMID- 20203212 TI - Prefrontal beta2 subunit-containing and alpha7 nicotinic acetylcholine receptors differentially control glutamatergic and cholinergic signaling. AB - One-second-long increases in prefrontal cholinergic activity ("transients") were demonstrated previously to be necessary for the incorporation of cues into ongoing cognitive processes ("cue detection"). Nicotine and, more robustly, selective agonists at alpha4beta2* nicotinic acetylcholine receptors (nAChRs) enhance cue detection and attentional performance by augmenting prefrontal cholinergic activity. The present experiments determined the role of beta2 containing and alpha7 nAChRs in the generation of prefrontal cholinergic and glutamatergic transients in vivo. Transients were evoked by nicotine, the alpha4beta2* nAChR agonist ABT-089 [2-methyl-3-(2-(S)-pyrrolindinylmethoxy) pyridine dihydrochloride], or the alpha7 nAChR agonist A-582941 [2-methyl-5-(6 phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole]. Transients were recorded in mice lacking beta2 or alpha7 nAChRs and in rats after removal of thalamic glutamatergic or midbrain dopaminergic inputs to prefrontal cortex. The main results indicate that stimulation of alpha4beta2* nAChRs evokes glutamate release and that the presence of thalamic afferents is necessary for the generation of cholinergic transients. ABT-089-evoked transients were completely abolished in mice lacking beta2* nAChRs. The amplitude, but not the decay rate, of nicotine evoked transients was reduced by beta2* knock-out. Conversely, in mice lacking the alpha7 nAChR, the decay rate, but not the amplitude, of nicotine-evoked cholinergic and glutamatergic transients was attenuated. Substantiating the role of alpha7 nAChR in controlling the duration of release events, stimulation of alpha7 nAChR produced cholinergic transients that lasted 10- to 15-fold longer than those evoked by nicotine. alpha7 nAChR-evoked cholinergic transients are mediated in part by dopaminergic activity. Prefrontal alpha4beta2* nAChRs play a key role in evoking and facilitating the transient glutamatergic-cholinergic interactions that are necessary for cue detection and attentional performance. PMID- 20203213 TI - Predictive coding as a model of response properties in cortical area V1. AB - A simple model is shown to account for a large range of V1 classical, and nonclassical, receptive field properties including orientation tuning, spatial and temporal frequency tuning, cross-orientation suppression, surround suppression, and facilitation and inhibition by flankers and textured surrounds. The model is an implementation of the predictive coding theory of cortical function and thus provides a single computational explanation for a diverse range of neurophysiological findings. Furthermore, since predictive coding can be related to the biased competition theory and is a specific example of more general theories of hierarchical perceptual inference, the current results relate V1 response properties to a wider, more unified, framework for understanding cortical function. PMID- 20203214 TI - Internal and external features of the face are represented holistically in face selective regions of visual cortex. AB - The perception and recognition of familiar faces depends critically on an analysis of the internal features of the face (eyes, nose, mouth). We therefore contrasted how information about the internal and external (hair, chin, face outline) features of familiar and unfamiliar faces is represented in face selective regions. There was a significant response to both the internal and external features of the face when presented in isolation. However, the response to the internal features was greater than the response to the external features. There was significant adaptation to repeated images of either the internal or external features of the face in the fusiform face area (FFA). However, the magnitude of this adaptation was greater for the internal features of familiar faces. Next, we asked whether the internal features of the face are represented independently from the external features. There was a release from adaptation in the FFA to composite images in which the internal features were varied but the external features were unchanged, or when the internal features were unchanged but the external features varied, demonstrating a holistic response. Finally, we asked whether the holistic response to faces could be influenced by the context in which the face was presented. We found that adaptation was still evident to composite images in which the face was unchanged but body features were varied. Together, these findings show that although internal features are important in the neural representation of familiar faces, the face's internal and external features are represented holistically in face-selective regions of the human brain. PMID- 20203215 TI - Inhibition of neutrophil function following exposure to the Aspergillus fumigatus toxin fumagillin. AB - The filamentous fungus Aspergillus fumigatus produces a variety of enzymes and toxins that may facilitate fungal colonization of tissue and evasion of the host immune response. One such toxin, fumagillin, was investigated for its ability to inhibit the action of neutrophils, which are a central component of the innate immune response to microbial infection. Neutrophils exposed to 2 microg fumagillin ml(-1) for 25 min showed a significantly reduced ability to kill yeast cells (P<0.02), to phagocytose conidia of A. fumigatus (P<0.023) and to consume oxygen (P<0.032). The ability of neutrophils to generate superoxide is dependent upon the action of a functional NADPH oxidase complex which is composed of cytosolic (p40phox, p47phox, p67phox, Rac2) and membrane (gp91phox) proteins. Exposure of neutrophils to fumagillin inhibited the formation of the NADPH oxidase complex by blocking the translocation of p47phox from the cytosolic to the membrane fraction (P=0.02). In addition to the production of superoxide, neutrophils also undergo degranulation, which leads to the release of proteolytic enzymes that contribute to the microbicidal activity of the cell. Fumagillin treated neutrophils showed reduced degranulation as evidenced by lower myeloperoxidase activity (P<0.019). Fumagillin-treated cells demonstrated reduced levels of F-actin, thus indicating that retarding the formation of F-actin may contribute to the inhibition of the structural rearrangements required in the activated neutrophil. This work indicates that fumagillin may contribute to reducing the local immune response by altering the activity of neutrophils and thus facilitate the continued persistence and growth of A. fumigatus in the host. PMID- 20203216 TI - Comparison of the performance of direct fluorescent antibody staining, a point-of care rapid antigen test and virus isolation with that of RT-PCR for the detection of novel 2009 influenza A (H1N1) virus in respiratory specimens. AB - Although infections with the novel pandemic 2009 influenza A (H1N1) virus (A/H1N1/2009) appeared to be relatively mild during the first summer of circulation ('off season'), there has been significant morbidity and hospitalization and several fatal cases. Thus, rapid detection of A/H1N1/2009 is crucial for efficient treatment and infection control measures. In contrast to seasonal influenza, where point-of-care (POC) rapid antigen tests and direct fluorescent antibody (DFA) staining ensure rapid detection, diagnosis of A/H1N1/2009 has so far been based on RT-PCR. This study retrospectively compared the performance of the Quidel QuickVue POC test, DFA staining and virus isolation with that of RT-PCR for A/H1N1/2009 detection in 526 respiratory specimens collected during the first wave of the outbreak from May to September 2009. A/H1N1/2009 was detected in 9.1% (48/526) of samples. One hundred and thirty seven of the A/H1N1/2009 PCR-negative samples were additionally tested using a RealAccurate Respiratory RT-PCR panel, revealing other respiratory viruses (mainly entero/rhino- and adenoviruses) in 42.3% (58/137). All methods analysed detected A/H1N1/2009 with excellent specificity but different sensitivities (POC test: 18.2%; DFA staining: 38.7%; virus isolation: 45.7%). Therefore, the POC test was not suitable for diagnosis, detecting A/H1N1/2009 only if present in high concentrations (corresponding median Ct value=19.0; range=16.5-21.4). DFA staining was also able to detect A/H1N1/2009 in specimens with a lower virus concentration (median Ct value=24.0; range=16.5-29.8). Virus isolation, which was positive after a median time of 7.5 days, was too time-consuming. In summary, DFA staining is superior to POC testing and may be appropriate for patients expected to have a rather high level of virus replication. Nevertheless, in DFA-negative specimens, A/H1N1/2009 should be excluded by RT-PCR. PMID- 20203217 TI - Fatal congenital tuberculosis due to a Beijing strain in a premature neonate. AB - Congenital tuberculosis (TB) remains a rare disease but is fatal if untreated. Early detection is difficult because of the non-specific nature of the symptoms in TB during pregnancy and infancy. This report summarizes a case of congenital TB in a very premature infant, born at 25 weeks gestation. Miliary TB was diagnosed in the mother when the neonate was 20 days old. Antituberculous therapy allowed a rapid improvement in the mother. The infant died at 27 days old. A Beijing genotype strain of Mycobacterium tuberculosis was isolated both in the mother, from pulmonary and urine specimens, and in the infant, from peritoneal fluid. PMID- 20203218 TI - My approach to cardiothoracic transplantation and the role of the histocompatibility and immunogenetics laboratory in a rapidly developing field. AB - Cardiothoracic transplantation presents specific challenges. The lack of long term replacement therapy (such as dialysis for kidney patients) creates a more urgent situation than for other forms of transplantation, necessitating a different approach. This review looks at ways in which the challenges are being met and the integral role of the histocompatibility and immunogenetics laboratory. PMID- 20203219 TI - My approach to the immunogenetics of haematopoietic stem cell transplant matching. AB - Haematopoietic stem cell transplantation (HSCT) is now viewed as an effective treatment modality for a wide and varied number of diseases including both malignant and non-malignant haematological diseases, bone marrow failures, inherited immunodeficiencies and congenital metabolic disorders. This review will discuss the immunogenetic factors that play an influential role in the successful outcome of HSCT, most importantly the human leucocyte antigens (HLAs). Advances in HLA typing techniques enabling the definition of HLA types at the allele level have made it possible to investigate the impact of mismatching at individual HLA loci on HSCT outcome. Such studies have informed the strategy used for selection of both related and unrelated donors. This strategy, including the histocompatibility and immunogenetics laboratory testing required, is discussed in the context of published data, guidelines and recommendations. PMID- 20203220 TI - Out of the darkness and into the light: bright field in situ hybridisation for delineation of ERBB2 (HER2) status in breast carcinoma. AB - Assessment of ERBB2 (HER2) status in breast carcinomas has become critical in determining response to the humanised monoclonal antibody trastuzumab. The current joint College of American Pathologists and the American Society of Clinical Oncology guidelines for the evaluation of HER2 status in breast carcinoma involve testing by immunohistochemistry and fluorescence in situ hybridisation (FISH). However, neither of these modalities is without limitations. Novel bright field in situ hybridisation techniques continue to provide viable alternatives to FISH testing. While these techniques are not limited to evaluation of the HER2 gene, the extensive number of studies comparing bright field in situ techniques with other methods of assessing HER2 status allow a robust evaluation of this approach. Analysis of the literature demonstrates that, when used to assess HER2 gene status, bright field in situ hybridisation demonstrates excellent concordance with FISH results. The average percentage agreement in an informal analysis of studies comparing HER2 amplification by chromogenic in situ hybridisation with FISH was 96% (SD 4%); kappa coefficients ranged from 0.76 to 1.0. Although a much smaller number of studies are available for review, similar levels of concordance have been reported in studies comparing HER2 amplification by methods employing metallography (silver in situ hybridisation) with FISH. A summary of the advancements in bright field in situ hybridisation, with focus on those techniques with clinical applications of interest to the practicing pathologist, is presented. PMID- 20203221 TI - Adenoid cystic carcinomas of the breast and salivary glands (or 'The strange case of Dr Jekyll and Mr Hyde' of exocrine gland carcinomas). AB - Adenoid cystic carcinoma (AdCC) is a tumour with myoepithelial differentiation and characterised by the presence of a dual population of basaloid and luminal cells arranged in specific growth patterns. These tumours, regardless of the anatomical site, are characterised by expression of the proto-oncogene and therapeutic target c-KIT, and seem to harbour a specific chromosomal translocation t(6;9) leading to the fusion gene MYB-NFIB and overexpression of the oncogene MYB. However, the clinical behaviour of salivary gland and breast AdCC differs; while salivary gland lesions have a relatively high proclivity to metastasise, patients with breast AdCCs have an excellent outcome. Here the clinical, morphological and molecular features, and potential therapeutic targets of salivary gland and breast AdCCs are reviewed. PMID- 20203222 TI - Lymphatics and D2-40/podoplanin expression in gastrointestinal stromal tumours of the stomach with and without lymph node metastasis: an immunohistochemical study with special reference to the Carney triad. AB - BACKGROUND: Lymph node metastasis of gastric gastrointestinal stromal tumours (GISTs) in children and young adults, especially those with the Carney triad, is common (approximately 29%) and contrasts with that of sporadic gastric GISTs (< or = 2%). The mechanism responsible for this difference in tumour behaviour is not understood. In previous studies, expression of the lymphatic endothelial marker D2-40/podoplanin in carcinoma cells and the presence of intratumoural/peritumoural lymphatics have been correlated with tumour invasiveness and nodal metastasis. METHODS: This study investigated the presence of intratumoural and peritumoural lymphatics, and expression of D2-40/podoplanin, in 16 patients with syndromic/paediatric gastric GISTs (11 patients had Carney triad, two had Carney-Stratakis syndrome and three had paediatric GISTs suspicious for the Carney triad) with histologically verified metastasis to regional lymph nodes. The results were compared with those found in 35 sporadic gastric GISTs lacking nodal spread using the antibody D2-40/podoplanin. RESULTS: The mean ages at GIST diagnosis in the patients with syndromic/paediatric GISTs and those with sporadic GISTs were 18 years and 67 years, respectively. Intratumoural lymphatics were detected with comparable frequency in the two tumour sets (25% and 17%, respectively; p=0.705). Peritumoural lymphatics were equally present in the tumours from both of the groups. Moderate/strong cytoplasmic/membranous staining for D2-40/podoplanin was frequent in the neoplastic cells of syndromic/paediatric GISTs (87%), and infrequent in sporadic GISTs (3%) (p<0.001). CONCLUSION: The results indicate that intratumoural lymphangiogenesis is probably not involved in lymphatic spread in syndromic/paediatric GISTs. The biological significance of D2-40/podoplanin expression in tumour cells of syndromic/paediatric GISTs and its possible role in lymphatic tumour spread remain to be further investigated. PMID- 20203223 TI - The clinicopathological characteristics of 'triple-negative' epithelial ovarian cancer. AB - BACKGROUND: 'Triple-negative' is traditionally used to define a specific subtype of breast cancer with negative oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-type 2 (HER2) expressions. ER/PR and HER2 testing is also widely used in the informative classification of ovarian cancer. AIM: To investigate whether a 'triple-negative' subtype also exists in ovarian cancer. METHODS: ER, PR and HER2 expressions in 116 Chinese women with primary epithelial ovarian cancer were reviewed. Triple-negative epithelial ovarian cancer (TNEOC) was defined based on negative ER, PR and HER2 expression. The clinicopathological characteristics and Ki-67, P53 and epidermal growth factor receptor (EGFR) expression in the TNEOC and non-TNEOC group were compared. RESULTS: 15.5% of cases (18/116) were identified as TNEOC among 116 ovarian carcinomas. Histological grade 3 was found in a higher percentage of the TNEOC than of the non-TNEOC group (94.4% vs 62.2%). TNEOC also correlated with a high level of Ki-67 and p53 expression. EGFR overexpression and other clinicopathological characteristics were not significantly associated with TNEOC subtype. TNEOC was associated with a shorter progression free survival and overall survival in univariate and multivariate analyses. CONCLUSIONS: A novel subtype of ovarian carcinoma, which is negative for ER, PR and HER2 expression, has been identified; this specific ovarian subtype tends to have aggressive characteristics and a poor prognosis, which is similar to triple-negative breast cancer in most respects. TNEOC should be considered in future investigations of informative classification of ovarian cancer. PMID- 20203224 TI - Natural killer cell cytotoxicity in patients with recurrent herpes infections: diagnostic utility of a flow cytometric assay. AB - BACKGROUND: Primary immune deficiencies of natural killer (NK) cells have been described in patients with a susceptibility to herpes infections. AIMS: To assess the diagnostic utility of measurement of NK cytotoxicity in patients with recurrent oral herpes infections. METHODS: A retrospective audit was carried out on results obtained over an 18-month period, from 28 NK cell cytotoxicity assays (24 patients; all with a history of recurrent oral herpes infections), and 24 control samples (three healthy donors). Percentage specific cytotoxicity (PSC) was determined by measurement of the percentage of K562 target cells lysed by NK cells after incubation, using the NK TEST. Comparison of PSC was made with reference ranges provided. RESULTS: No patient with absent NK/NKT cells or NK cell cytotoxicity was identified (95% CI 0 to 14.8%). Two patients had persistently low PSC. Two patients with reduced PSC showed PSC within the normal reference range on repeat testing. Patient and control samples were seen both above and below the reference ranges. A relationship was expected between NK cell percentage and PSC; however this correlation was not significant (r(s)=0.29, p=0.18, 95% CI -0.14 to 0.63). CONCLUSIONS: A deficiency of NK cell cytotoxicity has not been identified in this cohort. An apparent reduction in cytotoxicity may be due to normal interpersonal and intersample variability in NK cytotoxicity. Without reference ranges established from a large population of control samples to account for this, a reduction in PSC is difficult to define. Further studies are required to identify if a correlation exists between the percentage of NK cells and PSC. PMID- 20203225 TI - Prevalence of Trichomonas vaginalis infection in women attending a major gynaecological hospital in Greece: a cross-sectional study. AB - BACKGROUND: The prevalence of Trichomonas vaginalis is not accurately estimated, since it is not a reportable disease. AIMS: To assess the prevalence of T vaginalis infection in women attending a Greek gynaecological hospital and to evaluate four diagnostic methods for T vaginalis infection. METHODS: 255 symptomatic and 247 asymptomatic women were included in the study during 2006-07; 372 were Greek and 130 were immigrants. T vaginalis was detected in vaginal samples, using wet mount, culture in modified Diamond's medium, antigen detection and two PCR assays, targeting different regions of T vaginalis genome. Specimens were considered positive for T vaginalis, when tested positive either by culture or by both PCRs. RESULTS: 23 women (4.6%) were positive for T vaginalis. Seven of the 23 positive samples (30.4%) were only PCR-positive. Infection was more prevalent in symptomatic women (6.7%) than in asymptomatic ones (2.4%). T vaginalis was more frequently detected in immigrants (7.9%) than in Greek women (3.3%). Gardnerella vaginalis infection was significantly more frequent in women infected with T vaginalis. PCR was the most sensitive method (100%), followed by culture (69.6%), wet mount (69.6%) and latex agglutination (54.6%). Agreement between PCR and culture as well as wet mount examination was very good (kappa=0.79). CONCLUSIONS: The study shows a relatively low percentage of trichomoniasis in the female population living in Athens. The infection was more prevalent among immigrants, and a proportion of the infected women was asymptomatic. The tested methods had good agreement and PCR was found to improve the diagnostic yield considerably. PMID- 20203226 TI - Human herpesvirus type 8 in patients with cirrhosis independent of thrombocytopenia. AB - BACKGROUND: High seroprevalence of human herpesvirus type 8 (HHV-8) in patients with cirrhosis has been reported to be associated with thrombocytopenia. Severe cirrhosis is always complicated with ascites. HHV-8 DNA levels in effusion from patients with primary effusion lymphoma has been reported to be significantly greater than in blood. The status of HHV-8 antibody and DNA in cirrhotic ascites is unclear. AIMS: To assess the status of HHV-8 antibody and DNA in cirrhotic ascites compared to that in cirrhotic plasma. METHODS: Plasma and ascites samples were collected from 85 patients with cirrhosis. HHV-8 antibody and DNA were detected by immunofluorescence assay and PCR, respectively. RESULTS: Male patients seropositive for HHV-8 antibody were significantly younger than seropositive female patients (p=0.0039). The seropositive rate in patients with cirrhosis was not associated with thrombocytopenia (p=0.6860). Both positive rate and titres of antibody in plasma were much greater than in ascites (p<0.0001). More male or Child-Pugh class C than female or class B seropositive patients were positive for ascites. No hepatitis C virus-related ascites were positive for antibody. Neither plasma nor ascites samples from any subject were positive for HHV-8 DNA. CONCLUSIONS: In patients with cirrhosis, the seropositive rate for HHV 8 antibody is independent of thrombocytopenia. The positive rate for HHV-8 antibody in cirrhotic ascites seems to be associated with sex, disease severity and disease aetiology. PMID- 20203227 TI - In utero drugs of abuse exposure testing for newborn twins. AB - This report describes testing of a case of in utero drugs of abuse exposure in which discordant results were seen between urine and meconium, and between twin meconium samples. The discordance between urine and meconium could be explained by the differences in detection window, threshold concentration and screening technology, and the discordance between dizygotic twin meconium samples could be explained by the differences in drug diffusion and placental and fetal biotransformation of drugs. The meconium sample of one twin screened negative for benzodiazepines was reported positive in the confirmation assay with higher sensitivity and a lower cut-off concentration. Negative screening results of drugs of abuse should be interpreted with caution, taking into account matrix type, reactivity of drugs in the assay and cut-off concentration. If screening results are inconsistent with each other or with the clinical scenario, confirmation testing using more sensitive and specific methods with lower cut offs is warranted. PMID- 20203228 TI - Enterococcus raffinosus sinusitis post-Aspergillus flavus paranasal infection, in a patient with myelodysplastic syndrome: report of a case and concise review of pertinent literature. AB - A case of Enterococcus raffinosus nosocomial sinusitis which appeared to complicate a previous Aspergillus flavus paranasal infection is presented. This uncommon enterococcal species is rarely responsible for human diseases, and has never previously been associated with sinusitis. PMID- 20203229 TI - Intraductal carcinosarcoma with a heterologous mesenchymal component originating in intraductal papillary-mucinous carcinoma (IPMC) of the pancreas with both carcinoma and osteosarcoma cells arising from IPMC cells. AB - Carcinosarcoma of the pancreas is extremely rare and its histogenesis is still unclear. This is a report on a 64-year-old female patient with an intraductal carcinosarcoma arising from intraductal papillary-mucinous carcinoma (IPMC) in the pancreas tail. The carcinosarcoma grew as a polypoid mass within the main pancreatic duct. Histologically, the tumour consisted of adenocarcinoma covering the luminal surface of the lesion with minimal stromal invasion, and osteosarcoma occupying the stroma. Immunohistochemical and gene mutation analyses revealed that both the carcinomatous and sarcomatous tumour cells of the carcinosarcoma, as well as the IPMC cells, expressed TP53 and had identical mutations in KRAS and TP53 genes, indicating that these two neoplastic components of the carcinosarcoma shared a common tumorigenesis and arose from the IPMC. This is the first report of a carcinosarcoma originating in IPMC. These findings imply that carcinosarcoma with a heterologous mesenchymal component is of ductal origin. PMID- 20203230 TI - Novel epitheliomesenchymal biphasic stomach tumour (gastroblastoma) in a 9-year old: morphological, ultrastructural and immunohistochemical findings. AB - Gastroblastoma is a rare gastric epitheliomesenchymal biphasic tumour composed of spindle and epithelial cells, reported by Miettinen et al in a series of three cases in 2009. All those cases arose in stomachs of young adults. Neither the epithelial nor the mesenchymal component displayed sufficient atypia to diagnose a carcinosarcoma or other malignancy. On immunohistochemistry, the epithelial component expressed cytokeratin, and the mesenchymal component was positive for vimentin and CD10. Miettinen et al designated these neoplasms as gastroblastomas based on their similarities with other childhood blastomas such as pleuropulmonary blastoma and nephroblastoma. This report describes a probable fourth case of this unique type of neoplasm. The present case arose in the gastric antrum of a 9-year-old boy. While similarities were evident with the other cases, there were some differences. The epithelial component was more predominant and showed more mature morphology. Immunohistochemically, the epithelial component showed immunolabelling for c-KIT and CD56. The mesenchymal component was only focally positive for CD10. Ultrastructually, desmosomes and microvilli were found supporting a truly epithelial lesion. PMID- 20203231 TI - Does rituximab aggravate pre-existing hypogammaglobulinaemia? AB - Rituximab, an anti-CD20 chimeric antibody, is the first monoclonal agent to be used in the therapy of cancer. It has been hailed as one of the most important therapeutic developments of the decade. While transient peripheral B cell depletion is common after rituximab therapy, immunoglobulin levels are generally not affected. This is because CD20 is expressed on pre-B and mature B lymphocytes but not on stem cells or plasma cells. Two adult patients with pre-existing primary antibody deficiency who presented with recurrent infections immediately following rituximab use for the treatment of refractory idiopathic thrombocytopenic purpura (ITP) are described. Both were previously treated with various immunosuppressive agents without any notable infective problems. However, a few weeks after treatment with rituximab, these patients presented with clinically significant immunodeficiency requiring intravenous immunoglobulin replacement therapy. This striking temporal relationship between rituximab administration and onset of infections suggests that rituximab has accelerated the presentation of immune deficiency in these patients. Increased vigilance around the use of newer immunomodulatory agents such as rituximab is recommended. PMID- 20203232 TI - Ethnic differences in glycated haemoglobin between white subjects and those of South Asian origin with normal glucose tolerance. AB - OBJECTIVE: To determine whether ethnic differences exist in glycated haemoglobin between white subjects and those of South Asian origin with normal glucose tolerance (NGT) METHODS: Erythrocyte glycated haemoglobin (HbA(1c)) was compared between white subjects and those of South Asian origin with NGT defined by a 75 g oral glucose tolerance test (OGTT). RESULTS: 139 subjects with NGT comprising 36 people of South Asian origin (20 female) and 103 white subjects (49 female) were compared. Subjects of South Asian origin were younger (p<0.001) and weighed less (p<0.001) than white subjects. Fasting and 2 h capillary plasma glucose concentrations were similar in subjects of South Asian origin and white subjects, but HbA(1c) levels were higher (p<0.05) in subjects of South Asian origin (6.11+/ 0.58%) compared with levels in white subjects (5.90+/-0.40%). CONCLUSION: In subjects with similar fasting and postprandial glycaemia on OGTT, those of South Asian origin have higher HbA(1c) levels than white subjects. It is speculated that the higher glycaemia-independent HBA(1c) levels in people of South Asian origin could possibly contribute to their increase cardiovascular risk. PMID- 20203233 TI - Wiskott-Aldrich syndrome: acute retinal necrosis as a further late complication. PMID- 20203234 TI - Umbilical mucosal polyp. PMID- 20203235 TI - Humphrey Melville Edward Kay: an appreciation. PMID- 20203237 TI - Functional characterization of phytochrome autophosphorylation in plant light signaling. AB - Plant phytochromes, molecular light switches that regulate various aspects of plant growth and development, are phosphoproteins that are also known to be autophosphorylating serine/threonine kinases. Although a few protein phosphatases that directly interact with and dephosphorylate phytochromes have been identified, no protein kinase that acts on phytochromes has been reported thus far, and the exact site of phytochrome autophosphorylation has not been identified. In this study, we investigated the functional role of phytochrome autophosphorylation. We first mapped precisely the autophosphorylation sites of oat phytochrome A (phyA), and identified Ser8 and Ser18 in the 65 amino acid N terminal extension (NTE) region as being the autophosphorylation sites. The in vivo functional roles of phytochrome autophosphorylation were examined by introducing autophosphorylation site mutants into phyA-deficient Arabidopsis thaliana. We found that all the transgenic plants expressing the autophosphorylation site mutants exhibited hypersensitive light responses, indicating an increase in phyA activity. Further analysis showed that these phyA mutant proteins were degraded at a significantly slower rate than wild-type phyA under light conditions, which suggests that the increased phyA activity of the mutants is related to their increased protein stability. In addition, protoplast transfection analyses with green fluorescent protein (GFP)-fused phyA constructs showed that the autophosphorylation site mutants formed sequestered areas of phytochrome (SAPs) in the cytosol much more slowly than did wild-type phyA. These results suggest that the autophosphorylation of phyA plays an important role in the regulation of plant phytochrome signaling through the control of phyA protein stability. PMID- 20203238 TI - Cytoplasmic-nuclear genomic barriers in rice pollen development revealed by comparison of global gene expression profiles among five independent cytoplasmic male sterile lines. AB - Cytoplasmic male sterility (CMS) is one of the most ideal phenomena known in higher plants to describe the incompatibilities between mitochondrial-nuclear genomic interactions. To elucidate the dependency of pollen development on mitochondrial genotypes and cytoplasmic-nuclear genomic barriers, we employed five CMS isogenic lines of rice, CW-, W11-, LD-, BT- and WA-type CMS lines, that exhibit distinct pollen-defective phenotypes, and we characterized the CMS phenotypes and the nuclear gene expression patterns in conjunction with their mitochondrial genomic structures. These five CMS lines carried independent mitotypes, and W11, LD and BT mitochondrial genomes were relatively close with respect to their phylogeny. In anthers at the uninucleate microspore and bicellular pollen stages, 8,199 genes significantly changed their expression in at least one of the CMS lines. Common expression patterns were observed in BT, LD and W11 after k-means clustering. Among the genes encoding putative mitochondrial proteins, ALTERNATIVE OXIDASE 1A, a gene for the well-known mitochondrial stress marker, was included in the group ectopically up-regulated in anthers at the bicellular pollen stage of BT, LD and W11. Several other clusters were also regulated in a cytoplasm-specific manner during pollen development. These clear similarities in gene regulatory networks of BT-, LD- and W11-CMS lines indicate that the phylogenetic relationships of the mitochondrial genotypes are strongly correlated with nuclear gene expression patterns and pollen abortion phenotypes, providing evidence of the mitochondrial epistacy over the nuclear genome during pollen development. PMID- 20203239 TI - Analysis of the Rac/Rop small GTPase family in rice: expression, subcellular localization and role in disease resistance. AB - Plant-specific Rac/Rop small GTPases function as molecular switches for numerous signal transduction events, including defense responses. To understand the function of each of the seven Rac/Rop family members in rice, we studied the tissue-specific expression patterns of Rac/Rop genes by semi-quantitative reverse transcription-PCR (RT-PCR), and also Rac/Rop subcellular localization using green fluorescent protein (GFP) fusion proteins in transient expression systems. We also investigated the roles of these genes in disease resistance by testing single Rac/Rop-RNAi (RNA interference) plants against the rice blast pathogen Magnaporthe grisea. Our studies show that expression of OsRac2, 6 and 7 is very low in leaf blades, and reveal a strong correlation between the number of lysine and/or arginine (KR) residues in the polybasic region of Rac/Rop GTPases and their subcellular distribution in vivo. Infection assays showed that OsRac1 is a positive regulator of blast resistance, confirming previous observations, whereas OsRac4 and OsRac5 are negative regulators of blast resistance. OsRac6 may make minor contributions to disease resistance, while OsRac3 and OsRac7 are probably not involved in defense. Therefore, our study suggests that the rice Rac/Rop family plays multiple roles in diverse cellular activities and has both positive and negative functions in disease resistance. PMID- 20203240 TI - Pulmonary pathology in thyroid transcription factor-1 deficiency syndrome. AB - Thyroid transcription factor-1 (TTF-1) deficiency syndrome is characterized by neurologic, thyroidal, and pulmonary dysfunction. Children usually have mild-to severe respiratory symptoms and occasionally die of respiratory failure. Herein, we describe an infant with a constitutional 14q12-21.3 haploid deletion encompassing the TTF-1 gene locus who had cerebral dysgenesis, thyroidal dysfunction, and respiratory insufficiency. The clinical course was notable for mild hyaline membrane disease, continuous ventilatory support, and symmetrically distributed pulmonary cysts by imaging. He developed pneumonia and respiratory failure and died at 8 months. Pathologically, the lungs had grossly visible emphysematous changes with "cysts" up to 2 mm in diameter. The airway generations and radial alveolar count were diminished. In addition to acute bacterial pneumonia, there was focally alveolar septal fibrosis, pneumocyte hypertrophy, and clusters of airspace macrophages. Ultrastructurally, type II pneumocytes had numerous lamellar bodies, and alveolar spaces contained fragments of type II pneumocytes and extruded lamellar bodies. Although immunoreactivity for surfactant protein SP-A and ABCA3 was diminished, that for SP-B and proSP-C was robust, although irregularly distributed, corresponding to the distribution of type II pneumocytes. Immunoreactivity for TTF-1 protein was readily detected. In summation, we document abnormal airway and alveolar morphogenesis and altered expression of surfactant-associated proteins, which may explain the respiratory difficulties encountered in TTF-1 haploinsufficiency. These findings are consistent with experimental evidence documenting the important role of TTF-1 in pulmonary morphogenesis and surfactant metabolism. PMID- 20203241 TI - Pandemic 2009 influenza A in Argentina: a study of 337 patients on mechanical ventilation. AB - RATIONALE: The rapid spread of the 2009 Influenza A (H1N1) around the world underscores the need for a better knowledge of epidemiology, clinical features, outcomes, and mortality predictors, especially in the most severe presentations. OBJECTIVES: To describe these characteristics in patients with confirmed, probable, and suspected viral pneumonia caused by 2009 influenza A (H1N1) admitted to 35 intensive care units with acute respiratory failure requiring mechanical ventilation in Argentina, between June 3 and September 7. METHODS: Inception-cohort study including 337 consecutive adult patients. Data were collected in a form posted on the Argentinian Society of Intensive Care website. MEASUREMENTS AND MAIN RESULTS: Proportions of confirmed, probable, or suspected cases were 39%, 8%, and 53% and had similar outcomes. APACHE II was 18 +/- 7; age 47 +/- 17 years; 56% were male; and 64% had underlying conditions, with obesity (24%), chronic obstructive respiratory disease (18%), and immunosupression (15%) being the most common. Seven percent were pregnant. On admission, patients had severe hypoxemia (Pa(O(2))/Fi(O(2)) 140 [87-200]), extensive lung radiologic infiltrates (2.87 +/- 1.03 quadrants) and bacterial coinfection, (25%; mostly with Streptococcus pneumoniae). Use of adjuvants such as recruitment maneuvers (40%) and prone positioning (13%), and shock (72%) and acute kidney injury requiring hemodialysis (17%), were frequent. Mortality was 46%, and was similar across all ages. APACHE II, lowest Pa(O(2))/Fi(O(2)), shock, hemodialysis, prone positioning, and S. pneumoniae coinfection independently predicted death. CONCLUSIONS: Patients with 2009 influenza A (H1N1) requiring mechanical ventilation were mostly middle-aged adults, often with comorbidities, and frequently developed severe acute respiratory distress syndrome and multiorgan failure requiring advanced organ support. Case fatality rate was accordingly high. PMID- 20203242 TI - Endothelial progenitor cells and vascular dysfunction in children with obstructive sleep apnea. AB - RATIONALE: Endothelial dysfunction is a potential complication of obstructive sleep apnea syndrome (OSAS) in children ascribed to systemic inflammatory changes. However, not all children with OSAS will manifest endothelial dysfunction. OBJECTIVES: The variability in endothelial function in pediatric OSAS may be related to the ability to recruit repair mechanisms such as endothelial progenitor cells (EPCs). METHODS: Prepubertal nonhypertensive children with or without polysomonographically confirmed OSAS had endothelial function assessed in a morning fasted state using a modified hyperemic test involving cuff-induced occlusion of the radial and ulnar arteries. Blood was drawn and EPCs were assessed by flow cytometry and triple staining using antibodies against CD133, CD34, and vascular endothelial growth factor receptor-2 after isolation of peripheral blood mononuclear cells. SDF-1 levels were measured by ELISA. MEASUREMENTS AND MAIN RESULTS: Eighty children with OSAS (mean age 8.2 +/- 1.4 yr, mean body mass index [BMI] z-score, 1.43 +/- 0.3) and 20 controls (CO) matched for BMI, age, sex, and ethnicity were studied. Significant delays to peak capillary reperfusion after occlusion release (Tmax) occurred in OSAS children, but substantial variability was present. Despite similar OSAS severity, EPC counts, and stromal cell-derived factor-1 (SDF-1) levels were significantly lower among the 20 OSAS children with the longest Tmax, when compared with either the 20 children with normal Tmax values or to CO ( P < 0.01). Furthermore, Tmax was significantly and inversely correlated with EPCs (r(2), 0.51; P < 0.01), but neither EPCs nor Tmax were associated with apnea-hyponea index (AHI). CONCLUSIONS: Endothelial dysfunction is frequently present in OSAS. Variance in endothelial functional phenotype may not only reside in the individual susceptibility but also in the ability to recruit endothelial repair mechanisms. PMID- 20203243 TI - Neutralizing granulocyte/macrophage colony-stimulating factor inhibits cigarette smoke-induced lung inflammation. AB - RATIONALE: Cigarette smoke is the major cause of chronic obstructive pulmonary disease (COPD), and there is currently no satisfactory therapy to treat people with COPD. We have previously shown that granulocyte/macrophage colony stimulating factor (GM-CSF) regulates lung innate immunity to LPS through Akt/Erk activation of nuclear factor-kappaB and activator protein (AP)-1. OBJECTIVES: The aim of this study was to determine whether neutralization of GM-CSF can inhibit cigarette smoke-induced lung inflammation in vivo. METHODS: Male BALB/c mice were exposed to cigarette smoke generated from 9 cigarettes per day for 4 days. Mice were treated intranasally with 100 microg 22E9 (anti-GM-CSF mAb) and isotype control antibody on Days 2 and 4, 1 hour before cigarette smoke or sham exposure. On the fifth day mice were killed, and the lungs were lavaged with PBS and then harvested for genomic and proteomic analysis. MEASUREMENTS AND MAIN RESULTS: Cigarette smoke-exposed mice treated with anti-GM-CSF mAb had significantly less BALF macrophages and neutrophils, whole lung TNF-alpha, macrophage inflammatory protein (MIP)-2, and matrix metalloproteinase (MMP)-12 mRNA expression and lost less weight compared with smoke-exposed mice treated with isotype control. In contrast, smoke-induced increases in MMP-9 and net gelatinase activity were unaffected by treatment with anti-GM-CSF. In addition, neutralization of GM-CSF did not affect the phagocytic function of alveolar macrophages. CONCLUSIONS: GM CSF is a key mediator in smoke-induced airways inflammation, and its neutralization may have therapeutic implications in diseases such as COPD. PMID- 20203244 TI - Fluticasone reverses oxymetazoline-induced tachyphylaxis of response and rebound congestion. AB - RATIONALE: Chronic use of intranasal decongestants, such as oxymetazoline, leads to tachyphylaxis of response and rebound congestion, caused by alpha-adrenoceptor mediated down-regulation and desensitization of response. OBJECTIVES: We evaluated if tachyphylaxis can be reversed by intranasal fluticasone propionate, and the relative alpha(1)- and alpha(2)-adrenoceptor components of tachyphylaxis using the alpha(1)-antagonist prazosin. METHODS: In a randomized, double-blind, placebo-controlled, crossover design, 19 healthy subjects received intranasal oxymetazoline, 200 microg three times a day for 14 days, followed by the addition of fluticasone, 200 microg twice a day for a further 3 days. At Days 1, 14, and 17, participants received a single dose of oral prazosin, 1 mg, or placebo with measurements made before and 2 hours later. MEASUREMENTS AND MAIN RESULTS: Outcomes evaluated were peak nasal inspiratory flow, nasal resistance, blood flow, and oxymetazoline dose-response curve (DRC). On Day 14 versus Day 1, inspiratory flow decreased (mean difference, 95% confidence interval) (-47.9 L x min(-1); -63.9 to -31.9; P < 0.001) and the DRC shifted downward (24.8 L x min( 1); 20.3-29.3; P < 0.001). On Day 17 versus Day 14, after fluticasone, inspiratory flow increased (45 L x min(-1); 30-61; P < 0.001) and the DRC shifted upward (26.2 L x min(-1); 21.7-30.7; P < 0.001). On Day 1, prazosin reduced inspiratory flow (-52.6 L x min(-1); -19.2 to -86) compared with baseline. This effect was abolished on Day 14 (7.9 L x in(-1); -41.3 to 25.5). CONCLUSIONS: Oxymetazoline-induced tachyphylaxis and rebound congestion are reversed by intranasal fluticasone. Further studies are indicated to evaluate if combination nasal sprays of decongestant and corticosteroid are an effective strategy to obviate tachyphylaxis and rebound in rhinitis. Clinical trial registered with www.clinicaltrials.gov (NCT 00487032). PMID- 20203245 TI - Smoking, use of moist snuff, and risk of chronic inflammatory diseases. AB - RATIONALE: Cigarette smoking is emerging as a strong risk factor in the otherwise unknown etiology of chronic inflammatory diseases. Whether the same applies also to smokeless tobacco remains unknown. Nicotine is a powerful modifier of the inflammatory response. By comparing risks associated with tobacco smoking and with smokeless tobacco, the role of nicotine in the development of chronic inflammation may be evaluated. OBJECTIVES: To assess and compare the risks of rheumatoid arthritis (RA), ulcerative colitis (UC), Crohn's disease (CD), sarcoidosis, and multiple sclerosis (MS) associated with cigarette smoking and with the use of Swedish moist snuff. METHODS: We performed a cohort study of 277,777 males within a cohort of Swedish construction workers who had provided information about tobacco use in 1978-1993. Cross-linkage to the nationwide Swedish Hospital Discharge Register provided information about the occurrence of RA, UC, CD, sarcoidosis, and MS through 2004. MEASUREMENTS AND MAIN RESULTS: Age adjusted relative risks (RRs) associated with smoking and moist snuff, respectively, were estimated by Cox regression. Ever-smoking was associated with an increased risk for RA (RR, 2.1; 95% confidence interval [CI], 1.7-2.5), CD (RR, 1.5; 95% CI, 1.2-1.8), MS (RR, 1.9; 95% CI, 1.4-2.6), and UC (RR, 1.3; 95% CI, 1.1-1.5, confined to ex-smokers), and a decreased risk of sarcoidosis (RR, 0.5; 95% CI, 0.4-0.5). By contrast, ever-use of moist snuff, adjusted for smoking, was not associated with RA (RR, 1.0; 95% CI, 0.9-1.2), UC (RR, 1.1; 95% CI, 0.9-1.2), CD (RR, 0.9; 95% CI, 0.8-1.1), sarcoidosis (RR, 1.1; 95% CI, 0.8 1.5), or MS (RR, 1.0; 95% CI, 0.8-1.4). CONCLUSIONS: Smokeless tobacco does not increase the risk of chronic inflammatory diseases, suggesting that inhaled nonnicotinic components of cigarette smoke are more important than nicotine itself in the etiology of these diseases. PMID- 20203247 TI - Dust exposure assessed by a job exposure matrix is associated with increased annual decline in FEV1: a 5-year prospective study of employees in Norwegian smelters. AB - RATIONALE: The relationship between dust exposure and annual decline in lung function among employees in the smelting industry is unknown. OBJECTIVES: The aim of the study was to investigate the relationship between annual change in lung function and occupational dust exposure among workers in 15 Norwegian smelters. METHODS: All employees (n = 2,620) were examined annually for 5 years (11,335 health examinations). At each examination spirometry was performed and a respiratory questionnaire was completed. The smelters were grouped as follows: (1) ferrosilicon alloys (FeSi) and silicon metal (Si-metal); and (2) silicon manganese (SiMn), ferromanganese (FeMn), and ferrochromium (FeCr). A job exposure matrix was available on the basis of 2,619 personal dust exposure measurements. The association between lung function expressed as FEV(1) and FVC per squared height (height(2)) and dust exposure was investigated using multivariate linear mixed model analyses. MEASUREMENTS AND MAIN RESULTS: The annual change in FEV(1)/height(2) (deltaFEV(1)) related to dust exposure in the FeSi/Si-metal and SiMn/FeMn/FeCr smelters was -0.42 (95% confidence interval, -0.95 to 0.11) and 1.1 (-2.1 to -0.12) (ml/m(2)) x (mg/m(3))(-1) x year(-1), respectively. The annual decline in FEV(1)/height(2) was 1.6 ml/m(2) (0.15 to 3.1) steeper in smokers than in nonsmokers. The median geometric mean of the time-weighted dust exposure concentration levels of the employees was 2.3 mg/m(3) in the FeSi/Si metal smelters and 1.6 mg/m(3) in the SiMn/FeMn/FeCr smelters. Among nonsmokers, deltaFEV(1) was -0.86 (-1.6 to -0.10) and -1.1 (-2.5 to 0.25) (ml/m(2)) x (mg/m(3))(-1) x year(-1) in the FeSi/Si-metal and SiMn/FeMn/FeCr smelters, respectively. Thus, for a 1.80 m tall employee the annual decline in FEV(1) associated with average dust exposure was 5.7 ml/year in the SiMn/FeMn/FeCr smelters, and 6.4 ml/year for a nonsmoker in the FeSi/Si-metal smelters. CONCLUSIONS: In all smelters combined, the annual change in FEV(1) was negatively associated with increasing dust exposure. This association was also significant among workers in SiMn/FeMn/FeCr smelters and among nonsmokers in the FeSi/Si metal smelters. PMID- 20203248 TI - Localization and properties of cholinesterases in the common prawn (Palaemon serratus): A kinetic-histochemical study. AB - Due to the diversity in biochemical properties and tissue distribution of cholinesterase (ChE) enzymes, a characterization should be performed before they are used as biomarkers for monitoring pesticide contamination. In this study we investigate the distribution of ChEs and their kinetic properties in diverse tissues of the common prawn Palaemon serratus. The results concerning the histochemical localization of ChEs suggest that the highest amount of ChE activity occurs in prawn eyes, followed by the brain, gills, and digestive tract. Negligible staining was observed in the muscle. We describe the kinetic properties of ChEs in eyes, gills, and hepatopancreas, investigating their substrate preferences with different thiocholine esters and their sensitivity to inhibition with selective inhibitors. The results suggest that the studied enzymes are ChEs and not nonspecific esterases, due to their apparent affinity for choline esters, with a distinct preference for the substrate acetylthiocholine, and their high sensitivity to inhibition by eserine sulfate. P. serratus eyes can be considered the best tissue for recovery of ChE enzyme: this tissue is easy to isolate, it expresses high levels of ChE, and the enzyme shows properties of a vertebrate AChE. PMID- 20203246 TI - Diminished prostaglandin E2 contributes to the apoptosis paradox in idiopathic pulmonary fibrosis. AB - RATIONALE: Patients with idiopathic pulmonary fibrosis (IPF), a progressive disease with a dismal prognosis, exhibit an unexplained disparity of increased alveolar epithelial cell (AEC) apoptosis but reduced fibroblast apoptosis. OBJECTIVES: To examine whether the failure of patients with IPF to up-regulate cyclooxygenase (COX)-2, and thus the antifibrotic mediator prostaglandin (PG)E(2), accounts for this imbalance. METHODS: Fibroblasts and primary type II AECs were isolated from control and fibrotic human lung tissue. The effects of COX-2 inhibition and exogenous PGE(2) on fibroblast and AEC sensitivity to Fas ligand (FasL)-induced apoptosis were assessed. MEASUREMENTS AND MAIN RESULTS: IPF lung fibroblasts are resistant to FasL-induced apoptosis compared with control lung fibroblasts. Inhibition of COX-2 in control lung fibroblasts resulted in an apoptosis-resistant phenotype. Administration of PGE(2) almost doubled the rate of FasL-induced apoptosis in fibrotic lung fibroblasts compared with FasL alone. Conversely, in primary fibrotic lung type II AECs, PGE(2) protected against FasL induced apoptosis. In human control and, to a greater extent, fibrotic lung fibroblasts, PGE(2) inhibits the phosphorylation of Akt, suggesting that regulation of this prosurvival protein kinase is an important mechanism by which PGE(2) modulates cellular apoptotic responses. CONCLUSIONS: The observation that PGE(2) deficiency results in increased AEC but reduced fibroblast sensitivity to apoptosis provides a novel pathogenic insight into the mechanisms driving persistent fibroproliferation in IPF. PMID- 20203249 TI - Contrary effects of octopamine receptor ligands on behavioral and neuronal changes in locomotion of lymnaea. AB - The pond snail Lymnaea stagnalis moves along the sides and bottom of an aquarium, but it can also glide upside down on its back below the water's surface. We have termed these two forms of locomotion "standard locomotion" and "upside-down gliding," respectively. Previous studies showed that standard locomotion is produced by both cilia activity on the foot and peristaltic contraction of the foot muscles, whereas upside-down gliding is mainly caused by cilia activity. The pedal A neurons are thought to receive excitatory octopaminergic input, which ultimately results in increased cilia beating. However, the relationship between locomotory speed and the responses of these neurons to octopamine is not known. We thus examined the effects of both an agonist and an antagonist of octopamine receptors on locomotory speed and the firing rate of the pedal A neurons. We also examined, at the electron and light-microscopic levels, whether structural changes occur in cilia following the application of either an agonist or an antagonist of octopamine receptors to the central nervous system (CNS). We found that the application of an octopamine antagonist to the CNS increased the speed of both forms of locomotion, whereas application of octopamine increased only the firing rate of the pedal A neurons. Microscopic examination of the cilia proved that there were no changes in their morphology after application of octopamine ligands. These data suggest that there is an unidentified octopaminergic neuronal network in the CNS whose activation reduces cilia movement and thus locomotory speed. PMID- 20203250 TI - A "Mimic Octopus" in the Atlantic: Flatfish mimicry and camouflage by Macrotritopus defilippi. AB - The sand-dwelling octopus Macrotritopus defilippi was filmed or photographed in five Caribbean locations mimicking the swimming behavior (posture, style, speed, duration) and coloration of the common, sand-dwelling flounder Bothus lunatus. Each species was exceptionally well camouflaged when stationary, and details of camouflaging techniques are described for M. defilippi. Octopuses implemented flounder mimicry only during swimming, when their movement would give away camouflage in this open sandy habitat. Thus, both camouflage and fish mimicry were used by the octopuses as a primary defense against visual predators. This is the first documentation of flounder mimicry by an Atlantic octopus, and only the fourth convincing case of mimicry for cephalopods, a taxon renowned for its polyphenism that is implemented mainly by neurally controlled skin patterning, but also-as shown here-by their soft flexible bodies. PMID- 20203251 TI - Spirochete attachment ultrastructure: Implications for the origin and evolution of cilia. AB - The fine structure of spirochete attachments to the plasma membrane of anaerobic protists displays variations here interpreted as legacies of an evolutionary sequence analogous to that from free-living spirochetes to undulipodia (eukaryotic "flagella" and homologous structures). Attached spirochetes form a vestment, a wriggling fringe of motile cells at the edge of the plasma membrane of unidentified cellulolytic protist cells in the hypertrophied hindgut of the digestive system of Mastotermes darwiniensis, the large wood-feeding termite from northern Australia. From the membrane extend both undulipodia and a complex of comparably sized (10-12 microm x 0.2-0.3 microm) ectosymbiotic spirochetes that resembles unruly ciliated epithelium. In the intestines are helical (swimming) and round-body morphotypes. Round bodies (RBs) are slow or immotile spirochetes, propagules known to revert to typical swimming helices under culture conditions favorable for growth. The surfaces of both the spirochete gram-negative eubacteria and the parabasalid protists display distinctive attachment structures. The attached hypertrophied structures, some of which resemble ciliate kinetids, are found consistently at sites where the spirochete termini contact the protist plasma membranes. PMID- 20203252 TI - Effects of estradiol and progesterone on the reproduction of the freshwater crayfish Cherax albidus. AB - In this study we have investigated the role of 17beta-estradiol and progesterone in the reproduction of the crayfish Cherax albidus by using vitellogenin (VTG) as a biomarker. Early-vitellogenic (EV), full-vitellogenic (FV), and non vitellogenic (NV) females of Cherax albidus were treated with 17beta-estradiol, progesterone, or both for 4 weeks. Levels of VTG mRNA in the hepatopancreas were detected by RT-PCR. The PCR product was sequenced and showed 97% homology with Cherax quadricarinatus VTG. 17beta-estradiol was more effective than progesterone and 17beta-estradiol plus progesterone in increasing the vitellogenin transcript in the hepatopancreas of EV and FV females. On the contrary, progesterone was more effective than 17beta-estradiol and 17beta-estradiol plus progesterone in increasing the vitellogenin concentration in the hemolymph of EV and FV females. Hepatopancreas histology and fatty acid composition of females injected with hormones showed major modifications. No effects were registered in NV females. In conclusion, 17beta-estradiol and progesterone influence VTG synthesis, although our data indicate that they act through different pathways and are not effective until the proper hormonal environment is established, as demonstrated by their inefficacy in NV females. PMID- 20203253 TI - Ribosomal analysis of rapid rates of protein synthesis in the Antarctic sea urchin Sterechinus neumayeri. AB - Previous research has shown that developing stages of the Antarctic sea urchin Sterechinus neumayeri have high rates of protein synthesis that are comparable to those of similar species living in much warmer waters. Direct measurements of the biosynthetic capacities of isolated ribosomes have not been reported for marine organisms living in the extreme-cold environment of Antarctica. Such measurements are required for a mechanistic understanding of how the critical and highly complex processes involved in protein synthesis are regulated in animals living in the coldest marine environment on Earth (< -1 degrees C). We tested the hypothesis that high rates of protein synthesis in the cold are a direct result of high biosynthetic capacities of ribosomes engaged in protein synthesis. Our results show that the rate at which ribosomes manufacture proteins (i.e., the peptide elongation rate) at -1 degrees C is surprisingly similar to rates measured in other sea urchin species at temperatures that are over 15 degrees C warmer. Average peptide elongation rates for a range of developmental stages of the Antarctic sea urchin were 0.36 codons s(-1) (+/- 0.05, SE). On the basis of subcellular rate determinations of ribosomal activity, we calculated stage specific rates of protein synthesis for blastulae and gastrulae to be 3.7 and 6.5 ng protein h(-1), respectively. These findings support the conclusion that the high rates of biosynthesis previously reported for the Antarctic sea urchin are an outcome of high ribosomal activities. PMID- 20203254 TI - Identification and role of carbohydrates on the surface of gametes in the zebra mussel, Dreissena polymorpha. AB - The objective of this study is to identify surface carbohydrates on zebra mussel, Dreissena polymorpha, eggs and sperm and to analyze their potential role in fertilization. The lectins WGA, Con A, LcH, LTA, SBA, PNA, and GSII were tested for affinity to both eggs and sperm. WGA, Con A, and LcH uniformly labeled eggs. LTA, SBA, PNA, and GSII did not. WGA labeled the entire sperm surface including the unreacted acrosome. Labeling by Con A, LcH, LTA, SBA, PNA, and GSII was restricted to the inner acrosomal region of acrosome-reacted sperm. GSII labeling suggests the presence of N-acetyl-d-glucosamine (GlcNAc) only in the inner acrosomal membrane and not on eggs. GlcNAc blocked sperm-egg binding. GSII labeling was associated with a ring-like structure at the site of sperm entry intimately associated with sperm-egg binding. Nonfertilizing sperm were detached from the egg surface along with the GSII basal ring about 15 min postinsemination in a process blocked by trypsin inhibitors. PMID- 20203255 TI - Microalgal cell surface carbohydrates as recognition sites for particle sorting in suspension-feeding bivalves. AB - Cell surface carbohydrates play important roles in cell recognition mechanisms. Recently, we provided evidence that particle selection by suspension-feeding bivalves can be mediated by interactions between carbohydrates associated with the particle surface and lectins present in mucus covering bivalve feeding organs. In this study, we used lectins tagged with fluorescein isothiocyanate (FITC) to characterize carbohydrate moieties on the surface of microalgal species and evaluate the effect of oyster mucus on lectin binding. These analyses revealed that concanavalin A (Con A), one of six lectins tested, bound to Isochrysis sp., while Nitzschia closterium reacted with Pisum sativum agglutinin (PNA) and peanut agglutinin (PEA). The cell surface of Rhodomonas salina bound with PNA and Con A, and Tetraselmis maculata cell surface was characterized by binding with PNA, PEA, and Con A. Pre-incubation of microalgae with oyster pallial mucus significantly decreased the binding of FITC-labeled lectins, revealing that lectins present in mucus competitively blocked binding sites. This decrease was reversed by washing mucus-coated microalgae with specific carbohydrates. These results were used to design a feeding experiment to evaluate the effect of lectins on sorting of microalgae by oysters. Crassostrea virginica fed with an equal ratio of Con A-labeled Isochrysis sp. and unlabeled Isochrysis sp. produced pseudofeces that were significantly enriched in Con A-labeled Isochrysis sp. and depleted in unlabeled microalgae. Selection occurred even though two physical-chemical surface characteristics of the cells in each treatment did not differ significantly. This work confirms the involvement of carbohydrate-lectin interaction in the particle sorting mechanism in oysters, and provides insights into the carbohydrate specificity of lectins implicated in the selection of microalgal species. PMID- 20203256 TI - Difference in thermotolerance between green and red color variants of the Japanese sea cucumber, Apostichopus japonicus Selenka: Hsp70 and heat-hardening effect. AB - We studied thermal tolerance limits, heat-hardening, and Hsp70 to elucidate the difference in thermotolerance between two color variants of the sea cucumber Apostichopus japonicus. Green and Red variants occupy different habitats and have different aestivation responses to high temperature in summer. In the absence of heat-hardening, the variants showed no difference in the temperature at which 50% of the individuals died: Green, 31.49 degrees C; Red, 31.39 degrees C. However, Green specimens acquired higher thermotolerance than Red after a prior sublethal heat exposure. After 72 h of recovery from a heat-hardening treatment (30 degrees C for 2 h), the survival of Green variants was more than 50% and that of Red was less than 5% when they were treated at 33 degrees C for 2 h. Levels of mRNA and protein for Hsp70 were significantly higher in Green than Red after the heat shock of 30 degrees C, and the stability of hsp70 mRNA of Green was significantly higher than that of Red. Our findings suggest that within the same species, different variants that have similar thermal limits in the absence of heat hardening can acquire different thermotolerances after a prior sublethal heat shock. The difference in induced thermotolerance between Green and Red is closely related to the expression pattern of Hsp70, which was partly governed by the stability of hsp70 mRNA. PMID- 20203258 TI - Dynamic calibration of pharmacokinetic parameters in dose-finding studies. AB - We introduce a dose-finding algorithm to be used to identify a level of dose that corresponds to some given targeted response. Our motivation arises from problems where the response is a continuously measured quantity, typically some pharmacokinetic parameter. We consider the case where an agreed level of response has been determined from earlier studies on some population and the purpose of the current trial is to obtain the same, or a comparable, level of response in a new population. This relates to bridging studies. The example driving our interest comes from studies on drugs for HIV that have already been evaluated in adults and where the new studies are to be carried out in children. These drugs have the ability to produce some given mean pharmacokinetic response in the adult population, and the goal is to calibrate the dose in order to obtain a comparable response in the childhood population. In practice, it may turn out that the dose producing some desired mean response is also associated with an unacceptable rate of toxicity. In this case, we may need to reevaluate the target response and this is readily achieved. In simulations, the algorithm can be seen to work very well. In the most challenging situations for the method, those where the targeted response corresponds to a region of the dose-response curve that is relatively flat, the algorithm can still perform satisfactorily. PMID- 20203257 TI - Subcuticular bacteria associated with two common New Zealand echinoderms: Characterization using 16S rRNA sequence analysis and fluorescence in situ hybridization. AB - Many echinoderms contain subcuticular bacteria (SCB), symbionts which reside in the lumen between the host's epidermal cells and outer cuticle. This relationship is common, existing in about 60% of echinoderms studied so far, yet the function of SCB remains largely unknown. In this study, phylogenetic analysis was carried out on 16S rRNA sequences obtained from echinoderm-associated bacteria, resulting in the identification of four species of putative SCB. All four bacteria were identified from the holothurian Stichopus mollis, and two of the four were also found in the asteroid Patiriella sp. Two of these bacteria belong to the Alphaproteobacteria, and two to the Gammaproteobacteria. In addition to phylogenetic analysis, fluorescence in situ hybridization (FISH) assays were carried out on Patiriella sp., S. mollis, and the asteroid Astrostole scabra. Results showed that Patiriella sp. and S. mollis contain SCB, in agreement with the phylogenetic analysis, while SCB were not detected in A. scabra. Of the bacteria detected using FISH, more than 80% were recognized as belonging to the Alphaproteobacteria in both host species. However, in S. mollis about 20% of the detected SCB successfully hybridized with the Gammaproteobacteria-specific probe, whereas bacteria belonging to this class were never observed in Patiriella sp. This is only the second study to characterize SCB by molecular means, and is the first to identify SCB in situ using FISH. PMID- 20203259 TI - On quantifying the magnitude of confounding. AB - When estimating the association between an exposure and outcome, a simple approach to quantifying the amount of confounding by a factor, Z, is to compare estimates of the exposure-outcome association with and without adjustment for Z. This approach is widely believed to be problematic due to the nonlinearity of some exposure-effect measures. When the expected value of the outcome is modeled as a nonlinear function of the exposure, the adjusted and unadjusted exposure effects can differ even in the absence of confounding (Greenland , Robins, and Pearl, 1999); we call this the nonlinearity effect. In this paper, we propose a corrected measure of confounding that does not include the nonlinearity effect. The performances of the simple and corrected estimates of confounding are assessed in simulations and illustrated using a study of risk factors for low birth-weight infants. We conclude that the simple estimate of confounding is adequate or even preferred in settings where the nonlinearity effect is very small. In settings with a sizable nonlinearity effect, the corrected estimate of confounding has improved performance. PMID- 20203260 TI - Hematopoietic stem cell transplantation for multiple myeloma beyond 2010. AB - Autologous stem cell transplantation (ASCT) is considered the gold standard in the frontline therapy of younger patients with multiple myeloma because it results in higher complete remission (CR) rates and longer event-free survival than conventional chemotherapy. The greatest benefit from ASCT is obtained in patients achieving CR after transplantation, the likelihood of CR being associated with the M-protein size at the time of transplantation. The incorporation of novel agents results in higher pre- and posttransplantation CR rates. Induction with bortezomib-containing regimens is encouraging in patients with poor-risk cytogenetics. However, longer follow-up is required to assess the impact of this increased CR on long-term survival. The results of posttransplantation consolidation/maintenance with new drugs are encouraging. All this indicates that, in the era of novel agents, high-dose therapy should be optimized rather than replaced. Because of its high transplantation-related mortality, myeloablative allografting has been generally replaced by reduced intensity conditioning (reduced intensity conditioning allogeneic transplantation). The best results are achieved after a debulky ASCT, with a progression-free survival plateau of 25% to 30% beyond 6 years from reduced intensity conditioning allogeneic transplantation. The development of novel reduced-intensity preparative regimens and peri- and posttransplantation strategies aimed at minimizing graft-versus-host disease, and enhancing the graft versus-myeloma effect are key issues. PMID- 20203261 TI - Inhibition of NEDD8-activating enzyme: a novel approach for the treatment of acute myeloid leukemia. AB - NEDD8 activating enzyme (NAE) has been identified as an essential regulator of the NEDD8 conjugation pathway, which controls the degradation of many proteins with important roles in cell-cycle progression, DNA damage, and stress responses. Here we report that MLN4924, a novel inhibitor of NAE, has potent activity in acute myeloid leukemia (AML) models. MLN4924 induced cell death in AML cell lines and primary patient specimens independent of Fms-like tyrosine kinase 3 expression and stromal-mediated survival signaling and led to the stabilization of key NAE targets, inhibition of nuclear factor-kappaB activity, DNA damage, and reactive oxygen species generation. Disruption of cellular redox status was shown to be a key event in MLN4924-induced apoptosis. Administration of MLN4924 to mice bearing AML xenografts led to stable disease regression and inhibition of NEDDylated cullins. Our findings indicate that MLN4924 is a highly promising novel agent that has advanced into clinical trials for the treatment of AML. PMID- 20203263 TI - Leukemia-associated minor histocompatibility antigen discovery using T-cell clones isolated by in vitro stimulation of naive CD8+ T cells. AB - T-cell immunotherapy that targets minor histocompatibility (H) antigens presented selectively by recipient hematopoietic cells, including leukemia, could prevent and treat leukemic relapse after hematopoietic cell transplantation without causing graft-versus-host disease. To provide immunotherapy that can be applied to a majority of transplantation recipients, it is necessary to identify leukemia associated minor H antigens that result from gene polymorphisms that are balanced in the population and presented by common human leukocyte antigen alleles. Current approaches for deriving minor H antigen-specific T cells, which provide essential reagents for the molecular identification and characterization of the polymorphic genes that encode the antigens, rely on in vivo priming and are often unsuccessful. We show that minor H antigen-specific cytotoxic T lymphocyte precursors are found predominantly in the naive CD8(+) T-cell subset and provide an efficient strategy for in vitro priming of native T cells to generate T cells to a broad diversity of minor H antigens presented with common human leukocyte antigen alleles. We used this approach to derive a panel of stable cytotoxic T lymphocyte clones for discovery of genes that encode minor H antigens and identify a novel antigen expressed on acute myeloid leukemia stem cells and minimally in graft-versus-host disease target tissues. PMID- 20203262 TI - Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups. AB - Warfarin-dosing algorithms incorporating CYP2C9 and VKORC1 -1639G>A improve dose prediction compared with algorithms based solely on clinical and demographic factors. However, these algorithms better capture dose variability among whites than Asians or blacks. Herein, we evaluate whether other VKORC1 polymorphisms and haplotypes explain additional variation in warfarin dose beyond that explained by VKORC1 -1639G>A among Asians (n = 1103), blacks (n = 670), and whites (n = 3113). Participants were recruited from 11 countries as part of the International Warfarin Pharmacogenetics Consortium effort. Evaluation of the effects of individual VKORC1 single nucleotide polymorphisms (SNPs) and haplotypes on warfarin dose used both univariate and multi variable linear regression. VKORC1 1639G>A and 1173C>T individually explained the greatest variance in dose in all 3 racial groups. Incorporation of additional VKORC1 SNPs or haplotypes did not further improve dose prediction. VKORC1 explained greater variability in dose among whites than blacks and Asians. Differences in the percentage of variance in dose explained by VKORC1 across race were largely accounted for by the frequency of the -1639A (or 1173T) allele. Thus, clinicians should recognize that, although at a population level, the contribution of VKORC1 toward dose requirements is higher in whites than in nonwhites; genotype predicts similar dose requirements across racial groups. PMID- 20203264 TI - A key role for ATF3 in regulating mast cell survival and mediator release. AB - Activating transcription factor 3 (ATF3) is a basic leucine zipper transcription factor that plays a regulatory role in inflammation, cell division, and apoptosis. Mast cells (MCs) initiate many inflammatory responses and have a central role in allergy and allergic diseases. We report here that ATF3 has a central role in MC development and function. Bone marrow-derived MC populations from ATF3-deficient mice are unresponsive to interleukin-3 (IL-3)-induced maturation signals, and this correlates with increased apoptosis, diminished activation of the Akt kinase, and decreased phosphorylation of the proapoptotic protein Bad. Furthermore, ATF3-null mice lacked MCs in the peritoneum and dermis, showing that the in vitro results are recapitulated in vivo. ATF3-null MCs also showed functional defects; high-affinity immunoglobulin E receptor-mediated degranulation was significantly inhibited, whereas IL-4 and IL-6 expression was enhanced. This dual role of ATF3 provides insight into the complex interplay between MC development and its subsequent physiologic role. PMID- 20203265 TI - NF-kappaB balances vascular regression and angiogenesis via chromatin remodeling and NFAT displacement. AB - Extracellular factors control the angiogenic switch in endothelial cells (ECs) via competing survival and apoptotic pathways. Previously, we showed that proangiogenic and antiangiogenic factors target the same signaling molecules, which thereby become pivots of angiogenic balance. Here we show that in remodeling endothelium (ECs and EC precursors) natural angiogenic inhibitors enhance nuclear factor-kappaB (NF-kappaB) DNA binding, which is critical for antiangiogenesis, and that blocking the NF-kappaB pathway abolishes multiple antiangiogenic events in vitro and in vivo. NF-kappaB induction by antiangiogenic molecules has a dual effect on transcription. NF-kappaB acts as an activator of proapoptotic FasL and as a repressor of prosurvival cFLIP. On the FasL promoter, NF-kappaB increases the recruitment of HAT p300 and acetylated histones H3 and H4. Conversely, on cFLIP promoter, NF-kappaB increases histone deacetylase 1 (HDAC1), decreases p300 and histone acetylation, and reduces the recruitment of NFAT, a transcription factor critical for cFLIP expression. Finally, we found a biphasic effect, when HDAC inhibitors (HDACi) were used to test the dependence of pigment epithelial-derived factor activity on histone acetylation. The cooperative effect seen at low doses switches to antagonistic as the concentrations increase. Our study defines an interactive transcriptional network underlying angiogenic balance and points to HDACi as tools to manipulate the angiogenic switch. PMID- 20203267 TI - Delineation of precursors in murine spleen that develop in contact with splenic endothelium to give novel dendritic-like cells. AB - Hematopoietic cell lineages are best described in terms of distinct progenitors with limited differentiative capacity. To distinguish cell lineages, it is necessary to define progenitors and induce their differentiation in vitro. We previously reported in vitro development of immature dendritic-like cells (DCs) in long-term cultures (LTCs) of murine spleen, and in cocultures of spleen or bone marrow (BM) over splenic endothelial cell lines derived from LTCs. Cells produced are phenotypically distinct CD11b(hi)CD11c(lo)CD8(-)MHC-II(-) cells, tentatively named L-DCs. Here we delineate L-DC progenitors as different from known DC progenitors in BM and DC precursors in spleen. The progenitor is contained within the lineage-negative (Lin)(-)c-kit(+) subset in neonatal and adult spleen. This subset has multipotential reconstituting ability in mice. In neonatal spleen, the progenitor is further enriched within the c-kit(lo) and CD34(+) subsets of Lin(-)c-kit(+) cells. These cells seed cocultures of splenic endothelial cells, differentiating to give L-DCs that can activate T cells. L-DC progenitors are distinguishable from described splenic CD11c(lo) DC precursors and from Fms-like tyrosine kinase 3(+) DC progenitors in BM. Overall, this study confirms that LTCs are a physiologically relevant culture system for in vitro development of a novel DC type from spleen progenitors. PMID- 20203266 TI - Multilineage dysplasia has no impact on biologic, clinicopathologic, and prognostic features of AML with mutated nucleophosmin (NPM1). AB - NPM1-mutated acute myeloid leukemia (AML) is a provisional entity in the 2008 World Health Organization (WHO) classification of myeloid neoplasms. The significance of multilineage dysplasia (MLD) in NPM1-mutated AML is unclear. Thus, in the 2008 WHO classification, NPM1-mutated AML with MLD is classified as AML with myelodysplasia (MD)-related changes (MRCs). We evaluated morphologically 318 NPM1-mutated AML patients and found MLD in 23.3%. Except for a male predominance and a lower fms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) incidence in the MLD(+) group, no differences were observed in age, sex, cytogenetics, and FLT3--tyrosine kinase domain between NPM1 mutated AML with and without MLD. NPM1-mutated AML with and without MLD showed overlapping immunophenotype (CD34 negativity) and gene expression profile (CD34 down-regulation, HOX genes up-regulation). Moreover, overall and event-free survival did not differ among NPM1-mutated AML patients independently of whether they were MLD(+) or MLD(-), the NPM1-mutated/FLT3-ITD negative genotype showing the better prognosis. Lack of MLD impact on survival was confirmed by multivariate analysis that highlighted FLT3-ITD as the only significant prognostic parameter in NPM1-mutated AML. Our findings indicate that NPM1 mutations rather than MLD dictate the distinctive features of NPM1-mutated AML. Thus, irrespective of MLD, NPM1-mutated AML represents one disease entity clearly distinct from AML with MRCs. PMID- 20203268 TI - The transcription factor Gfi1 regulates G-CSF signaling and neutrophil development through the Ras activator RasGRP1. AB - The transcription factor growth factor independence 1 (Gfi1) and the growth factor granulocyte colony-stimulating factor (G-CSF) are individually essential for neutrophil differentiation from myeloid progenitors. Here, we provide evidence that the functions of Gfi1 and G-CSF are linked in the regulation of granulopoiesis. We report that Gfi1 promotes the expression of Ras guanine nucleotide releasing protein 1 (RasGRP1), an exchange factor that activates Ras, and that RasGRP1 is required for G-CSF signaling through the Ras/mitogen activated protein/extracellular signal-regulated kinase (MEK/Erk) pathway. Gfi1 null mice have reduced levels of RasGRP1 mRNA and protein in thymus, spleen, and bone marrow, and Gfi1 transduction in myeloid cells promotes RasGRP1 expression. When stimulated with G-CSF, Gfi1-null myeloid cells are selectively defective at activating Erk1/2, but not signal transducer and activator of transcription 1 (STAT1) or STAT3, and fail to differentiate into neutrophils. Expression of RasGRP1 in Gfi1-deficient cells rescues Erk1/2 activation by G-CSF and allows neutrophil maturation by G-CSF. These results uncover a previously unknown function of Gfi1 as a regulator of RasGRP1 and link Gfi1 transcriptional control to G-CSF signaling and regulation of granulopoiesis. PMID- 20203269 TI - MicroRNA and proliferation control in chronic lymphocytic leukemia: functional relationship between miR-221/222 cluster and p27. AB - We investigated functional relationships between microRNA 221/222 (miR-221/222) cluster and p27, a key regulator of cell cycle, in chronic lymphocytic leukemia (CLL). The enforced expression of miR-221/222 in the CLL cell line MEC1 induced a significant down-regulation of p27 protein and conferred a proliferative advantage to the transduced cells that exhibited faster progression into the S phase of the cell cycle. Accordingly, expression of miR-221/miR-222 and p27 was found to be inversely related in leukemic cells obtained from peripheral blood (PB) of 38 patients with CLL. Interestingly, when miR-221/222 and p27 protein were evaluated in different anatomic compartments (lymph nodes or bone marrow) of the same patients, increased expression of the 2 miRNAs became apparent compared with PB. This finding was paralleled by a low expression of p27. In addition, when CLL cells were induced in vitro to enter cell cycle (eg, with cytosine phosphate guanine oligodeoxynucleotide), a significant increase of miR-221/222 expression and a marked down-regulation of p27 protein were evident. These data indicate that the miR-221/222 cluster modulates the expression of p27 protein in CLL cells and lead to suggest that miR-221/222 and p27 may represent a regulatory loop that helps maintaining CLL cells in a resting condition. PMID- 20203270 TI - IVIg immune inhibitory activity: APC is key. PMID- 20203271 TI - HIT: more than just heparin. PMID- 20203272 TI - p38: signaling improved platelet storage? PMID- 20203273 TI - Separation of GVHD and GVL. PMID- 20203274 TI - Glandular odontogenic cyst: systematic review. AB - OBJECTIVES: The aim of this study was to evaluate the principal features of "glandular odontogenic cyst" (GOC), by systematic review (SR), and to compare their frequencies among four global groups. METHODS: The databases searched were the PubMed interface of MEDLINE and LILACS. Only those reports of GOCs that occurred in a series in the reporting authors' caseload were considered. All cases were confirmed histopathologically. RESULTS: 18 reports on 17 series of consecutive cases were included in the SR. GOC affected males twice as frequently and the mandible almost three times as frequently. The mean age at first presentation was 44 years, coincident with that of the Western global group, in which the largest proportion of reports and cases first presented in the second half of the fifth decade. However, age at presentation of GOCs in the East Asian and sub-Saharan African global groups was nearly a decade younger, this was significant. Six reports included details of at least one clinical presentation. Eight reports included at least one conventional radiological feature. There were some significant differences between global groups. The Western global group had a particular predilection for the anterior sextants of both jaws. The sub-Saharan African group displayed buccolingual expansion (as did the Latin American group) and tooth displacement in every case. 18% of GOCs recurred overall, except in the sub-Saharan African global group. CONCLUSIONS: GOCs have a marked propensity to recur in most global groups. GOCs presented in older patients and with swellings, affected the anterior sextants of both jaws, and radiologically were more likely to present as a well-defined unilocular radiolucency with buccolingual expansion. Tooth displacement, root resorption and an association with unerupted teeth occurred in 50%, 30% and 11% of cases, respectively. PMID- 20203275 TI - Comparison between computed tomography and clinical evaluation in tumour/node stage and follow-up of oral cavity and oropharyngeal cancer. AB - OBJECTIVES: The aim was to verify the concordance of CT evaluation among four radiologists (two oral and maxillofacial and two medical radiologists) at the TN (tumour/node) stage and in the follow-up of oral cavity and oropharyngeal cancer patients. The study also compared differences between clinical and CT examinations in determining the TN stage. METHODS: The following clinical and tomographic findings of 15 non-treated oral cavity and oropharyngeal cancer patients were compared: tumour size, bone invasion and lymph node metastases. In another 15 patients, who had previously been treated, a clinical and tomographic analysis comparison for the presence of tumoural recurrence, post-therapeutic changes in muscles and lymph node metastases was performed. The concordances of tomographic evaluation between the radiologists were analysed using the kappa index. RESULTS: Significant agreement was verified between all radiologists for the T stage, but not for the N stage. In the group of treated patients, CT disclosed post-therapeutic changes in muscles, tumour recurrence and lymph node metastases, but no concordance for the detection of lymph node metastases was found between radiologists. In the first group, for all radiologists, no concordance was demonstrated between clinical and tomographic staging. CT was effective for delimitating advanced lesions and for detecting lymph node involvement in N0 stage patients. CT revealed two cases of bone invasion not clinically detected. CONCLUSIONS: Interprofessional relationships must be stimulated to improve diagnoses, and to promote a multidisciplinary approach to oral cavity and oropharyngeal cancer. Although CT was important in the diagnosis and follow-up of cancer patients, differences between medical and dental analyses should be acknowledged. PMID- 20203276 TI - Correlation between disc displacements and locations of disc perforation in the temporomandibular joint. AB - OBJECTIVES: The aim of this study was to investigate the correlation between disc displacement types and locations of disc perforation in the temporomandibular joint (TMJ). METHODS: 157 patients (162 joints) with disc perforation observed through arthroscopy were included in this study. The types of disc displacement were analysed by TMJ MRI before operation. The locations of disc perforation under arthroscopy were recorded. The correlation between types of disc displacement and locations of disc perforation was analysed by Fisher's exact test. RESULTS: Medial disc perforation was observed in 55.6% of patients with anterolateral displacement without reduction, but was observed in only 3.7% of patients with pure anterior displacement, and was not observed in patients with anteromedial displacement without reduction. There was a statistically significant difference between these groups in the incidence of medial disc perforation. CONCLUSIONS: There is a correlation between different disc displacements and locations of disc perforation. The incidence of medial disc perforation in patients with anterolateral displacement was significantly higher. The types of disc displacement may have direct influence over the locations of disc perforation. PMID- 20203277 TI - Evaluation of the reproducibility in the interpretation of magnetic resonance images of the temporomandibular joint. AB - OBJECTIVES: The aim was to determine the intra- and interexaminer reproducibility in the interpretation of MRI of the temporomandibular joint among independent observers, with respect to six specific articular characteristics, and to discover which of these had greater and lesser agreement. METHODS: 30 magnetic resonance examinations of temporomandibular joints of adults were independently interpreted by 9 experienced and trained observers at 2 different times. Observers were divided into three groups according to their specialties: surgeon dentists specialized in temporomandibular dysfunction and orofacial pain, surgeon dentists specialized in radiology and medical doctors specialized in radiology. The reproducibility analysis was carried out using Cohen's kappa coefficient. RESULTS: The interexaminer reproducibility ranged from slight to fair. The intraexaminer reproducibility ranged from slight to no agreement. In the interexaminer evaluation, anterior disc displacement without reduction presented greater agreement, whereas change in condylar head shape showed the poorest agreement. In the intraexaminer evaluation, anterior disc displacement without reduction presented slight agreement, whereas, for the other characteristics, no agreement was observed. CONCLUSION: Examiners do not demonstrate reproducibility in the interpretation of MRI of temporomandibular joints. Therefore, more efforts are necessary with respect to understanding the changes that may be detected in these images in terms of diagnosis and appropriate treatment approaches. PMID- 20203278 TI - The relationship between idiopathic bone cavity and orthodontic tooth movement: analysis of 44 cases. AB - OBJECTIVES: Idiopathic bone cavity (IBC), also named simple or traumatic bone cyst, is a common lesion of unknown cause. The mandible is a very common location, although it may occur in any bone of the body. The authors performed a retrospective analysis of 44 cases in order to assess the causation of this entity. METHODS: Each case was analysed by two of the authors (IV and SM) for medical and dental history, history of mandibular/maxillary trauma, clinical presentation, radiographic appearance, surgical findings and histopathology. RESULTS: This retrospective study suggested a possible relationship between IBCs and orthodontic treatment. This association was noted in 10/44 cases (22.73%). All of these cases were located in the mandible and were well-circumscribed radiolucencies. Evaluation of these cases disclosed that 6/44 (13.64%) demonstrated scalloping, and 3/44 (6.82%) revealed bony expansion. The age range of the patients evaluated was 9-74 years. None of these cases had a history of trauma or extractions in the area. CONCLUSIONS: The findings of this retrospective study suggest an association between orthodontic treatment and the development of this IBC. This occurrence may be multifactorial; further research in the dental science is required. PMID- 20203279 TI - Keratocystic odontogenic tumour in a Hong Kong community: the clinical and radiological features. AB - OBJECTIVES: The aim of this study was to evaluate the clinical and conventional radiological features of a consecutive series of cases of "keratocystic odontogenic tumour" (KCOT) affecting a Hong Kong Chinese community and to determine their outcome by follow-up. METHODS: All cases were accompanied by appropriate radiography and were histopathologically confirmed. RESULTS: 33 consecutive KCOTs were reviewed. 18 patients were male. The mean age at first presentation was 30.6 years. Swelling was the most frequent presenting symptom. Those patients first presenting with pain were significantly older, whereas those first presenting with a maxillary lesion were significantly younger. The maxilla and mandible were affected in 13 and 20 cases, respectively. KCOTs were most frequently confined to the posterior sextants of both jaws. KCOTs affecting the maxilla were mainly unilocular, whereas those affecting the mandible were multilocular. Patients with multilocular KCOTs were significantly older. Patients with KCOTs associated with root resorption were significantly older, whereas patients associated with unerupted teeth were significantly younger. 69% displaced teeth, 41% resorbed them and 56% were associated with unerupted teeth. All but two were followed up for at least 2 years. Three lesions recurred. CONCLUSIONS: KCOTs in this community displayed some differences from those reported in the literature. PMID- 20203280 TI - Effect of explaining radiographic information to the patient before third molar surgery. AB - OBJECTIVES: The aim of this study was to compare patient satisfaction with the pre-operative information before and after explaining the radiograph and to compare patient satisfaction with the radiographic information when based on a digital or a conventional image, as well as on extraoral or intraoral images. METHODS: 263 patients (with 301 mandibular third molars) were given pre-operative information by one of two trained scholar students before removal of the third molar. The course of the surgery and possible post-operative complications and risks were explained to the patient. The patients rated their satisfaction with the information on a 100 mm visual analogue scale (VAS). The radiograph was displayed and the radiographic information was explained to the patient, with emphasis on tooth-specific risk factors. The patients again rated their satisfaction on a VAS. RESULTS: There was no significant difference in patient satisfaction score before (mean VAS = 92.5 mm) and after (mean VAS = 91.7 mm) the radiographic information was explained (P = 0.15). No difference in satisfaction was found between patients who were shown either digital or conventional images or between patients who were shown either extraoral or intraoral images (P > 0.5). CONCLUSIONS: No additional patient satisfaction was obtained by showing and explaining the radiograph to the patient before lower third molar surgery. If the dentist still wishes to show the patient the radiograph, the type of image seems not to be important. PMID- 20203281 TI - Rating the extent of surface scratches on photostimulable storage phosphor plates in a dental school environment. AB - OBJECTIVE: The aims of this study were (1) to subjectively quantify the degree of scratching and smudging that had taken place in the junior clinic in the 9 months following the implementation of digital radiology; (2) to compare the findings with a previously published report; and (3) to identify areas in the protocol and training that can be refined to minimize future scratching and smudging. METHODS: Seven sets of blank clinical photostimulable storage phosphor (PSP) plates were scanned after exposing them at 65 kV and 7 mA for 0.80 s. Scanned plates were lightly wiped with a soft cloth and alcohol, repackaged in plastic sleeves, re exposed and rescanned. The two sets of resulting images were subjectively rated independently by two investigators for artefacts and placed in five categories. RESULTS: Of all the images, approximately 75% were rated in the top 3 categories (most readable), leaving 17% and 8% in the poor and unsatisfactory categories, respectively. Mean rated values of the two image sets (before and after wiping) were not statistically different, but ratings slightly improved after cleaning the plates. CONCLUSIONS: Wiping all plates to remove surface contamination may not always be necessary or desirable. Systems that are designed to minimize handling of the plates may help minimize scratching of them. PMID- 20203282 TI - Chronic recurrent multifocal osteomyelitis involving the mandible: case reports and review of the literature. AB - Chronic recurrent multifocal osteomyelitis (CRMO) is an aseptic inflammatory disorder of unknown cause occurring in children and adolescents. It is characterized by multifocal bone lesions with pain and swelling recurring over months to years. Lesions usually involve the metaphyses of the long bones and involvement of the jaw is rare. The clinical presentation, radiographic appearance and histology of a case of CRMO involving the mandible in an 8-year old girl are documented. The radiographic appearance of another three cases is also described. PMID- 20203283 TI - Influenza virus receptor specificity: disease and transmission. PMID- 20203284 TI - Lymphangioleiomyoma cells and lymphatic endothelial cells: expression of VEGFR-3 in lymphangioleiomyoma cell clusters. PMID- 20203285 TI - Function of EWS-POU5F1 in sarcomagenesis and tumor cell maintenance. AB - POU5F1 is a transcription factor essential for the self-renewal activity and pluripotency of embryonic stem cells and germ cells. We have previously reported that POU5F1 is fused to EWSR1 in a case of undifferentiated sarcoma with chromosomal translocation t(6;22)(p21;q12). In addition, the EWS-POU5F1 chimeras have been recently identified in human neoplasms of the skin and salivary glands. To clarify the roles of the EWS-POU5F1 chimera in tumorigenesis and tumor cell maintenance, we used small-interfering RNA-mediated gene silencing. Knockdown of EWS-POU5F1 in the t(6;22) sarcoma-derived GBS6 cell line resulted in a significant decrease of cell proliferation because of G1 cell cycle arrest associated with p27(Kip1) up-regulation. Moreover, senescence-like morphological changes accompanied by actin polymerization were observed. In contrast, EWS POU5F1 down-regulation markedly increased the cell migration and invasion as well as activation of metalloproteinase 2 and metalloproteinase 14. The results indicate that the proliferative activity of cancer cells and cell motility are discrete processes in multistep carcinogenesis. These findings reveal the functional role of the sarcoma-related chimeric protein as well as POU5F1 in the development and progression of human neoplasms. PMID- 20203286 TI - Lack of CXC chemokine receptor 3 signaling leads to hypertrophic and hypercellular scarring. AB - CXC chemokine receptor 3 (CXCR3) signaling promotes keratinocyte migration while terminating fibroblast and endothelial cell immigration into wounds; this signaling also directs epidermal and matrix maturation. Herein, we investigated the long-term effects of failure to activate the "stop-healing" CXCR3 axis. Full thickness excisional wounds were created on CXCR3 knockout((-/-)) or wild-type mice and examined at up to 180 days after wounding. Grossly, the CXCR3(-/-) mice presented a thick keratinized scar compared with the wild-type mice in which the scar was scarcely noticeable; histological examination revealed thickening of both the epidermis and dermis. The dermis was disorganized with thick and long collagen fibrils and contained excessive collagen content in comparison with the wild-type mice. Interestingly, the CXCR3(-/-) wounds presented lower tensile/burst strength, which correlates with decreased alignment of collagen fibers, similar to published findings of human scars. Persistent Extracellular matrix turnover and immaturity was shown by the elevated expression of proteins of the immature matrix as well as expression of matrix metallopeptidase-9 MMP-9. Interestingly, the scars in the CXCR3(-/-) mice presented evidence of de novo development of a sterile inflammatory response only months after wounding; earlier periods showed resolution of the initial inflammatory stage. These in vivo studies establish that the absence of CXCR3(-/-) signaling network results in hypertrophic and hypercellular scarring characterized by on-going wound regeneration, cellular proliferation, and scars in which immature matrix components are undergoing increased turnover resulting in a chronic inflammatory process. PMID- 20203287 TI - Evaluation of peritoneal membrane characteristics: clinical advice for prescription management by the ERBP working group. PMID- 20203288 TI - Phylogeography takes a relaxed random walk in continuous space and time. AB - Research aimed at understanding the geographic context of evolutionary histories is burgeoning across biological disciplines. Recent endeavors attempt to interpret contemporaneous genetic variation in the light of increasingly detailed geographical and environmental observations. Such interest has promoted the development of phylogeographic inference techniques that explicitly aim to integrate such heterogeneous data. One promising development involves reconstructing phylogeographic history on a continuous landscape. Here, we present a Bayesian statistical approach to infer continuous phylogeographic diffusion using random walk models while simultaneously reconstructing the evolutionary history in time from molecular sequence data. Moreover, by accommodating branch-specific variation in dispersal rates, we relax the most restrictive assumption of the standard Brownian diffusion process and demonstrate increased statistical efficiency in spatial reconstructions of overdispersed random walks by analyzing both simulated and real viral genetic data. We further illustrate how drawing inference about summary statistics from a fully specified stochastic process over both sequence evolution and spatial movement reveals important characteristics of a rabies epidemic. Together with recent advances in discrete phylogeographic inference, the continuous model developments furnish a flexible statistical framework for biogeographical reconstructions that is easily expanded upon to accommodate various landscape genetic features. PMID- 20203289 TI - Parallelism in evolution of highly repetitive DNAs in sibling species. AB - Characterization of heterochromatin in the flour beetle Tribolium audax revealed two highly repetitive DNA families, named TAUD1 and TAUD2, which together constitute almost 60% of the whole genome. Both families originated from a common ancestral approximately 110-bp repeating unit. Tandem arrangement of these elements in TAUD1 is typical for satellite DNAs, whereas TAUD2 represents a dispersed family based on 1412-bp complex higher-order repeats composed of inversely oriented approximately 110 bp units. Comparison with repetitive DNAs in the sibling species Tribolium madens showed similarities in nucleotide sequence and length of basic repeating units and also revealed structural and organizational parallelism in tandem and dispersed families assembled from these elements. In both Tribolium species, one tandem and one dispersed family build equivalent distribution patterns in the pericentromeric heterochromatin of all chromosomes including supernumeraries. Differences in the nucleotide sequence and in the complexity of higher-order structures between families of the same type suggest a scenario according to which rearranged variants of the corresponding ancestral families were formed and distributed in genomes during or after the speciation event, following the same principles independently in each descendant species. We assume that random effects of sequence dynamics should be constrained by organizational and structural features of repeating units and possible requirements for spatial distribution of particular sequence elements. An interspersed pattern of repetitive families also points to the intensive recombination events in heterochromatin. Synergy between the meiotic bouquet stage and satellite DNA sequence dynamics could make a positive feedback loop that promotes the observed genome-wide distribution. At the same time, considering the abundance of these DNAs in heterochromatin spanning the (peri)centromeric chromosomal segments, we speculate that diverged repetitive sequences might represent the DNA basis of reproductive barrier between the two sibling species. PMID- 20203290 TI - A new histology scoring system for the assessment of the quality of human cartilage repair: ICRS II. AB - BACKGROUND: A reliable and reproducible method is needed to assess cartilage repair. PURPOSE: This study was undertaken to test the reproducibility of 2 established histological scoring systems, the Modified O'Driscoll Scale (MODS) and International Cartilage Research Society (ICRS) Visual Assessment Scale (ICRS I), and subsequently to develop and evaluate a new grading system for cartilage repair. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A total of 107 cartilage biopsy specimens were graded using MODS and ICRS I, and the reader variability was measured. The new grading system, ICRS II, was developed and the inter- and intrareader variability determined by 3 independent readers. Collagen type II deposition was assessed immunohistochemically. RESULTS: The MODS and ICRS I demonstrated high interreader variability, with MODS also showing high intrareader variability. A new histological scoring system, ICRS II, was developed comprising 14 criteria to assess parameters related to chondrocyte phenotype and tissue structure. The ICRS II demonstrated lower inter- and intrareader variability compared with MODS or ICRS I. The overall assessment and matrix staining scores had the best correlation coefficients for inter- and intrareader variability (r = .81 and .82, respectively). The extent of collagen type II in cartilage, considered a marker of differentiation toward hyaline cartilage, could represent a measure of good cartilage repair. A correlation coefficient of .56 was obtained between the extent of collagen type II staining and the overall assessment score. CONCLUSION: The ICRS II represents an improvement over current histological cartilage repair grading systems in terms of reader reproducibility. The clinical relevance and its ability to predict long term repair durability will be assessed once long-term clinical data become available. PMID- 20203291 TI - MARCKS and related chaperones bind to unconventional myosin V isoforms in airway epithelial cells. AB - We have shown previously that myristoylated alanine-rich C kinase substrate (MARCKS) is a key regulatory molecule in the process of mucin secretion by airway epithelial cells, and that part of the secretory mechanism involves intracellular associations of MARCKS with specific chaperones: heat shock protein 70 (Hsp70) and cysteine string protein (CSP). Here, we report that MARCKS also interacts with unconventional myosin isoforms within these cells, and further molecular interactions between MARCKS and these chaperones/cytoskeletal proteins are elucidated. Primary human bronchial epithelial cells and the HBE1 cell line both expressed myosin V and VI proteins, and both MARCKS and CSP were shown to bind to myosin V, specifically Va and Vc. This binding was enhanced by exposing the cells to phorbol-12-myristate-13-acetate, an activator of protein kinase C and stimulator of mucin secretion. Binding of MARCKS, Hsp70, and CSP was further investigated by His-tagged pull down assays of purified recombinant proteins and multiple transfections of HBE1 cells with fusion proteins (MARCKS-HA; Flag-Hsp70; c-Myc-CSP) and immunoprecipitation. The results showed that MARCKS binds directly to Hsp70, and that Hsp70 binds directly to CSP, but that MARCKS binding to CSP appears to require the presence of Hsp70. Interrelated binding(s) of MARCKS, chaperones, and unconventional myosin isoforms may be integral to the mucin secretion process. PMID- 20203292 TI - beta1, beta2, and beta3 adrenoceptors and Na+/H+ exchanger regulatory factor 1 expression in human bronchi and their modifications in cystic fibrosis. AB - To date, three beta-adrenoceptor (beta-AR) subtypes have been identified, but only beta(1)-ARs and beta(2)-ARs have been characterized in human lungs. Moreover, beta(2)-ARs physically interact with the cystic fibrosis transmembrane conductance regulator (CFTR) through the Na(+)/H(+) Exchanger Regulatory Factor 1 (NHERF1) protein. beta(3)-ARs, which stimulate CFTR activity in transfected cells, have not been identified in human lungs. This study aimed (1) to characterize the presence of beta-AR subtypes, especially beta(3)-AR, in human bronchi, and (2) to compare their expression as well as that of NHERF1 in non cystic fibrosis (CF) versus advanced CF lung samples. In human non-CF bronchi, beta(1)-AR, beta(2)-AR, beta(3)-AR, and NHERF1 transcripts and proteins were expressed mainly in bronchial epithelial cells. Those results were strengthened by the native expression of beta(1)-AR, beta(2)-AR, and beta(3)-AR in a human epithelial cell line, 16HBE14o(-). All beta-AR subtypes stimulated CFTR activity. In CF bronchi, we demonstrated beta(1)-AR and beta(3)-AR overexpression, and NHERF1 and beta(2)-AR underexpression. The origin of this protein remodeling (involving the physical or functional absence of CFTR, infection, inflammation, or high adrenergic tone) deserves further investigation. These results evidence for the first time, to the best of our knowledge, the presence of beta(3)-ARs in human bronchi, and suggest their usefulness as a putative new pharmacologic target in lung diseases where fluid homeostasis is altered. Furthermore, NHERF1 may be a new therapeutic target in patients with CF, to facilitate the trafficking of mutated CFTR to plasma membrane. PMID- 20203293 TI - Transient receptor potential canonical channel 6 links Ca2+ mishandling to cystic fibrosis transmembrane conductance regulator channel dysfunction in cystic fibrosis. AB - In cystic fibrosis (CF), abnormal control of cellular Ca(2+) homeostasis is observed. We hypothesized that transient receptor potential canonical (TRPC) channels could be a link between the abnormal Ca(2+) concentrations in CF cells and cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. We measured the TRPC and CFTR activities (using patch clamp and fluorescent probes) and interactions (using Western blotting and co-immunoprecipitation) in CF and non-CF human epithelial cells treated with specific and scrambled small interfering RNA (siRNA). The TRPC6-mediated Ca(2+) influx was abnormally increased in CF compared with non-CF cells. After correction of abnormal F508 deletion (del)-CFTR trafficking in CF cells, the level of TRPC6-dependent Ca(2+) influx was also normalized. In CF cells, siRNA-TRPC6 reduced this abnormal Ca(2+) influx. In non-CF cells, siRNA-TRPC6 reduced the Ca(2+) influx and activity wild type (wt)-CFTR. Co-immunoprecipitation experiments revealed TRPC6/CFTR and TRPC6/F508 del-CFTR interactions in CF or non-CF epithelial cells. Although siRNA CFTR reduced the activity of wt-CFTR in non-CF cells and of F508 del-CFTR in corrected CF cells, it also enhanced TRPC6-dependent Ca(2+) influx in non-CF cells, mimicking the results obtained in CF cells. Finally, this functional and reciprocal coupling between CFTR and TRPC6 was also detected in non-CF ciliated human epithelial cells freshly isolated from lung samples. These data indicate that TRPC6 and CFTR are functionally and reciprocally coupled within a molecular complex in airway epithelial human cells. Because this functional coupling is lost in CF cells, the TRPC6-dependent Ca(2+) influx is abnormal. PMID- 20203294 TI - Selective ascorbate toxicity in malignant mesothelioma: a redox Trojan mechanism. AB - We studied the mechanism of ascorbate toxicity in malignant mesothelioma (MMe) cells. Neutral red uptake showed that ascorbate, but not dehydroascorbate, was highly toxic in the MMe cell lines REN and MM98, and less toxic in immortalized (human mesothelial cells-htert) and primary mesothelial cells. Ascorbate transport inhibitors phloretin, sodium azide, and ouabain did not reduce ascorbate toxicity. Ascorbate promoted the formation of H(2)O(2) in the cell medium, and its toxicity was suppressed by extracellular catalase, but the concentration of endogenous catalase was higher in MMe cells than in normal cells. The confocal imaging of cells loaded with the dihydrhodamine 123 reactive oxygen species probe showed that ascorbate caused a strong increase of rhodamine fluorescence in MMe cells, but not in mesothelial cells. MMe cells showed a higher production of superoxide and NADPH oxidase (NOX)4 expression than did mesothelial cells. Two inhibitors of cellular superoxide sources (apocynin and rotenone) reduced ascorbate toxicity and the ascorbate-induced rise in rhodamine fluorescence. NOX4 small interfering RNA also reduced ascorbate toxicity in REN cells. Taken together, the data indicate that ascorbate-induced extracellular H(2)O(2) production induces a strong oxidative stress in MMe cells because of their high rate of superoxide production. This explains the selective toxicity of ascorbate in MMe cells, and suggests its possible use in the clinical treatment of malignant mesothelioma. PMID- 20203296 TI - Examining demographic and situational factors on animal cruelty motivations. AB - Because of the limited number of studies that have examined the motives for childhood animal cruelty, researchers continue to suggest that further systematic study is needed. In a replication of the Hensley and Tallichet study and based on survey data from 180 inmates at one medium- and one maximum-security prison in a southern U.S. state, the present study seeks to further develop this understanding by examining the impact of demographic and situational factors on a range of animal cruelty motivations. Of the 180 inmates, 103 (57%) committed acts of animal cruelty. Logistic regression analyses revealed that respondents who committed childhood animal cruelty out of anger were less likely to cover up their behavior and to be upset by their actions but were more likely to have repeated it. Those who committed animal cruelty to shock others were more likely to reside in urban areas and to have done it alone. Furthermore, respondents who committed animal cruelty for sexual reasons were more likely to have covered up their actions and to have engaged in it repeatedly. PMID- 20203295 TI - Prostaglandin E2 inhibits human lung fibroblast chemotaxis through disparate actions on different E-prostanoid receptors. AB - The migration of fibroblasts is believed to play a key role in both normal wound repair and abnormal tissue remodeling. Prostaglandin E (PGE)(2), a mediator that can inhibit many fibroblast functions including chemotaxis, was reported to be mediated by the E-prostanoid (EP) receptor EP2. PGE(2), however, can act on four receptors. This study was designed to determine if EP receptors, in addition to EP2, can modulate fibroblast chemotaxis. Using human fetal lung fibroblasts, the expression of all four EP receptors was demonstrated by Western blotting. EP2 selective and EP4-selective agonists inhibited both chemotaxis toward fibronectin in the blindwell assay and migration in a wound-closure assay. In contrast, EP1 selective and EP3-selective agonists stimulated cell migration in both assay systems. These results were confirmed using EP-selective antagonists. The role of both EP2 and EP4 receptors in mediating the PGE(2) inhibition of chemotaxis was also confirmed by small interfering RNA suppression. Furthermore, the role of EP receptors was confirmed by blocking the expected signaling pathways. Taken together, these results demonstrate that PGE(2) can act on multiple EP receptors in human lung fibroblasts, to exert disparate effects. Alterations in EP receptor expression may have the potential to alter PGE(2) action. Targeting specific EP receptors may offer therapeutic opportunities in conditions characterized by abnormal tissue repair and remodeling. PMID- 20203297 TI - Sex offenders, juvenile offenders, and cross-cultural crime research: new findings, all interesting. PMID- 20203298 TI - Cholate-containing high-fat diet induces the formation of multinucleated giant cells in atherosclerotic plaques of apolipoprotein E-/- mice. AB - OBJECTIVE: To determine the role of multinucleated giant cells (MGCs) in cardiovascular diseases. METHODS AND RESULTS: MGCs are a hallmark of giant cell arteritis. They are also described in atherosclerotic plaques from aortic aneurysms and carotid and coronary arteries. Herein, we demonstrate that the cholate-containing Paigen diet yields many MGCs in atherosclerotic plaques of apolipoprotein E-/- mice. These mice revealed a 4-fold increase in MGC numbers when compared with mice on a Western or Paigen diet without cholate. Most of the MGCs stained intensively for cathepsin K and were located at fibrous caps and close to damaged elastic laminae, with associated medial smooth muscle cell depletion. During in vitro experiments, MGCs demonstrated a 6-fold increase in elastolytic activity when compared with macrophages and facilitated transmigration of smooth muscle cells through a collagen-elastin matrix. An elastin-derived hexapeptide (Val-Gly-Val-Ala-Pro-Gly [VGVAPG]) significantly increased the rate of macrophage fusion, providing a possible mechanism of in vivo MGC formation. Comparable to the mouse model, human specimens from carotid arteries and aortic aneurysms contained cathepsin K-positive MGCs. CONCLUSIONS: Apolipoprotein E-/- mice fed a Paigen diet provide a model to analyze the tissue destructive role of MGCs in vascular diseases. PMID- 20203299 TI - Simvastatin decreases endothelial progenitor cell apoptosis in the kidney of hypertensive hypercholesterolemic pigs. AB - OBJECTIVE: Hypertension and hypercholesterolemia might interfere with renal repair mechanisms. We hypothesized that simvastatin improves the survival of endothelial progenitor cells (EPC) in the renal microenvironment imposed by concurrent renovascular hypertension and dietary hypercholesterolemia (HTC). METHODS AND RESULTS: Pigs were studied after 12 weeks of no intervention (n=6), HTC (n=6), or HTC+ oral simvastatin supplementation (80 mg/day, n=5). EPC were also isolated and studied in vitro after exposure to the proapoptotic oxidized low-density lipoprotein with or without coincubation with simvastatin. Renal hemodynamics, function, and endothelial function were evaluated in vivo, and the number of CD34+/KDR+ EPC, apoptosis, oxidative stress, inflammation, and fibrosis in renal tissue studied ex vivo. Compared with normal kidney, the HTC kidney showed endothelial dysfunction and increased oxidative stress, interstitial macrophage filtration, and fibrosis. The number of EPC in the kidney increased, as did their apoptosis (0.85+/-0.24% versus 0.22+/-0.07%, P<0.05 versus normal). Simvastatin did not affect blood pressure, cholesterol levels, basal renal function, or number of renal EPC in HTC, but it improved endothelial function; blunted renal oxidative stress, inflammation, and fibrosis; and attenuated EPC apoptosis (to 0.37+/-0.09%, P<0.05 versus HTC). Simvastatin also significantly decreased oxidized low-density lipoprotein-induced EPC apoptosis in vitro. CONCLUSION: EPC are recruited but undergo apoptosis in the HTC kidney, likely because of a hostile microenvironment. Simvastatin rescues renal repair mechanisms in HTC and counteracts renal damage, which may account for its protective effects on the kidney during exposure to cardiovascular risk factors. PMID- 20203300 TI - Histamine H1 receptor promotes atherosclerotic lesion formation by increasing vascular permeability for low-density lipoproteins. AB - OBJECTIVE: Enhanced endothelial permeability leading to intimal accumulation of low-density lipoproteins (LDL) stimulates the formation of atherosclerotic lesions. Histamine is known to increase vascular permeability. Whether this affects the formation of atherosclerotic lesions, however, remains elusive. METHODS AND RESULTS: Apolipoprotein E-null (ApoE(-/-)) mice treated with a histamine H1 receptor but not an H2 receptor antagonist developed 40% fewer atherosclerotic lesions in the aorta than placebo-treated controls. Similarly, genetic deletion of the H1 but not the H2 receptor resulted in a 60% reduction of lesions compared with ApoE(-/-) controls. The H1 receptor enhanced LDL permeability and lipid accumulation in the aorta, whereas plasma lipoprotein levels remained unaltered. In contrast, the H1 receptor did not affect proliferation and migration of vascular smooth muscle cells. Bone marrow transplantation confirmed that the formation of atherosclerotic lesions depended on the H1 receptor in vascular cells, whereas its presence in bone marrow-derived cells was irrelevant for plaque development. Mice expressing the H1 receptor exhibited higher levels of the chemokine (C-C motif) ligand 5 and higher numbers of macrophages and T-helper lymphocytes in plaques, higher numbers of circulating lymphocytes, and larger spleens. CONCLUSION: These data indicate that H1 but not H2 receptor activation drives the formation of atherosclerotic lesions through an increased vascular permeability for LDL, which is associated with an enhanced secondary aortic and systemic inflammation. These data open novel perspectives for the prevention and treatment of atherosclerotic vascular disease. PMID- 20203301 TI - Improved lipid and glucose metabolism in transgenic rats with increased circulating angiotensin-(1-7). AB - OBJECTIVE: Obesity and diabetes remain among the world's most pervasive health problems. Although the importance of angiotensin II for metabolic regulation is well documented, the role of the angiotensin-(1-7)/Mas axis in this process is poorly understood. The aim of this study was to evaluate the effect of increased angiotensin-(1-7) plasma levels in lipid and glucose metabolism using transgenic rats that express an angiotensin-(1-7)-releasing fusion protein, TGR(A1-7)3292 (TGR). METHODS AND RESULTS: The increased angiotensin-(1-7) levels in TGR induced enhanced glucose tolerance, insulin sensitivity, and insulin-stimulated glucose uptake. In addition, TGR presented decreased triglycerides and cholesterol levels, as well as a significant decrease in abdominal fat mass, despite normal food intake. These alterations were accompanied by a marked decrease of angiotensinogen expression and increased Akt in adipose tissue. Furthermore, augmented plasma levels and expression in adipose tissue was observed for adiponectin. Accordingly, angiotensin-(1-7) stimulation increased adiponectin production by primary adipocyte culture, which was blocked by the Mas antagonist A779. Circulating insulin and muscle glycogen content were not altered in TGR. CONCLUSION: These results show that increased circulating angiotensin-(1-7) levels lead to prominent changes in glucose and lipid metabolism. PMID- 20203302 TI - Sustained inhibition of oxidized low-density lipoprotein is involved in the long term therapeutic effects of apheresis in dialysis patients. AB - OBJECTIVE: Low-density lipoprotein (LDL) apheresis is a potential therapy for conventional therapy-resistant peripheral artery disease. In the present study, we examined the chronic effects of LDL apheresis on clinical parameters in vivo and endothelial cell functions in vitro in hemodialysis patients who had the complication of peripheral artery disease. METHODS AND RESULTS: Twenty-five patients were enrolled, and the responses of 19 patients to LDL apheresis were analyzed. Patients were classified into 2 groups according to change in ankle brachial pressure index (ABI) after treatment: patients with improved ABI (responders, n=10) and patients with worsened ABI (nonresponders, n=9). In the responders, apheresis resulted in a long-term reduction of circulating levels of oxidized LDL, C-reactive protein, and fibrinogen. In human umbilical vein endothelial cells (HUVECs), the serum from the responders increased expression of activated endothelial nitric oxide synthase protein and proliferative activity. Furthermore, there was a significant correlation between ABI and activated endothelial nitric oxide synthase protein level in HUVECs treated with responder serum (R=0.427, P<0.05). CONCLUSION: These results demonstrate that LDL apheresis decreases oxidized LDL and inflammation and improves endothelial cell function in the responders. This may be one of the mechanisms involved in the long-term therapeutic effect of LDL apheresis on peripheral circulation in hemodialysis patients. PMID- 20203303 TI - Platelets play an essential role in separating the blood and lymphatic vasculatures during embryonic angiogenesis. AB - RATIONALE: Several mutations that impair the development of blood lineages in the mouse also impair the formation of the lymphatic vasculature and its separation from the blood vasculature. However, the basis for these defects has remained unknown because the mutations characterized affect more than one blood lineage. OBJECTIVE: We tested the hypothesis that megakaryocytes/platelets are required for the formation of the lymphatic vasculature and its separation from the blood vascular system. METHODS AND RESULTS: We characterized the vascular patterning defects of mice deficient for the homeodomain transcription factor Meis1 (myeloid ecotropic viral integration site 1), which completely lack megakaryocyte/platelets. Meis1 null embryos fail to separate the blood and lymphatic vasculature, showing blood-filled primary lymphatic sacs and superficial lymphatic vessels. To test the involvement of megakaryocytes/platelets in this phenotype, we generated megakaryocyte/platelet specific deficient mice by targeted lineage ablation, without affecting other blood lineages. This model reproduces the lymphatic/blood vasculature separation defects observed in Meis1 mutants. A similar phenotype was induced by antibody mediated ablation of circulating platelets in wild type mice. Strong association of platelets with vascular endothelium at regions of contact between lymphatic sacs and veins confirmed a direct role of platelets in the separation of the 2 vasculatures. CONCLUSIONS: In addition to their known protective function in the response accidental vascular injury, platelets are also required during embryonic lymphangiogenesis for the separation of the nascent lymphatic vasculature from blood vessels. PMID- 20203304 TI - SIRT1 promotes proliferation and prevents senescence through targeting LKB1 in primary porcine aortic endothelial cells. AB - RATIONALE: Endothelial senescence causes endothelial dysfunction, promotes atherogenesis and contributes to age-related vascular disorders. SIRT1 is a conserved NAD(+)-dependent deacetylase possessing beneficial effects against aging-related diseases, despite that the detailed functional mechanisms are largely uncharacterized. OBJECTIVE: The present study is designed to evaluate the protective effects of SIRT1 on endothelial senescence and to elucidate the underlying mechanisms. METHODS AND RESULTS: An in vitro senescence model was established by prolonged culture of primary endothelial cells isolated from porcine aorta. The freshly isolated "young" cells gradually underwent senescence during 1 month of repetitive passages. Both mRNA and protein expressions of SIRT1 were progressively decreased. In contrast, the protein levels of LKB1, a serine/threonine kinase and tumor suppressor, and the phosphorylation of its downstream target AMPK(Thr172) were dramatically increased in senescent cells. Overexpression of LKB1 promoted cellular senescence and retarded endothelial proliferation, which could be blocked by increasing SIRT1 levels. Knocking down of SIRT1 induced senescence and elevated the protein levels of LKB1 and phosphorylated AMPK(Thr172). Regardless of the nutritional status, hyperactivation of AMPK was able to induce endothelial senescence. SIRT1 antagonized LKB1-dependent AMPK activation through promoting the deacetylation, ubiquitination and proteasome-mediated degradation of LKB1. The survival signaling of Akt was also found to be modulated by SIRT1 and LKB1, and could cross-regulate AMPK activity. CONCLUSIONS: SIRT1 and LKB1/AMPK are the 2 key sensor systems for regulating endothelial cell survival, proliferation and senescence. The protective activities of SIRT1 may be achieved at least in part by fine tuning the acetylation/deacetylation status and stabilities of LKB1 protein. PMID- 20203305 TI - Gene deletion screen for cardiomyopathy in adult Drosophila identifies a new notch ligand. AB - RATIONALE: Drosophila has been recognized as a model to study human cardiac diseases. OBJECTIVE: Despite these findings, and the wealth of tools that are available to the fly community, forward genetic screens for adult heart phenotypes have been rarely performed because of the difficulty in accurately measuring cardiac function in adult Drosophila. METHODS AND RESULTS: Using optical coherence tomography to obtain real-time analysis of cardiac function in awake Drosophila, we performed a genomic deficiency screen in adult flies. Based on multiple complementary approaches, we identified CG31665 as a novel gene causing dilated cardiomyopathy. CG31665, which we name weary (wry), has structural similarities to members of the Notch family. Using cell aggregation assays and gamma-secretase inhibitors we show that Wry is a novel Notch ligand that can mediate cellular adhesion with Notch expressing cells and transactivates Notch to promote signaling and nuclear transcription. Importantly, Wry lacks a DSL (Delta-Serrate-Lag) domain that is common feature to the other Drosophila Notch ligands. We further show that Notch signaling is critically important for the maintenance of normal heart function of the adult fly. CONCLUSIONS: In conclusion, we identify a previously unknown Notch ligand in Drosophila that when deleted causes cardiomyopathy. Our study suggests that Notch signaling components may be a therapeutic target for dilated cardiomyopathy. PMID- 20203307 TI - Using serum transforming growth factor-beta to predict myocardial fibrosis. PMID- 20203306 TI - Pim-1 kinase protects mitochondrial integrity in cardiomyocytes. AB - RATIONALE: Cardioprotective signaling mediates antiapoptotic actions through multiple mechanisms including maintenance of mitochondrial integrity. Pim-1 kinase is an essential downstream effector of AKT-mediated cardioprotection but the mechanistic basis for maintenance of mitochondrial integrity by Pim-1 remains unexplored. This study details antiapoptotic actions responsible for enhanced cell survival in cardiomyocytes with elevated Pim-1 activity. OBJECTIVE: The purpose of this study is to demonstrate that the cardioprotective kinase Pim-1 acts to inhibit cell death by preserving mitochondrial integrity in cardiomyocytes. METHODS AND RESULTS: A combination of biochemical, molecular, and microscopic analyses demonstrate beneficial effects of Pim-1 on mitochondrial integrity. Pim-1 protein level increases in the mitochondrial fraction with a corresponding decrease in the cytosolic fraction of myocardial lysates from hearts subjected to 30 minutes of ischemia followed by 30 minutes of reperfusion. Cardiac-specific overexpression of Pim-1 results in higher levels of antiapoptotic Bcl-X(L) and Bcl-2 compared to samples from normal hearts. In response to oxidative stress challenge, Pim-1 preserves the inner mitochondrial membrane potential. Ultrastructure of the mitochondria is maintained by Pim-1 activity, which prevents swelling induced by calcium overload. Finally, mitochondria isolated from hearts created with cardiac-specific overexpression of Pim-1 show inhibition of cytochrome c release triggered by a truncated form of proapoptotic Bid. CONCLUSION: Cardioprotective action of Pim-1 kinase includes preservation of mitochondrial integrity during cardiomyopathic challenge conditions, thereby raising the potential for Pim-1 kinase activation as a therapeutic interventional approach to inhibit cell death by antagonizing proapoptotic Bcl-2 family members that regulate the intrinsic apoptotic pathway. PMID- 20203309 TI - Eric Olson: fulfilling a dream of freedom. Interview by Ruth Williams. PMID- 20203310 TI - Calcium channels are ganging up in the sarcolemma. PMID- 20203311 TI - Polyphenols and cholesterol efflux: is coffee the next red wine? PMID- 20203312 TI - DiGeorge syndrome, Tbx1, and retinoic acid signaling come full circle. PMID- 20203316 TI - Biological therapies for cardiac arrhythmias: can genes and cells replace drugs and devices? AB - Cardiac rhythm disorders reflect failures of impulse generation and/or conduction. With the exception of ablation methods that yield selective endocardial destruction, present therapies are nonspecific and/or palliative. Progress in understanding the underlying biology opens up prospects for new alternatives. This article reviews the present state of the art in gene- and cell based therapies to correct cardiac rhythm disturbances. We begin with the rationale for such approaches, briefly discuss efforts to address aspects of tachyarrhythmia, and review advances in creating a biological pacemaker to cure bradyarrhythmia. Insights gained bring the field closer to a paradigm shift away from devices and drugs, and toward biologics, in the treatment of rhythm disorders. PMID- 20203314 TI - The cardiomyocyte circadian clock: emerging roles in health and disease. AB - Circadian misalignment has been implicated in the development of obesity, diabetes mellitus, and cardiovascular disease. Time-of-day-dependent synchronization of organisms with their environment is mediated by circadian clocks. This cell autonomous mechanism has been identified within all cardiovascular-relevant cell types, including cardiomyocytes. Recent molecular- and genetic-based studies suggest that the cardiomyocyte circadian clock influences multiple myocardial processes, including transcription, signaling, growth, metabolism, and contractile function. Following an appreciation of its physiological roles, the cardiomyocyte circadian clock has recently been linked to the pathogenesis of heart disease in response to adverse stresses, such as ischemia/reperfusion, in animal models. The purpose of this review is therefore to highlight recent advances regarding the roles of the cardiomyocyte circadian clock in both myocardial physiology and pathophysiology (ie, health and disease). PMID- 20203315 TI - A coupled SYSTEM of intracellular Ca2+ clocks and surface membrane voltage clocks controls the timekeeping mechanism of the heart's pacemaker. AB - Ion channels on the surface membrane of sinoatrial nodal pacemaker cells (SANCs) are the proximal cause of an action potential. Each individual channel type has been thoroughly characterized under voltage clamp, and the ensemble of the ion channel currents reconstructed in silico generates rhythmic action potentials. Thus, this ensemble can be envisioned as a surface "membrane clock" (M clock). Localized subsarcolemmal Ca(2+) releases are generated by the sarcoplasmic reticulum via ryanodine receptors during late diastolic depolarization and are referred to as an intracellular "Ca(2+) clock," because their spontaneous occurrence is periodic during voltage clamp or in detergent-permeabilized SANCs, and in silico as well. In spontaneously firing SANCs, the M and Ca(2+) clocks do not operate in isolation but work together via numerous interactions modulated by membrane voltage, subsarcolemmal Ca(2+), and protein kinase A and CaMKII dependent protein phosphorylation. Through these interactions, the 2 subsystem clocks become mutually entrained to form a robust, stable, coupled-clock system that drives normal cardiac pacemaker cell automaticity. G protein-coupled receptors signaling creates pacemaker flexibility, ie, effects changes in the rhythmic action potential firing rate, by impacting on these very same factors that regulate robust basal coupled-clock system function. This review examines evidence that forms the basis of this coupled-clock system concept in cardiac SANCs. PMID- 20203313 TI - S-nitrosylation in cardiovascular signaling. AB - Well over 2 decades have passed since the endothelium-derived relaxation factor was reported to be the gaseous molecule nitric oxide (NO). Although soluble guanylyl cyclase (which generates cyclic guanosine monophosphate, cGMP) was the first identified receptor for NO, it has become increasingly clear that NO exerts a ubiquitous influence in a cGMP-independent manner. In particular, many, if not most, effects of NO are mediated by S-nitrosylation, the covalent modification of a protein cysteine thiol by an NO group to generate an S-nitrosothiol (SNO). Moreover, within the current framework of NO biology, endothelium-derived relaxation factor activity (ie, G protein-coupled receptor-mediated, or shear induced endothelium-derived NO bioactivity) is understood to involve a central role for SNOs, acting both as second messengers and signal effectors. Furthermore, essential roles for S-nitrosylation have been implicated in virtually all major functions of NO in the cardiovascular system. Here, we review the basic biochemistry of S-nitrosylation (and denitrosylation), discuss the role of S-nitrosylation in the vascular and cardiac functions of NO, and identify current and potential clinical applications. PMID- 20203317 TI - Medical complications among hospitalizations for ischemic stroke in the United States from 1998 to 2007. AB - BACKGROUND AND PURPOSE: The common medical complications after ischemic stroke are associated with increased mortality and resource use. METHOD: The study population consisted of 1 150 336 adult hospitalizations with ischemic stroke as a primary diagnosis included in the 1998 to 2007 Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project. Multiple logistic regression analyses were used to examine changes between 1998 to 1999 and 2006 to 2007 in the prevalence of acute myocardial infarction, pneumonia, deep venous thrombosis, pulmonary embolism, or urinary tract infection, in-hospital mortality, and length of stay. RESULTS: In 2006 to 2007, the prevalence of hospitalizations with a secondary diagnosis of acute myocardial infarction, pneumonia, deep venous thrombosis, pulmonary embolism, and urinary tract infection was 1.6%, 2.9%, 0.8%, 0.3%, and 10.1%, respectively. The adjusted ORs for a hospitalization in 2006 to 2007 complicated by acute myocardial infarction, deep venous thrombosis, pulmonary embolism, or urinary tract infection, using 1998 to 1999 as the referent, were 1.39, 1.68, 2.39, and 1.18, respectively. The odds of pneumonia did not change significantly between 1998 to 1999 and 2006 to 2007. In-hospital mortality was significantly lower in 2006 to 2007 than in 1998 to 1999. Despite the overall length of stay decreasing significantly from 1998 to 1999 to 2006 to 2007, it remained the same for hospitalizations with acute myocardial infarction, pneumonia, deep vein thrombosis, and pulmonary embolism. CONCLUSIONS: Although in hospital mortality decreased over the study period, 4 of the 5 complications were more common in 2006 to 2007 than they were 8 years earlier with the largest increase observed for deep venous thrombosis and pulmonary embolism. PMID- 20203319 TI - Diffusion-weighted imaging and cognition in the leukoariosis and disability in the elderly study. AB - BACKGROUND AND PURPOSE: The mechanisms by which leukoariosis impacts on clinical and cognitive functions are not yet fully understood. We hypothesized that ultrastructural abnormalities of the normal-appearing brain tissue (NABT) assessed by diffusion-weighted imaging played a major and independent role. METHODS: In addition to a comprehensive clinical, neuropsychologic, and imaging work-up, diffusion-weighted imaging was performed in 340 participants of the multicenter leukoariosis and disability study examining the impact of white matter hyperintensities (WMH) on 65- to 85-year old individuals without previous disability. WMH severity was rated according to the Fazekas score. Multivariate regression analysis served to assess correlations of histogram metrics of the apparent diffusion coefficient (ADC) of whole-brain tissue, NABT, and of the mean ADC of WMH with cognitive functions. RESULTS: Increasing WMH scores were associated with a higher frequency of hypertension, a greater WMH volume, more brain atrophy, worse overall cognitive performance, and changes in ADC. We found strong associations between the peak height of the ADC histogram of whole-brain tissue and NABT with memory performance, executive dysfunction, and speed, which remained after adjustment for WMH lesion volume and brain atrophy and were consistent among centers. No such association was seen with the mean ADC of WMH. CONCLUSIONS: Ultrastructural abnormalities of NABT increase with WMH severity and have a strong and independent effect on cognitive functions, whereas diffusion weighted imaging metrics within WMH have no direct impact. This should be considered when defining outcome measures for trials that attempt to ameliorate the consequences of WMH progression. PMID- 20203318 TI - Combination treatment with VELCADE and low-dose tissue plasminogen activator provides potent neuroprotection in aged rats after embolic focal ischemia. AB - BACKGROUND AND PURPOSE: Treatment with a selective proteasome inhibitor, VELCADE, in combination with tissue plasminogen activator (tPA) extended the therapeutic window to 6 hours in young rats after stroke. However, stroke is a major cause of death and disability in the elderly. The present study investigated the effect of VELCADE in combination with a low-dose tPA on aged rats after embolic stroke. METHODS: Male Wistar rats at the age of 18 to 20 months were treated with VELCADE (0.2 mg/kg) alone, a low-dose tPA (5 mg/kg) alone, combination of VELCADE and tPA, or saline 2 hours after embolic middle cerebral artery occlusion. To test the contribution of endothelial nitric oxide synthase to VELCADE-mediated neuroprotection, endothelial nitric oxide synthase knockout and wild-type mice were treated with VELCADE (0.5 mg/kg) 2 hours after embolic stroke. RESULTS: Treatment with VELCADE significantly reduced infarct volume, whereas tPA alone did not reduce infarct volume and aggravated blood-brain barrier disruption in aged rats compared with saline-treated rats. However, the combination treatment significantly enhanced the reduction of infarct volume, which was associated with an increase in endothelial nitric oxide synthase activity compared with saline treated rats. Additionally, the combination treatment promoted thrombolysis and did not increase the incidence of hemorrhage transformation. VELCADE significantly reduced lesion volume in wild-type mice but failed to significantly reduce lesion volume in endothelial nitric oxide synthase knockout mice. CONCLUSIONS: Treatment with VELCADE exerts a neuroprotective effect in aged rats after stroke. The combination of VELCADE with the low-dose tPA further amplifies the neuroprotective effect. Endothelial nitric oxide synthase at least partly contributes to VELCADE-mediated neuroprotection after stroke. PMID- 20203321 TI - Dose-response relation between neuromuscular electrical stimulation and upper extremity function in patients with stroke. AB - BACKGROUND AND PURPOSE: The purpose of our study was to investigate the effects of different doses of neuromuscular electrical stimulation (NMES) on upper extremity function in acute stroke patients with severe motor deficit. METHODS: Sixty-six acute stroke patients were randomized to 3 groups: high NMES, low NMES, or control. The low-NMES group received 30 minutes of stimulation per day, and the high-NMES group received 60 minutes per day, for 4 weeks. The Fugl-Meyer Motor Assessment Scale, Action Research Arm Test, and Motor Activity Log were used to assess the patients at baseline, 4 weeks, and 12 weeks post baseline (follow-up). RESULTS: Both NMES groups showed significant improvement on Fugl Meyer Motor Assessment and Action Research Arm Test scales compared with the control group at week 4 and follow-up. The high-NMES group showed treatment effects similar to those of the low-NMES group. CONCLUSIONS: Higher and lower doses of NMES led to similar improvements in motor function. A minimum of 10 hours of NMES in combination with regular rehabilitation may improve recovery of arm function in stroke patients during the acute stage. PMID- 20203320 TI - The beta-hCG+erythropoietin in acute stroke (BETAS) study: a 3-center, single dose, open-label, noncontrolled, phase IIa safety trial. AB - BACKGROUND AND PURPOSE: Animal data suggest the use of beta-human chorionic gonadotropin followed by erythropoietin to promote brain repair after stroke. The current study directly translated these results by evaluating safety of this sequential growth factor therapy through a 3-center, single-dose, open-label, noncontrolled, Phase IIa trial. METHODS: Patients with ischemic stroke 24 to 48 hours old and National Institutes of Health Stroke Scale score of 6 to 24 started a 9-day course of beta-human chorionic gonadotropin (once daily on Days 1, 3, and 5 of study participation) followed by erythropoietin (once daily on Days 7, 8, and 9 of study participation). This study also evaluated performance of serially measured domain-specific end points. RESULTS: A total of 15 patients were enrolled. Two deaths occurred, neither related to study medications. No safety concerns were noted among clinical or laboratory measures, including screening for deep vein thrombosis and serial measures of serum hemoglobin. In several instances, domain-specific end points provided greater insight into impairments as compared with global outcome measures. CONCLUSIONS: Results support the safety of this sequential, 2-growth factor therapy initiated 24 to 48 hours after stroke onset. PMID- 20203322 TI - Acute corticospinal tract Wallerian degeneration is associated with stroke outcome. AB - BACKGROUND AND PURPOSE: In children with stroke, poor motor outcome is associated with early Wallerian degeneration of the corticospinal tract that is seen on diffusion-weighted MRI. In this study we test the hypothesis that early diffusion changes also occur in the corticospinal tract (CST) of adults after stroke and that these lesions are associated with poor outcome. METHODS: In this retrospective study, we assessed images from a serial MRI study of adults with acute middle cerebral/internal carotid artery stroke. MRI-negative TIA patients served as controls. Custom software measured signal along the CST on different sequences, including the apparent diffusion coefficient (ADC). Visual detection of abnormal signal by blinded neuroradiologists was also evaluated. We then determined associations between CST signal changes and 3-month motor outcome (NIHSS score). RESULTS: Thirty-eight patients (20 stroke/18 control) were included. ADC measures were much more accurate than other MRI sequences for detection of degeneration in the CST. The ADC decreased in a time-dependent fashion in the CST of patients with poor motor outcome but not in those with good outcome. Changes in ADC were maximal at 7 days. Neuroradiologists could visually detect these changes with accuracy comparable to the software method. CONCLUSION: CST ADC decreases after acute stroke in patients with poor motor outcome and may represent early Wallerian degeneration. Recognition of this imaging marker may improve early outcome prediction and patient selection for rehabilitation and neuroprotection trials. PMID- 20203324 TI - Stress, burnout, and renewal activities of dental hygiene education administrators in six U.S. Midwestern States. AB - The purpose of this study was to explore the patterns that emerge among stress, burnout, and renewal activities of dental hygiene education administrators in six midwestern states in the United States. The study investigated the effects of stress on these administrators by identifying when stress and burnout occur, what precautions they take to prevent it, and what actions might combat stress and/or burnout once it has occurred. The administrators were asked to complete a demographic questionnaire, the Maslach Burnout Inventory (MBI)-Educators Survey, and an in-depth interview. The response rate to the demographic questionnaire and MBI-Educators Survey was 54.5 percent (30/55). Respondents were primarily Caucasian females (93 percent), at least fifty-one years of age (67 percent), employed in dental hygiene education at least twenty-one years (56 percent), and dental hygiene education administrators for less than ten years (55 percent). Almost half (43 percent) reported a moderate to high Emotional Exhaustion burnout score, one of three characteristics measured by the MBI-Educators Survey. All participants (100 percent) responded that stress had affected their personal and/or professional lives. The findings indicate that dental hygiene education administrators a) experience stress, b) experience patterns of stress, and c) use preventive strategies. Study participants felt that the stress and burnout they experienced may be altered through personal and/or professional lifestyle modifications and that additional training in stress management is needed. PMID- 20203323 TI - Hepatocyte growth factor and the risk of ischemic stroke developing among postmenopausal women: results from the Women's Health Initiative. AB - BACKGROUND AND PURPOSE: Hepatocyte growth factor (HGF) is a potent angiogenic factor and may play a role in the development and progression of atherosclerotic lesions, the underlying mechanism of cardiovascular disease. However, there have been no prospective studies examining the relationship between HGF levels and risk of stroke. METHODS: We conducted a nested case-control study (972 incident stroke cases and 1:1 age-matched and race-matched controls) to prospectively evaluate the association between plasma HGF and risk of ischemic stroke within the Women's Health Initiative Observational Study, a cohort of postmenopausal women aged 50 to 79 years. RESULTS: Baseline HGF levels were correlated positively with body mass index, systolic blood pressure, low-density lipoprotein cholesterol, insulin resistance, and inflammatory markers, such as C-reactive protein, and inversely with high-density lipoprotein cholesterol (all P<0.05). Baseline HGF levels were higher among cases than controls (geometric means, 601.8 vs 523.2 pg/mL; P=0.003). Furthermore, the risk of incident ischemic stroke was significantly greater among women in the highest vs lowest quartile of plasma HGF levels (OR, 1.46; 95% CI, 1.12-1.91; P(trend)=0.003) in a conditional logistic regression model that adjusted for body mass index. These results were only slightly attenuated after further adjustment for additional stroke risk factors (OR, 1.39; 95% CI, 1.04-1.85; P(trend)=0.023). CONCLUSIONS: Circulating levels of HGF are associated with an increased risk of incident ischemic stroke, independent of obesity and other risk factors for cardiovascular disease, among postmenopausal women aged 50 to 79 years. PMID- 20203325 TI - Academic integrity violations: a national study of dental hygiene students. AB - The purpose of this study was to identify the prevalence of academic integrity violations reported by a national sample of dental hygiene students as compared to general undergraduate students. This study also examined the influence of student variables such as gender, age, and level of education, along with honor codes and other contextual factors, on academic integrity. A total of 2,050 surveys were mailed to a random selection of the schools with dental hygiene degree programs in each of the twelve American Dental Hygienists' Association (ADHA) districts. A total of 794 usable surveys were returned for an overall response rate of 39 percent. The respondents were predominantly twenty to twenty nine years of age (85 percent), and 97.7 percent were female. The largest percentage of respondents (38.5 percent) had completed four or more years of undergraduate education at the time of the survey, with the majority of the coursework taken in a community college setting (39 percent). Approximately 53 percent were from associate programs and 47 percent from baccalaureate programs. Of those responding, 11.3 percent reported cheating during their dental hygiene program, and 30.2 percent were aware of someone cheating in their program. A comparison of academic violations for dental hygiene students to students in other undergraduate programs reveals that a smaller proportion of dental hygiene students report violations. PMID- 20203326 TI - A mathematical simulation approach to testing innovative models of dental education. AB - A combination of the increasing costs associated with providing a complex clinical program and an ever-reducing education-based income finds dental schools throughout Australia continuing to face serious financial risk. Even more important is the growing workforce crisis in academic staffing faced in almost all dental schools as the impact of the widening gap between private practice incomes and academic remuneration takes effect. This study developed a model of core variables and their relationship that was then transformed into a mathematical simulation tool that can be applied to test various scenarios and variable changes. The simulation model was tested against a theoretical dental education arrangement and found that this arrangement was a commercially viable pathway for new providers to enter the dental education market. This type of mathematical simulation approach is an important technique for analysis of the complex financial and operational management of modern dental schools. PMID- 20203327 TI - A scholastic appeals process for dental hygiene student remediation and retention. AB - A scholastic appeals process tailoring individualized remediation for dental hygiene students not meeting academic standards was assessed retrospectively (1999-2008) to evaluate retention and academic failure rates, nature of academic problems, type of remediation, and success of recommendations. Academic records of students (n=55) not meeting academic standards and/or withdrawing were reviewed. Overall retention (92.7 percent) ranged from 86.7 percent to 96.6 percent. Of the fifty-five students whose records were reviewed, six students (10.91 percent) withdrew for medical/personal reasons, and forty-nine (89.1 percent) petitioned for individualized remediation. The number and percentage of students in each category of reasons are as follows: four (7.5 percent) preclinical; thirty-seven (69.8 percent) clinical; eight (15.1 percent) academic/clinical/personal reasons; and four (7.5 percent) academic dishonesty. The options approved were the following: continue in the program with grade below C- (n=3), summer clinical course with individualized contract (n=11), or independent study course during the academic year plus the summer course (n=13), all without delaying graduation; repeating a course with a one-semester delay in graduation (n=7); and auditing/repeating multiple courses with a one-year delay in graduation (n=3). Twelve students were dismissed after denial of a petition requesting remediation or second failure. The scholastic appeals process was successful for 75.5 percent (n=37) of the students who petitioned after failing to meet academic standards, thereby contributing to the 92.7 percent overall retention rate. Student-specific remediation plans based on individual academic appeals are viable options for ensuring success. PMID- 20203328 TI - Preparing faculty members for significant curricular revisions in a school of dental medicine. AB - Resistance to change is expected, especially when change involves and impacts many stakeholders. During the past year, the Curriculum Committee at the University of Pittsburgh School of Dental Medicine has been preparing the dental school for a major curricular revision of its predoctoral program. This article describes how a faculty retreat was designed to gain support for and involvement in this reform process. In particular, it examines the results of a faculty survey that was used to shape the retreat and was developed to determine the faculty's perceived knowledge about instructional design, barriers to innovations in teaching, and the influence of student evaluations and evidence-based dentistry principles on faculty teaching. Having identified strengths and weaknesses and areas of concern among faculty members through the survey, the Curriculum Committee was able to prepare a retreat that addressed faculty needs while simultaneously advancing the movement towards curriculum reform. PMID- 20203329 TI - Evolution of a humanitarian dental mission to Madagascar from 1999 to 2008. AB - In this article, we report on the evolution of a series of dental outreach missions sponsored by Stony Brook University to remote areas of Madagascar over a nine-year period. The project evolved from one dental resident performing only dental extractions in 1999 to a team comprised of two dentists, six third-year dental students, and two dental assistants performing dental restorations, extractions, and endodontic procedures using digital radiographic equipment in 2008. The ability during the latest mission to utilize digital radiography in remote areas lacking running water, electricity, and dental facilities significantly enhanced the range and efficacy of dental procedures. This long term project offered senior dental students and residents from Stony Brook University's School of Dental Medicine an educationally valuable opportunity to engage in international dental outreach and to make a significant contribution to the improvement of oral health in the underserved rural communities of Madagascar. PMID- 20203330 TI - Examining clinical assessment practices in U.S. dental hygiene programs. AB - Competency-based education (CBE) in dental hygiene education is intended to measure learned skills that prepare students to independently provide services for the public. A variety of standardized clinical assessment techniques (SCATs) are available to substantiate the competence of health care professionals, including, but not limited to, objective structured clinical examinations (OSCEs), triple jump exams, standardized patients, and simulations. Standardized clinical examinations test students' abilities to treat diverse patients in a consistent, controlled setting. SCATs help prepare clinicians to safely treat patients of various complexities. The objectives of this study were to examine the variety of techniques used to assess clinical competence in U.S. accredited dental hygiene programs and to obtain program directors' attitudes regarding clinic assessment, with a focus on how SCATs are used. An online survey collected data from 125 directors (48 percent response rate). Approximately 97 percent of the responding programs used observation-type assessments followed by case studies (90 percent), self-assessment (85 percent), and mock boards (75 percent), with SCATs being the least used. The majority of responding directors (74 percent) indicated an interest in learning more about these SCATs. A chi-square test identified no significant difference between the use of SCATs by associate and baccalaureate degree programs, with program location also being irrelevant. PMID- 20203331 TI - Evaluation of outcomes for tobacco cessation counseling in the Dalhousie University dental hygiene curriculum. AB - As part of their curriculum, senior dental hygiene students at Dalhousie University Faculty of Dentistry provide tobacco cessation counseling (TCC). This study was conducted to evaluate the effectiveness of the TCC didactic curriculum and its clinical extensions. Research methods included a comprehensive literature search, an assessment of available resources related to TCC, and a structured telephone interview. The interview, consisting of ten summative questions, was conducted to determine the current tobacco use status of clients who had been counseled by a dental hygiene student for tobacco cessation. A target population of 132 subjects was extracted from axiUm, Dalhousie University dental clinic's patient database. The population represented clients who had TCC from 2001 to 2008. The investigators wanted to know if the client was 1) advised to quit tobacco use; 2) informed of the health risks of using tobacco; 3) still using tobacco; 4) taught self-examination techniques for oral cancer; and 5) if any post-counseling follow-up was initiated. A convenience size of fifty-one subjects was obtained. Survey results, along with the assessment of resources, revealed that the current TCC program needed improvement. As a result of the research, changes were implemented aimed at improving the effectiveness of the TCC program, and recommendations were made for further changes to enhance the overall program effectiveness. PMID- 20203332 TI - Introduction of health literacy into the allied dental curriculum: first steps and plans for the future. AB - In 2003, the U.S. Department of Education's National Center for Education Statistics conducted the National Assessment of Adult Literacy (NAAL). The NAAL reported that over 90 million adults were functionally or marginally illiterate. When these individuals encounter the health care system, they often have difficulties with reading and understanding basic text and, as a result, have difficulty managing their disease or using medications. The purpose of this article is to describe our initial efforts to educate our students concerning health literacy, its consequences, and our assessment. As part of a new segment of the allied health curriculum, second-year dental hygiene students received a lecture concerning the prevalence of poor literacy in America and the possible consequences of poor literacy on their patients' ability to maintain oral health. To provide clinical experience with assessing health literacy, the students were instructed in the administration of a validated medical health literacy tool. This clinical exercise had two functions: 1) to familiarize students with assessing health literacy as part of their clinical experience and 2) to continue to gather preliminary data concerning the level of health literacy of adult patients at Indiana University School of Dentistry using a standardized methodology, the Short Test of Functional Health Literacy in Adults (S-TOFHLA). The results indicated that 13 percent of those assessed had "inadequate" or "marginal" literacy as measured by the S-TOFHLA. As a result, we plan to continue to expand our educational efforts and develop a larger investigation of the prevalence in our dental school population. With these data, we hope to develop effective educational programs and experiences for our students, faculty, and staff to improve their awareness and communication skills and ultimately improve the oral health of our patients. PMID- 20203333 TI - Clinical experiences of undergraduate dental students in pediatric dentistry at Cork University Dental School and Hospital, Ireland. AB - The objectives of this study were to evaluate the number and range of clinical procedures completed by undergraduate dental students in pediatric dentistry in Cork University Dental School and Hospital, Ireland, and to compare the number of procedures undertaken with the subsequent examination scores. The work comprised a retrospective audit of clinical logbooks for all of the undergraduate dental students in one cohort through their fourth and fifth clinical years between 2004 and 2006. Thirty-four quantitative logbooks were audited. Students had seen a total of 1,031 patients, and each student had completed a full course of dental treatment for an average of twenty-two children. Students completed means of 30.2 restorative procedures for children, fourteen in deciduous dentition (range six to twenty-eight), and seventeen in permanent dentition (range seven to twenty eight). Continuity of education and care (measured through children having their treatment fully completed by the same student) was 72 percent. A moderate positive correlation between levels of clinical experience and exam score was identified. All students gained experience in management of child patients with students providing care for an average of thirty children and a minimum of nineteen. PMID- 20203334 TI - Approach to the thyroid cancer patient with extracervical metastases. AB - Patients with distant, or extracervical, metastases from differentiated thyroid cancer require multimodality diagnostic, therapeutic, and monitoring approaches. Whereas cure is the initial goal, especially in those with small, radioiodine avid pulmonary metastases, improved survival and management of symptoms become the primary objective in many patients with persistent disease, especially those with bone metastases. Levothyroxine therapy with suppression of serum TSH is a primary therapy in all patients with advanced differentiated thyroid cancer, and this therapy has been shown to improve overall survival and slow disease progression. Radioiodine is also an important systemic therapy for those patients with radioiodine-avid disease who respond to this targeted therapy. In this review, we compare standard fixed-dose radioiodine therapy vs. the dosimetric approach. Directed therapy such as external beam radiotherapy, surgery, and embolization is generally considered for large or painful lesions. Careful collaborations with multiple specialties through tumor boards or other mechanisms help to optimize complex management decisions in these patients with advanced thyroid cancer. Multimodality monitoring focused on the organ of interest such as pulmonary [computed tomography (CT)], bone (magnetic resonance imaging, CT, bone scan), and brain (CT, magnetic resonance imaging) metastases as well as general metastatic surveillance (bone scan, (18)F-fluorodeoxyglucose-positron emission tomography) aid decision making about careful monitoring vs. directed or systemic therapy. (18)F-fluorodeoxyglucose-positron emission tomography imaging has an additional role in patient prognosis and guiding directed therapy for fluorodeoxyglucose-avid lesions. Patients with asymptomatic, stable, radioiodine resistant metastases may be carefully monitored for disease progression. Patients with symptomatic disease should receive directed therapy with the goal of symptom relief. Patients with progressive metastatic disease should be considered for clinical trials or targeted systemic therapy (sorafenib or sunitinib), although these agents are not Food and Drug Administration (FDA) approved for patients with thyroid cancer. The goals of therapy for patients with extracervical metastases should be to improve survival, relieve symptoms, and decrease the morbidity of disease progression and limit the morbidity associated with therapy. PMID- 20203335 TI - Rapid screening of cryopreservation protocols for murine prepubertal testicular tissue by histology and PCNA immunostaining. AB - Numerous parameters have to be tested to identify optimal conditions for prepubertal testicular tissue banking. Our study evaluated 19 different cryopreservation conditions for immature testicular tissue using a rapid screening method. Immature mice testes were cryopreserved using either 1,2 propanediol (PROH) or dimethyl sulfoxide (DMSO) at a concentration of 0.75 or 1.5 M using a controlled slow-cooling rate protocol with (S+) or without seeding (S+). Equilibration was performed either at room temperature or at 4 degrees C for 15 or 30 minutes. Seminiferous cord cryodamage was determined by scoring morphologic alterations. Cell proliferation ability was evaluated using a proliferating cell nuclear antigen (PCNA) antibody. Testes cryopreserved with optimal conditions were grafted into immunodeficient mice. The highest proportions of PCNA-positive nuclei and lowest morphologic alterations were observed with 1.5 M DMSO. Tissues were more altered with 0.75 M DMSO or PROH. Complete germ cell maturation was observed after allografting of testicular pieces previously frozen with 1.5 M DMSO, S+, 30 minutes. The 1.5 M DMSO, S+ or S+ protocol preserved prepubertal mice testicular tissue architecture and germ cell and Sertoli cell proliferation potential. Allografting of thawed testis fragments into immunodeficient mice confirmed that the 1.5 M DMSO, S+, 30 minutes protocol maintained testicular somatic and germ cell functions. Postthaw histologic evaluation and PCNA immunostaining are useful to rapidly test numerous freeze-thaw parameters. They may also be efficient tools to control human prepubertal frozen testis quality, within the context of a clinical application. PMID- 20203336 TI - The evaluation of saphenofemoral insufficiency in primary adult varicocele. AB - The aim of this study was to evaluate the possible relationship between varicocele and saphenofemoral insufficiency in patients diagnosed with primary varicocele. A total of 70 patients with the primary diagnosis of varicocele were included into the study. A total of 30 age-matched healthy adults were also included in the study as a control group. Varicocele was diagnosed by palpation and observation of each spermatic cord in standing position before and during a valsalva maneuver. Additionally, scrotal Doppler and lower extremity venous Doppler ultrasonography were performed. Patients who were with spermatic varicose vein larger than 3.0 mm were included in the study group as a varicocele patient. At the lower extremity venous Doppler ultrasonography, a retrograde flow lasting longer than 0.5 seconds during normal breathing or at the valsalva maneuver was considered to be meaningful for saphenofemoral junction insufficiency. Thirty-six (51.35%) patients had insufficiency in saphenofemoral junction in the study group (6 [8.5%] bilateral, 30 [42.85%] unilateral) whereas 8 (26.6%) had insufficiency in the control group (2 [6.6%] bilateral, 6 [20%] unilateral insufficiency). The patients with primary varicocele had a statistically significant (P = .02) higher rate of venous insufficiency in their saphenofemoral junctions when compared with the control group. In the present study, the rate of saphenofemoral insufficiency has been found to be statistically higher in patients with primary varicocele compared with healthy men. Depending on the common presence of valvular insufficiency, we believe that the presence of varicocele should be investigated in the young population suffering from saphenofemoral junction insufficiency. PMID- 20203337 TI - Deletion of the Igf1 gene: suppressive effects on adult Leydig cell development. AB - Deletion of the insulin-like growth factor 1 (Igf1) gene was shown in previous studies to result in reduced numbers of Leydig cells in the testes of 35-day-old mice, and in reduced circulating testosterone levels. In the current study, we asked whether deletion of the Igf1 gene affects the number, proliferation, and/or steroidogenic function of some or all of the precursor cell types in the developmental sequence that leads to the establishment of adult Leydig cells (ALCs). Decreased numbers of cells in the Leydig cell lineage (ie, 3beta hydroxysteroid dehydrogenase-positive cells) were seen in testes of postnatal day (PND) 14-90 Igf1(-/-) mice compared with age-matched Igf1(+/+) controls. The development of ALCs proceeds from stem Leydig cells (SLCs) through progenitor Leydig cells (PLCs) and immature Leydig cells (ILCs). The bromodeoxyuridine labeling index of putative SLCs was similar in the Igf1(-/-) and Igf1(+/+) mice. In contrast, the labeling index of PLCs was reduced in the Igf1(-/-) mice on each day of PND 14 through PND 35, and that of more mature Leydig cells (referred to herein as LCs, a combination of ILCs plus ALCs) was reduced from PND 21 through PND 56. In Igf1(-/-) mice that received recombinant IGF-I, the labeling indices of PLCs and LCs were similar to those of age-matched Igf1(+/+) mice, indicating that the reductions in the labeling indices seen in the PLCs and LCs of the Igf1( /-) mice were a consequence of reduced IGF-I. On each day of PND 21 through PND 90, testicular testosterone concentrations were significantly reduced in the Igf1(-/-) mice, as were the expressions of testis-specific mRNAs involved in steroidogenesis, including Star, Cyp11a1, and Cyp17a1. The increased expression of the gene for 5alpha-reductase (Srd5a1) in adult Igf1(-/-) testes suggests that the depletion of Igf1 might suppress or delay Leydig cell maturation. These observations, taken together, indicate that the reduced numbers of Leydig cells in the adult testes of Igf1(-/-) mice result at least in part from altered proliferation and differentiation of ALC precursor cells, but not of the stem cells that give rise to these cells. PMID- 20203338 TI - Bicarbonate-dependent serine/threonine protein dephosphorylation in capacitating boar spermatozoa. AB - This study investigates the dynamics of serine/threonine (S/T) protein phosphorylation in sperm incubated under capacitating (C) conditions using the boar as a model system. For the first time, this approach has identified multiple dephosphorylation events that occur in a bicarbonate-dependent fashion. Different phospho-(S/T) kinase substrate antibodies were used, and dephosphorylation of 5 S/T phosphoproteins was observed in C sperm compared with noncapacitated (N) cells. Specifically, dephosphorylation of 96-, 90-, 64-, and 55-kd proteins was detected by immunoblotting using 2 phospho-Akt substrate antibodies and a phosphoprotein kinase A substrate antibody. In addition, dephosphorylation of a 105-kd protein was detected using a phospho-ATM/ATR substrate antibody. In contrast, no dephosphorylation was observed using a phosphoprotein kinase C substrate antibody, and increased tyrosine phosphorylation of 32- and 20-kd proteins was detected in C compared with N sperm. Immunolocalization experiments revealed subtle changes in the pattern expression as well as a reduction of phosphorylation in C sperm. Whereas sperm incubated in N medium containing dibutyryl cAMP (dbcAMP) and 3-isobutyl-1-methylxanthine (IBMX) did not show protein dephosphorylation, incubation in C medium with dbcAMP/IBMX showed dephosphorylation as well as increased phosphorylation of other proteins (p68, p51, and p29). Finally, calyculin A, a phosphatase inhibitor, prevented dephosphorylation of p96, p90, p64, and p55 but not p105. Based on these data, we propose 2 pathways of protein dephosphorylation that are active during capacitation and independent of cAMP. Together, this provides direct evidence for more complex S/T phosphorylation dynamics than has been previously described for sperm undergoing capacitation. PMID- 20203339 TI - Effect of experimental diabetes and STZ on male fertility capacity. Study in rats. AB - To assess the effect of experimental Type 1 diabetes on male fertility, male Sprague Dawley rats were injected with either streptozotocine (STZ) to induce diabetes or with citrate buffer as controls. Diabetic animals and 2 control groups (STZ-resistant and buffer-injected rats) were sacrificed at 2 different times after injection: 6 weeks (6W) and 20 weeks (20W). We analyzed serum testosterone (sTT), epididymal sperm parameters, and weight of testicles and epididymides, and carried out a histological evaluation of testicular tissue. Diabetic animals presented a significant increase in teratozoospermia (20W, P < .01) and a decrease in sTT (P < .01), tubular diameter (6W, P < .05), and testicular (6W, P < .01) and epididymal (P < .01) weight. STZ-resistant animals showed significantly decreased sTT (6W, P < .01), epididymal weight (6W, P < .05), and sperm count (6W, P < .01) compared with buffer-injected controls. Experimental STZ diabetes increases teratozoospermia and decreases sTT, testicular weight (reverting at medium-term), and epididymal weight. PMID- 20203340 TI - Various attitudes to the use of corrective exercises in conservative treatment of scoliosis. AB - In acquired scoliosis, the degree of the curve is initially low and its type becomes apparent only after it has progressed. The characteristics of scoliosis include an abnormal spatial arrangement of individual body segments, which the central nervous system (CNS) interprets as a defect and automatically launches compensatory mechanisms. Neglecting low-degree scoliosis poses a two-fold danger. It usually leads to the development of structural changes, while the child gets used to the abnormal body arrangement, thus reinforcing the poor postural habits. The basic aim of early rehabilitation is to manage the compensatory mechanisms and prevent the development of adverse secondary changes, rehabilitation in scoliosis being no exception.Some cases of scoliosis require surgery. The point is to minimise the changes resulting from the progression of scoliosis. The role of corrective exercises seems to be significant here. However, views on the usefulness of such exercises are sometimes extremely varied, even though both favourable and sceptical opinions are not fully supported by the literature. However, a number of reports indicate that corrective exercises are useful.
The selection and of corrective exercises and how they should be performed are another question. A number of methods of conservative treatment of scoliosis have been devised. Currently, none of them is considered a comprehensive regimen since each patient requires an individual approach. The most difficult aspect is to ensure that local correction translates to the automatic maintenance of the corrected body posture in a standing position. This is facilitated by corrective exercises supported with biofeedback.
The aim of this paper is to elucidate this complex issue that often leads to divergent and improper attitudes to the conservative treatment of scoliosis. PMID- 20203341 TI - Usefulness of ct scans and radiographs in the assessment of cervical spine injuries in polytrauma patients - own experience. AB - INTRODUCTION: This paper evaluates the usefulness of spiral CT and conventional radiographs in the assessment of cervical spine injuries in polytrauma patients. The data are used as a basis for determining a precise and quick method for the assessment of the severity of cervical spine injuries that is also possibly least inconvenient for the patient.This approach is important due to the high risk of cervical spine injuries in patients with severe polytrauma and head injuries, as appropriate diagnostic work-up will help avoid unnecessary examinations and shorten time to diagnosis. MATERIAL AND METHODS: The study population consisted of 46 polytrauma patients hospitalized at the Intensive Care Unit of the Regional Hospital in Olsztyn. The efficacy of the diagnosis of cervical spine injuries on the basis of conventional radiographs and spiral CT studies was compared. RESULTS: Conventional radiographs failed to cover the entire cervical spine in all patient, and the assessment of most radiographic images was either difficult or unclear. Spiral CT studies with reformations were able to provide complete image of injuries to bony structures in all patients. CONCLUSIONS: Spiral CT with reformations (MPR and VRT) should be the basic modality in the diagnosis of cervical spine fractures. An appropriate treatment method may be selected and mistakes in the interpretation of injuries may be avoided on the basis of CT studies. Its other advantages are the short time required to perform the scan and the possibility of supporting vital functions in polytrauma patients during the examination. PMID- 20203342 TI - Quality of life-oriented evaluation of late functional results of hand replantation. AB - BACKGROUND: Forearm amputation in different zones via a similar mechanism in a group of patients of similar age is associated with different possibilities of functional recovery. The degree of postoperative recovery of function is invariably partial compared to pre-amputation function; this kind of trauma inevitably leads to disability. The patients adapt to their new circumstances to a different extent. That is why a quality of life evaluation should be included in the assessment of replantation outcomes. The aim of the study was to evaluate functional outcomes in patients after replantation at the metacarpal, wrist and mid-forearm level with regard to the quality of life of this patients. MATERIAL AND METHODS: Thirty patients (29 men, 1 woman) of an average age of 41 years who had had replantation or revascularization surgery of an upper limb at different levels took part in a randomized study. The patients were divided into 3 groups depending on the level of amputation: metacarpal, wrist, mid-forearm, with 10 patients in each group. Amputations had been done by a circular saw (21) or via a guillotine mechanism (9). The patients were evaluated on average 4.2 years postoperatively. The following parameters were assessed: total range of active motion (the long finger with the greatest range of motion was assessed) (TAM), grip strength, and sensation; patients performed the Nakamura-Tamai test (modified). Overall functional outcomes were assessed according to Chen's classification. The quality of life (QoL) was measured with the SF-36 questionnaire (0-136 points). The correlation of functional and QoL results was assessed by Spearman's non-parametric test. RESULTS: Average TAM was: 167 degrees in metacarpal, 174 degrees in wrist, 114 degrees in mid-forearm group; grip strength was 0.7 N, 0.9 N and 0.6 N respectively. All patients had at least protective sensation, whereas a 2PD of less then 10 mm was present in 4 patients in the metacarpal group, and 6 patients in the wrist group. In Chen's classification 5 patients in metacarpal group were rated as grade I and II, compared to 7 in the wrist group, and 2 in the forearm group. QoL scores were 98.9, 104 and 82 respectively. A strong QoL-function correlation was confirmed in the wrist and forearm groups (0.73 - 0.81 respectively), and in the metacarpal group it was weak (0.43). CONCLUSION: The quality of life of patients of the designated groups was correlated with their functional results. PMID- 20203343 TI - Clinical results of meniscus repair. AB - BACKGROUND: The paper presents the results of clinical assessment of meniscal repair outcomes after a minimum of two years post-suturing. MATERIAL AND METHODS: The first stage of the treatment involved arthroscopic repair of 34 menisci in 31 knees of 30 patients, and the second stage was anterior cruciate ligament reconstruction. The menisci were repaired mainly with PDS sutures, using an inside-out technique. A clinical evaluation of meniscal healing was performed at a mean of 3.9 years following the meniscal repair and involved an orthopaedic examination and a Lysholm score-based assessment of the knees. It was determined which factor (such as age, sex, trauma-to-suturing time, meniscal type, location and extent of tear, and extent of anterior tibial laxity) had had an effect on the results. RESULTS: 26 out of the 31 menisci evaluated (84%) were healed. Five menisci had failed to heal (16%). Lysholm scoring classified 16 results as excellent, nine as good and two as fair. A statistical analysis revealed that the location of the meniscal tear was the only factor possessing a statistically significant effect on the results. CONCLUSION: 1. In this study, 84% of meniscal symptoms and 13% of the evaluated meniscal healing after a minimum of two years post-surgery, whereas 3% showed meniscal symptoms and 13% of the evaluated menisci were resected. 2. Out of all analysed factors (patient age, sex, trauma to-repair time, meniscus type, and the location, length and extent of the tear), only the location of the meniscal tear correlated significantly with the result of meniscal healing determined by clinical evaluation. 3. There was no statistically significant relationship between Lysholm scores and patient age, sex, trauma-to-repair time, or the location of the meniscal tear. PMID- 20203344 TI - Early evaluation of quality of life and clinical parameters after total knee arthroplasty. AB - BACKGROUND: Gonarthrosis is the most frequent indication to perform arthroplasty of the knee joint. The purpose of the study was to examine the effect of selected factors on quality of life evaluation in patients after a knee arthroplasty for gonarthrosis. MATERIAL AND METHODS: Forty patients aged 40 to 85 years (mean age 71.2 years) who underwent knee arthroplasty were examined. The Knee Injury and Osteoarthritis Outcome Score (KOOS) and Short Form-36 (SF-36) questionnaires were used to assess the quality of life of the patients. The questionnaires were completed by patients twice: 1-3 days before the operation and 6 weeks post surgery. Age, gender, BMI, preoperative knee joint range of motion and limb axis, the presence of other implants, and the presence of a knee contracture before surgery were analysed. RESULTS: The analysis demonstrated that sex, age, presence of other implants, axis and a preoperative knee contracture did not significantly influence questionnaire scores. As regards the range of knee flexion, outcomes after the arthroplasty were significantly better in patients with pre-operative ranges below 90 masculine than in patients with pre-operative ranges above 90 masculine. BMI had a significant influence on questionnaire scores. CONCLUSIONS: The BMI value and range of knee flexion before the arthroplasty significantly influenced the quality of life after knee arthroplasty, whereas gender, age, the presence of an additional endoprosthesis or pre-operative joint deformity did not. PMID- 20203345 TI - The effects of previous meniscus and anterior cruciate ligament injuries in patients with total knee arthroplasty. AB - BACKGROUND: Patients undergoing total knee replacements constitute a suitable population to study the natural history of traumatic joint injuries. MATERIAL AND METHODS: We studied all the patients who received a TKA (Total knee arthroplasty) over the course of one year, in five different centers. The study included 474 patients who had undergone primary TKA for knee OA over a one-year period. In each patient, we analyzed age, sex, side of operation, weight, height and body mass index (BMI, kg/m2). BMI were stratified into four groups according to the WHO classification: normal (<25), overweight (>25 and <30), obese (>30 and <40), and morbidly obese (>40). RESULTS: In the TKA group, 74% of the patients were women, while in the THA group the percentage of men and women was similar. No differences were found in the sides operated on. Differences between both groups were found in knee alignment. Women were operated on more frequently for TKA, as there was a higher incidence of OA of the knee joints in women aged over 65. CONCLUSIONS: Patients who required a total knee arthroplasty are likely to have previously undergone surgery or trauma to the knee joints. PMID- 20203346 TI - Surgical treatment of dysplasia fibrosa and defectus fibrosus with bone allografts. AB - BACKGROUND: A common feature of dysplasia fibrosa and defectus fibrosus is the development of foci of disordered fibrous tissue in bone that tend to grow and displace regular bone tissue. The objective of this study was to evaluate the efficacy of surgical treatment with bone allografts in patients with fibrous dysplasia and fibrous defect of bone. MATERIAL AND METHODS: The study group consisted of 99 patients aged from 9 to 58 years (mean age 22 years), including 56 men and 43 women. A total of 145 surgical procedures were performed in this group at the Bone Tumour and Neoplasm Unit between 1999 and 2005. In all cases histopathological verification confirmed fibrous dysplasia or fibrous defect of bone. The follow-up period was from 1 to 5 years (mean 2.5 years). RESULTS: In 85 patients there were no recurrences. A total of 96 surgical procedures were performed in this group. The other 14 patients experienced recurrences and no graft remodelling. Forty-nine surgical procedures were performed in this group because of multiple (from 2 to 6) relapses of the tumours. CONCLUSIONS: 1. Resection surgery and filling the defect with bone graft in the basic tyep of treatment in fibrous dysplasia and bibrous defect of bone and leads to good outcomes. 2. Frozen cortico-cancelleous allografts are well incorporated and bone remodeling is not assocaited with inflammatory complications, resulting into good outcomes of the operative treatment. PMID- 20203347 TI - The role of laser biostimulation in early post-surgery rehabilitation and its effect on wound healing. AB - BACKGROUND: The aim of this paper is to investigate whether laser biostimulation starting on the first day after surgery of the brachial plexus or peripheral nerves has a positive therapeutic effect on wound healing. MATERIAL AND METHODS: Surgical procedures were carried out on 44 male Wistar rats. The animals were divided into a control group (Group 1), where the surgical wounds were allowed to heal spontaneously, and an experimental Group 2, where the wounds were exposed to laser irradiation with the following parameters: wavelength 810 nm, power 100 mW, energy 15 J, laser exposure surface 3 cm(2), single application time 2 min. 30 sec., continuous mode. The results were assessed with pathomorphological tests (gross appearance of the wound, light and electron microscopy studies) and breaking strength examination. Statistical analysis used arithmetic means, standard deviations and Student's t test for independent samples. RESULTS: Low energy infrared laser radiation had a beneficial effect on the covering of the scar with stratified squamous cornifying epithelium and intensified wound healing. CONCLUSIONS: The gross and microscopic findings indicated a beneficial effect of laser stimulation on wound healing. These results underscore the utility of biostimulation lasers in the early post-operative period. Physicomechanical investigations did not reveal an effect of infrared laser biostimulation on the breaking strength of the cutaneous scar. PMID- 20203348 TI - The dynamics of physical activity in palliative care patients. AB - BACKGROUND: Active and passive physical exercises in patients under palliative (long term) care in palliative wards and home hospices are a necessary means of prevention or reduction of pulmonary complications, disorders of respiratory function, vascular complications, disorders of lymphatic and venous function, and musculoskeletal dysfunction. The goal of this study was to assess the dynamics of physical activity in patients under long term care. MATERIAL AND METHOD: The study group consisted of 60 patients staying in a palliative care ward or a home hospice. The dynamics of physical ability was assessed with the Karnofsky Performance Scale, and the quality of life was evaluated using the 6-point scale of the Rotterdam Symptom Checklist. The study was conducted over eight weeks, with patient information recorded once a week. RESULTS: Over consecutive weeks, physical activity increased by 10-20% in 20% of the participants, did not change in 36% of the participants, and 44% of the study group showed a decrease in activity. We found an increase in the quality of life in the consecutive weeks of the study and a correlation with the physical activity level. A higher score on the Karnofsky Scale corresponded with a higher quality of life measured in the six-point scale of the Rotterdam Symptom Checklist. Significant correlations were found both for specific weeks and for the entire study period. CONCLUSIONS: 1. The rehabilitation of palliative care patients resulted in a significant improvement in the quality of life. 2. The results indicate that there is a need to provide palliative patients with optimum rehabilitation regardless of their pre-rehabilitation clinical status. 3. The Karnofsky Performance Scale and the Rotterdam Symptom Checklist are strongly correlated with each other, which makes them robust investigative instruments for evaluating palliative patients. PMID- 20203349 TI - Hand transplant - outcome after 6 months, preliminary report. AB - BACKGROUND: Hand transplant still remains a partly experimental procedure because of the small number of patients and short follow-up (not longer than 10 years). Most hand transplantations have been performed at the distal forearm level. MATERIAL AND METHOD: The transplant recipient was a 29-year-old man who had lost his dominant right hand 3 years before in a milling machine accident; the donor was a 52-year-old woman. The procurement and transport of the limb were performed according to standard procedures. Preparation of the donor limb and the patient's stump was performed simultaneously by two surgical teams. Anastomoses were done in the following order : bones-tendons-nerves-veins-artery. The radial artery and 3 large veins were anastomosed. The operative wound was closed without a skin graft. Ischemia time was 9 hours. Pharmacological treatment was similar to that usually administered to replantation patients; immunotherapy consisted of Simulect, Prograf, Cell-Cept, and steroids. Physiotherapy was started on the second postoperative day; it consisted of early protective active motion (EPM), continuous passive motion (CPM), splinting, and sensory stimulation. The function of internal organs was monitored; the early outcome was evaluated at 6 months after the transplantation. RESULTS: The function of internal organs remained undisturbed, no rejection episodes were observed. Bony union was achieved after 11 weeks and progressed steadily, as did the range of motion and reinnervation. On the day of the preliminary assessment, the active range of motion was 200 degrees , 2PD exceeded 15 mm, and electromyography demonstrated temperature sensation and hypothenar muscle function. Functional assessment according to the DASH questionnaire was rated at 67 points, and a quality of life evaluation with the SF-36 questionnaire produced a score of 110 points. CONCLUSION: The distal third of the forearm is a replantation zone promoting early functional recovery. PMID- 20203350 TI - Low density MOVPE grown InGaAs QDs exhibiting ultra-narrow single exciton linewidths. AB - Low density (approximately 10(7) cm(-2)), small sized InGaAs quantum dots were grown on a GaAs substrate by metal-organic vapor-phase epitaxy and a special annealing technique. The structural quantum dot properties and the influence of the annealing technique was investigated by atomic force microscope measurements. High-resolution micro-photoluminescence spectra reveal narrow photoluminescence lines, with linewidths down to 11 microeV and fine structure splittings of 25 microeV. High signal to noise ratios (approximately 140) and a nearly background free autocorrelation measurement indicate an excellent optical quality and single photon emission behavior. Furthermore, time resolved measurements reveal excitonic decay times typically in the range between 800 and 2300 ps and biexcitonic decay times around 300 ps. PMID- 20203351 TI - Magnetoresistive phenomena in an Fe-filled carbon nanotube/elastomer composite. AB - DC magnetoresistive effects were observed in above-percolation-threshold loaded Fe-filled carbon nanotube/polyurethane-urea composite samples. A phenomenological model is derived from interpretation of resistance relaxation for a range of axial strains. The large instantaneous magnetoresistance of + 90% observed at low axial strain was a result of conduction pathway breaking caused by preferential orientation of the conducting nanotubes perpendicular to the axial current flow: a result of the magnetic torque experienced by the ferromagnetic nanotube core. At large strain the observed large instantaneous change in resistance of - 90% resulted from voltage-driven relaxation in the conducting nanotube network. At high axial strain the competition between voltage-driven relaxation and a magnetic torque gave rise to an oscillatory component of resistance relaxation. PMID- 20203352 TI - Selective sensing of volatile organic compounds using novel conducting polymer metal nanoparticle hybrids. AB - Conducting polymer-metal nanoparticle hybrids, fabricated by assembling metal nanoparticles on top of functionalized conducting polymer film surfaces using conjugated linker molecules, enable the selective sensing of volatile organic compounds (VOCs). In these conducting polymer-metal nanoparticle hybrids, selectivity is achieved by assembling different metals on the same conducting polymer film. This eliminates the need to develop either different polymers chemistries or device configurations for each specific analyte. In the hybrids, chemisorption of the analyte vapor induces charge redistribution in the metal nanoparticles and changes their work function. The conjugated linker molecule causes this change in the work function of the tethered nanoparticles to affect the electronic states in the underlying conducting polymer film. The result is an easily measurable change in the resistance of the hybrid structure. The fabrication of these sensing elements involved the covalent assembly of nickel (Ni) and palladium (Pd) metal nanoparticles on top of poly(3,4 ethylenedioxythiophene-co-thiophene-3-acetic acid), poly(EDOT-co-TAA), films using 4-aminothiophenol linker molecules. The change in resistance of hybrid Pd/poly(EDOT-co-TAA) and Ni/poly(EDOT-co-TAA) hybrid films to acetone and toluene, respectively, is observed to be in proportion to their concentrations. The projected detection limits are 2 and 10 ppm for toluene and acetone, respectively. A negligible response (resistance change) of the Pd/poly(EDOT-co TAA) films to toluene exposure confirmed its selectivity for detecting acetone. Similarly, lack of response to acetone confirmed the selectivity of the Ni/poly(EDOT-co-TAA) stacks for detecting toluene. It is anticipated that the assembly of other metals such as Ag, Au and Cu on top of poly(EDOT-co-TAA) would provide selectivity for detecting and discriminating other VOCs. PMID- 20203353 TI - Controlling the morphology of multi-branched gold nanoparticles. AB - We demonstrate a simple and versatile way to achieve high yield synthesis of shape- and size-controlled multi-branched gold nanoparticles (MBNPs). Control over the shape of the MBNPs was achieved by varying the ratio of gold to the mild reducing agent ascorbic acid, using a seed-mediated growth approach. Higher ascorbate concentrations resulted in the smoothing of branches, leading to the yield of relatively more isotropic particles. Furthermore, we found that using much higher silver concentrations in the growth solution resulted in the formation of rod-shaped micro-features together with MBNPs; we postulate them to be cetyltrimethyl ammonium silver bromide crystals. The as-prepared MBNPs show interesting tunable optical properties that are strongly influenced by the particle shape. The results are discussed in terms of plasmon coupling between the core and branches of the MBNPs. PMID- 20203354 TI - Two-terminal nanoelectromechanical bistable switches based on molybdenum-sulfur iodine molecular wire bundles. AB - We demonstrate the application of Mo(6)S(3)I(6) molecular wire bundles for electrically controllable two-terminal on-off switches. We investigate how changes in the contact electrode material and geometry influence the device characteristics, hysteretic switching behavior and device stability. We also determine the device operating parameters, particularly the Young's moduli (40 270 GPa), operating current densities (3.2 x 10(5)-7 x 10(6) A m(-2)) and force constants. Although qualitatively, the properties of Mo(6)S(3)I(6) nanowires in nanoelectromechanical (NEM) switches are similar to those of carbon nanotubes (CNTs), their lower friction coefficient, higher mechanical stability and higher operation voltages give specific advantages in terms of smaller differences in on off operating potentials, higher switching speeds and lower energy consumption than CNTs, which are critical for applications in NEM devices. PMID- 20203355 TI - Spin-glass-like freezing and enhanced magnetization in ultra-small CoFe2O4 nanoparticles. AB - The magnetic properties of ultra-small (3 nm) CoFe(2)O(4) nanoparticles have been investigated by DC magnetization measurements as a function of temperature and magnetic field. The main features of the magnetic behaviour are blocking of non interacting particle moments (zero-field-cooled magnetization T(max) approximately 40 K), a rapid increase of saturation magnetization (up to values higher than for the bulk material) at low T and an increase in anisotropy below 30 K due to the appearance of exchange bias. The low temperature behaviour is determined by a random freezing of surface spins. Localized spin-canting and cation distribution between the two sublattices of the spinel structure account quantitatively for the observed increase in saturation magnetization. PMID- 20203356 TI - The fabrication of low-impedance nanoporous gold multiple-electrode arrays for neural electrophysiology studies. AB - Neural electrodes are essential tools for the study of the nervous system and related diseases. Low electrode impedance is a figure of merit for sensitive detection of neural electrical activity and numerous studies have aimed to reduce impedance. Unfortunately, most of these efforts have been tethered by a combination of poor functional coating adhesion, complicated fabrication techniques, and poor fabrication repeatability. We address these issues with a facile method for reliably producing multiple-electrode arrays with low impedance by patterning highly adherent nanoporous gold films using conventional microfabrication techniques. The high surface area-to-volume ratio of self assembled nanoporous gold results in a more than 25-fold improvement in the electrode-electrolyte impedance, where at 1 kHz, 850 kOmega impedance for conventional Au electrodes is reduced to 30 kOmega for nanoporous gold electrodes. Low impedance provides a superior signal-to-noise ratio for detection of neural activity in noisy environments. We systematically studied the effect of film morphology on electrode impedance and successfully recorded field potentials from rat hippocampal slices. Here, we present our fabrication approach, the relationship between film morphology and impedance, and field potential recordings. PMID- 20203357 TI - Synthesis and luminescence of CePO4:Tb/LaPO4 core/sheath nanowires. AB - CePO(4):Tb/LaPO(4) nanowires with a core/sheath architecture have been successful synthesized by a facile aqueous chemical method mediated by original CePO(4):Tb aggregation seeds. The seed crystals serve as both a luminescence center and a nucleation site for epitaxial growth. The seed nanocrystals have an irregular sphere-like shape with an average size of around 6.8 nm and a narrow size distribution. When the seed crystals are coated with LaPO(4), the resulting core/sheath CePO(4):Tb/LaPO(4) nanowires have mean diameters of about 7.6 nm and lengths up to 331 nm. Both photo- and x-ray luminescence demonstrate that the LaPO(4) coating increases the luminescence efficiency. These core/sheath structured nanowires may find potential applications in solid state lighting, medical imaging and radiation detection. PMID- 20203358 TI - NMR-based metabonomic study of the sub-acute toxicity of titanium dioxide nanoparticles in rats after oral administration. AB - As titanium dioxide nanoparticles (TiO(2) NPs) are widely used commercially, their potential toxicity on human health has attracted particular attention. In the present study, the oral toxicological effects of TiO(2) NPs (dosed at 0.16, 0.4 and 1 g kg( - 1), respectively) were investigated using conventional approaches and metabonomic analysis in Wistar rats. Serum chemistry, hematology and histopathology examinations were performed. The urine and serum were investigated by (1)H nuclear magnetic resonance (NMR) using principal components and partial least squares discriminant analysis. The metabolic signature of urinalysis in TiO(2) NP-treated rats showed increases in the levels of taurine, citrate, hippurate, histidine, trimethylamine-N-oxide (TMAO), citrulline, alpha ketoglutarate, phenylacetylglycine (PAG) and acetate; moreover, decreases in the levels of lactate, betaine, methionine, threonine, pyruvate, 3-D-hydroxybutyrate (3-D-HB), choline and leucine were observed. The metabonomics analysis of serum showed increases in TMAO, choline, creatine, phosphocholine and 3-D-HB as well as decreases in glutamine, pyruvate, glutamate, acetoacetate, glutathione and methionine after TiO(2) NP treatment. Aspartate aminotransferase (AST), creatine kinase (CK) and lactate dehydrogenase (LDH) were elevated and mitochondrial swelling in heart tissue was observed in TiO(2) NP-treated rats. These findings indicate that disturbances in energy and amino acid metabolism and the gut microflora environment may be attributable to the slight injury to the liver and heart caused by TiO(2) NPs. Moreover, the NMR-based metabolomic approach is a reliable and sensitive method to study the biochemical effects of nanomaterials. PMID- 20203359 TI - Assembly of magnetic nanoparticles into higher structures on patterned magnetic beads under the influence of magnetic field. AB - The self-assembly of nanoparticles into higher organizations in a controlled manner has critical importance for the utility of the unique properties of nanoparticles. The behavior of magnetic Fe(3)O(4) nanoparticles (MNPs) with an average size of 6 nm under an enhanced magnetic force is reported. Upon evaporation of the solvent where the MNPs are suspended, formation of unique micrometer-sized structures is achieved only when there is a patterned surface constructed from sub-micrometer size magnetic beads in between the applied magnetic field and the MNPs. The preliminary results indicate that the combined effect of magnetic field and evaporation rate might help the control of nanoparticle behavior on surfaces and interfaces in constructing higher structures. PMID- 20203360 TI - Memristive switching of single-component metallic nanowires. AB - Memristors have recently generated significant interest due to their potential use in nanoscale logic and memory devices. Of the four passive circuit elements, the memristor (a two-terminal hysteretic switch) has so far proved hard to fabricate out of a single material. Here we employ electromigration to create a reversible passive electrical switch, a memristive device, from a single component metallic nanowire. To achieve resistive switching in a single-component structure we introduce a new class of memristors, devices in which the state variable of resistance is the system's physical geometry. By exploiting electromigration to reversibly alter the geometry, we repeatedly switch the resistance of single-component metallic nanowires between low and high states over many cycles. The reversible electromigration causes the nanowire to be cyclically narrowed to approximately 10 nm in width, resulting in a change in resistance by a factor of two. As a result, this work represents a potential route to the creation of nanoscale circuits from a single metallic element. PMID- 20203361 TI - L-cysteine-capped CdTe QD-based sensor for simple and selective detection of trinitrotoluene. AB - Trinitrotoluene, usually known as TNT, is a kind of chemical explosive with hazardous and toxic effects on the environment and human health. National and societal security concerns have dictated an increasing need for the analytical detection of TNT with rapidity, high sensitivity and low cost. This work demonstrates a novel method using L-cysteine-capped CdTe quantum dots (QDs) to assay TNT, based on the formation of a Meisenheimer complex between TNT and cysteine. The fluorescence (FL) of quantum dots quench because electrons of the QDs transfer to the TNT molecules via the formation of a Meisenheimer complex. TNT can be detected with a low detection limit of 1.1 nM. Studies on the selectivity of this method show that only TNT can generate an intense signal response. The synthesized QDs are excellent nanomaterials for TNT detection. In addition, TNT in soil samples is also analyzed by the proposed method. PMID- 20203363 TI - The effect of carbon monoxide poisoning on hemorheological parameters in rats and the alterations in these parameters in response to three kinds of treatments. AB - This study aimed to investigate the short term effects of carbon monoxide (CO) poisoning and three kinds of poisoning treatments; namely room air, normobaric and hyperbaric oxygen on hemorheological parameters such as red blood cell (RBC) deformability, aggregation, blood and plasma viscosity. 43 Wistar rats were divided into 5 groups. Poisoning was induced by exposure to 4000 ppm CO (1 h). The poisoning protocol was followed by 3 types of treatments; room air, normobaric 100% oxygen and hyperbaric oxygen for 1 h. RBC deformability and aggregation were determined using an ektacytometer (LORCA) and a cone-plate rotational viscometer was used for the viscosity measurements. RBC deformability of CO poisoned rats were found to be elevated and the treatments applied, caused decrement of this parameter. A no significant increment tendency was found in erythrocyte aggregation after CO exposure. Although room air and hyperbaric oxygen treatments caused further significant elevations in the amplitude of aggregation, normobaric oxygen therapy induced decrement in this parameter towards control levels. No significant alterations were observed in viscosity values among the groups. The results of this study demonstrate normobaric oxygen therapy as a better choice of treatment after CO poisoning in hemorheological point of view. PMID- 20203362 TI - Cardiovascular benefits in moderate increases of blood and plasma viscosity surpass those associated with lowering viscosity: Experimental and clinical evidence. AB - Decreasing blood viscosity has been proposed since the advent of hemodilution as a means for increasing perfusion in many pathological conditions, and increased plasma viscosity is associated with the presence of pathological conditions. However, experimental studies show that microvascular functions as represented by functional capillary density in conditions of significantly decreased viscosity is impaired, a problem corrected by increasing plasma and blood viscosity. Blood viscosity, primarily dependent on hematocrit (Hct) is a determinant of peripheral vascular resistance, and therefore blood pressure. In the healthy population Hct presents a variability, which is not reflected by the variability of blood pressure. This is due to a regulatory process at the level of the endothelium, whereby the increase of Hct (and therefore blood viscosity) leads to increased shear stress and the production of the vasodilator nitric oxide (NO), a finding supported by experimental studies showing that the acute increase of Hct lowers blood pressure. Studies that in the healthy population show that blood pressure and Hct have a weak positive correlation. However, when the effect of blood viscosity is factored out, blood pressure and Hct are negatively and significantly correlated, indicating that as blood viscosity increases, the circulation dilates. Conversely, lower Hct and blood viscosity conditions lead to a constricted circulation, associated with a condition of decreased NO bioavailability, and therefore a pro-inflammatory condition. PMID- 20203364 TI - Semiquantitative characterization of hepatocellular carcinoma (HCC)--perfusion with contrast-enhanced ultrasound and perfusion analysis. AB - BACKGROUND: At the moment, there is only poor specificity of HCC-detection in tumors smaller than 2 cm in a cirrhotic liver. Thus, efforts have to be made to optimize the distinction between regenerative nodules and HCC. AIMS: The aim of our study was to describe the particular perfusion pattern of hepatocellular carcinoma using a specific quantification software. METHODS: We evaluated 25 patients with proven hepatocellular carcinoma, who underwent dynamic contrast enhanced ultrasound (CEUS) using a second generation contrast agent (SonoVue, Bracco, Germany). Retrospectively, we applied the quantification software Qontrast (Bracco, Milan, Italy) to obtain contrast-enhanced sonographic perfusion maps for each lesion. RESULTS: We found a close positive correlation of the perfusion parameters peak, time-to-peak and regional blood volume between the entire tumors, the center (center/total) and the periphery of the tumors (periphery/total), respectively. Moreover, we found significant higher peak values, a significant higher regional blood volume and a trend to lower time-to peak in the center of the tumors compared to the tumor periphery. CONCLUSION: These results suggest a better established vascular bed in the center of the tumors. This could be a sonographic marker of HCC in contrast to regenerative nodules. PMID- 20203365 TI - Echinocytosis in athletes with exercise-induced hypoxemia. AB - Abnormal hemorheology has been proposed previously as a possible genesis of exercise-induced hypoxemia (EIH) in humans. This study, in support of the hemorheological hypothesis, aims at determining if red blood cell shape changes might be related to EIH. Three groups of subjects: one without EIH (n=5); one developing mild-EIH (n=7); and, one with moderate EIH (n=5). Each group performed a progressive and maximal exercise test on cycle-ergometer. We evaluated the percent of stomatocytes, echinocytes and schizocytes in blood smears prepared from phlebotomy samples taken at rest and at maximal exercise. The percent of schizocytes or stomatocytes was not different between the three EIH groups at rest; and, exercise produced no change from the resting values of those cell types. The percent of echinocytes was not different between the three EIH groups at rest, however, exercise significantly increased the percent of echinocytes from the resting value of both the mild- and moderate-EIH groups, while the non EIH group remained unchanged. We suggested that the rigidity of echinocytes could have contributed to the genesis of EIH. PMID- 20203366 TI - Comparative efficiency and hemorheological consequences of hemotransfusion and epoetin therapy in anemic cancer patients. AB - The aim of our study was to compare hemorheological consequences of hemotransfusion and recombinant human erythropoetin treatment in anemic cancer patients. Forty anemic patients with solid nonmyeloid malignancies were enrolled in this prospective, open-label study. Both prior to and following treatment (epoetin beta, 10,000 units subcutaneously thrice weekly, for four weeks and transfusion of 400 ml of erythrocyte mass) hemorheological measurements including blood and plasma viscosity, hematocrit (Hct), hemoglobin, red blood cell aggregation (RBCA) and deformability were completed. It was found an increase of Hb from 76.07+/-3.68 g/l to 87.86+/-4.26 g/l after the transfusion. It was accompanied by Hct rise by 25% (from 23.67+/-1.85 to 29.50+/-1.96%, p<0.05). Under these conditions the whole blood viscosity (BV) was increased by 19% (p<0.05). Plasma viscosity did not change markedly. Therefore the main cause of the whole blood viscosity rise was an increase of Hct. After erythrocyte mass transfusion there were some increases of red cell deformability and aggregation (by 7%, p>0.05). Under these conditions the Hct/BV ratio as an index of oxygen transport efficiency was changed after transfusion only slightly. While after four weeks of epoetin treatment the hematocrit/viscosity ratio was raised by 14% (p<0.05), in spite of the high blood viscosity. In addition RBCA decreased (p<0.01) and their deformability was increased by 14% (p<0.05). In vitro microrheological data permit to suggest that epoetin has a direct effect on the microrheological properties of red cells due to activation of the cellular signal transduction system including the tyrosine kinases and phosphatases. Thus, Epoetin beta administered s.c. thrice weekly, during four weeks, increased hemoglobin levels, improved hemorheological profile and especially its microrheological part as well as the blood transport capacity in anemic cancer patients who were receiving chemotherapy and its hemorheological effect was more positive than under hemotransfusion. PMID- 20203367 TI - Effect of vitamin E on reperfusion injuries during reconstructive vascular operations on lower limbs. AB - INTRODUCTION: The challenge against reperfusion injury and tissue oxidative stress, especially in vascular surgical interventions has an essential importance to reach the optimal clinical result. Numerous experimental attempts have proved the positive antioxidant effect of vitamin E in both chronic and acute phase models. In our study we monitored the effect of continuous preoperative treatment with vitamin E, on oxidative stress and tissue inflammation reactions developed after reconstructive operations. PATIENTS AND METHODS: 32 patients have been involved in a randomized, prospective study, all suffering from AFS occlusion proved by angiography, and all undergone supragenual reconstruction. Duration of ischemia and amount of tissues under vascular clamping were almost the same in all patients. In the group treated with E-vitamin, we administered 1 x 200 mg of vitamin E p/o from the preoperative day till the 7th post operative day. Patients of the second group did not receive vitamin E. MATERIALS AND METHODS: Peripheral blood samples were collected immediately before operation and at the end of the second reperfusion hour (early reperfusion period). Late reperfusion period has been monitored by analyzing blood samples taken at 24th hour and 7th day next to the operative ischemia. Among oxidative stress parameters, direct measurement of reactive oxygen intermediator (ROI) and determination of antioxidant state (GSH, Total-SH group, SOD) have been performed. Malondialdehyde was chosen as marker for lipidperoxidation. Inflammation reactions were monitored up on expression of adhesion molecules (CD11a and CD18). We also controlled the oscillation of myeloperoxidase (MPO) activity. RESULTS: Our study has proved that preoperative (from the preoperative day till the 7th post operative day) administration of 200 mg vitamin E could reduce the level of oxidative stress developed after ischemic reperfusion insult (lipidproxidation, antioxidant enzymes). According to our results, the prooxidant-antioxidant imbalance also diminished in the group with E vitamin treatment. We proved that elective administration of vitamin E could decrease the WBC activity (MPO activity, free radicals production, expression of adhesion molecules) and its consequential local inflammation process, during early reperfusion. PMID- 20203368 TI - Alteration of serum thrombopoietin levels in patients with chronic hepatitis C under interferon therapy. AB - Thrombocytopenia is commonly observed during interferon-alpha (IFN-alpha) therapy in patients with chronic hepatitis C. Since thrombopoietin (TPO) is the main regulator of thrombopoiesis, thrombocytopenia may partially be due to a reduced TPO generation. Because of the developments of the second generation of TPO mimetic drugs patients with reduced TPO levels should be identified possibly having a benefit by medicinal stimulation of thrombopoiesis. Therefore, platelet count and serum TPO concentration of patients receiving an interferon-alpha therapy were determined.Twelve patients treated with IFN-alpha (daily 10 x 106 IU s.c. for four weeks) in cause of chronic hepatitis C were examined during the first month of therapy. Serum TPO concentration significantly decreased from 80.8+/-48.0 to 34.6+/-24.5 pg/ml (p<0.05, Mann-Whitney test), and platelet count declined from 214,417+/-48,292 to 151,333+/-44,726 platelets/microl. During the following three weeks platelet count remained at a low level, while serum TPO increased to normal range.In conclusion, an interferon treatment causes reduced serum TPO level during the first week of therapy accompanied by decreased platelet count. The reduction in TPO synthesis contributes to the development of thrombocytopenia in patients during interferon therapy. PMID- 20203369 TI - Does carbonyl stress cause increased blood viscosity during storage? AB - BACKGROUND: The structural and biochemical changes to erythrocytes during storage, called 'storage lesion', are important factors that contribute to decreases in the efficacy and safety of blood transfusions. However, the biochemical mechanisms are only partly understood. STUDY DESIGN AND METHODS: Fresh whole blood in citrate phosphate dextrose anticoagulant was preserved in storage bags at 1-4 degrees C for over 20 days. Aliquots of stored blood were withdrawn for analysis at the 1st, 5th, 10th, 15th and 20th day of storage. Whole blood viscosity, plasma reactive carbonyl species, erythrocyte membrane protein carbonylation, protein (tryptophan) fluorescence and the contents of thiols were quantified concurrently. RESULTS: There were significant increases in blood viscosity and plasma reactive carbonyl species level during storage. There were significant time-dependent increases in membrane protein carbonylation, increases in protein (tryptophan) fluorescence and a decrease in the content of thiols. CONCLUSION: Reactive carbonyl species, by attacking the amino and/or sulfhydryl groups of erythrocyte membrane proteins, induce a series of structural alterations in erythrocytes. These lead to an increase in blood viscosity and reduce the efficacy and safety of storage and transfusion. PMID- 20203371 TI - The second wave of quantitative pathology. PMID- 20203370 TI - PI3K-AKT-mTOR pathway is dominant over androgen receptor signaling in prostate cancer cells. AB - BACKGROUND: Androgen receptor (AR) and the phosphatidylinositol-3 kinase (PI3K) signaling are two of the most important pathways implicated in prostate cancer. Previous work has shown that there is crosstalk between these two pathways; however, there are conflicting findings and the molecular mechanisms are not clear. Here we studied the AR-PI3K pathway crosstalk in prostate cancer cells in vitro as well as in vivo. METHODS: Quantitative PCR, Western analysis, reporter assays, and proliferation analyses in vitro and in vivo were used to evaluate the effect of PI3K pathway inhibition on AR signaling and cell growth. RESULTS: Transcriptional activity of AR was increased when the PI3K pathway was inhibited at different levels. In the androgen responsive prostate cancer cell line LNCaP, androgen and the mTOR inhibitor rapamycin synergistically activated androgen target genes. Despite increased androgen signaling, rapamycin treatment reduced LNCaP cell growth; the AR antagonist bicalutamide potentiated this effect. Furthermore, the rapamycin derivative CCI-779 reduced the growth of CWR22 prostate cancer xenografts while increasing AR target gene expression. CONCLUSION: These findings suggest that inhibition of the PI3K pathway activates AR signaling. Despite the increase in AR signaling which has proliferative effects, the result of PI3K pathway inhibition is antiproliferative. These findings suggest that the PI3K pathway is dominant over AR signaling in prostate cancer cells which should be considered in developing novel therapeutic strategies for prostate cancer. PMID- 20203372 TI - Validation of a fully automated HER2 staining kit in breast cancer. AB - BACKGROUND: Testing for HER2 amplification and/or overexpression is currently routine practice to guide Herceptin therapy in invasive breast cancer. At present, HER2 status is most commonly assessed by immunohistochemistry (IHC). Standardization of HER2 IHC assays is of utmost clinical and economical importance. At present, HER2 IHC is most commonly performed with the HercepTest which contains a polyclonal antibody and applies a manual staining procedure. Analytical variability in HER2 IHC testing could be diminished by a fully automatic staining system with a monoclonal antibody. MATERIALS AND METHODS: 219 invasive breast cancers were fully automatically stained with the monoclonal antibody-based Oracle HER2 Bond IHC kit and manually with the HercepTest. All cases were tested for amplification with chromogenic in situ hybridization (CISH). RESULTS: HercepTest yielded an overall sharper membrane staining, with less cytoplasmic and stromal background than Oracle in 17% of cases. Overall concordance between both IHC techniques was 89% (195/219) with a kappa value of 0.776 (95% CI 0.698-0.854), indicating a substantial agreement. Most (22/24) discrepancies between HercepTest and Oracle showed a weaker staining for Oracle. Thirteen of the 24 discrepant cases were high-level HER2 amplified by CISH, and in 12 of these HercepTest IHC better reflected gene amplification status. All the 13 HER2 amplified discrepant cases were at least 2+ by HercepTest, while 10/13 of these were at least 2+ for Oracle. Considering CISH as gold standard, sensitivity of HercepTest and Oracle was 91% and 83%, and specificity was 94% and 98%, respectively. Positive and negative predictive values for HercepTest and Oracle were 90% and 95% for HercepTest and 96% and 91% for Oracle, respectively. CONCLUSION: Fully-automated HER2 staining with the monoclonal antibody in the Oracle kit shows a high level of agreement with manual staining by the polyclonal antibody in the HercepTest. Although Oracle shows in general some more cytoplasmic staining and may be slightly less sensitive in picking up HER2 amplified cases, it shows a higher specificity and may be considered as an alternative method to evaluate the HER2 expression in breast cancer with potentially less analytical variability. PMID- 20203374 TI - Dynamic changes in the cortico-subcortical network during early motor learning. AB - BACKGROUND: Failure of early motor learning due to damage in any brain area involved in this process may interfere with successful rehabilitation of such patients. OBJECTIVE: We investigated the changes in activation of the motor network during sequential finger motor learning to delineate the characteristics of the cortico-subcortical network during motor skill learning. METHODS: Twenty healthy, right-handed volunteers participated. Subjects were instructed to perform eight blocks of a sequential finger motor task while functional MRI (fMRI) was performed. RESULTS: The participants had an improvement in performance over time from block 1 to block 4, indicating that successful learning had occurred, followed by a plateau from block 5 to the last block. On fMRI, activities of the contralateral primary sensorimotor cortex, the premotor cortex, the supplementary motor area, and the posterior parietal cortex gradually increased from block 1 to block 4 and then decreased from block 5 to the last. In contrast, activity of the ipsilateral cerebellum showed a linear increase spanning the last block with peak activation. The thalamus and basal ganglia showed unilateral or bilateral activities at the unique stage of motor learning. CONCLUSIONS: These findings delineated the characteristic plastic changes and different roles of the cortico-subcortical network during the early phase of motor learning and automatization. PMID- 20203375 TI - SMART cognitive training combined with a parental coaching programme for three children treated for medulloblastoma. AB - In a pilot study we examined the feasibility of a condensed version of the Swedish Memory and Attention Re-Training on children treated for medulloblastoma combined with a structured coaching programme for their parents. Parental coaching contained the translation of the child's new skills into daily life, and education regarding their own stress mechanisms. Before and after intervention we assessed the children's cognitive performance, social relations and self image as well as their parents stress. All three families continued the programme without interruption. Observations revealed that this condensed version of the programme was more stressful to participants. However, several aspects of the children's attention and memory performance improved from pre to post-training assessment. In addition, all of the children reported enhancement of their social relations and self image. Initially, symptoms of parental stress were pronounced for the three mothers, but fairly low for the fathers. After training and coaching, the stress level of both mothers and fathers was low. Our findings encourage full scale studies examining whether this combination of condensed cognitive training and specific coaching programme for parents may influence not only the children's cognitive performance but also their social relations, self image and their parents stress. PMID- 20203376 TI - Transcutaneous electrical nerve stimulation of hip adductors improves gait parameters of children with spastic diplegic cerebral palsy. AB - BACKGROUND: Reduction of spasticity in hip adductor muscles is one of the essential factors to improve standing, gait, and personal hygiene of children with spastic diplegic cerebral palsy (CP). Surgical and medical methods have been commonly used for such purposes. These methods are expensive, required special skill and have side effects. OBJECTIVE: To study the effect of conventional TENS on spasticity in hip adductors and gait parameters of children with spastic diplegic CP. SUBJECT: An experimental group of twenty seven ambulant children with spastic diplegic CP and control group of fifteen healthy children were voluntary participants in the study. METHODS: The experimental group received two different TENS management programs. The 1st TENS program was a one-time trial management program that included an ongoing application of conventional TENS on bilateral hip adductors during passive hip abduction, and during walking for a pre-determined distance. The 2nd TENS program was a one-week trial management program that included 15 minutes of ongoing application of conventional TENS on bilateral hip adductors during walking, three sessions a day for a week. The effects of the TENS program was assessed using the Modified Ashworth Scale, the balance master system and visual observations of knee positions. RESULTS: A significant improvement was recorded in spasticity of hip adductors, gait parameters and knees position of the experimental group. CONCLUSION: Functional application of TENS to hip adductors of children with spastic diplegic CP can reduce spasticity and improve gait pattern. PMID- 20203377 TI - The effect of the audio-visual-tactile system on sensory recovery following ulnar nerve repair: a case report. AB - INTRODUCTION: The aim of this study is to test if deprivation of tactile sense can be compensated by the hearing sense, early after nerve repair in the hand. METHOD: This tool was used early after repair of the ulnar nerve with the intention of improving recovery of hand sensibility by maintaining an active sensory map of the hand in the somatosensory cortex during the deafferentation period. "Audiovisual tactile" was used early after repair of the ulnar nerve repair in a 25-years-old man. Sensory evaluation was done at regular intervals in 2, 5 and 7 months after introduction of the intervention. RESULTS: Results showed that sensory results are better in the patient who used the artificial sensibility regimen compared with the one who did not. DISCUSSION: This result suggests that deprivation of one sense can be compensated by another sense. PMID- 20203378 TI - Locomotor and resistance training restore walking in an elderly person with a chronic incomplete spinal cord injury. AB - OBJECTIVE: To determine the effects of 10~weeks of locomotor training (LT) using body weight supported (BWS) treadmill training and resistance training (RT) programs on over-ground walking recovery, walking speed and distance, functional independent measure (FIM), walking index for spinal cord injury (WISCI) and Berg Balance Score in an elderly person with an incomplete spinal cord injury (SCI). DESIGN: A 66 year-old-male with a chronic incomplete SCI at C5/C6 ASIA Impairment Scale (AIS) D was admitted for rehabilitation following posterior laminectomy at L3-L5. The participant was a short distance ambulator relying primarily on his power wheelchair for mobility. He completed 10~weeks of LT using manual BWS treadmill twice weekly and RT for knee extensor muscle groups twice a week. A weekly test of the over-ground distance and speed were recoded over the course of the 10~weeks. Additionally, the participant underwent a three month evaluation after discharge. RESULTS: The 10-week program resulted in independent use of bilateral Canadian crutches to ambulate for 200 feet and increased over-ground walking speed. The FIM score increased from 3 to 6 and Berg balance score increased from 11 to 41. The WISCI score increased from 1 to 10. Three months post-discharge, the participant maintained his functional independency in sit to stand activity and over-ground walking. CONCLUSION: A combined program of LT and RT could enhance walking recovery in a person with a long-term SCI. The findings suggest that twice a week of LT can promote motor recovery if it is accompanied with an approach that effectively loads the paralyzed lower extremities. PMID- 20203379 TI - Encoding, storage and retrieval processes of the memory and the implications for motor practice in stroke patients. AB - This study intended to evaluate the influence of stroke on memory processes (encoding, storage and retrieval) of visual and verbal stimuli and its implications to the motor practice. Twelve patients (6 with right and 6 with left brain lesions; 6-36 months post-lesion) and 12 healthy subjects, 45-65 years old from both sexes were studied. The encoding and storage processes were evaluated during test sessions where each subject had three attempts to identify two lists with 10 stimuli each (10 figures and 10 words referring to animals and objects). The retrieval process was evaluated by immediate free retrieval and by recognition tests. Data were analyzed by Mann-Whitney test. Performance was worse in patients (encoding - visual: p=0.0001 and verbal: p=0.0001; storage - verbal: p=0.0001) and those with right lesions had worse performance in visual encoding (p=0.0005) and those with left lesions had in verbal storage (p=0.0246) and retrieval (p=0.0001). According to results it is suggested that the patients were not able to adequately codify and store the information, however, they were adequately able to recover by recognition and this implicates the necessity to make a observational, distributed and varied practice in cerebrovascular disease patients therapy. PMID- 20203380 TI - Home-based personalized cognitive training in MS patients: a study of adherence and cognitive performance. AB - OBJECTIVES: To explore unprompted adherence to a personalized, home-based, computerized cognitive training program in patients with multiple sclerosis (MS), and to examine the impact of training on cognitive performance. METHODS: Participants were assigned to a training (n=59) or a control group (n=48). Those in the training group were instructed to train three times a week for 12 weeks. The control group received no training. All participants were evaluated with a Neuropsychological Examination (N-CPC) at baseline and at the end of the study. RESULTS: In the training group, 42 (71.2%) participants adhered to the training schedule and 22 (37.3%) completed the entire training regimen. In the control group, 24 (50.0%) participants agreed to be retested on the N-CPC. The training group showed a significant improvement over that shown by the control group in three memory-based cognitive abilities (general memory, visual working memory and verbal working memory). Post-hoc exploration of data from the N-CPC showed that cognitive training was also associated with increased naming speed, speed of information recall, focused attention and visuo-motor vigilance. CONCLUSIONS: The appreciable rates of adherence and cognitive improvements observed indicate that personalized cognitive training is a practical and valuable tool to improve cognitive skills and encourage neuronal plasticity in patients with MS. PMID- 20203381 TI - A prospective study of mechanical physiotherapy for lumbar disk prolapse: five year follow-up and final report. AB - OBJECTIVES: To evaluate the long-term effect of a specific conservative treatment method for patients with lumbar disc prolapse. BACKGROUND DATA: Low back pain and symptoms of disc herniation have a good prognosis. Yet the rates of disability and sick-leave because of recurrences are high and cost-intensive. METHODS: Fifty consecutive patients with clinically and neuroradiologically confirmed lumbar disk prolapse, who responded to the first five daily physiotherapy sessions with pain centralization, were prospectively treated with mechanical physiotherapy with repeated end range spinal movements and leg movements. The results after one year of follow-up have been published previously (J Neurology 250 (2003), 746 749). RESULTS: From the initial cohort of 50 patients, 5 patients were operated within one year after discharge and one patient died. One patient had surgery for disc prolapse 13 months after discharge. Three patients were lost for follow-up. None of the 40 remaining patients has had surgery until the last follow-up. CONCLUSION: Pain centralization during the first 5 treatment sessions of mechanical physiotherapy is a useful diagnostic tool to predict a good longterm outcome. Mechanical physiotherapy with end range spinal movements and leg movements is an effective treatment strategy for many patients with lumbar disk disease. PMID- 20203382 TI - Polymyositis in patients taking antiviral clevudine therapy: a report of two cases. AB - The new antivirals clevudine, telbivudine and emtricitabine may be potent agents for the treatment of hepatitis B virus (HBV). However, there have been no reports on serious adverse events associated with the use of clevudine. A son and his mother both had HBV infection (ages: 27 and 47 years, respectively), and they had received antivirus treatment with clevudine (30 mg daily). They developed progressive weakness of the lower extremities and difficulty arising from the ground. Both the patients had symptoms for the previous 3 approximately 4 months in process of 14 approximately 17 months of clevudine therapy. The physical examinations showed positive Gower's sign, a decreased gait velocity and symmetrical proximal weakness (MRC grade 4/5). Their blood tests at admission revealed elevated or positive HBs Ag, HBV DNA, AST, ALT, creatine kinase, LDH, myoglobin and CK-MB. For both patients, the electrodiagnostic studies indicated myopathy and the pathologic findings of biopsied muscles revealed myositis. Drug induced polymyositis was suspected and the clevudine was finally withdrawn. The muscle weakness and laboratory findings were improved for both patients after conservative care. We report here on the first cases of polymyositis that may have been caused by administering the new nucleoside analog clevudine for treating HBV infection. PMID- 20203383 TI - Cortical reorganization of sensori-motor function in a patient with cortical infarct. AB - PURPOSE: We describe a patient with cortical infarct, whose sensori-motor function for the hand seemed to be reorganized into the lateral area, as demonstrated by functional MRI (fMRI). METHODS: A 59-year-old male patient presented with severe sensori-motor dysfunction of the left hand, which first occurred at the onset of an infarct in the right primary sensori-motor cortex (SM1) centered on the precentral knob. The sensori-motor function of the affected hand recovered to a normal state at 6 months from onset. fMRI was performed using the blood oxygen level-dependent technique at 1.5T with a standard head coil (at 6 months from onset). The active and passive movements were performed at the metacarpophalangeal joint using a specially equipped apparatus, and touch stimulation was applied on the dorsum of the hand using a rubber brush. RESULTS: The contralateral SM1 centered on the precentral knob was found to be activated during the active movements, passive movements, and touch of the unaffected (right) hand movements. By contrast, the lateral area of the infarcted SM1 of the right hemisphere was activated during the three kinds of stimulation of the affected hand. CONCLUSIONS: We conclude that the sensori-motor function of the affected hand seemed to have been reorganized into the lateral area of the infarcted SM1. PMID- 20203384 TI - Motor function reorganization in a patient with a brainstem lesion: DTT, fMRI and TMS study. AB - OBJECTIVE: We report on a hemiparetic patient who showed a new motor pathway posterior to the lesion in the midbrain and upper pons, demonstrated by three combined method of diffusion tensor tractography(DTT)/functional MRI(fMRI)/transcranial magnetic stimulation(TMS). METHODS: A 21-year-old left hemiparetic male who suffered from tuberous meningitis at the age of 12 months after birth. The evaluations were performed at 20 years after onset. Brain MRI showed focal encephalomalatic lesions~due to infarcts in right anterior thalamus, midbrain and upper pons. DTT, fMRI and TMS were performed simultaneously. RESULTS: The contralateral primary sensori-motor cortex was activated during either affected or unaffected hand movements. DTT showed that the motor tracts descended along the known pathway of the CST, with the exception of the motor tract of the affected hemisphere, which descended along the posterior portion to the lesion in the right midbrain and the pons, and then rejoined the CST in the mid-pons. The TMS results suggested that the motor tract of the affected hemisphere had the characteristics of a CST. CONCLUSION: We believe that the motor function of the affected hand in this patient had been recovered through the pathway posterior to the lesion in the midbrain and upper pons. PMID- 20203385 TI - Motor function reorganization lateral to congenital brain lesion: a functional MRI study. AB - PURPOSE: The object of this study was to demonstrate the reorganization of the affected hand motor function lateral to the congenital brain lesion in a patient using functional MRI (fMRI). METHODS: Twelve normal control subjects and a 23 year-old man with a congenital brain lesion including the precentral knob were evaluated. FMRI was performed using the blood oxygen level-dependent technique at 1.5-T system with timed hand grasp-lease motor tasks. RESULTS: The contralateral primary sensorimotor cortex centered on the precentral knob was activated during hand movements of the right side of the patient and of control subjects. However, only the lateral area of the lesion was activated during left hand movements of the patient. CONCLUSIONS: It seems that the motor function of the left hand was reorganized into the lateral area of the lesion in this patient. This finding may reflect a cortical reorganization of the motor area. PMID- 20203388 TI - La2Pb(SiS4)2. AB - Crystals of La(2)Pb(SiS(4))(2), dilanthanum(III) lead(II) bis[tetrasulfidosilicate(IV)], were obtained from the La-Pb-Si-S system and structurally characterized using X-ray single-crystal diffraction. The La and Pb atoms are coordinated in bicapped trigonal prisms of S atoms, with the Si atoms in tetrahedra. An occupational disorder of the La and Pb centres was refined for one position in the structure. The bicapped trigonal prisms and tetrahedra share edges. A gap located 2.629 (1) A from the sulfide anions was found around the coordination polyhedra, which makes La(2)Pb(SiS(4))(2) a prospective material in crystal engineering. The Si and one S atom lie on a threefold axis. PMID- 20203389 TI - Ba5Cl4(H2O)8(VPO5)8: a novel three-dimensional framework solid. AB - The novel hydrothermally synthesized title compound, pentabarium tetrachloride octahydrate octakis(oxovanadium phosphate), Ba(5)Cl(4)(H(2)O)(8)(VPO(5))(8), crystallizes in the orthorhombic space group Cmca with a unit cell containing four formula units. Two Ba(2+) cations, two Cl(-) anions and the O atoms of four water molecules are situated on the (100) mirror plane, while the third independent Ba(2+) cation is on the intersection of the (100) plane and the twofold axis parallel to a. Two phosphate P atoms are on twofold axes, while the remaining independent P atom and both V atoms are in general positions. The structure is characterized by two kinds of layers, namely anionic oxovanadium phosphate (VPO(5)), composed of corner-sharing VO(5) square pyramids and PO(4) tetrahedra, and cationic barium chloride hydrate clusters, Ba(5)Cl(4)(H(2)O)(8), composed of three Ba(2+) cations linked by bridging chloride anions. The layers are connected by Ba-O bonds to generate a three-dimensional structure. PMID- 20203390 TI - The new ternary phases of La3(Zn0.874Mg0.126)11 and Ce3(Zn0.863Mg0.137)11. AB - The new ternary intermetallic title compounds, namely trilanthanum undeca(zinc/magnesium), La(3)(Zn(0.874)Mg(0.126))(11), (I), and tricerium undeca(zinc/magnesium), Ce(3)(Zn(0.863)Mg(0.137))(11), (II), are isostructural and crystallize in the orthorhombic La(3)Al(11) structure type. These three phases belong to the same structural family, the representative members of which may be derived from the tetragonal BaAl(4) structure type by a combination of internal deformation and multiple substitution. Compared to the structure of La(3)Al(11), in (I), a significant decrease of 11.9% in the unit-cell b axis and an increase in the other two directions, of 3.6% along a and 5.2% along c, are observed. Such an atypical deformation is caused by the closer packing of atoms in the unit cell due to atom shifts that reflect strengthening of metallic-type bonding. This structural change is also manifested in a significant difference in the coordination around the smaller atoms at the 8l Wyckoff position (site symmetry m). The Al atom in La(3)Al(11) is in a tricapped trigonal prismatic environment (coordination number 9), while the Zn atoms in (I) and (II) are situated in a tetragonal antiprism with two added atoms (coordination number 10). PMID- 20203391 TI - Ba2Gd2(Si4O13): a silicate with finite Si4O13 chains. AB - The title compound, dibarium digadolinium(III) tetrasilicate, crystallized from a molybdate-based flux. It represents a new structure type and contains finite zigzag-shaped C(2)-symmetric Si(4)O(13) chains and Gd(2)O(12) dimers built of edge-sharing GdO(7) polyhedra. The [9+1]-coordinated Ba atoms are located in voids in the atomic arrangement. All atoms are in general positions except for one O atom, which lies on a twofold axis. The structure is compared with those of the few other known tetrasilicates. PMID- 20203392 TI - The solid solution (Fe0.81Al0.19)(H2PO4)3 with a strong hydrogen bond. AB - Single crystals of the solid solution iron aluminium tris(dihydrogenphosphate), (Fe(0.81)Al(0.19))(H(2)PO(4))(3), have been prepared under hydrothermal conditions. The compound is a new monoclinic variety (gamma-form) of iron aluminium phosphate (Fe,Al)(H(2)PO(4))(3). The structure is based on a two dimensional framework of distorted corner-sharing MO(6) (M = Fe, Al) polyhedra sharing corners with PO(4) tetrahedra. Strong hydrogen bonds between the OH groups of the H(2)PO(4) tetrahedra and the O atoms help to consolidate the crystal structure. PMID- 20203393 TI - Crystal structure and stability of Tl2CO3 at high pressures. AB - The crystal structure of dithallium carbonate, Tl(2)CO(3) (C2/m, Z = 4), was investigated at pressures of up to 7.4 GPa using single-crystal X-ray diffraction in a diamond anvil cell. It is stable to at least 5.82 GPa. All atoms except for one of the O atoms lie on crystallographic mirror planes. At higher pressures, the material undergoes a phase transition that destroys the single crystal. PMID- 20203394 TI - Two polymorphs of chlorido(cyclohexyldiphenylphosphine)gold(I). AB - The title compound, [AuCl(C(18)H(21)P)], a monomeric two-coordinate gold(I) complex, has been characterized at 100 K as two distinct monoclinic polymorphs, one from a single crystal, (Is), and one from a pseudo-merohedrally twinned crystal, (It). The molecular structures in the two monoclinic [P2(1)/n for (Is) and P2(1)/c for (It)] polymorphs are similar; however, the packing arrangements in the two lattices differ considerably. The structure of (It) is pseudo merohedrally twinned by a twofold rotation about the a* axis. PMID- 20203395 TI - Tetrakis(mu2-4-aminobenzoato)di-mu3-oxido-tetrakis[dibutyltin(IV)]. AB - The molecule of the title compound, [Sn(4)(C(4)H(9))(8)(C(7)H(6)NO(2))(4)O(2)], lies about an inversion centre and is a tetranuclear bis(tetrabutyldicarboxylatodistannoxane) complex containing a planar Sn(4)O(2) core in which two mu(3)-oxide O atoms connect an Sn(2)O(2) ring to two exocyclic Sn atoms. Each Sn atom has a highly distorted octahedral coordination. In the molecule, the carboxylate groups of two aminobenzoate ligands bridge the central and exocyclic Sn atoms, while two further aminobenzoate ligands have highly asymmetric bidentate chelation to the exocyclic Sn atoms plus long O...Sn interactions with the central Sn atoms. Each Sn atom is also coordinated by two pendant n-butyl ligands, which extend roughly perpendicular to the plane of the Sn(4)O(10) core. Only one of the four unique hydrogen-bond donor sites is involved in a classic N-H...O hydrogen bond, and the resulting supramolecular hydrogen-bonded structure is an extended two-dimensional network which lies parallel to the (100) plane and consists of a checkerboard pattern of four connected molecular cores acting as nodes. The amine groups not involved in the hydrogen-bonding interactions have significant N-H...pi interactions with neighbouring aminobenzene rings. PMID- 20203396 TI - Mono- and bis-tolylterpyridine iridium(III) complexes. AB - The first structure report of trichlorido[4'-(p-tolyl)-2,2':6',2'' terpyridine]iridium(III) dimethyl sulfoxide solvate, [IrCl(3)(C(22)H(17)N(3))] x C(2)H(6)OS, (I), is presented, along with a higher-symmetry setting of previously reported bis[4'-(p-tolyl)-2,2':6',2''-terpyridine]iridium(III) tris(hexafluoridophosphate) acetonitrile disolvate, [Ir(C(22)H(17)N(3))(2)](PF(6))(3) x 2 C(2)H(3)N, (II) [Yoshikawa, Yamabe, Kanehisa, Kai, Takashima & Tsukahara (2007). Eur. J. Inorg. Chem. pp. 1911-1919]. For (I), the data were collected with synchrotron radiation and the dimethyl sulfoxide solvent molecule is disordered over three positions, one of which is an inversion center. The previously reported structure of (II) is presented in the more appropriate C2/c space group. The iridium complex and one PF(6)(-) anion lie on twofold axes in this structure, making half of the molecule unique. PMID- 20203397 TI - A synchrotron radiation study of the one-dimensional complex of sodium with (1S) N-carboxylato-1-(9-deazaadenin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol, a member of the 'immucillin' family. AB - The sodium salt of [immucillin-A-CO(2)H](-) (Imm-A), namely catena poly[[[triaquadisodium(I)](mu-aqua)[mu-(1S)-N-carboxylato-1-(9-deazaadenin-9-yl) 1,4-dideoxy-1,4-imino-D-ribitol][triaquadisodium(I)][mu-(1S)-N-carboxylato-1-(9 deazaadenin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol]] tetrahydrate], {[Na(2)(C(12)H(13)N(4)O(6))(2)(H(2)O)(7)] x 4 H(2)O}(n), (I), forms a polymeric chain via Na(+)-O interactions involving the carboxylate and keto O atoms of two independent Imm-A molecules. Extensive N,O-H...O hydrogen bonding utilizing all water H atoms, including four waters of crystallization, provides crystal packing. The structural definition of this novel compound was made possible through the use of synchrotron radiation utilizing a minute fragment (volume approximately 2.4 x 10(-5) mm(-3)) on a beamline optimized for protein data collection. A summary of intra-ring conformations for immucillin structures indicates considerable flexibility while retaining similar intra-ring orientations. PMID- 20203398 TI - Hydrogen-bonded network structures in dipyridinium, bis(2-methylpyridinium), bis(3-methylpyridinium) and bis(4-methylpyridinium) dioxidobis(oxydiacetato)uranate(VI). AB - Four complexes containing the [UO(2)(oda)(2)](2-) anion (oda is oxydiacetate) are reported, namely dipyridinium dioxidobis(oxydiacetato)uranate(VI), (C(5)H(6)N)(2)[U(C(4)H(4)O(5))(2)O(2)], (I), bis(2-methylpyridinium) dioxidobis(oxydiacetato)uranate(VI), (C(8)H(8)N)(2)[U(C(4)H(4)O(5))(2)O(2)], (II), bis(3-methylpyridinium) dioxidobis(oxydiacetato)uranate(VI), (C(8)H(8)N)(2)[U(C(4)H(4)O(5))(2)O(2)], (III), and bis(4-methylpyridinium) dioxidobis(oxydiacetato)uranate(VI), (C(8)H(8)N)(2)[U(C(4)H(4)O(5))(2)O(2)], (IV). The anions are achiral and are located on a mirror plane in (I) and on inversion centres in (II)-(IV). The four complexes are assembled into three dimensional structures via N-H...O and C-H...O interactions. Compounds (III) and (IV) are isomorphous; the [UO(2)(oda)(2)](2-) anions form a porous matrix which is nearly identical in the two structures, and the cations are located in channels formed in this matrix. Compounds (I) and (II) are very different from (III) and (IV): (I) forms a layered structure, while (II) forms ribbons. PMID- 20203399 TI - Ammine(2,2'-bipyridine-kappa(2)N,N')silver(I) nitrate: a dimer formed by pi-pi stacking and ligand-unsupported Ag...Ag interactions. AB - Reaction of AgNO(3) and 2,2'-bipyridine (bipy) under ultrasonic treatment gave the title compound, [Ag(C(10)H(8)N(2))(NH(3))]NO(3). The crystal structure consists of dimers formed by two symmetry-related Ag(I)-bipy monomers connected through intra-dimer pi-pi stacking and ligand-unsupported Ag...Ag interactions. A crystallographic C2 axis passes through the mid-point of and is perpendicular to the Ag...Ag(i)(-x + 1, y, -z + 1/2) axis. In addition, each Ag(I) cation is coordinated by one chelating bipy ligand and one ammine ligand, giving a trigonal coordination environment capped by the symmetry-equivalent Ag atom. Molecules are assembled by Ag...Ag, pi-pi, hydrogen-bond (N-H...O and C-H...O) and weak Ag...pi interactions into a three-dimensional framework. Comparing the products synthesized under different mechanical treatments, we found that reaction conditions have a significant influence on the resulting structures. The luminescence properties of the title compound are also discussed. PMID- 20203400 TI - 2-(Diphenylphosphinoylmethyl)pyrrole-2-(diphenylphosphinomethyl)pyrrole (0.43/0.57) and tetrachlorido(5-diphenylphosphinomethyl-2H-pyrrole kappa(2)N,P)titanium(IV). AB - The title phosphine oxide-phosphine, 0.43C(17)H(16)NOP.0.57C(17)H(16)NP, (I)/(II), was obtained as a 0.861 (6):1.139 (6) cocrystallized mixture. Hydrogen bonding between the two constituents leads to the formation of 2:2 solid-state assemblies. Instead of forming the expected simple N,P-chelated system via loss of the N-bound H atom, reaction of 2-(diphenylphosphinomethyl)pyrrole, (II), with TiCl(4) leads to the formation of the title titanium(IV) complex, [TiCl(4)(C(17)H(16)NP)], (IV), containing a rearranged neutral ligand in which the N-bound H atom moves to one of the pyrrole C atoms, giving a partially unsaturated ring. PMID- 20203401 TI - A copper-polyol complex: [Na2(C2H6O2)6][Cu(C2H4O2)2]. AB - The ionic title complex, bis(mu-ethylene glycol)-kappa(3)O,O':O';kappa(3)O:O,O' bis[(ethylene glycol-kappa(2)O,O')(ethylene glycol-kappaO)sodium] bis(ethylene glycolato-kappa(2)O,O')copper(II), [Na(2)(C(2)H(6)O(2))(6)][Cu(C(2)H(4)O(2))(2)], was obtained from a basic solution of CuCl(2) in ethylene glycol and consists of discrete ions interconnected by O-H...O hydrogen bonds. This is the first example of a disodium-ethylene glycol complex cation cluster. The cation lies about an inversion center and the Cu(II) atom of the anion lies on another independent inversion center. PMID- 20203402 TI - The ansa-zirconocene [bis(eta(5) cyclopentadienyl)phenylphosphine]dichloridozirconium(IV). AB - In the title compound, [Zr(C(16)H(13)P)Cl(2)], the geometry at the metal atom is distorted tetrahedral; the Cl-Zr-Cl angle is 101.490 (16) degrees and the cyclopentadienyl (Cp) centroids subtend an angle of 122.63 (3) degrees at the Zr atom. The P atom lies 0.474 (3) and 0.496 (3) A out of the planes of the Cp rings. The C-P-C angle of 91.42 (7) degrees reflects the pincer effect of the two Cp rings. Three C-H...Cl, one C-H...P, one C-H...pi and one Cl...P interaction link the molecules to form thick layers parallel to the bc plane. PMID- 20203403 TI - 2-Amino-5-(3,4-dimethoxybenzylidene)-1-methylimidazol-4(5H)-one N,N dimethylformamide monosolvate. AB - The crystal structure of the title compound, C(13)H(15)N(3)O(3) x C(3)H(7)NO, was determined as part of a larger project focusing on creatinine derivatives as potential pharmaceuticals. The molecule is essentially planar, in part because of intramolecular hydrogen bonding. Inversion-related pairs of molecules result from intermolecular hydrogen bonding. The pi systems of 2-amino-5-(3,4 dimethoxybenzylidene)-1-methylimidazol-4(5H)-one and an inversion-related molecule overlap slightly, indicating a small amount of pi-pi stacking. Bond lengths, angles and torsion angles are consistent with similar structures, except in the imidazolone ring near the doubly bonded C atom, where significant differences occur. PMID- 20203404 TI - Hydrogen-bonded supramolecular motifs in pyrimethaminium 4-methylbenzoate, pyrimethaminium 3-hydroxypicolinate and pyrimethaminium 2,4-dichlorobenzoate. AB - In 2,4-diamino-5-(4-chlorophenyl)-6-ethylpyrimidin-1-ium (pyrimethaminium, PMNH) 4-methylbenzoate, C(12)H(14)ClN(4)(+) x C(8)H(7)O(2)(-), (I), pyrimethaminium 3 hydroxypicolinate, C(12)H(14)ClN(4)(+) x C(6)H(4)NO(3)(-), (II), and pyrimethaminium 2,4-dichlorobenzoate, C(12)H(14)ClN(4)(+) x C(7)H(3)Cl(2)O(2)(-), (III), the PMNH cations interact with the carboxylate groups of the corresponding anion via nearly parallel N-H...O hydrogen bonds, forming R(2)(2)(8) ring motifs. A description of the observed arrays of quadruple hydrogen bonds in (I) and (II) in terms of hydrogen donors and acceptors (the DA model), their graph-set motifs and the resulting supramolecular ladder is given. In (III), supramolecular chains along the b axis and helical chains along the a axis are formed via N-H...O hydrogen bonds involving the 2-amino and 4-amino groups of the PMNH cation, respectively. Weak Cl...Cl interactions are also found in (III). PMID- 20203405 TI - Dihydrogen phosphate mediated supramolecular frameworks in 2- and 4 chloroanilinium dihydrogen phosphate salts. AB - The title compounds, 2-chloroanilinium dihydrogen phosphate (2CADHP) and 4 chloroanilinium dihydrogen phosphate (4CADHP), both C(6)H(7)NCl(+) x H(2)PO(4)( ), form two-dimensional supramolecular organic-inorganic hybrid frameworks. In 2CADHP, the dihydrogen phosphate anions form a double-stranded anionic chain generated parallel to the [010] direction through O-H...O hydrogen bonds, whereas in 4CADHP they form a two-dimensional supramolecular net extending parallel to the crystallographic (001) plane into which the cations are linked through strong N-H...O hydrogen bonds. PMID- 20203406 TI - Two solid phases of pyrimidin-1-ium hydrogen chloranilate monohydrate determined at 225 and 120 K. AB - The crystal structures of two solid phases of the title compound, C(4)H(5)N(2)(+) x C(6)HCl(2)O(4)(-) x H(2)O, have been determined at 225 and 120 K. In the high temperature phase, stable above 198 K, the transition temperature of which has been determined by (35)Cl nuclear quadrupole resonance and differential thermal analysis measurements, the three components are held together by O-H...O, N...H...O, C-H...O and C-H...Cl hydrogen bonds, forming a centrosymmetric 2+2+2 aggregate. In the N...H...O hydrogen bond formed between the pyrimidin-1-ium cation and the water molecule, the H atom is disordered over two positions, resulting in two states, viz. pyrimidin-1-ium-water and pyrimidine-oxonium. In the low-temperature phase, the title compound crystallizes in the same monoclinic space group and has a similar molecular packing, but the 2+2+2 aggregate loses the centrosymmetry, resulting in a doubling of the unit cell and two crystallographically independent molecules for each component in the asymmetric unit. The H atom in one N...H...O hydrogen bond between the pyrimidin-1-ium cation and the water molecule is disordered, while the H atom in the other hydrogen bond is found to be ordered at the N-atom site with a long N-H distance [1.10 (3) A]. PMID- 20203407 TI - Two pentadehydropeptides with different configurations of the DeltaPhe residues. AB - Comparison of the crystal structures of two pentadehydropeptides containing DeltaPhe residues, namely (Z,Z)-N-(tert-butoxycarbonyl)glycyl-alpha,beta phenylalanylglycyl-alpha,beta-phenylalanylglycine (or Boc(0)-Gly(1) Delta(Z)Phe(2)-Gly(3)-Delta(Z)Phe(4)-Gly(5)-OH) methanol solvate, C(29)H(33)N(5)O(8) x CH(4)O, (I), and (E,E)-N-(tert-butoxycarbonyl)glycyl alpha,beta-phenylalanylglycyl-alpha,beta-phenylalanylglycine (or Boc(0)-Gly(1) Delta(E)Phe(2)-Gly(3)-Delta(E)Phe(4)-Gly(5)-OH), C(29)H(33)N(5)O(8), (II), indicates that the Delta(Z)Phe residue is a more effective inducer of folded structures than the Delta(E)Phe residue. The values of the torsion angles phi and psi show the presence of two type-III' beta-turns at the Delta(Z)Phe residues and one type-II beta-turn at the Delta(E)Phe residue. All amino acids are linked trans to each other in both peptides. Beta-turns present in the peptides are stabilized by intramolecular 4-->1 hydrogen bonds. Molecules in both structures form two-dimensional hydrogen-bond networks parallel to the (100) plane. PMID- 20203408 TI - Peracetylated alpha-D-glucopyranosyl fluoride and peracetylated alpha-maltosyl fluoride. AB - The X-ray analyses of 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl fluoride, C(14)H(19)FO(9), (I), and the corresponding maltose derivative 2,3,4,6-tetra-O acetyl-alpha-D-glucopyranosyl-(1-->4)-2,3,6-tri-O-acetyl-alpha-D-glucopyranosyl fluoride, C(26)H(35)FO(17), (II), are reported. These add to the series of published alpha-glycosyl halide structures; those of the peracetylated alpha glucosyl chloride [James & Hall (1969). Acta Cryst. A25, S196] and bromide [Takai, Watanabe, Hayashi & Watanabe (1976). Bull. Fac. Eng. Hokkaido Univ. 79, 101-109] have been reported already. In our structures, which have been determined at 140 K, the glycopyranosyl ring appears in a regular (4)C(1) chair conformation with all the substituents, except for the anomeric fluoride (which adopts an axial orientation), in equatorial positions. The observed bond lengths are consistent with a strong anomeric effect, viz. the C1-O5 (carbohydrate numbering) bond lengths are 1.381 (2) and 1.381 (3) A in (I) and (II), respectively, both significantly shorter than the C5-O5 bond lengths, viz. 1.448 (2) A in (I) and 1.444 (3) A in (II). PMID- 20203409 TI - p-Phenylenediamine and its dihydrate: two-dimensional isomorphism and mechanism of the dehydration process, and N-H...N and N-H...pi interactions. AB - p-Phenylenediamine can be obtained as the dihydrate, C(6)H(8)N(2) x 2 H(2)O, (I), and in its anhydrous form, C(6)H(8)N(2), (II). The asymmetric unit of (I) contains one half of the p-phenylenediamine molecule lying about an inversion centre and two halves of water molecules, one lying on a mirror plane and the other lying across a mirror plane. In (II), the asymmetric unit consists of one molecule in a general position and two half molecules located around inversion centres. In both structures, the p-phenylenediamine molecules are arranged in layers stabilized by N-H...pi interactions. The diamine layers in (I) are isostructural with half of the layers in (II). On dehydration, crystals of (I) transform to (II). Comparison of their crystal structures suggests the most plausible mechanism of the transformation process which requires, in addition to translational motion of the diamine molecules, in-plane rotation of every fourth p-phenylenediamine molecule by ca 60 degrees. A search of the Cambridge Structural Database shows that the formation of hydrates by aromatic amines should be considered exceptional. PMID- 20203410 TI - 7-Amino-5-methyl-2-phenyl-6-(phenyldiazenyl)pyrazolo[1,5-a]pyrimidine crystallizes with Z' = 2: pseudosymmetry and the formation of complex sheets built from N-H...N and C-H...pi(arene) hydrogen bonds. AB - The title compound, C(19)H(16)N(6), crystallizes with Z' = 2 in the space group P2(1)/n. The two molecules in the selected asymmetric unit are approximate mirror images of one another; most corresponding pairs of atoms are related by an approximate half-cell translation along [100]. Each molecule contains an intramolecular N-H...N hydrogen bond and the molecules are linked into complex sheets by a combination of two intermolecular N-H...N and four C-H...pi(arene) hydrogen bonds. Comparisons are made with some other 7-aminopyrazolo[1,5 a]pyrimidines. PMID- 20203411 TI - (E)-N-{[6-chloro-4-(4-chlorophenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5 yl]methylene}benzene-1,2-diamine: a three-dimensional framework structure built from only two hydrogen bonds. AB - The molecules of the title compound, C(26)H(19)Cl(2)N(5), are conformationally chiral, with none of the aryl groups coplanar with the pyrazolo[3,4-b]pyridine core of the molecule. A single unique N-H...N hydrogen bond links the molecules into two symmetry-related sets of C(11) chains running parallel to the [011] and [011] directions, respectively, and these two sets of chains are linked into a continuous three-dimensional framework structure by a single unique C-H...N hydrogen bond which forms a chain parallel to the [100] direction. PMID- 20203412 TI - Hydrogen-bonding patterns in two aroylthiocarbamates and two aroylimidothiocarbonates. AB - In O-ethyl N-benzoylthiocarbamate, C(10)H(11)NO(2)S, the molecules are linked into sheets by a combination of two-centre N-H...O and C-H...S hydrogen bonds and a three-centre C-H...(O,S) hydrogen bond. A combination of two-centre N-H...O and C-H...O hydrogen bonds links the molecules of O-ethyl N-(4 methylbenzoyl)thiocarbamate, C(11)H(13)NO(2)S, into chains of rings, which are linked into sheets by an aromatic pi-pi stacking interaction. In O,S-diethyl N-(4 methylbenzoyl)imidothiocarbonate, C(13)H(17)NO(2)S, pairs of molecules are linked into centrosymmetric dimers by pairs of symmetry-related C-H...pi(arene) hydrogen bonds, while the molecules of O,S-diethyl N-(4-chlorobenzoyl)imidothiocarbonate, C(12)H(14)ClNO(2)S, are linked by a single C-H...O hydrogen bond into simple chains, pairs of which are linked by an aromatic pi-pi stacking interaction to form a ladder-type structure. PMID- 20203413 TI - Strong asymmetric hydrogen bonding in 2-(oxamoylamino)ethylammonium oxamate oxamic acid (1/1). AB - The title compound, C(4)H(10)N(3)O(2)(+) x C(2)H(2)NO(3)(-) x C(2)H(3)NO(3), contains at least 11 distinct hydrogen-bond interactions showing a great variety of bond strengths. The shortest and strongest hydrogen bond [O...O = 2.5004 (12) A] is found between the uncharged oxamic acid molecule and the oxamate monoanion. The grouping formed by such a strong hydrogen bond can thus be considered as a hydrogen bis(oxamate) monoanion. It lacks crystallographic symmetry and the two oxamate groups have different conformations, showing an asymmetric hydrogen-bond interaction. Significantly, the asymmetry allows us to draw a direct comparison of site basicity for the two inequivalent carboxylate O atoms in the planar oxamate anion. The constituent molecular ions of (I) form ribbons, where all amide and carboxylate groups are coplanar. Graph-set analysis of the hydrogen bonded networks reveals the R(2)(2)(10) and R(2)(2)(9) homodromic nets as important structure-directing motifs, which appear to be a common feature of many oxamate-containing compounds. PMID- 20203414 TI - Historical landmarks in the histochemistry of the cholinergic synapse: Perspectives for future researches. AB - Nearly one hundred years ago, acetylcholine (ACh) was proposed as a chemical agent responsible for nerve transmission at the synapse, the junction area between one neuron and its target cell. Since it has been proved that ACh played, indeed, a major role in the functioning of the nerve system in the vertebrates, cholinergic nerve transmission became a basic field of study in neuroscience. The birth of histochemistry and its ulterior developments allowed in situ localization of the molecular agents related to the functioning of the cholinergic synapse. This report presents historical landmarks in the histochemistry of major cholinergic agents (acetylcholinesterase, nicotinic acetylcholine receptor, choline acetyltransferase, and ACh), a domain which has greatly contributed to the knowledge of the nerve system. It is emphasized that despite extraordinary progresses made in this field, basic problems, such as in situ localization of ACh, still remain to be solved. PMID- 20203415 TI - Stromal thrombospondin-1 expression is a prognostic indicator and a new marker of invasiveness in intraductal papillary-mucinous neoplasm of the pancreas. AB - The invasion of intraductal papillary-mucinous neoplasm (IPMN) is sometimes difficult to diagnose using only ordinary hematoxylin-eosin sections. The aim of this study was to evaluate the invasion of IPMN more precisely using thrombospondin-1 (TSP1) immunohistochemistry as a useful adjunct to morphological examination. Eighty patients that underwent primary resection for pancreatic IPMNs were retrospectively analyzed. The 80 IPMNs were studied for the expression of TSP1, MUC1-CORE, MUC2, and MUC5AC. The cases were evaluated for dysplasia, the presence of invasion, hisological subtypes, and survival. The 80 IPMNs were classified into 29 intraductal papillary-mucinous adenomas (IPMAs), 10 borderline IPMNs, 18 noninvasive intraductal papillary-mucinous carcinomas (IPMCs), and 23 invasive IPMCs according to the WHO classification. Invasive IPMCs were further divided into 12 minimally invasive IPMCs (MI-IPMCs) and 11 invasive carcinomas originating from IPMCs (IC-IPMCs) according to the Japan Pancreatic Society classification. The rate of strongly positive cases with more than 30% of the cancer stroma area expressing TSP1 was significantly higher in MI-IPMC and IC IPMC than in noninvasive IPMC (P = 0.035, 0.005). Furthermore, patients in the strongly positive group had a significantly poorer prognosis compared to patients in the negative-weakly positive group (P = 0.008, log-rank test). Of the 80 tumors, 22 were classified into gastric-, 45 into intestinal-, 7 into pancreatobiliary-, and 6 into oncocytic-type IPMNs according to criteria described previously. The cases with a strongly positive expression of TSP1 were frequently detected in the pancreatobiliary and oncocytic types (P = 0.001). In conclusion, stromal TSP1 expression is a prognostic indicator and a new marker of invasiveness in IPMN. PMID- 20203416 TI - Rapid LED-based fluorescence microscopy distinguishes between live and dead bacteria in oral clinical samples. AB - Despite the existence of several methods for the diagnosis of oral infectious diseases, few rapid and quantitative methods exist for discriminating between live and dead bacterial cells in oral clinical samples. In this study, we characterized a light-emitting diode (LED) fluorescence microscopic technique for quantifying live and dead oral bacterial cells stained with 4',6'-deamidino-2 phenyllindole and propidium iodide. Four bacterial strains representative of the human oral microflora were used in this study. In addition, saliva and subgingival fluid specimens were collected from healthy volunteers. Saliva was obtained from the donors without stimulation, whereas subgingival fluid was obtained by inserting a sterile endodontic paper point into the subgingival sites of the first molar. The samples were cultured on agar plates and subjected to LED microscopy. The correlations between both methods were analyzed. The number of live bacterial cells as determined by LED-based fluorescence microscopy and standard colony counts on agar plates correlated well for the known oral bacterial strains and bacterial cells in the clinical specimens. The LED illumination method characterized in this study can be used for the rapid enumeration of living and dead cells. However, to show specificity, this method requires further innovations. PMID- 20203417 TI - Hair growth stimulated by conditioned medium of adipose-derived stem cells is enhanced by hypoxia: evidence of increased growth factor secretion. AB - Adipose-derived stem cells (ADSCs) and their secretomes mediate diverse skin regeneration effects, such as wound-healing and antioxidant protection, that are enhanced by hypoxia. We investigated the hair-growth-promoting effect of conditioned medium (CM) of ADSCs to determine if ADSCs and their secretomes regenerate hair and if hypoxia enhances hair regeneration. If so, we wanted to identify the factors responsible for hypoxia-enhanced hair-regeneration. We found that ADSC-CM administrated subcutaneously induced the anagen phase and increased hair regeneration in C(3)H/NeH mice. In addition, ADSC-CM increased the proliferation of human follicle dermal papilla cells (HFDPCs) and human epithelial keratinocytes (HEKs), which are derived from two major cell types present in hair follicles. We investigated the effect of hypoxia on ADSC function using the same animal model in which hypoxia increased hair regrowth. Forty-one growth factors in ADSC-CM from cells cultured under hypoxic or normoxic conditions were analyzed. The secretion of insulin-like growth factor binding protein (IGFBP)-1, IGFBP-2, macrophage colony-stimulating factor (M-CSF), M-CSF receptor, platelet-derived growth factor receptor-beta, and vascular endothelial growth factor was significantly increased by hypoxia, while the secretion of epithelial growth factor production was decreased. It is reasonable to conclude that ADSCs promote hair growth via a paracrine mechanism that is enhanced by hypoxia. PMID- 20203418 TI - Comparative study of the properties of tendinocytes derived from three different sites in the equine superficial digital flexor tendon. AB - This aim of this study was to determine the characteristic differences in tendinocytes derived from three sites of the equine superficial digital flexor tendon (SDFT)-proximally the myotendinous junction (MTJ), mid-metacarpal (mM) and osteotendinous junction (OTJ)-in morphology, proliferation, and ability for synthesis of collagen and matrix metalloproteinases (MMPs). Little difference was observed in cell proliferation. Addition of tumor necrosis factor (TNF) alpha to the culture medium resulted in increased collagen synthesis by tendinocytes from all three sites. The amount of collagen synthesized by tendinocytes derived from the mM and OTJ was much larger than that synthesized by untreated tendinocytes. A collagen zymogram revealed that proMMP-13 synthesis was increased towards the distal site. However, TNFalpha treatment resulted in a significant decrease in the amount of proMMP-13 synthesized by tendinocytes from all three sites. On the other hand, a gelatin zymogram showed that the synthesis level of proMMP-9 tended to decrease towards the distal site, but there was little difference between synthesis levels of proMMP-9 before and after TNFalpha treatment. These results indicated that tendinocytes in the same tendon have different characteristics and that these characterisities would reflect the function of tendinocytes in vivo. Also, the isolated tendinocytes provided much information on the characteristics and properties of tendons for the ECM turnover system and on the responsiveness of tendinocytes to complex inflammatory responses in a tendinopathy condition. PMID- 20203419 TI - 4-Methylcatechol-induced heme oxygenase-1 exerts a protective effect against oxidative stress in cultured neural stem/progenitor cells via PI3 kinase/Akt pathway. AB - 4-Methylcatechol (4MC), a stimulator of the synthesis of neurotrophin family members in various cells, was able to up-regulate the expression of heme oxygenase (HO)-1, a redox-sensitive inducible stress protein, in neural stem/progenitor cells (NS/PCs). RT-PCR analysis showed that 4MC induced HO-1 mRNA expression in a dose- and a time-dependent manner. The increase in HO-1 mRNA was followed by an increase in HO-1 protein content, which was confirmed by ELISA and Western blotting analysis. When NS/PCs were pretreated with 4MC before exposure to hydrogen peroxide (H(2)O(2)), most of the cells were rescued from the H(2)O(2) induced death. 4MC enhanced the phosphorylation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated protein kinase (ERK) and Akt in a time-dependent manner. Pretreatment of cultures with a selective inhibitor of PI3 kinase (PI3K)/Akt, but not with one of MAPK/ERK, inhibited both the 4MCinduced HO 1 expression and neuroprotective effect, demonstrating that PI3K/Akt signaling pathway played a significant role in 4MC-induced HO-1 induction and neuroprotection. Taken together, our results suggest that 4MC activates the expression of HO-1 through the PI3K/Akt signaling pathway and that the HO-1 protein inhibits the death of NS/PCs induced by oxidative stress. PMID- 20203420 TI - Transformation of breast milk macrophages by HTLV-I: implications for HTLV-I transmission via breastfeeding. AB - Human T cell leukemia virus type I (HTLV-I), a causative agent of adult T-cell leukemia (ATL), is transmitted from mother to child predominantly by breastfeeding. The source of HTLV-I-infected cells in breast milk has been thought to be T cells, however, the majority of cells in breast milk are CD14(+) macrophages but not CD3(+) T lymphocytes, and no data are available regarding HTLV-I transmission through breast milk macrophages (BrMMpsi). To explore the potential of BrMMpsi as a possible source of infection in mother to child transmission (MTCT) of HTLV-I, an immortalized cell line (HTLV-BrMMpsi) has been established from BrMMpsi by infection with HTLV-I. HTLV-BrMMpsi retained macrophage characteristics and did not express a complete dendritic cell (DC) phenotype; nevertheless, HTLV-BrMMpsi efficiently promoted T cell proliferation in primary allogeneic mixed lymphocyte reaction (MLR) like DC. Moreover, HTLV-I infection could be transmitted from HTLV-BrMMpsi to activated T cells in the peripheral blood. These findings suggested that BrMMpsi might be an appropriate HTLV-I reservoir involved in MTCT transmission via breastfeeding. PMID- 20203421 TI - Comparison of hyaluronan effects among normal, osteoarthritis, and rheumatoid arthritis cartilages stimulated with fibronectin fragment. AB - High molecular weight hyaluronan (HA) is widely used in the treatment of osteoarthritis (OA) and rheumatoid arthritis (RA) by intra-articular injection. However, comparative studies of HA actions on catalytically activated cartilages in different pathologic conditions have rarely been investigated. This study was aimed to compare the inhibitory effects of HA on nitric oxide (NO) production by COOH-terminal heparin-binding fibronectin fragment (HBFN-f) between normal and diseased cartilages. When articular cartilage explants from normal, OA, or RA joints were incubated with HBFN-f, the RA and OA cartilages produced higher levels of NO compared with normal cartilage. Pretreatment with 2700 kDa HA resulted in significant suppression of HBFN-f-stimulated NO production in OA and RA cartilages. While CD44 was up-regulated in OA and RA cartilages, anti-CD44 antibody reversed HA inhibition of HBFN-f action in those cartilages. The present results clearly demonstrated that HA blocked HBFN-f actions in OA and RA cartilages through interaction with CD44. HA, which targets CD44 highly expressed on OA and RA chondrocytes, could suppress catabolic actions by fibronectin fragments like HBFN-f in diseased cartilage. PMID- 20203422 TI - Molecular diversity in venom proteins of the Russell's viper (Daboia russellii russellii) and the Indian cobra (Naja naja) in Sri Lanka. AB - To examine the molecular diversity of the venom proteins of the Russell's viper (Daboia russellii russellii) and the Indian cobra (Naja naja) in Sri Lanka, we isolated 38 venom proteins through a combination of anion exchange chromatography followed by reversed-phase high performance liquid chromatography. From the venom of D. r. russellii we isolated 15 proteins: 5 isozymes of phospholipase A(2) (PLA(2)), 4 serine proteases, 2 C-type lectin-like proteins, 2 L-amino acid oxidases, 1 cysteine-rich secretory protein (CRISP), and 1 metalloproteinase. From the venom of N. naja we isolated 23 proteins: 10 isoforms of cytotoxins (CTX), 7 PLA(2) isozymes, 2 muscarinic toxinlike proteins, 2 CRISPs, 1 nerve growth factor, and 1 new thrombin-like serine protease. Most of these proteins contained new amino acid sequences for each species, indicating molecular diversity in venom proteins. The entire amino acid sequences of PLA(2)3 from D. r. russellii and CTX7 from N. naja were determined. Additionally, the polymorphic amino acid residues of PLA(2)3 were preferentially localized on the potential antigenic sites. While 2 types of PLA(2) (N and S types) were found in D. r. russellii (India) and D. r. siamensis (Java), all the PLA(2)s from D. r. siamensis (Burma) were N type, and those from D. r. russellii (Sri Lanka) were primarily S type. PMID- 20203423 TI - Contiguous gene deletion of Ptprk and Themis causes T-helper immunodeficiency (thid) in the LEC rat. AB - The LEC rat has a spontaneous mutation of T-helper immunodeficiency (thid), which causes a marked defect in T cell maturation from double positive (DP) to CD4 single positive (SP) cells in the thymus. Previously, we identified the contiguous gene deletion of Ptprk and Themis genes in the thid locus that causes the simultaneous loss of expression of both genes, and the exogenous Ptprk expression partially rescued this phenotype. To determine whether the deletion of Themis influences thid phenotype, bone marrow (BM) cells were transduced with lentiviral vector expressing Themis gene, and were transplanted into X-ray irradiated LEC rats. Interestingly, the exogenous Themis expression rescued the development of CD4 SP cells as well as Ptprk. The result suggests that the deficiency of both genes is responsible for the thid mutation, and that both genes are indispensable for the development of SP cells from DP cells in the thymus. PMID- 20203424 TI - Gender differences in serum GH and IGF-I levels and the GH response to dynamic tests in patients with acromegaly. AB - Gender affects the GH secretory pattern both in normal subjects and in patients with acromegaly by an uncertain mechanism. Here, we report the influence of gender on the relationship between serum GH and IGF-I levels and the GH response to dynamic tests in patients with acromegaly. Seventy-four patients with untreated acromegaly (M/F 27/47, age range 22-86 yr.) were studied. The serum GH levels did not differ between male and female (6.1 vs. 8.7 ng/ml; p=0.26), while serum IGF-I levels, IGF-I SDS and the IGF-I/GH ratio were lower in female than those in male (679 vs. 769 ng/ml; p<0.02, 7.3 vs. 9.2 SDS; p<0.02 and 79.6 vs. 141.5; p<0.05). When the subjects were divided into two groups: age 50 yr, serum IGF-I levels and IGF-I/GH ratios were lower in female than those in male in patients 50 yrs (684 vs. 680 ng/ml; p=0.39 and 98.7 vs. 118.4; p=0.40). The GH responses to OGTT, TRH, octreotide, and bromocriptine tests were similar in male and female. In conclusion, IGF-I/GH ratio was significantly lower in female than that in male particularly in younger patients with acromegaly. These data suggest that gender, presumably sex steroids in female, may partially modulate the relationship between circulating IGF-I and GH levels in patients with acromegaly. PMID- 20203425 TI - Secretogranin III: a bridge between core hormone aggregates and the secretory granule membrane. AB - Secretory granules in endocrine cells selectively store bioactive peptide hormones and amines, which are secreted in a regulated manner upon appropriate stimulation. In addition to bioactive substances, various proteins and lipids characteristic of secretory granules are likely recruited to a restricted space at the trans-Golgi Network (TGN), and the space then matures to the secretory granule. Although experimental findings so far have strongly suggested that aggregation- and receptor-mediated processes are essential for the formation of secretory granules, the putative link between these two processes remains to be clarified. Recently, secretogranin III (SgIII) has been identified as a specific binding protein for chromogranin A (CgA), a representative constituent of the core aggregate within secretory granules, and it was later revealed that SgIII can also bind to the cholesterol-rich membrane domain at the TGN. Based on its multifaceted binding properties, SgIII may act as a central player in the formation of cholesterol-rich membrane platforms. Upon these platforms, essential processes for secretory granule biogenesis coordinately occur; that is, selective recruitment of prohormones, processing and modifying of prohormones, and condensation of mature hormones as an aggregate. This review summarizes the findings and theoretical concepts on the issue to date and then focuses on the putative role of SgIII in secretory granule biogenesis in endocrine cells. PMID- 20203426 TI - [Development of automatic navigation measuring system using template-matching software in image guided neurosurgery]. AB - An image-guided neurosurgery and neuronavigation system based on magnetic resonance imaging has been used as an indispensable tool for resection of brain tumors. Therefore, accuracy of the neuronavigation system, provided by periodic quality assurance (QA), is essential for image-guided neurosurgery. Two types of accuracy index, fiducial registration error (FRE) and target registration error (TRE), have been used to evaluate navigation accuracy. FRE shows navigation accuracy on points that have been registered. On the other hand, TRE shows navigation accuracy on points such as tumor, skin, and fiducial markers. This study shows that TRE is more reliable than FRE. However, calculation of TRE is a time-consuming, subjective task. Software for QA was developed to compute TRE. This software calculates TRE automatically by an image processing technique, such as automatic template matching. TRE was calculated by the software and compared with the results obtained by manual calculation. Using the software made it possible to achieve a reliable QA system. PMID- 20203427 TI - [Image examination of malignant tumors in lungs observed on the basis of cost analysis using diagnosis procedure combination data]. AB - Recently, the environment of medical treatment in our country has become more strict. The purpose of this study is to find changes in the implementation of diagnostic imaging from the point of view of cost analysis, through the use of diagnosis procedure combination (DPC) data. The patient data has been extracted from the DPC data. We compared patients (n=693) in terms of their daily income, cost, and image examination cost ratio for malignant tumors in lungs. The results of this study indicated the ratio of the image examination cost of 040040xx99100x was 25.2% in the old grading sheet. The ratio of the image examination cost increased 42.4% in the new grading sheet. The implementation of diagnostic imaging was able to be made visible simply by analyzing the cost. We found one of the methodologies that connected the improvement of that standard treatment with the examination of each DPC. PMID- 20203428 TI - [Non-helical overlapping scan (NHOS) for the application of 3D-CT angiography of cerebral blood vessels]. AB - To improve of cerebral blood vessel visualization and reduce cone beam artifacts from high absorbance materials such as bone structure in 3D-CTA of cerebral blood vessels, we suggest that a non-helical overlapping scan (NHOS) be used. We found that the NHOS and the conventional helical scan optimized the conditions for clinical use of the NHOS. Z-resolution in the NHOS was much higher than that in the non-helical scan without slice overlap. FWHM of the NHOS were thin, about 47%, in comparison with that of the helical scan, and NHOS was superior in Z resolution to that of the helical scan. Moreover, the NHOS had very few artifacts caused by the skull, and was useful for 3D-CTA of cerebral blood vessels. PMID- 20203429 TI - Study on reproduction of captive marine mammals. AB - The reproductive endocrinological characteristics of beluga, killer whale, spotted seal and bottlenose dolphin were evaluated and used in conjunction with applied reproductive research to enhance captive breeding programs. Results from 8 y of biweekly serum progesterone determination in a female beluga indicated that sexual maturity occured at approximately age 13, two to seven estrous cycles, lasting 37 +/- 3.9 days, per yr began in April-May every year. Rectal temperature was positively correlated with serum progesterone levels and negatively associated with behavioral estrus. In five cases of pregnancy of two female killer whale, positive relationship was found between serum progesterone concentration and temperature during the first period of 18 month-gestation. In the normal parturitions (n=4), rectal temperature decreased 0.8 C lower than average rectal temperature during pregnancy. Sexual maturity of female killer whales occurred at age nine. Yearly contraception in the mono-estrus captive spotted seals (n=10) using a single dose of the progestagen (proligestone(TM); 5 or 10 mg/kg s.c.) was achieved in 94% (33/35) of the attempts over 5 yr when the hormone was administered two months prior to the breeding season. Artificial insemination trials (n=4) were conducted in female bottlenose dolphin (n=3) using fresh and frozen-thawed semen. Estrus synchronization using regumate (27 days) resulted in ovulation occurring 19 to 24 days post withdrawal. Conception was confirmed in 75% of the attempts, with two females successfully delivering calves. PMID- 20203430 TI - Nitric oxide and luteal blood flow in the luteolytic cascade in the cow. AB - The corpus luteum (CL) of the estrous cycle in the cow is a dynamic organ which has a lifespan of approximately 17-18 days. The main function of the CL is to produce progesterone (P) that requires for achievement and maintenance of pregnancy. If pregnancy does not occur successfully, the CL must regress within a few days to induce the next chance of ovulation. As the CL matures, the steroidogenic cells establish contact with many capillary vessels, consequently the CL is composed of a large number of vascular endothelial cells that can account for up to 50% of all cells. Therefore, blood vessels and blood flow within the CL have an essential role in luteal function. Nitric oxide (NO), a strong vasorelaxant, is now known to play key roles in a variety of physiological process. Indeed, NO has established itself as a polyvalent molecule which plays a decisive role in regulating multiple functions within female reproductive system. In the CL, NO is produced and regulates luteal blood flow, P secretion and apoptosis of luteal cells as well as endothelial cells. This review describes the current investigation for possible roles of NO in the luteolytic cascade within the bovine CL. PMID- 20203431 TI - Induction of oocyte maturation by hyaluronan-CD44 interaction in pigs. AB - In most mammals, the oocyte is surrounded with compact multilayers of cumulus cells; these form cumulus-oocyte complexes (COCs). During oocyte maturation, the COCs dramatically expand and this is termed "cumulus expansion". We have previously demonstrated that cumulus expansion is the result of hyaluronan synthesis and accumulation in the extracellular space between cumulus cells in the COCs and that hyaluronan accumulation within the COCs affects oocyte maturation. We have also demonstrated that CD44, the principal hyaluronan receptor, is expressed in the COCs during cumulus expansion and that the interaction between hyaluronan and CD44 appears to be closely related to gap junctional communication of the COCs during the process of meiotic resumption. Based on our previous studies, we review herein that the physiological significance and the molecular mechanism of cumulus expansion for porcine oocyte maturation. PMID- 20203432 TI - How to improve the success rate of mouse cloning technology. AB - It has now been 13 years since the first cloned mammal Dolly the sheep was generated from somatic cells using nuclear transfer (SCNT). Since then, this technique has been considered an important tool not only for animal reproduction but also for regenerative medicine. However, the success rate is still very low and the mechanisms involved in genomic reprogramming are not yet clear. Moreover, the NT technique requires donated fresh oocyte, which raises ethical problems for production of human cloned embryo. For this reason, the use of induced pluripotent stem cells for genomic reprogramming and for regenerative medicine is currently a hot topic in this field. However, we believe that the NT approach remains the only valid way for the study of reproduction and basic biology. For example, only the NT approach can reveal dynamic and global modifications in the epigenome without using genetic modification, and it can generate offspring from a single cell or even a frozen dead body. Thanks to much hard work by many groups, cloning success rates are increasing slightly year by year, and NT cloning is now becoming a more applicable method. This review describes how to improve the efficiency of cloning, the establishment of clone-derived embryonic stem cells and further applications. PMID- 20203433 TI - Introduction of various vietnamese indigenous pig breeds and their conservation by using assisted reproductive techniques. AB - Pigs are one of the most important domesticated animals in Vietnam. They are the main source of meat for the Vietnamese. According to FAO statistics, Vietnam is among the top 5 countries raising pigs in the world, with nearly 27 million hogs. This review article introduces the distribution, morphology, growth potential, meat-producing ability and reproductive efficiency of six Vietnamese indigenous pig breeds: I, Mong Cai, Muong Khuong, Soc, Meo and Co. The collected data showed that these Vietnamese pigs are less effective in comparison with Western pigs in terms of reproductive and meat-producing ability as well as weight growth. However, these Vietnamese indigenous breeds have some special characteristics, such as very early sexual maturity, and good adaptability to harsh raising conditions or poor feeding. Moreover, recent genetic research has shown that Vietnamese pigs are genetically diverse. Thus, conservation of these pig breeds using assisted reproductive techniques is urgent and important. PMID- 20203434 TI - Salmonella isolated from the feces of migrating cranes at the Izumi Plain (2002 2008): serotype, antibiotic sensitivity and PFGE type. AB - From November 2002 to February 2008, 2,251 crane feces were collected at the Izumi Plain in Kagoshima Prefecture. Salmonella enterica was isolated from 359 feces (15.9%), of which 332 (92.5%) were Salmonella Typhimurium (ST), 9 were S. Hvittingfoss/II, 4 were S. Abaetetuba, 3 were S. Enteritidis, 2 were S. Konstanz, 1 was S. Pakistan and 8 were untyped isolates, respectively. Against 12 antimicrobial agents, no resistant strains were found in 154 isolates examined, but one was found to be resistant to ampicillin. By pulsed-field gel electrophoresis (PFGE), all but one of the 68 ST isolates tested showed indistinguishable banding patterns; one had a different pattern. The results suggest that ST strains from the same origin would spread in crane flocks during their stay at Izumi Plain every winter. PMID- 20203435 TI - Physiological responses of erythrocytes of goats to transportation and the mondulatory role of ascorbic acid. AB - Experiments were performed with the aim of investigating the effect of road transportation for 12 hr on erythrocytes of goats during the hot-dry season and the modulatory role of ascorbic acid. Forty 2.5-3-year-old Red Sokoto goats weighing 23-25 kg and belonging to both sexes served as the subjects of the study. Twenty of the goats served as the experimental group and were administered ascorbic acid (AA) per os at a dosage rate of 100 mg/kg body weight; the other 20 served as controls and were given 10 ml each of sterile water. Forty minutes after the administration and loading, the goats were transported for 12 hr. EDTA blood samples collected before loading, after loading, immediately after transportation and subsequently on the 3rd and 7th days of post-transportation were used to determine the red blood cell (RBC) count, packed cell volume (PCV), hemoglobin (Hb), erythrocyte osmotic fragility (EOF), hematimetric (intrinsic) indices and hemoglobin index levels. The obtained results showed that handling, loading and transportation of the control goats induced significant (P<0.05) increases in RBC, Hb, EOF and hypochromic erythrocytes and a decrease (P<0.05) in the volume and average Hb content in RBCs. AA administration ameliorated all these changes. The present results suggest that road transportation for 12 hr during the hot-dry season could induce serious stress, resulting in hemolysis of erythrocytes, which was ameliorated by AA administration. In addition, the results demonstrated that EOF could be used as a diagnostic tool in road transportation stress. PMID- 20203436 TI - First detection of Cryptosporidium baileyi in Ruddy Shelduck (Tadorna ferruginea) in China. AB - Fecal samples from Ruddy Shelduck, Tadorna ferruginea, were screened microscopically for Cryptosporidium oocysts. Five samples out of 148 ones (3.38%) were confirmed to be positive. DNA was extracted individually from positive samples and used for PCR amplification of SSU rDNA and HSP70 gene loci. The obtained PCR products were cloned in E. coli (TG1 strain) using pMD18-T vector and sequenced using standard methods. Microscopical and molecular analyses identified the obtained isolates as Cryptosporidium baileyi. To our knowledge, this is the first report of detection of C. baileyi from Ruddy Shelduck, Tadorna ferruginea, in China. PMID- 20203437 TI - Comparative analysis of vocalizations of thoroughbred mares (Equus caballus) between estrus and diestrus. AB - We investigated the differences between vocalizations of mares in estrus and diestrus and determined the spectrographic parameters to discriminate estrus from diestrus. Thoroughbred brood mares (n=89) were exposed to a teasing procedure for 3 min, and we recorded all vocalizations emitted from them. Among the mares, 56.5% of estrus and 78.6% of diestrus mares emitted calls toward an approaching stallion, indicating that there was higher tendency in the occurrence rate of vocal responses in diestrus than estrus mares. We analyzed the spectrographic data of the mares (25 estrus and 22 diestrus mares) emitting calls in the form of a squeal toward an approaching stallion. Based on broad bandwidth spectrographic analysis, the duration and third formant of the call have a significant effect on discriminating estrus from diestrus. PMID- 20203438 TI - [Extermination of gastric cancer from Japan]. PMID- 20203439 TI - [Recent progress in pathology, diagnosis and treatment for neuroendocrine tumors]. PMID- 20203440 TI - [Histopathological diagnosis of neuroendicrine tumor]. PMID- 20203441 TI - [Surgical management of the gastroenteropancreatic neuroendocrine tumors]. PMID- 20203442 TI - [Recent progress in the molecular-targeting treatment of neuroendocrine tumors]. PMID- 20203443 TI - [Gemcitabine therapy for unresectable pancreatic cancer in elderly patients]. AB - We evaluated the therapeutic effect of gemcitabine (GEM) therapy in 153 unresectable pancreatic cancer (UPC) patients, divided into younger patients (under 65), early-stage elderly patients (age 65-74) and advanced-stage elderly patients (age 75 and over). Among those patients who received only best supportive care (BSC), the most common reasons to be selected for BSC were family requests in the advanced-stage elderly patients, and poor general condition in the rest. Among the patients who received GEM therapy, there were no significant differences in response rate, or adverse events including the rate of dose reduction, postponement or cessation of GEM administration due to toxicity. Multivariate analysis using patient backgrounds and response to GEM therapy showed that CA 19-9 response and performance status did not change with age. GEM therapy for both early-stage and advanced-stage elderly UPC patients was as safe and useful as in younger patients. PMID- 20203444 TI - [A case of hepatic portal venous gas caused by transient type ischemic enteritis]. AB - We report a case of hepatic portal venous gas (HPVG) caused by transient type ischemic enteritis. The patient was a 65-year-old woman, previously given a diagnosis of hypertension and diabetes mellitus. She was admitted to our hospital because of vomiting and epigastric pain. Abdominal computed tomography showed dilatation of the stomach and small intestine, with hepatic portal and superior mesenteric venous gas. Upper gastrointestinal endoscopy showed diffuse edematous and erosive change, and an extensive ulcer in the duodenum. There was no muscular defence, and physical and laboratory examinations did not indicate necrotic bowel. We diagnosed as HPVG caused by ischemic enteritis, and she responded to conservative treatment. We discuss a rare case of HPVG caused by transient type ischemic enteritis with references. PMID- 20203445 TI - [A case of intestinal tuberculosis associated with ileo-ileal fistula]. AB - A 25-year-old woman was admitted with fever and right lower abdominal pain that had started 3 days after the administration of antituberculosis agents for pulmonary tuberculosis. She was given a diagnosis of intestinal tuberculosis with ileo-ileal fistula formation on computed tomography, colonoscopy and laboratory test findings. She was kept on anti-tuberculosis agents. Soon after, ileus and a micro abscess appeared near the fistula. Ileocecal resection with partial ileal resection resulted in a good postoperative clinical course. Tuberculosis is still a major infectious disease. Intestinal tuberculosis is very rarely associated with fistula formation, and when it occurs, is difficult to differentiate from Crohn disease. Our case strongly suggests that typical intestinal tuberculosis findings can help in differential diagnosis between intestinal tuberculosis and Crohn disease. PMID- 20203446 TI - [A Japanese family with adult-onset familial Mediterranean fever and periodic episodes of high fever and abdominal pain]. AB - Familial Mediterranean fever (FMF) is an autoinflammatory disease. The patient was a 28-year-old Japanese man with attacks of fever and abdominal pain, which recurred at 1-to 3-month intervals. These symptoms usually improved spontaneously 1 week later. Physical examination showed tenderness in the right lateral abdomen. Routine laboratory tests demonstrated an increase in inflammatory reactions in the serum with leukocytosis. No abnormal findings were found on either chest, or abdominal CT scans, or endoscopic examinations of the upper or lower gastrointestinal tracts. Renal and hepatic function were within the normal limits, and no positive results were obtained for an anti-nuclear antibody. DNA analysis demonstrated a heterozygous mutation in the MEFV gene, the compound pyrin variant E148Q/M694I, leading to a diagnosis of FMF. His father had also had the same symptoms for 30 years, and was also heterozygous for the pyrin variant E148Q/M694I. They both responded dramatically to colchicine treatment and have remained in full remission until the time of writing. PMID- 20203447 TI - [Spontaneous regression of hepatocellular carcinomas]. AB - We report a rare case of spontaneous regression (SR) of hepatocellular carcinoma (HCC). A 70-year-old man consulted us for general fatigue. Enhanced abdominal computed tomography (CT) showed two HCCs, of 5cm in the posterior segment and 8cm around the right Glissonean pedicle with tumor thrombus in the main portal trunk. He refused to undergo any treatment, but 28 months later, CT showed complete disappearance of the hilar tumor and portal tumor thrombus, and partial regression in the posterior tumor with shrinkage of the right lobe of the liver. His PIVKA-II levels decreased from 23358 to 217mAU/ml. In the present case, tumor infarction of the portal thrombus, and the administration of imidapuril hydrochloride and Hochu-ekki-to may have caused SR. PMID- 20203448 TI - [Successful treatment of a gastrointestinal stromal tumor with liver metastases in a case that tolerated imatinib administration, by radiofrequency ablation using contrast-enhanced ultrasonography]. AB - We report a case of gastrointestinal stromal tumor (GIST) with liver metastases which was undetectable by B-mode ultrasonography, effectively treated by radiofrequency ablation using contrast-enhanced ultrasonography US. A 43-year-old woman was admitted for the treatment of 6 lesions up to 4cm in diameter, which had emerged from necrotic sites within the liver after imatinib treatment. The recurrent lesions were not detected on B-mode US, and it was difficult to perform radiofrequency ablation (RFA) treatment. Using a contrast-enhanced agent (sonazoid), the recurrent lesions were detected and treated by RFA. RFA is considered to be an effective treatment for GIST with liver metastases that tolerate imatinib administration. PMID- 20203449 TI - [A case of primary liver carcinoma of intermediate (hepatocyte-cholangiocyte) phenotype: comparison of hemodynamics and histopathology]. AB - A 58-year-old man was followed up for HBV-associated chronic hepatitis. A low echoic hepatic nodule 1.6cm in diameter developed in segment 8 of the liver. The tumor was hypervascular and showed enhancement on CV during hepatic arteriography (CTHA) and a defect on CT during arterial portography (CTAP). Strong enhancement, which lasted for 30 seconds, was observed at the margin of the tumor on single level dynamic CTHA. The resected tumor was whitish, had no capsule, and consisted mainly of intermediate immature cells together with HCC-like and CCC-like tumor cells. These findings led to the diagnosis of primary liver carcinoma of intermediate (hepatocyte-cholangiocyte) phenotype. Cytokeratin (CK) 7, CK8, CK19, EMA and vimentin were positive and HP-1 and c-kit tests were negative on immunohistochemical staining. Staining with CD34+alphaSMA showed more muscular arterial vessels and sinusoid-like vessels in the peripheral zone of the tumor than in the central zone. Six months after the resection of the tumor, swollen abdominal lymph nodes were observed on US and CT, which aspiration needle biopsy showed to be metastasis of a hepatic tumor. PMID- 20203450 TI - [Cholangiocarcinoma with bile duct adenoma and hamartoma-like lesion in the bile duct]. AB - A 76-year-old man presented with fever of unknown origin. Diagnostic imaging showed a liver tumor measuring 3cm in maximum dimension. The tumor was subsequently resected, and histopathology showed a moderately differentiated adenocarcinoma. This showed a number of bile ductules with variable amounts of stroma, well circumscribed but not encapsulated, so the lesion was diagnosed as a cholangiocarcinoma. Within the tumor there was also a cholangiolocarcinoma-like lesion. In addition, cystically dilated ductules resembling bile duct hamartoma and bile duct adenoma adjacent to the tumor were found, but with no area of transition among them. In the Glisson's capsule around the tumor, there was also a bile duct hamartoma. PMID- 20203452 TI - LDL-C goal attainment in patients who remain on atorvastatin or switch to equivalent or non-equivalent doses of simvastatin: a retrospective matched cohort study in clinical practice. AB - BACKGROUND: As clinical trials have shown the benefits of more intensive cholesterol control, treatment targets for low-density lipoprotein cholesterol (LDL-C) have decreased progressively. At the same time, physicians have been encouraged to contain costs by prescribing cheaper, generic statins for cholesterol management. To determine how these possibly conflicting goals are managed in clinical practice, we examined LDL-C control in patients switched from a potent, branded statin (atorvastatin) to a less potent, generic statin (simvastatin). METHODS: Patients who switched from atorvastatin to simvastatin between July 2006 and January 2008 were retrospectively identified from a US medical and pharmacy claims database, and matched with controls remaining on atorvastatin. Outcomes measured were the number of switched patients receiving a simvastatin milligram dose>or=2 times their previous atorvastatin dose, changes in LDL-C levels, and percentage of patients achieving recommended LDL-C targets. All study variables were analyzed descriptively. RESULTS: After applying exclusion and inclusion criteria, 1048 patients who switched from atorvastatin to simvastatin and 1048 matched controls who remained on atorvastatin were included. Among the switchers, 379 (36%) received an inappropriately low dose of simvastatin (<2 times atorvastatin dose). In patients remaining on atorvastatin, mean LDL-C decreased from 105.7 mg/dL to 102.3 mg/dL after 44 weeks, whereas in switched patients, LDL-C remained similar, at 105.9 mg/dL on atorvastatin and 105.8 mg/dL on simvastatin. Before switching, when all patients were receiving atorvastatin, 67.4% of switchers and 69.9% of controls achieved recommended LDL-C targets. After switching, significantly fewer switchers than controls met LDL-C targets (69.1% vs 74.6%; P=0.005). However, among patients who switched to an equivalent dose of simvastatin (>or=2 times prior atorvastatin dose), similar proportions met LDL-C targets (72.8% vs 74.6% of controls; P=0.402), whereas among patients who switched to inappropriate non-equivalent dose of simvastatin, a significantly lower proportion met LDL-C targets (62.5% vs 74.6% of controls; P=0.001). CONCLUSIONS: Continuing atorvastatin was associated with lower LDL-C levels and better LDL-C target attainment compared with switching to simvastatin. Patients switched to an equivalent simvastatin dose had lower LDL-C levels and were more likely to achieve LDL-C targets than patients switched to a non equivalent dose, suggesting physicians must consider dosage equivalence when switching statins, and should measure LDL-C and titrate statins as necessary to achieve LDL-C control. PMID- 20203453 TI - Cardiorenal interaction: appropriate treatment of cardiovascular risk factors to improve outcomes in chronic kidney disease. AB - Chronic kidney disease (CKD) is a recognized risk multiplier for the development of cardiovascular disease (CVD), with CVD events representing the leading cause of morbidity and mortality in patients with CKD. The nature of CKD as a risk state relates both to the nature of CKD and the antecedent development of CVD. In addition, patients with CKD have increased rates of multiple conventional cardiac risk factors. Although early data regarding the relationship between CVD and CKD were limited because of the need for large data sets and multivariable analysis, the importance of recognizing this complex relationship is now clear. The essence of the relationship appears to be bidirectional, and therapy directed at improving natural history of chronic disease on one system generally improves prognosis in the other. Specifically, CVD outcomes have been shown to improve with the treatment of risk factors commonly found in association with CKD, including hypertension, diabetes, dyslipidemia, albuminuria, and smoking, as well as appropriate renin-angiotensin-aldosterone system blockade and antiplatelet therapy. Once hospitalized, management of acute coronary syndromes represents a key area of clinical investigation. The goal of this article is to highlight the importance of these topics in improving cardiovascular outcomes and use of appropriate treatment in CKD. PMID- 20203451 TI - Design and rationale of a real-life study to compare treatment strategies for cardiovascular risk factors: the CRUCIAL study. AB - The CRUCIAL trial was designed to compare the relative reduction in calculated Framingham coronary heart disease risk when a multiple risk factor intervention strategy, based on single-pill amlodipine besylate/atorvastatin calcium, was compared with a usual-care strategy. Eligible patients had treated or untreated hypertension, >or=3 additional cardiovascular risk factors, and baseline total cholesterol1 billion smokers worldwide, and globally the use of tobacco products is increasing, with the epidemic shifting to the developing world. Tobacco dependence is a chronic condition that often requires repeated intervention for success. Just informing a patient about health risks, although necessary, is usually not sufficient for a decision to change. Smokers should be provided with counseling when attempting to quit. Pharmacologic smoking cessation aids are recommended for all smokers who are trying to quit, unless contraindicated. Evidence-based guidelines recommend nicotine replacement therapy, bupropion SR, and varenicline as effective alternatives for smoking cessation therapy, especially when combined with behavioral interventions. Combination pharmacotherapy is indicated for highly nicotine-dependent smokers, patients who have failed with monotherapy, and patients with breakthrough cravings. An additional form of nicotine replacement therapy or an addition of a non-nicotine replacement therapy oral medication (bupropion or varenicline) may be helpful. The rate of successful smoking cessation at 1 year is 3% to 5% when the patient simply tries to stop, 7% to 16% if the smoker undergoes behavioral intervention, and up to 24% when receiving pharmacological treatment and behavioral support. PMID- 20203459 TI - Customizing inhaled therapy to meet the needs of COPD patients. AB - Chronic obstructive pulmonary disease (COPD) is a progressive disease characterized by airflow limitation resulting from emphysema and chronic bronchitis. Inhaled therapy is the major therapeutic approach for treating COPD. Multiple inhaler medications are available in the United States and are delivered by a variety of different devices: metered-dose inhalers, dry powdered inhalers, and nebulizers. Each inhaler device has unique requirements for use that must be correctly performed by the patient for successful drug delivery. Patients with COPD represent a medically diverse population, with each patient having distinct characteristics, such as lung function, comorbidities, cognitive functions, hand strength, and lifestyle. These characteristics impact the patient's ability to properly use specific inhaler devices and therefore affect adherence to therapy, therapeutic outcomes, and quality of life. It is estimated that between 28% to 68% of patients do not use metered-dose inhalers or dry powder inhalers correctly. Worsening symptoms or increased frequency of exacerbations may not always indicate disease progression but may indicate a patient's inability to use their inhaler device properly. This review discusses the patient- and device specific factors to be considered when choosing an inhaled therapy, which will be concordant with the patient's medical needs, preferences, and lifestyle. The review also considers how the ideas underlying the patient-centered medical home model can be incorporated into the choice and use of inhaler device for a given patient with COPD to improve treatment outcomes. PMID- 20203460 TI - Determining an association between having a medical home and uncontrolled asthma in US school-aged children: a population-based study using data from the National Survey of Children's Health. AB - INTRODUCTION: The American Academy of Pediatrics and the American Academy of Family Physicians believe that infants, children, and adolescents benefit from having a medical home, characterized by accessible, continuous, comprehensive, family-centered, coordinated, compassionate, and culturally effective care. Several studies suggest that patients with asthma benefit from having a medical home. However, no national study has been conducted examining the relationships between having a medical home and asthma control in school-aged children with asthma. The purpose of this study was to examine the hypothesis that having an adequate medical home is protective against uncontrolled asthma in children. METHODS: To test this hypothesis, cross-sectional data from the 2003-2004 National Survey of Children's Health were analyzed. Analyses entailed creating the variables "medical home" as well as "uncontrolled asthma" from multiple variables. Multivariate analysis was performed using children with uncontrolled asthma as the dependent variable. RESULTS: The logistic regression model performed yielded that school-aged children with uncontrolled asthma were more likely to: speak a primary language other than English (OR, 1.069; 95% CI, 1.045 1.093); live in households with incomes<100% of the federal poverty level (FPL) (OR, 1.826; 95% CI, 1.810-1.842); not have health insurance (OR, 2.296; 95% CI, 2.263-2.330); live in rural rather than metropolitan areas (OR, 1.275; 95% CI, 1.262-1.287); and be non-Caucasian (OR, 2.067; 95% CI, 2.050-2.085). Multivariate analysis also yielded that children with uncontrolled asthma were more likely to have a medical home (OR, 1.138; 95% CI, 1.128-1.148). CONCLUSIONS: After controlling for possible confounding variables, this study did not detect an association between having a medical home and asthma control for children with asthma aged 5 to 17 years. Additional research should examine the relationship between variables, such as poverty, place of residence, health insurance status, and the medical home, not only in the instance of uncontrolled asthma, but for other childhood health conditions. PMID- 20203461 TI - Importance of early diagnosis in patients with irritable bowel syndrome. AB - Patients with irritable bowel syndrome (IBS) account for >$20 billion in direct and indirect costs annually, a large portion of which relates to making the diagnosis. The diagnosis of IBS is challenging because symptoms can vary between patients and overlap with those of other disorders. This review examines the current diagnostic approach in IBS and discusses new tools that may improve diagnostic confidence earlier in the process. The prevalence of organic disease among patients who meet symptom-based criteria for IBS (eg, Rome III) is generally low; therefore, in the absence of "alarm features," the probability for organic disease is very low. Increased public awareness of IBS symptoms and physician awareness of symptom-based criteria for IBS are needed to facilitate earlier diagnosis. Accumulating evidence suggests that fecal and/or serum biomarkers may be helpful in differentiating IBS from non-IBS disorders. These tools may help minimize unnecessary testing and diagnostic delays. As biomarkers are further studied and developed, they are likely to become an integral part of the diagnosis of IBS and reduce the potential for incorrect diagnosis and treatment delays. PMID- 20203462 TI - Impact of metformin-induced gastrointestinal symptoms on quality of life and adherence in patients with type 2 diabetes. AB - AIMS: Gastrointestinal (GI) symptoms are common in patients with type 2 diabetes mellitus (T2DM). This study assesses the impact of 1) metformin on GI symptoms and health-related quality of life (HRQoL) and 2) metformin-associated GI symptoms on medication adherence in patients with type 2 diabetes newly beginning therapy. METHODS: Patients with T2DM aged>or=18 years starting metformin from January to June 2007 who filled their prescriptions for >or=3 months were identified from a health benefits company database. Via telephone, GI symptom impact was evaluated in a 360-patient sample using the validated Bowel Symptom Questionnaire and Medical Outcomes Study 36-Item Short-Form Health (SF-36) survey. Adherence was assessed using the medication possession ratio (MPR). Logistic regression adjusting for demographic and clinical covariates was used to assess the relationship between GI symptoms and MPR<80%. RESULTS: The most and least common GI symptoms reported were diarrhea (62.1%) and retching (21.1%), respectively. Most GI symptoms were associated with lower physical and mental HRQoL (P<0.05). Most changes in specific HRQoL reached the minimum important difference of 3 points. Bloating, nausea, and abdominal pain were significantly associated with MPR<80%. Adjustment for demographic, clinical, and HRQoL factors made these relationships less evident. CONCLUSIONS: Metformin-associated GI symptoms in patients with T2DM lead to lower physical and mental HRQoL, which may result in patient nonadherence or physician reluctance to optimally titrate the metformin dose. PMID- 20203463 TI - Epidemiology, clinical manifestations, and recent advances in vaccination against human papillomavirus. AB - In October 2009, the Advisory Committee on Immunization Practices (ACIP) approved a newly licensed vaccine, Cervarix, directed against human papillomavirus (HPV) to prevent cervical cancer. The ACIP also expanded its recommendations against HPV by giving permission to physicians to vaccinate males aged 9 to 26 years with the previously licensed vaccine, Gardasil, to prevent genital warts, in addition to its previous recommendation for females aged 9 to 26 years to prevent cervical cancer and genital warts. The marketing, expense, safety, and reactivity of Gardasil continue to be the subject of controversy. Of the >100 types of HPVs, approximately 40 are sexually transmitted, and HPV is the most common sexually transmitted disease. By age 50 years, 80% of women will have contracted a sexually transmitted HPV infection. While most individuals are clear of infection by 2 years, some types of HPV carry a high risk for progressing to cancer, and HPV is identified in >99% of patients with cervical cancer. Each year in the United States approximately 12,000 women develop cervical cancer and nearly 4000 die of it. Human papillomavirus is also associated with genital warts and other anogenital cancers. The United States has now licensed 2 vaccines against HPV, Gardasil and Cervarix. Gardasil has been shown to be safe and effective in preventing HPV infections by types 6, 11, 16, and 18; types 16 and 18 are associated with 2 high-risk types of cervical cancer and are associated with 70% of all cervical cancers. Types 6 and 11 are associated with 90% of anogenital warts. Cervarix has also been shown to be safe and effective in preventing HPV infections by types 16 and 18, but offers no known protection against anogenital warts. PMID- 20203464 TI - Burden of community-acquired pneumonia in North American adults. AB - To determine the burden of community-acquired pneumonia (CAP) affecting adults in North America, a comprehensive literature review was conducted to examine the incidence, morbidity and mortality, etiology, antibiotic resistance, and economic impact of CAP in this population. In the United States, there were approximately 4.2 million ambulatory care visits for pneumonia in 2006. Pneumonia and influenza continue to be a common cause of death in the United States (ranked eighth) and Canada (ranked seventh). In 2005, there were >60,000 deaths due to pneumonia in persons aged>or=15 years in the United States alone. The hospitalization rate for all infectious diseases increased from 1525 hospitalizations per 100 000 persons in 1998 to 1667 per 100 000 persons in 2005. Admission to an intensive care unit was required in 10% to 20% of patients hospitalized with pneumonia. The mean length of stay for pneumonia was >or=5 days and the 30-day rehospitalization rate was as high as 20%. Mortality was highest for CAP patients who were hospitalized; the 30-day mortality rate was as high as 23%. All-cause mortality for CAP patients was as high as 28% within 1 year. Streptococcus pneumoniae continues to be the most frequently identified pathogen associated with CAP, and pneumococcal resistance to antimicrobials may make treatment more difficult. The economic burden associated with CAP remains substantial at >$17 billion annually in the United States. Despite the availability and widespread adherence to recommended treatment guidelines, CAP continues to present a significant burden in adults. Furthermore, given the aging population in North America, clinicians can expect to encounter an increasing number of adult patients with CAP. Given the significance of the disease burden, the potential benefit of pneumococcal vaccination in adults is substantial. PMID- 20203465 TI - Case report: acute renal failure after administering intravenous immunoglobulin. AB - We report the case of an 87-year-old white woman with myasthenia gravis who presented with nausea, shortness of breath, azotemia, and hyperkalemia shortly after completing a course of intravenous immunoglobulin (IVIG). She had been receiving monthly transfusions of IVIG, but this time had received daily infusions for 5 days rather than 1 day. She had received this same dose in the past without incident. Her history was significant for coronary artery disease, atrial fibrillation, deep venous thrombosis, pulmonary embolism, chronic steroid use, and recurrent urinary tract infection. On examination, she was slightly confused, mildly dehydrated, had a grade II systolic ejection murmur along the upper left sternal border, had bilateral and symmetric mild weakness of the upper and lower extremities, and exhibited mild edema of the lower extremities. Before transfer from the emergency room, she was found to have an elevated serum urea nitrogen and creatinine of 55 and 5.8 mg/dL (19.6 mmol/L and 512.7 micromol/L, respectively). Creatinine 8 days earlier was 0.9 mg/dL (79.6 micromol/L). The hospital course of the acute renal failure is presented with a review of the literature on cases of acute renal failure after IVIG. PMID- 20203466 TI - Clinical evaluation and treatment of chronic urticaria. AB - Chronic urticaria is a common disease characterized by recurrent pruritic wheals with surrounding erythema for >6 weeks. It is associated with a significant health care burden and affects patient quality of life. The etiology of chronic urticaria is often difficult to elucidate; however, known etiologies include autoimmune urticaria, physical urticarias (eg, cold, cholinergic, and delayed pressure urticaria), and idiopathic urticaria. The etiology is unknown in many patients, leading to a diagnosis of chronic idiopathic urticaria. The diagnosis of chronic idiopathic urticaria can be challenging for the primary care physician because of the disease's chronic symptoms. Diagnosis requires a detailed patient history and comprehensive physical examination, with additional testing tailored to the patient's history. Effective treatments include antihistamines, leukotriene receptor antagonists in combination with antihistamines, and oral immunomodulatory drugs, including corticosteroids, cyclosporine, dapsone, hydroxychloroquine, and sulfasalazine. Newer experimental therapies include intravenous immunoglobulin and omalizumab. This article reviews the pathophysiology, diagnosis, and treatment of chronic urticaria. PMID- 20203467 TI - Diagnosing and treating gout: a review to aid primary care physicians. AB - Generalist physicians, specifically general internists and primary care physicians, are often the first to see patients with gout and therefore play a critical role in the diagnosis and management of these patients. The aim of this review is to aid generalist physicians in diagnosing and treating gout. A case report example is presented to highlight some of the problems in diagnosing and treating gout. Practical practice points are also highlighted. PMID- 20203468 TI - Puzzles in practice. Case report. A 62-year-old black woman with known Graves' disease. Diagnosis: Graves' dermopathy (elephantiasic type) and Graves' acropachy. PMID- 20203469 TI - Review of the AMADEO study: reducing proteinuria in patients with diabetic nephropathy with telmisartan versus losartan. Commentary. PMID- 20203470 TI - Use of rosuvastatin in preventing vascular events in patients with elevated C reactive protein. Commentary. PMID- 20203471 TI - Postnatal development of arteriovenous malformations. Concerning the article by Drs Jefree and Stoodley, Pediatr Neurosurg 2009;45:296-304. PMID- 20203472 TI - Clinical features and treatment outcomes of vitiligo from the patients' perspective: results of a national survey in Germany. AB - BACKGROUND: Vitiligo causes substantial disease burden and patient needs still remain underestimated. OBJECTIVE: To assess the clinical features, treatment outcomes and satisfaction in patients with vitiligo. METHODS: A nationwide, cross sectional German postal survey was conducted. Clinical features and treatment outcomes of vitiligo (affected body surface, comorbidities, treatments applied, patient benefit index [PBI]) were evaluated using a standardized patient questionnaire. RESULTS: 1,023 patients (71.4% women, mean age 44.4 years) completed the questionnaire. The average onset of disease was at 24.1 years, and the mean disease duration was 20.3 years. The mean number of body sites affected was 6.9, and the mean affected body surface area was 14.9%. On average, 3.7 therapies had been applied previously, with a total PBI of 1.03 +/- 1.12. Only 38.7% experienced a PBI >1, which indicates a minimal patient benefit. CONCLUSIONS: Most therapeutic options are considered to be of low patient benefit. There is a need for more beneficial treatments and improved care in patients with vitiligo. PMID- 20203473 TI - Splice site mutations in the P-cadherin gene underlie hypotrichosis with juvenile macular dystrophy. AB - BACKGROUND: Hypotrichosis with juvenile macular dystrophy (HJMD; OMIM 601553) is a rare autosomal recessive disorder characterized by hypotrichosis with short scalp hair and progressive macular dystrophy leading to blindness between the second and the fourth decades of life. HJMD is caused by mutations in the P cadherin gene (CDH3), a member of the family of classical cadherins. METHODS: We analyzed the DNA from members of 2 consanguineous Pakistani families with HJMD for mutations in the P-cadherin gene through direct sequencing. RESULTS: We identified 2 splice site mutations in the P-cadherin gene in these families. One was a novel mutation, Ivs12-2A-->G and the other a recurrent mutation, Ivs10-1G- >T. A screening assay for the novel mutation ruled out the possibility of a polymorphism. Using haplotype analysis, we determined that the mutation, Ivs10-1G ->T, is a founder mutation in the Pakistani population. CONCLUSION: We identified 2 splice site mutations in the CDH3 gene leading to HJMD, further enriching our understanding of HJMD versus ectodermal dysplasia, ectrodactyly and macular dystrophy syndrome. PMID- 20203474 TI - Variability in sex-determining mechanisms influences genome complexity in reptilia. AB - In this review, we describe the history of amniote sex determination as a classic example of Darwinian evolution. We suggest that evolutionary changes in sex determination provide a foundation for understanding important aspects of chromosome and genome organization that otherwise appear haphazard in their origins and contents. Species with genotypic sex determination often possess heteromorphic sex chromosomes, whereas species with environmental sex determination lack them. Through a series of mutations followed by selection at key genes, sex-determining mechanisms have turned over many times throughout the amniote lineage. As a consequence, amniote genomes have undergone gains or losses of sex chromosomes. We review the genomic and ecological contexts in which either temperature-dependent or genotypic sex determination has evolved. Once genotypic sex determination emerges in a lineage, viviparity and heteromorphic sex chromosomes become more likely to evolve. For example, in extinct marine reptiles, genotypic sex determination apparently led to viviparity, which in turn facilitated their pelagic radiation. Sex chromosomes comprise genome regions that differ from autosomes in recombination rate, mutation rate, levels of polymorphism, and the presence of sex-determining and sexually antagonistic genes. In short, many aspects of amniote genome complexity, life history, and adaptive radiation appear contingent on evolutionary changes in sex-determining mechanisms. PMID- 20203475 TI - Chromosome evolution and diversification in North American spiny lizards (genus Sceloporus). AB - The genus Sceloporus is a diverse clade of lizards that exhibits substantial variation in chromosome numbers and sex chromosome heteromorphisms, 2 features of the genome that are static among most other pleurodont iguanian lizards. Evolutionary changes to the fundamental number of chromosomes are hypothesized to be a primary factor responsible for driving the diversification of Sceloporus. We explore the patterns of chromosome evolution in Sceloporus using a combination of ancestral state estimations and species diversification tests. Phylogenetic relationships and divergence times within Sceloporus (53 species representing all 19 species groups) are estimated using 4 nuclear genes (>3.3 kb) and relaxed clock analyses that incorporate a fossil calibration on the root of the tree. We test the hypothesis that chromosome evolution is correlated with shifts in species diversification using cross-validation predictive densities, a new Bayesian approach for modeling the number of species that are predicted to have evolved in the absence of a certain historical event (e.g., a change in chromosome numbers). Results of the cross-validation predictive densities approach indicate that chromosomal evolution is correlated with significantly higher species diversity than predicted under the background rate of diversification in Sceloporus. We conclude by discussing the future of comparative cytogenetic investigations in Sceloporus. PMID- 20203476 TI - Standardized reference ideogram for physical mapping in the saltwater crocodile (Crocodylus porosus). AB - Basic cytogenetic data, such as diploid number and general chromosome morphology, are available for many reptilian species. Here we present a detailed cytogenetic examination of the saltwater crocodile (Crocodylus porosus) karyotype, including the creation of the first fully annotated G-band standard ideogram for any crocodilian species. The C. porosus karyotype contains macrochromosomes and has a diploid number of 34. This study presents a detailed description of each chromosome, permitting unambiguous chromosome identification. The fully annotated standardized C. porosus ideogram provides the backbone to a standard nomenclature system which can be used to accurately identify specific band locations. Seven microsatellite containing fosmid clones were fluorescently labeled and used as fluorescent in situ hybridization (FISH) probes for physical localization. Chromosome locations for each of these FISH probes were successfully assigned, demonstrating the utility of the fully annotated ideogram for genome mapping. PMID- 20203477 TI - Understandings of basic genetics in the United States: results from a national survey of black and white men and women. AB - AIM: This study examined understandings of basic genetic concepts among Americans. METHOD: In a national telephone survey of 1,200 Americans with equal representation among Black and White men and women, subjects responded to 8 items developed by a multidisciplinary team of experts that assessed understanding of basic concepts in multiple domains, including inheritance, genetics and race, and genetics and behavior. RESULTS: Over 70% of subjects responded correctly on items about the genetic similarity of identical twins and siblings. Less than half of subjects responded correctly on all other items. Understanding of genetics was lowest in three areas: types/locations of genes in the body (29% correct), a genetic basis for race (25% correct), and the influence of single genes on behaviors (24% correct). Logistic regression models controlling for age and education showed some differences by race and gender on specific items but also showed that understandings are generally similar across these groups. CONCLUSION: Misunderstandings about genetics are common among Black and White American men and women. Responses appear to reflect personal experiences, group values and interests. These findings emphasize the need for initiatives to improve the public's genetic literacy as well as a need for further investigation in this domain. PMID- 20203478 TI - Cetacean brain evolution: Dwarf sperm whale (Kogia sima) and common dolphin (Delphinus delphis) - An investigation with high-resolution 3D MRI. AB - This study compares a whole brain of the dwarf sperm whale (Kogia sima) with that of a common dolphin (Delphinus delphis) using high-resolution magnetic resonance imaging (MRI). The Kogia brain was scanned with a Siemens Trio Magnetic Resonance scanner in the three main planes. As in the common dolphin and other marine odontocetes, the brain of the dwarf sperm whale is large, with the telencephalic hemispheres remarkably dominating the brain stem. The neocortex is voluminous and the cortical grey matter thin but expansive and densely convoluted. The corpus callosum is thin and the anterior commissure hard to detect whereas the posterior commissure is well-developed. There is consistency as to the lack of telencephalic structures (olfactory bulb and peduncle, olfactory ventricular recess) and neither an occipital lobe of the telencephalic hemisphere nor the posterior horn of the lateral ventricle are present. A pineal organ could not be detected in Kogia. Both species show a tiny hippocampus and thin fornix and the mammillary body is very small whereas other structures of the limbic system are well-developed. The brain stem is thick and underlies a large cerebellum, both of which, however, are smaller in Kogia. The vestibular system is markedly reduced with the exception of the lateral (Deiters') nucleus. The visual system, although well-developed in both species, is exceeded by the impressive absolute and relative size of the auditory system. The brainstem and cerebellum comprise a series of structures (elliptic nucleus, medial accessory inferior olive, paraflocculus and posterior interpositus nucleus) showing characteristic odontocete dimensions and size correlations. All these structures seem to serve the auditory system with respect to echolocation, communication, and navigation. PMID- 20203479 TI - Genetic screening in Europe. AB - Genetic screening has been defined as any kind of test performed systematically for the early detection or exclusion of a genetic disease, genetic predisposition or resistance to a disease, or to determine whether a person carries a gene variant that may produce disease in his or her offspring. In comparison to 'genetic testing', the term 'genetic screening' should be reserved for the explicit and systematic application of a diagnostic genetic test across a whole population of asymptomatic people (population screening) or a subset of a population such as pregnant women (prenatal/antenatal screening) or newborn infants (neonatal screening). This survey intends to present the current (2006 2008) status of genetic screening and the organization of genetic screening programmes in selected European countries as a background for future attempts to harmonize standards and procedures of genetic screening, an explicit aim of the European Network of Excellence, EuroGentest (www.eurogentest.org). Our report builds on the first comprehensive assessment of genetic screening programmes in Germany by the European Society of Human Genetics, starting with a workshop of experts in 1999, the production of background documentation in 2000, and a final report in 2003. PMID- 20203480 TI - Circulating very-low-density lipoprotein characteristics resulting from fatty liver in an insulin resistance rat model. AB - The close association between nonalcoholic fatty liver and insulin resistance is now widely recognized. While the former is characterized by excessive intrahepatic triglyceride accumulation, the latter induces overproduction of very low-density lipoprotein (VLDL) particles. It has not been well elucidated whether these apparently opposite mechanisms impact on VLDL characteristics or not. The aim of the present study was to evaluate the VLDL secretion and features resulting from insulin resistance and fatty liver in rats fed a sucrose-rich diet (SRD, i.e. addition of sucrose to drinking water during 12 weeks). No differences in calorie intake were observed in comparison to controls. Both groups showed similar weight gains throughout the treatment period. However, SRD rats showed an increased proportion of body fat as assessed by X-ray absorptiometry, increased visceral obesity, liver weight and fat accumulation in the liver (p < 0.04). Histological study revealed moderate micro- and macrovesicular steatosis. Fasting insulin, triglyceride and free fatty acid (FFA) levels increased while VLDLs decreased in SRD rats (p < 0.05). The chemical composition of VLDLs of SRD rats showed a higher percentage of triglycerides, and the VLDL triglyceride/protein ratio, an estimator of lipoprotein size, suggests that VLDL particles of SRD rats are larger than those of controls (p < 0.0005). FFA levels correlated with VLDL triglycerides (r = 0.49, p = 0.03) and liver fat content correlated with plasma triglycerides (r = 0.65), VLDL triglycerides (r = 0.55) and triglyceride/protein ratio (r = 0.52, p < 0.02). The VLDL secretion rate assay showed an increase in SRD rats (p < 0.02), confirming an overproduction despite liver fat accumulation. Our findings are consistent with an insulin resistance development model in which hepatic lipid content would constitute an important determinant of a triglyceride rich, large-particle VLDL secretion; both features would increase its atherogenic potential. PMID- 20203481 TI - Depth of electrode insertion and postoperative performance in humans with cochlear implants: a histopathologic study. AB - The depth of electrode insertion of a multichannel cochlear implant has been suggested as a clinical variable that may correlate with word recognition using the implant. The current study evaluates this relationship using the human temporal bone collection at the Massachusetts Eye and Ear Infirmary. Twenty-seven temporal bones of subjects with cochlear implants were studied. Temporal bones were removed at autopsy, fixed and prepared for histological study by standard techniques. Specimens were then serially sectioned, and reconstructed by two dimensional methods. Three measures of length were made from each subject's reconstruction: (1) depth of insertion (DI) of the cochlear implant electrode array, from the round window to the array's apical tip; (2) inserted length (IL) from the cochleostomy to the apical tip of the array, and (3) cochlear duct length (CDL) from the round window to the helicotrema. The active electrode length (AEL) was defined as the distance between the most apical and most basal electrodes of the array. Stepwise regression was used to identify whether subsets of six metrics associated with insertion depth (DI, DI/AEL, DI/CDL, IL, IL/AEL and IL/CDL), duration of deafness, sound-processing strategy, potential for central impairment and age at implantation accounted for significant across subject variance in the last recorded NU-6 word score measured during each subject's life. Age at implantation and potential for central impairment account for significant percentages of the across-subject variance in NU-6 word scores for the 27 subjects studied. None of the insertion metrics accounted for significant performance variance, even when the variance associated with the other variables was controlled. These results, together with those of previous studies, are consistent with a relatively weak association between electrode insertion depth and speech reception. PMID- 20203482 TI - A new model for utricular function testing using a sinusoidal translation profile during unilateral centrifugation. AB - The utricle plays an important role in orientation with respect to gravity. The unilateral centrifugation test allows a side-by-side investigation of both utricles. During this test, the subject is rotated about an earth-vertical axis at high rotation speeds (e.g. 400 degrees /s) and translated along an interaural axis to consecutively align the axis of rotation with the left and the right utricle. A simple sinusoidal translation profile (0.013 Hz; amplitude = 4 cm) was chosen. The combined rotation and translation induces ocular counter rolling (OCR), which is measured using 3-D video-oculography. This OCR is the sum of the reflexes generated by both the semicircular canals and the utricles. In this paper, we present a new physiological model that decomposes this total OCR into a canal and a utricular contribution, modelled by a second-order transfer function and a combination of 2 sine functions, respectively. This model yields parameters such as canal gain, cupular and adaptation time constants and a velocity storage component for the canals. Utricular gain, bias, phase and the asymmetry between the left and the right utricle are characteristic parameters generated by the model for the utricles. The model is presented along with the results of 10 healthy subjects and 2 patients with a unilateral vestibular loss due to acoustic neuroma surgery to illustrate the effectiveness of the model. PMID- 20203483 TI - Predicting cognitive dysfunctioning in nondemented patients early after stroke. AB - BACKGROUND: Cognitive dysfunctioning (CDF) is an important issue in stroke, interfering with recovery and social dysfunctioning. We aimed to investigate the clinical and imaging correlates of CDF in patients with a first-ever subacute ischemic stroke and no dementia. METHODS: We evaluated CDF 15 days after stroke in a prospective cohort of consecutive patients with a Mini Mental State Examination score > or =23 using a comprehensive neuropsychological battery. CDF was ranked into 3 categories according to Z scores calculated for each test and adjusted for age and education. CDF was analyzed in relation to stroke features. Imaging was assessed using MRI. An ordinal regression procedure was used to determine the clinical correlates of CDF and to compute probabilities. RESULTS: Cognitive evaluation was achieved in 177 consecutive patients (age 50.0 +/- 16.0 years). In bivariate analysis, CDF was associated with age, low level of education, depression, neurological deficit at day 15, stroke subtype, arterial territory and leukoaraiosis but not with stroke volume or location. The predictors of CDF were NIHSS score at day 15 (OR = 1.35; 95% CI = 1.05-1.73), middle cerebral artery infarct (OR = 2.96; 95% CI = 1.30-6.73), depression interacting with left stroke side (OR = 1.09; 95% CI = 1.03-1.15), and female gender interacting with high level of education (OR = 0.209; 95% CI = 0.085 0.514). CONCLUSIONS: Stroke features correlate with CDF in nondemented patients. These simple criteria may help to predict CDF at bedside in the subacute phase after stroke and to recommend a neuropsychological evaluation for patients' management. Modeling CDF soon after stroke using simple neurological criteria may be a useful tool for designing clinical trials. PMID- 20203484 TI - The significance of microembolic signals and new cerebral infarcts on the progression of neurological deficit in acute stroke patients with large artery stenosis. AB - BACKGROUND: Early neurological deterioration is common in the acute phase after stroke. We sought to investigate the correlation between the progression of microembolic signal (MES), ischemic infarcts and the neurological deficits in the acute phase of stroke patients with large artery occlusive disease. METHODS: Transient ischemic attack or stroke patients with relevant significant large artery stenosis (> or =50% diameter reduction) and admitted within 7 days of the symptom onset were recruited in this study. MES, infarcts on diffusion-weighted imaging and National Institutes of Health Stroke Scale (NIHSS) score were assessed on days 1 and 7 of recruitment. RESULTS: Among 67 patients, 50.7% (34 of 67) had MES on day 1. Presence of MES correlated with both a higher number of infarcts (p = 0.006) and the incidence of multiple infarcts (chi(2) test, p = 0.002), but not with the NIHSS score. On day 7, MES was detected in 25.4% of the patients (17 of 67), 11.8% of them (2 of 17) displayed new or extended infarct on DWI (p = 0.14) and 29.4% (5 of 17) showed neurological improvement (p = 0.039). Among the patients with positive MES at baseline, NIHSS reduction was positively correlated with disappearance of MES on day 7 (MES disappearance vs. persistence group, 2.05 vs. 0.73, p = 0.023). CONCLUSIONS: Neither the disappearance of MES nor the changes in NIHSS score correlated with the progression of infarct. Disappearance of MES indicated better neurological improvement in the acute phase. PMID- 20203485 TI - Influence of recanalization on uric acid patterns in acute ischemic stroke. AB - BACKGROUND: Most epidemiological studies have reported a significant association between elevated serum levels of uric acid (UA) and increased cardiovascular disease. On the other hand, UA is the most abundant antioxidant in the human body. We hypothesized that UA levels would change noticeably in association with the degree of oxidative stress in acute ischemic stroke. METHODS: We analyzed consecutive patients with acute ischemic stroke in the anterior circulation system within 24 h of symptom onset, confirmed by diffusion-weighted imaging (DWI), and with a modified NIH Stroke Scale (mNIHSS) score of 5 or greater. Baseline demographics, serial clinical scores, serial UA and allantoin (a nonenzymatic metabolite of UA) levels, UA change (baseline UA - UA at 48 h), and DWI lesion volumes were compared between 45 patients with recanalized vessels (RV) and 43 patients with nonrecanalized vessels (NV) in follow-up imaging. RESULTS: The RV (vs. NV) patients were more likely to receive thrombolytic treatment (p = 0.005), achieve a reduction in day-14-mNIHSS scores (p = 0.001), and greater changes in UA (p = 0.024) and allantoin levels (p = 0.003). The UA levels dropped at 48 h and gradually increased in a U-shaped pattern. UA change (r = 0.360; p = 0.001) rather than baseline UA (r = 0.044; p = 0.681) was significantly correlated with infarct volume. In the RV (vs. NV) patients, there was a stronger association between infarct volume and UA change (r = 0.483; p = 0.001) or allantoin levels (r = 0.466; p = 0.017). CONCLUSION: Our results suggest that UA might be a consumptive and reproducible antioxidant in acute ischemic stroke, and this pattern appears to be influenced by recanalization success and infarct volume size. PMID- 20203486 TI - Cerebral venous thrombosis with nonhemorrhagic lesions: clinical correlates and prognosis. AB - BACKGROUND AND PURPOSE: Brain imaging of patients with acute cerebral venous thrombosis often shows parenchymal hemorrhagic and nonhemorrhagic lesions. The clinical relevance of nonhemorrhagic lesions is poorly known. METHOD: In the International Study on Cerebral Vein and Dural Sinus Thrombosis cohort, demographic, clinical, risk factor, prognosis and imaging findings were compared between patients with parenchymal nonhemorrhagic lesions and no hemorrhagic lesions (NHL) and (1) patients with parenchymal hemorrhagic lesions (HL) and (2) patients without brain lesions. Predictors of prognosis at the end of follow-up in the NHL group were analyzed by bivariate and Cox regression methods. RESULTS: We identified 147 patients (23.6%) with NHL. When compared to patients without brain lesions (n = 309), those with NHL more often presented mental status disturbances, aphasia, decreased alertness, motor deficits, seizures, occlusions of the straight sinus, deep venous system and cortical veins. Patients with NHL had a better prognosis in the acute phase and at the end of follow-up than those with HL, but a worse one than patients without brain lesions, as more NHL patients were dead or dependent (modified Rankin Scale score = 3-6) at discharge (19.7 vs. 6.5%, p < 0.001) and final follow-up (14.3 vs. 7.4%, p = 0.03). In Cox regression analysis, coma (HR = 13.7; 95% CI = 4.3-43.7) and thrombosis of the deep venous system (HR = 3.5; 95% CI = 1.4-8.7) were associated with death or dependency at the end of follow-up. CONCLUSION: Cerebral venous thrombosis patients with NHL are intermediate between patients without brain lesions and those with HL, both in initial clinical picture and prognosis. PMID- 20203487 TI - Enlargement of acute intracerebral hematomas in patients on long-term warfarin treatment. AB - BACKGROUND: The relationship between warfarin administration and the frequent development of enlarged hematomas in patients with acute intracerebral hemorrhage (ICH) is controversial. The present study was carried out to examine this issue. METHODS: This study reviewed 41 patients with nontraumatic ICH within 24 h after stroke onset from 1999 to 2003 who received long-term warfarin treatment (29 men and 12 women, 70 +/- 12 years old) and 323 patients who had not been on warfarin (177 men and 146 women, 66 +/- 13 years old). The hematoma volume (HV) on admission, final HV, frequency of hematoma enlargement (HE) and other background characteristics were investigated. RESULTS: Both the HV on admission (p = 0.031) and final HV (p = 0.001) were larger in patients on warfarin than in those not receiving warfarin. HE occurred more frequently (p < 0.001), and mortality at 30 days or at discharge was higher (p = 0.003) in the warfarin group than in the control group. A multivariate adjusted logistic regression analysis showed that warfarin treatment (OR = 5.75, 95% CI = 2.41-13.8, p < 0.001), liver disease (OR = 2.59, 95% CI = 1.12-5.99, p = 0.026), and the National Institutes of Health Stroke Scale score (OR = 1.10, 95% CI = 1.04-1.15, p < 0.001, per 1-score increase) on admission were independently related to HE. CONCLUSIONS: Acute ICH in patients on long-term warfarin treatment appears to be associated with HE. PMID- 20203488 TI - The C677T polymorphism of the methylenetetrahydrofolate reductase gene is associated with idiopathic ischemic stroke in the young Mexican-Mestizo population. AB - BACKGROUND AND PURPOSE: Previous studies have demonstrated that a common polymorphism in the gene encoding 5,10-methylenetetrahydrofolate reductase (MTHFR) is associated with an increased risk for stroke. However, this relation remains controversial. Our aim was to investigate the possible association between the C677T polymorphism in the MTHFR gene and idiopathic ischemic stroke in the young Mexican-Mestizo population. METHODS: One hundred seventy-eight patients <45 years with idiopathic ischemic stroke and 183 controls were tested for the C677T polymorphism in the MTHFR gene. Causes of primary thrombophilia as well as classical risk factors for atherothrombotic disease were also evaluated. RESULTS: There was a significant difference in the genotype distribution between patients and controls (p = 0.01), but the allele frequency was similar in both groups (p = 0.09). The univariate analysis identified the T allele as a risk factor for ischemic stroke (TT and CT carriers), as compared with homozygous for C allele (p = 0.01). Hypertension and smoking prevalences were significantly higher in the group of patients. Also the T allele was significantly associated with large-vessel ischemic stroke. The postoral methionine load homocysteine levels were higher in patients with ischemic stroke versus controls (p < 0.001). There was a low prevalence of primary thrombophilia markers. CONCLUSIONS: The T allele from the C677T polymorphism of the MTHFR gene represents an independent risk factor for idiopathic ischemic stroke at young age in the Mexican-Mestizo population. Also, hypertension and smoking were independent risk factors in our study population. Primary thrombophilic risk factors were not associated with ischemic stroke in our population. PMID- 20203489 TI - Characteristics of plasmid-mediated quinolone resistance genes in extended spectrum cephalosporin-resistant isolates of Klebsiella pneumoniae and Escherichia coli in Korea. AB - BACKGROUND: Quinolone resistance is frequently associated with extended-spectrum cephalosporin resistance in Enterobacteriaceae. METHODS: The characteristics of plasmid-mediated quinolone resistance (PMQR) genes [qnr genes, aac(6')-Ib-cr and qepA] in clinical isolates of Klebsiella pneumoniae and Escherichia coli resistant to extended-spectrum cephalosporin were studied. RESULTS: 5 and 4 of 95 E. coli isolates but 46 (86/187) and 6% (12/187) of K. pneumoniae had qnr and aac(6')-Ib-cr, respectively, and 8 K. pneumoniae contained both genes.qepA was not identified. qnrB, especially qnrB4, was the predominant qnr subtype in K. pneumoniae [94 (88 qnrB of 94 qnr) and 88% (77 qnrB4 of 88 qnrB), respectively], and presence of qnrB4 was closely related with DHA-1 beta-lactamase (99%). However, K. pneumoniae isolates with qnrB4 and bla(DHA-1) were clonally diverse. beta-Lactamases produced by PMQR-containing isolates were variable: CMY-1, CTX-M 14, CTX-M-15, DHA-1, OXA type, SHV-2a, and SHV-12. CONCLUSION: PMQR genes are widely distributed among clinical isolates of K. pneumoniae, and qnrB4 associated with bla(DHA-1) was the most common PMQR gene in Korea. PMID- 20203490 TI - IBD and IBS: novel mechanisms and future practice. Preface. PMID- 20203491 TI - Visceral versus somatic pain: similarities and differences. AB - Inflammatory bowel disease and the irritable bowel syndrome are conditions characterized by chronic pain that generates persistent, hyperalgesic states in many regions of the body. It is difficult to explain the pain of conditions such as inflammatory bowel disease and irritable bowel syndrome by extrapolating directly from what is known about the mechanisms of somatic pain. Visceral and somatic pain show many differences not only in the psychophysics of the sensation, but also in the neurobiological mechanisms that mediate the sensory process. The activation and sensitization of visceral nociceptors are heavily influenced by the secretory and motor properties of the microenvironment where the sensory receptors are located. In some cases, epithelial cells can play a direct role in the activation of primary sensory neurons. Subclinical alterations of the epithelium can contribute to enhanced visceral sensitivity. Central hypersensitivity induced by visceral activation also shows differences with its somatic counterpart. Mobilization of AMPA receptors from the cytosol to the membrane of nociceptive neurons has been identified as a mechanism of sensitization of visceral pain pathways. Finally, functional pain syndromes, such as irritable bowel syndrome could be triggered or maintained by hormonal alterations, particularly those involving sex hormones such as estrogen. PMID- 20203492 TI - Inflammation and hypersensitivity in the context of the sensory functions of axonal membranes: what are the molecular mechanisms? AB - BACKGROUND: The axonal membrane of unmyelinated sensory nerve fibers is well equipped with different molecular transducer molecules that establish specific sensitivities, the capacity for sensitization by inflammation and generation of ectopic action potentials that contribute to spinal sensitization, leading to projected pain, allodynia and hyperalgesia. METHODS: We studied the sensory properties of unmyelinated axons in the midnerve by measuring stimulated neuropeptide release, recording from primary afferents and eliciting projected pain by stimulation of a surgically exposed superficial radial nerve in a conscious human subject. RESULTS: Capsaicin (TRPV1) receptor channels are expressed along the axonal membrane and respond to acidic, thermal and capsaicin stimulation with a graded and calcium-dependent calcitonin gene-related peptide release. These responses can be facilitated by bradykinin or prostaglandin, indicating functional BK and EP receptors along the axonal membrane. Sensitizing effects are lost in preparations from TRPV1 knockout mice. In the isolated vagus nerve, representing visceral innervation, the endovanilloid/endocannabinoid anandamide induced or sensitized calcitonin gene-related peptide release by activation of TRPV1. Our electrophysiological recordings revealed ectopic generation of action potentials. Intact unmyelinated axons showed sensory capacities that resembled those of their individual cutaneous nociceptive terminals, with respect to noxious heat sensitivity. In the human subject, noxious heat stimulation of the exposed skin nerve evoked intense burning pain sensation in the innervation territory. CONCLUSION: Different lines of evidence indicate that nociceptive axons exhibit essential parts of the signal transduction and spike generation machinery. When amplified (e.g. by inflammatory mediators), this axonal sensitivity may become a source of neuropathic pain. PMID- 20203493 TI - The role of emotion in determining pain. AB - One of the perplexing features of pain is the wide variety in patients' responses to ostensibly the same extent of physical pathology. One reason for this is that emotional states (feelings) and thoughts (cognitions) mediate our pain perception. Furthermore, it has been shown that maintenance of pain and disability as well as response to treatment is related to a number of factors such as self-efficacy beliefs and fear avoidance. Indeed, it has been shown that these pain-related beliefs are more important determinants of disability and functioning in some disorders than pain intensity or duration. This chapter attempts to outline the role of predisposing, precipitating and maintaining factors in patients with chronic pain. The importance of a multi-dimensional assessment of patients with pain that takes into account factors such as specific feelings (emotions), thoughts (cognitions), pain behaviours and pain-coping strategies is emphasised. The key role in certain patients of 'catastrophising', as well as causal beliefs and attributions on pain outcomes and disability, will be outlined. It is useful to adopt a 'stepped care' approach to treatment. Most patients with irritable bowel syndrome will respond to reassurance, whereas those with more enduring and/or difficult to manage symptoms may require treatments of a different type and level of complexity. This may include antidepressant drug treatment or, in certain situations, cognitive behavioural treatment. It is quite acceptable to adopt more than one treatment approach concurrently. Antidepressant treatment has also been shown to be effective in concert with psychological treatments and to lead to improved quality of life. PMID- 20203495 TI - Pharmacology of visceral pain: central factors. AB - Clinically, pain can be sub-classified into superficial, neuropathic and deep pain. Deep pain as a result of stimulation to structures such as the viscera is the most poorly understood and notoriously difficult to treat. The dorsal horn of the spinal cord is the gateway to conscious nociception and it is at this point in the pain processing pathway that the peripheral afferent input can be enhanced or inhibited by several mechanisms, the most important being central sensitisation. Long-term potentiation, another mechanism, can also be elicited in the spinal cord. Here nociceptor activity and/or peripheral tissue inflammation produces long-term changes in synaptic efficacy in the dorsal horns. This plays a major role in the generation of acute post-operative and post-traumatic pain, migraine and neuropathic pain. Behavioural consequences of central sensitisation can even be readily detected in human psychophysical experiments. Another important mechanism is 'wind-up', a form of homosynaptic activity-dependent plasticity characterised by a progressive increase in action potential output from dorsal horn neurones. There is an extensive body of literature which has highlighted the importance of central sensitisation. This review examines some of the most significant recent findings with regards to future pharmacology. As we are beginning to understand some of the mechanisms of central sensitisation and its importance in visceral pain, novel receptor sites have been identified, offering exciting possibilities with regards to future pharmacological development not only to visceral pain, but for pain management as a whole. PMID- 20203494 TI - Pharmacology of inflammatory pain: local alteration in receptors and mediators. AB - BACKGROUND: Inflammation is commonly associated with hyperalgesia. Ideally, this change should abate once inflammation is resolved, but this is not necessarily the case because phenotypic changes in the tissue can persist, as appears to be the case in post-infectious irritable bowel syndrome. Basically, all primary afferent neurons supplying the gut can be sensitized in response to pro inflammatory mediators, and the mechanisms whereby hypersensitivity is initiated and maintained are, thus, of prime therapeutic interest. EXPERIMENTAL AND CLINICAL FINDINGS: There is a multitude of molecular nocisensors that can be responsible for the hypersensitivity of afferent neurons. These entities include: (i) receptors and sensors at the peripheral terminals of afferent neurons that are relevant to stimulus transduction, (ii) ion channels that govern the excitability and conduction properties of afferent neurons, and (iii) transmitters and transmitter receptors that mediate communication between primary afferents and second-order neurons in the spinal cord and brainstem. Persistent increases in the sensory gain may result from changes in the expression of transmitters, receptors or ion channels; changes in the subunit composition and biophysical properties of receptors and ion channels; or changes in the structure, connectivity and survival of afferent neurons. Particular therapeutic potential is attributed to targets that are selectively expressed by afferent neurons and whose number and function are altered in abdominal hypersensitivity. CONCLUSION: Emerging targets of therapeutic relevance include distinct members of the transient receptor potential (TRP) channel family (TRPV1, TRPV4, TRPA1), acid sensing ion channels, protease-activated receptors, corticotropin-releasing factor receptors and sensory neuron-specific sodium channels. PMID- 20203496 TI - Inflammation, peptides and biological therapy. AB - Inflammatory bowel diseases are characterized by chronic relapsing inflammations of the gastrointestinal tract that are not caused by specific pathogens. Although the precise aetiology of inflammatory bowel diseases remains unclear, considerable progress has been made in the identification of critical cytokine mediated signalling pathways in the inflammatory process. It could be shown that these pathways induce augmented intestinal T cell resistance against apoptosis, which is a pivotal process in disease pathogenesis. These findings have facilitated our understanding of the disease and the development of new therapies, which aim at restoring mucosal T cell homeostasis based on a sound pathophysiological rationale. This development is best exemplified by the emergence of anti-tumour necrosis factor antibody therapy. The advent of other biological therapies, such as the anti-IL-6R antibody, offers hope for new strategies that may result in more effective and less toxic therapy. PMID- 20203497 TI - Overlap between irritable bowel syndrome and inflammatory bowel disease. AB - While recent studies have indicated that the colonic mucosa in irritable bowel syndrome (IBS) shows an increase in inflammatory cells, this 'inflammation' is quantitatively less than in inflammatory bowel disease (IBD) and of a different nature with a predominance of mast cells, particularly in female patients. Inflammation can arise via numerous pathways including infection, stress, food allergy and changes in gut microbiota. Low-grade mucosal inflammation throughout the colon and including the terminal ileum can be seen for many months after an attack of acute gastroenteritis and is a feature of post-infective IBS. Measurements of gut permeability also show a prolonged increase in both the small and large bowel in both post-infective IBS and IBS with diarrhoea predominance. This has been linked to visceral hypersensitivity, but whether this is causal or an epiphenomenon remains uncertain. Studying the risk factors for post-infective IBS has shown the importance of both local and microbiological factors, as well as psychological factors, including adverse life events, anxiety and depression. Stress in both animals and humans can activate mast cells, which (by increasing gut permeability) may allow activation of the systemic immune system. Demonstration of the importance of the low-grade inflammation observed awaits definitive large scale trials of agents designed to specifically reverse these changes. PMID- 20203498 TI - Experimental models of stress and pain: do they help to develop new therapies? AB - The majority of functional gastrointestinal disorders are characterised by recurrent abdominal pain, with stress playing an important role in first onset and exacerbation of existing symptoms. These disorders are currently defined by symptom criteria, while their pathophysiology remains controversial and incompletely understood. Modeling these disorders in humans and animals has been difficult. While some of the models have adequate face and construct validity, the predictive validity of most of the models has been disappointing, which has put into question the traditional modeling approach. Similar problems have been encountered in drug development for pain and psychiatric disorders. New approaches have been proposed in the form of reverse translation, which include better characterisation of biological intermediate phenotypes in human disease which can be modeled in humans and in animals. Continuation of the current approach focusing on complex clinical phenotypes is likely to be ineffective for the development of novel and effect treatments. PMID- 20203499 TI - The placebo response rate in irritable bowel syndrome and inflammatory bowel disease. AB - The placebo response is the efficacy attributable to a treatment that is thought to have no specific pharmacologic effect on the condition being treated. Although potentially helpful in clinical practice, high and unpredictable placebo response rates present a major impediment to the success of clinical trials in inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Diverse factors contribute to the placebo response rates observed in clinical trials. These include patient characteristics, physician factors, frequency of study visits, characteristics of the outcome measures, concomitant treatments, regression to the mean, properties of the intervention and treatment setting, timing of the primary endpoint and natural history of the condition. Measures that may minimize the placebo response in IBD clinical trials include early timing of the primary endpoint, minimizing the number of study visits, restricting the patient population to those with documented inflammation (such as elevated biomarkers of inflammation or evidence of mucosal inflammation), including patients with more severe symptoms (i.e. greater disease activity) and enrolling patients with prior failure of immune modulators or biologics. Attempts to limit the placebo response in IBS studies have proven more difficult. Factors associated with higher placebo response rates in IBS studies include longer duration of treatment, greater number of office visits, frequency of administration of study intervention and overall treatment effect of the active agent under study. In the future, improved understanding of the factors that drive the placebo response rate should lead to more efficient study design and drug development. PMID- 20203500 TI - Does stress influence inflammatory bowel disease? The clinical data. AB - There is increasing evidence that psychological stress and associated mood disorders are linked with, and can adversely affect the course of inflammatory bowel disease (IBD). Of 11 longitudinal studies of the effects of stress or depression on the course of IBD, most suggested that stress worsened IBD, the rest giving either negative or inconclusive results. If stress does have an adverse effect on the natural history of IBD, then measures which reduce stress should help symptoms and activity of IBD. Unfortunately, because of methodological difficulties inherent in undertaking appropriately targeted and blinded trials, good data about the effects on IBD of interventions aimed to ameliorate stress and mood disorders are limited. Emerging trial evidence supports the suggestion that psychologically orientated therapy may ameliorate IBD-associated mood disorders, but there is no strong data yet to indicate that stress management has a beneficial effect on the activity or course of IBD. More rigorous assessments are needed of the relation between psychological state and activity of IBD, and of the potential benefits of stress-reducing measures in IBD. PMID- 20203501 TI - How to avoid treating irritable bowel syndrome with biologic therapy for inflammatory bowel disease. AB - Some patients with an established diagnosis of Crohn's disease and symptoms compatible with a disease flare do not have evidence of active Crohn's disease by laboratory, endoscopic or radiographic criteria. In clinical trials, approximately 18% of patients with Crohn's disease and moderate to severe clinical symptoms have no evidence of ulceration at colonoscopy. There are multiple other causes of symptoms in patients with Crohn's disease, including the presence of disease complications (stricture, fistula and abscess), complications of surgical resection (bile salt diarrhea, steatorrhoea and small bowel bacterial overgrowth), concomitant irritable bowel syndrome, concomitant infections (Clostridium difficile, cytomegalovirus) and concomitant depression. In conclusion, the clinical impression of gastroenterologists based on the patient's history is frequently incorrect and is an insufficient basis for making therapeutic decisions. Colonoscopy and CT or MRI enterography should be employed routinely prior to any major changes in therapy: (1) before starting steroids, immunosuppressives or biologicals; (2) when patients fail to respond to steroids, immunosuppressives or biologicals; (3) when patients receiving maintenance therapy with immunosuppressives or biologicals relapse; (4) before surgery. Treatment of patients who have no evidence of active disease by imaging with steroids, immunosuppressives or biological agents will not address the cause of the symptoms and will expose the patient to risks that may be unnecessary. These patients should be systematically evaluated for bile acid diarrhoea, steatorrhoea, bacterial overgrowth, irritable bowel syndrome and depression. PMID- 20203502 TI - The role of pathogenic microbes and commensal bacteria in irritable bowel syndrome. AB - BACKGROUND: Irritable bowel syndrome (IBS) reflects several pathogenetic entities including a subgroup with low-grade colonic inflammation. We propose that pathogenic bacteria act as triggers and that disturbances of commensal bacteria maintain low-grade inflammation, that in turn leads to dysfunction in the gut or brain. METHODS: Studies were performed in mice under specific pathogen-free conditions. Visceral pain was assessed by the visceromotor response and motility was assessed by in vivo fluoroscopy and in vitro by muscle contractility. Brain chemistry was assessed by in situ hybridization and behavior by standard tests. The microbiota was monitored using 16s-based RT-PCR and DGGE. RESULTS: Mice transiently infected with the nematode Trichinella spiralis exhibited changes in motility and in visceral perception that persisted for up to 6 weeks post infection. This was accompanied by alterations in the microbiota and an upregulation of cyclooxygenase-2 which could be reversed by treatment with anti inflammatory agents or selected probiotics. To investigate the contribution of the microbiota, we treated mice with oral antibiotics and monitored visceral perception and behavior. Antibiotic therapy produced substantial changes in the microbiota, a small increment in inflammatory activity and an increase in substance P or pain perception. Oral, but not systemic antibiotic treatment, produced changes in brain chemistry and an increase in anxiety-like behavior. CONCLUSION: These studies provide proof of concept that pathogenic microbes can induce persistent gut dysfunction and that changes in microbial composition of the gut can maintain gut dysfunction as well as induce behavioral changes reminiscent of the psychiatric comorbidity that occurs in up to 60% of irritable bowel syndrome patients. PMID- 20203503 TI - Acquisition, evolution and maintenance of the normal gut microbiota. AB - The gut is sterile at birth, but is rapidly colonised by faecal and vaginal bacteria of maternal origin. Over the succeeding weeks, months and years, a complex microbiota develops that plays a major role in host physiology. While the digestive tract is colonised to varying degrees by micro-organisms throughout its length, due to acid pH and the short retention time of gastric contents, bacterial numbers in the stomach are usually low. The rapid passage of digestive materials through the upper gut does not provide time for significant bacterial growth to occur, but cell numbers increase considerably in the distal ileum. The rate of movement of intestinal contents slows in the colon, which facilitates the development of complex bacterial communities. The large intestine is an intricate ecosystem that contains a complex microbiota composed of several hundred different types of bacteria. The growth and metabolism of microbial communities in the large intestine are determined by many factors, such as diet, environment and host physiological processes, as well as the anatomic structure of the digestive tract, disease, immunity, host genetics, drugs and ageing. Modifications in diet and host immune system activity, as well as physiological changes in the digestive tract affect microbiota composition in older people. The elderly have fewer bifidobacteria and higher numbers of enterobacteria and clostridia than young adults. Increased antibiotic use in older people and simply going into hospital have been shown to change bacterial community structure in the colonic microbiota, although the metabolic significance of this is unclear. PMID- 20203504 TI - Bacterial flora in inflammatory bowel disease. AB - The pathogenesis of inflammatory bowel disease (IBD) involves an interaction between host susceptibility (which is partly genetically determined), mucosal immunity and the intestinal milieu. Micro-organisms have physiological effects on mucosal structure, epithelial turnover, the intestinal immune cells and, thus, on many intestinal functions. Toll-like receptors and nucleotide oligomerisation binding domain proteins in host cells recognise specific bacterial molecules and modify the immune response. Human studies have repeatedly shown that the microbiota of patients with IBD differs from that of controls and is unstable, both in the intestinal lumen and at the surface of the mucosa. A single pathogen has not been identified, but potentially pro-inflammatory micro-organisms have been found in samples from IBD patients more often than from healthy controls. These include Mycobacterium paratuberculosis, and enteroadherent and invasive Escherichia coli in Crohn's disease (CD). Ecological descriptions of the microbiota present in patients with IBD (either in the faeces or adherent to the mucosa) have repeatedly reported a decrease in usually dominant bacteria, especially those from the dominant phylum Firmicutes. A decrease in the biodiversity of Firmicutes has been observed in CD, while a recent study has shown that a decrease in Firmicutes, especially Faecalibacterium prausnitzii, was associated with CD and the post-operative recurrence of CD lesions in the ileum. Taken together, these results suggest that dysbiosis, or an imbalance within the (dominant) intestinal microbiota, may favour IBD. PMID- 20203505 TI - Yeasts: neglected pathogens. AB - BACKGROUND: Current research on Crohn's disease (CD) concerns molecular events related to loss of tolerance to microbes that could trigger or maintain inflammation in genetically susceptible individuals. CD is also associated with antimicrobial antibodies, including the antibodies we described against yeast oligomannosides (ASCA). This prompted us to investigate a role for another yeast, Candida albicans, a very common commensal of the human digestive tract and an important opportunistic pathogen. CLINICAL AND EXPERIMENTAL DATA: It has been revealed that the major oligomannose epitopes supporting ASCA are expressed by C. albicans in human tissues, suggesting that C. albicans is the immunogen for ASCA. This link has been reinforced by the demonstration that novel serological markers of CD (ALCA and ACCA), consisting of antibodies against chitin and glucan (two components of the C. albicans cell wall), are also generated during C. albicans infection. Mycological investigation of families with multiple cases of CD shows that patients with CD and their healthy relatives are colonized with C. albicans more commonly than control families. In healthy relatives, C. albicans colonization correlates with ASCA levels, whereas the onset of CD is associated with ASCA stability and is independent of the C. albicans intestinal load. Experimental studies show that chemically-induced colitis promotes C. albicans colonization in mice. In turn, C. albicans colonization generates ASCA, increases inflammation, histological scores and pro-inflammatory cytokine expression. PERSPECTIVES: Current investigations focus on interactions of TLRs and lectins with yeast epitopes that differently polarize the immune response to C. albicans cell wall glycans, which are the targets of an 'excessive' adaptive response associated with CD. PMID- 20203506 TI - Probiotics for inflammatory bowel disease: a critical appraisal. AB - The notion that the intestinal microbiota plays a key role for the development of intestinal inflammation, initially based on a series of clinical observations both in human inflammatory bowel disease and experimental colitis, has been reinforced by a growing body of evidence demonstrating that the abnormal recognition of bacterial and other microbiota antigens by the innate immune system is one of the earliest events in the pathogenesis of inflammatory bowel disease. In keeping with our present knowledge of inflammatory bowel disease pathophysiology, the search for therapeutic approaches aimed at modifying the composition of the intestinal microbiota to obtain new, more targeted treatments for inflammatory bowel disease that are basically free of side effects has been a subject of intense research activity. Probiotics are defined as live organisms capable of conferring health benefits beyond their nutritional properties. Numerous micro-organisms have been evaluated to induce or maintain remission, or both, in ulcerative colitis, Crohn's disease and pouchitis. Overall, probiotics have successfully demonstrated some efficacy in some inflammatory bowel disease scenarios. However, a critical review of the available scientific literature shows that: (1) in spite of great expectations, reflected by a high number of review and editorial articles in top journals, the number of published, well designed clinical trials using probiotics in inflammatory bowel disease is small, often with few patients; (2) the range of microbial agents makes it particularly difficult to draw global conclusions; (3) the quality of the evidence on the efficacy of probiotics in pouchitis is clearly better than that in ulcerative colitis, while there is virtually no evidence of probiotic efficacy in Crohn's disease. The appropriate selection of probiotic agents combined with convincing clinical trials will determine whether probiotics can jump from promise to reality in inflammatory bowel disease clinical practice. PMID- 20203507 TI - Aminosalicylates and other anti-inflammatory compounds for irritable bowel syndrome. AB - Growing evidence suggests that gastrointestinal immune activation may affect intestinal function and sensory perception, which contribute to symptom generation in patients with irritable bowel syndrome (IBS). The identification of higher counts of immunocytes (e.g. T cells and mast cells), mucosal and systemic immune activation, and increased mucosal permeability in patients with IBS has stimulated interest in the potential development of therapeutic approaches aimed at targeting the immune system and inflammation. Although an initial attempt in a pilot trial with steroids in patients with post-infective IBS failed, there has been renewed interest for mast cell stabilizers and the therapeutic potential of aminosalicylates. A recent randomized, double-blind, placebo-controlled pilot trial assessed the effect of mesalazine on intestinal immune cells and symptom perception in patients with IBS. Mesalazine markedly reduced mucosal immune cells and mast cells in particular, compared to placebo. In addition, mesalazine significantly improved general well-being. Mesalazine may enhance epithelial barrier function, and preliminary data suggest that it may alter faecal bacterial profiles in IBS patients. Nevertheless, the exact mechanism through which this drug affects immune activation in the intestine of patients with IBS remains unknown. There is a need for further studies to prove the efficacy of mesalazine for IBS. Further studies aimed at assessing the role of aminosalicylates and other approaches with potential anti-inflammatory activity, including probiotics, non-absorbable antibiotics, histamine receptor antagonists and protease inhibitors on IBS symptoms or pathophysiology are now warranted. PMID- 20203508 TI - Eosinophilic esophagitis. AB - Eosinophilic esophagitis is a clinicopathological disease characterized by GERD like symptoms, food impaction and dysphagia that occur with the histological finding of dense esophageal eosinophilia. Endoscopic features include linear furrows, white exudate and longitudinal shearing. Current concepts regarding the pathophysiology relate to a food allergen-induced overexpression of eosinophil related cytokines including Il-5, IL-13 and eotaxin-3. Effective treatments include topical and systemic corticosteroids and dietary restrictions. PMID- 20203509 TI - Mast cells and mastocytosis. AB - Mast cells (MCs) typically reside at barrier sites of the body, including the intestinal mucosa, and play a vital role in innate host defence. Activated MCs release a wide variety of bioactive mediators. These include preformed mediators stored in the granules (e.g. histamine and tryptase) and newly synthesised mediators (e.g. prostaglandins, leukotrienes and cytokines). MCs are present in all layers throughout the gastrointestinal (GI) tract and there is a close bi directional connection between MCs and enteric nerves that is of vital importance in the regulation of GI functions. Some gain-of-function mutations in c-kit, encoding the tyrosine kinase- receptor for stem cell factor, are associated with the rare disease entity, systemic mastocytosis. These patients present symptoms arising from MC mediator release or infiltration. GI manifestations are common in this patient group, mainly abdominal pain and diarrhoea. Endoscopy with biopsies reveals MC infiltration in the mucosa. Other diagnostic tools include bone marrow biopsy and serum tryptase. Treatment is symptomatic with antihistamines or cromoglycate in mild cases, whereas severe cases need cytoreductive therapy that should be managed with expert haematologists. From a day-to-day clinical perspective, the important role of MCs in neuroimmune interaction has been implicated in the intestinal response to stress, in alterations of mucosal and neuromuscular function in irritable bowel syndrome or inflammatory bowel disease, and in the pathogenesis of non-erosive oesophageal reflux disease. Thus, MCs have important regulatory and protective roles in innate defence, in addition to being a potential mediator of mucosal pathophysiology in GI diseases. We need to learn how to balance the response of these volatile cells to be able to benefit from their versatility. PMID- 20203510 TI - Collagenous and lymphocytic colitis: systematic review and update of the literature. AB - Collagenous and lymphocytic colitis are well-described conditions causing chronic watery diarrhoea. A peak incidence from 60 to 70 years of age with a female predominance mainly in collagenous colitis is observed. Both conditions are characterised by a (near) normal colonoscopy, but with specific histologic findings on colonic biopsies. Histopathologically, both conditions are characterised by distinct epithelial abnormalities and a dense lymphoplasmocytic infiltrate. Distinct features consist of a characteristic collagen band deposition in the subepithelial layer in collagenous colitis and a markedly increased number of intra-epithelial lymphocytes in lymphocytic colitis. Although most cases are idiopathic, certain drugs can induce microscopic colitis. In addition, either condition can be associated with coeliac disease. For a long time patients with microscopic colitis were treated with non-specific anti diarrhoeal agents, anti-inflammatory agents such as mesalazine, or systemic steroids, but with disappointing results. Bismuth subsalicylate was reported to be effective in a small controlled series of patients with collagenous colitis. Now, randomised controlled trials have shown the effectiveness of budesonide over placebo in collagenous colitis and more recently in lymphocytic colitis. The histologic response is variable, but a decrease in the subepithelial collagen layer and a decrease in the lymphoplasmocytic infiltrate in the lamina propria is observed in about half of the patients. In general, patients respond within 2 weeks with no major side effects. However, relapse is common (63-80% of patients) when budesonide is stopped. Longer-term treatment is effective but does not seem to reduce relapse rates upon discontinuation. PMID- 20203511 TI - Benign intraductal papillary-mucinous neoplasm of the pancreas associated with spontaneous pancreaticogastric and pancreaticoduodenal fistulas. AB - Invasive intraductal papillary-mucinous neoplasms (IPMNs) of the pancreas may be associated with pancreaticogastric fistulas as shown by case reports. We report the case of a benign IPMN associated with pancreaticogastric and pancreaticoduodenal fistulas. A 70-year-old woman was admitted with intestinal obstruction. Computed tomography and MRI showed a large dilatation of the main pancreatic duct (>1 cm) with intraductal nodules, and pancreaticogastric and pancreaticoduodenal fistulas. Several features in imaging were present to support a malignant IPMN, so that the patient underwent a pancreaticoduodenectomy. The histopathological examination of the surgical specimen showed a benign IPMN. This case proves that a benign IPMN can cause pancreaticogastric and pancreaticoduodenal fistulas, probably resulting from mechanical factors. PMID- 20203512 TI - Natural course of lugol-voiding lesions in patients with superficial esophageal squamous cell carcinoma. AB - BACKGROUND: The presence of multiple Lugol-voiding lesions (LVLs) in the esophageal mucosa can indicate a high risk of esophageal squamous cell carcinoma (ESCC) as well as a diagnosis of ESCC and dysplasia. However, there have been no reports on the natural course of LVLs. AIM: This study aimed to clarify the characteristics and natural course of LVLs. METHODS: Based on patients with ESCC who underwent endoscopic treatment, a retrospective study was conducted targeting 73 patients in whom the esophageal background mucosa was evaluated using Lugol staining and who were followed up for 12 months or more. LVLs were divided into groups A (none), B (several small), C (many small), and D (many irregular-shaped multiform). RESULTS: The average follow-up period was 42.0 months. Groups A-D consisted of 13, 34, 21, and 5 patients, respectively. In group B, 3 of 34 (8.8%) patients advanced to group C. In group C, 2 of 21 (9.5%) patients advanced to group D. In total, 5 of all 73 (6.8%) patients advanced to a higher group. CONCLUSION: These data suggest that a risk of ESCC may obviously increase in only some of the patients by evaluation of LVLs. PMID- 20203513 TI - New technique for picking up large colorectal tumors during endoscopic submucosal dissection. PMID- 20203514 TI - An autopsied case of an apparent pontine branch atheromatous disease. PMID- 20203515 TI - Transient global amnesia: a genetic disorder? PMID- 20203516 TI - A severe case of high cervical spinal cord injury without radiographic abnormality. PMID- 20203517 TI - Epileptic asystole. PMID- 20203518 TI - Excessive daytime sleepiness in Behcet's disease with diencephalic lesions and hypocretin dysfunction. PMID- 20203519 TI - Induction of lymphocyte apoptosis in rat liver allograft by adenoviral gene transfection of human interleukin-10. AB - BACKGROUND/AIMS: Gene therapy can provide a possible avenue in organ transplantation to treat acute allograft rejection. This study was designed to investigate the effect of adenovirus-mediated human IL-10 (hIL-10) gene transfer on the apoptosis of infiltrating lymphocytes and examine the efficacy of hIL-10 gene transfer in combination with subtherapeutic doses of cyclosporine A (CsA) in a rat liver transplantation model. METHODS: Inbred male DA and LEW rats were used for liver donors and recipients, respectively. The rats were divided into saline, Ad-lacZ, CsA, Ad-hIL-10 and Ad-hIL-10 + CsA groups. Graft survival, histopathological, enzyme-linked immunosorbent assay, reverse transcriptase polymerase chain reaction and flow cytometry were performed in liver specimens obtained from different time points after transplantation in the 5 groups. RESULTS: Ad-hIL-10 pretreatment inhibited allograft rejection, prolonged the survival of hepatic allografts, and downregulated the expression of IFN-gamma and IL-2 mRNA, with simultaneous upregulation of IL-4 mRNA. In addition, Ad-hIL-10 pretreatment upregulated the expression of Fas mRNA in the isolated graft infiltrating lymphocytes and induced graft-infiltrating lymphocyte apoptosis. A single subtherapeutic dose of CsA acted synergistically with it. CONCLUSION: hIL 10 gene therapy induced alloreactive lymphocyte apoptosis via Fas/FasL pathway. hIL-10 gene transfection in combination with subtherapeutic doses of CsA facilitates the long-term survival of liver grafts. PMID- 20203520 TI - The effect of external beam irradiation timing on skin graft survival. AB - BACKGROUND: The purpose of this study was to evaluate skin graft integrity after external beam irradiation in a rat model. METHODS: Forty-eight male Wistar rats were randomly assigned to 8 groups (A, B, C, D, A(c), B(c), C(c) and D(c)). A rectangular full-thickness skin graft was raised and reapplied to its original bed on the dorsum of each rat. Groups A(c), B(c), C(c) and D(c) were the control groups and were not given postoperative irradiation. After grafting, 25 Gy unfractioned cobalt(60) irradiation was administered to groups A, B, C and D on postoperative days 10, 20, 30 and 40, respectively. Histological samples were obtained 8 weeks after grafting. Dermal and epidermal thickness were measured by the KS-400 image analysis program. RESULTS: The difference in the epidermal and/or dermal thickness between the irradiated groups was not found to be significant. Furthermore, when histological features and the image analysis of the irradiated groups were compared with each other, there were no significant differences between the groups. CONCLUSIONS: Although we are aware that experimental results may not directly translate to the clinical setting, the present study indicates that external radiotherapy can be performed to skin grafted areas as early as 10 days postoperatively. PMID- 20203521 TI - Characteristics of progesterone changes in women with subtle progesterone rise in recombinant follicle-stimulating hormone and gonadotropin-releasing hormone antagonist cycle. AB - BACKGROUND: To assess the characteristics of progesterone (Prog) changes in women with a subtle Prog rise in recombinant follicle-stimulating hormone (r-FSH) and GnRH antagonist cycles. METHODS: We enrolled 233 patients undergoing controlled ovarian hyperstimulation with r-FSH and GnRH antagonist for IVF or ICSI. A subtle Prog rise 1 day before hCG administration was defined as a Prog value of > or =1.2 ng/ml. RESULTS: 100 of 233 cycles (42.9%) showed a subtle Prog rise in this study. The mean serum Prog levels and area under curve (AUC) in the group with Prog > or =1.2 ng/ml was significantly higher than that in the Prog <1.2 ng/ml group on cycle day 8 (1.17 +/- 0.4 and 0.80 +/- 0.3 ng/ml, respectively, for Prog level, p = 0.003; 571 +/- 123 and 763 +/- 250 for AUC, p = 0.001), and remained significantly higher until the day of hCG administration. Moreover, 55% of the patients on cycle day 9, 65% on cycle day 10, 75% on cycle day 11 and 85% on cycle day 12 in the Prog > or =1.2 ng/ml group have a serum Prog level of > or =1.2 ng/ml. CONCLUSION: A subtle Prog rise may occur as early as cycle day 8 in r FSH/GnRH antagonist cycles. PMID- 20203522 TI - Spontaneous hepatic rupture in a normotensive monoamniotic twin pregnancy: case report and review of the literature. AB - BACKGROUND: Spontaneous liver rupture during pregnancy is extremely rare, and often associated with hypertensive disorders. Maternal outcomes are poor and morbidity is high. CASE: A 27-year-old women (G1P0), pregnant with monochorionic monoamniotic twins, developed extensive abdominal pain while she was electively admitted at 32 weeks for fetal pulmonary maturation. Diagnosed with preterm labor, a caesarean section was performed. Postoperatively, our patient deteriorated and a second laparotomy revealed an extensive liver rupture. There was no evidence of hypertensive disorders or hepatic tumors. After perihepatic packing and embolization, our patient required long-term treatment in our intensive care unit. She survived, and both mother and children are healthy after 6 months. CONCLUSION: Despite being rare, spontaneous liver rupture in absence of hypertensive disorders during pregnancy is associated with high maternal morbidity and mortality. Adequate treatment requires a multidisciplinary approach. PMID- 20203523 TI - Yin yang haplotypes revisited - long, disparate haplotypes observed in European populations in regions of increased homozygosity. AB - OBJECTIVES: Yin yang haplotypes differ at every SNP. A previous study provided striking examples of these haplotypes, but claimed that their distribution across the genome could be attributed to chance. When we studied regions of homozygosity (ROHs) we found haplotypes that tended to differ at several SNPs simultaneously but did not subject this to formal testing. Here, we formally assess whether haplotypes from these regions provide evidence for the yin yang effect. METHOD: We identified 20 regions where ROHs are common in a sample of European subjects and studied the most frequent haplotypes of SNPs with high minor allele frequency. We calculated the average 'disparity' between all haplotype pairs using a 'disparity score' calculated as 2(d), where d is the number of SNPs at which a pair of haplotypes differ. We also studied these SNPs in HapMap samples. RESULTS: Overall, there was highly significant evidence for excess haplotype disparity. Three of the HapMap populations with European ancestry also had statistically significant haplotype disparity scores. CONCLUSION: Locations where ROHs are frequent harbour long common haplotypes showing surprising disparity. We believe these haplotypes must represent ancient founder effects and could be valuable for elucidating features of a population's history. PMID- 20203524 TI - Genetic susceptibility to type 2 diabetes is associated with reduced prostate cancer risk. AB - OBJECTIVE: To examine the collective effects of type 1 (T1D) and type 2 diabetes (T2D) risk alleles on prostate cancer (PCa) risk. METHODS: Using data on 14 and 18 single nucleotide polymorphisms (SNPs) that effect T1D and T2D risk, respectively, we generated risk scores (a 'risk allele count' and a 'genetic relative risk') for both T1D and T2D for 1,171 non-Hispanic white, PSA-screened PCa cases and 1,101 matched controls from the Cancer Genetic Markers of Susceptibility study. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between the diabetes risk scores and PCa risk. RESULTS: Both T2D risk scores, but neither T1D score, showed an inverse association with PCa (p < 0.01). These associations remained significant after excluding HNF1B SNP rs4430796 (a known PCa risk factor) from the analysis. The highest quartile of the T2D allele count (>20 risk alleles) was associated with reduced PCa risk (OR = 0.77; CI: 0.60-0.99) compared to the lowest category (<17 risk alleles). CONCLUSIONS: These results suggest that individuals with increased genetic susceptibility to T2D have decreased risk for PCa. This association is consistent with the observation that individuals with T2D are at decreased risk for PCa; however, data on T2D status was not available for this analysis. PMID- 20203525 TI - An extensive comparison of quantitative trait Loci mapping methods. AB - BACKGROUND: The choices of study design and statistical approach for mapping a quantitative trait (QT) are of great importance. Larger sibships and a study design based upon phenotypically extreme siblings can be expected to have a greater statistical power. On the other hand, selected samples and/or deviation from normality can influence the robustness and power. Unfortunately, the effects of violation of multivariate normality assumptions and/or selected samples are only known for a limited number of methods. Some recommendations are available in the literature, but an extensive comparison of robustness and power under several different conditions is lacking. METHODS: We compared eight freely available and commonly applied QT mapping methods in a Monte-Carlo simulation study under 36 different models and study designs (three genetic models, three selection schemes, two family structures and the possible effect of deviation from normality). RESULTS: Empirical type I error fractions and empirical power are presented and explained as a whole and for each method separately, followed by a thorough discussion. CONCLUSIONS: The results from this extensive comparison could serve as a valuable source for the choice of the study design and the statistical approach for mapping a QT. PMID- 20203526 TI - Using both cases and controls for testing hardy-weinberg proportions in a genetic association study. AB - OBJECTIVES: Assessment of the Hardy-Weinberg proportion (HWP) in controls has been widely used as a quality control measure in case-control association studies. However, when the disease being studied is common, controls might not represent the general population, which could result in inaccurate HWP test results. Such results could lead investigators to discard important single nucleotide polymorphisms (SNPs) that could potentially be causal. In this paper, we showed the inappropriateness of the HWP test in controls and proposed a mixture HWP (mHWP) exact test using a mixture sample that mimics the general population. METHODS: The mHWP exact test estimates HWP in a mixture sample that is a combination of both cases and controls proportional to the prevalence of disease. We implemented a re-sampling procedure to construct mixture samples and then obtained the empirical p value of HWP in the general population. Simulation studies were performed to investigate the performance of the proposed mHWP exact test. The method was also applied to a genetic association study of obesity. RESULTS: The results showed that the mHWP exact test is more likely than either the traditional HWP method in controls or the likelihood-based approach to keep causal SNPs for further analysis when the disease is more common. CONCLUSION: The mHWP exact test using a mixture sample is a better HWP test for case-control genetic association studies than the traditional HWP in controls or the likelihood-based approach, and it will improve our ability to keep causal SNPs in the case-control genetic association studies. PMID- 20203527 TI - Heparin and tranexamic Acid therapy may be effective in treatment-resistant chronic urticaria with elevated d-dimer: a pilot study. AB - BACKGROUND: Chronic urticaria (CU) patients often present activation of the coagulation cascade and fibrinolysis whose markers correlate with disease severity. AIM: We evaluated whether CU patients with elevated plasma D-dimer have a poor response to antihistamines, and anticoagulation and inhibition of fibrinolysis may be beneficial in these patients. METHODS: Sixty-eight consecutive patients with CU were prescribed cetirizine 10 mg daily for 2 weeks; plasma D-dimer was measured. Non-responders were given cetirizine 30 mg daily for 1 week and subsequently, in case of failure, systemic steroids. Patients with persistent uncontrolled CU and elevated D-dimer plasma levels were offered subcutaneous nadroparin 11,400 IU once a day and oral tranexamic acid 1 g three times a day for 2 weeks. RESULTS: D-dimer levels were elevated in 14/68 (20.6%) patients (range 306-7,317 ng/ml; normal values <278 ng/ml) and were associated with a more severe disease. Twelve of 14 patients with elevated D-dimer levels did not respond to antihistamine treatment (p = 0.0001). On the whole, 14 patients reported a poor or absent response to cetirizine 10 mg daily and only 1 of these responded satisfactorily to cetirizine 30 mg daily. Eight patients with elevated D-dimer and whose disease was not satisfactorily controlled by prednisone received nadroparin and tranexamic acid. A marked improvement of symptoms was observed in 5/8 cases. CONCLUSION: Our findings indicate that CU patients with elevated D-dimer often present a more severe disease with reduced response to antihistamines. Based on this short pilot study, some of these patients may benefit from treatment with nadroparin and tranexamic acid. PMID- 20203528 TI - Link between interleukin-10 level and outcome after ischemic stroke. AB - OBJECTIVES: The prognostic value of interleukin (IL)-10 in patients after acute ischemic stroke (IS) is not well understood. This study tested the hypothesis that serum levels of IL-10 are substantially increased after IS and predictive of IS outcome. METHODS: Serum IL-10 levels were examined 48 h after acute IS in 135 consecutive patients, and in 20 healthy and 30 at-risk controls. RESULTS: Mean serum IL-10 was significantly higher in IS patients than in both control groups (p < 0.0001, respectively). Additionally, serum IL-10 was significantly higher in patients with severe neurological impairment [defined as a score >or=12 on the National Institute of Health Stroke Scale (NIHSS)] than in patients with less severe neurological impairment (NIHSS score <12) 48 h after IS (p < 0.0001). Furthermore, higher serum IL-10 was strongly and independently correlated with severe neurological impairment (NIHSS >or=12) 48 h after acute IS (p < 0.0001), and independently predictive of combined major adverse clinical outcomes (defined as recurrent IS, any cause of death or NIHSS >or=12) on day 90 following IS (p < 0.0001). CONCLUSIONS: Serum IL-10 is an independent prognosticator of IS outcome. PMID- 20203529 TI - The effect of early-life stress on airway inflammation in adult mice. AB - BACKGROUND/AIMS: Neonatal stress induces permanent physiological changes that may influence the immune system. Early-life stress increases asthma disease severity in children. We investigated the effects of early-life stress on allergic airway inflammation using a murine model of asthma coupled to maternal separation as an early-life stress stimulus. METHODS: Maternally separated (MS) and unseparated control (CON) mice were sensitized with ovalbumin (OVA) beginning at day 31 after birth. RESULTS: Challenging mice with OVA increased airway hyperresponsiveness (AHR) and the number of inflammatory cells recovered in the bronchoalveolar lavage (BAL), compared to saline-challenged mice. Challenging MS mice with OVA resulted in less total inflammatory cells, eosinophils, interferon-gamma, and interleukin-4 in BAL compared to CON mice. However, MS mice challenged with OVA exhibited AHR similar to CON mice challenged with OVA. In contrast, an enhanced stress protocol (MS+) involving removal of pups from their home cages following the removal of the dam resulted in inflammatory cell accumulation and cytokine levels in the BAL similar to CON mice and higher than MS mice. CONCLUSIONS: These findings indicate that the effect of early-life psychological factors on the development of airway inflammatory diseases such as asthma is very complex and depends on the quality of the psychological stress stimulus. PMID- 20203530 TI - Prenatal lipopolysaccharide reduces social behavior in male offspring. AB - OBJECTIVE: This study investigated the relationship between maternal sickness behavior during pregnancy and offspring development and behavior. METHODS: Pregnant Wistar rats were administered with lipopolysaccharide (LPS, 100 microg/kg, i.p.) on gestation day (GD) 9.5. Dams' sickness behavior was analyzed, and at birth, offspring number and weight were evaluated. Male offspring was evaluated through physical development, play behavior, adult social interaction, plus maze studies and morphological analysis of the brain. RESULTS: Results, with respect to the control group, showed that: (1) LPS decreased general activity, food intake, and weight gain in dams, but no pyrexia was observed following treatment; (2) LPS reduced litter size, but no alterations in physical development were observed; (3) LPS reduced play behavior parameters in baby rats; (4) LPS decreased adult social interaction; (5) no alterations were observed between groups on plus maze studies; (6) no differences were observed between groups on morphological analyses of the brain. CONCLUSION: These data reveal that LPS administered on GD 9.5 impaired male offspring's social behavior in infancy and adulthood. These results may be related to an alteration in motivational states or/and increased anxiety. PMID- 20203531 TI - Neuroprotection without immunomodulation is not sufficient to reduce first relapse severity in experimental autoimmune encephalomyelitis. AB - OBJECTIVES: Multiple sclerosis can be characterized by a strong neuroinflammatory and progressive neurodegenerative component leading to prolonged disability. The synthetic compound R(+)WIN55,212-2 is reported to be neuroprotective at moderate doses and both neuroprotective and immunomodulatory at high doses, most likely due to differences in receptor affinities. In order to investigate the effects of neuroprotection and immunomodulation in an animal model of multiple sclerosis, we examined the impact of increasing concentrations of R(+)WIN55,212-2 on the inflammatory profile in CNS during first relapse and related this to demyelination, axonal degeneration and relapse severity. METHODS: Experimental autoimmune encephalomyelitis was induced in Dark Agouti rats and treatment with R(+)WIN55,212-2 was initiated at symptom debut. The animals were scored clinically throughout the experiment, and axonal degeneration, demyelination, T cells, microglia/macrophages, TNF-alpha, IL-12, IFN-gamma, IL-10 and the T(H)17 response were estimated at the peak of the first relapse. RESULTS: Treatment with high-dose R(+)WIN55,212-2 (10 and 20 mg/kg) significantly improved the clinical performance of the animals during relapse. Interestingly, treatment at any dosage did not affect the brain levels of TNF-alpha, IL-12 and IFN-gamma (T(H)1 response), whereas high-dose cannabinoid treatment reduced the number of T cells and microglia/macrophages in addition to the T(H)17 response. At the same time, we observed a significant reduction in axonal degeneration in all treatment groups whereas only high-dose treatment resulted in reduced demyelination. CONCLUSION: High-dose R(+)WIN55,212-2 treatment reduces demyelination and axonal degeneration and has immunomodulatory effects which significantly improve clinical performance, whereas a reduction in axonal degeneration on its own, induced by 5 mg/kg R(+)WIN55,212-2, has no impact on first relapse severity. PMID- 20203532 TI - Chronic individual housing-induced stress decreased expression of catecholamine biosynthetic enzyme genes and proteins in spleen of adult rats. AB - OBJECTIVE: Social isolation is regarded as one of the most relevant causes of diseases in mammalian species. The activation of the sympathoneural system represents one of the key components of the stress response. The sympathetic nervous system is one of the major pathways involved in immune-neuroendocrine interactions. The aim of the present study was to determine plasma epinephrine and norepinephrine in individually housed rats, as well as to find out whether splenic gene expression of catecholamine synthesizing enzymes and their protein levels are affected by chronic psychosocial stress. METHODS: Tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT) mRNA levels were quantified by quantitative real-time RT-PCR. The TH, DBH and PNMT immunoproteins were assayed by Western blot. RESULTS: Chronic social isolation of adult male rats produced a significant increase in plasma catecholamine levels and a decrease in splenic TH mRNA, DBH mRNA and PNMT mRNA. Protein levels of TH, DBH and PNMT were also reduced. CONCLUSION: These results suggest that increased plasma catecholamines and decreased gene expression and protein levels of catecholamine biosynthetic enzymes in the spleen of chronically individually housed animals might reduce catecholamine synthesis, thus leaving the immunocompetent tissues depleted of catecholamines and consequently leading to an impairment of immune response. PMID- 20203533 TI - Passive immunization with LINGO-1 polyclonal antiserum afforded neuroprotection and promoted functional recovery in a rat model of spinal cord injury. AB - LINGO-1 (leucine-rich repeat and Ig domain-containing, Nogo receptor-interacting protein) is an important component of the NgR receptor complex involved in RhoA activation and axon regeneration. The authors report on passive immunization with LINGO-1 polyclonal antiserum, a therapeutic approach to overcome NgR-mediated growth inhibition after spinal cord injury (SCI). The intrathecally administered high-titer rabbit-derived antiserum can be detected around the injury site within a wide time window; it blocks LINGO-1 in vivo with high molecular specificity. In this animal model, passive immunization with LINGO-1 antiserum significantly decreased RhoA activation and increased neuronal survival. Adult rats immunized in this manner show recovery of certain hindlimb motor functions after dorsal hemisection of the spinal cord. Thus, passive immunotherapy with LINGO-1 polyclonal antiserum may represent a promising repair strategy following acute SCI. PMID- 20203534 TI - Exhaustive exercise reduces tumor necrosis factor-alpha production in response to lipopolysaccharide in mice. AB - OBJECTIVE: Stressful exercise reduces the plasma pro-inflammatory cytokine concentration in response to lipopolysaccharide (LPS). The aim of this study was to clarify the mechanism of exhaustive exercise-induced suppression of the plasma tumor necrosis factor (TNF)-alpha concentration in response to LPS. METHODS: Male C3H/HeN mice (n = 66) were randomized to treadmill running to exhaustion (Ex) or a sedentary (Non-Ex) condition. Monocytes and splenic macrophages were collected from some animals, and other animals were injected with LPS (1 mg/kg) immediately after the exercise. The liver, lung and spleen tissues in the mice were removed 30 min after the LPS injection for determination of TNF-alpha mRNA expression. Blood and tissue samples were collected for determination of TNF-alpha and TNF receptors (TNFR) 1 h after the LPS injection. RESULTS: Although there was a significant suppression in LPS-induced plasma TNF-alpha in the Ex mice when compared to the Non-Ex mice (p < 0.01), soluble TNFR in plasma was not affected by the exercise. There was no change in cell-surface expression of Toll-like receptor 4 (TLR4) and in LPS-induced TNF-alpha mRNA expression and TNFR content in tissues between the Ex and Non-Ex groups. Interestingly, TNF-alpha contents in the liver, lung and spleen of the Ex mice were significantly lower than those of the Non-Ex group (p < 0.01, p < 0.01 and p < 0.05, respectively). CONCLUSION: These data suggest that exhaustive exercise-induced suppression of the plasma TNF alpha concentration despite LPS stimulation might depend on translation of TNF alpha in tissues. PMID- 20203535 TI - 'Heat and destroy': bronchoscopic-guided therapy of peripheral lung lesions. AB - Although the treatment of choice for stage I lung cancer patients is surgery, a lot of patients have a high comorbidity and are medically inoperable. Bronchoscopy, as a central technique in diagnosing lung cancer, has the potency to apply endoscopic therapy to small lung lesions in a minimally invasive way in patients with high risk for surgery. Unfortunately, bronchoscopy cannot always reach lesions in the peripheral lung, in particular the smaller lesions. Therefore, new guidance techniques like virtual bronchoscopy and electromagnetic navigation are now available and instead of using the systems as a diagnostic tool, these techniques may provide an option for therapeutic interventions to inoperable lung tumor patients. With endoscopic fiducial marker placement for robotic radiosurgery and endoluminal high-dose brachytherapy, local radiotherapy of peripheral lung tumors becomes feasible, reducing radiotherapy-induced toxicity. Radiofrequency tissue ablation through the working channel of a flexible bronchoscope may be a chance of making a diagnosis and a curative treatment in one endoscopic session. However, technical improvements of the ablation probes are currently necessary to expand the sizes of ablated areas. Even though the technologies are very attractive and pilot data are extremely encouraging, more studies establishing selection criteria and best utility are needed. PMID- 20203536 TI - cDNA cloning of blue gourami (Trichogaster trichopterus) prolactin and its expression during the gonadal cycles of males and females. AB - BACKGROUND: The blue gourami fish (Trichogaster trichopterus) provides a unique model for the study of reproduction endocrinology in teleost fish. Its oocyte development may be controlled easily, and the vitellogenic and final maturation phases may be separated artificially in the laboratory. Moreover, this gourami exhibits exclusive parental behavior. AIM: The aim of the present study was to clone and sequence the blue gourami PRL (bgPRL) cDNA in order to enable the determination of its mRNA levels in the male and female blue gourami during the gonadal cycles. MATERIALS AND METHODS: bgPRL was cloned by extracting total RNA from freshly excised pituitaries of gourami fish, followed by cDNA synthesis, rapid amplification of cDNA ends (RACE)-PCR and finally, sequencing. bgPRL mRNA expression was determined by realtime PCR, and results were normalized with 18S RNA. RESULTS: When bgPRL was compared to PRLs of other fish, it had the most homology with PRL of Perciformes and the least with those of Anguilliformes. bgPRL was expressed during the entire gonadal cycle in males and females. The average levels of PRL mRNA in juvenile and low vitellogenetic females were lower than in mature females (at high vitellogenesis and maturation), but the differences were not significant. On the other hand, the PRL mRNA levels in mature reproductive males (nestbuilders) and non-reproductive (non-nest-builders) were significantly higher in comparison to young males. CONCLUSIONS: The results of this study imply that PRL has a possible role in the endocrine control of gonadal development in fish, in addition to its role in reproductive behavior. PMID- 20203537 TI - Effects of renin-angiotensin system blockade on islet function in diabetic rats. AB - AIMS: To investigate the effects of renin-angiotensin system (RAS) blockade on islet structure and function in diabetic rats, and its mechanisms. METHODS: Diabetic rat models were created by high-fat high-caloric laboratory chow plus small dose (30 mg/kg) streptozotocin ip injection. After 8-week intervention with perindopril (AE, no.=10) or valsartan (AR, no.=10), all the animals' islet function was evaluated by iv glucose tolerance test. Pancreases were stained by immunohistochemistry technique to qualitative and/or quantitative analysis the content of insulin, inducible nitric oxide synthase (iNOS), transforming growth factors-beta1 (TGF-beta1) in islets. The apoptosis of islet cells was detected by transferase-mediated dUTP nick-end labeling dUTP nick end labeling (TUNEL). The expression level of angiotensinogen (AGT) and insulin mRNA in islets were detected by RT-PCR. RESULTS: Compared with normal control group (NC, no.=10), area under the curve of insulin from 0 to 10 min (AUCI0-10) of diabetes group (DM, no.=8) was decreased by 66.9%, the relative expression of local AGT was increased by 69.2%, the insulin relative concentration (IRC) of beta-cell and the expression of insulin mRNA were decreased significantly, the amount of apoptotic cells in unit islet area was increased by 2.1 times, the relative content of iNOS and TGF-beta1 positive cell relative volume (TRV) was increased by 23.0% and 2.52 times, respectively (all p<0.01). Compared with DM group, AUCI0-10 of AE and AR group was increased by 41.4% and 33.2%, respectively; the relative expression of local AGT was decreased by 21.4% and 23.4%, respectively; IRC and the expression of insulin mRNA were increased significantly; the amount of apoptotic islet cells was decreased by 79.0% and 36.2%, respectively; the relative content of iNOS was decreased by 16.5% and 18.9%, respectively; TRV was decreased by 43.8% and 35.6%, respectively (all p<0.01). There were no significant differences between group AE and AR. CONCLUSION: Blockade of RAS may improve diabetic rats islet function via the amelioration of intra-islets oxidative stress, fibrosis and apoptosis. PMID- 20203538 TI - Short- and long-term changes of quality of life in patients with acromegaly: results from a prospective study. AB - Quality of life (QoL) may be affected in acromegalic patients, although the role of disease activity is still unsettled. The aim of the study was to assess the QoL of acromegalic patients with a specific questionnaire (ACROQOL). ACROQOL was evaluated in a prospective study (at baseline, at 6 and 24 months) in 23 active untreated acromegalic patients. Control of acromegaly was defined by normal age matched serum IGF-I concentrations. Patient groups were defined as controlled or uncontrolled at 6 months and at 24 months: controlled or uncontrolled during the entire study period (ACRO(CC) or ACRO(NC), respectively) or uncontrolled at 6 months and controlled thereafter (ACRO(C)). At 6 months, ACROQOL scores improved globally (from 54.3+/-21 to 65.1+/-19, p=0.04) as did subdomains and were inversely related to IGF-I variation (r=-0.50, p=0.052). At 24 months, ACROQOL improved globally (from 54.3+/-21 to 65.7+/-18.0, p=0.04) and this was also seen in the appearance subdomains; however, no correlation was revealed between variation of serum IGF-I concentrations and changes in ACROQOL total score (r=0.008, p=0.87). ACROQOL scores did not significantly change in ACRO(NC) (p=0.310) and in ACRO(C) (p=0.583), whereas it improved globally (from 42.1+/ 22.1 to 58.8+/-16.04, p=0.021) and in psychological subdomains in ACRO(CC); however, it reflected the improvement occurred within the first 6 months of disease control. In conclusion, successful treatment, which normalizes disease activity, improves QoL in acromegaly in the short term. However, the lack of correlation between the ACROQOL score in the long term might suggest that factors other than serum IGF-I participate in the well-being of acromegalic patients; however, due to the small sample size, our results need to be confirmed in larger studies. PMID- 20203540 TI - Radiotherapy for eyelid, periocular, and periorbital skin cancers. PMID- 20203541 TI - Tracheostomy in the ICU: is timing everything? PMID- 20203539 TI - Growth and endocrine function in thalassemia major in childhood and adolescence. AB - BACKGROUND: Thalassemia major is an inherited hemoglobin disorder characterized by chronic anemia and iron overload due to transfusion therapy and gastrointestinal absorption. Iron overload causes most of the associated mortality and morbidity and frequently involves the endocrine glands. AIM: To review the most pertinent literature on the topic. METHODS: One hundred and twenty-three papers were evaluated. RESULTS: Disproportionate short stature is frequent and becomes more evident at puberty because of the lack of growth spurt. Later on, partial height recovery may occur. Long-term treatment with recombinant human GH seems ineffective to improve final height. Pubertal development is characterized by a clinical spectrum ranging from hypogonadism to a simple delay in starting and developing of puberty. Hormonal replacement is mandatory in cases of absent or arrested puberty. Pancreatic beta-cells function may be impaired during adolescence or later on. Its impairment ranges from hyperinsulinemia, secondary to insulin resistance, with normal glucose tolerance to beta-cells failure with insulin-dependent diabetes mellitus. Primary hypothyroidism may affect thalassemic patients from the second decade of life. The thyroid dysfunction may be reversible (if an intensive chelation therapy regimen is started in the precocious phase), stationary, or slowly progressive. Central hypothyroidism is less common and autoimmune thyroiditis absent. CONCLUSION: Despite the improvement of the treatment, the involvement of the endocrine system still burdens the life of these patients. Further therapeutic improvement would reasonably reduce morbidity and, hopefully, mortality of thalassemic patients and make the endocrine disorders easier to treat. PMID- 20203542 TI - Hemodynamic responses to laryngoscopy and intubation: etiological or symptomatic prevention? PMID- 20203543 TI - The use of prophylactic vancomycin to prevent MRSA colonization: does this double edged sword promote future vancomycin resistance or is it a safe preventative strategy that should be used in all patients in the context of MRSA endemicity? PMID- 20203544 TI - Echocardiography as a reliable tool in neonates with ductal shunting. PMID- 20203545 TI - Effects of tracheal intubation on ventilation with LMA classic for percutaneous dilation tracheostomy. AB - AIM: The classic laryngeal mask airway (cLMATM) can be used in place of an endotracheal tube (ETT) as the ventilatory device during percutaneous dilational tracheostomy (PDT). We aimed to investigate the possible loss of efficacy of cLMATM after tracheal intubation. METHODS: Severity of laryngeal lesions and efficacy of cLMATM were determined in two groups of thirty patients each who were switched from ETT ventilation to cLMA ventilation for PDT after a short (<4 days) or a long (>12 days) tracheal intubation. RESULTS: cLMATM allowed us to carry out PDT in all patients. Short tracheal intubations resulted in mild lesions of the larynx and mild gas leaks during cLMATM ventilation. Longer intubations caused moderate-to-severe (P<0.05) lesions of the larynx and larger gas leaks. A single complication occurred in one patient post-procedurally and in no patient at 6 month follow-up. CONCLUSION: Efficacy of cLMATM was maintained after short tracheal intubation and decreased after long intubation. PMID- 20203546 TI - Attenuation of hemodynamic responses to laryngoscopy and tracheal intubation during rapid sequence induction: remifentanil vs. lidocaine with esmolol. AB - AIM: This study was designed to compare the effectiveness of remifentanil vs. a lidocaine-esmolol combination in blunting the hemodynamic response to laryngoscopy and intubation during rapid sequence induction using thiopental and rocuronium in normotensive patients. METHODS: Sixty-six patients with American Society of Anesthesiologists (ASA) physical status class I who required tracheal intubation for elective surgery were randomly assigned to one of two groups. Group R received 0.9% saline 10 ml and remifentanil 1 microg/kg. Group LE received lidocaine 1.5 mg/kg and esmolol 1.0 mg/kg. Anesthesia was induced with thiopental sodium 5 mg/kg, followed by rocuronium 1.0 mg/kg. Mean arterial pressure and heart rate were recorded at baseline, after induction, immediately after intubation and every minute for five minutes after intubation. RESULTS: Changes in mean arterial pressure over time between the two groups were significantly different (P<0.0001). The maximum pressor response was observed immediately after intubation, at which time the mean arterial pressure change from baseline in group LE (29.7%) (95% confidence interval [CI]: 116.1, 121.9) was higher than that in group R (4.4%) (95% CI: 92.9, 98.5) (P<0.0001). Two patients in group R and 15 patients in group LE developed hypertension (odds ratio [OR]: 0.064) (P<0.001). Changes in heart rate over time between the two groups were not significantly different (P=0.465). CONCLUSION: The results of this study show that remifentanil 1 mg/kg is more effective than the combination of lidocaine 1.5 mg/kg and esmolol 1 mg/kg for attenuating the hemodynamic responses to rapid sequence intubation. PMID- 20203547 TI - Topical oropharyngeal vancomycin to control methicillin-resistant Staphylococcus aureus lower airway infection in ventilated patients. AB - AIM: Topical vancomycin applied to the oropharynx has been shown to control carriage and lower airway infection due to methicillin-resistant Staphylococcus aureus (MRSA). We undertook a three-year prospective observational study to evaluate the effectiveness of two policies for topical vancomycin administration on oropharyngeal carriage and lower airway infection due to MRSA in patients requiring mechanical ventilation. METHODS: All consecutive patients aged over 18 years and expected to require mechanical ventilation for more than 72 hours were enrolled. During period one, patients who were established MRSA carriers received 1 g of 4% vancomycin gel into the oropharynx four times a day until carriage was abolished. During period two, all enrolled patients received the same protocol immediately on admission, irrespective of their MRSA carrier state. RESULTS: One hundred ninety-one patients met the entry criteria (98 in period one and 93 in period two). During period one, 40 patients developed oropharyngeal MRSA carriage; of these, 29 acquired MRSA in the unit. In contrast, MRSA carriage was not demonstrated during period two (relative risk [RR] 0.018, 95% confidence interval [CI] 0-0.29; P=0.004). Twenty-one patients from period one suffered from an Intensive Care Unit-acquired lower airway infection due to MRSA, compared with five patients from period two (RR 0.25, 95% CI 0.10-0.64, P=0.004). Vancomycin intermediate Staphylococcus aureus and vancomycin-resistant enterococci were not isolated. CONCLUSION: In the setting of MRSA endemicity, the prevention of MRSA carriage by topical oropharyngeal vancomycin was more effective in reducing carriage and infection of the lower airways than treatment of established carriers. PMID- 20203548 TI - End-of-life care is still a challenge for Italy. AB - The aim of this paper was to review current end of life (EOL) practice in Italy. The authors have made an appraisal of the existing literature in order to understand current end of life care practice in Italy. This manuscript focuses on analyzing the dying process, the transoceanic similarities and differences in the end of life decision-making practice, and the family involvement. The authors acknowledge the importance of the recent Englaro court case verdict on current practice in Italy. Dying has changed as a process over the last century in term of causes of death, costs, communication of the prognosis, and needs of the patient's family. Regardless of national and international guidelines, there is no agreement among Italian doctors regarding the gold standards of daily clinical practice at the EOL. PMID- 20203549 TI - Echocardiographic evaluation and clinical management of ductal shunting in hemodynamically unstable preterm neonates without congenital heart disease in the pediatric intensive care unit. AB - Although significant steps have been taken to monitor complex hemodynamics in neonatal and pediatric intensive care units, cardiovascular function in neonates is still evaluated by measuring blood pressure, heart rate, diuresis, central venous pressure (if a central venous catheter was placed), capillary refill time and oxygen saturation measurement in the upper and lower extremities. The use of other non-invasive or invasive technologies (for example, continuous impedance cardiography, transesophageal Doppler and continuous pulse contour methods) is, in fact, quite problematic in neonates in whom relevant hemodynamic changes are common during the transition to postnatal life. For these reasons, use of transthoracic echocardiography, performed by skilled pediatric intensivists, is increasing in several dedicated centers to guide treatment choices in hemodynamically unstable neonates. PMID- 20203550 TI - Inhalation anesthetics: a review. AB - Inhalation agents represent a basic drug used in modern balanced anesthesia. In the present review, the pharmacokinetics, effectiveness and clinical effects of inhalation agents on different systems are discussed. Data concerning the metabolism and related toxicity of halogenated agents is reviewed, with particular regard to the problem of chronic exposure to traces of anesthetic gases in the operating room. The cardioprotective effect of halogenated agents and the actual role of nitrous oxide and xenon are discussed. The different mechanisms of action of the inhalation agents and the evolution from a unitary theory of inhaled anesthetics to a multiple mechanism concept are presented. PMID- 20203551 TI - Anesthetic management of an adult patient with Cornelia de Lange Syndrome. AB - Cornelia de Lange Syndrome is a well-known congenital disease characterized by multiple malformations that make anesthetic management a challenge. Since few individuals survive the earliest stage of life, papers describing the details of anesthetic management are mainly reported in the pediatric population. These individuals who move into adulthood develop physical changes that should be taken into consideration. This article reports the case of a 34-year-old patient undergoing an orthopedic procedure. The operation was performed under general anesthesia because the patient showed severe scoliosis and joint contractures, so extraordinary difficulty in neuroaxial and peripheral techniques was expected. The aggressive behavior of the patient impeded the proper assessment of a preoperative airway. Fiber optic intubation was performed under slight sedation after three unsuccessful attempts. Dental crowding, prominent upper central incisors that were more pronounced than in most children, a short and stiff neck, and poor patient cooperation due to mental retardation and occasional autistic behavior made airway management difficult. This case should alert anesthesiologists to the greater difficulties of managing patients with Cornelia de Lange Syndrome when they become adults. PMID- 20203552 TI - Importance of perioperative monitoring of cerebral tissue saturation in elderly patients: an interesting case. AB - The authors describe the case of an elderly diabetic patient with a hip fracture who developed neurocognitive dysfunction and dysarthria preoperatively. Upon arrival in the operating room, the monitoring of cerebral oxygenation by near infrared spectroscopy (NIRS) showed cerebral desaturation (44% on the left hemisphere and 46% on the right). Cerebral oximetry values were stabilized during the surgery after administration of crystalloid fluids and vasoconstrictive drugs and were ameliorated significantly after administration of two units of blood. The patient's cerebral saturation was 60% on the left and 58% on the right hemisphere after the end of surgery and he was in normal neurological status. Observations underlined the importance of preoperative evaluation of cerebral tissue oxygenation by non-invasive cerebral NIRS in elderly diabetic patients who develop hypovolemia and anemia due to major fracture. PMID- 20203553 TI - Malaria acquired in Haiti - 2010. AB - On January 12, 2010, a 7.0 magnitude earthquake struck Haiti, which borders the Dominican Republic on the island of Hispaniola. The earthquake's epicenter was 10 miles west of the Haiti capital city of Port-au-Prince (estimated population: 2 million). According to the Haitian government, approximately 200,000 persons were killed, and 500,000 were left homeless. Malaria caused by Plasmodium falciparum infection is endemic in Haiti, and the principal mosquito vector is Anopheles albimanus, which frequently bites outdoors. Thus, displaced persons living outdoors or in temporary shelters and thousands of emergency responders in Haiti are at substantial risk for malaria. During January 12-February 25, CDC received reports of 11 laboratory-confirmed cases of P. falciparum malaria acquired in Haiti. Patients included seven U.S. residents who were emergency responders, three Haitian residents, and one U.S. traveler. This report summarizes the 11 cases and provides chemoprophylactic and additional preventive recommendations to minimize the risk for acquiring malaria for persons traveling to Haiti. PMID- 20203554 TI - Identifying infants with hearing loss - United States, 1999-2007. AB - Congenital hearing loss affects two to three infants per 1,000 live births. Undetected hearing loss can delay speech and language development. A total of 41 states, Guam, and the District of Columbia have statutes or regulatory guidance to identify infants with hearing loss. All states and U.S. territories also have established Early Hearing Detection and Intervention (EHDI) programs, which embody evidence-based public health policy for addressing infant hearing loss. EHDI programs help ensure that newborns and infants are screened and receive recommended follow-up through data collection and outreach to hospitals, providers, and families. To determine the status of efforts to identify newborns and infants with hearing loss, CDC analyzed EHDI surveillance data from 1999 2007. Differences in how data were reported and collected limit comparability between 1999-2004 and 2005-2007 data; however, available data indicated an increase in infants screened from 46.5% in 1999 to 97.0% in 2007. In addition, the number of infants documented with hearing loss in 2007 increased by nearly 500 infants among the same 21 states reporting data in 2001 (1,736 identified in 2001 versus 2,212 in 2007). These findings demonstrate progress toward achieving benchmarks for screening, evaluation, and intervention and document the continued need to ensure infants receive recommended services in a timely manner. PMID- 20203555 TI - Severe isoniazid-associated liver injuries among persons being treated for latent tuberculosis infection - United States, 2004-2008. AB - Since the 1960s, 6 to 9 months of isoniazid (INH) has been the mainstay of treatment for latent tuberculosis infection (LTBI), but its application has been limited by concerns about the toxicity of INH and the long duration of treatment. To quantify the frequency of severe adverse events (SAEs) associated with LTBI treatment and to characterize the clinical features of affected patients, in January 2004 CDC began a national project to monitor SAEs associated with treatment for LTBI. State health departments were encouraged to report SAEs associated with any LTBI treatment regimen to a passive surveillance system. This report summarizes the results for 2004-2008, when 17 SAEs in 15 adults and two children (aged 11 and 14 years) were reported. All patients had received INH therapy and had experienced severe liver injury. Five patients, including one child, underwent liver transplantation. Five adults died, including one liver transplant recipient. These findings underscore the risk for an idiosyncratic drug-induced reaction in patients of any age treated with INH, including those with or without a putative predictor for INH-associated liver injury. Patients receiving INH for LTBI therapy should be monitored according to American Thoracic Society (ATS)/CDC recommendations because of the risk for drug-induced hepatoxicity. Providers should counsel patients to terminate INH therapy promptly and seek medical attention if they experience signs and symptoms of illness. PMID- 20203556 TI - Respiratory syncytial virus activity - United States, July 2008-December 2009. AB - Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis and pneumonia in children aged <1 year worldwide. Each year in the United States, an estimated 75,000-125,000 infants are hospitalized with RSV. Among adults aged >65 years, an estimated 177,000 hospitalizations and 14,000 deaths a year have been attributed to RSV infections. In temperate climates, the RSV season generally begins during the fall and continues through the winter and spring, but the exact timing of RSV circulation varies by location and year. In the United States, data from the National Respiratory and Enteric Virus Surveillance System (NREVSS) are used to monitor the seasonal occurrence of RSV. During the 2008-09 season, onset occurred from mid-October to late December in the 10 U.S. Department of Health and Human Services (HHS) regions, excluding Florida, which had onset in mid-July. Season offset in all regions occurred from mid-February to mid-April. Florida is reported separately because it has an earlier season onset and longer duration than the rest of the country. During the current 2009-10 season, onset occurred in all 10 HHS regions by February 20, 2010. These patterns are similar to previous years and confirm differences in RSV seasonal characteristics across regions. Knowledge of RSV seasonality can be used by clinicians and public health officials to determine when to consider RSV as a cause of acute respiratory illnesses and when to provide RSV immunoprophylaxis to children at high risk for serious disease. PMID- 20203557 TI - Dissection of organs from the adult zebrafish. AB - Over the last 20 years, the zebrafish has become a powerful model organism for understanding vertebrate development and disease. Although experimental analysis of the embryo and larva is extensive and the morphology has been well documented, descriptions of adult zebrafish anatomy and studies of development of the adult structures and organs, together with techniques for working with adults are lacking. The organs of the larva undergo significant changes in their overall structure, morphology, and anatomical location during the larval to adult transition. Externally, the transparent larva develops its characteristic adult striped pigment pattern and paired pelvic fins, while internally, the organs undergo massive growth and remodeling. In addition, the bipotential gonad primordium develops into either testis or ovary. This protocol identifies many of the organs of the adult and demonstrates methods for dissection of the brain, gonads, gastrointestinal system, heart, and kidney of the adult zebrafish. The dissected organs can be used for in situ hybridization, immunohistochemistry, histology, RNA extraction, protein analysis, and other molecular techniques. This protocol will assist in the broadening of studies in the zebrafish to include the remodeling of larval organs, the morphogenesis of organs specific to the adult and other investigations of the adult organ systems. PMID- 20203558 TI - The ratings game. PMID- 20203559 TI - Do scientists really need a PhD? PMID- 20203560 TI - The bigger picture. PMID- 20203567 TI - Journal club. A neuroscientist explores the network of cells in the retina. PMID- 20203573 TI - Model response to Chile quake? PMID- 20203574 TI - Unmanned planes take wing for science. PMID- 20203575 TI - University rankings smarten up. PMID- 20203576 TI - Fat rats skew research results. PMID- 20203578 TI - Weapons labs to thrive as Obama trims nukes. PMID- 20203577 TI - The labours of Fotis Kafatos. PMID- 20203579 TI - Chinese bioscience: The sequence factory. PMID- 20203580 TI - Non-proliferation: Borderline detection. PMID- 20203581 TI - World view: Curing climate backlash. PMID- 20203582 TI - South Africa: big science should stay on the agenda. PMID- 20203584 TI - South Africa: aiming to be premier global astronomy hub. PMID- 20203585 TI - South Africa: telescopes raise the nation's sights. PMID- 20203586 TI - Foundations could allocate money more productively. PMID- 20203587 TI - Esaki diode is still a radio star, half a century on. PMID- 20203588 TI - Spring awakening planned for Mars rover Spirit. PMID- 20203589 TI - Stop laser uranium enrichment. PMID- 20203593 TI - Q&A: Joanna Cole on writing science books for kids. Interview by Nicola Jones. PMID- 20203594 TI - Behavioural neurobiology: The treacherous scent of a human. PMID- 20203595 TI - Microscopy: When mica and water meet. PMID- 20203597 TI - Materials science: Hydrocarbon superconductors. PMID- 20203598 TI - Clinical immunology: Culprits with evolutionary ties. PMID- 20203599 TI - Materials science: Mind the helical crack. PMID- 20203600 TI - Developmental genetics: Time for teeth. PMID- 20203601 TI - Obituary: Marshall Nirenberg (1927-2010). PMID- 20203602 TI - Quantum computers. AB - Over the past several decades, quantum information science has emerged to seek answers to the question: can we gain some advantage by storing, transmitting and processing information encoded in systems that exhibit unique quantum properties? Today it is understood that the answer is yes, and many research groups around the world are working towards the highly ambitious technological goal of building a quantum computer, which would dramatically improve computational power for particular tasks. A number of physical systems, spanning much of modern physics, are being developed for quantum computation. However, it remains unclear which technology, if any, will ultimately prove successful. Here we describe the latest developments for each of the leading approaches and explain the major challenges for the future. PMID- 20203604 TI - Linking dwarf galaxies to halo building blocks with the most metal-poor star in Sculptor. AB - Current cosmological models indicate that the Milky Way's stellar halo was assembled from many smaller systems. On the basis of the apparent absence of the most metal-poor stars in present-day dwarf galaxies, recent studies claimed that the true Galactic building blocks must have been vastly different from the surviving dwarfs. The discovery of an extremely iron-poor star (S1020549) in the Sculptor dwarf galaxy based on a medium-resolution spectrum cast some doubt on this conclusion. Verification of the iron-deficiency, however, and measurements of additional elements, such as the alpha-element Mg, are necessary to demonstrate that the same type of stars produced the metals found in dwarf galaxies and the Galactic halo. Only then can dwarf galaxy stars be conclusively linked to early stellar halo assembly. Here we report high-resolution spectroscopic abundances for 11 elements in S1020549, confirming its iron abundance of less than 1/4,000th that of the Sun, and showing that the overall abundance pattern follows that seen in low-metallicity halo stars, including the alpha-elements. Such chemical similarity indicates that the systems destroyed to form the halo billions of years ago were not fundamentally different from the progenitors of present-day dwarfs, and suggests that the early chemical enrichment of all galaxies may be nearly identical. PMID- 20203605 TI - Superconductivity in alkali-metal-doped picene. AB - Efforts to identify and develop new superconducting materials continue apace, motivated by both fundamental science and the prospects for application. For example, several new superconducting material systems have been developed in the recent past, including calcium-intercalated graphite compounds, boron-doped diamond and-most prominently-iron arsenides such as LaO(1-x)F(x)FeAs (ref. 3). In the case of organic superconductors, however, no new material system with a high superconducting transition temperature (T(c)) has been discovered in the past decade. Here we report that intercalating an alkali metal into picene, a wide bandgap semiconducting solid hydrocarbon, produces metallic behaviour and superconductivity. Solid potassium-intercalated picene (K(x)picene) shows T(c) values of 7 K and 18 K, depending on the metal content. The drop of magnetization in K(x)picene solids at the transition temperature is sharp (<2 K), similar to the behaviour of Ca-intercalated graphite. The T(c) of 18 K is comparable to that of K-intercalated C(60) (ref. 4). This discovery of superconductivity in K(x)picene shows that organic hydrocarbons are promising candidates for improved T(c) values. PMID- 20203603 TI - A human gut microbial gene catalogue established by metagenomic sequencing. AB - To understand the impact of gut microbes on human health and well-being it is crucial to assess their genetic potential. Here we describe the Illumina-based metagenomic sequencing, assembly and characterization of 3.3 million non redundant microbial genes, derived from 576.7 gigabases of sequence, from faecal samples of 124 European individuals. The gene set, approximately 150 times larger than the human gene complement, contains an overwhelming majority of the prevalent (more frequent) microbial genes of the cohort and probably includes a large proportion of the prevalent human intestinal microbial genes. The genes are largely shared among individuals of the cohort. Over 99% of the genes are bacterial, indicating that the entire cohort harbours between 1,000 and 1,150 prevalent bacterial species and each individual at least 160 such species, which are also largely shared. We define and describe the minimal gut metagenome and the minimal gut bacterial genome in terms of functions present in all individuals and most bacteria, respectively. PMID- 20203606 TI - Reinventing germanium avalanche photodetector for nanophotonic on-chip optical interconnects. AB - Integration of optical communication circuits directly into high-performance microprocessor chips can enable extremely powerful computer systems. A germanium photodetector that can be monolithically integrated with silicon transistor technology is viewed as a key element in connecting chip components with infrared optical signals. Such a device should have the capability to detect very-low power optical signals at very high speed. Although germanium avalanche photodetectors (APD) using charge amplification close to avalanche breakdown can achieve high gain and thus detect low-power optical signals, they are universally considered to suffer from an intolerably high amplification noise characteristic of germanium. High gain with low excess noise has been demonstrated using a germanium layer only for detection of light signals, with amplification taking place in a separate silicon layer. However, the relatively thick semiconductor layers that are required in such structures limit APD speeds to about 10 GHz, and require excessively high bias voltages of around 25 V (ref. 12). Here we show how nanophotonic and nanoelectronic engineering aimed at shaping optical and electrical fields on the nanometre scale within a germanium amplification layer can overcome the otherwise intrinsically poor noise characteristics, achieving a dramatic reduction of amplification noise by over 70 per cent. By generating strongly non-uniform electric fields, the region of impact ionization in germanium is reduced to just 30 nm, allowing the device to benefit from the noise reduction effects that arise at these small distances. Furthermore, the smallness of the APDs means that a bias voltage of only 1.5 V is required to achieve an avalanche gain of over 10 dB with operational speeds exceeding 30 GHz. Monolithic integration of such a device into computer chips might enable applications beyond computer optical interconnects-in telecommunications, secure quantum key distribution, and subthreshold ultralow-power transistors. PMID- 20203607 TI - Helical crack-front instability in mixed-mode fracture. AB - Planar crack propagation under pure tension loading (mode I) is generally stable. However, it becomes universally unstable with the superposition of a shear stress parallel to the crack front (mode III). Under this mixed-mode (I + III) loading configuration, an initially flat parent crack segments into an array of daughter cracks that rotate towards a direction of maximum tensile stress. This segmentation produces stepped fracture surfaces with characteristic 'lance shaped' markings observed in a wide range of engineering and geological materials. The origin of this instability remains poorly understood and a theory with which to predict the surface roughness scale is lacking. Here we perform large-scale simulations of mixed-mode I + III brittle fracture using a continuum phase-field method that describes the complete three-dimensional crack-front evolution. The simulations reveal that planar crack propagation is linearly unstable against helical deformations of the crack front, which evolve nonlinearly into a segmented array of finger-shaped daughter cracks. Furthermore, during their evolution, facets gradually coarsen owing to the growth competition of daughter cracks in striking analogy with the coarsening of finger patterns observed in nonequilibrium growth phenomena. We show that the dynamically preferred unstable wavelength is governed by the balance of the destabilizing effect of far-field stresses and the stabilizing effect of cohesive forces on the process zone scale, and we derive a theoretical estimate for this scale using a new propagation law for curved cracks in three dimensions. The rotation angles of coarsened facets are also compared to theoretical predictions and available experimental data. PMID- 20203608 TI - Ecologically distinct dinosaurian sister group shows early diversification of Ornithodira. AB - The early evolutionary history of Ornithodira (avian-line archosaurs) has hitherto been documented by incomplete (Lagerpeton) or unusually specialized forms (pterosaurs and Silesaurus). Recently, a variety of Silesaurus-like taxa have been reported from the Triassic period of both Gondwana and Laurasia, but their relationships to each other and to dinosaurs remain a subject of debate. Here we report on a new avian-line archosaur from the early Middle Triassic (Anisian) of Tanzania. Phylogenetic analysis places Asilisaurus kongwe gen. et sp. nov. as an avian-line archosaur and a member of the Silesauridae, which is here considered the sister taxon to Dinosauria. Silesaurids were diverse and had a wide distribution by the Late Triassic, with a novel ornithodiran bauplan including leaf-shaped teeth, a beak-like lower jaw, long, gracile limbs, and a quadrupedal stance. Our analysis suggests that the dentition and diet of silesaurids, ornithischians and sauropodomorphs evolved independently from a plesiomorphic carnivorous form. As the oldest avian-line archosaur, Asilisaurus demonstrates the antiquity of both Ornithodira and the dinosaurian lineage. The initial diversification of Archosauria, previously documented by crocodilian-line archosaurs in the Anisian, can now be shown to include a contemporaneous avian line radiation. The unparalleled taxonomic diversity of the Manda archosaur assemblage indicates that archosaur diversification was well underway by the Middle Triassic or earlier. PMID- 20203609 TI - Changes in Hox genes' structure and function during the evolution of the squamate body plan. AB - Hox genes are central to the specification of structures along the anterior posterior body axis, and modifications in their expression have paralleled the emergence of diversity in vertebrate body plans. Here we describe the genomic organization of Hox clusters in different reptiles and show that squamates have accumulated unusually large numbers of transposable elements at these loci, reflecting extensive genomic rearrangements of coding and non-coding regulatory regions. Comparative expression analyses between two species showing different axial skeletons, the corn snake and the whiptail lizard, revealed major alterations in Hox13 and Hox10 expression features during snake somitogenesis, in line with the expansion of both caudal and thoracic regions. Variations in both protein sequences and regulatory modalities of posterior Hox genes suggest how this genetic system has dealt with its intrinsic collinear constraint to accompany the substantial morphological radiation observed in this group. PMID- 20203610 TI - Circulating mitochondrial DAMPs cause inflammatory responses to injury. AB - Injury causes a systemic inflammatory response syndrome (SIRS) that is clinically much like sepsis. Microbial pathogen-associated molecular patterns (PAMPs) activate innate immunocytes through pattern recognition receptors. Similarly, cellular injury can release endogenous 'damage'-associated molecular patterns (DAMPs) that activate innate immunity. Mitochondria are evolutionary endosymbionts that were derived from bacteria and so might bear bacterial molecular motifs. Here we show that injury releases mitochondrial DAMPs (MTDs) into the circulation with functionally important immune consequences. MTDs include formyl peptides and mitochondrial DNA. These activate human polymorphonuclear neutrophils (PMNs) through formyl peptide receptor-1 and Toll like receptor (TLR) 9, respectively. MTDs promote PMN Ca(2+) flux and phosphorylation of mitogen-activated protein (MAP) kinases, thus leading to PMN migration and degranulation in vitro and in vivo. Circulating MTDs can elicit neutrophil-mediated organ injury. Cellular disruption by trauma releases mitochondrial DAMPs with evolutionarily conserved similarities to bacterial PAMPs into the circulation. These signal through innate immune pathways identical to those activated in sepsis to create a sepsis-like state. The release of such mitochondrial 'enemies within' by cellular injury is a key link between trauma, inflammation and SIRS. PMID- 20203614 TI - Mass appeal. PMID- 20203611 TI - SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. AB - Sirtuins are NAD(+)-dependent protein deacetylases. They mediate adaptive responses to a variety of stresses, including calorie restriction and metabolic stress. Sirtuin 3 (SIRT3) is localized in the mitochondrial matrix, where it regulates the acetylation levels of metabolic enzymes, including acetyl coenzyme A synthetase 2 (refs 1, 2). Mice lacking both Sirt3 alleles appear phenotypically normal under basal conditions, but show marked hyperacetylation of several mitochondrial proteins. Here we report that SIRT3 expression is upregulated during fasting in liver and brown adipose tissues. During fasting, livers from mice lacking SIRT3 had higher levels of fatty-acid oxidation intermediate products and triglycerides, associated with decreased levels of fatty-acid oxidation, compared to livers from wild-type mice. Mass spectrometry of mitochondrial proteins shows that long-chain acyl coenzyme A dehydrogenase (LCAD) is hyperacetylated at lysine 42 in the absence of SIRT3. LCAD is deacetylated in wild-type mice under fasted conditions and by SIRT3 in vitro and in vivo; and hyperacetylation of LCAD reduces its enzymatic activity. Mice lacking SIRT3 exhibit hallmarks of fatty-acid oxidation disorders during fasting, including reduced ATP levels and intolerance to cold exposure. These findings identify acetylation as a novel regulatory mechanism for mitochondrial fatty-acid oxidation and demonstrate that SIRT3 modulates mitochondrial intermediary metabolism and fatty-acid use during fasting. PMID- 20203615 TI - Glittering prizes. PMID- 20203616 TI - Is nanotechnology too broad to practise? PMID- 20203618 TI - Can graphene set new standards? PMID- 20203619 TI - Making nanopores from nanotubes. PMID- 20203620 TI - Engineering the next generation. PMID- 20203621 TI - Memory grows up. PMID- 20203622 TI - Nanowire transistors made easy. PMID- 20203623 TI - AP-1/sigma1B-adaptin mediates endosomal synaptic vesicle recycling, learning and memory. AB - Synaptic vesicle recycling involves AP-2/clathrin-mediated endocytosis, but it is not known whether the endosomal pathway is also required. Mice deficient in the tissue-specific AP-1-sigma1B complex have impaired synaptic vesicle recycling in hippocampal synapses. The ubiquitously expressed AP-1-sigma1A complex mediates protein sorting between the trans-Golgi network and early endosomes. Vertebrates express three sigma1 subunit isoforms: A, B and C. The expressions of sigma1A and sigma1B are highest in the brain. Synaptic vesicle reformation in cultured neurons from sigma1B-deficient mice is reduced upon stimulation, and large endosomal intermediates accumulate. The sigma1B-deficient mice have reduced motor coordination and severely impaired long-term spatial memory. These data reveal a molecular mechanism for a severe human X-chromosome-linked mental retardation. PMID- 20203624 TI - The mycobacterial Mpa-proteasome unfolds and degrades pupylated substrates by engaging Pup's N-terminus. AB - Mycobacterium tuberculosis, along with other actinobacteria, harbours proteasomes in addition to members of the general bacterial repertoire of degradation complexes. In analogy to ubiquitination in eukaryotes, substrates are tagged for proteasomal degradation with prokaryotic ubiquitin-like protein (Pup) that is recognized by the N-terminal coiled-coil domain of the ATPase Mpa (also called ARC). Here, we reconstitute the entire mycobacterial proteasome degradation system for pupylated substrates and establish its mechanistic features with respect to substrate recruitment, unfolding and degradation. We show that the Mpa proteasome complex unfolds and degrades Pup-tagged proteins and that this activity requires physical interaction of the ATPase with the proteasome. Furthermore, we establish the N-terminal region of Pup as the structural element required for engagement of pupylated substrates into the Mpa pore. In this process, Mpa pulls on Pup to initiate unfolding of substrate proteins and to drag them toward the proteasome chamber. Unlike the eukaryotic ubiquitin, Pup is not recycled but degraded with the substrate. This assigns a dual function to Pup as both the Mpa recognition element as well as the threading determinant. PMID- 20203626 TI - Serum uric acid levels and renal damage in hyperuricemic hypertensive patients treated with renin-angiotensin system blockers. AB - BACKGROUND: A correlation between hyperuricemia and renal target organ damage (TOD) was shown in hypertensive patients, locally mediated by the activation of renin-angiotensin system (RAS). We investigated whether high serum uric acid (UA) levels could negatively affect tubulointerstitial damage in hyperuricemic essential hypertensive patients with normal renal function, on treatment with RAS blocking drugs. METHODS: We studied 40 patients with World Health Organization stage I-II essential hypertension, 9 with high serum UA levels (hyperuricemic group) and 31 with normal serum UA levels (normouricemic group, either normouricemics, n = 15, or formerly hyperuricemics in chronic allopurinol treatment, n = 16). All patients were on RAS-blocking drugs (either angiotensin converting enzyme inhibitors or angiotensin II receptors blockers). Evaluation of renal TOD included urinary albumin excretion (UAE), Doppler ultrasound renal resistive index (RRI) and renal volume-to-resistive index ratio (RV/RRI) measurements. RESULTS: Hyperuricemics had significantly higher RRI and lower RV/RRI values than normouricemics. Creatinine clearance and UAE were similar between groups. Linear regression analysis showed that RV/RRI values were inversely related to serum UA levels (r = -0.57, P < 0.01). The logistic regression analysis selected serum UA as an independent predictor of decreased RV/RRI (odds ratio 4.45, 95% CI 1.47-13.45, P = 0.01). CONCLUSIONS: In hyperuricemic hypertensives normal serum UA levels are associated with normal RV/RRI, integrated marker of tubulointerstitial damage and renal arteriolopathy, independently of RAS activation. PMID- 20203627 TI - Low vs. higher-dose dark chocolate and blood pressure in cardiovascular high-risk patients. AB - BACKGROUND: Dark chocolate may have blood pressure-lowering properties. We conducted a prospective randomized open-label blinded end-point design trial to study a potential dose dependency of the presumed antihypertensive effect of dark chocolate by directly comparing low vs. higher doses of dark chocolate over the course of 3 months. METHODS: We enrolled a total of 102 patients with prehypertension/stage 1 hypertension and established cardiovascular end-organ damage or diabetes mellitus. Patients were randomly assigned to receive either 6 or 25 g/day of flavanol-rich dark chocolate for 3 months. The difference in 24-h mean blood pressure between groups was defined as the primary outcome measure. RESULTS: Significant reductions in mean ambulatory 24-h blood pressure were observed between baseline and follow-up in both groups (6 g/day: -2.3 mm Hg, 95% confidence interval -4.1 to -0.4; 25 g/day: -1.9 mm Hg, 95% confidence interval 3.6 to -0.2). There were no significant differences in blood pressure changes between groups. In the higher-dose group, a slight increase in body weight was noted (0.8 kg, 95% confidence interval 0.06 to 1.6). CONCLUSIONS: The findings are consistent with the hypothesis that dark chocolate may be associated with a reduction in blood pressure (BP). However, due to the lack of a control group, confounding may be possible and the results should be interpreted with caution. PMID- 20203628 TI - Association of resistin with urinary albumin excretion in nondiabetic patients with essential hypertension. AB - BACKGROUND: Evidence suggests that resistin, a recently described protein, is associated with subclinical atherosclerosis in different clinical settings. In this study, we investigated the relationship of increased resistin levels with urinary albumin excretion, expressed as the albumin-to-creatinine ratio (ACR), an established index of diffuse vascular damage, in hypertensives. METHODS: Our population consisted of 132 untreated nondiabetic subjects with stage I-II essential hypertension (49 males, mean age = 54 years, mean office blood pressure (BP) = 159/100 mm Hg). In all patients, ACR was determined as the average of three nonconsecutive morning spot urine samples, and venous blood sampling was performed for estimation of resistin concentrations. The distribution of resistin was split by the median (4.63 ng/ml), and accordingly, subjects were stratified into those with high and low values. RESULTS: Hypertensive patients with high (n = 66) compared to those with low resistin (n = 66) exhibited higher ACR values (21.8 + or - 15.3 vs. 10.3 + or - 3.8 mg/g, P < 0.01), even after adjustment for confounders. In the total population, resistin was associated with 24-h systolic BP (r = 0.244, P < 0.05), serum creatinine (r = 0.311, P = 0.007), and ACR (r = 0.499, P < 0.01). Multiple regression analysis revealed that age (b = 0.193, P = 0.02), body mass index (b = 0.237, P = 0.02), 24-h systolic BP (b = 0.338, P < 0.0001), 24-h heart rate (b = 0.169, P = 0.04), and resistin (b = 0.77, P < 0.01) were independently associated with ACR (R(2) = 0.471, P < 0.01). CONCLUSIONS: Hypertensive subjects with augmented resistin levels exhibit higher albuminuria, independently of established risk factors. Moreover, the association of resistin with ACR suggests a link between resistin and microvascular disease in the early stages of essential hypertension. PMID- 20203629 TI - Obesity and receipt of clinical preventive services in veterans. AB - Although obese individuals utilize health care at higher rates than their normal weight counterparts, they may be less likely to receive certain preventive services. We conducted a retrospective cohort study of veterans with visits to 136 national Veterans Affairs (VA) outpatient clinics in the United States in the year 2000. The cohort included 1,699,219 patients: 94% men, 48% white, and 76% overweight or obese. Overweight and obese patients had higher adjusted odds of receiving each of the targeted clinical preventive services as recommended over 5 years compared with normal weight patients. The odds for receiving vaccinations increased linearly with BMI category: influenza (men: odds ratio (OR) = 1.13 for overweight to OR = 1.42 for obese class 3; women: OR = 1.15 for overweight to OR = 1.61 for obese class 3) and pneumococcus (men: OR = 1.02 for overweight to OR = 1.15 for obese class 3; women: OR = 1.08 for overweight to OR = 1.28 for obese class 3). The odds for receiving the cancer screening services typically peaked in the mild-moderately obese categories. The highest OR for prostate cancer screening was in obese class 2 (OR = 1.29); for colorectal cancer, obese class 1 (men: OR = 1.15; women OR = 1.10); for breast cancer screening, obese class 2 (OR = 1.19); and for cervical cancer screening, obese class 2 (OR = 1.06). In a large national sample, obese patients received preventive services at higher, not lower, rates than their normal weight peers. This may be due to the VA health service coverage and performance directives, a more homogeneous patient demographic profile, and/or unmeasured factors related to service receipt. PMID- 20203631 TI - Generation of a dominant-negative glycogen targeting subunit for protein phosphatase-1. AB - Modulation of the expression of the protein phosphatase-1 (PP1) glycogen targeting subunit PTG exerts profound effects on cellular glycogen metabolism in vitro and in vivo. PTG contains three distinct binding domains for glycogen, PP1, and a common site for glycogen synthase and phosphorylase. The impact of disrupting the PP1-binding domain on PTG function was examined in 3T3-L1 adipocytes. A full-length PTG mutant was generated as an adenoviral construct in which the valine and phenylalanine residues in the conserved PP1-binding domain were mutated to alanine (PTG-VF). Infection of fully differentiated 3T3-L1 adipocytes with the PTG-VF adenovirus reduced glycogen stores by over 50%. In vitro, PTG-VF competitively interfered with wild-type PTG action, suggesting that the mutant construct acted as a dominant-negative molecule. The reduction in cellular glycogen storage was due to a significantly increased rate of glycogen turnover. Interestingly, acute basal and insulin-stimulated glucose uptake and glycogen synthesis rates were enhanced in PTG-VF expressing cells vs. control 3T3 L1 adipocytes, likely as a compensatory response to the loss of glycogen stores. These results indicate that the mutation of the PP1-binding domain on PTG resulted in the generation of a dominant-negative molecule that impeded endogenous PTG action and reduced cellular glycogen levels, through enhancement of glycogenolysis rather than impairment of glycogen synthesis. PMID- 20203630 TI - Dietary calcium intake is associated with less gain in intra-abdominal adipose tissue over 1 year. AB - Calcium intake is reported to enhance weight loss with a preferential loss in trunk fat. Discrepant findings exist as to the effects of calcium intake on longitudinal changes in total fat mass and central fat deposition. Therefore, the purpose of this study was to determine associations between dietary calcium intake and 1-year change in body composition and fat distribution, specifically intra-abdominal adipose tissue (IAAT). A total of 119 healthy, premenopausal women were evaluated at baseline and 1 year later. Average dietary calcium was determined via 4-day food records. Total fat was determined by dual-energy X-ray absorptiometry (DXA) and subcutaneous abdominal adipose tissue (SAAT) and IAAT by computed tomography. Over the study period, participants' reported daily calcium and energy intakes were 610.0 +/- 229.9 mg and 1,623.1 +/- 348.5 kcal, respectively. The mean change in weight, total fat, IAAT, and SAAT was 4.9 +/- 4.4 kg, 5.3 +/- 4.0 kg, 7.7 +/- 19.5 cm(2), and 49.3 +/- 81.1 cm(2), respectively. Average calcium intake was significantly, inversely associated with 1-year change in IAAT (standardized beta: -0.23, P < 0.05) after adjusting for confounding variables. For every 100 mg/day of calcium consumed, gain in IAAT was reduced by 2.7 cm(2). No significant associations were observed for average calcium intake with change in weight, total fat, or SAAT. In conclusion, dietary calcium intake was significantly associated with less gain in IAAT over 1 year in premenopausal women. Further investigation is needed to verify these findings and determine the calcium intake needed to exert beneficial effects on fat distribution. PMID- 20203634 TI - Prospective assessment of inpatient gastrointestinal consultation requests in an academic teaching hospital. AB - OBJECTIVES: To assess the completeness of gastrointestinal (GI) inpatient consultations at an academic teaching hospital. METHODS: We conducted a prospective, cross-sectional study of 278 inpatient GI consultation requests evaluated from 1 July 2005 to 31 May 2007. A questionnaire assessing multiple aspects of the requesting health-care providers' knowledge and documentation of patient information was completed by first-year GI fellows. Completeness of the consultation was evaluated by the GI consultation attending physician. RESULTS: The most frequent consultation requests pertained to patients with GI hemorrhage (52.5%) and were made by first-year residents (56.8%). In 15% of requests, health care providers lacked basic knowledge about the patients for whom consultations were sought. Conversely, in 17% of consultations, pertinent information could not be located in patients' paper medical chart/electronic medical record. The strongest predictors for a complete consultation were requesters' knowledge of patients' past medical history (P < 0.001), documentation of patients' current illness (P < 0.001), and presence of the providers' admission note in the paper medical chart (P = 0.002). Consultations requested between 5 and 10 PM were assessed to be more complete (P = 0.02), and more incomplete consultations occurred in the first 3 months of the academic year (P = 0.04). CONCLUSIONS: In 16% of inpatient GI consultation requests analyzed, crucial patient data were missing or were unknown by the requesting provider. Several aspects of requesting providers' knowledge and documentation of patient information were strongly associated with completeness of inpatient GI consultations. PMID- 20203635 TI - Improving handoff communication: a gastroenterology fellowship performance improvement project. PMID- 20203636 TI - Pathology of gastric intestinal metaplasia: clinical implications. PMID- 20203639 TI - Dyspepsia, peptic ulcer, and H. pylori: a remembrance of things past. AB - Dyspepsia and gastroesophageal reflux disease are common conditions in clinical practice. Current management strategies emphasize testing and treatment for Helicobacter pylori in the initial management of patients presenting with dyspeptic symptoms in regions where the prevalence of H. pylori infection is >15%. Population-based studies in patients with dyspepsia suggest that peptic ulcer disease related to H. pylori infection is decreasing in prevalence, whereas gastroesophageal reflux disease is becoming a more common cause of dyspeptic symptoms. Unfortunately, symptoms are a poor predictor of endoscopic findings, and alarm features are not a good predictor of an underlying malignancy. Although peptic ulcer disease has declined in Western countries, specific populations such as immigrants and rural communities may have a high prevalence of infection and peptic ulcer disease that needs to be considered in initial dyspepsia management, even in areas where the general prevalence of H. pylori infection has declined below 15%. PMID- 20203640 TI - Push-and-pull enteroscopy: one balloon or two? AB - The past decade has seen several advances in small-bowel endoscopic technologies. Although the endoscopic literature is full of large case series, there are few published prospective randomized trials designed to compare any of the currently available techniques and devices for deep small-bowel endoscopy. In this edition of the American Journal of Gastroenterology, Dr May and colleagues present the results of a prospective, randomized trial comparing two techniques for performing "push-and-pull" enteroscopy: double balloon and single balloon. Although this study is not without limitations, it represents a step in the right direction toward answering several important questions that have surfaced, as techniques for deep small-bowel enteroscopy have become mainstream in endoscopic practice. PMID- 20203641 TI - Bile acid profiles in intrahepatic cholestasis of pregnancy: is this the solution to the enigma of intrahepatic cholestasis of pregnancy? AB - Intrahepatic cholestasis of pregnancy (ICP) is a rare pregnancy-related liver disease characterized by pruritus, abnormal liver function tests, and an increased risk of fetal complications. An increase in the levels of bile acids is considered to be the diagnostic hallmark of the disease. Ursodeoxycholic acid (UDCA) is currently the most effective therapy. Tribe et al. (this issue) hypothesized that measuring the longitudinal profiles of individual bile acids would provide further insight into the mechanisms of disease. They used a novel chromatography method, which allowed the simultaneous measurement of 15 serum bile acids between 16 weeks of pregnancy and 4 weeks post-partum. ICP was associated with a predominant rise in cholic acid conjugated with taurine and glycine from 24 weeks of pregnancy. UDCA treatment significantly reduced serum taurocholic and taurodeoxycholic acid concentrations. Finally, bile acid profiles were similar in normal pregnancy and pregnancy associated with pruritus gravidarum. The study by Tribe et al. (this issue) presents a significant contribution to the solution of this enigmatic disease by expanding our knowledge on the pathophysiology of ICP and proposing a convenient method for diagnosis and monitoring of this disorder. PMID- 20203642 TI - The radiological diagnosis of hepatocellular carcinoma. AB - The American Association for the Study of Liver Diseases (AASLD) guidelines on the management of hepatocellular carcinoma (HCC) includes an algorithm to assist in the diagnosis of small liver nodules found on surveillance. The algorithm was developed on the basis of expert opinion. The two authors of the guidelines have since validated the algorithm. In this issue, the first external validation of the diagnostic algorithm is presented. PMID- 20203643 TI - Non-alcoholic fatty liver disease after liver transplantation: a case of nurture and nature. AB - Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease. Most patients with cryptogenic cirrhosis are considered to have had "burned out NAFLD." Although the recurrence and progression of NAFLD after liver transplantation (LT) have been shown previously, the incidence of de novo NAFLD after LT has not been extensively reported. In this issue of the American Journal of Gastroenterology, Dumortier et al. report the incidence of de novo post-LT NAFLD. Although most of the risk factors for post-LT NAFLD are similar to those for primary NAFLD, hepatic steatosis in the donor livers and a pre-transplant diagnosis of alcoholic liver disease remain independent risk factors. Although there are some limitations, this study provides the largest cohort of patients for whom post-LT NAFLD is reported. PMID- 20203644 TI - Diabetes and hepatocellular carcinoma: what role does diabetes have in the presence of other known risk factors? AB - Known risk factors for hepatocellular carcinoma (HCC) include hepatitis C, hepatitis B, and alcoholic liver disease. Several studies have examined diabetes as a risk factor for HCC because of its association with fatty liver disease and non-alcoholic steatohepatitis. The current study by Tung et al. found that neither diabetes nor overweight was a risk factor for HCC. Results were consistent using both a cross-sectional and a case-control study approach. Findings from this study suggest that diabetes and overweight alone are not adequate to increase the risk of HCC in the absence of concomitant viral hepatitis or liver disease. PMID- 20203647 TI - Commentary on "anti-pituitary antibodies in children with newly diagnosed celiac disease: a novel finding contributing to linear growth". AB - The pathogenesis of celiac disease (CD)-associated short stature is still unclear. The authors showed that newly diagnosed CD patients have a high prevalence of positive antipituitary antibodies that correlates with height impairment. Given the association of CD with other autoimmune disease, these authors' findings show one possible etiology for the poor growth seen in children with CD. PMID- 20203648 TI - Francis Weld Peabody's classic quotation. PMID- 20203649 TI - Ideas on trial design in acupuncture for IBS. PMID- 20203650 TI - Acid-suppressive therapy and eosinophilic esophagitis: friends or foes? PMID- 20203651 TI - Recurrent ischemic colitis induced by colonoscopy bowel lavage. PMID- 20203652 TI - Comparison of the Glasgow alcoholic hepatitis score and the ABIC score for the assessment of alcoholic hepatitis. PMID- 20203653 TI - Pancreatic ductal abnormalities documented by secretin-enhanced MRCP in asymptomatic subjects with chronic pancreatic hyperenzymemia. PMID- 20203654 TI - Management of anticoagulation before and after gastrointestinal endoscopy. PMID- 20203655 TI - Calcium phosphate nephropathy from colonoscopy preparations: effect of body weight. PMID- 20203656 TI - Antibiotics prophylaxis in acute necrotizing pancreatitis: an update. PMID- 20203657 TI - Preparation of symmetric and asymmetric aromatic azo compounds from aromatic amines or nitro compounds using supported gold catalysts. AB - This protocol describes the aerobic oxidation of aromatic anilines to aromatic azo compounds using gold (Au) nanoparticles supported on TiO(2) as a catalyst. Yields above 98% are achieved under a few bars of oxygen pressure. It should be noted that the use of stoichiometric amounts of environmentally unfriendly reagents, e.g., transition metals and nitrites, commonly used in current syntheses of azo compounds, is avoided using this approach. The protocol is illustrated with the synthesis of parent azobenzene from aniline, and this reaction takes 22 h. Au on TiO(2) can also be used as a hydrogenation catalyst, making it possible to prepare azo compounds directly from nitroaromatics through a two-step (hydrogenation followed by aerobic oxidation), one-pot, one-catalyst reaction. In addition, the catalytic process is efficient for the synthesis of symmetric and a range of asymmetric aromatic azo compounds from the mixtures of two anilines substituted with electron-donor and electron-acceptor substituents. PMID- 20203658 TI - Generation of clonal zebrafish lines and transplantable hepatic tumors. AB - Transplantable tumors are an accepted gold standard in cancer studies in rodents. The progress of this model in zebrafish has long been constrained by the lack of true inbred lines in zebrafish. We have generated several lines of homozygous diploid clonal zebrafish lines, which allow serial transplantations of tumor cells from one fish to another without sublethal gamma-irradiation. The spectrum of transplantable tumors that were initially induced and maintained in inbred clonal zebrafish lines was limited to different types of spontaneous and diethylnitrosamine-induced hepatic tumors. However, this model can readily be extended to a broad range of extrahepatic tumors, transgenic tumors with defined mechanisms of induction and fluorescence-tagged tumor lines. These models will further facilitate in-depth analysis of invasive tumor growth, angiogenesis, metastasis and tumor-initiating cells by in vivo imaging and provide a cost effective system for high-throughput (HTP) screening of anticancer therapeutics, including biological response modifiers. In addition, homozygous zebrafish lines are an indispensable tool for immunogenetics, mapping of quantitative trait loci and other genetic applications. The whole procedure, from generation of a gynogenetic female homozygous fish (a founder) to obtaining 3-4 consecutive passages of a syngeneic tumor, takes approximately 12-18 months. This time-frame largely depends on methods of tumor induction, tumor type and tumor growth rate. PMID- 20203659 TI - Construction of a femtosecond laser microsurgery system. AB - Femtosecond laser microsurgery is a powerful method for studying cellular function, neural circuits, neuronal injury and neuronal regeneration because of its capability to selectively ablate sub-micron targets in vitro and in vivo with minimal damage to the surrounding tissue. Here, we present a step-by-step protocol for constructing a femtosecond laser microsurgery setup for use with a widely available compound fluorescence microscope. The protocol begins with the assembly and alignment of beam-conditioning optics at the output of a femtosecond laser. Then a dichroic mount is assembled and installed to direct the laser beam into the objective lens of a standard inverted microscope. Finally, the laser is focused on the image plane of the microscope to allow simultaneous surgery and fluorescence imaging. We illustrate the use of this setup by presenting axotomy in Caenorhabditis elegans as an example. This protocol can be completed in 2 d. PMID- 20203660 TI - Miniaturized parallel screens to identify chromatographic steps required for recombinant protein purification. AB - Methods development in chromatography is a time-consuming, trial-and-error process that requires laborious experimentation. We describe a high-throughput screening (HTS) protocol for the rapid identification of chromatographic steps for protein purification from cell-free expression broths. Broths containing the protein are loaded on different chromatographic resins aliquotted in membrane bottomed microtiter plates. Serial step elution of protein from resins results in fraction collection in 96-well plates. Choice of the optimal chromatographic operating conditions is based on protein purity in eluted fractions, determined using SDS-PAGE analysis or similar analytical techniques. The screening procedure is then repeated in order to identify the subsequent chromatographic steps, ultimately leading to high purities of the protein. The protocol takes approximately 24 h in order to determine the required sequence of chromatographic steps. The use of a miniaturized screen facilitates screening of a range of media and operating conditions (i.e., pH, salt concentration, and so on.) in parallel and is a novel approach to chromatographic methods development. PMID- 20203661 TI - Generation of mouse-induced pluripotent stem cells with plasmid vectors. AB - Reprogramming of somatic cells into pluripotent stem cells has been reported by introducing a combination of several transcription factors (Oct3/4, Sox2, Klf4 and c-Myc). The induced pluripotent stem (iPS) cells from patient's somatic cells could be a useful source for drug discovery and cell transplantation therapies. However, to date, most iPS cells were made using viral vectors, such as retroviruses and lentiviruses. Here we describe an alternative method to generate iPS cells from mouse embryonic fibroblasts (MEFs) by continual transfection of plasmid vectors. This protocol takes around 2 months to complete, from MEF isolation to iPS cell establishment. Although the reprogramming efficiency of this protocol is still low, the established iPS cells are most likely free from plasmid integration. This virus-free technique reduces the safety concern for iPS cell generation and application, and provides a source of cells for the investigation of the mechanisms underlying reprogramming and pluripotency. PMID- 20203663 TI - Chromatin immunoprecipitation (ChIP) of plant transcription factors followed by sequencing (ChIP-SEQ) or hybridization to whole genome arrays (ChIP-CHIP). AB - Chromatin immunoprecipitation (ChIP) is a powerful technique to study interactions between transcription factors (TFs) and DNA in vivo. For genome-wide de novo discovery of TF-binding sites, the DNA that is obtained in ChIP experiments needs to be processed for sequence identification. The sequences can be identified by direct sequencing (ChIP-SEQ) or hybridization to microarrays (ChIP-CHIP). Given the small amounts of DNA that are usually obtained in ChIP experiments, successful and reproducible sample processing is challenging. Here we provide a detailed procedure for ChIP of plant TFs, as well as protocols for sample preparation for ChIP-SEQ and for ChIP-CHIP. Our ChIP procedure is optimized for high signal-to-noise ratio starting with tissue fixation, followed by nuclei isolation, immunoprecipitation, DNA amplification and purification. We also provide a guide for primary data analysis of ChIP-SEQ data. The complete protocol for ChIP-SEQ/ChIP-CHIP sample preparation starting from plant harvest takes approximately 7 d. PMID- 20203664 TI - Separation of isomeric octadecenoic fatty acids in partially hydrogenated vegetable oils as p-methoxyphenacyl esters using a single-column silver ion high performance liquid chromatography (Ag-HPLC). AB - A protocol for separation of positionally isomeric trans- and cis-octadecenoic fatty acids as their p-methoxyphenacyl esters, using a single column silver ion high-performance liquid chromatography (Ag-HPLC) with UV detection, is described. The procedure involves hydrolysis of oil to free fatty acids, derivatization to p methoxyphenacyl esters, purification and separation by Ag-HPLC. The procedure is robust and relatively rapid. In total, it takes about 16 h or overnight and a further 5 h to carry out. Its feature and value consist in the application of p methoxyphenacyl esters in Ag-HPLC, thus ensuring excellent simultaneous separation of both configurational and positional fatty acid isomers on a single column by a single run. Quantification is not affected by the fatty acid structure, and the method is highly sensitive. As fatty acid isomerization is a strong evidence for adulteration of lipid-containing food products with chemically modified oils and fats, the procedure is especially appropriate for detection and authenticity analysis in many areas of food manufacturing and quality control. PMID- 20203662 TI - Optogenetic interrogation of neural circuits: technology for probing mammalian brain structures. AB - Elucidation of the neural substrates underlying complex animal behaviors depends on precise activity control tools, as well as compatible readout methods. Recent developments in optogenetics have addressed this need, opening up new possibilities for systems neuroscience. Interrogation of even deep neural circuits can be conducted by directly probing the necessity and sufficiency of defined circuit elements with millisecond-scale, cell type-specific optical perturbations, coupled with suitable readouts such as electrophysiology, optical circuit dynamics measures and freely moving behavior in mammals. Here we collect in detail our strategies for delivering microbial opsin genes to deep mammalian brain structures in vivo, along with protocols for integrating the resulting optical control with compatible readouts (electrophysiological, optical and behavioral). The procedures described here, from initial virus preparation to systems-level functional readout, can be completed within 4-5 weeks. Together, these methods may help in providing circuit-level insight into the dynamics underlying complex mammalian behaviors in health and disease. PMID- 20203665 TI - Methods for isolation of marine-derived endophytic fungi and their bioactive secondary products. AB - Marine-derived fungi have been shown in recent years to produce a plethora of new bioactive secondary metabolites, some of them featuring new carbon frameworks hitherto unprecedented in nature. These compounds are of interest as new lead structures for medicine as well as for plant protection. The aim of this protocol is to give a detailed description of methods useful for the isolation and cultivation of fungi associated with various marine organisms (sponges, algae and mangrove plants) for the extraction, characterization and structure elucidation of biologically active secondary metabolites produced by these marine-derived endophytic fungi, and for the preliminary evaluation of their pharmacological properties based on rapid 'in house' screening systems. Some results exemplifying the positive outcomes of the protocol are given at the end. From sampling in marine environment to completion of the structure elucidation and bioactivity screening, a period of at least 3 months has to be scheduled. PMID- 20203666 TI - Soft lithography for micro- and nanoscale patterning. AB - This protocol provides an introduction to soft lithography--a collection of techniques based on printing, molding and embossing with an elastomeric stamp. Soft lithography provides access to three-dimensional and curved structures, tolerates a wide variety of materials, generates well-defined and controllable surface chemistries, and is generally compatible with biological applications. It is also low in cost, experimentally convenient and has emerged as a technology useful for a number of applications that include cell biology, microfluidics, lab on-a-chip, microelectromechanical systems and flexible electronics/photonics. As examples, here we focus on three of the commonly used soft lithographic techniques: (i) microcontact printing of alkanethiols and proteins on gold-coated and glass substrates; (ii) replica molding for fabrication of microfluidic devices in poly(dimethyl siloxane), and of nanostructures in polyurethane or epoxy; and (iii) solvent-assisted micromolding of nanostructures in poly(methyl methacrylate). PMID- 20203667 TI - FLOTAC: new multivalent techniques for qualitative and quantitative copromicroscopic diagnosis of parasites in animals and humans. AB - Accurate diagnosis of parasitic infections is of pivotal importance for both individual patient management and population-based studies, such as drug efficacy trials and surveillance of parasitic disease control and elimination programs, in both human and veterinary public health. In this study, we present protocols for the FLOTAC basic, dual and double techniques, which are promising new multivalent, sensitive, accurate and precise methods for qualitative and quantitative copromicroscopic analysis. These various methods make use of the FLOTAC apparatus, a cylindrical device with two 5-ml flotation chambers, which allows up to 1 g of stool to be prepared for microscopic analysis. Compared with currently more widely used diagnostic methods for parasite detection in animals (e.g., McMaster and Wisconsin techniques) and humans (e.g., Kato-Katz and ether based concentration techniques), the FLOTAC techniques show higher sensitivity and accuracy. All FLOTAC techniques can be performed on fresh fecal material as well as preserved stool samples, and require approximately 12-15 min of preparation time before microscopic analysis. PMID- 20203668 TI - RNA-Seq analysis to capture the transcriptome landscape of a single cell. AB - We describe here a protocol for digital transcriptome analysis in a single mouse oocyte and blastomere using a deep-sequencing approach. In this method, individual cells are isolated and transferred into lysate buffer by mouth pipette, followed by reverse transcription carried out directly on the whole cell lysate. Free primers are removed by exonuclease I and a poly(A) tail is added to the 3' end of the first-strand cDNAs by terminal deoxynucleotidyl transferase. Single-cell cDNAs are then amplified by 20 + 9 cycles of PCR. The resulting 100 200 ng of amplified cDNAs are used to construct a sequencing library, which can be used for deep sequencing using the SOLiD system. Compared with cDNA microarray techniques, our assay can capture up to 75% more genes expressed in early embryos. This protocol can generate deep-sequencing libraries for 16 single-cell samples within 6 d. PMID- 20203669 TI - NMR-based metabolomic analysis of plants. AB - Nuclear magnetic resonance (NMR)-based metabolomics has many applications in plant science. Metabolomics can be used in functional genomics and to differentiate plants from different origin, or after different treatments. In this protocol, the following steps of plant metabolomics using NMR spectroscopy are described: sample preparation (freeze drying followed by extraction by ultrasonication with 1:1 CD(3)OD:KH(2)PO(4) buffer in D(2)O), NMR analysis (standard (1)H, J-resolved, (1)H-(1)H correlation spectroscopy (COSY) and heteronuclear multiple bond correlation (HMBC)) and chemometric methods. The main advantage of NMR metabolomic analysis is the possibility of identifying metabolites by comparing NMR data with references or by structure elucidation using two-dimensional NMR. This protocol is particularly suited for the analysis of secondary metabolites such as phenolic compounds (usually abundant in plants), and for primary metabolites (e.g., sugars and amino acids). This procedure is rapid; it takes not more than 30 min for sample preparation (multiple parallel) and a further 10 min for NMR spectrum acquisition. PMID- 20203670 TI - A protocol for isolation and culture of mesenchymal stem cells from mouse compact bone. AB - Unlike humans, mouse bone marrow-derived mesenchymal stem cells (MSCs) cannot be easily harvested by adherence to plastic owing to the contamination of cultures by hematopoietic cells. The design of the protocol described here is based on the phenomenon that compact bones abound in MSCs and hematopoietic cells exist in the marrow cavities and the inner interfaces of the bones. The procedure includes flushing bone marrow out of the long bones, digesting the bone chips with collagenase type II, deprivation of the released cells and culturing the digested bone fragments, out of which fibroblast-like cells migrate and grow in the defined medium. The entire technique requires 5 d before the adherent cells are readily passaged. Further identification assays confirm that these cells are MSCs. We provide an easy and reproducible method to harvest mouse MSCs that does not require depletion of hematopoietic cells by sorting or immunomagnetic techniques. PMID- 20203671 TI - Directed molecular evolution of DREADDs: a generic approach to creating next generation RASSLs. AB - G protein-coupled receptors (GPCRs) and their downstream signaling cascades contribute to most physiological processes and a variety of human diseases. Isolating the effects of GPCR activation in an in vivo experimental setting is challenging as exogenous ligands have off-target effects and endogenous ligands constantly modulate the activity of native receptors. Highly specific designer drug-designer receptor complexes are a valuable tool for elucidating the effects of activating particular receptors and signaling pathways within selected cell types in vivo. In this study, we describe a generic protocol for the directed molecular evolution of designer receptors exclusively activated by designer drugs (DREADDs). First, the yeast system is validated with the template receptor. Second, a mutant library is generated by error-prone PCR. Third, the library is screened by drug-dependent yeast growth assays. Mutants exhibiting the desired properties are selected for further rounds of mutagenesis or for characterization in mammalian systems. In total, these steps should take 6-8 weeks of experimentation and should result in the evolution of a receptor to be activated by the chosen ligand. This protocol should help improve the experimental targeting of select cell populations. PMID- 20203672 TI - Segmental isotopic labeling of multi-domain and fusion proteins by protein trans splicing in vivo and in vitro. AB - Segmental isotopic labeling is a powerful labeling technique for reducing nuclear magnetic resonance (NMR) signal overlap, which is associated with larger proteins by incorporating stable isotopes into only one region of a protein for NMR detections. Segmental isotopic labeling can not only reduce complexities of NMR spectra but also retain possibilities to carry out sequential resonance assignments by triple-resonance NMR experiments. We described in vivo (i.e., in Escherichia coli) and in vitro protocols for segmental isotopic labeling of multi domain and fusion proteins via protein trans-splicing (PTS) using split DnaE intein without any refolding steps or alpha-thioester modification. The advantage of PTS approach is that it can be carried out in vivo by time-delayed dual expression system with two controllable promoters. A segmentally isotope-labeled protein can be expressed in Escherichia coli within 1 d once required vectors are constructed. The total preparation time of a segmentally labeled sample can be as short as 7-13 d depending on the protocol used. PMID- 20203673 TI - An efficient and easy-to-use cryopreservation protocol for human ES and iPS cells. AB - Here we describe a simple and efficient human embryonic stem (ES) and induced pluripotent stem (iPS) cells cryopreservation protocol. This protocol involves the use of Rho-associated kinase (ROCK) inhibitor, Y-27632, for the feeder-free dissociated cells. The addition of ROCK inhibitor to both pre- and post-thaw culture media enhanced the cloning efficiency. The presence of Y-27632 in Matrigel further increased the cloning efficiency. As compared with other available protocols for human ES and iPS cells cryopreservation, our protocol differs in the technical simplicity, high cloning efficiency and post-thawing passaging. We believe that this protocol could be a generally applicable and robust platform for feeder-free cryopreservation and the expansion of present and future applications of human ES and iPS cells. The treatment with ROCK inhibitor, cell harvesting and the freezing-thawing process usually takes about 2 h excluding overnight incubation at -80 degrees C. PMID- 20203674 TI - Production of glycoprotein-deleted rabies viruses for monosynaptic tracing and high-level gene expression in neurons. AB - Recombinant rabies viruses rendered replication-deficient by the deletion of their envelope glycoprotein gene are useful tools for neuroscientists, permitting (1) extraordinarily high transgene expression levels within neurons, (2) retrograde infection of projection neurons through their axon terminals, (3) targeted infection of genetically specified neurons and (4) monosynaptic tracing of neuronal inputs. Here we present a detailed protocol for the production of high-titer and high-purity viral stocks, from initial generation of infectious virus from cDNA through amplification on complementing cell lines, pseudotyping if desired, purification by ultracentrifugation and titering. The procedure requires 3-4 weeks to complete. PMID- 20203675 TI - Alkyne-azide click reaction catalyzed by metallic copper under ultrasound. AB - This protocol is for the ultrasound (US)-assisted 1,3-dipolar cycloaddition reaction of azides and alkynes using metallic copper (Cu) as the catalyst. The azido group is a willing participant in this kind of organic reaction and its coupling with alkynes is substantially improved in the presence of Cu(I). This protocol does not require additional ligands and proceeds with excellent yields. The Cu-catalyzed azide-alkyne cycloaddition (CuAAC) is generally recognized as the most striking example of 'click chemistry'. Reactions involving metals represent the favorite domain of sonochemistry because US favors mechanical depassivation and enhances both mass transfer and electron transfer from the metal to the organic acceptor. The reaction rate increases still further when simultaneous US and microwave irradiation are applied. The US-assisted click synthesis has been applied for the preparation of a wide range of 1,4 disubstituted 1,2,3-triazole derivatives starting both from small molecules and oligomers such as cyclodextrins (CDs). Using this efficient and greener protocol, all the adducts can be synthesized in 2-4 h (including work-up and excluding characterization). Click chemistry has been shown to be able to directly link chemistry to biology, thus becoming a true interdisciplinary reaction with extremely wide applicability. PMID- 20203676 TI - Devolving therapeutic pyramids. PMID- 20203677 TI - GERD: increased gastric acid secretion as a possible cause of GERD. PMID- 20203678 TI - Crohn's disease: bacterial clearance in Crohn's disease pathogenesis. PMID- 20203679 TI - Imaging: NBI-detection and differentiation of colonic lesions. PMID- 20203680 TI - Rash induced by anti-tumor necrosis factor agents in an adolescent with Crohn's disease. AB - BACKGROUND: A 17-year-old white male with Crohn's disease who was receiving maintenance infusions of the anti-tumor necrosis factor (TNF) agent, infliximab, presented with a new-onset psoriasiform skin rash. The rash was not responsive to topical or oral corticosteroids and worsened after infliximab infusions and after subsequent administration of a second anti-TNF drug, adalimumab. INVESTIGATIONS: Full medical history and physical examination, including assessment of the morphology of rash and the temporal correlation with administration of anti-TNF agents. DIAGNOSIS: Anti-TNF-agent induced psoriasiform skin rash. MANAGEMENT: Discontinuation of anti-TNF therapy. The patient opted to have his gastrointestinal symptoms treated with oral mesalazine and metronidazole. PMID- 20203682 TI - Medical agents acting on the renin-angiotensin-aldosterone axis for the treatment of heart failure. PMID- 20203683 TI - A new systolic parameter defined as the ratio of brachial pre-ejection period to brachial ejection time predicts overall and cardiovascular mortality in hemodialysis patients. AB - Impaired left ventricular systolic function is an important cause of mortality in hemodialysis patients. An increase in the ratio of pre-ejection period (PEP) to ejection time (ET) is associated with a decrease in left ventricular systolic function. Brachial PEP (bPEP) and brachial ET (bET) can be automatically determined from an ankle-brachial index (ABI)-form device. The aim of this study was to investigate whether bPEP/bET was a useful predictor for overall and cardiovascular mortality in hemodialysis patients. We enrolled 212 hemodialysis patients in one regional hospital. The bPEP and bET were measured using an ABI form device. The mean follow-up period was 28.3+/-5.7 months. The relative mortality risk was analyzed by Cox-regression methods. Twenty-two deaths were recorded in 212 patients (10.4%). In a multivariate analysis, the bPEP/bET (hazard ratio [HR], 1.055; P=0.047) and serum creatinine level (P=0.029) were positively and negatively associated with overall mortality, respectively. In addition, increased bPEP/bET (HR, 1.080; P=0.017), increased fasting glucose (P=0.046) and decreased serum creatinine level (P=0.004) were independent predictors for cardiovascular mortality. Our findings show that bPEP/bET, a surrogate of left ventricular systolic function, is a useful predictor for overall and cardiovascular mortality in hemodialysis patients. Screening hemodialysis patients by means of bPEP/bET may help to identify a high-risk group for increased mortality. PMID- 20203684 TI - Diurnal blood pressure variation and sympathetic activity. AB - Blood pressure changes occurring over a 24-h period are under behavioral, humoral and reflex regulation. The sympathetic nervous system modulates blood pressure variation by affecting cardiac output and peripheral vascular resistance. This paper reviews evidence for the relationship between adrenergic neural drive and blood pressure as measured by direct and indirect approaches. This paper also reviews the sympathetic activity associated with increased 'in-office' and 'out of-office' blood pressure, that is, the white-coat and the masked-hypertensive states. Finally, this paper examines altered neuroadrenergic influences on nocturnal blood pressure reduction and blood pressure variability. PMID- 20203685 TI - New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease. AB - The renin-angiotensin-aldosterone system (RAAS) has a central function in the regulation of blood pressure. Aliskiren, the first direct renin inhibitor to be approved for the treatment of hypertension, blocks the RAAS at its point of activation. As renin inhibition acts at the top of the RAAS cascade, this mechanism has been proposed to offer advantages over existing modes of RAAS blockade. The RAAS is also considered to be a major factor in the pathogenesis of many renal diseases, especially diabetic nephropathy (DN), the main cause of end stage renal disease. Existing therapies to block the RAAS slow the progression of DN, but they do not halt the disease. Therefore, more effective modes of interventions are needed. Studies to determine the efficacy of aliskiren in human renal disease are in progress. This review summarizes in vivo studies in which the efficacy of aliskiren was tested in experimental models of renal disease, and presents in vitro studies that provide insights into the possible mechanisms by which aliskiren confers renoprotection in animals. These works are discussed in the framework of the intrarenal RAAS and suggest that aliskiren may act by unique renoprotective mechanisms. PMID- 20203686 TI - The influence of posture on the estimation of daily salt intake by the second morning urine method. AB - The second morning urine (SMU) method was developed to evaluate daily salt intake, but the posture that should be adopted until the SMU collection remains unclear. This study investigated the influence of posture in hypertensive patients who underwent this test. The subjects were 100 patients who could collect 24-h urine samples correctly and were on a diet containing 7 g of salt per day. Their daily salt intake was estimated for three consecutive days in the recumbent, sitting, and sitting and standing positions (one posture each day). Estimated salt intake in the recumbent position (10.9+/-2.4 g day(-1)) was higher than in the sitting position (7.5+/-2.0 g day(-1)) and the sitting and standing position (6.3+/-1.7 g day(-1)). The salt intake estimated in the sitting and standing position was similar to that obtained by 24-h urine collection (6.3+/ 1.6 g day(-1)) and was significantly (r=0.44, P<0.05) correlated with the 24-h urine value. The actual difference in estimated salt intake between the two methods was 0.0+/-1.7 g day(-1). There were no significant differences in estimated salt intake between the two methods in patients taking different classes of antihypertensive drugs. In conclusion, adopting the sitting and standing position until the SMU collection is important for the correct estimation of daily salt intake, and this method could replace the 24-h collection method because of its convenience, especially in outpatients. PMID- 20203687 TI - Heme-arginate suppresses phospholipase C and oxidative stress in the mesenteric arterioles of mineralcorticoid-induced hypertensive rats. AB - Induction of heme-oxygenase (HO) is an important cellular defense mechanism against oxidative and inflammatory insults. We analyzed the effects of the HO inducer, heme-arginate, on the phospholipase C (PLC)/inositol-triphosphate (IP(3)) pathway in the mesenteric arterioles of uninephrectomized (UnX) deoxycorticosterone acetate (DOCA)-salt hypertensive rats, which is a volume overload model characterized by elevated endothelin (ET-1) and mineralocorticoid induced oxidative/inflammatory insults. Our study included the following groups: (A) controls [(i) surgery-free Sprague-Dawley (SD) rats, (ii) UnX-Sham, (iii) UnX Salt (0.9% NaCl+0.2% KCl) and (iv) UnX-DOCA)]; (B) UnX-DOCA-salt hypertensive rats; (C) UnX-DOCA-salt+heme-arginate; (D) UnX-DOCA-salt+heme-arginate+chromium mesoporphyrin (CrMP), the HO inhibitor; (E) UnX-DOCA-salt+CrMP (F); SD+heme arginate, (G) UnX-DOCA-salt+vehicle dissolving heme-arginate and CrMP and (H) normal-SD+heme-arginate. Quantitative reverse transcriptase PCR, western blot, enzyme immunoassay and spectrophotometric analyses were used. Heme-arginate enhanced mesenteric arteriole HO-1, HO activity, cyclic guanosine monophosphate (cGMP) and anti-oxidants including bilirubin, ferritin, superoxide dismutase with potentiation of the total anti-oxidant capacity. Correspondingly, oxidative/inflammatory mediators such as 8-isoprostane, nuclear-factor kappaB (NF kappaB) and ET-1 were markedly reduced. Furthermore, heme-arginate suppressed PLC activity, attenuated IP(3) and reduced resting intracellular calcium. The effects of heme-arginate were nullified by the HO inhibitor, with aggravation of oxidative/inflammatory insults. In heme-arginate-treated SD rats, the HO system was potentiated to a lesser magnitude and the suppression of ET-1, PLC, IP(3) and NF-kappaB were less accentuated, suggesting greater selectivity of HO against the ET-1-PLC-IP(3)-NF-kappaB destructive axis in the pathological condition of mineralocorticoid-induced hypertension. Given that ET-1 stimulates PLC and IP(3), which in turn activates NF-kappaB, the concomitant reduction of ET-1, PLC, IP(3) and NF-kappaB alongside the corresponding decline of resting intracellular calcium may account for the reduction of blood pressure and attenuation of oxidative/inflammatory injury by heme-arginate. PMID- 20203688 TI - Combination of nutlin-3 and VX-680 selectively targets p53 mutant cells with reversible effects on cells expressing wild-type p53. AB - Chemotherapeutics (e.g., aurora kinase inhibitors) designed to target proliferative cells are often nonspecific for tumor cells as normal cycling cells are also susceptible. Indeed, one of the major dose-limiting toxicities of aurora kinase inhibitors is a dangerous depletion of neutrophils in patients. In this study we proposed a strategy to selectively target p53 mutant cells while sparing normal ones. The strategy is based on the understanding that normal cells have an intact p53 pathway but not tumor cells carrying p53 mutations. Nongenotoxic activation of p53 using nutlin led to a reversible activation of G1 and G2 arrest in normal cells, which prevents them from entering mitosis, thus protecting them from the side effects of aurora kinase inhibition (VX-680), namely endoreduplication and apoptosis. Cells carrying mutant p53 are selectively killed by the nutlin/VX-680 combination, whereas p53 wild-type cells retain their proliferative capacity. The major implications drawn from these results are: (1) reversible nongenotoxic activation of p53 may be used as a strategy for the chemoprotection of normal tissues, and (2) aurora kinase inhibitors may have alleviated side effects when used in combination with nutlin-like inhibitors. We highlight the distinct roles of p53 and p73 in mediating the cellular responses to VX-680 and suggest that dual protection by p53 and p73 are needed to guard against endoreduplication and polyploidy. PMID- 20203689 TI - Glucose deprivation induces an atypical form of apoptosis mediated by caspase-8 in Bax-, Bak-deficient cells. AB - Apoptosis induced by most stimuli proceeds through the mitochondrial pathway. One such stimulus is nutrient deprivation. In this study we studied death induced by glucose deprivation in cells deficient in Bax and Bak. These cells cannot undergo mitochondrial outer membrane permeabilization (MOMP) during apoptosis, but they undergo necrosis when treated with MOMP-dependent apoptotic stimuli. We find in these cells that glucose deprivation, rather than inducing necrosis, triggered apoptosis. Cell death required caspase activation as inhibition of caspases with peptidic inhibitors prevented death. Glucose deprivation-induced death displayed many hallmarks of apoptosis, such as caspase cleavage and activity, phosphatidyl serine exposure and cleavage of caspase substrates. Neither overexpression of Bcl xL nor knockdown of caspase-9 prevented death. However, transient or stable knockdown of caspase-8 or overexpression of CrmA inhibited apoptosis. Cell death was not inhibited by preventing death receptor-ligand interactions, by overexpression of c-FLIP or by knockdown of RIPK1. Glucose deprivation induced apoptosis in the human tumor cell line HeLa, which was prevented by knockdown of caspase-8. Thus, we have found that glucose deprivation can induce a death receptor-independent, caspase-8-driven apoptosis, which is engaged to kill cells that cannot undergo MOMP. PMID- 20203691 TI - TNF-alpha-induced ROS production triggering apoptosis is directly linked to Romo1 and Bcl-X(L). AB - Reactive oxygen species (ROS) produced by tumor necrosis factor-alpha (TNF-alpha) have an important function in cell death by activating c-Jun N-terminal kinase. However, the exact mechanism of mitochondrial ROS production, after TNF-alpha stimulation, is not clearly understood. In this study, we determined that ROS modulator 1 (Romo1) and B-cell lymphoma-extra large (Bcl-X(L)) are directly associated with TNF-alpha-induced ROS production. In response to TNF-alpha, TNF complex II, which consists of receptor-interacting protein 1, TNF receptor associated protein with death domain, TNF receptor-associated factor 2, Fas associated death domain protein, and pro-caspase-8, binds to the C-terminus of Romo1 located in the mitochondria. Concurrently, Romo1 recruits Bcl-X(L) to reduce the mitochondrial membrane potential, resulting in ROS production and apoptotic cell death. On the basis of these results, we suggest that Romo1 is a molecular bridge between TNF-alpha signaling and the mitochondria for ROS production that triggers TNF-alpha-mediated apoptosis, as well as a novel target in the development of anti-inflammatory agents that block the origin of ROS production. PMID- 20203690 TI - Activation of GPR30 inhibits the growth of prostate cancer cells through sustained activation of Erk1/2, c-jun/c-fos-dependent upregulation of p21, and induction of G(2) cell-cycle arrest. AB - G-protein-coupled receptor-30 (GPR30) shows estrogen-binding affinity and mediates non-genomic signaling of estrogen to regulate cell growth. We here showed for the first time, in contrast to the reported promoting action of GPR30 on the growth of breast and ovarian cancer cells, that activation of GPR30 by the receptor-specific, non-estrogenic ligand G-1 inhibited the growth of androgen dependent and androgen-independent prostate cancer (PCa) cells in vitro and PC-3 xenografts in vivo. However, G-1 elicited no growth or histological changes in the prostates of intact mice and did not inhibit growth in quiescent BPH-1, an immortalized benign prostatic epithelial cell line. Treatment of PC-3 cells with G-1 induced cell-cycle arrest at the G(2) phase and reduced the expression of G(2)-checkpoint regulators (cyclin-A2, cyclin-B1, cdc25c, and cdc2) and phosphorylation of their common transcriptional regulator NF-YA in PC-3 cells. With extensive use of siRNA-knockdown experiments and the MEK inhibitor PD98059 in this study, we dissected the mechanism underlying G-1-induced inhibition of PC 3 cell growth, which was mediated through GPR30, followed by sustained activation of Erk1/2 and a c-jun/c-fos-dependent upregulation of p21, resulting in the arrest of PC-3 growth at the G(2) phase. The discovery of this signaling pathway lays the foundation for future development of GPR30-based therapies for PCa. PMID- 20203692 TI - A functional epidermal growth factor (EGF) polymorphism, EGF serum levels and renal cell carcinoma risk in a Chinese population. AB - The epidermal growth factor (EGF) gene encodes a growth factor that binds to the EGF receptor (EGFR), which is involved in activating pathways that promote cellular proliferation, survival, migration and differentiation, and lack of control is characteristic of malignant development. Previous studies showed that serum EGF levels may influence the risk of cancer. In this study, we genotyped the EGF G61A polymorphism (rs4444903) and measured serum EGF levels using an enzyme immunoassay in a hospital-based case-control study of 345 patients with diagnosed renal cell carcinoma (RCC) and 346 cancer-free controls in a Chinese population. Compared with the EGF 61GG genotype, the AA genotype had a significantly increased RCC risk (odds ratio=1.80, 95% confidence interval=1.04 3.12). Besides, the mean serum EGF levels in RCC patients (858.94+/-391.54 pg ml( 1)) were significantly lower than those in controls (1281.52+/-568.42 pg ml(-1), P<0.001). In addition, individuals carrying AA genotype had lower serum EGF levels than GA or GG carriers. These results suggested that the EGF G61A polymorphism is involved in the etiology of RCC and thus may be a marker for genetic susceptibility to RCC in Chinese populations. Larger studies are warranted to validate our findings. PMID- 20203693 TI - The heritability of risk and age at onset of Parkinson's disease after accounting for known genetic risk factors. AB - We questioned whether the evidence for the genetic component in Parkinson's disease (PD) in Caucasians could be explained by the causative and susceptibility genes that have already been identified. We estimated heritability of risk and age at onset of PD in a well-characterized sample of 504 nuclear families (2828 individuals). After excluding families with known pathogenic mutations and accounting for the major susceptibility genes, the heritability of risk of developing PD was 0.41 (P=0.01). These data suggest that approximately 40% of the variation in susceptibility to PD is due to as-yet unidentified genes, the remainder is likely environmental. PMID- 20203694 TI - Resequencing of the CCL5 and CCR5 genes and investigation of variants for association with diabetic nephropathy. AB - Chemokine (C-C motif) ligand 5 (CCL5) and chemokine (C-C motif) receptor 5 are implicated in the pathogenesis of diabetic nephropathy (DN). We hypothesize that variants in these genes may be associated with DN. The CCL5 and chemokine receptor type 5 (CCR5) genes were resequenced, variants identified (n=58), allele frequencies determined in 46 individuals (92 chromosomes) and efficient haplotype tag single-nucleotide polymorphisms (htSNPs) selected to effectively evaluate the common variation in these genes. One reportedly functional gene variant and eight htSNPs were genotyped in a case-control association study involving Caucasian individuals with type 1 diabetes (267 cases with DN and 442 non-nephropathic diabetic controls). Genotyping was performed using MassARRAY iPLEX, TaqMan, gel electrophoresis and direct capillary sequencing. After correction for multiple testing, there were no statistically significant associations between variants in the CCL5 and CCR5 genes and DN. PMID- 20203695 TI - A remark on rare variants. AB - The genetic architecture of a disease determines the epidemiological methods for its examination. Recently, Bodmer and Bonilla suggested that moderately strong, moderately rare variants contribute substantially to the genetic population attributable risk (PAR) of common diseases. In the first part of this communication, I provide a concise reconstruction of their deliberation. Variants contributing to human disease can be identified by linkage or by association tests. Risch and Merikangas analyzed the power of these tests by comparing the affected sib-pair linkage test (ASP) and the transmission disequilibrium association test (TDT). In the second part of this paper, I give an accessible reconstruction of this comparison and derive simple approximations in the low allele frequency range, directly showing that the linkage test is much more sensitive to a decrease of frequency or effect size. In the third part, I analyze a disease model whose genetic architecture is proportional to Kimura's infinite sites model. The relation between a variant's selection coefficient and its effect size in disease generation is assumed to be simple, and the number of contributing genetic variants is determined by the sum of their approximative PAR contributions. An association test (TDT) is finally applied to this disease model. For different ranges of effect size and allele frequency, I derive the minimal sample size necessary to detect at least one contributing variant. It turns out that, although the majority of contributing variants is not accessible with realistic sample sizes, a minimum of sample size may be given for moderately strong variants in the 1% frequency range. PMID- 20203696 TI - Tame affairs: domesticated transposase and domestic pigs. PMID- 20203697 TI - Differences in the DNA replication of unicellular eukaryotes and metazoans: known unknowns. AB - Although the basic mechanisms of DNA synthesis are conserved across species, there are differences between simple and complex organisms. In contrast to lower eukaryotes, replication origins in complex eukaryotes lack DNA sequence specificity, can be activated in response to stressful conditions and require poorly conserved factors for replication firing. The response to replication fork damage is monitored by conserved proteins, such as the TIPIN-TIM-CLASPIN complex. The absence of this complex induces severe effects on yeast replication, whereas in higher eukaryotes it is only crucial when the availability of replication origins is limiting. Finally, the dependence of DNA replication on homologous recombination proteins such as RAD51 and the MRE11-RAD50-NBS1 complex is also different; they are dispensable for yeast S-phase but essential for accurate DNA replication in metazoans under unchallenged conditions. The reasons for these differences are not yet understood. Here, we focus on some of these known unknowns of DNA replication. PMID- 20203698 TI - NF-kappaB: no longer an island, but a piece of a continent. AB - The Keystone meeting on NF-kappaB in Inflammation and Disease held in January covered several aspects of NF-kappaB regulation. Many new concepts emerged in signalling, transcriptional control and the involvement of NF-kappaB in disease, particularly cancer. PMID- 20203699 TI - Retinal vasculitis as an early sign of bacterial post-operative endophthalmitis. PMID- 20203700 TI - Functional analysis of fungal polyketide biosynthesis genes. AB - Fungal polyketides have huge structural diversity from simple aromatics to highly modified complex reduced-type compounds. Despite such diversty, single modular iterative type I polyketide synthases (iPKSs) are responsible for their carbon skeleton construction. Using heterologous expression systems, we have studied on ATX, a 6-methylsalicylic acid synthase from Aspergillus terreus as a model iPKS. In addition, iPKS functions involved in fungal spore pigment biosynthesis were analyzed together with polyketide-shortening enzymes that convert products of PKSs to shorter ketides by hydrolytic C-C bond cleavage. In our studies on reducing-type iPKSs, we cloned and expressed PKS genes, pksN, pksF, pksK and sol1 from Alternaria solani. The sol gene cluster was found to be involved in solanapyrone biosynthesis and sol5 was identified to encode solanapyrone synthase, a Diels-Alder enzyme. Our fungal PKS studies were further extended to identify the function of PKS-nonribosomal peptide synthase involved in cyclopiazonic acid biosynthesis. PMID- 20203701 TI - JBIR-59, a new sorbicillinoid, from a marine-derived fungus Penicillium citrinum SpI080624G1f01. PMID- 20203702 TI - Prevalence of plasmid-mediated quinolone-resistance determinants in Shigella flexneri isolates from Anhui Province, China. AB - Quinolones are used extensively to treat Shigella flexneri infection, and plasmid mediated quinolone resistance (PMQR) determinants were recently reported. A total of 26 S. flexneri isolates collected from Anhui province, China, in 2005 were screened for PMQR determinants, bla gene, gyrA and parC genes, by PCR and sequencing. PMQR determinants were present in 53.8% (14 of 26) of isolates and qnrA(1), qnrS(1), qnrS(2), aac(6')-Ib-cr and qepA were present in 30.8, 11.5, 3.8, 19.2 and 11.5% of those isolates, respectively. All PMQR determinants' positive isolates exhibiting 8 different genetic clones had mutations in gyrA and parC genes, and 11 carried bla genes, including 7 bla(CTX-M) with resistance to cefotaxime. These isolates were resistant to nalidixic acid and 57.1% (8 of 14) of them were resistant to ciprofloxacin and levofloxacin. Our data show that there was a high prevalence of PMQR determinants in S. flexneri isolates from China. PMID- 20203704 TI - Response time of a liquid crystal image transducer. PMID- 20203703 TI - Nosokomycins, new antibiotics discovered in an in vivo-mimic infection model using silkworm larvae. II: Structure elucidation. AB - The structures of nosokomycins A, B, C and D, new anti-methicillin-resistant Staphylococcus aureus antibiotics produced by Streptomyces sp. K04-0144, were elucidated by spectroscopic studies including various NMR experiments. Nosokomycins A, B, C and D are new members of the moenomycin family consisting of an oligosaccharide moiety, a 2,3-dihydroxypropionic acid and an unusual sesterterpenoid moiety. All nosokomycins lack the cyclopentenone moiety in the oligosaccharide moiety of moenomycin A. PMID- 20203705 TI - Handling optical cables: safety aspects; author's reply to comments. PMID- 20203706 TI - Comparison between photographic and photoelectric measurements of the solar aureole almucantar radiance. PMID- 20203707 TI - Angular distribution of fluorescence from small particles. PMID- 20203709 TI - Applied optics of optics and opticists. PMID- 20203708 TI - Angular distribution of fluorescence from monodispersed particles. PMID- 20203711 TI - Handling optical cables: safety aspects; comments. PMID- 20203710 TI - Patents. AB - 3,980,391; 4,026,655; 4,027,948; 4,028,635; 4,025,200; 4,032,863; 4,035,742. PMID- 20203712 TI - Calculated temperature dependences of silver and gold absorptions in the infrared. PMID- 20203713 TI - Mapping of optical surfaces with quarter wavelength fringes: erratum. PMID- 20203714 TI - Video disk player optics. AB - The optics of a video disk player are described. The bandwidth and the playing time of a disk had been specified at 12 MHz and 30 min, respectively. A readout photodetector signal of high quality can be obtained with a well-corrected objective having a numerical aperture of at least 0.4. Some alternative readout modes and track formats are indicated. Methods for the generation of error signals for the radial and the vertical tracking are briefly discussed. PMID- 20203715 TI - Laser beam recording of video master disks. AB - A method for real time recording of video information on a disk by means of a laser beam is described. The laser beam is focused on a rotating substrate, covered with a thin film of positive photoresist. During exposure the laser beam is intensity modulated by means of an electrooptic modulator driven by the encoded video signal. After etching away the exposed areas of photoresist a master disk is obtained with pits, containing the video information in their periodicity and length. Such a master disk will serve as the source for generating submasters, stampers, etc. for the production of a large number of replicas as is usually done in the phonograph record industry. PMID- 20203716 TI - Noise in a video disk system: experiments with an (AIGa) As laser. AB - In this paper different noise sources are investigated which may be important in an optical readout system for video disks. These noise sources can be divided into three categories: (1) noise due to the light source; (2) noise due to the storage medium; and (3) noise due to the electronics of the detecting system. The relative importance of the three noise terms is discussed for different light levels. Finally an experimental readout scheme is discussed, based upon an AlGaAs diode laser, and it is shown that this laser, like the He-Ne laser, is suitable for video disk reading. PMID- 20203717 TI - Position sensing in video disk readout. AB - In video disk systems based on contactless optical readout, the position of the readout light spot is dynamically controlled with the aid of servo systems. The input of the radial or vertical servo systems in the readout unit is fed with a bipolar function of the position error that has to be corrected. This paper describes a method that generates a radial and a vertical error signal by making use of the phase relations between diffracted orders in the far field of the video disk. These phase relations are derived from the rf signals that appear at the different outputs of a composite photodetector. It is shown that in this way auxiliary beams or supplementary optical elements can be avoided in the readout system. PMID- 20203718 TI - Optical video disks with undulating tracks. AB - The signal components of a video signal (luminance, color, and sound) are modulated on a main carrier and several subcarriers and then recorded on the video master disk. Apart from the signal distortion that can arise during master and disk manufacture, the optical readout of the disk also yields a nonlinear transfer of the signal. The result of nonlinearities is intermodulation between signal components. Intermodulation products affect the quality of the final TV picture. In this paper a method is described which reduces the contribution of the optical readout system to the intermodulation. An optical coding is introduced such that two signal components hardly influence one another. The spacing of the pits in the track direction carries the luminance information, while the undulation of the track carries the color or sound information. A quadrant photodetector positioned in the far field of the video disk restores the luminance and color or sound bands with a very low amount of intermodulation. PMID- 20203719 TI - Laser beam reading of video records. AB - In optical video recording the information is usually read from the disk by a scanning laser beam. We apply the theory of imaging in partially coherent light to this, situation. We assume that the disk is a thin phase object, and that the information pattern consists of tracks of a width that is small compared to the diameter of the reading spot. We obtain simple expressions for the amplitudes of the signals generated by the playback system. Also intermodulation products and cross talk between the tracks are considered. PMID- 20203720 TI - Simplified diffraction theory of the video disk. AB - A simplified model is presented to describe the process of optically reading out a video disk. Although limited in versatility and accuracy, the model has the distinct advantage of not requiring computer solutions and of providing a direct physical insight into the diffraction mechanism of video disk readout. The model is semiquantitative in that predictions are in reasonable numerical agreement with more detailed methods of analysis and with experiments. PMID- 20203721 TI - Line-profile measurement of xerographic copy. AB - An algorithm is presented which permits easy and rapid characterization of lines typically observed in xerographic copy. The outputs of the algorithm are line edge width, line width, and peak density. Auxiliary outputs are line darkness and spatial frequency content. Data are presented which compare two major xerographic products with lithography and other reproduction processes. PMID- 20203722 TI - Imaging system using an intensity triple correlator. AB - A new imaging system for incoherent objects is constructed. In this system, the coherence function of the diffracted field is derived from the signals of three scanning intensity detectors by using computational manipulations. The concrete optical and electronic systems, the details of the signal processings for the derivation of the coherence function, and calculations for image reconstruction are shown. The reconstructed images of asymmetric objects show the usefulness of the system. PMID- 20203723 TI - Suppression of self-focusing through low-pass spatial filtering and relay imaging. AB - Self-focusing effects in large, high power laser amplifiers become manifest as small-scale beam instabilities and as large-scale phase aberrations. Spatial filtering has been shown to control instabilities; spatial filters constitute appropriate lens pair elements for image relaying as well. In this paper, image relaying is presented as a technique for preserving the transverse intensity profile of a high power beam as it propagates long distances through nonlinear elements. As a consequence, amplifier apertures can be filled more effectively, leading to a doubling of fixed-aperture system performance. A rationale for optimal selection of spatial filter bandpass is also presented. This selection, as might be expected, depends upon details of the beam's spatial structure as it enters any filter. A geometrical optics approach is used throughout; nevertheless, derived results remain valid when diffraction is included. PMID- 20203724 TI - Multichannel optical correlator for radar signal processing. AB - A multichannel coherent optical processor for radar signals is described in which pulse compression is achieved by matched spatial filtering. The optical system can be used for phased array, linear frequency modulated pulse burst, or other radar systems. However, only its application to linear phased array signal processing is discussed in depth. From the output optical pattern, one can obtain data on the target's fine range and azimuth (for a phased array) or fine range and Doppler (for a pulse burst radar) etc. PMID- 20203725 TI - Simple interferometer for monitoring Rayleigh waves. AB - An improved interferometer for monitoring Rayleigh waves is described. Consisting of a light source, reflective grating, lens, and detector, the design is simple and inexpensive. It can be employed with specular as well as diffuse reflecting surfaces to monitor surface deformations with the sensitivity of a Michelson interferometer. By spinning the grating element, sensitivity variations with grating position are removed, resulting in stable operation. The interferometer response does vary with acoustic wavelength; a discussion of acoustic bandwidth shows that proper design can result in either a wide or narrow bandwidth response. PMID- 20203726 TI - Acoustooptic beam deflection for spatial frequency multiplexing in high speed holocinematography. AB - Four holograms are recorded superimposed on the same plate at maximum repetition rates of about 10 kHz. A multiply Q-switched ruby laser produces the series of coherent light pulses for hologram exposure. Image separation of different holograms is achieved by spatial frequency multiplexing. The reference beam direction is altered by a unique acoustooptic beam splitter and deflector unit. The operating principle is a sound pulse-light pulse interception technique. Only one ultrasonic transducer is necessary. The quality of the holograms is demonstrated by the reconstructed images taken of laser produced cavitation bubbles following optical breakdown in water. PMID- 20203727 TI - Multimode fiber coupler. AB - Two types of multimode fiber couplers made from plastic-clad fibers are described: (1) cross type couplers with coupling efficiencies from 30 dB to 50 dB depending on the crossover angle; and (2) parallel type couplers with low transmission loss and coupling efficiencies from 15 dB to 30 dB depending on the coupling length. These experimental results are in good agreement with theory. PMID- 20203728 TI - Change of the refractive index in an optical fiber due to external forces. AB - This paper investigates experimentally the change of the refractive index, due to forces such as pulling and pure bending, in an optical fiber fabricated by the CVD technique. It is found that this phenomenon can be interpreted in terms of a simple model of the fiber, that is, a mechanically homogeneous circular rod. We compare the effect of the refractive-index change and that of a geometrical deformation of the fiber on transmission characteristics. A new method based on photoelasticity is also proposed to measure the curvature distribution of a fiber whose axis is deformed by external forces. PMID- 20203729 TI - Excitation of a doubly clad optical fiber by misaligned Gaussian beams. AB - The modal excitation efficiency of a doubly clad optical fiber is determined by using an approximate method which utilizes a series representation of the incident beam in terms of the orthogonal waveguide modes. The dependence of the excitation efficiency on the refractive index difference between the outer and inner cladding, the beam radius of curvature and spot size, as well as a tilt or offset misalignment is investigated. These factors have a pronounced effect on the efficiency and practical tolerances for efficient mode launching may be obtained from the results. PMID- 20203730 TI - Single-mode optical-waveguide fiber coupler. AB - A single-mode fiber coupler to the Ti diffused LiNbO(3) strip waveguide has been devised. The influences of three axial displacements and two angular misalignments on the coupling efficiency have been investigated at 6328-A wavelength. The coupler has a special feature wherein coupling degradation caused by fiber displacement after connection can be recovered to the initial state. The total optical insertion loss is 3 dB after fixing the fiber to the LiNbO(3) strip waveguide, which is 4 microm wide and 8 mm long. PMID- 20203731 TI - Laser optoacoustic absorption spectra for various explosive vapors. AB - Optoacoustic absorption spectra, using a CO(2) laser source, is reported for ethylene glycol dinitrate, 2, 4 dinitrotoluene, and nitrogylcerine vapors in a nitrogen background. Strong absorption was measured at all seventy-seven laser transitions in the 9.6-microm and 10.6-microm regions. Absorption coefficient data, necessary to evaluate performance as an explosive detector, were obtained for ethylene glycol dinitrate. The strongest feature showed a value of 7.42 atm( 1) cm(-1) giving a minimum detection sensitivity of 8.26 ppb W. PMID- 20203732 TI - Line parameter variations and the profile dependence of atmospheric transmittance. AB - Errors introduced by line parameter variations into atmospheric transmittance calculations in which the absorption line shape is assumed to be described accurately by the Galatry profile are compared with errors introduced by the use of approximate line profiles. Variations in two line parameters, the collision broadened halfwidth at half-maximum (HWHM) under standard conditions, and the temperature dependence of the collision cross section are found to be significant. Calculations are presented that illustrate conditions for which variations in these two parameters will mask the profile dependence in a given transmittance calculation. PMID- 20203733 TI - Ray tracing theory and mirage occurrence conditions. AB - The new ray tracing theory, deduced from geometrical optics and widely developed for radio propagation in cosmic atmospheres, is now applied to optics. This paper is confined to the duct mode propagation which represents a singularity. A narrow horizontal beam emitted inside the waveguide can propagate a long path around the earth with very good periodic focusing: the central circular path coincides with the stratification of the atmosphere while rays above or below it are more or less curved. Perfect symmetry is not needed; but two specific conditions must be satisfied, and their occurrence just coincides with conditions under which mirages occur: a quiet mirage with sharp contours, evidently not much affected by scatter, occurs only during a temperature inversion, above a large hot desert, above a hot rather convex asphalt road, or (under convenient conditions) above a quiet level sea, which means only when favorable conditions establish the very sporadically occurring waveguide. A density maximum need not occur at all. PMID- 20203734 TI - Water vapor: spectral transmission at wavelengths between 0.7 microm and 1 microm. AB - Spectral water vapor transmission of the bands between 0.7 microm and 1 microm is determined from ground-based measurements of direct solar radiation with a high resolution grating spectrometer. These transmission values are compared with those published by Moskalenko, which are the only spectral water vapor data below 1 microm applicable to real atmospheres. Our values of the spectral transmission and those reported by Moskalenko differ considerably. New beta(nu) values to calculate spectral transmission values by means of Moskalenko's transmission function are given. The resulting absorptions of the total bands agree better with absorptions obtained from Yamamoto than with those from Moskalenko. PMID- 20203735 TI - Interferometer-grating spectrograph for high resolution astronomical spectroscopy in the middle uv. AB - A high resolution spectrograph is described, which is to be used for a program of uv astronomical spectroscopy from a moderately stabilized, star pointing balloon borne platform. A spectral resolving power >10(5) is achieved using an optically contacted Fabry-Perot interferometer in crossed dispersion with a grating order sorter. PMID- 20203736 TI - Extinction of ir wavelengths by aerosols in coastal fog. PMID- 20203737 TI - Effect of cladding modes on the far-field radiation pattern for a multimode step index optical fiber. PMID- 20203738 TI - Viking infrared thermal mapper: erratum. PMID- 20203739 TI - Protected Al Mirrors With High Reflectance In The 8-12-muM Region From Normal To High Angles Of Incidence. PMID- 20203740 TI - Optical activities in the universities. PMID- 20203741 TI - Quasi-microscope concept for planetary missions: stereo. PMID- 20203742 TI - Generation of tunable coherent vacuum uv radiation in KB5: erratum. PMID- 20203744 TI - Calibration substrate for Abeles-equipment. PMID- 20203743 TI - Gaussian beam propagation in thin film waveguides. PMID- 20203745 TI - Collective oscillations of electrons in aggregated noble-metal films. PMID- 20203746 TI - Absorption coefficients of various pollutant gases at CO(2) laser wavelengths; application to the remote sensing of those pollutants: addenda. PMID- 20203747 TI - Signal current probability distribution for optical heterodyne receivers in the turbulent atmosphere. 1: theory. AB - Approximate expressions are derived for the probability density functions of the i.f. signal magnitudes from optical heterodyne detection systems operating in the presence of clear air turbulence. The effects of lognormal amplitude fluctuations and Gaussian phase perturbations, in addition to local oscillator shot noise, are considered for both passive receivers and those employing active tilt-tracking systems to eliminate angle-of-arrival fluctuations. In Part 2, experimental results are presented that verify the density functions developed here. PMID- 20203748 TI - Signal current probability distribution for optical heterodyne receivers in the turbulent atmosphere. 2: Experiment. AB - Experimental results are presented for the probability density functions of the i.f. signal magnitude from a static optical heterodyne receiver operating in the presence of clear air turbulence. These results are compared with the theory developed in Part 1 and are shown to give excellent agreement. The experimental system includes a He-Ne laser transmitter operating at 632.8 nm, a 1.6-km propagation path through the open atmosphere, and an optical heterodyne receiver. PMID- 20203749 TI - Information content of sky intensity and polarization measurements at right angles to the solar direction. AB - This paper presents the results of a Monte Carlo simulation study of the brightness and polarization at right angles to the solar direction both for ground-based observations (looking up) and for satellite-based systems (looking down). Calculations have been made for a solar zenith angle whose cosine was 0.6 and wavelengths ranging from 3500 A to 9500 A. We have succeeded in demonstrating a sensitivity of signatures to total aerosol loading, aerosol particle size distribution and refractive index, and the surface reflectance albedo. For Lambertian type surface reflection the albedo effects enters solely through the intensity sensitivity, and we have found very high correlations between the polarization term signatures for the ground-based and satellite-based systems. Potential applications of these results for local albedo predictions and satellite imaging systems recalibrations are discussed. PMID- 20203750 TI - Determination of diffractor size and shape from diffracted light. AB - Although equations are available for predicting Fraunhofer diffraction by many obstacles or openings, they are of limited value for the inverse problem, deducing diffractor geometry from observed diffracted light. Instead of trying to invert these equations, they were used to survey the functional relations between diffractor geometry and observable patterns. Then intuitive methods were used to obtain simple approximate expressions for determining the size and general shape of simple diffractors from diffracted light. It is found that some complex diffractors diffract almost like simple diffractors of equivalent dimensions. The results reveal some of the potential capabilities and limitations of diffracted light as a source of information about unknown diffracting systems. PMID- 20203751 TI - MTF measurement of TV zoom lenses: influence of distortion on the equivalence of normal and inverse conjugate techniques. AB - Influence of distortion is studied with regard to the equivalence of the normal and inverse conjugate techniques used in the measurement of MTFs of TV zoom lenses. The two techniques can be regarded as practically equivalent only when the local magnification (as distinguished from the conventional paraxial magnification) is utilized in frequency conversion needed in the inverse conjugate technique. A sample TV zoom lens is presented as a numerical example which supports the results of the discussion. A simple method is proposed for determining the local magnification simultaneously in the process of the MTF measurement. PMID- 20203752 TI - Two-point resolution of gaussian aperture operating in partially coherent light using various resolution criteria. AB - We have investigated the dependence of two-point resolution by an aberration-free Gaussian aperture on the real part of the complex degree of coherence. The Sparrow and the modified Rayleigh criteria have been used for the partially coherent optical systems, and a comparison between them has been made. To reveal important information concerning the characteristics of the image, the irradiance distribution from two mutually partially coherent point sources has also been computed. PMID- 20203753 TI - Coherent optical analog-to-digital conversion using a single halftone photograph. AB - Analog-to-digital (A-D) conversion of intensity transmittance (or reflectance) can be accomplished through nonlinear coherent optical image processing. Theoretically speaking, for any given positive integer N, 2(N) discrete levels of transmittance (or reflectance) can be digitized into binary form simultaneously via pure optical means, involving the proper design and fabrication of a specific halftone screen. The digital outputs of the N bit-planes are selected at the Fourier plane by spatial filtering the (2(n) - 1)th diffraction order, where n = 1, 2, ..., and N, respectively. The specific halftone screen must have (2(N) - 1) gray levels, and it should be emphasized that only a single halftone photograph is required for the optical A-D conversion. The general principle of this new method and a preliminary experimental result of an eight-level A-D conversion are described in this paper. PMID- 20203754 TI - Restoration of images degraded by spatially varying pointspread functions by a conjugate gradient method. AB - The problem of 2-D digital restoration of images degraded by spatially varying pointspread functions is considered. It is shown that the conjugate gradient method can be applied to this problem. This algorithm preserves the sparse matrix properties of other iterative approaches to least squares restoration but has improved convergence properties. The approximation of pointspread matrices by banded matrices is shown to improve the speed of the algorithm without significantly affecting the restoration. PMID- 20203755 TI - Incoherent processor for restoring images degraded by a linear smear. AB - An image degraded by linear smear is restored in a spatial filtering setup by using a sinusoidal distribution of amplitude transmittance in the frequency plane. The sinusoidal amplitude distribution is generated with the help of a Wollaston prism and two linear polarizers. The experimental arrangement permits the use of an extended incoherent source (angular width of the order of 2 degrees ). This provides redundancy in the image formation process and, consequently, eliminates the disturbing diffraction effects which are always present when highly directed light is used. The retrieved image is significantly improved if the degraded amplitude image is transformed by bleaching into a pure phase image, and the filtering is carried out subsequently. Some restored images are shown. PMID- 20203756 TI - Statistical analysis of errors in holographic interferometry. AB - A statistical analysis of the effect of measurement errors on the determination of small vector displacements of diffusely reflecting objects by holographic interferometry is reported. There are two sources of error: inaccurate measurement of fringe-order number and inaccurate measurement of illumination and observation directions. Standard deviations of errors in measured displacements due to these two sources are presented in graphical form for a variety of holographic system geometries. Absolute fringe orders should be measured whenever possible, because fringe readout by scanning leads to very large errors. PMID- 20203757 TI - Refracting leaky rays in graded-index fibers. AB - A local plane wave analysis is employed to derive the ray power transmission and attenuation coefficients for refracting leaky rays on graded-index fibers. These coefficients also reduce to established forms for tunneling rays and are compared with modal attenuation coefficients in the limit of strongly refracting rays. PMID- 20203758 TI - Automatic refractive-index profiling of optical fibers. AB - A video-based system, which analyzes the output field of an interference microscope directly, has been developed to measure automatically the refractive index distribution of optical fibers. Selected regions of the fringe field, detected with a silicon-vidicon, are digitized to 8-bit accuracy by an addressable video digitzer controlled with a programmable calculator. The calculator also makes fringe displacement measurements, corrects for certain misalignments, computes and plots the profile, and determines a best-fit power law (alpha) curve. Profiles, with relative Deltan measured accurate to a few parts in 10(5), obtained at different wavelengths and for different fiber orientations are presented. PMID- 20203759 TI - Lightwave fiber tap. AB - This paper describes a device which samples the optical signal in an optical fiber for use in source stabilization via feedback control. This device incorporates a beam splitter formed on the fiber ends to deflect a portion of the light traveling down the fiber into a P-I-N photodetector. Advantages of this device include low insertion loss, an output that is relatively independent of the modal distribution within the fiber, and is a rugged small package. PMID- 20203760 TI - Effects of beam displacement and front and back mistracking of junction lasers on lightwave transmitter output stability. AB - We have performed experiments to evaluate the sensitivity of the optical output power in lightwave transmitters to possible changes in coupling between the injection laser and the optical fiber. Specifically, coupling changes attributable to beam wander and moding in the laser as well as mechanical motion between the laser and fiber were considered. Since complete transmitters use feedback control circuitry to maintain the output power constant, the effects of beam wander and moding on the feedback sensors (photodiodes, either near the laser or in an optical-fiber tap) were also measured. Based on our results, a comparison of back-mirror monitoring vs fiber-tap monitoring for feedback control is presented. The effects of front/back-mirror mistracking often observed in injection lasers were also considered when comparing these two monitoring schemes. We conclude that fiber-tap monitoring is preferable from a system point of view. PMID- 20203761 TI - Spectrally narrow pulsed dye laser without beam expander. AB - We have developed a simplified version of the side-pumped pulsed dye laser which has a spectral halfwidth of 1.25 GHz and a peak power of 10 kW at 600 nm. The basic laser consists of only four components (output mirror, dye cell, diffraction grating, and tuning mirror) and is exceptionally easy to align. Since the beam expander has been eliminated, the laser cavity can be made quite compact. Under the condition of reduced gain, the laser has been operated in a single mode. PMID- 20203762 TI - Glasses with a large laser effect: Nd-phosphate and Nd-fluorophosphate. AB - Nd-phospate glasses with a great laser effect are described. They have large induced-emission cross sections and low thermal distortion. Those glasses can be used in small and medium laser equipment for processing of materials and for measuring techniques. Addition of fluorine (fluorophosphate glasses) produces a lowering of the nonlinear refractive index. Those glasses are particularly suitable for the final stages of large amplifier chains for nuclear fusion experiments. The nonlinear refractive index can be reduced as low as 0.5 x 10( 13) esu. PMID- 20203763 TI - Optical feedback effects in cw injection lasers. AB - A laser diode can simultaneously function as a light source and detector of its own radiation. The addition of a reflecting surface external to the laser produces changes in the laser output power, the current at constant voltage, and the voltage drop across the laser at constant current. The optical feedback reduces the gain necessary to reach the lasing threshold thus increasing the power output at a given dc current level. In this paper we describe the effects of such feedback on the operating characteristics of cw oxide defined stripe AlGaAs lasers. PMID- 20203764 TI - Mode losses in unstable resonators with rounded edges. AB - The waveguide approach to unstable resonators is employed for determining the eigenmode losses in unstable 2-D and 3-D resonators with perfectly reflecting round-edged mirrors. It is found that edge rounding in cylindrical mirror configurations leads to mode detachment at lower Fresnel numbers than for the sharp-edged case and that the loss behavior approaches more closely the geometric optical limit for infinite mirrors. Similar effects are observed in resonators with circular mirrors, where mode detachment does not occur at all when the mirror edges are sharp. It is also shown that edge rounding improves the separation between the low-loss detached mode and the next higher order modes. PMID- 20203765 TI - Chemical laser power spectral performance: a coupled fluid dynamic, kinetic, and physical optics model. AB - The simplified chemical fluid dynamic model employed by Sentman in his study of rotational nonequilibrium in cw chemical lasers has been coupled to a 1-D physical optics model of the cavity. Calculations have been performed for both rotational equilibrium and nonequilibrium cases for an unstable resonator with 50% geometric outcoupling. For the rotational equilibrium case, the solution resulted in most of the power being contained in one line (84% in J = 8, 10% in J = 9, and 6% in J = 4). For the rotational nonequilibrium case, 98% of the power is distributed over eleven lines, and the Fabry-Perot and unstable resonator power spectral distributions are almost identical, the major difference being that all lines whose saturated gain region does not extend into the central portion of the unstable resonator are cut off. Comparison of the results for the rotational equilibrium and nonequilibrium kinetic models shows that, for both resonators, the rotational nonequilibrium power is 30% less than the equilibrium case, whereas, for a given kinetic model, the unstable resonator produces only about 6% less power than the Fabry-Perot resonator. For the rotational nonequilibrium case, fluctuations in cw power are shown to occur on lines whose saturated gain zone does not fill the unstable resonator. The amplitude of the fluctuation is determined by the fraction of the resonator filled by the saturated gain zone of the oscillating line, and the frequency of the fluctuation is determined by the location of the intensity peak of the oscillating line. PMID- 20203766 TI - Wavelength dependence of GaAs directional couplers and electrooptic switches. AB - The characteristics of GaAs directional couplers and electrooptic switches have been studied at 0.92 microm, 1.06 microm, and 1.15, microm. The devices were formed from pairs of closely spaced low-loss (alpha~1 cm(-1) at 1.06 microm) single-mode p(+)n(-)n(+) channel-stop strip guides. It was found that the coupling length L(c) varies faster than inversely with wavelength, especially near 0.92 microm, and that for each guide width and spacing, L(c) increases as the guide thickness is increased. Modeling the couplers to first order as coupled slab waveguides, the wavelength-dependent results can be explained by a variation with wavelength of the effective guide index. This model also predicts a minimum in L(c) as a function of the difference in effective index between the guides and their surrounding regions and is in agreement with the experimental increase of L(c) with increasing guide thickness (i.e., decreasing confinement). Switching performance at each wavelength was evaluated using devices cleaved to their 1.06 microm coupling length. The zero-bias power isolation obtained at 1.06 microm was 17 dB. At optimum switching bias, i.e., power confined to the input guide, power isolation of 16 dB at 1.15 microm, 17 dB at 1.06 microm, and 18 dB at 0.92 microm was obtained. Total power output is constant to /=65 degrees C) of others. PMID- 20203856 TI - Multiple pulse detection in atmospheric turbulence. AB - Expressions are derived for the probability of detecting at least m threshold crossings in n transmitted laser pulses in the presence of atmospheric turbulence assuming uncorrelated Gaussian receiver noise. The limiting cases of no pulse-to pulse correlation and complete correlation are evaluated explicitly. In general, we find the presence of correlation can significantly modify the detection statistics and should be included in systems calculations. PMID- 20203857 TI - Effects of oxygen addition on pressure-broadened water-vapor absorption in the 10 microm region. AB - We have measured the monochromatic transmittances of pressure-broadened room temperature water vapor samples at five laser frequencies of the CO(2) laser in the 10.4-microm band. Three different buffer gases were used. They were pure nitrogen, an 80:20 mixture of nitrogen and oxygen, and a 60:40 mixture of nitrogen and oxygen. The measurements at the five laser lines imply that oxygen is a less efficient broadener than nitrogen. The ratio of the oxygen-broadening coefficient to the nitrogen-broadening coefficient was measured to be 0.75 based on the data at the R(20) laser line. Results of this study demonstrate that pure nitrogen should not be used as a broadener for atmospheric modeling of monochromatic transmittances in the laboratory. PMID- 20203858 TI - Effect of sea-state on the performance of laser fluorosensors. AB - The effect of the sea-state on the performance of laser fluorosensors operating in both spectral and temporal modes is estimated. For the spectral mode, calculations of the dependence of reflective losses on the angle of incidence show that the attenuation of the fluorescence return is not significantly affected for the range of sea-states expected in deep water. In the temporal mode the return signal is distorted by the sea-state. Fortuitously this distortion does not significantly alter the full width at half maximum (FWHM), a parameter from which decay times can be estimated. PMID- 20203859 TI - Detectivity estimation of the DAS lidar for NO(2). AB - The detectivity of an NO(2) spatial distribution by a DAS lidar was estimated under practical conditions, and its capability was clarified. PMID- 20203860 TI - Hybrid cryogenic cooler for space flight applications. AB - The hybrid cryogenic cooler is an intermittent Joule-Thomson refrigerator with a precooler in the form of a passive radiator. The properties of the J-T expansion and the gas storage vessel are used to select fluids on the basis of available refrigeration per unit mass. Surface forces and container geometry are used to confine and control the liquid cryogen in a zero-gravity environment. The precooler and vaporized liquid are used to reduce parasitic thermal inputs to the point where most of the heat of vaporization is available for useful purposes. Modifications can be made to increase the efficiency or extend the temperature range. Ambient storage combined with efficient operation make the hybrid cooler attractive for space flight applications. PMID- 20203861 TI - Method for the calculation of partially coherent imagery. AB - The tedious numerical computations associated with the calculation of partially coherent imagery are alleviated by a method which uses dimensionless coordinates and takes advantage of the properties of the Fourier transform. A 1-D periodic object function can model many objects of practical interest, including nonperiodic objects. The properties of a given optical system are described in terms of the transmission cross coefficient. For aberration-free systems with circular pupils, including annular sources (dark-field illumination), the cross coefficient can be calculated analytically. For aberrated or apodized systems, a 1-D approximation can be used. The effect of a convolving slit in the image plane of a scanning microscope can also be included. PMID- 20203862 TI - Fourier optical approach to the extraction of morphological parameters from the diffraction pattern of biological cells. AB - A new procedure for fast quantitative extraction of cell parameters from diffraction patterns was deduced from model calculations and applied to cervical gynecological material. Based on radial scans of the diffraction pattern, the technique permits simultaneous determination of the nuclear and cytoplasmic diameters by Fourier analysis of the radial scanning signals after compensation for the intensity falloff by an amplification proportional to the third power of the radial position in the diffraction plane. Illustrative examples of measurements on exfoliated cells of different types are presented. PMID- 20203863 TI - Acoustooptic snapshot PROM: a real-time optical-signal spectrum analyzer. AB - This paper describes a system which performs real-time optical processing of electrical signals. The signals of interest are recorded in a raster format on the Itek PROM (Pockels Readout Optical Modulator), a light addressed electrooptic imaging device. The PROM is then read out with laser light to perform optical Fourier transformation, achieving spectrum analysis in near real time. A technique called acoustooptic snapshot recording is used to generate the required low distortion raster at rf bandwidths. PMID- 20203864 TI - Image coding with far-field holograms. AB - Two image-coding capabilities associated with far-field holograms are analytically and experimentally evaluated. It is demonstrated that preprocessed information concerning the shape of a small object can be efficiently coded into the fringe structure associated with a far-field hologram. In addition, the resultant record has a smaller bandwidth than the original object, and this reduces the resolution requirements when the hologram is used as the input to an information processing system. PMID- 20203865 TI - Reading and optical erasure of holograms stored by the photorefractive effect in lithium niobate. AB - The reading and optical erasure (on and off the Bragg angle) of holograms stored in lithium niobate and similar materials by the photorefractive effect have been modeled using numerical methods for the case of a single trapping level and with the further restrictions of uniformly and completely illuminated crystals, short transport lengths, and constant applied voltage. For the first time, the model allowed simultaneously for finite dark conductivity, feedback effects due to space charge on the redistribution of photoliberated electrons, writing of a new hologram by interference between the reconstructed and the reading waves (causing enhancement or disenhancement of the original hologram according to the conditions), and nonuniformity of the hologram through the thickness of the crystal. The model generates all the reported types of behavior, and it is believed to be accurate enough for a meaningful comparison with experiment. Excluded are those effects due to the large scale field associated with the envelope of the illumination when this is nonuniform. PMID- 20203866 TI - Optical interference method for the approximate determination of refractive index and thickness of a transparent layer. AB - Optical interference fringe measurements of the thickness of transparent layers can be rapid, accurate, and nondestructive. If the refractive index n of the layer being measured is known, it may be combined directly with interference fringe information to yield the layer thickness t. If, however, n is unknown, the measurement procedure necessarily becomes more complicated. In this paper, a new and simpler optical interference method is presented for the approximate determination of both n and t of a transparent layer on a transparent substrate. The required experimental information is obtained from a single spectrophotometric recording of either the reflectance or transmittance of the layer and its substrate. The theory of the method is presented, and an application of the method to measurements of layers of SIPOS (Semi-Insulating POlycrystalline Silicon) is described. The method requires that the layer being measured must be uniformly deposited on a flat substrate, and it must neither absorb nor scatter the light passing through it. The major approximation inherent in the method is that both the layer and the substrate are assumed to be nondispersive over the wavelength region of interest. PMID- 20203867 TI - Interferometric measurement technique for the temperature field of axisymmetric buoyant phenomena. AB - A method is described to measure the temperature field of axisymmetric laminar thermals, plumes, and starting plume caps in a liquid. The sample liquid is placed in a Mach-Zender interferometer, and an infinite-fringe interferogram is recorded on photographic film. By comparison with a bar pattern interferogram, the fringe shift field was measured to an accuracy of +/-0.02. The Bockasten series approximation of the Abel transformation was applied to the fringe shift field to obtain the radial refractive index variation field, which in turn could be related to the temperature variation field through an empirical relationship. Temperature accuracies in the range of +/-0.05 to +/-0.5 degrees C were obtained. The radial temperature profile of the plume was found to be monotonically decreasing, while the cap had a local maximum offset from the axis. PMID- 20203868 TI - Scanning technique for obtaining linear fringe shift readout from a high resolution interferometer. AB - A technique is described for obtaining a linear readout of fringe shift from a high resolution Fabry-Perot interferometer. One mirror of the interferometer is mounted on a piezoelectric crystal driven by a high frequency sinusoidal voltage. A signal proportional to the mirror displacement is displayed on the Y axis of an oscilloscope, while the X axis is swept with time. Each time the interferometer passes through a transmission maximum, a pulse is produced which is fed to the Z axis of the oscilloscope, producing an intensified dot. The displacement of the resultant row of dots from its ambient position is linearly proportional to the fringe shift occurring within the interferometer, has no sign of ambiguity, and is independent of the finesse. All the circuits required for producing the readout were realized using the internal circuitry of a standard laboratory oscilloscope. PMID- 20203869 TI - Thin-film 2.8-microm and 3.8-microm absorption in single-layer films. AB - A systematic study was made of thin-film absorption at 2.8microm and 3.8 microm for a wide variety of transparent coating materials. The extinction and absorption coefficients were measured using HF/DF chemical laser calorimetry in single-layer films of PbF(2), LiF, YbF(3), NaF, ThF(4), As(2),S(3), As(2),Se(3), Si, MgO, ZnSe, and Al(2),O(3), on CaF(2), substrates. The lowest absorbing film materials were the As glasses, ZnSe, and some fluorides. In these cases, high purity starting material led to the lowest loss films. PMID- 20203870 TI - Development of thermoplastic-photoconductor tape for optical recording. AB - We report in this paper the continuous coating of the thermoplastic photoconductor medium on a transparent polyester tape base for holographic optical data recording. The tape performance is evaluated in a moving transport at speeds up to 15 ips (38.1 cm/sec). Uniform diffraction efficiencies for both 2 D and 1-D holograms have been demonstrated. Furthermore, we have recorded complex 1-D holograms on the moving tape with high quality readout, and we have also made complex spatial filters on the tape which produce good correlation results in a coherent optical data processor. Numerous material factors affecting the performance of the tape in a moving tape system have been defined and investigated. Factors such as coating uniformity, electrode reflectivity, photoconductor reciprocity, the pressure endurance of the surface relief, and the tape noise are singled out for discussion in this paper. PMID- 20203871 TI - Generation of intense subnanosecond 0.58-0.80-microm pulses with a flashlamp pumped dye laser. AB - Subnanosecond optical pulses (as short as 7 psec) have been generated over the 0.58-0.80-microm wavelength range with good beam quality, energies in excess of 1 microJ/pulse (up to 20 microJ/pulse), and repetition rates of at least 10 Hz using a flashlamp-pumped dye laser. The experimental details concerned with mode locking the dye laser and the selection of single pulses from the pulse train with an energy reproducibility of 10% are described. PMID- 20203872 TI - Sulfur as a proposed near infrared reflectance standard. AB - Powdered sulfur pressings were found to have uniform and high diffuse reflectances of approximately 97-98% in the region between 1.0 microm and 2.5 microm. The reflectance and physical properties of powdered sulfur indicate that it could be used as a reflectance standard in the near ir region. PMID- 20203873 TI - Tunable VUV photofragment monochromator. AB - A versatile tunable VUV photofragment monochromator is described. The instrument uses a unique flash-lamp and a single slit monochromator to produce the photofragments. A tunable dye laser is used to detect these fragments via laser induced fluorescence. The results of preliminary design parameter measurements are presented along with the first photofragment spectra obtained with this instrument. It is shown that the SNR is adequate to assign single quantum state photofragment distributions. PMID- 20203874 TI - Launch dependent loss in short lengths of graded-index multimode fibers. AB - In this paper we describe the effect of different launching conditions on the loss measured with a calorimeter in short (~1-m) lengths of multimode optical fiber. A qualitative description of the relation between the energy distribution in the fiber and various excitation variables is given, and many examples are presented that illustrate the effect that launch conditions have on the fiber loss. The use of launch-dependent loss phenomena to diagnose loss mechanisms in optical fibers is discussed. In particular, loss plots are shown for two germania doped silica-core fibers that indicate a strong absorption loss mechanism located deep within the fiber core. PMID- 20203875 TI - Propagation in graded-index fibers: comparison between experiment and three theories. AB - We compare the measured impulse response of a graded-index fiber by three different theories: the WKB method applied for an arbitrary profile; the alpha profile approximation; and perturbation theory. We find that the WKB method gives both a qualitatively and quantitatively good agreement. The perturbation theory gives a qualitatively good calculation of the width of the impulse response (the dispersion). The alpha-profile approximation gives a very poor result. We also investigate the influence of the launching conditions on the impulse response and find that the dispersion for this fiber decreases with the excitation of higher order modes. This is found to be in agreement with the WKB theory. PMID- 20203876 TI - Transmission characteristics of multimode W-type optical fiber: experimental study of the effect of the intermediate layer. AB - The transmission mechanism of a multimode W-type optical fiber is clarified by the experimental study of the effect of the intermediate layer on the transmission characteristics. It is shown that control of the layer width is an effective means for achieving the desired loss and bandwidth. A W-type fiber with a thick intermediate layer has a transmission loss on the order of 2 dB/km. To determine the transmission characteristics of a W-type fiber applicable to system design, the length dependence of several fiber characteristics is investigated. Concepts such as splices used as mode scramblers and the effect of the intermediate layer as a barrier against OH absorption loss are introduced. The wavelength dependence of microbending loss of a W-type fiber is also described. PMID- 20203877 TI - Mode excitation by tilted and offset Gaussian beams in W-type fibers. AB - The excitation efficiencies of a few lower order modes in a W-type fiber have been studied when the modes are excited with a tilted as well as offset Gaussian beams. The effect of beam size, angle of incidence, the radius of curvature of the incident wavefront, and the off-axis displacement has been obtained. It is found that in order to couple maximum power into the fundamental mode, the incident wavefront must be plane, and the beam must be incident axially along the fiber with a suitable value of the beam size. PMID- 20203879 TI - Shearing interferometer inaccuracies due to a misaligned test section. PMID- 20203878 TI - Splice loss evaluation for optical fibers with arbitrary-index profile. AB - A method is presented for calculating offset and tilt losses for fiber splices with axially symmetric arbitrary-index profiles by approximating the profile with a staircase function. This method is applied to a large-core dual-mode fiber with zero intermodal dispersion as well as to single-mode fibers with step- and parabolic-index profiles. When a splice loss of 0.2 dB is permitted, the normalized offset misalignment is found to be D(N) = 0.635 for the dual-mode fiber at normalized frequency v = 4.605 and a power-law exponent alpha = 4.5. The D(N) value compares favorably with the values 0.560 and 0.614 for conventional step- and parabolic-index single-mode fibers, respectively. The dual-mode fiber is superior to the step- and parabolic-index fibers with respect to permissible splice offset tolerances. PMID- 20203880 TI - Techniques of holographic displacement measurement: an experimental comparison; errata. PMID- 20203881 TI - Visual evaluation of defects in GaAs-based solar cells. PMID- 20203882 TI - Direction-sensitive simultaneous multivelocity component LDV. PMID- 20203883 TI - optics is light work. PMID- 20203884 TI - Optical activities in the universities. PMID- 20203885 TI - Effects of metal overlays on 3-D optical waveguides. PMID- 20203886 TI - Fiber optics strain gauge. PMID- 20203887 TI - Astigmatic Gaussian beams in an elliptical square-law medium. PMID- 20203888 TI - Retinal tissue damage induced by single ultrashort 1060 nm laser light pulses. PMID- 20203889 TI - Automated data acquisition and stabilization system for Fabry-Perot interferometry: erratum. PMID- 20203890 TI - Refraction correction for fluorescence spectra of aqueous solutions. PMID- 20203891 TI - Absorption curve of the 607-mum line in benzene. PMID- 20203892 TI - Resonant scanning optical microscope. AB - The enhancement of nonlinear interactions in the scanning optical microscope by placing the object in a resonant cavity is discussed. The effect of resonance of the primary radiation is also considered. Practical geometries for the resonant scanning optical microscope are given. PMID- 20203893 TI - Detection of low-contrast images in film-grain noise. AB - When low contrast photographic images are digitized by a very small aperture, extreme film-grain noise almost completely obliterates the image information. Using a large aperture to average out the noise destroys the fine details of the image. In these situations conventional statistical restoration techniques have little effect, and well chosen heuristic algorithms have yielded better results. In this paper we analyze the noisecheating algorithm of Zweig et al. [J. Opt. Soc. Am. 65, 1347 (1975)] and show that it can be justified by classical maximum likelihood detection theory. A more general algorithm applicable to a broader class of images is then developed by considering the signal-dependent nature of film-grain noise. Finally, a Bayesian detection algorithm with improved performance is presented. PMID- 20203894 TI - Aerial reconnaissance film screening using optical matched-filter image correlator technology. AB - The use of aerial photography for reconnaissance and the relatively high costs associated with human photo interpreters are responsible for the continuing interest in the development of automated screening systems. An optical matched filter image-correlator (OMFIC) system has the inherent capability to perform this task, especially when expanded to include multiple holographic lens-matched filter memory banks. An OMFIC system was investigated in detail, and a projection of its performance for the screening mission was made. This showed that a high probability of detection can be obtained at a low false alarm rate. For example, a memory bank of 23 (orientational) views of an M-60 tank would enable a probability of detection of 98% to be obtained with 1.4% false targets in a complex village scene even though the image scale changed by as much as +/-9.5% (linear scale). PMID- 20203895 TI - Forwardscattering corrections for optical extinction measurements in aerosol media. 1: Monodispersions. AB - This paper, Part 1 of two papers, presents a parametric study of the forwardscattering corrections for experimentally measured optical extinction coefficients in homogeneous aerosol media, since some forwardscattered light invariably enters, along with the direct beam, into the finite aperture of the detector. Part 1 treats the case of monodispersions; Part 2, that of polydispersions. Forwardscattering is considered a single-scattering phenomenon, and the corrections are computed by two methods: one, using the exact Mie theory, and the other, the approximate Rayleigh diffraction formula. A parametric study of the dependence of the corrections on the particle size parameter, real and imaginary parts of the complex refractive index, and the half-angle of the detector's view cone has been carried out. The parameter ranges in which the results obtained by the approximate formulation agree well with those obtained by the Mie theory are also investigated. The agreement is especially good for small view cone angles and large particles and improves even more for slightly absorbing aerosol particles. Also discussed is the dependence of these corrections upon the experimental design of the transmission measurement systems. PMID- 20203896 TI - Thermal-blooming compensation using the CLASP system. AB - A closed-loop system for phase compensation of thermal blooming has been designed and tested. This system-called CLASP for closed-loop adaptive single parameter-is a single-mode outgoing-wave dither system. CLASP has demonstrated stable convergence to the optimum thermal-blooming-correction amplitude in a laboratory experiment. PMID- 20203897 TI - Versatile high-precision multiple-pass reflectometer. AB - A confocal mirror assembly is used to measure radiant reflectances in excess of 0.99 with high precision. The mirrors can be either plano or curved with a few diopters of power, and the angle of incidence can vary from 5 degrees to 70 degrees . Multilayer dielectric reflectors consisting of alternate layers of tantalum pentoxide and silica were prepared by evaporation in a vacuum. A maximum reflectance of 0.9996 +/- 0.0002 was measured at 520 nm. PMID- 20203898 TI - Mirror system for uniform beam transformation in high-power annular lasers. AB - The conditions for transformation with uniform intensity from an annular to a cylindrical beam, as needed for mode control in high-power lasers, are analyzed. The equations for the shapes of the mirrors in two different arrangements are derived and evaluated for feasibility of fabrication. The shape of the inner mirrors as well as the major part of the outer mirrors should present no problem of fabrication. In either system, however, that edge of the outer mirror which reflects to the axis requires a sharp curvature, the machining of which might appear formidable. Nevertheless, recent work with diamond machining has accomplished even sharper curvatures than here required. PMID- 20203899 TI - Single-mode collapse in 6328-A He-Ne lasers. AB - Internal-mirror 6328-A He-Ne lasers have an intramode frequency difference when placed in a transverse magnetic field. When the magnetic field strength is increased until the Zeeman frequency shift approaches the mode spacing, mode coupling is nduced. In some multimode lasers, this mode coupling results in a collapse into single-mode operation with no loss of over-all laser power in the output. The intramode frequency difference can be exploited to produce a simple frequency stabilization system whose frequency variation is less than 1 part in 10(10). Plots of beat frequency variation and single-mode tuning range are included. PMID- 20203900 TI - Profile measurement using projection of running fringes. AB - A method of profile control or measurement using projected fringes is presented. The fringes are dynamically translated over the object, and the phase of the signal picked up at a selected point on the surface is used to determine the depth or the depth error of the profile at this point. The method has the advantage of being contact-free, fast, accurate, and easily automated. PMID- 20203901 TI - Achromatic imaging of distant objects in selected wavelength bands with plane and concave holographic gratings. AB - A combination of a plane grating and a spherically concave holographic grating is studied and optimized for imaging of distant objects in selected wavelength bands with a high degree of chromatic correction. The recording conditions for the holographic grating are given, and the aberrations of the image are studied. The arrangement comprises a new type of diffracting telescope. The achromatic imaging is verified by numerical ray-tracing and by experiment, the results of which are given. PMID- 20203902 TI - Optical computing for image bandwidth compression: analysis and simulation. AB - Image bandwidth compression is dominated by digital methods for carrying out the required computations. This paper discusses the general problem of using optics to realize the computations in bandwidth compression. A common method of digital bandwidth compression, feedback differential pulse code modulation (DPCM), is reviewed, and the obstacles to making a direct optical analogy to feedback DPCM are discussed. Instead of a direct optical analogy to DPCM, an optical system which captures the essential features of DPCM without optical feedback is introduced. The essential features of this incoherent optical system are encoding of low-frequency information and generation of difference samples which can be coded with a small number of bits. A simulation of this optical system by means of digital image processing is presented, and performance data are also included. PMID- 20203903 TI - Electrooptical array processor for complex signals. AB - An interdigital finger pattern is derived, which can modulate both the amplitude and phase of light in a total internal reflection configuration. An application to radio antenna array processing is illustrated. PMID- 20203904 TI - Interference measurement of continuous heterogeneities in optical materials. AB - A measuring method is described which is not limited by interferometer errors. Variations in the geometrical and optical thickness of the block under investigation and its refractive index may be measured by means of scanning three interferograms and using computer analysis. There also exists a possibility of calculating the rate of variation of these quantities according to coordinate alteration of the investigated block. Some measurement results are given, and analysis of measuring accuracy is carried out. Measuring accuracy for refractive index difference distribution may reach one part in 1 x 10(-7) for centimeter thick samples. PMID- 20203905 TI - Analytical description of a Fabry-Perot spectrometer. 4: Signal noise limitations in data retrieval; winds, temperature, and emission rate. AB - A quantitative investigation of the effects of noise inherent in the signal received by the detector of a Fabry-Perot spectrometer has been carried out in detail. The study also includes the effects of the instrumental profile width and the presence of unwanted continuum radiation in the signal, such as background radiation and detector dark current. The results show the spectrum of the noise in the transform plane to have a quantitative description in terms of the instrumental and line shapes as well as the signal strength, or emission rate, of both the line profile and the unwanted radiation. The magnitude and shape of this noise spectrum not only limits in a known quantitative manner the amount of useful information available from a given measured profile, but it also provides information on the profile itself, thus allowing for more information to be obtained from the measurement than would otherwise be possible. A detailed example is given for the retrieval of winds, temperature, and emission rate from line profile measurements, and it is quantitatively shown how the (noise) limited information available from a measured profile appears as uncertainties of determination. These uncertainties are shown to be dependent on the signal strength, more correctly the noise inherent in this signal, as well as the shapes and relative widths of the line and instrumental profiles, with the temperature uncertainty showing the most sensitivity to these factors. Although in some cases the results are qualitatively obvious, their quantitative nature allows the design of experiments for least uncertainty and/or define the limitations inherent in such experiments. PMID- 20203906 TI - Performance measurement techniques for simple Fourier transform lenses. AB - The use of simple off-the-shelf lenses as Fourier transform elements in an optical computer is considered. Several schemes for measuring those lens parameters that determine the performance of such simple lenses as Fourier transform elements are provided with emphasis on lens phase errors. It is assumed that no lens design data are available for the lens under test. PMID- 20203907 TI - Application of a microcomputer to optical spectroscopy. AB - A low-cost microcomputer-based scanning instrument controller is described which has been used with both a Fabry-Perot interferometer and a grating monochromator. The system is based on a commercially available single-board computer. The controller can be used in either a passive mode, where it functions as a replacement for a multichannel analyzer, or in an active-control mode. Only the read-only memory held program need be changed to adapt the device to a scanning instrument in either mode. Interface circuitry and typical programs are described. PMID- 20203908 TI - Fourier transform infrared spectroscopic study of molecular interactions in hemoglobin. AB - Infrared absorption spectra of the alpha-104 (G11) cysteine SH group have been observed for aqueous solutions of hemoglobin derivatives from humans, pigs, and horses. The center frequencies ((nu)SH) show ligand sensitive patterns that are similar for the three species, with (nu)SH (HbCO) <(nu)SH (HbO(2) ~ HbCN) < (nu)SH (Hb(+)) <<(nu)SH (deoxyHb) for human and pig hemoglobins. The alpha-104 SH group is most strongly H-bonded (smallest (nu)SH), has the greatest range of (nu)SH (Hb ? HbCO) in human hemoglobin, and is least strongly H-bonded and has the smallest range of (nu)SH (Hb ? HbCO) in horse hemoglobin. The beta-112 cysteine SH in human hemoglobin is more weakly H-bonded than is the alpha-104 SH. These studies illustrate how FTIR can be used to measure differences in protein structure that are related to biological control mechanisms. PMID- 20203909 TI - Systematic errors in Hadamard transform optics. AB - This paper analyzes the systematic errors in Hadamard transform optical instruments caused by moving masks, incorrect mask alignment, faulty mask fabrication, missing data, diffraction, etc. and describes techniques for reducing or eliminating these errors. In a great many cases the behavior of the instrument can be characterized by a single matrix equation of the form eta = TWa + e, where the components of eta are the measurements, T is a matrix characterizing the instrument, W specifies the mask configurations, a is a vector containing the unknown spectral intensities, and the components of e are small random errors. PMID- 20203910 TI - Aberrations of diffracted wave fields. AB - This paper is an attempt to provide new insight into the behavior of near-field scalar diffraction phenomena by showing that the Rayleigh-Sommerfeld diffraction integral is equivalent to the Fourier transform integral of a generalized pupil function which includes a term that represents phase errors in the aperture. This term can be interpreted as describing a conventional wavefront aberration function. The resulting aberration coefficients are calculated and expressed in terms of the aperture diameter, observation distance, and appropriate field parameter for several different geometrical configurations of incident beam and observation space. These aberrations, which are inherently associated with the diffraction process, are precisely the effects ignored when making the usual Fresnel and Fraunhofer approximations. PMID- 20203911 TI - Extending the field of view of KDP electrooptic modulators. AB - The use of KDP as a polarization rotator has been limited to small field of view instruments. To investigate this limitation, the index ellipsoid is used to describe the optical properties of KDP and to calculate the retardance and fast axis as a function of the angle of incidence and voltage. Computed converging light patterns are then compared with observed intensity patterns formed by KDP. Finally, computed intensity patterns are used to demonstrate how the field of view of KDP can be increased when properly aligned with a positive uniaxial crystal. PMID- 20203912 TI - Polarization characteristics of noncircular core single-mode fibers. AB - It is well known that geometrical or dielectric imperfections in conventional graded-index single-mode fibers depolarize light after a few centimeters. A slight improvement in the polarization performance of these fibers is achieved by introducing noncircularity in the core shape. This is evident from the measurements on borosilicate fibers with dumbbell shaped cores. This result is correlated with Marcatili's analysis, which shows that changing the core geometry, from square to rectangular, does not appreciably alter the difference in the propagation constants of the two fundamental modes with orthogonal polarizations. Thus, the noncircular geometry and the associated increase in stress-induced birefringence introduced during the manufacturing process alone are not sufficient to improve the polarization performance, and the enhancement of the anisotropic birefringence is necessary to achieve single-polarization fibers. PMID- 20203913 TI - Narrow resonance structure in the Mie scattering characteristics. PMID- 20203915 TI - Applied OpticsOf Optics and Opticists. PMID- 20203914 TI - Optical activities in industry. PMID- 20203916 TI - Confocal interferometer light-scattering sample cell. PMID- 20203917 TI - Definition weaknesses in atmospheric experiments in low visibility atmospheres. PMID- 20203918 TI - Optical properties of cigarette smoke aerosols. PMID- 20203919 TI - Effect of uv irradiation on the reflectance of silicon-oxide-protected aluminum in the far uv. PMID- 20203920 TI - Continuous-wave optical-fiber Raman oscillator employing a two-mirror resonator configuration. PMID- 20203921 TI - Optical frequency shifter for heterodyne interferometers using multiple rotating polarization retarders. PMID- 20203922 TI - Low-birefringence single-mode optical fibers: preparation and polarization characteristics. PMID- 20203923 TI - Optical thin film synthesis program based on the use of Fourier transforms. AB - In Sossi's formulation of the Fourier transform method of optical multilayer design the refractive-index profile is derived for an inhomogeneous layer of infinite extent having the desired spectral transmittance. This layer is then approximated by a finite system of discrete homogeneous layers. Because it does not make any assumptions about the refractive indices, thicknesses, or number of layers, it is the most powerful analytical method proposed so far. The method has been programmed for a computer and combined with other numerical design procedures. With the program it is possible to design filters with almost any desired transmittance characteristics using realistic refractive indices. PMID- 20203924 TI - Thermal emissivity of semitransparent and opaque films of cholesteric liquid crystal. AB - Thermal emissivity of cholesteric liquid crystal films is measured as a function of the film thickness d. increases from 0.2 to 0.4 in parallel with the increase of d from 13 microm to 33 microm and arrives at a constant value as high as 0.87 in the case of d ~ 1 mm. Reflectance at the air-to-liquid crystal interface and the absorption coefficient of the liquid crystal layer are found to be 0.130 and 7.24 x 10(-3) microm(-1), respectively. The dependency of on d is interpretable on the basis of McMahon's theory of radiant characteristics of semitransparent radiators. PMID- 20203925 TI - Effective infrared optical depths associated with the clear ocean. AB - The approximation that the effective optical depth of the clear ocean is equal to the reciprocal of the water optical absorption coefficient is considered for the 1-16-microm spectral region. The exact effective optical depth in general lies closer to the ocean surface than does the approximate result and depends on the specific temperature profile of water that underlies the thermal boundary layer. The effective optical depth is better approximated by the reciprocal of the absorption coefficient as the wavelength increases; errors in subsequent calculations by using the approximate result also decrease with increasing wavelength. The application of two-wavelength radiometry to infer properties of the thermal boundary layer becomes more accurate at wavelengths increasing beyond about 6 microm. PMID- 20203926 TI - Fourier transform plane superposition multiplier: theory, experimental results, and discussion. AB - Deuterated cesium dihydrogen arsenate (CDA) is used as a square-law device for optical processing. Placed in the Fourier transform plane, the device squares the incident optical radiation, thus producing the convolutions and correlations of the input functions at the output plane. The convolutions can be detected at the temporal angular frequency omega(a) + omega(b) and the correlations at omega(a) - omega(b), where omega(a) and omega(b) are the frequencies of the input radiation. This paper describes the experiment setup, presents the convolution data obtained, and develops an associated mathematical model of the crystal interaction in an optical data processing system. PMID- 20203927 TI - Electrically calibrated radiometer using a thin film thermopile. AB - The fabrication and principal characteristics of an electrically calibrated absolute radiometer are described. The receiver substrate incorporates an evaporated chromium-nickel thermopile, an electrical shield, a copper thermal diffuser disk, an evaporated chromium electrical heating element, and a goldblack absorber. All insulating layers are evaporated silicon monoxide; the thermopile and heater are made by a photoetching process. The performances of several radiometers are discussed. For example, a 28-junction version has a responsivity and NEP of 93 mV/W and 50 nW, respectively, in air, with a time constant of 15 sec and a surface responsivity uniform to better than 1%. The radiometers require only a few corrections of small magnitude. An analysis of sources of error and residual uncertainties shows that the over-all precision of this type of radiometer is at least 0.5% for a power level of 50 microW. Comparative radiometric measurements are described that support this claim. PMID- 20203928 TI - Fisheye field spectrograph. AB - The details of a new design of a fisheye field spectrograph are presented together with performance studies on the prototype. Spectra of different sources together with the microphotometer tracings for the spectra of skylight are given. Details of the calibration are also discussed. The condition for negligible astigmatism, achieved experimentally, has been derived theoretically. PMID- 20203929 TI - Spectroscopic analysis of the transverse excited C(3)Pi(u) ? B(3)Pi(g) (0-0) uv laser band of N(2) at room temperature. AB - A new high-resolution spectroscopic study of the 0-0 transition (3371 A) in the N(2) Second Positive System excited by a pulsed transverse electrical discharge has been carried out with a 14-m Czerny-Turner spectrograph. A detailed rotational analysis of the spectrum has pointed out a few misassignments in the earlier work of Dieke and Heath. The simple model proposed by Patel has been applied to the nitrogen laser in order to explain the optical gain formation on the different branches. The experimental results are in reasonable agreement with the theoretical model. PMID- 20203930 TI - Piezoelectric scanning of Fabry-Perot spectrometers: nonlinearities. AB - Piezoelectric materials used in mechanical scanning of Fabry-Perot spectrometers are found to have measurable nonlinearities. Dynamic scanning has been used in the present investigation in order to decrease the effects of some of the variables, such as creep, of the piezoelectric material in static operation. The results show mainly a decrease in the distance between corresponding maxima, or apparent free spectral range, as the driving voltage increases to higher values. A relationship between this voltage and displacement (in terms of orders) has been derived, and it is given by v(i) = In {1 - (x(i) - x(0))/[a/(1 - b) - x(0)]}/In b, where v(i) is the displacement in orders from an arbitrary starting point, x(i) is a quantity directly proportional to the voltage, while x(0) is also a quantity proportional to the voltage at the arbitrary reference point, a is the distance between the arbitrary reference point and the next order, and b is the nonlinearity constant for a given piezoelectric material. Examples are given for emission and absorption measurements where the usually large effects of the piezoelectric material nonlinearities are derived, as well as schemes to minimize or altogether remove the effects by suitable handling of the data or by changing the experiment such that the scanning is forced to be linear. PMID- 20203931 TI - Holography of a moving object using the frequency chirp of a Q-switched ruby laser. AB - This paper describes a new method offering relaxation of the traditional holographic restriction on the allowable velocity of a moving object, that is, that the change of path difference between the object and reference beams has to be negligible during exposure of a hologram. The proposed method depends on the frequency chirp of the laser pulse used for the hologram recording canceling the Doppler frequency shift due to the motion of the object. Experimental verification is also shown. PMID- 20203932 TI - Holographic interferometry of surface deformations of transparent fluids. AB - Holographic interferometry is employed to study deformations of a water surface by various disturbances. By using nondiffuse illumination and observing fringe patterns in the holographically reconstructed real image, high resolution even in the presence of large gradients in the surface deformation is achieved. Mathematical procedures for evaluating the fringe patterns are outlined. Several interesting applications (determination of surface tension, surface deformation by floating bodies) demonstrate the accuracy and versatility of the method. PMID- 20203933 TI - Comprehensive analysis of gratings for ultraviolet space instrumentation. AB - Comprehensive measurements in the vacuum uv range of 1200-3000 A of efficiency, polarization, and scattering of classically ruled and photoresist gratings are reported. The results show that the art of ruling gratings for vacuum uv use has reached a high level of sophistication and that careful analysis of grating properties can lead to useful improvement of the ruling art. PMID- 20203934 TI - Astronomical monochromatic imaging as applied to the lo sodium cloud. AB - We compare four types of instruments for recording monochromatic astronomical images: filters; slitless spectrographs; multislit spectrographs; and interferometers. Each of these instruments has been used on the sodium emission cloud of o, with varying degrees of success. Multislit spectrographs and interferometers encode the signal, and it can be extracted with a noise level close to that for photon statistics. This is not normally the case for filters and slitless spectrographs. On balance, we find that a Mach-Zehnder interferometer provides the best system for imaging faint monochromatic signals on a brighter continuum background. PMID- 20203935 TI - Direct recording and reconstruction of 3-D x-ray images. AB - Theoretical and experimental investigations of a method for direct recording and reconstruction of 3-D x-ray images are described. When recording, an x-ray source is placed at discrete positions, and an x-ray grid is fixed on the x-ray plate. When reconstructing, a lenticular sheet matched with the grid is overlayed on the developed plate, and a parallax-panoramagram type 3-D image is seen with the naked eye. Using a small x-ray source designed for use in dental clinics and an x ray grid matched with the lenticular sheet, 3-D x-ray images having a 0.001-rad resolvable angle and a 0.02-rad flipping angle are directly recognized with clear parallax. PMID- 20203936 TI - Application of optimum coding sequences to computerized classical tomography. AB - A variation of matched filtering using 1-D code sequences with near optimum correlation properties is applied to the reconstruction of coded-source or coded scan tomographic imagery. The reconstructed image enjoys a higher SNR than imagery reconstructed with conventional matched filtering. A major advantage of using code sequences is the elimination of noise and secondary images that result from the sidelobes of the autocorrelation function of nonnegative functions or sequences. PMID- 20203937 TI - Infrared refractometer measurements of adhesives. AB - The real part of the refractive index of the optical cements, Eastman Kodak, HE 79; Lensbond, M-62; Epotek, 301 and 310; and Loctites, 307, IS-06, IS-04E, IS-12 (the latter three are Super Bonders), have been measured. The values are reported in most part over the 1-5-microm wavelength range. The samples were measured in a setting to which they are subjected in normal optical use. The technique used to obtain the values in this manner was an Abbe ir refractometer. The composite range in indices is from 1.46 to 1.54. The precision of the instrument and the accuracy of the data are discussed. PMID- 20203938 TI - Ray tracing evaluation of a technique for correcting the refraction errors in satellite tracking data. AB - Refraction errors in satellite laser tracking data are evaluated by ray tracing through 3-D refractivity profiles. The results indicate that a range resolution of 1 cm or less appears feasible for satellite elevation angles above 10 degrees if the tracking data are corrected using both spherical and gradient correction formulas. PMID- 20203939 TI - Computer-graphics analysis of atmospheric refraction. AB - Interactive computer graphics is applied to the transmission of visual images through the lower atmosphere. The required input data to the computer consist of an atmospheric temperature profile and light-pen sketches of three objects at various distances from the observer. A transfer characteristic, computed from a bundle of rays leaving the observer, maps each object's actual location into a corresponding image. The three images, and the horizon line, are then simultaneously displayed on the graphics terminal, thus generating a pictoral version of what the observer would see. This program provides an essential aid to the study of atmospheric refraction. PMID- 20203940 TI - Effects of asphericity on single particle scattering. AB - Light scattered by single particles is frequently measured to determine particle volume. The particle is illuminated by a light beam; it scatters to one or more photodetectors. Usually no consideration has been given to effects of particle shape. This study applies recently developed theoretical techniques for predicting scattering by spheroids in order to compare representative scattered fluxes for several particle shapes and orientations. It is found that shape and orientation can strongly influence the measurement of whole particle size. The effects of refractive index are also found to be significant but smaller. PMID- 20203941 TI - Nonspherical extinction and absorption efficiencies. AB - Predictions concerning the scattering and absorption characteristics of electromagnetic radiation interacting with nonspherical particles are obtained by suppression of particle resonances (surface waves) in classical Mie scattering theory. The importance of the particle resonance phenomenon and thus the nonspherical corrections is related to the three classical variables n(i), n(r), and x, the imaginary and real components of the index of refraction and the size parameter, respectively. The resonance phenomenon becomes increasingly restricted to small values of x as n(r) increases. For solar wavelengths and cloud size particles resonance phenomenon may be neglected for n(r) greater, similar 2. As n(r), decreases the effect of nonsphericity becomes increasingly significant to both scattering and absorption. For n(r) less, similar 2.0 and n(i) approximately 10(-5), suppression of particle resonances in Mie theory predicts increases in absorption efficiency of several orders of magnitude in the region of the absorption peak. PMID- 20203942 TI - Forwardscattering corrections for optical extinction measurements in aerosol media. 2: Polydispersions. AB - This paper, second of two parts, presents a parametric study of the forwardscattering corrections for experimentally measured optical extinction coefficients in polydisperse particulate media, since some forward scattered light invariably enters, along with the direct beam, into the finite aperture of the detector. Forwardscattering corrections are computed by two methods: (1) using the exact Mie theory, and (2) the approximate Rayleigh diffraction formula for spherical particles. A parametric study of the dependence of the corrections on mode radii, real and imaginary parts of the complex refractive index, and half angle of the detector's view cone has been carried out for three different size distribution functions of the modified Gamma type. In addition, a study has been carried out to investigate the range of these parameters in which the approximate formulation is valid. The agreement is especially good for small-view cone angles and large particles, which improves significantly for slightly absorbing aerosol particles. Also discussed is the dependence of these corrections on the experimental design of the transmissometer systems. PMID- 20203943 TI - Picosecond light scattering measurements of cataract microstructure. AB - A picosecond range-gated light scattering technique is used to measure the microstructure of cataracts in the living eye, with a resolution of the order of the wavelength of light. The cataract is illuminated with ultrashort pulses of light derived from a mode-locked Nd:glass laser. The pulses backscattered by the opacity are collected at several angles simultaneously by an array of fiber-optic light guides whose outputs are sequentially sampled by a multichannel picosecond Kerr shutter. This shutter transmits only that light which is scattered from the desired depth in the eye, while blocking from the detector any light scattered by foreground or background tissue and reducing multiple scattering effects. The size distribution of scatterers in the cataract is deduced from the angular distribution of scattering intensities by application of Mie theory. The results of experiments with suspensions of latex microspheres and with rabbit cataracts in vivo are presented. Cataract microstructure down to 0.5 microm has been measured in a rabbit eye and verified with electron microscopy. PMID- 20203944 TI - High performance avalanche transistor switchout for external pulse selection at 1.06 microm. AB - The design and performance of an avalanche transistor switchout are described. The device selects a single pulse from a train of cw or Q-switched mode-locked pulses and introduces less than +/-1% amplitude variation in the selected pulse. The prepulse rejection ratio exceeds 10(7), and a lifetime of greater than 10(7) shots has been achieved. PMID- 20203945 TI - White light hologram technique. PMID- 20203946 TI - Symmetrical prism as input coupler for integrated optics (E). PMID- 20203947 TI - Phase transition changes in the molecular absorption coefficient of water in the infrared: evidence for clusters. PMID- 20203948 TI - Molecular interpretation of the ir water vapor continuum: comments. PMID- 20203949 TI - Rotational-translational models for interpretation of quasi-elastic light scattering spectra of motile bacteria. AB - Quasi-elastic light scattering is a powerful tool for studying dynamic behavior of motile bacteria in liquid suspension. Previously we proposed an ellipsoidal structural model to account for the straight line motion of E. coli bacteria. We have in this article extended our structural model to include rotational motions superimposed on the translational motion of the center of mass. A general formulation is given by which the light scattering spectrum of any rotational translational motion of a structured particle can be calculated. Specific calculations are carried out for three types of rotational motions, namely, planar wiggling motion, pure rotation, and helical rotation, around the average direction of motion. Further narrowing of the scattered field correlation function as compared with that of the straight line motion is observed in all three cases. We finally compare the helical rotation model with our previous experimental results for E. coli and find a substantial improvement over that of the straight line motion model. PMID- 20203950 TI - Paraxial analysis of light scattering by biological cells in a flow system. AB - A special mathematical model is developed to find the scattered light pattern of biological cells in a fluid flow system. A paraxial approximation to the diffraction integral is used to accommodate nonspherical and asymmetrical cells. The paraxial approximation results are in good agreement with Mie calculations for homogeneous spheres of comparable size and refractive index. A 2-D fast Fourier transform program is used to simulate variable cell morphology and experimental conditions. Distinct signature differences for two types of cells resembling normal and abnormal malignant human cervical cells are found useful as discriminant features. The ability to handle a variety of model cell shapes and distortions by these methods is demonstrated, and use of signature features for cell discrimination is shown experimentally. PMID- 20203951 TI - Atmospheric scattering of middle uv radiation from an internal source. AB - A Monte Carlo model has been developed which simulates the multiple-scattering of middle-uv radiation in the lower atmosphere. The source of radiation is assumed to be monochromatic and located at a point. The physical effects taken into account in the model are Rayleigh and Mie scattering, pure absorption by particulates and trace atmospheric gases, and ground albedo. The model output consists of the multiply scattered radiance as a function of look-angle of a detector located within the atmosphere. Several examples are discussed, and comparisons are made with direct-source and single-scattered contributions to the signal received by the detector. PMID- 20203952 TI - Light scattering in optical waveguides. AB - The coupling of scattered radiation from Raman-active core and cladding regions to the waveguide normal modes is analyzed by treating the scattered light as a classical incoherent effective source. Numerical results are presented for the limiting cases of single-mode or highly multimode excitation of the fiber. The effect of a finite frequency shift between the exciting and scattered fields is also considered. It is found that radiation produced by scattering of the evanescent field in the cladding is coupled to the guided modes with a peak efficiency of about one-fifth that of light scattered in the core. The implications of these effects for optical devices utilizing fibers are briefly discussed. PMID- 20203953 TI - Coupled power equations for lossy fibers. AB - Coupled power equations for multimode fibers were originally derived by neglecting mode losses, loss was later introduced by adding a phenomenological loss factor to the equation system. In this paper the time independent coupled power equations are derived taking mode losses into account from the beginning. The form of the equations so obtained is identical to the well known coupled power equations, but the coupling coefficients are different. The mode losses alter the analytical expressions for the coupling coefficients and cause the matrix of coupling coefficients to be asymmetrical. Some consequences of the coupled power theory incorporating mode losses are discussed for the specific example of a fiber supporting only two guided modes. Finally, we compare the steady-state losses of a fiber with two randomly coupled modes with the corresponding case of a fiber resonator and find that the resonator losses are equal to the steady-state losses of randomly coupled modes in the limit of very low and very high differential mode losses, for all other cases the resonator losses are much higher than the losses of randomly coupled modes. PMID- 20203954 TI - Measurement of mode conversion coefficients and mode dependent losses in a multimode fiber. AB - A new method for the simultaneous measurement of the loss and mode conversion coefficient in multimode fibers is proposed, which utilizes the differences of the mean transit time among modes. The principle is applied to a step-index fiber, and the mode conversion coefficient and mode dependent loss are obtained. A procedure to minimize the experimental errors is also discussed. In the experiment the mode conversion coefficient decreases gradually when the mode angle increases and increases rather quickly when the angle approaches the critical angle of the fiber. PMID- 20203955 TI - Side launch excitation of selected modes in graded-index optical fibers. AB - Excitation of single guided modes in a multimode graded-index optical fiber has been demonstrated. A side launch technique is employed which permits external selection of input conditions to match the axial and tangential wavenumber components of individual modes. Good agreement is obtained between observed mode order numbers and order numbers calculated from input parameters. PMID- 20203956 TI - Multimode fiber-optics coupler with low insertion loss. AB - A fiber-optics coupler is described which is simple to fabricate, is directional, leaves the fiber intact, and has an insertion loss of <0.05 dB. The coupler utilizes the energy contained in the leaky modes of the fiber. The coupling ratio may be varied by changing the type of light source and input conditions. Possible applications are to optical data bus links of up to a few hundred meters or as power or mode monitors. PMID- 20203957 TI - Optical demultiplexer using coupling between nonidentical waveguides. AB - A demultiplexer using wavelength dependent coupling between nonidentical waveguides is proposed and demonstrated for single-mode fiber transmission systems. The demultiplexer, consisting of rf-sputtered glass thin film layers, demultiplexes 4880-A, 5145-A, and 6328-A light waves with larger than 14-dB crosstalk attenuations and with less than 5.2-dB insertion losses. PMID- 20203958 TI - Electrooptic diffraction modulation in Ti-diffused LiTaO(3). AB - The design and fabriction of electrooptic Bragg diffraction modulators in Ti diffused LiTaO(3) waveguides are reported. The modulators developed have demonstrated 98% deflection efficiency for visible and near-ir operation with extinction ratios of at least 250:1 for both deflected (m = 1) and nondeflected (m = 0) beams. PMID- 20203959 TI - Channeled-substrate-planar structure Al(x)Ga(1-x) As lasers: an analytical waveguide study. AB - The waveguide mechanism in channeled-substrate-planar (CSP) structure (AlGa) As lasers is analyzed. The light leakage into the GaAs substrate outside the channel is shown to provide effective refractive index and loss differences, which function to stabilize the transverse mode in the junction plane. Observed light output vs current characteristics and mode patterns in the lasers justify the theoretical model. PMID- 20203960 TI - Efficient cavity dumped dye laser. AB - A theoretical and experimental investigation of cavity dumped flashlamp pumped dye lasers is described. Theory predicts that pulse time compressions of the order of 10-20 can be obtained without loss in energy efficiency. Experimental confirmation was obtained with a coaxial flashlamp dye laser. Over 300 mJ of output was obtained in a 20-nsec pulse at 490 nm. PMID- 20203961 TI - Possible high energy laser at 1.27 microm. AB - Preliminary theoretical and experimental evidence is presented that suggests the potential of lasing from the strongly forbidden O(2)((1)Delta(g)) ? C(2)((3)Sigma (-)(g)) transition of molecular oxygen. A rate equation model is developed which predicts pulse energies up to several hundred joules/liter atmosphere for typical mixtures of 10(3):2N(2) activated by uv photolysis in less than 10 microsec. Preliminary results from a flash photolysis laser apparatus demonstrating 1.27 microm lasing are presented. Results from a computer analysis assessing the possibility of using this system as a multipass amplifier are also given. PMID- 20203962 TI - Surface profile measurement and angular deflection monitoring using a scanning laser beam: a noncontact method. AB - A noncontact method for measuring the surface profile of a reflecting surface is presented. The scheme is based on the measurement of the phase difference between a surface reflected laser beam and a reference beam. Both beams are scanned past a photodetector by means of a rotating beam splitter. The slope of the surface at various points is electronically obtained, and then the surface profile in a plane is determined by direct integration. The accuracy of the method falls between the more elaborate interferometric techniques and mechanical contact schemes. A complete theoretical analysis of the method is presented as well as the results of various experimental tests. PMID- 20203963 TI - Color blur of the rainbow hologram. AB - The color blur of the rainbow hologram is calculated from first-order holographic theory. The result is applicable to most of the rainbow holographic processes, including the one-step recording technique. Horizontal color blur approaches zero if the rainbow hologram image is near the optical axis of the hologram aperture. PMID- 20203964 TI - Holographic light deflection. AB - An operational holographic laser light deflector is described, which is well suited for applications requiring fast constant-speed scanning, high resolution, and moderately large angles of deflection. A particularly unique application of this device as an opaque document scanner is also described. PMID- 20203965 TI - Pressure-scanned three-pass Fabry-Perot interferometer. AB - This paper describes a pressure-scanned three-pass Fabry-Perot interferometer. The design considerations relating plate reflectivity and desired transmission and contrast are presented together with the details of the beam positioning in the retroreflectors. Actual performance of the instrument is compared with predicted performance for transmission and contrast. A contrast of 1.4 x 10(8) and transmission of 29% were achieved. PMID- 20203966 TI - Tilt-compensated Michelson interferometer for Fourier transform spectroscopy. AB - A new Michelson interferometer built exclusively with spherical and plane mirrors provides tilt compensation for all mirrors. In particular, a staggering of the movable mirror generates no shift of the two images obtained from the two interferometer arms on the detector area. These properties are experimentally demonstrated by taking interferograms from a near ir source. The influence of small tilts of the movable component on the optical path difference is analyzed. PMID- 20203967 TI - Extreme ultraviolet reflection efficiencies of diamond-turned aluminum, polished nickel, and evaporated gold surfaces. AB - We report measurements of reflection efficiencies from 44 A to 1048 A for samples of polished nickel, diamond-turned aluminum, and various thicknesses of gold evaporated onto the nickel and aluminum samples. The reflection efficiencies are presented for grazing angles from 5 degrees to 75 degrees . For wavelengths longer than ~100 A, the gold-coated nickel surface provides the highest efficiencies, while for wavelengths shorter than 100 A the nickel is superior. The optimal thickness of gold is found to be ~500 A. The performance of grazing incidence optics using nickel and aluminum substrates for an evaporated gold surface is discussed. PMID- 20203968 TI - Attenuated total reflection angular spectra and associated resonant electromagnetic oscillations of a dielectric slab bounded by Ag films. AB - The attenuated total reflection (ATR) angular spectra of a layered system of Ag MgF(2)-Ag, sandwiched between glass and air, have been measured at three different wavelengths in the visible region. Resonant electromagnetic (EM) oscillations are detected as narrow minima in the reflectance and sometimes as accompanying maxima in the transmittance of both p- and s-polarized light. Detailed calculations of the resonant EM fields illustrate the nature of the oscillations. Discrepancies between theory and experiment are thought to be due largely to the surface roughness of evaporated MgF(2) films. A cermet layer is imagined to form at the MgF(2)-Ag interface, and also an induced roughness layer at the Ag-air interface. When the optical constants of the cermet and roughness layers are evaluated by the Maxwell Garnett theory, the discrepancies for both polarizations can be accounted for in a consistent manner at all three wavelengths. PMID- 20203969 TI - Reduction of diffraction errors in radiometry by means of toothed apertures. AB - Purcell and Koomen have shown [J. D. Purcell and M. J. Koomen, Coronagraph with Improved Scattered-Light Properties, Report of NRL Progress, 1962 (U.S. GPO, Washington, D.C., 1962)] that a toothed occulting disk greatly reduces diffraction problems in coronagraphy. In the present paper, the use of toothed apertures to reduce diffraction errors in radiometry is studied in detail. Simple formulas are derived which allow the design of toothed apertures for given applications. Experimental measurements are presented which demonstrate the usefulness of toothed apertures to reduce diffraction errors by at least an order of magnitude. This technique is shown to be particularly useful for radiometric measurements involving a series of apertures; in such cases, the diffraction errors of the individual apertures can simply add up, resulting in important over all errors if ordinary circular apertures are used. PMID- 20203970 TI - Degradation of an image due to Gaussian motion. AB - Degradation of an image due to its random motion is considered. Equations describing the effects of Gaussian random motion on the point-spread function, Strehl ratio, and encircled energy are given in terms of the degraded optical transfer function. These equations are used to obtain numerical results for several typical cases of motion of diffraction-limited images formed by imaging systems with obscured circular pupils. PMID- 20203971 TI - Unusual white light conoscopic figure in single crystal lithium metagermanate Li(2)GeO(3). PMID- 20203972 TI - Infrared reflectance of a variety of mirrors at 45 degrees incidence. PMID- 20203973 TI - Optical activities in the universities. PMID- 20203974 TI - Electromagnetic scattering from active objects. PMID- 20203975 TI - Extinction of ir wavelengths by aerosols in coastal fog: erratum. PMID- 20203976 TI - Some relationships between Secchi depth and inherent optical properties of natural waters. PMID- 20203977 TI - One-step rainbow holography with a field lens. PMID- 20203978 TI - Deconvolution of spectral lines by Fourier analysis. PMID- 20203979 TI - Transmittance and reflectance of a thin absorbing film on a thick substrate. PMID- 20203980 TI - Sulfur dioxide absorption cross sections for (12)C(18)O(2) laser lines around 9 microm. PMID- 20203981 TI - Resonant photoacoustic cells constructed from Uhv hardware. PMID- 20203982 TI - Generalized ellipsometry with a nonideal compensator. PMID- 20203983 TI - Wollaston prism as a beam splitter in convergent light. PMID- 20203984 TI - Insects as unidentified flying objects. AB - Five species of insects were subjected to a large electric field. Each of the insects stimulated in this manner emitted visible glows of various colors and blacklight (uv). It is postulated that the Uintah Basin, Utah, nocturnal UFO display (1965-1968) was partially due to mass swarms of spruce budworms, Choristoneura fumiferana (Clemens), stimulated to emit this type of St. Elmo's fire by flying into high electric fields caused by thunderheads and high density particulate matter in the air. There was excellent time and spatial correlation between the 1965-1968 UFO nocturnal sightings and spruce budworm infestation. It is suggested that a correlation of nocturnal UFO sightings throughout the U.S. and Canada with spruce budworm infestations might give some insight into nocturnal insect flight patterns. PMID- 20203985 TI - Optical design and analysis program. AB - An optical design and analysis program structured for operation on a minicomputer has been developed at NRC (National Research Council of Canada). It has been designed to be used interactively giving the user both flexibility and ease of operation. The computer on which it runs at present is a Digital PDP11 with a memory of around 28K, and this represents a great saving in computer costs when compared with those of a large computer upon which most lens design work is carried out. This program has capabilities for optimizing a lens system, for pupil exploration, for fitting the computed wavefront aberration to a polynomial, and for evaluating the diffraction optical transfer function. Although only ten finite rays are traced in the optimization routine, the aberrations computed, together with the Seidel aberrations obtained from the paraxial ray trace, provide the user with adequate control of the aberrations over both aperture and field. A Double Gauss and a Maksutov-Cassegrain system are used as practical examples to illustrate this. PMID- 20203986 TI - High aperture lens for laser compression experiments: a new type. AB - The lens is designed for use at 1.06 microm, but it is null tested for aspherizing with visible light, thus facilitating manufacture. PMID- 20203987 TI - Pseudo-second-derivative matrix and its application to automatic lens design. AB - A method of approximating the homogeneous second derivatives of a merit function with respect to a set of design variables is presented. If these derivatives are used in an automatic lens design program, the familiar problem of stagnation may usually be avoided. PMID- 20203988 TI - Yule-Nielsen effect in printing: a physical analysis. AB - The Yule-Nielsen curve-fitting parameter n is derived in terms of the point spread function describing the scattering of light in paper substrates upon which are printed halftone dot or line patterns. The value of n is shown not to depend strongly on either screen frequency or area coverage at low area coverages or highlight regions. However, when the shadow regions are considered, n becomes increasingly dependent on both of these parameters. This dependence is not explicitly allowed for by the Yule-Nielsen equation. It is analytically shown that the value of n approaches 1.0 as the substrate approaches a specular surface and approaches 2.0 as the substrate becomes a perfect diffuser. The value of this analysis is the following. First, it indicates that the Yule-Nielsen equation is physically adequate in highlight and medium shadow regions. Second, an accurate determination of n at any screen frequency can be made from a single measurement of n at any other frequency using an inferred scattering length. Third, this analysis shows that the empirical (Yule-Nielsen) determination of n from dot density and fractional area coverages is valid only in the regions below about 50% area coverage. PMID- 20203989 TI - Comparison of image restoration methods. AB - Three image restoration methods are compared in a variety of blur and noise conditions. Both numerical and subjective data are evaluated. It is demonstrated that, in certain conditions, one restoration method is preferable to others. PMID- 20203990 TI - Photosensitive characteristics of the optical information storage element using M centers in NaF crystals. AB - Effects of M-center concentration and thickness of the M-center layer on the photosensitive characteristics of optical information storage elements using M centers in NaF crystals are presented. It is shown that writing in the disordering mode and reading with crossed polarizers in white light provide good contrast and gray scale images just like conventional silver halide film. PMID- 20203991 TI - Statistical spatial filtering: application to aerial photographs. AB - Spatial filtering is shown to apply not only to the identification of deterministic signals but also to the classification of images. The spectral content of images is put into a classifier that extracts the dominant eigenvectors responsible for statistical features. Principal images that carry most of the information are obtained by using optical representations of eigenvectors as spatial filters. The statistical stability and the intrinsic dimensionality of Fourier spectra are related to the fast estimation of useful eigenvectors. PMID- 20203992 TI - Laser heterodyne correlation processing of optical thickness irregularities in transparencies. AB - Irregularities in optical thickness of a given nondiffuse transparency are statistically inferred using optical heterodyne detection techniques. The modulus and phase of its complex amplitude transmittance can be recovered from a beat photocurrent by rotating the transparency in a signal laser beam. The ensemble averaged autocorrelation of the transmittance is obtained by making correlation measurements of the recovered real and imaginary parts of the transmittance. This autocorrelation function has a nonvanishing imaginary part, so that the spatial spectral profile (i.e., its power spectrum) of the transparency becomes asymmetric. PMID- 20203993 TI - Bilinear processing of 1-D signals by use of linear 2-D coherent optical processors. AB - The capabilities of optical computers are extended to perform the class of bilinear transformations (of nonzero spread) on 1-D signals. Use is made of the additional degree of freedom in 2-D linear processing. The technique is applied to the study of partially coherent optical systems and to systems in which coherent optical processing is followed by postdetection linear spatial filtering. PMID- 20203994 TI - Processing optical data matrices. AB - The cross-correlation matrix of a set of signals is obtained by multiple Fourier holography. Various sources of error make this kind of matrix not directly interpretable. Global methods that correct deterministic fluctuations as well as random perturbations are proposed. They do not take into account any individual element of the matrix, but they minimize the over-all variance. The efficiency of these methods is illustrated by the example of the classification of sonagrams. PMID- 20203995 TI - Equalizing and coherence measure correlators. AB - A correlator is described that combines optical and electronic processing. The optical section is the first Fourier transform taking stage of a joint transform correlator; its output is electronically processed by a modified spectrum analyzer. Increased flexibility and various processing operations beyond those normally possible in an optical system result. PMID- 20203996 TI - Fog hole boring with pulsed high-energy lasers: an exact solution including scattering and absorption. AB - The exact time dependent solution for hole boring through fog is obtained for pulsed high energy lasers, which includes scattering, absorption, and the effect of realistic particle distributions. The results are applied to both haze burnout and fog hole boring. For the latter, at 10.6 microm, the calculated result is that 50% more laser pulse energy is required than that calculated from thermodynamic considerations alone. An absolute upper bound of 100% is also established. The results are compared to shorter wavelengths, e.g., 3.8 microm for which much larger fluences are required to evaporate fog or haze, and are also compared to other recent approximate results, which overestimate the required energy by a larger factor. PMID- 20203997 TI - Single-scattering solution for radiative transfer through a turbid atmosphere. AB - A solution is presented to the radiative transfer of the solar irradiation through a turbid atmosphere, bounded by a Lambert surface, based on the single scattering approximation, i.e., an assumption that a photon that underwent scattering either leaves the top of the atmosphere or strikes the surface. The solution depends on idealization of the scattering phase function of the aerosols. The equations developed here are subsequently applied to analyze quantitatively (1) the enhancement of the surface irradiation and (2) the enhancement of the scattered radiant emittance as seen from above the atmosphere, caused by the surface reflectance and subsequent atmospheric scattering. An order of-magnitude error analysis is presented. PMID- 20203998 TI - Estimation of soil moisture and components by measuring the degree of spectral polarization with a remote sensing simulator. AB - The components of an object and the moisture in it can be estimated by measuring the degree of spectral polarization of scattered light from that object. In this paper the degree of spectral polarization of scattered light from CuSO(4), CuCl(2), Fe(2)O(3), SiC, S, NiCl(2), and CoCl(2) as models of soil was measured and compared with that of volcanic ash and natural soil. From these results it is estimated that Fe appears in natural soil and Si appears in volcanic ash. The field capacity point of soil was obtained from measurements of the degree of spectral polarization, and it was detected more clearly in a shorter wavelength region (about 400 nm). PMID- 20203999 TI - Incoherent optical heterodyne detection and its application to air pollution detection. AB - Fundamental problems of incoherent optical heterodyne detection are analyzed. Output of the heterodyne detection depends on the spatial and temporal coherences of incoming incoherent signal light on the photodetector surface. The directivity of optical heterodyne detection is concluded to be the same as with that of direct detection in an ideal case in which the image of the object is well focused on the photodetector surface. This incoherent heterodyne detection is applied to air pollution monitoring. In the laboratory, the absorption spectra due to NH(3), Freon, and SF(6) are measured using an incoherent light source, and the concentrations of each gas were determined by using the least-squares method. PMID- 20204000 TI - Determination of wave slopes from photographs of the ocean surface: a new approach. AB - A general nonlinear technique is described for determining wave slopes from photographs of an area of the ocean surface that is illuminated by diffuse skylight. This technique is evaluated using uniform, overcast, and bright sky radiance distribution models, and results from its use are compared with the approximate results obtained by previous authors. Under certain clearly defined practical experimental conditions, it is theoretically possible to determine the total wave slope magnitude at the ocean surface. PMID- 20204001 TI - Excitation of surface electromagnetic waves on water. AB - Excitation of surface electromagnetic waves (SEW) on water was studied using optical coupling techniques at microwave frequencies. Excitation of SEW was also achieved using direct horn antenna coupling. The transmitted SEW power was increased by adding acid and salt to water. The horn antenna gave the maximum excitation efficiency 70%. It was increased to 75% by collimating the electromagnetic beam in the vertical direction. Excitation efficiency for the prism (0 degrees pitch angle) and grating couplers were 15.2% and 10.5% respectively. By changing the prism coupler pitch angle to +36 degrees , its excitation efficiency was increased to 82%. PMID- 20204002 TI - Signal-to-noise ratio in optical heterodyne detection for Gaussian fields. AB - The signal-to-noise ratio of optical heterodyne detection is discussed for Gaussian fields. The ratio of the aperture radius a of the detector to the smallest spot size w(s) of the signal has serious effects on the SNR. The conditions that maximize the SNR are obtained for a given signal or local oscillator field. The effects of field mismatching or misalignment are also discussed. Numerical analyses show that when such mismatching or misalignment exists, the spot size of the local oscillator field should be larger than that of the signal with a ratio of a/w(s) approximately 1.2. Then the heterodyne efficiency is rather insensitive to the errors and yet takes reasonable values (above 0.8). PMID- 20204003 TI - Trombay infrared pneumatic detector: theory of operational characteristics. AB - This paper explains in a simple manner the mechanism of formation of pressure pulse inside a pneumatic detector due to incident ir radiation. The detector had been designed earlier at Trombay. Experimentally observed characteristics of the detector have been explained on the basis of the theory derived. PMID- 20204004 TI - Surface damage and the optical reflectance of single-crystal silicon. AB - The reflectance of silicon measured at 4.3 eV can be used to determine the surface quality of silicon. Crystallographic damage, which occurs with abrasive polishing, and texture, which occurs with epitaxial film growth, can be detected. The effect of surface damage on the optical reflectance of silicon measured at 4.3 eV is reported. The reflectance measurement is nondestructive, simple, fast (on the order of seconds), and sensitive. The technique is readily adaptable to quality control inspection in silicon device manufacturing facilities. PMID- 20204005 TI - Steady state molecular luminescence radiance expressions assuming narrowband excitation. AB - Steady state luminescence radiance expressions for two-level and three-level molecular systems are derived in terms of transition probabilities, source irradiance, emission pathlength, absorption band halfwidth, total molecule concentration, frequencies of the transitions, statistical weights after transitions, and nonradiational activation and deactivation rate constants. Limiting radiance expressions are given for both low (conventional sources) and high (lasers) intensity sources. Saturation irradiances for the two-level and three-level molecular systems are also given. Conclusions concerning the expressions are given. One conclusion, which has special importance, involves the production of similar phosphorescence intensities whether the first triplet electronic state is excited directly or is excited via the first excited singlet with intersystem crossing to the first triplet state. PMID- 20204006 TI - Versatile high-temperature high-pressure vapor cell design for electron beam excited laser studies. AB - The design of a cell suitable for studying electron beam excited laser candidates at high temperatures such as organic dye and metal vapors is described. The cell is capable of handling temperatures up to 450 degrees C and pressures from 10(-6) Torr to 15 atm. Details of both the high-temperature laser performance of Ar-N(2) and the gain characteristics of the dye POPOP [2,2' phenylenebis(5 phenyloxazole)] are presented as an example of the use of such a cell. PMID- 20204007 TI - Intensity distribution properties of a Gaussian laser beam focus. AB - A generalized method for determining the properties of a Gaussian laser beam focus including waist radius, position, and intensity distribution is presented. Of significance to in situ laser diagnostic methods is a unique analysis of illuminated area as a function of intensity in a plane of the laser beam. The results apply for nontruncating diffraction-limited optical systems and are important in determination of the optical sampling volume of laser instruments for particulate and gaseous species analysis. PMID- 20204008 TI - Spatial coherence of a ruby laser beam by interferometry. AB - The importance of spatial coherence of a pulsed ruby laser beam is pointed out. The spatial and temporal coherences of light are defined. Spatial coherence of the beams from a ruby laser, operating in either the Q-switched or normal lasing modes, is deduced from the degree of visibility of fringes formed by a Michelson interferometer in which the laser beam interferes with itself after being rotated 180 degrees . The results are physically and analytically interpreted. PMID- 20204010 TI - Patents. PMID- 20204009 TI - Misalignment in imaging multifibers. AB - A statistical approach is used to characterize image transmission through misaligned multifibers, i.e., differently arranged at the input and output faces, leading to a spatially invariant line spread function. The resulting MTF is the product of the MTF for the aligned system and a function characterizing stochastic departures from alignment. The case of circular fibers with Gaussian misalignment is treated theoretically and is found to account satisfactorily for experimentally observed results. PMID- 20204012 TI - Determination of moments of the size distribution function in scattering by polydispersions: a comment. PMID- 20204013 TI - Update of the AFGL atmospheric absorption line parameters compilation. PMID- 20204014 TI - Optical characteristics of a clear epoxy. PMID- 20204015 TI - Measuring the magnifying power of Keplerian telescopes. PMID- 20204017 TI - Hybrid cryogenic cooler for space flight applications: errata. PMID- 20204016 TI - Plasma resonance in granular deposits of iron and interstellar dust. PMID- 20204018 TI - Technique for obtaining cw CO(2) sequence laser lines using an incavity NH(3) cell. PMID- 20204019 TI - Capacitor modification for the Schenck-Metcalf nitrogen laser. PMID- 20204020 TI - Lensless method of measuring Gaussian laser beam divergence. PMID- 20204021 TI - Alignment of a Fourier transform spectrometer for measuring high temperature reflectivities. PMID- 20204022 TI - Binary silica optical fibers: refractive index and profile dispersion measurements; corrigenda. PMID- 20204023 TI - Optical fiber switch driven by PZT bimorph. PMID- 20204024 TI - Frequency demultiplexing in GaAs EAP waveguide detectors. PMID- 20204025 TI - Real-time intensity autocorrelation interferometer. PMID- 20204026 TI - Laser-anemointerferometer for simultaneous measurements of velocity and density. PMID- 20204027 TI - Measurement by holographic interferometry of the deformation of the eye accompanying changes in intraocular pressure. PMID- 20204028 TI - Low-background large-aperture infrared measurement facility: design considerations. AB - Design features of a measurement facility for the prelaunch evaluation of ir space sensors are described. After a listing of the facility's major capabilities, an analysis of its internal calibration process is given. This is followed by a discussion of test beam characteristics and some performance limitations. Concepts for improvements are presented. PMID- 20204029 TI - Low-background large-aperture infrared measurement facility: performance. AB - A novel ir measurement facility that generates a 43-cm diam collimated beam of radiant flux in a simulated exoatmospheric environment has been built and evaluated. The broadband and spectral irradiance of the beam was measured with a calibrated integral three-grating spectroradiometer. The irradiance values cover a range of 10(8), with near Planckian distribution at higher flux densities. The beam source can also generate monochromatic radiation tunable from 2 microm to 32 microm. Diffraction losses at the source aperture have been estimated. PMID- 20204030 TI - Continuously tunable ir lidar with applications to remote measurements of SO(2) and CH(4). AB - Remote atmospheric measurements of SO(2) and CH(4) were performed using a differential absorption lidar with a continuously tunable LiNbO(3) parametric oscillator and amplifier source in the 1.4-4.0-microm region. A comparison of injected gas concentration in a remotely located sample chamber showed excellent agreement with a SO(2) detection sensitivity of 0.9 ppm-km. An ambient level measurement of methane at the 1.66-microm overtone transition gave 3.9 +/- 0.7 ppm Performance predictions indicate an order of magnitude gain in sensitivity is possible with recently demonstrated tunable source improvements. The wide tuning range capability allows the measurement of numerous other pollutant molecules in the 1.4-4.0-microm region. PMID- 20204031 TI - Coded aperture imaging: predicted performance of uniformly redundant arrays. AB - Uniformly redundant arrays (URA) have autocorrelation functions with perfectly flat sidelobes. The URA combines the high-transmission characteristics of the random array with the flat sidelobe advantage of the nonredundant pinhole arrays. A general expression for the signal-to-noise ratio (SNR) has been developed for the URA as a function of the type of object being imaged and the design parameters of the aperture. The SNR expression is used to obtain an expression for the optimum aperture transmission. Currently, the only 2-D URAs known have a transmission of (1/2). This, however, is not a severe limitation because the use of the nonoptimum transmission of (1/2) never causes a reduction in the SNR of more than 30%. The predicted performance of the URA system is compared to the image obtainable from a single pinhole camera. Because the reconstructed image of the URA contains virtually uniform noise regardless of the original object's structure, the improvement over the single pinhole camera is much larger for the bright points than it is for the low intensity points. For a detector with high background noise, the URA will always give a much better image than the single pinhole camera regardless of the structure of the object. In the case of a detector with low background noise, the improvement of the URA relative to the single pinhole camera will have a lower limit of ~(2f)(-(1/2)), where f is the fraction of the field of view that is uniformly filled by the object. PMID- 20204032 TI - Restoration of a smeared photographic image by incoherent optical processing. AB - A technique of restoration of smeared photographic images by white light optical processing is described. It is well known that the image quality and the degree of restoration obtainable by coherent optical processing techniques are severely limited by artifact noise. This new technique offers a lower artifact noise and possibly a higher degree of restoration. We stress that this incoherent restoration technique applies to 2-D objects, although the operation to be performed must be 1-D. PMID- 20204033 TI - Single-threshold detection of a random signal in noise with multiple independent observations. 1: Discrete case with application to optical communications. AB - A single-threshold processor is derived for a wide class of classical binary decision problems involving the likelihood-ratio detection of a signal embedded in noise. The class of problems we consider encompasses the case of multiple independent (but not necessarily identically distributed) observations of a nonnegative (nonpositive) signal, embedded in additive, independent, and noninterfering noise, where the range of the signal and noise is discrete. We show that a comparison of the sum of the observations with a unique threshold comprises optimum processing, if a weak condition on the noise is satisfied, independent of the signal. Examples of noise densities that satisfy and violate our condition are presented. The results are applied to a generalized photocounting optical communication system, and it is shown that most components of the system can be incorporated into our model. The continuous case is treated elsewhere [IEEE Trans. Inf. Theory IT-25, (March, 1979)]. PMID- 20204034 TI - Laser beam steerer-expander. AB - A two-mirror laser beam expander can be used to provide small amounts of beam steering by moving one mirror. Such a motion would generally introduce aberrations into the output wavefront that would restrict the amount of diffraction-limited beam steering achievable to very small amounts. This paper describes how some or all of the third-order aberrations introduced by moving one mirror can be eliminated. By proper design, substantial amounts of diffraction limited beam steering can be achieved. PMID- 20204035 TI - Split-pulse laser method for measuring attenuation coefficients of transparent liquids: application to deionized filtered water in the visible region. AB - Attenuation coefficients alpha(lambda) for collimated quasi-monochromatic radiation passing through deionized filtered water were measured throughout the 418.6-640.3-nm wavelength region by use of a split-pulse laser method, which employs reference and sample cells arranged in a geometry similar to that of a Michelson interferometer. The radiant source was a pulsed wavelength-tunable dye laser possessing a relatively short coherence time. This paper includes descriptions of theoretical and experimental techniques applicable to the split pulse laser method and includes a tabulation of alpha(lambda) measured for deionized filtered water at 26.4 +/- 1.7 degrees C. PMID- 20204036 TI - Infared diode laser double-beam spectrometer. AB - A complete spectrometer for recording high resolution ir absorption spectra with diode lasers is presented. The optical assembly has been adapted to the characteristics of diode lasers but can be used as well with other laser sources. With a double-beam technique variations in laser power are eliminated. Problems of optical alignment and electronic signal detection are discussed, and representative spectra are presented. PMID- 20204037 TI - Diffraction gratings for color filtering in the zero diffraction order. AB - Phase gratings with deep rectangular grooves have been successfully used in the zero diffraction order as transmission color filters. They form the basis of the ZOD microimage system for recording color images as surface-relief structures. ZOD images can be inexpensively replicated by hot embossing in a transparent sheet of plastic and read-out using conventional slide projectors or microfilm viewers. In this paper we use rigorous diffraction theory to derive optimum grating parameters for gratings with periods d < 2 microm to produce the three subtractive primary colors, cyan, magenta, and yellow, and also green. The theoretical results are in good agreement with the experiment. PMID- 20204038 TI - Determination of optical irradiance in nonlinear processes. AB - A method has been developed for experimentally measuring the irradiance (energy per unit area) of optical radiation required to stimulate nonlinear processes. The method involves examining the spatial dependence of the process in the vicinity of a laser beam focus. A laser operating in the lowest order transverse mode is required. The treatment is exact for multiphoton processes in the absence of relaxation of recombination and is approximate for other nonlinear processes. PMID- 20204039 TI - Fine calibration of large-aperture optical scintillometers and an optical estimate of inner scale of turbulence. AB - Large-aperture optical scintillometers [Ting-i Wang et al., J. Opt. Soc. Am. 68, 334 (1978)] lose their calibration if they are sensitive to portions of the spatial spectrum of temperature fluctuations where (K)(-11/3) fails to hold. The model temperature spectrum having the bump [R. J. Hill, J. Fluid Mech. 88, 541 (1978); R. J. Hill and S. F. Clifford, J. Opt. Soc. Am. 68, 892 (1978)] is used to find conditions under which the scintillometers maintain their calibration. We find that the aperture size D should be at least twenty times the inner scale l(0) if the contribution of the spectral bump is to be ignored. For application in the surface layer, one needs the height above ground of the optical path to be much greater than three times the aperture size if outer-scale effects are to be negligible. It is shown that the inner scale dependence of a scintillometer having D/l(0) approximately 2.0 and the lack of such dependence for a scintillometer having D/l(0) approximately 20.0 can be used to estimate both l(0) and C(2)(n) if the two systems are used simultaneously on the same path. A preliminary experiment was performed in the atmospheric surface layer with scintillometers having aperture sizes of 2.0 cm, 5.0 cm, and 15.0 cm; the results are consistent with the existence of the spectral bump. The inner scale is estimated by comparing data from the 2.0-cm and 15.0-cm systems. Using this inner scale, the C(2)(n) values from the 5.0-cm and 15.0-cm scintillometers are corrected for the spectral bump; the corrected values are in agreement. Other turbulence parameters are not deduced from the l(0) and C(2)(n) estimates because the l(0) values have been found to be insufficiently accurate. PMID- 20204040 TI - Holographic strain analysis: an experimental implementation of the fringe-vector theory. AB - The fringe-vector theory of holographic strain analysis was applied experimentally to determine strain and rotation tensors of rotated and deformed objects. One object was supported in a specially designed positioner, and the other was heated internally with a temperature controlled device. The rigid body motions and deformations were determined directly from the fringes that were observed on the surface of the object. This was done by taking photographs of the virtual image of the object from several different directions through the same hologram; the photographs were digitized manually, and the parameters obtained were, in turn, analyzed using a computer. The strains and rotations determined experimentally from holograms compared satisfactorily with the theoretical ones. PMID- 20204041 TI - Pulsed ir holography on Takiwax films. AB - Phase holograms have been recorded on Takiwax films with pulsed TEA CO(2) laser light. The reconstruction from these phase holograms is accomplished by transmission at a wavelength of 0.633 microm. Holographic characteristics of the recording medium, such as diffraction efficiency vs film thickness, exposure, and spatial frequency, are presented. The capability of Takiwax films to record ir holograms of plane objects and double-exposure holographic interferograms is demonstrated. PMID- 20204042 TI - Holographie en infrarouge sur de minces couches d'huile. AB - Oil films of approximately 1-microm thickness on glass plates are used as a holographic recording medium at a 10.6-microm wavelength. This dynamic recording medium (on which the recording is not permanent) shows diffraction efficiencies up to 20% when reconstructing at 632.8 nm, the spatial frequency at the recording being as high as ~50 cycles/mm. Furthermore, the response time of these oil films when recording ir can be as small as 2 msec so that ir holography of moving objects is possible in real time. PMID- 20204043 TI - Attenuated total reflection angular spectra of a system of alternating plasma dielectric layers. AB - The attenuated total reflection (ATR) angular spectra of a five-film system have been observed. Successive layers of Ag-LiF-Ag-LiF-Ag are evaporated onto the base of a glass prism. Surface plasma wave resonances corresponding to coupled oscillations at the plasma-dielectric interfaces were found for p-polarization. Guided light modes coupled between the two dielectric layers were observed in both p- and s-polarized spectra. If guided mode reflectance resonances occur at less than the critical angle they have associated with them resonance transmissions. In general the ATR resonances of the five-film system occur as doublets, which form a splitting of the resonances of a single dielectric slab bounded by Ag layers. The resonant oscillations are demonstrated by detailed calculations of the Poynting vector field and electric field oscillations, which also help in understanding the source of discrepancies between experimental and calculated ATR spectra. These discrepancies are thought to be due largely to the surface roughness of evaporated LiF films. The roughness is modeled as thin cermet layers at the LiF-Ag interfaces, and the optical constants of the cermets are calculated by the Maxwell Garnett theory. When the ATR spectra are then computed with the pseudolayers inserted, much improved agreement with experiment can be obtained. PMID- 20204044 TI - Fizeau interferometry for measuring refractive index and thickness of nearly transparent films. AB - A simple method for measuring refractive index and thickness of nearly transparent films from Fizeau interferograms is described. The method requires no polarizing optics, variation of wavelength or angle of incidence, or precise light intensity comparisons. Commercially available Fizeau surface relief measuring instruments can be used without modification, the only necessary change being a partial, rather than complete, metallization of the sample surface. Analysis of the contributions of different sources of error to the over-all error in the refractive-index measurement indicates that the measurement is quite insensitive to weak absorption in the dielectric film and to finite absorption in the metal layer. For typical values of index and thickness, the thickness error is about 0.005 wavelengths, and the refractive-index error is of the order 0.01. PMID- 20204045 TI - Interferometric measurement of laser fusion targets. AB - We describe techniques for the quantitative interferometric characterization of wall thickness variations of hollow glass microspheres. By using a combination of techniques, one can rapidly form a picture of the total configuration for most defect combinations. These techniques require only very simple calculations and do not involve detailed ray tracing through the sphere. We also show how ray tracing calculation can be done very simply for careful analysis of the interference phenomenon in a perfect sphere. These calculations show that if both a large illumination angle and a large aperture objective are used, the nonparallel illumination causes degradation of both the spatial and the phase resolution of the interferometer. These problems can be overcome by properly aperturing the illumination. PMID- 20204046 TI - Optical fiber refractometry by interference microscopy: a simplified method. AB - Index of refraction profiles of optical fibers are obtained by a new interference technique closely related to Mach-Zehnder microscope interferometry. Data are obtained from specially prepared samples using a conventional reflected light microscope. Excellent agreement is obtained with the results using the Mach Zehnder method but at a considerable reduction in the cost and complexity of instrumentation. PMID- 20204047 TI - Splicing and bending losses of single-mode optical fibers. AB - Splicing and bending losses are compared among step, power-law, W, ring-shaped, and M.W index singlemode optical fibers. A product of normalized offset and tilt misalignments D(N)Phi(N)is introduced to compare the permissible offset and tilt misalignments among these fibers. Permissible offset misalignment can be evaluated by D(N)/B(?) under constant bending loss condition. Here, B denotes the bending loss parameter. Numerical calculations on these parameters reveal that the required splicing accuracy is nearly identical for step, power-law, and W fibers. An index dip at the core center seems to cause deleterious effects on the splicing loss, provided that the fiber bending loss is kept constant. The effects of profile parameters on D(N)Phi(N) and D(N)/B(?) are investigated in detail. PMID- 20204048 TI - Mode mixing effects in optical fibers caused by sheathing and multistranding: measurements. AB - Mode coupling coefficients were measured in a multimode step-index fiber at different steps of the process of manufacturing a multistrand optical fiber cable. It was established that the mode coupling coefficients of the unsheathed fiber were relatively small and nearly the same for all the guided modes. By sheathing with nylon and by multistranding, the mode coupling coefficients between lower-order modes increased rapidly due to microbends, while in the vicinity of the highest-order mode, they remained unchanged. From impulse response waveforms and baseband frequency responses, it was observed that mode mixing effects became more noticeable as the mode coupling coefficients increased. Also, it was found that the excess loss caused by microbends was relatively small. PMID- 20204049 TI - Optical fiber phase discriminator. AB - Phase discriminators are devices widely used at rf and microwave frequencies to convert phase, or frequency, changes to amplitude changes. They find widespread use in generating audio feedback signals for frequency stabilization of oscillators and in angle demodulation applications. This paper demonstrates that similar devices, with similar functions, can be constructed in the visible region using optical fibers as delay-line elements. The operating principles of an optical-fiber delay-line phase discriminator are discussed. The sensitivity is shown to be proportional to the fiber propagation-delay time. A device working at 0.6328 microm is described and compared with predictions. PMID- 20204050 TI - Ray trajectories in optical fiber tapered sections. AB - Slab waveguide tapers with finite cladding thickness are analyzed using a geometrical optics approach, and the results are compared with an exact modal analysis. Iteration formulas are derived for the calculation of the propagation angles of the guided modes and the corresponding changes in the core and cladding thicknesses, assuming that the difference between the refractive indexes of the core and cladding is small. Numerical results are presented and compared with the values obtained by a successive step modal analysis, showing good agreement between the two approaches. This indicates that ray tracing techniques should be useful for the analysis and design of taper couplers. PMID- 20204051 TI - Moving optical-fiber switch experiment. AB - The switch uses a V-grooved connecting device. The mechanism is suitable for a large switch, which is desirable for an optical switching system. A moving fiber is inserted into one of the radially arranged V grooves using the elastic bending force as the drive current. The insertion condition, which realizes stable connection and high durability, is discussed. Switch structure and experimental results are described. Insertion loss was 0.33 dB, and the variation in transmissivity was 3%. PMID- 20204052 TI - Total internal reflection integrated-optics switch: a theoretical evaluation. AB - Previously demonstrated planar thin-film optical switch employing the total internal reflection phenomenon is given a full theoretical evaluation for its possible adaptability to an optical channel waveguide system and also to polarization insensitive immultiport fiber-channel switch. PMID- 20204053 TI - Electrooptic multiplexer system for multimode fiber communications. AB - The concept of internal reflectance at grazing incidence has been used to construct functional 4:1 electrooptic multiplexers for multimode single-fiber optical data communication. Individual multiplexer units having insertion losses as low as 10 dB and optical signal-to-crosstalk ratios as high as 15 dB have been fabricated. A complete time division multiplexed optical data link has been assembled using two 4:1 multiplexers. The operation of this link demonstrates the feasibility of optically multiplexing multimode signals and represents a benchmark in the progress to control and route multimode light energy. PMID- 20204054 TI - Molecular mechanisms underlying nutrient detection by incretin-secreting cells. AB - The hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted postprandially from intestinal K- and L-cells, respectively. As incretins, these hormones stimulate insulin secretion from the pancreatic beta-cell, and have independently been implicated in the control of food intake and lipid metabolism. Whilst the enteroendocrine cells producing GIP and GLP-1 are therefore attractive targets for the treatment of diabetes and obesity, our understanding of their physiology is fairly limited. The mechanisms employed to sense the arrival of carbohydrate, fat and protein in the gut lumen have been investigated using organ perfusion techniques, primary epithelial cultures and cell line models. The recent development of mice with fluorescently labeled GIP or GLP-1-expressing cells is now enabling the use of single cell techniques to investigate stimulus-secretion coupling mechanisms. This review will focus on the current knowledge of the molecular machinery underlying nutrient sensing within K- and L-cells. PMID- 20204055 TI - Surgical complications associated with fasciectomy for dupuytren's disease: a 20 year review of the English literature. AB - OBJECTIVE: Excisional surgery is the mainstay of treatment of Dupuytren's disease. Although outcomes are generally good, complications are common. The objective of this study was to evaluate intraoperative and postoperative complications associated with fasciectomy for Dupuytren's disease. METHODS: A literature search was conducted to identify published, original research that reported surgical complications associated with fasciectomy from 1988 to 2008. Search results were manually evaluated for relevance. Complication rates according to types of disease (primary or recurrent disease) and according to time (intraoperative vs postoperative) and type were collated. RESULTS: A total of 143 articles were identified; 41 met inclusion criteria, and of these, 28 reported overall surgical complication rates ranging from 3.6% to 39.1%. Major complications occurred in 15.7%, including digital nerve injury 3.4%, digital artery injury 2%, infection 2.4%, hematoma 2.1%, and complex regional pain syndrome 5.5%. Other common, more minor injuries included flare reaction in 9.9%, wound healing complications in 22.9%, and a range of other complications. In the few (n = 3) studies in which primary and recurrent diseases were directly compared, digital nerve injuries and digital artery injuries were approximately 10 times more common in patients with recurrent disease (20%) than those with primary disease (approximately 2%), though the numbers are too small for statistical significance. CONCLUSIONS: A review of published reports by surgeons shows that surgical fasciectomy for Dupuytren's disease has a high number of complications. Surgeons should be mindful of the potential for intraoperative and postoperative complications and counsel their patients accordingly. PMID- 20204056 TI - Two-dimensional liquid chromatography technique coupled with mass spectrometry analysis to compare the proteomic response to cadmium stress in plants. AB - Plants are useful in studies of metal toxicity, because their physiological responses to different metals are correlated with the metal exposure dose and chemical state. Moreover a network of proteins and biochemical cascades that may lead to a controlled homeostasis of metals has been identified in many plant species. This paper focuses on the global protein variations that occur in a Populus nigra spp. clone (Poli) that has an exceptional tolerance to the presence of cadmium. Protein separation was based on a two-dimensional liquid chromatography technique. A subset of 20 out of 126 peaks were identified as being regulated differently under cadmium stress and were fingerprinted by MALDI TOF. Proteins that were more abundant in the treated samples were located in the chloroplast and in the mitochondrion, suggesting the importance of these organelles in the response and adaptation to metal stress. PMID- 20204058 TI - Facilitating harvest of the serratus fascial flap with ultrasonic dissection. AB - OBJECTIVES: Upper extremity reconstruction presents a functional and aesthetic challenge in plastic surgery. Exposure of vital structures often requires vascularized soft tissue coverage to achieve primary wound healing and optimize functional results. Specifically, the serratus fascial flap may satisfy the functional and cosmetic requirements for small- to medium-sized soft tissue defects of the upper extremity with limited donor site morbidity. We describe our technique of serratus fascial flap harvest, using the Harmonic SYNERGY curved blade (Ethicon Endo-Surgery, Cincinnati, Ohio). MATERIAL AND METHODS: A 21-year old, right-hand-dominant, male carpenter and martial arts expert was involved in a motorcycle collision and sustained a left-hand dorsal degloving injury and extensor tendon rupture. Soft tissue reconstruction was performed with a serratus fascial free flap, immediate split-thickness skin graft, and palmaris longus tendon grafts. The flap was harvested with the Harmonic blade, which utilizes ultrasonic energy translated into mechanical energy, thereby allowing dissection and hemostasis simultaneously. RESULTS: Flap elevation proceeded facilely using the Harmonic curved blade. The patient had no postoperative complications involving his flap or donor site. The closed suction drain in the donor site was removed on postoperative day 3, and the patient was discharged on postoperative day 10. The patient is doing well at 4 months follow-up. CONCLUSION: The Harmonic blade may assist in the dissection of the serratus fascial flap by aiding with hemostasis and minimizing surrounding tissue damage. This may reduce flap damage associated with harvesting techniques as well as decrease donor site seroma formation. PMID- 20204057 TI - Upregulation of Salmonella-induced IL-6 production in Caco-2 cells by PJ-34, PARP 1 inhibitor: involvement of PI3K, p38 MAPK, ERK, JNK, and NF-kappaB. AB - Following Salmonella invasion, intestinal epithelial cells release a distinct array of proinflammatory cytokines. Interleukin (IL)-6 produced by enterocytes may have anti-inflammatory and cell-protective effects, and may counteract some of the injurious effects of sepsis and endotoxemia. Recent studies in a variety of rodent models of experimental colitis by using PJ-34, a potent poly (ADP ribose) polymerase-1 (PARP-1) inhibitor, support the concept that the marked beneficial effect of PJ-34 can be exploited to treat human inflammatory diseases. The present study was to investigate the effect of PJ-34 on Salmonella-induced enterocyte IL-6 production and its mechanisms. We found that PJ-34 enhanced Salmonella-induced IL-6 production in Caco-2 cells, either secreted protein or mRNA expression. PJ-34 treatment enhanced the activity of NF-kappaB in Salmonella infected Caco-2 cells. Besides, the involvement of PJ-34 in up-regulating IL-6 production in S. typhimurium-infected Caco-2 cells might be also through the ERK but not p38 MAPK, JNK or PI3K/Akt pathways, as demonstrated by Western blot of phosphorylated ERK, p38, JNK and Akt proteins. It suggests that PJ-34 may exert its protective effect on intestinal epithelial cells against invasive Salmonella infection by up-regulating IL-6 production through ERK and NF-kappaB but not P38 MAPK, JNK or PI3K/Akt signal pathways. PMID- 20204059 TI - A model of pressure distribution under peripherally secured foam dressings on a convex surface: does this contribute to skin graft loss? AB - BACKGROUND: Successful skin grafting requires multiple factors for success. An even distribution of constant pressure exerted upon the graft is necessary for successful graft take. It is well known that excessive pressure on a graft causes ischemia and may result in the failure of graft take. The aim of this study was to demonstrate the variation in skin pressure (tension) on curved surfaces, particularly relating to apical pressure on such surfaces at standard atmospheric pressure. METHODS: A synthetic Sawbone skull model was used to determine skin tension over a curved surface. A 10-cm diameter circle was centered on the parietal eminence, the area of maximum curvature. Peripheral screws gave fixed reproducible points to secure the foam dressing. Open-cell VAC dressing foam was used and calibrated Tekscan sensors were used to determine pressure variation under the foam dressing. RESULTS: Five hundred pressure readings were obtained for the unscored foam, and an additional 500 for the cross-scored foam. In the unscored foam, the pressure under the dressing was significantly higher at the apex. Cross-scoring the foam reduced the pressure, with the greatest reduction being at the apex. The pressure under the foam dressing was maximal at the apical point (95% confidence interval). CONCLUSION: Higher contact force at the apex of a curved graft bed may explain skin graft loss. Unequal pressure distribution can be reduced and equalized by scoring the foam. PMID- 20204060 TI - Changes in the gonial angle following bilateral sagittal split osteotomy and vertical ramus osteotomy for mandibular excess. AB - AIM: The gonial angle plays an important role in ensuring a harmonious facial profile. Changes in this angle after surgery may be an esthetic concern for both the patient and the surgeon. The aim of the present study was to evaluate gonial angle changes after mandibular setback by the bilateral sagittal split osteotomy (BSSO) and vertical ramus osteotomy (VRO) techniques. METHODS: Fifty-eight male patients with mandibular prognathism only were treated from 2004 to 2006 (deformities such as discrepancy of jaws, mandibular setback of more than 10 mm, asymmetry, and vertical discrepancy were excluded). Patients were randomly divided into 2 groups. In the first group, mandibular setback was performed using the Obwegeser technique and wire osteosynthesis with 4 weeks' fixation (IMF), and in the second group, mandibular setback via VRO without wire osteosynthesis and 4 weeks' IMF was carried out. Lateral cephalograms were obtained for all the patients before surgery (T(0)) and 1 year after surgery (T(1)). Gonial angle and occlusal plane-SN in T(0) and T(1) were evaluated. RESULTS: After surgery, the gonial angle had decreased in all patients. Decrease in the gonial angle in the VRO group was greater than the BSSO group. The average decrease in the gonial angle was significantly more (P < 0.05) in the VRO group (7 degrees) than in the BSSO group (2 degrees). CONCLUSION: Gonial angle decrease was observed in the present study following mandibular setback by the VRO and BSSO techniques. This decrease in the VRO group was significantly greater. PMID- 20204061 TI - IL-1beta suppresses the formation of osteoclasts by increasing OPG production via an autocrine mechanism involving celecoxib-related prostaglandins in chondrocytes. AB - Elevated interleukin (IL)-1 concentrations in synovial fluid have been implicated in joint bone and cartilage destruction. Previously, we showed that IL-1beta stimulated the expression of prostaglandin (PG) receptor EP4 via increased PGE(2) production. However, the effect of IL-1beta on osteoclast formation via chondrocytes is unclear. Therefore, we examined the effect of IL-1beta and/or celecoxib on the expression of macrophage colony-stimulating factor (M-CSF), receptor activator of NF-kappaB ligand (RANKL), and osteoprotegerin (OPG) in human chondrocytes, and the indirect effect of IL-1beta on osteoclast-like cell formation using RAW264.7 cells. OPG and RANKL expression increased with IL-1beta; whereas M-CSF expression decreased. Celecoxib blocked the stimulatory effect of IL-1beta. Conditioned medium from IL-1beta-treated chondrocytes decreased TRAP staining in RAW264.7 cells. These results suggest that IL-1beta suppresses the formation of osteoclast-like cells via increased OPG production and decreased M CSF production in chondrocytes, and OPG production may increase through an autocrine mechanism involving celecoxib-related PGs. PMID- 20204063 TI - Aminoterminal Pro B-Type Natriuretic Peptide (NT-proBNP) Levels for Monitoring Interventions in Paediatric Cardiac Patients with Stenotic Lesions. AB - Background. Serum concentration of NT-proBNP correlates well with the severity of cardiac disease in adults. Few studies have been performed on the applicability of NT-proBNP for monitoring children with congenital heart disease. Objective. To assess the potential of NT-proBNP for monitoring the success of interventions in children with stenotic cardiac lesions. Methods. NT-proBNP was measured in 42 children aged 1 day to 17 years (y) before and 6 to 12 weeks after surgical or interventional correction of obstructive lesions of the heart. Comparison is made with the clinical status and echocardiographic data of the child. Results. NT proBNP levels (median 280, range 10-263,000 pg/mL) were above the reference value in all but 6 patients (pts) prior to the intervention. Higher levels were found in more compromised patients. The 35 children with clinical improvement after the procedure showed a decline of their NT-proBNP level in all but 4 patients, whose levels remained unchanged. Five patients with unchanged gradients despite a therapeutic intervention also demonstrated unchanged NT-proBNP levels after the intervention. Thus, the success rate of the procedure correlated well to clinical and echocardiographic findings. Conclusion. NT-proBNP can be used to assess the efficiency of an intervention. PMID- 20204062 TI - A human recombinant autoantibody-based immunotoxin specific for the fetal acetylcholine receptor inhibits rhabdomyosarcoma growth in vitro and in a murine transplantation model. AB - Rhabdomyosarcoma (RMS) is the most common malignant soft tissue tumor in children and is highly resistant to all forms of treatment currently available once metastasis or relapse has commenced. As it has recently been determined that the acetylcholine receptor (AChR) gamma-subunit, which defines the fetal AChR (fAChR) isoform, is almost exclusively expressed in RMS post partum, we recombinantly fused a single chain variable fragment (scFv) derived from a fully human anti fAChR Fab-fragment to Pseudomonas exotoxin A to generate an anti-fAChR immunotoxin (scFv35-ETA). While scFv35-ETA had no damaging effect on fAChR negative control cell lines, it killed human embryonic and alveolar RMS cell lines in vitro and delayed RMS development in a murine transplantation model. These results indicate that scFv35-ETA may be a valuable new therapeutic tool as well as a relevant step towards the development of a fully human immunotoxin directed against RMS. Moreover, as approximately 20% of metastatic malignant melanomas (MMs) display rhabdoid features including the expression of fAChR, the immunotoxin we developed may also prove to be of significant use in the treatment of these more common and most often fatal neoplasms. PMID- 20204064 TI - Systemic embolism and septic shock complicated left atrial myxoma: case report. AB - Myxoma is the most common primary tumor of the heart. The rarity of infected cardiac myxomas leads to numerous diagnostic and therapeutic difficulties. We present a case of infected left atrial myxoma caused by methicillin-sensible Staphylococcus aureus in a 48-year-old woman complicated by systemic embolism and septic shock. PMID- 20204065 TI - Hypersensitivity vasculitis with leukocytoclastic vasculitis associated with alpha-1-proteinase inhibitor. AB - Prolastin is a commercially available form of alpha-1-antitrypsin (AAT) that is derived from pooled human plasma and used for treatment of severe alpha-1 antitrypsin deficiency (AATD). We describe a patient with AATD who developed presumed hypersensitivity vasculitis (HV) following a Prolastin infusion. Hypersensitivity vasculitis (HV), or cutaneous vasculitis, is characterized by inflammation of the small vessels of the skin with resultant ischemia to the distally supplied areas. To our knowledge, this is the first reported case of presumed hypersensitivity vasculitis following Prolastin infusion. PMID- 20204068 TI - Hunting for serine 276-phosphorylated p65. AB - The transcription factor nuclear factor kappaB (NF-kappaB) is one of the central mediators of inflammatory gene expression. Several posttranslational modifications of NF-kappaB, regulating its transactivation ability, have been described. Especially phosphorylation of the NF-kappaB subunit p65 has been investigated in depth and several commercial phosphospecific antibodies, targeting selected p65 residues, are available. One of the p65 residues, that is subject to phosphorylation by protein kinase A (PKA) as well as by mitogen stimulated kinase-1 (MSK-1), is the serine at position 276. Here, we have performed a detailed analysis of the performance of the most commonly used commercial anti-P-p65 Ser276 antibodies. Our findings indicate that at least three widely used anti-P-p65 Ser276 antibodies do not detect p65 in vivo via Western Blot, but instead crossreact with PKA-regulated proteins. As PKA is one of the main kinases responsible for phosphorylation of p65 at Ser276, this observation warrants cautious interpretation of data generated using the tested antibodies. PMID- 20204069 TI - Animal models of CNS viral disease: examples from borna disease virus models. AB - Borna disease (BD), caused by the neurotropic RNA virus, Borna Disease virus, is an affliction ranging from asymptomatic to fatal meningoencephalitis across naturally and experimentally infected warmblooded (mammalian and bird) species. More than 100 years after the first clinical descriptions of Borna disease in horses and studies beginning in the 1980's linking Borna disease virus to human neuropsychiatric diseases, experimentally infected rodents have been used as models for examining behavioral, neuropharmacological, and neurochemical responses to viral challenge at different stages of life. These studies have contributed to understanding the role of CNS viral injury in vulnerability to behavioral, developmental, epileptic, and neurodegenerative diseases and aided evaluation of the proposed and still controversial links to human disease. PMID- 20204066 TI - Rhombencephalitis Caused by Listeria monocytogenes in Humans and Ruminants: A Zoonosis on the Rise? AB - Listeriosis is an emerging zoonotic infection of humans and ruminants worldwide caused by Listeria monocytogenes (LM). In both host species, CNS disease accounts for the high mortality associated with listeriosis and includes rhombencephalitis, whose neuropathology is strikingly similar in humans and ruminants. This review discusses the current knowledge about listeric encephalitis, and involved host and bacterial factors. There is an urgent need to study the molecular mechanisms of neuropathogenesis, which are poorly understood. Such studies will provide a basis for the development of new therapeutic strategies that aim to prevent LM from invading the brain and spread within the CNS. PMID- 20204071 TI - Pericardial tamponade in a patient with inactive ulcerative colitis. AB - Cardiac tamponade is a rare extraintestinal manifestation of ulcerative colitis. We present a case report of tamponade occurring four years after curative proctocolectomy and in the absence of any medical therapy for ulcerative colitis. Options for medical management of this condition are also discussed. PMID- 20204067 TI - Anticancer Role of PPARgamma Agonists in Hematological Malignancies Found in the Vasculature, Marrow, and Eyes. AB - The use of targeted cancer therapies in combination with conventional chemotherapeutic agents and/or radiation treatment has increased overall survival of cancer patients. However, longer survival is accompanied by increased incidence of comorbidities due, in part, to drug side effects and toxicities. It is well accepted that inflammation and tumorigenesis are linked. Because peroxisome proliferator-activated receptor (PPAR)-gamma agonists are potent mediators of anti-inflammatory responses, it was a logical extension to examine the role of PPARgamma agonists in the treatment and prevention of cancer. This paper has two objectives: first to highlight the potential uses for PPARgamma agonists in anticancer therapy with special emphasis on their role when used as adjuvant or combined therapy in the treatment of hematological malignancies found in the vasculature, marrow, and eyes, and second, to review the potential role PPARgamma and/or its ligands may have in modulating cancer-associated angiogenesis and tumor-stromal microenvironment crosstalk in bone marrow. PMID- 20204072 TI - The lipid moiety of haemozoin (Malaria Pigment) and P. falciparum parasitised red blood cells bind synthetic and native endothelin-1. AB - Endothelin1 (ET-1) is a 21-amino acid peptide produced by the vascular endothelium under hypoxia, that acts locally as regulator of vascular tone and inflammation. The role of ET-1 in Plasmodium falciparum malaria is unknown, although tissue hypoxia is frequent as a result of the cytoadherence of parasitized red blood cell (pRBC) to the microvasculature. Here, we show that both synthetic and endothelial-derived ET-1 are removed by parasitized RBC (D10 and W2 strains, chloroquine sensitive, and resistant, resp.) and native haemozoin (HZ, malaria pigment), but not by normal RBC, delipidized HZ, or synthetic beta haematin (BH). The effect is dose dependent, selective for ET-1, but not for its precursor, big ET-1, and not due to the proteolysis of ET-1. The results indicate that ET-1 binds to the lipids moiety of HZ and membranes of infected RBCs. These findings may help understanding the consequences of parasite sequestration in severe malaria. PMID- 20204070 TI - Modulation of dendritic cell responses by parasites: a common strategy to survive. AB - Parasitic infections are one of the most important causes of morbidity and mortality in our planet and the immune responses triggered by these organisms are critical to determine their outcome. Dendritic cells are key elements for the development of immunity against parasites; they control the responses required to eliminate these pathogens while maintaining host homeostasis. However, there is evidence showing that parasites can influence and regulate dendritic cell function in order to promote a more permissive environment for their survival. In this review we will focus on the strategies protozoan and helminth parasites have developed to interfere with dendritic cell activities as well as in the possible mechanisms involved. PMID- 20204073 TI - Evolution and diversity of the human hepatitis d virus genome. AB - Human hepatitis delta virus (HDV) is the smallest RNA virus in genome. HDV genome is divided into a viroid-like sequence and a protein-coding sequence which could have originated from different resources and the HDV genome was eventually constituted through RNA recombination. The genome subsequently diversified through accumulation of mutations selected by interactions between the mutated RNA and proteins with host factors to successfully form the infectious virions. Therefore, we propose that the conservation of HDV nucleotide sequence is highly related with its functionality. Genome analysis of known HDV isolates shows that the C-terminal coding sequences of large delta antigen (LDAg) are the highest diversity than other regions of protein-coding sequences but they still retain biological functionality to interact with the heavy chain of clathrin can be selected and maintained. Since viruses interact with many host factors, including escaping the host immune response, how to design a program to predict RNA genome evolution is a great challenging work. PMID- 20204074 TI - "It's Not What You Say, But How You Say it": A Reciprocal Temporo-frontal Network for Affective Prosody. AB - Humans communicate emotion vocally by modulating acoustic cues such as pitch, intensity and voice quality. Research has documented how the relative presence or absence of such cues alters the likelihood of perceiving an emotion, but the neural underpinnings of acoustic cue-dependent emotion perception remain obscure. Using functional magnetic resonance imaging in 20 subjects we examined a reciprocal circuit consisting of superior temporal cortex, amygdala and inferior frontal gyrus that may underlie affective prosodic comprehension. Results showed that increased saliency of emotion-specific acoustic cues was associated with increased activation in superior temporal cortex [planum temporale (PT), posterior superior temporal gyrus (pSTG), and posterior superior middle gyrus (pMTG)] and amygdala, whereas decreased saliency of acoustic cues was associated with increased inferior frontal activity and temporo-frontal connectivity. These results suggest that sensory-integrative processing is facilitated when the acoustic signal is rich in affective information, yielding increased activation in temporal cortex and amygdala. Conversely, when the acoustic signal is ambiguous, greater evaluative processes are recruited, increasing activation in inferior frontal gyrus (IFG) and IFG STG connectivity. Auditory regions may thus integrate acoustic information with amygdala input to form emotion-specific representations, which are evaluated within inferior frontal regions. PMID- 20204076 TI - Mortality among HIV-Infected Patients in Resource Limited Settings: A Case Controlled Analysis of Inpatients at a Community Care Center. AB - PROBLEM STATEMENT: Despite massive national efforts to scale up Antiretroviral Therapy (ART) access in India since 2004, the AIDS death rate was 17.2 per 100,000 persons during 2003-2005. In the era of HAART in resource poor settings, it is imperative to understand and address the causes of AIDS related mortality. This collaborative study aimed at defining the predictors of mortality among people living with HIV/AIDS (PLHA) admitted during 2003-2005 to the Freedom Foundation (FF) Care and Support facility, Bangalore, India. APPROACH: Fifty consecutively selected HIV-infected patients who died during the study period and 50 HIV-infected patients matched by age, gender, route of transmission, nutrition status and stage of disease who survived at least 12 months post-ART were included in this study. The impact on mortality by factors such as: Hemoglobin, CD4+T lymphocyte counts, weight loss and Opportunistic Infections (OIs) were studied. Statistical analyses were done by Chi-square, Fisher's Exact Test, Kaplan-Meier and multivariate logistic regression. RESULTS: Recurrent diarrhea was a significant risk factor for mortality (OR = 12.25, p = 0.004), followed by a diagnosis of pulmonary tuberculosis (TB) at first admission (OR = 4.86) while TB in general also negatively impacted survival (p = 0.002). Though not statistically significant, Pneumocystis carinii pneumonia, Cryptococcal meningitis and Toxoplasmosis also negatively affected survival. Mortality was high among those not on HAART (81%) while it was significantly reduced (28%) among those on HAART (p<0.001). Patients who died had elevated liver enzymes (p = 0.027) and significant weight loss (p = 0.012). Mortality was high among patients irregular with their medical follow-up (p<0.001). CONCLUSION: Interventions that facilitate early OI diagnosis and treatment especially diarrhea and TB may reduce mortality in HIV. HAART alone without proper OI management and nutrition did not prevent mortality among PLHA. In resource poor settings, it becomes imperative to focus on low cost tools and increased capacity building along with regular clinical follow-up for diagnosis and early treatment of OIs. Further studies are warranted to explore benefits of initiating HAART earlier than currently recommended. PMID- 20204077 TI - Analysis of Mand Selection across Different Stimulus Conditions. AB - We conducted a three-phase study to evaluate the use of mands and the occurrence of problem behavior for 2 children with developmental disabilities. During Phase 1, a functional analysis identified the variables maintaining problem behavior. During Phase 2, functional communication training was implemented within a concurrent schedules design. The children were reinforced for using either a novel mand (communication card) or other existing mands (vocal speech, manual signs) that were not specifically trained but were observed to be part of the children's existing repertoire. We then conducted an assessment of mands and problem behavior across different stimulus conditions (card absent, card present) within an ABAB design (Phase 3). Results showed that during Phase 2, problem behavior decreased and participants used the card more frequently than they used other existing mands. Phase 3 showed that problem behavior remained low across both stimulus conditions. When the card was absent, the children used other existing mands; when the card was present, they primarily used the card. These results suggested that the presence of a communication card may function as a discriminative stimulus for a specific topography of manding, but that training with the card did not inhibit the use of other mands when the card was absent. PMID- 20204078 TI - Fragile Families and the Reproduction of Poverty. AB - In 1965, Daniel Patrick Moynihan warned that non-marital childbearing and marital dissolution were undermining the progress of African Americans. I argue that what Moynihan identified as a race-specific problem in the 1960s has now become a class-based phenomena as well. Using data from a new birth cohort study, I show that unmarried parents come from much more disadvantaged populations than married parents. I further argue that non-marital childbearing reproduces class and racial disparities through its association with partnership instability and multi partnered fertility. These processes increase in maternal stress and mental health problems, reduce the quality of mothers' parenting, reduce paternal investments, and ultimately lead to poor outcomes in children. Finally, by spreading fathers' contributions across multiple households, partnership instability and multi-partnered fertility undermine the importance of individual fathers' contributions of time and money which is likely to affect the future marriage expectations of both sons and daughters. PMID- 20204079 TI - The GRK2 Overexpression Is a Primary Hallmark of Mitochondrial Lesions during Early Alzheimer Disease. AB - Increasing evidence points to vascular damage as an early contributor to the development of two leading causes of age-associated dementia, namely Alzheimer disease (AD) and AD-like pathology such as stroke. This review focuses on the role of G protein-coupled receptor kinases (GRKs) as they relate to dementia and how the cardio and cerebrovasculature is involved in AD pathogenesis. The exploration of GRKs in AD pathogenesis may help bridge gaps in our understanding of the heart-brain connection in relation to neurovisceral damage and vascular complications of AD. The a priori basis for this inquiry stems from the fact that kinases of this family regulate numerous receptor functions in the brain, myocardium and elsewhere. The aim of this review is to discuss the finding of GRK2 overexpression in the context of early AD pathogenesis. Also, we consider the consequences for this overexpression as a loss of G-protein coupled receptor (GPCR) regulation, as well as suggest a potential role for GPCRs and GRKs in a unifying theory of AD pathogenesis through the cerebrovasculature. Finally, we synthesize this newer information in an attempt to put it into context with GRKs as regulators of cellular function, which makes these proteins potential diagnostic and therapeutic targets for future pharmacological intervention. PMID- 20204081 TI - Antibacterial honey (Medihoney) for wound care of immunocompromised pediatric oncology patients. AB - The physiologic process of wound healing is impaired and prolonged in paediatic patients receiving chemotherapy. Due to profound immunosuppression, wound infection can easily spread and act as the source of sepsis. Referring to in vitro studies, which confirmed the antibacterial potency of special honey preparations against typical isolates of nosocomially acquired wound infections (including MRSA and VRE) and considering the encouraging reports from other groups, Medihoney has now been used in wound care at the Department of Pediatric Oncology, Children's Hospital, University of Bonn for three years. Supplemented with exemplary clinical data from pediatric oncology patients, this presentation reviews the scientific background and our promising experience with Medihoney in wound care issues at our institution. PMID- 20204080 TI - Plasticity of horizontal connections at a functional border in adult rat somatosensory cortex. AB - Horizontal connections in superficial cortical layers integrate information across sensory maps by connecting related functional columns. It has been hypothesized that these connections mediate cortical reorganization via synaptic plasticity. However, it is not known if the horizontal connections from discontinuous cortical regions can undergo plasticity in the adult. Here we located the border between two discontinuous cortical representations in vivo and used either pairing or low-frequency stimulation to induce synaptic plasticity in the horizontal connections surrounding this border in vitro. Individual neurons revealed significant and diverse forms of synaptic plasticity for horizontal connections within a continuous representation and discontinuous representations. Interestingly, both enhancement and depression were observed following both plasticity paradigms. Furthermore, plasticity was not restricted by the border's presence. Depolarization in the absence of synaptic stimulation also produced synaptic plasticity, but with different characteristics. These experiments suggest that plasticity of horizontal connections may mediate functional reorganization. PMID- 20204082 TI - A review of current strategies to reduce intraoperative bacterial contamination of surgical wounds. AB - Surgical site infections are a mean topic in cardiac surgery, leading to a prolonged hospitalization, and substantially increased morbidity and mortality. One source of pathogens is the endogenous flora of the patient's skin, which can contaminate the surgical site. A number of preoperative skin care strategies are performed to reduce bacterial contamination like preoperative antiseptic showering, hair removal, antisepsis of the skin, adhesive barrier drapes, and antimicrobial prophylaxis. Furthermore we can also support the natural host defense by optimal intra-operative management of oxygen supply, normoglycemia, and temperature. Nevertheless we still have a number of patients, who develop a surgical site infection. Therefore new skin care strategies are introduced to reduce the contamination by the endogenous skin flora. We present the use of a new microbial sealant, InteguSeal((R)), which was evaluated in patients undergoing cardiac surgery. The preliminary results of this investigation showed a trend in surgical site infection reduction by the use of this new microbial sealant. PMID- 20204083 TI - Honey in wound care: antibacterial properties. AB - Honey is an ancient wound treatment that was re-introduced into modern medical practice in Australasia and Europe following the development of regulated wound care products. Its therapeutic properties are attributed to its antimicrobial activity and its ability to stimulate rapid wound healing. This review will briefly describe the evidence that demonstrates its antimicrobial activity in vitro and in vivo. PMID- 20204084 TI - Therapy of acute wounds with water-filtered infrared-A (wIRA). AB - Water-filtered infrared-A (wIRA) as a special form of heat radiation with a high tissue penetration and with a low thermal load to the skin surface acts both by thermal and thermic as well as by non-thermal and non-thermic effects. wIRA produces a therapeutically usable field of heat in the tissue and increases tissue temperature, tissue oxygen partial pressure, and tissue perfusion. These three factors are decisive for a sufficient tissue supply with energy and oxygen and consequently as well for wound healing and infection defense. wIRA can considerably alleviate the pain (with remarkably less need for analgesics) and diminish an elevated wound exudation and inflammation and can show positive immunomodulatory effects. wIRA can advance wound healing or improve an impaired wound healing both in acute and in chronic wounds including infected wounds. Even the normal wound healing process can be improved.A prospective, randomized, controlled, double-blind study with 111 patients after major abdominal surgery at the University Hospital Heidelberg, Germany, showed with 20 minutes irradiation twice a day (starting on the second postoperative day) in the group with wIRA and visible light VIS (wIRA(+VIS), approximately 75% wIRA, 25% VIS) compared to a control group with only VIS a significant and relevant pain reduction combined with a markedly decreased required dose of analgesics: during 230 single irradiations with wIRA(+VIS) the pain decreased without any exception (median of decrease of pain on postoperative days 2-6 was 13.4 on a 100 mm visual analog scale VAS 0-100), while pain remained unchanged in the control group (p<0.001). The required dose of analgesics was 57-70% lower in the subgroups with wIRA(+VIS) compared to the control subgroups with only VIS (median 598 versus 1398 ml ropivacaine, p<0.001, for peridural catheter analgesia; 31 versus 102 mg piritramide, p=0.001, for patient-controlled analgesia; 3.4 versus 10.2 g metamizole, p=0.005, for intravenous and oral analgesia). During irradiation with wIRA(+VIS) the subcutaneous oxygen partial pressure rose markedly by approximately 30% and the subcutaneous temperature by approximately 2.7 degrees C (both in a tissue depth of 2 cm), whereas both remained unchanged in the control group: after irradiation the median of the subcutaneous oxygen partial pressure was 41.6 (with wIRA) versus 30.2 mm Hg in the control group (p<0.001), the median of the subcutaneous temperature was 38.9 versus 36.4 degrees C (p<0.001). The overall evaluation of the effect of irradiation, including wound healing, pain and cosmesis, assessed on a VAS (0-100 with 50 as indifferent point of no effect) by the surgeon (median 79.0 versus 46.8, p<0.001) or the patient (79.0 versus 50.2, p<0.001) was markedly better in the group with wIRA compared to the control group. This was also true for single aspects: Wound healing assessed on a VAS by the surgeon (median 88.6 versus 78.5, p<0.001) or the patient (median 85.8 versus 81.0, p=0.040, trend) and cosmetic result assessed on a VAS by the surgeon (median 84.5 versus 76.5, p<0.001) or the patient (median 86.7 versus 73.6, p=0.001). In addition there was a trend in favor of the wIRA group to a lower rate of total wound infections (3 of 46, approximately 7%, versus 7 of 48, approximately 15%, p=0.208) including late infections after discharge, caused by the different rate of late infections after discharge: 0 of 46 in the wIRA group and 4 of 48 in the control group. And there was a trend towards a shorter postoperative hospital stay: 9 days in the wIRA group versus 11 days in the control group (p=0.037). The principal finding of this study was that postoperative irradiation with wIRA can improve even a normal wound healing process.A prospective, randomized, controlled, double-blind study with 45 severely burned children at the Children's Hospital Park Schonfeld, Kassel, Germany, showed with 30 minutes irradiation once a day (starting on the first day, day of burn as day 1) in the group with wIRA and visible light VIS (wIRA(+VIS), approximately 75% wIRA, 25% VIS) compared to a control group with only VIS a markedly faster reduction of wound size. On the fifth day (after 4 days with irradiation) decision was taken, whether surgical debridement of necrotic tissue was necessary because of deeper (second degree, type b) burns (11 of 21 in the group with wIRA, 14 of 24 in the control group) or non-surgical treatment was possible (second degree, type a, burns). The patients treated conservatively were kept within the study and irradiated till complete reepithelialization. The patients in the group with wIRA showed a markedly faster reduction of wound area: a median reduction of wound size of 50% was reached already after 7 days compared to 9 days in the control group, a median reduction of wound size of 90% was already achieved after 9 days compared to 13 days in the control group. In addition the group with wIRA showed superior results till 3 months after the burn in terms of the overall surgical assessment of the wound, cosmesis, and assessment of effects of irradiation compared to the control group. In a prospective, randomized, controlled study with 12 volunteers at the University Medical Center Charite, Berlin, Germany, within each volunteer 4 experimental superficial wounds (5 mm diameter) as an acute wound model were generated by suction cup technique, removing the roof of the blister with a scalpel and a sterile forceps (day 1). 4 different treatments were used and investigated during 10 days: no therapy, only wIRA(+VIS) (approximately 75% wIRA, 25% VIS; 30 minutes irradiation once a day), only dexpanthenol (= D-panthenol) cream once a day, wIRA(+VIS) and dexpanthenol cream once a day. Healing of the small experimental wounds was from a clinical point of view excellent with all 4 treatments. Therefore there were only small differences between the treatments with slight advantages of the combination wIRA(+VIS) and dexpanthenol cream and of dexpanthenol cream alone concerning relative change of wound size and assessment of feeling of the wound area. However laser scanning microscopy with a scoring system revealed differences between the 4 treatments concerning the formation of the stratum corneum (from first layer of corneocytes to full formation) especially on the days 5-7: fastest formation of the stratum corneum was seen in wounds treated with wIRA(+VIS) and dexpanthenol cream, second was wIRA(+VIS) alone, third dexpanthenol cream alone and last were untreated wounds. Bacterial counts of the wounds (taken every 2 days) showed, that wIRA(+VIS) and the combination of wIRA(+VIS) with dexpanthenol cream were able to inhibit the colonisation with physiological skin flora up to day 5 when compared with the two other groups (untreated group and group with dexpanthenol cream alone). At any investigated time, the amount of colonisation under therapy with wIRA(+VIS) alone was lower (interpreted as more suppressed) compared with the group with wIRA(+VIS) and dexpanthenol cream. During rehabilitation after hip and knee endoprosthetic operations the resorption of wound seromas and wound hematomas was both clinically and sonographically faster and pain was reduced by irradiation with wIRA(+VIS). wIRA can be used successfully for persistent postoperative pain e.g. after thoracotomy.As perspectives for wIRA it seems clinically prudent to use wIRA both pre- and postoperatively, e.g. in abdominal and thoracic operations. wIRA can be used preoperatively (e.g. during 1-2 weeks) to precondition donor and recipient sites of skin flaps, transplants or partial thickness skin grafts, and postoperatively to improve wound healing and to decrease pain, inflammation and infections at all mentioned sites. wIRA can be used to support routine pre- or intraoperative antibiotic administration or it might even be discussed to replace this under certain conditions by wIRA. PMID- 20204085 TI - Principles and working mechanisms of water-filtered infrared-A (wIRA) in relation to wound healing. AB - The experience of the pleasant heat of the sun in moderate climatic zones arises from the filtering of the heat radiation of the sun by water vapor in the atmosphere of the earth. The filter effect of water decreases those parts of infrared radiation (most parts of infrared-B and -C and the absorption bands of water within infrared-A), which would cause - by reacting with water molecules in the skin - only an undesired thermal load to the surface of the skin. Technically water-filtered infrared-A (wIRA) is produced in special radiators, whose full spectrum of radiation of a halogen bulb is passed through a cuvette, containing water, which absorbs or decreases the described undesired wavelengths of the infrared radiation. Within infrared the remaining wIRA (within 780-1400 nm) mainly consists of radiation with good penetration properties into tissue and therefore allows - compared to unfiltered heat radiation - a multiple energy transfer into tissue without irritating the skin, similar to the sun's heat radiation in moderate climatic zones. Typical wIRA radiators emit no ultraviolet (UV) radiation and nearly no infrared-B and -C radiation and the amount of infrared-A radiation in relation to the amount of visible light (380-780 nm) is emphasized. Water-filtered infrared-A as a special form of heat radiation with a high tissue penetration and with a low thermal load to the skin surface acts both by thermal (related to heat energy transfer) and thermic (temperature depending, with a relevant change of temperature) as well as by non-thermal (without a relevant transfer of heat energy) and non-thermic (not depending on temperature, without a relevant change of temperature) effects. wIRA produces a therapeutically usable field of heat in the tissue and increases tissue temperature, tissue oxygen partial pressure, and tissue perfusion. These three factors are vital for a sufficient tissue supply with energy and oxygen. As wound healing and infection defense (e.g. granulocyte function including their antibacterial oxygen radical formation) depend decisively on a sufficient supply with energy and oxygen, one explanation for the good clinical effect of wIRA on wounds and wound infections can be the improvement of both the energy supply per time (increase of metabolic rate) and the oxygen supply. In addition wIRA has non thermal and non-thermic effects, which are based on putting direct stimuli on cells and cellular structures.wIRA can considerably alleviate the pain (with remarkably less need for analgesics) and diminish an elevated wound exudation and inflammation and can show positive immunomodulatory effects. wIRA can advance wound healing or improve an impaired wound healing both in acute and in chronic wounds including infected wounds. Even the normal wound healing process can be improved.wIRA is contact-free, easily applied, without discomfort to the patient, with absent consumption of material and with a good effect in the depth. The irradiation of the typically uncovered wound is carried out with a wIRA radiator. PMID- 20204086 TI - Therapy of chronic wounds with water-filtered infrared-A (wIRA). AB - The central portion of chronic wounds is often hypoxic and relatively hypothermic, representing a deficient energy supply of the tissue, which impedes wound healing or even makes it impossible. Water-filtered infrared-A (wIRA) is a special form of heat radiation with a high tissue penetration and a low thermal load to the skin surface. wIRA produces a therapeutically usable field of heat and increases temperature, oxygen partial pressure and perfusion of the tissue. These three factors are decisive for a sufficient tissue supply with energy and oxygen and consequently as well for wound healing, especially in chronic wounds, and infection defense. wIRA acts both by thermal and thermic as well as by non thermal and non-thermic effects. wIRA can advance wound healing or improve an impaired wound healing process and can especially enable wound healing in non healing chronic wounds. wIRA can considerably alleviate the pain and diminish wound exudation and inflammation and can show positive immunomodulatory effects.In a prospective, randomized, controlled study of 40 patients with chronic venous stasis ulcers of the lower legs irradiation with wIRA and visible light (VIS) accelerated the wound healing process (on average 18 vs. 42 days until complete wound closure, residual ulcer area after 42 days 0.4 cm(2) vs. 2.8 cm(2)) and led to a reduction of the required dose of pain medication in comparison to the control group of patients treated with the same standard care (wound cleansing, wound dressing with antibacterial gauze, and compression garment therapy) without the concomitant irradiation. Another prospective study of 10 patients with non-healing chronic venous stasis ulcers of the lower legs included extensive thermographic investigation. Therapy with wIRA(+VIS) resulted in a complete or almost complete wound healing in 7 patients and a marked reduction of the ulcer size in another 2 of the 10 patients, a clear reduction of pain and required dose of pain medication, and a normalization of the thermographic image. In a current prospective, randomized, controlled, blinded study patients with non-healing chronic venous stasis ulcers of the lower legs are treated with compression garment therapy, wound cleansing, wound dressings and 30 minutes irradiation five times per week over 9 weeks. A preliminary analysis of the first 23 patients of this study has shown in the group with wIRA(+VIS) compared to a control group with VIS an advanced wound healing, an improved granulation and in the later phase of treatment a decrease of the bacterial burden. Some case reports have demonstrated that wIRA can also be used for mixed arterial-venous ulcers or arterial ulcers, if irradiation intensity is chosen appropriately low and if irradiation is monitored carefully. wIRA can be used concerning decubital ulcers both in a preventive and in a therapeutic indication. wIRA can improve the resorption of topically applied substances also on wounds. An irradiation with VIS and wIRA presumably acts with endogenous protoporphyrin IX (or protoporphyrin IX of bacteria) virtually similar as a mild photodynamic therapy (endogenous PDT-like effect). This could lead to improved cell regeneration and wound healing and to antibacterial effects. In conclusion, these results indicate that wIRA generally should be considered for the treatment of chronic wounds. PMID- 20204087 TI - Infection control consequences - early Staphylococcal Scalded Skin Syndrome or Kawasaki Syndrome? AB - Childhood exanthemata are caused by a broad spectrum of common pathogens. Many exanthemata initially present very similarly, even though caused by different organisms, ranging from virus to bacteria and their respective toxins. In the majority of cases the diagnosis is only of academic value, since therapy does hardly differ. However, in some cases accurate and prompt diagnosis is paramount, since therapy and appropriate hygiene measures prevent morbidity and mortality. We present a case with two differential diagnoses, Staphylococcal Scalded Skin Syndrome and Kawasaki Syndrome, which demonstrates the importance of considering relatively rare conditions as the cause of a childhood exanthema and discuss differences in therapeutic and infection control management. From an infection control point of view, Staphylococcal Scalded Skin Syndrome is, in contrast to Kawasaki Syndrome, highly transmittable to other paediatric patients via the hands of the staff. Therefore maintaining correct hand hygiene as well as other infection control measures are of importance until the final diagnosis is established. PMID- 20204088 TI - Influence of constant, alternating and cyclotron low-intensity electromagnetic fields on fibroblast proliferative activity in vitro. AB - Available data allow assuming the presence of stimulation of reparative processes under influence of low-intensity electromagnetic field, commensurable with a magnetic field of the Earth. Research of effects of low-intensity electromagnetic fields on fibroblast proliferative activity in human lungs in cell culture was performed.The influence of a constant electromagnetic field, an alternating electromagnetic field by frequency of 50 Hz and cyclotron electromagnetic field with identical intensity for all kinds of fields - 80 mcTl - on value of cellular mass and a correlation of live and dead cells in culture is investigated in three series of experiments. We used the universal electromagnetic radiator generating all three kinds of fields and supplied by a magnetometer which allows measuring the intensity of accurate within 0.1 mcTl including taking into account the Earth's magnetic field intensity.The peak value for stimulation cellular proliferation in the present experiences was two-hour influence by any of the specified kinds of electromagnetic fields. The irradiation by cyclotron electromagnetic field conducts positive dynamics in growth of live cells (up to 206+/-22%) and decreases the number of dead cells (down to 31+/-6%). Application of cyclotron magnetic fields promoted creation of optimum conditions for proliferation. As a result of researches we observed the reliable 30% increase of nitro-tetrazolium index (in nitro-tetrazolium blue test) after irradiation by cyclotron electromagnetic field in experience that testifies to strengthening of the cell breathing of living cells.In our opinion, it is necessary to pay attention not only to a pure gain of cells, but also to reduction of number dead cells that can be criterion of creation of optimum conditions for their specific development and valuable functioning. PMID- 20204089 TI - Wound dressings from a hygienic point of view using the example of sorbion sachet S. AB - Nosocomial infections present a growing challenge in wound care, especially in light of the rising distribution of multiresistant bacterial strains. Because wounds are an ideal breeding ground for pathogens, special care must be taken in choosing the right dressing. Following the traditional preventive approach, exposure of the nursing staff as well as the wounds to pathogens should be reduced. Dressings allowing a reduced frequency of dressing changes may help accomplish this. During dressing changes the dressing should allow for safe handling with a low risk of contamination. To protect the patient, the dressing should minimise exposure to pathogens during wear time as well as promote healing even if the dressing remains on the wound for a longer period of time. The dressing sorbion sachet S is used as an example to examine possible strategies. PMID- 20204090 TI - Water-filtered infrared-A (wIRA) in acute and chronic wounds. AB - Water-filtered infrared-A (wIRA), as a special form of heat radiation with a high tissue penetration and a low thermal load to the skin surface, can improve the healing of acute and chronic wounds both by thermal and thermic as well as by non thermal and non-thermic effects. wIRA increases tissue temperature (+2.7 degrees C at a tissue depth of 2 cm), tissue oxygen partial pressure (+32% at a tissue depth of 2 cm) and tissue perfusion. These three factors are decisive for a sufficient supply of tissue with energy and oxygen and consequently also for wound healing and infection defense. wIRA can considerably alleviate pain (without any exception during 230 irradiations) with substantially less need for analgesics (52-69% less in the groups with wIRA compared to the control groups). It also diminishes exudation and inflammation and can show positive immunomodulatory effects. The overall evaluation of the effect of irradiation as well as the wound healing and the cosmetic result (assessed on visual analogue scales) were markedly better in the group with wIRA compared to the control group. wIRA can advance wound healing (median reduction of wound size of 90% in severely burned children already after 9 days in the group with wIRA compared to 13 days in the control group; on average 18 versus 42 days until complete wound closure in chronic venous stasis ulcers) or improve an impaired wound healing (reaching wound closure and normalization of the thermographic image in otherwise recalcitrant chronic venous stasis ulcers) both in acute and in chronic wounds including infected wounds. After major abdominal surgery there was a trend in favor of the wIRA group to a lower rate of total wound infections (7% versus 15%) including late infections following discharge from hospital (0% versus 8%) and a trend towards a shorter postoperative hospital stay (9 versus 11 days). Even the normal wound healing process can be improved. The mentioned effects have been proven in six prospective studies, with most of the effects having an evidence level of Ia/Ib.wIRA represents a valuable therapy option and can generally be recommended for use in the treatment of acute as well as of chronic wounds. PMID- 20204091 TI - The limits of sterility assurance. AB - Sterility means the absence of all viable microorganisms including viruses. At present, a sterility assurance level (SAL) of 10(-6) is generally accepted for pharmacopoeial sterilization procedures, i.e., a probability of not more than one viable microorganism in an amount of one million sterilised items of the final product. By extrapolating the reduction rates following extreme artificial initial contamination, a theoretical overall performance of the procedure of at least 12 lg increments (overkill conditions) is demanded to verify an SAL of 10( 6). By comparison, other recommendations for thermal sterilization procedures demand only evidence that the difference between the initial contamination and the number of test organisms at the end of the process amount to more than six orders of magnitude. However, a practical proof of the required level of sterility assurance of 10(-6) is not possible. Moreover, the attainability of this condition is fundamentally dubious, at least in non-thermal procedures. Thus, the question is discussed whether the undifferentiated adherence to the concept of sterility assurance on the basis of a single SAL of 10(-6) corresponds with the safety requirements in terms of patient or user safety, costs and energy efficiency. Therefore, in terms of practical considerations, a concept of tiered SALs is recommended, analogous to the comparable and well-established categorization into "High-level disinfection", "Intermediate-level disinfection" and "Low-level disinfection". The determination of such tiered SALs is geared both to the intended application of the sterilized goods, as well as to the characteristics of the products and the corresponding treatment options.In the case of aseptic preparation, filling and production procedures, a mean contamination probability of 10(-3) is assumed. In automated processes, lower contamination rates can be realized. In the case of the production of re-usable medical devices, a reduction of at least 2 lg increments can be achieved through prior cleaning in validated cleaning and disinfecting devices. By chemical disinfection, a further reduction of >/=5 lg increments is achieved. In the case of sterilized surgical instruments, an additional concern is that they lay opened in contaminated air for the duration of the operation, at least in conventionally ventilated operating theaters. Finally, the amount of pathogens necessary to cause an infection must be considered. By logical consideration of all aspects, it seems possible to partially reduce sterility assurance levels without any loss of safety. Proceeding from this, we would like to make the following suggestions for tiered SAL values, adjusted according to the respective sterilization task:SAL 10(-6) for heat-resistant pharmaceutical preparations (parenterals), suggested term: "Pharmaceutical sterilization",SAL 10(-4) for heat-resistant medical devices, suggested term: "High-level sterilization",SAL 10(-3) for heat sensitive re-usable medical devices, under the precondition of a validated cleaning efficacy of >4 lg increments, suggested term: "Low-level sterilization". PMID- 20204092 TI - Ultrasound scissors: new single-use instruments vs. resterilised single-use instruments - a prospective randomised study. AB - BACKGROUND: The aim of this study was to compare reliability in handling and function of resterilised and single-use disposable ultrasonic scissors. METHODS: In a prospective randomized study, the surgeon blindly tested new and resterilised ultrasonic scissors. The parameters were force of activation, cutting effect, coagulation effect, error messages and disturbing generator noise. RESULTS: 51 new and 49 resterilised instruments in 94 operations were evaluated. The differences in force of activation, cutting effect and coagulation were not significant. Error messages and disturbing noises were rare in both groups. 6 new instruments and 2 resterilised instruments had to be exchanged because of problems during surgery. CONCLUSION: This study demonstrates comparable reliability in function and handling of resterilised and new ultrasonic scissors. The use of resterilised instruments leads to distinctly reduced costs and could contribute to efficiency in laparoscopic surgery. PMID- 20204093 TI - Processing single-use medical devices for use in surgery - importance, status quo and potential. AB - In summary, it is possible with the technology and scientific knowledge currently available to allow products intended for single use to be reprocessed using validated and certified processing procedures, while maintaining the full function and without any loss in quality. How many times a product can be re processed must be determined separately for each individual medical technology device; it is not possible to make any kind of blanket statement as to the permissible number of cycles. This is due to the differing construction, the various combinations of materials and the diverse demands made of each device during clinical use. The exigency of the reprocessing issue is evident both to the user and the primary manufacturer. For the user, where there is a correspondingly high-quality primary product with suitably costed, technically sound and certified reprocessing procedures, repeat usage can mean real savings while maintaining full functionality in each use. For the primary manufacturers of highly specialised instruments, only part of which can be represented by the medical facility in terms of a corresponding DRG (Diagnosis-Related Group), it is reprocessing that opens the door to widespread routine clinical use. The patient, in turn, benefits greatly from this, since his demand for medical treatment using the most up-to-date technology is taken into account. If processing complies in full with medical technology and hygiene directives, from the medical point of view (without being able to definitively evaluate each individual case using this criterion) the specific advantages of the reprocessing procedure are obvious. In order to establish broad acceptance for the purposes of good marketing, corresponding controlling and quality instruments have to be developed to allow the decision-making process regarding the permissibility of the reprocessing of a certain device and the number of times it can be reprocessed using this procedure to be made transparent.Taking this a step further, possibilities arise for the establishment of corresponding quality-assurance instruments on the part of the clinical establishments involved, within which reprocessed products, in the interest of quality assurance, can be referred back to the processor in the event of defective function and can also be removed from clinical use prior to completing the intended number of processing cycles. Furthermore, it can be assumed that the widespread use of reprocessing procedures in today's high-cost single-use medical device sector will have a long-term cost/price-regulating effect for the primary products, to the benefit of the users. Thus, the heated debate regarding the safety of processing procedures that have already been certified and validated in accordance with current industry standards should be evaluated in particular from the point of view of the justified fears of the leading manufacturers with regard to their currently established market share. From a purely surgical point of view, the reprocessing of disposable products should be welcomed as a revolution. The main criteria for surgeons and medics should always be the benefit for the patient. If the quality is ensured through corresponding processing and validation procedures based on recognised certificates, then economic arguments take precedence. Cases in which a DRG (and thus a payment calculation) does not fully cover the use of medical devices are conceivable. Withholding medically necessary services on grounds of the costs, or making these services available to a limited extent only, is not acceptable from the medical point of view and furthermore goes beyond what is ethically acceptable. Each procedure, even the systematic use of reprocessing of suitable medical technology disposable items, should, where the quality is guaranteed, be supported unequivocally. Taken a step further, this branch of the economy will have a long-lasting price-regulating effect on the primary producers market. PMID- 20204094 TI - Quality management for the processing of medical devices. AB - Rules on the reprocessing of medical devices were put into place in Germany in 2001. The present article explains the background situation and the provisions that are currently in force.The implementation of these statutory requirements is described using the example of the quality management system of Germany's market leader, Vanguard AG. This quality management system was successfully certified pursuant to DIN EN ISO 13485:2003 for the scope "reprocessing of medical devices", including class "critical C", in accordance with the recommendation of the Commission for Hospital Hygiene and the Prevention of Infection at the Robert Koch-Institute (RKI) and the German Federal Institute for Drugs and Medical Devices (BfArM) on the "Hygiene requirements for reprocessing of medical devices". PMID- 20204095 TI - Framework conditions and requirements to ensure the technical functional safety of reprocessed medical devices. AB - Testing and restoring technical-functional safety is an essential part of medical device reprocessing. Technical functional tests have to be carried out on the medical device in the course of the validation of reprocessing procedures. These ensure (in addition to the hygiene tests) that the reprocessing procedure is suitable for the medical device. Functional tests are, however, also a part of reprocessing procedures. As a stage in the reprocessing, they ensure for the individual medical device that no damage or other changes limit the performance. When determining which technical-functional tests are to be carried out, the current technological standard has to be taken into account in the form of product-specific and process-oriented norms. Product-specific norms primarily define safety-relevant requirements. The risk management method described in DIN EN ISO 14971 is the basis for recognising hazards; the likelihood of such hazards arising can be minimised through additional technical-functional tests, which may not yet have been standardised. Risk management is part of a quality management system, which must be bindingly certified for manufacturers and processors of critical medical devices with particularly high processing demands by a body accredited by the competent authority. PMID- 20204096 TI - Legal framework conditions for the reprocessing of medical devices. AB - The processing of single-use products is permissible pursuant to medical device law. This is apparent both from the wording of the German Law on Medical Devices and from the purpose and the objectives underpinning the legislative materials. The prerequisite for processing is, however, compliance with the the Joint Recommendation of the Commission for Hospital Hygiene and the Prevention of Infection at the Robert Koch Institute (RKI) and the Federal Institute for Drugs and Medical Products (BfArM).For medical devices in the category "critical C", the RKI/BfArM-recommendation provides that the processor's quality management system must be certified by a body accredited by the Central Authority of the Federal States for Health Protection with regard to Medicinal Products and Medical Devices (Zentralstelle der Lander fur Gesundheitsschutz bei Arzneimitteln und Medizinprodukten, ZLG). The certification must be carried out in accordance with EN ISO 13485:2003+AC:2007.On April 4, 2008 the Federal Health Ministry (Bundesministerium fur Gesundheit, BMG) presented a progress report on the processing of medical devices. The BMG concludes that the legal framework for the processing of medical devices is sufficient, and that a prohibition on the processing of single-use products is inappropriate. PMID- 20204097 TI - Ethical and hygiene aspects of the reprocessing of medical devices in Germany. AB - Based on safety and quality principles, for each medical device (MD), regardless of its declared status as single- or multi-use device, careful considerations must be made. This includes assessment whether reprocessing is economical and ecological meaningful, and technical feasible. So far, however, in Germany reprocessing of declared single use MD is legally allowed, provided that the above aspects are well covered. The purpose of this paper is to elucidate, when circumstances allow reprocessing of declared single-use MD. For reprocessing of single use MD the following preconditions must be fulfilled:The security level of the reprocessed MD must be equivalent to the status of the newly delivered item; this means that a patient is not exposed to a higher risk through a reprocessed disposable MD than through the new, i.e. un-processed product.The reprocessing must be based on a detailed risk assessment and risk analysis, and must be described in detail regarding selection of the reprocessing method. Additionally, all necessary safety- and quality assurance measures must be stated.The reprocessing measure needs to be accompanied with a quality management system which determines and documents the responsibility of all stages of reprocessing; where the corresponding reprocessing procedures are well defined; and the efficacy of the procedure is proven by product-specific or product-group-specific tests and reports. The process must be validated according to recognised methods of science and technology, taking into account potential negative influences of the reprocessing on the properties of the material and the technical and functional safety. For reprocessing of MDs of the category Critical C the quality assurance must be certified by an accredited certifying body. PMID- 20204098 TI - Antimicrobial resistance gene distribution: a socioeconomic and sociocultural perspective. AB - The appearance of resistance to many first-line antimicrobial agents presents a critical challenge to the successful treatment of bacterial infections. Antimicrobial resistant bacteria and resistance genes are globally distributed, but significant variations in prevalence have been observed in different geographical regions. This article discusses possible relationships between socioeconomic and sociocultural factors and regional differences in the prevalence of antibiotic-resistant bacteria and their associated resistance genes. Findings indicate that the few studies that have been conducted to understand relationships between socioeconomic and sociocultural factors and antimicrobial resistance have focused on patterns of phenotypic antibiotic resistance. Yet, a critical need exists for molecular studies of human influences on bacterial resistance and adaptation. We propose that the results of these studies, coupled with well-coordinated culturally appropriate interventions that address specific socioeconomic and sociocultural needs may be necessary to reduce the scourge of antimicrobial resistance in both developing and developed countries. PMID- 20204099 TI - The safe processing of medical devices in the interests of patient protection. PMID- 20204100 TI - Epidemiology of MRSA and current strategies in Europe and Japan. AB - The prevalence of health-care associated infections caused by multi-drug resistant organisms has significantly increased over the past decade. Among these organisms, Methicillin-resistant Staphylococcus aureus (MRSA) plays a prominent and increasing role. Because of consequences for patients and the economic burden in course of prolonged treatment following MRSA infections and additional indirect costs for e.g. isolation or antiseptic treatment, this trend will further damage European health-care systems.In 2006, a workshop was initiated at the 8(th) International Congress of the German Society of Hospital Hygiene held in Berlin. The aim of this workshop was to give an overview of the current situation of MRSA in selected European countries and to elaborate on potential strategies to prevent MRSA-infections and dissemination. A questionnaire encompassing 20 questions addressed topics such as epidemiology, current measures and future prospects was distributed to representatives from various European countries and Japan. A variety of widely different answers was obtained. It was shown that in all countries prevalence of MRSA is on a rising tide. This trend is observable in all European countries, albeit less strong in The Netherlands, Slovenia, France, Austria and Scandinavian countries. It was conclude that prevention strategies in a united and expanding European Community will become of utmost importance and that rapid screening strategies, e.g. PCR, might be of assistance in such an approach. A potential strategy to improve infection control measures could be the requirement of health-insurance providers to sign contracts only with hospitals able to proof having an infection control management in place. PMID- 20204101 TI - Recommendations for the prevention and control of methicillin-resistant Staphylococcus aureus isolates (MRSA) in hospitals and other healthcare facilities. AB - The Commission for Hospital Hygiene and Infection Control (KRINKO) at the Robert Koch-Institute Berlin published the "Recommendations for Preventing and Controlling Methicillin-Resistant Staphylococcus aureus (MRSA) Strains in Hospitals and Other Medical Facilities" in the Federal Health Gazette in 1999 [1]. These recommendations were translated for the current edition of GMS Krankenhaushygiene Interdisziplinar by the German Society of Hospital Hygiene.KRINKO's work is legitimated by section sign 23 para. 2 of the Infection Protection Act. Regarding the legal nature of the KRINKO recommendations, it should be noted that they are neither a formal act or an administrative regulation. The KRINKO recommendations are instead an evidence-based consensus of particularly qualified experts. The consensus is reached by including the Federal States' authorities and all competent professional bodies and associations. This is to guarantee that the KRINKO recommendations reflect the state-of-the-art of medical science, and are met with a high degree of user acceptance. The recommendations are published in the Federal Health Gazette and on the RKI's Internet pages (http://www.rki.de/).Link to the German original edition of the MRSA recommendations. PMID- 20204103 TI - Declaration of the 1 international workshop on plasma tissue interactions. PMID- 20204104 TI - Biomaterials in contact with soft tissue and blood. PMID- 20204105 TI - Electrical control of cell behaviour and wound healing. PMID- 20204102 TI - Implementing the MRSA recommendations made by the Commission for Hospital Hygiene and Infection Prevention (KRINKO) of 1999 - current considerations by the DGKH Management Board. AB - In Germany, recommendations on dealing with patients who are colonised with methicillin-resistant S. aureus (MRSA) for the inpatient sector have been published in 1999 by the Commission for Hospital Hygiene and Infection Prevention (KRINKO). Some challenges arise with regard to the practical implementation of the KRINKO recommendations. These challenges do not principally question the benefit of the recommendations but have come into criticism from users. In this commentary the German Society for Hospital Hygiene (DGKH) discusses some controversial issues and adds suggestions for unresolved problems regarding the infection control management of MRSA in healthcare settings. PMID- 20204106 TI - BIODECON - European project on plasma inactivation of bacteria and biomolecules. PMID- 20204107 TI - Implementation of ECIS technology for the characterization of potential therapeutic drugs that promote wound-healing. PMID- 20204108 TI - Impedance based methods for cell characterization and modeling. PMID- 20204109 TI - Cold atmospheric plasma destruction of solid proteins on stainless-steel surface and on real surgical instruments. PMID- 20204110 TI - Tissue processing with plasma needle. PMID- 20204111 TI - Biological and medical application of atmospheric plasmas. PMID- 20204112 TI - In vivo analysis of wound healing by optical methods. AB - The analysis of wound healing is important for the therapy control and for the development of drugs stimulating the healing process. Wounds cause damage to the skin barrier. A damaged stratum corneum leads to an increased water loss through the skin barrier. The standard measuring procedure for characterization of wound healing is the measurement of transepidermal water loss (TEWL). The disadvantage of this method is that it can be easily disturbed by the perspiration of the volunteers and by topically applied substances, for instance wound healing creams. In the study presented, in vivo laser scanning microscopy and optical coherent tomography were compared concerning the application for their analysis of wound healing processes. The laser scanning microscopy allows the analysis of the healing process on a cellular level. The course of wound healing determined by laser scanning microscopy was correlated with numerical values, allowing the numerical characterization of the wound healing process. PMID- 20204113 TI - Human skin equivalent as an alternative to animal testing. AB - The 3-D skin equivalent can be viewed as physiologically comparable to the natural skin and therefore is a suitable alternative for animal testing. This highly differentiated in vitro human skin equivalent is used to assess the efficacy and mode of action of novel agents. This model is generated from primary human keratinocytes on a collagen substrate containing human dermal fibroblasts. It is grown at the air-liquid interface which allows full epidermal stratification and epidermal-dermal interactions to occur. Future emphasis is the establishment of different test systems to investigate wound healing, melanoma research and infection biology. Key features of this skin model are that it can be used as an alternative for in vivo studies, donor tissue can be tailored to the needs of the study and multiple analyses can be carried out at mRNA and protein level. Driven by both ethical and economical incentives, this has already resulted in a shift of the test strategies used by the Pharmaceutical Industry in the early drug development process as reflected by the increased demand for application of cell based assays. It is also a suitable model for testing a wide variety of endpoints including cell viability, the release of proinflammatory mediators, permeation rate, proliferation and biochemical changes. PMID- 20204114 TI - Methods for the measurement of cell and tissue compatibility including tissue regeneration processes. AB - Biocompatibility is one of the main requirements for the safe use of medical devices. Determination of cytotoxicity is part of the initial evaluation stipulated by ISO standards for the biological evaluation of medical devices. The use of cell cultures to test the biocompatibility of drugs, biomaterials or treatment techniques used in various disciplines is gaining in importance. A wide variety of self-initiated and commercially available cell lines has been evaluated and used: cultured fibroblasts from human skin, buccal mucosa, periodontal membrane, embryonic lung, epithelial and HeLa cells; cultures of human keratinocytes and HaCaT cells; different murine cell lines (C3H-L, Balb/c 3T3, L929 and others) as well as murine cells cultured from liver and spleen; T lymphocytes from lymph nodes and macrophages obtained by lavage.All of the above cells are suitable for use in biocompatibility tests. Nevertheless, the general opinion is that toxicity tests in vitro will be more convincing when performed with cells that are homologous with the human tissue concerned. In accordance, appropriate cell lines for use in cytotoxicity and tolerance tests concerning the skin would be human dermal fibroblasts and human epidermal keratinocytes, as they take an active part in the immune response, inflammatory processes, and wound healing.The evaluation of the in vitro cytotoxicity of a biomaterial is often a qualitative analysis based on the morphological examination of cell damage and growth after direct or indirect contact with the material. Different commercial assays based on the determination of nucleic acids, metabolic activity, protein content or membrane integrity are available to measure cell proliferation and cell viability. A small selection - Pico Green((R)) DNA Cell Proliferation Assay, ATPLite Luminescence ATP Detection Assay, BC Assay: protein quantitation kit, AlamarBlue Proliferation Assay and Live/Dead Staining with SYTO-13 and EthD-2 - are discussed concerning sensitivity, reliability and applicability. PMID- 20204115 TI - Polypragmasia in the therapy of infected wounds - conclusions drawn from the perspectives of low temperature plasma technology for plasma wound therapy. AB - As long as a wound is infected, the healing process cannot begin. The indication for wound antiseptic is dependent on the interaction between the wound, the causative micro-organisms, and the host immune system. An uncritical colonisation is a condition whereby micro-organisms on a wound will proliferate, yet the immune system will not react excessively. Wound antiseptic is most often not necessary unless for epidemiologic reasons like colonisation with multi-resistant organisms. In most instances of a microbial contamination of the wound and colonisation, thorough cleaning will be sufficient.Bacterial counts above 10(5) to 10(6) cfu per gram tissue (critical colonisation) might decrease wound healing due to release of toxins, particularly in chronic wounds. Traumatic and heavily contaminated wounds therefore will require anti-infective measures, in particular wound antiseptic. In such situations, even a single application of an antiseptic compound will significantly reduce the number of pathogens, and hence, the risk of infection. If a wound infection is clinically manifest, local antiseptics and systemic antibiotics are therapeutically indicated.The prophylactic and therapeutic techniques for treatment of acute and chronic wounds (chemical antiseptics using xenobiotics or antibiotics, biological antiseptic applying maggots, medical honey or chitosan, physical antiseptic using water-filtered infrared A, UV, or electric current) mostly have been empirically developed without establishing a fundamental working hypothesis for their effectiveness.The most important aspect in controlling a wound infection and achieving healing of a wound is meticulous debridement of necrotic material. This is achieved by surgical, enzymatic or biological means e.g. using maggots. However, none of these methods (with some exception for maggots) is totally gentle to vital tissue and particularly chemical methods possess cytotoxicity effects.DERIVED FROM THE GENERAL PRINCIPLES OF ANTISEPTIC WOUND TREATMENT, THE FOLLOWING WORKING HYPOTHESIS IS POSTULATED: the most ideal constellation for treatment of wounds is the superficial destruction of microbial layers without deep tissue alteration, like it is caused by antiseptics, in order not to endanger the regenerative granulation tissue. At the same time, it is desirable to support and increase cell proliferation and granulation capacities. These two aspects might be achieved by using low temperature plasma technology. PMID- 20204116 TI - PLASMOSE - antimicrobial effects of modular atmospheric plasma sources. AB - The technological potential of non-thermal plasmas for the antimicrobial treatment of heat sensitive materials is well known and has been documented in a great number of research activities, but the realisation of industrial plasma based decontamination processes remains a great challenge. One of the reasons for this situation is the fact that an antimicrobial treatment process needs to consider all properties of the product to be treated as well as the requirements of the complete procedure, e.g. a reprocessing of a medical instrument. The aim of the BMBF-funded network project PLASMOSE is to demonstrate the applicability of plasma-based processes for the antimicrobial treatment on selected, heat sensitive products. Modular and selective plasma sources, driven at atmospheric pressure are used. This basic approach shall combine the technological advantages of atmospheric pressure plasmas (avoidance of vacuum devices and batch processing) with the flexibility and handling properties of modular devices. TWO DIFFERENT OBJECTIVES WERE SELECTED: the outer surface treatment of medical products and the treatment of hollow packaging for pharmaceutical products. The outer surface treatment of medical products, in particular catheters for intracardial electrophysiological studies, is investigated by means of RF-driven plasma jets in argon. Due to its compact design they are predestined for modularisation and can be adapted to nearly any complex 3-dimensional structure as given by the medical products. The realisation of an antimicrobial treatment process of hollow packaging for pharmaceutical products has quite different demands. Such a process is needed to be implemented in in-line filling procedures and to work without additional process gases. The idea is to use an atmospheric air, microwave-driven self propagating discharge. The plasma process is optimized for the decontamination of 200 ml bottles by field simulation studies combined with optical emissions spectroscopy and micro-biological tests. PMID- 20204117 TI - Argon plasma coagulation. AB - Argon Plasma Coagulation (APC) is an application of gas discharges in argon in electrosurgery, which is increasingly used especially in endoscopy. The major application fields are haemostasis, tissue devitalization and tissue reduction.This review describes the physics and technology of electrosurgery and APC. Some characteristics of the argon discharge are shown and discussed, and thermal effects in biological tissue are described. Subsequently, examples of medical applications are given. PMID- 20204118 TI - Plasma Medicine - its perspective for wound therapy. PMID- 20204119 TI - Recurrent breast cancer: treatment strategies for maintaining and prolonging good quality of life. AB - BACKGROUND: Recurrent breast cancer remains a challenge for interdisciplinary treatment even though new therapeutic options are available. METHODS: The PubMed database was selectively searched for articles that appeared from 1999 to 2009 and contained the key words "breast cancer," "recurrence," "metastatic," "advanced," and "treatment". Further sources consulted for this review included the German S3 guideline, the treatment recommendations of the German AGO-Mamma group, the NCCN guidelines, and the Cochrane database. RESULTS: Locoregional recurrences are treated with curative intent. Metastatic breast cancer must be treated on an individualized basis: The treatment should be continued as long as its benefits for the individual patient outweigh its adverse side effects. Endocrine treatment is indicated for all patients whose tumors are hormone receptor positive or of unknown receptor status and who have enough time for a response to be seen. Chemotherapy should be given if the tumor is hormone receptor negative, if a rapid response is urgently needed, or if endocrine treatment has failed to produce a response. Combination chemotherapy improves response rates and prolongs progression-free survival, yet it does not prolong overall survival in comparison to monochemotherapy. In HER2-positive patients, first-line treatment with trastuzumab and monochemotherapy prolongs overall survival. Other treatment options include angiogenesis inhibitors, various tyrosine kinases inhibitors, radiotherapy, bisphosphonates, surgical or other ablative treatment of metastases, or a combination of these approaches, applied either simultaneously or consecutively. CONCLUSIONS: While locoregional recurrences of breast cancer should be treated with curative intent, breast cancer with distant metastases is currently not curable. It is treated with the intention of restoring and maintaining good quality of life and relieving symptoms due to the metastases, rather than prolonging survival. PMID- 20204120 TI - Patient safety and error management: what causes adverse events and how can they be prevented? AB - BACKGROUND: Even in industrialized countries, health care is not as safe as it should be. The term "patient safety" denotes the non-occurrence of adverse events and the presence of measures to prevent them. METHODS: The literature was selectively reviewed to obtain information on the epidemiology and causes of preventable adverse events (PAE), as well as on measures that can increase patient safety. RESULTS: Preventable adverse events occur in Germany both in the hospital and in outpatient settings, although their precise frequency is currently a disputed matter. PAE should be analyzed systematically. They are caused both by active errors and by latent failures that are inherent in components of the health care system. CONCLUSION: Three main strategies should be pursued to improve patient safety. A safety management system involving error reporting, learning from errors, and the fair exchange of information should be established in hospitals and in doctors' outpatient practices. An error management system should be implemented in which critical incidents are identified, reported, and analyzed so that similar events can be prevented, and measures for the prevention of critical incidents and errors should also be implemented and evaluated. Finally, whenever preventable adverse events do occur, the persons involved should take action to prevent further harm to the patient and other involved individuals. PMID- 20204121 TI - Correspondence (letter to the editor): prosthetic care. PMID- 20204122 TI - Correspondence (letter to the editor): scheme not possible. PMID- 20204123 TI - Correspondence (letter to the editor): treatment after discharge. PMID- 20204125 TI - Correspondence (letter to the editor): benefits of cooling are not known. PMID- 20204127 TI - Glomus Tumor of the Stomach: Depiction by Multidetector CT and Three-Dimensional Volume Rendering Imaging. AB - Glomus tumors are uncommon tumors which can occur anywhere within the gastrointestinal tract but have been shown to occur most commonly in the gastric antrum. On CT, these tumors demonstrate hyperenhancement which may help distinguish them from other gastric masses. PMID- 20204128 TI - Papillocystic variant of acinar cell pancreatic carcinoma. AB - Acinar cell pancreatic carcinoma is a rare solid malignant neoplasm. Recent review of the literature showed occasional cases with papillary or papillocystic growth patterns, ranging from 2 to 5 cm in diameter. We report a large 10 cm pancreatic tumor with papillocystic pathology features involving the pancreatic head. The growth pattern of these tumors could be mistaken for intraductal papillary mucinous tumors or other pancreatic cystic neoplasms. PMID- 20204129 TI - Neutrophils compromise retinal pigment epithelial barrier integrity. AB - We hypothesized that neutrophils and their secreted factors mediate breakdown of the integrity of the outer blood-retina-barrier by degrading the apical tight junctions of the retinal pigment epithelium (RPE). The effect of activated neutrophils or neutrophil cell lysate on apparent permeability of bovine RPE Choroid explants was evaluated by measuring [3H] mannitol flux in a modified Ussing chamber. The expression of matrix metalloproteinase- (MMP-) 9 in murine peritoneal neutrophils, and the effects of neutrophils on RPE tight-junction protein expression were assessed by confocal microscopy and western blot. Our results revealed that basolateral incubation of explants with neutrophils decreased occludin and ZO-1 expression at 1 and 3 hours and increased the permeability of bovine RPE-Choroid explants by >3-fold (P < .05). Similarly, basolateral incubation of explants with neutrophil lysate decreased ZO-1 expression at 1 and 3 hours (P < .05) and increased permeability of explants by 75%. Further, we found that neutrophils prominently express MMP-9 and that incubation of explants with neutrophils in the presence of anti-MMP-9 antibody inhibited the increase in permeability. These data suggest that neutrophil derived MMP-9 may play an important role in disrupting the integrity of the outer blood-retina barrier. PMID- 20204131 TI - Soft tissue extramedullary plasmacytoma. AB - We present the uncommon case of a subcutaneous fascia-based extramedullary plasmacytoma in the leg, which was confirmed by the pathology report and followed up until its remission. We report the differential diagnosis with other more common soft tissue masses. Imaging findings are nonspecific but are important to determine the tumour extension and to plan the biopsy. PMID- 20204130 TI - Gene expression profiling of placentas affected by pre-eclampsia. AB - Several studies point to the placenta as the primary cause of pre-eclampsia. Our objective was to identify placental genes that may contribute to the development of pre-eclampsia. RNA was purified from tissue biopsies from eleven pre-eclamptic placentas and eighteen normal controls. Messenger RNA expression from pooled samples was analysed by microarrays. Verification of the expression of selected genes was performed using real-time PCR. A surprisingly low number of genes (21 out of 15,000) were identified as differentially expressed. Among these were genes not previously associated with pre-eclampsia as bradykinin B1 receptor and a 14-3-3 protein, but also genes that have already been connected with pre eclampsia, for example, inhibin beta A subunit and leptin. A low number of genes were repeatedly identified as differentially expressed, because they may represent the endpoint of a cascade of events effectuated throughout gestation. They were associated with transcriptional regulation and vasoregulative pathways, along with a number of hypothetical proteins and gene sequences with unknown functions. PMID- 20204132 TI - Massive fetomaternal hemorrhage caused by an intraplacental choriocarcinoma: a case report. AB - Background. Intraplacental choriocarcinoma is a rare but highly malignant trophoblastic neoplasm. When found near term the risk of maternal metastasis is high because of the late diagnosis. Case. We describe a case of an intraplacental choriocarcinoma diagnosed postpartum after a near-term delivery of a severely anemic infant. A fetomaternal hemorrhage resulted in a hemoglobin concentration in the infant of only 2,1 g/dL. Neither mother nor child showed signs of metastatic disease. The macroscopic examination showed a hydropic placenta weighing more than 1 kilogram. Microscopy showed an intraplacental choriocarcinoma 3 cm in diameter. The tumor had infiltrated the maternal basal plate. Conclusion. Fetomaternal bleeding is a rare form of presentation of choriocarcinoma but its presence should always warrant detailed examination of placenta, mother, and infant. PMID- 20204134 TI - Clinical Presentation and Conservative Management of Tympanic Membrane Perforation during Intrapartum Valsalva Maneuver. AB - Background. Tympanic membrane perforation may occur when ear pressures are excessive, including valsalva maneuver associated with active labor and vaginal delivery. A pressure differential across the eardrum of about 5 psi can cause rupture; the increased intraabdominal pressure spikes repeatedly manifested by "pushing" during second-stage labor easily approach (and may exceed) this level. Material and Method. We describe a healthy 21-year old nulliparous patient admitted in active labor at 39-weeks' gestational age. Results. Blood appeared asymptomatically in the left ear canal at delivery during active, closed-glottis pushing. Otoscopic examination confirmed perforation of the left tympanic membrane. Complete resolution of the eardrum rupture was noted at postpartum check-up six weeks later. Conclusion. While the precise incidence of intrapartum tympanic membrane rupture is not known, it may be unrecognized without gross blood in the ear canal or subjective hearing loss following delivery. Only one prior published report on tympanic membrane perforation during delivery currently appears in the medical literature; this is the first English language description of the event. Since a vigorous and repetitive valsalva effort is common in normal vaginal delivery, clinicians should be aware of the potential for otic complications associated with the increased intraabdominal pressure characteristic of this technique. PMID- 20204133 TI - Regulation of adrenal aldosterone production by serine protease prostasin. AB - A serine protease prostasin has been demonstrated to have a pivotal role in the activation of the epithelial sodium channel. Systemic administration of adenovirus carrying human prostasin gene in rats resulted in an increase in plasma prostasin and aldosterone levels. However, the mechanism by which the elevation of prostasin levels in the systemic circulation stimulated the plasma aldosterone levels remains unknown. Therefore, we examined if prostasin increases the aldosterone synthesis in a human adrenocortical cell line (H295R cells). Luciferase assay using CYP11B2 promoter revealed that prostasin significantly increased the transcriptional activity of CYP11B2. Prostasin significantly increased both CYP11B2 mRNA expression and aldosterone production in a dose dependent manner. Surprisingly, treatment with camostat mesilate, a potent prostasin inhibitor, had no effect on the aldosterone synthesis by prostasin and also a protease-dead mutant of prostasin significantly stimulated the aldosterone production. A T-type/L-type calcium channel blocker and a protein kinase C (PKC) inhibitor significantly reduced the aldosterone synthesis by prostasin. Our findings suggest a stimulatory effect of prostasin on the aldosterone synthesis by adrenal gland through the nonproteolytic action and indicate a new role of prostasin in the systemic circulation. PMID- 20204135 TI - Anti-inflammatory protein of Schistosoma japonicum directs the differentiation of the WEHI-3B JCS cells and mouse bone marrow cells to macrophages. AB - Sj16 is an anti-inflammatory protein identified from Schistosoma japonicum. Our previous studies showed that recombinant Sj16 (rSj16) could suppress host's inflammatory responses and inhibit macrophage maturation. In the present study, the effects of rSj16 on the differentiation of the murine myeloid leukemia WEHI 3B JCS cell line and on mouse hematopoiesis were investigated. Our data demonstrated that rSj16 expressed and purified from Escherichia coli could suppress the proliferation of the WEHI-3B JCS cells in a time- and concentration dependent manner, while not affect the viability of the cells. Further studies indicated that rSj16 induced macrophage differentiation of the WEHI-3B JCS cells, and arrested the cell cycle in the G1/G0 and G2/M phases. The macrophage differentiation of the rSj16-treated WEHI-3B JCS cells was confirmed by their expression of macrophage specific antigen F4/80 and phagocytic activity. Furthermore, our results revealed that rSj16 biased the colony formation of mouse bone marrow cells towards macrophage linage. PMID- 20204136 TI - 'The next step'--alumni students' views on their preparation for their first position as a physician. AB - BACKGROUND: Although medical programmes are often thoroughly evaluated, these evaluations more seldom include workplace points of view. The present study focuses on how well a Swedish medical programme was judged to prepare students for work as a physician. METHODS: Thirty-two competences in physicians' work were identified through interviews. A subsequent questionnaire was completed by 123 programme alumni who had worked for 1-2(1/2) years in different parts of the country. Alumni were asked to rate the importance of each competence, their self assessed competence as well as how these competences were addressed during their medical training. RESULTS: The subsequent analysis identified areas where their training programme, according to the alumni, failed to prepare them satisfactorily. Problem areas included competences in clinical skills, handling stressful situations and in applied rather than foundational knowledge about common symptoms and diseases. CONCLUSION: Despite extensive practical training, medical education still faces some problems in the transition from education to work. PMID- 20204137 TI - Re-thinking the role of the dorsal striatum in egocentric/response strategy. AB - Rats trained in a dual-solution cross-maze task, which can be solved by place and response strategies, predominantly used a response strategy after extensive training. This paper examines the involvement of the medial and lateral dorsal striatum (mDS and lDS) in the choice of these strategies after partial and extensive training. Our results show that rats with lDS and mDS lesions used mainly a response strategy from the early phase of training. We replicated these unexpected data in rats with lDS lesions and confirmed their tendency to use the response strategy in a modified cross-maze task. When trained in a dual-solution water-maze task, however, control and lesioned rats consistently used a place strategy, demonstrating that lDS and mDS lesioned rats can use a place strategy and that the shift towards a response strategy did not systematically result from extensive training. The present data did not show any clear dissociation between the mDS and lDS in dual solution tasks. They further indicate that the dorsal striatum seems to determine the strategies adopted in a particular context but cannot be considered as a neural support for the response memory system. Accordingly, the role of the lateral and medial part of the dorsal striatum in egocentric/response memory should be reconsidered. PMID- 20204138 TI - Effects of Pharmacological Block of GABA(A) Receptors on Pallidal Neurons in Normal and Parkinsonian State. AB - The globus pallidus plays a central integrative role in the basal ganglia circuitry. Morphological studies have revealed a high level of GABA and GABA(A) receptors in the globus pallidus. To further investigate the effects of endogenous GABA(A) neurotransmission in the globus pallidus of normal and parkinsonian rats, in vivo extracellular recording and behavioral tests were performed in the present studies. In normal rats, micro-pressure ejection of GABA(A) receptor antagonist gabazine (0.1 mM) increased the spontaneous firing rate of pallidal neurons by 28.3%. Furthermore, in 6-hydroxydopamine parkinsonian rats, gabazine increased the firing rate by 46.0% on the lesioned side, which was significantly greater than that on the unlesioned side (21.5%, P < 0.05), as well as that in normal rats (P < 0.05). In the behaving rats, unilateral microinjection of gabazine (0.1 mM) evoked consistent contralateral rotation in normal rats, and significantly potentiated the number of apomorphine-induced contralateral rotations in parkinsonian rats. The present electrophysiological and behavioral findings may provide a rational for further investigations into the potential of pallidal endogenous GABA(A) neurotransmission in the treatment of Parkinson's disease. PMID- 20204139 TI - Exercise can rescue recognition memory impairment in a model with reduced adult hippocampal neurogenesis. AB - Running is a potent stimulator of cell proliferation in the adult dentate gyrus and these newly generated hippocampal neurons seem to be implicated in memory functions. Here we have used a mouse model expressing activated Ras under the direction of the neuronal Synapsin I promoter (named synRas mice). These mice develop down-regulated proliferation of adult hippocampal precursor cells and show decreased short-term recognition memory performances. Voluntary physical activity reversed the genetically blocked generation of hippocampal proliferating cells and enhanced the dendritic arborisation of the resulting doublecortin newly generated neurons. Moreover, running improved novelty recognition in both wild type and synRas littermates, compensating their memory deficits. Brain-derived neurotrophic factor (BDNF) has been proposed to be a potential mediator of physical exercise acting in the hippocampus on dentate neurons and their precursors. This was confirmed here by the identification of doublecortin immunoreactive cells expressing tyrosine receptor kinase B BDNF receptor. While no difference in BDNF levels were detected in basal conditions between the synRas mice and their wild type littermates, running was associated with enhanced BDNF expression levels. Thus increased BDNF signalling is a candidate mechanism to explain the observed effects of running. Our studies demonstrate that voluntary physical activity has a robust beneficial effect even in mice with genetically restricted neurogenesis and cognition. PMID- 20204140 TI - Differential development of the ventral visual cortex extends through adolescence. AB - The ventral temporal cortex (VTC) in humans includes functionally defined regions that preferentially respond to objects, faces, and places. Recent developmental studies suggest that the face selective region in the fusiform gyrus ('fusiform face area', FFA) undergoes a prolonged development involving substantial increases in its volume after 7 years of age. However, the endpoint of this development is not known. Here we used functional magnetic resonance imaging (fMRI) to examine the development of face-, object- and place selective regions in the VTC of adolescents (12-16 year olds) and adults (18-40 year olds). We found that the volume of face selective activations in the right fusiform gyrus was substantially larger in adults than in adolescents, and was positively correlated with age. This development was associated with higher response amplitudes and selectivity for faces in face selective regions of VTC and increased differentiation of the distributed response patterns to faces versus non-face stimuli across the entire VTC. Furthermore, right FFA size was positively correlated with face recognition memory performance, but not with recognition memory of objects or places. In contrast, the volume of object- and place selective cortical regions or their response amplitudes did not change across these age groups. Thus, we found a striking and prolonged development of face selectivity across the VTC during adolescence that was specifically associated with proficiency in face recognition memory. These findings have important implications for theories of development and functional specialization in VTC. PMID- 20204141 TI - MicroRNA in Situ Hybridization in the Human Entorhinal and Transentorhinal Cortex. AB - MicroRNAs (miRNAs) play key roles in gene expression regulation in both healthy and disease brains. To better understand those roles, it is necessary to characterize the miRNAs that are expressed in particular cell types under a range of conditions. In situ hybridization (ISH) can demonstrate cell- and lamina specific patterns of miRNA expression that would be lost in tissue-level expression profiling. In the present study, ISH was performed with special focus on the human entorhinal cortex (EC) and transentorhinal cortex (TEC). The TEC is the area of the cerebral cortex that first develops neurofibrillary tangles in Alzheimer's disease (AD). However, the reason for TEC's special vulnerability to AD-type pathology is unknown. MiRNA ISH was performed on three human brains with well-characterized clinical and pathological parameters. Locked nucleic acid ISH probes were used referent to miR-107, miR-124, miR-125b, and miR-320. In order to correlate the ISH data with AD pathology, the ISH staining was compared with near adjacent slides processed using Thioflavine stains. Not all neurons or cortical lamina stain with equal intensity for individual miRNAs. As with other areas of brain, the TEC and EC have characteristic miRNA expression patterns. MiRNA ISH is among the first methods to show special staining characteristics of cells and laminae of the human TEC. PMID- 20204142 TI - A time for atlases and atlases for time. AB - Advances in neuroanatomy and computational power are leading to the construction of new digital brain atlases. Atlases are rising as indispensable tools for comparing anatomical data as well as being stimulators of new hypotheses and experimental designs. Brain atlases describe nervous systems which are inherently plastic and variable. Thus, the levels of brain plasticity and stereotypy would be important to evaluate as limiting factors in the context of static brain atlases. In this review, we discuss the extent of structural changes which neurons undergo over time, and how these changes would impact the static nature of atlases. We describe the anatomical stereotypy between neurons of the same type, highlighting the differences between invertebrates and vertebrates. We review some recent experimental advances in our understanding of anatomical dynamics in adult neural circuits, and how these are modulated by the organism's experience. In this respect, we discuss some analogies between brain atlases and the sequenced genome and the emerging epigenome. We argue that variability and plasticity of neurons are substantially high, and should thus be considered as integral features of high-resolution digital brain atlases. PMID- 20204143 TI - Individual Differences in Distinct Components of Attention are Linked to Anatomical Variations in Distinct White Matter Tracts. AB - Inter-subject variations in white matter tract properties are known to correlate with individual differences in performance in cognitive domains such as attention. The specificity of such linkages, however, is largely unexplored at the level of specific component operations of attention associated with distinct anatomical networks. This study examines individual performance variation within three functional components of attention - alerting, orienting, and conflict processing - identified by the Attention Network Task (ANT), and relates each to inter-subject variation in a distinct set of white matter tract regions. Diffusion tensor imaging data collected at 3T was used to calculate average fractional anisotropy within a set of individualized a priori defined regions of interest using the Reproducible Objective Quantification Scheme (ROQS) (Niogi and McCandliss, 2006; Niogi et al., 2007). Results demonstrate three functionally distinct components of attention that each correlate distinctly with three white matter tract regions. Structure-function correlations were found between alerting and the anterior limb of the internal capsule, orienting and the splenium of the corpus callosum, and conflict and the anterior corona radiata. A multiple regression/dissociation analysis demonstrated a triple dissociation between these three structure-function relationships that provided evidence of three anatomically and functionally separable networks. These results extend previous findings from functional imaging and lesion studies that suggest these three components of attention are subserved by dissociable networks, and suggest that variations in white matter tract microstructure may modulate the efficiency of these cognitive processes in highly specific ways. PMID- 20204144 TI - Membrane targeted horseradish peroxidase as a marker for correlative fluorescence and electron microscopy studies. AB - Synaptic dynamics and reorganization are fundamental features of synaptic plasticity both during synaptic circuit development and in the mature CNS underlying learning, memory, and experience-dependent circuit rearrangements. Combining in vivo time-lapse fluorescence imaging and retrospective electron microscopic analysis provides a powerful technique to decipher the rules governing dynamics of neuronal structure and synaptic connections. Here we have generated a membrane-targeted horseradish peroxidase (mHRP) that allows identification of transfected cells without obscuring the intracellular ultrastructure or organelles and in particular allows identification of synaptic sites using electron microscopy. The expression of mHRP does not affect dendritic arbor growth or dynamics of transfected neurons. Co-expression of EGFP and mHRP was used to study neuronal morphology at both the light and electron microscopic levels. mHRP expression greatly facilitates 3D reconstruction based on serial EM sections. We expect this reagent will be valuable for studying the mechanisms that guide construction of neuronal networks. PMID- 20204145 TI - Pupil dilation betrays the timing of decisions. AB - The notion of "mind-reading" by carefully observing another individual's physiological responses has recently become commonplace in popular culture, particularly in the context of brain imaging. The question remains, however, whether outwardly accessible physiological signals indeed betray a decision before a person voluntarily reports it. In one experiment we asked observers to push a button at any time during a 10-s period ("immediate overt response"). In a series of three additional experiments observers were asked to select one number from five sequentially presented digits but concealed their decision until the trial's end ("covert choice"). In these experiments observers either had to choose the digit themselves under conditions of reward and no reward, or were instructed which digit to select via an external cue provided at the time of the digit presentation. In all cases pupil dilation alone predicted the choice (timing of button response or chosen digit, respectively). Consideration of the average pupil-dilation responses, across all experiments, showed that this prediction of timing was distinct from a general arousal or reward-anticipation response. Furthermore, the pupil dilation appeared to reflect the post-decisional consolidation of the selected outcome rather than the pre-decisional cognitive appraisal component of the decision. Given the tight link between pupil dilation and norepinephrine levels during constant illumination, our results have implications beyond the tantalizing mind-reading speculations. These findings suggest that similar noradrenergic mechanisms may underlie the consolidation of both overt and covert decisions. PMID- 20204146 TI - Clinical Experience of a Diet Designed to Reduce Aging. AB - OBJECTIVE: Aging is associated with elevated levels of glucose, insulin, and triglycerides. Our objective was to assess the effect of a nutritional program designed to reduce these correlates of aging. DESIGN: This is a retrospective chart review of patients attending an outpatient metabolic management program including a high-fat, adequate-protein, low-carbohydrate diet, nutritional supplementation and periodic individual visits. Outcomes measured at baseline and follow-up included body weight, fasting serum glucose, insulin, leptin, lipids, and thyroid hormone. RESULTS: Thirty-one patients were identified with complete information. The mean age of patients was 57.6 +/- 2.4 consisting of 53% female and 47% male patients. The average duration between follow up visits was 91.5 +/- 8.5 days. Of the parameters measured at the follow-up visit, body weight, serum leptin, insulin, fasting glucose, triglyceride, and free T(3) significantly decreased by 8.1 +/- 0.8%, 48.2 +/- 3.8%, 40.1 +/- 4.7%, 7.6 +/- 2.1%, 28.3 +/- 5.7%, and 10.8 +/- 1.8%, respectively. Furthermore, the triglyceride/high density lipoprotein ratio decreased from 5.1 +/- 1.7 to 2.6 +/- 0.5. CONCLUSIONS: In the context of an outpatient medical clinic, a high-fat, adequate-protein, low carbohydrate diet with nutritional supplementation led to improvements in serum factors related to the aging process. Further research regarding this dietary approach and its relationship to aging is in order. PMID- 20204147 TI - Investigation of an albumin-enriched fraction of human serum and its albuminome. AB - The removal of albumin and other high abundance proteins is a routine first step in the analysis of serum and plasma proteomes. However, as albumin can bind proteins and peptides, there is a universal concern as to how the serum proteome is changed by the removal of albumin. To address this concern, the current study was designed to identify proteins and peptides removed from the serum during albumin depletion; to determine which of these are bound to albumin (rather than copurified) and whether the bound proteins are intact proteins or peptide fragments. Sequential, independent analyses including both anti-albumin antibody (anti-HSA) affinity chromatography and SEC were used to isolate albumin-bound proteins. RP-HPLC and 1-D SDS-PAGE were then used to further separate the proteins prior to identification by MS/MS. Finally, whole protein molecular weight (MW) MS measurements coupled with protein coverage obtained by MS were combined to assess whether the bound proteins were intact or peptide fragments. Combining the results from multiple approaches, 35 proteins, of which 24 are intact, were found to be associated with albumin, and they include both known high and low abundance proteins. PMID- 20204148 TI - Motivating Persons with Schizophrenia Spectrum Disorders to Exercise: Rationale and Design. AB - Persons with schizophrenia spectrum disorders (SSDs) are not only at risk because of disabling disease symptoms but because necessary medications create health risks associated with high rates of obesity. Despite the well-known benefits of exercise, persons with SSDs rarely adhere to such regimens; few interventions to motivate exercise behavior have been tested in this group.The purpose of this study is to examine effects of the Walk, Address sensations, Learn about exercise, Cue exercise behavior for persons with SSDs (WALC-S) motivational intervention upon exercise behavior. We will recruit a total of eighty outpatients 18-68 years, meeting these criteria: 1) chart diagnosis of schizophrenia, any subtype, schizoaffective disorder or schizophreniform disorder, according to the criteria described in the Diagnostic and Statistical Manual for Mental Disorders, 2) English speaking, 3) Stable medication regimen (defined as no medication changes within the last month), and 4) medical clearance for moderate exercise in writing from primary care provider. Participants will be randomly assigned to the experimental (4-week WALC-S motivational intervention), or the control group (4-week time and attention control). After the first 4 weeks, all participants will attend a 16-week walking group.The primary measures of the effectiveness of the WALC-S are attendance, persistence and compliance to the 16-week walking group. The study will be completed in approximately January 2010. In addition to hypothesis testing, this study will provide information to estimate effect sizes to calculate power and determine appropriate sample sizes for future inquiries. This paper describes the rationale and design of the study. PMID- 20204149 TI - Lifetime Trauma, Prayer, and Psychological Distress In Late Life. AB - The purpose of this study is to see whether prayer helps older people cope more effectively with the adverse effects of lifetime trauma. Data from a nationwide survey of older adults reveal that the size of the relationship between traumatic events and depressive symptoms is reduced for older people who believe that only God knows when it is best to answer a prayer, and when they believe that only God knows the best way to answer it. The findings further reveal that these beliefs about prayer outcomes are especially likely to offset the effects of traumatic events that arose during childhood. PMID- 20204150 TI - Interferometric switching of coherent anti-Stokes Raman scattering signals in microscopy. AB - Coherent anti-Stokes Raman scattering (CARS) interferometry is used to deplete the anti-Stokes radiation emerging from a tightly focused spot. Near-to-complete depletion of the anti-Stokes radiation is obtained when a phase-controlled local oscillator field at the anti-Stokes frequency is out of phase with the induced CARS field in the focal volume. Unlike in traditional interferometry, this depleted energy is not spatially redistributed. A theoretical analysis shows that the energy loss in the anti-Stokes channel is accompanied by an energy gain in the pump and Stokes channels. Interferometric switching of anti-Stokes radiation may offer a route toward developing high-resolution CARS microscopy. PMID- 20204152 TI - Comparison of circular and polygonal planar orbits for pinhole and slit-slat SPECT. AB - Analytic formulas and Monte Carlo simulation are used to calculate and compare the sensitivity of circular and polygonal orbits at different points in the Field of View (FoV) for both pinhole and slit-slat collimation. Results show that for a given slit-slat collimator an N-sided polygonal orbit tangent to the FoV generally provides average sensitivity lower than the tightest circular orbit consistent with the same aperture angle, but with better spatial resolution that can be traded for sensitivity for a constant-resolution comparison. This generally results in a slight advantage for the polygonal orbit. However, this advantage depends on the clearance that must be allowed between the orbit and the FoV and decreases quickly, vanishing when even a few millimeters of space are left, which in practice is necessary to accommodate mechanical constraints. For a pinhole collimator the advantage for the tangent polygonal orbit is more consistent, but similar conclusions are reached again when clearance is considered. A direct comparison at constant resolution between slit-slat and pinhole collimation in a single transverse plane is shown to be possible with parameters typical of small-animal imaging applications only for detectors with excellent intrinsic resolution; in this case, pinhole collimation is shown to be more sensitive in magnifying geometries, but reduced axial FoV and increased axial blurring should also be considered for a more complete comparison. PMID- 20204153 TI - Increased opioid dependence in a mouse model of panic disorder. AB - Panic disorder is a highly prevalent neuropsychiatric disorder that shows co occurrence with substance abuse. Here, we demonstrate that TrkC, the high affinity receptor for neurotrophin-3, is a key molecule involved in panic disorder and opiate dependence, using a transgenic mouse model (TgNTRK3). Constitutive TrkC overexpression in TgNTRK3 mice dramatically alters spontaneous firing rates of locus coeruleus (LC) neurons and the response of the noradrenergic system to chronic opiate exposure, possibly related to the altered regulation of neurotrophic peptides observed. Notably, TgNTRK3 LC neurons showed an increased firing rate in saline-treated conditions and profound abnormalities in their response to met(5)-enkephalin. Behaviorally, chronic morphine administration induced a significantly increased withdrawal syndrome in TgNTRK3 mice. In conclusion, we show here that the NT-3/TrkC system is an important regulator of neuronal firing in LC and could contribute to the adaptations of the noradrenergic system in response to chronic opiate exposure. Moreover, our results indicate that TrkC is involved in the molecular and cellular changes in noradrenergic neurons underlying both panic attacks and opiate dependence and support a functional endogenous opioid deficit in panic disorder patients. PMID- 20204154 TI - Personal familiarity influences the processing of upright and inverted faces in infants. AB - Infant face processing becomes more selective during the first year of life as a function of varying experience with distinct face categories defined by species, race, and age. Given that any individual face belongs to many such categories (e.g. A young Caucasian man's face) we asked how the neural selectivity for one aspect of facial appearance was affected by category membership along another dimension of variability. 6-month-old infants were shown upright and inverted pictures of either their own mother or a stranger while event-related potentials (ERPs) were recorded. We found that the amplitude of the P400 (a face-sensitive ERP component) was only sensitive to the orientation of the mother's face, suggesting that "tuning" of the neural response to faces is realized jointly across multiple dimensions of face appearance. PMID- 20204155 TI - Using a panel of immunomarkers to define homologies in Mammalian brains. AB - Brain mapping has relied on a small number of routine chemical stains for many decades. The advent of immunomarkers has had a major impact on the ability to define homologous nuclei from one species to another. The first atlas to present a panel of immunomarkers was that of Paxinos et al. (1999a,b) in the adult rat brain. The markers used were parvalbumin, calbindin, calretinin, SMI32, tyrosine hydroxylase, and NADPH diaphorase (plus nissl and acetylcholinesterase). The 'signature' of a nucleus of interest in a new species can be tested against the findings in the rat. Since the pattern of immunomarkers seems to be conserved in mammalian evolution, such extrapolations can be made with reasonable confidence. A marmoset brain stained with a comprehensive set of immunomarkers has recently been published on the internet (Tokuno et al., 2009) and we are in the process of defining nuclear homologies in this brain by comparison with the same markers in the rat. In this article, we present an example (mapping the amygdala in the marmoset) which demonstrates the application of this immunomarker panel in defining homologies. The technique is particularly valuable in situations where little data on hodology or electrophysiology are available. PMID- 20204156 TI - Three-dimensional reconstruction and segmentation of intact Drosophila by ultramicroscopy. AB - Genetic mutants are invaluable for understanding the development, physiology and behaviour of Drosophila. Modern molecular genetic techniques enable the rapid generation of large numbers of different mutants. To phenotype these mutants sophisticated microscopy techniques are required, ideally allowing the 3D reconstruction of the anatomy of an adult fly from a single scan. Ultramicroscopy enables up to cm fields of view, whilst providing micron resolution. In this paper, we present ultramicroscopy reconstructions of the flight musculature, the nervous system, and the digestive tract of entire, chemically cleared, drosophila in autofluorescent light. The 3D-reconstructions thus obtained verify that the anatomy of a whole fly, including the filigree spatial organization of the direct flight muscles, can be analysed from a single ultramicroscopy reconstruction. The recording procedure, including 3D-reconstruction using standard software, takes no longer than 30 min. Additionally, image segmentation, which would allow for further quantitative analysis, was performed. PMID- 20204157 TI - A new methodology for multiscale myocardial deformation and strain analysis based on tagging MRI. AB - Myocardial deformation and strain can be investigated using suitably encoded cine MRI that admits disambiguation of material motion. Practical limitations currently restrict the analysis to in-plane motion in cross-sections of the heart (2D + time), but the proposed method readily generalizes to 3D + time. We propose a new, promising methodology, which departs from a multiscale algorithm that exploits local scale selection so as to obtain a robust estimate for the velocity gradient tensor field. Time evolution of the deformation tensor is governed by a first-order ordinary differential equation, which is completely determined by this velocity gradient tensor field. We solve this matrix-ODE analytically and present results obtained from healthy volunteers as well as from patient data. The proposed method requires only off-the-shelf algorithms and is readily applicable to planar or volumetric tagging MRI sampled on arbitrary coordinate grids. PMID- 20204158 TI - Bioimaging of nucleolin aptamer-containing 5-(N-benzylcarboxyamide)-2' deoxyuridine more capable of specific binding to targets in cancer cells. AB - Chemically modified nucleotides have been developed and applied into SELEX procedure to find a novel type of aptamers to fit with targets of interest. In this study, we directly performed chemical modification of 5-(N benzylcarboxyamide)-2'-deoxyuridine (called 5-BzdU) in the AS1411 aptamer, which binds to the nucleolin protein expressed in cancer cells. Forty-seven compounds of AS1411-containing Cy3-labeled 5-BzdU (called Cy3-(5-BzdU)-modified-AS1411) were synthesized by randomly substituting thymidines one to twelve in AS1411 with Cy3-labeled 5-BzdU. Both statistically quantified fluorescence measurements and confocal imaging analysis demonstrated at least three potential compounds of interest: number 12, 29 and 41 that significantly increased the targeting affinity to cancer cells but no significant activity from normal healthy cells. These results suggest that the position and number of substituents in AS1411 are critical parameters to improve the aptamer function. In this study, we demonstrated that chemical modification of the existing aptamers enhanced the binding and targeting affinity to targets of interest without additional SELEX procedures. PMID- 20204160 TI - Nucleophilic cationization reagents. AB - Nucleophilic cationization reagents fitted with aminooxy groups are described. Practical syntheses of mono- and bis-aminooxy tetraalkylammonium iodides including N-hydroxyethyl-functionalized analogs are reported. An oximation example using one of the reagents is presented to illustrate their use in synthesis of cationic materials. PMID- 20204159 TI - PAI-1 Regulates the Invasive Phenotype in Human Cutaneous Squamous Cell Carcinoma. AB - The emergence of highly aggressive subtypes of human cutaneous squamous cell carcinoma (SCC) often reflects increased autocrine/paracrine TGF-beta synthesis and epidermal growth factor receptor (EGFR) amplification. Cooperative TGF beta/EGFR signaling promotes cell migration and induces expression of both proteases and protease inhibitors that regulate stromal remodeling resulting in the acquisition of an invasive phenotype. In one physiologically relevant model of human cutaneous SCC progression, TGF-beta1+EGF stimulation increases the production of several matrix metalloproteinases (MMPs), among the most prominent of which is MMP-10-an MMP known to be elevated in SCC in situ. Activation of stromal plasminogen appears to be critical in triggering downstream MMP activity. Paradoxically, PAI-1, the major physiological inhibitor of plasmin generation, is also upregulated under these conditions and is an early event in progression of incipient epidermal SCC. One testable hypothesis proposes that TGF-beta1+EGF dependent MMP-10 elevation directs focalized matrix remodeling events that promote epithelial cell plasticity and tissue invasion. Increased PAI-1 expression serves to temporally and spatially modulate plasmin-initiated pericellular proteolysis, further facilitating epithelial invasive potential. Defining the complex signaling and transcriptional mechanisms that maintain this delicate balance is critical to developing targeted therapeutics for the treatment of human cutaneous malignancies. PMID- 20204161 TI - How To Travel the World Without Jet lag. PMID- 20204162 TI - A Fluorescent Hydrogen Peroxide Probe Based on a 'Click' Modified Coumarin Fluorophore. AB - Herein a water-soluble 'click' modified coumarin-based fluorescent probe for hydrogen peroxide is reported. This probe shows significant intensity increases (up to 5 fold) in near-green fluorescence upon reaction with hydrogen peroxide, and good selectivity over other reactive oxygen species. PMID- 20204163 TI - Child Welfare Workers' Connectivity to Resources and Youth's Receipt of Services. AB - Youth involved in the child welfare system are at high risk for mental illness, substance abuse, and other behavioral health issues, which child welfare workers are expected to address through referrals. Child welfare workers (N=27) who participated in Project IMPROVE (Intervention for Multisector Provider Enhancement) reported on services they provided to youth (N=307) in their caseloads. Using survey and administrative data, this paper examines workers' service actions on behalf of youth. Results were consistent with the Gateway Provider Model and showed that youth received help from a greater variety of service sectors when their workers were able to identify behavioral health problems, and were familiar with and connected to other providers in the community. Improving service delivery to youth in child welfare may be accomplished by training workers in the signs and symptoms of behavioral health problems and familiarizing them with providers in the community. PMID- 20204164 TI - Brain-Computer Interfaces for Speech Communication. AB - This paper briefly reviews current silent speech methodologies for normal and disabled individuals. Current techniques utilizing electromyographic (EMG) recordings of vocal tract movements are useful for physically healthy individuals but fail for tetraplegic individuals who do not have accurate voluntary control over the speech articulators. Alternative methods utilizing EMG from other body parts (e.g., hand, arm, or facial muscles) or electroencephalography (EEG) can provide capable silent communication to severely paralyzed users, though current interfaces are extremely slow relative to normal conversation rates and require constant attention to a computer screen that provides visual feedback and/or cueing. We present a novel approach to the problem of silent speech via an intracortical microelectrode brain computer interface (BCI) to predict intended speech information directly from the activity of neurons involved in speech production. The predicted speech is synthesized and acoustically fed back to the user with a delay under 50 ms. We demonstrate that the Neurotrophic Electrode used in the BCI is capable of providing useful neural recordings for over 4 years, a necessary property for BCIs that need to remain viable over the lifespan of the user. Other design considerations include neural decoding techniques based on previous research involving BCIs for computer cursor or robotic arm control via prediction of intended movement kinematics from motor cortical signals in monkeys and humans. Initial results from a study of continuous speech production with instantaneous acoustic feedback show the BCI user was able to improve his control over an artificial speech synthesizer both within and across recording sessions. The success of this initial trial validates the potential of the intracortical microelectrode-based approach for providing a speech prosthesis that can allow much more rapid communication rates. PMID- 20204166 TI - Looking the Other Way: The Role of Gaze Direction in the Cross-race Memory Effect. AB - One of the most replicable findings reported in the social psychological literature is the cross-race memory effect. We argue this effect derives from higher-order interactions among social cues that determine the perceived relevance of a face to an observer. The current research tested this hypothesis by examining the combined influences of eye gaze direction and race on face memory. The physical subtlety of eye gaze belies its powerful influence on social perception, and in this case helps specify the relevance of same- versus other race faces. We found that only in faces making direct eye contact-not those displaying averted eye gaze-was the cross-race memory effect evident. Likewise, only in same-race faces did direct relative to averted gaze enhance face memory. These findings have implications for our general understanding of the combinatorial nature of social perception and help clarify the underlying cause of the cross-race memory effect. PMID- 20204167 TI - Bayesian Model Checking for Multivariate Outcome Data. AB - Bayesian models are increasingly used to analyze complex multivariate outcome data. However, diagnostics for such models have not been well-developed. We present a diagnostic method of evaluating the fit of Bayesian models for multivariate data based on posterior predictive model checking (PPMC), a technique in which observed data are compared to replicated data generated from model predictions. Most previous work on PPMC has focused on the use of test quantities that are scalar summaries of the data and parameters. However, scalar summaries are unlikely to capture the rich features of multivariate data. We introduce the use of dissimilarity measures for checking Bayesian models for multivariate outcome data. This method has the advantage of checking the fit of the model to the complete data vectors or vector summaries with reduced dimension, providing a comprehensive picture of model fit. An application with longitudinal binary data illustrates the methods. PMID- 20204165 TI - Diabetes is a proinflammatory state: a translational perspective. AB - The diabetic state confers an increased propensity to accelerated atherogenesis. Inflammation is pivotal in atherosclerosis; in addition to the established risk factors, inflammation appears to play a pivotal role in diabetes and its complications. Evidence for increased inflammation includes: increased levels of plasma C-reactive protein, the prototypic marker of inflammation; increased levels of plasminogen-activator inhibitor; increased monocyte superoxide and proinflammatory cytokine release (IL-1, IL-6 and TNF-alpha); increased monocyte adhesion to endothelium; increased NF-kappaB activity; and increased Toll-like receptor 2 and 4 expression and activity in diabetes. Thus, it appears that both Type 1 and Type 2 diabetes are proinflammatory states and that these could contribute to increased diabetic vasculopathies. PMID- 20204168 TI - Synthesis, magnetic characterization and sensing applications of novel dextran coated iron oxide nanorods. AB - Monodisperse, water-soluble dextran-coated iron oxide (Fe(3)O(4)) nanorods were synthesized using a facile and scalable approach. Our room temperature method involves the mixing of an acidic solution of iron salts with a basic solution of ammonium hydroxide to facilitate initial formation of iron oxide crystals. The stability, crystalinity and shape of these nanorods depends on the time of addition of the dextran, as well as the degree of purity of the polymer. The as synthesized nanorods exhibit unique magnetic properties, including superparamagnetic behavior and high spin-spin water relaxivity (R2). Additionally, they possess enhanced peroxidase activity when compared to those reported in the literature for spherical iron oxide nanoparticles. Thus, this high yield synthetic method for polymer-coated iron oxide nanorods will expedite their use in applications from magnetic sensors, devices and nanocomposites with magnetic and catalytic properties. PMID- 20204169 TI - "Teacher Effects" in Early Literacy Development: Evidence from a Study of Twins. AB - It is often assumed that differences in teacher characteristics are a major source of variability in children's educational achievements. We examine this assumption for early literacy achievement by calculating the correlations between pairs of twin children who either share or do not share a teacher in kindergarten, Grade 1, and Grade 2. Teacher effects, or more strictly classroom effects, would show up as higher correlations for same- than different-class twin pairs. Same-class correlations were generally higher than different-class correlations, though not significantly so on most occasions. On the basis of the results we estimate that the maximum variance accounted for by being assigned to same or different classrooms is 8%. This is an upper-bound figure for a teacher effect because factors other than teachers may contribute to variation attributable to classroom assignment. We discuss the limitations of the study and draw out some of its educational implications. PMID- 20204170 TI - Modifiable determinants of youth violence in Australia and the United States: A longitudinal study. AB - Youth violence is a global problem. The major research into youth violence has been conducted in the United States (U.S.) and there has been little research to investigate whether the prevalence or predictors are similar in comparable Western countries like Australia. In the current paper, analyses are conducted using two waves of data collected as part of a cross-national longitudinal study of adolescent development in approximately 4000 students aged 12 to 16 years in Victoria, Australia and Washington State, U.S.. Students completed a self-report survey of problem behaviours including violent behaviour, as well as risk and protective factors across five domains (individual, family, peer, school, community).Compared to Washington State, rates of attacking or beating another over the past 12-months were lower in Victoria for females in the first survey and higher for Victorian males in the follow-up survey. Preliminary analyses did not show state-specific predictors of violent behaviour. Therefore, the final multivariate model included the combined Washington State and Victorian samples. In the multivariate model, protective factors were being female and student emotion control. Risk factors were prior violent behaviour, family conflict, association with violent peers, community disorganisation, community norms favourable to drug use, school suspensions, and arrests. A major implication of these findings is that the range of factors that influence violent behaviour in North America may also apply in Australia. Hence, the application of U.S. early intervention and prevention programs may be warranted, with some tailoring to the Australian context. PMID- 20204173 TI - A semantic model to study neural organization of language in bilingualism. AB - A neural network model of object semantic representation is used to simulate learning of new words from a foreign language. The network consists of feature areas, devoted to description of object properties, and a lexical area, devoted to words representation. Neurons in the feature areas are implemented as Wilson Cowan oscillators, to allow segmentation of different simultaneous objects via gamma-band synchronization. Excitatory synapses among neurons in the feature and lexical areas are learned, during a training phase, via a Hebbian rule. In this work, we first assume that some words in the first language (L1) and the corresponding object representations are initially learned during a preliminary training phase. Subsequently, second-language (L2) words are learned by simultaneously presenting the new word together with the L1 one. A competitive mechanism between the two words is also implemented by the use of inhibitory interneurons. Simulations show that, after a weak training, the L2 word allows retrieval of the object properties but requires engagement of the first language. Conversely, after a prolonged training, the L2 word becomes able to retrieve object per se. In this case, a conflict between words can occur, requiring a higher-level decision mechanism. PMID- 20204174 TI - Molecular Characterization of the Tumor Suppressor Candidate 5 Gene: Regulation by PPARgamma and Identification of TUSC5 Coding Variants in Lean and Obese Humans. AB - Tumor suppressor candidate 5 (TUSC5) is a gene expressed abundantly in white adipose tissue (WAT), brown adipose tissue (BAT), and peripheral afferent neurons. Strong adipocyte expression and increased expression following peroxisome proliferator activated receptor gamma (PPARgamma) agonist treatment of 3T3-L1 adipocytes suggested a role for Tusc5 in fat cell proliferation and/or metabolism. However, the regulation of Tusc5 in WAT and its potential association with obesity phenotypes remain unclear. We tested the hypothesis that the TUSC5 gene is a bona fide PPARgamma target and evaluated whether its WAT expression or single-nucleotide polymorphisms (SNPs) in the TUSC5 coding region are associated with human obesity. Induction of Tusc5 mRNA levels in 3T3-L1 adipocytes by troglitazone and GW1929 followed a dose-response consistent with these agents' binding affinities for PPARgamma. Chromatin immunoprecipitation (ChIP) experiments confirmed that PPARgamma protein binds a approximately -1.1 kb promotor sequence of murine TUSC5 transiently during 3T3-L1 adipogenesis, concurrent with histone H3 acetylation. No change in Tusc5 mRNA or protein levels was evident in type 2 diabetic patients treated with pioglitazone. Tusc5 expression was not induced appreciably in liver preparations overexpressing PPARs, suggesting that tissue-specific factors regulate PPARgamma responsiveness of the TUSC5 gene. Finally, we observed no differences in Tusc5 WAT expression or prevalence of coding region SNPs in lean versus obese human subjects. These studies firmly establish the murine TUSC5 gene locus as a PPARgamma target, but the significance of Tusc5 in obesity phenotypes or in the pharmacologic actions of PPARgamma agonists in humans remains equivocal. PMID- 20204171 TI - Regulation of gene expression in protozoa parasites. AB - Infections with protozoa parasites are associated with high burdens of morbidity and mortality across the developing world. Despite extensive efforts to control the transmission of these parasites, the spread of populations resistant to drugs and the lack of effective vaccines against them contribute to their persistence as major public health problems. Parasites should perform a strict control on the expression of genes involved in their pathogenicity, differentiation, immune evasion, or drug resistance, and the comprehension of the mechanisms implicated in that control could help to develop novel therapeutic strategies. However, until now these mechanisms are poorly understood in protozoa. Recent investigations into gene expression in protozoa parasites suggest that they possess many of the canonical machineries employed by higher eukaryotes for the control of gene expression at transcriptional, posttranscriptional, and epigenetic levels, but they also contain exclusive mechanisms. Here, we review the current understanding about the regulation of gene expression in Plasmodium sp., Trypanosomatids, Entamoeba histolytica and Trichomonas vaginalis. PMID- 20204172 TI - Pro-inflammatory cytokine-mediated anemia: regarding molecular mechanisms of erythropoiesis. AB - Anemia of cancer and chronic inflammatory diseases is a frequent complication affecting quality of life. For cancer patients it represents a particularly bad prognostic. Low level of erythropoietin is considered as one of the causes of anemia in these pathologies. The deficiency in erythropoietin production results from pro-inflammatory cytokines effect. However, few data is available concerning molecular mechanisms involved in cytokine-mediated anemia. Some recent publications have demonstrated the direct effect of pro-inflammatory cytokines on cell differentiation towards erythroid pathway, without erythropoietin defect. This suggested that pro-inflammatory cytokine-mediated signaling pathways affect erythropoietin activity. They could interfere with erythropoietin-mediated signaling pathways, inducing early apoptosis and perturbing the expression and regulation of specific transcription factors involved in the control of erythroid differentiation. In this review we summarize the effect of tumor necrosis factor (TNF)alpha, TNF-related apoptosis-inducing ligand (TRAIL), and interferon (IFN) gamma on erythropoiesis with a particular interest for molecular feature. PMID- 20204175 TI - Necrotizing lymphocytic vasculitis limited to the peripheral nerves: report of six cases and review. AB - Background. The systemic vasculitides are syndromes characterized by inflammation and injury (necrosis or thrombosis) of blood vessels, resulting in clinical manifestations according to the affected vascular bed, but not classically in stocking-glove neuropathy. Objective. To describe a form of primary vasculitis affecting strictly peripheral nerves manifesting as stocking-glove neuropathy. Methods. Case series of 110 patients seen in three centers in Bogota who presented with symptoms and signs of polyneuropathy and/or were identified with vasculitis affecting only the peripheral nerves, and who underwent sural nerve biopsy. Results. Six patients had a vasculitis affecting only the peripheral nerves diagnosed on sural nerve biopsy which demonstrated a mixed infiltrate of monocytes/macrophages and lymphocytes especially in the small epineurial blood vessels. Over time, all had worsening of symptoms, with grip weakness and motor deficits in the hand and feet. Serologies and acute phase reactants were normal in all patients. Treatment response to immunosuppression was satisfactory in 5 patients; 1 patient had progressive neurologic damage. Conclusions. There is a distinct form of primary vasculitis of the peripheral nervous system characterized by distal sensory polyneuropathy with stocking-glove distribution with good prognosis, few and minor relapses and good response to treatment even after delayed diagnosis. PMID- 20204176 TI - Immune modulation by Schistosoma mansoni antigens in NOD mice: effects on both innate and adaptive immune systems. AB - We have shown that Schistosoma mansoni egg soluble antigen (SEA) prevents diabetes in the nonobese diabetic (NOD) mouse inducing functional changes in antigen presenting cells (APCs) and expanding T helper (Th) 2 and regulatory T cell (Treg) responses. A Th2 response to S. mansoni infection or its antigens is key to both the establishment of tolerance and successfully reproduction in the host. More recently we demonstrated that SEA treatment upregulates bioactive TGFbeta on T cells with consequent expansion of Foxp3+ Tregs, and these cells might be important in SEA-mediated diabetes prevention together with Th2 cells. In this study we profile further the phenotypic changes that SEA induces on APCs, with particular attention to cytokine expression and markers of macrophage alternative activation. Our studies suggest that TGFbeta from T cells is important not just for Treg expansion but also for the successful Th2 response to SEA, and therefore, for diabetes prevention in the NOD mouse. PMID- 20204177 TI - Use of a distal radius endoprosthesis following resection of a bone tumour: a case report. AB - Limited literature is available on the reconstruction of the distal radius using prosthetic replacement following resection of a bone tumour. We present the first reported case, in the English literature, of the use of an entirely metal endoprosthesis for the reconstruction of the distal radius. This case involves a 66-year-old male who was treated for giant cell tumour of the distal radius with surgical excision of the lesion and replacement of the defect using a predominantly titanium endoprosthesis. He was followed-up for 56 months following surgery and had a good functional outcome with no associated pain or complications. We propose that the use of a primarily titanium endoprosthesis for the reconstruction of a bone defect of the distal radius is a suitable alternative, providing good function of the forearm with satisfactory range of movement at the wrist and adequate pain relief. PMID- 20204178 TI - Comparison of the pharmacological effects of paricalcitol and doxercalciferol on the factors involved in mineral homeostasis. AB - Vitamin D receptor agonists (VDRAs) directly suppress parathyroid hormone (PTH) mRNA expression. Different VDRAs are known to have differential effects on serum calcium (Ca), which may also affect serum PTH levels since serum Ca regulates PTH secretion mediated by the Ca-sensing receptor (CaSR). In this study, we compared the effects of paricalcitol and doxercalciferol on regulating serum Ca and PTH, and also the expression of PTH, VDR, and CaSR mRNA. The 5/6 nephrectomized (NX) Sprague-Dawley rats on a normal or hyperphosphatemia-inducing diet were treated with vehicle, paricalcitol, or doxercalciferol for two weeks. Both drugs at the tested doses (0.042-0.33 mug/kg) suppressed PTH mRNA expression and serum PTH effectively in the 5/6 NX rats, but paricalcitol was less potent in raising serum Ca than doxercalciferol. In pig parathyroid cells, paricalcitol and the active form of doxercalciferol induced VDR translocation from the cytoplasm into the nucleus, suppressed PTH mRNA expression and inhibited cell proliferation in a similar manner, although paricalcitol induced the expression of CaSR mRNA more effectively. The multiple effects of VDRAs on modulating serum Ca, parathyroid cell proliferation, and the expression of CaSR and PTH mRNA reflect the complex involvement of the vitamin D axis in regulating the mineral homeostasis system. PMID- 20204179 TI - Mitral valve replacement and subaortic membrane resection following pneumonectomy. AB - The pulmonary status is a vital factor for patients undergoing open heart surgery. The cardiac surgery itself deteriorates the actual pulmonary functions. Today, patients are no longer living with a cardiac disease due to compromised respiratory functions secondary to various pathologies, patients with lung disorders more often seek solutions for their cardiac disease and they are commonly operated. However, the resection of a lobe or a whole lung is a major challenge for the patients planned for cardiac surgery. In this report, we present a 65-year-old patient, who had left pnemonectomy which had been performed 8 years ago and was admitted for mitral valve replacement and subaortic membrane resection. PMID- 20204180 TI - The Analysis of Multiple Genome Comparisons in Genus Escherichia and Its Application to the Discovery of Uncharacterised Metabolic Genes in Uropathogenic Escherichia coli CFT073. AB - A survey of a complete gene synteny comparison has been carried out between twenty fully sequenced strains from the genus Escherichia with the aim of finding yet uncharacterised genes implicated in the metabolism of uropathogenic strains of E. coli (UPEC). Several sets of adjacent colinear genes have been identified which are present in all four UPEC included in this study (CFT073, F11, UTI89, and 536), annotated with putative metabolic functions, but are not found in any other strains considered. An operon closely homologous to that encoding the L sorbose degradation pathway in Klebsiella pneumoniae has been identified in E. coli CFT073; this operon is present in all of the UPEC considered, but only in 7 of the other 16 strains. The operon's function has been confirmed by cloning the genes into E. coli DH5alpha and testing for growth on L-sorbose. The functional genomic approach combining in silico and in vitro work presented here can be used as a basis for the discovery of other uncharacterised genes contributing to bacterial survival in specific environments. PMID- 20204181 TI - Severe hyperkalemia and bilateral adrenal metastasis. AB - Adrenal metastases are a common finding in metastatic lung and breast cancer. Often there are no clinical symptoms suggesting them. In this paper, we present a case of a 66-year-old man with metastatic lung cancer suffering from severe hyperkaliemia due to hypoaldosteronism as a result of bilateral adrenal metastasis. PMID- 20204182 TI - Variations in the presentation of aphasia in patients with closed head injuries. AB - Impairments of speech and language are important consequences of head injury as they compromise interaction between the patient and others. A large spectrum of communication deficits can occur. There are few reports in the literature of aphasia following closed head injury despite the common presentation of closed head injury. Herein we report two cases of closed head injuries with differing forms of aphasia. We discuss their management and rehabilitation and present a detailed literature review on the topic. In a busy acute surgical unit one can dismiss aphasia following head injury as behaviour related to intoxication. Early recognition with prolonged and intensive speech and language rehabilitation therapy yields a favourable outcome as highlighted in our experience. These may serve as a reference for clinicians faced with this unusual outcome. PMID- 20204183 TI - Nanoscale Nonlinear dynamic characterization of the neuron-electrode junction. AB - Extracellular recordings from neurons using microelectrode and field effect transistor arrays suffer from many problems including low signal to noise ratio, signal attenuation due to counter-ion diffusion from the bulk extracellular medium and a modification of the shape of the cell-generated potentials due to the presence of a highly dispersive dielectric medium in the cell-electrode cleft. Attempts to date to study the neuron-electrode interface have focused on point or area contact linear-equivalent-circuit models. We present here the results obtained from a 'data-true' nonlinear dynamic characterization of the neuron-electrode junction using Volterra-Wiener modeling. For the characterization, NG108-15 cells were cultured on microelectrode arrays and stimulated with broadband Gaussian white noise under voltage clamp mode. A Volterra-Wiener model was then estimated using the input signal and the extracellular signal recorded on the microelectrode. The existence of the second order Wiener kernel confirmed that the recorded extracellular signal had a nonlinear component. The verification of the estimated model was carried out by employing the intracellular action potential as an input to the Volterra-Wiener model and comparing the predicted extracellular response with the corresponding extracellular signal recorded on the microelectrode. We believe that a 'data true' Volterra-Wiener model of the neuron-electrode junction shall not only facilitate a direct insight into the physicochemical processes taking place at the interface during signal transduction but will also allow one to evolve strategies for engineering the neuron-electrode interface using surface chemical modification of the microelectrodes. PMID- 20204184 TI - Acquired haemophilia a in the elderly: case reports. AB - Acquired hemophilia A (AHA) is a very rare disease, caused by the development of autoantibodies, directed against circulating factor VIII of coagulation. Age distribution is bimodal, with a first peak occurring among young women in the postpartum period, and a second major peak of incidence among elderly patients in whom it is frequently associated with malignancy and drugs. This disease often represents a life-threatening bleeding condition, especially in the elderly, thus requiring a prompt therapeutic intervention, including control of acute bleeding and eradication of the inhibitor by immunosuppressive therapy. The diagnosis of AHA should be considered in any elderly patient who presents with bleeding and prolonged activated Partial Thromboplastin Time. Moreover, the coexistence of a series of underlying diseases associated with AHA should be always searched for. An early recognition and an adequate treatment of this coagulation disorder and of the possible associated diseases play a significant role for a favourable outcome, but concomitant morbidities in the elderly may limit aggressive therapy and may complicate the clinical scenario. We report 3 consecutive elderly patients successfully treated with recombinant activated factor VII and standard immunosuppressive regimens, with remission of the disease. PMID- 20204185 TI - Vitamin d. PMID- 20204186 TI - Pathway-BasedFeature Selection Algorithm for Cancer Microarray Data. AB - Classification of cancers based on gene expressions produces better accuracy when compared to that of the clinical markers. Feature selection improves the accuracy of these classification algorithms by reducing the chance of overfitting that happens due to large number of features. We develop a new feature selection method called Biological Pathway-based Feature Selection (BPFS) for microarray data. Unlike most of the existing methods, our method integrates signaling and gene regulatory pathways with gene expression data to minimize the chance of overfitting of the method and to improve the test accuracy. Thus, BPFS selects a biologically meaningful feature set that is minimally redundant. Our experiments on published breast cancer datasets demonstrate that all of the top 20 genes found by our method are associated with cancer. Furthermore, the classification accuracy of our signature is up to 18% better than that of vant Veers 70 gene signature, and it is up to 8% better accuracy than the best published feature selection method, I-RELIEF. PMID- 20204191 TI - Synthesis of 3-substituted indoles via reactive alkylideneindolenine intermediates. AB - Elimination of suitable leaving groups from 3-substituted indoles under basic or acidic conditions readily provides alkylideneindolenine intermediates that may react with a large variety of nucleophilic reagents. This article highlights some recent developments of this synthetic approach for the preparation of functionalized indole derivatives. PMID- 20204192 TI - Synthesis of nucleoside 5'-O-alpha,beta-methylene-beta-triphosphates and evaluation of their potency towards inhibition of HIV-1 reverse transcriptase. AB - A polymer-bound alpha,beta-methylene-beta-triphosphitylating reagent was synthesized and subjected to reactions with unprotected nucleosides, followed by oxidation, deprotection of cyanoethoxy groups, and acidic cleavage to afford nucleoside 5'-O-alpha,beta-methylene-beta-triphosphates. Among all the compounds, cytidine 5'-O-alpha,beta-methylene-beta-triphosphate inhibited RNase H activity of HIV-1 reverse transcriptase with a K(i) value of 225 microM. PMID- 20204193 TI - Novel thiourea-amine bifunctional catalysts for asymmetric conjugate addition of ketones/aldehydes to nitroalkenes: rational structural combination for high catalytic efficiency. AB - A series of thiourea-amine bifunctional catalysts have been developed by a rational combination of prolines with cinchona alkaloids, which are connected by a thiourea motif. The catalyst 3a, prepared from L-proline and cinchonidine, was found to be a highly efficient catalyst for the conjugate addition of ketones/aldehydes to a wide range of nitroalkenes (up to 98/2 dr and 96% ee). The privileged cinchonidine backbone and the thiourea motif are essential to the reaction activity and enantioselectivity. PMID- 20204194 TI - Micro-scale process development of transaminase catalysed reactions. AB - A micro-scale technique has been developed for the process development of transaminase catalysed reactions. This pH indicator based, colorimetric assay can be used to investigate and optimise reaction conditions at 100 microL scale. Enzyme activity and stability as a function of various reaction parameters, including temperature, pH and co-solvent concentration, have been determined. Additionally, reactions have been scaled up from 100 microL to 25 mL under the optimal reaction conditions identified by the micro-scale process development activities. Excellent conversion (>99%) and enantioselectivity (>99% ee) were obtained. PMID- 20204195 TI - A flexible asymmetric synthesis of the tetracyclic core of berkelic acid using a Horner-Wadsworth-Emmons/oxa-Michael cascade. AB - The one-pot Horner-Wadsworth-Emmons/oxa-Michael cascade followed by spiroketalisation affords the tetracyclic benzannulated spiroketal core of berkelic acid, an extremophile natural product with selective activity against ovarian cancer. PMID- 20204196 TI - A concise synthesis of enantiopure circumdatins E, H and J. AB - A concise total synthesis of enantiopure circumdatins E, H and J has been developed using a reductive cyclization of chiral N-prolinoyl-2-nitrobenzamides to construct the core quinazolinone ring. PMID- 20204197 TI - An efficient synthesis of (+/-)-frondosin B using a Stille-Heck reaction sequence. AB - A concise, convergent synthesis of (+/-)-frondosin B has been developed based on the application of a Stille-Heck reaction sequence of 2-chloro-5 methoxybenzo[b]furan-3-yl triflate and 2-(3-butenyl)-3-(trimethylstannyl)cyclohex 2-enone giving the racemic natural product in a 34% overall yield. PMID- 20204190 TI - Synthesis and biological applications of collagen-model triple-helical peptides. AB - Triple-helical peptides (THPs) have been utilized as collagen models since the 1960s. The original focus for THP-based research was to unravel the structural determinants of collagen. In the last two decades, virtually all aspects of collagen structural biochemistry have been explored with THP models. More specifically, secondary amino acid analogs have been incorporated into THPs to more fully understand the forces that stabilize triple-helical structure. Heterotrimeric THPs have been utilized to better appreciate the contributions of chain sequence diversity on collagen function. The role of collagen as a cell signaling protein has been dissected using THPs that represent ligands for specific receptors. The mechanisms of collagenolysis have been investigated using THP substrates and inhibitors. Finally, THPs have been developed for biomaterial applications. These aspects of THP-based research are overviewed herein. PMID- 20204198 TI - Thiol-dependent DNA cleavage by aminomethylated Beaucage's reagent. AB - Aminomethylated Beaucage's reagent 1 was found to be more potent than 3H-1,2 benzodithiol-3-one 1,1-dioxide (Beaucage's reagent) in causing DNA cleavage. The current study demonstrated the importance of the amino functionality in enhancing DNA-cleaving activities, and such findings may facilitate development of novel sulfur-containing DNA-cleaving molecules in cancer therapy. PMID- 20204199 TI - Synthesis and fluorescence of the new environment-sensitive fluorophore 6-chloro 2,3-naphthalimide derivative. AB - Convenient and efficient synthesis of a new environmentally sensitive chlorine substituted 2,3-naphthalimide-based fluorophore is reported. Benzotriazole carboxyl group activation of the 6-chloro-fluorophore enabled quick labeling of free and Fmoc-protected amino acids. The photophysical properties of the compounds obtained include high quantum yields in solvents of different polarity: water, methanol, acetonitrile and hexane. PMID- 20204200 TI - Non-alpha-hydroxylated aldehydes with evolved transketolase enzymes. AB - Transketolase mutants previously identified for use with the non-phosphorylated aldehyde propanal have been explored with a series of linear and cyclic aliphatic aldehydes, and excellent stereoselectivities observed. PMID- 20204201 TI - A coumarin-thiourea conjugate as a fluorescent probe for Hg(II) in aqueous media with a broad pH range 2-12. AB - A coumarin-thiourea conjugate (1) behaves as a highly selective fluorescent probe for Hg(2+) in aqueous media. The probe 1 shows selective and quantitative fluorescence decrease upon Hg(2+) addition in aqueous media with a broad pH range, 2-12. Ab initio molecular orbital calculations reveal that the fluorescence decrease of 1 upon Hg(2+) addition is promoted by a Hg(2+)-induced desulfurization of the thiourea moiety, leading to a decrease in an intramolecular charge transfer (ICT) character of the excited-state coumarin moiety. PMID- 20204202 TI - Replacement of Ala by Aib improves structuration and biological stability in thymine-based alpha-nucleopeptides. AB - Three thymine-based nucleo-heptapeptides, each containing two nucleo-amino acids and zero, one or four Aib residues, respectively, have been synthesized. A single Aib residue is enough to promote the adoption of a helical structure in our nucleopeptides and to increase significantly their resistance towards enzymatic degradation. The insertion of four Aib residues, out of seven residues in the sequence, affords a rigid, 3(10)-helical nucleopeptide that is substantially unaffected by serum enzymes and is not cytotoxic. PMID- 20204203 TI - Stereochemistry of 10-sulfoxidation catalyzed by a soluble Delta9 desaturase. AB - The stereochemistry of castor stearoyl-ACP Delta(9) desaturase-mediated 10 sulfoxidation has been determined. This was accomplished by (19)F NMR analysis of a fluorine-tagged product, 18-fluoro-10-thiastearoyl ACP S-oxide, in combination with a chiral solvating agent, (R)-AMA. Sulfoxidation proceeds with the same stereoselectivity as hydrogen removal from the parent stearoyl substrate. These data validate the use of thia probes to determine the stereochemistry and cryptoregiochemistry of desaturase-mediated oxidations. PMID- 20204204 TI - Molecular recognition of N-protected dipeptides by pseudopeptidic macrocycles: a comparative study of the supramolecular complexes by ESI-MS and NMR. AB - The molecular recognition properties of pseudopeptidic macrocycles have been studied by ESI-MS and NMR spectroscopy, as highly complementary experimental techniques in solution and in the gas phase. We used ESI-MS competition experiments for the high throughput screening of the supramolecular interaction between four macrocyclic receptors and different peptide-like substrates in solution, rendering the best-fitted host-guest pairs. Further insights on the non covalent recognition process in the gas-phase were obtained through collision induced dissociation (CID) experiments. Solution studies using NMR spectroscopy ((1)H NMR titrations, NOESY and DOSY) were carried out to prove the validity of ESI-MS as a high-throughput screening method for studying the molecular recognition of the investigated pseudopeptidic macrocycles. A clear selectivity for N-protected dipeptides over N-protected amino acids, and a slight preference for dipeptides bearing aromatic side chains were observed. On the basis of the results obtained from this approach, a mode of binding has been proposed. PMID- 20204205 TI - One-electron oxidation of DNA: thymine versus guanine reactivity. AB - One-electron oxidation of anthraquinone (AQ)-linked DNA oligonucleotides containing A/T base pairs with repeating TT steps results in the distance dependent reaction of the resulting radical cation and base damage at the TT steps that is revealed by subsequent reaction as strand cleavage. However, the inclusion of a remote guanine or GG step inhibits the reaction at thymine and results in predominant reaction at the guanine bases. For the oligomers examined in this work, the results reveal that the specific sequence of nucleobases determines the distance dependence, location of reaction and the efficiency of radical cation migration. In particular, a sequence of A/T base pairs can behave either as a trap, shuttle or barrier, depending on the context of the entire oligomer. The A/T sequences act as a shuttle when reaction occurs at a remote G or GG step and the same sequence of A/T bases acts as a barrier when there is more than one GG step in the sequence. In contrast, the A/T steps act as a trap in sequences that lack guanines. PMID- 20204206 TI - Versatile chiroptics of peptide-induced assemblies of metalloporphyrins. AB - Zinc porphyrin functionalized with double long-chain alkylated L-glutamide (GTPP Zn) was synthesized for the first time, and its self-assembling behaviour was investigated in nonpolar organic solvents. The uniqueness of this functionalized porphyrin is characterized by its drastic colour change from dark green to purple via the formation of chirally stacked structures through selective axial coordination on zinc with pyridine derivatives. In this paper, we report the versatility of the GTPP-Zn assembly process as a stimuli-responsive chiroptical switching system and describe the remarkable ligand-specific induction of secondary chirality accompanied by aggregation morphological change. PMID- 20204207 TI - Exploring neoglycoprotein assembly through native chemical ligation using neoglycopeptide thioesters prepared via N-->S acyl transfer. AB - Sugars and simplified oligosaccharide "mimics" can be joined with protein fragments at pre-defined sites using reliable chemical reactions such as thiol alkylation and Cu(I) catalysed azide/acetylene ligation (click chemistry). These fragments have the potential to be assembled into neoglycoprotein therapeutics using native chemical ligation. PMID- 20204208 TI - A combined spin trapping/EPR/mass spectrometry approach to study the formation of a cyclic peroxide by dienolic precursor autoxidation. AB - The spontaneous addition of air oxygen to a dienolic compound, yielding a cyclic peroxide, was followed by spin trapping (ST) combined with EPR spectroscopy and mass spectrometry (MS). Using two different nitrones, the ST/EPR study allowed the detection of the spin adduct of a radical intermediate, and the radical centre in the addend was identified after similar experiments performed with two different (13)C-labelled analogues of the substrate. The media were also submitted to electrospray ionisation, in both positive and negative modes, for structural characterisation of the spin adducts by tandem mass spectrometry. This allowed the structure of the hydroxylamine derivatives of the nitroxides formed to be identified. Following these results, a mechanism pathway was proposed for this autoxidation. PMID- 20204209 TI - Direct asymmetric aldol reactions between aldehydes and ketones catalyzed by L tryptophan in the presence of water. AB - Primary amino acids and their derivatives were investigated as catalysts for the direct asymmetric aldol reactions between ketones and aldehydes in the presence of water, and L-tryptophan was shown to be the best catalyst. Solvent effects, substrate scope and the influence of water on the reactions were investigated. Quantum chemical calculations were performed to understand the origin of the observed stereoselectivity. PMID- 20204210 TI - A base-promoted desalicyloylative dimerization of 3-(1-alkynyl)chromones: an unusual approach to 2-alkynyl xanthones. AB - A novel base-promoted cascade desalicyloylative dimerization of 3-(1 alkynyl)chromones to produce 2-alkynyl xanthones has been developed. This tandem process involves multiple reactions, such as Michael additions/cyclizations/desalicyloylation without a transition metal catalyst and inert atmosphere. PMID- 20204211 TI - Towards identifying preferred interaction partners of fluorinated amino acids within the hydrophobic environment of a dimeric coiled coil peptide. AB - Phage display technology has been applied to screen for preferred interaction partners of fluoroalkyl-substituted amino acids from the pool of the 20 canonical amino acids. A parallel, heterodimeric alpha-helical coiled coil was designed such that one peptide strand contained one of three different fluorinated amino acids within the hydrophobic core. The direct interaction partners within the second strand of the dimer were randomized and coiled coil pairing selectivity was used as a parameter to screen for the best binding partners within the peptide library. It was found that despite their different structures, polarities and fluorine contents, the three non-natural amino acids used in this study prefer the same interaction partners as the canonical, hydrophobic amino acids. The same technology can be used to study any kind of non-canonical amino acids. The emerging results will provide the basis not only for a profound understanding of the properties of these building blocks, but also for the de novo design of proteins with superior properties and new functions. PMID- 20204212 TI - Organic co-solvents in aqueous DNA-based asymmetric catalysis. AB - Water-miscible organic co-solvents can be used in DNA-based catalytic asymmetric reactions at appreciable concentration without a negative effect on enantioselectivity. While the rate of the copper(II) Diels-Alder reaction is affected negatively by the presence of organic co-solvents, the copper(II) catalyzed Michael addition and Friedel-Crafts alkylation reaction are significantly faster. Additionally, the presence of organic co-solvents allows for reaction temperatures <0 degrees C, which results in higher ee's. This is used to perform enantioselective Michael additions and Friedel-Crafts alkylations at gram scale, using catalyst loadings as low as 0.75 mol%. These results are an important step towards application of the DNA-based catalysis concept in organic synthesis. PMID- 20204213 TI - Kinetics and regioselectivity in the Diels-Alder reaction of fulleroids vs. methanofullerene and C60. AB - Fulleroids, obtained from the 1,3-dipolar cycloaddition of fullerene with a diazoalkane, have a [5,6]-open methylene bridge and two highly twisted bridgehead double bonds. The [H,H]- and [H,CN]-substituted fulleroids were found to display significantly enhanced and regioselective Diels-Alder addition as compared with the [6,6] closed methanofullerene and C(60) with 2,3-dimethyl-1,3-butadiene, but reduced and nonregioselective addition with cyclopentadiene. NMR analysis of the 1:1 adduct and quantum calculations indicated that the high reactivity and the regioselective addition are due to pi-orbital misalignment at the bridgehead double bond. PMID- 20204214 TI - Bronsted acid-catalyzed efficient Strecker reaction of ketones, amines and trimethylsilyl cyanide. AB - A general method for the one-pot, three-component Strecker reaction of ketones was developed using Bronsted acids as organocatalysts. A series of alpha aminonitriles were obtained in good to excellent yields (79-99%). A preliminary extension to a catalytic enantioselective three-component Strecker reaction of ketones (up to 40% ee) is also described. PMID- 20204215 TI - Functionalized alkoxy arene diazonium salts from paracetamol. AB - Arene diazonium tetrafluoroborates can be synthesized from aromatic acetamides via a sequence of deacetylation, diazotation and precipitation, induced by anion exchange. The reaction is conducted as a convenient one-flask transformation with consecutive addition of the appropriate reagents. Exchange of solvents or removal of byproducts prior to isolation of the product is not required. The arene diazonium salts are isolated from the reaction mixture by simple filtration. Two complementary protocols are presented, and the utility of the reaction is exemplified for a synthesis of the diarylheptanoid natural product de-O-methyl centrolobine. PMID- 20204216 TI - Chemoenzymatic synthesis of the carbasugars carba-beta-L-galactopyranose, carba beta-L-talopyranose and carba-alpha-L-talopyranose from methyl benzoate. AB - The cis-dihydrodiol metabolite from methyl benzoate has been used as a synthetic precursor of carba-beta-L-galactopyranose, carba-beta-L-talopyranose and carba alpha-L-talopyranose. The structures and absolute configurations of these carbasugars were determined by a combination of NMR spectroscopy, stereochemical correlation and X-ray crystallography. PMID- 20204217 TI - CO2-induced amidobromination of olefins with bromamine-T. AB - The carbon dioxide (CO(2))-induced amidobromination of olefins with bromamine-T is described. The method can be used in reactions with a wide range of olefins, both aromatic and aliphatic, as well as electron-rich and deficient olefins, leading to the regioselective formation of amidobrominated compounds. PMID- 20204218 TI - Biocatalysed concurrent production of enantioenriched compounds through parallel interconnected kinetic asymmetric transformations. AB - Parallel interconnected kinetic asymmetric transformations were performed in order to obtain enantioenriched derivatives starting from a set of racemic or prochiral compounds. Thus, in a one-pot reaction using two redox biocatalysts (a BVMO and an ADH) and a catalytic amount of cofactor that acts as a mediator, enantioenriched ketones, sulfoxides, and sec-alcohols were concurrently obtained in a strict parallel way, minimising the quantity of reagents employed. By selecting the appropriate biocatalysts, this methodology represents a potential tool for performing stereodivergent transformations. PMID- 20204219 TI - Drug discovery: phosphinolactone, in vivo bioisostere of the lactol group. AB - In drug discovery, structural modifications over the lead molecule are often crucial for the development of a drug. Herein, we reported the first in vivo bioisosteric effect of phosphinolactone function in relation to the lactol group constituting the bioactive molecule: Hydroxybupropion. The preparation of phosphinolactone analogues and their antidepressant evaluation towards forced swimming test in mice showed that biological activity was regained and even strengthen. PMID- 20204220 TI - Synthesis and O-phosphorylation of 3,3,4,4-tetrafluoroaryl-C-nucleoside analogues. AB - Enantioenriched tetrafluorinated aryl-C-nucleosides were synthesised in four steps from 1-benzyloxy-4-bromo-3,3,4,4-tetrafluorobutan-2-ol. The presence of the tetrafluorinated ethylene group is compatible with O-phosphorylation of the primary alcohol, as demonstrated by the successful preparation of the tetrafluorinated naphthyl-C-nucleotide. PMID- 20204221 TI - Hydrogen bonding properties of non-polar solvents. AB - A combination of high-throughput NMR titration experiments, UV-Vis absorption titrations and data collected from the literature on 1:1 H-bonded complexes has been used to characterise the H-bond properties of non-polar organic solvents: alkanes, perfluorocarbons, aromatic and halogenated organic solvents. The results are analysed in the context of the electrostatic solvent competition model, which assumes that solvent effects on intermolecular interactions can be interpreted based on the exchange of specific functional group contacts, with minimal involvement of the bulk solvent. For solvents where the H-bond parameters have been measured as solutes in carbon tetrachloride solution, the H-bond parameters measured here for the same compounds as solvents are practically identical, i.e. solute and solvent H-bond parameters are directly interchangable. For the very non-polar solvents, alkanes and perfluorocarbons, the experimental H-bond parameters are significantly larger than expected based on calculated molecular electrostatic potential surfaces. This suggests an increase in the relative importance of van der Waals interactions when electrostatic effects are weak, but there is no detectable difference between the solvation properties of cyclic and linear alkanes, which have different van der Waals interaction properties. PMID- 20204222 TI - Reverse-direction (5'-->3') synthesis of oligonucleotides containing a 3'-S phosphorothiolate linkage and 3'-terminal 3'-thionucleosides. AB - The synthesis of oligodeoxynucleotides containing 3'-thionucleosides has been explored using a reverse-direction (5'-->3') approach, based on nucleoside monomers which contain a trityl- or dimethoxytrityl-protected 3'-thiol and a 5'-O phosphoramidite. These monomers are relatively simple to prepare as trityl-based protecting groups were introduced selectively at a 3'-thiol in preference to a 5' hydroxyl group. As an alternative approach, trityl group migration could be induced from the 5'-oxygen to the 3'-thiol function. 5'-->3' Synthesis of oligonucleotides gave relatively poor yields for the internal incorporation of 3' thionucleosides [to give a 3'-S-phosphorothiolate (3'-SP) linkage] and multiple 3'-SP modifications could not be introduced by this method. However, the reverse direction approach provided an efficient route to oligonucleotides terminating with a 3'-thionucleoside. The direct synthesis of these thio-terminating oligomers has not previously been reported and the methods described are applicable to 2'-deoxy-3'-thionucleosides derived from thymine, cytosine and adenine. PMID- 20204223 TI - New family of polyamine macrocycles containing 2,5-diphenyl[1,3,4]oxadiazole as a signaling unit. Synthesis, acid-base and spectrophotometric properties. AB - Synthesis and acid-base properties for three fluorescent polyamine macrocycles 9,12,15,24,25-pentaaza-26-oxatetracyclo[21.2.1.0(2,7).0(17,22)]hexaicosa 2,4,6,17,19,21,23,25(1)-octaene (L1), 9,12,15,18,27,28-hexaaza-29 oxatetracyclo[24.2.1.0(2,7).0(20,25)]enneicosa-2,4,6,20,22,24,26,28(1)-octaene (L2) and 9,12,15,18,21,30,31-heptaaza-32 oxatetracyclo[27.2.1.0(2,7).0(23,28)]diatriconta-2,4,6,23,25,27,29,31(1)-octaene (L3) are reported. Each ligand contains the 2,5-diphenyl[1,3,4]oxadiazole (PPD) unit incorporated in the polyamine macrocycle. The protonation constants of L1-L3 were determined by means of potentiometric measurements in 0.15 mol dm(-3) NaCl aqueous solution at 298.1 K. All the ligands are highly fluorescent in aqueous solution under acidic conditions (pH < 2) and their emission drastically decreases when the pH is increased. At pH > 8, a total quenching of fluorescence is observable in all the ligands. The fluorescence is given by the PPD unit, while the behavior as a function of pH can be rationalized on the basis of photoinduced intramolecular electron transfer (PET) from the HOMO of the donor macrocycle nitrogen atoms to the excited fluorophore unit. The insertion of PPD in a polyamine skeleton strongly improves the fluorescence quantum yield of this class of ligands with respect to those already known. PMID- 20204225 TI - [Gollop-Wolfgang complex and cloacal exstrophy, a strange association]. AB - Cloacal exstrophy and Gollop-Wolfgang complex are very rare pathologies and their association has been reported in only one patient. We present a case of a newborn of indeterminate sex with anomalies of the lower limbs, and an anterior abdominal wall defect. External genitalia were not observed, ectrodactyly of lower limbs, omphalocele, lipomeningocele and imperforate anus were detected. During the diagnostic and therapeutic surgery other anomalies were found, such as vesical exstrophy, cecal fistula, uterine duplication, vaginal agenesis, urethral agenesis, ectopic ureters, stenosis of the left ureter, biphid clitoris and patent urachus. The abdominal ecography showed ectopic right lower quadrant localization of right kidney. Radiographic images of lower limbs showed bifurcation of left femur and absent tibia in both limbs. Due to the findings a diagnosis of cloacal exstrophy and Gollop- Wolfgang complex was made. The patient developed sepsis, liver failure, metabolic acidosis and hyponatremia, she died at seven weeks of age. PMID- 20204226 TI - [The importance of a law on time: presentation of a girl with biotinidase deficiency who was not picked up through the neonatal screening]. AB - In August 2008, the province of Buenos Aires had not adhered to the National law number 26279, that establishes the obligatory nature of the neonatal screening for biotinidase deficiency, among other diseases. In that date, a girl was born in Buenos Aires. She was admitted in the Hospital "J. P. Garrahan" with lethargy, metabolic acidosis, hiperlactacidemia, alopecia, conjuntivitis and scaly erythematous eruption in trunk, at 58 days of life, from a pediatric intensive care unit. Due to this clinic (13 days of evolution), a biotinidase assay in serum was done. This was abnormally low. She initiates treatment with biotin and the biochemical abnormalities revert quickly. If the neonatal screening had been done, this girl wouldn't have been exposed at risk of death, and a normal development would have been assure (by the presymptomatic beginning of the treatment), since the neurological injuries not always go back ad integrum. PMID- 20204227 TI - [Rectal prolapse in a neonate with Shigella diarrhea]. AB - A case of neonatal rectal prolapse during Shigella diarrhea is described. A 10 days neonate exclusively breast fed, whose 2 years old brother has had the same process 2 weeks ago. Medical treatment with intravenous ceftriaxone resolved rectal prolapse in 48 hours. Stool cultures showed the presence of Shigella flexneri II resistant to amoxicillin; blood and cerebrospinal fluid, cultures were negative. CONCLUSION: Rectal prolapse is an uncommon complication seen in infants with Shigella diarrhea. It has been described in older children, but never before in neonates. PMID- 20204228 TI - [Dysplasia epiphysealis hemimelica (Trevor's disease)]. AB - Dysplasia epiphysealis hemimelica is a rare skeletal developmental disorder characterized by asymmetric overgrowth of cartilage in the epiphyses. Due to the unusual and variable clinical picture, there is no standardized treatment and evolution is variable. We report the case of an 8 year-old boy, who was referred for the gradual appearance of a mass in the anterior region of the right knee. Plain films matched with dysplasia epiphysealis hemimelica. The histological findings confirmed the diagnosis. Treatment of dysplasia epiphysealis hemimelica is not clearly defined in the literature. However, only surgically symptomatic lesions or those that interfere with the function should be treated. Prognosis is variable and depends on the location and size of the lesion. Due to the risk of recurrence, patients with this unusual dysplasia should be monitored on a regular basis. PMID- 20204229 TI - [Neonate with linear rows of vesiculobullous lesions]. AB - We report the case of an 8-days-old patient with linear rows of vesiculobullous lesions from birth. Along with these lesions, the neonate had eosinophilia, which made us arrive to the clinical diagnosis of Incontinentia Pigmenti. Incontinentia Pigmenti or Bloch Sulzberger disease is a multisystemic neuroectodermal disorder that affects mostly women, which includes as initial manifestation cutaneous lesions that evolve by outbreaks. Occasionally, it is associated with neurologic, ophthalmologic, and dental compromise. This must be considered as a differential diagnosis when a neonate presents vesiculobullous lesions. PMID- 20204230 TI - [CHARGE syndrome]. AB - The characteristic phenotype of CHARGE syndrome includes: coloboma, congenital heart defect, choanal atresia, retarded growth and development, genital abnormalities, ear anomalies with or without hearing loss, which give the name (an acronym) to this condition. The molecular cause in 60% of the cases are mutations in the chromodomain helicase DNAbinding protein gene (CHD7), with an estimated frequency of 1 in 10,000 live born infants. We describe 3, not related patients with a clinical diagnosis of CHARGE syndrome and each of them with a different mutation in the CHD7 gene sequence. PMID- 20204231 TI - [Some changes in Archivos]. PMID- 20204232 TI - [Chagas disease, 100 years after its identification]. PMID- 20204233 TI - [Clinical prediction rules]. PMID- 20204234 TI - [Presence of early risk markers of metabolic syndrome in prepubertal children with a history of intrauterine growth restriction]. AB - INTRODUCTION: Studies on people with low birth weight found metabolic syndrome associated with intrauterine growth restriction (IUGR). OBJECTIVE: To study the presence of early risk markers of metabolic syndrome in a prepubertal population with IUGR. DESIGN: We studied 45 prepubertal children with a history of IUGR, without apparent disease, and 47 children in a control group. BMI, weight, height, and BMI Z score, and body fat mass were calculated. Basal glycemia, insulin, proinsulin, cortisol, serum lipids and uric acid levels were analyzed. Insulin sensitivity was calculated by QUICKI and insulin resistance by HOMA-IR. RESULTS: Basal insulin levels were higher in the IUGR group compared with the controls (6.6 microU/ml vs. 4.4 microU/ml; p= 0.008). Similar results were found for the basal cortisol levels (18.8 ug/dl vs. 13.1 ug/dl; p= 0.006) and uric acid (4.2 mg/dl vs. 2.7 mg/dl; p= 0.0008). QUICKI index was lower in the IUGR group (2.06 vs. 2.86, p= 0.001). The IUGR children who developed obesity presented higher levels of proinsulin (26.04 ug/dl vs. 13.3 ug/dl; p= 0.05), insulin (11 microU/ml vs. 5.5 microU/ml, p= 0.005), and HOMA-IR (2.06 vs. 0.9, p= 0.004), and lower QUICKI (1.71 vs. 2.16, p= 0.01) than in the case of the IUGR children with appropriate weight; these differences weren't observed among the control group. CONCLUSIONS: Children with IUGR, without apparent disease, showed metabolic changes that were expressed through risk markers of metabolic syndrome in childhood. PMID- 20204235 TI - [Cesarean delivery at term in low risk pregnancies: effects on neonatal morbidity]. AB - INTRODUCTION: The rate of cesarean delivery (CD) has significantly increased over the last years, even in low risk pregnancies. Our objective was to compare the neonatal morbidity rate in low risk term infants delivered by vaginal or CD. DESIGN: Prospective observational and analytical cohort study. Main outcome measures. Incidence of any neonatal morbidity and respiratory morbidity. Population and methods. Infants < or = 37 weeks born at the Hospital Italiano de Buenos Aires between December 2004 and July 2006 were eligible. Exclusion criteria included: any maternal related disorder, acute or chronic fetal distress, breech presentation in primiparous women, multiple pregnancies, intrauterine growth restriction and newborns with major malformations. RESULTS: A total of 2021 infants were included, 1120 born vaginally and 901 by CD. Main indications for CD were failure to progress labor (46%) and previous CD (37%). Only 3% of CD was performed by maternal request. Any neonatal morbidity rate was 9% in infants born by CD and 6.6% in infants born vaginally (RR 1.36; 95%CI 1.01 1.8). Respiratory morbidity rate was 5.3% in infants born by CD and 3.1% in those born vaginally (RR 1.7; 95%CI 1.1-2.6). When stratified by gestational age, respiratory morbidity was higher only for infants < or =38 weeks (7.4% in CD vs. 2.1% in vaginal delivery; RR 3.5; 95%CI 1.5-8.1). Also, respiratory morbidity was higher in infants born < or =38 weeks by CD without labor vs. those with labor 10.5% and 3.9%, respectively (RR 1.35; 95%CI: 1.07-1.70). In a logistic regression analysis, CD and male sex were independently associated with higher respiratory morbidity. There were not significant differences in other morbidities. NICU admission was higher in infants born by CD (9.5% vs. 6.1%; RR 1.5; 95% CI: 1.1-2.1). Sixty-eight percent of the mothers from the CD group refereed having moderate to severe pain in the puerperium vs. 36% in the vaginal group (RR 1.9; 95% CI: 1.7-2.1). Exclusive breastfeeding at discharge was significantly lower in infants born by CD (90% vs. 96%; RR 0.94 95%CI 0.92-0.96). CONCLUSIONS: Low risk CD at term was associated with a higher neonatal morbidity, NICU admission and maternal pain in the puerperium. It also reduces exclusive breastfeeding rate at discharge. PMID- 20204236 TI - [Epidemiology of retinopathy of prematurity in public services from Argentina during 2008]. AB - INTRODUCTION: Increasing survival of preterm newborns and current care deficits result in high rates of retinopathy of prematurity (ROP), affecting patients with higher birth weight (BW) and gestational age (GA) than those at developed countries; unusual cases (UC) and missed opportunities (MO) are reported. OBJECTIVE: To describe epidemiology of ROP during 2008 compared with the previous year. POPULATION, MATERIAL AND METHOD: Observational, descriptive and retrospective study. POPULATION: Preterm babies with BW < 1,500 g and/or < or = 32 w GA and > or = 1,500 g and/or 33-36 w who received oxygen therapy. SOURCE: 31 public services from 20/24 Provinces. VARIABLES: BW, GA, ophthalmologic screening, age at 1st control, ROP Grade, treatment requirement, place of treatment and time of complete ROP screening. RESULTS: Responses were obtained from 24/31 services from 16 Provinces (84,200 newborns) identifying 3,371 newborns at risk, 956 < 1,500 g BW. Screening was done in 90%; it was late in 6%. Neonatal discharge before complete ROP screening occurred in 93%. ROP rate was 11.93%; 26.25% in < 1,500 g BW. Treatment was required at 2.60%; of them, 7% were < 1,500 g BW; 20.3% were UC, one infant was a MO. Treatment need increased 20% at 2008 vs. 2007, without significant difference. Changes were not observed at median BW and GA and UC. Treatment in situ was 75% in 2008, similar to 2007. CONCLUSIONS: Incidence of ROP in public hospitals of Argentina is worrisome. Rates in 2008 have not improved compared with 2007, expressing that criteria for prevention are not yet consolidated. Screening and access to treatment must improve. PMID- 20204237 TI - [Delivery room practices in infants born through meconium stained amniotic fluid: a national survey]. AB - Based on the results of two large RCTs, guidelines from NRP/AAP, ILCOR, ACOG, and from Argentinean scientific societies for intrapartum and postpartum management of pregnancies with Meconium Stained Amniotic Fluid (MSAF) have radically changed. However, there are no data as to current delivery room management of infants born through MSAF. OBJECTIVES: 1) To assess current delivery room approaches in infants born through MSAF in Argentina; 2) To evaluate the adherence to NRP/AAP recommendations among different centers. DESIGN/METHODS: A 20-question anonymous web-mail based survey was sent to 121 institutions with > or = 500 births a year. RESULTS: The response rate was 63% representing 182,540 deliveries/year (26% of the total number of births in the country). Among the surveyed institutions, 24% were located in the city of Buenos Aires and 72% were public hospitals. Although no longer recommended, the following procedures are frequently performed: 1) Oro-nasopharingeal suctioning of meconiumstained infants before the delivery of the shoulders: sometimes, 50% of centers; always, 7 %. 2) Routine tracheal suctioning in vigorous infants, 30%. 3) Glottis exposure under laryngoscopy, 13 % for thin-consistency MSAF and 43% for thick-consistency MSAF. On the contrary, and although strongly recommended, only 69% of depressed infants have tracheal suctioning before ventilation. Up to 7% of centers perform other non recommended procedures such as chest compression and pressure over the larynx, to avoid breathing, and gastric lavage. CONCLUSIONS: In spite of not being currently recommended, intrapartum suction and postnatal intubation and suction of vigorous infants with MSAF are commonly performed in Argentina while in depressed newborns the latter procedure is not always carried out. Our study confirms the frequent gaps observed between scientific evidence, guidelines and clinical practice. PMID- 20204238 TI - [Validation of a clinical prediction rule to distinguish bacterial from aseptic meningitis]. AB - INTRODUCTION: Despite most meningitis are not bacterial, antibiotics are usually administered on admission because bacterial meningitis is difficult to be rule out. Distinguishing bacterial from aseptic meningitis on admission could avoid inappropriate antibiotic use and hospitalization. We aimed to validate a clinical prediction rule to distinguish bacterial from aseptic meningitis in children, on arriving to the emergency room. METHODS: This prospective study included patients aged < 19 years with meningitis. Cerebrospinal fluid (CSF) and peripheral blood neutrophil count were obtained from all patients. The BMS (Bacterial Meningitis Score) described by Nigrovic (Pediatrics 2002; 110: 712), was calculated: positive CSF Gram stain= 2 points, CSF absolute neutrophil count > or = 1000 cells/mm(3), CSF protein > or = 80 mg/dl, peripheral blood absolute neutrophil count > or = 10.000/mm(3), seizure = 1 point each. Sensitivity (S), specificity (E), positive and negative predictive values (PPV and NPV), positive and negative likelihood ratios (PLR and NLR) of the BMS to predict bacterial meningitis were calculated. RESULTS: Seventy patients with meningitis were included (14 bacterial meningitis). When BMS was calculated, 25 patients showed a BMS= 0 points, 11 BMS= 1 point, and 34 BMS > or = 2 points. A BMS = 0 showed S: 100%, E: 44%, VPP: 31%, VPN: 100%, RVP: 1,81 RVN: 0. A BMS > or = 2 predicted bacterial meningitis with S: 100%, E: 64%, VPP: 41%, VPN: 100%, PLR: 2.8, NLR:0. CONCLUSIONS: Using BMS was simple, and allowed identifying children with very low risk of bacterial meningitis. It could be a useful tool to assist clinical decision making. PMID- 20204239 TI - [Eating habits, physical activity, smoking and alcohol consumption in adolescents attending school in the province of Buenos Aires]. AB - INTRODUCTION: Knowledge on dietary habits, tobacco and alcohol consumption in adolescents is crucial to plan early preventive programs. The objective was to assess the eating habits, physical activity and tobacco and alcohol consumption in adolescents of Buenos Aires, in order to get information on cardiovascular risk factors. MATERIAL AND METHODS: Cross-sectional observational study in adolescents aged 11-16 years of 12 urban and rural, public and private schools of the province of Buenos Aires. An anonymous survey was carried out including demographical data, eating habits, physical activity, smoking and alcohol consumption. RESULTS: 1230 adolescents were surveyed, 46% of rural zones. Of them, 42.5% restrained food intake to control weight; 92% performed physical activity at least 1 h a week; 29.3% were smokers and 38.4% drank alcoholic beverages. Females restrained more food intake (46.3% vs. 37.7%; p=0.003) and were heavier smokers (32.6% vs. 25.2%; p=0.005). Alcohol consumption and smoking were associated (OR 8.27; p<0.001). Having a smoker friend increased almost 4 times the chance of smoking. Alcohol consumption by the best friend (OR 10.0; p<0.001), father o brother also increased chance in the adolescent. Adolescents of rural zones performed less physical activity (89.6% vs. 94.2%; p=0.003) and smoked more cigarettes (32.1% vs. 26.8%; p=0.04). CONCLUSIONS: 42% restrained food intake to control weight, and almost all performed physical activity. Rates of smoking and alcohol consumption were 29.3% and 38.4%, and were strongly associated. Smoking was more common in females and in rural zones, and more associated to alcohol and a smoker friend. PMID- 20204240 TI - [Transfusional requirements for escharectomy in burned children]. AB - INTRODUCTION: Early excision has considerably improved outcome in extensive burns, but massive resections usually mean copious bleeding that must be conveniently corrected. The purpose of this study was to measure blood component use during escharectomies in children. MATERIAL AND METHODS: All pediatric patients with acute burns excised at the Burn Unit of the Hospital Garrahan during one year were included. Volume of blood component used during and immediately after surgery was analyzed and related to percent excised, time post burn, and the coexistence of infection and autograft at the time of excision. RESULTS: Ninety-four surgeries in 51 children aged 0-14 years with total burned body surface areas of 5-80% who underwent resections of 3-70% were studied. Total blood use (intra + post-operatively) was 2.07 ml/kg/%excised for red blood cells (60% during surgery) and 0.7 ml/kg/% excised for plasma. Only 12% of patients required platelet transfusion. There was no significant requirement variation with the existence of infection, grafting or time post-burn. CONCLUSIONS: Approximately 2 ml/kg/% excised of red blood cells (2/3 for surgery) and 1 ml/kg/% excised of plasma are needed for escharectomies in children. The need for platelets must be judged considering the individual patient. PMID- 20204241 TI - [Diagnostic criteria for fetal alcohol syndrome and fetal alcohol spectrum disorders]. AB - Prenatal ethanol exposure, in our professional practice, is an almost neglected condition as an important etiological factor for the induction of a wide spectrum of neuropsychiatric diseases that may appear during childhood, adolescence or adulthood. Children born to alcoholic mothers may show a profound mental retardation ranging to an apparent normality, and extending through epilepsy, attention deficit disorders with or without hyperactivity, autism and pervasive developmental disorders, and different types of learning disorders. When adolescents, they may develop different kinds of personality disorders and substance abuse disorders. Finally, in adulthood, they may suffer from different types of affective and psychotic disorders, among others. A great number of those children may not develop their full mental and social potentiality as free individuals. They usually have diverse types of cognitive, attentional, mnemonic and affective impairments. Not infrequently, they engage in antisocial behaviors or have school or work troubles. In this work, the present clinical classifications and diagnostic criteria for the disorders emerging from a prenatal ethanol exposure are reviewed in order to call attention to the medical pediatric and neuropsychiatric community about the increasingly, although underdiagnosed, frequency of these disorders in our country. PMID- 20204242 TI - [Blood pressure control and arterial hypertension in children and adolescents from a rural population in Argentina: preliminary data from Vela Proyect]. AB - Hypertension can start at an early age, however there are few data about blood pressure control in rural students in Argentina. Proyecto Vela is a survey about cardiovascular risk factors in the rural population of Maria Ignacia Vela, Argentina. We evaluated blood pressure levels, prevalence of arterial hypertension, sedentary lifestyle, overweight, and obesity in 331 children and adolescent students. In 70% of the subjects the blood pressure was measured for the first time. Prevalence of arterial hypertension was 4.3% in adolescents. Pre hypertension was detected in 1.9% and 1.7% of children and adolescents, respectively. The prevalence of smoking, sedentary lifestyle, overweight or obesity was 2.4%, 50% and 23.8% respectively. There was association (p <0.05) between hypertension and sedentary lifestyle. In our population the evaluation of blood pressure in adolescents is not a routine procedure. Prevalence of hypertension was low but these data show the importance of blood pressure controls and the need of official programs to modify sedentary lifestyle. PMID- 20204243 TI - [Antipoliomyelitic vaccination in children living in Buenos Aires City]. AB - Following the presentation of a confirmed case of paralytic polio Sabin-derived virus (VSD) in a child of 15 months we analyzed the coverage of poliomyelitis vaccination in children living in the City of Buenos Aires, in the 2006/2008 triennium. There was an improvement over the period analyzed, but values above 95% were reached only for the first dose. The proportion of inactivated vaccine (IPV) increased at the expense of live oral vaccine (OPV); in 2008, the first dose IPV coverage was 37.64% and 19.48% for the school entrance. The lack of intestinal immunity that occurs in children immunized with IPV, plus a poor coverage with OPV, allows the circulation of wild virus or VSD favoring the occurrence of paralytic poliomyelitis in unvaccinated or immunocompromised children. PMID- 20204244 TI - [Bordetella pertussis infection]. AB - Physiopathological, clinical, and epidemiological aspects of whooping cough, an acute highly contagious respiratory infection caused by Bordetella pertussis, are described. Different vaccination schedules are mentioned, since the vaccine was introduced, more than 40 years ago, until present; and the outbreaks occurred in Argentina during different periods. Moreover, the recrudescense of the disease observed in several countries during last years is highlighted, particularly in preschool children, and even more in adolescents, and young adults. PMID- 20204245 TI - [Subungueal exostosis]. PMID- 20204247 TI - [Addendum to the National Consensus on Allergic Rhinitis in children: incorporation of new concepts]. PMID- 20204249 TI - [Olive oil, immune system and infection]. AB - Polyunsaturated fatty acids contribute to the suppression of immune system functions. For this reason, n-3 polyunsaturated fatty acids have been applied in the resolution of inflammatory disorders. Although the inhibition of several immune functions promotes beneficial effects on the human health, this state may lead to a significant reduction of immune protection against infectious microorganisms (viruses, bacteria, fungi and parasites). Nevertheless, less attention has been paid to the action of olive oil in immunonutrition. Olive oil, a main constituent of the Mediterranean diet, is capable of modulating several immune functions, but it does not reduce host immune resistance to infectious microorganisms. Based on these criteria, we corroborate that olive oil administration may exert beneficial effects on the human health and especially on immune system, because it contributes to the reduction of typical inflammatory activity observed in patients suffering from autoimmune disorders, but without exacerbating the susceptibility to pathogen agents. The administration of olive oil in lipid emulsions may exert beneficial effects on the health and particularly on the immune system of immunocompromised patients. Therefore, this fact acquires a crucial importance in clinical nutrition. This review contributes to clarify the interaction between the administration of diets containing olive oil and immune system, as well as to determine the effect promoted by this essential component of Mediterranean diet in the immunomodulation against an infectious agent. PMID- 20204250 TI - Behavioural therapy in the treatment of obesity (II): role of the Mediterranean diet. AB - OBJECTIVES: Obesity is the consequence of an imbalance between energy intake and expenditure, food intake being affected by multiple factors -psychological, social, work-related, etc. This revision discusses the role of diet in the behavioural treatment (BT) of obesity, which faces multiple approaches and focuses on patients' behaviour rather than their mere energy intake. SETTING: Recent literature has been revised that deals with the health benefits of Mediterranean diet in order to assess its suitability for obesity treatment based on BT. RESULTS: BT helps patients to develop skills and techniques in order to adopt proper habits and attain their healthiest weight. Patients learn to establish realistic goals, both as regards weight and behaviour, and to evaluate their progress in modifying eating and exercising habits. The application of the Mediterranean diet in obesity treatment presents various advantages which are based on the principles of this diet -wide variety of food, high carbohydrate content, or high satiating capacity, which prevents specific hunger and ketogenesis-, and has been demonstrated to be effective in reducing body weight. CONCLUSIONS: BT based on the Mediterranean diet is a useful tool for obesity treatment. The Mediterranean diet provides the patients with a diet established on widely recognised nutritional benefits, suitable to their social and daily life, and that can be easily followed in the long term, according to the objectives of BT. For these reasons, Mediterranean diet-based BT helps to prolong both the treatment and maintenance periods and therefore contributes to a more stable weight loss. PMID- 20204251 TI - Use of carb counting in the dietary treatment of diabetes mellitus. AB - Currently, carb counting is a nutritional strategy that has allowed a greater adherence and dietary management of patients with diabetes mellitus, because it allows the consumption of a greater variety of foods. However, also requires greater adherence by the patient to maintain an adequate blood glucose monitoring and the ability to determine the amount of carbohydrates in the meals. Since diabetes mellitus is a chronic disease, a more flexible and varied diet will allow better monitoring, taking into account their glycemic control in long-term. The objective of this study was to examine the applicability of this method to a less restrictive diet and nutritionally adequate for the patient with diabetes mellitus, as well an individual dietary adjustment that is needed to better glycemic control, identifying nutritional advantages and disadvantages of the method. PMID- 20204252 TI - [Protocolisation of parenteral artificial nutrition: Methodological and organisational bases for process design and review]. AB - In the field of parenteral artificial nutrition (PN) there is debate over the application of such concepts as standardisation, individualisation, protocolisation and normalisation. Artificial Nutrition Units (ANU) that are designing or reviewing their PN provision system must take into account the existing methodological and regulatory references as well as the resources available for implementing the process. The aim of this article is to review and evaluate the possibilities that exist for designing an efficient, safe process, applying the methodology of continuous quality improvement. Current requirements are reviewed in terms of quality of formulation, safety, and cost containment, as well as the resources available to avoid jeopardising the possibilities of adapting the treatment to suit patient needs or compromising its efficacy. The solution to the problem of whether the chosen approach in the system of PN provision is appropriate must come from review of the quality of service through the evaluation of indicators both of process and results. In this task, the hospital pharmacist plays a significant role as an agent in guaranteeing compliance with good practice guidelines. PMID- 20204253 TI - G1359A polymorphism of the cannabinoid receptor gene (CNR1) and insulin resistance in patients with diabetes mellitus type 2. AB - BACKGROUND: A silent intragenic biallelic polymorphism (1359 G/A) (rs1049353) of the CB1 gene resulting in the substitution of the G to A at nucleotide position 1359 in codon 435 (Thr), was reported as a common polymorphism in Caucasian populations. OBJECTIVE: The aim of our study was to investigate the influence of the missense polymorphism (G1359A) of CB1 receptor gene on obesity anthropometric parameters, cardiovascular risk factors and adipocytokines in patients with obesity and diabetes mellitus type 2. DESIGN: A population of 60 naive diabetic patients was analyzed. An indirect calorimetry, tetrapolar electrical bioimpedance, blood pressure, a serial assessment of nutritional intake with 3 days written food records and biochemical analysis (lipid profile, adipocytokines, insulin, CRP and lipoprotein-a) were performed. The statistical analysis was performed for the combined G1359A and A1359A as a group and wild type G1359G as second group, with a dominant model. RESULTS: The mean age was 57.44 +/- 11.7 years and the mean BMI 37.84 +/- 6.4, with 14 males and 46 females. Thirty-five patients (58.3%) had genotype G1359G (wild type group) and 25 (42.7%) patients G1359A (mutant type group). Age was similar in both groups (wild type: 56.3 +/- 11.8 years vs mutant group: 58.7 +/- 10 years:ns). Sex distribution was similar in both groups (wild vs mutant type groups), males (22.9% vs 24%) and females (77.1% vs 76%). No differences were detected between groups in anthropometric parameters, cardiovascular risk factors, dietary intake and adipocytokines levels. CONCLUSION: The finding of this study is the lack of association of G1359A polymorphism of CB receptor 1 gene with obesity, cardiovascular risk factors and adipocytokines. PMID- 20204254 TI - Effect of etoricoxib, a cyclooxygenase-2 selective inhibitor on aberrant crypt formation and apoptosis in 1,2 dimethyl hydrazine induced colon carcinogenesis in rat model. AB - Etoricoxib, a second generation selective cyclooxygenase-2 (COX-2) inhibitor had been studied for the chemopreventive response at its therapeutic anti inflammatory dose in 1,2-dimethylhydrazine (DMH) induced colon carcinogenesis in rat model. Eight to ten weeks old male rats of Sprague-Dawley strain were divided into four groups. While group 1 served as control and received the vehicle of the drugs, group 2 and 3 were administered freshly prepared DMH in 1mM EDTA-saline (pH 7.0) (30 mg/kg body wt/week, subcutaneously). Group 3 was also given a daily treatment of etoricoxib (0.6 mg/kg body wt orally) while the group 4 received the same amount of etoricoxib only, prepared in 0.5% carboxymethyl cellulose. Animals were sacrificed at the end of 6 weeks, body weight recorded and the colons were subjected to macroscopic and histopathological studies. The maximum number of raised mucosal lesions called the multiple plaque lesions (MPL) were found in the DMH group which significantly reverted back in the DMH + etoricoxib group, while very few MPLs were recorded in the control and etoricoxib only group. Similarly, the number of aberrant crypt foci (ACF), the point of future carcinogenic growth, was recorded more in the DMH group and significantly less in the DMH + etoricoxib group. The histopathological analysis showed the presence of severe hyperplasia, occasional dysplasia and aggregates of lymphoid cells in the localized regions. Etoricoxib group showed near normal histological features with the crypt architecture and the surrounding stromal tissue remaining intact. To ascertain the molecular mechanism of such anti-carcinogenic features the colonocytes were isolated and studied in primary culture for the evidence of apoptosis by fluorescent staining and genotoxic changes by single cell gel electrophoresis assay (comet assay) which shows that the DMH treated animals produced much less apoptotic nuclei but more comet producing cell, while these features were reverted back with the etoricoxib treatment. The cytoplasmic expression of COX-2 protein was studied in paraffin sections of the colon by immunohistochemistry with COX-2 specific antibody which showed a very high presence of this inducible enzyme with the DMH group while in all other groups of animals it was not visible or weekly expressed. The anti-inflammatory effect of the drug, etoricoxib was also validated by a carrageenan-induced inflammation in rat model which showed an extremely high anti-inflammatory response within the dose range used in the present study. Also the growth profile of all the animals remained the same throughout the six week period of the investigation as there was no change in the body weight. It appears that apoptosis remains the dominant anti-proliferative end effect of this drug, mediated by an inhibition of the proinflammatory COX-2 isoform although further molecular probings are needed to arrive at a conclusive agreement in favor of the chemoprotective use of such drugs in colon cancers. PMID- 20204255 TI - Parenteral nutrition supplemented with glutamine in patients undergoing bone marrow transplantation. AB - The objective of the study is to evaluate if the administration of glutamine in parenteral nutrition (PN) solution reduces the need for antibiotics, the risk of liver disease and the duration of hospital stay in bone marrow transplantation. MATERIAL AND METHODS: Retrospective observational study in 68 adult patients undergoing a bone marrow transplantation who required PN for mucositis. Of these patients, 40 were given PN with 2,063 +/- 294 kcal/day and 98.6 +/- 13.9 g of amino acids/day, supplemented with Lglutamine (13.5-27 g/day), and 28 were given isocaloric (1,966 +/- 307 kcal/day) and isonitrogenated (92 +/- 16.3 g of amino acids/day) PN with standard glutamine-free amino acid solution. Antibiotic consumption and duration of hospital stay were analysed. Of the total cohort, hepatic profile was studied at the beginning and on day 7 of PN in 50 patients without liver disease at the start of PN. RESULTS: There were no differences between both groups with regard to total number and duration of antibiotics prescribed or hospital stay. Of the 50 patients without hepatic alterations at the beginning of PN, 2 patients in the control group and 5 in the glutamine group developed a hepatic profile compatible with liver disease secondary to PN. Comparing both groups, there were no differences in hepatic enzyme values. CONCLUSIONS: Supplementation with PN glutamine does not improve the variables studied, but the actual clinical use of glutamine in this haematological treatment should be studied further and its potential advantages identified. PMID- 20204256 TI - [Randomized clinical trial with a inulin enriched cookie on risk cardiovascular factor in obese patients]. AB - INTRODUCTION: Inulin is a prebiotic with potential benefit in cardiovascular risk factors. The aim of our work is to evaluate in obese patients the effect of a inulin enriched cookie on cardiovascular risk factors. MATERIAL AND METHODS: 34 patients were randomized in both branches: group I (inulin enriched cookie) Gullon SL(R) and group II (control cookie). Previous and after 1 month of the treatment, a nutritional and biochemical study was realized. RESULTS: 15 patients finished the procotol in each group. In group I, an increase in soluble fiber intake (inulin) was detected. In this group a significant decrease of total cholesterol (223.1 +/- 45.3 mg/dl vs 208.8 +/- 33.1 mg/dl; p < 0.05) and LDL cholesterol (142.9 +/- 39.2 mg/dl vs 131.4 +/- 28.6 mg/dl; p < 0.05) was reached. A non significant improvement in insulin levels and HOMA was detected in inulin enriched cookie group, too. Anthropometric parameters did not change in both groups. The increase in soluble fiber intake did not produce any gastrointestinal adverse effect. CONCLUSION: The increase of fiber intake (3 g of inulin) from an enriched cookie reduced LDL cholesterol levels in obese patients. PMID- 20204257 TI - Quality of dietary control in phenylketonuric patients and its relationship with general intelligence. AB - OBJECTIVES: Assessment of the quality of dietary treatment of phenylketonuria (PKU) patients and investigation of its relationship with the general intelligence of the patients. METHODS: Cross-sectional and longitudinal study of 105 PKU treated patients. The index of dietary control (IDC) was calculated as the phenylalanine (Phe) data reduction in half-year medians and the mean of all medians throughout the patient's life. We calculated four different IDCs related to age: IDC-A (< 6 years), IDC-B (6-12 years), IDC-C (13-18 years) and IDC-D (> 18 years). To evaluate the fluctuation of Phe values we calculated the standard error of the estimate of the regression of Phe concentration over age. Development quotient was calculated with the Brunet-Lezine test (< 4 years). Intelligence quotient was evaluated with the Kaufman Bit Intelligence Test (K Bit), Wechsler Intelligence Scale for Children-Revised (WISC-R) and Wechsler Adult Intelligence Scale Third Edition (WAIS III). RESULTS: Cross-sectional study: The IDC in age groups were significantly different and so were the number of patients with good, acceptable and poor IDC related to age (p < 0.001). Sampling frequency was good in 72, acceptable in 23 and poor in 10 patients. The general intelligence (101 +/- 10) correlated negatively with the IDC (p < 0.0001) and Phe fluctuations (p < 0.004). Longitudinal study: Significant differences were observed between the IDC through the patients' lifetime except in the adolescent/adult period. CONCLUSIONS: 85% of PKU patients showed good/acceptable quality of dietary control. General intelligence correlates with the IDC at all ages, which highlights the importance of good control to achieve good prognosis. PMID- 20204258 TI - [Effect of gastric bypass on the metabolic syndrome and on cardiovascular risk]. AB - BACKGROUND: Obesity is associated with increased morbimortality cardiovascular. Individual with metabolic syndrome (MS) are a high risk of developing cardiovascular disease (CVD). The aim of this study was to determine the prevalence of the MS in morbidly obese patients enrolling in a bariatric surgery program and to evaluate the impact of weigh loss induced by gastric bypass on the MS and on the predicted 10-year cardiovascular risk. MATERIAL AND METHODS: We studied 46 morbidly obese patients who underwent laparoscopic gastric bypass and were followed for 2 years. MS was defined following the IDF 2005 criteria and the insulin resistance (IR) was calculated by using HOMA index. Risk assessment for estimating 10-year ECV risk was carried out according to Framingham score. RESULTS: Before surgery, 67.2% of patients had IR and 60,9% met the definition of the MS. 17.3% of patients had an elevated cardiovascular risk category. 2 years after gastric bypass, the percentage of excess body weight lost was 72%. All patients restored their HOMA index and only 1 patient (3.6%) had MS. Resolution of hypertension, disglucemia and dislipemia has been observed in 85%, 93.8% and 95.6% of patients. Estimated cardiovascular risk decreased from 4.5% at baseline to 1% at 2 years after surgery. CONCLUSIONS: SM is common in morbidly obese patients. Bypass gastric is associated with an improvement or resolution in cardiovascular risk factors and IR and result in a significant reduction in MS prevalence and of predicted 10-year cardiovascular risk. PMID- 20204259 TI - [Effect of a high saturated fatty acids load on serum concentrations of C reactive protein, alpha1-antitrypsin, fibrinogen and alpha1-acid glycoprotein in obese women]. AB - Obesity is associated with increased inflammation. Creactive protein (CRP) and inflammation-sensitive plasma protein (ISPs) are inflammatory markers. Proinflammatory process may be influenced by high saturated fatty acid intake. OBJECTIVE: The aim of the present study was to evaluate the role of saturated fatty acids load on postprandial circulating levels of PCR and ISPs (alpha1 antitrypsin, alpha1-acid glucoprotein, and fibrinogen) in obese women. DESIGN: A total of 15 obese women (age = 31,7 +/- 4,5 years, BMI = 37,9 +/- 7,3 kg/m(2)) and 15 lean controls women (age = 30,6 +/- 4,6 years, BMI = 20,6 +/- 2,6 kg/m(2)) were recruited for this study. After and overnight fast subjects ate the fat load consisted of 75 g of fat (100% saturated fatty acid, 0% cholesterol), 5 g of carbohydrates, and 6 g of protein per m2 body surface area. Postprandial serum levels of CRP, alpha1-antitrypsin, alpha1-acid glucoprotein, and fibrinogen were measured. Anthropometry and blood biochemical parameters were measured in both groups. RESULTS: The obese women had fasting serum PCR levels higher (p = 0,013) and fibrinogen (p = 0,04) than those of control women. Serum CRP and fibrinogen levels was positively related to body mass index (BMI) in obese group. There weren't differences in fasting serum alpha1- antitrypsin levels (p = 0,40), and alpha1-acid glucoprotein (p = 0,28) levels in obese group in comparison to lean control group. Serum CRP, alpha1-antitrypsin, alpha1-acid glucoprotein, and fibrinogen did not change postprandially (p = > 0,05 difference to fasting levels). CONCLUSION: A high-saturated fatty acids load is not associated with serum CRP, alpha1-antitrypsin, alpha1-acid glucoprotein, and fibrinogen levels increase. Serum alpha1-antitripsin and alpha1-acid glucoprotein levels are not increased in obese women. Serum PCR and fibrinogen levels are increased in obese women, and are positively related to BMI. PMID- 20204260 TI - [Relation between leptin serun with weight and body fat distribution in postmenopausal women]. AB - Leptin is a peptidic hormone secreted by the fat tissue and plays an important role in body weight regulation. After menopause, weight gain increases as well as android-like obesity. Previous studies suggest a relationship between leptin level, body mass index (BMI) and fat distribution. OBJECTIVE: To establish the relationships between serum leptin, BMI, waist circumference (WC), and waist/hip ratio (WHR). METHODOLOGY: 48 women under the age of 60 years and with amenorrhea for longer than one year were assessed. Leptin and estradiol (ELISA) levels were determined; normal values: 3.63-11.09 ng/mL and 0-65 pg/Ml. BMI (WHO), WC > 88 cm, and WHR > 0.80 were considered as indicators of cardiometabolic risk. RESULTS: Mean age for the group was 54 +/- 3.9 years; leptin: 8.4 +/- 3.7 ng/mL, and estradiol: 17.6 +/- 10.0 pg/mL; BMI: 27.0 +/- 4.9 kg/m(2); WC: 86.2 +/- 8.6 cm; and WHR: 0.84 +/- 0.06. Twenty percent of the women had hyperleptinemia, 58.4% malnourishment due to excessive intake, 35% presented WC cardiovascular risk. The highest leptin value was found in obese women. There was no association between serum leptin levels and anthropometrical variables. There was a significantly positive correlation between weight, height, BMI, WC, hip circumference, and estradiol. CONCLUSIONS: Postmenopausal women presented a high prevalence of overweight/obesity, android-like body fat distribution and normal serum leptin levels. The group assessed is considered to be at risk for cardiometabolic diseases according to anthropometrical indicators. PMID- 20204261 TI - [Analysis of the feeding habits in cyclists of the SpanishNational Mountain Bike Team]. AB - OBJECTIVE: The aim of the study was to determine the feeding habits of the cyclists of the Spanish mountain bike (MTB) national team. METHOD: Forty cyclists were distributed in two categories according to time spent in training and competing category (25 Cadet/junior (C/J) -16.68 +/- 0.99 years-, and 15 Under 23/elite (U23/E) -25.33 +/- 4.25 years-. All the subjects completed a specific questionnaire about their feeding habits. Descriptive and contrast (Mann-Whitney) statistic was carried out in the 2 studied groups. RESULTS: Seventy Six per cent of the subjects of the C/J group showed incorrect feeding habit, and significantly less (36%) than the U23/E showed also incorrect patterns (p = 0.003). Seventy six per cent of the C/J and 60% of the U23/E do 3 intakes/day (p = 0.348), while 20% of C/J and 26.7% of the U23/E do 5 intakes/day. Sixty four per cent of the C/J and 26% of the U23/E eat between meals (p = 0.024). Also, 56% of C/J group and 20% of the U23/E group eat "fast food" (p = 0.028). CONCLUSIONS: Feeding habits of the C/J cyclists of the Spanish national team are considered inadequate, being significantly better for the U23/E group, although also in this older group there are basic aspects to improve. PMID- 20204262 TI - [Preoperative nutritional status and surgical risk. Identification of promissory biochemical markers]. AB - BACKGROUND: The fact that deficient or even marginal nutritional levels may contribute to increase morbidity and mortality in the surgical patient is well accepted. The usefulness of vitamin and mineral markers has not been much explored. OBJECTIVE: To evaluate the usefulness of vitamin and mineral indicators as nutritional markers of surgical risk. METHODS: Biomarkers of vitamin A (plasma retinol), carotenes (plasma carotenes), vitamin C (plasma vitamin C), iron (hematocrit, hemoglobin, serum iron, transferrin saturation and erythrocyte protoporphyrin), calcium (calcium/creatinine in basal urine) and zinc (zinc/creatinine in basal urine), were performed 24 ours before surgery. Appearance of complications was evaluated in 100 adult patients from programmed surgical procedures of hernia (n = 41) or gallbladder lithiasis (n = 59), two of the most frequent interventions in general surgery services. RESULTS: Patients were grouped in those that presented postoperative complications (C; n = 26) and those who did not (NC; n=74). Two of the studied markers presented significant differences between both groups: plasma retinol and erythrocyte protoporphyrin. Plasma retinol of C was significantly lower than that obtained in NC: 33.2 +/- 13.5 microg/dl vs. 40.2 +/- 16.3 microg/dl; P = 0.0495 and an association between values below 30 microg/dl and postoperative complications was founded (53.8% in C vs. 30.1% in NC; P = 0.0360). Erythrocyte protoporphyrin of C was significantly higher to that obtained in NC: 52.0 +/- 34.0 microg/dl RBC vs. 36.8 +/- 17.5 microg/dl RBC; P = 0.0453 and the association between values higher than 70 microg/dl RBC and presence of complications were highly significant (25.0% vs. 4.2%; P = 0.0069). CONCLUSIONS: On the basis of the obtained results is concluded that plasma retinol and erythrocyte protoporphyrin would provide useful tools in evaluating surgical risk since they had been allowed to identify patients who were at risk of suffering postoperative complications. PMID- 20204263 TI - [Nutrition and anaemias in critical illness]. AB - INTRODUCTION: We made a clinical study, about nutrition in seriously ill patients, which includes a typical heterogeneous group of critical ill patients, with/without anaemia's, that have been admitted to Intensive Care Unit, ICU. It is difficult to individualize and to generalize the relative importance of all the factors that can contribute to these anaemia's in the admission to the Unit, including nutritional deficiencies, inflammatory alterations, the immune response to aggressions, inmunitary modifications and the complex relations existing between these clinic processes. OBJECTIVE: Indirect valuation of the nutritional situation and anaemia's, in a typical heterogeneous group of critical ill patients. METHOD/RESULTS: We studied 202 patients admitted to ICU, of varied and heterogeneous origin, classifying them in 3 groups: control, post surgery and septic group's, becoming the indirect valuation of the nutritional situation on the basis of: Global Subjective Valuation, (VGS) and the nutritional analytical determinations of total lymphocytes, albumin, and transferrin. Also we made hemogram and determinations of sideremia and ferritinemia to all of them. In 57% of the patients, we observed levels haemoglobin < 12.5 g/dl, basically in the post surgery groups, 68 patients and septic group's, 10 patients. And with levels haemoglobin < 10 g/dl, in 25 patient's (12.3%). There were 87 patients, 23 of them in the control group's, 58 in the post surgery and 5 septic group's, with levels haemoglobin > 12.5 g/dl. Regarding the nutritional prognoses indicators, (VGS + nutritional profile), in the control group's, they did not present anaemia nor analytical clinical under nourishment, in the post surgery group's, anaemia and slight under nourishment and in the septic group's, anaemia and moderate under nourishment. There were significant differences between the surgery and septic group and control group's, in values of haemoglobin, iron, total lymphocytes, transferrin and albumin. A statistical correlation between sideremia and albumin was significative. (Spearman's Rho 0,277). CONCLUSIONS: The evaluation of the anaemia and nutritional valuation. and the ferroterapic treatment, as immune-nutrient, can be beneficial for the integrity of the immune system and its defense's abilities against the aggressions in critically ills. PMID- 20204264 TI - [Macronutrients consumption and lifestyle in patients whose received transplant of kidney in The Mexican Institute for Social Security]. AB - The transplant offer the best quality of life to patients whose suffer from advanced chronic renal failure. This work was undertaken to know the lifestyle and macronutrients consume patterns in patients from the Mexican Institute for Social Security whose received a transplanted kidney . Demographic and anthropometric information were obtained from 119 transplanted patients and consume patterns were obtained from them through the recall of 24 hours. The IMEVID questionnaire was used to assess the lifestyle in this population. This instrument was previously validated for its reliability, its showed a value of 0.681 for alpha of Cronbach and 0.685 for Spearman-Brown test. The 70% of the patients showed less favourable lifestyles and there were no differences between genders. There were significative differences among states of the country where the subjects lived; attending the following domains of the IMEVID questionnaire. Information, physical activity and adjustment to the treatment (p < 0.001). In those States near the american border the BMI was superior to the 25 kg/m(2), there were significatives differences attending ideal and real ingestion among States of the country, (p < 0.05). The protein consumption was higher in patients living in Michoacan to those reported from patients living in other states of the country (p < 0.05)and the lipids consumption was higher in Nuevo Leon in comparison with those reported from patients living in other states of the country (p < 0.05). It is frequent to find non favourable lifestyles in patients with transplant of the kidney, even when they practices physical exercise. The promotion of healthy lifestyles via educative strategies of high impact, in patients with transplant is necessary to avoid highly cost complications and rejection of the graft. PMID- 20204265 TI - [Nutritional support and treatment of chylothorax with octreotide]. AB - Patients with chylothorax present a high risk for malnourishment since continuous loss of chylo leads to a significant impairment of their nutritional status. Chylothorax treatment, which initially is conservative, includes dietary measures and medications such as octreotide that decreases chylothorax flow. In this paper we present the case of a patient with chylothorax treated by means of pleural drainage, parenteral nutrition, and octreotide, and we review the most appropriate nutritional support as well as the efficacy and safety of octreotide in chylothorax therapy. The types of nutritional intervention that may be done are a low-fat diet supplemented with intermediate-chain triglycerides (ICT), fat free enteral nutrition or EN with a high percentage of ICT, and parenteral nutrition. There is no consensus on which is the most appropriate measure. We found very few comparative studies, and the literature is based on single cases or case series. Some authors consider parenteral nutrition as the first choice, whereas others recommend starting with a specific diet and using parenteral nutrition only in specific cases. Parenteral nutrition must cover the patient's demands together with compensating the protein and energy losses due to chylothorax. The use of lipid emulsions is no contraindicated since they do not reach the lymphatic system. With regards to EN, the formulations may be lipid free or with low lipid content. There is no agreement on when to start them once the drainage of chylo decreases. There are cases and case series indicating that octreotide use in chylothorax seems to be safe and effective. There is no consensus on when to start the therapy, the most appropriate dose, or the time to withdraw the treatment. PMID- 20204266 TI - [Maternal and neonatal complications in a pregnant woman with biliopancreatic diversion]. AB - Biliopancreatic diversion (BPD) is a bariatric technique which can lead to the development of nutritional complications such as protein-calorie malnutrition and deficiencies in fat-soluble vitamins. Many women in childbearing age undergone DBP, pregnancy frequently occurs afterwards. Vitamin A is essential for the differentiation and growth of cell during embryonic development. Although BPD has shown beneficial effects in some obstetric and reproductive complications as infertility and macrosomia, several reports suggest a link between maternal malnutrition and fetal or neonatal complications. We present the case of a pregnant woman with a severe malnutrition associated with vitamin A deficiency as a result of a BPD. The patient delivered a premature infant, with low birth weight and significant eye and kidney malformations. We review and discuss the probable relationship between adverse neonatal outcome, malnutrition and vitamin A deficiency during pregnancy. PMID- 20204267 TI - Obesity and overall satisfaction with pork meat and derived pork-based products. PMID- 20204268 TI - [Prognosis of critically ill patients requiring enteral nutrition at discharge from the ICU]. PMID- 20204269 TI - Subjective aspects of the nutritional status and length of chemotherapy treatment in patients with neoplasias. PMID- 20204270 TI - Calphostin C, a remarkable multimodal photodynamic killer of neoplastic cells by selective nuclear lamin B1 destruction and apoptogenesis (Review). AB - Perylenequinones that generate reactive oxygen species (ROS) when illuminated with visible light have been recommended as photodynamic chemotherapeutic agents. One of these is calphostin C (CalC), the action of the photo-activated derivative of which, CalCphiE, has been ascribed to its ability to selectively and irreversibly inhibit protein kinase Cs (PKCs). But recent results of experiments with neoplastic rat fibroblasts and human breast and uterine cervix cancer cells have revealed that the action of CalCphiE involves more than PKC inhibition. Besides suppressing PKC activity, CalCphiE rapidly causes endoplasmic reticulum (ER) stress in breast cancer cells and the selective complete oxidation and proteasomal destruction of the functionally essential nuclear envelope protein lamin B1, in human cervical carcinoma (HCC) cells and neoplastic rat fibroblasts. When these lamin B1-lacking cells are placed in the dark, cytoplasmic membrane linked PKC activities suddenly rebound and apoptogenesis is initiated as indicated by the immediate release of cytochrome c from mitochondria and later on the activation of caspases. Hence, CalCphiE is a photodynamic cytocidal agent attacking multiple targets in cancer cells and it would be worth determining, even for their best applicative use, whether other perylenequinones also share the so far unexpectedly complex deadly properties of the CalCphiE. PMID- 20204271 TI - RNAi-mediated knockdown of Notch-1 leads to cell growth inhibition and enhanced chemosensitivity in human breast cancer. AB - Notch signaling plays a critical role in determining cell fate such as proliferation, differentiation, and apoptosis. Accumulating evidence indicates that aberrant Notch signaling has tumor-promoting function in breast cancer. We hypothesized that Notch signaling may be a potential therapeutic target for human breast cancer. To address this issue, we down-regulated the expression of the Notch-1 receptor by siRNA in human breast cancer cells. We found that the down regulation of Notch-1 signaling caused cancer cell growth inhibition by apoptosis induction. The effect of the down-regulation of Notch-1 may be through the inactivation of NF-kappaB. In addition, the down-regulation of Notch-1 signaling increased chemosensitivity to doxorubicin and docetaxel. Our results suggested that Notch signaling may be a promising target for breast cancer treatment. PMID- 20204272 TI - Promotion of melanoma growth by the metabolic hormone leptin. AB - We have previously shown that melanoma cells proliferate in response to the metabolic hormones TRH and TSH. The objective of the present study was to test the hypothesis that a third metabolic hormone, leptin, serves as a growth factor for melanoma. Using western blotting, indirect immunofluorescence, and RT-PCR, leptin receptors were found to be expressed by human melanoma cells. In contrast, cultured melanocytes expressed message for the receptor without detectable protein. Melanoma cells responded to treatment with leptin by activating the MAPK pathway and proliferating. Melanoma cells but not melanocytes, also expressed leptin protein, creating a potential autocrine loop. Examination of human melanoma tumors by immunohistochemistry revealed that melanomas and nevi expressed leptin at a high frequency. Melanomas also strongly expressed the leptin receptor, whereas nevi expressed this receptor to a much lesser degree. We conclude that leptin is a melanoma growth factor and that a leptin autocrine-loop may contribute to the uncontrolled proliferation of these cells. PMID- 20204273 TI - Expression of the HER-1-4 family of receptor tyrosine kinases in neuroendocrine tumours. AB - The type I receptor tyrosine kinase family comprises four homologous members: Epidermal growth factor receptor (EGFR), HER-2, HER-3 and HER-4. Studies have shown that EGFR and HER-2 play a critical role in oncogenesis. In this study we sought to determine the pattern of expression and the prognostic significance of EGFR, HER-2, HER-3 and HER-4 in a variety of neuroendocrine tumours using immunohistochemistry. HER family receptor expression in 82 paraffin-embedded specimens of neuroendocrine tumours using immunohistochemistry was examined. The pattern and protein expression levels for each receptor were correlated with clinical and pathological parameters. EGFR expression was identified in 86.6% samples, HER-2 was not expressed in any samples, HER-3 was expressed in 8.5% samples and HER-4 was expressed 91.5%. EGFR and HER-4 were co-expressed in 79.3% of cases. HER-3 was correlated with better survival. EGFR was not associated with poor prognosis. This study has demonstrated EGFR, HER-2 and HER-4 expression is not associated with poorer survival. HER-3 expression is correlated with better prognosis. Overexpression of EGFR and HER-4 may offer potential new therapeutic targets. PMID- 20204274 TI - Clinical significance of syndecan-1 and versican expression in human epithelial ovarian cancer. AB - Proteoglycans are ubiquitous components of the extracellular matrix and cell surface, and may mediate tumor progression and metastasis. The aim of this study was to evaluate the expression of syndecan-1 and versican in epithelial ovarian cancer. We immunohistochemically evaluated the expression of syndecan-1 and versican in 111 patients with epithelial ovarian cancer, and analyzed the correlation of this expression with various observed clinicopathological features, including patient outcome. There is a significant correlation between primary and metastatic sites with respect to syndecan-1 and versican expression. Epithelial syndecan-1 expression was significantly lower in patients with advanced disease. Epithelial versican expression was significantly higher in patients with early disease, especially in clear cell adenocarcinoma patients. Stromal syndecan-1 and versican expression was significantly higher in patients with advanced disease. Multivariate analysis showed that negative epithelial syndecan-1 expression was an independent prognostic factor for progression-free survival. Stromal syndecan-1 and versican co-expression was of borderline significance for progression-free and overall survival. Loss of epithelial syndecan-1 expression and induction of stromal syndecan-1 and versican expression may be associated with tumor progression in epithelial ovarian cancer. Syndecan-1 and versican expression status can serve as an indicator of prognosis in patients with epithelial ovarian cancer. PMID- 20204275 TI - Claudin expression profiles in Epstein-Barr virus-associated nasopharyngeal carcinoma. AB - Claudins are a family of proteins that are structural and functional components of tight junctions and have crucial roles in the maintenance of cellular arrangement, adhesion and paracellular transport. Recent studies have shown that changes and/or loss of claudin expression plays an important role in tumorigenesis and tumor progression, and altered expression of claudins has been reported in various human carcinomas. Non-keratinizing nasopharyngeal carcinoma (NPC) is a common Epstein-Barr virus (EBV)-associated carcinoma with characteristic clinicopathological features. The aim of this study was to investigate claudin expression profiles in EBV-associated non-keratinizing NPC. We analyzed expressions of claudin-1, -2, -3, and -4 in 18 cases of EBV associated non-keratinizing NPC by immunohistochemical methods. Claudin-1 was expressed in all 18 cases, but claudin-2 was not expressed in any of the 18 cases. Claudin-3 expression was variable, with 8 of the 18 cases (45%) showing no immunoreactivity for claudin-3. Claudin-4 displayed positive immunoreactivity in all cases, even in claudin-3-negative cases. Claudin-3 and -4 are receptors for cytotoxic Clostridium perfringens enterotoxin (CPE) and CPE has emerged as a potential therapeutic target for malignant tumors expressing claudin-3 and/or -4, because CPE specifically and rapidly lyses cells expressing these proteins. Clinically, treatment of distant metastases is a serious problem in EBV associated non-keratinizing NPC, because frequently there is lymph node involvement and distant metastasis before detection of the primary tumor. Therefore, CPE therapy may be a potential therapeutic target for EBV-associated non-keratinizing NPC, since our results clearly showed claudin-3 and/or -4 expression in all cases studied. PMID- 20204276 TI - HLA class I antigen and transporter associated with antigen processing downregulation in metastatic lesions of head and neck squamous cell carcinoma as a marker of poor prognosis. AB - HLA class I antigen processing machinery plays a crucial role in the generation of peptides from endogeneously synthesized proteins and in their presentation to cytotoxic T lymphocytes. The purpose of this study was to analyze the downregulation of HLA class I antigen, transporter associated with antigen processing (TAP) and tapasin in primary and metastatic lesions of head and neck squamous cell carcinoma (HNSCC) and to compare TAP, tapasin and HLA class I antigen downregulation in metastatic lesions with that of primary lesions. We analyzed expression levels of TAP1, TAP2, tapasin and HLA class I antigen in 25 primary and autologous metastatic lesions by staining formalin-fixed, paraffin embedded tissue sections in the immunoperoxidase reaction. We identified the expression levels of TAP1, TAP2, tapasin and HLA class I antigen were coordinately downregulated in both primary and metastatic lesions and were significantly lower in metastatic lesions than in autologous primary lesions tested. HLA class I antigen downregulation in metastatic lesion was significantly associated with reduced disease-free survival of patients (P<0.05). Multivariate Cox proportional hazards model analysis identified negativity of HLA class I antigen as an independent prognostic marker. HLA class I antigen and TAP are likely to be downregulated in metastatic lesions compared with primary lesions in HNSCC. The higher frequency of HLA class I antigen and TAP down-regulation in metastases play a role in the clinical course of the disease. PMID- 20204277 TI - The angiotensin-converting enzyme 2 in tumor growth and tumor-associated angiogenesis in non-small cell lung cancer. AB - Angiotensin II (AngII) is a multifunctional bioactive peptide and previous studies have shown that the renin-angiotensin system (RAS) of both host and tumor are important in tumor growth and angiogenesis in lung cancer. Angiotensin converting enzyme 2 (ACE2) is a newly identified component of RAS, with 42% amino acid homology to ACE. However, the expression and function of ACE2 in non-small cell lung cancer (NSCLC) are still unclear. In the present study, we analyzed ACE2 expression in NSCLC tissue by Western blot analysis and immunohistochemistry. AngII concentrations in the tissue homogenate were also detected using radio-immunoassay. We also examined the function of ACE2 by transducing A549 cells with MSCV-ACE2. We have shown for the first time that ACE2 expression decreased in NSCLC tissue in which AngII was higher than the matching non-malignant tissues. A concentration of 10(-6) mol/l of AngII significantly increased expression of vascular endothelial growth factor a (VEGFa) and AT1-R and decreased ACE2 expression. We also found that overexpression of ACE2 may have a protective effect by inhibiting cell growth and VEGFa production in vitro. ACE2 may become a target of novel strategies to treat NSCLC. PMID- 20204278 TI - Proteomics-based identification of a tumor-associated antigen and its corresponding autoantibody in gastric cancer. AB - Identification of novel tumor-related antigens and autoantibodies will lead to early diagnosis of cancer and the development of more effective immunotherapies. The purpose of this study was to identify novel tumor antigens from the gastric cancer cell lines MkN-1, MkN-45 and KATOIII, and their related autoantibodies in sera of patients with gastric cancer using a proteomics-based approach. Proteins from the gastric cancer cell lines (MkN-1, MkN-45 and KATOIII) were separated by two-dimensional polyacrylamide gel electrophoresis, followed by Western blotting and antibody reaction with sera from patients with gastric cancer, healthy individuals and patients with other cancers. Positive spots were excised from Coomassie blue stained gels and analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/TOF MS). Sera from patients with gastric cancer yielded multiple spots, one of which was identified as the 78 kDa glucose-regulated protein (GRP78) by MALDI-TOF/TOF MS. Western blots against recombinant GRP78 showed reactivity in sera from 17/60 (28.3%) patients with gastric cancer and 0/20 (0.0%) of healthy individuals. Autoantibodies against GRP78 were found in 4/15 (26.7%) and 3/15 (20.0%) patients with esophageal and colon cancer, respectively. We identified for the first time an autoantibody against GRP78 in gastric cancer patients. The proteomic approach implemented in this study offers a powerful tool for identifying novel serum markers that may display clinical usefulness in cancer. PMID- 20204279 TI - Antitumor effects of lapatinib (GW572016), a dual inhibitor of EGFR and HER-2, in combination with cisplatin or paclitaxel on head and neck squamous cell carcinoma. AB - The epidermal growth factor receptor (EGFR) and a related family member, HER-2, are often overexpressed simultaneously in patients with a variety of malignant tumors, and the combination may cooperatively promote cancer cell growth and survival. Heterodimerization of EGFR and HER-2 has been known to create intense proliferative signals. Lapatinib (GW572016) is a small molecule that is administrated orally and functions as a reversible inhibitor of both EGFR and HER 2 tyrosine kinases. In the present study, we evaluated the antitumor effect of lapatinib on head and neck squamous cell carcinoma (HNSCC) cell lines in vitro and in vivo. In vivo we examined the antitumor effects of combined treatment with lapatinib and either cisplatin or paclitaxel. In vitro lapatinib displayed antiproliferative effects on HNSCC cells. The IC50 of lapatinib ranged between 13.6 and 60.2 microM after 24-h exposure to lapatinib. A correlation was not observed between results of in vitro proliferation assays for lapatinib and the expression of EGFR or HER-2. In vivo lapatinib displayed antitumor activity, and induced apoptosis in nude mice bearing an established xenograft of YCU-H891 cells. Lapatinib did not significantly inhibit angiogenesis. Combination treatment of lapatinib with cisplatin or paclitaxel enhanced antitumor activity mainly by inducing apoptosis. Inhibition of antiangiogenesis was observed only for combination treatment of lapatinib with paclitaxel (compared to vehicle control). These results suggest that: i) lapatinib has antitumor effects in vitro and in vivo; ii) lapatinib may be more effective in combination with cisplatin or paclitaxel; and iii) lapatinib might provide useful clinical benefits to HNSCC patients. PMID- 20204280 TI - Multidrug resistance-associated protein 2 determines the efficacy of cisplatin in patients with hepatocellular carcinoma. AB - We hypothesized that expression of multidrug resistance-associated protein 2 (MRP2), a major cisplatin transporter, may determine the efficacy of cisplatin as a treatment for patients with hepatocellular carcinoma (HCC). A prospective analysis was conducted of 49 consecutive patients who underwent resection for HCC (16 patients treated with cisplatin-based neoadjuvant chemotherapy and 33 patients treated without neoadjuvant chemotherapy). Expression of MRP2 in resected specimens was assessed by immunohistochemical and Western blot analyses. The extent of tumor necrosis was assessed histologically in the greatest dimension of the tumor specimen from each patient. The median percentage of tumor necrosis was 81% (range: 0-100%) and complete tumor necrosis was found in 3 patients. Overexpression of MRP2 was detected in 24/46 (52%) tumor specimens. In 16 patients treated with cisplatin, tumor size and dose of cisplatin did not correlate with tumor necrosis of the resected specimens (P=0.706 and P=0.555, respectively). Of 13 tumor specimens containing vivid tumor from 16 patients treated with cisplatin, 8 had overexpression of MRP2. Tumor specimens with overexpression of MRP2 showed a lower percentage of tumor necrosis than those with non-overexpression (median percentage of tumor necrosis, 19% vs. 99%, P=0.003). In conclusion, overexpression of MRP2 correlates with a lower percentage of tumor necrosis in patients treated with cisplatin-based neoadjuvant chemotherapy for HCC, whereas either tumor size or dose of cisplatin does not. Expression of MRP2 determines the efficacy of cisplatin-based chemotherapy in patients with HCC. PMID- 20204281 TI - The expression of NAD(P)H:quinone oxidoreductase 1 is increased along with NF kappaB p105/p50 in human cutaneous melanomas. AB - NAD(P)H:quinone oxidoreductase 1 (NQO1) is a key enzyme involved in metabolism of quinones and may perform multiple functions within the cell. Recent studies demonstrated that NQO1 is overexpressed in many types of tumors, including the lung, ovary, adrenal gland, thyroid, liver, colon, breast, and pancreas. To investigate whether NQO1 plays a role in melanoma pathogenesis, we used tissue microarray technology and immunohistochemistry to examine NQO1 expression in 56 dysplastic nevi and 93 primary melanoma biopsies. Our data showed that NQO1 expression is significantly increased in primary melanomas compared with dysplastic nevi (P=0.015, chi2 test). Our results also revealed that the increase of NQO1 was not associated with patient age, tumor thickness, ulceration, tumor site, American Joint Committee on Cancer (AJCC) stage, and 5-year patient survival. Interestingly, we found that female patients had more NQO1 expression than male patients (P=0.022, chi2 test). Furthermore, NQO1 expression level was significantly higher in superficial spreading melanomas compared with other tumor subtypes (P=0.020, chi2 test). Moreover, we found that NQO1 expression is significantly correlated with the expression of NF-kappaB subunit p50 (P=0.032, chi2 test). Our findings suggest that NQO1 may play an important role in the initiation stage of melanoma development. PMID- 20204282 TI - Intratumoral injection of pEGFC1-IGFBP7 inhibits malignant melanoma growth in C57BL/6J mice by inducing apoptosis and down-regulating VEGF expression. AB - Malignant melanoma (MM) is a type of aggressive skin cancer, and the effective therapy for MM is highly desired. Recently, genome-wide RNA interference screening study revealed that loss of expression of insulin-like growth factor binding protein 7 (IGFBP-7) is a critical step in development of MM, and this secreted protein plays a central role in apoptosis of MM. Furthermore, a prostatic carcinoma cell line stably transfected with IGFBP-7 cDNA showed poor tumorigenicity. Thus, we supposed it to be an efficacious agent for inhibiting melanomas. In this study, we constructed pEGFC1-IGFBP7 to try to obtain high expression of IGFPB7 and then we demonstrated that this plasmid inhibited proliferation of B16-F10 melanoma cells efficiently in vitro. Moreover, intratumoral injection of pEGFC1-IGFBP7 inhibited MM growth in C57BL/6J mice. The inhibition of MM growth is due to apoptosis and reduced expression of VEGF induced by pEGFC1-IGFBP7. These results suggest a potential new clinical strategy for MM treatment. PMID- 20204283 TI - Prognostic significance of insulin growth factor-I receptor and insulin growth factor binding protein-3 expression in primary breast cancer. AB - We analyzed insulin-like growth factor receptor I (IGF-IR) and insulin growth factor binding protein-3 (IGFBP-3) expression with respect to overall survival and relapse-free survival (RFS) in 460 patients with primary invasive breast cancer using immunohistochemistry. IGF-IR expression had a significant positive correlation with positive estrogen receptor (ER), positive progesterone receptor (PR) and Bcl-2 expression. Univariate analysis showed significantly better overall survival (p=0.000) and RFS (p=0.004), in the IGF-IR-positive group. Multivariate analysis showed a significant reduction in relative risk for overall survival (p=0.019, HR=0.221, 95% CI=0.062-0.780) and RFS (p=0.026, HR=0.462, 95% CI=0.234-0.913) in the IGF-IR-positive group. IGF-IR expression in primary breast cancer is an independent favorable prognostic factor. IGFBP-3 expression in breast cancer is associated with poor outcome. PMID- 20204284 TI - MicroRNA-181a sensitizes human malignant glioma U87MG cells to radiation by targeting Bcl-2. AB - Radiotherapy is widely used in cancer treatment and biological studies. Multiple mechanisms induced by radiation, especially changes of the expression profile of genes, lead to the disruption of cellular homeostasis. MicroRNAs (miRNAs) are important post-transcriptional gene regulators and play an important role in response to cellular stress. Here we investigated the profiles of miRNA expression following exposure to radiation and the possible role of miRNAs in the modulation of radiosensitivity in the glioblastoma multiform U87MG cell line. MiRNA expression profiles revealed a limited set of miRNAs with altered expression in U87MG cells in response to radiation treatment. MiR-181a, a member of miR-181 family, was one of the down-regulated miRNAs, whose expression was further validated by qRT-PCR. The target mRNAs of radiation-responsive miRNAs were predicted with a target prediction tool. Transiently overexpressed miR-181a significantly sensitized malignant glioma cells to radiation treatment concurrent with the down-regulation of the protein Bcl-2 (B cell lymphoma/lewkmia-2). It indicates that miR-181a may modulate radiosensitivity by targeting Bcl-2 in human malignant glioma cells. These data suggest that radiation can affect miRNA expression, which regulates the cellular response, and miR-181a could be a target for enhancing the effect of radiation treatment on malignant glioma cells. PMID- 20204285 TI - The effect on radioresistance of manganese superoxide dismutase in nasopharyngeal carcinoma. AB - Failure to control nasopharyngeal carcinomas (NPC) is mainly due to a portion of radioresistant phenotype. Identifying gene targets for radiosensitization is an important strategy in improving anticancer treatments. Exposure of cells to ionizing radiation leads to the formation of reactive oxygen species that are associated with radiation-induced cellular apoptosis and necrosis. The antioxidant enzyme manganese superoxide dismutase (SOD2) catalyzes the dismutation of the superoxide anions into hydrogen peroxide. We reasoned that SOD2 could contribute to the radioresistant phenotype in NPC cells. We compared CNE1 cells with CNE2 cells in radiation character and SOD2 protein. SOD2 gene silencing through the plasmid transfer using a microRNA interference optimized for transcription in NPC cell lines inhibited the radioresistance of human NPC cells. We compared radio-resistant NPC with radiosensitive NPC in SOD2 expression. CNE1 cells and CNE2 cells demonstrated dose-modifying factors at 10% isosurvival of 1.529 and 1. CNE1 cells were 1.94-fold higher than CNE2 cells at SOD2 protein baseline, and CNE1 cells exposed to ionizing radiation demonstrated 1.15- to 1.39-fold increase in SOD2 immunoreactive protein. Radioresistance in CNE1 cells was reduced following expression of miRNA targeting SOD2. Radioresistant tumors (11/23) were SOD2-positive, and 2/46 radiosensitive tumors were SOD2-positive before commencement of radiotherapy. The results presented suggest that SOD2 expression can participate in radioresistance of NPC, being markers of a subset of tumors in which routine radiation treatment failure is likely. Combination of the SOD2 gene silencing therapy and conventional radiotherapy should be attempted to improved cancer therapy for NPC. PMID- 20204286 TI - RNA interference-mediated hTERT inhibition enhances TRAIL-induced apoptosis in resistant hepatocellular carcinoma cells. AB - TRAIL has been reported to induce apoptosis in a variety of tumor cell types including hepato-cellular carcinoma (HCC) cell lines. However, considerable numbers of HCC cells, especially some highly malignant tumors, show resistance to TRAIL-induced apoptosis. The molecular mechanisms that regulate sensitivity versus resistance of tumor cells to TRAIL-induced apoptosis remain poorly defined. It has been shown that human telomerase catalytic subunit (hTERT) is overexpressed in human HCCs. In this study, we investigated the effects and the mechanisms of hTERT RNAi on the TRAIL-induced apoptosis of HCC cells that exhibit resistance to TRAIL. Our results indicate that hTERT RNAi sensitizes TRAIL resistant HCC cells to TRAIL-induced apoptosis. hTERT RNAi-mediated sensitization to TRAIL-induced apoptosis is accompanied up-regulation of procaspases-8 and -9, inhibition of telomerase activity and loss of telomere length. Our results suggest that hTERT RNAi overcame the resistance of the HCC cells against TRAIL, at least in part, via the mitochondrial type II apoptosis pathway and telomerase dependent pathway. PMID- 20204287 TI - Radiosensitivity profiles from a panel of ovarian cancer cell lines exhibiting genetic alterations in p53 and disparate DNA-dependent protein kinase activities. AB - The variability of radiation responses in ovarian tumors and tumor-derived cell lines is poorly understood. Since both DNA repair capacity and p53 status can significantly alter radiation sensitivity, we evaluated these factors along with radiation sensitivity in a panel of sporadic human ovarian carcinoma cell lines. We observed a gradation of radiation sensitivity among these sixteen lines, with a five-fold difference in the LD50 between the most radiosensitive and the most radioresistant cells. The DNA-dependent protein kinase (DNA-PK) is essential for the repair of radiation induced DNA double-strand breaks in human somatic cells. Therefore, we measured gene copy number, expression levels, protein abundance, genomic copy and kinase activity for DNA-PK in all of our cell lines. While there were detectable differences in DNA-PK between the cell lines, there was no clear correlation with any of these differences and radiation sensitivity. In contrast, p53 function as determined by two independent methods, correlated well with radiation sensitivity, indicating p53 mutant ovarian cancer cells are typically radioresistant relative to p53 wild-type lines. These data suggest that the activity of regulatory molecules such as p53 may be better indicators of radiation sensitivity than DNA repair enzymes such as DNA-PK in ovarian cancer. PMID- 20204288 TI - BUBR1 expression in benign oral lesions and squamous cell carcinomas: correlation with human papillomavirus. AB - Oral squamous cell carcinoma (OSCC) is the most common head and neck cancer. Only in Brazil, the estimate is for 14,160 new cases in 2009. HPV is associated with increasing risk of oral cancer, but its role in carcinogenesis is still controversial. BUBR1, an important protein in the mitotic spindle assembly checkpoint (SAC), has been associated with some virus-encoded proteins and cancer. The aim of the present study was to evaluate the expression of BUBR1 in non-malignant oral lesions and OSCC with and without metastasis associated with HPV infection. We performed immunohistochemistry for BUBR1 in 70 OSCC biopsies divided into three groups (in situ tumors, invasive tumors without metastasis and invasive tumors with metastasis) with their respective lymph nodes from samples with metastasis and in 16 non-malignant oral lesions. PCR was performed in order to detect HPV DNA. Significantly higher BUBR1 expression associated with shorter survival (p=0.0479) was observed in malignant lesions. There was also a significant correlation (r=1.000) with BUBR1 expression in lesions with metastasis and their lymph nodes. Ninety percent of OSCC and 100% of benign lesions were HPV positive. HPV16 and HVP18 were present in 13 and 24% of HPV positive OSCC samples, respectively. HPV was more prevalent (76%) in samples with a high BUBR1 expression and the absence of viral DNA had no influence on BUBR1 expression. These findings suggest that HPV could be associated with overexpression of BUBR1 in OSCC, but not in benign oral lesions. PMID- 20204289 TI - Up-regulated expression of stathmin may be associated with hepatocarcinogenesis. AB - Stathmin is a microtubule-destabilizing protein ubiquitously expressed in vertebrates and overexpressed in a variety of human malignancies. Down-regulation of its expression will contribute to optimize therapeutic outcomes in the treatment of these malignancies. This research aimed to demonstrate effects of stathmin expression silencing on hepatocellular carcinoma (HCC) cell proliferation, apoptosis, cell adhesion and motility behavior in vitro and further reveal significance of stathmin expression in tissues associated with hepatocarcinogenesis. The expression of stathmin in normal liver, hepatitis, cirrhosis and HCC tissues was detected by immunohistochemistry analysis (IHC), stathmin expression was inhibited in an HCC cell line-HCCLM3 with high metastatic potential by small interfering RNAs (siRNAs). After transfection with siRNAs, HCCLM3 cells proliferation was detected by CCK-8 (cell count kit), cell apoptosis was analyzed by FACS, cell adhesion was investigated by cell adhesion assay and motility ability was demonstrated by in vitro migration and invasion assays. Stathmin expression was up-regulated in HCC tissues, especially in metastatic HCC tissues, compared with normal liver, hepatitis and hepatic cirrhosis tissues. Expression of stathmin in HCCLM3 cells was efficiently inhibited by specific siRNAs. Silencing of stathmin expression obviously suppressed HCCLM3 cell proliferation and markedly induced cell apoptosis. Moreover, defect of stathmin expression in HCCLM3 cell inhibited cell adhesion, restrained cell migration and repressed invasion. Stathmin expression correlates with hepatocarcinogenesis and tumor progression. This molecule may be a promising therapeutic target in patients with hepatocellular carcinoma. PMID- 20204290 TI - Co-expression of the androgen receptor and the transcription factor ZNF652 is related to prostate cancer outcome. AB - ZNF652, a DNA binding transcription factor, was previously suggested to be differentially expressed in prostate cancer. This study investigated if the expressions of ZNF652 and androgen receptor (AR) in prostate cancer are associated with prostate specific antigen (PSA) defined relapse. ZNF652 and AR immunoreactivity were evaluated in prostate tissues from a cohort of 121 patients with prostate cancer and associations with disease outcome determined. To assess if ZNF652 can influence AR expression, or vice versa, levels of expression of ZNF652, AR and PSA were determined in the prostate cell line LNCaP following induction of AR activity by 5alpha-dihydrotestosterone, or knockdown of ZNF652 expression. Two thirds of prostate tumors retained high levels of ZNF652 (71/109 cases) and 50% of tumors high levels of AR (57/113). There was a significant decrease (p=0.005) in relapse-free survival of patients with high expression levels of both ZNF652 and AR and this was independent of preoperative PSA and seminal vesicle involvement. Modulation of either AR or ZNF652 expression levels in LNCaP cells was not associated with any corresponding changes to the levels of either ZNF652 or AR, respectively. High levels of expression of both AR and ZNF652 in clinically organ-defined prostate cancer are associated with a statistically increased risk of relapse. The ZNF652 and AR transcription factors are acting independently and it is proposed that the continued maintenance of expression of ZNF652 in AR positive cells results in a gene expression pattern that contributes to the relapse. PMID- 20204291 TI - Cyclosporin A and sanglifehrin A enhance chemotherapeutic effect of cisplatin in C6 glioma cells. AB - Glioma is the most common type of brain tumors in adults, and treatment of high grade gliomas is still palliative. Studies to date have revealed only modest effect in attenuating growth of these tumors with single agent therapy, but combination treatment appears to be more effective. Cyclophilin A (CypA), a target of immunosuppressive drugs cyclosporin A (CsA) and sanglifehrin A (SFA), is an intracellular protein that has peptidyl-prolyl cis-trans isomerase (PPIase) enzymatic activity. Previously, we showed that overexpressed CypA induced chemoresistance in cancer cells. Here we provide evidence that combination of cisplatin with either CsA or SFA synergistically enhances apoptotic cell death in C6 glioma cells, compared with single agent treatment. Enhanced apoptotic cell death is a result of an increase in ROS generation and a decrease in intracellular glutathione levels. Consistently, CypA knockdown by siRNA also enhances cisplatin-induced apoptosis. Immunohistochemical analysis showed increased expression of CypA in human glioblastoma multiforme, but not in normal human astrocytes. CypA was also shown to be up-regulated in C6 glioma cells during hypoxia. In conclusion, CsA or SFA in combination with cisplatin synergistically enhances cisplatin-induced apoptosis in C6 glioma cells via inhibition of PPIase activity of CypA, indicating that development of new drugs that selectively inhibit the CypA PPIase activity without immune suppression may facilitate alleviation of chemoresistance in treatment of high-grade glioma. PMID- 20204292 TI - The universal overexpression of a cancer testis antigen hiwi is associated with cancer angiogenesis. AB - The aim of this study was to determine whether the universal overexpression of hiwi is associated with cancer angiogenesis. The difference of mRNA expression in blood vessels derived from DLBCL and RLNH tissues was detected, and hiwi was overexpressed in tumor vessels of lymphoma. The hiwi expression in cell lines and tissues was measured by using RT-PCR and immuno-staining, as well as the Ang-2 and Tie-2 expressions in tissues. Hiwi was significantly expressed in cancer cell lines Hela, MCF-7, MDA-MB-231, MDA-MB-435s, A2780, 111 and 113. Compared with that of chronic cervicitis (CC), hyperplasia of mammary glands (HMG), ovarian benign lesions (OBL) and endometrium benign lesions (EBL), the expression of hiwi, Ang-2 and Tie-2 was increased significantly in uterine cervical cancer (UCC), breast carcinoma (BC), ovarian cancer (OC) and endometrial cancer (EC) (P<0.01). Additionally, the hiwi expression was positively correlated with Ang-2 in UCC, BC and OC, and Tie-2 in OC. These results suggest that hiwi plays an important role in the oncogenesis and is a potential target for cancer angiogenesis. PMID- 20204293 TI - Use of 18F-fluorodeoxyglucose positron emission tomography for diagnosis of uterine sarcomas. AB - We evaluated the use of 18F-fluorodeoxyglucose positron emission tomography (FDG PET) for the diagnosis of uterine sarcomas. FDG-PET combined with serum lactate dehydrogenase (LDH) levels were compared with FDG-PET alone for the diagnosis of leiomyosarcomas (LMS), which are the most difficult uterine sarcomas to diagnose. FDG-PET imaging of endometrial cancer (EC) was used as a reference. Immunoreactivity for glucose transporter-1 (GLUT-I) correlated with FDG uptake was evaluated in sarcomas and leiomyomas (LM), including cases not examined by FDG-PET. FDG was injected after at least 5 h fasting and standardized uptake values (SUVs) were analyzed quantitatively 50-70 min after injection. Immunohistochemical expression of GLUT-1 was studied in paraffin sections of tumors using anti-GLUT-1 antibodies and GLUT-1 expression scores were derived based on staining intensities. FDG-PET was performed preoperatively in a total of 53 patients including 10 with sarcomas, 19 with EC and 24 with LM. Immunohistochemical examination was performed in 17 sarcomas, 6 EC and 9 LM [6 usual LM, 1 uterine smooth muscle tumor of uncertain malignant potential (UMP), and 2 bizarre LM (BLM)]. SUVs for uterine sarcomas and EC were significantly higher (p=0.0001) than those for LMs. There were no significant differences in SUVs among ECs, carcinosarcomas (CS) and LMS. Significant differences in SUVs existed between LM and LMS (p=0.003). However, the diagnostic accuracy for LMS was only 73%. The diagnostic accuracy of FDG-PET combined with serum LDH was 100%. GLUT-1 expression scores were significantly higher in sarcomas and EC than in LM (p<0.0001). Intermediate GLUT-1 scores were found in two of the three cases of UMP and BLM. In conclusion, FDG-PET is useful for diagnosing uterine sarcomas, while FDG-PET combined with serum LDH is useful for diagnosing LMS. Immunohistochemical examination of GLUT-1 confirmed the high FDG uptake in LMS patients. PMID- 20204294 TI - Hyperthermic isolated limb perfusion for recurrent melanomas and soft tissue sarcomas: feasibility and reproducibility in a multi-institutional Hellenic collaborative study. AB - Hyperthermic isolated limb perfusion with TNF-alpha and melphalan (TM-HILP) is a complicated surgical procedure. Herein, we present the experience of the Hellenic collaborating centers with TM-HILP for inoperable in-transit melanoma and soft tissue sarcoma (STS) of the extremities to examine safety and feasibility of collaborating as a multi-institutional group for future research studies. From 2001 to 2009, twenty patients (median age 63.5 years) underwent TM-HILP for locally advanced in-transit melanoma (n=14) or unresectable STS (n=6). All patients underwent a 90-min isolated limb perfusion with melphalan (10 mg/l limb volume) and TNF-alpha (1-2 mg) under mild hyperthermia (39-40 degrees C). No major intra-operative complications occurred and all patients completed the procedure successfully. One patient developed postoperative ischemic necrosis of the limb necessitating amputation. All melanoma patients showed a response to TM HILP with 7 (62%) of them experiencing complete response. All STS patients attained complete response after excision of residual tumor. The median disease specific and limb-relapse-free survival was 15 and 12 months, respectively. TM HILP can be safely applied even in low volume tertiary hospitals provided that technology to minimize intraoperative systemic leakage is available. Future prospective studies can be performed reproducibly by this multi-institutional collaborative group. PMID- 20204295 TI - Human papillomavirus is frequently detected in gefitinib-responsive lung adenocarcinomas. AB - A number of studies have reported the presence of human papillomavirus (HPV) in lung carcinoma. Interestingly, its detection rate appears to differ histologically and geographically. The present study examined 30 adenocarcinomas and 27 squamous cell carcinomas of the lung in a southern area of Japan, and detected high-risk HPV genome in 9 (30%) adenocarcinomas and 2 (7%) squamous cell carcinomas, using PCR with SPF10 primers and INNO-LiPA HPV genotyping assay. The difference of HPV detection rates in adenocarcinomas and squamous cell carcinomas was statistically significant (P=0.044, Fisher's exact test). HPV-16 was the most prevalent HPV genotype, and was detected in 27% (8/30) of adenocarcinomas and in 7% (2/27) of squamous cell carcinomas. High-risk-HPV positive carcinomas had decreased proportions of pRb (P=0.107) and significantly increased proportions of p16INK4a expressing cells (P=0.031) when compared to HPV-negative lung carcinomas. All HPV-16-positive cases were considered to have an integrated form of HPV-16 but its viral load was low (geometric mean = 0.02 copy per cell). In 20 additional adenocarcinomas treated with gefitinib, a tyrosine kinase inhibitor specific for epidermal growth factor receptor, the presence of HPV was examined. Note that East Asian ethnicity is a predictive factor of gefitinib response. High risk HPV genome was found in 75% (6/8) of adenocarcinomas with complete or partial response to gefitinib but was not found in the remaining 12, which did not respond to gefitinib. In conclusion, the present study suggests that high risk HPV may be more strongly related to adenocarcinomas, particularly gefitinib responsive adenocarcinomas, when compared to squamous cell carcinomas. However, its low viral load makes it difficult to determine the etiological significance of these findings. PMID- 20204296 TI - Persistence of HPV after radio-chemotherapy in locally advanced cervical cancer. AB - A causal association of high risk HPV persistent infections with cervical cancer is firmly established by epidemiological and experimental evidence. Since HPV is considered a necessary factor for cervix carcinoma development and disease severity, the HPV DNA persistence may represent an indicator of both therapy effectiveness and risk of recurrence. The presence of HPV in locally advanced cervical carcinoma was analysed at the beginning of therapy, shortly after treatment and during follow-up, in 18 patients with cervix carcinoma treated by radio/chemotherapy. Persistence of HPV DNA sequences was revealed in 62.5% (10/16) of HPV positive patients, in which the HPV type and its physical status were exactly the same as at the onset of therapy, even many years after surgery. Interestingly, in two patients the HPV18 sequence analysis detected the same point mutations in the samples before and after the chemotherapy, and during the follow-up. HPV DNA clearance was associated with a better patient outcome because the majority of the HPV cleared women showed a complete response (6/6), no disease recurrence (4/6), and are still alive. Nevertheless, statistically significant association was seen only with complete responses versus partial or no responses. In conclusion, we demonstrated that HPV DNA positive tumour cells might persist for years in the genital epithelia, even after the surgical removal of the cervix and that HPV DNA detection after therapy is a valid and significant (p=0.03) tool to assess the efficacy of the treatment. PMID- 20204297 TI - Hypomethylation-induced expression of S100A4 increases the invasiveness of laryngeal squamous cell carcinoma. AB - The present study aimed to identify genes related to 5AZA-CdR in laryngeal squamous cell carcinoma (LSCC) and to investigate the role of S100A4 in the development and aggression of LSCC. Differentially expressed proteins were identified in Hep-2 cells treated with 5AZA-CdR by two-dimensional gel electrophoresis combined with MALDI-TOF-MS. mRNA, protein levels and DNA methylation status of S100A4 were assessed by RT-PCR, Western blotting and methylation-specific PCR, respectively. The invasiveness of Hep-2 cells transfected by siRNA S100A4 was determined by transwell migration assay. Protein profiles from Hep-2 cells treated with 5AZA-CdR were obtained, and several differentially expressed proteins such as S100 calcium-binding protein A4 (S100A4) were identified. Results of RT-PCR and Western blotting revealed that both mRNA and protein levels of S100A4 were significantly higher in the metastatic lymph nodes than those in paired adjacent normal laryngeal (PANL) or tumor tissues. The DNA methylation status displayed significant differences between the LSCC and the PANL tissues. The expression level of S100A4 decreased in Hep-2 cells undergoing RNA interference of S100A4. The number of cells which crossed the basement membrane filter was significantly lower in the RNAi S100A4 group when compared with the number in the control group. The abnormal expression of S100A4 identified in Hep-2 cells treated with an inhibitor of DNA methyltransferase appeared to result from the aberrant DNA methylation status of S100A4. The abnormal expression of S100A4 altered the invasiveness of LSCC. PMID- 20204298 TI - The Wilms' tumor suppressor WT1 induces estrogen-independent growth and anti estrogen insensitivity in ER-positive breast cancer MCF7 cells. AB - A switch from estrogen-dependent to estrogen-independent growth is a critical step in malignant progression of breast cancer and is a major problem in endocrine therapy. However, the molecular mechanisms underlying this switch remain poorly understood. The Wilms' tumor suppressor gene, wt1, encodes a zinc finger protein WT1 that functions as a transcription regulator. High levels of the WT1 expression have been associated with malignancy of breast cancer. The goal of this study was to investigate the function of WT1 in malignant progression of breast cancer. We found that the high passage ER-positive breast cancer MCF7H cells expressed EGFR, HER2 and WT1 at higher levels compared to the low passage MCF7L cells. MCF7H cells responded weakly to estrogen stimulation, grew rapidly in the absence of estrogen and were insensitive to anti-estrogens such as ICI 182,780 and 4-hydroxy-tamoxifen (4OH-TAM). We also established stable cell lines from the low passage MCF7L cells to constitutively express exogenous WT1 and found elevated levels of EGFR and HER2 expression, estrogen-independent growth and anti-estrogen insensitivity in WT1-transfected MCF7L cells. These results suggested WT1 promotes estrogen-independent growth and anti-estrogen resistance in ER-positive breast cancer cells presumably through activation of the signaling pathways mediated by the members of EGFR family. PMID- 20204299 TI - Correlation between pathological data and the RNA expression of p53 or p53 targeted genes in primary invasive ductal breast carcinomas: a preliminary study. AB - The protein expression of the growth suppressive p53 transcription factor and its inhibitor human double minute 2 (Hdm2) is altered in ductal breast carcinomas (DBC). However, the assessment of p53 and/or Hdm2 protein levels in DBC tissues was found to have a questionable prognostic significance. We evaluated the RNA expression of p53, hdm2, and the p53-targeted p21waf-1 and thrombospondin (tsp)-1 by primary DBC tissues, then correlated the RNA levels with patient clinicopathological data. The mean RNA expression level of p53 and that of hdm2 were elevated in large-sized, poorly differentiated, node-positive DBC, while a high p21waf-1 or tsp-1 mean expression level comprised small-sized, low-grade, node-negative tumors. Further analyses found that the correlation between the RNA expression of p53 and that of its targeted genes was reduced as tumor aggressiveness increased. However, for all the examined genes, association of the intensity of RNA expression with the pathological data was not statistically significant (p>0.05). Altogether, our preliminary RNA data confirm the results from previous protein studies, indicating that despite p53 expression and activity show a trend to vary in association with DBC clinical features, neither p53 nor its transcriptional targets can accurately monitor the behaviour of invasive DBC. PMID- 20204300 TI - The prognostic value of cadherin switch in bladder cancer. AB - Loss of E-cadherin expression and gain of N-cadherin expression ('cadherin switch') is shown to be characteristic in epithelial to mesenchymal transition (EMT), a mechanism associated with cancer progression. Furthermore, the prognostic role of P-cadherin in different cancers is controversial. The aim of this study was to evaluate the prognostic significance of 'cadherin switch' on the gene expression level in bladder cancer. Frozen tissue samples of 181 bladder cancer patients and 7 control individuals were analyzed by quantitative real-time PCR. Kaplan-Meier log-rank test and Cox univariate and multivariate analysis were performed to assess the prognostic relevance of gene expression of E-, N- and P cadherin. Cox univariate analysis revealed that the decrease of E-cadherin and the gain of N-cadherin gene expression are risk factors for cancer-related death (P=0.087, P=0.005, respectively). Fourteen percent (13/92) of muscle-invasive bladder cancers were N-cadherin- negative. These patients had a significantly poorer prognosis than those with N-cadherin-positive muscle-invasive tumors (P=0.024). P-cadherin gene expression proved to be a significant independent prognostic factor for both cancer-specific and recurrence-free survival (P=0.011, P=0.036). The characteristic 'cadherin switch' between low- and high-stage tumors that we observed and the prognostic significance of E-, N- and P-cadherin suggests the importance of these markers in bladder cancer progression. The poor patient prognosis in N-cadherin-negative muscle-invasive tumors indicates an alternative, N-cadherin-independent way in bladder cancer progression. PMID- 20204301 TI - p38 MAPK plays a distinct role in sulforaphane-induced up-regulation of ARE dependent enzymes and down-regulation of COX-2 in human bladder cancer cells. AB - Sulforaphane, a well-characterised dietary isothiocyanate, has been demonstrated to be a potent anti-carcinogenic agent in numerous cancer models, including in bladder cancer cells. In the present study, sulforaphane up-regulated the expression of two Nrf2-dependent enzymes, glutathione transferase (GSTA1-1) and thioredoxin reductase (TR-1), and down-regulated cyclooxygenase 2 (COX-2) in human bladder cancer T24 cells. This action of sulforaphane was associated with the p38 MAPK activity. When a specific p38 MAPK inhibitor, SB202190, was used, both sulforaphane-induced up-regulation of GSTA1-1 and TR-1 and down-regulation of COX-2 were eliminated; in contrast, an activator of p38 MAPK, anisomycin, enhanced the effect of sulforaphane on modulation of GST, TR-1 and COX-2 expression. Moreover, it was established that anisomycin increased nuclear translocation of Nrf2, whereas SB202190 abrogated sulforaphane-induced Nrf2 translocation into the nucleus. In summary, these data suggest that p38 MAPK activation can regulate Nrf2-antioxidant response element (ARE)-driven enzymes and COX-2 expression, thereby facilitating the role of sulforaphane in cancer prevention. This study strongly supports the contention that p38 MAPK is a pivotal and efficient target of sulforaphane in the chemoprevention of bladder cancer. PMID- 20204302 TI - Dexamethasone treatment inhibits VEGF production via suppression of STAT3 in a head and neck cancer cell line. AB - Glucocorticoids (GCs) modulate the synthesis of many pro-inflammatory cytokines and influence multiple transduction pathways. GCs negatively or positively influence the transcription factors of their target genes. All of these transcription signals are closely connected to cancer survival or death. We investigated the action of dexamethasone (DEX) on head and neck cancer cell lines. When SNU-1041 and SNU-1076 were treated with DEX, the cell lines showed different patterns of responses. DEX inhibition of cell growth depended on concentration in SNU-1041, but not in SNU-1076. Furthermore, DEX suppressed vascular endothelial growth factor (VEGF) secretion from SNU-1041, but not from SNU-1076. We explored the mechanism that explains these distinct differences. After DEX treatment, the differences of NF-kappaB (p65), glucocorticoid receptor and p-AKT were not observed between the cell lines. However, phospho-signal transducer and activator of transcription 3 (STAT3) decreased in SNU-1041 only. Moreover, STAT3 inhibition using si-RNA suppressed VEGF secretion. When STAT3 was overexpressed after DEX treatment, the level of VEGF in the culture media was restored. Taken together, we suggest that p-STAT3 can be a mediating factor which regulates VEGF secretion in the DEX treatment. Because the relationship between the three molecules DEX, STAT3 and VEGF is scarcely known, our findings clarified one of the signaling pathways of DEX, which is often used in clinical conditions. PMID- 20204303 TI - Anti-leukaemic effects of two extract types of Lactuca sativa correlate with the activation of Chk2, induction of p21, downregulation of cyclin D1 and acetylation of alpha-tubulin. AB - The water extract of the lettuce Lactuca sativa, but not the ethyl acetate extract, inhibited the growth of HL-60 leukaemia cells and MCF-7 breast cancer cells. This correlated with the activation of checkpoint kinase 2 (Chk2), the induction of the tumour suppressor p21, and the severe downregulation of the proto-oncogene cyclin D1. The ethyl acetate extract, but not the water extract, induced HL-60 cell death, which correlated with the acetylation of alpha-tubulin. The acetylation of alpha-tubulin is indicative for microtubuli stabilisation such as induced by taxol. The calculated amount for human intake would require approximately 3 kg lettuce to reach the required concentration shown to inhibit 50% HL-60 proliferation. PMID- 20204304 TI - Propyl gallate inhibits the growth of HeLa cells via caspase-dependent apoptosis as well as a G1 phase arrest of the cell cycle. AB - Propyl gallate (PG) as a synthetic antioxidant exerts a variety of effects on tissue and cell functions. Here, we evaluated the effects of PG on the growth of HeLa cells in relation to apoptosis and the cell cycle. PG dose-dependently inhibited the growth of HeLa cells with an IC50 of approximately 800 microM at 24 h. DNA flow cytometric analysis indicated that PG significantly induced a G1 phase arrest of the cell cycle along with an increase in the cyclin-dependent kinase inhibitor (CDKI) p27. In addition, PG induced apoptosis, which was accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsim), activation of caspase-3 and caspase-8 and PARP cleavage. All the tested caspase inhibitors (pan-caspase, caspase-3, -8 or -9 inhibitor) significantly rescued HeLa cells from PG-induced cell death. However, none of the caspase inhibitors prevented the loss of MMP (DeltaPsim) induced by PG. In conclusion, PG inhibited the growth of HeLa cells via caspase-dependent apoptosis as well as a G1 phase arrest of the cell cycle. PMID- 20204305 TI - The effect of siRNA-Egr-1 and camptothecin on growth and chemosensitivity of breast cancer cell lines. AB - We have examined the effects of a siRNA targeting the Egr-1, alone or in combination with the breast cancer therapeutic camptothecin (Cpt), in suppressing breast cancer cell survival and anchorage-independent growth in the breast cancer cell lines SK-BR3 and MCF-7. In mammary and lung tumors, as well as most normal tissues, Egr-1 expression is low, suggesting a possible relation between the low levels of Egr-1 and the development of mammary neoplasias. However, analyses of the expression of Egr-1 in breast carcinoma cells, SK-BR3 and MCF-7 demonstrated a relatively high expression of the endogenous Egr-1 in these cells. To investigate the effect of the blocking of the endogenous Egr-1 in breast cancer cells, we used small interfering RNA (siRNA) against Egr-1 alone or in combination with Cpt, and expected that the cell sensitivity to chemotherapeutic drug would increase, when blocked with the Egr-1 gene and treated with Cpt. Thus, we performed in vitro experiment to clarify the effect of Egr-1 on tumor cell lines growth. We made control and siRNA-Egr-1 using vector plasmids and then transfected SK-BR3 and MCF-7 cells. After treating the cells with siRNA-Egr-1, the cell lines were assayed with Cpt to confirm the effect of Egr-1 siRNA using the cell expression of mRNA and protein, proliferation assay and anchorage activity with soft agar. Human SK-BR3 and MCF-7 breast carcinoma cell growth and capacity of anchorage transfected with siRNA-Egr-1 or treated with cpt was slower than that of the control group. This effect was increased when the cells were given simultaneously siRNA and camptothecin. The results strongly suggest that siRNA-Egr-1 alone or in combination with camptothecin could be a potent antineoplastic agent in suppressing the growth of breast tumor despite the known role of Egr-1 as a tumor-suppressor in several other types of human cancers. PMID- 20204306 TI - RAD001 offers a therapeutic intervention through inhibition of mTOR as a potential strategy for esophageal cancer. AB - Esophageal cancer is one of the most frequently occurring cancers in the world. Targeting therapy strategy of cancer with specific inhibitors is developing and has showed promising antitumor efficacy. It is known that mTOR is an important controller of cell growth. RAD001 (everolimus) is a specific inhibitor of mTOR that can block the mTOR signaling pathway. The purposes of this study was to explore the inhibitory effects of RAD001 on mTOR signaling and the mechanism of cell growth suppression by RAD001. We examined both the expression of mTOR, p70S6K and S6 in SEG-1 esophageal cancer cells and KOB-13 normal esophageal epithelial cells and the efficacy of RAD001 against SEG-1 esophageal cancer cells. mTOR, p70S6K and S6 were overexpressed in SEG-1 esophageal cancer cells compared with KOB-13 normal esophageal epithelial cells. SEG-1 esophageal cancer cells were sensitive to RAD001. The survival rate of the cells treated with RAD001 over 0.33 microM was significantly different compared with that of control (P<0.01). RAD001 inhibited the phosphorylation of mTOR (Ser2448) and S6 (Ser240/244) in different grades and the expressions of mTOR, p70S6K and S6. As a result, RAD001 induced a dose-dependent decrease in cell proliferation, G1/S arrest and damage of cell shape. Taken together, these data showed that RAD001 can inhibit mTOR signaling and proliferation in SEG-1 esophageal cancer cells in vitro. It offers a therapeutic intervention through inhibition of mTOR as a potential strategy for esophageal cancer. PMID- 20204307 TI - Inhibitory effects of melatonin on sulfatase and 17beta-hydroxysteroid dehydrogenase activity and expression in glioma cells. AB - Melatonin interacts with estradiol at the estrogen receptor level in different kinds of neoplasias and also regulates the expression and the activity of some enzymes involved in the biosynthesis of estrogens in peripheral tissues. Glioma cells express estrogen receptors and have the ability to synthesize estrogens locally. Since melatonin inhibits the growth of C6 cells, and this indoleamine has been demonstrated to be capable of decreasing aromatase expression and activity in these cells, the aim of the present study was to analyze whether the regulation of the sulfatase, the enzyme that catalyzes the rate-limiting step in the conversion of estrogen sulfates to estrogens, and 17beta-hydroxysteroid dehydrogenase, the enzyme which converts the relatively inactive estrone to the most potent 17beta-estradiol, could be involved in the inhibition of glioma cell growth by melatonin. We found that melatonin decreases the growth of C6 glioma cells and reduces the sulfatase and 17beta-hydroxysteroid dehydrogenase activity. Finally, we demonstrated that melatonin downregulates sulfatase and 17beta hydroxysteroid dehydrogenase mRNA steady state levels in these glioma cells. By analogy to the implications of these enzymes in other forms of estrogen-sensitive tumors, it is conceivable that their modulation by melatonin may play a role in the growth of glioblastomas. PMID- 20204308 TI - [Surgical research in Germany--an international comparison]. AB - Surgical research in Germany occupies a lower position in international ranking than expected. According to the size of the population, the economic impact, the gross domestic product and the research funding capacity, the impact of German surgical research should be much higher. Reasons are a more intensive commitment to patient care, structural differences and a changing lifestyle in younger doctors in comparison to many leading countries. If the situation is to be improved all factors have to be evaluated and, if possible, changed. Overall, German surgeons are underrepresented as readers and authors in the scientific market, which is mostly in the English language. PMID- 20204309 TI - [Does experimental surgery still exist?]. AB - During the last two decades research in surgery has changed from a specific to an interdisciplinary approach. Accordingly, the research approaches in surgery show marked overlap with those of other disciplines, such as oncology, immunology, gastroenterology, cardiology and intensive care medicine. This questions the need of experimental surgery in the future. A current survey, however, showed that experimental surgery still produces a multitude of excellent scientific studies, which substantially contribute to the development in surgery and, thus, to the improvement of surgical care. In addition experimental surgery coins the analytical thinking of young surgeons and mediates the enthusiasm and motivation to search for the undiscovered in surgery. Therefore, there is need to further support experimental surgery as an essential component of academic surgery. Thus, it can be concluded that experimental research still represents a prerequisite for innovations in operative medicine and also contributes to the improvement of scientific performance in surgery. PMID- 20204310 TI - [S1 guideline on the "diagnosis and treatment of snoring in adults"]. AB - Due to the frequency of this phenomenon and the often considerable distress caused to the affected person, competent advice, diagnosis and treatment of snoring in adults is of particular importance. The aim of this guideline is to promote high-quality medical care for patients affected by this problem. According to the three-level concept of the AWMF, it corresponds to an S1 guideline. Prior to any therapeutic intervention, relevant sleep medical history, clinical examination, as well as a mandatory objective diagnostic measure are performed. Snoring is only treated if the patient asks for it. In general, invasive methods should be viewed critically and the patient should be advised correspondingly. In the case of surgical therapy, minimally invasive techniques are preferred. Reducing body weight (in the case of overweight snorers), abstinence from alcohol, nicotine and sleep medication, as well as maintaining a healthy sleep-wake cycle can be recommended from a sleep-medicine perspective, although convincing clinical studies are not yet available. Since evidence for the effectiveness of muscle stimulation or various methods for toning and training of the muscles of the floor of mouth is not available, these methods are not recommended. Snoring can be successfully treated with the use of an intraoral device; however, careful patient selection is important. Avoiding a supine position during sleep can be helpful in some cases. Only limited data is available on the success rates of the surgical approaches and long term data is often lacking, and not all techniques have been sufficiently evaluated from a scientific point of view. Nasal surgery is only indicated if the patient suffers from nasal obstruction. Extensive data supports the effectiveness of laser assisted resection of excessive soft palate tissue (laser-assisted uvuloplasty, LAUP). In principle, however, such resections can be performed using other techniques. Placebo-controlled studies were able to prove the effectiveness of radiofrequency surgery of the soft palate. A reduction in snoring could also be achieved in many cases by means of soft palate implants with minimal post operative morbidity. The indication for tonsillectomy and uvulopalatopharyngoplasty should be made cautiously due to the comparatively high morbidity associated with these procedures. PMID- 20204311 TI - [Bacterial sialadenitis]. AB - The parotid gland is most commonly involved in bacterial sialadenitis. Predisposing factors for the ductally ascending infection, are dehydration, xerogenic drugs and salivary gland diseases associated with ductal obstructions or reduced saliva secretion. In the majority of cases the infection is caused by Staphylococcus aureus. However, a variety of other aerobic and anaerobic pathogens may be involved. Besides hydration, elimination of ductal obstruction and stimulation of saliva flow antibiotic treatment according to antibiogram is essential. In selected cases, for instance if a salivary gland abscess develops, surgical treatment may become necessary. Actinomycosis, tuberculosis and atypical mycobacteriosis are rare variations of bacterial sialadenitis which clinically may resemble a salivary gland tumor. PMID- 20204312 TI - [Viral sialadenitis]. AB - Beside a secondary, clinically latent salivary virus secretion, differentiation can be made between concomitant sialadenitis induced by various viruses and viral sialadenitis showing characteristic and/or pathognomonic morphological and clinical features, whereby sialadenotropism must also be present. Viremia induces a viral inflammatory reaction via a local cytopathogenetic effect. Clinically important viral diseases include epidemic parotitis (mumps), cytomegaly and HIV infection presenting with large lymphoepithelial cystic lesions. PMID- 20204313 TI - [Modern concepts for the diagnosis and therapy of sialolithiasis]. AB - Sialoliths are the underlying cause of salivary gland obstructive disease in 60% 70% of cases. Modern minimally invasive techniques have enabled accurate diagnosis and findings-specific therapy with the aim of full gland-function preservation. This article provides an overview of the current diagnostic measures for and therapy of sialolithaisis. Ultrasound is the investigation of first choice and is able to recognize stones in well over 90% of cases. Sialendoscopy is a directly visualizing technique which is superior to all other diagnostic measures for the assessment of pathologic changes in the salivary duct system and the detection of stones. Treatment was significantly improved with the introduction of extracorporal shock wave lithotripsy (ESWL), sialographic controlled techniques, surgical procedures of the duct system and in particular by interventional sialendoscopy. Interventional sialendoscopy, especially when combined with other treatment modalities, has a success rate of 85%-95%. Cases which respond poorly to therapy can be treated successfully with the endoscopic transcutaneous approach in about 90% of cases. When sialendoscopy is performed in combination with other minimally invasive treatment options the gland can be preserved in 95%-98% of all cases. PMID- 20204314 TI - [Sialadenitis and sialolithiasis]. PMID- 20204315 TI - [Pedunculated osteoma of the frontal sinus]. AB - Osteoma, the most frequent tumor of the paranasal sinuses (PNS), is often asymptomatic. Men are more commonly affected than women. A 52-year-old patient complained of increasing incidence of headaches following the resolution of frontal sinusitis. Computer tomography demonstrated a pedunculated osteoma of the frontal sinus. Histomorphologically, PNS osteomas usually show cortical bone differentiation with sparse medullary space and a lamellar configuration. At 6 months following surgical resection, the patient was still symptom-free. PMID- 20204316 TI - [Laryngopyocele. Rare cause of relapsing cervical infections]. AB - A laryngopyocele forms when a laryngocele, as a dilatation of the laryngeal ventricle, becomes infected and fills with mucopus. Laryngopyoceles are rare, as only few cases have been previously reported in the literature. The case of a 75 year-old woman who was treated twice because of a deep cervical infection is described. First of all the cause remained unknown but 3 years after the first manifestation air could be aspirated from a now non-infected neck swelling. A laryngocele was revealed as the cause of the relapsing infection. The surgical resection led to a final healing and the patient remained free from disease. When dealing with a clinical picture of an unknown deep cervical infection, an external or mixed laryngocele should be considered in the differential diagnosis as a rare cause. PMID- 20204317 TI - [Jugular vein thrombosis caused by a neuroendocrine non-small cell lung cancer]. AB - A 65-year-old patient presented with extensive swelling of the lateral neck. B mode ultrasound showed an oval, well defined, hypoechoic formation consisting of multiple circular layers extending from the base of the skull to the subclavian vein. On subsequent computed tomography the size of the lesion was confirmed and the cause, a mediastinal mass compressing the superior caval vein, was identified. Histological examination of the mass revealed a neuroendocrine active non-small-cell-cancer of the lung. Treatment with high-dose heparin and antibiotics was started immediately, combined with palliative chemotherapy.The differential diagnosis of neck masses includes congenital, infectious, neoplastic and secondary causes due to disease in other regions of the body. Etiologies for jugular vein thrombosis include prolonged central venous catheterization, trauma, obstruction, infection as well as hypercoagulation. In order to diagnose masses in the head and neck region, other parts of the body need to be successively included if no local cause can be identified. PMID- 20204318 TI - Brood comb as a humidity buffer in honeybee nests. AB - Adverse environmental conditions can be evaded, tolerated or modified in order for an organism to survive. During their development, some insect larvae spin cocoons which, in addition to protecting their occupants against predators, modify microclimatic conditions, thus facilitating thermoregulation or reducing evaporative water loss. Silk cocoons are spun by honeybee (Apis mellifera) larvae and subsequently incorporated into the cell walls of the wax combs in which they develop. The accumulation of this hygroscopic silk in the thousands of cells used for brood rearing may significantly affect nest homeostasis by buffering humidity fluctuations. This study investigates the extent to which the comb may influence homeostasis by quantifying the hygroscopic capacity of the cocoons spun by honeybee larvae. When comb containing cocoons was placed at high humidity, it absorbed 11% of its own mass in water within 4 days. Newly drawn comb composed of hydrophobic wax and devoid of cocoons absorbed only 3% of its own mass. Therefore, the accumulation of cocoons in the comb may increase brood survivorship by maintaining a high and stable humidity in the cells. PMID- 20204319 TI - Identification of a major QTL allele from wild soybean (Glycine soja Sieb. & Zucc.) for increasing alkaline salt tolerance in soybean. AB - Salt-affected soils are generally classified into two main categories, sodic (alkaline) and saline. Our previous studies showed that the wild soybean accession JWS156-1 (Glycine soja) from the Kinki area of Japan was tolerant to NaCl salt, and the quantitative trait locus (QTL) for NaCl salt tolerance was located on soybean linkage group N (chromosome 3). Further investigation revealed that the wild soybean accession JWS156-1 also had a higher tolerance to alkaline salt stress. In the present study, an F(6) recombinant inbred line mapping population (n = 112) and an F(2) population (n = 149) derived from crosses between a cultivated soybean cultivar Jackson and JWS156-1 were used to identify QTL for alkaline salt tolerance in soybean. Evaluation of soybean alkaline salt tolerance was carried out based on salt tolerance rating (STR) and leaf chlorophyll content (SPAD value) after treatment with 180 mM NaHCO(3) for about 3 weeks under greenhouse conditions. In both populations, a significant QTL for alkaline salt tolerance was detected on the molecular linkage group D2 (chromosome 17), which accounted for 50.2 and 13.0% of the total variation for STR in the F(6) and the F(2) populations, respectively. The wild soybean contributed to the tolerance allele in the progenies. Our results suggest that QTL for alkaline salt tolerance is different from the QTL for NaCl salt tolerance found previously in this wild soybean genotype. The DNA markers closely associated with the QTLs might be useful for marker-assisted selection to pyramid tolerance genes in soybean for both alkaline and saline stresses. PMID- 20204320 TI - The effect of pyramiding Phytophthora infestans resistance genes R Pi-mcd1 and R Pi-ber in potato. AB - Despite efforts to control late blight in potatoes by introducing R(pi)-genes from wild species into cultivated potato, there are still concerns regarding the durability and level of resistance. Pyramiding R(pi)-genes can be a solution to increase both durability and level of resistance. In this study, two resistance genes, R(Pi-mcd1) and R(Pi-ber), introgressed from the wild tuber-bearing potato species Solanum microdontum and S. berthaultii were combined in a diploid S. tuberosum population. Individual genotypes from this population were classified after four groups, carrying no R(pi)-gene, with only R (Pi-mcd1), with only R(Pi ber), and a group with the pyramided R(Pi-mcd1) and R (Pi-ber) by means of tightly linked molecular markers. The levels of resistance between the groups were compared in a field experiment in 2007. The group with R(Pi-mcd1) showed a significant delay to reach 50% infection of the leaf area of 3 days. The group with R ( Pi-ber ) showed a delay of 3 weeks. The resistance level in the pyramid group suggested an additive effect of R (Pi-mcd1) with R(Pi-ber). This suggests that potato breeding can benefit from combining individual R(pi)-genes, irrespective of the weak effect of R(Pi-mcd1) or the strong effect of R(Pi-ber). PMID- 20204321 TI - High normal fasting glucose level in obese youth: a marker for insulin resistance and beta cell dysregulation. AB - AIMS/HYPOTHESIS: A high but normal fasting plasma glucose level in adults is a risk factor for future development of type 2 diabetes mellitus and cardiovascular disease. We investigated whether normal fasting plasma glucose levels (<5.60 mmol/l) are associated with decreases in insulin sensitivity and beta cell function, as well as an adverse cardiovascular profile in obese youth. METHODS: We performed a cross-sectional analysis in a multiethnic sample of 1,020 obese youth (614 girls and 406 boys; mean age 12.9 years [CI 95% 12.7-13.1], BMI z score 2.34 [CI 95% 2.31-2.38]) with normal fasting plasma glucose. All participants had a standard OGTT, with calculation of indices of insulin sensitivity and beta cell function. For the analysis, prepubertal and pubertal participants were stratified into quartiles of normal fasting plasma glucose. RESULTS: We observed a significant increase in fasting insulin and AUC 2 h glucose across quartiles. Pronounced changes were observed in insulin sensitivity and secretion, particularly in the pubertal group. Moreover, the odds of presenting with impaired glucose tolerance increased by 4.5% with each 0.06 mmol/l increase in fasting plasma glucose. No significant differences in cardiovascular indices were seen across quartiles. CONCLUSIONS/INTERPRETATION: These data suggest that in obese youth, independent of age, BMI z score, sex, family history and ethnicity, insulin sensitivity and secretion decline when moving from low to high normal fasting plasma glucose. The simple measure of fasting plasma glucose could assist clinicians in identifying children for targeted diabetes screening and subsequent lifestyle management. PMID- 20204323 TI - Single incision mini-sling versus a transobutaror sling: a comparative study on MiniArc and Monarc slings. AB - INTRODUCTION AND HYPOTHESIS: A retrospective, dual-center, cohort study on the single incision MiniArc sling and the transobturator Monarc sling in the treatment of stress urinary incontinence is presented. We hypothesized that both systems would perform equally well. METHODS: One hundred thirty-one (MiniArc n = 75, Monarc n = 56) consecutive patients were evaluated. Evaluation was performed by cough stress test (CST), daily pad use, IIQ-7, UDI-6, and a 0-5 visual analog scale for quality of life. The 1-year data are presented. RESULTS: Six weeks after surgery, 91% of the patients in both populations had a negative CST. At 1 year, 85% of the MiniArc group and 89% of the Monarc group (p = 0.60) maintained a negative CST. QoL, symptom scores, and number of pads improved significantly and were comparable in both groups. Complication rates were similar. CONCLUSIONS: These results suggest that MiniArc sling and Monarc sling are equally effective in the treatment of stress incontinence at 1 year follow-up. PMID- 20204322 TI - Genome-based expression profiling study of Hunner's ulcer type interstitial cystitis: an array of 40-gene model. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to explore potential molecular mechanisms contributing to the pathogenesis of Hunner's ulcer type interstitial cystitis (IC). METHODS: Dataset acquisitions from Gene Expression Omnibus under platform accession no GSE 11783. We compared global gene expression profiles in bladder epithelial cells from IC patients with Hunner's ulcer corresponding to normal controls. We re-sampling and exploit the correlation structure presented in the dataset through the transcriptional response. For each patient, two bladder biopsies were studied, one from an ulcer area and one from a non-ulcer area. RNA was extracted, and all labeled samples were hybridized to Human Genome U133 Plus 2.0 Array (Affymetrix, CA, USA). RESULTS: The Mahalanobis distance in hierarchical cluster analysis revealed a model of 40 genes expression which is increased in IC and ulcerated IC. Our results can be summarized as follows: First, the expressions of major histocompatibility complex (MHC) class IF and II molecules, leukocyte immunoglobulin-like receptors, hepatitis A virus cellular receptor 2, and interleukin 32 were increased in bladder epithelial from IC and ulcerative IC area. Next, there is an indication of antigen-mediated aggregation of the high-affinity Fc epsilon and gamma RI leading to allergic inflammation through the disease status. Third, the high-affinity Fc gamma RI subunit facilitated T-cell-mediated immune response through the disease status. Such changes, jointly termed "bladder remodeling," can constitute an important long-term consequence of Hunner's ulcer type IC. CONCLUSIONS: Our results indicate that genome-based expression profiling can be used for the diagnostic tests of Hunner's ulcer type IC in clinical practice. PMID- 20204325 TI - Transurethral and suprapubic mesh resection after Prolift bladder perforation: a case report. AB - Bladder perforation is a complication which can occur after a Prolift procedure and may enhance vesicovaginal fistula formation. Different methods of management of bladder perforation caused by mesh procedures are described in the literature, and most authors advise complete excision of the mesh. In the case described in this article, we propose a combined transurethral and suprapubical approach as the optimal method for maximal tape removal, being both minimally invasive and less damaging to the vesical wall. A suprapubical catheter can be removed shortly after surgery to enable optimal tissue healing of the vesical mucosa. PMID- 20204326 TI - Tape functionality: position, change in shape, and outcome after TVT procedure- mid-term results. AB - INTRODUCTION AND HYPOTHESIS: This study evaluates the relevance of the tape position and change in shape (tape functionality) under in vivo conditions for mid-term outcome. METHODS: Changes in the sonographic tension-free vaginal tape (TVT) position relative to the percentage urethral length and the tape-urethra distance were determined after 6 and 48 months in 41 women with stress urinary incontinence. RESULTS: At 48 months, 76% (31/41) of women were cured, 17% (7/41) were improved, and 7% (3/41) were failures. Disturbed bladder voiding was present in 12% (5/41), de novo urge incontinence in 7% (3/41). The median TVT position was at 63% of urethral length. Median tape-urethra distance was 2.7 mm, ranging from 2.9 mm in continent patients without complications to 1.1 mm in those with obstructive complications. Patients with postoperative urine loss had a median distance of 3.9 mm. The tape was stretched at rest and C-shaped during straining in 15 of 41 women (37%) at 48 months (all continent). Patients with this tape functionality at 6 months were also cured at 48 months in 86% of cases (19/22), and only 14% (3/22) showed recurrent incontinence. CONCLUSIONS: Mid-term data suggest an optimal outcome if the tape is positioned at least 2 mm from the urethra at the junction of the middle and distal thirds. Patients with optimal tape functionality at 6 months are likely to show mid-term therapeutic success. PMID- 20204328 TI - Is computational toxicology withering on the vine? AB - The difficulties of developing predictive computational models of toxicity are discussed in relation to their internal and external validation, the selection of relevant physicochemical data and the need to characterise the structure-activity relationship landscapes obtained with training sets of chemicals by using recently published methods. It is concluded that the developers of in silico systems for toxicity prediction should apply such methods to ensure adequate and continuous sampling of chemical space, especially when external validation cannot be undertaken due to lack of sufficient test chemicals not used in the training set. This, combined with discriminate selection of molecular descriptors, and the use of reliable toxicity data, should improve model predictivity. PMID- 20204327 TI - Prevalence of major levator abnormalities in symptomatic patients with an underactive pelvic floor contraction. AB - INTRODUCTION AND HYPOTHESIS: Major levator ani abnormalities (LAA) may lead to abnormal pelvic floor muscle contraction (pfmC) and secondarily to stress urinary incontinence (SUI), prolapse, or fecal incontinence (FI). METHODS: A retrospective observational study included 352 symptomatic patients to determine prevalence of LAA in underactive pfmC and the relationship with symptoms. On 2D/3D transperineal ultrasound, PfmC was subjectively assessed as underactive (UpfmC) or normal (NpfmC) and quantified. LAA, defined as a complete avulsion of the pubic bone, was analyzed using tomographic ultrasound imaging. RESULTS: LAA were found in 53.8% of women with UpfmC versus 16.1% in NpfmC (P < 0.001). Patients with UpfmC were less likely to reduce hiatal area on pfmC (mean 7% reduction vs 25% in NpfmC (P < 0.001)). An UpfmC was associated with FI (P = 0.002), not with SUI or prolapse of the anterior and central compartment. CONCLUSION: An underactive pfmC is associated with increased prevalence of LAA and FI. PMID- 20204329 TI - Experimental design for optimization of microwave-assisted extraction of benzodiazepines in human plasma. AB - A simple and fast microwave-assisted-extraction (MAE) method has been evaluated as an alternative to solid-phase extraction (SPE) for the determination of six benzodiazepines widely prescribed in European countries (alprazolam, bromazepam, diazepam, lorazepam, lormetazepam and tetrazepam) in human plasma. For MAE optimization a Doehlert experimental design was used with extraction time, temperature and solvent volume as influential parameters. A desirability function was employed in addition to the simultaneous optimization of the MAE conditions. The analysis of variance showed that the solvent volume had a positive influence on the extraction of all the analytes tested, achieving a statistically significant effect. Also, the extraction time had a statistically significant effect on the extraction of four benzodiazepines. The selected MAE conditions-89 degrees C, 13 min and 8 mL of chloroform/2-propanol (4:1, v/v)-led to recoveries between 89.8 +/- 0.3 and 102.1 +/- 5.2% for benzodiazepines using a high performance liquid chromatography method coupled with diode-array detection. The comparison of MAE and SPE shows better results for MAE, with a lower number of steps in handling the sample and greater efficiency. The applicability of MAE was successfully tested in 27 plasma samples from benzodiazepine users. PMID- 20204330 TI - Preparation and certification of arsenate [As(V)] reference material, NMIJ CRM 7912-a. AB - Arsenate [As(V)] solution reference material, National Metrology Institute of Japan (NMIJ) certified reference material (CRM) 7912-a, for speciation of arsenic species was developed and certified by NMIJ, the National Institute of Advanced Industrial Science and Technology. High-purity As(2)O(3) reagent powder was dissolved in 0.8 M HNO(3) solution and As(III) was oxidized to As(V) with HNO(3) to prepare 100 mg kg(-1) of As(V) candidate CRM solution. The solution was bottled in 400 bottles (50 mL each). The concentration of As(V) was determined by four independent analytical techniques-inductively coupled plasma mass spectrometry, inductively coupled plasma optical emission spectrometry, graphite furnace atomic absorption spectrometry, and liquid chromatography inductively coupled plasma mass spectrometry-according to As(V) calibration solutions, which were prepared from the arsenic standard of the Japan Calibration Service system and whose species was guaranteed to be As(V) by NMIJ. The uncertainties of all the measurements and preparation procedures were evaluated. The certified value of As(V) in the CRM is (99.53 +/- 1.67) mg kg(-1) (k = 2). PMID- 20204331 TI - Avogadro constant challenge. PMID- 20204332 TI - Novel molecular tumour classification using MALDI-mass spectrometry imaging of tissue micro-array. AB - The development of tissue micro-array (TMA) technologies provides insights into high-throughput analysis of proteomics patterns from a large number of archived tumour samples. In the work reported here, matrix-assisted laser desorption/ionisation-ion mobility separation-mass spectrometry (MALDI-IMS-MS) profiling and imaging methodology has been used to visualise the distribution of several peptides and identify them directly from TMA sections after on-tissue tryptic digestion. A novel approach that combines MALDI-IMS-MSI and principal component analysis-discriminant analysis (PCA-DA) is described, which has the aim of generating tumour classification models based on protein profile patterns. The molecular classification models obtained by PCA-DA have been validated by applying the same statistical analysis to other tissue cores and patient samples. The ability to correlate proteomic information obtained from samples with known and/or unknown clinical outcome by statistical analysis is of great importance, since it may lead to a better understanding of tumour progression and aggressiveness and hence improve diagnosis, prognosis as well as therapeutic treatments. The selectivity, robustness and current limitations of the methodology are discussed. PMID- 20204333 TI - Characterisation of tribocorrosion behaviour of multilayer PVD coatings. AB - The effect of repassivation on tribocorrosion behaviour of two multilayer coatings of different structures is studied experimentally by measuring the variation of instantaneous open-circuit potential during friction. One coating consists of alternating Cr and CrN layers, while another consists of alternated layers of CrN and ZrN. Analysis of the results showed that friction force, i.e. the rate of the mechanical energy supplied to the material in the contact zone, has no direct influence on the tribocorrosion behaviour; however, the wear rate does strongly influence the tribocorrosion. A simple phenomenological model of repassivation of the multilayer coating is developed assuming "surface coverage" approach. This model establishes the relationship between the rate of mechanical activation of material by friction and the behaviour of the open-circuit potential. PMID- 20204334 TI - Electrocatalytic behaviour of citric acid at a cobalt phthalocyanine-modified screen-printed carbon electrode and its application in pharmaceutical and food analysis. AB - Cobalt phthalocyanine-modified screen-printed carbon electrodes (CoPC-SPCEs) have been investigated as disposable sensors for the measurement of citric acid. The analyte was found to undergo an electrocatalytic oxidation process involving the Co(2+)/Co(3+) redox couple. Calibration plots were found to be linear in the range 2 mM to 2.0 M; replicate determinations of a 5.2 mM citric acid (n = 4) solution gave a coefficient of variation of 1.43%. Additions of metal ions, such as Ag(+), Pb(2+), Cu(2+), Fe(3+) and Ca(2+), were found not to interfere. The effects of hesperidin, cysteine, ethylenediaminetetraacetic acid (EDTA), ascorbic, formic, malic, malonic, tartaric, oxalic and trichloroacetic acids on the determination of citric acid were examined and, under the conditions employed, only oxalic acid and EDTA were found to give any significant interference. The sensors were evaluated by carrying out citric acid determinations on spiked and unspiked samples of an acid citrate dextrose (ACD) formulation, lime flesh and juice. For lime juice, recoveries were calculated to be 96.8% (% CV = 2.7%) for a sample fortified with 5% citric acid and for ACD 99.4% (%CV = 2.6%) when fortified at 2.30% citric acid. Further studies showed the possibility of determining citric acid concentrations in lime juice and fruit directly, without the need for an added electrolyte. These performance characteristics indicate that reliable data may be obtained for citric acid measurements in such samples. To our knowledge, this is the first report on the electrocatalytic oxidation of citric acid and its application using a CoPC-SPCE. PMID- 20204335 TI - Determination of aflatoxin B(1) in alcoholic beverages: comparison of one- and two-photon-induced fluorescence. AB - The qualitative and quantitative analysis of aflatoxin B(1) in a model system (water/ethanol), in different wines and in beer using one- and two-photon-induced fluorescence is discussed. The absorption and fluorescence properties of aflatoxin B(1) depend on the solvent and pH. The two-photon-absorption cross section was calculated for aflatoxin B(1) in beer and wine (sigma (2) approximately 25 GM) for excitation at 720 nm. A comparison of the one- and two photon- induced fluorescence results showed that the disturbance due to background emission originating from matrix constituents is significantly reduced under two-photon-excitation conditions. The limit of detection for the one- and two-photon-induced fluorescence was determined. PMID- 20204336 TI - Warfarin-flucloxacillin interaction presenting as cardioembolic ischemic stroke. PMID- 20204337 TI - Use of non-specific intravenous human immunoglobulins in Spanish hospitals; need for a hospital protocol. AB - Intravenous immunoglobulin (IVIG) use in non-approved indications, the increase in consumption and its high cost recommend rationalisation in its utilisation. AIMS: To assess the use of IVIG in Spanish hospitals. METHODS: An observational, prospective and multicentre drug utilisation study was conducted in 13 tertiary Spanish hospitals. Data were collected for 3 months in patients receiving any IVIG. Patient demographics, indication for IVIG use, dosage regimen and cost of treatment were collected. RESULTS: Five hundred and fifty-four patients (mean age of 52 years) were included in the study. A total of 1,287 prescriptions were administered, and the average number of prescriptions per patient was 2.3. The mean daily dose was 24 g (range 0.6-90 g). Overall, IVIG was prescribed for authorised indications in 335 patients (60%) with 953 prescriptions (74%), for non-authorised indications with scientific evidentiary support in 86 patients (16%) with 137 prescriptions (11%), and non-authorised and non-accepted indications in 133 patients (24%) with 197 prescriptions (15%). The most frequent authorised indications were primary and secondary immunodeficiencies, and the most frequent non-authorised and non-accepted indications were multiple sclerosis and bullous dermatosis. The mean cost of IVIG per patient for authorised indications was 2,636.2 , non-authorised indications with scientific support 5,262.1 and non-accepted indications 3,555.8 . CONCLUSIONS: IVIG is prescribed for a significant number of non-authorised and non-accepted indications with a notable cost. There is an important variability in IVIG prescriptions between hospitals, indicating room for improvement in IVIG use and the need for a consensus of protocol use. PMID- 20204339 TI - Urinary chemokines/cytokines are elevated in patients with urolithiasis. AB - The prevalence of urolithiasis in the general population has been increasing recently. The inflammatory responses may play an important role in the development of urolithiasis. We aimed to investigate whether the urine inflammatory cytokine and chemokine profiles from patients with urolithiasis can be used as prognostic markers for urolithiasis. Multiplex immunoassays were used to simultaneously detect five inflammatory cytokines and five inflammatory chemokines in urine collected from 29 patients and 38 sex and age-matched healthy volunteers. After adjusting for urinary creatinine, urinary levels of interleukin 8 (IL-8), regulated on activation, normal T cell expressed and secreted, monocyte chemoattractant protein-1, interferon-gamma (IFN-gamma)-inducible 10-kDa protein, monokine induced by IFN-gamma and IL-6 were significantly increased in patients compared with healthy controls. However, concentrations of urinary IL-1beta, IL 10, IL-12, and tumor necrosis factor-alpha were not significantly different between those of patients and healthy controls. Using receiver operating characteristics curve analysis, we found that the adjusted IL-8 level of 6.2 pg/mg creatinine can reach a sensitivity of 90% and specificity of 68% to detect urolithiasis. Our data showed that urinary stones are associated with a cascade of inflammatory responses, including chemokine secretion, and urinary IL-8 levels. In addition, the elevation of urinary IL-8 could be a useful biomarker in healthy screening and clinical follow-up of urolithiasis. PMID- 20204340 TI - The influence of percutaneous nephrolithotomy on human systemic stress response, SIRS and renal function. AB - The objective of this study is to investigate the influences of percutaneous nephrolithotomy (PNL) and open surgery nephrolithotomy on the systemic stress response, SIRS and renal function. Forty patients with kidney calculi were enrolled in the study. Twenty cases were randomized to the PNL group and the other twenty cases to the open surgery group. Levels of C-reactive protein (CRP), interleukin-6(IL-6), beta(2)-microglobulin (beta(2)-MG), respiration rate, heart rate, body temperature and white blood cell counts were examined. CRP and IL-6 were measured in all patients pre-operatively and on post-operative days 1, 3 and 6, respectively. There was significant difference in their pre- and post operation levels (P < 0.05), with the peak of CRP and IL-6 observed at post operative days 3 and 1, respectively. There was significant difference in both CRP and IL-6 between the two groups (P < 0.05). At post-operative day 1, there were 5 cases of SIRS in PNL group and 12 cases in open surgery group; there was significant difference between the two groups (P < 0.05). Serum beta(2)-MG levels were measured as the same time as CRP and no significant changes were observed within or between the groups (P > 0.05). Urine beta(2)-MG levels were also measured. There was significant difference between pre- and the first day post PNL (P < 0.05); there was no significant difference between pre- and the third and sixth day post-PNL (P > 0.05). There was significant difference between pre- and first and third day post-open surgery (P < 0.05); but there was no significant difference between pre- and the sixth day post-open surgery (P > 0.05). There was significant difference between two groups at the first, third and sixth days (P < 0.05). CONCLUSIONS: The systemic stress response is activated both in PNL group and open surgery group to some extent. The degree of stress response of PNL is lower than that of open surgery, proving the advantages of PNL with reference to serum immunology. There were cases in both the groups with SIRS, but the degree of SIRS in PNL group was lesser than the other group. Both the groups have no obvious effect on glomerular filtration function after operation and have effect on renal tubular reabsorption in the early stage after operation; but the recovery of the PNL group is faster than the open surgery group. It is thus shown that PNL is much safer and more feasible and has lesser effect on renal function. PMID- 20204338 TI - Reassessment of models of facilitated transport and cotransport. AB - Most membrane transport models are determinate, requiring the transported ligand(s) to bind initially to a vacant site, which undergoes translation and releases ligand to the alternate side. The carrier reverts to its initial position to complete the net transport cycle. Ligand affinity may change during translation, but this must be compensated by an equivalent energy change(s) within the transport cycle. However, any asymmetric cyclic equilibrium deduced on this basis is thermodynamically fallacious. Determinate cotransport models imply lossless stoichiometric relationships between the complexed cotransported ligands. Independent ligand leakage apart from the mobile cotransport complex must occur outside the canonical cotransport pathway. In contrast, stochastic transport models assume independent ligand diffusion through a variably occluded channel(s) containing binding sites where ligands may undergo bimolecular exchanges. Energy dissipation is intrinsic to all stochastic transport models and occurs within the primary transport pathway. Frictional interactions within a shared path generate flow coupling between ligands. The primary driving forces causing transmembrane ligand flows are their electrochemical potential differences between the external solutions. Demonstrations that ligand exchanges in CLC and neurotransmitter transporters can be multimodal, encompassing both "channel"-like high and "transporter"-like lower conductance states and have independently regulated import and export exchange fluxes are major challenges to determinate models but are explicable by transient widening of a close-encounter region within the channel, leading to decreased coupling and enhanced efflux. PMID- 20204341 TI - Efficacy of retrograde ureteropyeloscopic holmium laser lithotripsy for intrarenal calculi >2 cm. AB - The objectives of this study are to assess the efficacy and safety of retrograde ureteroscopic holmium laser lithotripsy for intrarenal calculi greater than 2 cm in diameter. A total of 24 patients with a stone burden >2 cm were treated with retrograde ureteroscopic laser lithotripsy. Primary study endpoints were number of treatments until the patient was stone free and perioperative complications with a follow-up of at least 3 months after intervention. In 24 patients (11 women and 13 men, 20-78 years of age), a total of 40 intrarenal calculi were treated with retrograde endoscopic procedures. At the time of the initial procedure, calculi had an average total linear diameter of 29.75 +/- 1.57 mm and an average stone volume of 739.52 +/- 82.12 mm(3). The mean number of procedures per patient was 1.7 +/- 0.8 (range 1-3 procedures). The overall stone-free rate was 92%. After 1, 2 and 3 procedures 54, 79 and 92% of patients were stone free, respectively. There were no major complications. Minor postoperative complications included pyelonephritis in three cases (7.5%), of whom all responded immediately to parenteral antibiotics. In one patient the development of steinstrasse in the distal ureter required ureteroscopic fragment disruption and basketing. Ureteroscopy with holmium laser lithotripsy represents an efficient treatment option and allows the treatment of large intrarenal calculi of all compositions and throughout the whole collecting system even for patients with a stone burden of more than 2 cm size. PMID- 20204342 TI - Oxalate content of green tea of different origin, quality, preparation and time of harvest. AB - The purpose of the study was to analyse the oxalate content of green tea (Camellia sinensis) depending on origin, quality, time of harvest and preparation. Fifty-two green tea samples were received from different regions of China. The oxalate content of each tea infusion was measured using a validated HPLC-enzyme-reactor method. The soluble oxalate content of green tea ranged from 8.3 to 139.8 mg/l. In samples from known provenances, the highest oxalate concentration was found in green tea from Zhe Jiang. Low grade tea showed a tendency to lower oxalate concentration. Leaves reaped in the autumn when grown to full size yielded more oxalate than small and young leaves reaped in the spring. Modifications in steeping duration of tea leaves had no significant influence on the oxalate content of the beverage. Patients at risk for recurrent stone formation should take into account the oxalate content of green tea. PMID- 20204343 TI - Polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyles (PCBs), hydroxylated and methoxylated-PBDEs, and methylsulfonyl-PCBs in bird serum from South China. AB - Polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), and their derivatives, hydroxylated (OH) and methoxylated (MeO) PBDEs and methylsulfonylated (MeSO(2)) PCBs, were measured in sera of eight bird species collected from an e-waste recycling region in South China. Concentrations of summation operatorPCBs, ranging from 38 to 1700 ng/g lipid weight (lw), were one to two orders of magnitude higher than concentrations of summation operatorPBDEs (0.64-580 ng/g lw). The significantly positive relationship between PCB and PBDE concentrations suggested a similar pathway of exposure to these compounds. Compared with muscle in birds, serum might prefer to accumulate and/or retain less brominated/chlorinated congeners. 3-OH-BDE47 and 2'-OH-BDE68 were detected in more than 80% of the collected bird serum samples (range: not detectable (nd) to 13 and nd to 7.8 ng/g lw, respectively). The other three OH-PBDE congeners (4' OH-BDE-17, 6-OH-BDE47, and 4'-OH-BDE-49) and two MeO-PBDE congeners (3-MeO-BDE47 and 6-MeO-BDE47) were occasionally detected in bird sera at concentrations ranging from nd to 2.5 ng/g lw. Both natural sources and metabolic transformation of PBDEs could contribute to the presence of these PBDE derivatives in the birds. The two MeSO(2)-PCB congeners (4-MeSO(2)-CB49 and 4-MeSO(2)-CB101) under investigation were detected at respective concentration ranges of nd to 12 and nd to 0.68 ng/g lw. 4-MeSO(2)-CB101 exhibited the highest concentration among the nine PCB and PBDE derivatives studied, indicating that biotransformation via the mercapturic acid pathway of PCBs might have occurred in the studied bird species. PMID- 20204344 TI - Properties of blood, porphyrins, and exposure to legacy and emerging persistent organic pollutants in surf scoters (Melanitta perspicillata) overwintering on the south coast of British Columbia, Canada. AB - The surf scoter (Melanitta perspicillata) is a little-studied species of North American sea duck. Estimates suggest it has experienced a precipitous decline in breeding numbers over the latter half of the past century. To investigate the potential role of contaminant uptake and toxicity in the population decline, this study undertook to measure blood chemistry, porphyrin concentrations, EROD, and organic contaminants in mature surf scoters wintering in the Strait of Georgia, BC, Canada. Hepatic organochlorine pesticide, polychlorinated dibenzo-p-dioxin, polychlorinated dibenzofuran, polychlorinated biphenyl (PCB), polybrominated diphenyl ether, and nonylphenol concentrations were relatively low; for example, SigmaTEQs (toxic equivalents) for PCBs, dioxins, and furans combined ranged from 4.7 ng/kg wet weight in reference-site (Baynes Sound) birds to 11.4 ng/kg wet weight in birds from Vancouver Harbour. Nonetheless, elevated EROD activity indicated that birds in Howe Sound were responding to an Ah-receptor-mediated stressor, which was also affecting hematocrit values and possibly vitamin A status. In addition, a low proportion of lymphocytes in individuals across locations in early spring samples was associated with poor body condition. The apparent loss of fitness just prior to the onset of northerly migrations to breeding grounds is of particular concern. Compromised health of mature birds at this point in the season might impact negatively on the productivity and survival of some individuals, particularly those overwintering in Howe Sound. PMID- 20204345 TI - Hepatic adenomatosis in a 7-year-old child treated earlier with a Fontan procedure. AB - Patients who undergo a Fontan procedure experience some degree of liver disease. Hemodynamic changes such as central venous hypertension, depressed dynamic cardiac output, and late ventricular dysfunction combined with long-standing hypoxia preceding the Fontan procedure all are recognized risk factors for hepatic injury. The histopathologic changes associated with cardiac hepatopathy include chronic passive congestion, centrilobular necrosis, and cardiac cirrhosis. However, hepatic adenoma and hepatic adenomatosis (HA) are not well known pathologies during the course of cardiac hepatopathy. This study focused on a 7-year-old girl with chronic hepatic changes and HA who had undergone a Fontan procedure. Hepatic adenomatosis was diagnosed on the basis of magnetic resonance imaging (MRI) and MRI-guided liver biopsy. To the best of the authors' knowledge, this case involved the youngest patient with hepatocellular adenomatosis documented in the literature. It was a unique case because the patient experienced HA after a Fontan procedure. PMID- 20204346 TI - Near infrared spectroscopy: guided tilt table testing for syncope. AB - Syncope is transient loss of consciousness. Neurocardiogenic syncope (NCS) is the most common cause of syncope. Head-up tilt-table test (HUTT) has been used to demonstrate physiologic events during graded orthostatic challenge in individuals with significant handicap from NCS. Near-infrared spectroscopy (NIRS) provides a noninvasive, continuous method to monitor trends of regional tissue oxygenation (rSO2). We hypothesize that multisite NIRS monitoring will show differential desaturation patterns in the brain and renal vascular beds during postural stresses. All patients age 7-21 years old scheduled to undergo HUTT were recruited. Two probes for NIRS monitoring were placed on the forehead and above the left paravertebral level at the T10 to L1 space. These leads were attached to the Somanetics monitor (Somanetics, Troy MI). Tissue saturations (rSO2) obtained at two sites were recorded at rest, during the test, and throughout a 5-min recovery period. All data routinely obtained in HUTT were included in the research study database. Thirteen patients were recruited. The average age was 12.9 years. Five patients had a positive tilt-table test. The patients with syncope had rSO2 trends distinctly different from the normal subjects. In these patients, cerebral rSO2 showed a sudden decreasing trend from hypoperfusion, soon followed by various clinical symptoms. The cerebral rSO2 trend, which showed a dramatic increase, was paralleled by renal rSO2. These rSO2 trends were progressive until the patient was brought back to the supine position, which resulted in the rSO2 in both beds returning to baseline. Multisite NIRS-guided HUTT shows differential trends in the different vascular beds during postural gravitational stresses, and these patterns underlie the systemic oxygen consumption to flow-coupling dynamics observed during syncope. PMID- 20204347 TI - A rare type of double aortic arch diagnosed by echocardiography in an asymptomatic 9-year-old patient. AB - A case of double aortic arch with an atretic left arch distal to the origin of the left subclavian artery was suspected by echocardiography (ECHO) in an asymptomatic 9-year-old girl and confirmed by magnetic resonance imaging (MRI). The authors report their ECHO findings, which could be an important diagnostic tool for symptomatic patients because confusion exists in the literature regarding the differentiation of the aforementioned rare malformation from a right arch with mirror image branching. The authors support their ECHO proposal with an explanation based on the hypothetical double aortic arch plan set by Edwards. PMID- 20204348 TI - Prenatal diagnosis of a rare case of hypoplastic left heart syndrome associated with pulmonary valve stenosis. AB - A rare case of hypoplastic left heart syndrome associated with pulmonary stenosis detached prenatally is reported. PMID- 20204349 TI - The influence of different land uses on the structure of archaeal communities in Amazonian anthrosols based on 16S rRNA and amoA genes. AB - Soil from the Amazonian region is usually regarded as unsuitable for agriculture because of its low organic matter content and low pH; however, this region also contains extremely rich soil, the Terra Preta Anthrosol. A diverse archaeal community usually inhabits acidic soils, such as those found in the Amazon. Therefore, we hypothesized that this community should be sensitive to changes in the environment. Here, the archaeal community composition of Terra Preta and adjacent soil was examined in four different sites in the Brazilian Amazon under different anthropic activities. The canonical correspondence analysis of terminal restriction fragment length polymorphisms has shown that the archaeal community structure was mostly influenced by soil attributes that differentiate the Terra Preta from the adjacent soil (i.e., pH, sulfur, and organic matter). Archaeal 16S rRNA gene clone libraries indicated that the two most abundant genera in both soils were Candidatus nitrosphaera and Canditatus nitrosocaldus. An ammonia monoxygenase gene (amoA) clone library analysis indicated that, within each site, there was no significant difference between the clone libraries of Terra Preta and adjacent soils. However, these clone libraries indicated there were significant differences between sites. Quantitative PCR has shown that Terra Preta soils subjected to agriculture displayed a higher number of amoA gene copy numbers than in adjacent soils. On the other hand, soils that were not subjected to agriculture did not display significant differences on amoA gene copy numbers between Terra Preta and adjacent soils. Taken together, our findings indicate that the overall archaeal community structure in these Amazonian soils is determined by the soil type and the current land use. PMID- 20204350 TI - Brownian dynamics simulation of substrate motion near active site of enzyme entrapped inside reverse micelle. AB - Brownian dynamics simulation has been applied to analyze the influence of the electrostatic field of a reverse micelle on the enzyme-substrate complex formation inside a micelle. The probability that the enzyme-substrate complex will form from serine protease (trypsin) and the specific hydrophilic cationic substrate Nalpha-benzoyl-L: -arginine ethyl ester has been studied within the framework of the encounter complex formation theory. It has been shown that surfactant charge, dipole moments created by charged surfactant molecules and counterions, and permittivity of the inner core of reverse micelles can all be used as regulatory parameters to alter the substrate orientation near the active site of the enzyme and to change the probability that the enzyme-substrate complex will form. PMID- 20204351 TI - Interaction of gentamicin with phosphatidylserine/phosphatidylcholine mixtures in adsorption monolayers and thin liquid films: morphology and thermodynamic properties. AB - Gentamicin possesses strong adverse actions like oto and nephrotoxicity. The latter is a result of strong gentamicin-acid phospholipid interactions, resulting in cell fusion, fission, etc., ions as calcium interact with gentamicin and effectively deter its toxicity. In this work, the interactions of gentamicin and Ca(2+) with phosphatidylserine/phosphatidylcholine (PS/PC) mixtures of different ratio are experimentally characterized. Special attention is paid to bridge thermodynamic and morphological properties of adsorption monolayers and thin liquid films (TLFs) composed of these lipid mixtures. Our results show that gentamicin decreases the stability of common black TLFs formed of pure PS coupled with suppression of lipid surface adsorption to the monolayers at the air-water interface; also, gentamicin reveals effects of lowering of lipid spreading on the interface and significant loss of material during monolayer cycling, increase of condensed phase, and organization of dense net-like domain monolayer texture. Gentamicin addition results in opposite effects for films formed of DPPC/PS (95:5) mixture. It increases the stability of Newton black TLFs formed by DPPC/PS correlated with faster and stronger surface adsorption and better surface spreading; also, gentamicin lowers the amount of condensed phase and organization of domains of smaller size. We also showed that Ca(2+) itself decreases the stability of common black TLFs formed of PS accompanied with weaker surface adsorption, formation of higher amounts of condensed phase and organization of domains. In our experiments, Ca(2+) softens, even deters, the effects of gentamicin on both PS and DPPC/PS films. PMID- 20204353 TI - Histological evaluation of drill fragments obtained during osteoid osteoma radiofrequency ablation. AB - OBJECTIVE: Osteoid osteoma (OO) is a benign bone tumor diagnosed mainly on the basis of the patient's history and radiological data. Histological evaluation may not be available before treatment. The aim of this study was to assess the diagnostic value of a histological evaluation of the bone fragments obtained during radiofrequency ablation (RFA). MATERIALS AND METHODS: During a 2-year period, 39 patients diagnosed clinically with OO were entered into this study. The procedure was performed under computed tomography (CT) guidance. An 11-gauge needle was initially placed as a coaxial guide. After drill removal, RFA was performed. Bone fragments collected from the drill were examined by two experienced pathologists, independently. RESULTS: There was strong association between pathologists' reports (P <0.001). In 27 cases (69.2%) this diagnosis was confirmed pathologically. No significant relationship was found between nidus diameter and positive histological findings (P = 0.35). CONCLUSION: Histological confirmation of OO based on drill fragments is similarly frequent as previously reported for standard bone biopsy. PMID- 20204354 TI - Measurement of coronary flow reserve by noninvasive cardiac imaging. PMID- 20204355 TI - Diagnostic value of diffusion-weighted magnetic resonance imaging (DWI) compared to FDG PET/CT for whole-body breast cancer staging. AB - PURPOSE: The aim of the study was to prospectively compare the diagnostic value of whole-body diffusion-weighted imaging (DWI) and FDG PET/CT for breast cancer (BC) staging. METHODS: Twenty BC patients underwent whole-body FDG PET/CT and 1.5 T DWI. Lesions with qualitatively elevated signal intensity on DW images (b = 800 s/mm(2)) were rated as suspicious for tumour and mapped to individual lesions and different compartments (overall 552 lesions). The apparent diffusion coefficient (ADC) value was determined for quantitative evaluation. Histopathology, MRI findings, bone scan findings, concordant findings between FDG PET/CT and DWI, CT follow-up scans and plausibility served as the standards of reference defining malignancy. RESULTS: According to the standards of reference, breasts harboured malignancy in 11, regional lymph nodes in 4, M1 lymph nodes in 3, bone in 7, lung in 2, liver in 3 and other tissues in 3 patients. On a compartment basis, the sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) for the detection of malignancies were 94, 99, 98, 97 and 98% for FDG PET/CT and 91, 72, 76, 50 and 96% for DWI, respectively. Of the lesions seen on DWI only, 348 (82%) turned out to be false-positive compared to 23 (11%) on FDG PET/CT. The average lesion ADC was 820 +/- 300 with true-positive lesions having 929 +/- 252 vs 713 +/- 305 in false-positive lesions (p < 0.0001). CONCLUSION: Based on these initial data DWI seems to be a sensitive but unspecific modality for the detection of locoregional or metastatic BC disease. There was no possibility to quantitatively distinguish lesions using ADC. DWI alone may not be recommended as a whole-body staging alternative to FDG PET(/CT). Further studies are necessary addressing the question of whether full-body MRI including DWI may become an alternative to FDG PET/CT for whole-body breast cancer staging. PMID- 20204356 TI - FDG positron emission tomography/computed tomography studies of Wilms' tumor. AB - PURPOSE: The purpose of this analysis was to evaluate the utility of FDG PET/CT scanning in patients with Wilms' tumors. METHODS: A total of 58 scans were performed in 27 patients (14 male, 13 female; ages: 1.9-23 years, median: 7 years) with proven Wilms' tumor. Twenty-six patients (56 scans) were studied at the time of suspected relapse, progressive disease, persistent disease, or for monitoring of therapy. RESULTS: In the 27 patients with Wilms' tumor, 34 scans showed areas of abnormal uptake consistent with metabolically active tumors. Of the patients, 8 (24 scans) had pulmonary metastases larger than 10 mm in diameter, 10 (12 scans) had hepatic metastases, 11 (11 scans) had regional nodal involvement, 3 (3 scans) had bone metastases, 1 (1 scan) had chest wall involvement, 2 (2 scans) had pancreatic metastasis, and 5 (5 scans) had abdominal and pelvic soft tissue involvement. Two of eight patients with lung metastases had variable uptakes. Lung lesions 10 mm or smaller were not consistently visualized on PET scans. One patient with a liver metastasis showed no uptake on PET scan after treatment (size decreased from 45 to 15 mm). CONCLUSION: Most Wilms' tumors concentrate FDG. However, small pulmonary metastases may be better visualized with CT. FDG PET/CT appears useful for defining the extent of involvement and assessing the response to treatment. PMID- 20204357 TI - (18)F-FDG PET/CT for early detection of embolism and metastatic infection in patients with infective endocarditis. AB - PURPOSE: In the acute setting of endocarditis it is very important to assess both the vegetation itself, as well as potential life-threatening complications, in order to decide whether antibiotic therapy will be sufficient or urgent surgery is indicated. A single whole-body scan investigating inflammatory changes could be very helpful to achieve a swift and efficient assessment. METHODS: In this study we assessed whether (18)F-FDG can be used to detect and localize peripheral embolism or distant infection. Twenty-four patients with 25 episodes of endocarditis, enrolled between March 2006 and February 2008, underwent (18)F-FDG PET/CT imaging on a dedicated PET/CT scanner. RESULTS: PET/CT imaging revealed a focus of peripheral embolization and/or metastatic infection in 11 episodes (44%). One episode had a positive PET/CT scan result for both embolism and metastatic infection. PET/CT detected seven positive cases (28%) in which there was no clinical suspicion. Valve involvement of endocarditis was seen only in three patients (12%). CONCLUSION: PET/CT may be an important diagnostic tool for tracing peripheral embolism and metastatic infection in the acute setting of infective endocarditis, since a PET/CT scan detected a clinically occult focus in nearly one third of episodes. PMID- 20204358 TI - (18)F-FDG PET/CT bone/bone marrow findings in Hodgkin's lymphoma may circumvent the use of bone marrow trephine biopsy at diagnosis staging. AB - PURPOSE: Accurate staging of Hodgkin's lymphoma (HL) is necessary in selecting appropriate treatment. Bone marrow trephine biopsy (BMB) is the standard procedure for depicting bone marrow involvement. BMB is invasive and explores a limited part of the bone marrow. (18)F-FDG PET/CT is now widely used for assessing response to therapy in HL and a baseline study is obtained to improve accuracy. The aim of this retrospective analysis was to assess whether routine BMB remains necessary with concomitant (18)F-FDG PET/CT. METHODS: Data from 83 patients (newly diagnosed HL) were reviewed. All patients had received contrast enhanced CT, BMB and (18)F-FDG PET/CT. Results of BMB were not available at the time of (18)F-FDG PET/CT imaging. RESULTS: Seven patients had lymphomatous involvement on BMB. Four patients had bone involvement on conventional CT (two with negative BMB). All patients with bone marrow and/or bone lesions at conventional staging were also diagnosed on (18)F-FDG PET/CT scan. PET/CT depicted FDG-avid bone/bone marrow foci in nine additional patients. Four of them had only one or two foci, while the other had multiple foci. However, the iliac crest, site of the BMB, was not involved on (18)F-FDG PET/CT. Osteolytic/sclerotic lesions matching FDG-avid foci were visible on the CT part of PET/CT in three patients. MRI ordered in three other patients suggested bone marrow involvement. Interim and/or end-therapy (18)F-FDG PET/CT documented response of FDG-avid bone/bone marrow foci to chemotherapy in every patient. CONCLUSION: (18)F-FDG PET/CT highly improves sensitivity for diagnosis of bone/bone marrow lesions in HL compared to conventional staging. PMID- 20204360 TI - Aneurysm of an anomalous systemic artery supplying the normal basal segments of the left lower lobe: endovascular treatment with the Amplatzer Vascular Plug II and coils. AB - An anomalous systemic artery originating from the descending thoracic aorta supplying the normal basal segments of the lower lobe of the left lung without sequestration is a rare congenital anomaly. The published surgical treatments include lobectomy, segmentectomy, anastomosis, and ligation. In addition, endovascular treatment with coils has been reported. A second-generation occluder, the Amplatzer Vascular Plug II (AVP II), has a central plug and two occlusion disks and a finer, more densely woven nitinol wire, thus enabling faster embolization. This published case is the first successful occlusion of an aneurysm of an anomalous systemic artery with the AVP II and fibered coils, with 10 months of follow-up. PMID- 20204361 TI - Concomitant statin use does not impair the clinical outcome of patients with diffuse large B cell lymphoma treated with rituximab-CHOP. AB - Preclinical data indicated a detrimental effect of statins on the anti-lymphoma activity of rituximab. We evaluated the impact of concomitant statin medication on the response and survival of patients with diffuse large B cell lymphoma (DLBCL) receiving rituximab-cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) as first-line therapy. Medical histories of patients with DLBCL who were treated with R-CHOP as first-line therapy were assessed for concomitant statin use, response after completion of chemotherapy, event-free survival (EFS), and overall survival (OS). Furthermore, 2-[(18)F]fluor-2 deoxyglucose (FDG)-PET/CT results after completion of first-line therapy were compared between the groups. Overall, 145 patients with DLBCL treated with R-CHOP from January 2001 to December 2009 were analyzed. Twenty-one (15%) patients received statins throughout therapy. Five-year EFS was 67.3% in patients without statins compared with 79% in patients receiving statins during R-CHOP (HR, 0.47; 95% CI, 0.15-1.54, p = 0.2). Five-year OS was 81.4% for patients without statins compared with 93.3% for patients taking statins (HR, 0.58; 95% CI 0.07-4.55, p = 0.6). There were no statistically significant differences in the rates of complete remissions between the two groups (75% in the non-statin group versus 86% in the statin group, p = 0.45). A trend toward a lower rate of complete metabolic responses in FDG-PET/CT after chemotherapy was seen in patients without statin medication compared with the patients taking statins (84% versus 92%, p = 0.068). Concomitant statin use had no adverse impact on response to chemotherapy, EFS, and OS in patients treated with R-CHOP for DLBCL. PMID- 20204362 TI - Serological immune responses to influenza vaccine in patients with colorectal cancer. AB - BACKGROUND: The immune responses to influenza vaccination in patients with colorectal cancer on surveillance or active chemotherapy have not been previously reported. We conducted a prospective influenza vaccination study to determine the serological immune response rate in patients with colorectal cancer. METHODS: During the 2006-2007 influenza season, patients with colorectal cancer treated at Roswell Park Cancer Institute were offered vaccination with the trivalent influenza vaccine (Fluzone, 2006-2007). Blood samples for hemagglutination inhibition (HI) assay titers were collected before and 3 months after vaccination. Response to vaccination was determined using an endpoint of >= 1:40 HI titer ratio or a fourfold HI increase at 3 months from vaccination. A response in HI to at least one of the 3 strains was considered an immune response. RESULTS: Eighty-five patients with colorectal cancer participated in the study. The immune response in the overall population was 70.6%. No differences in response were noted between the 58 patients on active chemotherapy and the 27 patients on surveillance [Odds Ratio (OR) = 0.78; P = 0.8]. The odds of response did not vary by chemotherapy regimen or by chemotherapy-vaccination timing. HI response in all 3 titers concurrently were low in both the chemotherapy (12.1%) and surveillance groups (11.1%) (OR = 1.10; P = 1). CONCLUSIONS: Patients with colorectal cancer mount an immune response to influenza vaccination irrespective of their chemotherapy regimen or timing. However, concurrent responses to all three strains in the individual patient with colorectal cancer are uncommon. The investigation of a booster vaccine in this population is warranted. PMID- 20204363 TI - Spontaneous bilateral pneumothorax in metastatic renal cell carcinoma on sunitinib therapy. AB - Bilateral spontaneous pneumothorax is a rare occurrence in patients with both primary and metastatic lung cancer. Pneumothorax occurring as a complication of vascular endothelial growth factor receptor (VEGFR) inhibitor therapy has not been previously described in the medical literature. Sunitinib malate is a VEGFR inhibitor approved for the treatment of advanced renal cell carcinoma. We present a patient with metastatic renal cell carcinoma manifested as bilateral pulmonary nodules who developed a bilateral spontaneous pneumothorax 3 weeks after initiation of sunitinib therapy. We believe that sunitinib therapy resulted in necrosis of multiple pleural-based pulmonary nodules with central cavernization and ultimately rupture with bronchopleural fistula formation. Based on this experience, we advise that practitioners exercise caution when prescribing anti VEGFR therapy in patients with pleural-based pulmonary metastases and recognize that the efficacy and toxicity of these agents may be closely linked. PMID- 20204364 TI - An exploratory study of body composition as a determinant of epirubicin pharmacokinetics and toxicity. AB - PURPOSE: Although body composition has emerged as an important predictor of drug efficacy and toxicity, explanations for this association are unclear. Our goal was to investigate relationships between lean body mass (LBM), liver size/function and epirubicin pharmacokinetics (PK) and toxicity. METHODS: Data from a clinical study (n = 24) of patients with breast cancer receiving adjuvant intravenous FE(100)C chemotherapy were used to examine relationships between LBM, liver size, and epirubicin clearance. Muscle tissue and liver mass were measured by analysis of computerized tomography cross-sectional images, and an extrapolation of muscle mass to total LBM compartment was employed. Population PK analysis of epirubicin was undertaken to test effects of body composition on epirubicin clearance and area under the curve (AUC). RESULTS: Estimated LBM was extremely variable in this cohort ranging from 32.9 to 67.3 kg. LBM was associated with neutrophil nadir (r = 0.5, P = 0.023), and mean LBM was lower for patients presenting with toxicity compared to those where toxicity was absent (41.6 vs. 56.2 kg, P = 0.002); 33% of variance in clearance was explained by LBM and aspartate aminotransferase (AST). Liver mass was not related to epirubicin clearance likely due to larger livers presenting with larger fat content, but liver attenuation (degree of fat infiltration) and AST were associated with AUC. CONCLUSION: To our knowledge, this is the first study to examine relationships between LBM, liver mass/function and epirubicin PK and toxicity. This exploratory work investigates the notion of organs and tissues having distinctive contributions to the distribution and metabolism of antineoplastic drugs. PMID- 20204365 TI - DPD-based adaptive dosing of 5-FU in patients with head and neck cancer: impact on treatment efficacy and toxicity. AB - BACKGROUND: Fluoropyrimidine drugs are widely used in head and neck cancer (HNC). DPD deficiency is a pharmacogenetics syndrome associated with severe/lethal toxicities upon 5-FU or capecitabine intake. We have developed a simple, rapid, and inexpensive functional testing for DPD activity, as a means to identify deficient patients and to anticipate subsequent 5-FU-related toxicities. We present here the impact of fluoropyrimidine dose tailoring based on DPD functional screening in a prospective, open, non-controlled study, both in term of reduction in severe toxicities and of treatment efficacy. METHODS: About 65 patients with HNC (59 +/- 9 years, 52M/13F, Prospective Group) were entered into the study. Screening for DPD deficiency was performed prior to the beginning of the chemotherapy or radiochemotherapy. DPD status was evaluated by monitoring U/UH2 ratio levels in plasma as a surrogate marker for enzymatic functionality. 5 FU doses were reduced according to the extent of the detected DPD impairment, and adjusted on the basis of age, general condition, and other clinical/paraclinical covariates, if required. Treatment-related toxicities and subsequent impact on treatment delay were carefully monitored next for comparison with a retrospective, Reference subset of 74 other patients with HNC (mean age: 59 +/- 10, 58M/16F, Reference Group), previously treated in the same institute with similar schedule but using standard 5-FU dosage. RESULTS: Thirty-one out of 65 patients (48%) were identified as mildly (28%) to markedly (20%) DPD deficient. Subsequently, dose reductions ranging from 10 to 100% with 5-FU were applied in those patients. In this group, six patients (9%) experienced severe toxicities, none of them being life threatening, and no toxic death was encountered. In comparison, 16 out of 74 patients (22%) of the Reference Group displayed severe side effects after standard 5-FU administration, 13% being life-threatening toxicities (e.g., G4 neutropenia + sepsis). Moreover, one toxic death was observed in this Reference Group. No postponement or cancelation of forthcoming chemoradiotherapy courses occurred in the Prospective Group, whereas treatment had to be disrupted in six patients (8%) from the Reference Group. No difference in first-line therapy efficacy was evidenced between the two subsets (78 vs. 79% response, P = 0.790). CONCLUSIONS: Although non-randomized, this study strongly suggests that prospective determination of DPD status has an immediate clinical benefit by reducing the drug-induced toxicities incidence in patients treated with 5-FU, allowing an optimal administration of several courses in a row, while maintaining efficacy. Our preliminary results thus advocate for systematic DPD screening in patients eligible for treatment with fluoropyrimidine drugs in HNC. PMID- 20204366 TI - Sequential chemotherapy with dose-dense docetaxel, cisplatin, folinic acid and 5 fluorouracil (TCF-dd) followed by combination of oxaliplatin, folinic acid, 5 fluorouracil and irinotecan (COFFI) in metastatic gastric cancer: results of a phase II trial. AB - PURPOSE: To evaluate a new strategy of two sequential, intensified chemotherapy regimens in metastatic gastric cancer. PATIENTS AND METHODS: Chemo-naive patients with metastatic gastric cancer were enrolled to receive 4 cycles of TCF-dd (docetaxel initially 85 mg/m(2) and cisplatin initially 75 mg/m(2) on day 1 [later modified due to toxicity: 70 and 60 mg/m(2) respectively], l-folinic acid 100 mg/m(2) on days 1 and 2, 5-fluorouracil 400 mg/m(2) bolus and then 600 mg/m(2) as a 22 h continuous infusion on day 1 and 2, every 14 days). Subsequently, patients with CR, PR or SD received 4 cycles of COFFI (oxaliplatin 85 mg/m(2), irinotecan 140 mg/m(2), l-folinic acid 200 mg/m(2), 5-fluorouracil bolus 400 mg/m(2) on day 1 followed by 2,400 mg/m(2) as a 48 h continuous infusion, every 14 days). In both regimens pegfilgrastim 6 mg subcutaneously on day 3 was included. RESULTS: Forty consecutive patients were enrolled. TCF-dd regimen achieved an ORR of 55% (95% CI, 40-70). Twenty-three patients proceeded to COFFI. After this regimen the ORR was then increased to 60% (95% CI, 45-75). Among the 21 patients treated with TCF-dd after the protocol amendments, main grade 3-4 toxicities were: neutropenia (29%), thrombocytopenia (19%), asthenia (24%) and diarrhea (14%). COFFI caused grade 3-4 neutropenia (all not febrile) and diarrhea in 35% and 17% of patients respectively. CONCLUSIONS: A sequential strategy with TCF-dd followed by COFFI is very active and may be of special interest in selected patients. PMID- 20204367 TI - Sorafenib in combination with carboplatin and paclitaxel as neoadjuvant chemotherapy in patients with advanced ovarian cancer. AB - PURPOSE: Sorafenib is a novel oral anticancer agent targeting signal transduction and angiogenic pathways through inhibitory effects against MAP kinases and vascular endothelial growth factor receptor-2. The objectives of this neoadjuvant phase II-trial in patients with advanced epithelial ovarian cancer were to assess the activity and tolerability of the combination therapy of carboplatin/paclitaxel with multi-target tyrosine kinase inhibitor sorafenib. MATERIALS AND METHODS: Patients with histologically proven stage IIIC or IV disease and large volume ascites were eligible. Enrolled patients received 2 of 6 cycles carboplatin (area under the curve 5) and paclitaxel (175 mg/m(2)) preoperatively and concomitant sorafenib 400 mg twice daily. After four cycles of postoperative chemotherapy, a maintenance phase of single agent oral sorafenib through 1 year was planned. This phase II-study was planned with a sample size of 102 patients and progression-free survival as primary study endpoint. RESULTS: Four patients were enrolled. After preoperative treatment and cytoreductive surgery, all patients were excluded from protocol due to severe toxicities. Three patients had life threatening events (cardiac output failure, myocardial infarction, anastomotic leak); two patients had primary progressive disease. The study was terminated on the basis of the recommendation of an independent data safety monitoring board. CONCLUSION: The addition of sorafenib to carboplatin/paclitaxel chemotherapy was not feasible within this neoadjuvant regimen in primary advanced ovarian cancer. Although the occurrence of serious adverse events might have emerged at random, a detrimental effect of preoperative study medication could not be denied. Further evaluations of sorafenib in ovarian cancer are warranted. PMID- 20204368 TI - Phase I clinical trial of hepatic arterial infusion of cisplatin in combination with intravenous liposomal doxorubicin in patients with advanced cancer and dominant liver involvement. AB - PURPOSE: We conducted a phase I study of hepatic arterial infusion (HAI) cisplatin and systemic chemotherapy in patients with advanced cancer and dominant liver involvement. METHODS: Patients were treated with HAI cisplatin 100-125 mg/m(2) (and 3,000 IU heparin) intraarterially and liposomal doxorubicin (doxil) 20-35 mg/m(2) IV (day 1) every 28 days. A "3 + 3" study design was used. RESULTS: Thirty patients were treated (median age, 56 years). Diagnoses were breast cancer (n = 11), colorectal cancer (n = 8), ocular melanoma (n = 4), and other (n = 7). The median number of prior therapies was 5. The maximum tolerated dose (MTD) was at the 100/35 mg/m(2) level. Dose-limiting toxicities were Grade 4 neutropenia (2 of 4 patients), and Grade 4 thrombocytopenia (n = 1) at the cisplatin 125 mg/m(2) and systemic doxil 35 mg/m(2) dose level. The most common toxicities were nausea/vomiting and fatigue. Of 24 patients evaluable for response, 4 (17%) had a partial response (PR) and 7 (29%) had stable disease (SD) for >=4 months. Of the 11 patients with breast cancer, 3 (27%) had a PR and 5 (45%) had SD for >=4 months. Of 4 patients with ocular melanoma, 1 had a PR and 1 SD for 4 months. One patient with hepatocellular carcinoma had SD for 4 months. Of 12 evaluable patients treated at the MTD, 2 (17%) had a PR and 5 (42%) had SD. CONCLUSION: The MTD was HAI cisplatin 100 mg/m(2) and systemic doxil 35 mg/m(2). This regimen demonstrated antitumor activity, especially in breast cancer. PMID- 20204369 TI - Sonodynamically induced apoptosis and active oxygen generation by gallium porphyrin complex, ATX-70. AB - In this study, we investigated the induction of apoptosis by ultrasound in the presence of the photochemically active gallium-porphyrin complex, 7,12-bis(1 decyloxyethyl)-Ga(III)-3,8,13,17-tetramethyl-porphyrin 2,18-dipropionyl diaspartic acid (ATX-70). HL-60 cells were exposed to ultrasound for up to 3 min in the presence and absence of ATX-70, and the induction of apoptosis was examined by analyzing cell morphology, DNA fragmentation, and caspase-3 activity. Cells treated with 80 MUM ATX-70 and ultrasound clearly showed membrane blebbing and cell shrinkage, whereas significant morphologic changes were not observed in cells exposed to either ultrasound or ATX-70 alone. Also, DNA ladder formation and caspase-3 activation were observed in cells treated with both ultrasound and ATX-70 but not in cells treated with ultrasound or ATX-70 alone. In addition, the combination of ATX-70 and the same acoustical arrangement of ultrasound substantially enhanced nitroxide generation by the cells. Sonodynamically induced apoptosis, caspase-3 activation, and nitroxide generation were significantly suppressed by histidine. These results indicate that the combination of ultrasound and ATX-70 induces apoptosis in HL-60 cells. The significant reduction in sonodynamically induced apoptosis, nitroxide generation, and caspase-3 activation by histidine suggests that active species such as singlet oxygen are important in the sonodynamic induction of apoptosis. PMID- 20204371 TI - Traditional Chinese medicine in the treatment of rheumatoid arthritis: a general review. AB - Rheumatoid arthritis (RA) is difficult to cure. Many methods have been used for its treatment, among which traditional Chinese medicine (TCM) has been considered as an important strategy. All of the three parts of TCM: Chinese herbs, acupuncture, and massage have been reported with varying degrees of therapeutic effects on RA. Also the mechanism exploration is under process. Many effective ingredients of anti-rheumatic Chinese herbs have been found to inhibit RA development and some of the effective ingredients have been verified. Furthermore, greatly enhanced life quality of RA patients was obtained using acupuncture and massage to relieve pain, expand joint motion and modulate emotion which mainly correlated with the possible modulation of immune system, nerve system, endocrine system, etc. Thus, a systemic review on the therapeutic effect of TCM on RA is necessary. In our paper, the current status of TCM application in the clinic for the therapy of RA was summarized accompanied with the related mechanism exploration using modern test facilities. PMID- 20204370 TI - Lymphoid tyrosine phosphatase and autoimmunity: human genetics rediscovers tyrosine phosphatases. AB - A relatively large number of protein tyrosine phosphatases (PTPs) are known to regulate signaling through the T cell receptor (TCR). Recent human genetics studies have shown that several of these PTPs are encoded by major autoimmunity genes. Here, we will focus on the lymphoid tyrosine phosphatase (LYP), a critical negative modulator of TCR signaling encoded by the PTPN22 gene. The functional analysis of autoimmune-associated PTPN22 genetic variants suggests that genetic variability of TCR signal transduction contributes to the pathogenesis of autoimmunity in humans. PMID- 20204372 TI - Selectable marker elimination in the T0 generation by Agrobacterium-mediated co transformation involving Mungbean yellow mosaic virus TrAP as a non-conditional negative selectable marker and bar for transient positive selection. AB - Transient selection involving the bar gene and non-conditional negative selection against stable T-DNA integration through the use of the Mungbean yellow mosaic virus (MYMV) transcriptional activator protein gene (TrAP) were used in a novel co-transformation strategy to generate selectable marker gene (SMG)-eliminated transgenic tobacco plants in the T(0) generation itself. Two compatible binary plasmids, pCam-bar-TrAP-gus harbouring bar as an SMG and the MYMV TrAP gene as a non-conditional negative selectable marker, and pGA472 with the nptII gene as an unselected experimental gene of interest (GOI) were placed in the Agrobacterium tumefaciens strain EHA105 and used for co-transformation. Transient selection with 5 mg l(-1) phosphinothricin (PPT) for 2-4 weeks and subsequent establishment in a PPT-minus medium yielded 114 plants from 200 leaf discs. The unselected nptII gene was detected by Southern blot analysis in 13 plants, revealing a co transformation efficiency of 11.5%. Five of these plants harboured only the nptII gene (GOI) and not the bar gene (SMG). Thus, SMG elimination was achieved in the T(0) generation itself in 4.4% (5/114) of plants, which were transiently selected for 2-4 weeks on PPT. MYMV TrAP, a non-conditional negative selectable marker, effectively reduced the recovery of plants with stable integration of the SMG (bar). PMID- 20204373 TI - The superfamily of thaumatin-like proteins: its origin, evolution, and expression towards biological function. AB - Thaumatin-like proteins (TLPs) are the products of a large, highly complex gene family involved in host defence and a wide range of developmental processes in fungi, plants, and animals. Despite their dramatic diversification in organisms, TLPs appear to have originated in early eukaryotes and share a well-defined TLP domain. Nonetheless, determination of the roles of individual members of the TLP superfamily remains largely undone. This review summarizes recent advances made in elucidating the varied TLP activities related to host resistance to pathogens and other physiological processes. Also discussed is the current state of knowledge on the origins and types of TLPs, regulation of gene expression, and potential biotechnological applications for TLPs. PMID- 20204374 TI - Conserved regulatory motifs at phenylethanolamine N-methyltransferase (PNMT) are disrupted by common functional genetic variation: an integrated computational/experimental approach. AB - The adrenomedullary hormone epinephrine transduces environmental stressors into cardiovascular events (tachycardia and hypertension). Although the epinephrine biosynthetic enzyme PNMT genetic locus displays both linkage and association to such traits, genetic variation underlying these quantitative phenotypes is not established. Using an integrated suite of computational and experimental approaches, we elucidate a functional mechanism for common (minor allele frequencies > 30%) genetic variants at PNMT. Transcription factor binding motif prediction on mammalian PNMT promoter alignments identified two variant regulatory motifs, SP1 and EGR1, disrupted by G-367A (rs3764351), and SOX17 motif created by G-161A (rs876493). Electrophoretic mobility shifts of approximately 30 bp oligonucleotides containing ancestral versus variant alleles validated the computational hypothesis. Queried against chromaffin cell nuclear protein extracts, only the G-367 and -161A alleles shifted. Specific antibodies applied in electrophoretic gel shift experiments confirmed binding of SP1 and EGR1 to G 367 and SOX17 to -161A. The in vitro allele-specific binding was verified in cella through promoter reporter assays: lower activity for -367A haplotypes cotransfected by SP1 (p = 0.002) and EGR1 (p = 0.034); and enhanced inhibition of -161A haplotypes (p = 0.0003) cotransfected with SP1 + SOX17. Finally, we probed cis/trans regulation with endogenous factors by chromatin immunoprecipitation using SP1/EGR1/SOX17 antibodies. We describe the systematic application of complementary computational and experimental techniques to detect and document functional genetic variation in a trait-associated regulatory region. The results provide insight into cis and trans transcriptional mechanisms whereby common variation at PNMT can give rise to quantitative changes in human physiological and disease traits. Thus, PNMT variants in cis may interact with nuclear factors in trans to govern adrenergic activity. PMID- 20204375 TI - Congenic and bioinformatics analyses resolved a major-effect Fob3b QTL on mouse Chr 15 into two closely linked loci. AB - We previously identified a Chr 15 quantitative trait locus (QTL) Fob3b in lines of mice selected for high (Fat line) and low (Lean line) body fat content that represent a unique model of polygenic obesity. Here we genetically dissected the Fob3b interval by analyzing the phenotypes of eight overlapping congenic lines and four F(2) congenic intercrosses and prioritized candidates by bioinformatics approaches. Analyses revealed that the Fob3b QTL consists of at least two separate linked QTLs Fob3b1 and Fob3b2. They exhibit additive inheritance and are linked in coupling with alleles originating from the Lean line, decreasing obesity-related traits. In further analyses, we focused on Fob3b1 because it had a larger effect on obesity-related traits than Fob3b2, e.g., the difference between homozygotes for adiposity index (ADI) percentage was 1.22 and 0.77% for Fob3b1 and Fob3b2, respectively. A set of bioinformatics tools was used to narrow down positional candidates from 85 to 4 high-priority Fob3b1 candidates. A previous single Fob3b QTL was therefore resolved into another two closely linked QTLs, confirming the fractal nature of QTLs mapped at low resolution. The interval of the original Fob3b QTL was narrowed from 22.39 to 4.98 Mbp for Fob3b1 and to 7.68 Mbp for Fob3b2, which excluded the previously assigned candidate squalene epoxidase (Sqle) as the causal gene because it maps proximal to refined Fob3b1 and Fob3b2 intervals. A high-resolution map along with prioritization of Fob3b1 candidates by bioinformatics represents an important step forward to final identification of the Chr 15 obesity QTL. PMID- 20204376 TI - Redo-urethroplasty in pelvic fracture urethral distraction defect: an audit. AB - PURPOSE: To predict the outcome of redo-urethroplasty after failed single or multiple open urethral procedures for pelvic fracture urethral distraction defects. METHODS: From January 1997 to December 2006, 43 patients underwent redo urethroplasty for pelvic fracture urethral distraction defect. Forty-one were referred from other centers. All had undergone open surgery along with an endoscopic procedure (one or more procedures in each patient) which included endoscopic internal urethrotomy, urethral stenting or urethral dilations. RESULTS: There were 43 men with mean age of 29 (range 11-52). Eleven had associated injuries: intraperitoneal bladder rupture (3), bladder neck (2), rectum (3), anal sphincter (2), combined bladder, rectum and anal sphincter (1). Trocar suprapubic cystostomy was performed in 22, rail-road procedures in 10 and open suprapubic cystostomy in 11 along with the management of associated injuries as immediate treatment. Of 43 patients, 28 had progressive perineal, and 12 had transpubic repair. Three patients had total bulbar necrosis, and they underwent prepuceal tube reconstruction (1) and staged substitution with BMG and standard scrotal inlay (2). Analysis of various factors like number of attempts at previous surgery and stricture length did not affect the outcome. A successful result was achieved in 36 (83.72%), improved and stable in five and failure in two. CONCLUSIONS: The overall result of redo-urethroplasty for pelvic fracture urethral distraction defect continues to be gratifying. Failures happen usually within the first 3 months. Substitution urethroplasty can be reserved for those who have long distraction defect. Long-term follow-up is essential using stringent criteria to measure success. PMID- 20204377 TI - The minimally invasive management of ureteropelvic junction obstruction in horseshoe kidneys. AB - PURPOSE: Data regarding the treatment of ureteropelvic junction obstruction (UPJO) in horseshoe kidneys are limited. We performed a retrospective analysis of our experience with minimally invasive treatment of UPJO in patients with this anomaly. METHODS: Between March of 1996 and March 2008, 9 patients with horseshoe kidneys were treated for UPJO at our institution. Of these patients, 6 were managed with retrograde endopyelotomy, 2 with laparoscopic pyeloplasty, and one by robotic pyeloplasty. Outcomes of these procedures were retrospectively reviewed. RESULTS: A total of nine patients were available for analysis. Four of six patients who underwent endopyelotomy had available follow-up, with a mean of 56 months. The success rate for these patients was 75%. Two of three patients (67%) in the laparoscopic/robotic cohort were successfully treated with a mean follow-up of 21 months. CONCLUSIONS: UPJO in horseshoe kidneys can pose a therapeutic dilemma. The minimally invasive treatment of these patients is feasible with good success rates for both endopyelotomy and laparoscopic/robotic pyeloplasty. PMID- 20204378 TI - Thulium: YAG 2 mum cw laser prostatectomy: where do we stand? AB - INTRODUCTION: Tm:YAG 2 mum cw laser prostatectomy was introduced in the treatment of benign ptostatic obstruction (BPO). Since then numerous studies have been published proving efficacy during follow-up. However, different surgical techniques were introduced with different names for similar techniques that complicate comparison. This reviews aim was to compare published data and break down surgical techniques to core points. The authors define validate appellations for different surgical techniques and propose further use of these names to ensure homogenous nomenclature. MATERIALS AND METHODS: All publications on Thulium:YAG prostatectomy have been included in this review. Articles were reviewed and associated due to the nature of the surgical approach. A systematic review of published data was performed. RESULTS: Sixteen peer-reviewed publications dealing with Tm:YAG laser prostatectomy were printed since 2005. Four different surgical principles are described, including vaporization, resection and enucleation. Follow-up, up to 24 months, showed durable functional results. CONCLUSION: Efficacy of Tm:YAG prostatectomy was shown. Surgical techniques include "Tm:YAG Vaporization of the prostate (ThuVAP)", "Tm:YAG VapoResection of the prostate (ThuVaRP)" and "Tm:YAG VapoEnucleation of the prostate (ThuVEP)". The almost blunt enucleation is introduced as "Tm:YAG laser enucleation of the prostate (ThuLEP)". The authors recommend the use of this neologism in the future. Further, large-scale prospective studies are needed to prove long-term durability. To initiate and canalize these upcoming studies, the Urothulium Study Group was founded, combining international experts on Thulium:YAG laser prostatectomy under its roof. PMID- 20204380 TI - Intervertebral disc calcification with neurological symptoms in children: report of conservative treatment in two cases. AB - PURPOSE: Intervertebral calcifications are rare in the paediatric population. Two cases of children with symptomatic intervertebral calcifications responsible for spinal cord compression and neurological compromise are presented. METHODS: The data of two children treated conservatively for a symptomatic intervertebral calcification responsible for spinal cord compression and neurological compromise were retrospectively reviewed. RESULTS: Frontal and lateral radiographs are usually sufficient to determine the presence and extent of the calcified cervical disc protrusion. Conservative treatment with antalgics and bracing was applied in both cases. The two patients were completely free of symptoms 4 weeks after initial treatment. Magnetic resonance imaging screening showed a complete vertebral canal clearance at final follow-up. CONCLUSION: Despite the lack of significance due to the small number of patients, conservative treatment should be considered in children with moderate neurological symptoms due to calcified disc protrusion. PMID- 20204379 TI - Laparoscopic partial nephrectomy for large renal masses: results of a European survey. AB - OBJECTIVE: To evaluate the perioperative effectiveness of laparoscopic partial nephrectomy (LPN) for large (4-7 cm) renal masses, with a review of the experience of six European advanced laparoscopic centres. PATIENTS AND METHODS: A survey was planned; data were extracted from each institutional data base to obtain information about patients who had undergone LPN for renal masses larger than 4 cm. Demographic, radiological growth patterns of the tumours and intraoperative data were collected. Post-operative complications and pathological data were also recorded. All data were processed through statistical software. RESULTS: Data on 63 patients were collected. Radiological tumour size was 4.7 cm (4.1-7), growth pattern was cortical in 33 cases and cortico-medullar in 30 cases. Warm ischemia time (WIT) was 25.7 min in 7.3% cases bleeding occurred intra-operatively, post-operative surgical complications occurred in 14.6% cases. Pathological analyses revealed malignant lesion in 73% and positive margins in 6.5%. Complications and positive margins are more frequent for cortico-medullar lesions. CONCLUSIONS: This survey confirms that LPN for tumours 4-7 cm in size is feasible in experienced hands. WIT and overall complication rate remain questionable points. PMID- 20204381 TI - Surgical morbidity and mortality of pediatric brain tumors: a single center audit. AB - OBJECTIVES: The primary aim of this study is to perform an internal quality control of pediatric brain tumor surgery in the neurosurgical department of the VU University Medical Center Amsterdam (The Netherlands). Secondly, this study aims to contribute to the accumulating data concerning outcome in pediatric neurosurgery, in order to establish institutional practice benchmarks. METHODS: We report the surgical mortality and morbidity of 121 patients (0-18 years) surgically treated for a brain tumor from January 1999 to August 2007. Patients, in whom only a brain tumor biopsy was performed, were excluded. RESULTS: Mean age at first surgery was 8.2 years. Of the 121 patients, 14 had a second surgery, and two underwent a third surgery (for a total of 137 operations). Of all 121 primary surgeries, 66% were total resections, 26% subtotal resections, and 8% partial resections. The overall surgical morbidity rate in this study was 69% after first surgery, 50% after second surgery, and one out of two after third surgery. CONCLUSION: These overall morbidity rates are comparable to other published mixed case series. The surgical mortality rate was 0.8%; this is comparable to the lowest rates reported for high-volume neurosurgical centers. We encourage other neurosurgical centers to collect, analyze, and publish their data. These data can then serve as a basis for comparison with other pediatric neurosurgical centers and will eventually lead to an improvement of pediatric neurosurgical practice and patient care. PMID- 20204382 TI - Multi-institutional study of risk factors of liver metastasis from colorectal cancer: correlation with CD10 expression. AB - BACKGROUND: The risk factors for liver metastasis from colorectal cancer are still unclear. We therefore evaluated the relationships between various clinicopathological factors, including CD10 expression, liver metastasis, and survival, in patients with colorectal cancer. METHODS: Clinicopathological data for 1,025 patients with stage II or III colorectal cancer who underwent curative surgery in four participating hospitals were collected and evaluated. Three pathologists examined focal dedifferentiation, venous invasion, and CD10 expression without knowledge of the clinical outcome. RESULTS: Univariate analysis showed that pathological T (pT), pathological N (pN), venous invasion, focal dedifferentiation, and CD10 expression were significantly associated with liver metastasis. Multivariate analysis selected pT, pN, and CD10 expression as significant risk factors for liver metastasis. pT, pN and CD10 were also shown by univariate and multivariate analyses to be significantly associated with disease free survival. The incidence of liver metastasis was 3% in pN0 patients with CD10 negative or pT2 or pT3 tumors and 28% in pN2 patients with CD10-positive or pT4 tumors. CONCLUSIONS: CD10 expression is a significant risk factor for liver metastasis in patients with colorectal cancer and is correlated with prognosis. Patients with a high risk of liver metastasis can be selected on the basis of pT, pN, and CD10 expression. PMID- 20204383 TI - [Caregiver burden with dementia patients. A validation study of the German language version of the Zarit Burden Interview]. AB - Despite the large number of studies dealing with dementia caregivers in Europe, a valid German version of the most widely used measurement of caregiver burden, the Zarit Burden Interview, has not been published. The purpose of this study was to evaluate the psychometric properties of the German Zarit Burden Interview (G ZBI). A sample of community-dwelling older couples (n=37) with the husband suffering from dementia and the wife being the primary caregiver participated in this study. The G-ZBI and related constructs were assessed in order to test for reliability and construct validity. The G-ZBI revealed psychometric properties comparable with those of the original instrument and empirically validated translations. Results indicate high internal consistency (Cronbach's alpha=0.91) and good validity due to strong correlations with caregiver life satisfaction and depression, as well as patients' dependency, neuropsychiatric symptoms, and dementia severity. The psychometric qualities of the G-ZBI indicate that it is both a reliable and valid instrument to assess caregiver burden and to detect highly stressed individuals. PMID- 20204384 TI - Concealed accessory pathways: Historical notes. AB - Concealment of an accessory pathway is caused by its ability to conduct retrogradely only. This variant of accessory pathway conduction could not be confirmed until invasive electrophysiology was introduced in the 1970s. As a rule, it is reported that concealed accessory pathways were predicted from animal experiments in 1971. However, even earlier studies suggested an accessory pathway or mechanisms comparable to those of the Wolff-Parkinson-White syndrome to be the cause of supraventricular tachycardias even though preexcitation during sinus rhythm had been lacking. Such interpretations were derived from clinical considerations, from patients having lost their ventricular preexcitation spontaneously, and from the disappearance of the delta wave after drug administration. Some authors postulated but did not provide the correct interpretation. Even a few contributions published before the paper of Wolff, Parkinson, and White in 1930 are worth considering in this context. PMID- 20204385 TI - Skin biopsy as an additional diagnostic tool in non-systemic vasculitic neuropathy. AB - Sural nerve biopsy is considered mandatory for diagnosing non-systemic vasculitic neuropathy (NSVN). This invasive technique may be associated with unpleasant sequelae and cannot easily be repeated. Skin punch biopsy from an affected area may be a less invasive and repeatable diagnostic method. Here we assessed the potential diagnostic value of skin punch biopsies in NSVN by analyzing skin biopsies in 20 patients with sural nerve biopsy-proven NSVN and in 11 patients with non-inflammatory axonal neuropathy. As further controls, skin biopsies were studied in nine healthy volunteers. Five millimeter skin punch biopsies were taken under local anesthesia from the distal lateral calf and T cells and macrophages were quantified after immunostaining. The diagnostic sensitivity and specificity compared to sural nerve biopsy was determined using receiver operating characteristic (ROC) analysis. ROC analysis revealed that the highest sensitivity (94%) and specificity (79%) for NSVN was obtained when perivascular macrophages were quantified. Quantification of scattered T cells yielded a sensitivity and specificity of 65%. Inflammatory cells were very rare in controls. Quantification of inflammatory cells in skin biopsies may thus be a sensitive and specific additional tool for diagnosing NSVN. PMID- 20204386 TI - Prevalence of dementia disorders in the oldest-old: an autopsy study. AB - The prevalence of Alzheimer disease (AD) and vascular dementia (VD) increases with advancing age, but less so after age 90 years. A retrospective hospital based study of the relative prevalence of different disorders was performed in 1,110 consecutive autopsy cases of demented elderly in Vienna, Austria (66% females, MMSE <20; mean age 83.3 +/- 5.4 SD years). It assessed clinical, general autopsy data and neuropathology including immunohistochemistry. Neuropathologic diagnosis followed current consensus criteria. Four age groups (7-10th decade) were evaluated. In the total cohort AD pathology was seen in 82.9% ("pure" AD 42.9%; AD + other pathologies 39.9%), VD in 10.8% (mixed dementia, MIX, i.e. AD + vascular encephalopathy in 5.5%); other disorders in 5.7%, and negative pathology in 0.8%. The relative prevalence of AD increased from age 60 to 89 years and decreased slightly after age 90+, while "pure" VD diagnosed in the presence of vascular encephalopathy of different types with low neuritic AD pathology (Braak stages <3; mean 1.2-1.6) decreased progressively from age 60 to 90+; 85-95% of these patients had histories of diabetes, morphologic signs of hypertension, 65% myocardial infarction/cardiac decompensation, and 75% a history of stroke(s). Morphologic subtypes, subcortical arteriosclerotic (the most frequent), multi infarct encephalopathy, and strategic infarct dementia showed no age-related differences. The relative prevalence of AD + Lewy pathology remained fairly constant with increasing age. Mixed dementia and AD with minor cerebrovascular lesions increased significantly with age, while other dementias decreased. This retrospective study using strict morphologic criteria confirmed increased prevalence of AD with age, but mild decline at age 90+, and progressive decline of VD, while AD + vascular pathologies including MIX showed considerable age related increase, confirming that mixed pathologies account for most dementia cases in very old persons. A prospective clinicopathologic study in oldest-old subjects showed a significant increase in both AD and cerebral amyloid angiopathy (CAA), but decrease in VD over age 85, while in a small group of old subjects CAA without considerable AD pathology may be an independent risk factor for cognitive decline. PMID- 20204387 TI - Toll-like receptor expression and function in human dendritic cell subsets: implications for dendritic cell-based anti-cancer immunotherapy. AB - Dendritic cells (DCs) are central players of the immune response. To date, DC based immunotherapy is explored worldwide in clinical vaccination trials with cancer patients, predominantly with ex vivo-cultured monocyte-derived DCs (moDCs). However, the extensive culture period and compounds required to differentiate them into DCs may negatively affect their immunological potential. Therefore, it is attractive to consider alternative DC sources, such as blood DCs. Two major types of naturally occurring DCs circulate in peripheral blood, myeloid DCs (mDCs) and plasmacytoid (pDCs). These DC subsets express different surface molecules and are suggested to have distinct functions. Besides scavenging pathogens and presenting antigens, DCs secrete cytokines, all of which is vital for both the acquired and the innate immune system. These immunological functions relate to Toll-like receptors (TLRs) expressed by DCs. TLRs recognize pathogen-derived products and subsequently provoke DC maturation, antigen presentation and cytokine secretion. However, not every TLR is expressed on each DC subset nor causes the same effects when activated. Considering the large amount of clinical trials using DC-based immunotherapy for cancer patients and the decisive role of TLRs in DC maturation, this review summarizes TLR expression in different DC subsets in relation to their function. Emphasis will be given to the therapeutic potential of TLR-matured DC subsets for DC-based immunotherapy. PMID- 20204388 TI - Seventh annual meeting of the Italian Network for Tumor Biotherapy (NIBIT), Siena, 1-3 October 2009. PMID- 20204389 TI - A histological and ultrastructural study of femoral head cartilage in a new type II collagenopathy. AB - A new type II collagenopathy, caused by the p.Gly1170Ser mutation of COL2A1, which presents as premature hip osteoarthritis (OA), avascular necrosis of the femoral head (ANFH) or Legg-Calve-Perthes (LCP) disease, was recently found in several families with an inherited disease of the hip joint. In this study, femoral head cartilage was harvested for histological and ultrastructural examination to determine the pre-existing generalised abnormalities of the mutant cartilage. The histological results showed that the hierarchical structure of the mutant cartilage and the embedded chondrocytes were markedly abnormal. The expression and distribution of type II collagen was non-uniform in sections of the mutant cartilage. Ultrastructural examination showed obvious abnormal chondrocytes and disarrangement of collagen fibres in the mutant cartilage. Furthermore, the predicted stability of type II collagen dramatically decreased with the substitution of serine for glycine. Our study demonstrated that the p.Gly1170Ser mutation of COL2A1 caused significant structural alterations in articular cartilage, which are responsible for the new type II collagenopathy. PMID- 20204390 TI - Shepard grommet tympanostomy tube complications in children with chronic otitis media with effusion. AB - The objective of this study was to determine tympanostomy tube complications in children with chronic otitis media with effusion who were treated with Shepard grommet tympanostomy tube insertion. This tube type was selected as it is the most commonly used one in our clinic. The medical records of 162 ears of 87 children (52 male and 35 female) were reviewed retrospectively. The children were between 3 to 16 years old (mean age = 8.1 +/- 3.1). The patients were followed up 6-66 months (mean 23.3 +/- 14.9 months) after tympanostomy tube insertion. We reviewed age, sex, time to tube extrusion and complications. In all patients the indication for surgery was chronic middle ear effusion. Otorrhea occurred in nine ears (5.6%). Granulation tissue was seen in two ears (1.2%). Complications after tympanostomy tube extrusion included myringosclerosis (34.6%), persistent perforation (5.6%), atrophy (23.5%), retraction (16.7%) and medial displacement of tubes (1.2%). The average extrusion time was 8.5 +/- 4.6 months (range 1-24) for Shepard grommet tympanostomy tubes. Complications of tympanostomy tube insertion are common. Myringosclerosis, tympanic membrane atrophy and otorrhea are the most frequently appearing complications. But they are generally insignificant and cosmetic. Consequently, in the majority of these complications there is no need for any management. PMID- 20204391 TI - Non-organic hearing loss: new and confirmed findings. AB - Although non-organic hearing losses are relatively rare, it is important to identify suspicious findings early to be able to administer specific tests, such as objective measurements and specific counseling. In this retrospective study, we searched for findings that were specific ti or typical for non-organic hearing losses. Patient records from a 6 year period (2003-2008) from the University ENT Department of Bern, Switzerland, were reviewed. In this period, 40 subjects were diagnosed with a non-organic hearing loss (22 children, ages 7-16, mean 10.6 years; 18 adults, ages 19-57, mean 39.7 years; 25 females and 15 males). Pure tone audiograms in children and adults showed predominantly sensorineural and frequency-independent hearing losses, mostly in the range of 40-60 dB. In all cases, objective measurements (otoacoustic emissions and/or auditory-evoked potentials) indicated normal or substantially better hearing thresholds than those found in pure tone audiometry. In nine subjects (22.5%; 2 children, 7 adults), hearing aids had been fitted before the first presentation at our center. Six children (27%) had a history of middle ear problems with a transient hearing loss and 11 (50%) knew a person with a hearing loss. Two new and hitherto unreported findings emerged from the analysis: it was observed that a small air bone gap of 5-20 dB was typical for non-organic hearing losses and that speech audiometry might show considerably poorer results than expected from pure tone audiometry. PMID- 20204392 TI - What is the role of sentinel lymph node biopsy in the management of oral cancer in 2010? PMID- 20204395 TI - Assessing cortico-hippocampal functional connectivity under anesthesia and kainic acid using generalized partial directed coherence. AB - A significant challenge in modern neuroscience lies in determining the functional connectivity between discrete populations of neurones and brain regions. In this study, a variation of partial directed coherence, the generalized partial directed coherence (gPDC), along with a newly proposed critical value for gPDC, were applied on recorded local field potentials (LFPs) and single-unit activity, in order to assess information flow between medial prefrontal cortex (mPFC) and hippocampus and within the hippocampus of the rat brain, under isoflurane anesthesia and kainic acid-induced enhanced neuronal activity. Our findings suggest that, under anesthesia, there exists a continuous information flow from hippocampus towards mPFC, reversed mostly during activity bursts occurring in the mPFC. Moreover, there was a clear directional connection from the lateral towards medial dorsal hippocampus, most prominent in the beta frequency band (10-30 Hz). Kainic acid resulted in partially disrupting the reciprocal cortico-hippocampal connectivity and reversing the intra-hippocampal one. The biological implications of these findings on the effects of anesthesia and kainic acid in brain connectivity, along with implementation issues of gPDC analysis on field potentials and spike trains, are extensively discussed. PMID- 20204393 TI - The close relationship between life-threatening breathing disorders and urine storage dysfunction in multiple system atrophy. AB - Survival of multiple system atrophy (MSA) depends on whether a variety of sleep related breathing problems as well as autonomic failure (AF) occur. Since the brainstem lesions that cause respiratory and autonomic dysfunction overlap with each other, these critical manifestations might get worse in parallel. If so, the detection of AF, which is comparatively easy, might be predictive of a latent life-threatening breathing disorder. In 15 patients with MSA, we performed autonomic function tests composed of postural challenges and administered a questionnaire on bladder condition, as well as polysomnography and laryngoscopy during wakefulness and under anesthesia. Polysomnographic variables such as the apnea-hypopnea index (AHI) and oxygen saturation (SpO(2)) and the findings of laryngoscopy were compared with the degree of cardiac and urinary autonomic dysfunction. AHI, mean SpO(2) and the lowest SpO(2) showed significant correlations with urine storage dysfunction. In addition, patients with vocal cord abductor paralysis (VCAP) or central sleep apnea (CSA) contributing to nocturnal sudden death had more severe storage disorders than those without. On the other hand, no significant relationship between polysomnographic variables and orthostatic hypotension was observed except in the case of mean SpO(2). These results indicate that life-threatening breathing disorders have a close relationship with AF, and especially urine storage dysfunction. Therefore, longitudinal assessment of deterioration of the storage function might be useful for predicting the latent progress of VCAP and CSA. PMID- 20204396 TI - How stimulus shape affects lateral-line perception: analytical approach to analyze natural stimuli characteristics. AB - We revisit the method of conformal mapping and apply it to the setting found in mechanosensory detection systems such as the lateral-line system of fish. We derive easy-to-use equations capable of describing analytically the influence of the stimulus shape on the flow field and thus on the input to the lateral line. The present approach shows that the shape of a submerged moving object affects its perception if its distance to a detecting animal does not exceed the object's body length. PMID- 20204394 TI - Progressive nature of a higher level gait disorder: a 3-year prospective study. AB - The objective of the study was to characterize the natural history of patients with a higher level gait disorder (HLGD) of the cautious/disequilibrium type in a 3-year prospective study. Subjects were taken from an outpatient setting in a movement disorders clinic. Twenty-two mobile, community-living patients with a HLGD of the cautious/disequilibrium type and 26 age- and gender-matched healthy controls were evaluated at baseline and approximately 3 years later. Detailed medical history, a complete, structured geriatric and neurological examination, mental and affective state, gait and balance assessment were obtained. At follow up, marked declines were observed in gait, mobility and functional independence in the patients, but not in the controls. For example, 23% of the patients could not complete the Timed Up and Go test, compared to only 4% of the control group, and among those who could complete the test, time to completion was almost three times longer (P < 0.0001) in the patients (23 s), compared to the controls (8 s). At follow-up, 50% of the patients required a personal live-in caregiver compared to only 4% of the controls (P < 0.0001). Although mild extra-pyramidal, pyramidal, cognitive and affective alterations were observed at baseline in the patients, those symptoms were stable over time. Unexpectedly, there was no association between the presence of HLGD or its progression and vascular risk factors. HLGD is a debilitating, rapidly progressive disease. The profound deterioration in functional independence in a relatively short period of time suggests that early multidisciplinary interventions may be the appropriate clinical approach to the treatment of these patients who are at risk for a rapid decline in functional abilities. PMID- 20204397 TI - On population encoding and decoding of auditory information for bat echolocation. AB - In this article, we study the neural encoding of acoustic information for FM-bats (such as Eptesicus fuscus) in simulation. In echolocation research, the frequency time sound representation as expressed by the spectrogram is often considered as input. The rationale behind this is that a similar representation is present in the cochlea, i.e. the receptor potential of the inner hair cells (IHC) along the length of the cochlea, and hence similar acoustic information is relayed to the brain. In this article, we study to what extent the latter assumption is true. The receptor potential is converted into neural activity of the synapting auditory nerve cells (ANC), and information might be lost in this conversion process. Especially for FM-bats, this information transmission is not trivial: in contrast to other mammals, they detect short transient signals, and consequently neural activity can only be integrated over very limited time intervals. To quantify the amount of information transmitted we design a neural network-based algorithm to reconstruct the IHC receptor potentials from the spiking activity of the synapting auditory neurons. Both the receptor potential and the resulting neural activity are simulated using Meddis' peripheral model. Comparing the reconstruction to the IHC receptor potential, we quantify the information transmission of the bat hearing system and investigate how this depends on the intensity of the incoming signal, the distribution of auditory neurons, and previous masking stimulation (adaptation). In addition, we show how this approach allows to inspect which spectral features survive neural encoding and hence can be relevant for echolocation. PMID- 20204398 TI - Fully decentralized control of a soft-bodied robot inspired by true slime mold. AB - Animals exhibit astoundingly adaptive and supple locomotion under real world constraints. In order to endow robots with similar capabilities, we must implement many degrees of freedom, equivalent to animals, into the robots' bodies. For taming many degrees of freedom, the concept of autonomous decentralized control plays a pivotal role. However a systematic way of designing such autonomous decentralized control system is still missing. Aiming at understanding the principles that underlie animals' locomotion, we have focused on a true slime mold, a primitive living organism, and extracted a design scheme for autonomous decentralized control system. In order to validate this design scheme, this article presents a soft-bodied amoeboid robot inspired by the true slime mold. Significant features of this robot are twofold: (1) the robot has a truly soft and deformable body stemming from real-time tunable springs and protoplasm, the former is used for an outer skin of the body and the latter is to satisfy the law of conservation of mass; and (2) fully decentralized control using coupled oscillators with completely local sensory feedback mechanism is realized by exploiting the long-distance physical interaction between the body parts stemming from the law of conservation of protoplasmic mass. Simulation results show that this robot exhibits highly supple and adaptive locomotion without relying on any hierarchical structure. The results obtained are expected to shed new light on design methodology for autonomous decentralized control system. PMID- 20204400 TI - Biophysical characterisation of the persistent sodium current of the Nav1.6 neuronal sodium channel: a single-channel analysis. AB - Na(v)1.6 is the major voltage-gated sodium channel at nodes of Ranvier. This channel has been shown to produce a robust persistent inward current in whole cell experiments. Na(v)1.6 plays an important role in axonal conduction and may significantly contribute to the pathophysiology of the injured nervous system through this persistent current. However, the underlying molecular mechanisms and regulation of the persistent current are not well understood. Using the whole cell configuration of the patch-clamp technique, we investigated the Na(v)1.6 transient and persistent currents in HEK-293. Previous studies have shown that the persistent current depended on the content of the patch electrode. Therefore, we characterised the single-channel properties of the persistent current with an intact intracellular medium using the cell-attached configuration of the patch clamp technique. In HEK-293 cells, the Na(v)1.6 persistent current recorded in the whole-cell configuration was 3-5% of the peak transient current. In single channel recording, the ratio between peak and persistent open probability confirmed the magnitude of the persistent current observed in the whole-cell configuration. The cell-attached configuration revealed that the molecular mechanism of the whole-cell persistent current is a consequence of single Na(v)1.6 channels reopening. PMID- 20204399 TI - CaV2.1 channelopathies. AB - Mutations in the CACNA1A gene that encodes the pore-forming alpha1 subunit of human voltage-gated CaV2.1 (P/Q-type) Ca2+ channels cause several autosomal dominant neurologic disorders, including familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2, and spinocerebellar ataxia type 6 (SCA6). For each channelopathy, the review describes the disease phenotype as well as the functional consequences of the disease-causing mutations on recombinant human CaV2.1 channels and, in the case of FHM1 and SCA6, on neuronal CaV2.1 channels expressed at the endogenous physiological level in knockin mouse models. The effects of FHM1 mutations on cortical spreading depression, the phenomenon underlying migraine aura, and on cortical excitatory and inhibitory synaptic transmission in FHM1 knockin mice are also described, and their implications for the disease mechanism discussed. Moreover, the review describes different ataxic spontaneous cacna1a mouse mutants and the important insights into the cerebellar mechanisms underlying motor dysfunction caused by mutant CaV2.1 channels that were obtained from their functional characterization. PMID- 20204401 TI - The chromosome content and genotype of two wheat cell lines and of their somatic fusion product with oat. AB - Somatic hybridization seeks to genetically combine phylogenetically distant parents. An effective system has been established in bread wheat (Triticum aestivum L.) involving protoplasts from a non-totipotent cell line adapted to in vitro culture (T(1)) in combination with totipotent protoplasts harvested from embryogenic calli (T(2)). Here, we report the karyotype and genotype of T(1) and T(2). Line T(1) carries nine A (A-genome of wheat), seven B (B-genome of wheat) and eight D (D-genome of wheat) genome chromosomes, while T(2) cells have 12 A, 10 B and 12 D genome chromosomes. Rates of chromosome aberration in the B- and D genomes were more than 25%, higher than in the A-genome. DNA deletion rates were 55.6% in T(1) and 19.4% in T(2), and DNA variation rates were 8.3% in T(1) and 13.9% in T(2). Rate of DNA elimination was B- > D- > A-genome in both T(1) and T(2). The same set of cytological and genetic assays was applied to a derivative of the somatic fusion between protoplasts of T(1), T(2) and oat (Avena sativa L.). The regenerant plants were near euploid with respect to their wheat complement. Six wheat chromosome arms-4AL, 3BS, 4BL, 3DS, 6DL and 7DL-carried small introgressed segments of oat chromatin. A genotypic analysis of the hybrid largely confirmed this cytologically-based diagnosis. PMID- 20204402 TI - Analysis of common germline polymorphisms as prognostic factors in patients with lymph node-positive breast cancer. AB - PURPOSE: Women with breast cancer that initially involves local lymph nodes have a higher risk for local recurrence or developing metastases. Recent data suggest that germline polymorphism is a significant, previously unrecognized factor in breast cancer progression and metastasis. We assessed the influence of 16 selected common germline polymorphisms in disease-free survival and overall survival among 216 women diagnosed with lymph node-positive breast cancer. RESULTS: The rare allele of FAS 1377G>A was significantly associated with prolonged disease-free survival (P = 0.012, risk ratio of recurrence (RR) = 0.557, 95% confidence interval (CI) = 0.353-0.878) in univariate analysis. After adjusting for known breast cancer prognostic factors the association remained significant (P = 0.050, RR = 0.500, CI = 0.309-0.809). In overall survival analysis we found a significant association of the FAS 1377G>A (P = 0.040, RR = 0.451, CI = 0.496-1.188) and IL10 592C>A polymorphisms (P = 0.020, RR = 1.707, CI = 1.087-2.680) in the univariate Cox regression. The effect remained statistically significant in the multivariate analysis for the IL10 592C>A polymorphism (P = 0.013, RR 1.841, CI 1.140-2.973). No association was found for MTHFR 677C>T, VEGF 936C>T, CCND1 870G>A, TGFB1 29T>C, FASLG 844C>T, FAS 670A>G, GPB3 825C>T, ITGA2 807C>T, ITGA2 1648G>A, ITGB3 176T>C, MMP1 -1607 1G/2G, MMP3 5A/6A, PTGS2 8473T>C, IL10 592C>A and SULT1A1 638G>A polymorphisms and disease free survival or overall survival. CONCLUSIONS: Our data suggest that the FAS 1377G>A and IL10 592C>A polymorphisms could modify disease-free and overall survival in women with lymph node-positive breast cancer. PMID- 20204403 TI - Serum Cyfra 21.1 and galectin-3 protein levels in relation to immunohistochemical cytokeratin 19 and galectin-3 expression in patients with thyroid tumors. AB - PURPOSE: The aim of this study was to assess the clinical utility of circulating preoperative Cyfra 21.1 [soluble fragment of cytokeratin (CK) 19] and galectin-3 (gal-3) in patients with thyroid tumors, to compare their serum values with tissue expression and to analyze the prognostic significance of these markers in relation to the clinical status of postsurgical differentiated thyroid carcinoma (DTC) patients. PATIENTS: Concentrations of Cyfra 21.1 and gal-3 were evaluated by immunoassays in sera of 9 healthy subjects, 97 preoperative patients with diverse thyroid tumors (10 FTA, 63 PTC, 11 FTC, 5 PDTC, 4 ATC, 4 LNM) and 25 postoperative DTC patients (14 remissions and 11 metastases). RESULTS: Low Cyfra 21.1 values were found in all subgroups, but with a tendency toward higher values in poorly differentiated DTC patients. Compared to the control (0.23 ng/mL), serum levels of gal-3 were significantly elevated in patients with thyroid tumors but with overlapping between adenoma (4.16 ng/mL) and carcinoma (3.85, 4.37, 4.64, 6.07 ng/mL for PTC, PDTC, ATC and LNM, respectively). The tissue expression of CK19 and gal-3 was immunohistochemically determined on 45 matched paraffin embedded sections. Most thyroid carcinomas showed positive CK19 (27/35) and gal-3 immunostaining (31/35), while adenomas were mostly immunonegative (8/10 and 7/10, respectively). However, there was no significant correlation between their serum and tissue levels. Clinical status of postoperative DTC patients had no influence on serum concentrations of the tested markers. CONCLUSIONS: While CK19 and gal-3 are accurate as tissue markers, their serum levels could not be used as reliable markers for identification of thyroid malignancy or in thyroid cancer follow-up. On the other hand, a tendency toward higher serum levels of Cyfra 21.1 in the small number of PDTC patients examined adds weight to previous reports postulating a role for cytokeratins in predicting a high degree of malignancy. PMID- 20204404 TI - PI3K/Akt and GSK-3beta prevents in a differential fashion the malignant phenotype of colorectal cancer cells. AB - PURPOSE: During colorectal cancer progression, the loss of differentiation and cell-cell adhesion as well as a higher migratory potential are well-defined features; however, the signaling mechanism governing these events is not fully elucidated. The aim of this study was to investigate the role that PI3K and downstream effectors play in controlling colon cancer malignant phenotypes. METHODS: HCT-116 cells, a human model of colon cancer, which are highly metastatic and undifferentiated, were treated with LY294002, a specific inhibitor of PI3K. Cell differentiation and apical junctional complex (AJC) formation were monitored using alkaline phosphatase and electron microscopy analysis. Immunofluorescence and Western blotting were used to accompany the subcellular localization of AJC proteins. PI3K downstream molecules were analyzed by western blotting, and proliferation, wound healing, and colony formation techniques to determine malignant phenotype alterations. RESULTS: PI3K inhibition increased alkaline phosphatase activity, led to an enterocyte-like growth and formed a functional AJC. LY294002 treatment was able to recruit E-cadherin, beta-catenin, claudin-3, and ZO-1 to the cell-cell contact region, and this effect was essential for AJC assembly and association of these proteins to the cytoskeleton. Furthermore, we provided evidence that PI3K inhibition leads to a decrease in p Akt and p-GSK-3beta and increased p-beta-catenin levels, which in turn controlled cell proliferation, motility, and colony formation. CONCLUSION: Our results demonstrate that PI3K/Akt and GSK-3beta prevents in a differential fashion the malignant phenotype of HCT-116 colorectal cancer cells, which could constitute a potential therapeutic target for treatment of this cancer type. PMID- 20204405 TI - Targeting monoamine oxidase A in advanced prostate cancer. AB - PURPOSE: Inhibitors of monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades neurotransmitters including serotonin and norepinephrine, are commonly used to treat neurological conditions including depression. Recently, we and others identified high expression of MAOA in normal basal prostatic epithelium and high-grade primary prostate cancer (PCa). In contrast, MAOA is low in normal secretory prostatic epithelium and low-grade PCa. An irreversible inhibitor of MAOA, clorgyline, induced secretory differentiation in primary cultures of normal basal epithelial cells and high-grade PCa. Furthermore, clorgyline inhibited several oncogenic pathways in PCa cells, suggesting clinical value of MAOA inhibitors as a pro-differentiation and anti-oncogenic therapy for high-risk PCa. Here, we extended our studies to a model of advanced PCa, VCaP cells, which were derived from castration-resistant metastatic PCa and express a high level of MAOA. METHODS: Growth of VCaP cells in the presence or absence of clorgyline was evaluated in vitro and in vivo. Gene expression changes in response to clorgyline were determined by microarray and validated by quantitative real-time polymerase chain reaction. RESULTS: Treatment with clorgyline in vitro inhibited growth and altered the transcriptional pattern of VCaP cells in a manner consistent with the pro-differentiation and anti-oncogenic effects seen in treated primary PCa cells. Src, beta-catenin, and MAPK oncogenic pathways, implicated in androgen independent growth and metastasis, were significantly downregulated. Clorgyline treatment of mice bearing VCaP xenografts slowed tumor growth and induced transcriptome changes similar to those noted in vitro. CONCLUSION: Our results support the possibility that anti-depressant drugs that target MAOA might find a new application in treating PCa. PMID- 20204406 TI - Prognostic factors and treatment options in patients with leptomeningeal metastases of different primary tumors: a retrospective analysis. AB - PURPOSE: Leptomeningeal metastases (LM) are associated with very poor prognosis and data on outcome are limited. We evaluated prognostic factors and treatment options in patients (pts) with LM of different malignancies in a single center experience. METHODS: Single center data on characteristics, treatment and outcome of 135 consecutive pts (73 solid tumors and 62 hematologic malignancies) with LM between 1989 and 2005 were retrospectively analyzed. RESULTS: Treatment consisted of systemic chemotherapy (SC) plus intrathecal chemotherapy (ITC) in 28%, ITC alone in 22%, radiotherapy (RT) plus ITC in 12% and other modalities (SC, RT, SC + RT) in 7%. Thirteen percent of pts received supportive care only (4% not evaluable on treatment). Median survival from diagnosis of LM was 2.5 months. Univariate analysis revealed age >50, interval between diagnosis of primary tumor and LM <=12 months, lung cancer and malignant melanoma, and Karnofsky performance status <=70 as significant negative predictors for overall survival. Positive predictive factors were response in cerebrospinal fluid and application of SC. In multivariate analysis, only SC was significantly associated with longer median survival (5.6 vs. 1.7 months). CONCLUSIONS: In patients with LM an age >50, performance status <=70%, interval between diagnosis of primary tumor and LM <=12 months, primary tumor (lung cancer, malignant melanoma) and lack of cytologic response present negative prognostic factors. Systemic chemotherapy is significantly associated with longer survival time than local treatment modalities. PMID- 20204407 TI - Comparison of microarray-based RNA expression with ELISA-based protein determination of HER2, uPA and PAI-1 in tumour tissue of patients with breast cancer and relation to outcome. AB - PURPOSE: Prognostic and predictive markers in breast cancer are currently determined by single analysis of protein amounts. If RNA-based multi-gene analyses enter clinical practice, simultaneous determination of currently established markers like human epidermal growth factor receptor 2 (HER2), urokinase plasminogen activator (uPA) and its inhibitor (PAI-1) would represent an elegant simplification. To investigate the correlation between RNA and protein levels, we assessed HER2, uPA and PAI-1 in patients with breast cancer. In addition, we evaluated the influence of these factors on patient outcome. METHODS: We collected tumour samples from 133 patients with primary breast cancer. Protein and mRNA levels were measured for HER2, uPA and PAI-1. Protein concentration was measured by ELISA, mRNA expression was analysed by Affymetrix A133U Gene Chip and validated by quantitative PCR. RESULTS: We were able to demonstrate a statistically significant correlation between mRNA and protein expression for HER2 (r = 0.67, P < 0.001) and uPA (r = 0.7, P < 0.001) but not for PAI-1 (r = 0.27). We observed a prognostic information for PAI-1 mRNA and protein values. Patients with high PAI-1 mRNA expression had a reduced 10-year disease-free survival (DFS) rate (60 vs. 70%, P = 0.071) and 10-year overall survival (OS) rate (68 vs. 79%, P = 0.034). Patients with PAI-1 protein levels above 14 ng/mg protein had a reduced disease-free (10-year DFS rate 54 vs. 71%, P = 0.006) and overall survival rate (10-year OS-rate 63 vs. 83%, P = 0.018). In the patient cohort with no chemotherapy, PAI-1 mRNA levels were the strongest prognostic factor for OS in univariate and multivariate analysis. CONCLUSIONS: Results of RNA-based multi-gene analyses of the prognostic and predictive markers HER2 and uPA correlate with the corresponding protein levels. This is not the case for PAI-1. However, PAI-1 mRNA expression might reveal new clinically relevant information in addition to PAI protein levels. PMID- 20204408 TI - Beta2-GPI: a novel factor in the development of hepatocellular carcinoma. AB - PURPOSE: This study investigated the effect and clinical significance of beta2 GPI in hepatocellular carcinoma (HCC). METHODS: Double fluorescent immunostaining analysis was performed in paraffin wax-embedded histological sections of nine HCC parenchyma, seven adjacent non-cancerous tissues and seven control liver tissues from hepatitis B virus (HBV) infected patients using a beta2-GPI polyclonal antibody and a HBV surface antibody. NF-kappaB activation was assessed by a non radioactive electrophoretic mobility shift assay (EMSA) and immunofluorescence assay in SMMC-7721 HCC cells exposed to various treatments. The cells were transiently transfected with vectors expressing beta2-GPI (group one), HBsAg (group two), both beta2-GPI and HBsAg (group three), or with a control vector (group four). Untransfected cells (group five) were also used as a control. Alpha fetoprotein (AFP) expressions were also detected by ELISA in all groups. RESULTS: The highest degree of co-localization of beta2-GPI and HBsAg proteins was seen in the endochylema and occurred at the nuclear border in the cancer tissues. Weak beta2-GPI protein staining was present in the endochylema, with a strong signal for HBsAg protein in HBV control samples. Adjacent non-tumorous liver tissue samples also showed HBsAg staining but stronger beta2-GPI signals in the endochylema. In experiments with SMMC-7721 HCC cells, groups one and two had induced activation of NF-kappaB with the relative NF-kappaB DNA-binding activities of 55.84 and 51.12, respectively. However, the highest relative NF kappaB DNA-binding activity was observed in group three (80.5). The percentages of cells with NF-kappaB translocated from the cytoplasm to nucleus in groups one, two, three, four and five compared with total cells were 13.5, 8.7, 24.9, 5.7 and 0.95%, respectively. The mean AFP levels were significantly higher in group three (0.0640 +/- 0.0059) than in group five (P < 0.001). It appeared higher in group three than in group one (0.0562 +/- 0.0060, P < 0.05) and group four (0.0585 +/- 0.0040, P < 0.05), while no significant differences were seen between groups three and two, and between groups four and five. CONCLUSIONS: Beta2-GPI may play a role in the development of HBV-related HCC by activating NF-kappaB via interaction of beta2-GPI and HBsAg. PMID- 20204409 TI - Knockdown of Li-cadherin increases metastatic behaviors of LoVo cells. AB - PURPOSE: The aim of this study was to investigate the role of Li-cadherin in invasion and metastasis in LoVo cells. METHODS: We applied RNA interference mediated downregulation of Li-cadherin expression in LoVo cells. Li-cadherin expression in LoVo cells was examined by semiquantitative polymerase chain reaction, immunofluorescence, western blot, and immunoprecipitation, respectively. Effect of suppression of Li-cadherin expression on cell migration, invasion, and adhesion was detected by wound healing assay, migration assay, invasion assay, and adhesion assay. Expression and activity of MMP-2 and MMP-9 were analyzed by gelatin zymography. RESULTS: Cell migration, invasion, and adhesion were increased concomitantly with the reduction in Li-cadherin protein expression. Furthermore, downregulation of Li-cadherin expression induced secretion of proMMP-9, active MMP-9 and active MMP-2. CONCLUSIONS: This study suggests that silencing Li-cadherin has positive actions in the processes of LoVo cells invasion and metastasis, and the interactions among MMP-2, MMP-9, and Li cadherin participate in the multiple steps of invasion and metastasis in LoVo colorectal cancer cells. PMID- 20204410 TI - Spatial variation in abiotic and biotic factors in a floodplain determine anuran body size and growth rate at metamorphosis. AB - Body size at metamorphosis is a critical trait in the life history of amphibians. Despite the wide-spread use of amphibians as experimental model organisms, there is a limited understanding of how multiple abiotic and biotic factors affect the variation in metamorphic traits under natural conditions. The aim of our study was to quantify the effects of abiotic and biotic factors on spatial variation in the body size of tadpoles and size at metamorphosis of the European common toad (Bufo b. spinosus). Our study population was distributed over the riverbed (active tract) and the fringing riparian forest of a natural floodplain. The riverbed had warm ponds with variable hydroperiod and few predators, whereas the forest had ponds with the opposite characteristics. Spatial variation in body size at metamorphosis was governed by the interactive effects of abiotic and biotic factors. The particular form of the interaction between water temperature and intraspecific tadpole density suggests that abiotic factors laid the foundation for biotic factors: intraspecific density decreased growth only at high temperature. Predation and intraspecific density jointly reduced metamorphic size. Interspecific density had a negligible affect on body size at metamorphosis, suggesting weak inter-anuran interactions in the larval stage. Population density at metamorphosis was about one to two orders of magnitudes higher in the riverbed ponds than in the forest ponds, mainly because of lower tadpole mortality. Based on our results, we conclude that ponds in the riverbed appear to play a pivotal role for the population because tadpole growth and survival is best in this habitat. PMID- 20204411 TI - Unusual location of primary hydatid cyst: soft tissue mass in the parapharyngeal region. AB - Hydatid cyst is a cyclozoonotic infection caused by the cestode Echinococcus granulosus. Hydatid cyst in the head and neck region is very rare, even in countries where echinococcus infestation is endemic. We report the case of a 17 year-old male patient presenting with a hydatid cyst in the parapharyngeal and neck region. There was no pulmonary or hepatic involvement. The definitive therapy comprised excision of the cystic mass and postoperative medical treatment. PMID- 20204412 TI - Evaluation of swallowing using 320-detector-row multislice CT. Part II: kinematic analysis of laryngeal closure during normal swallowing. AB - The purpose of this study was to (1) depict normal dynamic swallowing and (2) measure (a) the temporal characteristics of three components of laryngeal closure, i.e., true vocal cord (TVC) closure, closure of the laryngeal vestibule at the arytenoid to epiglottic base, and epiglottic inversion, and (b) the temporal relationship between these levels of laryngeal closure and other swallowing events, hyoid elevation, and the pharyngoesophageal segment (PES) using 320-detector-row multislice computed tomography (320-MSCT). The swallowing of a 10-ml portion of honey-thick liquid (5% w/v) was examined in six healthy volunteers placed in a 45 degrees reclining position. Three-dimensional CT images were created in 29 phases at an interval of 0.10 s over a 2.90-s duration. Dynamic swallowing and TVC movement were depicted clearly. The sequence for laryngeal closure was the following: (1) the hyoid started to elevate, (2) the PES opened, (3) TVC closure and closure at the arytenoid to epiglottic base occurred almost simultaneously during the hyoid elevation, and (4) the epiglottic maximum inversion occurred after the hyoid maximum displacement. Those results indicated that the onset of hyoid elevation and the early opening of the PES occurring before three levels of laryngeal closure are critical components for airway protection. 320-MSCT allowed the 3D depiction and kinematic analysis of target structures, which will increase our knowledge of airway protection mechanisms during swallowing. PMID- 20204413 TI - Wide-mouthed sacculation of the esophagus: a cause of dysphagia after radiation therapy. AB - We describe a patient who presented with dysphagia after radiation therapy for Hodgkin's lymphoma secondary to wide-mouthed sacculation of the upper esophagus on barium esophagography, most likely resulting from localized radiation necrosis of the muscular layer of the esophageal wall. Despite its rarity, radiologists should be aware of this finding as a potential cause of dysphagia after radiation therapy to the neck or chest. Unlike radiation strictures, radiation-induced sacculation of the esophagus probably can be managed conservatively without need for endoscopic dilatation procedures. PMID- 20204414 TI - The validation of the Chinese version of the Swallow Quality-of-Life Questionnaire (SWAL-QOL) using exploratory and confirmatory factor analysis. AB - The aim of this work was to study the psychometric properties of the Chinese version of the Swallow Quality-of-Life Questionnaire (CSWAL-QOL) validated in the Hong Kong Chinese-speaking population. With convenience sampling, a cross sectional survey was launched to evaluate the validity and reliability of the CSWAL-QOL. One hundred subjects with swallowing problems were recruited to evaluate the construct validity and internal consistency, and 20 subjects were recruited for the test-retest reliability. Construct validity was validated through factor analysis (both exploratory and confirmatory) and a correlation study between the CSWAL-QOL and the World Health Organization Quality-of-Life Questionnaire-abbreviated version [WHOQOL-BREF (HK)]. Reliability was estimated using tests of internal consistency and test-retest reliability. The psychometric properties of the CSWAL-QOL were found to be largely similar to those of the SWAL QOL, except the three-item eating desire scale of the CSWAL-QOL, which showed insignificant results in the validity and reliability tests. The CSWAL-QOL is the first validated Chinese version of the SWAL-QOL in Hong Kong. It is a clinically valid and reliable tool for assessing the quality of life in dysphagic Chinese patients in Hong Kong, regardless of the causes of dysphagia. PMID- 20204415 TI - Thoracolaparoscopy in the lateral position for esophageal cancer: the experience of a single institution with 112 consecutive patients. AB - BACKGROUND: Esophagectomy has been performed using a thoracoabdominal, transhiatal, or transthoracic approach. All these methods have an acknowledged high intra- and postoperative morbidity. The principle of minimally invasive esophagectomy is to perform the operation the same as by the open approach but through a smaller incision, thus reducing the operative trauma without compromising the principles of the operation. The authors report their experience with thoracoscopic esophagectomy performed for 112 patients in left lateral position. METHODS: Patients with resectable thoracic or gastroesophageal junction cancer and medically fit for a three-stage esophagectomy underwent thoracoscopic esophagectomy in left lateral position. The procedure was converted to open surgery for 2 (1.79%) of the 112 patients. RESULTS: Since June 2005, 112 patients have undergone thoracoscopic esophagectomy in left lateral position. Of these patients, 80 patients had middle-third esophageal cancer. The pathology of 100 patients showed squamous cell carcinoma. The average thoracoscopic operating time was 85 min (range, 40-120 min). The average blood loss was 200 ml, and the average number of harvested mediastinal nodes was 20. Postoperative morbidity occurred for 16 patients, with 8 patients (7.27%) experiencing respiratory complications. Postoperative mortality was experienced by three patients. The median follow-up period was 18 months. CONCLUSIONS: Thoracoscopic esophagectomy is surgically safe and oncologically adequate. Thoracoscopy for patients in the left lateral position does not require prolonged single-lung ventilation. The anatomic orientation in the left lateral position is the same as that for open surgery, reducing the learning curve for thoracic surgeons. The potential advantages and the morbidity trend of prone instead of left lateral thoracoscopic esophagectomy needs to be evaluated. PMID- 20204416 TI - Prospective single-site case series utilizing an endolumenal tissue anchoring system for revision of post-RYGB stomal and pouch dilatation. AB - INTRODUCTION: Interventional therapy for weight regain after gastric bypass surgery has been tempered by higher complications associated with revisional surgery. Endolumenal reduction of post-bypass stomal and pouch dilatation offers the promise of a safer approach. Questions still remain regarding safety and efficacy with these procedures. We report intra- and postoperative results to date utilizing an endolumenal suturing platform for this patient subset. METHODS: Patients who had regained significant weight 2+ years after Roux-en-Y gastric bypass (RYGB) after losing >= 50% of excess body weight (EBW) post RYGB underwent endolumenal stomal and pouch reduction if they endoscopically displayed post bypass stomal and/or pouch dilatation. The platform was utilized to endolumenally reduce stoma size by creating circumferential folds with a tissue anchoring system. Anchors were also utilized to approximate gastric pouch tissue. Information regarding patient baseline status and data on procedural safety, intraoperative performance, postoperative weight loss, and anchor durability were recorded to date with use of this system. RESULTS: In 20/21 subjects we were able to successfully place anchors (one patient had occult G-G fistula which impaired visualization). Weight regain post RYGB averaged 59 lbs (N = 20). Stomal diameter was reduced on average by 53%, with pouch reduction averaging 41%. The number of anchors placed on average per case was 5.3. Operating room (OR) time averaged 91 min. There were no significant complications. Three- and 12-month esophagogastroduodenoscopy (EGD) results revealed preservation of most of the intraoperative stoma and pouch reduction, and presence of fibrotic tissue folds with continued presence of anchors at their original locations. Mean percentage excess weight loss (%EWL) at 6 months was 18% to date (N = 18). Mean weight loss at 6 months was 17.3 +/- 15 lbs. CONCLUSION: Clinical study of this endolumenal tissue approximation system has shown intraoperative safety and efficacy in reducing stoma and pouch dilatation post RYGB. Follow-up anchor durability to date is encouraging. Continuing weight loss is being tracked through ongoing endoscopic and clinical follow-up. PMID- 20204417 TI - Laparoscopic subtotal colectomy for medically refractory ulcerative colitis: the time has come. AB - PURPOSE: To evaluate laparoscopic versus open subtotal colectomy (STC) in patients with ulcerative colitis (UC) requiring urgent or emergent operative intervention. METHODS: A retrospective review was performed of 90 patients with medically refractory UC who underwent STC with end ileostomy at The Mount Sinai Medical Center from 2002 to 2007. Patients with toxic megacolon were excluded. Univariate analysis was conducted by unpaired Student t-test and chi-square test. Results are presented as mean +/- 95% confidence interval. RESULTS: Ninety patients underwent STC, 29 by laparoscopic and 61 by open approach. In patients undergoing laparoscopic versus open STC, intraoperative blood loss was decreased (130.4 +/- 38.4 vs. 201.4 +/- 43.2 ml, p < 0.05) and operative time prolonged (216.4 +/- 20.2 vs. 169.9 +/- 14.4 min, p < 0.01). In the absence of postoperative complication, hospital length of stay (4.5 +/- 0.7 vs. 6 +/- 1.3 days, p < 0.001) was shorter in laparoscopic versus open group. No mortalities occurred. Overall morbidity, 30-day readmission, and reoperation were equivalent regardless of operative approach. Wound complications were absent in the laparoscopic group compared with 21.4% in the open group (p < 0.01). Follow-up at a mean of 36 months demonstrated no difference in restoration of gastrointestinal continuity. CONCLUSION: Laparoscopic STC confers the benefits of improved cosmesis, reduced intraoperative blood loss, negligible wound complications, and shorter hospital stay. Laparoscopy is a feasible and safe alternative to open STC in patients with UC refractory to medical therapy requiring urgent or emergent operation. PMID- 20204418 TI - Communication and informed consent in phase 1 trials: a review of the literature from January 2005 to July 2009. AB - OBJECTIVE AND METHODS: A review conducted in 2005 identified many of the communication difficulties experienced by patients and doctors when discussing phase 1 (P1) oncology trials. The current paper is an update of the area and focuses on studies that measure patient comprehension of information given during the P1 trial discussion and ways to enhance understanding. A literature search was performed for relevant articles published between January 2005 and July 1st 2009. RESULTS: Only 12/109 studies met the criteria for inclusion in the review. One study recorded the actual trial discussion and compared patients' understanding with what the clinician had communicated. The others used interview techniques and surveys to elicit patients' understanding of P1 trials, motivations for considering trials and expectations of benefit. Two examined interventions to aid patient understanding. CONCLUSION: Explaining potential participation in a P1 trial with a patient with cancer is not an easy task: the doctor must ensure that the patient has an accurate understanding of their condition and that standard treatments have now been exhausted. This must be followed by admission of the probable lack of any therapeutic benefit from the P1 drug together with the possibility that there might be unwanted side effects, many of which are unknown. These are all challenging subjects. New educational initiatives informed through research conducted with patients and health care professionals are currently being developed and clearly much needed. PMID- 20204419 TI - Establishing a cancer nutrition rehabilitation program (CNRP) for ambulatory patients attending an Australian cancer center. AB - PURPOSE: To establish a multidisciplinary Cancer Nutrition Rehabilitation Program (CNRP) for the management of the anorexia-cachexia syndrome (ACS) in an Australian cancer center and to evaluate outcomes of 2 months participation in the CNRP METHOD: Patients were eligible if they had significant anorexia/weight loss, identified by their oncologist or the Malnutrition Screening Tool. In the 9 months that funding was available, 54 participants (37 males, 17 females; median age, 62 years) enrolled. They had mainly lung or gastrointestinal cancers, with 67% receiving chemotherapy concomitantly. Baseline assessments of nutrition and physical status were: median weight 62.7 kg, median weight loss 10.2%, median BMI 21.2 kg/m(2), and 78% malnourished according to PG-SGA. Median baseline Karnofsky performance score (KPS) was 70%, with reduced right-hand grip strength (RGHS; median, 27 kg) and endurance (median, 6 min walk test 6MWT 442 m). Patients received individualized nutritional interventions, exercise programs, and symptom management and were followed prospectively for up to 6 months. RESULTS: Twenty five (58%) of 41 evaluable CNRP participants attended the 2-month follow-up. Median weight (63.4 kg), KPS (80%), endurance (6MWT 570 m), and strength (RGHS 28 kg) were all improved. Edmonton symptom assessment scores (36 vs 27) and C reactive protein levels (39 vs 22) fell. Participants were significantly more likely to return for re-evaluation if at baseline they were having anticancer therapy (odds ratio [OR] 4.7, 95% confidence interval [CI] 1.3-16.2) or could walk >420 m in 6 min (OR 21, 95% CI 1.9-227). CONCLUSION: A CNRP may be beneficial for patients with advanced cancer and the ACS, but identification of patients who are likely to stay on the program is needed. PMID- 20204420 TI - The Cross Cancer Institute Multidisciplinary Summer Studentship in Palliative and Supportive Care in Oncology: teaching students to see through patients' eyes. AB - PURPOSE: In this paper, the psychosocial oncology-themed Cross Cancer Institute Multidisciplinary Summer Studentship in Palliative and Supportive Care in Oncology is described from the perspective of the first participants and supervising faculty. METHODS: This 6-week inter-professional elective exposed pre licensure students to issues facing patients and their families following a diagnosis of cancer, through treatment, recovery, recurrence, palliation, and end of-life. RESULTS: Participants gained experience in team-based skills and compassionate care, were introduced to other disciplines, and formed collaborative partnerships. The Studentship encompasses the features of best practice cooperative learning through clinical experience, facilitated weekly discussion, an exploratory investigation and presentation.The authors' backgrounds and interest in this area are discussed, as well as pre-existing expectations and goals, reflections on their interactions, challenges faced, and lasting impressions from their experiences seeing through patients' eyes, framed by the essential tenets of psycho-oncology practice. CONCLUSIONS: Our multidisciplinary placement is feasible, successful, and potentially transferable to other academic settings. PMID- 20204421 TI - Attitude of Italian medical oncologists toward palliative care for patients with advanced cancer: results of the SIO project. AB - PURPOSE: The aim of this survey was to describe the attitude of Italian oncologists towards palliative care. METHODS: A survey on palliative care was carried out among 400 Italian oncologists. RESULTS: Seventy-two percent indicated that the management of patients with advanced stage cancer represents the majority of their practice. They are often involved in the management of pain (78%) and complications of chemotherapy (61%), and frequently, in the treatment of terminal patients (60%). Only 8.5% reported having frequent collaboration with psychiatrists in support of emotional and psychological patients' disturbances. About 40% are often directly involved in the management of existential or spiritual distress. Discussions on euthanasia and assisted suicide, which are illegal in Italy, took place never (68%) or occasionally (27%). CONCLUSIONS: Respondents agreed that all oncology centres should have access to palliative care service. These results are in line with those of the European Society of Medical Oncology survey and may be usefully employed to improve the organisation of palliative care. PMID- 20204422 TI - Use of the Coopdech Bronchial Blocker as a tracheal tube introducer in a patient with difficult laryngoscopy. PMID- 20204424 TI - Clasped position for measurement of sagittal spinal alignment. AB - Lateral whole-spine radiography is a useful tool in the management of spinal deformity, but the most appropriate arm position during radiography has yet to be determined. In this prospective study, we evaluated 26 adult volunteers and 22 patients with lumbar spinal canal stenosis. Lateral whole-spine radiographs were acquired in the most stable and relaxed position while the subjects were standing with their arms extended and their hand gently clasped in front of the trunk (clasped position). The following parameters were measured: sagittal vertical axis (SVA), lumbar lordotic angle (LLA), pelvic angle (PA), pelvic lordosis angle (PRS1), pelvic tilt (PT), and pelvic incidence (PI). The reliability of measurements was assessed by interclass correlation coefficients. The SVA was slightly positive in volunteers. LLA, PA, PRS1, PT, and PI were compatible with standard normal values. The results showed "almost perfect agreement" with regard to intra- and interobserver reliability. The clasped position can be used effectively and reliably for measurement of sagittal spinal alignment for the lumbar region in adults. PMID- 20204423 TI - Paraspinal extramedullary hematopoiesis in patients with thalassemia intermedia. AB - Ineffective erythropoiesis in patients with thalassemia intermedia drives extramedullary hematopoietic tumor formation in several parts of the body. Paraspinal involvement has received increasing attention due to the associated morbidity secondary to spinal cord compression. Although the history and physical examination may help narrow the differential diagnosis, radiographic imaging remains essential to confirm the existence of hematopoietic tissue. Characteristic appearance has been observed mainly on magnetic resonance imaging. Several treatment options have been described, including transfusion therapy, laminectomy, radiotherapy, and the use of fetal hemoglobin inducing agents that decrease the hematopoietic drive. However, the ideal management scheme remains controversial. Until large prospective trials evaluate the efficacy and safety of the available treatment options, both in single and in combination therapy, an individualized approach should be entertained. PMID- 20204425 TI - Determination of axial vertebral rotation in MR images: comparison of four manual and a computerized method. AB - Axial vertebral rotation (AVR) of 14 normal and 14 scoliotic vertebrae from magnetic resonance (MR) images was determined by three observers using four manual methods and a computerized method, which were based on the evaluation of vertebral symmetry in two dimensions (2D) and in three dimensions (3D). The method of Aaro and Dahlborn proved to be the manual method with the highest intra observer (1.7 degrees SD) and inter-observer (1.2 degrees SD) reliabilities, and was also most in agreement with the computerized method (1.3 degrees SD, 1.0 degrees MAD). The computerized method yielded higher intra-observer (1.3 degrees SD) and inter-observer (1.4 degrees SD) reliabilities than the manual methods, indicating it to be an efficient alternative for repeatable and reliable AVR measurements. PMID- 20204426 TI - Nucleus pulposus deformation in response to lumbar spine lateral flexion: an in vivo MRI investigation. AB - Whilst there are numerous studies examining aspects of sagittal plane motion in the lumbar spine, few consider coronal plane range of motion and there are no in vivo reports of nucleus pulposus (NP) displacement in lateral flexion. This study quantified in vivo NP deformation in response to side flexion in healthy volunteers. Concomitant lateral flexion and axial rotation range were also examined to evaluate the direction and extent of NP deformation. Axial T2- and coronal T1-weighted magnetic resonance images (MRI) were obtained from 21 subjects (mean age, 24.8 years) from L1 to S1 in the neutral and left laterally flexed position. Images were evaluated for intersegmental ranges of lateral flexion and axial rotation. A novel methodology derived linear pixel samples across the width of the disc from T2 images, from which the magnitude and direction of displacement of the NP was determined. This profiling technique represented the relative hydration pattern within the disc. The NP was displaced away from the direction of lateral flexion in 95/105 discs (p < 0.001). The extent of NP displacement was associated strongly with lateral flexion at L2-3 (p < 0.01). The greatest range of lateral flexion occurred at L2-3, L3-4 and L4-5. Small intersegmental ranges of axial rotation occurred at all levels, but were not associated with NP displacement. The direction of NP deformation was highly predictable in laterally flexed healthy lumbar spines; however, the magnitude of displacement was not consistent with the degree of intersegmental lateral flexion or rotation. PMID- 20204427 TI - Distributional characteristics of CD25 and CD127 on CD4+ T cell subsets in chronic HCV infection. AB - Attenuated CD4+ T-cell-mediated immune responses are involved in persistence of HCV infection, but the mechanism remains undefined. In this study, the proportions of CD4+ T cell subsets, naive, central memory, effector memory and effector cells, along with CD25 (IL-2R alpha) and CD127 (IL-7R alpha) expression on different CD4+ T cell subsets, were measured by polychromatic flow cytometry in 24 chronic HCV-infected individuals and 21 healthy controls. A significant decrease in naive CD4+ T cells and an increase of central memory and effector memory CD4+ T cells were found in HCV-infected patients compared with healthy controls. HCV-infected patients showed a lower level of CD127 expression in all CD4+ T cells subsets, especially in central memory and effector CD4+ T cells. In terms of total CD4+ T cells, an increase in CD25+ regular T cells (CD4+ CD25+ CD127lo) was found in HCV-infected patients. Interestingly, naive CD4+ T cells showed increased CD25 expression, while effector memory and effector CD4+ T cells had lower CD25 expression. These data indicated that variations in different fractions of CD4+ T cells, including the phenotypic profile and expression level of CD25 and CD127, may be associated with low efficiency of immune response in chronic HCV infection. These results will strengthen the understanding of pathogenesis and dysfunction of CD4+ T cell immunity during long-term HCV persistence. PMID- 20204428 TI - Hydroxyurea as an inhibitor of hepatitis C virus RNA replication. AB - Hepatitis C virus (HCV) is the main causative agent of chronic liver disease, which may develop into liver cirrhosis and hepatocellular carcinoma. By using a recently developed reporter assay system in which genome-length HCV RNA replicates efficiently, we found that hydroxyurea (HU), a DNA synthesis inhibitor, inhibited HCV RNA replication. Moreover, we demonstrated that the anti HCV activity of the combination of IFN-alpha and HU was higher than that of IFN alpha alone. These results suggest that HU may be an effective anti-HCV reagent that can be used not only singly but also in combination with IFN-alpha to treat chronic hepatitis C. PMID- 20204429 TI - Antigenic variation between Newcastle disease viruses of goose and chicken origin. AB - Newcastle disease virus (NDV) is believed to infect only domestic avian species, with waterfowl such as geese either not being infected, even by virulent strains, or developing only inapparent infection. Since the late 1990s, a new infectious disease producing high morbidity and mortality among geese broke out in many provinces of China. This disease was caused by a serotype I avian paramyxovirus known as (APMV-1)-NDV. To investigate how NDV spreads between chickens and geese, the serological similarities of NDV strains (goose-origin NDV/NA-1 and chicken origin NDV/F48E9, F48E8) were assessed by cross-neutralization assays both in vivo and in vitro. The results indicated that antigenic variation had occurred between NDV/NA-1 strains and NDV/F48E9, F48E8 strains. Notably, NDV/NA-1 effectively protected vaccinated birds from morbidity and mortality against NDV/NA-1 strain challenge and significantly reduced virus shedding from the vaccinated birds when compared with F48E9-vaccinated birds. This might provide clues to the evolution of the goose NDV. PMID- 20204430 TI - Clarification and guidance on the proper usage of virus and virus species names. AB - A pivotal step in the development of a consistent nomenclature for virus classification was the introduction of the virus species concept by the International Committee on Taxonomy of Viruses (ICTV) in 1991. Yet, almost two decades later, many virologists still are unable to differentiate between virus species and actual viruses. Here we attempt to explain the origin of this confusion, clarify the difference between taxa and physical entities, and suggest simple measures that could be implemented by ICTV Study Groups to make virus taxonomy and nomenclature more accessible to laboratory virologists. PMID- 20204431 TI - L-Arginine reduces thioflavin T fluorescence but not fibrillation of bovine serum albumin. AB - This work examines the effects of L-arginine (L-Arg) on the aggregation and amyloid fibrillation of bovine serum albumin (BSA). We demonstrate that L-Arg dose-dependently reduces thioflavin T (ThT) fluorescence of BSA within the L-Arg concentration range used (0-1.4 M). However, as revealed by electron microscopy, size exclusion chromatography, and dynamic light scattering results, L-Arg does not prevent amyloid-like fibril formation by BSA. We conclude that L-Arg competes against ThT for binding sites on BSA amyloid-like fibrils, leading to biased results in ThT fluorescence measurements. Moreover, the use of ThT fluorescence assay to screen for potential inhibitors against amyloid fibrillation can give misleading results. PMID- 20204432 TI - Synthesis of a novel Fmoc-protected nucleoaminoacid for the solid phase assembly of 4-piperidyl glycine/L-arginine-containing nucleopeptides and preliminary RNA: interaction studies. AB - In this work, we report the synthesis of a novel Fmoc-protected nucleoaminoacid, based on 4-piperidinyl glycine, carrying the DNA nucleobase on the secondary amino group, suitable for the solid-phase synthesis of nucleopeptides. After ESI MS and NMR characterization this building block was used for the assembly of a thymine-functionalized tetrapeptide, composed of 4-piperidinyl glycine and L arginine moieties alternated in the backbone. The ability to interact with RNA and the efficiency in interfering with the reverse transcription of eukaryotic mRNA of the novel nucleo-tetrapeptide found in this study are in favour of the employment of chiral nucleopeptides based on alternate 4-piperidinyl glycine/L arginine backbone in biomedicine. PMID- 20204433 TI - The impact of histone post-translational modifications on developmental gene regulation. AB - Eukaryotic genomic DNA is orderly compacted to fit into the nucleus and to inhibit accessibility of specific sequences. DNA is manipulated in many different ways by bound RNA and proteins within the composite material known as chromatin. All of the biological processes that require access to genomic DNA (such as replication, recombination and transcription) therefore are dependent on the precise characteristics of chromatin in eukaryotes. This distinction underlies a fundamental property of eukaryotic versus prokaryotic gene regulation such that chromatin structure must be regulated to precisely repress or relieve repression of particular regions of the genome in an appropriate spatio-temporal manner. As well as playing a key role in structuring genomic DNA, histones are subject to site-specific modifications that can influence the organization of chromatin structure. This review examines the molecular processes regulating site-specific histone acetylation, methylation and phosphorylation with an emphasis on how these processes underpin differentiation-regulated transcription. PMID- 20204434 TI - S100B: a multifunctional role in cardiovascular pathophysiology. AB - S100B, a calcium-binding protein of the EF-hand type exerts both intracellular and extracellular functions. S100B is induced in the myocardium of human subjects and an experimental rat model following myocardial infarction. Forced expression of S100B in neonatal rat myocyte cultures, and high level expression of S100B in transgenic mice hearts and aortic smooth muscle cells inhibit cardiac hypertrophy and the associated phenotype, arterial smooth muscle proliferation, respectively, but demonstrate increased apoptosis following alpha(1)-adrenergic stimulation or myocardial infarction. Knocking out S100B, augmented hypertrophy, decreased apoptosis and preserved cardiac function following myocardial infarction. S100B induces apoptosis by an extracellular mechanism by interacting with the receptor for advanced glycation end products and activating ERK1/2 and p53 signaling. The intracellular, and extracellular, roles of S100B are attractive therapeutic targets for the treatment of both cardiac and vascular disease. PMID- 20204435 TI - Proline metabolism and transport in plant development. AB - Proline fulfils diverse functions in plants. As amino acid it is a structural component of proteins, but it also plays a role as compatible solute under environmental stress conditions. Proline metabolism involves several subcellular compartments and contributes to the redox balance of the cell. Proline synthesis has been associated with tissues undergoing rapid cell divisions, such as shoot apical meristems, and appears to be involved in floral transition and embryo development. High levels of proline can be found in pollen and seeds, where it serves as compatible solute, protecting cellular structures during dehydration. The proline concentrations of cells, tissues and plant organs are regulated by the interplay of biosynthesis, degradation and intra- as well as intercellular transport processes. Among the proline transport proteins characterized so far, both general amino acid permeases and selective compatible solute transporters were identified, reflecting the versatile role of proline under stress and non stress situations. The review summarizes our current knowledge on proline metabolism and transport in view of plant development, discussing regulatory aspects such as the influence of metabolites and hormones. Additional information from animals, fungi and bacteria is included, showing similarities and differences to proline metabolism and transport in plants. PMID- 20204436 TI - Protective effect of isoflavones against homocysteine-mediated neuronal degeneration in SH-SY5Y cells. AB - Previously, we reported that isoflavones exert a protective effect against the endoplasmic reticulum (ER) stress-mediated neuronal degeneration, and ER stress mediated homocysteine toxicity may play an important role in the pathogenesis of neurodegeneration. Therefore, in this study we investigated the effects of isoflavones (genistein and daidzein) against homocysteine-mediated neurotoxicity in SH-SY5Y human neuroblastoma cells. The treatment of cells with either 17beta estradiol or isoflavones significantly protected the cells against homocysteine mediated apoptosis. Isoflavones repressed homocysteine-mediated ER stress, reflected in the reduced expression of the immunoglobin heavy chain-binding protein mRNA, spliced X-box-protein-1 mRNA and the phosphorylated form of eukaryotic translation initiation factor 2alpha protein. Homocysteine caused significant increases in intracellular S-adenosylhomocysteine (SAH) and DNA damage. Isoflavones significantly alleviated DNA damage, but did not change SAH levels. Furthermore, the treatment of cells with isoflavones significantly reduced the microtubule-associated protein tau hyperphosphorylation by inactivating glycogen synthase kinase-3beta and activating serine/threonine protein phosphatase 2A. These results clearly demonstrate that isoflavones alleviate the ER stress- and DNA damage-mediated neurodegeneration caused by homocysteine. PMID- 20204437 TI - An on-column derivatization method for the determination of homocysteine thiolactone and protein N-linked homocysteine. AB - Homocysteine (Hcy) is incorporated into protein via a reaction of the thioester Hcy-thiolactone with epsilon-amino group of a protein lysine residue generating N Hcy-protein. This reaction impairs and alters protein's function and has been implicated in atherothrombotic disease. Here, we describe new high-performance liquid chromatography assays for the determination of Hcy-thiolactone, protein N linked Hcy, and Hcy based on an on-column derivatization with o-phthaldialdehyde and fluorescence detection. The on-column derivatization generates narrow peaks, which allows fast run times (3-5 min) and facilitates determination of N-linked Hcy directly from acid hydrolysates of plasma protein. Utility of these assays was demonstrated with human urine and plasma samples. PMID- 20204439 TI - Birth weight is an independent determinant of whole body bone mineral content and bone mineral density in a group of Lebanese adolescent girls. AB - The aim of this study was to explore the relation between birth weight and bone mass in a group of adolescent girls. This study included 40 post-menarchal adolescent (aged 13-20 years) girls. Anthropometric characteristics (height and weight) were measured and birth weights were obtained from the obstetric records. Body composition, bone mineral content (BMC) and bone mineral density (BMD) of the whole body (WB) were assessed by dual-energy X-ray absorptiometry (DXA). Calculations of the ratio BMC/height and of the bone mineral apparent density (BMAD) were completed for the WB. Birth weight was positively correlated to BMC and to the ratio BMC/height even after adjusting for weight and maturation index (years since menarche). Finally, birth weight was correlated to BMD even after adjusting for weight. In conclusion, this study suggests that birth weight is an independent determinant of whole body BMC and BMD in adolescent girls. PMID- 20204440 TI - Rare incarcerated giant scrotal hernia associated with congenital pouch colon. PMID- 20204441 TI - Enigmatic images: inguinal hernia of a 'third kind,' pantaloon hernia, 'direct pantaloon' hernia, or direct hernia and supravesical hernia? PMID- 20204442 TI - Prevention of oxidative stress in porcine islet isolation. AB - High yields of pure and viable porcine islet cells (PICs) to be used for microencapsulation are crucial for successful xenotransplantation. Mechanical disruption of the pancreas, enzymes used for digestion, digestion temperature and time are among the factors known to cause oxidative stress and to impact on the yield, purity and viability of PICs. The aim of our study was to optimize conventional procedures in order to minimize the oxidative stress that occurs during the isolation and purification of PICs. Porcine pancreatic tissue was harvested at a local slaughterhouse, and 15 consecutive isolations of PICs were performed with a modified automated Ricordi method (Graz method) using a shorter digestion time, a lower digestion temperature and minimal mechanical stress. PICs were purified with the Lymphoprep density gradient medium. Purity and viability were assessed immediately after the isolation process and after overnight culture. PIC function was tested in glucose stimulation experiments and insulin concentration was determined by ELISA. Oxidative stress was assessed by measuring isoprostanes (IP), malondialdehyde (MDA) and lipase levels using a HPLC-based, colorimetric liquid assay or ELISA, respectively. The mean yield of PICs was 3479 +/- 542 IEQs/g pancreas, with 96.4% viability and 97.7% purity. There was no significant loss in PIC viability after overnight culture. Insulin secretion in response to glucose was not impaired after isolation and purification. IP, MDA and lipase levels did not change significantly during the isolation procedure. With our new Graz method we seem to have succeeded in preventing oxidative stress and achieving high yields of pure and viable PICs. PMID- 20204443 TI - X-linked CMT: genes and gene loci in an Australian cohort. PMID- 20204444 TI - Antimicrobial resistance and molecular characterization of Staphylococcus haemolyticus in a Chinese hospital. AB - The aim of this study was to perform the molecular characterization of methicillin-resistant Staphylococcus haemolyticus (MRSH) from clinical specimens of patients in a Chinese hospital. One hundred and thirty-three strains of S. haemolyticus collected from April 2002 to April 2003 were analyzed. Antimicrobial susceptibility to 15 antimicrobial agents was determined by the broth microdilution method. The resistant rates to penicillin G and oxacillin were higher than 90%. There were no isolates resistant to linezolid or vancomycin, and only 6.0% of the strains were resistant to teicoplanin. The positivity rate for mecA genes was 90.2% by polymerase chain reaction (PCR). Ninety MRSH (isolated from inpatients and mecA-gene-positive) were genotyped by pulsed-field gel electrophoresis (PFGE) after SmaI digestion. Twenty-five different PFGE patterns (A approximately Y) were found and a major clone (type A; n = 36) with five subtypes was identified. Clone A was detected during a 1-year period. Identical PFGE types were found in different wards and patients. The results of this study suggest the clonal spread of MRSH within our hospital. This emphasizes the need for control and prevention measures. PMID- 20204445 TI - Comparison of Copan eSwab with the Copan Venturi Transystem for the quantitative survival of Escherichia coli, Streptococcus agalactiae and Candida albicans. AB - Swab transport systems should preserve the viability and stability of micro organisms in clinical specimens throughout transport and storage. eSwab, a nylon tipped swab in liquid medium, designed for better specimen collection and less micro-organism entrapment, was evaluated for the maintenance of viability and quantitative survival of Escherichia coli, Streptococcus agalactiae and Candida albicans. The quantitative elution method was used to evaluate eSwab in vitro. In vitro, the recovery of the three micro-organisms was higher in eSwab (97-100%) as compared to the Copan Venturi Transystem (CVT) (86-96%) at room temperature (RT) for time point 0 h and remained similar after 6 h. E. coli and C. albicans proliferated in both transport systems when preserved beyond 6 h. At 4 degrees C, the recovery of eSwab was higher (>94%) compared to CVT (77-94%) for the micro organisms tested. eSwab did not only meet the Clinical Laboratory and Standards Institute (CLSI) criteria for microbiological transport devices, but as its recovery rate in vitro was higher than that of CVT, it might also enhance the sensitivity of bacterial culture in the future. PMID- 20204446 TI - Simulation of bone tissue formation within a porous scaffold under dynamic compression. AB - A computational model of mechanoregulation is proposed to predict bone tissue formation stimulated mechanically by overall dynamical compression within a porous polymeric scaffold rendered by micro-CT. Dynamic compressions of 0.5-5% at 0.0025-0.025 s(-1) were simulated. A force-controlled dynamic compression was also performed by imposing a ramp of force from 1 to 70 N. The model predicts homogeneous mature bone tissue formation under strain levels of 0.5-1% at strain rates of 0.0025-0.005 s(-1). Under higher levels of strain and strain rates, the scaffold shows heterogeneous mechanical behaviour which leads to the formation of a heterogeneous tissue with a mixture of mature bone and fibrous tissue. A fibrous tissue layer was also predicted under the force-controlled dynamic compression, although the same force magnitude was found promoting only mature bone during a strain-controlled compression. The model shows that the mechanical stimulation of bone tissue formation within a porous scaffold closely depends on the loading history and on the mechanical behaviour of the scaffold at local and global scales. PMID- 20204447 TI - A computational biomimetic study of cell crawling. AB - Cell locomotion is a result of a series of synchronized chemo-mechanical processes. Previous extensive experimental studies have revealed many chemo mechanical processes that may contribute to cell locomotion. In parallel, theoretical works have been developed to provide deeper insight. To date, however, direct simulations of cell locomotion on a substrate have not been seen. In this paper, a finite element-based computational model is developed to study amoeboid type of cell crawling phenomenon. Here, a cell is modeled as a 2D fluid filled elastic vesicle, which establishes its interaction with a rigid substrate through a kinetics-based cellular adhesion model. The cell derives its motion through a differential bond breaking at the trailing edge and bond formation at the leading edge. This mechanism of crawling authenticates the hypothesis that cell locomotion can be facilitated by breaking the adhesive bonds at the rear edge, which was initially proposed by Chen (J Cell Biol 90: 187-200, 1981). PMID- 20204448 TI - Assessment of performance and reliability of computer-aided detection scheme using content-based image retrieval approach and limited reference database. AB - Content-based image retrieval approach was used in our computer-aided detection (CAD) schemes for breast cancer detection with mammography. In this study, we assessed CAD performance and reliability using a reference database including 1500 positive (breast mass) regions of interest (ROIs) and 1500 normal ROIs. To test the relationship between CAD performance and the similarity level between the queried ROI and the retrieved ROIs, we applied a set of similarity thresholds to the retrieved similar ROIs selected by the CAD schemes for all queried suspicious regions, and used only the ROIs that were above the threshold for assessing CAD performance at each threshold level. Using the leave-one-out testing method, we computed areas under receiver operating characteristic (ROC) curves (A(Z)) to assess CAD performance. The experimental results showed that as threshold increase, (1) less true positive ROIs can be referenced in the database than normal ROIs and (2) the A(Z) value was monotonically increased from 0.854 +/ 0.004 to 0.932 +/- 0.016. This study suggests that (1) in order to more accurately detect and diagnose subtle masses, a large and diverse database is required, and (2) assessing the reliability of the decision scores based on the similarity measurement is important in application of the CBIR-based CAD schemes when the limited database is used. PMID- 20204449 TI - Tubulin chaperone E binds microtubules and proteasomes and protects against misfolded protein stress. AB - Mutation of tubulin chaperone E (TBCE) underlies hypoparathyroidism, retardation, and dysmorphism (HRD) syndrome with defective microtubule (MT) cytoskeleton. TBCE/yeast Pac2 comprises CAP-Gly, LRR (leucine-rich region), and UbL (ubiquitin like) domains. TBCE folds alpha-tubulin and promotes alpha/beta dimerization. We show that Pac2 functions in MT dynamics: the CAP-Gly domain binds alpha-tubulin and MTs, and functions in suppression of benomyl sensitivity of pac2Delta mutants. Pac2 binds proteasomes: the LRR binds Rpn1, and the UbL binds Rpn10; the latter interaction mediates Pac2 turnover. The UbL also binds the Skp1-Cdc53-F box (SCF) ubiquitin ligase complex; these competing interactions for the UbL may impact on MT dynamics. pac2Delta mutants are sensitive to misfolded protein stress. This is suppressed by ectopic PAC2 with both the CAP-Gly and UbL domains being essential. We propose a novel role for Pac2 in the misfolded protein stress response based on its ability to interact with both the MT cytoskeleton and the proteasomes. PMID- 20204451 TI - Inhibition of degranulation and cytokine production in bone marrow-derived mast cells by hydrolyzed rice bran. AB - OBJECTIVE: We investigated the effects of hydrolyzed rice bran (HRB), an arabinoxylan extracted from rice bran, on mast cell degranulation and cytokine production. MATERIALS AND METHODS: HRB was obtained by treating rice bran with an extract obtained from shiitake mushrooms. Bone marrow-derived mast cells (BMMCs) were prepared by culturing bone marrow cells from BALB/c mice in the presence of interleukin-3 and stem cell factor for 4 weeks. BMMCs were pretreated with HRB (0 3 mg/ml) for 30 min and were then antigen activated. RESULTS: Pretreatment of BMMCs with HRB significantly inhibited antigen-induced degranulation and cytokine production (tumor necrosis factor-alpha and interleukin-4) in a dose-dependent manner. HRB also diminished membrane fusion between liposomes in which soluble N ethyl maleimide-sensitive factor attachment protein receptors were reconstituted. Phosphorylation of RelA and mitogen-activated kinases after antigen stimulation was suppressed by pretreatment of BMMCs with HRB. CONCLUSIONS: These findings suggest that HRB may have an anti-inflammatory effect by inhibiting mast cell degranulation and cytokine production. PMID- 20204452 TI - Lipid production from Jerusalem artichoke by Rhodosporidium toruloides Y4. AB - Jerusalem artichoke (JA) is a perennial herbaceous plant widely available as non grain raw material. Microbial lipid has been suggested as a potential feedstock for large scale biodiesel production. This paper describes lipid production using JA tuber processed by oleaginous yeast Rhodosporidium toruloides Y4. Batch and fed-batch modes were tested with feeding of concentrated JA extracts or JA hydrolysates. Cultivation of R. toruloides Y4 with JA extracts gave a moderate cellular lipid content of 40% (w/w), whereas lipid titer and cellular lipid content reached 39.6 g l(-1) and 56.5% (w/w), respectively, when JA hydrolysates were fed. Our results suggested that JA tubers may be further explored as raw material for large scale microbial lipid production. PMID- 20204453 TI - Purification and characterization of the exopolygalacturonase produced by Aspergillus giganteus in submerged cultures. AB - Polygalacturonases are pectinolytic enzymes that catalyze the hydrolysis of the plant cell-wall pectin backbone. They are widely used in the food industry for juice extraction and clarification. Aspergillus giganteus produces one polygalacturonase (PG) on liquid Vogel medium with citrus pectin as the only carbon source. In specific applications, such as those used in the food and medicine industries, the PG must be free of substances that could affect the characteristics of the product and the process, such as color, flavor, toxicity, and inhibitors. We present here an efficient, simple, and inexpensive method for purifying the A. giganteus PG and describe the characteristics of the purified enzyme. Purified PG was obtained after two simple steps: (1) protein precipitation with 70% ammonium sulfate saturation and (2) anion-exchange chromatography on a DEAE-Sephadex A-50 column. The final enzyme solution retained 86.4% of its initial PG activity. The purified PG had a molecular weight of 69.7 kDa, exhibited maximal activity at pH 6.0 and 55-60 degrees C, and was stable in neutral and alkaline media. It had a half-life of 115, 18, and 6 min at 40, 50 and 55 degrees C, respectively. Purified PG showed its highest hydrolytic activity with low-esterified and nonesterified substrates, releasing monogalacturonic acid from substrate, indicating that it is an exopolygalacturonase. PG activity was enhanced in the presence of beta mercaptoethanol, dithiothreitol, Co(2+), Mn(2+), Mg(2+), NH(4) (+), and Na(+) and was resistant to inhibition by Pb(2+). PMID- 20204450 TI - Biogenesis of bacterial inner-membrane proteins. AB - All cells must traffic proteins into and across their membranes. In bacteria, several pathways have evolved to enable protein transfer across the inner membrane, the periplasm, and the outer membrane. The major route of protein translocation in and across the cytoplasmic membrane is the general secretion pathway (Sec-pathway). The biogenesis of membrane proteins not only requires protein translocation but also coordinated targeting to the membrane beforehand and folding and assembly into their protein complexes afterwards to function properly in the cell. All these processes are responsible for the biogenesis of membrane proteins that mediate essential functions of the cell such as selective transport, energy conversion, cell division, extracellular signal sensing, and motility. This review will highlight the most recent developments on the structure and function of bacterial membrane proteins, focusing on the journey that integral membrane proteins take to find their final destination in the inner membrane. PMID- 20204455 TI - Production of a novel extracellular acidic lipase from Pseudomonas gessardii using slaughterhouse waste as a substrate. AB - An isolate exhibiting high extracellular lipolytic activity was identified as Pseudomonas gessardii by 16S rDNA gene sequence analysis. The slaughterhouse waste, goat tallow, was used as a lipid substrate for the production of acidic lipase by P. gessardii. The maximum lipase activity of 156 U/ml was observed at an acidic pH of 3.5 and at 0.31 g substrate concentration. The purification steps resulted in the isolation of acidic lipase with a specific activity of 1,473 U/mg and a molecular weight of 94 kDa. One interesting feature of this purified lipase is its stability at highly acidic pH ranging from 2.0 to 5.5 with a high molecular weight. The amino acid composition was determined using HPLC. This acidic lipase has potential applications in the medicinal field as a substitute for pancreatic lipases for enzyme therapy, oleochemical and in biotechnological industries. PMID- 20204454 TI - Genetic factors that influence moenomycin production in streptomycetes. AB - Moenomycin, a natural phosphoglycolipid product that has a long history of use in animal nutrition, is currently considered an attractive starting point for the development of novel antibiotics. We recently reconstituted the biosynthesis of this natural product in a heterologous host, Streptomyces lividans TK24, but production levels were too low to be useful. We have examined several other streptomycetes strains as hosts and have also explored the overexpression of two pleiotropic regulatory genes, afsS and relA, on moenomycin production. A moenomycin-resistant derivative of S. albus J1074 was found to give the highest titers of moenomycin, and production was improved by overexpressing relA. Partial duplication of the moe cluster 1 in S. ghanaensis also increased average moenomycin production. The results reported here suggest that rational manipulation of global regulators combined with increased moe gene dosage could be a useful technique for improvement of moenomycin biosynthesis. PMID- 20204456 TI - The influence of nitrogen limitation on mcl-PHA synthesis by two newly isolated strains of Pseudomonas sp. AB - The nucleotide composition of key enzymes involved in medium-chain-length polyhydroxyalkanoates (mcl-PHA) synthesis was analyzed in two newly isolated strains of Pseudomonas. The isolated strains were tested for their abilities to synthesize polyhydroxyalkanoates using three different substrates as a carbon source: sodium octanoate, oleic acid, and sodium gluconate. Both analyzed strains were able to accumulate mcl-PHA in a range from 2.07 to 21.40%, which depended on the substrate used. Potential nitrogen-dependent regulation of mcl-PHA synthesis was analyzed by cell cultivation in nitrogen-limiting and non-limiting conditions. The analyzed strains demonstrated an incremental increase of mcl-PHAs in response to nitrogen starvation when oleic acid and sodium gluconate were applied as the carbon source. The transcriptional analysis showed that the induction of gene coding for PHA synthases was correlated with an increment in mcl-PHAs content. Both analyzed strains revealed differences in terms of the studied gene's expression, showing a dependence on the carbon source used. PMID- 20204458 TI - Late mortality in pediatric patients with craniopharyngioma. AB - Ten year survival rates for patients with craniopharyngioma vary from 24 to 100%. A review of the database of all children diagnosed with craniopharyngioma in British Columbia (BC) revealed that several patients died >10 years after diagnosis. This retrospective study investigates the causes and timing of deaths and reports the overall survival in this population based group of patients. A chart review was conducted on all patients aged <17 years, diagnosed in BC with craniopharyngioma between 1967 and 2003. Imaging studies were reviewed by a neuroradiologist. All deaths in the province are reported to a central agency, which allowed identification of patients who died after being lost to clinical follow up. Forty-one patients were identified with nine deaths (aged 11.9-36.9 years). The four patients who died more than 10 years after diagnosis represent 23% of the 17 patients followed for more than 10 years. Three died more than 20 years after diagnosis. The known causes of death were progressive disease (1), uncontrolled diabetes insipidus (1), panhypopituitarism with multi-organ failure (1), pontine infarction (1) and middle cerebral artery infarction in a patient with Moyamoya disease secondary to radiotherapy (1). Two deaths appeared to be seizure related and 1 occurred after orthopedic surgery and remains unexplained. One patient died due to liver failure of unknown etiology. The 10 year overall survival (OS) was 84.1% (95% CI 71.2, 97.1) and the 20 year OS 76.5% (95% CI 58.1, 94.9). Patients remain at risk of premature death more than 10 years after diagnosis. The cause specific late mortality was multifactorial but was rarely due to disease progression. New approaches to craniopharyngioma treatment and life long follow up of cases are required. PMID- 20204459 TI - Decreased pygopus 2 expression suppresses glioblastoma U251 cell growth. AB - Gliomas are common malignant tumors of the human neural system, and Wnt signaling activation is closely related to glioma malignancy. Human Pygopus 2 (Pygo2) was recently discovered to be a component of the Wnt signaling pathway, which is required for beta-catenin/Tcf-dependent transcription. However, the role of Pygo2 in glioblastoma cell growth and survival remains uncertain. In the present study, Pygo2 expression was evaluated in 80 glioma tissue samples. Results demonstrated that tumor grade exhibited a positive correlation with overexpression of Pygo2. In addition, small hairpin RNA (shRNA) was used to specifically knockdown Pygo2 expression in human glioblastoma U251 cell lines. Results showed that inhibition of Pygo2 expression resulted in inhibited cell proliferation and invasiveness, as well as increased cell cycle arrest at the G(1) stage and decreased expression of the Wnt target gene cyclin D1. These results demonstrated that Pygo2 was highly expressed in glioma tissue and required for growth of glioblastoma cells. PMID- 20204460 TI - Clinical characteristics of intermediate uveitis in Tunisian patients. AB - To analyze the pattern of intermediate uveitis (IU) in a referral center in Tunisia, North Africa. A retrospective, descriptive study of 87 consecutive patients (145 eyes) examined at the Department of Ophthalmology of Monastir (Tunisia) from January 1996 to August 2008. All patients underwent an extensive ocular and systemic history, a complete ophthalmic examination, and fluorescein angiography. Standard diagnostic criteria of IU were employed. The mean follow-up period was 43.2 months (range, 4-65 months). The mean age at diagnosis of IU was 29.1 years (range, 5-54 years). The male-to-female ratio was 1:1.6. Both eyes were affected in 58 patients (66.7%). The best-corrected visual acuity at onset of uveitis ranged from light perception to 20/20 (mean, 20/32). The most frequent ocular findings were vitritis (100%), snowballs (53.8%), and retinal vasculitis (28.3%). Concurrent anterior uveitis was noted in 38.6% of affected eyes. Intermediate uveitis was most commonly idiopathic (86.2%). Systemic associations were found in 13.8%; sarcoidosis (9.2%) and multiple sclerosis (2.3%) were the most common systemic diseases. The ocular complications that developed during the follow-up period included cystoid macular edema (39.3%), cataract (31.7%), inflammatory optic disc involvement (26.2%), and glaucoma or ocular hypertension (9%). One hundred-twelve affected eyes (77.2%) had a final visual acuity more than or equal to 20/40. Factors of poor visual outcome were initial VA less than 20/40 (P = 0.00011), CME (P = 0.0016), and vitritis more than 3+ cells (P = 0.023). In a hospital population in Tunisia, intermediate uveitis started frequently at the 3rd decade. This type of uveitis was most commonly idiopathic. Cystoid macular edema and cataract were the most frequent complications. Visual prognosis appeared to be fairly good. PMID- 20204461 TI - Accuracy assessment of pharmacogenetically predictive warfarin dosing algorithms in patients of an academic medical center anticoagulation clinic. AB - The objectives of this retrospective cohort study are to evaluate the accuracy of pharmacogenetic warfarin dosing algorithms in predicting therapeutic dose and to determine if this degree of accuracy warrants the routine use of genotyping to prospectively dose patients newly started on warfarin. Seventy-one patients of an outpatient anticoagulation clinic at an academic medical center who were age 18 years or older on a stable, therapeutic warfarin dose with international normalized ratio (INR) goal between 2.0 and 3.0, and cytochrome P450 isoenzyme 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) genotypes available between January 1, 2007 and September 30, 2008 were included. Six pharmacogenetic warfarin dosing algorithms were identified from the medical literature. Additionally, a 5 mg fixed dose approach was evaluated. Three algorithms, Zhu et al. (Clin Chem 53:1199-1205, 2007), Gage et al. (J Clin Ther 84:326-331, 2008), and International Warfarin Pharmacogenetic Consortium (IWPC) (N Engl J Med 360:753-764, 2009) were similar in the primary accuracy endpoints with mean absolute error (MAE) ranging from 1.7 to 1.8 mg/day and coefficient of determination R (2) from 0.61 to 0.66. However, the Zhu et al. algorithm severely over-predicted dose (defined as >or=2x or >or=2 mg/day more than actual dose) in twice as many (14 vs. 7%) patients as Gage et al. 2008 and IWPC 2009. In conclusion, the algorithms published by Gage et al. 2008 and the IWPC 2009 were the two most accurate pharmacogenetically based equations available in the medical literature in predicting therapeutic warfarin dose in our study population. However, the degree of accuracy demonstrated does not support the routine use of genotyping to prospectively dose all patients newly started on warfarin. PMID- 20204467 TI - Assessing the correlation between anaerobic toluene degradation activity and bssA concentrations in hydrocarbon-contaminated aquifer material. AB - The assessment of biodegradation activity in contaminated aquifers is critical to demonstrate the performance of bioremediation and natural attenuation and to parameterize models of contaminant plume dynamics. Real time quantitative PCR (qPCR) was used to target the catabolic bssA gene (coding for benzylsuccinate synthase) and a 16S rDNA phylogenetic gene (for total Bacteria) as potential biomarkers to infer on anaerobic toluene degradation rates. A significant correlation (P = 0.0003) was found over a wide range of initial toluene concentrations (1-100 mg/l) between toluene degradation rates and bssA concentrations in anaerobic microcosms prepared with aquifer material from a hydrocarbon contaminated site. In contrast, the correlation between toluene degradation activity and total Bacteria concentrations was not significant (P = 0.1125). This suggests that qPCR targeting of functional genes might offer a simple approach to estimate in situ biodegradation activity, which would enhance site investigation and modeling of natural attenuation at hydrocarbon contaminated sites. PMID- 20204468 TI - Hydrolysis of benzonitrile herbicides by soil actinobacteria and metabolite toxicity. AB - The soil actinobacteria Rhodococcus rhodochrous PA-34, Rhodococcus sp. NDB 1165 and Nocardia globerula NHB-2 grown in the presence of isobutyronitrile exhibited nitrilase activities towards benzonitrile (approx. 1.1-1.9 U mg(-1) dry cell weight). The resting cell suspensions eliminated benzonitrile and the benzonitrile analogues chloroxynil (3,5-dichloro-4-hydroxybenzonitrile), bromoxynil (3,5-dibromo-4-hydroxybenzonitrile) and ioxynil (3,5-diiodo-4 hydroxybenzonitrile) (0.5 mM each) from reaction mixtures at 30 degrees C and pH 8.0. The products were isolated and identified as the corresponding substituted benzoic acids. The reaction rates decreased in the order benzonitrile >> chloroxynil > bromoxynil > ioxynil in all strains. Depending on the strain, 92 100, 70-90 and 30-51% of chloroxynil, bromoxynil and ioxynil, respectively, was hydrolyzed after 5 h. After a 20-h incubation, almost full conversion of chloroxynil and bromoxynil was observed in all strains, while only about 60% of the added ioxynil was converted into carboxylic acid. The product of ioxynil was not metabolized any further, and those of the other two herbicides very slowly. None of the nitrilase-producing strains hydrolyzed dichlobenil (2,6 dichlorobenzonitrile). 3,5-Dibromo-4-hydroxybenzoic acid exhibited less inhibitory effect than bromoxynil both on luminescent bacteria and germinating seeds of Lactuca sativa. 3,5-Diiodo-4-hydroxybenzoic acid only exhibited lower toxicity than ioxynil in the latter test. PMID- 20204469 TI - Performance of calcium deficient hydroxyapatite-polyglycolic acid composites: an in vitro study. AB - The strategic incorporation of bioresorbable polymeric additives to calcium deficient hydroxyapatite cement may provide short-term structural reinforcement and modify the modulus to closer match bone. The longer-term resorption properties may also be improved, creating pathways for bone in-growth. The aim of this study was to investigate the resorption process of a calcium phosphate cement system containing either in polyglycolic acid tri-methylene carbonate particles or polyglycolic acid fibres. This was achieved by in vitro aging in physiological conditions (phosphate buffered solution at 37 degrees C) over 12 weeks. The unreinforced CPC exhibited an increase in compressive strength at 12 weeks, however catastrophic failure was observed above a critical loading. The fracture behaviour of cement was improved by the incorporation of PGA fibres; the cement retained its cohesive structure after critical loading. Gravimetric analysis and scanning electron microscopy showed a large proportion of the fibres had resorbed after 12 weeks allowing for the increased cement porosity, which could facilitate cell infiltration and faster integration of natural bone. Incorporating the particulate additives in the cement did not provide any mechanism for mechanical property augmentation or did not demonstrate any appreciable level of resorption after 12 weeks. PMID- 20204470 TI - Abundance estimation of Ixodes ticks (Acari: Ixodidae) on roe deer (Capreolus capreolus). AB - Despite the importance of roe deer as a host for Ixodes ticks in central Europe, estimates of total tick burden on roe deer are not available to date. We aimed at providing (1) estimates of life stage and sex specific (larvae, nymphs, males and females, hereafter referred to as tick life stages) total Ixodes burden and (2) equations which can be used to predict the total life stage burden by counting the life stage on a selected body area. Within a period of 1(1/2) years, we conducted whole body counts of ticks from 80 hunter-killed roe deer originating from a beech dominated forest area in central Germany. Averaged over the entire study period (winter 2007-summer 2009), the mean tick burden per roe deer was 64.5 (SE +/- 10.6). Nymphs were the most numerous tick life stage per roe deer (23.9 +/- 3.2), followed by females (21.4 +/- 3.5), larvae (10.8 +/- 4.2) and males (8.4 +/- 1.5). The individual tick burden was highly aggregated (k = 0.46); levels of aggregation were highest in larvae (k = 0.08), followed by males (k = 0.40), females (k = 0.49) and nymphs (k = 0.71). To predict total life stage specific burdens based on counts on selected body parts, we provide linear equations. For estimating larvae abundance on the entire roe deer, counts can be restricted to the front legs. Tick counts restricted to the head are sufficient to estimate total nymph burden and counts on the neck are appropriate for estimating adult ticks (females and males). In order to estimate the combined tick burden, tick counts on the head can be used for extrapolation. The presented linear models are highly significant and explain 84.1, 77.3, 90.5, 91.3, and 65.3% (adjusted R (2)) of the observed variance, respectively. Thus, these models offer a robust basis for rapid tick abundance assessment. This can be useful for studies aiming at estimating effects of abiotic and biotic factors on tick abundance, modelling tick population dynamics, modelling tick-borne pathogen transmission dynamics or assessing the efficacy of acaricides. PMID- 20204471 TI - Critical evaluation of Nanoparticle Tracking Analysis (NTA) by NanoSight for the measurement of nanoparticles and protein aggregates. AB - PURPOSE: To evaluate the nanoparticle tracking analysis (NTA) technique, compare it with dynamic light scattering (DLS) and test its performance in characterizing drug delivery nanoparticles and protein aggregates. METHODS: Standard polystyrene beads of sizes ranging from 60 to 1,000 nm and physical mixtures thereof were analyzed with NTA and DLS. The influence of different ratios of particle populations was tested. Drug delivery nanoparticles and protein aggregates were analyzed by NTA and DLS. Live monitoring of heat-induced protein aggregation was performed with NTA. RESULTS: NTA was shown to accurately analyze the size distribution of monodisperse and polydisperse samples. Sample visualization and individual particle tracking are features that enable a thorough size distribution analysis. The presence of small amounts of large (1,000 nm) particles generally does not compromise the accuracy of NTA measurements, and a broad range of population ratios can easily be detected and accurately sized. NTA proved to be suitable to characterize drug delivery nanoparticles and protein aggregates, complementing DLS. Live monitoring of heat-induced protein aggregation provides information about aggregation kinetics and size of submicron aggregates. CONCLUSION: NTA is a powerful characterization technique that complements DLS and is particularly valuable for analyzing polydisperse nanosized particles and protein aggregates. PMID- 20204472 TI - Classification of annular bed flow patterns and investigation on their influence on the bottom spray fluid bed coating process. AB - PURPOSE: This study aims to classify annular bed flow patterns in the bottom spray fluid bed coating process, study their influence on coat uniformity and investigate the feasibility of developing real-time annular bed flow pattern detection as a PAT tool. METHODS: High-speed imaging and particle image velocimetry were used to visualize annular bed flow. Color coating and subsequent tristimulus colorimetry were employed to determine influence of annular bed flow pattern on coat uniformity. Feasibility of monitoring annular bed flow pattern through an observation window was tested using miniaturized particle velocity field and time series particle velocity orientation information. RESULTS: Three types of annular bed flow patterns were identified. Plug flow gave the best coat uniformity followed by global and localized fluidization. Plug flow may be advantageous for high spray-rate conditions, large-scale coating and prevention of particle segregation. Plug flow could be differentiated from the other flow patterns through a simulated observation window. CONCLUSION: Annular bed flow patterns were classified and found to influence particle coat uniformity noticeably. Availability of annular bed flow information for large-scale coaters would enable adjustments for process optimization. This study highlights the potential of monitoring annular bed flow pattern as a PAT tool. PMID- 20204473 TI - Basic PK/PD principles of drug effects in circular/proliferative systems for disease modelling. AB - Disease progression modelling can provide information about the time course and outcome of pharmacological intervention on the disease. The basic PK/PD principles of proliferative and circular systems within the context of modelling disease progression and the effect of treatment thereupon are illustrated with the goal to better understand/predict eventual clinical outcome. Circular/proliferative systems can be very complex. To facilitate the understanding of how a dosing regimen can be defined in such systems we have shown the derivation of a system parameter named the Reproduction Minimum Inhibitory Concentration (RMIC) which represents the critical concentration at which the system switches from growth to extinction. The RMIC depends on two parameters (RMIC = (R(0) - 1) x IC(50)): the basic reproductive ratio (R(0)) a fundamental parameter of the circular/proliferative system that represents the number of offspring produced by one replicating species during its lifespan, and the IC(50), the potency of the drug to inhibit the proliferation of the system. The RMIC is constant for a given system and a given drug and represents the lowest concentration that needs to be achieved for eradication of the system. When exposure is higher than the RMIC, success can be expected in the long term. Time varying inhibition of replicating species proliferation is a natural consequence of the time varying inhibitor drug concentrations and when combined with the dynamics of the circular/proliferative system makes it difficult to predict the eventual outcome. Time varying inhibition of proliferative/circular systems can be handled by calculating the equivalent effective constant concentration (ECC), the constant plasma concentration that would give rise to the average inhibition at steady state. When ECC is higher than the RMIC, eradication of the system can be expected. In addition, it is shown that scenarios that have the same steady state ECC whatever the dose, dosage schedule or PK parameters have also the same average R (0) in the presence of the inhibitor (i.e. R (0-INH)) and therefore lead to the same outcome. This allows predicting equivalent active doses and dosing schedules in circular and proliferative systems when the IC(50) and pharmacokinetic characteristics of the drugs are known. The results from the simulations performed demonstrate that, for a given system (defined by its RMIC), treatment success depends mainly on the pharmacokinetic characteristics of the drug and the dosing schedule. PMID- 20204474 TI - A novel laparoscopic pulse oximeter device. An easy, efficient and cost- effective way of detecting arterial structures. AB - The introduction of laparoscopy has revolutionized surgery. However, these new techniques have brought new problems into the surgical field. Due to the loss of depth and tactile sensation, time- consuming efforts must be made in order to identify normal anatomy and detect any aberrations. Even well experienced surgeons could face difficulties during demanding procedures, such as operations on inflammatory conditions. Therefore, there is still a strong need for developing additional tools to help mapping the anatomy. We designed a laparoscopic pulse oximeter device, which offers an easy, efficient and cost- effective way of using pulse oximetry in combination with a standard laparoscopic clamp in order to identify arterial structures. PMID- 20204475 TI - Catch me if you can! Novel aspects of cadmium transport in mammalian cells. AB - Cadmium (Cd(2+)) is a nonessential divalent metal ion that causes toxicity in multiple organs in humans. In order for toxicity to occur Cd(2+) must first enter cells by utilizing transport pathways for essential metals. This review focuses on studies in which Cd(2+) transport was directly demonstrated by electrophysiological, radiotracer or Cd(2+)-sensitive fluorescent dye techniques. The chemistry of Cd(2+) and metal ions in general is addressed in the context of properties relevant for transport through membrane proteins, such as hydration energy. Apart from transport by the ZIP transporters SLC39A8 and SLC39A14, which is not topic of the review, uptake of free Cd(2+) has been demonstrated for the Fe(2+)/H(+) cotransporter divalent metal transporter 1. Moreover, the multiligand endocytic receptors megalin and cubilin take up cadmium-metallothionein complexes via receptor-mediated endocytosis. The role of ATP binding cassette transporters in Cd(2+) efflux from cells is also discussed. Both the multidrug resistance associated protein 1 and cystic fibrosis transmembrane conductance regulator are likely to transport cadmium-glutathione complexes out of cells, whereas transport of free Cd(2+) by the multidrug resistance P-glycoprotein remains controversial. Finally, arguments for and against Cd(2+) transport by Ca(2+) channels are presented. Most N- and L-type Ca(2+) channels are closed at resting membrane potential (with the exception of CaV1.3 channels) and therefore unlikely to allow significant Cd(2+) influx under physiological conditions. CaV3.1 and CaV3.2 T type calcium channels are permeated by divalent metal ions, such as Fe(2+) and Mn(2+) because of considerable "window" currents close to resting membrane potential and could be responsible for tonic Cd(2+) entry. TRPM7 and the mitochondrial Ca(2+) uniporter are other likely candidates for Cd(2+) transporters, whereas the role of Orai proteins, the store-operated calcium channels carrying Ca(2+) release-activated Ca(2+) current, in Cd(2+) influx remains to be investigated. PMID- 20204476 TI - Electron paramagnetic studies of the copper and iron containing soluble ammonia monooxygenase from Nitrosomonas europaea. AB - Soluble ammonia monooxygenase (AMO) from Nitrosomonas europaea was purified to homogeneity and metals in the active sites of the enzyme (Cu, Fe) were analyzed by electron paramagnetic resonance (EPR) spectroscopy. EPR spectra were obtained for a type 2 Cu(II) site with g(parallel) = 2.24, A(parallel) = 18.4 mT and g(perpendicular) = 2.057 as well as for heme and non heme iron present in purified soluble AMO from N. europaea. A second type 2 Cu(II) EPR signal with g(parallel) = 2.29, A(parallel) = 16.1 mT and g(perpendicular) = 2.03 appeared in the spectrum of the ferricyanide oxidized enzyme and was attributed to oxidation of cuprous sites. Comparison of EPR-detectable Cu(2+) with total copper determined by inductively coupled plasma-mass spectrometry (ICP-MS) suggests that there are six paramagnetic Cu(2+) and three diamagnetic Cu(1+) per heterotrimeric soluble AMO (two paramagnetic and one diamagnetic Cu per alphabetagamma protomer). A trigonal EPR signal at g = 6.01, caused by a high-spin iron, indicative for cytochrome bound iron, and a rhombic signal at g = 4.31, characteristic of specifically bound Fe(3+) was detectable. The binding of nitric oxide in the presence of reductant resulted in a ferrous S = 3/2 signal, characteristic of a ferrous nitrosyl complex. Inactivation of soluble AMO with acetylene did neither diminish the ferrous signal nor the intensity of the Cu(2+) EPR signal. PMID- 20204477 TI - Differential suppression of heat-killed lactobacilli isolated from kimchi, a Korean traditional food, on airway hyper-responsiveness in mice. AB - RATIONALE: Probiotics have been shown to be effective in reducing allergic symptoms. However, there are few studies to evaluate the therapeutic effects of lactobacilli on allergen-induced airway inflammation. OBJECTIVE: We investigated whether three heat-killed lactobacilli, Lactobacillus plantarum, Lactobacillus curvatus and Lactobacillus sakei subsp. sakei, isolated from kimchi, exerted inhibitory effects on airway hyper-responsiveness in a murine asthma model. METHODS: Heat-killed lactic acid bacteria were orally administered into BALB/c mice, followed by challenge with aerosolized ovalbumin, after which allergic symptoms were evaluated. RESULTS: Airway inflammation was suppressed in the L. plantarum- and L. curvatus-treated mice. Interleukin (IL)-4 and IL-5 levels were significantly lower in the L. plantarum- and L. curvatus-treated mice than in those treated with L. sakei subsp. sakei. Importantly, heat-killed L. plantarum administration induced Foxp3 expression in intestinal lamina propria cells, and heat-killed L. curvatus induced IL-10 as a way of inducing tolerance. CONCLUSION: Specific strains of lactobacilli isolated from kimchi can effectively suppress airway hyper-responsiveness. PMID- 20204478 TI - Predicting outcomes for youth transferred to adult court. AB - Extant research regarding juvenile transfer has focused primarily on the negative effects of current policies, with little consistent and rigorous work on the variation among the adolescents transferred to adult court and their later adjustment in the community. Using a sample of 193 transferred youth from Arizona, we consider how certain individual characteristics are related to four post-release outcomes (antisocial activity, re-arrest, re-institutionalization, and gainful activity). We find considerable variability in outcomes, with adjustment significantly and consistently related to certain legal and risk-need factors. These results indicate that some transferred youth may experience negative outcomes, and that refinements to transfer policy may benefit from consideration of these factors in determining which serious adolescent offenders are most appropriate for transfer. PMID- 20204479 TI - U.S. provider reported folic acid or multivitamin ordering for non-pregnant women of childbearing age: NAMCS and NHAMCS, 2005-2006. AB - Folic acid use started prior to pregnancy confers a decreased risk of neural tube defects, and yet 20-50% of pregnancies are unplanned. We sought to determine whether medical providers order folic acid (FA) or folic acid-containing multivitamins (MVI) for their non-pregnant female patients of childbearing age. This is a cross-sectional study using data from the CDC's National Ambulatory Medical Care Survey (NAMCS) and National Hospital Ambulatory Medical Care Survey (NHAMCS) (2005 and 2006). Among non-pregnant, female patients of childbearing age (15-44), the proportion of preventive visits during which a provider ordered FA/MVI supplements was determined and compared to pregnant patients. Next, the rates of FA/MVI orders were examined according to race/ethnicity, age, insurance status, region of the country, provider type, contraceptive care, income and education. Analyses were conducted using SAS-callable Sudaan to account for survey design and to obtain population estimates. There were 4,634 preventive visits for non-pregnant women of childbearing age, representing 32.1 million visits nationally. Of these visits, 7.2% included provider-ordered FA/MVI. Multivariable logistic regression analyses revealed that provider-ordered FA/MVI was most common for women ages 30-34, who receive Medicaid, and whose race/ethnicity was other than White, Black or Hispanic. Preventive care visits represent an important venue for counseling regarding the benefits of FA for women of childbearing age, but appear to be under-utilized in all women. Our findings suggest that annually there may be over 29 million missed opportunities to recommend folic acid to non-pregnant women seeking preventive care. PMID- 20204480 TI - Continuing education mitigates the negative consequences of adolescent childbearing. AB - Beginning childbearing during adolescence is consistently linked with negative outcomes for both children and parents. Many have attributed this association to maternal background characteristics which are often difficult to change through policy. Though maternal educational attainment is often a side effect of adolescent childbearing, it also represents a potential avenue through which we can help young mothers overcome the obstacles associated with an early birth. The data for this study come from the 1997 Child Development Supplement of the Panel Study of Income Dynamics, a nationally representative sample of mothers and their children (N = 3,193). Data are used to explore the cognitive stimulation and emotional support in the home, measured using the HOME Scale (Caldwell and Bradley in Home observation for measurement of the environment. University of Arkansas at Little Rock, Little Rock, 1984). OLS regression models how maternal education moderates the association between age at first birth and quality of children's home environment. Adolescent mothers scored significantly lower on the indicator of home environment than older mothers. However, when continuing education was considered, maternal age at first birth was no longer significantly associated with the home environment. The negative consequences of early births were mediated by adolescent mothers' continuing education efforts. While interventions are needed to reduce adolescent childbearing, these results highlight the need to ensure that adolescent mothers are provided support to continue their education following delivery. The negative consequences of adolescent births are not inevitable. Encouraging school retention may help young mothers form a safe, healthy, nurturing, and developmentally appropriate home environment. PMID- 20204481 TI - Effect of body image on pregnancy weight gain. AB - The majority of women gain more weight during pregnancy than what is recommended. Since gestational weight gain is related to short and long-term maternal health outcomes, it is important to identify women at greater risk of not adhering to guidelines. The objective of this study was to examine the relationship between body image and gestational weight gain. The Body Image Assessment for Obesity tool was used to measure ideal and current body sizes in 1,192 women participating in the Pregnancy, Infection and Nutrition Study. Descriptive and multivariable techniques were used to assess the effects of ideal body size and discrepancy score (current-ideal body sizes), which reflected the level of body dissatisfaction, on gestational weight gain. Women who preferred to be thinner had increased risk of excessive gain if they started the pregnancy at a BMI <=26 kg/m(2) but a decreased risk if they were overweight or obese. Comparing those who preferred thin body silhouettes to those who preferred average size silhouettes, low income women had increased risk of inadequate weight gain [RR = 1.76 (1.08, 2.88)] while those with lower education were at risk of excessive gain [RR = 1.11 (1.00, 1.22)]. Our results revealed that body image was associated with gestational weight gain but the relationship is complex. Identifying factors that affect whether certain women are at greater risk of gaining outside of guidelines may improve our ability to decrease pregnancy related health problems. PMID- 20204482 TI - Impact of the Red River catastrophic flood on women giving birth in North Dakota, 1994-2000. AB - To document changes in birth rates, birth outcomes, and pregnancy risk factors among women giving birth after the 1997 Red River flood in North Dakota. We analyzed detailed county-level birth files pre-disaster (1994-1996) and post disaster (1997-2000) in North Dakota. Crude birth rates and adjusted fertility rates were calculated. The demographic and pregnancy risk factors were described among women delivering singleton births. Logistic regression was conducted to examine associations between the disaster and low birth weight (<2,500 g), preterm birth (<37 weeks), and small for gestational age infants adjusting for confounders. The crude birth rate and direct-adjusted fertility rate decreased significantly after the disaster in North Dakota. The proportion of women giving birth who were older, non-white, unmarried, and had a higher education increased. Compared to pre-disaster, there were significant increases in the following maternal measures after the disaster: any medical risks (5.1-7.1%), anemia (0.7 1.1%), acute or chronic lung disease (0.4-0.5%), eclampsia (0.3-2.1%), and uterine bleeding (0.3-0.4%). In addition, there was a significant increase in births that were low birth weight (OR 1.11, 95% CI 1.03-1.21) and preterm (OR 1.09, 95% CI 1.03-1.16) after adjusting for maternal characteristics and smoking. Following the flood, there was an increase in medical risks, low birth weight, and preterm delivery among women giving birth in North Dakota. Further research that examines birth outcomes of women following a catastrophic disaster is warranted. PMID- 20204484 TI - Reversibility of hepatic encephalopathy after liver transplantation. AB - Until the advent of Liver transplantation, it was widely believed that Hepatic Encephalopathy (HE) was usually reversible. The exceptions were the so called "Acquired Hepatocerebral Degeneration cases" which were considered irreversible. Paradoxically, it seems, with liver transplantation, we have seen cases that contradict these rules. Whether the "residual effects" of HE, degenerative brain injury or independent neurological insults are causing post transplant neurological deficits is not easy to discern. As more emphasis is being put on maintaining brain 'status' after liver transplantation, we are finding confirmation of the largely reversible nature of HE. But, enough important exceptions to this rule are occurring to make further research on this topic mandatory. PMID- 20204483 TI - Neurocognitive-neurological complications of liver transplantation: a review. AB - Neurological complications are common after liver transplantation (LT) and they are associated with a significant morbidity. Long-term effects of LT on cognitive and psychological outcomes are not clear. The objective of this study was to summarize the present knowledge on the neurological and cognitive complications of LT, resulting from a systematic review of the literature in the last 10 years. Several studies have investigated the incidence and the pathophysiology of neurological complications; in contrast, the knowledge of cognitive and psychological status after LT is poor. Currently, the effect of LT on mental performance is debated. Some studies have shown an improvement of cognitive function after OLTX and, at the same time, a persistence of different cognitive deficits. In addition, the quality of life (QoL) and the psychological status after LT seem to improve but LT recipients have significant deficiencies in most QoL domains. Consequently, future studies are necessary in order to investigate cognitive alterations and QoL in LT recipients. PMID- 20204485 TI - Involvement of SRC-suppressed C kinase substrate in neuronal death caused by the lipopolysaccharide-induced reactive astrogliosis. AB - Src-suppressed C kinase substrate (SSeCKS), a protein kinase C substrate, is a major lipopolysaccharide (LPS) response protein, regulating the inflammatory process. In the process of spinal inflammatory diseases by LPS intraspinal injection, expression of SSeCKS in the spinal cord was increased, mainly in active astrocytes and neurons. Induced SSeCKS was colabeled with terminal deoxynucleotidyl transferase-mediated biotinylated-dUTP nick-end labeling (an apoptosis maker) in the late inflammation processes. These results indicated that SSeCKS might correlate with the inflammatory reaction and late neurodegeneration after LPS injection. A cell type-specific action for SSeCKS was further studied within C6 cells and PC12 cells. Knockdown of SSeCKS by small-interfering RNAs (siRNAs) blocked the LPS-induced inducible nitric oxide synthase (iNOS) expression in C6 cells, while overexpression SSeCKS enhanced iNOS expression. SSeCKS is also participated in regulation of PC12 cell viability. Loss of SSeCKS rescued PC12 cell viability, and excessive SSeCKS exacerbated the cell death upon conditioned medium and tumor necrosis factor-alpha exposure. This study delineates that SSeCKS may be important for host defenses in spinal inflammation and suggests a valuable molecular mechanism by which astrocytes modify neuronal viability during pathological states. PMID- 20204487 TI - A critique of the proposed DSM-V diagnosis of pedophilia. PMID- 20204486 TI - Zileuton reduces inflammatory reaction and brain damage following permanent cerebral ischemia in rats. AB - 5-Lipoxygenase inhibitor zileuton has been demonstrated to attenuate ischemic brain damage in rats of permanent focal cerebral ischemia in previous work. To further investigate the mechanism underlying zileuton's neuroprotection, adult male Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (MCAO), then received treatment with zileuton or vehicle after the onset of ischemia. Neurological deficit, cerebral infarction, and morphological characteristic were measured 6 and 24 h after MCAO. The enzymatic activity of myeloperoxidase (MPO) was assessed 6 and 24 h after MCAO and the lipid peroxidation levels were evaluated by malondialdehyde assay. Expression of nuclear factor-kappa B (NF-kappaB) p65 in rat brain was detected by immunohistochemistry and Western blot. Expression of inducible nitric oxide synthase (iNOS) in rat brain was determined by RT-PCR and Western blot. Nitric oxide production in rat brain was also measured 24 h after MCAO. The concentration of TNF-alpha and IL-1beta in serum were detected by ELISA. Zileuton significantly reduced neurological deficit scores, cerebral infarct volume, MPO activity, and the lipid peroxidation levels. It also inhibited the expression of NF-kappaB and decreased the expression and activity of iNOS in rat brain. In addition, zileuton attenuated the release of TNF-alpha and IL-1beta in serum. Our results suggest that zileuton reduces inflammatory reaction and brain damage in a rat model of permanent focal cerebral ischemia. The neuroprotective effect of zileuton in cerebral ischemia might be associated with the inhibition of inflammatory reaction. PMID- 20204488 TI - Sexual preference for 14-year-olds as a mental disorder: you can't be serious!! PMID- 20204489 TI - Blood pressure reactivity predicts somatic reactivity to stress in daily life. AB - The purpose of the present study was to examine whether stress-somatic symptom associations may be more pronounced among individuals whose bodies exhibit higher levels of cardiovascular reactivity to a laboratory social stress task. During an initial laboratory session, participants delivered a 5-min speech and individual differences in cardiovascular reactivity were quantified. The same participants subsequently completed a 15-day experience sampling protocol, in which daily levels of stress and somatic symptoms were assessed. Multi-level modeling was used to assess associations among laboratory cardiovascular reactivity, daily stress and somatic symptoms. Daily symptom reports included a set of commonly experienced physical symptoms reflective of general bodily dysfunction. Individuals displaying high levels of laboratory systolic blood pressure reactivity experienced more somatic symptoms on high-stress days, but this was not the case for individuals low in systolic blood pressure reactivity. The results bridge two hitherto distinct health psychology literatures showing that cardiovascular and somatic reactivity to stress are associated. Stress reactivity individual differences in one system may indicate more general differences in bodily reactivity across systems. PMID- 20204490 TI - Stress generation over the course of breast cancer survivorship. AB - Depressive symptoms are frequently elevated following breast cancer diagnosis. The stress generation hypothesis states that people with depression generate stressful events and these stressors lead to subsequent depression. This study tested the stress generation hypothesis over the first 5 years of cancer survivorship. Women with stage II or III breast cancer (N = 113) were accrued. Five mediation models were constructed, one for each year. Each model tested whether stressful events in each year mediated the relationship between depression at the beginning and end of that year. Stress generation was observed in the first 2 years following cancer diagnosis but not from 2 to 5 years after diagnosis. The relationship of depression to future stress in breast cancer patients may be moderated by phase of survivorship. Screening and treatment of depressive symptoms in cancer survivors may need to consider the generation of stressful events. PMID- 20204491 TI - The influence of quality of life and depressed mood on smoking cessation among medically ill smokers. AB - Disease diagnosis and poor quality of life has been suggested as a "teachable moment" that facilitates smoking cessation, yet many patients continue to smoke. One reason for this inconsistency may be the potential moderating role of depressed mood. This study prospectively examined the role of depressed mood on the relationship between physical quality of life (PQoL) and smoking cessation among medically ill smokers. We hypothesized that poorer PQoL will be associated with smoking cessation, but only among those with little to no depressed mood. Nurses delivered smoking cessation counseling to medically ill patients (N = 273) who continued to smoke despite past hospitalization. Participants were assessed at baseline and at 2, 6, and 12-months later. The interaction between PQoL and depressed mood significantly predicted 1) 7-day point prevalence abstinence rates at both 2 and 12 months post-treatment [2 months: adjusted OR = 1.005, 95%CI 1.001-1.009, p < .05; 12 months: adjusted OR = 1.007, 95%CI 1.002-1.011, p < .005)] and 2) continuous abstinence rates at both 2 and 12 months post-treatment [2 months: adjusted OR = 1.011, 95%CI 1.004-1.019, p < .005; 12 months: adjusted OR = 1.006, 95%CI 1.001-1.011, p < .05] even after controlling for important covariates. The odds of quitting smoking increased for every one-unit decrease in PQoL, but only among those with little to no depressed mood. Medically ill smokers with poor quality of life may need more intensive smoking cessation interventions that include mood management to help them quit smoking. PMID- 20204492 TI - Components associated with adequacy of help for consumers with severe mental disorders. AB - Needs assessment is key in mental health rehabilitation. Using a representative sample of consumers with severe mental disorders living in supervised housing in Montreal, Quebec, the study describes consumer needs and variables associated with the adequacy of help provided. Descriptive, component, and regression analyses were performed. Four needs components, including 20 domains, were examined. Greater adequacy of help was found to be associated with five variables: "daytime social relations"; number of needs; number of unmet needs; gender; and help from services. Components associated with "daytime social relations" and "higher social needs" would be more effectively addressed by integrated healthcare providers. PMID- 20204493 TI - Cancer risk in DES daughters. AB - OBJECTIVE: We examined long-term risk of cancer in women exposed to diethylstilbestrol (DES) in utero. METHODS: A total of 12,091 DES-exposed women in the Netherlands were followed prospectively from December 1992 till June 2008. Cancer incidence was assessed through linkage with the Dutch pathology database (PALGA) and the Netherlands Cancer Registry and compared with the Dutch female population. RESULTS: A total of 348 medically verified cancers occurred; median age at end of follow-up was 44.0 years. No overall increased risk of cancer was found (standardized incidence ratio [SIR] = 1.01; 95% confidence interval [CI] = 0.91, 1.13). The risk of clear cell adenocarcinoma of the vagina and cervix (CCA) was statistically significantly increased (SIR = 24.23; 95% CI = 8.89, 52.74); the elevated risk persisted above 40 years of age. The risk of melanoma diagnosed before age 40 was increased (SIR = 1.59; 95% CI = 1.08, 2.26). No excess risks were found for other sites, including breast cancer. CONCLUSIONS: Except for an elevated risk of CCA, persisting at older ages, and an increased risk of melanoma at young ages, we found no increased risk of cancer. Longer follow-up is warranted to examine cancer risk at ages when cancer occurs more frequently. PMID- 20204494 TI - Risk of non-Hodgkin lymphoma and nitrate and nitrite from the diet in Connecticut women. AB - It has been estimated that 65,980 individuals were diagnosed with non-Hodgkin lymphoma (NHL) and 19,500 died from NHL in the United States in 2009. Although established risk factors such as immunodeficiency and viral infections may be responsible for a portion of the cases, the majority of NHL cases remain unexplained. Dietary nitrate and nitrite intake are exposures of particular interest for NHL risk as they are precursors in the endogenous formation of N nitroso compounds, which cause lymphomas in animal studies. We investigated NHL risk overall and by histologic type in relation to dietary nitrate and nitrite intake in a population-based case-control study of 1,304 women in Connecticut. Nitrate and nitrite intake were assessed using a 120-item food frequency questionnaire. We found no association between risk of NHL overall and dietary nitrate and a slightly increased risk of NHL with higher dietary nitrite intake (highest vs. lowest intake quartile OR = 1.4; 95% CI: 0.9-2.2). When we evaluated intake by subtype, a significant positive trend was observed for follicular lymphoma and nitrate (p-trend = 0.04) and nitrite (p-trend < 0.01) with an over twofold risk in the highest nitrite intake quartile (OR = 2.3; 95% CI: 1.1-4.9). An increased risk in the highest quartile of nitrite intake was also observed for T-cell lymphoma (OR = 3.4; 95% CI: 1.0-11.9). Animal products containing nitrite were more strongly associated with risk of follicular lymphoma; whereas, both animal and plant sources of nitrite were associated with elevated ORs for T-cell lymphoma. Our results confirm a previous finding for nitrite intake and NHL risk and highlight the importance of evaluating histologic type. We conclude that these results should be replicated in a larger study with data on drinking water as well as dietary sources of nitrate intake. PMID- 20204495 TI - Functional centromeres in soybean include two distinct tandem repeats and a retrotransposon. AB - The centromere as a kinetochore assembly site is fundamental to the partitioning of genetic material during cell division. In order to determine the functional centromeres of soybean, we characterized the soybean centromere-specific histone H3 (GmCENH3) protein and developed an antibody against the N-terminal end. Using this antibody, we cloned centromere-associated DNA sequences by chromatin immunoprecipitation. Our analyses indicate that soybean centromeres are composed of two distinct satellite repeats (GmCent-1 and GmCent-4) and retrotransposon related sequences (GmCR). The possible allopolyploid origin of the soybean genome is discussed in view of the centromeric satellite sequences present. PMID- 20204496 TI - A paradox revealed: karyotype evolution in the four-horned antelope occurs by tandem fusion (Mammalia, Bovidae, Tetracerus quadricornis). AB - The four-horned antelope, Tetracerus quadricornis, is a karyotypic novelty in Bovidae since chromosomal evolution in this species is driven by tandem fusions in contradiction to the overwhelming influence of Robertsonian fusions in other species within the family. Using a combination of differential staining and molecular cytogenetic techniques, we provide the first description of the species' karyotype, draw phylogenetic inferences from the cytogenetic data and discuss possible mechanisms underlying the formation of the tandem fusions in this species. We show (a) that pairs 1-6 of Tetracerus correspond to a combination of Bos taurus orthologous chromosomes that are tandemly fused head to tail, (b) the presence of interstitial centromeric satellite DNA at the junctions of orthologous blocks defined by the cross-species painting data and (c) that in some instances, residual telomeric sequences persist at these sites. We conclude that the attendant result of each fusion is an enlarged acrocentric fusion element comprising a single functional centromere and two terminal telomeres that, collectively, led to a reduction of the 2n = 58 bovid ancestral acrocentric chromosomal complement to the 2n = 38 detected in the four-horned antelope. PMID- 20204497 TI - Locus of control and self-efficacy: potential mediators of stress, illness, and utilization of health services in college students. AB - Although many studies examine the biological phenomena that mediate the relationship between stress and illness, more research is needed regarding psychological variables that may mediate this relationship. Thus, the current study investigates the mediating effects of locus of control and self-efficacy in the relationships among stress, illness, and the utilization of health services in a sample of 159 college students. Results suggest that participants who endorse higher levels of stress also endorse higher levels of illness, higher levels of external locus of control, and lower levels of self-efficacy. In addition, structural equation modeling suggests that there are direct relationships between stress and illness and between illness and the utilization of health services. Further, locus of control appears to be a partial mediator in the relationship between stress and illness. Given the link established between stress and illness and the individual differences associated with reactions to stressful situations, it is important for future examinations to continue to identify potential mediators of the stress-illness link. PMID- 20204498 TI - Dietary energy availability affects primary and metastatic breast cancer and metformin efficacy. AB - Dietary energy restriction has been shown to repress both mammary tumorigenesis and aggressive mammary tumor growth in animal studies. Metformin, a caloric restriction mimetic, has a long history of safe use as an insulin sensitizer in diabetics and has been shown to reduce cancer incidence and cancer-related mortality in humans. To determine the potential impact of dietary energy availability and metformin therapy on aggressive breast tumor growth and metastasis, an orthotopic syngeneic model using triple negative 66cl4 tumor cells in Balb/c mice was employed. The effect of dietary restriction, a standard maintenance diet or a diet with high levels of free sugar, were tested for their effects on tumor growth and secondary metastases to the lung. Metformin therapy with the various diets indicated that metformin can be highly effective at suppressing systemic metabolic biomarkers such as IGF-1, insulin and glucose, especially in the high energy diet treated animals. Long-term metformin treatment demonstrated moderate yet significant effects on primary tumor growth, most significantly in conjunction with the high energy diet. When compared to the control diet, the high energy diet promoted tumor growth, expression of the inflammatory adipokines leptin and resistin, induced lung priming by bone marrow derived myeloid cells and promoted metastatic potential. Metformin had no effect on adipokine expression or the development of lung metastases with the standard or the high energy diet. These data indicate that metformin may have tumor suppressing activity where a metabolic phenotype of high fuel intake, metabolic syndrome, and diabetes exist, but may have little or no effect on events controlling the metastatic niche driven by proinflammatory events. PMID- 20204499 TI - The predictive value of the 70-gene signature for adjuvant chemotherapy in early breast cancer. AB - Multigene assays have been developed and validated to determine the prognosis of breast cancer. In this study, we assessed the additional predictive value of the 70-gene MammaPrint signature for chemotherapy (CT) benefit in addition to endocrine therapy (ET) from pooled study series. For 541 patients who received either ET (n = 315) or ET + CT (n = 226), breast cancer-specific survival (BCSS) and distant disease-free survival (DDFS) at 5 years were assessed separately for the 70-gene high and low risk groups. The 70-gene signature classified 252 patients (47%) as low risk and 289 (53%) as high risk. Within the 70-gene low risk group, BCSS was 97% for the ET group and 99% for the ET + CT group at 5 years with a non-significant univariate hazard ratio (HR) of 0.58 (95% CI 0.07 4.98; P = 0.62). In the 70-gene high risk group, BCSS was 81% (ET group) and 94% (ET + CT group) at 5 years with a significant HR of 0.21 (95% CI 0.07-0.59; P < 0.01). DDFS was 93% (ET) versus 99% (ET + CT), respectively, in the 70-gene low risk group, HR 0.26 (95% CI 0.03-2.02; P = 0.20). In the high risk group DDFS was 76 versus 88%, HR of 0.35 (95% CI 0.17-0.71; P < 0.01). Results were similar in multivariate analysis, showing significant survival benefit by adding CT in the 70-gene high risk group. A significant and clinically meaningful benefit was observed by adding chemotherapy to endocrine treatment in 70-gene high risk patients. This benefit was not significant in low risk patients, who were at such low risk for recurrence and cancer-related death, that adding CT does not appear to be clinically meaningful. PMID- 20204500 TI - XPD Lys751Gln polymorphism and breast cancer susceptibility: a meta-analysis involving 28,709 subjects. AB - Published data on the association between Xeroderma Pigmentosum complementation group D (XPD) Lys751Gln polymorphism and breast cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Crude ORs with 95% CIs were used to assess the strength of association between them. A total of 30 studies including 14,283 cases and 14,426 controls were involved in this meta-analysis. Overall, significantly elevated breast cancer risk was associated with XPD 751Gln allele when all studies were pooled into the meta-analysis (Lys/Gln vs. Lys/Lys: OR = 1.13, 95% CI = 1.02-1.25; Gln/Gln vs. Lys/Lys: OR = 1.21, 95% CI = 1.06-1.38; dominant model: OR = 1.16, 95% CI = 1.05-1.29; and recessive model: OR = 1.14, 95% CI = 1.02-1.27). In the subgroup analysis by ethnicity, borderline significantly increased risks were found for Caucasians (Lys/Gln vs. Lys/Lys: OR = 1.09, 95% CI = 0.98-1.22; dominant model: OR = 1.10, 95% CI = 0.99-1.22) and significantly increased risks were found for Africans in dominant model (OR = 1.10, 95% CI = 1.04-1.15). When stratified by study design, statistically significantly elevated risk was found in population-based studies (Lys/Gln vs. Lys/Lys: OR = 1.10, 95% CI = 1.01-1.20; Gln/Gln vs. Lys/Lys: OR = 1.15, 95% CI = 1.01-1.31; dominant model: OR = 1.12, 95% CI = 1.03-1.23). In conclusion, this meta-analysis suggests that the XPD 751Gln allele is a low-penetrant risk factor for developing breast cancer. PMID- 20204501 TI - Are there racial/ethnic disparities among women younger than 40 undergoing mammography? AB - While the probability of a woman developing invasive breast cancer at age <40 is low (<1%), mammography use reported among younger women (age <40) is substantial, and varies by race/ethnicity. Little detail is known about mammography use among women aged <40, particularly by race/ethnicity. We describe racial/ethnic differences in: (1) mammography indication after considering underlying risk factors (breast symptoms and family history); (2) follow-up recommendations, and (3) mammography outcomes for first mammograms in women aged <40. These 1996-2005 Breast Cancer Surveillance Consortium data are prospectively pooled from seven U.S. mammography registries. Our community-based sample included 99,615 women aged 18-39 who self-reported race/ethnicity and presented for a first mammogram (screening or diagnostic) with no history of breast cancer. Multivariable analyses controlled for registry site, age, family history of breast cancer, symptoms, and exam year. Overall, 73.6% of the women in our sample were seen for a screening mammogram. Following screening mammography, African American (AA) women were more likely than white women to be recommended for additional workup [relative risk (RR): 1.15 (95% CI: 1.07-1.23)]. Following diagnostic mammography, AA [RR: 1.30 (95% CI: 1.17-1.44)] and Asian [RR: 1.44 (95% CI: 1.26-1.64)] women were more likely to be recommended for biopsy, fine-needle aspiration, or surgical consultation. Depending on race/ethnicity, and considering the rate of true positive to total first screening mammograms of younger women, a women has a likelihood of a true positive of 1 in 363-1,122; she has a likelihood of a false positive of 1 in 7-10. This study of community-based practice found racial/ethnic variability in mammography indication, recommendations, and outcomes among women undergoing first mammography before 40. These findings highlight important areas for future research to understand the motivating factors for these practice patterns and the implications of early mammography use. PMID- 20204502 TI - Penetrance of breast cancer, ovarian cancer and contralateral breast cancer in BRCA1 and BRCA2 families: high cancer incidence at older age. AB - Accurate estimations of lifetime risks of breast and ovarian cancer are crucial for counselling women from BRCA1/2 families. We therefore determined breast and ovarian cancer penetrance in BRCA1/2 mutation families in the northern Netherlands and compared them with the incidence of cancers in the general population in this region. We identified 1188 female mutation carriers and first degree female relatives in 185 families with a pathogenic BRCA1 or BRCA2 mutation. The occurrence of breast cancer, contralateral breast cancer and ovarian cancer was recorded. The cumulative incidence of breast cancer by age 70 was 71.4% (95% CI 67.2-82.4%) in BRCA1 and 87.5% (82.4-92.6%) in BRCA2 mutation carriers. For ovarian cancer at age 70, it was 58.9% (53.5-64.3%) in BRCA1 and 34.5% (25.0-44.0%) in BRCA2 mutation carriers. For breast cancer we saw a rise of 24.2% in the cumulative incidence in the seventh decade for BRCA2 mutation carriers versus 6.3% for BRCA1. For ovarian cancer the rise in the seventh decade was 17.3% for BRCA1 mutation carriers and 15.1% for BRCA2. The 10-year risk for contralateral breast cancer was 34.2% (29.4-39.0%) in BRCA1 families and 29.2% (22.9-35.5%) in BRCA2. We show that the incidence of breast and ovarian cancer in BRCA2 mutation carriers and of ovarian cancer in BRCA1 mutation carriers is still high after 60 years. This may justify intensive breast screening as well as oophorectomy even after age 60. The risk of contralateral breast cancer rises approximately 3% per year, which may affect preventive choices. PMID- 20204503 TI - The association between two polymorphisms of eNOS and breast cancer risk: a meta analysis. AB - Breast cancer is one of the most common malignant tumors worldwide. Endothelial nitric oxide synthase (eNOS) plays a key role in breast cancer development. The associations between the two eNOS polymorphisms (E298D rs1799983, -786T>C rs2070744) and breast cancer risk are inconclusive. A meta-analysis was performed in this study. By searching Medline, ISI Web of Knowledge, ScienceDirect, EBSCO, CNKI, and SinoMed database, six case-control studies were collected for the eNOS E298D polymorphism (3,038 cases and 2,508 controls) and three case-control studies were eligible for the eNOS -786T>C polymorphism. Crude ORs with 95% CIs were used to assess the strength of association between the two eNOS polymorphisms and breast cancer risk. The pooled ORs were performed for codominant model, dominant model, and recessive model, respectively. Overall, significantly decreased risk was observed for E298D (for EE vs. DD: OR = 0.74, 95% CI = 0.59-0.94; for ED vs. DD: OR = 0.78, 95% CI = 0.61-0.98; for dominant model: OR = 0.77, 95% CI = 0.61-0.96) and -786T > C (for TT vs. CC: OR = 0.60, 95% CI = 0.42-0.86; for dominant model: OR = 0.66, 95% CI = 0.47-0.94). In the subgroup analysis by ethnicity, significant decreased risks were found for E298D (for EE vs. DD: OR = 0.75, 95% CI = 0.56-0.99) and -786T>C (for TT vs. CC: OR = 0.53, 95% CI = 0.35-0.81; for dominant model: OR = 0.61, 95% CI = 0.41-0.91; for recessive model: OR = 0.70, 95% CI = 0.55-0.91) among Caucasians; significant decreased risks were observed for E298D (for ED vs. DD: OR = 0.12, 95% CI = 0.02 0.96; for dominant model: OR = 0.13, 95% CI = 0.02-1.00) among Asians. In conclusion, this meta-analysis suggests that both eNOS E298D and -786T>C polymorphisms are associated with reduced breast cancer risk. PMID- 20204504 TI - Is adiponectin a bystander or a mediator in heart failure? The tangled thread of a good-natured adipokine in aging and cardiovascular disease. AB - Adiponectin is an adipose tissue-derived adipokine abundant in human plasma. Increasing evidence from experimental studies suggests that adiponectin plays a protective role in the cardiovascular system. However, epidemiological studies revealed that high levels of adiponectin were associated with increased mortality and severity of congestive heart failure. Furthermore, several prospective studies indicated that high levels of adiponectin were positively correlated with increased total and cardiovascular disease mortality in the elderly. These results are completely opposite to our expectation based on the beneficial effects of adiponectin. Clinical observations demonstrated that plasma adiponectin levels were positively associated with B-type natriuretic peptide levels. Clinical and experimental studies indicated that the administration of atrial natriuretic peptide enhanced adiponectin production. It is still controversial whether increased adiponectin production is a bystander or a key mediator in the development of heart failure. However, recent investigations strongly suggest that increased adiponectin production in patients with heart failure is a part of compensatory mechanisms against oxidative stress and inflammation. In addition, complicated "adiponectin resistance" will accelerate a counter-regulatory increase in adiponectin in patients with advanced heart failure, although direct evidence that patients with heart failure have "adiponectin resistance" is still lacking. Increased adiponectin production might contribute, at least in part, to the metabolic and structural remodeling of the failing heart via activation of AMP-activated protein kinase and induction of cyclooxygenase-2. Further investigation is needed to clarify the exact role of increased adiponectin production under pathophysiological conditions. PMID- 20204505 TI - Endosulfan and its metabolite, endosulfan sulfate, in freshwater ecosystems of South Florida: a probabilistic aquatic ecological risk assessment. AB - Endosulfan is an insecticide-acaricide used in South Florida and is one of the remaining organochlorine insecticides registered under the Federal Insecticide Fungicide and Rodenticide Act by the U.S.EPA. The technical grade material consists of two isomers (alpha-, beta-) and the main environmental metabolite in water, sediment and tissue is endosulfan sulfate through oxidation. A comprehensive probabilistic aquatic ecological risk assessment was conducted to determine the potential risks of existing exposures to endosulfan and endosulfan sulfate in freshwaters of South Florida based on historical data (1992-2007). The assessment included hazard assessment (Tier 1) followed by probabilistic risk assessment (Tier 2). Tier 1 compared actual measured concentrations in surface freshwaters of 47 sites in South Florida from historical data to U.S.EPA numerical water quality criteria. Based on results of Tier 1, Tier 2 focused on the acute and chronic risks of endosulfan at nine sites by comparing distributions of surface water exposure concentrations of endosulfan [i.e., for total endosulfan (summation of concentrations of alpha- and beta-isomers plus the sulfate), alpha- plus beta-endosulfan, and endosulfan sulfate (alone)] with distributions of species effects from laboratory toxicity data. In Tier 2 the distribution of total endosulfan in fish tissue (whole body) from South Florida freshwaters was also used to determine the probability of exceeding a distribution of whole body residues of endosulfan producing mortality (critical lethal residues). Tier 1 showed the majority of endosulfan water quality violations in South Florida were at locations S-178 followed by S-177 in the C 111 system (southeastern boundary of Everglades National Park (ENP)). Nine surface water sampling sites were chosen for Tier 2. Tier 2 showed the highest potentially affected fraction of toxicity values (>10%) by the estimated 90th centile exposure concentration (total endosulfan) was at S-178. At all other freshwater sites there were <5% of the toxicity values exceeded. Potential chronic risk (9.2% for total endosulfan) was only found at S-178 and all other sites were <5%. Joint probability curves showed the higher probability of risk at S-178 than at S-177. The freshwater fish species which contain tissue concentrations of endosulfan (total) with the highest potential risk for lethal whole body tissue residues were marsh killifish, flagfish and mosquitofish. Based on existing surface water exposures and available aquatic toxicity data, there are potential risks of total endosulfan to freshwater organisms in South Florida. Although there are uncertainties, the presence of tissue concentrations of endosulfan in small demersal fish, is of ecological significance since these fish support higher trophic level species, such as wading birds. PMID- 20204506 TI - Light-induced tyrosine phosphorylation of rod outer segment membrane proteins regulate the translocation, membrane binding and activation of type II alpha phosphatidylinositol-5-phosphate 4-kinase. AB - Type II phosphatidylinositol 5-phosphate 4-kinase (PIPKIIalpha) catalyzes the synthesis of phosphatidylinositol-4,5-bisphosphate (PI-4,5-P(2)), an essential lipid second messenger that may be involved in the regulation of phototransduction, neuroprotection, and morphogenesis in the vertebrate retina. Here we report that in rodent and transgenic frogs, the light-mediated activity and membrane binding of PIPKIIalpha in rod outer segments (ROS) is dependent on tyrosine phosphorylation of ROS proteins. The greater type II alpha PIP kinase activity in the light-adapted ROS membrane results from light-driven translocation of PIPKIIalpha from the rod inner segment to ROS, and subsequent binding to the ROS membrane, thus improving access of the kinase to its lipid substrates. These results indicate a novel mechanism of light regulation of the PIPKIIalpha activity in photoreceptors, and suggest that the greater PIPKIIalpha activity in light-adapted animals and the resultant accumulation of PI-4,5-P(2) within the ROS membrane may be important for the function of photoreceptor cells. PMID- 20204507 TI - Expression of the hippocampal NMDA receptor GluN1 subunit and its splicing isoforms in schizophrenia: postmortem study. AB - There is accumulating evidence that disturbances in N-methyl-D: -aspartate receptor (NMDA-R) functioning are associated with the pathogenesis of schizophrenia. To assess actual changes in the expression of the GluN1 subunit and its isoforms, we measured absolute differences in the levels of mRNA/protein for panGluN1 (eight isoforms altogether) as well as the mRNA individual isoforms in the postmortem left/right hippocampus of patients with schizophrenia in comparison with non-psychiatric subjects. There were no significant differences in the panGluN1 subunit mRNA expression, but the absolute left/right differences were much more pronounced in the patients with schizophrenia. Protein levels of the GluN1 subunit in the left hippocampus in male schizophrenic patients were lower than controls. The expression of the NR1-4b isoform was attenuated in the left, whereas the NR1-2b was reduced in the right hippocampus of schizophrenic patients. Isoforms associated with the efficiency of NMDA-induced gene expression and with phosphorylation occurred more commonly in schizophrenic hippocampi. In summary, our study suggests that NMDA-R hypofunction in schizophrenia might be selectively dependent on the dysregulation of GluN1 subunit expression, which exhibits a somewhat different expression in the left/right hippocampus of psychotic patients. PMID- 20204508 TI - Prevalence, risk factors, and distribution of Cysticercus tenuicollis in visceral organs of slaughtered sheep and goats in central Ethiopia. AB - An abattoir survey was conducted to determine the prevalence of Cysticercus tenuicollis, to find out the association between prevalence and potential risk factors as well as to assess the distribution of C. tenuicollis in visceral organs of slaughtered sheep and goats. Out of the total 768 goats and 630 sheep visceral organs inspected, C. tenuicollis was found in 358 goats (46.6%) and 252 sheep (40.0%), respectively. Adult goats (51.8%) and sheep (47.4%) were more infected than kids (41.4%) and lambs (35.8%), respectively. Goats (58.1%) and sheep (46.5%) from highland areas were more infected than goats (35.2%) and sheep (33.8%) from lowland areas. C. tenuicollis was more frequently detected in the omentum of goats and sheep than any other visceral organs. Appropriate control measures need to be introduced to reduce the prevalence of these parasites in small ruminants. PMID- 20204509 TI - Mycobacterium bovis, but also M. africanum present in raw milk of pastoral cattle in north-central Nigeria. AB - Using deletion typing technique, five mycobacteria isolated from unpasteurised milk samples from cows in north-central Nigeria were characterized as Mycobacterium bovis (n = 4) and M. africanum (n = 1). This report emphasizes that transmission between the animal and human reservoir is a serious threat in Nigeria. PMID- 20204510 TI - Isolation and identification of virulent peste des petits ruminants viruses from PPR outbreaks in India. AB - In this study, three outbreaks of peste des petits ruminants (PPR) in goats and sheep flocks with high morbidity and considerable mortality were recorded at Jhansi and Revati in Uttar Pradesh and Bhopal in Madhya Pradesh, India during 2003-2006. Clinical samples were collected from the affected flocks for laboratory investigation. The PPR virus (PPRV) antigen/nucleic acid in the infected tissues/swab materials was demonstrated by using sandwich enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction techniques, and the antibody to PPRV in serum samples was detected by competitive ELISA. The causative agent of the outbreaks, PPRV, was successfully isolated in Vero cells at first passage itself, and its identity was confirmed. The isolated PPR viruses belong to lineage IV based on phylogenetic analysis of partial fusion gene sequences and are closely related to other Asian or Indian PPRV isolates/strains. PMID- 20204511 TI - A randomized trial: are care navigators effective in connecting patients to primary care after psychiatric crisis? AB - Persons with serious mental illnesses suffer excess medical morbidity compared to the general population. This RCT aimed to determine whether navigators are effective in helping patients connect to primary care after psychiatric crisis. Adults presenting for emergency care were randomly assigned to a navigator versus usual care. Navigators facilitated access to primary care. Outcomes were connection rates to medical care and the impact of health insurance, hospitalization and mental health care on primary care attendance. After 1 year, the intervention group was statistically more likely to access care, versus controls (62.4 vs. 37.6%, P < .001). Navigators were effective in helping patients connect to primary care after a psychiatric crisis. Improved access to primary care is important given the complex chronic health problems of this vulnerable cohort. PMID- 20204512 TI - Observations on the flow characteristics of blood flow in arteriovenous fistulae (experimental). AB - Hemodynamic play a very significant role in the pathophysiology of intracranial arteriovenous malformation. The surgical decisions are based on the understanding of the complexities of the flow. Quantification of the abnormal flow is difficult. The mathematical models provide limited information due to the simplicity of the design of these models. Flow of fluid in a tube is very sensitive to small changes in the diameter. We studied the flow characteristics of a fistula by introducing accurately machined acrylic fistulae between the femoral arteries and veins of dogs. The influences of systemic arterial pressure, diameter of the arterial feeders, volume of blood flow, velocity of flow and the diameter of the shunt on the flow of blood across the shunt were studied. Our experiments suggest that the flow characteristics of an arteriovenous fistulae are complex and are influenced by small changes in the diameters of the fistula and the feeding artery. Our model demonstrates the occurrence of the anomalous flow reduction in the fistula and steal phenomenon and is therefore a more realistic representation of the clinical situation. The design of a mathematical model should include the diameter of the fistula if it is intended to replicate the hemodynamic characteristics of an arteriovenous malformation more faithfully. PMID- 20204513 TI - Anterior-posterior impedance cardiography: a new approach to accurate, non invasive monitoring of cardiac function. AB - The conventional impedance cardiogram is a record of pulsatile changes in the electrical impedance of the chest with each heartbeat. The signal seems intuitively related to cardiac stroke volume. However doubts persist about the validity of stroke volume measurements based on electrical impedance. This paper presents a new electrical axis for impedance cardiography that is perpendicular to the conventional head-to-foot axis in an anterior-posterior direction. Dual chest and back electrodes are concentric, permitting tetrapolar technique. A relatively simple analytical model is developed, and this model is validated in a three-dimensional finite element model of current flow through the human chest. Three-dimensional simulations show predictable relationships between the fractional increase in anterior-posterior chest impedance and the ventricular ejection fraction (cardiac stroke volume/ventricular end-diastolic volume). Ejection fraction can be computed accurately with a roughly 30-fold increase in signal level compared to the conventional impedance cardiogram. Breathing causes only modest changes in the signal. When the axis of current flow is optimized, one can interpret the impedance changes during the cardiac cycle with greater confidence as noninvasive, beat-by-beat indicators of ventricular ejection fraction in a wide variety of clinical settings. PMID- 20204514 TI - Toward understanding errors in inpatient psychiatry: a qualitative inquiry. AB - While prior research has identified the impact, nature, and causes of medical error in general medical settings, little is known about errors in inpatient psychiatry. Understanding the broad range of errors that occur in inpatient psychiatry is a critical step toward improving systems of care for a vulnerable patient population. An explorative qualitative analysis of key informant interviews identified a preliminary typology of errors and the contextual factors that precipitate them in inpatient psychiatry. The types of errors and their contextual factors fall broadly within the rubric of categories identified in medicine and surgery. However, many of the specific errors and contextual factors manifest themselves differently and are shaped by the uniqueness of the inpatient psychiatric setting and patient population. Interventions geared toward improving systems of care for psychiatric patients should draw on best practices for safety in medicine and surgery, but also be complemented with new strategies specifically tailored to the inpatient psychiatric setting. PMID- 20204515 TI - Hepatitis B virus infection among refugees resettled in the U.S.: high prevalence and challenges in access to health care. AB - Hepatitis B virus infection (HBV) remains highly endemic in many parts of the world. Refugees resettling in their host countries may carry a significant burden of disease due to HBV and may require long-term medical care. A retrospective descriptive study was conducted to assess the epidemiology of HBV and entry into medical care in refugee communities resettled in the State of Georgia over a five year period: 2003-2007. Among 6,347 refugees (89.7% of those resettled) screened for HBV infection, six hundred and eighty (10.7%) were found to be HBsAg seropositive. Those between the ages of 10-39 years of age contributed to the majority of cases; and most originated from Africa (71%). All HBsAg positive cases were adequately referred to a primary care physician for further management but there are no formal feedback mechanisms in place to learn if those who tested positive for HBsAg accessed the primary healthcare system. HBV infection is a frequent infection among refugees resettled in the US. but their entry into healthcare to treat those with chronic infection is often unknown. Further efforts are required to assure their entry into the healthcare system. Primary care physicians caring for refugee patients should think about verifying HBV infection status as part of health maintenance protocols. PMID- 20204516 TI - Nativity status and mammography use: results from the 2005 National Health Interview Survey. AB - Disparities exist in mammography use based on nativity status. Using the 2005 National Health Interview Survey, we examined the link between nativity status and mammography use in the past 2 years among women (>=40 years) and investigated whether acculturation was associated with mammography use among foreign-born women using multivariate analyses. Foreign-born women were less likely (OR = 0.75; 95% CI = 0.65, 0.87) to report mammography use compared to US born women. After adjusting for selected covariates, results were no longer statistically significant. Foreign-born women (>=65 years) who were not US citizens (i.e. less acculturated) were less likely (OR = 0.17; 95% CI = 0.06, 0.46) to report mammography use compared to naturalized citizens. Based on our findings, mammography use did not differ between US and foreign-born women. Therefore, the disparities in incidence and mortality rates observed between these groups may be due to other factors. PMID- 20204517 TI - Is it useful to have a clear-cut definition of life? On the use of fuzzy logic in prebiotic chemistry. AB - Many scientists, including one of the authors of the present paper, have devoted time to try to find a definition for life (Bersini and Reisse 2007). It is clear that a consensus will never be reached but, more importantly, it seems that the issue itself could be without major interest. It is indeed impossible to define a "natural" frontier between non-living and living systems and therefore also impossible to define dichotomic criteria which could be used in order to classify systems in one of these two classes (living or non-living). Fuzzy logic provides a natural way to deal with problems where class membership lacks sharply defined criteria. It also offers the possibility to avoid losing time with unnecessary controversies such as deciding whether a virus is, or is not, a living system. PMID- 20204518 TI - Defining life: connecting robotics and chemistry. AB - Life is commonly referred as open systems driven by organic chemistry capable to self reproduce and to evolve. The notion of life has also been extended to non chemical systems such as robots. The key characteristics of living systems, i.e. autonomy, self-replication, self-reproduction, self-organization, self aggregation, autocatalysis, as defined in chemistry and in robotics, are compared in a dialogue between a chemist and a robotitian. PMID- 20204519 TI - Software replica of minimal living processes. AB - There is a long tradition of software simulations in theoretical biology to complement pure analytical mathematics which are often limited to reproduce and understand the self-organization phenomena resulting from the non-linear and spatially grounded interactions of the huge number of diverse biological objects. Since John Von Neumann and Alan Turing pioneering works on self-replication and morphogenesis, proponents of artificial life have chosen to resolutely neglecting a lot of materialistic and quantitative information deemed not indispensable and have focused on the rule-based mechanisms making life possible, supposedly neutral with respect to their underlying material embodiment. Minimal life begins at the intersection of a series of processes which need to be isolated, differentiated and duplicated as such in computers. Only software developments and running make possible to understand the way these processes are intimately interconnected in order for life to appear at the crossroad. In this paper, I will attempt to set out the history of life as the disciples of artificial life understand it, by placing these different lessons on a temporal and causal axis, showing which one is indispensable to the appearance of the next and how does it connect to the next. I will discuss the task of artificial life as setting up experimental software platforms where these different lessons, whether taken in isolation or together, are tested, simulated, and, more systematically, analyzed. I will sketch some of these existing software platforms: chemical reaction networks, Varela's autopoietic cellular automata, Ganti's chemoton model, whose running delivers interesting take home messages to open-minded biologists. PMID- 20204520 TI - Defining Life: conference proceedings. PMID- 20204521 TI - A spiritual person. AB - When asked in a questionnaire to describe a spiritual person, William James named one instead: Phillips Brooks. This article focuses on Brooks--his life, his sermons, and his poem "O Little Town of Bethlehem"--to make the case that he exemplified James' view of spirituality as "a susceptibility to ideals, but with a certain freedom to indulge in imagination about them." It also supports Belzen's (Mental Health, Religion & Culture, 12:205-222, 2009) view that there is no spirituality in general but only individual manifestations of it, a point that James' nomination of Brooks implicitly supports. PMID- 20204522 TI - A search for hepatoprotective activity of fruit extract of Mangifera indica L. against oxidative stress cytotoxicity. AB - Mango (Mangifera indica L.) and their components are commonly used in folk medicine for many curative effects. The protective effects of different concentrations of aqueous extract of Mangifera indica L. fruit (Mango Extract) (20, 50 and 100 microg/ml) and also gallic acid (100 microM) as a pure compound in the extract were examined against oxidative stress toxicity induced by cumene hydroperoxide (CHP) in isolated rat hepatocytes. The extracts and gallic acid (100 microM) protected the hepatocyte against all oxidative stress markers including cell lysis, ROS generation, lipid peroxidation, glutathione depletion, mitochondrial membrane potential decrease, lysosomal membrane oxidative damage and cellular proteolysis. Mango Extracts (20, 50 and 100 microg/ml) were more effective than gallic acid (100 microM) in protecting hepatocytes against CHP induced lipid peroxidation. On the other hand gallic acid (100 microM) acted more effective than Mango Extracts (20, 50 and 100 microg/ml) at preventing lysosomal membrane damage. In addition H(2)O(2) scavenging effect of all extracts were determined in hepatocytes and compared with gallic acid (100 microM). There were no significance differences (P<0.05) between all plant extracts and gallic acid (100 microM) in H(2)O(2) scavenging activity. These results suggest a hepatoprotective role for Mango Extract against liver injury associated with oxidative stress. PMID- 20204523 TI - Rapid separation of human globin chains in normal and thalassemia patients by RP HPLC. AB - The present study describes a rapid and sensitive high-performance liquid chromatography (HPLC) method for the detection of human globin chains in blood. The method involves direct injection of globin chains which prepared by a standard method onto a micro bondapack C18 reversed-phase column (7.8 mm I.D.) with UV detection at 280 nm. The detection limit of hemoglobin (Hb) was 0.1 MUg, which is equivalent to about 1 ml of fresh whole blood. We report here the rapid procedure for globin chain analysis. The present method will be useful for the determination of globin chain analysis in clinical laboratories, as well as in thalassemia and sickle cell disease patients. PMID- 20204524 TI - Melanization of appressoria is critical for the pathogenicity of Diplocarpon rosae. AB - Previous studies have shown the role of melanized appressoria in the pathogenicity of various fungi. Diplocarpon rosae is a worldwide outdoor fungal pathogen of rose plants causing black spot disease of rose leaves. To fully understand how this fungus colonizes its host, which is critical for the development of an efficient and sustainable disease management program, we studied the fungal (especially the appressoria) structures of D. rosae in detail at an early stage of infection. Using both microscopic and biochemical analyses, we observed strong melanized appressoria formation localized at the point of D. rosae penetration, which forms the pathogen-plant interface. Treatment of infected plants with melanin biosynthesis inhibitors (MBIs) prevented melanization of D. rosae appressoria and positively correlated with significant reductions in black spot disease symptoms, suggesting that melanization of appressoria might be a critical factor for the pathogenicity of D. rosae. Our findings were confirmed and validated by the lack of melanized appressorial ring formation on an artificial surface and on a D. rosae-non host plant system, Arabidopsis thaliana. Our findings suggest that localized melanization of appressoria is a crucial factor for the pathogenicity of D. rosae and treatment of the fungus with MBIs seems to be a promising disease management alternative for black spot disease of roses. PMID- 20204525 TI - Effect of high hydrostatic pressure on hydration and activity of ribozymes. AB - Formation and stabilization of RNA structure in the cell depends on its interaction with solvent and metal ions. High hydrostatic pressure (HHP) is a convenient tool in an analysis of the role of small molecules in the structure stabilization of biological macromolecules. Analysis of HHP effect and various concentrations of ions showed that water induce formation of the active ribozyme structure. So, it is clear that water is the driving force of conformational changes of nucleic acid. PMID- 20204526 TI - Association of FATP1 gene polymorphisms with chicken carcass traits in Chinese meat-type quality chicken populations. AB - In this study, we aimed to detect the single nucleotide polymorphisms (SNPs) of the chicken FATP1 gene and discern the potential association between FATP1 SNPs and chicken carcass traits. A total of 620 meat-type quality chickens from six commercial pure lines (S01, S02, S03, S05, S06 and D99) and two cross lines (S05 * S01 and S06 * S01) were screened by using the single-strand conformational polymorphism analysis (SSCP) and DNA sequencing. Five SNPs [g.49360G > A, g.48195G > A, g.46847A > G, g.46818A > G, and g.46555A > G] were identified in chicken FATP1 gene. SNP g.46818 A > G was a rare variant and was not considered in the subsequent analysis. Sixteen haplotypes were reconstructed on the basis of the other four SNPs. The linear regression model analysis indicated that there were significant associations of certain diplotypes with part of carcass traits, such as live weight (LW), carcass weight (CW), and semi-eviscerated weight (SEW) (P < 0.05). In particular, diplotype H2H4 had a negative effect on LW, CW, SEW, and abdominal fat weight (AW); diplotype H6H10 had the highest reducing effect on subcutaneous fat thickness (SFT). Our results suggested that FATP1 gene polymorphisms were associated with chicken carcass traits or was linked with the major gene. The SNPs in this gene may be utilized as potential markers for marker assisted selection (MAS) during chicken breeding. PMID- 20204527 TI - A second protein disulfide isomerase plays a protective role against nitrosative and nutritional stresses in Schizosaccharomyces pombe. AB - In the present work, a second gene encoding protein disulfide isomerase (PDI2) was cloned and characterized from Schizosaccharomyces pombe, and its regulation was studied. The structural gene encoding PDI2 was amplified from the genomic DNA using PCR, and ligated into the E. coli-yeast shuttle vector pRS316 to generate the recombinant plasmid pYPDI2. The determined DNA sequence carries 2,578 bp and is able to encode a protein of 726 amino acid sequence with CGAC at the putative active site. The fission yeast cells harboring pYPDI2 contained 1.62- and 2.73 fold higher PDI activity than the control yeast cells in exponential and stationary phases, respectively, indicating that the cloned gene is in vivo functioning. The PDI2 mRNA levels in both vector control and pYPDI2-containing yeast cells were found to be significantly higher in the stationary phase than in the exponential phase, suggesting that expression of the PDI2 gene is under stationary control. The yeast cells harboring pYPDI2 showed enhanced survival on minimal media plates containing nitric oxide (NO)-generating sodium nitroprusside (SNP) and no nitrogen. The synthesis of beta-galactosidase from the PDI2-lacZ fusion gene was markedly enhanced in the Pap1-positive KP1 cells by SNP and nitrogen starvation. However, the enhancement in the synthesis of beta galactosidase from the PDI2-lacZ fusion gene by SNP and nitrogen starvation appeared to be relatively reduced in the Pap1-negative TP108-3C cells than in the Pap1-positive KP1 cells. The PDI2 mRNA level was elevated by SNP and nitrogen starvation in the Pap1-positive cells but not in the Pap1-negative cells. In brief, the S. pombe PDI2 plays a protective role against nitrosative and nutritional stresses, and is positively regulated by NO and nitrogen starvation in a Pap1-dependent manner. PMID- 20204528 TI - Characterization of the specific and sustained GH1 expression induced by rAAV2/1 in normal adult male rats. AB - Our aim was to investigate the long-term effects of intramuscular injection of rAAV2/1-CMV-GH1 viral particles on GH1 expression in normal adult male rats. We found that specific and sustained GH1 expression did not improve muscle exercise performance despite inducing local muscle hypertrophy. Injection of rAAV2/1-CMV GH1 had some systemic effects on the liver and heart and on lipid metabolism in the healthy rats. Serum levels of hGH (human growth hormone), insulin, glucose and leptin increased significantly, which might induce insulin resistance. The serum concentration of IGF-1 (insulin-like growth factor 1), IGF-BP3 (insulin like growth factor binding protein 3) and PIIINP (N-terminal propeptide of type III procollagen) markedly increased at 24 weeks after injection of GH1. In conclusion, GH1 expression driven by AAV2/1 in normal animals did not improve muscle strength but did increase muscle mass and may have systemic effects in healthy animals. PMID- 20204529 TI - A simplified arthropod genomic-DNA extraction protocol for polymerase chain reaction (PCR)-based specimen identification through barcoding. AB - Genomic DNA extraction protocols generally require the use of expensive and hazardous reagents necessary for decontamination of phenolic compounds from the extracts. In addition, they are lengthy, hindering large-scale sample extractions necessary for high-throughput analyses. Here we describe a simple, time and cost efficient method for genomic DNA extraction from insects. The extracted DNA was successfully used in a Polymerase Chain Reaction (PCR), making it suitable for automation for large-scale genetic analysis and barcoding studies. The protocol employs a single purification step to remove polysaccharides and other contaminating compounds using a non-hazardous reagent buffer. In addition, we conducted a bioinformatics database analysis as proof of concept for the efficiency of the DNA extraction protocol by using universal barcoding primers specific for cytochrome c oxidase I gene to identify different arthropod specimens through Barcode of Life Database (BOLD) database search. The usefulness of this protocol in various molecular biology and biodiversity studies is further discussed. PMID- 20204530 TI - Overview of the importance of glycaemic control for cardiovascular events in the in-and out-patient setting. AB - Worldwide prevalence of diabetes mellitus in the adult population is increasing and when explicitly searched within specific groups of patients, as those presenting cardiovascular disease (CVD), dysglycaemia is detected in about three quarters of the patients. Dysglycaemia alone is a major risk factor for microvascular and macrovascular complications that impair quality of life and diminish survival. The coexistence of CVD and dysglycaemia in the same individual increases its cardiovascular risk considerably. Since a significant proportion of dysglycaemic individuals develop vascular damage and the disturbed glucose metabolism remains undetected until the first cardiovascular event, there is imperative need for improved strategies for glucometabolic health assessment and management in patients with CVD. The present review has the aim to discuss the importance of glycaemic control for future cardiovascular events starting from the in-hospital setting and continuing to long-term management based on available literature and recently updated international guidelines. PMID- 20204531 TI - Improved results of a surgical resection for the recurrence of hepatocellular carcinoma after living donor liver transplantation. AB - PURPOSE: This study was designed to analyze the clinical outcomes of the recurrence of hepatocellular carcinoma (HCC) after living donor liver transplantation (LDLT) and to evaluate the efficacy of a surgical resection in treating such a recurrence. METHODS: A total of 101 adult LDLT recipients with HCC between 1996 and 2007, including 17 who had recurrent HCC, were reviewed. The endpoints analyzed were survival from time of transplant and survival from time of recurrence. Recipient demographics, laboratory valuables, and tumor characteristics were analyzed. Any medical or surgical treatments that had been administered for any recurrence also were considered. RESULTS: The mean duration until the initial recurrence after LDLT and the mean duration until death after the initial recurrence were 12.9 months and 12.0 months, respectively. A univariate analysis showed that gender, interferon therapy, early posttransplant tumor recurrence, and eligibility for a surgical resection all had a beneficial impact on survival from tumor recurrence. A surgical resection of tumor relapse was the most important variable in our study, and therefore the patients were divided into two groups: surgical therapy group (n = 9), and nonsurgical therapy group (n = 7). Interestingly, the overall survival rates of the surgical group were significantly better than those of the nonsurgical group and were similar to that of the patients without HCC recurrence. CONCLUSIONS: Surgical therapy might be useful for patients who experience a recurrence of HCC after LDLT to improve their outcome, when such treatment is available. PMID- 20204532 TI - Clinical significance of tumor necrosis factor receptor superfamily member 11b polymorphism in prostate cancer. AB - BACKGROUND: Bone metastases are the most critical complication of prostate cancer (PCa), resulting in severe morbidity and mortality. Tumor necrosis factor receptor superfamily member 11b (TNFRSF11B) is a critical regulator between PCa cells and the bone environment. Recently, TNFRSF11B rs10505346 has been implicated in PCa risk in the Cancer Genetic Markers of Susceptibility genomewide association study. However, the association between this variant and biochemical failure in PCa patients receiving radical prostatectomy (RP) has not been determined. METHODS: Associations of TNFRSF11B rs10505346 with age at diagnosis, preoperative prostate-specific antigen (PSA) level, Gleason score, pathologic stage, surgical margin, and PSA recurrence were evaluated in a cohort of 314 localized PCa patients receiving RP. The prognostic significance on PSA recurrence was assessed by Kaplan-Meier analysis and Cox regression model. RESULTS: The mean level of preoperative PSA and the relative risks of PSA recurrence after RP were lower in individuals with T allele than in those with the G allele at TNFRSF11B rs10505346 (P = 0.019 and 0.014, respectively). The T allele of rs10505346 remained a protective factor against PSA recurrence (P = 0.022) in multivariate Cox regression model after considering all clinicopathological risk factors except PSA level. CONCLUSIONS: Our data suggest that TNFRSF11B rs10505346 is associated with PSA level and might be a prognostic factor for the recurrence of PSA in PCa patients receiving RP. PMID- 20204533 TI - Increased use of percutaneous technique for totally implantable venous access devices. Is it real progress? A 27-year comprehensive review on early complications. AB - BACKGROUND: First implantation of a totally implantable venous access device (TIVAD) was performed in 1982 with surgical technique. Since then, these devices have permitted infusion of total parenteral nutrition, antibiotics, blood products, and, above all, they have definitively changed the quality of life of patients with cancer. However, with the increase of percutaneous procedures, we have assisted with a concomitant raise of immediate postprocedural life threatening complications. The aim of this study was to review the literature during a 27-year period, with regard to the changes of incidence of immediate complications after percutaneous or surgical cutdown for TIVAD's implant. MATERIALS AND METHODS: An extensive search of relevant literature was carried out by using MEDLINE (PubMed) and Google Scholar. We gathered articles from 1982 to 2009 that quoted patient's number, type of pathology, specialist involved, number of devices implanted, site and technique of implantation (surgical cutdown or percutaneous technique), and immediate complications occurrence. RESULTS: A total of 952 reports were screened, and finally only 45 articles addressing all inclusion criteria were used for the present study. A total of 11,430 TIVADs implanted in 11,381 patients were analyzed. Pneumothorax, hemothorax, arterial puncture, and hemoptysis developed only after percutaneous procedures. Atrial fibrillation, hematomas, and malpositioning were more frequent after percutaneous approach. The total amount of immediate complications in patients submitted to percutaneous implant was 4.5%, compared with 0.9% subsequent to cutdown technique. CONCLUSIONS: Despite the increased use of percutaneous technique for TIVADs' implantation, surgical cutdown, because of its safety, remains the best approach to avoid possible fatal immediate complications. PMID- 20204534 TI - The need for pressure changes in CPAP therapy 2-3 months after initial treatment: a prospective trial in 905 patients with sleep-disordered breathing. AB - OBJECTIVE: The aim of the study was to investigate the need for pressure change in patients with sleep-disordered breathing (SDB) several weeks after therapy initiation. We prospectively studied 905 consecutive patients (740 men and 165 women) with SDB and therapeutic intervention with continuous positive airway pressure (CPAP)/bilevel PAP. METHODS: Several weeks after therapy initiation, patients were restudied for control, and pressure was optimized if it was necessary. The differences in CPAP pressure from initial treatment and control night were assessed. Anthropometric data, polysomnography data, Epworth sleepiness scale, and Berlin questionnaire scores were correlated to pressure differences from the first and control titration nights. RESULTS: Pressure change was needed in 511 patients (58.2%). Pressure increase was more frequent than pressure reduction (41.7% vs. 11.7%). Mean pressure increase in CPAP was 1.3 mbar, and mean decrease, 1.6 mbar. In the bilevel PAP group, the mean increase in inspiratory pressure was 1.2 mbar, and in expiratory pressure, 0.8 mbar; the mean decrease in inspiratory pressure was 1.9 mbar, and in expiratory pressure, 1.4 mbar. No correlation was found between anthropometric data, sleep efficacy, the amount of rapid eye movement sleep per night, or questionnaire scores and pressure change. CONCLUSION: Our results show that pressure changes are necessary in the majority of patients several weeks after therapy initiation. Therefore, re evaluation of therapy pressure is useful. PMID- 20204535 TI - Auto bi-level with pressure relief during exhalation as a rescue therapy for optimally treated obstructive sleep apnoea patients with poor compliance to continuous positive airways pressure therapy--a pilot study. AB - BACKGROUND: Continuous positive airways pressure (CPAP) is the accepted therapy for obstructive sleep apnoea (OSA), but compliance is variable. We hypothesised that an auto bi-level device with pressure relief during exhalation (auto bi level) would treat OSA as well as CPAP and that transitioning non-compliant CPAP patients without modifiable causes of poor compliance to this device would improve compliance and clinical outcomes. MATERIALS AND METHODS: OSA patient's on positive airways pressure therapy with compliance below 4 h of use on >=70% of nights over the past 3 months despite having no modifiable causes of poor compliance were transitioned onto an auto bi-level device for 10 weeks. Patients completed an Epworth sleepiness scale and Functional Outcomes of Sleep Questionnaire (FOSQ) at 15 days and 10 weeks and had their compliance and therapy data downloaded. Additionally, patients underwent polysomnography on their auto bi-level device at week 10. RESULTS: Thirty-five patients were included. The apnoea-hypopnoea index, arousal index, sleep efficiency, total sleep time and sleep stage distribution were similar at baseline and week 10. Compliance, excessive daytime sleepiness and several FOSQ domains improved significantly at day 15 and week 10. Patients requiring an effective pressure >=10 cmH(2)0 during the lead-in period on CPAP experienced greater significant improvements compliance than those requiring an effective pressure <10 cmH(2)0. CONCLUSIONS: Auto bi-level with pressure relief during exhalation treats OSA as effectively as CPAP without inducing additional arousals. Transitioning non-compliant CPAP patients without modifiable causes of poor compliance from their CPAP to this new device improves compliance and clinical outcomes over a 10-week period. PMID- 20204536 TI - Tracking abnormal cervical cancer screening: evaluation of an EMR-based intervention. AB - INTRODUCTION: System level barriers have been associated with inadequate follow up of abnormal cervical cytology. OBJECTIVE: The aim of this study was to develop and evaluate an electronic tracking system to improve follow-up of abnormal Pap tests. PROGRAM DESCRIPTION: We implemented an electronic medical record (EMR) based Pap test tracking system at two clinical practices at an inner-city academic health center. The system generated a provider-specific monthly report of all abnormal Pap results, and provided a patient-specific Pap tracking table embedded in the EMR for each subject. EVALUATION: We compared abnormal Pap test follow-up rates for the 24 months pre-intervention with rates 12 months following its implementation (post-intervention). The evaluation followed all subjects for 12 months from the date of their abnormal Pap test, looking for diagnostic resolution. RESULTS: Subjects were young women (mean age = 30.5) of primarily white (42%) and African American (37%) descent, who spoke English (88%). Forty eight percent were insured through publicly subsidized insurance. Controlling for type of abnormality and practice location, the adjusted mean time to resolution decreased significantly from 108 days (confidence interval, CI 105-112 days) in the pre-intervention period to 86 days (CI 81-91 days). CONCLUSION: Our study cannot demonstrate that with follow up, we directly avoided cases of invasive cervical cancer. However, we show that in an at-risk urban population, an automated, EMR-based tracking system reduced the time to resolution, and increased the number of women who achieved diagnostic resolution. PMID- 20204537 TI - From the editors' desk: medicine as a service industry. PMID- 20204538 TI - Cost-effectiveness of strategies to improve HIV testing and receipt of results: economic analysis of a randomized controlled trial. AB - BACKGROUND: The CDC recommends routine voluntary HIV testing of all patients 13 64 years of age. Despite this recommendation, HIV testing rates are low even among those at identifiable risk, and many patients do not return to receive their results. OBJECTIVE: To examine the costs and benefits of strategies to improve HIV testing and receipt of results. DESIGN: Cost-effectiveness analysis based on a Markov model. Acceptance of testing, return rates, and related costs were derived from a randomized trial of 251 patients; long-term costs and health outcomes were derived from the literature. SETTING/TARGET POPULATION: Primary care patients with unknown HIV status. INTERVENTIONS: Comparison of three intervention models for HIV counseling and testing: Model A = traditional HIV counseling and testing; Model B = nurse-initiated routine screening with traditional HIV testing and counseling; Model C = nurse-initiated routine screening with rapid HIV testing and streamlined counseling. MAIN MEASURES: Life years, quality-adjusted life-years (QALYs), costs and incremental cost effectiveness. KEY RESULTS: Without consideration of the benefit from reduced HIV transmission, Model A resulted in per-patient lifetime discounted costs of $48,650 and benefits of 16.271 QALYs. Model B increased lifetime costs by $53 and benefits by 0.0013 QALYs (corresponding to 0.48 quality-adjusted life days). Model C cost $66 more than Model A with an increase of 0.0018 QALYs (0.66 quality adjusted life days) and an incremental cost-effectiveness of $36,390/QALY. When we included the benefit from reduced HIV transmission, Model C cost $10,660/QALY relative to Model A. The cost-effectiveness of Model C was robust in sensitivity analyses. CONCLUSIONS: In a primary-care population, nurse-initiated routine screening with rapid HIV testing and streamlined counseling increased rates of testing and receipt of test results and was cost-effective compared with traditional HIV testing strategies. PMID- 20204539 TI - Intra-aortic mural thrombosis and splenic infarction in association with ulcerative colitis. AB - BACKGROUND: Arterial thrombosis is a very rare, but recognised complication of inflammatory bowel disease that can result in significant morbidity and mortality. CASE PRESENTATION: We present the case of a 48-year-old female with previously well-controlled ulcerative colitis who presented with severe left upper quadrant abdominal pain. Imaging investigations subsequently revealed a large intra-aortic mural thrombus extending into the coeliac axis complicated by splenic infarction. This occurred in the absence of other prothrombotic states such as thrombophilias or vasculitis. CONCLUSION: This case highlights the frequently overlooked association between inflammatory bowel disease and arterial thrombosis. PMID- 20204540 TI - Hypoglycemia, an atypical early sign of hepatocellular carcinoma. AB - BACKGROUND: Hypoglycemia is extremely uncommon as the first presentation of hepatocellular carcinoma, and it occurs predominantly as a paraneoplastic manifestation. METHODS: We report a case of a 38-year-old-man positive for hepatitis B surface antigen with high-serum viremia who presented with symptoms of acute severe hypoglycemia. RESULTS: Laboratory tests confirmed hypoglycemia (serum glucose 1.54 mmol/L) with undetectable serum-C peptide (<0.5 uIU/mL) and slightly increased serum insulin concentration (35 uIU/mL). Alpha-fetoprotein serum level was 75,625 ng/mL. Abdominal ultrasonography and computed tomography revealed a big vascularized mass of 13 cm in diameter occupying most of the right lobe of the liver and an (18)F-fluoro-2-deoxy-D-glucose positron-emission tomography revealed a predominant uptake of glucose by the tumor mass. CONCLUSIONS: These findings indicate that hepatocellular carcinoma-associated hypoglycemia may be due exclusively to increased glucose utilization by the tumor mass. PMID- 20204541 TI - Recurrent differentiation syndrome or septic shock? Unresolved dilemma in a patient with acute promyelocytic leukemia. AB - Differentiation syndrome (DS) is a life-threatening complication observed in patients with acute promyelocytic leukemia (APL) receiving induction therapy with all-trans-retinoic acid (ATRA). A bimodal incidence of DS has been observed, with a majority of cases occurring during the first week of ATRA treatment ("early" DS), but a substantial number of cases occurring during the third or even fourth week of ATRA treatment ("late" DS). However, to our knowledge occurrence of both early and late DS in the same patient has not been reported. We report an APL patient treated with the AIDA regimen, who experienced both early and late DS, a situation where differential diagnosis was difficult. PMID- 20204542 TI - Zoledronic acid and clodronate in the treatment of malignant bone metastases with hypercalcaemia; efficacy and safety comparative study. AB - The aim of this study is to conduct a comparison study between the efficacy and safety of zoledronic acid and clodronate in malignant hypercalcemia secondary to bone metastases in Egyptian adult patients. This is a prospective observational study conducted 80 patients (40 in each group), who were assigned to receive either zoledronic acid (4 mg over a 30 min infusion) every 3-4 weeks or clodronate (a single dose of 1,500 mg over a 4 h infusion) monthly for 3 months. The primary efficacy analysis was the proportion of patients with at least one skeletal-related event. The safety was assessed based on the frequencies of the reported adverse effects as nausea, vomiting, anemia, etc. The calcium level significantly decreased in both groups. At least one skeletal-related event occurred in 15 (37.5%) patients receiving zoledronic acid and 32 (80%) patients receiving clodronate. Radiotherapy and fractures represented the highest event observed in both groups. At least one adverse event was experienced by 20 (50%) patients treated with zoledronic acid, while 26 (65%) patients on clodronate recorded one or more adverse event. Pyrexia was the most commonly reported side effect and flare phenomena. Both treatment groups were comparable regarding the reported adverse events. Both medications did not show any significant nephrotoxicity detected by elevation in the creatinine level. Zoledronic acid and clodronate have demonstrated clinical utility in the treatment of hypercalcaemia in cancer patients. Zoledronic acid provides a more effective and convenient treatment than clodronate, while both maintaining a similar safety profile. PMID- 20204543 TI - Multidrug resistance gene (MDR1) polymorphisms correlate with imatinib response in chronic myeloid leukemia. AB - The human multidrug resistance gene (MDR1, ABCB1) codes for P-glycoprotein (P-gp) that affects the pharmacokinetics of many drugs. MDR1 single nucleotide polymorphisms (SNPs) are associated with drug clearance. Imatinib is a substrate of P-gp-mediated efflux. We investigated the MDR1 T1236C, G 2677T/A, and C3435T polymorphism in 52 patients with chronic myeloid leukemia treated with imatinib. The distribution of MDR1 1236, 2677, or 3435 genotypes was significantly different between the resistance patients and sensitivity patients. The resistance incidence correlated with the number of T alleles at locus 1236 and 3435. Resistance was higher for patients homozygous for the 1236T allele when compared to patients with CT/CC genotype groups (75% vs. 31.3%, P = 0.004). For the G2677T/A polymorphism, a better complete cytogenetic remission was observed for patients with genotype AG/AT/AA, when compared to other genotype groups (TT/GT/GG, P = 0.02). Patients with 3435 TT/CT genotypes showed a higher resistance when compared with patients with CC genotype (59.4% vs. 25%, P = 0.023). In conclusion, determination of 1236T, C3435T, and G2677T MDR1 polymorphisms might be useful in response prediction to therapy with imatinib in patients with CML. PMID- 20204544 TI - Validation of a clinical prognostic model in Chinese patients with metastatic and advanced pretreated non-small cell lung cancer treated with gefitinib. AB - A clinical prognostic model derived from BR.21 trial was established by Florescu et al., which helped to identify a small group of patients with non-small cell lung cancer (NSCLC) who might be less likely to benefit from erlotinib therapy. Whether the prognostic model derived from Caucasian patients treated with erlotinib will be applied to Asian patients treated with gefitinib is still an open question. We reviewed a multi-center clinical trial of Chinese patients with NSCLC treated with gefitinib. The data were collected and analyzed according to the prognostic model reported by Florescu et al. One hundred and nineteen patients were included in the validation study. Twenty-eight patients, 61 patients, 27 patients, and 3 patients were classified into the Low Risk (LR) group, Intermediate Low Risk (ILR) group, Intermediate High Risk/High Risk (IHR/HR) group, respectively. The median overall survival of LR group was not reached, ILR and IHR/HR group was 8.9 months and 4.5 months, respectively. There was a significant difference in overall survival between LR group versus ILR group and IHR/HR group (P = 0.0003 and 0.0001, respectively). While IHR/HR group appeared to have less survival benefit than ILR group, the difference was not statistically significant (P = 0.148). The result has shown a similar effect as that seen by Florescu et al. in differentiating patient risk groups. Our study provides the potential evidence that the prognostic model might be applied to Asian patients with NSCLC treated with gefitinib and helps clinicians to select patients for gefitinib therapy and stratify patients within second-line clinical trials. PMID- 20204545 TI - Postmortem toxicology. AB - Results from toxicological analyses in death investigations are used to determine whether foreign substances were a cause of death, whether they contributed to death, or whether they caused impairment. Drug concentrations are likely to change during pre-terminal stages due to altered pharmacokinetics, to treatment during resuscitation or in the intensive care unit, to concomitant illness or to the presence of drug tolerance. The potential for postmortem changes must be considered in all but a few drugs. Formation of new entities as well as degradation of drugs may occur, especially in putrefied corpses; in addition, body fluids and tissues may be severely affected by autolysis and putrefaction. Specimens should be selected based on individual case history and on their availability. Analytical procedures should be performed in accordance with a proper quality assurance program for toxicological investigations. Problems are most likely to occur during the isolation and identification of a drug. Interpretation of analytical results is often limited by the inadequate information provided in a particular case. PMID- 20204546 TI - Hyperthermia deaths among children in parked vehicles: an analysis of 231 fatalities in the United States, 1999-2007. AB - Motor vehicle-related child hyperthermia fatalities (MVRCHF) have risen slightly in the past decade, but little research has been done investigating the circumstances surrounding MVRCHF. In order to address gaps in our understanding, the current study describes MVRCHF circumstances among children <1-14 years of age in the United States from 1999 to 2007. Three sources were used to identify child hyperthermia death cases in the United States from 1999 to 2007: the Centers for Disease Control and Prevention's Compressed Mortality File (1999 2004), the Golden Gate Weather Service's public MVRCHF database (2003-Present), and an independent internet search. Data about the victim's characteristics and the circumstances surrounding the death were extracted. From 1999 to 2007, 231 MVRCHF were identified. Children were left unattended in >80% of cases, 25% of victims were playing at the time of death, and 60% were male. On average, the core body temperature was 107.2 degrees F after being left inside the vehicle for an average of 4.6 h. The largest number of deaths occurred in the South, followed by the West, Midwest, and Northeast. Parents were found to be accountable for 2/3 of the hyperthermia deaths. The geographic distribution of incidence may be attributable to two major influences: (1) regional climate differences; and (2) population characteristics. The accountability of parents for MVRCHF is likely due to the exposure-risk concept, in which the situation/circumstances increase the injury probability. PMID- 20204547 TI - Sweet eating: a definition and the development of the Dutch Sweet Eating Questionnaire. AB - BACKGROUND: Previous studies have suggested that patients who are defined as so called sweet eaters have more difficulties to lose weight and to maintain weight loss after both conservative treatment and restrictive bariatric surgery, such as gastric banding. There is, however, no agreement on the definition of sweet eating. Also, a questionnaire to measure sweet eating is not available. Therefore, the aim of our study was to agree on a definition of sweet eating and to construct a valid and reliable questionnaire that might be of help to assess the influence of sweet eating on weight loss after bariatric surgery. METHODS: A Delphi Study design was chosen to define sweet eating. Based on the Delphi rounds, a questionnaire with self-reported sweets intake was constructed and validated. RESULTS: Nine experts with different scientific backgrounds participated in the Delphi Study which consisted of four rounds. They finally agreed on the definition that sweet eating can be defined as an eating behavior in which at least 50% of daily consumed carbohydrates consist of simple carbohydrates and which can be triggered by emotional factors (i.e., stress). They did not include the intake of artificial sweeteners in the definition. The Dutch Sweet Eating Questionnaire built on the four Delphi rounds was tested in 138 female patients and appeared to be both valid and reliable. CONCLUSION: A shortcoming of this study is that the results may not be applicable to males and to non-Western populations. The definition and the questionnaire may be useful in future research regarding sweet eating and bariatric surgery outcomes in morbidly obese patients. PMID- 20204548 TI - Oral mucosa patch test: a new tool to recognize and study the adverse effects of dietary nickel exposure. AB - On contact with the skin, nickel may cause allergic contact dermatitis, which can be diagnosed by an epicutaneous patch test. Nickel exposure via the intestinal mucosa can induce diarrhea, abdominal pain, and swelling. The aim of the present study was to investigate the relationship between these symptoms and nickel intake by means of a novel oral mucosa patch test. Eighty-six patients with intestinal symptoms related to ingestion of nickel-containing foods were submitted to epicutaneous and oral mucosa patch tests for nickel. All patients with positive oral mucosa patch test results were subject to a low-nickel diet and monitored over time. Skin lesions were observed in 33 out of 86 (38.4%) patients evaluated by the epicutaneous patch test. Mucosal lesions were seen in 53 out of 86 (61.6%) patients given the oral mucosa patch test. After 2 months of a low-nickel diet, 52 out of 53 (98.1%) patients showed an improvement of their symptoms. There is a significant correlation between response time of the oral mucosa patch test and the latency of symptoms after ingestion of nickel containing foods. Consequently, the oral mucosa patch test can be used to recognize and study the adverse effects of dietary nickel exposure that could be defined as allergic contact mucositis. A low-nickel diet is also shown to be an effective treatment for this condition. PMID- 20204549 TI - Cell wall accumulation of cu ions and modulation of lignifying enzymes in primary leaves of bean seedlings exposed to excess copper. AB - Copper is both a nutrient and an environmental toxin that is taken up by plants. In order to determine the subcellular localization of copper and to assess the resulting metabolic changes, we exposed 14-day-old bean seedlings to nutrient solutions containing varying concentrations of Cu(2+) ions for 3 days. Biochemical analyses revealed that the cell wall was the major site of Cu(2+) accumulation in the leaves of treated plants. Excess copper modified the activity of lignifying peroxidases in both soluble and ionic cell wall-bound fraction. The activity of ionic GPX (guaiacol peroxidase, EC 1.11.1.7) was increased by 50 and 75 uM CuSO4. The activities of both ionic CAPX (coniferyl alcohol peroxidase, EC 1.11.1.4) and NADH oxidase were increased by both copper concentrations tested. While soluble CAPX activity decreased in leaves treated by all copper concentrations tested, the activity of soluble NADH oxidase remained unchanged at 50 uM and was enhanced at 75 uM. Treatment with CuSO4 also increased the abundance of total phenol compounds and induced stimulation in the activity of PAL (phenylalanine ammonia lyase, EC. 4.3.1.5). Using histochemistry in combination with fluorescence microscopy we show that bean leaves from copper exposed plants displayed biochemical and structural modifications reinforcing the cell walls of their xylem tissues. On the other hand, the perivascular fiber sclerenchyma appeared to be less developed in treated leaves. PMID- 20204550 TI - A comparative study of the oxidative profile in Graves' disease, Hashimoto's thyroiditis, and papillary thyroid cancer. AB - The aim of this study was to evaluate and compare the oxidative profiles of three thyroid disorders: Graves' disease (GD), Hashimoto thyroiditis (HT), and papillary thyroid cancer (PTC). Malondialdehyde levels (MDA), glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) activities were examined in the plasma of 52 patients (29 untreated HT, 16 untreated GD, and 7 PTC who underwent surgical therapy). Results were compared with those of 30 healthy controls and among the three groups of patients. The GD, HT, and PTC patients exhibited increased plasma MDA levels and SOD activities compared with the controls (p < 0.05, p < 0.05, and p < 0.001, respectively). CAT activities significantly increased only for the PTC and HT patients (p < 0.001 and p < 0.05, respectively), whereas GPx activities significantly decreased only in the GD and PTC (p < 0.05 and p < 0.01, respectively). The comparison among the three groups of patients has shown increased MDA level and SOD activity for the PTC patients as compared to the GD patients (p < 0.01 and p < 0.001, respectively). Compared with HT, PTC patients exhibited significant higher MDA level, SOD, and CAT activities and a significant lower GPx activity (p < 0.01, p < 0.001, p < 0.05, and p < 0.05, respectively). No significant discrepancies were noted between the GD and HT patients. Our results have clearly shown an oxidative profile that is highly disturbed for the PTC patients as compared to those of autoimmune disorders. Future studies are needed to determine whether or not the oxidative stress has a prognostic value in this pathology. PMID- 20204551 TI - Questionnaire survey of hospitals in Saitama Prefecture regarding the shortage of 99mTc-labeled radiopharmaceuticals and 99Mo/99mTc generators. AB - OBJECTIVE AND METHODS: A questionnaire survey was conducted at all 32 hospitals in Saitama Prefecture to investigate the current difficult situation in terms of nuclear medicine management in the face of the (99m)Tc shortage due to insufficient supply, and 29 hospitals (90.6%) replied. RESULTS: Of the 29, 15 (51.7%) reported a reduction in the number of nuclear medicine studies performed due to the shortage of supply, although the reduction was small. The decrease per month was less than 20 studies in 73% of the institutions. Of the nuclear medicine studies that involve the use of (99m)Tc, the studies whose reduction in number most seriously affected patient management were, in decreasing order: (99m)Tc-MAA lung perfusion scans, (99m)Tc-MAG(3), (99m)Tc-DTPA, or (99m)Tc-DMSA renoscans, (99m)Tc-MDP bone scans, (99m)Tc-HMPAO or ECD brain SPECT studies, (99m)Tc-MIBI or tetrofosmin myocardial SPECT studies, (99m)Tc-radiocolloid sentinel lymphoscintigraphy, (99m)Tc-HSA-D or pyrophosphate bleeding scans, (99m)Tc-GSA hepatic function reserve scans, and (99m)Tc-MIBI parathyroid scans. The reduction is probably ascribable to factors such as cancellations of emergency studies, absence of substitute studies, sequential studies using the same radiopharmaceutical, and higher cost of the syringe-type products than the vial-type products. Substitutes for (99m)Tc studies were performed at 52% (15/29) of the institutions. Myocardial perfusion imaging with (201)Tl chloride was the most common substitute study. CONCLUSIONS: The results of this survey suggested the several procedures to resolve the issues related to the shortage. The staffs at all institutions except one gave the impression that their nuclear medicine ordering systems had been greatly affected by the shortage of supply. This adverse circumstance, however, may provide a good opportunity to educate the public about nuclear medicine studies that use (99m)Tc and SPECT, with which citizen are now unfamiliar. PMID- 20204552 TI - Associations between liver (18)F fluoro-2-deoxy-D-glucose accumulation and various clinical parameters in a Japanese population: influence of the metabolic syndrome. AB - PURPOSE: Liver demonstrates a heterogeneous (18)F fluoro-2-deoxy-D: -glucose ((18)F-FDG) uptake pattern and sometimes shows an abnormally increased uptake even when there is no malignant tissue. The aim of this study was to evaluate the relationships of liver (18)F-FDG uptake as related to physical factors, fatty liver, blood glucose (BG), and other biochemical data. METHODS: (18)F-FDG positron emission tomography (PET) imaging was performed in 101 consecutive subjects for cancer screening. Multiple stepwise regression analysis was used to define the best predictors of the liver standardized uptake value (SUV) among height, weight, waist circumference, body mass index (BMI), systolic and diastolic blood pressure, BG and other biochemical data, i.e., aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase, total cholesterol, high-density lipoprotein cholesterol, triglycerides, total protein, total bilirubin, and alkaline phosphatase. Furthermore, we evaluated the association between liver (18)F-FDG uptake and the metabolic syndrome. RESULTS: The independent factors for increased liver (18)F-FDG uptake (mean SUV > or = 2) were BMI (P < 0.0001), triglycerides (P = 0.0007), and high-density lipoprotein cholesterol (P = 0.0013). Other factors were not significantly associated with liver (18)F-FDG uptake. In addition, the liver (18)F-FDG uptake of metabolic syndrome subjects was significantly higher than that of a non-metabolic syndrome subjects. CONCLUSIONS: BMI was the strongest determinant of liver (18)F-FDG uptake, and the liver (18)F-FDG uptake of metabolic syndrome subjects was significantly higher than that of non-metabolic syndrome subjects. This result suggests that a subject with a high liver (18)F-FDG uptake should be screened for the metabolic syndrome. PMID- 20204553 TI - Rates of pathological underestimation for 9 and 12 gauge breast needle core biopsies at surgical excision. AB - BACKGROUND: The clinical implementation of needle core biopsies has given radiologists an invaluable tool for the diagnostic evaluation of suspicious breast lesions. Despite improvements made to the technology of breast biopsy, the underestimation of disease in tissue samples retrieved continues. This can be attributed to many factors, including variability between different needle gauges. This study was undertaken to assess the pathological underestimation for 9 and 12 gauge breast needle core biopsies at surgical excision. MATERIALS AND METHODS: A retrospective review of image-guided consecutive core needle biopsies performed from 2003 to 2006 yielded a total of 1,201 needle core biopsies: 837 twelve gauge and 364 nine gauge. Further analysis was completed to distinguish needle biopsies whose pathological outcome was underestimated at core needle biopsy when compared to their subsequent surgical excision. Ninety-seven lesions in 88 patients were reviewed and comprise the study cohort. RESULTS: Underestimation was found in 97 needle core procedures in 88 patients. Of the 97, 67 were performed with 12 gauge vacuum-assisted biopsy devices and 30 with 9 gauge vacuum-assisted biopsy devices, resulting in an underestimation rate of 8.00 and 8.24% for 12 gauge and 9 gauge, respectively. The difference in underestimation rate was not statistically significant per Pearson's chi squared test (P = 0.8898). CONCLUSION: In this analysis, the underestimation of needle biopsy results with surgical pathology was found to be 8.00% for the 12 gauge group and 8.24% for the 9 gauge group. These results support our current clinical practice of utilizing either needle gauge. PMID- 20204554 TI - Immunohistochemical expression of epidermal growth factor receptor in breast cancer. AB - BACKGROUND: Molecular-targeting drugs able to treat breast cancer expressing epidermal growth factor receptor (EGFR) would be clinically valuable. The aim of the current study was to determine the further significance of immunohistochemical expression of EGFR in breast cancer. METHODS: The immunohistochemical expression of EGFR was examined in 37 women with breast cancer who had been treated with surgical resection. Relationship of EGFR expression and clinicopathological characteristics was investigated. RESULTS: EGFR expression proved to be comparatively more frequent among triple-negative (estrogen receptor negative, progesterone receptor negative, and human epidermal growth factor receptor 2 negative) breast cancers (P = 0.067). CONCLUSIONS: Knowledge of a patient's immunohistochemical EGFR expression, which could be one of the key molecular findings related to molecular-targeting therapy, might be useful information to treat triple-negative breast cancer. PMID- 20204555 TI - Suspicious calcifications in benign breast lesions: a radio-pathologic correlation. AB - BACKGROUND: Breast cancer screening by mammography (MMG) has recently increased in Japan. Suspicious lesions are therefore being detected more and more by MMG and the number of benign biopsies is increasing. It is thus important to examine which pathologically benign lesions were read as suspicious on MMG to reduce the number of biopsies in the case of benign breast lesions. METHODS: Of 299 category 3 or 4 lesions on MMG, 39 histologically benign lesions with calcification were reviewed and compared with the mammograms by a pathologist and a radiologist. The Japan Mammography Guidelines were used for MMG interpretation. RESULTS: In mastopathy lesions, small round segmental calcifications and pleomorphic clustered calcifications were assessed as suspicious. The suspicious type of calcification in fibroadenoma was small round clustered. The calcifications in fibroadenoma may be seen as small round when the fibroadenoma is rather young, and assessed as suspicious. CONCLUSIONS: Some types of calcifications in mastopathy and fibroadenoma were assessed as borderline by MMG. We should therefore collect data from more benign cases with suspicious calcifications on MMG and elucidate the diagnostic criteria in MMG findings of such calcifications. PMID- 20204556 TI - Pilot study of radiofrequency ablation therapy without surgical excision for T1 breast cancer: evaluation with MRI and vacuum-assisted core needle biopsy and safety management. AB - BACKGROUND: There is increasing demand for minimally invasive treatments for small breast cancer mainly because of the desire for better cosmetic results. Although radiofrequency ablation (RFA) is an attractive approach as a local control method for small breast cancer, the problems of histological effectiveness and safety management remain. METHODS: A total of 29 patients including one patient with bilateral breast cancer were enrolled in this study. The mean tumor size of 30 breasts was 12.8 mm (range 5-19 mm). Under general anesthesia, RFA was performed with a Cool-tip RF system (Valleylab, Boulder, CO, USA) after sentinel lymph node biopsy. Postoperative evaluation with magnetic resonance imaging (MRI) and vacuum-assisted core needle biopsy was done 3-4 weeks after RFA before radiotherapy. Ablated tumors were evaluated with hematoxylin eosin (H&E) and nicotinamide adenine dinucleotide (NADH)-diaphorase staining. If needed, adjuvant chemo and/or endocrine therapy was performed. RESULTS: All patients except one completed one session of RFA. The mean temperature near the center of the tumors was 89.6 degrees C (range 78-100 degrees C). Postoperative MRI showed the ablated zone clearly in all patients. MRI revealed no hypervascularity of the tumors in the ablated zone. Evaluation with H&E staining of the tumors showed remarkable degenerative changes in only three patients. NADH diaphorase staining showed no viable tumor tissue in 24 patients out of 26 examined. Three patients received small diameter grade 3 skin burns, two on the outside of the thigh from the grounding pad and one on the breast skin. One patient had a breast lesion like a chronic granulomatous mastitis resulting from overreaction of the ablated zone. CONCLUSIONS: RFA therapy appeared relevant and applicable for patients with small breast cancer. Because small skin burns were observed as adverse events, close attention should be paid in the course of the RFA procedure. PMID- 20204557 TI - Early experience with a novel nonmetallic cable in reconstructive hip surgery. AB - BACKGROUND: Metallic wires and cables are commonly used in primary and revision THA for fixation of periprosthetic fractures and osteotomies of the greater trochanter. These systems provide secure fixation and high healing rates but fraying, third-body generation, accelerated wear of the bearing surface, and injury to the surgical team remain concerning. QUESTIONS/PURPOSES: We determined the rate of cable failure, union, and complications associated with a novel, nonmetallic cerclage cable in periprosthetic fracture and osteotomy fixation during THA. METHODS: We retrospectively reviewed 29 patients who had primary and revision THAs using nonmetallic cables. Indications for use included fixation of an extended trochanteric osteotomy, intraoperative fracture of the proximal femur, strut allograft fixation, and a Vancouver B1 periprosthetic fracture of the femur. All patients were evaluated clinically and radiographically immediately postoperatively, at 3 weeks, 6 weeks, 3 months, and then annually thereafter. The minimum followup was 13 months (mean, 21 months; range, 13-30 months). RESULTS: Two of the 29 patients (7%) developed a nonunion; all remaining osteotomies, fractures and allografts had healed at the time of most recent evaluation. Four patients (14%) dislocated postoperatively; two were treated successfully with closed reduction, while the other two required reoperation. We identified no evidence of breakage or other complications directly attributable to the cables. CONCLUSIONS: The nonmetallic periprosthetic cables used in this series provided adequate fixation to allow for both osteotomy and fracture healing. We did not observe any complications directly related to the cables. Level of Evidence Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 20204558 TI - Morphologic evaluation of chronic radial head dislocation: three-dimensional and quantitative analyses. AB - BACKGROUND: Treatment of chronic radial head dislocation is controversial, considering whether to reduce and reconstruct the proximal radioulnar joint. The anatomic alteration that influences the decision to reduce the dislocation is not completely understood. QUESTIONS/PURPOSES: We attempted to clarify the changes of the proximal radioulnar joint that occur in chronic radial head dislocations to clarify how they might influence the decision to perform repair. PATIENTS AND METHODS: We evaluated 15 patients with chronic radial head dislocations categorized by duration of "early" (< 3 years) (n = 8) and "longstanding" (> 3 years) (n = 7) groups. We measured the angle and depth of the radial notch of the proximal ulna and evaluated radial head deformity using 3-D bone models created from CT data. RESULTS: For the early group, no differences were observed in the shape of the radial notch between affected and normal sides. For the longstanding group, the radial notch angle was greater on the affected side (mean +/- SD, 45.5 degrees +/- 9.7 degrees ) than on the normal side (29.7 degrees +/- 6.3 degrees ), and the radial notch depth was smaller on the affected side (0.2 +/- 1.6 mm) than on the normal side (2.3 +/- 1.3 mm). The shape of the radial head was nearly normal in the early group, whereas the longstanding group had a dome-shaped deformity. CONCLUSIONS: In longstanding chronic radial head dislocation, deformation develops in the radial head and radial notch of the ulna, which is remodeled in a manner corresponding to the dislocated position of the radial head. LEVEL OF EVIDENCE: Level III, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 20204559 TI - Gender differences in the correlation between symptom and radiographic severity in patients with knee osteoarthritis. AB - BACKGROUND: The effects of gender on the relationship between symptom manifestations and radiographic grades of knee osteoarthritis are not well understood. QUESTIONS/PURPOSES: We therefore determined the increments of symptom progression with regard to radiographic grades of knee osteoarthritis and asked if those increments differed by gender and whether symptom severity was differentially manifested by gender within the same grade. METHODS: We recruited 660 community residents; 368 (56%) women and 292 (44%) men. The mean subject age was 71.5 years (range, 65-91 years). Severity of symptoms was measured using the WOMAC and SF-36 scales, and the radiographic severity using Kellgren-Lawrence grades. Incremental changes in WOMAC and SF-36 scores were compared between adjacent Kellgren-Lawrence grades separately in men and women, and in the overall population. We compared symptom severity between men and women with the same radiographic grade. RESULTS: For the entire cohort, the mean incremental change in symptom severity was not gradual between the adjacent radiographic grades but was greater between Kellgren-Lawrence Grades 1 and 2 and Grades 2 and 3 than between Grades 0 and 1 or Grades 3 and 4. The patterns of incremental changes in symptom severity differed between men and women: women had more severe symptom progression between Kellgren-Lawrence Grades 2 and 3 and Grades 3 and 4 than men. Furthermore, women had worse mean WOMAC and SF-36 scores than men with the same radiographic grade of knee osteoarthritis. CONCLUSIONS: These data suggest symptom progression is not gradual between adjacent radiographic grades, and for the same radiographic grade, symptoms are worse in women. LEVEL OF EVIDENCE: Level III, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 20204561 TI - Role of cannabinoids in the development of fatty liver (steatosis). AB - Emerging evidence suggests that cannabinoids play an important role in the modulation of fatty liver, which appears to be mediated via activation of cannabinoid receptors. Steatogenic agents such as ethanol and high-fat diet can upregulate the activity of cannabinoid 1 (CB1) receptors via increasing synthesis of endocannabinoids, 2-arachidonoylglycerol, and anandamide. CB1 receptors can also be upregulated by obesity. CB1 receptor activation results in upregulation of lipogenic transcription factor, sterol regulatory element-binding protein 1c and its target enzymes, acetyl-CoA carboxylase-1, and fatty acid synthase and concomitantly, downregulation of carnitine palmitoyltransferase-1. This leads to increased de novo fatty acid synthesis as well as decreased fatty acid oxidation, culminating into the development of fatty liver. High-fat diet, in addition to CB1 receptor activation, appears to activate CB2 receptors that may also contribute to fatty liver. In non-alcoholic fatty liver disease, CB2 receptor activation is associated with the development of fatty liver. Cannabis smoking can increase the severity of fatty liver in hepatitis C patients although the precise mechanism is unknown. As the mechanisms involved in endocannabinoid receptor signaling are being increasingly well understood and the biosynthetic regulatory elements elucidated, these present good opportunity for the pharmaceutical scientists to design drugs to treat liver diseases, including steatosis, based on the cannabinoids, endocannabinoids, and related templates. PMID- 20204562 TI - The salvage of knee-exposed prosthesis using neurofasciocutaneous sural flap. AB - Prosthetic exposure is a severe complication of total knee arthroplasty. Many factors are responsible for failed wound healing, and successful salvage of total knee arthroplasty requires early identification of infection, antecedent events related with wound healing failure, aggressive surgical debridement and early appropriate soft-tissue coverage with local skin, fasciocutaneous, muscle, neurocutaneous or perforator flaps. In this report, we present 15 cases of exposed knee prosthesis treated with island sural neurocutaneous flap. Follow-up showed favorable clinical outcomes: all flaps survived and only two cases of hematoma and one of aseptic phystula occurred. According to our results, the island neurofasciocutaneous sural flap represents a sensate reconstructive alternative for providing fine and dependable soft tissue for covering skin defects around the knee. PMID- 20204563 TI - ASNC 2009 plenary session II: the federal government and cardiac imaging. PMID- 20204564 TI - An open-source framework of neural networks for diagnosis of coronary artery disease from myocardial perfusion SPECT. AB - BACKGROUND: The purpose of this study is to develop and analyze an open-source artificial intelligence program built on artificial neural networks that can participate in and support the decision making of nuclear medicine physicians in detecting coronary artery disease from myocardial perfusion SPECT (MPS). METHODS AND RESULTS: Two hundred and forty-three patients, who had MPS and coronary angiography within three months, were selected to train neural networks. Six nuclear medicine residents, one experienced nuclear medicine physician, and neural networks evaluated images of 65 patients for presence of coronary artery stenosis. Area under the curve (AUC) of receiver operating characteristics analysis for networks and expert was .74 and .84, respectively. The AUC of the other physicians ranged from .67 to .80. There were no significant differences between expert, neural networks, and standard quantitative values, summed stress score and total stress defect extent. CONCLUSIONS: The open-source neural networks developed in this study may provide a framework for further testing, development, and integration of artificial intelligence into nuclear cardiology environment. PMID- 20204565 TI - Eighth Annual Mario S. Verani, MD Memorial Lecture: Nuclear cardiology in the era of multimodality cardiac imaging: Can we survive? AB - Nuclear cardiology is the best noninvasive imaging method for measuring myocardial blood flow to diagnose coronary artery disease, assess the risk for adverse cardiac events, and identify long-term cardiac outcome. Our strengths include: reliance on physiology rather than anatomic definition; standardized and efficient techniques that can be performed in large hospitals and academic centers and in small hospitals and outpatient offices; a large body of evidence based supporting clinical data; and profitability. We have defined training; committed to quality improvement through development of guidelines and appropriateness criteria; certified physicians and accredited laboratories; and implemented a strong payer advocacy program. Despite success, we find ourselves under attack for not being relevant within the new paradigm of atherosclerosis, being complacent, being used inappropriately, and exposing patients to radiation. We are facing cuts in reimbursement that will make it nearly impossible to provide services. By failing to develop new radiotracers and techniques, we find ourselves measuring only myocardial perfusion. Advances in echocardiography, cardiovascular magnetic resonance imaging, and computed tomography are providing alternative robust methods and redefining available options for noninvasive cardiovascular imaging. Given the attacks on nuclear cardiology and the existence of alternative methods, we have the option of becoming defensive and protective of our turf, or embracing the opportunity to build on our accomplishments and redefine the new practice of noninvasive cardiovascular imaging. It is in the best interest of nuclear cardiology and patients to pursue the latter course. PMID- 20204566 TI - Osteoinductivity potential of rhBMP-2 associated with two carriers in different dosages. AB - The objective of this study was to evaluate bone formation after application of different doses of recombinant human bone morphogenetic protein-2 (rhBMP-2) combined with monoolein or poloxamer gels, in critical bone defects of rats. Forty-five Wistar rats were divided into nine treatment groups with five animals each: I: application of 1 ug rhBMP-2 + monoolein; II: 3 ug rhBMP-2 + monoolein; III: 7 ug rhBMP-2 + monoolein; IV: 1 ug rhBMP-2 + poloxamer; V: 3 ug rhBMP-2 + poloxamer; VI: 7 ug rhBMP-2 + poloxamer; VII: monoolein only; VIII: poloxamer only; and IX: critical bone defect only. A critical-sized defect of 6 mm diameter was produced in the left parietal bone and it was filled with gels of the above mentioned treatments. After 2 weeks, the calvarial bones were removed for histological processing. Bone formation in the groups that received poloxamer gel and rhBMP-2 was not significantly different from the control group (IX). Groups receiving monoolein and rhBMP-2 (1 and 3 ug) and those that received only the carriers (VII and VIII) had less bone formation in relation to the control. The association of rhBMP-2 to both poloxamer and monoolein did not exhibit any significant differentiation in bone formation in comparison with the control group. PMID- 20204567 TI - Ethanol increases TIEG2-MAO B cell death cascade in the prefrontal cortex of ethanol-preferring rats. AB - Brain cell loss has been reported in subjects with alcoholism. However, the molecular mechanisms are unclear. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and monoamine oxidase B (MAO B) reportedly play a role in cellular dysfunction with regards to ethanol exposure. We have recently reported that GAPDH protein expression was increased in the brains of rats fed with ethanol. Furthermore, GAPDH interacts with the transcriptional activator, transforming growth factor-beta-inducible early gene 2 (TIEG2), to augment TIEG2-mediated MAO B activation, resulting in neuronal cell damage due to ethanol exposure. The current study investigates whether the TIEG2-MAO B cascade is also active in the brains of rats fed with ethanol. Ten ethanol-preferring rats were fed with a liquid diet containing ethanol, with increasing amounts of ethanol up to a final concentration of 6.4% representing a final diet containing 36% of calories for 28 days. Ten control rats were fed the liquid diet without ethanol. The expression of TIEG2 protein, MAO B mRNA levels, MAO B catalytic activity, and the levels of anti-apoptotic protein Bcl 2 and apoptotic protein caspase 3 were determined in the prefrontal cortex of the rats. Ethanol significantly increased protein levels of TIEG2, active caspase 3, MAO B mRNA and enzyme activity, but significantly decreased Bcl 2 protein expression compared to control rats. In summary, ethanol increases the TIEG2-MAO B brain cell death cascade in rat brains, suggesting that the TIEG2-MAO B pathway is a novel pathway for brain cell damage resulting from ethanol exposure, and may contribute to chronic alcohol-induced brain damage. PMID- 20204569 TI - The inception and evolution of a unique masters program in cancer biology, prevention and control. AB - The University of the District of Columbia (UDC) and the Lombardi Comprehensive Cancer Center (LCCC), Georgetown University Medical Center established a Masters Degree Program in Cancer Biology, Prevention and Control at UDC that is jointly administered and taught by UDC and LCCC faculty. The goal of the Masters Degree Program is to educate students as master-level cancer professionals capable of conducting research and service in cancer biology, prevention, and control or to further advance the education of students to pursue doctoral studies. The Program's unique nature is reflected in its philosophy "the best cancer prevention and control researchers are those with a sound understanding of cancer biology". This program is a full-time, 2-year, 36-credit degree in which students take half of their coursework at UDC and half of their coursework at LCCC. During the second year, students are required to conduct research either at LCCC or UDC. Unlike most cancer biology programs, this unique Program emphasizes both cancer biology and cancer outreach training. PMID- 20204570 TI - A pilot study of lay health worker outreach and colorectal cancer screening among Chinese Americans. AB - The research team recruited eight Chinese American (seven females, one male) lay health workers (LHWs). They received 12 h of training about colorectal cancer (CRC), its screening, and basic health education techniques. Each LHW were asked to recruit ten participants and conduct two educational sessions. Of the 81 participants recruited, 73 had not received colorectal cancer screening. Their mean age was 63.0 years, and 72.6% were women. Knowledge of colorectal cancer, its causes, and its screening increased significantly. Receipt of first colorectal cancer screening test increased from 0.0% at baseline to 55.7% for fecal occult blood tests, 7.1% for sigmoidoscopy, and 7.1% for colonoscopy. LHW outreach is feasible and may be effective in promoting CRC screening among Chinese Americans. PMID- 20204571 TI - Physicians' approaches to recommending colorectal cancer screening: a qualitative study. AB - Little is known about strategies that physicians use to encourage receipt of colorectal cancer screening (CRCS). This study conducted focus groups with physicians. Twenty-seven physicians participated in four focus groups. Physicians described four categories of approaches: (1) why screening is important, (2) providing test information, (3) motivational strategies, and (4) tailoring strategies. Participants reported tailoring based on their relationship with a patient, as well as to patient gender, education, and language. Tailoring to cultural background or ethnicity was not prominent. Most physicians reported a typical approach to CRCS and reported some tailoring based on gender, education, and language, but not on ethnicity. PMID- 20204572 TI - "Waiting and the waiting room: how do you experience them?" emotional implications and suggestions from patients with cancer. AB - Waiting can increase discomfort. The goal of this study was to identify moods and fears of cancer patients while in a waiting room and to capture their concrete suggestions for an anthropocentric transformation of waiting itself. A 15-item questionnaire was given to 355 patients who came to our Out-patient Oncology Clinic. Eighty-three percent of patients felt that waiting has an emotional cost, 35% were upset by talking about their condition with others while waiting, and 26% suffered a major emotional impact seeing other sick people and witnessing their clinical decline. Eighty-nine percent of patients suggested that alternative activities, such as meetings with professionals, doctors, and psychologists, be organized during the waiting period; 65% suggested fun activities (music therapy, drawing courses, library, TV). Most patients asked to have the freedom to leave the waiting room. This option, feasibly by means of IMs/"beepers," would limit their sense of having a lack of freedom or being robbed of their time. This study highlighted the complexity and heterogeneity of emotional implications that waiting causes in patients with cancer and collected many patients' suggestions about how to create a constructive, free, and personalized waiting period, overcoming the boredom, distress, and psychological suffering it causes. PMID- 20204573 TI - How do cancer patients navigate the public information environment? Understanding patterns and motivations for movement among information sources. AB - Little is known about how patients move among information sources to fulfill unmet needs. We interviewed 43 breast, prostate, and colorectal cancer patients. Using a grounded theory approach, we identified patterns and motivations for movement among information sources. Overall, patients reported using one source (e.g., newspaper) followed by the use of another source (e.g., Internet), and five key motivations for such cross-source movement emerged. Patients' social networks often played a central role in this movement. Understanding how patients navigate an increasingly complex information environment may help clinicians and educators to guide patients to appropriate, high-quality sources. PMID- 20204574 TI - Community health workers speak out about the Kin KeeperSM model. AB - Community health workers (CHWs) informed students and researcher alike on the Kin Keeper(SM) Cancer Prevention Intervention. Students interested in medicine, guided by faculty, conducted a focus group session with 13 CHWs to find out if the intervention was effective for delivering breast and cervical cancer education. Strengths reported were (1) cultural appropriateness, (2) home visits, (3) CHW resource kits, and (4) increased awareness. The barriers were privacy perceptions and scheduling home visits. Overall, the CHWs indicated that the intervention was effective and flexible enough to accommodate the African American, Latina, and Arab groups of women. PMID- 20204575 TI - Oral and pharyngeal cancer control and early detection. AB - Sixty-four standardized continuing education courses were given for dentists throughout the ten public health districts of the USA to determine if certain behaviors regarding oral and pharyngeal cancer (OPC) control could be modified. Questionnaires were obtained at baseline and at 6 months along with matched control groups. One thousand eight hundred two general dentists participated at baseline and 988 at a 6-month questionnaire follow-up. Analysis of the data indicated that continuing education courses had a positive influence on participants' oral cancer attitudes, knowledge, and behavior that potentially could make a difference on prevention, early detection, and ultimately OPC control. PMID- 20204576 TI - Oral and pharyngeal cancer control through continuing education. AB - A standardized continuing education course was developed to determine if behavior in dental practices could be modified to improve office participation in oral and pharyngeal cancer control through early detection and tobacco-use cessation. PMID- 20204577 TI - Evaluating the impact of pain management (PM) education on physician practice patterns--a continuing medical education (CME) outcomes study. AB - California Assembly Bill AB487 mandates that all practicing physicians are required to obtain 12 h of Continuing Medical Education in Pain Management and End of Life Care before the year 2006 in order to renew their state license to practice medicine. In order to determine the effectiveness of this bill in influencing the practice of medicine, we conducted the first of five planned annual Pain Management seminars and utilized physician questionnaires to determine possible practice changes as a result of this seminar. Eighty-one physicians representing 17 multiple specialties of medicine enrolled in this seminar. The topics included: management of malignant and non-malignant pain, pharmacology and management of side effects of opiate and non-opiate analgesics, and adjunctive therapies including depression management and spirituality issues. Physicians were asked to respond to an immediate post-seminar questionnaire and were subsequently queried 4 months following the conference. Fifty-one out of 81 physician registrants responded to an immediate post-attendance questionnaire, and 31 responded to the 4-month follow-up questionnaire. Responses included: [Please see text]. This audience represents the most motivated group of practitioners electing to receive Pain Management Education long before the mandated deadline. Sixty-seven percent expressed an interest in changing their practice following this intensive educational experience. Ninety percent responding to the follow-up evaluation indicated that their practices had changed, suggesting that this seminar series is effective in altering physician practice patterns (supported by Cancer Center Support Grant CA 33572 and Sarnat Foundation). PMID- 20204578 TI - Evidence for the need of educational programs for cervical screening in rural Tanzania. AB - The Ocean Road Cancer Institute (ORCI) in Tanzania sees about 3,000 new cancer patients annually, 47% of whom have advanced cervical cancer. We interviewed 98 women from the screening clinic and 49 women from the new cancer treatment clinic about their education, income, occupation, residence, medical history, and knowledge about cancer. Women in the screening clinic had higher socioeconomic levels, as shown by more education and employment than women in the new-patient clinic. Patients from the screening clinic were also younger, lived in near ORCI, and had better knowledge of cancer than women from the new-patient treatment clinic. Educational programs focused on the importance of cervical screening in rural remote areas of Tanzania may have a positive impact on the early detection and identification of patients at early disease stages. PMID- 20204581 TI - From Materia Medica to veterinary pharmacology and therapeutics. Introduction. PMID- 20204580 TI - Abacavir/lamivudine fixed-dose combination antiretroviral therapy for the treatment of HIV. AB - In the past 15 years, improvements in the treatment of HIV infection have dramatically reduced morbidity and mortality. Nucleoside reverse transcriptase inhibitors are the backbone of combination antiretroviral therapy for the treatment of HIV. One of the recommended and commonly used therapies in this class is the once-daily fixed-dose combination of abacavir/lamivudine. Clinical studies and practice have shown these drugs to be potent, safe, and easy to use in a variety of settings; however, several recent reports have challenged the safety and efficacy claims among certain patient populations, including those at risk for cardiovascular disease and in those with high viral loads prior to treatment initiation. We reviewed abacavir/lamivudine as a treatment for HIV and discussed limitations of its use due to these controversial issues. PMID- 20204582 TI - Species differences in pharmacokinetics and pharmacodynamics. AB - Veterinary medicine faces the unique challenge of having to treat many types of domestic animal species, including mammals, birds, and fishes. Moreover, these species have evolved into genetically unique breeds having certain distinguishable characteristics developed by artificial selection. The main challenge for veterinarians is not to select a drug but to determine, for the selected agent, a rational dosing regimen because the dosage regimen for a drug in a given species may depend on its anatomy, biochemistry, physiology, and behaviour as well as on the nature and causes of the condition requiring treatment. Both between- and within-species differences in drug response can be explained either by variations in drug pharmacokinetics (PK) or drug pharmacodynamics (PD), the magnitude of which varies from drug to drug. This chapter highlights selected aspects of species differences in PK and PD and considers underlying physiological and patho-physiological mechanisms in the main domestic species. Particular attention was paid to aspects of animal behaviour (food behaviour, social behavior, etc.) as a determinant of interspecies differences in PK or/and PD. Modalities of drug administration are many and result not only from anatomical, physiological and/or behavioural differences across species but also from management options. The latter is the case for collective/group treatment of food-producing animals, frequently dosed by the oral route at a herd or flock level. After drug administration, the main causes of observed inter-species differences arise from species differences in the handling of drugs (absorption, distribution, metabolism, and elimination). Such differences are most common and of greatest magnitude when functions which are phylogenetically divergent between species, such as digestive functions (ruminant vs. non-ruminant, carnivore vs. herbivore, etc.), are involved in drug absorption. Interspecies differences also exist in drug action but these are generally more limited, except when a particular targeted function has evolved, as is the case for reproductive physiology (mammals vs. birds vs. fishes; annual vs. seasonal reproductive cycle in mammals; etc.). In contrast, for antimicrobial and antiparasitic drugs, interspecies differences are more limited and rather reflect those of the pathogens than of the host. Interspecies difference in drug metabolism is a major factor accounting for species differences in PK and also in PD (production or not of active metabolites). Recent and future advances in molecular biology and pharmacogenetics will enable a more comprehensive view of interspecies differences and also between breeds with existing polymorphism. Finally, the main message of this review is that differences between species are not only numerous but also often unpredictable so that no generalisations are possible, even though for several drugs allometric approaches do allow some valuable interspecies extrapolations. Instead, each drug must be investigated on a species-by-species basis to guarantee its effective and safe use, thus ensuring the well-being of animals and safeguarding of the environment and human consumption of animal products. PMID- 20204583 TI - Comparative and veterinary pharmacogenomics. AB - Pharmacogenomics is the study of the impact of genetic variation on drug effects, with the ultimate goal of achieving "personalised medicine". Since the completion of the Human Genome Project, great strides have been made towards the goal of personalised dosing of drugs in people, as exemplified by the development of gene guided dosing of the anticoagulant drug, warfarin. Although the pharmacogenomics of domestic animals is still at an early stage of development, there is great potential for advances in the coming years as the direct result of complete genome sequences currently being derived for many of the species of significance to veterinary and comparative medicine. This sequence information is being used to discover sequence variants in candidate genes associated with altered drug response, as well as to develop whole genome high density single nucleotide polymorphism arrays for genotype-phenotype linkage analysis. This review summarises the current state of veterinary pharmacogenomics research, including drug response variability phenotypes with either known genetic aetiology or strong circumstantial evidence for genetic involvement. Polymorphisms and rarer gene variants affecting drug disposition (pharmacokinetics) and drug effect (pharmacodynamics) are discussed. In addition to providing the veterinary clinician with useful information for the practise of therapeutics, it is envisaged that the increasing knowledge base will also provide a resource for individuals involved in veterinary and comparative biomedical research. PMID- 20204584 TI - Drug delivery systems in domestic animal species. AB - Delivery of biologically active agents to animals is often perceived to be the poor relation of human drug delivery. Yet this field has a long and successful history of species-specific device and formulation development, ranging from simple approaches and devices used in production animals to more sophisticated formulations and approaches for a wide range of species. While several technologies using biodegradable polymers have been successfully marketed in a range of veterinary and human products, the transfer of delivery technologies has not been similarly applied across species. This may be due to a combination of specific technical requirements for use of devices in different species, inter species pharmacokinetic, pharmacodynamic and physiological differences, and distinct market drivers for drug classes used in companion and food-producing animals. This chapter reviews selected commercialised and research-based parenteral and non-parenteral veterinary drug delivery technologies in selected domestic species. Emphasis is also placed on the impact of endogenous drug transporters on drug distribution characteristics in different species. In vitro models used to investigate carrier-dependent transport are reviewed. Species specific expression of transporters in several tissues can account for inter animal or inter-species pharmacokinetic variability, lack of predictability of drug efficacy, and potential drug-drug interactions. PMID- 20204585 TI - Population medicine and control of epidemics. AB - Population medicine is an important component of veterinary care in livestock (farm animals) and companion animals (pets). This chapter covers some of the chemotherapeutic approaches undertaken at population level to control infectious diseases in domestic animals. Optimisation of health, productivity and welfare in livestock commonly entails implementation of whole-herd or whole-flock strategies to effectively counter the negative impact of infectious diseases. Gastro intestinal and liver parasites of grazing cattle and sheep are endemic in most parts of the world and can result in significant production losses. Strategically timed anthelmintic treatments are instituted with the double objective of reducing worm burdens in infected animals and ensuring reduction of pasture contamination with infective larvae. Mastitis is another major endemic problem, particularly in cattle, which causes significant economic losses to dairy farmers globally. As a painful inflammatory condition of the cow's udder, clinical mastitis also raises animal welfare concerns. Prevention of clinical mastitis requires rigorous post-milking hygiene, identification and culling of chronically infected cows, attention to the cow's environment and therapeutic management of udder health during the dry period. A third condition that can cause high levels of morbidity and mortality is bacterial respiratory disease. Pneumonia in young livestock is often exacerbated by stressful transportation and co-mingling of animals from different herds. The welfare consequences and production losses can be significant. Antimicrobial treatment of pneumonic animals and, when appropriate, of in-contact animals living in the same air-space is an integral part of whole-herd respiratory disease management. The role of the veterinary profession is to also ensure that principles of population medicine are understood and adhered to by pet owners. The increase in pet ownership and the importance of the human-animal bond in modern developed societies give rise to zoonotic risks, which require vigilance and intervention. Regular internal parasite control in dogs and cats, particularly in endemic areas, contributes to animal welfare and minimises public health hazards. PMID- 20204586 TI - Interspecies allometric scaling. AB - Lack of approved pharmaceutical agents and very limited pharmacokinetic data in the scientific literature for exotic, wildlife, and zoo species are a major issue for veterinarians treating these species. There are fewer than 15 compounds approved in the United States for zoo and wildlife species compared to nearly 300 drugs licensed for cattle. Zoo veterinarians are therefore required to extrapolate the use of approved agents (veterinary or human) to nonapproved species, often with little or no scientific basis to support drug or dose schedule selection. In general, species differences in drug absorption, metabolism, distribution, and excretion have been well documented for domestic species. However, there has been limited research to provide similar data for nondomestic species. Consequently, with the possible exception of pet bird species, there is little published information on the pharmacokinetic parameters of drugs in nondomestic species. Additionally, because of the commercial value of many zoo species, the traditional method of "trial and error" for drug and dose selection and related compliance issues is often inappropriate. There is an understandable concern, whereby the zoo veterinarian does not wish to be the first to administer an agent or formulation in an untested species. "One medicine" is a central concept in treating zoo species, in that vertebrate species are generally more similar than dissimilar. However, drug absorption can vary within as well as between species. Considering the anatomical differences between true monogastrics (canine and feline species), hind-gut fermentors (rodents, rabbits, horses, and elephants), fore-gut fermentors (Colobus monkeys and kangaroos), and ruminants (cattle, goats, sheep, and antelope), the potential for differences in pharmacokinetic profiles are marked. Moreover, there are potential differences between organisms in a single class. An example is the ability of several snake species to up- and down-regulate their digestive systems. This renders the time course of oral drug absorption dependent on both body temperature and time after feeding. Plasma protein binding may vary considerably between species and may also be temperature dependent. This is very significant when treating poikilothermic (reptiles, amphibians, and fish) species and when conducting pharmacokinetic studies with highly protein-bound drugs. The large body sizes of some zoo species create additional considerations for treatment with drugs and can place significant limitations on delivery of an effective drug dose. PMID- 20204587 TI - Pain and analgesia in domestic animals. AB - The biggest challenge to the use of analgesic agents in animals is the determination of the efficacy of these agents. In humans, the verbal communication of the alleviation of pain is fundamental to the effective use of analgesics. In animals, the lack of verbal communication not only confounds the diagnosis and characterisation of the experience of pain, but also challenges the evaluation of the analgesic therapy. As animals possess the same neuronal pathways and neurotransmitter receptors as humans, it seems reasonable to expect that their perceptions of painful stimuli will be similar, and this is a basis for the use of laboratory animals for screening of analgesics for human use. However, as the evaluation in the laboratory animal tests is based mainly on behavioural responses, and although some physiological responses do occur, it is often difficult to separate these from stress responses. The use of behavioural responses to evaluate analgesics in a range of species is complicated by the fact that different species show different behaviours to a similar pain stimulus, and different pain stimuli produce different pain responses in the same species. Thus behaviours may be species- and pain-specific and this can complicate analgesic evaluation. As most animals possess similar neuronal mechanisms to humans for pain perception, it is not surprising that the standard human pain control strategies can be applied to animals. For instance, local anaesthetics, opioids, non-steroidal anti-inflammatory drugs (NSAIDs), as well as other analgesics used in humans are all found to be effective for animal use. Differences in metabolism and distribution between various species, as well as financial considerations in larger animals can affect efficacy and thus limit their use. In addition, the use of any drug in a species that may be intended for human consumption will be limited by residue considerations. The treatment of pain in animals presents many challenges, but the increasing public concerns regarding animal welfare will ensure that studies into the nature and control of animal pain will continue to have a high profile. PMID- 20204588 TI - New technologies for application to veterinary therapeutics. AB - The purpose of this contribution is to review new technologies and make an educated prediction as to how they will impact veterinary pharmacology over the coming decades. By examining past developments, it becomes evident that change is incremental and predictable unless either a transforming discovery or a change in societal behaviour occurs. In the last century, both discoveries and behaviours have dramatically changed medicine, pharmacology and therapeutics. In this chapter, the potential effects of six transforming technologies on veterinary therapeutics are examined: continued advances in computer technology, microfluidics, nanotechnology, high-throughput screening, control and targeted drug delivery and pharmacogenomics. These should lead to the more efficacious and safer use of existing medicants, and the development of novel drugs across most therapeutic classes through increases in our knowledge base, as well as more efficient drug development. Although this growth in technology portends major advances over the next few decades, economic and regulatory constraints must still be overcome for these new drugs or therapeutic approaches to become common practise. PMID- 20204589 TI - Genetically modified animals and pharmacological research. AB - This chapter reviews the use of genetically modified animals and the increasingly detailed knowledge of the genomes of the domestic species. The different approaches to genetic modification are outlined as are the advantages and disadvantages of the techniques in different species. Genetically modified mice have been fundamental in understanding gene function and in generating affordable models of human disease although these are not without their drawbacks. Transgenic farm animals have been developed for nutritionally enhanced food, disease resistance and xenografting. Transgenic rabbits, goats, sheep and cows have been developed as living bioreactors producing potentially high value biopharmaceuticals, commonly referred to as "pharming". Domestic animals are also important as a target as well as for testing genetic-based therapies for both inherited and acquired disease. This latter field may be the most important of all, in the future development of novel therapies. PMID- 20204590 TI - Antimicrobial drug resistance. AB - This chapter provides an overview of our current understanding of the mechanisms associated with the development of antimicrobial drug resistance, international differences in definitions of resistance, ongoing efforts to track shifts in drug susceptibility, and factors that can influence the selection of therapeutic intervention. The latter presents a matrix of complex variables that includes the mechanism of drug action, the pharmacokinetics (PK) of the antimicrobial agent in the targeted patient population, the pharmacodynamics (PD) of the bacterial response to the antimicrobial agent, the PK/PD relationship that will influence dose selection, and the integrity of the host immune system. Finally, the differences between bacterial tolerance and bacterial resistance are considered, and the potential for non-traditional anti-infective therapies is discussed. PMID- 20204591 TI - Drug residues. AB - The use of veterinary drugs in animal production is necessary for the prevention and treatment of disease; however, such use may result in residues. Regulatory authorities administer legislative frameworks which ensure that foods derived from animals treated with approved veterinary drugs are safe for human consumption. A human food safety evaluation is conducted as follows: it estimates the risk to human health and safety--based on scientific assessment of the available information and data--formulates measures for controlling the risks identified, and communicates the findings and implications of the risk assessment to interested parties. Foods derived from animals are monitored for the presence of drug residues. The reported incidence of illegal residues from these programmes is very low. These findings reassure the public that veterinary drugs are effectively regulated and that food obtained from treated animals does not contain residues that might constitute a health hazard to consumers. Non regulatory organizations, including the veterinary pharmaceutical industry, producer organisations, veterinarians and food processors, all contribute to a safe food supply. The food safety risk analysis framework is continually refined to ensure that the health of all consumers is protected. PMID- 20204592 TI - Veterinary medicines and the environment. AB - Veterinary medicines may be emitted either directly or indirectly into the environment, following its use. As veterinary medicines are biologically active compounds, there is a concern that their occurrence in the environment may have an adverse impact on aquatic and terrestrial organisms. This chapter reviews the major sources by which veterinary medicines enter the environment, the fate, behaviour and occurrence of veterinary medicines in the environment and the potential effects on environmental and human health. Finally, gaps in the current knowledge are identified and recommendations provided on priorities for future research. PMID- 20204593 TI - Veterinary medicines and competition animals: the question of medication versus doping control. AB - In racing and other equine sports, it is possible to increase artificially both the physical capability and the presence of a competitive instinct, using drugs, such as anabolic steroids and agents stimulating the central nervous system. The word doping describes this illegitimate use of drugs and the primary motivation of an equine anti-doping policy is to prevent the use of these substances. However, an anti-doping policy must not impede the use of legitimate veterinary medications and most regulatory bodies in the world now distinguish the control of illicit substances (doping control) from the control of therapeutic substances (medication control). For doping drugs, the objective is to detect any trace of drug exposure (parent drug or metabolites) using the most powerful analytical methods (generally chromatographic/mass spectrometric techniques). This so-called "zero tolerance rule" is not suitable for medication control, because the high level of sensitivity of current screening methods allows the detection of totally irrelevant plasma or urine concentrations of legitimate drugs for long periods after their administration. Therefore, a new approach for these legitimate compounds, based upon pharmacokinetic/pharmacodynamic (PK/PD) principles, has been developed. It involves estimating the order of magnitude of the irrelevant plasma concentration (IPC) and of the irrelevant urine concentration (IUC) in order to limit the impact of the high sensitivity of analytical techniques used for medication control. The European Horserace Scientific Liaison Committee (EHSLC), which is the European scientific committee in charge of harmonising sample testing and policies for racehorses in Europe, is responsible for estimating the IPCs and IUCs in the framework of a Risk Analysis. A Risk Analysis approach for doping/medication control involves three sequential steps, namely risk assessment, risk management, and risk communication. For medication control, the main task of EHLSC in the risk management procedure is the establishment of harmonised screening limits (HSL). The HSL is a confidential instruction to laboratories from racing authorities to screen in plasma or urine for the presence of drugs commonly used in equine medication. The HSL is derived from the IPC (for plasma) or from the IUC (for urine), established during the risk assessment step. The EHSLC decided to keep HSL confidential and to inform stakeholders of the duration of the detection time (DT) of the main medications when screening is performed with the HSL. A DT is the time at which the urinary (or plasma) concentration of a drug, in all horses involved in a trial conducted according to the EHSLC guidance rules, is shown to be lower than the HSL when controls are performed using routine screening methods. These DTs, as issued by the EHSLC (and adopted by the Federation Equestre Internationale or FEI) provide guidance to veterinarians enabling them to determine a withdrawal time (WT) for a given horse under treatment. A WT should always be longer than a DT because the WT takes into account the impact of all sources of animal variability as well as the variability associated with the medicinal product actually administered in order to avoid a positive test. The major current scientific challenges faced in horse doping control are those instances of the administration of recombinant biological substances (EPO, GH, growth factors etc.) having putative long-lasting effects while being difficult or impossible to detect for more than a few days. Innovative bioanalytical approaches are now addressing these challenges. Using molecular tools, it is expected in the near future that transcriptional profiling analysis will be able to identify some molecular "signatures" of exposure to doping substances. The application of proteomic (i.e. the large scale investigation of protein biomarkers) and metabolomic (i.e. the study of metabolite profiling in biological samples) techniques also deserve attention for establishing possible unique fingerprints of drug abuse. PMID- 20204594 TI - [Radiological diagnosis of osteoporosis]. AB - Having at their disposal a wide range of imaging techniques, radiologists play a crucial role in the diagnostic evaluation of patients with osteoporosis. The radiological tests range from dual energy X-ray absorptiometry (DXA), which is the only reference method accepted by the WHO, to conventional radiographs for fracture characterization, to more recent techniques for analyzing trabecular structure, and the findings are decisive in initiating correct management of osteoporosis patients. This review provides an overview of established radiological techniques and an outline of new diagnostic approaches. PMID- 20204596 TI - Strontium ranelate decreases the incidence of new caudal vertebral fractures in a growing mouse model with spontaneous fractures by improving bone microarchitecture. AB - Young mice over-expressing Runx2 fail to gain bone relative to wild type mice with growth and present spontaneous fractures. It allows, for the first time in rodents, direct assessment of anti-fracture efficacy of strontium ranelate which was able to decrease caudal vertebrae fracture incidence through an improvement of trabecular and cortical architecture. INTRODUCTION: The aim was to investigate whether strontium ranelate was able to decrease fracture incidence in mice over expressing Runx2, model of severe developmental osteopenia associated with spontaneous vertebral fractures. METHODS: Transgenic mice and their wild type littermates were treated by oral route with strontium ranelate or vehicle for 9 weeks. Caudal fracture incidence was assessed by repeated X-rays, resistance to compressive loading by biochemical tests, and bone microarchitecture by histomorphometry. RESULTS: Transgenic mice receiving strontium ranelate had significantly fewer new fractures occurring during the 9 weeks of the study ( 60%, p < 0.05). In lumbar vertebrae, strontium ranelate improves resistance to compressive loading (higher ultimate force to failure, +120%, p < 0.05) and trabecular microarchitecture (higher bone volume and trabecular number, lower trabecular separation, +60%, +50%, -39%, p < 0.05) as well as cortical thickness (+17%, p < 0.05). In tibiae, marrow cavity cross-section area and equivalent diameter were lower (-39%, -21%, p < 0.05). The strontium level in plasma and bone was in the same range as the values measured in treated postmenopausal women. CONCLUSIONS: This model allows, for the first time, direct assessment of anti-fracture efficacy of strontium ranelate treatment in rodents. In these transgenic mice, strontium ranelate was able to decrease caudal vertebral fracture incidence through an improvement of trabecular and cortical architecture. PMID- 20204597 TI - Functional data modelling approach for analysing and predicting trends in incidence rates--an application to falls injury. AB - SUMMARY: Policy decisions about the allocation of current and future resources should be based on the most accurate predictions possible. A functional data analysis (FDA) approach improves the understanding of current trends and future incidence of injuries. FDA provides more valid and reliable long-term predictions than commonly used methods. INTRODUCTION: Accurate information about predicted future injury rates is needed to inform public health investment decisions. It is critical that such predictions derived from the best available statistical models to minimise possible error in future injury incidence rates. METHODS: FDA approach was developed to improve long-term predictions but is yet to be widely applied to injury epidemiology or other epidemiological research. Using the specific example of modelling age-specific annual incidence of fall-related severe head injuries of older people during 1970-2004 and predicting rates up to 2024 in Finland, this paper explains the principles behind FDA and demonstrates their superiority in terms of prediction accuracy over the more commonly reported ordinary least squares (OLS) approach. RESULTS: Application of the FDA approach shows that the incidence of fall-related severe head injuries would increase by 2.3-2.6-fold by 2024 compared to 2004. The FDA predictions had 55% less prediction error than traditional OLS predictions when compared to actual data. CONCLUSIONS: In summary, FDA provides more accurate predictions of long-term incidence trends than commonly used methods. The production of FDA prediction intervals for future injury incidence rates gives likely guidance as to the likely accuracy of these predictions. PMID- 20204595 TI - Osteocyte: the unrecognized side of bone tissue. AB - INTRODUCTION: Osteocytes represent 95% of all bone cells. These cells are old osteoblasts that occupy the lacunar space and are surrounded by the bone matrix. They possess cytoplasmic dendrites that form a canalicular network for communication between osteocytes and the bone surface. They express some biomarkers (osteopontin, beta3 integrin, CD44, dentin matrix protein 1, sclerostin, phosphate-regulating gene with homologies to endopeptidases on the X chromosome, matrix extracellular phosphoglycoprotein, or E11/gp38) and have a mechano-sensing role that is dependent upon the frequency, intensity, and duration of strain. DISCUSSION: The mechanical information transmitted into the cytoplasm also triggers a biological cascade, starting with NO and PGE(2) and followed by Wnt/beta catenin signaling. This information is transmitted to the bone surface through the canalicular network, particularly to the lining cells, and is able to trigger bone remodeling by directing the osteoblast activity and the osteoclastic resorption. Furthermore, the osteocyte death seems to play also an important role. The outcome of micro-cracks in the vicinity of osteocytes may interrupt the canalicular network and trigger cell apoptosis in the immediate surrounding environment. This apoptosis appears to transmit a message to the bone surface and activate remodeling. The osteocyte network also plays a recognized endocrine role, particularly concerning phosphate regulation and vitamin D metabolism. Both the suppression of estrogen following menopause and chronic use of systemic glucocorticoids induce osteocyte apoptosis. On the other hand, physical activity has a positive impact in the reduction of apoptosis. In addition, some osteocyte molecular elements like sclerostin, connexin 43, E11/gp38, and DKK1 are emerging as promising targets for the treatment of various osteo-articular pathologies. PMID- 20204598 TI - Race/ethnic differences in bone mineral densities in older men. AB - SUMMARY: BMD was compared across race/ethnic groups. There were substantial race/ethnic differences in BMD even within African or Asian origin. Additional adjustment for body size greatly attenuated or reversed the differences between US Caucasian men vs Asian men. It illustrates the role of body size on the difference between these groups. INTRODUCTION: There is insufficient epidemiologic information about men's bone mineral density (BMD) levels across race/ethnic groups and geographic locations. METHODS: In a cross-sectional design, we compared BMD in older men across seven race/ethnic groups in four countries. Femoral neck, total hip, and lumbar spine BMD were measured in men (age 65 to 78 years) from the Osteoporotic Fractures in Men (MrOS) Study (4,074 Caucasian, 208 African-American, 157 Asian, and 116 Hispanic men in USA), Tobago Bone Health Study (422 Afro-Caribbean men), MrOS Hong Kong Study (1,747 Hong Kong Chinese men), and the Namwon Study (1,079 South Korean men). BMD was corrected according to the cross-site calibration results for all scanners. RESULTS: When compared with US Caucasian men, Afro-Caribbean and African-American men had, respectively, 8-20% and 6-11% higher age-adjusted mean BMD at all three bone sites. Hip BMD was similar in US Caucasian and Hispanic men, US Asian, Hong Kong Chinese, and Korean men had 3-14% lower BMD at all bone sites except femoral neck in Korean men. Additional adjustment for weight and height greatly attenuated or reversed the differences between US Caucasian men vs Asian men including US Asian, Hong Kong Chinese, and South Korean men. Among Asian groups, Korean men had higher femoral neck BMD and lower total hip BMD. CONCLUSION: These findings show substantial race/ethnic differences in BMD even within African or Asian origin and illustrate the important role of body size on the difference between Asian men and others. PMID- 20204599 TI - The hormonal profile of hip fracture female patients differs from community dwelling peers over a 1-year follow-up period. AB - Hormone levels were compared over a 1-year period between elderly women who had sustained a hip fracture and women of similar age and functional ability. Our study suggests progressive hormonal changes that may contribute to severe bone loss during the year following hip fracture. INTRODUCTION: Alterations in hormones affecting the musculoskeletal system may increase risk of hip fracture or poor post-fracture recovery in postmenopausal women. Most studies lack appropriate reference groups, and thus cannot assess the extent to which these alterations are attributable to hip fracture. METHODS: Women aged >=65 years hospitalized for an acute hip fracture (Baltimore Hip Studies, BHS-3; n = 162) were age-matched to 324 women enrolled in the Women's Health and Aging Study I, a Baltimore-based cohort with similar functional status to the pre-fracture status of BHS-3 women. Both studies enrolled participants from 1992 to 1995. Insulin like growth hormone-1 (IGF-1), parathyroid hormone (PTH), 1,25 dihydroxyvitamin D [1,25(OH)2D], and osteocalcin were evaluated at baseline and 2, 6, and 12 months post-fracture, and at baseline and 12 months in the comparison group. Between group differences in trajectories of each hormone were examined. RESULTS: Baseline mean IGF-1 levels were significantly lower in hip fracture patients than the comparison group (75.0 vs. 110.5 MUg/dL; p < 0.001). Levels increased by 2 months post-fracture, but remained significantly lower than those in the comparison group throughout the 12-month follow-up (p < 0.01). Levels of PTH and osteocalcin were similar between groups at baseline, but rose during the year post-fracture to significantly differ from the comparison women (p < 0.001). 1,25(OH)2D levels did not differ between the hip fracture and comparison women at any time. CONCLUSIONS: Older women who have sustained a hip fracture have progressive changes in hormonal milieu that exceed those of women of similar health status during the year following fracture. PMID- 20204600 TI - Comparison of the effects of alendronate sodium and calcitonin on bone-prosthesis osseointegration in osteoporotic rats. AB - Alendronate (ALO) and calcitonin (CT), as commonly used antiosteoporosis drugs in current clinical practice, have been experimentally confirmed to produce the effectiveness of promoting osseointegration at the interface between prosthesis and host bone and enhancing the long-term stability of the prosthesis. Our current study compared these two drugs' effects on the osseointegration of prosthesis and found that both of them could promote bone attachment between prosthesis and host bone; moreover, ALO produced more pronounced effectiveness. INTRODUCTION: A series of findings confirmed that ALO and CT improved bone attachment of implant in animals. However, which one shows stronger effectiveness has not yet been reported by previous researches. Our study compared the effects of the two commonly used antiosteoporosis drugs on the bone-prosthesis osseointegration so as to provide valuable reference for current clinical options of medication. METHODS: Forty female SD rats aged 5 months were randomly set into A, B, C, and D groups. Except for group A, the others were ovariectomized to establish osteoporosis model (lumbar bone mineral density (BMD) decreased by 20% 4 weeks after ovariectomy). All the rats received prosthesis implantation at their tibial plateau. Then, the rats in groups C and D were given ALO (7 mg/kg/w) orally and CT (5 IU/kg/day) subcutaneously for 12 weeks, respectively. Prior to the execution, application of tetracycline hydrochloride for staining in vivo was done. After harvesting and embedding, the tibia with implants were cut into thin slides, then the bone histomorphometry was measured to observe the new bone around prosthesis and to calculate the osseointegration rate of the implants. By comparison, the effect of the two drugs on osseointegration was evaluated. RESULTS: (1) Both ALO and CT can effectively enhance the volume of bone mass surrounding the hydroxyapatite (HA) prosthesis and also significantly lever up osseointegration rate to 63.7% and 45.7%, respectively (p < 0.05). However, ALO produced more periprosthesis osseointegration rate than CT, with difference of 18% (p < 0.05). (2) The rats' lumber BMD increased in both ALO and CT groups, from 0.081 +/- 0.009 and 0.078 +/- 0.009 to 0.116 +/- 0.008 and 0.109 +/- 0.010 g/cm(2), respectively. Moreover, the effect of ALO was observed more pronounced than that of CT. CONCLUSIONS: In osteoporotic conditions, both administration of ALO orally and CT subcutaneously can enhance periprosthesis bone mass and the effects on osseointegration between host bone and prosthesis. Compared with CT, the effect of ALO is more pronounced. PMID- 20204601 TI - Laser 904 nm action on bone repair in rats with osteoporosis. AB - SUMMARY: The aim of the present study was to determine the action of AsGA laser irradiation on bone repair in the tibia of osteopenic rats. The animals were randomly divided into eight experimental groups according to the presence of ovarian hormone (sham group) or the absence of the hormone (OVX group), as well as being irradiated or non-irradiated. Low-level 904-nm laser (50 mJ/cm(2)) accelerated the repair process of osteopenic fractures, especially in the initial phase of bone regeneration. INTRODUCTION: The development of new techniques to speed the process of bone repair has provided significant advances in the treatment of fractures. Some attention recently focused on the effects of biostimulation on bone. METHODS: Forty-eight adult rats were randomly divided into eight experimental groups (six animals in each group) according to the presence of ovarian hormone (sham group) or absence of the hormone (ovariectomized (OVX) group) as well as being irradiated or non-irradiated. For the application of low-level laser therapy, the animals were anesthetized with one third of the dose sufficient to immobilize the animal and irradiated with AsGa laser (904 nm, 50 mJ/cm(2) for 2 s, point form and in contact). The control animals received the same type of manipulation as the irradiated animals, but with the laser turned off. Half of the animals were killed 7 days following the confection of the bone defect, and the other half were killed 21 days after the surgery. After complete demineralization, the tibias were cut cross-sectionally in the central region of the bone defect and embedded in paraffin blocks. The blocks were then cut in semi-seriated slices and stained with hematoxylin and eosin. RESULTS: There was new bone formation in the animals in the OVX group with laser treatment killed after 7 days (p < 0.001). The lowest percentage of bone formation was observed in the OVX without laser killed after 7 days (p > 0.05). All animals killed after 21 days exhibited linear closure of the lesion. CONCLUSION: Low-level 904-nm laser (50 mJ/cm(2)) accelerated the repair process of osteopenic fractures, especially in the initial phase of bone regeneration. PMID- 20204602 TI - Depression, fracture risk, and bone loss: a meta-analysis of cohort studies. AB - Whether depression can increase the risk of bone fractures is uncertain. This meta-analysis, which pooled results from 14 qualifying individual cohort studies, found that depression was associated with a significantly increased risk of fractures and bone loss. INTRODUCTION: The effect of depression on the risk of bone fractures is controversial. We conducted a meta-analysis of prospective studies that examined the risk of osteoporotic fractures and bone loss associated with depression. METHODS: We searched databases and reviewed citations in relevant articles to identify cohort studies that met prestated inclusion criteria; 14 studies were identified. Information on study design, participant characteristics, exposure and outcome measures, control for potential confounders, and risk estimates was abstracted independently by two investigators using a standardized protocol. Data were pooled by use of a random-effects model. RESULTS: In studies that reported fracture outcomes as hazard ratios (HRs) (six studies [n = 108,157]), depression was associated with a 17% increase in fracture risk (HR = 1.17; 95% confidence interval [CI], 1.00-1.36; P = 0.05); in studies that reported risk ratios as fracture outcomes (four studies [n = 33,428]), depression was associated with a 52% increase in risk (risk ratio, 1.52; 95% CI, 1.26-1.85; P < 0.001). In studies that reported bone mineral density as an outcome (five studies [n = 8,931]), depression was associated with a reduced annualized bone loss rate of 0.25% (0.05-0.45%; P = 0.02) at the hip and 0.29% ( 0.07-0.64%; P = 0.11) at the spine. The HR for the three studies (n = 14,777) that did not adjust for antidepressant treatment was 1.30 (95% CI, 1.11-1.52; P = 0.01), and the HR for the three studies (n = 93,380) that did adjust for antidepressant treatment was 1.05 (95% CI, 0.86-1.29; P = 0.6). CONCLUSION: Evidence supports an association between depression and increased risk of fracture and bone loss that may be mediated by antidepressants. PMID- 20204603 TI - Circulating osteocalcin concentrations are associated with parameters of liver fat infiltration and increase in parallel to decreased liver enzymes after weight loss. AB - SUMMARY: The expression of liver genes was associated with insulin action in osteocalcin knockout mice. Our findings suggest that osteocalcin may play a role in the development of insulin resistance-associated fatty liver disease. INTRODUCTION: The expression of insulin target genes was decreased in the liver of mice lacking osteocalcin. We aimed to explore the association of liver enzymes with osteocalcin. METHODS: The associations were evaluated in a cross-sectional study (266 men) and following weight loss in 28 obese subjects (nine male, 19 females). RESULTS: In the cross-sectional study, circulating osteocalcin concentration was negatively associated with alanine transaminase (ALT) (p = 0.002) and aspartate transaminase (AST) levels (p = 0.008). These associations were especially significant in non-obese subjects (n = 191). In a multiple linear regression analysis, age (p = 0.008), insulin sensitivity (p = 0.001), and osteocalcin (p = 0.04) independently contributed to 22% of ALT variance in these latter subjects. In the weight loss study, the increase in circulating osteocalcin concentration (+70.6 +/- 29.3 vs. +32 +/- 13.5%, p = 0.021) was significantly greater in subjects with the highest decrease in ALT levels, despite similar baseline BMI, insulin resistance and degree of weight loss than remaining subjects. In fact, the change in ALT levels were linearly associated with those of osteocalcin (r = -0.55, p = 0.003). CONCLUSIONS: In summary, our findings suggest a bone-liver axis in which osteocalcin might be the active regulator. PMID- 20204604 TI - Effect of calcium and vitamin D supplementation on bone mineral density in women aged 65-71 years: a 3-year randomized population-based trial (OSTPRE-FPS). AB - SUMMARY: The Osteoporosis Risk Factor and Prevention-Fracture Prevention Study (OSTPRE-FPS) was a randomized population-based open trial (n = 593). The supplementation group (n = 287) received daily cholecalciferol 800 IU + calcium 1,000 mg for 3 years while the control group (n = 306) received neither supplementation nor placebo. Daily vitamin D and calcium supplementation have a positive effect on the skeleton in ambulatory postmenopausal women. INTRODUCTION: vitamin D deficiency is common in the elderly, and vitamin D levels are associated with low bone mineral density (BMD). The working hypothesis was that vitamin D and calcium supplementation could prevent bone loss in ambulatory postmenopausal women. METHODS: the OSTPRE-FPS was a randomized population-based open trial with a 3-year follow-up in 3,432 women (aged 66 to 71 years). A randomly selected subsample of 593 subjects underwent BMD measurements. The supplementation group (n = 287) received daily cholecalciferol 800 IU + calcium 1,000 mg for 3 years while the control group (n = 306) received neither supplementation nor placebo. RESULTS: in the intention-to-treat analysis, total body BMD (n = 362) increased significantly more in the intervention group than in the control group (0.84% vs. 0.19%, p = 0.011). The BMD change differences at the lumbar spine (p = 0.372), femoral neck (p = 0.188), trochanter (p = 0.085), and total proximal femur (p = 0.070) were statistically nonsignificant. Analyses in compliant women (>= 80% of use) resulted in stronger and statistically significant effects at the total body and femoral regions. CONCLUSION: daily vitamin D and calcium supplementation have a positive effect on the skeleton in ambulatory postmenopausal women with adequate nutritional calcium intake. PMID- 20204607 TI - The effect of voluntary lateral trunk bending on balance recovery following multi directional stance perturbations. AB - Stabilising shifts of the centre of mass (COM) are observed during balance recovery when subjects simultaneously execute voluntary unilateral knee flexion or unilateral arm raising. Here, we examined whether voluntary lateral trunk bending provided more beneficial stabilising effects, and how motor programs of balance corrections are combined with those of the focal voluntary action. The upright balance of 24 healthy young subjects (19-33 years of age) was perturbed using multi-directional rotations of the support-surface. The perturbations consisted of combined pitch and roll rotations (7.5 degrees and 60 degrees/s) presented randomly in six different directions. Three conditions were tested: perturbation of stance only (PO); combined balance perturbation and cued uphill bending of the trunk (CONT); and combined perturbation and cued downhill bending of the trunk (IPS). For comparison, subjects were required to perform trunk bending alone (TO). Outcome measures were biomechanical responses and surface EMG activity of several muscles. Calculated predicted outcomes (PO + TO) were compared with combined measures (CONT or IPS). CONT trunk bending uphill showed two phases of benefit in balance recovery for laterally but, in contrast to voluntary knee bending, not for posterior directed components of the perturbations. IPS trunk bending had negative effects on balance. Early balance correcting muscle responses were marginally greater than PO responses. Prominent secondary balance correcting responses, having a similar timing as voluntary responses observed under TO conditions, were seen under CONT only in trunk muscles. These, and later stabilising, responses had amplitudes as expected from PO + TO conditions being significantly greater than PO responses. The ability with which different muscle synergies for balance corrections and voluntary trunk bending were integrated into one indicates a flexible adjustment of the CNS programs to the demands of both tasks. PMID- 20204605 TI - To investigate the role of the nervous system of bone in steroid-induced osteonecrosis in rabbits. AB - SUMMARY: Glucocorticoid treatment frequently causes osteonecrosis of the femoral head. The precise mechanism in the pathogenesis of osteonecrosis remains highly controversial. Normal bone metabolism requires a coordinated interaction between the sensory/sympathetic nervous system and cells within the bone tissue. So we speculated that neural lesions may be involved in osteonecrosis. OBJECTIVE: using a rabbit model, we investigated the relationship between neural factors and steroid-induced osteonecrosis of the femoral head. METHODS: Japanese white rabbits weighing about 3.5 kg each were injected with a single intramuscular dose of methylprednisolone 4 mg/kg and then divided into three groups (groups A, B and C) consisting of 15 rabbits each. The rabbits of group A were killed after 3 days, those of group B after 1 week, and those of group C after 2 weeks. As a control group, 10 rabbits (group N) were fed under the same conditions but did not receive a steroid injection. An immunohistochemical study of the femoral heads was conducted using the monoclonal antibodies CGRP, SP, VIP, NPY and NGF. Also, using the software Image Pro Plus, the areas showing positive immunoreactivity in each group were calculated and the four groups were compared. RESULTS: significant changes were seen in the expression of CGRP, SP, VIP and NPY nerve fibres and of NGF immunoreactivity in the subchondral bone of the femoral head and these changes were associated with the process of osteonecrosis. Furthermore, CGRP, SP, NPY and NGF (but not VIP) showed marked changes in expression 1 week after steroid administration, and this is the time when osteonecrosis is thought to occur in this model. CONCLUSION: This study showed that osteonecrosis in rabbits is chronologically associated with changes in neural factors. PMID- 20204608 TI - Probing the mechanism of saccade-associated head movements through observations of head movement propensity and cognition in the elderly. AB - Humans may accomplish gaze shifts by eye-only saccades or combined eye-head saccades. The mechanisms that determine whether the head moves remain poorly understood. Many observations can be explained if phylogenetically ancient circuits generate eye-head saccades by default and frontal cerebral structures interrupt this synergy when eye-only saccades are preferable. Saccade-associated head movements have been reported to increase in the elderly. To test the hypothesis of frontal inhibition of head movements, we investigated whether the increase is associated with a decline in frontal cognitive function. We measured head movement tendencies and cognition in volunteers aged 61-80. Measures of head movement tendency included the customary range of eye eccentricity, customary range of head eccentricity, range of target eccentricities evoking predominantly eye-only saccades, and two measures of head amplitude variation as a function of target eccentricity. Cognitive measures encompassed verbal fluency, verbal memory, non-verbal memory, and executive function. There was no correlation between cognition and any measure of head movement tendency. We combined these elderly data with measurements of head movements in a group aged 21-67 and found mildly reduced, not increased, head movement tendencies with age. However, when confronted with a task that could be accomplished without moving the head, young subjects were more likely to cease all head movements. While inconclusive regarding the hypothesis of inhibition of saccade-associated head movements by cerebral structures, the results indicate the need to distinguish between mechanisms that define head movement tendencies and mechanisms that adapt head motion to the geometry of a specific task. PMID- 20204609 TI - Preproenkephalin (Penk) is expressed in differentiated osteoblasts, and its deletion in Hyp mice partially rescues their bone mineralization defect. AB - Although our understanding of the molecular mechanisms controlling osteoblast differentiation and function is steadily increasing, there are still many open questions, especially regarding the regulation of bone matrix mineralization. For instance, while there is hallmark evidence for the importance of the endopeptidase Phex, whose inactivation in Hyp mice or human patients causes X linked hypophosphatemic rickets, it is still largely unknown how Phex controls bone mineralization since a physiological substrate for its endopeptidase activity has not been identified yet. Using a genome-wide expression analysis comparing primary calvarial osteoblasts, we have identified preproenkephalin (Penk) as a gene that is selectively expressed in mineralized cultures. Since a role of enkephalin in the regulation of bone remodeling has been suggested previously and since Leu-enkephalin is known to be cleaved by Phex, we analyzed whether Penk expression in osteoblasts is physiologically relevant. Through skeletal analysis of a Penk-deficient mouse model, we found that Penk expression is dispensable for bone development and remodeling since we could not detect any defect following nondecalcified bone histology and histomorphometry compared to wild-type littermates. When Penk was deleted in Phex-deficient Hyp mice, however, we observed a significant reduction of the osteoid enrichment at 24 weeks of age, whereas their disturbance of mineral homeostasis was not affected by the additional absence of the Penk gene. Taken together, our data provide the first in vivo analysis concerning the role of Penk in osteoblasts. PMID- 20204610 TI - The rate of unequal crossing over in the dumpy gene from Drosophila melanogaster. AB - The PIGSFEAST (PF) exon of the Drosophila dumpy gene is undergoing concerted evolution by the process of unequal crossing over. We have developed a long-range PCR-based assay to amplify the approximately 12 kb long exon which contains variable numbers of 303 or 306 nt long repeats in a tandem array. We applied this procedure to mutation accumulation lines of Drosophila melanogaster established by M. Wayne and L. Higgins. Nine new repeat length variants were found in these lines allowing us to measure the rate of unequal crossing over in the PF exon. The rate, which for several reasons is an underestimate, is 7.05 x 10(-4) exchanges per generation. PMID- 20204611 TI - Use and accuracy of US guidance for image-guided injections of the temporomandibular joints in children with arthritis. AB - BACKGROUND: Juvenile idiopathic arthritis (JIA) has an incidence that ranges from 1 to 22 per 100,000 children worldwide, with involvement of the temporomandibular joint (TMJ) in 17-87% of patients. Intraarticular corticosteroid injections are beneficial in the local treatment of JIA and of other types of arthritis. OBJECTIVE: To describe and assess the accuracy of an US-guided technique for visualization of needle placement within the TMJ in children. MATERIALS AND METHODS: Between January 2000 and November 2007, 180 TMJ injections were performed during 116 encounters in 83 children with arthritis (71 girls, 12 boys; mean age 12.0 years). Access was obtained under sterile conditions using US guidance (linear 15-MHz or curvilinear 8-MHz transducers) in a coronal plane, and confirmed with CT. To minimize radiation, a limited focused CT protocol was developed. RESULTS: A bilateral injection was performed in 65 encounters (57%). Twenty-three children had repeat TMJ injections. All injections were performed using US guidance. CT confirmation was used in 127/180 TMJs (70%). In those confirmed with CT, the needle tip was intra-articular in 91% of cases. Triamcinolone hexacetonide was used in 92% of injections and triamcinolone acetonide in 8%. One major complication was encountered (skin atrophy at the injection site). CONCLUSION: In our experience, TMJ injections using sonographic guidance is a safe, effective and accurate procedure. PMID- 20204612 TI - The mosaic of KIR haplotypes in rhesus macaques. AB - To further refine and improve biomedical research in rhesus macaques, it is necessary to increase our knowledge concerning both the degree of allelic variation (polymorphism) and diversity (gene copy number variation) in the killer cell immunoglobulin-like receptor (KIR) gene cluster. Pedigreed animals in particular should be studied, as segregation data will provide clues to the linkage of particular KIR genes/alleles segregating on a haplotype and to its gene content as well. A dual strategy allowed us to screen the presence and absence of genes and the corresponding transcripts, as well as to track differences in transcription levels. On the basis of this approach, 14 diverse KIR haplotypes have been described. These haplotypes consist of multiple inhibitory and activating Mamu-KIR genes, and any gene present on one haplotype may be absent on another. This suggests that the cost of accelerated evolution by recombination may be the loss of certain framework genes on a haplotype. PMID- 20204613 TI - Short template amplicon and multiplex megaprimer-enabled relay (STAMMER) sequencing, a simultaneous approach to higher throughput sequence-based typing of polymorphic genes. AB - Sequence-based typing (SBT) is a powerful method of genotyping in highly polymorphic gene systems. In standard SBT methods, both strands of a double stranded template amplicon are sequenced in separate reactions in order to achieve high quality data across the region of interest. The amount of informative data that is obtained from the second strand sequence is often low, whilst the impact of performing second strand sequencing on costs and throughput are significant. Here we present short template amplicon and multiplex megaprimer enabled relay (STAMMER) sequencing, a novel simultaneous sequence-based typing methodology that allows the detection of any practical amount of useful sequence from a plurality of distinct polymerase chain reaction products in a single sequencing reaction. In addition to simultaneous bidirectional sequencing, we show how the STAMMER approach can be used to simultaneously sequence a number of regions of interest that are not physically linked within the range of a single sequencing reaction. The efficiencies of this method could impact significantly on the output of SBT laboratories. PMID- 20204614 TI - Searching for monooxygenases and hydrolases in bacteria from an extreme environment. AB - Microbial oxidation potentials of extremophiles recovered from Pampo Sul oil field, Campos Basin, Brazil, in pure culture or in consortia, were investigated using high-throughput screening (HTS) and multibioreactions. Camphor (1), cis jasmone (2), 2-methyl-cyclohexanone (3), 1,2-epoxyoctane (4), phenylethyl acetate (5), phenylethyl propionate (6), and phenylethyl octanoate (7) were used to perform multibioreaction assays. Eighty-two bacterial isolates were recovered from oil and formation water samples and those presenting outstanding activities in HTS assays were identified by sequencing their 16S rRNA genes. These results revealed that most microorganisms belonged to the genus Bacillus and presented alcohol dehydrogenase, monooxygenase, epoxide hydrolase, esterase, and lipase activities. PMID- 20204615 TI - Chemoinformatics-assisted development of new anti-biofilm compounds. AB - Bacterial biofilms are associated with a large number of infections. Biofilm dwelling bacteria are particularly resistant to antibiotics, making it hard to eradicate biofilm-associated infections. Here, we use a novel cross-disciplinary approach combining microbiology and chemoinformatics to identify new and efficient anti-biofilm drugs. We found that ellagic acid (present in green tea) significantly inhibited biofilm formation of Streptococcus dysgalactiae. Based on ellagic acid, we performed in silico screening of the Chinese Natural Product Database to predict a 2nd-generation list of compounds with similar characteristics. One of these, esculetin, proved to be more efficient in preventing biofilm formation by Staphylococcus aureus. From esculetin a 3rd generation list of compounds was predicted. One of them, fisetin, was even better to abolish biofilm formation than the two parent compounds. Fisetin dramatically inhibited biofilm formation of both S. aureus and S. dysgalactiae. The compounds did not affect planktonic growth in concentrations where they affected biofilm formation and appeared to be specific antagonists of biofilms. Arguably, since all three compounds are natural ingredients of dietary plants, they should be well-tolerated by humans. Our results indicate that such small plant components, with bacterial lifestyle altering properties are promising candidates for novel generations of antimicrobial drugs. The study underlines the potential in combining chemoinformatics and biofilm research. PMID- 20204616 TI - The culture of mouse embryonic stem cells and formation of embryoid bodies. AB - Embryonic stem (ES) cells are pluripotent cells isolated from the inner cell mass of the pre-implantation blastocyst. They have the capacity to undergo indefinite rounds of self-renewing cell division and differentiate into all the cell lineages of the developing embryo. In suspension culture, ES cells will differentiate into aggregates known as embryoid bodies in a manner similar to the early embryo. This culture system therefore provides a useful model to study the relatively inaccessible stages of mammalian development. We describe methods for the routine maintenance of mouse embryonic stem cells in culture, assays of stem cell self-renewal potential in monolayer culture and the generation of embryoid bodies to study differentiation pathways. PMID- 20204617 TI - Derivation of primary mouse embryonic fibroblast (PMEF) cultures. AB - Primary mouse embryonic fibroblasts (PMEFs) have a number of properties that make them an attractive cell culture model. Relative to other primary explant cultures they are easy to establish and maintain, proliferate rapidly and, as a result, large numbers of cells can be produced from a single embryo within several days following explantation. This allows, for instance, for ready comparison of wild type and knockout cells derived from the same litter of animals. PMEFs can be expanded through several passages before they reach crisis and can be used to establish cell lines following spontaneous transformation or following derivation from strains carrying mutations, such as in the gene encoding the tumour suppressor Trp53. They have been widely used as feeders to support other cultured cell types, notably embryonic stem cells, as well as for the study of a diverse range of cellular phenomena using microscopic, biochemical and molecular biological techniques. Here, we describe a simple and reliable method for the derivation and maintenance of PMEFs. PMID- 20204618 TI - Embryonic skeletal muscle microexplant culture and isolation of skeletal muscle stem cells. AB - Cultured embryonic and adult skeletal muscle cells have a number of different uses. The microdissected explant technique described in this chapter is a robust and reliable method for isolating relatively large numbers of proliferative skeletal muscle cells from juvenile, adult or embryonic muscles as a source of skeletal muscle stem cells. The authors have used microdissected explant cultures to analyse the growth characteristics of skeletal muscle cells in wild-type and dystrophic muscles. Each of the components of tissue growth, namely cell survival, proliferation, senescence and differentiation can be analysed separately using the methods described here. The net effect of all components of growth can be established by means of measuring explant outgrowth rates. The microexplant method can be used to establish primary cultures from a wide range of different muscle types and ages and, as described here, has been adapted by the authors to enable the isolation of embryonic skeletal muscle precursors. Uniquely, microexplant cultures have been used to derive clonal (single cell origin) skeletal muscle stem cell (SMSc) lines which can be expanded and used for in vivo transplantation. In vivo transplanted SMSc behave as functional, tissue specific, satellite cells which contribute to skeletal muscle fibre regeneration but which are also retained (in the satellite cell niche) as a small pool of undifferentiated stem cells which can be re-isolated into culture using the microexplant method. PMID- 20204619 TI - The embryonic kidney: isolation, organ culture, immunostaining and RNA interference. AB - Embryonic mouse kidneys develop well in organ culture. This, coupled with the fact that renal organogenesis includes a range of developmental processes, has made cultured kidney rudiments a popular model for the study of organogenesis. Although cultured kidneys do not replicate every event that takes place in vivo, they do allow close observation of events as they happen and they allow easy access for experiments that use drugs, antibodies, exogenous growth factors and interfering RNAs. Renal organ culture therefore offers a much quicker method to address certain problems than would the generation of transgenic mice. Requiring only material from freshly killed healthy animals, it also avoids some ethical problems connected with subjecting living animals to treatments (or the effect of mutations) that are harmful. PMID- 20204620 TI - Explant culture of mouse embryonic whole lung, isolated epithelium, or mesenchyme under chemically defined conditions as a system to evaluate the molecular mechanism of branching morphogenesis and cellular differentiation. AB - Lung primordial specification as well as branching morphogenesis, and the formation of various pulmonary cell lineages, requires a specific interaction of the lung endoderm with its surrounding mesenchyme and mesothelium. Lung mesenchyme has been shown to be the source of inductive signals for lung branching morphogenesis. Epithelial-mesenchymal-mesothelial interactions are also critical to embryonic lung morphogenesis. Early embryonic lung organ culture is a very useful system to study epithelial-mesenchymal interactions. Both epithelial and mesenchymal morphogenesis proceed under specific conditions that can be readily manipulated in this system (in the absence of maternal influence and blood flow). More importantly this technique can be readily done in a serumless, chemically defined culture media. Gain and loss of function can be achieved using expressed proteins, recombinant viral vectors, and/or analysis of transgenic mouse strains, antisense RNA, as well as RNA interference gene knockdown. Additionally, to further study epithelial-mesenchymal interactions, the relative roles of epithelium versus mesenchyme signaling can also be determined using tissue recombination (e.g., epithelial and mesenchymal separation) and microbead studies. PMID- 20204621 TI - Isolation, culture, and characterisation of mouse embryonic oesophagus and intestine. AB - The gastrointestinal tract of vertebrates is lined by epithelium that develops from the endodermal germ layer. The oesophagus and intestine form part of the gastrointestinal tract and studying the normal development of both tissues is difficult due to lack of suitable in vitro model systems. One of the criteria for a reliable culture model includes the ability to carry out real-time observations in vitro. The method we describe here is based on the isolation of embryonic oesophagus and intestine from 11.5-day-old embryos and culture on fibronectin coated coverslips in basal Eagle's medium and 20% fetal bovine serum. This model permits real-time observations of both tissues and over a few days in culture, markers of differentiation appear. This culture system appears to recapitulate normal oesophagus and intestine development. PMID- 20204622 TI - Isolation and culture of embryonic pancreas and liver. AB - Culturing embryonic tissue in an in vitro setting offers the unique ability to manipulate the external medium and therefore to investigate the pathways involved in regulating normal organogenesis as well as providing models for developmental disorders. Here we describe a system for the in vitro culture of the dorsal pancreatic buds and liver buds from mouse embryos. The tissues are dissected from day 9.0 or 11.5 mouse embryos. The tissues are placed on fibronectin-coated coverslips in serum-containing medium and allowed to attach. Over the next few days, the buds grow as flattened structures which are thin enough to allow the use of wholemount immunostaining methods. PMID- 20204623 TI - Isolation and culture of mouse satellite cells. AB - Muscle tissue culture provides a system for studying the growth and differentiation of muscle cells in a controlled environment. In mature muscle tissue, terminally differentiated myocytes form multinucleate syncytia in which structural and regulatory genes are expressed and the contractile apparatus is assembled. Adult muscle fibres are characterized by the presence of satellite cells. These are a quiescent population of myogenic cells that reside between the basal lamina and the plasmalemma of terminally differentiated muscle fibres and are rapidly activated in response to appropriate stimuli. This chapter describes protocols used in our laboratory for isolating and culturing satellite cells isolated from mouse skeletal muscles. In particular we discuss the technical aspect of satellite cell isolation, the methods necessary to enrich the satellite cell fraction, and the culture conditions which optimize proliferation and myotube formation of mouse satellite cells. PMID- 20204624 TI - Analysis of cardiac myocyte biology in transgenic mice: a protocol for preparation of neonatal mouse cardiac myocyte cultures. AB - We describe a method of isolating and maintaining primary cultures of mouse neonatal cardiac myocytes (NCM). This is derived from the well-established procedure for making NCM cultures from rat neonates by sequential digestion of rat ventricular myocardial pieces using a collagenase/pancreatin mixture. One-day old mouse neonates are taken and the heart excised. The great vessels, atria, and top section of the ventricular chambers are cut away and the remaining ventricular myocardium is cut into small cubes (about 1-2 mm(3)). Heart pieces from at least 30 animals are then subjected to short (15-25 min) digestion in a shaking water bath in the presence of collagenase and pancreatin. Cell supernatants are taken and pooled together for a total of five digestion steps. The cells are then plated on gelatinized culture dishes and allowed to attach overnight. Myocyte cultures were inspected microscopically for up to 4 days, revealing that many myocytes beat throughout this period. This protocol may be of use for making primary cardiac myocyte cultures from transgenic mice and for investigating gene transcription and cell signalling. PMID- 20204625 TI - Short- and long-term cultivation of embryonic and neonatal murine keratinocytes. AB - Studies using cultured cells allow one to dissect complex cellular mechanisms in greater detail than when studying living organisms alone. However, before cultured cells can deliver meaningful results they must accurately represent the in vivo situation. Over the last three to four decades considerable effort has been devoted to the development of culture media which improve in vitro growth and modeling accuracy. In contrast to earlier large-scale, non-specific screening of factors, in recent years the development of such media has relied increasingly on a deeper understanding of the cell's biology and the selection of growth factors to specifically activate known biological processes. These new media now enable equal or better cell isolation and growth, using significantly simpler and less labor-intensive methodologies. Here we describe a simple method to isolate and cultivate epidermal keratinocytes from embryonic or neonatal skin on uncoated plastic using a medium specifically designed to retain epidermal keratinocyte progenitors in an undifferentiated state for improved isolation and proliferation and an alternative medium to support terminal differentiation. PMID- 20204626 TI - Isolation, culture and analysis of mouse mammary epithelial cells. AB - Limited understanding of the cell biology of the breast and breast cancer hampers our ability to develop new therapeutic approaches. Mouse models of mammary gland development and tumourigenesis are key to developing new insights into the biology of both the normal and diseased tissues. Recent advances have enabled the isolation, molecular characterisation and functional analysis of mouse mammary epithelial cell subpopulations from the normal gland, including subpopulations enriched for stem cell behaviour. Application of these techniques both to the normal mammary gland and to tumour models will promote a better understanding of the nature of the different epithelial cell types in the mammary gland, the origins of mammary tumours and the role of tumour stem cells. PMID- 20204627 TI - Isolation and culture of mouse pancreatic islets for ex vivo imaging studies with trappable or recombinant fluorescent probes. AB - The endocrine pancreas contains small clusters of 1,000-2,000 neuroendocrine cells termed islets of Langerhans. By secreting insulin, glucagon, or other hormones as circumstances dictate, islets play a central role in the control of glucose homeostasis in mammals. Islets are dispersed throughout the exocrine tissue and comprise only 1-2% of the volume of the whole organ; human pancreas contains about 10(6) islets whereas rodents have approximately 2 x 10(3) islets. The isolation of islets from the exocrine tissue usually begins with digestion of the pancreas with collagenase. Collagenase-containing medium is either injected into the pancreatic duct, and the organ left to digest in situ, or added after isolation of the pancreas and its dissection into small pieces ex vivo. Islets can then be separated from the exocrine tissue by gradient density or by handpicking. The islets obtained can either be used intact, for example, to measure insulin or glucagon secretion or be dispersed into single cells with a Ca(2+)-free medium or with trypsin/dispase. The latter facilitates the introduction of recombinant or trappable probes and microimaging studies of, for example, changes in cytosolic-free Ca(2+) concentration or the dynamics of individual organelles or proteins. PMID- 20204628 TI - Isolation and culture of adult mouse hepatocytes. AB - The liver performs a multitude of functions including the regulation of carbohydrate, fat, and protein metabolism, the detoxification of endo- and xenobiotics, and the synthesis and secretion of plasma proteins and bile. Isolated hepatocytes constitute a useful technique for studying liver function in an in vitro setting. Here we describe a method for the isolation of hepatocytes from adult mouse liver. The principle of the method is the two-step collagenase perfusion technique which involves sequential perfusion of the liver with ethylenediaminetetraacetic acid and collagenase. Following isolation, the cells can either be used for short-term studies or, alternatively, maintained in culture for prolonged periods to study long-term changes in gene expression. The protocol for mouse hepatocyte isolation may be applied to both normal and transgenic mice. PMID- 20204629 TI - Isolation and culture of mouse intestinal cells. AB - Complex cell signal transduction mechanisms regulate intestinal epithelial shape, polarity, motility, organelles, cell membrane components as well as physical and mechanical properties to influence alimentary digestion, absorption, secretion, detoxification and fluid balance. Interactions between the epithelial cells and adjacent mesenchyme are central to intestinal homeostasis although the key regulatory molecules of specific differentiation steps remain unclear. Isolation and primary culture of heterotypic murine intestinal cells provides a model system for elucidation of essential molecular cross-talk between epithelium and mesenchyme that may provide several biological and practical advantages over transformed cell lines. An in vitro primary culture system for neonatal rat or mouse intestinal cells has been established that forms monolayers, expresses intestine-specific epithelial features including intestinal brush borders and appropriate hydrolase enzymes. Our studies confirm the promise of this method which may advance our understanding of heterotypic cellular interactions implicated in intestinal function and may provide important insights into the pathobiology of disease. PMID- 20204630 TI - Derivation of primary choroid plexus epithelial cells from the mouse. AB - Choroid plexus epithelial cells form an integral and important part of the barrier between blood and cerebrospinal fluid. Culture of choroid plexus epithelium in vitro has been achieved from several mammalian species and this provides opportunities for the study of choroid plexus development and function, including the capacity of the epithelial cells to control the movement of bioactive molecules, such as novel drug candidates, from the bloodstream to the brain. Here we describe a method for the derivation of primary cell cultures from mouse choroid plexus epithelium, together with characterisation by immunofluorescence using antibodies specific to markers of mature choroid plexus epithelial cells. With this method, relatively pure choroid plexus epithelial cell monolayers are established using the DNA synthesis inhibitor cytosine arabinoside (Ara-C), which is cytotoxic to contaminating cell types such as fibroblasts, but not the epithelial cells. These cells are shown to express the diagnostic choroidal marker, transthyretin (TTR), as well as markers of epithelial cell differentiation and are thus suitable for studies that address the transport and barrier functions of the choroid plexus. PMID- 20204631 TI - The preparation of primary cortical neuron cultures and a practical application using immunofluorescent cytochemistry. AB - Traditionally, cultures of primary cortical neurons are prepared from embryonic animals because at prenatal stages neurons have not yet developed extensive axonal and dendritic arbors and are not highly innervated, thus rendering the cells less susceptible to damage during dissociation of the neuronal tissue. The appropriate developmental age for preparing primary cultures of any cell type is determined by the time at which the cells of interest are generated and abundant. Most cerebral cortical neurons are generated between embryonic days (E) 11 and 17 in the mouse (embryos being considered 0.5 days old when a vaginal plug is detected in the morning). Here we describe a method to obtain short-term cultures of mouse primary cortical neurons at E15.5 and a practical application using fluorescent immunocytochemistry. PMID- 20204632 TI - Cell culture of primary cerebellar granule cells. AB - Cerebellar granule cells are often used as a model system for the study of neuronal development, function and pathology, including the analysis of activity dependent survival/apoptosis of neurons and the mechanisms of neuroprotection. Cerebellar granule cells are generated postnatally and constitute the largest homogeneous neuronal population of the mammalian brain. In addition, cerebellar granule cells cultured in vitro develop characteristics of mature cerebellar granule cells seen in vivo, such as an extensive neuritic network, expression of excitatory amino acid receptors and production and release of -L: glutamate. Taken together, these features make cerebellar granule cells a unique model system that has been extensively characterised and used for in vitro studies. PMID- 20204633 TI - Isolation and generation of neurosphere cultures from embryonic and adult mouse brain. AB - Neural stem cells are defined as cells that either gives rise to or derives from the cells of the central nervous system and have the unique properties of stem cells, i.e. self-renewal and multipotentiality. One of the widely used methods of expanding neural stem cells under culture conditions is based on the capacity of these cells to divide continuously when cultured in serum-free medium supplemented with various growth factors. One common method used is to grow neural stem cells as free-floating aggregates of cells called neurospheres. Neurospheres can be generated from several structures of the embryonic and adult mammalian brain. Although viable lines can be generated from crude extracts of brain, a precise dissection is crucial to get a pure population of cells. Here we describe methods for dissection, isolation and generation of neurospheres from embryonic ganglionic eminences and adult subventricular zone of mice and rats. PMID- 20204634 TI - Ecosystem-based analysis of a marine protected area where fisheries and protected species coexist. AB - The Gulf of California Biosphere Reserve (UGC&CRDBR) is a Marine Protected Area that was established in 1993 with the aim of preserving biodiversity and remediating environmental impacts. Because remaining vigilant is hard and because regulatory measures are difficult to enforce, harvesting has been allowed to diminish poaching. Useful management strategies have not been implemented, however, and conflicts remain between conservation legislation and the fisheries. We developed a transdisciplinary methodological scheme (pressure-state-response, loop analysis, and Geographic Information System) that includes both protected species and fisheries modeled together in a spatially represented marine ecosystem. We analyzed the response of this marine ecosystem supposing that conservation strategies were successful and that the abundance of protected species had increased. The final aim of this study was to identify ecosystem level management alternatives capable of diminishing the conflict between conservation measures and fisheries. This methodological integration aimed to understand the functioning of the UGC&CRDBR community as well as to identify implications of conservation strategies such as the recovery of protected species. Our results suggest research hypotheses related to key species that should be protected within the ecosystem, and they point out the importance of considering spatial management strategies. Counterintuitive findings underline the importance of understanding how the community responds to disturbances and the effect of indirect pathways on the abundance of ecosystem constituents. Insights from this research are valuable in defining policies in marine reserves where fisheries and protected species coexist. PMID- 20204635 TI - Application of two quality indices as monitoring and management tools of rivers. Case study: the Imera Meridionale River, Italy. AB - On the basis of the European Water Framework Directive (2000/60), the water resources of the member states of the European Community should reach good quality standards by 2015. Although such regulations illustrate the basic points for a comprehensive and effective policy of water monitoring and management, no practical tools are provided to face and solve the issues concerning freshwater ecosystems such as rivers. The Italian government has developed a set of regulations as adoption of the European Directive but failed to indicate feasible procedures for river monitoring and management. On a local scale, Sicilian authorities have implemented monitoring networks of watersheds, aiming at describing the general conditions of rivers. However, such monitoring programs have provided a relatively fragmentary picture of the ecological conditions of the rivers. In this study, the integrated use of environmental quality indices is proposed as a methodology able to provide a practical approach to river monitoring and management. As a case study, the Imera Meridionale River, Sicily's largest river, was chosen. The water quality index developed by the U.S. National Sanitation Foundation and the floristic quality index based on the Wilhelm method were applied. The former enabled us to describe the water quality according to a spatial-temporal gradient, whereas the latter focused on the ecological quality of riparian vegetation. This study proposes a holistic view of river ecosystems by considering biotic and abiotic factors in agreement with the current European regulations. How the combined use of such indices can guide sustainable management efforts is also discussed. PMID- 20204636 TI - Ramification of Glisson's sheath peripheral branches and clinical implications in the era of local ablation therapy. AB - PURPOSE: Classical anatomical resection does not always guarantee tumor-free margins when the tumor overrides traditional anatomical planes. Surgeons and interventionists frequently need to focus on the peripheral branches of Glisson's sheath in patients with poor hepatic reserves, particularly when the tumor is deep seated. The present study used anatomical liver dissection to investigate the spatial distribution of the branches of Glisson's sheath in each of four liver sectors. METHODS: Sixty-four adult human liver specimens were dissected. The size and ramification patterns of Glisson's sheath in each sector were analyzed in terms of bilateral homology within two paramedian sectors and within two lateral sectors. RESULTS: Each liver sector had a characteristic Glisson's sheath in terms of trunk shape and ramification pattern. The two paramedian sectors showed point symmetry. Most of the branches of the two paramedian sectors emerged from the top of a short stout trunk. Although the two paramedian sectors were similar in terms of basic configuration, the ramification axes were almost perpendicular to each other. Unlike the paramedian sectors, the two lateral sectors showed not much homology. CONCLUSIONS: The peripheral branches of Glisson's sheath were generally longer (approximately 5 cm) and thicker than anticipated. Extirpation strategies should take into account that each liver sector has a characteristic Glisson's sheath ramification pattern. PMID- 20204637 TI - A novel approach for anterior sciatic nerve block: cadaveric feasibility study. AB - BACKGROUND: Sciatic nerve block is a commonly used technique for providing anesthesia and analgesia to the lower extremity. It is classically performed through posterior or lateral approaches. However, an anterior approach should be considered in certain conditions where patient positioning would be complicated. The success rate of the sciatic nerve block with previously defined approaches has been reported to be low, however, the complication rate with such approaches has been found to be high. Therefore, we aimed to conduct an anatomical study defining a new anterior approach to block the sciatic nerve and also to examine if the femoral nerve can be blocked via the same approach. METHODS: Initially, various landmarks and practical measurements were examined on 11 lower extremities. Eight of the lower extremities were used for defining the best approach to the sciatic nerve anteriorly. Once defined, Indian ink was injected into two cadaveric extremities with an anesthetic needle through such an approach. The route of the needle was evaluated via dissection and we observed whether the ink stained the sciatic nerve or injured regional neurovascular structures. The remaining extremity was cut axially to observe the route of the needle after injection. RESULTS: The ideal site of needle insertion was found to be 4-5 cm distal to the inguinal crease and 1-2 cm lateral to the femoral artery. On average, this point corresponded to a point located 8.0 +/- 0.7 cm distal to a perpendicular line drawn midway through the straight line connecting the anterior superior iliac spine (ASIS) and the pubic tubercle (PT). The distance of this point to the straight line drawn between the ASIS and PT was approximately equal to half the distance of this line. CONCLUSION: The technique described herein appears anatomically safe with a lower risk of damage to major neurovascular structures. Additionally, the femoral nerve can be blocked simultaneously to obtain a larger area of anesthesia of the lower limb. PMID- 20204638 TI - Morphology and general characteristics of bacteriophages infectious to Robinia pseudoacacia mesorhizobia. AB - Four phages infectious to Mesorhizobium strains were identified in soil samples taken from local Robinia pseudoacacia stands. Based on their polyhedral heads and short noncontractile tails, three of the phages, Mlo30, Mam12, and Mam20, were assigned to group C of Bradley's classification, the Podoviridae family, while phage Mlo1, with its elongated hexagonal head and a long flexible tail represented subgroup B2 bacteriophages, the Siphoviridae family. The phages were homogeneous in respect of their virulence, as they only lysed Mesorhizobium strains, but did not affect strains of Rhizobium or Bradyrhizobium. On the basis of one-step growth experiments, the average virus yield was calculated as approximately 10-25 phage particles for phages Mlo30, Mam12 and Mam20, and as many as 100-120 for phage Mlo1. The rate of phage adsorption to heat-treated cells showed differences in the nature of their receptors, which seemed to be thermal sensitive, thermal resistant, or a combination of the two. Only the receptor for phage Mlo30 was likely to be an LPS molecule, which was supported by a neutralization test. The smooth LPS with O-antigenic chains of the phage sensitive M. loti strain completely reduced the bactericidal activity of virions at a concentration of 1 MUg/ml. The molecular weights of phage DNAs estimated from restriction endonuclease cleavage patterns were in the range from approximately 39 kb for group C phages to approximately 80 kb for B2. PMID- 20204639 TI - Image fusion of coronary CT angiography and cardiac perfusion MRI: a pilot study. AB - OBJECTIVE: To develop a tool for the image fusion of computed tomography coronary angiography (CTCA) and cardiac magnetic resonance imaging (CMR). METHODS: Surface representations and volume-rendered images from fused CTCA/CMR data of five patients with significant coronary artery disease (CAD) on CTCA and perfusion deficits on CMR were generated using a newly developed software prototype. The spatial relationship of significant coronary artery stenosis at CTCA and myocardial defects at CMR was evaluated. RESULTS: Registration of CTCA and CMR images was possible in all patients. The comprehensive three-dimensional visualisation of fused CTCA and CMR data accurately demonstrated the relationship between coronary artery stenoses and myocardial defects in all patients. CONCLUSION: The introduced tool enables image fusion of CTCA and CMR data sets and allows for correct superposition of the coronary arteries derived from CTCA onto the corresponding myocardial segments derived from CMR. The method facilitates the comprehensive assessment of the functionally relevant CAD by the exact allocation of culprit coronary stenoses to corresponding myocardial defects at a low radiation dose. PMID- 20204640 TI - An open source toolkit for medical imaging de-identification. AB - OBJECTIVE: Medical imaging acquired for clinical purposes can have several legitimate secondary uses in research projects and teaching libraries. No commonly accepted solution for anonymising these images exists because the amount of personal data that should be preserved varies case by case. Our objective is to provide a flexible mechanism for anonymising Digital Imaging and Communications in Medicine (DICOM) data that meets the requirements for deployment in multicentre trials. METHODS: We reviewed our current de identification practices and defined the relevant use cases to extract the requirements for the de-identification process. We then used these requirements in the design and implementation of the toolkit. Finally, we tested the toolkit taking as a reference those requirements, including a multicentre deployment. RESULTS: The toolkit successfully anonymised DICOM data from various sources. Furthermore, it was shown that it could forward anonymous data to remote destinations, remove burned-in annotations, and add tracking information to the header. The toolkit also implements the DICOM standard confidentiality mechanism. CONCLUSION: A DICOM de-identification toolkit that facilitates the enforcement of privacy policies was developed. It is highly extensible, provides the necessary flexibility to account for different de-identification requirements and has a low adoption barrier for new users. PMID- 20204641 TI - Imaging of pulmonary vein anatomy using low-dose prospective ECG-triggered dual source computed tomography. AB - OBJECTIVE: To prospectively investigate the feasibility, image quality and radiation dose estimates for computed tomography angiography (CTA) of the pulmonary veins and left atrium using prospective electrocardiography (ECG) triggered sequential dual-source (DS) data acquisition at end-systole in patients with paroxysmal atrial fibrillation undergoing radiofrequency ablation. METHODS: Thirty-five patients (mean age 66.2 +/- 12.6 years) with paroxysmal atrial fibrillation underwent prospective ECG-triggered sequential DS-CTA with tube current (250 mAs/rotation) centred 250 ms past the R-peak. Tube voltage was adjusted to the BMI (<25 kg/m(2): 100 kV, >25 kg/m(2): 120 kV). Presence of motion or stair-step artefacts was assessed. Effective radiation dose was calculated from the dose-length product. RESULTS: All data sets could be integrated into the electroanatomical mapping system. Twenty-two patients (63%) were in sinus rhythm (mean heart rate 69.2 +/- 11.1 bpm, variability 1.0 +/- 1.7 bpm) and 13 (37%) showed an ECG pattern of atrial fibrillation (mean heart rate 84.8 +/- 16.6 bpm, variability 17.9 +/- 7.5 bpm). Minor step artefacts were observed in three patients (23%) with atrial fibrillation. Mean estimated effective dose was 1.1 +/- 0.3 and 3.0 +/- 0.5 mSv for 100 and 120 kV respectively. CONCLUSION: Imaging of pulmonary vein anatomy is feasible using prospective ECG-triggered sequential data acquisition at end-systole regardless of heart rate or rhythm at the benefit of low radiation dose. PMID- 20204642 TI - Radiofrequency ablation of renal tumours: diagnostic accuracy of contrast enhanced ultrasound for early detection of residual tumour. AB - OBJECTIVE: To evaluate the diagnostic accuracy of contrast-enhanced ultrasound (CEUS) in the early detection of residual tumour after radiofrequency ablation (RFA) of renal tumours. METHODS: Patients referred to our institution for RFA of renal tumours prospectively underwent CEUS and computed tomography (CT) or magnetic resonance imaging (MRI) before, within 1 day and 6 weeks after treatment. Identification of residual tumour was assessed by three blinded radiologists. Reference standard was CT/MRI performed at least 1 year after RFA. RESULTS: A total of 66 renal tumours in 43 patients (median age 62 years; range 44-71.5) were studied. Inter-reader agreement (kappa value) was 0.84 for CEUS. Prevalence of residual disease was 19%. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV), respectively, were as follows: 64% [confidence interval (CI) 39-84], 98% [CI 91-100], 82% [CI 52-95] and 92% [CI 83-97] on 24-h CEUS; 79% [CI 52-92], 100% [CI 94-100], 100% [CI 74 100] and 95% [CI 87-100] on 6-week CEUS; 79% [CI 52-92], 95% [CI 86-98], 79% [CI 52-92] and 95% [CI 86-98] on 24-h CT/MRI; and 100% [CI 72-100], 98% [CI 90-100], 91% [CI 62-98] and 100% [CI 93-100] on 6-week CT/MRI. CONCLUSION: CEUS has high specificity for the early diagnosis of residual tumour after renal RFA. PMID- 20204643 TI - New observations from MR velocity-encoded flow measurements concerning diastolic function in constrictive pericarditis. AB - OBJECTIVE: To assess diastolic function in patients with constrictive pericarditis (CP) by using velocity-encoded flow measurements at the atrioventricular valves and to evaluate whether conclusions regarding increased ventricular pressure can be drawn. METHODS: Twenty-two patients with CP and 20 healthy subjects were examined on a 1.5-T MR system. In addition to evaluation of pericardial thickness, ventricular volumes and septal movement, velocity-encoded flow measurements were performed at the level of the atrioventricular valves for assessment of diastolic function. Amplitudes of the e- and a-waves were measured and e- to a-wave ratios were calculated. The correlation of transtricuspid e- to a-wave ratios and right ventricular end-diastolic pressures (RVEDP) was calculated. RESULTS: Right ventricular volumes were significantly smaller in patients with CP (p < 0.001). Abnormal septal movement was detected in all patients except one with CP and in none of the healthy subjects. In patients with CP mean transtricuspid e- to a-wave ratios were significantly smaller compared with healthy subjects. Individual transtricuspid e- to a-wave ratios were highly correlated with RVEDP (r = 0.6, p = 0.01). CONCLUSIONS: An elaborate MR examination can identify patients with CP. Velocity-encoded flow measurements with calculation of transtricuspid e- to a-wave ratios are a valuable tool for detection of diastolic dysfunction in patients with CP. The value of e- to a-wave ratios may indicate elevated RVEDP. PMID- 20204646 TI - Letter to the editor re: Diffusion-weighted magnetic resonance imaging of pancreas tumours. PMID- 20204644 TI - Diffuse interstitial lung disease: overlaps and uncertainties. AB - Histopathological analysis of lung biopsy material allows the diagnosis of idiopathic interstitial pneumonias; however, the strength of this diagnosis is sometimes subverted by interobserver variation and sampling. The American Thoracic Society and European Respiratory Society recommendations of 2002 provide a framework for the diagnosis of interstitial lung disease (ILD) and proposed an integrated clinical, radiological and histopathological approach. These recommendations represent a break with tradition by replacing the 'gold standard' of histopathology with the combined 'silver standards' of clinical, imaging and histopathological information. One of the pitfalls of a rigid classification system for the diagnosis of interstitial lung disease is its failure to accommodate the phenomenon of overlapping disease patterns. This article reviews the various ways that interstitial lung disease may be classified and discusses their applicability. In addition the issue of overlap disease patterns is considered in the context of histopathological interobserver variation and sampling error and how a pigeonhole approach to disease classification may overlook these hybrid entities. PMID- 20204647 TI - Computer-aided interpretation of dynamic magnetic resonance imaging reflects histopathology of invasive breast cancer. AB - OBJECTIVE: To perform a semiautomated software-based comparison of invasive breast carcinoma dynamic enhancement patterns in MR mammography with histological prognostic factors considering whole lesion volumes. MATERIAL AND METHODS: A total of 128 patients with 145 invasive breast carcinomas underwent dynamic MR mammography. Kinetic features from the invasive breast lesions were obtained using commercially available software to automatically assess volume enhancement characteristics of a manually chosen lesion. Findings were compared with histological factors determining tumour aggressiveness (lymph node status, LN; oestrogen/progesterone receptor (ER/PR) status; HER-2/neu status; tumour grade) by using nonparametric rank tests and binary logistic regression analysis (BLRA). RESULTS: Volume enhancement characteristics were significantly influenced by LN, ER/PR and HER-2/neu status (P < 0.05). BLRA implied that total lesion and plateau voxel volume were independent predictors of ER/PR and HER-2/neu status. Strongest initial enhancement predicted negative ER/PR, and time to peak of the most suspect curve was inversely correlated with positive LN status. On the other hand, no statistical significance could be observed between histological tumour grading and kinetic features. CONCLUSION: Histopathological criteria associated with poor prognosis lead to significantly more aggressive dynamic enhancement patterns in MR mammography. In this study, higher lesion volumes as well as higher and earlier initial enhancement were independent covariates predicting higher tumour aggressiveness. PMID- 20204648 TI - The cardiothoracic ratio--an inaccurate and outdated measurement: new data from CT. AB - Cardiomegaly (and left ventricular size in particular) is well recognized to have cardiovascular prognostic significance. Cardiac assessment should be routinely performed when evaluating imaging studies encompassing the thorax, whether cross sectional or projectional. However, such measurements should be robust, readily available and practical. In this issue of European Radiology, Schlett et al. describe such a technique based on single level area and transverse diameter measurements on transverse CT and projection digitally acquired radiographs. This paper is significant as it makes a simple tool for left ventricular assessment readily available to all cross-sectional imagers and highlights the established limitation of cardiothoracic ratio on the chest radiograph. PMID- 20204649 TI - Simple area-based measurement for multidetector computed tomography to predict left ventricular size. AB - OBJECTIVE: Measures of left ventricular (LV) mass and dimensions are independent predictors of morbidity and mortality. We determined whether an axial area-based method by computed tomography (CT) provides an accurate estimate of LV mass and volume. METHOD: A total of 45 subjects (49% female, 56.0 +/- 12 years) with a wide range of LV geometry underwent contrast-enhanced 64-slice CT. LV mass and volume were derived from 3D data. 2D images were analysed to determine LV area, the direct transverse cardiac diameter (dTCD) and the cardiothoracic ratio (CTR). Furthermore, feasibility was confirmed in 100 Framingham Offspring Cohort subjects. RESULTS: 2D measures of LV area, dTCD and CTR were 47.3 +/- 8 cm(2), 14.7 +/- 1.5 cm and 0.54 +/- 0.05, respectively. 3D-derived LV volume (end diastolic) and mass were 148.9 +/- 45 cm(3) and 124.2 +/- 34 g, respectively. Excellent inter- and intra-observer agreement were shown for 2D LV area measurements (both intraclass correlation coefficients (ICC) = 0.99, p < 0.0001) and could be confirmed on non-contrast CT. The measured 2D LV area was highly correlated to LV volume, mass and size (r = 0.68; r = 0.73; r = 0.82; all p < 0.0001, respectively). On the other hand, CTR was not correlated to LV volume, mass, size or 2D LV area (all p > 0.27). CONCLUSION: Compared with traditionally used CTR, LV size can be accurately predicted based on a simple and highly reproducible axial LV area-based measurement. PMID- 20204650 TI - Long-term outcome of surgically managed necrotizing enterocolitis in a developing country. AB - Necrotizing enterocolitis (NEC) is a serious condition with a high morbidity and mortality commonly affecting premature babies. Data for the impact of the long term disease burden in developing countries are limited although poor long-term outcome of surgically managed patients has been shown in terms of increased risk of neurodevelopmental delay, increased infectious disease burden and abnormal neurological outcomes in the developed world. PURPOSE: To evaluate the long-term outcome of a pre-human immunodeficiency virus pandemic NEC cohort to characterize common risk factors and outcome in a developing world setting. METHODS: A retrospective review of medical records was carried out on a cohort of 128 premature neonates with surgical NEC (1992-1995). Morbidity, mortality and long term outcome were evaluated. RESULTS: Data for 119 of 128 sequentially managed neonates with surgically treated NEC was available. Mean gestational age was 32 weeks and average birth weight was 1,413 g. Early (30-day postoperative) survival was 69% (n = 82) overall and 71% in the <1,500 g birth weight group (n = 68; 53%). Overwhelming sepsis (n = 16) or pan-intestinal necrosis (n = 18) accounted for most of the early deaths. Late deaths (>30 days postoperatively, n = 22) resulted from short bowel syndrome (5), sepsis (9), intraventricular hemorrhage (1) and undetermined causes (7). On follow-up (mean follow-up 39 months, 30 for >2 years), long-term mortality increased to 50%. Late surgical complications included late colonic strictures (9), incisional hernias (2) and adhesive bowel obstruction (3). Fifteen patients had short bowel syndrome, of which 10 (66%) survived. Of the long-term survivors, 8 (20%) had severe neurological deficits and 20 (49%) had significant neurodevelopmental delay. Neurological deficits included severe auditory impairment [5 (12%)] and visual impairment [4 (10%)]. Recurrent infections and gastrointestinal tract complaints requiring hospital admission occurred in 16 (39%) of survivors. CONCLUSION: Necrotizing enterocolitis in premature infants impacts morbidity and mortality considerably. A number do well in a developing country, but septic complications may be ongoing and recurrent. The high risk of neurodevelopmental and other problems continue beyond the neonatal period and patients should be "flagged" on for careful follow up. PMID- 20204651 TI - Effects of retinoic acid and zinc on the treatment of caustic esophageal burns. AB - PURPOSE: An experimental study was carried out to investigate the efficacy of an anti-inflammatory and antiproliferative agent all-trans retinoic acid (ATRA) and an antioxidant agent zinc sulphate (ZnSO(4)) in the prevention of stricture after caustic esophageal burn in rats. METHODS: Esophageal burn was induced using 50% NaOH. Rats were divided into four groups as follows: group A (sham; n = 8), group B (control; n = 8), group C (treated with ATRA; n = 8) and group D (treated with ZnSO(4); n = 8). All rats were killed on the 28th day and esophageal tissues were evaluated for histopathologic damage score, hydroxyproline (HP) content and TGF beta1 expression. RESULTS: Significant difference was detected in terms of histopathologic damage score between groups B and C (p = 0.002). Although mean HP levels of groups C and D were lower than group B, statistical comparison was not significant. TGF-beta1 expression in group C was significantly lower than group B. CONCLUSION: Zinc has not been found effective in the prevention of stricture formation. The results indicate that ATRA has a preventive effect in the development of fibrosis in an experimental model of caustic esophageal burns in rats. PMID- 20204653 TI - Identification a novel missense mutation p.R761L in Chinese patients with Darier's disease. AB - Darier's disease (DD, MIM 124200) is an autosomal dominant inherited disease. It is usually present in teenagers or adults with multiple keratotic papules or plaques in seborrheic areas. Pathogenic mutations in the ATP2A2 gene have been identified. It encodes the sarcoplasmic or endoplasmic reticulum Ca(2+) ATPase isoform 2 (SERCA2). Polymerase chain reaction and direct sequencing of the full coding sequence of ATP2A2 gene were performed to identify the mutation in this family. In this report, we identified a novel mutation of ATP2A2 gene in a Chinese family with DD. It is a novel heterozygous nucleotide G --> T transition at position 2,282 in exon 15 of the ATP2A2 gene. Our study expands the database on the ATP2A2 gene mutations in DD. PMID- 20204652 TI - Cross-sectional and longitudinal relation between serum 25-hydroxyvitamin D and body mass index: the Tromso study. AB - PURPOSE: The serum 25-hydroxyvitamin D (25(OH)D) levels are lower in obese than lean subjects. The present study examines the cross-sectional and longitudinal relations between body mass index (BMI) and serum 25(OH)D, and the serum 25(OH)D response to vitamin D supplementation in relation to BMI. METHODS: The Tromso study is a longitudinal population-based multipurpose study. The fourth survey was conducted in 1994 and the sixth in 2008. The intervention study was a 1-year placebo-controlled randomized intervention trial, where the results from the 93 subjects given 40,000 IU per week are presented. RESULTS: A total of 10,229 subjects were included in the 2008 cross-sectional study. There was a significant negative association between serum 25(OH)D levels and BMI which was also present during the winter months. Serum 25(OH)D levels varied through seasons, but not BMI. In the longitudinal study from 1994 to 2008 which included 2,656 subjects, change in BMI was a significant negative predictor of change in 25(OH)D. In the intervention study, there was a significant and negative correlation between BMI and serum 25(OH)D both at baseline and at the end of the study. The increase in serum 25(OH)D after 1 year was significantly and inversely related to baseline BMI. CONCLUSIONS: We have confirmed the strong association between serum 25(OH)D and BMI. The very obese need higher vitamin D doses than lean subjects to achieve the same serum 25(OH)D levels. PMID- 20204654 TI - Pharmacokinetics of imiquimod 3.75% cream applied daily for 3 weeks to actinic keratoses on the face and/or balding scalp. AB - Imiquimod 3.75% cream is a topical formulation of imiquimod intended for daily application to treat actinic keratoses of the entire face or balding scalp. The objective of the study was to characterize serum imiquimod and metabolite pharmacokinetics. Nineteen subjects with actinic keratoses applied two packets of imiquimod 3.75% cream (18.75 mg imiquimod total) once daily for 21 days to a treatment area approximately 200 cm(2) in size on the face and/or balding scalp. Blood samples were obtained prior to application of doses 1, 7, 14 and 21, and at selected timepoints after application of doses 1 and 21. After multiple dosing (day 21) serum imiquimod mean C (max) was 0.323 (standard deviation 0.159) ng/mL, mean AUC(0-24) 5.974 (3.088) ng h/mL, and mean T(1/2) 29.3 (17.0) h. Steady-state was achieved by day 14; multiple dose accumulation ratios were 2.8 based on imiquimod C (max) and 3.9 based on AUC. Serum concentrations of imiquimod metabolites were only sporadically quantifiable in three subjects. One subject discontinued from study for adverse events of body aches and fatigue that were attributed to study drug. Treatment-related adverse events occurred in 42.1% (8/19) of the subjects. Systemic imiquimod exposure, as reflected by serum drug concentration, was low after daily application of two packets of imiquimod 3.75% cream for 21 days. Steady state was achieved by day 14, and the observed half life of approximately 29 h supports daily dosing of the product. PMID- 20204655 TI - Increased angiogenesis and mast cells in the centre compared to the periphery of vitiligo lesions. AB - The larger number of T-lymphocytes in the periphery of vitiligo lesions and their association with angiogenesis are reported. The objective of this study was to investigate angiogenesis, VEGF and mast cell in vitiligo lesions. Specimens of 30 patients' biopsies, from lesional and perilesional nondepigmented skin were stained for mast cells, CD34 and VEGF. The evaluation was made by image analysis and the measured variables were statistically analyzed. A significantly increased number of CD34 and VEGF positive vessels and mast cells were detected in the centre of the lesion than in the periphery (p < 0.0001, p < 0.0001 and p = 0.001). There was a positive correlation of CD34, VEGF and mast cell number between the centre and the periphery of the lesions (r = 0.877, p < 0.0001; r = 0.946, p < 0.0001 and r = 0.863, p < 0.0001, respectively). The increased angiogenesis and mast cell numbers in the area where lymphocyte number is lower may be explained with the stepwise inflammatory process in vitiligo. PMID- 20204657 TI - Genetic diversity and medicinal drug response in eye care. AB - BACKGROUND: Individual variation in drug response and adverse drug reactions are a serious problem in medicine. This inter-individual variation in drug response could be due to multiple factors such as disease determinants, environmental and genetic factors. Much has been published in the literature in recent years about the potential of pharmacogenetic testing and individualized medicine. The development of personalized medicine is truly an exciting area of research. METHODS: This pharmacogenetic concept in ophthalmology has existed for more than a century. Although substantial studies that link genetic variants to inter individual difference in drug response have been reported in several diseases such as cancer and heart diseases, such studies are progressing slowly in the eye field. In this short article, an attempt has been made to summarize these results. RESULTS: Recently, there have been some small-scale studies that seem to associate the drug response to the genotype of patients in two major eye disorders, namely age-related macular degeneration (ARMD) and glaucoma. CONCLUSION: These studies are still in their infancy, and do not suggest that a pharmacogenetic basis of drug development is a credible concept and can become reality in the future. This is because most drug responses involve a large number of genes that have several polymorphisms and it is unlikely that any one single gene dictates the drug response. Therefore, a polygenic approach, whole genome single nucleotide polymorphism (SNP) analysis and a molecular understanding of disease itself may provide a better insight in the future about genetic predisposing factors for adverse drug reactions. PMID- 20204658 TI - Retinal re-detachment after scleral buckling procedure. PMID- 20204661 TI - Don't forget potassium! PMID- 20204659 TI - Treatment of neovascular age-related macular degeneration with a variable ranibizumab dosing regimen and one-time reduced-fluence photodynamic therapy: the TORPEDO trial at 2 years. AB - BACKGROUND: The combination of verteporfin photodynamic therapy (PDT) and anti angiogenics has been shown to be safe and efficacious in the treatment of choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). The purpose of this study is to demonstrate long-term prevention of vision loss and improvement in best-corrected visual acuity (BCVA) after treatment with one-time reduced-fluence-rate PDT followed by administration of ranibizumab on a variable dosing regimen over 24 months in patients with neovascular AMD. Secondary outcome measures included the change in central macular thickness (CMT), reinjection frequency, and safety. METHODS: This prospective, nonrandomized, open-label, single-center study enrolled 27 consecutive patients (27 eyes) presenting at the Leuven University Eye Hospital with previously untreated, active neovascular AMD between September 2006 and January 2007. All patients were treated with one-time, reduced-fluence-rate verteporfin PDT, followed by intravitreal ranibizumab 0.5 mg on the same day. A second and third ranibizumab injection were given at weeks 4 and 8, respectively, after which patients were followed up monthly for 24 months. Additional treatment with ranibizumab was administered to eyes with active neovascularization as indicated clinically and on imaging studies. Retreatment was based on the following criteria: (1) presence of subretinal fluid (SRF), intraretinal edema or sub retinal pigment epithelial fluid, as seen on OCT; (2) increase of CMT by >100 mm on OCT; (3) signs of active CNV leakage on fluorescein angiography; (4) new sub- or intraretinal hemorrhage; and (5) BCVA decreased of > or =5 letters on the Early Treatment of Diabetic Retinopathy Study (ETDRS) chart. If any single criterion for reinjection was fulfilled, retreatment with ranibizumab was administered. RESULTS: Twenty-five patients completed the 2-year study. Occult CNV was present in 64% and retinal angiomatous proliferative (RAP) lesions were present in 24% of the study eyes. The remaining three eyes had lesions classified as classic (one eye) or predominantly classic (two eyes) CNV. Month 24 data are available for 25 eyes (25 patients; age 55-86 years; mean 77; standard deviation (SD) = 7.2). Mean baseline VA was 58.6 letters (range: 35-70; SD = 8.4); 24-month VA was 66.2 letters (35-82; 12.7), not including one warfarin-treated patient who suffered vitreous hemorrhage. The mean visual acuity improved by 7.2 letters (p < 0.05) and the mean CMT decreased by 146 mum. VA improved >3 lines (15 letters) in 16%; improved 1-3 lines in 20%; remained within one line of baseline in 32%, decreased 1-3 lines in 16%, and decreased >3 lines in 16%. Losses of >3 lines were due to vitreous hemorrhage, geographic atrophy, fibrosis, and growth of an initially small CNV lesion. An average of 5.1 injections (range: 3-9) were administered during the first 12 months, and 7.1 injections (3-13) over 24 months. A total of 178 injections were performed; no systemic side-effects, uveitis, or choroidal collateral vascular damage were observed. Two patients were lost to follow-up. CONCLUSION: Combined PDT and ranibizumab injection the same day was well tolerated in all patients. Eighty-four percent of patients had stable or improved vision at month 24. PMID- 20204662 TI - Effect of redox potential regulation on succinic acid production by Actinobacillus succinogenes. AB - The effects of redox potential used as a control parameter on the process of succinic acid production in batch cultures of Actinobacillus succinogenes NJ113 have been investigated. In batch fermentation, cell growth and metabolite distribution were changed with redox potential levels in the range of -100 to 450 mV. From the results, the ORP level of -350 mV was preferable, which resulted in high succinic acid yield (1.28 mol mol(-1)), high succinic acid productivity (1.18 g L(-1) h(-1)) and high mole ratio of succinic acid to acetic acid (2.02). The mechanism of redox potential regulation was discussed by metabolic flux analysis and the ratio of NADH/NAD+. We expected that redox potential can be used as a valuable parameter to monitor and control much more anaerobic fermentation production. PMID- 20204663 TI - Studies on substrate utilisation in L-valine-producing Corynebacterium glutamicum strains deficient in pyruvate dehydrogenase complex. AB - The pyruvate dehydrogenase complex was deleted to increase precursor availability in Corynebacterium glutamicum strains overproducing L: -valine. The resulting auxotrophy is treated by adding acetate in addition glucose for growth, resulting in the puzzling fact of gluconeogenic growth with strongly reduced glucose uptake in the presence of acetate in the medium. This result was proven by intracellular metabolite analysis and labelling experiments. To increase productivity, the SugR protein involved in negative regulation of the phosphotransferase system, was inactivated, resulting in enhanced consumption of glucose. However, the surplus in substrate uptake was not converted to L-valine; instead, the formation of up to 289 microM xylulose was observed for the first time in C. glutamicum. As an alternative to the genetic engineering solution, a straightforward process engineering approach is proposed. Acetate limitation resulted in a more efficient use of acetate as cosubstrate, shown by an increased biomass yield Y(X/Ac) and improved L-valine formation. PMID- 20204664 TI - The retrogasserian zone versus dorsal root entry zone: comparison of two targeting techniques of gamma knife radiosurgery for trigeminal neuralgia. AB - BACKGROUND: We performed a comparative study of the retrogasserian zone (RGZ) with the dorsal root entry zone (DREZ) target to determine effective gamma knife radiosurgery (GKRS) technique in patients with medically refractory trigeminal neuralgia (TN). METHODS: We retrospectively reviewed the records of 39 patients with refractory TN undergoing GKRS between April 2005 and October 2008. Until October 2007, DREZ was used as the primary target point. Since November 2007, RGZ has been targeted, located anterior to DREZ. The pain outcome of patient, pain recurrence, and treatment-related complications were evaluated. FINDINGS: Using the Barrow Neurologic Index (BNI) pain score, 15 (93.8%) RGZ and 20 (87.0%) DREZ cases achieved treatment success (BNI pain score I-IIIb) (p = 0.631). Seven (43.8%) RGZ and four (17.4%) DREZ patients reported complete pain relief without medications (BNI pain score I). The time to a response after the GKRS was significantly shorter in the RGZ group (mean 4.1 weeks) than in the DREZ group (mean 6.4 weeks) (p = 0.044). The total complication rate (25.0%) in the RGZ group was similar to the DREZ group (26.1%); however, frequency of bothersome facial numbness and dry eye syndrome was lower in the RGZ group (0%, 0%) compared to the DREZ group (13.1%, 8.7%) (p = 0.255 and 0.503). CONCLUSIONS: The RGZ targeting technique in the GKRS for TN had a better treatment success, with fewer bothersome complications compared to the DREZ target. PMID- 20204665 TI - In silico point mutation and evolutionary trace analysis applied to nicotinic acetylcholine receptors in deciphering ligand-binding surfaces. AB - The nicotinic acetylcholine receptors (nAChRs) are members of the Cys-loop superfamily and contain ligand gated ion channels (LGIC). These receptors are located mostly in the central nervous system (CNS) and peripheral nervous system (PNS). nAChRs reside at pre-synaptic regions to mediate acetylcholine neurotransmission and in the post synaptic membrane to propagate nerve impulses through neurons via acetylcholine. Malfunction of this neurotransmitter receptor is believed to cause various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and schizophrenia, and nAChRs are thus important drug targets. In the present work, starting from an earlier model of pentameric alpha7nAChR, a considerable effort has been taken to investigate interaction with ligands by performing docking studies with a diverse array of agonists and antagonists. Analysis of these docking complexes reveals identification of possible ligand-interacting residues. Some of these residues, e.g. Ser34, Gln55, Ser146, and Tyr166, which are evolutionarily conserved, were specifically subjected to virtual mutations based on their amino acid properties and found to be highly sensitive in the presence of antagonists by docking. Further, the study was extended using evolutionary trace analysis, revealing conserved and class specific residues close to the putative ligand-binding site, further supporting the results of docking experiments. PMID- 20204666 TI - Influenza H1N1 infection in a patient with psoriatic arthritis in treatment with Adalimumab: a case report. AB - In March 2009 was the beginning of an epidemic flue caused by avian influenza A virus H1N1. The disease varies from mild to serious and fatal cases. There are many hypotheses explaining why this virus infection would be fatal. One of these is the impaired immune response of the infected patient. The use of tumor necrosis factor-alpha inhibitors may cause decreased immune response and greater susceptibility to infections. We presented a case of a patient using adalimumab that have developed H1N1 without complications. This is the first case of H1N1 in a patient using adalimumab reported in Brazil. We discuss the possibility that anti-TNF may not predisposes to a serious form of the disease or fatal complications. PMID- 20204667 TI - Vitamin D status, dependence on age, and seasonal variations in the concentration of vitamin D in Croatian postmenopausal women initially screened for osteoporosis. AB - Vitamin D deficiency is associated with secondary hyperparathyroidism, increased bone turnover, and bone loss, leading to increased risk for osteoporotic fractures. The objective of this study was to investigate the prevalence of inadequate (insufficient or deficient) serum vitamin D levels in Croatian postmenopausal women initially screened for osteoporosis. Assessment of 25 hydroxyvitamin D (25(OH)D) was performed in 120 Croatian postmenopausal women aged > or =50 years. Three cut-off levels of vitamin D inadequacy were investigated: <75, <50, and <30 nmol/L. Among the included patients, only 14.2% of women complied with diagnostic criteria for osteoporosis. A total of nine (7.5%) had vitamin D levels greater than 75 nmol/L, suggesting that 92.5% of postmenopausal women had inadequate vitamin D status. The prevalence of two different cut-off point groups was 63.3% (<50 nmol/L) and 14.2% (<30 nmol/L). Mean (+/-SD) serum level of 25(OH)D was 46.94 (16.77) nmol/L. Vitamin D was exhibiting declining values with increasing age (r = -0.28; P = 0.002). The prevalence of vitamin D levels below 30 nmol/L was high in patient aged > or =65 years (23.8%). The highest mean level of vitamin D was detected in summer, with significant differences from spring and winter (P = 0.015 and P = 0.022, respectively). The results of this study indicate a high prevalence of vitamin D inadequacy in Croatian postmenopausal women initially screened for osteoporosis. High prevalence coupled with the rising recognition of potential clinical significance of the vitamin D inadequacy makes this highly interesting intervention target, suggesting that the attempts to increase the awareness on this issue are needed. PMID- 20204668 TI - Retrospective clinical study of the efficacy of lower-dose methotrexate and infliximab therapy in patients with rheumatoid arthritis. AB - The objective of this study is to compare the long-term outcomes of infliximab therapy with lower-dose methotrexate (MTX; < or = 4 mg per week) and with standard-dose MTX (> or = 6 mg per week) in Japanese rheumatoid arthritis (RA) patients. One hundred thirty-eight patients with refractory RA were treated with intravenous infliximab; 106 patients underwent lower-dose MTX therapy, and 32 patients underwent standard-dose MTX therapy. Treatment responses at 54 weeks or last observation carried forward (LOCF) assessed using the European League Against Rheumatism (EULAR) response criteria were compared between the two groups. Eighty-eight patients (81.1%) in the lower-dose MTX group and 27 patients (84.3%) in the standard-dose MTX therapy completed 54 weeks of infliximab treatment. A EULAR response criteria good and moderate response was seen in 70.9% in the lower-dose group and 74.1% in the standard-dose group. Good and moderate treatment responses at 54 weeks or LOCF were seen in 66.0% in the lower-dose group and 68.7% in the standard-dose group. The outcome in the lower-dose MTX group was not significantly different from that in the standard-dose group. Therapy with MTX and infliximab was effective in Japanese RA patients, regardless of MTX dosage. PMID- 20204670 TI - Vegetative phenology of alpine plants at Tateyama Murodo-daira in central Japan. AB - The vegetative phenology of 29 alpine species, including herbaceous and woody summergreens and evergreens, was investigated. Summergreen species initiated and completed leaf growth earlier than evergreen species. The green period of leaves in summergreen plants was determined largely by the time of growth initiation. Early initiation of growth in summergreen plants contributes to the increase in photosynthetic carbon gain. Early cessation of growth in summergreens is advantageous for the growth in the following year because it leads to an increase in stored photosynthates. The growth period of leaves and stems in alpine plants correlated with the time of growth initiation more strongly than with the time of growth cessation, indicating the importance of early growth initiation for the increase in plant growth. The growth period of leaves was positively correlated with the sum of leaf lengths and the number of leaves. Herbs with a long growth period of more than 50 days had perennial shoot axes not terminated by inflorescences, suggesting a relationship between the growth period and shoot habit. Two summergreen species were completely dead by mid-September, before the air temperature decreased below 0 degrees C. The remaining summergreen species died immediately after the air temperature decreased to -1.4 degrees C in late September. PMID- 20204669 TI - Endothelial dysfunction in ankylosing spondylitis improves after tumor necrosis factor-alpha blockade. AB - Chronic inflammation in ankylosing spondylitis (AS) is associated with vascular endothelial dysfunction. Infliximab improves inflammatory disease activity in AS patients, but its effect on endothelial dysfunction has still not been tested in these patients. Twelve anti-TNF naive AS patients (mean age, 32.6 +/- 3.94 years; disease duration, 5.6 +/- 0.8 years) with high disease activity [Bath ankylosing spondylitis disease activity index (BASDAI score > 4)] despite treatment with stable doses of conventional disease modifying anti-rheumatic drugs (DMARDs) were investigated. Inflammatory disease activity [BASDAI and Bath ankylosing spondylitis functional index (BASFI) scores, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels], serum nitrite concentration, and endothelium-dependent and endothelium-independent vasodilation of the brachial artery were measured at baseline and 12 weeks of therapy after single intravenous infusion of infliximab (5 mg/kg). Previous DMARD(s) regimen remained unchanged throughout the study period. After treatment with infliximab, flow-mediated vasodilation improved from 9.81 +/- 1.70% to 26.93 +/- 2.34% (p < 0.001), whereas there was no significant change in endothelium-independent vasodilation with nitroglycerin and baseline diameter (13.65 +/- 2.10% versus 14.59 +/- 1.93%, p = 0.08, and 4.45 +/- 0.15 versus 4.46 +/- 0.15 mm, p = 0.3, respectively). Nitrite concentration reduced from 6.50 +/- 0.21 to 2.57 +/- 0.18 micromol/l (p < 0.001), ESR from 40.90 +/- 6.00 to 11.50 +/- 1.38 mm in the first hour (p < 0.001), and CRP level from 29.08 +/- 4.11 to 2.69 +/- 0.43 mg/dl (p < 0.001). BASDAI and BASFI scores were significantly reduced from 5.40 +/- 1.14 to 1.40 +/- 0.70 (p < 0.05) and 5.05 +/- 1.76 to 0.20 +/- 0.63 (p < 0.05), respectively. The study suggests that in ankylosing spondylitis, endothelial dysfunction is a part of the disease process and infliximab improves both endothelial dysfunction and inflammatory disease activity. PMID- 20204671 TI - Autotrophic and heterotrophic respiration in needle fir and Quercus-dominated stands in a cool-temperate forest, central Korea. AB - To investigate annual variation in soil respiration (R (S)) and its components [autotrophic (R (A)) and heterotrophic (R (H))] in relation to seasonal changes in soil temperature (ST) and soil water content (SWC) in an Abies holophylla stand (stand A) and a Quercus-dominated stand (stand Q), we set up trenched plots and measured R (S), ST and SWC for 2 years. The mean annual rate of R (S) was 436 mg CO(2) m(-2) h(-1), ranging from 76 to 1,170 mg CO(2) m(-2) h(-1), in stand A and 376 mg CO(2) m(-2) h(-1), ranging from 82 to 1,133 mg CO(2) m(-2) h(-1), in stand Q. A significant relationship between R (S) and its components and ST was observed over the 2 years in both stands, whereas a significant correlation between R (A) and SWC was detected only in stand Q. On average over the 2 years, R (A) accounted for approximately 34% (range 17-67%) and 31% (15-82%) of the variation in R (S) in stands A and Q, respectively. Our results suggested that vegetation type did not significantly affect the annual mean contributions of R (A) or R (H), but did affect the pattern of seasonal change in the contribution of R (A) to R (S). PMID- 20204672 TI - Diet and feeding patterns in the kipunji (Rungwecebus kipunji) in Tanzania's Southern Highlands: a first analysis. AB - The diet and feeding behaviour of the kipunji (Rungwecebus kipunji) was studied over 45 months, the first dietary analysis for this species. During 9498 h of direct observation of 34 kipunji groups, a list of 122 identified foodplants was recorded. The list represents 60 families, including 64 trees, 30 herbs, 9 climbers, 7 shrubs, 6 lianas, 3 grasses and 3 ferns. Kipunji were observed eating bark, young and mature leaves, ripe and unripe fruits, flowers, pith, seed pods, rhizomes, tubers, shoots and stalks. Invertebrates, fungi, moss, lichen, and soil were also eaten. Macaranga capensis var. capensis, an early successional tree, was the most commonly consumed species, with leaves, leaf stalks, pith, flowers and bark all eaten. We demonstrate that the kipunji is an omnivorous dietary generalist, favouring mature and immature leaves, ripe and unripe fruits and bark in similar proportions, with an almost comparable fondness for leaf stalks and flowers. Kipunji appear to be adaptable foragers able to modify their diet seasonally, being more folivorous in the dry season and more frugivorous in the wet. Whereas more ripe fruit is eaten in the wet season, the proportion of unripe fruit remains similar across the year. The proportion of mature leaves and pith increases throughout the dry season at the expense of ripe fruits and bark, and this may compensate nutritionally for the lack of available dry-season ripe fruits. Relatively more pith is eaten in the dry season, more stalks at the end of the dry and beginning of the wet seasons, and bark consumption increases as the rainfall rises. PMID- 20204673 TI - Baicalin induces human mucoepidermoid carcinoma Mc3 cells apoptosis in vitro and in vivo. AB - Mucoepidermoid carcinoma (MEC) is the most common malignant tumor in salivary glands and high-grade MEC in particular demonstrates little response to chemotherapy which has been used largely for palliative treatment of metastatic disease. Baicalin, one of the main active compounds of Scutellaria baicalensis, possesses anti-inflammatory, antioxidant and antitumor properties. In the present study, we investigated the growth inhibiting and apoptosis-inducing effects of baicalin on a highly metastatic human mucoepidermoid carcinoma cell line Mc3 for the first time. Baicalin exerted dose- and time-dependent antiproliferative potential against Mc3 cells as assessed by MTT assay. Baicalin treatment of Mc3 cells resulted in an accumulation of cells at the G0/G1 and G2/M phase with a concomitant decrease in cells processing to S phase as assessed by flow cytometry. Furthermore, baicalin induced apoptosis of Mc3 cells as determined by annexin V binding and PI dual staining, DNA fragmentation, nuclear condensation and in vivo tumor inhabitation. Rhodamine 123 assay indicated that baicalin caused cytotoxicity and induced apoptosis through decreasing the mitochondrial membrane potential in Mc3 cells. Our results suggest that baicalin seems to be very attractive as a new anticancer drug and a potential chemotherapeutic agent against human high-grade mucoepidermoid carcinoma. PMID- 20204674 TI - A randomized phase II study of raltitrexed and gefitinib versus raltitrexed alone as second line chemotherapy in patients with colorectal cancer. (1839IL/0143). AB - PURPOSE: To determine the efficacy of the addition of gefitinib to raltitrexed in patients with colorectal cancer (CRC) that have progressed after first line chemotherapy. The study also sought to explore the safety of the combination and to investigate biomarkers predictive outcome. METHODS: A total of 76 patients were randomized to raltitrexed (3 mg/m(2) i.v.) every 21 days plus either daily gefitinib (250 mg p.o.) or placebo. The primary endpoint of the study was progression free survival (PFS). Tumor tissues were collected to determine the expression of EGFR, pEGFR, pMAPK, and pAkt. RESULTS: Both groups were well balanced with regard to prognostic factors. Treatment was well tolerated with no increased in toxicity except diarrhea and skin rash in the combination group. There were no differences in PFS between the combination arm [63 days (95% CI: 57 84)] compared to the raltitrexed alone arm [72 days (95% CI: 59-132)], or overall survival 361 days (95% CI: 283-533 days) versus 291 days (95% CI: 255-539 days) respectively. The objective response rate was 7.9% (3 patients) (CI 95%: 1,66 21,38) versus 5.3% (2 patients) (CI 0,64-17,75), respectively. The biomarker studies were not conclusive. CONCLUSION: The combination of raltitrexed and gefitinib was well tolerated although was not associated with improved progression free survival in patients with refractory CRC. PMID- 20204675 TI - TMKP1 is a novel wheat stress responsive MAP Kinase phosphatase localized in the nucleus. AB - The regulation of plant signalling responses by Mitogen-Activated Protein Kinases (MAPKs)-mediated protein phosphorylation is well recognized. MAP kinase phosphatases (MKPs) are negative regulators of MAPKs in eukaryotes. We report here the identification and the characterization of TMKP1, the first wheat MKP (Triticum turgidum L. subsp. Durum). Expression profile analyses performed in two durum wheat cultivars showing a marked difference in salt and drought stress tolerance, revealed a differential regulation of TMKP1. Under salt and osmotic stress, TMKP1 is induced in the sensitive wheat variety and repressed in the tolerant one. A recombinant TMKP1 was shown to be an active phosphatase and capable to interact specifically with two wheat MAPKs (TMPK3 and TMPK6). In BY2 tobacco cells transiently expressing GFP::TMKP1, the fusion protein was localized into the nucleus. Interestingly, the deletion of the N-terminal non catalytic domain results in a strong accumulation of the truncated fusion protein in the cytoplasm. In addition, when expressed in BY2 cells, TMPK3 and TMPK6 fused to red fluorescent protein (RFP) were shown to be present predominantly in the nucleus. Surprisingly, when co-expressed with the N-terminal truncated TMKP1 fusion protein; both kinases are excluded from the nuclear compartment and accumulate in the cytoplasm. This strongly suggests that TMKP1 interacts in vivo with TMPK3 and TMPK6 and controls their subcellular localization. Taken together, our results show that the newly isolated wheat MKP might play an active role in modulating the plant cell responses to salt and osmotic stress responses. PMID- 20204676 TI - Antiproliferative effect of peripheral benzodiazepine receptor antagonist PK11195 in rat mammary tumor cells. AB - This study aims to establish the antiproliferative effects of PK11195, a peripheral benzodiazepine receptor antagonist (PBR) in rat mammary tumor cells. Breast tumors were induced by administration of a carcinogen, dimethylbenz[a]anthracene to 50-day-old female rats maintained on a standard AIN 76A diet with casein as the protein source. The tumors were developed approximately after 120 days. The tumors were of grade I (20%), grade II (60%), and grade III (20%). The tumors were isolated and cultured in DMEM/F12 media with supplements. We characterized the properties of the isolated cells and study the effect of PK11195 on those cells. We were successful in growing breast tumor cells up to 30 passages for cellular characterization. These cells had high reactivity with Ki-67 and PCNA antibodies suggesting high proliferation rate. These cells were highly invasive as evident by matrigel invading ability. Furthermore, these cells acquired a positive response for CD-31 and VEGF antibodies suggesting angiogenic potential, and also possessed migrating ability/motility as evident by the wound healing properties. These cells expressed elevated levels of PBR, a cancer promoting gene. The proliferation, invasion and migration appear to decrease when treated with PK11195, a PBR antagonist. Furthermore, PK11195 treatment caused an increase in apoptosis as evident by increase in the levels of annexin V. However, the inhibition of cell proliferation by PK11195 was counteracted by Ro5-4864, a PBR agonist. Thus, PBR antagonist may be a potential therapeutic agent for the control of aggressiveness of breast cancer. PMID- 20204677 TI - ROS-NFkappaB mediates TGF-beta1-induced expression of urokinase-type plasminogen activator, matrix metalloproteinase-9 and cell invasion. AB - TGF-beta1 has been postulated as a pro-oncogenic factor in the late step of the tumoral progression. In transformed cells, TGF-beta1 enhances the capacity to degrade the extracellular matrix, cell invasiveness and epithelial-mesenchymal transition, which are crucial steps for metastasis. Urokinase-type plasminogen activator (uPA) and matrix metalloproteinase-9 (MMP-9) are critical components in cell migration and invasion induced by TGF-beta1, however, the exact mechanism by which TGF-beta1 regulates uPA and MMP-9 is not well elucidated so far. In the present study, we analyzed the role of ROS-NFkappaB, signal as mediator in the cell malignity enhancement by TGF-beta1. We found that TGF-beta1 activates NFkappaB, through Rac1-NOXs-ROS-dependent mechanism. Our results shows that TGF beta1 stimulation of uPA and MMP-9 expression involve NOXs-dependent ROS and NFkappaB, activation, demonstrated by using DPI, NOXs inhibitor, ROS scavenger N acetylcysteine and SN50, an NFkb inhibitor. Furthermore, we found that the inhibition of ROS and NFkappaB, abrogates TGF-beta1 stimulation of EMT, cell motility and invasion. Thus, ROS-NFkappaB acts as the crucial signal in TGF-beta1 induced uPA and MMP-9 expression thereby mediating the enhancement of cellular malignity by TGF-beta1. PMID- 20204678 TI - The glycan profile of endothelial cells in the present of tumor-conditioned medium and potential roles of beta-1,6-GlcNAc branching on HUVEC conformation. AB - Endothelium plays a vital role in the logistics of the immune system, as well as the maintenance of the homeostasis. The major objective of this study is to unravel the relationship between expression changes of carbohydrate structures and the dysfunction of human umbilical vein endothelial cells (HUVEC) stimulated with tumor-conditioned medium (TCM), which is involved in tumor cell extravasation. Using flow cytometry (FCM) assay, the expression profiles of a selected group of 9 carbohydrate structures have been determined in HUVEC under control conditions and TCM-treated conditions, six of which increased significantly in expression after induction. Particularly, the expression level of beta-1,6-GlcNAc branching glycan was extremely higher after the stimulation. In parallel, the conformation change of HUVEC monolayer has been detected with inverted phase contrast microscopy and confocal microscopy. Under TCM stimulation, the actin cytoskeleton underwent rearrangement and formed abundant stress fiber within cells; therefore cell contraction was induced, which resulted in paracellular gap formation and barrier dysfunction. We furthered our study to investigate the mechanism underlying the conformation change of HUVEC. The results demonstrated that TCM induced the increase in beta-1,6-GlcNAc branching expression of PECAM-1, accompanied by the tyrosine phosphorylation of PECAM-1. The downstream effector RhoA was activated in consequence of the activation of PECAM-1. In conclusion, our results strongly suggested that the carbohydrate composition of endothelial cell surface is very important for the cells to exert their physiological effects correlated with cancer extravasation. PMID- 20204679 TI - Kynurenine-induced photo oxidative damage to lens in vitro: protective effect of caffeine. AB - Photochemical generation of reactive species of oxygen in the lens and aqueous and consequent physiological damage to the tissue has been implicated in the genesis of human cataracts. The present studies were undertaken to examine the feasibility of possible prevention of such damage to the lens initiated by UV activation of kynurenine, a well-known photosensitizer in the human lens. The studies were done by organ culturing intact mouse lenses in medium containing kynurenine and exposed to UVA. Tissue damage was assessed by the inhibition of its ability to carry active transport of rubidium ions and the associated decrements in the levels of GSH and ATP. These deleterious effects were significantly prevented by caffeine, an alkaloid present in many common beverages and known to chemically deactivate the said oxygen derivatives. Further studies on the pharmacological significance of the findings are hence in progress. PMID- 20204680 TI - Interaction between visual and olfactory cues during host finding in the tomato fruit fly Neoceratitis cyanescens. AB - Herbivorous insects searching for a host plant need to integrate a sequence of multimodal sensory inputs. We conducted a series of no-choice experiments in a laboratory wind tunnel to examine the behavioral response of the specialist fruit fly, Neoceratitis cyanescens (Diptera: Tephritidae), to host visual and olfactory stimuli presented singly or in combination (e.g., colored fruit model with or without host fruit odor). We also studied the influence of wind flow, age, and sex on the response of flies. In two-choice experiments, we evaluated the ability of mature females to discriminate between two fruit models emitting host vs. non host fruit odor or clean air. Neoceratitis cyanescens mature females can use independently or interactively olfactory and visual stimuli to locate their host, whereas immature females and males respond primarily to host fruit odor. In the absence of wind, mature females mainly use visual information to locate the host fruit. In wind, host fruit odor significantly increases the probability and speed of locating the host fruit. In a two-choice situation between two bright orange spheres, flies accurately detected the sphere emitting host fruit odor vs. non host fruit odor or odorless air. Nevertheless, they preferred to land on the bright orange sphere when the sphere emitting host fruit odor was blue. Furthermore, when odor source and fruit model were spatially decoupled (90 or 180 degrees ), >50% flies that landed on the fruit model initially performed an oriented flight toward the odor source, then turned back to the fruit model while in flight or after one landing, thus suggesting visual information to be the ultimate indicator of host fruit. PMID- 20204681 TI - A spectroscopic study of 2-[4'-(dimethylamino)phenyl]-benzothiazole binding to insulin amyloid fibrils. AB - The spectroscopic properties of 2-[4'-(dimethylamino)phenyl]-benzothiazole (BTA 2) in solution and in the presence of amyloid fibrils were investigated using absorption and fluorescence spectroscopy. Solution studies show that BTA-2 forms micelles in aqueous solutions, but that the dye can be solvated upon the addition of acetonitrile (CH(3)CN). BTA-2 binds to amyloid fibrils in solution leading to a characteristic blue-shift in the emission spectrum and an increase in fluorescence intensity. However, in solutions with increasing CH(3)CN concentration, there was a marked decrease in binding of the BTA-2 to fibrils. Studies demonstrating the effect of BTA-2 concentration on binding were performed. A comparison with the standard amyloid fluorescent marker, thioflavin T (ThT), showed that BTA-2 is more fluorescent, making it an excellent dye to label amyloid samples. PMID- 20204682 TI - Fluorescence enhancement of the silver nanoparticales--curcumin cetyltrimethylammonium bromide-nucleic acids system and its analytical application. AB - It is found that silver nanoparticles (AgNPs) can further enhance the fluorescence intensity of curcumin (CU)-cetyltrimethylammonium bromide (CTAB) nucleic acids and improve its anti-photobleaching activity. Under optimum conditions, the enhanced fluorescence intensity is proportion to the concentration of nucleic acids in the range of 2.0 x 10(-8)-1.0 x 10(-6) g mL(-1) for fish sperm DNA (fsDNA), 2.0 x 10(-8)-1.0 x 10(-6) g mL(-1) for calf thymus DNA (ctDNA), 1.0 x 10(-8)-1.0 x 10(-6) g mL(-1) for yeast RNA (yRNA), and their detection limits (S/N = 3) are 8.0 ng mL(-1), 10.5 ng mL(-1) and 5.8 ng mL(-1), respectively. This method is used for determining the concentration of DNA in actual sample with satisfactory results. The interaction mechanism is also studied. PMID- 20204683 TI - Conformational and functional transitions in class II alpha-mannosidase from Aspergillus fischeri. AB - The conformational transitions in an oligomeric and high molecular weight class II alpha-mannosidase from Aspergillus fischeri were examined using fluorescence and CD spectroscopy under chemical, thermal and acid denaturing conditions. The enzyme lost the activity first and then the overall folded conformation and secondary structure. The midpoint values of GdnHCl mediated changes measured by inactivation; fluorescence and negative ellipticity were 0.48 M, 1.5 M and 1.9 M, respectively. The protein almost completely unfolded in 4.0 M GdnHCl but not at 90 degrees C. The inactivation and unfolding were irreversible. At pH 2.0, the protein exhibited molten-globule like intermediate with rearranged secondary and tertiary structures and exposed hydrophobic amino acids on the surface. This species showed increased accessibility of Trp to the quenchers and got denatured with GdnHCl in a different manner. The insoluble aggregates of a thermally denatured protein could be detected only in the presence of 0.25-0.75 M GdnHCl. PMID- 20204684 TI - Interaction of imidacloprid with hemoglobin by fluorescence and circular dichroism. AB - Imidacloprid belongs to a major new class of insecticides, called neonicotinoids, which are accounting for 11-15% of the total insecticide market. The binding characteristics of insecticide imidacloprid with hemoglobin (Hb) have been studied by employing different spectroscopic techniques. The results proved the formation of complex between imidacloprid and Hb. Hydrophobic interaction and hydrogen bond dominated in the association reaction. Hydrophobic probe 8-anilino 1-naphthalenesulfonic acid (ANS) competitive experiments indicated that the binding of imidacloprid to Hb primarily took place in hydrophobic regions. The distance between Hb donor and acceptor imidacloprid was 4.88 nm as derived from Forster's theory. Alternations of Hb secondary structure in the presence of imidacloprid were confirmed by synchronous fluorescence, circular dichroism (CD) and three-dimensional fluorescence spectra. This study enriches our understanding of toxic effect of imidacloprid to the physiologically important protein Hb. PMID- 20204685 TI - Spectroscopic properties and energy transfer analysis of Tm3+-doped BaF2-Ga2O3 GeO2-La2O3 glass. AB - This paper reports on the spectroscopic properties and energy transfer analysis of Tm(3+)-doped BaF(2)-Ga(2)O(3)-GeO(2)-La(2)O(3) glasses with different Tm(2)O(3) doping concentrations (0.2, 0.5, 2.0, 2.5, 3.0, 3.5, 3.5, 4.0 wt%). Mid IR fluorescence intensities in the range of 1,300 nm-2,200 nm have been measured when excited under an 808 nm LD for all the samples with the same pump power. Energy level structure and Judd-Ofelt parameters have been calculated based on the absorption spectra of Tm(3+), cross-relaxation rates and multi-phonon relaxation rates have been estimated with different Tm(2)O(3) doping concentrations. The maximum fluorescence intensity at around 1.8 mum has been obtained in Tm(2)O(3)-3 wt% sample and the maximum value of calculated stimulated emission cross-section of Tm(3+) in this sample is about 0.48 x 10(-20) cm(2) at 1,793 nm, and there is not any crystallization peak in the DSC curve of this sample, which indicate the potential utility of Tm(3+)-doped BaF(2)-Ga(2)O(3) GeO(2)- La(2)O(3) glass for 2.0-microm optical fiber laser. PMID- 20204686 TI - Influences of neighborhood context, individual history and parenting behavior on recidivism among juvenile offenders. AB - This study examined the effects of neighborhood context on juvenile recidivism to determine if neighborhoods influence the likelihood of reoffending. Although a large body of literature exists regarding the impact of environmental factors on delinquency, very little is known about the effects of these factors on juvenile recidivism. The sample analyzed includes 7,061 delinquent male juveniles committed to community-based programs in Philadelphia, of which 74% are Black, 13% Hispanic, and 11% White. Since sample youths were nested in neighborhoods, a hierarchical generalized linear model was employed to predict recidivism across three general categories of recidivism offenses: drug, violent, and property. Results indicate that predictors vary across the types of offenses and that drug offending differs from property and violent offending. Neighborhood-level factors were found to influence drug offense recidivism, but were not significant predictors of violent offenses, property offenses, or an aggregated recidivism measure, despite contrary expectations. Implications stemming from the finding that neighborhood context influences only juvenile drug recidivism are discussed. PMID- 20204687 TI - Life satisfaction and student engagement in adolescents. AB - Situated within a positive psychology perspective, this study explored linkages between adolescent students' positive subjective well-being and their levels of engagement in schooling. Specifically, using structural equation modeling techniques, we evaluated the nature and directionality of longitudinal relationships between life satisfaction and student engagement variables. It was hypothesized that adolescents' life satisfaction and student engagement variables would show bidirectional relationships. To test this hypothesis, 779 students (53% female, 62% Caucasian) in a Southeastern US middle school completed a measure of global life satisfaction and measures of cognitive, emotional, and behavioral engagement at two time points, 5 months apart. A statistically significant bidirectional relationship between life satisfaction and cognitive engagement was found; however, non-significant relationships were found between life satisfaction and emotional and behavioral student engagement. The findings provide important evidence of the role of early adolescents' life satisfaction in their engagement in schooling during the important transition grades between elementary and high school. The findings also help extend the positive psychology perspective to the relatively neglected context of education. PMID- 20204688 TI - Parents' self-efficacy beliefs and their children's psychosocial adaptation during adolescence. AB - Research has shown that parents' perceived parental self-efficacy (PSE) plays a pivotal role in promoting their children's successful adjustment. In this study, we further explored this issue by comparing psychosocial adaptation in children of parents with high and low PSE during adolescence. One hundred and thirty Italian teenagers (55 males and 75 females) and one of their parents (101 mothers and 29 fathers) participated in the research. Data were collected at T1 (adolescents' mean age = 13.6) and T2 (mean age = 17.5). Parents reported their PSE at T1. At T1 and T2, adolescents reported their perceived academic self efficacy, aggressive and violent conducts, well-being, and perceived quality of their relationships with parents. At T2, they were also administered questions by using Experience Sampling Method to assess their quality of experience in daily life. As hypothesized, adolescents with high PSE parents reported higher competence, freedom and well-being in learning activities as well as in family and peer interactions. They also reported fewer problematic aspects and more daily opportunities for optimal experience. Findings pointed to the stability of adolescents' psychosocial adaptation and highlighted possible directions in future research. PMID- 20204689 TI - Promoting social skill development in children with pervasive developmental disorders: a feasibility and efficacy study. AB - A randomized controlled design was employed to evaluate a social skills intervention for children with pervasive developmental disorders. Aims included evaluating the acceptability of the program and gathering preliminary evidence on efficacy. Forty-four children, ages 8-11 years, were randomly assigned to treatment or wait list. Treatment consisted of a 16-week group intervention designed to teach appropriate social behavior. Between group comparisons showed that children in treatment were rated as improved on the primary outcome measure, (unblinded parent report), but not on the secondary outcome measure, a parent questionnaire. Parents reported a high level of satisfaction with the intervention. The study supports the feasibility of this intervention to families and highlights challenges for future research in social skills intervention. PMID- 20204690 TI - Characterizing community-based mental health services for children with autism spectrum disorders and disruptive behavior problems. AB - This study describes the characteristics of children with autism spectrum disorders (ASD) with disruptive behavior problems served in community-based mental health clinics, characterizes psychotherapy process and outcome, and examines differences between children with ASD and a non-ASD comparison group. Results indicate that children with ASD served in this setting are high functioning and diagnostically complex. Certain research-based behavioral and cognitive behavioral psychotherapeutic strategies were observed frequently, while parent training strategies and active teaching strategies were observed less frequently. The intensity or thoroughness with which strategies were pursued was relatively low. Outcome analyses indicate improvement in child symptoms and family functioning. Treatment delivery and outcome were similar for children with and without ASD. These findings represent the first detailed observational data characterizing community-based mental health services for children with ASD. PMID- 20204691 TI - Digestive enzyme supplementation for autism spectrum disorders: a double-blind randomized controlled trial. AB - To examine the effects of a digestive enzyme supplement in improving expressive language, behaviour and other symptoms in children with Autism Spectrum Disorder. Randomized, double-blind placebo-controlled trial using crossover design over 6 months for 43 children, aged 3-8 years. Outcome measurement tools included monthly Global Behaviour Rating Scales, Additional Rating Scales of other symptoms by parents and therapists, and monthly completion of the Rescorla Language Development Survey. Compared with placebo, treatment with enzyme was not associated with clinically significant improvement in behaviour, food variety, gastrointestinal symptoms, sleep quality, engagement with therapist, or the Language Development Survey Vocabulary or Sentence Complexity Scores. A small statistically significant improvement on enzyme therapy was seen for the food variety scores. No clinically significant effect improvement of autism symptoms with enzyme use was shown with this trial, however, possible effects on improvement in food variety warrants further detailed investigation. PMID- 20204692 TI - Behavioral surveillance of heterosexual exchange-sex partnerships in San Francisco: context, predictors and implications. AB - Using San Francisco local data from the 2006 National HIV Behavioral Surveillance (NHBS), we initiated a study of male and female heterosexuals' involvement in exchange sex (money or goods for sex). We examined risk factors for engaging in exchange sex and the prevalence of risk behaviors amongst exchange and non exchange partnerships. Overall, 13.2% of women and 7.6% of men engaged in exchange sex in the past 6 months; 130 of 1,230 (10.6%) opposite-sex partnerships involved exchange. Women of low socioeconomic status and those who inject drugs were more likely to engage in exchange sex. Men involved in exchange sex were no different from those who did not by age, socio-economic status, marital status, drug use, or history of incarceration or sexually transmitted diseases. Within exchange partnerships, high or drunk sex was more common than unprotected sex. Exchange partnerships had fewer instances of risky sex. In comparison to exchange partnerships, non-exchange partnerships had four times as many episodes of unprotected vaginal sex and twice as many episodes of high or drunk vaginal sex. Prevention efforts addressing exchange sex need to address substance use. Future research and surveillance are needed to better understand the sources of HIV risk and measure and track trends in risk within sexual dyads and networks. PMID- 20204693 TI - The evolutionarily conserved interaction between LC3 and p62 selectively mediates autophagy-dependent degradation of mutant huntingtin. AB - Mammalian p62/sequestosome-1 protein binds to both LC3, the mammalian homologue of yeast Atg8, and polyubiquitinated cargo proteins destined to undergo autophagy mediated degradation. We previously identified a cargo receptor-binding domain in Atg8 that is essential for its interaction with the cargo receptor Atg19 in selective autophagic processes in yeast. We, thus, sought to determine whether this interaction is evolutionally conserved from yeast to mammals. Using an amino acid replacement approach, we demonstrate that cells expressing mutant LC3 (LC3 K30D, LC3-K51A, or LC3-L53A) all exhibit defective lipidation of LC3, a disrupted LC3-p62 interaction, and impaired autophagic degradation of p62, suggesting that the p62-binding site of LC3 is localized within an evolutionarily conserved domain. Importantly, whereas cells expressing these LC3 mutants exhibited similar overall autophagic activity comparable to that of cells expressing wild-type LC3, autophagy-mediated clearance of the aggregation-prone mutant Huntingtin was defective in the mutant-expressing cells. Together, these results suggest that p62 directly binds to the evolutionarily conserved cargo receptor-binding domain of Atg8/LC3 and selectively mediates the clearance of mutant Huntingtin. PMID- 20204694 TI - Accumulation of heavy metals with water quality parameters in Kizilirmak River Basin (Delice River) in Turkey. AB - Kizilirmak River has been used as Ankara's drinking water source for approximately 1.5 years. Therefore, this region's water, sediment, and fish samples are measured for detecting the heavy metals. This is important for the current situation as well as the future in terms of potential impact. The amount of heavy metals in drinking water should be within the limited values; otherwise, the accumulation of heavy metals will cause many problems to living organisms. Especially high levels of arsenic, cadmium, nickel, mercury, etc. are very dangerous to freshwater ecosystems as for human if the water is being use as drinking water. In this study, water, sediment samples, muscle, and gills of three fish species (Capoeta tinca, Capoeta capoeta, Leuciscus cephalus) were analyzed for the presence of heavy metals such as (Al, Fe, As, Cd, Ni, Mn, Se, Si) to determine present accumulation levels and possible toxic effect. The accumulation pattern of heavy metals in the water, sediment, and fish tissue follows the sequence: Si>Fe>Al>Mn>As>Ni>Se>Cd, Fe>Al>Mn>Ni>As>Se>Cd, and Fe>Al>Mn>As>Ni>Si>Cd. In addition, the detected concentrations of heavy metals in the Kizilirmak and Delice Rivers are compared with other heavy metal studies in the other main rivers and lakes in Turkey. PMID- 20204695 TI - Transgenic expression in citrus of single-chain antibody fragments specific to Citrus tristeza virus confers virus resistance. AB - Citrus tristeza virus (CTV) causes one of the most destructive viral diseases of citrus worldwide. Generation of resistant citrus genotypes through genetic engineering could be a good alternative to control CTV. To study whether production of single-chain variable fragment (scFv) antibodies in citrus could interfere and immunomodulate CTV infection, transgenic Mexican lime plants expressing two different scFv constructs, separately and simultaneously, were generated. These constructs derived from the well-referenced monoclonal antibodies 3DF1 and 3CA5, specific against CTV p25 major coat protein, whose mixture is able to detect all CTV isolates characterized so far. ScFv accumulation levels were low and could be readily detected just in four transgenic lines. Twelve homogeneous and vigorous lines were propagated and CTV challenged by graft inoculation with an aggressive CTV strain. A clear protective effect was observed in most transgenic lines, which showed resistance in up to 40 60% of propagations. Besides, both a delay in symptom appearance and attenuation of symptom intensity were observed in infected transgenic plants compared with control plants. This effect was more evident in lines carrying the 3DF1scFv transgene, being probably related to the biological functions of the epitope recognized by this antibody. This is the first report describing successful protection against a pathogen in woody transgenic plants by ectopic expression of scFv recombinant antibodies. PMID- 20204696 TI - CMV in moderately active colitis: much ado about nothing? PMID- 20204697 TI - Endoscopic resection of small gastrointestinal stromal tumors. AB - BACKGROUND: The common treatment principle of gastrointestinal stromal tumors (GISTs) is complete resection of the tumor. The rapid development of endoscopic skill makes it possible to resect GISTs en-bloc through the endoscopic approach. AIMS: The aim of this study is to evaluate the feasibility of endoscopic resection for small-size (<30 mm) gastric GISTs. METHODS: A total of 25 patients with gastric GISTs underwent endoscopic resection assisted with needle knife, loop, and snare. Clinical data, perioperative outcomes, tumor size and microscopic characteristics, immunohistochemical staining results, and follow-up outcomes were recorded. RESULTS: Endoscopic resection was successfully accomplished in 25 patients at age of 56.72 +/- 11.42 years. The average operation time was 58.52 +/- 21.84 min. Perforation for 2-6 mm occurred in seven patients (28%) and was closed well with clips, with no conversions to open surgery. No mortalities occurred. All tumors were located in the stomach, and had an average size of (11.64 +/- 6.12) mm (5-30 mm). The average length of hospitalization was 4.28 +/- 0.84 days. Out of the total of 25 patients, 21 (84%) were at very low risk and only one (4%) was at intermediate risk. Positive rate of CD117 and CD34 was 92 and 84%, respectively. A follow-up for 11.44 +/- 5.79 months (2-23 months) showed no recurrence or metastasis. CONCLUSIONS: Endoscopic resection is feasible, safe, and effective for small-size gastric GISTs (<30 mm). Short-term follow-up evaluation merits favorable clinical results. PMID- 20204699 TI - Evaluation of the potential clinical application of low-intensity ultrasound stimulation for preventing osteoporotic bone fracture. AB - This study evaluated the possible clinical application of low-intensity ultrasound (LIUS) stimulation for preventing osteoporotic bone fracture. Eight virgin 14-week-old ICR mice (weight 24.0 +/- 0.7 g) were ovariectomized to induce osteoporosis. The right hind limbs (US limbs) were stimulated with LIUS, whereas the left hind limbs (CON limbs) were not stimulated. LIUS was applied for 20 min a day, 5 days a week over a 6-week period using the following parameters: 1.5 MHz frequency, 1.0 kHz pulse repetition, 30 mW/cm(2) intensity, and 200 mus pulse length. The effective structural modulus increased significantly (p < 0.05) in the US limbs over time with the increased bone quantity, whereas that in CON limbs remained statistically constant (p > 0.05). In addition, the elastic modulus in the US limbs was generally enhanced by an increased bone quality, compared with the CON limbs. Therefore, LIUS stimulation may effectively reduce the risk of osteoporotic bone fracture by increasing the mechanical characteristics of bone via improvements in both the effective structural and elastic modulus of the osteoporotic bone. In conclusion, LIUS may potentially prove very effective clinically for preventing osteoporotic bone fractures. PMID- 20204698 TI - Prescreening of a high-risk group for gastric cancer by serologically determined Helicobacter pylori infection and atrophic gastritis. AB - BACKGROUND: Though gastric cancer screening by X-ray examination has been confirmed to be effective for reducing gastric cancer mortality, decreases in efficiency have been pointed out. Establishment of an effective screening system, focusing on high-risk status such as Helicobacter pylori infection and atrophic gastritis, is desirable. To date, combined use of serum anti-Helicobacter pylori antibodies and pepsinogen measurement has been assessed prospectively in participants in opportunistic and workplace health check-ups; however, there are no reports of population-based cohort study. AIMS: To clarify the population based risk of Helicobacter pylori infection and atrophic gastritis for gastric cancer, a cohort study was conducted in rural towns in Kyoto Prefecture. METHODS: Subjects were 1,011 males and 1,848 females recruited in a health check-up in 1987. Their serum was examined for anti-Helicobacter pylori antibodies and pepsinogen I and II. Gastric cancer cases were assessed from the cancer registry of those towns. RESULTS: Up to the end of 1996, 33 males and 28 females developed gastric cancer. A sex- and age-adjusted hazard ratio was calculated by Cox's proportional model. Helicobacter pylori infection increased the risk of gastric cancer even when the subjects had no atrophy (hazard ratio =4.20; 95% confidence interval, 0.96-18.40). The risk increased further when they had both Helicobacter pylori infection and atrophy (hazard ratio =11.23; 95% confidence interval, 2.71 46.51). Subjects with atrophy but negative for anti-Helicobacter pylori antibodies had the highest risk (hazard ratio =14.81; 95% confidence interval, 2.47-88.80). CONCLUSIONS: A high-risk group for gastric cancer can be selected by serological prescreening. PMID- 20204700 TI - Binary segmentation masks can improve intrasubject registration accuracy of bone structures in CT images. AB - Registration of bone structures is a common problem in medical research as well as in clinical applications. Intrasubject rigid 3D monomodality registration of segmented bone structures of CT images and multimodality registration of muMR and segmented muCT bone images were performed with the multiresolution intensity based technique implemented in ITK. The registration results for binary volumes of interest (VOI) masks and for segmented gray value VOIs were compared. To determine the registration quality, in the monomodality case the sum of squared difference, the sum of absolute differences, and the normalized symmetric difference of binary masks and in the multimodality case Mattes mutual information were applied. The use of binary VOI masks was significantly superior to the use of gray value VOIs. PMID- 20204701 TI - Simplified pulse reactor for real-time long-term in vitro testing of biological heart valves. AB - Long-term function of biological heart valve prostheses (BHV) is limited by structural deterioration leading to failure with associated arterial hypertension. The objective of this work was development of an easy to handle real-time pulse reactor for evaluation of biological and tissue engineered heart valves under different pressures and long-term conditions. The pulse reactor was made of medical grade materials for placement in a 37 degrees C incubator. Heart valves were mounted in a housing disc moving horizontally in culture medium within a cylindrical culture reservoir. The microprocessor-controlled system was driven by pressure resulting in a cardiac-like cycle enabling competent opening and closing of the leaflets with adjustable pulse rates and pressures between 0.25 to 2 Hz and up to 180/80 mmHg, respectively. A custom-made imaging system with an integrated high-speed camera and image processing software allow calculation of effective orifice areas during cardiac cycle. This simple pulse reactor design allows reproducible generation of patient-like pressure conditions and data collection during long-term experiments. PMID- 20204702 TI - Droplet-based microsystem for multi-step bioreactions. AB - A droplet-based microfluidic platform was used to perform on-chip droplet generation, merging and mixing for applications in multi-step reactions and assays. Submicroliter-sized droplets can be produced separately from three identical droplet-generation channels and merged together in a single chamber. Three different mixing strategies were used for mixing the merged droplet. For pure diffusion, the reagents were mixed in approximately 10 min. Using flow around the stationary droplet to induce circulatory flow within the droplet, the mixing time was decreased to approximately one minute. The shortest mixing time (10 s) was obtained with bidirectional droplet motion between the chamber and channel, and optimization could result in a total time of less than 1 s. We also tested this on-chip droplet generation and manipulation platform using a two-step thermal cycled bioreaction: nested TaqMan PCR. With the same concentration of template DNA, the two-step reaction in a well-mixed merged droplet shows a cycle threshold of approximately 6 cycles earlier than that in the diffusively mixed droplet, and approximately 40 cycles earlier than the droplet-based regular (single-step) TaqMan PCR. PMID- 20204703 TI - Fast and continuous plasma extraction from whole human blood based on expanding cell-free layer devices. AB - This paper presents promising microfluidic devices designed for continuous and passive extraction of plasma from whole human blood. These designs are based on red cells lateral migration and the resulting cell-free layer locally expanded by geometric singularities such as an enlargement of the channel or a cavity adjacent to the channel. After an explanation of flow patterns, different tests are described that confirm the advantages of both proposed singularities, providing a 1.5 and 2X increase in extraction yield compared to a reference device, for 1:20 diluted blood at 100 microL/min. Devices have also been successively optimized, with extraction yields up to 17.8%, and biologically validated for plasma extraction, with no protein loss or denaturation, no hemolysis and with excellent cell purity. Finally, the dilution effect has been experimentally investigated. PMID- 20204704 TI - Association between utility and treatment among patients with prostate cancer. AB - PURPOSE: To analyze the association between utility, treatment, and generic and prostate-specific health-related quality of life (HRQoL) among patients with prostate cancer. METHODS: In this longitudinal cohort study, we recruited 201 (>or=45 years) newly diagnosed patients with prostate cancer from urology clinics of an urban academic hospital. Participants completed Quality of Wellbeing (QWB SA), generic (SF-36), and prostate-specific (UCLA-PCI) HRQoL surveys prior to treatment and up to 24 months post-treatment. Clinical and demographic data were obtained via medical chart review, and utility scores were computed using QWB-SA. To analyze the relationship between treatment and utility, we used linear mixed effects models, after adjusting for covariates and propensity score. Similar models were used to examine the association between generic and prostate-specific HRQoL and utility. RESULTS: Mean baseline utility was comparable between radical prostatectomy (RP) and external beam radiation therapy (EBRT) groups (0.73 vs. 0.69, P=0.1750). Mixed effects models indicated that RP was associated with higher utility at 24 month (OR=1.12, P=0.027), after controlling for covariates. RP was associated with improved functioning for role physical, role emotional, vitality, mental health and bodily pain, and impaired urinary function. Higher scores on generic health subscales were indicative of higher utility. Also, for prostate-specific HRQoL, higher scores on bowl function, sexual function, urinary bother, and bowel bother were associated with higher utility. CONCLUSIONS: Treatment appears to have significant association with post-treatment utility. Thus, utility assessment provides an important quantitative tool to support patient and physician clinical treatment decision-making process in prostate cancer care. PMID- 20204705 TI - Estimating importance weights for the IWQOL-Lite using conjoint analysis. AB - PURPOSE: Our objective was to estimate preference-based weights for the IWQOL Lite that reflect the relative importance overweight and obese people place on the domains included in the instrument. METHODS: US residents, 18 years of age or older, who are overweight (BMI=25.0-29.9) or obese (BMI>or=30) completed an online survey instrument consisting of 12 choice questions. The survey included eight attributes: problems doing usual daily activities, physical symptoms, worry about health, low self-esteem, sexual problems, problems moving around or sitting in public places, teasing or discrimination, and problems at work. Ordered probit was used to estimate importance weights for the attributes and levels. RESULTS: Five hundred and two subjects completed the survey. Sexual problem was the most important attribute. The remaining attributes can be ranked on the order of importance as follows: low self-esteem, physical symptoms, daily activities, teasing or discrimination, moving around or sitting, problems at work, and worry about health. CONCLUSIONS: Our results confirm previous findings that weighting the individual items in the IWQOL-Lite by the importance of outcomes to overweight and obese subjects may provide a more meaningful evaluation of the effect of changes in weight on patient well-being than a nonpreference-based measure of HRQOL. PMID- 20204706 TI - Sampling plan and patient characteristics of the PROMIS pediatrics large-scale survey. AB - PURPOSE: This paper describes a large-scale administration of the Patient Reported Outcomes Measurement Information System (PROMIS) pediatric items to evaluate measurement characteristics. METHODS: Each child completed one of seven test forms containing items from a pool of 293 PROMIS items and four legacy scales. PROMIS items covered six domains (physical function, emotional distress, social role relationship, fatigue, pain, and asthma). RESULTS: From January 2007 to May 2008, 4,129 children aged 8-17 were enrolled. The sample was 51% female, 55% aged 8-12, 42% minority race and 17% were Hispanic ethnicity. Approximately, 35% of the children participating in the survey consulted a clinician for a chronic illness diagnosis or treatment within 6 months prior to study enrollment. CONCLUSIONS: The final PROMIS pediatric item banks include physical function (n = 52 items), emotional distress (n = 35 items), social role relationships (n = 15 items), fatigue (n = 34 items), pain (n = 13 items), and asthma (n = 17 items). The initial calibration data were provided by a diverse set of children with varying health states (e.g., children with a variety of common chronic illnesses) and racial/ethnic backgrounds. PMID- 20204707 TI - Proxy and patients ratings on quality of life in patients with schizophrenia and bipolar disorder in Korea. AB - PURPOSE: This study aimed to assess the agreement between patient and proxy ratings of Quality of life (QoL) in patients with psychotic mental illnesses. METHODS: The abbreviated version of the WHO quality of life scale (WHOQOL-BREF) and 36-item short-form health survey (SF-36) were administered to patient-family proxy pairs of 81 schizophrenia patients with mild symptoms and 50 euthymic bipolar disorder patients. Paired t-tests and the intraclass correlation coefficient (ICC) were used to evaluate the level of agreement between patient and proxy ratings of QoL. RESULTS: At the group level, small standardized differences (0.0-0.3 for schizophrenia, 0.0-0.5 for bipolar disorder) between patient and proxy mean scores were found for most domains in both QoL measures. At the individual level, moderate to good agreement (ICC) was found (schizophrenia: ICC 0.4-0.7 on WHOQOL-BREF; 0.4-0.7 on SF-36; bipolar disorder: ICC 0.4-0.7 on WHOQOL-BREF; 0.6-0.7 on SF-36). The reported agreement was higher than that reported for similar measures in the psychiatric population. These results may be due to the fact that our subjects had mild clinical symptoms and frequent family interaction. CONCLUSION: These findings suggest that family proxy rating of patients' QoL can be used as a reasonable estimate of the patients' QoL for stable schizophrenia and bipolar patients in Korea. PMID- 20204708 TI - Responsiveness of the EQ-5D and 8-item Parkinson's Disease Questionnaire (PDQ-8) in a 4-year follow-up study. AB - OBJECTIVE: The purpose of this study was to evaluate the responsiveness of the EQ 5D and the Parkinson's Disease Questionnaire (PDQ-8) to deterioration in health related quality of life (HRQoL) in patients with Parkinson's disease (PD). METHODS: HRQoL and clinical data collected from 31 patients with PD (male: 74.2%, mean age: 61 years) who were surveyed with the EQ-5D and the PDQ-8 questionnaires in 2002 and 2006/2007 were analyzed. Responsiveness of the EQ-5D, PDQ-8, and Hoehn and Yahr (H&Y) staging were assessed according to Cohen's effect size (ES) and standardized response mean (SRM). RESULTS: The mean (standard deviation) EQ 5D index and PDQ-8 summary index (PDQ-8SI) scores were 0.76 (0.23) and 17.7 (14.2) at baseline and 0.52 (0.33) and 35.1 (17.4) at year four. Based on both ES and SRM indices, the rank order of responsiveness of the studied measures, from high to low, was PDQ-8SI (ES = 1.22), EQ-5D index score (ES = 1.06), H&Y score (ES = 0.82), and the EQ-VAS score (ES = 0.24). CONCLUSION: Both the EQ-5D and PDQ 8 are responsive to changes in health burden of the Parkinson's disease over a 4 year period. PMID- 20204709 TI - Asymptotics of conduction velocity restitution in models of electrical excitation in the heart. AB - We extend a non-Tikhonov asymptotic embedding, proposed earlier, for calculation of conduction velocity restitution curves in ionic models of cardiac excitability. Conduction velocity restitution is the simplest non-trivial spatially extended problem in excitable media, and in the case of cardiac tissue it is an important tool for prediction of cardiac arrhythmias and fibrillation. An idealized conduction velocity restitution curve requires solving a non-linear eigenvalue problem with periodic boundary conditions, which in the cardiac case is very stiff and calls for the use of asymptotic methods. We compare asymptotics of restitution curves in four examples, two generic excitable media models, and two ionic cardiac models. The generic models include the classical FitzHugh Nagumo model and its variation by Barkley. They are treated with standard singular perturbation techniques. The ionic models include a simplified "caricature" of Noble (J. Physiol. Lond. 160:317-352, 1962) model and Beeler and Reuter (J. Physiol. Lond. 268:177-210, 1977) model, which lead to non-Tikhonov problems where known asymptotic results do not apply. The Caricature Noble model is considered with particular care to demonstrate the well-posedness of the corresponding boundary-value problem. The developed method for calculation of conduction velocity restitution is then applied to the Beeler-Reuter model. We discuss new mathematical features appearing in cardiac ionic models and possible applications of the developed method. PMID- 20204710 TI - Modeling optimal intervention strategies for cholera. AB - While cholera has been a recognized disease for two centuries, there is no strategy for its effective control. We formulate a mathematical model to include essential components such as a hyperinfectious, short-lived bacterial state, a separate class for mild human infections, and waning disease immunity. A new result quantifies contributions to the basic reproductive number from multiple infectious classes. Using optimal control theory, parameter sensitivity analysis, and numerical simulations, a cost-effective balance of multiple intervention methods is compared for two endemic populations. Results provide a framework for designing cost-effective strategies for diseases with multiple intervention methods. PMID- 20204711 TI - Mathematical model of hyperbaric oxygen therapy applied to chronic diabetic wounds. AB - The failure of certain wounds to heal (including diabetic foot ulcers) is a significant socioeconomic issue for countries worldwide. There is much debate about the best way to treat these wounds and one approach that is shrouded with controversy is hyperbaric oxygen therapy (HBOT), a technique that can reduce the risk of amputation in diabetic patients.In this paper, we develop a six species mathematical model of wound healing angiogenesis and use it to investigate the effectiveness of HBOT, compare the response to different HBOT protocols and study the effect of HBOT on the healing of diabetic wounds that fail to heal for a variety of reasons. We vary the pressure level (1 atm-3 atm), percentage of oxygen inspired by the patient (21%-100%), session duration (0-180 minutes) and frequency (twice per day-once per week) and compare the simulated wound areas associated with different protocols after three weeks of treatment.We consider a variety of etiologies of wound chronicity and show that HBOT is only effective in treating certain causes of chronic wounds. For a wound that fails to heal due to excessive, oxygen-consuming bacteria, we show that intermittent HBOT can accelerate the healing of a chronic wound but that sessions should be continued until complete healing is observed. Importantly, we also demonstrate that normobaric oxygen is not a replacement for HBOT and supernormal healing is not an expected outcome. Our simulations illustrate that HBOT has little benefit for treating normal wounds, and that exposing a patient to fewer, longer sessions of oxygen is not an appropriate treatment option. PMID- 20204712 TI - A new steroid-transforming strain of Mycobacterium neoaurum and cloning of 3 ketosteroid 9alpha-hydroxylase in NwIB-01. AB - Using enrichment procedures, five strains that can utilize soybean phytosterols as the sole carbon source were isolated from steroids-contaminated soil samples. Among the isolated strains, the strain NwIB-01 with the highest steroid degradation ability was identified as Mycobacterium neoaurum by morphological, physiological, biochemical tests and 16S rRNA sequence analysis. Meanwhile, the key enzyme gene, which was involved in steroid metabolism and encoding 395-amino acid 3-ketosteroid 9alpha-hydroxylase (KSH), was obtained from M. neoaurum NwIB 01 with the assistance of homology analysis and chromosome walking. To our best knowledge, this is the first report to the gene of key enzyme KSH from M. neoaurum. Strain NwIB-01 exhibited powerful ability of cleaving the side chain specifically from soybean phytosterols to accumulate 4-androstene-3,17-dione (AD) and 1,4-androstadiene-3,17-dione (ADD). It was showed that when cultured in 15 g/l phytosterols, the yield of ADD reached 4.23 g/l while accompanied by 1.76 g/l AD in 96-h-old culture (the molar yield of AD + ADD is 64.7%). The strain NwIB-01 can be applied as excellent phytosterols-transformation strains in potential industrial applications. PMID- 20204713 TI - Production of plant bioactive triterpenoid saponins: elicitation strategies and target genes to improve yields. AB - Triterpenoid saponins are a class of plant secondary metabolites with structure derived from the precursor oxidosqualene in which one or more sugar residues are added. They have a wide range of pharmacological applications, such as antiplatelet, hypocholesterolemic, antitumoral, anti-HIV, immunoadjuvant, anti inflammatory, antibacterial, insecticide, fungicide and anti-leishmanial agents. Their accumulation in plant cells is stimulated in response to changes mediated by biotic and abiotic elicitors. The enhancement of saponin yields by methyl jasmonate in plants and cell cultures in several species indicates the involvement of these metabolites in plant defence mechanisms. The elucidation of their biosynthesis at the molecular level has advanced recently. Most studies to date have focused on the participation of early enzymes in the pathway, including oxidosqualene cyclase, squalene synthase and dammarenediol synthase, as well as in isolating and characterizing genes that encode beta-amyrin synthase. Yields of bioactive saponins in various plant species and experimental systems have been successfully increased by treating cells and tissues with jasmonate or by exposing these to oxidative stress. These elicitation and molecular studies are consolidating a robust knowledge platform from which to launch the development of improved sources for commercial supply of bioactive saponins. PMID- 20204714 TI - 1H and 13C resonance assignments of a guanine sensing riboswitch's terminator hairpin. AB - Here we report the nearly complete base assignments and partial sugar assignments of the 35-residue terminator hairpin of the Bacillus subtilis xpt-pbuX-mRNA guanine sensing riboswitch. PMID- 20204715 TI - Naked plasmid DNA formulation: effect of different disaccharides on stability after lyophilisation. AB - Since plasmid DNA (pDNA) is unstable in solution, lyophilisation can be used to increase product shelf life. To prevent stress on pDNA molecules during lyophilisation, cryo- and lyoprotectants have to be added to the formulation. This study assessed the effect of disaccharides on naked pDNA stability after lyophilisation using accelerated stability studies. Naked pDNA was lyophilised with sucrose, trehalose, maltose or lactose in an excipient/DNA w/w ratio of 20. To one part of the vials extra residual moisture was introduced by placing the vials half opened in a 25 degrees C/60% RH climate chamber, before placing all vials in climate chambers (25 degrees C/60% RH and 40 degrees C/75% RH) for stability studies. An ex vivo human skin model was used to assess the effect of disaccharides on transfection efficiency. Lyophilisation resulted in amorphous cakes for all disaccharides with a residual water content of 0.8% w/w. Storage at 40 degrees C/75% RH resulted in decreasing supercoiled (SC) purity levels (sucrose and trehalose maintained approximately 80% SC purity), but not in physical collapse. The addition of residual moisture (values between 7.5% and 10% w/w) resulted in rapid collapse except for trehalose and decreasing SC purity for all formulations. In a separate experiment disaccharide formulation solutions show a slight but significant reduction (<3% with sucrose and maltose) in transfection efficiency when compared to pDNA dissolved in water. We demonstrate that disaccharides, like sucrose and trehalose, are effective lyoprotectants for naked pDNA. PMID- 20204716 TI - Uterine tumors with neuroectodermal differentiation. A report of 4 cases. AB - We report four cases of uterine tumors with neuroectodermal differentiation. One tumor had neuroectodermal component only; in the three other tumors, the neuroectodermal component was admixed with another component, namely rhabdomyosarcoma (1 case), and endometrioid adenocarcinoma (2 cases). Histologically, the neuroectodermal component consisted of small to medium sized cells arranged in diffuse sheets. The tumor cells had round nuclei with stippled to coarsely granular chromatin, mostly with non-prominent nucleoli, and scant eosinophilic or amphophilic cytoplasm. Immunohistochemically, 4/4 tumors showed expression of vimentin, synaptophysin and CD56; 3/4 tumors were CD99 and NSE positive; 2/4 tumors showed focal expression of S-100 protein; and 1/4 tumors had focal dot-like cytoplasmic positivity for cytokeratin AE1/AE3. FLI-1 was negative in all cases. FISH examination was performed and none of the tumors showed rearrangement of EWSR1 gene. Uterine tumors with neuroectodermal differentiation are rare; to the best of our knowledge only 44 cases have been reported in the literature to date, referred to as Ewing sarcoma, peripheral PNET (pPNET), PNET (not otherwise specified) and uterine tumors with neuroendocrine differentiation. PMID- 20204717 TI - Ventricular tachycardia after ondansetron administration in a child with undiagnosed long QT syndrome. AB - PURPOSE: To describe a case of ventricular tachycardia after co-administration of ondansetron and dimenhydrinate to a child with occult congenital QT prolongation. CLINICAL FEATURES: A previously healthy 11-yr-old girl presented for surgical excision of a thyroglossal duct cyst under general anesthesia. Induction and maintenance of anesthesia were unremarkable, and the surgery was carried out without incident. Prior to emergence, ondansetron 0.1 mg.kg(-1) and dimenhydrinate 0.4 mg.kg(-1) were administered. Within approximately two minutes, polymorphic premature ventricular contractions developed and, subsequently, polymorphic ventricular tachycardia ensued. A 12-lead electrocardiogram revealed a profoundly prolonged QT interval that decreased but failed to normalize completely postoperatively. Our patient was diagnosed subsequently with congenital QT prolongation. CONCLUSION: The QT interval is prolonged by the administration of ondansetron in a manner similar to that seen with droperidol, whereas dimenhydrinate is not considered to exert significant effects on the QT interval. Individuals with occult QT prolongation are at risk of experiencing malignant dysrhythmias when ondansetron is administered, especially in conjunction with anesthetic agents that also prolong the QT. The incidence of congenital QT prolongation in the general population has been estimated to be 1:2,500, and it may be undiagnosed preoperatively, especially in pediatric patients. PMID- 20204719 TI - [Implant allergies]. AB - An increasing number of patients receive and benefit from osteosynthesis materials or artificial joint replacement. The most common complications are mechanical problems or infection. Metals like nickel, chromium and cobalt as well as bone cement components like acrylates and gentamicin are potential contact allergens which can cause intolerance reactions to implants. Eczema, delayed wound/bone healing, recurrent effusions, pain and implant loosening all have been described as manifestation of implant allergy. In contrast to the high incidence of cutaneous metal allergy, allergies associated with implants are rare. Diagnosis of metal implant allergy is still difficult. Thus differential diagnoses--in particular infection--have to be excluded and a combined approach of allergologic diagnostics by patch test and histopathology of peri-implant tissue is recommended. It is still unknown which conditions induce allergic sensitization to implants or trigger peri-implant allergic reactions in the case of preexisting cutaneous metal allergy. Despite the risk of developing complications being unclear, titanium based osteosynthesis materials are recommended for metal allergic patients and the use of metal-metal couplings in arthroplasty is not recommended for such patients. If the regular CoCr polyethylene articulation is employed, the patient should give informed written consent. PMID- 20204720 TI - The role of ion channels in hypoxic pulmonary vasoconstriction. AB - Hypoxic pulmonary vasoconstriction (HPV) is an important mechanism by which localized flow of blood in small resistance pulmonary arteries is matched to alveolar ventilation. This chapter discusses the role of several potassium and calcium channels in HPV, both in enhancing calcium influx into smooth muscle cells (SMCs) and in stimulating the release of calcium from the sarcoplasmic reticulum, thus increasing cytosolic calcium. The increase in calcium sensitivity caused by hypoxia is reviewed in Chapter 19. Particular attention is paid to the activity of the L-type calcium channels which increase calcium influx as a result of membrane depolarization and also increase calcium influx at any given membrane potential in response to hypoxia. In addition, activation of the L-type calcium channel may, in the absence of any calcium influx, cause calcium release from the sarcoplasmic reticulum. Many of these mechanisms have been reported to be involved in both HPV and in normoxic contraction of the ductus arteriosus. PMID- 20204721 TI - Two-pore domain k(+) channels and their role in chemoreception. AB - A number of tandem P-domain K(+)- channels (K(2)P) generate background K(+) currents similar to those found in enteroreceptors that sense a diverse range of physiological stimuli including blood pH, carbon dioxide, oxygen, potassium and glucose. This review presents an overview of the properties of both cloned K(2)P tandem-P-domain K-channels and the endogenous chemosensitive background K currents found in central chemoreceptors, peripheral chemoreceptors, the adrenal gland and the hypothalamus. Although the identity of many of these endogenous channels has yet to be confirmed they show striking similarities to a number of K(2)P channels especially those of the TASK subgroup. Moreover these channels seem often (albeit not exclusively) to be involved in pH and nutrient/metabolic sensing. PMID- 20204722 TI - Intricate interaction between store-operated calcium entry and calcium-activated chloride channels in pulmonary artery smooth muscle cells. AB - Ca(2+)-activated Cl-() channels (Cl(Ca)) represent an important excitatory mechanism in vascular smooth muscle cells. Active accumulation of Cl-() by several classes of anion transporters results in an equilibrium potential for this ion about 30 mV more positive than the resting potential. Stimulation of Cl(Ca) channels leads to membrane depolarization, which enhances Ca(2+) entry through voltage-gated Ca(2+) channels and leads to vasoconstriction. Cl(Ca) channels can be activated by distinct sources of Ca(2+) that include (1) mobilization from intracellular Ca(2+) stores (ryanodine or inositol 1,4,5 trisphosphate [InsP(3)]) and (2) Ca(2+) entry through voltage-gated Ca(2+) channels or reverse-mode Na(+)/Ca(2+) exchange. The present study was undertaken to determine whether Ca(2+) influx triggered by store depletion (store-operated calcium entry, SOCE) activates Cl(Ca) channels in rabbit pulmonary artery (PA) smooth muscle. Classical store depletion protocols involving block of sarcoplasmic reticular Ca(2+) reuptake with thapsigargin (TG; 1 microM) or cyclopiazonic acid (CPA; 30 microM) led to a consistent nifedipine-insensitive contraction of intact PA rings and rise in intracellular Ca(2+) concentration in single PA myocytes that required the presence of extracellular Ca(2+). In patch clamp experiments, TG or CPA activated a time-independent nonselective cation current (I (SOC)) that (1) reversed between -10 and 0 mV; (2) displayed the typical "N"-shaped current-voltage relationship; and (3) was sensitive to the (I (SOC)) blocker by SKF-96365 (50 microM). In double-pulse protocol experiments, the amplitude of I (SOC) was varied by altering membrane potential during an initial step that was followed by a second constant step to +90 mV to register Ca(2+)-activated Cl(-) current, I (Cl(Ca)). The niflumic acid-sensitive time dependent I (Cl(Ca)) at +90 mV increased in proportion to the magnitude of the preceding hyperpolarizing step, an effect attributed to graded membrane potential dependent Ca(2+) entry through I (SOC) and confirmed in dual patch clamp and Fluo 5 experiments to record membrane current and free intracellular Ca(2+) concentration simultaneously. Reverse-transcription polymerase chain reaction (RT PCR) experiments confirmed the expression of several molecular determinants of SOCE, including transient receptor potential canonical (TRPC) 1, TRPC4, and TRPC6; stromal interacting molecule (STIM) 1 and 2; and Orai1 and 2, as well as the novel and probable molecular candidates thought to encode for Cl(Ca) channels transmembrane protein 16A (TMEM16A) Anoctamin 1 (ANO1) and B (ANO2). Ourpreliminary investigation provides new evidence for a Ca(2+) entry pathway consistent with store-operated Ca(2+) entry signaling that can activate Ca(2+) activated Cl-() channels in rabbit PA myocytes. We hypothesize that this mechanism may be important in the regulation of membrane potential, Ca(2+) influx, and tone in these cells under physiological and pathophysiological conditions. PMID- 20204723 TI - The role of intracellular ion channels in regulating cytoplasmic calciumin pulmonary arterial mmooth muscle: which store and where? AB - The mobilisation of intracellular Ca(2+) stores plays a pivotal role in the regulation of arterial smooth muscle function, paradoxically during both contraction and relaxation. Moreover, different spatiotemporal Ca(2+) signalling patterns may trigger differential gene expression while mediating the same functional response. These facts alone serve to highlight the importance of the growing body of evidence in support of the view that different Ca(2+) storing organelles may be selected by the discrete or co-ordinated actions of multiple Ca(2+) mobilising messengers. In this respect, it is generally accepted that sarcoplasmic reticulum stores may be mobilised by the ubiquitous messenger inositol 1,4,5 trisphosphate. However, relatively little attention has been paid to the role of Ca(2+) mobilising pyridine nucleotides in arterial smooth muscle, namely cyclic adenosine diphosphate-ribose and nicotinic acid adenine dinucleotide phosphate. This review will, therefore, focus on the role of these novel Ca(2+) mobilising messengers in pulmonary arterial smooth muscle, with particular reference to hypoxic pulmonary vasoconstriction. PMID- 20204724 TI - Ca(2+) oscillations regulate contraction of intrapulmonary smooth muscle cells. AB - Pulmonary blood pressure is a function of the resistance of the intrapulmonary blood vessels. Consequently, the mechanisms controlling blood vessel smooth muscle cell (SMC) contraction serve as potential sites for hypertension therapy. To explore these mechanisms, access to the intrapulmonary vessels is required and this is provided by the observation of a unique lung slice preparation with microscopy. There are 2 major processes that determine SMC tone; the intracellular Ca(2+) concentration and the sensitivity of the SMCs to Ca(2+). Agonist-induced increases in Ca(2+) occur in the form of propagating Ca(2+) oscillations that predominately utilize internal Ca(2+) stores and inositol trisphosphate receptors. The frequency of these Ca(2+) oscillations correlates with contraction. Agonists also increase Ca(2+) sensitivity of SMCs to enhance contraction. Changes in membrane potential mediated by KCl also stimulate contraction via slow Ca(2+) oscillations and increased sensitivity. However, these slow Ca(2+) oscillations rely on Ca(2+) influx to drive the cyclic release of over-filled Ca(2+) stores via the ryanodine receptor. The relaxation of SMC tone can be induced by the reduction of the frequency of the Ca(2+) oscillations and the Ca(2+) sensitivity by b(2)-adrenergic agonists or nitric oxide. PMID- 20204725 TI - Introduction to TRP channels: structure, function, and regulation. AB - Transient receptor potential or TRP families of ion channels demonstrate great diversity in activation and inhibition, and they are diverse in selectivity of ion conductance. TRP ion channels function as signal integrators through their ion conductance properties, and in some cases kinase activity. They mediate processes such as vision, taste, olfaction, hearing, touch, and thermo- and osmosensation. TRP cation channels function by mediating the flux of Na(+) and Ca(2+) across the plasma membrane and into the cytoplasm. The influx of cations into the cytoplasm depolarizes cells and is necessary for action potentials in excitable cells such as neurons. In non-excitable cells, membrane depolarization by TRP ) and-channels stimulates voltage- dependent channels (Ca(2+), K(+), Cl(-) influences many cellular events, such as transcription, translation, contraction, and migration. TRP channels are important in human physiology, and mutations in TRP genes are associated with at least four diseases. Furthermore, altered expression, function, and/or regulation of TRP channels have been implicated in diseases such as pulmonary hypertension. PMID- 20204726 TI - Physiological functions of transient receptor potential channels in pulmonary arterial smooth muscle cells. AB - The transient receptor potential (TRP) gene superfamily, which consists of 7 subfamilies with at least 28 mammalian homologues, is known to encode a wide variety of cation channels with diverse biophysical properties, activation mechanisms, and physiological functions. Recent studies have identified multiple TRP channel subtypes, belonging to the canonical (TRPC), melastatin-related (TRPM), and vanilloid-related (TRPV) subfamilies, in pulmonary arterial smooth muscle cells (PASMCs). They operate as specific Ca(2+) pathways responsive to stimuli, including Ca(2+) store depletion, receptor activation, reactive oxygen species, growth factors, and mechanical stress. Increasing evidence suggests that these channels play crucial roles in agonist-induced pulmonary vasoconstriction, hypoxic pulmonary vasoconstriction, smooth muscle cell proliferation, vascular remodeling, and pulmonary arterial hypertension. This chapter highlighted and discussed these putative physiological functions of TRP channels in pulmonary vasculatures. Since Ca(2+) ions regulate many cellular processes via specific Ca(2+) signals, future investigations of these novel channels will likely uncover more important regulatory mechanisms of pulmonary vascular functions in health and in disease states. PMID- 20204727 TI - The contribution of TRPC1 and STIM1 to capacitative Ca(2+) entry in pulmonary artery. AB - Capacitative calcium entry (CCE) through store-operated channels (SOCs) has been shown to contribute to the rise in intracellular calcium concentration ([Ca(2+)](i)) and mediate pulmonary artery smooth muscle contraction. CCE is activated as a result of depletion of intracellular Ca(2+) stores but there is a great deal of controversy surrounding the underlying signal that active CCE and the molecular makeup of SOCs. The discovery of canonical subgroup of transient receptor potential channels (TRPC) and recent identification of stromal interacting molecule 1 (STIM1) protein have opened a door to the study of the identity of SOCs and the signal that activates these channels. Among all the TRPC channels, TRPC1 is widely studied in many cell types and shown to be part of SOCs components, whereas STIM1 protein is found to act as a Ca(2+) sensor in the intracellular Ca(2+) stores and activates SOCs. However, there is very little evidence for the roles of TRPC1 and STIM1 in the contribution of CCE in pulmonary artery. This chapter outlines the roles of TRPC1 and STIM1 in pulmonary artery smooth muscle cells and discusses our recent findings that TRPC1 and STIM1 are functionally interact with each other to mediate CCE in these cells. We also propose a model for the molecular makeup of SOCs formed by TRPC1 and STIM1 in pulmonary artery. PMID- 20204728 TI - Store-operated calcium entry channels in pulmonary endothelium: the emerging story of TRPCS and Orai1. AB - Cells of diverse origin utilize shifts in cytosolic calcium concentrations as intracellular signals to elicit physiological responses. In endothelium, inflammatory first messengers increase cytosolic calcium as a signal to disrupt cell-cell borders and produce inter-cellular gaps. Calcium influx across the plasma membrane is required to initiate barrier disruption, although the calcium entry mechanism responsible for this effect remains poorly understood. This chapter highlights recent efforts to define the molecular anatomy of the ion channel responsible for triggering endothelial cell gap formation. Resolving the identity and function of this calcium channel will pave the way for new anti inflammatory therapeutic targets. PMID- 20204729 TI - TRPM2 channel regulates endothelial barrier function. AB - Oxidative [Au1]stress, through the production of oxygen metabolites such as hydrogen peroxide[Au2] (H(2)O(2)), increases vascular endothelial permeability and plays a crucial role in several lung diseases. The transient receptor potential (melastatin) 2 (TRPM2) is an oxidant-sensitive, nonselective cation channel that is widely expressed in mammalian tissues, including the vascular endothelium. We have demonstrated the involvement of TRPM2 in mediating oxidant induced calcium entry and endothelial hyperpermeability in cultured pulmonary artery endothelial cells. Here, we provide evidence that neutrophil activation dependent increase in endothelial permeability and neutrophil extravasation requires TRPM2 in cultured endothelial cells. In addition, protein kinase Calpha (PKCalpha) that rapidly colocalizes with the short (nonconducting) TRPM2 isoform after exposure to hydrogen peroxide positively regulates calcium entry through the functional TRPM2 channel. Thus, increase in lung microvessel permeability and neutrophil sequestration depends on the activation of endothelial TRPM2 by neutrophilic oxidants and on PKCalpha regulation of TRPM2 channel activity. Manipulating TRPM2 function in the endothelium may represent a novel strategy aimed to prevent oxidative stress-related vascular dysfunction. PMID- 20204730 TI - A proposed mitochondrial-metabolic mechanism for initiation and maintenance of pulmonary arterial hypertension in fawn-hooded rats: the Warburg model of pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a disease of the pulmonary vasculature that is characterized by vascular obstruction and progressive right ventricular failure. One hallmark of clinical PAH is its very poor survival, with PAH mortality rates approximating those of many malignancies. The discovery that the fawn-hooded rat strain (FHR) spontaneously develops PAH has allowed for major insights into the pathophysiology of PAH. These findings have revealed that cancer and PAH not only share a similarly poor prognosis but also demonstrate similar resistance to apoptosis and activation of cell proliferation as a major pathophysiologic mechanism. One of the causes for the resistance to apoptosis and increased proliferation of pulmonary vascular smooth muscle cells in PAH is a cancer-like metabolic shift towards a glycolytic metabolism (Warburg effect) and down-regulation of mitochondrial glucose oxidation. This book chapter will review the role of such a metabolic shift in the pathophysiology of PAH and also highlight emerging anti-proliferative PAH therapies that correct the metabolic dysregulation in PAH. PMID- 20204731 TI - The role of classical transient receptor potential channels in the regulation of hypoxic pulmonary vasoconstriction. AB - Hypoxic pulmonary vasoconstriction (HPV) is an essential mechanism of the lung matching blood perfusion to ventilation during local alveolar hypoxia. HPV thus optimizes pulmonary gas exchange. In contrast chronic and generalized hypoxia leads to pulmonary vascular remodeling with subsequent pulmonary hypertension and right heart hypertrophy. Among other non-selective cation channels, the family of classical transient receptor potential channels (TRPC) has been shown to be expressed in pulmonary arterial smooth muscle cells. Among this family, TRPC6 is essential for the regulation of acute HPV in mice. Against this background, in this chapter we give an overview about the TRPC family and their role in HPV. PMID- 20204732 TI - Developmental regulation of oxygen sensing and ion channels in the pulmonary vasculature. AB - The increase in oxygen tension occurring at birth causes sustained and progressive pulmonary vasodilation. The oxygen-induced perinatal pulmonary vasodilation depends on the production of nitric oxide (NO) from the pulmonary endothelium and activation of various K(+) channels in pulmonary artery smooth muscle cells. This chapter reviews a) the oxygen-sensing mechanism that stimulates endothelial NO production; b) how K(+) channels sense changes in oxygen tension; c) whether hypoxia-inducible factor-1alpha (HIF-1alpha), a well defined hypoxia-sensitive transcription factor in adult, contributes to the regulation of NO production and K(+) channel activation; and d) whether and how dysfunctional K(+) channels contribute to the development of pulmonary hypertension in the newborns. PMID- 20204733 TI - Hypoxic regulation of ion channels and transporters in pulmonary vascular smooth muscle. AB - Exposure to prolonged alveolar hypoxia, as occurs with many chronic lung diseases or residence at high altitude, results in the development of pulmonary hypertension, significantly worsening patient prognosis. While the structural and functional changes that occur in the pulmonary vasculature in response to chronic hypoxia have been well characterized, less is known regarding the cellular mechanisms underlying this process. The use of animals models of hypoxic pulmonary hypertension have provided important insights into the changes that occur in the pulmonary vascular smooth muscle cells and some of the mediators involved. In this chapter, the effect of chronic hypoxia on various pulmonary arterial smooth muscle cell ion channels and transporters, and the role of the transcription factor, hypoxia-inducible factor 1, in regulating these changes, will be discussed. PMID- 20204734 TI - CLC-3 chloride channels in the pulmonary vasculature. AB - Volume-sensitive outwardly rectifying anion channels (VSOACs) are expressed in pulmonary artery smooth muscle cells (PASMCs) and have been implicated in cell proliferation, growth, apoptosis and protection against oxidative stress. In this chapter, we review the properties of native VSOACs in PASMCs, and consider the evidence that ClC-3, a member of the ClC superfamily of voltage dependent Cl- channels, may be responsible for native VSOACs in PASMCs. Finally, we examine whether or not native VSOACs and heterologously expressed ClC-3 channels function as bona fide chloride channels or as chloride/proton antiporters. PMID- 20204735 TI - Role of bone morphogenetic protein receptors in the development of pulmonary arterial hypertension. AB - The identification of mutations in the bone morphogenetic protein (BMP) type II receptor in the majority of cases of familial pulmonary arterial hypertension (PAH) has provided a focus for researchers studying the complex pathobiology of this condition. Mutations are also found in a proportion of idiopathic PAH cases and it is now emerging that dysfunctional BMP signaling plays a role in other more common forms of PAH, even in the absence of mutations in the gene. Study of the role of BMP signaling in endothelial, smooth muscle cell, progenitor cell and inflammatory cell biology may reveal novel pathways lending themselves to therapeutic intervention in PAH. This chapter summarizes the present status of our understanding of the role of BMPR-II mutations in PAH and indicates future directions for research. PMID- 20204736 TI - Cross talk between Smad, MAPK, and actin in the etiology of pulmonary arterial hypertension. AB - The gene for the type 2 receptor for the bone morphogenic pathway, BMPR2, is mutated in a large majority of familial pulmonary arterial hypertension (PAH),. However, the mechanisms linking BMPR2 mutation to disease remain obscure. BMPR2 potentially signals through multiple immediate downstream pathways, including Smad, MAPK, LIM domain kinase 1 (LIMK) and dynein, light chain, Tctex-type 1 (TCTEX), v-src sarcoma viral oncogene homolog (SRC), and nuclear factor kappa-B (NFkB). Functional consequences of BMPR2 mutation, largely ascertained from animal models, include a shift from contractile to synthetic phenotype in smooth muscle, probably downstream of Smad signal; alterations in expression of actin organization related genes, possibly related to focal adhesions; alterations in cytokines and inflammatory cell recruitment; increased proliferation and apoptosis; and increased collagen and matrix. A synthesis of the available data suggests that the normal role of BMPR2 in adult animals is to assist in injury repair. BMPR2 is suppressed in injured tissue, which facilitates inflammatory response, shift to a synthetic cellular phenotype, and alterations in migration or permeability of cells in the vascular wall. We thus hypothesize that BMPR2 mutation thus leads to an impaired ability to terminate the injury repair process, leading to strong predisposition to PAH. PMID- 20204737 TI - Notch signaling in pulmonary hypertension. AB - Proteins of the Notch receptor family are cell surface receptors that transduce signals between neighboring cells. The Notch signaling pathway is highly evolutionarily conserved and critical for cell fate determination during embryogenesis and early postnatal life, including many aspects of vascular development. The interaction of Notch receptor with its membrane-bound ligands leads to cleavage of the receptor into an intracellular domain that translocates to the nucleus and activates the transcription factor, C-promoter binding factor 1 (CBF1; also known as Recombination signal-binding protein for immunoglobulin kappa J region, RBPJ). To date, four Notch receptors have been characterized in humans. Of these, Notch3 is expressed only in arterial smooth muscle cells in the human. The functional importance of Notch3 signaling in human vascular smooth muscle cells has been recognized. Notch3 receptor signaling has been shown in several model systems to control vascular smooth muscle cell proliferation and maintain smooth muscle cells in an undifferentiated state. This review focuses on recent findings of the role of Notch3 in regulating vascular smooth muscle cell behavior and phenotype and discusses the potential role of Notch3 signaling in the genesis of pulmonary arterial hypertension. PMID- 20204738 TI - Rho kinase-mediated vasoconstriction in pulmonary hypertension. AB - Rho kinase-mediated vasoconstriction rather than fixed arterial wall thickening is responsible for increased pulmonary vascular resistance and pulmonary hypertension in chronically hypoxic and monocrotaline-injected rats. In the absence of vascular tone, the medial and adventitial thickening in these models has only minimal impact on the cross-sectional area of the pulmonary arterial bed. In contrast, increased pulmonary vascular resistance in left pneumonectomized plus monocrotaline-injected rats and VEGF receptor blocker injected plus chronic hypoxia rats is attributable to both Rho kinase-mediated vasoconstriction and formation of lumen obliterating lesions in small pulmonary arteries. The upstream signals responsible for activation of RhoA/Rho kinase signaling in hypertensive pulmonary arteries and whether or not they differ in different forms of pulmonary hypertension are unclear. The RhoA/Rho kinase pathway is a convergence point of several different vasoconstrictor signals, including those mediated by G protein-coupled receptors, receptor tyrosine kinases, and integrin clustering. Both isoforms of Rho kinase can also be constitutively activated by cleavage, and cleaved Rho kinase 1 has been detected in the hypertensive lungs of left-pneumonectomized plus monocrotaline-injected rats. That such diverse stimuli can lead to activation of Rho kinase, which may cause hypercontraction of smooth muscle by promoting both actomyosin interaction and remodeling of the cytoskeleton, may explain why in various rat models of pulmonary hypertension Rho kinase inhibitors are more effective pulmonary vasodilators than conventional agents such as nitric oxide, prostacyclin, and nifedipine. We suspect the same will be true in at least some forms of human pulmonary arterial hypertension. PMID- 20204739 TI - The serotonin hypothesis of pulmonary hypertension revisited. AB - The serotonin hypothesis of pulmonary arterial hypertension (PAH) arose after an outbreak of PAH in patients taking the anorexigenic drugs aminorex and dexfenfluramine. Both of these drugs are serotonin transporter (SERT) substrates and indirect serotinergic agonists. There is now a wealth of evidence to support a role for serotonin in the pathobiology of PAH. Synthesis of serotonin can occur in pulmonary artery endothelial cells by the enzyme tryptophan hydroxylase 1 (TPH1). Serotonin then acts at the 5-HT(1B) receptor and the SERT to mediate constriction and proliferation of pulmonary artery smooth muscle cells. Downstream signalling molecules which play a role in serotonin-induced constriction and proliferation include reactive oxygen species (ROS), Rho-kinase (ROCK) p38 and extracellular signal-regulated kinase (ERK). There is also evidence to suggest that serotonin may interact with the bone morphogenetic receptor type II (BMPRII) to provide a 'second hit' risk factor for PAH. PMID- 20204740 TI - Impaired vascular endothelial growth factor signaling in the pathogenesis of neonatal pulmonary vascular disease. AB - Abstract Of diverse growth factors that contribute to normal lung development, vascular endothelial growth factor (VEGF) plays an especially prominent role in the normal growth and development of the pulmonary circulation in the fetus and newborn. Strong experimental and clinical data support the role of impaired VEGF signaling in the pathogenesis of two major clinical disorders of the developing lung circulation: persistent pulmonary hypertension of the newborn (PPHN) and bronchopulmonary dysplasia (BPD). These disorders are each characterized by impaired vascular growth, structure and reactivity, which are at least partly due to endothelial cell dysfunction. This chapter will briefly discuss VEGF signaling during normal lung development and how disruption of VEGF signaling contribute to the pathogenesis of neonatal pulmonary vascular disease in these settings. PMID- 20204741 TI - Mitochondrial regulation of oxygen sensing. AB - Hypoxia promotes physiological processes such as energy metabolism, angiogenesis, cell proliferation, and cell viability through the transcription factor Hypoxia Inducible Factor (HIF). Hypoxia also diminishes the activity of ATP consuming processes to promote cell survival. The mechanism(s) by which hypoxia activates HIF and diminishes ATP demand are a subject of intensive research. Here we outline the model in which mitochondrial complex III regulate the activity of HIF and diminish ATP utilization processes through the increased production of ROS during hypoxia. PMID- 20204742 TI - Reactive oxygen species and RhoA signaling in vascular smooth muscle: role in chronic hypoxia-induced pulmonary hypertension. AB - Increases in myofilament Ca2+ sensitivity resulting from stimulation of RhoA and Rho kinase represent a primary mechanism of vasoconstriction and associated pulmonary hypertension resulting from chronic hypoxia (CH). This chapter summarizes recent advances in the understanding of RhoA/Rho kinase signaling mechanisms in pulmonary vascular smooth muscle (VSM) that increase the sensitivity of the contractile apparatus to Ca2+ and contribute to vasoconstriction in this setting. Such advances include the discovery of myogenic tone in small pulmonary arteries from CH rats that contributes to vasoconstriction through a mechanism inherent to the VSM, dependent on Rho kinase induced Ca2+ sensitization but independent of L-type voltage-gated Ca2+ channels. Additional studies have revealed an important contribution of superoxide anion (O2-)-induced RhoA activation to both receptor-mediated and membrane depolarization-induced myofilament Ca2+ sensitization in hypertensive pulmonary arteries. Xanthine oxidase and NADPH oxidase isoforms are potential sources of O2 that mediate RhoA-dependent vasoconstriction and associated pulmonary hypertension. PMID- 20204743 TI - Polyamine regulatory pathways as pharmacologic targets in pulmonary arterial hypertension. AB - Decades of studies in animal models and in humans with pulmonary artery hypertension have left little doubt that the processes culminating in hyper tensive pulmonary vascular remodeling and sustained increases in pulmonary vascular resistance are complex. Modulations in phenotype, proliferative state, and survival of multiple lung vascular cell populations, changes in the local milieu of growth and differentiation factors, and alterations in the extracellular connective tissue environment all seem to contribute to the pathogenesis of the disorder. From a pharmacologic vantage point, identifying which of these is the most suitable target is challenging. Our studies are predicated on the concept that pathways "distal" in the signaling cascades - upon which multiple stimuli dictating vascular cell structure and function converge - might be effective drug targets in PAH. In this regard, we found that the polyamines, putrescine, spermidine, and spermine, a family of low molecular weight organic cations required for cell growth and differentiation, along with their biosynthetic pathways and transmembrane transporters, are altered in rational animal models of pulmonary arterial hypertension. In this article, we summarize these data incriminating polyamines and their regulatory pathways in hypertensive pulmonary vascular disease and advance the contention that polyamine synthesis inhibitors and transport blockers should indeed be considered for clinical trials in human pulmonary arterial hypertension. PMID- 20204744 TI - 5-HT receptors and K(V) channel internalization. AB - Serotonin (5-HT) and voltage-gated potassium (KV) channels have emerged as two major factors in the pathogenesis of pulmonary arterial hypertension (PAH). In pulmonary artery smooth muscle cells (PASMC), KV channels play a major role in the regulation of pulmonary arterial tone and proliferation. Thus, activation of KV channels leads to vasodilatation and enhances apoptosis, while their inhibition is associated with vasoconstriction and proliferation in PASMC. Moreover, these channels have a prominent role as a common target for pulmonary vasoconstrictors. Modulation of these channels by vasoconstrictors involves the activation of a variety of protein kinases. Here we review the role of localization and internalization as a novel mechanism for acute regulation of KV channels and pulmonary vascular tone by agonists such as serotonin. PMID- 20204745 TI - KCNQ potassium channels: new targets for pulmonary vasodilator drugs? AB - Smooth muscle cells regulate the diameter of pulmonary arteries and the resistance to blood flow in the pulmonary circulation. These cells are normally relaxed to maintain low intrinsic vessel tone, but are contracted in pulmonary arterial hypertension (PAH). Potassium channels in the smooth muscle cell help to maintain low tone by polarising the membrane and preventing Ca(2+) influx through voltage-operated Ca(2+) channels. There is a loss of K(+) channel activity in PAH, so drugs that open K(+) channels are predicted to have a beneficial effect, provided their action can be restricted to the pulmonary circulation. Here we review the myriad of K(+) channels that are expressed in pulmonary arteries and suggest the roles that each might play in regulating pulmonary artery tone. We conclude that members of the KCNQ family of K(+) channels, the most recent K(+) channels to be discovered in pulmonary artery, may be a useful therapeutic target for the treatment of PAH. KCNQ channels appear to be preferentially expressed in pulmonary arteries and drugs that modulate their activity have potent effects on pulmonary artery tone. PMID- 20204747 TI - PDGF receptor and its antagonists: role in treatment of PAH. AB - Pulmonary Hypertension is a severe lung disease, which is characterized by vasoconstriction and remodelling of the vessel wall. Mostly addressing the increased vascular tone, prostacyclin and its analogues, endothelin-receptor antagonists and phosphodiesterase type 5 inhibitors have been approved for treatment of PAH and represent the current therapeutic options. Mechanistically, these vasodilators decrease pulmonary vascular resistance and reduce thereby shear stress, which is a strong proliferative stimulus per se. Beside the development of new vasodilators, current research focuses on the development of causal treatment regimens aiming a normalization of the vessel structure. Mechanistically, increased proliferation, migration and a resistance to apoptosis of vascular cells represent key events in disease progression. In this context, tyrosine kinase inhibitors like imatinib have been shown to possess reverse remodelling potential in preclinical models of pulmonary hypertension by inducing apoptosis and blocking proliferation. This book chapter describes the role of the platelet derived growth factor (PDGF) receptor and its antagonists for treatment of pulmonary hypertension. PMID- 20204748 TI - PPARgamma and the pathobiology of pulmonary arterial hypertension. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor that functions as a transcription factor to regulate adipogenesis and metabolism by binding to PPAR response elements (PPAREs) in the promoter region of various target genes. Activation of PPARgamma suppresses smooth muscle cell proliferation and migration. This chapter discusses the potential protective role of PPARgamma and its downstream signaling cascades in the development of pulmonary arterial hypertension. Furthermore, the chapter also provides an overview on the cellular and molecular mechanisms involved in PPARgamma-mediated inhibitory effect on pulmonary vascular remodeling, a major contributor to the elevated pulmonary vascular resistance in patients with pulmonary arterial hypertension. PMID- 20204746 TI - Receptor tyrosine kinase inhibitors in rodent pulmonary hypertension. AB - Pulmonary hypertension (PH) is a disorder characterized by vascular remodeling and proliferation, a phenotype dependent upon unimpeded growth factor and kinase pathway activation with strong similarities to malignant tumors. This chapter details our novel application of the multikinase inhibitor, sorafenib, in rodent models of PH to improved hemodynamic parameters and attenuates PH structural changes1. Sorafenib is a Raf kinase inhibitor and our biochemical and genomic evidence supported the potential involvement of the MAPK cascade system and TGFB3 in PH development and the response to therapy. Integration of expression genomic analyses coupled with intense bioinformatics identified gene expression and ontology signatures in the development of PH and implicated the role of cytoskeletal protein such as caldesmon or nmMLCK as potentially key participants in PH-induced vascular remodeling and proliferation. Our studies suggest the PKI sorafenib as a potentially novel treatment for severe PH with the MAPK cascade a potential canonical target profoundly effecting vascular cytoskeletal rearrangements and remodeling1. PMID- 20204749 TI - Targeting TASK-1 channels as a therapeutic approach. AB - The voltage-independent background two-pore domain K(+) channel TASK-1 sets the resting membrane potential in excitable cells and renders these cells sensitive to a variety of vasoactive factors. There is clear evidence for TASK-1 in human pulmonary artery smooth muscle cells and TASK-1 channels are likely to regulate the pulmonary vascular tone through their regulation by hypoxia, pH, inhaled anesthetics, and G protein-coupled pathways. Furthermore, TASK-1 is a strong candidate to play a role in hypoxic pulmonary vasoconstriction. On the other hand, consistent with the activation of TASK-1 channels by volatile anesthetics, TASK-1 contributes to the anesthetic-induced pulmonary vasodilation. TASK-1 channels are unique among K(+) channels because they are regulated by both, increases and decreases from physiological pH, thus contributing to their protective effect on the pulmonary arteries. Moreover, TASK-1 may also have a critical role in mediating the vasoactive response of G protein-coupled pathways in resistance arteries which can offer promising therapeutic solutions to target diseases of the pulmonary circulation. PMID- 20204750 TI - Pharmacological targets for pulmonary vascular disease: vasodilation versus anti remodelling. AB - Two gross mechanisms of pathology are central to pulmonary arterial hypertension increased pulmonary vascular tone and remodelling of the pulmonary arteries. These pathologies can be caused by a variety of aberrant processes, and combine to cause an increase in pulmonary vascular resistance and consequent right ventricular hypertrophy, eventually leading to dysfunction and death. Current therapeutic strategies have focused on altering the vasoconstrictive elements of the disease. Whilst improvements in life expectancy have been observed, current therapies have not managed to halt or reverse progression of the disease. Here we discuss said unmet medical need and postulate as to the impact on disease anti remodelling therapy might provide. The mechanisms of remodelling in pulmonary arterial hypertension are reviewed, and leading examples of potential targets within such mechanisms are discussed. PMID- 20204751 TI - Infections in the immunocompromised. AB - Infections in the immunocompromised differ significantly from those in the immunocompetent. They can be more serious, more often life threatening, more difficult to diagnose and are caused by more unusual organisms. Children can be immunocompromised for a variety of reasons and the numbers, worldwide, are growing. PMID- 20204752 TI - Host biomarkers and paediatric infectious diseases: from molecular profiles to clinical application. AB - Infectious diseases are an important cause of death among children under the age of 5 (Stein et al., 2004). Most of these deaths are caused by preventable or curable infections. Limited access to medical care, antibiotics, and vaccinations remains a major problem in developing countries. But infectious diseases also continue to be an important public health issue in developed countries. With the help of modern technologies, some infections have been effectively controlled; however, new diseases such as SARS and West Nile virus infections are constantly emerging. In addition, other diseases such as malaria, tuberculosis, and bacterial pneumonia are increasingly resistant to antimicrobial treatment. PMID- 20204753 TI - The epidemiology and management of non typhoidal salmonella infections. PMID- 20204754 TI - Where does Campylobacter come from? A molecular odyssey. PMID- 20204755 TI - Why are some babies still being infected with HIV in the UK? PMID- 20204756 TI - The use and abuse of antibiotics and the development of antibiotic resistance. PMID- 20204757 TI - Vaccination against varicella: what's the point? PMID- 20204758 TI - What can we learn from the retina in severe malaria? PMID- 20204759 TI - Epidemiology and prevention of neonatal candidiasis: fluconazole for all neonates? PMID- 20204760 TI - Current status of treatment of hepatitis B in children. PMID- 20204761 TI - Treatment of neonatal fungal infections. PMID- 20204762 TI - Malaria in pregnancy and the newborn. PMID- 20204763 TI - Adenovirus infection in the immunocompromised host. PMID- 20204764 TI - Strategies for global prevention of hepatitis B virus infection. PMID- 20204765 TI - Unfinished physiology. AB - The following was an invited pre-dinner commentary to the standing group waiting for supper, light heartedly suggesting several still unsettled physiologic problems in need of study. PMID- 20204766 TI - Cell respiration under hypoxia: facts and artefacts in mitochondrial oxygen kinetics. AB - When oxygen supply to tissues is limiting, mitochondrial respiration and ATP production are compromised. To assess the bioenergetic consequences under normoxia and hypoxia, quantitative evaluation of mitochondrial oxygen kinetics is required. Using high-resolution respirometry, the "apparent K (m)" for oxygen or p (50) of respiration in 32D cells was determined at 0.05 +/- 0.01 kPa (0.4 mmHg, 0.5 microM, 0.25% air saturation). Close agreement with p (50) of isolated mitochondria indicates that intracellular gradients are small in small cells at routine activity. At intracellular p (O2) <2 kPa (15 mmHg, 10% air saturation) in various tissues under normoxia, respiration is limited by >2% with a p (50) of 0.05 kPa. Over-estimation of p (50) at 0.4 kPa (3 mmHg) would imply significant (>17%) oxygen limitation of respiration under intracellular normoxia. Based on a critical review, we conclude that p (50) ranges from 0.01 to 0.10 kPa in mitochondria and small cells in the absence of inhibitors of cytochrome c oxidase, whereas experimental artefacts explain the controversial >200-fold range of p (50) in the literature on mitochondrial oxygen kinetics. PMID- 20204767 TI - Alveolar hypoxia-induced systemic inflammation: what low PO(2) does and does not do. AB - Reduction of alveolar PO(2) (alveolar hypoxia, AH) may occur in pulmonary diseases such as chronic obstructive pulmonary disease (COPD), or in healthy individuals ascending to altitude. Altitude illnesses may develop in non acclimatized persons who ascend rapidly. The mechanisms underlying these illnesses are not well understood, and systemic inflammation has been suggested as a possible contributor. Similarly, there is evidence of systemic inflammation in the systemic alterations present in COPD patients, although its role as a causative factor is not clear.We have observed that AH, induced by breathing 10% O(2) produces a rapid (minutes) and widespread micro vascular inflammation in rats and mice. This inflammation has been observed directly in the mesenteric, skeletal muscle, and pial microcirculations. The inflammation is characterized by mast cell degranulation, generation of reactive O(2) species, reduced nitric oxide levels, increased leukocyte-endothelial adherence in post-capillary venules, and extravasation of albumin. Activated mast cells stimulate the renin angiotensin system (RAS) which leads to the inflammatory response via activation of NADPH oxidase. If the animals remain in hypoxia for several days, the inflammation resolves and exposure to lower PO(2) does not elicit further inflammation, suggesting that the vascular endothelium has "acclimatized" to hypoxia.Recent experiments in cremaster microcirculation suggest that the initial trigger of the inflammation is not the reduced tissue PO(2), but rather an intermediary released by alveolar macrophages into the circulation. The putative intermediary activates mast cells, which, in turn, stimulate the local renin angiotensin system and induce inflammation. PMID- 20204768 TI - The influence of oxygen supply, hemorheology and microcirculation in the heart and vascular systems. AB - The microcirculation is an important system, containing resistance arterioles, capillaries and venules, whose main function is to transport oxygen and nutrients to the tissues. Endothelial cells are the main cell types of the microcirculation; their homeostasis is modulated by constant shear stress. Altered hemorheology induces a change in the production of vasodilator and vasoconstrictor agents. The most important pattern inducing endothelium dysfunction is an increase in oxidative stress, which decreases the amount of nitric oxide and favors microvascular phlogosis. In this review we will consider the main scientific reports about the cardiovascular risk factors such as smoking, hypercholesterolemia, hyperviscosity, hypertension, diabetes, stress and increased homocysteine levels, all having as common etiopathogenetic factor alterations in microcirculation and in tissue oxygenation. We also focus on their influence on endothelial cells, inducing endothelial changes and dysfunction related to altered oxygen supply and linked to increased oxidative stress. Also important are endothelial stem cells, that are able to repair vascular endothelial damage, especially in cardiovascular patients, with or without endothelial dysfunction. Under these circumstances the numbers of these stem cells are altered, which means there is a decrease in regeneration capability (post ischaemia modified albumin, etc.). This could be an important negative prognostic factor. Microcirculation and tissue oxygenation are very important factors strongly linked to hemorheology, especially in cardiovascular patients, and their alterations could cause impairment, or initiate cardiovascular pathologies. PMID- 20204769 TI - Could dilated cardiomyopathy alter the peripheral microcirculation and blood rheology? AB - Our aim was to perform a preliminary study of blood flow in the peripheral microcirculation in patients with heart failure. Cardiac patients were investigated to establish possible microcirculatory changes due to this pathology. We evaluated 16 patients (non-smokers, dislipidemic with hypercholesterolemia), receiving oral treatment and in NYHA class 2.3 +/- 0.5. A dilated cardiomyopathy (DCM) group was evaluated before cardiac resynchronization therapy (CRT) obtained by biventricular intra-cardiac defibrillator (ICD) implantation, and again 3 months after its implantation. We measured the ejection fraction (EF), peripheral blood flow (using laser Doppler) at the left wrist on the volar side, capillary morphology (using computerized videocapillaroscopy) on the nail bed of the 4th finger of the left hand, rheological status (using the LORCA), as well as hematocrit, hemoglobin concentration, red blood cell (RBC) surface acetylcholinesterase (AchE), and homocysteine. Our data show that in the DCM vs. control group, peripheral flow did not depend only on the heart: throughout the study, blood flow did not change significantly compared to controls and was increased after CRT. There was no decrease in aggregation time. The blood flow did not alter RBC deformability or RBC surface AchE. Due to the lower oxygenation and to a non-significant increase in the number of capillaries after CRT, DCM patients are at higher cardiovascular risk than healthy subjects. PMID- 20204770 TI - The role of glyoxalase system in renal hypoxia. AB - Methylglyoxal (MG), a highly reactive alpha-oxoaldehyde generated by oxidation of carbohydrate and glycolysis, binds to proteins and forms advanced glycation end products (AGE). MG and MG adducts have been implicated in oxidative stress related diseases, therefore, MG detoxifying system such as the glyoxalase system (glyoxalase I) also contributes to progression of these diseases. Recent papers have emphasized the pathophysiological effects of MG and the glyoxalase system in acute hypoxic injury, which is associated with acute oxidative stress. We investigated the kinetics of MG level and glyoxalase I activity in renal acute hypoxic injury induced by ischemia-reperfusion (I/R). I/R induced tubulointerstitial injury and the histological changes were associated with a significant decrease in renal glyoxalase I activity and an increase in MG level in the damaged tubular cells. Of note, rats over expressing human glyoxalase I showed amelioration of I/R-induced histological and functional damages and it was associated with a decrease in MG level in the lesion resulting in reduction of oxidative stress and tubular cell apoptosis. In conclusion, glyoxalase I has renoprotective effects in renal hypoxia such as I/R injury via a reduction in cytotoxic MG level in tubular cells. PMID- 20204771 TI - Intracortical microcirculatory change induced by anesthesia in rat somatosensory cortex. AB - The present study aimed to characterize microcirculatory responses to anesthesia in brain tissue. With multi-photon excitation fluorescence microscopy, intra cortical capillary dimension and red blood cell (RBC) flow were successfully visualized up to a depth of approximately 0.6 mm from the cortical surface in rats anesthetized with either isoflurane or alpha-chloralose. We observed that the diameter of the major cerebral artery was approximately 100 microm under isoflurane, but approximately 75 microm under alpha-chloralose. The capillary diameter was observed to be larger under alpha-chloralose than isoflurane: 5.1 +/ 1.2 microm vs. 4.8 +/- 1.1 microm, respectively. A significant difference in the mean RBC speed measured in single capillaries was observed: 0.4 +/- 0.4 mm/s under alpha-chloralose vs. 1.5 +/- 0.4 mm/s under isoflurane. In agreement with these observations, arterio-venous transit-time and laser-Doppler flowmetry consistently showed a significant reduction of the RBC and plasma blood speed under alpha-chloralose relative to isoflurane. These findings may indicate that local blood flow regulatory mechanisms exist at the capillary level for the balance of oxygen supply and demand induced by anesthesia in the brain tissue. PMID- 20204772 TI - Macrophages that survive hyperoxia exposure have higher superoxide dismutase activities in their mitochondria. AB - Prolonged exposure to hyperoxia, which is routinely used in patients with severe respiratory failure, leads to the generation of excessive reactive oxygen species, resulting in lung injury. In the present study, we focused on macrophages and their survival, superoxide dismutase (SOD) activity in mitochondria (Mn-SOD activity), and mitochondrial DNA (mtDNA) mutation after exposure to hyperoxia. Macrophages were cultured under two different conditions: normoxia and intermittent hyperoxia. The number of cells exposed to intermittent hyperoxia for 3 weeks significantly decreased, compared with the number of cells exposed to normoxia. The Mn-SOD activity of the cells that survived intermittent hyperoxia exposure was significantly higher than that of the cells exposed to normoxia. Direct sequencing and a PCR-RFLP assay did not provide any evidence of mutation in the cells that survived intermittent hyperoxia exposure. In conclusion, an increase in the antioxidative activity of mitochondria is important for the survival of macrophages exposed to hyperoxia, and the increased activity level possibly enhances protective effects against mtDNA mutations in surviving cells. PMID- 20204773 TI - Diet-induced ketosis improves cognitive performance in aged rats. AB - Aging is associated with increased susceptibility to hypoxic/ischemic insult and declines in behavioral function which may be due to attenuated adaptive/defense responses. We investigated if diet-induced ketosis would improve behavioral performance in the aged rats. Fischer 344 rats (3- and 22-month-old) were fed standard (STD) or ketogenic (KG) diet for 3 weeks and then exposed to hypobaric hypoxia. Cognitive function was measured using the T-maze and object recognition tests. Motor function was measured using the inclined-screen test. Results showed that KG diet significantly increased blood ketone levels in both young and old rats. In the aged rats, the KG diet improved cognitive performance under normoxic and hypoxic conditions; while motor performance remained unchanged. Capillary density and HIF-1alpha levels were elevated in the aged ketotic group independent of hypoxic challenge. These data suggest that diet-induced ketosis may be beneficial in the treatment of neurodegenerative conditions. PMID- 20204774 TI - Fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, improves hepatic microcirculatory patency and oxygen availability in a high-fat-diet induced fatty liver in mice. AB - Nonalcoholic fatty liver disease (NAFLD) is a common disease of chronic liver diseases. Peroxisome proliferator-activated receptor alpha (PPARalpha) has been implicated to play important roles in the development of the disease. Beyond its effects on lipid metabolisms, PPARalpha activation in the vascular system has emerged as an attractive therapeutic potential for NAFLD, although its actions in the microcirculatory system are not fully understood. In this study, we investigated the effects of fenofibrate, a PPARalpha synthetic agonist, on hepatic microcirculation in a high-fat diet (HFD)-induced fatty liver in mice. In vivo imaging analysis revealed the adverse effects of HFD on hepatic vasculature with narrowing of hepatic sinusoids and hepatic microcirculatory perfusion. Oxygen tension was significantly decreased in portal venules, while NADH autofluorescence in hepatocytes was greatly elevated. Fenofibrate treatment remarkably improved microvascular patency, tissue oxygenation and redox states in the affected liver. These results suggest beneficial roles of PPARalpha activated by fenofibrate on the regulation of both lipid metabolisms and microvascular environments of oxygen metabolism in HFD-induced fatty liver. PMID- 20204775 TI - Renal vasoconstriction in rats causes a decrease in capillary density and an increase in alkaline phosphatase expression in cardiac capillary nets. AB - In the rat, experimental renal vasoconstriction induced by the use of a Goldblatt clamp caused arterial hypertension, cardiomyocyte hypertrophy and an increased capillary to cardiomyocyte ratio, the latter indicating the formation of new cardiac capillaries. Total capillary density decreased, but capillary portions expressing alkaline phosphatase increased. This suggested a greater arterialization of capillaries which would increase the flow of arterial blood to the myocardial capillary nets. However, the observed increase in the area of the capillary domains means the extra arterialization was not sufficient to compensate for the lengthening of the oxygen diffusion pathway caused by the hypertrophy. Since the effects of renal vasoconstriction were not seen in rats treated with an inhibitor of angiotensin converting enzyme (ACE) it is suggested they are induced by angiotensin II via activation of the renin-angiotensin system (RAS). PMID- 20204776 TI - The effects of cilostazol on tissue oxygenation upon an ischemic-reperfusion injury in the mouse cerebrum. AB - Although cilostazol, an inhibitor of cyclic nucleotide phosphodiesterase 3 (PDE3), is known to exert a potent antiplatelet function by raising intracellular cAMP concentration, its effect on cerebral microcirculation upon an ischemic insult is not clearly understood. To examine effects of cilostazol on the global ischemic injury in the brain, we first measured the plasma leakage using modified Miles assay after mice had been subjected to 60 min of a bilateral common carotid artery (BCCA) occlusion followed by reperfusion for 4 h. Oral treatment with cilostazol (30 mg/kg) significantly increased plasma leakage. This result led us to examine if the treatment with cilostazol recruits more capillaries leading to an increase in surface area for exchange and oxygen transport to tissues. To do so, we simultaneously measured degrees of tissue hypoxia and vessel perfusion. Pimonidazol was injected intraperitoneally 1 h before sacrifice and capillary patency was assessed by fluorescein isothiocyanate-labeled Lycopersicon esculentum lectin bound to the endothelial surface. Treatment with cilostazol markedly increased the capillary patency which was accompanied by a reduction in the hypoxic area. Although the treatment with cilostazol caused an increase in the flux of plasma proteins across endothelial barrier that may imply an adverse role after a BCCA occlusion, this increase in protein leakage was attributable to the increased surface area for exchange which in turn brought about a reduction in tissue hypoxia. Taken together cilostazol appears to produce a protective effect against the ischemic-reperfusion injury. PMID- 20204777 TI - Effect of transient forebrain ischemia on flavoprotein autofluorescence and the somatosensory evoked potential in the rat. AB - In order to evaluate the effect of cerebral ischemia on the flavoprotein fluorescence (FPF), we compared the changes in the FPF and somatosensory evoked potential (SEP) during transient cerebral ischemia in the rat. We measured the FPF and SEP simultaneously via a cranial window made over the right sensorimotor cortex during the left median nerve stimulation in F344 rats. We compared change in FPF and SEP during cerebral ischemia for 60 min. The rCBF were rapidly recovered after reperfusion. However, the recovery rates of the FPF were significantly faster than those of the SEP after reperfusion. These findings indicate that activity-dependent changes of the FPF do not necessarily correlate with the electrical activity after transient cerebral ischemia. PMID- 20204778 TI - Assessing a shift of glucose biotransformation by LC-MS/MS-based metabolome analysis in carbon monoxide-exposed cells. AB - Carbon monoxide (CO) is the stress-inducible gas generated by heme oxygenase (HO). Although the HO/CO system appears to contribute to cell protection and tissue repair under stress conditions, its mode of actions remains largely unknown. We hypothesized that CO might alter the cellular energetic conditions and thereby modulate oxygen metabolism. To examine this hypothesis, we attempted to establish a method to follow the global flux of (13)C-glucose in the cells using metabolomic approaches with liquid chromatography-mass spectrometry (LC MS/MS). The human monoblastic leukemia cell line U937 was exposed to the CO releasing molecule (CORM). The CO exposure attenuated the conversion of the mass labeled glucose to its downstream metabolites, while significantly stimulating its conversion to those for pentose phosphate pathway, suggesting roles of stress inducible CO in a shift of glucose biotransformation. PMID- 20204779 TI - T-state stabilization of hemoglobin by nitric oxide to form alpha-nitrosyl heme causes constitutive release of ATP from human erythrocytes. AB - Upon hypoxia, erythrocytes utilize hemoglobin (Hb) to trigger activation of glycolysis through its interaction with band 3. This process contributes to maintenance of ATP, a portion of which is released extracellularly to trigger endothelium-dependent vasorelaxation. However, whether the ATP release results either from metabolic activation of the cells secondarily or from direct regulation of the gating through Hb allostery remains unknown. This study aimed to examine if stabilization of T-state Hb could induce steady-state and hypoxia induced alterations in glycolysis and the ATP release from erythrocytes. Treatment of deoxygenated erythrocytes with a nitric oxide (NO) donor generated alpha-NO Hb that is stabilized T-state allostery. Under these circumstances, the release of ATP was significantly elevated even under normoxia and not further enhanced upon hypoxia. These events did not coincide with activation of glycolysis of the cells, so far as judged by the fact that intracellular ATP was significantly decreased by the NO treatment. Collectively, the present study suggests that hypoxia-induced ATP release is triggered through mechanisms involving R-T transition of Hb, and the gating process might occur irrespective of hypoxia-responsive regulation of glycolysis. PMID- 20204780 TI - Age-related changes in the trachea in healthy adults. AB - To investigate age-related changes in the shape of trachea, normal male volunteers (n = 83, mean +/- SD: 47.7 +/- 20.2 years old) underwent inspiratory CT scans at full inspiration and lung function tests. Subjects who showed VC < 80% predicted or FEV1 < 80% predicted on lung function tests were excluded. The CT data, which is located at 2.0 cm above the aortic arch, were transferred to a personal computer. The tracheal area (St) and two parameters, Tracheal index (Ti) and Circularity (Ci) indicating the shape of the trachea, were automatically calculated. Ti was defined the ratio of the coronal to the sagittal diameter of the trachea, and the Ci (Ci = 4piS/L2, S: tracheal area, L: tracheal perimeter) was used to indicate the roundness of the trachea. A Ci value of less than 1 indicated the distortion of the roundness. Both St and St/BSA (body surface area) showed a significant correlation with age (r = 0.37, r = 0.52; p = 0.0006, p < 0.0001). Ti was not correlated with age (r = -0.20; p = 0.0697), whereas Ci was significantly correlated with age (r = -0.32; p = 0.00364). There were measurable age related changes of the trachea both in the area and the shape. Aging results in the increased tracheal area and a distortion of the roundness. PMID- 20204781 TI - Polycythemia and changes in erythropoietin concentration in rats exposed to intermittent hypoxia. AB - It is not clear whether blood hemoglobin concentration ([Hb]) increases with an increase in the exposure period of intermittent hypoxia (IHx) and reaches a constant level. Furthermore, it is not known whether plasma erythropoietin concentration ([EPO]) also increases with an increase in the exposure period. Using a rat model, first, we evaluated changes in [EPO] every hour after single exposure of 10% O(2) for 120 min in order to determine a peak level of [EPO]. Second, we evaluated the effect of IHx of 10% O(2), 120 min/day for 0 (control), 1, 2, 3, 4, 6 and 8 weeks on [Hb], arterial blood pressure (BP), heart rate (HR), arterial blood gases (ABGs) and [EPO]. [EPO] increased after cessation of the single hypoxic exposure, reached a peak at 1 h, and decreased gradually to the control levels within 18 h. IHx of 10% O(2), 120 min/day, produced a time dependent increase in [Hb], and [Hb] reached a constant level after the exposure for 6 weeks. BP increased after the exposure for 4 weeks and remained elevated. There was no significant difference in HR and ABGs. [EPO] increased significantly and remained elevated at the same level for 1-3 weeks, however, the peak level of [EPO] declined markedly after [Hb] reached a constant level. PMID- 20204782 TI - A case of HAPE on K2 and literature review. AB - HAPE (High Altitude Pulmonary Edema) is a serious and fatal disease in mountains. Early diagnosis and immediate descent are important for successful treatment. One of the authors (GS), who was healthy and a well trained climber, participated in the expedition to K2 (8611 m) in 2006 and developed HAPE. Under the severe environmental condition, it was difficult to evaluate his condition in its early stage. The earliest symptoms were nonspecific for HAPE as reported in many papers. Neither had he suffered from HAPE on the previous expeditions. These facts probably delayed the diagnosis in spite of its typical onset. This is a rare case report by a medical doctor who suffered from HAPE. The present case may remind the climbers of the difficulties in diagnosing HAPE on a mountain. PMID- 20204783 TI - Synchronization between cardiac and respiratory rhythms in healthy subjects and patients. AB - Synchronization between cardiac and respiratory rhythms may be important for oxygen transport to tissues. The aim of this study was to investigate the synchronization between cardiac and respiratory rhythms. We evaluated the rhythms in 12 healthy males and 24 patients. The incidence rates of heart beats were obtained in each time interval relative to the initiation time point of inspiration. A simple index of timing variability of heart beats was defined. When the variability is large, the link between cardiac and respiratory rhythms was considered to be strong. The variability value of patients with disorder in the autonomic nervous system was larger than that of healthy subjects (p < 0.05). The variability of patients on controlled ventilation was lower than that of healthy subjects (p < 0.01), whereas the value on cardiac pacemaker did not differ from healthy subjects. In conclusion, the synchronization between cardiac and respiratory rhythms was confirmed, and it is suggested that the synchronization is enhanced when feed-back signals from respiratory movement to respiratory center were decreased. PMID- 20204784 TI - Time-resolved near-infrared spectroscopy and imaging of the adult human brain. AB - Near-infrared spectroscopy (NIRS) of the human brain is aiming at the non invasive determination of concentration changes of oxy- and deoxyhemoglobin in the cortex. However, it usually relies on the assumption of spatially homogeneous absorption changes. To overcome this limitation we performed instrumental and methodological developments of time-resolved NIRS with the aim to achieve depth resolution. We present our recently developed time-domain near-infrared brain imager based on picosecond diode lasers and time-correlated single photon counting (TCSPC) which can be used at the bedside. To achieve depth localization of absorption changes we analysed statistical moments (integral, mean time of flight and variance) of measured time-of-flight distributions of diffusely reflected photons. In particular, variance has a selective sensitivity to deep absorptions changes and provides a suitable representation of cerebral signals. The separation of cerebral and extracerebral changes of hemoglobin concentrations is demonstrated for a motor stimulation experiment. PMID- 20204785 TI - Clinical electron paramagnetic resonance (EPR) oximetry using India ink. AB - Electron paramagnetic resonance (EPR) oximetry can be used to provide direct absolute measurements of pO(2) in living tissue using India ink as an O(2) reporter. In vivo measurements are made using low frequency (1.2 GHz) EPR spectroscopy and surface loop resonators, which enable measurements to be made at superficial sites through a non-invasive (after placing the ink in the tissues) and repeatable measurement procedure. Ongoing EPR oximetry studies in human subjects include measurement of subcutaneous pO(2) in the feet of healthy volunteers to develop procedures that could be used in the treatment of peripheral vascular disease and oximetry in tumors during courses of radiation and chemotherapy, to follow pO(2) so oxygen-dependent therapies can be optimized. In each case, we aim to provide quantitative measurements of tissue pO(2) which will aid physicians in the characterization of disease status and the effects of therapeutic measures, so that treatments can be applied with optimal effectiveness by taking into account the oxygen-dependent aspects of the therapy. The overall goal is to enhance clinical outcomes. Oximetry measurements of subcutaneous tissue on dorsal and plantar foot surfaces have been made in 9 volunteers, with measurements ongoing for each and the longest set of measurements carried out successfully over the last 5 years. Tumor oximetry measurements have been performed in tumor tissues of 10 patients during courses of radiation and chemotherapy. Tumor types include melanoma, basal cell, soft tissue sarcoma, and lymphoma, and measurement sites have ranged from the feet to the scalp. These studies demonstrate the feasibility of EPR oximetry in a clinical setting and the potential for more widespread use in the treatment of these and other oxygen-dependent diseases. PMID- 20204786 TI - Measurement of oxygen in the microcirculation using phosphorescence quenching microscopy. AB - According to the classical concept of Krogh, O(2) is delivered to the tissues solely by capillaries and intra-capillary resistance to O(2) diffusion is negligible. Over the past three decades longitudinal PO(2) and SO(2) gradients in arterioles have been observed with a transmural PO(2) gradient in small arterioles of only 1-2 mmHg. Application of phosphorescence quenching microscopy to measurements of PO(2) in arterioles of the rat mesentery by Tsai et al. (1998) found a large transmural PO(2) in these arterioles. That led to the provocative conclusion that the arteriolar wall is the major sink for O(2) in the microcirculation. Our studies indicate that many of these results can be explained by photo-activated O(2) consumption following phosphor excitation, combined with a large excitation area and high frequency of flash excitation. We have developed the basic principles for phosphorescence quenching microscopy including the need to use a small excitation area, a low excitation frequency and a scanning excitation for stationary samples. PMID- 20204787 TI - Optimization of the coherence measurement computed by means of the Welch averaged periodogram method for assessment of impaired cerebral autoregulation. AB - The coherence method (COH) has been widely used to study the concordance between continuously measured signals intervening in the assessment of cerebral autoregulation in neonates. Several research groups have applied this method to mean arterial blood pressure (MABP) combined with cerebral signals such as the intravascular oxygenation (HbD), cerebral tissue oxygenation (TOI), and regional oxygen saturation (rSO(2)) measured by near-infrared spectroscopy (NIRS). All groups contributed in a particular way to the fine-tuning of the application of COH with the Welch averaged periodogram (WAP) method. We have made a comparative study of all published results coupled with an optimization of the use of the WAP method within COH. We have also proposed a pre-processing algorithm to remove signal artefacts, and defined a new critical score value (CSV) for COH to distinguish infants with impaired autoregulation from those without. PMID- 20204788 TI - A hybrid multi-distance phase and broadband spatially resolved spectrometer and algorithm for resolving absolute concentrations of chromophores in the near infrared light spectrum. AB - For resolving absolute concentration of tissue chromophores in the human adult brain with near-infrared spectroscopy it is necessary to calculate the light scattering and absorption, at multiple wavelengths with some depth resolution. To achieve this we propose an instrumentation configuration that combines multi distance frequency and broadband spectrometers to quantify chromophores in turbid media by using a hybrid spatially resolved algorithm. Preliminary results in solid phantoms as well as liquid dynamic homogeneous and inhomogeneous phantoms and in-vivo muscle measurements showed encouraging results. PMID- 20204789 TI - Comparison of local adipose tissue content and SRS-derived NIRS muscle oxygenation measurements in 90 individuals. AB - Adipose content in the region over the vastus lateralis muscle was measured in a young (21.1 +/- 3.1 years old, mean +/- SD) population of males (n = 62) and females (n = 28). Three techniques were used: skinfold thickness, ultrasound and near infrared spectroscopy. All techniques closely correlated with each other and all showed a significantly larger adipose content in females and a limited overlap with the range of values in males. Spatially resolved near infrared spectroscopy (SRS-NIRS) was then used to measure the tissue oxygenation index (TOI) at the same site. A source-detector separation of 4 cm was used to allow for significant light penetration into muscle tissue. TOI at rest was significantly higher in the female (65.3 +/- 7.0, mean +/- SD) than the male (61.9 +/- 5.1, mean +/- SD) group. There was a strong positive correlation between adipose content and TOI in male subjects. However, no correlation was seen in the female group. The possible optical and physiological explanations for these results are discussed. PMID- 20204790 TI - Muscle oxygen saturation measured using "cyclic NIR signals" during exercise. AB - A new approach to measure muscle oxygen saturation (SmO(2)) using near infrared spectroscopy (NIRS) has been proposed in this paper. This approach exploits the cyclic NIRS signals seen during exercise which are often regarded as "movement artefacts". This new measure, which we term the "cyclic SmO(2)", has the potential to be less affected by the myoglobin which is traditionally believed to be indistinguishable from haemoglobin using NIRS techniques. The cyclic SmO(2) also has fewer assumptions than the conventional SmO(2) measured using time, phase and spatially resolved spectroscopy methods. In a cycling exercise study, NIRS measurements were made over the Vastus lateralis muscle of 11 subjects. In a light exercise protocol, the group mean of the conventional SmO(2) was 51.7 +/- 4.3% and that of the cyclic SmO(2) was 56.0 +/- 3.9%. It was immediately followed by a hard exercise protocol and the group mean of the conventional SmO(2) was reduced to 42.6 +/- 6.1% and that of the cyclic SmO(2) to 48.5 +/- 5.6%. The reduction agrees with the general expectation. The cyclic SmO(2) is a promising new measure of muscle oxygenation. PMID- 20204791 TI - Determination of oxygen dosage effects on cytochrome oxidase after anoxia in brain. AB - Recent evidence reports that high doses of O(2) administered via hyperbaric oxygen therapy (HBOT) improve the return of spontaneous circulation (ROSC), and the outcome of damage to the heart following a 25 min normothermic cardiac arrest. However, excessive O(2) during HBOT can be toxic. Near infrared absorbance spectroscopy (NIRS) measures and determines when cytochrome oxidase (aa(3)), the O(2) end user, changes from reduced to oxidized, signifying adequate dosage. Present NIRS monitoring methods do not account for change in scattering expected in severe anoxia. Given this limitation, we simultaneously measured changes in intensity and scattering that occurred over time after 830 nm light traveled 4.25 cm through brain tissue during both normoxia and anoxia. Results indicated increased intensity and scattering during anoxia with correlation between the two, demonstrating that scattering does not remain constant and is associated with intensity. With this additional insight in concurrent scattering and intensity change during anoxia, we believe improvements can be made to our aa(3) measuring technique resulting in a method to ascertain adequate O(2) dosage during HBOT. PMID- 20204792 TI - A mathematical model for analyses of muscle oxygenation measurements using NIR spectroscopy. AB - Near-infrared spectroscopy (NIRS) enables noninvasive measurement of muscle oxygenation. However, since NIRS does not enable direct measurement of muscle metabolism, it is necessary to analyze the dynamic changes in metabolism during exercise using other methods in order to understand the relationship between NIRS measurements and muscle metabolism. A model of muscle metabolism that is composed of aerobic and anaerobic metabolic systems and O(2) transport to tissue system was developed. Using the model, the temporal profiles of muscle oxygenation during exercise with different intensities (20, 40 and 70% maximum voluntary contraction), measured using NIRS in a single subject, were sufficiently reproduced. In addition, analyses of simulation results of (i) aerobic and anaerobic metabolic systems and (ii) O(2) consumption were performed, and the intensity-dependent differences in the temporal responses during exercise and recovery periods were estimated. The initial results show the usefulness of the model for simulating the kinetics of NIRS measurement data and for systematic interpretation of the relationship between NIRS data and muscle metabolism. PMID- 20204793 TI - Mapping of optical pathlength of human adult head at multi-wavelengths in near infrared spectroscopy. AB - Measurement of multichannel continuous-wave near-infrared spectroscopy (CW-NIRS) is dependent on the modified Beer-Lambert law, which includes optical pathlength (PL) as an essential parameter. PLs are known to differ across different head regions and different individuals, but the distribution of PLs for the whole head has not been evaluated so far. Thus, using time-resolved near-infrared spectroscopy (TR-NIRS), we measured the optical characteristics including PL, scattering coefficients (mu'(s)), and absorption coefficients (mu(a)) at three wavelengths (760, 800, 830 nm). Then, we constructed maps of these parameters on the subjects' head surface. While the PLs in nearby channels are similar, they differ depending on the regions of the head. The PLs in the region above the Sylvian fissure tended to be shorter than those in the other regions at all of the wavelengths. The difference in the distribution of PLs may be attributed to differences in tissue absorption and scattering properties. The current study suggests the importance of considering PL differences in interpreting functional data obtained by CW-NIRS. PMID- 20204794 TI - Changes of evoked cerebral blood oxygenation and optical pathlength in the frontal lobe during language tasks: a study by multi-channel, time-resolved near infrared spectroscopy and functional MRI. AB - To determine the alterations in optical characteristics and cerebral blood oxygenation (CBO) in the frontal lobe during language tasks, we evaluated the changes in mean optical pathlength (MOP) and CBO induced by a verbal fluency task (VFT) in the right and left frontal lobes in normal adults (n = 9, mean age = 29.6 +/- 4.8 years). We employed a newly developed 8-channel time-resolved near infrared spectroscopy (TRS) instrument. The results demonstrated differences in MOP in the fronto-temporal areas with subject and wavelength; however, there was no significant difference between the right and left sides (p > 0.05). Also, the VFT did not affect the MOP significantly as compared to that before the tasks (p > 0.05). In all of the recording regions, the VFT caused increases in concentration of oxyhemoglobin and total hemoglobin associated with a decrease in deoxyhemoglobin concentration, indicating that these cortical areas were activated by the VFT. However, the mean concentration changes of oxyhemoglobin and total hemoglobin on the left side were larger than those on the right side. In addition, functional MRI demonstrated that the inferior frontal gyrus on the left side was activated in the subjects who exhibited increases in oxyhemoglobin concentration in these areas. These results suggest that TRS may be useful to study language function and to assess hemispheric dominance for language. PMID- 20204795 TI - The partial coherence method for assessment of impaired cerebral autoregulation using near-infrared spectroscopy: potential and limitations. AB - The most important forms of brain injury in premature infants are partly caused by disturbances in cerebral autoregulation. As changes in cerebral intravascular oxygenation (HbD), regional cerebral oxygen saturation (rSO(2)), and cerebral tissue oxygenation (TOI) reflect changes in cerebral blood flow (CBF), impaired autoregulation can be measured by studying the concordance between HbD/rSO(2)/TOI and the mean arterial blood pressure (MABP), assuming no changes in oxygen consumption, arterial oxygen saturation (SaO(2)), and in blood volume. We investigated the performance of the partial coherence (PCOH) method, and compared it with the coherence method (COH). The PCOH method allows the elimination of the influence of SaO(2) on HbD/rSO(2)/TOI in a linear way. We started from long-term recordings measured in the first days of life simultaneously in 30 infants from three medical centres. We then compared the COH and PCOH results with patient clinical characteristics and outcomes, and concluded that PCOH might be a better method for assessing impaired autoregulation. PMID- 20204796 TI - Active muscle oxygenation dynamics measured during high-intensity exercise by using two near-infrared spectroscopy methods. AB - Near-infrared spectroscopy is a noninvasive optical technique used to monitor tissue oxygenation. Generally, the modified Beer-Lambert's law (MBL) using continuous-wave light has been used to measure active muscle oxygenation during exercise; however, it cannot measure absolute changes in the oxy- (oxy-[Hb + Mb]), deoxy- (deoxy-[Hb + Mb]), and total hemoglobin/myoglobin concentrations (total-[Hb + Mb]) because the pathlength and scattering coefficient are not measured. In contrast, the time-resolved spectroscopy (TRS) using a ultra short pulsed laser can be used to determine absolute changes in the concentration, although the temporal resolution is inferior to that in MBL. This study evaluated the absolute changes in active muscle oxygenation and the optical mean pathlength and scattering and absorption coefficient during high-intensity exercise by using the TRS system. In addition, the difference between the changes determined using TRS and MBL measurements was assessed. When the TRS and MBL measurements obtained during high-intensity exercise were compared, the total-[Hb + Mb] and oxy-[Hb + Mb] dynamics differed markedly during high-intensity exercise, while the deoxy [Hb + Mb] dynamics and kinetics did not differ. PMID- 20204797 TI - Theoretical and experimental investigation of the influence of frontal sinus on the sensitivity of the NIRS signal in the adult head. AB - The sensitivity of the near-infrared spectroscopy signal to the brain activation depends on the thickness and structure of the superficial tissues. The influence of the frontal sinus, which is void region in the skull, on the sensitivity to the brain activation is investigated by the time-resolved experiments and the theoretical modelling of the light propagation in the head. In the time-resolved experiments, the mean-time of flight for the forehead scarcely depends upon the existence of the frontal sinus when probe spacing was shorter than 30 mm. The partial optical path length in the brain, which indicates the sensitivity of the near-infrared spectroscopy signal to the brain activation, in a simplified head model is predicted by Monte Carlo simulation. The influence of the frontal sinus on the sensitivity of the signal depends on the thickness of the skull and the depth of the frontal sinus. PMID- 20204798 TI - Functional optical topography analysis using statistical parametric mapping (SPM) methodology with and without physiological confounds. AB - Functional optical topography (OT) measures the changes in oxygenated and deoxygenated hemoglobin (HbO(2), HHb) across multiple brain sites which occur in response to neuronal activation of the cerebral cortex. However, identification of areas of cortical activation is a complex task due to intrinsic physiological noise and systemic interference and careful statistical analysis is therefore required. A total of 10 young healthy adults were studied. The activation paradigm comprised of anagrams followed by finger tapping. 12 channels of the OT system were positioned over the frontal cortex and 12 channels over the motor cortex while the systemic physiology (mean blood pressure (MBP), heart rate (HR), scalp flux) was simultaneously monitored. Analysis was done using the functional Optical Signal Analysis (fOSA) software and Statistical Parametric Mapping (SPM), where we utilized two approaches: (i) using only HbO(2) as a regressor in the general linear model (GLM) and (ii) using all of the explanatory variables (HbO(2), MBP, HR and scalp flux) as regressors. Group analysis using SPM showed significant correlation in a large number of OT channels between HbO(2) and systemic regressors; however no differences in activation areas were seen between the two approaches. PMID- 20204799 TI - Comparison of somatosensory evoked potentials and cerebral blood oxygenation changes in the sensorimotor cortex during activation in the rat. AB - The relationship between changes in cerebral blood oxygenation and neuronal activity remains to be fully established. We compared somatosensory evoked potentials (SEP) and evoked cerebral blood oxygenation (CBO) changes in the sensorimotor cortex of the rat. In rats anesthetized with urethane and alpha chloralose, we measured SEP and CBO using visible light spectroscopy (VLS) during neuronal activity. Increase of stimulus frequency caused a decrease of SEP amplitude, but an increase in concentration changes of deoxy-Hb and oxygen saturation. The difference in frequency responses between SEP and CBO might be caused by activation of inhibitory neurons, which could suppress excitatory neurons at high stimulus frequencies; activation of inhibitory neurons could reduce SEP amplitude, and increase oxygen saturation due to an increase of evoked cerebral blood flow. PMID- 20204800 TI - Individual differences in blood volume and oxygenation in the brain during a cognitive task based on time-resolved spectroscopic measurements. AB - Although a time-resolved near-infrared spectroscopy (TRS) system is difficult to make a measurement into 10 s or less at the moment, the system has a great advantage that it measures absolute values of hemoglobin concentrations. In the present study, using a device equipped with a TRS system, we examined individual differences in changes in cerebral oxygenated, deoxygenated, and total hemoglobin concentrations during two repetitive executions of a cognitive task, and compared these with data from our previous studies performed with a CWS system. As a result, large individual differences were also observed in changes in the cerebral hemoglobin concentrations during a cognitive task in this study using a TRS system. We therefore conclude that large individual differences observed in changes in the cerebral hemoglobin concentrations during a cognitive task in our previous studies using a continuous wave near-infrared spectroscopy (CWS) system would probably be universal, although a CWS system includes the limitation that the absolute value is unable to be measured in the system. PMID- 20204801 TI - Cerebral oxygenation in the frontal lobe cortex during incremental exercise tests: the regional changes influenced by volitional exhaustion. AB - The present study examined the regional differences of cortical oxygenation in the frontal lobe by near-infrared spectroscopy (NIRS) during incremental exercise tests and the precise location of NIRS was examined by brain magnetic resonance imaging (MRI). Pulmonary gas exchange and NIRS measurement during incremental cycling ergometry tests were investigated in 14 men. In 7 of these subjects, the right middle cerebral artery mean velocity (MCA Vmean) was simultaneously measured by transcranial Doppler (TCD). In the right medial of the frontal lobe cortex, Tissue Oxygenation Index (TOI) increased by 8.8% with its peak value at respiratory compensation threshold (RCT) and Normalized Tissue Hemoglobin Index (nTHI) increased until endpoint by 16.2%. During incremental exercise tests, the changing pattern of TOI was different according to the distribution of the probes. Volitional exhaustion by exercise induced the deteriorated TOI and MCA Vmean, whereas nTHI increased. PMID- 20204802 TI - Implantable resonators--a technique for repeated measurement of oxygen at multiple deep sites with in vivo EPR. AB - EPR oximetry using implantable resonators allows measurements at much deeper sites than are possible with surface resonators (> 80 vs. 10 mm) and achieves greater sensitivity at any depth. We report here the development of an improved technique that enables us to obtain the information from multiple sites and at a variety of depths. The measurements from the various sites are resolved using a simple magnetic field gradient. In the rat brain multi-probe implanted resonators measured pO(2) at several sites simultaneously for over 6 months under normoxic, hypoxic, and hyperoxic conditions. This technique also facilitates measurements in moving parts of the animal such as the heart, because the orientation of the paramagnetic material relative to the sensing loop is not altered by the motion. The measured response is fast, enabling measurements in real time of physiological and pathological changes such as experimental cardiac ischemia in the mouse heart. The technique also is quite useful for following changes in tumor pO(2), including applications with simultaneous measurements in tumors and adjacent normal tissues. PMID- 20204803 TI - Use of visible spectrophotometry to assess tissue oxygenation in the colostomy stoma. AB - The aims of this study were to determine the normal range of tissue oxygenation (SO(2)) in the "mature" colostomy stomacolostomy stoma and to investigate whether there were any diurnal variationsdiurnal variations in the SO(2) values. Ten patients with an end colostomy for a minimum duration of three months and using conventional colostomy bags were included in this study. Tissue SO(2) Tissue SO(2) was measured on the stoma using visible wavelength spectroscopy (Whitland RM 200, Whitland Research, Whitland, UK) The measurements were carried out on each patient on three occasions: the first early in the morning (designated "baseline"), a second after 6 h and the third on the next day at 24 h. The results showed that the mean baseline SO(2) in the colostomy stoma was 77.6 +/- 6.8 and there were no differences in the SO(2) measurements between the baseline, 6 h and the 24 h values. There were also no differences in the SO(2) values between the four quadrants of the stomas. In conclusion, visible wavelength spectrophotometry can reliably measure stomal SO(2) in a non-invasive way. No significant diurnal variations in the stomal SO(2) values were detected. PMID- 20204804 TI - Automatic detection of motion artifacts in infant functional optical topography studies. AB - A key advantage of optical topography (OT) for cognitive neurodevelopmental studies over other imaging techniques such as magnetic resonance (MRI) or positron emission tomography (PET) is that it is less intrusive in the experimental set up. This is, in part, because in OT there is no need to impose strict movement constraints on the participants. However, large head movements can cause signal disruption, thus there is a need to (i) detect artifacts caused by movement and (ii) implement strategies to remove the noise component from the optical data. We have developed a motion sensor compatible with our in-house OT system and suitable for infant studies. With the data collected we have adjusted the thresholds that were used in the past to automatically discard data affected by movement artifacts. We have also compared the performance of two different head probe designs by measuring the amount of signal disruption present in recordings with each design. Finally, we have studied the feasibility of using the sensor data as external input of an adaptive filter to reduce the movement component of the optical data. PMID- 20204805 TI - Modelling of mitochondrial oxygen consumption and NIRS detection of cytochrome oxidase redox state. AB - In recent years there has been widespread use of near infrared spectroscopy (NIRS) to monitor the brain. The signals of interest include changes in the levels of oxygenated and deoxygenated haemoglobin and tissue oxygen saturation. In addition to oxy- and deoxy-haemoglobin, the Cu(A) centre in cytochrome-c oxidase (CCO) is a significant NIR absorber, giving rise to another signal termed the DeltaoxCCO signal. This signal has great potential as a marker of cellular oxygen metabolism, but is also the hardest to interpret. Here we use a recently constructed model to predict NIRS signal changes, and compare the model output to data from an in vivo hypoxia study in healthy adults. Our findings indicate strongly that the DeltaoxCCO signal contains useful information despite the noise, and has responses consistent with the known physiology. PMID- 20204806 TI - Forced oscillation technique as a non-invasive assessment for lung transplant recipients. AB - We usually use spirometry for the medical follow-up of respiratory mechanics after lung transplantation. However, especially in the first few post-operative weeks, it is easily affected by postoperative pain and the patient's co-operation during forced breathing effort. To avoid missing out on assessing pulmonary function, we perform non-invasive forced oscillation techniques on the patients who cannot perform forced breathing maneuvers. In this paper, we discuss the application of forced oscillation techniques on a patient with suspicion of acute lung rejection, whose spirometry could not be correctly performed and seemed to be unreliable. The respiratory impedance measurements had good correlation with the patient's clinical symptoms before and after steroid therapy. Thus, postoperative pulmonary function follow-up using forced oscillation technique was useful in assessing peripheral airway condition in critically ill patients, and may be able to detect acute rejection. PMID- 20204807 TI - Muscle microcirculatory O(2) exchange in health and disease. AB - Much of our understanding of blood-muscle O(2) and substrate exchange is predicated on the presumption that, in resting muscle, a substantial proportion of the capillary bed does not sustain red blood cell (RBC) or plasma flux. According to this notion, with contractions, more capillaries are "recruited" (i.e., begin flowing) and increased metabolic demands are supported by blood myocyte O(2) and substrate flux in these newly recruited capillaries. This scenario is attractive because additional exchange vessels are added, and radial intercapillary diffusion distances reduced, as demands increase - but is it correct? The compelling weight of evidence gathered over the last 3 decades using intravital microscopy, phosphorescence quenching and near infrared spectroscopy (NIRS) techniques challenges conventional "wisdom" and indicates that the majority of capillaries support RBC flux at rest. Thus, at the onset of contractions blood-myocyte O(2) and substrate flux must increase in vessels that were already flowing at rest. This concept forces a radical revision of the control of blood-myocyte O(2) and substrate flux. This revision is essential if we are to understand the control of microcirculatory O(2) and substrate flux in health and resolve the mechanistic bases by which these processes are compromised in diseases such as chronic heart failure. PMID- 20204808 TI - Arteriolar vasomotor control and contractile performance during fatiguing tetanic contractions in rat skeletal muscle: role of sympathetic system. AB - Using a fatiguing stimulation protocol designed specifically to enhance sympathetically-mediated vasoconstrictor tone, we explored the temporal profile of the evoked vasoconstrictor response, evaluated the presence of sympatholysis, and assessed the role of alpha1-adrenergic receptor-mediated vasoconstriction on muscle performance. Spinotrapezius muscles of Wistar rats were exteriorized and stimulated tetanically (100 Hz, 4-7 V, stimulus duration 700 ms) every 3 s for 2.5 min under control and prazosin (1 muM) superfused conditions. The extent and time course of diameter changes in arterioles (2 A) and venules (2 V) were determined after each of 10 discrete sets of muscle stimulation at 5-min intervals. A significant decrease of luminal diameter was observed in arterioles after tetanic contractions at 8-10 sets (8 sets: -34.4%, 9 sets: -39.4%, 10 sets: -38.6% vs pre-contraction at each set, p < 0.01). Prazosin significantly reduced but did not abolish the contraction-induced vasoconstriction. In both conditions, there was no reduction of venules diameter observed. Tetanic contractions force at the final 10th set was significantly decreased to 29.3 +/- 11.9% from pre fatigue conditions, while tetanic contractions with prazosin force production was maintained at 70.4 +/- 14.2% at the 10th set. We conclude that in sequential bouts of contractions there was a progressively greater degree of arteriolar (but not venular) vasoconstriction which was attenuated substantially by prazosin. PMID- 20204809 TI - The influence of passive stretch on muscle oxygen saturation. AB - Previous studies have suggested that chronic stretch might be able to produce skeletal muscle hypertrophy. However, stretching might also restrict blood flow, which could in turn influence any stretch-training program. This study evaluated the influence of muscle stretch on muscle oxygen saturation using near infrared spectroscopy (NIRS). A 16 channel NIRS probes were placed on the medial gastrocnemius, quadriceps, and hamstring muscles of young healthy adults. Oxygen saturation during maximal tolerated stretch was measured and normalized with cuff induced ischemia and reperfusion. Oxygen saturation decreased in the gastrocnemius and quadriceps in a position dependent fashion, but did not change in the hamstring muscles. Passive stretching may also have a significant hypoxic component in some muscles but not others. PMID- 20204810 TI - NIRS measurement of O(2) dynamics in contracting blood and buffer perfused hindlimb muscle. AB - In order to obtain evidence that Mb releases O(2) during muscle contraction, we have set up a buffer-perfused hindlimb rat model and applied NIRS to detect the dynamics of tissue deoxygenation during contraction. The NIRS signal was monitored on hindlimb muscle during twitch contractions at 1 Hz, evoked via electrostimulator at different submaximal levels. The hindlimb perfusion was carried out by perfusion of Krebs Bicarbonate buffer. The NIRS still detected a strong signal even under Hb-free contractions. The deoxygenation signal (Delta[deoxy]) was progressively increased at onset of the contraction and reached the plateau under both blood- and buffer-perfused conditions. However, the amplitude of Delta[deoxy] during steady state continued to significantly increase as tension increased. The tension-matched comparison of the Delta[deoxy] level under buffer-perfused and blood perfused conditions indicate that Mb can contribute approximately 50% to the NIRS signal. These results clarify the Mb contribution to the NIRS signal and show a falling intracellular PO(2) as workload increases. PMID- 20204811 TI - Muscle reoxygenation difference between superficial and deep regions of the muscles during static knee extension. AB - The purpose of this study was to test the hypothesis that differences in vertical spatial difference in reoxygenation after exercise exists, reflecting heterogeneity of muscle oxygenation during exercise might be due to the difference in dominantly recruited muscle fiber type. METHODS: Ten healthy female subjects performed 1 min static knee extension exercise at low (30%) and high (60%) fraction of maximal voluntary contraction (MVC). Muscle oxygenation in the vastus lateralis (VL) was monitored using multi channel near-infrared spectroscopy. Half time reoxygenation (T(1/2)reoxy) after exercise was calculated from oxygenated hemoglobin in the eight channels which changed the distance between light source and detector distances at 2,3,4,5 cm. Blood flow (BF) in the femoral artery was measured by Doppler ultrasound. Mean arterial blood pressure (BP) at the end of the exercise was assessed by a Finometer device. RESULTS: BF during exercise did not differ significantly during exercise at low and high intensity, whereas BP was elevated at high intensity. T(1/2)reoxy tended to be prolonged at high intensity. It would be due to a transition of muscle fiber recruitment from type I toward type II fiber dominance, and/or insufficient oxygen supply for increased demand in the muscle. T(1/2)reoxy in different light source and detector distances was not different among them. CONCLUSION: This study demonstrated that the reoxygenation in the superficial region did not differ from that in the deeper region, including superficial, even when exercise intensity was high. PMID- 20204812 TI - Arterial oxygen desaturation response to repeated bouts of sprint exercise in healthy young women. AB - The decline in arterial oxygen saturation of hemoglobin during exercise has been termed exercise-induced arterial hypoxemia (EIAH). We examined whether repeated bouts of sprint exercise (SprE) would induce EIAH in healthy young men and women. Ten men and 11 women (20.4 +/- 0.3 year) performed an anaerobic power test (three bouts of 10 s cycling with 120 s intervals) using a cycle ergometer. Arterial oxygen saturation of hemoglobin measured by pulse oximeter (SpO(2)), heart rate (HR), rate perceived exertion (RPE), and the blood lactate concentration ([La](b)) were assessed at rest, during, and 5 min after repeated bouts of SprE. Women exhibited a lower maximal anaerobic power (MAnP) compared to men (498 +/- 23 vs. 759 +/- 22 watts, respectively, p < 0.01). HR, RPE, and [La](b) in women were comparable with those in men throughout the test. However, the only significant decline in SpO(2) after a single bout of SprE (95.5 +/- 0.7%) from the resting value (97.9 +/- 0.2%) was observed in women, and further declines occurred following heavier SprE (< 95%). In 8 of 11 women, mild to moderate EIAH developed, whereas only 2 men showed mild EIAH. Thus, these findings suggest that repeated bouts of SprE might induce mild EIAH in young women but not men. PMID- 20204813 TI - The effect of endurance training on resting oxygen stores in muscle evaluated by near infrared continuous wave spectroscopy. AB - The purpose of this study was to examine the effects of endurance training (ET) on resting oxygen store (r-O(2)mus) using near infrared continuous wave spectroscopy (NIR(CWS)), and the validity of using this method for the evaluation of resting muscle oxygen consumption (r-VO(2)mus) in a training study. Ten female subjects were tested in the following study. All subjects were physically active, but did not participate in any regular training besides this study. The subjects were fully informed of the risks and gave their consent before the start of the experiments. For ET subjects cycled for 40 min at 60-70% VO(2)peak, three times a week, for 4 weeks. Before and after the period of ET, VO(2)peak and r-O(2)mus for the vastus lateralis muscle were measured. r-O(2)mus was defined as the amount of O(2) consumed by the muscle, which was determined from r-VO(2)mus measured by NIR(CWS) (HEO200, Omron) during arterial occlusion induced by a pneumatic tourniquet. In order to verify the measurements using NIR(CWS), oxygen consumption for both the whole body (40%-VO(2)) and vastus lateralis muscle (40% VO(2)mus) were measured at pre and post ET. 40%-VO(2)mus was calculated from the ratio of the declining rates of Hb/MbO(2) immediately post-exercise and during rest (r-VO(2)mus). As a result, VO(2)peak significantly increased after ET. r O(2)mus also significantly increased (p < 0.05). Neither 40%-VO(2) nor 40% VO(2)mus changed following ET. Therefore these findings suggest the increase in r O(2)mus calculated from r-VO(2)mus reflects an increase in resting oxygen stores in the trained muscle. Under the condition when resting muscle oxygen consumption is unchanged, NIR(CWS) can be a useful non-invasive tool for measuring muscle oxygen stores. PMID- 20204814 TI - Cerebrovascular response during heavy upper body exercise: effect of mode of ventilation on blood flow velocity in the middle cerebral artery. AB - Heavy resistance exercise may be associated with a small risk of cerebral aneurysm rupture, subarachnoid hemorrhage, and symptoms of dizziness or outright weight-lifters' blackout, which may be induced by a rapid change in the cerebral blood flow. We hypothesized that these changes during heavy exercise could be associated with the mode of ventilation. The purpose of the present study was to elucidate the effect of the mode of ventilation on cerebral blood flow response during heavy upper body exercise. Subjects performed 15-s static exercises at 80% maximum voluntary contraction (MVC) under different modes of ventilation. In this study, we observed that heavy exercise with breath holding induced marked and rapid changes in the cerebral blood flow velocity in the middle cerebral artery during and after exercise as compared with that with continued normal ventilation. We also observed that hyperventilation before exercise could largely contribute to a lower cerebral blood flow velocity during exercise and which even extended to the recovery phase. Our data suggested that even during heavy upper body exercise, the mode of ventilation is very important for maintaining cerebral circulation. PMID- 20204815 TI - Unchanged muscle deoxygenation heterogeneity during bicycle exercise after 6 weeks of endurance training. AB - The purpose of this study was to examine the changes in muscle oxygen saturation (SmO(2)) level and its heterogeneity after 6 weeks of endurance training using multi-channel near infrared spatially resolved spectroscopy (NIR(SRS)). Nine healthy subjects participated in this study (Male = 6, Female = 3, age: 27 +/- 5 years, height: 168.7 +/- 7.4 cm, weight: 62.4 +/- 12.4 kg). The subjects performed a 30 W ramp incremental bicycle exercise test until exhaustion before and after endurance training. The NIR(SRS) probe was attached to the left vastus lateralis muscle along the direction of the long axis. The subjects performed bicycle exercise for 30 min/day, 3 days/week for 6 weeks. The work rate during training was set at 60%V(O)(2peak) and increased every 5%V(O)(2peak) when the subjects could maintain the work rate three times consecutively. After training, V(O)(2peak) was significantly increased (Pre: 42.7 +/- 9.9 ml/kg/min, Post: 52.3 +/- 7.2 ml/kg/min, p < 0.001) and the mean SmO(2) within measurement sites at was significantly decreased (Pre: 56.1 +/- 1.1 %, Post: 53.3 +/- 2.2 %, p < 0.05). Conversely, the heterogeneity of the SmO(2) during exercise was not changed by training. These results suggest that the functional heterogeneity of O(2) balance did not change due to endurance training, and the O(2) balance heterogeneity may not interfere with O(2) exchange in the activating muscle in healthy individuals. PMID- 20204816 TI - Comparison of muscle O(2) dynamics at different sites of the forearm flexor muscles during incremental handgrip exercise. AB - This study investigated heterogeneity of muscle O(2) consumption (diffusive m VO(2)) and muscle oxygenation difference (m-O(2) difference) within the forearm flexor muscles using multi-optical fibers near-infrared continuous wave spectroscopy (NIRcws) during incremental exercise. Nine healthy male subjects performed incremental dynamic handgrip exercise until exhaustion. The workload was increased by 5% maximal voluntary contraction (MVC) every 1 min, starting at 10% MVC. The NIRcws probes (10 channels) were placed on the right forearm flexor muscles to monitor muscle oxygenation. The diffusive m-VO(2) and the m-O(2) difference were evaluated at each exercise stage. The diffusive m-VO(2) at the medial site was significantly greater than the lateral site at 25% MVC (p < 0.05). Similarly, m-O(2) difference at the medial site increased significantly over the lateral site (p < 0.05), whereas there were no significant differences in diffusive m-VO(2) or m-O(2) difference between the proximal and distal sites. These results in forearm muscle were different from the previous study which found that there were longitudinal differences in muscle VO(2) in the femoral muscle. PMID- 20204817 TI - Blood flow and arterial vessel diameter change during graded handgrip exercise in dominant and non-dominant forearms of tennis players. AB - The training effect on exercise-induced maximal blood flow remains unclear. The purpose of this study was to clarify the difference of exercise-induced blood flow, blood flow velocity and vessel diameter of brachial artery in dominant and non-dominant forearms of tennis players during graded hand-grip exercise. Ten female tennis players aged 20.1 +/- 0.1 years. (mean +/- SD) performed 30-s static handgrip exercise in the supine position with either the dominant or non dominant hand by increasing load at 30-s intervals until exhaustion. Brachial arterial blood flow velocity (Doppler ultrasound method) did not differ between both limbs, whereas the vessel diameter (2-D method) was significantly larger in the dominant limb during diastole both at baseline (p < 0.01) and after exercise (p < 0.05), but no difference was found during systole. As a result, the blood flow was significantly higher (p < 0.05) in the dominant limb during post exercise condition. Muscle thickness of the forearm muscles and maximal handgrip strength were significantly higher in the dominant limb. Thus, the effect of training on exercise-induced blood flow specific to the dominant limb was confirmed during post-exercise due to the enlarged vessel diameter during diastole of cardiac cycle. The dimensional change in the vasculature specific to the dominant side will be included in the training effects associated with the dimensional muscular changes in the dominant forearm. PMID- 20204818 TI - Changes in perfusion related to muscle length affect the pressor response to isometric muscle contraction. AB - To test the hypothesis that the dependence of the pressor response on muscle length is caused by changes in perfusion, we compared the cardiovascular responses to static contraction at short and long muscle lengths during free perfusion with those during circulatory arrest. Five males performed 2-min static knee extension exercise at 30% of maximal voluntary torque at each of two muscle lengths at a knee angle of 40 degrees (short) and 90 degrees (long). The subjects performed two trials - a free perfusion trial and a circulatory arrest trial. For circulatory arrest, an occlusion cuff placed around the proximal portion of the thigh was inflated to 250 mmHg 2 min before exercise. Mean arterial pressure (MAP), minute ventilation (V(E)), and the muscle oxygenation index in the vastus lateralis muscle were measured using near-infrared spectroscopy. In the free perfusion trial, MAP and V(E) were significantly greater during contractions at 90 degrees than at 40 degrees (p < 0.05). The muscle oxygenation index was significantly lower during contractions at 90 degrees than at 40 degrees (p < 0.05). Circulatory arrest diminished these differences. These results suggest that the relationship between muscle length and the pressor response can be explained by changes in perfusion, which are related to muscle length. PMID- 20204819 TI - Decreased muscle oxygenation and increased arterial blood flow in the non exercising limb during leg exercise. AB - We evaluated arterial blood flow, muscle tissue oxygenation and muscle metabolism in the non-exercising limb during leg cycling exercise. Ten healthy male volunteers performed a graded leg cycling exercise at 0, 40, 80, 120 and 160 watts (W) for 5 min each. Tissue oxygenation index (TOI) of the non-exercising left forearm muscle was measured using a near-infrared spatially resolved spectroscopy (NIR(SRS)), and non-exercising forearm blood flow ((NONEX)FBF) in the brachial artery was also evaluated by a Doppler ultrasound system. We also determined O(2) consumption of the non-exercising forearm muscle (NONEXV(O)(2mus)) by the rate of decrease in O(2)Hb during arterial occlusion at each work rate. TOI was significantly decreased at 160 W (p < 0.01) compared to the baseline. The (NONEX)V(O)(2mus) at each work rate was not significantly increased. In contrast, (NONEX)FBF was significantly increased at 120 W (p < 0.05) and 160 W (p < 0.01) compared to the baseline. These results suggest that the O(2) supply to the non-exercising muscle may be reduced, even though (NONEX)FBF increases at high work rates during leg cycling exercise. PMID- 20204820 TI - Effects of acute hypoxia on the inflection point of muscle oxygenation. AB - The purpose of this study was to investigate the effects of acute hypoxia on the inflection point of muscle oxygenation (IPMO) using near-infrared spectroscopy during incremental bicycle exercise. Eight male subjects (age: 22 +/- 2 years) performed two ramp incremental bicycle exercise tests until exhaustion under each normoxic and hypoxic (F(I)O(2): 0.12) condition. Pulmonary gas exchange and locomotor muscle oxygenation were continuously measured. IPMO was determined as the attenuated point of muscle deoxygenation. Muscle oxygenation level was significantly lower in hypoxia than normoxia throughout the tests. IPMO was found in both conditions, and V(O)(2) at IPMO was significantly decreased in hypoxia. However the percent rate of V(O)(2peak) between normoxia and hypoxia was not significantly different. These results suggest that IPMO was not associated with absolute exercise intensity, but relative exercise intensity. PMID- 20204821 TI - No sustained improvement in tumor oxygenation after localized mild hyperthermia. AB - This study has attempted to address the controversy concerning sustained increases in tumor oxygenation upon localized mild hyperthermia. While some previous studies have reported transient increases, others have reported persistent increases in tumor oxygenation, lasting for upto 2 days after application of mild hyperthermia. In order to determine changes in oxygenation at clinically relevant tumor temperatures, experimental tumors in rats underwent localized hyperthermia at either 40, 41.8 degrees C or 43 degrees C for 1 h using water-filtered infrared-A irradiation. Oxygenation was continuously measured before, during and upto 60 min after hyperthermia in the tumors of anesthetized rats using oxygen-sensitive catheters. The data obtained indicate that localized hyperthermia can lead, on average to an improved tumor oxygenation, although this improvement is generally transient and no longer evident 1 h after heating. Since clinically relevant increases in oxygenation enduring beyond the heating period were rarely seen, it would appear that an improvement in the efficacy of oxygen dependent cancer therapy is unlikely to be achieved in the post-hyperthermia period. PMID- 20204822 TI - HIF-mediated hypoxic response is missing in severely hypoxic uterine leiomyomas. AB - Results from our laboratory have put a question mark on the existence of a direct quantitative relationship between tumor hypoxia and HIF-mediated protein expression in cancers of the uterine cervix. In the present study, this subject has been further explored by the analysis of HIF-related marker expression in a benign tumor entity - uterine leiomyomas - using immunohistochemistry, western blotting and RT-PCR. The oxygenation status of 17 leiomyomas was assessed by means of intraoperative polarographic needle electrode measurements. Results show that these tumors are severely and uniformly hypoxic, but do not induce HIF 1alpha, HIF-2alpha, glucose transporter (GLUT)-1 or carbonic anhydrase (CA) IX. Furthermore, this downregulation of the HIF-system was not caused by an overexpression of the hypoxia-inducible prolyl hydroxylase domain proteins (PHDs) 2 and 3. Compared with normal myometrium, leiomyomas also show a poorer vascularization. Conversely, leiomyosarcomas show abundant expression of HIF related markers despite a similar microvascular density. In conclusion, these results indicate that the strong activation of the HIF system observed in solid malignant tumors may be mechanistically linked to their transformed phenotype, rather than being a physiological reaction activated in a pathological context. PMID- 20204823 TI - FRET-like fluorophore-nanoparticle complex for highly specific cancer localization. AB - Fluorophore mediated bio-signal retrieval has been extensively used in molecular imaging. However, only a limited number of fluorophores can be used for humans and their quantum yield is usually low. Another important issue is emitting fluorescence at the disease site, with a minimal non-specific emission at any other sites. Artificial quenching and enhancing of fluorescence was found to be possible by manipulating the distance between a fluorophore and a certain type of nanometal particle. Utilizing this unique property, we have designed a novel, FRET-like, fluorophore-nanoparticle complex. The complex emits fluorescence conditionally only at a disease site at an enhanced level. As a model system, our complex is designed to target breast cancer. As an initial step for developing this cancer locator, fluorescence alteration was studied when a spacer at various lengths is placed between a nanogold particle and a safe fluorophore. PMID- 20204824 TI - Design of novel hypoxia-targeting IDO hybrid inhibitors conjugated with an unsubstituted L-TRP as an IDO affinity moiety. AB - We presented here design, syntheses and inhibitory activities of novel hypoxia targeting IDO hybrid inhibitors conjugated with an unsubstituted L-Trp as an IDO affinity moiety without inhibitor 1MT, such as L-Trp-TPZ hybrids 1 (TX-2274), 2 (UTX-3), 3 (UTX-4), and 4 (UTX-2). TPZ-monoxide hybrids 1 and 3 were good competitive IDO inhibitors, while TPZ hybrids 2 and 4 were uncompetitive IDO inhibitors. Among them TPZ-monoxide hybrid 1 have the strongest IDO inhibitory activity. It suggests that TPZ-monoxide hybrids 1 and 3 are able to bind the active site of IDO, TPZ hybrids 2 and 4 are able to bind the enzyme-substrate complex. We proposed the possible mechanism of action of TPZ hybrid 2 that may first affect as a hypoxic cytotoxin, and then metabolized to TPZ-monoxide hybrid 1, which may do as an IDO inhibitor more effectively than its parent TPZ hybrid 2. PMID- 20204825 TI - Phosphorescence-assisted microvascular O(2) measurements reveal alterations of oxygen demand in human metastatic colon cancer in the liver of superimmunodeficient NOG mice. AB - We aimed to examine metabolism of human cancer in vivo and utilized superimmunodeficient NOG mice as an experimental model of hepatic metastasis, where human colon cancer cell line HCT116 transfected with Venus, the mutant GFP was injected intrasplenically. The mice were pretreated with Pd-porphyrin to quantify local O(2) tension through intravital phosphorescence assay. In this model, a majority of metastatic foci occurred in periportal regions but not in central regions. At 1 week after the transplantation, a PO(2) drop in periportal regions was minimal without any notable decrease in microvascular blood flow. Under these conditions, there was a negative correlation between the size of metastatic foci and the lobular O(2) consumption, suggesting that the tumor O(2) consumption is smaller than that in the residual liver. At 2 weeks, portal PO(2) was significantly smaller than controls, while the central PO(2) was not comparably decreased, indicating that metastatic foci increased the O(2) consumption, while the residual liver decreased it. These results suggest metastatic tumors derived from human colon cancer exhibit notable aerobic metabolism during their developmental process, compromising respiration of the rest of the tissue regenerated during tumor development. PMID- 20204826 TI - Hemoglobin-vesicle, a cellular artificial oxygen carrier that fulfils the physiological roles of the red blood cell structure. AB - Hb-vesicles (HbV) are artificial O(2) carriers encapsulating concentrated Hb solution (35 g/dL) with a phospholipid bilayer membrane (liposome). The concentration of the HbV suspension is extremely high ([Hb] = 10 g/dL) and it has an O(2) carrying capacity that is comparable to that of blood. HbV is much smaller than RBC (250 vs. 8000 nm), but it recreates the functions of RBCs; (i) the slower rate of O(2) unloading than Hb solution; (ii) colloid osmotic pressure is zero; (iii) the viscosity of a HbV suspension is adjustable to that of blood; (iv) HbV is finally captured by and degraded in RES; (v) co-encapsulation of an allosteric effector to regulate O(2) affinity; (vi) the lipid bilayer membrane prevents direct contact of Hb and vasculature; (vii) NO-binding is retarded to some extent by an intracellular diffusion barrier, and HbV does not induce vasoconstriction. (viii) Both RBC and HbV can be a carrier of not only O(2) but also exogenous CO. However, HbV has limitations such as a shorter functional half life when compared with RBCs. On the other hand, the advantages of HbV are that it is pathogen-free and blood-type-antigen-free; moreover, it can withstand long term storage of a few years, none of which can be achieved by the RBC transfusion systems. PMID- 20204827 TI - Safer surgery using zymogen protein C concentrate. AB - This is the first case (November 12, 2007) of peri-operative use of zymogen protein C (ZPC) for a heterozygote Protein C deficient (50%) patient with heterozygosity for the prothrombin gene mutation. The surgery involved total left hip replacement. The patient was 74 years of age and at very high-risk for Deep Vein Thrombosis (DVT) thus possible lung emboli. He was a survivor of Venous thrombo-embolism (VTE) in 1999.For this case the need for increased heparin to prevent a reoccurrence of thrombosis led to a further concern of internal bleeding and possible infection. As proposed by the authors in previous publications the use of a ZPC concentrate would decrease the chance of a thrombosis, with minimum or no internal bleeding. ZPC is activated at the endothelium cell surface and on the surface of the platelets where and when it is needed, therefore providing a safer procedure.This protocol was implemented by administering ZPC concentrate 1 day prior to surgery and continuing for 10 days after. Slightly higher than normal blood loss occurred, however, a safe procedure was achieved without dangerous side effects while several additional benefits were experienced (level of PC activity as high as 235% above normal were measured during the procedure.). It is felt that positive effects were the result of increased blood flow and oxygen transport to the tissues by reducing blood sludging in the microcirculation. Further studies on Protein C dose levels will be necessary to provide economical, safe and efficacious use of Protein C products.It is suggested that ZPC should be considered for patients with high probability of VTE which could cause thrombotic occlusion of the pulmonary and peripheral vasculature. These phenomena can result in hypoxia and hypo perfusion causing organ failure and death.Our research includes a focused effort to optimize upstream and downstream bio-processing to produce both zymogen and activated Protein C at a lower cost and to examine the medical indications that could benefit from a more available and affordable Protein C product. PMID- 20204828 TI - Cerebral and peripheral tissue oxygenation in children supported on ECMO for cardio-respiratory failure. AB - Extracorporeal membrane oxygenation (ECMO) is a rescue therapy for patients with cardio-respiratory failure. Establishing, maintaining and weaning from ECMO may increase the risk for intracranial injury. We used a dual channel near infrared system to monitor cerebral and peripheral tissue oxygenation in 3 venoarterial (VA) and 1 venovenous (VV) ECMO patients undergoing manipulations in the ECMO circuit flows. Spectral analysis was performed on the oxyhaemoglobin data collected from these patients with the aim of comparing oscillations at range of frequencies appearing in the two measurement sites. PMID- 20204829 TI - Effects of acupuncture on autonomic nervous function and prefrontal cortex activity. AB - Acupuncture is helpful in treating various diseases, including autonomic nervous system (ANS) dysfunction caused by mental stress. On the other hand, the frontal lobe is suggested to play an important role in stress responses by modulating the ANS. The aim of the study was to evaluate the effects of acupuncture on ANS and frontal lobe activities. We investigated 18 normal adults. We measured the activity of prefrontal cortex (PFC) caused by real acupuncture (WHO-LI4) and sham acupuncture, employing optical topography. To evaluate ANS function, we analyzed heart rate variability (HRV). Analysis of HRV revealed a decrease of the LF/HF ratio, and an increase of the HF power by real acupuncture, indicating a shift to parasympathetic dominancy. Acupuncture also caused cerebral blood oxygenation changes in both directions, that is, an increase and/or a decrease of oxyhemoglobin (Oxy-Hb) in the bilateral PFC. However, the Oxy-Hb change was not correlated with HRV parameters in the majority of cases. One of the possible explanations of the poor correlations might be that the PFC activity induced by acupuncture is not closely linked with ANS function. PMID- 20204830 TI - The effect of glycaemia on the cerebral oxygenation in very low birthweight infants as measured by near-infrared spectroscopy. AB - The cerebral tissue oxygenation index (TOI) and fractional tissue oxygen extraction (FTOE) reflect the cerebral oxygenation. We studied the effect of glycaemia on the TOI and FTOE, as measured by near-infrared-spectroscopy (NIRS). We continuously measured TOI, glycaemia, mean arterial blood pressure (MABP), saturation (SaO(2)) and transcutaneous carbon dioxide pressure (tPCO(2)) for at least 4 h during the first week of life in neonates with gestational age (GA) < 32 weeks and weight < 1500 g. FTOE was calculated. 24 measurements in 11 neonates were analyzed. We found a significant negative correlation (r = -0.077; p = 0.0344) between glycaemia and TOI, also after correction for MABP, SaO(2) and tPCO(2) (r = -0.118; p = 0.002) and a significant positive correlation between glycaemia and FTOE (r = 0.147; p < 0.000) which remained significant after correction for MABP and tPCO(2) (r = 0.116; p = 0.001). Our results indicate that in neonates during the first days of life glycaemia - even within the normal ranges and after correction for MABP, SaO(2) and tPCO(2) - influences the cerebral oxygenation. PMID- 20204831 TI - A novel approach to evaluate the vessel function determined by near infrared spectroscopy. AB - The purpose of this study was to evaluate arterial function by near infrared spectroscopy (NIRS). 16 elderly subjects were studied: 8 were arteriosclerosis obliterans patients (ASO), and 8 were healthy elderly (non-ASO). A cuff around the thigh was inflated to a pressure of 20% above their ankle systolic blood pressure for 3 min. The NIRS probe was positioned over the gatrocnemius muscle to measure oxygenated hemoglobin (O(2)Hb), and the recovery time and rate for DeltaO(2)Hb after occlusion were calculated. Compared with the non-ASO group, the ASO group had a longer recovery time (p < 0.05) and a shallower recovery rate gradient (p < 0.01). The ankle to brachial index was correlated with recovery time (r = -0.61, p < 0.01) and recovery rate (r = 0.80, p < 0.001). These data suggest that NIRS may provide an effective non-invasive method for evaluating arterial function in patients with arteriosclerosis obliterans. PMID- 20204832 TI - Effects of aging on activity of the prefrontal cortex and autonomic nervous system during mental stress task. AB - We evaluated the effect of aging on the prefrontal cortex (PFC) activity and heart rate during the task. Employing near infrared spectroscopy (NIRS), we measured hemoglobin concentration changes in the bilateral PFC during a mental arithmetic task in young and older females. We selected the subjects who exhibited an increase in oxyhemoglobin with a decrease in deoxyhemoglobin during the task. We observed that right PFC activity predominantly modulates sympathetic effects during the task in both groups. However, the changes of oxyhemoglobin and heart rate during the task in older subjects were significantly smaller than those in young subjects. These results indicate that aging affects evoked cerebral blood oxygenation (CBO) response patterns of the PFC during a mental stress task. Aging did not affect the laterality of PFC activity in modulation of ANS function in the subjects who exhibited increases of oxyhemoglobin and deoxyhemoglobin associated with a decrease of deoxyhemoglobin during the task. However, aging reduced the heart rate increase during the task. PMID- 20204833 TI - Activity in the premotor area related to bite force control--a functional near infrared spectroscopy study. AB - The purpose of this study was to elucidate the influence of bite force control on oxygenated hemoglobin (OxyHb) levels in regional cerebral blood flow as an indicator of brain activity in the premotor area. Healthy right-handed volunteers with no subjective or objective symptoms of problems of the stomatognathic system or cervicofacial region were included. Functional near-infrared spectroscopy (fNIRS) was used to determine OxyHb levels in the premotor area during bite force control. A bite block equipped with an occlusal force sensor was prepared to measure clenching at the position where the right upper and lower canine cusps come into contact. Intensity of clenching was shown on a display and feedback was provided to the subjects. Intensity was set at 20, 50 and 80% of maximum voluntary teeth clenching force. To minimize the effect of the temporal muscle on the working side of the jaw, the fNIRS probes were positioned contralaterally, in the left region. The findings of this study are: activation of the premotor area with bite force control was noted in all subjects, and in the group analysis OxyHb in the premotor cortex was significantly increased as the clenching strengthened at 20, 50 and 80% of maximum voluntary clenching force. These results suggest there is a possibility that the premotor area is involved in bite force control. PMID- 20204834 TI - Functional near-infrared spectroscopy study on primary motor and somatosensory cortex response to biting and finger clenching. AB - The purpose of this study was to compare the influence of biting and finger clenching intensity on the concentration of oxygenated hemoglobin (OxyHb) in regional cerebral blood flow (rCBF) as an indicator of brain activity in the primary motor (MI) and somatosensory (SI) cortices. Functional near-infrared spectroscopy (fNIRS) was used in 8 healthy subjects. Subjects were required to do biting (bite) and finger clenching (fclench) at 20, 50 and 80% of maximum force. To minimize the effect of temporal muscle activity on the working side of the jaw, the fNIRS probes were positioned contralaterally, in the left temporal region. Activation of MI and SI cortices with bite and fclench was noted in all subjects, irrespective of the intensity of bite and fclench. A significant increase was observed in OxyHb in MI and SI between 20% and both 50 and 80% intensity. In MI cortex, OxyHb showed a significant increase between 80% and both 20 and 50% fclench intensity. The results suggest that intensity of bite and fclench influences activation levels in MI and SI. Further, an activation was more obvious with bite than fclench. PMID- 20204835 TI - Changes in cerebral blood oxygenation and hemodynamics after endovascular treatment of vascular malformation measured by time-resolved spectroscopy. AB - Although endovascular treatment has a high success rate, it is not clear how endovascular treatment affects cerebral perfusion and hemodynamics during the perioperative period. We evaluated changes in cerebral blood oxygenation (CBO) repeatedly after endovascular treatment employing time-resolved spectroscopy (TRS). We investigated a patient (10 months old, female) who suffered cerebral arteriovenous fistula. Cerebral angiography demonstrated a pial arteriovenous fistula with three feeders (left PICA, SCA, and AICA). TRS demonstrated a decrease of oxyhemoglobin, total hemoglobin, and oxygen saturation associated with an increase of deoxyhemoglobin in all of the regions measured just after embolization, indicating that embolization improved hyperemia caused by the AV shunt. Interestingly, progressive improvement of hyperemia was observed 3 and 8 days after embolization of the feeders. The present study demonstrated that embolization of the feeders caused progressive changes in CBO and hemodynamics during the perioperative period. TRS may be a useful tool for monitoring cerebral blood perfusion changes after endovascular surgery. PMID- 20204836 TI - Development of a new rehabilitation system based on a brain-computer interface using near-infrared spectroscopy. AB - We describe the set-up for an electrical muscle stimulation device based on near infrared spectroscopy (NIRS), designed for use as a brain-computer interface (BCI). Employing multi-channel NIRS, we measured evoked cerebral blood oxygenation (CBO) responses during real motor tasks and motor-imagery tasks. When a supra-threshold increase in oxyhemoglobin concentration was detected, electrical stimulation (50 Hz) of the biceps brachii muscle was applied to the side contralateral to the hand grasping task or ipsilateral to the motor-imagery task. We observed relatively stable and reproducible CBO responses during real motor tasks with an average accuracy of 100%, and during motor imagery tasks with an average accuracy of 61.5%. Flexion movement of the arm was evoked in all volunteers in association with electrical muscle stimulation and no adverse effects were noted. These findings suggest that application of the electrical muscle stimulation system based on a NIRS-BCI is non-invasive and safe, and may be useful for the physical training of disabled patients. PMID- 20204838 TI - Development of an artificial vital sign generator for pulse oximeter. AB - This paper presents an artificial vital sign generator that enables medical trainees to measure SpO(2) and the pulse rate of a patient simulator using a pulse oximeter. The proposed system has a biological model that possesses a structure that is the inverse of a pulse oximeter probe, and it works using the inverse procedure to that of pulse oximetry. The SpO(2) generating function has been validated using two commercially available pulse oximeters. PMID- 20204837 TI - Bedside assessment of cerebral vasospasms after subarachnoid hemorrhage by near infrared time-resolved spectroscopy. AB - We examined the usefulness of near infrared time-resolved spectroscopy (TRS) for detection of vasospasm in subarachnoid hemorrhage (SAH). We investigated seven aneurysmal SAH patients with poor clinical conditions (WFNS grade V) who underwent endovascular coil embolization. Employing TRS, we measured the oxygen saturation (SO(2)) and baseline hemoglobin concentrations in the cortices. Measurements of TRS and transcranial Doppler sonography (TCD) were performed repeatedly for 14 days after SAH. In four of the seven patients, the SO(2) and hemoglobin concentrations measured in the brain tissue of the middle cerebral artery territory remained stable after SAH. However, in three patients, TRS revealed abrupt decreases in SO(2) and total hemoglobin between 5 and 9 days after SAH. Cerebral angiography performed on the same day revealed severe vasospasms in these patients. Although TCD detected the vasospasm in two of three cases, it failed to do so in one case. TRS could detect vasospasms after SAH by evaluating the cortical blood oxygenation. PMID- 20204839 TI - EC-IC bypass function in Moyamoya disease and non-Moyamoya ischemic stroke evaluated by intraoperative indocyanine green fluorescence angiography. AB - Indocyanine green (ICG) emits near-infrared fluorescence when it is excited by near-infrared light. The near infrared fluorescence of ICG was applied to the imaging of cerebral vessels during neurosurgical operations such as clipping of aneurysms. In this study, ICG angiography was applied to extracranial intracranial (EC-IC) bypass surgery to evaluate the hemodynamic changes induced by bypass in moyamoya disease (MD) and non-moyamoya ischemic diseases (non-MD). These patients underwent superficial temporal artery-middle cerebral artery (STA MCA) anastomosis. We compared the cortical areas where the bypass supplied blood flow between MD and non-MD. ICG angiography clearly demonstrated the bypass blood flow from the anastomosed STA to the cortical vessels including arteries, capillaries, and veins in both MD and non-MD. Interestingly, the anastomosed STA supplied blood flow to a larger cortical area in MD than non-MD. The bypass supplied greater extent of blood flow to the ischemic brain in MD than in non-MD. This difference might be caused by the fact that the perfusion pressure was lower in MD than in non-MD. PMID- 20204840 TI - Effects of revascularisation on evoked cerebral blood oxygenation responses in stroke patients. AB - We demonstrated that ischemic strokes exhibit an increase of deoxyhemoglobin during activation. We evaluated the effect of revascu-larization on the abnormal evoked cerebral blood oxygenation (CBO) re-sponses in these patients, employing near-infrared spectroscopy (NIRS). We selected five patients who exhibited an increase of deoxyhemoglobin associated with increases of oxyhemoglobin and total hemoglobin during activation for this study. These patients showed marked reductions of base-line regional cerebral blood flow and cerebrovascular reserve capacity, which were improved 1 week after revascularization. Postoperative NIRS demonstrated that the increase of deoxyhemoglobin during activa-tion was not observed after revascularization. This preliminary study demonstrated that the abnormal evoked-CBO response in ischemic stroke patients could be improved by revascularization. PMID- 20204841 TI - Effects of oral single-dose administration of sarpogrelate hydrochloride on saturation O(2) of calf muscle during plantar flexion exercise. AB - To investigate the effects of a 100-mg oral single-dose administration of sarpogrelate hydrochloride (SH) on saturation O(2) (StO(2)) of calf muscle in healthy subjects experiencing simulated peripheral arterial disease (0.6 ankle brachial pressure index). Ten subjects performed three kinds of plantar flexion exercises at a work rate of 50% of maximal volunteer contraction for 4 min by using cuff occlusion ischemia,. Subjects performed a control test (C) without ischemia and SH, an ischemia test (I) without SH, and an I + SH test with ischemia. StO(2), blood pressures (BP), and heart rate (HR) were measured through all experiments. At the end of the exercise, the decrease in StO(2) from baseline in the C and I + SH tests was significantly less than that in the I test (p < 0.05, respectively). However, there were no significant differences in mean BP or HR in any of the exercise conditions. These results indicated that an oral single dose administration of SH might improve peripheral circulation independent of any changes in BP and HR. PMID- 20204842 TI - Oxidative capacity of the skeletal muscle and lactic acid kinetics during exercise in healthy subjects and patients with COPD. AB - [Background] In patients with chronic obstructive pulmonary disease (COPD), early lactic acidosis during exercise should be considered as playing a role in the limitation of exercise tolerance. It was hypothesized that the relationship between blood lactate concentrations (LA) and tissue oxygenation index (TOI) is available for the prediction of aerobic capacity of skeletal muscle. [Methods] Changes of LA and TOI in the vastus lateralis muscle were measured during incremental cycling exercise in 12 healthy subjects and 4 patients with COPD. The relationship between TOI and LA was examined in 12 healthy subjects and 4 COPD patients, and changes in the relationship were examined at an interval of several years (3.3 +/- 1.0). [Results] (1) From the pattern LA as related to TOI, the healthy subjects were classified into the three groups. Group A (n = 3); LA increased slowly with a decrease in TOI. Group B (n = 3); LA increased steeply after the half point of maximal exercise. Group C (n = 6); LA increased steeply before the half point of maximal exercise. (2) In 3 patients with COPD, the relationship between TOI and LA shifted rightward at the second examination. [Conclusion] The steep increase in LA from the approximate resting value of TOI during exercise suggests that the aerobic capacity of working skeletal muscle decreased. PMID- 20204843 TI - Cell-free protein preparation through prokaryotic transcription-translation methods. AB - We have been developing and using an Escherichia coli cell extract-based coupled transcription-translation cell-free system. The development includes many different issues such as cell extract preparation, template construction, reaction condition, reaction format, and automation. These developments improved the efficiency, productivity, and throughput of our prokaryotic cell-free system, enabling us to use the system as one of the standard expression methods in our group. Our system certainly has the largest successful applications especially to the protein production for the structure determination, among the existing cell free protein synthesis systems. PMID- 20204844 TI - PURE technology. AB - The Escherichia coli-based reconstituted cell-free protein synthesis system, which we named the PURE (Protein synthesis Using Recombinant Elements) system, provides several advantages compared with the conventional cell-extract-based system. Stability of RNA or protein is highly improved because of the lack of harmful degradation enzymes. The system can be easily engineered according to purposes or the proteins to be synthesized, by manipulating the components in the system. In this chapter, we describe the construction and exploitation of the PURE system. Methods for preparing and assembling the components composing the PURE system for the protein synthesis reaction are shown. PMID- 20204845 TI - The cell-free protein synthesis system from wheat germ. AB - The wheat-germ cell-free protein synthesis system had been one of the most efficient eukaryotic cell-free systems since it was first developed in 1964. However, radio-labeled amino acids had long been essential for detection of the products. Since the discovery of a method for prevention of the contamination by a protein synthesis inhibitor originated from endosperm, the wheat cell-free system has found a wide variety of applications in postgenomic high-throughput screening, structural biology, medicine, and so on. In this chapter, we describe a method for preparation of the cell-free extract and a standard protein synthesis method, as the methods for the applications are found in later chapters. PMID- 20204846 TI - A cell-free protein synthesis system from insect cells. AB - The Transdirect insect cell is a newly developed in vitro translation system for mRNA templates, which utilizes an extract from cultured Spodoptera frugiperda 21 (Sf21) insect cells. An expression vector, pTD1, which includes a 5'-untranslated region (UTR) sequence from a baculovirus polyhedrin gene as a translational enhancer, was also developed to obtain maximum performance from the insect cell free protein synthesis system. This combination of insect cell extract and expression vector results in protein productivity of about 50 microg/mL of the translation reaction mixture. This is the highest protein productivity yet noted among commercialized cell-free protein synthesis systems based on animal extracts. PMID- 20204847 TI - Cell-free protein synthesis systems with extracts from cultured human cells. AB - Cell-free protein synthesis systems have been established with extracts from cultured human cells, HeLa, and hybridoma cells. The former cell line is used to prepare extracts for robust translation, whereas the extract from the latter is primarily employed for expression of glycoproteins. Productivity of both systems can be enhanced by addition of K3L and GADD34, factors that diminish phosphorylation of eIF2alpha. The coupled transcription/translation system is also available as a convenient tool, particularly for the production of large recombinant proteins. PMID- 20204848 TI - Analysis of protein functions through a bacterial cell-free protein expression system. AB - Cell-free protein synthesis is a suitable protein expression method for the high throughput use because a PCR-amplified linear DNA fragment is utilized as a template for protein synthesis without any cloning procedures. We have developed a two-step PCR method for high-throughput and robust production of linear templates ready for cell-free protein synthesis. A high-throughput protein expression method has been established by combining the batch-mode cell-free protein synthesis with the two-step PCR, which is performed on multiwell plates, and is thus adapted for robotics. In this chapter, our two-step PCR method and the batch-mode cell-free protein synthesis are described. PMID- 20204849 TI - Cell-free-based protein microarray technology using agarose/DNA microplate. AB - Protein microarray is considered to be one of the key analytical tools for high throughput protein function analysis. We found that Arabidopsis HY5 protein functions as a novel DNA-binding tag (DBtag), and DBtagged proteins are immobilized and purified on a newly designed agarose/DNA microplate. In this chapter, we demonstrate a protocol for making the DBtag-based protein microarray and will provide protocols for two applications using the microarray: (1) detection of autophosphorylation activity of DBtagged human protein kinases and inhibition of their activity by staurosporine, and (2) detection of a protein protein interaction between the DBtagged UBE2N and UBE2v1. PMID- 20204850 TI - An efficient approach to the production of vaccines against the malaria parasite. AB - In malaria vaccine research, one of the major obstacles has been the difficulty of expressing recombinant malarial proteins and it is mainly due to the lack of an efficient methodology for the synthesis of sufficient quantity of quality proteins. We demonstrate that the wheat germ cell-free protein synthesis system can be applied for the successful production of leading malaria vaccine candidate antigens and, thus, prove that it may be a key tool for malaria vaccine research. PMID- 20204851 TI - Protein engineering accelerated by cell-free technology. AB - Utilization of structural information from homologous proteins to design novel enzymes is one of the practical applications of structural biology. Structure based protein engineering is a more reasonable strategy compared with general random mutagenesis. Here, we describe a useful method for production of a series of mutant enzymes based on a cell-free translation system. We employed PCR mediated in vitro site-directed mutagenesis in combination with wheat-embryo cell free protein synthesis to establish a high-throughput system. The efficient generation of a series of mutant enzymes facilitates high-throughput screening of functionally improved enzymes. PMID- 20204852 TI - Cell-free protein production system with the E. coli crude extract for determination of protein folds. AB - Escherichia coli cell extract-based coupled transcription-translation cell-free system has been developed for large-scale production of protein samples for both X-ray crystallography (selenomethionine substitution) and NMR (stable-isotope labeling). For both cases, higher labeling/substitution efficiency can be achieved compared with the production using cell-based expression system. In addition, as the system is easily adapted to automated and/or high-throughput procedures, it is an especially suitable protein expression method for structural genomics and proteomics project. In this chapter, the procedure for large-scale protein production for structure determination using our E. coli cell-free system is presented. PMID- 20204853 TI - NMR assignment method for amide signals with cell-free protein synthesis system. AB - Nuclear magnetic resonance (NMR) methods are widely used to determine the three dimensional structures of proteins, to estimate protein folding, and to discover high-affinity ligands for proteins. However, one of the problems to apply such NMR methods to proteins is that we should obtain mg quantities of (15)N and/or (13)C labeled pure proteins of interest. Here, we describe the method to produce dual amino acid-selective (13)C-(15)N labeled proteins for NMR study using the improved wheat germ cell-free system, which enables sequence-specific assignments of amide signals simply even for very large protein. PMID- 20204854 TI - Cell-free protein synthesis technology in NMR high-throughput structure determination. AB - This chapter describes the current implementation of the cell-free translation platform developed at the Center for Eukaryotic Structural Genomics (CESG) and practical aspects of the production of stable isotope-labeled eukaryotic proteins for NMR structure determination. Protocols are reported for the use of wheat germ cell-free translation in small-scale screening for the level of total protein expression, the solubility of the expressed protein, and the success in purification as predictive indicators of the likelihood that a protein may be obtained in sufficient quantity and quality to initiate structural studies. In most circumstances, the small-scale reactions also produce sufficient protein to permit bioanalytical and functional characterizations. The protocols incorporate the use of robots specialized for small-scale cell-free translation, large-scale protein production, and automated purification of soluble, His(6)-tagged proteins. The integration of isotopically labeled proteins into the sequence of experiments required for NMR structure determination is outlined, and additional protocols for production of integral membrane proteins in the presence of either detergents or unilamellar liposomes are presented. PMID- 20204855 TI - Cell-free protein synthesis for structure determination by X-ray crystallography. AB - Structure determination has been difficult for those proteins that are toxic to the cells and cannot be prepared in a large amount in vivo. These proteins, even when biologically very interesting, tend to be left uncharacterized in the structural genomics projects. Their cell-free synthesis can bypass the toxicity problem. Among the various cell-free systems, the wheat-germ-based system is of special interest due to the following points: (1) Because the gene is placed under a plant translational signal, its toxic expression in a bacterial host is reduced. (2) It has only little codon preference and, especially, little discrimination between methionine and selenomethionine (SeMet), which allows easy preparation of selenomethionylated proteins for crystal structure determination by SAD and MAD methods. (3) Translation is uncoupled from transcription, so that the toxicity of the translation product on DNA and its transcription, if any, can be bypassed. We have shown that the wheat-germ-based cell-free protein synthesis is useful for X-ray crystallography of one of the 4-bp cutter restriction enzymes, which are expected to be very toxic to all forms of cells retaining the genome. Our report on its structure represents the first report of structure determination by X-ray crystallography using protein overexpressed with the wheat germ-based cell-free protein expression system. This will be a method of choice for cytotoxic proteins when its cost is not a problem. Its use will become popular when the crystal structure determination technology has evolved to require only a tiny amount of protein. PMID- 20204856 TI - Production of multi-subunit complexes on liposome through an E. coli cell-free expression system. AB - Recently cell-free translation systems became a laboratory research tool to obtain an objective protein. However, a general method for in vitro protein synthesis and multi-subunit complex formation on lipid membrane has not been established. Here, we describe the procedure for the production of subcomplexes of F(o)F(1)-ATP synthase using a reconstructed cell-free translation system. As for the membrane part F(o) (a(1)b(2)c((10-15))), cosynthesis of c-subunit and UncI proteins, which are integral membrane proteins, and further c (11)-ring formation in lipid bilayer are performed by use of a liposomes-containing cell free system. Moreover, as for the cytoplasm part F(1) (alpha(3)beta(3)gammadeltaepsilon), subcomplex formations are successfully achieved by mixing the translation products. PMID- 20204857 TI - Synthesis of a hetero subunit RNA modification enzyme by the wheat germ cell-free translation system. AB - Cell-free translation systems are a powerful tool for the production of many kinds of proteins. However, there are some barriers to improve the system in order to make it a more convenient approach. These include the fact that the production of proteins made up of hetero subunits is difficult. In this chapter, we describe the synthesis of yeast tRNA (m(7)G46) methyltransferase as a model protein. This enzyme catalyzes transfer of a methyl group from S-adenosyl-L methionine to guanine at position 46 in tRNA and generates N(7)-methylguanine. Yeast tRNA (m(7)G46) methyltransferase is composed of two protein subunits, Trm8 and Trm82. To obtain the active Trm8-Trm82 complex, co-translation of both subunits is necessary. Preparation of mRNAs, in vitro synthesis and purification of the complex are explained in this chapter. PMID- 20204858 TI - Strategies for the cell-free expression of membrane proteins. AB - Cell-free expression offers an interesting alternative method to produce membrane proteins in high amounts. Elimination of toxicity problems, reduced proteolytic degradation and a nearly unrestricted option to supply potentially beneficial compounds like cofactors, ligands or chaperones into the reaction are general advantages of cell-free expression systems. Furthermore, the membrane proteins may be translated directly into appropriate hydrophobic and membrane-mimetic surrogates, which might offer significant benefits for the functional folding of the synthesized proteins. Cell-free expression is a rapidly developing and highly versatile technique and several systems of both, prokaryotic and eukaryotic origins, have been established. We provide protocols for the cell-free expression of membrane proteins in different modes including their expression as precipitate as well as their direct synthesis into detergent micelles or lipid bilayers. PMID- 20204859 TI - Production of membrane proteins through the wheat-germ cell-free technology. AB - Membrane proteins play crucial roles in various processes. However, biochemical characterization of the membrane proteins remains challenging due to the difficulty in producing membrane proteins in a functional state. Here, we describe a novel method for the production of functional membrane proteins based on a wheat germ cell-free translation system. Using this method, functional membrane proteins are successfully synthesized in the presence of liposomes and a detergent. In addition, the synthesized membrane proteins are easily purified from the cell-free translation mixture as proteoliposomes by sucrose density gradient ultracentrifugation. These advantages over conventional approaches are very helpful for the clarification of the function of membrane proteins. PMID- 20204860 TI - Ribosome display with the PURE technology. AB - The ribosome display utilizes the formation of the mRNA-ribosome-polypeptide ternary complex in the cell-free protein synthesis system as the linking of the genotype (mRNA) to the phenotype (polypeptide). However, the presence of intrinsic components such as nucleases in the cell-extract based cell-free protein synthesis systems inevitably reduces the stability of the ternary complex, which would prevent attainment of reliable results. We have developed an efficient and highly controllable ribosome display system using the Protein synthesis Using Recombinant Elements (PURE) system. The mRNA-ribosome-polypeptide ternary complex is highly stable in the PURE system and then the selected mRNA can be easily recovered, because activities of nucleases and other inhibitory factors are very low in the PURE system. Furthermore, omission of the release factors within the original PURE system can aid stalling of the ribosome at the termination codon to form the mRNA-ribosome-polypeptide ternary complex. We believe that these advantages assure the usability of the modified PURE system for ribosome display. PMID- 20204861 TI - Incorporation of 3-azidotyrosine into proteins through engineering yeast tyrosyl tRNA synthetase and its application to site-selective protein modification. AB - An efficient method for site-selective introduction of 3-azidotyrosine into proteins has been developed. This method utilizes the yeast amber suppressor tRNA(Tyr)/mutant tyrosyl-tRNA synthetase (Y43G) pair as the carrier of 3 azidotyrosine in an Escherichia coli cell-free translation system. Using rat calmodulin (CaM) as a model protein, we prepared an unnatural CaM molecule carrying a 3-azidotyrosine residue at the predetermined position 80. The synthesized CaM containing 3-azidotyrosine was site-specifically modified via azido group with a fluorescent alkyne derivative by click chemistry. This method will be useful to prepare not only a cross-linkable protein containing 3 azidotyrosine but also a fluorescent protein with a single fluorophore to facilitate the elucidation of molecular mechanisms of protein functions and protein-to-protein networks. PMID- 20204862 TI - Synthesis of functional proteins within liposomes. AB - In living cells, biochemical reaction systems are enclosed in the small lipidic compartments. To experimentally simulate various biochemical reactions occurring in extant cells, cell-sized lipid vesicles (liposomes) are used to reconstruct an artificial model cell. We present methods for encapsulation of the protein synthesis system inside liposomes and for measurement of the in liposome synthesis reaction using a fluorescence-activated cell sorter. These techniques would enable us to perform detailed analysis of the biochemical reactions occurring in the microcompartments and have the potential to reveal the role of compartmentalization in cellular systems. PMID- 20204863 TI - Analysis of DNA methylation in plants by bisulfite sequencing. AB - Methylation of cytosines is a very important epigenetic modification of genomic DNA in many different eukaryotes, and it is frequently involved in transcriptional regulation of genes. In plants, DNA methylation is regulated by a complex interplay between several methylating and demethylating enzymes. Analysis of the resulting cytosine methylation patterns with the highest resolution is achieved after sodium bisulfite treatment, deaminating nonmethylated cytosines to uracil. Subsequent PCR and sequence analysis of individual amplicons displays the degree, position, and sequence context of methylation of every cytosine residue in individual genomic sequences. We describe the application of bisulfite sequencing for the analysis of DNA methylation at defined individual sequences of plant genomic DNA. PMID- 20204864 TI - Analysis of bisulfite sequencing data from plant DNA using CyMATE. AB - Amplifying and sequencing DNA after bisulfite treatment of genomic DNA reveals the methylation state of cytosine residues at the highest resolution possible. However, a thorough analysis is required for statistical evaluation of methylation at all sites in each genomic region. Several software tools were developed to assist in quantitative evaluation of bisulfite sequencing data from complex methylation patterns occurring in plants. This chapter describes the application of Cytosine Methylation Analysis Tool for Everyone (CyMATE). From aligned sequences, CyMATE quantifies and illustrates general and pattern-specific methylation at CG, CHG, and CHH (H = A, C, or T) sites, both per sequence and per position. CyMATE is also able to perform a quality control of sequences and to detect redundancy among individual clones. The software is able to reveal methylation patterns on complementary strands by handling data from hairpin bisulfite sequencing. The tool is freely available for non-commercial use at http://www.cymate.org . PMID- 20204865 TI - Analysis of locus-specific changes in methylation patterns using a COBRA (combined bisulfite restriction analysis) assay. AB - DNA methylation is a major mechanism for the reversible control of gene expression, chromatin structure, and genome stability. Methylation analysis at a given locus allows one to evaluate levels of chromatin packaging, gene expression, and even homologous recombination. We have shown that the combined bisulfite restriction analysis (COBRA) assay makes it possible to analyze methylation levels at a defined locus. The major steps are: bisulfite conversion of nonmethylate cytosines to uracils, locus-specific PCR amplification of converted DNA, restriction digestion, and analysis of restriction patterns on the gel. Due to the availability of various restriction enzymes that have cytosines in the restriction recognition sequence, the assay allows analysis of various cytosines, including those potentially targeted for symmetrical and nonsymmetrical methylation. PMID- 20204866 TI - Detection of changes in global genome methylation using the cytosine-extension assay. AB - Methylation is a reversible covalent chemical modification of DNA intended to regulate gene expression, genome stability, and chromatin structure. Although there are various methods of methylation analysis, most of them are either laborious or expensive, or both. Here, we describe a quick, inexpensive method for analysis of global genome methylation using a cytosine extension assay. The assay can be used for analysis of the total level of CpG, CNpG, and asymmetrical methylation in a given cell culture or in a plant tissue sample. PMID- 20204867 TI - In situ analysis of DNA methylation in plants. AB - Epigenetic changes in the plant genome are associated with differential genome methylation, histone modifications, and the binding of various chromatin-binding factors. Methylation of cytosine residues is one of the most versatile mechanisms of epigenetic regulation. The analysis of DNA methylation can be performed in different ways. However, most of these procedures involve the extraction of chromatin from cells with further isolation and analysis of DNA. Modest success has been achieved in DNA methylation analysis in plant tissues in situ. Here, we present an in situ method for DNA methylation analysis, which has high sensitivity and good reproducibility. PMID- 20204868 TI - Analysis of mutation/rearrangement frequencies and methylation patterns at a given DNA locus using restriction fragment length polymorphism. AB - Restriction fragment length polymorphism (RFLP) is a difference in DNA sequences of organisms belonging to the same species. RFLPs are typically detected as DNA fragments of different lengths after digestion with various restriction endonucleases. The comparison of RFLPs allows investigators to analyze the frequency of occurrence of mutations, such as point mutations, deletions, insertions, and gross chromosomal rearrangements, in the progeny of stressed plants. The assay involves restriction enzyme digestion of DNA followed by hybridization of digested DNA using a radioactively or enzymatically labeled probe. Since DNA can be digested with methylation sensitive enzymes, the assay can also be used to analyze a methylation pattern of a particular locus. Here, we describe RFLP analysis using methylation-insensitive and methylation-sensitive enzymes. PMID- 20204869 TI - Isoschizomers and amplified fragment length polymorphism for the detection of specific cytosine methylation changes. AB - Different molecular techniques have been developed to study either the global level of methylated cytosines or methylation at specific gene sequences. One of them is a modification of the Amplified Fragment Length Polymorphism (AFLP) technique that has been used to study methylation of anonymous CCGG sequences in different fungi, plant and animal species. The main variation of this technique is based on the use of isoschizomers with different methylation sensitivity (such as HpaII and MspI) as a frequent cutter restriction enzyme. For each sample, AFLP analysis is performed using both EcoRI/HpaII and EcoRI/MspI digested samples. Comparative analysis between EcoRI/HpaII and EcoRI/MspI fragment patterns allows the identification of two types of polymorphisms: (1) "Methylation-insensitive polymorphisms" that show common EcoRI/HpaII and EcoRI/MspI patterns but are detected as polymorphic amplified fragments among samples; and (2) "Methylation sensitive polymorphisms" that are associated with amplified fragments differing in their presence or absence or in their intensity between EcoRI/HpaII and EcoRI/MspI patterns. This chapter describes a detailed protocol of this technique and discusses modifications that can be applied to adjust the technology to different species of interest. PMID- 20204870 TI - Analysis of small RNA populations using hybridization to DNA tiling arrays. AB - Small RNA (sRNA) populations extracted from Arabidopsis plants submitted or not to biotic stress, were reverse-transcribed into cDNAs, and these were subsequently hybridized after labelling to a custom-made DNA tiling array covering Arabidopsis chromosome 4. We first designed a control experiment with eight cDNA clones corresponding to sequences located on chromosome 4 and obtained robust and specific hybridization signals. Furthermore, hybridization signals along chromosome 4 were in good agreement with sRNA abundance as previously determined by Massive Parallel Sequence Signature (MPSS) in the case of untreated plants, but differed substantially after stress treatment. These results demonstrate the utility of hybridization to DNA tiling arrays to detect major changes in small RNA populations. PMID- 20204871 TI - Northern blotting techniques for small RNAs. AB - In eukaryotes, RNA silencing encompasses a range of biochemical processes mediated by approximately 20-25 nt small RNAs (smRNAs). This chapter describes northern blot hybridization techniques optimized for detection of such smRNAs, whether extracted from plant or animal tissues. The basic protocol is described, and control blots illustrate the detection specificity and sensitivity of this method using DNA oligonucleotide probes. Known endogenous smRNAs are analyzed in samples prepared from several model plant species, including Arabidopsis thaliana, Nicotiana benthamiana, Oryza sativa, Zea mays, and Physcomitrella patens, as well as the animals Drosophila melanogaster and Mus musculus. Finally, the usefulness of northern blotting in dissecting smRNA biogenesis is shown for the particular case of DNA virus infection. PMID- 20204872 TI - qRT-PCR of Small RNAs. AB - Plant small RNAs are a class of 19- to 25-nucleotide (nt) RNA molecules that are essential for genome stability, development and differentiation, disease, cellular communication, signaling, and adaptive responses to biotic and abiotic stress. Small RNAs comprise two major RNA classes, short interfering RNAs (siRNAs) and microRNAs (miRNAs). Efficient and reliable detection and quantification of small RNA expression has become an essential step in understanding their roles in specific cells and tissues. Here we provide protocols for the detection of miRNAs by stem-loop RT-PCR. This method enables fast and reliable miRNA expression profiling from as little as 20 pg of total RNA extracted from plant tissue and is suitable for high-throughput miRNA expression analysis. In addition, this method can be used to detect other classes of small RNAs, provided the sequence is known and their GC contents are similar to those specific for miRNAs. PMID- 20204873 TI - Cloning new small RNA sequences. AB - Small RNAs are key molecules in RNA silencing pathways that exert sequence specific regulation of gene expression and chromatin modifications in many eukaryotes. In plants, endogenous small RNAs, including microRNAs (miRNAs) and trans-acting small interfering RNAs (tasiRNAs) play an important role in biological processes such as development and stress responses. In addition, viral genome-derived siRNAs are produced during viral infection, and they exhibit anti viral defense by an RNA silencing pathway. These endogenous and exogenous small RNAs are mainly 21-24 nucleotides in length. Here, we describe a method to identify small RNA sequences from plant tissues. Small RNAs are purified by column fractionation and gel excision from total RNAs. These small RNAs are ligated at both termini to DNA/RNA chimeric adapters and reverse-transcribed to produce cDNAs. By the following PCR amplification, BanI restriction sites are added to cDNAs, which enables directional concatamerization. Concatamerized fragments are cloned and sequenced. This method could be applied to identify small RNA sequences from many sources, e.g., mutant plants, plants in various stress environments, and virus-infected plants. PMID- 20204874 TI - Genome-wide mapping of protein-DNA interaction by chromatin immunoprecipitation and DNA microarray hybridization (ChIP-chip). Part A: ChIP-chip molecular methods. AB - Chromatin immunoprecipitation in combination with DNA-microarray hybridization (ChIP-chip) allows the identification of chromatin regions that are associated with modified forms of histones on a genomic scale. The ChIP-chip workflow consists of the following steps: generation of biological material, in vivo formaldehyde-fixation of protein-DNA and protein-protein interactions, chromatin preparation and shearing, immunoprecipitation of chromatin with specific antibodies, fixation reversal and DNA purification, DNA amplification, microarray hybridization, and data analysis. In Part A of this chapter, we describe molecular methods of the experimental procedure employed to identify chromosomal regions of Arabidopsis thaliana associated with H3K27me3. In addition, some general information on the microarray platform from Roche-NimbleGen will be provided. Part B of this chapter focuses on ChIP-chip data analysis of H3K27me3 on the Roche-NimbleGen platform. PMID- 20204875 TI - Genome-wide mapping of protein-DNA interaction by chromatin immunoprecipitation and DNA microarray hybridization (ChIP-chip). Part B: ChIP-chip data analysis. AB - Genome-wide targets of chromatin-associated factors can be identified by a combination of chromatin-immunoprecipitation and oligonucleotide microarray hybridization. Genome-wide mircoarray data analysis represents a major challenge for the experimental biologist. This chapter introduces ChIPR, a package written in the R statistical programming language that facilitates the analysis of two color microarrays from Roche-Nimblegen. The workflow of ChIPR is illustrated with sample data from Arabidopsis thaliana. However, ChIPR supports ChIP-chip data preprocessing, target identification, and cross-annotation of any species for which genome annotation data is available in GFF format. This chapter describes how to use ChIPR as a software tool without the requirement for programming skills in the R language. PMID- 20204876 TI - Metaanalysis of ChIP-chip data. AB - Genome-wide analysis of histone modifications via ChIP-chip (chromatin immunoprecipitation followed by whole genome tiling array hybridization) may generate lists of up to several thousand potential target genes. In the case of the model organism Arabidopsis thaliana, several databases are available to alleviate further characterization and classification of genomic data sets. The term metaanalysis has been coined for this type of multidatabase comparison. In this chapter, we describe open source software and web tools that perform transcriptional and functional analysis of target genes. Sources of transcription data and clustering tools to subdivide genes according to their expression pattern are described. The user is guided through all necessary steps, including data download and formatting. In addition, the Gene Ontology (GO) vocabulary and methods to uncover over- or underrepresented functions among target genes are introduced. Genomic targets of the histone H3K27me3 modification are presented as a case study to demonstrate that metaanalysis can uncover novel functions that were hidden in genomic data sets. PMID- 20204877 TI - Chromatin immunoprecipitation protocol for histone modifications and protein-DNA binding analyses in Arabidopsis. AB - Epigenetic gene regulation via histone modifications controls different processes ranging from embryonic development, vegetative development, floral induction, floral organ development, to pollen tube growth. The identification of an increasing number of epigenetically regulated processes was greatly advanced by genome-wide histone modification and chromatin-protein interaction surveys. However, genome-wide approaches are too global to access in detail a large number of histone modifications taking place at a single locus. Here we provide a robust Chromatin Immunoprecipitation (ChIP) protocol, allowing in vivo analyses of multiple chromatin modifications and binding of histone modifiers in different plant organs and tissues. This method is quantitative and provides a way to study the dynamic state of chromatin during plant development and also in response to different environmental stimuli. PMID- 20204878 TI - cDNA libraries for virus-induced gene silencing. AB - Virus-induced gene silencing (VIGS) exploits endogenous plant antiviral defense mechanisms to posttranscriptionally silence the expression of targeted plant genes. VIGS is quick and relatively easy to perform and therefore serves as a powerful tool for high-throughput functional genomics in plants. Combined with the use of subtractive cDNA libraries for generating a collection of VIGS-ready cDNA inserts, VIGS can be utilized to screen a large number of genes to determine phenotypes resulting from the knockdown/knockout of gene function. Taking into account the optimal insert design for VIGS, we describe a methodology for producing VIGS-ready cDNA libraries enriched for inserts relevant to the biological process of interest. PMID- 20204879 TI - Detection and quantification of DNA strand breaks using the ROPS (random oligonucleotide primed synthesis) assay. AB - DNA double strand breaks (DSBs) arise from spontaneous DNA damage due to metabolic activities or from direct and indirect damaging effects of stress. DSBs are also formed transiently during such processes as replication, transcription, and DNA repair. The level of DSBs positively correlates with the activities of homologous and nonhomologous DNA repair pathways, which in turn inversely correlate with methylation levels and chromatin structure. Thus, measurement of strand breaks can provide an informative picture of genome stability of a given cell. The use of random oligonucleotide-primed synthesis for the analysis of DSB levels is described. Applications of the assay for quantitative detection of 3'OH, 3'P, or DNA strand breaks at a cleavage site of the deoxyribose residue are discussed. PMID- 20204880 TI - Reporter gene-based recombination lines for studies of genome stability. AB - Homologous recombination is a double-strand break repair mechanism operating in somatic cells and involved in meiotic crossovers in plants. It is responsible for the maintenance of genome stability and thus plays a crucial role in adaptation to stress. Recombination between homologous loci is believed to be regulated in part by epigenetic machinery such as methylation. Therefore, the recombination frequency at a specific locus can reflect the chromatin status.Several reporter gene-based recombination constructs have been developed to study HR frequencies in plants. Among them, the luciferase and beta-glucuronidase-based recombination reporter systems are the most widely used. Here, we explain how reporter gene recombination assays operate and in which applications they are used. We also present a conceptually new system for analysis of sequence-specific recombination frequency. These assays can be effectively used for analysis of locus-specific endogenous and stress-induced recombination frequencies. PMID- 20204881 TI - Plant transgenesis. AB - Epigenetic effects such as gene silencing and variable expression are unintended consequences of plant transformation, a problem that is present in the transformation of all plant species. There is not yet a reliable way to prevent epigenetic silencing; however, the probability of epigenetic effects may be reduced by choosing an appropriate method of transgene introduction into a plant cell. Most methods used in plant biotechnology, such as direct gene transfer and particle bombardment, result in the introduction of multiple DNA molecules and, as a consequence, multi-copy multi-locus insertion patterns. These multiple insertions may lead to variations in transgene expression, epigenetic silencing being the most extreme. In contrast, Agrobacterium-mediated plant transformation procedures rarely cause such unintended effects. In this chapter, we present advantages and disadvantages of the Agrobacterium-mediated plant transformation method as well as protocols for transformation of Arabidopsis generative tissues and tobacco seedlings as the most classical techniques in these model plants, i.e., vacuum infiltration of explants and floral dip methods. Moreover, epigenetic effects of transgenes such as silencing related to the position and insertion effects as well as effects of the regeneration procedure causing somaclonal variation will be briefly discussed. PMID- 20204882 TI - A point system for resident scholarly activity. PMID- 20204883 TI - Family medicine is alive at Columbia. PMID- 20204884 TI - Physicians, patients, and society: a long and complex history. PMID- 20204885 TI - The role of a rural medical school campus in developing a sense of place: the first 10 years. PMID- 20204886 TI - Factors associated with refusal of colonoscopy. PMID- 20204887 TI - Filling the leadership void. PMID- 20204888 TI - Integrating quality improvement into a family medicine clerkship. PMID- 20204889 TI - Valuable wisdom. PMID- 20204890 TI - Life as a survivor. PMID- 20204891 TI - The impact of film in teaching cultural medicine. PMID- 20204892 TI - Influence of community preceptor specialty and method of assignment in an early clinical experience course. AB - OBJECTIVES: Although early clinical experience courses are often the purview of family medicine faculty, students may receive training with community physicians from varying specialties. Little is known about the influence of preceptor specialty and method of assignment on students' performance and course satisfaction. METHODS: Second-year medical students spent one half day per month with a preceptor to practice clinical skills. Preceptors were either assigned randomly or assigned by student recruitment or specialty request. We analyzed whether preceptor specialty, method of assignment, and practice site (the independent variables) were associated with the dependent variables of course evaluation ratings and student performance on objective structured clinical examinations (OSCEs). RESULTS: Analyses found no differences in students' overall course satisfaction or OSCE scores and little difference in satisfaction with specific course components. There was a positive relationship between overall course rating and the rating of the preceptor experience and between the preceptor experience and more time spent in ambulatory clinics and direct patient interaction. CONCLUSIONS: Because students were equally satisfied and performed comparably regardless of specialty or matching method, early clinical exposure may be accomplished equally well using specialist or generalist physicians, potentially giving primary care educators greater latitude to focus their efforts on teaching students in clinical clerkships and those interested in primary care. PMID- 20204893 TI - Live and Web-based orientations are comparable for a required rotation. AB - BACKGROUND AND OBJECTIVES: Studies show equivalency in knowledge when measured following Web-based learning and live lecture. However, the effectiveness of a Web-based orientation for a required clinical rotation is unknown. METHODS: Medical students viewed a Web-based orientation and completed a 13-item evaluation before beginning a required 6-week community medicine rotation. Evaluation data from 2007-2008 live orientation sessions were compared to responses from 2008-2009 Web-based orientation sessions. Data were analyzed by two-sample tests of proportion. RESULTS: A total of 169 students completed surveys during the study period--78 following the live and 91 following the Web based orientation. Response rates were equal in the two groups. The survey tool had a high level of reliability (Cronbach's alpha=0.96). There was no statistical difference in student evaluations for 12 of 13 orientation evaluation items. CONCLUSIONS: Live and Web-based formats are comparable for presenting orientation materials to a required clinical rotation. Students felt the purpose of the rotation, educational goals, course structure, and requirements were clearly presented regardless of format. Transition from a live to Web-based format reduced faculty time required to present at rotation orientations. PMID- 20204894 TI - Traumatic events and mental health in civilian primary care: implications for training and practice. AB - BACKGROUND AND OBJECTIVES: Primary care research into post-traumatic stress disorder (PTSD) is less developed than primary care depression research. This study documents lifetime traumatic events and past month depression and PTSD in adult patients of a large family medicine residency practice. METHODS: We used a telephone survey of 411 adult patients from a family medicine residency practice in the Southeastern United States. Standardized measures were used. RESULTS: Seventy-nine percent of study enrollees completed the study. Women were significantly more likely than men to have been diagnosed with PTSD (35.8% versus 20.0%) or depression (36.1% versus 21.1%), with a high degree of diagnosis overlap (76.5%). Most adults (>90%) reported one or more traumatic events. Men reported more war zone/combat events; women reported more sexual victimization. More than 80% of patients thought family physicians should ask about traumatic events; only a minority recalled being asked (26.8% men, 43.6% women). Regression models determined that current depression and several traumatic events were significant correlates of current PTSD. CONCLUSIONS: Key gender differences in frequency of lifetime traumatic events, past month depression and PTSD, and patient attitudes about trauma questions existed. Current PTSD was best predicted by a combination of coexisting depression and traumatic events. Discussion explores training and practice implications. PMID- 20204895 TI - Using the Guidelines for Adolescent Preventive Services to estimate adolescent depressive symptoms in school-based health centers. AB - BACKGROUND AND OBJECTIVES: The study objective was to understand the relationship between depressive symptoms and demographic, behavioral, and environmental risk variables among adolescents attending school-based health centers (SBHCs) using the Guidelines for Adolescent Preventive Services (GAPS) questionnaires. METHODS: Using GAPS questionnaires, we conducted a retrospective medical record review of 672 adolescents attending two Detroit-area school-based health clinics. Bivariate and multivariate analyses were conducted to determine which factors were associated with depressive symptoms while adjusting for other relevant factors. RESULTS: Overall, 26.5% of adolescents reported depressive symptoms. Bivariate analysis revealed associations between depressive symptoms and female gender, older age, disordered eating, lack of physical activity, sexual activity, poor school performance, substance use of all types, violence, law trouble, and an abuse history. Multivariate regression models revealed that female gender, sexual activity, weapon carrying, law trouble, poor physical activity, and a history of abuse were most strongly related to self-reported depressive symptoms. Substance use was not a significant factor after controlling for potential confounders. CONCLUSIONS: Targeting the above factors during routine adolescent examinations may help providers at SBHCs and other clinics identify those at highest risk for depression and provide appropriate interventions. PMID- 20204896 TI - WellBabies: mothers' perspectives on an innovative model of group well-child care. AB - BACKGROUND AND OBJECTIVES: Typical well-child visits are often unsatisfactory both to providers and patients. Group visits have been shown effective in some settings but have not been recently assessed for well-child care. Here we describe a model for infant well-child visits, WellBabies, along with participating mothers' perspectives and comparisons of quality outcomes. METHODS: We invited mothers receiving prenatal care in our practice to participate in WellBabies after delivery. Thirteen women participated, and 11 were available for individual interviews. We identified and summarized common themes in interview transcripts and compared quality outcomes with babies who had standard individual well-child visits. RESULTS: Participants expressed largely positive reactions to WellBabies, identifying mutual support, information sharing, parental involvement in care, and time spent in the visit as particularly valuable. One participant expressed concern about lack of individual time with a provider. Quality outcomes were similar to those in the comparison group. CONCLUSIONS: Group well-child visits can effectively address important issues in children's health care and are well-received by participants. PMID- 20204897 TI - Reflections on 18 years in the editor's chair. PMID- 20204899 TI - [Editorial]. PMID- 20204898 TI - Guidance for expanding family physician medical home scope of practice. PMID- 20204900 TI - [Do general practitioners diagnose and treat patients with alcohol use problems?]. AB - AIM: To determine the primary health care working general practitioners' knowledge, attitude and behavior towards alcohol use disorders. METHOD: In this descriptive and cross-sectional study 135 general practitioners (GPs) completed the questionnaire. RESULTS: Pre and post graduate education on alcohol use disorders is low (25.4 % and 11.7% respectively). Most of the GPs do not know the levels of risky alcohol use, screening tests, and biochemical markers. The mean knowledge score is 6.67+/-1.70. Most GPs think that alcohol use disorders are not an important issue in primary health care (57%), they do not have time to deal with patients' alcohol problems (74.1%), it is difficult to diagnose risky alcohol users without clear symptoms (91.1%), patients do not follow advice on alcohol use (85.2%), and physicians themselves are tolerant towards alcohol (71.1%). Half of the GPs reported that they find it difficult to talk about alcohol use with patients and think that patients may be angered by alcohol consumption questions. Mean attitude score is 4.44+/-2.15. Most of the GPs reported that they would ask questions about alcohol use to their patients (91.7%) and declare that the patients' problems were related to alcohol (90.2%). More than half of them reported that they would refer the patient to a specialist or an alcohol treatment center (58.5%). The mean behavior score is 5.96+/-1.46. CONCLUSION: In our country it is clear that more education and support for GPs is needed due to their important role in intervention for alcohol use problems. PMID- 20204901 TI - [Psychiatrist views on stigmatization toward people with mental illness and recommendations]. AB - OBJECTIVE: The aim of this study is to understand and discover the processes of stigmatization toward people with mental illnesses through the experience of psychiatrists. This paper focuses on the views of psychiatrists concerning the role of psychiatric diagnosis and the attitudes of general medical professionals toward people with mental illnesses, together with the recommendations of psychiatrists for dealing with the stigmatization process. METHOD: The purposive sampling technique was used in this study. Nine psychiatrists and eight assistant psychiatrists from various health institutions in Ankara were interviewed between 2006 and 2007. The interviews were tape recorded and transcribed verbatim. The process of analysis evolved from concrete to more abstract categories. RESULTS: Psychiatrists proposed different views concerning the role played by psychiatric diagnosis in stigmatization. While some do not want to write their diagnoses on prescriptions, others argue that merely changing the name of the diagnosis cannot be regarded as a solution. Most of the psychiatrists interviewed stated that stigmatizing attitudes exist among physicians. The hesitancy among physicians and ignorance displayed by emergency services were the proof given of institutionalized stigma. CONCLUSION: It seems that psychiatrists need more time to come to an agreement concerning the role played by psychiatric diagnosis in stigmatization. Psychiatrists who participated in our research highlighted their informative and resistive role in anti-stigma strategies and proposed educational strategies for different groups in collaboration with various institutions. Concerning stigmatization in non-psychiatric health services, they proposed reorganization in medical education along with seminars for physicians and an increase of consultation-liaison. PMID- 20204902 TI - [Evaluation of the effectiveness of a cognitive-behavioral therapy program for alleviating the symptoms of social anxiety in adolescents]. AB - OBJECTIVE: The aim of this research project is to investigate the effects of cognitive-behavioral group therapy on adolescents suffering from symptoms of social anxiety. METHOD: cognitive behavioral group therapy program for reducing social anxiety was developed by the authors, after which a pilot study was conducted, evaluated for deficiencies, finalized, and implemented in the following study. The final program entailed 13 sessions covering relaxation training, cognitive restructuring and exposure components. To recruit the participants for the intervention program screening tests were applied to 711 students of three different junior high schools in Izmir. 44 students (treatment=24, control= 20) who met the inclusion criteria in the seventh and eighth grades participated in the main study. Evaluation of the therapy program was ascertained using the following instruments; for students, Negative Cognitive Errors Questionnaire (CNCEQ), Cape Social Phobia Scale for Children and Adolescents (CSPSCA), Social Anxiety Scale for Adolescents (SAS-A); and for parents, (SAS-P) was used to compare their pre-program and post-program tests results. RESULTS: Repeated measures ANOVAs yielded significant Group X Time interactions for SAS-A (F (1, 42) =7.511, p< 0.01, eta2 =0.15), CSPSCA (F (1, 42) =6.54, p<.05) and CNCEQ (F (1, 42) = 8.295, p<0.01, eta2 =0.16) scores. Results from parents further indicated that social anxiety in the treatment group had decreased after program completion (F (1, 42) = 9.496, p=0.004, eta2 =0.18). CONCLUSION: Consistent with the literature of school based Cognitive-Behavioral Group Treatment (CBGT) programs for social anxiety, it was found that adolescents in the treatment group exhibited a significant decrease in social anxiety and related cognitive errors. PMID- 20204903 TI - [The reliability and validity of the Turkish Version of the World Health Organization Quality of Life Instrument-Older Adults Module (WHOQOL-Old)]. AB - PURPOSE: To determine the psychometric properties of the Turkish version of the World Health Organization Quality of Life Instrument-Older Adults Module (WHOQOL Old). METHODS: The Turkish version of the WHOQOL-OLD was administered to 527 older (> 65 years) adults living in urban, suburban, and rural areas of Manisa Province, Turkey. The WHOQOL-OLD module consists of 24 items assigned to 6 facets (sen------sory abilities, autonomy, past, present and future activities, so-cial participation, death and dying, and intimacy) and is a supplementary module of WHOQOL-BREF. The WHOQOL-BREF and GDS-30 were also administered to the participants. A confirmatory approach was used during reliability and validity analysis. SPSS v.10.0 and LISREL v.8.54 were used for analysis. RESULTS: Mean age of the participants was 71.06 +/- 5.20 years and the overall WHOQOL-OLD score was 56.02 +/- 11.86. In all, 54.5% of the participants were female and 60.5% reported to be in poor health. Both ceiling and floor effects of the WHOQOL-OLD were satisfactory (< 0.05%). Alpha values for the facets and overall scale (range: 0.68-0.88) (> 0.70), and item total correlations and overall scale success were satisfactory. As a measure of the construct validity of the scale, confirmatory factor analysis showed very high CFI values (range: 0.936-0.999) for each of the domains. Convergence of WHOQOL-OLD facet scores on WHOQOL-BREF domains and WHOQOL OLD were very fine in general. CONCLUSIONS: The psychometric properties of the Turkish version of the WHOQOL-OLD were acceptable, indicating that the scale is reliable and valid for use with older Turkish adults (> 65 years). PMID- 20204904 TI - [The accuracy of HADS and GHQ-12 in detecting psychiatric morbidity in breast cancer patients]. AB - OBJECTIVE: Psychological problems should be identified in breast cancer patients proactively if doctors and nurses are to help them cope with the challenges imposed by their illness. Screening is one possible way to identify emotional problems proactively. Self-report questionnaires can be useful alternatives to carrying out psychiatric interviews during screening, because interviewing a large number of patients can be impractical due to limited resources. Two such measures are the Hospital Anxiety and Depression Scale (HADS) and the General Health Questionnaire-12 (GHQ-12). METHOD: The present study aimed to compare the performance of the GHQ-12, and the HADS Unitary Scale and its subscales to that of the Schedule for Affective Disorders and Schizophrenia (SADS) in identifying patients with affective disorders, including DSM major depression and generalized anxiety disorder. The sample consisted of 296 female breast cancer patients who underwent surgery for breast cancer a year previously. RESULTS: A small number of patients (11%) were identified as having DSM major depression or generalized anxiety disorder based on SADS score. The findings indicate that the optimal thresholds in detecting generalized anxiety disorder and DSM major depression with the HADS anxiety and depression subscales were > or = 8 and > or = 7, with 93.3% and 77.3% sensitivity, respectively, and 77.9% and 87.1% specificity, respectively. They also had a 21% and 36% positive predictive value, respectively. Using the HADS Unitary Scale the optimal threshold for detecting affective disorders was > or = 12, with 88.9% sensitivity, 80.7% specificity, and a 35% positive predictive value. In detecting affective disorders, the optimal threshold on the GHQ-12 was > or = 2, with 77.8% sensitivity and 70.2% specificity. This scale also had a 24% positive predictive value. In detecting generalized anxiety disorder and DSM major depression, the optimal thresholds on the GHQ-12 were > or = 2 and > or = 4 with 73.3% and 77.3% sensitivity, respectively, and 67.5% and 82% specificity, respectively. The scale also had 12% and 29% positive predictive values, respectively. CONCLUSION: The HADS Unitary Scale and its subscales were effective in identifying affective disorders. They can be used as screening measures in breast cancer patients. The GHQ-12 was less accurate in detecting affective disorders than the HADS, but it can also be used as a screening instrument to detect affective disorders, generalized anxiety disorder, and DSM major depression. PMID- 20204905 TI - [Depressive realism: happiness or objectivity]. AB - Realism is described as objective evaluations and judgments about the world; however, some research indicates that judgments made by "normal" people include a self-favored, positive bias in the perception of reality. Additionally, some studies report that compared to normal people, such cognitive distortions are less likely among depressive people. These findings gave rise to the depressive realism hypothesis. While results of several studies verify the notion that depressive people evaluate reality more objectively, other studies fail to support this hypothesis. Several causes for these inconsistent findings have been proposed, which can be characterized under 3 headings. One proposed explanation suggests that what is accepted as "realistic" in these studies is not quite objective and is in fact ambiguous. According to another perspective, the term "depressive" used in these studies is inconsistent with the criteria of scientific diagnostic methods. Another suggests that the research results can only be obtained under the specific experimental conditions. General negativity and limited processing are popular approaches used for explaining the depressive realism hypothesis. Nowadays, the debate over this hypothesis continues. The present review focuses on frequently cited research related to depressive realism and discusses the findings. PMID- 20204906 TI - [Neurobiology of motherhood]. AB - Motherhood is a physiological status in which certain behavioural patterns are exhibited. Maintenance of the life of the species in mammals is dependent upon the presentation of motherhood services in a certain period that the child is dependent on the mother. Absence of the mother causes some deficiencies in social, behavioural and cognitive abilities, an abnormal development of the stress response system, learning and memory disorders, and later, inadequate motherhood skills of the mature offspring during their own maternity period. Because maternal care is extremely important for the survival of the child and thus, for the species to maintain, nature seems to have provided the development of a healthy mother-child relationship. Therefore, motherhood is programmed by the evolutionary process in the female brain before birth. It is certain that the brain of the mother is very different from the brains of the nulliparous women who are within the same age range, and is very sensitive to her own child's needs. For maternal behaviour to develop in human beings and animals, special neural networks, which are cooperatively developed by genetic, environmental and hormonal factors, are necessary. It also seems likely that non-genetic (epigenetic) transmission responsible for the internalization of maternal behaviours learned from the mother and hormonal exposure of the brain both during the foetal period, throughout the growth, and during the gestation of the woman as well as genetic factors, play an important role in the development of these maternal neural networks and systems. In this paper, which was prepared by obtaining the necessary publications by means of a search for the words related to motherhood in the PubMed search engine, the physical and mental changes that prepare females for motherhood and enable them to tolerate it will be reviewed. PMID- 20204907 TI - [Valproate induced hypoactive delirium in a bipolar disorder patient with psychotic features]. AB - Delirium may present with hyperactive, hypoactive or mixed clinical pictures. The signs of hypoactive delirium are lethargy, confusion, apathy, hypersomnia, muttering, difficulty in maintaining attention, and difficulty in understanding and performing commands. Valproate is commonly used for the treatment of epilepsy and bipolar disorders. It is also used for the management of alcohol withdrawal delirium and agitative-aggressive deliriums. However, few reports are available about the valproate-induced delirium. In this report, we present a 46 years-old woman with bipolar disorder for 14 years. During her last two hospital admissions, she had been diagnosed with manic episode with psychotic features and she had received valproate. She experienced three hypoactive delirium episodes lasting 2-3 days throughout the treatment period of first week. The patient predominantly had the following signs; vomiting, hypersalivation, confusion, drowsiness, dysphasia, and hypoactivity. At the first day of delirium episode, serum valproate level was found to be within the therapeutic range (98.4, 117.1, and 65.6 mug/ml; respectively). In addition, she had normal results of cranial MRI, complete blood count, urine analysis, electrocardiogram, ALT, AST, albumin, bilirubin, BUN, creatinine and electrolytes. The serum ammonia level of the patient could not been measured due to limitations of laboratory facilities. The patient's consciousness improved dramatically 2-3 days after cessation of valproate. In conclusion, valproate can induce delirium at therapeutic blood levels in some patients via various mechanisms and this side effect has to be considered during valproate use. PMID- 20204908 TI - [Psychogenic purpura with hematuria and sexual pain disorder: a case report]. AB - Psychogenic purpura (Gardner-Diamond syndrome) is the occurrence and spontaneous recurrence of painful ecchymosis following emotional stress and minor trauma. Although the exact mechanism of this syndrome remains unknown, apart from skin lesions, different types of hemorrhaging have been reported, such as epistaxis, gastrointestinal bleeding, and bleeding from the ear canals and eyes. We report a psychogenic purpura case that presented with hematuria in addition to skin lesions. Based on the psychiatric evaluation she was diagnosed with major depressive disorder, generalized anxiety disorder, and obsessive-compulsive disorder. Additionally, sexual pain disorder accompanied these disorders. With the help of antidepressant and supportive psychotherapy, the patient's ecchymosis and bleeding disappeared. During 8 months of follow-up the symptoms did not return. Vaginismus has not been reported in patients with psychogenic purpura. The presence of vaginismus, which is seen more frequently in eastern cultures and is thought to be related to sociocultural determinants, suggests that some cultural factors may be common to both psychogenic purpura and vaginismus. The aim of this case report was to call attention to a syndrome that is rarely seen and diagnosed, and to discuss its relationship to psychosocial factors. This syndrome should be considered in the differential diagnosis of not only ecchymotic lesions, but also various types of bleeding, including hematuria. Despite the fact that its etiology and treatment are not clearly understood, it should be noted that psychological factors play a role in this disease and therefore, psychopharmacological and psychotherapeutic approaches can be effective. PMID- 20204909 TI - Preparing for highly active antiretroviral therapy rollout in rural South Africa: an assessment using the information, motivation, and behavioral skills model. AB - Following a controversial history and before South Africa started the world's largest highly active antiretroviral therapy (HAART) rollout, little was known about community-level information, motivation, and behavioral skills (IMB) regarding HAART in high-HIV-prevalence rural communities. The IMB model has been shown to predict behaviors that are associated with desirable HAART outcomes. We conducted an anonymous, cross-sectional "HAART-Felt Prospects" survey among HIV serostatus-unknown young adults in Tugela Ferry, KwaZulu-Natal. We aimed to identify behavioral aspects of HAART preparedness that could be targeted by local interventions to enhance HAART outcomes. Data analysis included: percent correct, thematic means based on a four-point Likert-scale, and composite quotients. Subjects (N=176) were Zulu (99%), young (mean 19 years), and severely impoverished (55%). Relatively high levels of information were reported: overall correct score was 46%, secondary-transmission-of-resistance information was highest (81%), and only 15% reported traditional or government-advocated folk remedies cure or treat HIV/AIDS. Motivation quotient was "consistent" with favorable HAART behaviors; attitudes toward medication-taking behaviors (3.48) and condom use during HAART (3.43) ranked the highest. Desire for HIV testing (71%) was associated with HIV treatment optimism [adjusted odds ratio (AOR)=4.0, p=0.0004] and previous experience with good treatment outcome [AOR=3.2, p=0.01]. Acceptance of HAART (93%) was associated with HIV optimism [AOR=18.0, p=0.001] and not believing government-advocated folk remedies cure or treat HIV/AIDS [AOR=10.0, p=0.04]. Behavioral skills quotient was "neutral" for favorable HAART behaviors; side effects self-efficacy was the highest (3.16); and medication taking self-efficacy the lowest (2.51). Only 47% believed disclosing HIV serostatus would be easy. Despite controversy surrounding HAART initiation, these results suggest that local South African at-risk youth were relatively well poised for HAART rollout. This conclusion is supported by subsequent successful HAART rollout locally. Community-based assessments are urgently needed as HAART rollouts continue. Adaptation of this IMB-based survey may better inform efforts to enhance HAART-program implementation in resource-limited settings globally. PMID- 20204910 TI - Jaw motor plasticity in health and disease. AB - The human jaw's structure-function relationships are complex. A recent example of this complexity is the lateral pterygoid muscle which we now consider as a single unit made up of functional regions with activity in each dependent on the biomechanical demands of the task. We have also characterised the effects on the jaw motor system of pain or exercise, as examples of how the jaw motor system adapts. Synchronised jaw tracking and electromyographic acquisition systems were used to study the effects on jaw muscle activity of experimentally induced masseter muscle pain or resistance exercises during goal-directed tasks. With both interventions, subjects were able to perform the same movement with different muscle co-activation strategies. In future, the biomechanical effects on the orofacial structures of motor changes with pain/exercise interventions may be investigated with mathematical jaw modelling. Such models could propose clinical interventions that could alter jaw motor function to reduce adverse joint and muscle loads. PMID- 20204911 TI - A procedure for estimating the relevant forces in the human knee using a four-bar mechanism. AB - Knee injuries, especially those that affect the cruciate and lateral ligaments, are one of the most serious and frequent pathologies that affect the lower human extremity. Hence, the aim of this study is to develop a dynamic model for the lower extremity capable of estimating forces, forces in the cruciate and collateral ligaments and those normal to the articular cartilage, generated in the knee. The proposed model considers a four-bar mechanism in the knee, a spherical joint in the pelvis and a revolute one in the ankle. The four-bar mechanism is obtained by a synthesis process. The dynamic model includes the inertial properties of the femur, tibia, patella and the foot, the ground reaction force and the most important muscles in the knee. Muscle forces are estimated using an optimisation technique. Results from the application of the model on a real human task are presented. PMID- 20204913 TI - Holding-side influences on infant's view of mother's face. AB - Recently we found that adult children whose mothers had had a right-arm preference for holding infants have a reduced left bias for recognising faces, suggesting that they are less well right-hemisphere lateralised for perceiving faces. One possible explanation of this finding is that early visual exposure to faces is suboptimal for right-held infants. To test this idea, we asked mothers to pick up a doll with an inbuilt camera in its face and to start bottle-feeding it. The results showed that less was visible of the face of mothers who held the doll on their right arm in comparison to those who held the doll on their left arm: From the right arm, the mother's left half of the face was less visible when the mothers were looking up and their right half of the face was less visible when they were looking at the doll. These results suggest that right-held infants receive suboptimal information from faces. Because early face exposure is important for face-processing development, the suboptimal face exposure probably experienced by right-held infants may have consequences for their ability to recognise faces and facial emotion later in life. PMID- 20204912 TI - Trichothecene and beauvericin mycotoxin production and genetic variability in Fusarium poae isolated from wheat kernels from northern Italy. AB - The importance and widespread incidence of Fusarium poae as a natural contaminant of wheat in different climatic areas warrants investigation into the genetic diversity and toxin profile of a northern Italy population. Eighty-one strains of F. poae isolated from durum wheat kernels, identified by species-specific polymerase chain reaction and translation elongation factor-1alpha gene sequence analysis, were genetically characterized by the amplified fragment length polymorphism (AFLP) technique and analysed by high-pressure liquid chromatography for their ability to produce the beauvericin (BEA) and trichothecene mycotoxins. A high level of variability was observed by using AFLP analyses, with the lowest level of genetic similarity among the strains being approximately 61%. Most of the strains, 95%, produced BEA at <2655 microg g(-1); 88% produced the trichothecene nivalenol at <865 microg g(-1) and 76% produced the trichothecene fusarenon-X at <167 microg g(-1). These data show that F. poae can produce high amounts of BEA together with trichothecenes, and can represent a high potential mycotoxin risk in Italy for wheat colonized by this species. PMID- 20204914 TI - Handbook of developmental social neuroscience. PMID- 20204915 TI - Growing evidence for the influence of meditation on brain and behaviour. PMID- 20204916 TI - The mindfulness-based relapse prevention adherence and competence scale: development, interrater reliability, and validity. AB - The present study describes the development of the Mindfulness-Based Relapse Prevention Adherence and Competence Scale (MBRP-AC), a measure of treatment integrity for mindfulness-based relapse prevention (MBRP). MBRP is a newly developed treatment integrating core aspects of relapse prevention with mindfulness practices. The MBRP-AC was developed in the context of a randomized controlled trial (RCT) of MBRP efficacy and consists of two sections: Adherence (adherence to individual components of MBRP and discussion of key concepts) and Competence (ratings of therapist style/approach and performance). Audio recordings from 44 randomly selected group treatment sessions (50%) were rated by independent raters for therapist adherence and competence in the RCT. Findings evinced high interrater reliability for all treatment adherence and competence ratings, and adequate internal consistency for Therapist Style/Approach and Therapist Performance summary scales. Ratings on the MBRP-AC suggested that therapists in the recent RCT adhered to protocol, discussed key concepts in each session, and demonstrated the intended style and competence in treatment delivery. Finally, overall ratings on the Adherence section were positively related to changes in mindfulness over the course of the treatment. PMID- 20204917 TI - Neurocognitive profile in a case of maple syrup urine disease. AB - Maple Syrup Urine Disease (MSUD) is a metabolic disease with associated enzyme deficiency and an inability to break down amino acids. Neurotoxic levels can occur resulting in neurological sequelae. Information regarding cognitive functions has suggested greater verbal than visuospatial abilities. Specific neuropsychological functions have not been studied. The objective of this study is to examine the neuropsychological profile in a case of MSUD. We present a case study of a 7-year-old female who has a history of late diagnosis (7 days of age) and poor metabolic control. Consistent with existing literature, a profile of stronger verbal reasoning and memory skills compared with visual-perceptual and nonverbal memory was revealed. Additional weaknesses were demonstrated with attention, emerging executive functions, and fine motor control. The results suggest that while previously described nonverbal reasoning and visuospatial impairments are present, there is likely a more complex pattern of neuropsychological impairments in children with MSUD, especially those with poor metabolic control. PMID- 20204918 TI - Theoretical accounts of spatial learning: a neurobiological view (commentary on Pearce, 2009). AB - Theories of learning have historically taken, as their starting point, the assumption that learning processes have universal applicability. This position has been argued on grounds of parsimony, but has received two significant challenges: first, from the observation that some kinds of learning, such as spatial learning, seem to obey different rules from others, and second, that some kinds of learning take place in processing modules that are separate from each other. These challenges arose in the behavioural literature but have since received considerable support from neurobiological studies, particularly single neuron studies of spatial learning, confirming that there are indeed separable (albeit highly intercommunicating) processing modules in the brain, which may not always interact (within or between themselves) according to classic associative principles. On the basis of these neurobiological data, reviewed here, it is argued that rather than assuming universality of associative rules, it is more parsimonious to assume sets of locally operating rules, each specialized for a particular domain. By this view, although almost all learning is associative in one way or another, the behavioural-level characterization of the rules governing learning may vary depending on which neural modules are involved in a given behaviour. Neurobiological studies, in tandem with behavioural studies, can help reveal the nature of these modules and the local rules by which they interact. PMID- 20204919 TI - Intact implicit learning in autism spectrum conditions. AB - Individuals with autism spectrum condition (ASC) have diagnostic impairments in skills that are associated with an implicit acquisition; however, it is not clear whether ASC individuals show specific implicit learning deficits. We compared ASC and typically developing (TD) individuals matched for IQ on five learning tasks: four implicit learning tasks--contextual cueing, serial reaction time, artificial grammar learning, and probabilistic classification learning tasks--that used procedures expressly designed to minimize the use of explicit strategies, and one comparison explicit learning task, paired associates learning. We found implicit learning to be intact in ASC. Beyond no evidence of differences, there was evidence of statistical equivalence between the groups on all the implicit learning tasks. This was not a consequence of compensation by explicit learning ability or IQ. Furthermore, there was no evidence to relate implicit learning to ASC symptomatology. We conclude that implicit mechanisms are preserved in ASC and propose that it is disruption by other atypical processes that impact negatively on the development of skills associated with an implicit acquisition. PMID- 20204920 TI - The modulation of conditional assertions and its effects on reasoning. AB - The theory of mental models postulates that conditionals of the sort, if A then C, have a "core" meaning referring to three possibilities: A and C, not-A and C, and not-A and not-C. The meaning of a conditional's clauses and general knowledge can modulate this meaning, blocking certain possibilities or adding relations between the clauses. Four experiments investigated such interpretations in factual and deontic domains. In Experiment 1, the participants constructed instances of what was possible and what was impossible according to various conditionals. The results corroborated the general predictions of the model theory and also the occurrence of modulation. The resulting interpretations governed the conclusions that participants accepted in Experiment 2, which also yielded the predicted effects of a time limit on responding. In Experiment 3, the participants drew the predicted conclusions for themselves. In Experiment 4, modulation led to predicted temporal relations between A and C. We relate these results to current theories of conditionals. PMID- 20204921 TI - Avoidant instructions induce ironic and overcompensatory movement errors differently between and within individuals. AB - Giving avoidant instructions can ironically result in the forbidden act being carried out, especially when the person is anxious or cognitive loaded. However, the consistency with which individuals make ironic errors across conditions remains unexamined. Forty participants were instructed to avoid moving a cursor above, below, left, and right when tracing an invisible line connecting two points while rehearsing seven-digit numbers on half of trials. Results showed that, without cognitive load, 26 participants made consistent overcompensatory movements, 10 made consistent ironic errors, and 4 showed no distinct error bias, with levels of somatic anxiety predicting this pattern. However, 21 (52.5%) participants changed their error tendency when cognitive loaded, indicating that movement effects of avoidant instruction were not experienced as general phenomena but rather differed between and within individuals. Overcompensatory errors made by participants grouped as overcompensatory performers under low load were significantly larger than the ironic errors made by participants grouped as ironic performers under low load, yet, paradoxically, ironic performers reported higher state and trait anxiety. Overall, results demonstrate a clear experimenter bias inherent in the use of avoidant instructions to direct participants' motor control. PMID- 20204923 TI - Personality and perfectionism in chronic fatigue syndrome: a closer look. AB - OBJECTIVE: To test the hypothesis that people with chronic fatigue syndrome (CFS) would differ significantly from a healthy control group on measures of general personality and perfectionism, specifically on measures of neuroticism and unhealthy perfectionism. METHOD: A total of 27 female CFS outpatients and 30 female healthy controls completed questionnaires, including the NEO Personality Inventory-Revised, the Multi-dimensional Perfectionism Scale and measures of anxiety and depression. RESULTS: The CFS group was significantly more fatigued, anxious and depressed than healthy controls. They scored significantly higher on neuroticism and unhealthy perfectionism. Healthy and unhealthy perfectionism were positively correlated in the CFS group, but not in the control group. CONCLUSION: The present study confirms the link between neuroticism and fatigue and finds a link between unhealthy perfectionism and fatigue. A 'healthy trait', such as healthy perfectionism, when coupled with evaluative concerns is not necessarily healthy in a fatigued population. Researchers and clinicians should note the context in which apparently benign traits are expressed, and how they interact with other traits. PMID- 20204925 TI - Reducing overestimated intentions and expectations for physical activity: The effect of a corrective entreaty. AB - We assessed whether intentions and expectations formed in a hypothetical physical activity situation are different from those formed in a real situation; and whether the intentions and expectations of participants who are hypothetically given a free pass to attend a fitness class to better match their behaviour if they are administered a corrective entreaty (CE), than if they are not. In two separate studies, undergraduate university students were randomised into three groups: (a) Hypothetical (H); (b) Hypothetical with CE (HE) and (c) Real (R), and were asked to rate their intention and expectation to use a fitness pass. As hypothesised, significantly more participants expected that they would use the free fitness pass in the H group compared to the R group in both studies. Significantly fewer participants in the HE condition expected to use their free pass compared to the H group in Study 2. Also, significantly more corresponding expectation-behaviour relationships were found in the HE and R groups compared to the H group in both studies. Administering a CE influenced expectations formed in a hypothetical situation making them more similar to expectations formed in a real situation, and increased the specificity of tests of correspondence between expectation and behaviour. PMID- 20204926 TI - Stress, psychiatric co-morbidity and coping in patients with chronic idiopathic urticaria. AB - This study examined life event stress, perceived stress and psychiatric co morbidity among patients with Chronic Idiopathic Urticaria (CIU). It also investigated the relationship between coping, stress, the severity of CIU and psychiatric co-morbidity. Total of 100 CIU patients and 60 allergy patients participated in the study. They completed the General Health Questionnaire, the Social Readjustment Rating Scale, the Perceived Stress Scale, and the Ways of Coping Checklist. Compared with allergy patients, CIU patients had worse co morbidity and higher levels of life event stress and perceived stress. Emotion focussed coping was associated with the severity of CIU; perceived stress was associated with co-morbidity. PMID- 20204927 TI - The development and initial validation of a new measure of lay definitions of health: The wellness beliefs scale. AB - The objective was to develop a psychometrically sound questionnaire measure of lay people's beliefs about the importance of different signs of wellness (the Wellness Beliefs Scale, WBS). Questionnaire items were derived from qualitative literature. Nine hundred and forty two people (recruited from the community and patient-support groups) participated in two cross-sectional studies using paper and web-based questionnaires. Study 1 participants completed the initial version of the WBS and Study 2 participants completed the revised version of the WBS and existing measures of health beliefs, illness perceptions and health status. Factor analysis confirmed that the WBS measures three distinct wellness beliefs: belief in the importance of biomedical (absence of illness), functional (ability to carry out daily tasks) and wellbeing (vitality) indicators of wellness. All the three resulting subscales had good internal consistency and could be used to cluster participants into three groups. Wellness belief scores were related to gender, health status and subjective health; there were few associations with health beliefs. In conclusion, the WBS is a promising new measure of three distinct wellness beliefs, with good initial psychometric properties, which could potentially be used to better target individualised health promotion interventions. PMID- 20204928 TI - Self-efficacy moderates message-framing effects: The case of skin-cancer detection. AB - Health-promoting messages can be framed in terms of the gains associated with healthy behaviour, or the losses associated with unhealthy behaviour. Studies show inconsistent results as to which type of framing is more effective. In this study, we examined the influence of self-efficacy to perform skin self examination on the effects of gain- and loss-framed skin-cancer detection messages among 124 university students. For participants with high self-efficacy, a loss-framed message resulted in a higher intention to perform skin self examination than a gain-framed message. For participants with low self-efficacy, there were no differences in intention between the gain- and loss-framed message conditions. Our results suggest that self-efficacy levels play an important role in message-framing effects. For health communication strategies promoting the active detection of skin-cancer symptoms, messages stressing losses may be more effective than messages stressing gains, but only in persons with high self efficacy. In addition, our results suggest that health promoting messages can be framed to match recipients' self-efficacy levels. PMID- 20204929 TI - Relationship between meaning in life and intensity of smoking: do gender differences exist? AB - Little is known about the relationship between smoking and meaning in life, although the association of meaninglessness with other addictive behaviours has been widely investigated. The aim of this study is to examine whether a relationship exists between meaning in life and intensity of smoking as measured by cigarettes smoked per day. The study population was 3506 current smokers from the Hungarostudy 2002 Hungarian representative cross-sectional survey. Age, educational level, marital status, subjective financial status, household income, coffee consumption, hazardous alcohol use, general well-being, anxiety, and depressive symptomatology were included in the analyses as covariates. On the bivariate level, life meaning was associated with smoking intensity in the total sample and among women (p < 0.001), while for males, only a tendency was found (p = 0.069). In the multivariate analyses, life meaning proved to be a significant negative predictor of smoking intensity for females (p = 0.005) even after controlling for the covariates, whereas in men, meaning in life completely lost its significance (p = 0.852). In the total sample, both meaning in life (p = 0.005) and its interaction with gender (p = 0.024) related to the dependent variable. Further research is needed to confirm these explorative findings concerning the protective role of life meaning against more intense smoking among women. PMID- 20204930 TI - Making sense of being at 'high risk' of coronary heart disease within primary prevention. AB - Current National Health Service policy advocates screening to identify individuals at 'high risk' of cardio-vascular disease (CHD) in primary care. This article utilizes the work of Radley to explore how 'high risk' of CHD patients make sense of their new risk status. Results are presented here from a nested qualitative study within a quantitative randomized trial of a CHD risk intervention in primary care. 'Discovery' interviews were conducted with 'high risk' participants (n = 38, mean age = 55) two weeks after intervention and thematically analysed. In response to perceived threat, many participants sought to both 'minimize' and 'normalize' their risk status. They also reported intentions to act, particularly concerning dietary change and exercise, although less so for smoking amongst the lower socio-economic status participants. Such perceptions and intentions were contextualized within the life-course of later middle-age, so that both being at risk, and being treated for risk, were normalized as part of growing older. Social position, such as gender and SES, was also implicated. CHD risk interventions should be context-sensitive to the life course and social position of those who find themselves at 'high risk' of CHD in later middle-age. PMID- 20204931 TI - Patients' illness schemata of hypertension: the role of beliefs for the choice of treatment. AB - The aims of this study were (1) to investigate what are the illness perceptions of hypertensive patients and their relationship with beliefs about specific medicines, and (2) to identify different illness schemata and how they relate to the choice of medication. This was a cross-sectional study in which 191 Portuguese patients (59% females), with a hypertension diagnosis, aged over 18 years old, were recruited from a hospital clinic in the Lisbon Metropolitan area. The questionnaire included measures of choice of medication, beliefs about specific medicines (BMQ-Specific), illness perception (Brief-IPQ), and socio demographic information. The results indicated that the components of the illness perceptions were associated with patients' beliefs about necessity and concerns about medication. Patients seem to differ in their choice of medication (generic or brand names) according to the three illness schemata identified. Patients with more negative illness schemata were more likely to choose a brand medicine, whereas patients with a more positive perception of hypertension were more likely to choose a generic medicine. Our findings support the argument that illness perceptions and beliefs about medicines play a role in influencing patients' preferences of medicines for the treatment of hypertension. PMID- 20204932 TI - Unhealthy weight control behaviours in adolescent girls: a process model based on self-determination theory. AB - This study used self-determination theory (Deci, E.L., & Ryan, R.M. (2000). The 'what' and 'why' of goal pursuits: Human needs and the self-determination of behavior. Psychological Inquiry, 11, 227-268.) to examine predictors of body image concerns and unhealthy weight control behaviours in a sample of 350 Greek adolescent girls. A process model was tested which proposed that perceptions of parental autonomy support and two life goals (health and image) would predict adolescents' degree of satisfaction of their basic psychological needs. In turn, psychological need satisfaction was hypothesised to negatively predict body image concerns (i.e. drive for thinness and body dissatisfaction) and, indirectly, unhealthy weight control behaviours. The predictions of the model were largely supported indicating that parental autonomy support and adaptive life goals can indirectly impact upon the extent to which female adolescents engage in unhealthy weight control behaviours via facilitating the latter's psychological need satisfaction. PMID- 20204933 TI - Understanding the experience of ambivalence in anorexia nervosa: the maintainer's perspective. AB - People with anorexia often feel ambivalent about whether they wish to maintain it or recover from it. One place where individuals can communicate their experiences of wanting to maintain their anorexia is through pro-anorexia websites. This study investigated the experiences and understandings of those who wish to maintain their anorexia and looked at how these understandings may affect their treatment experiences. Data were collected online and analysed using interpretative phenomenological analysis (IPA). Anorexia denoted meanings of a 'tool', an 'entity' and a 'disease'. Participants felt ambivalent about whether their anorexia gave them control or controlled them, whether it played a positive or negative role and whether they wished to maintain their behaviours or recover. Participants also discussed barriers to recovery. Theoretical and treatment implications are discussed. PMID- 20204934 TI - Mechanisms of health: Education and health-related behaviours partially mediate the relationship between conscientiousness and self-reported physical health. AB - The personality trait of conscientiousness is an important predictor of health and longevity. The present research examined how conscientiousness, in combination with educational attainment and health-related behaviours, predicted self-reported physical health across adulthood. These relations were investigated in two studies, one using a large, representative sample of Illinois residents (N = 617) and the other using a community sample with a multi-method assessment of conscientiousness (N = 274). Across both studies, structural path analyses provided evidence for a model wherein conscientiousness predicted health, in part, through its relationship to both educational attainment and health-related behaviours. The findings suggest conscientiousness predicts health through a diverse set of mechanisms including, but not limited to, educational attainment and health-related behaviours. PMID- 20204935 TI - Intention versus identification as determinants of adolescents' health behaviours: evidence and correlates. AB - The present study used a within-participants design to (a) assess the predictive validity of prototype identification versus intention for adolescents' health behaviours and (b) examine whether control of health behaviour by intention relative to identification is associated with key individual difference variables. Participants were school children (N = 136) who completed measures of intention, perceived behavioural control and prototype identification for 14 health-related behaviours at Time 1, and reported their behaviour 2 weeks later (Time 2). A hierarchical regression showed that prototype identification and intention exhibited similar predictive validity in the prediction of adolescents' health behaviour. Importantly, identification contributed an additional 6% to the variance in behaviour, after controlling for intention and perceived behavioural control from the theory of planned behaviour [TPB: Ajzen, I. ( 1991 ). The theory of planned behavior. Organizational Behavior and Human Decision Processes, 50, 179-211.]. Additional analyses showed that greater social comparison tendencies, lower agreeableness, greater intellect and less emotional stability were all related to greater control of behaviour by prototype identification. The theoretical and practical implications of these findings are discussed. PMID- 20204936 TI - Adherence to pharmacological treatment of non-malignant chronic pain: the role of illness perceptions and medication beliefs. AB - The objective was to identify the degree to which illness perceptions and medication beliefs explain variations in reported adherence to medication prescribed for the treatment of non-malignant chronic pain and to test the applicability of an extended version of the self-regulatory model to the chronic pain population. A cross-sectional design included 217 clinic patients completing validated questionnaires assessing their illness perceptions, medication beliefs and reported adherence to medication. Perceptions of illness (pain) as chronic, uncontrollable and unremitting were associated with greater adherence, fewer medication concerns and a belief that treatment was necessary. Structural equation modelling supports an extended SRM for chronic pain. It suggests that patients holding perceptions of serious consequences of pain and high emotion levels have more concerns about medication and are less adherent. Perceptions of serious illness consequences are also associated with stronger beliefs about the necessity of medicines and greater adherence. Beliefs about illness and medication are associated with adherence to treatment in chronic pain and this can be explained by an extended SRM. Results are preliminary and require replication. Further studies should explore the role that emotion has on coping strategies in chronic pain. Interventions should focus on altering unhelpful beliefs that reduce adherence. PMID- 20204937 TI - What is an adequate sample size? Operationalising data saturation for theory based interview studies. AB - In interview studies, sample size is often justified by interviewing participants until reaching 'data saturation'. However, there is no agreed method of establishing this. We propose principles for deciding saturation in theory-based interview studies (where conceptual categories are pre-established by existing theory). First, specify a minimum sample size for initial analysis (initial analysis sample). Second, specify how many more interviews will be conducted without new ideas emerging (stopping criterion). We demonstrate these principles in two studies, based on the theory of planned behaviour, designed to identify three belief categories (Behavioural, Normative and Control), using an initial analysis sample of 10 and stopping criterion of 3. Study 1 (retrospective analysis of existing data) identified 84 shared beliefs of 14 general medical practitioners about managing patients with sore throat without prescribing antibiotics. The criterion for saturation was achieved for Normative beliefs but not for other beliefs or studywise saturation. In Study 2 (prospective analysis), 17 relatives of people with Paget's disease of the bone reported 44 shared beliefs about taking genetic testing. Studywise data saturation was achieved at interview 17. We propose specification of these principles for reporting data saturation in theory-based interview studies. The principles may be adaptable for other types of studies. PMID- 20204938 TI - Living with type 1 diabetes: a by-person qualitative exploration. AB - Type 1 diabetes is a chronic condition which places enormous demands on the individual diabetic. A strict care routine is necessitated, yet even the most controlled and disciplined diabetic is likely to experience associated health problems and automatically faces a reduced life expectancy. The current study explores the psychological repercussions of this situation via a small scale qualitative study which focuses on the very different viewpoints and experiences of four adults living with Type 1 diabetes. A new and original form of by-person (or by-case) qualitative analysis is employed in order to capture, in a rich and holistic fashion, each participant's current relationship with their condition, their experience of living and dealing with diabetes and the ways in which diabetes is integrated within their lives and identities. The findings have implications for, and are discussed in relation to, issues of control, regimen adherence, and what it means to be a 'good' or 'successful' diabetic. The conclusion is drawn that the satisfaction of personal goals and a focus on psychological as well as physical health may be very important if positive quality of life outcomes are to be attained in the context of Type 1 diabetes. PMID- 20204939 TI - From theory to practice: An explorative study into the instrumentality and specificity of implementation intentions. AB - OBJECTIVE: The present study explores the behavioural impact of instrumentality and specificity of implementation intentions. METHOD: At baseline, 764 participants in a smoking cessation contest were asked to formulate three implementation intentions on how they planned to cope with difficult situations. Two independent researchers evaluated all formulated plans and rated them according to their instrumentality (instrumental and non-instrumental) and specificity (non-specific, medium and highly specific). Point prevalence and continuous smoking abstinence rates were measured 7 months after baseline. RESULTS: One in four participants (23%) made at least one non-instrumental implementation intention. On average, participants made medium to highly specific plans. The mere instrumentality of plans did not significantly affect smoking abstinence. Plan specificity positively predicted point prevalence abstinence; medium to highly specific planning resulted in higher abstinence rates than less specific planning. Smoking abstinence rates did not differ between respondents with medium and highly specific planning. Women, higher educated participants, and experienced quitters were more likely to formulate instrumental implementation intentions. Women and highly motivated participants were more specific in their planning. CONCLUSION: By encouraging participants to furnish goal-directed actions with sufficient detail the efficacy of implementation intention formation can be increased. Implications for future studies and interventions are discussed. PMID- 20204940 TI - Young mothers' decisions to use marijuana: a test of an expanded Theory of Planned Behaviour. AB - The current study examines the Theory of Planned Behaviour's (TPB) ability to predict marijuana use among young women who experienced a premarital pregnancy before the age of 18 years, using longitudinal data. The validity of the TPB assumption that all other variables work through TPB constructs is also tested. Indicators of four constructs that have been shown in the literature to be predictive of marijuana use-persistent environmental adversity, emotional distress, adolescent marijuana use and drug use in the social network-were tested as predictors of attitudes, norms and self-efficacy, in a structural equation modelling framework. All paths from distal predictors were through the mediating TPB constructs, in accordance with the tenets of the model. Implications of these findings for the TPB model and for understanding factors that lead to marijuana use are discussed. PMID- 20204941 TI - Cardiac patient-spouse dissimilarities in illness perception: Associations with patient self-rated health and coping strategies. AB - The study examined the illness perception dissimilarities between chronic cardiac patients and their spouses, as well as the associations of perception dissimilarities with patients' overall self-rated health (SRH) and illness related coping strategies. Seventy-three patients (65 males, 8 females) with an old myocardial infarction and subsequent cardiovascular problems, and their spouses completed the Revised Illness Perceptions Questionnaire. Patients also completed a coping measure (the Coping with Health Injuries and Problems Scale) and a question regarding SRH. Significant differences, with spouses scoring higher than patients, were found in perceptions regarding illness chronicity, personal control and the emotional impact of the illness. The correlations of dissimilarity scores to SRH and coping were sporadic and weak. Additionally, after controlling for patients' own perceptions, the effects of dissimilarity scores almost disappeared. However, when three different groups were constructed reflecting whether both partners scored high, low, or in an opposing way on each IPQ-R subscale, the overall matching in several illness perceptions was associated with certain coping strategies, even after controlling for the effects of the patients' own perceptions. With respect to SRH, no significant effects were found. PMID- 20204942 TI - Healthy masculinities? How ostensibly healthy men talk about lifestyle, health and gender. AB - Research on men's health has predominantly focussed on links between 'hegemonic' masculinities (e.g. perceived invulnerability) and health-averse practices (e.g. high fat diets). However, it seems reasonable to assume that not all men adopt conventional 'unhealthy' masculine positions, so it is important to study those men who are engaged in healthy practices to see how masculinity is constructed in this context. The research reported here derives from an interview study with men categorised as pursuing health-promoting lifestyles (regular exercise, no/low alcohol intake etc.). The focus is on how these apparently 'healthy' men (n = 10) account for their health-promoting practices, with a particular focus on the role of masculinities in framing these practices. Following intensive analysis of the interview transcripts drawing upon elements of discourse analysis, we identify a variety of accounts used by the men to frame their health-promoting practices. For example, all the men disavowed a direct interest in talking/thinking about health, construed as excessive and feminine, and instead justified their practices variously in terms of action-orientation, sporting targets, appearance concerns and being autonomous. These findings are discussed with respect to the relationships between masculinities and health, and implications for health promotion work with men are discussed. PMID- 20204943 TI - Self-regulation of commitment to reduce cigarette consumption: mental contrasting of future with reality. AB - The model of fantasy realisation (Oettingen, 2000) specifies mental contrasting of a positive future with negative reality as a strategy that creates strong goal commitments. We propose that fantasies about a positive and negative future produce strong goal commitments when contrasted with the respective reality. The present study supports this hypothesis in the area of reducing cigarette consumption. Mental contrasting of a positive future with negative reality as well as mental contrasting of a negative future with positive reality led to taking immediate action when participants had high expectations of success. Results indicate that both fantasies about a positive future and a negative future can be used to commit to goals that benefit health and prevent disease. PMID- 20204944 TI - How benefits of expressive writing vary as a function of writing instructions, ethnicity and ambivalence over emotional expression. AB - Written emotional disclosure has been reported to confer a variety of benefits on physical and psychological well-being. However, variable findings suggest that outcomes may vary systematically as a function of specific parameters of the experimental design. This study aims to investigate the unique and combined effects of disclosure instructions focusing on emotional expression and instructions facilitating cognitive reappraisal and to examine how ambivalence over emotional expression and ethnicity moderate the effects of these writing instructions. Seventy-one Asian and 59 Caucasian undergraduates (N = 130) with at least minimal physical or depressive symptoms were randomly assigned to one of the four writing conditions: emotional disclosure (ED), cognitive reappraisal (COG), the combination of ED and COG, or a control condition. Self-reported physical symptoms, positive affect (PA) and negative affect were assessed at baseline and three follow-ups spanning 4 months. Mixed linear models revealed that COG writing reduced physical symptoms, ED buffered a decrease in PA over time, and the combination of ED and COG (i.e. self-regulation; SR) was most effective. Asians and highly ambivalent participants benefited most from expressive writing. Findings contribute to the development of a SR moderator model and carry implications for designing expressive disclosure studies, particularly for ethnic minorities. PMID- 20204945 TI - Enhanced counselling for women undergoing BRCA1/2 testing: Impact on knowledge and psychological distress-results from a randomised clinical trial. AB - This randomised controlled trial evaluated the impact of an enhanced counselling (EC) intervention on knowledge about the heritability of breast and ovarian cancer and distress, as a function of BRCA test result, among high-risk women. Before deciding about whether or not to undergo genetic testing, participants were randomly assigned to the EC intervention (N = 69), designed to promote cognitive and affective processing of cancer risk information (following the standard individualised counselling session), or to the control condition (N = 65), which involved standard individualised counselling followed by a general health information session to control for time and attention. Women in the EC group exhibited greater knowledge than women in the control group, 1 week after the intervention. Further, at the affective level, the intervention was found to be the most beneficial for women testing positive: specifically 1 week after test result disclosure, women in the intervention group who tested positive experienced lower levels of distress than women in the control group who tested positive. The findings suggest that the design of counselling aids should include a component that explicitly activates the individual's cognitive-affective processing system. PMID- 20204946 TI - Lifestyle changes are related to reductions in depression in persons with elevated coronary risk factors. AB - This observational study investigates whether persons with elevated coronary risk factors (CRFs > 3 and/or diabetes) and depression [i.e., >= 16 on the Center for Epidemiological Scale - Depression (CES-D)] can make changes in health behaviours over 3 months and improve depressive symptoms and other CRFs. Analyses were based on data from 310 men and 687 women enrolled in the high-risk arm of the Multisite Cardiac Lifestyle Intervention Program, targeting diet (10% fat), exercise (3 h per week) and stress management (7 h per week). As expected, at study entry, depressed persons had a more adverse medical status, consumed more dietary fat and practiced less stress management than non-depressed persons. To examine 3 month changes, participants were grouped into (1) depressed persons who became non-depressed (CES-D <= 16, n = 248; 73%), (2) persons who remained or became depressed (CES-D > 16, n = 76) and (3) non-depressed persons who remained non depressed (n = 597). All persons, regardless of group, met program goals. The greatest improvements (i.e., diet, exercise, perceived stress, hostility and mental health) were observed in Group 1 relative to Groups 2 and 3, which did not differ from each other. Comprehensive lifestyle changes appear to be feasible and beneficial for initially depressed persons with elevated CRFs. PMID- 20204947 TI - Perceived autonomy and self-esteem in Dutch dialysis patients: the importance of illness and treatment perceptions. AB - Compared to healthy people, end-stage renal disease (ESRD) patients participate less in paid jobs and social activities. This study explored the perceived autonomy, state self-esteem and labour participation in ESRD patients on dialysis, and the role illness and treatment perceptions play in these concepts. Patients completed questionnaires at home or in the dialysis centre (N = 166). Data were analysed using bivariate and multivariate analyses. Labour participation among dialysis patients was low, the average autonomy levels were only moderate, and the average self-esteem level was rather high. On the whole, positive illness and treatment perceptions were associated with higher autonomy and self-esteem, but not with labour participation. Multiple regression analyses demonstrated that illness and treatment perceptions explained 18 to 27% of the variance in autonomy and self-esteem. Perceptions of personal control, less impact of the illness and treatment, and less concern were important predictors. Our results indicate that dialysis patients' beliefs about their illness and treatment play an important role in their perceived autonomy and self-esteem. Stimulating positive (realistic) beliefs and altering maladaptive beliefs might contribute to a greater sense of autonomy and self-esteem, and to social participation in general. Interventions focusing on these beliefs may assist patients to adjust to ESRD. PMID- 20204948 TI - The adaptive effect of personal control when facing breast cancer: cognitive and behavioural mediators. AB - This prospective study examines the cognitive and behavioural mediators of the relation between personal control and the initial response to a breast cancer diagnosis as well as subsequent psychological adjustment. A total of 143 patients participated immediately after diagnosis (T1), after surgery (T2) and 2 months after the end of treatment (T3), of whom 92 also completed a questionnaire pre diagnosis (T0). The buffering effect of personal control on psychological distress shortly after diagnosis was mediated by cancer-specific cognitions, i.e. threat appraisal and coping self-efficacy. Moreover, a strong sense of personal control predicted lower levels of anxiety 2 months after the end of treatment, but was unrelated to distress at T3. The adaptive effect on anxiety was mediated by threat appraisal and active engagement in social life after surgery, but not by active patient participation or coping self-efficacy. These results confirm and explain the adaptive effect of control. Apparently, women with a low sense of control appraise cancer and their personal coping skills more negatively, which makes them vulnerable to distress in response to diagnosis. Furthermore, women with a strong sense of control might regulate anxiety by remaining engaged in social life. PMID- 20204949 TI - The role of attitudes towards the targets of behaviour in predicting and informing prenatal testing choices. AB - Research considering the role of attitudes in prenatal testing choices has commonly focused on the relationship between the attitude towards undergoing testing and actual testing behaviour. In contrast, this study focused on the relationship between testing behaviour and attitudes towards the targets of the behaviour (in this case people with Down syndrome (DS) and having a baby with DS). A cross-sectional, prospective survey of 197 pregnant women measured attitudes towards the targets of prenatal testing along with intentions to use screening and diagnostic testing, and the termination of an affected pregnancy. Screening uptake was established via patient records. Although attitudes towards DS and having a baby with DS were significantly associated with screening uptake and testing and termination intentions, unfavourable attitudes were better than favourable ones at predicting these outcomes. For example, in the quartile of women with the 'most favourable' attitude towards people with DS 67% used screening although only 8% said they would terminate an affected pregnancy. Qualitative data suggested that not all women considered personal attitudes towards DS to be relevant to their screening decisions. This finding has implications for the way in which informed choice is currently understood and measured in the prenatal testing context. PMID- 20204950 TI - Psychological adjustment to gynaecological cancer: patients' illness representations, coping strategies and mood disturbance. AB - This study examined associations between illness representation dimensions specified by the self-regulation model, coping and mood in recently diagnosed gynaecological cancer patients. Participants were 61 patients recruited from a specialist outpatient gynaecology clinic. Patients completed a survey measuring their cognitive illness representations (IPQ-R), coping strategies (COPE) and mood (POMS-SF). Consistent with research into other illnesses, the study found theoretically congruent cross-sectional associations between illness representations and mood disturbance. Support was found for a possible path whereby higher denial and avoidant coping might mediate the relationships between cyclical timeline and illness coherence representations and more negative mood. There were no mediational relationships for other coping strategies. Mediation of the relationship between illness representations and mood by avoidant coping has important theoretical and practical implications. These are discussed, as are direct relationships between illness representations and mood. PMID- 20204951 TI - Application of the limited strength model of self-regulation to understanding exercise effort, planning and adherence. AB - The limited strength model posits that self-regulatory strength is a finite, renewable resource that is drained when people attempt to regulate their emotions, thoughts or behaviours. The purpose of this study was to determine whether self-regulatory depletion can explain lapses in exercise effort, planning and adherence. In a lab-based experiment, participants exposed to a self regulatory depletion manipulation generated lower levels of work during a 10 min bicycling task, and planned to exert less effort during an upcoming exercise bout, compared with control participants. The magnitude of reduction in planned exercise effort predicted exercise adherence over a subsequent 8-week period. Together, these results suggest that self-regulatory depletion can influence exercise effort, planning and decision-making and that the depletion of self regulatory resources can explain episodes of exercise non-adherence both in the lab and in everyday life. PMID- 20204952 TI - Predictors of physical activity, healthy eating and being smoke-free in teens: a theory of planned behaviour approach. AB - This paper elicited context specific underlying beliefs for physical activity, fruit and vegetable consumption and smoke-free behaviour from the Theory of Planned Behaviour (TPB), and then determined whether the TPB explained significant variation in intentions and behaviour over a 1 month period in a sample of grade 7-9 (age 12-16 years) adolescents. Eighteen individual interviews and one focus group were used to elicit student beliefs. Analyses of this data produced behavioural, normative and control beliefs which were put into a TPB questionnaire completed by 183 students at time 1 and time 2. The Path analyses from the main study showed that the attitude/intention relationship was moderately large for fruit and vegetable consumption and small to moderate for being smoke free. Perceived behavioural control had a large effect on being smoke free and a moderately large effect for fruit and vegetable consumption and physical activity. Intention had a large direct effect on all three behaviours. Common (e.g. feel better, more energy) and behaviour-specific (e.g., prevent yellow fingers, control my weight) beliefs emerged across the three health behaviours. These novel findings, to the adolescent population, support the importance of specific attention being given to each of the behaviours in future multi-behavioural interventions. PMID- 20204953 TI - Adoption of community-based cardiac rehabilitation programs and physical activity following phase III cardiac rehabilitation in Scotland: a prospective and predictive study. AB - Little is known about levels of physical activity and attendance at phase IV community-based Cardiac Rehabilitation (CR) programs following completion of exercise-focussed, hospital-based phase III CR. This study aims to test, compare and combine the predictive utility of the Common-Sense Self-Regulation Model (CS SRM) and the extended Theory of Planned Behaviour (TPB) with action planning for two rehabilitation behaviours: physical activity and phase IV CR attendance. Individuals diagnosed with coronary heart disease (n = 103) completed baseline measures of illness perceptions, intentions, perceived behavioural control (PBC), action planning and past physical activity in the last week of a phase III CR program, and 95 participants completed follow-up measures of physical activity and attended phase IV CR (objectively confirmed) 2 months later. Only one predictor (PBC/cyclical timeline) significantly predicted levels and change of physical activity. While illness perceptions were not predictive of phase IV CR attendance, the extended TPB model showed good predictive power with action planning and intention as the most powerful predictors. Amongst participants who planned when and where to attend phase IV CR at the end of phase III rehabilitation, 65.9% subsequently attended a phase IV CR program compared to only 18.5% of those who had not made a plan. This study adds to our understanding of cardiac rehabilitation behaviour after completion of health service delivered programs. Comparing theoretical models and rehabilitation behaviours contributes to the development of behaviour theory. PMID- 20204954 TI - The role of prior quitting experience in the prediction of smoking cessation. AB - AIMS: In the Transtheoretical Model (TTM), the preparation stage (as applied to smoking cessation) is defined as planning to quit in the next 30 days plus having quit for at least 24 h in the last year. This study examined the value of prior quitting experience as a stage classification criterion by investigating whether prediction of making a quit attempt differed as a function of prior quitting experience. PARTICIPANTS: One thousand and forty-six participants, all planning to quit in the next 30 days, in a randomised trial of the effectiveness of a telephone counselling and computer-generated tailored advice intervention were followed up at 3 months. FINDINGS: A multivariate predictive model had markedly greater capacity to predict making a quit attempt among participants with prior quitting experience (as defined in several different ways), compared to analyses of the overall sample. A previous attempt of 24 h in the previous month was associated with the greatest difference in prediction. A quit attempt in the previous year (the TTM definition) did not discriminate. CONCLUSIONS: Recent prior quitting experience moderated the predictive capacity of some variables that influence smoking cessation. The findings provide some support for a stage model of smoking cessation but not its operationalisation by the TTM. PMID- 20204955 TI - The acceptability of computerised cognitive behavioural therapy for the treatment of depression in people with chronic physical disease: a qualitative study of people with multiple sclerosis. AB - BACKGROUND: People with chronic physical conditions are at elevated risk of depression. Due to a shortage of Cognitive Behavioural Therapy (CBT) practitioners, computerised CBT (CCBT) is recommended for people with mild to moderate depression. We assessed the applicability of CCBT for the treatment of depression in people with multiple sclerosis (MS). METHODS: Depth interviews with 17 people with MS and mild to moderate depression who used one of the two CCBT packages for either eight (Beating the Blues; n = 8) or five (MoodGym; n = 9) weekly sessions were analysed using 'Framework'. RESULTS: Participants found CCBT use burdensome due to their physical symptoms. In addition to perpetuating social isolation, the lack of human input meant some participants were unable to define problems, set goals or distinguish between events, thoughts and beliefs as required. CCBT did not legitimise their grief over losses concomitant with their MS. They characterised depression symptom inventories as contaminated by somatic symptoms of their MS. One CCBT package (MoodGym) was perceived as using inappropriate case material for people with the symptoms of MS. CONCLUSIONS: It is likely that generic CCBT packages for the treatment of depression will need to be adapted for people with chronic physical conditions to maximise their potential for health benefit. PMID- 20204956 TI - Experiences of and perspectives on genetic testing for breast/ovarian cancer in and outside of the customary clinical setting. AB - Recently, genetic testing has begun to move from the customary clinical setting (with restrictive entry criteria) into the offices of GPs and the homes of consumers (Williams-Jones, 2003). This research aimed to look at participants' experiences of genetic testing for hereditary breast and ovarian cancer in a clinical environment, and subsequently ascertain potential psychosocial issues associated with genetic testing outside the customary clinical setting. Semi structured interviews were conducted with eight female participants who had undergone genetic testing within a clinical setting. Transcripts were analysed using Interpretative Phenomenological Analysis. Three super-ordinate themes emerged. Participants' 'battle for control' reflected a perceived loss of control due to their cancer experiences. The 'psychological impact of having experienced/witnessed cancer' highlighted the psychological burden that many participants and their family members lived with. Finally, 'scepticism towards testing outside the clinical setting' was expressed by all participants; they were suspicious of this method of testing. These themes highlighted the potential psychological strain of undergoing genetic testing outside the clinical setting. They also highlighted the wariness with which participants approached the possible introduction of testing outside the customary clinical setting. Psychosocial implications of genetic testing outside the clinical setting were discussed in light of these findings. PMID- 20204957 TI - Considering adult living donor liver transplantation: a qualitative study of patients and their potential donors. AB - In April 2006, the Scottish Liver Transplant Unit became the first NHS transplant unit in the UK to offer adult Living Donor Liver Transplantation (LDLT). However, within the first 21 months of its availability, no patients on the transplant waiting list had pursued this treatment option. A qualitative interview study was devised to elicit the views of patients and their families with regards to LDLT. Interviews were conducted with 21 patients and 20 potential donors. The main reason why recipients did not pursue LDLT was their perception of risk to their donor. The anticipated feelings of guilt if the donor was harmed resulted in LDLT being rejected. However, despite this, many recipients would possibly consider LDLT as a 'last option'. For donors, considering becoming a donor was an automatic response, driven by their need to help their loved one to survive. However, consideration of the effects of donating upon their own immediate family often superseded their wish to donate. Whilst donors need to be given time to consider the implications of LDLT upon their own lives, it is essential that recipients understand that LDLT cannot be a last option, in order to allow them to reconsider their options realistically. PMID- 20204958 TI - Autonomy and reactions to health-risk information. AB - It has been suggested that autonomy promotes enhanced reflection on novel information and reduces defensive or biased information processing. This study investigated how autonomy affected people's reactions to known versus novel health-risk information in relation to three behaviours: sun exposure, alcohol consumption and salt intake. Participants (N=321) completed a measure of autonomy, read either known or novel health-risk information and reported their relative autonomous motivation, attitudes, perceived behavioural control, subjective norm and intentions towards reducing the health-risk behaviour concerned. In line with our hypotheses, the results showed that higher autonomy participants reported greater relative autonomous motivation towards reducing health-risk behaviours than did lower autonomy participants; this effect was mediated by perceptions of the information as less freedom-threatening. The expected interaction between Autonomy and Information Type was not observed. The results indicate that autonomy is associated with greater relative autonomous motivation to engage in health behaviours, and that autonomous motivation may subsequently influence intentions to reduce health-risk behaviour following exposure to health-risk information. PMID- 20204959 TI - The impact of intolerance of uncertainty on anxiety after receiving an informational intervention about HPV: a randomised controlled study. AB - This study examined the impact of intolerance of uncertainty (IU) and an informational intervention about human papillomavirus (HPV) infection on perceived uncertainty about one's HPV testing status (referred to as 'HPV uncertainty') and anxiety. IU, HPV uncertainty and other pre-intervention measures were assessed through mailed questionnaires. Participants were then randomly assigned to receive either a long (N = 125) or short (N = 124) HPV specific information pamphlet or a long (N = 131) or short (N = 115) control pamphlet about cancer prevention. Participants subsequently completed measures of HPV uncertainty and anxiety. Providing a lot of HPV information increased HPV uncertainty more than providing little HPV information and cancer prevention information. Among women who received the long HPV or the short control pamphlet, those with higher IU were more anxious than those with lower IU. Women with higher IU are more likely to seek HPV information, but they may also be at risk for experiencing higher anxiety because factual uncertainties about HPV cannot be resolved through the provision of more information. PMID- 20204960 TI - The impact of assuming the primary caregiver role following traumatic spinal cord injury: An interpretative phenomenological analysis of the spouse's experience. AB - This study aimed to explore the lived experience of assuming the primary caregiver role in a group of spouses of individuals living with a traumatic spinal cord injury (SCI) (injuries ranged from paraplegia to quadriplegia). Individual in-depth interviews were conducted with 11 participants who were both the spouse and primary caregiver of an individual with a SCI; of these, 10 were female and 1 was male. All interviews were transcribed verbatim and were subjected to interpretative phenomenological analysis (IPA). Here we present three inter-related master themes: 'The emotional impact of SCI'; 'Post-injury shift in relationship dynamics' and 'Impact of caregiving on identity'. Regarding the emotional impact of spinal injury, participants reported an almost instantaneous sense of loss, emptiness and grief during the injured person's rehabilitative period and feelings of anxiety were reported in anticipation of their return to the family home. A distinct change in role from spouse and lover to care provider was reported and this ultimately contributed to relationship change and a loss of former identity. The findings are discussed in relation to extant caregiver literature and recommendations for future caregiver support are highlighted. PMID- 20204961 TI - Negative affective pictures can elicit physical symptoms in high habitual symptom reporters. AB - The present study aimed to explore the role of a brief negative affective state on symptom reporting. Non-clinical high (n = 24) and low (n = 24) habitual symptom reporters viewed four picture series (160 s per series) varying in affective content: neutral, general positive, general negative and symptom related. Participants rated each picture series on valence, dominance and arousal, and reported their affective state and somatic symptoms experienced during the series. Results showed that all participants reported higher levels of negative affect during the negative and symptom-related picture series compared with the positive and neutral picture series. Only high habitual symptom reporters also reported more bodily symptoms after viewing the negative and symptom-related pictures. The findings allude to a learned association between negative emotional states and symptom reporting in high habitual symptom reporters. PMID- 20204962 TI - Racial disparities in smoking knowledge among current smokers: data from the health information national trends surveys. AB - Although African-Americans (Blacks) smoke fewer cigarettes per day than European Americans (Whites), there is ample evidence that Blacks are more susceptible to smoking-related health consequences. A variety of behavioural, social and biological factors have been linked to this increased risk. There has been little research, however, on racial differences in smoking-related knowledge and perceived risk of lung cancer. The primary goal of the current study was to evaluate beliefs and knowledge that contribute to race disparities in lung cancer risk among current smokers. Data from two separate nationally representative surveys (the Health Information National Trends surveys 2003 and 2005) were analysed. Logistic and hierarchical regressions were conducted; gender, age, education level, annual household income and amount of smoking were included as covariates. In both studies, Black smokers were significantly more likely to endorse inaccurate statements than were White smokers, and did not estimate their lung cancer risk to be significantly higher than Whites. Results highlight an important racial disparity in public health knowledge among current smokers. PMID- 20204963 TI - Planning bridges the intention-behaviour gap: age makes a difference and strategy use explains why. AB - OBJECTIVE: This study examines age-differential association patterns between intentions, planning and physical activity in young and middle-aged individuals. The effectiveness of planning to bridge the intention-behaviour gap is assumed to increase with advancing age. We explore the use of behaviour change strategies that include selection, optimisation and compensation (SOC) as underlying mechanisms for age differences. METHODS: In N = 265 employees of a national railway company (aged 19-64 years), intentions, planning, SOC strategy use and physical activity were assessed at baseline (Time 1) and again 1 month later (Time 2). Hypotheses were tested in two different path models. RESULTS: Age moderates the extent to which planning mediates the intention-behaviour relation due to an increasing strength of the planning-behaviour link. As a possible psychological mechanism for these age differences, we identified SOC strategy use as a mediator of the age by planning interaction effect on physical activity. CONCLUSION: These findings suggest differential mechanisms in behaviour regulation in young and middle-aged individuals. PMID- 20204964 TI - Explaining adolescents' cigarette smoking: a comparison of four modes of action control and test of the role of self-regulatory mode. AB - The present study compared how well four modes of action control (intentional, habitual, reactive and stereotype activation) explain adolescents' cigarette smoking, and examined whether individual differences in self-regulation (locomotion and assessment tendencies; Higgins, Kruglanski, & Pierro, 2003) moderate the behavioural impact of the respective modes. Findings from a prospective questionnaire survey showed that (a) willingness, prototype perceptions and past behaviour--but not intention--predicted smoking behaviour, and explained 63% of the variance, and (b) the assessment mode of self-regulation moderated the past behaviour-future behaviour relation such that past behaviour had less impact on future smoking behaviour at high levels of assessment. These findings suggest that adolescents' smoking is controlled by stereotype activation, habitual and reactive processes. Implications of the results for designing effective adolescent smoking cessation programmes are considered. PMID- 20204965 TI - Psychological distress in rheumatoid arthritis patients: an evaluation within the conservation of resources theory. AB - Rheumatoid arthritis (RA) is a chronic disease, which can lead to considerable psychological distress. The present study evaluated anxiety and depression symptoms for this chronic and painful illness within the framework of the conservation of resources (COR) theory. Coping strategies, coping self-efficacy, religiousness and social support are very important personal resources, which have been found to protect individuals from psychological distress. The aim of the present study was to examine the predictive values of socio-demographic and illness-related variables, perceived social support, ways of coping, religiousness, arthritis self-efficacy and resource loss for psychological distress in a sample of 117 RA patients from Turkey, a secular, Islamic, non western developing country. The results revealed that RA patients experience considerable anxiety and depressive symptoms. The results of the regression analysis showed that gender, helplessness coping and resource loss are significant predictors of anxiety, whereas arthritis self-efficacy and resource loss are significant predictors of depression. Resource loss appeared as an important predictor for both anxiety and depression. This finding was consistent with the COR theory. The clinical implications of these findings are discussed. PMID- 20204966 TI - Evidence that boosters augment the long-term impact of implementation intentions on fruit and vegetable intake. AB - The present study tests the efficacy of a single implementation intention to increase intake over a 6-month period, and investigates whether deploying a second implementation intention at 3 months can sustain the long-term impact, compared with passive and active control groups. Participants (N = 650) completed single-item and FFQ measures of behaviour and motivation at baseline before being randomised to one of six conditions in a between-persons design. Intention to treat analysis revealed that for the single-item measure: (1) a single implementation intention is an effective means of initiating fruit and vegetable increase over a 3-month period, but this effect is not sustained over 6 months; (2) administering a second implementation intention at 3 months was successful in increasing intake over 6 months, and acted as a booster on the initial impact; and (3) neither the passive nor active control condition had any impact on behaviour. However, no effects of the manipulations on fruit and vegetable intake were found when behaviour was assessed by the FFQ measure. Secondary analyses showed that reported increases in intake were not related to demand characteristics. The findings are discussed in relation to their conceptual and practical value. PMID- 20204967 TI - Moving beyond the function of the health behaviour: the effect of message frame on behavioural decision-making. AB - Health messages that provide gain- or loss-framed arguments have a differential impact on behavioural decision-making (Rothman & Salovey, 1997). Typically, gain framed messages more effectively promote preventive health behaviours, which maintain health and minimise the risk of a health problem, whereas loss-framed messages more effectively promote detection behaviours, which involve the risk of finding a health problem. Two experiments tested the thesis that the risk implications of the behaviour are an important determinant of the persuasive impact of gain- and loss-framed appeals. Results revealed that when the risk associated with a health behaviour (either a prevention behaviour in Experiment 1 or a detection behaviour in Experiment 2) was low, participants responded more favourably to gain-framed messages. However, when the risk associated with the health behaviour (either prevention or detection) was high, participants responded more favourably to loss-framed messages. Discussion focuses on the importance of taking into account how individuals construe a behaviour when constructing framed appeals. PMID- 20204968 TI - Psychosocial and behavioural contributors to health: age-related increases in physical disability are reduced by physical fitness. AB - The aging process is associated with increased risk for disease which can cause physical and economic burden for older adults. In a national longitudinal sample of 3910 participants aged 24-75 years (55% women), we examined psychosocial and behavioural factors associated with physical health in adulthood. With hierarchical regression analyses controlling for Time 1 values of the dependent variable and demographic characteristics, we found that participants reporting better social relations, a higher sense of control, a smaller waist circumference and greater physical activity at Time 1 reported better self-rated physical health (Adj. R(2) = 0.33, F (11, 3661) = 164.66, p < 0.001) and less physical disability (Adj. R(2) = 0.44, F (13, 3659) = 226.25, p < 0.001) 9 years later than their counterparts reported. Furthermore, significant interactions showed that smaller waist circumference and greater physical activity at Time 1 attenuated age-related increases in physical disability. Beneficial effects of physical fitness are considered within the context of lifespan theories of health, and implications for interventions are discussed. PMID- 20204969 TI - The nature of youth care tasks in families experiencing chronic illness/disability: development of the Youth Activities of Caregiving Scale (YACS). AB - The purpose of this study was to develop an empirically derived multi-item scale of care tasks performed by young people in the context of family illness/disability: the Youth Activities of Caregiving Scale (YACS). A total of 135 youngsters aged 10-24 years with an ill/disabled family member completed questionnaires. Factor analyses performed on the YACS yielded four factors, instrumental care, social/emotional care, personal/intimate care and domestic/household care, accounting for 57.78% of the variance. The internal reliabilities of all factors ranged from 0.74 to 0.92. Higher scores on the YACS related to higher youth age and several caregiving context variables (i.e. household type [single or dual-parent household], relationship with care recipient and perceived choice in caregiving). Higher scores on the YACS also related to care-recipient illness/disability variables (onset, functional impairment, prognosis, predictability and illness/disability type). Strong positive correlations between the YACS and a conceptually related measure of young caregiving experiences provided good convergent validity data. Criterion validity was established with evidence that the YACS predicted youth adjustment in the domains of health and prosocial behaviour. PMID- 20204970 TI - A biopsychosocial model for depressive symptoms following acute coronary syndromes. AB - A partial latent structural regression analysis was used to evaluate the influence of perceived stress and coping resources on depression following acute coronary syndromes (ACS) in a sample of 113 participants (25 females and 88 males with a mean age of 57.61 years (SD = 12.63). Out of them, 55 participants were Australian born and 48 were born elsewhere, with 53 of the patients scoring in the mild to high depression range on the Beck Depression Inventory and the Cardiac Depression Scale. Perceived stress and coping resources, after controlling for age and smoking explained 89% of the variance in the latent variable depression. Higher perceived stress levels and fewer coping resources predicted higher levels of depression. Higher levels of perceived stress predicted fewer coping resources and fewer coping resources predicted higher levels of depression. There was a significant direct and indirect effect of perceived stress through coping on depression. Cognitive and physical coping resources were the best predictors of the depression construct. These results have potential implications for the treatment of depression post-ACS. In particular, cognitive and physical coping mechanisms and perceived stress reduction need to be addressed when treating depression post-ACS. PMID- 20204971 TI - When message-frame fits salient cultural-frame, messages feel more persuasive. AB - The present study examines the persuasive effects of tailored health messages comparing those tailored to match (versus not match) both chronic cultural frame and momentarily salient cultural frame. Evidence from two studies (Study 1: n = 72 European Americans; Study 2: n = 48 Asian Americans) supports the hypothesis that message persuasiveness increases when chronic cultural frame, health message tailoring and momentarily salient cultural frame all match. The hypothesis was tested using a message about health risks of caffeine consumption among individuals prescreened to be regular caffeine consumers. After being primed for individualism, European Americans who read a health message that focused on the personal self were more likely to accept the message-they found it more persuasive, believed they were more at risk and engaged in more message-congruent behaviour. These effects were also found among Asian Americans who were primed for collectivism and who read a health message that focused on relational obligations. The findings point to the importance of investigating the role of situational cues in persuasive effects of health messages and suggest that matching content to primed frame consistent with the chronic frame may be a way to know what to match messages to. PMID- 20204972 TI - The effects of leader gender on self-presentational concerns in exercise. AB - The present study examined the impact of the exercise leader's gender on the self presentational concerns of women in a live exercise class. Eighty-seven college aged non- or infrequent exercisers participated in a group exercise class led by either a female or male instructor. Participants completed measures of Self Presentational Efficacy (SPE), State Social Anxiety (SSA) and State Social Physique Anxiety (SPA-S) prior to and following completion of a group exercise class. A repeated measures Multivariate Analysis of Variance (MANOVA), with time as the within-subjects factor and leader gender as the between-subjects factor, was conducted. A significant main effect for time was found (F(3, 80) = 19.65, p < 0.001). Estimated marginal means indicated that all participants reported significantly higher SPE and lower SSA and SPA-S post-exercise. Completing an exercise class may override any self-presentational concerns that can arise from the exercise environment. Future studies should adopt ecologically valid research designs to gain a clearer picture of self-presentational concerns in exercise classes. PMID- 20204973 TI - The effects of scenario-based risk information on perceptions of susceptibility to Chlamydia and HIV. AB - The simulation heuristic of Kahnemann and Tversky (1982) suggests that the subjective ease by which a risky situation can be mentally construed, positively influences the person's perceived susceptibility to the presented threat. Assuming that a detailed outline of how a risky event can end up negatively increases the ease of imagination, we tested the hypothesis that scenario-based risk information enhances perceived susceptibility towards contracting a sexually transmitted infection (STI). In an experimental design, undergraduate students were exposed to one or two risk scenario messages or no scenario message (control). The results confirmed the hypothesis, but only when more than one risk scenario message was provided. This adds to the evidence that presenting scenario based messages could be a feasible method to influence risk perceptions. PMID- 20204974 TI - Computer-assisted dieting: effects of a randomised controlled intervention. AB - In this pilot study, the effects of two computer-assisted dieting (CAD) interventions on weight loss and blood chemistry were examined among overweight and obese adults. Participants (91 community members, average age 42.6 years) were randomly assigned to CAD-only (a single-session introduction and provision of a dieting software, n = 30), CAD plus an additional four-session self management group training (CAD+G, n = 31) and a waitlist control group whose members were randomised into the two interventions at the 3-month follow-up (n = 30). A three (group)-by-two (time) repeated measures ANOVA revealed no significant group by time interaction during the initial 3-month period. However, the two intervention groups combined showed a significant, though moderate weight loss relative to the control group. Further, although a general improvement was found with regard to the lipid panel results during the first 3 months of the trial, the treatment by time interaction was not significant. A comparison of the developments in the two intervention groups during the 3- to 6-month follow-up time period revealed a tendency towards greater weight regain in the CAD-only condition. The evidence suggests that CAD supports initial weight loss; however, additional self-management training might be necessary to support maintenance. PMID- 20204975 TI - Effects of rewards, peer-modelling and pedometer targets on children's physical activity: a school-based intervention study. AB - This study evaluated a physical activity intervention for children that comprised peer-modelling, pedometer step goals and tangible rewards. A version of the intervention without the reward component was also tested. Participants (n = 386) were from three primary schools, which were randomly assigned to one of three conditions: (i) full intervention, where children received "Fit 'n' Fun Dude" peer-modelling materials and were given daily pedometer goals to receive rewards, (ii) no-rewards intervention, where children received peer-modelling materials and pedometer goals but rewards were not used and (iii) control, where children wore pedometers with no further intervention. Physical activity was measured at baseline, intervention and at the end of a 14-week 'taper' phase. During the intervention, the full intervention school showed the largest increase in physical activity relative to baseline (+2456 steps per day, p < 0.001). There was a smaller increase in the no-rewards school (+1033 steps per day, p < 0.03), and no significant change in the control. At the end of the taper phase, physical activity in the no-rewards school continued to increase (+2030 steps per day, p < 0.001) but had returned to baseline in the full intervention school. The intervention that used only peer-modelling and pedometer goals produced better effects over time. PMID- 20204976 TI - Negative perfectionism increases the risk of fatigue following a period of stress. AB - Cognitive-behavioural models of excessive fatigue suggest that people who believe that failure to meet high standards indicates unacceptability to others (a form of 'negative perfectionism') are at risk of fatigue after a period of illness or stress. The present study investigates this using a prospective design and possible mediating factors between such beliefs and fatigue were also investigated. Undergraduate students completed questionnaires at the beginning of the academic year (time 1; n = 436) and again following a time of academic pressure, 16 weeks later (time 2; n = 206). Participants were significantly more fatigued at time 2 than at time 1. Negative perfectionism was positively associated with all measures of fatigue and predicted subsequent levels of physical fatigue after controlling for time 1 fatigue. Time 1 negative perfectionism was not associated with time 2 perfectionist studying behaviours, distress about academic work or specific health behaviours, but was associated with time 2 depression. Results also indicated that time 2 depression may account for the relationship between baseline negative perfectionism and subsequent fatigue. This is the first prospective study to demonstrate a significant relationship between perfectionism and subsequent fatigue. PMID- 20204977 TI - Relationships between explanatory style, posttraumatic growth and posttraumatic stress disorder symptoms among Chinese breast cancer patients. AB - Many existing models posit that cognitive processing style is an important factor affecting self-perceived positive changes. In this study, the effects of explanatory style (the manner in which people cognitively process and explain why they experience good and bad events) on both posttraumatic growth (PTG) and posttraumatic stress disorder (PTSD) symptoms were examined among 90 Chinese women with breast cancer. It was found that explanatory style for good events, but not for bad events, was significantly associated with self-reported PTG. Women who attributed the causes of positive events to internal, global and stable factors tended to report more posttraumatic growth. In contrast, explanatory style for bad events, as opposed to good events, was significantly and positively correlated with PTSD symptoms. Among the three dimensions of explanatory style (internal, stable and global), the tendency to globalise the causes of good and bad events were the most important predictors of self-reported PTG and PTSD symptoms, respectively. While enhancing an optimistic explanatory style for bad events might reduce posttraumatic stress symptoms, cultivating an optimistic explanatory style for good events is likely to increase self-perceived positive changes after breast cancer diagnosis and treatment. PMID- 20204978 TI - The role of overprotection by the partner in coping with diabetes: a moderated mediation model. AB - This study examined whether diabetes-specific self-efficacy mediates the association between overprotection and distress and whether this mediation depends on glycemic control and gender. The research sample of 215 individuals with diabetes and their partners completed a measure of partners' overprotective behaviours towards the patient. Patients also completed measures of diabetes specific self-efficacy and diabetes-related distress. Further, HbA1c values were obtained as an indication of glycemic control. Diabetes-specific self-efficacy mediated the association between overprotection by the partner and diabetes related distress especially when glycemic control was relatively poor. Furthermore, diabetes-specific self-efficacy mediated the association between overprotection and diabetes-related distress more strongly in female than in male patients. The findings underscore the importance of studying both moderators and mediators in the association between partner behaviour and distress in patients. PMID- 20204980 TI - Emotional eating: eating when emotional or emotional about eating? AB - This article examines the extent to which self-reported emotional eating is a predictor of unhealthy snack consumption or, alternatively, an expression of beliefs about the relation between emotions and eating derived from concerns about eating behaviour. Three studies were conducted. Study 1 (N = 151) and Study 2 (N = 184) investigated the predictive validity of emotional eating compared to habit strength in snack consumption, employing 7-day snack diaries. Both studies demonstrated that snack consumption was not predicted by emotional eating but depended on the habit of unhealthy snacking and on restraint eating. As emotional eating was not a significant predictor of snack intake, Study 3 addressed the alternative hypothesis of emotional eating being an expression of concerns about eating behaviour. Results from this cross-sectional survey (N = 134) showed that emotional eating was significantly associated with several concerns. Together, these studies show that snack intake is better predicted by habit strength and restraint eating than by emotional eating. Additionally, the results suggest that in normal-weight women the concept of emotional eating may not capture the tendency to eat under emotional conditions, but rather reflects beliefs about the relation between emotions and eating. PMID- 20204979 TI - New dimensions of abnormal illness behaviour derived from the Illness Behaviour Questionnaire. AB - The primary aim was to explore the factor structure of the Illness Behaviour Questionnaire (IBQ) and the generalisability of the derived dimensions to both general community members and four chronic illness groups. A questionnaire was administered to 675 participants, comprising 344 from the community, 80 with asthma, 95 with diabetes, 79 with chronic pain and 77 with chronic fatigue syndrome (CFS). Illness severity was calculated for all chronic illness participants (self-rated health for community members). Three IBQ scales were derived following an exploratory factor analysis for the whole sample: Affirmation of Illness (alpha = 0.71 (CFS)-0.79 (asthma, diabetes)), Concern for Health (alpha = 0.71 (asthma)-0.78 (pain)) and General Affective State (alpha = 0.70 (CFS)-0.80 (asthma)). Patterns of response across the five samples, and intercorrelations among the new scales and the original seven scales, were largely in accord with expectation. Long-standing criticisms of the IBQ were addressed by using systematic statistical principles to identify meaningful and psychometrically sound IBQ dimensions. The derived structure offers a more parsimonious account of possible illness responses, with the availability of a more concise yet informative index of abnormal illness behaviour having practical utility for researchers and clinicians alike. PMID- 20204981 TI - Advanced multiple sclerosis and the psychosocial impact on families. AB - This study explores family relationships and support needs when adapting to a relative's advanced-multiple sclerosis (MS) around transition into care. A multi site qualitative study of relatives of people with advanced-MS was conducted. A purposive sample of 25 relatives was selected and interviewed either in the care home or participants' homes. Interviews were recorded, transcribed and analysed using grounded theory methodology and Atlas.ti 5.2 software. Data quality enhancement involved: a self-report questionnaire; triangulation and member checking. Themes derived from the data were: information, communication and understanding; family relationships, roles and responsibilities; emotions, coping and support; life outlook and reflection. Provision of information and support for families around the transition into care appears to be inconsistent despite there being a need for family members to ask questions and discuss the impact of the condition. Relatives reported that as a family and as individuals they faced significant challenges and were in great need of support at times, but reflected that they would have found it very difficult to accept. Relatives were also often unsure what type of support would have helped. For care providers, there needs to be a shift from the traditional health care professional 'patient-centred' mindset towards more proactive family-centred approaches and steps to encourage this are articulated. PMID- 20204982 TI - Self-affirmation moderates effects of unrealistic optimism and pessimism on reactions to tailored risk feedback. AB - We examined whether self-affirmation would facilitate intentions to engage in colorectal cancer (CRC) screening among individuals who were off-schedule for CRC screening and who were categorised as unrealistically optimistic, realistic or unrealistically pessimistic about their CRC risk. All participants received tailored risk feedback; in addition, one group received threatening social comparison information regarding their risk factors, a second received this information after a self-affirmation exercise and a third was a no-treatment control. When participants were unrealistically optimistic about their CRC risk (determined by comparing their perceived comparative risk to calculations from a risk algorithm), they expressed greater interest in screening if they were self affirmed (relative to controls). Non-affirmed unrealistic optimists expressed lower interest relative to controls, suggesting that they were responding defensively. Realistic participants and unrealistically pessimistic participants who were self-affirmed expressed relatively less interest in CRC screening, suggesting that self-affirmation can be helpful or hurtful depending on the accuracy of one's risk perceptions. PMID- 20204983 TI - Beliefs about surgery: Development and validation of an instrument to assess cognitive representations about surgery, in the context of a chronic illness. AB - OBJECTIVES: Within a trial of medical and surgical treatments for gastro esophageal reflux disease (GORD), involving randomised arms and preference arms, we tested the applicability of the Beliefs about Medicines Questionnaire (BMQ) and developed and tested the validity of a new Beliefs about Surgery Questionnaire (BSQ). METHODS: Patients with GORD (N = 43) were interviewed to elicit their beliefs about medical and surgical treatments. These contributed to the development of BSQ items. The BMQ and BSQ were completed by trial participants at baseline (randomised trial: N = 325; preference trial: N = 414). Factor analysis and discriminant function analysis were used to assess validity. RESULTS: Principal components analysis (PCA) largely replicated the four-factor BMQ structure. PCA of the combined BMQ/BSQ yielded six factors explaining 54.5% variance. BSQ items loaded onto distinct factors, demonstrating divergence from BMQ. As predicted, BMQ/BSQ scores enabled correct classification of 78.5% of participants to medication and surgery groups in the preference trial (chi(2)(6) = 205.9, p < 0.001) but only 54.5% (no better than chance) in the randomised trial (chi(2)(6) = 9.4, p = 0.154). CONCLUSIONS: The BSQ is a valid measure of perceptions about surgical treatments for GORD. With the BMQ, it provides information that may guide patients' choices about treatment. This measure may be applicable to other conditions. PMID- 20204984 TI - Cortisol changes interact with the effects of a cognitive behavioural psychological preparation for surgery on 12-month outcomes for surgical heart patients. AB - Previous studies offer contradictory evidence regarding the effects of cortisol changes on health outcomes for surgical heart patients. Increased cortisol and inflammation have been related to psychological stress while separate studies have found an inverse relation between cortisol and inflammation. Psychological preparations for surgery can reduce stress and improve outcomes and may interact with cortisol changes. Following from these relationships, we hypothesised that a preparation for surgery will interact with changes in cortisol to affect outcomes. Measures were the SF 36 General Health and Activities, medical visits and satisfaction. Eighty-five patients were randomly assigned to standard care plus a psychological preparation or standard care alone using a single-blind methodology. Data on psychological and biological functioning were collected at admission, 1 day prior and 5 days post-surgery, and 12-months after hospital discharge. General health and activities, and medical visits were related to the interaction of cortisol change and psychological preparation in support of the hypothesis. Patients were more satisfied in the preparation group than controls. Based on these findings, some outcomes from psychological preparations may be affected by changes in levels of cortisol. These results caution against a one size-fits-all approach to psychological preparations. PMID- 20204985 TI - What psychological and behaviour changes are initiated by 'expert patient' training and what training techniques are most helpful? AB - The Expert Patient Programme (EPP) is a lay-led, group-based, self-management training course available through the UK National Health Service for persons with long-term health conditions. Thirty-two patients who attended EPP courses in East London were interviewed about their experiences. Grounded theory coding of transcripts was employed to identify recurring accounts. Thematic analysis was used to theorise and organise participants' accounts, identifying commonly reported changes, helpful techniques and disappointments and frustrations. Results highlighted the role of information provision, especially face-to-face information exchange as well as the impact of in-class instruction and modelling of physical skills. Personal goal setting, using graded tasks, self-monitoring and goal review were regarded as the most useful techniques. Adoption and use of these self-management techniques depended on the establishment of an empathic and self-validating interpersonal context. Findings also imply that EPP may not be ideal for all participants and suggested modifications and improvements are discussed. PMID- 20204986 TI - The experience of attending a lay-led, chronic disease self-management programme from the perspective of participants with multiple sclerosis. AB - A lay-led, community-based intervention, the Chronic Disease Self-Management Course (CDSMC) is effective for a range of long-term health conditions (e.g. arthritis, heart disease). However, the perceived value and experience of the CDSMC for people with Multiple Sclerosis (MS) has not been examined. The present qualitative study addressed this omission. Ten participants with MS (7 female; age range 35 to 60 years; disease duration 4 to 19 years) were interviewed before attending the CDSMC and at 4-month follow-up. Data were analysed using Framework Analysis. Some participants learned new self-management techniques and reported enhanced confidence (self-efficacy), whereas other participants were already confident in their self-management ability and found the CDSMC acted as a reminder of techniques previously used. Relaxation, pacing, and goal setting were particularly valuable for managing fatigue. Goal setting helped some participants to build confidence. Participants valued meeting similar others including those with different conditions. The CDSMC was an opportunity for social comparison and inspirational role modelling. Improvements to the CDSMC were suggested, including the addition of specific MS information. Overall, the CDSMC was viewed as a valuable source of new skills and a reminder of previously learned self management skills, particularly in the context of managing fatigue. Gender differences emerged. PMID- 20204987 TI - Illness representations, coping and psychological adjustment to Parkinson's disease. AB - The present study reports an application of the common sense model (CSM) of illness representations to the prediction of psychological distress in people with Parkinson's disease (PD). The study sought to (i) examine cross-sectional and prospective associations between illness representations, coping and psychological distress, and (ii) test the hypothesis that coping would mediate any relationships between illness representations and psychological distress. Patients with PD (n = 58) completed the Illness Perception Questionnaire-Revised, the Medical Coping Modes Questionnaire and the Hospital Anxiety and Depression Scale. Patients (n = 57) were followed-up at 6 months. Illness representations explained large amounts of variance in time 1 anxiety (R(2) = 0.42) and depression (R(2) = 0.44) as well as additional variance in time 2 anxiety (DeltaR(2) = 0.12) and depression (DeltaR(2) = 0.09) after controlling for baseline scores. In addition, avoidance mediated the effect of emotional representations on time 1 anxiety, and acceptance-resignation mediated the effects of both consequences and emotional representations on time 1 depression. The present study therefore provides partial support for the mediational model outlined in the CSM, as significant mediation effects were found only in the cross-sectional analyses. PMID- 20204988 TI - The structure of adversarial growth in a sample of cancer patients 8 years post diagnosis: a revision of the SLQ-38. AB - Stressful and traumatic events may trigger positive life changes, so-called adversarial growth. Despite growing interest in this topic, the structure and dimensionality of this concept has not been established. Recently, empirical reviews have suggested that the factors underlying this construct are highly related. Currently, the use of confirmatory factor analysis to test this hypothesis is advocated. Using data from cancer patients (n = 206), this study investigated the dimensionality of a Dutch translated version of the Silver Lining Questionnaire (SLQ-38). A 16-item SLQ (SLQ-16), with three subscales or first-order factors (enhanced personal relationships, changes in life philosophy and changes within the self) loading on a second-order general adversarial growth factor, was a good fitting model. In conclusion, the SLQ-16 may prove useful in the assessment of adversarial growth following illness. PMID- 20204989 TI - The psychometric properties of the Greek version of the State-Trait Anxiety Inventory in cancer patients receiving palliative care. AB - OBJECTIVES: To validate the Greek version of the State-Trait Anxiety Inventory (STAI) in a sample of cancer patients. DESIGN: The scale was administered twice, with a 3-day interval, to 99 eligible patients with cancer. Together with the Greek version of STAI scale, the patients also completed the anxiety subscale from the Hospital Anxiety and Depression scale (HAD). OBSERVATIONS: Factor analysis yielded a three-factor solution, explaining 47.143% of the variance. Cronbach alpha for three scales was between 0.729 and 0.852. Inter-scale correlations were moderate-to-high and ranged from 0.282 to 0.563 (p < 0.0005, p < 0.005). The assessment of the relationships among the Greek STAI scales and HAD Anxiety showed statistically significant correlations between them (r ranged between 0.428 and 0.596, p < 0.0005). The test/retest reliability of scale (Pearson's 'r'), showed that the coefficient agreement ranged between 0.85 and 0.90 (p < 0.0005). Univariate analysis revealed significant correlations between female gender, metastasis, performance status, chemotherapy, mild opioids and low education level with increased anxiety. CONCLUSIONS: These results support that the Greek version of STAI is an instrument with satisfactory psychometric properties, and is a valid research tool for Greek cancer patients. PMID- 20204990 TI - End of living: maintaining a lifeworld during terminal illness. AB - The narrative responses of 32 people with AIDS or cancer with survival prognoses of 6 months to a year to monthly interview questions about their daily lives were analysed with a team-based qualitative methodology. Two groups emerged: (a) a Maintained Lifeworld Group characterised by one or more of the following: continued engagement with family, friends, and community; the ability to relinquish untenable goals and substitute new, realistic ones; engagement in spirituality and a spiritual practice; and, (b) a Lifeworld Interrupted Group characterised by one or more of the following: relocation just before or during the study, cognitive impairment, commitment to untenable goals, ongoing substance abuse. Understanding how people with a terminal illness can maintain a lifeworld and experience well-being while also managing the physical challenges of their illness could help inform the support offered by professional and family caregivers to improve care recipients' quality of life. PMID- 20204991 TI - Beyond good intentions: The role of proactive coping in achieving sustained behavioural change in the context of diabetes management. AB - This study examines the effectiveness of a brief self-management intervention to support patients recently diagnosed with type-2 diabetes to achieve sustained improvements in their self-care behaviours. Based on proactive coping, the intervention emphasizes the crucial role of anticipation and planning in maintaining self-care behaviours. In a randomised controlled trial among recent screen-detected patients, participants who received the intervention were compared with usual-care controls, examining changes in proximal outcomes (intentions, self-efficacy and proactive coping), self-care behaviour (diet, physical activity and medication) and weight over time (0, 3 and 12 months). Subsequently, the contribution of proactive coping in predicting maintenance of behavioural change was analysed using stepwise hierarchical regression analyses, controlling for baseline self-care behaviour, patient characteristics, and intentions and self-efficacy as measured after the course. The intervention was effective in improving proximal outcomes and behaviour with regard to diet and physical activity, resulting in significant weight loss at 12 months. Furthermore, proactive coping was a better predictor of long-term self-management than either intentions or self-efficacy. Proactive coping thus offers new insights into behavioural maintenance theory and can be used to develop effective self-management interventions. PMID- 20204992 TI - Predicting short and long-term exercise intentions and behaviour in patients with coronary artery disease: A test of protection motivation theory. AB - The purpose of this study was to examine the utility of protection motivation theory (PMT) in the prediction of exercise intentions and behaviour in the year following hospitalisation for coronary artery disease (CAD). Patients with documented CAD (n = 787), recruited at hospital discharge, completed questionnaires measuring PMT's threat (i.e. perceived severity and vulnerability) and coping (i.e. self-efficacy, response efficacy) appraisal constructs at baseline, 2 and 6 months, and exercise behaviour at baseline, 6 and 12 months post-hospitalisation. Structural equation modelling showed that the PMT model of exercise at 6 months had a good fit with the empirical data. Self-efficacy, response efficacy, and perceived severity predicted exercise intentions, which, in turn predicted exercise behaviour. Overall, the PMT variables accounted for a moderate amount of variance in exercise intentions (23%) and behaviour (20%). In contrast, the PMT model was not reliable for predicting exercise behaviour at 12 months post-hospitalisation. The data provided support for PMT applied to short term, but not long-term, exercise behaviour among patients with CAD. Health education should concentrate on providing positive coping messages to enhance patients' confidence regarding exercise and their belief that exercise provides health benefits, as well as realistic information about disease severity. PMID- 20204993 TI - Two alternative models of health behaviour and recovery from activity limitations due to acute injury: A prospective study. AB - Cognitions influence recovery from activity limitations. In this study we aimed to independently test, compare and combine the common sense self-regulation model (CS-SRM) and social cognitive theory (SCT) in predicting recovery from activity limitations due to acute injury. Measures were gathered at two time points 5-6 weeks apart. The sample consisted of 146 university students (Mean age: 21.86, SD: 4.83, 62% female) with a heterogeneous range of injuries that limited their participation in physical activity. The dependent variable was recovery from activity limitations (Physical Functioning - Short Form-36). The predictor variables were measured using the Brief Illness Perception Questionnaire and SCT items designed according to theoretical recommendations. Time-line (TL) and self efficacy (SE) were significant predictors of recovery in a multivariate analysis, controlling for reported pain at Time 1. A combined model including the best predictors from both models, TL (beta = -0.25, p < 0.05, R(2) change = 0.17, p < 0.01) and SE (beta =0.31, p < 0.05, R(2) change = 0.05, p < 0.05), accounted for a significant amount of the variance in recovery from activity limitations. A combination of key variables from both models may be particularly useful for understanding the cognitive factors that influence recovery from activity limitations. PMID- 20204994 TI - Depressive mood and smoking onset: A comparison of adolescents with and without asthma. AB - This prospective population-based study aimed to compare associations between depressive feelings and smoking behaviour of adolescents with and without asthma. Data were collected from a two-wave 22-24 months prospective study among 5938 adolescents who completed self-report questionnaires. Logistic regression analyses showed that depressive feelings and smoking were related both cross sectionally and longitudinally. Smoking behaviour was similar for adolescents with and without asthma, as well as its correlation with depressive feelings. However, participants with asthma were more likely to report depressive feelings than those without asthma, implying an indirect relationship between asthma and smoking behaviour. Implications for prevention are addressed. PMID- 20204995 TI - Gender differences in smoking: A longitudinal study of beliefs predicting smoking in 11-15 year olds. AB - This longitudinal study investigated differences in beliefs and perceived behavioural control between smokers and non-smokers in a large sample of adolescents. Positive and negative instrumental beliefs, normative beliefs, perceived behavioural control (PBC) and smoking status were assessed in the same participants at 11, 13 and 15 years of age. Prospective analyses among non smokers revealed that for boys, negative instrumental beliefs in non-smokers at age 11 predicted smoking at age 15 years. For girls, normative beliefs and PBC in non-smokers at age 11 predicted smoking status at age 13; normative beliefs at age 11 predicted smoking at age 15; and positive instrumental beliefs and normative beliefs at age 13 predicted smoking status at age 15. Cross-sectional data revealed that smokers were significantly more likely than non-smokers to endorse positive instrumental beliefs, less likely to agree with negative instrumental belief items, more likely than non-smokers to perceive social pressure to smoke, and less likely to report control over smoking, and that female smokers reported less control over smoking and fewer negative instrumental beliefs than all other groups including male smokers at age 13. The need for belief-based preventative interventions that are age- and gender-relevant is discussed. PMID- 20204996 TI - Comparing implementation intention interventions in relation to young adults' intake of fruit and vegetables. AB - This study tests whether the effectiveness of implementation intention-based interventions to increase fruit and vegetable intake in a young adult population can be enhanced using additional pre-intervention instructions and alternative formats; namely, an 'if-then' implementation intention versus a more general, 'global' plan that does not explicitly link a situational cue with a goal directed response. Participants (N = 557) completed pre-test measures of planning, motivation and behaviour with respect to increasing their fruit and vegetable intake before being randomised to a 3 (intervention format: control vs. 'if-then' vs. 'global' implementation intentions) x 2 (pre-intervention instruction vs. no pre-intervention instruction) between-participants design. Results revealed a significant intervention format by time interaction, such that intake significantly increased by 0.50 portions in the if-then format condition compared with 0.31 in the global format and 0.01 in the control condition. These results suggest that 'if-then' manipulations are superior in promoting behaviour change in an applied setting. The use of pre-intervention instructions had no additional effect on behaviour, providing evidence for the efficacy of implementation intentions even when experimenter demand is reduced. Evidence is also presented to suggest that reported increases in intake are not related to demand characteristics. PMID- 20204997 TI - Time orientation and health-related behaviour: measurement in general population samples. AB - Research on health behaviour and time orientation has been hindered by a lack of consensus about appropriate measurement. Study 1 assessed the reliability of the Consideration of Future Consequences Scale (CFC) and the Zimbardo Time Perspective Inventory (ZTPI) in a general population sample (n = 300). Although more reliable, the CFC was less readable. Study 2 assessed the validity of a shortened ZTPI, measuring future and present orientation, and the full CFC. The measures had good discrimination to distinguish interpersonal differences. Construct validity of present, but not future, orientation as measured by the ZTPI, was evidenced by its mediation of the association between socioeconomic status and expectations of participating in diabetes screening. The CFC mediated this relationship more weakly. Further investigation of present orientation in understanding health-related behaviour is warranted. PMID- 20204999 TI - Current issues and new directions in Psychology and Health: The costs and benefits of self-regulation - a call for experimental research. PMID- 20204998 TI - The time course of attentional allocation while women high and low in body dissatisfaction view self and model physiques. AB - The purpose of this study was to examine trait levels of dissatisfaction with specific bodily regions and attentional characteristics associated with those regions among women high (HBD, n = 15) and low (LBD, n = 14) in body dissatisfaction. Separate laboratory visits were completed, during, which eye movements were recorded as participants viewed slides of self-physiques or model physiques. Comparisons of search tendencies were made across the entire 5 s of slide presentation, and then within each of the ten 500 ms epochs that comprised the 5 s viewing period. The HBD group made initial fixations to the pelvis region proportionately more than the LBD group, and avoided looking at their own bodies relative to the LBD group. They also viewed the model's legs significantly longer than the LBD group. When considering the time course of attentional allocation, the HBD group preferentially viewed areas typical of dissatisfaction during the latter viewing periods, regardless of whether they were looking at themselves or the model. Results are discussed in the context of an integrated social cognitive view with regard to the formation of a negative body schema that both results from and then perpetuates the negative affective consequences that characterize individuals who are symptomatic for eating disorders. PMID- 20205000 TI - The dimensional structure of benefit finding in multiple sclerosis and relations with positive and negative adjustment: A longitudinal study. AB - Benefit finding is a meaning making construct that has been shown to be related to adjustment in people with MS and their carers. This study investigated the dimensions, stability and potency of benefit finding in predicting adjustment over a 12 month interval using a newly developed Benefit Finding in Multiple Sclerosis Scale (BFiMSS). Usable data from 388 persons with MS and 232 carers was obtained from questionnaires completed at Time 1 and 12 months later (Time 2). Factor analysis of the BFiMSS revealed seven psychometrically sound factors: Compassion/Empathy, Spiritual Growth, Mindfulness, Family Relations Growth, Lifestyle Gains, Personal Growth, New Opportunities. BFiMSS total and factors showed satisfactory internal and retest reliability coefficients, and convergent, criterion and external validity. Results of regression analyses indicated that the Time 1 BFiMSS factors accounted for significant amounts of variance in each of the Time 2 adjustment outcomes (positive states of mind, positive affect, anxiety, depression) after controlling for Time 1 adjustment, and relevant demographic and illness variables. Findings delineate the dimensional structure of benefit finding in MS, the differential links between benefit finding dimensions and adjustment and the temporal unfolding of benefit finding in chronic illness. PMID- 20205001 TI - Life values and mental health: A longitudinal study comparing chronically ill women to women without chronic disease. AB - We tested the hypothesis that among women who are chronically ill, a re-ordering of life values maintains mental health. A community-based prospective longitudinal study was conducted in which data were obtained from 601 women in 1986, when the women were with mean age 42 and again in 2003, when the women were with mean age 58. There was a significant change in life values as women aged with more change among women with chronic disease (n = 476) than those without chronic disease (n = 125). Increased valuation of intrinsic life values (health and love) and decreased valuation of extrinsic life values (power, fame and attractiveness) were associated with subsequent better mental health for women with chronic disease, but not for those without chronic disease. PMID- 20205002 TI - Psychosocial resources and subjective well-being of cancer patients. AB - Based on Taylor's theory of cognitive adaptation to cancer and on the distinction between psychological and social resources, we analyse whether optimism, internal health locus of control, self-esteem, purpose in life, and perceived availability of social support assessed prior to the commencement of chemotherapy predict concurrent subjective well-being (SWB), SWB at a 9-month follow-up, and change in SWB over time. Longitudinal data were collected from 163 cancer patients. Analyses showed that social support, self-esteem, and to a lesser extent, optimism and purpose in life showed concurrent associations with SWB. In addition, social support and purpose in life at T(1) predicted improvement in SWB over time. However, when resources at T(1) and T(2) are included in the analysis simultaneously, only concurrent resources were related to SWB at T(2) and to change in SWB over time. It is concluded that the effect of initial resources on change in SWB is mediated by the levels of later resources. PMID- 20205003 TI - Measuring multiple dimensions of perceived control in women with newly diagnosed breast cancer. AB - A multidimensional approach to the study of focus of perceived control (FPC) can provide a more specific understanding of associations between FPC and adjustment to cancer. We developed and tested a measure to capture multiple dimensions of FPC and examined FPC dimensions in relation to positive expectancies and three indices of psychosocial adjustment in 219 women with breast cancer. Confirmatory factor analysis supported a 6-factor model of FPC (chi(2)(284 df) = 433.67, p < 0.001; CFI = 0.94; RMSEA = 0.049, 90% C.I. = 0.040, 0.058) that included PC over physical symptoms, emotions, relationships, medical care, cancer outcomes and life in general. Specific associations between FPC and adjustment were observed: more emotional PC was associated with less emotional distress, more physical PC was associated with better physical quality of life (QOL), and more medical PC was associated with better medical QOL. Positive expectancies were also associated with better outcomes. These results indicate dimensions of FPC as differentially associated with indices of adjustment, suggesting multiple targets of interventions aimed at benefiting breast cancer survivors. PMID- 20205004 TI - Partner support and distress in women with breast cancer: The role of patients' awareness of support and level of mastery. AB - The aim of the present study was to investigate the associations between partners' ways of providing support (both active engagement and protective buffering) and distress in women with breast cancer as a function of patients' awareness of the support received and their sense of mastery. These associations were investigated both cross-sectionally and longitudinally (i.e. changes in distress over time). At 3 months (T1) after diagnosis, women with breast cancer and their partners (n = 82 couples) were assessed regarding partners' supportive behaviour. Women also indicated their sense of mastery. At both 3 and 9 months (T2) after diagnosis, women reported their level of distress. Cross-sectional as well as longitudinal analyses showed that active engagement was unrelated to distress, regardless of patients' awareness of the support received and their feelings of mastery. In contrast, perceived protective buffering was found to be associated with more concurrent distress (i.e. cross-sectionally). Moreover, protective buffering that was reported by partners but remained unnoticed by patients was associated with higher levels of concurrent distress, but only for patients who were low in mastery. Over time, protective buffering that remained unnoticed by patients was associated with more distress, regardless of women's sense of mastery. PMID- 20205005 TI - Post-traumatic growth in women after childbirth. AB - Childbirth is a complex event that leads to a variety of psychological outcomes. This cross-sectional study examined post-traumatic growth in women following childbirth (N = 219) using an online questionnaire, and explored associations between growth, support and control during birth, coping after birth and symptoms of post-traumatic stress disorder (PTSD). At least moderate degrees of growth were reported by 50.2% of women and average levels of growth were similar to those reported following accidents and assaults. Growth was positively related to approach coping and the avoidant strategy of seeking alternative rewards, but was unrelated to support and control during birth, other avoidant coping strategies after birth, and PTSD symptoms. It is concluded that growth does occur following childbirth. Further research is needed to clarify factors associated with growth in women following childbirth and to determine if growth is associated with psychological benefits in this population. PMID- 20205006 TI - Developing a spouse version of the Illness Perception Questionnaire-Revised (IPQ R) for husbands of women with rheumatoid arthritis. AB - A husband's beliefs about his wife's rheumatoid arthritis (RA) may be important to his provision of support and well-being. We adapted seven subscales of the Illness Perception Questionnaire-Revised to assess husbands' beliefs about their wives' RA. We recruited 190 couples (average years married = 22; average years with RA = 14) from community settings to complete surveys assessing illness perceptions, psychosocial and illness variables at baseline and four-month follow up. We conducted exploratory factor analyses, calculated Cronbach's alphas for each factor, and examined construct validity. This process yielded six parallel wife and husband subscales assessing beliefs about the (a) timeline, (b) consequences and (c) cyclical nature of RA, and women's RA (d) emotional responses, (e) control and (f) illness coherence. All items loaded above 0.50 on their respective factors and Cronbach's alphas ranged from 0.72 to 0.86. Subscales were inter-related in a manner consistent with previous research and husbands' beliefs were related to a variety of illness and adjustment variables. The factor structure was replicated in the same sample at follow-up (n = 165). This study introduces an instrument to assess spouse beliefs about RA that may help to elucidate the role of spousal relationships in illness adaptation. PMID- 20205007 TI - Type D personality and cardiac output in response to stress. AB - Type D personality is predictive of adverse clinical outcome and psychological distress in cardiac patients. However, the mechanisms by which Type D affects health are largely unknown. This study (1) investigated the relationship between Type D and cardiovascular reactivity to experimentally induced stress and (2) tested the influence of Type D on subjective feelings of stress. Eighty four healthy young adults (50% males, mean (SD) age 22 (6.84) years), completed measures of Type D personality, stress arousal and a stress-inducing procedure involving a taxing mental arithmetic task. Cardiovascular measures were recorded throughout the experiment. Mixed measures ANOVA showed a significant main effect of Type D and a significant group by time effect of Type D on cardiac output in male participants. Type D males exhibit significantly higher cardiac output during the stressor phase compared to non-Type D males. However, there was no relationship between Type D and cardiovascular reactivity in females. In addition, Type D individuals exhibited significantly higher feelings of subjective stress compared to non-Type D's. These findings provide new evidence on Type D and suggest that Type D may affect health through increased cardiac output and higher subjective feelings of stress following acute stress. PMID- 20205008 TI - Affective and behavioural reactions to positive and negative health-related social control in HIV+men. AB - We examined associations between the receipt of positive and negative health related social control (i.e. influence) from a primary network member, affective and behavioural reactions (i.e. behaviour change) to social control, and psychosocial well-being in a cross-sectional study of 91 HIV+ men living with HIV (MLWH). Receiving positive control was associated with more self-care behaviours, more active coping efforts, and fewer depressive symptoms. In contrast, receiving negative control was associated with fewer self-care behaviours and more depressive symptoms. Negative affective reactions to control mediated the associations between positive and negative control and depressive symptoms, and between positive control and active coping efforts. Behaviour change only mediated the association between positive control and self-care behaviours. Post hoc analyses further revealed that men who were not at risk for clinical depression engaged in more behaviour change as a result of receiving negative control. Social control that elicits behaviour change and does not arouse negative affect is effective in promoting better self-care behaviours and psychosocial well-being in MLWH. PMID- 20205009 TI - Defensive responses to an emotive anti-alcohol message. AB - We investigated the idea that emotive imagery used in health promotion advertising can facilitate a defensive response that adversely affects risk perceptions. One hundred student drinkers were exposed to either a printed message accompanied by images designed to maximise emotional distress or the same message presented using less emotive images. A three-way interaction was found, whereby the presentation of distressing images caused lower personal risk estimates in participants higher in denial and vulnerability to alcohol-related problems. This effect may have been mediated by lower reading times, suggesting that participants avoided the messages. Moderation by denial suggests that the effect is attributable to defensiveness, whilst moderation by vulnerability suggests that it is threat specific. These findings suggest that emotive images might trigger defensive avoidance responses that reduce risk estimates in some audience sub-populations. PMID- 20205010 TI - Motivational and behavioural consequences of self-affirmation interventions: a study of sunscreen use among women. AB - The reported study compared the efficacy of three self-affirmation manipulations in reducing defensive processing and instigating behaviour change in response to personally relevant information about the health risks of sunbathing. White female sunbathers (N = 162) were recruited on a beach in the south of England. Participants were randomly allocated to a 'values affirmation' condition, a 'kindness affirmation' condition, a 'positive traits affirmation' condition, or a no affirmation 'control' condition. In the 'positive traits affirmation' condition the self-affirmation task was incorporated into a leaflet presenting the health risk information. Findings supported the hypothesis that participants in the three self-affirmation conditions would engage in less-defensive processing of the health-risk information than those in the 'control' condition. For the behavioural measure, however, only those participants in the 'positive traits affirmation' condition were more likely to request a free sample of sunscreen than those in the control condition. The implications of these findings for self-affirmation theory and the development of effective health promotion campaigns are discussed. PMID- 20205011 TI - Changes in self-regulatory cognitions as predictors of changes in smoking and nutrition behaviour. AB - Most longitudinal, correlational studies on health-behaviour change examine effects of Time1 social-cognitive predictors on subsequent behaviour. In contrast, our research focuses on associations between changes in predictors with change in behaviour. The Health Action Process Approach (HAPA) distinguishes between motivational predictors for intention formation and volitional predictors for behavioural change and served as theoretical basis. Two online-studies were launched targeting different behaviours (low-fat diet, smoking), different samples (Study 1: N = 469; Study 2: N = 441) and different time spans (Study 1: 3 months, Study 2: 4 weeks). Data were analysed by means of structural equation modelling with latent difference scores. Both studies resulted in almost parallel prediction patterns. Change in risk awareness and change in outcome expectancies did not result in change in intentions, whereas change in self-efficacy was of crucial importance. Change in behaviour was associated with change in action planning and action control over and above the effects of intentions. In one study, increases in self-efficacy yielded increases in behaviour change. Results demonstrate that change in action planning and especially action control was of great importance for behaviour change across two different behaviours. Analysing change in social-cognitive predictors allows drawing precise conclusions for interventions. PMID- 20205012 TI - Mammograms and the management of existential discomfort: threats associated with the physicality of the body and neuroticism. AB - The current research employs ideas from terror management theory to investigate why mammograms may be psychologically problematic. This perspective suggests that individuals, particularly those high in neuroticism, are threatened by that which reminds them of their physical and mortal nature. In Study 1, a laboratory experiment demonstrated that when concerns about mortality were primed, reminders of one's physical nature (i.e. creatureliness) led women who were high in neuroticism to report reduced willingness to imagine undergoing a mammogram. In Study 2, a field experiment among women receiving a mammogram showed that priming creatureliness increased perceptions of discomfort with the procedure for women high in neuroticism. Theoretical and practical implications are discussed. PMID- 20205013 TI - Well-being, posttraumatic growth and benefit finding in long-term breast cancer survivors. AB - This study evaluates posttraumatic growth, benefit finding and well-being, and their mutual association in a random sample of disease-free 10-year breast cancer survivors. The population-based Eindhoven Cancer Registry (ECR) was used to select all women diagnosed with breast cancer in 1993 in six hospitals. Of the 254 breast cancer survivors, 183 (72%) returned a completed questionnaire. Measures included the Posttraumatic Growth Inventory (posttraumatic growth), the Perceived Disease Impact Scale (benefit finding) and the CentERdata Health monitor (life satisfaction, health status and psychological well-being). Self reported health status and psychological well-being were similar in survivors compared to general population norms, whereas life satisfaction was significantly higher among survivors. In addition, posttraumatic growth was seen in the following domains: relationships with others, personal strength and appreciation of life. The number of patients reporting benefit finding was high (79%, N = 145). Benefit finding showed a moderately positive correlation with posttraumatic growth. In addition, women who stated that their satisfaction with life was high reported higher levels of posttraumatic growth in comparison to women who did not. Radiotherapy was negatively associated with posttraumatic growth. Women with a higher tumour stage at diagnosis experienced less benefit finding in comparison to women with a lower tumour stage at diagnosis. The above results can help to identify those patients who will probably experience posttraumatic growth and benefit finding after cancer. However, it is important to be aware that the positive effects of cancer on a patient's life do not occur in all cancer patients and all phases of the disease trajectory. PMID- 20205014 TI - The psychometric property and validation of a fatalism scale. AB - In this article, we conceptualised fatalism as a set of health beliefs that encompass the dimensions of predetermination, luck and pessimism. A 20-item scale was developed as a measurement instrument. Confirmatory factor analyses were performed to test the dimensionality of the scale. Three external variables (i.e. genetic determinism, perceived benefits of lifestyle change and intention to engage in healthy behaviour) were used as reference variables to test the construct validity of the scale. Data from a web-based national survey (N = 1218) showed that the scale was unidimensional on the second order, and with good reliability (alpha = 0.88). The relationships between the external variables and the first- and second-order factors provided evidence of the scale's external consistency and construct validity. PMID- 20205015 TI - Current issues and new directions in Psychology and Health: What is the future of digital interventions for health behaviour change? PMID- 20205016 TI - Seeking support: An interpretative phenomenological analysis of an Internet message board for people with Complex Regional Pain Syndrome. AB - In this article, we report on the findings of a qualitative inquiry into how an online message board for people who have Complex Regional Pain Syndrome (CRPS) was used by its members. All messages (and responses) posted on the CRPS message board over a 4-month period were collected retrospectively. The data were analysed using the method of Interpretative Phenomenological Analysis. Members used the message board to seek (and provide) support to those with CRPS, and also to express their emotions, feelings and experiences linked to their condition. The message board provided an important source of support for a patient group that can otherwise become isolated as a result of their mobility problems. Furthermore, the analysis revealed the unrealistic hopes that patients can hold concerning the anticipated outcomes of their treatment. This is an important issue for healthcare professionals to explicitly address when interacting with the patient group. PMID- 20205017 TI - Don't derogate this message! Self-affirmation promotes online type 2 diabetes risk test taking. AB - The aim of the present study was to examine whether self-affirmation promotes acceptance of threatening type 2 diabetes information and risk-testing behaviour. In an experimental study (N = 84), we manipulated self-affirmation by allowing participants to affirm a value that was either personally important or unimportant to them, and measured participants' risk level prior to reading threatening type 2 diabetes information. As dependent variables, we measured message derogation, intentions to do an online type 2 diabetes risk test and online risk-testing behaviour. Findings showed that self-affirmation decreased message derogation, increased intentions to do an online risk test and promoted online risk test taking among at-risk participants. Among participants not at risk, self-affirmation decreased intentions and online risk test taking. Therefore, it is concluded, that for an at-risk population self-affirmation can decrease defensive responses to threatening health information and promote (online) risk test taking for diseases. PMID- 20205018 TI - Effectiveness of online word of mouth on exposure to an Internet-delivered intervention. AB - The use of online word of mouth (WOM) seems a promising strategy to motivate young people to visit Internet-delivered interventions. An Internet-delivered intervention aimed at changing implicit attitudes related to alcohol was used in two experiments to test effectiveness of e-mail invitations on a first visit to the intervention. The results of the first experiment (N = 196) showed that an invitation by e-mail from a friend was more effective to attract young adults (aged 18-24 years) to the intervention website than an invitation from an institution. A 2 x 2 design was used in the second experiment (N = 236) to test manipulations of argument strength and the use of peripheral cues in invitations. Results showed that weak arguments were more effective to attract young adults to the intervention website when an incentive was withheld. These results need to be taken into account when using online WOM as a strategy to improve exposure to Internet-delivered interventions. PMID- 20205019 TI - Effects of incentives in web-based prevention for adolescents: Results of an exploratory field study. AB - This study examines if the willingness of adolescents to participate in a web based prevention program can be increased by providing an incentive for participation. Eighth graders (n = 166) were instructed to work on an online stress-prevention program via the internet from home. A subgroup of n = 80 subjects from three school classes were told that they would take part in a raffle if they completed the program. The remaining n = 86 participants (again three classes) served as a control group. The school classes were randomly allocated to the training conditions. During the 8-week intervention period, compliance rates were recorded by means of an online tracking system. In addition, self-reported compliance and training acceptance were assessed. The application of an incentive had considerable effects on retention rates, on training acceptance and self-assessed effectiveness of the intervention. Adolescents in the 'incentive condition' completed three times as many program lessons as control subjects did, and-as their self-reports suggest-they worked as attentively. Validity of self-reported compliance was higher among participants of the incentive group and they reported significantly higher program acceptance. As a consequence, the application of incentive systems is recommended for future implementation of web-based prevention programs targeting adolescents. PMID- 20205020 TI - Can the effects of implementation intentions on exercise be enhanced using text messages? AB - Implementation intentions planning in advance the situation in which one will act, have been proposed to be an effective self-regulatory technique for changing health behaviour. Encouraging people to receive text message reminders of their implementation intentions should enhance their strength and, thus, it was predicted that this combined approach would be particularly effective in increasing exercise. Participants (N = 155) were randomly allocated to one of five conditions (implementation intentions and SMS, implementation intention, SMS or one of two control groups) then completed self-report measures of exercise behaviour and motivation. Four weeks later, they responded to similar items. Results suggested that the combined intervention increased exercise frequency significantly more than the other strategies including the implementation intention group. It is proposed, therefore, that implementation intention effects can be enhanced via plan reminders. PMID- 20205021 TI - Teacher, peer and parent autonomy support in physical education and leisure-time physical activity: A trans-contextual model of motivation in four nations. AB - An extended trans-contextual model of motivation for health-related physical activity was tested in samples from four nations. The model proposes a motivational sequence in which perceived autonomy support from teachers in a physical education (PE) context and from peers and parents in a leisure-time physical activity context predict autonomous motivation, intentions and physical activity behaviour in a leisure-time context. A three-wave prospective correlational design was employed. High-school pupils from Britain, Estonia, Finland and Hungary completed measures of perceived autonomy support from PE teachers, autonomous motivation in both contexts, perceived autonomy support from peers and parents, attitudes, subjective norms, perceived behavioural control and intentions from the Theory of Planned Behaviour (TPB), and measures of behaviour and past behaviour in a leisure-time context. Path-analyses controlling for past behaviour supported trans-contextual model hypotheses across all samples. Effects of perceived autonomy support from peers and parents on leisure-time autonomous motivation were small and inconsistent, while effects on TPB variables were stronger. There was a unique effect of perceived autonomy support from PE teachers on leisure-time autonomous motivation. Findings support the model, which provides an explanation of the processes by which perceived autonomy support from different sources affects health-related physical activity motivation across these contexts. PMID- 20205022 TI - Effects of a physical exercise session on state body image: The influence of pre experimental body dissatisfaction and concerns about weight and shape. AB - The effects of a physical exercise session on state body image and mood were examined. In a cross-over design, participants were randomised to two groups starting either with physical exercise (PE; experimental condition) or with reading a newspaper (RN; control condition). Before and after PE and RN, participants (N = 65) rated their body dimensions using a digital photo distortion technique and indicated their attitudinal body image and mood. Participants' judgements of their 'felt' body dimensions and attitudes toward their own body were affected differently by PE and RN, indicating that participants felt slightly slimmer and were more satisfied with their bodies after PE. Exercise-induced changes in body perception were greater, the higher the pre-experimental drive for thinness, body dissatisfaction and weight/shape concerns were. Especially in those participants with higher body image disturbances, physical exercise can have a reinforcing effect on immediate body image and mood improvement. PMID- 20205023 TI - Predicting attention and avoidance: when do avoiders attend? AB - Three avoidance measures, the Miller Behavioural Style Scale (MBSS), Index of Self-Regulation of Emotion (ISE) and Mainz Coping Inventory (MCI), were compared in their ability to predict attention and avoidance of threats in the emotional Stroop task. It was also examined if the avoidance mechanism of individuals who would normally avoid threat-indicating words becomes disrupted under conditions of dopamine reduction. Results show that only the ISE predicted attention/avoidance of threat-indicating words. In addition, the avoidance mechanism, as measured by the ISE and MCI, was not activated when regular smokers abstained from smoking. PMID- 20205024 TI - Causal attributions of obese men and women in genetic testing: implications of genetic/biological attributions. AB - The present study sought to investigate genetic/biological attributions of obesity, their associations with a predisposition to obesity and their crossectional and longitudinal implications for weight regulation in obese individuals presenting for genetic testing and counselling. A total of 421 obese men and women underwent psychological and anthropometric assessment and a mutation screen of the melanocortin-4 receptor gene. At study entry, women revealed more genetic/biological attributions than men on the Revised Illness Perception Questionnaire adapted to obesity (86.2% versus 59.7%). Genetic/biological attributions of obesity were associated in both sexes with a family history of obesity, assessed through Stunkard's Figure Rating Scale. In both sexes, genetic/biological attributions were unrelated to weight regulation beliefs and behaviour (i.e. self-efficacy, controllability beliefs, restrained eating and physical activity), assessed through standardised questionnaires or interview at baseline and at six-month follow-up. In addition, causal attributions and weight regulation beliefs and behaviour were not predictive of body mass index at six-month follow-up. Overall, the results indicate that causal attributions of obesity to genetic/biological factors in obese individuals presenting for genetic screening and counselling are crossectionally and longitudinally unrelated to weight regulation and longer-term weight outcome. Those who attribute their obesity to genetic/biological factors likely have a familial obesity risk. PMID- 20205025 TI - How much behaviour change should we expect from health promotion campaigns targeting cognitions? An approach to pre-intervention assessment. AB - For those planning interventions based on social cognition models, it is usually not clear what impact on behaviour will follow from attempts to change the cognitions specified in these models. We describe a statistical simulation technique to assess the likely impact of health promotion targeting Theory of Reasoned Action (TRA)-based predictors of condom use. We apply regression-based simulation techniques to data from the SHARE project (n = 756 Scottish adolescents) to assess the potential impact of changes in cognitions on condom use. Results support the predictive utility of TRA-based models of psychological antecedents of condom use but also provide a cautionary warning about the magnitude of behaviour change likely to be achieved by interventions based on such models. PMID- 20205026 TI - Effect of pretesting on intentions and behaviour: a pedometer and walking intervention. AB - This study addressed the influence of pedometers and a pretest on walking intentions and behaviour. Using a Solomon four-group design, 63 female university students were randomly assigned to one of four conditions: pedometer and pretest (n = 16), pedometer and no pretest (n = 16), no pedometer and pretest (n = 15), no pedometer and no pretest (n = 16). The pretest conditions included questions on walking, intentions to walk 12,500 steps per day, and self-efficacy for walking 12,500 steps per day. In the pedometer conditions a Yamax Digi-Walker SW 650 pedometer was worn for one week. All participants completed posttest questions. While significant pretest x pedometer interactions would have indicated the presence of pretest sensitisation, no such interactions were observed for either intention or self-reported walking. Wearing pedometers reduced intentions for future walking and coping self-efficacy. However, after controlling for pretest self-reported walking, pedometer use resulted in more self-reported walking. We conclude that wearing a pedometer increased self reported walking behaviour but that a pretest did not differentially influence walking intentions, behaviour, or self-efficacy. PMID- 20205027 TI - Disengagement beliefs in smokers: do they influence the effects of a tailored persuasive message advocating smoking cessation? AB - Disengagement beliefs function to reduce cognitive dissonance and a number of predictions with regard to disengagement beliefs have been tested and verified. However, the influence of disengagement beliefs on persuasion has not been studied yet. In a field-experiment, 254 smokers were randomly assigned to a persuasive message condition or a no-information control condition. First, it was assessed to what extent disengagement beliefs influenced persuasion. In smokers with low adherence to disengagement beliefs, quitting activity (attempting to quit) in the control condition was high, but this was not further increased by persuasive information on the negative outcomes of smoking. In contrast, smokers who strongly adhered to disengagement beliefs showed low quitting activity in the control condition, but significantly more quitting activity when they received the persuasive message. Second, it was studied what smokers do when they experience negative affect caused by the persuasive message. The results show that in smokers who strongly adhered to disengagement beliefs, negative affect was associated with less quitting activity. Although these results show that quitting activity as assessed at 2 and 8 months follow-ups was influenced by disengagement beliefs, point prevalence seven-day quitting was not. This study shows that adherence to disengagement beliefs is a relevant individual difference in understanding effects of smoking cessation interventions. PMID- 20205028 TI - Development and exploratory cluster-randomised opportunistic trial of a theory based intervention to enhance physical activity among adolescents. AB - This article reports the development and exploratory testing of a school-based intervention programme designed to enhance levels of physical activity in adolescents. The intervention is based on social cognitive theory (SCT), self regulation theory (SRT) and planning as evidence-based mediators of physical activity changes. Two classes, paired on socio-economic variables, were selected from each of eight Portuguese schools and randomly assigned to an intervention or control group (N = 291). Primary outcome was 'moderate to vigorous physical activity' (International Physical Activity Questionnaire) measured pre and post intervention and at three and nine months follow-up. SCT, SRT and planning variables were secondary outcomes measured pre and post intervention. At post test, participants in the intervention group reported 18 min per week more physical activity (PA), adjusted for pre-intervention, age and sex, than those in the control group (95% confidence interval -10 to 46; p = 0.249). This difference increased to 33 min (95% CI-4 to 71; p = 0.082) at three months and to 57 min (95% CI 13 to 101, p = 0.008) at nine month follow-up. Moreover, the intervention resulted in changes of some of the theoretical target variables, including outcome expectancies and coping planning. However, no evidence was found for the changes in theoretical moderators to mediate the intervention effects on behaviour. Implications for theory and for future research are discussed. PMID- 20205029 TI - Parental communication appears not to be an effective strategy to reduce smoking in a sample of Dutch adolescents. AB - This longitudinal study examined the reciprocal effects of the frequency of parent-adolescent communication on tobacco-related issues (smoking-specific communication), and adolescents' smoking. Participants were 428 Dutch older and younger siblings between 13 and 16 years old. Smoking-specific communication did not affect youth smoking in general; however, among younger, but not older, siblings, smoking-specific communication was associated with a higher likelihood of smoking over time. In addition, when adolescents already smoked parents started to talk more frequently about smoking-related issues with their older and younger adolescents later on. Neither the quality of smoking-specific communication, the quality of parent-adolescent relationship, nor parental smoking moderated these reciprocal effects. In conclusion, prevention campaigns encouraging parents to undertake smoking-specific communication might not be desirable. PMID- 20205030 TI - Applying multiple models to predict clinicians' behavioural intention and objective behaviour when managing children's teeth. AB - This study used multiple theoretical approaches simultaneously to predict an objectively measured clinical behaviour. The six theoretical approaches were: The Theory of Planned Behaviour (TPB), Social Cognitive Theory (SCT), Common Sense Self-Regulation Model (CS-SRM), Operant Learning Theory (OLT), Action Planning (AP) and the Precaution Adoption Process (PAP), with knowledge as an additional predictor. Data on variables from these models were collected by postal survey. Data on the outcome behaviour, the evidence-based practice of placing fissure sealants, was collected from clinical records. Participants were 133 dentists (64% male) in Scotland. Variables found to predict the behaviour were: intention, attitude, perceived behavioural control, risk perception, outcome expectancies, self efficacy, habit, anticipated consequences, experienced consequences and action planning. The TPB, SCT, AP, OLT and PAP significantly predicted behaviour but the CS-SRM did not. A combined (Stepwise) regression model included only intention and action planning. Post hoc analyses showed action planning mediated effect of intention on behaviour. Taking a theory-based approach creates a replicable methodology for identifying factors predictive of clinical behaviour and for the design and choice of interventions to modify practice as new evidence emerges, increasing current options for improving health outcomes through influencing the implementation of best practice. PMID- 20205031 TI - Current issues and new direction in psychology and health: epidemiology and health psychology--please bridge the gap. AB - Epidemiology has and continues to play a vital role in furthering our understanding of risks for disease development. Large scale studies provide the necessary statistical power to identify biological and environmental factors associated with disease onset and severity. However, association does not confirm causality and in theoretical terms, epidemiology is somewhat limited. In this editorial, we argue that bringing together the methodological strengths of epidemiology with the theoretical rigour of psychology enables researchers to go beyond risk-finding and develop causative [or explanatory] models of disease development which pave the way for directed, evidence-based interventions to improve health. PMID- 20205032 TI - The health benefits of writing about positive experiences: the role of broadened cognition. AB - This study tested the potential to elicit a broadened attentional focus through writing about a positive life experience and to derive health benefits from such writing. Participants (n = 38) wrote for 20 min each day for 3 consecutive days about either a positive life experience or a control topic. Writing about positive experiences led to improved physical health (measured 4-6 weeks after writing) compared to control and higher levels of global cognitive focus after writing mediated this effect. Notably, while the positive writing condition was more broadened than control, positive affect was not responsible for this difference. Implications for disclosive writing and the broaden and build model are discussed. PMID- 20205033 TI - Do I feel sadness, fear or both? Comparing self-reported alexithymia and emotional task-performance in children with many or few somatic complaints. AB - Children with many somatic complaints seem to report problems with emotion identification and communication ('alexithymia'). The aim of this study was to verify whether children with somatic complaints do indeed show signs of alexithymia. We compared 35 children (M age = 10.99, SD = 13 months) with many somatic complaints with 34 children (M age = 11.03, SD = 12 months) reporting few complaints on the basis of a self-report alexithymia scale and tasks that require the skill to identify and communicate emotions: an emotional attention task, a structured interview about own emotions, and a mixed-emotion task. Children were also asked about the intensity of the reported emotions. Compared to children with few complaints, children with many complaints seemed to have higher self reports of alexithymia. However, these results were explained by difficulty in communicating negative internal states and experiencing indefinable internal states, rather than difficulty in identifying emotions. In addition, children with many complaints reported higher intensities of fear and sadness. The children did not differ in their attention to emotions or causes of emotions. Children with many somatic complaints more often described previous emotional experiences and showed better abilities in identifying multiple emotions. Children with many somatic complaints thus show more negative emotional processing, but the alexithymia-hypothesis was unsupported. PMID- 20205034 TI - Responding to negative health events: a test of the bad news response model. AB - People can respond to bad news in a variety of ways. The Bad News Response Model suggests that three aspects of bad news (the controllability, likelihood, and severity of negative consequences) predict which response (Watchful Waiting, Active Change, or Acceptance) people are likely to choose. This article presents an initial test of the predictions of the Bad News Response Model. College students (N = 234) and older adults (N = 116) read a scenario about a person with a suspicious mole that varied in the controllability, likelihood, and severity of the outcomes. Consistent with our predictions, people prefer Watchful Waiting when controllability, likelihood, and severity are low, Active Change when controllability and likelihood are high, and Acceptance when controllability is low. These findings provide support for the Bad News Response Model and suggest that responses to bad news may be foreseeable based on the type of news people receive. PMID- 20205035 TI - The effects of monitoring and ability to achieve cognitive structure on the psychological distress during HIV testing. AB - Many people undergoing HIV testing experience substantial psychological distress. The psychological distress associated with testing may be influenced by monitoring. Monitoring refers to a strategy wherein a person tends to seek out information concerning threatening events. Furthermore, the ability to achieve cognitive structure (AACS) may influence the relationship between monitoring and psychological distress. The present study examined individuals who were undergoing HIV testing. Specifically, the researchers examined the association among monitoring and AACS on psychological distress during HIV testing. Results indicated that there was no interaction between monitoring and AACS on psychological distress. It was found that AACS was related to participants' level of psychological distress. However, the level of monitoring was not related to participants' psychological distress. Limitations of the study, clinical implications and suggestions for future research are also discussed. PMID- 20205036 TI - The relationship between mental vitality and cardiovascular health. AB - Past measurement of vitality has included both emotional and physical components. Since aspects of physical vitality such as fatigue can be indicative of physical illness, the usefulness of existing measures of vitality to predict health is limited. This research was designed to examine the psychometric properties of a new Mental Vitality Scale and to test its associations with measures of cardiovascular health over the course of 2 years. The measure of mental vitality was administered in a two-part study using three different samples. In part 1, the reliability and validity of the scale was assessed with a student and a clinic sample. In part 2, medical data on mental and physical health were abstracted over a two-year period from 1041 patient records from a multi specialty medical practice, and mental vitality assessed through a mailed questionnaire. The findings indicate that the Mental Vitality Scale is a valid and reliable questionnaire for measuring this construct. Mental vitality was also associated with reduced odds of several cardiovascular outcomes and prospective analyses suggest that mental vitality may serve a protective function in the development of cardiovascular disease. The results lend support for the importance of mental vitality as a construct that may be relevant for considering resilience in relation to cardiovascular disease. PMID- 20205037 TI - Rural breast cancer patients, coping and depressive symptoms: a prospective comparison study. AB - Many studies have revealed that individual differences in coping responses to the diagnosis and treatment of breast cancer are associated with psychological adjustment. The vast majority of these studies, however, focus exclusively on urban breast cancer survivors despite that rural breast cancer survivors are likely to have distinct experiences both in general and in relation to breast cancer. The current study quantitatively examined the coping strategies employed by both rural and urban breast cancer patients while they were undergoing radiation therapy. Further, the influence of these coping behaviours on concurrent as well as subsequent depressive symptoms (3 and 6 months later) was examined. The results revealed that the rurality of breast cancer patients was unrelated to the ways in which they coped, but did influence the relationships between some coping responses and depressive symptoms. Specifically, active coping and positive reinterpretation were negatively related to depressive symptoms for more rural breast cancer patients, but not their relatively urban counterparts. Similarly, behavioural disengagement was more strongly related to depressive symptoms for more rural patients. Possible reasons for this pattern of results and implications are discussed. PMID- 20205038 TI - Perceived stigma, self-blame, and adjustment among lung, breast and prostate cancer patients. AB - People who suffer from disease have often been stigmatised. The internalisation of stigma leads to the experience of self-blame. The relationship among stigma, self-blame and adjustment was framed with two theoretical perspectives: the looking-glass self and learned helplessness models. These models were studied in 96 lung, 30 breast and 46 prostate cancer patients. Consistent with the looking glass-self model, we predicted that perceived stigma and self-blame would be associated with poorer psychological adjustment; the data supported these hypotheses. Consistent with the learned helplessness model, we predicted that self-blame would mediate the link between perceived stigma and psychological adjustment; data supported these hypotheses. The mediation model explained a greater percentage of the variance in adjustment in the lung cancer sample compared to the breast and prostate cancer sample. Participants who reported internal causal attributions reported poorer psychological adjustment. Lung cancer patients were more likely than breast or prostate cancer patients to report internal causal attributions for their cancer. Future research and cancer care are discussed in light of these findings. PMID- 20205040 TI - Gender role conflict and emotional approach coping in men with cancer. AB - The utility of emotional approach coping (EAC), or expressing and processing emotions, has been equivocal for men. Gender role conflict, or the negative cognitive, emotional and behavioural consequences associated with male gender role socialisation, likely shape coping responses and may negatively affect the efficacy of men's emotion-directed coping efforts and adjustment to cancer. Perceptions of receptiveness of one's interpersonal environment may be particularly important to the effectiveness of EAC. This study examined the relationships among EAC, gender role conflict, and distress in a group of 183 men with cancer. Structural equation modelling revealed that higher gender role conflict was associated with lower emotional expression, which in turn was associated with greater distress. Gender role conflict was not related to emotional processing. Higher gender role conflict also was associated directly with more distress. In subsequent analyses, social constraints and age were examined as possible moderators of EAC. Emotional expression was related to more psychological distress for those in highly constrained environments; and emotional processing was associated with more distress with younger age. Emotional expression may be particularly affected by social influences related to gender and social receptivity. More research is needed to better distinguish constructive and unconstructive emotional processing. PMID- 20205041 TI - Current issues and new directions in psychology and health: the genetics of obesity--what is the role for health psychology? PMID- 20205039 TI - Fatigued breast cancer survivors: the role of sleep quality, depressed mood, stage and age. AB - Cancer-related fatigue is associated with lower health-related quality of life and the majority of breast cancer survivors experience persistent fatigue after finishing treatment. The present study examines age, cancer stage, sleep quality and depressed mood as predictors of five dimensions of fatigue in 70 fatigued breast cancer survivors who no longer evidenced any signs of cancer and were finished with treatment. Discriminant function analyses were used to predict fatigue subgroup membership (higher, lower) from age, stage, mood and sleep for five subtypes: General, Mental, Emotional, and Physical fatigue, and Vigour. Significant discriminant functions were found for all subtypes. Findings suggest that age, staging, mood and sleep are all important predictors, but there are differential relationships when subtypes of fatigue are considered. Given current limitations in treating fatigue directly, interventions targeting mood and sleep should be considered as alternate approaches to reduce fatigue. PMID- 20205042 TI - Why women of lower educational attainment struggle to make healthier food choices: the importance of psychological and social factors. AB - Women of lower educational attainment are more likely to eat unhealthy diets than women of higher educational attainment. To identify influences on the food choices of women with lower educational attainment, 11 focus groups (eight with women of lower, and three with women of higher educational attainment) were held. Using a semi-structured discussion guide, environmental, social, historical and psychological factors known to be associated with food choice were explored. Audio recordings were transcribed verbatim and thematically analysed. Compared to women of higher educational attainment, women of lower educational attainment had less control over their families' food choices, less support for attempts to eat healthily, fewer opportunities to observe and learn good food-related practices, more negative affect, more perceived environmental constraints and more ambiguous beliefs about the consequences of eating a nutritious diet. These findings provide a starting point for taking forward the design of an intervention to improve the diets of young women. PMID- 20205043 TI - Weight-based discrimination, body dissatisfaction and emotional eating: the role of perceived social consensus. AB - OBJECTIVE: Discrimination can have a negative impact on psychological well-being, attitudes and behaviour. This research evaluates the impact of experiences of weight-based discrimination upon emotional eating and body dissatisfaction, and also explores whether people's beliefs about an ingroup's social consensus concerning how favourably overweight people are regarded can moderate the relationship between experiences of discrimination and negative eating and weight related cognitions and behaviours. RESEARCH METHODS AND PROCEDURES: 197 undergraduate students completed measures about their experiences of weight-based discrimination, emotional eating and body dissatisfaction. Participants also reported their beliefs concerning an ingroup's attitude towards overweight people. RESULTS: Recollections of weight-based discrimination significantly contributed to emotional eating and body dissatisfaction. However, the relationships between experiencing discrimination and body dissatisfaction and emotional eating were weakest amongst participants who believed that the ingroup held a positive attitude towards overweight people. DISCUSSION: Beliefs about ingroup social consensus concerning overweight people can influence the relationships between weight-based discrimination and emotional eating and body dissatisfaction. Changing group perceptions to perceive it to be unacceptable to discriminate against overweight people may help to protect victims of discrimination against the negative consequences of weight-based stigma. PMID- 20205044 TI - Watching your weight? The relations between watching soaps and music television and body dissatisfaction and restrained eating in young girls. AB - Although previous research showed that the thin ideal provided by the media affects body image and eating behaviour in young children, less is known about specific media contents that are related to body image and eating behaviour. This study tested the associations between watching soaps and music television and body dissatisfaction and restrained eating directly, and indirectly through thin ideal internalisation. We conducted a survey in class, in which 245 girls (aged 7 9) completed scales on their television watching behaviour, thin ideal internalisation, body dissatisfaction and restrained eating. Additionally, height and weight were measured. Watching soaps and music television often was associated with higher thin ideal internalisation, which in turn was associated with higher body dissatisfaction and restrained eating. Furthermore, a direct association between watching soaps and music television and restrained eating was found. If watching other types of children's programmes or maternal encouragement to be thin were included in the models, watching soaps and music television remained an important factor, especially with regard to restrained eating. Therefore, our results suggest that if young girls watch soaps and music television often, this is related to higher restrained eating and body dissatisfaction, directly or indirectly, through higher thin ideal internalisation. PMID- 20205045 TI - Neuroticism, conscientiousness and fruit consumption: exploring mediator and moderator effects in the theory of planned behaviour. AB - Integrating the theory of planned behaviour (TPB) with the five-factor model (FFM) of personality may provide insight into the cognitive and motivational mechanisms linking personality with health behaviour, but this issue has received very little attention regarding fruit consumption. Mediator effects of TPB concepts in the personality-fruit consumption link, as well as moderator effects of personality in the intention-fruit consumption link, were therefore investigated in the present study. Data on fruit consumption, TPB concepts and FFM dimensions were gathered among 405 respondents in face-to-face interviews using questionnaires. Structural equation modelling was used to investigate the mediator and moderator effects. The direct effect of conscientiousness on fruit consumption was mediated by attitude and perceived behavioural control, while no direct effect of neuroticism on fruit consumption was found. Neuroticism moderated the intention-fruit consumption relationship with the weakest relationship for those scoring high on neuroticism. Conscientiousness did not moderate the intention-fruit consumption relationship. TPB variables are mediators in the conscientiousness-fruit consumption link. Whether fruit consumption is intentional may be dependent upon the personality dimension neuroticism. Personality dimensions may be a useful addition to the TPB and should be considered in health behaviour change interventions. PMID- 20205046 TI - Comparison of the role of self-efficacy and illness representations in relation to dietary self-care and diabetes distress in adolescents with type 1 diabetes. AB - This cross-sectional study examined the joint effects of self-efficacy and illness representations on dietary self-care and diabetes distress in adolescents with type 1 diabetes by comparing two theoretical models: the Self-regulation Model (Leventhal, H., Meyer, D., & Nerenz, D. (1980). The common-sense representations of illness danger. In S. Rachman (Ed.), Medical Psychology (Vol. 2, pp. 7-30). New York: Pergamon.) and Social Cognitive Theory (Bandura, A. (1997). Self efficacy: The exercise of control. New York: W.H. Freeman.). One hundred and fifty-one adolescents with type 1 diabetes completed self-report measures of dietary self-efficacy, illness representations, dietary self-care and diabetes distress. Data were analysed using structural equation modelling. The model best supported by the data (Leventhal's Self-regulation Model) showed that dietary self-efficacy, perceived consequences and treatment effectiveness had direct and independent effects on both dietary self-care and diabetes distress. Together with dietary self-efficacy, perceived short-term treatment effectiveness was a significant predictor of dietary self-care. Age was found to be a negative predictor of short-term treatment effectiveness beliefs. Diabetes distress was best predicted by self-efficacy and perceived consequences. It can be concluded that to target effectively dietary self-care and distress, clinicians should focus on key illness representation variables (perceived short-term treatment effectiveness and perceived consequences) in conjunction with self-efficacy. PMID- 20205047 TI - Direct, mediated and moderated impacts of personality variables on smoking initiation in adolescents. AB - Role of 'Big Five' personality traits as predictors of smoking and moderators of the intention-smoking relationship was tested. Five hundred and fifty-three adolescents (aged 11-12) completed measures of self-reported past smoking, gender, intentions to smoke, perceived behavioural control, family smoking, friends smoking at times 1 and 2 (6 months apart). At time 3, 2 years later, the same adolescents completed measures of the Big Five and self-reported smoking (a subset of 300 also provided an objective smoking measure). At time 4, two years after time 3, a sub-sample of 122 adolescents provided a self-report measure of recent smoking. Simple correlations indicated significant direct effects of conscientiousness (self-reported smoking, times 3 and 4), extraversion (time 4 smoking) and neuroticism (all smoking measures) on smoking. Logistic regression showed intention, and the interaction between conscientiousness and intention to significantly predict both self-reported and objectively assessed smoking (both at time 3) after controlling for other variables. Multiple regression showed intentions, family smoking and the interaction between conscientiousness and intention to significantly predict self-reported smoking at time 4 after controlling for other variables. The findings indicate that the impact of personality variables on smoking is through mediated (through cognitions) and moderated (conscientiousness by intention interaction) pathways. PMID- 20205048 TI - Associations between visual attention, implicit and explicit attitude and behaviour for physical activity. AB - The current study explored associations between previous physical activity and both implicit and explicit attitudes, as well as visual attention and activity motivation (intention). Analyses were performed on participants initially unaware of the physical activity focus of the study (N = 98). Higher levels of physical activity were associated with positive implicit attitudes and an attentional bias towards exercise cues. There was a quadratic ('U' shaped) relationship between implicit attitude and attention: the more extreme individuals' implicit attitudes towards exercise (positive or negative) the greater their attentional bias to exercise cues. Furthermore, explicit attitude moderated the relationship between attentional bias and physical activity: attentional bias to exercise cues was associated with higher levels of physical activity only for those who had a strong positive explicit attitude. Findings suggested that implicit cognitions are linked with previous physical activity. Future research should consider strategies for strengthening positive implicit and explicit attitudes and directing attention to cues signalling healthy behaviour. PMID- 20205049 TI - Toward the optimization of stent-based treatment for coronary artery disease. AB - Coronary artery disease consists of obstruction (stenosis) of the coronary arteries by the deposition of atherosclerotic plaques, resulting in an insufficient supply of oxygen to the heart muscle. Treatment options include the insertion of a stent - a metal mesh tube - into the obstructed vessel to keep the artery open, thus preventing acute occlusion and restenosis. The occlusion of vessels resulting from subacute stent thrombosis and late in-stent restenosis are potential complications after successful revascularization. However, the rate of stent thrombosis has been reduced dramatically by means of adequate antiplatelet therapy, and in-stent restenosis has been addressed successfully with drug eluting stents. These drug-eluting stents are engineered to release bioactive agents into the affected blood vessels, plaques or tissues adjacent to the stent. Various antimitotic, anti-inflammatory, and anticoagulant immunosuppressive agents have been attached to stents, including sirolimus and tacrolimus. Future opportunities include the use of gene therapies released from gene-eluting stents. These advances highlight some of the opportunities for optimizing stent based treatment for coronary artery disease. PMID- 20205050 TI - Molecular basis of different outcomes for drug-eluting stents that release sirolimus or tacrolimus. AB - Sirolimus and tacrolimus are potent immunosuppressants that are delivered by drug eluting stents (DES) for the prevention of in-stent restenosis. Balloon angioplasty with stent implantation has emerged as a successful treatment for coronary stenoses; angioplasty dilates the vessel lumen and the stent prevents elastic recoil of the vessel walls. However, angioplasty and stent placement both produce vascular injuries that potently stimulate the proliferation of smooth muscle cells, resulting in a thickening of the vascular wall. The purpose of DES is to deliver pharmacological agents that counteract neointimal hyperplasia. The sirolimus-eluting-stent reduces the incidence of in-stent restenosis significantly, whereas the tacrolimus-eluting-stent demonstrates no improvement in clinical benefit compared with a bare stent. Although sirolimus and tacrolimus have similar molecular structures, these drugs regulate immune activation via different mechanisms of action. The effects of this class of drugs are mediated by binding to the FK-506-binding proteins (FKBPs), which are highly evolutionarily conserved across species. This review highlights the structure and function of sirolimus, tacrolimus and FKBPs, with particular focus on recent observations that the two drugs target signaling pathways involved in the control of vascular smooth muscle apoptosis and proliferation directly. PMID- 20205051 TI - HSV-1-derived helper-independent defective vectors, replicating vectors and amplicon vectors, for the treatment of brain diseases. AB - HSV-1 is a neurotropic virus that displays several important adaptations to the nervous system of the host organism, each of which can be rationally exploited in the design of gene therapy vectors for neurological applications. Replication incompetent (replication-defective) helper-independent recombinant vectors are nontoxic tools for gene transfer that preserve most of the neurotropic features of HSV-1, particularly the ability to express genes after establishing latent infections, and are thus proficient candidates for therapeutic gene transfer in neurons. A clinical trial with the use of a replication-incompetent vector, NP-2 (Diamyd Inc), for the treatment of pain has been initiated. Attenuated replication-competent (oncolytic) vectors are becoming suitable and powerful tools to eradicate brain tumors, such as malignant gliomas, as a result of the ability to replicate and spread only within the tumor mass. Some attenuated replication-competent vectors, such as G-207 and HSV-1716 (Crusade Laboratories Ltd), have been used in clinical trials for the treatment of cancers including recurrent malignant glioma. Helper-dependent amplicon vector technology takes advantage of the capacity of the virus particle to accommodate < or = 150 Kbp of foreign DNA, enabling these vectors to deliver complete genomic loci to the nucleus of mammalian cells, making amplicons particularly useful agents in protocols that require stable and physiological transgene expression. However, difficulties in obtaining large stocks of helper-free amplicons continue to limit the use of these vectors in the clinic. PMID- 20205052 TI - Contemporary immunotherapy of solid tumors: from tumor-associated antigens to combination treatments. AB - The possibility of using the immune system of patients to control tumor outgrowth in a therapeutic setting has always been highly appealing to both clinicians and researchers. However, although cancer cells express tumor-associated antigens that can be targeted by T-cells, clinical trials suggest that the induction of specific immune responses per se may be insufficient to achieve clinical goals. Based on these trial data, in addition to experimental data revealing the complexity of mechanisms controlling immune responsiveness, a reassessment of immunotherapy procedures is underway. As a result, a second generation of antitumor treatments that includes reagents of potential pharmaceutical relevance is being developed. In this review, the most recent literature addressing issues related to immunotherapy for solid tumors is discussed. PMID- 20205053 TI - Hsp90 inhibitors: clinical development and future opportunities in oncology therapy. AB - The development of small molecular mass Hsp90 inhibitors has become an increasingly competitive field of research in recent years. Progress in preclinical and clinical research has provided increasing evidence that Hsp90 represents a promising molecular target for the treatment of cancer and other diseases. Although many challenges remain, recent clinical trial results for the most clinically advanced inhibitors indicate that clinical proof of concept in oncology therapy is achievable, and that Hsp90 inhibitors have the potential to contribute to the collection of anticancer treatments available to clinicians and patients in the near future. PMID- 20205055 TI - Current and future treatments for relapsing-remitting multiple sclerosis. AB - The last decades of the twentieth century ushered in the first treatments proven to modify the disease course of multiple sclerosis (MS). These breakthroughs in MS therapy stimulated an increase in the search for drugs with improved efficacy and greater ease of administration. This review summarizes the latest developments in the search for improved disease-modifying therapies and defines the efficacies and potential risks of such compounds. As with all new drugs, accurate assessments of risk:benefit ratios will be essential for the successful use of any agent targeting MS. PMID- 20205054 TI - Site-specific gene therapy for cardiovascular disease. AB - Gene therapy holds considerable promise for the treatment of cardiovascular disease and may provide novel therapeutic solutions for both genetic disorders and acquired pathophysiologies such as arteriosclerosis, heart failure and arrhythmias. Recombinant DNA technology and the sequencing of the human genome have made a plethora of candidate therapeutic genes available for cardiovascular diseases. However, progress in the field of gene therapy for cardiovascular disease has been modest; one of the key reasons for this limited progress is the lack of gene delivery systems for localizing gene therapy to specific sites to optimize transgene expression and efficacy. This review summarizes progress made toward the site-specific delivery of cardiovascular gene therapy and highlights selected promising novel approaches. PMID- 20205056 TI - Improving the power of diagnostics in the era of targeted therapy and personalized healthcare. AB - The field of diagnostics has unprecedented opportunities to contribute to the practice of medicine in the era of targeted therapy and personalized healthcare. Rather than simply providing information regarding the presence and classification of disease, innovative molecular diagnostic tests will directly inform patient-management decisions, such as which targeted therapies to prescribe or whether a patient should be treated more aggressively. However, in order for diagnostics to deliver this high level of medical value, several challenges ranging from technical, pre-analytical, developmental, regulatory, reimbursement and quality perspectives need to be overcome. This review focuses on recent developments in each of these areas that are expected to improve the power and impact of diagnostics. PMID- 20205058 TI - Legislative initiatives in Europe, Canada and the US for market authorization of follow-on biologics. AB - The formulation and application of legal and regulatory requirements for the market authorization of follow-on versions of biological drugs present challenges. This review discusses relevant regulatory guidelines and legislative initiatives related to market authorization for follow-on biologics in Europe, Canada and the US. The respective positions of these three markets is analyzed with regard to several factors: criteria for the choice of reference products; requirements for the comparability exercise between a candidate follow-on biologic and the selected reference product, with an emphasis on considerations of quality, safety and efficacy data; the interchangeability of a reference product with related follow-on drugs; data exclusivity provisions; and the application of specialized patent enforcement mechanisms to follow-on biologics. PMID- 20205059 TI - [Complex regional pain syndrome (CRPS)]. PMID- 20205060 TI - [History, classification and clinic of the complex regional pain syndrome (CRPS)]. AB - Almost 150 years are gone since the first description of the classic symptoms, what is today summarized under the term CRPS. From a big number of different names, it has been agreed in 1986 to this term and has also defined more exactly the corresponding terms to it. In the pathophysiology of this complex of symptoms is today accepted that it is a combination of inflammatory, vegetative and central-nervous processes in different size and weight as a key position. There are hardly new findings in epidemiology and frequency. In opposite to this a number of results are produced by better methods for examination which let appear the connections in a new view and make new therapy options possible. PMID- 20205057 TI - Novel therapeutics for Alzheimer's disease: an update. AB - As the most prevalent form of dementia worldwide, Alzheimer's disease (AD) continues to be a burden for patients and their families. In addition, with the global population of aged individuals increasing exponentially, AD represents a significant economic burden to society. The development of an effective approach for the treatment of AD is thus of major importance, as current treatment strategies are limited to agents that attenuate disease symptomatology without addressing the causes of disease. A considerable need exists for the development of an effective therapy to prevent, or at least delay, the progression of AD. Current hypotheses for the pathogenesis of AD are discussed in this review, with a particular emphasis on the implications of these hypotheses with respect to treatment strategies and preventive measures. PMID- 20205061 TI - [Current concepts in pathophysiology of CRPS I]. AB - Knowledge about the pathophysiology underlying the complex regional pain syndrome (CRPS) has increased over the last years. Classically, CRPS has been considered to be mainly driven by sympathetic dysfunction with sympathetically maintained pain being its major pathogenetic mechanism. Currently, the disease is understood as result of a complex interplay between altered somatosensory, motor, autonomic and inflammatory systems. Peripheral and central sensitization is a common feature in CRPS as in other neuropathic pain syndromes. One important mechanism is the sensitization of spinal dorsal horn cells via activation of postsynaptic NMDA-receptors by chronic C-fiber input. Differential activity of endogenous pain modulating systems may play a pivotal role in the development of CRPS, too. Neuronal plasticity of the somatosensory cortex accounts for central sensory signs. Also the motor system is subject to central adaptive changes in patients with CRPS. Calcitonin-gene related peptide (CGRP) and substance P mediate neurogenic inflammation. Additionally other proinflammatory cytokines involved in the inflammatory response in CRPS have been identified. In terms of the sympathetic nervous system, recent evidence rather points to a sensitization of adrenergic receptors than to increased efferent sympathetic activity. Particularly the expression of alpha (1)-adrenoceptors on nociceptive C-fibers may play a major role. These pathophysiological ideas do not exclude each other. In fact they complement one another. The variety of the involved systems may explain the versatile clinical picture of CRPS. PMID- 20205062 TI - [Differential diagnosis of CRPS from a dermatologist's viewpoint]. AB - Because of clinical similarities many dermatological diseases must be differentiated from both the acute and chronic phases of the complex regional pain syndrome (CRPS). The differential diagnosis of CRPS in the acute phase includes erythema migrans, early inflammatory lesions of acrodermatitis chronica atrophicans, hypodermitis in chronic venous insufficiency, eosinophilic fasciitis, erythromelalgia and an acute contact dermatitis. The chronic phase of CRPS with trophic disturbances of the skin, joints, and bones needs to be distinguished from the atrophic stage of acrodermatitis chronica atrophicans, dermatoliposclerosis and scleroderma. PMID- 20205063 TI - [Drug treatment of CRPS]. AB - The main symptoms of excruciating pain, trophic and inflammatory changes, as well as functional impairment of limbs are the hallmark of the complex regional pain syndrome (CRPS). While functional impairments have to be treated by physical and occupational therapy, the former three symptoms are amendable to drug treatment: antidepressants, antiepileptic drugs and opioids are the most important drug classes for alleviating neuropathic pain whereas acute nociceptive pain may be positively influenced by non-steroidal anti-inflammatory drugs and steroids. In addition, calcitonin and the biphosphonates inhibit osteoclasts and therefore loss of bone mass and may thus also reduce pain. The use of sympatholytic agents beyond locoregional anesthesia techniques (which are covered elsewhere in this issue) is not unequivocal. In general, the evidence level for treatment strategies specifically for the complex regional pain syndrome is very poor; most recommendations and algorithms rely on results derived from studies testing drugs against other conditions where chronic (neuropathic) pain is prevalent, like diabetic polyneuropathy or postherpetic neuralgia, or medications are used on the basis of pathomechanistic considerations. PMID- 20205064 TI - [Complex regional pain syndrome (CRPS I) in hand surgery--misfortune of fate or avoidable? The viewpoint of a hand surgeon with many years of experience in this problem]. AB - The complex regional pain syndrome type I (CRPS I) is a complication of the healing process of the whole body, not solely a part of it (e. g., the hand), which is caused by a multiplicity of factors. My conviction that the CRPS should less be considered as a misfortune of fate but rather can be avoided in the majority of cases is based on my experience from the last 25 years. The most important prognostic factor is the time period between the first symptoms and the beginning of the therapy. PMID- 20205065 TI - [Complex regional pain syndrome versus chronic regional pain syndrome (Hand Finger Syndrome)]. AB - Dystrophy is a main factor of CRPS. A large number of patients do not develop dystrophy but, instead, they suffer from pain with limitation in movement, possible paraesthesia and/or swelling. This is then a chronic regional pain syndrome or (shoulder-arm-) hand-finger syndrome. These patients should never be confronted with the diagnosis Morbus Sudeck or algodystrophy, which are today also well known among non-professionals, to avoid pushing them into a status of constant severe invalidity. Histories, clinical examination, as well as a good personal understanding of the patient are indispensable. Knowing that pain, or the extent of pain, remains subjective until today, the clinical diagnosis depends on the absence of side differences in: a) the circumference of soft tissues of both upper extremities; b) the callosity of the palm; c) the bone density. These three parameters allow verification of the consequences of the pain complaints (indirect pain verification). It is essential to find the cause for their suffering and to treat it as far as possible: 1) Too long and inappropriate immobilisation (patient's suffering not considered sufficiently). These patients can recover quickly when the right diagnosis is made in good time. 2) Limitation of movement due to scar, neuroma, or elongation pain: a) bizarre functional disabilities can develop; b) due to the patient's complaints, one or several operations would finally be performed, which will not lead to an improvement but rather to an aggravation of the pain; c) socially-induced purposeful pain increase, the typical statement of the patient will be: "I can't stand it any longer". Patients who are socially over-burdened, or have psycho social problems, may experience a decline of performance or a post-traumatic stress disorder. Several patients will be introduced as illustrations for each of the relevant groups. PMID- 20205066 TI - [Increased sympathetic activity assessed by spectral analysis of heart rate variability in patients with CRPS I]. AB - PURPOSE: The complex regional pain syndrome type I (CRPS I) is a painful neuropathic disorder with an antecedent disproportionate trauma leading to spontaneous pain, hyperalgesia, impaired motor function, swelling, changes in sweating and vascular abnormalities without nerve injury. Whether this syndrome is the result of central or peripheral autonomic dysfunction is still a matter of debate. The purpose of this study was to determine the activity of the sympathetic nervous system in patients with CRPS I by power spectral analysis of heart rate variability. PATIENTS AND METHODS: This is a pilot study on 6 patients (mean age 50 years; 4 female, 2 male) diagnosed as suffering from CRPS I and 6 age-matched healthy controls. In the pain-free interval and after taking rest for 5 min, 512 subsequent heart beats were obtained with an ECG standard lead II in the supine and then sitting position. Using an autoregressive model, power spectral densities were calculated for the following frequency bands: <0.040 Hz (very low frequency; VLF), 0.040-0.150 Hz (low frequency; LF) and 0.150-0.4 Hz (high frequency; HF). The sympatho-vagal balance is expressed by the ratio of the low-frequency component (LF) to the high-frequency component (HF) of the power spectrum. RESULTS: Significant differences in the mean LF/HF ratios were found in the patients with CRPS I compared to the healthy controls in the supine position (LF/HF=4.01 vs. LF/HF=1.27; p=0.041). The application of stress by changing to the sitting position even increased that difference (6.72 vs. 1.93). CONCLUSIONS: Our results support the hypothesis that the pathogenesis of the early stage CRPS I might be related to an increased sympathetic activity. By assessing the autonomic influence on the heart rate variability in CRPS I patients we could also conclude that this disturbance occurs rather at a central level. PMID- 20205067 TI - [Factitious disorder and self-mutilation in hand and plastic surgery]. AB - Self-mutilation in the context of factitious disorder can lead to prolonged and complicated treatment in every medical field. Because of a prevalence of 1-5% in hospitalised patients, it is important to be aware of this disorder to protect patients from self- and foreign-induced harm. Often the patient history gives important hints. The different manifestations of this disorder, the specific doctor-patient relationship, several techniques of confrontation and current treatment are presented. Clinical cases from the fields of hand and plastic surgery are presented. PMID- 20205068 TI - [DASH data of non-clinical versus clinical groups of persons--a comparative study of T-norms for clinical use]. AB - AIM: The aim of this study was to determine a) data for the disabilities of arm, shoulder and hand (DASH) score of a non-clinical group as well as to establish b) a comparison of DASH data between different groups of people. PATIENTS AND METHODS: After collection of 716 DASH questionnaires from healthy, working individuals (non-clinical sample) and 795 questionnaires from patients with injuries and conditions of the upper extremity (clinical sample), the data were assessed according to age, gender, manually or non-manually working into DASH total, DASH activity, DASH impairment, DASH music/sport and DASH work scores. In order to establish a comparability, these data were transformed using T-norms. RESULTS: Median DASH data of the non-clinical sample showed a functional impairment, since they deviated from 0. Men, aged 50-65, who were working manually showed the highest DASH score. Age did not have a significant effect on the DASH score of the clinical sample. The median overall DASH score of the clinical sample was higher than the scores seen with the non-clinical sample. CONCLUSION: Using T-norms a reference framework has been established for DASH scores, thus making it possible to interpret and compare individual scores between patients. PMID- 20205069 TI - [Littler tenodesis for correction of swan neck deformity in rheumatoid arthritis]. AB - PURPOSE: The aim of this study was to assess the results of operative treatment for rheumatoid swan neck deformity using Littler's technique consisting in the reconstruction of the oblique retinacular ligament. PATIENTS AND METHOD: From 2004 to 2007 twenty rheumatoid patients with 30 PIP-joints affected by swan neck deformity underwent surgical correction. In all cases the tenodesis described by Littler was used. Modification of the operative procedure because of insufficiency of the Cleland ligament or the A2-pulley was in no case necessary. Twenty six PIP-joints in 17 patients could be examined after an average follow-up of 22 months. In two PIP-joints the deformity was contract and in 12 PIP-joints partially contract. In 10 joints a dorsal arthrolysis had to be performed and in one a lengthening of the central slip. All PIP-joints were transfixed in 30 degrees flexion. After 6 weeks the transfixing wire was removed and active PIP- joint mobilisation was allowed. Active extension was limited to 20 degrees of flexion until the end of the 12 (th) postoperative week. During this time an extension blocking splint was used. After the 12 (th) week free active and passive mobilisation of the PIP-joint was allowed. In a retrospective study pre- and postoperative range of motion, X-ray findings, pain and patient's content were examined. RESULTS: Swan neck deformity was corrected in all cases. Preoperative hyperextension of 21 degrees on average was corrected to 24 degrees of flexion. Thereby the ROM of 48 degrees was shifted from the extension sector to a ROM of 51 degrees towards the flexion sector. Recurrence of the deformity or complications were not noted. Pain could be reduced except in one patient. Radiologic changes were classified Larsen grade 2.2 before and 2.3 after operation. CONCLUSION: With the oblique retinacular ligament repair described by Littler reliable results can be achieved in rheumatoid swan neck deformity. It is indicated in contract and non-contract rheumatoid swan neck deformity when th PIP joints are radiologically in a stage of less than Larsen grade 3. It corrects the deformity at the level of the PIP-joint as well as the DIP-joint. PMID- 20205070 TI - [The primarly overlooked scaphoid fracture--a diagnostic challenge?]. AB - INTRODUCTION: Scaphoid fractures represent the most common carpal bone fractures. These fractures may be overlooked due to insufficient diagnostics and lead to non union and disability. A standardized diagnostic procedure with X-ray examinations, CT scans and/or MRI is recommended. We report on a case where a scaphoid fracture was overlooked, probably because of an incorrect technique of the computed tomography. CASE REPORT: A 42-year-old man was admitted to our emergency room after a fall on the out-stretched wrist. X-rays showed no evidence of a bony lesion. In the follow-up examination on the next day, a scaphoid fracture was still suspected clinically. Because of that a CT scan in thin slice technique with axial layers and multiplanar reconstruction was performed but showed no sign of a fracture. Six weeks after the trauma the patient presented with persistent wrist pain. X-rays and a CT scan of the wrist now demonstrated an old waist fracture of the scaphoid. -Operative treatment with iliac crest bone grafting and screw fixation was performed. DISCUSSION: Early diagnosis and a correct description of the fracture pattern are of high value in the treatment of scaphoid fractures. X-rays combined with a CT scan or an MRI scan of the affected wrist are considered as the diagnostic standard. The reported case demonstrates that even with a thin thickness layer CT scan in axial planes, a scaphoid fracture can be overlooked. Therefore we recommend after primarily inconspicuous X-rays a CT scan with primary -oblique-sagittal layers in the longitudinal axis of the scaphoid. If this shows no fracture and the clinical suspicion persists, an MRI scan should be performed. PMID- 20205072 TI - Natural orifice transluminal endoscopic surgery: cardiopulmonary safety of transesophageal mediastinoscopy. AB - BACKGROUND AND STUDY AIMS: Physiological reactions during natural orifice transluminal endoscopic surgery (NOTES) mediastinoscopy may lead to cardiorespiratory depression. The aim of the current study was to assess cardiopulmonary changes during transesophageal mediastinoscopy in an acute porcine model. METHODS: Transesophageal mediastinoscopy was performed under general anesthesia in eight female pigs with a bodyweight of 39 +/- 6 kg. Mediastinal access was achieved via a submucosal tunnel. The cardiac index and global end-diastolic volume index (reflecting preload) were measured every 3 minutes by transpulmonary thermodilution. The following parameters were also recorded: mediastinal pressure, heart rate, mean arterial pressure, systemic vascular resistance index (SVRI; reflecting afterload), peak inspiratory pressure, pH, pCO (2), and pO (2). RESULTS: In three animals, small tears in the parietal pleura resulted in tension pneumothoraces. The associated cardioplumonary deterioration was fatal in one pig. The other two pigs recovered after decompression with a chest tube. In the remaining five animals there were only mild hemodynamic and respiratory changes during mediastinoscopy. There was a significant ( P = 0.005) but minor transient fall in cardiac index, which correlated with a small rise in SVRI (r = - 0.857, P < 0.001). In the pigs with uncomplicated mediastinoscopy, on-demand insufflation via the endoscope resulted in median mediastinal pressures of 4.5 mm Hg (range 2.3 - 10.2 mm Hg). Overall, mediastinal and thoracic structures could be identified without difficulty via the transesophageal approach. CONCLUSIONS: NOTES mediastinoscopy carries a substantial risk of inadvertent development of a pneumothorax. Otherwise, it leads to negligible hemodynamic and pulmonary changes. In conclusion, close monitoring for the presence of a pneumothorax during NOTES mediastinoscopy appears to be mandatory. PMID- 20205073 TI - [Stromal tumour of uncertain malignant potential of the prostate (STUMP) - a case report]. AB - A prostatic stromal tumour of uncertain malignant potential (STUMP) is a non epithelial, mesenchymal spindle-cell tumour that can be classified as a specialised stromal tumour of the prostate. Although in most cases STUMP is not of an aggressive nature, occasional cases have been documented with an extension into adjacent tissues or recurrence after resection. A minority of cases develop a sarcomatous dedifferentiation.We report the case of a 53-year-old male with symptoms of febrile prostatitis. After consolidation we performed TUR-P due to urinary retention. Finally, we made the pathological diagnosis of prostatic STUMP. The patient is being seen -frequently in our clinic to take prostate biopsies to exclude a progression into a stromal sarcoma (active surveillance). After 13 months the STUMP is still detectable, but with no signs of sarcoma. PMID- 20205074 TI - Long-term assessment of Asenapine vs. Olanzapine in patients with schizophrenia or schizoaffective disorder. AB - INTRODUCTION: We conducted a double-blind 1-year trial of asenapine in patients with schizophrenia or schizoaffective disorder. METHODS: Patients were randomized to asenapine (5 or 10 mg BID; n=913) or olanzapine (10-20 mg QD; n=312), and monitored regularly. RESULTS: Trial completion rates were 38% with asenapine, 57% with olanzapine; main reasons for discontinuation were withdrawal of consent (22%, 16%) and insufficient response (25%, 14%); fewer discontinuations were due to adverse events (6%, 7%). Mean weight gain was 0.9 kg with asenapine, 4.2 kg with olanzapine. Extrapyramidal symptoms reported as adverse events were more common with asenapine. Mean reductions in PANSS total score with asenapine and olanzapine were -21.0 and -27.5 ( P<0.0001); the exclusion of patients who had previous poor experience with olanzapine may have biased the results in favor of olanzapine. Scores on the subjective well-being on neuroleptics scale and functionality measures were similar between groups. CONCLUSION: Asenapine was well tolerated over 1 year of treatment, causing less weight gain than olanzapine but more frequent extrapyramidal symptoms. PANSS total score improved with both agents; the improvement was greater with olanzapine than with asenapine using last observations carried forward but not in an observed-case analysis. PMID- 20205075 TI - Quetiapine improves sleep disturbance in acute bipolar disorder: a case series. PMID- 20205077 TI - [Associations between early-onset mental disorders and educational attainment in Belgium; a population study]. AB - BACKGROUND: There is no sufficient knowledge on the association between early onset mental disorders and subsequent school dropout on the level of the Belgian general population. AIM: To investigate the associations between early-onset mental disorders and subsequent school dropout. METHOD: As part of the European Study on the Epidemiology of Mental Disorders of the World Mental Health Surveys of the World Health Organization, a representative random sample of non institutionalised Belgians aged 18 or older (n = 1,043) were interviewed between April 2001 and June 2002. With the Composite International Diagnostic Interview (version 3.0), respondents were assessed for the presence and age of onset of 15 dsm-iv mental disorders. Logistic regression analyses were performed in order to investigate the association between mental disorders and subsequent failure to complete elementary and/or secondary education, failure to proceed to tertiary education (when holding a secondary education leaving certificate) and failure to completion of tertiary education. RESULTS: Mood disorders were significantly associated with premature termination of secondary education (or = 2.4). Anxiety disorders (or = 2.0), drug abuse disorders (or = 11.2), and drug dependence disorders (or = 19.4) were significantly associated with failure to proceed to tertiary education. The cumulative proportion of early school terminations attributable to earlyonset mental disorders was estimated at 6.3%. CONCLUSION: Early-onset mental disorders have a considerable impact on school termination prior to completion in Belgium. PMID- 20205079 TI - [Positive visual perceptual disorders. Nomenclature and classification]. AB - BACKGROUND: Our knowledge about the neurobiological correlates of positive visual perceptual disorders is increasing rapidly. If we are to understand and integrate this emerging knowledge, the nomenclature needs to be clear and unambiguous. AIM: To provide an overview of the different classifications of visual hallucinations to reach a better understanding of new neurobiological views in these phenomena. METHOD: Relevant data were obtained from books, PubMed, Embase, and the Cochrane Library. RESULTS: The results are presented in the form of various classifications of visual hallucinations, grouped according to the following guiding principles: shape, size, content, relation to the sleepwake cycle, co occurrence with percepts in any of the other sensory modalities, and association with neurobiological correlates. In addition, a classification system for visual illusions and distortions is presented. CONCLUSION: The overview emphasizes how important it is to reappraise the concepts of positive visual perceptual disorders that were developed during the era of classical psychiatry. By becoming familiar with these concepts we will find it easier to design, execute and interpret neurobiological studies of these frequently occurring phenomena. PMID- 20205078 TI - [Numbers and patterns in compulsory admissions in 3 Dutch cities; problems in urban areas and regional differences in the implementation of the law on special admissions to psychiatric hospitals]. AB - BACKGROUND: In the Netherlands little research has been done on the regional variability in the implementation of the law on Special Admissions to Psychiatric Hospitals (Dutch acronym Bopz). AIM: To investigate regional variability in the numbers, combinations and characteristics of emergency compulsory admissions and other types of legally authorised admissions. METHOD: Data from the Bopz information system covering a 12-month period were analysed. Missing data were supplied by the courts in Maastricht, Groningen and Rotterdam. RESULTS: There was regional variability in the way in which compulsory measures were implemented, particularly as far as emergency compulsory admissions were concerned. The relative number of Bopz measures increased in relation to the degree of urbanisation. Rotterdam had the highest percentage of emergency compulsory admissions. Patients in Maastricht and Rotterdam were more often involved in legally authorised admissions only. In Rotterdam an unlinked combination of emergency compulsory admissions and legally authorised admissions was more common. In Maastricht a larger number of patients were admitted because they were a danger to themselves, whereas in Groningen and Rotterdam admissions were also used as a means of safeguarding the public. CONCLUSION: The number of admissions and the diversity of Bopz measures are highest in urban areas. Regional variations in the way in which compulsory measures are applied persist, but there is room for improvement in the monitoring of the effects of these differences and the types of services that are available. PMID- 20205080 TI - [Routine Outcome Monitoring for patients with severe mental illness: a consensus document]. AB - BACKGROUND: Routine outcome monitoring (ROM) means the assessment of the patient's condition on a routine basis using instruments. So far there is no consensus about which instruments should be used for ROM with severely mentally ill patients (ROM-SMI). AIM: To reach a consensus about instruments for ROM-SMI in the Netherlands and Belgium and to create possibilities for comparison of ROM data. METHOD: This article discusses the consensus document of the National Remission Working Group for ROM in patients with smi and covers the following topics: reasons for ROM-SMI, domains for ROM-SMI and appropriate instruments, logistics and analyses of the data. RESULTS: Patients with SMI have problems in several domains. These can be assessed by collecting information about psychiatric symptoms, addiction, somatic problems, general functioning, needs, quality of life and care satisfaction. Potential instruments for ROM-SMI are short, valid, reliable and assess several domains, taking the patient's perspective into account, and have been used in national and international research. The working group advises institutions to choose from a limited set of instruments. After the scores have been aggregated and standardised, comparisons can be drawn. ROM-SMI data can be interpreted more meaningfully, if outcome data are supplemented with data regarding patient characteristics and the treatment interventions already applied. CONCLUSION: It should be possible to reach a consensus about instruments for ROM-SMI and the way in which they should be used. The use of identical instruments will lead to improvements in mental health care and create possibilities for comparison (benchmarking) and research. PMID- 20205081 TI - [First generation versus second generation antipsychotics: little benefit in the real world]. AB - In the last five years seven independently financed studies comparing first and second generation antipsychotics (FGAS and SGAS) have been published. Most of these studies were conducted among patients attending regular psychiatric practices. The results show that very few or no advantages are to be gained from using SGAS rather than FGAS. In general, the clinical effectiveness is not increased, but the side-effects are different. The effectiveness studies in fact definitely justify the selection of FGAS (particularly those of low and medium potency) if a change in medication is indicated. PMID- 20205082 TI - [Imaginal exposure treatment for a post-traumatic stress disorder in a patient with a comorbid psychotic disorder]. AB - A patient suffering from both post-traumatic stress disorder (PTSD) and a comorbid schizoaffective disorder was treated with imaginal exposure treatment. After 26 sessions the ptsd symptoms were in full remission. This was still the case at follow-up after 12 and 24 months. Furthermore, the patient was no longer on antipsychotic medication. The case shows that ptsd can be treated successfully even if patients have a psychotic disorder. In view of the severity of both disorders it is at least worth trying imaginal exposure treatment. PMID- 20205084 TI - [What is your diagnosis?]. PMID- 20205083 TI - [Depression]. PMID- 20205085 TI - [Controlled release hydromorphone for visceral, somatic and neuropathic pain]. AB - The aim of this multicentre, longitudinal investigation was to document the efficacy and tolerability profiles of controlled release hydromorphone in patients with heavy visceral, somatic or neuropathic pain under practical conditions. To this end, a prospective observational study was conducted in 57 centres in Switzerland, on a total of 196 patients. After an average of 43 days of treatment with controlled release hydromorphone, the intensity of momentary pain dropped by 46.5% and that of maximum pain dropped by 41.3%, with the efficacy of the treatment being most pronounced with visceral and somatic pain. At the same time, the prevalence of sleep disorders as a result of pain decreased from initially 86.7% to 21.0%. Controlled release hydromorphone was excellently tolerated in this group of elderly (average age 70.6 years), multimorbid pain patients receiving various medical treatments (average of 2.4 drugs in addition to pain medication), even in the voluntary long-term extension study of up to 96 days. No medical interactions were reported. Six and thirteen weeks after introducing the treatment, 89.8% and 85.2%, respectively, were still taking controlled release hydromorphone. Controlled release hydromorphone is a recommendable option for practical treatment of heavy and extremely heavy pain of various genesis. PMID- 20205086 TI - [Comments on rule of fist 8]. PMID- 20205087 TI - [Glioblastoma multiforme--new hope due to modern therapeutical approaches]. AB - Glioblastoma multiforme (GBM) is the most frequently encountered malignant cerebral tumor. Despite significant improvements in the treatment of GBM, this disease remains associated with a high morbidity and mortality, with more than half of all affected patients dying within the first year after diagnosis. Typical symptoms include focal neurological symptoms, seizures, personality changes and neurocognitive symptoms. GBM can be identified by means of cerebral imaging modalities and subsequently confirmed histopathologically through biopsy or resection. At present, surgical resection followed by radiotherapy with concomitant chemotherapy with temozolomide and subsequent adjuvant chemotherapy with temozolomide is considered the standard therapy for patients with GBM. Currently, many interdisciplinary studies with glioblastoma patients are accomplished with the aim to further improve the prognosis of the affected patients. PMID- 20205088 TI - [Tennis elbow]. PMID- 20205089 TI - [Confusion, gait ataxia and ophthalmoplegia in a patient with chronic alcohol consumption]. AB - Wernicke encephalopathy is a neurological disorder, often caused by a lack of thiamine. Immediate diagnosis and therapy are important to prevent significant morbidity and mortality. Based on a clinical case radiologic imaging features on MRI are demonstrated. PMID- 20205090 TI - [Myoclonia in an oldest old woman: a frequent and reversible etiology]. AB - A 98-year-old woman was referred to our hospital because of myoclonia. The concentration of calcium and vitamin D in the serum was low. In this context, we concluded of neuromuscular irritability secondary to hypocalcaemia. The symptoms disappeared after a treatment of intravenous calcium. This case shows how important it is to investigate electrolytes in case of neuromuscular irritability symptoms in elderly people. PMID- 20205091 TI - [Prognosis in chronic backache not as bad as assumed up to now]. PMID- 20205092 TI - [Carpal tunnel syndrome: surgical treatment better than non-surgical therapy]. PMID- 20205093 TI - [Answers to questions on subacute and chronic cough from PRAXIS No. 4]. PMID- 20205094 TI - [CME--Laboratory 15/ Solution]. PMID- 20205095 TI - [The physicians' art column]. PMID- 20205096 TI - [Physicians' literature riddle]. PMID- 20205097 TI - Problems in diagnostics of primary aldosteronism - analysis of the own data. AB - INTRODUCTION: During the last few years, increasing evidence suggests that primary aldosteronism is the cause of over 10% of arterial hypertension (AH). There are no "gold standard" methods for PA screening. The aim of study was plasma renin activity (PRA), plasma aldosterone concentration (PAC), and ARR assessment as criteria for diagnosis of PA and their usefulness in clinical practice. MATERIAL AND METHODS: Eighty-one consecutive patients were admitted for diagnosis of primary aldosteronism: 51 women and 30 men, aged 31-69 years. In each patient, PAC and PRA were evaluated by radioimmunoassay. In 65 patients, urine concentration of catecholamine metabolites was assayed, and in 51 patients, diagnostics for hypercortisolaemia was carried out. In patients with adrenal incidentaloma, 16-row computer tomography was performed. RESULTS: The proportion of patients with PAC over 150 pg/ml was 35% (n = 28). The number of patients with PRA under 0.07 ng/ml/h was 19 (n = 15). The ratio of patients whose values of ARR exceeded over 20, 30, 40, 50, and 180 were 55, 47, 37, 28, and 15%, respectively. CONCLUSIONS: The most common indication for primary screening was the presence of incidentally found adrenal mass. The quotient of plasma aldosterone concentration/plasma renin activity at whichever cut-off point is not effective enough for the selection of patients for further diagnostics or its cessation. (Pol J Endocrinol 2010; 61 (1): 2-5). PMID- 20205098 TI - Serum endostatin levels in patients with metastatic and non-metastatic well differentiated thyroid cancer. AB - INTRODUCTION: The growth of a tumour is limited by its neovascularisation. Angiogenesis is dependent on a dynamic balance between its activators and inhibitors. One of the most important antiangiogenic factors is endostatin. The aim of the study was to assess the usefulness of serum endostatin levels as a potential marker of metastases of well-differentiated thyroid cancer, and to estimate the effect of endogenous TSH stimulation on serum endostatin levels. MATERIAL AND METHODS: The study group consisted of 68 patients with differentiated thyroid cancer. We provided a cross-sectional analysis of the study group divided into patients with distant and/or locoregional metastases and patients with remission, and compared it with serum endostatin levels of healthy volunteers. Serum endostatin concentration was measured by ELISA kits (R & D Systems). RESULTS: Median endostatin concentration was significantly higher in patients with distant metastases than in patients with remission (141.95 v. 105.345 ng/ml, p < 0.05). This was not observed in patients with locoregional metastases. Serum endostatin levels were significantly higher in the study group, including patients with remission, than in the control group of healthy volunteers (remission v. healthy median 105.3 v. 88.1 ng/ml, p < 0.05). During endogenous TSH stimulation, endostatin levels significantly decreased (122.94 v. 93.60 ng/ml, p < 0.05). CONCLUSIONS: The study indicates that endogenous TSH stimulation plays a role in the regulation of endostatin secretion. Although median serum endostatin levels are higher in patients with distant metastases than in patients with remission, its clinical usefulness is limited due to the overlapping data between the study groups. (Pol J Endocrinol 2010; 61 (1): 7-12). PMID- 20205099 TI - Bone mineral density and metabolism in levothyroxine-treated adolescent girls with euthyroid diffuse goiter. AB - INTRODUCTION: Bone and mineral metabolism is influenced by thyroid hormones, and levothyroxine (LT(4)) therapy may be associated with reduced bone mass in postmenopausal women. MATERIAL AND METHODS: The aim of the study was to assess the influence of one year of LT(4) treatment in a group of 21 adolescent girls with euthyroid diffuse goiter. Lumbar (L(2)-L(4)) and total body bone mineral density (TOBMD) (Lunar - DXA), serum PTH, osteocalcin, bone alkaline phosphate, vitamin D(3), calcium, and phosphorus levels and urinary excretion of Ca, P, and hydroxyproline were measured before and after one year of combined LT(4) and iodine treatment. RESULTS: Patients were matched for age, sex, BMI, and maturation status, with controls treated with iodine only. Markers of bone turnover changed in a similar manner in both groups. There was no significant difference in TOBMD value after one year of therapy between LT(4) treated group and controls. Densitometric lumbar spine parameters increased significantly after 12 months in both groups, with no significant differences between them. CONCLUSION: It can be concluded that one year of LT(4) treatment of adolescent girls with euthyroid diffuse goiter does not have a negative impact on their bone remodelling and metabolism. (Pol J Endocrinol 2010; 61 (1): 14-19). PMID- 20205100 TI - Cilazapril increases plasma ghrelin concentration in obese patients with arterial hypertension. AB - INTRODUCTION: Ghrelin is a polypeptide hormone secreted mainly by the stomach cells, stimulating food intake and growth hormone release. Decreased plasma ghrelin concentration was found in obese subjects. Clinical and experimental data suggest that ghrelin also exerts a blood pressure lowering property. The influence of antihypertensive medication on plasma ghrelin concentration has not been studied, yet. MATERIAL AND METHODS: Plasma ghrelin concentration was estimated in 52 hypertensive obese (HA + O), 14 normotensive obese (O), and 15 lean healthy subjects in the fasting state, and after ingestion of a standard meal. HA + O patients were randomly allocated into 4 groups treated alternatively with: cilazapril, bisoprolol, amlodipine, or indapamide. After 6 weeks of antihypertensive monotherapy, the assessments were repeated. RESULTS: Similar fasting [HA + O - 780 (676-960) pg/ml; O - 751 (619-899) pg/ml] and postprandial plasma ghrelin concentrations were found in hypertensive and normotensive obese subjects. Plasma ghrelin concentrations in lean healthy subjects were significantly higher (987 (765-1366) pg/ml) in comparison to O and HA + O. Treatment with cilazapril was followed by a 28.0% increase of plasma ghrelin concentration (p = 0.04), while with bisoprolol, a 18.9% decrease (p = 0.01). No significant changes of ghrelinaemia were observed in HA + O treated with amlodipine or indapamide. No significant correlation between blood pressure and plasma ghrelin concentration before the therapy and their changes after 6 weeks of medication were found. CONCLUSIONS: 1. Our data do not support the major role of ghrelin in blood pressure regulation in obesity. 2. An increase of plasma ghrelin concentration after treatment with cilazapril was observed. (Pol J Endocrinol 2010; 61 (1): 21-27). PMID- 20205101 TI - The prevalence of benign and malignant neoplasms in acromegalic patients. AB - INTRODUCTION: In acromegalic patients, the prevalence of certain benign and malignant neoplasms is higher than that in the healthy population. We retrospectively evaluated the prevalence of tumours in acromegalic patients treated at our department: the regional centre for acromegalic patients for the Malopolskie voivodeship in Poland. MATERIAL AND METHODS: During the years 1983 2008, a hundred and one acromegalic patients (30 males and 71 women), of mean age 51.8 +/- 15.4 years, were diagnosed and treated. Pituitary macroadenoma and microadenoma were stated in 63.4% and 25.7% of these patients, respectively. In 10.9% of these patients no data on tumour diameter were available. The mean observation period was 9.4 +/- 6.5 years. The median levels of hGH and IGF-1 prior to neurosurgery were 20.2 (IQR = 34.9) ng/ml and 764.5 (IQR = 569.6) ng/ml, respectively. RESULTS: In the studied group of patients, we found the following prevalence of various tumours: nodular goitre - 64/101 patients (63.0%), polyps of the colon - 13/101 patients (13.0%); uterine polyps - 4/101 patients (4.0%); and prostate adenoma - 2/101 patients (2.0%). Among malignant tumours, thyroid cancer, endometrium and cervix cancer were the most frequent, each of these occurring in 3 patients (3.0%). Colon cancer prevalence was 2.0% (in 2 patients). CONCLUSIONS: From our retrospective study, we suggest an overall increase of tumour incidence in acromegalic patients. Prospective multicentre studies are required to resolve the significance of this observation. In our study group, the number of malignant neoplasms was significantly higher in patients with long lasting uncontrolled disease (over 5 years), compared to patients with controlled disease. (Pol J Endocrinol 2010; 61 (1): 29-34). PMID- 20205102 TI - The serum profile of adipokines in overweight patients with metabolic syndrome. AB - INTRODUCTION: Obesity is a disease that brings several complications and increases the risk of other diseases like metabolic syndrome, diabetes mellitus type 2, or coronary heart disease. Disturbances in secretion of adipokines caused by obesity have an influence on the development of metabolic complications. The aim of this study was an investigation of adipokines profile in overweight or obese people with metabolic syndrome in comparison to overweight/obese patients without metabolic syndrome. MATERIAL AND METHODS: The studied groups consisted of 38 obese or overweight patients without metabolic syndrome (nonMS) and 17 with recognized metabolic syndrome (MS), according to International Diabetes Federation (IDF) criteria. All individuals underwent anthropometrical and blood pressure examination as well as biochemical analyses such as: serum concentrations of glucose, insulin, adiponectin, resistin, leptin, TNF-alpha, IL 6, hs-CRP, total cholesterol, HDL, and triglycerides. RESULTS: A significantly lower concentration of adiponectin, and a higher concentration of IL-6, was observed in patients with metabolic syndrome (MS) in comparison to nonMS. Moreover, higher concentrations of hs-CRP and TNF-alpha were observed in patients with metabolic syndrome. CONCLUSIONS: A decreased concentration of adiponectin in obese people is an early predictor of metabolic syndrome. A low adiponectin level could be a marker of high risk of cardiovascular disease in obese patients. (Pol J Endocrinol 2010; 61 (1): 36-41). PMID- 20205103 TI - Germinal mutations of RET, SDHB, SDHD, and VHL genes in patients with apparently sporadic pheochromocytomas and paragangliomas. AB - INTRODUCTION: Pheochromocytomas and paragangliomas are derived from neural crest cells and are localized mainly in adrenal medulla and sympathetic or parasympathetic ganglia. They can be inherited (25%) and be part of multi endocrine syndromes such as MEN2 syndrome, von Hippel-Lindau syndrome, pheochromocytoma/paraganglioma syndrome, neurofibromatosis type 1, and Sturge Weber syndrome. Clinical presentation can sometimes be atypical and does not always allow proper diagnosis. In such situations, DNA analysis can be helpful, especially when the pheochromocytoma is the first and only symptom. MATERIAL AND METHODS: We analyzed DNA from 60 patients diagnosed and treated in the Centre of Oncology with a diagnosis of pheochromocytoma or paraganglioma. DNA analysis was carried out for RET (exons 10, 11, 13, and 16), SDHB, SDHD, and VHL genes. Techniques used for the analysis were direct sequence analysis, MSSCP, and RFLP. RESULTS: Germinal mutations were found in 16 patients (26,7%). Most frequent were mutations in RET proto-oncogene, followed by VHL gene, one mutation in SDHB, and one in SDHD genes. A comparison of some of the clinical features of both groups (with and without mutation) showed statistically significant differences. CONCLUSIONS: The results of our study show that genetic predisposition is frequent in chromaffin tissue tumours, which indicates that DNA analysis is necessary in every case, also because of possible atypical clinical presentation. (Pol J Endocrinol 2010; 61 (1): 43-48). PMID- 20205104 TI - Evaluation of concentrations of FGF-21 - a new adipocytokine in type 2 diabetes. AB - INTRODUCTION: Fibroblast growth factor 21 FGF-21 is a newly discovered adipocytokine which may play a vital role in improvement of insulin sensitivity and pathogenesis of type 2 diabetes. The aim of the study was to assess FGF-21 concentrations in the serum of patients with type 2 diabetes, in comparison to a control group, and evaluate the possible relationships between the studied cytokine and selected clinical and biochemical parameters MATERIAL AND METHODS: The study was conducted in 64 patients with type 2 diabetes, 28 women and 36 men aged 47-70 (median age 61.5), with a median duration of diabetes of 8.5 years. In fasting serum samples, concentrations of glucose, insulin, lipids profile parameters, creatinine, C-reactive protein (CRP), fibrinogen, HbA(1c), adiponectin, and FGF-21 were determined. The control group comprised 20 healthy persons matched for age to the study group, with no disturbances in carbohydrate metabolism: 14 women and 8 men. RESULTS: We found significant differences concerning the medians of body mass index (BMI) 32.4 kg/m(2) v. 24.1 kg/m(2), p < 0.001; waist circumference 114 cm v. 81 cm, p < 0.001; HDL cholesterol 42.5 mg/dl v. 62.5 mg/dl, p < 0.001; triglyceride (TG) 152 mg/dl v. 99 mg/dl, p < 0.01 in the studied group, in comparison with the control group, respectively. In patients with diabetes, median FGF-21 concentration was 239.9 pg/ml and was significantly greater in comparison to the control group: 112.6 pg/ml p < 0.01. Median adiponectin concentration in patients with type 2 diabetes was significantly lower in comparison to the control group, 7.5 ng/ml v. 9.95 ng/ml, p < 0.05. Significant correlations between FGF-21 concentrations and adiponectin (r = -0.24, p < 0.05), weight (r = 0.27, p < 0.05), glucose (r = 0.27, p < 0.05), HDL cholesterol (r = -0.26, p < 0.05), TG (r = 0.27, p < 005), and estimated glomerular filtration rate (eGFR) (r = -0.28, p < 0.05) were observed. No significant correlations between FGF-21 and parameters of metabolic control, markers of inflammatory status, and insulin resistance, or the presence of vascular complications of diabetes, were noticed. CONCLUSIONS: On the basis of the conducted studies it can be concluded that the greater FGF-21 concentration observed in the examined group of patients with type 2 diabetes may result from a compensatory reaction to metabolic disturbances or tissue resistance to this cytokine. The negative correlation between FGF-21 and eGFR suggests renal elimination of the examined compound. (Pol J Endocrinol 2010; 61 (1): 50-54). PMID- 20205105 TI - The influence of thiamazole, lithium carbonate, or prednisone administration on the efficacy of radioiodine treatment ((131)I) in hyperthyroid patients. AB - INTRODUCTION: The effects of selected drugs (see below) on the efficacy of ((131)I) radioiodine therapy were examined. MATERIAL AND METHODS: The study involved 200 hyperthyroid patients, treated with radioactive iodine. They were divided into five groups (40 persons in each). In Group I - patients were administered (131)I and thiamazole; in Group II they were given - (131)I and lithium carbonate; in Group III they were given - (131)I only (the assumed absorbed dose - 150-200 Gy, the same as in Groups I and II, for which Group III was a control group); in Group IV they were given - (131)I and prednisone; and in Group V they were given - (131)I only (250-350 Gy, the same as in Group IV, for which Group V was a control group). Therapeutic results were analyzed after six months based on clinical and hormonal status. The evaluation also included effects of the initial hormonal status on the outcome of (131)I therapy in Groups II and IV (v. respective controls, i.e. Groups III and V); such analysis was not performed in Group I because all the patients in that group were initially hyperthyroid. RESULTS: In 145 patients (72.5%) the therapy with (131)I was effective. In 55 patients (27.5%) the therapy was ineffective. The application of thiamazole during the peritherapeutic period in patients treated with 131I reduced the effectiveness of radioiodine, while lithium carbonate had no effect on the therapy outcome. Prednisone increased the effectiveness of the therapy with (131)I. Normalisation of the initial concentration of TSH was advantageous for the (131)I therapeutic outcome only when the assumed absorbed doses of 150 200 Gy were applied, while being of no avail for doses above 250 Gy. CONCLUSIONS: The present results indicate the necessity of careful analysis of administered drugs in hyperthyroid patients while qualifying them to (131)I therapy. The initial concentration of TSH has no effect on the efficacy of radioiodine therapy in cases where absorbed doses are regarded to be ablative. (Pol J Endocrinol 2010; 61 (1): 56-61). PMID- 20205106 TI - Plurihormonality of pituitary adenomas in light of immunohistochemical studies. AB - INTRODUCTION: Plurihormonality of pituitary adenomas can be defined as the ability of an adenoma to express more than one pituitary hormone. The application of immunohistochemistry to diagnose surgically removed pituitary tumours revealed that a great number of pituitary adenomas are in fact plurihormonal. However, data on the incidence and the clinical relevance of the pituitary adenoma plurihormonality are still scarce and controversial. MATERIAL AND METHODS: Hundred fifty-five pituitary adenomas, surgically removed, were studied immunohistochemically with the antibodies against pituitary hormones or their subunits. Additionally, 40 adenomas were immunostained with Ki-67 antibody to evaluate the proliferative potential. RESULTS: According to the World Health Organization (WHO) recommendations, we did not consider tumours expressing both FSH and LH (gonadotropinomas) or somatoprolactinomas expressing both GH and prolactin as plurihormonal. Even with this limitation, plurihormonality was found to be a frequent finding in both hormonally active and clinically non-functioning pituitary adenomas. It was shown that over one-third (36.1%) of the investigated adenomas expressed more than one hormone. Plurihormonality, especially that which is connected with co-expression of ACTH, seems to be more frequent in the recurrent tumours. Plurihormonal adenomas also possess higher Ki-67 indices, as compared to monohormonal tumours. CONCLUSIONS: Plurihormonality is a frequent phenomenon in both hormonally active and clinically non-functioning pituitary adenomas. It also seems to predict a higher risk of tumour recurrence. (Pol J Endocrinol 2010; 61 (1): 63-66). PMID- 20205107 TI - Bilateral, incidentally found adrenal tumours - results of observation of 1790 patients registered at a single endocrinological centre. AB - INTRODUCTION: During the last 22 years we registered 1790 patients with incidentally found adrenal tumours (AI, adrenal incidentalomas). In 351 of them, bilateral tumours were detected. The aim of our study was to analyze the character of bilateral tumours and summarize the methods of their management. MATERIAL AND METHODS: In the whole group of 1790 patients, there were 1311 women and 479 men, aged 11-87 years. The group of patients with bilateral adrenal tumours included 258 women and 93 men, 25-83 years old. Hormonal investigations and imaging examinations were performed to search for subclinical adrenal hyperfunction and to define the malignant potential of the tumours. RESULTS: Sixty-nine patients were treated by surgery for oncological or endocrinological purposes (mainly pre-Cushing's syndrome). Histological findings included malignant tumours: metastases - 9, adrenal cancer - 7, and lymphomas - 5; and non malignant tumours: adenomas - 24, nodular hyperplasia - 14, myelolipomas - 4, and pheochromocytomas - 4. Subclinical Cushing's syndrome was relatively more frequent in nodular hyperplasia (40%) than in adenomas (30%). CONCLUSIONS: Indications for surgery were recommended in 20% of patients with bilateral AI, most frequently for adenomas, nodular hyperplasia, and oncological pathologies, with a good prognosis in the non-malignant group. (Pol J Endocrinol 2010; 61 (1): 69-73). PMID- 20205109 TI - The role of fibrinogen and CRP in cardiovascular risk in patients with acromegaly. AB - INTRODUCTION: Patients with active acromegaly have 2- to 3-fold increased cardiovascular mortality. Alterations of acute phase proteins, observed in acromegaly, could lead to cardiovascular diseases. Aim of the study was to evaluate fibrinogen and C-reactive protein (CRP) secretion in patients with acromegaly. MATERIAL AND METHODS: Seventy-seven patients were divided into groups with active (AA, n = 56) and controlled acromegaly (CA, n = 21). Twenty age- and sex-matched healthy subjects served as controls. Serum fibrinogen, CRP, fasting glucose, insulin, total cholesterol, LDL and HDL cholesterol, and triglycerides were measured, and body mass index (BMI) was calculated. RESULTS: Comparison between the groups revealed: higher fibrinogen, triglycerides, glucose levels, and BMI values in AA than in the controls; higher CRP, fibrinogen, triglyceride levels, and BMI values in CA than in the controls; higher LDL cholesterol and insulin levels and lower CRP levels and BMI values in the AA group than in the CA group. Fibrinogen concentration was highest in the AA group and lowest in the control group. Fibrinogen levels were high in all patients with acromegaly, irrespective of disease status, and they were significantly higher than in healthy subjects. CRP concentration was highest in the CA group and lowest in the control group. CRP levels were significantly and paradoxically lower in patients with AA than in patients with well-controlled disease and did not explain the increased cardiovascular mortality in acromegaly. CONCLUSIONS: Fibrinogen plays an important role as a cardiovascular risk factor in acromegaly, irrespective of the cure of the disease. The role of CRP as a cardiovascular risk factor in patients with uncontrolled acromegaly should be better explained in future studies. (Pol J Endocrinol 2010; 61 (1): 83-88). PMID- 20205108 TI - Does cellular glucose transport respond to a controlled diet and sulfonylurea therapy in type 2 diabetes mellitus? AB - INTRODUCTION: The normalization of cellular glucose assimilation is the basic aim of therapy in diabetes mellitus. This process should be accompanied by a proportional increase of the cellular glucose transport (CGT). The level of CGT should react to therapy typically recommended in Type 2 diabetes mellitus (T2DM), composed of diet and sulfonylurea. In order to explore this clinically significant hypothesis, a clinical-experimental study was undertaken. Its aim was to determine the clinical pharmacotherapeutic significance of CGT measurements. MATERIAL AND METHODS: CGT testing was performed on peripheral blood lymphocytes. CGT was assessed with 2-[(3)H(G)] glucose: before, and after the addition of sulfonylurea or sulfonylurea plus insulin to the incubation medium. Tests were performed at baseline in 28 persons with newly diagnosed, "therapeutically naive" T2DM and in 20 control subjects. In diabetic patients the tests for CGT were repeated after 3 months of routine diet and sulfonylurea therapy. In addition, the level of GLUT4 expression was assessed by flow cytometry before and after this therapy. RESULTS: Before treatment, CGT was significantly decreased in all subjects with T2DM. Incubated in-vitro cells responded directly to the addition of sulfonylurea with a moderate increase of CGT. This response was augmented by the addition of insulin to sulfonylurea in the incubation medium. The monitored three-month routine, controlled therapy with diet and sulfonylurea resulted in a significant increase of CGT process in all types of incubation tests. CONCLUSIONS: The basal and reactive CGT is significantly decreased in lymphocytes of persons with T2DM before the introduction of therapy. Effective therapy with diet and sulfonylurea normalizes both types of CGT - basal and reactive. It is related to the near normalization of GLUT4 expression in the studied cells. This phenomenon may be used as a new marker for diabetes mellitus pharmacotherapy. (Pol J Endocrinol 2010; 61 (1): 75-81). PMID- 20205110 TI - Emotions and features of temperament in patients with Addison's disease. AB - INTRODUCTION: Patients with Addison's disease experience many somatic and psychic changes, which decrease their quality of life. The aim of the study was to evaluate the "psychological equipment" of these patients to cope with stress connected with this chronic disease and the challenge of constant treatment. MATERIAL AND METHODS: Fifteen patients (13 female, 2 male) were included in the study. Standard psychological tests were used to assess anxiety, temperament, depression, and emotional intelligence. RESULTS: The results show that patients with Addison's disease have not only increased levels of anxiety and fear, and over-reaction to stimuli, but decreased performance efficiency and need for social contact as well. Such psychological characteristics may result in difficulties in doctor-patient communication, aggravation of patients' feelings, limitation of patients' involvement in therapy, and, finally, a decrease the effectiveness of therapy. CONCLUSIONS: The temperamental characteristics and personal traits of patients with Addison's disease seem not to be useful in stressful events, and psychological support can be helpful in the effective therapy of these patients. (Pol J Endocrinol 2010; 61 (1): 90-92). PMID- 20205111 TI - From open to laparoscopic adrenalectomy: thirty years' experience of one medical centre. AB - INTRODUCTION: Laparoscopic adrenalectomy (LA) has become the standardized treatment of benign adrenal lesions over the last two decades, making the indications to open adrenalectomy (OA) limited. The purpose of this study was to show the thirty years of experience in open (OA) and laparoscopic adrenalectomy (LA) gained in one medical centre as well as to compare the results of OA and LA performed for benign adrenal lesions. MATERIAL AND METHODS: Three hundred patients underwent 127 open and 173 laparoscopic adrenalectomies between 1979 and 2009 at M. Curie Hospital in Szczecin, Poland. Analyzed factors included patients demographic data, ASA score, indication for surgery, tumour size and side, characteristics of the removed tumours, intraoperative and postoperative outcome of LA and OA, postoperative pain sensation, intraoperative and postoperative complications, and conversion rate from LA to OA. Tumours with diameter exceeding 8 cm were excluded. RESULTS: There were no significant differences regarding the analyzed preoperative data in both groups of patients. The mean operative time was longer in the LA group (137 v. 82 min., p < 0.0001) and the blood loss was lower in LA group (110 v. 254 mL, p < 0.0001). The mean time until resumption of normal diet was shorter after LA (22 v. 44 h), as was the mean time until ambulation (17 v. 36 h), mean length of the hospital stay (4.6 v. 6.8 days), and mean time until return to normal activities (14 v. 23 days, p < 0.0001 for each difference). The analgesic requirement on the first and the second day postoperatively was lower in the LA group (p < 0.0001). The incidence of intraoperative and postoperative complications did not differ significantly between both analyzed groups. The rate of the conversion from LA to OA was 16%. The histopathological diagnosis was adenoma of the adrenal gland in the majority of cases. CONCLUSIONS: This study shows that LA is a safe, effective, and well tolerated procedure. It may be recommended as a "gold standard" surgery in a case of benign functioning or non-functioning adrenal tumours with diameter less than 8 cm. (Pol J Endocrinol 2010; 61 (1): 94-101). PMID- 20205112 TI - Mean daily plasma concentrations of beta-endorphin, leu-enkephalin, ACTH, cortisol, and DHEAS in epileptic patients with complex partial seizures evolving to generalized tonic-clonic seizures. AB - INTRODUCTION: A multitude of mechanisms have been implicated in the pathophysiology of epilepsy. OBJECTIVE: To assess mean daily plasma concentrations of ACTH, cortisol, DHEAS, leu-enkephalin, and beta-endorphin in epileptic patients with complex partial seizures evolving to tonic-clonic in relation to frequency of seizure occurrence (groups with seizure occurrences - several per week and several per year) and duration of the disease (groups less than and more than 10 years). We decided to analyse mean daily values of beta endorphin and leu-enkephalin because of significant differences in concentrations of these substances in blood during the day. MATERIAL AND METHODS: The study was performed on 17 patients (14 males + 3 females; mean age 31.8 yrs) treated with carbamazepine (300-1800 mg/day). The control group consisted of six age-matched healthy volunteers. Blood was collected at 8 a.m., 2 p.m., 8 p.m., and 2 a.m. Intergroup analysis was performed with the use of ANOVA Kruskal-Wallis test. RESULTS: Mean daily concentrations of ACTH and cortisol in the blood of the patients with epilepsy were higher in comparison with those of the healthy volunteers, independently of the frequency of seizures and duration of the disease. Mean daily concentrations of beta-endorphin in the blood of the patients with epilepsy were higher in the groups of patients with more severe clinical course of disease (with more frequently occurring epilepsy seizures and longer duration of the disease) in comparison with healthy subjects. Mean daily concentrations of leu-enkephalin in the blood of the patients with epilepsy were higher in the group of patients with short duration of the disease in comparison with the group with long duration of the disease. CONCLUSIONS: 1. Pituitary adrenal axis hyperactivity is observed in patients with clinically active epilepsy, independently of the frequency of seizures and duration of the disease. 2. Changes in endogenous opioid system activity are related to the clinical activity of epilepsy - beta-endorphin concentrations are connected with frequency of seizures and duration of the disease and leu-enkephalin concentrations with duration of the disease. 3. Endogenous opioid peptides might take part in the neurochemical mechanism of human epilepsy. (Pol J Endocrinol 2010; 61 (1): 103 110). PMID- 20205113 TI - Serum concentrations of leptin, adiponectin, and interleukin-6 in postmenopausal women with Hashimoto's thyroiditis. AB - INTRODUCTION: Leptin and adiponectin are involved in the pathogenesis of several autoimmune diseases. Very little is known about adipocytokine production in autoimmune thyroid diseases. Interleukin-6 (IL-6) plays an important role in the inflammatory and autoimmune processes. MATERIAL AND METHODS: The aim of this study was to assess the serum levels of leptin, adiponectin, and IL-6 in postmenopausal euthyroid women with Hashimoto's thyroiditis and compared them with concentrations in control women. Ninety-eight euthyroid women with Hashimoto's thyroiditis were enrolled in the study. The diagnosis was confirmed with elevated thyroid peroxidise autoantibody (TPOAb) levels in serum and typical hypoechogenic pattern on thyroid ultrasound. The control group, matched for body mass index (BMI), consisted of 105 healthy postmenopausal euthyroid women. Serum levels of leptin, adiponectin, IL-6, thyroid-stimulating hormone (TSH), free thyroxine (fT(4)), and TPOAbs were determined. RESULTS: When compared with controls, the women with Hashimoto's thyroiditis were characterized by significantly elevated serum concentrations of IL-6, whereas concentrations of leptin and adiponectin were not different. Hashimoto's thyroiditis patients had significantly higher serum levels of TSH than the controls. The simple linear regression analyses of the Hashimoto's thyroiditis group and all of the studied women indicated that serum leptin levels correlated positively with BMI, waist to hip ratio (WHR), TSH, and IL-6 and negatively with adiponectin. No correlation was observed between serum adiponectin and TSH, fT(4), or TPOAbs. There were no associations between serum IL-6 levels, TPOAbs, and TSH levels; however, positive correlations between IL-6 and BMI, WHR, and leptin were observed. TSH correlated positively with leptin, age, and TPOAbs. CONCLUSIONS: Hashimoto's thyroiditis is characterized by an increased production of IL-6 but does not have a direct influence on leptin or adiponectin serum levels. The correlations between TSH and leptin demonstrated in this study highlight the need for future investigations. (Pol J Endocrinol 2010; 61 (1): 112-116). PMID- 20205114 TI - Melatonin, the RANKL/RANK/OPG system, and bone metabolism in girls with anorexia nervosa. AB - INTRODUCTION: Young women and girls with anorexia nervosa (AN) suffer from abnormalities in melatonin (MEL) secretion, especially in the nocturnal phase. This is paralleled by a considerable bone mass loss and abnormalities of bone metabolism. As melatonin has been implicated in playing a role in inducing osteoporosis and that the effect could be mediated by the RANKL/RANK/OPG system, we decided to investigate the potential associations between MEL and bone status in girls with AN. AIM: To evaluate the relationship between MEL, bone metabolism (as assessed by serum levels of bone turnover markers [OC and CTx]), and OPG and sRANKL in girls with AN. MATERIAL AND METHODS: A total of 57 girls with AN and 13 healthy girls, between 13 and 18 years of age, were enrolled in the study, and we evaluated BMI, fasting levels of OC, CTx, OPG and sRANKL, and levels of MEL (fasting levels and the levels at 2 a.m., at which time the secretion of the hormone peaks). RESULTS: We found a significantly increased mean serum level of MEL at 2 a.m. and an increased amplitude between nocturnal and morning levels of the hormone in girls with AN. We also showed a considerable suppression of the mean OC and CTx levels and an increase in serum OPG and RANKL levels paralleled by a significantly reduced OPG/sRANKL ratio. The changes in the MEL levels at 2 a.m. showed a statistically significant negative correlation with levels of the bone markers and a positive correlation with sRANKL. The changes in the amplitude between the nocturnal and morning levels of MEL showed a negative correlation with CTx levels and the OPG/sRANKL ratio. CONCLUSIONS: Our results indicate that the abnormalities of bone metabolism in girls with AN are associated with changes in the nocturnal levels of MEL with RANKL appearing to play an important role in this mechanism. The increased amplitude between the nocturnal and morning levels of MEL may adversely affect the bone tissue in girls with AN with the effect most likely resulting from influences on the OPG/RANKL balance. (Pol J Endocrinol 2010; 61 (1): 117-123). PMID- 20205115 TI - Aromatase research and its clinical significance. AB - Aromatase is a member of the cytochrome P450 superfamily that catalyzes the conversion of androgens (C(19)), namely testosterone and androstenedione, into oestrogens (C(18)), oestradiol, and oestrone, respectively. The enzyme is active in various tissues in both females and males, thus oestrogens are produced not only in gonads but also in extra-gonadal localizations such as brain, adipose tissue, breast, skin, and bone. Aromatase gene CYP19A1 located on chromosome 15 comprises nine coding exons and a number of alternative non-coding first exons that regulate tissue-specific expression. Studies on local regulation of aromatase expression and activity are important for understanding processes such as growth of oestrogen-dependent breast cancer. Rare clinical conditions of aromatase deficiency and excess have revealed some new and unexpected oestrogen functions in metabolism and bone health in both women and men. They were further studied using transgenic animal models such as aromatase knockout mice (ArKO) or (AROM+) mice overexpressing human aromatase. Research on aromatase was important for its practical outcome as it contributed to the development of aromatase inhibitors (AIs), an effective and safe group of drugs for the first-line endocrine therapy of breast cancer. Further studies are needed to establish AIs application in other oestrogen-dependent conditions, to overcome the resistance in breast cancer patients, and to develop tissue-specific selective inhibitors. (Pol J Endocrinol 2010; 61 (1): 126-134). PMID- 20205116 TI - Iodine-deficiency prophylaxis and the restriction of salt consumption - a 21st century challenge. AB - The World Health Organization (WHO) issued a recommendation (Technical Consultation: Paris 2006, Luxembourg 2007) that salt consumption, as a risk factor for hypertension, atherosclerosis, myocardial infarction, stroke, and select cancers, should be restricted. The European Commission looked to adhere to this recommendation by creating the High Level Group on Nutrition and Physical Activity. According to WHO recommendations, a daily allowance of 5 g NaCl (i.e., 2 g Na) for individual salt consumption should not be exceeded. At present, mean individual salt consumption in Poland totals 13.5 g, of which salt used in household constitutes 8.8 g. In some regions of Poland, this number reaches upwards of 15.0 g/person. The Position Paper on Initiatives Aimed at Decreasing Salt Consumption in Poland, developed by an expert group at the National Food and Nutrition Institute, set the course for intervention, including changing recipes for massproduced food products and large-scale catering, improving oversight by food control agencies, and continuing legislative changes. These interventions should also include education directed towards consumers, food producers, public health professionals, healthcare workers, and media representatives. The Position Paper of the Polish Hypertension Society also sets the course for promoting restricted salt consumption and controlling hypertension on a population level. However, household salt is the main carrier of iodine in the Polish model of iodine prophylaxis. Thus, any interventions also require synchronized action with the Polish Council for Control of Iodine Deficiency Disorders. Current efforts aimed at preventing iodine-deficiency look to increase consumption of other iodine-rich products (e.g., milk, mineral water) with standardized levels of iodine. Once they achieve an iodine concentration of 0.1-0.2 mg, these products can easily supplement any decrease in physiological iodine levels resulting from reduced salt consumption. Also required are wide-ranging educational campaigns which will be coordinated by the new designated WHO Collaborating Centre for Nutrition at the Chair of Endocrinology at Jagiellonian University, Collegium Medicum in Krakow. (Pol J Endocrinol 2010; 61 (1): 135-140). PMID- 20205117 TI - Congenital adrenal hyperplasia due to 21-hydroxylase deficiency - management in adults. AB - Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is one of the most common autosomal recessive hereditary diseases. The impairment of cortisol synthesis leads to excessive stimulation of the adrenal glands by adrenocorticotropic hormone (ACTH), adrenal hyperplasia, and excessive androgen synthesis. The syndrome is characterised by a considerable correlation between the genotype and the phenotype with the type of CYP21A2 gene mutation affecting the severity of 21-hydroxylase deficiency. The clinical manifestations of CAH in adults result from adrenocortical and adrenomedullary insufficiency, hyperandrogenism, and the adverse effects of glucocorticosteroids used for the treatment of the condition. Non-classic CAH may sometimes be asymptomatic. In patients with classic CAH obesity, hyperinsulinaemia, insulin resistance, and hyperleptinaemia are more often seen than in the general population. These abnormalities promote the development of metabolic syndrome and its sequelae, including endothelial dysfunction, and cardiovascular disease. Long-term glucocorticosteroid treatment is also a known risk factor for osteoporosis. Patients with CAH require constant monitoring of biochemical parameters (17a hydroxyprogesterone [17-OHP] and androstenedione), clinical parameters (body mass, waist circumference, blood pressure, glucose, and lipids), and bone mineral density by densitometry. The principal goal of treatment in adults with CAH is to improve quality of life, ensure that they remain fertile, reduce the manifestations of hyperandrogenisation in females, and minimise the adverse effects of glucocorticosteroid treatment. Patients with classic CAH require treatment with glucocorticosteroids and, in cases of salt wasting, also with a mineralocorticosteroid. Radical measures, such as bilateral adrenalectomy, are very rarely needed. Asymptomatic patients with non-classic CAH require monitoring: treatment is not always necessary. Medical care for patients with CAH should be provided by reference centres, as the management of such patients requires collaboration between an endocrinologist, diabetologist, gynaecologist, andrologist, urologist, and psychologist. PMID- 20205118 TI - The need for international seafarer medical fitness standards. AB - The text of this paper is based on a presentation at the First International Congress of Maritime, Tropical, and Hyperbaric Medicine, 4th July 2009, Gdynia, Poland. The assessment of fitness to work at sea is an important aspect of maritime risk management. The risks in the industry, the approaches used for assessment, and the evidence on which they are based have changed over time. The transition from an industry in which the nationality of seafarers and the ships on which they worked were the same to one in which ownership and crewing have become global means that, as is true for most other aspects of maritime risk management, compatible international criteria for decisions regarding fitness to work are required. Many parties, including flag states, employers and their insurers, and seafarers and their trade unions, are involved in agreeing international medical fitness criteria. While all have a common interest in improved health and safety at sea, each has their own more detailed agenda of sectional interests. The scope for development of agreed standards and the role of the parties involved is reviewed, and the current arrangements for taking this process forward are discussed. Contributions from maritime health professionals and other medical and scientific experts are essential to the development of rational and valid criteria, but the decisions on the level of authority to be given to these and the means adopted for ensuring compliance with them are essentially political issues where the voice of those with subject knowledge is only one among many in the processes for adoption and implementation of any new arrangements. PMID- 20205120 TI - Comparison of alertness levels in ship crew. An experiment on rotating versus fixed watch schedules. AB - A short pilot study was conducted during a shipboard training deployment to compare alertness levels in the same crew members while working a fixed watch schedule, and then a rotating watch schedule. Alertness levels were assessed before and after each duty watch using measurements of oculomotor function (Fitness Impairment Tester). Saccadic velocity was shown to have the greatest correlation with duration of sleep deprivation and was significantly slower (indicating decreased alertness) in the crew working the rotating watch schedule than the crew working the fixed watch schedule. This pilot study corroborates previous studies' recommendations that fixed watch schedules allow better acclimatization of sleep patterns, thus minimizing fatigue and increasing operational alertness. PMID- 20205121 TI - Collaborative, cross-national studies on health and safety in seafaring for evidence-based Maritime policy and regulations. AB - BACKGROUND: Until recently, maritime health and safety policies and regulations were sparsely based on health and safety research, and only a small number of countries contributed to new research. OBJECTIVES: To strengthen maritime health and safety research activities by presenting a study example and discussing the possibilities and needs for more national and cross-national research. METHODS: In a cross-national epidemiological study example, the seafarers from eleven countries completed small, anonymous questionnaires concerning the working conditions on their latest tours at sea while waiting for their health examinations. RESULTS: Significant disparities were pointed out among the nationalities, e.g., the length of the tours at sea, the proportional distribution of officers and non-officers, the mean age structure, the injury incidence rates, and the differences of occupational safety standards. The analysis of all data together increased the statistical strength of the multivariate analyses and allowed for valid comparisons among the nationalities. CONCLUSIONS: The questionnaire data was used successfully in the collaborative study example, but other data sources and methods are useful for health and safety research in seafaring as well. More national and cross-national research on maritime health and safety is warranted. PMID- 20205122 TI - Successful hand replantation in a seafarer after long-distance helicopter evacuation. A case report. AB - After sustaining a clean-cut mid-carpal hand amputation on a tanker 120 miles north of Lanzarote, a 28- -year-old seafarer was evacuated by helicopter to a microsurgical unit in Gran Canaria. The amputated hand was cooled according to precise instructions. The 6-hour flight time included two refuelling stops and transfer time. The hand had been revascularized thirteen hours after the accident and was still well circulated at repatriation 3 weeks later. PMID- 20205123 TI - Alcohol and nicotine dependence in French seafarers. AB - BACKGROUND: To study the relationship between alcohol abuse or dependence as diagnosed by the CAGE questionnaire, and nicotine dependence as diagnosed by Fagerstrom Test of Nicotine Dependence (FTND) in French seamen. MATERIALS AND METHODS: French seamen were recruited from a stratified survey of 19 ports in France. The subjects completed a questionnaire during their annual medical check up with occupational physicians and nurses of the Occupational Health Department (Service de sante des gens de mer). FINDINGS: Approximately forty-four per cent of male subjects were current smokers, and approximately sixty-three per cent of these were nicotine dependent according to FTND. More than 11% of male subjects drank alcohol every day. About 16% of these were alcohol dependent according to CAGE. A strong positive relationship has been shown between alcohol dependence and nicotine dependence. There was a highly significant difference between alcohol dependent and non-alcohol dependent subjects in the FTND. Conversely, nicotine dependent and non-nicotine dependent subjects significantly differed regarding several alcohol-related variables. CONCLUSIONS: Alcohol and nicotine consumption is a major public health issue in seamen. A strong positive correlation was found between alcohol abuse or dependence and nicotine abuse or dependence. Some alcohol-related behaviours were associated with nicotine dependence, and some tobacco-related behaviours were also associated with alcohol dependence. These findings are novel for this kind of population in France. In view of these results, combined smoking cessation and alcohol consumption reduction policies should be developed in this population. Finally, future studies could analyze the work environment, which seems to be associated with consumption and dependency. PMID- 20205124 TI - Malaria among seamen in Klaipeda in 1999-2008. AB - In the 10 years from 1999 to 2008, 33 imported malaria cases were recorded in Klaipeda, in 31 people from Lithuania and in 2 foreigners, from 1 to 8 cases per year. Among them, there were 28 infections of seafarers, who were probably infected in West Africa, Nigeria, Cameroon, or Angola. For all of them, malaria was a work-related health risk. Plasmodia of all species were detected in their blood, but in the majority of cases (24) it was Plasmodium falciparum. In all cases, the diagnosis was confirmed by blood examination - thick and thin films. About 10% of patients had the severe form of the disease. Two seafarers died of falciparum malaria, one in Angola and one in Klaipeda. Preventive measures such as chemoprophylaxis and avoidance of mosquito bites were not always used by them. Therefore, the staff of the Klaipeda Public Health Centre focus their work on the health training of seafarers, explaining the risk of infection, advising how to avoid mosquito bites, and how to use antimalarial drugs for prophylaxis. PMID- 20205125 TI - Cruise ship doctor: demands and challenges versus qualifications and training. PMID- 20205126 TI - Maritime telemedicine - where to go and what to do. PMID- 20205127 TI - Medical and psychological challenges in the offshore petroleum industry. PMID- 20205128 TI - "SAR-First-Responder Sea" - backgrounds to a medical education concept in German SAR service. AB - We present backgrounds to a medical education concept for the full-time rescue men on the vessels of the German Maritime Search and Rescue Service (DGzRS, English: GSRS). In contrast to land-bound emergency services, the daily work spectrum of the GSRS rescue men is mainly characterised by technical assistance for sea-going ships, and searching procedures but not medical emergencies. Nevertheless, severe medical exigencies might occur aboard sea-going ships, with immediate need of professional medical treatment. Thus, a professional medical training course adapted to the needs and costs of maritime search and rescue procedures at German Coasts was set up and has now been unveiled. PMID- 20205129 TI - Promotion of healthy nutrition of seafarers. AB - Nutrition disorders arise from various interacting factors: cultural, environmental, genetic, physiological, and psychological. Excessive consumption of highly processed food, sugar, salt, alcohol, and saturated fats is a problem nowadays, and consumption of fish, vegetables, and fruit is insufficient. Overeating and an unbalanced diet are often accompanied by stress and a lack of physical activity. This is intensified by easy access to "comfort food", "fast food", and "junk food". The number of people suffering from overweight and obesity, so-called diseases of civilization, is increasing. Not only is being overweight a risk factor for the development many other metabolic diseases, but it also significantly worsens the quality of life. This also concerns people working at sea. Obesity is favoured by emotional eating disorders (EED), uncontrolled/compulsive eating - binge eating disorders (BED), and night eating disorders (NED). Most frequently, eating is a reaction to stress or boredom. It alleviates tension and improves the mood, also of seafarers. PMID- 20205130 TI - Guidance to the International Medical Guide for Ships 3(rd) edition: interim advice regarding the best use of the medical chest for ocean-going merchant vessels without a doctor onboard: joint statement of WHO Collaborating Centres for the health of seafarers and the International Maritime Health Association - 2009 version. PMID- 20205131 TI - Malaria prevention. AB - Malaria is a parasitic disease transmitted by the bites of Anopheles mosquitoes. It is a common and life-threatening disease in tropical and subtropical countries. There is no vaccination available, and prevention is based on a combination of chemoprophylaxis and avoidance of mosquito bites. PMID- 20205132 TI - Institute of Maritime and Tropical Medicine in Gdynia on the 70(th) anniversary of foundation (1939-2009) - history, staff, achievements. PMID- 20205133 TI - Strategies, means and models of health care in the Polish maritime industry, 1945 2007: summary of the presentation made at the time of the First International Congress of Maritime, Tropical, and Hyperbaric Medicine held on 4-6 June 2009 in Gdynia, Poland. AB - AIM: To define, characterize, and explain the main goals and tools used for the functioning of health care in the Polish maritime industry. BACKGROUND: The Polish merchant and fishing fleet grew significantly after 1945, and the number of the national seamen and deep-sea fishermen reached about 50,000 in the 1970s. But in the last two decades the number of Polish merchant ships and fishing boats has gradually decreased, and fewer crewmembers are employed on them. The analysis of the occupational health policy in the maritime industry in Poland points at the different strategies used and the means and models applied throughout the years for the organization of health care for seafarers. MATERIALS AND METHODS: Analysis included: collection of data on morbidity and mortality among seamen, fishermen, and other maritime workers; health care systems for seafarers onboard ships and on land; prevention of diseases and accidents among crewmembers; pre employment and periodic medical examinations and health standards for seafarers; and legal regulations. The main principles governing the model of health care for workers in this branch of industry in Poland in the years 1945-2007 were presented. RESULTS: Three different strategies, means, and models of health care in the Polish maritime industry were employed during this period of time. PMID- 20205134 TI - International Maritime Health - 60 years of the scientific and practical activity on behalf of maritime community. PMID- 20205135 TI - The tenth International Symposium on Maritime Health: 23-26 September 2009, Goa, India. PMID- 20205136 TI - [Non-motor disorders in Parkinson's disease: introduction and general features]. AB - INTRODUCTION: Two hundred years ago James Parkinson accurately described the disease that bears his name today, focusing not only on motor aspects but also on non-motor symptoms suffered by these patients. DEVELOPMENT: Non-motor symptoms are prevalent and decrease the quality of life of the patients with Parkinson's disease. In recent years, some non-motor scales have been developed to avoid the problem of underdiagnosis. Moreover, some of them have been proposed as clinical predictors for Parkinson's disease and it is has been suggested that individuals with any of these non-motor symptoms and without motor manifestations of the disease could be the aim for neuroprotective therapies when they become available. CONCLUSIONS: Non-motor symptoms are prevalent and have a great impact in the quality of life of patients. Therefore, it is important to detect and treat them. Their role as predictors of the disease is unclear yet. PMID- 20205137 TI - [Sleep disorders in Parkinson's disease: REM sleep behaviour disorder and restless legs syndrome]. AB - INTRODUCTION: It is well known that patients with Parkinson's disease (PD) and other neurodegenerative diseases very commonly present sleep disorders, and that they possibly share common pathophysiological mechanisms with motor signs. DEVELOPMENT: In the case of REM sleep behaviour disorder, a number of studies have shown that it may appear more than ten years before the motor signs. Although there is no evidence to prove that patients with restless legs syndrome have an increased risk of suffering from PD, the high prevalence of this symptom in PD and the good response to dopamine agonists suggest the existence of a relation between the two conditions. CONCLUSIONS: The impact that these conditions have on patients' quality of life makes it very important to know how to diagnose and treat them. PMID- 20205138 TI - [Sleep disorders in Parkinson's disease: insomnia and sleep fragmentation, daytime hypersomnia, alterations to the circadian rhythm and sleep apnea syndrome]. AB - INTRODUCTION: Sleep disorders in Parkinson's disease are present in 60-98% of patients and reduce their quality of life. AIMS: To review the pathophysiology, diagnostic approach and management of the different sleep disorders. DEVELOPMENT: We describe the pathophysiology associated with neurodegeneration, due to symptoms (motor and nonmotor) and drug therapies. This article reviews insomnia, excessive daytime sleepiness, circadian sleep disorders and sleep apnea. CONCLUSIONS: Subjective or objective sleepiness assessment should routinely be performed by physicians looking after Parkinson's disease patients. Management is difficult and should be targeted to the specific sleep disorder and its likely cause. PMID- 20205139 TI - [Urinary disorders, sexual dysfunction and hypersexuality in Parkinson's disease]. AB - INTRODUCTION: As Parkinson's disease progresses, its non-motor manifestations become increasingly more apparent to the point where, in advances phases of the disease, they are the most important clinical symptoms. A very wide range of non motor symptoms can appear in Parkinson's disease. Impairment of the urinary function and the sexual function (understood as the capacity to carry out sexual activity) can be seen as belonging to the dysautonomic disorders. Hypersexuality would be included within the group of impulse control disorders. DEVELOPMENT: This study reviews the epidemiology, phenomenology and treatment of urinary disorders, sexual dysfunction and hypersexuality as non-motor symptoms of Parkinson's disease. CONCLUSIONS: Urinary disorders are the most frequent non motor symptom in Parkinson's disease. They usually present as nocturia, urgency and increased mictional frequency (pollakiuria). Preferred treatment is with anticholinergic agents. Sexual dysfunction is a frequent complaint in patients with Parkinson. It has a multifactorial aetiology and is more frequent in males than in females. In males it manifests mainly as incapacity to achieve an erection, premature ejaculation or loss of the capacity to ejaculate, whereas in females the predominant signs are decreased libido, lowered arousal and difficulty in reaching an orgasm. Hypersexuality affects young males above all and has been related to the use of dopamine agonists. PMID- 20205140 TI - [Cognitive and neuropsychiatric disorders in Parkinson's disease]. AB - INTRODUCTION: In Parkinson's disease there are patients with isolated and multiple cognitive impairment, and their cognitive performance ranges from normal to an advanced degree of dementia. Most patients present an executive deficit, either in isolation or combined with other cognitive disorders, which is considered to be the most characteristic aspect of the disease, and 30-40% of those affected will end up with a clinically-defined dementia. DEVELOPMENT: The presence of a mild cognitive disorder in patients with Parkinson means that the risk of dementia appearing at some time during the development of the disease is high. The dementia associated with Parkinson's disease is specifically related with neuropsychiatric signs and symptoms, which may have three possible explanations: disorders affecting the mesolimbic pathways, diffuse limbic and cortical compromise, or associated Alzheimer-type phenomenology. Psychotic episodes tend to present more often in patients with dopaminergic treatment and the clinical spectrum of Parkinson-related psychosis covers visual illusions, visual-audio-olfactory hallucinations, delirium and severe paranoid hallucinatory psychosis. All the antiparkinsonian drugs can give rise to hallucinations and psychosis, but the dopamine agonists are the ones with the greatest capacity to do so. CONCLUSIONS: In managing these problems, it is crucial for prevention as well as diagnosis and treatment to be carried out as soon as they are detected. Doses of antiparkinsonian drugs must be reduced, although this is not usually enough, and so it will be necessary to associate atypical antipsychotics, which act mainly on 5-HT receptors and, in most cases, do not produce D2 blockage. PMID- 20205141 TI - [Disorders affecting the emotional sphere and impulse control in Parkinson's disease]. AB - INTRODUCTION: Parkinson's disease (PD) is associated with mood and behavioral symptoms contributing to morbidity and reduced quality of life of the patients. Most characteristic are depression, anxiety and impulse control disorder. DEVELOPMENT: Identification and treatment of neuropsychiatric symptoms is necessary for an appropriate management of PD. Affective symptoms may be the initial manifestation of PD, are highly prevalent and pathogenically complex. Impulse control disorders are usually not a spontaneous complaint, so asking about these symptoms may be the only way to detect and treat a serious socio familial problem. Pharmacological treatment of these manifestations is difficult to balance with an adequate control of motor symptoms. Psychological support from early stages and throughout the evolution of PD is fundamental. CONCLUSIONS: Neurologist and other healthcare professionals treating PD patients need to be aware of behavioral and emotional manifestations of the disease. This will lead to an appropriate patient management and better adaptation of the familial and social situation. PMID- 20205142 TI - [Digestive disorders in Parkinson's disease: dysphagia and sialorrhea]. AB - INTRODUCTION: The non-motor symptoms of Parkinson's disease are a frequent and often under-diagnosed disorder. Two of the most significant non-motor symptoms are perhaps dysphagia and sialorrhea (which are relatively common in advanced stages of the disease) owing to their important functional repercussions and to the associated comorbidity. DEVELOPMENT AND CONCLUSIONS: In recent years, different evaluation scales have been developed for clinical use and in screening the aforementioned symptoms. Of the different therapeutic options available, botulinum toxin represents the preferred treatment for sialorrhea. In contrast, speech therapy and an optimisation of the antiparkinsonian therapy are generally useful measures to treat dysphagia, percutaneous endoscopic gastrostomy being reserved for patients suffering from Parkinson who have severe dysphagia. PMID- 20205143 TI - [Digestive disorders in Parkinson's disease: gastric atony, malabsorption and constipation]. AB - INTRODUCTION: Constipation and gastric atony are two of the most important non motor symptoms of the disease. The first is made significant by its high prevalence and precocity, since it may appear several years before the motor symptoms, and the second because of the repercussions it has on the absorption of oral medication used in this disease. DEVELOPMENT: Both the symptoms and their possible treatment are reviewed. CONCLUSIONS: In both cases treatment is based on hygienic-dietary measures that avoid substances that reduce peristalsis, prokinetic drugs like domperidone and, sometimes, infiltration of botulinum toxin, electrical stimulation or even surgical treatment. PMID- 20205144 TI - [Cardiovascular disorders in Parkinson's disease]. AB - INTRODUCTION: In Parkinson's disease (PD) there is a post-gangliar cardiac sympathetic denervation that is present from the pre-symptomatic phases of the disease onwards and which can be demonstrated by means of the Valsalva manoeuvre and cardiac scintigraphy with [123]I-meta-iodobenzylguanidine. AIM: To describe the techniques for studying the cardiac noradrenergic function and the main cardiovascular manifestations in patients with PD. DEVELOPMENT: Orthostatic hypotension is the most disabling autonomic dysfunction in patients with PD and is related with an increase in morbidity due to falls and traumatic injuries. Loss of neurones in the intermediolateral columns of the spinal cord, cardiac autonomic dysfunction and the presence of Lewy bodies in the vegetative plexuses have all been related with its origin. Affected patients can benefit from a series of dietetic and postural measures and, if necessary, can use medication, such fludrocortisone, midodrine and pyridostigmine. Supine hypertension is a potentially serious complication that can appear in patients being treated for orthostatic hypotension with fludrocortisone or midodrine. CONCLUSIONS: Suitable recognition and treatment of the cardiovascular complications of PD, especially orthostatic hypo-tension, can improve these patients' quality of life to a significant extent. PMID- 20205145 TI - [Sensory symptoms in Parkinson's disease]. AB - INTRODUCTION: In addition to the motor disturbances experienced by the patients suffering from Parkinson's disease (PD), several non-motor symptoms also affect the PD patients: neurobehavior symptoms (dementia, depression, anxiety, psychosis), autonomic (postural hypotension, urinary symptoms, gastro intestinal symptoms, diaphoresis), sleep disorders (insomnia, somnolence, REM sleep behavior disorder, apnea), sensitive-motor (fatigue, diplopia, restless legs syndrome), and sensory symptoms. DEVELOPMENT: We review the most relevant about sensory symptoms in PD: visual dysfunction, olfactory dysfunction, taste, hearing loss, and pain and other sensitive associate symptoms. CONCLUSIONS: Pain is frequently observed in patients with PD, being its prevalence high and probably infra diagnosed. Its identification and classification is very important for a correct treatment. Hyposmia is a common symptom in PD and could be a predictor of future PD. Visual dysfunction and hearing dysfunction among others must be considered in patients with PD. PMID- 20205146 TI - [Pathophysiological bases of the non-motor symptoms in Parkinson's disease]. AB - INTRODUCTION: The neuro-anatomical and neurochemical substrates underlying most of the non-motor symptoms (NMS) of Parkinson's disease (PD) are not understood in depth. AIM: To review the current knowledge on the pathophysiology of the different NMS of PD based on recent studies. DEVELOPMENT: In most of the NMS the pathophysiological foundation is complex. In addition to the dopaminergic dysfunction, the degeneration of non-dopaminergic (i.e. noradrenergic, serotoninergic and cholinergic) cellular systems is thought to underlie the development of most of the NMS and can be applied in dementia, depression, sleep disorders and vegetative disorders. Dementia, moreover, is essentially caused by different alterations that take place with the cerebral cortex. Dysfunction of the ventral striatum and of the mesolimbic projections exerts a crucial influence in impulsive-compulsive spectrum disorder. Loss of the sense of smell appears to be due to the neuronal degeneration of the olfactory bulb and the pain has an extremely varied pathogenetic basis and may be musculoskeletal, dystonic, radicular or central. CONCLUSIONS: Despite the fact that a huge amount of progress has been made in research on the pathophysiology of the NMS of PD, further clinicopathological and pathobiochemical comparative studies are needed to explain the pathophysiological bases of PD and to provide a broader foundation for future therapeutic strategies to treat NMS. PMID- 20205147 TI - [Other non-motor disorders in Parkinson's disease]. AB - INTRODUCTION: In addition to the classic triad (tremor, rigidity and akinesia), Parkinson's disease (PD) is also accompanied by several non-motor disorders. AIM: To carry out an updated review of these non-motor symptoms in terms of their pathophysiology, epidemiology, clinical features and treatment. DEVELOPMENT: Autonomic disorders such as seborrhoeic dermatitis and disorders involving sweating, fatigue, weight loss or respiratory problems (dyspnea, inspiratory stridor) are highly prevalent and very disabling symptoms. In addition, they may be the main problem in a particular phase of PD (fatigue, stridor) and condition the quality of life of patients with Parkinson. They are often neglected and remain undetected. Although they may respond to dopaminergic agents, they usually require a different therapeutic approach. Studies are needed to evaluate new therapeutic perspectives that act against the pathophysiological mechanisms of these disorders. CONCLUSIONS: PD affects systems other than the dopaminergic nigrostriatal. A better understanding of this pathology will make it possible to approach and optimise the treatment of the conditioning symptoms, thereby enhancing the welfare of patients with PD. PMID- 20205148 TI - [Dopaminergic stimulation in the non-motor symptoms of Parkinson's disease]. AB - INTRODUCTION AND DEVELOPMENT: The non-motor symptoms of Parkinson's disease have a great impact in terms of quality of life. They are frequently underdiagnosed and clinical experience suggests that not only is dopamine therapy ineffective but that in many cases it is also responsible for the appearance of some of these symptoms. Different studies have drawn attention to the involvement of the dopaminergic pathways in the pathogenesis of some non-motor symptoms. It has been observed that they can undergo fluctuations in relation to dopaminergic stimulation, generally in wearing off states, while displaying a significant correlation with motor fluctuations and a clinical response with continuous dopaminergic therapy. CONCLUSIONS: Although recent reviews offer insufficient evidence for treatment of non-motor symptoms with dopaminergic therapy, involvement of the dopaminergic pathways in the aetiopathogenesis of some of these disorders and the clinical observation that such symptoms undergo fluctuations in relation to pulsatile dopaminergic stimulation may lead us to reconsider the possible role of dopaminergic therapy in the treatment of these symptoms. PMID- 20205149 TI - [Nonmotor symptoms in Parkinson's disease and deep brain stimulation]. AB - INTRODUCTION: The efficacy of deep brain stimulation (DBS) for the motor symptoms of advanced Parkinson's disease (PD) is well established. However, the effects of DBS on nonmotor symptoms (NMS) are less clear. AIM: To review the published literature on nonmotor aspects of DBS for PD. DEVELOPMENT: The outcome of NMS after DBS in PD varies across studies. Some symptoms improve -sleep disorders, pain or sensory complaints, obsessive-compulsive disorder- and other aspects decline or appear -word fluency, apathy, body weight gain-. Isolated studies note mild improvements in working memory, visuomotor sequencing and conceptual reasoning, some gastrointestinal, urogenital, sweating and olfactory disturbances; whereas other studies have reported declines in verbal memory (long delay recall), visuospatial memory, processing speed and executive function; orthostatic hypotension remains without changes. The reasons for such a range of symptoms observed is due to the multifactorial etiology of the NMS, including preoperative vulnerability, changes in dopaminergic medications, surgical and stimulation effects, underlying PD-related factors and psychosocial effects. Specific patient subgroups may be at greater risk of cognitive deficits -e.g., those older than 69 years or with cognitive impairment prior to surgery- or depression, mania and suicide -e.g., those ones with preoperative psychiatric symptoms-. CONCLUSIONS: Patients who undergo DBS must be well-selected, weighing the risks and benefits, in order to obtain the best results with this treatment. Further multicentre studies are necessary to understand the role of DBS on NMS. PMID- 20205150 TI - Interpersonal predictors of outcome following short-term group therapy for complicated grief: a replication. AB - The current study represented a replication of previous research, addressing measures of interpersonal relatedness as predictors of outcome for dynamically oriented, short-term group (STG) psychotherapy for patients presenting with complicated grief. In an analysis of data from a comparative trial of two forms (interpretive, supportive) of STG therapy (n = 107), Ogrodniczuk, Piper, McCallum, Joyce and Rosie reported that three distinct indices of interpersonal relatedness-quality of object relations, current social functioning and attachment insecurity-each had significant relationships with measures of treatment outcome, with attachment insecurity emerging as the strongest predictor. The current study (n = 110) was based on data from a subsequent trial of the two therapy approaches that examined the effect of group composition on outcome, by Piper, Ogrodniczuk, Joyce, Weideman and Rosie. Predictor variables and outcome factors involved in the current analyses were similar or identical to those employed by Ogrodniczuk et al., and an identical analytic strategy was followed. Only the patient's attachment insecurity emerged as a strong predictor of psychotherapy outcome, providing a replication of the key finding from the previous study. The clinical implications and limitations of the results are discussed. PMID- 20205151 TI - The 'question mark' sign as a new ultrasound marker of tetralogy of Fallot in the fetus. AB - OBJECTIVE: To describe a new ultrasonographic marker, the 'question-mark' sign, to assist in the diagnosis of tetralogy of Fallot (TOF) in the fetus, and to evaluate its prevalence in TOF as compared with other cardiac defects. METHODS: A prospective evaluation over a 5-year period of a consecutive series of 3998 pregnant women undergoing fetal echocardiography from 12 to 40 weeks' gestation due to high risk for congenital heart disease (CHD). Standard echocardiographic planes with color Doppler assessment and evaluation of the whole aortic arch, from the left ventricular outflow tract to the descending aorta in the axial upper mediastinum views, were performed. The question-mark sign corresponded with an enlarged and dilated ascending aorta and aortic arch in the three-vessel view of the upper fetal mediastinum. The frequency of this sign was evaluated in cases with TOF and in other cases of cardiac defects, as well as in fetuses with normal cardiac scans in this series. RESULTS: CHD was diagnosed in a total of 447 (11.2%) fetuses at a median gestational age of 24 (range, 12-40) weeks. Forty-two of the 447 (9.4%) had TOF, of which 29 cases (69.0%) had classical TOF (pulmonary stenosis), nine (21.4%) pulmonary atresia and four (9.5%) absent pulmonary valve syndrome. A question-mark sign was observed in 16/29 (55.2%) cases of classical TOF and in 8/9 (88.9%) cases of TOF with pulmonary atresia. The sign was never observed in any of the cases of TOF with a right-sided aortic arch. Likewise, the sign was observed in 1/405 (0.2%) cases with other cardiac anomalies (a fetus with a complex cardiac defect) and in none of the fetuses with normal hearts. CONCLUSIONS: The finding of an enlarged aorta with a question-mark shape should raise a strong suspicion of tetralogy of Fallot, in particular the variant with pulmonary atresia. This sign may be useful in screening considering that prenatal diagnosis of TOF by routine ultrasonography remains a challenge. PMID- 20205152 TI - Degree of cervical shortening after initial induction of labor as a predictor of subsequent successful induction. AB - OBJECTIVE: To evaluate whether the degree of cervical length shortening is valuable in predicting the success of serial induction of labor on the second day in women in whom it failed on the first day, and to compare its performance with that of cervical length. METHODS: This was a prospective observational study. We enrolled 92 consecutive women with singleton gestations at > 34.0 weeks' gestation who failed labor induction on the first day of serial induction. Transvaginal sonographic measurement of cervical length and determination of the Bishop score were undertaken before performing each labor induction on the first and second days. RESULTS: The overall success rate of labor induction performed on the second day was 65% (60/92). Multiple logistic regression analysis demonstrated that the degree of cervical length shortening and cervical length were significantly associated with the successful induction of labor after adjustment for body mass index, parity, use of prostaglandin and Bishop score. There were no significant differences between areas under the ROC curves for degree of cervical length shortening and cervical length. CONCLUSIONS: The degree of cervical length shortening is valuable in predicting the success of induction of labor on the second day in women in whom induction failed on the first day. However, compared with sonographic cervical length it is no better at predicting the success of subsequent induction of labor. PMID- 20205153 TI - Impact of a regional training program in fetal echocardiography for sonographers on the antenatal detection of major congenital heart disease. AB - OBJECTIVES: The aims of this study were to ascertain the effect of a regional training program in fetal echocardiography for obstetric radiographers on the antenatal detection of major congenital heart disease (CHD) and to document short term outcomes for major CHD. METHODS: All 87 obstetric radiographers in Northern Ireland were invited to attend 2.5 days of training during a 1-year period. Data were collected before and after the training, over a 5-year study period, to assess the effect of training on the antenatal detection of CHD in the population. RESULTS: The antenatal detection of major CHD rose significantly, from 28% (72/262) pretraining to 43% (36/84) in the year of training (P = 0.008). Antenatal diagnosis of four-chamber-view defects rose significantly (from 38% to 54%; P = 0.04), as did detection of outflow-tract-view defects (from 8% to 21%; P = 0.05). Twelve per cent (13/108) of cases died spontaneously in utero and 8% (9/108) were terminated. Only 78% (67/86) of live-born cases in which CHD had been diagnosed antenatally survived the neonatal period, compared to 93% (221/238) with a postnatal diagnosis of CHD (P < 0.001). CONCLUSIONS: Even with a relatively simple training program, significant improvements can be made in the antenatal detection of CHD. With training, obstetric sonographers can successfully assess outflow tracts. Antenatally diagnosed cases have more complex CHD and this probably contributes to poor neonatal survival. PMID- 20205154 TI - Impact of tissue harmonic imaging on measurement of nuchal translucency thickness. AB - OBJECTIVES: To evaluate the effect of tissue harmonic imaging (THI) on the measurement of fetal nuchal translucency thickness (NT). METHODS: One-hundred and three pregnant women underwent first-trimester NT measurement according to The Fetal Medicine Foundation criteria. NT was evaluated using conventional ultrasonography (CUS) and THI without modifying any other ultrasound parameter (e.g. gain). For each patient three images with CUS and three images with THI were stored and then measured independently on the ultrasound system by two different operators. The maximum measurements using CUS and THI were compared. Differences between the values of CUS and THI NT measurements were tested using the Wilcoxon signed-rank test. Bland-Altman plots were constructed, and intraobserver and interobserver variabilities were assessed by calculation of the intraclass correlation coefficient. Probability values of < 0.05 were considered significant. RESULTS: Mean maternal age was 32.8 (range, 20-42) years, mean gestational age at examination was 12 + 1 (11 + 0 to 13 + 6) weeks and mean crown rump length (CRL) was 55.8 (SD, 7.2) mm. Median fetal NT was 1.4 (0.8-3.5) mm using CUS and 1.2 (0.6-3.3) mm using THI (P < 0.001) for the first operator. A second operator remeasured the first 51 cases: median fetal NT was 1.4 (0.8-3.8) mm using CUS and 1.1 (0.6-3.1) mm using THI (P < 0.001). Fetal NT measurements were above the expected median value according to CRL in 49 cases (47.6%) using CUS and in only 24 cases (23.3%) using THI. CONCLUSIONS: THI leads to a small, but significant, reduction of the NT measurement and this could reduce the sensitivity of screening for Down syndrome. PMID- 20205155 TI - The fetal venous system, part I: normal embryology, anatomy, hemodynamics, ultrasound evaluation and Doppler investigation. AB - Since its introduction in the mid-1980s sonographic evaluation of the human fetal venous system has advanced dramatically. The venous system is well-recognized as a target for investigation in cases of circulatory compromise, and a broad spectrum of malformations affecting this system has been described. Appreciation of the normal embryology, anatomy and physiology of this system is essential to an understanding of structural anomalies and the sequential changes encountered in intrauterine growth restriction or other developmental disorders. We review the normal embryology, anatomy, and hemodynamics of the human fetal venous system, and provide an overview of Doppler investigation, as well as three- and four-dimensional ultrasound modalities and their application to this system. PMID- 20205156 TI - Prenatal transient alveolomaxillary defect in a case of mucolipidosis II (I-cell disease). PMID- 20205157 TI - Additive manufacturing models of fetuses built from three-dimensional ultrasound, magnetic resonance imaging and computed tomography scan data. AB - OBJECTIVE: To generate physical fetal models using images obtained by three dimensional ultrasonography (3DUS), magnetic resonance imaging (MRI) and computed tomography (CT) to guide additive manufacturing technology. METHODS: Images from 33 fetuses, including three sets of twins, were used. Fifteen fetuses were normal and evaluated only by 3DUS. Eighteen cases had abnormalities such as conjoined twins, tumors, aneuploidy, skeletal abnormalities, central nervous system abnormalities and facial or thoracic defects. Scans were performed using high resolution 3DUS. In cases of abnormalities, MRI and CT were performed on the same day as 3DUS. The images obtained with 3DUS, CT or MRI were exported to a workstation in DICOM format. A single observer performed slice-by-slice manual segmentation using a digital high-definition screen. Software that converts medical images into numerical models was used to construct virtual 3D models, which were physically realized using additive manufacturing technologies. RESULTS: Physical models based on 3DUS, MRI and CT images either separately or combined were successfully generated. They were remarkably similar to the postnatal appearance of the aborted fetus or newborn baby, especially in cases with pathology. CONCLUSION: The use of 3DUS, MRI and CT may improve our understanding of fetal anatomical characteristics, and these technologies can be used for educational purposes and as a method for parents to visualize their unborn baby. The images can be segmented and applied separately or combined to construct 3D virtual and physical models. PMID- 20205158 TI - The fetal venous system, Part II: ultrasound evaluation of the fetus with congenital venous system malformation or developing circulatory compromise. AB - The human fetal venous system is well-recognized as a target for investigation in cases of circulatory compromise, and a broad spectrum of malformations affecting this system has been described. In Part I of this review, we described the normal embryology, anatomy and physiology of this system, essential to the understanding of structural anomalies and the sequential changes encountered in intrauterine growth restriction and other developmental disorders. In Part II we review the etiology and sonographic appearance of malformations of the human fetal venous system, discuss the pathophysiology of the system and describe venous Doppler investigation in the fetus with circulatory compromise. PMID- 20205159 TI - Maternal plasma soluble endoglin at 11-13 weeks' gestation in pre-eclampsia. AB - OBJECTIVES: To examine the performance of screening for pre-eclampsia (PE) by a combination of maternal factors, soluble endoglin (sEng), pregnancy associated plasma protein-A (PAPP-A), placental growth factor (PlGF) and uterine artery lowest pulsatility index (L-PI) at 11-13 weeks' gestation. METHODS: Uterine artery L-PI, sEng, PAPP-A and PlGF were measured at 11-13 weeks in 90 singleton pregnancies that subsequently developed PE, including 30 that required delivery before 34 weeks (early PE) and 60 with late PE, and 180 unaffected controls. Screening performance for PE by maternal factors, sEng, PAPP-A, PlGF and uterine artery L-PI and their combinations was determined. RESULTS: In early PE, compared to controls, plasma sEng and uterine L-PI were significantly increased and serum PAPP-A and PlGF were decreased. In late PE, compared to controls, serum PlGF was decreased and uterine L-PI was increased but plasma sEng and serum PAPP-A were not significantly different. In screening for early PE, the detection rate for a 10% false-positive rate was 46.7% for sEng alone and 96.3% for a combination of maternal factors, sEng, PlGF and uterine artery L-PI. CONCLUSIONS: Effective screening for early PE can be provided by a combination of maternal factors, sEng, PlGF and uterine artery L-PI at 11-13 weeks' gestation. PMID- 20205160 TI - Continuous supply of TGFbeta3 via adenoviral vector promotes type I collagen and viability of fibroblasts in alginate hydrogel. AB - In recent years, transforming growth factor-beta3 (TGFbeta3) has interested more and more researchers with its competence in engineered histogenesis. In the present study we employed recombinant adenoviral vectors to deliver the constitutively active TGFbeta3 gene to human dermal fibroblasts, which could maintain the continuous secretion of TGFbeta3 from the cells. The expression of type I collagen in the Ad-TGFbeta3 group increased significantly in comparison with other three groups: Neg (cells without treatment of the adenovirus), Ad-null (cells with treatment of the adenovirus, without the inserted gene) and Ad-shRNA (cells with treatment of the adenovirus encoding shRNA specific for type I collagen). Additionally, we demonstrated that TGFbeta3 enhanced the expression of Smad4 while inhibiting that of MMP-9, thus promoting the collagen transcription via the Smad signal transduction pathway and restraining collagen degradation by MMP-9, which contributed to the increasing type I collagen expression level. As type I collagen mediates cell-material interactions by providing anchorage, the viability of encapsulated fibroblasts in Ad-TGFbeta3 group was significantly higher than that in other three groups. Accordingly, this approach forms an effective way to improve the compatibility of non-adhesive hydrogels containing anchorage-dependent cells. PMID- 20205161 TI - Alternating current electric field effects on neural stem cell viability and differentiation. AB - Methods utilizing stem cells hold tremendous promise for tissue engineering applications; however, many issues must be worked out before these therapies can be routinely applied. Utilization of external cues for preimplantation expansion and differentiation offers a potentially viable approach to the use of stem cells in tissue engineering. The studies reported here focus on the response of murine neural stem cells encapsulated in alginate hydrogel beads to alternating current electric fields. Cell viability and differentiation was studied as a function of electric field magnitude and frequency. We applied fields of frequency (0.1-10) Hz, and found a marked peak in neural stem cell viability under oscillatory electric fields with a frequency of 1 Hz. We also found an enhanced propensity for astrocyte differentiation over neuronal differentiation in the 1 Hz cultures, as compared to the other field frequencies we studied. PMID- 20205162 TI - Advances in clone selection using high-throughput bioreactors. AB - Effective clone selection is a crucial step toward developing a robust mammalian cell culture production platform. Currently, clone selection is done by culturing cells in well plates and picking the highest producers. Ideally, clone selection should be done in a stirred tank bioreactor as this would best replicate the eventual production environment. The actual number of clones selected for future evaluation in bioreactors at bench-scale is limited by the scale-up and operational costs involved. This study describes the application of miniaturized stirred high-throughput bioreactors (35 mL working volume; HTBRs) with noninvasive optical sensors for clone screening and selection. We investigated a method for testing several subclones simultaneously in a stirred environment using our high throughput bioreactors (up to 12 clones per HTBR run) and compared it with a traditional well plate selection approach. Importantly, it was found that selecting clones solely based on results from stationary well plate cultures could result in the chance of missing higher producing clones. Our approach suggests that choosing a clone after analyzing its performance in a stirred bioreactor environment is an improved method for clone selection. PMID- 20205163 TI - Separation of viable and nonviable animal cell using dielectrophoretic filter. AB - Selective separation of cells using dielectrophoresis (DEP) has recently been studied and methods have been proposed. However, these methods are not applicable to large-scale separation because they cannot be performed efficiently. In DEP separation, the DEP force is effective only when it is applied close to the electrodes. Utilizing a DEP filter is a solution for large-scale separation. In this article, the separation efficiency for viable and nonviable cells in a DEP filter was examined. The effects of an applied AC electric field frequency and the gradient of the squared electric field intensity on a DEP velocity for the viable and nonviable animal cells (3-2H3 cell) were discussed. The frequency response of the DEP velocity differed between the viable and the nonviable cells. We deducted an empirical equation that can be used as guiding principle for the DEP separation. The results indicate that the viable and the nonviable cells were separated using the DEP filter, and the best operating conditions such as the applied voltage and the flow rate were discussed. PMID- 20205164 TI - Pretransplant predictors of recovery of renal function after liver transplantation. AB - The Model for End-Stage Liver Disease system has given priority on the liver transplant waiting list to candidates with renal failure. This study determined the predictors of spontaneous recovery of renal function after transplantation in 1041 liver transplant recipients on renal replacement therapy (RRT) at the time of transplant (from February 2002 to January 2007). Data from these patients were obtained from the US Organ Procurement and Transplantation Network and US Renal Data System databases. Univariate and multivariate survival models were constructed along with multivariate logistic regression models to find independent predictors of spontaneous renal recovery. Seven hundred seven recipients (67.9%) had spontaneous recovery of renal function after liver transplantation. Those recovering spontaneously had a significantly shorter course of RRT in the pretransplant time period (15.6 versus 36.6 days, P < 0.001). Recovery of renal function was observed in 70.8% and 11.5% of recipients on RRT for less than 30 days and more than 90 days, respectively. Other statistically significant pretransplant variables independently associated with recovery of renal function included recipient age, recipient pretransplant diabetes, and donor age. In conclusion, the duration of pretransplant RRT is highly predictive of spontaneous renal recovery post-transplant. Liver transplant candidates requiring less than 30 days of pretransplant RRT are likely to spontaneously recover renal function after liver transplantation, whereas those on RRT for more than 90 days are not. PMID- 20205165 TI - Angiogenesis in vestibular schwannomas: expression of extracellular matrix factors MMP-2, MMP-9, and TIMP-1. AB - OBJECTIVES/HYPOTHESIS: Vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) are potent mediators of tumor angiogenesis. It has been demonstrated that vestibular schwannoma VEGF expression correlates with tumor growth pattern, whereas knowledge on the expression of MMPs is lacking. This study targets the angiogenic process by investigation of tumor expression of MMP 2, MMP-9, and tissue inhibitors of metalloproteinase (TIMP)-1. A possible correlation with gender, patient age, symptom duration, tumor size, and the absolute and relative growth rate is explored. STUDY DESIGN: Prospective vestibular schwannoma tissue sampling for ELISA and immunohistochemical determination of MMP-2, MMP-9 and TIMP-1. METHODS: Thirty-four patients with a sporadic, noncystic, vestibular schwannoma were selected prospectively. Repeated, preoperative magnetic resonance imaging determined the tumor growth pattern. Following translabyrinthine resection, an enzyme-linked immunosorbent assay was used for determination of the MMP-2, MMP-9, and TIMP-1 concentration in tumor sample homogenates. Immunohistochemical labeling was performed in 12 randomly selected tumors. RESULTS: : All tumor homogenates expressed measurable MMP-9, MMP 2, and TIMP-1. Immunolabeling localized MMP-9 expression to the tumor cells, whereas MMP-2 and TIMP-1 was found interstitially. A significant correlation existed between the concentration MMP-9 and absolute tumor growth rate, whereas a weak correlation occurred for the relative growth rate. CONCLUSIONS: Vestibular schwannomas express MMP-2, MMP-9, and TIMP-1 and the tumor concentration of MMP-9 correlates with absolute tumor growth rate, but not with age, gender, symptom duration, or preoperative tumor size. No correlations existed between any clinical parameter and MMP-2 or TIMP-1 expression. We conclude that MMP-9 appears to be involved in the growth of vestibular schwannomas. PMID- 20205166 TI - Calcium requirements and metabolism in Chinese-American boys and girls. AB - Calcium requirements of North American adolescents were set at 1300 mg/day based on data from white girls. Calcium requirements for Asian-American adolescents have not been studied. Using metabolic balance protocols and a range in calcium intakes, skeletal calcium retention was determined in Chinese-American adolescents. A sample of 29 adolescents, 15 boys aged 12 to 15 years and 14 girls aged 11 to 15 years, was studied twice on paired calcium intakes ranging between 629 to 1835 mg/day using a randomized-order crossover design. Calcium absorption and bone turnover rates using double-stable calcium isotope kinetic analysis on two calcium intakes per subject were measured and compared in boys and girls. Girls and boys had low habitual mean calcium intakes of 648 and 666 mg/day, respectively, and low mean serum 25-hydroxyvitamin D concentrations of 19.1 and 22.2 ng/mL, respectively. True fractional calcium absorption varied inversely with calcium load. Boys had significantly higher bone turnover rate than girls at the same calcium intake. Calcium retention increased with calcium intake; calcium intakes to achieve maximal calcium retention were 1100 mg/day in boys and 970 mg/day in girls. Recommendations for calcium requirements should be lowered for Chinese-American adolescents. PMID- 20205167 TI - Cross-sectional association between serum vitamin D concentration and walking speed measured at usual and fast pace among older women: the EPIDOS study. AB - The purpose of this study was to determine whether there was an association between serum 25-hydroxyvitamin D [25(OH)D] concentration and walking speed measured at usual and fast pace among older women. Usual- and fast-pace walking speeds and 25(OH)D concentrations were assessed in 739 randomized older women (mean age 80.2 +/- 3.5 years) from the EPIDOS study. The following 25(OH)D thresholds were used: 10, 20, and 30 ng/mL. Walking speed was dichotomized on being in the worst quintile or not. Age, body mass index, number of chronic diseases, physical activity, quadriceps strength, cognition, use of psychoactive drugs, and serum parathyroid hormone were used as potential confounders. The results show that 90% of subjects had 25(OH)D insufficiency. Only fast-pace walking speed was significantly different between groups (p = .021) and decreased from normal serum 25(OH)D concentrations to severe insufficiency (trend p = .007). Serum 25(OH)D concentration was associated with walking speed at both usual and fast pace in the unadjusted linear regression (beta = 0.16, p = .027 and beta = 0.23, p = .009, respectively). This association remained significant only for fast-pace walking after adjustment (adjusted beta = 0.18, p = .033) and was strengthened from a lower 25(OH)D value compared with usual pace [25(OH)D = 27.15 ng/mL for fast pace and 38.65 ng/mL for usual pace). Lastly, logistic regression showed a stronger association of serum 25(OH)D insufficiency with fast pace walking speed whatever the 25(OH)D thresholds used [30 to 20 ng/mL: adjusted odds ratio (adjOR) = 6.01, p = .003; 20 to 10 ng/mL: adjOR = 4.10, p = .014; <10 ng/mL: adjOR = 6.95, p = .001) compared with usual pace (30 to 20 ng/mL: adjOR = 3.79, p = .022; 20 to 10 ng/mL: adjOR = 3.76, p = .016; <10 ng/mL: adjOR = 5.44, p = .003). The findings show a stronger positive association between 25(OH)D concentrations and fast-pace walking speed that is a more sensitive marker of neuromuscular functioning compared with usual-pace walking. PMID- 20205169 TI - Osteosarcoma. AB - It has been difficult to identify the molecular features central to the pathogenesis of osteosarcoma owing to a lack of understanding of the cell or origin, the absence of identifiable precursor lesions, and its marked genetic complexity at the time of presentation. Interestingly, several human genetic disorders and familial cancer syndromes, such as Li-Fraumeni syndrome, are linked to an increased risk of osteosarcoma. Association of these same genetic alterations and osteosarcoma risk have been confirmed in murine models. Osteosarcoma is associated with a variety of genetic abnormalities that are among the most commonly observed in human cancer; it remains unclear, however, what events initiate and are necessary to form osteosarcoma. The availability of new resources for studying osteosarcoma and newer research methodologies offer an opportunity and promise to answer these currently unanswered questions. Even in the absence of a more fundamental understanding of osteosarcoma, association studies and preclinical drug testing may yield clinically relevant information. PMID- 20205168 TI - Genetic variation in the RANKL/RANK/OPG signaling pathway is associated with bone turnover and bone mineral density in men. AB - The aim of this study was to determine if single-nucleotide polymorphisms (SNPs) in RANKL, RANK, and OPG influence bone turnover and bone mineral density (BMD) in men. Pairwise tag SNPs (r(2) > or = 0.8) were selected for RANKL, RANK, and OPG and their 10-kb flanking regions. Selected tag SNPs plus five SNPs near RANKL and OPG, associated with BMD in published genome-wide association studies (GWAS), were genotyped in 2653 men aged 40 to 79 years of age recruited for participation in a population-based study of male aging, the European Male Ageing Study (EMAS). N-terminal propeptide of type I procollagen (PINP) and C-terminal cross-linked telopeptide of type I collagen (CTX-I) serum levels were measured in all men. BMD at the calcaneus was estimated by quantitative ultrasound (QUS) in all men. Lumbar spine and total-hip areal BMD (BMD(a)) was measured by dual-energy X-ray absorptiometry (DXA) in a subsample of 620 men. Multiple OPG, RANK, and RANKL SNPs were associated with bone turnover markers. We also identified a number of SNPs associated with BMD, including rs2073618 in OPG and rs9594759 near RANKL. The minor allele of rs2073618 (C) was associated with higher levels of both PINP (beta = 1.83, p = .004) and CTX-I (beta = 17.59, p = 4.74 x 10(-4)), and lower lumbar spine BMD(a) (beta = -0.02, p = .026). The minor allele of rs9594759 (C) was associated with lower PINP (beta = -1.84, p = .003) and CTX-I (beta = -27.02, p = 6.06 x 10(-8)) and higher ultrasound BMD at the calcaneus (beta = 0.01, p = .037). Our findings suggest that genetic variation in the RANKL/RANK/OPG signaling pathway influences bone turnover and BMD in European men. PMID- 20205170 TI - Office-based injection laryngoplasty in the irradiated larynx. AB - OBJECTIVES/HYPOTHESIS: To review the clinical results of office-based injection laryngoplasty with two different therapeutic materials in patients with vocal fold paralysis and history of radiation therapy to the larynx. STUDY DESIGN: Retrospective study. METHODS: Chart review of 11 patients who underwent office based injection laryngoplasty with calcium hydroxylapatite or micronized Alloderm. All patients had a history of radiation therapy to the neck, with the larynx included in the radiation field. Voice analyses, clinical outcomes, and complications were reviewed. Efficacy of the procedure was evaluated by comparing pre- and postinjection mean phonation time (MPT) results from voice analysis data. RESULTS: A total of 15 injections were performed in 11 patients with vocal fold paralysis (one females, 10 males, mean age 62 years). Data from voice analyses before and after the procedure were available for nine injections. The MPT was significantly increased among patients undergoing the procedure (P < .05). All procedures were successful, and only one self-limited complication was reported. CONCLUSIONS: Office-based injection laryngoplasty is a safe procedure with acceptable clinical results in patients with vocal fold paralysis who have a history of radiation therapy to the larynx. PMID- 20205171 TI - Suprathreshold gustatory stimuli cause biphasic respiratory responses during resting respiration in humans. AB - OBJECTIVES/HYPOTHESIS: Until now there has been no standardized and internationally accepted method available to objectify taste perception. Such a method would be useful for expert opinions in the assessment of gustatory disorders. The aim of our study was to develop and evaluate an analogous method for the gustatory sense. STUDY DESIGN: Nonrandomized, controlled clinical trial. METHODS: A continuous flow of water was presented to the tongues of 34 healthy adult subjects (15 men, 19 women). In this stream, suprathreshold gustatory stimuli were applied during regular resting respiration. Nasal respiration was measured unilaterally with a differential pressure transducer. RESULTS: No significant differences were measured between the different tastants but were between tastants and blanks. Gustatory-evoked changes in the breathing pattern resulted frequently in a prolongation of the first poststimulatory breath. The second and third breath became frequently shorter. CONCLUSIONS: The observed gustatory-evoked respiratory responses are probably orienting reflex (OR) reactions. The deceleration of the first breath could be related to attention toward any chemosensory input. The acceleration of the second and third breath could reflect the subject's intention to recognize the four taste qualities. The measurement of respiratory OR evoked by gustatory stimuli can be used as a simple, inexpensive, and reliable objectifying clinical tool to prove intact central gustatory processing. PMID- 20205172 TI - Fluid flow through a high cell density fluidized-bed during centrifugal bioreactor culture. AB - An increasing demand for products such as tissues, proteins, and antibodies from mammalian cell suspension cultures is driving interest in increasing production through high-cell density bioreactors. The centrifugal bioreactor (CCBR) retains cells by balancing settling forces with surface drag forces due to medium throughput and is capable of maintaining cell densities above 10(8) cells/mL. This article builds on a previous study where the fluid mechanics of an empty CCBR were investigated showing fluid flow is nonuniform and dominated by Coriolis forces, raising concerns about nutrient and cell distribution. In this article, we demonstrate that the previously reported Coriolis forces are still present in the CCBR, but masked by the presence of cells. Experimental dye injection observations during culture of 15 microm hybridoma cells show a continual uniform darkening of the cell bed, indicating the region of the reactor containing cells is well mixed. Simulation results also indicate the cell bed is well mixed during culture of mammalian cells ranging in size from 10 to 20 microm. However, simulations also allow for a slight concentration gradient to be identified and attributed to Coriolis forces. Experimental results show cell density increases from 0.16 to 0.26 when centrifugal force is doubled by increasing RPM from 650 to 920 at a constant inlet velocity of 6.5 cm/s; an effect also observed in the simulation. Results presented in this article indicate cells maintained in the CCBR behave as a high-density fluidized bed of cells providing a homogeneous environment to ensure optimal growth conditions. PMID- 20205173 TI - Degrees of dysplasia and the use of cidofovir in patients with recurrent respiratory papillomatosis. AB - OBJECTIVES/HYPOTHESIS: Recurrent respiratory papillomatosis (RRP) is a benign disease characterized by recurrent lesions in the airway. The prevalence and degree of dysplasia that is present in the natural course of RRP is not well established. Adjuvant therapies, such as cidofovir, have been tried with the goal of decreasing the interval between repeat surgical treatments, the mainstay of therapy. Although, the off-label use of cidofovir to treat RRP has been common, there have been concerns regarding carcinogenic transformation following the use of cidofovir. This study aims to explore the association between increasing degree of papilloma dysplasia and the use of cidofovir in the context of the natural progression of dysplasia in RRP. STUDY DESIGN: Retrospective case series. METHODS: Demographic data and surgical history were obtained through chart reviews for this retrospective case series of 13 patients with RRP who had histopathologic biopsies done before and after exposure to cidofovir. Pathologic data collected over 10 years from serial excisions at the University of Iowa Hospitals were reviewed by a single pathologist, and the highest degree of dysplasia was noted per excision time. RESULTS: Of the 176 specimens collected in these 13 patients with serial papilloma biopsies, 5.7% had no dysplasia, 57.4% had mild dysplasia (grade 1), 28.4% had moderate dysplasia (grade 2), and 8.5% had severe dysplasia (grade 3). A comparison of each patient's multiple biopsies across time suggested that the dysplastic grade was worse in two patients, better in four patients, and virtually unchanged in seven patients. There was no clear cut pattern between the use of cidofovir and the degree of dysplasia over time. CONCLUSIONS: These results strongly suggest that intralesional cidofovir therapy does not correlate with worsening dysplastic progression. Dysplasia is relatively common in the setting of RRP; however, the prognostic significance of this finding is unknown. Additional research is needed to delineate the natural progression of dysplasia and its clinical significance in RRP, as well as the efficacy of cidofovir. PMID- 20205174 TI - The history of pediatric airway reconstruction. AB - OBJECTIVES/HYPOTHESIS: To review the history of pediatric laryngotracheal reconstruction and to highlight those who made major contributions in the field. STUDY DESIGN: Retrospective literature review. METHODS: A literature search using the PubMed database from 1950 to the present. Earlier references were obtained from the Adams Center, the National Library of Medicine, and Virginia Commonwealth University Library. RESULTS: A total of 20 articles were identified. The articles reported 274 airway reconstructions of which 79% were in children. Pre-1935 infection was the leading cause of laryngotracheal stenosis. Laryngostomy, pioneered by Chevalier Jackson, was the most common method of reconstruction. Between 1935 and 1970, trauma was the predominant cause of laryngotracheal stenosis. The most common procedure was the anterior/posterior cricoid split or Rethi procedure. It marked the introduction of bony grafts in laryngotracheal surgery as pioneered by Looper. Post-1970, prolonged intubation in neonates was the most common cause of subglottic stenosis. The field was revolutionized by the work of Evans and Cotton, with widespread use of costal cartilage grafts and laryngotracheoplasty leading to a decannulation rate of over 90%. Advances included decreased morbidity, tolerability, shorter recovery time, and fewer stages of reconstruction. CONCLUSIONS: The pioneering work of many leaders in the field of airway reconstruction over the last 100 years has resulted in a number of effective airway reconstructive procedures that have led to the majority of children being successfully decannulated. In the future, more extensive surgeries, such as tracheal transplantation, may address the small number of children who presently cannot be decannulated. PMID- 20205175 TI - Long-term results of morbidity after parotid gland surgery in benign disease. AB - OBJECTIVES/HYPOTHESIS: To determine the incidence of major and minor complications and their impact on patients' comfort after parotid surgery in benign disease. STUDY DESIGN: Retrospective. METHODS: Four hundred ninety-two patients were included. Total parotidectomy (TP) was performed in 65.8%, superficial parotidectomy (SP) in 27.2%, and partial superficial parotidectomy (PSP) in 7.0%. Patients were interviewed using a self-designed questionnaire. Incidence of complications was evaluated depending on the extent of surgery and intensity of complaints. To ascertain the impact of morbidity on their daily lives, patients were asked to estimate it according to a visual analog scale. RESULTS: Frey's syndrome occurred in 63.4%, and temporary facial nerve palsy in 32.7% of all cases. Both rates were significantly reduced after PSP. Permanent facial nerve paresis was observed in 2.3% of the cases, but in no case after PSP. Perception of patients and their scores reflected these results. Scores regarding Frey's syndrome and facial nerve paresis showed a significant positive correlation with extent of surgery. The recurrence rate was 2.2%; no recurrences were noted after PSP. Scores of perceived general condition indicated an excellent state. CONCLUSIONS: The incidence of complications was reduced after PSP compared to SP or TP. Patient scores, which represent their perception of these complications, reflected these data and may be an additional instrument to measure outcome. These data suggest that less invasive operative techniques should be considered in case of a benign disease. PMID- 20205176 TI - Pulp necrosis during septorhinoplasty. AB - OBJECTIVES/HYPOTHESIS: Bony manipulation near the nasal spine or maxillary crest trimming can predispose teeth to injury during septorhinoplasty, especially when there is an aberrant vascular supply or a highly situated root apex in the premaxilla. STUDY DESIGN: Prospective cross-sectional study. METHODS: A prospective cross-sectional study was carried out on 438 teeth (maxillary incisors and canines) that were supposedly affected and 73 control teeth (mandibular lateral incisors) in 73 candidates of septorhinoplasty before and after surgery to determine the frequency of pulp necrosis using electrical, heat, and cold pulpal tests. Those with difficult intubation, history of root canals or orthodontic procedures, history of dental trauma, or a positive preoperative test were excluded from the study. Patients were followed up 2 weeks, 3 months, and 6 months postoperatively, and test results were compared before and at three intervals after the surgery. RESULTS: Seventy-three consecutive patients, including 11 males and 62 females, met the study criteria. Septoplasty with anterior maxillary crest trimming and anterior nasal spine manipulation was performed in 63 and 52 cases, respectively. Only 10 cases underwent septoplasty without manipulation of the maxillary crest or the anterior nasal spine. Based on pulp testing, no case of pulp necrosis was seen during the 6-month follow-up. CONCLUSIONS: Considering there are very few reports of dental problems during septorhinoplasty, it is an unlikely cause of serious dental complications such as pulp necrosis. An abnormal anatomy might be a good explanation for rare cases. PMID- 20205177 TI - Modified vertical dome division technique for rhinoplasty in Asian patients. AB - OBJECTIVES/HYPOTHESIS: Vertical dome division (VDD) is a useful nasal tip surgery technique. However, it is associated with postoperative complications and has never been studied in Asian patients. This study examined results following application of our modified VDD approach in Asian patients requiring nasal tip surgery. STUDY DESIGN: A retrospective clinical chart review. METHODS: We retrospectively studied 37 patients who underwent rhinoplasty using our modified VDD procedure. The indications were thick tip skin and relatively strong and well developed lower lateral cartilages. Outcome measurements were made using preoperative and postoperative photographs. Doctors and patients separately indicated satisfaction using a visual analogue scale (from 1 = satisfied, to 4 = dissatisfied). RESULTS: Following surgery, the mean tip projection increment across the population was 15.8%, and the nasofrontal and nasolabial angle increments were 1.4 degrees and 5.5 degrees, respectively. Doctor and patient satisfaction scores were 1.54 +/- 0.76 and 1.61 +/- 0.81, respectively. Most patients showed prominent tip projection and good cosmetic results. Two patients (5.4%) were dissatisfied, one due to a narrow tip and the other due to nostril asymmetry. CONCLUSIONS: The modified VDD was an effective method for nasal tip projection and rotation in selected Asian patients. PMID- 20205178 TI - Middle ear aneurysm treated with an innovative, vessel-preserving, aneurysm occluding stent. AB - Middle ear aneurysms are rare and difficult to treat. An innovative, parent vessel-preserving, aneurysm occlusion stent is a treatment alternative. It redirects blood flow away from the aneurysm, resulting in stasis within, and ultimate aneurysm thrombosis. Concurrent coiling is not needed with this stent, eliminating the risk of coils extruding or migrating, or acting as a nidus for infection in the middle ear. We review a successful treatment using this device. PMID- 20205179 TI - Conceptual relations between anxiety disorder and fearful temperament. AB - Fearful temperaments have been identified as a major risk factor for anxiety disorders. However, descriptions of fearful temperament and several forms of anxiety disorder show strong similarities. This raises the question whether these terms may simply refer to different aspects of the same underlying construct. The current review examines evidence for the overlap and distinction between these constructs. Although strong conclusions cannot be drawn from the extant literature, the bulk of the evidence appears to support a distinction between them. PMID- 20205180 TI - Factors contributing to the emergence of anxiety among behaviorally inhibited children: the role of attention. AB - Behavioral inhibition (BI) is a temperament that can be identified early in childhood. Children with BI are socially reticent, withdraw from engaging unfamiliar peers, and often have problems in forming friendships. They are also at risk for developing anxiety disorders as they get older. There is, however, as much discontinuity as continuity in the expression of BI over time. One set of processes that appear to moderate the continuity of BI involve attention. Children with BI who display heightened orienting towards threat and more error monitoring are more likely to remain stable in BI and develop anxiety in early adolescence. PMID- 20205181 TI - Parents, peers, and social withdrawal in childhood: a relationship perspective. AB - In this chapter, the authors review the history of the Waterloo Longitudinal Project (WLP), the first longitudinal study (1980-1992) dedicated to the study of social withdrawal, its correlates, and consequences. Theories underlying the WLP are described, as are its empirical findings. Recent research from other labs that has extended the findings of the original WLP is briefly described. The authors' research that draws on the findings of WLP are noted as well. An underlying theme in this work is that relationships (and interactions) with parents and friends can serve as protective or exacerbating factors in the developmental course of social withdrawal and its concomitants (including social anxiety). PMID- 20205182 TI - Social anxiety in childhood: bridging developmental and clinical perspectives. AB - In this introductory chapter, guided by developmental psychopathology and developmental science as overarching integrative theoretical frameworks, the authors define three constructs related to social anxiety in childhood (behavioral inhibition, anxious solitude/withdrawal, and social anxiety disorder) and analyze commonalities and differences in the content and assessment of these constructs. They then highlight controversies between developmental and clinical approaches to the definition of these constructs, the role of biology in social anxiety, age of onset of social anxiety, information processing biases in social anxiety, heterogeneity in the social and emotional adjustment of socially anxious children, and targets of intervention for childhood social anxiety. PMID- 20205183 TI - Familial and temperamental risk factors for social anxiety disorder. AB - Social anxiety disorder (SAD) is a common disorder that can lead to significant impairment. In this chapter, the author provides background on the disorder and reviews hypothesized familial and temperamental risk factors. In particular, it highlights the Massachusetts General Hospital (MGH) Longitudinal Study of Children at Risk for Anxiety, now in its fifteenth year, and describes how this study has identified some factors that contribute to risk for SAD. PMID- 20205184 TI - A glance to the past: subfossils, stable isotopes, seed dispersal, and lemur species loss in Southern Madagascar. AB - The Spiny Thicket Ecoregion (STE) of Southern and southwestern Madagascar was recently home to numerous giant lemurs and other "megafauna," including pygmy hippopotamuses, giant tortoises, elephant birds, and large euplerid carnivores. Following the arrival of humans more than 2,000 years ago, dramatic extinctions occurred. Only one-third of the lemur species which earlier occupied the STE survive today; other taxa suffered even greater losses. We use stable isotope biogeochemistry to reconstruct past diets and habitat preferences of the recently extinct lemurs of the STE. We show that the extinct lemurs occupied a wide range of niches, often distinct from those filled by coeval non-primates. Many of the now-extinct lemurs regularly exploited habitats that were drier than the gallery forests in which the remaining lemurs of this ecoregion are most often protected and studied. Most fed predominantly on C3 plants and some were likely the main dispersers of the large seeds of native C3 trees; others included CAM and/or C4 plants in their diets. These new data suggest that the recent extinctions have likely had significant ecological ramifications for the communities and ecosystems of Southern and southwestern Madagascar. PMID- 20205185 TI - Papain-gel degrades intact nonmineralized type I collagen fibrils. AB - Papain-gel has been utilized as a chemo-mechanical material for caries removal due to its ability to preserve underlying sound dentin. However, little is known about the effect of the papain enzyme on intact type I collagen fibrils that compose the dentin matrix. Here we sought to define structural changes that occur in intact type I collagen fibrils after an enzymatic treatment with a papain-gel. Intact and nonmineralized type I collagen fibrils from rat tail were obtained and treated with a papain-gel (Papacarie) for 30 s, rinsed with water and imaged using an atomic force microscope (AFM). Additionally, polished healthy dentin specimens were also treated using the same protocol described above and had their elastic modulus (E) and hardness (H) measured by means of AFM-based nanoindentation. AFM images showed that the papain-gel induced partial degradation of the fibrils surface, yet no rupture of fibrils was noticed. The distinction between gap and overlap zones of fibrils vanished in most regions after treatment, and overlap zones appeared to be generally more affected. Mechanical data suggested a gradual decrease in E and H after treatments. A significant two-fold drop from the values of normal dentin (E=20+/-1.9, H=0.8+/ 0.08 GPa) was found after four applications (E=9.7+/-3.2, H=0.24+/-0.1 GPa) (P<0.001), which may be attributed to the degradation of proteoglycans of the matrix. In summary, this study provided novel evidence that intact nonmineralized type I collagen fibrils are partially degraded by a papain-gel. PMID- 20205186 TI - Using the NCBI map viewer to browse genomic sequence data. AB - This unit includes a Basic Protocol with an introduction to the Map Viewer, describing how to perform a simple text-based search of genome annotations to view the genomic context of a gene, navigate along a chromosome, zoom in and out, and change the displayed maps to hide and show information. It also describes some of NCBI's sequence-analysis tools, which are provided as links from the Map Viewer. The Alternate Protocols describe different ways to query the genome sequence, and also illustrate additional features of the Map Viewer. Alternate Protocol 1 shows how to perform and interpret the results of a BLAST search against the human genome. Alternate Protocol 2 demonstrates how to retrieve a list of all genes between two STS markers. Finally, Alternate Protocol 3 shows how to find all annotated members of a gene family. PMID- 20205187 TI - Using the DFCI gene index databases for biological discovery. AB - The DFCI Gene Index Web pages provide access to analyses of ESTs and gene sequences for nearly 114 species, as well as a number of resources derived from these. Each species-specific database is presented using a common format with a home page. A variety of methods exist that allow users to search each species specific database. Methods implemented currently include nucleotide or protein sequence queries using WU-BLAST, text-based searches using various sequence identifiers, searches by gene, tissue and library name, and searches using functional classes through Gene Ontology assignments. This protocol provides guidance for using the Gene Index Databases to extract information. PMID- 20205188 TI - miRBase: microRNA sequences and annotation. AB - miRBase is the central repository for microRNA (miRNA) sequence information. miRBase has a role in defining the nomenclature for miRNA genes and assigning names to novel miRNAs for publication in peer-reviewed journals. The online miRBase database is a resource containing all published miRNA sequences, together with textual annotation and links to the primary literature and to other secondary databases. The database provides a variety of methods to query the data, by specific searches of sequences and associated text and literature. All miRBase data are also available for download from the miRBase FTP site. PMID- 20205189 TI - Census for proteome quantification. AB - Quantitative analysis has become increasingly important in the proteomics field; however, the large amount of mass spectrometric data and the different types of quantitative strategies make data analysis ever challenging. Here we describe a quantitative software tool called Census to analyze high-throughput mass spectrometry data from shotgun proteomics experiments in an efficient way. Census is capable of analyzing various stable isotope labeling experiments (using, e.g., (15)N, (18)O, SILAC, iTRAQ, TMT) in addition to labeling-free experiments. With high-resolution data, Census increases the quantitative accuracy by minimizing the contributions of interfering peaks and chemical noise with a small accuracy tolerance for each isotope peak. Census provides various scoring algorithms including least-squares correlation, weight average, singleton peptide detection with discriminant analysis, and probability score for each peptide. Furthermore, Census has built-in multiple statistical filters to maintain robust quality control on quantitative results. PMID- 20205190 TI - Computing multiple sequence/structure alignments with the T-coffee package. AB - In this unit, we describe assembly of a multiple sequence alignment using the T Coffee package. T-Coffee is much more flexible than most related methods (e.g., ClustalW) because it makes it possible to combine many alternative alignments into a single one, based on an estimate of consistency between these alignments. This strategy can be especially useful when one has to decide among the output produced by several alternative methods. PMID- 20205192 TI - Vitamin E supplementation and mammalian lifespan. AB - Vitamin E refers to a family of several compounds that possess a similar chemical structure comprising a chromanol ring with a 16-carbon side chain. The degree of saturation of the side chain, and positions and nature of methyl groups designate the compounds as tocopherols or tocotrienols. Vitamin E compounds have antioxidant properties due to a hydroxyl group on the chromanol ring. Recently, it has been suggested that vitamin E may also regulate signal transduction and gene expression. We previously reported that lifelong dietary vitamin E (alpha tocopherol) supplementation significantly increased median lifespan in C57BL/6 mice by 15%. This lifespan extension appeared to be independent of any antioxidant effect. Employing a transcriptional approach, we suggest that this increase in lifespan may reflect an anti-cancer effect via induction of the P21 signalling pathway, since cancer is the major cause of death in small rodents. We suggest that the role of this pathway in life span extension following supplementation of vitamin E now requires further investigation. PMID- 20205191 TI - Digestibility and allergenicity assessment of enzymatically crosslinked beta casein. AB - Crosslinking enzymes are frequently used in bioprocessing of dairy products. The aim of this study was to examine the effects of enzymatic crosslinking on IgE binding, allergenicity and digestion stability of beta-casein (CN). beta-CN was crosslinked by transglutaminase, tyrosinase, mushroom tyrosinase/caffeic acid and laccase/caffeic acid. The IgE binding to beta-CN was compared in vitro by CAP inhibition assay, ELISA inhibition as well as ex vivo by basophil activation assay. Crosslinked CNs were digested by simulated gastric fluid for 15 and 60 min and obtained digests analyzed for their ability to inhibit IgE binding by CAP inhibition assay and SDS-PAGE. The ability of crosslinked CNs to activate basophils was significantly reduced in seven patients in the case of CN crosslinked by laccase and moderately reduced in the case of tyrosinase/caffeic acid crosslinked CN (in two cow's milk allergy patients tested with different allergen concentrations). The response to various crosslinked CNs differed individually among patients' sera tested by ELISA inhibition assay. The presence of caffeic acid hampered digestion by pepsin, and this effect was most pronounced for the tyrosinase/caffeic acid crosslinked CN. The laccase/caffeic acid and mushroom tyrosinase/caffeic acid had the highest potential in mitigating IgE binding and allergenicity of the beta-CN out of all investigated enzymes. The presence of a small phenolic compound also increased digestion stability of beta CN. PMID- 20205195 TI - The making of hemidesmosome structures in vivo. AB - Hemidesmosomes are evolutionarily conserved attachment complexes linked to intermediate filaments that connect epithelial cells to the extracellular matrix. They provide tissue integrity and resistance to mechanical forces. Alterations in hemidesmosome structures are responsible for skin blistering, carcinoma invasion, and wound-healing defects. Valuable information about hemidesmosome assembly and disassembly has been obtained from in vitro cell culture studies. However, how these processes take place in vivo still remains elusive. Here, we discuss recent data about the formation and reorganization of hemidesmosomes in several in vivo model systems, particularly zebrafish and Caenorhabditis elegans, focusing on various factors affecting their dynamics. Mechanisms found in different organisms reveal that hemidesmosome formation and maintenance in vivo are carefully controlled by ECM protein folding, ECM-receptor expression and trafficking, and by post-translational modification of hemidesmosome components. These findings validate and extend the in vitro studies, and shed light on our understanding about hemidesmosomes across species. PMID- 20205193 TI - Molecular mechanisms of membrane transport of vitamin E. AB - Vitamin E is an essential fat-soluble micronutrient for higher mammals and functions as an antioxidant for lipids and also as a regulator of gene expression and a modulator of cell signaling and proliferation. To exert its physiological functions, vitamin E must achieve an appropriate disposition throughout the body via several processes, such as intestinal absorption, uptake and efflux in peripheral tissues and biliary secretion. In this review, we mainly discuss membrane proteins involved in these transport processes (ATP-binding cassette transporter A1, scavenger receptor class B type I, Niemann-Pick C1-like 1 and multidrug resistance 3) and vitamin E-mediated regulation of their expression. PMID- 20205196 TI - Fragmentations of the heptapeptides containing alpha- or beta-aspartate by ESI-MS and low-energy CAD. PMID- 20205197 TI - Synthesis, in-vitro antimicrobial and cytotoxic studies of novel azetidinone derivatives. AB - Developing novel antimicrobial drugs is increasingly important in the modern pharmaceutical industry. A series of novel 3-chloro-4-[4-(2-oxo-2H-chromen-4 ylmethoxy)phenyl]-1-phenylazetidin-2-ones 5a-o have been synthesized from 4 bromomethylcoumarins 1a-e and 4-aryliminomethyl-phenols 3a-c. These compounds were screened for their in-vitro antibacterial activity against two Gram-positive (Staphylococcus aureus and Vancomycin resistant enteroccoccus) and two Gram negative (Escherichia coli and Shigella dysentery) bacterial strains and antifungal activity against Aspergillus fumigatus, Candida albicans, and Penicillium. Results revealed that compounds 5c, 5f, 5h, 5j, and 5m showed excellent activity against a panel of microorganisms. The brine-shrimp bioassay was also carried out to study their in-vitro cytotoxic properties and two compounds, 5h and 5m, possessing LD(50) = 7.154x10(-4 )M and 5.782x10(-4) M, respectively, displayed potent cytotoxic activity against Artemia salina. The presence of a chlorine group in the coumarin moiety, its effect on their antibacterial, antifungal, and cytotoxic activities is discussed. All newly synthesized compounds were characterized by elemental analysis, IR, (1)H-NMR,( 13)C-NMR, and MS. PMID- 20205198 TI - Synthesis and antimycobacterial activity of azetidine-, quinazoline-, and triazolo-thiadiazole-containing pyrazines. AB - The re-emergence of tuberculosis (TB) as a global health problem over the past few decades, accompanied by the rise of drug-resistant strains of Mycobacterium tuberculosis, emphasizes the need for the discovery of new therapeutic drugs against this disease. The emerging serious problem both in terms of TB control and clinical management prompted us to synthesize a novel series of N-[2 (substituted aryl)-3-chloro-4-oxoazetidin-1-yl]-2-(pyrazin-2-yloxy)acetamide, 6 (substituted aryl)-3-[(pyrazin-2-yloxy)methyl][1,2,4]triazolo[3,4 b][1,3,4]thiadiazole, and N-[6-({2-[(pyrazin-2-yloxy)acetyl] hydrazino}sulfonyl) 2-methyl-4-oxo-1,4-dihydroquinazolin-3(2H)yl]-substituted aryl sulfonamides. The compounds were synthesized using the appropriate synthetic route. All synthesized compounds were assayed in vitro for antimycobacterial activity against the H37 Rv strain of Mycobacterium tuberculosis. The minimum inhibitory concentration (MIC) was determined for the test compounds as well as for the reference standards. The compound which exhibited good antimycobacterial activity contains the substituents fluorine and methoxy. These electron-withdrawing or -donating substituents amend the lipophilicity of the test compounds which, in turn, alter the permeability across the bacterial cell membrane. Compounds 28, 37, and 43 showed good antimycobacterial activity while compound 51 showed a promising antimycobacterial activity. PMID- 20205199 TI - Micromechanics and advanced designs for curved photodetector arrays in hemispherical electronic-eye cameras. AB - The fabrication of a hemispherical electronic-eye camera with optimized designs based upon micromechanical analysis is reported. The photodetector arrays combine layouts with multidevice tiles and extended, non-coplanar interconnects to improve the fill factor and deformability, respectively. Quantitative comparison to micromechanics analysis reveals the key features of these designs. Color images collected with working cameras demonstrate the utility of these approaches. PMID- 20205201 TI - Congenital malformations after assisted reproduction: risks and implications for prenatal diagnosis and fetal medicine. PMID- 20205202 TI - The added value of 3D/4D ultrasound imaging in fetal cardiology: has the promise been fulfilled? PMID- 20205203 TI - Fluorescent-magnetic hybrid nanoparticles induce a dose-dependent increase in proinflammatory response in lung cells in vitro correlated with intracellular localization. AB - Iron-platinum nanoparticles embedded in a poly(methacrylic acid) (PMA) polymer shell and fluorescently labeled with the dye ATTO 590 (FePt-PMA-ATTO-2%) are investigated in terms of their intracellular localization in lung cells and potential to induce a proinflammatory response dependent on concentration and incubation time. A gold core coated with the same polymer shell (Au-PMA-ATTO-2%) is also included. Using laser scanning and electron microscopy techniques, it is shown that the FePt-PMA-ATTO-2% particles penetrate all three types of cell investigated but to a higher extent in macrophages and dendritic cells than epithelial cells. In both cell types of the defense system but not in epithelial cells, a particle-dose-dependent increase of the cytokine tumor necrosis factor alpha (TNFalpha) is found. By comparing the different nanoparticles and the mere polymer shell, it is shown that the cores combined with the shells are responsible for the induction of proinflammatory effects and not the shells alone. It is concluded that the uptake behavior and the proinflammatory response upon particle exposure are dependent on the time, cell type, and cell culture. PMID- 20205204 TI - Characterization of peptide-nanostructure-modified electrodes and their application for ultrasensitive environmental monitoring. AB - Dense arrays of self-assembled nanostructures are highly important for the fabrication of high-performance sensors of large surface area. The organized incorporation of novel biocompatible organic nanostructures into extremely sensitive amperometric biosensors is demonstrated. Peptide nanoforest biosensors for phenol detection were 17-fold more sensitive than uncoated electrode and more sensitive than those modified with carbon nanotubes or combined coating. The high sensitivity reported, together with the biocompatibility and the ability to chemically and biologically modify these elements, may provide a novel platform for biosensors design and fabrication for environmental monitoring, homeland security, and other applications. PMID- 20205205 TI - 13-14-week fetal anatomy scan: a 5-year prospective study. AB - OBJECTIVES: To assess the potential value of an early (first-trimester) ultrasound examination in depicting fetal anomalies by transabdominal (TAS) and transvaginal (TVS) sonography, to compare it with the traditional mid-trimester anomaly ultrasound examination and to evaluate the degree of patient acceptance of early sonography by the transvaginal route. METHODS: In this prospective study over a 5-year period (January 2002 to January 2007) 2876 pregnant women underwent a 13-14-week ultrasound examination. The scan was performed by TAS at first and then, if a full fetal anatomical survey was not achieved, by TVS. A mid-trimester fetal anatomy scan was then performed in patients who had not dropped out, miscarried or undergone pregnancy termination (n = 2834). RESULTS: In the early scan, analyzable data for 2876 TAS and 1357 TVS examinations showed that TVS was significantly better in visualizing the cranium, spine, stomach, kidneys, bladder and upper and lower limbs (P < 0.001). Complete fetal anatomical surveys were achieved by TAS in 64% of cases versus 82% of the cases in which it was attempted by TVS (P < 0.001). Patient body mass index significantly affected the ability of the sonographer to achieve a complete anatomical survey by both TAS and TVS (P < 0.001 and P = 0.004, respectively). The duration of the scan was significantly longer using TVS. The heart and kidneys were not properly visualized in 42% and 27% of cases, respectively, at the 13-week scan compared with 1.6% and 0% at the mid-trimester scan. The total number of cases in which anomalies were detected was 31. At the first-trimester scan, anomalies were detected in 21 fetuses and in 14 of these cases the parents chose pregnancy termination. At the second trimester scan, anomalies were detected in 17 fetuses: 10 new anomalous cases along with seven cases already detected in the first-trimester scan. CONCLUSION: Besides its importance in screening for chromosomal abnormalities, the early scan has great potential in visualizing with precision fetal anatomy. TVS can be used to compliment difficult TAS examinations; however, patients do not always agree to undergo TVS. The mid-trimester scan remains crucial for detailed fetal anatomical survey. PMID- 20205206 TI - Validation of 3D simulations of reverse osmosis membrane biofouling. AB - The increasing demand for drinking water and its stricter quality requirements have resulted in an exponentially expanding industry of membrane filtration processes. Currently, reverse osmosis (RO) is the most common method of desalination, able to produce water that is virtually free of pollutants and pathogenic micro-organisms. Biofouling of these devices however is a significant limitation. Here we present a 3D simulation of RO membrane biofouling based on a lattice Boltzmann (LB) platform that we subsequently favorably compare with experimental data. This data consists of temporally (and spatially) resolved velocity measurements acquired for a RO membrane using magnetic resonance techniques. The effect of biofilm cohesive strength on system pressure drop is then explored; weaker biomass is observed to have a reduced impact on pressure drop (per unit biomass accumulated). PMID- 20205207 TI - Structure and stereochemistry of novel ecdysteroids from the roots of Serratula wolffii. AB - Three new natural ecdysteroids viz. 22-dehydro-20-deoxy-ajugasterone C (1), 1 hydroxy-22-deoxy-20,21-didehydro-ecdysone (2) and 22-deoxy-20,21-didehydro ecdysone (3) were isolated from the methanol extract of the roots of Serratula wolffii. The structures of compounds 1-3 were established by various spectroscopic techniques, including one- and two-dimensional NMR, circular dichroism and mass spectroscopic methods. PMID- 20205208 TI - Dlx homeobox gene family expression in osteoclasts. AB - Skeletal growth and homeostasis require the finely orchestrated secretion of mineralized tissue matrices by highly specialized cells, balanced with their degradation by osteoclasts. Time- and site-specific expression of Dlx and Msx homeobox genes in the cells secreting these matrices have been identified as important elements in the regulation of skeletal morphology. Such specific expression patterns have also been reported in osteoclasts for Msx genes. The aim of the present study was to establish the expression patterns of Dlx genes in osteoclasts and identify their function in regulating skeletal morphology. The expression patterns of all Dlx genes were examined during the whole osteoclastogenesis using different in vitro models. The results revealed that Dlx1 and Dlx2 are the only Dlx family members with a possible function in osteoclastogenesis as well as in mature osteoclasts. Dlx5 and Dlx6 were detected in the cultures but appear to be markers of monocytes and their derivatives. In vivo, Dlx2 expression in osteoclasts was examined using a Dlx2/LacZ transgenic mouse. Dlx2 is expressed in a subpopulation of osteoclasts in association with tooth, brain, nerve, and bone marrow volumetric growths. Altogether the present data suggest a role for Dlx2 in regulation of skeletal morphogenesis via functions within osteoclasts. PMID- 20205209 TI - Physcion, a natural anthraquinone derivative, enhances the gene expression of leaf-specific thionin of barley against Blumeria graminis. AB - BACKGROUND: Physcion is a key active ingredient of the ethanol extract from roots of Chinese rhubarb (Rheum officinale Baill.) that has been commercialised in China for controlling powdery mildews. The biological mechanism of action of physcion against the barley powdery mildew pathogen was studied using bioassay and microarray methods. RESULTS: Bioassay indicated that physcion did not directly affect conidial germination of Blumeria graminis Speer f. sp. hordei Marchal, but significantly inhibited conidial germination in vivo. Challenge inoculation indicated that physcion induced localised resistance rather than systemic resistance against powdery mildew. Gene expression profiling of physcion treated barley leaves detected four upregulated and five downregulated genes (ratio >or= 2.0 and P-value < 0.05) by using an Affymetrix Barley GeneChip. The five upregulated probe sequences blasted to the same barley leaf-specific thionin gene, with significant changes varying from 4.26 to 19.91-fold. All downregulated genes were defence-related, linked to peroxidase, oxalate oxidase, bsi1 protein and a pathogenesis-related protein. These changes varied from - 2.34 to - 2.96. Quantitative real-time PCR data confirmed that physcion enhanced the gene expression of leaf-specific thionin of barley. CONCLUSION: Results indicated that physcion controls powdery mildew mainly through changing the expression of defence-related genes, and especially enhancing expression of leaf-specific thionin in barley leaves. PMID- 20205212 TI - Nanotechnology and its applications in surgery. PMID- 20205214 TI - Letter 3: Meta-analysis of randomized controlled trials comparing laparoscopic with open mesh repair of recurrent inguinal hernia (Br J Surg 2010; 97: 4-11). PMID- 20205215 TI - Letter 2: Meta-analysis of randomized controlled trials comparing laparoscopic with open mesh repair of recurrent inguinal hernia (Br J Surg 2010; 97: 4-11). PMID- 20205216 TI - Letter 1: Meta-analysis of randomized controlled trials comparing laparoscopic with open mesh repair of recurrent inguinal hernia (Br J Surg 2010; 97: 4-11). PMID- 20205219 TI - Endoscopic retroperitoneal neurectomy for chronic pain after groin surgery (Br J Surg 2009; 96: 1076-1081). PMID- 20205221 TI - Nationwide study of early outcomes after incisional hernia repair (Br J Surg 2009; 96: 1452-1457). PMID- 20205223 TI - Systematic review of atraumatic splenic rupture (Br J Surg 2009; 96: 1114-1121). PMID- 20205224 TI - Randomized clinical trial comparing laparoscopic and open surgery in patients with rectal cancer (Br J Surg 2009; 96: 982-989). PMID- 20205225 TI - Randomized controlled trial of preoperative oral carbohydrate treatment in major abdominal surgery (Br J Surg 2010; 97: 485-494). PMID- 20205227 TI - Randomized controlled trial of preoperative oral carbohydrate treatment in major abdominal surgery. AB - BACKGROUND: Major surgery is associated with postoperative insulin resistance which is attenuated by preoperative carbohydrate (CHO) treatment. The effect of this treatment on clinical outcome after major abdominal surgery has not been assessed in a double-blind randomized trial. METHODS: Patients undergoing elective colorectal surgery or liver resection were randomized to oral CHO or placebo drinks to be taken on the evening before surgery and 2 h before induction of anaesthesia. Primary outcomes were postoperative length of hospital stay and fatigue measured by visual analogue scale. RESULTS: Sixty-nine and 73 patients were evaluated in the CHO and placebo groups respectively. The groups were well matched with respect to surgical procedure, epidural analgesia, laparoscopic procedures, fasting period before induction and duration of surgery. Postoperative changes in fatigue score from baseline did not differ between the groups. Median (range) hospital stay was 7 (2-35) days in the CHO group and 8 (2 92) days in the placebo group (P = 0.344). For patients not receiving epidural blockade or laparoscopic surgery (20 CHO, 19 placebo), values were 7 (3-11) and 9 (2-48) days respectively (P = 0.054). CONCLUSION: Preoperative CHO treatment did not improve postoperative fatigue or length of hospital stay after major abdominal surgery. A benefit is not ruled out when epidural blockade or laparoscopic procedures are not used. REGISTRATION NUMBER: ACTRN012605000456651 (http://www.anzctr.org.au). PMID- 20205228 TI - Systematic review and meta-analysis of the diagnostic and therapeutic role of water-soluble contrast agent in adhesive small bowel obstruction. AB - BACKGROUND: This meta-analysis assessed the diagnostic and therapeutic role of water-soluble contrast agent (WSCA) in adhesive small bowel obstruction (SBO). METHODS: PubMed, Embase and Cochrane databases were searched systematically. The primary outcome in the diagnostic role of WSCA was its ability to predict the need for surgery. In the therapeutic role, the following were evaluated: resolution of SBO without surgery, time from admission to resolution, duration of hospital stay, complications and mortality. To assess the diagnostic role of WSCA, pooled estimates of sensitivity, specificity, positive and negative predictive values, and likelihood ratios were derived. For the therapeutic role of WSCA, weighted odds ratio (OR) and weighted mean difference (WMD) were obtained. RESULTS: Fourteen prospective studies were included. The appearance of contrast in the colon within 4-24 h after administration had a sensitivity of 96 per cent and specificity of 98 per cent in predicting resolution of SBO. WSCA administration was effective in reducing the need for surgery (OR 0.62; P = 0.007) and shortening hospital stay (WMD -1.87 days; P < 0.001) compared with conventional treatment. CONCLUSION: Water-soluble contrast was effective in predicting the need for surgery in patients with adhesive SBO. In addition, it reduced the need for operation and shortened hospital stay. PMID- 20205229 TI - Radioembolization with yttrium microspheres for neuroendocrine tumour liver metastases. AB - BACKGROUND: (90)Y microsphere radioembolization is performed by injecting the microspheres through a hepatic artery catheter placed percutaneously via the femoral or brachial artery. This study assessed the efficacy of (90)Y microsphere therapy for patients with unresectable neuroendocrine tumour liver metastases (NETLMs). Potential prognostic factors were analysed for their impact on overall survival. METHODS: A prospectively collected database for patients with NETLMs treated by (90)Y microspheres in two centres from 2003 to 2008 was examined retrospectively. Serial radiographic evidence was collected during follow-up to assess response. RESULTS: Fifty-eight patients were included, 51 of whom had evaluable disease at most recent follow-up. Six patients achieved a complete response, 14 a partial response, 14 had stable disease and 17 had disease progression. Overall survival rates at 1, 2 and 3 years were 86, 58 and 47 per cent respectively; median survival was 36 (range 1-61) months. Extent of tumour involvement, radiographic response to treatment, extrahepatic disease and tumour grade were significant prognostic factors for overall survival. CONCLUSION: (90)Y microsphere radioembolization achieved a radiographic response in a significant proportion of patients with NETLMs. PMID- 20205230 TI - Bioactivity against Tribolium castaneum Herbst (Coleoptera: Tenebrionidae) of Cymbopogon citratus and Eucalyptus citriodora essential oils grown in Colombia. AB - BACKGROUND: Essential oils isolated from Cymbopogon citratus (DC) Stapf. and Eucalyptus citriodora Hook grown in Colombia were analysed by gas chromatography mass spectrometry (GC-MS) and tested for repellent activity and contact toxicity against Tribolium castaneum (Herbst.) (Coleoptera: Tenebrionidae). RESULTS: The main components of C. citratus oil were geranial (34.4%), neral (28.4%) and geraniol (11.5%), whereas those of E. citriodora were citronellal (40%), isopulegol (14.6%) and citronellol (13%). The mean repellent doses after 4 h exposure were 0.021 and 0.084 mL L(-1) for C. citratus and E. citriodora oils respectively-values lower than that observed for the commercial product IR3535 (0.686 mL L(-1)). CONCLUSION: These studies showed the composition and repellent activity of essential oils of C. citratus and E. citriodora, suggesting that these are potential candidates as insect repellents. PMID- 20205231 TI - Contact toxicity of insecticides for attract-and-kill applications against adult Plodia interpunctella (Hubner) (Lepidoptera: Pyralidae). AB - BACKGROUND: The Indian meal moth (IMM), Plodia interpunctella (Hubner), is an important pest of stored food products. Contact toxicities of 13 insecticides applied to different surfaces were evaluated at registered label and a higher dose for killing adult males. The ultimate objective was to develop attract-and kill technologies for P. interpunctella. Two-day-old adult males were exposed to treated surfaces for 2.0 s and then paired with virgin females for mating and oviposition over a 24 h period. RESULTS: Permethrins and pyrethrins (organic pyrethrin and pyrethrin plus a synergist) caused over 70% mortality to males. Oviposition was impacted by these insecticides, while egg hatch was not. A second experiment tested the 8 week residual toxicity of cyfluthrin, permethrin and pyrethrin at label and at a higher dose of 20 g AI L(-1) on five surfaces: plastic-coated paper, metal, painted plastic, unpainted plastic and wood. Permethrin at 20 g AI L(-1) suppressed males at over 80% for up to 8 weeks and retained activity on surfaces made with plastic-coated paper, metal or plastic. Oviposition was variable among treatments. Egg hatch was generally unaffected by treatment. CONCLUSION: Effective attract-and-kill surfaces can be developed for killing IMM males and thereby potentially lead to reduced reproduction and, ultimately, population suppression. PMID- 20205232 TI - Autosomal inheritance of deltamethrin resistance in field populations of Triatoma infestans (Heteroptera: Reduviidae) from Argentina. AB - BACKGROUND: Triatoma infestans (Klug) is the major Chagas disease vector in the Southern Cone area of South America, and its chemical control is based on the use of pyrethroid insecticides. Resistance to deltamethrin in Salta Province, Argentina, has been detected in field populations since 2002, causing the failure of vector control campaigns in this disease-endemic area. The inheritance of deltamethrin resistance in T. infestans was evaluated through reciprocal crosses conducted between resistant and susceptible insects. RESULTS: The response of the reciprocally mated insects' progeny to deltamethrin was intermediate between the highly resistant and the susceptible parent colonies. Lack of significant differences between the LD(50) and resistance ratios of the reciprocally mated insects indicated no sex linkage on this trait. CONCLUSION: Bioassay results, in addition to degree of dominance calculations, suggest that the resistance to deltamethrin in T. infestans is controlled by semi-dominant, autosomally inherited factors. PMID- 20205233 TI - Insecticidal efficacy of fipronil against four stored-product insect pests: influence of commodity, dose, exposure interval, relative humidity and temperature. AB - BACKGROUND: Fipronil is an insecticidal pyrazole that is commonly used as an insecticide in field crops, urban pesticide and veterinary medicine, but there are no reports of its evaluation against stored-product insects. Three series of laboratory bioassays were conducted to assess fipronil as a potential grain protectant against adults of Sitophilus oryzae (L.), Tribolium confusum Jacquelin du Val, Rhyzopertha dominica (F.) and Prostephanus truncatus (Horn). Factors such as dose (0.01, 0.1, 1 and 10 mg fipronil kg(-1) grain), exposure interval (24 h, 48 h, 7 days and 14 days), temperature (20, 25 and 30 degrees C), relative humidity (RH; 55 and 65%) and commodity (wheat, maize, barley and paddy rice) were evaluated with regard to their impact on the insecticidal activity of fipronil. Progeny production was assessed after 64 days of exposure. RESULTS: At doses of < 1 mg fipronil kg(-1) grain, efficacy of fipronil was enhanced by an increase in temperature from 20 to 25 degrees C against S. oryzae or R. dominica for exposures of > 48 h and against T. confusum or P. truncatus for exposures of > 24 h. A further increase in temperature from 25 to 30 degrees C, although it enhanced efficacy at doses of < 1 mg fipronil kg(-1) grain against S. oryzae at all exposure intervals and against T. confusum after 7 days of exposure, it was negatively associated with efficacy against R. dominica or P. truncatus for exposures of > 24 h. By contrast, increase in RH did not have a significant impact on efficacy of fipronil. Although the performance of fipronil among the tested commodities was species dependent, this substance appeared to be less effective in paddy rice than in barley, maize and wheat. Regardless of the treated commodity, progeny production of all the tested species was almost suppressed with doses higher than 0.1 mg fipronil kg(-1) grain. CONCLUSIONS: Fipronil appeared to be a very effective alternative to the existing substances in stored-grain protection at doses equal to or higher than 1 mg fipronil kg(-1) grain, and thus these doses require further evaluation in terms of safety for the consumer and residues on stored products. PMID- 20205234 TI - Severe novel H1N1 influenza A infection in the immediate postoperative period of a liver transplant patient. AB - In 2009, the World Health Organization recognized the novel H1N1 influenza A virus as a pandemic infection. Since April 2009, thousands of cases of novel H1N1 influenza A infection have been reported worldwide, and they have resulted in thousands of deaths. South American countries were affected by this infection during their winter season, and Chile presented one of the highest incidence rates. We have recently managed a liver transplant patient who presented with a severe novel H1N1 influenza A infection in the early postoperative period and required prolonged mechanical ventilation. The early suspicion of this infection during the current pandemic influenza in Chile made possible a timely treatment with oseltamivir. We decided to report this case because no other cases of liver transplant patients affected by H1N1 influenza A have been reported so far. We intend to alert clinicians about this potentially devastating viral infection in view of the current pandemic scenario, and here we review some of the recommendations for its prevention, diagnosis, therapy, and possible complications. PMID- 20205235 TI - Curcumin stimulates glucose uptake through AMPK-p38 MAPK pathways in L6 myotube cells. AB - Curcumin has been shown to exert a variety of beneficial human health effects. However, mechanisms by which curcumin acts are poorly understood. In this study, we report that curcumin activated AMP-activated protein kinase (AMPK) and increased glucose uptake in rat L6 myotubes. In addition, curcumin activated the mitogen-activated protein kinase kinase (MEK)3/6-p38 mitogen-activated protein kinase (MAPK) signaling pathways in the downstream of the AMPK cascade. Moreover, inhibition of either AMPK or p38 MAPK resulted in blockage of curcumin-induced glucose uptake. Furthermore, the administration of curcumin to mice increased AMPK phosphorylation in the skeletal muscles. Taken together, these results indicate that the beneficial health effect of curcumin can be explained by its ability to activate AMPK-p38 MAPK pathways in skeletal muscles. PMID- 20205237 TI - NGF release from thermo-responsive collagen-polyNIPAam polymer networks supports neuronal cell growth and differentiation. AB - The combination of thermo-sensitive polymer and natural macromolecules such as collagen type I can produce biomimetic scaffolds with enhanced properties for clinical translation. This study describes the preparation of semi Interpenetrated Networks (semi-IPNs) of crosslinked poly(N-isopropylacrylamide), or PNIPAam, with collagen type I. The collagen-PNIPAam networks with varying collagen content were characterized using Fourier transform infrared spectroscopy techniques and their thermal responsiveness was evaluated by swelling experiments, differential scanning calorimetric (DSC) analysis. Rheological studies were performed at constant frequency and oscillating stress. PNIPAam and semi-IPNs were preloaded with nerve growth factor (NGF), and the NGF releasing profiles at different temperatures were studied using Enzyme-Linked ImmunoSorbent Assay (ELISA). The growth and differentiation of PC12 cells on NGF PNIPAam and collagen-PNIPAam scaffolds were investigated in this study. Neurite length and neurite number of differentiated PC12 cells increased with the increase in collagen content in the scaffolds. PMID- 20205236 TI - Contractility modulates cell adhesion strengthening through focal adhesion kinase and assembly of vinculin-containing focal adhesions. AB - Actin-myosin contractility modulates focal adhesion assembly, stress fiber formation, and cell migration. We analyzed the contributions of contractility to fibroblast adhesion strengthening using a hydrodynamic adhesion assay and micropatterned substrates to control cell shape and adhesive area. Serum addition resulted in adhesion strengthening to levels 30-40% higher than serum-free cultures. Inhibition of myosin light chain kinase or Rho-kinase blocked phosphorylation of myosin light chain to similar extents and eliminated the serum induced enhancements in strengthening. Blebbistatin-induced inhibition of myosin II reduced serum-induced adhesion strength to similar levels as those obtained by blocking myosin light chain phosphorylation. Reductions in adhesion strengthening by inhibitors of contractility correlated with loss of vinculin and talin from focal adhesions without changes in integrin binding. In vinculin-null cells, inhibition of contractility did not alter adhesive force, whereas controls displayed a 20% reduction in adhesion strength, indicating that the effects of contractility on adhesive force are vinculin-dependent. Furthermore, in cells expressing FAK, inhibitors of contractility reduced serum-induced adhesion strengthening as well as eliminated focal adhesion assembly. In contrast, in the absence of FAK, these inhibitors did not alter adhesion strength or focal adhesion assembly. These results indicate that contractility modulates adhesion strengthening via FAK-dependent, vinculin-containing focal adhesion assembly. PMID- 20205238 TI - Polyester copolymer scaffolds enhance expression of bone markers in osteoblast like cells. AB - In tissue engineering, the resorbable aliphatic polyester poly(L-lactide) (PLLA) is used as scaffolds in bone regeneration. Copolymers of poly(L-lactide)-co (epsilon-caprolactone) [poly(LLA-co-CL)] and poly(L-lactide)-co-(1,5-dioxepan-2 one) [poly(LLA-co-DXO)], with superior mechanical properties to PLLA, have been developed to be used as scaffolds, but the influence on the osteogenic potential is unclear. This in vitro study of test scaffolds of poly(LLA-co-CL) and poly(LLA co-DXO) using PLLA scaffolds as a control demonstrates the attachment and proliferation of human osteoblast-like cells (HOB) as measured by SEM and a methylthiazol tetrazolium (MTT) colorimetric assay, and the progression of HOB osteogenesis for up to 3 weeks; expressed as synthesis of the osteoblast differentiation markers: collagen type 1 (Col 1), alkaline phosphatase, bone sialoprotein, osteocalcin (OC), osteopontin and runt related gene 2 (Runx2). Surface analysis disclosed excellent surface attachment, spread and penetration of the cells into the pores of the test scaffolds compared to the PLLA. MTT results indicated that test scaffolds enhanced the proliferation of HOBs. Cells grown on the test scaffolds demonstrated higher synthesis of Col 1 and OC and also increased bone markers mRNA expression. Compared to scaffolds of PLLA, the poly(LLA-co-CL) and poly(LLA-co-DXO) scaffolds enhanced attachment, proliferation, and expression of osteogenic markers by HOBs in vitro. Therefore, these scaffolds might be appropriate carriers for bone engineering. PMID- 20205239 TI - Anti-inflammatory properties of bioactive titanium metals. AB - Anti-inflammatory properties of bioactive titanium metals prepared by anodic oxidation (AO-Ti) and alkali-heat (AH-Ti) treatments were studied by bacterial adhesion test and myeloperoxidase (MPO) activity assay methods. The bioactivities of the metals were also evaluated by apatite formation ability and osteoblasts culture experiments. Both metals could induce apatite formation and support osteoblasts proliferation. At the condition with normal incandescent light shine, both bioactive titanium metals had antibacterial adhesion properties compared with the titanium metal without treatment. The MPO activity assay proved that they both showed anti-inflammatory properties in vivo. The bioactive AO-Ti had better anti-inflammatory properties than the AH-Ti. It indicated that it is possible to optimize the anti-inflammatory properties of the bioactive titanium metals by different preparation methods. PMID- 20205240 TI - Anxious solitude/withdrawal and anxiety disorders: conceptualization, co occurrence, and peer processes leading toward and away from disorder in childhood. AB - This chapter contains (1) an analysis of commonalities and differences in anxious solitude and social anxiety disorder, and a review of empirical investigations examining (2) correspondence among childhood anxious solitude and anxiety and mood diagnoses and (3) the relation between peer difficulties and temporal stability of anxious solitude and depressive symptoms. Findings support a diathesis-stress model in which anxious solitude forecasts symptoms of psychopathology primarily in the context of interpersonal stress. Additionally, evidence for individual and environmental factors which moderate risk for peer difficulties among anxious solitary children is reviewed. Implications for intervention are discussed. PMID- 20205241 TI - Clinical behavior of follicular variant of papillary thyroid carcinoma: presentation and survival. AB - OBJECTIVES/HYPOTHESIS: To determine the prevalence and extent of disease characteristics of the follicular variant of papillary thyroid carcinoma (FV-PTC) and the survival impact of this histopathological diagnosis compared to classical papillary thyroid carcinoma (C-PTC). STUDY DESIGN: Cross-sectional population analysis of a national cancer database. METHODS: Cases of C-PTC and FV-PTC were extracted from the Surveillance, Epidemiology and End Results database for 1988 to 2006 and staged. Surgical extent and radioactive iodine (RAI) use were determined. Demographic and staging parameters were statistically compared according to tumor histology. Survival differences according to histology were determined with a Cox proportional hazards model, adjusting for age, sex, T stage, N stage, surgical therapy, and RAI. RESULTS: A total of 46,699 patients were identified (68.4% C-PTC and 31.6% FV-PTC). Age at presentation and sex distribution were similar between FV-PTC (47.9 years; 79.3% female) and C-PTC patients (46.2 years; 77.3% female). Although nodal disease prevalence was significantly lower in FV-PTC compared to C-PTC (14.8% vs. 27.8%, respectively; P < .001), T stage was not significantly different (P = .450). Mean overall survivals for patients with FV-PTC (204.5 months) and C-PTC (205.3 months) were not significantly different (P = .373). Cox regression analysis revealed that advanced age (P < .001), male sex (P < .001), advanced T stage (P < .001), and positive nodal disease (P < .001) were associated with reduced overall survival, whereas histopathological subtype was not (P = .360). CONCLUSIONS: Disease presentation (with exception of nodal metastasis) and survival in patients with FV-PTC are statistically similar to that of C-PTC, and accordingly these patients carry very similar prognoses. PMID- 20205242 TI - Adjustable laterofixation of the vocal fold in bilateral vocal fold paralysis. AB - OBJECTIVES/HYPOTHESIS: To describe a modification of VF laterofixation in patients with bilateral vocal fold paralysis (VFP), which allows adjusting the sutures tension according to voice and airway patency in the first postoperative day. STUDY DESIGN: Prospective case study. METHODS: Twenty-one patients with recent bilateral VFP were treated by the modified laterofixation technique in Ain Shams University hospitals between May 2007 and February 2009. Eight male patients and 13 females were included. The median age of the group was 36 years. The standard laterofixation procedure was performed; the Prolene sutures were inserted through the thyroid ala cartilage and looped around the paralyzed VF just anterior to the vocal process. The ultimate tension of the suture was adjusted later in the first postoperative day to gain feedback from the conscious patient about the airway patency and voice quality. RESULTS: Satisfactory immediate result was achieved in 16 patients, with adequate airway, voice, and swallowing. Three other patients required bilateral procedures, one patient needed revision surgery. The procedure failed to achieve a satisfactory airway in one patient who remained dependent on a tracheotomy. CONCLUSIONS: The modified laterofixation technique is a reliable first line treatment for recent bilateral VFP. PMID- 20205243 TI - What makes a good flap go bad? A critical analysis of the literature of intraoperative factors related to free flap failure. AB - OBJECTIVES/HYPOTHESIS: The purpose of this article is to discuss the various factors related to poor outcome in free flap reconstructions of the head and neck (H&N). Free tissue transfer has become the standard reconstruction technique for complex H&N defects. With the evolution of free flap use in H&N surgery, numerous factors have been proposed that adversely affect flap outcome, many with the support of only anecdotal experience. We seek to critically review the literature to assess what evidence exists for the relation of various intraoperative factors to free flap complications. STUDY DESIGN: Literature review. METHODS: A review of the contemporary literature (1995 to present) on free flap reconstruction of the H&N was undertaken. A PubMed search using the terms head and neck, reconstruction, free flap, microvascular, failure, complications, fluids, intraoperative, hypertension, hypotension, nitrous oxide, temperature, and morbidity in various combinations was completed. Appropriate articles were selected and analyzed. RESULTS: Studies report various factors thought to influence flap outcomes, often with divergent conclusions. Nonetheless, the body of evidence implicates several intraoperative factors to contribute to free flap complications including: >7 L intraoperative fluid administration, significant medical comorbidity, and prolonged operative time. There is no evidence supporting hypotension, pressors, colloids, and nitrous use in free flap failure. CONCLUSIONS: Although various dogmas related to the intraoperative care of free flap patients exist, including avoidance of hypotension and pressor use, there is no available clinical evidence to support these practices. Although free flap failure is uncommon, a better understanding of its causes is necessary to avoid this disastrous complication. PMID- 20205244 TI - The envious brain: the neural basis of social comparison. AB - Humans have a drive to evaluate themselves by examining their abilities and outcomes in comparison to others. The present study examined the emotional and neural correlates of upward social comparison (comparison with those who have more) and downward social comparison (comparison with those who have less). Two experiments were conducted with volunteers in an interactive game of chance, in which a putative player won or lost more money than the participant. The results showed that even when participants lost money, they expressed joy and schadenfreude (gloating) if the other player had lost more money. On the other hand when they actually won money, but the other player had won more they expressed envy. This pattern was also demonstrated in a differential BOLD response in the ventral striatum. Comparing the activations between an actual gain and a relative gain indicated that even when a person loses money, merely adding information about another person's greater loss may increase ventral striatum activations to a point where these activations are similar to those of an actual gain. We suggest that the ventral striatum plays a role in mediating the emotional consequences of social comparison. PMID- 20205245 TI - Disorder-specific inferior prefrontal hypofunction in boys with pure attention deficit/hyperactivity disorder compared to boys with pure conduct disorder during cognitive flexibility. AB - BACKGROUND: Problems with cognitive flexibility have been observed in patients with attention deficit hyperactivity disorder (ADHD) and in patients with conduct disorder (CD), characterized by the violation of societal rules and the rights of others. Functional magnetic resonance imaging (fMRI) of cognitive switching, however, has only been investigated in patients with ADHD, including comorbidity with CD, finding frontostriatal and temporoparietal underactivation. This study investigates disorder-specific functional abnormalities during cognitive flexibility between medication-naive children and adolescents with noncomorbid CD and those with noncomorbid ADHD compared to healthy controls. METHODS: Event related fMRI was used to compare brain activation of 14 boys with noncomorbid, childhood-onset CD, 14 boys with noncomorbid ADHD, and 20 healthy comparison boys during a visual-spatial Switch task. RESULTS: Behaviorally, children with ADHD compared to children with CD had significantly slower reaction times to switch compared to repeat trials. The fMRI comparison showed that the patients with ADHD compared to both controls and patients with CD showed underactivation in right and left inferior prefrontal cortex. No disorder-specific brain underactivation was observed in patients with CD. Only when compared with controls alone, the disruptive behavior group showed reduced activation in bilateral temporoparietal and occipital brain regions. CONCLUSIONS: The findings extend previous evidence for disorder-specific underactivation in patients with ADHD compared to patients with CD in inferior prefrontal cortex during tasks of inhibitory control to the domain of cognitive flexibility. Inferior prefrontal underactivation thus appears to be a disorder-specific neurofunctional biomarker for ADHD when compared with patients with CD. PMID- 20205246 TI - Cortical activation by tactile stimulation to face and anterior neck areas: an fMRI study with three analytic methods. AB - The main purpose of this study was to investigate the sensory cortical activation of the anterior neck region and the relationship between the neck and face representation areas. Functional MRI by blood oxygenation level dependent measurements was performed while tactile stimulation was applied to the face or neck area. Nonpainful tactile stimuli were manually delivered by an experimenter at a frequency of ~1 Hz. Block (epoch) design was adopted with a block duration of 30 s and a whole run duration of 6 min. For each location, two runs were performed. After the image data were preprocessed, both parameteric and nonparametric methods were performed to test the group results. The results showed that (1) unilateral face or neck stimulation could elicit bilateral cortical activation, (2) mainly the face representation and face-hand junction areas, but not the conventional neck representation area, were activated by face or neck stimulation, and (3) the activation areas were larger when right face or neck was stimulated. In conclusion, the sensory cortical representation area of the anterior neck region was mainly at the junction of hand and face representation area and the activated area was larger when the right face or neck was stimulated. PMID- 20205247 TI - How much are clinical fMRI reports influenced by standard postprocessing methods? An investigation of normalization and region of interest effects in the medial temporal lobe. AB - Recent evidence has indicated that standard postprocessing methods such as template-based region of interest (ROI) definition and normalization of individual brains to a standard template may influence final outcome of functional magnetic resonance imaging investigations. Here, we provide the first comprehensive investigation into whether ROI definition and normalization may also change the clinical interpretation of patient data. A series of medial temporal lobe epilepsy patients were investigated with a clinical memory paradigm and individually delineated as well as template-based ROIs. Different metrics for activation quantification were applied. Results show that the application of template-based ROIs can significantly change the clinical interpretation of individual patient data. This relates to sensitivity for brain activation and hemispheric dominance. We conclude that individual ROIs should be defined on nontransformed functional data and that use of more than one metric for activation quantification is beneficial. PMID- 20205248 TI - Electrophysiology meets fMRI: neural correlates of the startle reflex assessed by simultaneous EMG-fMRI data acquisition. AB - The startle reflex provides a unique tool for the investigation of sensorimotor gating and information processing. Simultaneous EMG-fMRI acquisition (i.e., online stimulation and recording in the MR environment) allows for the quantitative assessment of the neuronal correlates of the startle reflex and its modulations on a single trial level. This serves as the backbone for a startle response informed fMRI analysis, which is fed by data acquired in the same brain at the same time. We here present the first MR study using a single trial approach with simultaneous acquired EMG and fMRI data on the human startle response in 15 healthy young men. It investigates the neural correlates for isolated air puff startle pulses (PA), prepulse-pulse inhibition (PPI), and prepulse facilitation (PPF). We identified a common core network engaged by all three conditions (PA, PPI, and PPF), consisting of bilateral primary and secondary somatosensory cortices, right insula, right thalamus, right temporal pole, middle cingulate cortex, and cerebellum. The cerebellar vermis exhibits distinct activation patterns between the startle modifications. It is differentially activated with the highest amplitude for PPF, a lower activation for PA, and lowest for PPI. The orbital frontal cortex exhibits a differential activation pattern, not for the type of startle response but for the amplitude modification. For pulse alone it is close to zero; for PPI it is activated. This is in contrast to PPF where it shows deactivation. In addition, the thalamus, the cerebellum, and the anterior cingulate cortex add to the modulation of the startle reflex. PMID- 20205250 TI - Intracellular chloride regulates cell proliferation through the activation of stress-activated protein kinases in MKN28 human gastric cancer cells. AB - Recently, we reported that reduction of intracellular Cl(-) concentration ([Cl( )](i)) inhibited proliferation of MKN28 gastric cancer cells by diminishing the transition rate from G(1) to S cell-cycle phase through upregulation of p21, cyclin-dependent kinase inhibitor, in a p53-independent manner. However, it is still unknown how intracellular Cl(-) regulates p21 expression level. In this study, we demonstrate that mitogen-activated protein kinases (MAPKs) are involved in the p21 upregulation and cell-cycle arrest induced by reduction of [Cl(-)](i). Culture of MKN28 cells in a low Cl(-) medium significantly induced phosphorylation (activation) of MAPKs (ERK, p38, and JNK) and G(1)/S cell-cycle arrest. To clarify the involvement of MAPKs in p21 upregulation and cell growth inhibition in the low Cl(-) medium, we studied effects of specific MAPKs inhibitors on p21 upregulation and G(1)/S cell-cycle arrest in MKN28 cells. Treatment with an inhibitor of p38 or JNK significantly suppressed p21 upregulation caused by culture in a low Cl(-) medium and rescued MKN28 cells from the low Cl(-)-induced G(1) cell-cycle arrest, whereas treatment with an ERK inhibitor had no significant effect on p21 expression or the growth of MKN28 cells in the low Cl(-) medium. These results strongly suggest that the intracellular Cl(-) affects the cell proliferation via activation of p38 and/or JNK cascades through upregulation of the cyclin-dependent kinase inhibitor (p21) in a p53-independent manner in MKN28 cells. PMID- 20205249 TI - Somatosensory-evoked cortical activity in spastic diplegic cerebral palsy. AB - Somatosensory deficits have been identified in cerebral palsy (CP), but associated cortical brain activity in CP remains poorly understood. Functional MRI was used to measure blood oxygenation level-dependent (BOLD) responses during three tactile tasks in 10 participants with spastic diplegia (mean age: 18.70 years, SD: 7.99 years; 5 females) and 10 age-matched controls (mean age: 18.60 years, SD: 3.86 years; 5 females). Tactile stimulation involved servo-controlled translation of smooth or embossed surfaces across the right index finger pad; the discrimination tasks with embossed surfaces involved judging whether (1) paired shapes were similar or different, and (2) a rougher set of horizontal gratings preceded or followed a smoother one. Velocity and duration of surface translation was identical across all trials. In addition, an event-related design revealed response dynamics per trial in both groups. Compared to controls, individuals with spastic diplegia had significantly reduced spatial extents in activated cortical areas and smaller BOLD response magnitudes in cortical areas for somatosensation, motor, and goal-directed/attention behaviors. These results provide mechanisms for the widespread somatosensory deficits in CP. The reduced activation noted across multiple cortical areas might contribute to motor deficits in CP. PMID- 20205251 TI - Peripheral olfactory sensitivity in rodents after treatment with docetaxel. AB - OBJECTIVES/HYPOTHESIS: Clinical studies have documented that cytotoxic chemotherapy is often associated with body weight loss and decreased enjoyment of food. Besides taste, olfaction plays a role in food intake. We assessed whether systemic chemotherapeutic cancer treatment compromises olfactory function in rats and mice treated with docetaxel (Taxotere; Sanofi-Aventis, Paris, France). STUDY DESIGN: Randomized, controlled trials on mice and rats. METHODS: Male mice received a single and male rats either a single, two, or three docetaxel administrations. Olfactory function was tested by means of electroolfactograms (EOGs) from the chemosensory epithelium of the nasal septum and the endoturbinates. We evaluated and compared the magnitude of EOG responses evoked by different odorants recorded at different time points after treatment. RESULTS: In both animal species, docetaxel administration reduced body weight gain, thus evidencing the general toxic effect of the drug. In both animal species, the olfactory mucosa remained responsive to stimulation of odorants during the whole course of experiment, but treatment revealed regional differences of docetaxel susceptibility and induced marked transitory electrophysiological changes. In mice and rats a significant transitory decrease in EOG response magnitude occurred after a single administration. Unexpectedly, in rats we also observed an increase of the olfactory response following the second administration of the drug. CONCLUSIONS: Docetaxel exerts a neurotoxic effect on olfactory epithelia of rodents at doses similar to human doses, thus inducing transitory functional alterations. Although moderate, they are consistent with the hypothesis of a dysfunction of olfactory function. Further experiments are needed to elucidate the origin of the electrophysiological effects and their impact on the olfactory perception. PMID- 20205252 TI - Diffusion tensor imaging reliably differentiates patients with schizophrenia from healthy volunteers. AB - The objective of this research was to determine whether fractional anisotropy (FA) and mean diffusivity (MD) maps derived from diffusion tensor imaging (DTI) of the brain are able to reliably differentiate patients with schizophrenia from healthy volunteers. DTI and high resolution structural magnetic resonance scans were acquired in 50 patients with schizophrenia and 50 age- and sex-matched healthy volunteers. FA and MD maps were estimated from the DTI data and spatially normalized to the Montreal Neurologic Institute standard stereotactic space. Individuals were divided randomly into two groups of 50, a training set, and a test set, each comprising 25 patients and 25 healthy volunteers. A pattern classifier was designed using Fisher's linear discriminant analysis (LDA) based on the training set of images to categorize individuals in the test set as either patients or healthy volunteers. Using the FA maps, the classifier correctly identified 94% of the cases in the test set (96% sensitivity and 92% specificity). The classifier achieved 98% accuracy (96% sensitivity and 100% specificity) when using the MD maps as inputs to distinguish schizophrenia patients from healthy volunteers in the test dataset. Utilizing FA and MD data in combination did not significantly alter the accuracy (96% sensitivity and specificity). Patterns of water self-diffusion in the brain as estimated by DTI can be used in conjunction with automated pattern recognition algorithms to reliably distinguish between patients with schizophrenia and normal control subjects. PMID- 20205253 TI - Remission re-induction chemotherapy with clofarabine, topotecan, thiotepa, and vinorelbine for patients with relapsed or refractory leukemia. AB - BACKGROUND: We determined the maximum tolerated dose (MTD) of clofarabine when administered with topotecan, vinorelbine, thiotepa, and dexamethasone (TVTC) for children with relapsed or refractory acute leukemia, and observed the efficacy and toxicities of this therapy. PROCEDURE: Twelve patients with acute lymphoblastic or myeloblastic leukemia were given a 14-day remission induction therapy. Clofarabine was administered at a dose of 30 or 40 mg/m(2)/day over 2 hr for five consecutive days in six patients each. Patients who achieved a remission proceeded to a stem cell transplant (HSCT). A second cycle could be administered prior to HSCT. RESULTS: Of the six patients at the 30 mg/m(2) clofarabine dose, two achieved a complete response (CR) and one a PR and proceeded to BMT. Three patients had progressive disease. Five of the six patients at the 40 mg/m(2) achieved a CR. Four proceeded to HSCT, and one relapsed prior to HSCT. One patient died on day 45 with marrow hypoplasia without evidence of leukemia. Hematologic and infectious adverse events were universal. The one dose limiting non-infectious toxicity observed was prolonged marrow hypoplasia. CONCLUSION: TVTC has significant anti-leukemic activity in both acute lymphoblastic and myeloblastic leukemia. The MTD of clofarabine is 40 mg/m(2)/day in this combination. This is the recommended dose for the phase II study in patients with refractory or relapsed leukemia, a population which has limited therapeutic options. PMID- 20205255 TI - Syndrome of inappropriate secretion of antidiuretic hormone as a leading cause of hyponatremia in children who underwent chemotherapy or stem cell transplantation. AB - BACKGROUND: Hyponatremia is a common metabolic disorder in cancer patients. However, little information is available for patients receiving chemotherapy or stem cell transplantation (SCT). We analyzed the frequency, characteristics, and various causes of hyponatremia including routine use of hypotonic fluids in children following chemotherapy or SCT. PROCEDURE: We reviewed the clinical and laboratory data of 63 children who received chemotherapy or SCT at the Department of Pediatrics, Hanyang University Medical Center from July 2005 to July 2008. RESULTS: All 63 patients at admission received routine parenteral fluids of 0.25% or 0.45% NaCl and 82 episodes of hyponatremia were observed in 40 (63.5%) patients. Of these 82 episodes, 50 episodes of hyponatremia developed in 29 children following chemotherapy and 32 episodes in 16 children following SCT. Seventy-six out of 82 episodes (92.7%) of hyponatremia developed in 37 patients receiving hypotonic fluids with NaCl concentrations between 30 and 150 mEq/L. The frequency of SIADH in the SCT setting was more frequent (14/21, 66.6%) than in the chemotherapy setting (18/58, 31.0%) (P = 0.02), even though the leading cause of hyponatremia was SIADH in both settings. CONCLUSIONS: SIADH is a leading cause of hyponatremia in children following chemotherapy or SCT, and more frequent in SCT settings than in chemotherapy settings. Furthermore, the routine use of hypotonic fluids which could aggravate the development of hyponatremia for these patients should be avoided and then switched to isotonic fluids. PMID- 20205256 TI - Severe life threatening neurotoxicity in a child with acute lymphoblastic leukemia receiving posaconazole and vincristine. PMID- 20205254 TI - Clinical presentation and outcome of epidemic Kaposi sarcoma in Ugandan children. AB - BACKGROUND: Kaposi sarcoma (KS) is one of the most common pediatric cancers in sub-Saharan Africa. Few data are available about the clinical presentation or response to treatment of children with epidemic (HIV-associated) KS. METHODS: Medical records of all children with KS and HIV infection referred to the Uganda Cancer Institute in Kampala, Uganda from October 2004 to June 2007 were reviewed. Charts were abstracted for age, sex, location of KS lesions at presentation, biopsy results, CD4 T-cell count and percentage, and KS treatment and outcome. RESULTS: Seventy-three children with epidemic KS were identified, 37 males and 36 females. The median age was 10.1 years (range 2-18). KS presented with lymph node (LN) involvement in 60% of cases. The median absolute and percentage CD4 T-cells at presentation were 210 cells/microl and 7.4%, respectively. Those children with lymphadenopathic KS were younger (mean difference 3.7 years; P = 0.01) and had higher CD4 T-cell counts (mean difference 242 cells/microl; P = 0.03) than those without LN involvement. Of 32 patients for whom outcome data were available, a complete response to chemotherapy and/or antiretroviral therapy was documented in 20 (62.5%) patients. CONCLUSIONS: In comparison to cutaneous involvement, LN involvement of epidemic KS occurs at younger ages and at higher CD4 levels. This clinical presentation may reflect recent infection with human herpesvirus 8 followed by a rapid progression to malignancy. Favorable response to treatment was observed in the majority of cases, but prospective studies are needed to determine optimal management. PMID- 20205257 TI - Genomic instability in Hoyeraal-Hreidarsson syndrome. PMID- 20205258 TI - Immunogenicity of trivalent influenza vaccine in children with acute lymphoblastic leukemia during maintenance therapy. AB - PURPOSE: The aim of this study was to assess the immune response of children with acute lymphoblastic leukemia (ALL) to influenza vaccine and to compare it with healthy controls. PROCEDURE: Thirty-two children aged 1-18 years with ALL on maintenance therapy and 30 healthy sibling controls were enrolled in the study. All children were vaccinated with trivalent inactivated influenza vaccine. Hemagglutinin-inhibition (HI) antibody titers were determined in sera of both patient and control groups just before and 4 weeks after vaccination. The ability of each group to mount a protective (> or =40) and/or fourfold titer was measured. RESULTS: The protective response for virus subunits among patients and healthy controls were 43.4% versus 88% for H1N1 (P = 0.04), 63.3% versus 80% for H3N2 antigens (P = 0.06), and 26% versus 73% for B antigen (P = 0.001). Responses for H1N1 and B subunits were significantly lower in patients than controls. In the patient group, the significant response to each virus was demonstrated in the analysis of pre- and post-vaccination geometric mean titer (GMT) (P = 0.001). The percentage of patients and controls with fourfold increase in HI titers were 56.2% versus 80% for H1N1 (P = 0.04), 40.6% versus 53.3% for H3N2 (P = 0.31), and 59.4% versus 83.3% for B (P = 0.038). Immune responses for H1N1 and B subunits were significantly lower in patients than controls. CONCLUSIONS: Influenza vaccine is tolerated well in ALL patients with acceptable but limited immune response compared to healthy controls. These findings support the recommendation for annual influenza vaccination in children with ALL. PMID- 20205259 TI - Can CDA deficiency explain tumour lysis syndrome in a child with neuroblastoma receiving gemcitabine? PMID- 20205260 TI - The improvement of chloroperoxidase activities in the presence of ammonium salts and cationic surfactants. AB - The catalytic activities of chloroperoxidase (CPO) including halogenation, oxidation, and peroxidation were investigated in the presence of ammonium salts: tetramethylammonium bromide (TMABr), tetraethylammonium bromide (TEABr), tetrapropylammonium bromide (TPABr), tetrabutylammonium bromide (TBABr), and cationic surfactants: dodecyltrimethylammonium bromide (DTABr) and cetyltrimethylammonium bromide (CTABr). All the mentioned activities were promoted in most cases. The highest modified activity (ABTS peroxidation) was 18.16 times higher in the presence of TMABr than that in pure buffer. The activity enhancement was strongly dependent on the concentration and the hydrophobic chain length of additives, and the structure of substrates. The kinetic parameters showed that the activation was mainly attributed to an increase in k(cat) due probably to a catalytically favorable conformation of CPO induced by the additives. Moreover, a lower K(m) and higher ratio of k(cat)/K(m) (specificity constant) was obtained, indicating that both the affinity and specificity of CPO to substrates were improved in the presence of additives. PMID- 20205261 TI - Optimization of the fermentation media for sophorolipid production from Candida bombicola ATCC 22214 using a simplex centroid design. AB - This article describes the use of a simplex centroid mixture experimental design to optimize the fermentation medium in the production of sophorolipids (SLs) using Candida bombicola. In the first stage, 16 media ingredients were screened for the ones that have the most positive influence on the SL production. The sixteen ingredients that were chosen are five different carbohydrates (fructose, glucose, glycerol, lactose, and sucrose), five different nitrogen sources (malt extract, peptone extract, soytone, urea, and yeast extract), two lipid sources (mineral oil and oleic acid), two phosphorus sources (K(2)HPO(4) and KH(2)PO(4)), MgSO(4), and CaCl(2). Multiple regression analysis and centroid effect analysis were carried out to find the sugar, lipid, nitrogen source, phosphorus source, and metals having the most positive influence. Sucrose, malt extract, oleic acid, K(2)HPO(4), and CaCl(2) were selected for the second stage of experiments. An augmented simplex centroid design for five ingredients requiring 16 experiments was used for the optimization stage. This produced a quadratic model developed to help understand the interaction amongst the ingredients and find the optimal media concentrations. In addition, the top three results from the optimization experiments were used to obtain constraints that identify an optimal region. The model together with the optimal region constraints predicts the maximum production of SLs when the fermentation media is composed of sucrose, 125 g/L; malt extract, 25 g/L; oleic acid, 166.67 g/L; K(2)HPO(4), 1.5 g/L; and CaCl(2), 2.5 g/L. The optimal media was validated experimentally and a yield of 177 g/L was obtained. PMID- 20205262 TI - Individualism, collectivism, and Chinese adolescents' aggression: intracultural variations. AB - This study examined the relations between cultural values (i.e., individualism and collectivism) and aggression among 460 (234 girls) Chinese adolescents. Conflict level and social status insecurity were examined as potential explaining mechanisms for these relations. The results showed that adolescents' endorsement of collectivism was negatively related to their use of overt and relational aggression as reported by teachers and peers, whereas positive associations were found between the endorsement of individualism and adolescent aggression. Adolescents' conflict level and social status insecurity accounted for a significant part of these associations. Findings of this study demonstrate the importance of examining intracultural variations of cultural values in relation to adolescent aggression as well as the process variables in explaining the relations. PMID- 20205263 TI - Effects of early rearing conditions on problem-solving skill in captive male chimpanzees (Pan troglodytes). AB - Early rearing conditions of captive chimpanzees characterize behavioral differences in tool use, response to novelty, and sexual and maternal competence later in life. Restricted rearing conditions during early life hinder the acquisition and execution of such behaviors, which characterize the daily life of animals. This study examined whether rearing conditions affect adult male chimpanzees' behavior skills used for solving a problem with acquired locomotion behavior. Subjects were 13 male residents of the Chimpanzee Sanctuary Uto: 5 wild born and 8 captive-born. A pretest assessed bed building and tool use abilities to verify behavioral differences between wild- and captive-born subjects, as earlier reports have described. Second, a banana-access test was conducted to investigate the problem-solving ability of climbing a bamboo pillar for accessing a banana, which might be the most efficient food access strategy for this setting. The test was repeated in a social setting. Results show that wild-born subjects were better able than captive-born subjects to use the provided materials for bed building and tool use. Results of the banana-access test show that wild-born subjects more frequently used a bamboo pillar for obtaining a banana with an efficient strategy than captive-born subjects did. Of the eight captive-born subjects, six avoided the bamboo pillars to get a banana and instead used, sometimes in a roundabout way, an iron pillar or fence. Results consistently underscored the adaptive and sophisticated skills of wild-born male chimpanzees in problem-solving tasks. The rearing conditions affected both the behavior acquisition and the execution of behaviors that had already been acquired. PMID- 20205264 TI - Clinical analysis of PMS2: mutation detection and avoidance of pseudogenes. AB - Germline mutation detection in PMS2, one of four mismatch repair genes associated with Lynch syndrome, is greatly complicated by the presence of numerous pseudogenes. We used a modification of a long-range PCR method to evaluate PMS2 in 145 clinical samples. This modification avoids potential interference from the pseudogene PMS2CL by utilizing a long-range product spanning exons 11-15, with the forward primer anchored in exon 10, an exon not shared by PMS2CL. Large deletions were identified by MLPA. Pathogenic PMS2 mutations were identified in 22 of 59 patients whose tumors showed isolated loss of PMS2 by immunohistochemistry (IHC), the IHC profile most commonly associated with a germline PMS2 mutation. Three additional patients with pathogenic mutations were identified from 53 samples without IHC data. Thirty-seven percent of the identified mutations were large deletions encompassing one or more exons. In 27 patients whose tumors showed absence of either another protein or combination of proteins, no pathogenic mutations were identified. We conclude that modified long range PCR can be used to preferentially amplify the PMS2 gene and avoid pseudogene interference, thus providing a clinically useful germline analysis of PMS2. Our data also support the use of IHC screening to direct germline testing of PMS2. PMID- 20205265 TI - The anatomy of anatomy: a review for its modernization. AB - Anatomy has historically been a cornerstone in medical education regardless of nation or specialty. Until recently, dissection and didactic lectures were its sole pedagogy. Teaching methodology has been revolutionized with more reliance on models, imaging, simulation, and the Internet to further consolidate and enhance the learning experience. Moreover, modern medical curricula are giving less importance to anatomy education and to the acknowledged value of dissection. Universities have even abandoned dissection completely in favor of user-friendly multimedia, alternative teaching approaches, and newly defined priorities in clinical practice. Anatomy curriculum is undergoing international reformation but the current framework lacks uniformity among institutions. Optimal learning content can be categorized into the following modalities: (1) dissection/prosection, (2) interactive multimedia, (3) procedural anatomy, (4) surface and clinical anatomy, and (5) imaging. The importance of multimodal teaching, with examples suggested in this article, has been widely recognized and assessed. Nevertheless, there are still ongoing limitations in anatomy teaching. Substantial problems consist of diminished allotted dissection time and the number of qualified anatomy instructors, which will eventually deteriorate the quality of education. Alternative resources and strategies are discussed in an attempt to tackle these genuine concerns. The challenges are to reinstate more effective teaching and learning tools while maintaining the beneficial values of orthodox dissection. The UK has a reputable medical education but its quality could be improved by observing international frameworks. The heavy penalty of not concentrating on sufficient anatomy education will inevitably lead to incompetent anatomists and healthcare professionals, leaving patients to face dire repercussions. PMID- 20205266 TI - A human dissection training program at Indiana University School of Medicine Northwest. AB - As human cadavers are widely used in basic sciences, medical education, and other training and research venues, there is a real need for experts trained in anatomy and dissection. This article describes a program that gives individuals interested in clinical and basic sciences practical experience working with cadavers. Participants are selected through an open application process and attend sessions focused on anatomical terminology, gross anatomy and radiography, and some of the educational applications of human cadavers. Dissection skills are honed during an intensive, two-day cadaver dissection and orthopedic workshop. Participants communicate the knowledge they gain through table-side discussions, reflect upon the experience during a memorial service, and submit written program evaluations. Additionally, the dissection and preparation of cadaveric materials accomplished in this course are used in the medical school gross anatomy course during the next academic year. From 2004 through 2008, the annual number of applicants increased from 40 to 167, and the number of participants increased from 25 to 43 per year. Program participants have represented diverse ethnic, educational, and professional backgrounds. Feedback from participants has been remarkably positive, including comments on the large amount of learning that takes place during the sessions, the positive impact the program has had on career choice, and the desire for program expansion. This program, which could be replicated at other institutions, teaches anatomy, prepares cadaveric prosections for teaching and training others, and encourages participants to pursue careers in anatomical and biomedical sciences. PMID- 20205267 TI - Post-infectious bronchiolitis obliterans: can CT scan findings at early age anticipate lung function? AB - BACKGROUND: The image findings of post-infectious bronchiolitis obliterans (PIBO) have been described, however, we do not know if such findings can predict lung function (LF) deterioration with increasing patient age. AIM: To assess whether computed tomography (CT) abnormalities detected at an early stage of the disease can anticipate abnormal LF a decade later in children with PIBO. METHODS: We compared CT scans of 21 children with PIBO, done within their first 3 years of life, and their actual LF. To evaluate CT scans we used a modified Bhalla score and, for LF, FEV1 as percentage of predicted values. We calculated prevalence ratios (PRs) by comparing the proportion of patients with worst CT score and worst LF, with the proportion of those with best CT score and worst LF. RESULTS: PR was 1.17 (CI 1.02; 1.34, P = 0.02). CONCLUSIONS: The CT finding early in the life of children with PIBO, when assessed by the Bhalla, score seem to anticipate future LF status. PMID- 20205268 TI - Churg-Strauss syndrome in a 14-year-old girl. PMID- 20205269 TI - A weighted combination of pseudo-likelihood estimators for longitudinal binary data subject to non-ignorable non-monotone missingness. AB - For longitudinal binary data with non-monotone non-ignorably missing outcomes over time, a full likelihood approach is complicated algebraically, and with many follow-up times, maximum likelihood estimation can be computationally prohibitive. As alternatives, two pseudo-likelihood approaches have been proposed that use minimal parametric assumptions. One formulation requires specification of the marginal distributions of the outcome and missing data mechanism at each time point, but uses an 'independence working assumption,' i.e. an assumption that observations are independent over time. Another method avoids having to estimate the missing data mechanism by formulating a 'protective estimator.' In simulations, these two estimators can be very inefficient, both for estimating time trends in the first case and for estimating both time-varying and time stationary effects in the second. In this paper, we propose the use of the optimal weighted combination of these two estimators, and in simulations we show that the optimal weighted combination can be much more efficient than either estimator alone. Finally, the proposed method is used to analyze data from two longitudinal clinical trials of HIV-infected patients. PMID- 20205270 TI - A metastasis or a second independent cancer? Evaluating the clonal origin of tumors using array copy number data. AB - When a cancer patient develops a new tumor it is necessary to determine if it is a recurrence (metastasis) of the original cancer, or an entirely new occurrence of the disease. This is accomplished by assessing the histo-pathology of the lesions. However, there are many clinical scenarios in which this pathological diagnosis is difficult. Since each tumor is characterized by a distinct pattern of somatic mutations, a more definitive diagnosis is possible in principle in these difficult clinical scenarios by comparing the two patterns. In this article we develop and evaluate a statistical strategy for this comparison when the data are derived from array copy number data, designed to identify all of the somatic allelic gains and losses across the genome. First a segmentation algorithm is used to estimate the regions of allelic gain and loss. The correlation in these patterns between the two tumors is assessed, and this is complemented with more precise quantitative comparisons of each plausibly clonal mutation within individual chromosome arms. The results are combined to determine a likelihood ratio to distinguish clonal tumor pairs (metastases) from independent second primaries. Our data analyses show that in many cases a strong clonal signal emerges. Sensitivity analyses show that most of the diagnoses are robust when the data are of high quality. PMID- 20205271 TI - On Bayesian shared component disease mapping and ecological regression with errors in covariates. AB - Recent literature on Bayesian disease mapping presents shared component models (SCMs) for joint spatial modeling of two or more diseases with common risk factors. In this study, Bayesian hierarchical formulations of shared component disease mapping and ecological models are explored and developed in the context of ecological regression, taking into consideration errors in covariates. A review of multivariate disease mapping models (MultiVMs) such as the multivariate conditional autoregressive models that are also part of the more recent Bayesian disease mapping literature is presented. Some insights into the connections and distinctions between the SCM and MultiVM procedures are communicated. Important issues surrounding (appropriate) formulation of shared- and disease-specific components, consideration/choice of spatial or non-spatial random effects priors, and identification of model parameters in SCMs are explored and discussed in the context of spatial and ecological analysis of small area multivariate disease or health outcome rates and associated ecological risk factors. The methods are illustrated through an in-depth analysis of four-variate road traffic accident injury (RTAI) data: gender-specific fatal and non-fatal RTAI rates in 84 local health areas in British Columbia (Canada). Fully Bayesian inference via Markov chain Monte Carlo simulations is presented. PMID- 20205272 TI - Novel image-enhanced endoscopy with i-scan technology. AB - i-scan technology is the newly developed image-enhanced endoscopy technology from PENTAX, Japan. This consists of three types of algorithms: surface enhancement (SE), contrast enhancement (CE), and tone enhancement (TE). SE enhances light dark contrast by obtaining luminance intensity data for each pixel and applying an algorithm that allows detailed observation of a mucosal surface structure. CE digitally adds blue color in relatively dark areas, by obtaining luminance intensity data for each pixel and applying an algorithm that allows detailed observation of subtle irregularities around the surface. Both enhancement functions work in real time without impairing the original color of the organ, therefore, SE and CE are suitable for screening endoscopy to detect gastrointestinal tumors at an early stage. TE dissects and analyzes the individual RGB components of a normal image. The algorithm then alters the color frequencies of each component and recombines the components to a single, new color image. This is designed to enhance minute mucosal structures and subtle changes in color. TE works in real time and consists of three modes such as TE-g for gastric tumors, TE-c for colonic tumors, and TE-e for esophageal tumors. TE is suitable mainly for detailed examination of the lesions that are detected in a screening endoscopy. i-scan technology leads us to easier detection, diagnosis and treatment of gastrointestinal diseases. PMID- 20205273 TI - Inflammatory bowel disease in the dog: differences and similarities with humans. AB - Inflammatory bowel diseases (IBD) represent important chronic conditions affecting the gastrointestinal tract in man. However, similar disorders are found in several animal species and the IBD affecting dogs are particularly important. These are encompassed by an umbrella of probably several different entities with common symptoms, some of which seem to share striking similarities with human conditions. This review will focus on the actual knowledge of IBD in dogs, and attempt to identify differences and similarities with human IBD conditions. PMID- 20205274 TI - Even low-grade inflammation impacts on small intestinal function. AB - Independent of the cause and location, inflammation - even when minimal - has clear effects on gastrointestinal morphology and function. These result in altered digestion, absorption and barrier function. There is evidence of reduced villus height and crypt depth, increased permeability, as well as altered sugar and peptide absorption in the small intestine after induction of inflammation in experimental models, which is supported by some clinical data. Identification of inflammatory factors which may promote the process of gastrointestinal dysfunction as well as clinical research to verify experimental observations of inflammatory modulation of gastrointestinal function are required. Moreover, nutritional strategies to support functional restitution are needed. PMID- 20205276 TI - Mindin is upregulated during colitis and may activate NF-kappaB in a TLR-9 mediated manner. AB - AIM: To investigate the regulation of mindin expression and the signaling pathway involved during inflammation. METHODS: C57BL/6 mice were treated with 3% dextran sulfate sodium (DSS) in drinking water for 6 d to induce acute colitis, and then the colon was harvested for histological analysis or for RNA isolation. mRNA expression of mindin and nuclear factor (NF)-kappaB p65 was analyzed by quantitative real time polymerase chain reaction (RT-PCR) and mindin expression construct was confirmed by Western blotting. Mouse macrophage and intestinal epithelial lineage cells were stimulated with different cytokines and toll-like receptor (TLR) ligands, before pNF-kappaB-luciferase activity was assessed using the Dual-Luciferase reporter assay system. RESULTS: mRNA expression of mindin was upregulated 4.7 + or - 1.1 fold compared with the baseline during DSS-induced intestinal inflammation in the mice. Stimulation with CpG-ODN (a known TLR-9 ligand) induced 4.2 + or - 0.3 fold upregulation of mindin expression in RAW 264.7 cells. Full-length of mindin was cloned from cDNA of mouse mesenteric lymph node, then the pCMV-Mindin-Flag expression vector was established and the protein expression level was confirmed. Transfection of the mindin construct and stimulation with CpG-ODN significantly increased the NF-kappaB-luciferase activity by 2.5 + or - 0.3 and 4.5 + or - 0.5 fold in RAW264.7 and CMT93 cells, respectively (P < 0.01). CONCLUSION: Mindin expression is upregulated during intestinal inflammation and may induce NF-kappaB promoter activation in a TLR-9 mediated manner. PMID- 20205275 TI - Factors influencing intercellular spaces in the rat esophageal epithelium. AB - AIM: To evaluate the effect of acute stress, hydrochloric acid, ethanol, aspirin, and prednisolone on the intercellular spaces of the esophageal epithelium. METHODS: Part I, male Sprague-Dawley rats were randomly divided into eight groups and treated with the damaging or control factors. The esophagus of each rat was macroscopically inspected. Histological changes in mucosal biopsies were examined by light microscopy, and the widths of intercellular spaces were determined by transmission electron microscopy (TEM). Part II, in part I, we found that acute stress and aspirin induced dilated intercellular spaces (DIS) of the esophageal epithelium. Therefore, the effect of acid suppression pretreatment with esomeprazole on esophageal epithelial DIS induced by water immersion and restraint stress (WRS) and aspirin was further investigated to determine the association of DIS with acid reflux. After administration of 0.9% sodium chloride solution or esomeprazole solution orally for five days, rats underwent WRS or intragastric administration of aspirin solution. Esophageal epithelial intercellular spaces were investigated by TEM. RESULTS: (1) The five damaging factors produced no lesions or inflammation in esophageal mucosa of rats under either gross or routine histological inspections. Esophageal epithelial intercellular space diameters in stress and aspirin groups were significantly greater, nearly three or two-fold respectively, than those in their corresponding control groups (stress model: 0.38 + or - 0.05 microm vs 0.13 + or - 0.02 microm, P < 0.01; aspirin model: 0.32 + or - 0.12 microm vs 0.19 + or - 0.05 microm, P < 0.01). Neither intragastric administration of hydrochloric acid or ethanol, nor hypodermic injection of prednisolone produced DIS compared with their corresponding control groups (hydrochloric acid model: 0.24 + or - 0.03 microm vs 0.19 + or - 0.05 microm, P > 0.05; ethanol model: 0.25 + or - 0.10 microm vs 0.19 + or - 0.05 microm, P > 0.05; prednisolone model: 0.20 + or - 0.03 microm vs 0.14 + or - 0.03 microm, P > 0.05); and (2) No significant difference in the intercellular space diameters was observed between the group pretreated with esomeprazole and the control group, in both the stress and aspirin models (stress model: 0.35 + or - 0.05 microm vs 0.37 + or - 0.05 microm, P > 0.05; aspirin model: 0.24 + or - 0.02 microm vs 0.27 + or - 0.03 microm, P > 0.05). CONCLUSION: Acute stress and aspirin can induce DIS of the esophageal epithelium in rats, and it is not correlated with acid reflux. PMID- 20205277 TI - Mechanisms mediating CCK-8S-induced contraction of proximal colon in guinea pigs. AB - AIM: To investigate the effects of sulfated cholecystokinin octapeptide (CCK-8S) on the contractile activity of guinea-pig proximal colon. METHODS: Proximal colonic smooth muscle (PCSM) strips were obtained from adult female guinea pigs and contractile response of PCSM strips was recorded using a polyphysiograph. PCSM cells were isolated by enzymatic digestion. Resting potential (RP), action potential (AP), large conductance potassium channel currents (I(BKCa)) and L-type calcium currents (I(Ca-L)) were recorded by patch-clamp techniques. RESULTS: (1) CCK-8S (10(-7) mol/L) enhanced the mean contractile amplitude of colonic circular muscle and longitudinal muscle (LM) strips by 56.53% + or - 11.92% (P = 0.038) and 65.93% + or - 12.98% (P = 0.019), respectively, as well as the mean frequency of LM by 31.69% + or - 13.58% (P = 0.023), which were significantly attenuated by pretreating strips with devazepide, nifedipine, iberiotoxin, thapsigargin (TG) and BAPTA-AM (BA) respectively; (2) CCK-8S (10(-7) mol/L) increased the AP amplitude by 38.6% + or - 3.2% (P = 0.015), decreased AP duration by 36.9% + or - 8.7% (P = 0.026), and depolarized the RP from -61.3 + or - 2.7 mV to -29.8 + or - 5.9 mV (P = 0.032); and (3) Compared with the normal control group, CCK-8S (10( 7) mol/L) enhanced the peak current of I(BKCa) by 18.7% + or - 2.1% (from 916 + or - 183 pA to 1088 + or - 226 pA; at +60 mV; P = 0.029), which was inhibited by respective pretreatment with iberiotoxin and devazepide. Additionally, CCK-8S (10(-7) mol/L) intensified the peak current of I(Ca-L) by 40% (from 60 + or - 8 pA to 84 + or - 11 pA; at +10 mV; P = 0.012), compared to the normal control group, which was apparently suppressed by respective pretreatment with nifedipine, devazepide, TG and BA. In the respective presence of heparin and staurosporine, CCK-8S did not significantly enhance I(BKCa) and I(Ca-L). CONCLUSION: The results suggest that CCK-8S promotes guinea-pig proximal colon contraction by CCK1 receptors, following activation of the inositol triphosphate protein kinase C signal transduction pathway. PMID- 20205278 TI - Blocking effects of siRNA on VEGF expression in human colorectal cancer cells. AB - AIM: To investigate the expression of vascular endothelial cell growth factor (VEGF) and its receptors Fms-like tyrosine kinase 1 (FLT-1) and fetal liver kinase 1 (FLK-1) in colorectal carcinoma (CRC), and the blocking effects of small interfering RNAs (siRNAs) on VEGF expression in human colorectal cancer HCT116 cells. METHODS: Immunohistochemical staining for VEGF, FLT-1 and FLK-1 proteins was performed in 82 cases of CRC and 14 normal colorectal mucosae. A siRNA targeting VEGF was synthesized and transfected into HCT116 cells using lipofectamine 2000. Immunocytochemical staining and Western blotting analyses were performed to detect the expression of VEGF protein. The suppressive effect of the siRNA on cell proliferation was detected using the 3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyltertrazolium bromide (MTT) assay. Cellular apoptosis was detected using flow cytometry (FCM). RESULTS: The expression of VEGF, FLT-1 and FLK-1 in tumor tissues was significantly higher than that in normal tissues (P = 0.008, P = 0.000, P = 0.000). The expression of VEGF was positively correlated with both lymph node metastasis and clinical stage (P = 0.009 and P = 0.025, respectively). Immunocytochemistry showed that the expression of VEGF was weakly positive and Western blotting indicated a significant reduction in VEGF-siRNA cell protein levels. VEGF-siRNA cell growth inhibition was assessed by the MTT assay, and the tumor cell proliferation rate was significantly different at 24, 48, and 72 h after transfection. FCM results showed that the VEGF-siRNA group had an apparent aneuploid peak. CONCLUSION: VEGF, FLT-1 and FLK-1 are associated with colorectal carcinogenesis. siRNA silencing of the VEGF gene suppresses proliferation, and induces apoptosis in HCT116 cells. The results suggest that VEGF may be a new gene therapy target for colorectal cancer. PMID- 20205279 TI - Predictors of loss of hepatitis B surface antigen in HIV-infected patients. AB - AIM: To study factors associated with loss of hepatitis B surface antigen (HBsAg) in patients co-infected with human immunodeficiency virus (HIV) and hepatitis B virus (HBV). METHODS: We retrospectively reviewed the medical records of 5681 patients followed up at two New York City HIV clinics from January 1999 to May 2007. Clinical and laboratory parameters including baseline and follow-up HIV viral loads, CD4 cell counts, alanine transaminase levels, demographics, presence of hepatitis C infection, and treatment with highly active antiretroviral therapy dually active against both HIV and HBV infection, were analyzed to determine factors associated with loss of HBsAg. RESULTS: Three hundred and fifty five patients (355/5681, 6.84%) were co-infected with HIV and HBV and were evaluated. Of these, 226 patients with more than 12 mo follow-up were included in further analysis to determine factors associated with loss of HBsAg in the long-term follow-up. In the univariate analysis, baseline CD4 cell count was associated with loss of HBsAg (P = 0.052). Cox regression analysis revealed that loss of HBsAg was associated with baseline CD4 cell count > 500 cells/mm(3) (P = 0.016, odds ratio: 76.174, 95% confidence interval: 2.233-2598.481). CONCLUSION: Our study showed an interesting association of loss of HBsAg in HIV-HBV co-infected patients with higher CD4 cell count, suggesting that T-cell cytolytic activity against HBV may still be effective in clearing HBV infection. PMID- 20205280 TI - Omeprazole induces gastric transmucosal permeability to the peptide bradykinin. AB - AIM: To investigate omeprazole-induced transepithelial gastric leak and its effects on the permeability of the peptides bradykinin and oxytocin. METHODS: Rat gastric corpus tissue was isolated and mounted in an Ussing chamber apparatus to evaluate the permeability of (3)H-bradykinin, (3)H-oxytocin, and (14)C-EDTA in the presence or absence of omeprazole. Thin-layer chromatography was performed to identify any metabolic breakdown products of the peptides resulting from permeation through the gastric tissue, and thereby calculate the true flux of the peptide. RESULTS: The flux rate of intact (3)H-bradykinin increased substantially after omeprazole addition (109.5%) compared to the DMSO vehicle control (14%). No corresponding change in flux of intact (3)H-oxytocin was observed under the same conditions (11.9% and 6.4% in the DMSO- and omeprazole-treated conditions, respectively). After exposure to omeprazole, the flux rate of (14)C-EDTA also increased dramatically (122.3%) compared to the DMSO condition (36.3%). CONCLUSION: The omeprazole-induced gastric leak allows for transmucosal permeability to charged molecules as well as non-electrolytes. This induced leak will allow certain peptides to permeate. PMID- 20205281 TI - New means to monitor the effect of glucocorticoid therapy in children. AB - AIM: To study the individual effects of glucocorticoid (GC) therapy on the state of immune activation in patient serum. METHODS: We developed a novel assay in which the effect of corticosteroid-treated patient serum on healthy donor peripheral blood mononuclear cells (target cells) was studied, with a panel of markers for effector [interferon (IFN)gamma and interleukin (IL)-5] and regulatory T cells (FOXP3 and glucocorticoid-induced tumor necrosis factor receptor, GITR). The study group comprised 19 children with inflammatory bowel disease. The individual effect of patient serum on target cells was analyzed prior to GC therapy and 2 wk later. RESULTS: The effect of GC therapy mediated by patient serum was seen as a decrease in the target cells expression of regulatory T-cell-related markers GITR (median suppression 24%, range of suppression 1%-63%, in 2 cases increase of 6% and 77%, P < 0.01 for mitogen-activated target cells) and FOXP3 (median suppression 33%, range of suppression 0%-79%, in one case an increase of 173%, P < 0.05 for resting cells), and secretion of IFNgamma [from a mean of 87 700 pg/mL (SD 33 900 pg/mL) to 60 900 pg/mL (SD 44 200 pg/mL) in mitogen-activated target cells, 13 of the cases showed a decrease, P < 0.01]. The total or weight-related prednisolone dose did not correlate with the patient serum-induced changes in the target cell markers. CONCLUSION: GC response could be monitored at an individual level by studying the effect of patient serum on signaling pathways of target immune cells. PMID- 20205282 TI - Prediction of flare-ups of ulcerative colitis using quantitative immunochemical fecal occult blood test. AB - AIM: To examine the feasibility of predicting the flare-up of ulcerative colitis (UC) before symptoms emerge using the immunochemical fecal occult blood test (I FOBT). METHODS: We prospectively measured fecal hemoglobin concentrations in 78 UC patients using the I-FOBT every 1 or 2 mo. RESULTS: During a 20 mo-period, 823 fecal samples from 78 patients were submitted. The median concentration of fecal hemoglobin was 41 ng/mL (range: 0-392 500 ng/mL). There were three types of patients with regard to the correlation between I-FOBT and patient symptoms; the synchronous transition type with symptoms (44 patients), the unrelated type with symptoms (19 patients), and the flare-up predictive type (15 patients). In patients with the flare-up predictive type, the values of I-FOBT were generally low during the study period with stable symptoms. Two to four weeks before the flare-up of symptoms, the I-FOBT values were high. Thus, in these patients, I FOBT could predict the flare-up before symptoms emerged. CONCLUSION: Flare-up could be predicted by I-FOBT in approximately 20% of UC patients. These results warrant periodical I-FOBT in UC patients. PMID- 20205283 TI - Laboratory characteristics of recent hepatitis A in Korea: ongoing epidemiological shift. AB - AIM: To evaluate seroprevalence of hepatitis A virus (HAV) antibody and investigate demographic, clinical, and laboratory features of recent cases in Korea. METHODS: For the evaluation of hepatitis A seroprevalence, we analyzed the data from 3127 subjects including, healthcare workers and patients who visited Konkuk University Hospital, a secondary referral center, from January to October 2009. The sera with positive IgM were excluded from seroprevalence data for total HAV antibody. We retrospectively reviewed the electronic medical records of 419 patients with HAV, who were diagnosed by the presence of serum IgM antibodies against HAV. All patients presented at Konkuk University Hospital between August 2005 and September 2008. RESULTS: Among 3127 sera tested, 1428 (45.7%) were positive for anti-HAV antibody. The seroprevalence was very low in teenagers or those in their twenties, increased in those in their thirties, and was > 90% in older patients. In children younger than 10 years, seroprevalence was increased again. Most patients with HAV hepatitis were in their twenties and thirties. The gamma-glutamyl transpeptidase increased with age and was significantly higher in patients older than 30 years. Indicators of severity, such as decreased albumin and increased bilirubin, were also more prominent in the older age group; however, the leukocyte count was higher and the frequency of leukopenia was lower in younger patients than in older adults. CONCLUSION: There has been an apparent epidemiological shift in HAV seroprevalence and a change in the peak age of HAV hepatitis. This study could provide baseline data of recent hepatitis A in Asia. PMID- 20205284 TI - Colonoscopy in Hong Kong Chinese children. AB - AIM: To investigate the safety and diagnostic yield of colonoscopy in Chinese children in whom the procedure is not often done. METHODS: We conducted a retrospective review of all colonoscopies in consecutive children who underwent their first diagnostic colonoscopy from Jan 2003 to 2008. RESULTS: Seventy-nine children (48 boys, 31 girls; mean age 9.2 +/- 4.2 years) were identified and reviewed with a total of 82 colonoscopies performed. Successful caecal and ileal intubation rates were 97.6% and 75.6% respectively. Forty patients (50.6%) had a positive diagnosis made in colonoscopy and that included colonic polyps (23), Crohn's disease (12), ulcerative colitis (1), and miscellaneous causes (4). 80% of polyps were in the rectosigmoid colon. All but one were juvenile hamartomatous polyps. The exception was an adenomatous polyp. The mean ages for children with inflammatory bowel disease (IBD) and polyps were 11.3 and 4.3 years respectively. There was no procedure-related complication. CONCLUSION: Colonoscopy is a safe procedure in our Chinese children. The increasing diagnosis of IBD in recent decades may reflect a rising incidence of the disease in our children. PMID- 20205285 TI - Prognostic factors in the surgical treatment of caudate lobe hepatocellular carcinoma. AB - AIM: To evaluate the short- and long-term outcomes of liver resection for caudate lobe hepatocellular carcinoma (HCC). METHODS: We retrospectively analyzed 114 consecutive patients with HCC, originating from the caudate lobe, who underwent resection between January 2001 and January 2007. Univariate and multivariate analyses were performed on several clinicopathologic variables to determine the factors affecting long-term outcome and intrahepatic recurrence. RESULTS: Overall mortality and morbidity were 0% and 18%, respectively. After a median follow-up of 31 mo (interquartile range, 11-66 mo), tumor recurrence had occurred in 76 patients (66.7%). The 1-, 3-, and 5-year disease-free survival rates were 65.7%, 38.1%, and 18.4%, respectively. The 1-, 3-, and 5-year overall survival rates were 76.1%, 54.7%, and 31.8%, respectively. Univariate analysis showed that subsegmental location of the tumor (45.7% vs 16.2%, P = 0.01), liver cirrhosis (12.3% vs 47.9%, P = 0.03), surgical margin (18.5% vs 54.6%, P = 0.04), vascular invasion (37.9% vs 23.2%, P = 0.04) and extended caudate resection (42.1% vs 15.4%, P = 0.04) were related to poorer long-term survival. Multivariate analysis showed that only subsegmental location of the tumor, liver cirrhosis and surgical margin were significant independent prognostic factors. CONCLUSION: Hepatectomy was an effective treatment for HCC in the caudate lobe. The subsegmental location of the tumor, liver cirrhosis and surgical margin affected long-term survival. PMID- 20205286 TI - Alterations of tumor-related genes do not exactly match the histopathological grade in gastric adenocarcinomas. AB - AIM: To investigate the diverse characteristics of different pathological gradings of gastric adenocarcinoma (GA) using tumor-related genes. METHODS: GA tissues in different pathological gradings and normal tissues were subjected to tissue arrays. Expressions of 15 major tumor-related genes were detected by RNA in situ hybridization along with 3' terminal digoxin-labeled anti-sense single stranded oligonucleotide and locked nucleic acid modifying probe within the tissue array. The data obtained were processed by support vector machines by four different feature selection methods to discover the respective critical gene/gene subsets contributing to the GA activities of different pathological gradings. RESULTS: In comparison of poorly differentiated GA with normal tissues, tumor related gene TP53 plays a key role, although other six tumor-related genes could also achieve the Area Under Curve (AUC) of the receiver operating characteristic independently by more than 80%. Comparing the well differentiated GA with normal tissues, we found that 11 tumor-related genes could independently obtain the AUC by more than 80%, but only the gene subsets, TP53, RB and PTEN, play a key role. Only the gene subsets, Bcl10, UVRAG, APC, Beclin1, NM23, PTEN and RB could distinguish between the poorly differentiated and well differentiated GA. None of a single gene could obtain a valid distinction. CONCLUSION: Different from the traditional point of view, the well differentiated cancer tissues have more alterations of important tumor-related genes than the poorly differentiated cancer tissues. PMID- 20205287 TI - Systematic review of D2 lymphadenectomy versus D2 with para-aortic nodal dissection for advanced gastric cancer. AB - AIM: To evaluate the feasibility and therapeutic effects of para-aortic nodal dissection (PAND) for advanced gastric cancer. METHODS: Randomized controlled trials (RCTs) and non-randomized studies comparing D2 + PAND with D2 lymphadenectomy were identified using a pre-defined search strategy. Five-year overall survival rate, post-operative mortality, and wound degree of surgery between the two operations were compared by using the methods provided by the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: Four RCTs (1120 patients) and 4 non-randomized studies (901 patients) were identified. Meta analysis showed that there was no significant difference between these two groups in 5-year overall survival rate [risk ratio (RR) 1.04 (95% CI: 0.93-1.16) for RCTs and 0.96 (95% CI: 0.83-1.10) for non-randomized studies] and post-operative mortality [RR 0.99 (95% CI: 0.44-2.24) for RCTs and 2.06 (95% CI: 0.69-6.15) for non-randomized studies]. There was a significant difference between these two groups in wound degree of surgery, operation time was significantly longer [weighted mean difference (WMD) 195.32 min (95% CI: 114.59-276.05) for RCTs and 126.07 min (95% CI: 22.09-230.04) for non-randomized studies] and blood loss was significantly greater [WMD 301 mL (95% CI: 151.55-450.45) for RCTs and 302.86 mL (95% CI: 127.89-477.84) for non-randomized studies] in D2 + PAND. CONCLUSION: D2 + PAND can be performed as safely as standard D2 resection without increasing post-operative mortality but fail to benefit overall survival in patients with advanced gastric cancer. PMID- 20205289 TI - Splenic lymphangiomatosis showing rapid growth during lactation: a case report. AB - Splenic lymphangiomatosis is a very rare condition that, from 1990 to date, has been described only nine times. In the present report, we describe the first case of splenic lymphangiomatosis with rapid growth during lactation in a 35-year-old woman. We also underline the difficultly in making an accurate preoperative diagnosis, despite more modern imaging techniques. Total splenectomy was considered to be the treatment needed, both to make a definitive diagnosis and to exclude the presence of malignancy. PMID- 20205288 TI - Hepatic arterial infusion of gemcitabine-oxaliplatin in a large metastasis from colon cancer. AB - Hepatic arterial infusion (HAI) of chemotherapy can be performed in cases of liver-confined metastatic disease, resulting in increased local drug concentrations. Here we report the case of a 61-year-old man who presented with an isolated large unresectable liver metastasis of colon cancer after failure of surgery and multiple administration of systemic chemotherapy. The patient was treated with a combination of gemcitabine and oxaliplatin using HAI. The tolerance was excellent and a radiological complete response was obtained after 8 cycles of HAI. The rationale for the use of gemcitabine and oxaliplatin as well as that for the combination of the 2 drugs is discussed in this paper. HAI of gemcitabine-oxaliplatin should be evaluated in further clinical trials. PMID- 20205290 TI - Transjugular intrahepatic portosystemic shunt with accidental diagnosis of persistence of the left superior vena cava. AB - Transjugular intrahepatic portosystemic shunt (TIPSS) is considered a valid therapeutic option for the treatment of portal hypertension and its complications. The guidelines for this procedure have already been established on the basis of the normal vascular anatomy and of various technical radiological aspects. In some few rare cases, diagnosis of a congenital vascular anomaly can be made accidentally by interventional radiologists, making the procedure of the TIPSS placement extremely difficult or in some cases technically impossible. This report describes a rare vascular malformation characterized by the absence of the right superior vena cava and persistence of the left superior vena cava in a patient with a diagnosis of advanced liver cirrhosis who needed a TIPSS placement in order to control refractory ascites. PMID- 20205291 TI - Simultaneous surgery for critical aortic stenosis and gastric cancer: a case report. AB - We describe simultaneous surgery performed on a 71-year-old woman with critical aortic stenosis and gastric cancer that were diagnosed at the same time. The patient qualified for simultaneous surgery for both these diseases. Good early outcome was achieved. There is a lack of standards for treatment of patients with coexistence of two life-threatening conditions. We discuss surgical tactics and potential benefits of such management. PMID- 20205293 TI - Interhemispheric motor cortex influence during bimanual unloading. AB - Using the transcranial magnetic stimulation (TMS) of motor cortex we examined changes in the motor evoked potential (MEP) during natural bimanual unloading, during lifting of an equivalent weight by the contralateral arm while the ipsilateral forearm was held stationary (CONTRA) and during practice of unnatural unloading. During natural unloading, MEP amplitude decreased proportionally to the muscle activity. In CONTRA task MEP amplitude decreased, but the muscle activity was not changed. It suggests that the motor cortex activity related to the "postural" arm was inhibited by the contralateral motor cortex related to the "lifting" arm. This inhibition was diminished during the unloading task. When learning the unnatural unloading, the muscle activity decreased significantly with insignificant changes of MEP amplitude. Active role of the motor cortex during learning of the new task might be related to the reduction of the contralateral inhibition. This suggestion is supported by the observation that MEP amplitude decreased stronger than muscle activity in the first learning session similar to that in CONTRA task. MEP amplitude and background activity of the muscle proportionally decreased in the last learning trial. The results show that motor cortex activity in natural and unnatural unloading task might be related to the reduction of the interhemispheric inhibition. PMID- 20205294 TI - Influence of simple verbal and non-verbal stimuli on brain electrical activity. AB - In this study, the influence of analysis stimulus content on the reaction time (RT) and parameters of the brain activity was investigated. Thirty healthy right handed volunteers (mean age 24 years) participated in the study. The dynamics of RT, characteristics of electroencephalogram (EEG) and event-related potentials (ERP) components during perception of digits and non-verbal stimuli were analyzed. The specificity of RT's asymmetry in simple and complex visual-motor reactions depended on stimulus type was revealed. The similarity of early ERP components (peak latency of 100-200 ms) for both stimuli types in simple and complex visual-motor reaction was shown. We also described the formation of specific ERP configuration for digits differentiation such as a left-sided asymmetry of component N200, and increase of peak latency of the late negative component with their extension to the parietal region. PMID- 20205292 TI - Ileocolonic mucormycosis in adult immunocompromised patients: a surgeon's perspective. AB - We report three cases of ileocolic mucormycosis in adult immunocompromised patients presenting as acute abdomen. All patients underwent laparotomy but two of them died from multiorgan failure before the diagnoses were confirmed. The diagnosis of gastrointestinal mucormycosis is rarely suspected, and antemortem diagnosis is made in only 25%-50% of cases. These cases illustrate the difficulty encountered by surgeons in managing acute abdomen in neutropenic patients with hematological malignancy. The management of colonic mucormycosis in the published literature is also reviewed. PMID- 20205295 TI - Laminar distribution of gap-junctions in rat somatic cortical columns. AB - Results about the spindle-like activity peculiarities and the dendro-dendritic gap-junctions numbers in the infragranular and supragranular layers (modules) of the rat somatic cortex columns are presented. During simultaneous recording of extracellular field potentials from the cortical columns, the following was revealed: (i) the spindle-like activity was more synchronized inside one cortical column than in different columns; (ii) in most of the experiments (9 out of 10) an amplitude of the spindle waves was two times more in the supragranular layers than in the infragranular layers. During electron microscopy investigation of the experimental objects used in the electrophysiological study, it was shown that the number of the gap-junctions was more in the supragranular columnar layers as compared with the infragranular layers (4.15% and 2.84% out of the total number of chemical synapses and gap-junctions identified in each module, respectively). The results obtained are discussed as possible structural base of the local electrotonic synchronization of the neuronal activity inside a cortical column. PMID- 20205296 TI - Cellular structures involved in the transport processes and neuroglial interactions in the crayfish stretch receptor. AB - In order to explore neuroglial relationships in a simple nervous system, the ultrastructure of crayfish stretch receptor, which consists of only two sensory neurons enveloped by satellite glial cells, was studied. Neuronal Golgi complex was oriented such that its output trans-Golgi network usually faced the bundles of microtubules within the neuronal cytoplasm and very rarely to the outer membrane. Therefore, it participates mainly in the processing of proteins transported along microtubules to distal neuron parts rather than those transported to glial cells. Structural triads of submembrane cisterns-vesicles mitochondria were involved in formation of glial protrusions into the neuronal cytoplasm. The double-wall vesicles within the neuron body were the captured parts of such glial protrusions. Glial protrusions and double-wall vesicles facilitated the neuroglial transport and large-scale delivery of the glial material into the neuron. The neuroglial transport could also be performed by diffusion across the intercellular space. These data indicate the significant neuroglial exchange with cellular components. PMID- 20205297 TI - Role of different dendrites in the functional activity of the central neuron controlling goldfish behavior. AB - The structural mechanisms that control the neuronal functional activity maintaining the brain functional asymmetry were studied using the relationship between the function and structure of goldfish Mauthner neurons (MNs) responsible for fish motor asymmetry as a model. It was shown for the first time that the dominant activity in one of the two counter neurons symmetrically situated in the medulla oblongata directly correlates with changes in its integral volume and is inversely regulated by the size of its ventral dendrite. It is known that the variability of the neuron dimensions is due to changes in the actin component of the cytoskeleton. The experimental data presented are discussed in terms of the involvement of cytosol actin in the control of the volume of somata and the main dendrites of MNs with the participation of dopamine and glutamate, two major neurotransmitters that are known to regulate the function of MNs. PMID- 20205298 TI - Principles of cellular-molecular mechanisms underlying neuron functions. AB - In the present work, it was experimentally shown that a neuron in vitro was capable of responding in a manner similar to habituation, Pavlov's reflex and avoidance of the reinforcements. The locality of plastic property modifications and molecular morphology, as well as the connection between functional activity and cytoskeleton have been revealed. A hypothesis is formulated that the neuron is a molecular system which may exercise the control, forecast, recognition, and classification. The basic principles of the molecular mechanisms of the responses underlying integrative activity, learning and memory at the neuronal level are discussed. PMID- 20205299 TI - N1 wave in the P300 BCI is not sensitive to the physical characteristics of stimuli. AB - One of the widely used paradigms for the brain-computer interface (BCI), the P300 BCI, was proposed by Farwell and Donchin as a variation of the classical visual oddball paradigm, known to elicit the P300 component of the brain event-related potentials (ERP). We show that this paradigm, unlike the standard oddball paradigm, elicit not only the P300 wave but also a strong posterior N1 wave. Moreover, we present evidence that the sensitivity of this ERP component to targets cannot be explained by the variations of the perceived stimuli energy. This evidence is based on comparing the ERP obtained for usual P300 BCI stimuli and for the "inverted" stimulation scheme with low stimulus related variations of light energy (gray letters on the light gray background, "highlighted" by very light darkening). Despite the dramatic difference between the stimuli in the standard and "inverted" schemes, no difference between N1 amplitudes were found, supporting the view that this component's sensitivity to targets cannot be based simply on "foveating" the target, but may be related to spatial attention mechanisms, which involvement is natural for the P300 BCI. Efforts to optimize the P300 BCI should address better use of both P300 and N1 waves. PMID- 20205300 TI - Temporal dynamics of fixation duration, saccade amplitude, and viewing trajectory. AB - The prospective goal of our study is a quantitative estimation of the contribution of various factors and mechanisms during image viewing. In this paper, experimental data about temporal dynamics of eye movement parameters and viewing trajectory are considered. Three images were presented to each subject (n = 12) under two experimental conditions: "free viewing of initial images" and "search for modified regions in previously presented images". Averaged fixation duration and saccade amplitude, as well as type of viewing trajectory were determined in each consequent period of trials having 30 fixation points. Viewing trajectories were classified into three types: (1) scanning, (2) grouped, and (3) mixed. In spite of individual variations (subject and image), several common peculiarities of temporal dynamics of image viewing were revealed. Specifically: (i) fixation duration in the first and last trial periods were less than during the second one; (ii) saccade amplitude had opposite dynamics; (iii) the scanning trajectories dominated in the first and last periods as compared with the second one; (iv) the mixed and grouped trajectories are more pronounced in the second period; (v) independent of their temporal consequence, the periods with maximal fixation duration differed from those with minimal duration by saccade amplitude and dominating viewing trajectories. PMID- 20205301 TI - How do bilinguals handle interhemispheric integration? Evidence from a cross language study. AB - The focus on interhemispheric interaction and integration has become a prominent aspect of laterality research. The aim of the present behavioral study was to determine whether hemisphere advantage differs between language groups. This was done by comparing how hemisphere advantage affects interhemispheric integration in monolingual and in bilingual individuals. Sixty university students (20 English monolinguals, 20 Hebrew bilinguals, and 20 balanced Arabic bilinguals) participated in two experiments, in which a lexical decision task was performed in the left and/or right visual field. Stimuli were presented unilaterally and bilaterally, whereby participants were cued to respond to the stimuli. In Experiment 1, all three groups showed an effect of lexicality, that is, participants responded to word stimuli faster than to non-word stimuli, with the Hebrew and Arabic groups showing a word advantage in spotting errors. In addition, all groups except the Hebrew group showed the expected right visual field advantage in accuracy, and the English group demonstrated this advantage in reaction time as well. In Experiment 2, responses to non-word stimuli were equally accurate in the left and right visual fields, but reaction time were faster for stimuli presented in the left visual field. The performance of balanced bilingual Arabic and unbalanced bilingual Hebrew reading groups was significantly better in the bilateral condition than in the unilateral condition. The results supported the notion that bilingual individuals show more effective interhemispheric communication and that they enjoy relative superiority in their interhemispheric processing in response to task demands. PMID- 20205303 TI - Identification of QTLs for yield and yield components of barley under different growth conditions. AB - Waterlogging is a major abiotic stress limiting barley (Hordeum vulgare L.) yield and its stability in areas with excessive rainfall. Identification of genomic regions influencing the response of yield and its components to waterlogging stress will enhance our understanding of the genetics of waterlogging tolerance and the development of more tolerant barley cultivars. Quantitative trait loci (QTLs) for grain yield and its components were identified using 156 doubled haploid (DH) lines derived from a cross between the cultivars Yerong (waterlogging-tolerant) and Franklin (waterlogging-sensitive) grown under different conditions (waterlogged and well drained). A total of 31 QTLs were identified for the measured characters from two experiments with two growth environments. The phenotypic variation explained by individual QTLs ranged from 4.74% to 55.34%. Several major QTLs determining kernel weight (KW), grains per spike (GS), spikes per plant (SP), spike length (SL) and grain yield (GY) were detected on the same region of chromosome 2H, indicating close linkage or pleiotropy of the gene(s) controlling these traits. Some different QTLs were identified under waterlogging conditions, and thus different markers may have to be used in selecting cultivars suitable for high rainfall areas. PMID- 20205302 TI - Review: Global nutrient profiling by Phenotype MicroArrays: a tool complementing genomic and proteomic studies in conidial fungi. AB - Conidial fungi or molds and mildews are widely used in modern biotechnology as producers of antibiotics and other secondary metabolites, industrially important enzymes, chemicals and food. They are also important pathogens of animals including humans and agricultural crops. These various applications and extremely versatile natural phenotypes have led to the constantly growing list of complete genomes which are now available. Functional genomics and proteomics widely exploit the genomic information to study the cell-wide impact of altered genes on the phenotype of an organism and its function. This allows for global analysis of the information flow from DNA to RNA to protein, but it is usually not sufficient for the description of the global phenotype of an organism. More recently, Phenotype MicroArray (PM) technology has been introduced as a tool to characterize the metabolism of a (wild) fungal strain or a mutant. In this article, we review the background of PM applications for fungi and the methodic requirements to obtain reliable results. We also report examples of the versatility of this tool. PMID- 20205304 TI - Catalytic ozonation-biological coupled processes for the treatment of industrial wastewater containing refractory chlorinated nitroaromatic compounds. AB - A treatability study of industrial wastewater containing chlorinated nitroaromatic compounds (CNACs) by a catalytic ozonation process (COP) with a modified Mn/Co ceramic catalyst and an aerobic sequencing batch reactor (SBR) was investigated. A preliminary attempt to treat the diluted wastewater with a single SBR resulted in ineffective removal of the color, ammonia, total organic carbon (TOC) and chemical oxygen demand (COD). Next, COP was applied as a pretreatment in order to obtain a bio-compatible wastewater for SBR treatment in a second step. The effectiveness of the COP pretreatment was assessed by evaluating wastewater biodegradability enhancement (the ratio of biology oxygen demand after 5 d (BOD(5)) to COD), as well as monitoring the evolution of TOC, carbon oxidation state (COS), average oxidation state (AOS), color, and major pollutant concentrations with reaction time. In the COP, the catalyst preserved its catalytic properties even after 70 reuse cycles, exhibiting good durability and stability. The performance of SBR to treat COP effluent was also examined. At an organic loading rate of 2.0 kg COD/(m(3)xd), with hydraulic retention time (HRT)=10 h and temperature (30+/-2) degrees C, the average removal efficiencies of NH(3)-N, COD, BOD(5), TOC, and color in a coupled COP/SBR process were about 80%, 95.8%, 93.8%, 97.6% and 99.3%, respectively, with average effluent concentrations of 10 mg/L, 128 mg/L, 27.5 mg/L, 25.0 mg/L, and 20 multiples, respectively, which were all consistent with the national standards for secondary discharge of industrial wastewater into a public sewerage system (GB 8978-1996). The results indicated that the coupling of COP with a biological process was proved to be a technically and economically effective method for treating industrial wastewater containing recalcitrant CNACs. PMID- 20205305 TI - Effects of 60-day NO2 fumigation on growth, oxidative stress and antioxidative response in Cinnamomum camphora seedlings. AB - OBJECTIVE: To study the oxidative stress and antioxidative response of Cinnamomum camphora seedlings exposed to nitrogen dioxide (NO(2)) fumigation. METHODS: Measurements were made up of the growth, chlorophyll content, chlorophyll fluorescence, antioxidant system and lipid peroxidation of one-year-old C. camphora seedlings exposed to NO(2) (0.1, 0.5, and 4 microl/L) fumigation in open top chambers over a period of 60 d. RESULTS: After the first 30 d, 0.5 and 4.0 microl/L NO(2) showed insignificant effects on the growth of C. camphora seedlings. However, exposure to 0.5 and 4.0 microl/L NO(2) for 15 d significantly reduced their chlorophyll content (P<0.05), enhanced their malondialdehyde (MDA) content and superoxide dismutase (SOD) activity (P<0.05), and also significantly reduced the maximal quantum yield of PSII in the dark [the ratio of variable fluorescence to maximal fluorescence (F(v)/F(m))] (P<0.05). In the latter 30 d, 0.5 microl/L NO(2) showed a positive effect on the vitality of the seedlings, which was reflected by a recovery in the ratio of F(v)/F(m) and chlorophyll content, and obviously enhanced growth, SOD activity, ascorbate (AsA) content and glutathione reductase (GR) activity (P<0.05); 4.0 microl/L NO(2) then showed a negative effect, indicated by significant reductions in chlorophyll content and the ratio of F(v)/F(m), and inhibited growth (P<0.05). CONCLUSION: The results suggest adaptation of C. camphora seedlings to 60-d exposure to 0.1 and 0.5 microl/L NO(2), but not to 60-d exposure to 4.0 microl/L NO(2). C. camphora seedlings may protect themselves from injury by strengthening their antioxidant system in response to NO(2)-induced oxidative stress. PMID- 20205306 TI - Effects of moniliformin and selenium on human articular cartilage metabolism and their potential relationships to the pathogenesis of Kashin-Beck disease. AB - OBJECTIVE: To investigate the effects of mycotoxin moniliformin (MON) on the metabolism of aggrecan and type II collagen in human chondrocytes in vitro and the relationship between MON and Kashin-Beck disease (KBD). METHODS: Human chondrocytes were isolated and cultured on bone matrix gelatin to form an artificial cartilage model in vitro with or without MON toxin. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The expression of aggrecan and type II collagen in the cartilage was determined using immunocytochemical staining. RESULTS: MON toxin inhibited chondrocyte viability in dose-dependent and time-dependent manners. MON reduced aggrecan and type II collagen syntheses in the tissue-engineered cartilage. MON also increased the expression of matrix metalloproteinase-1 (MMP-1), MMP-13, BC4 epitopes, and CD44 in cartilages. However, the expression of 3B3(-) epitopes in cartilages was inhibited by MON. Selenium partially alleviated the damage of aggrecan induced by MON toxin. CONCLUSION: MON toxin promoted the catabolism of aggrecan and type II collagen in human chondrocytes. PMID- 20205308 TI - Case Report: Recurrent severe vomiting due to hyperthyroidism. AB - Thyrotoxicosis may present in many ways; severe vomiting as a prominent symptom of thyrotoxicosis is uncommon. In this paper, we report a 24-year-old Chinese male with hyperthyroidism who presented with recurrent severe vomiting. The patient had had intermittent vomiting for seven years and had lost approximately 15 kg of weight. Gastroscopic examinations revealed chronic gastritis and one occasion peptic ulcer. He was treated with antacid and proton pump inhibitors, but his symptoms had no relief. His presenting symptoms suggested hyperthyroidism and were confirmed by laboratory data. After a month of propylthiouracil therapy, his symptoms were relieved. It should be noted that hyperthyroidism patients can have unexplained vomiting, and that hyperthyroidism may coexist with peptic ulcer in rare cases. Awareness of such atypical presentations of hyperthyroidism may help to make a correct diagnosis. PMID- 20205307 TI - Psychosocial impact of mothers with perinatal loss and its contributing factors: an insight. AB - OBJECTIVE: To evaluate the psychosocial impact among mothers with perinatal loss and its contributing factors. METHODS: A cross sectional study was conducted in University Kebangsaan Malaysia Medical Centre (UKMMC) from April 2008 to May 2009 using Edinburgh Postnatal Depression Scale (EPDS) and self administered questionnaire. RESULTS: Sixty-two respondents were included and most of them were working mothers (77.4%). The mean age of the respondents was (31.0+/-5.6) years and a majority of the subjects aged between 20-34 years (77.4%). According to the EPDS score, 53.2% of the respondents had a psychosocial impact with a total score of >9, out of 30. There was a significant relationship between psychosocial impact after perinatal loss and support from friends (P=0.019). However, there were no significant differences between psychosocial impact and history of previous perinatal loss, ethnicity, occupation, educational level, age or total income. CONCLUSION: Mothers with perinatal loss should be screened for psychosocial impact and offered support when needed. Family and friends should continue to provide emotional support. People who have experienced similar problem before will be able to provide better support than those who have not. PMID- 20205310 TI - [Diagnosis and treatment of kidney disease with renal failure. Proceedings of a meeting. November 8-10, 2007. Grado, Italy]. PMID- 20205309 TI - Science letters: Proteomic analysis of differentially expressed proteins in mice with concanavalin A-induced hepatitis. AB - OBJECTIVE: To find new protein biomarkers for the detection and evaluation of liver injury and to analyze the relationship between such proteins and disease progression in concanavalin A (Con A)-induced hepatitis. METHODS: Twenty-five mice were randomly divided into five groups: an untreated group, a control group injected with phosphate buffered saline (PBS), and groups with Con A-induced hepatitis evaluated at 1, 3 and 6 h. Two-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS) were used to identify differences in protein expression among groups. Quantitative real-time polymerase chain reaction (qRT PCR) was performed to verify the results. RESULTS: In mice with Con A-induced hepatitis, expression levels of four proteins were increased: RIKEN, fructose bisphosphatase 1 (fbp1), ketohexokinase (khk), and Chain A of class pi glutathione S-transferase. Changes in fbp1 and khk were confirmed by qRT-PCR. CONCLUSION: Levels of two proteins, fbp1 and khk, are clearly up-regulated in mice with Con A-induced hepatitis. PMID- 20205311 TI - [Preventions in nephrology, dialysis and kidney transplantation. Proceedings of the 4th Mantua Meeting. June 10-11, 2006. Mantova, Italy]. PMID- 20205313 TI - Proceedings of the 2nd International Symposium on Optimization and Systems Biology (OSB 2008). October 31-November 3, 2008. Lijiang, China. PMID- 20205312 TI - [Prevention in nephrology, dialysis and kidney transplantation. Proceedings of the 5th Conference. May 23-24, 2008. Mantova, Italy]. PMID- 20205314 TI - Proceedings of the 14th International Congress on Molecular Plant-Microbe Interactions. Quebec City, Quebec, Canada. July 19-23, 2009. PMID- 20205315 TI - Insects and illnesses: contributions of the history of medical entomology. Proceedings of a conference in three sessions: London, April 2005; Paris, April 2006; Rome, October 2007. PMID- 20205316 TI - Radioiodine therapy a successful tool in treating thyroid cancer. Foreword. PMID- 20205317 TI - Acquired reactive perforating collagenosis: a clinicopathologic study of 15 cases from Saudi Arabia. AB - BACKGROUND: Perforating dermatoses include a family of disease characterized by transepidermal elimination of collagen. Despite being described many years ago in association with systemic disease, it is still clinically misdiagnosed. OBJECTIVE: A retrospective clinical and pathologic review that will increase clinical and pathologic diagnostic awareness of this entity and explore associated systemic disease. PATIENTS AND METHODS: In this report, we present from Saudi Arabia for the first time details of a series of patients seen at the King Abdulaziz Medical City, WR, Jeddah, Saudi Arabia, during the period 2002 2009. RESULTS: The study revealed 15 histologically confirmed cases of acquired reactive perforating collagenosis (ARPC). Patients were predominantly adult females with a mean age of 54 years. The lesions were pruritic, predominantly multiple, erythematous excoriated papules and umblicated nodules centrally crusted with an average duration of 6 months, involving the extremities with or without the trunk in 12 patients. Associated systemic disease included diabetes mellitus in 12 patients and chronic renal failure on dialysis in 8 patients. The provisional clinical differential diagnosis included perforating collagenosis in only eight patients. CONCLUSION: ARPC is not uncommon in Saudi Arabia. The noduloulcerative lesions involve predominantly the extremities, and diabetes mellitus is the most common associate. It is hoped that this article will increase awareness for recognition of this entity to start appropriate therapy. PMID- 20205318 TI - Comment on Hedayati, et al. PMID- 20205319 TI - Study on association between polymorphism of HLA-DRB1 alleles and Behcet's disease. AB - BACKGROUND: Behcet's disease (BD) is known to be associated with human leucocyte antigen (HLA)-B*51 in many ethnic groups. However, the association of HLA class II gene with BD has been described to be different according to different countries and regions. OBJECTIVE: This study aims to investigate the association between polymorphism of HLA-DRB1 alleles and BD. METHODS: Forty patients with BD and 100 healthy controls were typed for HLA-DRB1 alleles by the LABType SSO method. RESULTS: The frequency of HLA-DRB1*14 was significantly higher in BD patients than in controls (P < 0.05), while the frequency of HLA-DRB1*15 was markedly lower in BD patients (P < 0.05). Regarding clinical manifestations, the frequency of HLA-DRB1*15 was significantly decreased in BD patients with genital ulcerations compared with controls (P < 0.05); the frequency of HLA-DRB1*14 was significantly increased in BD patients with erythema nodosum-like lesions and in BD patients with folliculitis-like lesions when compared to controls (P < 0.05, respectively). Moreover, the frequency of HLA-DRB1*14 was significantly increased in BD patients under 20 years of age at the onset of disease (P < 0.01), while the frequency of HLA-DRB1*15 was significantly decreased in them (P < 0.05), compared with controls. CONCLUSION: The results suggested that HLA-DRB1 alleles might play an important role in the onset and clinical manifestations of BD. PMID- 20205320 TI - [Multicentre study "Epidemiology of gastroesophageal reflux disease in Russia"(MEGRE): first results]. AB - We aimed to determine the prevalence and clinical spectrum of GERD in the urban population of 6 cities in different parts of Russia (St. Petersburg, Ryazan, Kazan, Kemerovo, Krasnoyarsk and Saransk). A previously validated reflux questionnaire developed at the Mayo Clinic was translated into Russian, culturally adapted and administered. Data was collected from 7812 randomly selected subjects greater than 18 years old with the assistance of the yellow pages. 'Frequent symptoms' were defined as a major symptom (heartburn and/or regurgitation) occurring at least once a week or more. "Occasional symptoms" were defined as an episode of one of the major symptoms occurring less than once a week within the past 12 months. Patients were defined as having GERD if they reported frequent heartburn and/or regurgitation. The average prevalence of frequent and occasional GERD symptoms in Russia was 9% and 38.5% for heartburn and 7.6% and 35.3% for regurgitation respectively within the last 12 months. The average prevalence of GERD in Russia was 13.3% (11.3-14.3%). The prevalence of frequent heartburn decreased with age (r = -0.3); however, frequent regurgitation increased (r = 0.7) with age. As a result, we found that prevalence of GERD increased with age. The average prevalence of GERD was statistically the same in men (12.5%) and in women (13.9%). This prevalence didn't change with age in men but did increase with age in elderly women to 24%. Frequent heartburn and regurgitation (GERD) were significantly associated with frequent belching (24.3%), chronic cough (22.9%), dyspepsia (19.8%), non-cardiac chest pain (15.1%), nausea (14.9%), hoarseness (11.4%), dysphagia (8.1%), odynophagia (7.3%) and constipation (37.8%). Alcohol consumption (prevalence of 60.4% among respondents) and smoking (prevalence of 25.4% among respondents) didn't yield any significant difference in subjects with frequent symptoms. Importantly, we also found that only 52.8% of subjects with frequent chest pain and 29.3% of respondents with frequent heartburn had seen a physician for these symptoms. PMID- 20205321 TI - [Anorexia like severe extraintestinal diseases manifestations]. AB - Patients with intra- and extrabowel diseases often have severe malnutrition as result of anorexia neuropsychica. The first investigators of this problem were W. Gull, Lasegue et al. There are clinical symptoms and phases, different diagnostic and treatment of such type of anorexia discribe in the article. PMID- 20205322 TI - [Electrophysiological evaluation of effectiveness of enteral nutritional therapy at bowel diseases]. AB - The enteral nutritional therapy for patients with Crohn disease in postoperative period, as well as with left-sided colon resection and right colon resection was assessed. The electromotor activity of the colon was examined before and after the Klinipit and the Mucofalk administration. The colon alterations correspond the intestinal failure clinical symptoms. This has been confirmed that the method of electromyography may be recommended for the noninvasive assessment of enteral nutrition therapy of patients with colon hemicolectomy. PMID- 20205323 TI - [Effectively of combined farmaconutritive and surgical treatment of colorectal cancer]. AB - In this article the role of immunoregulative system and cellular genome (p53 and sFAS/FASL) pathology biomarkers and oncological markers (cancer fetal antigene and CA19-9) was estimated in results of surgical treatment in complex with the various kinds of a clinical nutrition in the early postoperative period after colon cancer. PMID- 20205324 TI - [Correction of protein-energy metabolism in hepatorenal failure in surgical patients]. AB - Infringements of a protein-energetic metabolism in hepatorenal complications are an actual problem in urgent surgery. 358 patients with a acute surgical pathology of intestines were analyzed, in 27.4% of patients infringements of functions of a liver and kidneys were revealed, necessity for normalization of the protein energetic metabolism was noted in 47-70% of cases. As a result the scheme for protein-energetic metabolism correction was specified in depending of a kind of intestinal impassability and a degree of severity of surgical disease. The early correction of a protein-energetic metabolism in complex with the extracorporeal support methods of a detoxication has provided the expressed positive clinical effect. PMID- 20205325 TI - [Optimization of treatment of patients with diseases associated with Helicobacter pylori infection: justifying of bismuth preparations using]. PMID- 20205326 TI - [Application of allogeneic mesenchymal stem cells in complex patients treatment with ulcerative colitis]. AB - Systemic transplantation of mesenchymal stem cells (MSC) is known to promote reparative process in a number of tissue damage as well as mucous healing one. It provided the basis for our study which was aimed to the effect of systemic transplantation of allogenic MSC (intravenous transfusion) in complex therapy of patients with Ulcerative Colitis. PMID- 20205327 TI - [Expression of proliferation and apoptosis markers in neoplasms of colon mucosa after cholecystectomy]. AB - The cholecystectomy results in change of cholic acids flow into intestine. Permanent type of the bile flow provokes the increase of proliferation of colic epithelial cells and increases the risk for development of right-sided colorectal tumors. Meanwhile morphological features of colorectal tumors at the patients with cholecystectomy are still remaining to be clarified. The goal of the study was to investigate immunohistochemical markers of proliferation and apoptosis in colorectal adenomas and adenocarcinomas at the patients with cholecystectomy. Fifty patients (40 with retained function of gallbladder and 10 patients with cholecystectomy) histologically diagnosed as proximal colon adenoma or adenocarcinoma were included into the study. Colonoscopic biopsies have been taken from the lesion in cancer patients, and colonoscopic polypectomy has been performed for adenomas. In addition, biopsies have been taken from the adjacent healthy colon mucosa at least 5 cm from the lesion in each patient. 83 tumors and 49 samples of mucosa were immunostained with monoclonal mouse anti-human p53 protein (Dako) and monoclonal mouse anti-human Ki-67 antigen (Novocastra). The index of Ki-67 expression in healthy colon mucosa at the patients with cholecystectomy was 37,5 +/- 1,8% (p < 0,05) as compared to 31,36 +/- 1,9 at the patients without cholecystectomy. No significant difference was detected in the comparison of Ki-67 expression levels between the healthy mucosa and adenomas at the patients with cholecystectomy 43,4 +/- 3,45 (p > 0,05), but more prominent increase was revealed in adenocarcinomas 64,33 +/- 7,67% (p < 0,01). Protein p53 expression in healthy mucosa at the patients with a cholecystectomy was at the same level as at the patients without cholecystectomy (37%). At the patients without cholecystectomy the frequency of revealing p53 in adenomas does not vary, compared with healthy mucosa, however in adenocarcinomas p53 was not revealed at none case. As a contrast, in group of the patients with cholecystectomy the frequency of revealing p53 in adenomas is considerably increased (up to 80%), and even in adenocarcinomas, p53 was revealed in 30,8% of cases. Thus, in benign colorectal tumors at the patients with retained function of gallbladder intensifying of epithelial cells proliferation is not accompanied with intensifying of apoptosis, and in malignant tumors a complete supression of apoptosis is observed. At the patients with a cholecystectomy, the increase of proliferative activity is accompanied by increased apoptosis in adenomas and maintained apoptosis in adenocarcinomas. The retaining of apoptosis in colorectal tumors compensates intensive proliferative activity with expectation of better prognosis. PMID- 20205328 TI - [Some pathogenic aspects of intestinal manifestations in postcholecystectomy syndrome]. AB - Digestive/absorptive function of small intestine was determined using loading tests in postcholecystectomy patients. Disturbances of both uptaking/excretory liver function and biochemical composition of hepatic bile in patients with early and late terms after cholecystectomy were studied. Interactions between the disturbances in hepatobiliary system and the small intestine as well as their influence on the pathogenesis of PCES were estimated. PMID- 20205329 TI - [Usage of Nexium (ezomeprazole) at children with acid depended inflammatory diseases of upper gastrointestinal tract]. PMID- 20205330 TI - [Pepsin-R clinical efficacy in patients with adverse endoscopic GERD]. PMID- 20205331 TI - [Adalimumab therapy in Crohn's disdease]. AB - In spite of using biologic agents for treatment of Crohn's disease (CD), the problem of therapy of CD hasn't been resolved yet. As was shown, approximately 60% patients can't continue treatment with Infliximab because of its primary non response or secondary loss of response or intolerance. The fully-human monoclonal antibody against tumor necrosis factor-alpha (TNF-alpha), Adalimumab, was significantly effective in randomized placebo-controlled studies for induction remission and for maintaining therapy of CD as well. The drug proved to be effective in patient with previous Infliximab experience, independently of the cause of failure treatment. PMID- 20205332 TI - [Innovations in the postanalytical phase in clinical biochemistry. Functional heterogeneity of the arterial bed and pathogenesis of essential hypertension]. AB - Early in phylogenesis during formation of paracrine-regulated communities of cells--the structural and functional units of future organs--each of them comprised a pool of specialized cells, interstitial tissue elements, and a local peristaltic pump. The pump within the community fulfilled the biological functions of homeostasis and the endoenvironment (intercellular environment purity). This community is, say, the nephron that consists of a renal capillary, interstitial tissue, and an afferent arteriole. The renal capillary cells regulate the activity of a muscle arteriole (a local pump) on the basis of glomerulotubular direct coupling and feedback to give rise to municipal regulation. Later on, the heart and elastic arteries pooled million local peristaltic pumps that operated over ages. Phylogenetically, the arterial bed comprises two portions: proximal (the heart + elastic arteries) and distal (muscle arterioles). Regulation of the proximal arterial bed takes place at the federal level; this is accomplished by the vasomotor center via sympathetic and parasympathetic innervation. Control of the distal arterial bed, the peripheral peristaltic pumps, is exercised by municipal regulation at the level of paracrine communities. When the biological functions of homeostasis and the endoenvironment are realized, federal regulation comes into conflict with municipal one; this imbalance is implicated in the pathogenesis of essential hypertension. Blood pressure measurement provides data on the state of the proximal arterial bed and the endothelium-dependent vasodilation test characterizes the state of the distal portion and that of peripheral peristaltic pumps and muscle arterioles. Confrontation of federal and municipal regulations in the nephron paracrine community is a principal cause of arterial hypertension, glomerulosclerosis, or tubulointerstitial inflammation. PMID- 20205333 TI - [The free radical oxidation and antioxidant defense systems as indicators of the activity of keratinocytic proliferation in psoriasis]. AB - The free radical oxidation and antioxidant defense (AOD) systems in the keratinocyte cultures were studied in patients with psoriasis before and after the use of combinations of liposomal preparations. Hyperproliferation of keratinocytes was found to be attended by suppressed lipid peroxidation and high cell antioxidant activity. On the contrary, the liposomal combinations-induced suppression of cell proliferation was characterized by a drastic increase in prooxidant activity in reference to the AOD of epidermal keratinocyte cultures. PMID- 20205334 TI - [Determination of the Willebrandt factor antigen by immunoenzyme technique]. AB - The purpose of the study was to determine the normal values of Willebrandt factor antigen (WF:Ag) in accordance with AB0 blood group affiliation and to compare the results of its determination when two test systems were used. Ninety-four plasma samples from healthy individuals aged 18 to 62 years (median 38) were tested. The test systems manufactured by Technoclone and Axis-Shield were employed. In the samples from blood group 0 subjects, the level of WF:Ag was significantly lower than that in those from blood group A, B, and AB subjects (p < 0.05). There were no significant differences in the determination results between blood groups A, B, and AB subjects (p > 0.05). Great discrepancies were found in the results of some tests when WF:Ag was determined using various test systems. This is accountable to different specificity of the anti-WF antibodies obtained by various manufacturers. Nevertheless, the revealed differences, the lower normal ranges calculated from the results obtained using these test systems agree and no great differences were found between the samples (p > 0.05). Therefore, both test systems have the equal value in the diagnosis of Willebrandt disease. PMID- 20205335 TI - [High-frequency electrosurgical apparatuses with a low-temperature plasma generation mode]. PMID- 20205336 TI - [Use of terahertz electromagnetic waves for correcting the hemostasis functions]. PMID- 20205337 TI - [A stroke volume monitoring device for electrophysiological systems]. PMID- 20205338 TI - [Technological and metrological issues in measuring arterial pressure by the oscillometric technique]. PMID- 20205340 TI - [A system for studying specific features of attention and memory]. PMID- 20205339 TI - [A software-hardware system for correction of pronounced internal organ dysfunctions based on the analysis of the rhythmic activity of the brain]. PMID- 20205341 TI - [In 2010, let us consolidate what we have acquired!]. PMID- 20205342 TI - [Aging of the population and transfer of competencies]. PMID- 20205343 TI - [Changing the social attitude to cancer]. PMID- 20205344 TI - Proceedings of biomolecular dynamics and protein-water interactions-a neutron scattering workshop. September 2008. Feldafing, Germany. PMID- 20205345 TI - Potential clinical and economic impact of nonadherence with osteoporosis medications. AB - This study aims to estimate the potential clinical and economic implications of therapeutic adherence to bisphosphonate therapy. A validated Markov microsimulation model was used to estimate the impact of varying adherence to bisphosphonate therapy on outcomes (the number of fractures and the quality adjusted life-years [QALYs]), health-care costs, and the cost-effectiveness of therapy compared with no treatment. Adherence was divided into persistence and compliance, and multiple scenarios were considered for both concepts. Analyses were performed for women aged 65 years with a bone mineral density T-score of 2.5. Health outcomes and the cost-effectiveness of therapy improved significantly with increasing compliance and/or persistence. In the case of real-world persistence and with a medical possession ratio (MPR; i.e., the number of doses taken divided by the number of doses prescribed) of 100%, the QALY gain and the number of fractures prevented represented only 48 and 42% of the values estimated assuming full persistence, respectively. These proportions fell to 27 and 23% with an MPR value of 80%. The costs per QALY gained, for branded bisphosphonates (and generic alendronate), were estimated at 19,069 euros (4,871 euros), 32,278 euros (11,985 euros), and 64,052 euros (30,181 euros) for MPR values of 100, 80, and 60%, respectively, assuming real-world persistence. These values were 16,997 euros (2,215 euros), 24,401 euros (6,179 eruos), and 51,750 euros (20,569 euros), respectively, assuming full persistence. In conclusion, poor compliance and failure to persist with osteoporosis medications results not only in deteriorating health outcomes, but also in a decreased cost-effectiveness of drug therapy. Adherence therefore remains an important challenge for health-care professionals treating osteoporosis. PMID- 20205347 TI - Frequency, prevention, outcome and treatment of ventilator-associated tracheobronchitis: systematic review and meta-analysis. AB - OBJECTIVE: To clarify issues regarding the frequency, prevention, outcome, and treatment of patients with ventilator-associated tracheobronchitis (VAT), which is a lower respiratory tract infection involving the tracheobronchial tree, while sparing the lung parenchyma. METHODS: We performed a systematic review and meta analysis of relevant available data, gathered though searches of PubMed, Scopus, and reference lists, without time restrictions. A conservative random effects model was used to calculate pooled odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Out of the 564 initially retrieved articles, 17 papers were included. Frequency of VAT was 11.5%. Selective digestive decontamination was not proved an effective preventive strategy against VAT (OR: 0.62, 95% CI: 0.31e1.26). Presence, as opposed to the absence, of VAT was not associated with higher attributable mortality (OR: 1.02, 95% CI: 0.57e1.81). Administration of systemic antimicrobials (with or without inhaled ones), as opposed to placebo or no treatment, in patients with VAT was not associated with lower mortality (OR: 0.56, 95% CI: 0.27e1.14). Most of the studies providing relevant data noted that administration of antimicrobial agents, as opposed to placebo or no treatment, in patients with VAT was associated with lower frequency of subsequent pneumonia and more ventilator-free days, but without shorter length of intensive care unit stay or shorter duration of mechanical ventilation. CONCLUSIONS: Approximately one tenth of mechanically ventilated patients suffer from VAT. Antimicrobial treatment of patients with VAT may protect against the development of subsequent ventilator-associated pneumonia and improve weaning outcome. PMID- 20205348 TI - CYP2D6 polymorphism screening in a selected population of Spain (La Alpujarra): no effect of geographical isolation. AB - BACKGROUND: There is growing interest in the CYP2D6 gene because of its key role in the metabolism of numerous commonly used drugs. AIM: We compared the frequency of the most frequent null CYP2D6 alleles (CYP2D6*3, CYP2D6*4,CYP2D6*5, CYP2D6*6, CYP2D6*7 and CYP2D6*8) between individuals from the Spanish population and from La Alpujarra. SUBJECTS AND METHODS: The present study comprises Spanish cohort (n = 185) and from La Alpujarra (n = 104). The latter is a small mountainous region of Spain that shows a remarkable degree of geographical and cultural isolation. We genotyped six polymorphisms in the coding region of the CYP2D6 gene, i.e. five single nucleotide polymorphisms (SNP) (CYP2D6*3, CYP2D6*4, CYP2D6*6,CYP2D6*7 and CYP2D6*8) and one deletion (CYP2D6*5). RESULTS: No significant differences were observed between groups in allelic and genotype distributions of the aforementioned variants. The total frequency of functional alleles was comparable between the two groups (79% and 81.3% in controls and La Alpujarra, respectively). CONCLUSION: Despite demographic and cultural isolation in La Alpujarra, the distribution of CYP2D6 polymorphisms in inhabitants of this area is similar to that reported in the rest of Spain. At present, there seems to be little allele heterogeneity in CYP2D6 amongst different European populations (e.g., amongst different Spanish populations) that have shown diversity in other loci. PMID- 20205346 TI - Influence of lifestyle factors on quantitative heel ultrasound measurements in middle-aged and elderly men. AB - We examined the distribution of quantitative heel ultrasound (QUS) parameters in population samples of European men and looked at the influence of lifestyle factors on the occurrence of these parameters. Men aged between 40 and 79 years were recruited from eight European centers and invited to attend for an interviewer-assisted questionnaire, assessment of physical performance, and quantitative ultrasound (QUS) of the calcaneus (Hologic; Sahara). The relationships between QUS parameters and lifestyle variables were assessed using linear regression with adjustments for age, center, and weight. Three thousand two hundred fifty-eight men, mean age 60.0 years, were included in the analysis. A higher PASE score (upper vs. lower tertile) was associated with a higher BUA (beta coefficient = 2.44 dB/ Mhz), SOS (beta = 6.83 m/s), and QUI (beta = 3.87). Compared to those who were inactive, those who walked or cycled more than an hour per day had a higher BUA (beta = 3.71 dB/Mhz), SOS (beta = 6.97 m/s), and QUI (beta = 4.50). A longer time to walk 50 ft was linked with a lower BUA (beta = 0.62 dB/ Mhz), SOS (beta = -1.06 m/s), and QUI (beta = -0.69). Smoking was associated with a reduction in BUA, SOS, and QUI. There was a U-shaped association with frequency of alcohol consumption. Modification of lifestyle, including increasing physical activity and stopping smoking, may help optimize bone strength and reduce the risk of fracture in middle-aged and elderly European men. PMID- 20205349 TI - Long-pulsed dye laser vs. intense pulsed light for the treatment of facial telangiectasias: a randomized controlled trial. AB - OBJECTIVE: This study aims to compare the efficacy and adverse effects of long pulsed dye laser (LPDL) and intense pulsed light (IPL) in the treatment of facial telangiectasias. METHODS: We used intra-individual, randomized, controlled trial with split-face treatments and single-blind outcome evaluations in this study. Forty patients with symmetrically located facial telangiectasias received a series of three LPDL (V-beam, 595 nm, Candela Laser Corp.) and three IPL treatments (Ellipse Flex, PR and VL2 applicators, Danish Dermatologic Development) at 6-week intervals. Patients were evaluated 3 months after the final treatment. Outcome measures were clinical efficacy (five-point ordinal scale), pain (10-point numerical scale), adverse effects, patient satisfaction (10-point numerical scale) and preferred treatment. RESULTS: Thirty-nine of 40 patients completed the study. All but 2 patients obtained a reduction in facial telangiectasias from both IPL and LPDL treatments. Both treatments were effective with good or excellent response in 30 of 39 patients. The LPDL was superior in the overall reduction of telangiectasias by blinded photographic evaluations: Excellent clearance (75% to 100% vessel clearance) was found in 18 patients treated with LPDL (46%) and in 11 patients treated with IPL (28%) (P = 0.01). Patients experienced less pain from LPDL [4 (2-6)] than IPL treatments [7 (3-9)] (P < 0.001). No adverse effects (hypo-/hyperpigmentation or scarring) were seen from any of the treatments. Patients were satisfied with both LPDL [8 (2-10)] and IPL treatments [7 (2-10)] (P = 0.05). Twenty-five patients preferred the LPDL (64%), 8 patients preferred IPL (21%) and 6 patients had no preference (15%) (P < 0.001). CONCLUSION: This study was based on two specific types of laser and IPL equipment, which effectively clear telangiectasias; however, the most beneficial outcome was from the LPDL. PMID- 20205350 TI - Comparison of diffusion-weighted whole body MRI and skeletal scintigraphy for the detection of bone metastases in patients with prostate or breast carcinoma. AB - PURPOSE: To prospectively compare the diagnostic accuracy of diffusion-weighted whole body imaging with background whole body signal suppression (DWIBS) with skeletal scintigraphy for the diagnosis and differentiation of skeletal lesions in patients suffering from prostate or breast cancer. MATERIAL AND METHODS: A diagnostic cohort of 36 patients was included in skeletal scintigraphy and 1.5 T DWIBS MRI. Based on morphology and signal intensity patterns, two readers each identified and classified independently, under blinded conditions, all lesions into three groups: (1) malignant, (2) unclear if malignant or benign and (3) benign. Finally, for the definition of the gold standard all available imaging techniques and follow-up over a minimum of 6 months were considered. RESULTS: Overall, 45 circumscribed bone metastases and 107 benign lesions were found. DWIBS performed significantly better in detecting malignant skeletal lesions in patients with more than 10 lesions (sensitivity: 0.97/0.91) compared to skeletal scintigraphy (sensitivity: 0.48/0.42). No statistical difference could be found between DWIBS (0.58/0.33) and skeletal scintigraphy (0.67/0.58) in the sensitivity values for malignant skeletal lesions in patients with less than 5 lesions. For benign lesions, scintigraphy scored best with a sensitivity of 0.93/0.87 compared to 0.20/0.13 for DWIBS. Interobserver agreement with Cohen's kappa coefficient was calculated as 0.784 in the case of scintigraphy and 0.663 for DWIBS. CONCLUSION: With respect to staging, in prostate and breast carcinoma, the DWIBS technique is not superior to skeletal scintigraphy, but ranks equally. However, in the cases with many bone lesions, markedly more metastases could be discovered using the DWIBS technique than skeletal scintigraphy. PMID- 20205351 TI - Magnetic resonance imaging, ultrasound and real-time ultrasound elastography of the thigh muscles in congenital muscle dystrophy. AB - Congenital muscle dystrophy includes a range of genetic disorders characterized by muscle weakness and contractures. We report the magnetic resonance (MR), ultrasound (US) and real-time sonoelastography (RTE) imaging findings of the thigh muscles of a 15-year-old boy with Bethlem myopathy diagnosed with clinical, electromyographic and histopathological criteria. Ultrasound and MR showed hyperechoic appearance and high signal intensity on T1- and T2-weighted sequences respectively at the periphery of the vastus lateralis and the long head of the biceps femoris muscles, and at a central area within the rectus femoris muscles. RTE was employed to examine the elastic properties of the muscle. The elastograms were presented as colour-coded maps superimposed on the B-mode images and revealed that the elastographic pattern correlated with the MR and US pattern of involvement. The abnormal muscle areas were stiffer (blue) than the normal appearing areas (green), a finding that probably correlates with the presence of dystrophic collagen at the affected areas. This report suggests that RTE could be used as an additional imaging tool to evaluate the pattern of muscle changes in congenital myopathy. Further studies are needed to investigate the specificity and clinical value of RTE in the diagnosis and monitoring of neuromuscular disease. PMID- 20205352 TI - Reconciling stochastic origin firing with defined replication timing. AB - Eukaryotic chromosomes replicate with defined timing patterns. However, the mechanism that regulates the timing of replication is unknown. In particular, there is an apparent conflict between population experiments, which show defined average replication times, and single-molecule experiments, which show that origins fire stochastically. Here, we provide a simple simulation that demonstrates that stochastic origin firing can produce defined average patterns of replication firing if two criteria are met. The first is that origins must have different relative firing probabilities, with origins that have relatively high firing probability being likely to fire in early S phase and origins with relatively low firing probability being unlikely to fire in early S phase. The second is that the firing probability of all origins must increase during S phase to ensure that origins with relatively low firing probability, which are unlikely to fire in early S phase, become likely to fire in late S phase. In addition, we propose biochemically plausible mechanisms for these criteria and point out how stochastic and defined origin firing can be experimentally distinguished in population experiments. PMID- 20205353 TI - Genome-wide analysis of the replication program in mammals. AB - Microarray technology has facilitated the research of eukaryotic DNA replication on a genome-wide scale. Recent studies have shed light on the association between time of replication and chromosome structure, on the organization principles of the replication program, and on the correlation between replication timing and transcription. In this review, we summarize various genomic measurement approaches and the biological insights achieved through applying them in the study of the mammalian replication program. PMID- 20205354 TI - Mathematical modelling of eukaryotic DNA replication. AB - Eukaryotic DNA replication is a complex process. Replication starts at thousand origins that are activated at different times in S phase and terminates when converging replication forks meet. Potential origins are much more abundant than actually fire within a given S phase. The choice of replication origins and their time of activation is never exactly the same in any two cells. Individual origins show different efficiencies and different firing time probability distributions, conferring stochasticity to the DNA replication process. High-throughput microarray and sequencing techniques are providing increasingly huge datasets on the population-averaged spatiotemporal patterns of DNA replication in several organisms. On the other hand, single-molecule replication mapping techniques such as DNA combing provide unique information about cell-to-cell variability in DNA replication patterns. Mathematical modelling is required to fully comprehend the complexity of the chromosome replication process and to correctly interpret these data. Mathematical analysis and computer simulations have been recently used to model and interpret genome-wide replication data in the yeast Saccharomyces cerevisiae and Schizosaccharomyces pombe, in Xenopus egg extracts and in mammalian cells. These works reveal how stochasticity in origin usage confers robustness and reliability to the DNA replication process. PMID- 20205355 TI - Urinary biomarker of oxidative stress in patients with psoriasis vulgaris and atopic dermatitis. AB - BACKGROUND: The involvement of oxidative stress in the pathogenesis of various skin disorders has been suggested for decades. However, few clinical studies have assessed oxidative stress in skin diseases. The easiest and least invasive method to assess oxidative stress in patients may be the measurement of oxidation products in urine. OBJECTIVE: This study aims to assess oxidative stress in psoriasis and atopic dermatitis patients. METHODS: Urine samples were collected from 29 psoriasis patients (25 males and 4 females), 21 atopic dermatitis patients (14 males and 7 females) and 20 healthy controls (16 males and 4 females). The severity and extent of psoriasis and atopic dermatitis was assessed by their area and severity index. We measured nitrate as a metabolite of nitric oxide, malondialdehyde as a major lipid oxidation product, and 8 hydroxydeoxyguanosine (8-OHdG) as a DNA oxidation marker. RESULTS: Urinary nitrate and 8-OHdG levels, but not malondialdehyde, were significantly higher in psoriasis patients than those in healthy controls. On the contrary, only urinary nitrate level was significantly higher in atopic dermatitis patients than those in healthy controls. The severity and extent of both psoriasis and atopic dermatitis significantly correlated with urinary nitrate level and malondialdehyde level, but it did not correlate with urinary 8-OHdG level. CONCLUSIONS: Measurement of these three urinary oxidative products is non invasive. Above all, measurement of urinary nitrate may be most useful in the clinical assessment of oxidative stress in both psoriasis and atopic dermatitis patients. There is a possibility that urinary 8-OHdG level may indicate the different pathogenesis between psoriasis and atopic dermatitis. PMID- 20205356 TI - Acute haemorrhagic oedema of infancy associated with Wiskott-Aldrich syndrome. PMID- 20205357 TI - Topography-guided transepithelial surface ablation in treatment of recurrent epithelial ingrowths. AB - PURPOSE: To describe a new, single-step, transepithelial and trans-LASIK flap topography-guided surface ablation technique in a case of recurrent epithelial ingrowth with visual disturbances caused by irregular astigmatism, scattering, and decreased corneal transparency after LASIK. METHODS: Custom ablation through both the epithelium and the LASIK flap performed by 1-kHz flying spot excimer laser was used to transform an irregular corneal surface into a regular aspheric surface and in the same continuous process to ablate the epithelial ingrowth causing the irregularity. RESULTS: Visual rehabilitation was achieved, the corneal surface was regularized, and epithelial ingrowth was removed within the ablation. CONCLUSIONS: The transepithelial topography-guided surface ablation technique was safe and effective in this case of visually disturbing epithelial ingrowth after LASIK, and may also be applied to treat other types of flap/interface complications. PMID- 20205358 TI - Topographic stability after hyperopic LASIK. AB - PURPOSE: To analyze and compare time-dependent topographic changes after hyperopic LASIK. METHODS: Sixty-six consecutive eyes of 37 patients treated for hyperopic astigmatism with the SCHWIND ESIRIS excimer laser with follow-up of > or = 3 months were retrospectively evaluated. In all cases, standard examinations and 3-, 12-, and 36-month topographic analyses with a Keratron topographer (Optikon 2000 SpA) were performed. Topographic changes in Maloney index, simulated keratometry (sim K), and keratometry (K) readings at 3, 5, and 7 mm were evaluated. RESULTS: Postoperatively, 92% of eyes were within +/- 0.50 diopters (D) manifest refraction after 3-month follow-up, compared with 83% after 12 months, and 72% after 36 months. No significant regression between the 3-month and 1-year follow-up as well as 1 to 3 years postoperatively was noted. Evaluation of mean regression (increasing hyperopia) between 3 and 36 months postoperatively resulted in a Maloney index of 0.016 D/month, regression of 0.013 D/month for the sim K readings, and regression of 0.010 D/month, < 0.001 D/month, and 0.004 D/month for the 3-, 5-, and 7-mm zones, respectively. Refractive stability was comparable to the Maloney index and sim K index stability. CONCLUSIONS: Topography can be used as an objective method to analyze regression after treatment of hyperopia. This method allows differentiation as to whether there is regression, topographic change, or latent hyperopia, which becomes manifest after a certain time period. Following hyperopic LASIK with the SCHWIND ESIRIS laser, no topographic regression between 3- and 36-month follow-up could be observed. PMID- 20205360 TI - LASIK for Myopic Astigmatism and Presbyopia Using Non-Linear Aspheric Micro Monovision with the Carl Zeiss Meditec MEL 80 Platform. AB - PURPOSE: to evaluate the monocular and binocular visual outcomes of LASIK with a non-linear aspheric micro-monovision protocol for the correction of myopic astigmatism and presbyopia. METHODS: a retrospective, noncomparative case series included 310 eyes of 155 consecutive patients with myopic astigmatism and presbyopia who were treated with LASIK-induced micro-monovision. The Carl Zeiss Meditec CRS-Master software and MEL 80 excimer laser were used. The target refraction was plano for distance eyes (dominant eye) and between -0.75 and -2.00 diopters (D) for near eyes. Patients were followed for 1 year. Mean attempted spherical equivalent refraction (SE) correction was -3.59 +/- 1.79 D (range: 0.20 to -8.31 D). Mean attempted cylinder correction was 0.84 +/- 0.63 D (range: 0 to 2.50 D). Median patient age was 49 years (range: 43 to 63 years). Median follow-up was 12.5 months. RESULTS: outcome measures after all treatments were as follows. Achieved SE correction was within +/- 0.50 D in 92% and within +/- 1.00 D in 99% of eyes. Monocular uncorrected distance visual acuity was 20/20 in 99% and 20/32 in 100% of distance eyes. Binocular uncorrected near visual acuity was J2 in 96% and J5 in 100% of patients. Binocular uncorrected visual acuity was 20/20 and J5 in 99% of patients. No eyes lost 2 or more lines of corrected distance visual acuity. There was no change in mesopic contrast sensitivity (CSV 1000) at all spatial frequencies. The average change in refraction between 3 months and 1 year was -0.0 6+/- 0.31 D. CONCLUSIONS: this non-linear aspheric myopic micro-monovision protocol was well-tolerated, stable, and effective for treating patients with presbyopia in moderate to high myopic astigmatism. PMID- 20205361 TI - Radiologic case study. Diagnosis: juvenile tillaux fracture. PMID- 20205362 TI - Disaster response. PMID- 20205363 TI - Penetrating trauma trumps backboards. PMID- 20205364 TI - Frederick Francois Chopin. PMID- 20205365 TI - Anatomic coracoclavicular and acromioclavicular ligament reconstruction for high grade acromioclavicular separations: the gracilis weave. PMID- 20205366 TI - Intramedullary nailing of tibial fractures: review of surgical techniques and description of a percutaneous lateral suprapatellar approach. PMID- 20205367 TI - Venous thromboembolism in the pediatric population. PMID- 20205368 TI - MRI and arthroscopic analysis of collateral knee ligament injuries in combined knee ligament injuries. PMID- 20205369 TI - The Maisonneuve injury: a comprehensive review. PMID- 20205371 TI - Gold-catalyzed intermolecular hydrophenoxylation of unactivated internal alkynes. AB - A general and simple strategy for the synthesis of functionally diverse arylvinyl ethers is reported through gold-catalyzed intermolecular addition of electronically and sterically substituted phenols with unactivated alkynes. Addition of phenols to unsymmetrical alkynes provides the corresponding mixture of regioisomers with appreciable selectivity. Multiple hydrophenoxylations of polyphenols with diphenylacetylene are demonstrated successfully. PMID- 20205372 TI - Molecular dynamics simulations of flexible polymer chains wrapping single-walled carbon nanotubes. AB - The goal of this study is to explore the interface between single-walled carbon nanotubes (SWCNTs) and polymer chains with flexible backbones in vacuo via molecular dynamics (MD) simulations. These simulations investigate whether the polymers prefer to wrap the SWCNT, what the molecular details of that interface are, and how the interfacial interaction is affected by the chemical composition and structure of the polymer. The simulations indicate that polymers with flexible backbones tend to wrap around the SWCNT, although not in any distinct conformation; no helical conformations were observed. PAN with the cyano side group showed a preference for transversing the length of the SWCNT rather than wrapping around its diameter, and the cyano group prefers to align parallel to the SWCNT surface. Flexible backbone polymers with bulky and aromatic side groups such as PS and PMMA prefer intrachain coiling rather than wrapping the SWCNT. Moment of inertia plots as a function of time quantify the interplay between intrachain coiling and adsorption to the SWCNT surface. PMID- 20205373 TI - Laser-power-induced multiphonon resonant raman scattering in laser-heated CdS nanocrystal. AB - The size stability of nanoparticles is crucial from an application point of view. We probe, using Raman spectroscopy, particle size evolution of CdS nanoparticles by varying laser power. Multiphonon resonant Raman scattering has also been demonstrated. With increase in laser power, the intensity ratio of 2-longitudinal optical (LO) to 1-LO is found to increase dramatically, and LO phonon overtones up to fourth order are observed. Resonant Raman scattering has been achieved by suitably matching the band gap with the excitation photon energy, by varying the local temperature. The effect of increase in local temperature on the band gap is also discussed. PMID- 20205374 TI - Investigation of free-radical copolymerization propagation kinetics of vinyl acetate and methyl methacrylate. AB - The free-radical copolymerization propagation kinetics of vinyl acetate (VAc) and methyl methacrylate (MMA) at 50 degrees C were investigated through an experimental study combined with a computational analysis based on quantum chemistry. Copolymer composition data, obtained using pulsed laser polymerization followed by size exclusion chromatography (PLP-SEC) and proton nuclear magnetic resonance (NMR), were well represented by the terminal model using monomer reactivity ratios obtained with the computational approach (r(VAc) = 0.001 and r(MMA) = 27.9). Concerning the composition-averaged copolymerization propagation rate coefficient k(p,cop), the differences between the terminal model and the implicit penultimate unit effect (IPUE) model (s(MMA) = 0.544 and s(VAc) = 0.173) are small for VAc/MMA, with the terminal model sufficient to describe the experimental k(p,cop) data measured by PLP-SEC. Monomer and radical charge distributions determined computationally are used to explain the reactivity exhibited by the VAc/MMA system. PMID- 20205375 TI - Phase transitions of hexadecane in poly(alkyl methacrylate) core-shell microcapsules. AB - Microcapsules containing subfemtoliter volumes of n-hexadecane (HD) within a 4-40 nm thick shell of poly(alkyl methacrylates) were prepared. The size of the HD drop was varied between 50 and 140 nm. The alkyl substituents on the methacrylate monomer were varied to alter the surface tension between the HD and the polymer shell in order to investigate the effects of surface tension on the freezing point of the HD. The size dependence of the supercooling as predicted by the G-T equation was not observed in our systems. An effect on the magnitude of supercooling with variation in the side chains was observed, where freezing the HD in capsules with bulkier side chains requires a greater magnitude of supercooling. This is in agreement with the increased hydrophobic character of the polymers and also correlates with the decrease in glass transition temperature of the polymer. We also observed aging of the capsules, which could be accelerated by heating. PMID- 20205376 TI - Protochlorophyllide excited-state dynamics in organic solvents studied by time resolved visible and mid-infrared spectroscopy. AB - Protochlorophyllide (PChlide) is a precursor in the biosynthesis of chlorophyll. Complexed with NADPH to the enzyme protochlorophyllide oxidoreductase (POR), it is reduced to chlorophyllide, a process that occurs via a set of spectroscopically distinct intermediate states and is initiated from the excited state of PChlide. To obtain a better understanding of these catalytic events, we characterized the excited state dynamics of PChlide in the solvents tetrahydrofuran (THF), methanol, and Tris/Triton buffer using ultrafast transient absorption in the visible and mid-infrared spectral regions and time-resolved fluorescence emission experiments. For comparison, we present time-resolved transient absorption measurements of chlorophyll a in THF. From the combined analysis of these experiments, we derive that during the 2-3 ns excited state lifetime an extensive multiphasic quenching of the emission occurs due to solvation of the excited state, which is in agreement with the previously proposed internal charge transfer (ICT) character of the S1 state ( Zhao , G. J. ; Han , K. L. Biophys. J. 2008 , 94 , 38 ). The solvation process in methanol occurs in conjunction with a strengthening of a hydrogen bond to the Pchlide keto carbonyl group. We demonstrate that the internal conversion from the S2 to S1 excited states is remarkably slow and stretches out on to the 700 fs time scale, causing a rise of blue-shifted signals in the transient absorption and a gain of emission in the time-resolved fluorescence. A triplet state is populated on the nanosecond time scale with a maximal yield of approximately 23%. The consequences of these observations for the catalytic pathway and the role of the triplet and ICT state in activation of the enzyme are discussed. PMID- 20205377 TI - Ag(+)-mediated assembly of 5'-guanosine monophosphate. AB - Polymorphic forms of nucleic acids provide platforms for new nanomaterials, and transition metal cations give access to alternative arrangements of nucleobases by coordinating with electron-rich functional groups. Interaction of Ag(+) with 5'-guanosine monophosphate (5'-GMP) is considered in this work. Ag(+) promotes nucleotide stacking and aggregation, as indicated by the increased viscosity of 5'-GMP solutions with Ag(+), magnification of the circular dichroism response of guanine by Ag(+), and exothermic reactions between Ag(+) and guanine derivatives. Isothermal titration calorimetry studies show that the reaction is favored starting at 10 microM 5'-GMP. Utilizing the exothermic heat change associated with reaction of Ag(+) with 5'-GMP, local structure within the aggregate was assessed. On the basis of the salt dependence of the reaction and comparison with the corresponding nucleoside, the dianionic phosphate of 5'-GMP is one binding site for Ag(+), although this electrostatic interaction is not a dominant contribution to the overall heat change. Another binding site is the N7 on the nucleobase, as determined via studies with 7-deazaguanosine. Besides this binding site, Ag(+) also associates with the O6, as earlier studies deduced from the shift in the carbonyl stretching frequency associated with adduct formation. With these two binding sites on the nucleobase, the empirical stoichiometry of approximately 1 Ag(+):nucleobase derived from the calorimetry studies indicates that Ag(+) coordinates two nucleobases. The proposed structural model is a Ag(+) mediated guanine dimer within a base stacked aggregate. PMID- 20205378 TI - A nanocellulose polypyrrole composite based on microfibrillated cellulose from wood. AB - It is demonstrated that it is possible to coat the individual fibers of wood based nanocellulose with polypyrrole using in situ chemical polymerization to obtain an electrically conducting continuous high-surface-area composite. The experimental results indicate that the high surface area of the water dispersed material, to a large extent, is maintained upon normal drying without the use of any solvent exchange. Thus, the employed chemical polymerization of polypyrrole on the microfibrillated cellulose (MFC) nanofibers in the hydrogel gives rise to a composite, the structure of which-unlike that of uncoated MFC paper-does not collapse upon drying. The dry composite has a surface area of approximately 90 m(2)/g and a conductivity of approximately 1.5 S/cm, is electrochemically active, and exhibits an ion-exchange capacity for chloride ions of 289 C/g corresponding to a specific capacity of 80 mAh/g. The straightforwardness of the fabrication of the present nanocellulose composites should significantly facilitate industrial manufacturing of highly porous, electroactive conductive paper materials for applications including ion-exchange and paper-based energy storage devices. PMID- 20205379 TI - Matrix-isolation and ab initio study of HNgCCF and HCCNgF molecules (Ng = Ar, Kr, and Xe). AB - We report three new noble-gas molecules prepared in low-temperature Kr and Xe matrices from the HCCF precursor by UV photolysis and thermal annealing. The identified molecules are two noble-gas hydrides HNgCCF (Ng = Kr and Xe) and a molecule of another type, HCCKrF. These molecules are assigned with the help of ab initio calculations. All strong absorptions predicted by theory are found in experiments with proper deuteration shifts. The experiments and theory suggest a higher stability against dissociation of HNgCCF molecules compared to HNgCCH reported previously. Surprisingly, only very tentative traces of HCCXeF, which is computationally very stable, are found in experiments. No strong evidence of similar argon compounds is found here. PMID- 20205380 TI - Application of label-free absolute quantitative proteomics in human gingival crevicular fluid by LC/MS E (gingival exudatome). AB - Periodontal disease is perhaps the most common infectious disease in humans. Gingival crevicular fluid (GCF) is a local inflammatory exudate of the periodontal tissues. Its composition greatly varies between health and periodontal disease. GCF collection is rapid and noninvasive, but previous approaches aiming to analyze its composition have mainly involved single protein biomarkers. The aim of this study was to perform analysis of the GCF exudatome from healthy and periodontally diseased sites by LC/MS(E), a label-free mass spectrometry method that enables simultaneous protein identification and absolute quantification in biological fluids. In total, 154 proteins of human, bacterial, and viral origin were identified in the 40 GCF samples obtained from the 10 subjects (five healthy and five generalized aggressive periodontitis). The proportion of bacterial, viral, and yeast protein was increased in disease, compared to health. The presence of host defense-related proteins, such as Cystatin-B and defensins, was confirmed to be present only in health. Among the newly identified GCF proteins were L-plastin detected only in disease (15.6 +/- 12.1 fmol) and Annexin-1 detected in 5-fold higher levels in health. Nevertheless, pro-inflammatory cytokines or periodontal pathogen proteins were rarely detected. Conclusively, the LC/MS(E) technology may facilitate characterization of GCF proteome in periodontal health and disease, thus conferring prognostic and diagnostic value. Larger cohort studies are required to characterize the complete GCF proteome in health and disease. PMID- 20205381 TI - Mixed alkali metal/transition metal coordination polymers with the mellitic acid hexaanion: 2-dimensional hexagonal magnetic nets. AB - The hexaanion of mellitic acid, mel = (C(6)(CO(2))(6))(6-), links metal ions into extensively connected magnetic coordination polymers. Reaction of alkali metal mellitate salts, M(6)(mel) (M = K, Rb), with M'Cl(2) precursors (M' = Mn, Co, Ni) under mild (473 K) hydrothermal conditions yields an extensive family of isostructural 3-dimensional mixed alkali metal/transition metal polymers of general formula M(2)[M'(2)(mel)(OH(2))(2)] (M/M' = K/Mn (1a); K/Co (1b); K/Ni (1c); Rb/Mn (2a); Rb/Co (2b); Rb/Ni (2c)). These materials incorporate distorted 2-dimensional magnetic hexagonal nets with a honeycomb topology that are exclusively based on metal-carboxylate-metal bridging interactions. A further isostructural alkali metal-free Co(2+) material with NH(4)(+) cations, (NH(4))(2)[Co(2)(mel)(OH(2))(2)] (3), produced by reaction of H(6)mel with [Co(NH(3))(6)]Cl(3) is also presented. The magnetic susceptibility data for 1a-c, 2a-c, and 3 are presented. The susceptibility data for the Mn(II)- and Ni(II) containing phases have been analyzed using a simple Mean Field Theory approach, and have been modeled using a high temperature series expansion. The comparative magnetism of the Co(II) phases is also presented, and is more complicated because of significant spin-orbit coupling effects. PMID- 20205382 TI - Dynamic planar solid phase microextraction-ion mobility spectrometry for rapid field air sampling and analysis of illicit drugs and explosives. AB - A preconcentration device that targets the volatile chemical signatures associated with illicit drugs and explosives (high and low) has been designed to fit in the inlet of an ion mobility spectrometer (IMS). This is the first reporting of a fast and sensitive method for dynamic sampling of large volumes of air using planar solid phase microextraction (PSPME) incorporating a high surface area for absorption of analytes onto a sol-gel polydimethylsiloxane (PDMS) coating for direct thermal desorption into an IMS. This device affords high extraction efficiencies due to strong retention properties at ambient temperature, resulting in the detection of analyte concentrations in the parts per trillion range when as low as 3.5 L of air are sampled over the course of 10 s (absolute mass detection of less than a nanogram). Dynamic PSPME was used to sample the headspace over the following: 3,4-methylenedioxymethamphetamine (MDMA) tablets resulting in the detection of 12-40 ng of piperonal, high explosives (Pentolite) resulting in the detection of 0.6 ng of 2,4,6-trinitrotoluene (TNT), and low explosives (several smokeless powders) resulting in the detection of 26 35 ng of 2,4-dinitrotoluene (2,4-DNT) and 11-74 ng of diphenylamine (DPA). PMID- 20205383 TI - Air pollution in Accra neighborhoods: spatial, socioeconomic, and temporal patterns. AB - This study examined the spatial, socioeconomic status (SES), and temporal patterns of ambient air pollution in Accra, Ghana. Over 22 months, integrated and continuous rooftop particulate matter (PM) monitors were placed at a total of 11 residential or roadside monitoring sites in four neighborhoods of varying SES and biomass fuel use. PM concentrations were highest in late December and January, due to dust blown from the Sahara. Excluding this period, annual PM(2.5) ranged from 39 to 53 microg/m(3) at roadside sites and 30 to 70 microg/m(3) at residential sites; mean annual PM(10) ranged from 80 to 108 microg/m(3) at roadside sites and 57 to 106 microg/m(3) at residential sites. The low-income and densely populated neighborhood of Jamestown/Ushertown had the single highest residential PM concentration. There was less difference across traffic sites. Daily PM increased at all sites at daybreak, followed by a mid-day peak at some sites, and a more spread-out evening peak at all sites. Average carbon monoxide concentrations at different sites and seasons ranged from 7 to 55 ppm, and were generally lower at residential sites than at traffic sites. The results show that PM in these four neighborhoods is substantially higher than the WHO Air Quality Guidelines and in some cases even higher than the WHO Interim Target 1, with the highest pollution in the poorest neighborhood. PMID- 20205384 TI - Geographical PCB and DDT patterns in shearwaters (Calonectris sp.) breeding across the NE Atlantic and the Mediterranean archipelagos. AB - Although seabirds have been proposed as useful biomonitors for organochlorine contaminants (OCs) in marine environments, their suitability is still unclear. To understand the geographic variability and the influence of seabird trophic ecology in OC levels, we analyzed PCBs, DDTs, delta(13)C, and delta(15)N in the blood of adult Calonectris shearwaters throughout a vast geographic range within the northeast Atlantic Ocean (from Cape Verde to Azores) and the Mediterranean Sea (from the Alboran Sea to Crete). OC concentrations were greater in birds from the Mediterranean than in those from the Atlantic colonies, showing higher and lower chlorinated PCB profiles, respectively. This large-scale pattern may reflect the influence of historical European runoffs in the Mediterranean basin and diffused sources for OCs in remote Atlantic islands. Spatial patterns also emerged within the Atlantic basin, probably associated with pollutant long-range transport and recent inputs of DDT in the food webs of shearwaters from Cape Verde and the Canary islands. Moreover, a positive association of OC concentrations with delta(15)N within each locality points out diet specialization as a major factor explaining differences in OCs at the intraspecific level. Overall, this study highlights wide range breeding seabirds, such as Calonectris shearwaters, as suitable organisms for biomonitoring large geographic trends of organochlorine contamination in the marine environment. PMID- 20205385 TI - Measurement of protein phosphorylation stoichiometry by selected reaction monitoring mass spectrometry. AB - The stoichiometry of protein phosphorylation at specific amino acid sites may be used to infer on the significance of the modification, and its biological function in the cell. However, detection and quantification of phosphorylation stoichiometry in tissue remain a significant challenge. Here we describe a strategy for highly sensitive, label-free quantification of protein phosphorylation stoichiometry. Method development included the analysis of synthetic peptides in order to determine constants to relate the mass spectrometry signals of cognate peptide/phosphopeptide pairs, and the detection of the cognate peptides by using high resolution Fourier Transform mass spectrometry (FTMS) and selected reaction monitoring mass spectrometry (SRM). By analyzing extracted ion currents by FTMS, the phosphorylation stoichiometries of two tyrosine residues (tyrosine-194 and tyrosine-397) in the protein tyrosine kinase Lyn were determined in transfected human HEK293T cells and two cultured human multiple myeloma strains. To achieve high sensitivity to measure phosphorylation stoichiometry in tissue, SRM methods were developed and applied for the analysis of phosphorylation stoichiometries of Lyn phospho-sites in multiple myeloma xenograft tumors. Western immuno-blotting was used to verify mass spectrometry findings. The SRM method has potential applications in analyzing clinical samples wherein protein phosphorylation stoichiometries may represent important pharmacodynamic biomarkers. PMID- 20205386 TI - Correlation between the structural distortions and thermoelectric characteristics in La(1-x)A(x)CoO(3) (A = Ca and Sr). AB - Detailed structures and thermoelectric (TE) properties are investigated for the perovskite La(1-x)Ca(x)CoO(3) and La(1-x)Sr(x)CoO(3) with 0 1. Owing to their small critical thickness, wetting films destabilized by intermolecular forces always display long-wave instability regardless of their viscoelasticity. Furthermore, our numerical simulations based on energy minimization for unstable wetting elastic films show the formation of islands for ultrathin films and a morphological phase transition to holes embedded in the film for relatively thicker films. Unlike viscous films, however, unstable elastic films do not display a unique dominant wavelength but a bimodal distribution of wavelengths. PMID- 20205404 TI - Computer simulation of chiral nanoporous networks on solid surfaces. AB - A lattice Monte Carlo (MC) model was proposed with the aim of understanding the factors affecting the chiral self-assembly of tripod-shaped molecules in two dimensions. To that end a system of flat symmetric molecules adsorbed on a triangular lattice was simulated by using the canonical ensemble method. Special attention was paid to the influence of size and composition of the building block on the morphology of the adsorbed overlayer. The obtained results demonstrated a spontaneous self-assembly into extended chiral networks with hexagonal cavities, highlighting the ability of the model to reproduce basic structural features of the corresponding experimental systems. The simulated assemblies were analyzed with respect to their structural and energetic properties resulting in quantitative estimates of the unit cell parameters and mean potential energy of the adsorbed layer. The predictive potential of the model was additionally illustrated by comparison of the obtained superstructures with the recent STM images that have been recorded for different organic tripod-shaped molecules adsorbed at the liquid/pyrolytic graphite interface. PMID- 20205405 TI - Silicon surface structure-controlled oleophobicity. AB - Superoleophobic surfaces display contact angles >150 degrees with liquids that have lower surface energies than does water. The design of superoleophobic surfaces requires an understanding of the effect of the geometrical shape of etched silicon surfaces on the contact angle and hysteresis observed when different liquids are brought into contact with these surfaces. This study used liquid-based metal-assisted etching and various silane treatments to create superoleophobic surfaces on a Si(111) surface. Etch conditions such as the etch time and etch solution concentration played critical roles in establishing the oleophobicity of Si(111). When compared to Young's contact angle, the apparent contact angle showed a transition from a Cassie to a Wenzel state for low-surface energy liquids as different silane treatments were applied to the silicon surface. These results demonstrated the relationship between the re-entrant angle of etched surface structures and the contact angle transition between Cassie and Wenzel behavior on etched Si(111) surfaces. PMID- 20205406 TI - Orthogonal functionalization of silicon substrates using self-assembled monolayers. AB - A fabrication process for multifunctional surfaces is designed leading to five different functional moieties (amine, thiol, carboxylic acid, fluoro, and methyl) being present on a single structured surface. The multifunctional surface is created by combining UV-ozone patterning, electro-oxidative lithography, the local deposition of self-assembled monolayers (SAMs), and surface modification schemes. Besides the characterization with conventional surface-sensitive techniques, the nature of the locally functionalized regions is demonstrated by self-assembly of three different probe nanomaterials (Si nanoparticles, Au nanoparticles, and hydroxyl functionalized micelles). A versatile fabrication approach for complex surfaces with addressable functionalities can be created, and it was possible to integrate five different functionalized areas on one substrate. PMID- 20205407 TI - The intermediate state of DMPG is stabilized by enhanced positive spontaneous curvature. AB - 1,2-Dimyristoyl-sn-glycero-3-phospho-rac-glycerol (DMPG) at low salt concentrations has a complex endotherm with at least four components and extending over the span of 20 degrees. During this ongoing melting, the solution becomes viscous and scatters light poorly. This multipeak endotherm was suggested to result from the effects of curvature on the relative free energies of gel and fluid DMPG bilayers, further relating to the formation of an intermediate sponge phase between the lamellar gel and fluid phases. Although later studies appear to exclude a connected bilayer network, the relation of the endotherm peaks to curvature remains an appealing hypothesis. This was tested by including in the system both water-soluble small molecules (dimethyl sulfoxide, ethanol, and urea) as well as amphiphiles (myristoyl-lyso-PG, cholesterol, cholesterol-3-sulfate, and dimyristoylglycerol) known to alter the spontaneous curvature of bilayers. All compounds increasing the monolayer positive spontaneous curvature (ethanol, urea, myristoyl-lyso-PG, cholesterol-3-sulfate) increased the temperature span of the intermediate state and elevated the temperature of its dissolution, while all compounds increasing the negative spontaneous curvature (dimethyl sulfoxide, cholesterol, dimyristoylglycerol) had the opposite effect, implying that the intermediate state contains a structure with positive curvature. The results support the view that the intermediate state consists of vesicles with a large number of holes. The viscosity increase could be related to vesicle expansion needed to accommodate the numerous holes. PMID- 20205408 TI - PM-IRRAS assessment of the compression-mediated orientation of the nanocavity of a monoacylated beta-cyclodextrin in monolayers at the air-water interface. AB - The structural orientation adopted along the compression-decompression isotherm by a monoacylated beta-cyclodextrin (C16-betaCD) at the air-water interface was assessed by polarization-modulation infrared reflection-adsorption spectroscopy (PM-IRRAS). The adoption of different orientations of the cyclic oligosaccharide unit, relative to the interfacial plane, was interpreted analyzing the PM-IRRAS band intensity ratios of specific vibrations corresponding to the cyclodextrin moiety as a function of the surface pressure for successive compression/decompression cycles. The spectroscopic analysis revealed that the cyclic oligosaccharide modifies its position under compression from one in which the plane of the cavity of the monoacylated beta-cyclodextrin lies almost parallel to the interface to another in which the plane of the cavity is perpendicular to the interface. Through the PM-IRRAS analysis, it was also possible to evidence the establishment of an intermolecular hydrogen bonding network that may play an important role in the dynamic properties of the monolayer packing. The hydrogen bonding network becomes more important with the increases of surface pressure, up to a molecular packing limit, and it imparts the surface properties of the film for future compression-decompression cycles. PMID- 20205409 TI - Sliding of water droplets on microstructured hydrophobic surfaces. AB - Sliding behaviors of liquid droplets on solid surfaces are among the fundamental results of wettability. To remedy the lack of quantitative correlation between sliding angle and roughness of the surface, which is known to be effective at enhancing wettability, we report in this paper the observation that the onset of water droplets sliding under gravity on inclined micropillar-structured hydrophobic surfaces always starts with detachment of the rear contact lines of the droplets from the pillar tops. We also establish an explicit analytical model, based on the observed mechanism, by which the sliding angle is fully determined by the fraction of water-solid interface area, droplet volume, and Young's contact angle. This model gives predictions of sliding angles that agree well with experimental measurements. PMID- 20205410 TI - Effects of the nanostructuring of gold films upon their thermal stability. AB - We report results relating to the thermal stability of nanoparticles and show a remarkable effect of nanostructuring of the metal. Au films are nanostructured by focused ion beam sputtering (FIB) to produce isolated areas of metal, which are imaged by atomic force microscopy (AFM). Images of the surface show that, if the islands are made small enough, the metal in the islands is lost by evaporation, whereas the nonfabricated areas outside are relatively stable and the nanoparticles remain present there. PMID- 20205411 TI - Spatial correlation of confocal Raman scattering and secondary ion mass spectrometric molecular images of lignocellulosic materials. AB - A detailed chemical and structural understanding of pre-enzymatic processing of lignocellulosic materials (LCMs) is a key objective in the development of renewable energy. Efficient rendering of biomass components into fermentable substrates for conversion into biofuel feedstocks would benefit greatly from the development of new technologies to provide high-quality, spatially resolved chemical information about LCMs during the various processing states. In an effort to realize this important goal, spatially correlated confocal Raman and mass spectrometric images allow the extraction of three-dimensional information from the perennial grass, Miscanthus x giganteus. An optical microscopy-based landmark registry scheme was developed that allows samples to be transferred between laboratories at different institutions, while retaining the capability to access the same physical regions of the samples. Subsequent to higher resolution imaging via confocal Raman microscopy and secondary ion mass spectrometry (SIMS), laser desorption-ionization mass spectrometry was used to place these regions within the overall sample architecture. Excellent sample registry was evident in the highly correlated Raman and SIMS images. In addition, the correlation of vibrational Raman scattering with mass spectra from specific spatial locations allowed confirmation of the assignment of intracellular globular structures to hemicellulose-rich lignin complexes, an assignment which could only be made tentatively from either image alone. PMID- 20205412 TI - Analytical potential energy surface and kinetics of the NH(3) + H --> NH(2) + H(2) hydrogen abstraction and the ammonia inversion reactions. AB - Based on accurate electronic structure calculations, a new analytical potential energy surface (PES) was fitted to simultaneously describe the hydrogen abstraction reaction from ammonia by a hydrogen atom, and the ammonia inversion. Using a wide spectrum of properties of the reactive system (equilibrium geometries, vibrational frequencies, and relative energies of the stationary points, topology of the reaction paths, and points on the reaction swaths) as reference, the resulting analytical PES reproduces reasonably well the input ab initio information obtained at the CCSD(T)/cc-pVTZ level, which represents a severe test for the new surface. As a first application, on this analytical PES we perform an extensive kinetics study using variational transition-state theory with semiclassical transmission coefficients over a wide temperature range, 200 2000 K. For the hydrogen abstraction reaction, the forward rate constants reproduce the experimental measurements, while the reverse ones are slightly underestimated. Another severe test of the new surface is the analysis of the kinetic isotope effects (KIEs). The KIEs between unsubstituted and all deuterated reactions agree with experiment in the common temperature range. For the ammonia inversion reaction, the splitting of the degenerate vibrational levels of the double well due to the tunneling contribution, which is very important in this reaction representing 93% of the reactivity at 200 K, was calculated for the NH(3) and ND(3) species. The values found were 3.6 and 0.37 cm(-1), respectively, which although higher than experimental values, reproduce the experimental behavior on isotopic substitution. PMID- 20205413 TI - Reversible attachment of platinum alloy nanoparticles to nonfunctionalized carbon nanotubes. AB - The formation of monodisperse, tunable sized, alloyed nanoparticles of Ni, Co, or Fe with Pt and pure Pt nanoparticles attached to carbon nanotubes has been investigated. Following homogeneous nucleation, nanoparticles attach directly to nonfunctionalized single-walled and multi-walled carbon nanotubes during nanoparticle synthesis as a function of ligand nature and the nanoparticle work function. These ligands not only provide a way to tune the chemical composition, size, and shape of the nanoparticles but also control a strong reversible interaction with carbon nanotubes and permit controlling the nanoparticle coverage. Raman spectroscopy reveals that the sp(2) hybridization of the carbon lattice is not modified by the attachment. In order to better understand the interaction between the directly attached nanoparticles and the nonfunctionalized carbon nanotubes, we employed first-principles calculations on model systems of small Pt clusters and both zigzag and armchair single-walled carbon nanotubes. The detailed comprehension of such systems is of major importance since they find applications in catalysis and energy storage. PMID- 20205414 TI - Shot noise suppression at room temperature in atomic-scale Au junctions. AB - Shot noise encodes additional information not directly inferable from simple electronic transport measurements. Previous measurements in atomic-scale metal junctions at cryogenic temperatures have shown suppression of the shot noise at particular conductance values. This suppression demonstrates that transport in these structures proceeds via discrete quantum channels. Using a high-frequency technique, we simultaneously acquire noise data and conductance histograms in Au junctions at room temperature and ambient conditions. We observe noise suppression at up to three conductance quanta, with possible indications of current-induced local heating and 1/f noise in the contact region at high biases. These measurements demonstrate the quantum character of transport at room temperature at the atomic scale. This technique provides an additional tool for studying dissipation and correlations in nanodevices. PMID- 20205415 TI - Palladium-catalyzed direct oxidation of alkenes with molecular oxygen: general and practical methods for the preparation of 1,2-diols, aldehydes, and ketones. AB - 1,2-Diols, aldehydes, and ketones are important intermediates in chemical synthesis, and alkenes are possible precursors for 1,2-diols, aldehydes, and ketones. Herein, novel and environmentally benign methods for palladium-catalyzed dihydroxylation and oxidative cleavage of olefins with oxygen as sole oxidant are presented. The cleavage reactions were performed with acid as additive in aqueous solution, whereas 1,2-diols were formed in the presence of base. A broad substrate scope has been demonstrated allowing monosubstituted aromatic and aliphatic terminal alkenes, 1,2-disubstituted, and 1,1-disubstituted olefins. The cleavage reactions of dioxo-Pd(II) complexes implicate 1,2-diol might act as a key intermediate of olefin cleavage. PMID- 20205416 TI - Effect of charge distribution on RDX adsorption in IRMOF-10. AB - Quantum mechanical (QM) calculations, classical grand canonical Monte Carlo (GCMC) simulations, and classical molecular dynamics (MD) simulations are performed to test the effect of charge distribution on hexahydro-1,3,5-trinitro 1,3,5-triazine (RDX) adsorption and diffusion in IRMOF-10. Several different methods for mapping QM electron distributions onto atomic point charges are explored, including the electrostatic potential (ESP) method, Mulliken population analysis, Lowdin population analysis, and natural bond orbital analysis. Classical GCMC and MD simulations of RDX in IRMOF-10 are performed using 15 combinations of charge sources of RDX and IRMOF-10. As the charge distributions vary, interaction potential energies, the adsorption loading, and the self diffusivities are significantly different. None of the 15 combinations are able to quantitatively capture the dependence of the energy of adsorption on local configuration of RDX as observed in the QM calculations. We observe changes in the charge distributions of RDX and IRMOF-10 with the introduction of an RDX molecule into the cage. We also observe a large dispersion contribution to the interaction energy from QM calculations that is not reproduced in the classical simulations, indicating that the source of discrepancy may not lie exclusively with the assignment of charges. PMID- 20205417 TI - Trace detection of triphenylene by surface enhanced Raman spectroscopy using functionalized silver nanoparticles with bis-acridinium lucigenine. AB - Surface enhanced raman scattering (SERS) of triphenylene (TP) has been recorded on Ag nanoparticles functionalized with the molecular assembler bis-acridinium lucigenine dication (LG) which approaches the adsorbate to the metal surface allowing for its detection. Structural information on the host and the analyte can be extracted from the SERS spectra of LG and LG/TP complex. The acridinium planes in LG are staggered, so cavities into which hydrophobic TP can be allocated are created. Moreover, the orientation of LG with respect to the metal surface changes from tilted to perpendicular when concentration of TP increases. However, perpendicular orientation of TP with respect to the metal surface is preferred according to the in-plane enhanced bands recorded in the SERS spectrum. The dependence of the Raman signal of TP on LG concentration has been checked, and trace concentrations of TP have been detected by this technique which therefore can be used as a chemical sensor of organic pollutants. PMID- 20205418 TI - Hybrids of nonviral vectors for gene delivery. AB - Gene transfer has been a critical step for gene therapy. Viral vectors and nonviral vectors are commonly used for gene transfer. It has been shown that nonviral vectors have the advantage over viral ones, as they are nonimmunogenic, easy to produce, and not oncogenic. However, they have the major limitation of inefficient transfection; the hybridized usage of nonviral vectors may provide a partial solution. This article reviews the hybrids (different materials used in one delivery system) of nonviral vectors for gene delivery including hybrids between cationic lipids and helper lipids, conjugates of peptides or targeting moieties and lipids, and hybrids of cationic liposomes and polymers. PMID- 20205419 TI - S4(13)-PV cell-penetrating peptide forms nanoparticle-like structures to gain entry into cells. AB - Despite increasing interest in cell-penetrating peptides (CPPs) as carriers for drugs and in gene therapy, the current understanding of their exact internalization mechanism is still far from complete. The cellular translocation of CPPs and their payloads has been mostly described by fluorescence- and activity-based methods, leaving the more detailed characterization at the ultrastructural level almost out of attention. Herein, we used transmission electron microscopy to characterize the membrane interaction and internalization of a cell-penetrating peptide S4(13)-PV. We demonstrate that S4(13)-PV peptide forms spherical nanoparticle-like regular structures upon association with cell surface glycosaminoglycans on the plasma membrane. Insertion of S4(13)-PV particles into plasma membrane induces disturbances and leads to the vesicular uptake of peptides by cells. We propose that for efficient cellular translocation S4(13)-PV peptides have to assemble into particles of specific size and shape. The spherical peptide particles are not dissociated in intracellular vesicles but often retain their organization and remain associated with the membrane of vesicles, destabilizing them and promoting the escape of peptides into cytosol. Lowering the temperature and inhibition of dynamins' activity reduce the internalization of S4(13)-PV peptides, but do not block it completely. Our results provide an ultrastructural insight into the interaction mode of CPPs with the plasma membrane and the distribution in cells, which might help to better understand how CPPs cross the biological membranes and gain access into cells. PMID- 20205420 TI - DNA scissors device used to measure MutS binding to DNA mis-pairs. AB - MutS is a DNA repair protein that recognizes unpaired and bulged bases. When it binds to DNA, it bends the double helix. We have developed a novel DNA-based nanomechanical device that measures the amount of work that a DNA-bending protein can do when it binds to the double helix. The device we report here is a scissors like device consisting of two double-crossover (DX) molecules connected to each other by a flexible Holliday junction. The two DX components are connected by a double helix that contains the binding site for MutS; when the binding site duplex is bent, the scissors contracts. The two DX molecules are also joined by sticky ends on an edge adjacent to the binding site; the sticky ends can be disrupted if the protein binds with sufficient free energy. Those sticky ends are flanked by a pair of dyes; when the sticky ends are disrupted, the dyes separate, and the fluorescence resonance energy transfer signal can monitor the disruption. The strength of the sticky ends is readily varied, so that the ability of the protein to disrupt them can be quantitated. We use this device to measure work in conjunction with a second device that measures the bending angle resulting from protein binding, so as to calibrate the system. Our data are in good agreement with previous measurements of MutS binding, indicating that this device is able to measure the strength of binding correctly. PMID- 20205421 TI - Hydroformylation reaction of alkylidenecyclopropane derivatives: a new pathway for the formation of acyclic aldehydes containing quaternary stereogenic carbons. AB - The rhodium-catalyzed hydroformylation reaction of methylene- and alkylidenecyclopropane derivatives proceeds under mild conditions to lead to the exclusive formation of linear aldehydes and the stereointegrity of the quaternary carbon center remains unaffected in the process. PMID- 20205422 TI - Phytochrome as molecular machine: revealing chromophore action during the Pfr --> Pr photoconversion by magic-angle spinning NMR spectroscopy. AB - The cyanobacterial phytochrome Cph1 can be photoconverted between two thermally stable states, Pr and Pfr. The photochemically induced Pfr --> Pr back-reaction has been followed at low temperature by magic-angle spinning (MAS) NMR spectroscopy, allowing two intermediates, Lumi-F and Meta-F, to be trapped. Employing uniformly (13)C- and (15)N-labeled open-chain tetrapyrrole chromophores, all four states-Pfr, Lumi-F, Meta-F, and Pr-have been structurally characterized. In the first step, the double bond photoisomerization forming Lumi F occurs. The second step, the transformation to Meta-F, is driven by the release of the mechanical tension. This process leads to the break of the hydrogen bond of the ring D nitrogen to Asp-207 and triggers signaling. The third step is protonically driven allowing the hydrogen-bonding interaction of the ring D nitrogen to be restored. Compared to the forward reaction, the order of events is changed, probably caused by the different properties of the hydrogen bonding partners of N24, leading to the directionality of the photocycle. PMID- 20205423 TI - Selective insertion of oxygen and selenium into an electron-precise paramagnetic selenium-manganese carbonyl cluster [Se(6)Mn(6)(CO)(18)](4-). AB - The facile synthesis of a novel electron-precise paramagnetic hexamanganese carbonyl selenide cluster [Se(6)Mn(6)(CO)(18)](4-) (1) was discovered, which demonstrates contrasting reactivity toward O(2) and Se(8) under markedly mild conditions to afford the O- and Se-inserted clusters [Se(6)Mn(6)(CO)(18)(O)](4-) (2) and [Se(10)Mn(6)(CO)(18)](4-) (3), respectively. Clusters 1-3 represent the first examples of electron-precise paramagnetic main-group transition metal carbonyl clusters, and their formation and bonding properties are further elucidated by theoretical calculations. PMID- 20205424 TI - Photodeoxygenation of dibenzothiophene S-oxide derivatives in aqueous media. AB - The use of atomic oxygen (O((3)P)) as potent oxidant in water has suffered from the lack of a facile, efficient source. The photodeoxygenation of aromatic sulfoxides to the corresponding sulfides in organic solvents has been suggested to produce O((3)P) in low quantum yields. The photolysis of 4,6 dihydroxymethyldibenzothiophene S-oxide and 2,8-dihydroxymethyldibenzothiophene S oxide in water results in deoxygenation at significantly higher quantum yields than in organic solvents. Depending upon conditions, a variable amount of oxidation of the hydroxymethyl substituent into an aldehyde was observed to accompany deoxygenation. Analysis of the photoproducts indicated the deoxygenation occurred by at least two different pH-sensitive mechanisms. Under basic conditions, photoinduced electron transfer yielding a hydroxysulfuranyl radical that decomposed by heterolytic S-O cleavage was thermodynamically feasible. The thermodynamics of photoinduced electron transfer were expected to become increasingly unfavorable as the pH of the solution decreased. Thus, at neutral and acidic pH, an S-O bond scission mechanism was suspected. The observed increase in the photodeoxygenation quantum yields was consistent with charge separation accompanying S-O bond scission. Oxidative cleavage of alkenes in aerobic conditions suggested O((3)P) was produced during photolysis in these conditions; however, the formation of discrete O(*-)/HO(*) may occur, particularly at low pH. PMID- 20205425 TI - Radical migration of substituents of aryl groups on quinazolinones derived from N acyl cyanamides. AB - A newly designed radical cascade involving N-acyl cyanamides is reported. It builds on aromatic homolytic substitutions as intermediate events and leads to complex heteroaromatic structures via an unprecedented radical migration of a substituent on aryl groups of quinazolinones (hydrogen or alkyl). Mechanistic considerations are detailed, which allowed us to devise fine control over the domino processes. The latter could be predictably stopped at several stages, depending on the reaction conditions. Finally, a surgical introduction of a trifluoromethyl substituent on a quinazolinone was achieved via the reported migration. PMID- 20205426 TI - Liposomal circular dichroism. Assignment of remote stereocenters in plakinic acids K and L from a Plakortis-Xestospongia sponge association. AB - Two new omega-phenyl polyketide peroxides, plakinic acids K and L, were isolated from a two-sponge association of Plakortis halichondroides and Xestospongia deweerdtae. The absolute configurations of the remote dimethyl-branched stereocenters in plakinic acid K were assigned by degradation of plakinic acid K to a long-chain naphthamide and analysis by liposomal circular dichroism (L-CD) and comparison with synthetic standards. PMID- 20205428 TI - Diastereoselective, synergistic dual-mode optical switch with integrated chirochromic helicene and photochromic bis-azobenzene moieties. AB - An unprecedented dual-mode optical switch by combining helicene and bis azobenzene moieties in proximity allows for cooperative, highly diastereoselective chirochromic (92/8 to 3/97) and photochromic (>99/<1 to 19/81) switchings both in solution and in nematic LC with tunable pitches and handedness by permutation of four different metastable states. PMID- 20205427 TI - Piperazine bridged resorcinarene cages. AB - The one-pot Mannich condensation of resorcinarenes with piperazine and an excess of formaldehyde under high dilution conditions results in a helical cage, namely, a covalently linked dimer of two resorcinarenes connected via four piperazine bridges in yields ranging from 20 to 40%. The compounds were analyzed by NMR spectroscopy, ESI mass spectrometry, and single crystal X-ray diffraction. The helical cages can encapsulate small guest molecules by adapting the cavity volume by changing the helical pitch according to the guest size. PMID- 20205429 TI - Direct organocatalytic asymmetric aldol reaction of alpha-isothiocyanato imides to alpha-ketoesters under low ligand loading: a doubly stereocontrolled approach to cyclic thiocarbamates bearing chiral quaternary stereocenters. AB - The first doubly stereocontrolled organocatalytic asymmetric aldol reaction of alpha-isothiocyanato imides with alpha-ketoesters by using rosin-derived tertiary amine-thiourea under low ligand loading to form cyclic thiocarbamates bearing quaternary stereogenic centers with high levels of enantio- and diastereoselectivity (up to 99% ee, and 97:3 dr) is presented. This reaction provides a convenient doubly stereocontrolled method to access synthetic useful multiply substituted cyclic thiocarbamates with high optical purity. PMID- 20205432 TI - Flexibility of N-heterocyclic carbene ligands in ruthenium complexes relevant to olefin metathesis and their impact in the first coordination sphere of the metal. AB - We present a detailed static and dynamics characterization of 11 N-heterocyclic carbene (NHC) ligands in Ru complexes of the general formula (NHC)Cl(2)Ru horizontal lineCH(2). Analysis of the dynamic trajectories indicates that the nature of the N substituent can result in extremely different flexibilities of the Ru complexes. In almost all the cases the N substituent trans to the Ru ylidene bond is severely folded so that it protects the vacant coordination position at the Ru center. Limited flexibility is instead associated with the N substituent on the side of the Ru-ylidene bond. NHCs with a single ortho substituent, either a simple Me or a bulkier i-Pr group, have a preferential folding that bends the unsubstituted side of the ring toward the halide-Ru-halide plane. Analysis of the dynamics trajectories in terms of buried volume indicates that the real bulkiness of these systems can be somewhat modulated, and this flexibility is a key feature that allows NHCs to modulate their encumbrance around the metal in order to make room for bulky substrates. Analysis of the buried volume in terms of steric maps showed that NHCs with mesityl or 2,6 diisopropylphenyl N substituents have quite different reactive pockets: rather flat with constant pressure on the halide-Ru-halide plane in the former and vault shaped with higher pressure on the sides in the latter. Regarding the NHCs with an ortho tolyl or i-Pr group on the N substituent, the steric maps quantify the higher impact of the unsubstituted side of the ligand in the first coordination sphere of the metal and evidence the overall C(s)- and C(2)-symmetric reactive pockets of the corresponding complexes. We believe that a detailed characterization of the differently shaped reactive pockets is a further conceptual tool that can be used to rationalize the experimentally different performances of catalysts bearing these ligands or to devise new applications. PMID- 20205433 TI - Hydrates of trans- and gauche-difluoroacetic acids: a high-resolution microwave spectroscopic study. AB - Although identical in formula, trans- and gauche-difluoroacetic acids behave as different molecules in rotational spectra due to their distinct sets of rotational constants. In this study, high-resolution microwave spectra of monohydrates, dihydrates, and trihydrates of both trans- and gauche difluoroacetic acids were recorded using a Fourier transform microwave spectrometer. Rotational and centrifugal distortion constants of these hydrates were obtained with high accuracy via fitting their microwave spectra. It was found that the subtle structural difference between the trans and gauche forms of the acid gives different tunneling motions in their monohydrates. An unusual mixing of wave functions of energetically nondegenerate conformations was observed in the monohydrate of gauche-difluoroacetic acid. Ab initio calculations using the second-order Moller-Plesset perturbation method were also performed to optimize structures and to predict magnitudes of dipole moments of these hydrates. Close agreement between experimental and theoretical rotational constants confirms the feature of hydrogen-bonded ring structures in which all incoming H(2)O molecules bind to the carboxylic group for all hydrates. PMID- 20205431 TI - Quantum mechanical pairwise decomposition analysis of protein kinase B inhibitors: validating a new tool for guiding drug design. AB - Quantum mechanical semiempirical comparative binding energy analysis calculations have been carried out for a series of protein kinase B (PKB) inhibitors derived from fragment- and structure-based drug design. These protein-ligand complexes were selected because they represent a consistent set of experimental data that includes both crystal structures and affinities. Seven scoring functions were evaluated based on both the PM3 and the AM1 Hamiltonians. The optimal models obtained by partial least-squares analysis of the aligned poses are predictive as measured by a number of standard statistical criteria and by validation with an external data set. An algorithm has been developed that provides residue-based contributions to the overall binding affinity. These residue-based binding contributions can be plotted in heat maps so as to highlight the most important residues for ligand binding. In the case of these PKB inhibitors, the maps show that Met166, Thr97, Gly43, Glu114, Ala116, and Val50, among other residues, play an important role in determining binding affinity. The interaction energy map makes it easy to identify the residues that have the largest absolute effect on ligand binding. The structure-activity relationship (SAR) map highlights residues that are most critical to discriminating between more and less potent ligands. Taken together the interaction energy and the SAR maps provide useful insights into drug design that would be difficult to garner in any other way. PMID- 20205434 TI - Effects of progressive halogen substitution on the photoluminescence properties of an erbium-porphyrin complex. AB - We have investigated the photoluminescence properties of porphyrin-based erbium and gadolinium complexes at different levels of halogen substitution. Both the intensity and the decay time of the erbium near-infrared emission correlate with the degree of the halogenation. Conversely, no clear correlation is found with the triplet-state energy levels nor with the intensity of the residual visible emission. Such findings confirm that the key role in the low efficiency of the near-infrared emission is played by the nonradiative quenching of the erbium emitting level due to the vibrational modes of the surrounding C-H bonds. PMID- 20205435 TI - Vibrational autodetachment-intramolecular vibrational relaxation translated into electronic motion. AB - If a negative ion has vibrational energy in excess of the binding energy of its most weakly bound electron, the anion can undergo vibrational autodetachment, similar to thermionic emission. When this effect occurs after targeted infrared excitation of a specific vibrational mode in the anion, it encodes information on the intramolecular vibrational relaxation processes that take place between excitation and electron emission. We present examples on how vibrational autodetachment can be used to obtain infrared spectra of molecular anions, and we discuss how a vibrational autodetachment photoelectron spectrum can be modeled, using vibrational autodetachment after excitation of CH stretching modes of nitromethane anions as a case study. PMID- 20205436 TI - Reaction-path dynamics calculations of the Cl + NH(3) hydrogen abstraction reaction: the role of the intermediate complexes. AB - Using ab initio information at the CCSD(T)/cc-pVTZ level, the reaction path for the Cl + NH(3) hydrogen abstraction reaction was traced, and the coupling terms between the reaction coordinate and the normal modes were analyzed along it. Two intermediate complexes were located in the entry channel and characterized close to the reactants. One of them presents a typical Cl...H-N bond, while the second presents a two-center/three-electron Cl[symbol:see text]N bond. Both complexes are on the reaction path and contribute to the final rate constants. With this information, the rate constants were calculated over the temperature range 200 2000 K, using variational transition state theory with multidimensional tunneling contributions, and were found to reproduce the experimental evidence in the common temperature range. Finally, analysis of the coupling terms showed qualitatively that vibrational excitation of the N-H stretch and the bending and umbrella modes in the reactant NH(3) enhances the forward thermal rate constants, and that, in the products, the H-Cl stretch mode and the bending mode in NH(2) could appear vibrationally excited, although the randomization of the energy in the well in the exit channel might diminish this excitation. PMID- 20205437 TI - Liquid-solid transition of confined water in silica-based mesopores. AB - Cooling and heating curves of water confined in partially filled Vycor porous glass were measured for both adsorption and desorption processes. One endothermic and two exothermic peaks were observed for almost all cases. The peak temperature and the enthalpy of the exothermic peak located below 232 K increased initially and then decreased with further increases in the filling factor. These abnormal changes were analyzed based on the liquid-solid transition of nanoconfined water using a core/shell model, and the initial adsorption process of water in this typical mesoporous material with disordered pores is discussed. In addition, an interesting observation is that different peak temperatures for the endothermic peak and an almost constant peak temperature for the exothermic peak were observed at the same filling factor obtained under different sample preparation conditions, that is, adsorption and desorption processes. To compare with the liquid-solid transition temperatures of confined water in fully filled silica based mesopores of different pore radius, a parameter of the ratio of pore inner surface area to confined liquid volume is proposed in this paper. Referring to this parameter, the core part of confined water in silica-based nanopores has the same liquid-solid transition temperatures. This suggestion is valid for the freezing process of water confined in either fully filled ordered or fully or partially filled disordered pores. For the melting process, different linear changes of melting temperature with the ratio of pore inner surface area to liquid volume were observed for water in disordered and ordered pores. PMID- 20205438 TI - Adsorption layer characteristics of mixed oxyethylated surfactant solutions. AB - In the presented work, bubble profile analysis tensiometry is used to study the equilibrium surface tensions and the rheological behavior of solutions of mixed oxyethylated alcohols (C(12)EO(5)/C(14)EO(8)) and their mixtures with polyethylene glycol octylphenyl ethers (Triton X45/Triton X165). For the analysis of the experimental data, a new theoretical model for mixtures of two nonionic oxyethylated surfactants was employed which assumes two states of surfactant molecules with different molar areas in the surface layer and an intrinsic compressibility of the molecules in the state of closest packing. The theoretical models allow an accurate description of the experimental equilibrium surface tensions for all studied mixed solutions. For the analysis of the rheological behavior of the studied mixed surfactant solutions, the theory for a diffusional adsorption mechanism was applied, and a satisfactory agreement between the experimental data and the calculated viscoelasticity modulus and phase angle was achieved. PMID- 20205439 TI - 1,3-Dipolar cycloaddition reactions of vinylidenecyclopropane-diesters with aromatic diazomethanes generated in situ. AB - 1,3-Dipolar cycloaddition reactions of VDCP-diesters with aromatic diazomethanes generated in situ from the corresponding aromatic aldehydes and tosylhydrazine mediated by base produce pyrazole derivatives in good yields under mild conditions. A plausible reaction mechanism has been proposed on the basis of control experiments along with the discussion on the regioselectivity. PMID- 20205440 TI - Effect of nanoparticle size on the morphology of adsorbed surfactant layers. AB - The surface aggregate structure of dimethyldodecylamine-N-oxide (C(12)DAO) in three silica dispersions of different particle sizes (16-42 nm) was studied by small-angle neutron scattering (SANS) in a H(2)O/D(2)O solvent mixture matching the silica. At the experimental conditions (pH 9), the surfactant exists in its nonionic form, and the structure of the adsorbed layer is not affected by added electrolyte. It is found that C(12)DAO forms spherical surface micelles of 2 nm diameter on the 16 nm silica particles, but oblate ellipsoidal surface micelles are formed on the 27 and 42 nm particles. The dimensions of these oblate surface aggregates (minor and major semiaxes R(n) and R(lat)) are similar to those of C(12)DAO micelles in the aqueous solutions. It is concluded that the morphological transition from spherical to ellipsoidal surface aggregates is induced by the surface curvature of the silica particles. A comparison of the shape and dimensions of the surface aggregates formed by C(12)DAO and C(12)E(5) on the 16 nm silica particles demonstrates that the nature of the surfactant head group does not determine the morphology of the surface aggregates but has a strong influence on the number of surface aggregates per particle due to the different interactions of the head groups with the silica surface. PMID- 20205441 TI - Single molecule observation of DNA electrophoresis in pluronic f127. AB - Single molecule fluorescence microscopy is used to follow the motion of long DNA molecules undergoing electrophoresis in Pluronic gels. We find that for low fields most DNA molecules follow tortuous paths through the gels, at an angle up to 90 degrees from the field direction, while some molecules find paths along the field lines. In high fields, virtually all of the DNA molecules follow the field lines. In many cases, the molecules travel as compact coils with optically discernible radii smaller than in free solution. In other cases, the molecules extend and contract or travel in an extended configuration. PMID- 20205442 TI - Controlling the reactivity of ruthenium(II) arene complexes by tether ring opening. AB - The closed- and open-tethered Ru(II) eta(6)-arene complexes [Ru(II)(eta(6):eta(1) C(6)H(5)(C(6)H(4))NH(2))(en)]Cl(2) (2) and [Ru(II)(eta(6) C(6)H(5)(C(6)H(4))NH(2))Cl(en)]Cl (3), where en is ethylenediamine, have been synthesized and their X-ray structures determined. Interconversion between 2 and 3, that is, tethered-arene ring-closure and ring-opening, in different solvents has been investigated. Complex 2 opens in dimethylsulfoxide (DMSO) by solvent induced dissociation of the NH(2) group of the pendant arm. In methanol, however, equilibrium between 2 and 3 is reached after 12 h when both species coexist in solution in a ratio of 2:1 (open/closed). In water (pH 7), complete ring closure of 3 to 2 at 298 K occurs in less than 2 h. The tether ring of complex 2 opens at basic pH and closes at neutral pH. Complex 2 opens over time (18 h) in concentrated HCl. The opening-closing process is fully reversible in the pH range 2-12. Density Functional Theory calculations have been used to obtain insights into the electronic structure of complexes 2 and 3, their UV-vis properties, and their stability compared to their aqua derivatives. Control of tether-ring opening can contribute toward a strategy for activation and for achieving cytotoxic selectivity of ruthenium arene anticancer drugs. PMID- 20205443 TI - Conductivity and viscosity behavior of asymmetric phosphonium iodides. AB - In this work, we report the physicochemical properties of a variety of aliphatic phosphonium iodide (API) salts, including thermal degradation. Also, we compared the conductivity, viscosity, and fragility behavior of APIs to similar molten systems and related these properties to their structure. Our investigation has found that APIs have an intermediate fragility behavior. We plotted the conductivity and viscosity data of APIs according to Walden's rule and found that they can be classified as an associated ionic liquid (AIL), an intermediate between a true ionic liquid and a molecular species. Lastly, we correlated the structure and behavior of APIs and similar polarizable anions, such as the diacetamide anion. PMID- 20205430 TI - Fluorescent analogs of biomolecular building blocks: design, properties, and applications. PMID- 20205444 TI - Proton and hydride affinities in excited states: magnitude reversals in proton and hydride affinities between the lowest singlet and triplet states of annulenyl and benzannulenyl anions and cations. AB - Aromaticity has importance for proton and hydride affinities in the singlet ground state (S(0)) of annulenyl anions and cations so that, e.g., cyclopentadiene is an acidic hydrocarbon. For the lowest pipi* excited triplet state (T(1)), Baird's rule concludes that annulenes with 4n pi-electrons are aromatic and those with 4n+2 pi-electrons are antiaromatic, opposite to Huckel's rule for aromaticity in S(0). Our hypothesis is now that the relative magnitudes of proton and hydride affinities of annulenyl anions and cations reverts systematically as one goes from S(0) to T(1) as a result of the opposite electron counting rules for aromaticity in the two states. Using quantum chemical calculations at the G3(MP2)//(U)B3LYP/6-311+G(d,p) level we have examined the validity of this hypothesis for eight proton and eight hydride addition reactions of anions and cations, respectively, of annulenyl and benzannulenyl type. We categorize the (4n+2)pi-electron systems in S(0) and the 4npi-electron systems in T(1) to be of A-character and 4npi-electron systems in S(0) and (4n+2)pi-electron systems in T(1) to be of AA-character (A, aromatic; AA, anti/nonaromatic). The average proton affinities of anions of A- and AA-characters in S(0) are 1447 and 1521 kJ/mol, respectively, and in T(1) they are 1365 and 1493 kJ/mol. The average hydride affinities of A- and AA-character cations in S(0) are 826 and 996 kJ/mol, and in T(1) they are 790 and 879 kJ/mol, respectively. Thus, the calculated proton and hydride affinities are in general lower for anions and cations of A character than for those of AA-character, in good support of our hypothesis. The findings could likely be applied in synthetic organic photochemistry and other areas where excited state acid-base chemistry plays a role. PMID- 20205446 TI - Crystal phase quantum dots. AB - In semiconducting nanowires, both zinc blende and wurtzite crystal structures can coexist. The band structure difference between the two structures can lead to charge confinement. Here we fabricate and study single quantum dot devices defined solely by crystal phase in a chemically homogeneous nanowire and observe single photon generation. More generally, our results show that this type of carrier confinement represents a novel degree of freedom in device design at the nanoscale. PMID- 20205447 TI - New methodologies for the conservation of cultural heritage: micellar solutions, microemulsions, and hydroxide nanoparticles. AB - Modern civilization's inherited artworks have a powerful impact on society, from political, sociological, and anthropological points of view, so the conservation of our Cultural Heritage is fundamental for conveying to future generations our culture, traditions, and ways of thinking and behaving. In the conservation of cultural artifacts, scientists intervene in the degradation of often unique handcrafts, resulting from a delicate balance of aging, unpredicted events, environmental conditions, and sometimes incorrect previous restoration treatments, the details of which are often not precisely known. Nanoscience and nanotechnology are revolutionizing materials science in a pervasive way, in a manner similar to polymer chemistry's revolution of materials science over the preceding century. The continuous development of novel nanoparticle-based materials and the study of physicochemical phenomena at the nanoscale are creating new approaches to conservation science, leading to new methodologies that can "revert" the degradation processes of the works of art, in most cases "restoring" them to their original magnificent appearance. Until recently, serendipity and experiment have been the most frequent design principles of formulations for either cleaning or consolidation of works of art. Accordingly, the past has witnessed a number of actively detrimental treatments, such as the application of acrylic and vinyl resins to wall paintings, which can irreversibly jeopardize the appearance (or even the continued existence) of irreplaceable works of art. Current research activity in conservation science is largely based on the paradigm that compatibility of materials is the most important prerequisite for obtaining excellent and durable results. The most advanced current methodologies are (i) the use of water-based micelles and microemulsions (neat or combined with gels) for the removal of accidental contaminants and polymers used in past restorations and (ii) the application of calcium hydroxide nanoparticles for the consolidation of works of art. In this Account, we highlight how conservation science can benefit from the conceptual and the methodological background derived from both soft (microemulsions and micelles for cleaning) and hard (nanoparticles for consolidation) nanoscience. A combination of different nanotechnologies allows today's conservators to provide, in each restoration step, interventions respectful of the physicochemical characteristics of the materials used by artists. The "palette" of methods provided by nanoscience is continuously enriching the field, and the development of novel nanomaterials and the study of nanoscale physicochemical phenomena will further improve the performance of restoration formulations and our comprehension of degradation mechanisms. PMID- 20205445 TI - Protein pockets: inventory, shape, and comparison. AB - The shape of the protein surface dictates what interactions are possible with other macromolecules, but defining discrete pockets or possible interaction sites remains difficult. First, there is the problem of defining the extent of the pocket. Second, one has to characterize the shape of each pocket. Third, one needs to make quantitative comparisons between pockets on different proteins. An elegant solution to these problems is to sort all surface and solvent points by travel depth and then collect a hierarchical tree of pockets. The connectivity of the tree is determined via the deepest saddle points between each pair of neighboring pockets. The resulting pocket surfaces tessellate the entire protein surface, producing a complete inventory of pockets. This method of identifying pockets also allows one to easily compute important shape metrics, including the problematic pocket volume, surface area, and mouth size. Pockets are also annotated with their lining residue lists and polarity and with other residue based properties. Using this tree and the various shape metrics pockets can be merged, grouped, or filtered for further analysis. Since this method includes the entire surface, it guarantees that any pocket of interest will be found among the output pockets, unlike all previous methods of pocket identification. The resulting hierarchy of pockets is easy to visualize and aids users in higher level analysis. Comparison of pockets is done by using the shape metrics, avoiding the complex shape alignment problem. Example applications show that the method facilitates pocket comparison along mutational or time-dependent series. Pockets from families of proteins can be examined using multiple pocket tree alignments to see how ligand binding sites or how other pockets have changed with evolution. Our method is called CLIPPERS for complete liberal inventory of protein pockets elucidating and reporting on shape. PMID- 20205448 TI - Lipase-catalyzed synthesis of poly(amine-co-esters) via copolymerization of diester with amino-substituted diol. AB - Candida antarctica lipase B (CALB) was found to be an efficient catalyst for copolymerization of diesters with amino-substituted diols to form poly(amine-co esters) in one step. The copolymerization reactions were carried out at 50-100 degrees C in two stages: first stage oligomerization under 1 atm pressure of nitrogen followed by second stage polymerization under 1-2 mmHg vacuum. The formed copolymers possessed molecular weight (M(w)) up to 59000 and typical polydispersity (M(w)/M(n)) between 1.5 and 2.3. The enzymatic reaction appears to be quite general and accommodates a large number of comonomer substrates with various chain length and substituents. Thus, C(4)-C(12) diesters (i.e., from succinate to dodecanedioate) and diethanolamine comonomers with either an alkyl (methyl, ethyl, n-butyl, t-butyl) or an aryl (phenyl) substituent on nitrogen were successfully incorporated into the poly(amine-co-ester) chains. Biodegradable polyesters bearing tertiary amino groups have been reported to be efficient carriers for gene delivery. The high tolerance of the lipase toward tertiary amino functional groups as described in this paper provides new routes for synthesizing poly(amine-co-esters) with tailored structures for specific biomedical applications. PMID- 20205449 TI - Interactions of Kraft lignin and wheat gluten during biomaterial processing: evidence for the role of phenolic groups. AB - The chemical interactions between Kraft lignin and wheat gluten under processing conditions were investigated by determining the extent of the protein network formation. To clarify the role of different chemical functions found in lignin, the effect of Kraft lignin was compared with that of an esterified lignin, in which hydroxyl groups had been suppressed by esterification, and with a series of simple aromatics and phenolic structures with different functionalities (conjugated double bonds, hydroxyl, carboxylic acid, and aldehyde). The protein solubility was determined by using the Kjeldahl method. The role of the hydroxyl function was assessed by the significantly lower effect of esterified lignin. The importance of the phenolic radical scavenging structure is evidenced by the effect of guaiacol, which results in a behavior similar to that of the Kraft lignin. In addition, the significant effect of conjugated double bonds on gluten reactivity, through nucleophilic addition, was demonstrated. PMID- 20205450 TI - Comparison of three extraction methods used to evaluate phenolic ripening in red grapes. AB - Because there is not a single method for carrying out phenolic ripening analysis, it is very difficult to compare the results obtained by different researchers. In this study, the three most widely used extraction methods of polyphenols (Glories, AWRI, and ITV) have been analytically compared by evaluating two of the most important parameters for the wine industry: total polyphenols and total anthocyanins. Samples from different grape varieties (Tempranillo, Garnacha, Carinena, Syrah, Merlot, and Cabernet Sauvignon), from three different vintages (2006, 2007, and 2008), and at different ripening states (from the beginning of ripeness until harvest) were analyzed to obtain a wide range of representative phenolic contents. To avoid external interferences on the comparisons, the same grape puree was used to make the maceration assays using the different solvents according to each extraction method. Although every extraction method exhibits a different extraction efficiency, the correlation between the results obtained with each one was very good both for total anthocyanins and for total polyphenols. Thus, after having determined a parameter value of the phenolic ripeness using a specific method, the relationship found can be used to predict the parameter value of the phenolic ripeness provided by the other two methods. PMID- 20205451 TI - Novel alkoxyamine linker to load ketones for solid-phase synthesis: application of the synthesis of 1,4-benzodiazepine-2-ones. PMID- 20205452 TI - Structure, physical, and digestive properties of starch from wx ae double-mutant rice. AB - Amylopectin is the principal component of starch. The amylose extender (ae) gene encodes the starch-branching enzyme IIb, which is critical in determining the fine structure of endosperm starch. To determine the relationship between the fine structure of amylopectin and its physical properties, rice mutant lines defective in the ae function with altered fine structure of amylopectin and in combination with the waxy (wx) background were selected for comparative studies with primary wild-type and ae starches. The ae mutant endosperms accumulated a high amylose content starch with long amylopectin chains. The ae and wx ae starches showed no significant difference in the unit chain-length distribution of amylopectin and starch granule morphology. The wx ae starch displayed a higher pasting temperature and higher peak viscosity. The gelatinization peak temperatures of the wx, ae, and wx ae starches were 2.2, 13.1, and 17.1 degrees C higher, respectively, than that of the wild-type starch, and the wx ae starch showed a retrogradation peak with a shorter cooling period than that of ae starch. The raw ae and wx ae starches were almost indigestible by alpha-amylase in vitro. Rats fed the wx ae starch showed slowly increasing blood glucose at a lower level than the rats fed the wx or wild-type starch. These results indicate that the primary structure of the rice wx ae amylopectin with enriched long chains changes the granular structure of the starch, including its crystal structure, and results in resistance to in vitro or in vivo degradation. PMID- 20205453 TI - Synthesis of sintering-resistant sorbents for CO2 capture. AB - Sorbents for high temperature CO2 capture are under intensive development owing to their potential applications in advanced zero emission power, sorption enhanced steam methane reforming for hydrogen production and energy storage systems in chemical heat pumps. One of the challenges in the development is the prevention of sintering of the sorbent (normally a calcium oxide derivative) which causes the CO2 capture capacity of the material to deteriorate rapidly after a few cycles of utilization. Here we show that a simple wet mixing method can produce sintering-resistant sorbents from calcium and magnesium salts of d gluconic acid. It was found that calcium oxide was well distributed in the sorbents with metal oxide nanoparticles on the surface acting as physical barriers, and the CO2 capture capacity of the sorbents was largely maintained over multiple cycles of utilization. This method was also applied to other organometallic salts of calcium and magnesium/aluminum and the produced sorbents showed similarly high reversibility. PMID- 20205454 TI - Artificial photosynthesis in ranaspumin-2 based foam. AB - We present a cell-free artificial photosynthesis platform that couples the requisite enzymes of the Calvin cycle with a nanoscale photophosphorylation system engineered into a foam architecture using the Tungara frog surfactant protein Ranaspumin-2. This unique protein surfactant allowed lipid vesicles and coupled enzyme activity to be concentrated to the microscale Plateau channels of the foam, directing photoderived chemical energy to the singular purpose of carbon fixation and sugar synthesis, with chemical conversion efficiencies approaching 96%. PMID- 20205455 TI - Exfoliation and characterization of bismuth telluride atomic quintuples and quasi two-dimensional crystals. AB - Bismuth telluride (Bi(2)Te(3)) and its alloys are the best bulk thermoelectric materials known today. In addition, stacked quasi-two-dimensional (2D) layers of Bi(2)Te(3) were recently identified as promising topological insulators. In this Letter we describe a method for "graphene-inspired" exfoliation of crystalline bismuth telluride films with a thickness of a few atoms. The atomically thin films were suspended across trenches in Si/SiO(2) substrates, and subjected to detail material characterization, which included atomic force microscopy and micro-Raman spectroscopy. The presence of the van der Waals gaps allowed us to disassemble Bi(2)Te(3) crystal into its quintuple building blocks-five monatomic sheets-consisting of Te((1))-Bi-Te((2))-Bi-Te((1)). By altering the thickness and sequence of atomic planes, we were able to create "designer" nonstoichiometric quasi-2D crystalline films, change their composition and doping, the type of charge carriers as well as other properties. The exfoliated quintuples and ultrathin films have low thermal conductivity, high electrical conductivity, and enhanced thermoelectric properties. The obtained results pave the way for producing stacks of crystalline bismuth telluride quantum wells with the strong spatial confinement of charge carriers and acoustic phonons, beneficial for thermoelectric devices. The developed technology for producing free-standing quasi-2D layers of Te((1))-Bi-Te((2))-Bi-Te((1)) creates an impetus for investigation of the topological insulators and their possible practical applications. PMID- 20205456 TI - Aquatic photochemistry of fluoroquinolone antibiotics: kinetics, pathways, and multivariate effects of main water constituents. AB - The ubiquity of fluoroquinolone antibiotics (FQs) in surface waters urges insights into their fate in the aqueous euphotic zone. In this study, eight FQs (ciprofloxacin, danofloxacin, levofloxacin, sarafloxacin, difloxacin, enrofloxacin, gatifloxacin, and balofloxacin) were exposed to simulated sunlight, and their photodegradation was observed to follow apparent first-order kinetics. Based on the determined photolytic quantum yields, solar photodegradation half lives for the FQs in pure water and at 45 degrees N latitude were calculated to range from 1.25 min for enrofloxacin to 58.0 min for balofloxacin, suggesting that FQs would intrinsically photodegrade fast in sunlit surface waters. However, we found freshwater and seawater constituents inhibited their photodegradation. The inhibition was further explored by a central composite design using sarafloxacin and gatifloxacin as representatives. Humic acids (HA), Fe(III), NO(3)(-), and HA-Cl(-) interaction inhibited the photodegradation, as they mainly acted as radiation filters and/or scavengers for reactive oxygen species. The photodegradation product identification and ROS scavenging experiments indicated that the FQs underwent both direct photolysis and self-sensitized photo-oxidation via *OH and (1)O(2). Piperazinyl N(4)-dealkylation was primary for N(4)-alkylated FQs, whereas decarboxylation and defluorination were comparatively important for the other FQs. These results are of importance toward the goal of assessing the persistence of FQs in surface waters. PMID- 20205457 TI - Size-resolved organic speciation of wintertime aerosols in California's Central Valley. AB - Size-resolved aerosol samples, including the entire ultrafine fraction, were simultaneously collected along a transect in California's Central Valley during the winter of 2009. The samples were analyzed for PAHs, alkanes, organic acids, and sugars. The results showed that the organic constituents of aerosols did not follow the same pattern as PM(10), thus indicating that simple PM measurements are not good indicators of trace toxic organic chemicals. Levoglucosan, a tracer of wood smoke, was the most abundant organic chemical detected, thus demonstrating the predominance of wood smoke in the valley. The size profile of levoglucosan showed a maximum in the 0.34-0.56 microm size mode, which is larger than published emission profiles. This suggests that wood smoke aerosols increased in size as they aged in the environment. Some chemicals, such as benzo[a]pyrene, had similar aerosol size profiles as levoglucosan and likely arose from the same source. Other chemicals, such as coronene and sugars, had very different size profiles, indicating that they have different sources. One unexpected result was the relatively large fraction of certain chemicals present in the ultrafine fraction, which highlights the importance of collecting the entire ultrafine fraction. PMID- 20205458 TI - On the cation dependence of interlamellar and interparticular water and swelling in smectite clays. AB - The osmotic character of long-range interlamellar swelling in smectite clays is widely accepted and has been evidenced in the interlayer space by X-ray diffraction. Such a behavior in mesopores was not experimentally confirmed until the determination of the mesopore size distribution in Na-montmorillonite prepared from MX80 bentonite using thermoporometry experiments. This is confirmed here for other montmorillonite samples where the interlayer cations are alkaline and Ca(2+) cations. The nature of the interlayer cation is found as strongly influencing the behavior of the size and the swelling of mesopores. These results are supported by the BJH (Barrett, Joyner and Halenda) pore radius values issued from the nitrogen adsorption-desorption isotherms at the dry state. Thermoporometry results as a function of relative humidity ranging from 11% to 97% have shown an evolution of the mesopore sizes for a purified Na montmorillonite. New thermoporometry data are presented in this article and confirm that the interparticle spaces in K-, Cs-, or Ca-montmorillonites are not strongly modified for all the range of relative humidity: the swelling is not observed or is strongly limited. It appears in contrast that only Li- and Na montmorillonites undergo a mesopore swelling, distinct from the interlayer swelling. More generally, our results confirm the possibility to use thermoporometry or differential scanning calorimetry to study the structure and the evolution of swelling materials in wetting conditions such as natural clays or biological cells. In this paper, we describe the different key steps of the hydration of swelling clays such as montmorillonites saturated with alkaline cations. Using thermoporometry results combined with X-ray diffraction data, we distinguish the evolution of the porosity at the two different scales and propose a sequence of hydration dependent on the interlayer cation. From this study, it is shown that the interlayer spaces are not completely filled when the mesopores start to fill up. This implies that the swelling observed in the mesopores for Li and Na samples is due to an osmotic swelling. For the other samples, it is difficult to conclude definitively. Furthermore, we determine the different proportion of water (interlayer water and mesopore water) present in our samples by the original combination of (1) X-ray diffraction data, (2) the pore size distribution obtained by thermoporometry, and (3) recent adsorption isotherm results. It is found that the interlayer space is never completely filled by water at the studied relative humidity values for all samples except for the Cs sample. PMID- 20205459 TI - Single-step process to reconstitute cell membranes on solid supports. AB - A new technique is presented to create supported lipid bilayers from whole cell lipids without the use of detergent or solvent extraction. In a modification of the bubble collapse deposition (BCD) technique, an air bubble is created underwater and brought into contact with a population of cells. The high-energy air/water interface extracts the lipid component of the cell membrane, which can subsequently be redeposited as a fluid bilayer on another substrate. The resulting bilayers were characterized with fluorescence microscopy, and it was found that both leaflets of the cell membrane are transferred but the cytoskeleton is not. The resulting supported bilayer was fluid over an area much larger than a single cell, demonstrating the capacity to create large, continuous bilayer samples. This capability to create fluid, biologically relevant bilayers will facilitate the use of high-resolution scanning microscopy techniques in the study of membrane-related processes. PMID- 20205460 TI - Hexagonal organic nanopillar array from the melamine-cyanuric acid complex. AB - We report a well-defined, organic, hexagonal nanopillar array on a gold surface. The array was prepared from a cyanuric acid-melamine complex by means of sequential mixing on the gold surface. These nanopillars had uniform diameters of 200-400 nm and were 1 microm in length. They were well faceted with hexagonal cross sections. The nanopillars had a crystalline structure, and the pillars exhibited a layered texture in the longitudinal direction. PMID- 20205461 TI - Multilayer buildup and biofouling characteristics of PSS-b-PEG containing films. AB - Thin films exhibiting protein resistance are of interest in diverse areas, ranging from low fouling surfaces in biomedicine to marine applications. Herein, we report the preparation of low protein and cell binding multilayer thin films, formed by the alternate deposition of a block copolymer comprising polystyrene sulfonate and poly(poly(ethylene glycol) methyl ether acrylate) (PSS-b-PEG), and polyallylamine hydrochloride (PAH). Film buildup was followed by quartz crystal microgravimetry (QCM), which showed linear growth and a high degree of hydration of the PSS-b-PEG/PAH films. Protein adsorption studies with bovine serum albumin using QCM demonstrated that multilayer films of PSS/PAH with a terminal layer of PSS-b-PEG were up to 5-fold more protein resistant than PSS-terminated films. Protein binding was dependent on the ionic strength at which the terminal layer of PSS-b-PEG was adsorbed, as well as the pH of the protein solution. It was also possible to control the protein resistance of the films by coadsorption of the final layer with another component (PSS), which showed an increase in protein resistance as the proportion of PSS-b-PEG in the adsorption solution was increased. In addition, protein resistance could also be controlled by the location of a single PSS-b-PEG layer within a PSS/PAH film. Finally, the buildup of PSS-b-PEG/PAH films on colloidal particles was demonstrated. PSS-b-PEG terminated particles exhibited a 6.5-fold enhancement in cell binding resistance compared with PSS-terminated particles. The stability of PSS-b-PEG films combined with their low protein and cell binding characteristics provide opportunities for the use of the films as low fouling coatings in devices and other surfaces requiring limited interaction with biological interfaces. PMID- 20205462 TI - T-shaped molecular building blocks by combined bridgehead and bridge substitution on bicyclo[1.1.1]pentanes. AB - Derivatives of bicyclo[1.1.1]pentane differentially substituted in bridgehead (1,3) and bridge (2,4) positions have been synthesized. They represent a new T shaped structural module consisting of a rigid rod with a nearly freely rotating side arm, possibly useful as a molecular building block in syntheses of more complex covalent or supramolecular scaffolds useful in bottom-up construction of molecular level devices or materials. For good chemical connectivity in the axial direction, carboxylates, ethynyls, and acetylsulfanyl groups were installed at the bridgeheads. Quinoxalines were attached in the transverse direction through a highly reactive alpha-diketone system located at the bridges. PMID- 20205463 TI - Iodide impurities in hexadecyltrimethylammonium bromide (CTAB) products: lot-lot variations and influence on gold nanorod synthesis. AB - Recent reports [Smith and Korgel Langmuir 2008, 24, 644-649 and Smith et al. Langmuir 2009, 25, 9518-9524] have implicated certain hexadecyltrimethylammonium bromide (CTAB) products with iodide impurities, in the failure of a seed mediated, silver and surfactant-assisted growth protocol, to produce gold nanorods. We used two of the three "suspect" CTAB products and a "good" CTAB product in the protocol, varying silver nitrate solutions in the growth solutions. We obtained excellent gold nanorod samples as witnessed in signature longitudinal plasmon peaks in optical extinction spectra, which we substantiated using electron microscopy. Analysis of these samples using inductively coupled plasma mass spectroscopy (ICP-MS) failed to detect iodide. We subsequently learnt from discussions with Smith et al. that different lot numbers within the same product had been analyzed by our respective laboratories. We can conclude that iodide impurities can vary significantly from lot to lot within a product, to such an extent that there is no guarantee that gold nanorods can be synthesized with one or other CTAB product. Conversely, labeling a CTAB product, identified by a product number or supplier name, as one whose use precludes the formation of nanorods, is also hasty. PMID- 20205464 TI - Context dependence of trinucleotide repeat structures. AB - Long repeated sequences of DNA and their associated secondary structure govern the development and severity of a significant class of neurological diseases. Utilizing the effect of base stacking on fluorescence quantum yield, 2 aminopurine substitutions for adenine previously demonstrated sequestered bases in the stem and exposed bases in the loop for an isolated (CAG)(8) sequence. This study evaluates (CAG)(8) that is incorporated into a duplex, as this three-way junction is a relevant model for intermediates that lead to repeat expansion during DNA replication and repair. From an energetic perspective, thermally induced denaturation indicates that the duplex arms dictate stability and that the secondary structure of the repeated sequence is disrupted. Substitutions with 2-aminopurine probe base exposure throughout this structure, and two conclusions about secondary structure are derived. First, the central region of (CAG)(8) is more solvent-exposed than single-stranded DNA, which suggests that hairpin formation in the repeated sequence is disrupted. Second, base stacking becomes compromised in the transition from the duplex to (CAG)(8), resulting in bases that are most similar to single-stranded DNA at the junction. Thus, an open (CAG)(8) loop and exposed bases in the arms indicate that the strand junction profoundly influences repeated sequences within three-way junctions. PMID- 20205465 TI - Synthesis of 2-indolylphosphines by palladium-catalyzed annulation of 1 alkynylphosphine sulfides with 2-iodoanilines. AB - Palladium-catalyzed annulation of 1-alkynylphosphine sulfides with 2-iodoanilines followed by desulfidation affords 3-substituted 2-indolylphosphines. This annulation/desulfidation sequential protocol offers a conceptually new approach to bulky heteroarylphosphines. PMID- 20205466 TI - Rhodium(NHC)-catalyzed amination of aryl bromides. AB - A rhodium-catalyzed amination reaction of aryl halides with amines has been developed with the use of a N-heterocyclic carbene (NHC) ligand (IiPr = 1,3 diisopropylimidazol-2-ylidene). The active metal species responsible for the reaction progress was identified. The developed procedure of the Rh-catalyzedN arylation is convenient to carry out under mild reaction conditions displaying a wide range of substrate scope and high degree of functional group tolerance. PMID- 20205468 TI - Marked alkyl- vs alkenyl-substitutent effects on squaraine dye solid-state structure, carrier mobility, and bulk-heterojunction solar cell efficiency. AB - We report two new squaraine dyes substituted at the pyrrolic rings with n-hexyl (squaraine 1) or n-hexenyl (squaraine 2) chains. Although internal molecular structure variations are minimal, the presence of the terminal double bond results in a much more compact solid-state structure, dramatically affecting charge transport in the thin films; the hole mobility of 2 is approximately 5x that of 1, and the BHJ OPV power conversion efficiency (PCE) of 2 is approximately 2x that of 1. PCEs surpassing 2% for ambient solution-processed devices are demonstrated, the largest so far achieved for squaraine-based organic solar cells. PMID- 20205469 TI - Virus' (MS2, phiX174, and Aichi) attachment on sand measured by atomic force microscopy and their transport through sand columns. AB - Atomic force microscopy (AFM) was used to study the attachment of phiX174, MS2, and Aichi viruses on sands of different surface properties: oxide-removed (clean), goethite-coated, and aluminum oxide-coated. Interaction forces between viruses and sand surfaces were measured by contact mode AFM using tips coated with particles of each virus. Column experiments were conducted to quantify the macroscopic transport and retention of the viruses in sand. The average adhesion force measured with AFM was highest between aluminum oxide-coated sand and all three viruses, followed by goethite-coated sand, and was significantly lower on oxide-removed sand. Among the viruses, adhesion on goethite-coated and aluminum oxide-coated sands followed the order of MS2 > Aichi > phiX174, and on oxide removed sand it was phiX174 > Aichi > MS2. Column breakthrough results revealed the same retention trend, which was completely consistent with AFM force measurements. Strong electrostatic attraction and, to a lesser extent, hydrophobic interactions are responsible for the much greater removal of all three viruses observed in the oxide-coated sands compared to the oxide-removed sand. Mass recovery data indicate that the removal of phiX174, MS2, and Aichi was largely reversible when eluted with 3% beef extract solution at pH 9.5. The Derjaguin-Landau-Verwey-Overbeek (DLVO) and extended DLVO theories provided correct qualitative predictions on the deposition trend observed in the experiments. This study, to the best of our knowledge, was the first to employ AFM to directly measure interaction forces between viruses and solid surfaces; and it was the first to evaluate the retention and transport behavior of Aichi virus, a human pathogen. PMID- 20205470 TI - Formation of Pent-4-en-1-amine, the counterpart of acrylamide from lysine and its conversion into piperidine in lysine/glucose reaction mixtures. AB - Isotope labeling studies performed using lysine/glucose model systems have indicated that lysine can generate piperidine, a reactive amine capable of undergoing Maillard type interactions. Two possible mechanisms were identified for the formation of piperidine: one arising through decarboxylation of lysine alone to generate cadaverine (1,5-diaminopentane) followed by deamination to form pent-4-en-1-amine which in turn can cyclize into piperidine where both Nepsilon and Nalpha atoms of lysine can be equally involved in its generation due to the symmetrical nature of the precursor diamine. On the other hand, in the presence of sugars, lysine, similarly to asparagine and phenylalanine, can undergo carbonyl-assisted decarboxylative deamination reaction to generate pent-4-en-1 amine, the counterpart of acrylamide. The pent-4-en-1-amine can then cyclize to form piperidine through the Nepsilon atom of lysine. To confirm the formation of pent-4-en-1-amine in the lysine/glucose model system, a useful strategy based on Py-GC/MS analysis was developed using isotope labeling technique to identify sugar adducts of pent-4-en-1-amine. Products simultaneously possessing five lysine carbon atoms (C2'-C6') and the Nepsilon-amino group from lysine in addition to glucose carbon atoms were targeted using specifically labeled precursors such as [(15)Nalpha]lysine.2HCl, [(15)Nepsilon]lysine.2HCl, [U (13)C(6)]lysine.2HCl, [(13)C-6]lysine.2HCl and [U-(13)C(6)]glucose. The complete labeling studies along with structural analysis using synthetic and other available precursors have shown the presence of a peak that satisfies the above criteria, and the peak was tentatively identified as N-(5-methylfuran-2 yl)methylidene]penta-1,3-dien-1-amine incorporating pent-4-en-1-amine in its structure. PMID- 20205471 TI - Differential effects of divalent manganese and magnesium on the kinase activity of leucine-rich repeat kinase 2 (LRRK2). AB - Various mutations in leucine-rich repeat kinase 2 (LRRK2) have been linked to susceptibility for both familial and idiopathic late-onset Parkinson's disease (PD). In this study, we have demonstrated that phosphorylation of MBP and LRRKtide by the LRRK2 G2019S mutant was activated by Mn(2+) in vitro. This enhanced G2019S kinase activity was due to the combination of an increase in kinase and a decrease in ATPase activity by Mn(2+). Compared to 10 mM Mg(2+), 1 mM Mn(2+) reduced ATP K(m) for G2019S from 103 to 1.8 muM and only modestly reduced k(cat) (2.5-fold); as a result, the Mn(2+) increased its k(cat)/K(m) by 22-fold. This change in ATP K(m) was due in large part to an increase in nucleotide affinity. While Mn(2+) also increased ATP affinity and had similar effects on k(cat)/K(m) for LRRK2 WT and R1441C enzymes, it reduced their k(cat) values significantly by 13-17-fold. Consequently, the difference in the kinase activity between G2019S and other LRRK2 variants was enhanced from about 2-fold in Mg(2+) to 10-fold in Mn(2+) at saturating ATP concentrations relative to its K(m). Furthermore, while Mg(2+) yielded optimal V(max) values at Mg(2+) concentration greater than 5 mM, the optimal Mn(2+) concentration for activating LRRK2 catalysis was in the micromolar range with increasing Mn(2+) above 1 mM causing a decrease in enzyme activity. Finally, despite the large but expected differences in IC(50) tested at 100 muM ATP, the apparent K(i) values of a small set of LRRK2 ATP-competitive inhibitors were within 5-fold between Mg(2+)- and Mn(2+)-mediated reactions except AMP-CPP, an ATP analogue. PMID- 20205472 TI - Isozyme-specific fluorescent inhibitor of glutathione s-transferase omega 1. AB - Recently, the glutathione S-transferase omega 1 (GSTO1) is suspected to be involved in certain cancers and neurodegenerative diseases. However, profound investigation on the pathological roles of GSTO1 has been hampered by the lack of specific methods to determine or modulate its activity in biological systems containing other isoforms with similar catalytic function. Here, we report a fluorescent compound that is able to inhibit and monitor the activity of GSTO1. We screened 43 fluorescent chemicals and found a compound (6) that binds specifically to the active site of GSTO1. We observed that compound 6 inhibits GSTO1 by covalent modification but spares other isoforms in HEK293 cells and demonstrated that compound 6 could report the activity of GSTO1 in NIH/3T3 or HEK293 cells by measuring the fluorescence intensity of the labeled amount of GSTO1 in SDS-PAGE. Compound 6 is a useful tool to study GSTO1, applicable as a specific inhibitor and an activity reporter. PMID- 20205474 TI - Vitamin E TPGS P-glycoprotein inhibition mechanism: influence on conformational flexibility, intracellular ATP levels, and role of time and site of access. AB - Previous work conducted in our laboratories established the notion that TPGS 1000 (d-alpha-tocopheryl polyethylene glycol 1000 succinate), a nonionic surfactant, modulates P-glycoprotein (P-gp) efflux transport via P-gp ATPase inhibition. The current in vitro research using Caco-2 cells was conducted to further explore the P-gp ATPase inhibition mechanism. Using a monoclonal CD243 P-gp antibody shift assay (UIC2), we probed P-gp conformational changes induced via TPGS 1000. In the presence of TPGS 1000, UIC2 binding was slightly decreased. TPGS 1000 does not appear to be a P-gp substrate, nor does it function as a competitive inhibitor in P-gp substrate efflux transport. The reduction in UIC2 binding with TPGS 1000 was markedly weaker than with orthovanadate, data ruling out trapping P-gp in a transition state by direct interaction with one or both of the P-gp ATP nucleotide binding domains. An intracellular ATP depletion mechanism could be ruled out in the UIC2 assay, and by monitoring intracellular ATP levels in the presence of TPGS 1000. Indicating slow distribution of TPGS 1000 into the membrane, and in agreement with an intramembranal or intracellular side of action, Caco-2 cell monolayer experiments preincubated with TPGS 1000 produce stronger substrate inhibitory activity than those conducted by direct substrate and surfactant coapplication. PMID- 20205473 TI - Nitric oxide-releasing silica nanoparticle inhibition of ovarian cancer cell growth. AB - Although the potent antitumor activity of nitric oxide (NO) supports its promise as an antineoplastic agent, effective and selective delivery and action on tumor and not normal cells remains a limiting factor. Nanoparticle-based delivery of NO has been considered as one approach to overcome these limitations. Therefore, we determined the utility of NO delivery using silica nanoparticles and evaluated their antitumor efficacy against human ovarian tumor and nontumor cells. The NO releasing nanoparticles exhibited enhanced growth inhibition of ovarian tumor cells when compared to both control nanoparticles and a previously reported small molecule NO donor, PYRRO/NO. In addition, the NO-releasing nanoparticles showed greater inhibition of the anchorage-independent growth of tumor-derived and Ras transformed ovarian cells. Confocal microscopy analysis revealed that fluorescently labeled NO-releasing nanoparticles entered the cytosol of the cell and localized to late endosomes and lysosomes. Furthermore, we observed a nanoparticle size dependency on efficacy against normal versus transformed ovarian cells. Our study provides the first application of nanoparticle-derived NO as an antitumor therapy and merits future studies examining nanoparticle formulation for in vivo applications. PMID- 20205475 TI - Snake venomic of Crotalus durissus terrificus--correlation with pharmacological activities. AB - The snake venomic of Crotalus durissus terrificus was analyzed by 2-D and 1-D electrophoresis and subsequent MS/MS and enzymatic assays. The venomic of the South American rattlesnake comprises toxins from seven protein families: phospholipases A(2), serine proteinases, ecto-5'-nucleotidases, metalloproteinases, nerve growth factors, phosphodiesterases, and glutaminyl cyclase. The venom toxin composition correlates with the clinical manifestation of the crotalinae snake bites and explains pathological effects of the venom such as neurotoxicity, systemic myonecrosis, hemostatic disorders, myoglobinuria, and acute renal failure. The vast majority of toxins are potentially involved in neurotoxicity, myotoxicity, and coagulopathy. The predominant venom components are neurotoxic phospholipases A(2) and serine proteinases. The venom is a rich source of 5'-nucleotidases (7.8% of the identified toxins) inducing hemostatic disorders. Analysis of the venom protein composition provided a catalogue for secreted toxins. The venomic composition of Crotalus d. terrificus and venom gland transcriptome of the synonymous subspecies Crotalus d. collilineatus show differences in the occurrence of protein families and in the abundance of toxins. Some of the venom components identified by the proteomic analysis were not reported in the transcriptome of the Crotalus d. collilineatus venom gland. Enzymatic activities of the Crotalus d. terrificus venom were determined and correlated with the proteomic composition. PMID- 20205476 TI - Shell-sheddable micelles based on dextran-SS-poly(epsilon-caprolactone) diblock copolymer for efficient intracellular release of doxorubicin. AB - Reduction-responsive biodegradable micelles were developed from disulfide-linked dextran-b-poly(epsilon-caprolactone) diblock copolymer (Dex-SS-PCL) and applied for triggered release of doxorubicin (DOX) in vitro and inside cells. Dex-SS-PCL was readily synthesized by thiol-disulfide exchange reaction between dextran orthopyridyl disulfide (Dex-SS-py, 6000 Da) and mercapto PCL (PCL-SH, 3100 Da). Dynamic light scattering (DLS) measurements showed that Dex-SS-PCL yielded micelles with an average size of about 60 nm and a low polydispersity index (PDI 0.1-0.2) in PB (50 mM, pH 7.4). Interestingly, these micelles formed large aggregates rapidly in response to 10 mM dithiothreitol (DTT), most likely due to shedding of the dextran shells through reductive cleavage of the intermediate disulfide bonds. DOX could be efficiently loaded into the micelles with a drug loading efficiency of about 70%. Notably, the in vitro release studies revealed that Dex-SS-PCL micelles released DOX quantitatively in 10 h under a reductive environment, mimicking that of the intracellular compartments such as cytosol and the cell nucleus, whereas only about 27% DOX was released from reduction insensitive Dex-PCL micelles in 11.5 h under otherwise the same conditions and about 20% DOX released from Dex-SS-PCL micelles in 20 h under the nonreductive conditions. The cell experiments using fluorescence microscopy and confocal laser scanning microscopy (CLSM) showed clearly that DOX was rapidly released to the cytoplasm as well as to the cell nucleus. MTT studies revealed a markedly enhanced drug efficacy of DOX-loaded Dex-SS-PCL micelles as compared to DOX loaded reduction-insensitive Dex-PCL micelles. These reduction-responsive biodegradable micelles have appeared highly promising for the targeted intracellular delivery of hydrophobic chemotherapeutics in cancer therapy. PMID- 20205477 TI - Desymmetrization of cyclohexadienones via Bronsted acid-catalyzed enantioselective oxo-Michael reaction. AB - Desymmetrization of cyclohexadienones via enantioselective oxo-Michael reaction catalyzed by chiral phosphoric acid to afford highly enantioenriched 1,4-dioxane and tetrahydrofuran derivatives in excellent yields has been realized. The newly established methodology allows the facile enantioselective synthesis of cleroindicins C, D, and F. PMID- 20205478 TI - Enhancement of incident photon-to-current conversion efficiency for phthalocyanine-sensitized solar cells by 3D molecular structuralization. AB - Enlarging the molecular size of zinc phthalocyanine (Pc) dyes three dimensionally with 2,6-diphenylphenoxy substituents significantly reduced the aggregation of the dyes on a TiO(2) surface. As a result, the incident photon-to-current conversion efficiency was improved not only in the Q band but over the whole absorption range, achieving 4.6% energy conversion efficiency under one-sun conditions. Electron lifetime measurements indicated that these Pc dyes do not enhance charge recombination, encouraging further development of Pc. PMID- 20205480 TI - Mild two-step process for the transition-metal-free synthesis of carbon-carbon bonds from allylic alcohols/ethers and grignard reagents. AB - A mild two-step process for the regioselective, transition-metal-free preparation of carbon-carbon bonds from allylic alcohols/ethers and Grignard reagents is described. This process obviates the need for the harsh deprotection conditions usually required for removal of methyl ethers. The synthesis is accomplished by photochemically promoted allylic substitution reactions of allylic alcohols and ethers with diethylphosphorothioic acid followed by sp(3)-sp(3) or sp(2)-sp(3) bond formation with various Grignard reagents under transition-metal-free conditions. Depending on the nature of the nucleophile, the regioselectivity of the carbon-carbon bond-forming event can be controlled to furnish either quaternary or tertiary carbon centers. PMID- 20205479 TI - Radiosynthesis and bioimaging of the tuberculosis chemotherapeutics isoniazid, rifampicin and pyrazinamide in baboons. AB - The front-line tuberculosis (TB) chemotherapeutics isoniazid (INH), rifampicin (RIF), and pyrazinamide (PZA) have been labeled with carbon-11 and the biodistribution of each labeled drug has been determined in baboons using positron emission tomography (PET). Each radiosynthesis and formulation has been accomplished in 1 h, using [(11)C]CH(3)I to label RIF and [(11)C]HCN to label INH and PZA. Following iv administration, INH, PZA, RIF, and/or their radiolabeled metabolites clear rapidly from many tissues; however, INH, PZA, and/or their radiolabeled metabolites accumulate in the bladder while RIF and/or its radiolabeled metabolites accumulates in the liver and gall bladder, consistent with the known routes of excretion of the drugs. In addition, the biodistribution data demonstrate that the ability of the three drugs and their radiolabeled metabolites to cross the blood-brain barrier decreases in the order PZA > INH > RIF, although in all cases the estimated drug concentrations are greater than the minimum inhibitory concentration (MIC) values for inhibiting bacterial growth of Mycobacterium tuberculosis (MTB). The pharmacokinetic (PK) and drug distribution data have important implications for treatment of disseminated TB in the brain and pave the way for imaging the distribution of the pathogen in vivo. PMID- 20205481 TI - A systematic data review of the cost of rehydration therapy. AB - Dehydration secondary to acute gastroenteritis is a commonly encountered condition among patients presenting to physicians' offices and hospital EDs. Treatment options consist of oral rehydration therapy (ORT), intravenous rehydration therapy (IVRT) and subcutaneous rehydration therapy (SCRT). Although most patients with dehydration can be effectively treated in an outpatient setting, hospitalization is frequently warranted, with estimated annual inpatient costs for dehydration therapy exceeding $US1 billion in the US in 1999 for elderly patients alone. Although most treatment guidelines recommend ORT as first line treatment for mild to moderate dehydration, IVRT remains the predominant route of administration for rehydration fluids in the acute care setting in the US. To evaluate the current state of the literature examining costs associated with dehydration therapy, a systematic review of articles published on MEDLINE from 2000 to 2009 was conducted. A total of 20 reports containing pharmacoeconomic data on rehydration therapy were evaluated. Findings suggest that ORT and SCRT may be less costly than IVRT in the treatment of mild to moderate dehydration; however, variability in cost parameters examined or data collection methods described in the literature precluded a comprehensive comparative cost-effectiveness analysis of treatment options. Future pharmacoeconomic analyses of rehydration therapy should incorporate time-motion analyses comprising a consistent set of variables to determine the most cost effective treatment modality for patients with mild to moderate dehydration. PMID- 20205482 TI - Sodium-glucose co-transport inhibitors: progress and therapeutic potential in type 2 diabetes mellitus. AB - The kidney plays a major role in glucose homeostasis because of its role in gluconeogenesis and the glomerular filtration and reabsorption of glucose in the proximal convoluted tubules. Approximately 180 g of glucose is filtered daily in the glomeruli of a normal healthy adult. Typically, all of this glucose is reabsorbed with <1% being excreted in the urine. The transport of glucose from the tubule into the tubular epithelial cells is accomplished by sodium-glucose co transporters (SGLTs). SGLTs encompass a family of membrane proteins that are responsible for the transport of glucose, amino acids, vitamins, ions and osmolytes across the brush-border membrane of proximal renal tubules as well as the intestinal epithelium. SGLT2 is a high-capacity, low-affinity transporter expressed chiefly in the kidney. It accounts for approximately 90% of glucose reabsorption in the kidney and has thus become the focus of a great deal of interest in the field of diabetes mellitus. SGLT2 inhibitors block the reabsorption of filtered glucose leading to glucosuria. This mechanism of action holds potential promise for patients with type 2 diabetes mellitus (T2DM) in terms of improvements in glycaemic control. In addition, the glucosuria associated with SGLT2 inhibition is associated with caloric loss, thus providing a potential benefit of weight loss. Dapagliflozin is the SGLT2 inhibitor with the most clinical data available to date, with other SGLT2 inhibitors currently in the developmental pipeline. Dapagliflozin has demonstrated sustained, dose dependent glucosuria over 24 hours with once-daily dosing in clinical trials. Although long-term safety data are lacking, studies to date have generally found dapagliflozin to be safe and well tolerated. Concerns related to SGLT2 inhibition include the fact that by their very nature they cause glucose elevation in the urine that can theoretically lead to urinary tract and genital infections, electrolyte imbalances and increased urinary frequency. Although studies to date have been promising in terms of these and other concerns, longer-term studies evaluating the usual safety and efficacy outcomes will need to be conducted. Similarly, head-to-head comparator trials are needed to determine the role of SGLT2 inhibitors in relation to the many other therapeutic options available for the treatment of T2DM. If significant reductions in haemoglobin A(1c) are associated with SGLT2 inhibitor therapy, and these agents are determined to be safe and well tolerated in the long term, they could become a major breakthrough in the T2DM treatment armamentarium. PMID- 20205483 TI - Pharmacological management of low back pain. AB - Low back pain is one of the most common conditions encountered in clinical practice and medications are the most commonly used type of treatment. In most patients, low back pain is nonspecific, in that the pain cannot be reliably attributed to a specific condition or abnormality in the back. Although a number of medications are available to treat nonspecific low back pain, selecting a therapy can be a challenge because each one is associated with a unique set of benefits and harms. In addition, the evidence supporting the use of different medications varies, and issues such as costs and patient preferences may also affect treatment choices. A guideline published in 2007 from the American Pain Society and the American College of Physicians on diagnosis and treatment of low back pain includes recommendations on the use of medications, based on the quality of supporting evidence and the estimated magnitude of benefits relative to harms. For most patients with low back pain, regardless of the duration of symptoms, paracetamol (acetaminophen) and NSAIDs are first-line options for pain relief. Opioids are more potent analgesics, but are not a first-line option due to their abuse potential. Skeletal muscle relaxants and benzodiazepines can be used as adjunctive medications for acute low back pain, but have a high incidence of sedation. Tricyclic antidepressants may be an option for chronic low back pain, but their effects on pain appear small or uncertain. Nonetheless, depression is common in patients with low back pain and should be treated appropriately. When choosing medications for treatment of low back pain, practice guidelines provide a useful starting point for making decisions, but clinicians should base therapeutic choices on individualized consideration and discussion with patients regarding the potential benefits and risks. PMID- 20205485 TI - Atypical antipsychotics for acute manic and mixed episodes in children and adolescents with bipolar disorder: efficacy and tolerability. AB - The diagnosis of bipolar disorder (BD) in children is increasing, and often requires a comprehensive treatment plan to address a complex array of symptoms and associated morbidities. Pharmacotherapy, in combination with psychotherapeutic interventions, is essential for the treatment and stabilization of disrupted mood. Current evidence collectively demonstrates, by randomized controlled design, that atypical antipsychotics have efficacy for the treatment of acute manic or mixed symptoms in children and adolescents with BD. Additional longitudinal and biological studies are warranted to characterize the effects of atypical antipsychotics on all phases and stages of bipolar illness development in children and adolescents. PMID- 20205484 TI - Pharmacotherapy options for locally advanced and advanced cervical cancer. AB - Cervical cancer continues to be a significant health burden worldwide. Globally, the majority of cancers are locally advanced at diagnosis; hence, radiation remains the most frequently used therapeutic modality. Currently, the value of adding cisplatin or cisplatin-based chemotherapy to radiation for the treatment of locally advanced cervical cancer is strongly supported by randomized studies and meta-analyses. Nevertheless, despite these significant achievements, therapeutic results are far from optimal; thus, novel therapies need to be investigated. A recent, randomized, phase III trial has shown for the first time that combination chemotherapy with cisplatin and gemcitabine concurrently with radiation improves parameters of survival over cisplatin alone and establishes a new standard for the management of locally advanced cervical cancer. On the other hand, advanced disease, presenting either as an International Federation of Gynecology and Obstetrics (FIGO) stage IVB or as persistent or recurrent to primary therapy without local curative options, remains a devastating group of diseases with no options other than palliative chemotherapy. Recent results from the GOG (Gynecologic and Oncologic Group)-204 study demonstrate that cisplatin doublets with paclitaxel, vinorelbine, gemcitabine or topotecan only produce small improvements in survival, although with different toxicity patterns; hence, patient-related factors are important when choosing any one of these regimens. The role of targeted therapies both in locally advanced and advanced disease is promising, but still at an investigational stage. PMID- 20205486 TI - Tolvaptan. AB - Tolvaptan is an orally administered, nonpeptide, selective arginine vasopressin V(2) receptor antagonist that increases free water clearance, thereby correcting low serum sodium levels. SALT-1 and -2, two identical, randomized, double-blind, placebo-controlled, multicentre trials, included patients with hypervolaemic or euvolaemic hyponatraemia (serum sodium <135 mmol/L) associated with heart failure, cirrhosis or the syndrome of inappropriate antidiuretic hormone secretion. In both trials, patients receiving (in addition to standard medical treatment) tolvaptan 15-60 mg once daily (titrated according to response) for up to 30 days (n = 95 and 118) experienced significantly greater improvements than those receiving placebo (n = 89 and 114) for the co-primary endpoints of the change in average daily area under the curve for the serum sodium level from baseline to day 4 and from baseline to day 30. This beneficial effect of tolvaptan on serum sodium levels in SALT-1 and -2 was observed in patients with mild (serum sodium <135 mmol/L) and in those with marked (serum sodium <130 mmol/L) hyponatraemia at baseline. Tolvaptan was also superior to placebo in increasing serum sodium levels from baseline to day 7 in a subgroup of 323 patients with hyponatraemia (serum sodium <134 mmol/L) in the randomized, double blind, multicentre EVEREST trials, which included patients who were hospitalized for worsening heart failure. Tolvaptan was generally well tolerated in clinical trials. The most frequently reported adverse events were thirst and dry mouth, which result from the pharmacodynamic effects of the drug. PMID- 20205487 TI - Pilsicainide. AB - Pilsicainide is a class Ic antiarrhythmic agent used for the treatment of supraventricular and ventricular tachycardia. The pharmacodynamic effects of pilsicainide are achieved via selective sodium channel blockade. In randomized, multicentre trials in patients with atrial fibrillation, restoration of sinus rhythm was achieved in significantly more patients treated with a single oral dose of pilsicainide than those who received placebo, and in a numerically higher proportion of oral pilsicainide than intravenous disopyramide recipients. In another well designed trial in patients with persistent atrial fibrillation, the proportion of patients whose arrhythmia converted to normal sinus rhythm was significantly higher among those randomized to receive 2 weeks of oral pilsicainide therapy than among patients who received placebo. Over a 1-year period, both pilsicainide and cibenzoline (another class Ic agent) were effective in preventing recurrence of atrial fibrillation in a substantial proportion of patients in a single-centre crossover trial. There were no between-group differences in the subgroup of patients with shorter-duration atrial fibrillation, but actuarial results over 1 year significantly favoured cibenzoline over pilsicainide in patients with longer-duration atrial fibrillation. Both oral and intravenous pilsicainide have demonstrated efficacy in ventricular tachyarrhythmias, including ventricular extrasystole. Clinical trial and postmarketing surveillance data indicate that pilsicainide is generally well tolerated in most patients. PMID- 20205488 TI - Fospropofol. AB - Fospropofol (fospropofol disodium), a sedative/hypnotic agent, is a water-soluble prodrug of propofol, metabolized in vivo to produce liberated propofol (producing the sedative effect), phosphate and formaldehyde. Intravenous fospropofol 6.5 mg/kg was significantly more effective than fospropofol 2.0 mg/kg (a placebo surrogate) as sedation in patients undergoing colonoscopy or flexible bronchoscopy, with regard to the primary endpoint of sedation success rate in randomized, double-blind, phase III trials. In patients undergoing colonoscopy, the sedation success rate was >3-fold higher among fospropofol 6.5 mg/kg (n = 158) than fospropofol 2.0 mg/kg recipients (n = 102). Similar results were observed in patients undergoing flexible bronchoscopy; the sedation success rate was >3-fold greater among fospropofol 6.5 mg/kg (n = 150) than among fospropofol 2.0 mg/kg recipients (n = 102). Fospropofol was generally well tolerated in clinical trials. Adverse events were mostly of mild to moderate severity, and were transient and self-limiting. Patients undergoing flexible bronchoscopy appeared to have a higher rate of sedation-related adverse events requiring airway assistance than did those undergoing colonoscopy or minor procedures. PMID- 20205489 TI - Tadalafil: in pulmonary arterial hypertension. AB - Tadalafil is a selective cyclic guanosine monophosphate-specific phosphodiesterase type 5 inhibitor that is effective in improving exercise ability, the time to clinical worsening and health-related quality of life (HR QOL) scores in patients with pulmonary arterial hypertension (PAH). In a large, 16-week, randomized, double-blind, placebo-controlled, multicentre, phase III trial (PHIRST) in patients aged >or=14 years with PAH (WHO group I), tadalafil 40 mg once daily (the recommended dosage) significantly increased the mean placebo corrected 6-minute walk distance (6MWD) by 33 m from baseline (primary endpoint). In treatment-naive patients, tadalafil 40 mg once daily significantly increased the mean placebo-corrected 6MWD by 44 m at week 16, whereas in patients receiving bosentan 125 mg twice daily as background therapy there was a mean change of 23 m, which was not significant. Both the time to the first occurrence of clinical worsening and the incidence of clinical worsening were significantly reduced in recipients of tadalafil 40 mg once daily compared with recipients of placebo. Furthermore, at week 16, tadalafil improved most HR-QOL outcomes from baseline to a significantly greater extent than placebo. Preliminary data from an extension of the PHIRST trial suggest that the improvements in 6MWD are maintained for up to 1 year in recipients of tadalafil 20 or 40 mg once daily. Treatment with tadalafil was generally well tolerated, with adverse events that were transient in nature and of mild to moderate intensity. PMID- 20205490 TI - Sitagliptin: a review of its use in the management of type 2 diabetes mellitus. AB - Sitagliptin (Januvia, Glactiv(R), Tesavel(R)) is a dipeptidyl peptidase-4 inhibitor indicated for the treatment of type 2 diabetes mellitus. Oral sitagliptin as monotherapy or combination therapy was generally well tolerated and improved glycaemic control in well designed clinical trials in patients with type 2 diabetes. Glycosylated haemoglobin (HbA(1c)) levels were significantly reduced with sitagliptin monotherapy relative to voglibose monotherapy or placebo, and with sitagliptin as initial combination therapy with metformin or pioglitazone relative to monotherapy with these agents or placebo. Moreover, sitagliptin monotherapy was noninferior to metformin monotherapy in terms of the reduction in HbA(1c) levels. Significant reductions in HbA(1c) levels, relative to background therapy, were also observed with sitagliptin add-on therapy to ongoing treatment with thiazolidinediones, sulfonylureas or insulin with or without metformin, or metformin alone. In terms of the reduction in HbA(1c) levels as add-on treatment to metformin, sitagliptin was noninferior to glipizide and generally did not differ from rosiglitazone, and as add-on treatment to pioglitazone, it did not differ significantly from metformin. Sitagliptin had a low risk of hypoglycaemia (except when used in combination with agents that may be associated with hypoglycaemia, such as sulfonylureas or insulin) and was generally weight-neutral. Although additional comparative data and longer-term studies with glycaemic and clinical outcomes are required to definitively position sitagliptin relative to other antihyperglycaemic agents, current evidence suggests that it is a useful treatment option for patients with type 2 diabetes, with potential advantages including oral administration, a generally weight-neutral effect and a low risk of hypoglycaemia. PMID- 20205491 TI - Inpatient rehabilitation utilization for acute stroke under a universal health insurance system. AB - OBJECTIVE: To explore the population-level utilization and factors associated with the use of inpatient stroke rehabilitation services under a single-payer government-based National Health Insurance (NHI) program in Taiwan. STUDY DESIGN: Retrospective cohort study based on claims data. METHODS: Inpatients with stroke were sampled from a nationally representative cohort of 200,000 NHI program enrollees. Multiple inpatient claims for individuals were merged to create a patient-level file; the first-ever admission was considered the index stroke. Proxy indicators to represent stroke severity, comorbidity, and complications were constructed. Predisposing, need, and enabling characteristics associated with rehabilitation use were explored. RESULTS: Among 2639 identified patients with stroke from January 1, 1997, to December 31, 2002, the overall inpatient rehabilitation utilization was 34.0% (33.0% for physical therapy, 19.6% for occupational therapy, and 5.3% for speech therapy). Stroke type and stroke severity were immediate causes of rehabilitation use. Except in neurology wards, rehabilitation use was unaffected by physician or facility characteristics. Among 898 patients receiving rehabilitation services, the median number of treatment sessions was 8 (interquartile range, 4-19), and the total rehabilitation costs were US $114.00 (interquartile range, $47.80-$258.30), with a mean (SD) length of stay of 22.2 (21.8) days. CONCLUSIONS: In a setting in which ability to pay is neutralized, inpatient stroke rehabilitation service in this universal NHI program was equitable but inadequate relative to use elsewhere or estimated need. Less severe case mix and financial or human resources constraints might partially account for the low utilization. Further studies measuring stroke severity and functional status are needed to clarify the actual utilization, requirements, and cost-effectiveness of inpatient stroke rehabilitation services. PMID- 20205492 TI - Economics of influenza vaccine administration timing for children. AB - OBJECTIVES: To determine how much should be invested each year to encourage and operationalize the administration of influenza vaccine to children before November and how late the vaccine should be offered each year. STUDY DESIGN: Monte Carlo decision analytic computer simulation models. METHODS: The children's influenza vaccination timing model quantified the incremental economic value of vaccinating a child earlier in the influenza season and the incremental cost of delaying vaccination. The children's monthly influenza vaccination decision model evaluated the cost-effectiveness of vaccinating versus not vaccinating for every month of the influenza season. RESULTS: Getting children vaccinated by the end of October rather than when they are currently getting vaccinated could save society between $6.4 million and $9.2 million plus 653 and 926 quality-adjusted life years (QALYs) and third-party payers between $4.1 million and $6.1 million plus 647 to 942 QALYs each year. Decision makers may want to continue offering influenza vaccination to children at least through the end of December. Vaccinating with trivalent inactivated virus vaccine was more cost-effective than vaccinating with live attenuated influenza vaccine for every month. CONCLUSION: Policymakers could invest up to $6 million to $9 million a year to get children vaccinated in September or October without expending any net costs. PMID- 20205493 TI - Medical care costs among patients with established cardiovascular disease. AB - OBJECTIVE: To estimate direct medical costs among patients with established cardiovascular disease (CVD). STUDY DESIGN: Observational longitudinal cohort study. METHODS: We identified 12,278 patients who were added to the Kaiser Permanente Northwest CVD registry from 2000 to 2005. We observed patients until they died or left the health plan or until June 30, 2008. Total direct medical costs were calculated over an individual's entire follow-up and were then annualized by dividing by the months of follow-up. We also calculated and compared age- and sex-adjusted incidence rates per 1000 person-years of secondary CVD hospitalization and all-cause mortality and a composite outcome of both. RESULTS: The total mean (SD) annual direct medical costs for the entire sample were $18,953 ($39,036). With approximately 22 million US residents having prevalent CVD or stroke, this extrapolates to direct costs of more than $400 billion. Inpatient costs accounted for 42.8% of total costs (mean [SD], $8114 [$25,410]). The greatest differences in costs were found when comparing patients who did versus did not experience a secondary CVD hospitalization ($62,755 vs $13,509, P <.001). Other large differences were found in comparisons of patients with versus without diabetes ($27,258 vs $17,210), an estimated glomerular filtration rate of less than 60 mL/min/1.73 m(2) ($29,498 vs $16,326), depression ($26,681 vs $17,303), and death ($28,689 vs $17,779) (P <.001 for all). CONCLUSIONS: The economic burden of providing care to patients with CVD may be substantially greater than current American Heart Association estimates. Although several comorbid conditions undoubtedly contribute to these costs, avoidance of secondary CVD hospitalization may be the key to substantially reducing healthcare consumption. PMID- 20205494 TI - Editorial: personality disorders and mood disorders. PMID- 20205495 TI - Personality disorders and mood disorders: phenomenological resemblances vs. pathogenetic pathways. AB - Diagnosis in psychiatry is currently based on phenomenology, because etiology and pathogenesis are largely unknown, and because biological markers for disease have not been identified. The unitary model of depression and the model of a bipolar spectrum are based on resemblances in phenomenology between symptoms whose pathogenetic pathways are likely to differ. Both models have sometimes considered the diagnosis of personality disorder as an affective variant, even when patients present with qualitatively distinct mood features. Biological reductionism lies behind a concept of mood as the primary driver of psychopathology, a view that may be detrimental to treatment. PMID- 20205496 TI - Personality structure as an organizing construct. AB - For a number of reasons, including the high levels of co-occurrence (or comorbidity) between personality and other mental disorders, doubts about the stability of what was thought to be a persistent diagnosis, and a growing tendency to think of personality and mental state disorders as being part of a spectrum of disorders, many argue that a separate axis for personality disorder is now unjustified in psychiatric classification, and that DSM-V should go back to classifying personality disturbances with other mental disorders in Axis I (as has been consistently maintained in the ICD classification). It is argued here that such a move would be a major mistake, as the construct of personality, assessed in its three components of personality function, traits, and organization, offers an integrating perspective for the clinician that helps to both understand and predict the future of mental disturbance and gives an extra dimension to clinical practice. PMID- 20205497 TI - The quality of depression in borderline personality disorder and the diagnostic process. AB - The quality of the depressive experience in borderline personality disorder has always been perceived to be different from the depression experienced in major depression (MDD). This paper reviews those observations and studies of the particular ways in which this borderline personality disorder (BPD) depression/dysphoria has been described in the literature and makes note of the fact the patients with BPD often score more highly on self-rated scales of depression than on corresponding observer-rated scales. Often patients with BPD without MDD score as highly on depression rating scales as BPD patients with MDD and as highly as patients with MDD without BPD. Clinician-rated scales and operationalized diagnostic interviews do not easily capture the distinction between the depression of BPD and the depression of MDD. A fuller appreciation of the BPD patient's object relations, i.e., the nature of the interpersonal relationships and the person's reactions and affects to and within those relationships holds the key to understanding the nature of the quality of the depression of BPD. PMID- 20205498 TI - Phenotype, endophenotype, and genotype comparisons between borderline personality disorder and major depressive disorder. AB - Borderline personality disorders (BPD) and major depressive disorder (MDD) are distinct disorders with overlapping biological processes pertaining to emotional regulatory functions. However, while both disorders share affective symptomatology, the disturbance central to BPD is affective lability and its character is entirely different from the affective disturbance of MDD. This review highlights data from the last ten years and compares the two disorders' phenotypes, putative endophenotypes and genotypes, focusing heavily on neuroimaging findings. The familiality and phenotypic differences suggest that BPD differs in important ways with respect to symptomatology, prognosis, and heritability. The neurobiological findings in both MDD and BPD are still preliminary at present, and no coherent model for either disorder can be said to have emerged. Overlapping biological processes including amygdala hyperreactivity, volume changes in subgenual anterior cingulate cortex, and deficient serotonergic function appear to underlie emotional dysregulation in both disorders. However, the disorders seem to differ in their patterns of brain region involvement, neurohormonal indices, and sleep architecture. At present, the minimal data available for putative genotypes of BPD is still emerging, nonspecific to the disorder and demonstrates significant overlap with MDD. The ability to discern commonalities and differences in the neurobiology of these two disorders is limited by the differing methodologies applied in different studies. Definitive clarification of what MDD and BPD have in common and in what ways they are distinct will only be derived from studies that examine both illnesses using the same study design and methodology. PMID- 20205499 TI - Affective instability: toward an integration of neuroscience and psychological perspectives. AB - Affective instability is a prominent feature of a wide variety of psychiatric and neurological disorders, yet it has not been systematically studied. It encompasses a number of distinct phenomena, including: (1) frequent affective category shifts, (2) disturbances in affect intensity, (3) excessively rapid emotion rise-times, (4) delayed return to emotional baseline, (5) excessive reactivity to psychosocial cues, (6) endogenously driven, random, chaotic or rapid-cycling changes, and (7) overdramatic expression. To further clarify the construct of affective instability, this article examines the manifestations of affective instability in a range of psychiatric and neurologic disorders, reviews relevant neurobiological and psychological emotion regulatory processes, and considers the psychology of affective instability. PMID- 20205500 TI - Personality disorders and mood disorders: perspectives on diagnosis and classification from studies of longitudinal course and familial associations. AB - The results of three rigorous studies of the naturalistic course of personality disorders indicate the following: (1) personality psychopathology improves over time at unexpectedly significant rates; (2) particular maladaptive personality traits are more stable than personality disorder diagnoses; (3) although personality psychopathology improves, residual effects are usually seen in the form of persistent functional impairment and ongoing Axis I psychopathology; and (4) improvement in personality psychopathology may eventually be associated with reduction in ongoing personal and social burden. A comparison of the longitudinal stability of personality disorders and mood disorders does not support a clear distinction between them based on differential stability of either psychopathology (at least based on remission rates) or functional impairment. Differences may yet emerge with respect to relapse rates over the longer term. Both types of disorders may share some common underlying vulnerabilities best conceptualized in term of personality traits. A group of promising, though methodologically flawed, family studies suggest familiality of at least BPD among the personality disorders and the coaggregation of BPD and depressive disorders (but not bipolar disorders) that may contribute to their frequent co-occurrence. Again, underlying personality traits may prove to be more heritable than either type of disorder. PMID- 20205501 TI - Interpersonal dependency in borderline personality disorder: clinical context and empirical evidence. AB - Personality theorists and practicing clinicians agree that high levels of interpersonal dependency play a role in Borderline Personality Disorder (BPD), and this link has been codified in several editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM). Although there is widespread agreement that dependency is linked to BPD, there has never been a systematic review of empirical evidence bearing on this issue. This article reviews research in three areas: (1) the comorbidity of Dependent Personality Disorder (DPD) and BPD; (2) the association between trait dependency and BPD; and (3) differences in free-response (i.e., Rorschach) dependency scores in BPD and non-BPD patients. Results support DSM assertions of DPD-BPD comorbidity, confirm that high levels of trait dependency are associated with BPD traits and symptoms, and show that high levels of implicit dependency needs are present in BPD-diagnosed inpatients, but not BPD outpatients. Theoretical, clinical, and empirical implications of these patterns are discussed. PMID- 20205502 TI - Empirical evidence for a four factor framework of personality disorder organization: multigroup confirmatory factor analysis of the Millon Clinical Multiaxial Inventory-III personality disorder scales across Belgian and Danish data samples. AB - The factor structure of the Millon Clinical Multiaxial Inventory-III (Millon, Millon, Davis, & Grossman, 2006) personality disorder scales was analyzed using multigroup confirmatory factor analysis on data obtained from a Danish (N = 2030) and a Belgian (N = 1210) sample. Two-, three-, and four factor models, a priori specified using structures found by Dyce, O'Connor, Parkins, and Janzen (1997), were fitted to the data. The best fitting model was a four factor structure (RMSEA = .066, GFI = .98, CFI = .93) with partially invariant factor loadings. The robustness of this four-factor model clearly supports the efforts to organize future personality disorder description in a four-factor framework by corroborating four domains that were predominant in dimensional models (Widiger & Simonsen, 2005): Factor 1, 2, 3, and 4 respectively corresponded to emotional dysregulation versus stability, antagonism versus compliance, extraversion versus introversion, and constraint versus impulsivity. PMID- 20205503 TI - Assessment of normal bowel habits in the general adult population: the Popcol study. AB - OBJECTIVE: Defining normal stool habit is important when evaluating diarrhoea or constipation, but common confounders such as irritable bowel syndrome (IBS) or the intake of medications with gastrointestinal side effects have not been considered in earlier population based studies defining what is normal. We hypothesized that the exclusion of subjects with common confounders would help to better understand what are "normal bowel habits". We aimed to prospectively study bowel habits in a carefully studied random sample of the general population. MATERIAL AND METHODS: Two hundred and sixty-eight randomly selected subjects between 18 and 70 years completed symptom diaries for one week and were clinically evaluated by a gastroenterologist. They also had a colonoscopy and laboratory investigations to exclude organic disease. RESULTS: One hundred and twenty-four subjects had no organic gastrointestinal abnormality, IBS, or relevant medication; 98% of them had between three stools per day and three per week. Seventy-seven percent of all stools were normal, 12% hard, and 10% loose in consistency. Urgency was reported by 36%; straining by 47% and incomplete defecation by 46%. After the exclusion of subjects with organic abnormalities, women had significantly more symptoms than men in terms of abdominal pain, bloating, constipation, urgency, and feeling of incomplete evacuation but these gender differences disappeared after excluding subjects with IBS. CONCLUSIONS: This study confirms that normal stool frequency is between three per week and three per day. We could not demonstrate any gender or age differences in terms of stool frequency, defecatory symptoms or abdominal bloating. Some degree of urgency, straining, and incomplete evacuation should be considered normal. PMID- 20205504 TI - Contrast-enhanced harmonic EUS with novel ultrasonographic contrast (Sonazoid) in the preoperative T-staging for pancreaticobiliary malignancies. AB - OBJECTIVE: Sonazoid is a new second-generation microbubble contrast for ultrasonography. In this pilot study, the diagnostic role of contrast-enhanced harmonic imaging endoscopic ultrasonography (CH-EUS) with Sonazoid was prospectively evaluated in preoperative T-staging of pancreaticobiliary malignancies. PATIENTS AND METHODS: Patients with suspected pancreaticobiliary malignancies underwent CH-EUS by a single examiner. After the lesions were observed carefully with conventional harmonic imaging EUS (H-EUS), CH-EUS was performed with intravenous injection of Sonazoid. A reviewer who was blinded reviewed the recordings of H-EUS and CH-EUS and assessed the T-staging. The accuracy of H-EUS and CH-EUS for T-staging was compared to the results of surgical histopathology in patients who underwent surgery. RESULT: Twenty-six patients underwent surgical resection and could be included in the study. The final diagnosis were pancreatic cancer in 11, bile duct cancer in 7, gallbladder cancer in 4 and ampullary cancer in 4. The overall accuracy of H-EUS and CH-EUS for T-staging were 69.2 (18/26) and 92.4% (24/26), respectively (p < 0.05). There were disagreement in six cases between H-EUS and CH-EUS. CH-EUS staged correctly in all of these six cases, whereas H-EUS misdiagnosed the depth of invasion in one case of gallbladder cancer and one case of ampullary cancer, and invasion of portal vein in two cases of pancreatic cancer and two cases of bile duct cancer. CONCLUSION: The depth of invasion of biliary cancer and vascular invasion of pancreatic and biliary cancer could be demonstrated more clearly with CH-EUS compared to H-EUS. CH-EUS has the potential to improve the diagnostic accuracy of preoperative T-staging of pancreaticobiliary malignancies. PMID- 20205505 TI - Outcome of patients after endoluminal stent placement for benign colorectal obstruction. AB - OBJECTIVE: Self-expanding metal stents (SEMS) have been successfully used as a "bridge to surgery" or as palliation for acute malignant colorectal obstruction. Little data on the use of stents for benign obstruction exists and the results vary. The purpose of this study was to evaluate the efficacy and safety of SEMS in benign colorectal obstruction. MATERIAL AND METHODS: A total of 21 patients with 23 SEMS procedures between the years 1998 and 2008 were retrospectively studied. Eight patients had an obstruction in the surgical anastomosis. In addition, there were two patients with anastomotic strictures due to Crohn's disease. In 10 patients the obstruction was caused by diverticular disease and one patient had a stricture after radiation therapy. RESULTS: Technical success was achieved for all the patients. Clinical success was achieved for 76% (16/21) of the patients. The anastomotic strictures were resolved with SEMS in 5 out of 8 cases (63%). Three patients with diverticular stricture (30%) were eventually resolved with SEMS. Nine (43%) patients in 10 out of 23 procedures (43%) had a complication, the majority being in patients with diverticular stricture. CONCLUSIONS: SEMS is a good treatment option for patients with anastomotic stricture of the colon and for patients with benign colonic stricture who are unfit for surgery. SEMS can be used as a bridge to surgery in diverticular obstruction but there seems to be a considerable risk of complications. If a SEMS is placed into a diverticular stricture, the planned bowel resection should be performed within a month. PMID- 20205506 TI - Clinical outcomes in a prospective study of community-acquired hepatitis C virus infection in Northern Norway. AB - OBJECTIVE: Knowledge on the natural course of the morbidity of unselected community-acquired hepatitis C virus (HCV) infection is limited. The aim of our study was to characterize the clinical outcomes of both hepatic and extrahepatic morbidity in patients infected with HCV in a community-based setting in Northern Norway. MATERIAL AND METHODS: This prospective cohort study included 1010 HCV positive patients diagnosed by recombinant immunoblot assay (RIBA), between 1 January 1990 and 1 January 2000. Questionnaires were sent to those physicians in Northern Norway who had requested the RIBA tests during the relevant period. Data were collected from medical records in the period between 1 January 2004 and 30 June 2006. Access to confidential information was obtained from the Norwegian Directorate of Health. RESULTS: Median age at follow-up was 39 and 41 years in females and males, respectively. In patients with positive HCV RNA status following results were found: Alanine aminotransferase was elevated in 27.4%, decompensated liver disease in 2.9% and hepatocellular carcinoma in 0.4%. Median observation period from estimated acquisition of the disease to follow-up in these patients was 26 years. Depression was reported in 10.7% of chronic infected subjects. Renal failure caused by membranoproliferative glomerulonephritis occurred in 0.2%. CONCLUSIONS: In an unselected HCV-RNA positive population severe liver disease developed in a sub-group of patients. These observations suggest that chronic HCV disease in relatively young subjects may cause a substantial burden on the health system in the future. PMID- 20205507 TI - Antiangiogenic and antitumor effects of IMMUNEPOTENT CRP in murine melanoma. AB - BACKGROUND: Skin cancers are common, and there has recently been a dramatic increase in their incidence, particularly in the occurrence of melanoma. Furthermore, relapse after curative surgical treatment of melanoma remains a significant clinical challenge and accounts for most of the mortality of this disease. OBJECTIVE: The aim of this study was to determine whether IMMUNEPOTENT CRP affects B16F10 melanoma cells and tumors growth and vascular endothelial growth factor (VEGF) production in vivo and in vitro. METHODS: B16F10 cells and B16F10-inoculated mice were treated with different concentrations of IMMUNEPOTENT CRP. Outcomes were then evaluated using MTT, TUNEL, Caspase-3, senescence, ELISA and colorimetric assays. Parameters related to survival and tumor weight were also assessed. RESULTS: IMMUNEPOTENT CRP decreased the viability of B16F10 cells by increasing apoptosis of the treated cells, and VEGF production was decreased both in vitro and in vivo. Furthermore, treatment prevented metastasis, delayed the appearance of tumors, decreased tumor weight and improved the survival of tumor-bearing mice. DISCUSSION: These observations suggest that IMMUNEPOTENT CRP can be used to suppress growth and metastasis by using targeting proteins such as VEGF. PMID- 20205508 TI - Immunotoxicity of zearalenone in Balb/c mice in a high subchronic dosing study counteracted by Raphanus sativus extract. AB - Radish (Raphanus sativus) is a cruciferous plant, rich on flavonoids, isothiocyanates, and phenolic acids. They show anti-inflammatory and immunomodulatory activity both in vitro and in vivo. Isothiocyanates and flavonoids have been reported previously to prevent low-sub-chronic dose of zearalenone (ZEN) causing immunotoxicity. The present study focuses on the amelioration of fusarotoxicosis in Balb/c mice by feeding two concentrations of radish extract. The extract at 15 and 30 mg/kg bw, was evaluated to reduce the deleterious effects in immunological parameters of high subchronic doses of 40 and 80 mg of ZEN/kg bw on modulation of lipopolysaccharide (LPS). ZEN consuming mice showed a "dose-related" decrease in weight gain and in the immune relative weights organs. Moreover, Atrophy and lymphoid depletion were seen in the histopathology of spleen. Ingestion of ZEN at either level had a significant effect on total red blood cell numbers and on their relative number of lymphocytes. Likewise, ZEN alters the production of regulatory cytokines and antibody of LPS stimulated mice. By contrast, the additions of radish extract with a low or high dose of ZEN moderately decreased the affected mice and/or the severity of lesions, and all tested parameters were normal or at least near normal levels. In addition, the radish extract alone did not produce any significant changes in all tested parameters compared with the controls. In conclusion, radish extract was effective for the protection of high dose ZEN immunotoxication in mice and it could contribute to a solution of the ZEN immunotoxicity in humans and in farm animals. PMID- 20205509 TI - Early optical detection of cerebral edema in vivo. AB - OBJECT: Cerebral edema is a significant cause of morbidity and mortality in diverse disease states. Currently, the means to detect progressive cerebral edema in vivo includes the use of intracranial pressure (ICP) monitors and/or serial radiological studies. However, ICP measurements exhibit a high degree of variability, and ICP monitors detect edema only after it becomes sufficient to significantly raise ICP. The authors report the development of 2 distinct minimally invasive fiberoptic near-infrared (NIR) techniques able to directly detect early cerebral edema. METHODS: Cytotoxic brain edema was induced in adult CD1 mice via water intoxication by intraperitoneal water administration (30% body weight intraperitoneally). An implantable dual-fiberoptic probe was stereotactically placed into the cerebral cortex and connected to optical source and detector hardware. Optical sources consisted of either broadband halogen illumination or a single-wavelength NIR laser diode, and the detector was a sensitive NIR spectrometer or optical power meter. In one subset of animals, a left-sided craniectomy was performed to obtain cortical biopsies for water content determination to verify cerebral edema. In another subset of animals, an ICP transducer was placed on the contralateral cortex, which was synchronized to a computer and time stamped. RESULTS: Using either broadband illumination with NIR spectroscopy or single-wavelength laser diode illumination with optical power meter detection, the authors detected a reduction in NIR optical reflectance during early cerebral edema. The time intervals between water injection (Time Point 0), optical trigger (defined as a 2-SD change in optical reflectance from baseline), and defined threshold ICP values of 10, 15 and 20 mm Hg were calculated. Reduction in NIR reflectance occurred significantly earlier than any of the ICP thresholds (p < 0.001). Saline-injected control mice exhibited a steady baseline optical signal. There was a significant correlation between reflectance change and tissue specific gravity of the cortical biopsies, further validating the dual-fiberoptic probe as a direct measure of cerebral edema. CONCLUSIONS: Compared with traditional ICP monitoring, the aforementioned minimally invasive NIR techniques allow for the significantly earlier detection of cerebral edema, which may be of clinical utility in the identification and thus early treatment of cerebral edema. PMID- 20205510 TI - Mechanical and chemical thrombolysis of cerebral sinus thrombosis: evolution of a technique. AB - Cerebral sinus thrombosis, although uncommon, can be lethal if not recognized and treated quickly. Systemic heparin has become the treatment standard of care; however, some patients' conditions continue to deteriorate even while taking heparin. Endovascular techniques for thrombolysis have continued to evolve. The authors present a case of cerebral sinus thrombosis treated with a combination of mechanical and chemical intrasinus thrombolysis. PMID- 20205511 TI - Extensive dural sinus thrombosis: successful recanalization with thrombolysis and a novel thrombectomy device. AB - The author presents a novel endovascular treatment approach to extensive dural venous sinus thrombosis using the Penumbra clot aspiration system and local administration of recombinant tissue plasminogen activator. The clinical course, technical treatment aspects, and follow-up are described. PMID- 20205512 TI - Accumulation of CD133-positive glioma cells after high-dose irradiation by Gamma Knife surgery plus external beam radiation. AB - OBJECT: Recent evidence suggests that a glioma stem cell subpopulation might contribute to radioresistance in malignant gliomas. To investigate this hypothesis, the authors examined recurrent malignant gliomas for histopathological changes after high-dose irradiation with Gamma Knife surgery (GKS) and external beam radiation therapy (EBRT). METHODS: Thirty-two patients with malignant gliomas (Grade 3 in 8 patients, Grade 4 in 24) underwent GKS in combination with EBRT. Serial MR and L-[methyl-(11)C] methionine PET images were employed to assess remnant or recurrent tumors after GKS. Twelve patients underwent surgical removal after GKS and EBRT. Histological sections were subjected to immunohistochemistry for MIB-1, factor VIII, and stem cell markers, nestin and CD133. RESULTS: The site of GKS treatment failure was local in 16 (76.2%) of 21 patients with glioblastomas showing progression; in 9 of these 16 patients, the recurrence clearly arose within the target lesion of GKS. Histopathological examination after GKS and EBRT showed variable mixtures of viable tumor tissues and necrosis. Viable tumor tissues exhibited high MIB-1 indices but reduced numbers of tumor blood vessels. There was marked accumulation of CD133-positive glioma cells, particularly in remnant tumors within the necrotic areas, in sections obtained after GKS plus EBRT, whereas CD133-positive cells appeared very infrequently in primary sections prior to adjuvant treatment. CONCLUSIONS: The results indicate that CD133-positive glioma stemlike cells can survive high-dose irradiation, leading to recurrence, despite prolonged damage to tumor blood vessels. This could be an essential factor limiting the effectiveness of GKS plus EBRT for malignant gliomas. PMID- 20205513 TI - The anti-inflammatory and neuroprotective effects of ghrelin in subarachnoid hemorrhage-induced oxidative brain damage in rats. AB - To elucidate the putative neuroprotective effects of ghrelin in subarachnoid hemorrhage (SAH)-induced brain injury, Wistar albino rats (n = 54) were divided into sham-operated control, saline-treated SAH, and ghrelin-treated (10 microg/kg/d IP) SAH groups. The rats were injected with blood (0.3 mL) into the cisterna magna to induce SAH, and were sacrificed 48 h after the neurological examination scores were recorded. In plasma samples, neuron-specific enolase (NSE), S-100beta protein, TNF-alpha, and IL-1beta levels were evaluated, while forebrain tissue samples were taken for the measurement of malondialdehyde (MDA), glutathione (GSH), reactive oxygen species levels, myeloperoxidase (MPO), Na(+) K(+)-ATPase activity, and DNA fragmentation ratio. Brain tissue samples containing the basilar arteries were obtained for histological examination, while cerebrum and cerebellum were removed for the measurement of blood-brain barrier (BBB) permeability and brain water content. The neurological scores were impaired at 48 h after SAH induction, and SAH caused significant decreases in brain GSH content and Na(+)-K(+)-ATPase activity, and increases in chemiluminescence, MDA levels, and MPO activity. Compared with the control group, the protein levels of NSE, S-100beta, TNF-alpha, and IL-1beta in plasma were also increased, while ghrelin treatment prevented all SAH-induced alterations observed both biochemically and histopathologically. The results demonstrate that ghrelin alleviates SAH-induced oxidative brain damage, and exerts neuroprotection by maintaining a balance in oxidant-antioxidant status, by inhibiting proinflammatory mediators, and preventing the depletion of endogenous antioxidants evoked by SAH. PMID- 20205515 TI - The role of endothelial progenitor cells in prevascularized bone tissue engineering: development of heterogeneous constructs. AB - In vitro prevascularization of bone grafts with endothelial progenitor cells (EPCs) is a promising strategy to improveimplant survival. In this study we show bone formation in constructs that contain multipotent stromal cells (MSCs) and EPCs. Early and late EPCs from peripheral blood and bone marrow of adult goats were characterized for differentiation markers and functional responses. EPCs from peripheral blood are more proliferative than bone-marrow-derived EPCs, express higher numbers of endothelial markers for longer periods of time, and form more intricate networks. We demonstrate that EPCs derived from peripheral blood contribute to osteogenic differentiation by MSCs in vitro, and that MSCs support the proliferation of EPCs and stabilize the formed cellular networks. In vivo, EPCs from peripheral blood assemble into early blood vessel networks, which are more pronounced in the presence of MSCs. These results show that the EPCs isolated from peripheral blood are suitable for prevascularization strategies, and that coseeding of EPCs and MSCs is favorable for bone formation after 6 weeks. PMID- 20205514 TI - Genetic analysis of the role of tumor necrosis factor receptors in functional outcome after traumatic brain injury in mice. AB - We previously reported that tumor necrosis factor-alpha (TNF-alpha) and Fas receptor induce acute cellular injury, tissue damage, and motor and cognitive deficits after controlled cortical impact (CCI) in mice (Bermpohl et al. 2007 ); however, the TNF receptors (TNFR) involved are unknown. Using a CCI model and novel mutant mice deficient in TNFR1/Fas, TNFR2/Fas, or TNFR1/TNFR2/Fas, we tested the hypothesis that the combination of TNFR2/Fas is protective, whereas TNFR1/Fas is detrimental after CCI. Uninjured knockout (KO) mice showed no differences in baseline physiological variables or motor or cognitive function. Following CCI, mice deficient in TNFR2/Fas had worse post-injury motor and Morris water maze (MWM) performance than wild-type (WT) mice (p < 0.05 group effect for wire grip score and MWM performance by repeated measures ANOVA). No differences in motor or cognitive outcome were observed in TNFR1/Fas KO, or in TNFR2 or TNFR1 single KO mice, versus WT mice. Additionally, no differences in propidium iodide (PI)-positive cells (at 6 h) or lesion size (at 14 days) were observed between WT and TNFR1/Fas or TNFR2/Fas KO mice. Somewhat surprisingly, mice deficient in TNFR1/TNFR2/Fas also had PI-positive cells, lesion size, and motor and MWM deficits similar to those of WT mice. These data suggest a protective role for TNFR2/Fas in the pathogenesis of TBI. Further studies are needed to determine whether direct or indirect effects of TNFR1 deletion in TNFR2/Fas KO mice mediate improved functional outcome in TNFR1/TNFR2/Fas KO mice after CCI. PMID- 20205516 TI - Mechanisms of lung tumorigenesis by ethyl carbamate and vinyl carbamate. AB - Vinyl carbamate (VC) and ethyl carbamate (EC) induce the formation of lung tumors. The mechanism involves a two-step oxidation of EC to VC and VC to an epoxide, both of which are mediated mainly by CYP2E1. Interaction of the epoxide with DNA leads to the formation of DNA adducts, including 1,N(6)ethenodeoxyadenosine and 1,N(4)-ethenodeoxycytidine. The production of DNA adducts correlated with capacities for the bioactivation of VC, which are higher in the lungs of A/J than in C57BL/6 mice. Importantly, CYP2E1 is higher in the lungs of A/J than in C57BL/6 mice. Studies using F(1) (Big Blue x A/J) transgenic mice revealed the formation of mutations in the lambda cII gene after treatment with VC. Mutations induced by VC were mainly A:T-->G:C transitions and A:T-->T:A transversions, while mutations induced by EC were mainly G:C-->A:T transitions. An EC dose that was 17-fold higher than that for VC was required to produce a similar level of mutant frequency in the lung. Pretreatment of mice with the CYP2E1 inhibitor, diallyl sulfone, significantly inhibited the mutant frequencies induced by VC. Mutations in the endogeneous Kras2 gene were found in codon 61 of exon 2 and were identified as A:T transversions and A-->G transitions in the second base and A-->T transversions in the third base. These mutations were reduced by treatment of mice with diallyl sulfone before VC and coincided with a reduction in the number of lung tumors with Kras2 mutations. These findings affirmed that the metabolism of EC and VC is a prerequisite for, or at least substantially contributes to, initiation of the cascade of events leading to lung tumor formation. PMID- 20205517 TI - A sustained release of lovastatin from biodegradable, elastomeric polyurethane scaffolds for enhanced bone regeneration. AB - Scaffolds prepared from biodegradable polyurethanes (PUR) have been investigated as a supportive matrix and delivery system for skin, cardiovascular, and bone tissue engineering. In this study, we combined reactive two-component PUR scaffolds with lovastatin (LV), which has been reported to have a bone anabolic effect especially when delivered locally, for effective bone tissue regeneration. To incorporate LV into PUR scaffolds, LV was combined with the hardener component before scaffold synthesis. The PUR scaffolds containing LV (PUR/LV) demonstrated a highly porous structure with interconnected pores, which supported in vitro cell attachment and proliferation and in vivo osteoconductive potential. The PUR/LV scaffolds showed sustained release of biologically active LV, as evidenced by the fact that LV releasates significantly enhanced osteogenic differentiation of osteoblastic cells in vitro. A study of bone formation in vivo using a rat plug defect model showed that the PUR/LV scaffolds were biocompatible. Further, locally delivered LV enhanced new bone formation in the PUR scaffolds at week 4, while there were no obvious effects at week 2. These results suggest that the sustained LV delivery system from PUR scaffolds is a potentially safe and effective device for bone regeneration. PMID- 20205519 TI - Biopolitics today. PMID- 20205520 TI - What rough beast? AB - Synthetic biology seeks to create modular biological parts that can be assembled into useful devices, allowing the modification of biological systems with greater reliability, at lower cost, with greater speed, and by a larger pool of people than has been the case with traditional genetic engineering. We assess the offensive and defensive security implications of synthetic biology based on the insights of leading synthetic biologists into how the technology may develop, the projections of practicing biosecurity authorities on changes in the security context and potential security applications of synthetic biology, and joint appraisals of policy relevant sources of uncertainty. Synthetic biology appears to have minimal security implications in the near term, create modest offensive advantages in the medium term, and strengthen defensive capabilities against natural and engineered biological threats and enable novel potential offensive uses in the long term. To maximize defensive and minimize offensive effects of synthetic biology despite uncertainty, this essay suggests a combination of policy approaches, including community-based efforts, regulation and surveillance, further research, and the deliberate design of security and safety features into the technology. PMID- 20205521 TI - Enhancing genetic virtue. AB - The Genetic Virtue Project (GVP) is a proposed interdisciplinary effort between philosophers, psychologists and geneticists to discover and enhance human ethics using biotechnology genetic correlates of virtuous behavior. The empirical plausibility that virtues have biological correlates is based on the claims that (a) virtues are a subset of personality, specifically, personality traits conceived of as "enduring behaviors," and (b) that there is ample evidence that personality traits have a genetic basis. The moral necessity to use the GVP for moral enhancement is based on the claims that we should eliminate evil (as understood generically, not religiously), as some evil is a function of human nature. The GVP is defended against several ethical and political criticisms. PMID- 20205522 TI - Debating restrictions on embryonic stem cell research. AB - This study investigates the emotional and behavioral effects of interpersonal online communication, focusing on the controversy surrounding the loosening of restrictions on human embryonic stem cell research. The issue, central to national and statewide elections in 2008, generated heated debate among candidates and voters and evoked strong emotional sentiments among partisans. Using the theory of affective intelligence, this study proposes a predictive model connecting levels of enthusiasm and anxiety with behavioral and information seeking outcomes. Cognitive appraisal theory is also employed to provide a role for political emotion in accounting for interactive media effects. To investigate the ways that online deliberation may influence discussions surrounding stem cell research, a between-subjects experimental study was conducted that systematically varied the tone of feedback received (reinforcing or challenging) and type of interaction (synchronous or asynchronous) experienced by users. Results indicate that emotional responses play a significant role in predicting behavioral intentions arising from the user-to-user interactive experience. PMID- 20205523 TI - Competitive exclusion. AB - The Principle of Competitive Exclusion, first articulated by Gause in 1934, states that two species or populations cannot inhabit the same niche: one will consistently out-compete the other. Of four possible outcomes, the logistic equations that describe such interaction present only one possibility for coexistence, that being when the density-dependent mechanisms of one population become activated before intergroup competition eliminates the other. In applying Gause's Principle as an explanatory model to the Israeli-Palestinian conflict, this research explores the present bantustanization of the West Bank as a logical outcome of interspecific competition, but sees the competition coefficients of the equations as the key factors in promoting a stable equilibrium. PMID- 20205525 TI - The Illinois Biology and Politics summer institute. PMID- 20205526 TI - Biopolitics and the road ahead. PMID- 20205527 TI - Biopolitics and international security studies. PMID- 20205528 TI - Health privacy in genetic research. PMID- 20205529 TI - But what is government itself but the greatest of all reflections on human nature? PMID- 20205530 TI - Tissue distribution and pulmonary targeting studies of cefpiramide sodium-loaded liposomes. AB - The aim of this study was to evaluate the pharmacokinetics (PK), tissue distribution, and the specific drug targeting of cefpiramide sodium-loaded liposomes (CPMS-Lips) compared with cefpiramide sodium solution (CPMS-Sol) in mice. CPMS-Lips were prepared by reverse phase evaporation method. In the PK and biodistribution study, mice received a single intravenous (i.v.) injection of 152 mg/kg of either CPMS-Lips or CPMS-Sol. Plasma and tissues were treated using liquid-liquid extraction and determined using reversed-phase high-performance liquid chromatography (RP-HPLC). The results showed that the CPMS-Lips prepared in this study had an average diameter of 7.146 +/- 0.29 MUm. In the plasma, the bioavailability (F) and the mean residence times (MRT) of the CPMS-Lips were 2.8- and 4.5-fold larger, respectively, than those of CPMS-Sol. CPMS-Lips also showed a significant difference in the tissue distribution profile in mice when compared with the conventional. The value of the intake rate (r(e)) for the lung was 2.97, which was the highest among the tested tissues. Meanwhile, the ratio of targeting efficiency (Te(liposome)/Te(injection)) of lung to that of other tissues for CPMS Lips elevated significantly. These showed that CPMS-Lips can improve the bioavailability and biodistribution of CPMS in the lung. In conclusion, the liposome was a promising sustained-release and drug-targeting system for antibiotic drugs. PMID- 20205531 TI - Osteogenic differentiation and immune response of human bone-marrow-derived mesenchymal stem cells on injectable calcium-silicate-based bone grafts. AB - Calcium silicate cement (CSC) is biocompatible and possesses in vitro bioactivity. The aim of this study was to improve the handling and enhance osteogenic and immune properties of CSC by the addition of adjuvants to modify the cement. Human bone-marrow-derived mesenchymal stem cells were used to study the osteogenic behavior and immune response of cells on hybrid cements with added gelatin (GLT) and chitosan oligosaccharides (COS), which are analogs of the extracellular matrix components collagen and glycosaminoglycan, respectively. The addition of COS to the liquid phase slightly prolonged the setting time of CSC, whereas GLT in the solid phase significantly (p < 0.05) extended the hydration reaction. However, the addition of GLT appreciably improved the injectability of CSC, compared to COS. Cell viability was higher on CSC-COS than on the CSC control or on CSC-GLT at all culture times. The hybrid bone cements elicited less immune response than the CSC control. Additionally, COS inhibited expression of inducible nitric oxide synthase and interleukin-1 and activated interleukin-10 more effectively than GLT. Osteocalcin production and bone sialoprotein production were higher, and more calcium was detected in human bone-marrow derived mesenchymal stem cells cultured on a CSC-GLT-COS surface than on CSC, CSC GLT, or CSC-COS. These synergistic improvements in injectability, immune response, and osteogenesis suggest that the combination of bioactive calcium silicate, GLT, and COS has potential for use in clinical applications. PMID- 20205532 TI - The effects of insulin-like growth factor-1 and basic fibroblast growth factor on the proliferation of chondrocytes embedded in the collagen gel using an integrated microfluidic device. AB - This work presents an integrated microfluidic device on which the proliferation of rabbit chondrocytes was investigated in the presence of insulin-like growth factor-1 (IGF-1), basic fibroblast growth factor (bFGF), and their combinations. The microfluidic device was mainly composed of an upstream concentration gradient generator and a downstream perfusion-based three-dimensional cell culture module. The rabbit articular chondrocytes were cultured for 2 weeks at the different concentrations of growth factors generated by concentration gradient generator. IGF-1, up to 57.14 ng/mL, had the ability to promote the proliferation of chondrocytes in a dose-dependent manner, and there were no further promotions at higher concentrations. bFGF increased chondrocyte proliferation dose dependently up to 5.72 ng/mL, and then the proliferation rate decreased when the concentration was increased. The combination of IGF-1 and bFGF could synergistically promote the proliferation, and the group of 85.73 ng/mL IGF-1 and 1.43 ng/mL bFGF presented an optimal effect (up to 4.76-fold), which had statistically significant differences compared with IGF-1 and bFGF, respectively. Moreover, the proliferation test using the conventional method was performed simultaneously and revealed similar results. The results obtained in this study demonstrated that the microfluidic device is an effective platform for cartilage tissue engineering. With this device, experimental conditions are flexible and can be optimized by changing either the category of growth factors or the concentration of input growth factor. Further, the small number of cells (1-100) required, with which parallel experiments could be performed simultaneously, makes it an attractive platform for the high-through screening at the cellular level in autologous chondrocyte implantation. PMID- 20205533 TI - Spatial and spatiotemporal pattern analysis of coconut lethal yellowing in Mozambique. AB - Coconut lethal yellowing (LY) is caused by a phytoplasma and is a major threat for coconut production throughout its growing area. Incidence of LY was monitored visually on every coconut tree in six fields in Mozambique for 34 months. Disease progress curves were plotted and average monthly disease incidence was estimated. Spatial patterns of disease incidence were analyzed at six assessment times. Aggregation was tested by the coefficient of spatial autocorrelation of the beta binomial distribution of diseased trees in quadrats. The binary power law was used as an assessment of overdispersion across the six fields. Spatial autocorrelation between symptomatic trees was measured by the BB join count statistic based on the number of pairs of diseased trees separated by a specific distance and orientation, and tested using permutation methods. Aggregation of symptomatic trees was detected in every field in both cumulative and new cases. Spatiotemporal patterns were analyzed with two methods. The proximity of symptomatic trees at two assessment times was investigated using the spatiotemporal BB join count statistic based on the number of pairs of trees separated by a specific distance and orientation and exhibiting the first symptoms of LY at the two times. The semivariogram of times of appearance of LY was calculated to characterize how the lag between times of appearance of LY was related to the distance between symptomatic trees. Both statistics were tested using permutation methods. A tendency for new cases to appear in the proximity of previously diseased trees and a spatially structured pattern of times of appearance of LY within clusters of diseased trees were detected, suggesting secondary spread of the disease. PMID- 20205534 TI - Identification of genomic regions controlling adult-plant stripe rust resistance in Chinese landrace Pingyuan 50 through bulked segregant analysis. AB - ABSTRACT Stripe rust, caused by Puccinia striiformis f. sp. tritici, is one of the most widespread and destructive wheat diseases worldwide. Growing resistant cultivars with adult-plant resistance (APR) is an effective approach for the control of the disease. In this study, 540 simple sequence repeat markers were screened to map quantitative trait loci (QTL) for APR to stripe rust in a doubled haploid (DH) population of 137 lines derived from the cross Pingyuan 50 x Mingxian 169. The DH lines were planted in randomized complete blocks with three replicates in Gansu and Sichuan provinces during the 2005-06, 2006-07, and 2007 08 cropping seasons, providing data for four environments. Artificial inoculations were carried out in Gansu and Sichuan with the prevalent Chinese race CYR32. Broad-sense heritability of resistance to stripe rust for maximum disease severity was 0.91, based on the mean value averaged across four environments. Inclusive composite interval mapping detected three QTL for APR to stripe rust on chromosomes 2BS, 5AL, and 6BS, designated QYr.caas-2BS, QYr.caas 5AL, and QYr.caas-6BS, respectively, separately explaining from 4.5 to 19.9% of the phenotypic variation. QYr.caas-5AL, different from QTL previously reported, was flanked by microsatellite markers Xwmc410 and Xbarc261, and accounted for 5.0 to 19.9% of phenotypic variance. Molecular markers closely linked to the QTL could be used in marker-assisted selection for APR to stripe rust in wheat breeding programs. PMID- 20205535 TI - Rapid differentiation and identification of potential severe strains of Citrus tristeza virus by real-time reverse transcription-polymerase chain reaction assays. AB - A multiplex Taqman-based real-time reverse transcription (RT) polymerase chain reaction (PCR) assay was developed to identify potential severe strains of Citrus tristeza virus (CTV) and separate genotypes that react with the monoclonal antibody MCA13. Three strain-specific probes were developed using intergene sequences between the major and minor coat protein genes (CPi) in a multiplex reaction. Probe CPi-VT3 was designed for VT and T3 genotypes; probe CPi-T36 for T36 genotypes; and probe CPi-T36-NS to identify isolates in an outgroup clade of T36-like genotypes mild in California. Total nucleic acids extracted by chromatography on silica particles, sodium dodecyl sulfate-potassium acetate, and CTV virion immunocapture all yielded high quality templates for real-time PCR detection of CTV. These assays successfully differentiated CTV isolates from California, Florida, and a large panel of CTV isolates from an international collection maintained in Beltsville, MD. The utility of the assay was validated using field isolates collected in California and Florida. PMID- 20205536 TI - Population genetic analyses of Fusarium asiaticum populations from barley suggest a recent shift favoring 3ADON producers in southern China. AB - Fusarium asiaticum is the predominant causal agent of Fusarium head blight (FHB) in southern China. The genetic diversity was assessed by analyzing 448 single spore F. asiaticum isolates from 18 sampling sites that were 10 to 2,000 km apart, using seven highly informative variable number of tandem repeat (VNTR) markers. This analysis showed a significant degree of population subdivision (P < 0.001) among populations from upper, middle, and lower valleys of the Yangtze River, with little gene flow (Nm = 1.210). We observed a strong association between this genetic population subdivision and the mycotoxin produced. Our results show that the dramatic cline in trichothecene chemotypes may be explained by a recent and significant invasion of 3-acetyldeoxynivalenol (3ADON) producers in FHB pathogen composition in the middle valley. Using Bayesian statistics, we found a biased gene flow from 3ADON to nivalenol (NIV) populations. In addition, we observed significant genetic differentiation and linkage disequilibrium between NIV- and 3ADON-producing isolates at the same sampling sites. The impact of the changed agronomy and trade of cereal commodities on the spread of the new Fusarium population and the consequent increase of FHB observed in southern China are discussed. PMID- 20205537 TI - Evaluation of resistance to Rhabdocline needlecast in Douglas fir variety Shuswap, with quantitative polymerase chain reaction. AB - A quantitative polymerase chain reaction assay was developed that could detect DNA of Rhabdocline pseudotsugae and R. oblonga among DNA of Douglas fir needles to a limit as low as three copies of target DNA. Differential infection rates of two varieties (seed sources) of Douglas fir interplanted in a field were studied in relation to staggered bud breaks. Infection of Douglas fir var. San Isabel corresponded to ascospore release times for Rhabdocline spp., whereas infection of var. Shuswap Lake did not occur throughout the spore release period during 2 years of study, despite abundant inoculum and adequate moisture during bud break. Rhabdocline spp. DNA was never detected in Shuswap Lake and disease symptoms were not observed in any year. We provide evidence that Shuswap Lake is resistant and probably immune to Rhabdocline spp. infection and Rhabdocline needlecast under Michigan conditions. PMID- 20205538 TI - Diversity and biogeography of sooty blotch and flyspeck fungi on apple in the eastern and midwestern United States. AB - Sooty blotch and flyspeck (SBFS) fungi on apple fruit were sampled from nine orchards in four midwestern U.S. states during 2000 and 30 orchards in 10 eastern U.S. states during 2005 in order to estimate taxonomic diversity and discern patterns of geographic distribution. Forty apple fruit per orchard were arbitrarily sampled and colonies of each mycelial phenotype were counted on each apple. Representative colonies were isolated, cultures were purified, and DNA was extracted. For representative isolates, the internal transcribed spacer (ITS) and large subunit (LSU) regions of ribosomal DNA were amplified and sequenced. In total, 60 SBFS putative species were identified based on ITS sequences and morphological characteristics; 30 of these were discovered in the 2005 survey. Modified Koch's postulates were fulfilled for all 60 species in an Iowa orchard; colonies resulting from inoculation of apple fruit were matched to the original isolates on the basis of mycelial type and ITS sequence. Parsimony analysis for LSU sequences from both surveys revealed that 58 putative SBFS species were members of the Dothideomycetes, 52 were members of the Capnodiales, and 36 were members of the Mycosphaerellaceae. The number of SBFS species per orchard varied from 2 to 15. Number of SBFS species and values of the Margalef and Shannon indexes were significantly (P < 0.05) lower in 21 orchards that had received conventional fungicide sprays during the fruit maturation period than in 14 unsprayed orchards. Several SBFS species, including Schizothyrium pomi, Peltaster fructicola, and Pseudocercosporella sp. RH1, were nearly ubiquitous, whereas other species, such as Stomiopeltis sp. RS5.2, Phialophora sessilis, and Geastrumia polystigmatis, were found only within restricted geographic regions. The results document that the SBFS complex is far more taxonomically diverse than previously recognized and provide strong evidence that SBFS species differ in geographic distribution. To achieve more efficient management of SBFS, it may be necessary to understand the environmental biology of key SBFS species in each geographic region. PMID- 20205539 TI - Identification, characterization, and expression analyses of class II and IV chitinase genes from Douglas-fir seedlings infected by Phellinus sulphurascens. AB - Laminated root rot (LRR) disease, caused by the fungus Phellinus sulphurascens, is a major threat to coastal Douglas-fir (DF) (Pseudotsuga menziesii) forests in western North America. Understanding host-pathogen interactions of this pathosystem is essential to manage this important conifer root disease. Our research objectives were to identify DF pathogenesis-related (PR) genes and analyze their expression patterns over the course of infection. We constructed a cDNA library of Phellinus sulphurascens-infected DF seedling roots and sequenced a total of 3,600 random cDNA clones from this library. One of the largest groups of identified genes (203 cDNA clones) matched with chitinase genes reported in other plant species. We identified at least three class II and six class IV chitinase genes from DF seedlings. Quantitative reverse-transcriptase polymerase chain reaction analyses showed significant differential expression patterns locally in root tissues and systemically in needle tissues after fungal invasion. Nonetheless, there was a common trend in gene expression patterns for most of the chitinase genes: an upregulation within 12 h of pathogen inoculation followed by down-regulation within 2 to 3 days postinoculation (dpi), and then further upregulation within 5 to 7 dpi. Western immunoblot data showed differential accumulation of class IV chitinases in Phellinus sulphurascens-infected DF seedlings. Further detailed functional analyses will help us to understand the specific role of DF chitinases in defense against Phellinus sulphurascens infection. PMID- 20205540 TI - Microbial aspects of accelerated degradation of metam sodium in soil. AB - Preplant soil fumigation with metam sodium is used worldwide to control soilborne diseases. The development of accelerated degradation of pesticides in soil, including metam sodium, results in reduced pesticide efficacy. Therefore, we studied microbial involvement in accelerated degradation of methyl isothiocyanate (MITC) following repeated soil applications of the parent compound, metam sodium. MITC degradation was reduced in soil with a history of metam sodium applications following sterilization, indicating the key role of microorganisms in accelerated degradation. Accelerated degradation of MITC was induced by inoculation of soil with no previous application of metam sodium with soil with a history of metam sodium applications. We developed a method to extract the active microbial fraction responsible for MITC degradation from soil with a history of metam sodium applications. This concentrated soil extract induced accelerated degradation of MITC when added to two different soils with no previous application of metam sodium. An extensive shift in total bacterial community composition in concentrated soil extracts occurred after a single metam sodium application. Two Oxalobacteraceae strains, MDB3 and MDB10, isolated from Rehovot soil following triple application of metam sodium rapidly degraded MITC in soil with no previous application of metam sodium. Polymerase chain reaction denaturing gradient gel electrophoresis analysis of bacterial community composition showed relative enrichment of MDB3 following metam sodium application, suggesting its potential in situ involvement in accelerated degradation development in Rehovot soil. Responses of resident Oxalobacteraceae community members to metam sodium applications differed between Rehovot and En Tamar soils. Isolate MDB10 did not induce accelerated degradation of MITC in En Tamar soil and, with the slow dissipation of MITC, soil suppressiveness of accelerated degradation is suggested. The isolation and identification of MITC degrading bacteria might be helpful in developing tools for managing accelerated degradation. PMID- 20205541 TI - Genetic differentiation within the Puccinia triticina population in South America and comparison with the North American population suggests common ancestry and intercontinental migration. AB - Leaf rust, caused by Puccinia triticina, is the most prevalent and widespread disease of wheat in South America. The objective of this study was to determine whether genetically differentiated groups of P. triticina are currently present in South America and to compare the South American population with the previously characterized population in North America. In total, 130 isolates of P. triticina from the wheat-growing regions of Argentina, Brazil, Chile, Peru, and Uruguay, mostly from the 1990s to 2008, were tested for virulence on 20 lines of wheat with single genes for leaf rust resistance and for molecular genotypes with 23 simple-sequence repeat (SSR) markers. After removal of isolates with identical virulence and SSR genotypes, 99 isolates were included for further analysis. Principal coordinate analysis plots indicated five different groups of isolates based on SSR genotypes that also differed for virulence to leaf rust resistance genes. All pairs of groups, except for one pair, were significantly differentiated for SSR genotypes according to R(ST) statistics. All but two pairs of groups were significantly differentiated for virulence phenotype according to Phi(PT) statistics. Isolates in all five groups had high values of fixation index for SSR alleles and linkage disequilibrium was high across all isolates that indicated the clonal reproduction of urediniospores. Only one of the five P. triticina groups from South America was differentiated for SSR genotypes from all of the six P. triticina groups from North America. The high degree of similarity for SSR genotype of isolates from both South America and North America suggested a common European origin of P. triticina that was introduced to both continents. The emergence of the same P. triticina virulence phenotypes with highly related SSR genotypes in the United States in 1996 and in Uruguay in 1999 indicated the likely intercontinental migration of these genotypes from Mexico to both South America and North America. PMID- 20205542 TI - Transmission competency of single-female Xiphinema index lines for Grapevine fanleaf virus. AB - Grapevine fanleaf virus (GFLV) is vectored specifically from grapevine to grapevine by the ectoparasitic nematode Xiphinema index. Limited information is available on the vector competency of X. index populations from diverse geographical origins. We determined the transmissibility of two GFLV strains showing 4.6% amino acid divergence within their coat protein (e.g., strains F13 and GHu) by seven clonal lines of X. index developed from seven distinct populations from the Mediterranean basin (Cyprus, southern France, Israel, Italy, and Spain), northern France, and California. X. index lines derived from single adult females were produced on fig (Ficus carica) plants to obtain genetically homogenous aviruliferous clones. A comparative reproductive rate analysis on Vitis rupestris du Lot and V. vinifera cv. Cabernet Sauvignon showed significant differences among clones, with the single-female Cyprus line showing the highest rate (30-fold the initial population) and the Spain and California lines showing the lowest rate (10-fold increase), regardless of the grapevine genotype. However, there was no differential vector competency among the seven X. index lines for GFLV strains F13 and GHu. The implications of our findings for the dynamic of GFLV transmission in vineyards and screening of Vitis spp. for resistance to GFLV are discussed. PMID- 20205543 TI - Phloem cytochemical modification and gene expression following the recovery of apple plants from apple proliferation disease. AB - Recovery of apple trees from apple proliferation was studied by combining ultrastructural, cytochemical, and gene expression analyses to possibly reveal changes linked to recovery-associated resistance. When compared with either healthy or visibly diseased plants, recovered apple trees showed abnormal callose and phloem-protein accumulation in their leaf phloem. Although cytochemical localization detected Ca(2+) ions in the phloem of all the three plant groups, Ca(2+) concentration was remarkably higher in the phloem cytosol of recovered trees. The expression patterns of five genes encoding callose synthase and of four genes encoding phloem proteins were analyzed by quantitative real-time reverse transcription-polymerase chain reaction. In comparison to both healthy and diseased plants, four of the above nine genes were remarkably up-regulated in recovered trees. As in infected apple trees, phytoplasma disappear from the crown during winter, but persist in the roots, and it is suggested that callose synthesis/deposition and phloem-protein plugging of the sieve tubes would form physical barriers preventing the recolonization of the crown during the following spring. Since callose deposition and phloem-protein aggregation are both Ca(2+) dependent processes, the present results suggest that an inward flux of Ca(2+) across the phloem plasma membrane could act as a signal for activating defense reactions leading to recovery in phytoplasma-infected apple trees. PMID- 20205544 TI - Working together to address disability in a culturally-appropriate and sustainable manner. AB - PURPOSE: Disability has an enormous impact throughout the world. An increasing amount of important disability research and practice is being undertaken in low income settings; however, success and sustainability of programmes in these contexts can often be challenging. We share lessons from our experiences. METHOD: We reviewed past literature and international consensus statements relating to disability and development practice. We then held several face to face and email discussions to document the key lessons we have learnt from working in this context. We report on these in this paper. RESULTS: The key lessons are to invest adequate time and develop trusting relationships, undertake sufficient consultation and collaboration, include and empower persons with disability, and view capacity building as a two-way process. CONCLUSIONS: Improving the lives of persons with disability in development contexts is likely to be best achieved through processes that are inclusive, owned and driven by local communities. PMID- 20205545 TI - A critical review of the evidence on the use of videotapes or DVD to promote patient compliance with home programmes. AB - PURPOSE: The purpose of this paper is to critically review published research in order to evaluate the evidence surrounding the provision of video or DVD technology to promote patient compliance with home exercise or health programmes. METHOD: A literature search of the MEDLINE, CINAHL and Cochrane databases was undertaken. Critical appraisal of selected studies was undertaken using a previously validated tool. Inclusion criteria were: research related to DVD or videotape technology to improve compliance; published in peer-reviewed journals and full-text English language articles. Compliance was the main outcome measure. RESULTS: Eleven eligible studies were reviewed. All but one, which used a before after design, were randomised controlled trials. Study quality tended medium to high in the critical appraisal scoring system, but an overall low quality on the Jadad score for randomisation; with only one study from 11 scoring well on both these measures. Research into the use of video or DVD showed mainly positive effects on compliance; however, methodological issues limit clinical applicability. CONCLUSIONS: Future well-designed randomised controlled trials with adequate sample sizes and reliable outcome measures will provide clearer evidence into the effectiveness of this technology in improving home exercise or health programme compliance, particularly for rural and remote populations. PMID- 20205546 TI - What symptoms predict the diagnosis of autism or PDD-NOS in infants and toddlers with developmental delays using the Baby and Infant Screen for aUtIsm Traits. AB - PURPOSE: Autism Spectrum Disorders (ASD) are characterized by life-long and severe symptoms such as stereotypies, social skills deficits and language delays. Previous research has demonstrated that children who receive early intensive behavioural intervention have a better prognosis than those who do not receive services. It is for this reason that assessments designed specifically for early identification of ASD are of paramount important. METHOD: In Study 1, 957 infants with autism, PDD-NOS and atypical development were evaluated using an assessment screener for ASD traits, the Baby and Infant Screen for aUtIsm Traits (BISCUIT). In Study 2, only those with an autism or PDD-NOS diagnosis were evaluated. RESULTS: The BISCUIT was found to have an excellent overall classification rate for children in the target population. A sub-set of BISCUIT items was found that distinguished children with ASD from atypically developing children. Items were also found which could accurately predict autism vs PDD-NOS diagnosis. CONCLUSIONS: These data suggest that the core features of ASD are distinct and can be identified early in life. Furthermore, the presence of specific core behaviours can allow for a more accurate clinical and diagnostic picture for young children with autism or PDD-NOS vs general developmental delays. PMID- 20205547 TI - Screening for mathematical disabilities in kindergarten. AB - OBJECTIVE: This article is devoted to the potential early markers for mathematical learning disabilities in kindergarten in order to prevent children from falling further behind and from developing unrecognized mathematical disabilities later on. METHODS: Performances in preparatory arithmetic tasks were studied in 361 kindergartners focusing on differences between children at risk for mathematical disabilities and children who were at least moderately achieving in numerical arithmetic tasks. RESULTS: Evidence was found for several markers in kindergarten. Children at risk had lower scores on procedural counting knowledge, conceptual counting knowledge, seriation, classification, conservation and magnitude comparison tasks. Based on these kindergarten abilities, 77% of children who were at risk for mathematical disabilities could be detected. CONCLUSION: Procedural and conceptual counting knowledge, seriation and classification skills and magnitude comparison abilities could possibly serve as powerful early screeners in the detection of mathematical disabilities. PMID- 20205548 TI - Changes in gait following continuous intrathecal baclofen infusion in ambulant children and young adults with cerebral palsy. AB - OBJECTIVE: To assess the effect of continuous intrathecal baclofen infusion (ITB) on gait parameters of ambulant children with cerebral palsy (CP). METHODS: The assessment before and 16 months after ITB on seven children with CP (mean age 15 years, SD 5.4) included: Ashworth scale score, range of motion (hip, knee, ankle), Gillette functional assessment questionnaire (FAQ), joint kinematics, spatiotemporal parameters and Gillette Gait Index (GGI). RESULTS: Gillette FAQ significantly improved from 6.1 to 7.1. Mean GGI improved from 554.50 to 489.25, which was not significant although the improvement was large for three children. Parameters in the sagittal plane were significantly modified with a significant increase in step length (0.65 m to 0.74 m) and a significant increase in hip extension during stance phase (32.25 degrees to 21.6 degrees ). These results were correlated to clinical assessments. CONCLUSION: ITB seems to improve sagittal gait parameters of children and young adults with CP. PMID- 20205549 TI - Discrepancy between severity obtained from examination and classification conducted by experienced examiners and classifiers and documented severity in paediatric spinal cord injury. AB - OBJECTIVE: The International Standards for Neurological Classification of Spinal Cord Injury (ISCSCI) motor and sensory examinations provides a mechanism for severity classification via the American Spinal Injury Association Impairment Scale (AIS). The purpose of this study is to explore agreement between reported severity in medical charts to severity determine via the International Standards examination and classification by trained examiners and classifiers. METHODS: The agreement between severities from ISCSCI classification from experienced classifiers for all subjects was compared to severities from medical records using percentage agreement and the kappa statistic. RESULTS: Severity classification between ISCSCI and medical record documentation was assessed for agreement in 157 subject examinations. Among the five medical records source documentation, agreement with the study ISCSCI classification on injury severity classification ranged from poor to high. CONCLUSION: The implication in this study provides justification for clinical practice guidelines and better documentation policy to improve documentation of injury severity. PMID- 20205550 TI - Evaluation of technology-assisted learning setups for undertaking assessment and providing intervention to persons with a diagnosis of vegetative state. AB - OBJECTIVE: To evaluate the viability of technology-assisted learning setups for undertaking assessment and providing intervention to persons in vegetative state. METHOD: Study I investigated whether three persons with a diagnosis of vegetative state could associate eye blinking or hand closure responses with contingent, positive stimulation, thus increasing their frequencies (showing signs of learning). Study II extended the learning process (introducing a new response and new stimuli) for one of the participants of Study I. RESULTS: Two of the participants of Study I succeeded in increasing their responses, indicating signs of learning. Study II showed that the participant (one of the two succeeding in Study I) acquired a new response to access new stimuli and could alternate this response with the one acquired in Study I. CONCLUSION: Learning might represent a basic level of knowledge and consciousness. Detecting signs of learning might help modify a previous diagnosis of vegetative state and support intervention/rehabilitation efforts. PMID- 20205551 TI - The NeuroPage system for children and adolescents with neurological deficits. AB - OBJECTIVE: Several studies have demonstrated the effectiveness of a paging system, NeuroPage, in helping survivors of brain injury compensate for everyday memory and planning problems. This study examines the effectiveness of the paging system in the sub-group of 12 children and adolescents with neurological deficits who took part in a larger study. METHODS: Twelve participants aged 8-17 years took part in a randomized controlled crossover trial in which their completion of everyday goals was monitored prior to and during use of the NeuroPage system, where participants were sent reminder messages regarding tasks they should complete. RESULTS: All 12 young people showed significant improvements in carrying out everyday tasks between the baseline and treatment phases. CONCLUSIONS: The NeuroPage system can be successfully used by children and adolescents with neurological deficits and can alleviate some of the everyday difficulties caused by their memory and planning difficulties. PMID- 20205552 TI - Bipolar disorder in young people: Description, assessment and evidence-based treatment. AB - OBJECTIVE: The literature on bipolar in children and adolescents was reviewed to provide an update for clinicians. REVIEW PROCESS: Literature of particular relevance to evidence-based practice was selected for critical review. OUTCOMES: An up-to-date overview of clinical features, epidemiology, prognosis, aetiology, assessment and intervention was provided. CONCLUSIONS: Bipolar disorder in children and adolescence is a relatively common, multifactorially determined and recurring problem which persists into adulthood. Psychometrically robust screening questionnaires and structured interviews facilitate reliable assessment. Multimodal chronic care programmes involving medication (notably lithium) and family-oriented psychotherapy are currently the treatment of choice. PMID- 20205553 TI - Biofeedback therapy for bowel problems in adults after surgical treatment for childhood Hirschsprung's disease. AB - OBJECTIVE: To describe the use of biofeedback therapy in management of bowel symptoms after definitive surgery for Hirschsprung's disease. METHODS: This study describes two cases that exemplify the complex nature of these problems. These patients presented with constipation and faecal seepage several years after receiving treatment for Hirschsprung's disease. The approach to management of these patients including the use of biofeedback therapy is described. RESULTS: After biofeedback therapy, there was improvement in bowel symptoms in both subjects. In case 1 (constipation), stool frequency increased from 0.5-1 time/week to 5-6 times/week together with improved stool consistency. In case 2 (faecal seepage), the number of incontinence episode decreased from >1/day to complete continence, together with decreased stool frequency. They were still satisfied with their bowel movement at 1-year follow-up. CONCLUSION: Recognition of the underlying problems and therapy directed towards correcting these abnormalities may lead to significant symptomatic improvement in these patients. PMID- 20205554 TI - Feeding-induced rapid resetting of the hepatic circadian clock is associated with acute induction of Per2 and Dec1 transcription in rats. AB - The synchronization of the master clock to photic cues is associated with a rapid induction of Per1, which plays an important role in initiating light-induced circadian resetting. However, the transcriptional mechanisms of clock gene expression in food-entrainable peripheral clocks have not been fully assessed. To understand how food cues might entrain a mammalian peripheral clock, we examined the responses in the expression of clock genes in rat livers to different feeding stimuli. The food-entrainable liver clock is more flexible than the light entrainable SCN clock and can be reset rapidly at any time of day. A 30 min feeding stimulus was sufficient to significantly induce the expression of Per2 and Dec1 within 1 h and alter the transcript levels and circadian phases of other selected clock genes (Bmal1, Cry1, Per1, Per3, Dec2, and Rev-erba) in the liver clock at longer time intervals. Moreover, among the examined clock genes, Per2 was most sensitive to food cues, which could be significantly induced by a minimal amount of food. Furthermore, in contrast to the other hepatic clock genes, the feeding reversal-induced 12 h phase shift of Per2 could be rapidly and consistently accomplished, regardless of the shift of the light/dark cycle. In conclusion, the feeding-induced resetting of the circadian clock in the liver is associated with the acute induction of Per2 and Dec1 transcription, which may serve as the main and secondary input regulators that initiate this feeding induced circadian resetting. PMID- 20205555 TI - Molecular cloning, tissue distribution, and daily rhythms of expression of per1 gene in European sea bass (Dicentrarchus labrax). AB - Circadian rhythms are controlled by interlocked autoregulatory feedback loops consisting of interactions of a group of circadian clock genes and their proteins. The Period family is a group of genes that are essential components of the molecular clock. In the present study, we cloned a period gene (per1) of the European sea bass, a marine teleost of chronobiological interest. The cloned sequence encoded a protein consisting of 1436 amino acids that homology and phylogenic analyses showed to be related with fish PER1 proteins possessing very high identity with Oryzias latipes (Medaka) per1. Polymerase chain reaction screening of per1 expression showed that this gene is expressed in all the tissues analyzed (brain, heart, liver, gill, muscle, digestive tract, adipose tissue, spleen, and retina). In addition, a daily expression rhythm, with an acrophase (peak time) approximately ZT0 (lights-on), was found in the two tissue types investigated: neural (brain) and peripheral (liver and heart). In conclusion, identification and characterization of the gene encoding sea bass per1 provide valuable information for understanding the circadian mechanism at the molecular level in this species, although further research is needed to clarify the exact role that per1 plays in the circadian oscillator and the dual behavior of European sea bass. PMID- 20205556 TI - Circadian modulation of crustacean hyperglycemic hormone in crayfish eyestalk and retina. AB - Previous studies suggested the retina could be a putative locus of daily crustacean hyperglycemic hormone (CHH) secretion, as it possesses its own metabolic machinery and is independent of the well-known CHH eyestalk locus responsible for the circadian secretion of this peptide. However, it has been proposed that hemolymph glucose and lactate concentrations play a dual role in the regulation of CHH in crayfish. To elucidate the temporal relationship between these two different CHH production loci and to examine their relationship with glucose regulation, we investigated the expression of CHH daily and circadian rhythms in the eyestalk and retina of crayfish using biochemical methods and time series analysis. We wanted to determine whether (1) putative retina and eyestalk CHH rhythmic expressions are correlated and if the oscillations of the two metabolic products of lactate and glucose in the blood due to CHH action on the target tissue correlate, and (2) retina CHH (RCHH) and the possible retinal substrate glycogen and its product glucose are temporally correlated. We found a negative correlation between daily and circadian changes of relative CHH abundance in the retina and eyestalk. This correlation and the cross-correlation values found between eyestalk CHH and hemolymph and glucose confirm that CHH produced by the X-organ sinus gland complex is under the previously proposed dual feedback control system over the 24 h time period. However, the presence of both glycogen and glucose in the retina, the cross-correlation values found between these parameters and hemolymph lactate and glucose, as well as RCHH and hemolymph and retina metabolic markers suggest RCHH is not under the same temporal metabolic control as eyestalk CHH. Nonetheless, their expression may be linked to common rhythms-generating processes. PMID- 20205557 TI - Daily variation of constitutively activated nuclear factor kappa B (NFKB) in rat pineal gland. AB - In mammals, the production of melatonin by the pineal gland is mainly controlled by the suprachiasmatic nuclei (SCN), the master clock of the circadian system. We have previously shown that agents involved in inflammatory responses, such as cytokines and corticosterone, modulate pineal melatonin synthesis. The nuclear transcription factor NFKB, detected by our group in the rat pineal gland, modulates this effect. Here, we evaluated a putative constitutive role for the pineal gland NFKB pathway. Male rats were kept under 12 h:12 h light-dark (LD) cycle or under constant darkness (DD) condition. Nuclear NFKB was quantified by electrophoretic mobility shift assay on pineal glands obtained from animals killed throughout the day at different times. Nuclear content of NFKB presented a daily rhythm only in LD-entrained animals. During the light phase, the amount of NFKB increased continuously, and a sharp drop occurred when lights were turned off. Animals maintained in a constant light environment until ZT 18 showed diurnal levels of nuclear NFKB at ZT15 and ZT18. Propranolol (20 mg/kg, i.p., ZT 11) treatment, which inhibits nocturnal sympathetic input, impaired nocturnal decrease of NFKB only at ZT18. A similar effect was observed in free-running animals, which secreted less nocturnal melatonin. Because melatonin reduces constitutive NFKB activation in cultured pineal glands, we propose that this indolamine regulates this transcription factor pathway in the rat pineal gland, but not at the LD transition. The controversial results regarding the inhibition of pineal function by constant light or blocking sympathetic neurotransmission are discussed according to the hypothesis that the prompt effect of lights-off is not mediated by noradrenaline, which otherwise contributes to maintaining low levels of nuclear NFKB at night. In summary, we report here a novel transcription factor in the pineal gland, which exhibits a constitutive rhythm dependent on environmental photic information. PMID- 20205558 TI - Lack of calbindin-D28k alters response of the murine circadian clock to light. AB - A strong stimulus adjusting the circadian clock to the prevailing light-dark cycle is light. However, the circadian clock is reset by light only at specific times of the day. The mechanisms mediating such gating of light input to the CNS are not well understood. There is evidence that Ca(2+) ions play an important role in intracellular signaling mechanisms, including signaling cascades stimulated by light. Therefore, Ca(2+) is hypothesized to play a role in the light-mediated resetting of the circadian clock. Calbindin-D28k (CB; gene symbol: Calb1) is a Ca(2+) binding protein implicated in Ca(2+) homeostasis and sensing. The absence of this protein influences Ca(2+) buffering capacity of a cell, alters spatio-temporal aspects of intracellular Ca(2+) signaling, and hence might alter transmission of light information to the circadian clock in neurons of the suprachiasmatic nuclei (SCN). We tested mice lacking a functional Calb1 gene (Calb1(-/-)) and found an increased phase-delay response to light applied at circadian time (CT) 14 in these animals. This is accompanied by elevated induction of Per2 gene expression in the SCN. Period length and circadian rhythmicity were comparable between Calb1(-/-) and wild-type animals. Our findings indicate an involvement of CB in the signaling pathway that modulates the behavioral and molecular response to light. PMID- 20205559 TI - Nocturnal illumination dimmer than starlight altered the circadian rhythm of adult locomotor activity of a fruit fly. AB - The effects of nocturnal irradiance tenfold dimmer than starlight intensity on the locomotor activity rhythm of Drosophila jambulina were investigated in two types of light-dark (12 h:12 h) cycles, in which light intensity of the photophase was 10 lux while that of the scotophase was either 0 lux for control flies or 0.0006 lux for experimental flies. Activity onset in the experimental flies was approximately 5.4 h prior to lights-on, so it occurred around midnight. However, activity onset of the control flies coincided almost with the lights-on. Nevertheless, activity offset was the same in both groups, occurring at lights off. Duration of the active phase (alpha) and activity passes/fly/cycle (APC) in the experimental flies was far greater than in controls. After-effects of the nocturnal illumination of the light-dark cycles when the flies were transferred to constant darkness were evident as the period of the free-running rhythm was shortened, alpha was lengthened, and APC was enhanced in the experimental compared to control flies. Thus, very low photic sensitivity of these flies appears to be a physiological adaptation to dim-light ambiance in its natural breeding site in the field. PMID- 20205560 TI - Effects of light on the circadian activity rhythm of Djungarian hamsters (Phodopus sungorus) with delayed activity onset. AB - A number of Djungarian hamsters (Phodopus sungorus) of our institute show activity patterns that seem incompatible with proper adjustment to a periodic environment. The activity onset of those animals is continuously delayed, whereas the activity offset is stably coupled to "lights-on", leading to compression of activity time. A series of experiments was conducted to evaluate the possible causes of the deteriorated ability of DAO (delayed activity onset) hamsters to synchronize. Thus, we investigated the properties of the endogenous circadian rhythm plus parametric and non-parametric light effects on hamsters of DAO and Wild type (WT) phenotypes. Free-running rhythms were studied in constant darkness (DD) or constant light (LL) of different intensities (1, 10, 100 lux). To investigate photic phase responses, hamsters were kept in DD and exposed to light pulses (100 lux, 15 min), at circadian time (CT) CT14 and CT22. Differences were verified statistically by ANOVA. Light intensity exerted significant effect on the free-running period (tau). In DD, tau was significantly longer in DAO than WT hamsters. With increasing light intensity, tau lengthened in both phenotypes, though not at a similar rate. In 10 and 100 lux LL, however, tau did not differ between the two phenotypes. The robustness of the circadian activity rhythm was highest in DD and decreased in LL. No differences between phenotypes were noted. The percentage of arrhythmic animals was low in DD, but remarkably high in LL, and always higher in WT hamsters. The total amount of activity/day was highest in DD; DAO hamsters were less active than WT hamsters under each lighting condition. Light pulses induced phase delays when applied at CT14 and phase advances at CT22, with advances being stronger than delays. Also at CT14, the response of the activity onset was stronger than the activity offset. The opposite was observed at CT22. At CT14, the phase response did not differ between the phenotypes. However, at CT22 the phase advance was significantly weaker in DAO than WT hamsters despite their longer tau. The results provide further evidence that the distinct activity pattern of DAO hamsters is due to an altered interaction between the circadian clock and photic zeitgeber. PMID- 20205561 TI - Presence of a conspecific renders survival advantages in the migratory redheaded bunting: test through the effects of restricted feeding on circadian response and survivorship. AB - This study investigated the effects of a conspecific on survival advantages in a challenged feeding environment created through restricted food availability periods. We measured the daily activity-rest pattern as the circadian response indicator, and changes in body mass and mortality as the survivorship indicator. Migratory male redheaded buntings (Emberiza bruniceps) were housed alone (single, Group 1) or with a conspecific (pair, Group 2) in activity cages that continuously recorded the activity-rest pattern. Cages were individually placed within the isolated photoperiodic boxes providing short-day conditions (8 h light: 16 h darkness, LD 8/16; L = 15 lux; D = 0.5 lux at the cage floor level) with food freely available (ad libitum). Beginning from day 11 of the experiment, food availability was restricted for two weeks to only during the 8 h daytime (zeitgeber time [ZT 0-8]; ZT 0 = time of lights-on). Thus, birds were concurrently subjected to a food zeitgeber cycle, PA 8/16, synchronous (in phase) with the LD 8/16. Thereafter, food availability was changed to only during the 16 h of darkness (ZT 8-0; ZT 8 = time of lights-off). Thus, the food cycle, PA 16/8 (16 h food present: 8 h food absent) was in conflict with the LD 8/16; the LD and PA cycles were in antiphase. This was considered for diurnal redheaded buntings as the challenged feeding environment. After four weeks, singles were returned to the ad libitum food condition; those in pairs remained on the nighttime (darkness) food regimen but were separated to confirm the effects of the nighttime food condition on isolates. The results show that the presence of a conspecific within the cage influenced the daily activity-rest pattern, maintained body mass, and reduced mortality. It is suggested that the presence of a conspecific within the same cage improved the circadian performance of the members forming the pair and enhanced their survivorship. PMID- 20205562 TI - Cardiovascular rhythms and cardiac baroreflex sensitivity in AT(1A) receptor gain of-function mutant mice. AB - A mutant mouse expressing a gain-of-function of the AT(1A) angiotensin II receptor was engineered to study the consequences of a constitutive activation of this receptor on blood pressure (BP). Cardiovascular rhythms and spontaneous cardiac baroreflex sensitivity (BRS) were evaluated using telemetric BP recordings of five transgenic (AT(1A)MUT) and five wild (AT(1A)WT) mice. The circadian rhythms were described with the Chronos-Fit program. The gain of the transfer function between systolic BP (SBP) and pulse intervals used to estimate the spontaneous BRS (ms/mmHg) was calculated in the low frequency (0.15-0.60 Hz) band. Transgenic AT(1A)MUT exhibited higher BP and heart rate (HR) levels compared to controls (SBP AT(1A)MUT 134.6 +/- 5.9 mmHg vs. AT(1A)WT 110.5 +/- 5.9; p < 0.05; HR AT(1A)MUT 531.0 +/- 14.9 vs. AT(1A)WT 454.8 +/- 5.4 beats/min; p = 0.001). Spontaneous BRS was diminished in transgenic mice (AT(1A)MUT 1.23 +/- 0.17 ms/mmHg vs. AT(1A)WT 1.91 +/- 0.18 ms/mmHg; p < 0.05). Motor activity did not differ between groups. These variables exhibited circadian changes, and the differences between the strains were maintained throughout the cycle. The highest values for BP, HR, and locomotor activity were observed at night. Spontaneous BRS varied in the opposite direction, with the lowest gain estimated when BP and HR were elevated (i.e., at night, when the animals were active). It is likely the BP elevation of the mutant mice results from the amplification of the effects of AngII at different sites. Future studies are necessary to explore whether AT(1A) receptor activation at the central nervous system level effectively contributed to the observed differences. PMID- 20205563 TI - Circadian study of decompression sickness symptoms and response-associated variables in rats. AB - In order to study circadian rhythms and decompression sickness (DCS), we determined: 1) the baseline circadian time structure in noncompressed rats of potential response variables to compression/decompression (C/D), and 2) whether rats subjected to C/D display a circadian time-dependent difference in inflammatory response intensity and biological tolerance. Subgroups of male rats, standardized to a 12 h light/12 h dark schedule, were evaluated every 4 h over 24 h after they were either compressed to 683 kPa (group E) or remained at sea level (group C). During 60 min recovery, evaluation included gross DCS symptoms and pulmonary edema in all E rats, and cell counts, nitric oxide, protein, thromboxane B(2,) and leukotriene E(4) levels in survivors. Chi-square, ANOVA, and 24 h cosinor analyses were used to test for time-of-day effects. C/D exposures near the end of dark/activity or during light/resting were generally better tolerated, with lowest signs of DCS symptoms and lowest responses by most of the variables monitored. More deaths were observed in the first half of the dark/activity span. Of the 16 subsets of inflammatory-associated variables, overall increases were observed in 13 and decreases in 2. Significant or borderline significant circadian time effects were found in 14 variables in group C, 12 variables in group E, and 13 variables in response (E%C). Thus, nearly all baseline indices of DCS demonstrated circadian time-dependencies in the sea-level exposed control rats (group C), and nearly all were modified by the circadian time of C/D. Such time-of-day effects of DCS are potentially relevant to the operational concerns of occupations involving decompression exposures and the investigation of prevention and treatment intervention strategies of DCS. PMID- 20205565 TI - Circadian typology and temperament and character personality dimensions. AB - The purpose of the present study is to explore the relationships between circadian typology and Cloninger's model of the seven dimensions of personality, taking into account the possible sex interactions. This model considers four temperament dimensions (viz., HA, harm avoidance; NS, novelty seeking; RD, reward dependence; and PS, persistence) and three character dimensions (viz., SD, self directedness; C, cooperativeness; and ST, self-transcendence). A sample of 862 university students (500 women), between 18 and 30 (21.94 +/- 2.64) yrs of age completed the short versions of the Temperament and Character Inventory (TCI-56) and the reduced Morningness-Eveningness Questionnaire (rMEQ). Women showed higher values for HA, RD, and C, while men showed higher values for NS. Evening-type subjects had higher NS but lower HA, PS, and SD scores. Moreover, circadian typology modulated the sex differences in HA and NS, and only evening-type men showed a lower HA score and higher NS score. Circadian typology is related to Cloninger's model of Temperament and Character personality dimensions. Future studies should further examine possible implications, regarding both the vulnerability of developing psychopathological disorders and the prognosis of response to different treatments. PMID- 20205564 TI - Circadian rhythms of psychomotor vigilance, mood, and sleepiness in the ultra short sleep/wake protocol. AB - Despite its advantages as a chronobiological technique, the ultra-short sleep/wake protocol remains underutilized in circadian rhythm research. The purpose of this study was to examine circadian rhythms of psychomotor vigilance (PVT), mood, and sleepiness in a sample (n=25) of healthy young adults while they adhered to a 3 h ultra-short sleep/wake protocol. The protocol involved 1 h sleep intervals in darkness followed by 2 h wake intervals in dim light, repeated for 50-55 h. A 5 min PVT test was conducted every 9 h with the standard metrics of mean reaction time (RT; RT(mean)), median RT (RT(med)), fastest 10% of responses (RT(10fast)), and reciprocal of the 10% slowest responses (1/RT(10slow)). Subjective measures of mood and sleepiness were assessed every 3 h. A cosine fit of intra-aural temperature, assessed three times per wake period, established the time of the body temperature minimum (T(min)). Mood, sleepiness, and PVT performances were expressed relative to individual means and compared across eight times of day and twelve 2 h intervals relative to T(min). Significant time of-day and circadian patterns were demonstrated for each of the PVT metrics, as well as for mood and sleepiness. Most mood subscales exhibited significant deterioration in day 2 of the protocol without alteration of circadian pattern. However, neither sleepiness nor performance was worse on the second day of observation compared to the first day. These data provide further support for the use of the ultra-short sleep/wake protocol for measurement of circadian rhythms. PMID- 20205566 TI - Associations of metabolic parameters and ethanol consumption with messenger RNA expression of clock genes in healthy men. AB - Recent studies suggest that the impairment of circadian clock function causes various pathological conditions, such as obesity, diabetes, and alcoholism, and an altered mRNA expression of clock genes was found under these conditions. However, it remains to be determined whether clock gene expression varies depending on metabolic conditions even in healthy people. To address this issue, we investigated the associations of metabolic parameters and alcohol consumption with mRNA expression of clock genes (CLOCK, BMAL1, PER1, PER2, and PER3) in peripheral blood cells obtained from 29 healthy non-obese elderly men (age 51-78 yrs) who adhered to a regular sleep-wake routine, through a single time-of-day venous blood sampling at approximately 09:00 h. There were significant correlations between (1) waist circumference and mRNA level of PER1 (r =-0.43), (2) plasma glucose concentration and PER2 (r =-0.50), (3) ethanol consumption and BMAL1 (r =-0.43), and (4) serum gamma-GTP concentration (a sensitive marker of alcohol consumption) and PER2 (r =-0.40). These results suggest mRNA expression of clock genes is associated with obesity, glucose tolerance, and ethanol consumption even in healthy people. PMID- 20205570 TI - Minocycline attenuates HIV infection and reactivation by suppressing cellular activation in human CD4+ T cells. AB - Treatment of human immunodeficiency virus (HIV) infection with highly active antiretroviral therapy (HAART) is effective but can be associated with toxic effects and is expensive. Other options may be useful for long-term therapy. The immunomodulatory antibiotic minocycline could be an effective, low-cost adjunctive treatment to HAART. Minocycline mediated a dose-dependent decrease in single-cycle CXCR4-tropic HIV infection and decreased viral RNA after infection of CD4+ T cells with HIV NL4-3. Reactivation from latency was also decreased in a primary CD4+ T cell-derived model and in resting CD4+ T cells from HIV-infected patients. Minocycline treatment resulted in significant changes in activation marker expression and inhibited proliferation and cytokine secretion of CD4+ T cells in response to activation. This study demonstrates that minocycline reduces HIV replication and reactivation and decreases CD4+ T cell activation. The anti HIV effects of minocycline are mediated by altering the cellular environment rather than directly targeting virus, placing minocycline in the class of anticellular anti-HIV drugs. PMID- 20205572 TI - A novel use for an old drug: the potential for minocycline as anti-HIV adjuvant therapy. PMID- 20205571 TI - Estrogen receptor beta agonism increases survival in experimentally induced sepsis and ameliorates the genomic sepsis signature: a pharmacogenomic study. AB - BACKGROUND: Nonsteroidal agonists have been developed that selectively bind to and activate estrogen receptor beta (ERbeta) rather than estrogen receptor alpha (ERalpha). ERbeta is expressed equally in both male and female mammals in multiple extragonadal tissues. Work reported elsewhere has demonstrated that ERbeta agonists have beneficial effects in multiple (but not all) models of inflammatory diseases and also increase survival in experimentally induced sepsis. METHODS: In these experiments, ERbeta agonists (ERB-041 or WAY-202196) were compared with vehicle control in the murine cecal ligation and puncture (CLP) model and in the pneumococcal pneumonia model of sepsis. The effect of WAY 202196 on the gene expression profile in the CLP model was further studied by transcriptome analysis of lung and small intestine tissue samples. RESULTS: ERbeta agonists provided a significant survival benefit in both experimental models of bacterial sepsis. This survival advantage was accompanied by reduced histologic evidence of tissue damage, reduced transcription of multiple proinflammatory proteins by transcriptome analysis and was not associated with increased bacterial outgrowth. CONCLUSIONS: ERbeta agonist administration provided a survival advantage in septic animals and appears to be a promising therapeutic modality in sepsis. PMID- 20205573 TI - Workplace involvement improves return to work rates among employees with back pain on long-term sick leave: a systematic review of the effectiveness and cost effectiveness of interventions. AB - PURPOSE: Long-term sickness absence among workers is a major problem in industrialised countries. The aim of the review is to determine whether interventions involving the workplace are more effective and cost-effective at helping employees on sick leave return to work than those that do not involve the workplace at all. METHODS: A systematic review of controlled intervention studies and economic evaluations. Sixteen electronic databases and grey literature sources were searched, and reference and citation tracking was performed on included publications. A narrative synthesis was performed. RESULTS: Ten articles were found reporting nine trials from Europe and Canada, and four articles were found evaluating the cost-effectiveness of interventions. The population in eight trials suffered from back pain and related musculoskeletal conditions. Interventions involving employees, health practitioners and employers working together, to implement work modifications for the absentee, were more consistently effective than other interventions. Early intervention was also found to be effective. The majority of trials were of good or moderate quality. Economic evaluations indicated that interventions with a workplace component are likely to be more cost effective than those without. CONCLUSION: Stakeholder participation and work modification are more effective and cost effective at returning to work adults with musculoskeletal conditions than other workplace linked interventions, including exercise. PMID- 20205574 TI - Immediate effects of the central posteroanterior mobilization technique on pain and range of motion in patients with mechanical neck pain. AB - PURPOSE: To determine the immediate effects of the central posteroanterior (PA) mobilization technique on both pain and active cervical range of motion in patients with mechanical neck pain presenting with central or bilateral symptoms. METHODS: A randomized controlled trial was conducted in 60 patients who were randomly allocated into either 'central PA' or 'random' mobilization group. Two physical therapists and one assessor participated. Outcome measures included neck pain at rest, pain on the most painful movement, and active cervical range of motion taken before and immediately 5 min after the mobilization treatment. RESULTS: Significant reductions in pain at rest and on the most painful movement were noted within-group comparisons (p < 0.001). However, the 'central PA' mobilization group obtained a significantly greater reduction in pain on the most painful movement than the 'random' mobilization group (p < 0.05). Both mobilization techniques had no effects on the active cervical range of motion. However, the differences in the means of pain reduction between both mobilization techniques were modest (<10 mm). CONCLUSION: The clinical recommendation regarding the selection of the central PA mobilization technique for treating patients with central or bilateral mechanical neck pain is therefore arguably. PMID- 20205575 TI - Becoming mothers. Multiple sclerosis and motherhood: a qualitative study. AB - PURPOSE: This study aimed to provide a better understanding of the experiences of women with multiple sclerosis (MS) in becoming or being a mother. The research also focused on eliciting their perspectives of strategies that helped them and their families manage mothering young children whilst living with MS. METHOD: A qualitative, interpretive, descriptive approach using individual interviews to elicit and analyze women's experiences of MS and pregnancy, birth, and mothering young children. RESULTS: Analysis of interviews with nine women produced six key themes: becoming a mother as a public private experience, keeping the baby safe; support; conserving energy; being the ideal mother; and backgrounding of their MS. Having MS required the women to set in place specific strategies for managing pregnancy and motherhood associated with a number of these issues such as gathering information and identifying sources of physical and social support. CONCLUSION: This study highlights how pregnancy and motherhood are valued, but challenging times, for women with MS. Recommendations about how services might respond to the specific challenges for women with MS considering or becoming mothers are proposed. PMID- 20205577 TI - Best practise use in stroke rehabilitation: from trials and tribulations to solutions! AB - PURPOSE: This article explores the use of best practises among stroke rehabilitation professionals, salient barriers that influence their knowledge uptake/application and effective knowledge translation (KT) strategies that meet the needs of this clinician group. METHOD: Relevant literature on evidence-based practise in stroke rehabilitation and the use of KT strategies among rehabilitation professionals is summarised and discussed. RESULTS: Although adherence to rehabilitation guidelines translates into improved patient outcomes, best practises are not routinely applied by clinicians when treating individuals with a stroke. Lack of protected work time to search and appraise the research literature is by far the largest organisational barrier to knowledge uptake/application. Personal barriers, such as the lack of confidence and skills to interpret, synthesise and apply research findings, also limit clinicians' uptake of best practises. Studies involving rehabilitation professionals found that active KT strategies were more effective than passive strategies to produce change in their evidence-based knowledge and practise behaviours. As such, interactive e-learning resources are likely to be a relevant KT solution to meet rehabilitation professionals' specific learning needs, guide their clinical decision-making and ultimately increase their best practise behaviours. CONCLUSION: We have the knowledge of best practises in stroke rehabilitation, a means to disseminate that knowledge internationally through interactive e learning resources, and information about effective KT interventions. With these opportunities in place, rehabilitation professionals can expand their capacity by adopting stroke best practises and producing better outcomes for patients. PMID- 20205576 TI - Are features of the neighborhood environment associated with disability in older adults? AB - PURPOSE: To explore the association of features of a person's neighborhood environment with disability in daily activities. METHOD: We recruited 436 people aged 65 years and over (mean 70.4 years (SD = 3.9)) with functional limitations from the Multicenter Osteoarthritis Study (MOST). Features of the neighborhood environment were assessed using the Home and Community Environment (HACE) survey. The Late-Life Disability Instrument (LLDI) was used to assess disability in daily activities. We used logistic regression to examine the association of individual environmental features with disability. RESULTS. Older adults whose neighborhoods did not have parks and walking areas less frequently engaged in a regular fitness program (OR = 0.4, 95% CI (0.2, 0.7)), and in social activities (OR = 0.5, 95% CI (0.3, 1.0)). Those whose neighborhoods had adequate handicap parking had 1.5-1.8 higher odds of engagement in several social and work role activities. The presence of public transportation was associated with 1.5-2.9 higher odds of not feeling limited in social, leisure, and work role activities, and instrumental activities of daily living. CONCLUSION: Our exploratory study suggests that parks and walking areas, adequate handicap parking, and public transportation are associated with disability in older adults. PMID- 20205578 TI - Disability and return to work outcomes after traumatic brain injury: results from the Washington State Industrial Insurance Fund. AB - INTRODUCTION: This article contains a description of community traumatic brain injury (TBI) treatment patterns and outcomes based solely on workers' compensation administrative records for Washington State. METHODS: Administrative records available from the Washington State Department of Labor and Industries data warehouse of administrative records are used to describe medical rehabilitation services and return to work (RTW) referrals for cases of TBI between 1 January 1998 and 31 December 2002. These data represent official records for disability determination and referral for vocational rehabilitation (VR) services. RESULTS: At total of 797 cases were identified all of which had identifiable treatment trajectories. No disability was the outcome in 9.0% of cases; temporary disability in 53.5% of cases, permanent disability in 31.1% of cases. Only 48% of surviving cases include a medical rehabilitation phase. This phase included only inpatient services in 26.5% of referred cases, only ambulatory services in 59.6% and both inpatient and ambulatory services in 13.9%. Only about half of surviving cases were referred for RTW services. Employment rates were similar to those published from other state rehabilitation programs. CONCLUSIONS: State/community treatment and disability outcome patterns are more diverse than the expected sequence of acute treatment, medical rehabilitation and VR. Employment rates after referral for VR were 65%. PMID- 20205579 TI - Establishing a training programme for rehabilitation aides in Haiti: successes, challenges, and dilemmas. AB - BACKGROUND: In Haiti, there are scarce resources available for physical rehabilitation. Healing Hands for Haiti International Foundation has established a rehabilitation aide programme as a means of providing rehabilitation services. This article illustrates some of the successes, challenges, and dilemmas that arise in the provision of such an education. METHODS: Graduates and students answered a 23-item questionnaire designed to investigate respondents' perceptions of the training programme. These responses were then coded and quantified for analysis. RESULTS: The author interviewed 32 of 49 graduates and current students. Forty-five percent of graduates were working as rehabilitation aides, and the majority of those were working in urban areas. Graduate's earnings differed greatly. Respondents suggested that the programme needed to help the graduates find employment after graduation and to provide continuing training. The most common limitation in education mentioned by the graduates was a need for basic nursing skills and first-aid education. CONCLUSION: The most common difficulties and dilemmas in providing a rehabilitation aide programme were: lack of resources including job opportunities for graduates, and lack of proper support available from supervising healthcare providers. Curricula for similar programs must be culturally sensitive, help create employment opportunities, and provide continuing educational opportunities for their graduates. PMID- 20205580 TI - USA paralympic team archer with McCune Albright Syndrome: a retrospective case report. AB - PURPOSE: This retrospective case report describes a 22-year-old woman with McCune Albright Syndrome who was an archery Bronze Medalist at the 2008 USA Paralympic Games. METHODS: The subject completed the Medical Outcome Survey Short Form-36 (SF-36) and the Hip Dysfunction and Osteoarthritis Score (HOOS). RESULTS: SF-36 scores met or exceeded those for National Collegiate Athletic Association (NCAA) female athletes, and age and gender matched USA norms for vitality, mental health and role emotional subscales. General health was lower than NCAA female athletes. Physical functioning, role: physical, bodily pain and social functioning subscale scores were lower than both comparison groups. HOOS symptom subscale scores revealed disabilities with walking (performed with crutches), hip abduction and stair climbing. CONCLUSIONS: Target archery does not require the lower extremity strength and motion required by many other sports. Identifying the ideal time to undergo total hip arthroplasty is difficult. As total hip arthroplasty becomes less invasive, more durable, with greater modular options, and with lower revision rates, more young patients will likely benefit. Serial SF-36 and HOOS surveys may help patients and surgeons better delineate symptom, functional limitation and disability changes across the early lifespan assisting surgical timing decisions while balancing existing function, quality of life values and near future technological advances. PMID- 20205581 TI - Effects of an intensive, task-specific rehabilitation program for individuals with chronic stroke: a case series. AB - PURPOSE: The purpose of this case series was to determine feasibility and evaluate changes in activity and participation outcomes in persons with chronic stroke after an intensive, task-specific rehabilitation program incorporating whole-body and client-centred interventions. METHOD: Participants with chronic stroke (N = 12) who were ambulatory and had at least minimal arm/hand function were recruited. The program included whole-body goal-focused activities, gait training and strengthening exercises for 4 h, 5 days per week for 2 weeks. Daily educational sessions and a home activities program were also included. Activity based measures including the Wolf motor function test, Berg balance scale, timed up and go test and 6-min walk test and participation-based measures including the Stroke Impact Scale and Canadian Occupational Performance Measure were collected at pre-test, immediate post-test and 5-month retention. RESULTS: The effect of the intervention on participation-based outcomes was much greater than on the activity-based outcomes. Minimal detectable differences in self-perceived participation were reported for most participants. CONCLUSIONS: The intensive, task-specific intervention was a feasible program for these participants with stroke. Although minimal changes in activity-based outcomes were found, the participants perceived improvements in participation with personal goal-related activities that resulted in large effect sizes that were maintained for 5-months after the intervention. PMID- 20205582 TI - Effects of dance on balance and gait in severe Parkinson disease: a case study. AB - PURPOSE: Dance may improve functional mobility in individuals with mild-to moderate Parkinson disease (PD), yet dance effects in severe PD remain unexamined. This study's purpose was to evaluate the feasibility and effects of partnered tango classes on balance, endurance and quality of life in an individual with severe PD. DESIGN: Over 10 weeks, the participant attended 20, 1 h tango classes for individuals with PD. Balance, walking, and quality of life were evaluated before and after the intervention and at a 1-month follow-up in this single case design. Caregiver burden was also assessed at all time points. RESULTS: The participant improved on the Berg Balance Scale, 6-min walk test, and functional reach. He reported increased balance confidence and improved quality of life as measured by the Parkinson Disease Questionnaire-39 summary index. Gains were maintained at the 1-month follow-up. Caregiver burden increased from baseline immediately post-intervention and at follow-up. CONCLUSION: Twenty partnered tango lessons improved balance, endurance, balance confidence, and quality of life in a participant with severe PD. This is the first report of the use of dance as rehabilitation for an individual with advanced disease who primarily used a wheelchair for transportation. PMID- 20205583 TI - A note on the theoretical framework of World Health Organization Disability Assessment Schedule II. PMID- 20205584 TI - An investigation of the factors affecting handwriting skill in children with hemiplegic cerebral palsy. AB - PURPOSE: This study investigated the effects of sensory-perceptual-motor and cognitive functions on handwriting skill in primary-school children with left hemiplegic cerebral palsy, compared with that of their healthy peers. METHODS: The study included 26 children aged 8-12 years with left hemiplegic cerebral palsy and 32 typically developing children of similar age with dominant right hand. The Minnesota Handwriting Assessment was used to evaluate handwriting skill. The Bruininks-Oseretsky Test of Motor Proficiency was used to assess motor performance. Cognitive function was assessed by the Lowenstein Occupational Therapy Cognitive Assessment. The Ayres Southern California Sensory Integration Tests were used to assess visual perception, kinaesthesia and graphesthesia. RESULTS: Statistically significant differences were found between the two groups in sensory-perceptual-motor and cognitive function and handwriting skill (p < 0.05). There were also significant correlations between handwriting parameters and upper-extremity speed and dexterity, proprioception, bilateral coordination, visual and spatial perception and, visual-motor organisation in children with cerebral palsy (p < 0.05). CONCLUSIONS: The results showed that left-hemiplegic children with cerebral palsy whose right sides were dominant were significantly less competent at handwriting than their right-dominant, healthy peers. It was found that the impairment in proprioception seen in the non-hemiplegic side in children with cerebral palsy, and also the impairment in bilateral coordination, speed and dexterity of the upper extremities, visual and spatial perception, visual-motor organization, and tactile-sensory impairments negatively affected their handwriting skills. In the treatment approaches for children with hemiplegic cerebral palsy, comprehensive sensory-perceptual-motor assessments that involve both extremities must be performed in detail at the earliest possible stage, in order to minimize the existing problems with early-treatment policies. Developing the sensory-perceptual-motor and cognitive function of hemiplegic children would thus be possible, and they would be able to develop handwriting skill as a tool for their academic lives as healthy peers. PMID- 20205586 TI - Biochemical principles of small RNA pathways. AB - The discovery of RNA interference (RNAi) is among the most significant biomedical breakthroughs in recent history. Multiple classes of small RNA, including small interfering RNA (siRNA), micro-RNA (miRNA), and piwi-interacting RNA (piRNA), play important roles in many fundamental biological and disease processes. Collective studies in multiple organisms, including plants, Drosophila, Caenorhabditis elegans, and mammals indicate that these pathways are highly conserved throughout evolution. Thus, scientists across disciplines have found novel pathways to unravel, new insights in probing pathology, and nascent technologies to develop. The field of RNAi also provides a clear framework for understanding fundamental principles of biochemistry. The current review highlights elegant, reason-based experimentation in discovering RNA-directed biological phenomena and the importance of robust assay development in translating these observations into mechanistic understanding. This biochemical template also provides a conceptual framework for overcoming emerging challenges in the field and for understanding an expanding small RNA world. PMID- 20205585 TI - Copper metallochaperones. AB - The current state of knowledge on how copper metallochaperones support the maturation of cuproproteins is reviewed. Copper is needed within mitochondria to supply the Cu(A) and intramembrane Cu(B) sites of cytochrome oxidase, within the trans-Golgi network to supply secreted cuproproteins and within the cytosol to supply superoxide dismutase 1 (Sod1). Subpopulations of copper-zinc superoxide dismutase also localize to mitochondria, the secretory system, the nucleus and, in plants, the chloroplast, which also requires copper for plastocyanin. Prokaryotic cuproproteins are found in the cell membrane and in the periplasm of gram-negative bacteria. Cu(I) and Cu(II) form tight complexes with organic molecules and drive redox chemistry, which unrestrained would be destructive. Copper metallochaperones assist copper in reaching vital destinations without inflicting damage or becoming trapped in adventitious binding sites. Copper ions are specifically released from copper metallochaperones upon contact with their cognate cuproproteins and metal transfer is thought to proceed by ligand substitution. PMID- 20205587 TI - Dengue hemorrhagic fever: the sensitivity and specificity of the world health organization definition for identification of severe cases of dengue in Thailand, 1994-2005. AB - BACKGROUND: Dengue virus infection causes a spectrum of clinical manifestations, usually classified according to the World Health Organization (WHO) guidelines into dengue fever (DF) and dengue hemorrhagic fever (DHF). The ability of these guidelines to categorize severe dengue illness has recently been questioned. METHODS: We evaluated dengue case definitions in a prospective study at a pediatric hospital in Bangkok, Thailand, during 1994-2005. One thousand thirteen children were enrolled within the first 3 days after onset of fever and observed with standardized data collection. Cases were classified on the basis of application of the strict WHO criteria. All dengue virus infections were laboratory confirmed. We retrospectively grouped patients on the basis of whether they received significant intervention based on fluid replacement and/or requirements for blood transfusion. RESULTS: Eighty-five (58%) of 150 persons with DHF, 40 (15%) of 264 with DF, and 73 (12%) of 599 with other febrile illnesses (OFIs) received significant intervention. Sixty-eight percent of dengue cases requiring intervention met strict WHO criteria for DHF. In contrast, only 1% of OFI cases met WHO criteria for DHF. Plasma leakage and thrombocytopenia were the 2 components contributing to the specificity of the WHO case definition and identified dengue cases that required intervention. Hemorrhagic tendency did not reliably differentiate DF and DHF. In DF cases, thrombocytopenia and bleeding were associated with severity. CONCLUSIONS: Dengue illness is heterogeneous in severity, and severe clinical features occurred in patients whose cases were not characterized as DHF. The WHO case definition of DHF demonstrated sensitivity of 62% and specificity of 92% for identification of dengue illness requiring intervention, without the need for laboratory confirmation of dengue virus infection, in an area of endemicity. PMID- 20205588 TI - Management and outcomes after multiple corneal and solid organ transplantations from a donor infected with rabies virus. AB - BACKGROUND: This article describes multiple transmissions of rabies via transplanted solid organ from a single infected donor. The empirical Milwaukee treatment regimen was used in the recipients. METHODS: Symptomatic patients were treated by deep sedation (ketamine, midazolam, and phenobarbital), ribavirin, interferon, and active and passive vaccination. Viral loads and antibodies were continuously monitored. RESULTS: Recipients of both cornea and liver transplants developed no symptoms. The recipient of the liver transplant had been vaccinated approximately 20 years before transplantation. Two recipients of kidney and lung transplants developed rabies and died within days of symptomatic disease. Another kidney recipient was treated 7 weeks before he died. The cerebrospinal fluid viral load remained at constant low levels (<10,000 copies/mL) for approximately 5 weeks; it increased suddenly by almost 5 orders of magnitude thereafter. After death, no virus was found in peripheral compartments (nerve tissue, heart, liver, or the small intestine) in this patient, in contrast to in patients in the same cohort who died early. CONCLUSIONS: Our report includes, to our knowledge, the longest documented treatment course of symptomatic rabies and the first time that the virus concentration was measured over time and in different body compartments. The postmortem virus concentration in the periphery was low, but there was no evidence of a reduction of virus in the brain. PMID- 20205590 TI - Discussion of a genome-wide association approach to determine HIV-1 set point in African Americans. PMID- 20205589 TI - Case-crossover study of Burkholderia cepacia complex bloodstream infection associated with contaminated intravenous bromopride. AB - OBJECTIVE: To investigate an outbreak of healthcare-associated Burkholderia cepacia complex (BCC) primary bloodstream infections (BCC-BSI). DESIGN AND SETTING: Case-crossover study in a public hospital, a university hospital and a private hospital in Rio de Janeiro, Brazil, from March 2006 to May 2006. PATIENTS: Twenty-five patients with BCC-BSI. DESIGN: After determining the date BCC-BSI symptoms started for each patient, 3 time intervals of data collection were defined, each one with a duration of 3 days: the case period, starting just before BCC-BSI symptoms onset; the control period, starting 6 days before BCC-BSI symptoms onset; and the washout period, comprising the 3 days between the case period and the control period. Exposures evaluated were intravascular solutions and invasive devices and procedures. Potential risk factors were identified by using the McNemar chi(2) adjusted test. Cultures of samples of potentially contaminated solutions were performed. BCC strain typing was performed by pulsed field gel electrophoresis using SpeI. RESULTS: The statistical analysis revealed that the use of bromopride and dipyrone was associated with BCC-BSI. A total of 21 clinical isolates from 17 (68%) of the 25 patients and an isolate obtained from the bromopride vial were available for strain typing. Six pulsotypes were detected. A predominant pulsotype (A) accounted for 11 isolates obtained from 11 patients (65%) in the 3 study hospitals. CONCLUSION: Our investigation, using a case-crossover design, of an outbreak of BCC-BSI infections concluded it was polyclonal but likely caused by infusion of contaminated bromopride. The epidemiological finding was validated by microbiological analysis. After recall of contaminated bromopride vials by the manufacturer, the outbreak was controlled. PMID- 20205591 TI - Host determinants of HIV-1 control in African Americans. AB - We performed a whole-genome association study of human immunodeficiency virus type 1 (HIV-1) set point among a cohort of African Americans (n = 515), and an intronic single-nucleotide polymorphism (SNP) in the HLA-B gene showed one of the strongest associations. We use a subset of patients to demonstrate that this SNP reflects the effect of the HLA-B*5703 allele, which shows a genome-wide statistically significant association with viral load set point (P = 5.6 x 10( 10)). These analyses therefore confirm a member of the HLA-B*57 group of alleles as the most important common variant that influences viral load variation in African Americans, which is consistent with what has been observed for individuals of European ancestry, among whom the most important common variant is HLA-B*5701. PMID- 20205592 TI - Respiratory syncytial virus F and G proteins induce interleukin 1alpha, CC, and CXC chemokine responses by normal human bronchoepithelial cells. AB - Human respiratory syncytial virus (RSV) is a ubiquitous respiratory virus that causes serious lower respiratory tract disease in infants and young children worldwide. Studies have shown that RSV infection modulates chemokine expression patterns, suggesting that particular cytokine expression profiles may be indicators of disease severity. In this study, we show that RSV F or G protein treatment of fully differentiated primary normal human bronchial epithelial cells induces apical and basolateral secretion of interleukin 8 (IL-8), interferon inducible protein 10 (IP-10), monocyte chemotactic protein 1 (MCP-1), and RANTES (regulated on activation, normal T cell expressed and secreted). Purified RSV G (attachment) protein was shown to stimulate the secretion of interleukin 1alpha and RANTES, whereas purified F (fusion) protein elicited the production of IL-8, IP-10, and RANTES. Studies of ultraviolet-inactivated RSV showed that treatment of normal human bronchial epithelial cells induces apical IL-8, IP-10, and MCP-1 secretion independent of infection, suggesting that RSV proteins alone modify the chemokine response pattern, which may affect the early immune response before infection. PMID- 20205593 TI - Role of nitric oxide in hyperpnea-induced bronchoconstriction and airway microvascular permeability in guinea pigs. AB - The present study aimed to evaluate the role of nitric oxide (NO) on hyperpnea induced bronchoconstriction (HIB) and airway microvascular hyperpermeability (AMP). Sixty-four guinea pigs were anesthetized, tracheotomized, cannulated, and connected to animal ventilator to obtain pulmonary baseline respiratory system resistance (Rrs). Animals were then submitted to 5 minutes hyperpnea and Rrs was evaluated during 15 minutes after hyperpnea. AMP was evaluated by Evans blue dye (25 mg/kg) extravasation in airway tissues. Constitutive and inductible NO was evaluated by pretreating animals with N(G)-nitro-L-arginine methyl ester (L-NAME) (50 mg/kg), aminoguadinine (AG) (50 mg/kg), and L-arginine (100 mg/kg) and exhaled NO (NOex) was evaluated before and after drug administration and hyperpnea. The results show that L-NAME potentiated (57%) HIB and this effect was totally reversed by L-arginine pretreatment, whereas AG did not have effect on HIB. L-NAME decreased basal AMP (48%), but neither L-NAME nor AG had any effect on hyperpnea-induced AMP. NOex levels were decreased by 50% with L-NAME, effect that was reversed by L-arginine treatment. These results suggest that constitutive but not inducible NO could have a bronchoprotective effect on HIB in guinea pigs. The authors also observed that neither constitutive nor inducible NO seems to have any effect on hyperpnea-induced AMP. PMID- 20205594 TI - Decoy oligodeoxynucleotide against STAT transcription factors decreases allergic inflammation in a rat asthma model. AB - Leukocyte infiltration and activation of the CD40-CD40 ligand costimulatory pathway may promote inflammatory processes such as asthma. The aim of this study was to investigate whether a single intratracheal application of a decoy oligodeoxynucleotide (ODN) specific for signal transducer and activator of transcription (STAT) family members 1 and 3 influences leukocyte influx and pulmonary CD40 expression in a rat model of allergic airway inflammation. In comparison with the corticosteroid budesonide, the authors investigated the efficacy of the STAT decoy ODN in ovalbumin-induced allergic asthma in a Brown Norway rat asthma model. Leukocytes of the bronchoalveolar lavage (BAL) and lung tissue were analyzed and expression of CD40 was assessed by Western blotting. Single administration of the STAT decoy ODN but not of a mutated control ODN or budesonide resulted in a significant decrease of eosinophils and T lymphocytes in the BAL fluid. Cell numbers of CD4+ and CD8+ lymphocytes were significantly decreased in the lung tissue after decoy ODN application. CD40 expression in protein extracts from lung tissue was also reduced significantly following STAT decoy ODN treatment. These findings indicate that a single, local application of a transcription factor decoy ODN specific for STAT1 and STAT3 caused an attenuation of the allergen-induced cellular inflammatory reaction and is at least as effective as a topical steroid. PMID- 20205595 TI - Primary bronchial epithelial cell culture from explanted cystic fibrosis lungs. AB - Lung disease is responsible for more than 95% of morbidity and mortality in cystic fibrosis. The exact pathogenesis of cystic fibrosis lung disease remains poorly understood. Experimental models are therefore vital for use in research. Animal models and immortalized cell lines both have inherent limitations. Explanted lungs removed from people with cystic fibrosis at the time of transplantation represent a potentially valuable but technically and logistically challenging source of primary cystic fibrosis bronchial epithelial cells. In this study, pieces of segmental bronchus from explanted lungs were treated with patient-specific antimicrobials prior to isolation of bronchial epithelial cells. Cultured cells were characterized by their morphology under light microscopy, cytokeratin and hematoxylin-eosin staining, and electrophysiological profile. Primary bronchial epithelial cells were successfully cultured from 15 of 22 patients attempted. The cells exhibited typical epithelial morphology, staining for cytokeratin, lack of responsiveness to forskolin treatment, and remained viable after storage in liquid nitrogen. Seven unsuccessful cultures failed due to early infection with bacteria known to colonize the airways pretransplant. The results show that primary bronchial epithelial cell culture is possible from explanted cystic fibrosis lungs. This provides an important cellular model to elucidate the pathogenic mechanisms in cystic fibrosis lung disease and to investigate potential therapeutic targets. PMID- 20205596 TI - Toll-like receptor 4-deficient mice are resistant to chronic hypoxia-induced pulmonary hypertension. AB - Current data suggest that Toll-like receptor 4 (TLR4), a key molecule in the innate immune response, may also be activated following tissue injury. Activation of this receptor is known to induce the production of several proinflammatory cytokines. Given that pulmonary inflammation has been shown to be a key contributor to chronic hypoxia-induced pulmonary vascular remodeling, the authors hypothesized that TLR4-deficient mice would be less susceptible to pulmonary hypertension (PH) as compared to mice with intact TLR4. TLR4-deficient and TLR4 intact strains of inbred mice were exposed to 4, 8, and 16 weeks of hypoxia (0.10 FiO(2)) or normoxia (0.21 FiO(2)) in a normobaric chamber. After chronic hypoxic exposure, TLR4-intact mice developed significant PH evidenced by increased right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary artery medial thickening. In contrast, TLR4-deficient mice had no significant change in any of these parameters and this was associated with decreased pulmonary vascular inflammatory response as compared to the TLR4-intact mice. These results suggest that TLR4 deficiency may decrease the susceptibility to developing PH by attenuating the pulmonary vascular inflammatory response to chronic hypoxia. PMID- 20205597 TI - Rosiglitazone inhibits migration, proliferation, and phenotypic differentiation in cultured human lung fibroblasts. AB - Recent studies have indicated that peroxisome proliferator-activated receptor gamma (PPARgamma) is capable of modulating inflammation, which prompted us to investigate the potential of PPARgamma ligands as lung protective agents in pulmonary fibrosis. The present study was undertaken to investigate the effects of rosiglitazone (RSG), a highly potent ligand of PPARgamma, on migration, proliferation, and phenotypic differentiation of human lung fibroblasts (MRC-5) and to explore its potential for therapy of pulmonary fibrosis. The cell migration potential was observed in a scratch wound model. Cell proliferation was determined by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) method, immunocytochemical staining, and flow cytometry, and protein expression by Western blot analysis. RSG slowed cell migration distance induced by fetal bovine serum (FBS), decreased cell proliferation initiated by FBS or platelet-derived growth factor-BB (PDGF-BB), and decreased alpha-smooth muscle actin (alpha-SMA) protein expression induced by transforming growth factor-beta1 (TGF-beta1). In addition, RSG incubation reduced the ratio of phospho extracellular signal-regulated kinases 1/2 (p-ERK1/2) to ERK1/2 expression stimulated by FBS, PDGF-BB, and TGF-beta1. These findings show that RSG treatment inhibits lung fibroblast migration and proliferation and myofibroblast transdifferentiation stimulated by FBS and growth factors in vitro, which suggests that PPARgamma agonists could antagonize pulmonary fibrosis and have potential for therapeutic application in pulmonary fibrosis. PMID- 20205599 TI - Aerosolized recombinant human lysozyme ameliorates Pseudomonas aeruginosa-induced pneumonia in hamsters. AB - As an alternative to conventional antibiotics, aerosolized recombinant human lysozyme (rhLZ) was used to treat experimentally induced pneumonia. Syrian hamsters were inoculated intratracheally with a nonmucoid strain of Pseudomonas aeruginosa (PA), then exposed to a 1.0% solution of rhLZ in water for 2 hours per day for 3 consecutive days (controls were treated with aerosolized water alone). Compared to controls, the rhLZ-treated group showed statistically significant reductions in the following parameters: (1) lung histopathological changes, (2) bacterial colony-forming units in whole lung and bronchoalveolar lavage fluid (BALF), (3) total BALF leukocytes, (4) percent BALF neutrophils, and (5) alveolar septal apoptosis. Exposure to aerosolized rhLZ also resulted in a large increase in BALF lysozyme activity. These findings indicate that aerosolized rhLZ may be potentially useful in reducing the level of bacterial colonization and inflammation in the lungs of patients with PA pneumonia. PMID- 20205598 TI - Inhibition of myristoylated alanine-rich C kinase substrate (MARCKS) protein inhibits ozone-induced airway neutrophilia and inflammation. AB - Evidence suggests inhibition of leukocyte trafficking mitigates, in part, ozone induced inflammation. In the present study, the authors postulated that inhibition of myristoylated alanine-rich C kinase substrate (MARCKS), an 82-kDa protein with multiple biological roles, could inhibit ozone-induced leukocyte trafficking and cytokine secretions. BALB/c mice (n = 5/cohort) were exposed to ozone (100 ppb) or forced air (FA) for 4 hours. MARCKS-inhibiting peptides, MANS, BIO-11000, BIO-11006, or scrambled control peptide RNS, were intratracheally administered prior to ozone exposure. Ozone selectively enhanced bronchoalveolar lavage (BAL) levels of killer cells (KCs; 6 +/- 0.9-fold), interleukin-6 (IL-6; 12.7 +/- 1.9-fold), and tumor necrosis factor (TNF; 2.1 +/- 0.5-fold) as compared to cohorts exposed to FA. Additionally, ozone increased BAL neutrophils by 21% +/ 2% with no significant (P > .05) changes in other cell types. MANS, BIO-11000, and BIO-11006 significantly reduced ozone-induced KC secretion by 66% +/- 14%, 47% +/- 15%, and 71.1% +/- 14%, and IL-6 secretion by 69% +/- 12%, 40% +/- 7%, and 86.1% +/- 11%, respectively. Ozone-mediated increases in BAL neutrophils were reduced by MANS (86% +/- 7%) and BIO-11006 (84% +/- 2.5%), but not BIO-11000. These studies identify for the first time the novel potential of MARCKS protein inhibitors in abrogating ozone-induced increases in neutrophils, cytokines, and chemokines in BAL fluid. BIO-11006 is being developed as a treatment for chronic obstructive pulmonary disorder (COPD) and is currently being evaluated in a phase 2 clinical study. PMID- 20205600 TI - Pharmacodynamics of a losartan transdermal system for the treatment of hypertension. AB - AIMS: Transdermal therapeutic systems were developed using the polymers, Eudragit E 100 and polyvinyl pyrrolidone VA 64 in a film casting assembly. The medicated films were evaluated for physical properties, in vitro drug release studies, in vitro skin permeation studies, and pharmacodynamic studies. RESULTS: The physical parameters were found to be very satisfactory with high drug content (>99%). The in vitro drug release studies were performed using paddle-over-disc assembly specified in USP XXIII. The pharmacodynamic studies were carried out using tail cuff method in Wistar albino rats. Hypertension was induced by methyl prednisolone acetate subcutaneously for 2 weeks. The developed matrix patch was found to decrease the blood pressure (25.42% reduction in mean systolic blood pressure of rats) significantly (P < 0.001) in proximity of the normal value and it was maintained for 24 hours. CONCLUSION: It can be concluded that the developed transdermal matrix patch holds promise for the management of hypertension that needs to be validated by clinical trials. PMID- 20205601 TI - Two-photon polymerization of microneedles for transdermal drug delivery. AB - IMPORTANCE OF THE FIELD: Microneedles are small-scale devices that are finding use for transdermal delivery of protein-based pharmacologic agents and nucleic acid-based pharmacologic agents; however, microneedles prepared using conventional microelectronics-based technologies have several shortcomings, which have limited translation of these devices into widespread clinical use. AREAS COVERED IN THIS REVIEW: Two-photon polymerization is a laser-based rapid prototyping technique that has been used recently for direct fabrication of hollow microneedles with a wide variety of geometries. In addition, an indirect rapid prototyping method that involves two-photon polymerization and polydimethyl siloxane micromolding has been used for fabrication of solid microneedles with exceptional mechanical properties. WHAT THE READER WILL GAIN: In this review, the use of two-photon polymerization for fabricating in-plane and out-of-plane hollow microneedle arrays is described. The use of two-photon polymerization micromolding for fabrication of solid microneedles is also reviewed. In addition, fabrication of microneedles with antimicrobial properties is discussed; antimicrobial microneedles may reduce the risk of infection associated with the formation of channels through the stratum corneum. TAKE HOME MESSAGE: It is anticipated that the use of two-photon polymerization as well as two-photon polymerization-micromolding for fabrication of microneedles and other microstructured drug delivery devices will increase over the coming years. PMID- 20205602 TI - Delivery of celecoxib for treating diseases of the eye: influence of pigment and diabetes. AB - IMPORTANCE OF THE FIELD: Age-related macular degeneration (AMD) and diabetic retinopathy (DR) are two major causes of blindness. In these disorders, growth factors such as vascular endothelial growth factor (VEGF) are upregulated, leading to either enhanced vascular permeability or proliferation of endothelium. While corticosteroid therapies available at present suffer from side effects including cataracts and elevated intraocular pressure, anti-VEGF antibody therapies require frequent intravitreal injections, a procedure that can potentially lead to retinal detachment or endophthalmitis. Thus, there is a need to develop safe, sustained release therapeutic approaches for treating AMD and DR. AREAS COVERED IN THIS REVIEW: This review discusses the pharmacological basis for using celecoxib, an anti-inflammatory drug capable of selectively inhibiting cycloxygenase 2, in treating AMD and DR. In addition, this article discusses the safety, delivery advantage and efficacy of celecoxib by transscleral retinal delivery, a periocular delivery approach that is less invasive to the globe compared with intravitreal injections. WHAT THE READER WILL GAIN: The reader will gain insights into the development of a pharmacological agent and a sustained release delivery system for treating DR and AMD. Further, the reader will gain insights into the influence of eye physiology including pigmentation and disease states such as DR on retinal drug delivery. TAKE HOME MESSAGE: Transscleral sustained delivery of anti-inflammatory agents is a viable option for treating retinal disorders. PMID- 20205603 TI - Triggered drug delivery from biomaterials. AB - IMPORTANCE OF THE FIELD: Conventional dosing methods are frequently unable to deliver the clinical requirement of the patient. The ability to control the delivery of drugs from implanted materials is difficult to achieve, but offers promise in diverse areas such as infection-resistant medical devices and responsive implants for diabetics. AREAS COVERED IN THIS REVIEW: This review gives a broad overview of recent progress in the use of triggers that can be used to achieve modulation of drug release rates from implantable biomaterials. In particular, these can be classified as being responsive to one or more of the following stimuli: a chemical species, light, heat, magnetism, ultrasound and mechanical force. WHAT THE READER WILL GAIN: An overview of the potential for triggered drug delivery to give methods for tailoring the dose, location and time of release of a wide range of drugs where traditional dosing methods are not suitable. Particular emphasis is given to recently reported systems, and important historical reports are included. TAKE HOME MESSAGE: The use of externally or internally applied triggers of drug delivery to biomaterials has significant potential for improved delivery modalities and infection resistance. PMID- 20205605 TI - Dissolution-modulating mechanism of pH modifiers in solid dispersion containing weakly acidic or basic drugs with poor water solubility. AB - IMPORTANCE OF THE FIELD: Although the solid dispersion method has been known to increase the dissolution rate of poorly water-soluble drugs by dispersing them in hydrophilic carriers, one obstacle of the solid dispersion method is its limited solubilization capacity, especially for pH-dependent soluble drugs. AREAS COVERED IN THIS REVIEW: pH-modified solid dispersion, in which pH modifiers are incorporated, may be a useful method for increasing the dissolution rate of weakly acidic or basic drugs. Sufficient research, including the most recent reports, was undertaken in this review. WHAT THE READER WILL GAIN: How could the inclusion of the pH the pH modifiers in the solid dispersion system change drug structural behaviors, molecular interactions, microenvironmental pH, and/or release rate of pH modifiers, relating with the enhanced dissolution of weakly acidic or weakly basic drugs with poor water solubility? These questions have been investigated to determine the dissolution-modulating mechanism of pH modifiers in solid dispersion containing weakly acidic or basic drugs. TAKE HOME MESSAGE: It is believed that step-by-step mechanistic approaches could provide the ultimate solution for solubilizing several poorly water-soluble drugs with pH dependent solubility from a solid dispersion system, as well as provide ideas for developing future dosage systems. PMID- 20205606 TI - The sequential therapy regimen for Helicobacter pylori eradication. AB - IMPORTANCE OF THE FIELD: Standard triple therapy (STT) is the most used treatment for Helicobater pylori infection. The prevalence of antibiotic resistance has increased substantially in recent years and there has been a corresponding decrease in efficacy. AREAS COVERED IN THIS REVIEW: Bibliographical searches were performed in MEDLINE and international congresses up to 2009 for 'Helicobacter pylori' AND 'sequential regimen/therapy'. WHAT THE READER WILL GAIN: Several meta analyses have demonstrated that sequential therapy (SQT) is more effective than STT. SQT is not affected by bacterial and host factors that have, until now, predicted the outcome of STT. Primary clarithromycin resistance is the only factor reducing the efficacy of SQT; however, even in these patients an acceptable > 75% eradication can be achieved. So far, almost all the studies have been performed in Italy. The advantages of SQT over STT should be confirmed in different countries. Whether it is necessary to provide the drugs sequentially or if the four components of SQT can be given concurrently is unclear. TAKE HOME MESSAGE: SQT is a promising new treatment approach that deserves consideration as a treatment strategy for H. pylori infection. However, further robust assessment across a much broader range of patients is required before SQT could supplant existing treatment regimens and be generally recommended in clinical practice. PMID- 20205604 TI - Current aspects of formulation efforts and pore lifetime related to microneedle treatment of skin. AB - IMPORTANCE OF THE FIELD: The efficacy of microneedles in the area of transdermal drug delivery is well documented. Multiple studies have shown that enhancement of skin permeation by means of the creation of microscopic pores in the stratum corneum can greatly improve the delivery rates of drugs. However, skin pretreatment with microneedles is not the only factor affecting drug transport rates. Other factors, including drug formulation and rate of micropore closure, are also important for optimizing delivery by this route. AREAS COVERED IN THIS REVIEW: This review aims to highlight work that has been done in these areas, with an emphasis on drug formulation parameters that affect transdermal flux. WHAT THE READER WILL GAIN: This review creates an appreciation for the many factors affecting microneedle-enhanced delivery. Most results clearly indicate that microneedle skin pretreatment by itself may have different effects on drug transport depending on the formulation used, and formulation characteristics have different effects on the transport through untreated skin and microneedle-treated skin. Several formulation approaches are reported to optimize microneedle enhanced drug delivery, including co-solvent use, vesicular, nanoparticulate and gel systems. TAKE HOME MESSAGE: In addition to well-established factors that affect microneedle-assisted delivery (geometry, type of microneedle, etc.), formulation and pore viability are also critical factors that must be considered. PMID- 20205607 TI - Intravesical therapy for bladder cancer. AB - IMPORTANCE OF THE FIELD: Although transurethral resection of bladder tumor (TURBT) is effective therapy, up to 45% of patients will have a recurrence within 1 year after TURBT alone. Further, there is a 3 - 15% risk of tumor progression to muscle invasive and/or metastatic cancer. Depending on patient and tumor characteristics, a number of patients may benefit from some form of intravesical therapy. Adjuvant therapy is effective in avoiding post-TURBT implantation of tumor cells, eradicating residual disease, preventing tumor recurrence, and to delay or reduce tumor progression through direct cytoablation or immunostimulation. AREAS COVERED IN THIS REVIEW: The role of risk assessment in the management of nonmuscle invasive bladder cancer (NMIBC) and the indications for the use of intravesical agents are discussed. Findings from major randomized clinical trials on BCG, interferon and various chemotherapeutic agents are summarized; key aspects of drug pharmacology, drug efficacy, side effects, and toxicity are also covered. WHAT THE READER WILL GAIN: The reader will gain a basic understanding of the role of risk assessment in determining the need for intravesical therapy, as well as an overview of the different types of agents in use in the United States today. TAKE HOME MESSAGE: The type of intravesical therapy used is based on the risk groups as noted in the European prognostic tables. Bacillus Calmette-Guerin (BCG) is the most commonly used first-line agent immunotherapeutic agent for prophylaxis and treatment of carcinoma in situ and high-grade bladder cancer. Other immunotherapeutic options include the interferons, interleukins 2 and 12, and tumor necrosis factor, all of which have activity in BCG refractory patients, although with low durable remission rates. Studies have shown that chemotherapy prevents recurrence but not progression. The available data on intravesical chemotherapy do not indicate that any single agent currently in use is clearly better than any other. Therefore, the selection of a chemotherapeutic agent is usually based on cost, toxicity, and availability as well as on physician preference and experience. PMID- 20205608 TI - Novel substituted heteroaromatic compounds as inhibitors of stearoyl-CoA desaturase. AB - Stearoyl-CoA desaturase 1 (SCD1) has been implicated as a novel therapeutic target for the treatment of a variety of metabolic diseases, including diabetes, obesity, hepatic steatosis, atherosclerosis and cardiovascular disease. The application WO2009129625 from Merck Frosst Canada claims novel substituted heteroaromatic compounds as inhibitors of SCD and potential drugs for the pharmacological treatment of metabolic disorders, when used alone or in combination with other drugs. Based on in vitro activity of the patented compounds, these molecules may be considered as potential SCD inhibitors and could be of therapeutic value. However, further preclinical studies are needed to evaluate their curative potential and safety before clinical development. PMID- 20205609 TI - Are mid-pregnancy androgen levels negatively associated with breastfeeding? PMID- 20205610 TI - Teen motherhood in cross-cultural perspective. AB - Teen motherhood is the prevalent childbearing pattern in most traditional populations. Yet early motherhood is associated with negative biological and social outcomes in the developed world. We review the teen pregnancy literature in light of this discrepancy, emphasizing two core debates. The first debate centers on whether teens have poor pregnancy outcomes compared to older women, and whether negative outcomes are biologically based. Second, we consider the debate over the confounding effects of socio-economic conditions associated with being young. When teens are considered as a group, results are inconsistent across studies. When teens are disaggregated by age, the strongest finding across studies is that biological risk is concentrated in only the youngest of mothers. Negative consequences are associated with teen motherhood not because of chronological age per se, but because of relative developmental maturity and the availability of non-maternal support. In most traditional societies as well as in some sectors of developed societies, teen motherhood occurs within the context of extended kin networks and is subsidized through reliable economic and childcare assistance. Child-rearing practices, rather than pregnancy per se, may explain much of the discrepancy in the prevalence, success and attitudes toward teen motherhood in traditional and developed societies. PMID- 20205611 TI - Early spatiotemporal progress of myelinated nerve fiber regenerating through biological chitin conduit after injury. AB - Chitin conduits to bridge nerve injuries with a small gap (2 mm) give us a biological window in which the peripheral nerve regeneration process can be observed. In this study, the regeneration process was observed on different intervals postoperatively. Histological analysis revealed that the early regeneration process occurred in three phase: degeneration and matrix phase, axonal and Schwann migration phase, myelination and maturation phase. Schwann cells grew into the lumen from both the proximal and distal nerve segments. Axonal regrowth progressed at an average rate of 1.4 mm/d. Regenerating axonal fibers were myelinated by Schwann cells from both sides of the conduit. PMID- 20205612 TI - The immunological properties of stroma-free polyhemolysate containing catalase and superoxide dismutase activities prepared by polymerized bovine stroma-free hemolysate. AB - Crosslinking of ultrapure hemoglobin, crystalline catalase, and superoxide dismutase resulted in a soluble nanodimensional complex of polyhemoglobin catalase-superoxide dismutase. A less expensive and more convenient way is to crosslink bovine stroma-free hemolysate (stroma-free hemolysate) that already contains hemoglobin, catalase, and superoxide dismutase into polyhemoglobin with catalase and superoxide dismutase activities (stroma-free polyhemolysate) [21]. The objective of the present study is to evaluate the immunological properties of this stroma-free polyhemolysate. Each of three groups of rats received weekly subcutaneous injections of one of the stroma-free polyhemolysate, stroma-free hemolysate, and saline for four weeks. One week after the four cycles of weekly immunization, serum and plasma were collected for C3a complement activation tests and Ouchterlony antibody-antigen precipitation tests, respectively. Results show that stroma-free polyhemolysate retained significant antioxidant enzyme activity. The C3a complement activation test and Ouchterlony test show that four weekly subcutaneous injections of bovine stroma-free polyhemolysate did not result in any immunological reaction in rats when tested this way. PMID- 20205613 TI - Intestinal permeability, vitamin A absorption and serum alpha-tocopherol during therapy with gefitinib. AB - Measurement of intestinal permeability represents one of the potential methods of noninvasive laboratory assessment of gastrointestinal toxicity of anticancer therapy. We have assessed intestinal permeability (by measuring absorption of lactulose, mannitol, and xylose), vitamin A absorption and serum alpha-tocopherol in patients with non-small cell lung carcinoma or head and neck carcinomas treated with gefitinib. Lactulose, mannitol and xylose were determined by capillary gas chromatography, and retinol, alpha-tocopherol, retinyl stearate and retinyl palmitate were determined by high-performance liquid chromatography. Compared to healthy controls, patients had significantly increased lactulose/mannitol ratio and lower postprandial retinyl palmitate and retinyl stearate concentrations. Compared with pre-treatment values, xylose absorption was decreased and lactulose/mannitol and lactulose/xylose ratios were increased during the therapy. A significant decrease of serum alpha-tocopherol was evident throughout the course of therapy. In contrast, only minor alterations of vitamin A absorption were observed. In conclusion, an alteration in intestinal permeability reflected in increased lactulose/mannitol and lactulose/xylose ratios was observed during gefitinib therapy. Potential association between decreased serum alpha-tocopherol concentrations and the toxicity of gefitinib therapy should be further investigated. PMID- 20205614 TI - Does osteoprotegerin relate to micro- and macrovascular complications in long term type 1 diabetes? AB - PURPOSE: Markers of micro- and macrovascular disease are needed in type 1 diabetes in order to identify patients at risk of severe complications. Osteoprotegerin (OPG) is expressed in vascular myocytes, and increasing levels have been reported in type 1 diabetes. Consequently, we investigated OPG as a non invasive marker of micro- and macrovascular complications in long-term type 1 diabetic patients. METHODS: This was a cross-sectional study of 200 type 1 diabetic patients with long diabetes duration from a population-based cohort from Fyn County, Denmark. Patients were examined in 2007-2008, and OPG was measured and correlated to diabetes-associated complications: retinopathy, nephropathy, neuropathy and macrovascular disease. RESULTS: Median age and duration of diabetes was 58.7 years (range 37.7-84.4 years) and 43 years (range 34-70 years), respectively. Median level of OPG was 1257 pg/ml (range 379-5706 pg/ml). In univariate analyses, OPG was related to age, duration of diabetes, female gender, nephropathy and inversely to diastolic blood pressure. In an age- and sex adjusted model, higher levels of OPG were associated with a higher risk of nephropathy (OR 2.54, 95% confidence interval 1.09-5.90 for third vs. first tertile). Statistical significance was, however, lost in a multivariate model, and proliferative diabetic retinopathy, neuropathy and macrovascular disease was not associated with OPG in either model. CONCLUSIONS: Some associations of OPG and nephropathy were found in a long-term type 1 diabetic cohort. Prospective studies are needed in order to determine whether OPG can be used to predict nephropathy. PMID- 20205615 TI - Relation of coffee consumption and serum liver enzymes in Japanese men and women with reference to effect modification of alcohol use and body mass index. AB - OBJECTIVE: Previous studies have shown that coffee consumption is inversely related to serum levels of liver enzymes such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT), but few have addressed the relation in women and effect modifications of alcohol use and obesity. We examined the association of coffee and green tea consumption with serum activities of liver enzymes in free-living Japanese men and women, focusing on sex difference and effect modifications of alcohol and obesity. MATERIAL AND METHODS: The data were derived from the baseline survey of the Kyushu University Fukuoka Cohort Study, and included 12,020 Japanese men and women aged 49-76 years who were free of chronic liver diseases. RESULTS: There was an inverse association between coffee consumption and elevated ALT in men, and the association between the two was weaker in women. In the analyses stratified by aminotransferases category, inverse associations of coffee consumption with serum activities of liver enzymes were observed in both men and women within the whole range and among those with aminotransferases within the reference range (ALT/AST or= 100 MPa) as an alternative method for the inactivation of tumor cells. HHP is a technique that has been known for more than 100 years to successfully inactivate micro organisms and to alter biomolecules. In the studies here, we show that the treatment of MCF7, B16-F10, and CT26 tumor cells with HHP >or= 300 MPa results in mainly necrotic tumor cell death forms displaying degraded DNA. Only CT26 cells yielded a notable amount of apoptotic cells after the application of HHP. All tumor cells treated with >or= 200 MPa lost their ability to form colonies in vitro. Furthermore, the pressure-inactivated cells retained their immunogenicity, as tested in a xenogeneic as well as syngeneic mouse models. We conclude that the complete tumor cell inactivation, the degradation of the cell's nuclei, and the retention of the immunogeneic potential of these dead tumor cells induced by HHP favor the use of this technique as a powerful and low-cost technique for the inactivation of tumor cells to be used as a vaccine. PMID- 20205626 TI - Maternal plasma P-selectin at 11 to 13 weeks of gestation in hypertensive disorders of pregnancy. AB - OBJECTIVE: To determine if development of preeclampsia is preceded by altered maternal plasma P-selectin and if the levels are related with uterine artery pulsatility index. METHODS: Plasma P-selectin and uterine artery pulsatility index were measured at 11-13 weeks in 121 cases that subsequently developed preeclampsia, 87 cases that developed gestational hypertension and 208 unaffected controls. RESULTS: In the preeclampsia group the median multiple of the median in controls (MoM) P-selectin and uterine artery PI were significantly increased (1.2 MoM and 1.3 MoM). There was no significant association between P-selectin and uterine artery pulsatility index in either the preeclampsia or control group. CONCLUSION: In pregnancies that develop preeclampsia there is evidence of platelet activation from the first trimester. However, there is no direct link between the degree of impaired placentation and platelet activation. PMID- 20205627 TI - Maternal plasma plasminogen activator inhibitor-2 at 11 to 13 weeks of gestation in hypertensive disorders of pregnancy. AB - OBJECTIVE: In patients with preeclampsia maternal plasma concentration of plasminogen activator inhibitor-2 (PAI-2) is reduced. The objective of the study was to determine if the altered levels of PAI-2 precede the onset of the disease. METHODS: Plasma PAI-2 was measured at 11-13 weeks of gestation in 119 pregnancies that developed preeclampsia, 85 that developed gestational hypertension and 204 controls. RESULTS: There were no significant differences in PAI-2 between the preeclampsia, gestational hypertension and controls (1.07 MoM, 1.08 MoM and 0.96 MoM). CONCLUSION: The decrease in plasma PAI-2 observed in preeclampsia does not precede the clinical onset of the disease. PMID- 20205628 TI - Preparation of some pyrazoline derivatives and evaluation of their antifungal activities. AB - The synthesis of a new series of 1-[(benzazole-2-yl)thioacetyl]-3,5-diaryl-2 pyrazoline derivatives was obtained by reacting 1-(chloroacetyl)-3,5-diaryl pyrazolines with 2-mercaptobenzimidazole/benzoxazole/benzothiazole. The chemical structures of the compounds were elucidated by (1)H-NMR, (13)C-NMR, and FAB(+)-MS spectral data. Their antifungal activities against Candida albicans, Candida glabrata, Candida utilis, Candida tropicalis, Candida krusei, and Candida parapsilosis were investigated. A significant level of activity was observed. PMID- 20205629 TI - Cruciferous plants: phytochemical toxicity versus cancer chemoprotection. AB - The Cruciferae (also known as the Brassicaceae) are the family of plants that include the various familiar members of the species Brassica oleracea (e.g., broccoli, cabbage, cauliflower, kale, Brussels sprouts) as well as many other plants that are widely consumed in various parts of the world. Forage and root brassicas are widely used as winter feeds for cattle and sheep. A striking and characteristic chemical property of cruciferous plants is their high content of glucosinolates (more than 120 types), which often approaches 1% or more of their dry weight. The interest devoted to this group of natural products is caused by the appreciable biological effects of both the intact glucosinolates (GSLs) and especially the complex group of glucosinolate transformation products produced in non-enzymatic and enzymatic reactions. Depending on the concentration and structural types of these compounds, their biological effects can be toxic, anti nutritional or beneficial to health. Most serious economic problems in livestock seem to result from rapeseed meal; arising from GSLs or their breakdown products. In contrast, GSLs and their isothiocyanate (ITC) hydrolysis products are reportedly well-known protectors against carcinogenesis. GSLs play further protective and evolutionarily important roles in plants. These include allelopathy (suppression of growth of neighboring plants), specific positive and negative feeding cues for some insects and broad antibiotic properties including nematocidal, antimicrobial, antifungal, antiprotozoal and insecticidal activities. The controversy in the referred actions contributed to crucifers' phytochemicals has been exclusively discussed. PMID- 20205630 TI - Antioxidant profile of hyaluronan: physico-chemical features and its role in pathologies. AB - Many findings have evidenced antioxidant properties of hyaluronan, both in vitro and in vivo, by means of which it can scavenge free radicals and exert its effect on pathologies. The aim of this review is to summarize the available data on the features and clinical profile of hyaluronan, with regard in particular to its antioxidant capacity and to its related physico-chemical properties. Additionally, hyaluronan and its derivatives are examined, with the focus on their therapeutic uses, protection against cellular damage, and their role as inflammatory mediators. Finally, therapies associated to the antioxidant effect of hyaluronan are discussed. PMID- 20205631 TI - New platinum and ruthenium complexes--the latest class of potential chemotherapeutic drugs--a review of recent developments in the field. AB - New Platinum and Ruthenium complexes display antitumour and antimetastatic potentials and lower host toxicities. This mini-review examines some the more recent developments in this field, and explores their interactions with biologically-relevant species. The article also refers to more recent work in the area of molybdenum and copper(II) chemistry. PMID- 20205632 TI - Polymeric materials and formulation technologies for modified-release tablet development. AB - Over the last years significant advances have been made in the area of drug delivery with the development of modified-release (MR) dosage forms. The present review is divided into two parts, one dealing with technologies for the design of modified-release drug delivery tablets and the other with the use of synthetic and natural polymers that are capable of controlling drug release. PMID- 20205633 TI - Involvement of L-carnitine in cellular metabolism: beyond Acyl-CoA transport. AB - Carnitine is well-known for its role in the transport of fatty acids to the mitochondrial matrix, where beta-oxidation takes place. This work describes novel functions for this compound and novel data on its pharmacokinetics. PMID- 20205634 TI - Mechanisms of the resistance and tolerance to beta-lactam and glycopeptide antibiotics in pathogenic gram-positive cocci. AB - Beta-lactams are the most frequently used antimicrobials in combating infections. In the case of gram-positive bacteria resistant to beta-lactams, glycopeptides are the first choice. The occurrence, mechanisms and genetic background of the resistance of pathogenic staphylococci, streptococci and enterococci to beta lactam and glycopeptide antibiotics were discussed. The resistances to well established antimicrobials, as well as new agents (ceftobiprole, oritavancin, telavancin, dalbavancin) were taken into consideration in the text. PMID- 20205635 TI - Altered hyaluronan biosynthesis and cancer progression: an immunological perspective. AB - Hyaluronan is a glycosaminglycan present in practically all tissues as an important component of the extracellular matrix. In spite of its apparent simple chemical structure, hyaluronan is a molecule with multiple and complex physiogical and pathological functions, Hyaluronan is able to regulate a variety of biological processes such as cellular growth, migration, differentiation and inflammation, not only in normal but also in cancer tissues. Besides, increasing evidence suggests hyaluronan as a potent modulator of immune responses which supports a potential role of this molecule in cancer immunotherapy. PMID- 20205636 TI - Anticancer agents derived from natural products. AB - Advances in the prevention and treatment of cancer require the continued development of novel and improved chemopreventive and chemotherapeutic agents. Throughout history, natural products have afforded a rich source of anticancer agents with diverse chemical structures and bioactivities. Recent technological and methodologic advances in structure elucidation, organic synthesis, and biological assay have resulted in the isolation and clinical evaluation of various novel anticancer agents. In this review, we will present the anticancer activities, mechanism of action, structure and activity relationships of six important anticancer agents from natural products, that is, taxol, betulinic acid, camptothecin, resveratrol, podophyllotoxin and curcumin. PMID- 20205637 TI - Spermicides, microbicides and antiviral agents: recent advances in the development of novel multi-functional compounds. AB - Non-ionic surfactants have been proposed as dual action anti-viral and spermicidal agents to tackle viral infections, namely HIV. Given very promising in vitro results, nonoxynol-9 has been widely used. However, toxic effects were reported, paradoxically increasing the incidence of transmission of HIV/Sexually Transmitted Diseases in vivo. Thus, there has been a growing interest in identifying and evaluating a new generation of accessible and easy-to-use molecules with simultaneous spermicidal and microbicide action. Different biochemical compounds and mechanisms of action are currently being studied. This article reviews the diverse strategies and mechanisms of action of these novel compounds, as well the necessary systematic studies needed to evaluate their possible toxicity. PMID- 20205638 TI - Nandrolone decanoate enhances the activities of cholanthrene induced glutathione s-transferase in liver tissue of albino mice. AB - A concrete study is still fragmentary to correlate the effect of Nandrolone decanoate, a anabolic steroid, on the cholanthrene induced Glutathione-s transferases (GST) activities in liver tissues. Administration of Nandrolone and 3-Methylcholanthrene in alone and combination is found to increase the activity of hepatic GST activity significantly (p< 0.01) suggesting Nandrolone as a potent inducer of GST activity. PMID- 20205641 TI - Re-balancing of inflammation and abeta immunity as a therapeutic for Alzheimer's disease-view from the bedside. AB - Morbidities of aging and Alzheimer's disease (AD) have been related to defective functions of both T cells and macrophages leading to brain amyloidosis and inflammation. In AD patients, "inflammaging" may be associated with an increase of incompetent memory T cells and inflammatory cytokines produced by macrophages, whereas defective clearance of amyloid-beta 1-42 (Abeta) may be related to defective transcription of immune genes necessary for Abeta phagocytosis, beta 1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase and Toll-like receptors. However, AD shows considerable heterogeneity of disease manifestations and mechanisms. The approaches to re-balancing Abeta immunity and inflammation are being pursued in transgenic animal models and peripheral blood mononuclear cells of patients. The regulatory signaling pathways of microglial phagocytosis and inflammation involving co-receptors and transforming growth factor-beta have been considerably clarified in animal studies. Natural immunostimulating therapies using vitamin D3 and curcuminoids have been developed in macrophages of AD patients. AD patients possess two types of macrophages: a majority has "Type I", which are improved by curcuminoids and vitamin D3; whereas a minority has "Type II" responding positively to vitamin D3 but not to curcuminoids. Other nutritional substances, such as plant polyphenols and omega-3 fatty acids, may inhibit inflammation and stimulate immunity. More invasive immune approaches involve Abeta vaccine and cytokine antagonists. Increased inflammation may represent the "first hit", and defective transcription of immune genes the "second hit" in the pathogenesis of AD. PMID- 20205640 TI - Amyloid-beta immunotherapy for Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive, degenerative disorder of the brain and the most common form of dementia among the elderly. As the population grows and lifespan is extended, the number of AD patients will continue to rise. Current clinical therapies for AD provide partial symptomatic benefits for some patients; however, none of them modify disease progression. Amyloid-beta (Abeta) peptide, the major component of senile plaques in AD patients, is considered to play a crucial role in the pathogenesis of AD thereby leading to Abeta as a target for treatment. Abeta immunotherapy has been shown to induce a marked reduction in amyloid burden and an improvement in cognitive function in animal models. Although preclinical studies were successful, the initial human clinical trial of an active Abeta vaccine was halted due to the development of meningoencephalitis in approximately 6% of the vaccinated AD patients. Some encouraging outcomes, including signs of cognitive stabilization and apparent plaque clearance, were obtained in subset of patients who generated antibody titers. These promising preliminary data support further efforts to refine Abeta immunotherapy to produce highly effective and safer active and passive vaccines for AD. Furthermore, some new human clinical trials for both active and passive Abeta immunotherapy are underway. In this review, we will provide an update of Abeta immunotherapy in animal models and in human beings, as well as discuss the possible mechanisms underlying Abeta immunotherapy for AD. PMID- 20205639 TI - Abeta DNA vaccination for Alzheimer's disease: focus on disease prevention. AB - Pre-clinical and clinical data suggest that the development of a safe and effective anti-amyloid-beta (Abeta) immunotherapy for Alzheimer's disease (AD) will require therapeutic levels of anti-Abeta antibodies, while avoiding proinflammatory adjuvants and autoreactive T cells which may increase the incidence of adverse events in the elderly population targeted to receive immunotherapy. The first active immunization clinical trial with AN1792 in AD patients was halted when a subset of patients developed meningoencephalitis. The first passive immunotherapy trial with bapineuzumab, a humanized monoclonal antibody against the end terminus of Abeta, also encountered some dose dependent adverse events during the Phase II portion of the study, vasogenic edema in 12 cases, which were significantly over represented in ApoE4 carriers. The proposed remedy is to treat future patients with lower doses, particularly in the ApoE4 carriers. Currently there are at least five ongoing anti-Abeta immunotherapy clinical trials. Three of the clinical trials use humanized monoclonal antibodies, which are expensive and require repeated dosing to maintain therapeutic levels of the antibodies in the patient. However in the event of an adverse response to the passive therapy antibody delivery can simply be halted, which may provide a resolution to the problem. Because at this point we cannot readily identify individuals in the preclinical or prodromal stages of AD pathogenesis, passive immunotherapy is reserved for those that already have clinical symptoms. Unfortunately those individuals have by that point accumulated substantial neuropathology in affected regions of the brain. Moreover, if Abeta pathology drives tau pathology as reported in several transgenic animal models, and once established if tau pathology can become self propagating, then early intervention with anti-Abeta immunotherapy may be critical for favorable clinical outcomes. On the other hand, active immunization has several significant advantages, including lower cost and the typical immunization protocol should be much less intrusive to the patient relative to passive therapy, in the advent of Abeta-antibody immune complex-induced adverse events the patients will have to receive immuno-supperssive therapy for an extended period until the anti Abeta antibody levels drop naturally as the effects of the vaccine decays over time. Obviously, improvements in vaccine design are needed to improve both the safety, as well as the efficacy of anti-Abeta immunotherapy. The focus of this review is on the advantages of DNA vaccination for anti-Abeta immunotherapy, and the major hurdles, such as immunosenescence, selection of appropriate molecular adjuvants, universal T cell epitopes, and possibly a polyepitope design based on utilizing existing memory T cells in the general population that were generated in response to childhood or seasonal vaccines, as well as various infections. Ultimately, we believe that the further refinement of our AD DNA epitope vaccines, possibly combined with a prime boost regime will facilitate translation to human clinical trials in either very early AD, or preferably in preclinical stage individuals identified by validated AD biomarkers. PMID- 20205642 TI - Assessing activation states in microglia. AB - Since the original identification of microglia as a principal player in the brain's innate immune response, microglial activation has been widely studied. Recent studies suggest that microglial responses are heterogeneous, requiring a more precise definition of the functional outcomes of their participation in disease. Similarly to other tissue macrophages, microglia respond to inflammatory or injurious stimuli in the CNS in a pre-programmed manner that is designed to both kill and to set the stage for repair and resolution of the disease. In vitro studies on acute immune responses have provided key information on the initiation, signaling pathways and products of activated macrophages. However, in chronic neurodegenerative diseases such as Alzheimer's disease where in vivo analyses are critical to understanding the long-term disease processes, our knowledge of the integrated tissue immune response and the outcome of this immune activity to neurons and other glia over the extended course of disease is more limited. This is due in part to the complexity of microglial activation states and to the location of microglia in a dense neuronal network. Classical activation, alternative activation and acquired deactivation are each found in the brain during chronic neuroinflammatory diseases and may demonstrate regional differences in expression levels. This review will identify "markers" that can be used to explore inflammatory states in the brain and will discuss the likely functional outcomes when these cytoactive factors are expressed. A broad-based functional view is provided that is designed to more fully explore the balance between inflammo-toxic and inflammo-resolution factors that govern chronic disease progression. PMID- 20205643 TI - Mechanisms of mononuclear phagocyte recruitment in Alzheimer's disease. AB - Alzheimer's disease (AD) is associated with a significant neuroinflammatory component. Mononuclear phagocytes including monocytes and microglia are the principal cells involved, and they accumulate at perivascular sites of beta amyloid (Abeta) deposition and in senile plaques. Recent evidence suggests that mononuclear phagocyte accumulation in the AD brain is dependent on chemokines. CCL2, a major monocyte chemokine, is upregulated in the AD brain. Interaction of CCL2 with its receptor CCR2 regulates mononuclear phagocyte accumulation in a mouse model of AD. CCR2 deficiency leads to lower mononuclear phagocyte accumulation and is associated with higher brain Abeta levels, specifically around blood vessels, suggesting that monocytes accumulate at sites of Abeta deposition in an initial attempt to clear these deposits and stop or delay their neurotoxic effects. Indeed, enhancing mononuclear phagocyte accumulation delays progression of AD. Here we review the mechanisms of mononuclear phagocyte accumulation in AD and discuss the potential roles of additional chemokines and their receptors in this process. We also propose a multi-step model for recruitment of mononuclear phagocytes into the brain. The first step involves egress of monocyte/microglial precursors from the bone marrow into the blood. The second step is crossing the blood-brain barrier to the perivascular areas and into the brain parenchyma. The final step includes movement of monocytes/microglia from areas of the brain that lack any amyloid deposition to senile plaques. Understanding the mechanism of recruitment of mononuclear phagocytes to the AD brain is necessary to further understand the role of these cells in the pathogenesis of AD and to identify any potential therapeutic use of these cells for the treatment of this disease. PMID- 20205644 TI - Microglia and inflammation in Alzheimer's disease. AB - One hundred and fifty years have elapsed since the original discovery of the microglial cell by Virchow. While this cell type has been well studied, the role of microglia in the pathology of many central nervous system diseases still remains enigmatic. It is widely accepted that microglial-mediated inflammation contributes to the progression of Alzheimer's disease (AD); however, the precise mechanisms through which these cells contribute to AD-related inflammation remains to be elucidated. In the AD brain, microglial cells are found in close association with amyloid beta (Abeta) deposits. Histological examination of AD brains as well as cell culture studies have shown that the interaction of microglia with fibrillar Abeta leads to their phenotypic activation. The conversion of these cells into a classically 'activated' phenotype results in production of chemokines, neurotoxic cytokines and reactive oxygen and nitrogen species that are deleterious to the CNS. However, microglia also exert a neuroprotective role through their ability to phagocytose Abeta particles and clear soluble forms of Abeta. These cells have been documented to play integral roles in tissue repair and inflammation, and in recent years it has been appreciated that this cell type is capable of facilitating a more complex response to pathogens by changing their activation status. A variety of new findings indicate that their role in the central nervous system is far more complex than previously appreciated. In this review we discuss the role of microglia in the normal brain and their phenotypic heterogeneity and how this may play a role in AD-related pathophysiology. We touch on what is known about their ability to recognize and clear Abeta peptides as well as more controversial topics, including various activation states of microglia and the ability of peripheral macrophages or monocytes to infiltrate the brain. PMID- 20205645 TI - Impact of the CD40-CD40L dyad in Alzheimer's disease. AB - As the number of elderly individuals rises, Alzheimer's disease (AD), marked by amyloid-beta deposition, neurofibrillary tangle formation, and low-level neuroinflammation, is expected to lead to an ever-worsening socioeconomic burden. AD pathoetiologic mechanisms are believed to involve chronic microglial activation. This phenomenon is associated with increased expression of membrane bound CD40 with its cognate ligand, CD40 ligand (CD40L), as well as increased circulating levels of soluble forms of CD40 (sCD40) and CD40L (sCD40L). Here, we review the role of this inflammatory dyad in the pathogenesis of AD. In addition, we examine potential therapeutic strategies such as statins, flavonoids, and human umbilical cord blood transplantation, all of which have been shown to modulate CD40-CD40L interaction in mouse models of AD. Importantly, therapeutic approaches focusing on CD40-CD40L dyad regulation, either alone or in combination with amyloid-beta immunotherapy, may provide for a safe and effective AD prophylaxis or treatment in the near future. PMID- 20205647 TI - Non-steroidal anti-inflammatory drugs and Alzheimer's disease: the epidemiological evidence. AB - Alzheimer's disease imposes a significant public health burden that will only worsen as the population ages. Thus, there is considerable motivation to develop effective strategies to treat, or more ideally, prevent the disease. Epidemiologic evidence has suggested that non-steroidal anti-inflammatory drugs (or NSAIDs) may be neuro-protective. However, this evidence is controversial. Observational studies in humans have found that the use of NSAIDs is associated with a lower risk of developing Alzheimer's disease. By contrast, randomized trials have reported that NSAIDs are not effective in treating patients with clinically established disease nor in preventing the onset of dementia among those who are cognitively normal or have mild cognitive impairment. In this article, we review the existing epidemiologic evidence on the relationship between NSAIDs and Alzheimer's disease and discuss several hypotheses to explain the divergent findings. PMID- 20205646 TI - Mechanisms of action of non-steroidal anti-inflammatory drugs for the prevention of Alzheimer's disease. AB - Alzheimer's disease (AD) is accompanied by an activation of the innate immune system, and many epidemiological studies have shown reduced risk for dementia or AD associated with chronic consumption of non-steroidal anti-inflammatory drugs (NSAIDs). These observations led to animal model studies to test the hypothesis that NSAIDs can be disease-modifying for some aspects of AD pathogenesis. NSAIDs cannot only suppress inflammatory targets, which could contribute to neuroprotection, they also slow amyloid deposition by mechanisms that remain unclear. Several large clinical trials with NSAID therapies with AD subjects have failed, and cyclooxygenase-2 does not appear to be a useful target for disease modifying therapy. However, there may be apolipoprotein E E4 pharmacogenomic effects and a real but delayed positive signal in a large primary prevention trial with naproxen. This encourages researchers to re-address possible mechanisms for a stage-dependent NSAID efficacy, the subject of this review. PMID- 20205648 TI - Inflammation, immunity, and Alzheimer's disease. AB - Few topics in the field of Alzheimer's disease (AD) research have brought about the level of excitement and interest as the role of inflammation and immunity in the pathobiology and treatment of the disease. In this special issue of the journal, experts in the field give their views on how inflammatory processes and the immune system intersect- at both etiological and treatment levels- with disease biology. Collectively, nearly three decades of work are covered in this special issue, beginning with the first epidemiologic studies that showed an inverse risk relationship between AD and use of non-steroidal anti-inflammatory drugs, and ending with "immunotherapy" approaches and recent studies examining the roles of innate immune cells including microglia and peripheral mononuclear phagocytes in AD. Despite considerable work in this area, many important questions remain concerning the nature and timing of immune/inflammatory responses in the context of AD, and at what point and how to therapeutically intervene. PMID- 20205649 TI - Salt effect on substrate specificity of a subtilisin-like halophilic protease. AB - Enzyme-substrate interaction under the presence of high concentration of salts is of great interest for biotechnology applications and basic enzymology. In our previous work, the salt effect on halophilic subtilase SR5-3 was evaluated with Suc-AAPF-MCA and with the FRET peptide Abz-AAPFSSKQ-EDDnp. It was demonstrated that the magnitude of catalytic activity enhancement was affected by the presence of the prime site residues (Okamoto et al., 2009). In this work, a detailed analysis of the salt effect on SR5-3 protease substrate specificity was performed using chromogenic and coumarin substrates as well as FRET peptides derived from Abz-KLRSSKQ-EDDnp. The followings were demonstrated: 1) Preference of amino acid of SR5-3 protease at the P(3), P(2), P(1), P(1)' or P(2)' position of FRET substrates was almost similar with that of subtilisin. 2) Under the presence of the salts (3M NaCl or 1M Na(2)SO(4)), SR5-3 protease showed higher kcat values, lower Km values and totally 2-6 times higher kcat/Km values compared with those of control for FRET substrates, and salts did not significantly affect the preference of amino acid residues at the primary positions (P1 and P1'), but it affected the preference at the P(2) and P(2)' position. In contrast, for smaller substrates with only non-prime sites, SR5-3 protease showed 20-75 times higher kcat/Km values compared with those of control. These findings are in agreement with the notion that increases in enzyme-substrate interactions in subtilases alter the rate-determining step in peptide hydrolysis. PMID- 20205650 TI - The two pathways for effective orthogonal protection of L-ornithine, for amino acylation of 5'-O-pivaloyl nucleosides, describe the general and important role for the successful imitation, during the model substrates for the ribosomal mimic reaction. AB - Bz(NO(2))-Orn(Boc)-OCH(2)CN was synthesized as an amino acid component with effective and successful orthogonal protection for amino acylation of 5'-O Pivaloyl nucleosides and preparation of substrates for model ribosome reactions. The synthesis was carried out using suitable combinations of the methods of peptide synthesis and modification of amino acids. PMID- 20205651 TI - Transient expression of recombinant sPDGFR alpha-Fc in CHO DG44 cells using 50-mL orbitally shaking disposable bioreactors. AB - Overactivity of platelet-derived growth factor (PDGF) has been linked to malignant cancers. High levels of PDGF result in the activation of its receptors (PDGFRs) and the over-proliferation of cells. Therefore, interfering with this signaling pathway in cancer cells could be significant for anti-cancer drug development. In a previous study, the sPDGFR alpha-Fc fusion protein expressed in static CHO-k(1) cells showed an anti-proliferative effect on vascular endothelial cells. However, it was difficult to obtain a large quantity of this fusion protein for further functional studies. In the present study, the sPDGFR alpha-Fc fusion protein was transiently expressed in Chinese Hamster Ovary (CHO) DG44 cells in 50-mL orbital shaking bioreactors. sPDGFR alpha-Fc was expressed as a 250-kDa dimeric protein with potential glycosylation. The final yield of sPDGFR alpha-Fc in the culture supernatant was as high as 16.68 mg/L. Our results suggest that transient expression in orbital shaking bioreactors may be feasible for preparation of recombinant proteins used for preclinical studies. PMID- 20205652 TI - Why inverse proteins are relatively abundant. AB - Studies have shown that inverse proteins are relatively abundant. In this work, we investigate the proposition that the repeat patterns they share with protein sequences explain this phenomenon. Using a new artificial set of peptide sequences which also display these features and a random set, we show that the presence of repeats contributes to protein sequence similarity. Further analysis confirms that most inverse proteins exhibit repeats. Therefore, we suggest the relative abundance of inverse proteins can be explained by the fact they display the same repeat structures and amino acid propensity of existing proteins. PMID- 20205654 TI - In vitro unfolding of insulin: characterization of intermediates and putative unfolding pathway. AB - The in vitro insulin unfolding had been studied using the "equilibrium unfolding" method where protein is unfolded by reducing reagents in the presence of trace amounts of oxidants such as oxidized glutathione. Nine intermediates were captured in the unfolding process, named as P1A, P2A, P3A, P4A, P3B, P4B, P5B, P6B, and P7B, which were all either A chain derivatives or B chain derivatives. No intermediate with inter-A-B chain disulfide was captured. Based on the character of the intermediates, their distribution during the unfolding process and the hypothetic "transient" intermediates, an in vitro putative unfolding pathway of insulin had been proposed. Besides, the comparison of the intermediates captured in unfolding with the intermediates captured in the refolding process of insulin revealed that both unfolding/refolding processes of insulin shared common intermediates. Based on these observations we suggested that the unfolding pathway of insulin was similar to the refolding pathway but flowed in the opposite direction. PMID- 20205655 TI - Protein engineering of bacterial histidine kinase receptor systems. AB - Two-component systems (TCS) involving the His-Asp phosphotransfer are commonly utilized for signal transduction in prokaryotes in which the two essential components are a sensor histidine kinase (HK) receptor and a response regulator (RR). Despite great efforts in structural and functional characterization of signal perception mechanisms, the exact signaling mechanisms remain elusive for many TCSs. Mimicking the natural TCS signaling pathways, chimeric receptor kinases and response regulators have been constructed through the process of swapping modular domains of related TCSs. To design chimeras with new signaling pathways, domains from different proteins that have little relationship at the primary structural level but carrying desirable functional properties can be conjoined to engineer novel TCSs. These chimeras maintain the ability to respond to environmental stimulants by regulating protein phosphorylation to produce downstream output signals. Depending on the nature of external signals, chimeric TCSs can serve as a novel tool not only to examine the natural signaling mechanisms in TCSs, but also for industrial and clinical applications. PMID- 20205656 TI - N-(tert)-butyloxycarbonyl)-beta,beta-cyclopentyl-cysteine (acetamidomethyl) methyl ester for synthesis of novel peptidomimetic derivatives. AB - It has been recently reported that thiol groups could play an important role in the protection of neuronal cells in Alzheimer's disease (AD), prion disease (CJD) and Parkinson's disease (PD). Also bucillamine, that is a pseudo dipeptide possessing a thiol group capable to form an internal disulfide bridge, has relevant scavenger properties used in therapy for the treatment of arthritis. Furthermore, many sulphur containing compounds show strong chelating properties to heavy metals. Due to the crucial role of thiol groups in a variety of detoxicant biological systems, we report the synthesis of a racemic beta,beta dialkyl-substituted, fully protected, cysteine derivative as a suitable intermediate in the synthesis of novel biological active peptides. PMID- 20205657 TI - Development of tools and database for analysis of metal binding sites in protein. AB - In this study, we have developed a standalone tool called as ANAMBS (Analysis of Metal Binding Site) to derive metal neighbourhood information using PERL as the programming language. The tool accepts the structures in the pdb format. The cut off distance to define the metal binding region can be specified. The metal binding site composition, orientation of various amino acids and atoms along with the Hydropathy index within the metal binding site region can be measured. Its speed and efficiency makes it a beneficial tool for various structural biology projects, especially when the characterization of the metal binding domain is needed. Additionally, the database MEDB (Metal Environment Database) was developed which presents quantitative information on metal-binding sites in protein structures. It can be used for identification of trends or patterns in the metal-binding sites. The information obtained can be used to generate structural templates from metal binding sites of known enzymes and to develop constraints for computational modeling of metalloproteins. The tool and database are available at http://www.uohyd.ernet.in/anambs/ PMID- 20205658 TI - Study on the influences of palindromes in protein coding sequences on the folding rates of peptide chains. AB - Taking all the proteins of four virus genomes as samples, the segments of alpha helix and beta-strand in proteins of the four viruses were obtained. Linear regression analyses between the average polarities and the folding rates of peptide chains were performed for alpha-helices and beta-strands respectively. The results indicated that the folding rates show significant positive linear correlation for alpha-helices and negative linear correlation for beta-strands with the average polarities. Based on the corresponding protein coding sequences of these amino acid segments, the influences of GC content of palindromes and palindrome densities in protein coding segments on the relations between the folding rates and the average polarities were studied. Results showed that the folding rates correlated positively with the GC content of palindromes and the palindrome density, and protein coding sequences do carry the information which can influence the folding rates of peptide chains or protein structures. Our analysis indicated that this kind of effects mostly comes from the information palindrome structure itself or from the synonymous codon usage, but not from the translation information from codons to amino acids. PMID- 20205659 TI - Pharmacogenetics in psychiatry--a useful clinical tool or wishful thinking for the future? AB - More than fifty years of pharmacogenetic research have produced many examples of the impact of inherited variability in the response to psychotropic drugs. These successes, however, have as yet failed to translate into broadly applicable strategies for the improvement of individual drug treatment in psychiatry. One important argument against the widespread adoption of pharmacogenetics as a clinical tool is the lack of evidence showing its impact on medical decision making and on risk benefit ratio for the patients. The individual drug metabolizing capacity is assessed by genotyping drug metabolizing enzymes. The potential implications of information gained from genotyping are dose adjustments according to genotype. However, even when the consequences of genotype on pharmacokinetics are significant and well known, as in the case of many tricyclic antidepressants and several SSRIs, there is still considerable controversy on whether adjustment of dosage driven by genetic information may improve therapeutic efficacy, and/or adverse events is prevented, to an extent of any practical importance in clinical practice. Different types of pharmacogenetic studies may improve our understanding of the functional consequence of a genetic variant in the clinical setting. The use of intermediate phenotypes instead of broad outcome parameters such as drug response or remission might improve our knowledge on what exactly happens if an individual with a specific genotype takes a certain drug. Here, we review the potential impact of an integrated approach, including the assessment of intermediate phenotypes for the effect of genetic polymorphism, the monitoring of therapy progress, and response prediction in depression. PMID- 20205660 TI - Pharmacogenetics of thiopurines in inflammatory bowel disease. AB - Thiopurines are widely used in the treatment of inflammatory bowel disease (IBD). However, in clinical practice azathioprine (AZA) or 6-mercaptopurine (6-MP) are not effective in one-third of patients and up to one-fifth of patients discontinue thiopurine therapy due to adverse reactions. The observed interindividual differences in therapeutic response and toxicity to thiopurines are explained to a large extent by the variable formation of active metabolites, which is at least partly caused by genetic polymorphisms of the genes encoding crucial enzymes in thiopurine metabolism. In this in-depth review we discuss the genetic polymorphisms of genes encoding for glutathione S-tranferases, xanthine oxidase, thiopurine S-methyltransferase, inosine triphosphate pyrophosphatase, hypoxanthine phosphoribosyltransferase, inosine monophosphate dehydrogenase and multidrug resistance proteins. Pharmacogenetic knowledge in this field has increased dramatically and is still rapidly increasing, but the translation into practical guidelines with tailored advices will cost much effort in the near future. PMID- 20205661 TI - Pharmacogenetics in oncology: a promising field. AB - Pharmacogenetics is a rapidly developing field, especially in oncology. In the most ideal situation pharmacogenetics will allow oncologists to individualize therapy based on patients' individual germline genetic test results. This can help to improve efficacy, reduce toxicity and predict non-responders in a way that alternative therapy can be chosen or individual dose adjustments can be made. Multiple pathways have been studied extensively of which a brief review is presented here. Increased 5FU toxicity is associated with variations in the DPYD gene, TYMS gene and MTHFR gene. Furthermore variations in the UGT1A gene and the ABCB1 gene influence irinotecan metabolism and disposition. Other genetic changes result in reduced DNA repair capacity related to platinum efficacy or reduced cytochrome P450 2D6 activity related to tamoxifen efficacy. Despite the extensive number of pharmacogenetic studies and promising results, it is still unclear when and how pretreatment genetic screening should be implemented in oncology. Future prospective studies should focus on the effect of pharmacogenetics on patient outcome and combine this with cost effectiveness evaluations. Thus supplying us with predictive models helping in deciding when pretreatment genetic screening is useful. PMID- 20205662 TI - Pharmacogenetics in treatment of rheumatoid arthritis. AB - Over the last decades important progress is being made regarding disease modifying anti-rheumatic drugs (DMARDs) in the treatment of rheumatoid arthritis (RA). Nevertheless, a substantial part of the patients fail to achieve a good response and/or experience toxicity, which limits further treatment leading to progression of inflammation and destruction of joints. These high interindividual differences in drug response gave rise to the need for prognostic markers in order to individualize and optimize therapy with these antirheumatic agents. Besides demographic and clinical factors, studies in the research field of pharmacogenetics have reported potential markers associated with clinical response on treatment with methotrexate and TNF inhibitors. However, publicized conflicting results and underlying interpretation difficulties inhibit drawing definitive conclusions. Presently, clinical implementation of pharmacogenetics as an important step for individualizing drug therapy in RA is not feasible yet. Replication and prospective validation in large patient cohorts are required before pharmacogenetics can be used in clinical practice. This review provides the current state of art in genotyping RA patients as a potential guide for clinical decision making. PMID- 20205663 TI - Individualizing calcineurin inhibitor therapy in renal transplantation--current limitations and perspectives. AB - Patient variability in clinical response to the calcineurin inhibitors (CNIs) cyclosporine A and tacrolimus partly results from differences in CNI exposure. For tacrolimus drug interactions and genetic variability relate to tacrolimus exposure. Patients carrying the CYP3A5*1 allele have an increased tacrolimus metabolism, hence lower drug exposure. Adjusting the tacrolimus dose to this genotype is a tool to optimize therapy from a pharmacokinetic perspective. In contrast, no genetic variants have been found to clearly relate to cyclosporine A exposure. Despite therapeutic drug monitoring aimed at individualizing CNI therapy, patients still suffer from acute or chronic rejection and CNI toxicity. To further optimize CNI therapy future research may incorporate genetic polymorphisms in proteins involved in CNI pharmacodynamics (i.e. drug target). Proteins potentially relevant for drug response are calcineurin and the CNI binding proteins immunophilins. Moreover, since the expression of the nuclear factor of activated T-cells (NFAT) is reduced after calcineurin inhibition, genetic polymorphisms in the genes encoding NFAT may also be interesting candidates for studying inter-patient differences in CNI efficacy and toxicity. In addition, the existence of isoforms and differences in tissue distribution of the calcineurin protein could potentially explain variable drug response. At present, the focus has been on the metabolism of CNIs and not on variability in the drug target. Therefore, future improvements in CNI therapy are likely to occur from a systems pharmacology approach taking into account genetic markers for both CNI pharmacokinetics and pharmacodynamics. PMID- 20205664 TI - Pharmacogenetics of oral anticoagulant therapy. AB - The identification of the genes encoding CYP2C9, the principal metabolizing enzyme of the coumarins, and VKORC1, the molecular target for coumarins, has strongly stimulated the research on pharmacogenetics of vitamin K antagonists, also designated as coumarins. From 1999 to 2004 a number of observational studies firmly established associations between being carrier of the CYP2C9*2 and especially the CYP2C9*3 allele and reduced coumarin dose requirements and increased risks of overanticoagulation and even major bleeding compared to CYP2C9 wild type patients. The identification of the VKORC1 gene in 2004 gave rise to more observational studies, which mostly indicated a larger contribution of variants of these gene to the interindividual variability in dose requirements. However, whereas overanticoagulation in the initial period of therapy appears to be associated with VKORC1 as well as CYP2C9 genotype, the CYP2C9 genotype could be a more important predictor for major bleeding and retarded stabilisation. The recent discovery that only one single nucleotide polymorphism in the VKORC1 gene, the -1639G>A polymorphism, is representative for VKORC1 activity and the recent conclusion from a genome-wide scan that VKORC1 and CYP2C9 are the only genes with relevant effects on coumarin response, seem to be definitive demarcations of the genetic information which could be needed for improvement of the existing coumarin dosing algorithms. The observational studies from the last decade provided valuable insights into the effects of genetic factors on variability in coumarin response. During the forthcoming years randomized clinical trials are needed to evaluate whether this genetic information will improve the benefit-risk ratio of coumarins. PMID- 20205665 TI - Pharmacogenetics and the pharmaceutical industry. AB - The detailed knowledge of the human genome has not fulfilled its promise as yet. It seems fair to say that we are far from treating existing diseases by therapeutic interventions developed on the basis of genetic knowledge. However, pharmacogenetics has shown to be useful in improving our understanding of pharmacotherapy. Industry is starting to embed this knowledge in the design of innovative drugs and there are three important areas of interest: safety, efficacy and target identification. Application of pharmacogenetics e.g. in patient selection are leading to the direction of more personalised medicine. The future will bring more of such applications. However, current knowledge also leads to a more integrated approach of pharmacogenetics as part of systems biology, providing an even more complete image of reality surrounding disease and therapy, including for example environmental factors and behaviour. In addition, collaborative efforts with academic partners are very much welcomed by the pharmaceutical industry and are expected to have a synergistic effect on progression in this field. PMID- 20205666 TI - Ethical and social issues in pharmacogenomics testing. AB - In genomics research, pathways that lead to disease and the role of drugs in these pathways are being unravelled at a high rate. In this paper ethical and social challenges related to pharmacogenomics research are discussed as well as clinical applications. In research, ethical thinking evolves due to the fast pace of research. Genome-wide association studies trying to identify genes that contribute a small risk to common diseases can only be performed on an international scale. Meanwhile, it is becoming more and more clear that genomic information is hard to hide. Thus the traditional promise in research that privacy will be protected appears to be less realistic. Nowadays, adequate information (veracity) and protection against potential risks of discrimination based on predictive medical information is required. A new balance needs to be found. In the clinic, different ethical and social challenges become apparent. The promise to improve diagnosis, treatment and prevention is genuine, but many potentially useful applications do not reach the bedside. There is a need for both translation and for assessment of evidence if "do good and do not harm" is to be taken seriously. In addition, sustainable use of pharmacogenetic knowledge holds promises for developed and developing countries but these promises will only materialize if evidence is built, translated into guidelines, incorporated into education, implemented in pharmacy databases, and evaluated. While translational research in health care progresses slowly, direct-to-consumer testing is being implemented rapidly. International validated quality criteria should apply both to health care and to this commercial field. PMID- 20205667 TI - Alzheimer's disease and retinal neurodegeneration. AB - Alzheimer's disease (AD) is the major cause of dementia in the world. Although the entorhinal cortex and hippocampal complex are best known as the sites of early pathology in AD, increasing evidence shows that the eye, particularly the retina, is also affected. The AD-related changes in the retina are associated with degeneration and loss of neurons, reduction of the retinal nerve fibres, increase in optic disc cupping, retinal vascular tortusity and thinning, and visual functional impairment. Given the fact that evaluating pathologic changes in the brain during life has always been an indirect process, largely shielded from view by the barrier of the skull, the eye can be used as a window into diseases of the brain. Using modern techniques, the changes in the retina can be visualized in real-time. In addition to the changes in the eyes of AD patients, similar mechanisms of neurodegeneration in the brain have also been demonstrated in the eye. Targeting AD-liked changes in the retina has been recently shown to be effective in the reduction of retinal neuronal degeneration and loss in eye diseases. This review will cover recent findings on retinal degeneration in AD, pathological similarities between AD and eye diseases, and highlight the potential of modern technologies for the detection of prospective biomarkers in the eye in early AD. PMID- 20205668 TI - Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI) patients are characterized by increased BDNF serum levels. AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline with loss of memory. In the last years there has been a great interest on the early phases of AD, trying to identify the pathogenic mechanisms of AD and define early treatment modalities. In particular, Mild Cognitive Impairment (MCI) is attractive because it represents a transitional state between normal aging and dementia, although not all MCI patients automatically convert to AD. The neurotrophin brain-derived neurotrophic factor (BDNF) is critical for survival and function of neurons that degenerate in AD and represents a potential neuroprotective agent. However, opposite data on serum levels of BDNF have been reported in AD patients, probably reflecting differences in patient recruitment and stage of the disease. Thus, in this study we measured BDNF serum levels in AD patients (with different degree of severity), MCI patients and healthy subjects. We found that serum BNDF levels were significantly increased in MCI and AD patients when compared to healthy subjects and this increase in AD patients was neither dependent on illness severity, nor on treatment with Acetylcholinesterase inhibitors and/or antidepressant medications. Our findings indicate that BDNF serum levels increase in MCI and AD patients, supporting the hypothesis of an upregulation of BDNF in both preclinical phase of dementia (MCI) and clinical stages of AD. Other studies are necessary to establish a direct link between BDNF peripheral levels and AD longitudinal course, as well as the role of other factors, such as blood cell activation, in determining these events. PMID- 20205669 TI - Familial Alzheimer's disease mutations in presenilin 1 do not alter levels of the secreted amyloid-beta protein precursor generated by beta-secretase cleavage. AB - Alzheimer's disease (AD) is an insidious and progressive disease with a genetically complex and heterogenous etiology. More than 200 fully penetrant mutations in the amyloid beta-protein precursor (APP), presenilin 1 (or PSEN1), and presenilin 2 (PSEN2) have been linked to early-onset familial AD (FAD). 177 PSEN1 FAD mutations have been identified so far and account for more than approximately 80% of all FAD mutations. All PSEN1 FAD mutations can increase the Abeta42:Abeta40 ratio with seemingly different and incompletely understood mechanisms. A recent study has shown that the 286 amino acid N-terminal fragment of APP (N-APP), a proteolytic product of beta-secretase-derived secreted form of APP (sAPPbeta), could bind the death receptor, DR6, and lead to neurodegeneration. Here we asked whether PSEN1 FAD mutations lead to neurodegeneration by modulating sAPPbeta levels. All four different PSEN1 FAD mutations tested (in three mammalian cell lines) did not alter sAPPbeta levels. Therefore PS1 mutations do not appear to contribute to AD pathogenesis via altered production of sAPPbeta. PMID- 20205670 TI - Nicotinic acetylcholine receptor interaction with beta-amyloid: molecular, cellular, and physiological consequences. AB - Elevated amyloid-beta peptide (Abeta) and loss of nicotinic acetylcholine receptors (nAChRs) stand prominently in the etiology of Alzheimer's disease (AD). Since the discovery of an Abeta - nAChR interaction, much effort has been expended to characterize the consequences of high versus low concentrations of Abeta on nAChRs. This review will discuss current knowledge on the subject at the molecular, cellular, and physiological levels with particular emphasis on understanding how Abeta - nAChR interaction may contribute to normal physiological processes as well as the etiology of AD. PMID- 20205671 TI - High PIB retention in Alzheimer's disease is an early event with complex relationship with CSF biomarkers and functional parameters. AB - BACKGROUND: New in vivo amyloid PET imaging tracers, such as (11)C-PIB, provide possibilities to deeper understand the underlying pathological processes in Alzheimer's disease (AD). In this study we investigated how (11)C-PIB retention is related to cerebral glucose metabolism, episodic memory and CSF biomarkers. METHOD: Thirty-seven patients with mild AD and 21 patients with mild cognitive impairment (MCI) underwent PET examinations with the amyloid tracer (11)C-PIB, (18)F-FDG for measurement of regional cerebral metabolic rate of glucose (rCMRglc), assessment of episodic memory and assay of cerebral spinal fluid (CSF) levels of amyloid-beta (Abeta(1-42)), total tau and phosphorylated tau respectively. Analyses were performed using Statistical Parametric Mapping (SPM) and regions of interest (ROIs). RESULTS: Pooled data from AD and MCI patients showed strong correlations between (11)C-PIB retention, levels of CSF biomarkers (especially Abeta(1-42)), rCMRglc and episodic memory. Analysis of the MCI group alone revealed significant correlations between (11)C-PIB retention and CSF biomarkers and between CSF biomarkers and episodic memory respectively. A strong correlation was observed in the AD group between rCMRglc and episodic memory as well as a significant correlation between (11)C-PIB retention and rCMRglc in some cortical regions. Regional differences were observed as sign for changes in temporal patterns across brain regions. CONCLUSIONS: A complex pattern was observed between pathological and functional markers with respect to disease stage (MCI versus AD) and brain regions. Regional differences over time were evident during disease progression. (11)C-PIB PET and CSF Abeta(42) allowed detection of prodromal stages of AD. Amyloid imaging is useful for early diagnosis and evaluation of new therapeutic interventions in AD. PMID- 20205672 TI - Effects of cholinesterase inhibitors on the activities and protein levels of cholinesterases in the cerebrospinal fluid of patients with Alzheimer's disease: a review of recent clinical studies. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline associated with a deficit in cholinergic function. Inhibitors of acetylcholinesterase (AChE) and/or butyrylcholinesterase (BuChE), such as donepezil, galantamine or rivastigmine, are widely prescribed as symptomatic treatments for AD. These agents exhibit a wide variation in their pharmacological properties. Here we review clinical data from 1998 to 2009 investigating the effect of different cholinesterase inhibitor treatments on the levels and activities of cholinesterases in the cerebrospinal fluid (CSF) of AD patients. These studies suggest that treatment with rapidly-reversible cholinesterase inhibitors (e.g. donepezil, galantamine, tacrine) are associated with marked and significant upregulation of AChE activities and protein levels in the CSF of AD patients. In contrast, pseudo-irreversible cholinesterase inhibition (e.g. rivastigmine) is associated with a significant decrease in both CSF AChE and BuChE activities, with no upregulation of CSF protein levels. Additionally, donepezil is associated with a decrease in the level of the AChE-R isoform relative to the synaptic AChE-S isoform, whereas rivastigmine seems to increase this ratio. These findings suggest that these agents exert different effects on CSF cholinesterases. The clinical effects of these pharmacological differences are yet to be fully established. PMID- 20205673 TI - Protein conformational pathology in Alzheimer's and other neurodegenerative diseases; new targets for therapy. AB - The whole set of so-called >>conformational<< disorders, among them systemic amyloidoses, various dementias and other neurodegenerative diseases such as Parkinson's, Alzheimer's and amyotropic lateral sclerosis, may have similar molecular backgrounds: changes in protein conformation and aggregation lead to toxic amyloid oligomers and fibrils. The so called aggresomes in eukaryotes (equivalent to inclusion bodies in prokaryotes), located at the centriole by the nucleus and composed of aggregated proteins, are believed to sequester the toxic material. They eventually get cleared from the cell by autophagy. When the cell defence system fails due to continuous production of a mutated protein or to other damage to the cell such as oxidative stress or protein modification as part of normal aging, familial or sporadic neurodegenerative diseases develop. Initially - for years - they are silent with no or mild symptoms. It could well be that aggregates represent a response to some other trigger or even a means of defence. However, the inherited cases with mutations leading to increased aggregation suggest the opposite to be the case. Evidence has accumulated that the soluble oligomers of amyloidogenic proteins are themselves cytotoxic and trigger a cascade of detrimental events in the cell, as summarized in the "amyloid cascade hypothesis". Among other plausible hypotheses for the mechanism of toxicity is the "channel hypothesis", which states that the soluble oligomers interact with cell membranes, causing influx of Ca2+ ions, which is an early sign of pathology and contributes to uncontrolled neurotransmission. Another factor are metal ions, such as Zn(2+), Cu(2+), Fe(3+), Al(3+), etc., leading to the "metal hypothesis". The delicate balance of metal ions in the brain is important to prevent oxidative stress, which can itself modify proteins and make them aggregation-prone. The advances in molecular and cellular studies will hopefully lead to novel therapies and eventually to a cure. PMID- 20205674 TI - Properties of CA3 dendritic excrescences in Alzheimer's disease. AB - CA3 pyramidal neurons and hilar mossy neurons possess large and branched dendritic spines, named thorny excrescences. Studies on experimental animals have shown great morphologic adaptation of the excrescences and the whole dendritic tree of CA3 pyramidal neurons in changes of environmental conditions. However, the available data about the excrescences in human brain is short and insufficient about their properties in Alzheimer's disease. In the present study, these dendritic structures were studied and compared in CA3 area of hippocampus in patients suffered from Alzheimer's disease, age matched controls and young individuals. Golgi impregnated material under light microscopy was used for the description of the structural characteristics of the excrescences. Morphometric estimation of their density on the apical and basilar dendritic tree and their average length revealed reduced density and significantly increased size in Alzheimer's disease patients. The mean density of the excrescences on the apical dendritic tree of the patients compared to age matched controls is reduced 32.8% (p<0.001), while the mean number of long excrescences (longer than 5microm) is increased 32.6% (p<0.05). On the basilar dendritic tree, the reduction in density is 26.3% (p<0.05) and the increase in the number of long excrescences is 23.3% (p>0.05). These enlarged thorny excrescences can be even longer than 10microm, appearing as "giant spines". The increased size of the excrescences is considered as a remodeling procedure (compensative mechanism) of the CA3 pyramidal neurons for the balancing of the reduction in the spinal density. PMID- 20205675 TI - Serum albumin concentration and cognitive impairment. AB - Results from clinical samples suggest low serum albumin may be associated with cognitive impairment, though evidence from population-based studies is inconclusive. Participants were 1,752 adults (699 men and 1,053 women) aged 65 years and over from the Health Survey for England 2000, a nationally representative population-based study. Cognitive impairment was assessed using the Abbreviated Mental Test Score. The cross-sectional relation of serum albumin quartiles to cognitive impairment was modelled using logistic regression. Two hundred and twelve participants were cognitively impaired (68 men and 144 women). Odds ratios (95% confidence intervals) for cognitive impairment in the first (2.2 3.8 g/dl), second (3.9-4.0 g/dl), and third (4.1-4.3 g/dl) quartiles of serum albumin compared with the fourth (4.4-5.3 g/dl) were 2.5 (1.3-5.1), 1.7 (0.9 3.5), and 1.5 (0.7-2.9), after adjustment for age, sex, education and additional risk factors for cognitive impairment (p for linear trend = 0.002). A highly similar pattern of associations was observed for men and women. Our data provide new evidence to suggest that low serum albumin is independently associated with increased odds of cognitive impairment in the elderly population. PMID- 20205676 TI - Regulatory roles of the ubiquitin-proteasome system in cardiomyocyte apoptosis. AB - Cardiovascular disease is the leading cause of death in the western world. The major contributor of all cardiovascular deaths is myocardial infarction, which often progresses into end-stage heart failure. The loss of cardiomyocytes is a key problem in the development of cardiovascular disease. Two main processes mediate cardiomyocyte loss: necrosis and apoptosis. In contrast to necrosis, apoptosis is a well regulated process essential in normal development and tissue homeostasis. Tight regulation of this process is crucial, especially in post mitotic cells lacking regenerative capacity, like cardiomyocytes. The ubiquitin proteasome system, accounting for 80 to 90% of intracellular protein degradation, appears to be involved in the regulation of apoptosis. In this process, regulation is performed through the degradation of pro- and anti-apoptotic proteins involved in cell cycle control and specific apoptotic pathways. On the one hand, disturbances in this normally well regulated process are associated with a number of cardiovascular diseases. On the other hand, proteasomal dysfunction may result from ischemia, hypertrophy and heart failure, and a number of cardiomyopathies. This paper reviews the current knowledge on the role of the ubiquitin-proteasome system-mediated regulation of cardiomyocyte apoptosis in cardiovascular disease. Finally, within the ubiquitin-proteasome system new molecular targets for treatment of cardiovascular disease are suggested. PMID- 20205677 TI - Anabolics in osteoporosis: the emerging therapeutic tool. AB - Anabolic therapy for osteoporosis has become the most desirable therapeutic option for menopausal osteoporosis. The anabolic agents currently in clinical use are reviewed. Teriparatide (recombinant human 1-34 parathyroid hormone) is used to treat women with menopausal osteoporosis and men at high risk for fractures. Despite PTH's clinical use, the mechanism underlying its anabolic action requires greater elucidation. Proteol (strontium ranelate) acts by inhibiting bone resorption and presumably promoting bone formation. Though clinical trials have shown that strontium ranelate reduces the frequency of both vertebral and non vertebral fractures, its molecular target remains controversial. Lately, with the discontinuation of estrogen replacement therapy, phytoestrogens are gaining much attention, chiefly as prophylactic agents. Though ipriflavone stimulates osteoblast function in vitro and favorably influences bone turnover and spinal bone mineral density in peri- and postmenopausal women, its clinical use is currently rather limited. As with PTH and strontium ranelate, the mode of action of ipriflavone requires much greater elucidation. Since osteoporosis therapies are long-term, safety is a major consideration. PTH has been reported to be associated with incidence of osteosarcoma and strontium ranelate with DRESS syndrome. Therefore, target-based (and osteoblast-specific) development of molecules is expected to improve the safety profile of anabolics. Calcium-sensing receptor, insulin-like growth factor-1, members of wingless tail signaling family, and sclerostin are emerging concepts in bone anabolic therapy. We will cover the preclinical development of some bone anabolic agents under active investigation. PMID- 20205678 TI - Microaerophilic respiratory metabolism of Plasmodium falciparum mitochondrion as a drug target. AB - The Plasmodium falciparum mitochondrion is an organelle that presents structural and physiological characteristics different from mitochondria in other eukaryotes. Moreover, there are substantial differences in the properties of asexual and sexual mitochondria. One of the reasons is the adaptation of the parasite to different environments, in particular the great differences in oxygen tension between the host and the mosquito. In this review, we present a synthesis of the recent data on the ultrastructure, the genome and the physiology of the mitochondrion. We try to clarify the mitochondrial role in the intraerythrocytic environment and particularly focus on mitochondrial metabolic pathways that relate to oxidative phosphorylation, including the tricarboxylic acid cycle, de novo pyrimidine biosynthesis via dihydroorotate dehydrogenase and the particularities of the electron transport chain. In addition, we provide details on certain characteristics like the lack of pyruvate dehydrogenase, the existence of a rotenone-insensitive NADH-dehydrogenase, the possible existence of an alternative oxidase, and uncoupled proteins. Such unique particularities of parasite mitochondria could be promising targets for development of a new therapy. The elucidation of the role of this organelle in microaerophilic respiratory metabolism and the association of antimalarial drugs with hyperbaric oxygen therapy might provide new treatments for infection by P. falciparum. PMID- 20205679 TI - Implication of gut immunology in the design of oral vaccines. AB - In developing countries, oral immunization is more readily accepted than parenteral, as it accompanies the ease and safety of administration and induces the desired mucosal immune response against highly infectious pathogen transmitted through mucosal routes. Despite the obvious need and apparent merits, the success in the field of oral vaccination is limited due to factors including harsh gastric environment, enzymatic barrier, intestinal epithelium barrier and the fear of oral tolerance reported in case of mucosal vaccination. The number of strategies has been focused at conquering the mucosal barrier for maximization of the intestinal uptake and stabilization of the biological at all stages before they reach their target. Although, considerable success has been attained using these strategies but none of these have achieved commercial status. Therefore a rationally designed oral vaccine should be successfully delivered to the intestinal mucosal immune cells, and induce both humoral and cellular counterparts of immunity along with the mucosal immune response. The aim of this review article is to describe the recent development in the understanding of the molecular mechanism and implication of gastrointestinal epithelium and cytokines interplay in the induction of immunity and tolerance. The review has been elaborated to discuss the rationale of design of suitable carrier in conjunction with the peculiar necessities of gastrointestinal tract for induction of well balanced immune response. PMID- 20205680 TI - Osteopontin: an effector and an effect of tumor metastasis. AB - Osteopontin (OPN) is a matricellular protein that is produced by multiple tissues in our body and is most abundant in bone. It is also produced by cancer cells and plays a determinative role in the growth, progression and metastasis of cancer. Clinically, OPN has been reported to be upregulated in tumor cells per se; this is also reflected by increased levels of OPN in the circulation. Thus, increased OPN levels the plasma are an effect of tumor growth and progression. Functionally, high OPN levels are determinative of higher incidence of bone metastases in mouse models and are clinically correlated with metastatic bone disease and bone resorption in advanced breast cancer patients. Several research efforts have been made to therapeutically target and inhibit the activities of OPN. In this article we have reviewed OPN in its role as an effector of critical steps in tumor progression and metastasis, with a particular emphasis on its role in facilitating bone metastasis of breast cancer. We have also addressed the role of the host-derived OPN in influencing the malignant behavior of the tumor cells. PMID- 20205681 TI - Protein processing and inflammatory signaling in Cystic Fibrosis: challenges and therapeutic strategies. AB - Cystic Fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) that regulates epithelial surface fluid secretion in respiratory and gastrointestinal tracts. The deletion of phenylalanine at position 508 (DeltaF508) in CFTR is the most common mutation that results in a temperature sensitive folding defect, retention of the protein in the endoplasmic reticulum (ER), and subsequent degradation by the proteasome. ER associated degradation (ERAD) is a major quality control pathway of the cell. The majority (99%) of the protein folding, DeltaF508-, mutant of CFTR is known to be degraded by this pathway to cause CF. Recent studies have revealed that inhibition of DeltaF508-CFTR ubiquitination and proteasomal degradation can increase its cell surface expression and may provide an approach to treat CF. The finely tuned balance of ER membrane interactions determine the cytosolic fate of newly synthesized CFTR. These ER membrane interactions induce ubiquitination and proteasomal targeting of DeltaF508- over wild type- CFTR. We discuss here challenges and therapeutic strategies targeting protein processing of DeltaF508-CFTR with the goal of rescuing functional DeltaF508-CFTR to the cell surface. It is evident from recent studies that CFTR plays a critical role in inflammatory response in addition to its well-described ion transport function. Previous studies in CF have focused only on improving chloride efflux as a marker for promising treatment. We propose that methods quantifying the therapeutic efficacy and recovery from CF should not include only changes in chloride efflux, but also recovery of the chronic inflammatory signaling, as evidenced by positive changes in inflammatory markers (in vitro and ex vivo), lung function (pulmonary function tests, PFT), and chronic lung disease (state of the art molecular imaging, in vivo). This will provide novel therapeutics with greater opportunities of potentially attenuating the progression of the chronic CF lung disease. PMID- 20205683 TI - The potential of lifestyle changes for improving the clinical outcome of patients with coronary heart disease: mechanisms of benefit and clinical results. AB - There is overwhelming evidence that smoking cessation, regular physical activity, and combined dietary changes are beneficial in patients with coronary heart disease. Effect size estimates for these lifestyle goals vary between 20% and 35% of mortality rate reductions. Despite the evidence, achieving healthy lifestyles remains the most difficult problem in secondary prevention. In this paper, I review the effects of lifestyle changes on the clinical outcome of patients with coronary heart disease and the underlying mechanisms of benefit, as well as two recently published, controlled, clinical trials addressing the issue of achieving therapeutic lifestyle changes in coronary heart disease patients. PMID- 20205684 TI - Current therapeutic paradigms in glioblastoma. AB - Glioblastoma (GBM), a WHO grade IV malignant glioma, is the most common and lethal adult primary brain tumor. Median survival rates range from 12-15 months. The current standard of care for GBM has evolved from resection followed by adjuvant radiotherapy to resection, concurrent adjuvant chemotherapy (temozolomide) and radiation, and additional adjuvant chemotherapy. The expression of specific molecular biomarkers, especially O-6-methylguanine methyltransferase (MGMT) status, may determine the response of the tumor to treatment, and helps in identifying the magnitude of benefit from this regimen. By identifying further biological subtypes of GBM at the molecular level, specific targeted therapies could be developed and used in the future for more individualized therapeutic regimens. This article will review the current therapies for GBM and the investigation of new molecular and targeted therapies, such as EGFR inhibitors, mTOR/PI3Kinase inhibitors, and anti-angiogenesis agents. PMID- 20205685 TI - Stenting renal artery stenosis: what is the fuss all about? AB - Renal artery stenosis is the most common cause of secondary hypertension after exclusion of renal parenchymal disease and/or hypertensive nephrosclerosis. Atherosclerotic processes comprise the major contributors to this condition and account for 90% of the disease burden. Usually, the disease comes to light when there has been substantial morbidity resulting from several years of uncontrolled blood pressures and renal failure. Early recognition and intervention is warranted. Interventions include both medical and surgical modalities. Currently, there are several reliable diagnostic procedures to identify renal artery stenosis. However, once the disease process is identified, the management differs quite dramatically based on the patient population, the goals of therapy such as control of hypertension versus amelioration of ischemic nephropathy, availability of interventionists and so on. In this review, we discuss the importance of identifying atherosclerotic renal artery stenosis, the diagnostic modalities available and some of the interventions used to manage this disorder. We emphasize evidence based medicine and recent clinical trials such as the STAR trial. PMID- 20205682 TI - Perspectives on tissue interactions in development and disease. AB - From the morphogenetic movements of the three germ layers during development to the reactive stromal microenvironment in cancer, tissue interactions are vital to maintaining healthy organ morphologic architecture and function. The stromal compartment is thought to be complicit in tumor progression and, as such, represents an opportune target for disease therapies. However, recent developments in our understanding of the diversity of the stromal compartment and the lack of appropriate models to study its relevance in human disease have limited our further understanding of the role of tissue interactions in tumor progression. The failure any model to fully recapitulate the complexities of systemic biology continue to create a higher imperative for incorporating various perspectives into a broader understanding for the ultimate goal of designing interventional therapies. Understanding this potential, this review examines the biological models used to study stromal-epithelial interactions and includes an attempt to incorporate behavioral terminology to define and mathematically model ecological relationships in stromal-epithelial interactions. In addition, the current attempt to incorporate these diverse ecological perspectives into in silico mathematical models through cross-disciplinary coordination is reviewed, which will provide a fresh perspective on defining cell group behavior and tissue ecology in disease and hopefully lead to the generation of new hypotheses to be empirically validated. PMID- 20205686 TI - The role of continuous positive airway pressure in the treatment of hypertension in patients with obstructive sleep apnea-hypoapnea syndrome: a review of randomized trials. AB - Obstructive sleep apnea-hypoapnea syndrome (OSA) is a disorder that results in repetitive occlusion of the airway and hypoxemia during sleep. Epidemiologic studies have associated this disorder with increased cardiovascular morbidity and mortality. Systemic hypertension is prevalent among patients with OSA and has been recognized as a common identifiable cause of hypertension. Nasal continuous positive airway pressure (nCPAP) ventilation is an effective therapy for OSA and it may additionally reduce blood pressure. The use of nCPAP ventilation to treat hypertension in patients with OSA has been studied extensively. However, whether it is effective in treating hypertension in this population remains unclear. This review evaluates the recent literature that investigates the effects of nCPAP ventilation on hypertension in patients with OSA. PMID- 20205687 TI - What else in gemcitabine-pretreated advanced pancreatic cancer? An update of second line therapies. AB - Advanced pancreatic cancer is usually treated with first-line gemcitabine (GEM) (alone or in combination). More recently, GEM has become an established part of an adjuvant therapy based on two recently-reported randomized trials. There remains unresolved the problem of second-line therapy in patients relapsed during or after adjuvant or first-line GEM-based treatment. As of today, platinum analogues in combination with fluoropyrimidine or with GEM represent the most common schedule in clinical practice with data from single-centre or multicentric phase II studies. In 2008, for the first time, a randomized phase III trial conducted on good performance status GEM-refractory patients (CONKO 003) confirmed their benefit in progression-free and overall survival by adding oxaliplatin to a bolus 5-FU/folinic acid schedule. Other agents (irinotecan, taxanes, antifolates, biological) have been tested, although only dismal results have been achieved, as they turned out to be too toxic in combination and to have too low activity when used as single agents. Which the optimal candidate is for second-line therapies, is debatable. Good performance status and discrete progression-free survival since the beginning of the GEM therapy (more than 6 months?) are likely to be the best indicators of subsequent line benefit. The benefit of biological agents is unknown, also given the poor results achieved in the first-line treatment. In summary, as of today, there is one randomized study that confirms the benefit of second-line chemotherapy for the treatment of GEM relapsed pancreatic cancer. Current data indicate 5-FU plus a platinum agent (oxaliplatin) as the standard of care for PS 0-1 patients. Ongoing clinical trials will clarify whether there is obviously a place for improvement and for other agents. At present, even though no data on benefits in unfit patients (Karnofsky < 70) are available, a fluopyrimidine agent still remains a reasonable treatment option. PMID- 20205688 TI - The pulse of drug development for Alzheimer's disease. AB - Therapies that are believed to target the underlying mechanisms of Alzheimer's disease have now reached human clinical trials, with the number of agents in late stage development having increased dramatically in recent years. Primary targets include beta-amyloid, whose presence and accumulation in the brain is thought to contribute to the development of Alzheimer's disease, and tau protein which, when hyperphosphorylated, results in the formation of neurofibrillary tangles of paired helical filaments, also believed to be involved in the pathogenesis of Alzheimer's disease. In this review, the current status of Alzheimer's Disease therapies under study is discussed, including the scientific basis for each strategy. PMID- 20205689 TI - Antidepressant use in children and adolescents diagnosed with major depressive disorder: what can we learn from published data? AB - OBJECTIVE: The consequences of major depression disorder (MDD) in youths are likely to be devastating for both the patient and his/her family. Thus, this review analyzes systematically the effectiveness of antidepressant drugs (ADDs) in managing such patients. DATA SOURCES: Medical literature reporting primary data on use of ADDs in children and adolescents was identified through searches (1966-January 2010) of MEDLINE/PubMed, EMBASE, SCOPUS, and The Cochrane Library databases. Additional studies were manually identified from the reference lists of published articles. SEARCH STRATEGY: Search terms (variously combined) were: children, childhood, adolescents, adolescence, MDD, mood/affective disorders, depression, tricyclic antidepressants (TCAs) SSRIs, Serotonin-Norepinephrine Reuptake inhibitors (SNRIs), noradrenergic/specific serotoninergic antidepressants (NaSSA). A separate search was conducted to complete the profile of effectiveness of each single antidepressant agent. DATA SELECTION: 43 peer reviewed articles met the inclusion criteria. DATA SYNTHESIS: Reviewed information does not definitively support the use of antidepressants in children younger than 10 years old. In contrast, robust information suggests that fluoxetine should be considered as first-line agent in depressed adolescents whose clinical conditions require psychopharmacological approach. CONCLUSIONS: Depressed children should be primarily approached with non-pharmacological interventions that should include the evaluation of potential parental psychiatric disorders. In adolescents with MDD, the decision to use fluoxetine should be associated with specific social and health protocols focused to reinforce self-esteem, improve the quality of relationships with parents and peers, facilitate healthy life-style changes, and identify the potential onset/worsening of suicidality. PMID- 20205691 TI - Environmental control for secondary prevention of asthma. PMID- 20205692 TI - Induction of regulatory T cells by probiotics: potential for treatment of allergy? PMID- 20205693 TI - Modification of the innate immune function of dendritic cells by allergen specific immunotherapy. PMID- 20205694 TI - BSACI guidelines for the investigation of suspected anaphylaxis during general anaesthesia. AB - Investigation of anaphylaxis during general anaesthesia requires an accurate record of events including information on timing of drug administration provided by the anaesthetist, as well as timed acute tryptase measurements. Referrals should be made to a centre with the experience and ability to investigate reactions to a range of drug classes/substances including neuromuscular blocking agents (NMBAs) intravenous (i.v.) anaesthetics, antibiotics, opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), local anaesthetics, colloids, latex and other agents. About a third of cases are due to allergy to NMBAs. Therefore, investigation should be carried out in a dedicated drug allergy clinic to allow seamless investigation of all suspected drug classes as a single day case. This will often require skin prick tests, intra-dermal testing and/or drug challenge. Investigation must cover the agents administered, but should also include most other commonly used NMBAs and i.v. anaesthetics. The outcome should be to identify the cause and a range of drugs/agents likely to be safe for future use. The allergist is responsible for a detailed report to the referring anaesthetist and to the patient's GP as well as the surgeon/obstetrician. A shorter report should be provided to the patient, adding an allergy alert to the case notes and providing an application form for an alert-bracelet indicating the wording to be inscribed. The MHRA should be notified. Investigation of anaphylaxis during general anaesthesia should be focussed in major allergy centres with a high throughput of cases and with experience and ability as described above. We suggest this focus since there is a distinct lack of validated data for testing, thus requiring experience in interpreting tests and because of the serious consequences of diagnostic error. PMID- 20205695 TI - The role of paracetamol in the pathogenesis of asthma. AB - Paracetamol use represents a putative risk factor for the development of asthma. There is convincing epidemiological evidence that the risk of asthma may be increased with exposure to paracetamol in the intrauterine environment, infancy, later childhood and adult life. A dose-dependent association has also been observed in these different age groups in different populations world-wide. An association has also been shown between paracetamol use in both rhinoconjunctivitis and eczema. There is biological plausibility with paracetamol use leading to decreased glutathione levels resulting in increased oxidant induced inflammation and potentially enhanced T-helper type 2 responses. At the population level, patterns of paracetamol use might explain, to some extent, the world-wide variation in the prevalence of asthma and related disorders, particularly the high rates in English-speaking countries, which have high per capita prescription and over-the-counter use of paracetamol. A temporal association also exists between the international trends of increasing paracetamol use and increasing prevalence of asthma over recent decades. Further research is urgently required, in particular randomized-controlled trials (RCTs) into the long-term effects of frequent paracetamol use in childhood, to determine the magnitude and characteristics of any such risk. Importantly, RCTs will also enable evidence-based guidelines for the recommended use of paracetamol to be developed. PMID- 20205696 TI - The A to E of airway disease. AB - The terms asthma and chronic obstructive pulmonary disease have evolved from their original very specific physiology-based definition to describe additional disease entities such as symptoms, airway inflammation and airway structure. We argue that as a result there is widespread confusion about what the terms mean. This has become a significant hurdle to optimal disease management and drug development. We propose that these disease labels should be replaced with a new alphabetical assessment tool for characterizing airway disease, which provides a checklist of five relatively independent factors potentially responsible for morbidity in patients with airway disease: Airway hyperresponsiveness, Bronchitis, Cough reflex hypersensitivity, Damage to the airway and surrounding lung and Extrapulmonary factors. We speculate that the use of this system to characterize airway disease will improve outcomes by promoting better targeting of new and existing treatments. PMID- 20205697 TI - Increased cytokines, chemokines and soluble adhesion molecules in exhaled breath condensate of asthmatic children. AB - BACKGROUND: Airway inflammation in asthma is characterized by the production of cytokines, chemokines and soluble adhesion molecules. The assessment of these inflammatory biomarkers in exhaled breath condensate (EBC) is hampered by low detection rates. However, the use of a glass condenser system combined with a sensitive analytical technique may increase the possibility to assess these biomarkers in EBC in a reliable way. OBJECTIVE: (1) To assess the detection rates of cytokines (IL-1alpha, -1beta, -2, -4, -5, -6, -10, -12p70, -13, -18, IFN gamma, TNF-alpha), chemokines [MIP1alpha (CCL3), MIF, eotaxin (CCL11), RANTES (CCL5), IP10 (CXCL10), IL8 (CXCL8), MCP1] and soluble adhesion molecules [soluble intercellular adhesion molecule (sICAM), soluble vascular adhesion molecule (sVCAM)] in EBC of children with asthma and healthy control children; (2) To study the differences in the biomarker concentration between children with asthma and controls. METHODS: Sixty children were included: 31 asthmatics (71% atopic) and 29 controls. Exhaled breath condensate was collected using a glass condenser system. The inflammatory markers (IM) were analysed using multiplex immunoassay technology. RESULTS: Detection percentages of cytokines, chemokines and adhesion molecules ranged from 94% to 100%, except for eotaxin (CCL11) and RANTES (CCL5) (detection rates of 10% and 45% in healthy controls, respectively). The intra subject variability of biomarkers in EBC in the group as a whole ranged from 5.2% to 35.0%. In asthmatics, the levels of cytokines (IL-2, -4, -5, -6, -13, IFN gamma), chemokines (MIP1alpha [CCL3], MIF, RANTES [CCL5], IP10 [CXCL10], IL8 [CXCL8], MCP1) and adhesion molecules (sICAM, sVCAM) were significantly increased in comparison with controls (P<0.05). CONCLUSION: If collected with a glass condenser and analysed by multiplex immunoassay technology, cytokines, chemokines and soluble adhesion molecules can be reliably demonstrated in EBC of children. Most of these IM were elevated in EBC of asthmatics compared with controls. PMID- 20205698 TI - Subcutaneous allergen immunotherapy restores human dendritic cell innate immune function. AB - BACKGROUND: We recently reported that human blood dendritic cells from allergic subjects have impaired IFN-alpha production following toll-like receptor 9 (TLR9) dependent innate immune stimulation. It is not known how subcutaneous allergen immunotherapy (SCIT) affects dendritic cell immune responses. OBJECTIVE: The aim of this study is to determine how SCIT affects human dendritic cell function. METHODS: Peripheral blood mononuclear cell (PBMC) and plasmacytoid dendritic cells (pDCs) were isolated from the blood of seven dust mite allergic subjects at baseline and upon reaching a standard SCIT maintenance dose that included dust mite and other aeroallergens. Cells were stimulated with various adaptive and innate immune receptor stimuli, or media alone for 20 h with secreted cytokine levels determined by ELISA. A portion of the cells were used to measure intracellular signalling proteins by flow cytometry. Humoral immune responses were measured from plasma. RESULTS: SCIT resulted in a threefold increase in PBMC production of IFN-alpha in response to CpG at 100 nM (P=0.015) and at 500 nM (P=0.015), n=7. The predominant cell type known to produce IFN-alpha in response to CpG (CpG ODN-2216) and other TLR9 agonists is the pDC. As expected, a robust innate immune response from isolated pDCs was re-established among allergic subjects undergoing SCIT resulting in a fivefold increase in IFN-alpha production in response to CpG at 500 nM (P=0.046), n=7. In contrast, IL-6 production was unaffected by SCIT (P=0.468). Consistent with published reports, IgG4 blocking antibody increased 10-fold with SCIT (P=0.031), n=7. There was no significant increase in the frequency of pDCs or the expression of TLR9 that would account for the rise in IFN-alpha production. CONCLUSIONS: Allergen immunotherapy increases dendritic cell TLR9-mediated innate immune function, which has previously been shown to be impaired at baseline in allergic subjects. PMID- 20205699 TI - Surfactant protein D inhibits mite-induced alveolar macrophage and dendritic cell activations through TLR signalling and DC-SIGN expression. AB - BACKGROUND: Surfactant protein D (SP-D), a secreted pattern recognition molecule associated with pulmonary innate immunity, has been shown to mediate the clearance of pathogens in multiple ways. However, how SP-D interacts with alveolar macrophages (AMs) and dendritic cells (DCs) during allergen exposure remains unclear. OBJECTIVE: This study was performed to characterize the immunomodulatory effects of SP-D on mite allergen (Dermatophagoides pteronyssinus, Der p)-induced inflammatory signalling in AMs and DCs. METHODS: Murine AM, alveolar macrophage cell line derived from BALB/c mice (MH-S cells), and human monocyte-derived dendritic cells (MDDC) were used as model systems. The production of nitric oxide (NO) and TNF-alpha, expression of surface Toll-like receptors (TLRs), and expression of the C-type lectin receptor known as dendritic cell (DC)-specific ICAM-grabbing non-integrin (DC-SIGN) were measured as a function of pretreatment with SP-D and subsequent exposure to Der p. Der p dependent cellular activations that were modified by SP-D in these model systems were then identified. RESULTS: Pretreatment of MH-S cells with SP-D reduced Der p dependent production of NO, TNF-alpha, and the downstream activations of IL-1 receptor-associated kinase, mitogen activated protein kinase (MAPK) kinase, and nuclear factor-kappaB. SP-D interacted with CD14 such that CD14 binding to Der p was inhibited and Der p-induced signalling via TLRs was blocked. DC-SIGN expression was suppressed by Der p in MH-S and MDDC; this down-regulation of DC SIGN expression was prevented by pretreatment with SP-D. CONCLUSIONS: These results indicated that the inhibition of Der p-induced activation of MH-S and MDDC by SP-D is mediated through suppression of the CD14/TLR signalling pathway and maintenance of DC-SIGN expression, which may protect allergen-induced airway inflammation. PMID- 20205700 TI - Genetic determinants of both ethanol and acetaldehyde metabolism influence alcohol hypersensitivity and drinking behaviour among Scandinavians. AB - BACKGROUND: Although hypersensitivity reactions following intake of alcoholic drinks are common in Caucasians, the underlying mechanisms and clinical significance are not known. In contrast, in Asians, alcohol-induced asthma and flushing have been shown to be because of a single nucleotide polymorphism (SNP), the acetaldehyde dehydrogenase 2 (ALDH2) 487lys, causing decreased acetaldehyde (the metabolite of ethanol) metabolism and high levels of histamine. However, the ALDH2 487lys is absent in Caucasians. OBJECTIVES: To investigate the genetic determinants of self-reported alcohol-induced hypersensitivity reactions in Caucasians. METHODS: The study included two population-based studies of 1216 and 6784 adults living in Copenhagen. Assessment of alcohol consumption and hypersensitivity reactions (in a subgroup) was performed by a questionnaire and was related to common SNPs of genes encoding alcohol dehydrogenases (ADHs) and ALDHs. RESULTS: In both populations, alcohol drinkers with a genetically determined fast metabolism of ethanol (the A allele of the ADH1b rs1229984) had an increased risk of alcohol-induced hypersensitivity reactions (odds ratio AA/AG vs. GG in combined populations: 1.82, 95% CI 1.04-3.17). In both populations, a common SNP encoding ALDH1b1 (rs2228093) was found to be significantly associated with alcohol-induced hypersensitivity (odds ratio TT vs. CC in combined populations: 2.53, 95% CI 1.31-4.90). CONCLUSIONS: Our data support that alcohol sensitivity in Caucasians is genetically determined and suggest that a histamine releasing effect of acetaldehyde represents a plausible biological mechanism. Furthermore, we present the first report of a clinically significant SNP within the acetaldehyde-metabolizing system in a Caucasian population. PMID- 20205701 TI - Characterization of IgE epitopes of Cuc m 2, the major melon allergen, and their role in cross-reactivity with pollen profilins. AB - BACKGROUND: Plant profilins are described as minor allergens, although with some exceptions in foods such as melon, watermelon or orange. In fact, they could be responsible for many cross-reactions among distantly related species. This is likely to be a consequence of the presence of common epitopes. OBJECTIVE: To characterize the B epitopes of Cuc m 2, a model of plant food profilin, using phage display techniques and to compare with other profilins, such as those of timothy grass and birch pollen, and human I profilin, to understand the mechanism of cross-reaction among members of this family. METHODS: IgE of melon-allergic patients was used to select clones from a phage display 12 mer peptide library. After two rounds of screening, Cuc m 2-specific clones were eluted and the DNA insertion sequenced. The residues of each clone were mapped on the Cuc m 2 surface to define a mimotope, which was also localized on the three-dimensional surfaces of other profilins. RESULTS: Seventeen melon-allergic patients were selected. Sera from each of them recognized the melon profilin, Cuc m 2, but the majority also recognized Phl p 12 or Bet v 2, timothy grass-, and birch-pollen profilins, respectively. A Cuc m 2 mimotope was defined and mapped onto its surface giving the following sequence: S(2)W(3)A(5)Y(6)D(9)H(10)T(111)P(112)G(113)Q(114)N(116)M(117)R(121)L(122). The homologous residues in Phl p 12 and Bet v 2 had almost identical sequences. By contrast, the homologous sequence in human profilin showed many differences. CONCLUSIONS: The identified mimotope could be involved in cross-reactions among food and pollen profilins. Many of these cross-reactions observed in the clinical realm could be explained by the presence of a common epitope found in food and pollen allergens. A new strategy of immunotherapy based on this IgE region could be used in alternative immunotherapy strategies. PMID- 20205702 TI - Searching for the elusive typhoid diagnostic. AB - Typhoid (enteric) fever is still a common disease in many developing countries but current diagnostic tests are inadequate. Studies on pathogenesis and genomics have provided new insight into the organisms that cause enteric fever. Better understanding of the microorganisms explains, in part, why our current typhoid methodologies are limited in their diagnostic information and why developing new strategies may be a considerable challenge. Here we discuss the current position of typhoid diagnostics, highlight the need for technological improvements and suggest potential ways of advancing this area. PMID- 20205703 TI - Spatial distribution and risk factors of Brucellosis in Iberian wild ungulates. AB - BACKGROUND: The role of wildlife as a brucellosis reservoir for humans and domestic livestock remains to be properly established. The aim of this work was to determine the aetiology, apparent prevalence, spatial distribution and risk factors for brucellosis transmission in several Iberian wild ungulates. METHODS: A multi-species indirect immunosorbent assay (iELISA) using Brucella S-LPS antigen was developed. In several regions having brucellosis in livestock, individual serum samples were taken between 1999 and 2009 from 2,579 wild bovids, 6,448 wild cervids and4,454 Eurasian wild boar (Sus scrofa), and tested to assess brucellosis apparent prevalence. Strains isolated from wild boar were characterized to identify the presence of markers shared with the strains isolated from domestic pigs. RESULTS: Mean apparent prevalence below 0.5% was identified in chamois (Rupicapra pyrenaica), Iberian wild goat (Capra pyrenaica), and red deer (Cervus elaphus). Roe deer (Capreolus capreolus), fallow deer (Dama dama), mouflon (Ovis aries) and Barbary sheep (Ammotragus lervia) tested were seronegative. Only one red deer and one Iberian wild goat resulted positive in culture, isolating B. abortus biovar 1 and B. melitensis biovar 1, respectively. Apparent prevalence in wild boar ranged from 25% to 46% in the different regions studied, with the highest figures detected in South-Central Spain. The probability of wild boar being positive in the iELISA was also affected by age, age-by-sex interaction, sampling month, and the density of outdoor domestic pigs. A total of 104 bacterial isolates were obtained from wild boar, being all identified as B. suis biovar 2. DNA polymorphisms were similar to those found in domestic pigs. CONCLUSIONS: In conclusion, brucellosis in wild boar is widespread in the Iberian Peninsula, thus representing an important threat for domestic pigs. By contrast, wild ruminants were not identified as a significant brucellosis reservoir for livestock. PMID- 20205704 TI - Effect of an individually tailored one-year energy balance programme on body weight, body composition and lifestyle in recent retirees: a cluster randomised controlled trial. AB - BACKGROUND: The increased prevalence of overweight and obesity warrants preventive actions, particularly among people in transitional stages associated with lifestyle changes, such as occupational retirement. The purpose is to investigate the effect of a one year low-intensity computer-tailored energy balance programme among recent retirees on waist circumference, body weight and body composition, blood pressure, physical activity and dietary intake. METHODS: A randomised controlled trial was conducted among recent retirees (N = 413; mean age 59.5 years). Outcome measures were assessed using anthropometry, bio impedance, blood pressure measurement and questionnaires. RESULTS: Waist circumference, body weight and blood pressure decreased significantly in men of the intervention and control group, but no significant between-group-differences were observed at 12 or at 24-months follow-up. A significant effect of the programme was only observed on waist circumference (-1.56 cm (95%CI: -2.91 to 0.21)) at 12 month follow up among men with low education (n = 85). Physical activity and dietary behaviours improved in both the intervention and control group during the intervention period. Although, these behaviours changed more favourably in the intervention group, these between-group-differences were not statistically significant. CONCLUSIONS: The multifaceted computer-tailored programme for recent retirees did not appear to be effective. Apparently the transition to occupational retirement and/or participation in the study had a greater impact than the intervention programme. TRIAL REGISTRATION: Clinical Trials NCT00122213. PMID- 20205705 TI - Correlation between stress, stress-coping and current sleep bruxism. AB - BACKGROUND: Stress is discussed as a potential factor in the development of sleep bruxism (SB). The aim of this study was to investigate whether specific stress factors correlate with SB-activity. METHODS: Sixty-nine subjects, of which 48 were SB-patients, completed three German questionnaires assessing different stress-parameters and stress-coping-strategies: Short questionnaire for recognition of stress-factors (Kurzer Fragebogen zur Erfassung von Belastungen, KFB), Questionnaire for recuperation and strain (Erholungs-Belastungs-Fragebogen, EBF-24 A/3) and the stress-coping questionnaire (Stressverarbeitungsfragebogen 78, SVF-78). The diagnosis of SB was based on the clinical criteria of the American Academy of Sleep Medicine (AASM). The degree of SB-activity was measured by the Bruxcore-Bruxism-Monitoring-Device (BBMD, Bruxcore, Boston, USA), worn for five consecutive nights and analyzed using a computer-based method. Non parametric Spearman correlation coefficients, rho, were calculated between the psychometric data and the amount of SB-activity measured by a pixel score of the BBMD. RESULTS: Significant correlations were found for 'daily problems' (r = 0.461, p < 0.01), 'trouble at work' (r = 0.293), 'fatigue' (r = 0.288), 'physical problems' (r = 0.288) and the coping-strategy 'escape' (r = 0.295) (all p < 0.05). CONCLUSIONS: Within the limitations of this study it could be shown that subjects with high SB-activity tend to feel more stressed at work and in their daily life, which in turn might influence their physical state. These subjects also seem to deal with stress in a negative way. However, due to the rather low to almost moderate correlation coefficients and the descriptive character of the study, further investigations are necessary to examine a possible causal relationship. PMID- 20205706 TI - TRAF1/C5 polymorphism is not associated with increased mortality in rheumatoid arthritis: two large longitudinal studies. AB - INTRODUCTION: Recently an association between a genetic variation in TRAF1/C5 and mortality from sepsis or cancer was found in rheumatoid arthritis (RA). The most prevalent cause of death, cardiovascular disease, may have been missed in that study, since patients were enrolled at an advanced disease stage. Therefore, we used an inception cohort of RA patients to investigate the association between TRAF1/C5 and cardiovascular mortality, and replicate the findings on all-cause mortality. As TRAF1/C5 associated mortality may not be restricted to RA, we also studied a large cohort of non-RA patients. METHODS: 615 RA patients from the Leiden Early Arthritis Clinic (EAC) (mean follow-up 7.6 years) were genotyped for rs10818488. In addition 5634 persons enrolled in the PROspective Study of Pravastatin in the Elderly at Risk (mean follow-up 3.2 years) were genotyped for rs2416808 (R(2) >0.99 with rs10818488). The life/death status was determined and for the deceased persons the cause of death was ascertained. Cox proportional hazards and regression models were used to assess hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Seventy-seven RA patients died. The main death causes in RA patients were cardiovascular diseases (37.7%), cancer (28.6%) and death due to infections (9.1%). No association was observed between the rs10818488 susceptible genotype AA and cardiovascular mortality (HR 1.08 95%CI 0.54 to 2.15) and all-cause mortality (HR 0.81 95%CI 0.27 to 2.43). Similar findings were observed for rs2416808 susceptible genotype GG in the non-RA cohort (HR 0.99; 95%CI 0.79 to 1.25 and HR 0.89; 95%CI 0.64 to 1.25, respectively). CONCLUSIONS: The TRAF1/C5 region is not associated with an increased mortality risk. PMID- 20205707 TI - Lateral sacral meningocele presenting as a gluteal mass: a case report. AB - INTRODUCTION: Lateral meningocele is a very rare disorder. It has been reported in patients with neurofibromatosis or Marfan's syndrome. Previous reports have described lateral meningoceles in the thoracic or cervical region. Lateral meningocele in the sacral area was reported in the literature only once. CASE PRESENTATION: We describe a 3.5-year-old Iranian girl who presented with a lateral gluteal mass. Neuroimaging and intra-operative evaluation showed that the mass was a lateral sacral meningocele with spinal communication through the iliac bone. We also present a review of the literature about this entity. CONCLUSIONS: Although lateral meningoceles especially in the sacral region are rare disorders, their possibility should always be considered in young patients presenting with a paravertebral or gluteal mass. PMID- 20205708 TI - Automated detection of near falls: algorithm development and preliminary results. AB - BACKGROUND: Falls are a major source of morbidity and mortality among older adults. Unfortunately, self-report is, to a large degree, the gold-standard method for characterizing and quantifying fall frequency. A number of studies have demonstrated that near falls predict falls and that near falls may occur more frequently than falls. These studies suggest that near falls might be an appropriate fall risk measure. However, to date, such investigations have also relied on self-report. The purpose of the present study was to develop a method for automatic detection of near falls, potentially a sensitive, objectivemarker of fall risk and to demonstrate the ability to detect near falls using this approach. FINDINGS: 15 healthy subjects wore a tri-axial accelerometer on the pelvis as they walked on a treadmill under different conditions. Near falls were induced by placing obstacles on the treadmill and were defined using observational analysis. Acceleration-derived parameters were examined as potential indicators of near falls, alone and in various combinations. 21 near falls were observed and compared to 668 "non-near falls" segments, consisting of normal and abnormal (but not near falls) gait. The best single method was based on the maximum peak-to-peak vertical acceleration derivative, with detection rates better than 85% sensitivity and specificity. CONCLUSIONS: These findings suggest that tri-axial accelerometers may be used to successfully distinguish near falls from other gait patterns observed in the gait laboratory and may have the potential for improving the objective evaluation of fall risk, perhaps both in the lab and in at home-settings. PMID- 20205709 TI - Assembly dynamics of PML nuclear bodies in living cells. AB - The mammalian cell nucleus contains a variety of organelles or nuclear bodies which contribute to key nuclear functions. Promyelocytic leukemia nuclear bodies (PML NBs) are involved in the regulation of apoptosis, antiviral responses, the DNA damage response and chromatin structure, but their precise biochemical function in these nuclear pathways is unknown. One strategy to tackle this problem is to assess the biophysical properties of the component parts of these macromolecular assemblies in living cells. In this study we determined PML NB assembly dynamics by live cell imaging, combined with mathematical modeling. For the first time, dynamics of PML body formation were measured in cells lacking endogenous PML. We show that all six human nuclear PML isoforms are able to form nuclear bodies in PML negative cells. All isoforms exhibit individual exchange rates at NBs in PML positive cells but PML I, II, III and IV are static at nuclear bodies in PML negative cells, suggesting that these isoforms require additional protein partners for efficient exchange. PML V turns over at PML Nbs very slowly supporting the idea of a structural function for this isoform. We also demonstrate that SUMOylation of PML at Lysine positions K160 and/or K490 are required for nuclear body formation in vivo.We propose a model in which the isoform specific residence times of PML provide both, structural stability to function as a scaffold and flexibility to attract specific nuclear proteins for efficient biochemical reactions at the surface of nuclear bodies.MCS code: 92C37. PMID- 20205710 TI - Evidence that low endocytic activity is not directly responsible for human serum resistance in the insect form of African trypanosomes. AB - BACKGROUND: In Trypanosoma brucei, the African trypanosome, endocytosis is developmentally regulated and substantially more active in all known mammalian infective stages. In both mammalian and insect stages endocytic activity is likely required for nutrient acquisition, but in bloodstream forms increased endocytosis is involved in recycling the variant surface glycoprotein and removing host immune factors from the surface. However, a rationale for low endocytic activity in insect stages has not been explored. Here we asked if endocytic down-regulation in the procyclic form was associated with resistance to innate trypanolytic immune factors in the blood meal or tsetse fly midgut. FINDINGS: Using a well-characterized procyclic parasite with augmented endocytic flux mediated via TbRab5A overexpression, we found that insect stage parasites were able to grow both in the presence of trypanosome lytic factor (TLF) provided in human serum, and also in tsetse flies. Additionally, by placing blood stage parasites in restricted glucose medium, we observed that enlargement of the flagellar pocket, a key morphology associated with defective endocytosis, manifests in parallel with loss of cellular ATP levels. CONCLUSIONS: These observations suggest that a high rate of endocytosis per se is insufficient to render insect form parasites sensitive to TLF or tsetse-derived trypanocidal factors. However, the data do suggest that endocytosis is energetically burdensome, as endocytic activity is rapidly compromised on energy depletion in bloodstream stages. Hence an important aspect of endocytic modulation in the nutrient-poor tsetse midgut is likely energetic conservation. PMID- 20205711 TI - Two-color STED microscopy reveals different degrees of colocalization between hexokinase-I and the three human VDAC isoforms. AB - The voltage-dependent anion channel (VDAC, also known as mitochondrial porin) is the major transport channel mediating the transport of metabolites, including ATP, across the mitochondrial outer membrane. Biochemical data demonstrate the binding of the cytosolic protein hexokinase-I to VDAC, facilitating the direct access of hexokinase-I to the transported ATP. In human cells, three hVDAC isoforms have been identified. However, little is known on the distribution of these isoforms within the outer membrane of mitochondria and to what extent they colocalize with hexokinase-I. In this study we show that whereas hVDAC1 and hVDAC2 are localized predominantly within the same distinct domains in the outer membrane, hVDAC3 is mostly uniformly distributed over the surface of the mitochondrion. We used two-color stimulated emission depletion (STED) microscopy enabling a lateral resolution of ~40 nm to determine the detailed sub mitochondrial distribution of the three hVDAC isoforms and hexokinase-I. Individual hVDAC and hexokinase-I clusters could thus be resolved which were concealed in the confocal images. Quantitative colocalization analysis of two color STED images demonstrates that within the attained resolution, hexokinase-I and hVDAC3 exhibit a higher degree of colocalization than hexokinase-I with either hVDAC1 or hVDAC2. Furthermore, a substantial fraction of the mitochondria bound hexokinase-I pool does not colocalize with any of the three hVDAC isoforms, suggesting a more complex interplay of these proteins than previously anticipated. This study demonstrates that two-color STED microscopy in conjunction with quantitative colocalization analysis is a powerful tool to study the complex distribution of membrane proteins in organelles such as mitochondria.PACS: 87.16.Tb, 87.85.Rs. PMID- 20205712 TI - Nanoscopy of the cellular response to hypoxia by means of fluorescence resonance energy transfer (FRET) and new FRET software. AB - BACKGROUND: Cellular oxygen sensing is fundamental to all mammalian cells to adequately respond to a shortage of oxygen by increasing the expression of genes that will ensure energy homeostasis. The transcription factor Hypoxia-Inducible Factor-1 (HIF-1) is the key regulator of the response because it coordinates the expression of hypoxia inducible genes. The abundance and activity of HIF-1 are controlled through posttranslational modification by hydroxylases, the cellular oxygen sensors, of which the activity is oxygen dependent. METHODS: Fluorescence resonance energy transfer (FRET) was established to determine the assembly of the HIF-1 complex and to study the interaction of the alpha-subunit of HIF-1 with the O2-sensing hydroxylase. New software was developed to improve the quality and reliability of FRET measurements. RESULTS: FRET revealed close proximity between the HIF-1 subunits in multiple cells. Data obtained by sensitized FRET in this study were fully compatible with previous work using acceptor bleaching FRET. Interaction between the O2-sensing hydroxylase PHD1 and HIF-1alpha was demonstrated and revealed exclusive localization of O2-sensing in the nucleus. The new software FRET significantly improved the quality and speed of FRET measurements. CONCLUSION: FRET measurements do not only allow following the assembly of the HIF-1 complex under hypoxic conditions but can also provide important information about the process of O2-sensing and its localisation within a cell.MCS codes: 92C30, 92C05, 92C40. PMID- 20205713 TI - Assessing the future threat from vivax malaria in the United Kingdom using two markedly different modelling approaches. AB - BACKGROUND: The world is facing an increased threat from new and emerging diseases, and there is concern that climate change will expand areas suitable for transmission of vector borne diseases. The likelihood of vivax malaria returning to the UK was explored using two markedly different modelling approaches. First, a simple temperature-dependent, process-based model of malaria growth transmitted by Anopheles atroparvus, the historical vector of malaria in the UK. Second, a statistical model using logistic-regression was used to predict historical malaria incidence between 1917 and 1918 in the UK, based on environmental and demographic data. Using findings from these models and saltmarsh distributions, future risk maps for malaria in the UK were produced based on UKCIP02 climate change scenarios. RESULTS: The process-based model of climate suitability showed good correspondence with historical records of malaria cases. An analysis of the statistical models showed that mean temperature of the warmest month of the year was the major factor explaining the distribution of malaria, further supporting the use of the temperature-driven processed-based model. The risk maps indicate that large areas of central and southern England could support malaria transmission today and could increase in extent in the future. Confidence in these predictions is increased by the concordance between the processed-based and statistical models. CONCLUSION: Although the future climate in the UK is favourable for the transmission of vivax malaria, the future risk of locally transmitted malaria is considered low because of low vector biting rates and the low probability of vectors feeding on a malaria-infected person. PMID- 20205714 TI - Lung cancer and COPD rates in Apulia: a multilevel multimember model for smoothing disease mapping. AB - BACKGROUND: If spatial representations of hospitalization rates are used, a problem of instability arises when they are calculated on small areas, owing to the small number of expected and observed cases. Aim of this study is to assess the effect of smoothing, based on the assumption that hospitalization rates, when calculated at the municipal level, may be influenced by both the neighboring municipalities and the health service organization, as well as by environmental risk factors associated with the disease under study. METHODS: To smooth rates we hypothesize that each municipality belongs to two independent hierarchical levels; at one of these levels subjects may belong to a plurality of superior hierarchical objects. Two different models, so-called Multilevel Multimembership Models, are fitted. In the first the structure of random effects was: the municipality heterogeneity, the spatial dependence of the municipalities and the local health service organization. In the second we replaced the local health service organization effect with the environmental risk effect for each municipality area.The models were applied to spatially represent the rates of hospitalization for lung cancer and chronic obstructive pulmonary disease, determined through the hospital discharge forms recorded in Apulia for the year 2006. RESULTS: The effect of smoothing was greater in smaller municipalities and in those with a more unstable Risk Adjusted Rate (RAR) due to the small number of cases and of population at risk. When a hierarchical level representing the ASL is inserted, the model fits the data better. CONCLUSION: Maps of hospitalization rates for lung cancer and chronic obstructive pulmonary disease, shaded with the rates obtained at the end of the smoothing procedure, change the visual picture of the disease distribution over the whole territory, and if detected by the model, seem to express a geographical distribution pattern in specific areas of the region. In the case of lung cancer, the models show a clear difference between RAR and smoothed RAR. The inclusion of a random effect indicating the ASL contributed to improve the graphic representation of the results, whereas the environmental risk was not found to be a better hierarchical level than the municipality for fitting of the model. PMID- 20205715 TI - Identification of 5 novel genes methylated in breast and other epithelial cancers. AB - BACKGROUND: There are several high throughput approaches to identify methylated genes in cancer. We utilized one such recently developed approach, MIRA (methylated-CpG island recovery assay) combined with CpG island arrays to identify novel genes that are epigenetically inactivated in breast cancer. RESULTS: Using this approach we identified numerous CpG islands that demonstrated aberrant DNA methylation in breast cancer cell lines. Using a combination of COBRA and sequencing of bisulphite modified DNA, we confirmed 5 novel genes frequently methylated in breast tumours; EMILIN2, SALL1, DBC1, FBLN2 and CIDE-A. Methylation frequencies ranged from between 25% and 63% in primary breast tumours, whilst matched normal breast tissue DNA was either unmethylated or demonstrated a much lower frequency of methylation compared to malignant breast tissue DNA. Furthermore expression of the above 5 genes was shown to be restored following treatment with a demethylating agent in methylated breast cancer cell lines. We have expanded this analysis across three other common epithelial cancers (lung, colorectal, prostate). We demonstrate that the above genes show varying levels of methylation in these cancers. Lastly and most importantly methylation of EMILIN2 was associated with poorer clinical outcome in breast cancer and was strongly associated with estrogen receptor as well as progesterone receptor positive breast cancers. CONCLUSION: The combination of the MIRA assay with CpG island arrays is a very useful technique for identifying epigenetically inactivated genes in cancer genomes and can provide molecular markers for early cancer diagnosis, prognosis and epigenetic therapy. PMID- 20205717 TI - Pattern and determinants of HIV research productivity in sub-Saharan Africa: bibliometric analysis of 1981 to 2009 PubMed papers. AB - BACKGROUND: Several bibliometric studies have been published on AIDS. The findings obtained from these studies have provided a general picture of the history and growth of AIDS literature. However, factors related to variation in HIV research productivity in sub-Saharan Africa have not been examined. Therefore, this study aims to fill some of the gap in existing research to provide insights into factors associated with HIV research productivity in sub Saharan Africa. METHODS: A bibliometric analysis regarding sub-Saharan Africa HIV/AIDS research was conducted in the PubMed database for the period of 1981 to 2009. The numbers of HIV research articles indexed in PubMed was used as surrogate for total HIV research productivity. Series of univariable and multivariable negative binomial regression models were used to explore factors associated with variation in HIV research productivity in sub-Saharan Africa. RESULTS: First authors from South Africa, Uganda and Kenya contributed almost half of the total number of HIV articles indexed in PubMed between 1981 and 2009. Uganda, Zimbabwe and Malawi had better records when the total production was adjusted for gross domestic product (GDP). Comoros, the Gambia and Guinea-Bissau were the most productive countries when the total products were normalized by number of people with HIV. There were strong positive and statistically significant correlation between countries number of indexed journal (Pearson correlation r = 0.77, p = .001), number of higher institutions (r = 0.60, p = .001), number of physicians (r = 0.83, p = .001) and absolute numbers of HIV articles. CONCLUSIONS: HIV research productivity in Africa is highly skewed. To increase HIV research output, total expenditure on health (% of GDP), private expenditure on health, and adult literacy rate may be important factors to address. PMID- 20205716 TI - Effects of lovastatin on breast cancer cells: a proteo-metabonomic study. AB - INTRODUCTION: Statins are cholesterol-lowering drugs with pleiotropic activities including inhibition of isoprenylation and reduction of signals driving cell proliferation and survival responses. METHODS: In this study we evaluated the effects of lovastatin acid and lactone on breast cancer MDAMB231 and MDAMB468 cells using a combination of proteomic and metabonomic profiling techniques. RESULTS: Lovastatin inhibited proliferation of breast cancer cell lines. MDAMB231 cells were more sensitive to its effects, and in most cases lovastatin acid showed more potency towards the manipulation of protein expression than lovastatin lactone. Increased expression of Rho inhibitor GDI-2 stabilized the non-active Ras homolog gene family member A (RhoA) leading to a decreased expression of its active, membrane-bound form. Its downstream targets cofilin, CDC42 and G3BP1 are members of the GTPase family affected by lovastatin. Our data indicated that lovastatin modulated the E2F1-pathway through the regulation of expression of prohibitin and retinoblastoma (Rb). This subsequently leads to changes of E2F-downstream targets minichromosome maintenance protein 7 (MCM7) and MutS homolog 2 (MSH2). Lovastatin also regulated the AKT-signaling pathway. Increased phosphatase and tensin homolog (PTEN) and decreased DJ-1 expression lead to a down-regulation of the active pAkt. Lovastatin's involvement in the AKT signaling pathway was confirmed by an upregulation of its downstream target, tumor progressor NDRG1. Metabolic consequences to lovastatin exposure included suppression of glycolytic and Krebs cycle activity, and lipid biosynthesis. CONCLUSIONS: The combination of proteomics and metabonomics enabled us to identify several key targets essential to the antitumor activity of lovastatin. Our results imply that lovastatin has the potential to reduce the growth of breast cancer cells. PMID- 20205718 TI - Prediction of breast cancer sensitivity to neoadjuvant chemotherapy based on status of DNA damage repair proteins. AB - INTRODUCTION: Various agents used in breast cancer chemotherapy provoke DNA double-strand breaks (DSBs). DSB repair competence determines the sensitivity of cells to these agents whereby aberrations in the repair machinery leads to apoptosis. Proteins required for this pathway can be detected as nuclear foci at sites of DNA damage when the pathway is intact. Here we investigate whether focus formation of repair proteins can predict chemosensitivity of breast cancer. METHODS: Core needle biopsy specimens were obtained from sixty cases of primary breast cancer before and 18-24 hours after the first cycle of neoadjuvant epirubicin plus cyclophosphamide (EC) treatment. Nuclear focus formation of DNA damage repair proteins was immunohistochemically analyzed and compared with tumor response to chemotherapy. RESULTS: EC treatment induced nuclear foci of gammaH2AX, conjugated ubiquitin, and Rad51 in a substantial amount of cases. In contrast, BRCA1 foci were observed before treatment in the majority of the cases and only decreased after EC in thirteen cases. The presence of BRCA1-, gammaH2AX , or Rad51-foci before treatment or the presence of Rad51-foci after treatment was inversely correlated with tumor response to chemotherapy. DNA damage response (DDR) competence was further evaluated by considering all four repair indicators together. A high DDR score significantly correlated with low tumor response to EC and EC + docetaxel whereas other clinicopathological factors analyzed did not. CONCLUSIONS: High performing DDR focus formation resulted in tumor resistance to DNA damage-inducing chemotherapy. Our results suggested an importance of evaluation of DDR competence to predict breast cancer chemosensitivity, and merits further studying into its usefulness in exclusion of non-responder patients. PMID- 20205719 TI - TRPA1 modulation of spontaneous and mechanically evoked firing of spinal neurons in uninjured, osteoarthritic, and inflamed rats. AB - BACKGROUND: There is growing evidence supporting a role for TRPA1 receptors in the neurotransmission of peripheral mechanical stimulation. In order to enhance understanding of TRPA1 contributions to mechanotransmission, we examined the effects a selective TRPA1 receptor antagonist, A-967079, on spinal neuronal activity following peripheral mechanical stimulation in uninjured, CFA-inflamed, and osteoarthritc (OA) rats. RESULTS: Systemic injection of A-967079 (30 micromol/kg, i.v.) decreased the responses of wide dynamic range (WDR), and nociceptive specific (NS) neurons following noxious pinch stimulation of the ipsilateral hind paw in uninjured and CFA-inflamed rats. Similarly, A-967079 reduced the responses of WDR neurons to high-intensity mechanical stimulation (300 g von Frey hair) of the knee joint in both OA and OA-sham rats. WDR neuronal responses to low-intensity mechanical stimulation (10 g von Frey hair) were also reduced by A-967079 administration to CFA-inflamed rats, but no effect was observed in uninjured rats. Additionally, the spontaneous activity of WDR neurons was decreased after A-967079 injection in CFA-inflamed rats but was unaltered in uninjured, OA, and OA-sham animals. CONCLUSIONS: Blockade of TRPA1 receptors disrupts transmission of high-intensity mechanical stimulation to the spinal cord in both uninjured and injured rats indicating that TRPA1 receptors have an important role in noxious mechanosensation in both normal and pathological conditions. TRPA1 receptors also contribute to the transmission of low-intensity mechanical stimulation, and to the modulation of spontaneous WDR firing, but only after an inflammatory injury. PMID- 20205720 TI - Transient Receptor Potential Vanilloid 1 is essential for cisplatin-induced heat hyperalgesia in mice. AB - BACKGROUND: Cisplatin is primarily used for treatment of ovarian and testicular cancer. Oxaliplatin is the only effective treatment for metastatic colorectal cancer. Both are known to cause dose related, cumulative toxic effects on the peripheral nervous system and thirty to forty percent of cancer patients receiving these agents experience painful peripheral neuropathy. The mechanisms underlying painful platinum-induced neuropathy remain poorly understood. Previous studies have demonstrated important roles for TRPV1, TRPM8, and TRPA1 in inflammation and nerve injury induced pain. RESULTS: In this study, using real time, reverse transcriptase, polymerase chain reaction (RT-PCR), we analyzed the expression of TRPV1, TRPM8, and TRPA1 induced by cisplatin or oxaliplatin in vitro and in vivo. For in vitro studies, cultured E15 rat dorsal root ganglion (DRG) neurons were treated for up to 48 hours with cisplatin or oxaliplatin. For in vivo studies, trigeminal ganglia (TG) were isolated from mice treated with platinum drugs for three weeks. We show that cisplatin and oxaliplatin-treated DRG neurons had significantly increased in TRPV1, TRPA1, and TRPM8 mRNA expression. TG neurons from cisplatin treated mice had significant increases in TRPV1 and TRPA1 mRNA expression while oxaliplatin strongly induced only TRPA1. Furthermore, compared to the cisplatin-treated wild-type mice, cisplatin-treated TRPV1-null mice developed mechanical allodynia but did not exhibit enhancement of noxious heat- evoked pain responses. Immunohistochemistry studies showed that cisplatin-treated mice had no change in the proportion of the TRPV1 immunopositive TG neurons. CONCLUSION: These results indicate that TRPV1 and TRPA1 could contribute to the development of thermal hyperalgesia and mechanical allodynia following cisplatin-induced painful neuropathy but that TRPV1 has a crucial role in cisplatin-induced thermal hyperalgesia in vivo. PMID- 20205721 TI - Antiretroviral treatment adherence among HIV patients in KwaZulu-Natal, South Africa. AB - BACKGROUND: Successful antiretroviral treatment is dependent on sustaining high rates of adherence. In the southern African context, only a handful of studies (both quantitative and qualitative) have looked at the determinants including a health behaviour theory of adherence to antiretroviral therapy. The aim of this study is to assess factors including the information, motivation and behavioural skills model (IMB) contributing to antiretroviral (ARV) adherence six months after commencing ARVs at three public hospitals in KwaZulu-Natal, South Africa. METHODS: Using systematic sampling, 735 HIV-positive patients were selected prior to commencing on ART from outpatient departments from three hospitals and followed-up at six months and interviewed with a questionnaire. RESULTS: A good proportion of patients were found to be adherent using both adherence instruments (visual analog scale = VAS 82.9%; Adult AIDS Clinical Trials Group = AATCG 70.8%). After adjusting for significant socio-economic variables, both the VAS and the dose, schedule and food adherence indicator found levels of adherence amongst urban residents to be almost 3 times greater than that of rural residents. After adjusting for health-related variables, for both indicators better adherence was associated with low depression and poorer adherence was associated with poor environmental factors. Adjusted odds ratios for adherence when taking into account different behavioural variables were for both adherence indicators, discrimination experiences were associated with lower adherence, and higher scores in adherence information and behavioural skills were associated with higher adherence. For the VAS adherence indicator, higher social support scores were associated with higher adherence. For the dose, schedule and food adherence indicator, using herbal medicines for HIV was associated with lower adherence. CONCLUSION: For the patients in this study, particularly those not living in urban areas, additional support may be needed to ensure patients are able to attend appointments or obtain their medications more easily. Adherence information and behavioural skills as part of the IMB model should be strengthened to improve adherence. Further psychological support is also required and patients' perceived need for ARTs should be routinely assessed. PMID- 20205723 TI - A displaced stress fracture of the femoral neck in an adolescent female distance runner with female athlete triad: A case report. AB - This report presents a case of a displaced stress fracture of the femoral neck in an adolescent female distance runner with amenorrhea. Both reduction and internal fixation were performed early after the injury. At 24 months postoperatively, magnetic resonance imaging and bone scintigraphy showed no positive signs of femoral head necrosis and bone union was confirmed on plain X ray. A medical examination for the presence of the signs of the female athlete triad by checking weight, calorie intake and menstrual cycles is most important to prevent such stress fractures. Athletes as well as their coaches or parents therefore need to understand female athlete triad. PMID- 20205722 TI - Variations in atherosclerosis and remodeling patterns in aorta and carotids. AB - BACKGROUND: Atherosclerosis is a progressive disease that causes vascular remodeling that can be positive or negative. The evolution of arterial wall thickening and changes in lumen size under current "standard of care" in different arterial beds is unclear. The purpose of this study was to examine arterial remodeling and progression/regression of atherosclerosis in aorta and carotid arteries of individuals at risk for atherosclerosis normalized over a 1 year period. METHODS: In this study, 28 patients underwent at least 2 black-blood in vivo cardiovascular magnetic resonance (CMR) scans of aorta and carotids over a one-year period (Mean 17.8 +/- 7.5 months). Clinical risk profiles for atherosclerosis and medications were documented and patients were followed by their referring physicians under current "standard of care" guidelines. Carotid and aortic wall lumen areas were matched across the time-points from cross sectional images. RESULTS: The wall area increased by 8.67%, 10.64%, and 13.24% per year (carotid artery, thoracic aorta and abdominal aorta respectively, p < 0.001). The lumen area of the abdominal aorta increased by 4.97% per year (p = 0.002), but the carotid artery and thoracic aorta lumen areas did not change significantly. The use of statin therapy did not change the rate of increase of wall area of carotid artery, thoracic and abdominal aorta, but decreased the rate of change of lumen area of carotid artery (-3.08 +/- 11.34 vs. 0.19 +/- 12.91 p < 0.05). CONCLUSIONS: Results of this study of multiple vascular beds indicated that different vascular locations exhibited varying progression of atherosclerosis and remodeling as monitored by CMR. PMID- 20205724 TI - Health system performance at the district level in Indonesia after decentralization. AB - BACKGROUND: Assessments over the last two decades have showed an overall low level of performance of the health system in Indonesia with wide variation between districts. The reasons advanced for these low levels of performance include the low level of public funding for health and the lack of discretion for health system managers at the district level. When, in 2001, Indonesia implemented a radical decentralization and significantly increased the central transfer of funds to district governments it was widely expected that the performance of the health system would improve. This paper assesses the extent to which the performance of the health system has improved since decentralization. METHODS: We measured a set of indicators relevant to assessing changes in performance of the health system between two surveys in three areas: utilization of maternal antenatal and delivery care; immunization coverage; and contraceptive source and use. We also measured respondents' demographic characteristics and their living circumstances. These measurements were made in population-based surveys in 10 districts in 2002-03 and repeated in 2007 in the same 10 districts using the same instruments and sampling methods. RESULTS: The dominant providers of maternal and child health in these 10 districts are in the private sector. There was a significant decrease in birth deliveries at home, and a corresponding increase in deliveries in health facilities in 5 of the 10 districts, largely due to increased use of private facilities with little change in the already low use of public facilities. Overall, there was no improvement in vaccination of mothers and their children. Of those using modern contraceptive methods, the majority obtained them from the private sector in all districts. CONCLUSIONS: There has been little improvement in the performance of the health system since decentralization occurred in 2001 even though there have also been significant increases in public funding for health. In fact, the decentralization has been limited in extent and structural problems make management of the system as a whole difficult. At the national level there has been no real attempt to envision the health system that Indonesia will need for the next 20 to 30 years or how the substantial public subsidy to this lightly regulated private system could be used in creative ways to stimulate innovation, mitigate market failures, improve equity and quality, and to enhance the performance of the system as a whole. PMID- 20205725 TI - Baseline correction of phase-contrast images in congenital cardiovascular magnetic resonance. AB - BACKGROUND: One potential source of error in phase contrast (PC) congenital CMR flow measurements is caused by phase offsets due to local non-compensated eddy currents. Phantom correction of these phase offset errors has been shown to result in more accurate measurements of blood flow in adults with structurally normal hearts. We report the effect of phantom correction on PC flow measurements at a clinical congenital CMR program. RESULTS: Flow was measured in the ascending aorta, main pulmonary artery, and right and left pulmonary arteries as clinically indicated, and additional values such as Qp/Qs were derived from these measurements. Phantom correction in our study population of 149 patients resulted in clinically significant changes in 13% to 48% of these phase-contrast measurements in patients with known or suspected heart disease. Overall, 640 measurements or calculated values were analyzed, and clinically significant changes were found in 31%. Larger vessels were associated with greater phase offset errors, with 22% of the changes in PC flow measurements attributed to the size of the vessel measured. In patients with structurally normal hearts, the pulmonary-to-systemic flow ratio after phantom correction was closer to 1.0 than before phantom correction. There was no significant difference in the effect of phantom correction for patients with tetralogy of Fallot as compared to the group as a whole. CONCLUSIONS: Phantom correction often resulted in clinically significant changes in PC blood flow measurements in patients with known or suspected congenital heart disease. In laboratories performing clinical CMR with suspected phase offset errors of significance, the routine use of phantom correction for PC flow measurements should be considered. PMID- 20205727 TI - Diagnostic challenge: bilateral infected lumbar facet cysts--a rare cause of acute lumbar spinal stenosis and back pain. AB - Symptomatic synovial lumbar facet cysts are a relatively rare cause of radiculopathy and spinal stenosis. This case and brief review of the literature, details a patient who presented with acutely symptomatic bilateral spontaneously infected synovial facet (L4/5) cysts. This report highlights diagnostic clues for identifying infection of a facet cyst. PMID- 20205726 TI - Comprehensive analysis of MHC class I genes from the U-, S-, and Z-lineages in Atlantic salmon. AB - BACKGROUND: We have previously sequenced more than 500 kb of the duplicated MHC class I regions in Atlantic salmon. In the IA region we identified the loci for the MHC class I gene Sasa-UBA in addition to a soluble MHC class I molecule, Sasa ULA. A pseudolocus for Sasa-UCA was identified in the nonclassical IB region. Both regions contained genes for antigen presentation, as wells as orthologues to other genes residing in the human MHC region. RESULTS: The genomic localisation of two MHC class I lineages (Z and S) has been resolved. 7 BACs were sequenced using a combination of standard Sanger and 454 sequencing. The new sequence data extended the IA region with 150 kb identifying the location of one Z-lineage locus, ZAA. The IB region was extended with 350 kb including three new Z-lineage loci, ZBA, ZCA and ZDA in addition to a UGA locus. An allelic version of the IB region contained a functional UDA locus in addition to the UCA pseudolocus. Additionally a BAC harbouring two MHC class I genes (UHA) was placed on linkage group 14, while a BAC containing the S-lineage locus SAA (previously known as UAA) was placed on LG10. Gene expression studies showed limited expression range for all class I genes with exception of UBA being dominantly expressed in gut, spleen and gills, and ZAA with high expression in blood. CONCLUSION: Here we describe the genomic organization of MHC class I loci from the U-, Z-, and S lineages in Atlantic salmon. Nine of the described class I genes are located in the extension of the duplicated IA and IB regions, while three class I genes are found on two separate linkage groups. The gene organization of the two regions indicates that the IB region is evolving at a different pace than the IA region. Expression profiling, polymorphic content, peptide binding properties and phylogenetic relationship show that Atlantic salmon has only one MHC class Ia gene (UBA), in addition to a multitude of nonclassical MHC class I genes from the U-, S- and Z-lineages. PMID- 20205728 TI - BIAdb: a curated database of benzylisoquinoline alkaloids. AB - BACKGROUND: Benzylisoquinoline is the structural backbone of many alkaloids with a wide variety of structures including papaverine, noscapine, codeine, morphine, apomorphine, berberine, protopine and tubocurarine. Many benzylisoquinoline alkaloids have been reported to show therapeutic properties and to act as novel medicines. Thus it is important to collect and compile benzylisoquinoline alkaloids in order to explore their usage in medicine. DESCRIPTION: We extract information about benzylisoquinoline alkaloids from various sources like PubChem, KEGG, KNApSAcK and manual curation from literature. This information was processed and compiled in order to create a comprehensive database of benzylisoquinoline alkaloids, called BIAdb. The current version of BIAdb contains information about 846 unique benzylisoquinoline alkaloids, with multiple entries in term of source, function leads to total number of 2504 records. One of the major features of this database is that it provides data about 627 different plant species as a source of benzylisoquinoline and 114 different types of function performed by these compounds. A large number of online tools have been integrated, which facilitate user in exploring full potential of BIAdb. In order to provide additional information, we give external links to other resources/databases. One of the important features of this database is that it is tightly integrated with Drugpedia, which allows managing data in fixed/flexible format. CONCLUSIONS: A database of benzylisoquinoline compounds has been created, which provides comprehensive information about benzylisoquinoline alkaloids. This database will be very useful for those who are working in the field of drug discovery based on natural products. This database will also serve researchers working in the field of synthetic biology, as developing medicinally important alkaloids using synthetic process are one of important challenges. This database is available from http://crdd.osdd.net/raghava/biadb/. PMID- 20205729 TI - The Chinese government's response to drug use and HIV/AIDS: a review of policies and programs. AB - Illicit drug use has become popular in China. Acknowledging the challenge of illicit drug use, China has adopted several new policies on the management of illicit drug use in recent years. This study reviews the current policies on drug use and assesses the harm reduction interventions among drug users in China. The review documents that the new policies on drug use provide a variety of choices of detoxification treatment for drug users. The methadone maintenance treatment and needle exchange programs have been adopted as harm reduction models in China. Most of the reviewed harm reduction programs have been successfully implemented and yielded positive effects in reducing drug related risk behaviors among drug users. Although there remain barriers to the effective implementation of policies on drug use and harm reduction programs, Chinese government has shown their commitment to support the expansion of harm reduction interventions for drug users throughout the country. PMID- 20205730 TI - A high-throughput de novo sequencing approach for shotgun proteomics using high resolution tandem mass spectrometry. AB - BACKGROUND: High-resolution tandem mass spectra can now be readily acquired with hybrid instruments, such as LTQ-Orbitrap and LTQ-FT, in high-throughput shotgun proteomics workflows. The improved spectral quality enables more accurate de novo sequencing for identification of post-translational modifications and amino acid polymorphisms. RESULTS: In this study, a new de novo sequencing algorithm, called Vonode, has been developed specifically for analysis of such high-resolution tandem mass spectra. To fully exploit the high mass accuracy of these spectra, a unique scoring system is proposed to evaluate sequence tags based primarily on mass accuracy information of fragment ions. Consensus sequence tags were inferred for 11,422 spectra with an average peptide length of 5.5 residues from a total of 40,297 input spectra acquired in a 24-hour proteomics measurement of Rhodopseudomonas palustris. The accuracy of inferred consensus sequence tags was 84%. According to our comparison, the performance of Vonode was shown to be superior to the PepNovo v2.0 algorithm, in terms of the number of de novo sequenced spectra and the sequencing accuracy. CONCLUSIONS: Here, we improved de novo sequencing performance by developing a new algorithm specifically for high resolution tandem mass spectral data. The Vonode algorithm is freely available for download at http://compbio.ornl.gov/Vonode. PMID- 20205731 TI - Altered neuromuscular control mechanisms of the trapezius muscle in fibromyalgia. AB - BACKGROUND: fibromyalgia is a relatively common condition with widespread pain and pressure allodynia, but unknown aetiology. For decades, the association between motor control strategies and chronic pain has been a topic for debate. One long held functional neuromuscular control mechanism is differential activation between regions within a single muscle. The aim of this study was to investigate differences in neuromuscular control, i.e. differential activation, between myalgic trapezius in fibromyalgia patients and healthy controls. METHODS: 27 fibromyalgia patients and 30 healthy controls performed 3 minutes bilateral shoulder elevations with different loads (0-4 Kg) with a high-density surface electromyographical (EMG) grid placed above the upper trapezius. Differential activation was quantified by the power spectral median frequency of the difference in EMG amplitude between the cranial and caudal parts of the upper trapezius. The average duration of the differential activation was described by the inverse of the median frequency of the differential activations. RESULTS: the median frequency of the differential activations was significantly lower, and the average duration of the differential activations significantly longer in fibromyalgia compared with controls at the two lowest load levels (0-1 Kg) (p < 0.04), but not at the two highest load levels (2 and 4 Kg). CONCLUSION: these findings illustrate a different neuromuscular control between fibromyalgia patients and healthy controls during a low load functional task, either sustaining or resulting from the chronic painful condition. The findings may have clinical relevance for rehabilitation strategies for fibromyalgia. PMID- 20205732 TI - The use of partial exchange blood transfusion and anaesthesia in the management of sickle cell disease in a perioperative setting: two case reports. AB - INTRODUCTION: Homozygous sickle cell carriers have an increased perioperative mortality. Some indications may justify an exchange blood transfusion to reduce the proportion of haemoglobin S. The advantages of general blood transfusion in a perioperative setting have not been proven and thus remain controversial. It is not clear whether reducing the proportion of haemoglobin S minimizes perioperative complications or whether patients with sickle cell disease in a stable clinical condition benefit from an exchange blood transfusion in a perioperative setting. CASE PRESENTATION: We report the case of two Angolan children aged 10 and 11 respectively, of African origin with sickle cell anaemia who underwent surgery to treat chronic necrosis, fistula of the bones and bone destruction. This presentation describes the perioperative course, including general anaesthesia. A partial exchange blood transfusion decreased S-haemoglobin levels from 81% to 21% and simultaneously treated the anaemia. CONCLUSION: There is a consensus that imbalances in homoeostasis, including operative procedures, can cause a critical exacerbation of sickle cell disease. The case presented here illustrates a strategy for successfully managing sickle cell disease in the perioperative period to minimize its complications. It is important for the anaesthesiologist to carefully manage pulmonary gas exchange and to ensure sufficient tissue perfusion, balanced fluid resuscitation and normothermia, while keeping in mind the level of organ impairment in order to prevent an acute exacerbation of sickle cell disease.We performed a partial exchange blood transfusion due to the following factors: high haemoglobin S-fraction, anaemia, operating procedure at several sites, and difficult management of body temperature. Esmarch ischemia is an established tool for preventing uncontrolled blood loss. There is no known contraindication for this, but attention must be paid to prevent uncontrolled tissue ischemia and acidosis. The use of regional anaesthesia should be considered for postoperative pain management. PMID- 20205733 TI - The course of specialization in public health in Rio de Janeiro, Brazil, from 1926 to 2006: lessons and challenges. AB - BACKGROUND: Public health, as a field of knowledge, depends on its professionals. Their education and training, therefore, is considered to be an important factor for the quality of health services. In Brazil, the Course of Specialization in Public Health of the National School of Public Health is one of the oldest in the country. The course has existed for over 80 years, during which it has had an eventful history, with modifications in its organization, interruptions in its delivery, threats to its survival and changes in the institutions hosting it, reflecting the wider transformation in Brazilian society and public life over that period. METHODS: In this article we analyse this course via its history, disciplines, organization and characteristics of the student body. RESULTS: Insights were gained into the advancement of public health in Brazil and the progress of education for professionals in this field was highlighted. The course has formed nearly 2000 specialists in public health. CONCLUSIONS: An analysis of the course's history provides valuable lessons for other schools of public health trying to train professionals in developing countries. PMID- 20205734 TI - Tactile-dependant corticomotor facilitation is influenced by discrimination performance in seniors. AB - BACKGROUND: Active contraction leads to facilitation of motor responses evoked by transcranial magnetic stimulation (TMS). In small hand muscles, motor facilitation is known to be also influenced by the nature of the task. Recently, we showed that corticomotor facilitation was selectively enhanced when young participants actively discriminated tactile symbols with the tip of their index or little finger. This tactile-dependent motor facilitation reflected, for the large part, attentional influences associated with performing tactile discrimination, since execution of a concomitant distraction task abolished facilitation. In the present report, we extend these observations to examine the influence of age on the ability to produce extra motor facilitation when the hand is used for sensory exploration. METHODS: Corticomotor excitability was tested in 16 healthy seniors (58-83 years) while they actively moved their right index finger over a surface under two task conditions. In the tactile discrimination (TD) condition, participants attended to the spatial location of two tactile symbols on the explored surface, while in the non discrimination (ND) condition, participants simply moved their finger over a blank surface. Changes in amplitude, in latency and in the silent period (SP) duration were measured from recordings of motor evoked potentials (MEP) in the right first dorsal interosseous muscle in response to TMS of the left motor cortex. RESULTS: Healthy seniors exhibited widely varying levels of performance with the TD task, older age being associated with lower accuracy and vice-versa. Large inter-individual variations were also observed in terms of tactile-specific corticomotor facilitation. Regrouping seniors into higher (n = 6) and lower performance groups (n = 10) revealed a significant task by performance interaction. This latter interaction reflected differences between higher and lower performance groups; tactile-related facilitation being observed mainly in the former group. Latency measurements and SP durations were not affected by task conditions. CONCLUSIONS: The present findings provide further insights into the factors influencing task dependent changes in corticomotor excitability in the context of aging. Our results, in particular, highlight the importance of adjusting task demands and controlling for attention when attempting to elicit task-specific motor facilitation in older persons engaged in fine manual actions. Such information could be critical in the future for planning interventions to re-educate or maintain hand function in the presence of neurological impairments. PMID- 20205735 TI - Specific fibre composition and metabolism of the rectus abdominis muscle of bovine Charolais cattle. AB - BACKGROUND: An important variability of contractile and metabolic properties between muscles has been highlighted. In the literature, the majority of studies on beef sensorial quality concerns M. longissimus thoracis. M. rectus abdominis (RA) is easy to sample without huge carcass depreciation and may appear as an alternative to M. longissimus thoracis for fast and routine physicochemical analysis. It was considered interesting to assess the muscle fibres of M. rectus abdominis in comparison with M. longissimus thoracis (LT) and M. triceps brachii (TB) on the basis of metabolic and contractile properties, area and myosin heavy chain isoforms (MyHC) proportions. Immuno-histochemical, histochemical, histological and enzymological techniques were used. This research concerned two populations of Charolais cattle: RA was compared to TB in a population of 19 steers while RA was compared to LT in a population of 153 heifers. RESULTS: RA muscle had higher mean fibre areas (3350 microm(2) vs 2142 to 2639 microm(2)) than the two other muscles. In RA muscle, the slow-oxidative fibres were the largest (3957 microm(2)) and the fast-glycolytic the smallest (2868 microm(2)). The reverse was observed in TB muscle (1725 and 2436 microm(2) respectively). In RA muscle, the distinction between fast-oxidative-glycolytic and fast-glycolytic fibres appeared difficult or impossible to establish, unlike in the other muscles. Consequently the classification based on ATPase and SDH activities seemed inappropriate, since the FOG fibres presented rather low SDH activity in this muscle in comparison to the other muscles of the carcass. RA muscle had a higher proportion of I fibres than TB and LT muscles, balanced by a lower proportion either of IIX fibres (in comparison to TB muscle) or of IIA fibres (in comparison to LT muscle). However, both oxidative and glycolytic enzyme activities were lower in RA than in TB muscle, although the LDH/ICDH ratio was higher in RA muscle (522 vs 340). Oxidative enzyme activities were higher in RA than in LT muscle, whereas glycolytic enzyme activity was lower. In RA muscle, contractile and metabolic properties appeared to be less well-correlated than in the two other muscles. CONCLUSIONS: RA muscle has some particularities in comparison to the LT and TB muscles, especially concerning the unusual large cross-section surface of SO fibres and the very low oxidative activity of intermediate IIA fibres. PMID- 20205736 TI - Incorporating statistical uncertainty in the use of physician cost profiles. AB - BACKGROUND: Physician cost profiles (also called efficiency or economic profiles) compare the costs of care provided by a physician to his or her peers. These profiles are increasingly being used as the basis for policy applications such as tiered physician networks. Tiers (low, average, high cost) are currently defined by health plans based on percentile cut-offs which do not account for statistical uncertainty. In this paper we compare the percentile cut-off method to another method, using statistical testing, for identifying high-cost or low-cost physicians. METHODS: We created a claims dataset of 2004-2005 data from four Massachusetts health plans. We employed commercial software to create episodes of care and assigned responsibility for each episode to the physician with the highest proportion of professional costs. A physicians' cost profile was the ratio of the sum of observed costs divided by the sum of expected costs across all assigned episodes. We discuss a new method of measuring standard errors of physician cost profiles which can be used in statistical testing. We then assigned each physician to one of three cost categories (low, average, or high cost) using two methods, percentile cut-offs and a t-test (p-value < or = 0.05), and assessed the level of disagreement between the two methods. RESULTS: Across the 8689 physicians in our sample, 29.5% of physicians were assigned a different cost category when comparing the percentile cut-off method and the t-test. This level of disagreement varied across specialties (17.4% gastroenterology to 45.8% vascular surgery). CONCLUSIONS: Health plans and other payers should incorporate statistical uncertainty when they use physician cost-profiles to categorize physicians into low or high-cost tiers. PMID- 20205737 TI - Astaxanthin decreased oxidative stress and inflammation and enhanced immune response in humans. AB - BACKGROUND: Astaxanthin modulates immune response, inhibits cancer cell growth, reduces bacterial load and gastric inflammation, and protects against UVA-induced oxidative stress in in vitro and rodent models. Similar clinical studies in humans are unavailable. Our objective is to study the action of dietary astaxanthin in modulating immune response, oxidative status and inflammation in young healthy adult female human subjects. METHODS: Participants (averaged 21.5 yr) received 0, 2, or 8 mg astaxanthin (n = 14/diet) daily for 8 wk in a randomized double-blind, placebo-controlled study. Immune response was assessed on wk 0, 4 and 8, and tuberculin test performed on wk 8. RESULTS: Plasma astaxanthin increased (P < 0.01) dose-dependently after 4 or 8 wk of supplementation. Astaxanthin decreased a DNA damage biomarker after 4 wk but did not affect lipid peroxidation. Plasma C-reactive protein concentration was lower (P < 0.05) on wk 8 in subjects given 2 mg astaxanthin. Dietary astaxanthin stimulated mitogen-induced lymphoproliferation, increased natural killer cell cytotoxic activity, and increased total T and B cell subpopulations, but did not influence populations of Thelper, Tcytotoxic or natural killer cells. A higher percentage of leukocytes expressed the LFA-1 marker in subjects given 2 mg astaxanthin on wk 8. Subjects fed 2 mg astaxanthin had a higher tuberculin response than unsupplemented subjects. There was no difference in TNF and IL-2 concentrations, but plasma IFN-gamma and IL-6 increased on wk 8 in subjects given 8 mg astaxanthin. CONCLUSION: Therefore, dietary astaxanthin decreases a DNA damage biomarker and acute phase protein, and enhances immune response in young healthy females. PMID- 20205738 TI - Unified translation repression mechanism for microRNAs and upstream AUGs. AB - BACKGROUND: MicroRNAs (miRNAs) are endogenous small RNAs that modulate gene expression at the post-transcriptional level by binding complementary sites in the 3'-UTR. In a recent genome-wide study reporting a new miRNA target class (miBridge), we identified and validated interactions between 5'-UTRs and miRNAs. Separately, upstream AUGs (uAUGs) in 5'-UTRs are known to regulate genes translationally without affecting mRNA levels, one of the mechanisms for miRNA mediated repression. RESULTS: Using sequence data from whole-genome cDNA alignments we identified 1418 uAUG sequences on the 5'-UTR that specifically interact with 3'-ends of conserved miRNAs. We computationally identified miRNAs that can target six genes through their uAUGs that were previously reported to suppress translation. We extended this meta-analysis by confirming expression of these miRNAs in cell-lines used in the uAUG studies. Similarly, seven members of the KLF family of genes containing uAUGs were computationally identified as interacting with several miRNAs. Using KLF9 as an example (whose protein expression is limited to brain tissue despite the mRNA being expressed ubiquitously), we show computationally that miRNAs expressed only in HeLa cells and not in neuroblastoma (N2A) cells can bind the uAUGs responsible for translation inhibition. Our computed results demonstrate that tissue- or cell line specific repression of protein translation by uAUGs can be explained by the presence or absence of miRNAs that target these uAUG sequences. We propose that these uAUGs represent a subset of miRNA interaction sites on 5'-UTRs in miBridge, whereby a miRNA binding a uAUG hinders the progression of ribosome scanning the mRNA before it reaches the open reading frame (ORF). CONCLUSIONS: While both miRNAs and uAUGs are separately known to down-regulate protein expression, we show that they may be functionally related by identifying potential interactions through a sequence-specific binding mechanism. Using prior experimental evidence that shows uAUG effects on translation repression together with miRNA expression data specific to cell lines, we demonstrate through computational analysis that cell-specific down-regulation of protein expression (while maintaining mRNA levels) correlates well with the simultaneous presence of miRNA and target uAUG sequences in one cell type and not others, suggesting tissue-specific translation repression by miRNAs through uAUGs. PMID- 20205739 TI - A new method to analyse the pace of child development: Cox regression validated by a bootstrap resampling procedure. AB - BACKGROUND: Various perinatal factors influencing neuromotor development are known from cross sectional studies. Factors influencing the age at which distinct abilities are acquired are uncertain. We hypothesized that the Cox regression model might identify these factors. METHODS: Neonates treated at Aachen University Hospital in 2000/2001 were identified retrospectively (n = 796). Outcome data, based on a structured interview, were available from 466 children, as were perinatal data. Factors possibly related to outcome were identified by bootstrap selection and then included into a multivariate Cox regression model. To evaluate if the parental assessment might change with the time elapsed since birth we studied five age cohorts of 163 normally developed children. RESULTS: Birth weight, gestational age, congenital cardiac disease and periventricular leukomalacia were related to outcome in the multivariate analysis (p < 0.05). Analysis of the control cohorts revealed that the parents' assessment of the ability of bladder control is modified by the time elapsed since birth. CONCLUSIONS: Combined application of the bootstrap resampling procedure and multivariate Cox regression analysis effectively identifies perinatal factors influencing the age at which distinct abilities are acquired. These were similar as known from previous cross sectional studies. Retrospective data acquisition may lead to a bias because the parental memories change with time. This recommends applying this statistical approach in larger prospective trials. PMID- 20205740 TI - Impact of vital signs screening & clinician prompting on alcohol and tobacco screening and intervention rates: a pre-post intervention comparison. AB - BACKGROUND: Though screening and intervention for alcohol and tobacco misuse are effective, primary care screening and intervention rates remain low. Previous studies have increased intervention rates using vital signs screening for tobacco misuse and clinician prompts for screen-positive patients for both alcohol and tobacco misuse. This pilot study's aims were: (1) To determine the feasibility of combined vital signs screening for tobacco and alcohol misuse, (2) To assess the impact of vital signs screening on alcohol and tobacco screening and intervention rates, and (3) To assess the additional impact of tobacco assessment prompts on intervention rates. METHODS: In five outpatient practices, nurses measuring vital signs were trained to routinely ask a single tobacco question, a prescreening question that identified current drinkers, and the single alcohol screening question for current drinkers. After 4-8 weeks, clinicians were trained in tobacco intervention and nurses were trained to give tobacco abusers a tobacco questionnaire which also served as a clinician intervention prompt. Screening and intervention rates were measured using patient exit interviews (n = 622) at baseline, during the "screening only" period, and during the tobacco prompting phase. Changes in screening and intervention rates were compared using chi square analyses and test of linear trends. Clinic staff were interviewed regarding patient and staff acceptability. Logistic regression was used to evaluate the impact of nurse screening on clinician intervention, the impact of alcohol intervention on concurrent tobacco intervention, and the impact of tobacco intervention on concurrent alcohol intervention. RESULTS: Alcohol and tobacco screening rates and alcohol intervention rates increased after implementing vital signs screening (p < .05). During the tobacco prompting phase, clinician intervention rates increased significantly for both alcohol (12.4%, p < .001) and tobacco (47.4%, p = .042). Screening by nurses was associated with clinician advice to reduce alcohol use (OR 13.1; 95% CI 6.2-27.6) and tobacco use (OR 2.6; 95% CI 1.3-5.2). Acceptability was high with nurses and patients. CONCLUSIONS: Vital signs screening can be incorporated in primary care and increases alcohol screening and intervention rates. Tobacco assessment prompts increase both alcohol and tobacco interventions. These simple interventions show promise for dissemination in primary care settings. PMID- 20205742 TI - Fluvoxamine for aripiprazole-associated akathisia in patients with schizophrenia: a potential role of sigma-1 receptors. AB - BACKGROUND: Second-generation antipsychotic drugs have been reported to cause fewer incidences of extrapyramidal side effects (EPSs) than typical antipsychotic drugs, but adverse events such as akathisia have been observed even with atypical antipsychotic drugs. Although understanding of the pathophysiology of akathisia remains limited, it seems that a complex interplay of several neurotransmitter systems might play a role in its pathophysiology. The endoplasmic reticulum protein sigma-1 receptors are shown to regulate a number of neurotransmitter systems in the brain. METHODS: We report on two cases in which monotherapy of the selective serotonin reuptake inhibitor and sigma-1 receptor agonist fluvoxamine was effective in ameliorating the akathisia of patients with schizophrenia treated with the antipsychotic drug aripiprazole. RESULTS: The global score on the Barnes Akathisia Scale in the two patients with schizophrenia treated with aripiprazole decreased after fluvoxamine monotherapy. CONCLUSION: Doctors may wish to consider fluvoxamine as an alternative approach in treating akathisia associated with antipsychotic drugs such as aripiprazole. PMID- 20205741 TI - Exploring Tai Chi in rheumatoid arthritis: a quantitative and qualitative study. AB - BACKGROUND: Rheumatoid arthritis (RA) is a chronic, inflammatory and systemic disease which affects the musculoskeletal system. Exercise programmes are reported to improve physical functioning in patients with RA. Tai Chi is a traditional Chinese martial art which combines slow and gentle movements with mental focus. The purpose of this study was to study in which way Tai Chi group exercise impacted on disease activity, physical function, health status and experience in RA patients, applying quantitative and qualitative methods. METHODS: Fifteen patients with RA (13 females, age 33-70 years) were recruited from a rheumatology department into a single group study. The patients were instructed in Tai Chi exercise twice weekly for 12 weeks. Assessments at baseline, 12 weeks, and 12 weeks follow-up were performed with a wide range of measures, including disease activity, self-reported health status, physical performance tests (Walking in Figure of Eight, Timed-Stands Test, and Shoulder Movement Impairment Scale). Qualitative data were obtained from a focus group interview conducted after completed intervention with taping and verbatim transcription. Review of the transcripts identified themes important to patients practicing Tai Chi. RESULTS: Within the group, Tai Chi practice lead to improved lower-limb muscle function at the end of intervention and at 12 weeks follow-up. Qualitative analyses showed that patients experienced improved physical condition, confidence in moving, balance and less pain during exercise and in daily life. Other experience included stress reduction, increased body awareness, confidence in moving and indicated that Tai Chi was a feasible exercise modality in RA. CONCLUSIONS: Improved muscle function in lower limbs was also reflected when patient experiences with Tai Chi were studied in depth in this explorative study. The combination of qualitative and quantitative research methods shows that Tai Chi has beneficial effects on health not related to disease activity and standardised health status assessment, and may contribute to an understanding of how Tai Chi exerts its effects. TRIAL REGISTRATION: NCT00522054. PMID- 20205743 TI - Predicting results of mycobacterial culture on sputum smear reversion after anti tuberculous treatment: a case control study. AB - BACKGROUND: Little is currently known regarding sputum smear reversion (acid-fast smear becomes positive again after negative conversion) during anti-tuberculous treatment. This study aimed to evaluate its occurrence in patients with pulmonary tuberculosis (TB) and identify factors predicting results of mycobacterial culture for smear-reversion of sputum samples. METHODS: The retrospective review was performed in a tertiary referral center and a local teaching hospital in Taiwan. From 2000 to 2007, patients with smear-positive culture-confirmed pulmonary TB experiencing smear reversion after 14 days of anti-tuberculous treatment were identified. RESULTS: The 739 patients with smear-positive pulmonary TB had 74 (10%) episodes of sputum smear reversion that grew Mycobacterium tuberculosis in 22 (30%) (Mtb group). The remaining 52 episodes of culture-negative sputum samples were classified as the non-Mtb group. The anti tuberculous regimen was modified after confirming smear reversion in 15 (20%). Fourteen episodes in the Mtb group and 15 in the non-Mtb group occurred during hospitalization. All were admitted to the negative-pressure rooms at the time of smear reversion. Statistical analysis showed that any TB drug resistance, smear reversion within the first two months of treatment or before culture conversion, and the absence of radiographic improvement before smear reversion were associated with the Mtb group. None of the smear reversion was due to viable M. tuberculosis if none of the four factors were present. CONCLUSIONS: Sputum smear reversion develops in 10% of patients with smear-positive pulmonary TB, with 30% due to viable M. tuberculosis bacilli. Isolation and regimen modification may not be necessary for all drug-susceptible patients who already have radiographic improvement and develop smear reversion after two months of treatment or after sputum culture conversion. PMID- 20205744 TI - Management of the infertile couple: an evidence-based protocol. AB - BACKGROUND: Infertility is defined as inability of a couple to conceive naturally after one year of regular unprotected sexual intercourse. It remains a major clinical and social problem, affecting perhaps one couple in six. Evaluation usually starts after 12 months; however it may be indicated earlier. The most common causes of infertility are: male factor such as sperm abnormalities, female factor such as ovulation dysfunction and tubal pathology, combined male and female factors and unexplained infertility. OBJECTIVES: The aim of this study is to provide the healthcare professionals an evidence-based management protocol for infertile couples away from medical information overload. METHODS: A comprehensive review where the literature was searched for "Management of infertility and/or infertile couples" at library website of University of Bristol (MetaLib) by using a cross-search of different medical databases besides the relevant printed medical journals and periodicals. Guidelines and recommendations were retrieved from the best evidence reviews such as that from the American College of Obstetricians and Gynaecologists (ACOG), American Society for Reproductive Medicine (ASRM), Canadian Fertility and Andrology Society (CFAS), and Royal College of Obstetricians and Gynaecologists (RCOG). RESULTS: A simple guide for the clinicians to manage the infertile couples. CONCLUSIONS: The study deploys a new strategy to translate the research findings and evidence-base recommendations into a simplified focused guide to be applied on routine daily practice. It is an approach to disseminate the recommended medical care for infertile couple to the practicing clinicians. PMID- 20205745 TI - DNA-PKcs plays a dominant role in the regulation of H2AX phosphorylation in response to DNA damage and cell cycle progression. AB - BACKGROUND: When DNA double-strand breaks (DSB) are induced by ionizing radiation (IR) in cells, histone H2AX is quickly phosphorylated into gamma-H2AX (p-S139) around the DSB site. The necessity of DNA-PKcs in regulating the phosphorylation of H2AX in response to DNA damage and cell cycle progression was investigated. RESULTS: The level of gamma H2AX in HeLa cells increased rapidly with a peak level at 0.25 - 1.0 h after 4 Gy gamma irradiation. SiRNA-mediated depression of DNA-PKcs resulted in a strikingly decreased level of gamma H2AX. An increased gamma H2AX was also induced in the ATM deficient cell line AT5BIVA at 0.5 - 1.0 h after 4 Gy gamma rays, and this IR-increased gamma H2AX in ATM deficient cells was dramatically abolished by the PIKK inhibitor wortmannin and the DNA-PKcs specific inhibitor NU7026. A high level of constitutive expression of gamma H2AX was observed in another ATM deficient cell line ATS4. The alteration of gamma H2AX level associated with cell cycle progression was also observed. HeLa cells with siRNA-depressed DNA-PKcs (HeLa-H1) or normal level DNA-PKcs (HeLa-NC) were synchronized at the G1 phase with the thymidine double-blocking method. At approximately 5 h after the synchronized cells were released from the G1 block, the S phase cells were dominant (80%) for both HeLa-H1 and HeLa-NC cells. At 8 - 9 h after the synchronized cells released from the G1 block, the proportion of G2/M population reached 56 - 60% for HeLa-NC cells, which was higher than that for HeLa H1 cells (33 - 40%). Consistently, the proportion of S phase for HeLa-NC cells decreased to approximately 15%; while a higher level (26 - 33%) was still maintained for the DNA-PKcs depleted HeLa-H1 cells during this period. In HeLa-NC cells, the gamma H2AX level increased gradually as the cells were released from the G1 block and entered the G2/M phase. However, this gamma H2AX alteration associated with cell cycle progressing was remarkably suppressed in the DNA-PKcs depleted HeLa-H1 cells, while wortmannin and NU7026 could also suppress this cell cycle related phosphorylation of H2AX. Furthermore, inhibition of GSK3 beta activity with LiCl or specific siRNA could up-regulate the gamma H2AX level and prolong the time of increased gamma H2AX to 10 h or more after 4 Gy. GSK3 beta is a negative regulation target of DNA-PKcs/Akt signaling via phosphorylation on Ser9, which leads to its inactivation. Depression of DNA-PKcs in HeLa cells leads to a decreased phosphorylation of Akt on Ser473 and its target GSK3 beta on Ser9, which, in other words, results in an increased activation of GSK3 beta. In addition, inhibition of PDK (another up-stream regulator of Akt/GSK3 beta) by siRNA can also decrease the induction of gamma H2AX in response to both DNA damage and cell cycle progression. CONCLUSION: DNA-PKcs plays a dominant role in regulating the phosphorylation of H2AX in response to both DNA damage and cell cycle progression. It can directly phosphorylate H2AX independent of ATM and indirectly modulate the phosphorylation level of gamma H2AX via the Akt/GSK3 beta signal pathway. PMID- 20205746 TI - Mechanisms of tumor necrosis factor-alpha-induced interleukin-6 synthesis in glioma cells. AB - BACKGROUND: Interleukin (IL)-6 plays a pivotal role in a variety of CNS functions such as the induction and modulation of reactive astrogliosis, pathological inflammatory responses and neuroprotection. Tumor necrosis factor (TNF)-alpha induces IL-6 release from rat C6 glioma cells through the inhibitory kappa B (IkappaB)-nuclear factor kappa B (NFkappaB) pathway, p38 mitogen-activated protein (MAP) kinase and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK). The present study investigated the mechanism of TNF-alpha-induced IL-6 release in more detail than has previously been reported. METHODS: Cultured C6 cells were stimulated by TNF-alpha. IL-6 release from the cells was measured by an enzyme-linked immunosorbent assay, and the phosphorylation of IkappaB, NFkappaB, the MAP kinase superfamily, and signal transducer and activator of transcription (STAT)3 was analyzed by Western blotting. Levels of IL-6 mRNA in cells were evaluated by real-time reverse transcription-polymerase chain reaction. RESULTS: TNF-alpha significantly induced phosphorylation of NFkappaB at Ser 536 and Ser 468, but not at Ser 529 or Ser 276. Wedelolactone, an inhibitor of IkappaB kinase, suppressed both TNF-alpha-induced IkappaB phosphorylation and NFkappaB phosphorylation at Ser 536 and Ser 468. TNF-alpha-stimulated increases in IL-6 levels were suppressed by wedelolactone. TNF-alpha induced phosphorylation of STAT3. The Janus family of tyrosine kinase (JAK) inhibitor I, an inhibitor of JAK 1, 2 and 3, attenuated TNF-alpha-induced phosphorylation of STAT3 and significantly reduced TNF-alpha-stimulated IL-6 release. Apocynin, an inhibitor of NADPH oxidase that suppresses intracellular reactive oxygen species, significantly suppressed TNF-alpha-induced IL-6 release and mRNA expression. However, apocynin failed to affect the phosphorylation of IkappaB, NFkappaB, p38 MAP kinase, SAPK/JNK or STAT3. CONCLUSION: These results strongly suggest that TNF-alpha induces IL-6 synthesis through the JAK/STAT3 pathway in addition to p38 MAP kinase and SAPK/JNK in C6 glioma cells, and that phosphorylation of NFkappaB at Ser 536 and Ser 468, and NADPH oxidase are involved in TNF-alpha-stimulated IL 6 synthesis. PMID- 20205747 TI - Malignant peripheral nerve sheath tumor associated with neurofibromatosis type 1, with metastasis to the heart: a case report. AB - A rare case is presented of a 61-year-old man with a malignant peripheral nerve sheath tumor associated with neurofibromatosis type 1, with metastasis to the heart. The primary tumor originated in the right thigh in 1982. Since then, the patient has had repeated local recurrences in spite of repeated surgical treatment and adjuvant chemotherapy. He has developed previous metastases of the lung and heart. The patient died of cardiac involvement. PMID- 20205748 TI - The anti-inflammatory effects of the tellurium redox modulating compound, AS101, are associated with regulation of NFkappaB signaling pathway and nitric oxide induction in macrophages. AB - BACKGROUND: LPS-activated macrophages produce mediators which are involved in inflammation and tissue injury, and especially those associated with endotoxic shock. The non toxic tellurium compound ammonium tri-chloro(dioxoethylene-O,O' )tellurate, AS101, has been recently shown to exert profound anti-inflammatory properties in animal models, associated with its Te(IV) redox chemistry. This study explores the anti-inflammatory properties of AS101 with respect to modulation of inflammatory cytokines production and regulation of iNOS transcription and expression in activated macrophages via targeting the NFkB complex. RESULTS: AS101 decreased production of IL-6 and in parallel down regulated LPS-induced iNOS expression and NO secretion by macrophages. AS101 reduced IkB phosphorylation and degradation, and reduced NFkB nuclear translocalization, albeit these effects were exerted at different kinetics. Chromatin immunoprecipitation assays showed that AS101 treatment attenuated p50 subunit ability to bind DNA at the NFkB consensus site in the iNOS promotor following LPS induction. CONCLUSIONS: Besides AS101, the investigation of therapeutic activities of other tellurium(IV) compounds is scarce in the literature, although tellurium is the fourth most abundant trace element in the human body. Since IKK and NFkB may be regulated by thiol modifications, we may thus envisage, inview of our integrated results, that Te(IV) compounds, may have important roles in thiol redox biological activity in the human body and represent a new class of anti-inflammatory compounds. PMID- 20205749 TI - Scaling up proven public health interventions through a locally owned and sustained leadership development programme in rural Upper Egypt. AB - INTRODUCTION: In 2002, the Egypt Ministry of Health and Population faced the challenge of improving access to and quality of services in rural Upper Egypt in the face of low morale among health workers and managers.From 1992 to 2000, the Ministry, with donor support, had succeeded in reducing the nationwide maternal mortality rate by 52%. Nevertheless, a gap remained between urban and rural areas. CASE DESCRIPTION: In 2002, the Ministry, with funding from the United States Agency for International Development and assistance from Management Sciences for Health, introduced a Leadership Development Programme (LDP) in Aswan Governorate. The programme aimed to improve health services in three districts by increasing managers' ability to create high performing teams and lead them to achieve results.The programme introduced leadership and management practices and a methodology for identifying and addressing service delivery challenges. Ten teams of health workers participated. DISCUSSION AND EVALUATION: In 2003, after participation in the LDP, the districts of Aswan, Daraw and Kom Ombo increased the number of new family planning visits by 36%, 68% and 20%, respectively. The number of prenatal and postpartum visits also rose.After the United States funding ended, local doctors and nurses scaled up the programme to 184 health care facilities (training more than 1000 health workers). From 2005 to 2007, the Leadership Development Programme participants in Aswan Governorate focused on reducing the maternal mortality rate as their annual goal. They reduced it from 85.0 per 100,000 live births to 35.5 per 100,000. The reduction in maternal mortality rate was much greater than in similar governorates in Egypt. Managers and teams across Aswan demonstrated their ability to scale up effective public health interventions though their increased commitment and ownership of service challenges. CONCLUSIONS: When teams learn and apply empowering leadership and management practices, they can transform the way they work together and develop their own solutions to complex public health challenges. Committed health teams can use local resources to scale up effective public health interventions. PMID- 20205750 TI - The betaine content of sweat from adolescent females. AB - BACKGROUND: This study was developed to establish whether betaine was present in the sweat of females and to determine any correlations with other sweat components. METHODS: Sweat patches were placed on eight trained adolescent Highland dancers (age = 13.6 +/- 2.3 yr), who then participated in a dance class for 2 hours. Patches were removed, and the sweat recovered via centrifugation. The sweat was subsequently analyzed for betaine, choline, sodium, potassium, chloride, lactate, glucose, urea and ammonia. RESULTS: Betaine was present in the sweat of all subjects (232 +/- 84 mumol.L-1), which is higher than typically found in plasma. The concentration of several sweat components were correlated, in particular betaine with most other measured components. CONCLUSION: Betaine, an osmoprotectant and methyl donor, is a component of sweat that may be lost from the body in significant amounts. PMID- 20205751 TI - Moderate energy restriction with high protein diet results in healthier outcome in women. AB - BACKGROUND: The present study compares two different weight reduction regimens both with a moderately high protein intake on body composition, serum hormone concentration and strength performance in non-competitive female athletes. METHODS: Fifteen normal weighted women involved in recreational resistance training and aerobic training were recruited for the study (age 28.5 +/- 6.3 yr, height 167.0 +/- 7.0 cm, body mass 66.3 +/- 4.2 kg, body mass index 23.8 +/- 1.8, mean +/- SD). They were randomized into two groups. The 1 KG group (n = 8; energy deficit 1100 kcal/day) was supervised to reduce body weight by 1 kg per week and the 0.5 KG group (n = 7; energy deficit 550 kcal/day) by 0.5 kg per week, respectively. In both groups protein intake was kept at least 1.4 g/kg body weight/day and the weight reduction lasted four weeks. At the beginning of the study the energy need was calculated using food and training diaries. The same measurements were done before and after the 4-week weight reduction period including total body composition (DXA), serum hormone concentrations, jumping ability and strength measurements RESULTS: During the 4-week weight reduction period there were no changes in lean body mass and bone mass, but total body mass, fat mass and fat percentage decreased significantly in both groups. The changes were greater in the 1 KG group than in the 0.5 KG group in total body mass (p < 0.001), fat mass (p < 0.001) and fat percentage (p < 0.01). Serum testosterone concentration decreased significantly from 1.8 +/- 1.0 to 1.4 +/- 0.9 nmol/l (p < 0.01) in 1 KG and the change was greater in 1 KG (30%, p < 0.001) than in 0.5 KG (3%). On the other hand, SHBG increased significantly in 1 KG from 63.4 +/- 17.7 to 82.4 +/- 33.0 nmol/l (p < 0.05) during the weight reducing regimen. After the 4-week period there were no changes in strength performance in 0.5 KG group, however in 1 KG maximal strength in bench press decreased (p < 0.05) while endurance strength in squat and counter movement jump improved (p < 0.05) CONCLUSION: It is concluded that a weight reduction by 0.5 kg per week with ~1.4 g protein/kg body weight/day can be recommended to normal weighted, physically active women instead of a larger (e.g. 1 kg per week) weight reduction because the latter may lead to a catabolic state. Vertical jumping performance is improved when fat mass and body weight decrease. Thus a moderate weight reduction prior to a major event could be considered beneficial for normal built athletes in jumping events. PMID- 20205752 TI - Sexual dimorphism and population divergence in the Lake Tanganyika cichlid fish genus Tropheus. AB - BACKGROUND: With about 120 colour morphs currently assigned to six nominal species, the genus Tropheus is an ideal model to study evolutionary divergence of populations in allopatry. The morphology of Tropheus has been described as relatively static, but reproductive constraints are sexually dimorphic due to mouthbrooding in females. We analysed phenotypic variation in six populations of T. moorii and one population of T. polli using geometric morphometrics to assess morphological differences among sexes in relation to the differentiation of populations and species. RESULTS: The mean shapes differed significantly between sexes, populations, and species even though within-sex variation exceeded the divergence among populations. The first principal component of Procrustes shape coordinates revealed differences between populations and species in mouth position and ventral head shape. The second principal component reflected sex specific shape differences, mainly comprising a relatively larger female viscerocranium and, in particular, a larger buccal area. While shape variation between populations and between sexes was primarily located in the cranial region, within-sex variation was relatively uniform across all landmarks. CONCLUSIONS: Deviations of the between-population and between-sex pattern of shape variation from that within sex indicate that the differences in head shape likely result from both adaptations to female mouthbrooding and population specific foraging strategies. PMID- 20205753 TI - Neuromuscular development of Aeolidiella stephanieae Valdez, 2005 (Mollusca, Gastropoda, Nudibranchia). AB - BACKGROUND: Studies on the development of the nervous system and the musculature of invertebrates have become more sophisticated and numerous within the last decade and have proven to provide new insights into the evolutionary history of organisms. In order to provide new morphogenetic data on opisthobranch gastropods we investigated the neuromuscular development in the nudibranch Aeolidiella stephanieae Valdez, 2005 using immunocytochemistry as well as F-actin labelling in conjunction with confocal laser scanning microscopy (cLSM). RESULTS: The ontogenetic development of Aeolidiella stephanieae can be subdivided into 8 stages, each recognisable by characteristic morphological and behavioural features as well as specific characters of the nervous system and the muscular system, respectively. The larval nervous system of A. stephanieae includes an apical organ, developing central ganglia, and peripheral neurons associated with the velum, foot and posterior, visceral part of the larva. The first serotonergic and FMRFamidergic neural structures appear in the apical organ that exhibits an array of three sensory, flask-shaped and two non-sensory, round neurons, which altogether disappear prior to metamorphosis. The postmetamorphic central nervous system (CNS) becomes concentrated, and the rhinophoral ganglia develop together with the anlage of the future rhinophores whereas oral tentacle ganglia are not found. The myogenesis in A. stephanieae begins with the larval retractor muscle followed by the accessory larval retractor muscle, the velar or prototroch muscles and the pedal retractors that all together degenerate during metamorphosis, and the adult muscle complex forms de novo. CONCLUSIONS: Aeolidiella stephanieae comprises features of the larval and postmetamorphic nervous as well as muscular system that represent the ground plan of the Mollusca or even the Trochozoa (e. g. presence of the prototrochal or velar muscle ring). On the one hand, A. stephanieae shows some features shared by all nudibranchs like the postmetamorphic condensation of the CNS, the possession of rhinophoral ganglia and the lack of oral tentacle ganglia as well as the de novo formation of the adult muscle complex. On the other hand, the structure and arrangement of the serotonergic apical organ is similar to other caenogastropod and opisthobranch gastropods supporting their sister group relationship. PMID- 20205754 TI - Cerebrospinal fluid sodium rhythms. AB - BACKGROUND: Cerebrospinal fluid (CSF) sodium levels have been reported to rise during episodic migraine. Since migraine frequently starts in early morning or late afternoon, we hypothesized that natural sodium chronobiology may predispose susceptible persons when extracellular CSF sodium increases. Since no mammalian brain sodium rhythms are known, we designed a study of healthy humans to test if cation rhythms exist in CSF. METHODS: Lumbar CSF was collected every ten minutes at 0.1 mL/min for 24 h from six healthy participants. CSF sodium and potassium concentrations were measured by ion chromatography, total protein by fluorescent spectrometry, and osmolarity by freezing point depression. We analyzed cation and protein distributions over the 24 h period and spectral and permutation tests to identify significant rhythms. We applied the False Discovery Rate method to adjust significance levels for multiple tests and Spearman correlations to compare sodium fluctuations with potassium, protein, and osmolarity. RESULTS: The distribution of sodium varied much more than potassium, and there were statistically significant rhythms at 12 and 1.65 h periods. Curve fitting to the average time course of the mean sodium of all six subjects revealed the lowest sodium levels at 03.20 h and highest at 08.00 h, a second nadir at 09.50 h and a second peak at 18.10 h. Sodium levels were not correlated with potassium or protein concentration, or with osmolarity. CONCLUSION: These CSF rhythms are the first reports of sodium chronobiology in the human nervous system. The results are consistent with our hypothesis that rising levels of extracellular sodium may contribute to the timing of migraine onset. The physiological importance of sodium in the nervous system suggests that these rhythms may have additional repercussions on ultradian functions. PMID- 20205755 TI - The effects of practice distribution upon the regional oscillatory activity in visuomotor learning. AB - BACKGROUND: The aim of this study was to investigate the effects of a massed compared to a distributed practice upon visuomotor learning as well as upon the regional oscillatory activity in the sensorimotor cortex. METHODS: A continuous visuomotor tracking task was used to assess visuomotor learning; the underlying neuronal correlates were measured by means of EEG. The massed practice group completed a continuous training of 60 minutes, while the distributed practice group completed four 15 minutes practice blocks separated by rest intervals. RESULTS: While the massed and the distributed practice group did not differ in performance, effects of practice distribution were evident in the regional oscillatory activity. In the course of practice, the massed training group showed a higher task-related theta power and a strong task-related power decrease in the upper alpha frequency over the sensorimotor cortex compared to the distributed practice group. CONCLUSIONS: These differences in the regional oscillatory activity indicate a higher cognitive effort and higher attention demands in the massed practice group. The results of this study support the hypothesis, that a distributed practice is superior to a massed practice in visuomotor learning. PMID- 20205756 TI - Follicular thyroid carcinoma invades venous rather than lymphatic vessels. AB - Follicular thyroid carcinoma (FTC) tends to metastasize to remote organs rather than local lymph nodes. Separation of FTC from follicular thyroid adenoma (FTA) relies on detection of vascular and/or capsular invasion. We investigated which vascular markers, CD31, CD34 and D2-40 (lymphatic vessel marker), can best evaluate vascular invasion and why FTC tends to metastasize via blood stream to remote organs. Thirty two FTCs and 34 FTAs were retrieved for evaluation. The average age of patients with FTA was 8 years younger than FTC (p = 0.02). The female to male ratio for follicular neoplasm was 25:8. The average size of FTC was larger than FTA (p = 0.003). Fourteen of 32 (44%) FTCs showed venous invasion and none showed lymphatic invasion, with positive CD31 and CD34 staining and negative D2-40 staining of the involved vessels. The average number of involved vessels was 0.88 +/- 1.29 with a range from 0 to 5, and the average diameter of involved vessels was 0.068 +/- 0.027 mm. None of the 34 FTAs showed vascular invasion. CD31 staining demonstrated more specific staining of vascular endothelial cells than CD34, with less background staining. We recommended using CD31 rather than CD34 and/or D2-40 in confirming/excluding vascular invasion in difficult cases. All identified FTCs with vascular invasions showed involvement of venous channels, rather than lymphatic spaces, suggesting that FTCs prefer to metastasize via veins to distant organs, instead of lymphatic vessels to local lymph nodes, which correlates with previous clinical observations. PMID- 20205757 TI - Damaged-DNA Binding Protein-2 Drives Apoptosis Following DNA Damage. AB - Apoptosis induced by DNA damage is an important mechanism of tumor suppression and it is significant also in cancer chemotherapy. Mammalian cells activate the pathways of p53 to induce apoptosis of cells harboring irreparable DNA damages. While p53 induces expression of various pro-apoptotic genes and directly participates in the disruption of mitochondrial membrane polarization, it also increases expression of the cell cycle inhibitor p21 that is a dominant inhibitor of caspase-activation and apoptosis. Here we discuss how Damaged-DNA Binding Protein-2 (DDB2) subdues the level of p21 in cells harboring irreparable DNA damage to support activation of the caspases. We speculate a model in which DDB2 detects and couples the presence of un-repaired DNA damages to the proteolysis of p21, leading to the induction of apoptosis. PMID- 20205758 TI - Information exchange networks for chronic illness care in primary care practices: an observational study. AB - BACKGROUND: Information exchange networks for chronic illness care may influence the uptake of innovations in patient care. Valid and feasible methods are needed to document and analyse information exchange networks in healthcare settings. This observational study aimed to examine the usefulness of methods to study information exchange networks in primary care practices, related to chronic heart failure, diabetes and chronic obstructive pulmonary disease. METHODS: The study was linked to a quality improvement project in the Netherlands. All health professionals in the practices were asked to complete a short questionnaire that documented their information exchange relations. Feasibility was determined in terms of response rates and reliability in terms of reciprocity of reports of receiving and providing information. For each practice, a number of network characteristics were derived for each of the chronic conditions. RESULTS: Ten of the 21 practices in the quality improvement project agreed to participate in this network study. The response rates were high in all but one of the participating practices. For the analysis, we used data from 67 health professionals from eight practices. The agreement between receiving and providing information was, on average, 65.6%. The values for density, centralization, hierarchy, and overlap of the information exchange networks showed substantial variation between the practices as well as between the chronic conditions. The most central individual in the information exchange network could be a nurse or a physician. CONCLUSIONS: Further research is needed to refine the measure of information networks and to test the impact of network characteristics on the uptake of innovations. PMID- 20205759 TI - Transient basilar artery occlusion monitored by transcranial color Doppler presenting with a spectacular shrinking deficit: a case report. AB - INTRODUCTION: We describe the case of a 79-year-old Caucasian Italian woman with a transient basilar occlusion monitored by transcranial Doppler, with subsequent recanalization and clinical shrinking deficit. This is the first case of transient basilar occlusive disease diagnosed and monitored by transcranial Doppler. This case is important and needs to be reported because transient basilar occlusion may be easily diagnosed if transcranial Doppler is performed. CASE PRESENTATION: A 79-year-old woman affected by chronic atrial fibrillation and not treated with oral anticoagulants, cardioverted to sinus rhythm during a gastric endoscopy. She then showed a sudden-onset loss of consciousness, horizontal and vertical gaze palsy, tetraparesis and bilateral miosis and coma. Two hours later, the symptoms resolved quickly, leaving no residual neurologic deficits. Transcranial Doppler examination showed a dampened flow in the basilar artery in the emergency examination and a restored flow when the symptoms resolved. CONCLUSION: This is the first case of transient basilar occlusive disease diagnosed and monitored by transcranial Doppler. We believe that transcranial Doppler should be performed in all cases of unexplained acute loss of consciousness, in particular, if associated with signs of brainstem dysfunctions. PMID- 20205760 TI - Hodgkin's lymphoma presenting with heart failure: a case report. AB - INTRODUCTION: Cardiac involvement in malignant lymphoma is one of the least investigated subjects in oncology. This article reports a case of cardiac involvement in Hodgkin's lymphoma which presented as heart failure. CASE PRESENTATION: We report the case of an 8-year-old Afghan girl with Hodgkin's lymphoma. The disease presented with systemic signs and symptoms, including abdominal distension, weakness, pallor, chills, fever, generalized edema, hepatosplenomegaly and generalized lymphadenopathy, as well as signs of heart failure. Test results showed a rare form of heart metastasis. CONCLUSION: We report a case of Hodgkin's lymphoma with metastasis to the heart, detected premortem. Although the involvement of the heart in a malignancy is relatively common, premortem detection is unusual and only few studies have reported it in the literature. PMID- 20205761 TI - Non-puerperal uterine inversion due to submucous myoma in a young woman: a case report. AB - INTRODUCTION: Inversion of the uterus is an uncommon complication of the puerperium and it is an even rarer complication of the non-puerperal period. A submucous myoma is mostly the cause of the non-puerperal inversion but diagnosis can be difficult. In young women, non-puerperal uterine inversion is likely associated with a malignancy. CASE PRESENTATION: A 19-year-old nulliparous woman presented with abnormal vaginal bleeding, dysmenorrhoea, and a large mass protruding from her cervix. The mass was interpreted as a prolapsed pedunculated submucosal myoma. After extirpation of the mass by clamping and twisting its pedicle, a laparotomy was required under suspicion of a uterine rupture. The diagnosis was confirmed and the patient's uterus could be preserved. Pathological examination revealed a submucous myoma. The uterine inversion happened when the uterus retracted to expel the submucous myoma with fundal attachment. By extirpating the stalk the fundus was also resected, causing a uterine rupture. CONCLUSION: We report a case of non-puerperal uterine inversion associated with a benign submucous myoma. Non-puerperal uterine inversion is very uncommon in women of reproductive age and is usually caused by a malignant tumour. However, uterine sparing surgery should be attempted in young women until the final pathology is known. PMID- 20205762 TI - BglBricks: A flexible standard for biological part assembly. AB - BACKGROUND: Standard biological parts, such as BioBricks parts, provide the foundation for a new engineering discipline that enables the design and construction of synthetic biological systems with a variety of applications in bioenergy, new materials, therapeutics, and environmental remediation. Although the original BioBricks assembly standard has found widespread use, it has several shortcomings that limit its range of potential applications. In particular, the system is not suitable for the construction of protein fusions due to an unfavorable scar sequence that encodes an in-frame stop codon. RESULTS: Here, we present a similar but new composition standard, called BglBricks, that addresses the scar translation issue associated with the original standard. The new system employs BglII and BamHI restriction enzymes, robust cutters with an extensive history of use, and results in a 6-nucleotide scar sequence encoding glycine serine, an innocuous peptide linker in most protein fusion applications. We demonstrate the utility of the new standard in three distinct applications, including the construction of constitutively active gene expression devices with a wide range of expression profiles, the construction of chimeric, multi-domain protein fusions, and the targeted integration of functional DNA sequences into specific loci of the E. coli genome. CONCLUSIONS: The BglBrick standard provides a new, more flexible platform from which to generate standard biological parts and automate DNA assembly. Work on BglBrick assembly reactions, as well as on the development of automation and bioinformatics tools, is currently underway. These tools will provide a foundation from which to transform genetic engineering from a technically intensive art into a purely design-based discipline. PMID- 20205764 TI - A rare case of pulmonary tuberculosis with simultaneous pulmonary and skin sarcoidosis: a case report. AB - BACKGROUND: Tuberculosis and sarcoidosis are chronic diseases that rarely occur concomitantly. Sarcoidosis is a multisystem granulomatous disorder characterized pathologically by the presence of non-caseating granulomas in involved tissues. Tuberculosis is infectious disease caused by Mycobacterium tuberculosis characterized by granulomas with caseous necrosis. CASE PRESENTATION: We present a case of 43-year-old female refugee from Kosovo with microbiological confirmation of pulmonary tuberculosis and pulmonary and skin sarcoidosis at the same time. Three weeks after corticosteroid therapy for pulmonary sarcoidosis was introduced, positive finding of mycobacterium culture of bronchial aspirate was observed. Based on these results, corticosteroid therapy was excluded and antituberculous therapy was introduced for six months. In the meantime, new nodes on face and nose appeared and skin sarcoidosis was diagnosed. The patient was given corticosteroids and colchicine according to the skin and pulmonary sarcoidosis therapy recommendation. CONCLUSION: The authors of this study suggest that in cases when there is a dilemma in diagnosis between tuberculosis and sarcoidosis we should advance with corticosteroid therapy until we have microbiological confirmation of mycobacterium culture. This case is remarkable because this is a third described case of sarcoidosis and tuberculosis together (the first reported in Asia, the second in South Africa), and to authors knowledge, this is a first case report in Europe. PMID- 20205763 TI - DREAM (downstream regulatory element antagonist modulator) contributes to synaptic depression and contextual fear memory. AB - The downstream regulatory element antagonist modulator (DREAM), a multifunctional Ca2+-binding protein, binds specifically to DNA and several nucleoproteins regulating gene expression and with proteins outside the nucleus to regulate membrane excitability or calcium homeostasis. DREAM is highly expressed in the central nervous system including the hippocampus and cortex; however, the roles of DREAM in hippocampal synaptic transmission and plasticity have not been investigated. Taking advantage of transgenic mice overexpressing a Ca2+ insensitive DREAM mutant (TgDREAM), we used integrative methods including electrophysiology, biochemistry, immunostaining, and behavior tests to study the function of DREAM in synaptic transmission, long-term plasticity and fear memory in hippocampal CA1 region. We found that NMDA receptor but not AMPA receptor mediated current was decreased in TgDREAM mice. Moreover, synaptic plasticity, such as long-term depression (LTD) but not long-term potentiation (LTP), was impaired in TgDREAM mice. Biochemical experiments found that DREAM interacts with PSD-95 and may inhibit NMDA receptor function through this interaction. Contextual fear memory was significantly impaired in TgDREAM mice. By contrast, sensory responses to noxious stimuli were not affected. Our results demonstrate that DREAM plays a novel role in postsynaptic modulation of the NMDA receptor, and contributes to synaptic plasticity and behavioral memory. PMID- 20205765 TI - Synchronous testicular liposarcoma and prostate adenocarcinoma: a case report. AB - Prostate adenocarcinoma is the most common malignancy and the second leading cause of cancer related deaths in men. Testicular liposarcomas are uncommon soft tissue neoplasms. We report coexistence of prostate cancer and testicular liposarcoma in a 69 year-old-man because while orchiectomy endications are decreasing day by day, these second malignancies should not be missed. PMID- 20205766 TI - Perforating eyelid injury extending to the brain stem in a 17-year-old woman: a case report. AB - INTRODUCTION: This case report describes a patient who had a perforating eyelid injury that extended to the brain stem. CASE PRESENTATION: A 17-year-old Japanese woman complained of decreased vision in her right eye, with severe ocular pain and headaches, after the metal tip of an umbrella struck her upper right eyelid accidentally. Her vision in the right eye decreased to light perception with commotio retinae, intraretinal hemorrhage, and severe lid swelling. Magnetic resonance imaging (MRI) demonstrated edema of the head of the caudate nucleus and putamen, and the edema extended to the hypothalamus. The MRI findings indicated that the umbrella tip had penetrated through the eyelid and the posterior orbital wall. Vision improved to 20/50 in the right eye, with subretinal fibrosis caused by the choroidal rupture. CONCLUSIONS: We recommend that MRI be performed on the orbit and brain in patients who appear to have symptoms that are inconsistent with the observed injury and when a severe orbitocranial injury is suspected. PMID- 20205767 TI - Endometriosis-associated ovarian cancer: A ten-year cohort study of women living in the Estrie Region of Quebec, Canada. AB - OBJECTIVES: Endometriosis has been believed to increase the risk of developing ovarian cancer, but recent data supporting this hypothesis are lacking. The aim of this study was to verify whether the incidence of endometriosis, ovarian cancer and the both increased during the last 10 years among women living in the Estrie region of Quebec. METHODS: We collected data of women diagnosed with endometriosis, ovarian cancer or both, between 1997 and 2006, from a population living in the Estrie region of Quebec. We performed this retrospective cross sectional study from the CIRESSS (Centre Informatise de Recherche Evaluative en Services et Soins de Sante) system, the database of the CHUS (Centre Hospitalier Universitaire of Sherbrooke), Sherbrooke, Canada. RESULTS: Among the 2854 identified patients, 2521 had endometriosis, 292 patients had ovarian cancer and 41 patients had both ovarian cancer and endometriosis. We showed a constant increase in the number of ovarian cancer (OC) between 1997 and 2006 (r2 = 0.557, P = 0.013), which is not the case for endometriosis (ENDO) or endometriosis associated ovarian cancer (EAOC). The mean age +/- SD was 40.0 +/- 9.9 and 53.9 +/- 11.4 for patients having ENDO and OC, respectively. Mean age of women with EAOC was 48.3 +/- 10.8, suggesting an early onset of ovarian cancer in women having endometriosis of about 5.5 years average, P = 0.003. Women with ENDO were at increased risk for developing OC (Rate Ratio [RR] = 1.6; 95% Confidence Interval [CI] = 1.12-2.09). Pathological analyses showed the predominance of endometrioid type (24.4%) and clear-cell type (21.9%) types in EAOC compared to OC, P = 0.0070 and 0.0029, respectively. However, the serous type is the most widespread in OC (44.5%) in comparison to EAOC (19.51%), P = 0.0023. CONCLUSION: Our findings highlight that the number of cases of ovarian cancer is constantly increasing in the last ten years and that endometriosis represents a serious risk factor which accelerates its apparition by about 5.5 years. PMID- 20205768 TI - Highly active antiretroviral treatment for the prevention of HIV transmission. AB - In 2007 an estimated 33 million people were living with HIV; 67% resided in sub Saharan Africa, with 35% in eight countries alone. In 2007, there were about 1.4 million HIV-positive tuberculosis cases. Globally, approximately 4 million people had been given highly active antiretroviral therapy (HAART) by the end of 2008, but in 2007, an estimated 6.7 million were still in need of HAART and 2.7 million more became infected with HIV.Although there has been unprecedented investment in confronting HIV/AIDS - the Joint United Nations Programme on HIV/AIDS estimates $13.8 billion was spent in 2008 - a key challenge is how to address the HIV/AIDS epidemic given limited and potentially shrinking resources. Economic disparities may further exacerbate human rights issues and widen the increasingly divergent approaches to HIV prevention, care and treatment.HIV transmission only occurs from people with HIV, and viral load is the single greatest risk factor for all modes of transmission. HAART can lower viral load to nearly undetectable levels. Prevention of mother to child transmission offers proof of the concept of HAART interrupting transmission, and observational studies and previous modelling work support using HAART for prevention. Although knowing one's HIV status is key for prevention efforts, it is not known with certainty when to start HAART.Building on previous modelling work, we used an HIV/AIDS epidemic of South African intensity to explore the impact of testing all adults annually and starting persons on HAART immediately after they are diagnosed as HIV positive. This theoretical strategy would reduce annual HIV incidence and mortality to less than one case per 1000 people within 10 years and it would reduce the prevalence of HIV to less than 1% within 50 years. To explore HAART as a prevention strategy, we recommend further discussions to explore human rights and ethical considerations, clarify research priorities and review feasibility and acceptability issues. PMID- 20205769 TI - Non-traumatic fractures following seizures: two case reports. AB - INTRODUCTION: Seizures with or without trauma may cause fractures that occur commonly in epileptic seizures. Fracture risk is less reported in non-epileptic seizures. Some metabolic conditions leading to a decrease in bone mineral density may cause fractures secondary to non-epileptic seizure. CASE PRESENTATION: We describe two cases of non-traumatic acetabular and vertebrae fractures following seizures without history of epilepsy. They occurred in two male patients, 18 and 48 years old suffering respectively from hypercorticism and poorly controlled diabetes mellitus. Seizures, occurring inside hospital, were secondary to hypertensive encephalopathy crisis with hypokaliemia in the first case and severe hypoglycaemia in the second one. Fracture was promoted by a decrease in mineral bone density caused respectively by hypercorticism and diabetic chronic renal failure. CONCLUSION: These observations emphasize that fracture prevention among patients with decreased mineral bone density should include the avoidance of metabolic causes of seizure. PMID- 20205770 TI - A case of aspergillus endophthalmitis in an immuncompetent woman: intra-ocular penetration of oral voriconazole: a case report. AB - BACKGROUND: There are very few reports of Aspergillus fumigatus causing endogenous endophthalmitis (EAE) in immunocompetent individuals although it is well recognised in the immunocompromised. Treatment can be with intravitreal, intravenous and oral antifungal agents. The benefit of an oral agent is clear however the concentration of voriconazole in the inflamed eye after oral administration has not previously been documented. CASE PRESENTATION: We present a case of EAE in an immunocompetent 78-year-old Caucasian female who was subsequently managed with oral voriconazole. Using a bioassay, we show an appropriate voriconazole concentration in serum and vitreous samples. CONCLUSION: This case adds to the limited literature on the prevalence of endogenous endophthalmitis in immunocompetent patients and supports the use of voriconazole in such cases. PMID- 20205771 TI - Creatine-induced activation of antioxidative defence in myotube cultures revealed by explorative NMR-based metabonomics and proteomics. AB - BACKGROUND: Creatine is a key intermediate in energy metabolism and supplementation of creatine has been used for increasing muscle mass, strength and endurance. Creatine supplementation has also been reported to trigger the skeletal muscle expression of insulin like growth factor I, to increase the fat free mass and improve cognition in elderly, and more explorative approaches like transcriptomics has revealed additional information. The aim of the present study was to reveal additional insight into the biochemical effects of creatine supplementation at the protein and metabolite level by integrating the explorative techniques, proteomics and NMR metabonomics, in a systems biology approach. METHODS: Differentiated mouse myotube cultures (C2C12) were exposed to 5 mM creatine monohydrate (CMH) for 24 hours. For proteomics studies, lysed myotubes were analyzed in single 2-DGE gels where the first dimension of protein separation was pI 5-8 and second dimension was a 12.5% Criterion gel. Differentially expressed protein spots of significance were excised from the gel, desalted and identified by peptide mass fingerprinting using MALDI-TOF MS. For NMR metabonomic studies, chloroform/methanol extractions of the myotubes were subjected to one-dimensional 1H NMR spectroscopy and the intracellular oxidative status of myotubes was assessed by intracellular DCFH2 oxidation after 24 h pre incubation with CMH. RESULTS: The identified differentially expressed proteins included vimentin, malate dehydrogenase, peroxiredoxin, thioredoxin dependent peroxide reductase, and 75 kDa and 78 kDa glucose regulated protein precursors. After CMH exposure, up-regulated proteomic spots correlated positively with the NMR signals from creatine, while down-regulated proteomic spots were negatively correlated with these NMR signals. The identified differentially regulated proteins were related to energy metabolism, glucose regulated stress, cellular structure and the antioxidative defence system. The suggested improvement of the antioxidative defence was confirmed by a reduced intracellular DCFH2 oxidation with increasing concentrations of CMH in the 24 h pre-incubation medium. CONCLUSIONS: The explorative approach of this study combined with the determination of a decreased intracellular DCFH2 oxidation revealed an additional stimulation of cellular antioxidative mechanisms when myotubes were exposed to CMH. This may contribute to an increased exercise performance mediated by increased ability to cope with training-induced increases in oxidative stress. PMID- 20205772 TI - Semantic Web for data harmonization in Chinese medicine. AB - Scientific studies to investigate Chinese medicine with Western medicine have been generating a large amount of data to be shared preferably under a global data standard. This article provides an overview of Semantic Web and identifies some representative Semantic Web applications in Chinese medicine. Semantic Web is proposed as a standard for representing Chinese medicine data and facilitating their integration with Western medicine data. PMID- 20205773 TI - Melanotic oncocytic metaplasia of the nasopharynx as a benign mimicker of malignant melanoma: a case report. AB - INTRODUCTION: Melanotic variant of oncocytic metaplasia of the nasopharynx is an extremely rare condition. CASE REPORT: A 73-year-old Japanese man presented with nasal congestion and chill. Nasoscopic examination revealed multiple black nodules around the bilateral torus tubarius. The nodules were biopsied to determine the histology. The clinical differential diagnosis was malignant melanoma or hemangioma. Microscopically, there were oncocytic plump cells with abundant brown pigmented granules showing glandular pattern. No significant atypia was found. The pigment was positive for Fontana-Masson staining, and negative for Berlin blue staining, showing that it was melanin pigment. Immunohistochemically, S100-positive HMB45-negative dendritic cells were also found. CONCLUSION: Such a pigmented variant of benign oncocytic lesion is very rare, and only 15 cases have been reported in the English literature. As a benign mimicker of malignant melanoma, melanocytic oncocytic metaplasia should be always taken into consideration in the clinical setting. PMID- 20205774 TI - Pancreatic intraductal papillary mucinous neoplasm with concomitant heterotopic pancreatic cystic neoplasia of the stomach: a case report and review of the literature. AB - A 60-year-old Caucasian male underwent a total pancreatectomy for a mixed type pancreatic intraductal papillary mucinous neoplasm (IPMN) arising in the main and secondary pancreatic ducts. During surgery, a subserosal polypoid mass was noted at the greater curvature of the gastric antrum and was enucleated. This mass was proven to be heterotopic pancreatic tissue with cystic neoplasia of the IPMN histologic subtype. Through an extensive search of the literature, we found that this is the first case ever reported with simultaneous existence of IPMN changes, in the main and secondary ducts of the orthotopic pancreas and in the heterotopic pancreatic tissue of the gastric wall. PMID- 20205775 TI - Identification of tissue of origin in carcinoma of unknown primary with a microarray-based gene expression test. AB - BACKGROUND: Carcinomas of unknown primary (CUP) represent approximately 3%-5% of malignant neoplasms. Identifying the tissue of origin (TOO) in these tumors allows for more specific treatment and improves outcomes. However, primary classification remains a challenge in many cases. We evaluated the ability of a microarray-based gene expression test to identify the TOO in tumor specimens from 21 patients with a diagnosis of CUP. METHODS: The Pathwork TOO Test was used to measure gene expression patterns for 1550 genes; these were compared for similarity to patterns from 15 known tissue types. RESULTS: The TOO Test yielded a clear single positive call for the primary site in 16 of 21 (76%) specimens and was indeterminate in 5 (24%). The positive results were consistent with clinicopathologic suggestions in 10 of the 16 cases (62%). In the remaining six cases the positive results were considered plausible based on clinical information. Positive calls included colorectal (5), breast (4), ovarian (3), lung (2), and pancreas (2). The TOO Test ruled out an average of 11 primary tissues in each CUP specimen. CONCLUSION: The Pathwork TOO Test reduced diagnostic uncertainty in all CUP cases and could be a valuable addition or alternative to current diagnostic methods for classifying uncertain primary cancers. PMID- 20205777 TI - Practice nurses' workload, career intentions and the impact of professional isolation: A cross-sectional survey. AB - BACKGROUND: Practice nurses have a key role within UK general practice, especially since the 2004 GMS contract. This study aimed to describe that role, identify how professionally supported they felt and their career intentions. An additional aim was to explore whether they felt isolated and identify contributory factors. METHODS: A cross-sectional questionnaire survey in one large urban Scottish Health Board, targeted all practice nurses (n = 329). Domains included demographics, workload, training and professional support. Following univariate descriptive statistics, associations between categorical variables were tested using the chi-square test or chi-square test for trend; associations between dichotomous variables were tested using Fisher's Exact test. Variables significantly associated with isolation were entered into a binary logistic regression model using backwards elimination. RESULTS: There were 200 responses (61.0% response rate). Most respondents were aged 40 or over and were practice nurses for a median of 10 years. Commonest clinical activities were coronary heart disease management, cervical cytology, diabetes and the management of chronic obstructive pulmonary disease. Although most had a Personal Development Plan and a recent appraisal, 103 (52.3%) felt isolated at least sometimes; 30 (15.5%) intended leaving practice nursing within 5 years.Isolated nurses worked in practices with smaller list sizes (p = 0.024) and nursing teams (p = 0.003); were less likely to have someone they could discuss a clinical/professional (p = 0.002) or personal (p < 0.001) problem with; used their training and qualifications less (p < 0.001); had less productive appraisals (p < 0.001); and were less likely to intend staying in practice nursing (p = 0.009). Logistic regression analysis showed that nurses working alone or in teams of two were 6-fold and 3.5-fold more likely to feel isolated. Using qualifications and training to the full, having productive appraisals and planning to remain in practice nursing all mitigated against feeling isolated. CONCLUSIONS: A significant proportion of practice nurses reported feeling isolated, at least some of the time. They were more likely to be in small practices and more likely to be considering leaving practice nursing. Factors contributing to their isolation were generally located within the practice environment. Providing support to these nurses within their practice setting may help alleviate the feelings of isolation, and could reduce the number considering leaving practice nursing. PMID- 20205776 TI - Equity of access to cardiac rehabilitation: the role of system factors. AB - BACKGROUND: When patient selection processes determine who can and cannot use healthcare there can be inequalities and inequities in individuals' opportunities to benefit. This paper evaluates the influence of a hospital selection process on opportunities to access outpatient cardiac rehabilitation (CR). METHODS: A secondary data analysis was conducted on a cohort of inpatients (n = 2,375) who were all eligible for invitation to an Australian CR program. Eligibility was determined by hospital discharge diagnosis codes. Only invited patients could attend. Logistic regression analysis tested the extent to which individual patient characteristics were statistically significantly associated with the outcome 'invitation' after adjusting for cardiac disease and other factors. RESULTS: Less than half of the eligible patients were invited to the CR program. After allowing for known factors that may have justified not being selected, there was bias towards inviting males, younger patients, married patients, and patients who nominated English as their preferred language. CONCLUSIONS: Health service managers typically monitor service utilisation patterns as indicators of access but often pay little attention to ways in which locally determined system factors influence access to care. The paper shows how a hospital selection process can unreasonably influence patients' opportunities to benefit from an evidence-based healthcare program. PMID- 20205778 TI - What "best practice" could be in Palliative Care: an analysis of statements on practice and ethics expressed by the main Health Organizations. AB - BACKGROUND: In palliative care it would be necessary to refer to a model. Nevertheless it seems that there are no official statements which state and describe that model. We carried out an analysis of the statements on practice and ethics of palliative care expressed by the main health organizations to show which dimensions of end-of-life care are taken into consideration. METHODS: The official documents by the most representative health organisations committed to the definition of policies and guidelines for palliative and end-of-life care had been considered. The documents were analysed through a framework of the components of end-of-life care derived from literature, which was composed of 4 main "areas" and of 12 "sub-areas". RESULTS: Overall, 34 organizations were identified, 7 international organisations, and 27 organisations operating on the national level in four different countries (Australia, Canada, UK and United States). Up to 56 documents were selected and analysed. Most of them (38) are position statements. Relevant quotations from the documents were presented by "areas" and "sub-areas". In general, the "sub-areas" of symptoms control as well as those referring to relational and social issues are more widely covered by the documents than the "sub-areas" related to "preparation" and to "existential condition". Indeed, the consistency of end-of-life choices with the patient's wishes, as well as completion and meaningfulness at the end of life is given only a minor relevance. CONCLUSIONS: An integrated model of the best palliative care practice is generally lacking in the documents. It might be argued that the lack of a fixed and coherent model is due to the relevance of unavoidable context issues in palliative care, such as specific cultural settings, patient-centred variables, and family specificity. The implication is that palliative care staff have continuously to adapt their model of caring to the specific needs and values of each patient, more than applying a fixed, although maybe comprehensive, care model. PMID- 20205779 TI - Correlating lesion size and location to deficits after ischemic stroke: the influence of accounting for altered peri-necrotic tissue and incidental silent infarcts. AB - BACKGROUND: Investigators frequently quantify and evaluate the location and size of stroke lesions to help uncover cerebral anatomical correlates of deficits observed after first-ever stroke. However, it is common to discover silent infarcts such as lacunes in patients identified clinically as 'first-ever' stroke, and it is unclear if including these incidental findings may impact lesion-based investigations of brain-behaviour relationships. There is also debate concerning how to best define the boundaries of necrotic stroke lesions that blend in an ill-defined way into surrounding tissue, as it is unclear whether including this altered peri-necrotic tissue region may influence studies of brain-behaviour relationships. Therefore, for patients with clinically overt stroke, we examined whether including altered peri-necrotic tissue and incidental silent strokes influenced either lesion volume correlations with a measure of sensorimotor impairment or the anatomical localization of this impairment established using subtraction lesion analysis. METHODS: Chronic stroke lesions of 41 patients were manually traced from digital T1-MRI to sequentially include the: necrotic lesion core, altered peri-necrotic tissue, silent lesions in the same hemisphere as the index lesion, and silent lesions in the opposite hemisphere. Lesion volumes for each region were examined for correlation with motor impairment scores, and subtraction analysis was used to highlight anatomical lesion loci associated with this deficit. RESULTS: For subtraction lesion analysis, including peri-necrotic tissue resulted in a larger region of more frequent damage being seen in the basal ganglia. For correlational analysis, only the volume of the lesion core was significantly associated with motor impairment scores (r = -0.35, p = 0.025). In a sub-analysis of patients with small subcortical index lesions, adding silent lesions in the opposite hemisphere to the volume of the index stroke strengthened the volume-impairment association. CONCLUSIONS: Including peri-necrotic tissue strengthened lesion localization analysis, but the influence of peri-necrotic tissue and incidental lesions on lesion volume correlations with motor impairment was negligible barring a small index lesion. Overall, the potential influence of incidental lesions and peri necrotic tissue on brain-behaviour relationships may depend on the characteristics of the index stroke and on whether one is examining the relationship between lesion volume and impairment or lesion location and impairment. PMID- 20205780 TI - Toxic environment and obesity pandemia: is there a relationship? AB - Obesity is a multi-factorial disease, resulting from genes, environment and behaviour interactions, and represents the most common metabolic disorder in the Western Hemisphere. Its prevalence has dramatically risen during the last three decades, reaching worldwide epidemic proportions. Recent cumulating evidence suggests that obesity may represent an adverse health consequence of exposure during the critical developmental windows to environmental chemicals disrupting endocrine function. Moreover, exposure to these chemicals seems to play a key role in the development of obesity-related metabolic and cardiovascular diseases. Further research is needed to elucidate the relationship between this exposure and the obesity pandemia and the involved mechanisms as well as to refine hazard identification. PMID- 20205781 TI - Cow's milk protein allergy in children: a practical guide. AB - A joint study group on cow's milk allergy was convened by the Emilia-Romagna Working Group for Paediatric Allergy and by the Emilia-Romagna Working Group for Paediatric Gastroenterology to focus best practice for diagnosis, management and follow-up of cow's milk allergy in children and to offer a common approach for allergologists, gastroenterologists, general paediatricians and primary care physicians.The report prepared by the study group was discussed by members of Working Groups who met three times in Italy. This guide is the result of a consensus reached in the following areas. Cow's milk allergy should be suspected in children who have immediate symptoms such as acute urticaria/angioedema, wheezing, rhinitis, dry cough, vomiting, laryngeal edema, acute asthma with severe respiratory distress, anaphylaxis. Late reactions due to cow's milk allergy are atopic dermatitis, chronic diarrhoea, blood in the stools, iron deficiency anaemia, gastroesophageal reflux disease, constipation, chronic vomiting, colic, poor growth (food refusal), enterocolitis syndrome, protein losing enteropathy with hypoalbuminemia, eosinophilic oesophagogastroenteropathy. An overview of acceptable means for diagnosis is included. According to symptoms and infant diet, three different algorithms for diagnosis and follow-up have been suggested. PMID- 20205782 TI - Could pre-diabetes be considered a clinical condition? opinions from an endocrinologist and a cardiologist. AB - The prevalence of pre-diabetes is increasing worldwide and may start 7 to 10 years before the clinical diagnosis of diabetes. In this stage the presence and accumulation of risk factors is common and already implies an increase in cardiovascular risk. Likewise, the onset of cardiovascular diseases (CVD), mainly coronary artery disease (CAD), peripheral vascular disease and cerebrovascular disease can also take place, all of which account for high rates of morbidity and mortality worldwide. Considering pre-diabetes as a clinical entity, non pharmacological and pharmacological treatments are indicated with drugs which have shown clinical benefits related to reduction in morbidity and mortality. However, there is still need for new long-term studies to assess the real benefits of several new therapeutical approaches, as well as its cost effectiveness. PMID- 20205783 TI - Paraganglioma of the endolarynx: a rare tumor in an uncommon location. AB - BACKGROUND: Less than 80 reported cases of paragangliomas of the larynx are reported in the literature. A role for external beam radiation in this disease has not yet been explored. We present four cases of laryngeal paragangliomas treated at a large tertiary-care cancer center over a 35-year period. METHODS: 124 cases of head and neck paragangliomas treated at a single institution from 1970 to 2005 were retrospectively studied. Patients with laryngeal paragangliomas were identified, and a comprehensive clinico-pathological review was undertaken. RESULTS: We identified 4 patients with tumors arising in the larynx at the following subsites: supraglottis (2), glottis (1), and subglottis (1). Three patients were treated with surgery and one with definitive radiation alone. CONCLUSIONS: Laryngeal paragangliomas are rare tumors and are adequately treated with surgical resection. We also present one patient who was treated with radiation and had disease stabilization. Accurate histological classification is critical, and the role of genetic testing is emerging. PMID- 20205784 TI - HIV-related restrictions on entry, residence and stay in the WHO European Region: a survey. AB - BACKGROUND: Back in 1987, the World Health Organization (WHO) concluded that the screening of international travellers was an ineffective way to prevent the spread of HIV. However, some countries still restrict the entrance and/or residency of foreigners with an HIV infection. HIV-related travel restrictions have serious implications for individual and public health, and violate internationally recognized human rights. In this study, we reviewed the current situation regarding HIV-related travel restrictions in the 53 countries of the WHO European Region. METHODS: We retrieved the country-specific information chiefly from the Global Database on HIV Related Travel Restrictions at hivtravel.org. We simplified and standardized the database information to enable us to create an overview and compare countries. Where data was outdated, unclear or contradictory, we contacted WHO HIV focal points in the countries or appropriate non-governmental organizations. The United States Bureau of Consular Affairs website was also used to confirm and complement these data. RESULTS: Our review revealed that there are no entry restrictions for people living with HIV in 51 countries in the WHO European Region. In 11 countries, foreigners living with HIV applying for long-term stays will not be granted a visa. These countries are: Andorra, Armenia, Cyprus (denies access for non-European Union citizens), Hungary, Kazakhstan, Moldova, the Russian Federation, Tajikistan, Turkmenistan, Ukraine and Uzbekistan. In Uzbekistan, an HIV-positive foreigner cannot even enter the country, and in Georgia, we were not able to determine whether there were any HIV-related travel restrictions due to a lack of information. CONCLUSIONS: In 32% of the countries in the European Region, either there are some kind of HIV-related travel restrictions or we were unable to determine if such restrictions are in force. Most of these countries defend restrictions as being justified by public health concerns. However, there is no evidence that denying HIV-positive foreigners access to a country is effective in protecting public health. Governments should revise legislation on HIV-related travel restrictions. In the meantime, a joint effort is needed to draw attention to the continuing discrimination and stigmatization of people living with HIV that takes place in those European Region countries where such laws and policies are still in force. PMID- 20205785 TI - Pattern and management of sports injuries presented by Lagos state athletes at the 16th National Sports Festival (KADA games 2009) in Nigeria. AB - BACKGROUND: There is a dearth of information on the epidemiology of sports injuries in Nigeria. The study was aimed at documenting sports injuries sustained by Lagos state athletes during the 16th National Sports Festival (KADA Games 2009). It was also aimed at providing information on treatments offered to injured athletes. METHODS: The study was carried out at Amadu Bello Stadium Complex, sporting arena of the Murtala Square and the team Lagos mini clinic. Participants were accredited Lagos state athletes who at one point in time during the games required treatment from any of the members of the medical team. Demographic data of athletes, type of injuries, body parts injured and treatment modalities used were documented and analysed using descriptive statistics. RESULTS: Within the period of the games, a total of 140 sports injuries were documented from 132 athletes with an approximate male to female ratio of 2:1 and age ranging from 15-38 years. Most of the injuries reported by the athletes were "minor" injuries. Muscle strain was the most common type of injury (31.4%) followed by ligament sprains (22.9%). The lower extremities were the most injured body region accounting for 50% of all injuries. Over 60% of injuries presented by the athletes were from basketball, cricket, hockey, rugby and baseball. Cryotherapy was the most frequently used treatment modality, followed by bandaging and massage with anti-inflammatory gels. CONCLUSION: Establishing injury prevention programmes directed at the lower extremities may help reduce the risk of injuries to the lower extremities. Since cryotherapy was the most used treatment modality, it is suggested that it should be made abundantly available to the medical team preferably in forms of portable cold sprays for easy transportation and application during the games. It is also important that physiotherapists form the core of the medical team since they are trained to apply most of these treatment modalities and they also play a major role in establishing injury prevention routines. This data provides information that will be useful to both state and federal medical teams in preparing for future games. PMID- 20205786 TI - Oral candidiasis in Chikungunya viral fever: a case report. AB - A 32 year old Indian male patient presented with chief complaints of a high fever, erythema on ear, severe polyarthritic joint pains & swelling, non pitting pedal oedema, facial puffiness and itching for past four days. He had no significant past medical and drug history and was serologically confirmed to have Chikungunya. Oral cavity inspection revealed whitish non erythematous pseudo membranous plaques on the hard palate, buccal surface of cheek and the floor of the mouth which was later microbiologically confirmed as Candidiasis. He tested negative for HIV and had leucopenia with severe CD4 T-lymphocytopenia. This is the first report of an opportunistic infection with CD4 T-lymphocytopaenia in Chikungunya fever. PMID- 20205787 TI - Processing of Agilent microRNA array data. AB - BACKGROUND: The Agilent microRNA microarray platform interrogates each microRNA with several copies of distinct oligonucleotide probes and integrates the results into a total gene signal (TGS), using a proprietary algorithm that makes use of the background subtracted signal. The TGS can be normalized between arrays, and the Agilent recommendation is either not to normalize or to normalize to the 75th percentile signal intensity. The robust multiarray average algorithm (RMA) is an alternative method, originally developed to obtain a summary measure of mRNA Affymetrix gene expression arrays by using a linear model that takes into account the probe affinity effect. The RMA method has been shown to improve the accuracy and precision of expression measurements relative to other competing methods. There is also evidence that it might be preferable to use non-corrected signals for the processing of microRNA data, rather than background-corrected signals. In this study we assess the use of the RMA method to obtain a summarized microRNA signal for the Agilent arrays. FINDINGS: We have adapted the RMA method to obtain a processed signal for the Agilent arrays and have compared the RMA summarized signal to the TGS generated with the image analysis software provided by the vendor. We also compared the use of the RMA algorithm with uncorrected and background-corrected signals, and compared quantile normalization with the normalization method recommended by the vendor. The pre-processing methods were compared in terms of their ability to reduce the variability (increase precision) of the signals between biological replicates. Application of the RMA method to non-background corrected signals produced more precise signals than either the RMA-background-corrected signal or the quantile-normalized Agilent TGS. The Agilent TGS normalized to the 75% percentile showed more variation than the other measures. CONCLUSIONS: Used without background correction, a summarized signal that takes into account the probe effect might provide a more precise estimate of microRNA expression. The variability of quantile normalization was lower compared with the normalization method recommended by the vendor. PMID- 20205788 TI - Haemoptysis in pregnancy caused by a well-differentiated fetal adenocarcinoma: a case report. AB - INTRODUCTION: Haemoptysis in pregnancy is frequently assumed to be caused by a pulmonary embolism. However, it can also be an indicator of serious pathology. CASE PRESENTATION: We report the case of a 27-year-old Caucasian woman who presented with haemoptysis in pregnancy that was discovered to be caused by a well-differentiated fetal adenocarcinoma of the lung. CONCLUSION: This case demonstrates the importance of establishing an accurate diagnosis when a pregnant woman presents with haemoptysis and that more serious pathology should be considered if the clinical symptoms persist and/or the presumed diagnosis of pulmonary embolism is not confirmed. PMID- 20205789 TI - Wnt-5a occludes Abeta oligomer-induced depression of glutamatergic transmission in hippocampal neurons. AB - BACKGROUND: Soluble amyloid-beta (Abeta;) oligomers have been recognized to be early and key intermediates in Alzheimer's disease (AD)-related synaptic dysfunction. Abeta oligomers block hippocampal long-term potentiation (LTP) and impair rodent spatial memory. Wnt signaling plays an important role in neural development, including synaptic differentiation. RESULTS: We report here that the Wnt signaling activation prevents the synaptic damage triggered by Abeta oligomers. Electrophysiological analysis of Schaffer collaterals-CA1 glutamatergic synaptic transmission in hippocampal slices indicates that Wnt-5a increases the amplitude of field excitatory postsynaptic potentials (fEPSP) and both AMPA and NMDA components of the excitatory postsynaptic currents (EPSCs), without modifying the paired pulse facilitation (PPF). Conversely, in the presence of Abeta oligomers the fEPSP and EPSCs amplitude decreased without modification of the PPF, while the postsynaptic scaffold protein (PSD-95) decreased as well. Co-perfusion of hippocampal slices with Wnt-5a and Abeta oligomers occludes against the synaptic depression of EPSCs as well as the reduction of PSD-95 clusters induced by Abeta oligomers in neuronal cultures. Taken together these results indicate that Wnt-5a and Abeta oligomers inversely modulate postsynaptic components. CONCLUSION: These results indicate that post synaptic damage induced by Abeta oligomers in hippocampal neurons is prevented by non-canonical Wnt pathway activation. PMID- 20205791 TI - Overview of a formal scoping review on health system report cards. AB - BACKGROUND: There is an extensive body of literature on health system quality reporting that has yet to be characterized. Scoping is a novel methodology for systematically assessing the breadth of a body of literature in a particular research area. Our objectives were to showcase the scoping review methodology in the review of health system quality reporting, and to report on the extent of the literature in this area. METHODS: A scoping review was performed based on the York methodology outlined by Arksey and O'Malley from the University of York, United Kingdom. We searched 14 peer reviewed and grey literature databases limiting the search to English language and non-English language articles with English abstracts published between 1980 and June 2006 with an update to November 2008. We also searched specific websites, reference lists, and key journals for relevant material and solicited input from key stakeholders. Inclusion/exclusion criteria were applied to select relevant material and qualitative information was charted from the selected literature. RESULTS: A total of 10,102 articles were identified from searching the literature databases, 821 were deemed relevant to our scoping review. An additional 401 were identified from updates, website searching, references lists, key journals, and stakeholder suggestions for a total of 1,222 included articles. These were categorized and catalogued according to the inclusion criteria, and further subcategories were identified through the charting process. Topic areas represented by this review included the effectiveness of health system report cards (n = 194 articles), methodological issues in their development (n = 815 articles), stakeholder views on report cards (n = 144 articles), and ethical considerations around their development (n = 69 articles). CONCLUSIONS: The scoping review methodology has permitted us to characterize and catalogue the extensive body of literature pertaining to health system report cards. The resulting literature repository that our review has created can be of use to researchers and health system stakeholders interested in the topic of health system quality measurement and reporting. PMID- 20205790 TI - Extensive proteomic screening identifies the obesity-related NYGGF4 protein as a novel LRP1-interactor, showing reduced expression in early Alzheimer's disease. AB - BACKGROUND: The low-density lipoprotein receptor related protein 1 (LRP1) has been implicated in Alzheimer's disease (AD) but its signalling has not been fully evaluated. There is good evidence that the cytoplasmic domain of LRP1 is involved in protein-protein interactions, important in the cell biology of LRP1. RESULTS: We carried out three yeast two-hybrid screens to identify proteins that interact with the cytoplasmic domain of LRP1. The screens included both conventional screens as well as a novel, split-ubiquitin-based screen in which an LRP1 construct was expressed and screened as a transmembrane protein. The split ubiquitin screen was validated in a screen using full-length amyloid protein precursor (APP), which successfully identified FE65 and FE65L2, as well as novel interactors (Rab3a, Napg, and ubiquitin b). Using both a conventional screen as well as the split-ubiquitin screen, we identified NYGGF4 as a novel LRP1 interactor. The interaction between LRP1 and NYGGF4 was validated using two hybrid assays, coprecipitation and colocalization in mammalian cells. Mutation analysis demonstrated a specific interaction of NYGGF4 with an NPXY motif that required an intact tyrosine residue. Interestingly, while we confirmed that other LRP1 interactors we identified, including JIP1B and EB-1, were also able to bind to APP, NYGGF4 was unique in that it showed specific binding with LRP1. Expression of NYGGF4 decreased significantly in patients with AD as compared to age-matched controls, and showed decreasing expression with AD disease progression. Examination of Nyggf4 expression in mice with different alleles of the human APOE4 gene showed significant differences in Nyggf4 expression. CONCLUSIONS: These results implicate NYGGF4 as a novel and specific interactor of LRP1. Decreased expression of LRP1 and NYGGF4 over disease, evident with the presence of even moderate numbers of neuritic plaques, suggests that LRP1-NYGGF4 is a system altered early in disease. Genetic and functional studies have implicated both LRP1 and NYGGF4 in obesity and cardiovascular disease and the physical association of these proteins may reflect a common mechanism. This is particularly interesting in light of the dual role of ApoE in both cardiovascular risk and AD. The results support further studies on the functional relationship between NYGGF4 and LRP1. PMID- 20205792 TI - Intracellular and extracellular rhomboid shaped crystalline inclusions in a case of IgG lambda restricted plasma cell myeloma: a case report and review of the literature. AB - The presence of crystalline inclusions in plasma cell myeloma is a rare phenomenon and cases have been reported with rod, needle, and rectangular shaped crystals. Here, we present a case of IgG lambda restricted plasma cell myeloma with rhomboid shaped intracellular crystalline inclusions and extracellular crystal depositions in the bone marrow. Since rhomboid crystal depositions can be seen in other clinical conditions such as pseudogout, this case invites consideration of plasma cell myeloma in the differential diagnosis of patients with rhomboid crystalline deposition in the bone marrow and in sites/organs other than the bone marrow. PMID- 20205793 TI - Amyloid-beta-Acetylcholinesterase complexes potentiate neurodegenerative changes induced by the Abeta peptide. Implications for the pathogenesis of Alzheimer's disease. AB - The presence of amyloid-beta (Abeta) deposits in selected brain regions is a hallmark of Alzheimer's disease (AD). The amyloid deposits have "chaperone molecules" which play critical roles in amyloid formation and toxicity. We report here that treatment of rat hippocampal neurons with Abeta-acetylcholinesterase (Abeta-AChE) complexes induced neurite network dystrophia and apoptosis. Moreover, the Abeta-AChE complexes induced a sustained increase in intracellular Ca2+ as well as a loss of mitochondrial membrane potential. The Abeta-AChE oligomers complex also induced higher alteration of Ca2+ homeostasis compared with Abeta-AChE fibrillar complexes. These alterations in calcium homeostasis were reversed when the neurons were treated previously with lithium, a GSK-3beta inhibitor; Wnt-7a ligand, an activator for Wnt Pathway; and an N-methyl-D aspartate (NMDA) receptor antagonist (MK-801), demonstrating protective roles for activation of the Wnt signaling pathway as well as for NMDA-receptor inhibition. Our results indicate that the Abeta-AChE complexes enhance Abeta-dependent deregulation of intracellular Ca2+ as well as mitochondrial dysfunction in hippocampal neurons, triggering an enhanced damage than Abeta alone. From a therapeutic point of view, activation of the Wnt signaling pathway, as well as NMDAR inhibition may be important factors to protect neurons under Abeta-AChE attack. PMID- 20205794 TI - Missed presentation of Crohn's disease in a patient with a fistulating thigh abscess: a case report. AB - BACKGROUND: Musculoskeletal presentations of Crohn's disease are rare and they include psoas abscess, thigh abscesses and in extreme cases septic arthropathy. CASE PRESENTATION: Herein, we present a 53 year old gentleman with bilateral thigh fistulae discovered to be a new diagnoses of extra-intestinal Crohn's disease CONCLUSION: It is important to consider Crohn's disease in patients that present with unusual or persistent fistulae and to consider this essential when there are atypical organisms present. PMID- 20205795 TI - Usefulness of molecular biology performed with formaldehyde-fixed paraffin embedded tissue for the diagnosis of combined pulmonary invasive mucormycosis and aspergillosis in an immunocompromised patient. AB - Immunocompromised patients who develop invasive filamentous mycotic infections can be efficiently treated if rapid identification of the causative fungus is obtained. We report a case of fatal necrotic pneumonia caused by combined pulmonary invasive mucormycosis and aspergillosis in a 66 year-old renal transplant recipient. Aspergillus was first identified during the course of the disease by cytological examination and culture (A. fumigatus) of bronchoalveolar fluid. Hyphae of Mucorales (Rhizopus microsporus) were subsequently identified by culture of a tissue specimen taken from the left inferior pulmonary lobe, which was surgically resected two days before the patient died. Histological analysis of the lung parenchyma showed the association of two different filamentous mycoses for which the morphological features were evocative of aspergillosis and mucormycosis. However, the definitive identification of the associative infection was made by polymerase chain reaction (PCR) performed on deparaffinized tissue sections using specific primers for aspergillosis and mucormycosis. This case demonstrates that discrepancies between histological, cytological and mycological analyses can occur in cases of combined mycotic infection. In this regard, it shows that PCR on selected paraffin blocks is a very powerful method for making or confirming the association of different filamentous mycoses and that this method should be made available to pathology laboratories. PMID- 20205796 TI - Association of LEC and tnpA Helicobacter pylori genes with gastric cancer in a Brazilian population. AB - BACKGROUND: H. pylori seroprevalence in Brazilians varies and is dependent on socioeconomic status, sanitation conditions and ethnicity; furthermore, H. pylori is not always associated with the incidence of gastric cancer, suggesting the role of more virulent strains. The purpose of this study was to analyze the association of more virulent H. pylori strains with gastric cancer. METHODS: DNA was extracted from gastric biopsies of thirty-four cases of gastric cancer (11 intestinal-type, 23 diffuse-type), and thirty-four of patients with endoscopic gastritis. The presence of cagPAI genes (cagA, cagA promoter, cagE, cagM, tnpB, tnpA, cagT and the left end of the cagII (LEC)) and babA were analyzed by PCR. RESULTS: Comparison of H. pylori isolates from gastric cancer and gastritis patients showed significant associations of tnpA and LEC with gastric cancer (73.5% [OR, 6.66; 95% CI, 2.30-19.25] and 58.8% [OR, 10.71; 95% CI, 3.07-37.28] of cases, respectively). Other cagPAI genes were detected in both groups at similar frequencies. CONCLUSIONS: tnpA and LEC of H. pylori cagPAI were associated with gastric cancer; nonetheless, these results were restricted within this group of patients and further studies are needed to confirm these results in a larger sample and determine their role in gastric carcinogenesis. PMID- 20205797 TI - Dentin dysplasia type I: a case report and review of the literature. AB - INTRODUCTION: Dentin dysplasia is a rare hereditary disturbance of dentin formation characterized by defective dentin development with clinically normal appearing crowns, severe hypermobility of teeth and spontaneous dental abscesses or cysts. Radiographic analysis shows obliteration of all pulp chambers, short, blunted and malformed or absent roots and peri-apical radiolucencies of non carious teeth. CASE PRESENTATION: We present a case of dentin dysplasia type I in a 12-year-old Iranian boy, and the clinical, radiographic and histopathologic findings of this condition and treatment are described. CONCLUSIONS: There are still many inconclusive issues in the diagnosis and management of patients with dentin dysplasia. The diagnostic features of this rare disturbance will remain incompletely defined until additional cases have been described. Early diagnosis of the condition and initiation of effective regular dental treatments may help these patients to prevent or delay loss of dentition. PMID- 20205798 TI - An alternative treatment of hyperlipidemia with red yeast rice: a case report. AB - INTRODUCTION: Hyperlipidemia is prevalent and is highly associated with coronary heart disease. Some patients are reluctant or opt not to take lipid-lowering prescription medications for fear of adverse drug reactions. There are currently few well-designed randomized controlled trials showing the possibility of reducing cholesterol using red yeast rice. Meanwhile, adverse effects have also been reported. CASE PRESENTATION: A 64-year-old Asian man was diagnosed with hyperlipidemia despite a healthy lifestyle. In addition to diet changes, the patient used red yeast rice and succeeded in lowering his level of serum lipids. CONCLUSION: Based on this case and a review of current literature, in addition to therapeutic lifestyle change, red yeast rice may be a useful alternative treatment for primary hyperlipidemia in patients with low cardiac risk and who refuse to take any lipid-lowering prescription medication or who maybe be statin intolerant.However, primary care physicians must be aware of the potential side effects of taking red yeast rice. PMID- 20205799 TI - Partial-thickness macular hole in vitreomacular traction syndrome: a case report and review of the literature. AB - INTRODUCTION: Vitreomacular traction syndrome has recently been recognized as a distinct clinical condition. It may lead to many complications, such as cystoid macular edema, macular pucker formation, tractional macular detachment, and full thickness macular hole formation. CASE PRESENTATION: We report a case of vitreomacular traction syndrome with eccentric traction at the macula and a partial-thickness macular hole in a 63-year-old Pakistani Punjabi man. The patient was evaluated using optical coherence tomography, and he underwent a successful pars plana vitrectomy. After the operation, his foveal contour regained normal configuration, and his visual acuity improved from 20/60 to 20/30. CONCLUSIONS: Pars plana vitrectomy prevents the progression of a partial thickness macular hole in vitreomacular traction syndrome. The relief of traction by vitrectomy restores foveal anatomy and visual acuity in this condition. PMID- 20205801 TI - Dockres: a computer program that analyzes the output of virtual screening of small molecules. AB - BACKGROUND: This paper describes a computer program named Dockres that is designed to analyze and summarize results of virtual screening of small molecules. The program is supplemented with utilities that support the screening process. Foremost among these utilities are scripts that run the virtual screening of a chemical library on a large number of processors in parallel. METHODS: Dockres and some of its supporting utilities are written Fortran-77; other utilities are written as C-shell scripts. They support the parallel execution of the screening. The current implementation of the program handles virtual screening with Autodock-3 and Autodock-4, but can be extended to work with the output of other programs. RESULTS: Analysis of virtual screening by Dockres led to both active and selective lead compounds. CONCLUSIONS: Analysis of virtual screening was facilitated and enhanced by Dockres in both the authors' laboratories as well as laboratories elsewhere. PMID- 20205800 TI - Complications related to deep venous thrombosis prophylaxis in trauma: a systematic review of the literature. AB - Deep venous thrombosis prophylaxis is essential to the appropriate management of multisystem trauma patients. Without thromboprophylaxis, the rate of venous thrombosis and subsequent pulmonary embolism is substantial. Three prophylactic modalities are common: pharmacologic anticoagulation, mechanical compression devices, and inferior vena cava filtration. A systematic review was completed using PRISMA guidelines to evaluate the potential complications of DVT prophylactic options. Level one evidence currently supports the use of low molecular weight heparins for thromboprophylaxis in the trauma patient. Unfortunately, multiple techniques are not infrequently required for complex multisystem trauma patients. Each modality has potential complications. The risks of heparin include bleeding and heparin induced thrombocytopenia. Mechanical compression devices can result in local soft tissue injury, bleeding and patient non-compliance. Inferior vena cava filters migrate, cause inferior vena cava occlusion, and penetrate the vessel wall. While the use of these techniques can be life saving, they must be appropriately utilized. PMID- 20205802 TI - Protein synthesis and degradation are required for the incorporation of modified information into the pre-existing object-location memory. AB - Although some reports indicate that protein synthesis dependent process may be induced by updating information, the role of protein synthesis and degradation in changing the content of pre-existing memory is yet unclear. In this study, we utilized an object rearrangement task, in which partial information related to a pre-existing memory is changed, promoting memory modification. Inhibitors of both protein synthesis and protein degradation impaired adequate incorporation of the altered information, each in a distinctive way. These results indicate that protein synthesis and degradation play key roles in memory modification. PMID- 20205803 TI - Chicken blood provides a suitable meal for the sand fly Lutzomyia longipalpis and does not inhibit Leishmania development in the gut. AB - BACKGROUND: The aim of this study was to address the role of chickens as bloodmeal sources for female Lutzomyia longipalpis and to test whether chicken blood is harmful to Leishmania parasite development within the sand flies. Bloodmeal ingestion, excretion of urate, reproduction, fecundity, as well as Leishmania infection and development were compared in sand flies fed on blood from chickens and different mammalian sources. RESULTS: Large differences in haemoglobin and protein concentrations in whole blood (dog>human>rabbit> chicken) did not correlate with differences in bloodmeal protein concentrations (dog = chicken>human>rabbit). This indicated that Lu. longipalpis were able to concentrate bloodmeals taken from different hosts using prediuresis and this was confirmed by direct observation. Sand flies fed on chickens or dogs produced significantly more eggs than those fed on human blood. Female Lu. longipalpis retained significantly more urate inside their bodies when fed on chicken blood compared to those fed on rabbit blood. However, when the amounts of urate excreted after feeding were measured, sand flies fed on rabbit blood excreted significantly more than those fed on chicken blood. There was no difference in female longevity after feeding on avian or mammalian blood.Sand flies infected via chicken blood produced Leishmania mexicana infections with a similar developmental pattern but higher overall parasite populations than sand flies infected via rabbit blood. CONCLUSIONS: The results of this study help to define the role that chickens play in the epidemiology of leishmaniasis. The present study using a Lu. longipalpis/L. mexicana model indicates that chickens are suitable hosts to support a Lu. longipalpis population and that chicken blood is likely to support the development of transmissible Leishmania infections in Lu. longipalpis. PMID- 20205804 TI - Fibrolipomatous hamartoma in the median nerve in the arm - an unusual location but with MR imaging characteristics: a case report. AB - Fibrolipomatous hamartoma of the median nerve are usually located distally in the forearm and may have characteristic features on MR imaging. Here we report a patient with an extensive fibrolipomatous hamartoma at an unusual location proximally in the arm, where a preoperative MR imaging was pathognomonic and diagnosis was verified by an incisional biopsy. We suggest that MRI should be performed in cases with nerve dysfunction without an obvious cause after a thorough clinical examination. PMID- 20205805 TI - Tricuspid valve myxoma in a patient with congestive heart failure. AB - Myxomas are the most frequent benign primary cardiac tumours (50% of benign heart tumours). This kind of tumour is most likely to be localized in the left atrium, followed by the right atrium, right ventricle and left ventricle. Quite exceptional is the presence of a myxoma originating from the tricuspid valve or from the Eustachian valve. We describe the case of a woman with moderate dyspnoea of unknown origin and the presence of tricuspid myxoma who underwent tricuspid valve curettage. PMID- 20205806 TI - Patient presenting with lipoma of the index finger: a case report. AB - INTRODUCTION: Lipomas can be found anywhere in the body with the majority located in the head and neck region as well as in the shoulder and back. They are not very common in the hand and those involving the fingers are very rare. Although, it is not the only case reported, lipoma of the index finger is very uncommon. CASE PRESENTATION: A 52-year-old Caucasian man presented with a lipoma of the right index finger. He complained of no pain but he had difficulty in manual movements. Treatment was surgical excision of the lipoma. There has been no recurrence for two years. CONCLUSION: Although lipomas of the fingers are rare entities, their awareness is imperative since the differential diagnosis from other soft tissue tumors and from the special lipomatous subtype involved is quite extensive. PMID- 20205807 TI - Hemangiopericytoma in the sacrococcygeal space: a case report. AB - INTRODUCTION: A hemangiopericytoma is a rare, soft-tissue tumor of vascular origin derived from a pericyte of Zimmerman, which is a modified smooth muscle cell that surrounds the small blood vessels. Hemangiopericytomas can occur wherever there are vascular capillaries. However, there are no previous reports of a hemangiopericytoma in the sacrococcygeal space. CASE PRESENTATION: We describe the first reported case of a hemangiopericytoma found in the sacrococcygeal space. A 47-year-old Japanese woman presented with a palpable tumor on the left side of her anus. Preoperative imaging indicated that the tumor was in the sacrococcygeal space without invasion of other organs. A complete resection was performed via a parasacral incision. The histological and immunohistochemical staining patterns supported the diagnosis of a hemangiopericytoma. CONCLUSION: A complete resection without piecemeal excision is the best way to treat a hemangiopericytoma. Recognizing the presence of a hemangiopericytoma in the sacrococcygeal space requires appropriate surgery. PMID- 20205809 TI - Neurofibromatosis of the nipple-areolar area: a case series. AB - INTRODUCTION: Neurofibromatosis type 1 is an autosomal dominant disorder that occurs across all ethnic groups and affects approximately one in 4000 individuals. One of the most noticeable characteristics of the disease is the development of neurofibromas. CASE PRESENTATION: A total of 258 patients (131 women, 127 men) with neurofibromatosis type 1 were evaluated between 1994 and 2004 in our hospital's dermatology department. Nine patients (3.45%, 95% confidence limits 1.22 to 5.68) had neurofibromas of the breast. One of these nine patients presented with an extensive congenital plexiform neurofibroma in the outer quadrants of her right breast, extending to the nipple-areolar complex. Meanwhile, three patients had more than one neurofibroma on the nipple-areolar complexes. Three patients had a family history of neurofibroma. Over the years 1994 to 2004, the cutaneous lesions were not associated with any malignancies. Presenting symptoms were related to conditions such as increasing size of the mass, and associated loss of function and pain. CONCLUSIONS: This study suggests that the changes are limited to particular subgroups. That neurofibromatosis is more prevalent in women (7 women and 2 men) suggests that being female could be a susceptibility factor for the development of neurofibromas of the nipple-areolar complexes. There are few reports in the literature describing breast carcinomas in association with von Recklinghausen disease. It has been speculated that the presence of multiple neurofibromas of the breast may obscure a breast mass at palpation, leading to a delay in clinical detection. We suggest that patients with neurofibromas of the breast have more rigorous clinical and mammographic screening of the breast during adulthood to determine the presence or absence of malignancies. The finding that both the neurofibromatosis type 1 gene and a breast cancer predisposition gene are located in close proximity on chromosome 17q makes the association of these two conditions intriguing. PMID- 20205808 TI - Association between dopaminergic polymorphisms and borderline personality traits among at-risk young adults and psychiatric inpatients. AB - BACKGROUND: In the development of borderline personality disorder (BPD) both genetic and environmental factors have important roles. The characteristic affective disturbance and impulsive aggression are linked to imbalances in the central serotonin system, and most of the genetic association studies focused on serotonergic candidate genes. However, the efficacy of dopamine D2 receptor (DRD2) blocking antipsychotic drugs in BPD treatment also suggests involvement of the dopamine system in the neurobiology of BPD. METHODS: In the present study we tested the dopamine dysfunction hypothesis of impulsive self- and other-damaging behaviors: borderline and antisocial traits were assessed by Structured Clinical Interview for Diagnosis (SCID) for DSM-IV in a community-based US sample of 99 young adults from low-to-moderate income families. For the BPD trait analyses a second, independent group was used consisting of 136 Hungarian patients with bipolar or major depressive disorder filling out self-report SCID-II Screen questionnaire. In the genetic association analyses the previously indicated polymorphisms of the catechol-O-methyl-transferase (COMT Val158Met) and dopamine transporter (DAT1 40 bp VNTR) were studied. In addition, candidate polymorphisms of the DRD2 and DRD4 dopamine receptor genes were selected from the impulsive behavior literature. RESULTS: The DRD2 TaqI B1-allele and A1-allele were associated with borderline traits in the young adult sample (p = 0.001, and p = 0.005, respectively). Also, the DRD4 -616 CC genotype appeared as a risk factor (p = 0.02). With severity of abuse accounted for in the model, genetic effects of the DRD2 and DRD4 polymorphisms were still significant (DRD2 TaqIB: p = 0.001, DRD2 TaqIA: p = 0.008, DRD4 -616 C/G: p = 0.002). Only the DRD4 promoter finding was replicated in the independent sample of psychiatric inpatients (p = 0.007). No association was found with the COMT and DAT1 polymorphisms. CONCLUSIONS: Our results of the two independent samples suggest a possible involvement of the DRD4 -616 C/G promoter variant in the development of BPD traits. In addition, an association of the DRD2 genetic polymorphisms with impulsive self-damaging behaviors was also demonstrated. PMID- 20205810 TI - Frequency of genetic diseases and health coverage of children requiring admission in a general pediatric clinic of northern Greece. AB - BACKGROUND: In order to estimate the causes of pediatric morbidity in our area, with particular emphasis on diseases with a genetic background, we retrospectively categorized the admissions of all children hospitalized in the Department of Pediatrics of the University General Hospital of Alexandroupolis, in the area of Evros, Thrace, Greece over the three year period 2005-2007. Finally, in order to guide health care administrators to improve the delivery of pediatric health care services, we estimated the percentage of hospitalized children who were uninsured and the type of health insurance of those who had medical coverage. PATIENTS AND METHODS: The causes of admission, as recorded in the medical records were categorized in terms of the major organ and/or system involved and/or the underlying pathology, with emphasis on diseases with a genetic background. Duplicate admissions, i.e., admissions of the same child for the same underlying disease were excluded. Additional information recorded was age, sex, and type of health insurance of all admitted children. Distribution of the causes of admission by study year was compared by chi-square. A p value < 0.05 was considered significant. RESULTS: Over the study period, there were 4,947 admissions in 2,818 boys and 2,129 girls. Respiratory diseases were the most common accounting for 30%, while infectious diseases followed with 26.4%. The frequency of chromosomal abnormalities among the hospitalized children was only 0.06%. However, if we consider diseases with an underlying genetic background, this percentage rises to 5%. Approximately 10.3% of the admitted children had no health insurance. CONCLUSIONS: The percentage of children hospitalized in our area due to a disease with an underlying genetic background was 5%. This percentage pertains to a Department of Pediatrics that has no inpatient subspecialty units and which is located within a General hospital, because hospitalizations for genetic diseases are more frequent in specialized pediatric hospitals, with competence in clinical genetics. The double figure of uninsured children is worrisome and dictates the need for governmental efforts for universal pediatric health coverage in our country. PMID- 20205811 TI - CD40mAb adjuvant induces a rapid antibody response that may be beneficial in post exposure prophylaxis. AB - Active vaccination can be effective as a post-exposure prophylaxis, but the rapidity of the immune response induced, relative to the incubation time of the pathogen, is critical. We show here that CD40mAb conjugated to antigen induces a more rapid specific antibody response than currently used immunological adjuvants, alum and monophosphoryl lipid A. PMID- 20205812 TI - Suppression of LPS-induced inflammatory responses in macrophages infected with Leishmania. AB - BACKGROUND: Chronic inflammation activated by macrophage innate pathogen recognition receptors such as TLR4 can lead to a range of inflammatory diseases, including atherosclerosis, Crohn's disease, arthritis and cancer. Unlike many microbes, the kinetoplastid protozoan pathogen Leishmania has been shown to avoid and even actively suppress host inflammatory cytokine responses, such as LPS induced IL-12 production. The nature and scope of Leishmania-mediated inflammatory cytokine suppression, however, is not well characterized. Advancing our knowledge of such microbe-mediated cytokine suppression may provide new avenues for therapeutic intervention in inflammatory disease. METHODS: We explored the kinetics of a range of cytokine and chemokine responses in primary murine macrophages stimulated with LPS in the presence versus absence of two clinically distinct species of Leishmania using sensitive multiplex cytokine analyses. To confirm that these effects were parasite-specific, we compared the effects of Leishmania uptake on LPS-induced cytokine expression with uptake of inert latex beads. RESULTS: Whilst Leishmania uptake alone did not induce significant levels of any cytokine analysed in this study, Leishmania uptake in the presence of LPS caused parasite-specific suppression of certain LPS-induced pro-inflammatory cytokines, including IL-12, IL-17 and IL-6. Interestingly, L. amazonensis was generally more suppressive than L. major. We also found that other LPS-induced proinflammatory cytokines, such as IL-1alpha, TNF-alpha and the chemokines MIP-1alpha and MCP-1 and also the anti-inflammatory cytokine IL-10, were augmented during Leishmania uptake, in a parasite-specific manner. CONCLUSIONS: During uptake by macrophages, Leishmania evades the activation of a broad range of cytokines and chemokines. Further, in the presence of a strong inflammatory stimulus, Leishmania suppresses certain proinflammatory cytokine responses in a parasite-specific manner, however it augments the production of other proinflammatory cytokines. Our findings highlight the complexity of inflammatory cytokine signalling regulation in the context of the macrophage and Leishmania interaction and confirm the utility of the Leishmania/macrophage infection model as an experimental system for further studies of inflammatory regulation. Such studies may advance the development of therapies against inflammatory disease. PMID- 20205813 TI - International society of sports nutrition position stand: caffeine and performance. AB - Position Statement: The position of The Society regarding caffeine supplementation and sport performance is summarized by the following seven points: 1.) Caffeine is effective for enhancing sport performance in trained athletes when consumed in low-to-moderate dosages (~3-6 mg/kg) and overall does not result in further enhancement in performance when consumed in higher dosages (>/= 9 mg/kg). 2.) Caffeine exerts a greater ergogenic effect when consumed in an anhydrous state as compared to coffee. 3.) It has been shown that caffeine can enhance vigilance during bouts of extended exhaustive exercise, as well as periods of sustained sleep deprivation. 4.) Caffeine is ergogenic for sustained maximal endurance exercise, and has been shown to be highly effective for time trial performance. 5.) Caffeine supplementation is beneficial for high-intensity exercise, including team sports such as soccer and rugby, both of which are categorized by intermittent activity within a period of prolonged duration. 6.) The literature is equivocal when considering the effects of caffeine supplementation on strength-power performance, and additional research in this area is warranted. 7.) The scientific literature does not support caffeine induced diuresis during exercise, or any harmful change in fluid balance that would negatively affect performance. PMID- 20205815 TI - How to integrate individual patient values and preferences in clinical practice guidelines? A research protocol. AB - BACKGROUND: Clinical practice guidelines are largely conceived as tools that will inform health professionals' decisions rather than foster patient involvement in decision making. The time now seems right to adapt clinical practice guidelines in such a way that both the professional's perspective as care provider and the patients' preferences and characteristics are being weighed equally in the decision-making process. We hypothesise that clinical practice guidelines can be adapted to facilitate the integration of individual patients' preferences in clinical decision making. This research protocol asks two questions: How should clinical practice guidelines be adapted to elicit patient preferences and to support shared decision making? What type of clinical decisions are perceived as most requiring consideration of individual patients' preferences rather than promoting a single best choice? METHODS: Stakeholders' opinions and ideas will be explored through an 18-month qualitative study. Data will be collected from in depth individual interviews. A purposive sample of 20 to 25 key-informants will be selected among three groups of stakeholders: health professionals using guidelines (e.g., physicians, nurses); experts at the macro- and meso-level, including guideline and decision aids developers, policy makers, and researchers; and patient representatives. Ideas and recommendations expressed by stakeholders will be prioritized by nominal group technique in expert meetings. DISCUSSION: One-for-all guidelines do not account for differences in patients' characteristics and for their preferences for medical interventions and health outcomes, suggesting a need for flexible guidelines that facilitate patient involvement in clinical decision making. The question is how this can be achieved. This study is not about patient participation in guideline development, a closely related and important issue that does not however substitute for, or guarantee individual patient involvement in clinical decisions. The study results will provide the needed background for recommendations about potential effective and feasible strategies to ensure greater responsiveness of clinical practice guidelines to individual patient's preferences in clinical decision-making. PMID- 20205816 TI - Retroperitoneal abscess with concomitant hepatic portal venous gas and rectal perforation: a rare triad of complications of acute appendicitis. A case report. AB - BACKGROUND: While retroperitoneal abscess is a known complication, hepatic portal venous gas and rectal perforation have not been reported as a concomitant sequelae of acute appendicitis. Here we report a case of a patient with a perforated appendicitis that was associated with these triad of complications. MATERIALS AND METHODS: In addition to report our case, we carefully reviewed the literature in order to detect similar cases and the causes of such rare conditions. RESULTS: Only 26 cases (including our patient) of acute appendicitis complicated by retroperitoneal abscesses have been published in the English literature between 1955 and 2008. There was one case having hepatic portal venous gas, and one further case with a rectal perforation associated with acute appendicitis. All patients with retroperitoneal abscess presented with non specific clinic symptoms that not revealed any suspicion for such a complicated disease. Hence, delayed diagnosis and treatment are not uncommon. CONCLUSIONS: So far, no patient has been described with such a triad of rare complications related to acute appendicitis. We want to emphasize the insidious onset of retroperitoneal abscess formation, and the need of prompt recognition and adequate treatment to avoid deleterious outcome. PMID- 20205817 TI - Chitosan nanoparticle-based neuronal membrane sealing and neuroprotection following acrolein-induced cell injury. AB - BACKGROUND: The highly reactive aldehyde acrolein is a very potent endogenous toxin with a long half-life. Acrolein is produced within cells after insult, and is a central player in slow and progressive "secondary injury" cascades. Indeed, acrolein-biomolecule complexes formed by cross-linking with proteins and DNA are associated with a number of pathologies, especially central nervous system (CNS) trauma and neurodegenerative diseases. Hydralazine is capable of inhibiting or reducing acrolein-induced damage. However, since hydralazine's principle activity is to reduce blood pressure as a common anti-hypertension drug, the possible problems encountered when applied to hypotensive trauma victims have led us to explore alternative approaches. This study aims to evaluate such an alternative - a chitosan nanoparticle-based therapeutic system. RESULTS: Hydralazine-loaded chitosan nanoparticles were prepared using different types of polyanions and characterized for particle size, morphology, zeta potential value, and the efficiency of hydralazine entrapment and release. Hydralazine-loaded chitosan nanoparticles ranged in size from 300 nm to 350 nm in diameter, and with a tunable, or adjustable, surface charge. CONCLUSIONS: We evaluated the utility of chitosan nanoparticles with an in-vitro model of acrolein-mediated cell injury using PC -12 cells. The particles effectively, and statistically, reduced damage to membrane integrity, secondary oxidative stress, and lipid peroxidation. This study suggests that a chitosan nanoparticle-based therapy to interfere with "secondary" injury may be possible. PMID- 20205818 TI - Vein of Galen arteriovenous malformation with PAPVR and use of serial B-type natriuretic peptide levels in the management: a case report and review of the literature. AB - BACKGROUND: Arteriovenous malformation of the vein of Galen with partial anomalous pulmonary venous return can lead to a critically challenging condition associated with a high morbidity and mortality. CASE REPORT: We report a case of a full term infant born with a vein of Gallen arteriovenous malformation complicated by partial anomalous pulmonary venous return and congestive heart failure where B-type natriuretic peptide was used as a vital tool in clinical assessment and treatment management. CONCLUSIONS: Rapid diagnosis and treatment in infants with complex conditions such as this are imperative to expedite appropriate treatments, preventing long term negative outcome. PMID- 20205819 TI - Intranodal palisaded myofibroblastoma: a case report. AB - Intranodal palisaded myofibroblastoma is a rare benign soft tissue tumor, almost always arising from inguinal lymph nodes. It usually presents as a painless, slow growing inguinal mass. We report herein a case of an intranodal palisaded myofibroblastoma occurring in a 36-year-old man. The salient clinicopathologic features of this unusual tumor are presented and the literature is briefly reviewed. PMID- 20205820 TI - A male presenting with a primary mucinous bladder carcinoma: a case report. AB - BACKGROUND: The primary mucinous adenocarcinoma of the bladder is an extremely rare urologic entity, which is found in less than 2% of all urinary bladder tumours and is often presented as metastatic. CASE PRESENTATION: A 69-year old male patient was diagnosed with a primary mucinous adenocarcinoma of the bladder after undergoing a transurethral resection of a bladder tumour and complete examination of the entire gastrointestinal tract to rule out other primary cites. Immunohistochemistry confirmed the nature of the tumour. The patient underwent a radical cystoprostatectomy with en block bilateral pelvic lymphadenectomy and urinary diversion with a Bricker ileostomy. CONCLUSION: The primary adenocarcinoma creates a diagnostic dilemma, since it cannot be easily differentiated by the adenocarcinoma that originates from the colon and the prostate. We advocate the radical surgical management, after exclusion of any primary malignant sites related to the gastrointestinal tract. The immunohistochemistry has a leading role, assisting with the differential diagnosis. PMID- 20205821 TI - Neutrophil elastase downmodulates native G-CSFR expression and granulocyte macrophage colony formation. AB - BACKGROUND: The granulocyte colony-stimulating factor receptor (G-CSFR) plays a critical role in maintaining homeostatic levels of circulating neutrophils (PMN). The mechanisms modulating G-CSFR surface expression to prevent chronic neutrophilia are poorly understood. Here, we report that neutrophil elastase (NE) proteolytically cleaves the G-CSFR on human PMN and blocks G-CSFR-mediated granulopoiesis in vitro. METHODS: Human peripheral blood PMN isolated from healthy donors were incubated with NE. Expression of the G-CSFR was analyzed by flow cytometry and western blot analyses. Detection of G-CSFR cleavage products from the culture supernatants was also performed. Human bone marrow mononuclear cells were also cultured in the presence or absence of NE to determine its effects on the proliferation of granulocyte-macrophage colony forming units (CFU GM). RESULTS: Treatment of PMN with NE induced a time-dependent decrease in G CSFR expression that correlated with its degradation and the appearance of proteolytic cleavage fragments in conditioned media. Immunoblot analysis confirmed the G-CSFR was cleaved at its amino-terminus. Treatment of progenitor cells with NE prior to culture inhibited the growth of granulocyte-macrophage colony forming units. CONCLUSIONS: These findings indicate that in addition to transcriptional controls and ligand-induced internalization, direct proteolytic cleavage of the G-CSFR by NE also downregulates G-CSFR expression and inhibits G CSFR-mediated granulopoiesis in vitro. Our results suggest that NE negatively regulates granulopoiesis through a novel negative feedback loop. PMID- 20205822 TI - Autism and classification systems: a study of 84 children. AB - BACKGROUND: A number of studies have shown that current classification systems (ICD 10, DSM IV TR) have limitation when applied to autistic children and the category PDD NOS (DSM IV TR) has in particular been criticized. To check the possible usefulness of other classification systems to better describe patient's functioning, we retrospectively studied 84 patients, seen consecutively in our Child Neurology and Psychiatry Department (excluding only those presenting for another disease even if with clinical signs of a PDD). METHODS: We tried to classify them according to ICD 10, DSM IV TR, CFTMEA-R, "operational classification" (Manzano and Palacio) and de Ajuriaguerra's classification. RESULTS: We found a good correspondence between DSM IV TR and ICD 10 and the use of psychodynamic classification systems (in particular CFTMEA-R) was useful to differentiate clinical subtypes collected under the PDD NOS etiquette according to DSM IV TR. CONCLUSIONS: To rationalize research efforts and find better tailored therapies, we need to improve PDD classification systems, using contributions coming from every field of child psychiatry and neurology: it's possible that 0-3 Classification could help this. PMID- 20205823 TI - How do ADHD children perceive their cognitive, affective, and behavioral aspects of anger expression in school setting? AB - BACKGROUND: Anger is an ignored research area in children and young adolescents with Attention deficit hyperactivity disorder (ADHD) in the school setting. This study compares school anger dimensions in children and young adolescents with ADHD and a control group. METHODS: The subjects were a clinical sample of 67 children and young adolescents with ADHD and their parents, with a sample of 91 children from the community of similar age and gender as control group. Anger was measured by the Farsi version of the Multidimensional School Anger Inventory (MSAI). RESULTS: The scores of the two components of "Hostile Outlook" and "Positive Coping" were different between the groups. The mean scores for the Anger components did not statistically differ between the children with ADHD and ODD and ADHD without ODD, boys and girls, or different types of ADHD. CONCLUSION: Children with ADHD do not report higher rates of experience of anger and they do not apply destructive strategies more than the control group. However, children with ADHD appear to have a more hostile outlook toward school and their coping strategy is weaker than that of the control group. PMID- 20205825 TI - Effects of MMP-9 inhibition by doxycycline on proteome of lungs in high tidal volume mechanical ventilation-induced acute lung injury. AB - BACKGROUND: Although mechanical ventilation (MV) is a major supportive therapy for patients with acute respiratory distress syndrome, it may result in side effects including lung injury. In this study we hypothesize that MMP-9 inhibition by doxycycline might reduce MV-related lung damage. Using a proteomic approach we identified the pulmonary proteins altered in high volume ventilation-induced lung injury (VILI). Forty Wistar rats were randomized to an orally pretreated with doxycycline group (n = 20) or to a placebo group (n = 20) each of which was followed by instrumentation prior to either low or high tidal volume mechanical ventilation. Afterwards, animals were euthanized and lungs were harvested for subsequent analyses. RESULTS: Mechanical function and gas exchange parameters improved following treatment with doxycycline in the high volume ventilated group as compared to the placebo group. Nine pulmonary proteins have shown significant changes between the two biochemically analysed (high volume ventilated) groups. Treatment with doxycycline resulted in a decrease of pulmonary MMP-9 activity as well as in an increase in the levels of soluble receptor for advanced glycation endproduct, apoliporotein A-I, peroxiredoxin II, four molecular forms of albumin and two unnamed proteins. Using the pharmacoproteomic approach we have shown that treatment with doxycycline leads to an increase in levels of several proteins, which could potentially be part of a defense mechanism. CONCLUSION: Administration of doxycycline might be a significant supportive therapeutic strategy in prevention of VILI. PMID- 20205824 TI - The Reinforcing Therapist Performance (RTP) experiment: study protocol for a cluster randomized trial. AB - BACKGROUND: Rewarding provider performance has been recommended by the Institute of Medicine as an approach to improve the quality of treatment, yet little empirical research currently exists that has examined the effectiveness and cost effectiveness of such approaches. The aim of this study is to test the effectiveness and cost-effectiveness of providing monetary incentives directly to therapists as a method to improve substance abuse treatment service delivery and subsequent client treatment outcomes. DESIGN: Using a cluster randomized design, substance abuse treatment therapists from across 29 sites were assigned by site to either an implementation as usual (IAU) or pay-for-performance (P4P) condition. PARTICIPANTS: Substance abuse treatment therapists participating in a large dissemination and implementation initiative funded by the Center for Substance Abuse Treatment. INTERVENTION: Therapists in both conditions received comprehensive training and ongoing monitoring, coaching, and feedback. However, those in the P4P condition also were given the opportunity to earn monetary incentives for achieving two sets of measurable behaviors related to quality implementation of the treatment. OUTCOMES: Effectiveness outcomes will focus on the impact of the monetary incentives to increase the proportion of adolescents who receive a targeted threshold level of treatment, months that therapists demonstrate monthly competency, and adolescents who are in recovery following treatment. Similarly, cost-effectiveness outcomes will focus on cost per adolescent receiving targeted threshold level of treatment, cost per month of demonstrated competence, and cost per adolescent in recovery. TRIAL REGISTRATION: TRIAL REGISTRATION NUMBER: NCT01016704. PMID- 20205826 TI - Assessment of cognitive status in patients with type 2 diabetes through the Mini Mental Status Examination: a cross-sectional study. AB - BACKGROUND: Diabetes is considered an independent risk factor for cognitive impairment and some studies observed through neuropsychological tests that cognitive disfunction affects both elderly and younger patients with diabetes. The aims of this study were to evaluate the cognitive status of outpatients with type 2 diabetes and to evaluate factors associated with impaired function. METHODS: A cross-sectional study was conducted in a group of type 2 diabetic outpatients. They were asked to undergo the Mini-Mental State Examination (MMSE) during routine ambulatory visits between April 2006 and January 2007, with the highest pontuation of the test being 30 points. Patients were classified as having possible dementia according to years of study. Exclusion criteria were blindness, illiteracy, stroke, Alzheimer disease and psychiatric disorder. Results are presented as median (interquartile range) or mean +/- SD. RESULTS: The study group was composed of 346 type 2 diabetic outpatients (216 females), aged 58,6 +/- 12,1 years and with duration of diabetes of 12,3 +/- 9,1 years. Hypertension was present in 77,2%. The total MMSE score achieved was 26 points (16 - 30) and was correlated with years of study (R2 = 0,39, p < 0,001) and 'per capita' income (R2 = 0,22, p < 0,0001) and duration of diabetes (R2 = - 0,13, p = 0,01). Patients who needed help to take their medications obtained worst performance in the MMSE (23,16 +/- 3,55 vs 25,7 +/- 2,84, p < 0,01) and were more likely to present possible dementia (p < 0,01). Forty two subjects (12.1%) had diagnosis of possible dementia and this was also associated with years of study (p = 0,045). No association was observed between possible dementia and total MMSE scores with A1C levels. CONCLUSIONS: We conclude that patients with type 2 diabetes should be regularly evaluated for their cognitive function, because duration of disease could be associated with decline in cognition. The early implementation of mini mental which is a simple method of execution can be done to detect early stages of dementia. This test could be an important tool to access the ability of patient to understand their disease and treatment. PMID- 20205827 TI - Severe odynophagia in a patient developing after azithromycin intake: a case report. AB - INTRODUCTION: Drug-induced esophageal ulcers most commonly cause heartburn, midsternal pain and dysphagia. In our clinic azithromycin is a relative widely used antibiotic for respiratory tract infections and otitis media because of its activity against Haemophilus influenzae and atypical pathogens, and its ease of administration. After a thorough search in Pubmed the present case is the first one to report azithromycin-induced esophageal ulcer and associated symptoms in the literature. CASE PRESENTATION: A 61-year-old Caucasian man was admitted to our endoscopy unit for the investigation of odynophagia and retrosternal pain of new onset. His past medical history was unremarkable but had used azithromycin 500 mg/d for three days in the previous week. An upper endoscopy revealed an extensive serpiginous midesophageal ulcer in the presence of a normal squamocolumnar junction and biopsies from the edges and center of the lesion disclosed no neoplasia or infectious causes but a dense acute inflammatory infiltrate. The patient was put on a liquid diet, sucralfate proton pump inhibitor treatment and was symptom-free within two weeks. After four weeks on therapy a repeated upper endoscopic control examination demonstrated normal findings. CONCLUSION: To our knowledge this is the first such a case of azithromycin -induced esophageal ulceration. We think that a little time taken by the physician to warn the patients for taking every oral drug with sufficient amount of water might prevent this kind of complications. PMID- 20205828 TI - Adenosquamous carcinoma of the pancreas: a case report. AB - Adenosquamous carcinoma of the pancreas is a rare variant of pancreatic exocrine carcinoma. We report a case of 70 year old man who came to our hospital with abdominal pain, anorexia and jaundice. Imaging of the abdomen showed a mass in the region of the head of the pancreas. Histological evaluation of the pancreatic tumor showed an adenosquamous carcinoma which was extensively infiltrative with perineural invasion, involvement of peripancreatic lymph nodes and all the thickness of the duodenum wall. The tumor exhibited a biphasic malignant growth identified as well to moderate differentiated adenocarcinoma and well to poorly differentiated squamous cell carcinoma. PMID- 20205829 TI - Safety and reliability of Radio Frequency Identification Devices in Magnetic Resonance Imaging and Computed Tomography. AB - BACKGROUND: Radio Frequency Identification (RFID) devices are becoming more and more essential for patient safety in hospitals. The purpose of this study was to determine patient safety, data reliability and signal loss wearing on skin RFID devices during magnetic resonance imaging (MRI) and computed tomography (CT) scanning. METHODS: Sixty RFID tags of the type I-Code SLI, 13.56 MHz, ISO 18000 3.1 were tested: Thirty type 1, an RFID tag with a 76 x 45 mm aluminum-etched antenna and 30 type 2, a tag with a 31 x 14 mm copper-etched antenna. The signal loss, material movement and heat tests were performed in a 1.5 T and a 3 T MR system. For data integrity, the tags were tested additionally during CT scanning. Standardized function tests were performed with all transponders before and after all imaging studies. RESULTS: There was no memory loss or data alteration in the RFID tags after MRI and CT scanning. Concerning heating (a maximum of 3.6 degrees C) and device movement (below 1 N/kg) no relevant influence was found. Concerning signal loss (artifacts 2 - 4 mm), interpretability of MR images was impaired when superficial structures such as skin, subcutaneous tissues or tendons were assessed. CONCLUSIONS: Patients wearing RFID wristbands are safe in 1.5 T and 3 T MR scanners using normal operation mode for RF-field. The findings are specific to the RFID tags that underwent testing. PMID- 20205830 TI - Carcinoid tumor of the verumontanum (colliculus seminalis) of the prostatic urethra with a coexisting prostatic adenocarcinoma: a case report. AB - INTRODUCTION: Urethral carcinoid tumors are very rare tumors with only four cases described in the literature. CASE PRESENTATION: We present the case of a 61-year old man with a primary carcinoid tumor of the verumontanum (colliculis seminalis) portion of the prostatic urethra with a coexisting prostatic adenocarcinoma. In addition to whole mount hematoxylin and eosin staining, special immunoperoxidase staining specific for chromogranin A, neuron specific enolase, synaptophysin, pan cytokeratin and PSA, and a special combined staining for racemase (alpha-methyl CoA) antigen and p63 antigen were performed. A review of the literature is included.A single focus of invasive prostatic adenocarcinoma was identified in the periphery of the mid-left, posterior quadrant of the prostate. Approximately 17 mm from this adenocarcinoma, within the verumontanum of the prostatic urethra, there was a 3 mm maximal dimension carcinoid tumor. CONCLUSION: Based on different histological features and antigenic profiles, we concluded that the two tumors were distinct. PMID- 20205832 TI - Role of Receptor-Interacting Protein 140 in human fat cells. AB - BACKGROUND: Mice lacking Receptor-interacting protein 140 (RIP140) have reduced body fat which at least partly is mediated through increased lipid and glucose metabolism in adipose tissue. In humans, RIP140 is lower expressed in visceral white adipose tissue (WAT) of obese versus lean subjects. We investigated the role of RIP140 in human subcutaneous WAT, which is the major fat depot of the body. METHODS: Messenger RNA levels of RIP140 were measured in samples of subcutaneous WAT from women with a wide variation in BMI and in different human WAT preparations. RIP140 mRNA was knocked down with siRNA in in vitro differentiated adipocytes and the impact on glucose transport and mRNA levels of target genes determined. RESULTS: RIP140 mRNA levels in subcutaneous WAT were decreased among obese compared to lean women and increased by weight-loss, but did not associate with mitochondrial DNA copy number. RIP140 expression increased during adipocyte differentiation in vitro and was higher in isolated adipocytes compared to corresponding pieces of WAT. Knock down of RIP140 increased basal glucose transport and mRNA levels of glucose transporter 4 and uncoupling protein 1. CONCLUSIONS: Human RIP140 inhibits glucose uptake and the expression of genes promoting energy expenditure in the same fashion as the murine orthologue. Increased levels of human RIP140 in subcutaneous WAT of lean subjects may contribute to economize on energy stores. By contrast, the function and expression pattern does not support that RIP140 regulate human obesity. PMID- 20205833 TI - Hypothyroidism among military infants born in countries of varied iodine nutrition status. AB - BACKGROUND: Iodine deficiency is a global problem representing the most common preventable cause of mental retardation. Recently, the impact of subtle deficiencies in iodine intake on children and pregnant women has been questioned. This study was designed to compare hypothyroidism among infants born to US military families in countries of varied iodine nutrition status. METHODS: A cohort design was used to analyze data from the Department of Defense Birth and Infant Health Registry for infants born in 2000-04 (n = 447,691). Hypothyroidism was defined using ICD-9-CM codes from the first year of life (n = 698). The impact of birth location on hypothyroidism was assessed by comparing rates in Germany, Japan, and US territories with the United States, while controlling for infant gender, plurality, gestational age, maternal age, maternal military status, and military parent's race/ethnicity. RESULTS: Hypothyroidism did not vary by birth location with adjusted odds ratios (OR) as follows: Germany (OR 0.82, [95% CI 0.50, 1.35]), Japan (OR 0.67, [95% CI 0.37, 1.22]), and US territories (OR 1.29, [95% CI 0.57, 2.89]). Hypothyroidism was strongly associated with preterm birth (OR 5.44, [95% CI 4.60, 6.42]). Hypothyroidism was also increased among infants with civilian mothers (OR 1.24, [95% CI 1.00, 1.54]), and older mothers, especially ages 40 years and older (OR 2.09, [95% CI 1.33, 3.30]). CONCLUSIONS: In this study, hypothyroidism in military-dependent infants did not vary by birth location, but was associated with other risk factors, including preterm birth, civilian maternal status, and advanced maternal age. PMID- 20205834 TI - Creatine supplementation spares muscle glycogen during high intensity intermittent exercise in rats. AB - BACKGROUND: The effects of creatine (CR) supplementation on glycogen content are still debatable. Thus, due to the current lack of clarity, we investigated the effects of CR supplementation on muscle glycogen content after high intensity intermittent exercise in rats. METHODS: First, the animals were submitted to a high intensity intermittent maximal swimming exercise protocol to ensure that CR supplementation was able to delay fatigue (experiment 1). Then, the CR-mediated glycogen sparing effect was examined using a high intensity intermittent sub maximal exercise test (fixed number of bouts; six bouts of 30-second duration interspersed by two-minute rest interval) (experiment 2). For both experiments, male Wistar rats were given either CR supplementation or placebo (Pl) for 5 days. RESULTS: As expected, CR-supplemented animals were able to exercise for a significant higher number of bouts than Pl. Experiment 2 revealed a higher gastrocnemius glycogen content for the CR vs. the Pl group (33.59%). Additionally, CR animals presented lower blood lactate concentrations throughout the intermittent exercise bouts compared to Pl. No difference was found between groups in soleus glycogen content. CONCLUSION: The major finding of this study is that CR supplementation was able to spare muscle glycogen during a high intensity intermittent exercise in rats. PMID- 20205835 TI - Mobile phone radiation health risk controversy: the reliability and sufficiency of science behind the safety standards. AB - There is ongoing discussion whether the mobile phone radiation causes any health effects. The International Commission on Non-Ionizing Radiation Protection, the International Committee on Electromagnetic Safety and the World Health Organization are assuring that there is no proven health risk and that the present safety limits protect all mobile phone users. However, based on the available scientific evidence, the situation is not as clear. The majority of the evidence comes from in vitro laboratory studies and is of very limited use for determining health risk. Animal toxicology studies are inadequate because it is not possible to "overdose" microwave radiation, as it is done with chemical agents, due to simultaneous induction of heating side-effects. There is a lack of human volunteer studies that would, in unbiased way, demonstrate whether human body responds at all to mobile phone radiation. Finally, the epidemiological evidence is insufficient due to, among others, selection and misclassification bias and the low sensitivity of this approach in detection of health risk within the population. This indicates that the presently available scientific evidence is insufficient to prove reliability of the current safety standards. Therefore, we recommend to use precaution when dealing with mobile phones and, whenever possible and feasible, to limit body exposure to this radiation. Continuation of the research on mobile phone radiation effects is needed in order to improve the basis and the reliability of the safety standards. PMID- 20205836 TI - Idiopathic sclerosing mesenteritis in paediatrics: Report of a successfully treated case and a review of literature. AB - A 6 year old female with symptoms of small bowel obstruction underwent an exploratory laparotomy which revealed widespread evidence of inflammatory fibrotic adhesions involving the jejunal mesentery. In view of persistent growth failure, chronic anaemia, elevated acute phase reactants and imaging evidence of a diffuse progressive inflammatory process, the child was treated with corticosteroids and methotrexate with complete response. The literature on juvenile idiopathic sclerosing mesenteritis has been reviewed. PMID- 20205837 TI - Bridging the gaps among research, policy and practice in ten low- and middle income countries: development and testing of a questionnaire for researchers. AB - BACKGROUND: A questionnaire could assist researchers, policymakers, and healthcare providers to describe and monitor changes in efforts to bridge the gaps among research, policy and practice. No questionnaire focused on researchers' engagement in bridging activities related to high-priority topics (or the potential correlates of their engagement) has been developed and tested in a range of low- and middle-income countries (LMICs). METHODS: Country teams from ten LMICs (China, Ghana, India, Iran, Kazakhstan, Laos, Mexico, Pakistan, Senegal, and Tanzania) participated in the development and testing of a questionnaire. To assess reliability we calculated the internal consistency of items within each of the ten conceptual domains related to bridging activities (specifically Cronbach's alpha). To assess face and content validity we convened several teleconferences and a workshop. To assess construct validity we calculated the correlation between scales and counts (i.e., criterion measures) for the three countries that employed both and we calculated the correlation between different but theoretically related (i.e., convergent) measures for all countries. RESULTS: Internal consistency (Cronbach's alpha) for sets of related items was very high, ranging from 0.89 (0.86-0.91) to 0.96 (0.95-0.97), suggesting some item redundancy. Both face and content validity were determined to be high. Assessments of construct validity using criterion-related measures showed statistically significant associations for related measures (with gammas ranging from 0.36 to 0.73). Assessments using convergent measures also showed significant associations (with gammas ranging from 0.30 to 0.50). CONCLUSIONS: While no direct comparison can be made to a comparable questionnaire, our findings do suggest a number of strengths of the questionnaire but also the need to reduce item redundancy and to test its capacity to monitor changes over time. PMID- 20205838 TI - Bridging the gaps among research, policy and practice in ten low- and middle income countries: development and testing of questionnaire for health-care providers. AB - BACKGROUND: The reliability and validity of instruments used to survey health care providers' views about and experiences with research evidence have seldom been examined. METHODS: Country teams from ten low- and middle-income countries (China, Ghana, India, Iran, Kazakhstan, Laos, Mexico, Pakistan, Senegal and Tanzania) participated in the development, translation, pilot-testing and administration of a questionnaire designed to measure health-care providers' views and activities related to improving their clinical practice and their awareness of, access to and use of research evidence, as well as changes in their clinical practice that they attribute to particular sources of research evidence that they have used. We use internal consistency as a measure of the questionnaire's reliability and, whenever possible, we use explanatory factor analyses to assess the degree to which questions that pertain to a single domain actually address common themes. We assess the questionnaire's face validity and content validity and, to a lesser extent, we also explore its criterion validity. RESULTS: The questionnaire has high internal consistency, with Cronbach's alphas between 0.7 and 0.9 for 16 of 20 domains and sub-domains (identified by factor analyses). Cronbach's alphas are greater than 0.9 for two domains, suggesting some item redundancy. Pre- and post-field work assessments indicate the questionnaire has good face validity and content validity. Our limited assessment of criterion validity shows weak but statistically significant associations between the general influence of research evidence among providers and more specific measures of providers' change in approach to preventing or treating a clinical condition. CONCLUSION: Our analysis points to a number of strengths of the questionnaire--high internal consistency (reliability) and good face and content validity--but also to areas where it can be shortened without losing important conceptual domains. PMID- 20205839 TI - Proteomic analysis of prolactinoma cells by immuno-laser capture microdissection combined with online two-dimensional nano-scale liquid chromatography/mass spectrometry. AB - BACKGROUND: Pituitary adenomas, the third most common intracranial tumor, comprise nearly 16.7% of intracranial neoplasm and 25%-44% of pituitary adenomas are prolactinomas. Prolactinoma represents a complex heterogeneous mixture of cells including prolactin (PRL), endothelial cells, fibroblasts, and other stromal cells, making it difficult to dissect the molecular and cellular mechanisms of prolactin cells in pituitary tumorigenesis through high-throughout omics analysis. Our newly developed immuno-laser capture microdissection (LCM) method would permit rapid and reliable procurement of prolactin cells from this heterogeneous tissue. Thus, prolactin cell specific molecular events involved in pituitary tumorigenesis and cell signaling can be approached by proteomic analysis. RESULTS: Proteins from immuno-LCM captured prolactin cells were digested; resulting peptides were separated by two dimensional-nanoscale liquid chromatography (2D-nanoLC/MS) and characterized by tandem mass spectrometry. All MS/MS spectrums were analyzed by SEQUEST against the human International Protein Index database and a specific prolactinoma proteome consisting of 2243 proteins was identified. This collection of identified proteins by far represents the largest and the most comprehensive database of proteome for prolactinoma. Category analysis of the proteome revealed a widely unbiased access to various proteins with diverse functional characteristics. CONCLUSIONS: This manuscript described a more comprehensive proteomic profile of prolactinomas compared to other previous published reports. Thanks to the application of immuno-LCM combined with online two-dimensional nano-scale liquid chromatography here permitted identification of more proteins and, to our best knowledge, generated the largest prolactinoma proteome. This enlarged proteome would contribute significantly to further understanding of prolactinoma tumorigenesis which is crucial to the management of prolactinomas. PMID- 20205840 TI - A low alpha-linolenic intake during early life increases adiposity in the adult guinea pig. AB - BACKGROUND: The composition of dietary fatty acids (FA) during early life may impact adult adipose tissue (AT) development. We investigated the effects of alpha-linolenic acid (ALA) intake during the suckling/weaning period on AT development and metabolic markers in the guinea pig (GP). METHODS: Newborn GP were fed a 27%-fat diet (w/w %) with high (10%-ALA group), moderate (2.4%-ALA group) or low (0.8%-ALA group) ALA content (w/w % as total FA) until they were 21 days old (d21). Then all animals were switched to a 15%-fat diet containing 2% ALA (as total FA) until 136 days of age (d136). RESULTS: ALA and docosapentaenoic acid measured in plasma triglycerides (TG) at d21 decreased with decreasing ALA intake. Total body fat mass was not different between groups at d21. Adipose tissue TG synthesis rates and proliferation rate of total adipose cells, as assessed by 2H2O labelling, were unchanged between groups at d21, while hepatic de novo lipogenesis was significantly 2-fold increased in the 0.8%-ALA group. In older GP, the 0.8%-ALA group showed a significant 15-%-increased total fat mass (d79 and d107, p < 0.01) and epididymal AT weight (d136) and tended to show higher insulinemia compared to the 10%-ALA group. In addition, proliferation rate of cells in the subcutaneous AT was higher in the 0.8%-ALA (15.2 +/- 1.3% new cells/5d) than in the 10%-ALA group (8.6 +/- 1.7% new cells/5d, p = 0.021) at d136. AT eicosanoid profiles were not associated with the increase of AT cell proliferation. CONCLUSION: A low ALA intake during early postnatal life promotes an increased adiposity in the adult GP. PMID- 20205841 TI - The impact of provider-initiated (opt-out) HIV testing and counseling of patients with sexually transmitted infection in Cape Town, South Africa: a controlled trial. AB - BACKGROUND: The effectiveness of provider-initiated HIV testing and counseling (PITC) for patients with sexually transmitted infection (STI) in resource constrained settings are of particular concern for high HIV prevalence countries like South Africa. This study evaluated whether the PITC approach increased HIV testing amongst patients with a new episode of sexually transmitted infection, as compared to standard voluntary counseling and testing (VCT) at the primary care level in South Africa, a high prevalence and low resource setting. METHODS: The design was a pragmatic cluster-controlled trial with seven intervention and 14 control clinics in Cape Town. Nurses in intervention clinics integrated PITC into standard HIV care with few additional resources, whilst lay counselors continued with the VCT approach in control clinics. Routine data were collected for a six month period following the intervention in 2007, on new STI patients who were offered and who accepted HIV testing. The main outcome measure was the proportion of new STI patients tested for HIV, with secondary outcomes being the proportions who were offered and who declined the HIV test. RESULTS: A significantly higher proportion of new STI patients in the intervention group tested for HIV as compared to the control group with (56.4% intervention versus 42.6% control, p = 0.037). This increase was achieved despite a significantly higher proportion intervention group declining testing when offered (26.7% intervention versus 13.5% control, p = 0.0086). Patients were more likely to be offered HIV testing in intervention clinics, where providers offered the HIV test to 76.8% of new STI patients versus 50.9% in the control group (p = 0.0029). There was significantly less variation in the main outcomes across the intervention clinics, suggesting that the intervention also facilitated more consistent performance. CONCLUSIONS: PITC was successful in three ways: it increased the proportion of new STI patients tested for HIV; it increased the proportion of new STI patients offered HIV testing; and it delivered more consistent performance across clinics. Recommendations are made for increasing the impact and feasibility of PITC in high HIV prevalence and resource-constrained settings. These include more flexible use of clinical and lay staff, and combining PITC with VCT and other community-based approaches to HIV testing. TRIAL REGISTRATION: Controlled trial ISRCTN93692532. PMID- 20205842 TI - A specific scoliosis classification correlating with brace treatment: description and reliability. AB - BACKGROUND: Spinal classification systems for scoliosis which were developed to correlate with surgical treatment historically have been used in brace treatment as well. Previously, there had not been a scoliosis classification system developed specifically to correlate with brace design and treatment. The purpose of this study is to show the intra- and inter- observer reliability of a new scoliosis classification system correlating with brace treatment. METHODS: An original classification system ("Rigo Classification") was developed in order to define specific principles of correction required for efficacious brace design and fabrication. The classification includes radiological as well as clinical criteria. The radiological criteria are utilized to differentiate five basic types of curvatures including: (I) imbalanced thoracic (or three curves pattern), (II) true double (or four curve pattern), (III) balanced thoracic and false double (non 3 non 4), (IV) single lumbar and (V) single thoracolumbar. In addition to the radiological criteria, the Rigo Classification incorporates the curve pattern according to SRS terminology, the balance/imbalance at the transitional point, and L4-5 counter-tilting. To test the intra-and inter observer reliability of the Rigo Classification, three observers (1 MD, 1 PT and 1 CPO) measured (and one of them, the MD, re-measured) 51 AP radiographs including all curvature types. RESULTS: The intra-observer Kappa value was 0.87 (acceptance >0.70). The inter-observer Kappa values fluctuated from 0.61 to 0.81 with an average of 0.71 (acceptance > 0.70). CONCLUSIONS: A specific scoliosis classification which correlates with brace treatment has been proposed with an acceptable intra-and inter-observer reliability. PMID- 20205843 TI - PrPSc accumulation in neuronal plasma membranes links Notch-1 activation to dendritic degeneration in prion diseases. AB - Prion diseases are disorders of protein conformation in which PrPC, the normal cellular conformer, is converted to an abnormal, protease-resistant conformer rPrPSc. Approximately 80% of rPrPSc accumulates in neuronal plasma membranes where it changes their physical properties and profoundly affects membrane functions. In this review we explain how rPrPSc is transported along axons to presynaptic boutons and how we envision the conversion of PrPC to rPrPSc in the postsynaptic membrane. This information is a prerequisite to the second half of this review in which we present evidence that rPrPSc accumulation in synaptic regions links Notch-1 signaling with the dendritic degeneration. The hypothesis that the Notch-1 intracellular domain, NICD, is involved in prion disease was tested by treating prion-infected mice with the gamma-secretase inhibitor (GSI) LY411575, with quinacrine (Qa), and with the combination of GSI + Qa. Surprisingly, treatment with GSI alone markedly decreased NICD but did not prevent dendritic degeneration. Qa alone produced near normal dendritic trees. The combined GSI + Qa treatment resulted in a richer dendritic tree than in controls. We speculate that treatment with GSI alone inhibited both stimulators and inhibitors of dendritic growth. With the combined GSI + Qa treatment, Qa modulated the effect of GSI perhaps by destabilizing membrane rafts. GSI + Qa decreased PrPSc in the neocortex and the hippocampus by 95%, but only by 50% in the thalamus where disease was begun by intrathalamic inoculation of prions. The results of this study indicate that GSI + Qa work synergistically to prevent dendrite degeneration and to block formation of PrPSc. PMID- 20205844 TI - Successful treatment of HIV-associated multicentric Castleman's disease and multiple organ failure with rituximab and supportive care: a case report. AB - INTRODUCTION: Multicentric Castleman's Disease (MCD), a lymphoproliferative disorder associated with Human Herpes Virus-8 (HHV-8) infection, is increasing in incidence amongst HIV patients. This condition is associated with lymphadenopathy, polyclonal gammopathy, hepato-splenomegaly and systemic symptoms. A number of small studies have demonstrated the efficacy of the anti CD20 monoclonal antibody, rituximab, in treating this condition. CASE PRESENTATION: We report the case of a 46 year old Zambian woman who presented with pyrexia, diarrhoea and vomiting, confusion, lymphadenopathy, and renal failure. She rapidly developed multiple organ failure following the initiation of treatment of MCD with rituximab. Following admission to intensive care (ICU), she received prompt multi-organ support. After 21 days on the ICU she returned to the haematology medical ward, and was discharged in remission from her disease after 149 days in hospital. CONCLUSION: Rituximab, the efficacy of which has thus far been examined predominantly in patients outside the ICU, in conjunction with extensive organ support was effective treatment for MCD with associated multiple organ failure. There is, to our knowledge, only one other published report of its successful use in an ICU setting, where it was combined with cyclophosphamide, adriamycin and prednisolone. Reports such as ours support the notion that critically unwell patients with HIV and haematological disease can benefit from intensive care. PMID- 20205845 TI - Primary bony non-Hodgkin lymphoma of the cervical spine: a case report. AB - INTRODUCTION: Non-Hodgkin lymphoma primarily originating from the bone is exceedingly rare. To our knowledge, this is the first report of primary bone lymphoma presenting with progressive cord compression from an origin in the cervical spine. Herein, we discuss the unusual location in this case, the presenting symptoms, and the management of this disease. CASE PRESENTATION: We report on a 23-year-old Caucasian-American man who presented with two months of night sweats, fatigue, parasthesias, and progressive weakness that had progressed to near quadriplegia. Magnetic resonance (MR) imaging demonstrated significant cord compression seen primarily at C7. Surgical management, with corpectomy and dorsal segmental fusion, in combination with adjuvant chemotherapy and radiation therapy, halted the progression of the primary disease and preserved neurological function. Histological analysis demonstrated an aggressive anaplastic large cell lymphoma. CONCLUSION: Isolated primary bony lymphoma of the spine is exceedingly rare. As in our case, the initial symptoms may be the result of progressive cervical cord compression. Anterior corpectomy with posterolateral decompression and fusion succeeded in preventing progressive neurologic decline and maintaining quality of life. The reader should be aware of the unique presentation of this disease and that surgical management is a successful treatment strategy. PMID- 20205846 TI - History of the discovery of the malaria parasites and their vectors. AB - Malaria is caused by infection with protozoan parasites belonging to the genus Plasmodium transmitted by female Anopheles species mosquitoes. Our understanding of the malaria parasites begins in 1880 with the discovery of the parasites in the blood of malaria patients by Alphonse Laveran. The sexual stages in the blood were discovered by William MacCallum in birds infected with a related haematozoan, Haemoproteus columbae, in 1897 and the whole of the transmission cycle in culicine mosquitoes and birds infected with Plasmodium relictum was elucidated by Ronald Ross in 1897. In 1898 the Italian malariologists, Giovanni Battista Grassi, Amico Bignami, Giuseppe Bastianelli, Angelo Celli, Camillo Golgi and Ettore Marchiafava demonstrated conclusively that human malaria was also transmitted by mosquitoes, in this case anophelines. The discovery that malaria parasites developed in the liver before entering the blood stream was made by Henry Shortt and Cyril Garnham in 1948 and the final stage in the life cycle, the presence of dormant stages in the liver, was conclusively demonstrated in 1982 by Wojciech Krotoski. This article traces the main events and stresses the importance of comparative studies in that, apart from the initial discovery of parasites in the blood, every subsequent discovery has been based on studies on non-human malaria parasites and related organisms. PMID- 20205847 TI - Giant cell tumor of the anterior rib masquerading as a breast mass: a case report and review of current literature. AB - INTRODUCTION: Giant cell tumor (GCT) is an aggressive, but usually benign bone neoplasm most commonly arising in the metaphysis/epiphyses of long bones. While they are categorized as benign tumors, they can be locally aggressive and clinically have metastatic potential. The most common locations of this tumor include the distal femur, proximal tibia, and distal radius. We report a GCT arising in an atypical location and mimicking a breast mass. CASE PRESENTATION: This case was diagnosed at a large cancer center in Florida. Pertinent clinical findings were obtained from chart review and inter-departmental consultation. Radiologically, the initial impression included a deep-seated breast cancer with local chest wall invasion. Further evaluation revealed the mass to be an expansile rib lesion with extraosseous soft tissue invasion. Histological examination of the biopsy specimen showed bland multi-nucleated giant cells and mononuclear cells whose nuclei were morphologically similar. No necrosis, pleomorphism or mitotic activity was identified. No chondroid or osseous elements were present. CONCLUSION: The histological features of bland mononuclear and multinucleated giant cells along with the lack of any additional mesenchymal elements led to the diagnosis of giant cell tumor. Resection of tumor was performed. The patient is disease free as of the last follow-up visit. This case is important as it shows where the physician must keep this diagnosis in mind whenever a deeply located breast mast is present. PMID- 20205848 TI - Subcutaneus leiomyosarcoma of the neck: a case report. AB - INTRODUCTION: Leiomyosarcomas are rare tumors. The most common site for head and neck leiomyosarcomas is the oral cavity, followed by sinonasal tract and skin. Subcutaneous leiomyosarcomas are thought to arise from small to medium-sized blood vessels in the subcutaneous tissue. CASE PRESENTATION: A 67-year-old female patient underwent excision of a slow growing neck mass of the left posterior neck triangle after a thorough clinical and laboratory examination. The lesion was located in the subcutis and fine needle aspiration biopsy revealed malignant features. Histology revealed subcutaneous leiomyosarcoma and the patient is free from local recurrence and distant metastases 3 years after wide excision of the lesion. CONCLUSIONS: The primary modality of therapy of subcutaneous leiomyosarcoma is surgery, adjuvant radiotherapy or chemotherapy may be used for control of local recurrence, in case of positive surgical margins, high-grade or large tumors. PMID- 20205849 TI - "Color Timer" mice: visualization of neuronal differentiation with fluorescent proteins. AB - The molecular mechanisms governing the differentiation of neural stem cells (NSCs) into neuronal progenitor cells and finally into neurons are gradually being revealed. The lack of convenient means for real-time determination of the stages of differentiation of individual neural cells, however, has been hindering progress in elucidating the mechanisms. In order to be able to easily identify the stages of differentiation of neural cells, we have been attempting to establish a mouse system that would allow progression of neuronal differentiation to be visualized based on transitions between fluorescence colors by using a combination of mouse genetics and the ever-expanding repertoire of fluorescent proteins. In this study we report the initial version of such a mouse system, which we call "Color Timer." We first generated transgenic (Tg; nestin/KOr Tg) mice in which production of the fluorescent protein Kusabira-Orange (KOr) is controlled by the gene regulatory elements within the 2nd intronic enhancer of the nestin gene, which is a good marker for NSCs, so that NSCs would emit orange fluorescence upon excitation. We then confirmed by immunohistochemical and immunocytochemical analyses that the KOr fluorescence closely reflected the presence of the Nestin protein. We also confirmed by a neurosphere formation assay that the intensity of the KOr fluorescence correlated with "stemness" of the cell and it was possible to readily identify NSCs in the two neurogenic regions, namely the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricle, in the brain of adult nestin/KOr Tg mice by the orange fluorescence they emitted. We then crossed nestin/KOr mice with doublecortin enhanced Green Fluorescent Protein Tg mice, whose immature neurons emit green fluorescence upon excitation, and it was possible to visualize the progress of NSC-to-neuron differentiation by the transition between fluorescence colors from orange to green. This two-color initial version of the "Color Timer" mouse system will provide a powerful new tool for neurogenesis research. PMID- 20205850 TI - Neonatal epididymo-orchitis caused by Pseudomonas aeruginosa: a case report. AB - Epididymitis and epididymo-orchitis are an uncommon causes of acute testicular pain in neonatal boys, epididymo-orchitis is infection or inflammation of epididymis and testis it's may be associated with urinary tract infections or reflux of urine predisposed by an underlying vasal anomaly. Pediatricians should examine the testicles meticulously after a baby is born.We report a 7 day-old boy with urinary malformations (ureteral duplication, ureterocel and right hydro ureteronephrosis) who presented with acute scrotum. The ultrasonography exploration of the testis showed findings consistent with epididymo-orchitis, confirmed by the needle scrotal aspiration of the pus. Further radiological investigations of urinary tract showed the multiples malformations. Epididymo orchitis should be suspected initially with abnormal physical signs and laboratory findings. Prompt prescription of antibiotics is mandatory, and appropriate therapeutic measures (antibiotics) should be undertaken to prevent recurrences and sequelae. PMID- 20205851 TI - Management of Tennis Elbow with sodium hyaluronate periarticular injections. AB - OBJECTIVES: To determine the efficacy and safety of peri-articular hyaluronic acid injections in chronic lateral epicondylosis (tennis elbow). DESIGN: Prospective randomized clinical trial in primary care sport medicine. PATIENTS: Three hundred and thirty one consecutive competitive racquette sport athletes with chronic (>3 months) lateral epicondylosis were administered 2 injections (first injection at baseline) into the subcutaneous tissue and muscle 1 cm. from the lateral epicondyle toward the primary point of pain using a two-dimensional fanning technique. A second injection was administered 1 week later. OUTCOMES MEASURES: Assessments were done at baseline, days 7, 14, 30, 90 and 356. Efficacy measures included patient's visual analogue scale (VAS) of pain at rest (0-100 mm) and following assessment of grip strength (0-100 mm). Grip strength was determined using a jamar hydraulic hand dynamometer. Other assessments included patients' global assessment of elbow injury (5 point categorical scale; 1 = no disability, 5 = maximal disability), patients' assessment of normal function/activity (5 point categorical scale), patients/physician satisfaction assessment (10 point categorical scale), time to return to pain-free and disability-free sport and adverse events as per WHO definition. Differences between groups were determined using an intent-to-treat ANOVA. RESULTS: Average age of the study population was 49 years (+/- 12 years). One hundred and sixty five patients were randomized to the HA and 166 were randomized to the control groups. The change in VAS pain was -6.7 (+/- 2.0) for HA vs -1.3 (+/- 1.5) for control (p < 0.001). The VAS post handgrip was -7.8 (+/- 1.3) vs +0.3 (+/- 2.0) (p < 0.001) which corresponded to a significant improvement in grip of 2.6 kg in the HA vs control groups (p < 0.01). Statistically significant improvement in patients' global assessment of elbow injury (p < 0.02), patients' assessment of normal function/activity (p < 0.05) and patients/physician satisfaction assessment (p < 0.05) were also observed favoring the HA group. Time to return to pain-free and disability-free sport was 18 (+/- 11) days in the HA group but was not achieved in the control group. VAS changes were maintained in the HA group at each followup while those in the control significantly declined from baseline. Assessment of patient and physician satisfaction continued to favor the HA group at subsequent followup. CONCLUSION: Peri-articular HA treatment for tennis elbow was significantly better than control in improving pain at rest and after maximal grip testing. Further, HA treatment was highly satisfactory by patients and physicians and resulted in better return to pain free sport compared to control. PMID- 20205852 TI - Four different malignancies in one patient: a case report. AB - Cancer survivors have a higher risk of new primary cancer, in the same or in another organ, than the general population. We report a 78-year-old women who has metachronous quadruple adenocarcinoma, includes bilateral breast cancer, ovarian cancer and retroperitoneal neuroendocrine carcinoma. The development of second cancer in cancer survivors can be expected but third or higher order malignancies are rare. PMID- 20205853 TI - The management of pneumothorax in patients with anorexia nervosa: A case report and review of the literature. AB - Of the many body systems adversely affected by severe anorexia nervosa (AN), the pulmonary system is relatively spared. However, in the face of severe malnutrition of AN, the lung may undergo architectural changes that adversely affect its integrity and healing capacity. We report herein a case of a pneumothorax in a patient with severe AN, in which standard approaches to manage the pneumothorax were unsuccessful. Despite prolonged tube thoracostomy drainage, and subsequent thoracoscopic pleuredesis, the patient continued to have an air leak and non-resolution of her pneumothorax. We review the literature and discuss alternative approaches in this patient population. PMID- 20205854 TI - Endovascular treatment of thoracoabdominal aortic aneurysm: a case report. AB - INTRODUCTION: Thoracoabdominal aortic aneurysms usually present in elderly patients with serious renal, pulmonary, cerebral, or cardiac comorbidities that pose a great challenge to the attending surgeon. Endovascular techniques for the treatment of thoracoabdominal aneurysms are not yet widely used due to limitations associated with them, such as spinal and visceral ischemia. CASE PRESENTATION: An 87-year-old Caucasian man with a symptomatic Crawford type I thoracoabdominal aortic aneurysm was treated successfully with a long tube stent graft using endovascular techniques and without any complication in follow-up examinations. The stent was placed distal to the left subclavian artery, and proximal to the celiac axis. CONCLUSION: The use of endovascular stents for long segment thoracoabdominal aortic aneurysms needs to undergo clinical investigation to determine whether this procedure decreases morbidity and mortality rates. PMID- 20205855 TI - Prolactinoma presenting as chronic anaemia with osteoporosis: a case report. AB - INTRODUCTION: Unexplained anaemia is a rare mode of presentation for prolactinoma. We describe a case of a man, with chronic anaemia ascribed to old age. Six years later, he was evaluated and diagnosed with a prolactinoma and resultant osteoporosis. Prolactinoma in old people may present insidiously with chronic anaemia and osteoporosis with or without sexual dysfunction. CASE PRESENTATION: We describe the case of a 70-year-old Caucasian man who presented with mild anaemia and tiredness. His anaemia was investigated and ascribed to senescence. Endocrine causes were not considered or tested for. Six years later, he was again referred. Reassessment and direct questioning revealed long-standing sexual dysfunction. It was also discovered that our patient had fractured his radius twice, with minor trauma, during the preceding year. His serum prolactin was massively increased and a magnetic resonance imaging (MRI) scan of the head demonstrated a pituitary mass consistent with a prolactinoma. Dual X-ray absorptiometry revealed osteoporosis. Treatment of the prolactinoma led to a reduction in his serum prolactin with a rise in his haemoglobin to normal levels. This suggested that the prolactinoma was present during the initial presentation and was the cause of his anaemia. CONCLUSION: This case highlights the importance of fully evaluating and investigating unexplained anaemia in older people and that endocrine causes should be considered. Osteoporosis also requires evaluation with secondary causes considered. PMID- 20205856 TI - Prompt improvement of a pressure ulcer by the administration of high viscosity semi-solid nutrition via a nasogastric tube in a man with tuberculosis: a case report. AB - INTRODUCTION: Semi-solid nutrition with high viscosity has the advantage of reducing gastroesophageal reflux and diarrhea and shortens the duration of administration compared with liquid nutrition. This is the first report describing the administration of semi-solid nutrition with high viscosity via a nasogastric tube, which achieved a remarkable improvement in the patient's nutritional state. CASE PRESENTATION: A 67-year-old man (mongoloid race, Japanese) with tuberculosis, a pressure ulcer and malnutrition was admitted to our hospital. He also had right hemiplegia, dysphagia and aphasia as sequelae of a cerebral hemorrhage. Before his admission, he had been treated at another hospital with 600 kcal/day of liquid nutrition via a nasogastric tube, which was insufficient and induced severe malnutrition. After he was admitted to our hospital, we increased the quantity of his liquid nutrition without success because of complications, specifically diarrhea and gastroesophageal reflux. As it was difficult to confirm whether or not he would accept gastrostomy feeding, we administered semi-solid nutrition with high viscosity (20,000 mPa x s) via a large-bore nasogastric tube (18 French). Soon after he was started on semi-solid nutrition, his pressure ulcer and malnutrition improved without diarrhea or complications accompanying the large-bore nasogastric tube. CONCLUSION: When patients have problems with liquid nutrition, such as diarrhea or gastroesophageal reflux, semi-solid nutrition via a nasogastric tube is a useful method of achieving improvements in nutritional state in a short period of time. PMID- 20205857 TI - Spatial distribution of African Animal Trypanosomiasis in Suba and Teso districts in Western Kenya. AB - BACKGROUND: Studies on the epidemiology of African Animal Trypanosomiasis (AAT) rarely consider the spatial dimension of disease prevalence. This problem is confounded by use of parasitological diagnostic methods of low sensitivity in field surveys. Here we report a study combining highly sensitive and species specific molecular diagnostic methods, and Geographical information system (GIS) for spatial analysis of trypanosome infection patterns, to better understand its epidemiology. Blood samples from 44 and 59 animals randomly selected from Teso and Suba districts respectively were screened for trypanosomes using PCR diagnostic assays. Spatial distribution of the positive cases was mapped and average nearest neighbour analysis used to determine the spatial pattern of trypanosome cases detected. FINDINGS: Trypanosome prevalence of 41% and 29% in Suba and Teso districts respectively was observed. T. vivax infections were most prevalent in both areas. Higher proportions of T. brucei infections (12%) were observed in Suba, a known sleeping sickness foci compared with 2% in Teso. Average nearest neighbour analysis showed the pattern of trypanosome infections as random. An overlay with tsetse maps showed cases lying outside the tsetse infested areas, mostly being cases of T. vivax which is known to be transmitted both biologically by tsetse and mechanically by biting flies. CONCLUSION: These findings suggest a need to design control strategies that target not just the biological vector tsetse, but also the parasite in cattle in order to clear the possibly mechanically transmitted T. vivax infections. There is need to also review the accuracy of available tsetse maps. PMID- 20205858 TI - From line to dots: an improved computerised rod and frame system for testing subjective visual vertical and horizontal. AB - BACKGROUND: Perception of subjective visual vertical (SVV) and horizontal (SVH) has traditionally been measured by rotating a mechanical rod either with or without a frame present. The computerised rod and frame (CRAF) system has previously only been used to measure SVV. We have expanded the use of this system by testing its feasibility to measure SVH. This was done by comparing two groups of subjects (n = 103) randomly assigned to be tested for SVV or SVH. FINDINGS: Preliminary results showed a higher than expected percentage of individuals with SVH errors < 0.5 degrees . This was attributed to additional visual cues provided by the changing appearance of the rod as it approached the horizontal. A solution to this problem was sought by replacing the rod by two dots to mark its ends. In a second investigation 30 subjects were tested using both the "rod as line" and "rod as dots" presentation. Bland and Altman analysis showed no difference between the rod and dots presentations in the measurement of SVV, but confirmed a fixed error of -0.93 degrees between rods and dots for SVH. Changing the rod from a line to dots in the computer system resulted in errors for both SVV and SVH that were comparable to previous studies using manual systems. CONCLUSIONS: The computerized rod and frame system may be improved by replacement of the line with two dots. This reduces clues provided to the subject by the appearance of the rod on the screen. PMID- 20205859 TI - Isolated pancreatic tuberculosis mimicking as carcinoma: a case report and review of the literature. AB - INTRODUCTION: Pancreatic tuberculosis is a rare disease even in endemic countries for tuberculosis. Here, we report a case of pancreatic tuberculosis from tuberculosis endemic zone presenting as obstructive jaundice mimicking pancreatic cancer. CASE PRESENTATION: A 41-year-old male presented with features of malignant obstructive jaundice. Ultrasonography and computed tomography scan showed mass in the pancreatic head and uncinate process. He underwent a pancreatoduodencetomy. Histological examination showed typical features of tuberculosis. Antitubercular drugs were started and he remains well six months after surgery. CONCLUSION: Tuberculosis should be considered as a differential diagnosis to an obscure pancreatic mass in younger or middle aged patient residing in tuberculosis endemic zone. PMID- 20205861 TI - Sedentary subjects have higher PAI-1 and lipoproteins levels than highly trained athletes. AB - Physical exercise protects against the development of cardiovascular disease, partly by lowering plasmatic total cholesterol, LDL-cholesterol and increased HDL cholesterol levels. In addition, it is now established that reduction plasmatic adiponectin and increased C-reactive protein (CRP) and plasminogen activator inhibitor-1 (PAI-1) levels play a role in the maintenance of an inflammatory state and in the development of cardiovascular disease. This study aimed to examine plasma lipid profile and inflammatory markers levels in individual with sedentary lifestyle and/or highly trained athletes at rest. METHODS: Fourteen male subjects (sedentary lifestyle n = 7 and highly trained athletes n = 7) were recruited. Blood samples were collected after an overnight fast (approximately 12 h). The plasmatic lipid profile (Triglycerides, HDL-cholesterol, LDL-cholesterol, total cholesterol, LDL-oxidized and total cholesterol/HDL-c ratio), glucose, adiponectin, C - reactive protein and PAI-1 levels were determined. RESULTS: Total cholesterol, LDL-cholesterol, TG and PAI-1 levels were lower in highly trained athletes group in relation to sedentary subjects (p < 0.01). In addition, we observed a positive correlation between PAI-1 and total cholesterol (r = 0.78; p < 0.0009), PAI-1 and LDL-c (r = 0.69; p < 0.006) and PAI-1 and TG levels (r = 0.56; p < 0.03). The plasma concentration of adiponectin, CRP, glucose, HDL cholesterol and total cholesterol/HDL-c ratio levels were not different. These results indicate that lifestyle associated with high intensity and high volume exercise induces changes favourable in the lipid profile and PAI-1 levels and may reduce risk cardiovascular diseases. PMID- 20205860 TI - Deposition and biokinetics of inhaled nanoparticles. AB - Particle biokinetics is important in hazard identification and characterization of inhaled particles. Such studies intend to convert external to internal exposure or biologically effective dose, and may help to set limits in that way. Here we focus on the biokinetics of inhaled nanometer sized particles in comparison to micrometer sized ones.The presented approach ranges from inhaled particle deposition probability and retention in the respiratory tract to biokinetics and clearance of particles out of the respiratory tract. Particle transport into the blood circulation (translocation), towards secondary target organs and tissues (accumulation), and out of the body (clearance) is considered. The macroscopically assessed amount of particles in the respiratory tract and secondary target organs provides dose estimates for toxicological studies on the level of the whole organism. Complementary, microscopic analyses at the individual particle level provide detailed information about which cells and subcellular components are the target of inhaled particles. These studies contribute to shed light on mechanisms and modes of action eventually leading to adverse health effects by inhaled nanoparticles.We review current methods for macroscopic and microscopic analyses of particle deposition, retention and clearance. Existing macroscopic knowledge on particle biokinetics and microscopic views on particle organ interactions are discussed comparing nanometer and micrometer sized particles. We emphasize the importance for quantitative analyses and the use of particle doses derived from real world exposures. PMID- 20205862 TI - Prostaglandin E2 regulates the expression of connective tissue growth factor (CTGF/CCN2) in human osteoarthritic chondrocytes via the EP4 receptor. AB - BACKGROUND: The regulatory mechanisms of the expression of connective tissue growth factor/CCN family member 2 (CTGF/CCN2) in human articular chondrocytes have not been clarified. We investigated the effect of prostaglandin E2 (PGE2) on CTGF/CCN2 expression in chondrocytes. FINDINGS: Articular cartilage samples were obtained from patients with osteoarthritis (OA) and chondrocytes were isolated and cultured in vitro. Chondrocytes were stimulated with PGE2, PGE receptor (EP) specific agonists, or interleukin (IL)-1. CTGF expression was analyzed using quantitative polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay. The inhibitory effects of EP receptor antagonists (for EP2 and EP4) against PGE2 stimulation were also investigated. Stimulation of chondrocytes with PGE2 or IL-1 significantly suppressed CTGF expression. The suppressive effect of PGE2 was reproduced by EP2/EP4 receptor agonists but not by EP1/EP3 receptor agonists, and was partially blocked by an EP4 receptor antagonist, suggesting that the EP4 receptor has a dominant role. CONCLUSIONS: PGE2 may be involved in the regulation of CTGF/CCN2 expression in human articular chondrocytes via the EP4 receptor. Elucidation of EP4-mediated signaling in chondrocytes may contribute to a better understanding of the effects of PGE2 in arthritis. PMID- 20205863 TI - Rupture of the ilio-psoas tendon after a total hip arthroplasty: an unusual cause of radio-lucency of the lesser trochanter simulating a malignancy. AB - Avulsion fracture or progressive radiolucency of lesser trochanter is considered a pathognomic finding in patients with malignancies. Although surgical release of the iliopsoas tendon may be required during a total hip arthroplasty (THA), there is no literature on spontaneous rupture of the ilio-psoas tendon after a THA causing significant functional impairment. We report here such a case, which developed progressive radiolucency of the lesser trochanter over six years after a THA, simulating a malignancy. The diagnosis was confirmed by MRI. Because of the chronic nature of the lesion, gross retraction of the tendon into the pelvis, and low demand of our patient, he was treated by physiotherapy and gait training. Injury to the ilio-psoas tendon can occur in various steps of the THA and extreme care should be taken to avoid this injury. Prevention during surgery is better, although there are no reports of repair in the THA setting. This condition should be considered in patients who present with progressive radioluceny of the lesser trochanter, especially in the setting of a hip/pelvic surgery. Awareness and earlier recognition of the signs and symptoms of this condition will aid in diagnosis and will direct appropriate management. PMID- 20205864 TI - Infant feeding modalities addressed in two different ways in Eastern Uganda. AB - BACKGROUND: Durations of exclusive breastfeeding (EBF) and predominant breastfeeding (PBF) from two different assessments, among the same mother-infant population, were investigated to determine the degree to which the assessments yielded overlapping results. METHODS: Thirty Ugandan mother-infant pairs were followed up weekly from birth to three months of age with weekly short-time feeding recall: the 24-hour recall asked prior to the 1-week recall. In addition, at week 6 and 12 dietary recalls since-birth were conducted. Variables for the duration of EBF and PBF were created from the short-time feeding recalls and the dietary recalls since-birth, respectively. Mean durations of EBF and PBF from the two assessments were compared with Kaplan Meier analysis at week 6 and 12. Reproducibility of dietary recall instruments was also assessed. RESULTS: At six weeks postpartum the mean durations of EBF were 0.50 weeks (95% CI: 0, 1.02) according to the weekly short-time recalls and 1.51 weeks (95% CI: 0.66, 2.35) according to the recall since-birth (Mantel-Cox test, p = 0.049). The mean durations of PBF were 4.07 weeks (95% CI: 3.38, 4.77) according to the frequent short-time recalls and 4.50 weeks (95% CI: 3.93, 5.07) according to the recall since-birth, (Mantel-Cox-test, p = 0.82). At twelve weeks the mean durations of EBF were 0.5 weeks (95% CI: 0, 1.1) according to the weekly short-time recalls and 1.4 weeks (95% CI: 0.1, 2.7) according to the recall since-birth (Mantel-Cox test, p = 0.15). The mean durations of PBF were 5.2 weeks (95% CI: 3.9, 6.5) according to the weekly short-time recalls and 6.6 weeks (95% CI: 5.4, 7.8) according to recall since-birth (Mantel-Cox-test, p = 0.20). Reports of feeding categories and early feeding practices showed high reproducibility. CONCLUSION: Comparing duration of EBF and PBF in this group of mother-infant pairs showed overlapping results from the weekly short-time assessment and the recall since birth at twelve weeks, with the latter yielding slightly longer duration of the respective feeding modalities. The retrospective recall since-birth could be assessed as a cost-reducing tool compared to the frequent follow-up addressing duration of respective infant feeding modalities for evaluation of programmes promoting safer infant feeding practices. TRIAL REGISTRATION: The study was part of formative studies for the ongoing study PROMISE EBF registered at http://clinicaltrials.gov, NCT00397150. PMID- 20205865 TI - Axotomy-induced neurotrophic withdrawal causes the loss of phenotypic differentiation and downregulation of NGF signalling, but not death of septal cholinergic neurons. AB - BACKGROUND: Septal cholinergic neurons account for most of the cholinergic innervations of the hippocampus, playing a key role in the regulation of hippocampal synaptic activity. Disruption of the septo-hippocampal pathway by an experimental transection of the fimbria-fornix drastically reduces the target derived trophic support received by cholinergic septal neurons, mainly nerve growth factor (NGF) from the hippocampus. Axotomy of cholinergic neurons induces a reduction in the number of neurons positive for cholinergic markers in the medial septum. In several studies, the reduction of cholinergic markers has been interpreted as analogous to the neurodegeneration of cholinergic cells, ruling out the possibility that neurons lose their cholinergic phenotype without dying. Understanding the mechanism of cholinergic neurodegeneration after axotomy is relevant, since this paradigm has been extensively explored as an animal model of the cholinergic impairment observed in neuropathologies such as Alzheimer's disease.The principal aim of this study was to evaluate, using modern quantitative confocal microscopy, neurodegenerative changes in septal cholinergic neurons after axotomy and to assess their response to delayed infusion of NGF in rats. RESULTS: We found that there is a slow reduction of cholinergic cells labeled by ChAT and p75 after axotomy. However, this phenomenon is not accompanied by neurodegenerative changes or by a decrease in total neuronal number in the medial septum. Although the remaining axotomized-neurons appear healthy, they are unable to respond to delayed NGF infusion. CONCLUSIONS: Our results demonstrate that at 3 weeks, axotomized cholinergic neurons lose their cholinergic phenotype without dying and down-regulate their NGF-receptors, precluding the possibility of a response to NGF. Therefore, the physiological role of NGF in the adult septal cholinergic system is to support phenotypic differentiation and not survival of neurons. This evidence raises questions about the relationship between transcriptional regulation of the cholinergic phenotype by retrograde-derived trophic signaling and the transcriptional changes experienced when retrograde transport is impaired due to neuropathological conditions. PMID- 20205866 TI - Blood feeding patterns of mosquitoes: random or structured? AB - BACKGROUND: The foraging behavior of blood-sucking arthropods is the defining biological event shaping the transmission cycle of vector-borne parasites. It is also a phenomenon that pertains to the realm of community ecology, since blood feeding patterns of vectors can occur across a community of vertebrate hosts. Although great advances in knowledge of the genetic basis for blood-feeding choices have been reported for selected vector species, little is known about the role of community composition of vertebrate hosts in determining such patterns. METHODS & RESULTS: Here, we present an analysis of feeding patterns of vectors across a variety of locations, looking at foraging patterns of communities of mosquitoes, across communities of hosts primarily comprised of mammals and birds. Using null models of species co-occurrence, which do not require ancillary information about host abundance, we found that blood-feeding patterns were aggregated in studies from multiple sites, but random in studies from a single site. This combination of results supports the idea that mosquito species in a community may rely primarily on host availability in a given landscape, and that contacts with specific hosts will be influenced more by the presence/absence of hosts than by innate mosquito choices. This observation stresses the importance of blood-feeding plasticity as a key trait explaining the emergence of many zoonotic mosquito transmitted diseases. DISCUSSION: From an epidemiological perspective our observations support the idea that phenomena promoting synchronization of vectors and hosts can promote the emergence of vector-borne zoonotic diseases, as suggested by observations on the linkages between deforestation and the emergence of several human diseases. PMID- 20205867 TI - Neurofeedback and biofeedback with 37 migraineurs: a clinical outcome study. AB - BACKGROUND: Traditional peripheral biofeedback has grade A evidence for effectively treating migraines. Two newer forms of neurobiofeedback, EEG biofeedback and hemoencephalography biofeedback were combined with thermal handwarming biofeedback to treat 37 migraineurs in a clinical outpatient setting. METHODS: 37 migraine patients underwent an average of 40 neurofeedback sessions combined with thermal biofeedback in an outpatient biofeedback clinic. All patients were on at least one type of medication for migraine; preventive, abortive or rescue. Patients kept daily headache diaries a minimum of two weeks prior to treatment and throughout treatment showing symptom frequency, severity, duration and medications used. Treatments were conducted an average of three times weekly over an average span of 6 months. Headache diaries were examined after treatment and a formal interview was conducted. After an average of 14.5 months following treatment, a formal interview was conducted in order to ascertain duration of treatment effects. RESULTS: Of the 37 migraine patients treated, 26 patients or 70% experienced at least a 50% reduction in the frequency of their headaches which was sustained on average 14.5 months after treatments were discontinued. CONCLUSIONS: All combined neuro and biofeedback interventions were effective in reducing the frequency of migraines with clients using medication resulting in a more favorable outcome (70% experiencing at least a 50% reduction in headaches) than just medications alone (50% experience a 50% reduction) and that the effect size of our study involving three different types of biofeedback for migraine (1.09) was more robust than effect size of combined studies on thermal biofeedback alone for migraine (.5). These non-invasive interventions may show promise for treating treatment-refractory migraine and for preventing the progression from episodic to chronic migraine. PMID- 20205868 TI - Trapped in freshwater: the internal anatomy of the entoproct Loxosomatoides sirindhornae. AB - BACKGROUND: Entoprocta is a small phylum of tentacle-bearing spiralian lophotrochozoans that comprises mainly marine representatives, with only two known freshwater species. One of them, Loxosomatoides sirindhornae Wood, 2005 was only recently described, and detailed information on its morphology including adaptations to life in freshwater are unknown. We analyzed the internal anatomy of L. sirindhornae using serial semi-thin sections, 3D reconstruction, as well as immunocytochemistry and confocal laserscanning microscopy. RESULTS: The nephridial system shows high complexity, strikingly similar to that of Urnatella gracilis, the only other known freshwater entoproct. It is composed of 105-120 large flame-bulb terminal organs that occur in the stalk and calyx. In the stalk they terminate in the epidermis, whereas efferent ducts in each terminal organ in the calyx lead to large, paired terminal ducts that fuse close to the central nervous system and open into the atrium by a nephridiopore. Compared to other stolonate entoprocts, L. sirindhornae shows a different stalk-calyx junction by possessing only a single, multicellular canopy instead of a stack of star cells. A sphincter muscle is situated below the diaphragm of the stalk. The remaining musculature is concentrated in the stalk, while the calyx musculature is sparsely developed. The central nervous system is dumbbell-shaped as in basal entoprocts. CONCLUSIONS: The nephridial system probably has mainly osmoregulatory function. Previous studies have shown that L. sirindhornae is unable to cope with higher salinities, suggesting that its adaptation to freshwater has reached such a high degree that it is unable to 'turn off' the nephridial system in higher salinities. The current data available show that the architecture of internal organ systems such as the musculature or the calyx-stalk junction hold more promising information for taxonomic and perhaps even evolutionary inferences in Entoprocta than external characters such as spination. Contrary to previous investigations, the longitudinal calyx musculature of the genus Loxosomatoides should not be classified as generally strong or conspicuous, since its extent and site of insertion differs between species. PMID- 20205869 TI - The structural insights of stem cell factor receptor (c-Kit) interaction with tyrosine phosphatase-2 (Shp-2): an in silico analysis. AB - BACKGROUND: Stem cell factor (SCF) receptor c-Kit is recognized as a key signaling molecule, which transduces signals for the proliferation, differentiation and survival of stem cells. Binding of SCF to its receptor triggers transactivation, leading to the recruitment of kinases and phosphatases to the docking platforms of c-Kit catalytic domain. Tyrosine phosphatase-1 (Shp 1) deactivates/attenuates 'Kit' kinase activity. Whereas, Asp816Val mutation in the Kit activation loop transforms kinase domain to a constitutively activated state (switch off-to-on state), in a ligand-independent manner. This phenomenon completely abrogates negative regulation of Shp-1. To predict the possible molecular basis of interaction between c-Kit and Shp-1, we have performed an in silico protein-protein docking study between crystal structure of activated c-Kit (phosphorylated c-Kit) and full length crystal structure of Shp-2, a close structural counterpart of Shp-1. FINDINGS: Study revealed a stretch of conserved amino acids (Lys818 to Ser821) in the Kit activation domain, which makes decisive H-bonds with N-sh2 and phosphotyrosine binding pocket residues of the phosphatase. These H-bonds may impose an inhibitory steric hindrance to the catalytic domain of c-Kit, there by blocking further interaction of the activation loop molecules with incoming kinases. We have also predicted a phosphotyrosine binding pocket in SH2 domains of Shp-1, which is found to be predominantly closer to a catalytic groove like structure in c-Kit kinase domain. CONCLUSIONS: This study predicts that crucial hydrogen bonding between N-sh2 domain of Shp-1 and Kit activation loop can modulate the negative regulation of c Kit kinase by Shp-1. Thus, this finding is expected to play a significant role in designing suitable gain-of-function c-Kit mutants for inducing conditional proliferation of hematopoietic stem cells. PMID- 20205870 TI - Towards the integration of mouse databases - definition and implementation of solutions to two use-cases in mouse functional genomics. AB - BACKGROUND: The integration of information present in many disparate biological databases represents a major challenge in biomedical research. To define the problems and needs, and to explore strategies for database integration in mouse functional genomics, we consulted the biologist user community and implemented solutions to two user-defined use-cases. RESULTS: We organised workshops, meetings and used a questionnaire to identify the needs of biologist database users in mouse functional genomics. As a result, two use-cases were developed that can be used to drive future designs or extensions of mouse databases. Here, we present the use-cases and describe some initial computational solutions for them. The application for the gene-centric use-case, "MUSIG-Gen" starts from a list of gene names and collects a wide range of data types from several distributed databases in a "shopping cart"-like manner. The iterative user-driven approach is a response to strongly articulated requests from users, especially those without computational biology backgrounds. The application for the phenotype-centric use-case, "MUSIG-Phen", is based on a similar concept and starting from phenotype descriptions retrieves information for associated genes. CONCLUSION: The use-cases created, and their prototype software implementations should help to better define biologists' needs for database integration and may serve as a starting point for future bioinformatics solutions aimed at end-user biologists. PMID- 20205871 TI - Comparative proteomic analysis of normal and tumor stromal cells by tissue on chip based mass spectrometry (toc-MS). AB - In carcinoma tissues, genetic and metabolic changes not only occur at the tumor cell level, but also in the surrounding stroma. This carcinoma-reactive stromal tissue is heterogeneous and consists e.g. of non-epithelial cells such as fibroblasts or fibrocytes, inflammatory cells and vasculature-related cells, which promote carcinoma growth and progression of carcinomas. Nevertheless, there is just little knowledge about the proteomic changes from normal connective tissue to tumor stroma. In the present study, we acquired and analysed specific protein patterns of small stromal sections surrounding head and neck cell complexes in comparison to normal subepithelial connective tissue. To gain defined stromal areas we used laser-based tissue microdissection. Because these stromal areas are limited in size we established the highly sensitive 'tissue on chip based mass spectrometry' (toc-MS). Therefore, the dissected areas were directly transferred to chromatographic arrays and the proteomic profiles were subsequently analysed with mass spectrometry. At least 100 cells were needed for an adequate spectrum. The locating of differentially expressed proteins enables a precise separation of normal and tumor stroma. The newly described toc-MS technology allows an initial insight into proteomic differences between small numbers of exactly defined cells from normal and tumor stroma. PMID- 20205873 TI - Translating three states of knowledge--discovery, invention, and innovation. AB - BACKGROUND: Knowledge Translation (KT) has historically focused on the proper use of knowledge in healthcare delivery. A knowledge base has been created through empirical research and resides in scholarly literature. Some knowledge is amenable to direct application by stakeholders who are engaged during or after the research process, as shown by the Knowledge to Action (KTA) model. Other knowledge requires multiple transformations before achieving utility for end users. For example, conceptual knowledge generated through science or engineering may become embodied as a technology-based invention through development methods. The invention may then be integrated within an innovative device or service through production methods. To what extent is KT relevant to these transformations? How might the KTA model accommodate these additional development and production activities while preserving the KT concepts? DISCUSSION: Stakeholders adopt and use knowledge that has perceived utility, such as a solution to a problem. Achieving a technology-based solution involves three methods that generate knowledge in three states, analogous to the three classic states of matter. Research activity generates discoveries that are intangible and highly malleable like a gas; development activity transforms discoveries into inventions that are moderately tangible yet still malleable like a liquid; and production activity transforms inventions into innovations that are tangible and immutable like a solid. The paper demonstrates how the KTA model can accommodate all three types of activity and address all three states of knowledge. Linking the three activities in one model also illustrates the importance of engaging the relevant stakeholders prior to initiating any knowledge-related activities. SUMMARY: Science and engineering focused on technology-based devices or services change the state of knowledge through three successive activities. Achieving knowledge implementation requires methods that accommodate these three activities and knowledge states. Accomplishing beneficial societal impacts from technology based knowledge involves the successful progression through all three activities, and the effective communication of each successive knowledge state to the relevant stakeholders. The KTA model appears suitable for structuring and linking these processes. PMID- 20205872 TI - Role of senescence and mitotic catastrophe in cancer therapy. AB - Senescence and mitotic catastrophe (MC) are two distinct crucial non-apoptotic mechanisms, often triggered in cancer cells and tissues in response to anti cancer drugs. Chemotherapeuticals and myriad other factors induce cell eradication via these routes. While senescence drives the cells to a state of quiescence, MC drives the cells towards death during the course of mitosis. The senescent phenotype distinguishes tumor cells that survived drug exposure but lost the ability to form colonies from those that recover and proliferate after treatment. Although senescent cells do not proliferate, they are metabolically active and may secrete proteins with potential tumor-promoting activities. The other anti-proliferative response of tumor cells is MC that is a form of cell death that results from abnormal mitosis and leads to the formation of interphase cells with multiple micronuclei. Different classes of cytotoxic agents induce MC, but the pathways of abnormal mitosis differ depending on the nature of the inducer and the status of cell-cycle checkpoints. In this review, we compare the two pathways and mention that they are activated to curb the growth of tumors. Altogether, we have highlighted the possibilities of the use of senescence targeting drugs, mitotic kinases and anti-mitotic agents in fabricating novel strategies in cancer control. PMID- 20205874 TI - Introduction to the "Scoliosis" Journal Brace Technology Thematic Series: increasing existing knowledge and promoting future developments. AB - Bracing is the main non-surgical intervention in the treatment of idiopathic scoliosis during growth, in hyperkyphosis (and Scheuermann disease) and occasionally for spondylolisthesis; it can be used in adult scoliosis, in the elderly when pathological curves lead to a forward leaning posture or in adults after traumatic injuries. Bracing can be defined as the application of external corrective forces to the trunk; rigid supports or elastic bands can be used and braces can be custom-made or prefabricated. The state of research in the field of conservative treatment is insufficient and while it can be stated that there is some evidence to support bracing, we must also acknowledge that today we do not have a common and generally accepted knowledge base, and that instead, individual expertise still prevails, giving rise to different schools of thought on brace construction and principles of correction. The only way to improve the knowledge and understanding of brace type and brace function is to establish a single and comprehensive source of information about bracing. This is what the Scoliosis Journal is going to do through the "Brace Technology" Thematic Series, where technical papers coming from the different schools will be published. PMID- 20205875 TI - Lateral femoral traction pin entry: risk to the femoral artery and other medial neurovascular structures. AB - BACKGROUND: Femoral skeletal traction assists in the reduction and transient stabilization of pelvic, acetabular, hip, and femoral fractures when splinting is ineffective. Traditional teaching has recommended a medial entry site for insertion of the traction pin in order to minimize injury to the femoral artery as it passes through Hunter's canal. The present anatomical study evaluates the risk to the femoral artery and other medial neurovascular structures using a lateral entry approach. METHODS: Six embalmed cadavers (twelve femurs) were obtained for dissection. Steinman pins were drilled from lateral to medial at the level of the superior pole of the patella, at 2 cm, and at 4 cm proximal to this point. Medial superficial dissection was then performed to identify the saphenous nerve, the superior medial geniculate artery, the adductor hiatus, the tendinous insertion of the adductor magnus and the femoral artery. Measurements localizing these anatomic structures relative to the pins were obtained. RESULTS: The femoral artery was relatively safe and was no closer than 29.6 mm (mean) from any of the three Steinman pins. The superior medial geniculate artery was the medial structure at most risk. CONCLUSIONS: Lateral femoral traction pin entry is a safe procedure with minimal risk to the saphenous nerve and femoral artery. Of the structures examined, only the superior medial geniculate artery is at a risk of iatrogenic injury due to its position. The incidence of such injury in clinical practice and its clinical significance is not known. Lateral insertion facilitates traction pin placement since it minimizes the need to move the contralateral extremity out of the way of the drilling equipment or the need to elevate or externally rotate the injured extremity relative to the contralateral extremity. PMID- 20205876 TI - Use of the novel hemostatic textile Stasilon(R) to arrest refractory retroperitoneal hemorrhage: a case report. AB - INTRODUCTION: Stasilon(R) is a novel hemostatic woven textile composed of allergen-free fibers of continuous filament fiberglass and bamboo yarn. The development of this product resulted from controlled in vitro thrombogenic analysis of an array of potentially hemostatic textile materials and it has been cleared for both external and internal use by the United States Food and Drug Administration for the arrest of hemorrhage. The goal of the study was to assess the hemostatic and adhesive properties of Stasilon(R) in the setting of life threatening refractory hemorrhage. CASE PRESENTATION: A 39-year-old Caucasian man presented with severe necrotic pancreatitis that failed multiple aggressive attempts to control associated bleeding with electrocautery, suture ligation, and sequential anatomic packing with cotton-based sponges. Subsequent retroperitoneal packing with Stasilon(R) produced a non-adherent wound-dressing interface and resulted in the achievement of persistent hemostasis in the operative field. CONCLUSION: In our patient, Stasilon(R) was demonstrated to be effective in the arrest of refractory hemorrhage. PMID- 20205877 TI - Primary hydatid cyst of the gallbladder: a case report. AB - INTRODUCTION: Echinococcosis, or hydatid disease, is endemic in some regions of the world, and has been a common pathology of surgical wards in Kosovo. Primary hydatid cyst of the gallbladder is an unusual and very rare localization of hydatid disease. So far, only five cases that fulfill the criteria of primary gallbladder hydatidosis have been published in the English medical literature. CASE PRESENTATION: We report a case of a 39-year-old Kosovan Albanian woman referred to the Abdominal Surgery Division of the University Clinical Center of Kosovo for "a calcified hydatid cyst of the liver with gallbladder involvement". Her history was significant for chronic right upper quadrant pain, characterized as intermittently colicky pain, accompanied by nausea. The patient underwent right subcostal laparotomy. Intra-operatively, a calcified primary hydatid cyst of the gallbladder was found. Its pericyst was tightly attached to the liver. Complete pericystectomy with cholecystectomy followed. The histopathology confirmed the presence of calcified hydatid cyst of the gallbladder, and that the cyst had developed entirely extra-mucosally. Five year follow-up showed no recurrence of disease. CONCLUSION: Primary hydatid cyst of the gallbladder is a very rare clinical entity. Accurate preoperative diagnostic localization is not always easy, particularly in centers with limited diagnostic tools. PMID- 20205878 TI - Chronic constipation due to presacral teratoma in a 36-year-old woman: a case report. AB - INTRODUCTION: Teratomas of the sacrococcygeal area are usually diagnosed in infancy and are rarely seen in adults. CASE PRESENTATION: We report the case of a 36-year-old Greek woman experiencing chronic constipation due to a benign presacral teratoma. Imaging examinations showed a pelvic mass without evidence of malignancy. An ovoid tumour with a maximum dimension of 6 cm was surgically removed. A histologic examination revealed a mature cystic teratoma. Two years after surgery, the patient is well, with no evidence of recurrence and no constipation. CONCLUSION: Sacrococcygeal teratomas are rare in adults. A high index of suspicion is important in making an early diagnosis. Rectal examination and radiologic evaluation are also valuable. PMID- 20205879 TI - Lymphocytic colitis presenting as difficult diarrhoea in an African woman: a case report and review of the literature. AB - INTRODUCTION: Lymphocytic colitis is an uncommon intestinal disorder that presents with chronic diarrhoea. It is treatable, but in the developing world, its diagnosis may often prove difficult. Data and reports of this condition in Africa are scarce because most medical centres lack a functional gastrointestinal endoscopy unit that would aid in the diagnosis. CASE PRESENTATION: We present the case of a 53-year-old Nigerian woman with pathogen-negative chronic diarrhoea and a family history of chronic diarrhoea. She responded well to treatment after colonoscopy and colonic biopsy successfully diagnosed her illness. CONCLUSION: Referral of patients with pathogen-negative chronic diarrhoea to medical centres that have facilities for colonoscopy and biopsy is important in the developing world. PMID- 20205880 TI - Transient bilateral abducens neuropathy with post-tetanic facilitation and acute hypokalemia associated with oxaliplatin: a case report. AB - INTRODUCTION: Oxaliplatin is a cytotoxic platinum compound that is in widespread use in the treatment of gastrointestinal cancers. It has been occasionally associated with acute motor neuropathy, but the precise mechanism is uncertain. To the best of our knowledge, we report the first case of a patient demonstrating post-tetanic facilitation in the setting of transient bilateral abducens neuropathy and hypokalemia, after being infused with oxaliplatin. CASE PRESENTATION: A 47-year-old Indian woman with metastatic gastric cancer was receiving an oxaliplatin infusion at the initiation of her third cycle of palliative chemotherapy. She developed acute bilateral abducens neuropathy with post-tetanic facilitation alongside acute laryngopharyngodysesthesia and hypokalemia. Following supportive management, including potassium infusion and warming, her neurological signs and symptoms were spontaneously resolved. This syndrome did not recur in subsequent cycles following prolongation of infusion duration and the addition of supportive calcium and magnesium infusions. CONCLUSION: The novel clinical observation of post-tetanic facilitation highlights a possible involvement of voltage-gated channels at the presynaptic terminals in the mechanism of acute oxaliplatin neurotoxicity. PMID- 20205881 TI - Olanzapine and pulmonary embolism, a rare association: a case report. AB - Venous thromboembolism is a very common pathological process for which there are many well known (and less well-known) predisposing factors. Likewise, olanzapine is a commonly used anti-psychotic medication.We present the case of a young Somali gentleman who developed venous thromboembolic disease after an overdose of olanzapine. The diagnosis was only made 48 hours after admission, due to the non specific presentation of the pulmonary embolus and the fact that the link between olanzapine and pulmonary embolus was not previously widely described and therefore it did not immediately figure in the differential diagnosis. The patient made a full recovery.There is an increasing body of circumstantial evidence linking olanzapine to pulmonary embolus. Clinicians should bear this possible association in mind when prescribing the drug and when faced with clinical situations where venous thromboembolism (VTE) is a possible diagnosis. VTE has occasionally been described in therapeutic dose olanzapine therapy, but never in the context of an acute overdose. Khat, a recreational drug, has been linked to arterial, but not venous thrombosis.It is hoped that this case report will further encourage research into these associations, which remain to be proven and quantified.In the context of changing population demographics and increasing global migration, a greater awareness of the potential effects of endemic practices and their potential consequences is essential to the modern-day doctor working in a multi-cultural society. PMID- 20205882 TI - A novel technique for the treatment of post operative retro-rectal haematoma: two case reports. AB - Rectal bleeding following any form of rectal surgery is a well recognised complication 1, 2, 3 & 4. However retro-rectal bleeding and tracking which then presents as rectal bleeding has not been reported in the literature. We describe a novel way of dealing with this technically difficult post-operative complication.We present two cases of significant rectal bleeding (one following STARR procedure and other after Delormes procedure). Both patients had to be taken back to theatre due to continuing, significant bleeding. Examination under anaesthesia on both occasions revealed a posterior boggy swelling, with an opening which admitted a finger. In both cases clots were evacuated and a corrugated drain was inserted in to the retro rectal space.The authors believe that following any form of rectal surgery, retro-rectal bleeding with tracking can present as rectal bleeding. Treatment in the form of EUA and insertion of corrugated helped to resolve the problem.We present both cases and literature review of the complications of stapled haemorrhoidopexy. PMID- 20205883 TI - Orbital tuberculosis in childhood with intracranial extension: a case report. AB - The common causes of orbital masses in pediatric age group include pseudotumour, lymphomas, hemangioma and dermoid cyst. Orbital tuberculosis is rare especially in children. We report a case of 5 year old child who presented with proptosis and gross diminution of vision due to orbital tuberculoma. Ocular examination of the left eye revealed proptosis with the eyeball displaced downwards and forwards. Vision was counting finger close to face. CT Scan showed an extraconal soft tissue mass along posteromedial side of left orbit with lateral displacement of medial rectus muscle. On antitubercular treatment, proptosis regressed and visual recovery was observed over a period of six month vision, in the left eye at the last followup was 20/30. PMID- 20205884 TI - At the end of a two-year follow-up elevated TSH levels normalize or remain unchanged in most the children with subclinical hypothyroidism. AB - Data about the natural evolution of subclinical hypothyroidism (SH) in pediatric age are very scanty. Moreover all the available reports in both aged and young patients were based on unselected study populations including also patients with either thyroid disorders or other pathological causes that are well known to be able to affect SH development and evolution. Aim of the study by Wasniewska et al was to prospectively evaluate for the first time the natural course of SH in children and adolescents with no underlying diseases and no risk factors that might interfere with the progression of SH. On the basis of the 2-year follow-up results, the Authors concluded that: a) the natural course of TSH values in a pediatric population with idiopathic SH is characterized by a progressive decrease over time; b) the majority of patients (88%) normalized or maintained unchanged their TSH; and c) TSH changes were not associated with changes of either FT4 values or clinical status or auxological parameters. Study design of this study is very accurate and the results are robust, thus supporting the Authors' conclusions. PMID- 20205885 TI - Acute mastoiditis: A one year study in the pediatric hospital of Cairo university. AB - BACKGROUND: Acute mastoiditis is a serious complication of acute otitis media especially in the pediatric age group. This study reports the authors' experience in the treatment of children admitted with acute mastoiditis to the Pediatric Hospital of Cairo University throughout the year 2007, also we aimed to evaluate our current management of this serious disease. METHODS: Nineteen children were included in this study, 11 females and 8 males, their ages ranged from 9 months to 11 years. All children were treated with intravenous antibiotic on initial admission, myringotomy was considered for cases that did not respond to medical treatment for 48 hours, while cortical mastoidectomy (with myringotomy) was reserved for cases that presented initially with subperiosteal abscess with or without post-auricular fistula, cases with intracranial complications and for cases that showed no response to myringotomy (after 48 hours). Follow up of the patients was carried out for at least 1 year. RESULTS: Medical management alone was enough in 5 cases (26%); all of them had erythematous tender mastoid on first presentation. Seven cases (37%) needed myringotomy; 2 of them showed no response and they needed cortical mastoidectomy and the other 5 cases responded well except for 1 case that developed post-auricular subperiosteal abscess 2 months later necessitating cortical mastoidectomy with no evidence of recurrence till the end of the follow-up period. Seven cases (37%) presented with subperiosteal abscess and they needed cortical mastoidectomy with myringotomy; they showed no recurrence till the end of the study. CONCLUSION: Conservative management is an effective method in the treatment of non-complicated acute mastoiditis, but myringotomy should be considered if there is no response within 48 hours. Cortical mastoidectomy should be used in conjunction with the medical management in the treatment of complicated cases. PMID- 20205886 TI - Curcumin, inflammation, ageing and age-related diseases. AB - A Symposium regarding the Pathophysiology of Successful and Unsuccessful Ageing was held in Palermo, Italy between April 7 and 8th 2009. Here the lecture by Sikora with some input from the chairpersons Scapagnini and Barbagallo is summarized. Ageing is manifested by the decreasing health status and increasing probability to acquire age-related disease such as cancer, Alzheimer's disease, atherosclerosis, metabolic disorders and others. They are likely caused by low grade inflammation driven by oxygen stress and manifested by the increased level of pro-inflammatory cytokines such as IL-1, IL-6 and TNF-alpha, encoded by genes activated by the transcription factor NF-kappaB. It is believed that ageing is plastic and can be slowed down by caloric restriction as well as by some nutraceuticals. Accordingly, slowing down ageing and postponing the onset of age related diseases might be achieved by blocking the NF-kappaB-dependent inflammation. In this review we consider the possibility of the spice curcumin, a powerful antioxidant and anti-inflammatory agent possibly capable of improving the health status of the elderly. PMID- 20205887 TI - Optical characterization of colloidal CdSe quantum dots in endothelial progenitor cells. AB - We have quantitatively analyzed the confocal spectra of colloidal quantum dots (QDs) in rat endothelial progenitor cells (EPCs) by using Leica TCS SP5 Confocal Microscopy System. Comparison of the confocal spectra of QDs located inside and outside EPCs revealed that the interaction between the QDs and EPCs effectively reduces the radius of the exciton confinement inside the QDs so that the excitonic energy increases and the QD fluorescence peak blueshifts. Furthermore, the EPC environment surrounding the QDs shields the QDs so that the excitation of the QDs inside the cells is relatively weak, whereas the QDs outside the cells can be highly excited. At high excitations, the occupation of the ground excitonic state in the QD outside the cells becomes saturated and high-energy states excited, resulting in a large relaxation energy and a broad fluorescence peak. This permits, in concept, to use QD biomarkers to monitor EPCs by characterizing QD fluorescence spectra. PMID- 20205888 TI - Plasma proteome analysis of patients with type 1 diabetes with diabetic nephropathy. AB - BACKGROUND: As part of a clinical proteomics program focused on diabetes and its complications we are looking for new and better protein biomarkers for diabetic nephropathy. The search for new and better biomarkers for diabetic nephropathy has, with a few exceptions, previously focused on either hypothesis-driven studies or urinary based investigations. To date only two studies have investigated the proteome of blood in search for new biomarkers, and these studies were conducted in sera from patients with type 2 diabetes. This is the first reported in depth proteomic study where plasma from type 1 diabetic patients was investigated with the goal of finding improved candidate biomarkers to predict diabetic nephropathy. In order to reach lower concentration proteins in plasma a pre-fractionation step, either hexapeptide bead-based libraries or anion exchange chromatography, was performed prior to surface enhanced laser desorption/ionization time-of-flight mass spectrometry analysis. RESULTS: Proteomic analysis of plasma from a cross-sectional cohort of 123 type 1 diabetic patients previously diagnosed as normoalbuminuric, microalbuminuric or macroalbuminuric, gave rise to 290 peaks clusters of which 16 were selected as the most promising biomarker candidates based on statistical performance, including independent component analysis. Four of the peaks that were discovered have been identified as transthyretin, apolipoprotein A1, apolipoprotein C1 and cystatin C. Several yet unidentified proteins discovered by this novel approach appear to have more potential as biomarkers for diabetic nephropathy. CONCLUSION: These results demonstrate the capacity of proteomic analysis of plasma, by confirming the presence of known biomarkers as well as revealing new biomarkers for diabetic nephropathy in plasma in type 1 diabetic patients. PMID- 20205889 TI - Impact of dietary protein on lipid metabolism-related gene expression in porcine adipose tissue. AB - BACKGROUND: High dietary protein can reduce fat deposition in animal subcutaneous adipose tissue, but little is known about the mechanism. METHODS: Sixty Wujin pigs of about 15 kg weight were fed either high protein (HP: 18%) or low protein (LP: 14%) diets, and slaughtered at body weights of 30, 60 or 100 kg. Bloods were collected to measure serum parameters. Subcutaneous adipose tissues were sampled for determination of adipocyte size, protein content, lipid metabolism-related gene expression, and enzyme activities. RESULTS: HP significantly reduced adipocyte size, fat meat percentage and backfat thickness, but significantly increased daily gain, lean meat percentage and loin eye area at 60 and 100 kg. Serum free fatty acid and triglyceride concentrations in the HP group were significantly higher than in the LP group. Serum glucose and insulin concentrations were not significantly affected by dietary protein at any body weight. HP significantly reduced gene expression of acetyl CoA carboxylase (ACC), fatty acid synthase (FAS) and sterol regulatory element binding protein 1c (SREBP 1c) at 60 kg and 100 kg; however, the mRNA level and enzyme activity of FAS were increased at 30 kg. HP promoted gene and protein expression and enzyme activities of lipoprotein lipase (LPL), carmitine palmtoyltransferase-1B (CPT-1B), peroxisome proliferator-activated receptor gamma (PPARgamma) and adipocyte-fatty acid binding proteins (A-FABP) at 60 kg, but reduced their expression at 100 kg.Gene expression and enzyme activity of hormone sensitive lipase (HSL) was reduced markedly at 60 kg but increased at 100 kg by the high dietary protein. Levels of mRNA, enzyme activities and protein expression of ACC, FAS, SREBP-1c and PPARgamma in both LP and HP groups increased with increasing body weight. However, gene and protein expression levels/enzyme activities of LPL, CPT-1B, A FABP and HSL in both groups were higher at 60 kg than at 30 and 100 kg. CONCLUSION: Fat deposition in Wujin pigs fed high dietary protein for 25 weeks was reduced mainly by depression of lipogenic gene expression. The mechanism of lipid transport, lipolysis and oxidation in adipose tissue regulated by dietary protein appeared to be different at 60 kg and 100 kg body weights. PMID- 20205890 TI - Saphenous neuropathy in a patient with low back pain. AB - Saphenous nerve, a pure sensory nerve, may compromise as a result or complication of a surgical procedure or secondary to trauma or insidiously. We present a male patient with low back pain concomitant with pain in medial portion of left thigh in addition to pain and numbness in medial part of leg and inferior part of patella after a strenuous activity. Preliminary diagnosis suggested that the patient had radiculopathy but electrodiagnostic tests revealed the absence of left saphenous response both in medial leg and infrapatellar region, while normal findings were recorded from right side. Needle electromyography in L4 innervated muscles were normal. The patient had saphenous nerve entrapment in left thigh. Two months later symptoms relieved with conservative therapy. PMID- 20205891 TI - Adenocarcinoma arising in a heterotopic pancreas (Heinrich type III): a case report. AB - INTRODUCTION: Heterotopic pancreatic cancer in the duodenum is a very rare disease. Only twelve cases have been reported worldwide to date. We report a rare case of malignant transformation of heterotopic pancreas (Heinrich type III) in the duodenum with long-term survival of the patient, and review the 12 cases in the literature. CASE PRESENTATION: A 75-year-old Japanese man was admitted to our hospital complaining of nausea and vomiting. Endoscopy and upper gastrointestinal contrast study showed marked duodenal stenosis. A pylorus-preserving pancreaticoduodenectomy was performed. Histopathological examination of the surgically resected specimen showed malignant transformation of heterotopic pancreas (Heinrich type III) in the duodenum. The postoperative course was uneventful, and the patient was discharged from the hospital on postoperative day 30. He is well and shows no signs of recurrence at the time of writing, six years after the surgery. CONCLUSION: Adenocarcinoma arising within the heterotopic pancreas appears to be rare. It is difficult to obtain a correct diagnosis preoperatively. The management of heterotopic pancreas depends on the presence or absence of symptoms. If the patient is asymptomatic or benign, conservative treatment with regular follow-up is recommended. When the patient is symptomatic or there is a suspicion of malignancy, surgical management with intra-operative frozen section diagnosis is indicated. PMID- 20205892 TI - Mopane worm allergy in a 36-year-old woman: a case report. AB - INTRODUCTION: The increasing incidence of new diseases as well as changing features of known diseases has partly been attributed to the impact of environmental changes. As a result, there have been calls from health experts for proper surveillance and monitoring of these changes.This is a report of mopane worm allergy in a 36 year old female from the Tswana tribe in Botswana. Mopane worm, the caterpillar stage of Gonimbrasia belina moths, is a seasonal delicacy to people in many communities in southern Africa. As a result, by adulthood, many residents of these communities have had substantial exposure to the worm. Gonimbrasia belina moths belong to the Lepidoptera order of insects. Though some members of this order are known to induce contact allergy, there is no reported incidence of ingestion allergy from mopane worm. Therefore, it is important to track this case for its epidemiological significance and to alert both clinicians and the vulnerable public on the incidence of mopane worm allergy in this region. CASE PRESENTATION: This is a case of a 36 year old woman from the Tswana ethnic group in Botswana, who was diagnosed with food allergy. She presented with itchy skin rash, facial swelling, and mild hypotension after eating mopane worm. She had no previous history of allergic reaction following contact or ingestion of mopane worm and had no atopic illness in the past. She was treated and her symptoms resolved after 4 days. CONCLUSION: The proper management of allergy involves patients' avoidance and clinicians' predictability. Though hypothetical, this report is expected to sensitize clinicians to anticipate and properly manage subsequent occurrence, as well as educate the public in these communities. In addition, tracking new disease patterns, with relationship to environmental changes, will compliment existing evidence in validating the importance of proper environmental surveillance and management. PMID- 20205893 TI - The orphaning experience: descriptions from Ugandan youth who have lost parents to HIV/AIDS. AB - The HIV/AIDS epidemic has continued to pose significant challenges to countries in Sub-Saharan Africa. Millions of African children and youth have lost parents to HIV/AIDS leaving a generation of orphans to be cared for within extended family systems and communities. The experiences of youth who have lost parents to the HIV/AIDS epidemic provide an important ingress into this complex, evolving, multi-dimensional phenomenon. A fundamental qualitative descriptive study was conducted to develop a culturally relevant and comprehensive description of the experiences of orphanhood from the perspectives of Ugandan youth. A purposeful sample of 13 youth who had lost one or both parents to HIV/AIDS and who were affiliated with a non-governmental organization providing support to orphans were interviewed. Youth orphaned by HIV/AIDS described the experience of orphanhood beginning with parental illness, not death. Several losses were associated with the death of a parent including lost social capitol, educational opportunities and monetary assets. Unique findings revealed that youth experienced culturally specific stigma and conflict which was distinctly related to their HIV/AIDS orphan status. Exploitation within extended cultural family systems was also reported. Results from this study suggest that there is a pressing need to identify and provide culturally appropriate services for these Ugandan youth prior to and after the loss of a parent(s). PMID- 20205894 TI - Massive GI bleeding in a patient with 2 small AVMs in the small intestine: a case report. AB - A 53 year-old Caucasian man with no previous history of gastrointestinal bleeding presented with sudden, massive hematochezia and abdominal pain; his hemoglobin dropped from 12 to 8.3. Colonoscopy revealed coagulated blood in a diverticulum, but bleeding recurred after cautery of the lesion.Repeated upper and lower gastrointestinal (GI) endoscopy, visceral selective angiogram, bleeding scan, and Meckel diverticulum scan did not locate the source of bleeding. Further investigation with capsule endoscopy demonstrated two arteriovenous malformations in the small bowel.Wireless capsule endoscopy is a sensitive and specific test for overt obscure gastrointestinal bleeding. Clinicians need not hesitate to employ this procedure when other diagnostic modalities fail. PMID- 20205895 TI - A case of pregnancy with Rhesus antibody and bicornuate uterus - a favourable outcome: a case report. AB - INTRODUCTION: In 1% of Rhesus negative women sensitisation occurs without any overt sensitising event during pregnancy. This accounts for late immunisation during a first pregnancy and is responsible for 18-27% of cases of alloimmunisation. The incidence of congenital uterine anomalies in a fertile population is 3.2% of which 5% are bicornuate uterus. Bicornuate uterus can lead to early miscarriages, preterm labor, fetal growth retardation and congenital malformations. CASE PRESENTATION: A 23-year-old lady in her first pregnancy developed Anti-D antibodies at 28 weeks of gestation without any known sensitising event. In view of increasing anti-D titres, at 36 weeks she was delivered. Incidentally during caesarean section she was found to have bicornuate uterus. The neonate was treated with phototherapy and blood transfusion following delivery. CONCLUSION: Rhesus antibodies when managed by close monitoring and timely delivery can lead to favourable outcome. Bicornuate uterus does not always lead to complications like miscarriage, growth retardation or preterm labour and does not need any special intervention. PMID- 20205897 TI - Pitt-Hopkins syndrome: report of a case with a TCF4 gene mutation. AB - AIMS: We will discuss the clinical and genetic diagnosis of a child with severe psychomotor delay, who at 3 years of age presented with paroxysms of hyperpnea apnea and seizures unrelated to breathing anomalies. METHODS: The child underwent genetic (karyotype, FISH telomeres) and neuroradiological (cranial CT and MRI) tests, which proved to be normal. He came under our clinical observation at 3 years and 5 months of age. Due to severe psychomotor delay and facial dysmorphisms we completed the genetic investigations based on his clinical feature and analysis of the available literature. RESULTS: The presence of severe mental retardation associated with anomalous breathing pattern may suggest the Joubert and Rett syndrome, however these were excluded on the basis of clinical and genetic examination. Angelman syndrome, suspected for facial dysmorphisms and absent language, was also excluded because of the presence of a normal pattern of methylation at SNRPN locus. Another possible diagnosis was the Pitt-Hopkins Syndrome (PHS), characterized by severe mental retardation, breathing anomalies (paroxisms of hyperpnea-apnea), dysmorphisms and sometimes epilepsy. Haploinsufficiency of TCF4 gene located at 18q21.2 region has been recently identified as causative of this syndrome. In our patient the research of TCF4 mutation by the Institute of Human Genetics, University Hospital Erlangen (Germany), showed a de novo mutation. CONCLUSIONS: The diagnosis of Pitt-Hopkins syndrome, an underdiagnosed cause of mental retardation, was based on clinical and genetic findings. Searching for TCF4 mutations is highly recommended when others overlapping syndromes was excluded. At our knowledge our patient is the first italian case of PHS diagnosed at molecular level. PMID- 20205896 TI - Impact of HIV-1 viral subtype on disease progression and response to antiretroviral therapy. AB - BACKGROUND: Our intention was to compare the rate of immunological progression prior to antiretroviral therapy (ART) and the virological response to ART in patients infected with subtype B and four non-B HIV-1 subtypes (A, C, D and the circulating recombinant form, CRF02-AG) in an ethnically diverse population of HIV-1-infected patients in south London. METHODS: A random sample of 861 HIV-1 infected patients attending HIV clinics at King's and St Thomas' hospitals' were subtyped using an in-house enzyme-linked immunoassay and env sequencing. Subtypes were compared on the rate of CD4 cell decline using a multi-level random effects model. Virological response to ART was compared using the time to virological suppression (< 400 copies/ml) and rate of virological rebound (> 400 copies/ml) following initial suppression. RESULTS: Complete subtype and epidemiological data were available for 679 patients, of whom 357 (52.6%) were white and 230 (33.9%) were black African. Subtype B (n = 394) accounted for the majority of infections, followed by subtypes C (n = 125), A (n = 84), D (n = 51) and CRF02-AG (n = 25). There were no significant differences in rate of CD4 cell decline, initial response to highly active antiretroviral therapy and subsequent rate of virological rebound for subtypes B, A, C and CRF02-AG. However, a statistically significant four-fold faster rate of CD4 decline (after adjustment for gender, ethnicity and baseline CD4 count) was observed for subtype D. In addition, subtype D infections showed a higher rate of virological rebound at six months (70%) compared with subtypes B (45%, p = 0.02), A (35%, p = 0.004) and C (34%, p = 0.01) CONCLUSIONS: This is the first study from an industrialized country to show a faster CD4 cell decline and higher rate of subsequent virological failure with subtype D infection. Further studies are needed to identify the molecular mechanisms responsible for the greater virulence of subtype D. PMID- 20205898 TI - Psychological distress among patients of an orthopaedic outpatient clinic: a study from a low-income country. AB - BACKGROUND: Depression is common among general trauma patients and is associated with a poor outcome. We evaluated the relationship of psychological distress to physical injury, musculoskeletal complaints, and social factors in a low-income country. METHODS: We administered the Self-Rating Questionnaire (SRQ), the Oslo social support questionnaire, and the Brief Disability Questionnaire (BDQ). RESULTS: An SRQ score of 9 or more, which indicates probable depressive disorder, occurred in 45.6% of men and 76.1% of women. A high SRQ score was associated with female sex, little or no education, low income and little social support. Even after these were controlled for there was a significantly higher SRQ score in patients with arthritis, backache/prolapsed disc, major fracture and other bone pathology. CONCLUSIONS: Depressive disorder appears to be very common in orthopaedic outpatients in Pakistan; both social circumstances and nature of bone pathology are associated with such depression. PMID- 20205899 TI - Low-concentration, continuous brachial plexus block in the management of Purple Glove Syndrome: a case report. AB - INTRODUCTION: Purple Glove Syndrome is a devastating complication of intravenous phenytoin administration. Adequate analgesia and preservation of limb movement for physiotherapy are the two essential components of management. CASE PRESENTATION: A 26-year-old Tamil woman from India developed Purple Glove Syndrome after intravenous administration of phenytoin. She was managed conservatively by limb elevation, physiotherapy and oral antibiotics. A 20G intravenous cannula was inserted into the sheath of her brachial plexus and a continuous infusion of bupivacaine at a low concentration (0.1%) with fentanyl (2 mug/ml) at a rate of 1 to 2 ml/hr was given. She had adequate analgesia with preserved motor function which helped in physiotherapy and functional recovery of the hand in a month. CONCLUSION: A continuous blockade of the brachial plexus with a low concentration of bupivacaine and fentanyl helps to alleviate the vasospasm and the pain while preserving the motor function for the patient to perform active movements of the finger and hand. PMID- 20205900 TI - Giant renal oncocytoma: a case report and review of the literature. AB - INTRODUCTION: Renal oncocytomas are benign neoplasms derived from cells of the distal renal tubule, and comprise 5% to 7% of primary renal neoplasms. Oncocytomas are mostly asymptomatic, and the majority of tumors are discovered incidentally. In this case report, we present a case of a patient with a giant oncocytoma arising from her left kidney. CASE PRESENTATION: We describe a 25-year old Turkish woman who was admitted to our hospital with abdominal pain and a 3 year palpable abdominal mass, which was found present since her second pregnancy. Examination revealed a 15 x 20-cm mass in her abdominal cavity. Computed tomography revealed a mass with regular outlines, measuring 18 x 11 x 12 cm, associated with the left kidney, and causing marked hydroureteronephrosis. We excised the mass and performed a left nephrectomy on our patient. The immunohistopathology of the mass was consistent with renal oncocytoma. No local or distant metastasis was seen at 6 months postoperatively. CONCLUSION: To the best of our knowledge, this is the second largest renal oncocytoma described in the English language literature. This is also the first reported giant oncocytoma that presented during pregnancy. PMID- 20205901 TI - Conflict-affected displaced persons need to benefit more from HIV and malaria national strategic plans and Global Fund grants. AB - BACKGROUND: Access to HIV and malaria control programmes for refugees and internally displaced persons (IDPs) is not only a human rights issue but a public health priority for affected populations and host populations. The primary source of funding for malaria and HIV programmes for many countries is the Global Fund to Fight AIDS, Tuberculosis and Malaria (Global Fund). This article analyses the current HIV and malaria National Strategic Plans (NSPs) and Global Fund approved proposals from rounds 1-8 for countries in Africa hosting populations with refugees and/or IDPs to document their inclusion. METHODS: The review was limited to countries in Africa as they constitute the highest caseload of refugees and IDPs affected by HIV and malaria. Only countries with a refugee and/or IDP population of > or = 10,000 persons were included. NSPs were retrieved from primary and secondary sources while approved Global Fund proposals were obtained from the organisation's website. Refugee figures were obtained from the United Nations High Commissioner for Refugees' database and IDP figures from the Internal Displacement Monitoring Centre. The inclusion of refugees and IDPs was classified into three categories: 1) no reference; 2) referenced; and 3) referenced with specific activities. FINDINGS: A majority of countries did not mention IDPs (57%) compared with 48% for refugees in their HIV NSPs. For malaria, refugees were not included in 47% of NSPs compared with 44% for IDPs. A minority (21-29%) of HIV and malaria NSPs referenced and included activities for refugees and IDPs. There were more approved Global Fund proposals for HIV than malaria for countries with both refugees and IDPs, respectively. The majority of countries with > or =10,000 refugees and IDPs did not include these groups in their approved proposals (61%-83%) with malaria having a higher rate of exclusion than HIV. INTERPRETATION: Countries that have signed the 1951 refugee convention have an obligation to care for refugees and this includes provision of health care. IDPs are citizens of their own country but like refugees may also not be a priority for Governments' NSPs and funding proposals. Besides legal obligations, Governments have a public health imperative to include these groups in NSPs and funding proposals. Governments may wish to add a component for refugees that is additional to the needs for their own citizens. The inclusion of forcibly displaced persons in funding proposals may have positive direct effects for host populations as international and United Nations agencies often have strong logistical capabilities that could benefit both populations. For NSPs, strong and concerted advocacy at global, regional and country levels needs to occur to successfully ensure that affected populations are included in their plans. It is essential for their inclusion to occur if we are to reach the stated goal of universal access and the Millennium Development Goals. PMID- 20205902 TI - Using Guasha to treat musculoskeletal pain: a systematic review of controlled clinical trials. AB - BACKGROUND: Guasha is a therapeutic method for pain management using tools to scrape or rub the surface of the body to relieve blood stagnation. This study aims to systematically review the controlled clinical trials on the effectiveness of using Guasha to treat musculoskeletal pain. METHODS: We searched 11 databases (without language restrictions): MEDLINE, Allied and Complementary Medicine (AMED), EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Korean Studies Information (KSI), DBPIA, Korea Institute of Science and Technology Information (KISTI), KoreaMed, Research Information Service System (RISS), China National Knowledge Infrastructure (CNKI) and the Cochrane Library. The search strategy was Guasha (OR scraping) AND pain. Risk of bias was assessed with the Cochrane criteria (i.e. sequence generation, blinding, incomplete outcome measures and allocation concealment). RESULTS: Five randomized controlled trials (RCTs) and two controlled clinical trials (CCTs) were included in the present study. Two RCTs compared Guasha with acupuncture in terms of effectiveness, while the other trials compared Guasha with no treatment (1 trial), acupuncture (4 trials), herbal injection (1 trial) and massage or electric current therapy (1 trial). While two RCTs suggested favorable effects of Guasha on pain reduction and response rate, the quality of these RCTs was poor. One CCT reported beneficial effects of Guasha on musculoskeletal pain but had low methodological quality. CONCLUSION: Current evidence is insufficient to show that Guasha is effective in pain management. Further RCTs are warranted and methodological quality should be improved. PMID- 20205903 TI - Quality evaluation of mycelial Antrodia camphorata using high-performance liquid chromatography (HPLC) coupled with diode array detector and mass spectrometry (DAD-MS). AB - BACKGROUND: Antrodia camphorata (AC) is an important fungus native to Taiwanese forested regions. Scientific studies have demonstrated that extracts of AC possess a variety of pharmacological functions. This study aims to identify the full profile fingerprint of nucleosides and nucleobases in mycelial AC and to assess the quality of two commercial mycelial AC products. METHODS: High performance liquid chromatography coupled with diode array detector and mass spectrometry was employed to identify the major components in mycelial AC. The chemical separation was carried out using a gradient program on a reverse phase Alltima C18 AQ analytical column (250 x 4.6 mm, 5 microm) with the mobile phase consisting of deionized water and methanol. RESULTS: Ten nucleosides and nucleobases, two maleimide derivatives, and a sterol were identified as the major constituents in mycelial AC. These groups of chemical compounds constitute the first chromatographic fingerprint as an index for quality assessment of this medicinal fungus. CONCLUSIONS: This study provides the first chromatographic fingerprint to assess the quality of mycelial AC. PMID- 20205904 TI - The role of nocturnal delivery and delivery during the holiday period in Finland on obstetric anal sphincter rupture rates- a population based observational study. AB - BACKGROUND: Obstetric anal sphincter rupture (OASR) is a serious complication of delivery, which frequently results in faecal incontinence despite primary repair and has serious implications for women's health. The objective of this study was to assess whether human factors, workload and staffing at night, at weekends and during holidays has an effect on the increasing OASR rates among all singleton vaginal deliveries (n = 514,741) having occurred between 1997 and 2007 in Finland. Women (n = 2,849) with OASR were compared in terms of possible risk factors to women without OASR using stepwise logistic regression analysis. FINDINGS: In Finland, the increase in OASR rate is striking, from 0.2% in 1997 to 0.9% in 2007. OASR rates varied from 0.49% to 0.58% (or= 12 mmHg/ml/min) in 44. The ICP pulse amplitude recorded over-night was elevated (i.e. mean ICP wave amplitude >or= 4 mmHg) in 68% of patients; 92% of these were shunt responders. In those with elevated overnight ICP pulse amplitude, we found also elevated CSFP pulse amplitude recorded during lumbar infusion testing, both during the opening phase following lumbar puncture and during a standardized period of lumbar infusion (15 ml Ringer over 10 min). The clinical response to shunting after 1 year strongly associated with the over-night ICP pulse amplitude, and also with the pulsatile CSFP during the period of lumbar infusion. Elevated CSFP pulse amplitude during lumbar infusion thus predicted shunt response with sensitivity of 88 and specificity of 60 (positive and negative predictive values of 89 and 60, respectively). CONCLUSIONS: In iNPH patients, shunt response can be anticipated in 9/10 patients with elevated overnight ICP pulse amplitude, while in only 1/10 with low ICP pulse amplitude. Additionally, the CSFP pulse amplitude during lumbar infusion testing was elevated in patients with elevated over-night ICP pulse amplitude. In particular, measurement of CSFP pulse amplitude during a standardized infusion of 15 ml Ringer over 10 min was useful in predicting response to shunt surgery and can be used as a screening procedure for selection of iNPH patients for shunting. PMID- 20205912 TI - Occult small bowel perforation in a patient with Ehlers Danlos syndrome: a case report and review of the literature. AB - Patients who present with a co-existing connective tissue disorder add a degree of complexity to operative intervention. We present an unusual case of a 53-year old Caucasian female patient with Ehlers Danlos syndrome who presented with an occult perforation of the distal ileum. The patient had known small bowel diverticulae yet the perforation occurred within the normal bowel wall. The pre operative CT only showed malrotation of the large bowel and did not correlate with the intra-operative findings. Our case has highlighted that although small bowel perforation is a rare occurrence, it may be more common in Ehlers Danlos and may present with atypical features. Perforation may also occur alongside normal bowel as well as diverticulae within the bowel. Where diverticulae exists within a patient with Ehlers Danlos syndrome and there is some diagnostic uncertainty, there should be a lower threshold for operative intervention. We present in the discussion a number of salient features and learning points. PMID- 20205913 TI - Stiff limb syndrome: a case report. AB - INTRODUCTION: Stiff limb syndrome is a clinical feature of the stiff person syndrome, which is a rare and disabling neurologic disorder characterized by muscle rigidity and episodic spasms that involve axial and limb musculature. It is an autoimmune disorder resulting in a malfunction of aminobutyric acid mediated inhibitory networks in the central nervous system. We describe a patient diagnosed by neurological symptoms of stiff limb syndrome with a good outcome after treatment, and a review of the related literature. CASE PRESENTATION: A 49 year-old male patient presented with a progressive stiffness and painful spasms of his both legs resulting in a difficulty of standing up and walking. The diagnosis of stiff limb syndrome was supported by the dramatically positive response to treatment using diazepam 25 mg/day and baclofen 30 mg/day. CONCLUSION: This clinical case highlights the importance of a therapeutic test to confirm the diagnosis of stiff limb syndrome especially when there is a high clinical suspicion with unremarkable electromyography. PMID- 20205914 TI - Progress towards the achievement of MDG4 in the Commonwealth of Independent States: uncertain data, clear priorities. AB - Data on under five mortality in the twelve countries of the Commonwealth of Independent States show important fluctuations over time due to variations in quality of data, definitions of neonatal deaths and methods of mortality estimation. Despite the uncertainties regarding mortality trends, the analysis of health and social information from different sources offers clues to identify priority areas and key strategic directions for accelerating the achievement of the 4th Millennium Development Goal. Neonatal deaths represent from 40% to over 50% of under five deaths in all these countries. Maternal mortality was above 50 per 100,000 in 2005, despite the good coverage with antenatal care and births assisted by skilled birth attendants. The scanty information on quality of perinatal care indicates widespread substandard care at all levels. Stunting in children under five is above 10% in ten out of twelve countries and coexists with emerging overweight. Exclusivity and duration of breastfeeding fall short of what is recommended. There are important inequalities in child and maternal mortality, malnutrition and access and use of health services within countries. Taken as a whole, the available information clearly indicates that priority should be given to improvement of the health of women in reproductive age and of the quality of perinatal care, including the establishment of reliable data collection systems. To achieve this, action will need to focus on strengthening the capacity of the health system to improve the technical content of service provision, and on improving access and appropriate use of services by the most disadvantaged groups. The involvement of other sectors will be necessary to improve reproductive health and nutrition at community level and to tackle inequity. Comparisons between countries with similar socioeconomic background but different health policies seem to indicate that gradual progression towards universal coverage with essential health care through a national health insurance system is associated with larger reduction of child mortality than troubled transition towards a privatized and unregulated health system. PMID- 20205915 TI - Community acquired methicillin-resistant Staphylococcus aureus pneumonia leading to rhabdomyolysis: a case report. AB - Community-acquired methicillin resistant Staphylococcus aureus (CA-MRSA) is considered an underreported entity in India. In this case report, the authors describe a thirty-five year old immunocompetent male presenting with severe respiratory distress requiring intubation. On further work up, a CT thorax showed features consistent with necrotizing pneumonia. The morphology and sensitivity pattern of the organism found in the bronchoalveolar lavage fluid and blood culture were consistent with MRSA. The patient's stay in the hospital was complicated by acute renal failure due to rhabdomyolysis with CPK levels of 9995 U/L. The patient was started on dialysis and improved there after. This case brings to light that CA-MRSA is becoming a problem in developing nations where antibiotics are frequently used empirically with little laboratory guidance. It also is a rare reporting of rhabdomyolysis due to CA-MRSA. PMID- 20205916 TI - Suicidality and depression among adult patients admitted in general medical facilities in Kenya. AB - AIM: To document Beck Depression Inventory (BDI) II suicidal symptoms among patients admitted to Kenyan non-psychiatric general medical facilities METHODS: All consenting adults admitted within a period of 4 weeks at 10 general medical facilities in Kenya were interviewed for suicidal symptoms and depression using the BDI-II. RESULTS: In all, 2,780 patients responded to item 9 (suicidal symptoms of the BDI-II). The prevalence of all BDI-II suicidal symptoms combined was 10.5%. Thoughts of 'killing oneself but have not carried them out' accounted for 9% of the suicidal symptoms. The younger age group had the highest prevalence of suicidal symptoms and the oldest age group had the least prevalence of suicidal symptoms. The more depressed the patients were on the overall BDI-II score, the higher the prevalence of suicidal symptoms. CONCLUSION: On average 1 out of 10 of the patients had suicidal symptoms, more so in younger than the older people and in the more depressed. These symptoms had not been clinically recognised and therefore not managed. This calls for clinical practice that routinely enquires for suicidal symptoms in general medical wards. PMID- 20205917 TI - Cigarette smoke regulates VEGFR2-mediated survival signaling in rat lungs. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2)-mediated survival signaling is critical to endothelial cell survival, maintenance of the vasculature and alveolar structure and regeneration of lung tissue. Reduced VEGF and VEGFR2 expression in emphysematous lungs has been linked to increased endothelial cell death and vascular regression. Previously, we have shown that CS down-regulated the VEGFR2 and its downstream signaling in mouse lungs. However, the VEGFR2-mediated survival signaling in response to oxidants/cigarette smoke (CS) is not known. We hypothesized that CS exposure leads to disruption of VEGFR2-mediated endothelial survival signaling in rat lungs. METHODS: Adult male Sprague-Dawley rats were exposed CS for 3 days, 8 weeks and 6 months to investigate the effect of CS on VEGFR2-mediated survival signaling by measuring the Akt/PI3-kinase/eNOS downstream signaling in rat lungs. RESULTS AND DISCUSSION: We show that CS disrupts VEGFR2/PI3-kinase association leading to decreased Akt and eNOS phosphorylation. This may further alter the phosphorylation of the pro-apoptotic protein Bad and increase the Bad/Bcl-xl association. However, this was not associated with a significant lung cell death as evidenced by active caspase-3 levels. These data suggest that although CS altered the VEGFR2-mediated survival signaling in the rat lungs, but it was not sufficient to cause lung cell death. CONCLUSION: The rat lungs exposed to CS in acute, sub-chronic and chronic levels may be representative of smokers where survival signaling is altered but was not associated with lung cell death whereas emphysema is known to be associated with lung cell apoptosis. PMID- 20205918 TI - Adolescent-parent interactions and communication preferences regarding body weight and weight management: a qualitative study. AB - BACKGROUND: This study aimed to canvass the nature of adolescent-parent interactions about weight, particularly overweight, and to explore ideas of how to foster supportive discussions regarding weight, both in the home and with family doctors. METHODS: A market research company was contracted to recruit and conduct a series of separate focus groups with adolescents and unrelated parents of adolescents from low-middle socio-economic areas in Sydney and a regional centre, Australia. Group discussions were audio recorded, transcribed, and then a qualitative content analysis of the data was performed. RESULTS: Nine focus groups were conducted; two were held with girls (n = 13), three with boys (n = 18), and four with parents (20 mothers, 12 fathers). Adolescent and parent descriptions of weight-related interactions could be classified into three distinct approaches: indirect/cautious (i.e. focus on eating or physical activity behaviors without discussing weight specifically); direct/open (i.e. body weight was discussed); and never/rarely discussing the subject. Indirect approaches were described most frequently by both adolescents and parents and were generally preferred over direct approaches. Parents and adolescents were circumspect but generally supportive of the potential role for family doctors to monitor and discuss adolescent weight status. CONCLUSIONS: These findings have implications for developing acceptable messages for adolescent and family overweight prevention and treatment interventions. PMID- 20205919 TI - Improving the yeast two-hybrid system with permutated fusions proteins: the Varicella Zoster Virus interactome. AB - BACKGROUND: Yeast two-hybrid (Y2H) screens have been among the most powerful methods to detect and analyze protein-protein interactions. However, they suffer from a significant degree of false negatives, i.e. true interactions that are not detected, and to a certain degree from false positives, i.e. interactions that appear to take place only in the context of the Y2H assay. While the fraction of false positives remains difficult to estimate, the fraction of false negatives in typical Y2H screens is on the order of 70-90%. Here we present novel Y2H vectors that significantly decrease the number of false negatives and help to mitigate the false positive problem. RESULTS: We have constructed two new vectors (pGBKCg and pGADCg) that allow us to make both C-terminal fusion proteins of DNA-binding and activation domains. Both vectors can be combined with existing vectors for N terminal fusions and thus allow four different bait-prey combinations: NN, CC, NC, and CN. We have tested all approximately 4,900 pairwise combinations of the 70 Varicella-Zoster-Virus (VZV) proteins for interactions, using all possible combinations. About approximately 20,000 individual Y2H tests resulted in 182 NN, 89 NC, 149 CN, and 144 CC interactions. Overlap between screens ranged from 17% (NC-CN) to 43% (CN-CC). Performing four screens (i.e. permutations) instead of one resulted in about twice as many interactions and thus much fewer false negatives. In addition, interactions that are found in multiple combinations confirm each other and thus provide a quality score. This study is the first systematic analysis of such N- and C-terminal Y2H vectors. CONCLUSIONS: Permutations of C- and N-terminal Y2H vectors dramatically increase the coverage of interactome studies and thus significantly reduce the number of false negatives. We suggest that future interaction screens should use such vector combinations on a routine basis, not the least because they provide a built-in quality score for Y2H interactions that can provide a measure of reproducibility without additional assays. PMID- 20205920 TI - Early detection of Varicella-Zoster virus (VZV)-specific T-cells before seroconversion in primary varicella infection: case report. AB - Here we report the case of a 54-year old, immunocompetent German patient with primary varicella whose Varicella-Zoster Virus (VZV)-specific T-cell responses could be detected early in infection and before the onset of seroconversion. This case demonstrates that the detection of VZV-specific T-cells may under certain circumstances support the diagnosis of a primary varicella infection, as for example in cases of atypical or subclinical varicella or in the absence of detectable VZV DNA in plasma. PMID- 20205921 TI - The effect of the combination of acids and tannin in diet on the performance and selected biochemical, haematological and antioxidant enzyme parameters in grower pigs. AB - BACKGROUND: The abolition of in-feed antibiotics or chemotherapeutics as growth promoters have stimulated the swine industry to look for alternatives such as organic acids, botanicals, probiotics and tannin. The objective of the present study was to compare the effects of a combination of acids and tannin with diet with organic acids and diet without growth promoters on the growth performance and selected biochemical, haematological and antioxidant enzyme parameters in grower pigs. Tannin is more natural and cheaper but possibly with the same effectiveness as organic acids with regard to growth performance. METHODS: Thirty six 7 week old grower pigs, divided into three equal groups, were used in a three week feeding trial. Group I was fed basal diet, group II basal diet with added organic acids and group III basal diet with added organic and inorganic acids and tannin. Pigs were weighed before and after feeding and observed daily. Blood was collected before and after the feeding trial for the determination of selected biochemical, haematological and antioxidant enzyme parameters. One-way ANOVA was used to assess any diet related changes of all the parameters. Paired t-test was used to evaluate changes of blood parameters individually in each group of growers before and after feeding. RESULTS: No clinical health problems related to diet were noted during the three week feeding trial. The average daily gain (ADG) and selected blood parameters were not affected by the addition to basal diet of either acids and tannin or of organic acids alone. Selected blood parameters remained within the reference range before and after the feeding trial, with the exception of total serum proteins that were below the lower value of reference range at both times. The significant changes (paired t-test) observed in individual groups before and after the feeding trial are related to the growth of pigs. CONCLUSION: Diet with acids and tannin did not improve the growth performance of grower pigs but had no deleterious effects on selected blood parameters. The possibility of beneficial effects of adding acids and tannin in diets on growth performance over a longer period, however, could not be excluded. PMID- 20205922 TI - Measuring the psychosocial health of adolescent and young adult (AYA) cancer survivors: a critical review. AB - BACKGROUND: Adolescent and young adult (AYA) cancer survivors require psychometrically rigorous measures to assess their psychosocial well-being. Without methodologically adequate scales the accuracy of information obtained on the prevalence of needs, predictors of risk, and the potential success of any interventions, can be questioned. This review assessed the psychometric properties of measures designed specifically to identify the psychosocial health of this unique population. METHODS: Medline, PsycINFO, CINAHL and EMBASE databases were searched to identify measures developed to assess the psychosocial health of AYA cancer survivors. Searches were limited to the years 1998-2008. A search of Medline revealed that the number of publications related to the assessment of psychosocial well-being in AYA cancer survivors prior to this period were minimal. The psychometric properties of identified measures were evaluated against pre-determined and generally accepted psychometric criteria including: reliability (internal consistency and test-retest); validity (face, content, construct, and criterion); responsiveness; acceptability; and feasibility. RESULTS: Seven quality of life measures met the inclusion criteria. No measures of unmet need were identified. All seven measures reported adequate internal consistency, face, content, and construct validity. Test-retest reliability, criterion (predictive) validity, responsiveness, acceptability, and feasibility were rarely examined. CONCLUSIONS: There is a need to further evaluate the psychometric properties of existing quality of life measures for AYA cancer survivors. Valid, reliable, and acceptable measures which can assess the psychosocial needs of this population should also be developed. PMID- 20205924 TI - Pancratistatin induces apoptosis in clinical leukemia samples with minimal effect on non-cancerous peripheral blood mononuclear cells. AB - BACKGROUND: Pancratistatin, a natural compound extracted from Hymenocallis littoralis, can selectively induce apoptosis in several cancer cell lines. In this ex vivo study, we evaluated the effect of pancratistatin on peripheral blood mononuclear cells obtained from 15 leukemia patients prior to clinical intervention of newly diagnosed patients, as well as others of different ages in relapse and at various disease progression states. RESULTS: Mononuclear cells from healthy volunteers and leukemia patients were exposed to 1 microM pancratistatin for up to 48 h. Irrespective of leukemia type, pancratistatin induced apoptosis in the leukemic samples, with minimal effects on non-cancerous peripheral blood mononuclear control cells. CONCLUSION: Our results show that pancratistatin is an effective and selective anti-cancer agent with potential for advancement to clinical trials. PMID- 20205923 TI - Is the drug-induced hypersensitivity syndrome (DIHS) due to human herpesvirus 6 infection or to allergy-mediated viral reactivation? Report of a case and literature review. AB - BACKGROUND: Drug-Induced Hypersensitivity Syndrome (DIHS) is a severe and rare systemic reaction triggered by a drug (usually an antiepileptic drug). We present a case of DISH and we review studies on the clinical features and treatment of DIHS, and on its pathogenesis in which two elements (Herpesvirus infection and the drug) interact with the immune system to trigger such a syndrome that can lead to death in about 20% of cases. CASE PRESENTATION: We report the case of a 26-year old woman with fever, systemic maculopapular rash, lymphadenopathy, hepatitis and eosinophilic leukocytosis. She had been treated with antibiotics that gave no benefit. She was taking escitalopram and lamotrigine for a bipolar disease 30 days before fever onset. Because the patient's general condition deteriorated, betamethasone and acyclovir were started. This treatment resulted in a mild improvement of symptoms. Steroids were rapidly tapered and this was followed with a relapse of fever and a worsening of laboratory parameters. Human herpesvirus 6 (HHV-6) DNA was positive as shown by PCR. Drug-Induced Hypersensitivity Syndrome (DIHS) was diagnosed. Symptoms regressed on prednisone (at a dose of 50 mg/die) that was tapered very slowly. The patient recovered completely. CONCLUSIONS: The search for rare causes of fever led to complete resolution of a very difficult case. As DIHS is a rare disease the most relevant issue is to suspect and include it in differential diagnosis of fevers of unknown origin. Once diagnosed, the therapy is easy (steroidal administration) and often successful. However our case strongly confirms that attention should be paid on the steroidal tapering that should be very slow to avoid a relapse. PMID- 20205925 TI - Comparative antilipidemic effect of N-acetylcysteine and sesame oil administration in diet-induced hypercholesterolemic mice. AB - BACKGROUND: There is an increasing number of novel antilipidemic therapies under consideration. The putative hypolipidemic effect of N-acetylcysteine (NAC) and sesame oil was studied in a mouse model of dietary-induced hypercholesterolemia. METHODS: Male C57bl/6 mice were assigned to the following groups: (NC) control group, (HC) group receiving test diet supplemented with 2% cholesterol and 0.5% cholic acid for 8 weeks, (HCN) group receiving the test diet with NAC supplementation (230 mg/kg p.o.) and (HCS) group fed the test diet enriched with 10% sesame oil. Total serum cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides were assayed at the beginning and at the end of the experiment. Total peroxides and nitric oxide (NO) levels were measured in the serum at the end of the experiment. Hepatic and aortic lesions were evaluated by haematoxylin eosin staining. RESULTS: Higher serum levels of total and LDL-cholesterol were recorded in all groups fed the high cholesterol diet. The HCN group presented reduced lipid levels compared to HC and HCS groups. No differences were observed between HCS and HC groups. Peroxide content in serum was markedly increased in mice consuming high cholesterol diet. NAC and sesame oil administration led to a significant decrease of serum lipid peroxidation in the levels of control group, whereas only NAC restored NO bioavailability. In terms of liver histology, the lesions observed in HCN group were less severe than those seen in the other high cholesterol groups. CONCLUSION: Co-administration of NAC, but not sesame oil, restored the disturbed lipid profile and improved hepatic steatosis in the studied diet-induced hypercholesterolemic mice. Both agents appear to ameliorate serum antioxidant defense. PMID- 20205926 TI - Prioritization strategies in clinical practice guidelines development: a pilot study. AB - OBJECTIVE: Few methodological studies address the prioritization of clinical topics for the development of Clinical Practice Guidelines (CPGs). The aim of this study was to validate a methodology for Priority Determination of Topics (PDT) of CPGs. METHODS AND RESULTS: Firstly, we developed an instrument for PDT with 41 criteria that were grouped under 10 domains, based on a comprehensive systematic search. Secondly, we performed a survey of stakeholders involved in CPGs development, and end users of guidelines, using the instrument. Thirdly, a pilot testing of the PDT procedure was performed in order to choose 10 guideline topics among 34 proposed projects; using a multi-criteria analysis approach, we validated a mechanism that followed five stages: determination of the composition of groups, item/domain scoring, weights determination, quality of the information used to support judgments, and finally, topic selection. Participants first scored the importance of each domain, after which four different weighting procedures were calculated (including the survey results). The process of weighting was determined by correlating the data between them. We also reported the quality of evidence used for PDT. Finally, we provided a qualitative analysis of the process. The main domains used to support judgement, having higher quality scores and weightings, were feasibility, disease burden, implementation and information needs. Other important domains such as user preferences, adverse events, potential for health promotion, social effects, and economic impact had lower relevance for clinicians. Criteria for prioritization were mainly judged through professional experience, while good quality information was only used in 15% of cases. CONCLUSION: The main advantages of the proposed methodology are supported by the use of a systematic approach to identify, score and weight guideline topics selection, limiting or exposing the influence of personal biases. However, the methodology was complex and included a number of quantitative and qualitative approaches reflecting the difficulties of the prioritization process. PMID- 20205927 TI - Evaluation of a pig femoral head osteonecrosis model. AB - BACKGROUND: A major cause of osteonecrosis of the femoral head is interruption of a blood supply to the proximal femur. In order to evaluate blood circulation and pathogenetic alterations, a pig femoral head osteonecrosis model was examined to address whether ligature of the femoral neck (vasculature deprivation) induces a reduction of blood circulation in the femoral head, and whether transphyseal vessels exist for communications between the epiphysis and the metaphysis. We also tested the hypothesis that the vessels surrounding the femoral neck and the ligamentum teres represent the primary source of blood flow to the femoral head. METHODS: Avascular osteonecrosis of the femoral head was induced in Yorkshire pigs by transecting the ligamentum teres and placing two ligatures around the femoral neck. After heparinized saline infusion and microfil perfusion via the abdominal aorta, blood circulation in the femoral head was evaluated by optical and CT imaging. RESULTS: An angiogram of the microfil casted sample allowed identification of the major blood vessels to the proximal femur including the iliac, common femoral, superficial femoral, deep femoral and circumflex arteries. Optical imaging in the femoral neck showed that a microfil stained vessel network was visible in control sections but less noticeable in necrotic sections. CT images showed a lack of microfil staining in the epiphysis. Furthermore, no transphyseal vessels were observed to link the epiphysis to the metaphysis. CONCLUSION: Optical and CT imaging analyses revealed that in this present pig model the ligatures around the femoral neck were the primary cause of induction of avascular osteonecrosis. Since the vessels surrounding the femoral neck are comprised of the branches of the medial and the lateral femoral circumflex vessels, together with the extracapsular arterial ring and the lateral epiphyseal arteries, augmentation of blood circulation in those arteries will improve pathogenetic alterations in the necrotic femoral head. Our pig model can be used for further femoral head osteonecrosis studies. PMID- 20205928 TI - A comparative epidemiologic analysis of SARS in Hong Kong, Beijing and Taiwan. AB - BACKGROUND: The 2002-2003 Severe Acute Respiratory Syndrome (SARS) outbreak infected 8,422 individuals leading to 916 deaths around the world. However, there have been few epidemiological studies of SARS comparing epidemiologic features across regions. The aim of this study is to identify similarities and differences in SARS epidemiology in three populations with similar host and viral genotype. METHODS: We present a comparative epidemiologic analysis of SARS, based on an integrated dataset with 3,336 SARS patients from Hong Kong, Beijing and Taiwan, epidemiological and clinical characteristics such as incubation, onset-to admission, onset-to-discharge and onset-to-death periods, case fatality ratios (CFRs) and presenting symptoms are described and compared between regions. We further explored the influence of demographic and clinical variables on the apparently large differences in CFRs between the three regions. RESULTS: All three regions showed similar incubation periods and progressive shortening of the onset-to-admission interval through the epidemic. Adjusted for sex, health care worker status and nosocomial setting, older age was associated with a higher fatality, with adjusted odds ratio (AOR): 2.10 (95% confidence interval: 1.45, 3.04) for those aged 51-60; AOR: 4.57 (95% confidence interval: 3.32, 7.30) for those aged above 60 compared to those aged 41-50 years. Presence of pre-existing comorbid conditions was also associated with greater mortality (AOR: 1.74; 95% confidence interval: 1.36, 2.21). CONCLUSION: The large discrepancy in crude fatality ratios across the three regions can only be partly explained by epidemiological and clinical heterogeneities. Our findings underline the importance of a common data collection platform, especially in an emerging epidemic, in order to identify and explain consistencies and differences in the eventual clinical and public health outcomes of infectious disease outbreaks, which is becoming increasingly important in our highly interconnected world. PMID- 20205929 TI - Mural granulosa cell gene expression associated with oocyte developmental competence. AB - BACKGROUND: Ovarian follicle development is a complex process. Paracrine interactions between somatic and germ cells are critical for normal follicular development and oocyte maturation. Studies have suggested that the health and function of the granulosa and cumulus cells may be reflective of the health status of the enclosed oocyte. The objective of the present study is to assess, using an in vivo immature rat model, gene expression profile in granulosa cells, which may be linked to the developmental competence of the oocyte. We hypothesized that expression of specific genes in granulosa cells may be correlated with the developmental competence of the oocyte. METHODS: Immature rats were injected with eCG and 24 h thereafter with anti-eCG antibody to induce follicular atresia or with pre-immune serum to stimulate follicle development. A high percentage (30-50%, normal developmental competence, NDC) of oocytes from eCG/pre-immune serum group developed to term after embryo transfer compared to those from eCG/anti-eCG (0%, poor developmental competence, PDC). Gene expression profiles of mural granulosa cells from the above oocyte-collected follicles were assessed by Affymetrix rat whole genome array. RESULTS: The result showed that twelve genes were up-regulated, while one gene was down-regulated more than 1.5 folds in the NDC group compared with those in the PDC group. Gene ontology classification showed that the up-regulated genes included lysyl oxidase (Lox) and nerve growth factor receptor associated protein 1 (Ngfrap1), which are important in the regulation of protein-lysine 6-oxidase activity, and in apoptosis induction, respectively. The down-regulated genes included glycoprotein 4-beta galactosyltransferase 2 (Ggbt2), which is involved in the regulation of extracellular matrix organization and biogenesis. CONCLUSIONS: The data in the present study demonstrate a close association between specific gene expression in mural granulosa cells and the developmental competence of oocytes. This finding suggests that the most differentially expressed gene, lysyl oxidase, may be a candidate biomarker of oocyte health and useful for the selection of good quality oocytes for assisted reproduction. PMID- 20205930 TI - Barriers to initiation of antiretroviral treatment in rural and urban areas of Zambia: a cross-sectional study of cost, stigma, and perceptions about ART. AB - BACKGROUND: While the number of HIV-positive patients on antiretroviral therapy (ART) in resource-limited settings has increased dramatically, some patients eligible for treatment do not initiate ART even when it is available to them. Understanding why patients opt out of care, or are unable to opt in, is important to achieving the goal of universal access. METHODS: We conducted a cross sectional survey among 400 patients on ART (those who were able to access care) and 400 patients accessing home-based care (HBC), but who had not initiated ART (either they were not able to, or chose not to, access care) in two rural and two urban sites in Zambia to identify barriers to and facilitators of ART uptake. RESULTS: HBC patients were 50% more likely to report that it would be very difficult to get to the ART clinic than those on ART (RR: 1.48; 95% CI: 1.21 1.82). Stigma was common in all areas, with 54% of HBC patients, but only 15% of ART patients, being afraid to go to the clinic (RR: 3.61; 95% CI: 3.12-4.18). Cost barriers differed by location: urban HBC patients were three times more likely to report needing to pay to travel to the clinic than those on ART (RR: 2.84; 95% CI: 2.02-3.98) and 10 times more likely to believe they would need to pay a fee at the clinic (RR: 9.50; 95% CI: 2.24-40.3). In rural areas, HBC subjects were more likely to report needing to pay non-transport costs to attend the clinic than those on ART (RR: 4.52; 95% CI: 1.91-10.7). HBC patients were twice as likely as ART patients to report not having enough food to take ART being a concern (27% vs. 13%, RR: 2.03; 95% CI: 1.71-2.41), regardless of location and gender. CONCLUSIONS: Patients in home-based care for HIV/AIDS who never initiated ART perceived greater financial and logistical barriers to seeking HIV care and had more negative perceptions about the benefits of the treatment. Future efforts to expand access to antiretroviral care should consider ways to reduce these barriers in order to encourage more of those medically eligible for antiretrovirals to initiate care. PMID- 20205932 TI - Endoscopic management of biliary fascioliasis: a case report. AB - INTRODUCTION: Fasciola hepatica, an endemic parasite common in Iraq and its neighboring countries, is a very rare cause of cholestasis worldwide. Humans can become definitive hosts of this parasite through their ingestion of a contaminated water plant, for example, contaminated watercress. Symptoms of cholestasis may appear suddenly and, in some cases, are preceded by long periods of fever, eosinophilia, and vague gastrointestinal symptoms. Here we report the case of a woman with a sudden onset of symptoms of cholangitis. Her infection was proved by endoscopic retrograde cholangiography to be due to Fasciola hepatica infestation. CASE PRESENTATION: A 38-year-old Kurdish woman from the northern region of Iraq presented with fever, right upper quadrant abdominal pain, and jaundice. An examination of the patient revealed elevated total serum bilirubin and liver enzymes. An ultrasonography also showed a dilatation of her common bile duct. During endoscopic retrograde cholangiopancreatography, a filling defect was identified in her common bile duct. After sphincterotomy and balloon extraction, one live Fasiola hepatica was extracted and physically removed. CONCLUSION: Fasciola hepatica should be a part of the differential diagnosis of common bile duct obstruction. When endoscopic retrograde cholangiopancreatography is available, the disease can be easily diagnosed and treated. PMID- 20205931 TI - The Sinorhizobium meliloti RNA chaperone Hfq influences central carbon metabolism and the symbiotic interaction with alfalfa. AB - BACKGROUND: The bacterial Hfq protein is able to interact with diverse RNA molecules, including regulatory small non-coding RNAs (sRNAs), and thus it is recognized as a global post-transcriptional regulator of gene expression. Loss of Hfq has an extensive impact in bacterial physiology which in several animal pathogens influences virulence. Sinorhizobium meliloti is a model soil bacterium known for its ability to establish a beneficial nitrogen-fixing intracellular symbiosis with alfalfa. Despite the predicted general involvement of Hfq in the establishment of successful bacteria-eukaryote interactions, its function in S. meliloti has remained unexplored. RESULTS: Two independent S. meliloti mutants, 2011-3.4 and 1021Deltahfq, were obtained by disruption and deletion of the hfq gene in the wild-type strains 2011 and 1021, respectively, both exhibiting similar growth defects as free-living bacteria. Transcriptomic profiling of 1021Deltahfq revealed a general down-regulation of genes of sugar transporters and some enzymes of the central carbon metabolism, whereas transcripts specifying the uptake and metabolism of nitrogen sources (mainly amino acids) were more abundant than in the wild-type strain. Proteomic analysis of the 2011-3.4 mutant independently confirmed these observations. Symbiotic tests showed that lack of Hfq led to a delayed nodulation, severely compromised bacterial competitiveness on alfalfa roots and impaired normal plant growth. Furthermore, a large proportion of nodules (55%-64%) elicited by the 1021Deltahfq mutant were non fixing, with scarce content in bacteroids and signs of premature senescence of endosymbiotic bacteria. RT-PCR experiments on RNA from bacteria grown under aerobic and microoxic conditions revealed that Hfq contributes to regulation of nifA and fixK1/K2, the genes controlling nitrogen fixation, although the Hfq mediated regulation of fixK is only aerobiosis dependent. Finally, we found that some of the recently identified S. meliloti sRNAs co-inmunoprecipitate with a FLAG-epitope tagged Hfq protein. CONCLUSIONS: Our results support that the S. meliloti RNA chaperone Hfq contributes to the control of central metabolic pathways in free-living bacteria and influences rhizospheric competence, survival of the microsymbiont within the nodule cells and nitrogen fixation during the symbiotic interaction with its legume host alfalfa. The identified S. meliloti Hfq-binding sRNAs are predicted to participate in the Hfq regulatory network. PMID- 20205933 TI - Involvement in emergency situations by primary care doctors on-call in Norway--a prospective population-based observational study. AB - BACKGROUND: Primary care doctors on-call in the emergency primary health care services in Norway are, together with the ambulances, the primary resources for handling emergencies outside hospitals. There is a lack of reliable data for Norway on how often the primary care doctors are alerted and on their responses in the most urgent emergency cases. The aim of this study was to investigate how doctors on-call are involved in red responses (highest priority), using three different emergency medical communication centres (EMCC) as catchment area for a prospective population-based study. METHODS: In the period from October to December 2007 three dispatch centres covering approximately 816,000 inhabitants prospectively recorded all acute emergency cases. Ambulance records, air ambulance records and records from the doctors on-call were collected. NACA score was used to define the severity of the emergencies. RESULTS: 5,105 cases were classified as red responses during the period. We have complete basic recordings (AMIS forms) from all and resaved ambulance records, air ambulance records and records from doctors on-call in 89% of the cases. Ambulances were alerted in 96% and doctors on-call in 47% of the cases, but there were large differences between the three EMCCs. Doctors on-call responded with call-out in 42% of the alerted cases. 28% of all patients were taken to a casualty clinic, 46% were admitted to hospital by a doctor and 24% were taken directly to hospital by ambulances. In total, primary care doctors on-call took active part in 42% of all red response cases, and together with GPs' daytime activity the primary health care services were involved in 50% of the cases. 29% of the cases were classified as life threatening. Call-out by doctors on-call were found to be more frequent in life threatening situations compared with not life-threatening situations. CONCLUSION: Doctors on-call and GPs on daytime were involved in half of all red responses. There were large differences between the EMCCs in the frequency of doctors alerted. The inhabitants in the three EMMCs were thus offered different levels of professional competency in emergency situations outside hospitals. PMID- 20205934 TI - Maternal consumption of canola oil suppressed mammary gland tumorigenesis in C3(1) TAg mice offspring. AB - BACKGROUND: Maternal consumption of a diet high in omega 6 polyunsaturated fats (n-6 PUFA) has been shown to increase risk whereas a diet high in omega 3 polyunsaturated fats (n-3 PUFA) from fish oil has been shown to decrease risk for mammary gland cancer in female offspring of rats. The aim of this study was to determine whether increasing n-3 PUFA and reducing n-6 PUFA by using canola oil instead of corn oil in the maternal diet might reduce the risk for breast cancer in female offspring. METHODS: Female SV 129 mice were divided into two groups and placed on diets containing either 10% w/w corn oil (which is 50% n-6 PUFA, control diet) or 10% w/w canola oil (which is 20% n-6 PUFA, 10% n-3 PUFA, test diet). After two weeks on the diets the females were bred with homozygous C3(1) TAg transgenic mice. Mother mice consumed the assigned diet throughout gestation and nursing of the offspring. After weaning, all female offspring were maintained on the control diet. RESULTS: Compared to offspring of mothers fed the corn oil diet (CO/CO group), offspring of mothers fed the canola oil diet (CA/CO group) had significantly fewer mammary glands with tumors throughout the experiment. At 130 days of age, the CA/CO group had significantly fewer tumors per mouse (multiplicity); the tumor incidence (fraction of mice with any tumor) and the total tumor weight (per mouse that developed tumor) was less than one half that of the CO/CO group. At 170 days of age, the total tumor weight per mouse was significantly less in the CA/CO group and if a tumor developed the rate of tumor growth rate was half that of CO/CO group. These results indicate that maternal consumption of canola oil was associated with delayed appearance of mammary gland tumors and slowed growth of the tumors that developed. CONCLUSIONS: Substituting canola oil for corn oil is an easy dietary change for people to make; such a change to the maternal diet may decrease risk for breast cancer in the daughter. PMID- 20205935 TI - Spatial clustering in the spatio-temporal dynamics of endemic cholera. AB - BACKGROUND: The spatio-temporal patterns of infectious diseases that are environmentally driven reflect the combined effects of transmission dynamics and environmental heterogeneity. They contain important information on different routes of transmission, including the role of environmental reservoirs. Consideration of the spatial component in infectious disease dynamics has led to insights on the propagation of fronts at the level of counties in rabies in the US, and the metapopulation behavior at the level of cities in childhood diseases such as measles in the UK, both at relatively coarse scales. As epidemiological data on individual infections become available, spatio-temporal patterns can be examined at higher resolutions. METHODS: The extensive spatio-temporal data set for cholera in Matlab, Bangladesh, maps the individual location of cases from 1983 to 2003. This unique record allows us to examine the spatial structure of cholera outbreaks, to address the role of primary transmission, occurring from an aquatic reservoir to the human host, and that of secondary transmission, involving a feedback between current and past levels of infection. We use Ripley's K and L indices and bootstrapping methods to evaluate the occurrence of spatial clustering in the cases during outbreaks using different temporal windows. The spatial location of cases was also confronted against the spatial location of water sources. RESULTS: Spatial clustering of cholera cases was detected at different temporal and spatial scales. Cases relative to water sources also exhibit spatial clustering. CONCLUSIONS: The clustering of cases supports an important role of secondary transmission in the dynamics of cholera epidemics in Matlab, Bangladesh. The spatial clustering of cases relative to water sources, and its timing, suggests an effective role of water reservoirs during the onset of cholera outbreaks. Once primary transmission has initiated an outbreak, secondary transmission takes over and plays a fundamental role in shaping the epidemics in this endemic area. PMID- 20205936 TI - Relationship between peripheral airway function and patient-reported outcomes in COPD: a cross-sectional study. AB - BACKGROUND: Health status, dyspnea and psychological status are important clinical outcomes in chronic obstructive pulmonary disease (COPD). However, forced expiratory volume in one second (FEV1) measured by spirometry, the standard measurement of airflow limitation, has only a weak relationship with these outcomes in COPD. Recently, in addition to spirometry, impulse oscillometry (IOS) measuring lung resistance (R) and reactance (X) is increasingly being used to assess pulmonary functional impairment. METHODS: We aimed to identify relationships between IOS measurements and patient-reported outcomes in 65 outpatients with stable COPD. We performed pulmonary function testing, IOS, high resolution computed tomography (CT), and assessment of health status using the St. George's Respiratory Questionnaire (SGRQ), dyspnea using the Medical Research Council (MRC) scale and psychological status using the Hospital Anxiety and Depression Scale (HADS). We then investigated the relationships between these parameters. For the IOS measurements, we used lung resistance at 5 and 20 Hz (R5 and R20, respectively) and reactance at 5 Hz (X5). Because R5 and R20 are regarded as reflecting total and proximal airway resistance, respectively, the fall in resistance from R5 to R20 (R5-R20) was used as a surrogate for the resistance of peripheral airways. X5 was also considered to represent peripheral airway abnormalities. RESULTS: R5-R20 and X5 were significantly correlated with the SGRQ and the MRC. These correlation coefficients were greater than when using other objective measurements of pulmonary function, R20 on the IOS and CT instead of R5-R20 and X5. Multiple regression analyses showed that R5-R20 or X5 most significantly accounted for the SGRQ and MRC scores. CONCLUSIONS: IOS measurements, especially indices of peripheral airway function, are significantly correlated with health status and dyspnea in patients with COPD. Therefore, in addition to its simplicity and non-invasiveness, IOS may be a useful clinical tool not only for detecting pulmonary functional impairment, but also to some extent at least estimating the patient's quality of daily life and well-being. PMID- 20205937 TI - Challenges faced by health workers in providing counselling services to HIV positive children in Uganda: a descriptive study. AB - BACKGROUND: The delivery of HIV counselling and testing services for children remains an uphill task for many health workers in HIV-endemic countries, including Uganda. We conducted a descriptive study to explore the challenges of providing HIV counselling and testing services to children in Uganda. METHODS: A descriptive study was conducted in the districts of Kampala and Kabarole in Uganda. The data were collected using semi-structured individual interviews and focus group discussions with health workers who are involved in the care of HIV positive children. Key informant interviews were conducted with the administrators of the 10 study healthcare institutions. Quantitative data were summarized using frequency tables, while qualitative data were analyzed using the content thematic approach. RESULTS: Counselling children was reported to be a difficult exercise due to some children being unable to express themselves, being dependent on adults for their care, being fearful, and requiring more time to open up during counselling. This was compounded by some caretakers' unwillingness and difficulty to disclose the HIV status of their children. Other issues about the caretakers were: lack of consistency in caretakers; old age; sickness; and poverty. Health workers mentioned the following as some of the challenges they face in the delivery of HIV counselling and testing services for children: lack of counselling skills; failure to cope with the knowledge demand; difficulty to facilitate disclosure; heavy work load; and lack of other support services. Institutions were found to be constrained by limited space and lack of antiretrovirals for children. CONCLUSIONS: The major challenges in the delivery of paediatric HIV services were related to the knowledge gap in paediatric HIV and the lack of counselling skills, as well as health system-related constraints. There is a need to train health workers in child-counselling skills, especially in the issues of disclosure, sexuality and sexual abuse, as well as in addressing fears related to death and an uncertain future, in order to improve paediatric HIV care. Provision of child-friendly services, guidelines and antiretroviral formulations for children may provide a window of hope to improve HIV counselling and testing services for children. PMID- 20205938 TI - Latent tuberculosis among pregnant mothers in a resource poor setting in Northern Tanzania: a cross-sectional study. AB - BACKGROUND: Untreated latent TB infection (LTBI) is a significant risk factor for active pulmonary tuberculosis, hence predisposing to adverse pregnancy outcomes and mother to child transmission. The prevalence of latent tuberculosis in pregnancy and its association, if any, with various socio-demographic, obstetric and clinical characteristics was evaluated. METHODS: Northern Tanzania was chosen as the study site. In a cross-sectional study, a total of 286 pregnant women from 12 weeks gestational age to term were assessed. Screening was undertaken using an algorithm involving tuberculin skin testing, symptom screening in the form of a questionnaire, sputum testing for acid fast bacilli followed by shielded chest X rays if indicated. HIV serology was also performed on consenting participants. RESULTS: Prevalence of latent infection ranged between 26.2% and 37.4% while HIV sero prevalence was 4.5%. After multivariate logistic analysis it was found that age, parity, body mass index, gestational age, and HIV sero status did not have any significant association with tuberculin skin test results. However certain ethnic groups were found to be less vulnerable to LTBI as compared to others (Chi square = 10.55, p = 0.03). All sputum smears for acid fast bacilli were negative. CONCLUSION: The prevalence of latent tuberculosis in pregnant women was found to be relatively high compared to that of the general population. In endemic areas, socio-demographic parameters alone are rarely adequate in identifying women susceptible to TB infection; therefore targeted screening should be conducted for all pregnant women at high risk for activation (especially HIV positive women). As opposed to the current policy of passive case detection, there appears to be an imminent need to move towards active screening. Ethnicity may provide important clues into genetic and cultural differences which predispose to latent tuberculosis, and is worth exploring further. PMID- 20205939 TI - Effects of manganese-excess on CO2 assimilation, ribulose-1,5-bisphosphate carboxylase/oxygenase, carbohydrates and photosynthetic electron transport of leaves, and antioxidant systems of leaves and roots in Citrus grandis seedlings. AB - BACKGROUND: Very little is known about the effects of manganese (Mn)-excess on citrus photosynthesis and antioxidant systems. Seedlings of sour pummelo (Citrus grandis) were irrigated for 17 weeks with nutrient solution containing 2 microM (control) or 500 microM (excess) MnSO4. The objective of this study were to understand the mechanisms by which Mn-excess leads to a decrease in CO2 assimilation and to test the hypothesis that Mn-induced changes in antioxidant systems differ between roots and leaves. RESULTS: Mn-excess decreased CO2 assimilation and stomatal conductance, increased intercellular CO2 concentration, but did not affect chlorophyll (Chl) level. Both initial and total ribulose-1,5 bisphosphate carboxylase/oxygenase (Rubisco) activity in Mn-excess leaves decreased to a lesser extent than CO2 assimilation. Contents of glucose, fructose, starch and total nonstructural carbohydrates did not differ between Mn excess leaves and controls, while sucrose content was higher in the former. Chl a fluorescence (OJIP) transients from Mn-excess leaves showed increased O-step and decreased P-step, accompanied by positive L- and K-bands. Mn-excess decreased maximum quantum yield of primary photochemistry (Fv/Fm) and total performance index (PItot,abs), but increased relative variable fluorescence at I-steps (VI) and energy dissipation. On a protein basis, Mn-excess leaves displayed higher activities of monodehydroascorbate reductase (MDAR), glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT) and guaiacol peroxidase (GPX) and contents of antioxidants, similar ascorbate peroxidase (APX) activities and lower dehydroascorbate reductase (DHAR) activities; while Mn-excess roots had similar or lower activities of antioxidant enzymes and contents of antioxidants. Mn excess did not affect malondialdehyde (MDA) content of roots and leaves. CONCLUSIONS: Mn-excess impaired the whole photosynthetic electron transport chain from the donor side of photosystem II (PSII) up to the reduction of end acceptors of photosystem I (PSI), thus limiting the production of reducing equivalents, and hence the rate of CO2 assimilation. Both the energy dissipation and the antioxidant systems were enhanced in Mn-excess leaves, while the antioxidant systems in Mn-excess roots were not up-regulated, but still remained high activity. The antioxidant systems in Mn-excess roots and leaves provided sufficient protection to them against oxidative damage. PMID- 20205940 TI - Small chloroplast-targeted DnaJ proteins are involved in optimization of photosynthetic reactions in Arabidopsis thaliana. AB - BACKGROUND: DnaJ proteins participate in many metabolic pathways through dynamic interactions with various components of these processes. The role of three small chloroplast-targeted DnaJ proteins, AtJ8 (At1 g80920), AtJ11 (At4 g36040) and AtJ20 (At4 g13830), was investigated here using knock-out mutants of Arabidopsis thaliana. Photochemical efficiency, capacity of CO2 assimilation, stabilization of Photosystem (PS) II dimers and supercomplexes under high light illumination, energy distribution between PSI and PSII and phosphorylation of PSII-LHCII proteins, global gene expression profiles and oxidative stress responses of these DnaJ mutants were analyzed. RESULTS: Knockout of one of these proteins caused a series of events including a decrease in photosynthetic efficiency, destabilization of PSII complexes and loss of control for balancing the redox reactions in chloroplasts. Data obtained with DNA microarray analysis demonstrated that the lack of one of these DnaJ proteins triggers a global stress response and therefore confers the plants greater tolerance to oxidative stress induced by high light or methyl viologen treatments. Expression of a set of genes encoding enzymes that detoxify reactive oxygen species (ROS) as well as a number of stress-related transcription factors behaved in the mutants at growth light similarly to that when wild-type (WT) plants were transferred to high light. Also a set of genes related to redox regulation were upregulated in the mutants. On the other hand, although the three DnaJ proteins reside in chloroplasts, the expression of most genes encoding thylakoid membrane proteins was not changed in the mutants. CONCLUSION: It is proposed that the tolerance of the DnaJ protein knockout plants to oxidative stress occurs at the expense of the flexibility of photosynthetic reactions. Despite the fact that the effects of the individual protein knockout on the response of plants to high light treatment are quite similar, it is conceivable that both specific- and cross-talk functions exist between the three small chloroplast-targeted DnaJ proteins, AtJ8, AtJ11 and AtJ20. PMID- 20205941 TI - Factors associated with low cure rate of tuberculosis in remote poor areas of Shaanxi Province, China: a case control study. AB - BACKGROUND: The directly observed therapy-short course (DOTS) strategy was introduced in Shaanxi province, China to improve tuberculosis (TB) control by means of improved case detection (target: > = 70%) and treatment success rates (target: > = 85%) in new smear positive (SS+) TB patients. At a provincial level the targets were both reached in 2005. However in 30 (28%) out of 107 counties of Shaanxi province the cure rate was below 85%. This study aimed to investigate patient and treatment characteristics associated with non-cure after tuberculosis (TB) treatment in these counties. METHODS: In this case-control study, new smear positive TB cases in 30 counties with a cure rate <85% were included. Cured patients were compared to non-cured patients using logistic regression analysis to assess determinants for non-cure. RESULTS: Of the 659 patients included, 153 (23.2%) did not have cure as treatment outcome. Interruption of treatment was most strongly associated with non-cure (OR = 8.7, 95% CI 3.9-18.4). Other independent risk factors were co-morbidity, low education level, lack of appetite as an initial symptom of TB disease, diagnosis of TB outside of the government TB control institutes, missing sputum re-examinations during treatment, and not having a treatment observer. Twenty-six percent of patients did not have a treatment observer. The non-cure rate was better for those with a doctor (odds ratio (OR) 0.38, 95% confidence interval (CI) 0.17-0.88) as treatment observer than for those with a family member (OR 0.62, 95%CI 0.37-1.03). The main reason for interrupted treatment mentioned by patients was presence of adverse effects during treatment (46.5%). CONCLUSIONS: Interruption of treatment was most strongly associated with non-cure. Although treatment observation by medical staff is preferred, in order to diminish the proportion of patients who do not have a treatment observer and thereby reduce the proportion of patients who interrupt treatment, we suggest making it possible for family members, after sufficient training, to be treatment observers in remote areas where it is logistically difficult to have village doctors observe treatment for all patients. PMID- 20205942 TI - Integrated syphilis/HIV screening in China: a qualitative analysis. AB - BACKGROUND: The last decade has seen enormous advances in HIV treatment and care, but how to implement scaled up HIV testing, prevention, and treatment in low income areas still presents a formidable public health challenge. South China faces expanding syphilis and sexually transmitted HIV epidemics, but health systems characteristics important for scaling up syphilis and HIV testing have not been defined. METHODS: A purposive sample to ensure public, private, and public-private hybrid STI clinic inclusion was selected in a South China city. Eight key informant interviews were conducted with the STI clinic manager, followed by eight focus group discussions with physicians. Data collection relied on a semi-structured format that included questions in each of the following domains: 1) clinical facilities; 2) laboratory capacity with a focus on syphilis/HIV diagnosis; 3) clinic personnel; 4) physical space with a focus on locations to disclose confidential results; 5) financial support. RESULTS: Public STI clinics had free syphilis testing/treatment and laboratory facilities to perform essential syphilis and HIV tests. However, despite serving a large number of STI patients, private STI clinics lacked nontreponemal syphilis testing, HIV testing, and had fewer connections to the public health infrastructure. Formally trained assistant physicians were 2.5 times as common as physicians at STI clinics. Only one of the 8 sites had onsite voluntary counseling and testing (VCT) services available. CONCLUSION: These STI case studies reveal the potential for expanding integrated syphilis/HIV services at public STI clinics in China. More health services research is needed to guide scale-up of syphilis/HIV testing in China. PMID- 20205943 TI - Small intestinal mucosa expression of putative chaperone fls485. AB - BACKGROUND: Maturation of enterocytes along the small intestinal crypt-villus axis is associated with significant changes in gene expression profiles. fls485 coding a putative chaperone protein has been recently suggested as a gene involved in this process. The aim of the present study was to analyze fls485 expression in human small intestinal mucosa. METHODS: fls485 expression in purified normal or intestinal mucosa affected with celiac disease was investigated with a molecular approach including qRT-PCR, Western blotting, and expression strategies. Molecular data were corroborated with several in situ techniques and usage of newly synthesized mouse monoclonal antibodies. RESULTS: fls485 mRNA expression was preferentially found in enterocytes and chromaffine cells of human intestinal mucosa as well as in several cell lines including Rko, Lovo, and CaCo2 cells. Western blot analysis with our new anti-fls485 antibodies revealed at least two fls485 proteins. In a functional CaCo2 model, an increase in fls485 expression was paralleled by cellular maturation stage. Immunohistochemistry demonstrated fls485 as a cytosolic protein with a slightly increasing expression gradient along the crypt-villus axis which was impaired in celiac disease Marsh IIIa-c. CONCLUSIONS: Expression and synthesis of fls485 are found in surface lining epithelia of normal human intestinal mucosa and deriving epithelial cell lines. An interdependence of enterocyte differentiation along the crypt-villus axis and fls485 chaperone activity might be possible. PMID- 20205944 TI - The quality of life of patients with genital warts: a qualitative study. AB - BACKGROUND: Genital warts, which are caused by infection with human papillomavirus (HPV), are one of the most common sexually transmitted diseases in Europe. Although genital warts are commonly perceived as a non-serious condition, treatment is often long, of varying effectiveness and the recurrence rate is high. Very few studies have been performed on the personal consequences of genital warts. The aim of this qualitative study, set in Denmark, was to examine the ways in which genital warts may affect patients' quality of life. METHODS: To obtain an in-depth understanding of patients' perceptions of genital warts, we used qualitative focus-group interviews with five men and five women aged between 18 and 30 years who had genital warts. The interview guide was based on a literature review that identified important issues and questions. The data were analysed using a medical anthropological approach. RESULTS: Patients' experiences were related to cultural conceptions of venereal diseases and the respective identities and sexuality of the sexes. The disease had negative psychological and social effects both for men and for women and it affected their sex and love lives, in particular. The psychological burden of the disease was increased by the uncertain timeline and the varying effectiveness of treatment. We identified a need for more patient information about the disease and its psycho-sexual aspects. CONCLUSIONS: The men and women participating in this study considered their quality of life to be significantly lowered because of genital warts. The experiences described by the participants give insights that may be valuable in treatment and counselling.The quadrivalent HPV vaccine that has now been added to the childhood vaccination programme for girls in Denmark for the prevention of cervical cancer can also prevent 90% of cases of genital warts. Our results suggest that HPV vaccination could considerably reduce the largely unacknowledged psychological and social burden associated with genital warts, in men as well as women. PMID- 20205945 TI - Comparative analysis of cell death induction by Taurolidine in different malignant human cancer cell lines. AB - BACKGROUND: Taurolidine (TRD) represents an anti-infective substance with anti neoplastic activity in many malignant cell lines. So far, the knowledge about the cell death inducing mechanisms and pathways activated by TRD is limited. The aim of this study was therefore, to perform a comparative analysis of cell death induction by TRD simultaneously in different malignant cell lines. MATERIALS AND METHODS: Five different malignant cell lines (HT29/Colon, Chang Liver/Liver, HT1080/fibrosarcoma, AsPC-1/pancreas and BxPC-3/pancreas) were incubated with increasing concentrations of TRD (100 microM, 250 microM and 1000 microM) for 6 h and 24 h. Cell viability, apoptosis and necrosis were analyzed by FACS analysis (Propidiumiodide/AnnexinV staining). Additionally, cells were co-incubated with the caspase Inhibitor z-VAD, the radical scavenger N-Acetylcystein (NAC) and the Gluthation depleting agent BSO to examine the contribution of caspase activation and reactive oxygen species in TRD induced cell death. RESULTS: All cell lines were susceptible to TRD induced cell death without resistance toward this anti neoplastic agent. However, the dose response effects were varying largely between different cell lines. The effect of NAC and BSO co-treatment were highly different among cell lines--suggesting a cell line specific involvement of ROS in TRD induced cell death. Furthermore, impact of z-VAD mediated inhibition of caspases was differing strongly among the cell lines. CONCLUSION: This is the first study providing a simultaneous evaluation of the anti-neoplastic action of TRD across several malignant cell lines. The involvement of ROS and caspase activation was highly variable among the five cell lines, although all were susceptible to TRD induced cell death. Our results indicate, that TRD is likely to provide multifaceted cell death mechanisms leading to a cell line specific diversity. PMID- 20205946 TI - Evaluation of immunological escape mechanisms in a mouse model of colorectal liver metastases. AB - BACKGROUND: The local and systemic activation and regulation of the immune system by malignant cells during carcinogenesis is highly complex with involvement of the innate and acquired immune system. Despite the fact that malignant cells do have antigenic properties their immunogenic effects are minor suggesting tumor induced mechanisms to circumvent cancer immunosurveillance. The aim of this study is the analysis of tumor immune escape mechanisms in a colorectal liver metastases mouse model at different points in time during tumor growth. METHODS: CT26.WT murine colon carcinoma cells were injected intraportally in Balb/c mice after median laparotomy using a standardized injection technique. Metastatic tumor growth in the liver was examined by standard histological procedures at defined points in time during metastatic growth. Liver tissue with metastases was additionally analyzed for cytokines, T cell markers and Fas/Fas-L expression using immunohistochemistry, immunofluorescence and RT-PCR. Comparisons were performed by analysis of variance or paired and unpaired t test when appropriate. RESULTS: Intraportal injection of colon carcinoma cells resulted in a gradual and time dependent metastatic growth. T cells of regulatory phenotype (CD4+CD25+Foxp3+) which might play a role in protumoral immune response were found to infiltrate peritumoral tissue increasingly during carcinogenesis. Expression of cytokines IL-10, TGF-beta and TNF-alpha were increased during tumor growth whereas IFN-gamma showed a decrease of the expression from day 10 on following an initial increase. Moreover, liver metastases of murine colon carcinoma show an up-regulation of FAS-L on tumor cell surface with a decreased expression of FAS from day 10 on. CD8+ T cells express FAS and show an increased rate of apoptosis at perimetastatic location. CONCLUSIONS: This study describes cellular and macromolecular changes contributing to immunological escape mechanisms during metastatic growth in a colorectal liver metastases mouse model simulating the situation in human cancer. PMID- 20205948 TI - Occult hepatitis B virus infection in ART-naive HIV-infected patients seen at a tertiary care centre in north India. AB - BACKGROUND: Co-infections of hepatitis B and C viruses are frequent with HIV due to shared routes of transmission. In most of the tertiary care health settings, HIV reactive patients are routinely tested for HBsAg and anti-HCV antibodies to rule out these co-infections. However, using the routine serological markers one can only detect active HBV infection while the occult HBV infection may be missed. There is insufficient data from India on HIV-HBV co-infection and even scarce on occult HBV infection in this group. METHODS: We estimated the burden of HBV infection in patients who were tested positive for HIV at a tertiary care centre in north India. We also attempted to determine the prevalence and clinical characteristics of occult HBV infection among these treatment-naive patients and compare their demographic features with other HIV patients. During a period of 6 years between January 2002 to December 2007, 837 HIV positive patients (631 males and 206 females (M: F :: 3.06:1) were tested for serological markers of HBV (HBsAg) and HCV (anti-HCV antibodies) infections in our laboratory. For comparison 1000 apparently healthy, HIV-negative organ donors were also included in the study. Data on demographics, sexual behaviour, medical history, laboratory tests including the serum ALT and CD4 count of these patients were recorded. A sub-group of 53 HBsAg negative samples from HIV positive patients were assessed for anti-HBs, anti-HBc total (IgG+IgM) and HBV-DNA using a highly sensitive qualitative PCR and analysed retrospectively. RESULTS: Overall, 7.28% of HIV positive patients showed presence of HBsAg as compared to 1.4% in the HIV negative control group. The prevalence of HBsAg was higher (8.55%) in males than females (3.39%). The study revealed that occult HBV infection with detectable HBV DNA was prevalent in 24.5% of patients positive for anti-HBc antibodies; being 45.5% in HBsAg negative patients. Most importantly the occult infection was seen in 20.7% patients who were positive for anti-HBs antibodies. However, in none of the seronegative patient HBV-DNA was detected. Five of the nine HBV-DNA positive (55.6%) patients showed raised alanine aminotransferase levels and 66.7% had CD4+ T cell counts below 200 cells/cumm. CONCLUSIONS: High prevalence of HIV-HBV co infection was found in our patients. A sizeable number of co-infected patients remain undiagnosed, if only conventional serological markers are used. Presence of anti-HBs antibodies was not a reliable surrogate marker to rule out occult HBV infection. The most reliable method to diagnose occult HBV co-infection in HIV seropositive patients is the detection of HBV-DNA. PMID- 20205947 TI - Role of casein kinase 1 in the glucose sensor-mediated signaling pathway in yeast. AB - BACKGROUND: In yeast, glucose-dependent degradation of the Mth1 protein, a corepressor of the glucose transporter gene (HXT) repressor Rgt1, is a crucial event enabling expression of several HXT. This event occurs through a signaling pathway that involves the Rgt2 and Snf3 glucose sensors and yeast casein kinase 1 and 2 (Yck1/2). In this study, we examined whether the glucose sensors directly couple with Yck1/2 to convert glucose binding into an intracellular signal that leads to the degradation of Mth1. RESULTS: High levels of glucose induce degradation of Mth1 through the Rgt2/Snf3 glucose signaling pathway. Fluorescence microscopy analysis indicates that, under glucose-limited conditions, GFP-Mth1 is localized in the nucleus and does not shuttle between the nucleus and cytoplasm. If glucose-induced degradation is prevented due to disruption of the Rgt2/Snf3 pathway, GFP-Mth1 accumulates in the nucleus. When engineered to be localized to the cytoplasm, GFP-Mth1 is degraded regardless of the presence of glucose or the glucose sensors. In addition, removal of Grr1 from the nucleus prevents degradation of GFP-Mth1. These results suggest that glucose-induced, glucose sensor-dependent Mth1 degradation occurs in the nucleus. We also show that, like Yck2, Yck1 is localized to the plasma membrane via C-terminal palmitoylation mediated by the palmitoyl transferase Akr1. However, glucose-dependent degradation of Mth1 is not impaired in the absence of Akr1, suggesting that a direct interaction between the glucose sensors and Yck1/2 is not required for Mth1 degradation. CONCLUSION: Glucose-induced, glucose sensor-regulated degradation of Mth1 occurs in the nucleus and does not require direct interaction of the glucose sensors with Yck1/2. PMID- 20205949 TI - Arterial embolization in patients with grade-4 blunt renal trauma: evaluation of the glomerular filtration rates by dynamic scintigraphy with 99mTechnetium diethylene triamine pentacetic acid. AB - BACKGROUND: High-grade blunt renal trauma has been treated by arterial embolization (AE). However, it is unknown whether AE preserves renal function, because conventional renal function tests reflect total renal function and not the function of the injured kidney alone. Dynamic scintigraphy can assess differential renal function. METHODS: We performed AE in 17 patients with grade-4 blunt renal trauma and determined their serum creatinine (sCr) level and glomerular filtration rate (GFR; estimated by dynamic scintigraphy) after 3 months. In 4 patients with low GFR of the injured kidney (<20 ml.min-1.1.73 m-2), the GFR and sCr were measured again at 6 months. Data are presented as median and interquartile range (25th, 75th percentile). RESULTS: The median GFR of the injured kidney, total GFR, and median sCr at 3 months were 29.3 (23.7, 35.3) and 96.8 (79.1, 102.6) ml.min-1.1.73 m-2 and 0.6 (0.5, 0.7) mg/dl, respectively. In the patients with low GFR (ml.min-1.1.73 m-2), the median GFR of the injured kidney, total GFR, and median sCr (mg/dl) were 16.2 (15.7, 16.3), 68.7 (61.1, 71.6), and 0.7 (0.7, 0.9), respectively, at 3 months and 34.5 (29.2, 37.0), 90.9 (79.1, 98.8), and 0.7 (0.7, 0.8), respectively, at 6 months. CONCLUSIONS: The function of the injured kidney was preserved in all patients, indicating the efficacy of AE for the treatment of grade-4 blunt renal trauma. PMID- 20205950 TI - The study protocol for a randomized controlled trial of a family-centred tobacco control program about environmental tobacco smoke (ETS) to reduce respiratory illness in Indigenous infants. AB - BACKGROUND: Acute respiratory illness (ARI) is the most common cause of acute presentations and hospitalisations of young Indigenous children in Australia and New Zealand (NZ). Environmental tobacco smoke (ETS) from household smoking is a significant and preventable contributor to childhood ARI. This paper describes the protocol for a study which aims to test the efficacy of a family-centred tobacco control program about ETS to improve the respiratory health of Indigenous infants in Australia and New Zealand. For the purpose of this paper 'Indigenous' refers to Australia's Aboriginal and Torres Strait Islander peoples when referring to Australian Indigenous populations. In New Zealand, the term 'Indigenous' refers to Maori. METHODS/DESIGN: This study will be a parallel, randomized, controlled trial. Participants will be Indigenous women and their infants, half of whom will be randomly allocated to an 'intervention' group, who will receive the tobacco control program over three home visits in the first three months of the infant's life and half to a control group receiving 'usual care' (i.e. they will not receive the tobacco control program). Indigenous health workers will deliver the intervention, the goal of which is to reduce or eliminate infant exposure to ETS. Data collection will occur at baseline (shortly after birth) and when the infant is four months and one year of age. The primary outcome is a doctor-diagnosed, documented case of respiratory illness in participating infants. DISCUSSION: Interventions aimed at reducing exposure of Indigenous children to ETS have the potential for significant benefits for Indigenous communities. There is currently a dearth of evidence for the effect of tobacco control interventions to reduce children's exposure to ETS among Indigenous populations. This study will provide high-quality evidence of the efficacy of a family-centred tobacco control program on ETS to reduce respiratory illness. Outcomes of our study will be important and significant for Indigenous tobacco control in Australia and New Zealand and prevention of respiratory illness in children. PMID- 20205951 TI - DNA methylation patterns in tissues from mid-gestation bovine foetuses produced by somatic cell nuclear transfer show subtle abnormalities in nuclear reprogramming. AB - BACKGROUND: Cloning of cattle by somatic cell nuclear transfer (SCNT) is associated with a high incidence of pregnancy failure characterized by abnormal placental and foetal development. These abnormalities are thought to be due, in part, to incomplete re-setting of the epigenetic state of DNA in the donor somatic cell nucleus to a state that is capable of driving embryonic and foetal development to completion. Here, we tested the hypothesis that DNA methylation patterns were not appropriately established during nuclear reprogramming following SCNT. A panel of imprinted, non-imprinted genes and satellite repeat sequences was examined in tissues collected from viable and failing mid-gestation SCNT foetuses and compared with similar tissues from gestation-matched normal foetuses generated by artificial insemination (AI). RESULTS: Most of the genomic regions examined in tissues from viable and failing SCNT foetuses had DNA methylation patterns similar to those in comparable tissues from AI controls. However, statistically significant differences were found between SCNT and AI at specific CpG sites in some regions of the genome, particularly those associated with SNRPN and KCNQ1OT1, which tended to be hypomethylated in SCNT tissues. There was a high degree of variation between individuals in methylation levels at almost every CpG site in these two regions, even in AI controls. In other genomic regions, methylation levels at specific CpG sites were tightly controlled with little variation between individuals. Only one site (HAND1) showed a tissue specific pattern of DNA methylation. Overall, DNA methylation patterns in tissues of failing foetuses were similar to apparently viable SCNT foetuses, although there were individuals showing extreme deviant patterns. CONCLUSION: These results show that SCNT foetuses that had developed to mid-gestation had largely undergone nuclear reprogramming and that the epigenetic signature at this stage was not a good predictor of whether the foetus would develop to term or not. PMID- 20205952 TI - Mortality among patients with tuberculosis requiring intensive care: a retrospective cohort study. AB - BACKGROUND: To describe the characteristics of patients with tuberculosis (TB) requiring intensive care and to identify the factors that predicts in-hospital mortality in a city of a developing country with intermediate-to-high TB endemicity. METHODS: We conducted a retrospective, cohort study, between November 2005 and November 2007. The patients with TB requiring intensive care were included. Predictors of mortality were assessed. The primary outcome was the in hospital mortality. RESULTS: During the study period, 67 patients with TB required intensive care. Of them, 62 (92.5%) had acute respiratory failure and required mechanical ventilation. Forty-four (65.7%) patients died. Coinfection with human immunodeficiency virus was present in 46 (68.7%) patients. Early intensive care unit admission and ventilator-associated pneumonia were independently associated with the in-hospital mortality. CONCLUSIONS: In this study we found a high mortality rate in TB patients requiring intensive care, especially in those with an early ICU admission. PMID- 20205953 TI - Elevation of IL-6 in the allergic asthmatic airway is independent of inflammation but associates with loss of central airway function. AB - BACKGROUND: Asthma is a chronic inflammatory disease of the airway that is characterized by a Th2-type of immune response with increasing evidence for involvement of Th17 cells. The role of IL-6 in promoting effector T cell subsets suggest that IL-6 may play a functional role in asthma. Classically IL-6 has been viewed as an inflammatory marker, along with TNFalpha and IL-1beta, rather than as regulatory cytokine. OBJECTIVE: To investigate the potential relationship between IL-6 and other proinflammatory cytokines, Th2/Th17 cytokines and lung function in allergic asthma, and thus evaluate the potential role of IL-6 in this disease. METHODS: Cytokine levels in induced sputum and lung function were measured in 16 healthy control and 18 mild-moderate allergic asthmatic subjects. RESULTS: The levels of the proinflammatory biomarkers TNFalpha and IL-1beta were not different between the control and asthmatic group. In contrast, IL-6 levels were specifically elevated in asthmatic subjects compared with healthy controls (p < 0.01). Hierarchical regression analysis in the total study cohort indicates that the relationship between asthma and lung function could be mediated by IL-6. Among Th2 cytokines only IL-13 (p < 0.05) was also elevated in the asthmatic group, and positively correlated with IL-6 levels (rS = 0.53, p < 0.05). CONCLUSIONS: In mild-moderate asthma, IL-6 dissociates from other proinflammatory biomarkers, but correlates with IL-13 levels. Furthermore, IL-6 may contribute to impaired lung function in allergic asthma. PMID- 20205954 TI - Moderately differentiated colorectal adenocarcinoma as a lymph node metastatic phenotype: comparison with well differentiated counterparts. AB - BACKGROUND: The differences between the metastatic property of moderately (Mod) and well (Wel) differentiated colorectal adenocarcinoma remain unclear. Since Mod is unable to form complete acini, therefore an epithelial-mesenchymal transition (EMT) can occur in that structure. Herein, we hypothesized that Mod metastasizes more easily than the Wel counterparts. METHODS: The medical records of 283 consecutive patients with Mod (n = 71) or Wel (n = 212) who underwent surgery were reviewed between January 1, 2001, and December 31, 2003, for actual 5-year overall survival. We examined the differences between the clinicopathological characteristics of the Mod and the Wel groups. RESULTS: The lymph node involvement (p < 0.0001), lymphatic permeation, venous permeation, depth of invasion, liver metastasis, and carcinomatous peritonitis were significantly higher in the Mod group in comparison to the Wel group. The independent risk factors by a logistic regression analysis for lymph node involvement were as follows: lymphatic permeation, liver metastasis, and Mod (p = 0.0291, Relative Risk of 1.991: 95% Confidence Interval: 1.073-3.697). A Kaplan-Meier survival curve showed that Mod had a trend towards a poor survival (p = 0.0517). CONCLUSION: Mod metastasizes to the lymph nodes more easily in comparison to Wel. Therefore, patients with Mod may be considered the existence of lymph node involvement. PMID- 20205955 TI - Functional significance of the hepaCAM gene in bladder cancer. AB - BACKGROUND: The hepaCAM gene encodes a new immunoglobulin-like cell adhesion molecule, and its expression is suppressed in a variety of human cancers. Additionally, hepaCAM possesses properties often observed in tumor suppressor genes. However, the expression and biological function of hepaCAM has not been investigated in bladder cancer. Therefore we sought to examine hepaCAM expression and the relationship between its structure and function in human transitional cell carcinoma of bladder (TCCB). MATERIALS AND METHODS: HepaCAM expression was evaluated in 28 normal and 34 TCCB bladder specimens and 2 TCCB cell lines using semi-quantitative RT-PCR. The wild-type hepaCAM and the extracellular domain truncated mutant gene were transfected into the TCCB cell line T24, and the biological properties of both the wild-type gene and the domain-truncated mutant were then assessed. RESULTS: HepaCAM expression was down-regulated in 82% (28/34) of TCCB specimens and undetectable in the 2 TCCB cell lines tested. The localization of hepaCAM appeared to be dependent on cell density in T24 cells. In widely spread cells, hepaCAM accumulated on the perinuclear membrane and the cell surface protrusions, whereas in confluent cells, hepaCAM was predominantly localized at the sites of cell-cell contacts on the cell membrane. Functionally, hepaCAM expressed not only increased cell spreading, delayed cell detachment, enhanced wound healing and increased cell invasion; it also inhibited cell growth (P < 0.01). When the extracellular domain was deleted, the localization of hepaCAM was significantly altered, and it lost both its adhesive function and its influence on cell growth. CONCLUSIONS: HepaCAM is involved in cell adhesion and growth control, and its expression is frequently silenced in TCCB. The extracellular domain of hepaCAM is essential to its physiological and biological functions. PMID- 20205956 TI - Functional outcome after perineal stapled prolapse resection for external rectal prolapse. AB - BACKGROUND: A new surgical technique, the Perineal Stapled Prolapse resection (PSP) for external rectal prolapse was introduced in a feasibility study in 2008. This study now presents the first results of a larger patient group with functional outcome in a mid-term follow-up. METHODS: From December 2007 to April 2009 PSP was performed by the same surgeon team on patients with external rectal prolapse. The prolapse was completely pulled out and then axially cut open with a linear stapler at three and nine o'clock in lithotomy position. Finally, the prolapse was resected stepwise with the curved Contour Transtar stapler at the prolapse's uptake. Perioperative morbidity and functional outcome were prospectively measured by appropriate scores. RESULTS: 32 patients participated in the study; median age was 80 years (range 26-93). No intraoperative complications and 6.3% minor postoperative complications occurred. Median operation time was 30 minutes (15-65), hospital stay 5 days (2-19). Functional outcome data were available in 31 of the patients after a median follow-up of 6 months (4-22). Preoperative severe faecal incontinence disappeared postoperatively in 90% of patients with a reduction of the median Wexner score from 16 (4-20) to 1 (0-14) (P < 0.0001). No new incidence of constipation was reported. CONCLUSIONS: The PSP is an elegant, fast and safe procedure, with good functional results. TRIAL REGISTRATION: ISRCTN68491191. PMID- 20205957 TI - Rapid differentiation of Francisella species and subspecies by fluorescent in situ hybridization targeting the 23S rRNA. AB - BACKGROUND: Francisella (F.) tularensis is the causative agent of tularemia. Due to its low infectious dose, ease of dissemination and high case fatality rate, F. tularensis was the subject in diverse biological weapons programs and is among the top six agents with high potential if misused in bioterrorism. Microbiological diagnosis is cumbersome and time-consuming. Methods for the direct detection of the pathogen (immunofluorescence, PCR) have been developed but are restricted to reference laboratories. RESULTS: The complete 23S rRNA genes of representative strains of F. philomiragia and all subspecies of F. tularensis were sequenced. Single nucleotide polymorphisms on species and subspecies level were confirmed by partial amplification and sequencing of 24 additional strains. Fluorescent In Situ Hybridization (FISH) assays were established using species- and subspecies-specific probes.Different FISH protocols allowed the positive identification of all 4 F. philomiragia strains, and more than 40 F. tularensis strains tested. By combination of different probes, it was possible to differentiate the F. tularensis subspecies holarctica, tularensis, mediasiatica and novicida. No cross reactivity with strains of 71 clinically relevant bacterial species was observed. FISH was also successfully applied to detect different F. tularensis strains in infected cells or tissue samples. In blood culture systems spiked with F. tularensis, bacterial cells of different subspecies could be separated within single samples. CONCLUSION: We could show that FISH targeting the 23S rRNA gene is a rapid and versatile method for the identification and differentiation of F. tularensis isolates from both laboratory cultures and clinical samples. PMID- 20205958 TI - Differential detection of nuclear envelope autoantibodies in primary biliary cirrhosis using routine and alternative methods. AB - BACKGROUND: Detection of autoantibodies giving nuclear rim pattern by immunofluorescence (anti-nuclear envelope antibodies - ANEA) in sera from patients with primary biliary cirrhosis (PBC) is a useful tool for the diagnosis and prognosis of the disease. Differences in the prevalence of ANEA in PBC sera so far reported have been attributed to the methodology used for the detection as well as to ethnic/geographical variations. Therefore, we evaluated the prevalence of ANEA in sera of Greek patients with PBC by using methods widely used by clinical laboratories and a combination of techniques and materials. METHODS: We screened 103 sera by immunoblotting on nuclear envelopes and indirect immunofluorescence (IIF) using cells and purified nuclei. Reactivities against specific autoantigens were assessed using purified proteins, ELISA, immunoprecipitation and mass spectrometry. RESULTS: We found higher prevalence of ANEA when sera were assayed by IIF on purified nuclei or cultured cells (50%) compared to Hep2 commercially available slides (15%). Anti-gp210 antibodies were identified in 22.3% and 33% of sera using ELISA for the C-terminal of gp210 or both ELISA and immunoprecipitation, respectively. Immunoblotting on nuclear envelopes revealed that immunoreactivity for the 210 kDa zone is related to anti gp210 antibodies (p < 0.0001). Moreover, we found that sera had antibodies for lamins A (6.8%), B (1%) and C (1%) and LBR (8.7%), whereas none at all had detectable anti-p62 antibodies. CONCLUSIONS: The prevalence of ANEA or anti-gp210 antibodies is under-estimated in PBC sera which are analyzed by conventional commercially available IIF or ELISA, respectively. Therefore, new substrates for IIF and ELISA should be included by clinical laboratories in the analysis of ANEA in autoimmune sera. PMID- 20205959 TI - Acquisition of antibodies to merozoite surface protein 3 among residents of Korogwe, north eastern Tanzania. AB - BACKGROUND: A polymorphic malaria parasite antigen, merozoite surface protein 3 (MSP3), is among the blood stage malaria vaccine candidates. It is believed to induce immunity through cytophilic antibodies that disrupt the process of erythrocytes invasion by merozoites. This study aimed at assessing natural acquisition of antibodies to MSP3 in individuals living in an area with different malaria transmission intensity in preparation for malaria vaccine trials. METHODS: The study was conducted in individuals aged 0-19 years from villages located in lowland, intermediate and highland strata in Korogwe district, northeastern Tanzania. Blood samples from 492 study participants were collected between May and June 2006 for malaria diagnosis and immunological investigations. Reactivity of MSP3 to different types of antibodies (immunoglobulin M, G and IgG subclass 1 and 3) were analysed by Enzyme Linked ImmunoSorbent Assay (ELISA). RESULTS: Malaria parasite prevalence was higher in the lowland (50%) compared to the intermediate (23.1%) and highland (9.8%) strata. Immunogloblin G subclasses 1 and 3 (IgG1 & IgG3), total IgG and IgM were found to increase with increasing age. IgG3 levels were significantly higher than IgG1 (p < 0.001). Furthermore, Plasmodium falciparum infection was associated with higher IgG3 levels (p = 0.008). Adjusting by strata and age in individuals who had positive blood smears, both IgG and IgM were associated with parasite density, whereby IgG levels decreased by 0.227 (95%CI: 0.064 - 0.391; p = 0.007) while IgM levels decreased by 0.165 (95%CI: 0.044 - 0.286; p = 0.008). CONCLUSION: Individuals with higher levels of IgG3 might be partially protected from malaria infection. Higher levels of total IgG and IgM in highlands might be due to low exposure to malaria infection, recent infection or presence of cross-reactive antigens. Further studies of longitudinal nature are recommended. Data obtained from this study were used in selection of one village (Kwashemshi) for conducting MSP3 phase 1b malaria vaccine trial in Korogwe. PMID- 20205960 TI - Trends of hospitalizations, fatality rate and costs for acute myocardial infarction among Spanish diabetic adults, 2001-2006. AB - BACKGROUND: Acute myocardial infarction (AMI) is one of the more frequent reasons diabetic patients are admitted to hospital, and there are reports that the long term prognosis after an AMI is much worse in these patients than in non-diabetic patients. This study aims to compare hospital admissions and costs in Spanish diabetic and non-diabetic subjects due to AMI during the period 2001-2006. METHODS: We conducted a retrospective study of 6 years of national hospitalization data associated with diabetes using the Minimum Basic Data Set. National hospitalization rates were calculated for AMI among diabetic and non diabetic adults. Fatality rates, mean hospital stay and direct medical costs related to hospitalization were analyzed. Costs were calculated using Diagnosis Related Groups for AMI in diabetics and non-diabetics patients. RESULTS: During the study period, a total of 307,099 patients with AMI were admitted to Spanish hospitals. Diabetic patients made up 29.6% of the total. The estimated incidence due to AMI in diabetics increased from 54.7 cases per 100,000 in 2001 to 64.1 in 2006. Diabetic patients had significantly higher mortality than nondiabetic patients after adjusting for age, gender, and year (OR 1.11 [95% CI, 1.08-1.14]). The cost among diabetic patients increased by 21.3% from 2001 to 2006. CONCLUSIONS: Diabetic patients have higher rates of hospital admission and fatality rates during the hospitalization after an AMI than nondiabetic patients. Diabetic adults who have suffered an AMI have a greater than expected increase in direct hospital costs over the period 2001-2006. PMID- 20205962 TI - Dietary starch source influences in growing goats: the intestinal losses of endogenous nitrogen and amino acids. AB - Four goats (20 (SD 2.5) kg) fitted with ruminal, duodenal and ileal cannulae were used in a 4 x 4 Latin square design to estimate the effects of a dietary starch source on the duodenal and ileal flows of endogenous N (EN) and endogenous amino acids (EAA) in growing goats. Goats were fed total mixed rations containing four starch sources (mainly from maize (MR), wheat (WR), paddy (PR) and sorghum (SR) treatments). There were no significant (P>0.05) effects of the dietary starch source on the intestinal flows of EN and EAA. The duodenal flows of EN were 2.40, 2.39, 2.18 and 1.56 g/d for the MR, WR, PR and SR treatments, respectively, as determined by the difference method, and the duodenal flows of EAA were 10.76, 11.29, 10.95 and 10.96 g/d by estimation with the amino acid profile method. The flows of EN and EAA at the ileum were 1.17, 1.12, 1.01, 0.70 and 4.87, 4.95, 4.94, 4.99 g/d, respectively, as estimated by the water-soluble method. The average intestinal reabsorption of EN and EAA was 57.5 %, and the endogenous Leu by the MR treatment was significantly (P < 0.05) lower than that of the other three treatments. The present results indicate that losses of endogenous protein in the intestine were not affected by the dietary starch source. PMID- 20205961 TI - Circulation of human influenza viruses and emergence of Oseltamivir-resistant A(H1N1) viruses in Cameroon, Central Africa. AB - BACKGROUND: While influenza surveillance has increased in most developing countries in the last few years, little influenza surveillance has been carried out in sub-Saharan Africa and no information is available in Central Africa. The objective of this study was to assess the prevalence of influenza viruses circulating in Yaounde, Cameroon and determine their antigenic and genetic characteristics. METHODS: Throat and/or nasal swabs were collected from November 2007 to October 2008 from outpatients with influenza-like illness (ILI) in Yaounde, Cameroon and analyzed by two different techniques: a one-step real time reverse transcription-polymerase chain reaction (RT-PCR) and virus isolation in MDCK cells. Typing and subtyping of virus isolates was performed by hemagglutination inhibition (HI), and viruses were sent to the WHO Collaborating Centre in London, UK for further characterization and analyses of antiviral resistance by enzyme inhibition assay and nucleotide sequencing. RESULTS: A total of 238 patients with ILI were sampled. During this period 70 (29%) samples were positive for influenza by RT-PCR, of which only 26 (11%) were positive by virus isolation. By HI assay, 20 of the 26 isolates were influenza type A (10 H3N2 and 10 H1N1) and 6 were influenza type B (2 B/Victoria/2/87 lineage and 4 B/Yagamata/16/88 lineage). Seven (70%) of the H1N1 isolates were shown to be resistant to oseltamivir due to a H275Y mutation. CONCLUSIONS: This study confirmed the circulation of influenza A(H1N1), A(H3N2) and B viruses in the human population in Central Africa and describes the emergence of oseltamivir resistant A(H1N1) viruses in Central Africa. PMID- 20205963 TI - Body mass index and the risk of infections in institutionalised geriatric patients. AB - The objective was to examine the effect of BMI on the incidence of various infectious diseases in institutionalised, geriatric subjects. In a retrospective cohort study we analysed medical records of 619 patients aged 75 years and older (mean age 87.6 (sd 6.4) years) who were treated in a geriatric hospital in Vienna, Austria. The total incidence rate of infection in this population was 0.80 per person-year. The most frequent infections were urinary tract infections (0.30 per person-year), followed by infections of the lower respiratory tract (0.19 per person-year), diarrhoea (0.12 per person-year) and other infections (0.20 per person-year). Incidence risk ratios were obtained by a multiplicative Poisson regression model. There was a J-shaped curve in the incidence of infections recorded by BMI with a nadir at 27-28 kg/m2. Compared with the reference group with a BMI of 24-27.9 kg/m2, subjects with a lower BMI had a higher incidence rate of infections. The incidence risk ratios, adjusted for sex, age and chronic diseases, were 1.62 (95 % CI 1.21, 2.17) for those with a BMI of < 20 kg/m2 and 1.84 (95 % CI 1.40, 2.42) for those with a BMI of 20-23.9 kg/m2. However, also patients with a BMI of 28 kg/m2 and above had a higher incidence rate of infections, with an incidence risk ratio of 1.54 (95 % CI 1.07, 2.22). These results show that both underweight and obesity are associated with a higher risk of infections in institutionalised geriatric patients. PMID- 20205964 TI - Gut microbiota composition is associated with body weight, weight gain and biochemical parameters in pregnant women. AB - Obesity is associated with complications during pregnancy and increased health risks in the newborn. The objective of the present study was to establish possible relationships between gut microbiota, body weight, weight gain and biochemical parameters in pregnant women. Fifty pregnant women were classified according to their BMI in normal-weight (n 34) and overweight (n 16) groups. Gut microbiota composition was analysed by quantitative real-time PCR in faeces and biochemical parameters in plasma at 24 weeks of pregnancy. Reduced numbers of Bifidobacterium and Bacteroides and increased numbers of Staphylococcus, Enterobacteriaceae and Escherichia coli were detected in overweight compared with normal-weight pregnant women. E. coli numbers were higher in women with excessive weight gain than in women with normal weight gain during pregnancy, while Bifidobacterium and Akkermansia muciniphila showed an opposite trend. In the whole population, increased total bacteria and Staphylococcus numbers were related to increased plasma cholesterol levels. Increased Bacteroides numbers were related to increased HDL-cholesterol and folic acid levels, and reduced TAG levels. Increased Bifidobacterium numbers were related to increased folic acid levels. Increased Enterobacteriaceae and E. coli numbers were related to increased ferritin and reduced transferrin, while Bifidobacterium levels showed the opposite trend. Therefore, gut microbiota composition is related to body weight, weight gain and metabolic biomarkers during pregnancy, which might be of relevance to the management of the health of women and infants. PMID- 20205965 TI - Daidzein-metabolising phenotypes in relation to serum lipids and uric acid in adults in Guangzhou, China. AB - Previous studies have suggested that daidzein's metabolites, equol and O desmethylangolensin (O-DMA), rather than daidzein itself may contribute to the beneficial effects of soya foods in the prevention of CVD. The present study aims to assess the proportion of equol and O-DMA producers, and to compare differences in anthropometric factors, serum lipids, glucose and uric acid between producers and non-producers in Chinese adults aged 20-69 years. For the present cross sectional study, 202 subjects (100 women and 102 men) were recruited. Twenty-four hour urinary daidzein and its metabolites were determined in these subjects while on their usual diet and again after a 3-d isoflavone challenge. Fasting serum lipids, glucose and uric acid were examined on their usual diet. Three days of 24 h dietary recalls were used to assess dietary intakes. Of the 202 subjects, 27 (13.4 %) and 27 (13.4 %) excreted equol and O-DMA on their usual diet, and 101 (50 %) and 94 (46.5 %) produced equol and O-DMA after a load of 80 mg/d isoflavones. Equol producers showed lower serum uric acid ( - 10.2 %, P = 0.001), TAG ( - 29.5 %, P = 0.007) and waist:hip ratio ( - 2.6 %, P = 0.032), and tended to have higher HDL cholesterol (6.3 %, P = 0.069) compared with equol non producers. There were no significant differences in serum lipids, glucose and uric acid between O-DMA producers and non-producers. In conclusion, equol phenotypes might influence cardiovascular risk. PMID- 20205966 TI - Effect of glycomacropeptide fractions on cholecystokinin and food intake. AB - Glycomacropeptide (GMP) is the hydrophilic 64-amino acid C-terminal glycopeptide released into cheese whey when kappa-casein is cleaved by chymosin. GMP exists as a mixture of different glycoforms due to the carbohydrates sialic acid (N acetylneuraminic acid, NeuNAc), galactose (Gal), galactosamine and glucosamine attached by O-glycosidic linkages. GMP reportedly stimulates the release of cholecystokinin (CCK), which may promote satiety. The objectives of the present study were to manufacture three glycoforms of GMP, minimally glycosylated GMP (3.5 (sd 0.1) % NeuNAc and 1.5 (sd 0.1) % Gal), glycosylated GMP (12.0 (sd 0.3) % NeuNAc and 4.2 (sd 0.2) % Gal) and a GMP-depleted whey protein concentrate, and to assess the effects of these fractions relative to glucose on CCK, subjective measures of satiety and food intake. In a randomised double-blind acute study, twenty overweight/obese males (56.9 (sd 7.2) years, 97.4 (sd 8.1) kg, 31.5 (sd 3.0) kg/m2) were recruited to consume four 50 g preloads (two GMP preparations, GMP-depleted whey and glucose) containing 895 kJ. Blood samples and subjective measures of satiety were collected before and at 15, 30, 60, 90, 120 and 180 min after the consumption of preload, and CCK levels were measured. A lunchtime meal of hot food was provided from which subjects ate ad libitum until satisfied. Energy and nutrient intakes from the food consumed were calculated. There was no significant difference in CCK levels, subjective measures of satiety or food intake between treatments at the given preload level. These results suggest that the protein fractions at the dose employed do not influence satiety, CCK levels or energy intake at a subsequent meal. PMID- 20205967 TI - Ageing, chronic alcohol consumption and folate are determinants of genomic DNA methylation, p16 promoter methylation and the expression of p16 in the mouse colon. AB - Older age, dietary folate and chronic alcohol consumption are important risk factors for the development of colon cancer. The present study examined the effects of ageing, folate and alcohol on genomic and p16-specific DNA methylation, and p16 expression in the murine colon. Old (aged 18 months; n 70) and young (aged 4 months; n 70) male C57BL/6 mice were pair-fed either a Lieber DeCarli liquid diet with alcohol (18 % of energy), a Lieber-DeCarli diet with alcohol (18 %) and reduced folate (0.25 mg folate/l) or an isoenergetic control diet (0.5 mg folate/l) for 5 or 10 weeks. Genomic DNA methylation, p16 promoter methylation and p16 gene expression were analysed by liquid chromatography-MS, methylation-specific PCR and real-time RT-PCR, respectively. Genomic DNA methylation was lower in the colon of old mice compared with young mice (P < 0.02) at 10 weeks. Alcohol consumption did not alter genomic DNA methylation in the old mouse colon, whereas it tended to decrease genomic DNA methylation in young mice (P = 0.08). p16 Promoter methylation and expression were higher in the old mouse colon compared with the corresponding young groups. There was a positive correlation between p16 promoter methylation and p16 expression in the old mouse colon (P < 0.02). In young mice the combination of alcohol and reduced dietary folate led to significantly decreased p16 expression compared with the control group (P < 0.02). In conclusion, ageing and chronic alcohol consumption alter genomic DNA methylation, p16 promoter methylation and p16 gene expression in the mouse colon, and dietary folate availability can further modify the relationship with alcohol in the young mouse. PMID- 20205968 TI - Meeting the needs of adolescent post-abortion care patients in the Dominican Republic. AB - Counselling on contraception and contraceptive method provision are key components of post-abortion care (PAC). Some studies have suggested that adolescent PAC patients receive worse care than older women seeking these services. This study aimed to evaluate an intervention whose goal was to improve the counselling and contraceptive uptake of PAC patients, with special attention given to the needs of adolescent patients, in the four public hospitals in the Dominican Republic where PAC services were not being routinely offered. The counselling intervention effort included provider training and the development of adolescent-friendly information, education and communication (IEC) materials. Eighty-eight providers were interviewed at baseline and 6 months after the intervention was implemented. Six months after providers were trained, 140 adolescent PAC patients (< or = 19 years of age) and 134 older PAC patients (20 35 years) were interviewed about the contraceptive counselling messages and contraceptive methods they received before they were discharged from hospital. The adolescent and older PAC patients were matched on study hospital and time of arrival. Significant improvements were noted in provider knowledge and attitudes. No changes were noted in provider-reported PAC counselling behaviours, with close to 70% of providers reporting they routinely assess patients' fertility intentions, discuss contraception, assess STI/HIV risk and discuss post-abortion complications. Adolescent and older PAC patients reported receiving PAC counselling messages at similar rates. Forty per cent of adolescent PAC patients and 45% of older PAC patients who wanted to delay pregnancy were discharged with a contraceptive method. Adolescents were more likely to receive an injectable contraceptive method whereas older women were discharged with a variety of methods. The PAC counselling intervention increased provider knowledge and improved their attitudes and benefited both adolescent and older patients. PMID- 20205969 TI - Observing the biofilm matrix of Staphylococcus epidermidis ATCC 35984 grown using the CDC biofilm reactor. AB - Bacteria flourish in nearly every environment on earth. Contributing to their ability to grow in many esoteric locations is their development into a biofilm structure. In an effort to more accurately model the growth environment of biofilms in nature, a Center for Disease Control and Prevention (CDC) biofilm reactor has been developed that mimics nature-like shear forces and renewable nutrient sources. To date, there has been no confirmation by scanning electron microscopy (SEM) that mature biofilms develop on a surface when grown using the CDC biofilm reactor. Three different SEM methods were used to collect images of Staphylococcus epidermidis ATCC 35984 that was to be grown using the CDC biofilm reactor. In addition, two different fixative techniques were used in each of the imaging methods. Results indicated that after 48 hours of growth in the reactor, S. epidermidis ATCC 35984 does produce a significant network of matrix components and 3D mushroom- or pillar-like structures with signs of water channel development. In conclusion, S. epidermidis ATCC 35984 grown using the CDC biofilm reactor does appear to display signs of mature biofilm development. These results could be important for studies wherein mature biofilms are needed for in vitro and/or in vivo applications. PMID- 20205970 TI - Trans fat information on food labels: consumer use and interpretation. AB - PURPOSE: Consumers' use and interpretation of trans fat information on food labels were explored. METHODS: Consumers completed an interviewer-administered questionnaire in one of three grocery stores selected purposively to represent geographical location. Data analysis involved examining the relationship of age, gender, grocery shopping habits, household size, and source of nutrition information with awareness, use, and interpretation of trans fat information. RESULTS: Ninety-eight percent (n=239) of participants were aware of trans fat, and most knew of the relationship between trans fat intake and cardiovascular disease. Although the majority of shoppers were aware of the "0 trans fat" nutrition claim on food packages (95%), they were more likely to use the Nutrition Facts panel (60%%) to reduce trans fat intake. Men and consumers under age 40 were least likely to be aware of food label information. While most consumers (75%) correctly interpreted the "0 trans fat" nutrition claim and thought foods with this claim could be healthy choices (64%), only 51% purchased these foods to reduce trans fat intake. CONCLUSIONS: Nutrition professionals should target messages to reduce trans fat intake at men and consumers under age 40. While general knowledge was good, further education is required to help consumers interpret trans fat information. PMID- 20205971 TI - Fruit and vegetable intake in Canadian ethnic populations. AB - PURPOSE: We explored whether Canada's diverse ethnic population consumes an adequate daily amount of fruit and vegetables. We also examined the association between fruit and vegetable consumption and long-term diseases. METHODS: The Canadian Community Health Survey, Cycle 2.2 (CCHS 2.2), was used to determine the fruit and vegetable intake (FVI) of 13 racial groups, as well as of the entire population. Specifically, we determined median intake and proportions of the group consuming five or more daily servings. Multiple pairwise comparisons among the proportions were performed to detect ethnic groups with significantly low FVI. Logistic regression was also used to describe the risk of long-term diseases associated with FVI and ethnicity. RESULTS: The percentages of Southeast Asian, Aboriginal (off-reserve), and Chinese people who consumed five or more daily servings of fruit and vegetables were significantly lower than percentages in all other ethnic groups surveyed. Aboriginal people with the lowest FVI demonstrated the highest propensity for developing most of the long-term diseases. CONCLUSIONS: The majority of Canada's ethnic groups identified in the CCHS 2.2 fell short of the recommended FVI target. This low-intake status might be a risk factor for common long-term diseases. PMID- 20205972 TI - Children's perceptions of healthful eating and physical activity. AB - PURPOSE: Healthful lifestyle habits established in childhood may continue through adulthood. Such habits may also be effective in preventing or reversing overweight and obesity. However, little is known about children's perceptions of healthful eating and physical activity. Thus, we sought a better understanding of how children perceive healthful eating and physical activity. METHODS: A purposeful selection was made of Winnipeg, Manitoba, boys (n=23) and girls (n=22) aged 11 to 12 years. The children were interviewed using a semi-structured, in depth interview guide. Data were analyzed using thematic coding. RESULTS: Although healthful eating was seen as necessary for health, high-fat, high-sugar foods were a source of pleasure and enjoyed during social times. Physical activity was a way of spending time with friends, either through active play or watching sports. Boys viewed screen time and homework as barriers to physical activity, while girls identified no common barriers. Children viewed physical activity as easier than healthful eating, describing the former as "play" and "fun." CONCLUSIONS: Knowing how children think about food choices will further our understanding of the disconnect between nutrition knowledge and dietary behaviours. Understanding conflicting pressures that influence children's healthful lifestyles may enhance communication about these topics among parents, educators, and children. PMID- 20205973 TI - A definition, description, and framework for advanced practice in dietetics. AB - PURPOSE: We explored advanced practice (AP) across the diversity of dietetics to develop a definition, description, and framework for guiding future education, research agendas, and policy development. METHODS: The process began with a literature review and discussion with dietitians exploring AP in other countries. Various concepts were identified, and these informed the phase 1 survey questions. Phase 1 was a 36-item survey created in SurveyMonkey, engaging a purposeful sample of key stakeholders (n=136). A modified Delphi approach, involving seven dietitians from different geographical locations and practice areas, finalized the phase 2 survey. An e-mail link to this 50-item survey was sent to a random sample of dietitians (n=885). The proposed AP framework entailed an iterative approach, integrating survey results with AP literature. RESULTS: Response rates were 40% for phase 1 and 35% for phase 2. In phase 1, 83% of respondents agreed that a depth and breadth definition captured all dietetic job roles, and 95% agreed that it differentiated AP from entry-level practice. Descriptive statistics are presented to provide demographic information and level of agreement with themes relevant to AP. CONCLUSIONS: A framework is presented, and discrepancies with phase 2 results indicate areas for professional development, such as leadership, mentorship, and outcome measurement. PMID- 20205974 TI - Vancouver dietitians' perspectives on their roles in long-term care. AB - PURPOSE: In this study, we sought insight into the clinical practice experiences of dietitians working independently (i.e., as the only dietitian in a facility) in long-term care (LTC). We hoped to learn about their work roles and identify specific factors that facilitate their success. METHODS: Grounded theory methods were used. Data were collected through 11 semi-structured interviews. Verbatim transcripts were analyzed using a constant comparative method, which included coding, memo writing, and ongoing discussion between the two researchers. RESULTS: When speaking about their roles, participants identified both specific tasks they had to complete and broader roles they fulfilled. Many of these roles focused on relationships with co-workers and building effective multidisciplinary teams. Effective teamwork was linked with dietitians' personal feelings of success in providing resident-focused nutritional care in the LTC setting. CONCLUSIONS: The LTC dietitians' various roles were generally self-appointed, and they focused more on the purpose of their work than on tasks. A primary focus of these roles was the multidisciplinary team and the promotion of effective teamwork, especially, but not exclusively, as it applies to the provision of nutritional care. Successful teamwork was linked to dietitians' reports of personal success in their work. PMID- 20205975 TI - Identification and treatment of protein-energy malnutrition in renal disease. AB - A web-based cross-country survey of renal registered dietitians (RRDs) was launched. It was used to assess whether or not their clinical practice in identifying and treating protein-energy malnutrition (PEM) in adults with end stage renal disease (ESRD) and dialysis was based on current nutrition practice guidelines (NPGs). The survey included questions on strategies, timelines, and markers used for the identification and treatment of PEM. Fifty-nine RRDs responded (21%). Sixty-seven percent did not base clinical practice on NPGs, while 33% indicated they followed the guidelines. Of those who followed guidelines, 76% use the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative nutrition guidelines. Strategies used to identify and treat PEM were not related to duration of RRD experience in nephrology, but were significantly different between guidelines users and non-users. Guideline users commonly used key nutrition treatment strategies that included enteral/parenteral nutrition and medication therapy. The clinical practice of RRD is typically based on expert opinion/consensus, rather than on evidence-based practice guidelines (EBPG). It remains unclear if differences in RRDs' adoption of clinical guidelines influences patient outcomes, particularly in the treatment of PEM. Up to-date EBPG need to be developed for the identification and treatment of PEM in patients with ESRD. PMID- 20205976 TI - Perceived roles, benefits, and supports for dietetic internship preceptors. AB - Evaluation of university-run dietetic internship programs will improve preceptors' experience and, ultimately, increase the capacity for training future dietitians. We attempted to identify preceptors' perceptions of their roles, benefits, and supports, as well as of the skills/traits that students need for internship, and suggested improvements for the internship program. Fifteen of 39 current program preceptors who had supervised more than one intern consented to participate in an ethics-approved research methodology. They responded anonymously to a series of questions posted in an online discussion group, and provided feedback on the subsequent reports. While no consensus emerged, more than 50% of participants perceived their role as providing a supportive learning experience for interns. Benefits noted most frequently were personal academic growth and contributions to their organizations from intern research projects. Effective supports included conventional communication methods and website materials. Participants identified self-motivation, independence, and communication skills as most important for interns. They also provided several suggestions for program improvements. The study methods and results could be helpful to other university-run internship programs seeking improvement and growth. PMID- 20205977 TI - Risks and benefits of fish consumption for childbearing women. AB - Pregnant women's fish consumption provides both benefits and risks to the developing fetus. Docosahexaenoic acid (DHA) from fish may enhance fetal neurodevelopment, while methylmercury (MeHg) can have detrimental effects. Dietitians would benefit from information on the frequency with which fish species may be consumed to increase DHA intake among Canadian women of childbearing age, and on minimizing the risks from MeHg, especially for those who consume fish frequently. Eighteen fish species were selected for DHA and mercury analysis from retail markets in the Toronto area. Consumption scenarios using analytical results for these fish species indicate that women of childbearing age can consume nine of 18 fish species every day (14 servings a week) or often (up to four servings a week) and remain below toxicological benchmarks for mercury. Moreover, women can also attain the recommended DHA level by consuming six of those nine fish: four 75-g servings of smelt, porgie, or bluefish a week, or two 75-g servings of milkfish, silver pomfret, or tilapia a day. Our analysis indicates that the DHA level recommended for childbearing women can be attained through fish consumption alone, without the need for supplementation and without posing a risk to the woman (or the fetus) from mercury. PMID- 20205978 TI - Charitable food programs in Victoria, BC. AB - PURPOSE: Few authors have investigated the institutional character of charitable food programs and their capacity to address food security in Canada. METHODS: We surveyed food program managers at charitable agencies in Greater Victoria, British Columbia. We discuss the structure of the "system" of charitable food provision, the value of sourced food, types of services provided, clients' demographic profile, and the estimated healthfulness of meals served. We also describe the proportion of major food types purchased and donated to agencies. RESULTS: Thirty-six agencies served approximately 20,000 meals a week to about 17,000 people. Food valued at $3.2 million was purchased or donated; approximately 50% was donated, mainly by corporations. The largest value of food purchased and donated was from meat and alternatives (40.9%) and nonperishable food items (16%). Dairy products made up the smallest share of donated foods. CONCLUSIONS: Charitable food programs in Victoria depend on food donations. The proportion of dairy products and produce is low, which raises questions about the healthfulness of foods currently fed to homeless and poor people in the city. PMID- 20205979 TI - Dietary vitamin D intake among elderly residents in a Veterans' Centre. AB - PURPOSE: Dietary vitamin D intake was assessed among residents in a long-term care (LTC) facility, so that recommendations could be made about vitamin D supplementation. METHODS: Three-day tray audits were completed for all meals and snacks, including nutritional supplements (Boost and/or high-protein pudding). Total daily and three-day vitamin D intake was calculated for each resident, and the total sample was compared with the recommended Adequate Intake (AI) of 600 IU. Vitamin D content was calculated using the Canadian Nutrient File and product labels. Resident charts were reviewed for micronutrient supplements and diagnoses. RESULTS: The daily average vitamin D available to and consumed by 30 residents was 414 IU and 295 IU, respectively. Those provided with nutritional supplements received an average of 480 IU and consumed 357 IU, while those without received an average of 245 IU and consumed 207 IU. Thirty-three percent of residents were diagnosed with osteoporosis, osteoarthritis, and falls and/or fractures. Vitamin D micronutrient supplementation varied from above 600 IU (43%) to below 600 IU (30%) to no supplementation (27%). CONCLUSIONS: None of the study participants met the recommended AI of 600 IU through dietary sources alone. Study results suggest that all LTC residents require vitamin D micronutrient supplementation of at least 400 IU to achieve the recommended AI of 600 IU. PMID- 20205981 TI - Anger rumination, social support, and cardiac symptoms in patients undergoing angiography. AB - OBJECTIVES: Socially isolated individuals report more cardiac symptoms, suffer increased cardiovascular morbidity and mortality, and experience higher levels of stress and anxiety than those with more effective support resources. However, the complex interactions of psychosocial factors implicated in the disease process remain to be fully elucidated. We sought to explore these relationships, with the addition of a novel psychosocial variable, anger rumination, which could be associated with increased cardiovascular risk. DESIGN: We examined the association of psychological stress, social support, and anger rumination, with surgical anxiety, self-reported cardiac symptoms, and angiographically documented coronary artery disease, using a correlational ex post facto design. METHODS: One hundred and one patients scheduled for elective coronary angiography completed questionnaires during the week prior to angiography. Disease severity was objectively assessed using the Gensini scoring system. RESULTS: Self-reported cardiac symptom severity was significantly correlated with higher perceived stress, less social support, and higher anger rumination, but none of the psychosocial variables predicted Gensini score. Social support partially mediated the relationship between anger rumination and surgical anxiety. Perceived stress mediated the relationship between anger rumination and cardiac symptoms. CONCLUSIONS: For patients awaiting angiography, stress, and lack of social support are important predictors of self-reported cardiac symptoms, irrespective of actual disease severity. Intervention could focus on reducing perceived stress by encouraging reappraisal and a support seeking, rather than a ruminative, anger coping style. PMID- 20205982 TI - Reactivity of measurement in health psychology: how much of a problem is it? What can be done about it? AB - PURPOSE: Measurement reactivity is defined as being present where measurement results in changes in the people being measured. The main aim of this review is to provide an overview of the current state of knowledge concerning the extent and nature of psychological measurement affecting people who complete the measures. Other aims are to describe how this may affect conclusions drawn in health psychology research and to outline where more research is needed. METHODS: Narrative review. RESULTS: Several studies, using a variety of methods, have found measurement procedures to alter subsequent cognition, emotion, and behaviour. In many instances, the effects obtained were of up to medium size. However, the extent to which such studies are representative is not clear: do other studies which find no reactive effects of measurement not exist or do they exist but are not reported? CONCLUSIONS: Although measurement reactivity can yield medium-sized effects, our understanding of this phenomenon is still rudimentary. We do not know the precise circumstances that are likely to result in measurement reactivity: we cannot predict when problems are more likely to arise. There is a particular absence of studies of the mechanisms by which measurement reactivity arises. There is a need for a systematic review of this literature, which should aim to quantify the extent of measurement reactivity effects and to provide a firmer evidence base for theorizing about the sources of reactivity. PMID- 20205983 TI - Not soy simple. PMID- 20205985 TI - Team science of nursing, engineering, statistics, and practitioner in the development of a robotic reflexology device. AB - The purpose of this article is to share the lessons learned in forming an interdisciplinary team that implements a team science approach to integrative medicine (IM) research. The disciplines of nursing, statistics, and engineering, along with consultants and a reflexology practitioner, formed this university based team to conceptualize and develop a prototype robotic device for reflexology for breast cancer patients. The nurse investigator contributed the intervention background and access to the population; the statistician guided the team thinking on factors that needed to be controlled for; the engineers provided the expertise in device design and development; consultants facilitated the team's thinking in new directions; and the reflexology practitioner prescribed the protocol. We discuss the contributions and achievements of each discipline, as well as the challenges, and share the team experiences with the intent to help guide the formation of new IM teams that promote a conducive atmosphere for carrying out cutting-edge IM research and advancing the science. PMID- 20205984 TI - Results of a randomized phase I dose-finding trial of several doses of isoflavones in men with localized prostate cancer: administration prior to radical prostatectomy. AB - The purpose of this phase I dose-finding randomized controlled trial was to evaluate the safe and effective dose of isoflavones to be used in future clinical trials for prostate cancer prevention. Forty-five eligible men were supplemented with 40, 60, and 80 mg of purified isoflavones or no supplement from biopsy to prostatectomy. Compliance with the study agent, toxicity, and changes in plasma isoflavones, serum steroid hormones, prostate-specific antigen (PSA), and tissue Ki-67 were analyzed from baseline to completion of the study. Forty-four subjects completed the study with a duration of intervention of 30 (+/- 3) days. We observed significant increases in plasma isoflavones with treatment for all doses compared with controls without producing any toxicity. Significant increases in serum total estradiol were observed in the 40 and 60 mg isoflavone-treated arms. However, a significant increase in serum free testosterone was observed in the 60 mg isoflavone-treated arm. Changes in serum sex hormone-binding globulin, PSA, and percentage of tissue Ki-67 were not statistically significant with treatment for this sample size and duration of intervention. Our results identify a safe dose of purified isoflavones for future clinical trials and establish the need for further definitive, well-powered trials to examine the role of isoflavones in prostate carcinogenesis. PMID- 20205986 TI - Phytoestrogens: science, evidence, and advice for breast cancer patients. AB - There are important safety concerns associated with dietary supplements and foods rich in phytoestrogens, especially for breast cancer patients with hormone sensitive disease. However, no consensus has been reached concerning specific dietary items that should be avoided, and safe levels of potentially problematic foods have yet to be determined. Excellent qualitative reviews of phytoestrogens and breast cancer have been published. These list agents that contain phytoestrogens and offer general cautions. Quantitative reviews, however, are needed but not yet available. Here we review quantitative data on phytoestrogens, their interaction with estrogen receptors, their bioavailability and pharmacokinetics, and their effects on breast cancer cells and animal models. We also note foods and botanicals with substances that interact with estrogen receptors and discuss the phytoestrogens they contain. Based on current evidence, we propose recommendations for advising breast cancer patients, which may also serve as a basis for the development of clinical practice guidelines. PMID- 20205987 TI - Panax ginseng. PMID- 20205988 TI - Parameterization of the duration of infection stages of serotype O foot-and-mouth disease virus: an analytical review and meta-analysis with application to simulation models. AB - Foot-and-mouth disease (FMD) is considered one of the most important infectious diseases of livestock because of the devastating economic consequences that it inflicts in affected regions. The value of critical parameters, such as the duration of the latency or the duration of the infectious periods, which affect the transmission rate of the FMD virus (FMDV), are believed to be influenced by characteristics of the host and the virus. Disease control and surveillance strategies, as well as FMD simulation models, will benefit from improved parameter estimation. The objective of this study was to quantify the distributions of variables associated with the duration of the latency, subclinical, incubation, and infectiousness periods of FMDV transmission. A double independent, systematic review of 19 retrieved publications reporting results from experimental trials, using 295 animals in four reference laboratories, was performed to extract individual values related to FMDV transmission. Probability density functions were fitted to data and a set of regression models were used to identify factors associated with the assessed parameters. Latent, subclinical, incubation, and infectious periods ranged from 3.1 to 4.8, 2 to 2.3, 5.5 to 6.6, and 3.3 to 5.7 days, respectively. Durations were significantly (p < 0.05) associated independently with route of exposure, type of donor, animal species, strains, characteristics of sampling, and clinical signs. These results will contribute to the improvement of disease control and surveillance strategies and stochastic models used to simulate FMD spread and, ultimately, development of cost-effective plans to prevent and control the potential spread of the disease in FMD-free regions of the world. PMID- 20205989 TI - [Pharmacologic treatment of insomnia in children and adolescent psychiatric patients]. AB - Sleep disturbances are frequent in children and adolescents with psychiatric disorders nevertheless there are few drugs available to treat them. Only certain antihistaminic H1 have the marketing authorization for treatment of childhood insomnia. Very few studies have been made in children about the hypnotics that are most widely used in adult patients: zopiclone, zolpidem and the hypnotic benzodiazepines. However, melatonin has recently become the most studied hypnotic drug in children since the marketing of a sustained-released form gave it the status of a drug and improved its pharmacokinetic properties. In child psychiatry, pharmacological treatment of insomnia should be considered in patients with attention deficit hyperactivity disorder in which sleep disturbances can be aggravated by psycho stimulant treatment, in autism spectrum disorders, and in the anxiety/depression. PMID- 20205990 TI - [Therapeutic drug monitoring of topiramate]. AB - Topiramate, a second generation anticonvulsant drug, is marketed in France since 1997. It is also indicated in the prophylaxis of headache and is used, except legal notices, in the treatment of neuropathic pains and bipolar disorders. The efficiency and the risk of adverse reactions are dose dependent. However, the good correlation between the dosage and the plasmatic concentrations, and the relatively low interindividual variability, when we take into account the age and the association with an enzyme inducer, are not in favour of the interest of a dosage. Furthermore, there is a covering range between the effective and not effective concentrations, and levels susceptible or not to facilitate the appearance of an adverse event. There is no validated therapeutic range, but to the usual dosages the plasma concentrations are included between 5 and 20 mg/L (15-60 micromol/L), mostly in the low part of this interval. For this molecule, the level of proof of the interest of the TDM was estimated in: possibly useful. PMID- 20205991 TI - [Therapeutic drug monitoring of vigabatrin]. AB - Vigabatrin is a second generation anticonvulsant drug available in France since 1995. It is an amino acid analogue of the GABA, marketed under the racemic form [R(-)/S(+)50/50], but only the S(+)-enantiomer is active. Neither the mechanism of action of vigabatrin, an irreversible enzymatic inhibition, nor its pharmacokinetic characteristics (no binding to plasma proteins, low metabolism, no interaction with CYP), are in favour of TDM. There is no validated therapeutic range, but to the recommended dosage of 1 to 3 g a day correspond plasma concentrations ranging from 0,8 to 36 mg/L (6 - 279 micromol/L). For this molecule, the level of proof of the interest of the TDM was estimated in: to be useless. PMID- 20205992 TI - [Therapeutic drug monitoring of zonisamide]. AB - Zonisamide is a second generation antiepileptic drug available in France since 2005. It provides a mechanism of action similar to those of phenytoin or carbamazepine. It is indicated in association in the treatment of partial epilepsy with or without secondary generalization. Zonisamide is well absorbed with maximum concentration achieved in 2 to 5 h. It is partly metabolized by the CYP3A4. Its elimination half-life is very long, around 60 h. Studies in adults and children show low concentration-efficacy and concentration-toxicity correlations, but a therapeutic range has been determined between 10 and 40 mg/L. Zonisamide is sensitive to the inductive molecules of CYP which will increase its clearance and decrease its half-life. A specific monitoring of patient is recommended in renal impairment. For this molecule, the interest of TDM has been evaluated: possibly useful. PMID- 20205993 TI - [Therapeutic drug monitoring of felbamate]. AB - Felbamate is a derivative of meprobamate used in second-line partial epilepsy and in the Lennox-Gastaut syndrome. Felbamate is well absorbed and has linear kinetics: C(max) and AUC increasing linearly with dose. The metabolism takes place in the liver. Metabolites represent 40 to 60% of excretion and are eliminated via the urine. The half-life is between 15 and 23 hours. Clearance is dependent on renal function. There is a concentration - efficacy and concentration - toxicity relationship. These arguments are in favour of a TDM but the therapeutic range is not clearly established. Potentially fatal side effects can be caused by felbamate (aplastic anemia, acute liver failure), which limits its use because they are dose-independant. PMID- 20205994 TI - [Therapeutic drug monitoring of lamotrigine]. AB - Lamotrigine is a second generation anticonvulsant drug available in France since 1996. As other anticonvulsant drugs, lamotrigine is also used in type I bipolar disorders and except legal notices, in the treatment of neuropathic pains. It is mainly metabolized by the UDP-glucuronyltransferase in inactive metabolites. Its average half-life of elimination is of the order of 22 h, but it is reduced approximately at 14 h if it is associated with enzymatic inductors and increased at 70 h if lamotrigine is administered with sodium valproate. The pharmacokinetic parameters are modified at the young child's, but not in the old population. During the pregnancy, the plasmatic concentrations are lowered and re-increase strongly after the delivery, if dosages were adapted. The renal insufficiency does not require adaptation of dosage, on the other hand in case of severe hepatic insufficiency a decrease of the dose is to be considered. The correlation concentration-efficiency does not seem demonstrated, but there are not enough published studies and they included few patients. Furthermore, they were led with a methodology more pragmatic than rigorous. The correlation concentration toxicity is better argued. The recommended therapeutic range is from 2.5 to 15 mg/L. For this molecule, the level of proof of the interest of the TDM was estimated in: possibly useful. PMID- 20205995 TI - [Therapeutic drug monitoring of pregabaline]. AB - Pregabaline, a second generation antiepileptic, is marketed in France since 2005. It is also indicated in the treatment of painful neuropathy and in generalized anxious disorder. Its pharmacokinetic profile: low metabolism and no binding to plasma proteins, is not in favour of the necessity of a TDM. But other studies would be necessary to concluded more definitively. Pregabalin however, required a dosage adjustment in case of renal insufficiency. The values of the plasma concentrations found after various doses are in agreement in the different studies, without that we can define a therapeutic range. For this molecule, the level of proof of the interest of TDM was estimated in: remaining to estimate. PMID- 20205996 TI - [Therapeutic drug monitoring of tiagabine]. AB - Tiagabine, a second-generation anticonvulsant drug, is marketed in France since 1997. It is also prescribed outside marketing authorization in the treatment of anxiety. They are few studies allowing arguing a relation exposure efficiency or toxicity, but intra and inter individual important variations in serum concentrations are described. Hepatic insufficiency requires a dose adaptation. In patients treated with therapeutic dose, serum levels are between 20 and 100 microg/L (50-250 nmol/L). For this molecule, the level of proof of the interest of TDM was estimated in: remaining to estimate. PMID- 20205997 TI - [Therapeutic drug monitoring of gabapentin]. AB - Gabapentin is a structural analogue of GABA used in the treatment of the partial epilepsies of adult and child of more than 12 years, in monotherapy or in association with other anticonvulsant drugs. In association, gabapentin presents the advantage of not interfering with the other anticonvulsant drugs. The interindividual pharmacokinetic variability and the saturable absorption are, with the adaptation in case of renal insufficiency, the only arguments in favor of TDM. During clinical studies, the plasma concentrations of gabapentin were generally included between 2 and 20 mg/L. For this molecule, the level of proof of the interest of therapeutic drug monitoring was estimated in: possibly useful. PMID- 20205998 TI - [Therapeutic drug monitoring of oxcarbazepine]. AB - Oxcarbazepine is an analogue of carbamazepine, used for the treatment of partial seizure with or without secondary generalization. The two forms R and S of the mono-hydroxylated derivatives (MHD) are responsible for most of the anti convulsant activity and it is the concentrations of MHD that are relevant in therapeutic drug monitoring (TDM). Analysis of currently literature provides no well-established relationship between plasma concentration of MHD and efficiency or toxicity. Although there is not a validated therapeutic range, the residual concentrations of usually observed therapeutic MHD are situated between 12 and 30 mg/L. In certain pathological or physiological circumstances, the pharmacokinetic variability of the oxcarbazepine can be considerable, but this strong unpredictability does not nevertheless justify the TDM of the MHD. Based on the available evidence, TDM of MHD is not routinely warranted but may be possibly useful in specific situations such as pregnancy or renal insufficiency. PMID- 20205999 TI - [Therapeutic drug monitoring of levetiracetam]. AB - Levetiracetam is an anticonvulsant drug used to treat partial seizures, myoclonic seizures of juvenile myoclonic epilepsy and primary generalized tonic-clonic seizures. A review of the literature with an evidence-based medicine method highlighted parameters (age, renal failure, pregnancy, combination with other anticonvulsant drugs) which affect levetiracetam pharmacokinetics but no significant relationship between plasma concentration of levetiracetam and efficacy or toxicity. Concentrations usually observed in therapeutics is from 6 to 18 mg/L. However, the determination of an individual therapeutic concentration, associated with an effective and well tolerated therapy, could be recommended particularly before pregnancy. Consequently, therapeutic drug monitoring of levetiracetam which is not currently recommended could be possibly useful in specific clinical situations. PMID- 20206000 TI - Modeling of combined electroosmotic and capillary flow in microchannels. AB - In the present study, theoretical model for the transient response of a capillary flow under the combined effects of electroosmotic and capillary forces at low Reynolds number is presented. The governing equation is derived based on the balance among the electrokinetic, surface, viscous and gravity forces. A non dimensional transient governing equation for the penetration depth as a function of time is obtained by normalizing the viscous, gravity and electroosmotic forces with surface tension force. A new non-dimensional group for the electroosmotic force, E(o), is obtained through the non-dimensional analysis. This new non dimensional group is a representation of combined electroosmosis and surface tension, i.e., capillarity. The numerical solution of governing equation is obtained to study the effect of different operating parameters on the flow front transport. In a combined flow, it is observed that the flow with positive and low negative magnitude E(o) numbers, the attainment of equilibrium penetration depth is similar to a capillary flow. In case of high negative magnitude E(o) numbers, complete filling of the channel is observed. The electrolyte with lower permittivity delays the progress of the flow front whereas a large EDL transports the electrolyte quickly. Higher viscous and gravity forces also delay the transport process in the combined flow. This model suggests that in combined flow the electrokinetic parameters also play an important role on the capillary flow and experiments are required to confirm this electrokinetic effect on capillary transport. PMID- 20206001 TI - Methods for the determination and speciation of mercury in natural waters--a review. AB - This review summarises current knowledge on Hg species and their distribution in the hydrosphere and gives typical concentration ranges in open ocean, coastal and estuarine waters, as well as in rivers, lakes, rain and ground waters. The importance of reliable methods for the determination of Hg species in natural waters and the analytical challenges associated with them are discussed. Approaches for sample collection and storage, pre-concentration, separation, and detection are critically compared. The review covers well established methods for total mercury determination and identifies new approaches that offer advantages such as ease of use and reduced risk of contamination. Pre-concentration and separation techniques for Hg speciation are divided into chromatographic and non chromatographic methods. Derivatisation methods and the coupling of pre concentration and/or separation methods to suitable detection techniques are also discussed. Techniques for sample pre-treatment, pre-concentration, separation, and quantification of Hg species, together with examples of total Hg determination and Hg speciation analysis in different natural (non-spiked) waters are summarised in tables, with a focus on applications from the last decade. PMID- 20206002 TI - Spectrometric study of the interaction between alpinetin and bovine serum albumin using chemometrics approaches. AB - The binding interaction of Alpinetin (APT) with bovine serum albumin (BSA) was studied by fluorescence, UV-visible and synchronous fluorescence spectroscopy (SFS) under simulated physiological conditions. The measured complex spectra were resolved by multivariate curve resolution-alternating least squares (MCR-ALS), yielding a host of data and information, which otherwise would have been impossible to obtain. The extracted profiles corresponded to the spectra of the single species in the APT/BSA mixture. In addition, the presence of the APT-BSA complex was demonstrated, and it was shown that the associated quenching of the fluorescence from the BSA protein resulted from the formation of APT-BSA complex via a static mechanism. The binding constant (K(a(ave))=2.34 x 10(6) L mol(-1)) and the number of sites (n=1) were obtained by fluorescence methods as were the thermodynamic parameters (DeltaH(0), DeltaS(0) and DeltaG(0)). This work suggested that the principal binding between APT to BSA was facilitated by hydrophobic interactions. The thermodynamic parameters for APT were compared to those from the structurally similar Chrysin and Wogonin molecules. It appeared that the entropy parameters were relatively more affected by the small structural changes. SFS from the interaction of BSA and APT showed that the ligand affected the conformation of BSA. The competitive interaction of APT and site makers with BSA indicated site I as the binding area of APT in BSA. PMID- 20206003 TI - An electrochemical immunosensor based on enzyme-encapsulated liposomes and biocatalytic metal deposition. AB - A novel electrochemical immunosensor based on double signal amplification of enzyme-encapsulated liposomes and biocatalytic metal deposition was developed for the detection of human prostate specific antigen (PSA). Alkaline phosphatase (ALP)-encapsulated and detection antibody-functionalized liposomes were first prepared and used as the detection reagent. In the sandwich immunoassay, the model analyte PSA was first captured by anti-PSA capture antibody immobilized on the electrode and then sandwiched with the functionalized liposomes. The bound liposomes were then lysed with surfactant to release the encapsulated ALP, which served as secondary signal amplification means. ALP on the electrode surface initiated the hydrolysis of ascorbic acid 2-phosphate (AA-p) to produce ascorbic acid. The latter, in turn, reduced silver ions on the electrode surface, leading to deposition of the metal silver on the electrode surface. Linear sweep voltammetry (LSV) was chosen to detect the amount of the deposited silver. The results showed that the anodic stripping peak current was linearly dependent on the PSA concentration in the range of 0.01-100 ng mL(-1), and a detection limit as low as 0.007 ng mL(-1) can be obtained. Since the cut-off value of human PSA is 4 ng mL(-1), the proposed electrochemical immunosensor would be expected to gain widespread applications for the detection of PSA in clinical diagnosis. PMID- 20206004 TI - Enzyme-free ethanol sensor based on electrospun nickel nanoparticle-loaded carbon fiber paste electrode. AB - We have developed a novel nickel nanoparticle-loaded carbon fiber paste (NiCFP) electrode for enzyme-free determination of ethanol. An electrospinning technique was used to prepare the NiCF composite with large amounts of spherical nanoparticles firmly embedded in carbon fibers (CF). In application to electroanalysis of ethanol, the NiCFP electrode exhibited high amperometric response and good operational stability. The calibration curve was linear up to 87.5 mM with a detection limit of 0.25 mM, which is superior to that obtained with other transition metal based electrodes. For detection of ethanol present in liquor samples, the values obtained with the NiCFP electrode were in agreement with the ones declared on the label. The attractive analytical performance and simple preparation method make this novel material promising for the development of effective enzyme-free sensors. PMID- 20206005 TI - Highly sensitive determination of hydroxylamine using fused gold nanoparticles immobilized on sol-gel film modified gold electrode. AB - We are reporting the highly sensitive determination of hydroxylamine (HA) using 2 mercapto-4-methyl-5-thiazoleacetic acid (TAA) capped fused spherical gold nanoparticles (AuNPs) modified Au electrode. The fused TAA-AuNPs were immobilized on (3-mercaptopropyl)-trimethoxysilane (MPTS) sol-gel film, which was pre assembled on Au electrode. The immobilization of fused TAA-AuNPs on MPTS sol-gel film was confirmed by UV-vis absorption spectroscopy and atomic force microscopy (AFM). The AFM image showed that the AuNPs retained the fused spherical morphology after immobilized on sol-gel film. The fused TAA-AuNPs on MPTS modified Au electrode were used for the determination of HA in phosphate buffer (PB) solution (pH=7.2). When compared to bare Au electrode, the fused AuNPs modified electrode not only shifted the oxidation potential of HA towards less positive potential but also enhanced its oxidation peak current. Further, the oxidation of HA was highly stable at fused AuNPs modified electrode. Using amperometric method, determination of 17.5 nM HA was achieved for the first time. Further, the current response of HA increases linearly while increasing its concentration from 17.5 nM to 22 mM and a detection limit was found to be 0.39 nM (S/N=3). The present modified electrode was also successfully used for the determination of 17.5 nM HA in the presence of 200-fold excess of common interferents such as urea, NO(2)(-), NH(4)(+), oxalate, Mn(2+), Na(+), K(+), Mg(2+), Ca(2+), Ba(2+) and Cu(2+). The practical application of the present modified electrode was demonstrated by measuring the concentration of HA in ground water samples. PMID- 20206006 TI - Trace analysis of endectocides in milk by high performance liquid chromatography with fluorescence detection. AB - An analytical method has been developed for the simultaneous determination of the following endectocide drugs in milk: ivermectin, abamectin, doramectin, moxidectin, eprinomectin, emamectin and nemadectin. Samples were extracted with acetonitrile, purified with solid-phase extraction on a reversed phase C(8), derivatised with N-methylimidazole, trifluoroacetic anhydride and acetic acid to a stable fluorescent derivative, and were further analysed by gradient high performance liquid chromatography (HPLC) on an endcapped reversed phase Supelcosil LC-8-DB. The derivatisation step was mathematically optimised and the method was validated according to the requirements of Commission Decision 2002/657/EC, using fortified raw bovine milk. Mean recovery was between 78 and 98%. The repeatability (CV(r)) and within-laboratory reproducibility (CV(W)) ranged from 4.6 to 13.4% and from 6.6 to 14.5%, respectively. Decision limits (CCalpha) for analytes with MRL values, namely eprinomectin and moxidectin, were determined to be 24.8 and 50.6 microg kg(-1), respectively. CCalpha values for unauthorised endectocides ranged from 0.1 to 0.2 microg kg(-1). Due to high acceptability regarding the required criteria and applicability to ovine and caprine milk, giving similar results, this multi-analyte method has been successfully implemented in pharmacokinetic research studies as well as statutory residue monitoring in Slovenia. PMID- 20206007 TI - Determination of ferrous and ferric iron in aqueous biological solutions. AB - A solvent extraction method was employed to determine ferrous and ferric iron in aqueous samples. Fe(3+) is selectively extracted into the organic phase (n heptane) using HDEHP (bis(2-ethylhexyl) hydrogen phosphate) and is then stripped using a strong acid. After separation, both oxidation states and the total iron content were determined directly by ICP-MS analysis. This extraction method was refined to allow determination of both iron oxidation states in the presence of strong complexing ligands, such as citrate, NTA and EDTA. The accuracy of the method was verified by crosschecking using a refinement of the ferrozine assay. Presented results demonstrate the ability of the extraction method to work in a microbiological system in the presence of strong chelating agents following the bioreduction of Fe(3+) by the Shewanella alga BrY. Based on the results we report, a robust approach was defined to separately analyze Fe(3+) and Fe(2+) under a wide range of potential scenarios in subsurface environments where radionuclide/metal contamination may coexist with strongly complexing organic contaminants. PMID- 20206008 TI - Mathematical modeling of dispersion in single interface flow analysis. AB - This work describes the optimization of the recently proposed fluid management methodology single interface flow analysis (SIFA) using chemometrics modelling. The influence of the most important physical and hydrodynamic flow parameters of SIFA systems on the axial dispersion coefficients estimated with the axially dispersed plug-flow model, was evaluated with chemometrics linear (multivariate linear regression) and non-linear (simple multiplicative and feed-forward neural networks) models. A D-optimal experimental design built with three reaction coil properties (length, configuration and internal diameter), flow-cell volume and flow rate, was adopted to generate the experimental data. Bromocresol green was used as the dye solution and the analytical signals were monitored by spectrophotometric detection at 614 nm. Results demonstrate that, independent of the model type, the statistically relevant parameters were the reactor coil length and internal diameter and the flow rate. The linear and non-linear multiplicative models were able to estimate the axial dispersion coefficient with validation r(2)=0.86. Artificial neural networks estimated the same parameter with an increased accuracy (r(2)=0.93), demonstrating that relations between the physical parameters and the dispersion phenomena are highly non-linear. The analysis of the response surface control charts simulated with the developed models allowed the interpretation of the relationships between the physical parameters and the dispersion processes. PMID- 20206009 TI - 8-Quinolineboronic acid as a potential phosphorescent molecular switch for the determination of alpha-fetoprotein variant for the prediction of primary hepatocellular carcinoma. AB - 8-Quinolineboronic acid phosphorescent molecular switch (8-QBA-PMS) in the "off" state emitted weak room temperature phosphorescence (RTP) of 8-QBA on the acetylcellulose membrane (ACM) with the perturbation of Pb(2+). When 8-QBA-PMS was used to label concanavalin agglutinin (Con A) to form 8-QBA-PMS-Con A based on the reaction between -OH of 8-QBA-PMS and -COOH of Con A, 8-QBA-PMS turned "on" automatically due to its structure change, and RTP of the system increased 2.7 times. Besides, -NH(2) of 8-QBA-PMS-Con A could carry out affinity adsorption (AA) reaction with the -COOH of alpha-fetoprotein variant (AFP-V) to form the product Con A-AFP-V-Con A-8-QBA-PMS containing -NH-CO- bond, causing the RTP of the system to further increase. Moreover, the amount of AFP-V was linear to the DeltaI(p) of the system in the range of 0.012-2.40 (fg spot(-1)). Thus, a new affinity sensitive adsorption solid substrate room temperature phosphorimetry using 8-QBA-PMS as labelling reagent (8-QBA-PMS-AASSRTP) for the determination of AFP-V was proposed with the detection limit (LD) of 9 x 10(-15) g mL(-1). It had been used to determine AFP-V in human serum with the results agreeing with enzyme link immunoassay (ELISA), showing promise for the prediction of PHC due to the intimate association between AFP-V and primary hepatocellular carcinoma (PHC). The mechanism of the promethod was also discussed. PMID- 20206010 TI - Capillary electrophoresis procedure for the simultaneous analysis and stoichiometry determination of a drug and its counter-ion by using dual-opposite end injection and contactless conductivity detection: application to labetalol hydrochloride. AB - In this work, a capillary electrophoresis (CE) procedure was developed for the simultaneous determination of a pharmaceutical drug and its counter-ion, namely labetalol hydrochloride. For this purpose, an uncoated fused-silica capillary, a low conductivity background electrolyte (BGE) and a capacitively coupled contactless conductivity detector (C(4)D) were employed. This detection system is highly sensitive and enables detection of inorganic as well as organic ions unlike with direct UV detection. Moreover, to be able to simultaneously analyze the cationic drug (labetalol(+)) and its anionic counter-ion (Cl(-)) in the same electrophoretic run without the need of a coated capillary, a dual-opposite end injection was performed. In this technique, the sample is hydrodynamically injected into both ends of the capillary. This method is simple and easy to perform since the different injection steps are automated by the CE software. This novel CE-C(4)D procedure with dual-opposite end injection has been successfully validated and applied for the analysis of chloride content in an adrenergic antagonist (labetalol hydrochloride). Thus, the hereby developed method has been shown to enable fast (analysis time<10 min), precise (repeatability of migration times<0.7% and of corrected-peak areas < 3.3%; n=6) and rugged analyses for the simultaneous determination of a pharmaceutical drug and its counter-ion. PMID- 20206011 TI - Immobilization of trypsin onto 1,4-diisothiocyanatobenzene-activated porous glass for microreactor-based peptide mapping by capillary electrophoresis: effect of calcium ions on the immobilization procedure. AB - The immobilization conditions and kinetic behaviour of trypsin, covalently immobilized via the 1,4-diisothiocyanatobenzene (DITC) linker onto aminopropylated controlled pore glass (CPG) particles, have been evaluated to establish a rapid and efficient protocol for fabrication of an immobilized enzyme microreactor (IMER) for protein hydrolysis and subsequent peptide mapping. Addition of calcium ions to either the immobilization reaction solution or hydrolysis assay was studied for a synthetic substrate. Activity was slightly higher when immobilization was carried out in the presence of Ca(2+) whereas more enzyme could be immobilized in its absence. A protocol requiring less than 3 h was devised to obtain maximal enzymatic activity with the lowest ratio of soluble trypsin to DITC-CPG particles. The resulting immobilized enzyme was found to retain an acceptable percentage (ca. 35%) of its activity after immobilization. The particles were dry-packed into a capillary to make a microscale IMER. Repeatability, reusability and digestion efficiency of the microIMER were investigated for the substrate beta-casein using capillary electrophoretic-based peptide mapping. In initial tests, a single device showed reproducible peptide maps for 21 digestions lasting 2 h each, carried out over a period of 2 months. Complete digestion of beta-casein could be achieved in a few minutes (86 s residence time in the microIMER followed by a wash step). PMID- 20206012 TI - Development of a fast and simple immunochromatographic method to purify alpha 1 acid glycoprotein from serum for analysis of its isoforms by capillary electrophoresis. AB - Alpha 1-acid glycoprotein (AGP) is a very heterogeneous glycoprotein presenting several isoforms due to variations in its polypeptidic and glycosidic moieties. Differences in AGP isoforms between healthy and diseased individuals have been related to different pathological situations such as cancer or cardiovascular diseases, among others. Capillary electrophoresis study of the role of AGP isoforms as biomarkers requires prior purification of AGP from biological samples. Current AGP purification methods are time- and labour-consuming, and generally they have not been proven to be compatible with capillary electrophoresis analysis. In this work, different methods for AGP purification from human serum are developed and compared. The applicability of acidic precipitation and immunoaffinity chromatographic methods for AGP purification are studied. Two different immunoaffinity approaches are employed; in the first one, interferents present in the AGP sample are captured and removed, and in the second one, AGP is retained in a house-made anti-AGP column, being in this way isolated from the rest of interferents of the sample. Best results in AGP purification from human serum to be analyzed by capillary zone electrophoresis (CZE) were obtained when acidic purification was combined with immunoaffinity chromatography (IAC) employing the house-made anti-AGP column. The method was shown not to alter the proportion of AGP peaks due to isoforms existing in AGP samples. The applicability of this fast and easy purification method developed for analyzing by CZE isoforms of AGP from natural serum samples by CZE is demonstrated. PMID- 20206014 TI - Advances in Parasitology. Preface. PMID- 20206013 TI - Chemically modified attapulgite with asparagine for selective solid-phase extraction and preconcentration of Fe(III) from environmental samples. AB - A new method that utilizes asparagine modified attapulgite as a solid phase extractant has been developed for preconcentration of trace Fe(III) prior to the measurement by inductively coupled plasma optical emission spectrometry. Characterization of the surface modification was performed on the basis of Fourier transform infrared spectra. The separation/preconcentration conditions of the analyte were investigated, including the pH value, the shaking time, the sample fl ow rate and volume, the elution condition and the interfering ions. At pH 4, the new adsorbent had relatively high capacity and enrichment factor compared to other methods reported so far. The adsorbed Fe(III) was quantitatively eluted by 2 mL of 0.5 mol L(-1) HCl. Common coexisting ions did not interfere with the separation. The detection limit of the method was 0.19 microg L(-1). The relative standard deviation was 3.4% (n=8) which indicated that the method had good precision for the analysis of trace Fe(III) in solution samples. The method was validated using two certified reference materials and has been applied for the determination of trace Fe(III) in biological and natural water samples with satisfactory results. PMID- 20206015 TI - Synthesis, molecular modeling and biological evaluation of novel tadalafil analogues as phosphodiesterase 5 and colon tumor cell growth inhibitors, new stereochemical perspective. AB - The synthesis of novel tadalafil analogues in which the benzodioxole moiety is replaced by 2-bromophenyl; the chiral carbons swing from R,R to R,S, S,R and S,S; the piperazinedione ring is maintained or reduced to the 5-membered imidazolidinedione or thioxoimidazolinone is described. The prepared analogues were evaluated for their capacity to inhibit the cyclic guanosine monophosphate (cGMP) selective phosphodiesterase 5 (PDE5) isozyme and the growth of human HT-29 colon adenocarcinoma cells. The R absolute configuration of C-5 in the beta carboline-hydantoin and C-6 in the beta-carboline-piperazinedione derivatives was found to be essential for the PDE5 inhibition. In addition, tadalafil analogues that were synthesized from l-tryptophan were more active than those derived from d-tryptophan, which is of economic value and expands the horizon for the discovery of new carbolines as PDE5 inhibitors. While some analogues displayed potent tumor cell growth inhibitory activity, there was no apparent correlation with their PDE5 inhibitory activity, which leads us to conclude that other PDE isozymes or PDE5 splice variants may be involved. PMID- 20206016 TI - American Society for Therapeutic Radiology and Oncology (ASTRO) Emerging Technology Committee report on electronic brachytherapy. AB - The development of novel technologies for the safe and effective delivery of radiation is critical to advancing the field of radiation oncology. The Emerging Technology Committee of the American Society for Therapeutic Radiology and Oncology appointed a Task Group within its Evaluation Subcommittee to evaluate new electronic brachytherapy methods that are being developed for, or are already in, clinical use. The Task Group evaluated two devices, the Axxent Electronic Brachytherapy System by Xoft, Inc. (Fremont, CA), and the Intrabeam Photon Radiosurgery Device by Carl Zeiss Surgical (Oberkochen, Germany). These devices are designed to deliver electronically generated radiation, and because of their relatively low energy output, they do not fall under existing regulatory scrutiny of radioactive sources that are used for conventional radioisotope brachytherapy. This report provides a descriptive overview of the technologies, current and future projected applications, comparison of competing technologies, potential impact, and potential safety issues. The full Emerging Technology Committee report is available on the American Society for Therapeutic Radiology and Oncology Web site. PMID- 20206017 TI - Imaging primary lung cancers in mice to study radiation biology. AB - PURPOSE: To image a genetically engineered mouse model of non-small-cell lung cancer with micro-computed tomography (micro-CT) to measure tumor response to radiation therapy. METHODS AND MATERIALS: The Cre-loxP system was used to generate primary lung cancers in mice with mutation in K-ras alone or in combination with p53 mutation. Mice were serially imaged by micro-CT, and tumor volumes were determined. A comparison of tumor volume by micro-CT and tumor histology was performed. Tumor response to radiation therapy (15.5 Gy) was assessed with micro-CT. RESULTS: The tumor volume measured with free-breathing micro-CT scans was greater than the volume calculated by histology. Nevertheless, this imaging approach demonstrated that lung cancers with mutant p53 grew more rapidly than lung tumors with wild-type p53 and also showed that radiation therapy increased the doubling time of p53 mutant lung cancers fivefold. CONCLUSIONS: Micro-CT is an effective tool to noninvasively measure the growth of primary lung cancers in genetically engineered mice and assess tumor response to radiation therapy. This imaging approach will be useful to study the radiation biology of lung cancer. PMID- 20206018 TI - Increased chromosomal radiosensitivity in women carrying BRCA1/BRCA2 mutations assessed with the G2 assay. AB - PURPOSE: Several in vitro studies suggest that BRCA1 and BRCA2 mutation carriers present increased sensitivity to ionizing radiation. Different assays for the assessment of deoxyribonucleic acid double-strand break repair capacity have been used, but results are rather inconsistent. Given the concerns about the possible risks of breast screening with mammography in mutation carrier women and the potentially damaging effects of radiotherapy, the purpose of this study was to further investigate the radiosensitivity of this population. METHODS AND MATERIALS: The G2 chromosomal radiosensitivity assay was used to assess chromosomal breaks in lymphocyte cultures after exposure to 1 Gy. A group of familiar breast cancer patients carrying a mutation in the BRCA1 or BRCA2 gene (n = 15) and a group of healthy mutation carriers (n = 5) were investigated and compared with a reference group of healthy women carrying no mutation (n = 21). RESULTS: BRCA1 and BRCA2 mutation carriers had a significantly higher number of mean chromatid breaks per cell (p = 0.006) and a higher maximum number of breaks (p = 0.0001) as compared with their matched controls. Both healthy carriers and carriers with a cancer history were more radiosensitive than controls (p = 0.002 and p = 0.025, respectively). Age was not associated with increased radiosensitivity (p = 0.868). CONCLUSIONS: Our results indicate that BRCA1 and BRCA2 mutation carriers show enhanced radiosensitivity, presumably because of the involvement of the BRCA genes in deoxyribonucleic acid repair and cell cycle control mechanisms. PMID- 20206019 TI - Accumulation of DNA double-strand breaks in normal tissues after fractionated irradiation. AB - PURPOSE: There is increasing evidence that genetic factors regulating the recognition and/or repair of DNA double-strand breaks (DSBs) are responsible for differences in radiosensitivity among patients. Genetically defined DSB repair capacities are supposed to determine patients' individual susceptibility to develop adverse normal tissue reactions after radiotherapy. In a preclinical murine model, we analyzed the impact of different DSB repair capacities on the cumulative DNA damage in normal tissues during the course of fractionated irradiation. MATERIAL AND METHODS: Different strains of mice with defined genetic backgrounds (SCID(-/-) homozygous, ATM(-/-) homozygous, ATM(+/-)heterozygous, and ATM(+/+)wild-type mice) were subjected to single (2 Gy) or fractionated irradiation (5 x 2 Gy). By enumerating gammaH2AX foci, the formation and rejoining of DSBs were analyzed in organs representative of both early-responding (small intestine) and late-responding tissues (lung, kidney, and heart). RESULTS: In repair-deficient SCID(-/-) and ATM(-/-)homozygous mice, large proportions of radiation-induced DSBs remained unrepaired after each fraction, leading to the pronounced accumulation of residual DNA damage after fractionated irradiation, similarly visible in early- and late-responding tissues. The slight DSB repair impairment of ATM(+/-)heterozygous mice was not detectable after single-dose irradiation but resulted in a significant increase in unrepaired DSBs during the fractionated irradiation scheme. CONCLUSIONS: Radiation-induced DSBs accumulate similarly in acute- and late-responding tissues during fractionated irradiation, whereas the whole extent of residual DNA damage depends decisively on the underlying genetically defined DSB repair capacity. Moreover, our data indicate that even minor impairments in DSB repair lead to exceeding DNA damage accumulation during fractionated irradiation and thus may have a significant impact on normal tissue responses in clinical radiotherapy. PMID- 20206020 TI - Significance of interleukin-6 signaling in the resistance of pharyngeal cancer to irradiation and the epidermal growth factor receptor inhibitor. AB - PURPOSE: Tumor eradication by chemoradiotherapy for pharyngeal cancer has not been particularly successful. Targeting epithelial growth factor receptor (EGFR) could be a potential treatment strategy providing additional benefits, but only a subset of these tumors gives a clinically significant response to EGFR inhibitors. The aim has been to identify the role of interleukin-6 (IL-6) signaling and its predictive power in the treatment response of pharyngeal cancer. METHODS AND MATERIALS: Human pharyngeal cancer cell lines, including the hypopharyngeal cancer cell line FaDu and its derived cell line FaDu-C225-R, were selected. Changes in tumor growth, response to treatment, and responsible signaling pathway were investigated in vitro. Furthermore, 95 pharyngeal cancer tissue specimens were analyzed by immunohistochemical staining, and correlations were made between levels of IL-6, IL-6 receptor (IL-6R), p-AKT, and p-STAT3 expression and the clinical outcome of patients. RESULTS: In vitro, either extrinsic IL-6 stimulation of cancer cells or intrinsically activated IL-6 signaling detected in FADu-C225-R cells results in resistance to irradiation and EGFR inhibitor. Blocking IL-6 signaling attenuated aggressive tumor behavior and sensitized the cells to treatments. The responsible mechanisms included decreased p-STAT3, less nuclear translocation of EGFR, and subsequently attenuated epithelial-mesenchymal transition. Regarding clinical data, staining of p-STAT3 and IL-6 was significantly linked with lower response rates to treatments and shorter survival in pharyngeal cancer patients. CONCLUSIONS: IL-6 and p-STAT3 may be significant predictors of pharyngeal carcinoma, and regulating IL-6 signaling can be considered a promising therapeutic approach. PMID- 20206021 TI - Inactivation of kupffer cells by gadolinium chloride protects murine liver from radiation-induced apoptosis. AB - PURPOSE: To determine whether the inhibition of Kupffer cells before radiotherapy (RT) would protect hepatocytes from radiation-induced apoptosis. MATERIALS AND METHODS: A single 30-Gy fraction was administered to the upper abdomen of Sprague Dawley rats. The Kupffer cell inhibitor gadolinium chloride (GdCl3; 10 mg/kg body weight) was intravenously injected 24 h before RT. The rats were divided into four groups: group 1, sham RT plus saline (control group); group 2, sham RT plus GdCl3; group 3, RT plus saline; and group 4, RT plus GdCl3. Liver tissue was collected for measurement of apoptotic cytokine expression and evaluation of radiation-induced liver toxicity by analysis of liver enzyme activities, hepatocyte micronucleus formation, apoptosis, and histologic staining. RESULTS: The expression of interleukin-1beta, interleukin-6, and tumor necrosis factor alpha was significantly attenuated in group 4 compared with group 3 at 2, 6, 24, and 48 h after injection (p <0.05). At early points after RT, the rats in group 4 exhibited significantly lower levels of liver enzyme activity, apoptotic response, and hepatocyte micronucleus formation compared with those in group 3. CONCLUSION: Selective inactivation of Kupffer cells with GdCl3 reduced radiation induced cytokine production and protected the liver against acute radiation induced damage. PMID- 20206022 TI - Response to "Predictors of prostate cancer-specific mortality in elderly men with intermediate-risk prostate cancer treated with brachytherapy with or without external beam radiation therapy" (Int J Radiat Oncol Biol Phys 2009, in press). PMID- 20206024 TI - Capecitabine initially concomitant to radiotherapy then perioperatively administered in locally advanced rectal cancer. In regard to MG Zampino et al. (Int J Radiat Oncol Biol Phys 2009;75:421-427). PMID- 20206026 TI - Response to "Helical tomotherapy for simultaneous multitarget radiotherapy for pulmonary metastasis." (Int J Radiat Oncol Biol Phys 2009;75:703-710). PMID- 20206029 TI - Response to "Intraoperative radiotherapy during radical prostatectomy for locally advanced prostate cancer: technical and dosimetric aspects" (Int J Radiat Oncol Biol Phys 2009; in press). PMID- 20206031 TI - Fractionated stereotactic radiotherapy as reirradiation for locally recurrent head and neck cancer: in regard to Roh et Al (Int J Radiat Oncol Biol Phys. 2009 Aug 1;74(5):1348-55. PMID- 20206032 TI - Rotator cuff repair: obviously. PMID- 20206033 TI - In Memoriam: Robert Wilson Jackson, O.C., M.D., F.R.C.S.C., Hon. F.R.C.S. (UK & Edin). PMID- 20206034 TI - Bob Jackson--a tribute. PMID- 20206035 TI - Is a magnetic resonance imaging scan necessary to diagnose knee arthritis? PMID- 20206036 TI - Snapping scapula. PMID- 20206038 TI - Arthroscopic repair of full-thickness rotator cuff tears: is there tendon healing in patients aged 65 years or older? AB - PURPOSE: The aim of this study was to assess tendon healing and clinical results of rotator cuff tears (RCTs) repaired arthroscopically in patients aged 65 years or older. METHODS: Between January 2001 and December 2004, 88 patients with a mean age of 70 years (range, 65 to 85 years) had arthroscopic RCT repair. The repair was performed on 54 women (61%). The dominant arm was involved in 72 patients (82%). RCT included more than 2 tendons in 45 cases. Functional outcomes were assessed by use of the Constant score and Simple Shoulder Test. Tendon healing was estimated by use of a computed tomography (CT) arthrogram, which was obtained 6 months postoperatively, and was classified into 3 categories: stage 1, watertight and anatomic healing; stage 2, watertight and partial healing; and stage 3, not watertight and retear. RESULTS: The mean duration of follow-up was 41 months (range, 24 to 77 months). The mean clinical outcome scores all improved significantly at the time of the final follow-up (P < .01). Computed tomography arthrogram imaging showed 27 shoulders with a stage 1 repair, 20 with a stage 2 repair, and 34 with a stage 3 repair. The retear rate was 42% (34 of 81). The patients with tendon healing stage 1 or 2 had a significantly superior functional outcome in terms of overall scores and strength compared with the stage 3 repairs (P < .01). In our study we had 39 isolated supraspinatus tears (small or medium tears); 11 (28.9%) had a retear (stage 3). CONCLUSIONS: Arthroscopic repair in patients aged 65 years or older can yield tendon healing resulting in significant functional improvement. Our data suggest that arthroscopic repair can be considered successful for the older patient specifically when the tear is limited to the supraspinatus tendon. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 20206039 TI - The incidence of early metallic suture anchor pullout after arthroscopic rotator cuff repair. AB - PURPOSE: The purpose of this study was to identify the incidence of metallic suture anchor pullout after arthroscopic rotator cuff repair and determine the impact of tear size on the risk of pullout. METHODS: A retrospective review of 269 patients (550 metallic suture anchors) who underwent arthroscopic rotator cuff repair between January 2006 and January 2009 was conducted. Inclusion criteria included patients aged 18 years or older, a minimum of 6 weeks' radiographic follow-up, and the use of 1 or more metallic suture anchors for partial or complete rotator cuff repair. The mean age of the cohort at the time of surgery was 55 years (range, 29 to 86 years), and there were 189 men and 80 women. RESULTS: Early anchor pullout occurred in 6 patients (9 anchors). The overall incidence of early metallic suture anchor pullout in this cohort was 2.4% (95% confidence interval, 0.5% to 4.3%). The incidence in rotator cuff tears less than or equal to 3 cm was 0.5%, and the incidence in tears greater than 3 cm was 11%. Patients undergoing arthroscopic rotator cuff repair of a tear greater than 3 cm in size were at a significantly higher risk of having early metallic suture anchor pullout than patients undergoing repair of a smaller tear (relative risk, 22; P = .001). Among the 61 patients undergoing arthroscopic subscapularis repair, no suture anchor failures were observed at the lesser tuberosity. Of the 9 anchors that failed, 8 (89%) pulled out of the posterior aspect of the greater tuberosity. CONCLUSIONS: There is a minimal risk of suture anchor pullout in small- to medium-sized tears; however, this risk increases with larger tear sizes. We recommend routine radiographic follow-up after use of metallic anchors to ensure identification of early failure by anchor pullout. LEVEL OF EVIDENCE: Level III, prognostic case series. PMID- 20206040 TI - Biomechanical advantages of triple-loaded suture anchors compared with double-row rotator cuff repairs. AB - PURPOSE: To evaluate the strength and suture-tendon interface security of various suture anchors triply and doubly loaded with ultrahigh-molecular weight polyethylene-containing sutures and to evaluate the relative effectiveness of placing these anchors in a single-row or double-row arrangement by cyclic loading and then destructive testing. METHODS: The infraspinatus muscle was reattached to the original humeral footprint by use of 1 of 5 different repair patterns in 40 bovine shoulders. Two single-row repairs and three double-row repairs were tested. High-strength sutures were used for all repairs. Five groups were studied: group 1, 2 triple-loaded screw suture anchors in a single row with simple stitches; group 2, 2 triple-loaded screw anchors in a single row with simple stitches over a fourth suture passed perpendicularly ("rip-stop" stitch); group 3, 2 medial and 2 lateral screw anchors with a single vertical mattress stitch passed from the medial anchors and 2 simple stitches passed from the lateral anchors; group 4, 2 medial double-loaded screw anchors tied in 2 mattress stitches and 2 push-in lateral anchors capturing the medial sutures in a "crisscross" spanning stitch; and group 5, 2 medial double-loaded screw anchors tied in 2 mattress stitches and 2 push-in lateral anchors creating a "suture bridge" stitch. The specimens were cycled between 10 and 180 N at 1.0 Hz for 3,500 cycles or until failure. Endpoints were cyclic loading displacement (5 and 10 mm), total displacement, and ultimate failure load. RESULTS: A single row of triply loaded anchors was more resistant to stretching to a 5- and 10-mm gap than the double-row repairs with or without the addition of a rip-stop suture (P < .05). The addition of a rip-stop stitch made the repair more resistant to gap formation than a double row repair (P < .05). The crisscross double row created by 2 medial double-loaded suture anchors and 2 lateral push-in anchors stretched more than any other group (P < .05). CONCLUSIONS: Double-row repairs with either crossing sutures or 4 separate anchor points were more likely to fail (5- or 10 mm gap) than a single-row repair loaded with 3 simple sutures. CLINICAL RELEVANCE: The triple-loaded anchors with ultrahigh-molecular weight polyethylene containing sutures placed in a single row were more resistant to stretching than the double-row groups. PMID- 20206041 TI - Effect of suture size and type on bone cutout in transosseous tendon repairs. AB - PURPOSE: We compared bone cutout of polyester and polyblend suture in 2 suture sizes with static and cyclic loading in a Sawbone model (Pacific Research Laboratories, Vashon, WA). METHODS: Polyester and polyblend sutures in both No. 2 and No. 5 sizes were placed through transosseous tunnels in closed-cell polyurethane foam and tied over the bar of an electromechanical load frame at a fixed height. Seven sutures in each group were pulled at a rate of 1 mm/s until bone cutout occurred. Another set of 28 sutures were cyclically loaded at increasing loads until failure. RESULTS: With static and cyclic loads, No. 5 polyester suture (Ethibond; Ethicon, Somerville, NJ) and No. 5 polyblend suture (FiberWire; Arthrex, Naples, FL) had a higher cutout load than the No. 2 sutures (P < .001). No. 2 polyblend suture had a higher static failure load than No. 2 polyester suture (P = .02). With cyclic loading, No. 2 polyblend suture had a higher load to cutout than No. 2 polyester suture (P = .01), and No. 5 polyblend suture had a higher load to cutout than No. 5 polyester suture (P = .003). CONCLUSIONS: No. 2 sutures showed bone cutout at lower forces under static and cyclic loading as compared with No. 5 sutures in this Sawbone model, and no decrease in performance with regard to bone cutout was noted with polyblend as compared with polyester. CLINICAL RELEVANCE: No. 5 polyester or polyblend suture may be preferable to No. 2 suture to avoid bone cutout in tendon-to-bone repair, and No. 5 polyblend may be preferable to No. 5 polyester to avoid bone cutout. PMID- 20206042 TI - Factors affecting recovery after arthroscopic labral debridement of the hip. AB - PURPOSE: The purpose of this study was to develop and validate a model predicting whether patients would have shorter-than-typical or longer-than-typical recoveries after hip arthroscopy for labral tears. METHODS: We retrospectively reviewed 268 cases of hip arthroscopy implemented between 2000 and 2007 by 2 orthopaedic surgeons at our institution. The development cohort consisted of patients with magnetic resonance angiography-identified labral tears and a history and physical examination consistent with either labral pathology or loose bodies. Univariate analysis targeted preoperative patient characteristics correlated with the risk of longer-than-typical recoveries. Multivariate logistic regression was applied to generate an algorithm predicting risk of longer-than typical recovery based on baseline characteristics. The algorithm was tested in the validation sample of 52 patients who were treated in 2007 and was found to be valid. RESULTS: Five predictors for longer-than-typical recovery were identified: Workers' Compensation status, female gender, use of pain medications, presence of a limp, and presence of a lateral labral tear. The multivariate algorithm was developed and successfully validated. CONCLUSIONS: This study identifies many new predictors of recovery, and it also corroborates those that have already been identified. The 5 predictors for longer-than-typical recovery identified by our validated multivariate algorithm were Workers' Compensation status, female gender, use of pain medications, presence of a limp, and presence of a lateral labral tear. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 20206043 TI - A biomechanical comparison of 3 reconstruction techniques for posterolateral instability of the knee in a cadaveric model. AB - PURPOSE: The objective of this study was to compare the varus and external rotatory laxity of reconstructed knees by use of 3 different reconstruction techniques that address posterolateral instability of the knee: popliteus tendon (PT) and lateral collateral ligament (LCL) reconstruction, PT and popliteofibular ligament (PFL) reconstruction, and PFL and LCL reconstruction. METHODS: We divided 36 fresh-frozen cadaveric knees into 3 groups of 12, and each group was assigned to a reconstruction technique: PT-LCL reconstruction with the posterior tibialis tendon, PT-PFL reconstruction with the patellar tendon and bone (Warren technique), and PFL-LCL reconstruction with the semitendinosus tendon (Larson technique). Each specimen was fixed with an Ilizarov external fixator and mounted on a custom-designed apparatus that was made to measure posterolateral instability of the knee, that is, external rotatory and varus laxity in the intact state, after cutting, and in the postoperative state at every 30 degrees from 0 degrees to 90 degrees . RESULTS: There were no significant differences between the 3 techniques with external rotation and varus laxity in all specimens. CONCLUSIONS: PT-LCL reconstruction was comparable to the other 2 established techniques: PT-PFL reconstruction (Warren technique) and PFL-LCL reconstruction (Larson technique). However, the original strength of the native knee could not be achieved with any of the techniques. CLINICAL RELEVANCE: All techniques restored the posterolateral stability of the knee to near normal, with none of them being superior. PMID- 20206044 TI - Transtibial versus anteromedial portal drilling for anterior cruciate ligament reconstruction: a cadaveric study of femoral tunnel length and obliquity. AB - PURPOSE: To compare the obliquity and length of femoral tunnels prepared with transtibial versus anteromedial portal drilling for anterior cruciate ligament (ACL) reconstruction and identify potential risks associated with the anteromedial portal reaming technique. METHODS: We used 18 human cadaveric knees (9 matched pairs) without ACL injury or pre-existing arthritis for the study. Femoral tunnels for ACL reconstruction were prepared by either a transtibial (n = 6) or anteromedial portal (n = 12) technique. For the anteromedial portal technique, a guidewire was advanced through the medial portal in varying degrees of knee flexion (100 degrees [n = 4], 110 degrees [n = 4], or 120 degrees [n = 4]) as measured with a goniometer. By use of a 6-mm femoral offset guide, two 6 mm femoral tunnels were reamed with the guide placed (1) as far posterior and lateral in the notch as possible and (2) as far medial and vertical in the notch as possible to define the range of maximal and minimal achievable coronal obliquity for each technique. All knees were imaged with high-resolution, 3 dimensional fluoroscopy to define (1) coronal tunnel obliquity relative to the lateral tibial plateau, (2) sagittal tunnel obliquity relative to the long axis of the femur, (3) intraosseous tunnel length, and (4) the presence of posterior cortical wall blowout. Data analysis was performed with a paired t-test and repeated-measures analysis of variance, with P < .05 defined as significant. RESULTS: Preparation of a vertical tunnel was possible with both transtibial and anteromedial portal drilling. The maximal achievable coronal obliquity, however, was significantly better with an anteromedial portal compared with transtibial drilling. However, 7 of 36 tunnels (19.4%) showed violation of the posterior tunnel wall, and all of these cases occurred with the anteromedial portal drilling technique. In addition, 1 of 6 oblique femoral tunnels (16.7%) drilled with the transtibial technique and 5 of 12 oblique femoral tunnels (41.7%) drilled with the anteromedial portal had an intraosseous length less than 25 mm. Increasing knee flexion with anteromedial portal drilling was associated with a significant reduction in tunnel length, increase in coronal obliquity, increase in sagittal obliquity, and increased risk of posterior wall blowout (P < .05). CONCLUSIONS: The anteromedial portal technique allows for slightly greater femoral tunnel obliquity compared with transtibial drilling. However, there is a substantially increased risk of critically short tunnels (<25 mm) and posterior tunnel wall blowout when a conventional offset guide is used. Increasing knee flexion with anteromedial portal drilling allows for greater coronal obliquity of the femoral tunnel but is accompanied by a greater risk of critically short tunnels and posterior wall compromise. CLINICAL RELEVANCE: Our findings provide insight into the potential risks and advantages of a transtibial versus an anteromedial femoral tunnel drilling technique in ACL reconstruction. PMID- 20206045 TI - Evaluation of a new femoral fixation device in a simulated anterior cruciate ligament reconstruction. AB - PURPOSE: The purpose of this in vitro biomechanical study was to determine the cyclic elongation and failure properties of a new anterior cruciate ligament (ACL) reconstruction device and compare the results with several devices that are currently available. METHODS: We performed 10 ACL reconstructions in 4 groups using fresh porcine femurs and doubled lateral extensor of the toes tendons. Manufacturer guidelines were followed for fixation by use of either of 2 cortical suspension devices (XO Button [ConMed Linvatec, Largo, FL] and EndoButton CL [Smith & Nephew, Andover, MA]), a bio-interference screw (BioScrew; ConMed Linvatec), or a corticocancellous fixation device (Pinn-ACL; ConMed Linvatec). Reconstructions were subjected to cyclic loading to 150 N for 2,000 cycles, followed by static failure tests. RESULTS: The two cortical suspension devices performed similarly to one another: the XO Button device had a significantly lower elongation amplitude than the EndoButton (P < .05). There were no significant differences in longer-term creep performance or static strength or stiffness. Compared with an interference screw, the XO Button had significantly less creep and higher failure load (P < .05). The corticocancellous device had the lowest creep and cyclic elongation amplitude and the highest strength and stiffness of the devices tested. CONCLUSIONS: In this in vitro evaluation, reconstructions with the XO Button and EndoButton exhibited very similar biomechanical performance, and our hypothesis was not supported: the XO Button did not limit creep more than the EndoButton. CLINICAL RELEVANCE: The results of this preclinical in vitro testing suggest that the new device is expected to provide clinical results similar to those of the EndoButton, a well-established device for ACL reconstruction. PMID- 20206046 TI - The effect of a nonanatomic repair of the meniscal horn attachment on meniscal tension: a biomechanical study. AB - PURPOSE: The purpose of this biomechanical study was to investigate the potential effect of a nonanatomic repair of the meniscal horn attachment on the resultant circumferential tension in a large animal model and to show that the circumferential tension of the meniscus affects the local stress of the cartilage. METHODS: All investigations were done in the medial compartment of porcine knees. First, the anterior horn attachment of the meniscus was mechanically separated from the surrounding tibial bone and fitted with a force transducer (n = 8). The femorotibial joint was loaded in compression at different flexion angles, and the resultant tension at the horn attachment was recorded. The measurements were done with the horn attachment at its anatomic position and repeated with the horn attachment being displaced medially or laterally by 3 mm. In the second part the local deformation of the cartilage under a femorotibial compressive load was measured at different levels of meniscal hoop tension (n = 5). RESULTS: A nonanatomic position of the horn attachment had a significant effect on the resultant tension (P < .01). Placing the horn attachment 3 mm medially decreased the tension at the horn attachment by 49% to 73%, depending on flexion angle and femorotibial load. The opposite placement resulted in a relative increase in the tension by 28% to 68%. Lower levels of meniscal hoop tension caused increased deformation of the cartilage (P < .05), indicating increased local stress. CONCLUSIONS: A nonanatomic position of the horn attachment strongly affects conversion of femorotibial loads into circumferential tension. There is a narrow window for a functionally sufficient repair of meniscal root tears. CLINICAL RELEVANCE: Although clinical inferences are limited because the specimens used were from a different species, there seems to be only a narrow window for a mechanically sufficient repair of root tears. PMID- 20206047 TI - The actual tendon-bone interface strength in a rabbit model. AB - PURPOSE: The purpose of this study was to evaluate the strength of the interface throughout the entire integration process by use of tendon graft reinforced with a suture material compared with nonreinforced tendon graft. METHODS: Using 60 skeletally mature female Japanese white rabbits, we performed biomechanical testing and histologic evaluation to compare tendon grafts reinforced with a suture material (suture group) and nonreinforced grafts (control group). The tendon graft was drawn through a bone tunnel measuring 2.5 mm in diameter and was tightly fixed. For biomechanical testing, the tendon graft was tested in tensile loading along the axis of the bone tunnel at a crosshead speed of 100 mm/min. RESULTS: On biomechanical testing, at 4, 6, 8, and 12 weeks, tendon grafts had pulled out of the bone tunnel in the suture group. In the control group all tendon grafts had pulled out at 4 and 6 weeks, and rupture at the midsubstance was seen at 8 and 12 weeks. The failure load-to-tunnel length ratio was significantly larger in the suture group compared with the control group at 8 and 12 weeks. On histologic evaluation, both groups had similar findings with direct attachments to bone by 12 weeks. CONCLUSIONS: In this study of the healing characteristics of augmented and nonaugmented tendon grafts placed in a bone tunnel, we found that the suture-augmented tendons had superior failure load-to tunnel length ratios at 8, 12, and 16 weeks compared with nonaugmented tendons. The failure mode in the augmented grafts was tendon pullout at all time points except 16 weeks, whereas the nonaugmented grafts failed by midsubstance rupture after 8 weeks. Histologically, both groups had similar findings with direct attachments to bone by 12 weeks. CLINICAL RELEVANCE: The tendon graft has the potential to be pulled out of the bone tunnel after complete integration. PMID- 20206048 TI - Electrospun synthetic polymer scaffold for cartilage repair without cultured cells in an animal model. AB - PURPOSE: The purpose of our study was to explore the possibility that an electrospun bioabsorbable scaffold could be used in the treatment of a full thickness articular defect without the addition of exogenous cells in a rabbit model. METHODS: Two types of poly(D,L-lactide-co-glycolide) (PLG) scaffolds, a solid cylindrical type and a cannulated tubular type, were made with the electrospinning method. Osteochondral defects, 5 mm in diameter and 5 mm in depth, made on the femoral condyles of rabbits were filled with these scaffolds, and the repair process was investigated histologically. RESULTS: In the groups in which the defect was filled with the scaffold, fibrous tissue at the articular surface of the scaffold was observed at postoperative week 2. Thereafter cartilage at the articular surface and bone at the subchondral zone were regenerated, and the repaired cartilage was maintained through postoperative week 24. By contrast, the untreated defect was filled with hematoma at postoperative week 2; thereafter regenerated cartilage and bone were observed. However, the surface of the articular cartilage was not regular, and regenerated cartilage was not well organized. The histologic scores of the groups in which the defect was filled with cannulated tubular electrospun PLG scaffolds were significantly higher than those of the untreated defect group at postoperative weeks 12 and 24 (P < .01). CONCLUSIONS: The electrospun PLG scaffold could repair a 5-mm osteochondral defect created in the rabbit model without exogenous cultured cells. CLINICAL RELEVANCE: The electrospun PLG scaffold could repair full thickness osteochondral defects. The cannulated type of PLG scaffold has the possibility to lead not only to good regeneration of cartilage but also to easy transplantation by use of a guidewire through the cannulas in the scaffold. PMID- 20206049 TI - Open versus endoscopic excision of a symptomatic os trigonum: a comparative study of 41 cases. AB - PURPOSE: To compare the clinical results of a consecutive series of 43 cases of excision of a symptomatic os trigonum performed with an open versus hindfoot endoscopic technique. METHODS: From 1994 to 2007, 43 patients underwent a symptomatic os trigonum excision. A subjective satisfaction questionnaire and a visual analog scale score for pain were obtained, and the American Orthopaedic Foot & Ankle Society ankle and hindfoot score and the time to return to previous sports level were determined in 41 of 43 patients at follow up. Of the ankles, 16 had an open os trigonum excision and 25 had hindfoot endoscopic surgery. Group A (16 ankles, open surgery) and group B (25 ankles, endoscopic excision) were comparable concerning age, sex, profession, and concomitant injury of the ankle. RESULTS: At follow-up evaluation (12 to 86 months after surgery), group B had a significantly shorter mean time to return to previous sports level. There was no difference in postoperative visual analog scale score, American Orthopaedic Foot & Ankle Society score, subjective satisfaction rating, or rating of sensory nerve loss between the 2 groups. CONCLUSIONS: Both open surgery and hindfoot endoscopic excision of a symptomatic os trigonum were effective and safe. Patients with an endoscopic excision had a shorter time to return to previous sports level. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 20206050 TI - Arthroscopic treatment of medial shelf syndrome. AB - Medial shelf or "plica" syndrome is a pathological condition of the knee that often follows knee injury in young athletes, the symptoms of which often mimic other internal derangements of the knee. Its anatomy, pathomechanics, and clinical presentation along with treatments suggested in the orthopedic literature are reviewed here. Two-year follow-up studies on the treatment of this syndrome by arthroscopic resection in 51 knees in 42 patients are presented as well. PMID- 20206051 TI - Does the literature confirm superior clinical results in radiographically healed rotator cuffs after rotator cuff repair? AB - PURPOSE: Because recurrent or persistent defects in the rotator cuff after repair are common, we sought to clarify the correlation between structural integrity of the rotator cuff and clinical outcomes through a systematic review of relevant studies. METHODS: Medline, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and the Cochrane Central Register of Controlled Trials were searched for all literature published from January 1966 to December 2008 that used the key words shoulder, rotator cuff, rotator cuff tear, rotator cuff repair, arthroscopic, integrity, healed, magnetic resonance imaging (MRI), computed tomography arthrography (CTA), and ultrasound. The inclusion criteria were studies (Levels I to IV) that reported outcomes after arthroscopic rotator cuff repair in healed and nonhealed repairs based on ultrasound, CTA, and/or MRI. Exclusionary criteria were studies that included open repair or subscapularis repair and studies that did not define outcomes based on healed versus nonhealed but rather used another variable (i.e., repair technique). Data were abstracted from the studies including patient demographics, tear characteristics, surgical procedure, rehabilitation, strength, range of motion, clinical scoring systems, and imaging studies. RESULTS: Thirteen studies were included in the final analysis: 5 used ultrasound, 4 used MRI, 2 used CTA, and 2 used combined CTA/MRI for diagnosis of a recurrent tear. Statistical improvement in patients who had an intact cuff at follow-up was seen in Constant scores in 6 of 9 studies; in University of California, Los Angeles scores in 1 of 2 studies; in American Shoulder and Elbow Surgeons scores in 0 of 3 studies; and in Simple Shoulder Test scores in 0 of 2 studies. Increased range of motion in forward elevation was seen in 2 of 5 studies and increased strength in forward elevation in 5 of 8 studies. CONCLUSIONS: The results suggest that some important differences in clinical outcomes likely exist between patients with healed and nonhealed rotator cuff repairs. Further study is needed to conclusively define this difference and identify other important prognostic factors related to clinical outcomes. LEVEL OF EVIDENCE: Level IV, systematic review. PMID- 20206052 TI - Femoral nerve block use in anterior cruciate ligament reconstruction surgery. AB - PURPOSE: The goal of this study was to determine whether femoral nerve blocks (FNBs) provide patients undergoing anterior cruciate ligament reconstruction greater pain relief or other benefits compared with more standard pain medication regimens. METHODS: We searched PubMed, EMBASE, and the Cochrane Database using the following search terms: "ACL or anterior cruciate ligament" and "femoral nerve block or peripheral nerve block" or "regional anesthesia." Thirteen studies were found that fit the inclusion criteria of being randomized controlled trials with a Level of Evidence of I or II, comparing FNB or 3-in-1 blocks with control groups undergoing various multimodal pain regimens. RESULTS: Only 5 of the 13 studies found a significant difference in pain relief with FNB compared with the control groups; however, the difference in several of the studies may not be clinically relevant. Of the 13 studies, 6 examined parameters other than pain, and only 1 study found a greater incidence of nausea and sedation in its control group. Patient satisfaction was examined in 2 studies, with both finding no difference between groups. Nine studies used a single graft type, and the two studies using multiple graft types accounted for this in their analyses. CONCLUSIONS: On the basis of the available Level I and II data from randomized controlled trials, there appears to be no evidence that FNBs add additional benefit over multimodal analgesia. FNBs have not been shown to significantly affect patient pain, readiness for discharge, or outcome scores. There is a small but identifiable risk associated with performing FNBs, with potentially catastrophic effects. LEVEL OF EVIDENCE: Level II, systematic review of Level I and II randomized controlled trials with minimal heterogeneity. PMID- 20206053 TI - The geometric classification of rotator cuff tears: a system linking tear pattern to treatment and prognosis. AB - A valuable classification system allows for communication among surgeons and/or other investigators and offers information on treatment and prognosis. It provides a means for comparison of epidemiologic data and treatment outcomes. There is no current standard classification for rotator cuff tears. Authors and practicing orthopaedists use a variety of descriptions when communicating about cuff tears. Older classifications do not use 3-dimensional information derived from the present use of arthroscopy and magnetic resonance imaging. The new geometric classification offers guidance on treatment and prognosis. Type 1, crescent-shaped tears are repaired end to bone and have a good to excellent prognosis. Type 2, longitudinal (L- or U-shaped) tears are repaired side to side with margin convergence and have a good to excellent prognosis. Type 3, massive contracted tears have coronal and sagittal dimensions greater than 2 x 2 cm on preoperative magnetic resonance imaging; are repaired with interval slides or partial repair; and have a fair to good prognosis. Type 4, rotator cuff arthropathy tears have end-stage degenerative changes of the glenohumeral joint and have articulation of the humeral head with the undersurface of the acromion; are irreparable; and require arthroplasty if surgery is considered. This classification describes complete tears of the superior and posterior rotator cuff, supraspinatus, infraspinatus, and teres minor. Additional notation can be made regarding the presence of related pathology including tears of the subscapularis, biceps, or labrum; instability or arthritic change of the glenohumeral or acromioclavicular joints; or fatty degeneration of the cuff. PMID- 20206054 TI - Arthroscopically induced posterior capsular fibrosis to correct symptomatic hyperextension of the knee. AB - We present a technical note on 2 patients with post-traumatic symptomatic hyperextension of the knee treated with a new arthroscopic technique. Both patients were of similar ages with similar injuries resulting in an excess of hyperextension at the knee with resulting instability and pain. Both patients had not improved with a variety of nonoperative measures and 1 attempt each at simple arthroscopic debridement of the damaged tissue. Our technique involves carefully scarring the damaged posterior capsule arthroscopically, followed by extension block bracing for 12 weeks. In 2 patients who had not improved with previously described techniques, we achieved a correction of the excess hyperextension with resulting improvement in their symptoms. Two years after surgery, both patients had significantly improved Lysholm and Tegner activity scores and had returned to work. We believe this technique to be reliable and reproducible. PMID- 20206055 TI - Medial-row failure after arthroscopic double-row rotator cuff repair. AB - We report 4 cases of medial-row failure after double-row arthroscopic rotator cuff repair (ARCR) without arthroscopic subacromial decompression (ASAD), in which there was pullout of mattress sutures of the medial row and knots were caught between the cuff and the greater tuberosity. Between October 2006 and January 2008, 49 patients underwent double-row ARCR. During this period, ASAD was not performed with ARCR. Revision arthroscopy was performed in 8 patients because of ongoing symptoms after the index operation. In 4 of 8 patients the medial rotator cuff failed; the tendon appeared to be avulsed at the medial row, and there were exposed knots on the bony surface of the rotator cuff footprint. It appeared that the knots were caught between the cuff and the greater tuberosity. Three retear cuffs were revised with the arthroscopic transtendon technique, and one was revised with a single-row technique after completing the tear. ASAD was performed in all patients. Three of the four patients showed improvement of symptoms and returned to their preinjury occupation. Impingement of pullout knots may be a source of pain after double-row rotator cuff repair. PMID- 20206056 TI - [Endothelin receptor antagonists in the new European guidelines on pulmonary hypertension]. PMID- 20206057 TI - [Debates surrounding COPD]. PMID- 20206058 TI - [Epidemiology of asthma and COPD in France]. PMID- 20206059 TI - [New international guidelines on pulmonary hypertension]. PMID- 20206060 TI - [Electrostimulation in the rehabilitation of patients with severe COPD: pertinent or not]. AB - INTRODUCTION: The degree of dyspnoea and muscular dysfunction during an exacerbation of COPD are so severe in some patients that they are unable to follow a traditional exercise training programme based on whole body activity (walking, cycling). Some alternative strategies like electrostimulation may be considered to initiate retraining as soon as possible, to break the vicious circle of exacerbations and improve the prognosis of these patients. LITERATURE: Five randomised studies with a control group have analysed the effects of electrostimulation in COPD. They show that this technique does not cause dyspnoea and is well tolerated by the patients regardless of their severity; that that it can improve peripheral muscular function, effort tolerance, dyspnoea and quality of life. CONCLUSIONS: The preliminary results seem to indicate that electrostimulation probably has a place in respiratory rehabilitation. We think that it should be considered as an alternative to classical retraining in COPD patients with loss of independence during an exacerbation. However, further larger, standardised studies are necessary to confirm the clinical and functional benefits of this technique, to understand the underlying mechanisms and define the precise therapeutic indications. PMID- 20206061 TI - [Long-term trials assessing pharmacological treatments in COPD: lessons and limitations]. AB - INTRODUCTION: Several long-term studies designed to assess pharmacological treatments for Chronic Obstructive Pulmonary Disease (COPD) have been published recently. Only such long-term studies allow an accurate analysis of the effect of treatments on criteria of effectiveness such as survival or decline in pulmonary function. A review of these studies is opportune. BACKGROUND: The high drop out rate, which is not a random event, leads to serious methodological problems that are of importance in the interpretation of these studies. Post hoc analysis of both the TORCH and UPLIFT trials suggest a positive effect of long-acting bronchodilators on survival. Up to now, no treatment has convincingly demonstrated an effect on the rate of decline of FEV(1). The treatments evaluated lead to a decrease in exacerbation rates and an improvement in quality of life although the effects of inhaled corticosteroids are subject to methodological concerns. The treatments are all well tolerated. VIEWPOINT: The design of future studies should avoid the withdrawal of treatments at enrolment into a study in order to limit the number of drop outs. CONCLUSION: Long-term studies have made important progress in the knowledge, not only of the effects of the treatments assessed but also of the methodological issues which need to be addressed. PMID- 20206062 TI - [Guidelines for the diagnosis and treatment of pulmonary hypertension]. AB - INTRODUCTION: A joint Task Force of the ESC and of the ERS has developed guidelines on the diagnosis and treatment of pulmonary hypertension (PH) to provide updated information on the management of patients with this condition. STATE OF THE ART: The term pulmonary hypertension (PH) describes a group of devastating and life-limiting diseases, defined by mean pulmonary artery pressure >25 mmHg at rest. The diagnosis of PH requires a series of investigations intended to confirm the diagnosis, clarify the clinical group and the specific aetiology and an algorithm for this is proposed. Several drugs are currently approved to try to correct endothelial dysfunction. They lead to a significant improvement in the prognosis of patients who are in NYHA functional class II, III or IV. The evaluation of the severity of PH has a pivotal role in the choice of initial treatment and evaluation of the response to therapy in individual patients. PERSPECTIVE: These guidelines should be widely disseminated and implemented in order to improve the management of patients with PH. CONCLUSION: These guidelines summarise recent advances in the understanding and management of PH. PMID- 20206063 TI - [Asthma in France: a review of descriptive epidemiological data]. AB - This article presents a review of the most recent data on descriptive epidemiology of asthma in France. The latest national surveys show a cumulative prevalence of asthma of more than 10% in children aged 10 years or more and a prevalence of current asthma from 6 to 7% in adults. In 2006, 1038 deaths from asthma were registered (64 deaths among people aged less than 45 years). After the peak observed in the 1980s, mortality from asthma has decreased. The decrease is also observed among children and young adults. According to data from the French discharge database (PMSI), there were 54 130 admissions for asthma (asthma as the principal diagnosis) in 2007. Between 1998 and 2007, the annual rate of admission for asthma decreased. However, no decreasing trend was observed in children and, in adults, admission rates seem to have been stable since 2004. The increase in the rate of admission for acute respiratory failure (ARF) associated with asthma (ARF as the principal diagnosis and asthma as an associated diagnosis) does not compensate for the decrease in the admission rate for asthma that was observed in adults. Data on emergency department visits show evidence of strong seasonal variations in asthma exacerbations. PMID- 20206064 TI - [Epidemiology of chronic obstructive pulmonary disease in France]. AB - This paper aims to summarize the most recent data on the descriptive epidemiology of chronic obstructive pulmonary disease (COPD) in France. Data are presented concerning the prevalence, mortality and hospital admissions. The prevalence of COPD is difficult to estimate due to the large degree of under-diagnosis and the difficulty of performing spirometry in population-based epidemiological surveys. The prevalence of chronic bronchitis was estimated at 4%, and the prevalence of COPD was estimated at 5-10%, among adults aged 45 years and older. Data from death certificates, although limited by the accuracy of certification, showed that the annual age-standardised mortality rates from COPD increased between 1979 and 2000 among women but remained stable among men. In 2006, about 16,500 death certificates mentioned COPD, of which 7400 identified it as the underlying cause of death. According to the French national hospital discharge database, the number of admissions related to an exacerbation of COPD ranged from 69,000 to 112,000 in 2006 according to the definition used. The admission rates have increased between 1998 and 2006 and this increase was more pronounced among women than among men. Large regional differences in COPD mortality and hospital admission rates were evident, with the highest rates in Northern and Eastern France and in Brittany. PMID- 20206065 TI - [Moulds in dwellings: health risks and involved species]. AB - INTRODUCTION: In industrialized countries the population spends 90% of its time in enclosed spaces. Since 1973, energy consumption for heating decreased on average by 36% per dwelling. Low-quality insulation, a fall in temperature and inadequate ventilation translated into high humidity in dwellings, which led to proliferation of moulds. BACKGROUND: The allergenic, toxic and infectious effects of moulds on human health are documented. However, the potential dose/effect relationship between measured concentrations of indoor moulds and respiratory disorders often remains difficult to assess accurately. In several cases, fungi were demonstrated only as a promoter of health disorders. In a few cases (hypersensitivity pneumonitis, invasive fungal infections), the pathogenesis is without doubt due to environmental fungal exposure in a limited number of patients. On the other hand, the role of fungi was suspected but not proven for some well-defined pathologies, and some ill-defined health disorders, affecting large numbers of patients, such as the Sick Building Syndrome, rhinitis, sinusitis and conjunctivitis, as well as asthma and exacerbations of bronchitis. Eighteen fungal species, suspected of playing a role in public health, have been listed by the French Superior Council of Public Health. For each species, the proliferation conditions, type of substrates contaminated and heath effects reported in the literature are described. VIEWPOINT: The lack of standardization of measurements of concentrations of fungal species, the interactions with chemical compounds (formaldehydes), organic compounds (mycotoxins, endotoxins) and between species, makes the analysis of indoor fungal contamination complicated. The time has come to establish clearly a relationship between exposure to fungi and health disorders, rather than continuing to investigate factors related to the level of indoor fungal contamination. PMID- 20206066 TI - [Non allergic disorders associated with domestic moulds]. AB - INTRODUCTION: Mouldy surfaces are encountered in up to 20 % of dwellings. Because this indoor air contamination is so widespread, respiratory physicians should be aware of its effects on health and especially of its impact on respiratory diseases. BACKGROUND: The air contaminants within mouldy dwellings are very diverse. Therefore, a given heath effect cannot be attributed specifically to an individual contaminant. In the field of respiratory diseases, excluding asthma and allergy, long-term exposure to indoor moulds has been recognized as a risk factor for both ENT and bronchial symptoms. Hydrophilic moulds seem to have a larger health impact than other mould species. Among respiratory diseases, inhalation fever and, to a lesser extent, childhood respiratory infections are linked to exposure to moulds. In contrast, the relationship between exposure to indoor moulds and diseases such as sinusitis, mucous irritation syndrome, recurrent respiratory infections in adults, COPD and pulmonary haemorrhage has not been clearly established. VIEWPOINT: There are still many scientific uncertainties in this field. However, the authorities are becoming more active in dealing with unhealthy buildings and encouraging research. CONCLUSION: The health impact of mouldy dwellings represents a major public health issue. It needs incentives from institutions and financial support as well as the involvement of many specialists. PMID- 20206067 TI - Exploring new indications for statins beyond atherosclerosis: Successes and setbacks. AB - Statins have been shown to reduce cardiovascular events across a broad spectrum of patients at risk, irrespective of baseline LDL-cholesterol levels. In a meta analysis of 14 statin trials involving more than 90,000 participants, statin therapy reduced the 5-year incidence of cardiovascular events by about 20% for each mmol/L of LDL-cholesterol reduction. The results of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) study suggest that the degree of reduction in Japanese subjects may be greater than this for the same degree of LDL-cholesterol reduction. Given the success of statins in preventing cardiovascular events, it is not surprising that they have been tested in a variety of related conditions, three of which are discussed in this article. Heart failure is characterized by inflammation, endothelial dysfunction and neurohumeral activation, conditions that are ameliorated by statin therapy. The Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) showed no significant benefit of rosuvastatin upon the primary endpoint, cardiovascular death, myocardial infarction and stroke. However, subgroups identified by the biomarkers plasma amino-terminal pro-brain natriuretic and C reactive protein showed a reduction in events. Aortic stenosis and atherosclerosis share common risk factors, including hypertension and hypercholesterolemia. Although non-randomized cohort studies have suggested that statins slow the progression of aortic stenosis, this was not shown in either of the two randomized placebo-controlled trials testing this hypothesis. Similarly, Alzheimer's disease shares many risk factors with atherosclerosis, and several observational studies have reported a lower risk of developing this condition in patients taking statins. However, two recently completed clinical trials indicate that neither atorvastatin nor simvastatin slow the progression of early Alzheimer's disease. In conclusion, although statins are effective, established therapy for the prevention of vascular events in patients at risk, they have as yet not proven to be successful for these newer indications. PMID- 20206068 TI - Generator-produced rubidium-82 positron emission tomography myocardial perfusion imaging-From basic aspects to clinical applications. AB - Cardiovascular disease is the leading cause of death in modern industrialized countries with an aging population. This fact has fueled the need for innovative diagnostic testing intended to improve coronary artery disease (CAD) patient care. Detection of myocardial ischemia using myocardial perfusion imaging (MPI) plays an important role for CAD diagnosis and the prediction of future risk of cardiovascular events. Positron emission tomography (PET) MPI has high diagnostic accuracy and can estimate regional myocardial blood flow (MBF) in patients with CAD. Rubidium-82 ((82)Rb) is a generator-produced PET myocardial perfusion tracer and has been widely used in North America in clinical practice. (82)Rb PET has recently become available in some cardiovascular centers in Europe and Japan. Clinical trials are expected in both regions. (82)Rb PET has high diagnostic accuracy and recent data have shown its prognostic value. Thus, (82)Rb PET would greatly contribute to CAD patients' care. (82)Rb PET can also be used to quantify MBF. This review describes the current status of (82)Rb MPI from basic principles to clinical implications. This paper also highlights the recent development of MBF quantification using (82)Rb PET. PMID- 20206069 TI - Efficacy of N-acetylcysteine and aminophylline in preventing contrast-induced nephropathy. AB - BACKGROUND: Contrast-induced nephropathy (CIN) is one of the important complications of coronary angiography (CAG) and percutaneous coronary intervention (PCI), especially in patients with chronic kidney disease (CKD). Prophylactic administration of N-acetylcysteine (NAC) and aminophylline has been reported to be effective in some trials, but the results still remain controversial. We investigated the efficacy of NAC or aminophylline in preventing CIN. METHODS AND RESULTS: Forty-five consecutive patients undergoing CAG and/or PCI were randomly assigned to receive hydration and NAC (704 mg orally twice daily; NAC group, n=15), hydration and aminophylline (250 mg intraveneously 30 min before CAG and/or PCI; aminophylline group, n=15), or hydration alone (control group, n=15). We compared serum creatinine (SCr), creatinine clearance (Ccr), blood beta-2 microglobulin, and urinary beta-2 microglobulin levels at baseline and 48h after CAG and/or PCI. In the NAC group, SCr decreased from 1.00 + or - 0.36 to 0.67 + or - 0.16 mg/dl (p<0.01), and Ccr significantly increased from 62.4 + or - 15.6 to 80.4 + or - 8.39 ml/min (p<0.01). In the aminophylline group, SCr and Ccr were unchanged. In the control group, SCr significantly increased from 0.94 + or - 0.21 to 1.28 + or - 0.21 mg/dl (p<0.01), and Ccr significantly decreased from 63.7 + or - 16.1 to 46.1 + or - 10.6 ml/min (p<0.01) after CAG and/or PCI. In the NAC group, mean blood beta-2 microglobulin significantly decreased from 2.38 + or - 0.58 to 1.71 + or - 0.38 mg/dl (p<0.01), and in the aminophylline group, mean urinary beta-2 microglobulin concentration significantly decreased from 337 + or - 31.0 to 239 + or - 34 microg/ml (p<0.01). CONCLUSIONS: These results suggest that both prophylactic NAC and aminophylline administration are effective in preventing CIN, but not with hydration alone. It appears that the two compounds work in different ways against CIN. PMID- 20206070 TI - Treatment of non-left main bifurcation lesions using the sirolimus-eluting stent: A comparison of chronic outcomes of cross-over single stenting and crush stenting. AB - BACKGROUND: It is said that the chronic outcomes of the two-stent technique for bifurcation lesions are inferior to that of cross-over single stenting. However, there are many cases where true bifurcations are difficult to treat by single stenting and, in particular, strategies for bifurcation lesions that are not left main trunk (LMT) bifurcations are still not clear. OBJECTIVE: This study aims to compare the usefulness of crush stenting with that of cross-over single stenting using the sirolimus-eluting stent (SES) on bifurcation lesions with the exclusion of LMT bifurcations. METHODS: Subjects were 92 consecutive patients (100 lesions) who underwent cross-over single stenting or crush stenting using SES for bifurcation lesions with the exclusion of LMT bifurcations. The patients were divided into 33 patients with 34 lesions, in whom the stent was implanted in the main vessel alone with the kissing balloon technique performed for the main vessel and side branch (Single-stenting group; S group), and 59 patients with 66 lesions, in whom the stent was implanted through crush stenting (Crush-stenting group; C group). The two groups were compared for target lesion revascularization (TLR) and major adverse cardiac events (MACE). RESULTS: There were no differences for TLR, with this conducted in the main vessel in 5.9% of S group and 4.5% of C group. There was no difference between the groups in MACE with 9.1% in S group and 8.5% in C group. No significant difference was seen in MACE-free survival rate in the chronic phase with 93.9% for S group and 94.9% for C group (P=NS). CONCLUSION: No differences in chronic clinical outcomes were revealed in a comparison between cross-over single stenting and crush stenting. Good clinical outcomes were achieved by both cross-over single stenting and crush stenting in the treatment of non-left main bifurcation lesions. PMID- 20206071 TI - Efficacy of thrombectomy for acute myocardial infarction-Special focus on its efficacy according to different infarct-related arteries. AB - BACKGROUND: The efficacy of thrombectomy during percutaneous coronary intervention (PCI) for ST-segment elevation acute myocardial infarction (STEMI) has not yet been fully evaluated. The aim of this retrospective study was to evaluate the usefulness of manual thrombectomy for STEMI and to clarify whether different infarct-related arteries (IRAs) influence the efficacy of thrombectomy. METHODS AND RESULTS: We enrolled 183 patients with STEMI who underwent PCI within 24h after onset between October 2001 and January 2004. We divided these patients into 2 groups, namely 88 patients who had undergone PCI after manual thrombectomy (Th+ group) and 95 patients who were treated with PCI alone (Th- group). The Th+ group had lower incidences of distal embolization and no-reflow phenomenon than the Th- group (6.8% vs. 27.4%, p=0.0003; and 5.7% vs. 23.2%, p=0.0009, respectively). The percentage of complete ST-segment resolution (STR) after PCI and left ventricular ejection fraction 6 months after the procedure were significantly higher in the Th+ group (43.2% vs. 20%, p=0.002; and 60.1% vs. 54.8%, p=0.004, respectively). Regarding different IRAs, the percentage of complete STR was significantly higher in patients with proximal left anterior descending coronary artery (LAD) and right coronary artery (RCA) lesions in the Th+ group (37.5% vs. 9.7%, p<0.05; and 59.5% vs. 30.3%, p<0.05, respectively). Incidences of adverse events were similar in both groups. CONCLUSIONS: Manual thrombectomy for STEMI can improve myocardial reperfusion after PCI and left ventricular function late after the procedure. With respect to different IRAs, manual thrombectomy for STEMI is more effective in proximal LAD and RCA lesions. PMID- 20206072 TI - Factors contributing to left atrial enlargement in adults with normal left ventricular systolic function. AB - BACKGROUND: Causes of left atrial (LA) enlargement and its gender difference in patients with normal left ventricular (LV) systolic function have not been clarified. We investigated the factors contributing to LA enlargement in patients with normal LV systolic function, addressing its gender difference. METHODS: We enrolled 380 patients (175 males and 205 females; mean age: 63 + or - 15 years) with LV ejection fraction > or = 50% who underwent Doppler echocardiography and blood tests at the same time as echocardiography. Patients with arrhythmias, significant valvular heart disease, and LV asynergy were excluded. The LA volume was measured by Simpson's method from apical 2- and 4-chamber views, and LA volume index (LAVI) was calculated as LA volume/body surface area. All patients, male and female were assigned to a group with a low or a high LAVI based on the median LAVI value, respectively. RESULTS: Age, female gender, hypertension, diabetes, hemoglobin concentration, LV mass index, Doppler parameters of LA contraction, and the ratio of mitral early diastolic velocity to early diastolic velocity of the mitral annulus (E/E') were significantly associated with a high LAVI in all patients. Multivariate analysis showed that LV mass index [odds ratio (OR) 1.05, 95% confidence interval (CI) 1.03-1.06, P<0.0001], hemoglobin concentration (OR 0.76, 95% CI 0.64-0.90, P<0.01), and female gender (OR 1.92, 95% CI 1.12-3.30, P<0.05) independently contributed to a high LAVI in all patients. In addition, LV mass index and hemoglobin concentration independently contributed to a high LAVI in both genders despite the absence of overt LV hypertrophy or anemia. CONCLUSION: Increased LV wall thickness and decreased hemoglobin concentration might contribute to LA enlargement in patients with normal LV systolic function irrespective of gender. PMID- 20206073 TI - Association of the manganese superoxide dismutase polymorphism with vasospastic angina pectoris. AB - BACKGROUND: Vasospastic angina (VSA) is closely related to endothelial dysfunction caused by oxidative damage. Manganese superoxide dismutase (MnSOD) is an antioxidant enzyme that functions in mitochondria. There are two genetic variants of MnSOD arising from a substitution of an alanine for a valine in the signal peptide. We previously reported that the valine allele of MnSOD decreases the mitochondrial MnSOD (mtMnSOD) activity. Here, we investigated the association of the MnSOD polymorphism (Ala16Val) with VSA. METHODS AND RESULTS: Blood samples were collected from 618 healthy subjects who did not have any symptoms or other evidence suggesting angina pectoris, and 228 patients who underwent coronary angiography on suspicion of angina, and were diagnosed to have VSA by acetylcholine test. MnSOD genotype of each subject was determined by real-time polymerase chain reaction. The valine allele frequency was higher in the VSA patients (0.890) than in the healthy subjects (0.839) [odds ratio (OR)=1.55, p=0.0085]. In healthy subjects the MnSOD genotype distribution was as follows: alanine/alanine 1.9%, alanine/valine 28.3%, and valine/valine 69.8%, and in VSA patients the prevalence was: alanine/alanine 1.3%, alanine/valine 19.3%, and valine/valine 79.4%. Thus, the valine allele was closely associated with VSA (p=0.019). Multivariate logistic regression analysis showed valine/valine homozygosity to be an independent risk factor for VSA (OR=2.02, 95% CI 1.43, 2.85; p=0.0012). CONCLUSION: The valine variant of MnSOD signal peptide increases the risk of VSA. PMID- 20206074 TI - Sleep apnea and ventricular arrhythmias: Clinical outcome, electrophysiologic characteristics, and follow-up after catheter ablation. AB - BACKGROUND AND OBJECTIVES: Sleep apnea is highly prevalent in patients with heart disease. However, the association between sleep apnea and ventricular arrhythmias is unclear. The aim of this study was to examine the relationship between sleep apnea and electrophysiologic characteristics and clinical outcome after catheter ablation in patients having ventricular arrhythmias. METHODS AND RESULTS: Forty four patients with ventricular tachycardia (VT) or premature ventricular complexes (PVCs) without structural heart diseases (57% men; mean age: 55 + or - 15 years) underwent a sleep study. Subjects with an apnea-hypopnea index (AHI) > or = 10/h were considered to have sleep apnea. Electrophysiologic studies were performed on all patients, and 35 patients underwent catheter ablation therapy. Seventeen patients (39%) had sleep apnea with an average AHI of 27 + or - 17/h. Electrophysiologic characteristics of ventricular arrhythmias showed that sites of VT/PVCs origin in the pulmonary artery and the aortic sinus of Valsalva were detected in 27% and 20% patients with sleep apnea, which was a relatively higher rate than that in patients without sleep apnea (8% and 0%, respectively). Successful catheter ablation was achieved in 11 patients (85%) with sleep apnea and 17 (77%) without sleep apnea. During a mean follow-up period of 13.5 + or - 7.3 months after catheter ablation, 5 patients (45%) with sleep apnea and 1 patient (6%) without sleep apnea experienced recurrent VT/PVCs. Comparing the outcome between the two groups, the VT/PVCs recurrence rate was significantly higher in patients with sleep apnea than in those without sleep apnea (p=0.02). CONCLUSIONS: Ventricular arrhythmia patients with sleep apnea have a high recurrence of arrhythmias after successful catheter ablation. Patients with ventricular arrhythmias should be systematically assessed for sleep apnea owing to the potential detrimental effects of sleep apnea in the follow-up period. PMID- 20206076 TI - Age-related differences in virtual histology-intravascular ultrasound findings in patients with coronary artery disease. AB - BACKGROUND: We assessed the age-related differences in pre-intervention virtual histology-intravascular ultrasound (VH-IVUS) findings at target lesion sites in patients with coronary artery disease. METHODS: A total of 553 patients who underwent pre-intervention VH-IVUS imaging were grouped according to age: non elderly (< or = 70 years, n=429) and elderly (>70 years, n=124); 191 had stable angina and 362 acute coronary syndrome. VH-IVUS classified the tissue into: fibrotic, fibro-fatty, dense calcium (DC), and necrotic core (NC). RESULTS: Overall, the absolute and percent volumes of DC (11.0 + or - 11.0mm(3) vs. 9.7 + or - 11.9 mm(3), P=0.033; 11.7 + or - 8.1% vs. 9.8 + or - 7.2%, P=0.014, respectively) and NC (18.5 + or - 17.6mm(3) vs. 16.6 + or - 18.9 mm(3), P=0.020; 18.8 + or - 8.8% vs. 16.5 + or - 9.3%, P=0.026, respectively) were significantly greater in the elderly than in the non-elderly. In stable angina patients, the absolute and percent volumes of DC (10.4 + or - 9.9 mm(3) vs. 7.2 + or - 7.6 mm(3), P=0.022; 13.4 + or - 10.0% vs. 9.2 + or - 6.5%, P=0.011, respectively) and NC (14.8 + or - 11.2 mm(3) vs. 12.0 + or - 11.9 mm(3), P=0.035; 19.6 + or - 8.8% vs. 15.5 + or - 8.4%, P=0.006, respectively) were significantly greater in the elderly. However, in acute coronary syndrome patients, there were no significant differences in absolute and percent volumes of DC (11.4 + or - 11.6 mm(3) vs. 10.9 + or - 13.4 mm(3), P=0.8; 10.7 + or - 6.5% vs. 10.1 + or - 7.5%, P=0.5, respectively) and NC (24.1 + or - 20.3 mm(3) vs. 23.9 + or - 21.2 mm(3), P=0.9; 22.0 + or - 8.8% vs. 21.3 + or - 9.6%, P=0.6, respectively) between the elderly and non-elderly groups. Myocardial infarction (OR: 2.56, 95% CI: 1.45-4.12, P=0.003), diabetes mellitus (OR: 2.23, 95% CI: 1.30-3.53, P=0.009), and high sensitivity C-reactive protein (OR: 1.44, 95% CI: 1.06-2.45, P=0.042), but not age, were independent predictors of percent NC volume >20% in lesion site. CONCLUSIONS: Myocardial infarction, diabetes mellitus, and high-sensitivity C reactive protein, but not age, were associated with NC-rich lesions. Clinical presentation, risk factors, and inflammatory status, but not age, are important factors for plaque components. PMID- 20206075 TI - Predictors of nonoptimal coronary flow after primary percutaneous coronary intervention with stent implantation for acute myocardial infarction. AB - BACKGROUND: Predictors of suboptimal coronary flow in the infarct-related artery (IRA) after stent-based primary percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI) have not been fully investigated. METHODS AND RESULTS: Using the AMI-Kyoto Multi-Center Risk Study database, we retrospectively compared clinical manifestations and in-hospital prognosis between AMI patients undergoing stent-based primary PCI with final Thrombolysis In Myocardial Infarction (TIMI) grade < or = 2 in the IRA (nonoptimal group, n=69) and those with final TIMI grade 3 (optimal group, n=1200). The nonoptimal group had higher prevalence of Killip class > or = 3 at admission, higher frequency of mechanical support devices during procedures, larger value of maximal creatine phosphokinase, and a significantly higher in-hospital mortality rate (27.5% for nonoptimal vs. 9.0% for optimal, P<0.001), compared with the optimal group. On multivariate analysis, Killip class > or = 3 at admission was the independent predictor of the final nonoptimal flow (odds ratio 2.33, 95% confidence intervals 1.27-4.26 P=0.006), but TIMI 3 flow before primary PCI and elapsed time (symptom onset-to-admission time)<24h were not. CONCLUSIONS: Killip class > or = 3 at admission is an independent predictor of the final nonoptimal flow in AMI patients undergoing primary PCI with stent implantation. PMID- 20206077 TI - Usefulness of rotational atherectomy for the implantation of drug-eluting stents in the calcified lesions of hemodialysis patients. AB - BACKGROUND: Drug-eluting stents (DES) have significantly reduced in-stent restenosis. But the calcification of coronary artery lesions in hemodialysis patients is a high-risk factor for restenosis after DES implantation. We hypothesized that percutaneous transluminal coronary rotational atherectomy (PTCRA) may be useful in the prevention of underexpansion and fracture of the stents, thereby reducing major adverse cardiac events. METHODS: We retrospectively compared the primary success and mid-term outcomes (major adverse cardiac events within 12 months) of hemodialysis patients with calcified coronary lesions undergoing DES implantation using PTCRA (n=26) with those where DES was implanted without PTCRA (n=28). RESULTS: The rates of target lesion revascularization in the PTCRA group were lower than those in the non-PTCRA group (11.5% vs 35.7%, p=0.026). The rates of restenosis and subacute thrombosis in the PTCRA group were modestly lower than those in the non-PTCRA group (restenosis rate, 17.4% vs 17.4%, p=0.061; subacute thrombosis rate, 0% vs 7.1%, p=0.31). CONCLUSION: PTCRA may be useful for improving the mid-term outcome of DES implantation in hemodialysis patients with calcified lesions. PMID- 20206078 TI - Effects of treatment with once-daily nifedipine CR and twice-daily benidipine on prevention of symptomatic attacks in patients with coronary spastic angina pectoris-Adalat Trial vs Coniel in Tokyo against Coronary Spastic Angina (ATTACK CSA). AB - BACKGROUND: We compared the efficacy of once-daily treatment with nifedipine CR 40 mg (NR) and twice-daily treatment with benidipine 4 mg (BD) in patients with coronary spastic angina (CSA) registered in 3 cardiovascular institutes in Tokyo. METHODS AND RESULTS: CSA was diagnosed by an ischemic ST change during Holter ECG monitoring or drug-induced test. Thirty patients were randomly allocated to either NR or BD group. The number of symptomatic attacks and the total frequency of short-acting nitrates were examined based on the data in diaries written by patients. There were no significant differences in the baseline characteristics between the two groups. The median number (25-75% quartile) of attacks per week was significantly decreased in NR group, i.e., 1.0 (0.8-2.0) at baseline, 0.0 (0.0-1.0) after 4 weeks of treatment, and 0.0 (0.0-0.0) after 8 weeks of treatment (P=0.0093, P=0.0002, Wilcoxon's rank-sum test). No significant decrease was observed in BD, i.e. 1.0 (0.5-2.0) at baseline, 1.3 (0.0-3.0) after 4 weeks, and 0.0 (0.0-1.0) after 8 weeks. The number of attacks was fewer in NR than in BD group (P=0.074, P=0.015, U-test for difference). CONCLUSION: Once-daily treatment with NR 40 mg was more effective than twice-daily treatment with BD in the prevention of CSA attacks. PMID- 20206079 TI - A novel echocardiographic index of inefficient left ventricular contraction resulting from mechanical dyssynchrony. AB - OBJECTIVES: The purpose of this study was to explore the possibility of using our novel echocardiographic index of inefficient left ventricular (LV) contraction in patient selection for cardiac resynchronization therapy (CRT). METHODS: Forty consecutive patients with LV ejection fraction < or = 35% were divided into 2 groups, 9 CRT candidates and 31 non-CRT candidates based on conventional criteria. A global LV time-area curve and regional LV time-area curves in 6 radial sectors were obtained using two-dimensional echocardiography in the short axis view with speckle tracking. Fractional inefficient contraction (FIC, %) was calculated as follows: (1-global LV area change/sum of regional LV area changes) x 100. LV dyssynergy and dyssynchrony were quantified as the standard deviations of minimal values of circumferential speckle-tracking strain and their timings in the 6 sectors, respectively. RESULTS: There was no significant difference in LV dyssynchrony between CRT candidates and non-CRT candidates (79 + or - 61 ms vs. 58 + or - 26 ms, respectively). In contrast, FIC was significantly larger in CRT candidates than in non-CRT candidates (15.7 + or - 11.0% vs. 5.4 + or - 3.5%, respectively, p=0.0018), with less overlap between groups. FIC showed a positive correlation with dyssynchrony (r=0.64) and a negative correlation with dyssynergy (r=-0.42). CONCLUSIONS: Our novel echocardiographic index of inefficient LV contraction, which increases with more dyssynchrony or less dyssynergy, may prove more useful in patient selection for CRT than other indices that focus on LV temporal dyssynchrony alone. PMID- 20206080 TI - Comprehensive evaluation of the apex beat using 64-slice computed tomography: Impact of left ventricular mass and distance to chest wall. AB - OBJECTIVES: Although physicians frequently perform palpation of the apex beat to evaluate left ventricular (LV) size and hypertrophy, the clinical significance of apex beat palpation is still unclear. The introduction of multislice computed tomography (MSCT) has enabled assessment not only of coronary stenoses but also LV volume, mass, and distance from heart to chest wall. The aim of this study was to evaluate the relationships among presence, location, and sustained or double apical impulse of apex beat and LV function, volume, mass, and distance from heart to chest wall determined by MSCT. METHODS AND RESULTS: The study population consisted of 200 consecutive patients clinically indicated for MSCT angiography for coronary artery evaluation. Apex palpation was performed with the patients in the supine and left lateral decubitus positions. Multivariate analysis revealed that LV mass index (p<0.01), distance (p<0.005), and being male (p<0.005) remained independent factors associated with presence of apex beat in the supine position, and that LV mass index was also associated with location of apex beat. Furthermore, in patients with a palpable apex beat, LV mass index was an independent factor associated with patterns of sustained or double apical impulse. In the group of all patients, patterns of sustained or double apical impulse in the supine position had a sensitivity of 57%, specificity of 90%, positive predictive value of 68%, and negative predictive value of 85% as an indicator of LV hypertrophy. CONCLUSION: Palpation of the apex beat is a sensitive diagnostic maneuver for excluding patients with increased LV mass. We believe that our observations have important implications for bedside clinical examination. PMID- 20206081 TI - Waist circumference reduction is more strongly correlated with the improvement in endothelial function after acute coronary syndrome than body mass index reduction. AB - BACKGROUND: Endothelial function predicts recurrence of adverse cardiac events in patients with acute coronary syndromes (ACS). Moreover, the recovery of endothelial function correlates with cardiac event-free survival. OBJECTIVES: The aim of this study was to determine which clinical factors correlate with the improvement in endothelial function after ACS. METHODS: Vascular endothelial function was assessed in 98 patients with ACS by flow-mediated dilation (FMD) of the brachial artery using high-resolution ultrasound at 2 weeks and 6 months after ACS. We measured several risk parameters including plasma markers of glucose homeostasis, lipids, and blood pressure at baseline and at 6 months after ACS. Body mass index (BMI) and waist circumference (WC) were also measured as anthropometric assessments. RESULTS: At baseline, FMD was significantly correlated with BMI, WC, high-density lipoprotein cholesterol, the homeostasis model assessment of insulin resistance, and brachial artery diameter (r=-0.32, p=0.001; r=-0.44, p<0.0001; r=0.34, p=0.0006; r=-0.21, p=0.04; r=-0.47, p<0.0001, respectively). In a stepwise multivariate regression analysis at baseline, larger WC and brachial artery diameter were independently correlated with lower brachial artery FMD (R(2)=0.319, p<0.0001). At 6 months, the change in FMD was significantly correlated with the change in WC and BMI (r=-0.59, p<0.0001; r= 0.33, p=0.001, respectively). In a stepwise multivariate regression analysis, WC reduction was independently correlated with improved FMD (R(2)=0.349, p<0.0001). CONCLUSIONS: WC reduction is more strongly correlated with the improvement of endothelial function after ACS than BMI reduction. PMID- 20206083 TI - Ambient weather conditions and the onset of acute myocardial infarction: The consociation between triggering factors and conventional risk factors. PMID- 20206082 TI - Left atrium volume index and pathological features of left atrial appendage as a predictor of failure in postoperative sinus conversion. AB - BACKGROUND: Previous studies showed that some parameters, including left atrium diameter and left atrium volume index (LAVI), predicted the success of sinus conversion. However, no previous studies have investigated the association of sinus conversion with LAVI and histopathological findings. This study was designed to investigate the relationship among LAVI, pathological assessment, and failure in sinus conversion after surgery for valvular atrial fibrillation (AF). METHODS AND RESULTS: A total of 78 patients with left atrium enlargement and valvular AF who underwent maze procedure concomitantly with various cardiac surgeries were classified into one of two groups: those who successfully underwent sinus conversion (Group 1; n=40) and those who did not achieve sinus conversion (Group 2; n=38). Histopathological assessment was performed in 9 cases using tissues derived from the left atrial appendage (LAA). The degree of histopathological change was classified into 1 of 4 grades. LAVI was significantly less in Group 1 than in Group 2 (81 + or - 22 ml/m(2) vs. 122 + or 49 ml/m(2), p<0.001). Preoperative LAVI predicted 100% failure of sinus conversion after surgery with a cut-off value of 135 ml/m(2). Histopathological analyses clearly showed that the grades for intercellular fibrosis, fatty infiltration, endocardial thickening, and nuclear enlargement/abnormalities were significantly and positively correlated with LAVI (r=0.75, p<0.05; r=0.74, p<0.05; r=0.69, p<0.05; r=0.77, p<0.05, respectively). CONCLUSIONS: LAVI associated with histopathological features of the resected LAA is a predictor of failure in sinus conversion following surgical intervention in patients with valvular AF. PMID- 20206084 TI - Considerations in non-Caucasian facial plastic surgery. Preface. PMID- 20206085 TI - A new paradigm for the aging face. AB - Fat transfer has become the primary method for facial rejuvenation in my clinical practice for all ethnicities. This technique can be effectively used to address panfacial volume loss so long as artistry, technical skill, and an in-depth understanding of fat grafting changes over the years are well applied and understood. Fat grafting can replace many traditional facial rejuvenation techniques or serve as an important adjunct to excisional and lifting procedures to temper the degree of excision and lifting that are required. PMID- 20206086 TI - Lower facial rejuvenation in the non-Caucasian face. AB - The goal would be similar to Caucasian patients in that all patients would like to have maximum improvement with minimal detectability of the surgical procedure. With regard to scars, the incisions must be no longer than necessary to accomplish the desired goal, and should be carefully placed so that color matches are ideal and there is no objectionable hair shift. In addition, the technique of making an incision for male patients should be made so that hairs will grow through the scars whenever possible. For non-Caucasian patients it is essential that attention be made to all of the known details and techniques, to avoid detection that surgery has been performed. PMID- 20206087 TI - Upper and midfacial rejuvenation in the non-Caucasian face. AB - The non-Caucasian face has many unique attributes, including skin tone, texture, elasticity, skin thickness, and subcutaneous fat content. These differences may place the patient at increased risk for scarring and pigmentation issues. In this paper, the authors discuss treatment options, surgical and nonsurgical, for rejuvenation of the upper face and midface, including the periorbital region. The selection of the proper treatment must be coupled with a thorough understanding of the age-related changes that occur in the non-Caucasian face to meet and hopefully exceed the patient's expectations. PMID- 20206088 TI - Hair restoration in the ethnic patient and review of hair transplant fundamentals. AB - Superior hair restoration requires the application of universal principles along with variations that apply to specific ethnic populations. This article serves as a primer on basic tenets of hair restoration, with additional attention given to the uniqueness and differences in technique and design that are warranted for a wide range of races and ethnicities. This article also gives prospective surgeons an insight on how to undertake further study and shore up their deficiencies so as to refine knowledge gaps and ensure patient safety and excellent surgical outcomes. PMID- 20206089 TI - Supratarsal crease creation in the Asian upper eyelid. AB - Supratarsal crease fixation in the Asian patient can provide a more open-eyed, awake look without compromising their ethnic appearance. A conservative supratarsal crease height and conservative to no removal of postseptal fat help to ensure this natural-appearing result. With the full-incision method, consistently excellent results have been achieved with durable crease fixation despite a prolonged recovery time. The supratarsal crease fixation provides an excellent method for the younger patient seeking cosmetic eyelid enhancement. However, for the aging Asian patient, the complexity of the strategy is greater. PMID- 20206090 TI - Midface alloplastic augmentation in the Asian and Latino patient. AB - The population of the United States is becoming increasingly more diverse as there is an ever expanding influx of various ethnic groups and races that comprise the general population. As a result, the singular concept of Nordic beauty that dominated the United States media throughout the middle of the twentieth century has given way to a more diverse multiracial aesthetic. There is also a growing trend in aesthetic surgery toward ethnic feature preservation and avoidance of a "westernized" look that was more popular in previous years. Today's facial plastic surgeon must be familiar with these trends and aesthetic goals within this rapidly growing patient population. This article describes the anatomy of the Asian and Latino face and describes the techniques of midface alloplastic augmentation. PMID- 20206091 TI - Forehead augmentation with alloplastic implants. AB - Methods of alloplastic forehead augmentation using soft expanded polytetrafluoroethylene (ePTFE) and silicone implants are described. Soft ePTFE forehead implantation has the advantage of being technically simpler, with better fixation. The disadvantages are a limited degree of forehead augmentation and higher chance of infection. Properly fabricated soft silicone implants provide potential for larger degree of forehead silhouette augmentation with less risk of infection. The corrugated edge and central perforations of the implant minimize mobility and capsule contraction. PMID- 20206092 TI - Lip reduction surgery (reduction cheiloplasty). AB - This article discusses and presents options related to the cosmetic reduction of enlarged lips, primarily in ethnic populations. No formal study is performed. The author presents a literature review and discusses his personal 26-year experiences in lip surgery. When basic tenets are followed, cosmetic lip reduction is a predictable procedure with very little morbidity. Although lip augmentation is a popular cosmetic procedure, a certain percentage of the population desires smaller lips. Reduction cheiloplasty is a safe and predictable procedure that has been performed over a half century. This procedure is relatively simple and has a moderate learning curve. Cosmetic lip reduction is safe and effective, and has a high level of patient acceptance when certain diagnostic and treatment criteria are fulfilled. PMID- 20206093 TI - The new "genetico-racial" skin classification: maximizing the safety of skin treatments for Asians. AB - Racial genetics play a significant role in determining a patient's response to any skin treatment. Contrary to traditional skin classifications, the new genetico-racial classification takes into consideration the racial origins of patients, as manifested in both their skin color and their feature contour characteristics, rather than their skin color alone. According to this new classification, patients may belong to 1 of 6 categories, originating from the 3 ancient continents: Africa, Europe, and Asia. In this article the Asian category, as well as its subcategories, are approached in a radically different way. This new geneticoracial classification ushers in a "paradigm shift" in the way Asian patients are perceived before, during, and after skin treatments. The new geneticoracial classification advances that Asians are excellent candidates to most peels and laser treatments, as long as their genetic disposition and their anticipated responses to those treatments are understood and respected. PMID- 20206094 TI - Laser treatment for ethnic skin. AB - With the growth of new technology and products over the last 10 years, there has been an increased ability to improve a patient's appearance with procedures that can be performed in an office setting, including laser procedures. Demand for these procedures has grown among all ethnic groups. Patients with ethnic skin can have varying response to lasers. This factor should be considered when planning their treatment. After laser treatment, Patients with ethnic skin are at greater risk for laser energy absorption by melanin, postinflammatory hyperpigmentation, and loss of pigment due to laser effects on melanin production leading to hypopigmentation. Therefore, any laser therapy should be planned carefully, especially in the treatment of patients with darker skin types. PMID- 20206095 TI - Chemical peels for darker skin types. AB - This article focuses on chemical peels for darker skin types. All races comprise a range of Fitzpatrick skin color types: light skin types in African Americans, Asians, Middle Easterners, and Latinos and dark skin types in whites. With the focus on Fitzgerald skin types IV to VI, this article discusses chemical peels, providing current information on types of peels, detailed techniques, preoperative and postoperative care, complications, hazards, and nuances of management. PMID- 20206096 TI - Botox facial slimming/facial sculpting: the role of botulinum toxin-A in the treatment of hypertrophic masseteric muscle and parotid enlargement to narrow the lower facial width. AB - Botulinum toxin A is a highly efficacious and cost-effective, nonsurgical option for reducing the width and shape of the lower face and jawline. The results can vary from the subtlest thinning of the face to an extremely thin, cachectic appearance. Many nuances can be achieved. The administration is simple, and the process takes barely 5 minutes in an office setting. Botulinum toxin A can also be effectively used to reduce the bulk of an enlarged parotid gland without affecting saliva production. PMID- 20206097 TI - Traumatic rhinoplasty in the non-Caucasian nose. AB - Traumatic injury resulting in nasal deformity poses unique challenges to the surgeon. Optimal management requires careful preoperative analysis and thoughtful surgical planning. The goals of rhinoplasty are to correct both cosmetic and functional problems that may not have otherwise been an issue prior to the injury. Although it is overly simplistic to group all individuals from one ethnicity as having one type of nose, the rhinoplasty surgeon must understand the common variations of nasal anatomy seen in various races of individuals. This article discusses ethnic anatomic differences in the non-Caucasian nose in the context of posttraumatic nasal deformity. The various rhinoplasty techniques and strategies to address these issues are reviewed. PMID- 20206098 TI - Asian rhinoplasty. AB - Asian rhinoplasty is one of the most challenging ethnic rhinoplasties that plastic surgeons perform because of the thick skin and soft-tissue envelope. There are three goals: pleasing the patient, achieving an aesthetically appealing result, and preserving a natural look. Of these goals, the most arduous is to satisfy the patient, as many patients have unrealistic goals and may desire an extremely narrow Western nose. Furthermore, patients may bring in celebrity or model photographs and expect that outcome, even though it may not be suitable for their face or appear over-resected and pinched. The surgeon's most important task is to attempt to persuade the patient that this result is nonfunctional, esthetically unfit, and difficult to achieve with their skin. For ethnic surgery, a clear and thorough grasp of nasal anatomy, function, and surgical techniques is paramount. An extensive preoperative discussion, including expectations, outcomes, and a detailed list of potential complications with the patient can prevent physician-patient miscommunication. Before surgery, it is essential to review the office examination, previous operative summary, photographs, nasal analysis sheet, problem list, and plan before proceeding with the surgical treatment. PMID- 20206099 TI - Hispanic/Mestizo rhinoplasty. AB - Rhinoplasty is one of the most common facial plastic procedures performed in the Hispanic/mestizo ethnic group. Today, emphasis is placed on ethnic and cultural backgrounds, definition of facial and nasal characteristics, and a clear understanding of patients' desires. This article highlights the different types of problems encountered in mestizo patients. It describes a graduated approach to the nose whereby support structures of the nose are strengthened by careful placement of sutures and grafts, trying to achieve greater definition and support without necessarily making the nose look bigger. PMID- 20206100 TI - Rhinoplasty in the patient of African descent. AB - We are in the midst of truly changing times, as patients of African descent actively embrace facial cosmetic surgery. Gaining surgical consistency in patients of African descent has proven to be elusive and unpredictable for many rhinoplasty surgeons. Surgical success relies on the surgeon's ability precisely to identify anatomic variables and reconcile these anatomic realities with the patient's expectations for aesthetic improvement and ethnic identity. An appreciation for underlying heritage provides a link culturally to connect with prospective patients and serves as a tool for establishing realistic aesthetic goals. This article highlights the significance of exploring ancestry in the rhinoplasty consultation; identifies key anatomic variables in the nasal tip, dorsum, and alar base; and reviews surgical logic that has facilitated the achievement of consistent, balanced aesthetic outcomes. PMID- 20206101 TI - Middle Eastern rhinoplasty. AB - The ethnic appearance of the Middle Eastern nose is defined by several unique visual features, particularly a high radix, wide overprojecting dorsum, and an amorphous hanging nasal tip. These external characteristics reflect distinct structural properties of the osseo-cartilaginous nasal framework and skin-soft tissue envelope in patients of Middle Eastern extraction. The goal, and the ultimate challenge, of rhinoplasty on Middle Eastern patients is to achieve balanced aesthetic refinement, while avoiding surgical westernization. Detailed understanding of the ethnic visual harmony in a Middle Eastern nose greatly assists in preserving native nasal-facial relationships during rhinoplasty on Middle Eastern patients. Esthetic alteration of a Middle Eastern nose follows a different set of goals and principles compared with rhinoplasties on white or other ethnic patients. This article highlights the inherent nasal features of the Middle Eastern nose and reviews pertinent concepts of rhinoplasty on Middle Eastern patients. Essential considerations in the process spanning the consultation and surgery are reviewed. Reliable operative techniques that achieve a successful aesthetic outcome are discussed in detail. PMID- 20206102 TI - Gastrointestinal lymphomas. Preface. PMID- 20206103 TI - Diagnosis and staging in gastrointestinal lymphoma. AB - The diagnosis gastrointestinal lymphoma can be made on endoscopic biopsies in the vast majority of cases. Definitive subtyping of the lymphoma according to the WHO classification with the use of additional immunological and molecular markers is the cornerstone for further decision making. Several lymphomas may occur multifocally or show both small cell and large cell components. Therefore, a second endoscopy with an extensive biopsy protocol (mapping) may be mandatory. Staging procedures are required for therapeutic decision making and should include CT-scan, laboratory studies and bone marrow examination as required in other lymphomas. Additional studies must be performed depending subtype and localisation of the lymphoma. In gastric lymphoma endosonography reveals prognostic information. In marginal zone lymphoma of MALT-type attention to other MALT-sites and autoimmune diseases is necessary. In enteropathy-associated T-cell lymphoma screening for coeliac disease and enteroscopy are required. In several lymphomas (diffuse large B-cell lymphoma and mantle cell lymphoma) a PET-scan is considered as standard of care. The value of staging procedures after treatment is less well defined. At least in gastric lymphomas, histology is the gold standard after treatment and during follow-up. PMID- 20206104 TI - Staging role of EUS. AB - Type of lymphoma and stage of disease are the two decisive prognostic factors and therapeutic determinants. For the locoregional staging, i.e. assessment of the gastric wall infiltration and perigastric lymphonodular involvement, endoscopic ultrasound (EUS) is highly useful. EUS has, therefore, to be integrated into the standard staging procedure of gastric lymphoma, although its impact on initial treatment decisions might be limited in the individual case. A benefit from the use of miniechoendoscopes, EUS elastography and EUS-guided biopsies has not yet been proven in gastric lymphoma. EUS also confers an important prognostic value regarding treatment responses to Helicobacter pylori eradication. On the contrary, EUS cannot be recommended as a regular part of follow-up investigations considering its limited value in predicting the response of the lymphoma to radiation or chemotherapy. PMID- 20206105 TI - Role of chemotherapy in gastric MALT lymphoma, diffuse large B-cell lymphoma and other lymphomas. AB - Primary gastrointestinal lymphomas are relatively common, with the large majority occurring in the stomach. In the commonest histological subtype, i.e. diffuse large B-cell lymphoma (DLCBL), chemotherapy has widely been applied in the past, either following surgery or - in more recent years - as part of conservative management in combination with radiotherapy. Relatively little data, however, exist for chemotherapy as sole treatment modality in localised gastric DLBCL, which nevertheless are highly promising and suggest that combination therapy might overtreat a substantial proportion of patients. In gastric MALT-lymphoma, the use of chemotherapy has been restricted either to patients with a priori disseminated disease or individuals judged to be at high risk or failing local treatment approaches. Only a few prospective phase II studies have been performed, and one controlled trial has shown that chemotherapy was superior in terms of event free survival at ten years when compared to radiation and surgery. These suggest that systemic treatment approaches might be highly effective both in gastric DLBCL as well as MALT-lymphoma, and the scope of this article is to briefly summarize current data on chemotherapy in gastric and GI-lymphomas according to histologic subtypes. PMID- 20206106 TI - Role of radiotherapy in the treatment of lymphomas of the gastrointestinal tract. AB - In patients with gastrointestinal lymphoma the most frequently involved site is the stomach (60%-75% of cases), followed by the small bowel, ileum, cecum, colon and rectum. The most common histological subtypes are extranodal marginal zone B cell lymphoma of the mucosa-associated lymphoid tissue (MALT) and diffuse large B cell lymphoma (DLBCL). The role of radiotherapy is most definite in early stage gastric lymphoma. The therapeutic approach for patients with gastric Non Hodgkin lymphoma (NHL) has changed significantly over the last decades. The primary treatment of limited gastric MALT lymphoma consists of Helicobacter pylori eradication. In case of insufficient response to H. pylori eradication or in case H. pylori is absent, irradiation of the stomach and perigastric lymph nodes to a dose of 30-40Gy in 15-20 fractions is indicated. In patients with gastric DLBCL conservative treatment with anthracycline-based chemotherapy alone or in combination with involved-field radiotherapy has become the therapy of choice. PMID- 20206107 TI - Primary gastrointestinal tract mantle cell lymphoma as multiple lymphomatous polyposis. AB - Primary gastrointestinal involvement of mantle cell lymphoma (MCL) is rare with a frequency reported between 4 and 9% of all gastrointestinal B-cell non-Hodgkin lymphomas. It was first described and so-called as multiple lymphomatous polyposis (MLP). Its clinical presentation is usually characteristic, with multiple lymphomatous polyps involving several digestive tract segments and a marked tendency towards extra-intestinal spread. The constant and typical phenotypic features of the small cleaved tumour cells, characterised as CD20+, CD5+ CD23- with a t(11;14) (q13;q32) and cyclin D1 overexpression on immunochemistry, allow MLP to be considered as the gastrointestinal counterpart of peripheral nodal MCL. They both share a very poor outcome. Response to intensive chemotherapy regimens usually results in regression of macroscopic and sometimes microscopic lesions but remissions are short and median survival from 3 to 4 years. Prognosis has been significantly improved since in younger patients, intensive front-line immunochemotherapy with autologous stem cell transplantation has been proposed. Earlier diagnosis with further studies integrating novel agents are still required to determine the optimal treatment with less toxicity. PMID- 20206108 TI - Enteropathy associated T-cell lymphoma and its precursor lesions. AB - Enteropathy Associated T-cell Lymphoma (EATL) is an intestinal tumour of intra epithelial lymphocytes. Based on morphology, immunohistochemistry and genetic profile EATL can be divided into two groups. EATL type I is a large cell lymphoma which is highly associated with Coeliac Disease (CD) and mostly presents with malabsorption, weight loss and CD-related symptoms. EATL type II consists of small to medium-sized cells and presents often with obstruction or perforation of the small bowel. This type of EATL has no known association with CD. When EATL has been diagnosed a thorough diagnostic work-up is needed. This work-up preferably includes video capsule enteroscopy (VCE), double-balloon enteroscopy (DBE), computed tomography (CT) combined with 18F-fluorodeoxyglucose positron emission tomography scan (18F-FDG-PET scan) if possible and magnetic resonance enteroclysis (MRE). Nowadays, most EATL patients are treated with chemotherapy mostly preceded by resection of the tumour and followed by stem cell transplantation. Despite these therapies outcome of EATL remains very poor with a 5-year survival of 8-20%. In order to improve survival prospective multicentre trials, studying new therapies are needed. The combination of chemotherapy, monoclonal antibodies and/or apoptosis inducing small molecules might be a potential treatment for EATL in the (nearby) future. PMID- 20206109 TI - GI-lymphomas in immunosuppressed patients (organ transplantation; HIV). AB - Gastrointestinal lymphoma plays a major role complicating different diseases presenting with immunosuppression, both primary and acquired immunodeficiency (incl. HIV, transplantation, immunosuppression following chemotherapy, or inflammatory bowel disease). Lymphoma in diseases with immunosuppression are clinically and pathologically heterogeneous, but share some features such as frequent involvement of extranodal sites, diffuse aggressive histology, B-cell lineage derivation, viral association with EBV and clinically aggressive courses. While gastrointestinal lymphoma in congenital immunodeficiency disorders seems to be a rare event inspite of higher prevalences, in post-transplant lymphoproliferative disorders (PTLD) the gastrointestinal tract is one of the most important organs of lymphoma. In HIV-associated non-Hodgkin's lymphoma, gastrointestinal lesions as the most frequent extranodal localisation occur in 30 50% of lymphoma patients, are late events of HIV infection with severe immunosuppression and are mainly diagnosed with advanced disease stages Ann Arbour III or IV. They are characterised by unusual, often multifocal localisation in the gastrontestinal tract, high rates of life-threatening complications (bleeding, perforation or obstruction) and high-grade B-cell histology. With the introduction of highly active antiretroviral therapy (HAART) in the therapeutic concept in AIDS, a decrease of AIDS-related GI lymphoma was noted with improved survival rates and prognosis of lymphoma. Therapy strategies including chemotherapy, immunotherapy and HAART will show promising results in response and survival rates. PMID- 20206110 TI - Long-term follow-up of gastric lymphoma after stomach conserving treatment. AB - The therapeutic strategy in gastric lymphoma has completely changed over the last two decades. This change is mainly characterised by the abandonment of surgery in favour of conservative therapies and the introduction of Helicobacter pylori eradication therapy. It became evident that conservative treatment with radiation and/or chemotherapy is at least as effective as surgical resection and additionally offers the advantage of stomach preservation and better quality of life. The therapeutic goal is undoubtedly complete remission of the lymphoma as a necessary basis for cure of the disease. Both radiotherapy and chemotherapy have a high curative potential in gastric MALT lymphoma and diffuse large B-cell lymphoma (DLBCL), respectively. An open question is the additional benefit of radiation following Rituximab-CHOP chemotherapy in DLBCL. In patients with gastric MALT lymphoma of stage I H. pylori eradication offers complete remission rates of up to 80% with excellent long-term prognosis and a real chance of cure. Patients with MALT lymphoma of stage II and those with DLBCL of stage I may also respond to eradication therapy in the individual case. It also emerged recently that there is no need for any oncological therapy in patients revealing minimal histological residuals after successful H. pylori eradication. A watch-and-wait strategy is the adequate management of this condition. In summary, therapy of gastric lymphoma is nowadays individualised with lymphoma type, stage, and H. pylori status as the determinants of the choice of treatment. Efficacy and quality of life are strong arguments for a definite conservative approach encompassing H. pylori eradication, radiation and chemotherapy. PMID- 20206111 TI - Anopheline fauna and malaria transmission in four ecologically distinct zones in Cameroon. AB - Knowledge of baseline malaria transmission intensity in a given environment is important to guide malaria control interventions. In Cameroon, recent information on malaria transmission intensity is insufficient. Therefore, an entomological study was conducted in four ecologically different sites throughout the country to assess the seasonal patterns in malaria transmission intensity. Anopheles arabiensis was the main vector in six of the nine study sites, while An. gambiae sensu stricto was the most important vector in the other three sites. Clear differences in entomological inoculation rates (EIR) were observed between the study sites, ranging from 0.1 infective bites per person per night in the sahelian zone of the country to 5.5 infective bites per person per night in the forest zone. Based on the observed behaviour of the vectors, insecticide-treated bed nets will be highly effective in controlling malaria. However, in the high transmission areas, additional measures will be needed to reduce the malaria burden to acceptable levels. PMID- 20206112 TI - Leptospirosis-associated disturbances of blood vessels, lungs and hemostasis. AB - The frequency of massive pulmonary hemorrhages seems to be increasing in different geographic areas; however, there is no clear explanation for this trend. Although data on the pathogenesis of such complications are scarce, recent research indicates a potential role of autoimmunity and/or multifactorial mechanisms. However, much information is already available on the disturbance of hemostasis and blood vessels in leptospirosis-related literature, even if some contradictory concepts coexist. The purpose of this review is to integrate both new and classical information from human and animal studies on severe pulmonary forms of leptospirosis and disorders of hemostasis and blood vessels. We propose that the involvement of blood vessels in leptospirosis must be understood as a sepsis-like, diffuse process of endothelial activation/damage rather than as a classical systemic vasculitis. Pulmonary hemorrhages are most likely multifactorial and there has recently been evidence against the role of autoimmunity; however, further investigation of strain variations, exposure to hydrocarbons and association with renal dysfunction is required. Thrombocytopenia is a consistent feature of leptospirosis but it is not clear whether it is attributable to sepsis-related mechanisms. In addition, further investigation is required to define whether platelet function is activated or inhibited during severe leptospirosis. PMID- 20206113 TI - Bartonella spp. infection in HIV positive individuals, their pets and ectoparasites in Rio de Janeiro, Brazil: serological and molecular study. AB - BACKGROUND: Bartonella is the agent of cat-scratch disease, but is also responsible for more severe conditions such as retinitis, meningoencephalitis, endocarditis and bacillary angiomatosis. Its seroprevalence is unknown in Brazil. METHODS: Patients in an AIDS clinic, asymptomatic at the time of the study, were enrolled prospectively. They answered a structured questionnaire and had blood taken for serological and molecular assays. Cat breeder's pets were tested serologically and collected ectoparasites were tested by molecular biology techniques. Blood donors, paired by age and sex, were tested for Bartonella IgG antibodies. RESULTS: 125 HIV positive patients with a median age of 34 were studied; 61 were male and 75% were on HAART. Mean most recent CD4 count was 351 500 cells/mm(3). A high rate of contact with ticks, fleas and lice was observed. Bartonella IgG seroreactivity rate was 38.4% in HIV positive individuals and breeding cats was closely associated with infection (OR 3.6, CI 1.1-11.9, p<0.05). No difference was found between the sexes. Titers were 1:32 in 39 patients, 1:64 in seven, 1:128 in one and 1:256 in one. In the control group, IgG seroreactivity to Bartonella spp. was 34%, and female sex was correlated to seropositivity. Fourteen of 61 (23%) males vs 29/64 (45.3%) females were seroreactive to Bartonella (OR 2.8, CI 1.2-6.5, p<0.01). Titers were 1:32 in 29 patients, 1:64 in ten and 1:128 in four. CONCLUSIONS: Bartonella spp. seroprevalence is high in HIV positive and in blood donors in Rio de Janeiro. This may be of public health relevance. PMID- 20206114 TI - Some statistical properties of differencing schemes for baseline correction of sedimentation velocity data. AB - For the detailed analysis of sedimentation velocity data, the consideration of radial-dependent baseline offsets is indispensable. Two main approaches are data differencing ("delta-c" approach) and explicit inclusion of baseline parameters in the model ("direct boundary model" of the raw data). The current work aims to clarify the relationships between the two approaches. To this end, a simple model problem is examined. We show that the explicit consideration of the baseline in the model is equivalent to a differencing scheme where the average value is subtracted from all data points. Pairwise differencing in the delta-c approach always results in higher parameter uncertainty. For equidistant time points, the increase is smallest when the reference points are taken at intervals of 1/3 or 2/3 of the total number of time points. If the difference data are misinterpreted to be statistically independent samples, errors in the calculation of the parameter uncertainties can occur. Contrary to claims in the literature, we observe that there is no distinction in the approaches regarding their "model dependence"; both approaches arise from the integral or differential form of the same model, and both approaches can and should provide explicit estimates of the baseline values in the original data space for optimal discrimination between macromolecular sedimentation models. PMID- 20206115 TI - Reversible Ponceau staining as a loading control alternative to actin in Western blots. AB - It is becoming standard practice to measure a housekeeping gene, typically actin, in Western blots, as it is the rule in RNA blots. We have applied reversible Ponceau staining to check equal loading of gels and measured actin in parallel under different conditions. Our results show that densitometric analysis is comparable with both techniques. Therefore, routine quantitation of Ponceau staining before antibody probing is validated as an alternative to actin blotting. PMID- 20206117 TI - Characterization of pertussis toxoid by two-dimensional liquid chromatography tandem mass spectrometry. AB - Pertussis toxoid, an acellular pertussis vaccine prepared by hydrogen peroxide treatment in the presence of Fe(3+), has not been well characterized. Because the toxoid has been a part of the DTaP vaccine for infants, it is of interest and significance to have a clear understanding of its structure. The five subunits of pertussis toxin (PT) have a combined molecular weight of approximately 95,000Da. The peroxide treatment in toxoid formation introduces additional complexity into the protein sequence. To maximize sequence coverage, a two-dimensional liquid chromatography-tandem mass spectrometry (2D LC-MS/MS) approach was used to analyze the tryptic digest of toxoid as a whole. An analytical-scale high performance liquid chromatography (HPLC) instrument using a pentafluorophenyl (PFP) column was used as the first-dimensional LC for fraction collection. The fractions were then analyzed by nanoLC-MS/MS using a C18 column to acquire collision-activated dissociation (CAD) spectra of the tryptic peptides. It is shown that a PFP column has a different peptide retention specificity from a C18 column. A combination of a PFP column and a C18 column is a viable approach for dispersing peptides in a complex mixture. From the structures of 65 peptides that represented approximately 50% of its sequence, PT was found to have sustained heavy oxidative damages during toxoid preparation. Nearly all methionine, cysteine, and (likely) tryptophan residues were oxidized. Evidence of histidine and tyrosine oxidation was also observed. In addition, a large percentage of asparagine was found hydrolyzed to aspartic acid. These findings corrrelate well with the reduction of PT toxicity by peroxide treatment. PMID- 20206116 TI - Stereoselective binding of chiral ligands to single nucleotide polymorphisms of the human organic cation transporter-1 determined using cellular membrane affinity chromatography. AB - Membranes from stably transfected cell lines that express two point mutations of the human organic cation transporter-1 (hOCT1), R488M and G465R, have been immobilized on the immobilized artificial membrane (IAM) liquid chromatographic stationary phase to form two cellular membrane affinity chromatography (CMAC) columns, CMAC(hOCT1(G465R)) and CMAC(hOCT1(R488M)). Columns were created using both stationary phases, and frontal displacement chromatography experiments were conducted using [(3)H] MMP(+) (1-methyl-4-phenylpyridinium) as the marker ligand and various displacers, including the single enantiomers of verapamil, fenoterol, and isoproterenol. The chromatographic data obtained were used to refine a previously developed pharmacophore for hOCT1. PMID- 20206118 TI - Zinc-imidazole negative staining of chromosomal-sized DNA molecules in agarose minigels. AB - We standardized the zinc-imidazole negative staining method for detecting chromosomal-sized DNA molecules separated by pulsed field minigel electrophoresis. The best experimental conditions were as follows: separating large DNA molecules in minigels of 0.4 cm thickness, further incubating them with 40 mM ZnSO4 solution, and finally incubating them with 0.1 and 2 M imidazole solutions successively. The lowest yeast cells/miniplug useful in DNA band detection was 3 x 10(7) cells, as occurred with ethidium bromide-stained minigel. Electrophoresis patterns were visualized as colorless bands contrasting against a white background after illuminating the minigel with white light. This negative staining method is nontoxic and preserves the chemical integrity of the DNA molecules. PMID- 20206119 TI - Detection of femtomole quantities of mature cathepsin K with zymography. AB - Cathepsin K, the most potent mammalian collagenase, has been implicated in osteoporosis, cancer metastasis, atherosclerosis, and arthritis. Although procathepsin K is stable and readily detected, the active mature cathepsin K eludes detection by in vitro methods due to its shorter half-life and inactivation at neutral pH. We describe, for the first time, reliable detection, visualization, and quantification of mature cathepsin K to femtomole resolution using gelatin zymography. The specificity of the method was validated with cathepsin K knockdown using small interfering RNA (siRNA) transfection of human monocyte-derived macrophages, and enzymatic activity confirmed with benzyloxycarbonyl-glycine-proline-arginine-7-amino-4-methylcoumarin (Z-GPR-AMC) substrate hydrolysis was fit to a computational model of enzyme kinetics. Furthermore, cathepsin K zymography was used to show that murine osteoclasts secrete more cathepsin K than is stored intracellularly, and this was opposite to the behavior of the macrophages from which they were differentiated. In summary, this inexpensive, species-independent, antibody-free protocol describes a sensitive method with broad potential to elucidate previously undetectable cathepsin K activity. PMID- 20206120 TI - Detection of residual toxin in tissues of ricin-poisoned mice by sandwich enzyme linked immunosorbent assay and immunoprecipitation. AB - This work aimed to evaluate a method to detect the residual ricin in animal tissues. Immunoprecipitation and sandwich enzyme-linked immunosorbent assay (ELISA) were used to detect ricin in the tissues of intoxicated mice. The monoclonal antibodies (Mabs) 4C13 and 3D74 were used to assay the whole ricin molecules via sandwich ELISA. Mab 4C13 was conjugated with Sepharose 4B to capture ricin or ricin A chain by immunoprecipitation. Mice injected intravenously with ricin at the dosage of 5 microg/mouse were killed at different time points after intoxication. The serum, liver, kidney, lung, and intestine were harvested. High levels of ricin were found in serum and liver samples at each poisoning time point by sandwich ELISA, suggesting the possibility of determining ricin intoxication by detecting residual ricin in the serum. However, this method turned out to be ineffective for examining ricin in the kidney, lung, and intestine of poisoned mice. Although the same tissue samples of intoxicated mice were analyzed by immunoprecipitation, positive bands were found. This indicated that some components in the kidney, lung, and intestine could bind with ricin and interfere in its binding activity with the coated antibody. Immunoprecipitation could be used to measure the existence of ricin in these samples. PMID- 20206122 TI - Substitution of chloride by bromide modifies the low-temperature tyrosine Z oxidation in active photosystem II. AB - Chloride is an essential cofactor for photosynthetic water oxidation. However, its location and functional roles in active photosystem II are still a matter of debate. We have investigated this issue by studying the effects of Cl- replacement by Br- in active PSII. In Br- substituted samples, Cl- is effectively replaced by Br- in the presence of 1.2 M NaBr under room light with protection of anaerobic atmosphere followed by dialysis. The following results have been obtained. i) The oxygen-evolving activities of the Br--PSII samples are significantly lower than that of the Cl--PSII samples; ii) The same S2 multiline EPR signals are observed in both Br- and Cl--PSII samples; iii) The amplitudes of the visible light induced S1TyrZ* and S2TyrZ* EPR signals are significantly decreased after Br- substitution; the S1TyrZ* EPR signal is up-shifted about 8G, whereas the S2TyrZ* signal is down-shifted about 12 G after Br- substitution. These results imply that the redox properties of TyrZ and spin interactions between TyrZ* and Mn-cluster could be significantly modified due to Br- substitution. It is suggested that Cl-/Br- probably coordinates to the Ca2+ ion of the Mn-cluster in active photosystem II. PMID- 20206121 TI - Thirty years of heme peroxidase structural biology. AB - The following is a brief review of peroxidase structural biology since the initial structure determination of cytochrome c peroxidase (CCP) 30 years ago. An emphasis will be placed on what CCP has taught us about peroxidase mechanisms, especially Compound I formation and electron transfer. PMID- 20206123 TI - Oscillations in energy metabolism. AB - Organisation of mitochondrial metabolism is a quintessential example of a complex dissipative system which can display dynamic instabilities. Several findings have indicated that the conditions inducing instabilities are within the physiological range and that mild perturbations could elicit oscillations. Different mathematical models have been put forth in order to explain the genesis of oscillations in energy metabolism. One model considers mitochondria as an organised network of oscillators and indicates that communication between mitochondria involves mitochondrial reactive oxygen species (ROS) production acting as synchronisers of the energy status of the whole population of mitochondria. An alternative model proposes that extramitochondrial pH variations could lead to mitochondrial oscillations. Oscillatory phenomena in energy metabolism have also been investigated in vivo on the basis of 31P magnetic resonance spectroscopy (MRS) measurements of phosphocreatine post-exercise recovery in human and animal skeletal muscle. The corresponding results provide experimental evidences about the role exerted by cytosolic pH on oscillations. Finally a new simple non-linear mathematical model describing the overall chemical reaction of phosphocreatine recovery predicting oscillatory recovery pattern under certain experimental conditions is presented and discussed in the light of the experimental results reported so far. PMID- 20206124 TI - Absence of uncoupling protein-3 leads to greater activation of an adenine nucleotide translocase-mediated proton conductance in skeletal muscle mitochondria from calorie restricted mice. AB - Calorie restriction (CR), without malnutrition, consistently increases lifespan in all species tested, and reduces age-associated pathologies in mammals. Alterations in mitochondrial content and function are thought to underlie some of the effects of CR. Previously, we reported that rats subjected to variable durations of 40% CR demonstrated a rapid and sustained decrease in maximal leak dependent respiration in skeletal muscle mitochondria. This was accompanied by decreased mitochondrial reactive oxygen species generation and increased uncoupling protein-3 protein (UCP3) expression. The aim of the present study was to determine the contribution of UCP3, as well as the adenine nucleotide translocase to these functional changes in skeletal muscle mitochondria. Consistent with previous findings in rats, short-term CR (2 weeks) in wild-type (Wt) mice resulted in a lowering of the maximal leak-dependent respiration in skeletal muscle mitochondria, without any change in proton conductance. In contrast, skeletal muscle mitochondria from Ucp3-knockout (KO) mice similarly subjected to short-term CR showed no change in maximal leak-dependent respiration, but displayed an increased proton conductance. Determination of ANT activity (by measurement of inhibitor-sensitive leak) and protein expression revealed that the increased proton conductance in mitochondria from CR Ucp3-KO mice could be entirely attributed to a greater acute activation of ANT. These observations implicate UCP3 in CR-induced mitochondrial remodeling. Specifically, they imply the potential for an interaction, or some degree of functional redundancy, between UCP3 and ANT, and also suggest that UCP3 can minimize the induction of the ANT-mediated 'energy-wasting' process during CR. PMID- 20206125 TI - Examination of adipose depot-specific PPAR moieties. AB - Molecular mechanisms of peroxisome proliferator activated receptors (PPARs) are being defined rapidly, as illustrated by the volume of papers published. Much of the research is directed towards a clinical end-point/application; however, the non-homogeneous nature of adipose depots in laboratory animals is spurring similar research in domestic meat animals (such as beef cattle). Moreover, the size of adipose depots in meat animals remains an attractive feature for using them to obtain cells for PPAR research. Examination of meat-animal depot-specific PPAR moieties may provide novel information about adipocyte regulation that might be extrapolated to all animals. PMID- 20206126 TI - Cardiac glycosides potently inhibit C-reactive protein synthesis in human hepatocytes. AB - Elevated plasma levels of C-reactive protein (CRP), the prototype acute-phase protein (APP), are predictive for future cardiovascular events. Controversial evidence suggests that CRP may play a causal role in cardiovascular disease. CRP synthesis inhibition is a potential approach for reducing cardiovascular mortality. We show here that endogenous and plant-derived inhibitors of the Na(+)/K(+)-ATPase, i.e. the cardiac glycosides ouabain and digitoxin, inhibit IL 1beta- and IL-6-induced APP expression in human hepatoma cells and primary human hepatocytes (PHH) at nanomolar concentrations. Inhibition is demonstrated on transcriptional and on protein level. The molecular target of cardiac glycosides, i.e. the alpha1 subunit of the Na(+)/K(+)-ATPase, is strongly expressed in human hepatocytes. Inhibition of APP synthesis correlates with the potency of cardiac glycosides at the Na(+)/K(+)-ATPase. The trigger for APP expression inhibition is an increase in intracellular calcium since the calcium ionophore calcimycin is also active. Qualified specificity of oubain for hepatocellular APP synthesis inhibition is demonstrated by lack of effectivity on IL-1beta-induced IL-6 release from primary human coronary artery smooth muscle cells. The inhibitory activity of cardiac glycosides on CRP expression may have important implications for the treatment of cardiovascular disease. Cardiac glycosides may be used for CRP synthesis inhibition in the future. PMID- 20206127 TI - Sp7/Osterix up-regulates the mouse pro-alpha3(V) collagen gene (Col5a3) during the osteoblast differentiation. AB - Type V collagen is a quantitatively minor collagen, but acts as critical regulator of fibril formation in the extracellular matrix. The purpose of this study is to clarify the mechanism responsible for the transcriptional regulation of the mouse Col5a3 gene in osteoblastic cells. Sp7/Osterix is a transcription factor specifically expressed by osteoblasts and is important for osteoblast differentiation. The overexpression of Sp7/Osterix significantly increased the promoter activity and the endogenous mRNA level of the Col5a3 gene in osteoblastic cells. Conversely, a reduction of Sp7/Osterix by siRNA treatment decreased the promoter activity and the endogenous mRNA level of the Col5a3 gene. A CHIP assay confirmed that Sp7/Osterix interacted with the Col5a3 core promoter in vivo at the Sp1 binding site. The data from the experiments using the osteoblast differentiation model and the co-overexpression of Sp7/Osterix with Sp1 suggest that Sp7/Osterix promotes the expression of the collagen gene, Col5a3, and thereby playing a role in bone formation. PMID- 20206128 TI - Bis(monoacylglycero)phosphate and ganglioside GM1 spontaneously form small homogeneous vesicles at specific concentrations. AB - The morphology and size of hydrated lipid dispersions of bis(monoacylglycero)phosphate (BMP) mixed with varying mole percentages of the ganglioside GM1 were investigated by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Electron paramagnetic resonance (EPR) spectroscopy of these same mixtures, doped at 0.5 mol% with doxyl labeled lipids, was used to investigate acyl-chain packing. Results show that for 20-30% GM1, hydrated BMP:GM1 mixtures spontaneously form small spherical vesicles with diameters approximately 100 nm and a narrow size distribution profile. For other concentrations of GM1, hydrated dispersions with BMP have non-spherical shapes and heterogeneous size profiles, with average vesicle diameters>400 nm. All samples were prepared at pH 5.5 to mimic the lumen acidity of the late endosome where BMP is an essential component of intraendosomal vesicle budding, lipid sorting and trafficking. These findings indicate that GM1 and BMP under a limited concentration range spontaneously form small vesicles of homogeneous size in an energy independent manner without the need of protein templating. Because BMP is essential for intraendosomal vesicle formation, these results imply that lipid lipid interactions may play a critical role in the endosomal process of lipid sorting and trafficking. PMID- 20206129 TI - Location of the analgesic domain in Scorpion toxin BmK AGAP by mutagenesis of disulfide bridges. AB - An increasing number of analgesic peptides have been found in the tail toxicyst, but there has been little research into their analgesic domains. Where are the analgesic domains in a conservative betaalphabetabeta topology conformation of the analgesic peptides? We have carried out research to address this question. On account of the importance of disulfide bonds in the study of protein structure, the conformational stability, catalytic activity and folding, and site-directed mutagenesis in disulfide bridges have been used to look for the analgesic domain in a mature antitumor-analgesic peptide from the venom of the Chinese scorpion Buthus martensii Karsch (BmK AGAP). The mouse-twisting assay was used to examine the analgesic activity of 12 mutants, in which two mutants (C22S, C46S) and (C16S, C36S), exhibited lower relative activity. Following the conformational analysis, one domain, called the "core domain", was found to be the key to the analgesic activity. PMID- 20206130 TI - Regulatory CD8+ T cells induced by exposure to all-trans retinoic acid and TGF beta suppress autoimmune diabetes. AB - Antigen-specific regulatory CD4(+) T cells have been described but there are few reports on regulatory CD8(+) T cells. We generated islet-specific glucose-6 phosphatase catalytic subunit-related protein (IGRP)-specific regulatory CD8(+) T cells from 8.3-NOD transgenic mice. CD8(+) T cells from 8.3-NOD splenocytes were cultured with IGRP, splenic dendritic cells (SpDCs), TGF-beta, and all-trans retinoic acid (ATRA) for 5days. CD8(+) T cells cultured with either IGRP alone or IGRP and SpDCs in the absence of TGF-beta and ATRA had low Foxp3(+) expression (1.7+/-0.9% and 3.2+/-4.5%, respectively). In contrast, CD8(+) T cells induced by exposure to IGRP, SpDCs, TGF-beta, and ATRA showed the highest expression of Foxp3(+) in IGRP-reactive CD8(+) T cells (36.1+/-10.6%), which was approximately 40-fold increase compared with that before induction culture. CD25 expression on CD8(+) T cells cultured with IGRP, SpDCs, TGF-beta, and ATRA was only 7.42%, whereas CD103 expression was greater than 90%. These CD8(+) T cells suppressed the proliferation of diabetogenic CD8(+) T cells from 8.3-NOD splenocytes in vitro and completely prevented diabetes onset in NOD-scid mice in cotransfer experiments with diabetogenic splenocytes from NOD mice in vivo. Here we show that exposure to ATRA and TGF-beta induces CD8(+)Foxp3(+) T cells ex vivo, which suppress diabetogenic T cells in vitro and in vivo. PMID- 20206131 TI - Galectin-9 induces osteoblast differentiation through the CD44/Smad signaling pathway. AB - Galectin-9 is a beta-galactoside-binding lectin expressed in various tissues. It binds various glycoconjugates and modulates a variety of biological functions in various cell types. Although galectin-9 is expressed in bone, its function in human osteoblasts remains unclear. We demonstrate that galectin-9 induces osteoblast differentiation through the CD44/Smad signaling pathway in the absence of bone morphogenetic proteins (BMPs). Galectin-9 increases alkaline phosphatase activities in human osteoblasts and induces the phosphorylation of Smad1/5/8 and translocation of Smad4 to the nucleus in the absence of BMPs. Galectin-9 also induces binding of Smad4 to the Id1 promoter and increases its activity. Anti CD44 antibody inhibits Smad1/5/8 phosphorylation by galectin-9. Galectin-9 binds to CD44 and induces the formation of a CD44/BMP receptor complex. Because Smad1 is phosphorylated by BMP receptors, we propose that formation of the CD44/BMP receptor complex induced by galectin-9 may provide a trigger for the activation of Smads. PMID- 20206132 TI - Development of a rapid culture method to induce adipocyte differentiation of human bone marrow-derived mesenchymal stem cells. AB - Human mesenchymal stem cells (hMSCs) derived from bone marrow are multipotent stem cells that can regenerate mesenchymal tissues such as adipose, bone or muscle. It is thought that hMSCs can be utilized as a cell resource for tissue engineering and as human models to study cell differentiation mechanisms, such as adipogenesis, osteoblastogenesis and so on. Since it takes 2-3weeks for hMSCs to differentiate into adipocytes using conventional culture methods, the development of methods to induce faster differentiation into adipocytes is required. In this study we optimized the culture conditions for adipocyte induction to achieve a shorter cultivation time for the induction of adipocyte differentiation in bone marrow-derived hMSCs. Briefly, we used a cocktail of dexamethasone, insulin, methylisobutylxanthine (DIM) plus a peroxisome proliferator-activated receptor gamma agonist, rosiglitazone (DIMRo) as a new adipogenic differentiation medium. We successfully shortened the period of cultivation to 7-8days from 2-3weeks. We also found that rosiglitazone alone was unable to induce adipocyte differentiation from hMSCs in vitro. However, rosiglitazone appears to enhance hMSC adipogenesis in the presence of other hormones and/or compounds, such as DIM. Furthermore, the inhibitory activity of TGF-beta1 on adipogenesis could be investigated using DIMRo-treated hMSCs. We conclude that our rapid new culture method is very useful in measuring the effect of molecules that affect adipogenesis in hMSCs. PMID- 20206133 TI - DEAD-box helicases: posttranslational regulation and function. PMID- 20206134 TI - TREP_DB: transcriptional regulatory elements pattern database. AB - Predicting and assigning functions for putative genes and hypothetical proteins are important goals in the post-genomic era. Many methods have been developed for this challenge, among which the straightforward way is function prediction using sequence homology. Homology-based function prediction applies sequence-alignment tools to find homology relationships between functions of known genes and putative genes, and transfers the most similar functions of known genes to putative genes. This approach fails completely for about 30% of genes, and only 3% have any supporting experimental evidence. According to supporting evidence, genes are known to be regulated by a common transcriptional regulatory element if the expression profiles of the coregulated genes are highly correlated. We propose a new conceptual approach and method for nonhomology-based function prediction methods for putative genes and hypothetical proteins. We have established patterns, also considered to be combinations, of common transcriptional regulatory elements for functional classes of mouse (Mus musculus) transcripts (the TREP_DB). Using these results, we have also established a function-prediction method for putative genes and hypothetical proteins. PMID- 20206135 TI - Glucose-induced expression of MIP-1 genes requires O-GlcNAc transferase in monocytes. AB - O-glycosylation has emerged as an important modification of nuclear proteins, and it appears to be involved in gene regulation. Recently, we have shown that one of the histone methyl transferases (MLL5) is activated through O-glycosylation by O GlcNAc transferase (OGT). Addition of this monosaccharide is essential for forming a functional complex. However, in spite of the abundance of OGT in the nucleus, the impact of nuclear O-glycosylation by OGT remains largely unclear. To address this issue, the present study was undertaken to test the impact of nuclear O-glycosylation in a monocytic cell line, THP-1. Using a cytokine array, MIP-1alpha and -1beta genes were found to be regulated by nuclear O glycosylation. Biochemical purification of the OGT interactants from THP-1 revealed that OGT is an associating partner for distinct co-regulatory complexes. OGT recruitment and protein O-glycosylation were observed at the MIP-1alpha gene promoter; however, the known OGT partner (HCF-1) was absent when the MIP-1alpha gene promoter was not activated. From these findings, we suggest that OGT could be a co-regulatory subunit shared by functionally distinct complexes supporting epigenetic regulation. PMID- 20206136 TI - Camptothecin disrupts androgen receptor signaling and suppresses prostate cancer cell growth. AB - The androgen receptor (AR) is the main therapeutic target for treatment of metastatic prostate cancers. The present study demonstrates that the topoisomerase I inhibitor camptothecin selectively inhibits androgen-responsive growth of prostate cancer cells. Camptothecin strikingly inhibited mutated and wild-type AR protein expression in LNCaP and PC-3/AR cells. This inhibition coincided with decreased androgen-mediated AR phosphorylation at Ser(81) and reduced androgen-mediated AR transcriptional activity in a dose-dependent manner. Additionally, camptothecin disrupted the association between AR and heat shock protein 90 and impeded binding of the synthetic androgen [3H]R1881 to AR in LNCaP cells. Camptothecin also blocked androgen-induced AR nuclear translocation, leading to downregulation of the AR target gene PSA. In addition to decreasing the intracellular and secreted prostate-specific antigen (PSA) levels, camptothecin markedly inhibited androgen-stimulated PSA promoter activity. Collectively, our data reveal that camptothecin not only serves as a traditional genotoxic agent but, by virtue of its ability to target and disrupt AR, may also be a novel candidate for the treatment of prostate cancer. PMID- 20206137 TI - Functionally selective cannabinoid receptor signalling: therapeutic implications and opportunities. AB - The CB(1) and CB(2) cannabinoid receptors are G protein-coupled receptors (GPCRs) recognized by a variety of endogenous ligands and activating multiple signalling pathways. This multiplicity of ligands and intracellular transduction mechanisms supports a complex control of physiological functions by the endocannabinoid system, but requires a finely tuned regulation of the signalling events triggered on receptor activation. Here we review the diverse signalling pathways activated by the cannabinoid receptors and discuss the mechanisms allowing for specificity in the associated functional responses triggered by endogenous or exogenous ligands. At variance with the classical concept that all agonists at a given GPCR induce a similar repertoire of downstream events in all tissues, we also summarize the experimental evidence supporting the existence of functional selectivity and protean agonism at cannabinoid receptors. By placing emphasis on the ligand- or constitutive activity-dependent specifications of receptor-G protein coupling, these concepts explain how distinct cannabinoid ligands may activate specific downstream mediators. Finally, although both the diversity and specificity in cannabinoid signalling are now established in vitro, few data are available from in vivo studies. Therefore, we conclude this review by examining the experimental evidence supporting the physiological relevance of this complexity in the cannabinoid system. The ability to selectively manipulate physiological functions, through activation of defined signalling cascades, will in all likelihood help in the development of efficacious and safe cannabinoid based therapeutics for a variety of indications. PMID- 20206138 TI - Falcarinol is a covalent cannabinoid CB1 receptor antagonist and induces pro allergic effects in skin. AB - The skin irritant polyyne falcarinol (panaxynol, carotatoxin) is found in carrots, parsley, celery, and in the medicinal plant Panax ginseng. In our ongoing search for new cannabinoid (CB) receptor ligands we have isolated falcarinol from the endemic Sardinian plant Seseli praecox. We show that falcarinol exhibits binding affinity to both human CB receptors but selectively alkylates the anandamide binding site in the CB(1) receptor (K(i)=594nM), acting as covalent inverse agonist in CB(1) receptor-transfected CHO cells. Given the inherent instability of purified falcarinol we repeatedly isolated this compound for biological characterization and one new polyyne was characterized. In human HaCaT keratinocytes falcarinol increased the expression of the pro-allergic chemokines IL-8 and CCL2/MCP-1 in a CB(1) receptor-dependent manner. Moreover, falcarinol inhibited the effects of anandamide on TNF-alpha stimulated keratinocytes. In vivo, falcarinol strongly aggravated histamine-induced oedema reactions in skin prick tests. Both effects were also obtained with the CB(1) receptor inverse agonist rimonabant, thus indicating the potential role of the CB(1) receptor in skin immunopharmacology. Our data suggest anti-allergic effects of anandamide and that falcarinol-associated dermatitis is due to antagonism of the CB(1) receptor in keratinocytes, leading to increased chemokine expression and aggravation of histamine action. PMID- 20206139 TI - Effects of monoamine oxidase inhibitor and cytochrome P450 2D6 status on 5 methoxy-N,N-dimethyltryptamine metabolism and pharmacokinetics. AB - 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a natural psychoactive indolealkylamine drug that has been used for recreational purpose. Our previous study revealed that polymorphic cytochrome P450 2D6 (CYP2D6) catalyzed 5-MeO-DMT O-demethylation to produce active metabolite bufotenine, while 5-MeO-DMT is mainly inactivated through deamination pathway mediated by monoamine oxidase (MAO). This study, therefore, aimed to investigate the impact of CYP2D6 genotype/phenotype status and MAO inhibitor (MAOI) on 5-MeO-DMT metabolism and pharmacokinetics. Enzyme kinetic studies using recombinant CYP2D6 allelic isozymes showed that CYP2D6.2 and CYP2D6.10 exhibited 2.6- and 40-fold lower catalytic efficiency (V(max)/K(m)), respectively, in producing bufotenine from 5 MeO-DMT, compared with wild-type CYP2D6.1. When co-incubated with MAOI pargyline, 5-MeO-DMT O-demethylation in 10 human liver microsomes showed significantly strong correlation with bufuralol 1'-hydroxylase activities (R(2)=0.98; P<0.0001) and CYP2D6 contents (R(2)=0.77; P=0.0007), whereas no appreciable correlations with enzymatic activities of other P450 enzymes. Furthermore, concurrent MAOI harmaline sharply reduced 5-MeO-DMT depletion and increased bufotenine formation in human CYP2D6 extensive metabolizer hepatocytes. In vivo studies in wild-type and CYP2D6-humanized (Tg-CYP2D6) mouse models showed that Tg-CYP2D6 mice receiving the same dose of 5-MeO-DMT (20mg/kg, i.p.) had 60% higher systemic exposure to metabolite bufotenine. In addition, pretreatment of harmaline (5mg/kg, i.p.) led to 3.6- and 4.4-fold higher systemic exposure to 5-MeO-DMT (2mg/kg, i.p.), and 9.9- and 6.1-fold higher systemic exposure to bufotenine in Tg-CYP2D6 and wild-type mice, respectively. These findings indicate that MAOI largely affects 5-MeO-DMT metabolism and pharmacokinetics, as well as bufotenine formation that is mediated by CYP2D6. PMID- 20206140 TI - New molecular targets for the treatment of osteoarthritis. AB - Osteoarthritis (OA) is a chronic degenerative joint disorder characterized by destruction of the articular cartilage, subchondral bone alterations and synovitis. Current treatments are focused on symptomatic relief but they lack efficacy to control the progression of this disease which is a leading cause of disability. Therefore, the development of effective disease-modifying drugs is urgently needed. Different initiatives are in progress to define the molecular mechanisms involved in the initiation and progression of OA. These studies support the therapeutic potential of pathways relevant in joint metabolism such as Wnt/beta-catenin, discoidin domain receptor 2 or proteinase-activated receptor 2. The dysregulation in cartilage catabolism and subchondral bone remodeling could be improved by selective inhibitors of matrix metalloproteinases, aggrecanases and other proteases. Another approach would favor the activity of anabolic processes by using growth factors or regulatory molecules. Recent studies have also revealed the role of oxidative stress and synovitis in the progression of this disease, supporting the development of a number of inhibitory strategies. Novel targets in OA are represented by genes involved in OA pathophysiology discovered using gene network, epigenetic and microRNA approaches. Further insights into the molecular mechanisms involved in OA initiation and progression may lead to the development of new therapies able to control joint destruction and repair. PMID- 20206141 TI - Sequential treatment with flavopiridol synergistically enhances pyrrolo-1,5 benzoxazepine-induced apoptosis in human chronic myeloid leukaemia cells including those resistant to imatinib treatment. AB - The Bcr-Abl kinase inhibitor, imatinib mesylate, is the front line treatment for chronic myeloid leukaemia (CML), but the emergence of imatinib resistance has led to the search for alternative drug treatments and the examination of combination therapies to overcome imatinib resistance. The pro-apoptotic PBOX compounds are a recently developed novel series of microtubule targeting agents (MTAs) that depolymerise tubulin. Recent data demonstrating enhanced MTA-induced tumour cell apoptosis upon combination with the cyclin dependent kinase (CDK)-1 inhibitor flavopiridol prompted us to examine whether this compound could similarly enhance the effect of the PBOX compounds. We thus characterised the apoptotic and cell cycle events associated with combination therapy of the PBOX compounds and flavopiridol and results showed a sequence dependent, synergistic enhancement of apoptosis in CML cells including those expressing the imatinib-resistant T315I mutant. Flavopiridol reduced the number of polyploid cells formed in response to PBOX treatment but only to a small extent, suggesting that inhibition of endoreplication was unlikely to play a major role in the mechanism by which flavopiridol synergistically enhanced PBOX-induced apoptosis. The addition of flavopiridol following PBOX-6 treatment did however result in an accelerated exit from the G2/M transition accompanied by an enhanced downregulation and deactivation of the CDK1/cyclin B1 complex and an enhanced degradation of the inhibitor of apoptosis protein (IAP) survivin. In conclusion, results from this study highlight the potential of these novel series of PBOX compounds, alone or in sequential combination with flavopiridol, as an effective therapy against CML. PMID- 20206142 TI - Endogenous N-acyl-dopamines induce COX-2 expression in brain endothelial cells by stabilizing mRNA through a p38 dependent pathway. AB - Cerebral microvascular endothelial cells play an active role in maintaining cerebral blood flow, microvascular tone and blood brain barrier (BBB) functions. Endogenous N-acyl-dopamines like N-arachidonoyl-dopamine (NADA) and N-oleoyl dopamine (OLDA) have been recently identified as a new class of brain neurotransmitters sharing endocannabinoid and endovanilloid biological activities. Endocannabinoids are released in response to pathogenic insults and may play an important role in neuroprotection. In this study we demonstrate that NADA differentially regulates the release of PGE(2) and PGD(2) in the microvascular brain endothelial cell line, b.end5. We found that NADA activates a redox-sensitive p38 MAPK pathway that stabilizes COX-2 mRNA resulting in the accumulation of the COX-2 protein, which depends on the dopamine moiety of the molecule and that is independent of CB(1) and TRPV1 activation. In addition, NADA inhibits the expression of mPGES-1 and the release of PGE(2) and upregulates the expression of L-PGD synthase enhancing PGD(2) release. Hence, NADA and other molecules of the same family might be included in the group of lipid mediators that could prevent the BBB injury under inflammatory conditions and our findings provide new mechanistic insights into the anti-inflammatory activities of NADA in the central nervous system and its potential to design novel therapeutic strategies to manage neuroinflammatory diseases. PMID- 20206143 TI - Dihydroartemisinin accelerates c-MYC oncoprotein degradation and induces apoptosis in c-MYC-overexpressing tumor cells. AB - Artemisinin and its derivatives (ARTs) are effective antimalarial drugs and also possess profound anticancer activity. However, the mechanism accounted for its distinctive activity in tumor cells remains unelucidated. We computed Pair wise Pearson correlation coefficients to identify genes that show significant correlation with ARTs activity in NCI-55 cell lines using data obtained from studies with HG-U133A Affymetrix chip. We found c-myc is one of the genes that showed the highest positive correlation coefficients among the probe sets analyzed (r=0.585, P<0.001). Dihydroartemisinin (DHA), the main active metabolite of ARTs, induced significant apoptosis in HL-60 and HCT116 cells that express high levels of c-MYC. Stable knockdown of c-myc abrogated DHA-induced apoptosis in HCT116 cells. Conversely, forced expression of c-myc in NIH3T3 cells sensitized these cells to DHA-induced apoptosis. Interestingly, DHA irreversibly down-regulated the protein level of c-MYC in DHA-sensitive HCT116 cells, which is consistent to persistent G1 phase arrest induced by DHA. Further studies demonstrated that DHA accelerated the degradation of c-MYC protein and this process was blocked by pretreatment with the proteasome inhibitor MG-132 or GSK 3beta inhibitor LiCl in HCT116 cells. Taken together, ARTs might be useful in the treatment of c-MYC-overexpressing tumors. We also suggest that c-MYC may potentially be a biomarker candidate for prediction of the antitumor efficacies of ARTs. PMID- 20206144 TI - Remarkable interference with telomeric function by a G-quadruplex selective bisantrene regioisomer. AB - The use of small molecules able to induce and stabilize selected G-quadruplex arrangements can cause telomerase inhibition and telomere dysfunction in cancer cells, thus providing very selective therapeutic approaches. Effective stabilizers usually comprise a planar aromatic portion to grant effective stacking onto the G-quartet and positively charged side chains to exploit the highly negative charge density on the quadruplex grooves. Since the relative position of these two pharmacophoric moieties is expected to play an important role in DNA folding stabilization, we evaluated a series of anthracene derivatives substituted with one or two 4,5-dihydro-1H-imidazol-2-yl-hydrazonic groups (the bisantrene side chain) at different positions of the aromatic system. Indeed, the various regioisomers showed distinct binding affinities for telomeric G-quadruplex, and the most effective was the 1,5 and 1,7 bis-substituted analogues. On turn, the 1,8 regioisomer was poorly effective. Interestingly, G quadruplex binding is clearly related to telomerase inhibition in this class of compounds, thus confirming their ability to shift the nucleic acid conformational equilibrium upon binding and consequently produce interference with the telomere processing enzyme. Additionally, the 1,5 regioisomer was shown to inhibit telomerase activity at lower concentrations than those required to reduce tumor cell proliferation. Comparative analysis of drug effects in telomerase-positive and telomerase-negative cancer cells showed consistent cell growth impairment, as a consequence of activation of the senescence pathway, which was mainly attributable to anthracene-mediated telomere dysfunction. PMID- 20206145 TI - The kappa-opioid receptor is upregulated in the spinal cord and locus ceruleus but downregulated in the dorsal root ganglia of morphine tolerant rats. AB - As a non-selective agonist of opioid receptors, morphine can also act on the kappa-opioid receptor (KOR) when activating the mu-opioid receptor (MOR) and delta-opioid receptor (DOR). Although previous findings indicate that KOR plays an important role in morphine analgesia and antinociceptive tolerance, the reasons for the paradoxical functions of KOR in analgesia and anti-analgesia responses are still unclear. The aim of this study was to explore the role of the KOR in morphine analgesia and antinociceptive tolerance. As such, the changes in KOR expression in different regions of the nervous system in morphine tolerant rats were examined. We were able to attain morphine tolerance in rats via subcutaneous injection of morphine (10 mg/kg) twice daily for 7-consecutive days. Competitive real-time PCR, immunohistochemistry, and Western blot analyses were used to assess KOR expression in related regions of the nervous system, including the thalamus, hypothalamus, hippocampus, locus ceruleus (LC), periaqueductal gray (PAG), lumber-sacral spinal cord, and dorsal root ganglia (DRG). The expression of KOR increased in the locus ceruleus and spinal cord, but was significantly decreased in the DRG of morphine tolerant rats (P<0.05). No other significant changes in KOR expression were observed in the other regions. Consequently, we propose that the locus ceruleus and spinal cord are likely the dominant CNS regions and the DRG is the main peripheral site in which chronic morphine exerts its effect on KOR. Prolonged morphine administration induces inconsistent changes of KOR in the central and peripheral nervous system. PMID- 20206146 TI - The phosphatidylinositol-3 kinase/Akt pathway mediates geranylgeranylacetone induced neuroprotection against cerebral infarction in rats. AB - Previous studies demonstrated the cytoprotective effect of geranylgeranylacetone (GGA), a heat shock protein inducer, against ischemic insult. Phosphatidylinositol-3 kinase/Akt (PI3K/Akt) is thought to be an important factor that mediates neuroprotection. However, the signaling pathways in the brain in vivo after oral GGA administration remain unclear. We measured and compared infarction volumes to investigate the effect of GGA on cerebral infarction induced by permanent middle cerebral artery occlusion in rats. We evaluated the effects of pretreatment with 5-hydroxydecanoate (5HD), a specific mitochondrial ATP-sensitive potassium (mitoK(ATP)) channel inhibitor; diazoxide (DZX), a selective mitoK(ATP) channel opener and wortmannin (Wort), a specific PI3K inhibitor of GGA-induced neuroprotection against infarction volumes. To clarify the relationship between PI3K/Akt activation and neuroprotection, we used immunoblot analysis to determine the amount of p-Akt proteins present after GGA administration with or without Wort treatment. Neuroprotective effects of GGA (pretreatment with a single oral GGA dose (800 mg/kg) 48 h before ischemia) were prevented by 5HD, DZX and Wort pretreatment, which indicates that the selective mitoK(ATP) channel and the PI3K/Akt pathway may mediate GGA-dependent protection. Oral GGA-induced p-Akt and GGA pretreatment enhanced ischemia-induced p-Akt, both of which were prevented by Wort pretreatment. These results suggest that a single oral dose of GGA induces p-Akt and that GGA plays an important role in neuroprotection against cerebral ischemia through the mitoK(ATP) channel opening. PMID- 20206147 TI - Theiler's murine encephalomyelitis virus preferentially infects immature stages of the murine oligodendrocyte precursor cell line BO-1 and blocks oligodendrocytic differentiation in vitro. AB - Theiler's murine encephalomyelitis virus (TMEV)-induced demyelination is an important animal model for multiple sclerosis. The presence of oligodendrocyte precursor cells (OPCs) within demyelinated lesions together with the limited extent of remyelination has raised the question of how OPCs are affected by TMEV. It is well established that oligodendrocytes, astrocytes and microglia are targets during the chronic phase of the disease. However, whether TMEV infection interferes with the capacity of OPCs to generate oligodendrocytes has remained unclear. In the present study, a bipotential murine OPC cell line termed BO-1 was used to determine the antigenic phenotype susceptible to TMEV and the impact of TMEV infection upon cell differentiation. We show here that retinoic acid increased oligodendrocytic differentiation and decreased proliferation and TMEV infection rates. TMEV under serum-free conditions infected about 75% and 60% of early OPCs (NG2(+) and A2B5(+)) and immature oligodendrocytes (CNPase(+)), respectively, but only approximately 18% of mature oligodendrocytes (MBP(+)). Infection with TMEV prior to application of retinoic acid significantly reduced the percentage of MBP(+) BO-1 cells. These data demonstrate that TMEV preferentially infects early stages of the oligodendrocytic lineage and blocks oligodendrocyte maturation. The first demonstration of TMEV-mediated effects on OPC differentiation may shed new light on the pathogenesis of TMEV-induced demyelination and offers an explanation for the limited remyelination observed in vivo. PMID- 20206148 TI - Ontogenesis and migration of metallothionein I/II-containing glial cells in the human telencephalon during the second trimester. AB - Metallothioneins (MT) belong to a widespread family of proteins characterized by a high metal content (mainly Cu(2+) and Zn(2+)) and by the presence of cysteine residues. The expression of metallothionein I-II (MT I/II), glial fibrillary acid protein (GFAP), and vimentin was examined in a series of 16 developing human brains of the second trimester. The brains of a stillborn/newborn individual and two postnatal individuals were studied for comparison. MT I/II-containing cells became consistently and clearly visible only from gestational week 21 onwards. On the other hand, several densely packed GFAP- and vimentin-containing elements were evident in the neuroepithelium at several periventricular locations and in the subventricular zone of all fetuses of the series. GFAP- and vimentin containing elements also entered the intermediate plate, but only a few elements were evident in the outer layers of the maturing cortex. The relatively late onset of MT I/II expression and their distribution are discussed in relation to the uptake of trace elements during the last trimester of pregnancy, and the role of astrocytes in neuronal guidance and maturation of cortical circuits. PMID- 20206149 TI - Directed neural lineage differentiation of adult hippocampal progenitor cells via modulation of hippocampal cholinergic neurostimulating peptide precursor expression. AB - Hippocampal cholinergic neurostimulating peptide (HCNP), originally purified from young rat hippocampus, has been known to promote the differentiation of septo hippocampal cholinergic neurons. Recently, the precursor protein of HCNP (HCNP pp) has also received attention as a multifunctional protein with roles, in addition to serving as the HCNP precursor, such as acting as an ATP-binding protein, a Raf kinase inhibitor protein (RKIP), and phosphatidylethanolamine binding protein (PEBP). In particular, the function of RKIP has attracted attention over several years for its role in controlling cellular proliferation and metastasis in cancer cells. HCNP-pp is also thought to be important in regulating the proliferation and differentiation of neuronal cells in vitro and in vivo by modification of the MAPK cascade. In the present study, we used cultured adult rat hippocampal progenitor cells (AHPs), which are thought to be important for memory formation, and focused on the role of HCNP-pp in adult neurogenesis, namely, the production of new neurons from neural stem/progenitor cells. We found that HCNP-pp expression in AHPs was closely associated with differentiation into MAP2ab-positive neurons and RIP-positive oligodendrocytes, but not into GFAP-positive astrocytes. By contrast, a down-regulated HCNP-pp expression in AHPs accompanied differentiation into GFAP-positive astrocytes. Direct manipulations of HCNP-pp via viral over-expression or siRNA downregulation further confirmed the HCNP-pp contribution to specific neural lineage commitment of AHPs. Our results show that the expression level of HCNP-pp acts as a key regulator for differentiation of cultured AHPs into specific neural lineages, indicating that the control of neural stem cell fate can be achieved via the HCNP pp pathway. PMID- 20206150 TI - Influence of 'feedback' signals on spatial integration in receptive fields of cat area 17 neurons. AB - 'Feedback' signals from mammalian extrastriate visual cortices are reported to exert primarily an excitatory influence on the classical receptive field (CRF) of neurons in the primary visual cortex (V1). However, given the much larger CRFs of neurons in extrastriate visual cortices it is not yet understood how feedback signals influence the spatial integration of visual signals by V1 neurons. To investigate this, we reversibly inactivated one of the 'form-processing' extrastriate visual cortices, the postero-temporal visual (PTV) cortex, and examined changes in responses of V1 neurons to drifting grating patches up to 28 degrees in diameter. We found that during inactivation of PTV cortex the magnitude of the responses to CRF-confined stimuli and that to large stimuli inducing maximum suppression (i.e. minimum responses) was significantly reduced, while the spatial extent of the CRF remained largely unaffected. As a result, the relative strength of the surround suppression increased marginally. This effect was apparent in both simple and complex cells. It was also strong and consistent in cells located in supragranular and infragranular layers. For those cells exhibiting some relief from surround suppression or 'counter-suppression' when large stimuli patches were applied, the effect on counter-suppression was heterogeneous. Overall, the relative integrated responses to the 28 degrees grating patches were also decreased when PTV cortex was inactivated. Thus, a substantial reduction in the CRF response and the largely unaffected spatial extent of the CRF as well as a weak surround effect observed in the present study are consistent with a multiplicative scaling effect. PMID- 20206152 TI - Structural characterization of the catalytic calcium-binding site in diisopropyl fluorophosphatase (DFPase)--comparison with related beta-propeller enzymes. AB - The calcium-dependent phosphotriesterase diisopropyl fluorophosphatase (DFPase) from the squid Loligo vulgaris efficiently hydrolyzes a wide range of organophosphorus nerve agents. The two calcium ions within DFPase play essential roles for its function. The lower affinity calcium ion located at the bottom of the active site participates in the reaction mechanism, while the high affinity calcium in the center of the protein maintains structural integrity of the enzyme. The activity and structures of three DFPase variants targeting the catalytic calcium-binding site are reported (D121E, N120D/N175D/D229N, and E21Q/N120D/N175D/D229N), and the effect of these mutations on the overall structural dynamics of DFPase is examined using molecular dynamics simulations. While D229 is crucial for enzymatic activity, E21 is essential for calcium binding. Although at least two negatively charged side chains are required for calcium binding, the addition of a third charge significantly lowers the activity. Furthermore, the arrangement of these charges in the binding site is important for enzymatic activity. These results, together with earlier mutational, structural, and kinetic studies, show a highly evolved calcium binding environment, with a specific electrostatic topology crucial for activity. A number of structural homologues of DFPase have been recently identified, including a chimeric variant of Paraoxonase 1 (PON1), drug resistance protein 35 (Drp35) from Staphylococcus aureus and the gluconolactonase XC5397 from Xanthomonas campestris. Surprisingly, despite low sequence identity, these proteins share remarkably similar calcium-binding environments to DFPase. PMID- 20206151 TI - Longitudinal characterization of white matter maturation during adolescence. AB - BACKGROUND: Late adolescence is comprised of considerable developmental transitions, though brain maturational changes during this period are subtle and difficult to quantitatively evaluate from standard brain imaging acquisitions. To date, primarily cross-sectional studies have characterized typical developmental changes during adolescence, but these processes need further description within a longitudinal framework. METHOD: To assess the developmental trajectory of typical white matter development, we examined 22 healthy adolescents with serial diffusion tensor images (DTI) collected at a mean age of 17.8 years and 16-months later. Diffusion parameters fractional anisotropy, and mean, radial, and axial diffusivity were subjected to whole-brain voxelwise time point comparisons using tract-based spatial statistics. RESULTS: At follow-up, adolescents showed a significant change (>or=153 contiguous voxels each at p<0.01) in diffusion properties, including in bilateral superior longitudinal fasciculi, superior corona radiata, anterior thalamic radiations, and posterior limb of the internal capsule. Overall, correlations with cognitive performances suggested behavioral improvement corresponding with white matter changes. CONCLUSION: These longitudinal DTI findings support continued microstructural change in white matter during late adolescence, and suggest ongoing refinement of projection and association fibers into early adulthood. PMID- 20206153 TI - How the cholinesterases got their modern names. AB - The classification of the cholinesterases into 'true' and 'pseudo' became obsolete when, some 60 years ago, the author and his co-workers showed that both enzymes had a broad specificity and differed mainly in their acyl group specificity. The importance of complementarity between enzyme and substrate was shown by the high rate of hydrolysis of carbon analogues of choline esters and this enabled pioneer studies of the intermolecular forces between the enzymes' active centres and their substrates to be carried out. PMID- 20206154 TI - Pseudo-catalytic scavenging: searching for a suitable reactivator of phosphorylated butyrylcholinesterase. AB - Butyrylcholinesterase is considered to be an endogenous stoichiometric bioscavenger of organophosphorus compounds (OPs), but due to limited concentration of BChE in the organism, stoichiometric reduction of OP is not always sufficient. This can be improved by creating a pseudo-catalytic scavenger adding oximes as reactivators of inhibited exogenous BChE. In order to improve the BChE bioscavenging function in tabun or paraoxon poisoning, we tested in vitro reactivation of phosphorylated human plasma BChE by bispyridinium oximes varying in the length and type of the linker between rings, and in the position of the oxime group on the ring. Among the tested oximes, the most potent reactivators of tabun-inhibited BChE were K117 [1,1'-(2,2'-oxybis(ethane-2,1 diyl))bis(4-hydroxyiminomethyl pyridinium) bromide] and K127 [4-carbamoyl-1-(2-(2 (4-(hydroxyiminomethyl) pyridinium-1-yl)ethoxy)ethyl)pyridinium bromide]. Reactivation by these oximes (1mM) reached about 50% of control activity after only 20 min; however, reactivation stopped at 70%. Reactivation of paraoxon inhibited BChE by all of the selected oximes was slow. Using molecular mechanics, we performed docking of the oximes to tabun-inhibited BChE in order to discuss possible structural modifications of bispyridinium oximes to improve reactivation of phosphorylated BChE. PMID- 20206155 TI - Multicenter evaluation of the first automated Elecsys sFlt-1 and PlGF assays in normal pregnancies and preeclampsia. AB - OBJECTIVES: Performance evaluation of Elecsys sFlt-1 and PlGF assays. DESIGN AND METHODS: Within-, between-run, total imprecision, functional sensitivity, inter laboratory comparison, method comparison and lot-to-lot reproducibility were evaluated. RESULTS: Within- and between-run CVs were below 4% for sFlt-1 >60 and PlGF > 20 pg/mL. Total imprecision CVs were below 4.3%. Functional sensitivity was < 5 pg/mL. Inter-laboratory CVs were <5%. Elecsys correlated well with Quantikine VEGF-R1 (r=0.960) and PlGF (r=0.968). Lot-to-lot comparisons yielded highly correlated results (r>0.999). In healthy pregnancies, the median levels of sFlt-1 remained constant in first (1107 pg/mL) and second trimesters (1437 pg/mL) but increased in the third trimester (2395 pg/mL), while median PlGF levels increased in the first (30 pg/mL) and second trimesters (279 pg/mL) and peaked at 29 to 32 weeks (626 pg/mL) and decreased thereafter (340 pg/mL). The sFlt-1/PlGF ratio is highest in the first trimester (median: 28) but remained constant in the second (median: 4.7) and third trimesters (median: 5.1). In PE/HELPP samples matched for gestational age the sFlt-1 levels were significantly higher (6894 34,624 pg/mL), whereas PlGF levels were lower (9.2-80 pg/mL) and the median sFlt 1/PlGF ratio is much higher (461; range: 121-2614) than in apparently healthy pregnancies (3.6; range: 0.3-105). CONCLUSION: The new Roche Elecsys sFlt-1 and PlGF immunoassay showed excellent precision and reliability. There was a clear difference in the Elecsys sFlt-1/PlGF ratio between samples obtained from women with apparently normal pregnancy at the time of blood collection and those diagnosed with PE/HELLP at the same age of gestation. PMID- 20206156 TI - Monoclonal gammopathy in a tertiary referral hospital. AB - OBJECTIVE: Monoclonal gammopathies reflect conditions of plasma B-cell disorders. Our objective was to identify the prevalence and types of these gammopathies in our population. METHODS: A 10year retrospective study was conducted. Serum and/or urine protein electrophoresis were performed on 6624 samples. Positive bands were further tested by immunofixation (IFE). RESULTS: Homogenous bands were detected in 7% of the patients. IFE method confirmed 6.3% in which 59% were males and 41% were females. The mean age was 64.7 for females and 66.5 for males. The sensitivity and specificity were 91% and 99% respectively. The most common protein was IgG kappa 41%, followed by IgG lambda 19%. Sixty-eight percent of these patients had monoclonal gammopathy of undetermined significance and 14.6% had multiple myeloma. CONCLUSION: The majority of the studied population had MGUS. This observation is in concord with other western populations. The sensitivity and specificity of protein electrophoresis is diagnostically and reasonably acceptable. PMID- 20206157 TI - Pretreatment with quercetin ameliorates lipids, lipoproteins and marker enzymes of lipid metabolism in isoproterenol treated cardiotoxic male Wistar rats. AB - Lipids and lipoproteins play an important role in the pathology of myocardial infarction. This manuscript reports the preventive effect of quercetin on lipids, lipoproteins and electrocardiogram in isoproterenol treated cardiotoxic male Wistar rats. Quercetin (10mg/kg) was administered orally as pretreatment to Wistar rats daily for seven days. After pretreatment, rats were induced with myocardial infarction by subcutaneous injection of isoproterenol (100mg/kg) at an interval of 24h for two days. Quercetin pretreatment significantly (P<0.05) lowered ST-segment elevation and decreased the levels of lipid peroxidation products in plasma and heart in isoproterenol treated cardiotoxic rats. Quercetin pretreatment also significantly (P<0.05) reduced the levels of total cholesterol, triglycerides and free fatty acids in serum, heart and heart mitochondria and serum phospholipids in isoproterenol treated cardiotoxic rats. Significantly (P<0.05) increased levels of heart and heart mitochondria phospholipids were observed in quercetin pretreated isoproterenol treated cardiotoxic rats. It's pretreatment also significantly (P<0.05) reduced the levels of serum low-density lipoprotein and very low-density lipoprotein-cholesterol and significantly (P<0.05) increased serum high density lipoprotein-cholesterol in isoproterenol treated cardiotoxic rats. In addition, quercetin significantly (P<0.05) decreased the activity of 3-hydroxy-3-methyl glutaryl-Coenzyme A reductase in plasma and liver and significantly (P<0.05) increased the activity of liver lecithin cholesterol acyl transferase in isoproterenol treated cardiotoxic rats. In vitro study on total antioxidant activity clearly revealed the antioxidant property of quercetin. Thus, the antioxidant activity of quercetin inhibits lipid peroxidation and prevents accumulation of lipids, alterations in lipoproteins and electrocardiogram in isoproterenol treated cardiotoxic rats. PMID- 20206158 TI - Mesenchymal stem cell-conditioned medium accelerates skin wound healing: an in vitro study of fibroblast and keratinocyte scratch assays. AB - We have used in vitro scratch assays to examine the relative contribution of dermal fibroblasts and keratinocytes in the wound repair process and to test the influence of mesenchymal stem cell (MSC) secreted factors on both skin cell types. Scratch assays were established using single cell and co-cultures of L929 fibroblasts and HaCaT keratinocytes, with wound closure monitored via time-lapse microscopy. Both in serum supplemented and serum free conditions, wound closure was faster in L929 fibroblast than HaCaT keratinocyte scratch assays, and in co culture the L929 fibroblasts lead the way in closing the scratches. MSC-CM generated under serum free conditions significantly enhanced the wound closure rate of both skin cell types separately and in co-culture, whereas conditioned medium from L929 or HaCaT cultures had no significant effect. This enhancement of wound closure in the presence of MSC-CM was due to accelerated cell migration rather than increased cell proliferation. A number of wound healing mediators were identified in MSC-CM, including TGF-beta1, the chemokines IL-6, IL-8, MCP-1 and RANTES, and collagen type I, fibronectin, SPARC and IGFBP-7. This study suggests that the trophic activity of MSC may play a role in skin wound closure by affecting both dermal fibroblast and keratinocyte migration, along with a contribution to the formation of extracellular matrix. PMID- 20206159 TI - Selenoproteins-What unique properties can arise with selenocysteine in place of cysteine? AB - The defining entity of a selenoprotein is the inclusion of at least one selenocysteine (Sec) residue in its sequence. Sec, the 21st naturally occurring genetically encoded amino acid, differs from its significantly more common structural analog cysteine (Cys) by the identity of a single atom: Sec contains selenium instead of the sulfur found in Cys. Selenium clearly has unique chemical properties that differ from sulfur, but more striking are perhaps the similarities between the two elements. Selenium was discovered by Jons Jacob Berzelius, a renowned Swedish scientist instrumental in establishing the institution that would become Karolinska Institutet. Written at the occasion of the bicentennial anniversary of Karolinska Institutet, this mini review focuses on the unique selenium-derived properties that may potentially arise in a protein upon the inclusion of Sec in place of Cys. With 25 human genes encoding selenoproteins and in total several thousand selenoproteins yet described in nature, it seems likely that the presence of that single selenium atom of Sec should convey some specific feature, thereby explaining the existence of selenoproteins in spite of demanding and energetically costly Sec-specific synthesis machineries. Nonetheless, most, if not all, of the currently known selenoproteins are also found as Cys-containing non-selenoprotein orthologues in other organisms, wherefore any potentially unique properties of selenoproteins are yet a matter of debate. The pK(a) of free Sec (approximately 5.2) being significantly lower than that of free Cys (approximately 8.5) has often been proposed as one of the unique features of Sec. However, as discussed herein, this pK(a) difference between Sec and Cys can hardly provide an evolutionary pressure for maintenance of selenoproteins. Moreover, the typically 10- to 100-fold lower enzymatic efficiencies of Sec-to-Cys mutants of selenoprotein oxidoreductases, are also weak arguments for the overall existence of selenoproteins. Here, it is however emphasized that the inherent high nucleophilicity of Sec and thereby its higher chemical reaction rate with electrophiles, as compared to Cys, seems to be a truly unique property of Sec that cannot easily be mimicked by the basicity of Cys, even within the microenvironment of a protein. The chemical rate enhancement obtained with Sec can have other consequences than those arising from a low redox potential of some Cys-dependent proteins, typically aiming at maintaining redox equilibria. Another unique aspect of Sec compared to Cys seems to be its efficient potency to support one-electron transfer reactions, which, however, has not yet been unequivocally shown as a Sec-dependent step during the natural catalysis of any known selenoprotein enzyme. PMID- 20206160 TI - HIF-1 and NDRG2 contribute to hypoxia-induced radioresistance of cervical cancer Hela cells. AB - Hypoxia inducible factor 1 (HIF-1), the key mediator of hypoxia signaling pathways, has been shown involved in hypoxia-induced radioresistance. However, the underlying mechanisms are unclear. The present study demonstrated that both hypoxia and hypoxia mimetic cobalt chloride could increase the radioresistance of human cervical cancer Hela cells. Meanwhile, ectopic expression of HIF-1 could enhance the resistance of Hela cells to radiation, whereas knocking-down of HIF-1 could increase the sensitivity of Hela cells to radiation in the presence of hypoxia. N-Myc downstream-regulated gene 2 (NDRG2), a new HIF-1 target gene identified in our lab, was found to be upregulated by hypoxia and radiation in a HIF-1-dependent manner. Overexpression of NDRG2 resulted in decreased sensitivity of Hela cells to radiation while silencing NDRG2 led to radiosensitization. Moreover, NDRG2 was proved to protect Hela cells from radiation-induced apoptosis and abolish radiation-induced upregulation of Bax. Taken together, these data suggest that both HIF-1 and NDRG2 contribute to hypoxia-induced tumor radioresistance and that NDRG2 acts downstream of HIF-1 to promote radioresistance through suppressing radiation-induced Bax expression. It would be meaningful to further explore the clinical application potential of HIF-1 and NDRG2 blockade as radiosensitizer for tumor therapy. PMID- 20206161 TI - Tolerant and diverse natural killer cell repertoires in the absence of selection. AB - Natural killer (NK) cells are innate lymphocytes that participate in the early control of viruses and tumors. The function of NK cells is under tight regulation by two complementary inhibitory receptor families that bind to classical and non classical HLA class I molecules: the CD94/NKG2A receptors and the killer cell immunoglobulin-like receptors (KIRs). In this mini-review, recent data on the structure of human NK cell receptor repertoires and its relation to functional responses and tolerance to self are discussed. We propose that no active selection is required to generate diverse NK cell repertoires characterized by a dominant expression of receptors with specificity for self-HLA class I. Instead, the primary consequence of interactions with HLA class I molecules is a functional tuning of randomly generated NK cell repertoires. PMID- 20206162 TI - Angiogenesis: What can it offer for future medicine? AB - Modulation of angiogenesis for disease therapy was proposed nearly 40 years ago and today various protein and chemical molecules are available for the treatment of human malignant and ophthalmological disorders. Angiogenesis research has emerged, as one of the most comprehensive research areas, in biomedicine and development of novel drugs by targeting angiogenesis has become one of the main focuses among pharmaceutical giants. If 30% of annually 12 million new cancer cases worldwide receive antiangiogenic therapy, over 60 million cancer patients would be treated by the end of 2060. In this mini-review, I discuss current available antiangiogenic drugs and future therapeutic options based on the angiogenesis principle. PMID- 20206163 TI - Macromolecular diffusion characteristics of ageing human Bruch's membrane: implications for age-related macular degeneration (AMD). AB - Macromolecular species such as retinal binding protein, transferrin, ceruloplasmin, etc., released by the fenestrated choroidal capillaries must diffuse across Bruch's membrane for interaction with the basal membranes of the retinal pigment epithelium (RPE) for delivery of essential metabolites to the neural retina. The patency of this pathway through ageing Bruch's was examined by quantifying the diffusional flux of a 21.2 kDa fluorescein-isothiocyanate labelled dextran. Dextran flux measurements across Bruch's membrane from the macular region of the human fundus showed a highly significant decrease (p < 0.001) with ageing of donor such that diffusional transport in the ninth decade was about 6.5% of that in the first decade of life. Peripheral regions also showed a highly significant decline (p < 0.001) but ageing changes were considerably slowed in comparison to the macula with diffusional rates in the ninth decade being about 44% of that in the first decade. Peripheral samples from AMD donors displayed diffusional rates that were lower than the control population. The age-related decline in macromolecular diffusion across Bruch's membrane suggests that in the elderly, the patency of the conducting pathways may be compromised and in the more advanced ageing of Bruch's associated with AMD, the metabolic trafficking of carrier proteins may be severely impaired. PMID- 20206164 TI - Repetetive hindlimb movement using intermittent adaptive neuromuscular electrical stimulation in an incomplete spinal cord injury rodent model. AB - The long-term objective of this work is to understand the mechanisms by which electrical stimulation based movement therapies may harness neural plasticity to accelerate and enhance sensorimotor recovery after incomplete spinal cord injury (iSCI). An adaptive neuromuscular electrical stimulation (aNMES) paradigm was implemented in adult Long Evans rats with thoracic contusion injury (T8 vertebral level, 155+/-2 Kdyne). In lengthy sessions with lightly anesthetized animals, hip flexor and extensor muscles were stimulated using an aNMES control system in order to generate desired hip movements. The aNMES control system, which used a pattern generator/pattern shaper structure, adjusted pulse amplitude to modulate muscle force in order to control hip movement. An intermittent stimulation paradigm was used (5-cycles/set; 20-second rest between sets; 100 sets). In each cycle, hip rotation caused the foot plantar surface to contact a stationary brush for appropriately timed cutaneous input. Sessions were repeated over several days while the animals recovered from injury. Results indicated that aNMES automatically and reliably tracked the desired hip trajectory with low error and maintained range of motion with only gradual increase in stimulation during the long sessions. Intermittent aNMES thus accounted for the numerous factors that can influence the response to NMES: electrode stability, excitability of spinal neural circuitry, non-linear muscle recruitment, fatigue, spinal reflexes due to cutaneous input, and the endogenous recovery of the animals. This novel aNMES application in the iSCI rodent model can thus be used in chronic stimulation studies to investigate the mechanisms of neuroplasticity targeted by NMES-based repetitive movement therapy. PMID- 20206165 TI - Estradiol therapy in adulthood reverses glial and neuronal alterations caused by perinatal asphyxia. AB - The capacity of the ovarian hormone 17beta-estradiol to prevent neurodegeneration has been characterized in several animal models of brain and spinal cord pathology. However, the potential reparative activity of the hormone under chronic neurodegenerative conditions has received less attention. In this study we have assessed the effect of estradiol therapy in adulthood on chronic glial and neuronal alterations caused by perinatal asphyxia (PA) in rats. Four-month old male Sprague-Dawley rats submitted to PA just after delivery, and their control littermates, were injected for 3 consecutive days with 17beta estradiol or vehicle. Animals subjected to PA and treated with vehicle showed an increased astrogliosis, focal swelling and fragmented appearance of MAP-2 immunoreactive dendrites, decreased MAP-2 immunoreactivity and decreased phosphorylation of high and medium molecular weight neurofilaments in the hippocampus, compared to control animals. Estradiol therapy reversed these alterations. These findings indicate that estradiol is able to reduce, in adult animals, chronic reactive astrogliosis and neuronal alterations caused by an early developmental neurodegenerative event, suggesting that the hormone might induce reparative actions in the Central Nervous System (CNS). PMID- 20206167 TI - A new faecal antigen detection system for Strongyloides venezuelensis diagnosis in immunosuppressed rats. AB - This study was performed with the objective of developing innovative procedures for the diagnosis of strongyloidiasis. Enzyme-linked immunosorbent assay (ELISA) was conducted to detect coproantigen in the faecal samples of normal and of immunosuppressed rats using an anti-L3 polyclonal antibody produced in rabbits. Analysis revealed the kinetics of egg shedding in the non-immunosuppressed and immunosuppressed rats infected with S. venezuelensis. Further analysis verified the ability of the immune serum to detect L3 antigens in faecal samples from infected animals. The number of eggs recovered in the faeces at 8 days p.i was significantly higher for both groups. Immunosuppressed animals eliminated increased quantities of eggs. The immune serum was able to detect 0.39 microg/ml of L3 antigens. The antigen recognition in the immunosuppressed group was anticipated on the 8th day p.i. In conclusion, these results may represent a first step in the development of a rapid coproantigen detection kit for strongyloidiasis. PMID- 20206166 TI - Chronic intermittent hypoxia reduces neurokinin-1 (NK(1)) receptor density in small dendrites of non-catecholaminergic neurons in mouse nucleus tractus solitarius. AB - Chronic intermittent hypoxia (CIH) is a frequent concomitant of sleep apnea, which can increase sympathetic nerve activity through mechanisms involving chemoreceptor inputs to the commissural nucleus of the solitary tract (cNTS). These chemosensory inputs co-store glutamate and substance P (SP), an endogenous ligand for neurokinin-1 (NK(1)) receptors. Acute hypoxia results in internalization of NK(1) receptors, suggesting that CIH also may affect the subcellular distribution of NK(1) receptors in subpopulations of cNTS neurons, some of which may express tyrosine hydroxylase, the rate-limiting enzyme for catecholamine synthesis (TH). To test this hypothesis, we examined dual immunolabeling for the NK(1) receptor and TH in the cNTS of male mice subjected to 10days or 35days of CIH or intermittent air. Electron microscopy revealed that NK(1) receptors and TH were almost exclusively localized within separate somatodendritic profiles in cNTS of control mice. In dendrites, immunogold particles identifying NK(1) receptors were prevalent in the cytoplasm and on the plasmalemmal surface. Compared with controls, CIH produced a significant region specific decrease in the cytoplasmic (10 and 35days, P<0.05, unpaired Student t test) and extrasynaptic plasmalemmal (35days, P<0.01, unpaired Student t-test) density of NK(1) immunogold particles exclusively in small (<0.1microm) dendrites without TH immunoreactivity. These results suggest that CIH produces a duration dependent reduction in the availability of NK(1) receptors preferentially in small dendrites of non-catecholaminergic neurons in the cNTS. The implications of our findings are discussed with respect to their potential involvement in the slowly developing hypertension seen in sleep apnea patients. PMID- 20206168 TI - Teladorsagia circumcincta: activation-associated secreted proteins in excretory/secretory products of fourth stage larvae are targets of early IgA responses in infected sheep. AB - A detailed proteomic analysis of excreted/secretory (ES) proteins derived from fourth stage larvae (L4) of Teladorsagia circumcincta identified a number of components, including N-type and C-type single domain activation-associated secreted proteins (ASPs). Immunoblotting of L4 ES extracts with abomasal mucus derived from infected, immune sheep demonstrated the immunogenicity of some of these components, including an N-type single-domain ASP, designated Tci-ASP-1. The full-length cDNA encoding this protein was isolated and sequenced. Homology searches using the inferred amino acid sequence of Tci-ASP-1 showed that it had highest identity (75% over 231 residues) to, a N-type, single-domain ASP from Ostertagia ostertagi. Phylogenetic analysis confirmed the relationship of Tci-ASP 1 with other N-type ASPs. Reverse-transcriptase (RT)-PCR experiments demonstrated the presence of transcript encoding Tci-ASP-1 in L4 and adult stage T. circumcincta but not in pre-parasitic stages such as eggs and third stage larvae. A recombinant version of Tci-ASP-1 was expressed in Escherichia coli and the purified protein was reactive with IgA present in abomasal mucus derived from immune sheep. PMID- 20206169 TI - Trypanosoma cruzi: synergistic cytotoxicity of multiple amphipathic anti microbial peptides to T. cruzi and potential bacterial hosts. AB - The parasite Trypanasoma cruzi is responsible for Chagas disease and its triatomine vector, Rhodnius prolixus, has a symbiotic relationship with the soil bacterium, Rhodococcus rhodnii. R. rhodnii that was previously genetically engineered to produce the anti-microbial peptide, cecropin A was co-infected with T. cruzi into R. prolixus resulting in clearance of the infectious T. cruzi in 65% of the vectors. Similar anti-microbial peptides have been isolated elsewhere and were studied for differential toxicity against T. cruzi and R. rhodnii. Of the six anti-microbial peptides tested, apidaecin, magainin II, melittin, and cecropin A were deemed potential candidates for the Chagas paratransgenic system as they were capable of killing T.cruzi at concentrations that exhibit little or no toxic effects on R. rhodnii. Subsequent treatments of T. cruzi with these peptides in pair-wise combinations resulted in synergistic killing, indicating that improvement of the 65% parasite clearance seen in previous experiments may be possible utilizing combinations of different anti-microbial peptides. PMID- 20206170 TI - Ghrelin inhibits insulin secretion through the AMPK-UCP2 pathway in beta cells. AB - Ghrelin inhibits insulin secretion partly via induction of IA-2beta. However, the orexigenic effect of ghrelin is mediated by the AMP-activated protein kinase (AMPK)-uncoupling protein 2 (UCP2) pathway. Here, we demonstrate that ghrelin's inhibitory effect on insulin secretion also occurs through the AMPK-UCP2 pathway. Ghrelin increased AMPK phosphorylation and UCP2 mRNA expression in MIN6 insulinoma cells. Overexpression or downregulation of UCP2 attenuated or enhanced insulin secretion, respectively. Furthermore, AMPK activator had a similar effect to ghrelin on UCP2 and insulin secretion in MIN6 cells. In conclusion, ghrelin's inhibitory effect on insulin secretion is partly mediated by the AMPK-UCP2 pathway, which is independent of the IA-2beta pathway. PMID- 20206171 TI - Evidence that the C-terminus of OprM is involved in the assembly of the VceAB OprM efflux pump. AB - Although the architecture of tripartite multiple drug resistance (MDR) efflux pumps of Gram-negative bacteria has been well characterized, the means by which the components recognize each other and assemble into a functional pump remains obscure. In this study we present evidence that the C-terminal domain of the Pseudomonas aeruginosa OprM and the alpha-helical hairpin domain of Vibrio cholerae VceA play an important role in the recognition/specificity/recruitment step in the assembly of a functional, VceAB-OprM chimeric efflux pump. To our knowledge, this is the first evidence directly linking the C-terminal domain of an outer membrane efflux protein to its recruitment during the assembly of a tripartite efflux pump. PMID- 20206172 TI - Computational prediction of nucleosome positioning by calculating the relative fragment frequency index of nucleosomal sequences. AB - We developed an accurate method to predict nucleosome positioning from genome sequences by refining the previously developed method of Peckham et al. (2007). Here, we used the relative fragment frequency index we developed and a support vector machine to screen for nucleosomal and linker DNA sequences. Our twofold cross-validation revealed that the accuracy of our method based on the area under the receiver operating characteristic curve was 81%, whereas that of Peckham's method was 75% when both of two nucleosomal sequence data obtained from independent experiments were used for validation. We suggest that our method is more effective in predicting nucleosome positioning. PMID- 20206173 TI - Structure of the p53 C-terminus bound to 14-3-3: implications for stabilization of the p53 tetramer. AB - The adaptor protein 14-3-3 binds to and stabilizes the tumor suppressor p53 and enhances its anti-tumour activity. In the regulatory C-terminal domain of p53 several 14-3-3 binding motifs have been identified. Here, we report the crystal structure of the extreme C-terminus (residues 385-393, p53pT387) of p53 in complex with 14-3-3sigma at a resolution of 1.28A. p53pT387 is accommodated by 14 3-3 in a yet unrecognized fashion implying a rationale for 14-3-3 binding to the active p53 tetramer. The structure exhibits a potential binding site for small molecules that could stabilize the p53/14-3-3 protein complex suggesting the possibility for therapeutic intervention. PMID- 20206174 TI - Thrombocytopenia exacerbates cholestasis-induced liver fibrosis in mice. AB - BACKGROUND & AIMS: Circulating platelet counts gradually decrease in parallel with progression of chronic liver disease. Thrombocytopenia is a common complication of advanced liver fibrosis and is thought to be a consequence of the destruction of circulating platelets that occurs during secondary portal hypertension or hypersplenism. It is not clear whether thrombocytopenia itself affects liver fibrosis. METHODS: Thrombocytopenic mice were generated by disruption of Bcl-xL, which regulates platelet life span, specifically in thrombocytes. Liver fibrosis was examined in thrombocytopenic mice upon bile duct ligation. Effect of platelets on hepatic stellate cells (HSCs) was investigated in vitro. RESULTS: Thrombocytopenic mice developed exacerbated liver fibrosis, with increased expression of type I collagen alpha1 and alpha2, during cholestasis. In vitro experiments revealed that, upon exposure to HSCs, platelets became activated, released hepatocyte growth factor (HGF), and then inhibited HSC expression of the type I collagen genes in a Met signal-dependent manner. In contrast to the wild-type mice, the thrombocytopenic mice did not accumulate hepatic platelets or phosphorylate Met in the liver following bile duct ligation. Administration of recombinant HGF to thrombocytopenic mice reduced liver fibrosis to the levels observed in wild-type mice and attenuated hepatic expression of the type I collagen genes. CONCLUSIONS: Thrombocytopenia exacerbates liver fibrosis; platelets have a previously unrecognized, antifibrotic role in suppressing type I collagen expression via the HGF-Met signaling pathway. PMID- 20206175 TI - Corticotropin-releasing hormone family of peptides regulates intestinal angiogenesis. AB - BACKGROUND & AIMS: The corticotrophin-releasing hormone (CRH) family of peptides modulates intestinal inflammation and the CRH receptor 2 (CRHR2) suppresses postnatal angiogenesis in mice. We investigated the functions of CRHR1 and CRHR2 signaling during intestinal inflammation and angiogenesis. METHODS: The activities of CRHR1 and CRHR2 were disrupted by genetic deletion in mice or with selective antagonists. A combination of in vivo, ex vivo, and in vitro measures of angiogenesis were used to determine their activity. CRHR1(-/-) mice and CRHR2( /-) mice with dextran sodium sulfate-induced colitis were analyzed in comparison with wild-type littermates (controls). RESULTS: Colitis was significantly reduced in mice in which CRHR1 activity was disrupted by genetic deletion or with an antagonist, determined by analyses of survival rate, weight loss, histological scores, and cytokine production. Inflammation was exacerbated in mice in which CRHR2 activity was inhibited by genetic deletion or with an antagonist, compared with controls. The inflamed intestines of CRHR1(-/-) mice had reduced microvascular density and expression of vascular endothelial growth factor (VEGF) A, whereas the intestines of CRHR2(-/-) mice had increased angiogenesis and VEGF A levels. An antagonist of VEGFR2 activity alleviated colitis in CRHR2(-/-) mice. Ex vivo aortic vessel outgrowth was reduced when CRHR1 was deficient but increased when CRHR2 was deficient. The CRHR1 preferred agonist CRH stimulated tube formation, proliferation, and migration of cultured intestinal microvascular endothelial cells by phosphorylating Akt, whereas the specific CRHR2 agonist Urocortin III had opposite effects. CONCLUSION: CRHR1 promotes intestinal inflammation, as well as endogenous and inflammatory angiogenesis whereas CRHR2 inhibits these activities. PMID- 20206176 TI - Hedgehog is an anti-inflammatory epithelial signal for the intestinal lamina propria. AB - BACKGROUND & AIMS: Epithelial Hedgehog (Hh) ligands regulate several aspects of fetal intestinal organogenesis, and emerging data implicate the Hh pathway in inflammatory signaling in the adult colon. Here, we investigated the effects of chronic Hh inhibition in vivo and profiled molecular pathways acutely modulated by Hh signaling in the intestinal mesenchyme. METHODS: The progression of inflammatory disease was characterized in a bi-transgenic mouse model of chronic Hh inhibition (VFHhip). In parallel, microarray and bioinformatic analyses (Gene Ontology terms overrepresentation analysis, hierarchical clustering, and MeSH term filtration) were performed on isolated cultured intestinal mesenchyme acutely exposed to Hh ligand. RESULTS: Six- to 10-month-old VFHhip animals exhibited villus smooth muscle loss and subsequent villus atrophy. Areas of villus loss became complicated by spontaneous inflammation and VFHhip animals succumbed to wasting and death. Phenotypic similarities were noted between the VFHhip phenotype and human inflammatory disorders, especially human celiac disease. Microarray analysis revealed that inflammatory pathways were acutely activated in intestinal mesenchyme cultured in the absence of epithelium, and the addition of Hh ligand alone was sufficient to largely reverse this inflammatory response within 24 hours. CONCLUSIONS: Hh ligand is a previously unrecognized anti-inflammatory epithelial modulator of the mesenchymal inflammatory milieu. Acute modulation of Hh signals results in changes in inflammatory pathways in intestinal mesenchyme, while chronic inhibition of Hh signaling in adult animals leads to spontaneous intestinal inflammation and death. Regulation of epithelial Hh signaling may be an important mechanism to modulate tolerogenic versus proinflammatory signaling in the small intestine. PMID- 20206177 TI - Role of scavenger receptor A and CD36 in diet-induced nonalcoholic steatohepatitis in hyperlipidemic mice. AB - BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is a disorder that consists of steatosis and hepatic inflammation. It is not known why only some people with steatosis develop NASH. Recently, we identified dietary cholesterol as a factor that directly leads to hepatic inflammation and hepatic foam cell formation. We propose a mechanism by which Kupffer cells (KCs) take up modified cholesterol-rich lipoproteins via scavenger receptors (SRs). KCs thereby accumulate cholesterol, become activated, and may then trigger an inflammatory reaction. Scavenging of modified lipoproteins mainly depends on CD36 and macrophage scavenger receptor 1. METHODS: To evaluate the involvement of SR mediated uptake of modified lipoproteins by KCs in the development of diet induced NASH, female low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice were lethally irradiated and transplanted with bone marrow from Msr1(+/+)/Cd36(+/+)or Msr1(-/-)/Cd36(-/-) mice and fed a Western diet. RESULTS: Macrophage and neutrophil infiltration revealed that hepatic inflammation was substantially reduced by approximately 30% in Msr1(-/-)/Cd36(-/-)-transplanted mice compared with control mice. Consistent with this, the expression levels of well-known inflammatory mediators were reduced. Apoptotis and fibrosis were less pronounced in Msr1(-/-)/Cd36(-/-)-transplanted mice, in addition to the protective phenotype of natural antibodies against oxidized low-density lipoprotein in the plasma. Surprisingly, the effect on hepatic inflammation was independent of foam cell formation. CONCLUSIONS: Targeted inactivation of SR pathways reduces the hepatic inflammation and tissue destruction associated with NASH, independent of hepatic foam cell formation. PMID- 20206178 TI - Noggin, retinoids, and fibroblast growth factor regulate hepatic or pancreatic fate of human embryonic stem cells. AB - BACKGROUND & AIMS: New sources of beta cells are needed to develop cell therapies for patients with diabetes. An in vitro, sequential method has been developed to derive pancreatic progenitors, but this technique has not been used for other cell lines. We investigated whether definitive endoderm derived from human embryonic stem (hES) cells might be used to create beta cells. METHODS: Five hES cell lines were induced to form pancreatic progenitors and analyzed for pancreas markers. Cells were incubated with a bone morphogenetic protein (BMP) antagonist, retinoids, a Hedgehog antagonist, or fibroblast growth factor (FGF) and phenotypes were analyzed. RESULTS: Four hES cell lines sequentially generated definitive endoderm, primitive gut, and posterior foregut equivalents, as described previously. However, functional hepatocytes, rather than pancreas progenitors, developed. Consistent with liver development, FGF and BMP signaling pathways were involved in this process; their inhibition disrupted hepatocyte differentiation. During early stages of development, exposure of cells to noggin and retinoid acid, followed by FGF10, generated pancreatic cells (PDX1+; 50%-80%) that coexpressed FOXA2, HNF6, and SOX9. CONCLUSIONS: These findings demonstrate the combined functions of endogenous BMP and supplemented FGF in inducing differentiation of hepatocytes from hES cells and the ability to shift developmental pathways from hepatic to pancreatic cell differentiation. Although additional signals appear to be required for full specification of PDX1(+) early pancreatic progenitors (via PTF1a and NKX6.1 coexpression), these findings indicate the signaling pathways required for differentiation of bipotential progenitors. PMID- 20206179 TI - Early laparoscopic cholecystectomy improves outcomes after endoscopic sphincterotomy for choledochocystolithiasis. AB - BACKGROUND & AIMS: Patients with choledochocystolithiasis generally undergo endoscopic sphincterotomy (ES) followed by laparoscopic cholecystectomy (LC). However, many patients receive this surgery 6-8 weeks after ES. There is a high conversion rate of elective LC after ES, and patients can develop recurrent biliary events during the waiting period. We investigated whether the timing of surgery influences outcome. METHODS: We performed a randomized trial of patients with choledochocystolithiasis who underwent successful ES. Patients were randomly assigned to groups that received early LC (within 72 hours after ES, n = 49) or delayed LC (after 6-8 weeks, n = 47), based on an expected difference in conversion rate of 25% vs 5%, respectively. Conversion rate, biliary events during follow-up, duration and difficulty of surgeries, postoperative morbidity, and hospital stay were scored. Intention-to-treat analyses were performed. RESULTS: Groups were comparable in age, sex, and comorbidity. There was no difference between groups in conversion rate (4.3% in early vs 8.7% in delayed group) nor were there differences in operating times and/or difficulties or hospital stays. During the waiting period for LC, 17 patients in the delayed group (36.2%) developed recurrent biliary events compared with 1 patient in the early group (P < .001). CONCLUSIONS: In a randomized trial to evaluate timing of LC after ES, recurrent biliary events occurred in 36.2% of patients whose LC was delayed for 6-8 weeks. Early LC (within 72 hours) appears to be safe and might prevent the majority of biliary events in this period following sphincterotomy. PMID- 20206180 TI - One to 2-year surveillance intervals reduce risk of colorectal cancer in families with Lynch syndrome. AB - BACKGROUND & AIMS: Two percent to 4% of all cases of colorectal cancer (CRC) are associated with Lynch syndrome. Dominant clustering of CRC (non-Lynch syndrome) accounts for 1%-3% of the cases. Because carcinogenesis is accelerated in Lynch syndrome, an intensive colonoscopic surveillance program has been recommended since 1995. The aim of the study was to evaluate the effectiveness of this program. METHODS: The study included 205 Lynch syndrome families with identified mutations in one of the mismatch repair genes (745 mutation carriers). We also analyzed data from non-Lynch syndrome families (46 families, 344 relatives). Patients were observed from January 1, 1995, until January 1, 2009. End points of the study were CRC or date of the last colonoscopy. RESULTS: After a mean follow up of 7.2 years, 33 patients developed CRC under surveillance. The cumulative risk of CRC was 6% after the 10-year follow-up period. The risk of CRC was higher in carriers older than 40 years and in carriers of MLH1 and MSH2 mutations. After a mean follow-up of 7.0 years, 6 cases of CRC were detected among non-Lynch syndrome families. The risk of CRC was significantly higher among families with Lynch syndrome, compared with those without. CONCLUSIONS: With surveillance intervals of 1-2 years, members of families with Lynch syndrome have a lower risk of developing CRC than with surveillance intervals of 2-3 years. Because of the low risk of CRC in non-Lynch syndrome families, a less intensive surveillance protocol can be recommended. PMID- 20206181 TI - Perinatal exposure to bisphenol-A impairs learning-memory by concomitant down regulation of N-methyl-D-aspartate receptors of hippocampus in male offspring mice. AB - Bisphenol-A (BPA) has been shown to influence development of the brain and behaviors. The purpose of the present report was to investigate the effects of perinatal exposure to BPA on learning/memory and its mechanism of action, especially focusing on N-methyl-d-aspartate receptor (NMDAR). Perinatal maternal exposure to BPA at 0.5, 5, and 50mg/kg/d significantly extended the escape length to find the hidden platform in Morris water maze, and BPA at 0.5 or 5mg/kg/d markedly decreased the percentage of time spent in the quadrant where the platform had been during training both in postnatal day (PND) 21 and PND 56 mice. The results of passive avoidance test showed that the error frequency to step down from a platform after received footshock was significantly increased, and the latency of the step-down response onto the grid floor 24h after received footshock was obviously reduced by exposure to BPA at 5 and 50mg/kg/d (P<0.01) in the PND 21 offspring or at 50mg/kg/d in the PND 56 offspring (P<0.01). Furthermore, perinatal exposure to BPA significantly inhibited the expressions of NMDAR subunits NR1, NR2A, and 2B in the hippocampus during the development stage, especially in PND 56 mice. The expressions of estrogen receptor beta (ERbeta) in both PND 21 and PND 56 mice were markedly down-regulated by BPA at 0.5, 5, and 50mg/kg/d. These results indicate that perinatal exposure to BPA affects normal behavioral development in both spatial memory and avoidance memory, and also permanently influences the behavior of offspring in adulthood. The inhibition of expressions of NMDAR subunits and ERbeta in hippocampus during postnatal development stage may be involved. PMID- 20206182 TI - An alternative technique for the induction of autoimmune valvulitis in a rat model of rheumatic heart disease. AB - We currently use a rat model in our investigations into human rheumatic heart disease (RHD). This model traditionally involves footpad immunization with antigen emulsified in complete Freund's adjuvant (CFA). Trials to find an alternative adjuvant to CFA which produced a Th1 type response in the rats resulting in carditis were unsuccessful. However, hock immunization was found to produce the desired valvular pathology without the adverse inflammatory side effects associated with CFA. We therefore consider the hock an ideal site for immunization, particularly when using CFA. PMID- 20206183 TI - Role of the multidrug resistance protein-1 (MRP1) for endothelial progenitor cell function and survival. AB - The multidrug resistance related protein-1 (MRP1) is a member of the ATP binding cassette (ABC) of cell surface transport proteins expressed in multiple cell lines and tissues including endothelial cells and haematopoietic stem cells. MRP1 blockade has been shown to prevent endothelial cell apoptosis and improve endothelial function. Besides mature endothelial cells vascular homing of endothelial progenitor cells (EPC) contributes to endothelial regeneration after vascular damage. Thus, we hypothesized that MRP1 influences number and function of EPCs and mechanisms of vascular repair. To test this, we investigated the effects of MRP1 inhibition in vitro and in vivo. MRP1 is abundantly expressed in cultured human early outgrowth EPCs. Pharmacological inhibition of MRP1 by MK571 increased intracellular glutathione levels and reduced intracellular reactive oxygen species levels. This stabilization of the intracellular redox homeostasis via inhibition of MRP1 prevented angiotensin II-induced apoptosis and increased the number of early outgrowth EPCs and colony forming units in vitro. To extend the observed cytoprotective effect of MRP1 blockade in EPCs to an in vivo situation, MRP1(-/-) knockout mice were investigated. MRP1(-/-) knockout mice showed significantly increased numbers of EPCs circulating in the peripheral blood and residing in the bone marrow. Consistently, colony forming unit formation was enhanced and rate of apoptosis reduced in early outgrowth EPCs derived from MRP1(-/-) knockout mice. In addition, MRP1(-/-) knockout mice showed improved reendothelialization after carotid artery injury, and transfusion of MNCs derived from MRP1(-/-) knockout mice into wild-type mice accelerated reendothelialization compared to transfusion of wild-type cells. These findings indicate that the enhanced function and survival of EPCs in MRP1(-/-) knockout mice resulted in improved reendothelialization. In conclusion, MRP1 negatively influences EPC function and survival via perturbation of the intracellular redox homeostasis which finally leads to increased cellular apoptosis. These results reveal novel mechanistic insights and may identify MRP1 as therapeutic target to improve reendothelialization after vascular damage. PMID- 20206185 TI - Molecular structure of the N-terminal domain of the APC/C subunit Cdc27 reveals a homo-dimeric tetratricopeptide repeat architecture. AB - The anaphase promoting complex/cyclosome (APC/C) is a large multi-subunit E3 ubiquitin ligase that targets specific cell cycle regulatory proteins for ubiquitin-dependent degradation, thereby controlling cell cycle events such as the metaphase to anaphase transition and the exit from mitosis. Biochemical and genetic studies are consistent with the notion that subunits of APC/C are organised into two distinct sub-complexes; a catalytic sub-complex including the cullin domain and RING finger subunits Apc2 and Apc11, respectively, and a tetratricopeptide repeat (TPR) sub-complex composed of the TPR subunits Cdc16, Cdc23 and Cdc27 (Apc3). Here, we describe the crystal structure of the N-terminal domain of Encephalitozoon cuniculi Cdc27 (Cdc27(Nterm)), revealing a homo-dimeric structure, composed predominantly of successive TPR motifs. Mutation of the Cdc27(Nterm) dimer interface destabilises the protein, disrupts dimerisation in solution, and abolishes the capacity of E. cuniculi Cdc27 to complement Saccharomyces cerevisiae Cdc27 in vivo. These results establish the existence of functional APC/C genes in E. cuniculi, the evolutionarily conserved dimeric properties of Cdc27, and provide a framework for understanding the architecture of full-length Cdc27. PMID- 20206184 TI - Unusual conformation of the SxN motif in the crystal structure of penicillin binding protein A from Mycobacterium tuberculosis. AB - PBPA from Mycobacterium tuberculosis is a class B-like penicillin-binding protein (PBP) that is not essential for cell growth in M. tuberculosis, but is important for proper cell division in Mycobacterium smegmatis. We have determined the crystal structure of PBPA at 2.05 A resolution, the first published structure of a PBP from this important pathogen. Compared to other PBPs, PBPA has a relatively small N-terminal domain, and conservation of a cluster of charged residues within this domain suggests that PBPA is more related to class B PBPs than previously inferred from sequence analysis. The C-terminal domain is a typical transpeptidase fold and contains the three conserved active-site motifs characteristic of penicillin-interacting enzymes. Whilst the arrangement of the SxxK and KTG motifs is similar to that observed in other PBPs, the SxN motif is markedly displaced away from the active site, such that its serine (Ser281) is not involved in hydrogen bonding with residues of the other two motifs. A disulfide bridge between Cys282 (the "x" of the SxN motif) and Cys266, which resides on an adjacent loop, may be responsible for this unusual conformation. Another interesting feature of the structure is a relatively long connection between beta 5 and alpha 11, which restricts the space available in the active site of PBPA and suggests that conformational changes would be required to accommodate peptide substrate or beta-lactam antibiotics during acylation. Finally, the structure shows that one of the two threonines postulated to be targets for phosphorylation is inaccessible (Thr362), whereas the other (Thr437) is well placed on a surface loop near the active site. PMID- 20206186 TI - Cysteine as a modulator residue in the active site of xenobiotic reductase A: a structural, thermodynamic and kinetic study. AB - Xenobiotic reductase A (XenA) from Pseudomonas putida 86 catalyzes the NADH/NADPH dependent reduction of various substrates, including 2-cyclohexenone and 8 hydroxycoumarin. XenA is a member of the old yellow enzyme (OYE) family of flavoproteins and is structurally and functionally similar to other bacterial members of this enzyme class. A characteristic feature of XenA is the presence of a cysteine residue (Cys25) in the active site, where in most members of the OYE family a threonine residue is found that modulates the reduction potential of the FMN/FMNH(-) couple. We investigated the role of Cys25 by studying two variants in which the residue has been exchanged for a serine and an alanine residue. While the exchange against alanine has a remarkably small effect on the reduction potential, the reactivity and the structure of XenA, the exchange against serine increases the reduction potential by +82 mV, increases the rate constant of the reductive half-reaction and decreases the rate constant in the oxidative half reaction. We determined six crystal structures at high to true atomic resolution (d(min) 1.03-1.80 A) of the three XenA variants with and without the substrate coumarin bound in the active site. The atomic resolution structure of XenA in complex with coumarin reveals a compressed active site geometry in which the isoalloxazine ring is sandwiched between coumarin and the protein backbone. The structures further reveal that the conformation of the active site and substrate interactions are preserved in the two variants, indicating that the observed changes are due to local effects only. We propose that Cys25 and the residues in its place determine which of the two half-reactions is rate limiting, depending on the substrate couple. This might help to explain why the genome of Pseudomonas putida encodes multiple xenobiotic reductases containing either cysteine, threonine or alanine in the active site. PMID- 20206187 TI - Sperm competition games: sperm size (mass) and number under raffle and displacement, and the evolution of P2. AB - We examine models for evolution of sperm size (i.e. mass m) and number (s) under three mechanisms of sperm competition at low 'risk' levels: (i) raffle with no constraint on space available for competing sperm, (ii) direct displacement mainly by seminal fluid, and (iii) direct displacement mainly by sperm mass. Increasing sperm mass increases a sperm's 'competitive weight' against rival sperm through a diminishing returns function, r(m). ESS total ejaculate expenditure (the product m(*)s(*)) increases in all three models with sperm competition risk, q. If r(m), or ratio r'(m)/r(m), is independent of ESS sperm numbers, ESS sperm mass remains constant, and the sperm mass/number ratio (m(*)/s(*)) therefore decreases with risk. Dependency of sperm mass on risk can arise if r(m) depends on competing sperm density (sperm number / space available for sperm competition). Such dependencies generate complex relationships between sperm mass and number with risk, depending both on the mechanism and how sperm density affects r(m). While numbers always increase with risk, mass can either increase or decrease, but m(*)/s(*) typically decreases with risk unless sperm density strongly influences r(m). Where there is no extrinsic loading due to mating order, ESS paternity of the second (i.e. last) male to mate (P(2)) under displacement always exceeds 0.5, and increases with risk (in the raffle P(2)=0.5). Caution is needed when seeking evidence for a sperm size-number trade off. Although size and number trade-off independently against effort spent on acquiring matings, their product, m(*)s(*), is invariant or fixed at a given risk level, effectively generating a size-number trade off. However, unless controlled for the effects of risk, the relation between m(*) and s(*) can be either positive or negative (a positive relation is usually taken as evidence against a size-number trade off). PMID- 20206188 TI - N-desmethylclozapine (NDMC) is an antagonist at the human native muscarinic M(1) receptor. AB - N-desmethylclozapine (NDMC) has been reported to display partial agonism at the human recombinant and rat native M(1) mAChR, a property suggested to contribute to the clinical efficacy of clozapine. However, the profile of action of NDMC at the human native M(1) mAChR has not been reported. The effect of NDMC on M(1) mAChR function was investigated in human native tissues by assessing its effect on (1) M(1) mAChR-mediated stimulation of [(35)S]-GTPgammaS-G(q/11)alpha binding to human post mortem cortical membranes and (2) the M(1) mAChR-mediated increase in neuronal firing in human neocortical slices. NDMC displayed intrinsic activities of 46+/-9%, compared to oxo-M, at the human recombinant M(1) receptor, in FLIPR studies and 35+/-4% at rat native M(1) receptors in [(35)S]-GTPgammaS G(q/11)alpha binding studies. In [(35)S]-GTPgammaS-G(q/11)alpha binding studies in human cortex, oxo-M stimulated binding by 240+/-26% above basal with a pEC(50) of 6.56+/-0.05. In contrast, NDMC did not stimulate [(35)S]-GTPgammaS G(q/11)alpha binding to human cortical membranes but antagonised the response to oxo-M (2microM) showing a pK(B) of 6.8, comparable to its human recombinant M(1) mAChR affinity (pK(i)=6.9) derived from [(3)H]-NMS binding studies. In human, contrary to the rat neocortical slices, NDMC did not elicit a significant increase in M(1) mAChR-mediated neuronal firing, and attenuated a carbachol induced increase in neuronal firing when pre-applied. These data indicate that, whereas NDMC displays moderate to low levels of partial agonism at the human recombinant and rat native M(1) mAChR, respectively, it acts as an antagonist at the M(1) mAChR in human cortex. PMID- 20206189 TI - On the characterization of the spatio-temporal profiles of brain activity associated with face naming and the tip-of-the-tongue state: a magnetoencephalographic (MEG) study. AB - The tip-of-the-tongue state (TOT) in face naming is a transient state of difficulty in access to a person's name along with the conviction that the name is known. The aim of the present study was to characterize the spatio-temporal course of brain activation in the successful naming and TOT states, by means of magnetoencephalography, during a face-naming task. Following famous face presentations, subjects indicated whether they knew the name, did not know the name, or experienced a TOT state. Next they produced the name aloud, if they could, although they did not indicate whether they retrieved any other information about the person. The TOT state was characterized by lower activation than for successful retrieval, in the 310-520 ms poststimulus interval, localized to left temporal and frontal areas, bilateral parahippocampal gyrus, and right fusiform gyrus, which may underlie the genesis of TOT. Greater activation was also found in the 740-820 ms interval, localized to bilateral occipital, left temporal, and right frontal and parietal areas, corresponding with the unfruitful search for the name after the TOT state was produced. These results showed the differential brain dynamics underlying searching for the name of a known individual according to whether the search was successful or subjectively rated as just short of success. PMID- 20206190 TI - The representational-hierarchical view of amnesia: translation from animal to human. AB - Animal research has, in our opinion, made an invaluable contribution to our understanding of human amnesia. In this article we summarise our and others' work in this area, focusing on a new view of amnesia we refer to as the representational-hierarchical view. According to this view-and in contrast to the prevailing paradigm in the field-the brain is best understood as a hierarchically organized continuum of representations, each of which is useful for a variety of cognitive functions. We focus our review on four visual discrimination paradigms that have been successfully translated into the human arena: configural concurrent discriminations, pair-wise "morph" discriminations, oddity discriminations, and configural oddity discriminations. The data from the animal studies are first reviewed, followed by illustrations of how the tasks have been utilized in human research. We then turn to the canonical impairment in animal models of amnesia, object recognition, and show how impairments in object recognition can be understood within the representational-hierarchical framework. This is followed by a discussion of predictions of the view related to classic issues in amnesia research, namely whether amnesia is due to a deficit of encoding, storage or retrieval, and the related issue of the role of interference in amnesia. Finally, we provide evidence from animal and human studies that even the hippocampus-almost universally regarded as a module for memory-may be better understood within the representational-hierarchical paradigm. PMID- 20206191 TI - Circular swimming in mice after exposure to a high magnetic field. AB - There is increasing evidence that exposure to high magnetic fields of 4T and above perturbs the vestibular system of rodents and humans. Performance in a swim test is a sensitive test of vestibular function. In order to determine the effect of magnet field exposure on swimming in mice, mice were exposed for 30 min within a 14.1T superconducting magnet and then tested at different times after exposure in a 2-min swim test. As previously observed in open field tests, mice swam in tight counter-clockwise circles when tested immediately after magnet exposure. The counter-clockwise orientation persisted throughout the 2-min swim test. The tendency to circle was transient, because no significant circling was observed when mice were tested at 3 min or later after magnet exposure. However, mice did show a decrease in total distance swum when tested between 3 and 40 min after magnet exposure. The decrease in swimming distance was accompanied by a pronounced postural change involving a counter-clockwise twist of the pelvis and hindlimbs that was particularly severe in the first 15s of the swim test. Finally, no persistent difference from sham-exposed mice was seen in the swimming of magnet-exposed mice when tested 60 min, 24h, or 96 h after magnet exposure. This suggests that there is no long-lasting effect of magnet exposure on the ability of mice to orient or swim. The transient deficits in swimming and posture seen shortly after magnet exposure are consistent with an acute perturbation of the vestibular system by the high magnetic field. PMID- 20206192 TI - Maternal separation produces, and a second separation enhances, core temperature and passive behavioral responses in guinea pig pups. AB - During separation in a novel cage, guinea pig pups exhibit passive behavior that appears due to increased proinflammatory activity. To determine if separation also produces a febrile response, the present study used telemetry to provide continuous core temperature measurement of pups exposed to a novel cage for 3h while either alone or with their mother on two consecutive days. Separation from the mother increased core temperature, with the clearest effects occurring early during separation the second day. The increased temperature was not associated with an increase in locomotor activity. Further, passive behavior during isolation exhibited pronounced sensitization from the first to second day of separation. These results show that separation produces an increase in core temperature in our testing situation, and suggest that this increase represents true fever. The findings also provide further support for the hypothesis that maternal separation induces aspects of an acute phase response in guinea pig pups. The potential role of proinflammatory activity in promoting change across days in temperature and behavior is discussed. PMID- 20206193 TI - GLP-1 antagonism with exendin (9-39) fails to increase spontaneous meal size in rats. AB - Intravenous and intraperitoneal (IP) administration of glucagon like peptide-1 (7 36)-amide (GLP-1) inhibits eating, but the physiological relevance of this satiating effect is not yet clear. We addressed this issue by testing the effects of the GLP-1 receptor antagonist exendin 9-39 (Ex (9-39)) on spontaneous eating and on the satiating effect of exogenous GLP-1. Adult, male Sprague-Dawley rats were equipped with chronic IP catheters and received intrameal infusions (0.2 ml/min, 2.5 min) that were remotely triggered 2-3 min after the onset of the first or the second spontaneous nocturnal meal. Infusions of 10, but not 5 or 2.5 nmol/kg body weight (BW) GLP-1 significantly reduced the size of the first spontaneous nocturnal meal compared to vehicle. The first intermeal interval, subsequent meal sizes and cumulative food intake were unchanged by 10 nmol/kg GLP 1. Infusions of 10 or 30 nmol/kg BW Ex (9-39) during the second spontaneous nocturnal meal did not affect the size of that meal and decreased rather than increased meal duration. Co-infusion of 30 nmol/kg BW Ex (9-39) prevented the satiating effect of 10 nmol/kg BW GLP-1 during the first spontaneous nocturnal meal, but again did not increase meal size by itself. That a dose of Ex (9-39) that is sufficient to block the satiating effect of exogenous GLP-1 failed to increase meal size when administered alone under comparable conditions suggests that endogenous intestinal GLP-1 is not required for the control of spontaneous meal size in rats under our conditions. The situations in which GLP-1 is of physiological relevance for satiation require further research. PMID- 20206194 TI - Multi-hormonal weight loss combinations in diet-induced obese rats: therapeutic potential of cholecystokinin? AB - Cholecystokinin (CCK) acutely synergizes with amylin to suppress food intake in lean mice. To extend on these findings, the present studies sought to identify neural correlates for the interaction of amylin and CCK, as well as further understand the therapeutic potential of CCK-based combinations in obesity. First, c-Fos activation was assessed in various brain nuclei after a single intraperitoneal injection of amylin (5microg/kg) and/or CCK (5microg/kg). Amylin and CCK additively increased c-Fos within the area postrema (AP), predominantly in noradrenergic (e.g., dopamine-beta-hydroxylase-containing) cells. Next, amylin (100 or 300microg/kg/d) and/or CCK (100 or 300microg/kg/d) were subcutaneously infused for 7days in diet-induced obese (DIO) rats. Amylin treatment of DIO rats for 7days induced significant body weight loss. CCK, while ineffective alone, significantly enhanced body weight loss when co-administered with the higher dose of amylin. Finally, the addition of CCK (300microg/kg/d) to leptin (125microg/kg/d), and to the combination of amylin (50microg/kg/d) and leptin (125microg/kg/d), was also explored in DIO rats via sustained subcutaneous infusion for 14days. Infusion of amylin/leptin/CCK for 14days exerted significantly greater body weight loss, inhibition of food intake, and reduction in adiposity compared to amylin/leptin treatment alone in DIO rats. However, co infusion of CCK and leptin was an ineffective weight loss regimen in this model. Whereas CCK agonism alone is ineffective at eliciting or maintaining weight loss, it durably augmented the food intake and body weight-lowering effects of amylin and amylin/leptin in a relevant disease model, and when combined with amylin, cooperatively activated neurons within the caudal brainstem. PMID- 20206195 TI - Synthesis of regioisomeric 17beta-N-phenylpyrazolyl steroid derivatives and their inhibitory effect on 17alpha-hydroxylase/C(17,20)-lyase. AB - The reaction of 3beta-hydroxy-21-hydroxymethylidenepregn-5-en-3beta-ol-20-one (1) with phenylhydrazine (2a) affords two regioisomers, 17beta-(1-phenyl-3 pyrazolyl)androst-3-en-3beta-ol (5a) and 17beta-(1-phenyl-5-pyrazolyl)androst-5 en-3beta-ol (6a). The direction of the ring-closure reactions of 1 with p substituted phenylhydrazines (2b-e) depends strongly on the electronic features of the substituents. Oppenauer oxidation of 3beta-hydroxy-17beta-exo-heterocyclic steroids 5a-e and 6a-e yielded the corresponding Delta(4)-3-ketosteroids 9a-e and 10a-e. The inhibitory effects (IC(50)) of these compounds on rat testicular C(17,20)-lyase were investigated by means of an in vitro radioligand incubation technique. PMID- 20206196 TI - Ciguatera fish poisoning and sea surface temperatures in the Caribbean Sea and the West Indies. AB - Ciguatera fish poisoning (CFP) is a circumtropical disease caused by ingestion of a variety of reef fish that bioaccumulate algal toxins. Distribution and abundance of the organisms that produce these toxins, chiefly dinoflagellates of the genus Gambierdiscus, are reported to correlate positively with water temperature. Consequently, there is growing concern that increasing temperatures associated with climate change could increase the incidence of CFP. This concern prompted experiments on the growth rates of six Gambierdiscus species at temperatures between 18 degrees C and 33 degrees C and the examination of sea surface temperatures in the Caribbean and West Indies for areas that could sustain rapid Gambierdiscus growth rates year-round. The thermal optimum for five of six Gambierdiscus species tested was >/=29 degrees C. Long-term SST data from the southern Gulf of Mexico indicate the number of days with sea surface temperatures >/=29 degrees C has nearly doubled (44 to 86) in the last three decades. To determine how the sea surface temperatures and Gambierdiscus growth data correlate with CFP incidences in the Caribbean, a literature review and a uniform, region-wide survey (1996-2006) of CFP cases were conducted. The highest CFP incidence rates were in the eastern Caribbean where water temperatures are warmest and least variable. PMID- 20206197 TI - Dramatic intraspecimen variations within the injected venom of Conus consors: an unsuspected contribution to venom diversity. AB - With the advent of highly sensitive mass spectrometry techniques, the minute amount of various secretions produced by living animals can be studied to a level of details never attained before. In this study, we used LC-ESI-MS to analyse the injected venom of an indo-pacific piscivorous cone snail, Conus consors. While long-term follow up of several captive specimens have revealed a typical "venom fingerprint" for this species, dramatic variations were also observed. In the most extreme case, a single cone snail unexpectedly produced two very distinct venom profiles containing completely different sets of peptides with no overlap of detected masses. Surprisingly, there was no correlation between the peptides produced in the venom duct and those obtained after milking live cone snails, implying yet unknown mechanisms of selection and regulation. Our study defines the notion of intraspecimen variation and demonstrates how this phenomenon contributes to the overall venom diversity. PMID- 20206198 TI - Cytotoxic effect of palytoxin on mussel. AB - Palytoxin is a large and complex polyhydroxylated molecule with potent neurotoxic activity. Dinoflagellates from the Ostreopsis genera were demonstrated to be producers of this compound and analogues. Even though initially palytoxin appearance was restricted to tropical areas, the recent occurrence of Ostreopsis outbreaks in Mediterranean Sea point to a worldwide dissemination probably related to climatic change. Those dinoflagellates can bioaccumulate in shellfish, especially in filter-feeding mollusks and have been involved in damaging effects in seafood or human toxic outbreaks. The present study describes palytoxins effect on metabolic activity of mantle and hepatopancreas cells from the mussel Mytilus galloprovincialis Lmk. Our results indicate that palytoxin is highly cytotoxic to mussel cells; unlike it happens with other toxins more common in European coasts such as okadaic acid and azaspiracid. These findings have a special significance for the marine environment and aquiculture since they are evidence for the ability of palytoxin to affect the integrity of bivalve mollusks that are not adapted to the presence of this toxin. PMID- 20206199 TI - Structural and pharmacological characterization of the crotamine isoforms III-4 (MYX4_CROCu) and III-7 (MYX7_CROCu) isolated from the Crotalus durissus cumanensis venom. AB - Two major crotamine isoforms (III-4 and III-7) were obtained combining two chromatographic steps on molecular exclusion chromatography (Sephadex G-75) and ion-exchange column (Protein Pack SP 5PW) of the rattlesnake Crotalus durissus cumanensis venom. The "in vivo" myotoxic effect of the venom, its "in vitro" cytotoxicity in myoblasts and myotubes (C2C12) and the neurotoxic and edema forming activity were characterized. The molecular masses of the crotamine isoforms were 4907.94 Da (III-4) and 4985.02 Da (III-7) and, as determined by mass spectrometry, both contained six Cys residues. Enzymatic hydrolysis followed by de novo sequencing through tandem mass spectrometry was used to determine the primary structure of both isoforms. III-4 and III-7 isoforms presented a 42-amino acid residues sequence and showed high molecular amino acid sequence identity with other crotamine-like proteins from Crotalus durissus terrificus. In vivo, both crotamine isoforms induced myotoxicty and a systemic interleukin-6 response upon intramuscular injection. These new crotamine isoforms induced low cytotoxicity in skeletal muscle myoblasts and myotubes (C2C12) and both induced a facilitatory effect on neuromuscular transmission in young chick biventer cervicis preparation. Edema-forming activity was also analyzed by injection of the crotamine isoforms into the right paw, since both crotamine isoforms exert a strong pro-inflammatory effect. PMID- 20206201 TI - The causes of cancer revisited: "mitochondrial malignancy" and ROS-induced oncogenic transformation - why mitochondria are targets for cancer therapy. AB - The role of oncoproteins and tumor suppressor proteins in promoting the malignant transformation of mammalian cells by affecting properties such as proliferative signalling, cell cycle regulation and altered adhesion is well established. Chemicals, viruses and radiation are also generally accepted as agents that commonly induce mutations in the genes encoding these cancer-causing proteins, thereby giving rise to cancer. However, more recent evidence indicates the importance of two additional key factors imposed on proliferating cells that are involved in transformation to malignancy and these are hypoxia and/or stressful conditions of nutrient deprivation (e.g. lack of glucose). These two additional triggers can initiate and promote the process of malignant transformation when a low percentage of cells overcome and escape cellular senescence. It is becoming apparent that hypoxia causes the progressive elevation in mitochondrial ROS production (chronic ROS) which over time leads to stabilization of cells via increased HIF-2alpha expression, enabling cells to survive with sustained levels of elevated ROS. In cells under hypoxia and/or low glucose, DNA mismatch repair processes are repressed by HIF-2alpha and they continually accumulate mitochondrial ROS-induced oxidative DNA damage and increasing numbers of mutations driving the malignant transformation process. Recent evidence also indicates that the resulting mutated cancer-causing proteins feedback to amplify the process by directly affecting mitochondrial function in combinatorial ways that intersect to play a major role in promoting a vicious spiral of malignant cell transformation. Consequently, many malignant processes involve periods of increased mitochondrial ROS production when a few cells survive the more common process of oxidative damage induced cell senescence and death. The few cells escaping elimination emerge with oncogenic mutations and survive to become immortalized tumors. This review focuses on evidence highlighting the role of mitochondria as drivers of elevated ROS production during malignant transformation and hence, their potential as targets for cancer therapy. The review is organized into five main sections concerning different aspects of "mitochondrial malignancy". The first concerns the functions of mitochondrial ROS and its importance as a pacesetter for cell growth versus senescence and death. The second considers the available evidence that cellular stress in the form of hypoxic and/or hypoglycaemic conditions represent two of the major triggering events for cancer and how oncoproteins reinforce this process by altering gene expression to bring about a common set of changes in mitochondrial function and activity in cancer cells. The third section presents evidence that oncoproteins and tumor suppressor proteins physically localize to the mitochondria in cancer cells where they directly regulate malignant mitochondrial programs, including apoptosis. The fourth section covers common mutational changes in the mitochondrial genome as they relate to malignancy and the relationship to the other three areas. The last section concerns the relevance of these findings, their importance and significance for novel targeted approaches to anti-cancer therapy and selective triggering in cancer cells of the mitochondrial apoptotic pathway. PMID- 20206202 TI - Structure-function characteristics of the biomaterials based on milk-derived proteins. AB - There is an impetus on development of implantable biomaterials with the characteristics of improved biodegradability, bio-absorbability and wound healing activities. The milk proteins have valuable nutritional and biological properties, which lead to the promotion of quality health. In this study, whey protein isolate or WPI (highly aggregated) and its component lactalbumin (less aggregated) were melt blended with polycaprolactone (PCL) and then compression moulded into thin sheets ( approximately 1mm thickness). The effects of structural morphologies of the proteins on the mechanical, morphological, in vitro enzymatic degradation, and cytotoxicity and cell proliferation characteristics of the biomaterials were examined. In general, the tensile strength and modulus of the biomaterials decreased with increasing protein content. Compared to WPI, lactalbumin showed a better compatibility with the PCL matrix as observed in the mechanical properties and scanning electron microscopic morphology. The biomaterials exhibited a good retention of the mechanical characteristics after digestion in a physiologically simulated fluid containing trypsin enzyme. However, lactalbumin containing biomaterials showed a better retention of the tensile properties compared to WPI containing biomaterials. The cell culture studies indicated that the biomaterials have no cytotoxic effects, moreover they enhanced the proliferation of L929 cells compared to the pure PCL. Finally, this study indicated that the PCL based biomaterials with a protein content of 20wt% may be applied in fabrication of implantable devices for soft tissue engineering, where it requires a reasonably low to moderate mechanical strength (e.g., approximately 10MPa tensile strength), and improved biodegradability, biocompatibility and tissue healing activities. PMID- 20206203 TI - Nanoscale measurements of the assembly of collagen to fibrils. AB - Observing the self-assembly of collagen from single collagen monomers to higher order fibrils and fibers provides a bottom-up approach to engineering its ultrastructure in comparison to structural studies of already formed collagen fibers. This approach can be used for the fabrication of controlled collagen based biomaterials with varying mechanical properties. Here, we investigate the time-dependent self-assembly of collagen into single fibrils in vitro through high resolution imaging of collagen type 1 prior to fibrillogenesis. This was confirmed by comparing persistence length and diameter in controlled experiments and studying the morphology and mechanical properties of nanoscale collagen fibrils through AFM nanoindentation measurements. The Young's modulus of these collagen fibrils was estimated to be around 1GPa in the dehydrated state. The stability and mechanical characteristics of collagen obtained in these experiments indicate the hierarchical assembly occurs at both a structural and mechanical level. PMID- 20206204 TI - Developmental determinants of sensitivity and resistance to stress: a tribute to Seymour "Gig" Levine. PMID- 20206205 TI - Neutrophil CD64 expression as marker of bacterial infection: a systematic review and meta-analysis. AB - OBJECTIVE: We performed a systematic review and meta-analysis of studies to evaluate the diagnostic accuracy of expression of CD64 on polymorphonuclear neutrophils (PMN) as a marker for bacterial infection. METHODS: The analysis included studies of patients from all age groups that prospectively evaluated CD64 expression on PMNs for the diagnosis of bacterial infection. We evaluated the methodological quality of the studies according to the 25-item criteria developed by the Standards for Reporting of Diagnostic Accuracy (STARD) committee. We calculated a summary receiver operating characteristic (SROC) curve across studies included in the meta-analysis. RESULTS: The methodological quality score of the 13 included studies ranged from 9 to 16 points (maximum score was 25 points). The pooled sensitivity and specificity for CD64 expression on PMNs were 79% (95% CI: 70-86%) and 91% (95% CI: 85-95%), respectively. The area under curve (AUC) was 0.94. CONCLUSIONS: On the basis of this meta-analysis, CD64 expression on PMNs could be a useful diagnostic cell-based parameter of bacterial infections. However, published studies about this topic showed a low methodological quality. PMID- 20206206 TI - Prion infection of differentiated neurospheres. AB - Until now only a few cell lines have been proved able to propagate prions and only limited prion strains have been replicated in cell models. Neurosphere lines isolated from the brains of mice at embryonic day 14 grow as aggregates and contain CNS stem cells. Others authors have previously reported that cultured neurospheres expressing cellular prion protein (PrP(C)) can be infected with prions. As potential neural progenitors the neurosphere cultures are supposed to differentiate into neurons and astrocytes which represent the main cell types infected by prions in vivo. Here we study the ability of undifferentiated and differentiated neurospheres to replicate several prion strains. Neurosphere cultures were isolated from 129/ola, FVB, Prnp(0/0) and Tga20 mice, which over express murine PrP. We were not able to detect PrP(res) accumulation in dividing neurosphere cultures after prion exposure to two different mouse adapted scrapie inocula (RML and 22L). In contrast, with differentiated neurosphere cultures expressing PrP(C) (129/ola, FVB and Tga20) a successful PrP(Res) amplification was observed in very short time experiments when infected with the same inocula, implying that cell differentiation improve prion replication in these cultured cells. The mouse BSE adapted inocula (301C) was not amplified in these neurosphere cultures neither before nor after differentiation, suggesting that these cell cultures showed a differential prion strain susceptibility. These results suggest that differentiated neurosphere cultures can complement prion bioassays in mouse models. PMID- 20206200 TI - Developmental gene x environment interactions affecting systems regulating energy homeostasis and obesity. AB - Most human obesity is inherited as a polygenic trait which is largely refractory to medical therapy because obese individuals avidly defend their elevated body weight set-point. This set-point is mediated by an integrated neural network that controls energy homeostasis. Epidemiological studies suggest that perinatal and pre-pubertal environmental factors can promote offspring obesity. Rodent studies demonstrate the important interactions between genetic predisposition and environmental factors in promoting obesity. This review covers issues of development and function of neural systems involved in the regulation of energy homeostasis and the roles of leptin and insulin in these processes, the ways in which interventions at various phases from gestation, lactation and pre-pubertal stages of development can favorably and unfavorably alter the development of obesity n offspring. These studies suggest that early identification of obesity prone humans and of the factors that can prevent them from becoming obese could provide an effective strategy for preventing the world-wide epidemic of obesity. PMID- 20206207 TI - Human dendritic cells contain cell surface sialyltransferase activity. AB - Human monocyte-derived dendritic cells (mo-DCs) express highly sialylated structures, with recognized but poorly understood function in maturation, immunogenicity and endocytosis capacity. We have previously shown that mo-DCs surface sialylation is changeable upon different stimuli, which led us to hypothesise the existence of cell surface (non-intracellular) sialyltransferases, rapidly restoring or altering mo-DC surface sialylation, thus modulating specific functions. Here, we demonstrate that, in the presence of exogenous CMP-Neu5Ac, mo DCs incorporate considerable amounts of sialic acids into cell surface, predominantly when mo-DCs were previously desialylated or matured. This is a genuine sialyltransferase activity, confirmed by specific inhibition assays, which is not influenced by secreted enzymes. Functionally, the ecto sialyltransferase activity causes a significant down-regulation of mo-DCs endocytic capacity, without affecting the maturation state. These findings suggest that ecto-sialyltransferases participate in a dynamic control of mo-DC sialylation, with functional repercussions. This activity is possibly related with specific physiological and pathological conditions, as inflammation and infection, contributing to protection and homeostasis regulation. PMID- 20206208 TI - Effects of hypoxia and/or lack of glucose on cellular energy metabolism and cytokine production in stimulated human CD4+ T lymphocytes. AB - Oxidative phosphorylation and/or glycolysis provide energy, mainly in the form of ATP, which ensures proper functioning of immune cells such as CD4(+) T lymphocytes. However, the main substrates, namely oxygen and glucose, are known to remain for a relatively short time in the inflamed tissue and in other clinical situations where immune cells need to function properly. Therefore, we examined the effect of hypoxia and/or lack of glucose on cellular energy metabolism and on cytokine secretion in stimulated human CD4(+) T lymphocytes. Human CD4(+) T cells were MACS-isolated using peripheral blood obtained from healthy donors. Stimulated cells were incubated in medium with or without glucose for 6h in a sealed chamber which led to cumulative hypoxia. During this incubation period, (i) oxygen saturation was measured continuously using a Clark type electrode, and (ii) samples were taken at different time points in order to quantify for each the viability of cells, intracellular reactive oxygen species (iROS), ATP levels, glycolytic enzyme activity, mRNA expression of hexokinase-1 and superoxide dismutase-1, and concentrations of several different cytokines. Stimulated CD4(+) T cells which were incubated under normoxic conditions served as controls. Under hypoxic conditions, lack of glucose exerted a biphasic effect on cellular oxygen consumption: initially higher but later lower respiration rates were measured when compared to conditions where glucose was available. Lack of glucose strongly increased the number of dead cells and the formation of iROS under normoxia but not under hypoxia. Under both normoxic and hypoxic conditions, intracellular ATP levels remained almost unchanged during the incubation period if glucose was present, but decreased significantly in the absence of glucose, despite the enhanced glycolytic enzyme activity. Measurements of stimulated cytokine production demonstrated (i) that cumulative hypoxia stimulates especially the secretion of IL-1beta, IL-10 and IL-8, and (ii) that lack of glucose results in lower cytokine concentrations. We demonstrate that CD4(+) T cells are highly adaptive in bioenergetic terms which ensure their proper function under extreme conditions of glucose and/or oxygen availability as found under physiological and pathophysiological conditions. Hypoxia seems to facilitate inflammatory reactions and angiogenesis. PMID- 20206209 TI - Nicotinic modulation of auditory attentional shift in the rat. AB - Numerous studies have demonstrated cognitive improvements resulting from the application of nicotine, especially in those tasks aimed at measuring attention. While the neuro-pharmacological relationship between nicotine and acetylcholine driven attentional processes has been examined, studies tend to focus on the duration of time in which a subject can attend to a specific stimulus or series of stimuli rather than on the subjects' adaptive attentional capabilities. The present study addresses the possibility that the cholinergic agonist nicotine could improve performance on a task testing the ability to shift attention between sensory modalities under both normal and pharmacologically impaired conditions. In a pilot set of experiments, we tested the effects of nicotine in a cross-modal experimental task designed to tax both the auditory and visual systems of male Sprague-Dawley rats. Nicotine (0.2 mg/kg) significantly improved performance on both auditory and visual trials, under repetitive trial conditions, and significantly decreased overall response latency. For the primary study, we tested the effects of decreasing cholinergic neurotransmission by systemic administration of the muscarinic antagonist atropine. Atropine (12.5 mg/kg) significantly impaired performance in auditory shift trials and perseverative trials, while significantly increasing the overall response latency. We then tested the effect of nicotine within the impaired model. Systemic administration of nicotine significantly improved performance in auditory and visual shift trials, while showing moderate improvements in response latency and perseverative trial conditions. These results indicate the potential therapeutic use of nicotine as a cognitive enhancer, as well as provide evidence for cholinergic system compensations. PMID- 20206210 TI - Voluntary exercise reduces the neurotoxic effects of 6-hydroxydopamine in maternally separated rats. AB - Maternal separation has been associated with development of anxiety-like behaviour and learning impairments in adult rats. This has been linked to changes in brain morphology observed after exposure to high levels of circulating glucocorticoids during the stress-hyporesponsive period (P4-P14). In the present study, adult rats that had been subjected to maternal separation (180 min/day for 14 days) during the stress-hyporesponsive period, received unilateral infusions of a small dose of 6-hydroxydopamine (6-OHDA, 5 microg/4 microl saline) into the medial forebrain bundle. The results showed that voluntary exercise had a neuroprotective effect in both non-stressed and maternally separated rats in that there was a decrease in forelimb akinesia (step test) and limb use asymmetry (cylinder test). Maternal separation increased forelimb akinesia and forelimb use asymmetry and reduced the beneficial effect of exercise on forelimb akinesia. It also reduced exploratory behaviour, consistent with anxiety-like behaviour normally associated with maternal separation. Exercise appeared to reduce dopamine neuron destruction in the lesioned substantia nigra when expressed as a percentage of the non-lesioned hemisphere. However, this appeared to be due to a compensatory decrease in completely stained tyrosine hydroxylase-positive neurons in the contralateral, non-lesioned substantia nigra. In agreement with reports that maternal separation increases the 6-OHDA-induced loss of dopamine terminals in the striatum, there was a small increase in dopamine neuron destruction when expressed as a percentage of the non-lesioned hemisphere but there was no difference in dopamine cell number, suggesting that exposure to maternal separation did not exacerbate dopamine cell loss. PMID- 20206211 TI - Dopaminergic modulation of the orbitofrontal cortex affects attention, motivation and impulsive responding in rats performing the five-choice serial reaction time task. AB - Understanding the neurobiological factors underlying individual differences in impulsivity may provide valuable insight into vulnerability to impulse control disorders. Recent data implicate both the orbitofrontal cortex (OFC) and the dopaminergic system in psychiatric disorders associated with high levels of impulsivity, including substance abuse, mania and obsessive-compulsive disorder. However, the consequences of modulating dopaminergic activity within the OFC on impulsive behaviour are largely unknown. The effects of direct intra-OFC infusions of agonists and antagonists at the dopamine D(1) and D(2) receptors were therefore assessed in rats performing the five-choice serial reaction time test (5CSRT) of attention and motor impulsivity. Intra-OFC administration of SCH23390, a D(1) receptor antagonist, decreased impulsive responding in highly impulsive (HI) rats, but did not affect behaviour in less impulsive (LI) animals. Furthermore, the D(2) agonist quinpirole caused significant deficits in task performance, impairing accuracy, increasing omissions and decreasing the number of trials completed, which resembled the effects of systemic administration. In contrast, the D(1) agonist SKF 81297 had little effect on behaviour. Neither agonist increased impulsivity. These data provide partial support for the suggestion that high levels of impulsivity are associated with increased dopamine levels within the OFC, but further indicate that simulating dopamine's actions selectively at the D(1) or D(2) receptor cannot reproduce a highly impulsive phenotype. Dopaminergic activity within the OFC may therefore modulate impulsivity indirectly, perhaps in conjunction with other neurotransmitter systems. Furthermore, D(2)-mediated neurotransmission within the OFC could make a more fundamental contribution to cognitive behaviour. PMID- 20206212 TI - Quinolinate phosphoribosyl transferase, a key enzyme in de novo NAD(+) synthesis, suppresses spontaneous cell death by inhibiting overproduction of active-caspase 3. AB - Quinolinate phosphoribosyl transferase (QPRT) is a key enzyme in de novo NAD(+) synthesis. QPRT enzyme activity has a restricted tissue distribution, although QPRT mRNA is expressed ubiquitously. This study was designed to elucidate the functions of QPRT protein in addition to NAD(+) synthesis. QPRT was identified as a caspase-3 binding protein using double layer fluorescent zymography, but was not a substrate for caspase-3. Surface plasmon resonance analysis using recombinant proteins showed interaction of QPRT with active-caspase-3 in a dose dependent manner at 55 nM of the dissociation constant. The interaction was also confirmed by immunoprecipitation analysis of actinomycin D-treated QPRT-FLAG expressing cells using anti-FLAG-agarose. QPRT-depleted cells showed increased sensitivity to spontaneous cell death, upregulated caspase-3 activity and strong active-caspase-3 signals. Considered together, the results suggested that QPRT protein acts as an inhibitor of spontaneous cell death by suppressing overproduction of active-caspase-3. PMID- 20206213 TI - Facial expression arousal level modulates facial mimicry. AB - We investigated the effect of facial expression arousal level and mode of presentation on facial mimicry. High- and low-arousal facial expressions indicating pleasant and unpleasant emotions were presented both statically and dynamically. Participants' facial electromyographic (EMG) reactions were recorded from the zygomatic major and corrugator supercilii muscles. Stronger zygomatic major muscle activity was evoked for high- compared to low-arousal pleasant expressions. Comparable activity was induced in the corrugator supercilii muscle in response to both high- and low-arousal unpleasant expressions, and this was true for both dynamic and static presentations. These results suggest that the arousal levels of pleasant, but not unpleasant, facial expressions can enhance facial mimicry. PMID- 20206214 TI - Isolation of a recombinant type 3/type 2 poliovirus with a chimeric capsid VP1 from sewage in Shandong, China. AB - The genetic and phenotypic characterization of poliovirus strain P3/Jinan/1/09, isolated from sewage sample in Jinan city, Shandong province, China, was described. The strain had a Sabin type 3/type 2/type 3 recombinant genome, with the first crossover site located in capsid VP1 coding region between nucleotide positions 3293 and 3294 (numbering according to Sabin 3), and the second crossover site in 3D region between positions 6374 and 6378. The recombinant had introduced six Sabin 2-derived amino acids into the carboxyl terminus of Sabin 3 VP1 capsid protein. The complete genome of the isolate revealed eight nucleotide substitutions in Sabin 3 region with two substitutions resulting in amino acid alteration, and two missense substitutions in the Sabin 2 region. An estimation based on the evolution rate of the P1 coding region of Sabin 3 background suggested that evolution time of strain P3/Jinan/1/09 might be 76-80 days. The person who excreted the recombinant was not known and no evidence was obtained for its circulation in population via acute flaccid paralysis surveillance. The virus showed Sabin 3 serological characterization in neutralization test, and it did not lose temperature sensitivity phenotype at 40 degrees C. The significance of environmental surveillance and the presence of natural capsid recombinant poliovirus strain in the context of the global polio eradication initiative are discussed. PMID- 20206215 TI - Curing of HeLa cells persistently infected with equine arteritis virus by a peptide-conjugated morpholino oligomer. AB - A significant consequence of equine arteritis virus (EAV) infection of horses is persistence of the virus in a variable percentage of infected stallions. We recently established an in vitro model of EAV persistence in cell culture for the purpose of furthering our understanding of EAV biology in general and viral persistence in the stallion in particular. In this study we investigated whether persistently infected HeLa cells could be cured of EAV infection by treatment with an antisense peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) designed to target the 5'-terminal region of the EAV genome. We found that persistently infected HeLa cells passaged three times in the presence of 5-10 microM EAV-specific PPMO produced no detectable virus. The PPMO-cured HeLa cells were free of infectious virus, viral antigen and EAV RNA as measured by plaque assay, indirect immunofluorescence assay and RT-PCR, respectively. Furthermore, when re-challenged with EAV at several passages after discontinuation of PPMO treatments, PPMO-cured HeLa cells were found to be refractory to re-infection and to the re-establishment of viral persistence. While these findings demonstrate that PPMO can be used to eliminate persistent EAV infection in cell culture, the efficacy of PPMO against EAV in vivo remains to be addressed. PMID- 20206216 TI - Hunger induced changes in food choice. When beggars cannot be choosers even if they are allowed to choose. AB - The present work was to examine the influence of food deprivation on food choice. For this purpose hungry versus satiated subjects were presented with a series of choices between two snacks in a complete block design of pairwise comparisons. Snacks systematically varied with respect to subjects' idiosyncratic taste preferences (preferred versus un-preferred snack), portion size (large portion versus very small portion), and availability in terms of time (immediately available versus available only after a substantial time delay). Food choices were analyzed with a conjoint analysis which corroborated the assumption that food deprivation decreases the relative importance of taste preference and increases the importance of immediate availability of food. PMID- 20206217 TI - Type of snack influences satiety responses in adult women. AB - The effect of different snack foods on satiety and plasma glucose and hormone responses was assessed. Nineteen fasted adult women (mean age: 39.2 + or - 0.7 years, mean BMI: 26.1 + or - 0.8 kg/m(2)) consumed test foods including dried plums, low-fat cookies, white bread and water only on separate days. The test foods (with the exception of water) provided 238 kcal and were similar in total carbohydrate, fat and protein content but differed in fiber and sugar content. Subjects rated their feelings of hunger using satiety index scales prior to snack consumption and again every 15 min for 2h following initiation of intake. Blood samples were collected at baseline and 15, 30, 45, 60, 90, and 120 min following intake. At the end of the 120-min test period, subjects were presented with a meal to be consumed until satisfied. The satiety index AUC was greater for the dried plum trial versus the low-fat cookie trial (p < or = 0.05). There was no difference in post-snack consumption between the dried plums and cookie trials. The dried plums trial elicited lower plasma glucose and insulin AUC than the low fat cookie trial (p < or = 0.05) and tended to promote a greater plasma ghrelin AOC (p = 0.056). These results demonstrate that consuming dried plums as a snack suppresses hunger relative to a low-fat cookie as evidenced by lower glucose and/or satiety-regulating hormone concentrations. PMID- 20206218 TI - Purification and identification of three novel antioxidant peptides from Cornu Bubali (water buffalo horn). AB - Cornu Bubali (water buffalo horn, WBH) has been used in Traditional Chinese Medicine (TCM) for thousands of years. In the present study, three peptides with antioxidant properties were purified from aqueous extract of Cornu Bubali (water buffalo horn, WBH) by consecutive chromatographic methods including gel filtration chromatography, ion-exchange chromatography and high performance liquid chromatography. The sequences of the three peptides were identified to be Gln-Tyr-Asp-Gln-Gly-Val (WBH-1, 708Da), Tyr-Glu-Asp-Cys-Thr-Asp-Cys-Gly-Asn (WBH 2, 1018Da) and Ala-Ala-Asp-Asn-Ala-Asn-Glu-Leu-Phe-Pro-Pro-Asn (WBH-3, 1271Da) by matrix assisted laser desorption ionization time-of-flight/time-of-flight mass spectrometry (MALDI-LIFT-TOF/TOF MS). The antioxidant activity of these peptides was tested using 1-diphenyl-2-picrylhydrazyl (DPPH) scavenging assay directly. Methylthiazol tetrazolium (MTT) assay and lactate dehydrogenase (LDH) release assay were also used to evaluate the protection of peptides against hydrogen peroxide (H(2)O(2)) induced injury. The results showed that these peptides could reduce the DPPH radical and protect rat cerebral microvascular endothelial cells (rCMECs) against H(2)O(2)-induced injury, thus demonstrating that these peptides had antioxidant activity. These results suggest that WBH-1, WBH-2 and WBH-3, isolated from the aqueous extract of water buffalo horn are natural antioxidants and may contribute to the efficacy of WBH. PMID- 20206219 TI - A palmitoyl conjugate of insect pentapeptide Yamamarin arrests cell proliferation and respiration. AB - A palmitoyl conjugate of an insect pentapeptide that occurs in diapausing insects causes a reversible cell-cycle arrest and suppresses mitochondrial respiration. This peptide compound also causes growth arrest in murine leukemic cell line expressing human gene Bcr/Abl and a farnesoyl peptide induces embryonic diapause in Bombyx mori. These results demonstrate that the insect peptide compounds can lead to the understanding of a common pathway in developmental arrest in animals and may provide a new peptidominetic analog in the development of biopharmaceuticals and pest management. PMID- 20206220 TI - Oral and pulmonary delivery of thioether-bridged angiotensin-(1-7). AB - Instability and proteolytic degradation limit the delivery options and in vivo efficacy of many therapeutic peptides. We previously generated a thioether stabilized angiotensin-(1-7) analog, cAng-(1-7), which is resistant against proteolytic degradation in the circulation. We here investigated oral and pulmonary delivery of this compound. In a first step we investigated the in vitro stability of the peptide under conditions that mimic those that will be met after oral administration. We demonstrated that cAng-(1-7) is stable at pH 2.0, a pH value close to that of the stomach, has enhanced resistance to breakdown by proteases from pancreas at pH 7.4, and is resistant to breakdown by proteases from liver at the lysosomal pH 5.0. We subsequently demonstrated that, in the absence of any delivery system or formulation, cAng-(1-7) can be delivered orally and via the lung, with bioavailabilities of 0.28+/-0.05% and 28+/-5%, whereas drug uptake was maximal after subcutaneous administration (bioavailability of 98+/-6%). Therapeutic concentrations could be reached via all three routes of administration. The data prove that introduction of a thioether bridge in peptides opens novel delivery options for medically important peptides. PMID- 20206221 TI - Proteolytic degradation by cathepsin D of glycated hemoglobin from diabetes patients gives rise to hemorphin-7 peptides. AB - Previous studies showed a significantly reduced level of hemorphins in the serum of diabetes patients. In order to elucidate the biochemical mechanisms responsible for this anomaly, the influence of hemoglobin glycation on hemorphin generation was studied. The glycation of hemoglobin occurs in the blood of diabetes patients and this could modify its enzymatic digestion and the resulting proteolytic products. Several samples of hemoglobin were obtained from the blood of type 1 diabetes patients (n=8) and normal healthy control subjects (n=2). The glycated hemoglobin samples were classified on the basis of their HbA1c values expressed as a percentage of total hemoglobin. Four solutions of glycated hemoglobin characterized by HbA1c values of 6%, 9.1%, 10.7% and 12.1% were treated with cathepsin D and the hemorphins obtained following the proteolysis were compared to controls. It was found that hemorphins were produced whatever the level of glycation of hemoglobin and also that the degree of glycation had no effect on the quantity of hemorphins released. Thus the alteration of hemoglobin does not seem to be the essential reason for the decrease in hemorphin concentrations in the sera of diabetic patients. PMID- 20206222 TI - Atrial natriuretic peptides and urodilatin modulate proximal tubule Na(+)-ATPase activity through activation of the NPR-A/cGMP/PKG pathway. AB - The signaling pathway mediating modulation of Na(+)-ATPase of proximal tubule cells by atrial natriuretic peptides (ANP) and urodilatin through receptors located in luminal and basolateral membranes (BLM) is investigated. In isolated BLM, 10(-11)M ANP or 10(-11)M urodilatin inhibited the enzyme activity (50%). Immunodetection revealed the presence of NPR-A in BLM and LLC-PK1 cells. Both compounds increased protein kinase G (PKG) activity (80%) and this effect did not occur with 10(-6)M LY83583, a specific inhibitor of guanylyl cyclase. The inhibitory effect of these peptides on Na(+)-ATPase activity did not occur after addition of 10(-6)M KT5823, a specific inhibitor of PKG. LLC-PK1 cells were used to investigate if ANP and urodilatin change the activity of sodium pumps by luminal receptor interaction. ANP and urodilatin inhibited Na(+)-ATPase activity (50%), with maximal effect at 10(-10)M, similar to 10(-7)M db-cGMP, and did not occur with 10(-7)M LY83583, a guanylyl cyclase inhibitor. ANP and urodilatin specifically inhibit Na(+)-ATPase activity by activation of the cGMP/PKG pathway through NPR-A located in luminal membrane and BLM, increasing understanding of the mechanism of natriuretic peptides on renal sodium excretion, with proximal tubule Na(+)-ATPase one possible target. PMID- 20206223 TI - Impairment of in vitro generation of monocyte-derived human dendritic cells by inactivated human immunodeficiency virus-1: Involvement of type I interferon produced from plasmacytoid dendritc cells. AB - In an attempt to simplify the protocol of DC generation in vitro, studies conducted herein show that functional DCs could be generated from bulk peripheral blood mononuclear cells (PBMCs) in media containing GM-CSF and IL-4. Interestingly, when PBMCs, but not purified monocytes, were exposed to either CCR5- or CXCR4-tropic inactivated HIV-1 isolates (iHIV-1) at the initiation of the culture, DC yields were significantly reduced in a dose-dependent manner because of monocyte apoptosis. Similar impairment of DC generation was noted using type I IFNs and poly IC not only in cultures of PBMCs but also using highly enriched monocytes. This effect was reversed by antihuman type I IFN receptor, but not by anti-FasL, anti-TRAIL, anti-TNF, or a mixture of these antibodies. iHIV-1-exposed PBMCs, but not monocytes, produced high levels of IFN-alpha but not IFN-beta. PBMCs depleted of CD123(+) plasmacytoid DCs produced low levels of IFN-alpha and were resistant to iHIV-1-mediated DC impairment. Interestingly, exogenously added TNF reversed the impairment by iHIV-1 in the PBMC cultures. In conclusion, the present results indicate that iHIV-1 impairs the in vitro generation of functional DCs from PBMCs through the induction of IFN-alpha from plasmacytoid DCs in a CD4-dependent fashion in the absence of TNF. PMID- 20206224 TI - Increased uric acid levels in drug-naive subjects with bipolar disorder during a first manic episode. AB - Recent evidence suggests that purinergic system dysfunction may play a role in the pathophysiology and therapeutics of bipolar disorder (BPD). Uric acid is a key nitrogenous end product of purine metabolism. In addition to being a potential marker of treatment response, high levels of uric acid may represent a state marker during mania. In this study, we assessed the presence of purinergic dysfunction in 20 treatment-naive first episode patients with BPD who were experiencing a manic episode. Patients were matched with 24 healthy controls. We found that acutely manic patients had significantly higher levels of plasma uric acid (4.85+/-1.60 mg/dL) compared to healthy controls (2.96+/-0.63 mg/dL, p<0.001; F=28.1). No association between uric acid levels with severity of manic symptoms was observed. These results support the role of purinergic system dysfunction in BPD early in the course of illness, and suggest that this phenomenon is not the result of chronicity or medication exposure. Overall, our findings suggest a novel mechanism in the pathophysiology of BPD. PMID- 20206225 TI - Hair growth promoting effect of Zizyphus jujuba essential oil. AB - This study was undertaken to examine the efficacy of essential oil from seeds of Zizyphus jujuba for its potential role on hair growth by in vivo method. Essential oil was applied at different concentrations (0.1%, 1% and 10%) over the shaved skin onto the backs of BALB/c mice and monitored for 21 days. After 21 days, mice treated with 1% and 10% of oil produced a greater effect on the length of hair which were measured to be 9.96 and 10.02 mm, respectively, as compared to the control (8.94 mm). We measured the weight of hair/cm(2) area of dorsal skin and also evaluated hair thickness and hair follicles microscopically after plucking the hair immediately from the shaved area of mice and found the best results for 1% of essential oil-treated mice. From this study, it is concluded that Z. jujuba essential oil possesses hair growth promoting activity. PMID- 20206226 TI - Pay attention to your manipulation checks! Reward impact on cardiac reactivity is moderated by task context. AB - Two experiments assessed the moderating impact of task context on the relationship between reward and cardiovascular response. Randomly assigned to the cells of a 2 (task context: reward vs. demand) x 2 (reward value: low vs. high) between-persons design, participants performed either a memory task with an unclear performance standard (Experiment 1) or a visual scanning task with an unfixed performance standard (Experiment 2). Before performing the task--where participants could earn either a low or a high reward--participants responded to questions about either task reward or task demand. In accordance with the theoretical predictions derived from Wright's (1996) integrative model, reactivity of pre-ejection period increased with reward value if participants had rated aspects of task reward before performing the task. If they had rated task demand, pre-ejection period did not differ as a function of reward. PMID- 20206227 TI - Autonomic and hypothalamic-pituitary-adrenal stress resilience: Impact of cardiac vagal tone. AB - Resilience refers to the ability to cope with stressful events. Variation in the activity of the stress-responsive sympatho-adrenal-medullary and hypothalamic pituitary-adrenal axes is particularly important for adaptive stress responses and thus may give rise to individual differences in resilience. Here, we investigated whether cardiac vagal tone and adult attachment style are related to psychophysiological stress resilience by exposing a sample of healthy young men and women (n=68) to a laboratory stress test while monitoring autonomic (heart rate, salivary alpha-amylase), hypothalamic-pituitary-adrenal (salivary cortisol), and psychological stress levels. Our results demonstrate that adult attachment style did not influence autonomic, hypothalamic-pituitary-adrenal, or psychological stress responses. In contrast, higher resting cardiac vagal tone was associated with stress-induced increases in cortisol. This suggests a role for sympathetic influences on heart rate regulation in hypothalamic-pituitary adrenal stress responses, and extends previous observations of a link between vagal tone and stress resilience. PMID- 20206229 TI - Identification of domains responsible for specific membrane transport and ligand specificity of the ACTH receptor (MC2R). AB - The adrenocorticotropic hormone (ACTH) receptor has highly specific membrane expression that is limited to adrenal cells; in other cell types the polypeptide fails to be transported to the cell surface. Unlike other evolutionarily related members of the melanocortin receptor family (MC1R-MC5R) that recognize different melanocortin peptides, ACTHR (MC2R) binds only ACTH. We used a mutagenesis approach involving systematic construction of chimeric ACTHR/MC4R receptors to identify the domains determining the selectivity of ACTHR membrane transport and ACTH binding. In total 15 chimeric receptors were created by replacement of selected domains of human ACTHR with the corresponding regions of human MC4R. We developed an analytical method to accurately quantify cell-membrane localization of recombinant receptors fused with enhanced green fluorescent protein by confocal fluorescence microscopy. The chimeric receptors were also tested for their ability to bind ACTH (1-24) and the melanocyte-stimulating hormone (MSH) analog, Nle4, DPhe7-alpha-MSH, and to induce a cAMP response. Our results indicate that substitution of the MC4R N-terminal segment with the homologous segment of ACTHR significantly decreased membrane transport. We also identified another signal localized in the third and fourth transmembrane regions as the main determinant of ACTHR intracellular retention. In addition, we found that the fourth and fifth transmembrane domains of the ACTHR are involved in ACTH binding selectivity. We discuss the mechanisms involved in bypassing these arrest signals via an interaction with melanocortin 2 receptor accessory protein (MRAP) and the possible mechanisms that determine the high ligand-binding specificity of ACTHR. PMID- 20206228 TI - Runx1 isoforms show differential expression patterns during hematopoietic development but have similar functional effects in adult hematopoietic stem cells. AB - OBJECTIVE: RUNX1 (also known as acute myeloid leukemia 1) is an essential regulator of hematopoiesis and has multiple isoforms arising from differential splicing and utilization of two promoters. We hypothesized that the rare Runx1c isoform has a distinct role in hematopoietic stem cells (HSCs). MATERIALS AND METHODS: We have characterized the expression pattern of Runx1c in mouse embryos and human embryonic stem cell (hESC)-derived embryoid bodies using in situ hybridization and expression levels in mouse and human HSCs by real-time polymerase chain reaction. We then determined the functional effects of Runx1c using enforced retroviral overexpression in mouse HSCs. RESULTS: We observed differential expression profiles of RUNX1 isoforms during hematopoietic differentiation of hESCs. The RUNX1a and RUNX1b isoforms were expressed consistently throughout hematopoietic differentiation, whereas the RUNX1c isoform was only expressed at the time of emergence of definitive HSCs. RUNX1c was also expressed in the AGM region of E10.5 to E11.5 mouse embryos, the region where definitive HSCs arise. These observations suggested that the RUNX1c isoform may be important for the specification or function of definitive HSCs. However, using retroviral overexpression to study the effect of RUNX1 isoforms on HSCs in a gain of-function system, no discernable functional difference could be identified between RUNX1 isoforms in mouse HSCs. Overexpression of both RUNX1b and RUNX1c induced quiescence in mouse HSCs in vitro and in vivo. CONCLUSIONS: Although the divergent expression profiles of Runx1 isoforms during development suggest specific roles for these proteins at different stages of HSC maturation, we could not detect an important functional distinction in adult mouse HSCs using our assay systems. PMID- 20206230 TI - Effect of glutathione redox state on Leydig cell susceptibility to acute oxidative stress. AB - The free radical, or oxidative stress, theory posits that imbalance in cells between prooxidants and antioxidants results in an altered redox state and, over time, an accumulation of oxidative damage. We hypothesized herein that cells with an increasingly prooxidant intracellular environment also might be particularly susceptible to acute oxidative stress. To test this hypothesis, MA-10 cells were used as a model because of their well-defined, measurable function, namely progesterone production. We first experimentally altered the redox environment of the cells by their incubation with buthionine sulfoximine (BSO) or diethyl maleate (DEM) so as to deplete glutathione (GSH), and then exposed the GSH depleted cells acutely to the prooxidant tert-butyl hydroperoxide (t-BuOOH). Neither BSO nor DEM by themselves affected progesterone production. However, when the GSH-depleted cells subsequently were exposed acutely to t-BuOOH, intracellular reactive oxygen species concentration was significantly increased, and this was accompanied by significant reductions in progesterone production. In striking contrast, treatment of control cells with t-BuOOH had no effect. Depletion of GSH and subsequent treatment of the cells with t-BuOOH-induced the phosphorylation of each of ERK1/2, JNK and p38, members of the MAPK family. Inhibition of p38 phosphorylation largely prevented the t-BuOOH-induced down regulation of progesterone production in GSH-depleted cells. These results suggest that, as hypothesized, alteration of the intracellular GSH redox environment results in the increased sensitivity of MA-10 cells to oxidative stress, and that this is mediated by activation of one or more redox-sensitive MAPK members. PMID- 20206231 TI - Tetramethylpyrazine promotes proliferation and differentiation of neural stem cells from rat brain in hypoxic condition via mitogen-activated protein kinases pathway in vitro. AB - This study investigated the effects of tetramethylpyrazine (TMP), an active element of traditional Chinese medicine Ligusticum Chuanxiong, on proliferation and differentiation of neural stem cells (NSCs) from rat brain in hypoxia condition and the activation of mitogen-activated protein kinases (MAPKs) signaling pathway during the processes. The results showed that TMP promoted the proliferation and differentiation of the NSCs into neurons. TMP increased the phosphorylation of ERK1/2 and decreased the phosphorylation of p38 at different time points. ERK inhibitor (U0126) in part blocked the differentiation of the NSCs into neurons induced by TMP. Our findings demonstrated that TMP enhanced the proliferation and differentiation of NSCs of rat after hypoxia in vitro, in which the phosphorylation of ERK and p38 was involved. PMID- 20206232 TI - Mitochondrial base excision repair pathway failed to respond to status epilepticus induced by pilocarpine. AB - Oxidative damage to mitochondrial DNA (mtDNA) has been implicated as an important mechanism underlying mitochondrial deficiency in epileptic seizures. In focusing on the role of the DNA repair pathway, we determined the response of the mitochondrial base excision repair (mtBER) pathway in pilocarpine-induced status epilepticus (SE) in hippocampi of male Wistar rats. The expression of 8 oxoguanine DNA glycosylase (OGG1) and polymerase gamma (polgamma) was decreased at both the cellular mRNA and mitochondrial protein levels at 3, 9 and 25h after the onset of SE. The mRNA and protein levels of APE1 were maintained, but the mitochondrial protein level decreased at 3 and 9h and recovered at 25h. Therefore, the mtBER pathway failed to respond to SE induced by pilocarpine. The failure of mitochondrial import might be an important factor responsible for the lowered mtBER enzymes in mitochondria. We hypothesize that the down-regulation of mtBER enzymes may aggravate mtDNA damage and mitochondrial deficiency after the onset of SE. PMID- 20206233 TI - Developmental regulation and neuroprotective effects of striatal tonic GABAA currents. AB - Striatal neurons are known to express GABA(A) receptor subunits that underlie both phasic and tonic inhibition. Striatal projection neurons, or medium spiny neurons (MSNs), are divided into two classes: MSNs containing the dopamine D1 receptor (D1-MSNs) form the direct pathway to the substantia nigra and facilitate movement while MSNs expressing the dopamine D2 receptor (D2-MSNs) form the pallidal pathway that inhibits movement. Consequently, modulating inhibition in distinct classes of MSNs will differentially impact downstream network activity and motor behavior. Given the powerful role of extrasynaptic inhibition in controlling neuronal excitability, we examined the nature of striatal tonic inhibition and its potential role in preventing excitotoxicity. Consistent with earlier studies in young (P16-P25) mice, tonic GABA currents in D2-MSNs were larger than in D1-MSNs. However, with age (>P30 mice) the tonic GABA currents increased in D1-MSNs but decreased in D2-MSNs. These data demonstrate a developmental switch in the MSN subtype expressing larger tonic GABA currents. Compared to wild-type, MSNs from adult mice lacking the GABA(A)R delta subunit (Gabrd(-/-) mice) had both decreased tonic GABA currents and reduced survival following an in vitro excitotoxic challenge with quinolinic acid. Furthermore, muscimol-induced tonic GABA currents were accompanied by reduced acute swelling of striatal neurons after exposure to NMDA in WT mice but not in Gabrd(-/-) mice. Our data are consistent with a role for tonic inhibition mediated by GABA(A)R delta subunits in neuroprotection against excitotoxic insults in the adult striatum. PMID- 20206234 TI - Cross-sectional area of the elephant corpus callosum: comparison to other eutherian mammals. AB - The current study reports our findings of the relationship between cross sectional area of the corpus callosum and brain mass in over 100 eutherian mammal species. We were specifically interested in determining whether the elephant had a corpus callosum the size that would be expected for eutherian mammal with a brain mass of approximately 5000 g, or whether a different morphology had evolved. To answer this question we first analysed data from primates, other eutherian mammals and cetaceans, finding that primates and other eutherian mammals showed a positive allometric relationship between the two variables, such that larger brains had a relatively larger corpus callosum. Interestingly, primates have a slightly larger corpus callosum than other eutherian mammals, but showed a similar allometric scaling to this group. The cetaceans had a both absolutely and relatively small corpus callosum compared to other mammals and showed isometric scaling with brain mass. The six elephants studied herein had the largest absolute corpus callosums recorded to date; however, relative to the mass of their brain, the size of the corpus callosum was what would be expected of a typical eutherian mammal with a brain mass of approximately 5000 g. The data for elephants hinted at sexual dimorphism in size of the corpus callosum, with female elephants having both an absolute and relatively larger callosum than the males. If this observation is supported in future studies, the elephants will be the first non-primate species to show sexual dimorphism in this neural character. The results are discussed in both an evolutionary and functional context. PMID- 20206235 TI - Noise trauma impairs neurogenesis in the rat hippocampus. AB - The hippocampus, a major site of neurogenesis in the adult brain, plays an important role in memory. Based on earlier observations where exposure to high intensity noise not only caused hearing loss but also impaired memory function, it is conceivably that noise exposure may suppress hippocampal neurogenesis. To evaluate this possibility, nine rats were unilaterally exposed for 2 h to a high intensity, narrow band of noise centered at 12 kHz at 126 dB SPL. The rats were also screened for noise-induced tinnitus, a potential stressor which may suppress neurogenesis. Five rats developed persistent tinnitus-like behavior while the other four rats showed no signs of tinnitus. Age-matched sham controls showed no signs of hearing loss or tinnitus. The inner ear and hippocampus were evaluated for sensory hair cell loss and neurogenesis 10 weeks post-exposure. All noise exposed rats showed severe loss of sensory hair cells in the noise-exposed ear, but essentially no damage in the unexposed ear. Frontal sections from the hippocampus were immunolabeled for doublecortin to identify neuronal precursor cells, or Ki67 to label proliferating cells. Noise-exposed rats showed a significant reduction of neuronal precursors and fewer dividing cells as compared to sham controls. However, we could not detect any difference between rats with behavioral evidence of tinnitus versus rats without tinnitus. These results show for the first time that high intensity noise exposure not only damages the cochlea but also causes a significant and persistent decrease in hippocampal neurogenesis that may contribute to functional deficits in memory. PMID- 20206236 TI - Endothelins-1/3 and endothelin-A/B receptors expressing glial cells with special reference to activated microglia in experimentally induced cerebral ischemia in the adult rats. AB - We reported previously that amoeboid microglial cells (AMC) in the developing brain exhibited endothelins (ETs) expression which diminished with advancing age and was undetected in microglia in the more mature brain. This study sought to explore if microglia in the adult would be induced to express ETs in altered conditions. By immunofluorescence microscopy, ETs and endothelin (ET)-B receptor were undetected in microglial cells in sham-operated and normal control rats. However, in adult rats subjected to middle cerebral artery occlusion (MCAO), lectin labeled activated microglia which occurred in large numbers in the marginal zones in the ischemic cortex at 3 days and 1 week intensely expressed ETs specifically endothelin (ET)-1 and ET-B receptor; ET-3 and ET-A receptor were absent in these cells. By RT-PCR and ELISA, ET-1 and -3 mRNA and protein expression level was progressively increased in the ischemic cerebral cortex after MCAO compared with the controls. ET-A and ET-B receptor mRNA and protein levels were concomitantly up-regulated. It is suggested that increased release of ET-1 following MCAO by massive activated microglia can exert an immediate constriction of local blood vessels bearing ET-A receptor. ET-1 may also interact with activated microglia endowed with ET-B receptor via an autocrine manner that may be linked to chemokines/cytokines production. ET-1, ET-3 and ET-B receptor were also localized in reactive astrocytes along with some oligodendrocytes. We conclude that activated microglia together with other glial cells in the marginal zone after MCAO are the main cellular source of ETs that may be involved in regulation of vascular constriction and glial chemokines/cytokines production. However, dissecting the role of individual component of the endothelin system in the various glial cells, notably activated microglia, would be vital in designing of an effective therapeutic strategy for clinical treatment of stroke in which microglial cells have been implicated. PMID- 20206237 TI - Chondroitin sulfate inhibits lipopolysaccharide-induced inflammation in rat astrocytes by preventing nuclear factor kappa B activation. AB - Chondroitin sulfate (CS) is a glucosaminoglycan (GAG) currently used for the treatment of osteoarthritis because of its antiinflammatory and antiapoptotic actions. Recent evidence has revealed that those peripheral effects of CS may also have therapeutic interest in diseases of the CNS. Since neuroinflammation has been implicated in different neuronal pathologies, this study was planned to investigate how CS could modulate the inflammatory response in the CNS by using rat astrocyte cultures stimulated with lipopolysaccharide (LPS). We have evaluated different proteins implicated in the nuclear factor kappa B (NFkappaB) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways employing RT-PCR, western blot and immunofluorescence techniques. At 10 microM, CS prevented translocation of p65 to the nucleus, reduced tumour necrosis factor alpha (TNF-alpha) mRNA and mitigated cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS) induction by LPS. However, it did not modify LPS-induced IP-10 and SOCS-1 mRNA, proteins that participate in the JAK/STAT pathway. The results of this study indicate that CS can potentially reduce neuroinflammation by inhibition of NFkappaB. Therefore endogenous GAGs could afford neuroimmunomodulatory actions under neurotoxic conditions. PMID- 20206239 TI - Divergent impact of the polysialyltransferases ST8SiaII and ST8SiaIV on polysialic acid expression in immature neurons and interneurons of the adult cerebral cortex. AB - Polysialic acid (PSA) is a negatively charged carbohydrate polymer, which confers antiadhesive properties to the neural cell adhesion molecule NCAM and facilitates cellular plasticity during brain development. In mice, PSA expression decreases drastically during the first postnatal weeks and it gets confined to immature neurons and regions displaying structural plasticity during adulthood. In the brain, PSA is exclusively synthesized by the two polysialyltransferases ST8SiaII and ST8SiaIV. To study their individual contribution to polysialylation in the adult, we analyzed PSA expression in mice deficient for either polysialyltransferase. Focusing on the cerebral cortex, our results indicate that ST8SiaIV is solely responsible for PSA expression in mature interneurons and in most regions of cortical neuropil. By contrast, ST8SiaII is the major polysialyltransferase in immature neurons of the paleocortex layer II and the hippocampal subgranular zone. The numbers of cells expressing PSA or doublecortin, another marker of immature neurons, were increased in the paleocortex layer II of ST8SiaIV-deficient mice, indicating altered differentiation of these cells. Analysis of doublecortin expression also indicated that the production of new granule neurons in the subgranular zone of ST8SiaII-deficient mice is not affected. However, many of the immature granule neurons showed aberrant locations and morphology, suggesting a role of ST8SiaII in their terminal differentiation. PMID- 20206240 TI - Lipid rafts: keys to neurodegeneration. AB - The increase in life expectancy seen in many countries has been accompanied by an increase in the number of people living with dementia and a growing need for health care. The large number of affected individuals emphasizes the need to identify causes for the phenotypes associated with diseases such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, Huntington's, and those caused by prions. This review addresses the hypothesis that changes in lipid rafts induced by alterations in their ganglioside and/or cholesterol content or the interaction of mutant proteins with them provide the keys to understanding the onset of neurodegeneration that can lead to dementia. The biological function(s) of raft associated gangliosides and cholesterol are discussed prior to reviewing what is known about their roles in lipid rafts in the aforementioned diseases. It concludes with some questions that need to be addressed in order to provide investigators with the basis for identifying small molecule agonists or antagonists to test as potential therapeutics. PMID- 20206238 TI - Short- and long-term effects of intermittent social defeat stress on brain derived neurotrophic factor expression in mesocorticolimbic brain regions. AB - Social defeat stress is an ethologically salient stressor which activates dopaminergic areas and, when experienced repeatedly, has long-term effects on dopaminergic function and related behavior. The mechanism for these long-lasting consequences remains unclear. A potential candidate for mediating these effects is brain-derived neurotrophic factor (BDNF), a neurotrophin involved in synaptic plasticity and displaying alterations in dopaminergic regions in response to various types of stress. In this study, we sought to determine whether repeated social defeat stress altered BDNF mRNA and protein expression in dopaminergic brain regions either immediately after the last stress exposure or 4 weeks later. Male Sprague-Dawley rats were subjected to social defeat stress consisting of brief confrontation with an aggressive male rat every third day for 10 days; control rats were handled according to the same schedule. Animals were euthanized either 2 h or 28 days after the last stress or handling episode. Our results show that 2 h after stress, BDNF protein and mRNA expression increased in the medial prefrontal cortex. At this time-point, BDNF mRNA increased in the amygdala and protein expression increased in the substantia nigra. Twenty-eight days after stress, BDNF protein and mRNA expression were elevated in the medial amygdala and ventral tegmental area. Given the role of BDNF in neural plasticity, BDNF alterations that are long-lasting may be significant for neural adaptations to social stress. The dynamic nature of BDNF expression in dopaminergic brain regions in response to repeated social stress may therefore have implications for lasting neurochemical and behavioral changes related to dopaminergic function. PMID- 20206241 TI - Reaction of Muller cells in an experimental rat model of increased intraocular pressure following timolol, latanoprost and brimonidine. AB - The aim of this study was to evaluate the reaction of Muller cells in an experimental rat model of intraocular pressure (IOP) and their response to treatment with ocular hypotensive drugs. Episcleral vein cauterization in unilateral eyes of Wistar rats was performed to produce elevated IOP. The animals were divided into five groups: control, experimental, and experimental treated with timolol, latanoprost or brimonidine. Histological sections of retina were studied by immunochemistry with antibodies to glial fibrillary acidic protein (GFAP), and the percentage of labeled area was measured to evaluate the degree of reactive gliosis. In the experimental group, the Muller cells showed hypertrophy and a significant increase in GFAP (4.39+/-0.32%) in relation to retinas of the control group (2.05+/-0.14%). Gliosis was detected in all three treated groups, with a varying increase in GFAP intensity. The timolol-treated group showed the most intense and persistent glial reactivity after 3 months of treatment (13.89+/ 0.63%). Treatment with brimonidine, however, resulted in a decrease in the level of GFAP immunoreactivity (8.37+/-0.4%). The group treated with latanoprost showed the lowest glial reactivity (4.8+/-0.36%). Given that all three drugs are effective hypotensive agents, their neuroprotective effect could be related with other factors, such as gliosis, which, over long periods may have noxious effects on the neurons. Thus, hypotensives like brimonidine, and specially latanoprost, may afford greater neuroprotection to the ganglion cells by attenuating the retinal glial reaction. PMID- 20206242 TI - A refined map of early gene expression in the dorsal rhombomere 1 of mouse embryos. AB - Rhombomere 1 (r1), a temporary structure in the early developing brain, is bounded rostrally by the isthmus organizer and caudally by the r2 domain. Many genes involved in r1 induction and patterning have been identified. However, our knowledge of a comprehensive map of r1 regionalization defined by these genes at early embryonic stages remains fragmentary. In the present study, we examined the expression of a variety of genes in the dorsal r1 of E9.0-E10.5 mouse embryos. The expression domains within ventricular zone of these genes examined allowed us to define four distinct regions along the anterior-posterior (A-P) axis of the dorsal r1: the Wnt1/Lmx1a/Gdf7/Msx1/Msx2-positive roof plate, Math1/Olig3/Msx1/Msx2-positive, upper rhombic lip, Mash1/Ngn1/Ngn2-positive intermediate domain, and Mash1/Ngn1/Ngn2-positive rostral domain. Moreover, we defined the distribution of several genes expressed in the mantle zone of the dorsal r1, including Lmx1b, Lhx2, Lhx9, Phox2a and Phox2b. Taken together, our gene expression data identify a refined subdivision of the dorsal r1 with four distinct domains along the A-P axis and a mantle zone at early embryonic stages. PMID- 20206243 TI - Identification and characterization of the human NOL7 gene promoter. AB - NOL7 is a candidate tumor suppressor gene that localizes to 6p23, a chromosomal region frequently associated with loss of heterozygosity in a number of malignancies including cervical cancer (CC). Re-expression of NOL7 in CC cells suppresses in vivo tumor growth by 95% and alters the angiogenic phenotype by modulating the expression of VEGF and TSP1. Here, we describe the determination of two NOL7 transcriptional start sites (TSS), the cloning of its regulatory promoter region, and the identification of transcription factors that regulate its expression. Using 5' Rapid amplification of complementary DNA ends (RACE), two transcriptional start sites were identified. Deletion analysis determined that the essential elements required for the optimal promoter activity of NOL7 were 560 bp upstream of its translation start site. In silico analysis suggested that the promoter region contained potential binding sites for the SP1, c-Myc and RXRalpha transcription factors as well as an overall GC content of greater than 60%. Chromatin immunoprecipitation (ChIP) confirmed that SP1, c-Myc and RXRalpha bound to the NOL7 promoter region. Finally, we demonstrate that NOL7 expression was positively regulated by c-Myc and RXRalpha. These results demonstrate that the NOL7 promoter region possesses each of the key elements of a TATA-less promoter. In addition, the positive regulation of NOL7 by c-Myc and RXRalpha provides additional mechanistic insights into the potential role of NOL7 in CC and other malignancies. PMID- 20206244 TI - Development of an efficient expression system for Flavobacterium strains. AB - Strong promoters were isolated from Flavobacterium johnsoniae in a promoter-trap vector incorporating a gfp reporter system, and were used to express fluorescent protein markers (including GFP, YFP, mOrange and mStrawberry) and insecticidal protein genes in Flavobacterium strains. Sequence analysis of trapped DNA fragments showed conserved Bacteroidetes promoter motifs (TTG-N(19)-TAnnTTTG) located upstream of putative open reading frames. Plasmids harboring these genomic DNA fragments from F. johnsoniae promoted strong production of fluorescent proteins in Flavobacterium hibernum but not in Escherichiacoli. The most potent promoter (PompA) identified in this work was cloned upstream of genes encoding fluorescent proteins, and these were co-expressed in Flavobacterium strains. The p42 and p51 genes (binary toxins from Bacillus sphaericus) when translationally fused to the 3'-end of gfp showed strong expression. Flavobacteria expressing these genes exhibited toxicity against larvae of the mosquitoes Culex quinquefasciatus, Anopheles gambiae, and Ochlerotatus triseriatus. However, transformants with the transcriptional fusion construct between cry11A with p20 from Bacillus thuringiensis did not express Cry11A protein indicating that constitutive expression of cry11A may be problematic in Flavobacterium. PMID- 20206245 TI - Scottish Mytilus trossulus mussels retain ancestral mitochondrial DNA: complete sequences of male and female mtDNA genomes. AB - Mytilus trossulus mussels occur in North America and in the Baltic Sea. Recently genetic markers for the three Mytilus subspecies M. edulis, M. galloprovincialis, and M. trossulus, have been detected at Loch Etive in Scotland suggesting mixed ancestry for this population. Of particular interest is the evidence that M. trossulus occurs at Loch Etive because it had not previously been reported in the British Isles. In the present study, analysis of subspecies-specific diagnostic nuclear DNA markers confirms the presence of a high frequency of mussels with M. trossulus ancestry at Loch Etive. The genetic structure suggests hybridisation at an intermediate stage compared with North American populations, where there is little hybridisation, and Baltic populations where there is extensive introgression. This points strongly against a Baltic origin for Loch Etive M. trossulus. The F and M mitochondrial DNA (mtDNA) genomes of Baltic M. trossulus are similar in sequence to the corresponding genomes in M. edulis and believed to be derived by introgression from that subspecies. Both F and M mtDNA genomes are observed at Loch Etive consistent with the presence of doubly uniparental inheritance. Here we provide the complete sequences of the three M. trossulus mtDNA genomes (one F and two M) from Loch Etive. These genomes are extremely similar to the corresponding genomes from ancestral M. trossulus in America but divergent from the genomes for Baltic M. trossulus. This is the first report of ancestral M. trossulus mtDNA genomes in Europe. The F and M genomes are diverged by 26% in nucleotide sequence, similar to other Mytilus F and M genomes. The gene arrangement in the sequenced genomes is also similar to that in other sequenced Mytilus mtDNA genomes. However the two sequenced M genomes differ by 960bp which is caused by a duplication in the main noncoding region (CR). This duplication has not so far been observed in North American populations of M. trossulus. The coding regions of the Loch Etive genomes have no features suggesting that they are other than functional genomes and have K(a)/K(s) values in coding regions less than one indicative of purifying selection. Estimates of divergence times were made for both genomes and are consistent with invasion of Loch Etive by M. trossulus towards the end of the last glacial period. PMID- 20206246 TI - Beclin-1 expression in normal bladder and in Cd2+ and As3+ exposed and transformed human urothelial cells (UROtsa). AB - The expression of beclin-1 in normal human bladder and in Cd(2+) and As(3+) exposed and transformed urothelial cells (UROtsa) was examined in this study. It was shown using a combination of real-time PCR, Western analysis and immunohistochemistry that beclin-1 was expressed in the urothelial cells of the normal bladder. It was also demonstrated that the parental UROtsa cell line expressed beclin-1 mRNA and protein at levels similar to that of the in situ urothelium. The level of beclin-1 expression underwent only modest alterations when the UROtsa cells were malignantly transformed by Cd(2+) or As(3+) or when the parental cells were exposed acutely to Cd(2+) or As(3+). While there were instances of significant alterations at individual time points and within cell line-to-cell line comparisons there was no evidence of a dose-response relationship or correlations to the phenotypic properties of the cell lines. Similar results were obtained for the expression of the Atg-5, Atg-7, Atg-12 and LC3B autophagy-related proteins. The findings provide initial evidence for beclin 1 expression in normal bladder and that large alterations in the expression of beclin-1 and associated proteins do not occur when human urothelial cells are malignantly transformed with, or exposed to, either Cd(2+) or As(3+.). PMID- 20206247 TI - Role of oxidative stress and MAPK signaling in reference moist smokeless tobacco induced HOK-16B cell death. AB - The use of smokeless tobacco products is often associated with an oral injury at the site of repeated use. To further our understanding of this injury process, the effect of reference moist smokeless tobacco extract (STE) on cell death, oxidative stress, and MAPK signaling in a human oral keratinocyte cell line, HOK 16B, was investigated. STE caused dose-dependent cell death and reactive oxygen species (ROS) production within 30 min to 3h of exposure. This same insult enhanced the activity of ERK1/2, JNK1/2, p38 MAPK and ASK1, an upstream activator of JNK1/2 and p38 MAPK. Inhibition of JNK1/2 and to a lesser extent p38 MAPK, but not ERK1/2, suppressed STE-induced cell death. Pretreatment with antioxidants and an iron chelator, deferoxamine suppressed ROS production, ASK1, JNK1/2 and p38 MAPK activation, and reduced cell death after STE exposure. Interestingly, extracellular free iron levels in STE (29.4+/-0.5 microM) were significantly elevated as compared with cell culture medium (4.9+/-0.6 microM) and the addition of extracellular free iron (14, 30 or 70 microM) to HOK-16B cultures (without STE) caused dose-dependent cell death after 3h. Thus, acute exposure to STE leads to HOK-16B cell death in part through oxidative stress via activation of ASK1 and the JNK1/2 and p38 MAPK pathways. PMID- 20206248 TI - Potential of an injectable chitosan/starch/beta-glycerol phosphate hydrogel for sustaining normal chondrocyte function. AB - An injectable hydrogel for chondrocyte delivery was developed by blending chitosan and starch derived from various sources with beta-glycerol phosphate (beta-GP) in the expectation that it would retain a liquid state at room temperature and gel at raised temperatures. Rheological investigation indicated that the system consisting of chitosan derived from crab shell and corn starch at 4:1 by weight ratio (1.53%, w/v of total polymers), and 6.0% (w/v) beta-GP (C/S/GP system) exhibited the sharpest sol-gel transition at 37+/-2 degrees C. The C/S/GP hydrogel was gradually degraded by 67% within 56 days in PBS containing 0.02 mg/ml lysozyme. The presence of starch in the system increased the water absorption of the hydrogel when compared to the system without starch. SEM observation revealed to the interior structure of the C/S/GP hydrogel having interconnected pore structure (average pore size 26.4 microm) whereas the pore size of the hydrogel without starch was 19.8 microm. The hydrogel also showed an ability to maintain chondrocyte phenotype as shown by cell morphology and expression of type II collagen mRNA and protein. In vivo study revealed that the gel was formed rapidly and localized at the injection site. PMID- 20206249 TI - The Burkholderia cenocepacia K56-2 pleiotropic regulator Pbr, is required for stress resistance and virulence. AB - Burkholderia cenocepacia is one of the most virulent species of the Burkholderia cepacia complex, a group of bacteria that emerged as important pathogens, especially to cystic fibrosis (CF) patients. In this study, we report the identification and characterization of a mutant strain derived form the CF isolate Burkholderia cenocepacia K56-2, carrying a plasposon insertion in a gene, located in a 3516 bp chromosomal region with an atypical G+C content, encoding a 80 amino acid putative regulatory protein named Pbr. Besides its inability to produce phenazines, the B. cenocepacia K56-2 pbr mutant exhibited a pleiotropic phenotype, including impaired survival to oxidative and osmotic stress, aromatic amino acid and prolonged nutrient starvation periods. In addition, the pbr mutant exhibited decreased virulence the nematode Caenorhabditis elegans. Altogether, our results demonstrate the involvement of Pbr on the regulation of phenazine biosynthesis, and an important role for this regulatory protein on several cellular processes related to stress resistance and virulence. PMID- 20206250 TI - Transcriptome profiling of zebrafish infected with Streptococcus suis. AB - Streptococcus suis is an important pathogen in swine, and it also represents an emerging zoonotic agent. Zebrafish as a model for the evaluation of virulence of S. suis has been demonstrated before. Here, an Affymetrix Zebrafish GeneChip was used to identify alterations in gene expression of zebrafish injected with S. suis serotype 2 strain HA9801. The results showed that 189 genes were differentially expressed, of which 125 genes were upregulated and 64 genes were downregulated. Gene Ontology category and KEGG pathway were analyzed for differentially expressed genes. Upregulated genes were involved in response to bacterium, immune response, inflammatory response, complement activation, defense response. Three genes (encoding serum amyloid protein A, matrix metalloproteinase 9 and apoptosis-related cysteine protease) and genes involved in the regulation of IL-6 biosynthetic process, which have previously been implicated in the response to S. suis infection in other organisms, were also upregulated. Downregulated genes played roles in glycolysis, carbohydrate metabolic process, amino acids metabolism, behavior and muscle. The reliability of the data obtained from the microarray was verified by performing quantitative real-time PCR on 12 representative genes. The data may provide further validation of this model, which will contribute to understanding of S. suis pathogenic mechanisms. PMID- 20206251 TI - Ethoxyresorufin O-deethylase induction by TCDD, PeCDF and TCDF in ring-necked pheasant and Japanese quail hepatocytes: Time-dependent effects on concentration response curves. AB - Ethoxyresorufin O-deethylase (EROD) activity was measured in primary cultures of ring-necked pheasant (Phasianuscolchicus) and Japanese quail (Coturnix japonica) embryonic hepatocytes exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) and 2,3,7,8-tetrachlorodibenzofuran (TCDF) for 12, 24, 36 and 48 h. In ring-necked pheasant hepatocytes there was a significant time-dependent increase in the EROD-inducing potency of TCDD, PeCDF and TCDF (i.e. decrease of the EC50). In Japanese quail hepatocytes there was no time-dependent change in the EROD-inducing potency of TCDD, PeCDF and TCDF. There was no time-dependent change in the relative potency of PeCDF and TCDF (i.e. compared to the potency of TCDD) in ring-necked pheasant hepatocytes and of PeCDF in Japanese quail hepatocytes. The results indicate that the relative potencies of these compounds at 24h are representative of their relative potencies between 12 and 48 h. However, in Japanese quail hepatocytes, the relative potency of TCDF decreased in a time-dependent manner (up to 3.6-fold difference). These results suggest that the effect of time on the EROD-inducing potency of TCDD, PeCDF and TCDF in ring-necked pheasant and Japanese quail hepatocytes is compound- and species-specific, but experimental conditions could also be involved in the differences observed. PMID- 20206252 TI - Genomic assessment of the evolution of the prion protein gene family in vertebrates. AB - Prion diseases are devastating neurological disorders caused by the propagation of particles containing an alternative beta-sheet-rich form of the prion protein (PrP). Genes paralogous to PrP, called Doppel and Shadoo, have been identified, that also have neuropathological relevance. To aid in the further functional characterization of PrP and its relatives, we annotated completely the PrP gene family (PrP-GF), in the genomes of 42 vertebrates, through combined strategic application of gene prediction programs and advanced remote homology detection techniques (such as HMMs, PSI-TBLASTN and pGenThreader). We have uncovered several previously undescribed paralogous genes and pseudogenes. We find that current high-quality genomic evidence indicates that the PrP relative Doppel, was likely present in the last common ancestor of present-day Tetrapoda, but was lost in the bird lineage, since its divergence from reptiles. Using the new gene annotations, we have defined the consensus of structural features that are characteristic of the PrP and Doppel structures, across diverse Tetrapoda clades. Furthermore, we describe in detail a transcribed pseudogene derived from Shadoo that is conserved across primates, and that overlaps the meiosis gene, SYCE1, thus possibly regulating its expression. In addition, we analysed the locus of PRNP/PRND for significant conservation across the genomic DNA of eleven mammals, and determined the phylogenetic penetration of non-coding exons. The genomic evidence indicates that the second PRNP non-coding exon found in even-toed ungulates and rodents, is conserved in all high-coverage genome assemblies of primates (human, chimp, orang utan and macaque), and is, at least, likely to have fallen out of use during primate speciation. Furthermore, we have demonstrated that the PRNT gene (at the PRNP human locus) is conserved across at least sixteen mammals, and evolves like a long non-coding RNA, fashioned from fragments of ancient, long, interspersed elements. These annotations and evolutionary analyses will be of further use for functional characterisation of the PrP-GF, and will be updatable in a semi-automated fashion as more genomes accumulate. PMID- 20206254 TI - An appreciation of Diether Neubert and Hans-Joachim Merker's contributions to Reproductive and Developmental Toxicology on their 80th birthday. AB - Diether Neubert, toxicologist, and Hans-Joachim Merker, histopathologist and embryologist, made significant contributions to the field of Developmental and Reproductive Toxicology. They worked under the same roof at the Institute of Toxicology and Embryopharmacology in Berlin, and actively collaborated with each other for over 25 years. Both scientists are now retired and turned 80 this year (2009). This celebratory article reports some remarkable events of their long and prolific scientific careers. PMID- 20206253 TI - Vigabatrin (VGB) administered during late gestation lowers maternal folate concentration and causes pregnancy loss, fetal growth restriction and skeletal hypoplasia in the mouse. AB - Vigabatrin (VGB) has several therapeutic advantages over older antiepileptic drugs (AED), but there is a lack of information about its potential reproductive toxicologic effects. Our aim was to evaluate the consequences of VGB administered during late gestation on fetal growth and development in the mouse. Based on the results of our previous study, we administered groups of mice a single dose of 450 mg/kg VGB on one of gestation days (GD) 15, 16 or 17. Fetuses were collected on GD 18. VGB groups had a significant incidence of fetal death, abortion, intrauterine growth restriction (IUGR), and hypoplasia of the axial skeleton, metacarpals, metatarsal and phalanges. Abortion was characterized by visible hemorrhagic expulsion of the embryos with their membranes. Maternal plasma folate (FA) and vitamin B12 concentrations were found to be markedly reduced within 12h of VGB treatment. Mice were supplemented with FA from GD 12 through GD 17 with or without a single dose of VGB on GD 15. This group had no abortions. Their fetuses had better body weight and lower frequency of IUGR than those of the non supplemented VGB group. These data suggest that reductions in maternal FA and vitamin B12 concentrations play an important role in fetal loss, IUGR and skeletal hypoplasia induced by VGB during late gestation in the mouse. In view of the finding that a significant maternal toxicity is associated with this dose regimen, additional groups of mice were treated with 350 mg/kg VGB during embryogenesis and late gestation. This treatment was found to be maternally nontoxic. However, this low dose also resulted in significant fetal loss and IUGR when treatment occurred during late gestation. These data support the hypothesis that late gestation is particularly susceptible to VGB-induced fetal loss and IUGR in the mouse. PMID- 20206255 TI - Membrane cholesterol contents modify the protective effects of quercetin and rutin on integrity and cellular viability in oxidized erythrocytes. AB - Flavonoids protect cells damaged by oxidative stress. This, together with other biological activities, is governed by structural features of flavonoids and the nature and physical state of the cell membrane. We have previously proved that membrane cholesterol contents modify the protective power of quercetin and rutin against oxidative stress in erythrocytes. Here we analyzed the lipid asymmetry, the integrity, and cell viability of native and cholesterol-modified erythrocytes exposed to tert-butyl hydroperoxide in presence of both antioxidants. Our results provides clear evidence that quercetin affords better protection than rutin against lipid peroxidation, ROS generation, erythrophagocytosis and cellular instability in oxidized erythrocytes with normal and modified cholesterol contents. Both antioxidants provided a high of protection for the transbilayer aminophospholipid asymmetry, only partly preserving cell morphology in oxidized control and cholesterol-depleted erythrocytes. Cholesterol depletion reduced the protection provided by both antioxidants against phosphatidylserine externalization, erythrophagocytosis and hemolysis, which is in accordance with the lower degree of preservation against lipid peroxidation observed in oxidized cholesterol-depleted erythrocytes. This lower degree of preservation is presumably attributable to the low antioxidant contents in these erythrocyte membranes, or even to a lower efficiency of the antioxidant in a modified lipid environment due to the removal of cholesterol. PMID- 20206256 TI - A toxicological evaluation of inhaled solid lipid nanoparticles used as a potential drug delivery system for the lung. AB - Inhalation is a non-invasive approach for both local and systemic drug delivery. This study aimed to define the therapeutic window for solid lipid nanoparticles (SLNs) as a drug delivery system by inhalation from a toxicological point of view. To estimate the toxic dose of SLNs in vitro, A549 cells and murine precision-cut lung slices (PCLS) were exposed to increasing concentrations of SLNs. The cytotoxic effect of SLNs on A549 cells was evaluated by MTT and NRU assays. Viability of lung tissue was determined with WST assay and by life/dead staining using calcein AM/EthD-1 for confocal microscopy (CLSM) followed by quantitative analysis with IMARIS. Inflammation was assessed by measuring chemokine KC and TNF-alpha levels. The in vivo effects were determined in a 16 day repeated-dose inhalation toxicity study using female BALB/c mice, which were daily exposed to different concentrations of SLN30 aerosols (1-200 microg deposit dose). Local inflammatory effects in the respiratory tract were evaluated by determination of total protein content, LDH, chemokine KC, IL-6, and differential cell counts, performed on days 4, 8, 12, and 16 in bronchoalveolar lavage fluid. Additionally, a histopathological evaluation of toxicologically relevant organs was accomplished. The in vitro and ex vivo dose finding experiments showed toxic effects beginning at concentrations of about 500 microg/ml. Therefore, we used 1 200 microg deposit doses/animal for the in vivo experiments. Even after 16 days of challenge with a 200-microg deposit dose, SLNs induced no significant signs of inflammation. We observed no consistent increase in LDH release, protein levels, or other signs of inflammation such as chemokine KC, IL-6, or neutrophilia. In contrast, the particle control (carbon black) caused inflammatory and cytotoxic effects at corresponding concentrations. These results confirm that repeated inhalation exposure to SLN30 at concentrations lower than a 200-microg deposit dose is safe in a murine inhalation model. PMID- 20206257 TI - Degradation of parabens by Pseudomonas beteli and Burkholderia latens. AB - p-Hydroxybenzoic acid esters (parabens) are commonly used antimicrobial preservatives in pharmaceutical formulations. Two microorganisms, isolated from non-sterile methyl paraben (MP) and propyl paraben (PP) solutions, were found to degrade the respective parabens. Identification by 16S rRNA partial gene sequencing revealed them to be Pseudomonas beteli and Burkholderia latens, respectively. The present work describes a previously unreported interaction of the parabens with P. beteli and B. latens. Degradation of MP at various concentrations by P. beteli, followed a logarithmic pattern, while that of PP by B. latens was found to be linear. It was subsequently observed that P. beteli could degrade only MP, while B. latens could degrade both the parabens. Absence of HPLC chromatogram peaks of expected degradation products indicated that the parabens were used up as a carbon source. The behaviour of pathogens (Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans and Aspergillus niger) of the pharmacopoeial preservative effectiveness test (PET), towards MP, showed that none had the ability to degrade the paraben. It was concluded that, for a paraben preserved multi-dose ophthalmic formulation, the sole use of the four pathogens that are recommended by the pharmacopoeia for PET can falsely indicate the formulation to be effective against 'in-use' contamination. PMID- 20206258 TI - Adaptation of cholesterol synthesis to fasting and TNF-alpha: profiling cholesterol intermediates in the liver, brain, and testis. AB - Key players in pathogenesis of metabolic disorders are disturbed cholesterol balance and inflammation. In addition to cholesterol also sterol intermediates are biologically active, however, surprisingly little is known about their synthesis and roles. The aim of our study was to assess the interplay between the inflammatory cytokine TNF-alpha and cholesterol synthesis by measuring cholesterol and its intermediates in the liver, brain, and testis. Liquid chromatography-mass spectrometry has been applied to profile sterols of normally fed mice, during fasting and after TNF-alpha administration. In mice on normal chow diet, sterols other than cholesterol represent 0.5% in the liver, 1% in brain and 5% in testis. In the liver only 7-dehydrocholesterol, lanosterol and desmosterol were detected. Major sterol intermediates of the brain are desmosterol, testis meiosis activating sterol (T-MAS), and 7-dehydrocholesterol while in testis T-MAS predominates (4%), followed by desmosterol, lanosterol, 7 dehydrocholesterol and others. In 20h fasting there is no significant change in cholesterol of the three tissues, and no significant change in intermediates of the liver. In the brain sterol intermediates are lowered (significant for zymosterol) while in the testis the trend is opposite. TNF-alpha provokes a significant raise of some intermediates whereas the level of cholesterol is again unchanged. The proportion of sterols in the liver rises from 0.5% in controls to 1.2% in TNF-alpha-treated mice, which is in accordance with published expression profiling data. In conclusion, our data provide novel insights into the interaction between the inflammatory cytokine TNF-alpha and the tissue-specific cholesterol biosynthesis of the liver, brain and testis. PMID- 20206259 TI - Expression of genes related to glucocorticoid action in human subcutaneous and omental adipose tissue. AB - Adipose tissue glucocorticoid action relies on local enzymatic interconversion and glucocorticoid receptor (GR) availability. 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1), 2 (11beta-HSD2) and hexose-6-phosphate dehydrogenase (H6PDH) are likely involved in glucocorticoid activation/inactivation within adipose tissue. We examined adipose tissue mRNA expression of genes related to glucocorticoid action and their association with total and visceral adiposity. Messenger RNA was measured in paired subcutaneous and omental fat samples obtained from 56 women (age: 47.3 +/- 4.8 years, BMI: 27.1 +/- 5.2 kg/m(2)) undergoing gynaecological surgery. Expression levels of 11beta-HSD2, H6PDH and GRalpha were higher in omental adipose tissue while 11beta HSD1 expression was similar between fat compartments. Subcutaneous and omental 11beta-HSD1 mRNA abundances were positively associated with total and visceral adiposity whereas omental H6PDH mRNA abundance was negatively associated with these measures. Only omental 11beta-HSD1 mRNA expression remained significantly associated with visceral adipose tissue area following statistical adjustment for fat mass, age and menopausal status. Omental 11beta-HSD1 mRNA expression explained 19.1% of the variance in visceral adipose tissue area. Omental fat tissue 11beta-HSD-1 protein and cortisol levels were higher in visceral obese women, supporting findings obtained with 11beta-HSD-1 mRNA. These results suggest that among the transcripts examined only omental 11beta-HSD1 is independently associated with visceral obesity in women. PMID- 20206260 TI - A single dose of dihydrotestosterone induced a myogenic transcriptional program in female intra-abdominal adipose tissue. AB - Sex steroids are key regulators of adipose tissue (AT) mass, determining gender specific differences in fat distribution and accumulation. With the aim of exploring the relevance and peculiarities of androgen action in female intra abdominal AT, we used the serial analysis of gene expression (SAGE) method to analyze the AT transcriptome in four groups of female mice: intact, ovariectomized (OVX), OVX plus dihydrotestosterone (DHT) injection at 3h or 24h before sacrifice (DHT3h, DHT24h). An average of 19555 transcript species was examined in retroperitoneal fat. We found a total of 321 transcripts differentially modulated by DHT and OVX, including 125 novel genes. Several genes involved in energy metabolism/ATP production were up-regulated by DHT, whereas important regulators of lipid metabolism were reduced. Transcripts involved in Ca(2+) uptake/release, cell signalling, cell defence and protein expression were differentially modulated by DHT. A surprising number of myogenic genes were up regulated, including myosin light and heavy polypeptides, troponins, as well as several actin-binding proteins. These results suggest that DHT24h may have induced a myogenic-like transcriptional program in adipocytes. The present study sheds light on the distinctive female transcriptional pattern acutely induced by androgens in intra-abdominal fat, and may add new insights into the global understanding of menopausal endocrinology and its association to intra-abdominal obesity. PMID- 20206261 TI - Inhibition of inducible nitric oxide synthase worsens liver damage regardless of lipopolysaccharide treatment in small-for-size liver transplantation. AB - OBJECTIVE: In small-for-size liver transplantation, portal hypertension aggravates endotoxin from the gut which accelerates the activation of inducible nitric oxide synthase (iNOS). However, there is little knowledge as to the effects of iNOS inhibitors on small-for-size graft damage. Our study was designed to investigate the role of an iNOS inhibitor both with and without lipopolysaccharide (LPS) treatment in ischemia-reperfusion injury of small-for size liver transplantation. METHODS: Subjecting Sprague-Dawley rats to small-for size grafts liver transplantation, we investigated the time course of changes in hepatic expression of iNOS and endothelial nitric oxide synthase (eNOS). Meantime, we also investigated the effects of iNOS inhibitor, both with and without LPS treatment, at 6h after reperfusion. RESULTS: While iNOS mRNA expression reached a peak at 3h, the highest protein level occurred at 6h after reperfusion. Aminoguanidine (AG) significantly inhibited mRNA and protein expressions of iNOS, but not that of eNOS. However, LPS accelerated activation of iNOS, but suppressed the expression of eNOS. Meanwhile, compared with the untreated group, those treated with AG or LPS experienced worsened liver function and tissue damage, promoting neutrophil infiltration in the liver tissue. The difference between the LPS group and the LPS+AG group was found to be significant. In addition, AG and LPS treatments up-regulated the protein expression of ICAM-1 and NF-kappaB p65. CONCLUSION: In a small-for-size model of rat liver transplantation, regardless of LPS treatment, the inhibitor of iNOS, AG, attenuated iNOS expression, but worsened liver function and tissue damage. The subsequent increased neutrophil infiltration in liver tissue may be associated with up-regulation of ICAM-1 and NF-kappaB expressions. PMID- 20206263 TI - Genes regulated in MPTP-treated macaques and human Parkinson's disease suggest a common signature in prefrontal cortex. AB - The presymptomatic phase of Parkinson's disease (PD) is now recognized as a prodromal phase, with compensatory mechanism masking its progression and non motor early manifestations, such as depression, cognitive disturbances and apathy. Those mechanisms were thought to be strictly dopamine-mediated until recent advances have shed light upon involvement of putative outside-basal ganglia, i.e. cortical, structures. We took advantage of our progressive 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaque model to monitor whole genome transcriptional changes in several brain areas. Our data reveals that transcriptomic activity changes take place from early stages, suggesting very early compensatory mechanisms or pathological activity outside the basal ganglia, including the PFC. Specific transcriptomic changes occurring in the PFC of fully parkinsonian MPTP-treated macaques have been identified. Interestingly, a large part of these transcriptomic changes were also observed in human post-mortem samples of patients with neurodegenerative diseases analysed by quantitative PCR. These results suggest that the PFC is able to detect the progression of dopamine denervation even at very early time points. There are therefore mechanisms, within the PFC, leading to compensatory alterations and/or participating to pathophysiology of prodromal PD manifestations. PMID- 20206262 TI - Identifying cellular pathways modulated by Drosophila palmitoyl-protein thioesterase 1 function. AB - Infantile-onset Neuronal Ceroid Lipofuscinosis (INCL) is a severe pediatric neurodegenerative disorder produced by mutations in the gene encoding palmitoyl protein thioesterase 1 (Ppt1). This enzyme is responsible for the removal of a palmitate post-translational modification from an unknown set of substrate proteins. To better understand the function of Ppt1 in neurons, we performed an unbiased dominant loss-of-function genetic modifier screen in Drosophila using a previously characterized Ppt1 gain-of-function system. The enhancers and suppressors identified in our screen make novel connections between Ppt1 and genes involved in cellular trafficking and the modulation of synaptic growth. We further support the relevance of our screen by demonstrating that Garland cells from Ppt1 loss-of-function mutants have defects in endocytic trafficking. Endocytic tracer uptake and ultrastructural analysis of these non-neuronal cells points to Ppt1 playing a role in modulating the early stages of vesicle formation. This work lays the groundwork for further experimental exploration of these processes to better understand their contributions to the INCL disease process. PMID- 20206264 TI - Thinking outside the box about COX-1 in Alzheimer's disease. AB - This article from Coma et al. shows that a salicylic acid derivative Triflusal, a platelet aggregation inhibitor and irreversible inhibitor of COX-1, can correct defects in axonal curvature and cognition in an AD transgenic mouse model (Tg2576) (Coma et al., 2010). Here we discuss the controversy over the role of COX-1 in AD, which has not been considered carefully in part due to the presumed adverse gastrointestinal effects of COX-1 antagonism. However, recent clinical data from this group as well as other groups challenges this assumption that COX 1 antagonism will be associated with side effects. Most importantly this article raises critical questions about the role of COX-1, versus COX-2 versus both in Abeta pathogenesis. The animal model data in this article as well as the recently published trial data suggest that COX-1 may play an important role in early pathogenesis and should not be ignored as a potential target for early intervention. PMID- 20206265 TI - Analysis of the opioid-opioid combinations according to the nociceptive stimulus in mice. AB - The purpose of the present study was to characterize the antinociceptive effects of tramadol, fentanyl and morphine, when two of them were systemically combined in a 1:1 potency ratio, in the hot plate, the acetic acid writhing, and the formalin tests in mice. Interaction indexes and isobolographic analysis were used to assess the type of interaction. Fentanyl was the most potent drug, followed by morphine and tramadol, with the exception in the phase I of formalin test. Synergistic interactions were obtained when tramadol was combined with fentanyl or with morphine in the writhing and formalin tests. But, in the hot plate only additive interactions were obtained. Changes were induced on the type of interaction depending on the level of effect of opioid-opioid combinations. Moreover, co-administration of fentanyl with morphine showed additivity, regardless of the type of stimulus. Standard rotarod test analysis confirmed intact motor coordination. The present findings suggest that the type of interaction between opioids is not only related to the nature of nociceptive stimulus but also to non-opioid analgesic pathways. PMID- 20206266 TI - Targeting farnesyl-transferase as a novel therapeutic strategy for mevalonate kinase deficiency: in vitro and in vivo approaches. AB - Mevalonate kinase deficiency (MKD) is a rare inborn auto-inflammatory disease due to the impairment of the pathway for the biosynthesis of cholesterol and non sterol isoprenoids. The shortage of isoprenoids compounds and in particular of geranylgeranylpyrophosphate (GGPP) was recently associated to the MKD characteristic inflammatory attacks. The aim of this study is to demonstrate that the normalization of the mevalonate pathway intermediates levels and in particular of GGPP, through the specific inhibition of farnesyl-transferase (FT) with Manumycin A could ameliorate the inflammatory phenotype of MKD patients. The effect of Manumycin A was first evaluated in MKD mouse and cellular models, chemically obtained using the aminobisphosphonate alendronate (ALD), and then in monocytes isolated from 2 MKD patients. Our findings were compared to those obtained by using natural exogenous isoprenoids (NEIs). Manumycin A was able to significantly reduce the inflammatory marker serum amyloid A in ALD-treated Balb/c mice, as well as IL-1 beta secretion in ALD-monocytes and in MKD patients. These results clearly showed that, through the inhibition of FT, an increased number of mevalonate pathway intermediates could be redirected towards the synthesis of GGPP diminishing the inflammatory response. The importance in limiting the shortage of GGPP was emphasized by the anti-inflammatory effect of NEIs that, due to their biochemical structure, can enter the MKD pathway. In conclusion, manumycin A, as well as NEIs, showed anti-inflammatory effect in MKD models and especially in MKD-monocytes, suggesting novel approaches in the treatment of MKD, an orphan disease without any efficacious treatment currently available. PMID- 20206267 TI - p53 family members in cancer diagnosis and treatment. AB - p53 is a much studied transcription factor which has a key role in the maintenance of genetic stability. It belongs to a larger family of genes including two other highly related proteins, p63 and p73. The p53 pathway has a vital role in the prevention of cancer formation and is ubiquitously lost in a high percentage of human cancers. In 60% of cancer cases this occurs via p53 gene mutation. In the remaining cancers expressing a WTp53 gene, loss of cell signalling upstream or downstream of p53 are responsible for the inactivation of the p53 pathway. It has recently been described that the p53 gene encodes for nine different p53 isoforms, whereas the p63 and p73 genes encode for at least other 6 and 29, respectively. This finding may have a profound impact on our comprehension of p53 tumour suppressor activity. Studies in several tumour types have shown abnormal expression of these protein isoforms. Hence, better understanding of p53 tumour suppressor activity and the interaction between p53 family members and their isoforms is likely to bring us closer to cancer therapy. Therapeutic manipulation of the p53 pathway is therefore a highly promising field and already the focus of extensive investigation. Many strategies are being developed to either restore inactive/suppressed wild-type p53 (WTp53) or reverse the p53 mutant phenotype into WTp53. As p53 pathway inactivation is a common denominator to all cancers, it is highly expected that these therapies will be able to target a broad range of cancers and will allow for more specific targeting of cancer cells, avoiding collateral damage to normal tissue. PMID- 20206268 TI - Therapeutic targeting of p53 by small molecules. AB - Aberrant p53 function is one of the major requirements for tumor development. Reactivation of p53 function by small molecules is a promising strategy to combat cancer due to potent tumor suppressor activities of p53. Recent developments in p53 biology reveal that manipulation of p53 function might pave way to a long cancer-free life. A number of small molecules which rescue p53 function by different mechanisms, acting upstream of p53 or targeting the p53 protein itself have been identified. Notably, these molecules trigger different biological outcomes, suggesting that it might be feasible to direct p53-mediated response in a desired way. In this review I discuss the latest developments in the search for small molecules which rescue p53 function by targeting the p53 protein. PMID- 20206269 TI - Exercise modulates insulin-like growth factor 1-dependent and -independent effects on adult hippocampal neurogenesis and behaviour. AB - While physical exercise clearly has beneficial effects on the brain, fomenting neuroprotection as well as promoting neural plasticity and behavioural modifications, the cellular and molecular mechanisms mediating these effects are not yet fully understood. We have analyzed sedentary and exercised animals to examine the effects of activity on behaviour (spatial memory and anxiety--as measured by a fear/exploration conflict test), as well as on adult hippocampal neurogenesis (a well-known form of neural plasticity). We have found that the difference in activity between sedentary and exercised animals induced a decrease in the fear/exploration conflict scores (a measure usually accepted as an anxiolytic effect), while no changes are evident in terms of spatial memory learning. The short-term anxiolytic-like effect of exercise was IGF1-dependent and indeed, the recall of hippocampus-dependent spatial memory is impaired by blocking serum IGF1 (as observed by measuring serum IGF levels in the same animals used to analyze the behaviour), irrespective of the activity undertaken by the animals. On the other hand, activity affected neurogenesis as reflected by counting the numbers of several cell populations, while the dependence of this effect on IGF1 varied according to the differentiation state of the new neurons. Hence, while proliferating precursors and postmitotic immature neurons (measured by means of doublecortin and calretinin) are influenced by serum IGF1 levels in both sedentary and exercised animals, premitotic immature neurons (an intermediate stage) respond to exercise independently of serum IGF1. Therefore, we conclude that physical exercise has both serum IGF1-independent and -dependent effects on neural plasticity. Furthermore, several effects mediated by serum IGF1 are induced by physical activity while others are not (both in terms of behaviour and neural plasticity). These findings help to delimit the role of serum IGF1 as a mediator of the effects of exercise, as well as to extend the role of serum IGF1 in the brain in basal conditions. Moreover, these data reveal the complexity of the interaction between neurogenesis, behaviour, and IGF1 under different levels of physical activity. PMID- 20206270 TI - Regulation of postsynaptic gephyrin cluster size by protein phosphatase 1. AB - The scaffolding protein gephyrin is essential for the clustering of glycine and GABA(A) receptors (GABA(A)Rs) at inhibitory synapses. Here, we provide evidence that the size of the postsynaptic gephyrin scaffold is controlled by dephosphorylation reactions. Treatment of cultured hippocampal neurons with the protein phosphatase inhibitors calyculin A and okadaic acid reduced the size of postsynaptic gephyrin clusters and increased cytoplasmic gephyrin staining. Protein phosphatase 1 (PP1) was found to colocalize with gephyrin at selected postsynaptic sites and to interact with gephyrin in transfected cells and brain extracts. Alanine or glutamate substitution of the two established serine/threonine phosphorylation sites in gephyrin failed to affect its clustering at inhibitory synapses and its ability to recruit gamma2 subunit containing GABA(A)Rs. Our data are consistent with the postsynaptic gephyrin scaffold acting as a platform for PP1, which regulates gephyrin cluster size by dephosphorylation of gephyrin- or cytoskeleton-associated proteins. PMID- 20206271 TI - In vivo analysis of mtDNA replication defects in yeast. AB - The yeast Saccharomyces cerevisiae has the capacity to survive large deletions or total loss of mtDNA (petite mutants), and thus in the last few years it has been used as a model system to study defects in mitochondrial DNA (mtDNA) maintenance produced by mutations in genes involved in mtDNA replication. In this paper we describe methods to obtain strains harboring mutations in nuclear genes essential for the integrity of mtDNA, to measure the frequency and the nature of petite mutants, to estimate the point mutation frequency in mtDNA and to determine whether a nuclear mutation is recessive or dominant and, in the latter case, the kind of dominance. PMID- 20206272 TI - Second harmonic generation imaging - a new method for unraveling molecular information of starch. AB - We present a new method, second harmonic generation (SHG) imaging for the study of starch structure. SHG imaging can provide the structural organization and molecular orientation information of bio-tissues without centrosymmetry. In recent years, SHG has proven its capability in the study of crystallized bio molecules such as collagen and myosin. Starch, the most important food source and a promising future energy candidate, has, for a decade, been shown to exhibit strong SHG response. By comparing SHG intensity from different starch species, we first identified that the SHG-active molecule is amylopectin, which accounts for the crystallinity in starch granules. With the aid of SHG polarization anisotropy, we extracted the complete chi((2)) tensor of amylopectin, which reflects the underlying molecular details. Through chi((2)) tensor analysis, three-dimensional orientation and packing symmetry of amylopectin are determined. The helical angle of the double-helix in amylopectin is also deduced from the tensor, and the value corresponds well to previous X-ray studies, further verifying amylopectin as SHG source. It is noteworthy that the nm-sized structure of amylopectin inside a starch granule can be determined by this far-field optical method with 1-MUm excitation wavelength. Since SHG is a relatively new tool for plant research, a detailed understanding of SHG in starch structure will be useful for future high-resolution imaging and quantitative analyses for food/energy applications. PMID- 20206273 TI - Dietary administration of Zooshikella sp. enhance the innate immune response and disease resistance of Paralichthys olivaceus against Sreptococcus iniae. AB - We report the growth, innate immune response, and disease resistance in olive flounder (Paralichthys olivaceus) challenged with Streptococcus iniae after feeding with diet enriched with Zooshikella sp. strain JE-34 three different concentration i.e. Low (3.4 x 10(4), n = 50), medium (3.5 x 10(6), n = 50), and high (3.4 x 10(8), n = 50) cfu ml(-1) supplemented diets, the changes were monitored on weeks 1, 2, 4, 8, 12, and 16. With all diets the innate immune parameters, such as superoxide anion production, phagocytic and lysozyme activity were not enhanced on week 1 and 4. On the other hand, all tested immune parameters in the treated groups significantly enhanced after 8th week; the weight gain significantly increased after 4th week in fish fed with enriched diets. The mortality in olive flounder after administration with high concentration diet showed 25%. With low and medium enriched diets the mortality was 40% and 35%, respectively. In the infected untreated group mortality was 85% while there was no mortality in the control group. The results suggested that Zooshikella sp. strain JE-34 enriched diets could be used to enhance the innate immune response and disease resistance of P. olivaceus against S. iniae. PMID- 20206274 TI - LONI MiND: metadata in NIfTI for DWI. AB - A wide range of computational methods have been developed for reconstructing white matter geometry from a set of diffusion-weighted images (DWIs), and many clinical studies rely on publicly-available implementations of these methods for analyzing DWI datasets. Unfortunately, the poor interoperability between DWI analysis tools often effectively restricts users to the algorithms provided by a single software suite, which may be suboptimal relative to those in other packages, or outdated given recent developments in the field. A major barrier to data portability and the interoperability between DWI analysis tools is the lack of a standard format for representing and communicating essential DWI-related metadata at various stages of post-processing. In this report, we address this issue by developing a framework for storing metadata in NIfTI for DWI (MiND). We utilize the standard NIfTI format extension mechanism to store essential DWI metadata in an extended header for multiple commonly-encountered DWI data structures. We demonstrate the utility of this approach by implementing a full suite of tools for DWI analysis workflows which communicate solely through the MiND mechanism. We also show that the MiND framework allows for simple, direct DWI data visualization, and we illustrate its effectiveness by constructing a group atlas for 330 subjects using solely MiND-centric tools for DWI processing. Our results indicate that the MiND framework provides a practical solution to the problem of interoperability between DWI analysis tools, and it effectively expands the analysis options available to end users. PMID- 20206276 TI - Phylogeny of entelegyne spiders: affinities of the family Penestomidae (NEW RANK), generic phylogeny of Eresidae, and asymmetric rates of change in spinning organ evolution (Araneae, Araneoidea, Entelegynae). AB - Penestomine spiders were first described from females only and placed in the family Eresidae. Discovery of the male decades later brought surprises, especially in the morphology of the male pedipalp, which features (among other things) a retrolateral tibial apophysis (RTA). The presence of an RTA is synapomorphic for a large clade of spiders exclusive of Eresidae. A molecular data matrix based on four loci was constructed to test two alternative hypotheses: (1) penestomines are eresids and the RTA is convergent, or (2) penestomines belong within the RTA clade. Taxon sampling concentrated on the Eresidae and the RTA clade, especially outside of the Dionycha and Lycosoidea. Evolution of the cribellum, conventionally characterized as a primitive araneomorph spinning organ lost multiple times, is explored. Parsimony optimization indicates repeated appearances of the cribellum. Exploration of asymmetric rates of loss and gain in both a likelihood framework and using a Sankoff matrix under parsimony reveals that cribellum homology is supported when losses are two times more likely than gains. We suggest that when complicated characters appear (under parsimony optimization) to evolve multiple times, investigators should consider alternative reconstructions featuring a relatively high rate of loss. Evolution of other morphological characters is also investigated. The results imply revised circumscription of some RTA-clade families, including Agelenidae, Amaurobiidae, Cybaeidae, Dictynidae and Hahniidae. Some nomenclatural changes are formally proposed here; others await further investigation. The family Penestomidae (NEW RANK) is established. Tamgrinia, not Neoramia, is the cribellate sister clade of the ecribellate Agelenidae. Tamgrinia and the subfamily Coelotinae are transferred from the family Amaurobiidae to the family Agelenidae. Zanomys and its relatives are not coelotines but belong to a clade tentatively identified as Macrobuninae. PMID- 20206277 TI - Analysis of the secondary structure of ITS transcripts in peritrich ciliates (Ciliophora, Oligohymenophorea): implications for structural evolution and phylogenetic reconstruction. AB - Despite extensive previous morphological work, little agreement has been reached about phylogenetic relationships among peritrich ciliates, making it difficult to study the evolution of the group in a phylogenetic framework. In this study, the nucleotide characteristics and secondary structures of internal transcribed spacers 1 and 2 (ITS1 and ITS2) of 26 peritrich ciliates in 12 genera were analyzed. Information from secondary structures of ITS1 and ITS2 then was used to perform the first systematic study of ITS regions in peritrich ciliates, including one species of Rhabdostyla for which no sequence has been reported previously. Lengths of ITS1 and ITS2 sequences varied relatively little among taxa studied, but their G+C content was highly variable. General secondary structure models of ITS1 and ITS2 were proposed for peritrich ciliates and their reliability was assessed by compensatory base changes. The secondary structure of ITS1 contains three major helices in peritrich ciliates and deviations from this basic structure were found in all taxa examined. The core structure of peritrich ITS2 includes four helices, with helix III as the longest and containing a motif 5'-MAC versus GUK-3' at its apex as well as a YU-UY mismatch in helix II. In addition, the structural motifs of both ITS secondary structures were identified. Phylogenetic analyses using ITS data were performed by means of Bayesian inference, maximum likelihood and neighbor joining methods. Trees had a consistent branching pattern that included the following features: (1) Rhabdostyla always clustered with members of the family Vorticellidae, instead of members of the family Epistylididae, in which it is now classified on the basis of morphology. (2) The systematically questionable genus Ophrydium closely associated with Carchesium, forming a clearly defined, monophyletic group within the Vorticellidae. This supported the hypothesis derived from previous study based on small subunit rRNA gene sequences that Ophrydium and its few relatives are morphologically anomalous vorticellids, not sufficiently distinct to be given familial status and should be placed within a more broadly defined family Vorticellidae. This study validated for the first time a secondary structure of ITS1 and ITS2 from peritrich ciliates and demonstrated its potential in helping to resolve deep phylogenetic relationships. PMID- 20206278 TI - Polyaminergic agents modulate contextual fear extinction in rats. AB - Polyamines, such as spermidine and spermine, have been reported to improve memory retention through the activation of N-methyl-d-aspartate receptors (NMDAr). However whether polyamine agonists and antagonists alter extinction remains unclear. In the current study, we investigated whether spermidine and polyamine antagonists that selectively block the NR2B subunit at the NMDAr alter the extinction of contextual conditioned fear in male Wistar rats. The bilateral intra-hippocampal administration of exogenous spermidine (2 nmol/site) immediately after, but not 6h after extinction training, facilitated the extinction of fear conditioning. The injection of the NMDAr antagonists arcaine (0.2 nmol/site), ifenprodil (20 nmol/site) and traxoprodil (0.2 nmol/site), disrupted fear extinction and, at doses that had no effect per se, reversed the facilitatory effect of spermidine on fear extinction. These results suggest that exogenous and endogenous polyamines facilitate the extinction of contextual conditioned fear through activation of NR2B subunit-containing NMDAr in the hippocampus. Since extinction-based exposure therapy is widely used as treatment for a number of anxiety-related disorders, including phobias and post-traumatic stress, the currently reported facilitation of extinction by polyaminergic agents suggest these compounds as putative candidates for drug development. PMID- 20206275 TI - Bridging the gene-behavior divide through neuroimaging deletion syndromes: Velocardiofacial (22q11.2 Deletion) and Williams (7q11.23 Deletion) syndromes. AB - Investigating the relationship between genes and the neural substrates of complex human behavior promises to provide essential insight into the pathophysiology of mental disorders. One approach to this inquiry is through neuroimaging of individuals with microdeletion syndromes that manifest in specific neuropsychiatric phenotypes. Both Velocardiofacial syndrome (VCFS) and Williams syndrome (WS) involve haploinsufficiency of a relatively small set of identified genes on the one hand and association with distinct, clinically relevant behavioral and cognitive profiles on the other hand. In VCFS, there is a deletion in chromosomal region 22q11.2 and a resultant predilection toward psychosis, poor arithmetic proficiency, and low performance intelligence quotients. In WS, there is a deletion in chromosomal region 7q11.23 and a resultant predilection toward hypersociability, non-social anxiety, impaired visuospatial construction, and often intellectual impairment. Structural and functional neuroimaging studies have begun not only to map these well-defined genetic alterations to systems level brain abnormalities, but also to identify relationships between neural phenotypes and particular genes within the critical deletion regions. Though neuroimaging of both VCFS and WS presents specific, formidable methodological challenges, including comparison subject selection and accounting for neuroanatomical and vascular anomalies in patients, and many questions remain, the literature to date on these syndromes, reviewed herein, constitutes a fruitful "bottom-up" approach to defining gene-brain relationships. PMID- 20206279 TI - Role of the hippocampus in goal-oriented tasks requiring retrieval of spatial versus non-spatial information. AB - The role of the hippocampus in non-spatial memory has been issue of some controversy. To investigate the nature of dorsal hippocampus engagement in spatial and non-spatial memory we performed discrete excitotoxic lesions of this region before mice (C57/BL6) were trained in one of two tasks that required the animals to retrieve a hidden food reward. In the visuospatial task animals had to remember a particular spatial location, independent of odor cues. In contrast, in a non-spatial olfactory task animals had to remember a particular odor, independent of spatial location. The mice were trained in one of these tasks over a period of three days. We found that lesions restricted to the dorsal hippocampus affected performance only in the spatial task. In contrast, lesions that also encompassed a larger portion of the ventral hippocampus caused a moderate deficit in the olfactory task. These results are consistent with the role of the dorsal hippocampus in long-term spatial episodic memory, and support the involvement of larger portions of the hippocampus on the encoding of non spatial olfactory representations. PMID- 20206280 TI - Mgat1-dependent N-glycans are essential for the normal development of both vertebrate and invertebrate metazoans. AB - UDP-GlcNAc:alpha3-D-mannoside beta1,2-N-acetylglucosaminyltransferase I (GnTI, encoded by Mgat1) first appeared in evolution at about the same time as metazoa suggesting that GnTI-dependent glycans are essential for the development of multicellular organisms. This review describes the effects of mutations in the Mgat1 gene on the development of Caenorhabditis elegans, Drosophila melanogaster and mice. PMID- 20206281 TI - Basidiosporogenesis, meiosis, and post-meiotic mitosis in the ectomycorrhizal fungus Pisolithusmicrocarpus. AB - Pisolithus microcarpus (Cooke and Massee) G. Cunn. is a model organism for the studies on the ecology, physiology, and genetics of the ectomycorrhizal associations. However, little is known about the basidiosporogenesis in this species and, in particular, the nuclear behavior after karyogamy. In this work, the events involved in basidiosporogenesis and meiosis in P. microcarpus were analyzed using fluorescence and scanning electron microscopy. The basidia are formed inside peridioles by the differentiation of the cells along the whole hyphae. Basidial cells measure 12-18 microm in length and 6-7 microm in diameter. P. microcarpus produces eight basidiospores per basidium imbibed in a gelatinous matrix in the basidiocarp. The basidiospores are globose, equinate, with blunt spines, and measure 6-8 microm. Karyogamy can take place inside basidia as well as in undifferentiated hyphal cells followed by nuclear migration to a newly developed basidium where meiosis takes place. After the formation of the meiotic tetrad, one round of post-meiotic mitosis occurs, resulting in the production of eight nuclei per basidium. The newly-formed nuclei migrate into the basidiospores asynchronously, resulting in the production of eight uninucleate spores. This corresponds to pattern A of post-meiotic mitosis. This work is the first report on meiosis and post-meiotic mitosis during basidiosporogenesis in P. microcarpus and contributes to clarify some aspects of the biology and genetics of this ectomycorrhizal species. PMID- 20206283 TI - Characterization of foot-and-mouth disease virus antigen by surface-enhanced laser desorption ionization-time of flight-mass spectrometry in aqueous and oil emulsion formulations. AB - We have used a novel method, surface-enhanced laser desorption ionization-time of flight-mass spectrometry (SELDI-TOF-MS), to characterize foot-and-mouth disease virus (FMDV) vaccine antigens. Using specific capture with FMDV binding recombinant antibody fragments and tryptic digestion of FMDV antigens the spectral peaks representing the FMDV structural proteins VP1, VP2, VP3 and VP4 were identified. VP1 existed as 2 variants differing by 0.2kDa and VP4 as 8 variants differing by 14-17Da. Such heterogeneities have not been reported earlier. They could represent oxidation of VP4 and N-glycation of VP1. We also detected FMDV proteolysis upon incubation at elevated temperatures and impurities in FMDV antigen preparations. Finally, we could also characterize FMDV antigen present in emulsions with oil adjuvant by SELDI-TOF-MS. Such FMDV antigen retained the VP4 protein which is known to be specifically present in intact (146S) FMDV particles but absent from specific (12S) degradation products. This indicates that virions do not dissociate upon emulsification. PMID- 20206282 TI - Role of the homologous recombination genes RAD51 and RAD59 in the resistance of Candida albicans to UV light, radiomimetic and anti-tumor compounds and oxidizing agents. AB - We have cloned and characterized the RAD51 and RAD59 orthologs of the pathogenic fungus Candida albicans. CaRad51 exhibited more than 50% identity with several other eukaryotes and the conserved the catalytic domain of a bacterial RecA. As compared to the parental strain, null strains of rad51 exhibited a filamentous morphology, had a decreased grow rate and exhibited a moderate sensitivity to UV light, oxidizing agents, and compounds that cause double-strand breaks (DSB), indicating a role in DNA repair. By comparison, the rad52 null had a higher percentage of filaments, a more severe growth defect and a greater sensitivity to DNA-damaging compounds. Null strains of rad59 showed a UV-sensitive phenotype but behaved similarly to the parental strain in the rest of the assays. As compared to Saccharomyces cerevisiae, C. albicans was much more resistant to bleomycin and the same was true for their respective homologous recombination (HR) mutants. These results indicate that, as described in S. cerevisiae, RAD52 plays a more prominent role than RAD51 in the repair of DSBs in C. albicans and suggest the existence of at least two Rad52-dependent HR pathways, one dependent and one independent of Rad51. PMID- 20206284 TI - The Immunisation Beliefs and Intentions Measure (IBIM): predicting parents' intentions to immunise preschool children. AB - In England, uptake of the second dose of MMR (against measles, mumps, rubella), and dTaP/IPV or DTaP/IPV booster (against diphtheria, tetanus, pertussis, polio), is lower than that of the primary course. The Immunisation Beliefs and Intentions Measure (IBIM), based on the theory of planned behaviour (TPB) and qualitative interviews, was used to predict parents' intentions to take preschoolers for these recommended vaccinations. Parents from 43 child groups in southern England were randomised to receiving questions about either MMR (N=193) or dTaP/IPV (N=159). Overall, 255 parents fully completed TPB-based items. Regression analyses revealed that parental attitudes about the protective benefits of immunising and perceived behavioural control were strong, reliable predictors of intention to immunise with MMR. For dTaP/IPV, perceived protective benefits and number of children reliably predicted intention to immunise. Differences between parents with 'maximum immunisation intentions' and those with 'less than maximum intentions' are described. The IBIM appears to be a useful measure for predicting parents' intentions to immunise preschoolers. Implications for improving uptake are discussed. PMID- 20206285 TI - Standardization and validation of assays determining cellular immune responses against influenza. AB - Influenza vaccine efficacy does not always correlate with humoral immune responses. Recent reports indicate that the cellular immune response also contributes to protection, however robust assays are lacking. We standardized and validated assays for detection of human influenza-specific cellular responses in four international laboratories. The production of granzyme B as marker of T cell mediated cytotoxicity and release of Th1 and Th2 cytokines were evaluated. The granzyme B and cytokine assays were specific, accurate, precise, and robust. Replicate stimulations with PBMC from the same donors showed an intra-laboratory robustness (coefficient of variation) for quantitation of granzyme B of 33% and for cytokines - including IFN-gamma, TNF-alpha, IL-2, IL-10, IL-4, IL-13, GM-CSF and including the log IFN-gamma/IL-10 ratio - of 52%. The inter-laboratory robustness for detection of granzyme B was 29% and for detection of all cytokines was 49%. The assays can now be used for determining cell-mediated immunity and explored as correlates of protection. Moreover, the precision and robustness of these cellular assays allow the reliable detection of cellular responses even in small study populations. PMID- 20206288 TI - Natural products as lead-structures: a role for biotechnology. PMID- 20206287 TI - Progress in corticotropin-releasing factor-1 antagonist development. AB - Corticotropin releasing factor (CRF) receptor antagonists have been sought since the stress-secreted peptide was isolated in 1981. Although evidence is mixed concerning the efficacy of CRF(1) antagonists as antidepressants, CRF(1) antagonists might be novel pharmacotherapies for anxiety and addiction. Progress in understanding the two-domain model of ligand-receptor interactions for CRF family receptors might yield chemically novel CRF(1) receptor antagonists, including peptide CRF(1) antagonists, antagonists with signal transduction selectivity and nonpeptide CRF(1) antagonists that act via the extracellular (rather than transmembrane) domains. Novel ligands that conform to the prevalent pharmacophore and exhibit drug-like pharmacokinetic properties have been identified. The therapeutic utility of CRF(1) antagonists should soon be clearer: several small molecules are currently in Phase II/III clinical trials for depression, anxiety and irritable bowel syndrome. PMID- 20206289 TI - Nanonization strategies for poorly water-soluble drugs. AB - Poor water solubility for many drugs and drug candidates remains a major obstacle to their development and clinical application. Conventional formulations to improve solubility suffer from low bioavailability and poor pharmacokinetics, with some carriers rendering systemic toxicities (e.g. Cremophor((r)) EL). In this review, several major nanonization techniques that seek to overcome these limitations for drug solubilization are presented. Strategies including drug nanocrystals, nanoemulsions and polymeric micelles are reviewed. Finally, perspectives on existing challenges and future opportunities are highlighted. PMID- 20206286 TI - Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD). AB - Age-related macular degeneration (AMD) is the most prevalent form of irreversible blindness worldwide in the elderly population. The pathology of dry AMD consists of macular degeneration of photoreceptors and the RPE, lipofuscin (A2E) accumulation, and drusen formation. Mice have been widely used for generating models that simulate human AMD features for investigating the pathogenesis, treatment and prevention of the disease. Although the mouse has no macula, focal atrophy of photoreceptors and RPE, lipofuscin accumulation, and increased A2E can develop in aged mouse eyes. However, drusen are rarely seen in mice because of their simpler Bruch's membrane and different process of lipofuscin extrusion compared with humans. Thus, analyzing basal deposits at the ultrastructural level and understanding the ultrastructural pathologic differences between various mouse AMD models are critical to comprehending the significance of research findings and response to possible therapeutic options for dry AMD. Based on the multifactorial pathogenesis of AMD, murine dry AMD models can be classified into three groups. First, genetically engineered mice that target genes related to juvenile macular dystrophies are the most common models, and they include abcr(-/ ) (Stargardt disease), transgenic ELOVL4 (Stargardt-3 dominant inheritary disease), Efemp1(R345W/R345W) (Doyne honeycomb retinal dystrophy), and Timp3(S156C/S156C) (Sorsby fundus dystrophy) mice. Other murine models target genes relevant to AMD, including inflammatory genes such as Cfh(-/-), Ccl2(-/-), Ccr2(-/-), Cx3cr1(-/-), and Ccl2(-/-)/cx3cr1(-/-), oxidative stress associated genes such as Sod1(-/-) and Sod2 knockdown, metabolic pathway genes such as neprilysin(-/-) (amyloid beta), transgenic mcd/mcd (cathepsin D), Cp(-/-)/Heph( /Y) (ferroxidase ceruloplasmin/hepaestin, iron metabolism), and transgenic ApoE4 on high fat and high cholesterol diet (lipid metabolism). Second, mice have also been immunologically manipulated by immunization with carboxyethylpyrrole (CEP), an oxidative fragment of DHA found in drusen, and found to present with dry AMD features. Third, natural mouse strains such as arrd2/arrd2 (Mdm gene mutation) and the senescence accelerated mice (SAM) spontaneously develop features of dry AMD like photoreceptor atrophy and thickening of Bruch's membrane. All the aforementioned models develop retinal lesions with various features that simulate dry AMD lesions: focal photoreceptor degeneration, abnormal RPE with increased lipofuscin, basal infolding, decreased melanosomes and degeneration. However, Bruch's membrane changes are less common. Most mice develop retinal lesions at an older age (6-24 months, depending on the models), while the Ccl2(-/-)/cx3cr1(-/-) mice develop lesions by 4-6 weeks. Although murine models present various degrees of retinal and/or RPE degeneration, classical drusen is extremely rare. Using electron microscopy, small drusenoid deposits are found between RPE and Bruch's membrane in a few models including Efemp1(R345W/R345W), Ccl2(-/-)/cx3cr1(-/-), neprilysin(-/-), transgenic mcd/mcd, and ApoE4 transgenic mice on a high fat diet. High A2E levels are measured in the retinas of abcr(-/-), transgenic ELOVL4, and Ccl2(-/-)/cx3cr1(-/-) mice. In summary, murine models provide useful tools for studying AMD pathogenesis and evaluating novel therapies for this disease. This review compares the major dry AMD murine models and discusses retinal pathology at the ultrastructural level. PMID- 20206290 TI - Impact of new technologies for cellular screening along the drug value chain. AB - High-information screening formats, using more physiologically relevant cellular models and readout approaches, are slowly replacing traditional, target orientated approaches in drug discovery programs. With improved access to primary cells, as well as label-free, non-intrusive methods of compound interrogation (such as automated electrophysiology), high-thoughput screening facilities have to adapt to more complex assay scenarios. The implementation of novel cellular systems, readout technologies and data management in a drug discovery company are essential to improve the current falling productivity evident in recent years throughout the pharmaceutical industry. PMID- 20206291 TI - Cadmium chloride, benzo[a]pyrene and cyclophosphamide tested in the in vitro mammalian cell micronucleus test (MNvit) in the human lymphoblastoid cell line TK6 at Covance laboratories, Harrogate UK in support of OECD draft Test Guideline 487. AB - The following genotoxic chemicals were tested in the in vitro micronucleus assay, at Covance Laboratories, Harrogate, UK in the human lymphoblastoid cell line TK6. Cadmium chloride (an inorganic carcinogen), benzo[a]pyrene (a polycyclic aromatic hydrocarbon requiring metabolic activation) and cyclophosphamide (an alkylating agent requiring metabolic activation) were treated with and without cytokinesis block (by addition of cytochalasin B). This work formed part of a collaborative evaluation of the toxicity measures recommended in the draft OECD Test Guideline 487 for the in vitro micronucleus test. The toxicity measures used, capable of detecting both cytostasis and cell death, were relative population doubling, relative increase in cell counts and relative cell counts for treatments in the absence of cytokinesis block, and replication index or cytokinesis blocked proliferation index in the presence of cytokinesis block. All of the chemicals tested gave significant increases in the percentage of micronucleated cells with and without cytokinesis block at concentrations giving approximately 60% toxicity (cytostasis and cell death) or less by all of the toxicity measures used. The outcomes from this series of tests support the use of relative increase in cell counts and relative population doubling, as well as relative cell counts, as appropriate measures of cytotoxicity for the non-cytokinesis blocked in the in vitro micronucleus assay. PMID- 20206292 TI - Genotoxicity and carcinogenicity testing of pharmaceuticals: correlations between induction of DNA lesions and carcinogenic activity. AB - This survey is a compendium of the results of DNA lesions assays (DNA adducts, DNA strand breaks, DNA repair synthesis) and of the results of carcinogenicity assays of 146 pharmaceuticals. Of these drugs, 55 (37.7%) tested negative in both DNA lesions assay(s) and in carcinogenicity assay(s); 65 (44.5%) tested negative in DNA lesions assay(s), but gave a positive response in at least one carcinogenicity assay; 6 (4.1%) tested positive in at least one DNA lesions assay, but negative in carcinogenicity assay(s); 20 (13.7%) tested positive in at least one DNA lesions assay and in at least one carcinogenicity assay. Concerning the predictivity of DNA lesions assays findings for the results of long-term carcinogenesis assays performed in mice, rats or other species, concordance was found to exist for the 46.2% of pharmaceuticals in the case of DNA adducts, for 63.1% in the case of DNA strand breaks, and for 47.3% in the case of DNA repair synthesis (UDS). PMID- 20206293 TI - Cystic echinococcosis in children - the seventeen-year experience of two large medical centers in Serbia. AB - Cystic echinococcosis (CE) is a public health problem in countries having such endemic areas. Epidemiological studies of CE, especially pediatric, are rare. The aim of this study was to evaluate epidemiological and clinical characteristics of CE in children in Serbia. Data were obtained retrospectively from the case records of patients under the age of 18 years admitted for surgical treatment of CE at two large pediatric medical institutions in the period 1990-2006. Patients' age, number of cysts and their anatomic location were evaluated in relation to differences by patients' gender and socio-geographic status (urban or rural origin). The study included 149 children with 272 hydatid cysts. The mean age of patients was 10.1+/-3.8 years. There were no significant differences in the number of patients in relation to gender and urban:rural origin. There were no significant differences in patients' age at the time of surgery or the number of cysts per patient when patients' gender or socio-geographic status was evaluated. The anatomic location of cysts was as follows: liver (N=165; 60.7%), lungs (N=82; 30.1%), and other locations (N=25; 9.2%). Multiple cysts, and combined liver/lung involvement were identified in 34.2% (N=51), and 6.0% (N=9) of patients, respectively. Hepatic cysts were significantly more common in girls than in boys. There were no significant differences in anatomic location of cysts between socio geographic groups. The large number of infected children during a long period of investigation indicates an active transmission of disease and a lack of program for control and prevention of CE in Serbia. PMID- 20206294 TI - Towards an ontological representation of resistance: the case of MRSA. AB - This paper addresses a family of issues surrounding the biological phenomenon of resistance and its representation in realist ontologies. The treatments of resistance terms in various existing ontologies are examined and found to be either overly narrow, internally inconsistent, or otherwise problematic. We propose a more coherent characterization of resistance in terms of what we shall call blocking dispositions, which are collections of mutually coordinated dispositions which are of such a sort that they cannot undergo simultaneous realization within a single bearer. A definition of 'protective resistance' is proposed for use in the Infectious Disease Ontology (IDO) and we show how this definition can be used to characterize the antibiotic resistance in Methicillin Resistant Staphylococcus aureus (MRSA). The ontological relations between entities in our MRSA case study are used alongside a series of logical inference rules to illustrate logical reasoning about resistance. A description logic representation of blocking dispositions is also provided. We demonstrate that our characterization of resistance is sufficiently general to cover two other cases of resistance in the infectious disease domain involving HIV and malaria. PMID- 20206295 TI - Spontaneous intramural esophageal hematoma in association with idiopathic thrombocytopenic purpura: a cause of non-cardiac chest pain. PMID- 20206296 TI - Why do thrombi form in the left but not the right atrium in atrial fibrillation: differences in platelet P-selectin levels? PMID- 20206297 TI - Therapeutic hypothermia and ventricular fibrillation storm in early repolarization syndrome. PMID- 20206299 TI - Ablation of long-standing persistent atrial fibrillation with multielectrode ablation catheter. PMID- 20206298 TI - Dynamic and site-specific impact of ventricular pacing on left ventricular ejection fraction. AB - BACKGROUND: Some studies suggest that right ventricular (RV) pacing has an adverse impact on left ventricular ejection fraction (LVEF), particularly in subjects with preexisting left ventricular (LV) dysfunction, and that direct LV pacing may be relatively protective. Interactions between pacing site and LVEF remain unclear. OBJECTIVE: The purpose of this study was to examine the relative impact of RV and LV pacing on LVEF by serial study during a period in which LV dysfunction, induced by tachypacing, was introduced and then resolved. METHODS: In each of five dogs, RV, LV, and simultaneous RV and LV (BiV) pacing modes were compared to native ventricular activation (1) prior to tachypacing (baseline), (2) weekly during a 5-week continuous tachypacing period, and (3) weekly during a 3-week post-tachypacing recovery period. At each evaluation, LVEF and LV contraction synchrony were assessed during each pacing mode. RESULTS: The decrease in LVEF during the tachypacing period was more pronounced during RV pacing than during native activation or LV or BiV pacing. The magnitude of this effect correlated with a diminishment in LV contraction synchrony that was not observed during native activation or LV or BiV pacing. During the post tachypacing period, gradual reversal of these changes toward baseline was observed. CONCLUSION: Compared to native activation, RV pacing worsens LVEF in a manner proportional to the severity of preexisting LV dysfunction, attributable to reduced LV contraction synchrony. In comparison, both LV and BiV pacing preserve LVEF and contraction synchrony. PMID- 20206300 TI - Stereotactic robotic radiosurgery (CyberHeart): a cyber revolution in cardiac ablation? PMID- 20206301 TI - Specific prebiotic oligosaccharides modulate the early phase of a murine vaccination response. AB - The immune-modulatory effect of specific prebiotic oligosaccharides was shown in previous preclinical and clinical studies. To enhance the understanding of this effect, kinetic aspects of immune modulation and the correlation between microbiological and immunological parameters were investigated in a murine vaccination model. C57BL/6 mice were supplemented with short-chain galactooligosaccharides and long-chain fructooligosaccharides (ratio 9:1; Immunofortis()) in combination with pectin-derived acidic oligosaccharides. The timing of supplementation was varied around the primary (day 0) and secondary (day 21) vaccinations. Supplementation before the primary vaccination was necessary to increase delayed-type hypersensitivity responses (DTH) significantly at day 30. Supplementation after day 8 did not affect the DTH response at day 30, indicating that immune modulation occurred during the early phase. Therefore, correlation analysis of microbiological and immunological parameters was performed in a shortened experiment to focus on the early phase. At day 9 post priming, the percentages of cecal lactobacilli were correlated to the DTH responses (p=0.01). Furthermore, the results suggested that yet unidentified factors may play a role. Additional analysis of intestinal Peyer's patch major lymphocyte populations did not show effects of supplementation. In conclusion, a specific oligosaccharide mixture was shown to exert its immune-modulatory effect during the early phase of a murine immune response. The results are consistent with a role of the microbiota and possibly other factors in oligosaccharide induced immune modulation. Furthermore, the results demonstrate that it is critical to consider kinetic aspects of immune-modulatory and prebiotic effects in order to study their interaction in a meaningful way. PMID- 20206302 TI - MnSOD activity protects mitochondrial morphology of quiescent fibroblasts from age associated abnormalities. AB - Previously, we have shown manganese superoxide dismutase (MnSOD) activity protects quiescent human normal skin fibroblasts (NHFs) from age associated loss in proliferative capacity. The loss in proliferative capacity of aged vs. young quiescent cells is often characterized as the chronological life span, which is clearly distinct from replicative senescence. We investigate the hypothesis that MnSOD activity protects the mitochondrial morphology from age associated damage and preserves the chronological life span of quiescent fibroblasts. Aged quiescent NHFs exhibited abnormalities in mitochondrial morphology including abnormal cristae formation and increased number of vacuoles. These results correlate with the levels of cellular reactive oxygen species (ROS) and mitochondrial morphology in MnSOD homozygous and heterozygous knockout mouse embryonic fibroblasts. The abnormalities in mitochondrial morphology in aged quiescent NHFs cultured in presence of 21% oxygen concentration were more severe than NHFs cultured in 4% oxygen environment. The alteration in mitochondrial morphology was associated with a significant increase in cell population doubling: 54h in 21% compared to 44h in 4% oxygen environment. Overexpression of MnSOD decreased ROS levels, and preserved mitochondrial morphology in aged quiescent NHFs. These results demonstrate that MnSOD activity protects mitochondrial morphology and preserves the proliferative capacities of quiescent NHFs from age associated loss. PMID- 20206303 TI - The role of mitochondria in the mammalian antiviral defense system. AB - Innate immunity is a crucial defense system against viral and bacterial pathogens, providing a rapid response to mitigate the effects of microbial attack. While more readily associated with respiration and metabolism, recent research has surprisingly identified a number of mitochondrial factors in the mammalian innate immune system. This review summarizes the novel mitochondrial proteins, such as MAVS and NLRX1, involved in this process and attempts to reconcile this new mitochondrial function with our previous knowledge of the organelle. PMID- 20206304 TI - How to measure lung structure--what for? On the "Standards for the quantitative assessment of lung structure". PMID- 20206305 TI - Determinants of oxygen consumption during exercise on cycle ergometer: the effects of gravity acceleration. AB - The hypothesis that changes in gravity acceleration (a(g)) affect the linear relationships between oxygen consumption VO2 and mechanical power (w ) so that at any w, VO2 increases linearly with a(g) was tested under conditions where the weight of constant-mass legs was let to vary by inducing changes in a(g) in a human centrifuge. The effects of a(g) on the VO2/w relationship were studied on 14 subjects at two pedalling frequencies (f(p), 1.0 and 1.5 Hz), during four work loads on a cycle ergometer (25, 50, 75 and 100 W) and at four a(g) levels (1.0, 1.5, 2.0 and 2.5 times normal gravity). VO2 increased linearly with w. The slope did not differ significantly at various a(g) and f(p), suggesting invariant mechanical efficiency during cycling, independent of f(p) and a(g). Conversely, the y-intercept of the VO2/w relationship, defined as constant b, increased linearly with a(g). Constant b is the sum of resting VO2 plus internal metabolic power (E (i)). Since the former was the same at all investigated a(g), the increase in constant b was entirely due to an increase in E (i). Since the VO2 versus w lines had similar slopes, the changes in E (i) entirely explained the higher VO2 at each w, as a(g) was increased. In conclusion, the effects of a(g) on VO2 are mediated through changes in E (i), and not in w or in resting VO2. PMID- 20206306 TI - Presence of paraneuronal pseudobranchial neurosecretory system in the gill region of two air-breathing clupeids, Notopterus chitala and Notopterus notopterus. AB - The pseudobranchial neurosecretory system (PNS) is a system of neurosecretion observed in certain groups of teleosts, which are air-breathing or known to tolerate low oxygen tension in the surrounding water. Like other neuroendocrine cells of gill, cells belonging to this system have also been observed to have a role in condition of hypoxia. Uniformly found in all catfish species, the system was reported to be present in few non-catfish groups also, viz.-Atheriniformes, Channiformes (Devi, 1987), Perciformes, and Clupeiformes (Srivastava et al., 1981; Gopesh, 1983). In an attempt to study the structure and organization of the pseudobranchial neurosecretory system in non-catfish species of teleost, present investigation was undertaken in two species of Notopterus, viz. Notopterus chitala and Notopterus notopterus. The histological observations, using neurosecretion specific stains, undertaken on two clupeids are reported and the findings are discussed in the light of association of PNS with Carotid gland-a structure of intermediate stage in the process of transformation of pseudobranch into the carotid labyrinth, in course of evolution and also the air-breathing habit of the fish. PMID- 20206307 TI - Synthesis of nanobioglass and formation of apatite rods to occlude exposed dentine tubules and eliminate hypersensitivity. AB - The occlusion of patent dentine tubules may reduce or eliminate hypersensitivity by restricting dentinal fluid movement. The efficacy of a novel sol-gel nanobioglass and a melt-derived bioglass to occlude tubules and promote apatite formation was tested by mechanically brushing a slurry of bioglass powder and human saliva onto dentine possessing exposed tubules. Scanning electron microscopy, focused ion beam and energy-dispersive X-ray spectroscopy were used to characterize the powders and assess tubule occlusion. Melt-derived bioglass possessed an irregular particle morphology and had a mean size of 3.30 +/- 0.42 microm. The sol-gel bioglass particles were spherical, with a mean size of 0.65 +/- 0.19 microm. Dentine treated with melt-derived bioglass exhibited a tightly adherent continuous apatite layer. Treatment with nanobioglass resulted in particle deposition within tubules and formation of apatite rods which were tightly adherent to tubule walls and continuous to a measured depth of 270 microm. PMID- 20206308 TI - The ins and outs of editing and splicing of plastid RNAs: lessons from parasitic plants. AB - In chloroplasts of higher plants, editing and splicing of transcripts is a prerequisite for the proper expression of the plastid genetic information and thereby for photosynthesis. Holoparasitic plants differ from photosynthetic plants in that they have abandoned a photoautotrophic life style, which has led to a reduction or loss of photosynthetic activity. The analysis of several parasitic plant plastid genomes revealed that coding capacities were reduced to different extent, encompassing genes that regulate plastid gene expression as well as photosynthesis genes. The reorganization of the plastid genome is also reflected in overall increases in point mutation rates that parallel the vanishing of RNA editing sites. Unprecedented in land plants is the parallel loss of the plastid gene coding for an intron maturase and all but one group IIa introns in two parasitic species. These observations highlight the plastome-wide effects that are associated with a relaxed evolutionary pressure in plants living a heterotrophic life style. PMID- 20206309 TI - Biological pretreatment of rice straw by fermenting with Dichomitus squalens. AB - Rice straw was fermented by a wood-rot fungus Dichomitus squalens as a biological pretreatment, to increase the enzymatic digestibility of lignocellulose and promote cellulose hydrolysis. Response surface methodology was employed to optimize the fermentation medium of D. squalens for achieving the maximum volumetric activity of manganese peroxidase. The fermentation of rice straw by D. squalens for 15 days resulted in the enzymatic digestibility of 58.1% of theoretical glucose yield for the remaining glucan. In addition, a significant reduction in the crystallinity index and microstructural changes in the fermented rice straw were revealed. When the fungal-fermented rice straw was used as a substrate for ethanol production in simultaneous saccharification and fermentation, the ethanol production yield and productivity were 54.2% of the theoretical maximum and 0.39 g/L/hour, respectively, after 24 hours. PMID- 20206310 TI - Exploring RNA structure by integrative molecular modelling. AB - RNA molecular modelling is adequate to rapidly tackle the structure of RNA molecules. With new structured RNAs constituting a central class of cellular regulators discovered every year, the need for swift and reliable modelling methods is more crucial than ever. The pragmatic method based on interactive all atom molecular modelling relies on the observation that specific structural motifs are recurrently found in RNA sequences. Once identified by a combination of comparative sequence analysis and biochemical data, the motifs composing the secondary structure of a given RNA can be extruded in three dimensions (3D) and used as building blocks assembled manually during a bioinformatic interactive process. Comparing the models to the corresponding crystal structures has validated the method as being powerful to predict the RNA topology and architecture while being less accurate regarding the prediction of base-base interactions. These aspects as well as the necessary steps towards automation will be discussed. PMID- 20206311 TI - Development of a new magnetic beads-based immunoprecipitation strategy for proteomics analysis. AB - Sample pre-treatment is a critical step for an efficient and reliable analysis and it is highly dependent on the complexity of the matrix. This work shows an example of application of an immunoprecipitation approach using a new magnetic beads-based format, which allows a selective/specific extraction of potential biomarkers from metastatic prostate cancer. Results obtained on the development of this method, and its application for the extraction and pre-concentration of certain biomarkers present in metastatic cell lines of prostate cancer, are presented and discussed. It is concluded that the efficiency of the immunoprecipitation step is clearly compromised by the crosslinking conditions and it is highly dependent on the specificity of selected antibodies. The epoxy magnetic beads used in this work allowed an effective crosslinking of the antibodies contributing to an increased efficiency of the immunoprecipitation step. The optimized conditions for the application of these epoxy magnetic beads for the immunoprecipitation of anti-TUBA3C in metastatic prostate cancer cell line (PC3) are discussed here, as an example of application of the immnuprecipitation approach developed, which resulted in a very efficient tool for a specific extraction and pre-concentration of the targeted protein and, therefore, contributing to the efficiency of further analysis. PMID- 20206312 TI - New roles and mechanism of action of BMP4 in postnatal tooth cytodifferentiation. AB - During the phase of overt tooth cytodifferentiation that occurs after birth in the mouse and using the 3.6Collagen1a-Cre and the BMP4 floxed and BMP4 knockout mice, the BMP4 gene was deleted in early collagen producing odontoblasts around postnatal day 1. BMP4 expression was reduced over 90% in alveolar osteoblasts and odontoblasts. There was decreased rate of predentin to dentin formation and decreased mature odontoblast differentiation reflected in reduced DMP1 expression and proper dentinal tubule formation, as well as reduced Collagen type I and Osteocalcin expression. We observed mutant dysmorphogenic odontoblasts that failed to properly elongate and differentiate. The consequence of this failed differentiation process leads to permanent loss of dentin thickness, apparent enlarged pulp chambers in the molars and reduced bone supporting the tooth structures in mice as old as 10-12 months. Deletion of the BMP4 gene in odontoblasts also indirectly disrupted the process of enamel formation that persisted throughout life. The mechanism for this altered differentiation program in the absence of the BMP4 gene in odontoblasts is from decreased BMP signaling, and decreased expression of three key transcription factors, Dlx3, Dlx5, and Osterix. BMP signaling, as well as Dlx3 and Amelogenin expression, is also indirectly reduced in the ameloblasts of the odontoblast BMP4 cKO mice. This supports a key paracrine or endocrine postnatal role of odontoblast derived BMP4 on the proper amelogenesis and formation of the enamel. PMID- 20206313 TI - Serum transforming growth factor-beta 1 is not a robust biomarker of incident and progressive radiographic osteoarthritis at the hip and knee: the Johnston County Osteoarthritis Project. AB - PURPOSE: To test whether serum transforming growth factor-beta 1 (TGF-beta1) predicts incident and progressive hip or knee radiographic OA (rOA). METHODS: Serum TGF-beta1 was measured for 330 participants aged 45 years and older in the Johnston County Osteoarthritis Project, with paired longitudinal films available for 618 hips and 658 knees. Incident and progressive rOA were defined using Kellgren-Lawrence (K-L) grade as well as osteophyte (OST) and joint space narrowing (JSN) scores. Natural logarithm transformation was used to produce near normal distributions for continuous TGF-beta1 (lnTGF-beta1). Separate multivariable Weibull regression models were used to provide hazard ratios (HRs) for a 1-unit increase lnTGF-beta1 with each rOA outcome, accounting for variable follow-up times and clustering by individual, adjusted for age, race, gender, and body mass index (BMI). Interaction terms were considered statistically significant at P<0.10. RESULTS: The mean (+/-SD) age of the sample was 61.9+/-9.7 years, the mean BMI was 30.3+/-6.9 kg/m(2), with 60.6% women and 42.4% AA. The mean (+/-SD) TGF-beta1 was 17.8+/-6.1 ng/ml; follow-up time was 6.1+/-1.3 years. There were no significant interactions by race or gender. HRs showed no significant relationship between lnTGF-beta1 and incident or progressive rOA, OST, or JSN, at the knee or the hip. CONCLUSIONS: Levels of TGF-beta1 do not predict incident or progressive rOA, OST, or JSN at the hip or knee in this longitudinal, population-based study, making it unlikely that TGF-beta1 will be a robust biomarker for rOA in future studies. PMID- 20206314 TI - Comparing two low-energy diets for the treatment of knee osteoarthritis symptoms in obese patients: a pragmatic randomized clinical trial. AB - OBJECTIVES: To evaluate in a prospective, randomized clinical trial (RCT), symptom response among obese knee osteoarthritis (OA) patients following a feasible, intensive weight-loss program for 16 weeks. METHODS: Eligible patients were obese [body mass index (BMI)>30 kg/m(2)]; >50 years old, with primary knee OA. Participants were randomized to either a very-low-energy diet (VLED) or a low energy diet (LED) (415 kcal/day and 810 kcal/day, respectively), using commercially available formula foods - only for the first 8 weeks, managed by dieticians. The 8 weeks were followed by an additional 8-week period of a hypo energetic diet consisting of normal food plus meal replacements (1200 kcal/day). The primary endpoint was the number of patients responding according to the Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT-OARSI) responder criterion. The statistical analysis was based on a non-responder intention-to-treat (ITT) population (baseline observation carried forward). RESULTS: One hundred and ninety two patients (155 (80.7%) females) with a mean age 62.5 years [standard deviation (SD) 6.4; range 50-78 years]; average BMI 37.3 (SD 4.8) were included. At 16 weeks, similar proportions of the VLED and LED groups, 59 (61.5%), and 63 (65.6%) patients, respectively, met the OMERACT-OARSI responder criteria, with no statistical significant difference between the groups (P=0.55). Combining the groups the pooled estimate was 64% meeting the responder criteria [95% confidence interval (CI) 57%, 70%]. There was an overall reduction in pain, corresponding to an average pain reduction on the visual analogue scale (VAS) of 11.1 (95%CI 13.6, 8.5) in the combined groups. At week 16 weight loss in the combined groups was 12.8 kg (95%CI: 11.84-13.66; P<0.001). 71% lost > or =10% body weight in both diet groups, with a pooled estimate of 74% (95%CI: 68-80%). CONCLUSION: No clinically significant differences were found between the 415 kcal/day and 810 kcal/day diets. A 16-week formula-diet weight-loss program resulted in a fast and effective weight loss with very few adverse events resulting in a highly significant improvement in symptoms in overweight patients with knee OA. PMID- 20206315 TI - From a chaotic to an organized tachyarrhythmia--how to predict the origin. PMID- 20206316 TI - Triple atrioventricular nodal response to an atrial impulse. PMID- 20206317 TI - Structural basis for K(V)7.1-KCNE(x) interactions in the I(Ks) channel complex. AB - The cardiac I(Ks) current is involved in action potential repolarization, where its primary function is to limit action potential prolongation during sympathetic stimulation. The I(Ks) channel is mainly composed of K(V)7.1 ion channels associated with KCNE1 auxiliary subunits. The availability of KCNE1 solution structure by nuclear magnetic resonance spectroscopy in conjunction with biochemical assays addressing K(V)7.1-KCNE1 residue interactions has provided new insights into the structural basis for K(V)7.1 modulation by KCNE1. Recent evidence further suggests that KCNE2 may associate with the K(V)7.1-KCNE1 channel complex and modulate its current amplitude. Here we review recent studies in this area and discuss potential roles for multiple KCNE(x) subunits in I(Ks) generation and modulation as well as the clinical relevance of the new information. PMID- 20206318 TI - Verapamil eliminates the hierarchical nature of activation frequencies from the pulmonary veins to the atria during paroxysmal atrial fibrillation. AB - BACKGROUND: There is evidence that verapamil promotes the persistence of paroxysmal atrial fibrillation (AF). Little is known about the underlying mechanisms. OBJECTIVE: The purpose of this study was to determine the effect of verapamil on dominant frequencies (DFs) in the pulmonary veins (PVs) and atria during paroxysmal AF with reference to its potential arrhythmogenicity. METHODS: Forty-three patients with paroxysmal AF were studied. Bipolar electrograms were recorded simultaneously during AF from the right atrial free wall (RAFW), coronary sinus (CS) and three PVs, or two PVs and the left atrial appendage (LAA). The DFs were obtained by fast Fourier transform analysis before and after infusion of verapamil (0.1 mg/kg, intravenously). RESULTS: At baseline, the maximum DF among the PVs (6.9 +/- 0.9 Hz) was significantly higher than the DF in the RAFW (6.2 +/- 0.7 Hz), CS (5.7 +/- 0.5 Hz), or LAA (5.9 +/- 0.7 Hz) (P<.01); there was a substantial PV-to-atrial DF gradient (RAFW 0.7 +/- 0.9, CS 1.1 +/- 0.7, LAA 0.7 +/- 0.9 Hz). Verapamil increased the atrial DF to 6.9 +/- 0.8, 6.6 +/- 0.7, and 7.2 +/- 1.0 Hz in the RAFW, CS, and LAA, respectively (P<.0001) but did not affect the maximum PV DF (7.1 +/- 0.7 Hz). The PV-to-atrial DF gradient was eliminated after verapamil (RAFW 0.2 +/- 0.8, CS 0.5 +/- 0.6, LAA -0.4 +/- 0.8 Hz; P<.01 vs. baseline). CONCLUSION: Verapamil increases the activation frequency in the atria but not in the PVs, eliminating the PV-to-atrial DF gradient during paroxysmal AF. PMID- 20206319 TI - High prevalence of early repolarization in short QT syndrome. AB - BACKGROUND: Short QT syndrome (SQTS) is characterized by an abnormally short QT interval and sudden death. Due to the limited number of cases, the characteristics of SQTS are not well understood. It has been reported recently that early repolarization is associated with idiopathic ventricular fibrillation and the QT interval is short in patients with early repolarization. OBJECTIVE: The purpose of this study was to study the association between early repolarization and arrhythmic events in SQTS. METHODS: The study consisted of three cohorts: SQTS cohort (N = 37), control cohort with short QT interval and no arrhythmic events (N = 44), and control cohort with normal QT interval (N = 185). ECG parameters were compared among the study cohorts. RESULTS: Heart rate, PR interval, and QRS duration were similar among the three study cohorts. Early repolarization was more common in the SQTS cohort (65%) than in the short QT control cohort (30%) and the normal QT control cohort (10%). Duration from T-wave peak to T-wave end was longer in the SQTS cohort than in the short QT control cohort, although QT and corrected QT intervals were similar. In the SQTS cohort, there were more males among patients with arrhythmic events than in those with a family history but without arrhythmic events. In multivariate models, early repolarization was associated with arrhythmic events in the SQTS cohort. ECG parameters including QT and QTc intervals were not associated with arrhythmic events in the SQTS cohort. CONCLUSION: There is a high prevalence of early repolarization in patients with SQTS. Early repolarization may be useful in identifying risk of cardiac events in SQTS. PMID- 20206320 TI - Outcomes of long-standing persistent atrial fibrillation ablation: a systematic review. AB - BACKGROUND: Ablation of long-standing persistent atrial fibrillation (AF) is highly variable, with differing techniques and outcomes. OBJECTIVE: The purpose of this study was to undertake a systematic review of the literature with regard to the impact of ablation technique on the outcomes of long-standing persistent AF ablation. METHODS: A systematic search of the contemporary English scientific literature (from January 1, 1990 to June 1, 2009) in the PubMed database identified 32 studies on persistent/long-standing persistent or long-standing persistent AF ablation (including four randomized controlled trials). Data on single-procedure, drug-free success, multiple procedure success, and pharmaceutically assisted success at longest follow-up were collated. RESULTS: Four studies performed pulmonary vein isolation alone (21%-22% success). Four studies performed pulmonary vein antrum ablation with isolation (PVAI; n = 2; 38% 40% success) or without confirmed isolation (PVA; n = 2; 37%-56% success). Ten studies performed linear ablation in addition to PVA (n = 5; 11%-74% success) or PVAI (n = 5; 38%-57% success). Three studies performed posterior wall box isolation (n = 3; 44%-50% success). Five studies performed complex fractionated atrial electrogram ablation (n = 5; 24%-63% success). Six studies performed complex fractionated atrial electrogram ablation as an adjunct to PVA (n = 2; 50% 51% success), PVAI (n = 3; 36%-61% success), or PVAI and linear (n = 1; 68% success) ablation. Five studies performed the stepwise ablation approach (38%-62% success). CONCLUSION: The variation in success within and between techniques suggests that the optimal ablation technique for long-standing persistent AF is unclear. Nevertheless, long-standing persistent AF can be effectively treated with a composite of extensive index catheter ablation, repeat procedures, and/or pharmaceuticals. PMID- 20206321 TI - Vagal tone augmentation to the atrioventricular node in humans: efficacy and safety of burst endocardial stimulation. AB - BACKGROUND: Control of atrioventricular (AV) nodal conduction by endocardial stimulation of efferent AV nodal vagal fibers [atrioventricular nodal vagal stimulation (AVNS)] is a promising approach for long-term device-based modulation of ventricular rate during atrial fibrillation (AF). However, few data on the efficacy of AVNS delivered as high-frequency stimulus packages (burst AVNS) in humans are available. OBJECTIVE: The purpose of this study was to determine whether burst AVNS can to modulate AV nodal conduction during AF and whether burst AVNS delivered during sinus rhythm (SR) in the effective atrial refractory period allows safe implantation of a permanent lead in a position suitable for AVNS. METHODS: Twenty patients (10 in SR and 10 in AF) who were candidates for dual-chamber pacemaker implantation for sick sinus syndrome were enrolled in the study. The posteroseptal right atrium was mapped to identify a location at which burst AVNS would achieve AV nodal conduction modulation (lengthening of PR interval in SR and reduction of ventricular rate in AF). Subsequently, a lead was screwed in at that site and burst stimulation (pulse rate 50 Hz, burst duration 180 ms) was delivered at different burst rates, pulse durations, and amplitudes. RESULTS: In all SR patients, PR-interval prolongation was evoked at 90 and 120 bursts/minute with pulse durations < or =1 ms. Specifically, the mean voltages required to obtain PR-interval prolongation and advanced AV block were 4.3 +/- 2.2 V and 5.4 +/- 1.8 V (at 90 bursts/minute and 1 ms), respectively. Similarly, ventricular rate reduction was obtained in all AF patients, starting from 90 bursts/minute and 0.5-ms pulse duration (at 5.4 +/- 1.8 V). Ventricular arrhythmias were never induced during AVNS. CONCLUSION: Endocardial right atrial burst AVNS reduces ventricular rate during AF. Burst AVNS delivered during SR in the effective atrial refractory period allows optimization of lead positioning for AVNS. PMID- 20206322 TI - Sleuthing safer epicardial access: pericardial pressure frequency "fingerprinting". PMID- 20206323 TI - Atrial fibrillation termination as a procedural endpoint during ablation in long standing persistent atrial fibrillation. AB - BACKGROUND: Ablation of long-standing persistent atrial fibrillation (AF) remains challenging, with a lower success rate than paroxysmal AF. A reliable ablation endpoint has not been demonstrated yet, although AF termination during ablation may be associated with higher long-term maintenance of sinus rhythm (SR). OBJECTIVE: The purpose of this study was to determine whether the method of AF termination during ablation predicts mode of recurrence or long-term outcome. METHODS: Three hundred six patients with long-standing persistent AF, free of antiarrhythmic drugs (AADs), undergoing a first radiofrequency ablation (pulmonary vein [PV] antrum isolation and complex fractionated atrial electrograms) were prospectively included. Organized atrial tachyarrhythmias (AT) that occurred during AF ablation were targeted. AF termination mode during ablation was studied in relation to other variables (characteristics of arrhythmia recurrence, redo procedures, the use of adenosine/isoproterenol for redo, and comparison of focal versus macroreentrant ATs). Long-term maintenance of SR was assessed during the follow-up. RESULTS: During AF ablation, six of 306 patients converted directly to SR, 172 patients organized into AT (with 38 of them converting in SR with further ablation), and 128 did not organize or terminate and were cardioverted. Two hundred eleven of 306 patients (69%) maintained in long-term SR without AADs after a mean follow-up of 25 +/- 6.9 months, with no statistical difference between the various AF termination modes during ablation. Presence or absence of organization during ablation clearly predicted the predominant mode of recurrence, respectively, AT or AF (P = .022). Among the 74 redo ablation patients, 24 patients (32%) had extra PV triggers revealed by adenosine/isoproterenol. Termination of focal ATs was correlated with higher long-term success rate (24/29, 83%) than termination of macroreentrant ATs (20/35, 57%; P = .026). CONCLUSION: AF termination during ablation (conversion to AT or SR) could predict the mode of arrhythmia recurrence (AT vs. AF) but did not impact the long-term SR maintenance after one or two procedures. AT termination with further ablation did not correlate with better long-term outcome, except with focal ATs, for which termination seems critical. PMID- 20206324 TI - Genotype-phenotype correlation in tissue models of Brugada syndrome simulating patients with sodium and calcium channelopathies. AB - BACKGROUND: Genetic defects in the sodium channel or in the calcium channel have been identified in patients with Brugada syndrome (BS). However, the differences in their genotype-phenotype correlations are still unclear. OBJECTIVE: We evaluated the phenotypic differences and therapeutic effects between the sodium channel and calcium channel abnormalities in in vitro models of BS. METHODS: We created two models of BS in 18 isolated and arterially perfused canine right ventricular preparations: (1) sodium channel dysfunction model (Na model, n = 11) by pilsicainide and pinacidil and (2) calcium channel dysfunction model (Ca model, n = 7) by verapamil; optically mapped action potentials (APs) on their transmural surface; and evaluated APs and electrocardiograms (ECGs) at pacing cycle lengths (CLs) of 2,000 and 1,000 ms. RESULTS: CL = 1,000 ms: Both models had coved-type ST elevation in the ECG, longer AP duration (APD) in the epicardium than in the endocardium, and a similar incidence of spontaneous ventricular arrhythmias. However, the Ca model had a higher incidence of T wave alternans (TWA) than the Na-model. CL = 2,000 ms: ECGs of the Ca model converted to saddleback-type ST elevation with shorter APDs in the epicardium than in the endocardium, whereas the Na model still had coved-type ST elevation and longer APDs in the epicardium. None of the Ca model preparations had ventricular arrhythmias or TWA, although the Na model had frequent ventricular arrhythmias and TWA. CONCLUSION: Although both sodium channel and calcium channel dysfunction produced similar BS ECGs and arrhythmogenesis at 60 bpm, calcium channel dysfunction was associated with a higher incidence of TWA at 60 bpm, less ST elevation, and fewer arrhythmias at 30 bpm compared with sodium channel dysfunction. PMID- 20206325 TI - Ventricular arrhythmias originating from papillary muscles in the right ventricle. AB - BACKGROUND: Premature ventricular complexes (PVCs) and ventricular tachycardia (VT) with origin in the left ventricular papillary muscle have recently been described. There are no prior studies describing the characteristics of the ventricular arrhythmias (VAs) arising from the right ventricular papillary muscles (RV PAPs). METHODS: Among 169 consecutive patients who underwent a catheter ablation of a VA, eight patients with RV PAPs were identified (seven men, mean PVC burden 17.0% +/- 20%). A control group consisted of 10 consecutive patients with arrhythmias originating from the right ventricle (10 women, mean PVC burden 13.9% +/- 12.8%). All patients underwent cardiac magnetic resonance imaging (MRI). Intracardiac echocardiography was used to identify the site of origin of the RV PAP arrhythmias. The site of origin of a total of 15 distinct PAP arrhythmias was mapped to the following papillary muscles: posterior (n = 3), anterior (n = 4), or septal (n = 8). RESULTS: Postablation echocardiograms did not reveal new tricuspid regurgitation. During a mean follow-up of 8 +/- 9 months, there were no adverse outcomes. The PVC burden was reduced from 17% +/- 20% preablation to 0.6% +/- 0.8% postablation in the RV PAP group and from 13.9% +/- 12.8% to 0.3% +/- 0.4% in the control group. The QRS complex was broader in the RV PAP group compared with in the control group (163 +/- 21 ms vs. 141 +/- 22 ms; P = .02). RV PAP arrhythmias originating from the posterior or anterior RV PAPs more often had a superior axis with late R-wave transition (>V4) compared with septal RV RAP arrhythmias, which more often had an inferior axis with an earlier R-wave transition in the precordial leads (200 kb. Sequence analysis of four polymorphic markers in the African, European, and Asian HAPMAP panels revealed 17 subtelomeric 4q and eight subtelomeric 10qter haplotypes. Haplotypes that are composed of a mixture of 4q and 10q sequences were detected at frequencies >10% in all three populations, seemingly supporting a mechanism of ongoing interchromosomal exchanges between these chromosomes. We constructed an evolutionary network of most haplotypes and identified the 4q haplotype ancestral to all 4q and 10q haplotypes. According to the network, all subtelomeres originate from only four discrete sequence-transfer events during human evolution, and haplotypes with mixtures of 4q- and 10q specific sequences represent intermediate structures in the transition from 4q to 10q subtelomeres. Haplotype distribution studies on a large number of globally dispersed human DNA samples from the HGDP-CEPH panel supported our findings and show that all haplotypes were present before human migration out of Africa. D4Z4 repeat array contractions on the 4A161 haplotype cause Facioscapulohumeral muscular dystrophy (FSHD), whereas contractions on most other haplotypes are nonpathogenic. We propose that the limited occurrence of interchromosomal sequence transfers results in an accumulation of haplotype-specific polymorphisms that can explain the unique association of FSHD with D4Z4 contractions in a single 4q subtelomere. PMID- 20206333 TI - Using principal components of genetic variation for robust and powerful detection of gene-gene interactions in case-control and case-only studies. AB - Many popular methods for exploring gene-gene interactions, including the case only approach, rely on the key assumption that physically distant loci are in linkage equilibrium in the underlying population. These methods utilize the presence of correlation between unlinked loci in a disease-enriched sample as evidence of interactions among the loci in the etiology of the disease. We use data from the CGEMS case-control genome-wide association study of breast cancer to demonstrate empirically that the case-only and related methods have the potential to create large-scale false positives because of the presence of population stratification (PS) that creates long-range linkage disequilibrium in the genome. We show that the bias can be removed by considering parametric and nonparametric methods that assume gene-gene independence between unlinked loci, not in the entire population, but only conditional on population substructure that can be uncovered based on the principal components of a suitably large panel of PS markers. Applications in the CGEMS study as well as simulated data show that the proposed methods are robust to the presence of population stratification and are yet much more powerful, relative to standard logistic regression methods that are also commonly used as robust alternatives to the case-only type methods. PMID- 20206334 TI - Mutations in FLVCR2 are associated with proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (Fowler syndrome). AB - Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (PVHH), also known as Fowler syndrome, is an autosomal-recessively inherited prenatal lethal disorder characterized by hydranencephaly; brain stem, basal ganglia, and spinal cord diffuse clastic ischemic lesions with calcifications; glomeruloid vasculopathy of the central nervous system and retinal vessels; and a fetal akinesia deformation sequence (FADS) with muscular neurogenic atrophy. To identify the molecular basis for Fowler syndrome, we performed autozygosity mapping studies in three consanguineous families. The results of SNP microarrays and microsatellite marker genotyping demonstrated linkage to chromosome 14q24.3. Direct sequencing of candidate genes within the target interval revealed five different germline mutations in FLVCR2 in five families with Fowler syndrome. FLVCR2 encodes a transmembrane transporter of the major facilitator superfamily (MFS) hypothesized to be involved in regulation of growth, calcium exchange, and homeostasis. This is the first gene to be associated with Fowler syndrome, and this finding provides a basis for further studies to elucidate the pathogenetic mechanisms and phenotypic spectrum of associated disorders. PMID- 20206335 TI - DNA methylome of familial breast cancer identifies distinct profiles defined by mutation status. AB - It is now understood that epigenetic alterations occur frequently in sporadic breast carcinogenesis, but little is known about the epigenetic alterations associated with familial breast tumors. We performed genome-wide DNA-methylation profiling on familial breast cancers (n = 33) to identify patterns of methylation specific to the different mutation groups (BRCA1, BRCA2, and BRCAx) or intrinsic subtypes of breast cancer (basal, luminal A, luminal B, HER2-amplified, and normal-like). We used methylated DNA immunoprecipitation (MeDIP) on Affymetrix promoter chips to interrogate methylation profiles across 25,500 distinct transcripts. Using a support vector machine classification algorithm, we demonstrated that genome-wide methylation profiles predicted tumor mutation status with estimated error rates of 19% (BRCA1), 31% (BRCA2), and 36% (BRCAx) but did not accurately predict the intrinsic subtypes defined by gene expression. Furthermore, using unsupervised hierarchical clustering, we identified a distinct subgroup of BRCAx tumors defined by methylation profiles. We validated these findings in the 33 tumors in the test set, as well as in an independent validation set of 47 formalin-fixed, paraffin-embedded familial breast tumors, by pyrosequencing and Epityper. Finally, gene-expression profiling and SNP CGH array previously performed on the same samples allowed full integration of methylation, gene-expression, and copy-number data sets, revealing frequent hypermethylation of genes that also displayed loss of heterozygosity, as well as of genes that show copy-number gains, providing a potential mechanism for expression dosage compensation. Together, these data show that methylation profiles for familial breast cancers are defined by the mutation status and are distinct from the intrinsic subtypes. PMID- 20206337 TI - Selective formation of glycosidic linkages of N-unsubstituted 4-hydroxyquinolin-2 (1H)-ones. AB - A comparative study for selective glucosylation of N-unsubstituted 4 hydroxyquinolin-2(1H)-ones into 4-(tetra-O-acetyl-beta-D glucopyranosyloxy)quinolin-2(1H)-ones is reported. Four glycosyl donors including tetra-O-acetyl-alpha-D-glucopyranosyl bromide, beta-D-glucose pentaacetate, glucose tetraacetate and tetra-O-acetyl-alpha-D-glucopyranosyl trichloroacetimidate were tested, along with different promoters and reaction conditions. The best results were obtained with tetra-O-acetyl-alpha-D glucopyranosyl bromide with Cs(2)CO(3) in CH(3)CN. In some cases the 4-O glucosylation of the quinolinone ring was accompanied by 2-O-glucosylation yielding the corresponding 2,4-bis(tetra-O-acetyl-beta-D glucopyranosyloxy)quinoline. Next, 4-(tetra-O-acetyl-beta-D glucopyranosyloxy)quinolin-2(1H)-ones were deacetylated into 4-(beta-D glucopyranosyloxy)quinolin-2(1H)-ones with Et(3)N in MeOH. In some instances the deacetylation was accompanied by the sugar-aglycone bond cleavage. Structure elucidation, complete assignment of proton and carbon resonances as well as assignment of anomeric configuration for all the products under investigation were performed by 1D and 2D NMR spectroscopy. PMID- 20206336 TI - Identification of a recurrent microdeletion at 17q23.1q23.2 flanked by segmental duplications associated with heart defects and limb abnormalities. AB - Segmental duplications, which comprise approximately 5%-10% of the human genome, are known to mediate medically relevant deletions, duplications, and inversions through nonallelic homologous recombination (NAHR) and have been suggested to be hot spots in chromosome evolution and human genomic instability. We report seven individuals with microdeletions at 17q23.1q23.2, identified by microarray-based comparative genomic hybridization (aCGH). Six of the seven deletions are approximately 2.2 Mb in size and flanked by large segmental duplications of >98% sequence identity and in the same orientation. One of the deletions is approximately 2.8 Mb in size and is flanked on the distal side by a segmental duplication, whereas the proximal breakpoint falls between segmental duplications. These characteristics suggest that NAHR mediated six out of seven of these rearrangements. These individuals have common features, including mild to moderate developmental delay (particularly speech delay), microcephaly, postnatal growth retardation, heart defects, and hand, foot, and limb abnormalities. Although all individuals had at least mild dysmorphic facial features, there was no characteristic constellation of features that would elicit clinical suspicion of a specific disorder. The identification of common clinical features suggests that microdeletions at 17q23.1q23.2 constitute a novel syndrome. Furthermore, the inclusion in the minimal deletion region of TBX2 and TBX4, transcription factors belonging to a family of genes implicated in a variety of developmental pathways including those of heart and limb, suggests that these genes may play an important role in the phenotype of this emerging syndrome. PMID- 20206338 TI - Synthesis of N-substituted iminosugar derivatives and their immunosuppressive activities. AB - Several N-alkyl and hydroxyethyl-substituted iminosugar derivatives, including L altro and D-galacto epimers, were synthesized and the effects of these synthetic iminosugars on proliferation of mouse splenocytes were evaluated in the MTT assay. The experimental data demonstrated that the N-alkylated D-galacto iminosugars showed better inhibitory activities than L-altro analogues, which might hold potential as immunosuppressive agents. PMID- 20206339 TI - Tumor necrosis factor alpha gene variants do not display allelic imbalance in circulating myeloid cells. AB - Carriage of the TNF -308 A allele (rs1800629 A) has been associated with increased serum TNF-alpha levels, the development of sepsis syndrome, and fatal outcome, in severely traumatized patients (Menges et al., 2008 [1]). Herein, we analysed the putative allelic imbalance of TNF-alpha release from myeloid cells. Circulating peripheral blood cells from healthy human blood donors (n=104) and monocyte-derived macrophages (n=158) were analysed for their ex vivo capacity of TNF-alpha expression. Our findings indicate that carriage of the TNF -308 A allele is not associated with high TNF-alpha expression in circulating human leucocytes and monocyte-derived macrophages. Other cellular sources, e.g. tissue resident cells like mast cells and/or tissue specific macrophages might be the cellular source of high TNF-alpha serum levels shortly after trauma. PMID- 20206341 TI - [Benign anastomotic strictures after oncologic rectal cancer surgery. Results of treatment with hydrostatic dilation]. AB - INTRODUCTION: Benign anastomotic strictures after rectal cancer surgery are common and their treatment can vary from conservative measures to surgical resection. PATIENTS AND METHODS: Between March 2001 and August 2008, 422 patients with rectal cancer underwent anterior resection and 83.8% were treated with primary anastomosis. Anastomotic stricture has been defined as the inability to pass a colonoscope. Hydrostatic balloon dilation was performed. Results of success and failure dilation were assessed. RESULTS: Twenty-six patients (7.34%) with anastomotic stricture were treated; 16 men and 10 women, with a median age of 66 years (57-74). A total of 26 anterior resections were performed, as well as 10 end-to-end anastomosis, 10 side-to-end, 4 j-pouch and 2 pouch coloplasties. The median stricture height was 10cms (4-12). Thirteen patients had preoperative radiotherapy (50%), and 9 patients had an ileostomy (34.7%). The median time of diagnosis was 6 months (3-10). The diagnosis was made by: rectal digital examination in 19.2%, colonoscopy 23.1% and clinical symptoms in 57.7%. The median number of dilation sessions required was 2 (1-4). The median of follow-up was 39 months (23 to 49). Results were successful 88.5,% and unsuccessful in 11.5%. Morbidity was 3.8% (one perforation after dilation). There was no mortality. CONCLUSIONS: Benign anastomotic strictures after rectal cancer surgery are frequent (7.05%), develop symptoms (52.9%) and can be successfully treated by hydrostatic dilation in more than 88% patients. PMID- 20206340 TI - [Local treatment of a chronic anal fissure with diltiazem vs. nitroglycerin. A comparative study]. AB - AIM: To assess the value of using smooth muscle relaxants drugs and assess the results of the topical use of 2% diltiazem as an alternative to 0.2% nitroglycerin in the treatment of chronic anal fissure (CAF). METHODS: Review of the CAF contained in a prospectively collected database of anal fissures including one hundred forty-five patients diagnosed with CAF and treated with standard measures (ST) in two consecutive periods. During the first period they were allocated alternatively to not receive further treatment (ST group) or to be treated with nitroglycerin ointment (NTG group). In the second period all were treated with local diltiazem (DTZ group). One hundred forty-five patients entered the study and 124 completed it. RESULTS: Initially there were significant differences in improvement rates (45% ST, 62.5% NTG and 80% DTZ, p<0.01), but not in the cure rates (27% ST, 40% NTG and 39% DTZ) and the treatment was completed by 124 patients (85.5%). There were more side effects and more dropouts in the NTG group. In the subsequent follow-up for a median period of 25 months there were 25% recurrences and almost all responded to repeated medical treatment. CONCLUSIONS: Smooth muscle relaxant drugs do not achieve a higher cure rate than the traditional measures used in CAF, but offer more symptomatic relief, providing an opportunity to avoid surgery. Topical diltiazem does not have the side effects of the nitroglycerin and is better accepted by patients. PMID- 20206342 TI - [Self-evaluation of a clinical pathway to improve the results of rectal cancer]. AB - OBJECTIVES: To analyse whether the self-evaluation of a clinical pathway improves the results of rectal cancer (RC) treatment. PATIENTS AND METHOD: Patients operated on for RC were divided into 3 groups according to biannual modifications of a clinical pathway analysing several indicators. RESULTS: 166 patients: Group A: 2002-3 n=50, B: 2004-5 n=53 and C: 2006-7 n=63, without any differences in age, gender or comorbidity. Preoperative study improved with the introduction of CT scan: 76% in Group C vs. 6% in Group A (P<0.001). All Group C tumours were staged using MR, rectal ultrasound or both, compared to 84% in Group A (P<0.001). The rate of abdominal-perineal resections was reduced from 42% (Group A) to 17% (Group C); (P=0.007) and about 48% of surgeons in Group A vs. 94% in the C had a specific activity in coloproctology (P<0.001). The average lymph node count was: Group A=6.2+/-4.5 vs. 13+/-6.5 in the C and circumferential margin analysis was reported in 24% of Group A vs. 76% in Group C (P<0.001). Parameters such as perioperative blood transfusion, ICU admission, use of nasogastric tube, early feeding or epidural analgesia also improved progressively. Operative mortality decreased non-significantly to 4.7% and anastomotic leaks from 24% to 9.5% with a reduction in postoperative stay from 15 to 11 days during the period analysed (P=0.029). CONCLUSIONS: Several indicators have significantly improved in a relatively short period of time due to self-evaluations of the process. PMID- 20206343 TI - [Spontaneous haematoma of the psoas muscle with femoral neuropathy associated with antiplatelet treatment with clopidogrel: Is surgical decompression indicated?]. PMID- 20206344 TI - [Multiple liver adenomatosis treated with surgical resection and radiofrequency]. PMID- 20206345 TI - [Laparoscopic approach in the treatment of visceral aneurysms by selective arterial embolisation]. PMID- 20206346 TI - Detection of broken rotor bars in induction motors using nonlinear Kalman filters. AB - This paper presents a model-based fault detection approach for induction motors. A new filtering technique using Unscented Kalman Filter (UKF) and Extended Kalman Filter (EKF) is utilized as a state estimation tool for on-line detection of broken bars in induction motors based on rotor parameter value estimation from stator current and voltage processing. The hypothesis on which the detection is based is that the failure events are detected by jumps in the estimated parameter values of the model. Both UKF and EKF are used to estimate the value of rotor resistance. Upon breaking a bar the estimated rotor resistance is increased instantly, thus providing two values of resistance after and before bar breakage. In order to compare the estimation performance of the EKF and UKF, both observers are designed for the same motor model and run with the same covariance matrices under the same conditions. Computer simulations are carried out for a squirrel cage induction motor. The results show the superiority of UKF over EKF in nonlinear system (such as induction motors) as it provides better estimates for rotor fault detection. PMID- 20206348 TI - The reliability and reproducibility of the Neer classification system--digital radiography (PACS) improves agreement. AB - INTRODUCTION: We investigated if the introduction of digital radiography, with its software permitting enhancement of plain radiographs, improved inter- and intra-observer agreement in the Neer classification. METHODS: Five observers participated in classifying 50 randomly selected radiographs with a confirmed proximal humeral fracture. The observers included a junior registrar, an upper limb fellow, a lower-limb orthopaedic consultant and two orthopaedic shoulder consultants. Agreement was quantified via kappa values. RESULTS: In general, good (0.61-0.80) results were obtained using kappa value for inter-observer reliability throughout all grades. On further analysis, however, discrepancies persist in the classification between Neer type 1/2 and Neer type 5 categories. The latter was not restricted to more inexperienced surgeons. Intra-observer agreement (> 0.81) was excellent throughout all grades. CONCLUSION: The introduction of digital radiography aids the improvement of Neer classification of proximal humeral fractures across all grades. With superior agreement in displacement and fracture patterns, improved communication and discussion of these injuries and similar treatment plans can be expected. This may help negate one aspect of the variability in outcome of proximal humeral shaft fractures. More complex fracture configurations continue to have difficulty in interpretation and may require further imaging analysis to conclude definitively. PMID- 20206349 TI - Report of the FIGO Working Group on Sexual Violence/HIV: Guidelines for the management of female survivors of sexual assault. AB - OBJECTIVE: To review the evidence and provide guidelines on the management of sexual violence against women, specifically, rape. OUTCOMES: Outcomes evaluated include effectiveness of post-rape care provision. EVIDENCE: The MEDLINE database was searched for articles published up to December 2008 on the topic of post-rape care and expert opinion was sought from the Sexual Violence Research Initiative membership. In addition, a search was performed for English-language protocols on Google. One Spanish language protocol was considered in the development of the guidelines. VALUES: The evidence was evaluated by authors and reviewers of the South African Department of Health's sexual assault curriculum, and by members of the FIGO Working Group and recommendations were made according to the guidelines developed by the Canadian Task Force on Preventive Health Care. BENEFITS, HARMS, AND COSTS: Implementation of the recommendations in this Guideline should result in more appropriate management of survivors of sexual violence and better physical and psychological outcomes. PMID- 20206350 TI - Increased complication rates associated with laparoscopic surgery among patients with genital tuberculosis. AB - OBJECTIVE: To compare the complications and surgical difficulties encountered during laparoscopy between women diagnosed with and without genital tuberculosis (TB). METHODS: Retrospective review of the records of women diagnosed with and without genital TB who underwent laparoscopy primarily for infertility and chronic pelvic pain from January 2006 through July 2009. Genital TB was diagnosed by laboratory studies and endoscopic findings. RESULTS: A total of 313 women were included in the study: 87 (27.8%) with genital TB and 226 (72.2%) without. Laparoscopy was performed in 48 (55.2%) patients with genital TB and 19 (8.4%) without; laparoscopy with hysteroscopy was performed in 39 (44.8%) with the disease and 132 (58.4%) without. Although individual complication rates were all higher in the genital TB group, significant differences were seen for inability to see the pelvis (10.3% vs 1.3%, P=0.027), excessive bleeding requiring transfusion (2.3% vs 0%, P=0.045), and peritonitis (8.0% vs 1.8%, P=0.037). Other complications encountered were inability to create pneumoperitoneum, bladder injury, trocar site discharge, and need for laparotomy. CONCLUSION: Laparoscopic surgery may be associated with increased complication rates in patients with genital TB compared with those without the disease. PMID- 20206351 TI - Characterization of pelvic floor symptoms in community-dwelling women of northeastern Liberia. PMID- 20206352 TI - Anthropometric characteristics and success rates of oral or vaginal misoprostol for pregnancy termination in the first and second trimesters. AB - OBJECTIVE: To assess the effect of anthropometric characteristics related to weight on medical pregnancy termination with misoprostol. METHODS: In this prospective cohort study, 454 women admitted for medical pregnancy termination in the first or second trimester took 400 microg of misoprostol sublingually plus 800 microg of misoprostol vaginally or orally. The regimen was readministered after 24 hours if there was no response or the abortion was incomplete, and surgical evacuation was done when needed. Linear regression was performed for possible correlations between the studied characteristics and treatment process and outcome. RESULTS: There was no correlation between the number of misoprostol administrations and any of the studied anthropometric characteristics. The numbers of both misoprostol administrations and surgical interventions were associated with oral administration. CONCLUSION: The route of misoprostol administration, but not anthropometric characteristics related to weight, were found to be associated with the success of pregnancy termination with misoprostol. PMID- 20206353 TI - Bone mineral density in women using the subdermal contraceptive implant Implanon for at least 2 years. AB - OBJECTIVE: To compare the effect of the long-term use of a subdermal single-rod contraceptive implant on bone mineral density (BMD) between users and a control group. METHODS: In this cross-sectional study, BMD was measured at the lumbar spine, femur, and distal radius and ulna in 100 Thai women of reproductive age, 50 who had used the Implanon implant for contraception for at least 2 years and 50 controls. RESULTS: Ethnicity, age, age at menarche, parity, menstrual pattern, and body mass index were similar in the 2 groups. The mean duration of Implanon use was 32.8+/-6.3 months. Although the prevalence of osteoporosis was rare at all sites in both groups, the Implanon users had a significantly lower BMD at the distal radius and ulna than the controls. CONCLUSION: The long-term use of Implanon seemed to have a negative impact on the mineral density of the distal radius and ulna. PMID- 20206354 TI - Feasibility, efficacy, safety, and acceptability of mifepristone-misoprostol for medical abortion in the Democratic People's Republic of Korea. AB - OBJECTIVE: To examine the feasibility, efficacy, safety, and acceptability of medical abortion among rural and urban women up to 56 days of pregnancy in the Democratic People's Republic of Korea. METHOD: A total of 199 women (rural n=95, urban n=104) recruited from 2 rural and 2 urban reproductive health clinics received 200mg of oral mifepristone followed 2 days later by 400 microg of sublingual misoprostol. The women's abortion status and satisfaction level were determined 2 weeks later. RESULTS: Overall complete abortion occurred in 96.0% of the women; there was no statistically significant difference between the groups (rural 95.8%, 95% confidence interval [CI], 89.6-98.8; urban 96.2%, 95% CI, 90.4 98.9). The 2 groups reported similar adverse effects. In total, 90.5% of rural and 88.5% of urban participants were satisfied or very satisfied with the method. CONCLUSION: The high efficacy and acceptability of medical abortion among rural and urban women suggest that medical abortion is a safe alternative to surgical abortion and can be scaled up to other reproductive health clinics in both rural and urban areas of the Democratic People's Republic of Korea, provided that there is appropriate training and supervision. PMID- 20206355 TI - Unethical female stereotyping in reproductive health. AB - Stereotypes are generalized preconceptions defining individuals by group categories into which they are placed. Women have become stereotyped as homemakers and mothers, with the negative effect of precluding them from other roles and functions. Legislation and judicial constructions show a history, and often a continuing practice, of confining women to these stereotypical functions. In access to reproductive and sexual health care, for instance, women's requests have been professionally subject to approval of their husbands, fathers or comparable males. Choice of abortion is particularly significant, because it embeds moral values. Women's capacity to act as responsible moral agents is denied by stereotypical attitudes shown by legislators, judges, heads of religious denominations, and healthcare providers who consider women incapable of exercising responsible moral choice. These attitudes violate ethical requirements of treating patients with respect and equal justice. They can also result in violations of human rights laws that prohibit discrimination against women. PMID- 20206356 TI - Cytokines release inhibition from activated monocytes, and reduction of in-stent neointimal growth in humans. AB - OBJECTIVE: Atherosclerosis and restenosis are largely ruled by inflammation. The aim of this study was to test the effects of a short-course, high-dose oral prednisone on the release of interleukin-6 (IL-6) and tumour necrosis factor (TNF)-alpha from circulating monocytes and on the neointimal growth that follows bare metal stent (BMS) implantation. In a sub-group of patients activated NF kappaB was also evaluated. METHODS: Out of 40 patients with coronary artery disease treated with BMS implantation, 20 were randomly assigned to receive oral prednisone during 40 days according to a standardized protocol. In non-stimulated and stimulated (LPS and PMA) monocytes we evaluated the release of IL-6 and TNF alpha, and NF-kappaB p50 subunit translocation at baseline, at 10 and 30 days. Late luminal loss (LLL) 9 months after angioplasty was calculated by quantitative coronary angiography. RESULTS: Plasma concentrations of prednisone correlated inversely with IL-6 and TNF-alpha release (R2=0.45, p=0.04 and R2=0.69, p=0.005, respectively) and NF-kappaB activation from monocytes (R2=0.58, p=0.01). The reduction of TNF-alpha release and NF-kappaB activation were significantly related (R2=0.56, p=0.01). Prednisone patients showed a significantly larger reduction of cytokine release and NF-kappaB activation compared to non-treated patients, at 10 days and 30 days. LLL was lower in the prednisone group (0.44+/ 0.35 mm versus 0.80+/-0.53 mm, p=0.02) and correlated with reduction of TNF-alpha (R2=0.41, p=0.01). CONCLUSIONS: High doses of oral prednisone reduce NF-kappaB pathway activation and pro-inflammatory cytokine release in circulating activated monocytes of patients treated with coronary stenting. TNF-alpha release reduction correlates with decreased LLL. PMID- 20206357 TI - Non-invasive assessment of soft-tissue artifact and its effect on knee joint kinematics during functional activity. AB - The soft-tissue interface between skin-mounted markers and the underlying bones poses a major limitation to accurate, non-invasive measurement of joint kinematics. The aim of this study was twofold: first, to quantify lower limb soft tissue artifact in young healthy subjects during functional activity; and second, to determine the effect of soft-tissue artifact on the calculation of knee joint kinematics. Subject-specific bone models generated from magnetic resonance imaging (MRI) were used in conjunction with X-ray images obtained from single plane fluoroscopy to determine three-dimensional knee joint kinematics for four separate tasks: open-chain knee flexion, hip axial rotation, level walking, and a step-up. Knee joint kinematics was derived using the anatomical frames from the MRI-based, 3D bone models together with the data from video motion capture and X ray fluoroscopy. Soft-tissue artifact was defined as the degree of movement of each marker in the anteroposterior, proximodistal and mediolateral directions of the corresponding anatomical frame. A number of different skin-marker clusters (total of 180) were used to calculate knee joint rotations, and the results were compared against those obtained from fluoroscopy. Although a consistent pattern of soft-tissue artifact was found for each task across all subjects, the magnitudes of soft-tissue artifact were subject-, task- and location-dependent. Soft-tissue artifact for the thigh markers was substantially greater than that for the shank markers. Markers positioned in the vicinity of the knee joint showed considerable movement, with root mean square errors as high as 29.3mm. The maximum root mean square errors for calculating knee joint rotations occurred for the open-chain knee flexion task and were 24.3 degrees , 17.8 degrees and 14.5 degrees for flexion, internal-external rotation and abduction-adduction, respectively. The present results on soft-tissue artifact, based on fluoroscopic measurements in healthy adult subjects, may be helpful in developing location- and direction-specific weighting factors for use in global optimization algorithms aimed at minimizing the effects of soft-tissue artifact on calculations of knee joint rotations. PMID- 20206358 TI - Compensation of large motion sensor displacements during long recordings of limb movements. AB - In motion capture applications using electromagnetic tracking systems the process of anatomical calibration associates the technical frames of sensors attached to the skin with the human anatomy. Joint centers and axes are determined relative to these frames. A change of orientation of the sensor relative to the skin renders this calibration faulty. This sensitivity regarding sensor displacement can turn out to be a serious problem with movement recordings of several minutes duration. We propose the "dislocation distance" as a novel method to quantify sensor displacement and to detect gradual and sudden changes of sensor orientation. Furthermore a method to define a so called fixed technical frame is proposed as a robust reference frame which can adapt to a new sensor orientation on the skin. The proposed methods are applied to quantify the effects of sensor displacement of 120 upper and lower limb movement recordings of newborns revealing the need for a method to compensate for sensor displacement. The reliability of the fixed technical frame is quantified and it is shown that trend and dispersion of the dislocation distance can be significantly reduced. A working example illustrates the consequences of sensor displacement on derived angle time series and how they are avoided using the fixed technical frame. PMID- 20206359 TI - Use of evaporative light scattering detection for the quality control of drug substances: influence of different liquid chromatographic and evaporative light scattering detector parameters on the appearance of spike peaks. AB - High performance liquid chromatography (HPLC) with evaporative light scattering detection (ELSD) is a versatile, easy to use and inexpensive alternative when it comes to the analysis of substances lacking a chromophor for UV detection. However, in pharmaceutical analysis injection of highly concentrated test solutions are normally required to control impurities at low levels. Under these conditions spike peaks were observed in the chromatograms of the test solutions making a proper evaluation of the impurity profile impossible. The influence of different eluent and ELSD parameters such as eluent composition, eluent flow rate, ELSD scavenger gas flow-rate and evaporation temperature on the appearance of spike peaks was investigated. It could be shown that spike peaks can be avoided when selecting elevated eluent flow-rates and ESLD scavenger gas flow rates. Moreover, eluents containing high amounts of organic modifier seem to foster the appearance of spike peaks. PMID- 20206360 TI - Temperature-responsive polymer-brush constructed on a glass substrate by atom transfer radical polymerization. AB - A polymer brush of 2-(2-methoxyethoxy)ethyl methacrylate (MDM) was prepared by atom transfer radical polymerization (ATRP) using a 11-(2 bromoisobutyroyloxy)undecyl moiety-carrying initiator covalently fixed to a glass substrate. An aqueous solution of the MDM polymer (E-PMDM), which had been prepared for comparison, turned to be opaque above certain temperature (26.2 degrees C for E-PMDM (M(n,GPC)=1.84*10(4))), which was corresponding to the lower critical solution temperature (LCST) of the polymer. The PMDM polymer brush accumulated on the glass surface also indicated temperature-responsive changes in contact angle of air bubble in the air-in-water system. Furthermore, non-specific adsorption of various proteins (bovine serum albumin (BSA), human immunoglobulin G (IgG) and bovine plasma fibrinogen (BPF)) to the surface of polymer brush on the glass plate was examined by the bicinchoninic acid method. The PMDM brush did not adsorb IgG and BPF significantly below the LCST of the polymer chain, whereas adsorbed a larger amount of the proteins above the LCST. A similar but less significant temperature-responsive adsorption was observed in the case of BSA. These results suggest usability of the temperature-responsive polymer-brushes with pendent omega-methoxy oligo(ethylene glycol) groups to coat various materials for bio-medical applications. PMID- 20206361 TI - Seismoelectric effect: a non-isochoric streaming current. 1. Experiment. AB - Propagation of ultrasound through a porous body saturated with liquid generates an electric response. This electroacoustic effect is called the "seismoelectric current"; the reverse process, when an electric field is the driving force, is called the "electroseismic current." Seismoelectric currents can be measured with electroacoustic devices originally designed for characterizing liquid dispersions. Such electroacoustic devices must first be calibrated with a liquid dispersion and then used to characterize a porous body. We demonstrated such measurements of the seismoelectric current with electroacoustic devices in three different types of porous bodies. The first porous body was a deposit of solid submicrometer particles. We monitored the kinetics of the deposit formation on the surface of the electroacoustic probe. It allowed us to unambiguously confirm that the measured signal was generated by the deposit. We were also able to extract information about the porosity of the forming deposits. The second type of porous body was again a deposit, but instead of solid submicrometer particles, we used very large, porous glass spheres. According to classical theory, these glass particles are not supposed to generate any electroacoustic signal because colloid vibration current decays with increasing particle size due to the particles inertia. Nevertheless, we measured a strong signal, which was apparently associated with the pores of the particles. We were able to derive some conclusions about the dependence of the seismoelectric current on the pore size. The last tests were performed with cylindrical sandstone cores. These porous bodies have a very high hydrodynamic resistance that prevents measurement of the classical streaming current. We are able to measure a strong seismoelectric current that correlates with porosity of the cores. PMID- 20206362 TI - On an isotherm thermodynamically consistent in Henry's region for describing gas adsorption in microporous materials. AB - The Dubinin-Astakhov and Dubinin-Radushkevich isotherms, originally formulated from the classical volume filling theory of micropores, constitute the most accepted models for describing gas adsorption in microporous materials. The most important weakness of these equations relies on the fact that they do not reduce to Henry's law at low pressures, not providing therefore a proper characterization of adsorbents in the early stage of adsorption. In this paper, we propose a way out of this inherent problem using the thermodynamic isotherm developed in a previous study [J. Llorens, M. Pera-Titus, J. Colloid Interface Sci. 331 (2009) 302]. This isotherm allows the generation of a series of equations that make available a comprehensive description of gas adsorption for the whole set of relative pressures (including Henry's region), also providing explicit information about energy heterogeneity of the adsorbent through the two characteristic m parameters of the thermodynamic isotherm (i.e., m(1) and m(2)). The obtained isotherm converges into the Dubinin-Astakhov isotherm for relative pressures higher than 0.1, the characteristic alpha parameter of this isotherm being expressed as alpha=m(2)-1 and the affinity coefficient (beta) as a sole function of m(2). An expression differing from the Dubinin-Astakhov isotherm has been obtained for describing Henry's region, providing relevant information about confinement effects when applied to zeolites. PMID- 20206363 TI - Recanalization and its correlation to outcome after cerebral venous thrombosis. AB - BACKGROUND: Only few small studies have assessed rates of recanalization and impact of recanalization on outcome in patients after cerebral vein thrombosis (CVT). METHODS: In this retrospective cohort study, we included 91 consecutive patients-treated in Helsinki University Central Hospital-who had non-invasively verified CVT and follow-up imaging at 4 months or later, or autopsy. We categorized vessel status at follow-up as complete, partial, or no recanalization. A complete recovery was defined as a score of 0 on the modified Rankin Scale. RESULTS: Of the 91 patients (median age, 36 years; 70% females), 43 (47%) achieved complete recanalization, in 31 (34%) patients recanalization was partial, and 17 (19%) had no recanalization. Males, patients aged > or =37 years, and those with no identified risk factors for CVT had more frequently partial or no recanalization. Patients aged > or =37 years, those with chronic onset of symptoms (>30 days), and those with no recanalization had worse outcome in univariate analysis. Only increasing age associated with no recanalization (OR, 1.04; 95% CI, 1.01-1.08) when adjusted for age, sex, and number of causes for CVT. Increasing age (OR 1.05; 95% CI 1.01-1.09) and chronic mode of onset (OR 9.41; 95% CI 1.02-87.07) predicted incomplete recovery or death when adjusted for age, sex, mode of onset, and status of recanalization. Headache was more common in patients with no recanalization (44%). CONCLUSIONS: Half of the patients after CVT had complete recanalization. Despite the univariate association, recanalization did not associate with poor outcome in multivariate analysis. However, residual headache was more common in those with no recanalization. PMID- 20206364 TI - Re: Effect of suturing technique and urethral plate characteristics on complication rate following hypospadias repair: a prospective randomized study O. Sarhan, M. Saad, T. Helmy and A. Hafez J Urol 2009; 182: 682-686. PMID- 20206366 TI - Relationships between persistent organic pollutants and carbonaceous materials in aquatic sediments of Taiwan. AB - Recent studies have shown that many persistent organic pollutants (POPs, e.g., polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs) and various pesticides), are strongly associated with carbonaceous materials (including organic carbon (OC) and black carbon (BC)). We hypothesize that carbonaceous materials can be used as a first-order pollution index, to indicate areas where POP pollution may require further investigation. We tested our hypothesis and found that strong, positive correlations between BC and OC contents versus the concentrations of PCBs (and PAHs) existed in estuarine sediments of the Danshui River in 2005 and 2008. Thus, our preliminary results demonstrate that POC and BC are potential indicators of the POP pollution potential in fluvial sediments of the Danshui River in Taiwan. This innovative approach can provide a simple, relatively inexpensive and expedient means to monitor concentrations of POPs in polluted aquatic sediments of Taiwan, and/or those having a legacy of POP inputs. PMID- 20206368 TI - Comments on a pilot study to test the effect of pulsatile insulin infusion on type 1 diabetes mellitus patients with proteinuria. PMID- 20206369 TI - [Controversies in breast cancer screening]. PMID- 20206370 TI - [Breast imaging]. PMID- 20206371 TI - High-overtone self-focusing acoustic transducers for high-frequency ultrasonic Doppler. AB - This work reports the potential use of high-overtone self-focusing acoustic transducers for high-frequency ultrasonic Doppler. By using harmonic frequencies of a thick bulk Lead Zirconate Titanate (PZT) transducer with a novel air reflector Fresnel lens, we obtained strong ultrasound signals at 60 MHz (3rd harmonic) and 100 MHz (5th harmonic). Both experimental and theoretical analysis has demonstrated that the transducers can be applied to Doppler systems with high frequencies up to 100 MHz. PMID- 20206372 TI - Melanoma differentiation-associated protein-5 (MDA-5) limits early viral replication but is not essential for the induction of type 1 interferons after Coxsackievirus infection. AB - Coxsackievirus infections are associated with severe diseases such as myocarditis, meningitis and pancreatitis. To study the contribution of the intracellular viral sensor melanoma differentiation-associated protein-5 (MDA-5) in the host immune response to Coxsackievirus B3 (CVB3) we infected C57BL/6 and 129/SvJ mice lacking mda-5. Mice deficient in MDA-5 showed a dramatically increased susceptibility to CVB3 infection. The loss of MDA-5 allowed the virus to replicate faster, resulting in increased liver and pancreas damage and heightened mortality. MDA-5 was not absolutely required for the induction of type 1 interferons (IFNs), but essential for the production of maximal levels of systemic IFN-alpha early after infection. Taken together, our findings indicate that MDA-5 plays an important role in the host immune response to CVB3 by preventing early virus replication and limiting tissue pathology. PMID- 20206373 TI - Effect of water-matrix composition on Trimethoprim solar photodegradation kinetics and pathways. AB - Direct photolysis and solar TiO(2) photocatalysis of Trimethoprim (TMP) in different water matrices (demineralised and simulated seawater) have been studied. Direct photolysis yielded a similar, slow TMP degradation rate in both water matrices, and the formation of very stable photo-transformation products. Dissolved organic carbon decreased slightly after prolonged irradiation. The main intermediate identified was a ketone derivative (trimethoxybenzoylpyrimidine), which was proved to be a photosensitizer of TMP degradation. During TiO(2) photocatalysis, TMP was completely eliminated in both water matrices at a similar rate, however, the mineralization rate was appreciably reduced in seawater, which can be explained by the presence of inorganic species acting as hydroxyl radical scavengers, and directly affecting photocatalytic efficiency. Identification of intermediates showed differences between the two processes but hydroxylation, demethylation and cleavage of the original drug molecule were observed in both. PMID- 20206374 TI - Adsorption of Triton X-series surfactants and its role in stabilizing multi walled carbon nanotube suspensions. AB - Surfactants can enhance the stabilization of carbon nanotubes (CNTs) in water through their adsorption, thus affecting the environmental behavior and application of CNTs. However, the quantitative relationship between adsorption and stabilization and the role of the surfactant structure in the surfactant-CNT interactions are largely unknown. Therefore, Triton X-series surfactants with a same hydrophobic functional group (4-(1,1,3,3-tetramethylbutyl)-phenyl) and different hydrophilic polyethoxyl chain lengths were selected to investigate their adsorption onto CNTs and their ability to stabilize CNT suspensions. Adsorption data were fitted well by Langmuir equation, indicating monolayer coverage on CNTs. Adsorption capacities of the surfactants increased with decreasing hydrophilic chain length: Triton-3051 mm) broke out on the skin and impaired the host tissue. The scaffold with the porosity of 95% and pore size of 0.3 mm could effectively retain the cells/gel mixture and indicated a fair cartilage regeneration. Regarding the composition, the tissue engineered cartilage was superior in PLGA and PLLA to that in PLA/CA and PDLA. The latter two showed the dense accumulation of macrophages, which may deteriorate the cartilage regeneration. Although PLGA or PLLA has been currently recommended for the scaffold of cartilage, the polymer for which biodegradation was exactly synchronized to the cartilage regeneration would improve the quality of the tissue-engineered cartilage. PMID- 20206381 TI - The use of injectable forms of fibrin and fibronectin to support axonal ingrowth after spinal cord injury. AB - Many studies have described biomaterial devices (conduits and scaffolds) that can be implanted into experimental lesions and which support axonal growth. However, a disadvantage of such pre-formed devices is that tissue needs to be excised to allow their insertion. In this study we have therefore examined four biomaterials that can be injected into an injury site and which gel in situ; namely collagen, viscous fibronectin, fibrin, and fibrin + fibronectin (FB/FN). The materials were tested in an experimental knife-cut cavity in the rat spinal cord, and evaluated at 1 week and 4 weeks survival for their biocompatibility, neuroprotective efficacy, and permissiveness for axonal growth. At one week, all four materials showed good integration with the host spinal cord and supported some degree of axonal ingrowth, which was associated with infiltration of Schwann cells and deposition of laminin. However axon growth in the collagen implants was uneven because implants contained dense inclusions which were not penetrated by axons. At 4 weeks, axon growth was greatest in the fibronectin and FB/FN implants, however the fibronectin implants had large cavities at the interface between the implant and host spinal cord. The fibronectin implants also had fewer surviving neurons in the intact spinal cord adjoining the implant site. The FB/FN mixture thus had the best combination of properties in that it was easy to handle, integrated with the host spinal cord tissue, and supported robust growth of axons. It therefore has promise as an injectable biomaterial for filling cavities at spinal cord injury sites. PMID- 20206382 TI - Phosphatidylserine immobilization of lentivirus for localized gene transfer. AB - Localized and efficient gene transfer can be promoted by exploiting the interaction between the vector and biomaterial. Regulation of the vector-material interaction was investigated by capitalizing on the binding between lentivirus and phosphatidylserine (PS), a component of the plasma membrane. PS was incorporated into microspheres composed of the copolymers of lactide and glycolide (PLG) using an emulsion process. Increasing the weight ratio of PS to PLG led to a greater incorporation of PS. Lentivirus, but not adenovirus, associated with PS-PLG microspheres, and binding was specific to PS relative to PLG alone or PLG modified with phosphatidylcholine. Immobilized lentivirus produced large numbers of transduced cells, and increased transgene expression relative to virus alone. Microspheres were subsequently formed into porous tissue engineering scaffolds, with retention of lentivirus binding. Lentivirus immobilization resulted in long-term and localized expression within a subcutaneously implanted scaffold. Microspheres were also formed into multiple channel bridges for implantation into the spinal cord. Lentivirus delivery from the bridge produced maximal expression at the implant and a gradient of expression rostrally and caudally. This specific binding of lentiviral vectors to biomaterial scaffolds may provide a versatile tool for numerous applications in regenerative medicine or within model systems that investigate tissue development. PMID- 20206383 TI - Bcr-Abl-independent mechanism of resistance to imatinib in K562 cells: Induction of cyclooxygenase-2 (COX-2) by histone deacetylases (HDACs). AB - Our previous studies have shown that overexpression of MDR1 and cyclooygenase-2 (COX-2) resulted in resistance development to imatinib in chronic myelogenous leukemia (CML) K562 (IR-K562) cells. In the present study, the regulatory mechanism of MDR1 induction by COX-2 was investigated. A gradual overexpression of MDR1 and COX-2 during the process of development was observed. Furthermore, down regulation of MDR1 upon COX-2 knockdown by siRNA showed a decrease in the PKC levels and activation of PKC by addition of PGE(2) to K562 cells, suggesting a role for PKC in the COX-2 mediated induction of MDR1. The present study demonstrates COX-2 induction by HDACs and MDR1 induction by COX-2 via PGE(2)-cAMP PKC-mediated pathway. PMID- 20206384 TI - Differential effect of equal copper, cadmium and nickel concentration on biochemical reactions in wheat seedlings. AB - Influence of 75 microM copper (Cu), cadmium (Cd) and nickel (Ni) on growth, tissue metal accumulation, non-protein thiols (NPT) and glutathione (GSH) contents, membrane damage, lipid peroxidation and protein oxidation as well as protease, glutathione S-transferase (GST) and peroxidase (POD) activities were studied in the shoots and roots of wheat seedlings after 7 days of metal exposure. The greatest growth reduction was found in response to Cu treatment; however accumulation of this metal in the wheat tissues was the lowest compared to the other metals used. All metals caused enhancement of electrolyte leakage from cells as well as increased lipid peroxidation and protein carbonylation. Proteolytic activity was enhanced only in Cu-exposed seedlings and in the roots it coincided with elevated protein carbonylation. The most pronounced increase in POD activity in the shoots was found after Ni treatment while in the roots in response to Cu. In contrast to Cu, application of Cd and Ni resulted in accumulation of NPT and induction of GST activity, which suggested involvement of these mechanisms in metal tolerance in wheat. PMID- 20206386 TI - Identification of novel variants in the TMIE gene of patients with nonsyndromic hearing loss. AB - OBJECTIVE: To determine whether variants of the TMIE gene are causes of nonsyndromic deafness in Taiwan. METHODS: A genetic survey was made from 370 individuals, with 250 nonsyndromic hearing loss and 120 normal hearing individuals. Genomic DNA was extracted from peripheral blood leukocytes and then subjected to PCR to amplify selected exons and flanking introns of the TMIE gene; the amplified products were screened for base variants by autosequence. Data from the two groups were then compared using Fisher's two-tailed exact test and Armitage's trend test. RESULTS: The analysis revealed 7 novel variants in the TMIE gene. Of the 7 variants, 5 variants were found in both nonsyndromic hearing loss and normal hearing group. Both allelic and genotype frequencies of these sequence changes did not differ significantly between patients and controls (P>0.05). However, a missense variant (c.257G>A) and one promoter variant (g.1 219A>T) were found in two patients with nonsyndromic hearing loss. Family study and microsatellite analysis found that c.257G>A variant is not inherited from his parents. The c.257G>A variant encodes a protein with glutamine at position 86 instead of arginine (p.R86Q), a residue that is conserved in mammals but different in fish, and predicted to be extracellular. CONCLUSIONS: Despite the fact that the frequency of TMIE variants in our study subjects was low, we suggested that c.257G>A (p.R86Q) variant is a de novo and may be as a risk factor for the development of hearing loss in Taiwanese. PMID- 20206385 TI - Type-D personality and depersonalization are associated with suicidal ideation in the German general population aged 35-74: results from the Gutenberg Heart Study. AB - BACKGROUND: Suicidal ideation (SID) is a major risk factor for suicide attempts. Mental disorders are among the strongest correlates of suicide, with depression and anxiety disorders playing a major role. The present study aims to investigate the contribution of under researched factors contributing to SID such as depersonalization, Type-D personality and cardiovascular risk factors. METHODS: Factors associated with SID were investigated in a sample of N=5000 participants (aged 35-74 years) of the community-based survey "Gutenberg Heart Study". The factors were assessed by self-report instruments, computer-assisted interviews and medical examination. RESULTS: 7.5% of the sample reported SID over the last 2 weeks. In the univariate analysis SID was significantly associated with female sex, living without a partner, low socioeconomic status, diagnosis of coronary heart disease, family history of myocardial infarction, smoking and mental distress. In the full adjusted model significant associations remained with age (in years) OR 1.02 (95%CI 1.01-1.04, p=0.002), self-reported depression OR 3.21 (95%CI 2.23-4.62, p<0.0001), panic disorder OR 1.56 (95%CI 1.03-2.36, p=0.036), depersonalization OR 2.45 (95%CI 1.78-3.38, p<0.0001), Type-D personality OR 1.98 (95%CI 1.49-2.63, p<0.0001) and impairment by mental distress OR 2.15 (95%CI 1.74 2.67, p<0.0001). LIMITATIONS: Main limitations are the reliance on self-report measures of SID and of mental distress. CONCLUSIONS: For the first time it has been shown that in the general population depersonalization and Type-D personality are uniquely associated with SID. These associations need further elucidation. PMID- 20206387 TI - Biomonitoring of perfluorochemicals and toxicity to the downstream fish community of Etobicoke Creek following deployment of aqueous film-forming foam. AB - On August 2, 2005, Air France Flight 358 descended on Lester B. Pearson International Airport (Toronto, ON, Canada) during adverse weather conditions and overran the runway, leading to an onboard fire which destroyed the aircraft. Large quantities (48000L) of aqueous film-forming foam (AFFF) were applied to the burning fuselage within meters of Etobicoke Creek. Local authorities could not confirm the identity of the AFFF formulation applied, but chemical analyses of fish livers collected 9 days post-AFFF application indicated that no perfluorinated acids (PFAs) were elevated at the site of application or downstream. This, and higher concentrations of a fluorotelomer sulfonate in fish liver collected downstream, suggests that an AFFF containing telomerized polyfluorinated material was likely used. However, as an urbanized stream within a heavily developed commercial, industrial, and residential watershed, background levels of perfluorinated compounds in Etobicoke Creek were considerable at all sites. Enlarged fish livers adjacent the AFFF-application site, commensurate with depressed peroxisomal beta-oxidation and hepatic oxidative stress, demonstrate some short-term impact of the AFFF on exposed fish within 9 days of its release. Most fish biochemical responses had recovered to normal values by 120 days, although there was some indication that AFFF-associated contamination shifted further downstream over this interval. This study suggests contemporary AFFFs exert relatively low toxicity on fish communities under realistic exposure scenarios. PMID- 20206388 TI - Toxicity of PAMAM dendrimers to Chlamydomonas reinhardtii. AB - In recent decades, a new class of polymeric materials, PAMAM dendrimers, has attracted marked interest owing to their unique nanoscopic architecture and their hopeful perspectives in nanomedicine and therapeutics. However, the potential release of dendrimers into the aquatic environment raises the issue about their toxicity on aquatic organisms. Our investigation sought to estimate the toxicity of cationic PAMAM dendrimers on the green alga, Chlamydomonas reinhardtii. Algal cultures were exposed to different concentrations (0.3-10 mgL(-1)) of low dendrimer generations (G2, G4 and G5) for 72 h. Potential adverse effects on Chlamydomonas were assessed using esterase activity (cell viability), photosynthetic O2 evolution, pigments content and chlorophyll a fluorescence transient. According to the median inhibitory concentration (IC50) appraised from esterase activity, toxicity on cell viability decreased with dendrimer generation number (2, 3 and 5 mgL(-1) for G2, G4 and G5 dendrimers, respectively). Moreover, the three generations of dendrimers did not induce the same changes in the photosynthetic metabolism of the green alga. O2 evolution was stimulated in cultures exposed to the lowest generations tested (i.e. G2 and G4) whereas no significant effects were observed with G5. In addition, total chlorophyll content was increased after G2 treatment at 2.5 mgL(-1). Finally, G2 and G4 had positive effects on photosystem II (PSII): the amount of active PSII reaction centers, the primary charge separation and the electron transport between Q(A) and Q(B) were all increased inducing activation of the photosynthetic electron transport chain. These changes resulted in stimulation of full photosynthetic performance. PMID- 20206389 TI - The effects of physical activity, body mass index (BMI) and waist circumference (WC) on glucose intolerance in older people: a nationwide study from Taiwan. AB - We investigated the gender-specific effects of physical activity, BMI and WC on glucose intolerance in an elderly Taiwanese population (n=1344) aged 65 and above, who participated in the Elderly Nutrition and Health Survey in Taiwan in 1999-2000. In this cross-sectional study, physical activity was assessed using the Modified Baecke Questionnaire for Older Adults (MBQOA). Categories of physical activity level were defined by tertiles of MBQOA scores. Glucose intolerance in subjects not previously diagnosed with diabetes was categorized according to 2003 American Diabetes Association criteria. After adjustment for potential confounders, physical activity was significantly inversely associated with the presence of undiagnosed type 2 diabetes and impaired fasting glucose (IFG) in older women. In older men, the association was less clear. BMI and WC were significantly positively associated with the presence of undiagnosed diabetes in men and were significantly associated with IFG in both sexes. In older women, undiagnosed diabetes was strongly associated with increased WC, but not with BMI. Our findings highlight that older women with low physical activity or high WC, and older men with high BMI or WC are important target populations for interventions to prevent glucose intolerance. PMID- 20206390 TI - Management and outcomes of delirious patients with hyperactive symptoms in a secured behavioral unit jointly used by geriatricians and pyschogeriatricians. AB - To compare the clinical outcomes and length of stay (LOS) between delirious patients with hyperactive symptoms admitted directly and those admitted indirectly from Emergency Department into a secured, behavioral unit jointly used by geriatricians and pyschogeriatricians (the Unit). A retrospective study analyzing data from the medical records of 122 patients with an admission diagnosis of delirium with hyperactive symptoms and subsequently discharged from the Unit, including restraint, one-to-one nursing care, falls, absconding, duration of delirium, recovery from delirium, destination and LOS. Significantly fewer patients with direct admission (n=68) required physical restraint or chemical restraint compared with those transferred (n=54). Patients admitted directly showed a higher discharge rate back home, shorter LOS, shorter duration of delirium and a higher rate of recovery from delirium than transferred patients. Of the transferred patients, more received one-to-one nursing care before transfer than after transfer. Three (5.6%) absconded before transfer, but none absconded from the Unit. The falls rate reduced from 14.2 to 6.7 falls/1000 patient delirium days after transfer. Delirious patients with hyperactive symptoms admitted directly to the Unit fared better in clinical outcomes and LOS. They also required less restraint, less intensive nursing and were unlikely to abscond compared to those transferred. PMID- 20206391 TI - Informed consent and transesophageal echocardiography: a review of patient responses. AB - OBJECTIVE: To identify whether our pre-procedure discussion of the risks of transesophageal echocardiography (TEE) as well as documentation in the electronic medical record (EMR) met the standard of care for informed consent. METHODS: Questionnaires were mailed to 500 patients who underwent a TEE at the Mayo Clinic Florida (MCF) requesting responses to questions that would identify how well the risks of the TEE procedure were discussed. RESULTS: A positive response to the questions regarding the risks of TEE ranged from 75 to 95% and adequate documentation in the EMR revealed a 66% compliance rate. CONCLUSIONS: Individual physician and institutional commitment to informed consent at MCF is reflected in the very positive response to our questionnaire for meeting the criteria of informed consent; however, the documentation of the procedure discussion fell below the desired rate. PMID- 20206392 TI - Treatment of Kounis syndrome. AB - Kounis syndrome is potentially a life-threatening medical emergency with both a severe allergic reaction and acute coronary syndrome. Most of the information about this syndrome has come from the case reports. The management of these patients may be challenging for clinicians, and unfortunately guidelines have not been established yet. In this article, we review the current guidelines of acute coronary syndromes and anaphylaxis along with the published cases with Kounis syndrome secondary to beta-lactam antibiotics. We have summarized our recommendations for the work-up and treatment of Kounis syndrome from available data. Obviously, larger prospective studies are needed to establish definitive treatment guidelines for these patients. PMID- 20206393 TI - Ironic effects and final target fixation in a penalty shooting task. AB - The aim of the present study was to find out whether ironic effects in a far aiming task were accompanied by shorter final fixations on the target. Generally, it is well known that a sufficiently long final fixation on the target is of crucial importance for accurate performance in far aiming. Recently, it has been shown that ironic effects in golf putts and penalty kicks (in which one does the opposite of what was intended, e.g., shoot close to the keeper while attempting to avoid this) were preceded by longer fixations on the to-be-avoided area, which may have resulted in shorter final fixations on the target area. Therefore, in the current study we examined football players taking penalties in a simulated penalty environment with and without instructions to avoid the goalkeeper. The findings revealed that ironic effects were indeed accompanied by significantly shorter final fixations on the target area, i.e., the open goal space. It is concluded that in far aiming tasks, ironic effects are accompanied by insufficiently long final fixations on the target. PMID- 20206394 TI - Hepatitis E virus load in swine organs and tissues at slaughterhouse determined by real-time RT-PCR. AB - Although uncommon in North America, Hepatitis E virus (HEV) has been identified in some industrialized countries in patients without a history of travel to HEV endemic countries. Its presence is ubiquitous worldwide in swine populations. Zoonotic transmission of swine HEV to non human primates has been achieved experimentally and transmission of HEV after ingestion of contaminated raw or undercooked meat is well documented. In Canada, so far, no HEV outbreak has been documented but HEV genotype 3 strains have been identified in sera and faecal samples of swine origin. The objective of the present study was to determine the viral load of HEV in liver, loin, bladder, hepatic lymph node, bile, tonsil, plasma and faeces samples of 43 pigs at slaughter. Feline calicivirus (FCV) was used as sample process control to validate the RNA extraction process, as a confirmation of the absence of sample inhibitors and as an amplification control. Using FCV/HEV multiplex TaqMan RT-qPCR system, HEV RNA was detected in 14 out of the 43 animals tested. HEV was detected in lymph nodes (11/43), bladder (10/43), liver (9/43), bile (8/43), faeces (6/43), tonsils (3/43), plasma (1/43) samples from infected animals. No HEV-positive loin samples were observed. Viral loads of 10(3) to 10(7) copies/g were estimated in positive liver and bile samples. PMID- 20206395 TI - Lentinula edodes enhances the biocontrol activity of Cryptococcus laurentii against Penicillium expansum contamination and patulin production in apple fruits. AB - Penicillium expansum is a post-harvest pathogen of apples which can produce the hazardous mycotoxin patulin. The yeast Cryptococcus laurentii (LS28) is a biocontrol agent able to colonize highly oxidative environments such as wounds in apples. In this study culture filtrates of the basidiomycete Lentinula edodes (LF23) were used to enhance the biocontrol activity of LS28. In vitro L. edodes culture filtrates improved the growth of C. laurentii and the activity of its catalase, superoxide dismutase and glutathione peroxidase, which play a key role in oxidant scavenging. In addition, LF23 also delayed P. expansum conidia germination. The biocontrol effect of LS28 used together with LF23 in wounded apples improved the inhibition of P. expansum growth and patulin production in comparison with LS28 alone, under both experimental and semi-commercial conditions. The biocontrol effect was confirmed by a semi-quantitative PCR analysis set up for monitoring the growth of P. expansum. PMID- 20206396 TI - Wide variety of bioserotypes of enteropathogenic Yersinia in tonsils of English pigs at slaughter. AB - The tonsils of 630 pigs from 45 English farms using three different rearing methods (Assured British Pigs, Open Management and Organic) were examined between 2003 and 2005 in order to investigate if the low incidence of human yersiniosis could be attributed to a low prevalence of enteropathogenic Yersinia among English pigs. In addition, different isolation methods were compared, possible differences in prevalence among pigs were studied, as well as the prevalence of different bioserotypes of enteropathogenic Yersinia. A high prevalence and a wide diversity of bioserotypes of enteropathogenic Yersinia compared to other European countries were observed. The prevalence of pathogenic Yersinia enterocolitica was 44% and of Yersinia pseudotuberculosis 18%. Overall, 60% of pigs carried enteropathogenic Yersinia. Y. pseudotuberculosis was detected on 78% of farms and Y. enterocolitica on 69%. The most common bioserotypes of Y. enterocolitica were 2/O:9 (33%) and 2/O:5 (26%), and of Y. pseudotuberculosis 2/O:3 (34%), 1/O:1 (26%) and 1/O:4 (24%). Cold enrichment gave the highest isolation rate for both species. Y. enterocolitica was more prevalent (P<0.001) and Y. pseudotuberculosis less prevalent (P<0.05) in winter than in summer in Eastern England. Y. enterocolitica was more common in Eastern England and in assured British pigs, whereas Y. pseudotuberculosis was more common in Western England and in organic pigs. Y. pseudotuberculosis 1/O:1 was predominant (P<0.05) in Western England. Types 1/O:4 (P<0.05) and 2/O:3 (P<0.001) predominated in Eastern England. The high prevalence of Y. enterocolitica bioserotypes 2/O:9 and 2/O:5 found in this study suggests that English pigs are an important reservoir of these bioserotypes whereas in other European countries bioserotype 4/O:3 predominates. PMID- 20206397 TI - Relative transcription of Listeria monocytogenes virulence genes in liver pates with varying NaCl content. AB - Quantitative real time polymerase chain reaction (qRT PCR) was used to compare the relative transcription of prfA, inlA, sigB and clpC for three Listeria monocytogenes strains after incubation in i) a standard liver pate versus brain heart infusion (BHI) broth and ii) the standard liver pate versus three liver pates with reduced NaCl content of which one also has been supplied with organic acids (Ca-acetate and Ca-lactate). The three strains (EGD-e: reference strain; O57: more NaCl sensitive; 6896: more NaCl tolerant) were selected out of twelve strains based on their growth in BHI broth adjusted to 6%, 8%, 10% (w/v) NaCl. The three strains were spiked into the liver pates (10(9) cfu/g) and the BHI (10(9) cfu/ml) and incubated for 48 h at 7 degrees C; all incubation conditions supported growth of the strains. Extraction of intact listerial RNA from the liver pates was complicated by the complexity of the liver pate matrix. However, a method has been optimized and described, and the quality of RNA extracted from liver pates was equal to the quality of RNA extracted from BHI. The amplification efficiencies of the six genes used for the transcription analyses (the four target genes and two reference genes, gap and rpoB) were within the acceptable range from 90% to 110% for all three strains in both liver pate and BHI. Comparison of the three strains after incubation in the standard liver pate and BHI showed that the relative transcription of prfA for O57 and the relative transcription of inlA and sigB for both O57 and 6896 were significantly higher when the strains were grown in BHI compared to the standard liver pate. Reducing the NaCl content of the standard liver pate did not change relative transcription levels of prfA, inlA, sigB or clpC (except for prfA in O57 and sigB in 6896). However, the presence of Ca-acetate and Ca-lactate induced relative transcription of the stress response gene, clpC, for all three strains. This study demonstrates that relative microbial gene transcription can be measured in complex food matrices and points to the need for designing experimental set-ups in real food matrices to replace the laboratory model systems. With respect to L. monocytogenes, it seems that the NaCl content of liver pate can be lowered within the investigated range without significant changes in relative virulence gene transcription while more caution should be taken when adding organic acids such as acetate and lactate. PMID- 20206398 TI - IGF activation in a molecular subclass of hepatocellular carcinoma and pre clinical efficacy of IGF-1R blockage. AB - BACKGROUND & AIMS: IGF signaling has a relevant role in a variety of human malignancies. We analyzed the underlying molecular mechanisms of IGF signaling activation in early hepatocellular carcinoma (HCC; BCLC class 0 or A) and assessed novel targeted therapies blocking this pathway. METHODS: An integrative molecular dissection of the axis was conducted in a cohort of 104 HCCs analyzing gene and miRNA expression, structural aberrations, and protein activation. The therapeutic potential of a selective IGF-1R inhibitor, the monoclonal antibody A12, was assessed in vitro and in a xenograft model of HCC. RESULTS: Activation of the IGF axis was observed in 21% of early HCCs. Several molecular aberrations were identified, such as overexpression of IGF2 -resulting from reactivation of fetal promoters P3 and P4-, IGFBP3 downregulation and allelic losses of IGF2R (25% of cases). A gene signature defining IGF-1R activation was developed. Overall, activation of IGF signaling in HCC was significantly associated with mTOR signaling (p=0.035) and was clearly enriched in the Proliferation subclass of the molecular classification of HCC (p=0.001). We also found an inverse correlation between IGF activation and miR-100/miR-216 levels (FDR<0.05). In vitro studies showed that A12-induced abrogation of IGF-1R activation and downstream signaling significantly decreased cell viability and proliferation. In vivo, A12 delayed tumor growth and prolonged survival, reducing proliferation rates and inducing apoptosis. CONCLUSIONS: Integrative genomic analysis showed enrichment of activation of IGF signaling in the Proliferation subclass of HCC. Effective blockage of IGF signaling with A12 provides the rationale for testing this therapy in clinical trials. PMID- 20206399 TI - Impaired liver regeneration of steatotic rats after portal vein ligation: a particular emphasis on (99m)Tc-DISIDA scintigraphy and adiponectin signaling. AB - BACKGROUND & AIMS: Portal vein ligation (PVL) is increasingly employed prior to major hepatectomy in order to enhance the volume of the future liver remnant (FLR) and to avoid post-hepatectomy liver failure. The efficacy of PVL on subjects with non-alcohol fatty liver disease (NAFLD) is largely unknown. METHODS: Sprague-Dawley rats fed with normal diet (control) and methionine choline deficient diet (MCD) were used. The animals underwent PVL and were sacrificed at indicated time points. RESULTS: Livers from MCD rats exhibited a decreased BrdU and Ki-67 labelling index, and an increased apoptotic index after PVL compared to normal rats; as a net effect, MCD rats exhibited a decrease in their restituted liver mass and redistributed volume ratio, compared to normal rats. Normal rats displayed similar serum levels of ICG15-R before and after PVL; whereas MCD rats displayed reduced ICG15-R after PVL. Using (99m)Tc-DISIDA scintigraphy examination, livers from MCD rats exhibited decreased HEF and prolonged TE(1/2) of FLR after PVL, indicating deteriorating hepatocyte function despite the shift in volume. The basal level of plasma TNFalpha, IL-1alpha, IL 1beta, and IL-10 of MCD rats was significantly increased before PVL compared to normal rats; however their plasma level did not increase in response to PVL as in normal rats. Hepatic adiponectin mRNA surged in MCD rats after PVL, whereas its receptors, AdipoR1 and AdipoR2, were paradoxically down-regulated. PPARalpha, a down-stream molecule of AdipoR2 axis, was also decreased in MCD rats. CONCLUSIONS: Reduced regenerated liver mass and deteriorated hepatocyte function of the FLR from steatotic rats after PVL may be associated with deranged Kupffer cell-mediated cytokine expression and disrupted adiponectin signalling. PMID- 20206400 TI - Hepatitis B surface antigen levels during the natural history of chronic hepatitis B: a perspective on Asia. AB - BACKGROUND & AIMS: Data from clinical trials suggest a potential role for on treatment monitoring of serum HBsAg titres during interferon-alpha (pegIFN) therapy in predicting virological responses. However, baseline HBsAg titres during the natural history of chronic hepatitis B (CHB) have not been well characterized. We aimed to define the serum HBsAg titres during the different phases of CHB in a cohort of Asian patients infected with either genotype B or C HBV. METHODS: Two-hundred and twenty patients were classified into immune tolerant (IT), immune-clearance (IC), non/low-replicative (LR) or hepatitis B e antigen negative hepatitis (ENH) phases. Serum HBsAg was quantified using the ARCHITECT platform (Abbott Laboratories, Chicago, USA). Correlation of HBsAg titre with HBV DNA and serum ALT within each phase of infection was performed. RESULTS: Median HBsAg titres were different between each phase of CHB (p=0.001): IT (4.53 log(10)IU/ml), IC (4.03 log(10)IU/ml), LR (2.86 log(10)IU/ml), and ENH (3.35 log(10)IU/ml). HBsAg titres were highest in the IT phase, and lowest in the LR phase. In general, median HBsAg titres were similar between genotypes B and C HBV. Serum HBsAg titres only correlated with HBV viral load in the IC phase. No correlation between the serum HBsAg level and ALT was observed. CONCLUSIONS: This study demonstrated significant differences in median baseline serum HBsAg titres across the different phases of CHB. These results provide further insight into the HBV viral life cycle in the setting of the various phases of CHB. Baseline HBsAg quantification may help refine future treatment algorithms for both immune modulator therapy and oral nucleos(t)ide analogue therapy. PMID- 20206401 TI - Relevance of the mTOR signaling pathway in the pathophysiology of splenomegaly in rats with chronic portal hypertension. AB - BACKGROUND & AIMS: Splenomegaly is a frequent hallmark of portal hypertension that, in some cases, can be very prominent and cause symptoms like abdominal pain, splenic infarction, and cytopenia. This study characterizes the pathogenetic mechanisms leading to spleen enlargement in portal hypertensive rats and focuses on mTOR pathway as a potential modulator of splenomegaly in portal hypertension. METHODS: Characterization of splenomegaly was performed by histological, hematological, immunohistochemical and Western blot analyses in rats with portal hypertension induced by portal vein ligation, and compared with sham-operated animals. The contribution of the mTOR signaling pathway to splenomegaly was determined in rats with fully developed portal hypertension and control rats by treatment with rapamycin or vehicle. RESULTS: Our results illustrate that splenomegaly in portal hypertensive rats arises as a consequence of the interplay of several factors, including not only spleen congestion, as traditionally thought, but also enlargement and hyperactivation of the splenic lymphoid tissue, as well as increased angiogenesis and fibrogenesis. Since mTOR signaling plays a central role in immunological processes, angiogenesis and fibrogenesis, we next determined the involvement of mTOR in splenomegaly. Interestingly, mTOR signaling was overactivated in the spleen of portal hypertensive rats, and mTOR blockade by rapamycin profoundly ameliorated splenomegaly, causing a 44% decrease in spleen size. This effect was most likely accounted for the inhibitory action of rapamycin on lymphocyte proliferation, neovascularization and fibrosis. CONCLUSIONS: These findings shed light on the pathogenesis of splenomegaly in portal hypertension, and identify mTOR signaling as a potential target for therapeutic intervention in this disease. PMID- 20206403 TI - Multi-criteria decision analysis to prioritize health interventions: Capitalizing on first experiences. AB - This paper capitalizes on a first set of experiences on the application of multi criteria decision analysis (MCDA) in seven low- and middle-income settings. It thereby reacts to a recent paper by Peacock et al., highlighting the potential of MCDA to guide policy makers in highly specific decision-making contexts. We argue that MCDA also has a broader application in setting priorities in health, i.e. to indicate general perceptions on priorities without defining the allocation of resources in a precise fashion. This use of MCDA can have far-reaching and constructive influences on policy formulation. PMID- 20206402 TI - Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosis. AB - BACKGROUND & AIMS: Saturated free fatty acids induce hepatocyte lipoapoptosis. This lipotoxicity involves an endoplasmic reticulum stress response, activation of JNK, and altered expression and function of Bcl-2 proteins. The mono unsaturated free fatty acid palmitoleate is an adipose-derived lipokine which suppresses free fatty acid-mediated lipotoxicity by unclear mechanisms. Herein we examined the mechanisms responsible for cytoprotection. METHODS: We employed isolated human and mouse primary hepatocytes, and the Huh-7 and Hep 3B cell lines for these studies. Cells were incubated in presence and absence of palmitate (16:0), stearate (18:0), and or palmitoleate (16:1, n-7). RESULTS: Palmitoleate significantly reduced lipoapoptosis by palmitate or stearate in both primary cells and cell lines. Palmitoleate accentuated palmitate-induced steatosis in Huh 7 cells excluding inhibition of steatosis as a mechanism for reduced apoptosis. Palmitoleate inhibited palmitate induction of the endoplasmic reticulum stress response as demonstrated by reductions in CHOP expression, eIF2-alpha phosphorylation, XBP-1 splicing, and JNK activation. Palmitate increased expression of the BH3-only proteins PUMA and Bim, which was attenuated by palmitoleate. Consistent with its inhibition of PUMA and Bim induction, palmitoleate prevented activation of the downstream death mediator Bax. CONCLUSIONS: These data suggest palmitoleate inhibits lipoapoptosis by blocking endoplasmic reticulum stress-associated increases of the BH3-only proteins Bim and PUMA. PMID- 20206404 TI - [Concordance in critical patients between the equations designed for the calculation of glomerular filtration rate and 24-hour creatinine clearance]. AB - OBJECTIVE: To study the behavior of the different equations used to estimate glomerular filtration rate (GFR) applied to critical care patients compared to the standard method: 24-hour creatinine clearance (24-CrCl). DESIGN: Retrospective analysis of data base from a previous observational prospective study. SETTING: Polyvalent ICU in a tertiary Hospital. POPULATION: All adult patients admitted to our Unit during the study who had a bladder catheter inserted. Anuric patients were excluded. INTERVENTIONS: We measured 24-CrCl and estimated GFR by MDRD, modified Jelliffe (JF), Mayo-Clinic (CM) and Cockroft Gault (C-G) equations. VARIABLES: To evaluate degree of agreement, we grouped patients regarding 24-CrCl as normal (>70), moderate dysfunction (69-50) or severe renal dysfunction (< 50 mL/min/1.73 m(2)). RESULTS: 307 patients, aged 54+/-18, 69.7% males. Measured 24-CrCl was 109.2+/-78.2 mL/min/1.73 m(2) and the estimate one 95.5+/-56.7 for JF, 87.4+/-53.4 for C-G, 86.9+/-55.9 for MDRD and 85.6+/-39.9 for CM. The difference was significant (p<0.001) for all estimates but lower for (13.7+/-53.2 mL/min/1.73 m(2)) than C-G (21.9+/-58.3), CM (23.6+/ 59.6) or MDRD (22.3+/-60.4). Correlation coefficient was 0.73 for JF, 0.67 C-G or CM and 0.64 for MDRD. The degree of agreement was only fair for all measures (Kappa 0.55 for JF or MDRD, 0.51 for C-G and 0.5 for CM). CONCLUSIONS: Modified Jelliffe equation showed higher agreement with 24-CrCl than Cockroft-Gault, MDRD or Mayo-Clinic equations when used in critically ill patients. However, when exact measurement is needed, none of the equations can be considered adequate and in these cases, the CrCl should be calculated. PMID- 20206405 TI - [In-hospital cardiac arrest. Signs of change]. PMID- 20206406 TI - [Begona Aranzadi, the first Spanish female intensivist has retired]. PMID- 20206407 TI - [Severe malaria due to Plasmodium falciparum]. PMID- 20206408 TI - [Aceclofenac-induced acute cholestatic lesion]. PMID- 20206409 TI - [Plasma levels of folate and vitamin B(12) in patients with chronic liver disease]. AB - BACKGROUND: Patients with liver disease frequently experience changes in their nutritional status. OBJECTIVE: To determine changes in vitamin B12 and folic acid plasma levels in patients with chronic cirrhosis and to assess whether these parameters may be useful in the etiologic diagnosis of this disease. PATIENTS AND METHODS: Thirty-nine patients admitted for decompensated cirrhosis (29 with alcoholic etiology and 10 with non-alcoholic etiology) and 35 controls were prospectively studied. Plasma levels of vitamin B(12), folate acid, mean corpuscular volume (MCV), aspartate aminotransferase (AST), alanine aminotransferase (ALT), AST/ALT ratio, and gamma-glutamyltransferase (GGT), among other parameters, were measured. RESULTS: Vitamin B(12) levels were 1151+/ 568pg/ml in patients with decompensated cirrhosis and 440+/-133pg/ml in controls (p<0.05). Plasma folate levels were 8.57+/-3.8ng/ml in controls and 6.68+/ 2.74ng/ml in patients with cirrhosis (p<0.05). Folate levels were lower in patients with alcoholic cirrhosis (mean value, 5.7+/-2.1) than in those with non alcoholic cirrhosis (9.3+/-2.6; p<0.0005). The vitamin B(12)/folate ratio discriminated alcoholic etiology better than other parameters such as AST, ALT, MCV, AST/ALT ratio and GGT. CONCLUSIONS: Plasma levels of vitamin B12 in patients with decompensated chronic liver disease are high, whereas plasma folate levels are low. The ratio between vitamin B12 and folic acid may be useful in the differential diagnosis of the etiology of chronic liver disease. PMID- 20206410 TI - Primary retroperitoneal liposarcoma: clinical and histological analysis of ten cases. AB - Retroperitoneal liposarcoma constitutes an uncommon and locally aggressive malignancy. We performed a retrospective analysis of 10 patients (6 males; mean age: 63.2+/-11 years) with histologically proven retroperitoneal liposarcoma seen at our institution between 1999 and 2007. Presence of a palpable abdominal mass was the main symptom at diagnosis. All patients underwent complete surgical resection. Negative microscopic margin was achieved in four cases. Histological analysis revealed the following subtypes: well-differentiated (6 cases), dedifferentiated (two cases), pleomorphic, and myxoid/round cell (one case each). Concomitant resection of adjacent organs was needed in five cases. Half of the patients developed tumor recurrence, mainly limited to the retroperitoneum or abdominal cavity. The mean recurrence-free survival was 43.3 months (95%CI: 25.7 60.8), with 3- and 5-year overall survival rates of 79% and 61%, respectively. Patients undergoing complete resection with clear margins showed a near significant trend toward increased recurrence-free survival (62.9 vs. 29.3 months; P=0.06). PMID- 20206411 TI - [Obesity and liver disease]. AB - Obesity is associated with a higher risk of developing non-alcoholic fatty liver disease (NAFLD) and contributes to the progression of liver diseases of distinct etiologies such as chronic hepatitis C virus (HCV) infection. The discovery that adipose tissue is submitted to a state of chronic inflammation able to secrete adipokines has allowed a connection to be established between the metabolic alterations that lead to triglyceride accumulation and liver inflammation, reinforcing the role of hepatocellular lipotoxicity in the pathogenesis of NAFLD. In addition, although HCV genotype 3 induces steatosis, it is currently believed that obesity and its associated alterations, such as insulin resistance, are involved in progression of HCV-mediated liver disease, as well as that of other chronic liver diseases of diverse etiologies. PMID- 20206412 TI - [Hepatitis C and metabolic syndrome]. AB - Insulin resistance is a predictive factor of response to treatment with peginterferon and ribavirin in patients with hepatitis C. Insulin resistance impairs sensitivity to interferon and can block its intracellular signalling. Insulin resistance also induces the development of steatosis, progression of fibrosis and proinflammatory cytokine release and reduces the bioavailability of interferon. Suppressor of cytokine signalling 3 and protein tyrosine phosphatases are involved in blocking the intracellular signalling of interferon and insulin. Insulin resistance can be treated through diet, physical exercise and the use of insulin-sensitizing agents such as biguanides or glitazones. The TRIC-1 study demonstrated that adding metformin to routine treatment improves the possibilities of cure in women and in patients whose insulin sensitivity returns to normal during treatment. PMID- 20206413 TI - [Portal hypertension in patients with inflammatory bowel disease]. AB - Portal hypertension (PH) is a complication that may occur in patients with inflammatory bowel disease (IBD). In these patients, the etiology of PH may not be alcoholic or viral cirrhosis (which cause 90% of cases in the general population). Consequently, etiologic study of PH in patients with IBD should always include a wide spectrum of possibilities. Moreover, the development of PH in IBD patients often requires a distinct therapeutic approach to IBD (both medical and surgical) as PH may be a contraindication for some drugs and is a risk factor for surgical morbidity and mortality. We present the cases of two patients with IBD who developed PH and review the most likely causes of PH in IBD, as well as preventive and therapeutic strategies. PMID- 20206414 TI - [Intraabdominal mass with difficult diagnosis: Solitary fibrous tumor]. AB - Solitary fibrous tumor (SFT) is a rare neoplasm of mesenchymal origin. The most commonly reported locations are the pleura and meninges. Less frequently, SFT manifests as an asymptomatic mass in the pancreas, liver, peritoneum or kidney. Clinical and radiological findings have failed to provide any specific diagnostic pattern but allow malignant development to be suspected due to infiltration or metastasis. In addition, preoperative cytology often yields inconclusive or misleading results. Therefore the definitive diagnosis is achieved after both surgical resection and immunohistochemical analysis, with markers such as CD34, vimentin and desmin. We present a case of SFT, which was difficult to diagnose, even after an extensive battery of tests based on imaging techniques. PMID- 20206415 TI - [Aging and ovariectomy cause a decrease in brain glucose consumption in vivo in Wistar rats]. AB - INTRODUCTION: The life expectancy of the population has been increased steadily over the twentieth century in both genders. The survival of women has always been higher compared to men and these differences in longevity are reproduced in other animal species such as rats. There must be some biological basis to support the differences in longevity between males and females. Differences can be explained by the effects of estrogens because ovariectomy cancels out the benefits shown in females compared to males. AIM: Our aims were to study the cerebral glucose consumption in vivo in young and old female Wistar rats and evaluate the effect of ovariectomy on the brain glucose uptake. MATERIAL AND METHODS: We used female Wistar rats, divided into young (4-7 months), young control (Sham) and ovariectomized (3 or 6 weeks) and old (22-24 months) groups. After intravenous administration of 18F-fluorodeoxyglucose (FDG) the cerebral glucose uptake was measured in vivo by Positron Emission Tomography (PET). RESULTS: There was a significant decrease in cerebral glucose consumption in old rats compared with young rats. Similar results were found in glucose uptake when comparing control rats with ovariectomized rats, i.e., ovariectomy significantly reduces the brain glucose consumption. CONCLUSIONS: Aging causes a decrease in cerebral glucose metabolism. Ovariectomy reduces cerebral glucose consumption significantly compared to control rats and is similar to the old group. PMID- 20206416 TI - [The influence of physical exercise on depressive symptoms and functional fitness in elderly residents of south Brazil]. AB - INTRODUCTION: The objective of this study was to investigate the influence of physical exercise on depressive symptoms and functional fitness in a sample of elderly people enrolled in a physical exercise program run by public sector Health Centers in Florianopolis, Brazil. METHODS: The sample comprised a total of 118 elderly people (101 women and 17 men), who had been receiving treatment for up to 1 year and 4 months and were assessed at predefined intervals, up to a maximum of five times. Evaluations were carried out using the Geriatric Depression Scale (GDS-15); International Physical Activity Questionnaire (IPAQ) and the physical test battery proposed by AAHPERD (American Alliance for Health, Physical Education, Recreation and Dance). RESULTS: A tendency for depression scores to reduce was observed. However, a statistically significant difference (p=0.008) was only detected among those elderly people who attended 75% or more of the treatment sessions. Analysis demonstrated that the tendency for overall mean functional fitness to increase was statistically significant (p<0.001). Inverse relationships were detected between functional fitness and depression scores at five assessment (r=-0.235, p=0.059; r=-0.206, p=0.099; r=-0.158, p=0.110; r=-0.068, p=0.565), although only one assessment had statistical significance (r=-0.226, p=0.033). CONCLUSIONS: The results demonstrated a positive effect from physical exercise in reducing depressive symptoms and improving functional fitness, suggesting that there is an inverse relationship between these variables. PMID- 20206417 TI - [Evaluation of the management of nonwork-related sick leave lasting more than 15 days in Catalonia (Spain)]. AB - OBJECTIVES: To compare the length of nonwork-related sick leave among cases managed by an insurance company versus those managed by the National Institute of Social Security (NISS). METHODS: We performed a retrospective cohort study of 289,686 cases of sick leave lasting for more than 15 days that began in 2005 after certification by a primary care physician in Catalonia, were reported to the Catalonian Institute of Medical Evaluations, and were followed to term. Of the total, 156,676 cases were managed by the NISS. To account for repeat episodes (approximately 25% of the total), the Wang-Chang estimator was used to calculate the median duration and percentiles; comparisons were made using log-logistic regression with shared gamma frailty models, with calculation of time ratios (TR) and their corresponding 95% confidence intervals (95% CI). RESULTS: The median duration of sick leave was 43 days for cases managed by the NISS and 39 days for those managed by the insurance company. This difference was statistically significant both for men employed under contract (TR=0.87; 95% CI: 0.85-0.88) and for those who were self-employed (TR=0.78; 95% CI: 0.75-0.80) as well as for women under contract (TR=0.85; 95% CI: 0.84-0.87) and self-employed women (TR=0.84; 95% CI: 0.81-0.88). These differences persisted after adjustment was performed for age and health region. CONCLUSIONS: For sick leave lasting more than 15 days, these results confirm that cases managed by an insurance company ended earlier than for those managed by the NISS, both for contract and self employed workers. Further research is needed to explore the reasons for these differences. PMID- 20206418 TI - 3D QSAR pharmacophore based virtual screening and molecular docking for identification of potential HSP90 inhibitors. AB - Chemical features based 3D pharmacophore models were developed for HSP90 based on the known inhibitors using Discovery Studio V2.1. An optimal pharmacophore model was brought forth and validated using a decoy set, external test set and Fischer's randomization method. The best five features pharmacophore model, Hypo1, includes two hydrogen bond acceptors, three hydrophobic features, which has the highest correlation coefficient (0.93), cost difference (73.88), low RMS (1.24), as well as it shows a high goodness of fit and enrichment factor. Hypo1 was used as a 3D query for virtual screening to retrieve potential inhibitors from Maybridge and Scaffold databases. The hit compounds were subsequently subjected to molecular docking studies and finally, 36 compounds were obtained based on consensus scoring function. PMID- 20206419 TI - Evaluation of 2-thioxo-2,3,5,6,7,8-hexahydropyrimido[4,5-d]pyrimidin-4(1H)-one analogues as GAA activators. AB - Pompe disease is a lysosomal storage disease (LSD) caused by a deficiency in the lysosomal enzyme acid alpha-glucosidase. In several LSDs, enzyme inhibitors have been used as small molecule chaperones to facilitate and increase the translocation of mutant protein from the endoplasmic reticulum to the lysosome. Enzyme activators with chaperone activity would be even more desirable as they would not inhibit the enzyme after translocation and might potentiate the activity of the enzyme that is successfully translocated. Herein we report our initial findings of a new series of acid alpha-glucosidase activators. PMID- 20206420 TI - [Type 2 diabetes mellitus associated with pancreatic and renal malformations]. AB - A 55-year-old woman presented with a recent diabetes mellitus associated with pancreatic and renal malformations. This atypical diabetes raised the possibility of maturity onset diabetes of the young (MODY) and a genetic research was performed. These malformations led to MODY5 diagnosis that was confirmed by the presence of HNF1beta gene mutation. PMID- 20206421 TI - Relationship between deposition and attachment rates in Jacobi room model. AB - It is shown in this work that parameters of the Jacobi model, which describes behavior of short-lived radon progeny, are not independent. The relationship between deposition rate of attached radon progeny and attachment rate of their unattached fraction was determined in this paper. It was found that deposition rate increases when the attachment rate is smaller; this effect is more pronounced for larger friction velocity. The deposition rate of attached radon progeny is presented here as a function of friction velocity, ventilation and attachment rate. Deposition rate of attached fraction was estimated in the range 0.012-0.46 h(-1), when attachment rate varies from 10 h(-1) to 100 h(-1). PMID- 20206422 TI - A Monte Carlo study of radon detection in cylindrical diffusion chambers. AB - The functioning of radon diffusion chambers was studied using the Monte Carlo code RAMMX developed here. The alpha particles from radon are assumed randomly produced in the volume of the cylinder, and those from the progeny are assumed to originate randomly at the cylindrical surface. The energy spectrum, the distribution of incident angles, and the distribution of path lengths of the alpha particles on the detector were obtained. These quantities vary depending on input parameters such as initial alpha particle energy, radius and depth of the diffusion chamber, detector size and atmospheric pressure. The calculated energy spectrum for both (222)Rn and (220)Rn was compared with experiment, permitting the identification of each peak and its origin, and a better understanding of radon monitoring. Three aspects not considered in previous calculations are progeny alphas coming from surfaces of the monitor, taking into account the atmospheric pressure, and including the isotope (220)Rn. PMID- 20206423 TI - Re "Prognostic factors in malignant tumours of the salivary glands" by Speight and Barrett [Br. J. Oral Maxillofac. Surg. 47 (8) (2009) 587-593]. PMID- 20206424 TI - Media portrayal of birth and the consequences of misinformation. PMID- 20206425 TI - Magnesium and the regulation of lead in three populations of the garden snail Cantareus aspersus. AB - Helicid snails appear to regulate Pb more closely than other toxic metals, though it is reported as the least toxic. No regulatory mechanism has been described in animals, and the possible role of Mg in limiting Pb assimilation is examined here for the first time. Three populations of Cantareus aspersus were fed Pb and Ca with three levels of Mg for up to 64 days. Metal assimilation and production efficiency was calculated for each of 108 snails. Populations differed in their pattern of uptake but soft tissue Pb was unaffected by dietary Mg. The proportion of Pb assimilated did not change as soft tissue concentrations increased, indicating no specific regulatory mechanism. The daily addition of Pb to the soft tissues increases with growth rate suggesting uptake is instead some function of growth or cell turnover. Bioconcentration factors varied with time and are unreliable indicators of an evolved regulatory mechanism for Pb. PMID- 20206426 TI - Hydroxypropyl-beta-cyclodextrin as non-exhaustive extractant for organochlorine pesticides and polychlorinated biphenyls in muck soil. AB - Hydroxypropyl-beta-cyclodextrin (HPCD) was used as a non-exhaustive extractant for organochlorine pesticides (OCs) and polychlorinated biphenyls (PCBs) in muck soil. An optimized extraction method was developed which involved using a HPCD to soil mass ratio of 5.8 with a single extraction period of 20 h. An aging experiment was performed by spiking a muck soil with (13)C-labeled OCs and non labeled PCBs. The soil was extracted with the optimized HPCD method and Soxhlet apparatus with dichloromethane over 550 d periodically. The HPCD extractability of the spiked OCs was greater than of the native OCs. A decreased in HPCD extractability was observed for the spiked OCs after 550 d of aging and their extractability approached those of the natives. The partition coefficient between HPCD and soil (logK(CD-Soil)) was negatively correlated with the octanol-water partition coefficient (logK(OW)) with r(2)=0.67 and p<0.05. PMID- 20206427 TI - The detection of dioxin- and estrogen-like pollutants in marine and freshwater fishes cultivated in Pearl River Delta, China. AB - In this study we aimed to assess the dioxin- and estrogen-like activities of contaminants extracted from twenty species of freshwater and seawater fishes, using luciferase reporter assays. Transfected MCF7 cells were treated with sample extracts and luciferase activities were then measured at 24-h of post-treatment. The mean values of the detected dioxin- and estrogen-like activities in the freshwater fishes were 25.3 pg TEQ/g ww and 102.3 pM EEQ/g ww whereas in the seawater fishes, the values were 46.2 pg TEQ/g ww and 118.8 pM EEQ/g ww. Using sample-relevant dosage of estrogen, inductions of cell proliferation markers (i.e. retinoblastoma, cyclin D) and stimulations of cell growth were revealed by Western blotting, colony formation and BrdU uptake assays. A cotreatment with TCDD significantly reduced these effects. Using the sample extracts with different dioxin- and estrogen-like activities, similar observation was revealed. The data highlighted the mixture effect of food contaminants on human health. PMID- 20206428 TI - Response of stable carbon isotope in epilithic mosses to atmospheric nitrogen deposition. AB - Epilithic mosses are characterized by insulation from substratum N and hence meet their N demand only by deposited N. This study investigated tissue C, total Chl and delta13C of epilithic mosses along 2 transects across Guiyang urban (SW China), aiming at testing their responses to N deposition. Tissue C and total Chl decreased from the urban to rural, but delta13C(moss) became less negative. With measurements of atmospheric CO2 and delta13CO2, elevated N deposition was inferred as a primary factor for changes in moss C and isotopic signatures. Correlations between total Chl, tissue C and N signals indicated a nutritional effect on C fixation of epilithic mosses, but the response of delta13C(moss) to N deposition could not be clearly differentiated from effects of other factors. Collective evidences suggest that C signals of epilithic mosses are useful proxies for N deposition but further works on physiological mechanisms are still needed. PMID- 20206429 TI - Analgesic and anti-inflammatory effects of oxaprozin and naproxen sodium after removal of impacted lower third molars: a randomized, double-blind, placebo controlled crossover study. AB - PURPOSE: In this study, oxaprozin, a long-acting nonsteroidal anti-inflammatory drug, and naproxen sodium were compared in terms of their effects on edema, pain, and trismus after surgery for impacted mandibular third molars. MATERIALS AND METHODS: Thirty healthy patients with bilaterally impacted mandibular third molars were included in this randomized, cross-over, double-blind, placebo controlled study. Patients were assigned randomly to 1 of 3 surgery groups and received postoperatively 1,200 mg oxaprozin, 550 mg naproxen sodium, or a placebo. Postoperative edema was measured with ultrasonography performed before and after surgery. Trismus was measured by comparison of preoperative and postoperative maximum interincisal mouth opening measurements by caliper. Pain was assessed by a visual analog scale (VAS) and by recording the number of rescue analgesic pills taken. RESULTS: After removal of impacted third molars, the patients administered oxaprozin and naproxen showed superior results over those given placebo in terms of pain parameters (P < .05), but these treatments had no statistically significant effect on facial swelling. Comparing the oxaprozin and naproxen groups, there were no differences in the mouth opening measurements, but naproxen showed a statistically superior effect over the placebo (P < .05). Although not statistically significant, oxaprozin showed a more pronounced effect in reducing trismus than did the placebo (P = .07). CONCLUSIONS: Administration of either oxaprozin or naproxen sodium during the postoperative period is effective and has similar effects in reducing pain but questionable benefit for the management of trismus. However, neither agent has clinical benefit in terms of reducing edema. PMID- 20206430 TI - Cabergoline versus bromocriptine for symptomatic treatment of premenstrual mastalgia: a randomised, open-label study. AB - OBJECTIVE: To compare the effectiveness and side effects of cabergoline with bromocriptine for the symptomatic treatment of cyclic mastalgia as a part of the premenstrual syndrome. STUDY DESIGN: 140 women with premenstrual mastalgia were enrolled in this randomised, open-label trial. Two groups were created (bromocriptine and cabergoline) and consisted of 61 and 67 patients respectively at the end of trial. Bromocriptine was administered 5 mg daily during second half of the menstrual cycle. Cabergoline was administered 0.5 mg weekly during the second half of the cycle. Relief of pain was evaluated using a visual analog scale (VAS). The mean percentage decrease in score for all patients in each group was calculated. A 50% or greater decrease at the end of the third month from the basal VAS score was accepted as a positive response to drug therapy. Data regarding side effects were collected systematically with review of a symptom diary. RESULTS: The positive response rates to treatment were similar (bromocriptine 66.6% and cabergoline 68.4%). The pain reduction rates for each month were also similar. Moreover, the pain reduction rate was maximum in the second month of treatment for both groups. Vomiting (28%), nausea (39%) and headaches (23%) recorded in the bromocriptine group were significantly more frequent than vomiting (4.5%), nausea (20.9%) and headache (6%) recorded in the cabergoline group (p=0.023, p=0.001, p=0.006 respectively). A difference in the rate of dizziness was not statistically significant (26.4% vs. 14.9%). There was no correlation between the baseline breast pain score and prolactin level but post-treatment pain reduction was well correlated with prolactin level. CONCLUSIONS: Cabergoline is as effective as bromocriptine for the treatment of cyclic mastalgia but has minimal side effects compared to bromocriptine. PMID- 20206431 TI - Detection of paternal alleles in maternal plasma for non-invasive prenatal diagnosis of beta-thalassemia: a feasibility study in southern Chinese. AB - OBJECTIVE: To evaluate in maternal plasma, the efficacy of detecting the paternal beta-gene mutation and informative single nucleotide polymorphisms (SNPs) linked to the paternal-mutant or -normal allele in non-invasive prenatal diagnosis (NIPND). STUDY DESIGN: In 20 at-risk pregnancies, using the allele-specific arrayed primer extension (AS-APEX) technology of the previously published "Thalassemia" array, cyanine-5-deoxycytosine triphosphate (Cy5-dCTP) was incorporated into the extended strands to matched PCR-amplified maternal plasma DNA templates, to detect both the paternal beta-gene mutation and informative paternal SNPs. RESULTS: Sensitivity experiment showed that 5pg DNA as starting template gave detectable signals on the array. In 13 cases (65%), the paternal derived beta-gene mutation and/or informative mutant-associated SNP were detected. A subsequent invasive procedure was required to determine if the fetus had a beta-thalassemia (thal) major or minor genotype. In 3 cases (15%), absence of the paternal mutant or mutant-associated SNP excluded a beta-thal major fetus; while in 4 cases (20%), this approach was non-discriminative as both parents carry the same mutation without any informative SNP. CONCLUSION: This approach was useful in 16 out of 20 (80%) pregnancies at risk for beta-thal in southern Chinese. PMID- 20206432 TI - Women with asymptomatic cervical polyps may not need to see a gynaecologist or have them removed: an observational retrospective study of 1126 cases. AB - OBJECTIVES: (1) To determine the prevalence of pathology in cervical polyps and whether referring and/or removing them is justified, (2) to assess the frequency of associated endometrial pathology and whether investigating the uterine cavity is warranted, and (3) to estimate the financial costs of processing cervical polyps. STUDY DESIGN: Retrospective review of the histopathology database and case notes of women who had cervical polyps examined at the pathology department of Ipswich Hospital, UK, over a seven-year period from 01/01/2002 to 31/12/2008. RESULTS: The number of cervical polyps removed from 988 women was 1126. Each case of polyps was considered as a separate episode. The recurrence rate was 15%. All polyps were benign except two (0.2%) symptomatic polyps that showed high grade cervical intraepithelial neoplasia. The cost of referring women with cervical polyps (excluding women aged >45 years with abnormal bleeding and those with abnormal smear) to see a gynaecologist and of examining polyps histologically was estimated to be pound 94816.40. Further investigations to assess the cervix and/or uterine cavity which were performed for 133 women (14.3%), because of the cervical polyps and for no other clinical indication, showed no significant pathology at cost of pound 41195.54. CONCLUSION: Our data do not justify referring women with asymptomatic cervical polyps to see a gynaecologist. Further, removing these polyps and investigating the uterine cavity is not warranted. A policy of removing polyps from only symptomatic women or those with abnormal smear and limiting histological examination to these polyps would result in significant savings. PMID- 20206433 TI - An increase in systolic blood pressure and abnormal circadian blood pressure regulation in lean women with polycystic ovary syndrome. PMID- 20206434 TI - Quantifying the interaction of the C-terminal regions of polycystin-2 and polycystin-1 attached to a lipid bilayer by means of QCM. AB - The pkd1 and pkd2 genes encode for the proteins polycystin-1 (PC1) and polycystin 2 (PC2). These genes are mutated in patients diagnosed with autosomal dominant polycystic kidney disease. PC1 and PC2 interact via their C-terminal, cytosolic regions, which is an essential step in the regulation of cell proliferation and differentiation. Here, we developed an assay that allowed us to quantitatively monitor the interaction of the C-terminal region of PC1 (cPC1) with that of PC2 (cPC2) to be able to answer the question of how Ca(2+) influences the PC1/PC2 complex formation. By means of the quartz crystal microbalance (QCM) technique, we were able to determine binding affinities and kinetic constants of the cPC1/cPC2 interaction using a model based on the scaled particle theory. The results suggest that cPC2 forms trimers in solution in the absence of Ca(2+), which bind in a one step process to cPC1. PMID- 20206435 TI - The effect of compatible solute ectoines on the structural organization of lipid monolayer and bilayer membranes. AB - Compatible solutes are small organic osmolytes responsible for osmotic balance and at the same time compatible with the cellular metabolism. Here, we have investigated the effect of the compatible solutes, ectoine and hydroxyectoine, on the fluid-rigid domain structure of lipid monolayer and bilayer membranes. Mainly saturated dipalmitoyl-phosphatidylcholine membranes exhibiting a clear le/lc phase transition were used. Fluorescence microscopy showed that ectoines added to the aqueous subphase expand and fluidize the lipid monolayers especially at surface pressures below 30mN/m. The domain structure at the le/lc phase transition is sensitively modified leading to smaller but more numerous domains in the presence of ectoines. Hydroxyectoine was more efficient than ectoine. These results are explained by the replacement theory assuming that the ectoines are likely to be expelled from the membrane surface thus favoring the hydration of the lipid membrane. This effect reduces the line tension, which is the interfacial energy at the domain edges leading to reduced domain sizes and increased number of rigid domains. Isotherms of negatively charged phosphatidylglycerol membranes show a similar expansion, while unsaturated lipids are less affected. Mixed phosphatidylcholine/phosphatidylglycerol membranes exhibit the same effect on the line tension increasing the tendency for a phase separation. This could be shown also in bilayer vesicles, where the compatible solutes have only a minor effect on the lipid main phase transition in pure DPPC membranes but reduce the extent of the pretransition. In mixed DPPC/DPPG bilayer membranes ectoines cause a phase separation leading to the enrichment of expanded DPPC domains. In conclusion, our study gives for the first time evidence that ectoines have an effect on lipid membranes increasing the hydration of the surface and thus increasing the mobility of the lipid head groups and fluidizing the lipid layer accordingly. This increased fluidity may be of advantage for cell membranes to withstand extreme conditions like temperature or osmotic pressure and might also accelerate cellular repair mechanisms. PMID- 20206436 TI - Assessing the sustainability of forest management: an application of multi criteria decision analysis to community forests in northern Ethiopia. AB - Continuous deterioration of the natural resource base has become a serious threat to both the ecological systems and economic production in Ethiopia. Many of these problems have been attributed directly or indirectly to the rapid dwindling of the country's forest cover which is associated with unsustainable forest use and management. Closing community woodlands from human and livestock intervention to promote natural regeneration of forests has been one of the environmental restoration strategies pursued in the degraded highland areas of northern Ethiopia. However, local pressure to use reforested community lands for economic benefit has become a major threat to forest sustainability. Using locally identified sets of criteria and indicators for sustainable community forest management, this paper applies a multi-criteria decision analysis tool to evaluate forest management problems in the northern province of Tigray, Ethiopia. Three MCA methods - ranking, pair-wise comparison, and scoring - were used in evaluating the sets of criteria and indicators and alternative forest management scenarios. Results from the study indicate a number of noteworthy points: 1) MCA techniques both for identifying local level sustainability criteria and indicators and evaluating management schemes in a participatory decision environment appear to be effective tools to address local resource management problems; 2) Evaluated against the selected sets of criteria and indicators, the current forest management regime in the study area is not on a sustainable path; 3) Acquainting local people with adequate environmental knowledge and raising local awareness about the long-term consequences of environmental degradation ranked first among the set of sustainability criteria; and 4) In order to harmonize both environmental and economic objectives, the present 'ecological biased' forest management regime needs to be substituted by an appropriate holistic scheme that takes into account stakeholders' multiple preferences and priority rankings. PMID- 20206437 TI - A prospective multicenter randomized comparative study between the U- and H-type methods of the TVT SECUR procedure for the treatment of female stress urinary incontinence: 1-year follow-up. AB - BACKGROUND: No studies have been published comparing the U- and H-type methods of the TVT SECUR (TVT-S) procedure. OBJECTIVE: Our aim was to compare the efficacy and safety of the two types of TVT-S for female stress urinary incontinence (SUI). DESIGN, SETTING, AND PARTICIPANTS: Women with urodynamic SUI were enrolled in this 12-mo multicenter randomized study. INTERVENTION: Subjects were randomly allocated to either the U- or H-type method of TVT-S. MEASUREMENTS: Pre- and postoperative evaluations included a standing stress test, the Sandvik questionnaire, the Incontinence Quality of Life (I-QOL) questionnaire, and the International Consultation on Incontinence Questionnaire-Female Lower Urinary Tract Symptoms (ICIQ-FLUTS). Patients' satisfaction and complications were evaluated. Objective and subjective cures were defined as no leakage on the stress test and responses on the Sandvik questionnaire, respectively. We compared the surgical outcomes between the two methods. RESULTS AND LIMITATIONS: Of 285 women, 144 had the U-type method and 141 had the H-type method. Objective cure rates were 87.5% for the U-type method and 80.1% for the H-type method (p=0.091). Subjective cure rates were 77.1% for the U-type method and 75.7% for the H-type method (p=0.786). Improvement in I-QOL and domain scores of the ICIQ-FLUTS (filling and incontinence sum, QOL score), and patients' satisfaction favored the U-type method. There were three cases of intraoperative vaginal wall perforation, one case of increased bleeding, and three cases of temporary postoperative retention. A power calculation was not performed, and some baseline characteristics were not balanced between the two methods. CONCLUSIONS: Both methods of TVT-S provided comparable cure rates for female SUI. However, QOL and treatment satisfaction favored the U-type method. TRIAL REGISTRATION: The protocol of this study was not registered. PMID- 20206438 TI - Intra- and inter-limb coherency during stance in non-dyskinetic and dyskinetic patients with Parkinson's disease. AB - OBJECTIVE: Examine the level of intra- and inter-limb coherency in non-dyskinetic and dyskinetic patients with Parkinson's disease (PD). PATIENTS & METHODS: Using a magnetic tracking system, whole-body 3D movements were assessed in 10 dyskinetic patients with clear monophasic peak-dose levodopa-induced dyskinesia (LID), in 10 non-dyskinetic patients and in 10 control subjects, standing with their arms out. Patients were tested during their best ON period. Coherency in the kinematics of pairs of body segments was assessed by spectral analysis. For each pair examined, we calculated the highest coherency between 0.5 and 3.0Hz and the frequency at which this maximum coherency occurred. RESULTS: Analysis of variance showed that for 34 out of the 44 (77.3%) comparisons we studied, there were significant differences between the means of coherencies of the groups. Typically, the control group had the highest coherency and the patients with LID had the lowest. Patients with LID also tended to have their maximum coherency at higher frequencies than the control and non-dyskinetic patient groups (30 out of 44 comparisons were significant). These trends appeared in all types of inter segment comparisons, including bilaterally symmetric segments, biomechanically linked segments (in which coherencies were higher overall in all groups, but still different between groups) and in other comparisons, but the trends were not so clear for comparisons involving the feet. CONCLUSION: LID is indeed incoherent in the frequency domain, suggesting that body segments may be driven by different neural outputs. The challenges of dealing with these incoherent involuntary movements when planning and executing voluntary movements must certainly play a role in motor difficulties observed in patients with LID. The fact that both dyskinetic and non-dyskinetic patients showed less coherency than controls suggests that levodopa may alter postural control by decreasing stiffness and increasing limb independence. PMID- 20206439 TI - Vanadium in the detection, prevention and treatment of cancer: the in vivo evidence. AB - Vanadium, a dietary micronutrient, is yet to be established as an essential part of the human diet. Over the past century, several biological effects of vanadium, such as insulin-mimetic action as well as amelioration of hyperlipidemia and hypertension, have been discovered. This transition element is known to influence a battery of enzymatic systems, namely phosphatases, ATPases, peroxidases, ribonucleases, protein kinases and oxidoreductases. Multiple biochemical and molecular actions of vanadium have been implicated in its inhibitory effects on various tumor cells of human origin. Successful in vitro studies over the past few decades have advanced the anticancer research on vanadium into the preclinical stage. Vanadium in several animal cancer models provides protection against all stages of carcinogenesis--initiation, promotion, and progression. This review focuses on the current advances in cancer prevention and treatment as well as early detection by vanadium compounds in preclinical animal models while pointing to possible mechanisms of such diverse beneficial effects. Clinical pharmacokinetic and potential toxicity studies on vanadium are also highlighted in this review. Supporting and challenging evidence as well as future directions of vanadium research exploring the possibility of using this dietary agent for detection, prevention and treatment of human cancers are critically discussed. PMID- 20206440 TI - A combination of a DNA-chimera siRNA against PLK-1 and zoledronic acid suppresses the growth of malignant mesothelioma cells in vitro. AB - Although novel agents effective against malignant mesothelioma (MM) have been developed, the prognosis of patients with MM is still poor. We generated a DNA chimeric siRNA against polo-like kinase-1 (PLK-1), which was more stable in human serum than the non-chimeric siRNA. The chimeric PLK-1 siRNA inhibited MM cell proliferation through the induction of apoptosis. Next, we investigated the effects of zoledronic acid (ZOL) on MM cells, and found that ZOL also induced apoptosis in MM cells. Furthermore, ZOL augmented the inhibitory effects of the PLK-1 siRNA. In conclusion, combining a PLK-1 siRNA with ZOL treatment is an attractive strategy against MM. PMID- 20206441 TI - GIPC mediates the generation of reactive oxygen species and the regulation of cancer cell proliferation by insulin-like growth factor-1/IGF-1R signaling. AB - Insulin-like growth factor-1 (IGF-1)/IGF-1 receptor signaling participates in a variety of cellular processes, including cell survival, growth, and proliferation. Increased expression of IGF-1R and activation of its downstream signaling components have been implicated in human cancers. Although a regulatory role for IGF-1R has been established, the relationship between IGF-1R and its binding partner, GAIP-interacting protein C-terminus (GIPC), in terms of promoting cell proliferation, remains unclear. We found that siRNA-mediated silencing of GIPC expression decreased IGF-1-mediated IGF-1R phosphorylation and cellular proliferation in breast cancer models. IGF-1-mediated cellular proliferation was also inhibited by N-acetylcysteine, which implicates reactive oxygen species generation. siRNA-mediated silencing of GIPC expression also decreased IGF-1-mediated reactive oxygen species generation. Taken together, these data suggest that GIPC contributes to IGF-1-induced cancer cell proliferation via the regulation of reactive oxygen species production. PMID- 20206442 TI - Lunasin promotes apoptosis in human colon cancer cells by mitochondrial pathway activation and induction of nuclear clusterin expression. AB - Lunasin is a naturally occurring peptide with arginine-glycine-aspartic acid motif associated to its reported biological activity. We aimed to determine the potential of lunasin from soybean to stimulate apoptosis in HT-29 colon cancer cells. Lunasin caused cytotoxicity to HT-29 cells and induced G2/M cell cycle arrest with simultaneous increased in p21 expression. Lunasin-induced apoptosis as evidenced by a twofold increase in the percentage of cells undergoing apoptosis, decreased Bcl-2:Bax ratio from 8.5 to 0.4, increased caspase-3 activity by 77% and increased expression of pro-apoptotic nuclear clusterin by five fold when compared to untreated cells. In conclusion, lunasin stimulated apoptosis in HT-29 cells by activating apoptotic mitochondrial pathways and inducing expression of the pro-apoptotic nuclear clusterin. PMID- 20206443 TI - Materials recovery from waste printed circuit boards by supercritical methanol. AB - The recovery of valuable materials from waste printed circuit boards (PCBs) is quite difficult due to the heterogeneous mix of polymer materials, multiple kinds of metals and glass fiber. A feasibility study was conducted using supercritical methanol (SCM) to simultaneously recover polymers and metals from waste PCBs. The study focused on the characteristics of both oils and solid products obtained from the SCM-treated waste PCBs. The operation conditions were temperature range of 300-420 degrees C, treatment time between 30 and 120 min and solid-to-liquid ratio (S/L) of 1:10-1:30 (g/mL) so as to understand the products and depolymerization mechanisms of waste PCBs in SCM. GC-MS results revealed that the oils mainly contained phenol and its methylated derivatives, and the methylated derivatives increased with the increase of reaction temperature. The methylated reaction occurred mainly above 400 degrees C. The liquid products also contained a significant number of phosphated fire retardant additives such as triphenyl phosphate, which decreased significantly with the increase of reaction temperature. The solid product mainly consisted of Cu, Fe, Sn, Pb and Zn, as well as lower concentrations of precious metals such as Ag and Au. PMID- 20206444 TI - Bright light activates a trigeminal nociceptive pathway. AB - Bright light can cause ocular discomfort and/or pain; however, the mechanism linking luminance to trigeminal nerve activity is not known. In this study we identify a novel reflex circuit necessary for bright light to excite nociceptive neurons in superficial laminae of trigeminal subnucleus caudalis (Vc/C1). Vc/C1 neurons encoded light intensity and displayed a long delay (>10s) for activation. Microinjection of lidocaine into the eye or trigeminal root ganglion (TRG) inhibited light responses completely, whereas topical application onto the ocular surface had no effect. These findings indicated that light-evoked Vc/C1 activity was mediated by an intraocular mechanism and transmission through the TRG. Disrupting local vasomotor activity by intraocular microinjection of the vasoconstrictive agents, norepinephrine or phenylephrine, blocked light-evoked neural activity, whereas ocular surface or intra-TRG microinjection of norepinephrine had no effect. Pupillary muscle activity did not contribute since light-evoked responses were not altered by atropine. Microinjection of lidocaine into the superior salivatory nucleus diminished light-evoked Vc/C1 activity and lacrimation suggesting that increased parasympathetic outflow was critical for light-evoked responses. The reflex circuit also required input through accessory visual pathways since both Vc/C1 activity and lacrimation were prevented by local blockade of the olivary pretectal nucleus. These findings support the hypothesis that bright light activates trigeminal nerve activity through an intraocular mechanism driven by a luminance-responsive circuit and increased parasympathetic outflow to the eye. PMID- 20206446 TI - Verification of surfactant CHAPS effect using AFM for making biomemory device consisting of recombinant azurin monolayer. AB - In this study, a protein-based biomemory device was developed using a surface modified recombinant azurin layer and its surface characteristics were analyzed by atomic force microscopy. The cysteine-modified azurin used for this purpose was a metalloprotein that had redox properties. To immobilize the metalloprotein on the Au substrates, the cysteine-modified azurin layer was self-assembled on the Au surface through a covalent bond between the thiol group on the cysteine and the Au surface. In our previous work, we showed that this protein layer was formed as cohesive clusters on Au surface through physical adsorption. To reduce the formation of these cohesion clusters, a zwitterionic surfactant, (3-[(3 cholamidopropyl) dimethylammonio]-1-propanesulfonate) (CHAPS) was introduced to modify the surface properties. Using this approach, we found that CHAPS significantly reduced the amount of cysteine-modified azurin aggregates that nonspecifically adsorbed to the Au substrate. Atomic force microscopy was used to analyze the modified-surface. Based on this analysis, the size of the recombinant azurin clusters when CHAPS was used were about 15-25nm whereas aggregates of 150 200nm were observed in the absence of CHAPS. In addition, Raman spectroscopy was performed to confirm the retention of azurin molecules self-assembled on the Au surface. Electrochemical results using cyclic voltammetry indicated that recombinant azurin was successfully immobilized onto the Au surface with CHAPS and its redox property remained intact. Chronoamperometry was then used to demonstrate the memory characteristics of this azurin-based fabricated memory device. The combined results of this study show that CHAPS can significantly reduce the size of protein aggregates that become immobilized on the surface without a loss of the electrochemical properties of the protein. PMID- 20206447 TI - Contrast inversion in non-contact Dynamic Scanning Force Microscopy: what is high and what is low? AB - The present work proves that when non-contact Dynamic Scanning Force Microscopy (DSFM) is performed in ambient conditions wrong height measurements of heterogeneous samples can be obtained. In some extreme cases even contrast inversion can be observed. Alkanethiol islands on Au (111) have been used as model system, where contrast inversion is observed with different DSFM modes and various data acquisition parameters. To understand this effect, spectroscopy measurements have been used to show that contrast inversion is really a consequence of the differences in the interaction measured between tip and sample on the bare Au substrate and on the alkanethiol islands. We propose that this interaction is mainly induced by liquid necks forming between tip and sample, which is much stronger on the hydrophilic Au substrate than on the hydrophobic alkanethiol islands. PMID- 20206445 TI - Peripheral endothelin B receptor agonist-induced antinociception involves endogenous opioids in mice. AB - Endothelin-1 (ET-1) produced by various cancers is known to be responsible for inducing pain. While ET-1 binding to ETAR on peripheral nerves clearly mediates nociception, effects from binding to ETBR are less clear. The present study assessed the effects of ETBR activation and the role of endogenous opioid analgesia in carcinoma pain using an orthotopic cancer pain mouse model. mRNA expression analysis showed that ET-1 was nearly doubled while ETBR was significantly down-regulated in a human oral SCC cell line compared to normal oral keratinocytes (NOK). Squamous cell carcinoma (SCC) cell culture treated with an ETBR agonist (10(-4)M, 10(-5)M, and 10(-6) M BQ-3020) significantly increased the production of beta-endorphin without any effects on leu-enkephalin or dynorphin. Cancer inoculated in the hind paw of athymic mice with SCC induced significant pain, as indicated by reduction of paw withdrawal thresholds in response to mechanical stimulation, compared to sham-injected and NOK-injected groups. Intratumor administration of 3mg/kg BQ-3020 attenuated cancer pain by approximately 50% up to 3h post-injection compared to PBS-vehicle and contralateral injection, while intratumor ETBR antagonist BQ-788 treatment (100 and 300microg/kg and 3mg/kg) had no effects. Local naloxone methiodide (500microg/kg) or selective mu-opioid receptor antagonist (CTOP, 500microg/kg) injection reversed ETBR agonist-induced antinociception in cancer animals. We propose that these results demonstrate that peripheral ETBR agonism attenuates carcinoma pain by modulating beta-endorphins released from the SCC to act on peripheral opioid receptors found in the cancer microenvironment. PMID- 20206448 TI - Nanoscale dielectric properties of insulating thin films: from single point measurements to quantitative images. AB - Dielectric relaxation (DR) has shown to be a very useful technique to study dielectric materials like polymers and other glass formers, giving valuable information about the molecular dynamics of the system at different length and time scales. However, the standard DR techniques have a fundamental limitation: they have no spatial resolution. This is of course not a problem when homogeneous and non-structured systems are analyzed but it becomes an important limitation for studying the local properties of heterogeneous and/or nano-structured materials. To overcome this constrain we have developed a novel approach that allows quantitatively measuring the local dielectric permittivity of thin films at the nanoscale by means of Electrostatic Force Microscopy. The proposed experimental method is based on the detection of the local electric force gradient at different values of the tip-sample distance. The value of the dielectric permittivity is then calculated by fitting the experimental points using the Equivalent Charge Method. Even more interesting, we show how this approach can be extended in order to obtain quantitative dielectric images of insulating thin films with an excellent lateral resolution. PMID- 20206449 TI - Droplets of black bile? Development of vulnerability and resilience to depression in young age. AB - Major depressive disorder is predicted by enduring anxiety-related personality traits, in particular by neuroticism, which have genetic foundations. Neuroticism in turn is strongly related with the genetic risk for depression. Search for gene variants associated with neuroticism and depression has led to some good candidates, but the consistency of findings is very far from ideal. Adverse life events are causal to development of mood disorders, and often the vulnerability genes can be detected only when environmental impact has been objectively assessed. Yet the continuity of depression diagnosis from early childhood to adulthood is limited, while childhood depression increases odds of other affect related disorders such as substance abuse and personality disorders. Whether specific genes have an impact seems to depend on the period of life both because of biological maturation and differences in major environmental factors, but also active engagement--or the failure to do so--of the vulnerable subjects with their environment. It is proposed that subjects with genetically determined neurotic tendencies are likely to attempt to select coping strategies that reduce events perceived as harmful and can by this means develop resilience towards affective disorders. PMID- 20206450 TI - Fetal androgen exposure and pragmatic language ability of girls in middle childhood: implications for the extreme male-brain theory of autism. AB - Prenatal exposure to testosterone has been shown to affect fetal brain maturation as well as postnatal cognition and behavior in animal studies. Although there are well-established sex-differences in the use of social communication (or 'pragmatic language') in humans, there has been limited investigation of the association between fetal testosterone exposure and postnatal pragmatic language ability. In this prospective study, pragmatic language skills, assessed using a pragmatic language score (PLS), were measured in 78 girls aged 10 years and correlated with testosterone levels in umbilical cord blood. A measure of the biologically active, 'free' fraction of testosterone, the free androgen index (FAI), was positively correlated with the PLS (R=.3). Regression analyses showed that the FAI was a significant, positive predictor of pragmatic language difficulties in girls after controlling for maternal and infant-health variables (B=0.02, 95% confidence interval=0.01-0.04, p=0.02). This is the first prospective study to identify an association between early life testosterone exposure and pragmatic language difficulties in girls. These novel findings are discussed with reference to the 'extreme male-brain' theory of autism. PMID- 20206451 TI - Evidence for greater cue reactivity among low-dependent vs. high-dependent smokers. AB - INTRODUCTION: Cue reactivity paradigms are well-established laboratory procedures used to examine subjective craving in response to substance-related cues. For smokers, the relationship between nicotine dependence and cue reactivity has not been clearly established. The main aim of the present study was to further examine this relationship. METHODS: Participants (N=90) were between the ages 18 40 and smoked > or =10 cigarettes per day. Average nicotine dependence (Fagerstrom Test for Nicotine Dependence; FTND) at baseline was 4.9 (SD=2.1). Participants completed four cue reactivity sessions consisting of two in vivo cues (smoking and neutral) and two affective imagery cues (stressful and relaxed), all counterbalanced. Craving in response to cues was assessed following each cue exposure using the Questionnaire of Smoking Urges-Brief (QSU-B). Differential cue reactivity was operationally defined as the difference in QSU scores between the smoking and neutral cues, and between the stressful and relaxed cues. RESULTS: Nicotine dependence was significantly and negatively associated with differential cue reactivity scores in regard to hedonic craving (QSU factor 1) for both in vivo and imagery cues, such that those who had low FTND scores demonstrated greater differential cue reactivity than those with higher FTND scores (beta=-.082; p=.037; beta=-.101; p=.023, respectively). Similar trends were found for the Total QSU and for negative reinforcement craving (QSU factor 2), but did not reach statistical significance. DISCUSSION: Under partially sated conditions, less dependent smokers may be more differentially cue reactive to smoking cues as compared to heavily dependent smokers. These findings offer methodological and interpretative implications for cue reactivity studies. PMID- 20206452 TI - Should the domestic buffalo (Bubalus bubalis) be considered in the epidemiology of Bovine Herpesvirus 1 infection? AB - Only limited information is available on the epidemiology and pathogenesis of Bovine Herpesvirus 1 (BoHV-1) in domestic buffalos. In this study, a virulent BoHV-1 field strain isolated from cattle was inoculated into buffaloes to evaluate their susceptibility to the virus and to investigate the establishment of viral latency through clinical, virological and serological investigations. Latency was also studied by attempting viral reactivation using pharmacological induction. Six of seven male, 5 months old buffaloes were intranasally inoculated with BoHV-1; the other animal was kept as negative control. The animals were clinically monitored during the post-infection (P.I.) and the post pharmacological induction (P.P.) periods. During these periods, nasal and rectal swabs, and blood samples, with and without anticoagulant, were collected at 2-3 day intervals. On culling the animals, 206 days P.I., their trigeminal ganglia and tonsils were collected. No clinical signs referable to BoHV-1 were observed throughout the experimental period. However, seropositivity was detected in all infected animals within day 20 P.I., using BoHV-1 glycoprotein E and glycoprotein B competitive ELISAs (IDEXX) and virus neutralisation test. In real-time PCR (RT PCR), five of these animals were positive, at least once, for nasal or rectal swabs, during the P.I. period. The sixth infected animal was found positive only in the trigeminal ganglia after culling. Ganglia were also positive for two other animals. Virus isolation in permissive cell-lines was successful for a part of the RT-PCR positive samples. The detected viruses were confirmed by genetic analysis as identical to the inoculated strain. No evidence of infection was observed in the negative control. This study represents the first experimental transmission of BoHV-1 in buffaloes, confirming their susceptibility to infection and their possible role as host/reservoirs of BoHV-1. PMID- 20206453 TI - A case of chronic otitis media caused by Mycobacterium abscessus. AB - Although it appears very uncommon in adult COM, Mycobacterium abscessus should be considered as a possible cause of a chronically draining ear. Multi-antibiotic chemotherapy including high-dose clarithromycin can effectively treat adult COM cased by M. abscessus. The first case report of adult chronic otitis media (COM) caused by M. abscessus is described here. A 61-year-old woman presented persistent otorrhea for 2 months, despite treatment with standard antimicrobial drugs. Physical examination revealed a small perforation of the tympanic membrane and edematous middle ear mucosa. Mycobacterial cultures and PCR yielded non tuberculous mycobacteria (NTM); M. abscessus. Intravenous panipenem/betamipron and amikacin and oral clarithromycin were administered for 36 days. Computed tomography of the temporal bone showed improved aeration in the tympanic cavity, but soft tissue shadow remained unchanged in the mastoid 31 days after starting medication. She therefore underwent tympano-mastoidectomy at 36 days. At surgery, inflammation remained in the middle ear, and edematous pale mucosal tissue was noted around the stapes and ossicular chain. Histopathologic examination showed inflammation and granulation tissue, but no caseating necrosis or acid-fast bacilli. After surgery the symptoms resolved and remained well without evidence of infection recurrence 12 months after the operation. PMID- 20206454 TI - PET/CT challenge for the non-invasive diagnosis of coronary artery disease. AB - This review will focus on the clinical potential of PET/CT for the characterization of cardiovascular diseases. We describe the technical challenges of combining instrumentation with very different imaging performance and discuss the clinical applications in the field of cardiology. PMID- 20206455 TI - Comparison of 16S rRNA gene phylogeny and functional tfdA gene distribution in thirty-one different 2,4-dichlorophenoxyacetic acid and 4-chloro-2 methylphenoxyacetic acid degraders. AB - 31 different bacterial strains isolated using the herbicide 2,4 dichlorophenoxyacetic acid (2,4-D) as the sole source of carbon, were investigated for their ability to mineralize 2,4-D and the related herbicide 4 chloro-2-methylphenoxyacetic acid (MCPA). Most of the strains mineralize 2,4-D considerably faster than MCPA. Three novel primer sets were developed enabling amplification of full-length coding sequences (CDS) of the three known tfdA gene classes known to be involved in phenoxy acid degradation. 16S rRNA genes were also sequenced; and in order to investigate possible linkage between tfdA gene classes and bacterial species, tfdA and 16S rRNA gene phylogeny was compared. Three distinctly different classes of tfdA genes were observed, with class I tfdA sequences further partitioned into the two sub-classes I-a and I-b based on more subtle differences. Comparison of phylogenies derived from 16S rRNA gene sequences and tfdA gene sequences revealed that most class II tfdA genes were encoded by Burkholderia sp., while class I-a, I-b and III genes were found in a more diverse array of bacteria. PMID- 20206456 TI - Efficacy of rosuvastatin among men and women with moderate chronic kidney disease and elevated high-sensitivity C-reactive protein: a secondary analysis from the JUPITER (Justification for the Use of Statins in Prevention-an Intervention Trial Evaluating Rosuvastatin) trial. AB - OBJECTIVES: We evaluated the efficacy of statin therapy in primary prevention among individuals with moderate chronic kidney disease (CKD). BACKGROUND: Whether patents with moderate CKD (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m(2)) benefit from statin therapy is uncertain, particularly among those without hyperlipidemia or known cardiovascular disease. METHODS: Within the JUPITER (Justification for the Use of statins in Prevention-an Intervention Trial Evaluating Rosuvastatin) primary prevention trial of rosuvastatin 20 mg compared with placebo among men and women free of cardiovascular disease who had low density lipoprotein cholesterol (LDL-C) <130 mg/dl and high-sensitivity C reactive protein (hsCRP) >or=2 mg/l, we performed a secondary analysis comparing cardiovascular and mortality outcomes among those with moderate CKD at study entry (n = 3,267) with those with baseline eGFR >or=60 ml/min/1.73 m(2) (n = 14,528). Median follow-up was 1.9 years (maximum 5 years). RESULTS: Compared with those with eGFR >or=60 ml/min/1.73 m(2), JUPITER participants with moderate CKD had higher vascular event rates (hazard ratio [HR]: 1.54, 95% confidence interval [CI]: 1.23 to 1.92, p = 0.0002). Among those with moderate CKD, rosuvastatin was associated with a 45% reduction in risk of myocardial infarction, stroke, hospital stay for unstable angina, arterial revascularization, or confirmed cardiovascular death (HR: 0.55, 95% CI: 0.38 to 0.82, p = 0.002) and a 44% reduction in all-cause mortality (HR: 0.56, 95% CI: 0.37 to 0.85, p = 0.005). Median LDL-C and hsCRP reductions as well as side effect profiles associated with rosuvastatin were similar among those with and without CKD. Median eGFR at 12 months was marginally improved among those allocated to rosuvastatin as compared with placebo. CONCLUSIONS: Rosuvastatin reduces first cardiovascular events and all-cause mortality among men and women with LDL-C <130 mg/dl, elevated hsCRP, and concomitant evidence of moderate CKD. (JUPITER-Crestor 20 mg Versus Placebo in Prevention of Cardiovascular [CV] Events; NCT00239681). PMID- 20206457 TI - Symptom complaints of patients prescribed either oral methadone or injectable heroin. AB - Many methadone patients and untreated heroin users have an ambivalent attitude toward methadone maintenance. This may be a result of the widespread belief that methadone produces various side effects not found with heroin. This study compared the symptom complaints of patients on oral methadone maintenance (MMT) with those of patients prescribed injectable heroin (IHT). A convenience sample of 117 (63 MMT, 54 IHT) patients was recruited from two maintenance clinics. With the use of a self-completion questionnaire, patients were interviewed about a range of symptoms they had experienced and which, in their view, were due to maintenance substance immediately after the last 10 opioid administrations, during the previous week and previous year. The complaints of the two groups overlapped considerably with only few significant differences; these appeared related to the route of administration. IHT patients reported a larger number of complications experienced immediately after administration than MMT patients (p = .007). From the patients' view, methadone does not produce many more or side effects very different from heroin and thus seems at least as tolerable as heroin for maintenance treatment. PMID- 20206458 TI - [Rhabdomyolysis and compartment syndrome of two forearms after robotic assisted prolonged surgery]. AB - Robotic assisted laparoscopic surgery allows for a more precise dissection than classical laparoscopic surgery. However, it sometimes imposes specific exaggerated postures and extralong procedure duration. Combining these two factors may increase the risk for postural complications in at-risk patients. We report the case of an obese 30-year-old female patient who underwent a 12-hour duration robotic laparoscopic surgery for severe endometriosis, in Trendelenburg position. This was complicated by a two forearms rhabdomyolysis, with subsequent compartment syndrome with multiple neuropathy. Physicians must be aware of the cumulative risk for postural complications when extreme positions are associated to long duration procedures in predisposed patients. PMID- 20206459 TI - [Forgetting guidewire during central venous catheterization]. PMID- 20206460 TI - [Arteriovenous malformations]. AB - Arteriovenous malformations are serious high-flow vascular malformations. Four progressive stages have been described: dormancy, expansion, destruction and heart failure. Progression from one stage to another is not systematic but depends on events - physiological or traumatic, sometimes iatrogenic. Pulsed Doppler imaging of venous waveforms and magnetic resonance imaging (MRI) are the most informative examinations for both diagnosis and follow-up of arteriovenous malformations.Arteriography and angio-MRI help guide treatment decisions. Treatment of the malformation must not be envisioned until it reaches a symptomatic stage. It most often combines an endovascular procedures and wide surgical excision. A syndromic form must be considered in cases of systemic angioma. PMID- 20206461 TI - Clinical trials on systemic necrotizing vasculitides. AB - Treatments of systemic necrotizing vasculitides have progressed markedly over the past few decades. The first attempts to obtain better-adapted therapeutic strategies evaluated the indications of conventional drugs, and their abilities to prolong survival and prevent relapses, while decreasing the severity and number of side effects. Most of the prospective clinical trials were organized by the French Vasculitis Study Group and the European Vasculitis Study Group, and have contributed to optimizing targeted treatment strategies. Recent therapeutic strategies include immunomodulating methods, like plasma exchanges, or products, like intravenous immunoglobulins, or, more recently, new agents called biotherapies. Some of the latter have achieved promising effects, for example, anti-tumor necrosis factor-alpha and anti-CD20 monoclonal antibodies, and are now being evaluated in prospective trials. PMID- 20206462 TI - [Classification of superficial vascular anomalies]. AB - All superficial vascular abnormalities are not angiomas even though this term continues - incorrectly - to be used. Because the suffix "oma" implies a tumor, it is necessary to differentiate true vascular tumors, such as infantile hemangioma, from vascular malformations. From a hemodynamic perspective, there are two types of vascular malformations: slow- and fast-flow. In addition to the functioning of the impaired or severely damaged vessels, we discuss slow-flow capillary, venous, or lymphatic malformations and rapid flow arterial and arteriovenous malformations. All combinations are possible. There are several types of childhood vascular tumors with different courses and different prognoses. Infantile hemangioma is by far the most frequent (8 to 10 children/100). The diverse other vascular tumors in children are sufficiently rare that they are described as orphan diseases. Since the end of the last century, a simple endothelial marker, GLUT-1, is available. This immunophenotype is present in all cases of infantile hemangioma at every stage and is negative in other tumors. Kasabach-Merritt syndrome and its accompanying severe thrombocytopenia never complicate childhood hemangioma, contrary to what has been said for nearly 60 years. When it is present, the tumor is either a tufted angioma or kaposiform hemangioendothelioma, and the GLUT1 marker can distinguish them from infantile hemangioma if the histologic diagnosis is uncertain (GLUT 1 is negative in both the latter cases). There are a wide variety of rare vascular tumors; many of them are benign, isolated, or limited; some are locally aggressive and recur after excision. A small number are low-grade malignant lesions with a risk of multivessel expansion, metastasis, and sometimes a fatal outcome. Major progress has been made in the imaging of these vascular abnormalities. Magnetic resonance imaging (MRI) in particular has revolutionized the non-invasive and especially the non-irradiating exploration of many of them. It provides information about the extent of the lesion and allows an etiological approach in many cases. Moreover, neuroradiologic evaluation of vascular cerebromeningeal lesions benefits not only from the now-standard diagnostic neurologic imaging methods of CT and MRI, but also from various advances in the techniques of functional imaging. Accordingly, for Sturge-Weber syndrome, functional imaging provides hope for an early prognosis, in particular cognitive, when these techniques are more widely used (SPECT, PET, especially the new advanced sequences of perfusion in MRI-DTI). Chronic - indeed lifelong - coagulation abnormalities, with phases of aggravation, occur in approximately half of the patients with venous malformations of the trunk and limbs, and more rarely in neck and face sites. This is not without consequences, but also not without therapeutic solutions: screening for it is therefore essential (measurement of dimer and fibrinogen levels). The discovery of gene mutations at the origin of some familial vascular malformations provides complementary data for the current classification of vascular abnormalities. It suggests that targeted therapy may be possible but probably not for quite a bit longer. PMID- 20206463 TI - The growing enthusiasm for transcranial magnetic stimulation (TMS). PMID- 20206464 TI - Torque measures of common therapies for the treatment of flexion contractures. AB - Efficacy of knee flexion contracture treatment protocols is dependent on the torque applied to the joint, but to date, no published reports have evaluated the torque applied by the available treatment options. The purpose of this study was to measure the torque applied by physical therapists (PTs), home exercises, and mechanical therapy devices. An instrumented test leg recorded peak torque applied by 14 PTs performing knee extension mobilization, 2 home exercises, and 3 types of mechanical therapy (dynamic splint, static progressive stretch, and patient actuated serial stretch). Physical therapists applied 68.0 N m, patient-actuated serial stretch mechanical therapy applied 53.0 N m, and the other therapies ranged between 4.6 and 12.4 N m. The reported torque values can be used to help improve the efficacy of flexion contracture treatment protocols. PMID- 20206465 TI - Intrapelvic displacement of a trial femoral head during total hip arthroplasty and a method to retrieve it. AB - We describe a technique to retrieve a dislodged femoral trial during total hip arthroplasty. During a revision total hip arthroplasty performed through a direct lateral approach, the femoral trial head was dislodged deep into the pelvis, superior and anterior to the hip joint and behind the anterior pelvic rim. This was retrieved via a posterior approach through the same incision by manipulating the trial head through the pelvis from the anterior to posterior direction. To our knowledge, this technique has not been described previously. PMID- 20206466 TI - Metal Ion release with large-diameter metal-on-metal hip arthroplasty. AB - Preoperative and postoperative ion concentrations were measured in 29 metal-on metal, large-diameter head total hip arthroplasty (LDH-THA) patients. Mean chromium, cobalt (Co), and titanium levels from LDH-THA were 1.3, 2.2, and 2.7 MUg/L at 12 months. The open femoral head design showed significantly higher Co concentrations than the closed design (3.0 vs 1.8 MUg/L, P = .037). Compared with previously published ion levels from a hip resurfacing system presenting the same bearing characteristics, Co levels were significantly higher in LDH-THA (2.2 vs 0.7 MUg/L, P < .001). This study has demonstrated that the addition of a sleeve with modular junctions and an open femoral head design of LDH-THA causes more Co release than bearing surface wear (157% and 67%, respectively). Even if no pathologic metal ion threshold level has been determined, efforts should be made to minimize its release. We recommend modification or abandonment of the modular junction and femoral head open design for this specific LDH-THA system. PMID- 20206467 TI - Human knee joint anatomy revisited: morphometry in the light of sex-specific total knee arthroplasty. AB - This study investigates differences in the anatomy of male and female knee joints to contribute to the current debate on sex-specific total knee implants. Morphometric data were obtained from 60 human cadaver knees, and sex differences were calculated. All data were corrected for height, and male and female specimens presenting with an identical length of the femur were analyzed as matched pairs. Male linear knee joint dimensions were significantly larger when compared with females. When corrected for differences in height, medial-lateral dimensions of male knees were significantly larger than female; however, matched paired analysis did not prove these differences to be consistent. Although implant design should focus interindividual variations in knee joint anatomy, our data do not support the concept of a female-specific implant design. PMID- 20206468 TI - Lateral and high-angle oblique radiographs of the pelvis aid in diagnosing pelvic discontinuity after total hip arthroplasty. AB - Diagnosis of a pelvic discontinuity before revision total hip arthroplasty is critical for adequate preoperative planning. The lateral view of the pelvis or high-angle oblique views can aid in visualizing the posterior column when hip hardware obscures the view on standard anteroposterior and Judet views of the pelvis. These views are easy to obtain and can provide valuable information when planning revision total hip arthroplasty. PMID- 20206469 TI - Repeat 2-stage revision for recurrent infection of total hip arthroplasty. AB - Eleven patients who developed reinfection after 2-stage revision for infected total hip arthroplasty (THA) were treated with a repeat 2-stage rerevision. Of the 11 rerevisions, 4 were successful, with no recurrent infection at mean follow up of 44 months. Reinfection occurred in 7 patients of whom 6 involved either a significantly compromised host or poor local wound status. Clinical symptoms of infection were controlled in 4 of the 7 reinfected cases with antibiotic therapy in 2, irrigation and debridement in 1, and a third 2-stage revision THA in 1. Repeat 2-stage treatment of infected THA is associated with a high failure rate. However, successful results can be achieved particularly if the host is not immunocompromised and healthy soft tissue coverage is present. PMID- 20206471 TI - Post-coma persons with motor and communication/consciousness impairments choose among environmental stimuli and request stimulus repetitions via assistive technology. AB - This study assessed whether a program based on microswitch and computer technology would enable three post-coma participants (adults) with motor and communication/consciousness impairments to choose among environmental stimuli and request their repetition whenever they so desired. Within each session, 16 stimuli (12 preferred and 4 non-preferred) were scheduled for the participants. For each stimulus, a computer system provided a sample of a 3-s duration. During the intervention, participants' responding (e.g., eye blinking and hand closure) in relation to a stimulus sample activated a microswitch and led the computer system to turn on that stimulus for 20 s. Participants' lack of responding led the computer system to pause briefly and then present the next scheduled stimulus sample. When participants responded immediately after (i.e., within 6s from) the end of a stimulus presentation, that stimulus was repeated. Intervention data showed response increases, which were very consistent for two participants and moderate for the third one. All participants asked for the repetition of preferred stimuli and showed minimal responding in relation to non-preferred stimuli. The results were discussed in light of their possible implications for new, person-centered rehabilitation programs for post-coma persons with multiple disabilities. PMID- 20206470 TI - Clinical characteristics of anxiety disordered youth. AB - Reports the characteristics of a large, representative sample of treatment seeking anxious youth (N=488). Participants, aged 7-17 years (mean 10.7 years), had a principal DSM-IV diagnosis of separation anxiety disorder (SAD), generalized anxiety disorder (GAD), or social phobia (SP). Although youth with a co-primary diagnosis for which a different disorder-specific treatment would be indicated (e.g., major depressive disorder, substance abuse) were not included, there were few other exclusion criteria. Participants and their parent/guardian underwent an extensive baseline assessment using a broad array of measures capturing diagnostic status, anxiety symptoms and severity, and areas of functional impairment. Means and standard deviations of the measures of psychopathology and data on diagnostic status are provided. The sample had moderate to severe anxiety disorder and was highly comorbid, with 55.3% of participants meeting criteria for at least one non-targeted DSM-IV disorder. Anxiety disorders in youth often do not present as a single/focused disorder: such disorders in youth overlap in symptoms and are highly comorbid among themselves. PMID- 20206472 TI - Psychopathology: differences among adults with intellectually disabled, comorbid autism spectrum disorders and epilepsy. AB - The goal of this study was to systematically examine group differences among adults with intellectual disabilities (ID), comorbid autism spectrum disorders (ASD), and epilepsy through a detailed exploration of the characteristics that these disorders present in the area of psychopathology. Previous studies indicating that individuals with ID have comorbid ASD and epilepsy tend to stop short of addressing these disorders' impact on the full range of psychosocial issues, particularly in adult samples. Assessment of psychopathology was made with the ASD-comorbidity-adult version (ASD-CA). One hundred participants, with ID held constant, were matched and compared across four equal groups comprising 25 participants with ID, 25 participants with epilepsy, 25 participants with ASD, and 25 participants with combined ASD and epilepsy. When controlling for age, gender, race, level of ID, and hearing and visual impairments, results of the MANOVA revealed significant differences among groups, Wilks's Lambda=.76, F(15, 254)=1.82, p<.05, eta(2)=.09. A one-way ANOVA was conducted for each of the five subscales of the ASD-CA as follow-up tests to the MANOVA. Groups differed significantly Anxiety/Repetitive Behavior subscale, F(3, 96)=2.93, p<.05, eta(2)=.08, Irritability/Behavior excess subscale, F(3, 96)=4.74, p<.01, eta(2)=.13, Attention/Hyperactivity subscale, F(3, 96)=5.18, p<.01, eta(2)=.14, and Depressive Symptoms subscale, F(3, 96)=3.73, p<.01, eta(2)=.10. Trend analysis demonstrated that individuals with ID expressing combined comorbid ASD and epilepsy were significantly more impaired than the control group (ID only) or groups containing only a single comorbid factor with ID (ASD or epilepsy only). Implications of these findings elucidate the nature of these disorders and their influence on patient care and management. PMID- 20206474 TI - Can parents predict obstructive sleep apnea in children with syndromic or complex craniosynostosis? AB - Obstructive sleep apnea (OSA) is a clinical syndrome characterized by snoring, apneas and difficulty in breathing. These symptoms can be rated and a risk score (Brouillette score) can be calculated to estimate the likelihood of OSA. This study aimed at establishing the predictive value of the Brouillette score and observation by parents at home in children with syndromic or complex craniosynostosis, compared with ambulatory polysomnography. This prospective study included 78 patients (37 boys, mean age 7.3 years). Sensitivity and negative predictive values were calculated. Polysomnography showed clinically significant OSA in 11 children. The Brouillette score had a negative predictive value of 90% and a sensitivity of 55% in comparison with polysomnography. More than three-quarters of all patients snored. The single question 'Is there difficulty with breathing during sleep?' showed a sensitivity of 64% and a high negative predictive value of 91%. Thus, asking parents whether the child has difficulty in breathing during sleep can exclude the presence of clinical significant OSA and avoid polysomnography in children with syndromic and complex craniosynostosis. PMID- 20206475 TI - Rate and predictors of service disengagement in an epidemiological first-episode psychosis cohort. AB - OBJECTIVES: To assess the prevalence and predictors of service disengagement in a treated epidemiological cohort of first-episode psychosis (FEP) patients. METHODS: The Early Psychosis Prevention and Intervention Centre (EPPIC) in Australia admitted 786 FEP patients from January 1998 to December 2000. Treatment at EPPIC is scheduled for 18 months. Data were collected from patients' files using a standardized questionnaire. Seven hundred four files were available; 44 were excluded, because of a non-psychotic diagnosis at endpoint (n=43) or missing data on service disengagement (n=1). Rate of service disengagement was the outcome of interest, as well as pre-treatment, baseline, and treatment predictors of service disengagement, which were examined via Cox proportional hazards models. RESULTS: 154 patients (23.3%) disengaged from service. A past forensic history (Hazard ratio [HR]=1.69; 95%CI 1.17-2.45), lower severity of illness at baseline (HR=0.59; 95%CI 0.48-0.72), living without family at discharge (HR=1.75; 95%CI 1.22-2.50) and persistence of substance use disorder during treatment (HR=2.30; 95%CI 1.45-3.66) were significant predictors of disengagement from service. CONCLUSIONS: While engagement strategies are a core element in the treatment of first-episode psychosis, particular attention should be paid to these factors associated with disengagement. Involvement of the family in the treatment process, and focusing on reduction of substance use, need to be pursued in early intervention services. PMID- 20206476 TI - Rapid induction of resistance to the fluoroquinolone enrofloxacin in Pseudomonas putida NCTC 10936. PMID- 20206477 TI - Macrolide-resistant Streptococcus pyogenes in Central Greece: prevalence; mechanism and molecular identification. PMID- 20206478 TI - Panton-Valentine leukocidin-producing Staphylococcus aureus necrotising pneumonia: measuring toxin levels in microbiological samples to attest of linezolid clinical efficacy. PMID- 20206479 TI - Detection of the first two Klebsiella pneumoniae isolates with sequence type 258 producing KPC-2 carbapenemase in Denmark. PMID- 20206480 TI - In vivo efficacy of the antimicrobial peptide ranalexin in combination with the endopeptidase lysostaphin against wound and systemic meticillin-resistant Staphylococcus aureus (MRSA) infections. AB - New treatments are urgently required for infections caused by meticillin resistant Staphylococcus aureus (MRSA) as these strains are often resistant to multiple conventional antibiotics. Earlier studies showed that ranalexin, an antimicrobial peptide (AMP), in combination with lysostaphin, an antistaphylococcal endopeptidase, synergistically inhibits the growth of MRSA, meaning that it deserved consideration as a new anti-S. aureus therapy. Using haemolysis and Vero cell viability assays, ranalexin with lysostaphin is proven to be non-toxic at antibacterial concentrations. In human serum, ranalexin with lysostaphin is significantly more effective against MRSA than treatment with either component alone. In a rabbit model of wound infection, ranalexin with lysostaphin reduced MRSA in the wound by ca. 3.5log(10) colony-forming units (CFU) compared with the untreated control. The combination is significantly more effective than treatment with ranalexin or lysostaphin alone. In a mouse model of systemic infection, ranalexin with lysostaphin reduced MRSA kidney burden by ca. 1log(10)CFU/g compared with untreated controls or treatment with ranalexin or lysostaphin alone. Importantly, the combination is synergistically bactericidal against various S. aureus isolates in vitro, including those with reduced susceptibility to lysostaphin or vancomycin. Ranalexin and lysostaphin could be incorporated in wound dressings for the prevention and treatment of topical S. aureus infections. That AMPs can enhance the antibacterial effectiveness of lysostaphin in vivo highlights a new avenue of research in the fight against drug resistant staphylococci. PMID- 20206481 TI - [Implementing palliative care for newborns in various care settings. Part 3 of "Palliative care in the neonatal period"]. AB - Palliative care in newborns may take place in the delivery room and then continued either in maternity wards or in the neonatal unit. For babies developing a chronic condition, going home may be advantageous. The population concerned includes babies born with a severe intractable congenital malformation and certain extremely preterm newborn babies at the limits of viability. Care procedures as well as withholding and withdrawing treatments are reviewed. PMID- 20206482 TI - [Palliative care in the neonatal period. Part one: general considerations]. AB - In France, the law dated 22 April 2005 required that all practitioners offer palliative care to patients as an alternative to unreasonable obstinacy. The practical development of palliative care during the neonatal period is not easy, even though obstetricians and neonatologists have always been aware of the ethical necessity of comfort in the dying newborn. The decision leading to palliative care begins with the recognition of patent or potential unreasonable obstinacy, followed by withdrawing treatment and technical support, and finally a palliative care plan is drawn up with the medical team and the parents. PMID- 20206483 TI - Excellent local control of paraganglioma in the head and neck with fractionated radiotherapy. AB - AIMS: Radiotherapy is an important treatment option for paraganglioma in the head and neck region. It seems to be highly effective and avoids important surgical morbidity, which can impair quality of life. The aim of this study was to evaluate the outcomes of radiotherapy for paraganglioma of the head and neck region in order to inform our future practice. MATERIALS AND METHODS: The cohort of patients for the present study comprised 21 patients who received radiotherapy between 1998 and 2008. Follow-up ranged from 6 to 132 months, median 55 months. The mean age was 48.7 years, range 20-78 years. The female:male ratio was 2 : 1. Two patients had confirmed familial tumour syndromes. The gross tumour volume in 20 cases ranged from 1.3 to 74 cm(3), mean 23.2 cm(3), median 14.7 cm(3). Five patients were treated with intensity-modulated radiotherapy. The median dose was 50 Gy in 30 fractions. RESULTS: The crude 5-year local control rate was 95% (20/21), although the 5-year actuarial local control rate was 87%. The one patient who relapsed, at 45 months after radiotherapy, had a comparatively small tumour of 10.8 cm(3). A relationship between tumour volume and local control seems unlikely. It was possible to obtain details of side-effects from electronic records for 11 patients. Grade 3 headache, which resolved, was the most serious acute side-effect. One patient had three teeth extracted due to exacerbation of dental caries, and one had deterioration of hearing thought to be due to a combination of tumour and radiotherapy. There were two serious complications in patients who had embolisation, which we no longer use. CONCLUSIONS: Our results show a high level of efficacy for fractionated external beam radiotherapy, with minimal toxicity, in keeping with other series. This should encourage the use of radiotherapy as primary treatment for paragangliomas of the head and neck region. PMID- 20206484 TI - Aquilegia vulgaris extract protects against the oxidative stress and the mutagenic effects of cadmium in Balb/c mice. AB - Cadmium (Cd) is a non-essential element and is a widespread environmental pollutant. Exposure to cadmium can result in cytotoxic, carcinogenic and mutagenic effects. The aim of the current work was to evaluate the protective effect of Aquilegia vulgaris extract against the oxidative stress and the genotoxicity induced by Cd using the chromosomal aberrations in somatic and germ cells assay and random amplified polymorphism DNA (RAPD-PCR) analysis. Forty male Balb/c mice were divided into four groups including the control group, Cd-treated group and the groups treated with the extract alone or plus Cd. The results indicated that Cd increased serum ALT, AST, urea, LDH, CK, lipid peroxidation in liver tissue accompanied with a significant decrease in GPX and SOD. Cd also increased the number of chromosomal aberrations in bone marrow and spermatocytes including structural and numerical aberrations. Animals treated with the extract alone were comparable to the control regarding all the tested parameters. The extract succeeded in preventing or diminishing the oxidative stress and the clastogenic effects of Cd. It could be concluded that Aquilegia vulgaris extract is a promising protective agent against oxidative stress and genotoxicity during the exposure to Cd. PMID- 20206485 TI - Elevated plasma fibrinogen caused by inadequate alpha-linolenic acid intake can be reduced by replacing fat with canola-type rapeseed oil. AB - The effects of canola-type rapeseed oil (RSO) on serum lipids, plasma fibrinogen, lipid oxidation and fatty acids were studied in three groups of subjects, two of which had not been consuming fish in their habitual diets. Forty-two volunteers (35 women, 7 men, 16-62 years) replaced fat with RSO for 6 weeks in a parallel design. The average cholesterol and fibrinogen concentrations were 5.0 mmol/l and 2.6 g/l, respectively. The intake of alpha-linolenic acid (alpha-LLA) was doubled. Efficient competitive inhibition by alpha-LLA was seen as a decrease in long-chain (LC) n-6 PUFA at 3 weeks. Elevated fibrinogen (2.6-3.9 g/l) decreased by 0.95 g/l at 6 weeks. Docosahexaenoic acid (22:6n-3) in plasma phospholipids increased at low fibrinogen levels only. The associations and changes in plasma C18 and LC PUFA followed the competitive and metabolic principles of the body, and especially in the case of n-3 PUFA according to the recycling pathway. PMID- 20206486 TI - Fatty acid transport across the cell membrane: regulation by fatty acid transporters. AB - Transport of long-chain fatty acids across the cell membrane has long been thought to occur by passive diffusion. However, in recent years there has been a fundamental shift in understanding, and it is now generally recognized that fatty acids cross the cell membrane via a protein-mediated mechanism. Membrane associated fatty acid-binding proteins ('fatty acid transporters') not only facilitate but also regulate cellular fatty acid uptake, for instance through their inducible rapid (and reversible) translocation from intracellular storage pools to the cell membrane. A number of fatty acid transporters have been identified, including CD36, plasma membrane-associated fatty acid-binding protein (FABP(pm)), and a family of fatty acid transport proteins (FATP1-6). Fatty acid transporters are also implicated in metabolic disease, such as insulin resistance and type-2 diabetes. In this report we briefly review current understanding of the mechanism of transmembrane fatty acid transport, and the function of fatty acid transporters in healthy cardiac and skeletal muscle, and in insulin resistance/type-2 diabetes. Fatty acid transporters hold promise as a future target to rectify lipid fluxes in the body and regain metabolic homeostasis. PMID- 20206487 TI - Lipid droplets in inflammation and cancer. AB - Accumulation of lipid droplets (also known as lipid bodies or adiposomes) within leukocytes, epithelial cells, hepatocytes and other non-adipocytic cells is a frequently observed phenotype in infectious, neoplastic and other inflammatory conditions. Lipid droplet biogenesis is a regulated cellular process that culminates in the compartmentalization of lipids and of an array of enzymes, protein kinases and other proteins, suggesting that lipid droplets are inducible organelles with roles in cell signaling, regulation of lipid metabolism, membrane trafficking and control of the synthesis and secretion of inflammatory mediators. Enzymes involved in eicosanoid synthesis are localized at lipid droplets and lipid droplets are sites for eicosanoid generation in cells during inflammation and cancer. In this review, we discuss the current evidence related to the biogenesis and function of lipid droplets in cell metabolism and signaling in inflammation and cancer. Moreover, the potential of lipid droplets as markers of disease and targets for novel anti-inflammatory and antineoplastic therapies will be discussed. PMID- 20206488 TI - Polyunsaturated docosahexaenoic acid suppresses oxidative stress induced endothelial cell calcium influx by altering lipid composition in membrane caveolar rafts. AB - OBJECTIVE: To determine whether DHA suppresses oxidative stress induced endothelial cell calcium influx by altering lipid composition and TRPC1 distribution in membrane rafts. METHODS: Endothelial cells (EC) were pretreated with DHA or stearic acid, then incubated for another 3h with media containing H(2)O(2). Membrane lipid rafts were isolated using the discontinuous sucrose density gradient ultracentrifugation method. Intracellular calcium was detected with laser scanning confocal microscope. TRPC1 protein in membrane fractions was detected by immunoblotting. Membrane fatty acids compositions were analyzed by gas chromatography; raft cholesterol level was assayed by an Amplex Red Cholesterol Assay kit, and DAG concentration was quantified by a DAG kinase assay. RESULTS: DHA significantly reduced oxidative stress induced calcium influx; pretreated with DHA the n-3 PUFAs were significantly increased in raft fractions, as well as saturated myristic acid, palmitic acid content of membrane rafts in EC; while the stearic acid, monounsaturated oleic acid and cis-oleic acid were decreased. Incubation with DHA also significantly reduced the amount of SM and cholesterol levels in the raft. Interestingly, we fractioned plasma membrane subcellular compartments and discovered that certain amounts of TRPC1 existed in detergent-resistant plasma membrane fractions of EC. After DHA treatment, TRPC1 was partly displaced from lipid raft to detergent-soluble membrane fractions. CONCLUSIONS: DHA significantly reduces oxidative stress induced endothelial calcium influx, this effect might be associated with, at least in part, altered raft lipid environment, and suppresses TRPC1-mediated calcium signaling pathway by partially displacing TRPC1 from membrane caveolar lipid rafts. PMID- 20206489 TI - Higher plasma n-3 fatty acid status in the moderately healthy elderly in southern Quebec: higher fish intake or aging-related change in n-3 fatty acid metabolism? AB - The elderly reportedly have a significantly higher % of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids in plasma and red cell lipids. However, these observations are from a few small studies and the health status of the elderly in these studies is for the most part unclear. Since the elderly are susceptible to cardiovascular and neurological illnesses that seem to be related in part to lower intake of n-3 fatty acids it seems paradoxical that their blood levels of EPA and DHA would be higher than in young adults. We report here plasma fatty acid profiles and their response to supplementation with two types of fish oils from several of our recent studies in the moderately healthy elderly. We define the moderately healthy elderly as those who were in good physical condition, had no cognitive decline and, if present, in whom hypothyroidism, hyperlipidemia and/or hypertension were well-controlled. As shown previously, we confirm the higher % EPA and % total n-3 fatty acids (but not DHA) in fasting plasma and extend these findings to include higher plasma concentrations (mg/L) of n-3 fatty acids as well. The EPA-predominant supplement raised DHA only in the young, whereas the DHA-predominant supplement raised EPA more in the young than in the elderly. The moderately healthy elderly clearly have higher plasma n-3 fatty acids but whether this reflects differences in intake versus aging-related changes in n-3 fatty acid metabolism remains to be elucidated. PMID- 20206490 TI - Unsaturated fatty acids as cytoprotective agents in the pancreatic beta-cell. AB - It is widely accepted that, in type 2 diabetes, elevated levels of free fatty acids and glucose contribute to a state of glucolipotoxicity in which beta-cell function declines and, ultimately, cell viability is compromised. This suggests that beta-cells do not readily tolerate chronic elevations in fatty acid levels. In vitro studies suggest, however, that beta-cells respond differentially to long chain fatty acids, such that saturated species are lipotoxic whereas long chain mono-unsaturated fatty acids can provide cytoprotection. This difference does not appear to be mediated by a mutual metabolic antagonism between saturated and unsaturated species (although differential alterations in neutral lipid disposition may occur in response to these fatty acids) and the mechanisms remain unclear. This review summaries the current understanding of the actions of mono unsaturated fatty acids in beta-cells and highlights areas of controversy as well as key unresolved issues which require to be addressed. PMID- 20206491 TI - Technological change in Swiss thermal waste treatment: an expert-based socio technical analysis. AB - Understanding technological change provides a crucial basis for governing sustainability transitions. In this paper we present an analysis of technological change using the example of Swiss thermal waste processing. In recent years, increased concerns about the low quality of residues from grate-firing systems led to the examination of alternative technologies. Yet despite clear indications of a potential better performance with respect to residue quality, none of these alternatives has been adopted. Based on a two-stage knowledge integration among 15 leading experts, in a retrospective analysis we identified factors that have significantly affected technological change in Swiss thermal waste processing. These factors were then related to three technological options representing different types of technological change, i.e., from incremental improvements of the existing to the implementation of a new technology. The results indicate that technological change is currently in a technological lock-in and provide detailed insights on the causes. The lock-in results in the step-wise further development of the status quo grate-firing system despite its limitations for improving the residue qualities. Almost all factors (legal, economic, societal, technological) of the existing 'thermal waste management' system have been well adapted to the cost- and energy-efficient grate-firing technology, blocking innovative technologies from entering the Swiss market. In addition, pressures from the context, e.g., societal pressure related to landfill risks, have not been strong enough to promote non-incremental change. PMID- 20206493 TI - Effects of composing on sorption capacity of bagasse-based chars. AB - A fresh bagasse sample (0-month) and two composted bagasse and pig manure mixed samples (1-month and 6-month) were used to produce carbon chars. Sample pyrolysis showed greater carbon char yields were obtained from the compost samples than from the bagasse sample. Fourier transform infrared spectra suggested that the chemical structures of the bagasse sample and the two compost samples were quite different, but that the three carbon chars obtained from those precursors were similar. Among the three pyrolyzed chars, the 0-month bagasse char displayed the largest sorption capacity of 3333 mg kg(-1) for the hydrophilic pollutant phenol, presumably resulting from its greater carbon content and O/C ratio. However, the sorption capacities for the hydrophobic pollutant naphthalene of the tow compost chars (3-month, 2001 mg kg(-1); 6-month, 1667 mg kg(-1)) were greater than that of the 0-month bagasse char (1428 mg kg(-1)). The results indicate that the compost chars had a greater preferential affinity for naphthalene than that in the bagasse char, suggesting that the compost chars possessed greater hydrophobicity. PMID- 20206494 TI - A disposable microfluidic biochip with on-chip molecularly imprinted biosensors for optical detection of anesthetic propofol. AB - This paper presents a disposable microfluidic biochip with on-chip molecularly imprinted biosensors for optical detection of anesthetic propofol. So far, the methods to detect anesthetic propofol in hospitals are liquid chromatography (LC), high-performance liquid chromatography (HPLC), and gas chromatography-mass spectroscopy (GC-MS). These conventional instruments are bulky, expensive, and not ease of access. In this work, a novel plastic microfluidic biochip with on chip anesthetic biosensor has been developed and characterized for rapid detection of anesthetic propofol. The template-molecule imprinted polymers were integrated into microfluidic biochips to be used for detecting anesthetic propofol optically at 655 nm wavelength after the reaction of propofol with color reagent. Experimental results show that the sensitivity of the microfluidic biochip with on-chip molecularly imprinted polymers (MIPs) biosensor is 6.47 mV/(ppm mm(2)). The specific binding of MIP to non-imprinted polymer (NIP) is up to 456%. And the detection limit of the microsystem is 0.25 ppm with a linear detection range from 0.25 to 10 ppm. The disposable microfluidic biochip with on chip anesthetic biosensor using molecularly imprinted polymers presented in this work showed excellent performance in separation and sensing of anesthetic propofol molecules. While compared to large-scale conventional instruments, the developed microfluidic biochips with on-chip MIP biosensors have the advantages of compact size, high sensitivity, high selectivity, low cost, and fast response. PMID- 20206495 TI - Flow cytometry for bacteria: enabling metabolic engineering, synthetic biology and the elucidation of complex phenotypes. AB - Flow cytometry (FC) and FC-based cell sorting have been established as critical tools in modern cell and developmental biology. Yet, their applications in bacteria, especially in the multiparametric mode, remain limited. We argue that FC technologies have the potential to greatly accelerate the analysis and development of microbial complex phenotypes through applications of metabolic engineering, synthetic biology, and evolutionary engineering. We demonstrate the importance of FC for elucidating population heterogeneity because of developmental processes or epigenetic regulation. FC can be engaged for both synthetic and analytical applications of complex phenotypes within a single species, multispecies, and microbial-library populations. Examples include methods to identify developmental microbial stages associated with productive metabolic phenotypes, select desirable promoters from a single species or metagenomic libraries, and to screen designer riboswitches for synthetic-biology applications. PMID- 20206496 TI - Building centromeres: home sweet home or a nomadic existence? AB - Centromere assembly and propagation is governed by genetic and epigenetic mechanisms. A centromere-specific histone H3 variant, CENP-A is strongly favored as the epigenetic mark that specifies centromere identity. Despite the critical importance of centromere function, centromeric sequences are not conserved. This has prompted exploration of other genomic and chromatin features to gain an understanding of where CENP-A is deposited. In this review we highlight recent papers that advance our understanding of how the cell builds a centromere. We focus on what influences the choice of site for CENP-A deposition and therefore the site of centromere formation. We then briefly discuss how centromeres are propagated once the site of centromere assembly is chosen. PMID- 20206497 TI - How do you (estimate you will) like them apples? Integration as a defining trait of orbitofrontal function. AB - The past 15 years have seen a rapid increase in our understanding of orbitofrontal function. Today this region is the focus of an enormous amount of research, including work on such complex phenomena as regret, ambiguity, and willingness to pay. The orbitofrontal cortex is also credited as a major player in a host of neuropsychiatric diseases. This transformation arguably began with the application of concepts derived from animal learning theory. We will review data from studies emphasizing these approaches to argue that the orbitofrontal cortex forms a crucial part of a network of structures that signals information about expected outcomes. Further we will suggest that, within this network, the orbitofrontal cortex provides the critical ability to integrate information in real-time to make what amounts to actionable predictions or estimates about future outcomes. As we will show, the influence of these estimates can be demonstrated experimentally in appropriate behavioral settings, and their operation can also readily explain the role of orbitofrontal cortex in much more complex phenomena such as those cited above. PMID- 20206498 TI - Oxidative stress-induced antioxidant enzyme expression is an early phenomenon in ovarian carcinogenesis. AB - Oxidative stress and antioxidant enzymes have been widely investigated in various carcinomas. However, there is only some information about their role in ovarian carcinogenesis or in ovarian carcinomas in vivo. We studied immunohistochemical nuclear and/or cytoplasmic expression of oxidative stress markers 8 hydroxydeoxyguanosine (8-OHdG) and nitrotyrosine, as well as major antioxidative enzymes peroxiredoxins (PRDX) I-VI and thioredoxin (TXN) in ovarian tumours. The material consisted of 20 benign (10 serous, 10 mucinous) and 51 borderline (33 serous, 18 mucinous) epithelial ovarian tumours. The markers of oxidative stress, 8-OHdG and nitrotyrosine, were seen already in benign tumours (in 20% and 45% of the tumours, respectively) and their expression patterns were similar in benign and borderline tumours. The levels of PRDX II, III, IV, V and VI were significantly higher in borderline than in benign tumours (p<0.02 for all). Specifically for PRDX II (for both nuclear and cytoplasmic expression, p<0.00005) and PRDX VI (for cytoplasmic expression, p=0.0003 and for nuclear expression, p=0.0005) the difference between benign and borderline tumours was remarkable. In general, serous benign and borderline tumours expressed higher antioxidant enzyme levels than mucinous ones. Nuclear TXN was expressed more strongly in benign than in borderline tumours (p=0.003). Oxidative stress occurs already in benign ovarian tumours and the levels are comparable to borderline tumours. However, some of the antioxidant enzymes, especially PRDX II and VI, are more profoundly induced in borderline ovarian tumours, reflecting their possible role as cancer preventers. This difference could also offer a potential tool for differential diagnosis between benign and borderline epithelial ovarian tumours. PMID- 20206499 TI - Glycoside hydrolase family 9 processive endoglucanase from Clostridium phytofermentans: heterologous expression, characterization, and synergy with family 48 cellobiohydrolase. AB - The glycoside hydrolase family 9 cellulase (Cel9) from Clostridium phytofermentans has a multi-modular structure and is essential for cellulose hydrolysis. In order to facilitate production and purification of Cel9, recombinant Cel9 was functionally expressed in Escherichia coli. Cel9 exhibited maximum activity at pH 6.5 and 65 degrees C on carboxymethyl cellulose in a 10 min reaction period. The hydrolysis products on regenerated amorphous cellulose (RAC) were cellotetraose (a major product), cellotriose, cellobiose and glucose, and 71-80% of the reducing sugars produced by Cel9 were in soluble form, suggesting that Cel9 was a processive endoglucanase. The highest synergy between C. phytofermentans Cel9 and C. phytofermentans cellobiohydrolase Cel48 on Avicel was about 1.8 at a ratio of about 1:5. Cel9 alone was sufficient to solublize filter paper while Cel48 was not; however, it enhanced the solublization process along with Cel9 synergistically. This study provided useful information for understanding of the cellulose hydrolysis mechanism of this cellulolytic bacterium with potential industrial importance. PMID- 20206500 TI - Effect of phenol addition on COD and nitrate removal in an anoxic suspension reactor. AB - In this study, a denitrifying culture was enriched in a continuously re circulated anoxic suspension reactor fed with glucose and nitrate for about 8 months (stage I) under different organic loading rates (OLR). At the end of stage I, the removal efficiency for NO(3)(-)-N was 80% with 93% COD (5 g/l) removal at an OLR of 2.5 g/ld. The mean COD/N removal ratio during the whole enrichment was 3.3. The response to phenol as a toxic substance on glucose enriched culture for long time period was investigated by introducing phenol as a co-substrate in the reactor feed in stage II. Phenol was increased gradually to 753 mg/l till termination of the reactor operation. After increasing the OLR or the phenol concentration, fluctuations in removal efficiencies were observed which were partly reversible. At the end of the reactor operation, NO(3)(-)-N removal was 65% with 81% COD removal at a phenol degradation rate of 207 mg/ld phenol. The OLR of the reactor was 4.3g/ld COD and a hydraulic retention time (HRT) of 1 day. Phenol degradation in batch assays under anoxic conditions and at low phenol concentrations (188 mg/l) proceeded a removal rate of 1.2g/l which decreased to 0.67 mg/ld at high phenol concentration (847 mg/l). PMID- 20206501 TI - An attempt towards simultaneous biobased solvent based extraction of proteins and enzymatic saccharification of cellulosic materials from distiller's grains and solubles. AB - Distiller's grains and solubles (DGS) is the major co-product of corn dry mill ethanol production, and is composed of 30% protein and 30-40% polysaccharides. We report a strategy for simultaneous extraction of protein with food-grade biobased solvents (ethyl lactate, d-limonene, and distilled methyl esters) and enzymatic saccharification of glucan in DGS. This approach would produce a high-value animal feed while simultaneously producing additional sugars for ethanol production. Preliminary experiments on protein extraction resulted in recovery of 15-45% of the protein, with hydrophobic biobased solvents obtaining the best results. The integrated hydrolysis and extraction experiments showed that biobased solvent addition did not inhibit hydrolysis of the cellulose. However, only 25-33% of the total protein was extracted from DGS, and the extracted protein largely resided in the aqueous phase, not the solvent phase. We hypothesize that the hydrophobic solvent could not access the proteins surrounded by the aqueous phase inside the fibrous structure of DGS due to poor mass transfer. Further process improvements are needed to overcome this obstacle. PMID- 20206502 TI - Harvesting algal biomass for biofuels using ultrafiltration membranes. AB - The objective of this paper is to develop efficient technologies for harvesting of algal biomass using membrane filtration. Foulants were characterized using scanning electron microscopy (SEM) and Fourier transform infrared (FTIR) spectroscopy. Anti-fouling strategies were established, such as using air assisted backwash with air scouring, and optimizing operational conditions. A model was also developed to predict the flux decline and final concentration based on a resistance-in-series analysis and a cake development calculation. The results showed that the buildup of the algal cake layer and adsorption of algogenic organic matter (AOM) (mainly protein, polysaccharides or polysaccharide like substances) on the membrane caused membrane fouling. The cake layer buildup was removed by conducting an air-assisted backwash every 15 min. The adsorbed AOM could be removed by soaking the membrane in 400mg/L NaClO for 1h. In our experiment the algal suspension was concentrated 150 times, to give a final cell concentration of 154.85g/L. The harvesting efficiency and average flux were 46.01 g/(m(2)h) and 45.50 L/(m(2)h), respectively. No algae were found in the permeate, which had an average turbidity of 0.018 Nephelometric Turbidity Units (NTU). The flux decline predicted by the model under different conditions was consistent with the experimental results. PMID- 20206503 TI - Evaluating inhibition conditions in high-solids anaerobic digestion of organic fraction of municipal solid waste. AB - High-solids anaerobic digestion (HSAD) processes, when applied to different types of organic fractions of municipal solid waste (OFMSW), may easily be subjected to inhibition due to organic overloading. In this study, a new approach for predicting these phenomena was proposed based on the estimation of the putrescibility (oxygen consumption in 20 h biodegradation, OD(20)) of the organic mixtures undergoing the HSAD process. Different wastes exhibiting different putrescibility were subjected to lab-scale batch-HSAD. Measuring the organic loading (OL) as volatile solids (VS) was found unsuitable for predicting overload inhibition, because similar VS contents corresponded to both inhibited and successful trials. Instead, the OL calculated as OD(20) was a very good indicator of the inhibiting conditions (inhibition started for OD(20)>17-18 g O(2)kg(-1)). This new method of predicting inhibition in the HSAD process of diverse OFMSW may be useful for developing a correct approach to the technology in very different contexts. PMID- 20206504 TI - Encapsulating benzoquinone and glucose oxidase with a PEDOT film: application to oxygen-independent glucose sensors and glucose/O2 biofuel cells. AB - A modified electrode was proposed based on the sequential coating to immobilize both p-benzoquinone (BZQ) and glucose oxidase (GOD). Three electrodes, A, B, and C, were prepared separately by drop-coating the BZQ solution dissolved in different solvents on the stainless-steel/carbon (ssteel/C). Among those three electrodes, electrode B shows the best sensitivity of 2.21mAM(-1)cm(-2), a linear concentration range of 1.1-15 mM and a response time of 100 s at a sensing potential of 0.3V. The responses of interferences, including ascorbic acid, dopamine, uric acid and acetaminophen, were approximately 0%, 1.4%, approximately 0% and 3%, respectively, taken the sensing current at 6.0mM glucose as 100%. In a test of the human blood sample, an error of +3.6% was noticed for electrode B. Besides, for the biofuel cell application, maximum power densities reached 18.9 and 22.5 microW/cm(2) at 25 and 37 degrees C, respectively, with an all-solution type biocathode. PMID- 20206505 TI - Techno-economic analysis of lignocellulosic ethanol: A review. AB - Lignocellulosic ethanol is expected to be commercialised during the next decade as renewable energy for transport. Competiveness with first generation bioethanol and with gasoline is commonly considered in techno-economic analyses for commercial stage. Several existing reviews conclude about the high spread of current and projected production costs of lignocellulosic ethanol due to the significant differences in assumptions concerning the following factors: composition and cost of feedstock, process design, conversion efficiency, valorisation of co-products, and energy conservation. Focusing on the studies in the United States of America and in Europe, the present review investigates the different natures of the techno-economic evaluations during the development process of the supply chain i.e., standard costing with respect to Value Engineering, and Target Costing based on the projected market price. The paper highlights the significant contribution of feedstock to the lignocellulosic ethanol production cost and the need to consider competition between different uses for resources. It is recommended the use of a value-based approach that considers sustainability characteristics and potential competition for resources complementarily to Target Costing and Value Engineering. PMID- 20206506 TI - Pretreatment by ultra-high pressure explosion with homogenizer facilitates cellulase digestion of sugarcane bagasses. AB - Sugarcane bagasse was treated with ultra-high pressure explosion (UHPE) in a homogenizer. UHPE significantly decreased the particle size and disrupt the microstructure of bagasse, which was changed from a rigid and highly ordered fibril to a distorted, poly-porous and "empty-inside" structure. UHPE decreased the crystallinity indexes (CrIs) from 54.8% (0 MPa) to 45.3% (100 MPa), and increased the accessible surface area (ASA) of bagasse nearly 3-fold. The effect of UHPE on composition was minor, only decreased the lignin slightly. However, UHPE increased enzymatic digestibility substantially from 29.5% (0 MPa) to 59.4% (100 MPa), and the microstructure disruption and thereby ASA increase were found to be the major factors to enhance the digestibility. UHPE combination with treatment of 0.5% NaOH at 125 degrees C for 120 min exhibited a significant delignification and increased enzymatic digestibility to 95.5% with 5.8 FPU cellulase/g solid, implying that UHPE combined with alkaline pretreatment can be a potential alternative for biomass pretreatment in biofuel production. PMID- 20206507 TI - Fabrication and properties of transparent polymethylmethacrylate/cellulose nanocrystals composites. AB - Nano-sized cellulose crystals were fabricated from microcrystalline cellulose (MCC) using combined sulfuric acid hydrolysis and high-pressure homogenization techniques. The crystals were then utilized to prepare polymethylmethacrylate (PMMA) nanocomposites by the solution casting method. The cellulose nanocrystals had diameters from about 8 to 10nm and lengths in the range of 60-120 nm. Wide angle X-ray diffraction (WXRD) results on the freeze-dried crystals revealed a slight increase in the degree of crystallinity after acid treatment. The composite sheets retained good transparency due to the size effect and dispersion of the cellulose nanocrystals. The thermogravimetric analysis indicated retained thermal stability of the composites. The storage modulus of the nanocomposite sheets from dynamic mechanical analysis showed significantly enhanced property in comparison with that of the pure PMMA sheets. The glass transition of the nanocomposites was shifted to lower temperatures with respect to the pure PMMA material. PMID- 20206508 TI - Biofuel production from catalytic cracking of woody oils. AB - The catalytic cracking reactions of several kinds of woody oils have been studied. The products were analyzed by GC-MS and FTIR and show the formation of olefins, paraffins and carboxylic acids. Several kinds of catalysts were compared. It was found that the fraction distribution of product was modified by using base catalysts such as CaO. The products from woody oils showed good cold flow properties compared with diesel used in China. The results presented in this work have shown that the catalytic cracking of woody oils generates fuels that have physical and chemical properties comparable to those specified for petroleum based fuels. PMID- 20206509 TI - Properties of dairy-manure-derived biochar pertinent to its potential use in remediation. AB - Conversion of waste products into biochar (BC) is being considered as one of several waste disposal and recycling options. In this study, we produced BC from dairy manures by heating at low temperatures (500 degrees C) and under abundant air condition. The resultant BC was characterized for physical, chemical, and mineralogical properties specifically related to its potential use in remediation. The BC from all manures behaved similarly. Surface area, ash content, and pH of the BC increased as temperature increased, while yield decreased with increasing temperature. The BC was rich in mineral elements such as N, Ca, Mg, and P in addition to C, and concentrations of C and N decreased with increasing temperature as a result of combustion and volatilization; while P, Ca, and Mg increased as temperature increased. For example, C significantly decreased from 36.8% at 100 degrees C to 1.67% at 500 degrees C; whereas P increased from 0.91% to 2.66%. Water soluble P, Ca, and Mg increased when heated to 200 degrees C but decreased at higher temperatures likely due to increased crystallization of Ca-Mg-P, as supported by the formation of whitlockite (Ca,Mg)(3)(PO(4))(2) following 500 degrees C treatment. The presence of whitlockite was evidenced by X-ray diffraction analysis. Quartz and calcite were present in all BC produced. The BC showed appreciable capability of adsorption for Pb and atrazine from aqueous solution, with Pb and atrazine removal by as high as 100% and 77%, respectively. The results indicated that dairy manure can be converted into biochar as an effective adsorbent for application in environmental remediation. PMID- 20206510 TI - Assessment of toxicity of tetrahydrofuran on the microbial community in activated sludge. AB - Activated sludge is widely used to treat industrial wastewater, but its efficiency is affected by a variety of factors, including toxic substances such as tetrahydrofuran (THF). In this study, we examined the toxicity of THF at different concentrations (0-320 mM) on the microbial community in activated sludge. A remarkable dose-dependent decrease in the total organic compound removal rate and culturable bacteria and fungi was observed. At THF concentrations higher than 160 mM, a decrease in pH to 3.0 was observed. The activities of five enzymes (catalase, dehydrogenase, urease, phosphatase and protease) analyzed were all significantly inhibited (p<0.01) at THF concentrations higher than 160 mM, especially dehydrogenase activity, which lost 95.4% of its activity at 320 mM THF. Microbial community analysis by PCR-DGGE revealed a substantial shift in the community structure and a reduction in diversity at a low THF concentration (20mM). These results suggest that THF is much more toxic than reported in the literature, indicating its acute toxicity to microorganisms. PMID- 20206511 TI - Effect of leachate injection modes on municipal solid waste degradation in anaerobic bioreactor. AB - Three pilots simulated landfill bioreactors were used to investigate the effect of leachate injection modes on anaerobic digestion and biogas production from municipal solid waste. The technical modes used to increase waste moisture consisted of an initial saturation of the waste by flushing with leachate followed by a quick drainage, or weekly leachate injections with two different rates. The results confirmed that increasing moisture content is a key parameter to boost the biological reactions. Weekly leachate injection with high flow rate led to better results than the initial saturation of the waste in terms of biogas production kinetics. Water percolation was found to be an important factor to accelerate the degradation of solid waste. However, a modelling of the collected data by Gompertz model clearly showed that the intrinsic biogas potential determined on the initial solid waste was not reached with any of the progressive leachate injection modes. PMID- 20206512 TI - Performance comparison of two photobioreactors configurations (open and closed to the atmosphere) treating anaerobically degraded swine slurry. AB - The purpose of the study was comparison of two configurations of photobioreactors an open-type photobioreactor open to atmosphere and a tubular type photobioreactor closed to the atmosphere. Organic matter was fairly removed under both configurations at 50-60% and biomass carbon content on dry weight basis accounted for 45%. Both configurations were able to completely exhaust ammonium, however different mechanism removals were responsible for the different influent loads applied. In terms of nitrogen recovery by biomass assimilation, the open configuration ranged 38-47% whereas the closed type presented 31%. It is worth to mention that nitrification-denitrification was taking place under both photobioreactor configurations. Approximately 80% phosphate removal was achieved regardless the configuration and biomass P content was slightly higher in the closed-type reactor. For nutrient recycling, biomass harvesting is described as the key issue of this technology. Nevertheless, the closed configuration highlighted the great potential of the biofilm formation by retaining 96% of the total biomass produced. PMID- 20206513 TI - Design and optimization of a substituted amino propanamide series of renin inhibitors for the treatment of hypertension. AB - The discovery and SAR of a new series of substituted amino propanamide renin inhibitors are herein described. This work has led to the preparation of compounds with in vitro and in vivo profiles suitable for further development. Specifically, challenges pertaining to oral bioavailability, covalent binding and time-dependent CYP 3A4 inhibition were overcome thereby culminating in the identification of compound 50 as an optimized renin inhibitor with good efficacy in the hypertensive double-transgenic rat model. PMID- 20206514 TI - A reverse transcriptase stop assay revealed diverse quadruplex formations in UTRs in mRNA. AB - Here, we developed a reverse transcriptase based method (RTase stop assay) to characterize quadruplex formations in guanine-rich RNAs with high sensitivity and specificity. By using the RTase stop assay, we also revealed a plausible structural polymorphism in biologically important RNAs. The RTase stop assay would provide helpful insight into RNA quadruplex structures and functions, together with other analytical methods, including various footprinting techniques. PMID- 20206515 TI - Stepwise synthesis of oligonucleotide-peptide conjugates containing guanidinium and lipophilic groups in their 3'-termini. AB - Two different series of oligonucleotide-peptide conjugates have been efficiently synthesized by stepwise solid-phase synthesis. First, oligonucleotides and oligonucleotide phosphorothioates containing polar groups at the 3'-termini, such as amine and guanidinium groups were prepared. ODNs conjugates carrying several lysine residues were obtained directly from Fmoc deprotection whereas ODN conjugates with guanidinium groups were obtained by post-synthetic guanidinylation. The second family contains different urea moieties that were achieved by standard protocols. All products were fully characterized by reversed phase HPLC and MALDI-TOF mass spectrometry yielding satisfactory results. Oligonucleotide-phosphorothioate conjugates were evaluated as potential antisense oligonucleotides in the inhibition of the luciferase gene. PMID- 20206516 TI - Discovery of sulfonamide-pyrazole gamma-secretase inhibitors. AB - Utilizing a pharmacophore hypothesis, previously described gamma-secretase inhibiting HTS hits were evolved into novel tricyclic sulfonamide-pyrazoles, with high in vitro potency, good brain penetration, low metabolic stability, and high clearance. PMID- 20206517 TI - Comparison of the antiplasmodial and falcipain-2 inhibitory activity of beta amino alcohol thiolactone-chalcone and isatin-chalcone hybrids. AB - The synthesis and biological evaluation of two novel series of natural-product like hybrids based on the chalcone, thiolactone and isatin scaffolds is herein described. Results for a 36-member beta-amino alcohol triazole library showed that the thiolactone-chalcones, with IC(50)s ranging from 0.68 to 6.08 microM, were more active against W2 strain Plasmodium falciparum than the isatin chalcones with IC(50)s of 14.9 microM or less. Also of interest is falcipain-2 inhibitory activity displayed by the latter, whereas the thiolactone-chalcones lacked enzyme inhibitory activity. PMID- 20206518 TI - Best practice in Duchenne muscular dystrophy. PMID- 20206519 TI - Best practice in Duchenne muscular dystrophy. PMID- 20206520 TI - Best practice in Duchenne muscular dystrophy. PMID- 20206521 TI - Best practice in Duchenne muscular dystrophy. PMID- 20206522 TI - Best practice in Duchenne muscular dystrophy. PMID- 20206523 TI - Best practice in Duchenne muscular dystrophy. PMID- 20206525 TI - Complexity increases working memory for mating signals. AB - Females often prefer to mate with males who produce complex signals. It is not clear why they do so. Females might prefer complexity if it predicts mate quality, or signals might evolve complexity to exploit females' sensory or cognitive biases. We tested whether complexity increases active time, the period over which a signal influences a receiver's response to that signal. Mating signals are often ephemeral, yet their active time has largely been ignored. Here we demonstrate that signal complexity influences active time in tungara frogs. Male advertisement calls consist of frequency sweeps (whines) followed by 0-7 high-frequency bursts (chucks). Females preferentially approach complex (whines with chucks) over simple (whines alone) calls but do not consistently prefer greater complexity, so the function of multiple chucks has been uncertain. We found that females remember which speaker previously broadcast complex calls when choosing between simple calls broadcast after a delay. This effect occurred for calls with multiple chucks, but not with single chucks. Neither motivation nor orientation behavior differed with chuck number, suggesting that results are due to differential memory. Thus, female memory could favor the evolution of increasing signal complexity through sexual selection. PMID- 20206526 TI - Functional diversity of Robo receptor immunoglobulin domains promotes distinct axon guidance decisions. AB - Recognition molecules of the immunoglobulin (Ig) superfamily control axon guidance in the developing nervous system. Ig-like domains are among the most widely represented protein domains in the human genome, and the number of Ig superfamily proteins is strongly correlated with cellular complexity. In Drosophila, three Roundabout (Robo) Ig superfamily receptors respond to their common Slit ligand to regulate axon guidance at the midline: Robo and Robo2 mediate midline repulsion, Robo2 and Robo3 control longitudinal pathway selection, and Robo2 can promote midline crossing. How these closely related receptors mediate distinct guidance functions is not understood. We report that the differential functions of Robo2 and Robo3 are specified by their ectodomains and do not reflect differences in cytoplasmic signaling. Functional modularity of Robo2's ectodomain facilitates multiple guidance decisions: Ig1 and Ig3 of Robo2 confer lateral positioning activity, whereas Ig2 confers promidline crossing activity. Robo2's distinct functions are not dependent on greater Slit affinity but are instead due in part to differences in multimerization and receptor-ligand stoichiometry conferred by Robo2's Ig domains. Together, our findings suggest that diverse responses to the Slit guidance cue are imparted by intrinsic structural differences encoded in the extracellular Ig domains of the Robo receptors. PMID- 20206527 TI - Crowding changes appearance. AB - Crowding is the breakdown in object recognition that occurs in cluttered visual environments and the fundamental limit on peripheral vision, affecting identification within many visual modalities and across large spatial regions. Though frequently characterized as a disruptive process through which object representations are suppressed or lost altogether, we demonstrate that crowding systematically changes the appearance of objects. In particular, target patches of visual noise that are surrounded ("crowded") by oriented Gabor flankers become perceptually oriented, matching the flankers. This was established with a change detection paradigm: under crowded conditions, target changes from noise to Gabor went unnoticed when the Gabor orientation matched the flankers (and the illusory target percept), despite being easily detected when they differed. Rotation of the flankers (leaving target noise unaltered) also induced illusory target rotations. Blank targets led to similar results, demonstrating that crowding can induce apparent structure where none exists. Finally, adaptation to these stimuli induced a tilt aftereffect at the target location, consistent with signals from the flankers "spreading" across space. These results confirm predictions from change-based models of crowding, such as averaging, and establish crowding as a regularization process that simplifies the peripheral field by promoting consistent appearance among adjacent objects. PMID- 20206528 TI - Trunk sway reductions in young and older adults using multi-modal biofeedback. AB - This study investigated whether real-time biofeedback of angular trunk displacement could alter balance performance among healthy older and young adults. Healthy community-dwelling older adults (n=32) and healthy young adults (n=32) were included in the randomized control trial study. The intervention group received combined vibrotactile, auditory and visual biofeedback of angular trunk displacement in real-time during training on a battery of static and dynamic balance tasks and during the subsequent post-training balance re assessment. The control group received balance training and were re-assessed in the absence of real-time biofeedback of their trunk displacement. The 90% range of angular trunk displacement was calculated for each balance task pre- and post training. Significant age-related differences were observed independent of the intervention. Biofeedback intervention significantly changed the angular displacement of the trunk for both young and older participants on a number of balance tasks compared to control treatment (40-60% reduction in angular displacement). In some cases, biofeedback influenced balance in older adults, but not younger adults. PMID- 20206529 TI - Balance is impaired in people with chronic obstructive pulmonary disease. AB - BACKGROUND: It has recently been suggested that people with chronic obstructive pulmonary disease have an increased risk of falls. Although falls risk is multifactorial, impaired balance may contribute. The primary aim of this study was to compare balance between people with and without chronic obstructive pulmonary disease and the secondary aim was to determine if balance deteriorates when respiratory demand is increased by upper limb exercise. METHODS: Twelve people with chronic obstructive pulmonary disease and 12 healthy control subjects participated in this study. Participants stood on a force plate to record centre of pressure displacement during a range of conditions that challenge balance. Lumbar spine and hip motion were measured with inclinometers. Balance trials were performed before and after participation in upper limb exercise that increased respiratory demand in those with chronic obstructive pulmonary disease. FINDINGS: People with chronic obstructive pulmonary disease had increased mediolateral centre of pressure displacement and increased angular motion of the hip compared to healthy controls. Mediolateral centre of pressure displacement was further increased in people with chronic obstructive pulmonary disease following exercise, but unchanged in controls. Anteroposterior centre of pressure displacement did not differ between groups. INTERPRETATION: People with chronic obstructive pulmonary disease have reduced control of balance in the mediolateral direction. This may contribute to an increased risk of falls in this population. PMID- 20206530 TI - Reversible cerebrospinal fluid edema and porencephalic cyst, a rare complication of ventricular catheter. AB - Cerebrospinal fluid (CSF) edema and porencephaly are rare postoperative complications of a ventricular shunt that result from obstruction of the distal catheter, especially in children with taut ventricles. We report a 10-year-old male with cerebellar germinoma complicated by obstructive hydrocephalus. Ventriculopuncture was performed and an Ommaya reservoir was implanted at the right frontal horn. A distal catheter was initially attached to the reservoir for drainage of hydrocephalus but was later removed. After surgery, multi-agent chemotherapy and radiation therapy, a brain MRI showed CSF edema and porencephaly in the right frontal white matter. These lesions were reduced by prompt removal of the ventricular catheter. It is important to recognize such complications and to remove the catheter as soon as possible, because the brain tissue affected by massive edema may develop irreversible changes. Advanced MRI techniques, including fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging may be helpful for assessing this pathological condition and its prognosis. PMID- 20206532 TI - Structure-activity relationship of novel DAPK inhibitors identified by structure based virtual screening. AB - Death-associated protein kinase (DAPK) is a serine/threonine protein kinase implicated in diverse programmed cell death pathways. DAPK is a promising target protein for the treatment of ischemic diseases. We identified novel potent and selective DAPK inhibitors efficiently by structure-based virtual screening, then further developed the hit compounds. In this paper, we describe the development of the hit compounds and the structure-activity relationship studies of the DAPK inhibitors in detail, including calculation of the solvated interaction energy (SIE), and verification of selectivity using a kinase panel. PMID- 20206531 TI - Increased binding of inhibitory neuronal receptors in the hippocampus in kainate treated rats with spontaneous limbic seizures. AB - To gain a better understanding of the relationship between epileptogenicity and inhibitory neuronal mechanisms, we examined variations in A1 adenosine (A1A) receptor binding in the hippocampi of rats with spontaneous limbic seizures in the chronic phase after systemic kainic acid treatment. Six weeks after kainate treatment, rats with spontaneous limbic seizures were killed for histological and in vitro autoradiographic analyses of the brain. The analyses were performed using [(3)H] 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), an A1A receptor antagonist. Relative to controls, DPCPX binding was increased in the CA3 region and in the molecular layer of the dentate gyrus in the kainate-treated rats. This is the first evidence of upregulation of the A1A receptor in a model of chronic temporal lobe epilepsy. Increased binding of the A1A receptor may contribute to epileptogenesis in the epileptic focus. PMID- 20206533 TI - Synthesis and structure-activity relationships of antimalarial 4-oxo-3-carboxyl quinolones. AB - Malaria is endemic in tropical and subtropical regions of Africa, Asia, and the Americas. The increasing prevalence of multi-drug-resistant Plasmodium falciparum drives the ongoing need for the development of new antimalarial drugs. In this light, novel scaffolds to which the parasite has not been exposed are of particular interest. Recently, workers at the Swiss Tropical Institute discovered two novel 4-oxo-3-carboxyl quinolones active against the intra-erythrocytic stages of P. falciparum while carrying out rationally directed low-throughput screening of potential antimalarial agents as part of an effort directed by the World Health Organization. Here we report the design, synthesis, and preliminary pharmacologic characterization of a series of analogues of 4-oxo-3-carboxyl quinolones. These studies indicate that the series has good potential for preclinical development. PMID- 20206534 TI - Morpho-physiological analysis of the insect fat body: a review. AB - The insect fat body is the main organ of the intermediate metabolism of insects. The majority of proteins of the haemolymph is synthesized in this tissue, which also presents the functions of lipids, carbohydrates and proteins storage. This tissue is also responsible for the synthesis of vitellogenins, proteins with an important role in the reproduction of the insects, being incorporated into the oocytes during vitellogenesis. The fat body consists of thin layers or strings, generally one or two cells thick, or small nodules suspended in the hemocele through connective tissues and trachea. Within a species, the structure of this tissue is more or less constant, but can have considerable differences between insects of different orders. In this way, this article makes a review about the main morpho-physiological features of the fat body cells of the insects, as well as a phylogenetic study of the fat body between basal and derived species of the Attini tribe ants. PMID- 20206535 TI - Polarity of prismatic facets delimiting WC grains in WC-Co alloys. AB - This study reports a determination of the polarity of WC facets in WC-Co alloys sintered at the liquid state. In these alloys, WC grains are delimited by basal facets and two sets of {10 10} prismatic facets, one set of facets being much more developed than the other. A variation of the shape is observed as a function of the composition of the alloy. High resolution transmission electron microscopy is used to investigate the polarity of the prismatic facets owing to the typical triangular patterns appearing on the images. The effect of the composition is investigated using two alloys with different carbon potentials and one containing VC and Cr(3)C(2) as grain growth inhibitors. The interpretation of the images shows that in all cases, the same set of prismatic planes is favoured. PMID- 20206536 TI - An Am/Be neutron source and its use in integral tests of differential neutron reaction cross-section data. AB - An Am/Be neutron source, installed recently at the Rajshahi University, is described. Neutron flux mapping was done using the nuclear reactions (197)Au(n,gamma)(198)Au, (113)In(n,gamma)(114m)In, (115)In(n,n'gamma)(115m)In and (58)Ni(n,p)(58)Co. An approximate validation of the neutron spectral shape was done using five neutron threshold detectors and the iterative unfolding code SULSA. Integral cross sections of the reactions (54)Fe(n,p)(54)Mn, (59)Co(n,p)(59)Fe and (92)Mo(n,p)(92m)Nb were measured with fast neutrons (E(n)>1.5MeV) and compared with data calculated using the neutron spectral distribution and the excitation function of each reaction given in data libraries: an agreement within +/-6% was found. PMID- 20206537 TI - Putrescine accumulation confers drought tolerance in transgenic Arabidopsis plants over-expressing the homologous Arginine decarboxylase 2 gene. AB - In Arabidopsis, a model genus missing a functional ornithine decarboxylase pathway, most of the key genes involved in polyamine biosynthesis are duplicated. This gene redundancy has been related to the involvement of certain gene isoforms in the response to specific environmental stimuli. We have previously shown that drought stress induces Arginine decarboxlase 2 expression, while transcript levels for Arginine decarboxlase 1 remain constant. Accumulation of putrescine and increased arginine decarboxlase activity (EC 4.1.1.19) levels in response to different abiotic stresses have been reported in many different plant systems, but the biological meaning of this increase remains unclear. To get a new insight into these questions, we have studied the response to drought of transgenic Arabidopsis thaliana lines constitutively expressing the homologous Arginine decarboxlase 2 gene. These lines contain high levels of putrescine with no changes in spermidine and spermine content even under drought stress. Drought tolerance experiments indicate that the different degree of resistance to dehydration correlates with Put content. Although no significant differences were observed in the number of stomata between wild-type and transgenic plants, a reduction in transpiration rate and stomata conductance was observed in the ADC2 over-expressor lines. These results indicate that one of the mechanisms involved in the drought tolerance of transgenic plants over-producing Put is related to a reduction of water loss by transpiration. PMID- 20206538 TI - 3D powder printed calcium phosphate implants for reconstruction of cranial and maxillofacial defects. AB - BACKGROUND: The aim of this study was to investigate the processing and the possible use of 3D powder printed calcium phosphate implants for the reconstruction of cranial and maxillofacial defects. MATERIALS: The fabrication of the implants was carried out with a commercial 3D powder printing system. Diluted phosphoric acid was printed onto tricalcium phosphate powder, leading to the formation of dicalcium phosphate dihydrate (Brushite). Hydrothermal conversion of the brushite matrices led to the formation of dicalcium phosphate anhydrous (Monetite). METHOD: Bony defects were generated using a human cadaver skull. The implants were computer-aided designed (CAD) using a mirror imaging procedure following computed tomography of the skull. Specific implants were manufactured by the 3D powder printing rapid prototyping technique. RESULT: The processing chain from data acquisition to printing of the implants proved to be practical and uncomplicated. The individual implants showed a high degree of accuracy of fit. Mechanical and physical investigations revealed suitable characteristics. CONCLUSION: 3D powder printing of calcium phosphate cement material provides a promising new method for the manufacturing of biodegradable synthetic patient-specific craniofacial implants. PMID- 20206539 TI - Fontan completion rate and outcomes after bidirectional cavo-pulmonary shunt. AB - OBJECTIVE: To determine outcomes of patients undergoing a bidirectional cavo pulmonary shunt (BCPS) in the Fontan era. METHODS: From 1990 to 2000, 212 patients underwent a BCPS in a single institution at a mean age of 2.6+/-5 years. RESULTS: Hospital mortality was 6% (13 patients). Five patients were lost to follow-up (3%). After a mean of 9+/-4 years, 15 patients had not yet been referred for Fontan surgery and their status was deemed satisfactory (11 1(1/2) ventricle repair, three BCPS and one patient converted to a bi-ventricular repair). Out of the remaining 179 patients who could potentially have reached a Fontan status, 141 had undergone the procedure and seven were awaiting Fontan completion. The expected completion rate of Fontan surgery after BCPS was 83% (148/179). Thirteen patients died and heart transplantation was necessitated in nine patients. Nine were deemed unsuitable for Fontan surgery for cardiac (seven), respiratory (one) or neurologic (one) reasons. After BCPS, the only predictors of late failure (death, heart transplantation or NYHA class III-IV) were not reaching Fontan status and the presence of bilateral superior vena cava (SVC). Ten-year survival was 99% (95% confidence interval (CI): 95-99%) for Fontan patients and 67% (95%CI: 50-80%) for those left with a BCPS. CONCLUSION: In the present era, staging with BCPS represents a selection process in the Fontan pathway. Almost a fifth of the patients will not reach Fontan status. Outstanding results after Fontan surgery may hide a high attrition rate between BCPS and Fontan. PMID- 20206540 TI - A prospective randomised multicentre clinical comparison of a minimised perfusion circuit versus conventional cardiopulmonary bypass. AB - OBJECTIVE: Minimised perfusion circuits (MPCs) are expected to reduce the side effects of conventional cardiopulmonary bypass (CCPB); however, conclusive data from sufficiently powered clinical trials are lacking. The purpose of this study was to evaluate the safety and efficacy of the ROCsafeRX minimised perfusion circuit. METHODS: A randomised, controlled, multicentre clinical trial comparing both perfusion circuits in patients subjected to elective coronary artery bypass and/or aortic valve replacement is described. The primary end points of safety, defined as procedure success without device-related complications, and secondary end point of efficacy, including reduction of transfusion requirement and incidence of atrial fibrillation, are analysed. RESULTS: To date, 291 patients have been enrolled and randomised (146 MPC vs 145 CCPB). With the exception of a significantly higher male population in the MPC group (83.6% vs 71.0%, p=0.01), both groups were well matched for demographic data and type of surgery. There were no device-related complications but a hard-shell reservoir had to be integrated in one MPC because of a tear in the right atrium that was managed uneventfully. Total transfusion requirement (329+/-599 ml vs 783+/-1638 ml, p < or = 0.001) and erythrocyte transfusion (181+/-341 ml vs 434+/-798 ml, p < or = 0.001) were significantly reduced in the MPC group. The incidence of atrial fibrillation was significantly lower in the MPC group (7.1% vs 19.5%, p < or = 0.01), while freedom of major adverse events showed no significant difference. CONCLUSIONS: Lack of device-related complications combined with a significant reduction in postoperative atrial fibrillation and transfusion requirements have shown the ROCsafeRX MPC to be both safe and efficient for large-scale use in cardiac patients. Additional data are expected to confirm these initial findings. PMID- 20206541 TI - Clinical characteristics and surgical treatment of oesophageal gastrointestinal stromal tumours. AB - OBJECTIVE: Oesophageal gastrointestinal stromal tumours (GISTs) are extremely rare. The preoperative diagnosis is complicated by lack of specificity and the clinical features of patients with oesophageal GISTs need to be fully studied. METHODS: We have reviewed retrospectively the medical records of those patients who are treated surgically for oesophageal GISTs in our two hospitals. RESULTS: Eight oesophageal GISTs were identified among the 63 oesophageal mesenchymal tumours in our two hospitals in the past 30 years. Of the eight patients, the male:female ratio was 5:3; the median age of the patients was 57 years (range 49 71 years). Dysphagia was the most common symptom, and all cases were diagnosed postoperatively. The tumours were resected by enucleation or oesophagectomy. The median follow-up was 59 months, ranging from 14 to 202 months, with four of the patients succumbing to the disease, among them two with recurrence and another two with metastasis. CONCLUSIONS: Our study indicates that oesophageal GIST is rather rare, and it has relatively high recurrence and mortality rates, especially for patients with large tumours (larger than 9 cm). At present, surgical resection and postoperative diagnosis remain the mainstay for treatment of patients with oesophageal GISTs in China. PMID- 20206542 TI - Trans-apical aortic valve implantation: univariate and multivariate analyses of the early results from the SOURCE registry. AB - OBJECTIVE: Trans-catheter aortic valve implantation is an alternative treatment option for patients facing high risk for aortic valve replacement. Currently, the results of trans-apical trans-catheter procedures performed outside controlled trials are unknown. METHODS: The Edwards SAPIEN Aortic Bioprosthesis European Outcome (SOURCE) Registry collects data of patients treated at European centres during the first year following commercialisation of the Edwards SAPIEN bioprosthesis. Only data from centres that could provide 100% of their consecutively treated patients (n=32) were included in the study population. This article provides the 30-day outcome data involving the trans-apical patients, including univariate and multivariate risk analyses for postoperative 30-day mortality. RESULTS: The interim results are based on a total number of 575 procedures performed between January 2008 and 31 January 2009. Mean age at implant was 80.7 years, and patients had a mean logistic EuroSCORE of 29.1%. Baseline characteristics included coronary artery disease 56%, prior coronary intervention 27.1%, prior coronary bypass grafting 26.9%, concomitant mitral valve disease 32.8%, porcelain aorta 11.5%, peripheral vascular disease 27.5%, prior stroke 6.3% and pulmonary disease 29.4%. Successful valve deployment was observed in 92.7% with a 3.5% conversion rate to open surgery, incidence of coronary obstruction of 0.7% and valve embolisation of 0.5%. The incidence of aortic regurgitation in excess of 2+ was 2.3% immediately following the procedure. The incidence of major postoperative complications included bleeding requiring re-operation 2.1%, dialysis 7.1%, pacemaker implantation 7.3%, stroke 2.6%, major vascular complications 2.4% and myocardial infarction 0.7%. The total 30-day mortality was 10.3%. Logistic EuroSCORE > or =30% and missing ejection fraction were found to be the only independent predictors for 30-day mortality. CONCLUSIONS: These results demonstrate that although trans-apical trans-catheter aortic valve implantation is a complex surgical technique, the learning curve can be minimised by appropriate training programmes. Very high logistic EuroSCOREs predict inferior survival and make it likely that in this subgroup of patients there may be some who, despite having had a successful trans-catheter aortic valve implantation procedure, do not benefit in the midterm. PMID- 20206543 TI - Oral sildenafil for persistent pulmonary hypertension early after congenital cardiac surgery in children. AB - OBJECTIVE: Sildenafil is a strong pulmonary vasodilator that increases the intracellular cyclic guanosine monophosphate concentration through inhibition of phosphodiesterase-5. We assessed the benefit of oral sildenafil for persistent pulmonary hypertension early after congenital cardiac surgery in paediatric patients. METHODS: Sildenafil was administered at a starting dose of 0.5 mg kg( 1) following admission to the intensive care unit. With careful monitoring of haemodynamics, the dose was increased stepwise by 0.5 mg kg(-1) every 4-6 h up to a maximum of 2 mg kg(-1). After successful weaning from a ventilator and from other vasodilators, sildenafil was gradually discontinued over the next 5-7 days. RESULTS: A retrospective review of medical records showed an age distribution of <1 month (n=26), > or = 1-<6 months (n=36), > or = 6-<12 months (n=19), 1-3 years (n=8), 4-9 years (n=9) and >10 years (n=2) at the time of surgery. The surgeries were performed for ventricular septal defect closure (n=17), arterial switch (n=30), truncus arteriosus repair (n=10), complete atrioventricular septal defect repair (n=12), total anomalous venous drainage repair (n=9), and other open-heart surgery (n=22). The aforementioned concomitant inhaled nitrous oxide treatment was performed in 66 patients. Pulmonary arterial pressure decreased in 28, was unchanged in five and elevated in one patient out of the total of 34 cases for which data from continuous pressure monitoring were available. Bosentan was added in three cases with persistent symptoms due to pulmonary hypertension despite sildenafil treatment. After sildenafil administration, modest oxygen desaturation occurred in seven cases, but no 'rebound' pulmonary hypertension occurred. There were no significant adverse events during sildenafil treatment. CONCLUSIONS: Our results suggest that oral sildenafil is a safe and effective alternate for persistent pulmonary hypertension following congenital heart surgery in children. PMID- 20206544 TI - The effect of a multidisciplinary thoracic malignancy conference on the treatment of patients with lung cancer. AB - INTRODUCTION: There is a paucity of data evaluating whether a multidisciplinary conference coordinating surgery, chemotherapy and radiation therapy translates into better patient care. This article compares the experiences of patients with lung cancer before and after the formation of a prospective, multidisciplinary thoracic malignancy care conference (TMC). METHODS: The records of patients with a non-small-cell lung cancer at a tertiary care hospital were reviewed for completeness of staging, multidisciplinary evaluation prior to the initiation of therapy, time from pathologic diagnosis to treatment, multimodality therapy and adherence to national treatment guidelines. The summary data of patients treated before and after the TMC were initiated, and then compared. RESULTS: Between 2001 and 2007, 535 patients were treated prior to the initiation of the TMC and 687 patients within the TMC. The number of patients receiving a complete staging evaluation (79%/93%: p<0.0001), multidisciplinary evaluation prior to therapy (62%/96%: p<0.0001) and adherence to the National Comprehensive Cancer Network (NCCN) treatment guidelines (81%/97%: p<0.0001) all increased significantly while mean days from diagnosis to treatment significantly decreased (29/17: p<0.0001) following the initiation of a TMC. CONCLUSION: A multidisciplinary thoracic malignancy conference increased the percentage of patients receiving complete staging, a multidisciplinary evaluation and adherence to nationally accepted care guidelines while decreasing the interval from diagnosis to treatment significantly. While the ultimate goal of treatment is to improve patient survival, the surrogate variables examined in this review indicate that patients with non-small-cell lung cancer benefit from being evaluated in a prospective, multidisciplinary care conference. PMID- 20206545 TI - Use of hematological parameters to assess the efficiency of quince (Cydonia oblonga Miller) leaf extract in alleviation of the effect of ultraviolet--A radiation on African catfish Clarias gariepinus (Burchell, 1822). AB - The present study aimed to elucidate the negative impacts of UVA on some biochemical and hematological variables of the economically important African catfish, Clarias gariepinus and investigates the putative role of quince (Cydonia oblonga Miller) leaf extract in protection and/or alleviation of such negative impacts. Changes in the hematological and blood biochemical values often reflect alteration of physiological state. Blood parameters can be useful for the measurement of physiological disturbances in stressed fish and thus provide information about the level of damage in the fish. We found a significant (P<0.05) decrease in the red blood cell counts, hemoglobin and hematocrit in the groups exposed to UVA compared to the control groups. Exposure to UVA induced marked red cell shrinkage (increased mean cell hemoglobin concentration) and showed an elevation in mean cell volume and mean cell hemoglobin in the blood of the exposed fish compared to the control. A significant (P<0.05) reduction in the total white blood cells was recorded in the exposed fish compared to the control. The biochemical parameters (blood glucose, total plasma protein, blood cholesterol, plasma creatinine, aspartic amino transferase and alanine amino transferase) exhibited a significant increase in the blood of fish exposed to UVA. Methanolic extract of quince leaf before ripening of the fruits was analyzed by GC/MS. To investigate the biological impact of this extract and its biologically active components, this extract was tested for its putative role in alleviation of UVA effect on catfish. Quince leaf extract had the ability to prevent hematotoxic stress induced by UVA and resulted in enhancement of the immune system of catfish represented by significant (P<0.05) increase in the number of white blood cells and lymphocytes of the catfish. Quince extract also protected the red blood cells from UVA damage. To our knowledge this is the first report of the effect of quince leaf extract on an aquatic organism. PMID- 20206547 TI - Psychological, behavioural and physical changes may contribute to cardiovascular risk in bereavement. PMID- 20206546 TI - What is the evidence for the use of high flow nasal cannula oxygen in adult patients admitted to critical care units? A systematic review. AB - BACKGROUND: Humidified high flow nasal cannula oxygen therapy is increasingly available in Australian adult intensive care units. Its use in paediatric populations has been extensively studied and has shown positive effects however its clinical effectiveness in adults has not been established. PURPOSE: A systematic review of the literature was conducted to critique current evidence, inform nursing practice and make recommendations for nursing research. METHODS: An extensive search strategy identified clinical studies comparing standard oxygen therapy with high flow therapy in critical care units. Two reviewers independently assessed articles for eligibility, methodological quality and inclusion. Outcomes of interest included oxygenation, ventilation, work of breathing, positive airway pressure, patient comfort and long term effect. A narrative synthesis was conducted to describe the emerging evidence. FINDINGS: Eight studies were included for review. All were abstracts or poster presentations from scientific meetings therefore the quality of data available for analysis was poor. Findings indicated there was preliminary evidence to support the use of high flow therapy to optimise oxygenation in adults. This therapy may reduce the effort of breathing and provide augmented airway pressures. Patients described the therapy as comfortable. No definitive evidence supported the claim that ventilation is improved or conclusively demonstrated a long-term effect. CONCLUSION: Humidified high flow nasal cannula may be used as an intermediate therapy to improve oxygenation in adult critical care patients. Further research is required to determine the duration of effect of the therapy, identify the patient population for whom it is most beneficial and evaluate long term outcomes; to enable definitive recommendations for practice to be made. PMID- 20206548 TI - Global graying, colorectal cancer and liver metastasis: new implications for surgical management. AB - Aging of the population - global graying - is occurring rapidly, with significant effects on epidemiology, treatment and outcomes for cancer patients. In colorectal cancer, outcomes for the elderly are worse than those for younger patients, partially driven by treatment disparities between the two groups. Nonetheless, standard-of-care treatment for the elderly results in equivalent long-term outcomes to those observed in the younger population; and available data support the use of aggressive surgery and adjuvant therapies in well selected patients. Data evaluating epidemiology, treatment patterns and outcomes in elderly patients with colorectal cancer liver metastasis are lacking. Liver resection offers the only curative approach, but it is rarely offered to older adults. Current data support the use of hepatectomy for well-selected elderly colorectal cancer patients with liver metastasis; however, this and other evolving therapies need to be assessed in the elderly to better define their role, indications, safety and outcomes. PMID- 20206549 TI - Interleukin-1 beta and interleukin-6 gene polymorphism associations with angiographically assessed coronary artery disease in Brazilians. AB - The inflammatory process has been considered an important mediator for the development of atherosclerosis. Interleukin-1 beta (IL1B) is a precursor of interleukin-6 (IL6) in the acute phase of inflammatory response and their levels are elevated in patients with coronary artery disease. The aim of the present study was to further investigate the association of IL-1B and IL-6 gene polymorphisms and angiographically assessed coronary artery disease (CAD) in African- and Caucasian-Brazilians. This report analyzed the IL-1B-511C>T and IL-6 174G>C polymorphisms in 667 patients (253 African-Brazilians and 414 Caucasian Brazilians) who underwent coronary angiography. Patients with a coronary obstructive lesion 50% presented a higher frequency of the IL-1B-511CC genotype (30.4%) compared to lesion-free individuals (16.5%, p=0.032) in African- but not in Caucasian-Brazilians. No significant genotype frequency difference was identified for the IL-6-174G>C polymorphism in either ethnic groups. However, after correction for other CAD risk factors using multivariate logistic regression, both the IL-1B-511CC [Odds ratio (OR)=2.3; p=0.019] and the IL-6 174GG (OR=2.0; p=0.028) genotypes were considered independent CAD risk predictors in African-Brazilians. This report shows that the IL-1B-511C>T and IL-6-174G>C polymorphisms were associated with CAD risk in African-Brazilians and no association was detected among Caucasian-Brazilians. PMID- 20206550 TI - The -251A>T polymorphism of interleukin-8 is associated with longer mechanical ventilation and hospital staying after coronary surgery. AB - BACKGROUND: Cardiac surgery is associated with inflammatory responses that are known to affect its outcome. The present study was designed to define whether post-operative release of interleukin (IL)-6, 8 and tumor necrosis factor-alpha (TNF-alpha) is related to the presence of a certain allele in functional polymorphism and its relationship to clinical outcome after off-pump coronary artery bypass (OPCAB). METHODS: One hundred and forty-five patients undergoing first time elective OPCAB were genotyped for IL-6(-174G>C), IL-8(-251A>T) and TNF alpha(-308G>A) polymorphisms using polymerase chain reaction (PCR) and gene sequencing. Cytokine levels were measured in plasma samples taken before the operation and 4, 24 and 72h postoperatively by suspension array system. RESULTS: Levels of IL-6 and IL-8 increased significantly after OPCAB. Patients with IL-6 174GG and IL-8-251AA genotypes had higher post-operative circulating levels of IL 6 and IL-8, respectively. Logistic regression showed that IL-8-251AA genotype was an independent risk factor of ventilation time more than 1day (OR=11.80, 95% CI: 1.87-74.48) and hospital staying more than 14days (OR=38.00, 95% CI: 4.15-347.87) after surgery. CONCLUSIONS: OPCAB results in post-operative inflammatory responses. Genetic backgrounds alter the extent of inflammatory response and might relate to clinical outcome of OPCAB. PMID- 20206551 TI - Structural analysis of prion proteins by means of drift cell and traveling wave ion mobility mass spectrometry. AB - The prion protein (PrP) is implicitly involved in the pathogenesis of transmissible spongiform encephalopathies (TSEs). The conversion of normal cellular PrP (PrP(C)), a protein that is predominantly alpha-helical, to a beta sheet-rich isoform (PrP(Sc)), which has a propensity to aggregate, is the key molecular event in prion diseases. During its short life span, PrP can experience two different pH environments; a mildly acidic environment, whilst cycling within the cell, and a neutral pH when it is glycosyl phosphatidylinositol (GPI) anchored to the cell membrane. Ion mobility (IM) combined with mass spectrometry has been employed to differentiate between two conformational isoforms of recombinant Syrian hamster prion protein (SHaPrP). The recombinant proteins studied were alpha-helical SHaPrP(90-231) and beta-sheet-rich SHaPrP(90-231) at pH 5.5 and pH 7.0. The recombinant proteins have the same nominal mass-to-charge ratio (m/z) but differ in their secondary and tertiary structures. A comparison of traveling-wave (T-Wave) ion mobility and drift cell ion mobility (DCIM) mass spectrometry estimated and absolute cross-sections showed an excellent agreement between the two techniques. The use of T-Wave ion mobility as a shape-selective separation technique enabled differentiation between the estimated cross-sections and arrival time distributions (ATDs) of alpha-helical SHaPrP(90-231) and beta sheet-rich SHaPrP(90-231) at pH 5.5. No differences in cross-section or ATD profiles were observed between the protein isoforms at pH 7.0. The findings have potential implications for a new ante-mortem screening assay, in bodily fluids, for prion misfolding diseases such as TSEs. PMID- 20206552 TI - Renal artery interventions during infrarenal endovascular aortic repair: a greater potential of subsequent failure? AB - PURPOSE: To determine the anatomic and functional outcomes of renal artery interventions during endovascular aortic aneurysm repair (EVAR) and compare them with renal artery interventions without EVAR. MATERIALS AND METHODS: A renal artery revascularization database (1987-2007) was reviewed to identify patients who underwent renal intervention during EVAR and those who had an intervention in the absence of EVAR. Outcomes were analyzed with respect to patient comorbidities, renal anatomy and function, procedural events, and postoperative complications. RESULTS: A total of 413 patients (239 men; 58%) underwent 589 renal artery revascularizations (51 with EVAR and 362 without). Mean age was 70 years +/- 10. Mean follow-up was 3.5 years (range, 1-13 y). Primary indications for renal intervention were hypertension (63%) and elevated creatinine level (27%). The EVAR group was more likely to incur an increased creatinine level at 1 month after intervention (33% vs 18%; P = .007). Freedom from restenosis was similar (P = .501), but arterial occlusion rate was higher in the EVAR group (96% +/- 3% vs 100% +/- 10% cumulative patency at 3 y; P = .005). At 3 years, freedom from recurrent symptoms (P = .26), freedom from adverse renal events (P = .12), and survival (85% +/- 8% vs 75% +/- 2%; P = .83) were not significantly different. CONCLUSIONS: Renal artery revascularization during EVAR should be considered higher risk because of the high incidence of procedural complications, early functional injury, and early occlusion rates. However, the long-term sequelae and benefits of such a procedure are similar to those of a renal revascularization procedure in the absence of EVAR. PMID- 20206553 TI - High-dose insulin in experimental myocardial infarction in rabbits: protection against effects of hyperglycaemia. AB - INTRODUCTION: Hyperglycaemia at the time of acute myocardial infarction (AMI) is a predictor of survival and is associated with increased mortality and morbidity in patients with or without diabetes mellitus. On the other hand, insulin has been shown to reduce myocardial injury in experimental studies but its benefits have not been confirmed in clinical studies. METHODS: The isolated perfused heart model was used to examine the direct effect of incremental doses of insulin and varying degrees of hyperglycaemia on infarct size and cardiomyocyte apoptosis in rabbit hearts. The rabbit hearts were subjected to 30-min ischaemia and 2.5-h reperfusion. RESULTS: Insulin, given alone just before reperfusion, dramatically reduced infarct size in a dose-dependent manner (75-300 MUU/ml) during experimental myocardial infarction (46%+/-2% to 10.9%+/-3%, P<.001). Acutely elevated glucose levels (33 mmol/L) induced a significantly greater infarct size and cardiomyocyte apoptosis compared to hearts subjected to normal glucose levels. On the other hand, high-dose insulin (300 MUU/ml) given 5 min before reperfusion attenuated the extent of infarction and reduced apoptosis in hearts that were exposed to high glucose levels. CONCLUSION: Acutely elevated levels of glucose induced larger infarct area during ischaemia-reperfusion, and this is mediated through proapoptotic pathways. Insulin, when given just before reperfusion, confers cardioprotection in a dose-dependent manner and reverses the detrimental effect of acute hyperglycaemia. High-dose insulin as well as maintaining normoglycaemia remain important factors that improve outcomes following myocardial infarction. PMID- 20206554 TI - Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages. AB - Enhancers determine tissue-specific gene expression programs. Enhancers are marked by high histone H3 lysine 4 mono-methylation (H3K4me1) and by the acetyl transferase p300, which has allowed genome-wide enhancer identification. However, the regulatory principles by which subsets of enhancers become active in specific developmental and/or environmental contexts are unknown. We exploited inducible p300 binding to chromatin to identify, and then mechanistically dissect, enhancers controlling endotoxin-stimulated gene expression in macrophages. In these enhancers, binding sites for the lineage-restricted and constitutive Ets protein PU.1 coexisted with those for ubiquitous stress-inducible transcription factors such as NF-kappaB, IRF, and AP-1. PU.1 was required for maintaining H3K4me1 at macrophage-specific enhancers. Reciprocally, ectopic expression of PU.1 reactivated these enhancers in fibroblasts. Thus, the combinatorial assembly of tissue- and signal-specific transcription factors determines the activity of a distinct group of enhancers. We suggest that this may represent a general paradigm in tissue-restricted and stimulus-responsive gene regulation. PMID- 20206556 TI - Ultrasound-guided sclerotherapy of the great saphenous vein with 1% vs. 3% polidocanol foam: a multicentre double-blind randomised trial with 3-year follow up. AB - OBJECTIVES: The aim of this study was to compare the efficacy and side effects of ultrasound-guided foam sclerotherapy of the great saphenous vein using 1% and 3% polidocanol foam with a 3-year follow-up. DESIGN: A multicentre prospective double-blind randomised clinical trial comparing the efficacy of 1% vs. 3% polidocanol sclerosant foam. MATERIALS AND METHODS: Patients with incompetence of the great saphenous vein (GSV) in CEAP clinical classes C2-5 (CEAP, Clinical Etiology-Anatomy-Pathophysiology), with or without incompetence of the sapheno femoral junction, were included. The Turbofoam method was used to create 1% and 3% polidocanol foam, which was injected into the GSV under ultrasound guidance, with a volume not exceeding 10 ml. Further foam sclerotherapy was carried out at 6 weeks, 3 and 6 months if required to abolish persistent venous reflux. The main outcome measure was the absence of saphenous reflux as assessed by ultrasound imaging at 6 months, 1, 2 and 3 years. Clinical severity (Venous Clinical Severity score (VCSS)) and quality of life (the Chronic Venous Insufficiency Questionnaire (CIVIQ)) scores were assessed. RESULTS: A total of 143 patients were included; 1% group men = 18, women = 55, 3% group men = 19, women = 51. The abolition of venous reflux was: 1% group, 69% and 3% group, 85% at 6 months; 1% group, 79% and 3% group, 78% at 3 years (including additional injections at 6 months). Three asymptomatic thrombo-embolic events (2%) occurred. Local side effects (principally pigmentation and matting) were 9% in the 3% group and 6% in the 1% group at 3 years (N.S.). Clinical severity and quality of life scores improved by more than 20% at 6 months in both the groups, with no difference between the groups. CONCLUSIONS: This is the first randomised clinical trial of ultrasound-guided foam sclerotherapy which is a 3-year follow-up and shows equivalent efficacy of 1% and 3% sclerosant foam. CLINICAL TRIAL REGISTRATION NUMBER: 2006-07-05. PMID- 20206557 TI - Below-the-ankle angioplasty is a feasible and effective intervention for critical leg ischaemia. AB - AIM: Occlusion or severe stenosis of pedal and plantar arteries limits surgical options for critical limb ischaemia (CLI). Below-the-ankle (BTA) angioplasty is potentially useful as an adjunct to proximal angioplasty. In this study, the feasibility and outcome of this procedure were explored, as they have not been evaluated previously. METHODS: Patients' demographics, indications, procedures and outcomes were recorded. Outcomes were determined by technical success, primary patency, limb salvage and amputation-free survival (AFS) rates. RESULTS: Between 2004 and 2008, 42 cases of BTA angioplasty were performed for 39 patients. Forty cases (95.2%) had CLI. Technical success was achieved in 88% of cases. At 6, 12 and 24 months, AFS was 70.7%, 60.9% and 57.1%, limb salvage was 84.9%, 81.9% and 81.9% and patient survival was 83.3%, 73.8% and 67.3, respectively. Seven major amputations (16.6%) were performed, four of which had failed angioplasty. Two patients required re-intervention. Univariate analysis showed insulin-dependent diabetics, occlusive lesions, failure of angioplasty and state of the run off to be the predictors of limb loss. CONCLUSIONS: BTA angioplasty for pedal and plantar arterial occlusive disease is technically feasible. It has good medium-term clinical outcome and limb salvage in a group of patients with poor surgical options. PMID- 20206555 TI - Delivery of cytosolic components by autophagic adaptor protein p62 endows autophagosomes with unique antimicrobial properties. AB - Autophagy allows cells to self-digest portions of their own cytoplasm for a multitude of physiological purposes, including innate and adaptive immunity functions. In one of its innate immunity manifestations, autophagy, is known to contribute to the killing of intracellular microbes, including Mycobacterium tuberculosis, although the molecular mechanisms have been unclear. Here, we delineated sequential steps of the autophagic pathway necessary to control intracellular M. tuberculosis and found that in addition to autophagy initiation and maturation, an accessory autophagy-targeting molecule p62 (A170 or SQSTM1) was required for mycobactericidal activity. The p62 adaptor protein delivered specific ribosomal and bulk ubiquitinated cytosolic proteins to autolysosomes where they were proteolytically converted into products capable of killing M. tuberculosis. Thus, p62 brings cytosolic proteins to autolysosomes where they are processed from innocuous precursors into neo-antimicrobial peptides, explaining in part the unique bactericidal properties of autophagic organelles. PMID- 20206558 TI - Deoxygenation affects tyrosine phosphoproteome of red cell membrane from patients with sickle cell disease. AB - Sickle cell disease (SCD) is a worldwide distributed hereditary red cell disorder related to the production of a defective form of hemoglobin, hemoglobin S (HbS). One of the hallmarks of SCD is the presence of dense, dehydrate highly adhesive sickle red blood cells (RBCs) that result from persistent membrane damage associated with HbS polymerization, abnormal activation of membrane cation transports and generation of distorted and rigid red cells with membrane perturbation and cytoskeleton dysfunction. Although modulation of phosphorylation state of the proteins from membrane and cytoskeleton networks has been proposed to participate in red cell homeostasis, much still remains to be investigated in normal and diseased red cells. Here, we report that tyrosine (Tyr-) phosphoproteome of sickle red cells was different from normal controls and was affected by deoxygenation. We found proteins, p55 and band 4.1, from the junctional complex, differently Tyr-phosphorylated in SCD RBCs compared to normal RBCs under normoxia and modulated by deoxygenation, while band 4.2 was similarly Tyr-phosphorylated in both conditions. In SCD RBCs we identified the phosphopeptides for protein 4.1R located in the protein FERM domain (Tyr-13) and for alpha-spectrin located near or in a linker region (Tyr-422 and Tyr-1498) involving protein areas crucial for their functions in the context of red cell membrane properties, suggesting that Tyr-phosphorylation may be part of the events involved in maintaining membrane mechanical stability in SCD red cells. PMID- 20206559 TI - Complex and cryptic chromosomal rearrangements involving the MLL gene in acute leukemia: a study of 7 patients and review of the literature. AB - Chromosomal rearrangements involving the MLL gene have been associated with many different types of hematological malignancies. Most of them are easily recognized by conventional cytogenetics. However, in some cases, complex, unusual or cryptic rearrangements make the MLL involvement difficult or impossible to be detected by conventional cytogenetics. Fluorescent in situ hybridization with a panel of probes coupled with long distance inverse-PCR was used to identify chromosomal rearrangements involving the MLL gene. Seven unusual chromosomal rearrangements were identified, including two complex translocations, three insertions of material of chromosome 11 in another chromosome and one insertion of chromosome material into the MLL gene. Conventional cytogenetics showed three patients to have a deletion of 11q; one had an unexpected t(6;11)(q27;q23) whereas the other two patients had also an insertion of MLL material in another chromosome. Concurrent 3' deletion in the MLL rearrangement was observed in two patients. We recommend a systematic approach to be used in all cases of acute leukemia starting with FISH analyses using a commercially available MLL split signal probe. Should an abnormality be discovered, the analysis has to be completed by further molecular cytogenetic and genomic PCR methods in order to unravel the recombination mechanism. PMID- 20206560 TI - Antinociceptive efficacy and plasma concentrations of transdermal buprenorphine in dogs. AB - To assess the antinociceptive efficacy of transdermal (TD) buprenorphine (B) in dogs, a prospective, positive-controlled experimental study was performed in 10 healthy Beagles. In an open label crossover design, the dogs initially received intravenous B (IVB, 0.02 mg kg(-1)) as a positive control, followed by TDB (52.5 MUg h(-1)) 4 months later. Blood was collected at regular intervals for determination of the plasma concentrations of B ([B]) and its metabolite norbuprenorphine. The antinociceptive efficacy was assessed using thermal and mechanical models of nociception. The peak concentration [B] was 1.54 ng mL(-1) (+/-1.98) 60 h after TDB application, although three dogs had no measurable [B] after TDB. Maximum thermal threshold (TT) was 52.6 degrees C (+/-0.48) at 1h after IVB administration and 51.63 degrees C (+/-1.01) 72 h after TDB application. The significant increase in TT indicated that effective antinociception was achieved beyond 36 h after the application of TDB, lasting until patch removal. There was hysteresis between [B] and the antinociceptive effect. PMID- 20206562 TI - PhDD: a new pharmacophore-based de novo design method of drug-like molecules combined with assessment of synthetic accessibility. AB - This account describes a new pharmacophore-based de novo design method of drug like molecules (PhDD). The method PhDD first generates a set of new molecules that completely conform to the requirements of a given pharmacophore model, followed by a series of assessments to the generated molecules, including assessments of drug-likeness, bioactivity, and synthetic accessibility. PhDD is tested on three typical examples, namely, pharmacophore hypotheses of histone deacetylase (HDAC), cyclin-dependent kinase 2 (CDK2) and HIV-1 integrase (IN) inhibitors. The test results demonstrate that PhDD is able to generate molecules with novel structures but having similar biological functions with existing inhibitors. The validity of PhDD together with its ability of assessing synthetic accessibility makes it a useful tool in rational drug design. PMID- 20206561 TI - In vivo 1D and 2D correlation MR spectroscopy of the soleus muscle at 7T. AB - AIM: This study aims to (1) undertake and analyse 1D and 2D MR correlation spectroscopy from human soleus muscle in vivo at 7T, and (2) determine T1 and T2 relaxation time constants at 7T field strength due to their importance in sequence design and spectral quantitation. METHOD: Six healthy, male volunteers were consented and scanned on a 7T whole-body scanner (Siemens AG, Erlangen, Germany). Experiments were undertaken using a 28cm diameter detunable birdcage coil for signal excitation and an 8.5cm diameter surface coil for signal reception. The relaxation time constants, T1 and T2 were recorded using a STEAM sequence, using the 'progressive saturation' method for the T1 and multiple echo times for T2. The 2D L-Correlated SpectroscopY (L-COSY) method was employed with 64 increments (0.4ms increment size) and eight averages per scan, with a total time of 17min. RESULTS: T1 and T2 values for the metabolites of interest were determined. The L-COSY spectra obtained from the soleus muscle provided information on lipid content and chemical structure not available, in vivo, at lower field strengths. All molecular fragments within multiple lipid compartments were chemically shifted by 0.20-0.26ppm at this field strength. 1D and 2D L-COSY spectra were assigned and proton connectivities were confirmed with the 2D method. CONCLUSION: In vivo 1D and 2D spectroscopic examination of muscle can be successfully recorded at 7T and is now available to assess lipid alterations as well as other metabolites present with disease. T1 and T2 values were also determined in soleus muscle of male healthy volunteers. PMID- 20206563 TI - Evaluation of an uncollimated printed paper transmission source used under scatter limiting conditions. AB - Transmission sources used for image attenuation correction, allowing image quantification, are collimated to reduce scatter. We propose the same effect can be achieved for an uncollimated source by increasing source to patient distance. The aim was to compare planar image performance characteristics and absorbed doses of uncollimated and collimated radioactive printed paper transmission sources. The scatter contribution to the uncollimated (99m)Tc source data was evaluated for different combinations of detector phantom distance, detector source distance and phantom source distance. Measurements were performed by increasing the Lucite phantom thickness in 1cm steps to 20 cm. Spatial resolution, detection efficiency and entrance absorbed dose rate were measured for the uncollimated and collimated transmission source images. Results derived from the energy spectra, obtained with the uncollimated transmission source indicate that scatter contribution increases with decreasing detector source distance. The scatter component in the uncollimated transmission images (detector source distances >= 60 cm; phantom source distances >= 40 cm) was comparable to that obtained with collimated transmission images. Attenuation coefficients obtained compared well (0.168 cm-1 vs. 0.171 cm-1). The full widths at half maxima differed by less than 0.9 mm. The detection efficiency of the uncollimated source was 2.5 times higher than obtained with the collimated source. The entrance absorbed dose obtained from an uncollimated source was 3.75 times larger than that obtained from the collimated source. An uncollimated transmission source (detector source distance >= 60 cm) results in acceptable image characteristics and presents a low cost, low dose, high efficiency option for transmission imaging. PMID- 20206565 TI - [New technologies applied to the medication-dispensing process, error analysis and contributing factors]. AB - OBJECTIVE: Calculate error prevalence occurred in different medication-dispensing systems, the stages of occurrence, and contributing factors. METHODOLOGY: Prospective observational study. The staging of the dispensing process were reviewed in five dispensing systems: Stock, Unitary-Dose dispensing systems (UDDS) without Computerized Prescription Order Entry (CPOE), CPOE-UDDS, Automated Dispensing Systems (ADS) without CPOE and CPOE-ADS. Dispensing errors were identified, together with the stages of occurrence of such errors and their contributing factors. RESULTS: 2,181 errors were detected among 54,169 opportunities of error. Error-rate: Stock, 10.7%; no-CPOE-UDDS, 3.7%, CPOE-UDDS, 2.2%, no-CPOE-ADS, 20.7%; CPOE-ADS, 2.9%. Most frequent stage when error occurs: Stock, preparation of order; no-CPOE-UDDS and CPOE-UDDS, filling of the unit dose cart; no-CPOE-ADS and CPOE-ADS, filling of the ADS. Most frequent error: Stock, no-CPOE-ADS and CPOE-ADS, omission; CPOE-UDDS, different amount of drug and no CPOE-UDDS, extra medication. Contributing factor: Stock, CPOE-ADS and no-CPOE ADS, stock out/supply problems; CPOE-UDDS, inexperienced personnel and deficient communication system between professionals; no-CPOE-UDDS, deficient communication system between professionals. CONCLUSIONS: Applying new technologies to the dispensing process has increased its safety, particularly, implementation of CPOE has enabled to reduce dispensing errors. PMID- 20206564 TI - [Analysis of the effectiveness of an antiemetic protocol used in an oncology division]. AB - OBJECTIVE: To analyse the effectiveness of an antiemetic protocol in patients receiving chemotherapy treatment. METHOD: Prospective study in patients with solid tumours receiving chemotherapy in an oncology day hospital between January 2006 and 2007. We conducted a literature review and an evaluation of the recommendations of different clinical practice guidelines. The emetogenic potential was calculated according to the Hesketh level (HL), and the antiemetic premedication was determined for each regimen. We evaluated the effectiveness of an antiemetic protocol by using a survey as a method for measuring emetic episodes and nausea in the acute and delayed phases. RESULTS: 172 patients completed the survey. 13.4% vomited in the acute phase and 16.9% in the delayed phase; the median number of times was 2 (1-8) and 1 (1-5) for each respective phase. With treatment regimens classed as HL 4-5, 18.5% experienced vomiting in the acute phase and 20.2% in the delayed phase, with 46% experiencing nausea in the acute phase and 38.4% in the delayed phase. Control of vomiting in patients with treatment regimens classed as HL 1-3 was 100% in acute phase and 91.7% in the delayed phase; nausea was reported by 27% in the acute phase and 31% in the delayed phase. The factors that contributed the most to the presence of vomiting and nausea were the emetogenic potential of the treatment regimen (p<0.05), vomiting in the previous cycle (p<0.05) and age younger than 50 years (p<0.002). DISCUSSION: The proposed antiemetic protocol is effective for controlling vomiting in chemotherapy regimens with an HL of 1-3. For highly emetogenic regimens, the antiemetic protocol is also effective, but protection is not complete. This protocol seems less effective for controlling nausea, although this is a subjective symptom which is difficult to assess and not routinely measured in clinical trials. PMID- 20206566 TI - [Approach to establishing and evaluating clinical relevance of drug interactions in HIV patients: 2009 update]. AB - OBJECTIVE: To update information on drug interactions in patients with HIV/AIDS. METHOD: PubMed was used to review English and Spanish articles published between 1 July 2007 and 30 April 2009 on antiretroviral drug interactions in humans. The search included a review of interactions between commonly-used medications in patients with HIV/AIDS and references from articles considered to be relevant. RESULTS: 52 new interactions were identified having to do with CYP3A4 metabolism and competition for intestinal absorption. New pharmacokinetic interactions were identified for medications that were already on the market, and we report interactions for drugs that were recently introduced: Tipranavir, Fosamprenavir, Darunavir, Raltegravir, Maraviroc and Etravirine. CONCLUSIONS: There is evidence of 52 new interactions between medications using metabolic routes in the CYP450 enzymatic system, and an explanation is given for others in the intestinal absorption process. PMID- 20206567 TI - [Cost minimisation analysis for darbepoetin alpha vs. epoetin alpha in chronic kidney disease patients on haemodialysis]. AB - INTRODUCTION: Multiple studies have shown that epoetin alpha (r-HuEpo) and darbepoetin alpha (NESP) are similarly effective and safe for maintaining haemoglobin levels in patients with chronic kidney disease (CKD). Nevertheless, there is some debate over their cost-effectiveness. The purpose of this study is to carry out a cost-minimisation analysis including a comparison of the costs to the hospital arising from treatment with r-HuEpo vs. NESP. METHODS: Prospective observational study. We included CRF patients on haemodialysis with no iron, vitamin B12 or folate deficiencies, treated with stable doses of IV r-HuEpo. Follow-up was performed over three periods: the first during six months, maintaining prior treatment with r-HuEpo; the second for eight months, after changing to NESP, and the third, during the final eight months, following resuming r-HuEpo treatment. For converting both treatments, the conversion factor established on technical sheet 1:200 was used. RESULTS: 51 patients completed the study and were valid for analysis. Their mean age was 68.3 years, and 18 were women (35.3%). The mean weekly doses at the end of each period were 8,058.8 (SD 3,911.1) IU for the EPO1 period, 39.4 (SD 21.6) microg for NESP and 7,882.4 (SD 4,594.1) IU for EPO2. The weekly costs for each treatment showed significant differences between NESP and r-HuEpo: the cost of NESP was higher. CONCLUSION: In our study, we found that r-HuEpo and NESP were similarly effective in patients with CRF on haemodialysis, but that there was a significant cost increase associated with NESP treatment. PMID- 20206568 TI - [Easier said than done: evaluation of quality programs of a hospital]. AB - OBJECTIVES: a) To evaluate the management of Quality Programs within the clinical services at Hospital Clinico Universitario Lozano Blesa (HCULB) and its impact on the improvement of the centre and its services. b) To propose recommendations to improve the management and impact of these programs. METHOD: A two-stage study was carried out: 1st stage: Analysis of the annual HCLUB Quality Program records for clinical services created in 2007. 2nd Stage: A structured interview with the physicians responsible for Quality Control regarding the aforementioned programs. RESULTS: Each Quality Program had an average of 5 objectives with a mean of complexity level of 76.1% (T and 16286C>T and two in the promoter region, 45996G>T and 46346C>A. We found that none of these polymorphisms alone had a significant effect on risk of SCCHN. However, when these four polymorphisms were evaluated together by the number of putative risk genotypes (i.e. 16195CC, 16286CC, 45996GT+TT, and 46346CA+AA), a statistically significantly increased risk of SCCHN was associated with the combined genotypes with three to four risk genotypes, compared with those with zero to two risk genotypes (adjusted odds ratio (OR)=1.27; 95% confidence interval (CI)=1.05-1.53). This increased risk was also more pronounced among young subjects (OR=1.81; 95% CI=1.11-2.96), men (OR=1.24; 95% CI=1.00-1.55), ever smokers (OR=1.25; 95%=1.01-1.56), ever drinkers (OR=1.29; 95% CI=1.04-1.60), patients with oropharyngeal cancer (OR=1.45; 95% CI=1.12-1.87), and oropharyngeal cancer with regional lymph node metastasis (OR=1.52; 95% CI=1.16-1.89). In conclusion, our results suggest that any one of MGMT variants may not have a substantial effect on SCCHN risk, but a joint effect of several MGMT variants may contribute to risk and progression of SCCHN, particularly for oropharyngeal cancer, in non-Hispanic whites. PMID- 20206584 TI - Investigation of degradation processes in IgG1 monoclonal antibodies by limited proteolysis coupled with weak cation-exchange HPLC. AB - A new cation-exchange high-performance liquid chromatography (HPLC) method that separates fragment antigen-binding (Fab) and fragment crystallizable (Fc) domains generated by the limited proteolysis of monoclonal antibodies (mAbs) was developed. This assay has proven to be suitable for studying complex degradation processes involving various immunoglobulin G1 (IgG1) molecules. Assignment of covalent degradations to specific regions of mAbs was facilitated by using Lys-C and papain to generate Fab and Fc fragments with unique, protease-dependent elution times. In particular, this method was useful for characterizing protein variants formed in the presence of salt under accelerated storage conditions. Two isoforms that accumulated during storage were readily identified as Fab-related species prior to mass-spectrometric analysis. Both showed reduced biological activity likely resulting from modifications within or in proximity of the complementarity-determining regions (CDRs). Utility of this assay was further illustrated in the work to characterize light-induced degradations in mAb formulations. In this case, a previously unknown Fab-related species which populated upon light exposure was observed. This species was well resolved from unmodified Fab, allowing for direct and high-purity fractionation. Mass spectrometric analysis subsequently identified a histidine-related degradation product associated with the CDR2 of the heavy chain. In addition, the method was applied to assess the structural organization of a noncovalent IgG1 dimer. A new species corresponding to a Fab-Fab complex was found, implying that interactions between Fab domains were responsible for dimerization. Overall, the data presented demonstrate the suitability of this cation-exchange HPLC method for studying a wide range of covalent and noncovalent degradations in IgG1 mAbs. PMID- 20206585 TI - Digestive amylase of a primitive animal, the scorpion: purification and biochemical characterization. AB - Scorpion, one of the most ancient invertebrates was chosen, as a model of a primitive animal, to purify and characterize an amylase located in the hepatopancreas. The scorpion digestive amylase (SDA) was purified. Pure SDA was obtained after heat treatment followed by ammonium sulfate fractionation and three steps of chromatography. The pure amylase is not glycosylated and has a molecular mass of 59,101 Da determined by MALDI-TOF MS analysis. The maximal amylase activity was measured at pH 7.0 and 50 degrees C, in the presence of Ca2+ and using potato starch as substrate. The enzyme was able to hydrolyze also, glycogen and amylose. The 23 NH2-terminal amino acid SDA residues were sequenced. The sequence obtained is similar to those of mammalian and avian pancreatic amylases. Nevertheless, polyclonal antibodies directed against SDA failed to recognize classical digestive amylases like the porcine pancreatic one. PMID- 20206586 TI - Abnormally low HbA1c secondary to hemoglobin J-Baltimore [beta 16(A13) Gly- >Asp]. Family study. PMID- 20206587 TI - Diagnosis of jejunal diverticulosis by means of double balloon enteroscopy. PMID- 20206588 TI - [Endobronchial chondromesenchymal hamartoma]. AB - Primary lung tumours are uncommon in childhood. Among these tumours, endobronchial masses are even less common and, among benign tumours, inflammatory pseudotumours and hamartomas have the highest incidence in children. We present the case of a 2.5-year-old girl with a left endobronchial chondromesenchymal hamartoma with obstruction of 90% of the bronchial lumen. Complete resection of the endobronchial mass was performed by rigid bronchoscopy and application of topical mitomycin C. After tumour resection and a 12-month follow-up, the patient has shown a favourable outcome with immediate disappearance of respiratory symptoms. Successive fibreoptic bronchoscopies have shown no residual tumour. PMID- 20206589 TI - Examination of a sociocultural model of excessive exercise among male and female adolescents. AB - There is substantial evidence that sociocultural pressures and body image disturbances can lead to disordered eating, yet few studies have examined their impact on excessive exercise. The study adapted a sociocultural model for disordered eating to predict excessive exercise using data from boys and girls in early adolescence (N=421). Perceived sociocultural pressures to lose weight and build muscle, body image disturbance and appearance investment were associated with a compulsive need to exercise. Adolescents' investment in appearance and body image disturbance fully mediated the relationship between sociocultural pressures and a compulsive need for exercise. There was no support for the meditational model in predicting adolescents' frequency or duration of exercise. Results support the sociocultural model as an explanatory model for excessive exercise, but suggest appearance investment and body image disturbance are important mediators of sociocultural pressures. PMID- 20206590 TI - An approach to bilateral facial paralysis. AB - Mobius syndrome is characterised by a congenital paralysis of the Facial and Abducens nerves. Treatment centres around functional free muscle transfers. We present 20 cases of Mobius reanimation, currently the largest published series. Our preferred approach has evolved over time to be a single stage bilateral procedure using segmental Latissimus dorsi muscles driven by the masseteric branch of the Trigeminal nerve. All cases showed significant improvement when reviewed by the senior surgeon and independent panel of observers. It was the senior authors' opinion that a more spontaneous smile was achieved in patients under ten years of age. PMID- 20206591 TI - Male pattern baldness and prostate cancer risk in a population-based case-control study. AB - PURPOSE: Male pattern baldness (MPB) and prostate cancer (PCa) share commonality as prevalent, heritable and androgen-related conditions. Studies exploring the relationship between the two conditions have been inconclusive. Using a population-based, case-control study of PCa, we explore the relationship between early-onset MPB and PCa risk. METHODS: Cases were men aged 35-74 diagnosed with PCa between 2002 and 2005 in King County, Washington. Controls were frequency matched by age and identified by random digit dialing. Hair pattern at age 30 and at 1 year prior to diagnosis (cases) or reference date (controls) was determined using showcards. PCa risk associated with balding was assessed with logistic regression. RESULTS: Data from 999 cases of PCa and 942 controls were analyzed. Hair loss at age 30 was more common in controls (25.2%) than cases (19.8%, p=0.005), and those with hair loss at age 30 had a 29% relative risk reduction for PCa (OR 0.71, 95% CI 0.56-0.91). No risk reduction was seen for men only reporting hair loss at referent age (OR 0.90, 95% CI 0.73-1.12). In men aged >60 at referent date, the risk reduction was greater for men with hair loss at age 30 from both the top of head and forehead (OR 0.55, 95% CI 0.33-0.93). CONCLUSION: Early-onset MPB was associated with a reduced relative risk of PCa in this population-based study. Further research into a possible mechanistic link between these prevalent and androgen-related conditions is warranted. PMID- 20206592 TI - Molecular characterization of Cryptosporidium isolates from humans in Ethiopia. AB - In this study, 1034 faecal samples from patients with diarrhoea were screened for Cryptosporidium oocysts. Samples were collected from nine different regions in Ethiopia. Of these, 79 samples (7.6%) were positive for Cryptosporidium by modified Ziehl-Neelson staining. From all positive samples DNA was extracted and PCR amplification of the COWP, SSU-rRNA and GP60 gene fragments was performed. A total of 41 samples (52%) were positive in any of the three typing methods. The majority of isolates (39 of 41) was identified as Cryptosporidium parvum, with one Cryptosporidium hominis and one mixed infection. Sequencing of the GP60 gene fragments of 13 isolates resulted in three different subgenotypes of C. parvum, all belonging to the zoonotic subtype family IIa and one subtype of C. hominis (Ib). These data identify C. parvum as the major cause of human cryptosporidiosis in Ethiopia and suggest a zoonotic transmission of the disease in contrast to reports from other developing countries. PMID- 20206593 TI - Visual detection of single-stranded target DNA using pyrroloquinoline-quinone loaded liposomes as a tracer. AB - The preparation of DNA-tagged liposomes containing an encapsulated prosthetic group tracer, pyrroloquinoline quinone (PQQ), and their application to the development of a sandwich-type hybridization assay for the visual detection of single-stranded DNA are described. Capture DNA is conjugated to the surface of microtiter plate wells through a biotin-streptavidin interaction. Target DNA is incubated with the plate in high salt concentrations. The reporter DNA-tagged liposomes encapsulating PQQ, the prosthetic group of the apo-enzyme glucose dehydrogenase (GDH), are used as the label to probe for bound target DNA. After washing away unbound liposomes and subsequent lysis of the bound fraction by surfactant, PQQ is released and available to activate the apo-enzyme. In the presence of glucose and a redox dye, 2,6-dichlorophenol indophenol (DCPIP), the dye is reduced to yield an optical color change from blue to colorless. This transition is observed visually or spectrophotometrically. The degree of optical change is proportional to the amount of PQQ present, which directly relates to the number of liposomes and, thus, the total amount of target DNA. An arbitrary target DNA sequence is used as a model system, and a limit of detection of 62 fmol is achieved. PMID- 20206594 TI - An analysis of substrate binding interactions in the heme peroxidase enzymes: a structural perspective. AB - The interactions of heme peroxidase enzymes with their substrates have been studied for many years, but only in the last decade or so has structural information begun to appear. This review looks at crystal structures for a number of heme peroxidases in complex with a number of (mainly organic) substrates. It examines the nature and location of the binding interaction, and explores functional similarities and differences across the family. PMID- 20206595 TI - The alternative complex III of Rhodothermus marinus and its structural and functional association with caa3 oxygen reductase. AB - An alternative complex III (ACIII) is a respiratory complex with quinol:electron acceptor oxidoreductase activity. It is the only example of an enzyme performing complex III function that does not belong to bc1 complex family. ACIII from Rhodothermus (R.) marinus was the first enzyme of this type to be isolated and characterized, and in this work we deepen its characterization. We addressed its interaction with quinol substrate and with the caa3 oxygen reductase, whose coding gene cluster follows that of the ACIII. There is at least, one quinone binding site present in R. marinus ACIII as observed by fluorescence quenching titration of HQNO, a quinone analogue inhibitor. Furthermore, electrophoretic and spectroscopic evidences, taken together with mass spectrometry revealed a structural association between ACIII and caa3 oxygen reductase. The association was also shown to be functional, since quinol:oxygen oxidoreductase activity was observed when the two isolated complexes were put together. This work is thus a step forward in the recognition of the structural and functional diversities of prokaryotic respiratory chains. PMID- 20206596 TI - Modulation of intracellular chloride channels by ATP and Mg2+. AB - We report the effects of ATP and Mg2+ on the activity of intracellular chloride channels. Mitochondrial and lysosomal membrane vesicles isolated from rat hearts were incorporated into bilayer lipid membranes, and single chloride channel currents were measured. The observed chloride channels (n=112) possessed a wide variation in single channel parameters and sensitivities to ATP. ATP (0.5-2 mmol/l) modulated and/or inhibited the chloride channel activities (n=38/112) in a concentration-dependent manner. The inhibition effect was irreversible (n=5/93) or reversible (n=15/93). The non-hydrolysable ATP analogue AMP-PNP had a similar inhibition effect as ATP, indicating that phosphorylation did not play a role in the ATP inhibition effect. ATP modulated the gating properties of the channels (n=6/93), decreased the channels' open dwell times and increased the gating transition rates. ATP (0.5-2 mmol/l) without the presence of Mg2+ decreased the chloride channel current (n=12/14), whereas Mg2+ significantly reversed the effect (n=4/4). We suggest that ATP-intracellular chloride channel interactions and Mg2+ modulation of these interactions may regulate different physiological and pathological processes. PMID- 20206597 TI - The Cdc48-Ufd1-Npl4 complex is central in ubiquitin-proteasome triggered catabolite degradation of fructose-1,6-bisphosphatase. AB - The switch from gluconeogenesis to glycolysis in yeast has been shown to require ubiquitin-proteasome dependent elimination of the key enzyme fructose-1,6 bisphosphatase (FBPase). Prior to proteasomal degradation, polyubiquitination of the enzyme occurs via the ubiquitin-conjugating enzymes Ubc1, Ubc4, Ubc5 and Ubc8 in conjunction with a novel multi-subunit ubiquitin ligase, the Gid complex. As an additional machinery required for the catabolite degradation process, we identified the trimeric Cdc48(Ufd1-Npl4) complex and the ubiquitin receptors Dsk2 and Rad23. We show that this machinery acts between polyubiquitination of FBPase and its degradation by the proteasome. PMID- 20206598 TI - Differentiation of primate ES cells into retinal cells induced by ES cell-derived pigmented cells. AB - PURPOSE: Photoreceptors cannot regenerate and recover their functions once disordered. Transplantation of retinal pigment epithelium (RPE) has recently become a possible therapeutic approach for retinal degeneration. In the present study, we investigated the induction of photoreceptors by coculturing primate embryonic stem cells (ESCs) with ESC-derived RPE cells. METHODS: RPE cells were derived by coculturing ESCs and Sertoli cells. Photoreceptors were then induced by using ESC-derived RPE cells and retinoic acid (RA) RESULTS: RPE cell generation was confirmed by morphological analysis, which revealed highly pigmented polygonal cells with a compact cell-cell arrangement. After coculturing ESCs and RPE cells, some ESC derivatives became immunopositive for rhodopsin. RT PCR analysis demonstrated the expression of retina-related gene markers such as Pax6, CRX, IRBP, rhodopsin, rhodopsin kinase, and Muschx10A. When RA was added, a distinct increase in the expression of photoreceptor-specific proteins and genes was found. In addition, the differentiation of bipolar horizontal cells was demonstrated by protein and gene expression. The ESCs that were cocultured with RPE cells and treated with RA were transplanted into the renal capsule or intra vitreal space of nude mice. Grafted ESC derivatives demonstrated extensive rhodopsin expression, and they survived and organized into recipient tissues, although they formed teratomas. CONCLUSION: These results indicate that coculturing ESCs with ESC-derived RPE cells is a useful and efficient method for inducing photoreceptors and providing an insight into the use of ESCs for retina regeneration. PMID- 20206599 TI - A novel cold-regulated gene from Camellia sinensis, CsCOR1, enhances salt- and dehydration-tolerance in tobacco. AB - In present research, the full-length cDNA and the genomic sequence of a novel cold-regulated gene, CsCOR1, were isolated from Camellia sinensis L. The deduced protein CsCOR1 contains a hydrophobic N-terminus as a signal peptide and a hydrophilic C-terminal domain that is rich in glycine, arginine and proline. Two internal repetitive tridecapeptide fragments (HSVTAGRGGYNRG) exist in the middle of the C-terminal domain and the two nucleotide sequences encoding them are identical. CsCOR1 was localized in the cell walls of transgenic-tobaccos via CsCOR1::GFP fusion approach. The expression of CsCOR1 in tea leaves was enhanced dramatically by both cold- and dehydration-stress. And overexpression of CsCOR1 in transgenic-tobaccos improved obviously the tolerance to salinity and dehydration. PMID- 20206600 TI - Quantification of cellular uptake and in vivo tracking of transduction using real time monitoring. AB - Protein transduction domains (PTDs) are short amino acid sequences that promote their own translocation across the cell plasma membrane and have been studied for possible use in drug delivery and gene therapy. However, no direct method to quantify transduction is available. Here, using a new luciferase-tagged human PTD, we show that cellular uptake levels can be determined in a reliable manner. Furthermore, we show that enhanced in vivo tracking by human PTD can be quantified in a mouse model. This is the first report on the direct quantification of PTD transduction in vitro and in vivo, which will be necessary for studying its possible therapeutic application in drug delivery and gene therapy. PMID- 20206601 TI - Atomic evidence that modification of H-bonds established with amino acids critical for host-cell binding induces sterile immunity against malaria. AB - Based on the 3D X-ray crystallographic structures of relevant proteins of the malaria parasite involved in invasion to host cells and 3D NMR structures of High Activity Binding Peptides (HABPs) and their respective analogues, it was found that HABPs are rendered into highly immunogenic and sterile immunity inducers in the Aotus experimental model by modifying those amino acids that establish H bonds with other HABPs or binding to host's cells. This finding adds striking and novel physicochemical principles, at the atomic level, for a logical and rational vaccine development methodology against infectious disease, among them malaria. PMID- 20206602 TI - Structural insights into mouse anti-apoptotic Bcl-xl reveal affinity for Beclin 1 and gossypol. AB - This study reports the crystal structures of Bcl-xl wild type and three Bcl-xl mutants (Y101A, F105A, and R139A) with amino acid substitutions in the hydrophobic groove of the Bcl-xl BH3 domain. An additional 12 ordered residues were observed in a highly flexible loop between the alpha1 and alpha2 helices, and were recognized as an important deamidation site for the regulation of apoptosis. The autophagy-effector protein, Beclin 1, contains a novel BH3 domain (residues 101-125), which binds to the surface cleft of Bcl-xl, as confirmed by nuclear magnetic resonance (NMR) spectroscopy and analytical gel-filtration results. Gossypol, a potent inhibitor of Bcl-xl, had a K(d) value of 0.9 microM. In addition, the structural and biochemical analysis of five Bcl-xl substitution mutants will provide structural insights into the design and development of anti cancer drugs. PMID- 20206603 TI - The Nop5-L7A-fibrillarin RNP complex and a novel box C/D containing sRNA of Halobacterium salinarum NRC-1. AB - RNA 2'O-methylation is a frequent modification of rRNA and tRNA and supposed to influence RNA folding and stability. Ribonucleoprotein (RNP) complexes, containing the proteins Nop5, L7A, fibrillarin, and a box C/D sRNA, are guided for 2'O-methylation by interactions of their RNA component with their target RNA. In vitro complex assembly was analyzed for several thermophilic Archaea but in vivo studies are rare, even unavailable for halophilic Archaea. To analyze the putative box C/D RNP complex in the extremely halophilic Halobacterium salinarum NRC-1 we performed pull-down analysis and identified the proteins Nop5, L7A, and fibrillarin and the tRNA(Trp) intron, as a typical box C/D sRNA of this RNP complex in vivo. We show for the first time a ribonucleolytic activity of the purified RNP complex proteins, as well as for the RNP complex containing pull down fractions. Furthermore, we identified a novel RNA (OE4630R-3'sRNA) as part of the complex, containing the typical boxes C/D and C'/D' sequence motifs and being twice as abundant as the tRNA(Trp) intron. PMID- 20206604 TI - Differentiation of mouse embryonic stem cells into dental epithelial-like cells induced by ameloblasts serum-free conditioned medium. AB - Embryonic stem cells (ESCs) possess an intrinsic self-renewal ability and can differentiate into numerous types of functional tissue cells; however, whether ESCs can differentiate toward the odontogenic lineage is still unknown. In this study, we developed an efficient culture strategy to induce the differentiation of murine ESCs (mESCs) into dental epithelial cells. By culturing mESCs in ameloblasts serum-free conditioned medium (ASF-CM), we could induce their differentiation toward dental epithelial cell lineages; however, similar experiments with the tooth germ cell-conditioned medium (TGC-CM) did not yield effective results. After culturing the cells for 14days in the differentiation inducing media, the expression of ameloblast-specific proteins such as cytokeratin (CK)14, ameloblastin (AMBN), and amelogenin (AMGN) was markedly higher in mESCs obtained with embryoid body (EB) formation than in mESCs obtained without EB formation. We observed that immunocompromised mice implanted with induced murine EBs (mEBs) showed tissue regenerative capacity and produced odontogenic epithelial-like structures, whereas those implanted with mSCE monolayer cells mainly formed connective tissues. Thus, for the first time, we report that ASF-CM provides a suitable microenvironment for inducing mESC differentiation along the odontogenic epithelial cell lineage. This result has important implications for tooth tissue engineering. PMID- 20206605 TI - The blood-brain barrier penetration and distribution of PEGylated fluorescein doped magnetic silica nanoparticles in rat brain. AB - PEGylated PAMAM conjugated fluorescein-doped magnetic silica nanoparticles (PEGylated PFMSNs) have been synthesized for evaluating their ability across the blood-brain barrier (BBB) and distribution in rat brain. The obtained nanoparticles were characterized by transmission electron microscopy (TEM), thermal gravimetry analyses (TGA), zeta potential (zeta-potential) titration, and X-ray photoelectron spectroscopy (XPS). The BBB penetration and distribution of PEGylated PFMSNs and FMSNs in rat brain were investigated not only at the cellular level with Confocal laser scanning microscopy (CLSM), but also at the subcellular level with transmission electron microscopy (TEM). The results provide direct evidence that PEGylated PFMSNs could penetrate the BBB and spread into the brain parenchyma. PMID- 20206606 TI - A novel copper(II) coordination at His186 in full-length murine prion protein. AB - To explore Cu(II) ion coordination by His(186) in the C-terminal domain of full length prion protein (moPrP), we utilized the magnetic dipolar interaction between a paramagnetic metal, Cu(II) ion, and a spin probe introduced in the neighborhood of the postulated binding site by the spin labeling technique (SDSL technique). Six moPrP mutants, moPrP(D143C), moPrP(Y148C), moPrP(E151C), moPrP(Y156C), moPrP(T189C), and moPrP(Y156C,H186A), were reacted with a methane thiosulfonate spin probe and a nitroxide residue (R1) was created in the binding site of each one. Line broadening of the ESR spectra was induced in the presence of Cu(II) ions in moPrP(Y148R1), moPrP(Y151R1), moPrP(Y156R1), and moPrP(T189R1) but not moPrP(D143R1). This line broadening indicated the presence of electron electron dipolar interaction between Cu(II) and the nitroxide spin probe, suggesting that each interspin distance was within 20 A. The interspin distance ranges between Cu(II) and the spin probes of moPrP(Y148R1), moPrP(Y151R1), moPrP(Y156R1), and moPrP(T189R1) were estimated to be 12.1 A, 18.1 A, 10.7 A, and 8.4 A, respectively. In moPrP(Y156R1,H186A), line broadening between Cu(II) and the spin probe was not observed. These results suggest that a novel Cu(II) binding site is involved in His186 in the Helix2 region of the C-terminal domain of moPrP(C). PMID- 20206607 TI - Beta-tricalcium phosphate exerts osteoconductivity through alpha2beta1 integrin and down-stream MAPK/ERK signaling pathway. AB - Beta-tricalcium phosphate (beta-TCP) has been clinically used as a bone graft substitute for decades because of its excellent osteoconductivity. However, the exact mechanism(s) by which beta-TCP exerts osteoconductivity are not fully documented. This study was aimed to investigate the molecular mechanism(s) by which beta-TCP modulates the biological response of primary human osteoblasts (HOBs). It was showed that HOBs seeded into the beta-TCP scaffolds expressed significantly higher levels of osteogenic genes, compared to those cultured on tissue culture plastic; meanwhile these cells showed 7-fold increase in alpha2 integrin subunit gene expression and the activation of the mitogen-activated protein kinase (MAPK)/extracellular related kinase (ERK) signaling pathway. In addition, the osteogenic conduction by beta-TCP scaffolds was attenuated directly by inhibiting MAPK/ERK or indirectly by blocking the alpha2beta1 integrin signaling pathway. We concluded that beta-TCP scaffold exerts osteoconductivity through alpha2beta1 integrin and down-stream MAPK/ERK signaling pathway, suggesting a feasible approach to consider when designing or fabricating the scaffolds for bone tissue engineering. PMID- 20206608 TI - Oncostatin M induces dendritic cell maturation and Th1 polarization. AB - Oncostatin M (OSM) is a pleiotropic cytokine and a member of the gp130/IL-6 cytokine family that has been found to be involved in both pro- and anti inflammatory responses in cell-mediated immunity. Maturation of dendritic cells (DCs) is crucial for initiation of primary immune responses and is regulated by several stimuli. In this study, the role of OSM in the phenotypic and functional maturation of DCs was evaluated in vitro. Stimulation with OSM upregulated the expression of CD80, CD86, MHC class I and MHC class II and reduced the endocytic capacity of immature DCs. Moreover, OSM induced the allogeneic immunostimulatory capacity of DCs by stimulating the production of the Th1-promoting cytokine IL 12. OSM also increased the production of IFN-gamma by T cells in mixed-lymphocyte reactions, which would be expected to contribute to the Th1 polarization of the immune response. The expression of surface markers and cytokine production in DCs was mediated by both the MAPK and NF-kappaB pathways. Taken together, these results indicate that OSM may play a role in innate immunity and in acquired immunity by enhancing DCs maturation and promoting Th1 immune responses. PMID- 20206609 TI - Inhibition of epidermal growth factor receptor-overexpressing cancer cells by camptothecin, 20-(N,N-diethyl) glycinate. AB - The epidermal growth factor receptor (EGFR) represents a prognostic marker for short survival of patients and therapy resistance of tumors. Despite clinical usefulness of EGFR tyrosine kinase inhibitors, resistance can develop. Therefore, there is an urgent need for novel EGFR inhibitors. Camptothecins have been characterized as inhibitors of DNA topoisomerase I (TOP1), although a correlation between TOP1 expression and activity is not well established in clinical biopsies. Hence, other targets may also be relevant. By molecular docking, we found that camptothecin 20-N,N-glycinate (CPTg) and camptothecin (CPT) bind to the same pharmacophore at EGFR as erlotinib, albeit to partly different amino acids. To validate the in silico results, CPT and CPTg were evaluated for their cytotoxic activity and downstream signaling mechanisms in U87MG glioblastoma cell lines transduced with different expression vectors for EGFR. All transduced cell lines were more susceptible to CPTg or CPT than the non-transduced cells, indicating a preferential activity towards EGFR-expressing tumor cells. Microarray-based mRNA hybridizations were performed in treated a non-treated cell lines. Subsets of genes were commonly regulated between the cell lines. By pathway analyses, we ranked canonical pathways according to differential gene expression after drug treatment. The pathways for G2/M DNA damage checkpoint regulation, aryl hydrocarbon receptor signaling, and xenobiotic metabolism and endoplasmatic reticulum stress were top ranked. In conclusion, binding of CPTg and CPT to the erlotinib pharmacophore and preferential cytotoxicity towards EGFR overexpressing cells indicate susceptibility towards erlotinib-resistant tumors. Multiple mechanisms may account for cytotoxicity of these camptothecins. PMID- 20206610 TI - A morphologically distinct granule cell type in the dentate gyrus of the red fox correlates with adult hippocampal neurogenesis. AB - Wild red foxes, proverbially cunning carnivores, are investigated for adult hippocampal neurogenesis and morphological characteristics of the dentate gyrus. Adult red foxes harbor almost 15-times more young, doublecortin-positive neurons in their dentate gyrus than domesticated dogs. The number of doublecortin positive cells corresponds to 4.4% of the total granule cell number, whereas dividing cells amount to only 0.06%. Compared to laboratory mice, proliferating (Ki67-positive) and dying cells are rare, but the percentage of new neurons is quite similar. The numbers of proliferating cells, young cells of neuronal lineage and dying cells correlate. Resident granule cells can be divided into two types with strikingly different morphologies, staining patterns and distinct septotemporal distributions. Small sized granule cells with a nuclear diameter of 7.3 microm account for approximately 83% of all granule cells. The remaining granule cells are significantly larger with a nuclear diameter of 9.4 microm diameter and stain heavily for NeuN. Septally and mid-septotemporally, densely packed small cells dominate. Here, only few large granule cells are scattered throughout the layer. Temporally, granule cells become more loosely packed and most of the cells are of the large type. High rates of neurogenesis are observed in foxes with high numbers of large granule cells, whereas the number of small granule cells does not correlate with any of the neurogenesis-related cell counts. Staining for parvalbumin, glutamate receptor 2/3, GAP-43 and dynorphin shows an anatomical context that is a composite of features common also to other mammalian species. In summary, we report a morphologically distinct granule cell type which correlates with adult hippocampal neurogenesis in the fox. Furthermore, the maturation phase of the young neurons may be prolonged as in other long living species such as primates. PMID- 20206611 TI - Actions of adiponectin on the excitability of subfornical organ neurons are altered by food deprivation. AB - Adiponectin (ADP) is a peptide produced by adipose tissue, which acts as an insulin sensitizing hormone. Recent studies have shown that adiponectin receptors (AdipoR1 and AdipoR2) are present in the CNS, and although adiponectin does appear in both circulation and the cerebrospinal fluid there is still some debate as to whether or not ADP crosses the blood brain barrier (BBB). Circumventricular organs (CVO) are CNS sites which lack normal BBB, and thus represent sites at which circulating adiponectin may act to directly influence the CNS. The subfornical organ (SFO) is a CVO that has been implicated in the regulation of energy balance as a consequence of the ability of SFO neurons to respond to a number of different circulating satiety signals including amylin, CCK, PYY and ghrelin. Our recent microarray analysis suggested the presence of adiponectin receptors in the SFO. We report here that the SFO shows a high density of mRNA for both adiponectin receptors (AdipoR1 and AdipoR2), and that ADP influences the excitability of dissociated SFO neurons. Separate subpopulations of SFO neurons were either depolarized (8.9+/-0.9 mV, 21 of 97 cells), or hyperpolarized (-8.0+/ 0.5 mV, 34 of 97 cells), by bath application of 10nM ADP, effects which were concentration dependent and reversible. Our microarray analysis also suggested that 48 h of food deprivation resulted in specific increases in AdipoR2 mRNA expression (no effect on AdipoR1 mRNA), observations which we confirm here using real-time PCR techniques. The effects of food deprivation also resulted in a change in the responsiveness of SFO neurons to adiponectin with 77% (8/11) of cells tested responding to adiponectin with depolarization, while no hyperpolarizations were observed. These observations support the concept that the SFO may be a key player in sensing circulating ADP and transmitting such information to critical CNS sites involved in the regulation of energy balance. PMID- 20206612 TI - Differential effects of temperature on acid-activated currents mediated by TRPV1 and ASIC channels in rat dorsal root ganglion neurons. AB - Elevated temperature and decreased extracellular pH are hallmarks of inflammatory pain states. Dorsal root ganglia (DRG) neurons are integral in transferring painful stimuli from the periphery to central sites. This study investigated the effect of elevated temperatures on the response of DRG neurons to acute application of acidic solutions. At room temperature (22 degrees C), in response to pH 5.5, there were a variety of kinetic responses consistent with differential expression of TRPV1 and ASIC channels. Increasing the temperature resulted in a significant increase in the peak and total current mediated by TRPV1 in response to an acidic solution. In contrast, the amplitude of a fast activating, rapidly inactivating ASIC1-like current was not affected by increasing the temperature but did result in an increased rate of desensitization that reduced the total current level. This effect on the rate of desensitization was temperature dependent and could be reversed by returning to 22 degrees C. Likewise, cells exhibiting slowly inactivating ASIC2-like responses also had temperature dependent increase in the rate of desensitization. The ASIC2-like responses and the TRPV1 responses tended to decrease in amplitude with repetitive application of pH 5.5 even at 22 degrees C. The rate of desensitization of ASIC-like currents activated by less acidic solutions (pH 6.8) was also increased in a temperature dependent manner. Finally, acidic pH reduced threshold to trigger action potentials, however, the pattern of action potential firing was shaped by the distribution of ASIC and TRPV1 channels. These results indicate that the ambient temperature at which acidosis occurs has a profound effect on the contribution of ASIC and TRPV1 channels, therefore, altering the neuronal excitability. PMID- 20206613 TI - Role of fatty acid chain length on the induction of apoptosis by newly synthesized catechin derivatives. AB - The catechins, a family of polyphenols found in tea, can evoke various responses, including apoptosis. In this study we investigated whether the chemical modification of (-)-epigallocatechin gallate (EGCG) could enhance its apoptosis activity. We found that one of the catechin conjugated with capric acid [(2R,3S) 3',4',5,7-tetrahydroxyflavan-3-yl decanoate; catechin-C10] was most potent to induce apoptosis in U937 cells. C10 treatment resulted in a significant increase in reactive oxygen species (ROS) formation, mitochondrial membrane potential (MMP) loss, cytochrome c release caspase-9 and caspase-3 activation. In addition to this C10 also activated extrinsic pathway significantly as evident by time dependent increase in Fas expression and caspase-8 activity. C10 mediated cleavage of Bid may be an important event for cross talk between intrinsic and extrinsic signaling. Moreover, pre-treatment of cells with anti-oxidant N-acetyl L-cysteine (NAC) significantly prevented C10-induced apoptosis but did not protect MMP loss. Treatment of cells with pan-caspase inhibitor significantly inhibited apoptosis indicating that caspases are playing key role. In addition to this C10 was found to induce apoptosis in human colon cancer (HCT116) cells while it showed resistance to human keratinocytes (HaCat). In short our results showed that the optimal fatty acid side chain length is required for the apoptosis inducing activity of catechin derivatives in U937 cells. PMID- 20206614 TI - Benzo[a]pyrene exposed to solar-simulated light inhibits apoptosis and augments carcinogenicity. AB - Polycyclic aromatic hydrocarbons (PAHs) such as benzo[a]pyrene (BaP) are widespread environmental pollutants and several lines of experimental evidence have suggested a role in carcinogenesis. PAHs in the environment are exposed to sunlight and photomodified PAHs have been detected in contaminated sediment and air particulate matter; however, the carcinogenicity of photomodified PAHs is not well understood. In this study, we found that solar-simulated light-irradiated BaP (LBaP) inhibited apoptosis, leading to cancer. LBaP suppressed apoptosis induced by cell detachment and serum depletion in a dose and light-irradiated time-dependent manner. The antiapoptotic effect was related to the production of reactive oxygen species from degraded BaP. The cells that survived apoptosis by LBaP treatment were transformed having the ability to form colonies in soft agar and tumors in nude mice. These capabilities were specific to LBaP, not BaP itself. The results suggested that the carcinogenicity of PAHs may be attributable not only to the genetic damage induced by their metabolites, but also to the antiapoptotic effects of oxidative products on exposure to sunlight. PMID- 20206615 TI - A rapid and fully-automated method for the quantitation of tricyclic antidepressants in serum using turbulent-flow liquid chromatography-tandem mass spectrometry. AB - BACKGROUND: We describe a fully-automated turbulent-flow liquid chromatography tandem mass spectrometry method for the detection of tricyclic antidepressant drugs (amitriptyline, desipramine, imipramine, and nortriptyline) in serum. METHODS: Human serum and an internal standard were injected directly onto a Cyclone-P online solid-phase extraction (SPE) column (0.5 x 50 mm). Following removal of serum proteins and other components the analytes were transferred to a Hypersil Gold C-18 (50 x 3 mm) analytical column. Elution occurred with a gradient of water and acetonitrile each with 0.1% formic acid. Analytes were ionized and detected over a 3.5 min analysis time by electrospray-ionization mass spectrometry with selected reaction monitoring (SRM). Matrix effects were well characterized and carryover, precision, linearity, recovery and limits of detection and quantitation were evaluated. RESULTS: The simple and complex precision CVs for all compounds were < or = 16%. The limits of detection and quantitation for all drugs were < or = 3 ng/ml and <20 ng/ml, respectively. Recoveries were between 97 and 114%. Slopes for method comparison plots were all >0.96. Proficiency testing materials had values within 2 SDI of peer group means for all drugs. CONCLUSION: Based on validation data, this is a specific, sensitive fully-automated method for rapid quantitation of tricyclic antidepressants in serum. PMID- 20206616 TI - Synovial joint morphogenesis requires the chondrogenic action of Sox5 and Sox6 in growth plate and articular cartilage. AB - The mechanisms underlying synovial joint development remain poorly understood. Here we use complete and cell-specific gene inactivation to identify the roles of the redundant chondrogenic transcription factors Sox5 and Sox6 in this process. We show that joint development aborts early in complete mutants (Sox5(-/-)6(-/ )). Gdf5 and Wnt9a expression is punctual in articular progenitor cells, but Sox9 downregulation and cell condensation in joint interzones are late. Joint cell differentiation is unsuccessful, regardless of lineage, and cavitation fails. Sox5 and Sox6 restricted expression to chondrocytes in wild-type embryos and continued Erg expression and weak Ihh expression in Sox5(-/-)6(-/-) growth plates suggest that growth plate failure contribute to this Sox5(-/-)6(-/-) joint morphogenesis block. Sox5/6 inactivation in specified joint cells and chondrocytes (Sox5(fl/fl)6(fl/fl)Col2Cre) also results in a joint morphogenesis block, whereas Sox5/6 inactivation in specified joint cells only (Sox5(fl/fl)6(fl/fl)Gdf5Cre) results in milder joint defects and normal growth plates. Sox5(fl/fl)6(fl/fl)Gdf5Cre articular chondrocytes remain undifferentiated, as shown by continued Gdf5 expression and pancartilaginous gene downregulation. Along with Prg4 downregulation, these defects likely account for joint tissue overgrowth and incomplete cavitation in adult mice. Together, these data suggest that synovial joint morphogenesis relies on essential roles for Sox5/6 in promoting both growth plate and articular chondrocyte differentiation. PMID- 20206618 TI - Neural crest migration requires the activity of the extracellular sulphatases XtSulf1 and XtSulf2. AB - In vertebrates, there are two related genes, Sulf1 and Sulf2 that code for extracellular heparan sulphate 6-0-endosulphatases. These enzymes act to post synthetically remodel heparan sulphate chains, generating structural diversity of cell surface HSPGs; this activity provides an important mechanism to modulate developmental cell signalling. Here we describe the expression and activity of Xenopus tropicalis Sulf2 (XtSulf2), which like XtSulf1, can act extracellularly to inhibit BMP4 and FGF4 signalling. Consistent with its discrete expression in regions of the anterior developing nervous system, we found that overexpression of XtSulf2 disrupts the expression of a set of neural markers and inhibits the migration of the neural crest. Using a combination of grafting experiments and antisense morpholino based knockdown studies in Xenopus embryos, we demonstrate that endogenous XtSulf1 and XtSulf2 play an important role during cranial neural crest cell migration in vivo. PMID- 20206617 TI - Stimulation of chondrocyte hypertrophy by chemokine stromal cell-derived factor 1 in the chondro-osseous junction during endochondral bone formation. AB - During endochondral bone formation, chondrocytes undergo differentiation toward hypertrophy before they are replaced by bone and bone marrow. In this study, we found that a G-protein coupled receptor CXCR4 is predominantly expressed in hypertrophic chondrocytes, while its ligand, chemokine stromal cell-derived factor 1 (SDF-1) is expressed in the bone marrow adjacent to hypertrophic chondrocytes. Thus, they are expressed in a complementary pattern in the chondro osseous junction of the growth plate. Transfection of a CXCR4 cDNA into pre hypertrophic chondrocytes results in a dose-dependent increase of hypertrophic markers including Runx2, Col X, and MMP-13 in response to SDF-1 treatment. In organ culture SDF-1 infiltrates cartilage and accelerates growth plate hypertrophy. Furthermore, a continuous infusion of SDF-1 into the rabbit proximal tibial physis results in early physeal closure, which is accompanied by a transient elevation of type X collagen expression. Blocking SDF-1/CXCR4 interaction suppresses the expression of Runx2. Thus, interaction of SDF-1 and CXCR4 is required for Runx2 expression. Interestingly, knocking down Runx2 gene expression results in a decrease of CXCR4 mRNA levels in hypertrophic chondrocytes. This suggests a positive feedback loop of stimulation of chondrocyte hypertrophy by SDF-1/CXCR4, which is mediated by Runx2. PMID- 20206619 TI - Genetic interaction between Sox10 and Zfhx1b during enteric nervous system development. AB - The involvement of SOX10 and ZFHX1B in Waardenburg-Hirschsprung disease (hypopigmentation, deafness, and absence of enteric ganglia) and Mowat-Wilson syndrome (mental retardation, facial dysmorphy and variable congenital malformations including Hirschsprung disease) respectively, highlighted the importance of both transcription factors during enteric nervous system (ENS) development. The expression and function of SOX10 are now well established, but those of ZFHX1B remain elusive. Here we describe the expression profile of Zfhx1b and its genetic interactions with Sox10 during mouse ENS development. Through phenotype analysis of Sox10;Zfhx1b double mutants, we show that a coordinated and balanced interaction between these two genes is required for normal ENS development. Double mutants present with more severe ENS defects due to decreased proliferation of enteric progenitors and increased neuronal differentiation from E11.5 onwards. Thus, joint activity between these two transcription factors is crucial for proper ENS development and our results contribute to the understanding of the molecular basis of ENS defects observed both in mutant mouse models and in patients carrying SOX10 and ZFHX1B mutations. PMID- 20206620 TI - Sustained delivery of sphingosine-1-phosphate using poly(lactic-co-glycolic acid) based microparticles stimulates Akt/ERK-eNOS mediated angiogenesis and vascular maturation restoring blood flow in ischemic limbs of mice. AB - Therapeutic angiogenesis is a promising strategy for treating ischemia. The lysophospholipid mediator sphingosine-1-phosphate (S1P) acts on vascular endothelial cells to stimulate migration and tube formation, and plays the critical role in developmental angiogenesis. We developed poly(lactic-co-glycolic acid) (PLGA)-based S1P-containing microparticles (PLGA-S1P), which are biodegradable and continuously release S1P, and studied the effects of PLGA-S1P on neovascularization in murine ischemic hindlimbs. Intramuscular injections of PLGA-S1P stimulated blood flow in C57BL/6 mice dose-dependently, with repeated administrations at a 3-day interval, rather than a single bolus or 6-day interval, over 28 days conferring the optimal stimulating effect. In Balb/c mice that exhibit limb necrosis and dysfunction due to retarded blood flow recovery, injections of PLGA-S1P stimulated blood flow with alleviation of limb necrosis and dysfunction. PLGA-S1P alone did not induce edema in ischemic limbs, and rather blocked vascular endothelial growth factor-induced edema. PLGA-S1P not only increased the microvessel densities in ischemic muscle, but promoted coverage of vessels with smooth muscle cells and pericytes, thus stabilizing vessels. PLGA-S1P stimulated Akt and ERK with increased phosphorylation of endothelial nitric oxide synthase in ischemic muscle. The effects of the nitric oxide synthase inhibitor, Nomega-nitro-L-arginine methylester, showed that PLGA S1P-induced blood flow stimulation was partially dependent on nitric oxide. Injections of PLGA-S1P also increased the expression of angiogenic factors and the recruitment of CD45-, CD11b- and Gr-1-positive myeloid cells, which are implicated in post-ischemic angiogenesis, into ischemic muscle. These results indicate that PLGA-based, sustained local delivery of S1P is a potentially useful therapeutic modality for stimulating post-ischemic angiogenesis. PMID- 20206621 TI - SAMe prevents the up regulation of toll-like receptor signaling in Mallory-Denk body forming hepatocytes. AB - Mallory-Denk body (MDB) formation is a component of alcoholic and non alcoholic hepatitis. In the present study, the role of the toll-like receptor (TLR) signaling pathway was investigated in the mechanism of MDB formation in the DDC fed mouse model. Microarray analysis data mining, performed on the livers of drug primed mice refed DDC, showed that TLR2/4 gene expression was significantly up regulated by DDC refeeding. SAMe supplementation prevented this up regulation and prevented the formation of MDBs. qRT-PCR analysis confirmed these results. TLR2/4 activates the adapter protein MyD88. The levels of MyD88 were increased by DDC refeeding. The increase of MyD88 was also prevented by SAMe supplementation. Results showed that MyD88-independent TLR3/4-TRIF-IRF3 pathway was not up regulated in the liver of DDC refed mice. Tumor necrosis factor receptor associated factor 6 (TRAF6) is the downstream protein recruited by the MyD88/IRAK protein complex, and is involved in the regulation of innate immune responses. Results showed a significant increase in the levels of TRAF-6. TRAF-6 activation leads to activation of NFkB and the mitogen-activated protein kinase (MAPK) cascade. The TRAF-6 increase was ameliorated by SAMe supplementation. These results suggest that DDC induces MDB formation through the TLR2/4 and MyD88 dependent signaling pathway. In conclusion, SAMe blocked the over-expression of TLR2/4, and their downstream signaling components MyD88 and TRAF-6. SAMe prevented the DDC-induced up regulation of the TLR signaling pathways, probably by preventing the up regulation of INF-gamma receptors by DDC feeding. INFgamma stimulates the up regulation of TLR2. The ability of SAMe feeding to prevent TLR signaling up regulation has not been previously described. PMID- 20206622 TI - Non-receptor tyrosine kinase Etk is involved in the apoptosis of small cell lung cancer cells. AB - Epithelial and endothelial tyrosine kinase (Etk), also known as Bmx (bone marrow X kinase) plays an important role in apoptosis of epithelial cells. The goal of this study was to investigate whether Etk is involved in apoptosis of small cell lung cancer (SCLC) cells and correlated with the expression levels of apoptosis associated proteins such as Bcl-2, Bcl-X(L) and p53. One hundred and seventy-one cases of lung cancer specimens including seventy-one SCLCs and one hundred NSCLCs were immunostained for Etk, Bcl-2, Bcl-X(L) and p53. Parental SCLC H446 cell line, and its subline (H446-Etk) that overexpresses Etk, were used to study the role of Etk in apoptosis induced by doxorubicin. It was found that high expression of Etk occurs in 74.6% of SCLC cases, but only in 40% of NSCLC cases, and there is marked difference in the expression levels of Bcl-2, Bcl-X(L) and p53 between Etk-positive and Etk-negative SCLC cases. Furthermore, the levels of Bcl-2 and Bcl-X(L) significantly increased in H446-Etk cells than that in H446 cells after doxorubicin treatment, and were positively associated with Etk expression. However, p53 did not correspond with Etk expression although its expression decreased greatly with apoptosis both in H446-Etk and H446 cells. After doxorubicin treatment, the cell viability was significantly higher in H446 Etk cells than in parental H446 cells. Downregulation of Etk by Etk siRNA sensitized H446 cells to doxorubicin. Our results indicate that upregulation of tyrosine kinase Etk may be a new mechanism involved in protection of SCLC cells from apoptosis. Bcl-2 and Bcl-X(L) but not p53 may contribute to doxorubicin induced apoptosis through Etk pathway. PMID- 20206623 TI - Identification of a Z-band associated protein complex involving KY, FLNC and IGFN1. AB - The KY protein underlies a form of muscular dystrophy in the mouse but its role in muscle remains elusive. Immunodetection of endogenous KY protein in C2C12 derived myotubes and expression of a recombinant form in neonatal cardiomyocytes indicated that KY is a Z-band associated protein. Moreover, characterization of a KY interacting protein fragment led to the identification of Igfn1 (Immunoglobulin-like and fibronectin type 3 domain containing 1). Igfn1 is a transcriptionally complex locus encoding many protein variants. A yeast two hybrid screen identified the Z-band protein filamin C (FLNC) as an interacting partner. Consistent with this, expression of an IGFN1 recombinant fragment showed that the three N-terminal globular domains, common to at least five IGFN1 variants, are sufficient to provide Z-band targeting. Taken together, the yeast two-hybrid, biochemical and immunofluorescence data support the notion that KY, IGFN1 and FLNC are part of a Z-band associated protein complex likely to provide structural support to the skeletal muscle sarcomere. PMID- 20206624 TI - Longitudinal multi-locus molecular characterisation of sporadic Australian human clinical cases of cryptosporidiosis from 2005 to 2008. AB - Cryptosporidium is a gastrointestinal parasite that is recognised as a significant cause of non-viral diarrhea in both developing and industrialised countries. In the present study, a longitudinal analysis of 248 faecal specimens from Australian humans with gastrointestinal symptoms from 2005 to 2008 was conducted. Sequence analysis of the 18S rRNA gene locus and the 60kDa glycoprotein (gp60) gene locus revealed that 195 (78.6%) of the cases were due to infection with Cryptosporidium hominis, 49 (19.8%) with Cryptosporidium parvum and four (1.6%) with Cryptosporidium meleagridis. A total of eight gp60 subtype families were identified; five C. hominis subtype families (Ib, Id, Ie, If and Ig), and two C. parvum subtype families (IIa and IId). The Id subtype family was the most common C. hominis subtype family identified in 45.7% of isolates, followed by the Ig subtype family (30.3%) and the Ib subtype family (20%). The most common C. parvum subtype was IIaA18G3R1, identified in 65.3% of isolates. The more rare zoonotic IId A15G1 subtype was identified in one isolate. Statistical analysis showed that the Id subtype was associated with abdominal pain (p<0.05) and that in sporadic cryptosporidiosis, children aged 5 and below were 1.91 times and 1.88 times more likely to be infected with subtype Id (RR 1.91; 95% CI, 1.7-2.89; p<0.05) and Ig (RR 1.88; 95% CI, 1.10-3.24; p<0.05) compared to children aged 5 and above. A subset of isolates were also analysed at the variable CP47 and MSC6-7 gene loci. Findings from this study suggest that anthroponotic transmission of Cryptosporidium plays a major role in the epidemiology of cryptosporidiosis in Western Australian humans. PMID- 20206626 TI - The structure of Get4 reveals an alpha-solenoid fold adapted for multiple interactions in tail-anchored protein biogenesis. AB - Tail-anchored proteins play important roles in protein translocation, membrane fusion and apoptosis. They are targeted to the endoplasmic reticulum membrane via the guided-entry of tail-anchored proteins (Get) pathway. We present the 2A crystal structure of Get4 which participates in early steps of the Get pathway. The structure shows an alpha-solenoid fold with particular deviations from the regular pairwise arrangement of alpha-helices. A conserved hydrophobic groove accommodates the flexible C-terminal region in trans. The structural organization of the Get4 helical hairpin motifs provides a scaffold for protein-protein interactions in the Get pathway. PMID- 20206625 TI - Role of chemokines in regulation of immunity against leishmaniasis. AB - Successful immunity to Leishmania depends on recruitment of appropriate immune effector cells to the site of infection and chemokines play a crucial role in the process. At the same time, Leishmania parasites possess the ability to modify the chemokine profiles of their host thereby facilitating establishment of progressive infection. Therapeutic and prophylactic strategies targeted at chemokines and their receptors provide a promising area for further research. This review highlights our current knowledge concerning the role of chemokines and their receptors in modulating leishmaniasis in both clinical settings and experimental disease models. PMID- 20206627 TI - Channel character of uncoupling protein-mediated transport. AB - Mitochondrial uncoupling proteins (UCPs) are pure anion uniporters, which mediate fatty acid (FA) uniport leading to FA cycling. Protonated FAs then flip-flop back across the lipid bilayer. An existence of pure proton channel in UCPs is excluded by the equivalent flux-voltage dependencies for uniport of FAs and halide anions, which are best described by the Eyring barrier variant with a single energy well in the middle of two peaks. Experiments with FAs unable to flip and alkylsulfonates also support this view. Phylogenetically, UCPs took advantage of the common FA-uncoupling function of SLC25 family carriers and dropped their solute transport function. PMID- 20206628 TI - Stress coping styles and singing behavior in the short-tailed singing mouse (Scotinomys teguina). AB - Stress coping styles have been characterized as a proactive/reactive dichotomy in laboratory and domesticated animals. In this study, we examined the prevalence of proactive/reactive stress coping styles in wild-caught short-tailed singing mice (Scotinomys teguina). We compared stress responses to spontaneous singing, a social and reproductive behavior that characterizes this species. To establish proactive/reactive profiles for singing mice, we measured exploratory and anxiety behavior using an open-field behavioral test. We examined correlations between open-field behaviors and fecal corticosterone (CORT) metabolites, baseline plasma CORT, and stress-induced CORT. Mice with proactive behavioral responses in the open-field had higher fecal CORT titers than reactive males, but did not differ in baseline or stress-induced plasma CORT. We suggest that individual differences in CORT metabolism may contribute to this surprising pattern. Males that sang in the open-field were behaviorally proactive and had lower stress-induced CORT, indicating a link between stress responses and singing in this species. Overall, the data demonstrate that singing mice offer an interesting model for exploring how stress reactivity can shape social behaviors. PMID- 20206629 TI - Locust flight activity as a model for hormonal regulation of lipid mobilization and transport. AB - Flight activity of insects provides a fascinating yet relatively simple model system for studying the regulation of processes involved in energy metabolism. This is particularly highlighted during long-distance flight, for which the locust constitutes a long-standing favored model insect, which as one of the most infamous agricultural pests additionally has considerable economical importance. Remarkably many aspects and processes pivotal to our understanding of (neuro)hormonal regulation of lipid mobilization and transport during insect flight activity have been discovered in the locust; among which are the peptide adipokinetic hormones (AKHs), synthesized and stored by the neurosecretory cells of the corpus cardiacum, that regulate and integrate lipid (diacylglycerol) mobilization and transport, the functioning of the reversible conversions of lipoproteins (lipophorins) in the hemolymph during flight activity, revealing novel concepts for the transport of lipids in the circulatory system, and the structure and functioning of the exchangeable apolipopotein, apolipophorin III, which exhibits a dual capacity to exist in both lipid-bound and lipid-free states that is essential to these lipophorin conversions. Besides, the lipophorin receptor (LpR) was identified and characterized in the locust. In an integrative approach, this short review aims at highlighting the locust as an unrivalled model for studying (neuro)hormonal regulation of lipid mobilization and transport during insect flight activity, that additionally has offered a broad and profound research model for integrative physiology and biochemistry, and particularly focuses on recent developments in the concept of AKH-induced changes in the lipophorin system during locust flight, that deviates fundamentally from the lipoprotein-based transport of lipids in the circulation of mammals. Current studies in this field employing the locust as a model continue to attribute to its role as a favored model organism, but also reveal some disadvantages compared to model insects with a completely sequenced genome. PMID- 20206631 TI - Physiological characterization of the cold-shock-induced humoral factor for wing color-pattern changes in butterflies. AB - Butterfly wing color patterns can be modified by the application of temperature shock to pupae immediately after pupation, which has been attributed to a cold shock-induced humoral factor called cold-shock hormone (CSH). Here, we physiologically characterized CSH and pharmacological action of tungstate, using a nymphalid butterfly Junonia orithya. We first showed that the precise patterns of modification were dependent on the time-point of the cold-shock treatment after pupation, and confirmed that the modification properties induced in a cold shocked pupa were able to be transferred to another pupa in a parabiosis experiment. Cold-shock application after removal of the head and prothorax together still produced modified wings, excluding major involvement of the brain retrocerebral neuroendocrine complex. Furthermore, tungstate injection induced modifications even in individuals whose head and prothorax were removed. Importantly, transplantation of tracheae isolated from cold-shocked pupae induced modifications in the recipient wings. We identified a chemical peak in hemolymph of the cold-shocked individuals using HPLC, which corresponded to dopamine, and demonstrated that dopamine and its related biogenic amines have ability to induce small color-pattern changes. Taken together, the present study suggests that CSH is likely to be secreted from trachea-associated endocrine cells upon cold-shock treatment and that tungstate may change color patterns via its direct action on wings. PMID- 20206630 TI - Meeting the challenges of on-host and off-host water balance in blood-feeding arthropods. AB - In this review, we describe water balance requirements of blood-feeding arthropods, particularly contrasting dehydration tolerance during the unfed, off host state and the challenges of excess water that accompany receipt of the bloodmeal. Most basic water balance characteristics during the off-host stage are applicable to other terrestrial arthropods, as well. A well-coordinated suite of responses enable arthropods to conserve water resources, enhance their desiccation tolerance, and increase their water supplies by employing a diverse array of molecular, structural and behavioral responses. Water loss rates during the off-host phase are particularly useful for generating a scheme to classify vectors according to their habitat requirements for water, thus providing a convenient tool with potential predictive power for defining suitable current and future vector habitats. Blood-feeding elicits an entirely different set of challenges as the vector responds to overhydration by quickly increasing its rate of cuticular water loss and elevating the rate of diuresis to void excess water and condense the bloodmeal. Immature stages that feed on blood normally have a net increase in water content at the end of a blood-feeding cycle, but in adults the water content reverts to the pre-feeding level when the cycle is completed. Common themes are evident in diverse arthropods that feed on blood, particularly the physiological mechanisms used to respond to the sudden influx of water as well as the mechanisms used to counter water shortfalls that are encountered during the non-feeding, off-host state. PMID- 20206632 TI - Differential ammonia metabolism in Aedes aegypti fat body and midgut tissues. AB - In order to understand at the tissue level how Aedes aegypti copes with toxic ammonia concentrations that result from the rapid metabolism of blood meal proteins, we investigated the incorporation of (15)N from (15)NH(4)Cl into amino acids using an in vitro tissue culture system. Fat body or midgut tissues from female mosquitoes were incubated in an Aedes saline solution supplemented with glucose and (15)NH(4)Cl for 10-40min. The media were then mixed with deuterium labeled amino acids, dried and derivatized. The (15)N-labeled and unlabeled amino acids in each sample were quantified by mass spectrometry techniques. The results demonstrate that both tissues efficiently incorporate ammonia into amino acids, however, the specific metabolic pathways are distinct. In the fat body, the (15)N from (15)NH(4)Cl is first incorporated into the amide side chain of Gln and then into the amino group of Gln, Glu, Ala and Pro. This process mainly occurs via the glutamine synthetase (GS) and glutamate synthase (GltS) pathway. In contrast, (15)N in midgut is first incorporated into the amino group of Glu and Ala, and then into the amide side chain of Gln. Interestingly, our data show that the GS/GltS pathway is not functional in the midgut. Instead, midgut cells detoxify ammonia by glutamate dehydrogenase, alanine aminotransferase and GS. These data provide new insights into ammonia metabolism in A. aegypti mosquitoes. PMID- 20206633 TI - A multi-season survey for infectious myonecrosis in farmed shrimp, Litopenaeus vannamei, in Pernambuco, Brazil. AB - Infectious myonecrosis (IMN), caused by infectious myonecrosis virus (IMNV), is the disease of greatest impact on shrimp farming in the northeast region of Brazil. The occurrence of IMN remained restricted to northeastern Brazil until 2006, when its presence was also confirmed in Indonesia. To determine the occurrence and evolution of IMN in Litopenaeus vannamei farmed along the coast of the state of Pernambuco, Brazil, histopathological examinations were performed on 60 samples collected from four farms in both predominant seasons in the northeastern region: dry and wet seasons. Samples made up of ten specimens were collected monthly from each pond. Histopathological results were associated to wet-mount exams and rearing performance data. Lesions suggestive of IMN (coagulative necrosis, hemocytic infiltration in the musculature, ectopic spheroids in the lymphoid organ) were identified in all the farms, with a higher occurrence during the dry season. Longer rearing periods and higher stocking densities were the variables with the most significant influence (p<0.05) in the occurrence of IMN. PMID- 20206634 TI - Adiponectin deficiency exacerbates cardiac dysfunction following pressure overload through disruption of an AMPK-dependent angiogenic response. AB - Although increasing evidence indicates that an adipokine adiponectin exerts protective actions on heart, its effects on coronary angiogenesis following pressure overload have not been examined previously. Because disruption of angiogenesis during heart growth leads to contractile dysfunction and heart failure, we hypothesized that adiponectin modulates cardiac remodeling in response to pressure overload through its ability to regulate adaptive angiogenesis. Adiponectin-knockout (APN-KO) and wild-type (WT) mice were subjected to pressure overload caused by transverse aortic constriction (TAC). APN-KO mice exhibited greater cardiac hypertrophy, pulmonary congestion, left ventricular (LV) interstitial fibrosis and LV systolic dysfunction after TAC surgery compared with WT mice. APN-KO mice also displayed reduced capillary density in the myocardium after TAC, which was accompanied by a significant decrease in expression of vascular endothelial growth factor (VEGF) and phosphorylation of AMP-activated protein kinase (AMPK). Inhibition of AMPK in WT mice resulted in aggravated LV systolic function, attenuated myocardial capillary density and decreased VEGF expression in response to TAC. The adverse effects of AMPK inhibition on cardiac function and angiogenic response following TAC were diminished in APN-KO mice relative to WT mice. Moreover, adenovirus-mediated VEGF delivery reversed the TAC-induced deficiencies in cardiac microvessel formation and ventricular function observed in the APN-KO mice. In cultured cardiac myocytes, adiponectin treatment stimulated VEGF production, which was inhibited by inactivation of AMPK signaling pathway. Collectively, these data show that adiponectin deficiency can accelerate the transition from cardiac hypertrophy to heart failure during pressure overload through disruption of AMPK-dependent angiogenic regulatory axis. PMID- 20206635 TI - Heparan sulfate Ndst1 regulates vascular smooth muscle cell proliferation, vessel size and vascular remodeling. AB - Heparan sulfate proteoglycans are abundant molecules in the extracellular matrix and at the cell surface. Heparan sulfate chains are composed of groups of disaccharides whose side chains are modified through a series of enzymatic reactions. Deletion of these enzymes alters heparan sulfate fine structure and leads to changes in cell proliferation and tissue development. The role of heparan sulfate modification has not been explored in the vessel wall. The goal of this study was to test the hypothesis that altering heparan sulfate fine structure would impact vascular smooth muscle cell (VSMC) proliferation, vessel structure, and remodeling in response to injury. A heparan sulfate modifying enzyme, N-deacetylase N-sulfotransferase1 (Ndst1) was deleted in smooth muscle resulting in decreased N- and 2-O sulfation of the heparan sulfate chains. Smooth muscle specific deletion of Ndst1 led to a decrease in proliferating VSMCs and the circumference of the femoral artery in neonatal and adult mice. In response to vascular injury, mice lacking Ndst1 exhibited a significant reduction in lesion formation. Taken together, these data provide new evidence that modification of heparan sulfate fine structure through deletion of Ndst1 is sufficient to decrease VSMC proliferation and alter vascular remodeling. PMID- 20206637 TI - Quantification of the effects of vasomotion on mass transport to tissue from axisymmetric blood vessels. AB - The process known as vasomotion, rhythmic oscillations in vessel diameter, has been proposed to act as a protective mechanism for tissue under conditions of reduced perfusion, since it is frequently only observed experimentally when perfusion levels are reduced. This could be due to a resultant increase in oxygen transport from the vasculature to the surrounding tissue, either directly or indirectly. It is thus potentially of significant clinical interest as a warning signal for ischemia. However, there has been little analysis performed to quantify the effects of vessel wall movement on time-averaged mass transport. We thus present a detailed analysis of such mass transport for an axisymmetric vessel with a periodically oscillating wall, by solving the non-linear mass transport equation, and quantify the differences between the time-averaged mass transport under conditions of no oscillation (i.e. the steady-state) and varying wall oscillation amplitude. The results show that if the vessel wall alone is oscillated, with an invariant wall concentration, the time-averaged mass transport is reduced relative to the steady-state, but if the vessel wall concentration is also oscillated, then mass transport is increased, although this is generally only true when these oscillate in phase with each other. The influence of Peclet number and the non-dimensional rate of consumption of oxygen in tissue, as well as the amplitude of oscillations, are fully characterised. We conclude by considering the likely implications of these results in the context of oxygen transport to tissue. PMID- 20206636 TI - Conformational dynamics of the Escherichia coli DNA polymerase manager proteins UmuD and UmuD'. AB - The expression of Escherichia coli umuD gene products is upregulated as part of the SOS response to DNA damage. UmuD is initially produced as a 139-amino-acid protein, which subsequently cleaves off its N-terminal 24 amino acids in a reaction dependent on RecA/single-stranded DNA, giving UmuD'. The two forms of the umuD gene products play different roles in the cell. UmuD is implicated in a primitive DNA damage checkpoint and prevents DNA polymerase IV-dependent -1 frameshift mutagenesis, while the cleaved form facilitates UmuC-dependent mutagenesis via formation of DNA polymerase V (UmuD'(2)C). Thus, the cleavage of UmuD is a crucial switch that regulates replication and mutagenesis via numerous protein-protein interactions. A UmuD variant, UmuD3A, which is noncleavable but is a partial biological mimic of the cleaved form UmuD', has been identified. We used hydrogen-deuterium exchange mass spectrometry (HXMS) to probe the conformations of UmuD, UmuD', and UmuD3A. In HXMS experiments, backbone amide hydrogens that are solvent accessible or not involved in hydrogen bonding become labeled with deuterium over time. Our HXMS results reveal that the N-terminal arm of UmuD, which is truncated in the cleaved form UmuD', is dynamic. Residues that are likely to contact the N-terminal arm show more deuterium exchange in UmuD' and UmuD3A than in UmuD. These observations suggest that noncleavable UmuD3A mimics the cleaved form UmuD' because, in both cases, the arms are relatively unbound from the globular domain. Gas-phase hydrogen exchange experiments, which specifically probe the exchange of side-chain hydrogens and are carried out on shorter timescales than solution experiments, show that UmuD' incorporates more deuterium than either UmuD or UmuD3A. This work indicates that these three forms of the UmuD gene products are highly flexible, which is of critical importance for their many protein interactions. PMID- 20206638 TI - Towards multi-scale modeling of muscle fibers with sarcomere non-uniformities. AB - A theoretical framework for studying the collective behavior of a large ensemble of half sarcomeres in a myofibril is presented. The approach is based on transforming the large system of discrete elements (half-sarcomeres) into a continuum for which macro-behavior is dictated by micro-properties. Specifically, we consider statistical properties of the ensemble rather than solving for each degree of freedom. This enables a reasonable computational effort and provides important insights. We demonstrate that such a multi-scale approach is indispensable for studying quantitatively the role of sarcomere non-uniformities in muscle mechanics. Specifically, we illustrate that adopting a model with a non physiological number of sarcomeres can lead to a non-realistic behavior and therefore to erroneous interpretation. Further, we demonstrate that the new modeling approach provides a suitable platform for addressing controversial phenomena, such as residual enhanced tension, creep, length redistribution, and damage due to eccentric contraction. PMID- 20206639 TI - The transcription factor GATA-4 regulates cytochrome P4502C19 gene expression. AB - AIMS: Cytochrome P4502C19 (CYP2C19) is an important enzyme involved in the metabolism of antiulcer drugs and antidepressants. However, despite the well documented drug-dependent variability of CYP2C19 expression, the mechanisms underlying the regulation of the enzyme remain unknown. In this study we investigated whether the transcription factor family GATA is involved in the regulation of CYP2C19 gene expression. MAIN METHODS: We identified a novel putative GATA binding site at position -165/-156 within the CYP2C19 gene promoter. 5'-Deletion fragments of the CYP2C19 promoter containing wild type or mutant variants of this GATA binding site were co-transfected with expression vectors encoding the transcription factors GATA-4 or GATA-2 and analyzed using dual luciferase gene reporter assays in HepG2 and Huh-7 hepatoma cells. Electrophoretic Mobility Shift Assay (EMSA) and Chromatin Immunoprecipitations (ChIP) were performed to proof a sequence-specific interaction of GATA proteins with the putative GATA binding site. KEY FINDINGS: The wild type fragments of CYP2C19 promoter were highly upregulated by GATA-4 and GATA-2 in luciferase gene reporter assay, whereas mutations introduced into the GATA binding sites caused a significant activity loss. Similar attenuation was observed upon co-transfection of GATA-4 with a known co-regulator of GATA activity, FOG-2. EMSA analysis revealed a sequence-specific binding of GATA-4 and GATA-6 to the wild type GATA binding site. In addition, the association of GATA-4 with the CYP2C19 promoter was confirmed by ChIP analysis. SIGNIFICANCE: These data indicate that GATA-4 plays an important role in the transcriptional regulation of CYP2C19 expression. PMID- 20206641 TI - Altered connectivity between prefrontal and sensorimotor cortex in conversion paralysis. AB - Conversion paralysis (CP) is a frequent and impairing psychiatric disorder, affecting voluntary motor function. Yet, we have previously shown that the motor system of CP patients with a unilateral conversion paresis is recruited to a similar degree during imagined movements of the affected and unaffected limb. In contrast, imagery of movements with the affected limb results in larger prefrontal activation. It remains unclear how this hand-specific increased prefrontal activity relates to the reduced responsiveness of motor and somatosensory areas, a consistent and important feature of CP patients. In the current study, we investigated changes in the inter-regional coupling between prefrontal cortex (PFC) and sensorimotor regions when CP patients imagined movements involving either the affected or the unaffected hand. We found that there were distinct connectivity patterns for different parts of the PFC. While ventromedial PFC was not functionally connected to the motor system, we observed strong functional coupling between the dorsolateral PFC and various sensorimotor areas. Furthermore, this coupling was modulated by whether patients imagined movements of their affected or unaffected hand. Together, these results suggest that the reduced motor responsitivity observed in CP may be linked to altered dorsolateral prefrontal-motor connectivity. PMID- 20206642 TI - Dopaminergic functioning and preschoolers' theory of mind. AB - Representational theory of mind (RTM) development follows a universal developmental timetable whereby major advances in reasoning about mental representations occur between the ages of 3 and 5 years old. This progression appears to be only absent in the case of specific neurodevelopmental impairments, such as autism. Taken together, this suggests that neuromaturational factors may play a role in RTM development. Recent EEG work has shown that one neuromaturational factor pacing this universal developmental timetable is the functional maturation of medial prefrontal cortex. The neurotransmitter dopamine (DA) is thought to play a crucial role in typical frontal lobe development. Therefore, the goal of the present study was to investigate the role that DA may play in RTM development. Ninety-one 48-62-month olds were given a battery of RTM tasks along with EEG measurement. EEG recordings were analyzed for eyeblinks, a reliable indicator of DA functioning, and we calculated their average eyeblinks per minute (EBR). Regression analyses showed that EBR was associated with RTM after controlling for children's performance on a Stroop-like measure, language ability, gender, and age. These findings provide evidence that DA functioning is associated with RTM in the preschool years, and are discussed with respect to how DA might provide a mechanism that helps to account for both neurobiological and experiential factors that are known to affect the timetable of preschoolers' RTM development. PMID- 20206640 TI - The PLC/IP 3 R/PKC pathway is required for ethanol-enhanced GABA release. AB - Research on the actions of ethanol at the GABAergic synapse has traditionally focused on postsynaptic mechanisms, but recent data demonstrate that ethanol also increases both evoked and spontaneous GABA release in many brain regions. Using whole-cell voltage-clamp recordings, we previously showed that ethanol increases spontaneous GABA release at the rat interneuron-Purkinje cell synapse. This presynaptic ethanol effect is dependent on calcium release from internal stores, possibly through activation of inositol 1,4,5-trisphosphate receptors (IP(3)Rs). After confirming that ethanol targets vesicular GABA release, in the present study we used electron microscopic immunohistochemistry to demonstrate that IP(3)Rs are located in presynaptic terminals of cerebellar interneurons. Activation of IP(3)Rs requires binding of IP(3), generated through activation of phospholipase C (PLC). We find that the PLC antagonist edelfosine prevents ethanol from increasing spontaneous GABA release. Diacylglycerol generated by PLC and calcium released by activation of the IP(3)R activate protein kinase C (PKC). Ethanol-enhanced GABA release was blocked by two PKC antagonists, chelerythrine and calphostin C. When a membrane impermeable PKC antagonist, PKC (19-36), was delivered intracellularly to the postsynaptic neuron, ethanol continued to increase spontaneous GABA release. Overall, these results suggest that activation of the PLC/IP(3)R/PKC pathway is necessary for ethanol to increase spontaneous GABA release from presynaptic terminals onto Purkinje cells. PMID- 20206643 TI - D-ring substituted 1,2,3-triazolyl 20-keto pregnenanes as potential anticancer agents: Synthesis and biological evaluation. AB - A facile synthesis of 21-triazolyl derivatives of pregnenolone and their potential antitumour activity is reported. The scheme involves the transformation of the starting pregnenolone acetate into pregnenolone, conversion of pregnenolone to 21-bromo pregnenolone and finally the one-pot, two-step in situ conversion of the bromo derivative to the 21-triazolyl pregnenolone using the 'click chemistry' approach. These derivatives were screened for their anticancer activity against seven human cancer cell lines. The compounds especially 5a, 5b, 5c, 5e, 5g and 5h exhibited significant anticancer activity with compound 5e as the most active in this study. PMID- 20206644 TI - Studies on novel D-ring substituted steroidal pyrazolines as potential anticancer agents. AB - An efficient and facile synthesis of 17-pyrazolinyl derivatives of pregnenolone and their evaluation as potential anticancer agents against various human cancer cell lines are reported. The scheme involves the transformation of the starting pregnenolone acetate into pregnenolone, conversion of pregnenolone to the corresponding benzylidine derivatives and finally the conversion of this derivative to the stable steroidal 17-pyrazoline. Various compounds 4b, 4c, 4e, 4f, 4h and 4j showed significant cytotoxic activity especially against HT-29, HCT 15, 502713 cell lines. PMID- 20206645 TI - Cross-talk between non-genomic and genomic signalling pathways--distinct effect profiles of environmental estrogens. AB - Estrogen receptor (ER) transcriptional cross-talk after activation by 17beta estradiol (E2) has been studied in considerable detail, but comparatively little is known about the ways in which synthetic estrogen-like chemicals, so-called xenoestrogens, interfere with these signalling pathways. E2 can stimulate rapid, non-genomic signalling events, such as activation of the Src/Ras/Erk signalling pathway. We investigated how activation of this pathway by E2, the estrogenic environmental contaminants o,p'-DDT, beta-HCH and p,p'-DDE, and epidermal growth factor (EGF) influences the expression of ER target genes, such as TFF1, ER, PR, BRCA1 and CCND1, and the proliferation of breast cancer cells. Despite commonalities in their estrogenicity as judged by cell proliferation assays, the environmental contaminants exhibited striking differences in their non-genomic and genomic signalling. The gene expression profiles of o,p'-DDT and beta-HCH resembled the effects observed with E2. In the case of beta-HCH this is surprising, considering its reported lack of affinity to the "classical" ER. The expression profiles seen with p,p'-DDE showed some similarities with E2, but overall, p,p'-DDE was a fairly weak transcriptional inducer of TFF1, ER, PR, BRCA1 and CCND1. We observed distinct differences in the non-genomic signalling of the tested compounds. p,p'-DDE was unable to stimulate Src and Erk1/Erk2 activations. The effects of E2 on Src and Erk1/Erk2 phosphorylation were transient and weak when compared to EGF, but beta-HCH induced strong and sustained activation of all tested kinases. Transcription of TFF1, ER, PR and BRCA1 by E2, o,p'-DDT and beta-HCH could be suppressed partially by inhibiting the Src/Ras/Erk pathway with PD 98059. However, this was not seen with p,p'-DDE. Our investigations show that the cellular activities of estrogens and xenoestrogens are the result of a combination of extranuclear (non-genomic) and nuclear (genomic) events and highlight the need to take non-genomic effects and signalling cross-talk into consideration, when screening for environmental estrogens. Otherwise, chemicals devoid of ER affinity, such as beta-HCH, but with an effect profile otherwise similar to estrogens might be overlooked in safety testing. PMID- 20206646 TI - Acute respiratory toxicity following inhalation exposure to soman in guinea pigs. AB - Respiratory toxicity and lung injury following inhalation exposure to chemical warfare nerve agent soman was examined in guinea pigs without therapeutics to improve survival. A microinstillation inhalation exposure technique that aerosolizes the agent in the trachea was used to administer soman to anesthetized age and weight matched male guinea pigs. Animals were exposed to 280, 561, 841, and 1121 mg/m(3) concentrations of soman for 4 min. Survival data showed that all saline controls and animals exposed to 280 and 561 mg/m(3) soman survived, while animals exposed to 841, and 1121 mg/m(3) resulted in 38% and 13% survival, respectively. The microinstillation inhalation exposure LCt(50) for soman determined by probit analysis was 827.2mg/m(3). A majority of the animals that died at 1121 mg/m(3) developed seizures and died within 15-30 min post-exposure. There was a dose-dependent decrease in pulse rate and blood oxygen saturation of animals exposed to soman at 5-6.5 min post-exposure. Body weight loss increased with the dose of soman exposure. Bronchoalveolar lavage (BAL) fluid and blood acetylcholinesterase and butyrylcholinesterase activity was inhibited dose dependently in soman treated groups at 24h. BAL cells showed a dose-dependent increase in cell death and total cell counts following soman exposure. Edema by wet/dry weight ratio of the accessory lung lobe and trachea was increased slightly in soman exposed animals. An increase in total bronchoalveolar lavage fluid protein was observed in soman exposed animals at all doses. Differential cell counts of BAL and blood showed an increase in total lymphocyte counts and percentage of neutrophils. These results indicate that microinstillation inhalation exposure to soman causes respiratory toxicity and acute lung injury in guinea pigs. PMID- 20206648 TI - Looking without seeing or seeing without looking? Eye movements in sustained inattentional blindness. AB - Inattentional blindness (IB) describes the failure to notice salient but unexpected stimuli when attention is partially engaged by another task. Few studies have explicitly investigated the role of eye movements in IB and the relative contributions of overt and covert attention. We recorded eye movements in a series of IB experiments using dynamic stimuli. Results indicate that eye movements do not predict IB; noticers and nonnoticers were equally likely to fixate on or near the unexpected item, often for similar durations. Perceptual load also determines whether observers will fixate the unexpected object. In a high perceptual load task, IB was high (81%) and most participants did not allocate overt attention to the unexpected object. Under lower perceptual load IB decreased to 54% and both noticers and nonnoticers fixated on the unexpected object. PMID- 20206647 TI - A high-throughput method for assessing chemical toxicity using a Caenorhabditis elegans reproduction assay. AB - The National Research Council has outlined the need for non-mammalian toxicological models to test the potential health effects of a large number of chemicals while also reducing the use of traditional animal models. The nematode Caenorhabditis elegans is an attractive alternative model because of its well characterized and evolutionarily conserved biology, low cost, and ability to be used in high-throughput screening. A high-throughput method is described for quantifying the reproductive capacity of C. elegans exposed to chemicals for 48 h from the last larval stage (L4) to adulthood using a COPAS Biosort. Initially, the effects of exposure conditions that could influence reproduction were defined. Concentrations of DMSO vehicle